PMID- 26568769 TI - Opportunity costs of carbon sequestration in a forest concession in central Africa. AB - BACKGROUND: A large proportion of the tropical rain forests of central Africa undergo periodic selective logging for timber harvesting. The REDD+ mechanism could promote less intensive logging if revenue from the additional carbon stored in the forest compensates financially for the reduced timber yield. RESULTS: Carbon stocks, and timber yields, and their associated values, were predicted at the scale of a forest concession in Gabon over a project scenario of 40 yr with reduced logging intensity. Considering that the timber contribution margin (i.e. the selling price of timber minus its production costs) varies between 10 and US$40 m -3, the minimum price of carbon that enables carbon revenues to compensate forgone timber benefits ranges between US$4.4 and US$25.9/tCO 2 depending on the management scenario implemented. CONCLUSIONS: Where multiple suppliers of emission reductions compete in a REDD+ carbon market, tropical timber companies are likely to change their management practices only if very favourable conditions are met, namely if the timber contribution margin remains low enough and if alternative management practices and associated incentives are appropriately chosen. PMID- 26568768 TI - Norovirus vaccines and potential antinorovirus drugs: recent advances and future perspectives. AB - Human noroviruses (HuNoVs) are a leading cause of acute, nonbacterial gastroenteritis worldwide. The lack of a cell culture system and smaller animal model has delayed the development and commercial availability of vaccines and antiviral drugs. Current vaccines rely on recombinant capsid proteins, such as P particles and virus-like particles (VLPs), which have been promising in clinical trials. Anti-HuNoV drug development is another area of extensive research, including currently available antiviral drugs for other viral pathogens. This review will provide an overview of recent advances in vaccine and antiviral development. The implication of recent advances in HuNoV cell culture for improving vaccine and antiviral development is also discussed. PMID- 26568770 TI - Intravenous tranexamic acid as an adjunct haemostat to ornipressin during open myomectomy. A randomized double blind placebo controlled trial. AB - BACKGROUND: Myomectomy is a surgical technique used for removal of uterine fibroids and historically hysterectomy has represented the mainstay of treatment. The options of conservative surgical approaches mainly aim at retention of fertility but have to be balanced against potential risks such as haemorrhage; blood loss at myomectomy still remains troublesome with use of various pharmacologic agents yielding inconclusive results. This trial aimed to explore the benefit of combining ornipressin and tranexamic acid during open myomectomy. STUDY DESIGN: A randomized double blind placebo controlled trial. METHODS: Women who satisfied eligibility criteria were enrolled into the study and randomized into one of two groups. The experimental group received 1 g of tranexamic acid diluted to 50 ml of saline administered at 100 ml per hour at cutting time (knife to skin). The control group received placebo diluted to 50 ml of saline administered at 100 ml per hour at cutting time. Both groups had five international units ornipressin diluted in 60 ml of saline administered during surgery. The primary outcome (blood loss) was assessed by determining the weight difference of dry and soaked swabs using a digital weighing scale by converting this to volume (ml). Operating time was noted from the time of uterine incision to the time of uterine closure. The need for transfusion was determined by anaesthetists' assessment of acceptable blood loss and clinical assessment of vital signs. Post-operative stay was calculated from the time of extubation to 8 am on the day of discharge. RESULTS: A total of thirty-four patients were randomized to two groups; 17 received ornipressin only and 17 received tranexamic acid and ornipressin. There was no difference in blood loss between the groups with a median blood loss in the ornipressin (n = 17) and ornipressin plus tranexamic acid arms of 398 ml (IQR: 251-630) ml and 251 ml (IQR: 158-501) ml respectively P = 0.361. CONCLUSIONS: Ornipressin administered along with tranexamic acid is not beneficial for blood loss reduction at open myomectomy. In settings such as ours where myomata are prevalent and severe anaemia rampant, blood donation and judicious use of scarce blood resources is key. Efforts to optimize preoperative haemoglobin levels and blood auto-donation seem the most promising options in pre-operative preparation prior to myomectomy. CLINICAL TRIALS REGISTRATION NUMBER: PACTR201203000369163. PMID- 26568771 TI - Surgeon accountability for patient safety in the Acute Care Surgery paradigm: a critical appraisal and need of having a focused knowledge of the patient and a specific subspecialty experience. AB - There is an increasing evidence in the literature showing that Acute Care surgical patients, likewise patients from every other surgical subspeciality, should be best first approached and managed only by attending surgeons with approriate expertise in the field of Emergency and Trauma Surgery, as well as the occurrence of postoperative complications can be prevented or safely and appropriately treated when arising, only by those attending surgeons having a focused knowledge of the patient and specific subspeciality experience. The advantages of a consultant-led, patient-centered surgical management come along with the opportunity of maintaining the principles of continuity of care and specificity of expertise in managing surgical patients and their complications and readmissions. These principles should be particularly valid in the well recognized subspeciality of Acute Care and Trauma Surgery; managing the challenging emergency surgical patients either in the preoperative and postoperative periods with the aim to improve the outcomes of Emergency Surgery, should only be by surgeons trained and experienced in both Acute Care Surgery and Trauma. PMID- 26568772 TI - Expression of REG Ialpha gene in type 2 diabetics in Pakistan. AB - BACKGROUND: The escalating rate of diabetes' has prompted researchers around the world to explore for early markers. A deficit of functional beta-cell mass plays a central role in the pathophysiology of type 2 diabetes. The REG (Regenerating) gene, encoding a 166 amino acid REG protein was discovered in rats and humans which is released in response to beta-cells damage and play a role in their regeneration. The objective of this study was to characterize serum levels of REG Ialpha proteins in type 2 diabetic patients as indicator of beta-cell apoptosis as well as regeneration. METHODS: Unrelated type 2 diabetic patients (n = 55) of different age groups and disease duration were recruited from the Medical OPD of PNS Shifa Hospital. Age and sex matched non diabetic controls (n = 20) without family history of diabetes were selected from the same setting. Demographical details were recorded on a structured questionnaire. Biochemical parameters like FBG, HbA1c, TC and TG levels were measured. Serum levels of REG Ialpha protein were determined by ELISA. RESULTS: Levels of REG Ialpha protein were found significantly raised in type 2 diabetic patients compared to controls (p < 001). Patients with short duration of the disease had higher levels of REG Ialpha as compared to patients with longer duration of the disease. Although the patients were on anti hyperglycemic agents, a positive correlation was found between REG Ialpha serum levels, FBG and HbA1c levels. Patients with higher BMI had higher levels of serum REG Ialpha levels. Serum TC, TG and Hb levels showed no correlation. CONCLUSION: REG Ialpha may be used as a marker/predictor of type 2 diabetes especially in the early stages of the disease. PMID- 26568773 TI - Associations between physical growth and general cognitive functioning in international adoptees from Eastern Europe at 30 months post-arrival. AB - BACKGROUND: Internationally adopted children have often experienced early adversity and growth suppression as a consequence of institutional care. Furthermore, these children are at risk for impaired cognitive development due to their early adverse experiences. This study examined the association between physical growth, the growth hormone (GH) system, and general cognitive functioning post-adoption. Based on previous research, we expected to find that a child's initial physical growth status and normalization of the growth hormone insulin-like growth factor 1 (GH-IGF-1) axis would be positive predictors of general cognitive functioning. METHODS: Post-institutionalized children (n = 46) adopted from Eastern Europe were seen approximately 1 month after their arrival into the USA to determine baseline measurements. They were seen again 6 and 30 months later for two follow-up sessions. Measures included anthropometry, insulin like growth factor-1 (IGF-1), IGF binding protein-3 (IGFBP-3), Mullen Scales of Early Learning, and Stanford-Binet Intelligence Scales. Information about parental education was also collected. RESULTS: We found that a child's general cognitive functioning at 30 months post-adoption was predicted by their general developmental scores at 6 months post-adoption, their initial height status, and markers of the growth hormone system. Children with lower initial IGFBP-3 standard deviation (SD) scores had higher verbal IQ scores at 30 months. Furthermore, a child's initial height was found to be a significant positive predictor of non-verbal IQ. CONCLUSIONS: These results suggest an association between a child's suppressed physical growth in response to early adversity and alterations in GH system functioning and subsequent recovery in cognitive functioning. PMID- 26568775 TI - The Needs for Quality Urban Rail Transit Life in Asian Metropolitan Cities. AB - The quality of people's lives in Asia has improved markedly since 2nd World War, with developing economies allowing people to pursue multifaceted lives instead of just working to meet basic physical requirements. In the last 30 to 40 years, urbanization in Asia has led to the emergence of urban rail transit (URT) systems in many cities. URT has become a significant part of city life, and the quality of a city's URT experience has become a significant social issue. This study aims to comprehensively define a quality URT experience in Asian metropolitan cities using a three-pronged comparison of the URTs in three densely populated Asian cities. Both quantitative and qualitative research methods are applied in each of the three aspects studied. The research methods include a case study, a questionnaire, observation, and interviews. The different requirements of diverse groups of users are categorized and a general needs pyramid of a quality URT experience is developed. The multidimensional comparison provides useful references for designers by demonstrating the distinct attitudes of different groups of people. Our understanding of a quality subway experience is based on a needs perspective and focuses on a specific type of public space. PMID- 26568774 TI - The effects of long-term daily folic acid and vitamin B12 supplementation on genome-wide DNA methylation in elderly subjects. AB - BACKGROUND: Folate and its synthetic form folic acid function as donor of one carbon units and have been, together with other B-vitamins, implicated in programming of epigenetic processes such as DNA methylation during early development. To what extent regulation of DNA methylation can be altered via B vitamins later in life, and how this relates to health and disease, is not exactly known. The aim of this study was to identify effects of long-term supplementation with folic acid and vitamin B12 on genome-wide DNA methylation in elderly subjects. This project was part of a randomized, placebo-controlled trial on effects of supplemental intake of folic acid and vitamin B12 on bone fracture incidence (B-vitamins for the PRevention Of Osteoporotic Fractures (B-PROOF) study). Participants with mildly elevated homocysteine levels, aged 65-75 years, were randomly assigned to take 400 MUg folic acid and 500 MUg vitamin B12 per day or a placebo during an intervention period of 2 years. DNA was isolated from buffy coats, collected before and after intervention, and genome-wide DNA methylation was determined in 87 participants (n = 44 folic acid/vitamin B12, n = 43 placebo) using the Infinium HumanMethylation450 BeadChip. RESULTS: After intervention with folic acid and vitamin B12, 162 (versus 14 in the placebo group) of the 431,312 positions were differentially methylated as compared to baseline. Comparisons of the DNA methylation changes in the participants receiving folic acid and vitamin B12 versus placebo revealed one single differentially methylated position (cg19380919) with a borderline statistical significance. However, based on the analyses of differentially methylated regions (DMRs) consisting of multiple positions, we identified 6 regions that differed statistically significantly between the intervention and placebo group. Pronounced changes were found for regions in the DIRAS3, ARMC8, and NODAL genes, implicated in carcinogenesis and early embryonic development. Furthermore, serum levels of folate and vitamin B12 or plasma homocysteine were related to DNA methylation of 173, 425, and 11 regions, respectively. Interestingly, for several members of the developmental HOX genes, DNA methylation was related to serum levels of folate. CONCLUSIONS: Long-term supplementation with folic acid and vitamin B12 in elderly subjects resulted in effects on DNA methylation of several genes, among which genes implicated in developmental processes. PMID- 26568776 TI - Inflammatory Myofibroblastic Tumor of the Lung: Unusual Imaging Findings of Three Cases. AB - BACKGROUND: Inflammatory myofibroblastic tumor (IMT), also known as inflammatory pseudotumor, is a benign disorder composed of fibrous tissues, myofibroblasts and inflammatory cell proliferation with obscure etiology. Although it is the most common lung tumor in children, it is seen rarely in adults constituting less than 1% of adult lung tumors. CASE REPORTS: In this report, we present different and rare CT manifestations of three adult patients with lung IMT. CONCLUSIONS: In conclusion, IMT is a rare lung tumor in adults and may simulate malignancy. It should be considered in the differential diagnosis when a large mass with lobulated contour or harboring coarse calcification is observed. PMID- 26568777 TI - Atypical Presentation of Ewing's Sarcoma with a Single Left Orbital Metastasis. AB - BACKGROUND: We present an uncommon case of Ewing's sarcoma in a 16-year-old boy. CASE REPORT: This case can be considered unique because of the atypical presentation, normal laboratory tests and absence of the typical symptoms such as pain, masses or swelling, fatigue or weight loss, breathing problems linked to lung metastases or pathologic fractures. The only event that brought the patient to our attention was the sudden onset of left proptosis. CONCLUSIONS: The final histopathology together with CT and PET-CT findings led to the diagnosis of a multi-metastatic Ewing's sarcoma involving the orbit, skeleton, bone marrow and lymph nodes. PMID- 26568778 TI - A REFERENCE-INVARIANT HEALTH DISPARITY INDEX BASED ON RENYI DIVERGENCE. AB - One of four overarching goals of Healthy People 2020 (HP2020) is to achieve health equity, eliminate disparities, and improve the health of all groups. In health disparity indices (HDIs) such as the mean log deviation (MLD) and Theil index (TI), disparities are relative to the population average, whereas in the index of disparity (IDisp) the reference is the group with the least adverse health outcome. Although the latter may be preferable, identification of a reference group can be affected by statistical reliability. To address this issue, we propose a new HDI, the Renyi index (RI), which is reference-invariant. When standardized, the RI extends the Atkinson index, where a disparity aversion parameter can incorporate societal values associated with health equity. In addition, both the MLD and TI are limiting cases of the RI. Also, a symmetrized Renyi index (SRI) can be constructed, resulting in a symmetric measure in the two distributions whose relative entropy is being evaluated. We discuss alternative symmetric and reference-invariant HDIs derived from the generalized entropy (GE) class and the Bregman divergence, and argue that the SRI is more robust than its GE-based counterpart to small changes in the distribution of the adverse health outcome. We evaluate the design-based standard errors and bootstrapped sampling distributions for the SRI, and illustrate the proposed methodology using data from the National Health and Nutrition Examination Survey (NHANES) on the 2001-04 prevalence of moderate or severe periodontitis among adults aged 45-74, which tracks Oral Health objective OH-5 in HP2020. Such data, which uses a binary individual-level outcome variable, are typical of HP2020 data. PMID- 26568780 TI - Letter to Our Readers. PMID- 26568779 TI - Feasibility of Valence-to-Core X-ray Emission Spectroscopy for Tracking Transient Species. AB - X-ray spectroscopies, when combined in laser-pump, X-ray-probe measurement schemes, can be powerful tools for tracking the electronic and geometric structural changes that occur during the course of a photoinitiated chemical reaction. X-ray absorption spectroscopy (XAS) is considered an established technique for such measurements, and X-ray emission spectroscopy (XES) of the strongest core-to-core emission lines (Kalpha and Kbeta) is now being utilized. Flux demanding valence-to-core XES promises to be an important addition to the time-resolved spectroscopic toolkit. In this paper we present measurements and density functional theory calculations on laser-excited, solution-phase ferrocyanide that demonstrate the feasibility of valence-to-core XES for time resolved experiments. We discuss technical improvements that will make valence-to core XES a practical pump-probe technique. PMID- 26568781 TI - Diagnosis and Management of Polycythemia Vera: Proceedings from a Multidisciplinary Roundtable. PMID- 26568783 TI - Best Practices in Rheumatoid Arthritis Quality Improvement: Interactive Panel Discussion. PMID- 26568782 TI - A Multistakeholder Approach to Improving Quality in Rheumatoid Arthritis: Proceedings from the Rheumatoid Arthritis Quality Expert Medical Panel. PMID- 26568784 TI - Complete genome sequence of the thermophilic Acidobacteria, Pyrinomonas methylaliphatogenes type strain K22(T). AB - Strain K22(T) is the type species of the recently- described genus Pyrinomonas, in subdivision 4 of the phylum Acidobacteria (Int J Syst Evol Micr. 2014; 64(1):220-7). It was isolated from geothermally-heated soil from Mt. Ngauruhoe, New Zealand, using low-nutrient medium. P. methylaliphatogenes K22(T) has a chemoheterotrophic metabolism; it can hydrolyze a limited range of simple carbohydrates and polypeptides. Its cell membrane is dominated by iso-branching fatty acids, and up to 40 % of its lipid content is membrane-spanning and ether lipids. It is obligately aerobic, thermophilic, moderately acidophilic, and non spore-forming. The 3,788,560 bp genome of P. methylaliphatogenes K22(T) has a G + C content of 59.36 % and contains 3,189 protein-encoding and 55 non-coding RNA genes. Genomic analysis was consistent with nutritional requirements; in particular, the identified transporter classes reflect the oligotrophic nature of this strain. PMID- 26568785 TI - Complete genome sequencing of Dehalococcoides sp. strain UCH007 using a differential reads picking method. AB - A novel Dehalococcoides sp. strain UCH007 was isolated from the groundwater polluted with chlorinated ethenes in Japan. This strain is capable of dechlorinating trichloroethene, cis-1,2-dichloroethene and vinyl chloride to ethene. Dehalococcoides bacteria are hardly cultivable, so genome sequencing has presented a challenge. In this study, we developed a differential reads picking method for mixed genomic DNA obtained from a co-culture, and applied it to the sequencing of strain UCH007. The genome of strain UCH007 consists of a 1,473,548 bp chromosome that encodes 1509 coding sequences including 29 putative reductive dehalogenase genes. Strain UCH007 is the first strain in the Victoria subgroup found to possess the pceA, tceA and vcrA genes. PMID- 26568786 TI - Genome sequence and description of Pantoea septica strain FF5. AB - Strain FF5 was isolated from the skin flora of a healthy Senegalese 35-year-old woman. This strain was identified as belonging to the species Pantoea septica based on rpoB sequence identity of 99.7 % with Pantoea septica strain LMG 5345(T) and a highest MALDI-TOF-MS score of 2.3 with Pantoea septica. Like P. septica, this FF5 strain is a Gram-negative, aerobic, motile, and rod-shaped bacterium. Currently, 17 genomes have been sequenced within the genus Pantoea but none for Pantoea septica. Herein, we compared the genomic properties of strain FF5 to those of other species within the genus Pantoea. The genome of this strain is 4,548,444 bp in length (1 chromosome, no plasmid) with a G + C content of 59.1 % containing 4125 protein-coding and 68 RNA genes (including 2 rRNA operons). We also performed an extensive phenotypic analysis showing new phenotypic characteristics such as the production of alkaline phosphatase, acid phosphatase and naphthol-AS-BI-phosphohydrolase. PMID- 26568787 TI - Encapsulation of Volatile Compounds in Silk Microparticles. AB - Various techniques have been employed to entrap fragrant oils within microcapsules or microparticles in the food, pharmaceutical, and chemical industries for improved stability and delivery. In the present work we describe the use of silk protein microparticles for encapsulating fragrant oils using ambient processing conditions to form an all-natural biocompatible matrix. These microparticles are stabilized via physical crosslinking, requiring no chemical agents, and are prepared with aqueous and ambient processing conditions using polyvinyl alcohol-silk emulsions. The particles were loaded with fragrant oils via direct immersion of the silk particles within an oil bath. The oil-containing microparticles were coated using alternating silk and polyethylene oxide layers to control the release of the oil from the microspheres. Particle morphology and size, oil loading capacity, release rates as well as silk-oil interactions and coating treatments were characterized. Thermal analysis demonstrated that the silk coatings can be tuned to alter both retention and release profiles of the encapsulated fragrance. These oil containing particles demonstrate the ability to adsorb and controllably release oils, suggesting a range of potential applications including cosmetic and fragrance utility. PMID- 26568788 TI - Organization of lipids in milks, infant milk formulas and various dairy products: role of technological processes and potential impacts. AB - The microstructure of milk fat in processed dairy products is poorly known despite its importance in their functional, sensorial and nutritional properties. However, for the last 10 years, several research groups including our laboratory have significantly contributed to increasing knowledge on the organization of lipids in situ in dairy products. This paper provides an overview of recent advances on the organization of lipids in the milk fat globule membrane using microscopy techniques (mainly confocal microscopy and atomic force microscopy). Also, this overview brings structural information about the organization of lipids in situ in commercialized milks, infant milk formulas and various dairy products (cream, butter, buttermilk, butter serum and cheeses). The main mechanical treatment used in the dairy industry, homogenization, decreases the size of milk fat globules, changes the architecture (composition and organization) of the fat/water interface and affects the interactions between lipid droplets and the protein network (concept of inert vs active fillers). The potential impacts of the organization of lipids and of the alteration of the milk fat globule membrane are discussed, and technological strategies are proposed, in priority to design biomimetic lipid droplets in infant milk formulas. PMID- 26568789 TI - Supporting evidence for robotic urological surgery. PMID- 26568790 TI - Long-term oncologic outcomes of postoperative adjuvant versus salvage radiotherapy in prostate cancer: Systemic review and meta-analysis of 5-year and 10-year follow-up data. AB - PURPOSE: To evaluate the oncologic outcomes between adjuvant radiotherapy (ART) and salvage radiotherapy (SRT) in patients with locally advanced prostate cancer or with adverse pathologic factors including positive surgical margin and high Gleason score. MATERIALS AND METHODS: We searched the literature published from January 2000 until December 2014 at MEDLINE, PubMed, Web of Science, Embase, ProQuest, and Cochrane Library. To be specific, included were studies comparing ART and SRT settings if they followed up oncologic outcomes more than 5 years. RESULTS: Overall, 3 retrospective, nonrandomized, observational studies, 1 matched control analysis, and 3 prospective randomized controlled studies met our inclusion criteria including a total of 2,380 patients (1,192 ART vs. 1,188 SRT). Higher favorable results were found in ART than in SRT was seen in the 5-year and 10-year biochemical recurrence (BCR)-free survival (risk ratio [RR], 0.61 and 0.70; 95% confidence interval [CI], 0.54-0.69 and 0.63-0.76). ART had a significantly higher 5-year progression-free survival rate than that in SRT (RR, 0.64; 95% CI, 0.51-0.80), but this was not the same for the 10-year progression free survival rate (RR, 0.88; 95% CI, 0.72-1.08). There was no significant difference for the 5-year and 10-year overall survival rates between ART and SRT (RR, 0.80 and 0.94; 95% CI, 0.59-1.07 and 0.80-1.11). CONCLUSIONS: ART showed favorable results in BCR-free survival during the 5-year follow-up period. However, the 10-year progression-free survival and overall survival did not show any difference between ART and SRT. PMID- 26568791 TI - Predictive factors of prolonged warm ischemic time (>=30 minutes) during partial nephrectomy under pneumoperitoneum. AB - PURPOSE: Current clinical data support a safe warm ischemia time (WIT) limit of 30 minutes during laparoscopic partial nephrectomy (LPN) or robot-assisted partial nephrectomy (RPN). We evaluated independent factors predicting prolonged WIT (more than 30 minutes) after LPN or RPN. MATERIALS AND METHODS: A retrospective data review was performed for 317 consecutive patients who underwent LPN or RPN performed by the same surgeon from October 2007 to May 2013. Patients were divided into two groups: group A was defined as prolonged WIT (>=30 minutes) and group B as short WIT (<30 minutes). We compared clinical factors between the two groups to evaluate predictors of prolonged WIT. RESULTS: Among 317 consecutive patients, 80 were in the prolonged WIT group. Baseline characteristics were not significantly different between the groups. In the univariable analysis, PADUA (preoperative aspects and dimensions used for an anatomical) score (p=0.001), approach method (transperitoneal or retroperitoneal approach; p<0.001), and surgeon experience (p<0.001) were significantly associated with prolonged WIT. In the multivariable analysis, PADUA score (p=0.032), tumor size (>=25 mm; odds ratio, 2.98; 95% confidence interval, 1.48 5.96; p=0.002), and surgeon experience (p<0.001) were independent predictors of prolonged WIT. CONCLUSIONS: Surgeon experience, tumor size, and PADUA score predicted prolonged WIT after RPN or LPN. Among these factors, increasing surgical experience with LPN or RPN is the most important factor for preventing prolonged WIT. PMID- 26568792 TI - Predictive value of pretreatment inflammation-based prognostic scores (neutrophil to-lymphocyte ratio, platelet-to-lymphocyte ratio, and lymphocyte-to-monocyte ratio) for invasive bladder carcinoma. AB - PURPOSE: Inflammation-based prognostic scores including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) are associated with oncologic outcomes in diverse malignancies. We evaluated the predictive value of pretreatment prognostic scores in differentiating nonmuscle invasive (NMIBC) and muscle invasive bladder cancer (MIBC). MATERIALS AND METHODS: Consecutive transurethral resection of bladder tumour (TURBT) cases from January 2011 to December 2013 were analysed retrospectively. Patient demographics, tumour characteristics and prognostic scores results were recorded. Receiver operating characteristics curves were used to determine prognostic score cutoffs. Univariate and multivariate binomial logistic regression analysis was performed to evaluate the association between variables and MIBC. RESULTS: A total of 226 patients were included, with 175 and 51 having NMIBC (stages Ta and T1) and MIBC (stage T2+) groups, respectively. Median age was 75 years and 174 patients were male. The NLR cutoff was 3.89 and had the greatest area under the curve (AUC) of 0.710, followed by LMR (cutoff<1.7; AUC, 0.650) and PLR (cutoff>218; AUC, 0.642). Full blood count samples were taken a median of 12 days prior to TURBT surgery. Multivariate logistic regression analysis identified tumour grade G3 (odds ration [OR], 32.848; 95% confidence interval [CI], 9.818-109.902; p=0.000), tumour size>=3 cm (OR, 3.353; 95% CI, 1.347-8.345; p=0.009) and NLR>=3.89 (OR, 8.244; 95% CI, 2.488 27.316; p=0.001) as independent predictors of MIBC. CONCLUSIONS: NLR may provide a simple, cost-effective and easily measured marker for MIBC. It can be performed at the time of diagnostic flexible cystoscopy, thereby assisting in the planning of further treatment. PMID- 26568793 TI - Concurrent and predictive validation of robotic simulator Tube 3 module. AB - PURPOSE: We previously described a new procedure specific module (Tube 3) to allow the practice of vesicourethral anastomosis after robot-assisted radical prostatectomy. Herein, we report a predetermined proficiency level of Tube 3 and preliminary validation to explore whether this new module can lead to performance improvement in the da Vinci system. MATERIALS AND METHODS: Eight urology residents and three urology fellows performed the Tube 3 module 1 hour daily for 7 days. The learning curve was depicted through a scatterplot and the stable point was identified through the cumulative sum chart. Concurrent and predictive validations were performed with the da Vinci system. The mean time to complete the task and end product rating score between Tube 3 training group and no Tube 3 training group were compared. RESULTS: Concerning the learning curve, about 41 repetitions comprising about 5 hours were needed to achieve this stable point when the mean time to complete Tube of 384 seconds was set as a target. With regarding to the concurrent and predictive validation, there significant differences were evident in the mean time to complete 16 needle passages and the vesicourethral anastomosis and the end product rating score. CONCLUSIONS: The virtual reality (VR) simulator can yield sufficient improvement in technical performance in Tube 3 within 5 hours. The acquired proficiency can be transferable to the vesicourethral anastomosis using the da Vinci system. PMID- 26568794 TI - The clinical application of the sliding loop technique for renorrhaphy during robot-assisted laparoscopic partial nephrectomy: Surgical technique and outcomes. AB - PURPOSE: To report the initial clinical outcomes of the newly devised sliding loop technique (SLT) used for renorrhaphy in patients who underwent robot assisted laparoscopic partial nephrectomy (RALPN) for small renal mass. MATERIALS AND METHODS: We reviewed the surgical videos and medical charts of 31 patients who had undergone RALPN with the SLT renorrhaphy performed by two surgeons (CWJ and CK) between January 2014 and October 2014. SLT renorrhaphy was performed after tumor excision and renal parenchymal defect repair. Assessed outcomes included renorrhaphy time (RT), warm ischemic time, perioperative complications, and perioperative renal function change. RT was defined as interval from the end of bed suture to the renal artery declamping. RESULTS: In all patients, sliding loop renorrhaphy was successfully conducted without conversions to radical nephrectomy or open approaches. Mean renorrhaphy and warm ischemic time were 9.0 and 22.6 minutes, respectively. After completing renorrhaphy, there were no adverse events such as dehiscence of approximated renal parenchyma, renal parenchymal tearing, or significant bleeding. Furthermore, no postoperative complications or significant renal function decline were observed as of the last follow-up for all patients. The limitations of this study include the small volume case series, the retrospective nature of the study, and the heterogeneity of surgeons. CONCLUSIONS: From our initial clinical experience, SLT may be an efficient and safe renorrhaphy method in real clinical practice. Further large scale, prospective, long-term follow-up, and direct comparative studies with other techniques are required to confirm the clinical applicability of SLT. PMID- 26568795 TI - A novel one lobe technique of thulium laser enucleation of the prostate: 'All-in One' technique. AB - PURPOSE: The thulium laser is the most recently introduced technology for the surgical treatment of benign prostatic hyperplasia (BPH). Until recently, most thulium laser enucleation of the prostate (ThuLEP) was performed by use of the three-lobe technique. We introduce a novel one-lobe enucleation technique for ThuLEP called the "All-in-One" technique. We report our initial experiences here. MATERIALS AND METHODS: From June 2013 to May 2014, a total of 47 patients underwent the All-in-One technique of ThuLEP for symptomatic BPH performed by a single surgeon. All patients were assessed with the International Prostate Symptom Score (IPSS), transrectal ultrasonography, serum prostate-specific antigen (PSA), maximal urine flow rate (Qmax), and postvoid residual urine volume (PVR) before and 1 month after surgery. We reassessed IPSS, Qmax, and PVR 3 months after surgery. To assess the efficacy of the All-in-One technique, we checked the PSA reduction ratio, transitional zone volume reduction ratio, and enucleation failure rate. RESULTS: The mean operative time was 82.1+/-33.3 minutes. The mean enucleation time and morcellation time were 52.7+/-21.7 minutes and 8.2+/-7.0 minutes, respectively. The mean resected tissue weight and decrease in hemoglobin were 36.9+/-24.6 g and 0.4+/-0.8 g/dL, respectively. All perioperative parameters showed significant improvement (p<0.05). No major complications were observed. The PSA reduction ratio, transitional zone volume reduction ratio, and enucleation failure rate were 0.81, 0.92, and 4.3%, respectively. CONCLUSIONS: The All-in-One technique of ThuLEP showed efficacy and effectiveness comparable to that of other techniques. We expect that this new technique could reduce the operation time and the bleeding and improve the effectiveness of enucleation. PMID- 26568796 TI - Peyronie's disease and low intensity shock wave therapy: Clinical outcomes and patient satisfaction rate in an open-label single arm prospective study in Australian men. AB - PURPOSE: To evaluate the efficacy, safety and patient satisfaction outcomes following low intensity extracorporeal shock wave therapy (LiESWT) in men with Peyronie's disease (PD) using a standardised protocol. MATERIALS AND METHODS: In this open-label single arm prospective study, patients with PD were enrolled following informed consent. Patient demographics, change in penile curvature and plaque hardness, International Index of Erectile Function (IIEF)-5 score, and overall satisfaction score (on a 5-point scale) were recorded. Treatment template consists of 3000 shock waves to the Peyronie's plaque over 20 minutes, twice weekly for 6 weeks. RESULTS: The majority of patients have PD history longer than 6 months (mean, 12.8 months; range, 6-28 months). Two thirds of patients have received and failed oral medical therapy. There were improvements in penile curvature (more than 15 degrees in 33% of men), plaque hardness (60% of men) and penile pain (4 out of 6 men) following LiESWT. There was a moderate improvement in IIEF-5 score (>5 points reported in 20% of men). No complication was reported and the majority of patients were satisfied (rated 4 out of 5; 70% of men) and would recommend this therapy to others. CONCLUSIONS: In a carefully selected group of men with PD, LiESWT appears to be safe, has moderate efficacy and is associated with high patient satisfaction rate in the short term. PMID- 26568797 TI - Single port laparoscopic orchidopexy in children using surgical glove port and conventional rigid instruments. AB - PURPOSE: We review the literature and describe our technique for laparoendoscopic single-site orchidopexy using a glove port and rigid instruments. We assessed the feasibility and outcomes of this procedure. MATERIALS AND METHODS: We retrospectively reviewed the case records of all children who had undergone laparoendoscopic single-site orchidopexy by use of a surgical glove port and conventional rigid instruments for a nonpalpable intraabdominal testis between January 2013 and September 2014. RESULTS: Data from a total of 20 patients were collected. The patients' mean age was 18 months. All cases had a nonpalpable unilateral undescended testis. Fourteen patients (70%) had an undescended testis on the right side and six patients (30%) had an undescended testis on the left side. Seventeen patients underwent primary orchidopexy. Three patients underwent single-port laparoscopic Fowler-Stephens orchidopexy for the first and the second stage. Average operating time was 57 minutes (range, 40 to 80 minutes). No patient was lost to follow-up. At follow-up, 2 testes were found to have retracted out of the scrotum and these were successfully dealt with in a second operation. One testis was hypoplastic in the scrotal pouch. There were no signs of umbilical hernia. CONCLUSIONS: Single-port laparoscopic orchidopexy using a glove port and rigid instruments is technically feasible and safe for various nonpalpable intraabdominal testes. However, surgical experience and long-term follow-up are needed to confirm the superiority of this technique. PMID- 26568798 TI - Repeated spurious elevation of serum prostate-specific antigen values solved by chemiluminescence analysis: A possible interference by heterophilic antibodies. AB - Heterophilic antibodies are human immunoglobulins directed against various animal antigens. They can produce false-positive results in the analysis of different tumor markers, including prostate-specific antigen. This interference can lead to misdiagnosis, unnecessary tests, and overtreatment in some cases. We present herein the case of a 52-year-old man with repeated spurious elevation of prostate specific antigen, reaching levels of 108.7 ng/mL, that were suspected to be caused by heterophilic antibodies. The interference was solved by changing the analysis technique. Real values of prostate-specific antigen were less than 1 ng/mL. PMID- 26568799 TI - Correlation Between Tympanosclerosis and Helicobacter pylori. AB - BACKGROUND: Tympanosclerosis is a condition caused by calcification of tissues in the middle ear mucosa that sometimes results hearing loss. Helicobacter pylori is one of the pathological and etiologic factors in the development of tympanosclerosis. OBJECTIVES: The purpose of this study was to show the role of H. pylori in the different aspects of chronic suppurative otitis media using the polymerase chain reaction (PCR) technique. PATIENTS AND METHODS: This case control and cross-sectional study was performed on all patients with chronic otitis media, candidates for surgical operations, in 2013. They were allocated into the case group with tympanosclerosis and the control group without tympanosclerosis. During the surgical operation, biopsy was done from middle ear and the samples were studied to see if they contained H. pylori using the PCR method. RESULTS: From a total of 19 patients with tympanosclerosis , 16 cases (84.2%) were H. pylori positive, while in the control group 15 (45.4%) cases out of the 37 cases were H. pylori positive, which showed a significant difference (P = 0.002). Age and gender of the patients, ear dryness and perforation size were not correlated with the presence or absence of H. pylori. CONCLUSIONS: There is a significant correlation between tympanosclerosis and H. pylori (P = 0.002). This correlation can single out H. pylori as a pathological factor in the development of tympanosclerosis; however, further studies are needed to prove this correlation. PMID- 26568800 TI - Efflux Pump Inhibitor Phenylalanine-Arginine Beta-Naphthylamide Effect on the Minimum Inhibitory Concentration of Imipenem in Acinetobacter baumannii Strains Isolated From Hospitalized Patients in Shahid Motahari Burn Hospital, Tehran, Iran. AB - BACKGROUND: Acinetobacter baumannii has emerged as a highly troublesome pathogen and a leading cause of mortality and morbidity among hospitalized burn patients. OBJECTIVES: The aims of this study were to determine the frequency of the AdeABC genes and the role of the efflux pump (s) in the imipenem resistance of A. baumannii strains isolated from burn patients. MATERIALS AND METHODS: This study was conducted on 60 A. baumannii isolates collected from 240 wound samples of burn patients admitted to the Burn Unit of Shahid Motahari Burn hospital, Tehran, Iran. Antibiotic susceptibility tests were performed using the Kirby-Bauer disc diffusion and broth microdilution according to the clinical and laboratory standards institute (CLSI) guidelines. The activity of the efflux pump was evaluated using the efflux pump inhibitor, the phenylalanine-arginine Beta naphthylamide (PABetaN). The AdeABC genes were detected by polymerase chain reaction (PCR) and sequencing. RESULTS: In this study, 100% of the isolates were resistant to cefotaxime, ceftazidime, ceftriaxone, ciprofloxacin, cefepime, piperacillin, meropenem, co-trimoxazole, and piperacillin/tazobactam; 56 (94%) to gentamicin; 50 (81%) to amikacin; 58 (97%) to imipenem; and 45 (76%) to tetracycline. Additionally,all the isolates were susceptible to colistin. The susceptibility of the strains to imipenem was highly increased in the presence of the efflux pump inhibitor such that for 58 (96.6%) of the isolates, the PABetaN reduced the minimum inhibitory concentrations (MIC) by 4- to 64-fold. The adeA and adeB genes were detected in 60 (100%) of the isolates, and the adeC gene was present in 51 (85%). CONCLUSIONS: The efflux pump may play a role in antibiotic resistance in A. baumannii isolates. The ability of A. baumannii isolates to acquire drug resistance by the efflux pump mechanism is a concern. Thus, new strategies are required in order to eliminate the efflux transport activity from resistant A. baumannii isolates causing nosocomial infections. PMID- 26568801 TI - Comparative Analysis of Denaturing Gradient Gel Electrophoresis and Temporal Temperature Gradient Gel Electrophoresis Profiles as a Tool for the Differentiation of Candida Species. AB - BACKGROUND: Candida species are usually opportunistic organisms that cause acute to chronic infections when conditions in the host are favorable. Accurate identification of Candida species is an essential pre-requisite for improved therapeutic strategy. Identification of Candida species by conventional methods is time-consuming with low sensitivity, yet molecular approaches have provided an alternative way for early diagnosis of invasive candidiasis. Denaturing gradient gel electrophoresis (DGGE) and temporal temperature gradient gel electrophoresis (TTGE) are polymerase chain reaction (PCR)-based approaches that are used for studying the community structure of microorganisms. By using these methods, simultaneous identification of multiple yeast species will be possible and reliable results will be obtained quickly. OBJECTIVES: In this study, DGGE and TTGE methods were set up and evaluated for the detection of different Candida species, and their results were compared. MATERIALS AND METHODS: Five different Candida species were cultured on potato dextrose agar medium for 24 hours. Next, total DNA was extracted by the phenol-chloroform method. Two sets of primers, ITS3-GC/ITS4 and NL1-GC/LS2 were applied to amplify the desired regions. The amplified fragments were then used to analyze DGGE and TTGE profiles. RESULTS: The results showed that NL1-GC/LS2 primer set could yield species-specific amplicons, which were well distinguished and allowed better species discrimination than that generated by the ITS3-GC/ITS4 primer set, in both DGGE and TTGE profiles. All five Candida species were discriminated by DGGE and TTGE using the NL1-GC/LS2 primer set. CONCLUSIONS: Comparison of DGGE and TTGE profiles obtained from NL1-GC/LS2 amplicons exhibited the same patterns. Although both DGGE and TTGE techniques are capable of detecting Candida species, TTGE is recommended because of easier performance and lower costs. PMID- 26568802 TI - Nasal Carriage of Staphylococcus aureus : Frequency and Antibiotic Resistance in Healthy Ruminants. AB - BACKGROUND: Staphylococcus aureus is a significant pathogen that can colonize the nares of different animals, causing a wide range of infections in various hosts. OBJECTIVES: We intended to determine the prevalence of S. aureus in the nasal cavity of healthy ruminants and also to investigate the presence of antibiotic resistance genes. MATERIALS AND METHODS: In the present study, healthy cattle (n = 79), sheep (n = 78) and goats (n = 44) were screened for nasal carriage of S. aureus by the Polymerase Chain Reaction (PCR). Staphylococcus aureus isolates were further assessed for the presence of blaZ (encoding penicillin resistance), mecA (encoding methicillin resistance), tetK and tetM (encoding tetracycline resistance), and ermA and ermC (encoding macrolide-lincosamide-streptogramin B resistance) genes. RESULTS: The proportion of S. aureus-positive nasal swabs from cattle, sheep and goats were four (5.06%), 11 (14.1%) and 11 isolates (25%), respectively. The blaZ gene was detected in 20 out of 26 S. aureus isolates (76.9%), including four cattle (100%), nine sheep (81.8%) and seven goats (63.6%). Two of the four cattle isolates possessing the blaZ gene also had the tetK gene. Of the nine sheep isolates harboring the blaZ gene, one possessed the mecA and tetK genes together. Of the seven goat isolates with blaZ gene, one harbored the tetM gene. None of the S. aureus isolates were positive for the ermA and ermC genes. CONCLUSIONS: In contrast to cattle, S. aureus is frequently present in the nose of sheep and goats, which may represent the primary reservoir of S. aureus in small ruminant flocks. This study also showed that nasal isolates of S. aureus from healthy ruminants might be a potential reservoir of antimicrobial-resistance. PMID- 26568803 TI - Utilization of Human Papillomavirus DNA Detection for Cervical Cancer Screening in Women Presenting With Abnormal Cytology in Lokoja, Nigeria. AB - BACKGROUND: Cervical cancer is regarded as the second highest cause of cancer deaths in Nigeria, with an overall prevalence similar to most developing countries. Screening for cervical cancer is primarily performed using papanicolaou (PAP) staining procedure, in Nigeria. OBJECTIVES: This study aimed to use human papillomavirus (HPV) DNA typing, as a means of ascertaining the presence of high risk HPV in cytology samples, which are positive for the presence of cervical intraepithelial neoplasia (CIN), using the PAP screening procedure. PATIENTS AND METHODS: Amplification of DNA was done using polymerase chain reaction. Gene sequencing was carried out to determine the presence of high risk HPV from cervical smears that were positive for abnormal cytology, from a cross-sectional study involving women between the ages of 16 - 65 years, screened for CIN and cervical cancer, in Lokoja, Nigeria. RESULTS: Result showed a 100% presence of high risk HPV in all the samples with abnormal cytology. The HPV genotype 35 accounted for the highest percentage of the HPVs cases, with a 40% incidence. The HPV genotype 31 accounted for 30% of samples, while HPV genotype 16 and 18 accounted for 20% and 10% of samples, respectively. CONCLUSIONS: The high prevalence of HPV in abnormal cytology underlines to the fact that the presence of HPV is a critical factor in the development of cervical cancer. The use of HPV DNA techniques could actually become an effective and fast means of ascertaining the presence of HPV in abnormal cytology. PMID- 26568804 TI - Study of the Frequency of Herpesvirus Infections Among Patients Suspected Aseptic Meningitis in the West of Iran. AB - BACKGROUND: Aseptic meningitis is the most common type of meningitis and is characterized by meningeal inflammation that is not linked to identifiable bacterial pathogens in cerebrospinal fluid (CSF). OBJECTIVES: This study aimed to evaluate the frequency of aseptic meningitis caused by herpesviruses, namely herpes simplex types I and II (HSV-1, HSV-2), Epstein-Barr virus (EBV), cytomegalovirus (CMV) and varicella-zoster virus (VZV). PATIENTS AND METHODS: A total of 196 CSF samples were collected from patients with suspected meningitis. All samples were smear- and culture-negative for bacterial pathogens. The biochemical and cytological findings of CSF samples were also recorded. DNA was extracted from samples and PCR with specific primers was carried out to detect viruses. RESULTS: The 196 samples derived from 100 (52%) men and 96 (48%) women ranging in age from one day to 86 years with an average age of 32.3 +/- 25.3 years. Of them, 8 (4.08%) samples yielded positive results, including 5 (2.55%) cases of VZV infection and 3 (1.53%) cases of HSV-1 infection. No cases of HSV-2, CMV or EBV infection were detected. CSF protein and glucose levels among positive cases were all in the normal range. CONCLUSIONS: The results indicate a considerable rate of herpesvirus infection in patients with aseptic meningitis, and that VZV is the most common herpesvirus to cause infection followed by HSV-1. Our results also showed that a moderate increase in the WBC count and predominance of lymphocytes can be valuable clues in diagnosing viral meningitis. Given the different approaches of drug therapy in bacterial and viral meningitis, use of molecular methods is necessary in hospitals to rapidly discriminate between them. PMID- 26568805 TI - Characterization of Leptospira interrogans Serovars by Polymorphism Variable Number Tandem Repeat Analysis. AB - BACKGROUND: Leptospirosis is recognized as a re-emerging infectious disease; therefore, understanding the epidemiology of the disease is vital for designing intervention programs and diminishing its transmission. Recently, Multilocus variable number tandem repeat analysis (MLVA) is used for segregating and identifying Leptospira serovars. The method has potential application in investigating the molecular epidemiology of Leptospira. OBJECTIVES: The propose of this study was genomic identification of pathogenic Leptospires in Iran by MLVA. MATERIALS AND METHODS: Leptospira serovars were obtained from National Reference Laboratory of Leptospira at Razi Vaccine and Serum Research Institute, Karaj, Iran. Serovars were cultured into the liquid EMJH medium and incubated at 28C for 7 days. DNA of serovars was extracted using the phenol-chloroform method. PCR was performed with 5 selected variable number tandem repeat analysis (VNTR) loci. The amplified products were analyzed by agarose gel electrophoresis. The size of the amplified products was estimated by 100 bp ladder and sequencing analysis. RESULTS: The saprophytic serovar showed no amplified fragments. PCR products in all pathogenic serovars were observed. The 12 reference serovars used for the development of technique displayed distinct patterns. CONCLUSIONS: Results showed that MLVA technique with its range of polymorphism is a good marker for identification of pathogenic serovars. Some VNTR loci are more powerful than the other ones with regard to differentiation. Serovars from the same geographical area have more genetic similarity than same serovars from different places. MLVA is a suitable technique for epidemiological survey. PMID- 26568806 TI - Evidence of Hepatitis D Virus Infection in HBsAg Positive Subjects of Mashhad, North-East of Iran. PMID- 26568807 TI - Chronic spontaneous urticaria: latest developments in aetiology, diagnosis and therapy. AB - Chronic urticaria is a debilitating disease characterized by itching and hives with or without angioedema lasting for more than 6 weeks. The disease carries a significant emotional and economic burden for the patient and often results in an odyssey between doctors of different specialities. Patients suffering from chronic urticaria are considered more difficult to satisfy, treat and to have a bigger emotional burden than the average patient in dermatology, paediatric and general practice settings. A joint initiative under the Dermatology section of the European Academy of Allergy and Clinical immunology (EAACI), the Global Allergy and Asthma European Network (GA(2)LEN), the European Dermatology Forum (EDF) and the World Allergy Organization (WAO) has resulted in recently published guidelines for the diagnosis, classification and treatment of chronic urticarial: these guidelines are clinically useful and have a high success rate when followed in daily clinical practice. The treatment of choice for chronic urticaria is still nonsedating antihistamines although other treatments are available, with omalizumab (humanized IgG anti IgE antibodies) as the newest therapy. The pathogenesis of urticaria is poorly understood but autoimmunity is considered as one of the major underlying causes for this disease, although other theories exist. PMID- 26568808 TI - Strategies for treating chronic HCV infection in patients with cirrhosis: latest evidence and clinical outcomes. AB - The burden of chronic hepatitis C virus (HCV) infection is significant and growing. HCV is considered one of the leading causes of liver disease worldwide and the leading cause of liver transplantation globally. While those infected is estimated in the hundreds of millions, this is likely an underestimation because of the indolent nature of this disease when first contracted. Approximately 20% of patients with HCV infection will progress to advanced fibrosis and cirrhosis. Those that do are at risk of decompensated liver disease including GI bleeding, encephalopathy, severe lab abnormalities, and hepatocellular carcinoma. Those individuals with advanced fibrosis and cirrhosis have historically been difficult to treat. The backbone of previous HCV regimens was interferon (IFN). The outcomes for IFN based regimens were poor and resulted in increased adverse events among those with advanced fibrosis and cirrhosis. Now, in the era of new direct acting antiviral (DAA's) medications, there is hope for curing chronic HCV in everyone, including those with advanced fibrosis and cirrhosis. This article provides a review on the most up to date data on the use of DAA's in patients with advanced fibrosis and cirrhosis. We are at a point where HCV could be truly eradicated, but to do so will require ensuring there are effective and safe treatments for those with advanced fibrosis and cirrhosis. PMID- 26568809 TI - Pharmacological treatment of spondyloarthritis: exploring the effectiveness of nonsteroidal anti-inflammatory drugs, traditional disease-modifying antirheumatic drugs and biological therapies. AB - Spondyloarthritis represents a heterogeneous group of articular inflammatory diseases that share common genetic, clinical and radiological features. The therapy target of spondyloarthritis relies mainly in improving patients' quality of life, controlling articular inflammation, preventing the structural joints damage and preserving the functional abilities, autonomy and social participation of patients. Among these, traditional disease-modifying antirheumatic drugs have been demonstrated to be effective in the management of peripheral arthritis; moreover, in the last decade, biological therapies have improved the approach to spondyloarthritis. In patients with axial spondyloarthritis, tumor necrosis factor alpha inhibitors are currently the only effective therapy in patients for whom conventional therapy with nonsteroidal anti-inflammatory drugs has failed. The aim of this review is to summarize the current experience and evidence about the pharmacological approach in spondyloarthritis patients. PMID- 26568810 TI - The effect of angiotensin II receptor blockers on hyperuricemia. AB - The objective of this review was to explore the efficacy of angiotensin II receptor blockers (ARBs) for the treatment of hyperuricemia in individuals diagnosed with gout or hyperuricemia defined as ?7 mg/dl at baseline. A literature search of MEDLINE (1946 to June 2015) and EMBASE (1947 to June 2015) was conducted. The following search terms were used: 'uric acid', 'urate transporter', 'gout', 'angiotensin II receptor blockers', 'hyperuricemia' and the names for individual ARBs, as well as any combinations of these terms. Studies were excluded that did not explore fractional excretion or serum uric acid as an endpoint, if patients did not have a diagnosis of gout or hyperuricemia at baseline, or if they were non-English language. A total of eight studies met the inclusion criteria. Of the eight studies identified, six explored ARB monotherapy and two studies investigated ARBs as adjunct therapy. Losartan demonstrated statistically significant reductions in serum uric acid levels or increases in fractional excretion of uric acid in all studies, whereas no other ARB reached statistical benefit. The effect of ARBs on the occurrence of gout attacks or other clinical outcomes were not represented. Four studies evaluated safety effects of these agents indicating abnormalities such as minor changes in lab values. In conclusion, losartan is the only ARB that has consistently demonstrated a significant reduction in serum uric acid levels, although the significance of impacting clinical outcomes remains unknown. Losartan appears to be a safe and efficacious agent to lower serum uric acid levels in patients with hyperuricemia. PMID- 26568812 TI - Insulin degludec and insulin aspart: novel insulins for the management of diabetes mellitus. AB - Patients with type 2 diabetes mellitus require insulin as disease progresses to attain or maintain glycaemic targets. Basal insulin is commonly prescribed initially, alone or with one or more rapid-acting prandial insulin doses, to limit mealtime glucose excursions (a basal-bolus regimen). Both patients and physicians must balance the advantages of improved glycaemic control with the risk of hypoglycaemia and increasing regimen complexity. The rapid-acting insulin analogues (insulin aspart, insulin lispro and insulin glulisine) all have similar pharmacokinetic and pharmacodynamic characteristics and clinical efficacy/safety profiles. However, there are important differences in the pharmacokinetic and pharmacodynamic profiles of basal insulins (insulin glargine, insulin detemir and insulin degludec). Insulin degludec is an ultra-long-acting insulin analogue with a flat and stable glucose-lowering profile, a duration of action exceeding 30 h and less inter-patient variation in glucose-lowering effect than insulin glargine. In particular, the chemical properties of insulin degludec have allowed the development of a soluble co-formulation with prandial insulin aspart (insulin degludec/insulin aspart) that provides basal insulin coverage for at least 24 h with additional mealtime insulin for one or two meals depending on dose frequency. Pharmacokinetic and pharmacodynamic studies have shown that the distinct, long basal glucose-lowering action of insulin degludec and the prandial glucose-lowering effect of insulin aspart are maintained in the co-formulation. Evidence from pivotal phase III clinical trials indicates that insulin degludec/insulin aspart translate into sustained glycaemic control with less hypoglycaemia and the potential for a simpler insulin regimen with fewer daily injections. PMID- 26568811 TI - Cardiovascular disease and type 1 diabetes: prevalence, prediction and management in an ageing population. AB - Cardiovascular disease (CVD) is a major cause of mortality in type 1 diabetes mellitus (T1D). However, evidence of its risks and management is often extrapolated from studies in type 2 diabetic (T2D) patients or the general population. This approach is unsatisfactory given that the underlying pathology, demographics and natural history of the disease differ between T1D and T2D. Furthermore, with a rising life expectancy, a greater number of T1D patients are exposed to the cardiovascular (CV) risk factors associated with an ageing population. The aim of this review is to examine the existing literature around CVD in T1D. We pay particular attention to CVD prevalence, how well we manage risk, potential biomarkers, and whether the studies included the older aged patients (defined as aged over 65). We also discuss approaches to the management of CV risk in the older aged. The available data suggest a significant CVD burden in patients with T1D and poor management of CV risk factors. This is underpinned by a poor evidence base for therapeutic management of CV risk specifically for patients with T1D, and in the most relevant population - the older aged patients. We would suggest that important areas remain to be addressed, particularly exploring the risks and benefits of therapeutic approaches to CVD management in the older aged. PMID- 26568813 TI - The diagnosis and treatment of chronic migraine: the case for daily scheduled opioid treatment in chronic headache. PMID- 26568814 TI - Catalytic arylsulfonyl radical-triggered 1,5-enyne-bicyclizations and hydrosulfonylation of alpha,beta-conjugates. AB - A catalytic bicyclization reaction of 1,5-enynes anchored by alpha,beta conjugates with arylsulfonyl radicals generated in situ from sulfonyl hydrazides has been established using TBAI (20 mol%) and Cu(OAc)2 (5 mol%) as co-catalysts under convenient conditions. In addition, the use of benzoyl peroxide (BPO) as the oxidant and pivalic acid (PivOH) as an additive was proven to be necessary for this reaction. The reactions occurred through 5-exo-dig/6-endo-trig bicyclizations and homolytic aromatic substitution (HAS) cascade mechanisms to give benzo[b]fluorens regioselectively. A similar catalytic process was developed for the synthesis of gamma-ketosulfones. These reactions feature readily accessible starting materials and simple one-pot operation. PMID- 26568815 TI - Species-specific modifications of mandible shape reveal independent mechanisms for growth and initiation of the coronoid. AB - BACKGROUND: The variation in mandibular morphology of mammals reflects specialisations for different diets. Omnivorous and carnivorous mammals posses large mandibular coronoid processes, while herbivorous mammals have proportionally smaller or absent coronoids. This is correlated with the relative size of the temporalis muscle that forms an attachment to the coronoid process. The role of this muscle attachment in the development of the variation of the coronoid is unclear. RESULTS: By comparative developmental biology and mouse knockout studies, we demonstrate here that the initiation and growth of the coronoid are two independent processes, with initiation being intrinsic to the ossifying bone and growth dependent upon the extrinsic effect of muscle attachment. A necessary component of the intrinsic patterning is identified as the paired domain transcription factor Pax9. We also demonstrate that Sox9 plays a role independent of chondrogenesis in the growth of the coronoid process in response to muscle interaction. CONCLUSIONS: The mandibular coronoid process is initiated by intrinsic factors, but later growth is dependent on extrinsic signals from the muscle. These extrinsic influences are hypothesised to be the basis of the variation in coronoid length seen across the mammalian lineage. PMID- 26568816 TI - Dp412e: a novel human embryonic dystrophin isoform induced by BMP4 in early differentiated cells. AB - BACKGROUND: Duchenne muscular dystrophy (DMD) is a devastating X-linked recessive genetic myopathy. DMD physiopathology is still not fully understood and a prenatal onset is suspected but difficult to address. METHODS: The bone morphogenetic protein 4 (BMP4) is a critical signaling molecule involved in mesoderm commitment. Human induced pluripotent stem cells (hiPSCs) from DMD and healthy individuals and human embryonic stem cells (hESCs) treated with BMP4 allowed us to model the early steps of myogenesis in normal and DMD contexts. RESULTS: Unexpectedly, 72h following BMP4 treatment, a new long DMD transcript was detected in all tested hiPSCs and hESCs, at levels similar to that found in adult skeletal muscle. This novel transcript named "Dp412e" has a specific untranslated first exon which is conserved only in a sub-group of anthropoids including human. The corresponding novel dystrophin protein of 412-kiloDalton (kDa), characterized by an N-terminal-truncated actin-binding domain, was detected in normal BMP4-treated hiPSCs/hESCs and in embryoid bodies. Finally, using a phosphorodiamidate morpholino oligomer (PMO) targeting the DMD exon 53, we demonstrated the feasibility of exon skipping validation with this BMP4 inducible hiPSCs model. CONCLUSIONS: In this study, the use of hiPSCs to analyze early phases of human development in normal and DMD contexts has led to the discovery of an embryonic 412 kDa dystrophin isoform. Deciphering the regulation process(es) and the function(s) associated to this new isoform can contribute to a better understanding of the DMD physiopathology and potential developmental defects. Moreover, the simple and robust BMP4-inducible model highlighted here, providing large amount of a long DMD transcript and the corresponding protein in only 3 days, is already well-adapted to high-throughput and high-content screening approaches. Therefore, availability of this powerful cell platform can accelerate the development, validation and improvement of DMD genetic therapies. PMID- 26568817 TI - SIRT1 inhibits adipogenesis and promotes myogenic differentiation in C3H10T1/2 pluripotent cells by regulating Wnt signaling. AB - BACKGROUND: The directed differentiation of mesenchymal stem cells (MSCs) is tightly controlled by a complex network. Wnt signaling pathways have an important function in controlling the fate of MSCs. However, the mechanism through which Wnt/beta-catenin signaling is regulated in differentiation of MSCs remains unknown. SIRT1 plays an important role in the regulation of MSCs differentiation. RESULTS: This study aimed to determine the effect of sirtuin 1 (SIRT1) on adipogenesis and myogenic differentiation of C3H10T1/2 cells. First, the MSC commitment and differentiation model was established by using 5-azacytidine. Using the established model, C3H10T1/2 cells were treated with SIRT1 activator/inhibitor during differentiation. The results showed that resveratrol inhibits adipogenic differentiation and improves myogenic differentiation, whereas nicotinamide promotes adipogenic differentiation. Notably, during commitment, resveratrol blocked adipocyte formation and promoted myotubes differentiation, whereas nicotinamide enhanced adipogenic potential of C3H10T1/2 cells. Furthermore, resveratrol elevated the expression of Cyclin D1 and beta catenin in the early stages. The luciferase assay showed that knockdown SIRT1 inhibits Wnt/beta-catenin signaling, while resveratrol treatment or overexpression SIRT1 activates Wnt/beta-catenin signaling. SIRT1 suppressed the expression of Wnt signaling antagonists sFRP2 and DACT1. Knockdown SIRT1 promoted adipogenic potential of C3H10T1/2 cells, whereas overexpression SIRT1 inhibited adipogenic differentiation and promoted myogenic differentiation. CONCLUSIONS: Together, our results suggested that SIRT1 inhibits adipogenesis and stimulates myogenic differentiation by activating Wnt signaling. PMID- 26568818 TI - "Slow" skeletal muscles across vertebrate species. AB - Skeletal muscle fibers are generally classified into two groups: slow (type I) and fast (type II). Fibers in each group are uniquely designed for specific locomotory needs based on their intrinsic cellular properties and the types of motor neurons that innervate them. In this review, we will focus on the current concept of slow muscle fibers which, unlike the originally proposed version based purely on amphibian muscles, varies widely depending on the animal model system studied. We will discuss recent findings from zebrafish neuromuscular junction synapses that may provide the framework for establishing a more unified view of slow muscles across mammalian and non-mammalian species. PMID- 26568819 TI - Differences in characteristics of pediatric patients undergoing computed tomography between hospitals and primary care settings: implications for assessing cancer follow-up studies. AB - BACKGROUND: Recently published analyses showed that computed tomography (CT) scans in pediatric patients are associated with increased risk of radiation related cancer. These analyses were based on data collected both from either hospitals and primary care services. Study objectives were to characterize cohorts of pediatric patients in Israel undergoing CT scans in primary care compared to hospitals settings. These cohorts will be further used for evaluating cancer risks. METHODS: The present study was conducted in Schneider Children Medical Center in Israel (SCMCI), the largest tertiary pediatric hospital in the country. Data were collected directly from the listings of the pediatric radiology department for the period 1985-2005. Results were compared with previously published data on pediatric CT in the primary healthcare service performed between 1999 and 2003 in a large health organization, Maccabi Healthcare Services (MHS). RESULTS: During the study observation periods, 38,351 and 22,223 examinations were documented in 13,726 and 18,075 pediatric patients in SCMCI and MHS, respectively. Compared to pediatric patients in the primary care, patients undergoing CT scans in the hospital were more likely to be younger, to have multiple CT scans, and to be scanned in the trunk. Also, cancer related indications accounted for nearly 50 % of all CT scans conducted in the hospital compared to only 3 % in primary care settings. CONCLUSIONS: The results indicate major differences in the characteristics of children and adolescents scanned in hospitals compared to primary care settings. Some of these characteristics may be associated with cancer risk later in life, and should be taken into account in cancer risk assessments. PMID- 26568820 TI - Undergraduate medical education in the U.S. and Israel: contrasts and common challenges. AB - In 2014, the Israeli Council for Higher Education (CHE) commissioned an international panel of outstanding educators to prepare an ad hoc report reviewing the four established medical schools in Israel. The report described the strengths, weaknesses and challenges facing medical education in Israel with a focus on three specific areas: workforce planning, the structure of the curriculum and the financing of medical education. There are interesting parallels between the challenges facing medical education in the U.S. and in Israel: a lack of clarity regarding the optimal size for the workforce and the optimal method for enhancing the number of primary care physicians; an absence of methodologies for evaluating innovations in medical education and a lack of transparency in funds flow. However, there are also important differences, one of the most important being an absence in Israel of students' hands-on responsibility for their patients until year six of their undergraduate medical education. The presence of a small number of medical schools with common funding and geographic proximity, in a relative sense, provides the Israeli medical schools with a unique opportunity to evaluate innovations in medical education and to set a high bar for inter-school collaboration and cooperation. PMID- 26568821 TI - The Genome Russia project: closing the largest remaining omission on the world Genome map. AB - We are witnessing the great era of genome exploration of the world, as genetic variation in people is being detailed across multiple varied world populations in an effort unprecedented since the first human genome sequence appeared in 2001. However, these efforts have yet to produce a comprehensive mapping of humankind, because important regions of modern human civilization remain unexplored. The Genome Russia Project promises to fill one of the largest gaps, the expansive regions across the Russian Federation, informing not just medical genomics of the territories, but also the migration settlements of historic and pre-historic Eurasian peoples. PMID- 26568822 TI - Risk factors for Candida colonization and Co-colonization with multi-drug resistant organisms at admission. AB - INTRODUCTION: Candida species are major causes of healthcare-associated infections with colonization preceding infection. Understanding risk factors for colonization by Candida species is important in prevention. However, data on risk factors for colonization by Candida species alone or with other healthcare associated pathogens is limited. METHODS: From 2002 to 2006, 498 patients were enrolled into a prospective cohort study at our institution. Surveillance perirectal, nasal and skin swab samples were obtained upon enrollment. Samples were cultured for the presence of Candida species, Methicillin Resistant Staphylococcus aureus, Vancomycin Resistant Enterococcus, and Resistant Gram Negative organisms. Data on demographics, comorbidities, device use, and antibiotic use were also collected for each subject and analyzed using univariate and multivariate logistic regression. RESULTS: Factors associated with Candida colonization at admission in univariate analysis included ambulatory status, a history of Candida colonization and the use of antibiotics prior to enrollment. In multivariate analysis, ambulatory status (odds ratio; OR = 0.45, 95 % CI: 0.27 0.73) and fluroquinolone use (OR = 3.01, 95 % CI: 1.80-5.01) were associated with Candida colonization at admission. Factors predicting Candida co-colonization with one or more MDROs at admission in univariate analysis included, older age, malnutrition, days spent in an ICU in the 2 years prior to enrollment, a history of MRSA colonization, and using antibiotics prior to enrollment. In multivariate analysis malnutrition (OR = 3.97, 95 % CI: 1.80-8.78) a history of MRSA (OR = 5.51, 95 % CI: 1.89-16.04) and the use of macrolides (OR = 3.75, 95 % CI: 1.18 11.93) and other antibiotics (OR = 4.94, 95 % CI: 1.52-16.03) were associated with Candida co-colonization at admission. DISCUSSION: Antibiotic use was associated with an increased risk of colonization by Candida species alone and in conjunction with other multidrug-resistant organisms (MDROs). Antibiotic stewardship may be an important intervention for preventing colonization and subsequent infection by Candida and other MDROs. PMID- 26568823 TI - Clinical presentations and outcomes of necrotizing fasciitis in males and females over a 13-year period. AB - BACKGROUND: Necrotizing fasciitis (NF) is a rapidly progressive infection of fascia and subcutaneous tissue resulting in serious outcomes. We aimed to evaluate the clinical presentations, hospital course and outcomes of NF based on patient gender. PATIENTS AND METHODS: All patients admitted with NF were enrolled in the study over a 13-year period in the main tertiary hospital in Qatar. Clinical presentations, co-morbidities, severity and outcomes were analyzed and compared in male and female patients. RESULTS: A total of 331 NF patients were identified with a mean age of 51 +/- 15 years and male to female ratio of 3:1. However, Arab Qatari females were more frequently affected by NF in comparison to their male counterparts and south Asian females (p < 0.001), respectively. Female patients were older and had significantly higher incidence of abdominal and groin NF (p < 0.004). There were 13 cases with recurrent NF; 85% of them were males. Male NF patients had significantly higher rate of organ failure (p = 0.02), but there was no significant difference in the hospital length of stay as well as mortality in both genders. Overall, there were 85 (25.7%) deaths (23 females and 62 males). CONCLUSION: Necrotizing fasciitis remains a life threatening entity. Although, NF is more common in males, Qatari females are more likely to develop NF than males. NF of abdominal wall and groin is significantly higher in females. Development of organ failure is more common in males with NF. NF remains a challenging clinical problem in Qatar with a mortality rate ranging from 25 to 27% for both genders. PMID- 26568824 TI - Mazabraud's syndrome: Report of its first incidence in the Middle East and a literature review. AB - INTRODUCTION: Mazabraud's syndrome, a rare benign disease with indolent course, is best described as an association between soft tissue myxoma and fibrous dysplasia of the bones. In this report, we describe the first case of this syndrome from Saudi Arabia. CASE PRESENTATION: A 24-year-old male in overall good health status, presented with progressive left knee swelling over 6 years with no other associated symptoms. The swelling measured 5 cm in diameter, with smooth surface, and soft palpable texture. Radiological examination followed by histopathological examination of the excised mass confirmed our diagnosis of Mazabraud's syndrome. The patient was closely followed up with systematic examination with no recurrence. DISCUSSION: Fibrous dysplasia, soft tissue myxoma and multiple endocrinological diseases like McCune-Albright syndrome characterize Mazabraud's syndrome. Furthermore, fibrous dysplasia is found to be associated with GNA1S gene mutation. Many patients can have asymptomatic course of the disease but may present with pathological fractures, pain, and limitation of movement when the myxoma is near the joints or just simple cosmetically disturbing swelling like in our case. CONCLUSION: Patients with such presentation need to be investigated thoroughly to rule out associated diseases and to evaluate the extent of such pathology. The improvement of radiological modalities can help in narrowing the differential diagnosis and following the patient to early detect the recurrence or any malignant transformation of the condition. PMID- 26568825 TI - Surgery for posterior mediastinal dumbbell tumors: A case report. AB - INTRODUCTION: Mediastinal dumbbell tumors are rare, and special cases provide valuable knowledge to the existing literature. PRESENTATION OF CASE: A 57-year old woman was diagnosed with a recurrent dumbbell-shaped nerve sheath tumor with intrathoracic and intraspinal components. We attempted to resect the tumor via combined biport thoracoscopy and laminectomy with the patient in a prone position. However, copious bleeding prevented complete removal of the intraspinal component of the tumor. Pathological examination of the operative specimens showed a mixed hemangioma. DISCUSSION: The first report on the use of triportal thoracoscopy for treatment of a posterior mediastinal dumbbell tumor with the patient in the prone position was published in 1995. However, this technique is not widely used. The technique used in our case is unique only in that biportal rather than triportal thoracoscopy was used to resect the intrathoracic component of the tumor. The differential diagnoses of posterior mediastinal dumbbell-shaped tumors include neurogenic tumors, meningiomas, and hemangiomas. Very rarely, cavernous and capillary hemangiomas also present as dumbbell-shaped lesions. To our knowledge, a mixed hemangioma presenting as a dumbbell-shaped lesion has not been previously reported. CONCLUSION: The intrathoracic component of a posterior mediastinal dumbbell tumor can be resected by biportal thoracoscopy with the patient in a prone position, reducing the operative time. If the diagnosis of a dumbbell tumor is inconclusive, an endoscopic biopsy should be performed before removing the tumor. PMID- 26568826 TI - Effects of different forms of yeast Saccharomyces cerevisiae on growth performance, intestinal development, and systemic immunity in early-weaned piglets. AB - The present study was conducted to determine effects of different forms of yeast (Saccharomyces cerevisiae, strain Y200007) on the growth performance, intestinal development, and systemic immunity in early-weaned piglets. A total of 96 piglets (14-d old, initial average body weight of 4.5 kg) were assigned to 4 dietary treatments: (1) basal diet without yeast (Control); (2) basal diet supplemented with 3.00 g/kg live yeast (LY); (3) basal diet supplemented with 2.66 g/kg heat killed whole yeast (HKY); and (4) basal diet supplemented with 3.00 g/kg superfine yeast powders (SFY). Diets and water were provided ad libitum to the piglets during 3-week experiment. Growth performance of piglets was measured weekly. Samples of blood and small intestine were collected at days 7 and 21 of experiment. Dietary supplementation with LY and SFY improved G:F of piglets at days 1-21 of the experiment (P < 0.05) compared to Control group. Serum concentrations of growth hormone (GH), triiodothyronine (T3), tetraiodothyronine (T4), and insulin growth factor 1 (IGF-1) in piglets at day 21 of the experiment were higher when fed diets supplemented with LY and SFY than those in Control group (P < 0.05). Compared to Control group, contents of serum urea nitrogen of piglets were reduced by the 3 yeast-supplemented diets (P < 0.05). Diets supplemented with LY increased villus height and villus-to-crypt ratio in duodenum and jejunum of piglets (P < 0.05) compared to other two groups at day 7 of the experiment. Feeding diets supplemented with LY and SFY increased (P < 0.05) serum concentrations of IgA, IL-2, and IL-6 levels in piglets compared to Control. The CD4(+)/CD8(+) ratio and proliferation of T-lymphocytes in piglets fed diets supplemented with LY were increased compared to that of Control group at day 7 of the experiment (P < 0.05). In conclusion, dietary supplementation with both LY and SFY enhanced feed conversion, small intestinal development, and systemic immunity in early-weaned piglets, with better improvement in feed conversion by dietary supplementation with LY, while dietary supplementation with SFY was more effective in increasing systemic immune functions in early-weaned piglets. PMID- 26568827 TI - Spatio-temporal hotspots of satellite-tracked arctic foxes reveal a large detection range in a mammalian predator. AB - BACKGROUND: The scale at which animals perceive their environment is a strong fitness determinant, yet few empirical estimates of animal detection ranges exist, especially in mammalian predators. Using daily Argos satellite tracking of 26 adult arctic foxes (Vulpes lagopus) during a single winter in the High Canadian Arctic, we investigated the detection range of arctic foxes by detecting hotspots of fox activity on the sea ice. RESULTS: While maintaining territories in the tundra, these solitary foragers occasionally used the sea ice where they sometimes formed spatio-temporal hotspots, likely scavenging on marine mammal carcasses. We detected 35 movements by 13 individuals forming five hotspots. Foxes often traveled more than 10 km, and up to 40 km, to reach hotspots, which lasted one-two weeks and could gather up to 12 individuals. The likelihood of a fox joining a hotspot was neither influenced by its distance from the hotspot nor by the distance of its home range to the coast. CONCLUSIONS: Observed traveling distances may indicate a high detection range in arctic foxes, and our results suggest their ability to detect food sources on the sea ice from their terrestrial home range. While revealing a wide knowledge gap regarding resource detection abilities in mammalian predators, our study provides estimates of detection range useful for interpreting and modeling animal movements. It also allows a better understanding of foraging behavior and navigation capacity in terrestrial predators. PMID- 26568828 TI - Can't stand the look in the mirror? Self-awareness avoidance in borderline personality disorder. AB - BACKGROUND: Patients with Borderline Personality Disorder (BPD) expect and perceive social rejection stronger than healthy individuals. Shifting ones attention from oneself to others has been suggested as a mechanism to deal with the experience of social rejection. Here, we investigated whether BPD participants avoid increased self-awareness and whether this is done intentionally. METHODS: Thirty BPD patients and 30 healthy control participants, all naive of the study's purpose, were asked to choose either a seat facing a mirror (self-awareness) or not facing the mirror (avoidance of self-awareness). Afterwards they were asked to indicate if they have chosen the seat intentionally. RESULTS: BPD patients avoided as a trend the chair facing the mirror more often than healthy control participants. 90 % of the patients reported that they made their seating decision intentionally in contrast to 26.7 % of the healthy participants (odd ratio = 24.75). CONCLUSIONS: Results revealed altered reactions to self-awareness cues in BPD. While BPD patients avoided such a cue slightly more often, they were more often aware of their behavior than healthy participants. As possible explanations, a negative body related, shame prone self-concept as well as a simultaneously increased degree of self-focused attention are suggested. PMID- 26568829 TI - Successful interdisciplinary radical treatment of Mycobacterium fortuitum infection in a lipotourist from Germany after abdominoplasty in Turkey. AB - We report a case of a 30-year-old woman who experienced recurrent infections of the abdominal wall after travelling to Turkey from Germany to undergo abdominoplasty for aesthetic reasons. The patient's Mycobacterium fortuitum infection was successfully treated by surgery and antibiotic therapy. Surgical tourism-in this case, lipotourism-is resulting in an increasing number of patients in Europe who may present uncommon disease patterns. PMID- 26568830 TI - Anxiety symptoms and occupational stress among young Korean female manufacturing workers. AB - BACKGROUND: The prevalence of anxiety disorders has been increasing in South Korea, with recent studies reporting anxiety disorders as the most common mental disorder among all South Korean females. Anxiety disorders, which are independent risk factors of suicidal ideation and suicide attempts, are significantly correlated with productivity loss, high medical costs, impaired work performance, and frequent worker absence, and thus are potentially serious problems affecting the health of South Korean female workers. In previous studies, anxiety disorders were shown to have a significant correlation with occupational stress. This study seeks to examine the prevalence of anxiety symptoms as well as the relationship between occupational stress and anxiety symptoms among South Korean female manufacturing workers. METHODS: A structured self-reported questionnaire was administered to 1,141 female workers at an electrical appliance manufacturing plant. The questionnaire collected data on general characteristics, health behaviors, sleep quality, job characteristics (shift work, shift work schedule, and job tenure), occupational stress, and anxiety symptoms. Sleep quality was measured using the Pittsburgh Sleep Quality Index, occupational stress with the Korean Occupational Stress Scale-Short Form (KOSS-SF), and anxiety symptoms with the Korean version of the Beck Anxiety Inventory. A chi square test was conducted to determine the distribution differences in anxiety symptoms based on general characteristics, health behaviors, job characteristics, and sleep quality. A linear-by-linear association test was used to determine the distribution differences between anxietysymptoms and the levels of occupational stress. Last, logistic regression analysis was used in order to determine the association between occupational stress and anxiety symptoms. RESULTS: The prevalence of anxiety symptoms was 15.2 %. In the multivariate logistic regression analysis that adjusted for sleep quality and general characteristics, a significantassociation was found for those with anxiety disorders; the odds ratios (OR) were significantly higher the greater the total KOSS-SF score (moderate-risk group OR=2.85, 95 % CI=1.79-4.56; high-risk group OR=5.34, 95 % CI=3.59-7.96). In addition, excluding insufficient job control, all other KOSS-SF subscales were significantly associated with anxiety symptoms, and a relatively high OR was seen in the high-risk group for job demand (OR=3.19, 95 % CI=2.27 4.49), job insecurity (OR=4.52, 95 % CI=2.86-7.13), and occupational culture (OR=4.52, 95 % CI=2.90-7.04). CONCLUSION: There was a significant association between anxiety symptoms and occupational stress stemming from the psychosocial work environment among these South Korean female manufacturing workers. Future longitudinal studies are needed to examine the association between the occupational stress caused by the psychosocial work environment and the incidence of anxiety disorders and anxiety symptoms. Furthermore, intervention programs that aim to address the prevalence of anxiety symptoms and improve the psychosocial work environment, especially for younger female manufacturing workers, are needed. PMID- 26568831 TI - Preliminary application of a single-port access technique for laparoscopic ovariohysterectomy in dogs. AB - Laparoscopic ovariohysterectomy using single-portal access was performed in nine selected owned dogs admitted for elective ovariohysterectomy and the surgical technique and outcomes were detailed. A multiport device (SILS Port, Covidien, USA) was placed at the umbilical area through a single 3 cm incision. Three cannulae were introduced in the multiport device through the access channels and laparoscopic ovariohysterectomy was performed using a 5-mm sealing device, a 5-mm articulating grasper and a 5-mm 30 degrees laparoscope. The mean total operative time was 52.66+/-15.20 minutes and the mean skin incision during surgery was 3.09+/-0.20 cm. Of the nine cases examined, in the one with an ovarian tumour, the technique was converted to multiport laparoscopy introducing an additional 5 mm trocar. No surgical complications were encountered and intraoperative blood loss was minimum in all animals. Clashing of the instruments and reduced triangulation were the main limitations of this technique. The combination of articulated and straight instruments facilitated triangulation towards the surgical field and dissection capability. One month after surgery a complete wound healing was observed in all animals. The present data showed that ovariohysterectomy performed with a single-port access is technically feasible in dogs. The unique abdominal incision minimises the abdominal trauma with good cosmetic results. PMID- 26568832 TI - Neurocognition after paediatric heart surgery: a systematic review and meta analysis. AB - Children with congenital heart disease (CHD) often experience difficulties in academic and daily functioning, which have been associated with intelligence and neurocognitive skills, including executive functions (EFs), attention and memory. We report the neurocognitive data of children with CHD who were included in the Leuven glucose control trial (LGC trial). Through a systematic review and meta analysis, we aimed to find which neurocognitive functions are most consistently and prominently affected. 365 children with CHD and 216 healthy control children underwent extensive neurocognitive testing in the LGC trial. A comprehensive search of electronic databases PubMed, EMBASE and Cochrane was conducted for studies measuring intelligence, EFs, attention and memory in children who underwent heart surgery for CHD. Standardised mean differences (SMDs) between the CHD group and a healthy control group were calculated for these neurocognitive functions. LGC trial data were included in the meta-analysis. Twelve studies with a healthy control group were included in the meta-analysis, involving 647 patients with CHD and 633 controls. The CHD group (median age 7.35 years at testing) had worse scores than healthy control children, for all investigated neurocognitive functions. A medium SMD was found for intelligence (SMD=-0.53 (95% CI -0.68 to -0.38), p<0.00001). Alertness, an attentional function, was also consistently poorer in the CHD group. Memory was less affected, while EF had a medium SMD with large heterogeneity. Children with CHD risk displayed lower performance on intelligence and alertness assessment, which may contribute to difficulties in daily life and school. Heterogeneity in neurocognitive assessment and small sizes in most studies limit the interpretation. TRIAL REGISTRATION NUMBER: clinicaltrials.gov Identifier NCT00214916. PMID- 26568833 TI - Copeptin in patients with heart failure and preserved ejection fraction: a report from the prospective KaRen-study. AB - INTRODUCTION: Underlying mechanisms of heart failure (HF) with preserved ejection fraction (HFPEF) remain unknown. We explored copeptin, a biomarker of the arginine vasopressin system, hypothesising that copeptin in HFPEF is elevated, associated with diastolic dysfunction and N-terminal pro-brain natriuretic peptide (NT-proBNP) and predictive of HF hospitalisation and mortality. METHODS AND ANALYSIS: In a prospective observational substudy of the The Karolinska Rennes (KaRen) 86 patients with symptoms of acute HF and ejection fraction (EF) >=45% were enrolled. After 4-8 weeks, blood sampling and echocardiography was performed. Plasma-copeptin was analysed in 86 patients and 62 healthy controls. Patients were followed in median 579 days (quartile 1; quartile 3 (Q1;Q3) 276;1178) regarding the composite end point all-cause mortality or HF hospitalisation. ETHICS AND DISSEMINATION: The patients with HFPEF had higher copeptin levels, median 13.56 pmol/L (Q1;Q3 8.56;20.55) than controls 5.98 pmol/L (4.15;9.42; p<0.001). Diastolic dysfunction, assessable in 75/86 patients, was present in 45 and absent in 30 patients. Copeptin did not differ regarding diastolic dysfunction and did not correlate with cardiac function but with NT proBNP (r=0.223; p value=0.040). In univariate Cox regression analysis log copeptin predicted the composite end point (HR 1.56 (95% CI 1.03 to 2.38; p value=0.037)) but not after adjusting for NT-proBNP (HR 1.39 (95% CI 0.91 to 2.12; p value=0.125)). CONCLUSIONS: In the present patients with HFPEF, copeptin is elevated, correlates with NT-proBNP but not markers of diastolic dysfunction, and has prognostic implications, however blunted after adjustment for NT-proBNP. The HFPEF pathophysiology may be better reflected by markers of neurohormonal activation than by diastolic dysfunction. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT00774709. PMID- 26568834 TI - Resilience as a correlate of acute stress disorder symptoms in patients with acute myocardial infarction. AB - OBJECTIVES: Myocardial infarction (MI) may be experienced as a traumatic event causing acute stress disorder (ASD). This mental disorder has an impact on the daily life of patients and is associated with the development of post-traumatic stress disorder. Trait resilience has been shown to be a protective factor for post-traumatic stress disorder, but its association with ASD in patients with MI is elusive and was examined in this study. METHODS: We investigated 71 consecutive patients with acute MI within 48 h of having stable haemodynamic conditions established and for 3 months thereafter. All patients completed the Acute Stress Disorder Scale and the Resilience Scale to self-rate the severity of ASD symptoms and trait resilience, respectively. RESULTS: Hierarchical regression analysis showed that greater resilience was associated with lower symptoms of ASD independent of covariates (b=-0.22, p<0.05). Post hoc analysis revealed resilience level to be inversely associated with the ASD symptom clusters of re experiencing (b=-0.05, p<0.05) and arousal (b=-0.09, p<0.05), but not with dissociation and avoidance. CONCLUSIONS: The findings suggest that patients with acute MI with higher trait resilience experience relatively fewer symptoms of ASD during MI. Resilience was particularly associated with re-experiencing and arousal symptoms. Our findings contribute to a better understanding of resilience as a potentially important correlate of ASD in the context of traumatic situations such as acute MI. These results emphasise the importance of identifying patients with low resilience in medical settings and to offer them adequate support. PMID- 26568835 TI - Are valve clinics a sound investment for the health service? A cost-effectiveness model and an automated tool for cost estimation. AB - BACKGROUND: Valve disease is using up an important, growing proportion of the resources allocated for healthcare. Clinical care is often suboptimal and while multidisciplinary clinics are the 'gold standard', their adoption has been patchy and inhomogeneous. METHODS: We hypothesised that adoption of valve clinics can deliver financial savings and set out to estimate differences in cost between a standard model in which the cardiologist sees every case and a multidisciplinary model in which some cases are devolved to sonographer-led or nurse-led clinics, assuming usage of various tests in accordance with practice at our institutions and to published data. We developed a tool that allows the modelling of limitless permutations in order to assess costs. RESULTS: Seeing 100 new patients in a valve clinic is more expensive than seeing them in the conventional set-up (excess cost L2700, $4252). Follow-up of both patients with native valve disease (maximal savings/100 patients-L5166, $8135) and with operated valves (maximal savings/100 patients-L5090, $8015) is cheaper in a valve clinic than in a general cardiology clinic and the savings offset the increased cost of seeing new patients in the valve clinic. CONCLUSIONS: The costing implications of valve clinics need to be worked out carefully. Our analysis suggests that important savings in healthcare costs could be achieved by their adoption. Clarifying the economic implications of this new model of care should become one of the priorities for the 'heart valve community'. PMID- 26568836 TI - Neuromyelitis optica (NMO) and autoimmune thyroiditis. AB - Neuromyelitis optica (NMO or Devic's syndrome) is a rare demyelinating disease of the CNS that predominantly affects the spinal cord and optic nerves and shares many clinical and radiological features with multiple sclerosis (MS). The association of NMO with autoimmune thyroiditis has been reported very rarely. Early differentiation between NMO and MS is very important because they have different natural courses and treatment regimens. We report a case regarding a 53 year-old woman who was admitted initially with hiccups and paraesthesias, but was not evaluated during first two episodes and presented with severe progression of NMO. Patient was found to have autoimmune thyroiditis with lymphocytic infiltration of thyroid which progressed to hypothyroidism. NMO was diagnosed with seropositivity for NMO-IgG and longitudinally extensive spinal cord lesions (three or more spinal segments). Patient poorly responded to treatment due to the lack of early diagnosis and aggressive immunosuppressant therapy. PMID- 26568837 TI - A case series of acquired haemophilia in a Malaysian hospital: unpredictably rare medical emergency. AB - Acquired haemophilia (AH) is a rare bleeding disorder characterized by the presence of acquired inhibitors against Factor VIII causing disruption of coagulation cascade. It has no known genetic inheritance, and diagnosis remains a challenge. The peculiar presentations are later age of onset as acute pain in weight-bearing joints and spontaneous muscle haematoma with isolated prolonged activated partial thrombin time (APTT). Prevalence is 1 per million per year affecting both genders equally where blood product transfusion is seen in almost 87% of cases. The direct cause of AH is still unknown, and autoimmune dysregulation has been postulated, which predisposes to the development of the factor inhibitors. Being extremely rare, we are reporting two consecutive patients diagnosed by unusual bleeding episodes with isolated prolonged APTT due to Factor VIII inhibitors. AH deserves a special mention as high index of suspicion is required. More studies are required to provide better guidance in diagnosis and management of this condition. PMID- 26568838 TI - Combined external counterpulsation and endovascular stenting treatment for symptomatic vertebrobasilar artery stenosis: two case reports. AB - Symptomatic vertebrobasilar artery (VBA) stenosis has a poor prognosis. Intravascular stents provide a new therapeutic approach, but the long-term outcome of stenting compared with medical outcome is controversial. External counterpulsation (ECP) is a noninvasive method to improve perfusion of vital organs. We report two cases of this combination with ECP treatment in addition to receiving endovascular stenting. Two patients experienced posterior ischemic stroke. Digital subtraction angiography revealed a severe basilar or vertebral artery stenosis. Computed tomographic perfusion revealed significantly decreased perfusion of posterior artery territories. Both of them underwent combined ECP treatment and endovascular stenting of the stenosed basilar or vertebral artery, without recurrent stroke within 30 days after stenting. The two patients were independent (modified Rankin scale <=2) at the 12-month follow-up time. Combined ECP treatment and endovascular stent placement may be effective and safe for patients with symptomatic VBA stenosis who failed aggressive medical treatment. PMID- 26568839 TI - Repeated treatment with bone marrow cell secretory products maintains long-term renoprotection in experimental chronic kidney disease: a placebo-controlled trial. AB - BACKGROUND: Bone marrow-derived early outgrowth cells (EOCs) secrete soluble factors that exert potent renoprotective effects, such that infusion of their conditioned medium recapitulates the affects of the cells themselves. OBJECTIVES: The objective of this study is to test whether the protective effect of conditioned medium infusion wanes with time and whether tachyphylaxis occurs with repeated administration. DESIGN: This is a placebo-controlled animal study. SETTING: The study was conducted at St. Michael's Hospital, Toronto, Ontario, Canada. SUBJECTS: Fischer 344 (F344) rats were used in this study. MEASUREMENTS: The following were measured: (1) urinary protein:creatinine ratio, (2) glomerular filtration rate, (3) systolic blood pressure, (4) body weight, (5) glomerular endothelial cell density, and (6) glomerular and tubulointerstitial type IV collagen deposition. METHODS: Subtotally nephrectomized F344 rats, a model of progressive chronic kidney disease, were randomized 4 weeks post-surgery to receive thrice-weekly intravenous injections of concentrated EOC-conditioned medium (EOC CM) or unconditioned medium (UCM) over 2 weeks. Three animal groups were studied, according to whether they were administered conditioned medium: once (Initial Therapy Only group), twice (Repeat Therapy group), or not at all (No Therapy group). RESULTS: Following initial therapy, EOC CM-treated animals excreted less urinary protein, a marker of renal injury, than their UCM-treated counterparts. At 10 weeks post-subtotal nephrectomy, however, mean urinary protein excretion in conditioned medium-treated animals was fourfold greater than at the completion of the initial treatment course. At this time point, conditioned medium-treated animals were randomized to receive a second course of either conditioned medium (Repeat Therapy group) or unconditioned medium (Initial Therapy Only group). At study end (14 weeks post-subtotal nephrectomy), Repeat Therapy animals demonstrated higher glomerular filtration rate, less proteinuria, preserved renal microvasculature, and diminished fibrosis when compared with the No Therapy group. Initial Therapy Only animals exhibited an intermediate effect. LIMITATIONS: Testing the effect of EOC-conditioned medium in a single model of chronic kidney disease (CKD) has limitations. CONCLUSIONS: These findings suggest that early outgrowth cell-derived factors, while renoprotective, have a limited duration of action. Repeated administration of these factors, however, is able to extend the duration of efficacy and attenuate the progression of experimental chronic kidney disease. PMID- 26568840 TI - Treatment of Clostridium difficile infection in mice with vancomycin alone is as effective as treatment with vancomycin and metronidazole in combination. AB - OBJECTIVE: Clostridium difficile is a major cause of nosocomial infectious diarrhoea. Treatment of C. difficile infection (CDI) depends on disease severity. A combination of vancomycin and metronidazole is often recommended in severe cases. The aim of this study was to examine, in a murine model of CDI, if mice treated with a combination of vancomycin and metronidazole had a better clinical outcome than mice treated with vancomycin or metronidazole alone. DESIGN: C57BL/6J mice pretreated with an antimicrobial mixture were challenged with C. difficile VPI 10463 or phosphate-buffered saline by oral gavage. After the challenge, the mice were treated with placebo, vancomycin, metronidazole or a combination of vancomycin and metronidazole for 10 days. The mice were monitored for 20 days with weight and a clinical score. Stool samples were examined for C. difficile spore load and presence of C. difficile toxins. RESULTS: None of the mice in the vancomycin-treated group died during the treatment phase compared to a mortality of 17%, 33% and 55% in the combination, metronidazole and infected control group, respectively. Mice treated with vancomycin alone or in combination with metronidazole recovered from CDI faster than mice treated with metronidazole alone. However, after discontinuation of treatment, vancomycin-treated and combination-treated mice succumbed to clinical and bacteriological relapse. CONCLUSIONS: Mice treated with vancomycin alone had a better clinical outcome in the treatment phase of CDI than mice treated with metronidazole alone. A combination of vancomycin and metronidazole did not improve the clinical outcome when compared to treatment with vancomycin alone. TRIAL REGISTRATION NUMBER: The trial registration number from the Danish Experimental Animal Inspectorate is J number 2012-15-2934-00422. PMID- 26568841 TI - Mental health disorders in child and adolescent survivors of post-war landmine explosions. AB - BACKGROUND: To describe the mental health status of 78 child and adolescent survivors of post-war landmine explosions. METHODS: Child and adolescent survivors of landmine explosions who were younger than 18 years old at the time of the study were identified and enrolled in this study. The mental health status of the participants was assessed by general health assessment and psychiatric examinations. Psychiatric assessment and diagnosis were undertaken using the Diagnostic and Statistical Manual for mental disorders (DSM-IV) criteria. A psychiatrist visited and interviewed each survivor and identified psychiatric disorders. RESULTS: Seventy-eight child and adolescent survivors with a mean age of 16.11 +/- 2 years old were identified and agreed to participate in the study. The mean age of the victims at the time of injury was 8.2 +/- 3.12 years old (range 2-15). Thirty-seven (47.4 %) of the adolescent survivors suffered from at least one psychiatric disorder. Twenty-nine survivors (37.1 %) were newly diagnosed and needed to start medication and psychiatric treatment. The most common findings were anxiety disorders (34.6 %), including posttraumatic stress disorder (PTSD) in 20 (25.6 %), and generalized anxiety disorder (GAD) in 7 (9 %) subjects. Mild-Moderate depression was found in 5 (6.4 %) subjects. No personality disorders were observed, and two patients suffered from mental retardation. The study results revealed a significant association between age of casualty, duration of injury and limb amputation, and types of psychological disorders. CONCLUSION: Child and adolescent survivors of landmine explosions had a high prevalence of psychiatric disorders. PMID- 26568842 TI - Autophagy limits proliferation and glycolytic metabolism in acute myeloid leukemia. AB - Decreased autophagy contributes to malignancies, however it is unclear how autophagy impacts on tumour growth. Acute myeloid leukemia (AML) is an ideal model to address this as (i) patient samples are easily accessible, (ii) the hematopoietic stem and progenitor population (HSPC) where transformation occurs is well characterized, and (iii) loss of the key autophagy gene Atg7 in hematopoietic stem and progenitor cells (HSPCs) leads to a lethal pre-leukemic phenotype in mice. Here we demonstrate that loss of Atg5 results in an identical HSPC phenotype as loss of Atg7, confirming a general role for autophagy in HSPC regulation. Compared to more committed/mature hematopoietic cells, healthy human and mouse HSCs displayed enhanced basal autophagic flux, limiting mitochondrial damage and reactive oxygen species in this long-lived population. Taken together, with our previous findings these data are compatible with autophagy limiting leukemic transformation. In line with this, autophagy gene losses are found within chromosomal regions that are commonly deleted in human AML. Moreover, human AML blasts showed reduced expression of autophagy genes, and displayed decreased autophagic flux with accumulation of unhealthy mitochondria indicating that deficient autophagy may be beneficial to human AML. Crucially, heterozygous loss of autophagy in an MLL-ENL model of AML led to increased proliferation in vitro, a glycolytic shift, and more aggressive leukemias in vivo. With autophagy gene losses also identified in multiple other malignancies, these findings point to low autophagy providing a general advantage for tumour growth. PMID- 26568843 TI - Sources and Severity of Perceived Stress Among Iranian Medical Students. AB - BACKGROUND: Studying medicine is perceived to be stressful, and a high level of stress may have a negative effect on cognitive functioning and mental health of the students. OBJECTIVES: In this study, we assessed perceived stress and its severity, sources and determinants. PATIENTS AND METHODS: In this cross-sectional study, we assessed the perceived stress and its severity, sources and demographic variables in 341 (136 males, 205 females) randomly selected medical students of Tehran university of medical sciences, Iran, in October 2013. A self-administered valid and reliable questionnaire with a possible range of scores from 0 to 56 was used to collect the data. Stress sources were determined using logistic regression analysis. RESULTS: The overall perceived stress mean was 32.02 (SD = 5.08). Eighty-three percent of the medical students perceived stress. Students in clinical phase perceived more stress than basic sciences ones [OR 2.25, 95% CI 1.809 - 4.032]. Logistic regression analysis showed demographic (including gender and residential status), psychosocial and academic factors and the phase of study as sources of stress. CONCLUSIONS: The results of this study show that most of the medical students declared perceived stress. So, a change in medical education environment and empowering students to effectively cope with the perceived stress sources and their families to support their children is needed. PMID- 26568844 TI - The Association of Family Support After Childbirth With Posttraumatic Stress Disorder in Women With Preeclampsia. AB - BACKGROUND: Stressful situations and life-threatening issues such as preeclampsia can lead to Post-traumatic stress disorders [PTSD]. It seems that within social supports, family support has more effect on mental health. OBJECTIVES: The aim of this study was to determine the association between family supports in the postpartum period with occurrence of post-traumatic stress disorder following preeclampsia. PATIENTS AND METHODS: In this descriptive longitudinal study, 100 women with preeclampsia admitted in government hospitals of Mashhad were selected using convenience sampling. Post-traumatic stress disorder was diagnosed by psychiatrist interview and perinatal posttraumatic stress questionnaire (PPQ) in sixth week postpartum and family support was measured by family support scale (FSS) in second and sixth weeks postpartum. Data analyzed by SPSS 16 using Spearman correlation coefficient, paired sample T-test and Kruskal-Wallis test. RESULTS: A reverse significant association was found between family support in weeks 2 and 6 (92.6 +/- 22.6, 83.7 +/- 21.6, respectively) and PTSD (mean score of 4.8 +/- 2.5) (respectively, P = 0.010 and P =0.011). The most important variables affecting PTSD with presence of family support in weeks 2 and 6 were postpartum depression in week 6 as well as trait anxiety at the time of admission. CONCLUSIONS: The more support in weeks 2 and 6 postpartum, the less PTSD occurs. Therefore, it is suggested to health care providers who face mothers after delivery to evaluate the support received by mothers and help those with inadequate or inappropriate support. PMID- 26568845 TI - Vitrification by Cryotop and the Maturation, Fertilization, and Developmental Rates of Mouse Oocytes. AB - BACKGROUND: Oocyte cryopreservation is an important part of modern fertility treatment. The effect of vitrification on the fertilization and developmental rates of embryo is still a matter of debate. OBJECTIVES: This study aimed to investigate the effect of vitrification on the success of mouse oocyte maturation, fertilization, and preimplantation development in vitro. MATERIALS AND METHODS: In this experimental study, a total of 200 germinal vesicle (GV) and 200 metaphase II (MII) oocytes were obtained from ovaries and fallopian tubes of NMRI mice, respectively and divided into two control and experimental (vitrified) groups. Oocytes in the experimental group were vitrified by Cryotop using vitrification medium (Origio, Denmark) and kept in liquid nitrogen for one month. Then, they were cultured in maturation medium for 24 hours. In vitro maturated metaphase 2 (IVM-MII) and ovulated metaphase 2 (OV-MII) oocytes were inseminated and the fertilized embryos assessed until the hatching blastocyst stage. Outcomes were assessed for statistical significance by Chi-square test using SPSS software. RESULTS: Vitrification caused a significant reduction in the maturation rate of oocytes. Of those that matured, the fertilization rate of vitrified IVM MII (44.1%) and OV-MII oocytes (50%) was not significantly different from each other but both were significantly lower than the control group (P < 0.05). There was no significant difference in developmental rates of both vitrified groups and the control group. CONCLUSIONS: The present study showed that vitrification using Cryotop and freezing medium can damage oocytes by reducing the maturation and fertilization rates in both developmental stages. PMID- 26568846 TI - Evaluation of Transtheoretical Model-Based Family Education Among Females of Zahedan (Southeast of Iran). AB - BACKGROUND: It cannot be denied that many improvements in female and child health have been achieved worldwide through international family planning programs. More than half of the females (57%) with unintended pregnancy admitted that they had not used birth control the month before conception. OBJECTIVES: The aim of this study was to promote family planning practice among females of Zahedan (southeast of Iran) through the transtheoretical model (TTM). PATIENTS AND METHODS: The current quasi-experimental study was conducted on 96 eligible females, who were allocated either to the case or the control group and were selected from homes in the border of Zahedan city (southeast of Iran) during 2010. Convenience sampling by door-to-door visits was used for finding eligible cases. A TTM-based self administrated family planning questionnaire was used for data collection. Participants in the intervention group received education in two groups, based on their stage of change: precontemplation, contemplation, preparation, action, maintenance, and all groups were followed for three months. RESULTS: The result of the chi-square test did not show any significant difference in the stage of change: precontemplation, contemplation, preparation, action, maintenance before education between the control and intervention groups (P = 0.55). After education, subjects in the intervention group moved forward through stage of change and got at least one step closer to the family planning behavior., with this change being significant (P < 0.001), while the movement of participants through stage of change not being significant in control group (P = 1). The results of statistical tests illustrated that the mean knowledge of the intervention group was 7.5 +/- 7.1 versus 0.5 +/- 4 for the control group (P < 0.001), mean of attitude of the intervention group was 5.5 +/- 5.41 versus 0.09 +/- 2.04 for the control group (P < 0.001), and practicing family planning methods (P < 0.007) in the intervention group was higher than the control group after education based on TTM. CONCLUSIONS: According to this study, the educational plan based on TTM was effective in changing knowledge, attitude, and practice and directing females towards taking action. Moreover, self-efficacy, perceived barriers and benefits are factors that affect the use of family planning methods. PMID- 26568847 TI - Low Dose of Octreotide Can be Helpful in the Management of Congenital Chylothorax. AB - INTRODUCTION: A rare condition in newborns called congenital chylothorax (CC) occurs when lymphatic fluid accumulates within the pleural cavity. Here is a presentation of a birth traumatic case with bilateral pleural effusion successfully treated by octreotide. CASE PRESENTATION: A 3100-g-term male newborn delivered vaginally from a 33-year-old mother was admitted to the neonatal intensive care unit with respiratory distress signs. Early chest x-ray (CXR) showed bilateral pleural effusion. The thoracentesis pleural fluid had been drained with these characteristics: glucose: 1.9425 mmol/l, protein: 11 g/l, cholesterol: 1.295 mmol/l, and triglycerides: 3.39 mmol/l. Counts of red blood cells and white blood cells were 10,000 and 2500 per Cu/mm, respectively; so, congenital chylothorax was diagnosed and total parenteral nutrition (TPN) were initiated. Accumulation of plural fluid was approximately stopped after begging TPN for two weeks. Therefore, we started feeding with a medium chain triglyceride (MCT), but plural effusion was seen once again and we had to restart TPN. We decided to start octreotide subcutaneously (1 MUg/kg/day). Finally, the CXR and ultrasound 'did not show any pleural effusion in both sides and the ultrasound done in the third month showed no pleural effusion either. CONCLUSIONS: Octreotide therapy as one of the conservative managements for CC can be considered before surgical methods. This treatment method also had some effects on the feeding initiation time and helped us to start feeding sooner. However, more studies like clinical trials are still necessary to investigate all aspects of octreotide treatment to determine the amount of its dose, initiation time, treatment duration, etc. PMID- 26568848 TI - Analysis of Occupational Accident Fatalities and Injuries Among Male Group in Iran Between 2008 and 2012. AB - BACKGROUND: Because of occupational accidents, permanent disabilities and deaths occur and economic and workday losses emerge. OBJECTIVES: The purpose of the present study was to investigate the factors responsible for occupational accidents occurred in Iran. PATIENTS AND METHODS: The current study analyzed 1464 occupational accidents recorded by the Ministry of Labor and Social Affairs' offices in Iran during 2008 - 2012. At first, general understanding of accidents was obtained using descriptive statistics. Afterwards, the chi-square test and Cramer's V statistic (Vc) were used to determine the association between factors influencing the type of injury as occupational accident outcomes. RESULTS: There was no significant association between marital status and time of day with the type of injury. However, activity sector, cause of accident, victim's education, age of victim and victim's experience were significantly associated with the type of injury. CONCLUSIONS: Successful accident prevention relies largely on knowledge about the causes of accidents. In any accident control activity, particularly in occupational accidents, correctly identifying high-risk groups and factors influencing accidents is the key to successful interventions. Results of this study can cause to increase accident awareness and enable workplace's management to select and prioritize problem areas and safety system weakness in workplaces. PMID- 26568849 TI - Sexual Self-Concept and General Health in Rheumatoid Arthritis Patients. AB - BACKGROUND: There are several studies regarding sexual dysfunction in chronic diseases such as diabetes and renal failure; however, no significant study has been done on Iranian rheumatoid arthritis (RA) patients. OBJECTIVES: In this study, we aimed to identify and compare sexual dysfunction between RA patients and the normal population. PATIENTS AND METHODS: In this case-control study, two groups of females (87 RA patients and 89 controls) were randomly selected from the rheumatology clinic of Baqiyatallah Hospital, Tehran, Iran. General health questionnaire (GHQ-28) and multidimensional sexual self-concept questionnaire (MSSCQ) were used to evaluate RA patients. We used SPSS for statistical analysis mainly by the t-test and chi-square test. P values less than 0.05 were considered significant. RESULTS: In the GHQ-28 evaluation, RA patients had lower social function; however somatization rated higher in normal patients (P < 0.05). Sexual health was lower in the RA population (P < 0.05). No significant difference was found in sexual desire. Except sexual pain, other sexual health parameters were lower in RA patients. The scores were as follow: sensation 13.6 +/- 4.4 vs. 12.2 +/- 4.5, P = 0.024; lubrication 6.9 +/- 2.1 vs. 6.2 +/- 2.1, P = 0.017; orgasm 10.4 +/- 2.8 vs. 9.5 +/- 3.2, P = 0.37; pain 10.1 +/- 2.2 vs. 10.8 +/- 1.9, P = 0.013; enjoyment 23.8 +/- 5.8 vs. 21.3 +/- 7.5, P = 0.009 and partner related 8.5 +/- 1.7 vs. 7.6 +/- 2.4, P = 0.005. Furthermore, the concern of losing their sexual partner was higher in the normal population. CONCLUSIONS: Our study demonstrated that almost all GHQ and MSSCQ parameters were lower in RA patients, which indicates lower quality sexual life in RA patients. We recommend further consideration for the treatment and care of these patients. PMID- 26568850 TI - Honey and Radiation-Induced Stomatitis in Patients With Head and Neck Cancer. AB - BACKGROUND: Stomatitis is a common oral complication which affects 100% of patients undergoing head and neck radiotherapy. Acute stomatitis might cause failure and delay radiotherapy. Attention to mouth hygiene, particularly using mouthwash, has a fundamental importance for these patients. OBJECTIVES: The current study came to addresses the effects of pure natural honey on radiation induced stomatitis in patients with a variety of head and neck cancers. PATIENTS AND METHODS: The present single-blinded nonrandomized controlled trial was conducted on 105 patients undergoing radiotherapy due to head and neck cancer at the radiation unit of Shafa hospital in Kerman, Iran, from October 2012 to March 2012. The research groups were selected by writing the names of the protocols (the mouthwashes of chamomile, honey and the common caring protocol at ward which uses water) on three cubes. The first extracted cube was related to the chamomile mouthwash (Matrica), the second to the honey mouthwash and the last cube to the water mouthwash. The first experimental group (n = 35) gurgled a solution containing 20 mL diluted honey, the second group gurgled a solution containing German chamomile, and the 35 patients in the control group were advised to gurgle 20 mL water (the ward routine). RESULTS: The results showed that severe stomatitis in groups of honey, chamomile and control was 0, 5.7%, and 17.6%, respectively. On the 14th day, it was 0, 0, and 17.6%, respectively. There were significant differences between the three groups regarding the severity of stomatitis in the 14th day (P < 0.001). CONCLUSIONS: The application of natural honey is effective in managing and preventing radiation-induced stomatitis in patients with head and neck cancers. PMID- 26568851 TI - Prevalence of Eating Disorders Among Adolescents in the Northwest of Iran. AB - BACKGROUND: Perceived sociocultural pressure to be thin has an important impact on disordered eating during early and middle adolescence, but less is known about late adolescence. Adolescents face special problems that are less common during childhood. Several studies indicate that the prevalence of eating disorders has been increased among adolescents. OBJECTIVES: The aim of the present study was to investigate the occurrence, prevalence and correlates of eating disorders (ED) among adolescents in two cities of Iran, Urmia and Tabriz. PATIENTS AND METHODS: This was a cross-sectional survey in which 1990 adolescent boys and girls were selected through multistage random sampling. The study was based on self-report questionnaires including eating attitudes test (EAT-26) and DSM-IV criteria for the presence of eating disorders. To analyze the obtained data we calculated measures of central tendency and dispersion, linear and logistic regression and Fisher's exact test. RESULTS: According to diagnostic criteria of EAT-26, 492 students (24.2%) were at risk of ED and scored above the recommended cut-off point on EAT-26. Among 1990 students, a total of 51 cases (0.25%) of eating disorder (14 anorexia nervosa, 18 bulimia nervosa, and 19 eating disorder not otherwise specified) were diagnosed. CONCLUSIONS: The obtained prevalence of ED in our study was higher than previous studies in Iran. We found high numbers of boys with ED. Overweight adolescents were shown to be more susceptible to strict dieting than normal-weight adolescents. These results suggest that it is necessary to provide screening and treatment services for Iranian adolescents. Further research is needed to develop intervention programs to control eating disorders among Iranian adolescents. PMID- 26568852 TI - Status of p53 and p27(KIP1) in Iranian Patients With Oral Squamous Cell Carcinoma. AB - BACKGROUND: Alterations in p53 and p27(KIP1) have been documented as important events in the carcinogenesis of various cancers, but their prognostic role in oral squamous cell carcinoma (OSCC) remains controversial. OBJECTIVES: The present investigation aimed to evaluate the clinicopathologic and prognostic significance of p53 and p27(KIP1) expression in a group of Iranian patients with OSCC. PATIENTS AND METHODS: In this analytical cross-sectional study, medical records of patients with primary OSCC, diagnosed from 1994 to 2004 were reviewed and 28 subjects were selected based on the inclusion/exclusion criteria. Immunohistochemical staining using monoclonal antibodies against p53 and p27(KIP1) was performed on representative archival paraffin blocks. Demographic data along with information on p53 and p27(KIP1) expression, recurrence, and tumor grade was statistically analyzed using the Fischer exact test. Prognostic factors for overall survival were determined by Cox regression analysis (P < 0.05). RESULTS: p53 and p27(KIP1) expression were found in 28.57% (8 positive versus 20 negative) and 67.85% (19 positive versus 9 negative) of OSCC cases, respectively. There was no significant association between these two proteins (P = 0.371), and neither of them showed a significant relationship with the studied clinicopathologic variables (P > 0.05). In survival analysis, only histopathologic differentiation (17 low and moderate, 11 poor) demonstrated a significant correlation with overall survival (P = 0.048). CONCLUSIONS: Despite the fact that abnormalities in p53 and p27(KIP1) may be involved in the development of OSCC, their clinical significance in the studied population seems limited. Further investigation on the combined p53/p27(KIP1) expression may be helpful in predicting the biologic behavior of this tumor. PMID- 26568853 TI - Treatment Following Intoxication With Lethal Dose of Paraquat: A Case Report and Review of Literature. AB - INTRODUCTION: Paraquat is a widely used nitrogen-based herbicide which is lethal and causes multi-organ failure by accumulation in cells, which subsequently leads to death. CASE PRESENTATION: The present case report introduced a 25-year-old male with nausea, vomiting, and severe substernal burning sensation after incidentally ingestion of a large amount of paraquat. The treatment of the patient with antioxidants (N-acetylcysteine and vitamin E) and hemodialysis started immediately after arriving to the hospital. CONCLUSIONS: Immediate and adequate use of antioxidants and hemodialysis has an undeniable and important role in survival of patients after ingestion of a large amount of paraquat. PMID- 26568854 TI - Efficacy of Attribution Retraining on Mental Health of Epileptic Children. AB - BACKGROUND: Epilepsy affects children's quality of life and leads to social and mental problems. Promoting the mental health of children, especially epileptic ones, and preventing problems affecting them constitute major concerns for every country. Mental health promotion requires intervention programs. OBJECTIVES: We sought to assess the efficacy of attribution retraining on the mental health of epileptic children. PATIENTS AND METHODS: The present study is a semi experimental investigation with a pretest and posttest design and includes a control group. Thirty children, comprising 17 boys and 13 girls, were selected randomly from the Iranian epilepsy association in Tehran and assigned to experimental and control groups. They answered to the general health questionnaire (Goldberg and Hiller, 1979). The experimental group participated in 11 training sessions (twice a week; 45 minutes for each session) and received attribution retraining. The data were analyzed using the multiple analysis of covariance. RESULTS: The findings showed that the experimental group, in comparison with the control group, experienced a reduction in physical symptoms, anxiety and insomnia, social dysfunction, and depression and an increase in mental health significantly (P < 0.01) after the training sessions. There were no significant differences, however, between the two groups at 6 weeks' follow-up. CONCLUSIONS: Attribution retraining improved mental health in the epileptic children in our study. It, therefore, seems to be an appropriate intervention for promoting the mental health of children. PMID- 26568855 TI - Cytotoxic Activity and Apoptosis Induction of Hypericum scabrum L. AB - BACKGROUND: One of the acquired biological hallmarks of tumor multistep development is the resistance of cancer cells to apoptosis; therefore, induction of apoptosis is an important therapeutic approach. Hypericum species are spread throughout the world and have been investigated for their biological properties. OBJECTIVES: Our previous studies had demonstrated cytotoxicity of Hypericum scabrum L. methanol extract against some tumor cell lines, suggesting the species for further studies. The objectives of the present study were to determine the most cytotoxic fraction of Hypericum scabrum L. and to assess the apoptosis induction ability of the most effective fraction as well as its methanol extract. The laboratory evidence has been presented to support the potency of Iranian Traditional Medicine (ITM) medicinal plants as a source of different biological activity surveys and drug discoveries. MATERIALS AND METHODS: The present research is a descriptive study. The sampling strategy was based on ITM data of cancer phytotherapy. Hypericum scabrum was collected from Alborz province, Iran (2012) and the herbarium specimen was taxonomically identified. The petroleum ether, dichloromethane, and methanol fractions have been evaluated for cytotoxicity against M-CF7, A-549, HT-29, and HepG-2 cell lines through 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide or MTT assay. The apoptosis induction ability has been assessed by activated caspase-3 inspection and Annexin V FITC/PI (propidium iodide) assays. RESULTS: Di-chloromethane fraction demonstrated IC50 values of 25.72 MUg/mL and 24.73 MUg/mL against HT-29 and HepG 2 cell lines, respectively and IC50 values of petroleum ether fraction were 22.6 MUg/mL and 18.31 MUg/mL against HT-29 and HepG-2, respectively. The methanol fraction did not show cytotoxic activity. Both the methanol extract and the petroleum ether fraction of Hypericum scabrum L. revealed apoptosis induction ability. CONCLUSIONS: Considering the strong historical background about the therapeutic potential of the genus Hypericum and the considerable cytotoxic and apoptosis induction ability of Hypericum scabrum, this species is suggested for future biological studies. PMID- 26568856 TI - Fatal Tenofovir-Associateacd Lactic Acidosis: A Case Report. AB - INTRODUCTION: The introduction of highly active antiretroviral therapy (HAART), in 1996, has resulted in marked reductions in the rate of illness and death, due to HIV infection. The HAART has transformed HIV infection into a manageable chronic disease. However, although many regimens lower plasma viral load, to below the limit of detection, in most patients, maintaining viral load suppression remains challenging, because of adverse effects and toxicity in the long term, which can lead to non-adherence, virologic failure and drug resistance. Although rare, lactic acidosis often develops fatal complications, as reported in several human immunodeficiency virus infected patients treated with nucleoside reverse transcriptase inhibitors (NRTIs). The purpose of this paper is to report a case of tenofovir induced lactic acidosis and review the literature. CASE PRESENTATION: A 52-year-old Malay gentleman, with hepatitis C virus and HIV infection was admitted to the intensive care unit for severe lactic acidosis, with concurrent Escherichia coli bacteremia with multiorgan dysfunction. The patient was started on highly active antiretroviral therapy, which included tenofovir, 5 weeks before presentation. Antimicrobial therapy, continuous veno venous hemofiltration, and other supportive treatments were instituted. However, the patient eventually succumbed to his illness. CONCLUSIONS: It is essential for clinicians to be able to recognize the signs and symptoms of lactic acidosis in NRTIs treated HIV patients, as an early diagnosis is important to institute treatment. PMID- 26568857 TI - Leukocyte and Platelet Rich Plasma (L-PRP) Versus Leukocyte and Platelet Rich Fibrin (L-PRF) For Articular Cartilage Repair of the Knee: A Comparative Evaluation in an Animal Model. AB - BACKGROUND: Articular cartilage injuries of the knee are among the most debilitating injuries leading to osteoarthritis due to limited regenerative capability of cartilaginous tissue. The use of platelet concentrates containing necessary growth factors for cartilage healing has recently emerged as a new treatment method. OBJECTIVES: The efficacy of two types of different platelet concentrates were compared in the treatment of acute articular cartilage injuries of the knee in an animal model. MATERIALS AND METHODS: Eighteen adult Iranian mixed breed male dogs were used to conduct this experimental study. Full thickness articular cartilage defects (diameter 6 mm, depth 5 mm) were created in the weight bearing area of femoral condyles of both hind limbs in all dogs (n = 72). Twelve dogs were randomly selected to receive treatment and their right and left hind limb defects were treated by L-PRP and L-PRF implantation respectively, while no treatment was undertaken in six other dogs as controls. The animals were euthanized at 4, 16 and 24 weeks following surgery and the resultant repair tissue was investigated macroscopically and microscopically. At each sampling time, 4 treated dogs and 2 control dogs were euthanized, therefore 8 defects per group were evaluated. RESULTS: Mean macroscopic scores of the treated defects were higher than the controls at all sampling times with significant differences (P < 0.05) observed between L-PRF treated and control defects (10.13 vs. 8.37) and L-PRP treated and control defects (10 vs. 8.5) at 4 and 16 weeks, respectively. A similar trend in mean total microscopic scores was observed with a significant difference (P < 0.05) between L-PRP treated and control defects at 4 (9.87 vs. 7.62) and 16 (13.38 vs. 11) weeks. No significant difference was observed between the platelet concentrate treated defects in either mean macroscopic scores or mean total microscopic scores. CONCLUSIONS: Both L-PRP and L-PRF could be used to effectively promote the healing of articular cartilage defects of the knee. PMID- 26568858 TI - Knowledge, Attitudes, and Practices Study on Hand Hygiene Among Imam Hossein Hospital's Residents in 2013. AB - BACKGROUND: Hand hygiene is considered one of the most important infection control measures for preventing health care-associated infections. Although the techniques involved in hand hygiene are simple, compliance with hand hygiene recommendations is poor worldwide. OBJECTIVES: We sought to perform a knowledge, attitudes, and practices (KAP) study on hand hygiene among medical residents at Imam Hossein hospital, Tehran, Iran. PATIENTS AND METHODS: This cross-sectional KAP study was conducted among medical residents in Imam Hossein hospital, Iran, 2013. All medical residents from different wards were invited to participate in this study (270 in total). The world health organization questionnaires and an observational checklist were used to collect data. The chi(2) test and the Fisher exact test were utilized to analyze the qualitative variables. Since the quantitative variables had no normal distribution, the Mann-Whitney test and the Kruskal-Wallis method were employed. A P value < 0.05 was considered statistically significant. The data were analyzed using SPSS, version 17. RESULTS: The mean overall score of the residents' knowledge was 14.2 +/- 2.6 (mean +/- SD). The residents received weak scores in attitudes and practices. Forty-nine percent (n = 124) of the residents responded to the questions on attitudes toward hand hygiene, and only 20.16% (n = 25) managed to identify the correct answer. Moreover, 3.1% (n = 8) of the residents adhered to the 8 standard steps, 12.1% (n = 31) washed their hands for 20 - 30 seconds, and only 2 residents observed the sequences of hand hygiene. Additionally, none of the residents performed hand washing with available means (water and hand-washing liquid) in the morning visit hours. CONCLUSIONS: Concerning hand hygiene, the residents had moderate knowledge but overall poor attitudes and practices. The present study underscores the need for further improvement in the existing training programs to address the gaps in KAP regarding hand hygiene. PMID- 26568859 TI - Diagnostic Value of Leukocyte Esterase Test Strip Reagents for Rapid Clinical Diagnosis of Spontaneous Bacterial Peritonitis in Patients Admitted to Hospital Emergency Departments in Iran. AB - BACKGROUND: Spontaneous bacterial peritonitis (SBP) is a common and important clinical problem and is life-threatening in decompensated liver disease. Ascites fluid test by leukocyte esterase test strip has been recently proposed as an effective and rapid method to diagnose SBP in patients with cirrhosis. OBJECTIVES: This study aimed to evaluate sensitivity and specificity of leukocyte esterase test strip in the diagnosis of SBP. PATIENTS AND METHODS: The population of this research was all patients with cirrhosis and ascites admitted to the emergency room at Imam Reza (AS) hospital, Mashhad. A written consent was taken for inclusion in the study. 50 mL ascites sample was taken from all patients for use in a urine test strip (LER) (Urine Test Strips Convergys(r)Urine Matrix 11). The patient's ascites samples were evaluated for cell counting. Positive dipstick test for LER in this study considered as grade 3 +. The values of WBC > 500 cell/mm(3) or PMN > 250 cell/mm(3) considered as positive result of the gold standard method for the diagnosis of SBP. RESULTS: In this study, 100 patients with ascites due to cirrhosis, with an average age of 38.9 +/- 6.54 years were evaluated. Twenty cases had positive results, of whom 17 cases were also detected based on the standard diagnostic criteria and other three cases were healthy individuals. Thus, sensitivity, specificity, positive and negative predictive values, and accuracy of the method were 95%, 96.3%, 85%, 97.5% and 95%, respectively. CONCLUSIONS: The use of leukocyte esterase urine dipstick test can be a quick and easy method in early diagnosis of SBP to start the treatment until preparation of SBP-cell count results. PMID- 26568860 TI - Healthy Eating Index in Patients With Cataract: A Case-Control Study. AB - BACKGROUND: Nutritional factors play an important role in cataract disease and the healthy eating index (HEI) is a unique approach to study the relationships between diet and diseases. OBJECTIVES: The current study aimed to evaluate and compare healthy eating index among the patients with cataract and healthy individuals. PATIENTS AND METHODS: This case-control study was conducted on 97 patients with cataract and 198 healthy people (as a control group) in Iran. Individuals were selected by the convenience sampling method and the food frequency questionnaire (FFQ) was completed for them. At first, HEI was calculated and then the HEI scores were compared in cataract patients and healthy individuals. RESULTS: The analysis of FFQ showed that the scores of vegetables (7.81 v. 10), nutritional variation (5.5 v. 7) and sodium (2 v. 6) groups (P < 0.001) were significantly lower among the patients with cataract than the healthy individuals. Also this significant difference was observed in the scores of total HEI and fruits (respectively 73.26 v.79.30 and 7.1 v. 9.8) (P < 0.01). On the other hand, the scores of saturated fatty acids (10 v. 9; P = 0.02), total fat (8 v. 7; P = 0.004) and cereals (10 v. 10; P < 0.001) were higher among the patients with cataract than the healthy individuals. The comparison of dietary intake among all types of cataract shows that the scores of the meat group were significantly higher in the patients with nuclear cataract and mixed cataract than the ones with posterior cataract (respectively 9.4 v. 6.5 and 9 v. 6.5) (P = 0.02). In addition, after adjusting the confounding factors the results showed that the HEI high score was associated with reducing the risk of coming down with cataract (OR = 0.18, CI: 95%, P < 0.001, 0.08 - 0.41). CONCLUSIONS: The results of the current study suggest that increasing the quality of the diet calculated according to HEI can reduce the risk of coming down with cataract. PMID- 26568861 TI - Roy's Adaptation Model-Guided Education and Promoting the Adaptation of Veterans With Lower Extremities Amputation. AB - BACKGROUND: Any defect in extremities of the body can affect different life aspects. OBJECTIVES: The purpose of this study was to investigate the effect of Roy's adaptation model-guided education on promoting the adaptation of veterans with lower extremities amputation. PATIENTS AND METHODS: In a randomized clinical trial, 60 veterans with lower extremities amputation referring to Kowsar Orthotics and Prosthetics Center of veterans clinic in Tehran, Iran, were recruited with convenience method and were randomly assigned to intervention and control groups during 2013 - 2014. For data collection, Roy's adaptation model questionnaire was used. After completing the questionnaires in both groups, maladaptive behaviors were determined in the intervention group and an education program based on Roy's adaptation model was implemented. After two months, both groups completed the questionnaires again. Data was analyzed with SPSS software. RESULTS: Independent t-test showed statistically significant differences between the two groups in the post-test stage in terms of the total score of adaptation (P = 0.001) as well as physiologic (P = 0.0001) and role function modes (P = 0.004). The total score of adaptation (139.43 +/- 5.45 to 127.54 +/- 14.55, P = 0.006) as well as the scores of physiologic (60.26 +/- 5.45 to 53.73 +/- 7.79, P = 0.001) and role function (20.30 +/- 2.42 to 18.13 +/- 3.18, P = 0.01) modes in the intervention group significantly increased, whereas the scores of self concept (42.10 +/- 4.71 to 39.40 +/- 5.67, P = 0.21) and interdependence (16.76 +/- 2.22 to 16.30 +/- 2.57, P = 0.44) modes in the two stages did not have a significant difference. CONCLUSIONS: Findings of this research indicated that the Roy's adaptation model-guided education promoted the adaptation level of physiologic and role function modes in veterans with lower extremities amputation. However, this intervention could not promote adaptation in self concept and interdependence modes. More intervention is advised based on Roy's adaptation model for improving the adaptation of veterans with lower extremities. PMID- 26568862 TI - Fatigue and Psychological Distress: A Case Study Among Shift Workers of an Iranian Petrochemical Plant, During 2013, in Bushehr. AB - BACKGROUND: Shift work is a well-recognized occupational health hazard in both industrialized and industrially developing countries. Prolonged working time, day/night shift rotation, circadian rhythm and sleep disorders, family and social problems are the most important features of shift working, which have serious complications. OBJECTIVES: The present study evaluated the fatigue and psychological distress and their relationship among shift workers, in a petrochemical plant (Southern Pars gas field) in Southwest Iran. MATERIALS AND METHODS: In this cross-sectional field study, 400 shift workers from a plant were involved, with participation rate of 72.5% (290 persons). The multidimensional fatigue inventory (MFI-20) and general health questionnaire (GHQ-28) were used to evaluate the level of fatigue and psychological distress, respectively. RESULTS: The results showed that the fatigue and psychological distress (particularly social dysfunction, anxiety and insomnia) are frequent among 12-hour shift workers (the total MFI and total GHQ scores were 42.68 +/- 17.88 and 34.66 +/- 18.56). A relatively strong positive correlation was found between fatigue and psychological distress (r = 0.62). The results of the stepwise regression model indicated that the psychological distress was significantly related only to general fatigue, mental fatigue and reduced motivation, whereas it was not to the physical fatigue and reduced activity. CONCLUSIONS: The study findings highlight the importance of the mental aspect of fatigue in this working group. These results have possible implications for workers' health and well-being and for the design of shift work systems, for industrial workers. PMID- 26568863 TI - Disease-Related Variables and Depression Among Iranian Patients with Parkinson Disease. AB - BACKGROUND: The factors affecting the correlation between Parkinson disease (PD) and depression have remained unclear. OBJECTIVES: We assessed the prevalence of depression among patients with PD and the association between PD-related variables and depression severity. PATIENTS AND METHODS: This is a cross sectional study performed in Kermanshah Province of Iran. Sampling was based on recruitment of subjects according to inclusion and exclusion criteria. Patients with confirmed Parkinson disease who were referred to clinics of Kermanshah University of Medical Sciences participated in this study. Depression was evaluated with Beck Depression Inventory-II (BDI-II). Clinical characteristics of PD, including tremor, rigidity, impaired posture, loss of autonomic movement, changes in speech and handwriting, masked face, and hyposmia were indexed. Anhedonia was assessed with Farsi version of Snaith-Hamilton Pleasure Scale. Data were collected between April 2010 and March 2014. RESULTS: A total of 350 patients (52.9% men and 47.1% women) participated in this investigation. Female gender (36.5% in women vs. 13.0% in men, P < 0.0001), impaired posture (27.2% in affected individuals vs. 18.8%, P = 0.002), masked face (39.0% vs. 5.2%, P < 0.0001), and hyposmia (48.7% vs. 21.0%, P = 0.001) were associated with higher susceptibility to profound depression. Lower scores of all domains of Farsi version of Snaith-Hamilton Pleasure Scale (including interest/pastimes, social interaction, sensory experience, and food/drink) were related to more severe depression (P < 0.0001 for all subscales). Severe and profound depression was found in 44% of the participants. CONCLUSIONS: This study estimated that the prevalence of major depression among Iranian individuals with PD living in Kermanshah as 44%. Major determinants of depression were female gender, rigidity, impaired posture, masked face, hyposmia, and anhedonia. PMID- 26568864 TI - Estimation of mortality and morbidity risk of radical cystectomy using POSSUM and the Portsmouth predictor equation. AB - INTRODUCTION: The Physiological and Operative Severity Score for the enumeration of Mortality and Morbidity (POSSUM) and the Portsmouth predictor equation (P POSSUM) are simple scoring systems used to estimate the risk of complications and death postoperatively. We investigated the use of these scores to predict the postoperative risk in patients undergoing radical cystectomy (RC). MATERIAL AND METHODS: In this retrospective study, we enrolled 280 patients who underwent RC for invasive bladder cancer between January 2003 and December 2011. Morbidity and mortality were predicted using the POSSUM and P-POSSUM equations. We further assessed the ability of the POSSUM and P-POSSUM to predict the mortality and morbidity risk in RC patients with a Clavien-Dindo classification of surgical complications of grade II or higher. RESULTS: The observed morbidity and mortality rates were 58.9% (165 patients) and 1.8% (5 patients), respectively. Predicted morbidity using POSSUM was 49.2% (138 patients) compared to the 58.9% (165 patients) observed (P <0.0001). Compared to the observed death rate of 1.8% (5 patients), predicted mortality using POSSUM and P-POSSUM was 12.1% (34 patients) and 3.9% (11 patients), respectively (P <0.0001 and P = 0.205). The mortality risk estimated by P-POSSUM was not significantly different from the observed mortality rate. CONCLUSIONS: The results of this study supported the efficacy of POSSUM combined with P-POSSUM to predict morbidity and mortality in patients undergoing RC. Further prospective studies are needed to better determine the usefulness of POSSUM and P-POSSUM for a comparative audit in urological patients undergoing RC. PMID- 26568865 TI - How to predict the risk of complication or death after radical cystectomy? PMID- 26568866 TI - Impact of stage and comorbidities on five-year survival after radical cystectomy in Poland: single centre experience. AB - INTRODUCTION: Long-term outcomes of patients treated for invasive bladder cancer in Poland are poorly documented in the literature. Impact of various clinical parameters on their survival is even less well studied. Radical cystectomy is a major surgery, so the patients' condition can be equally important as cancer stage. The aim of the study was to assess 5-year overall survival (OS) after cystectomy and impact of comorbidity on OS in a single Polish academic centre. MATERIAL AND METHODS: Clinical data of all patients who underwent cystectomy in years 2004-2006 for urothelial cancer were retrospectively reviewed. Survival status was determined at least 5 years after surgery. Pathological variables, comorbidities, surgery delay and complications were evaluated as potential predictors of OS. Kaplan-Meier estimates of the survival function as well as Cox proportional hazards models were utilized. RESULTS: Thirty-day, 1-year and 5-year OS for 63 patients was 98.4%, 58.7% and 31.7%, respectively. None of the investigated parameters were significantly related to five-year OS. However, a composite parameter consisting of stage, diabetes status and postoperative course was found as a significant predictor. Five-year OS in 16 patients with pT1-2 and without diabetes and without post-operative complications was higher than in the remaining 47 patients (56% vs. 23%; P = 0.02). CONCLUSIONS: Five-year OS in our group was lower than in most published international series but concordant with a previous Polish report. Improvement in survival after radical cystectomy may be expected when early diagnosis will be accompanied by optimal care of patients with diabetes mellitus and avoidance of postoperative complications. PMID- 26568867 TI - Bladder injury secondary to obturator reflex is more common with plasmakinetic transurethral resection than monopolar transurethral resection of bladder cancer. AB - INTRODUCTION: Transurethral resection (TUR) is the most common surgical technique for the diagnosis and initial treatment of bladder cancer. In this study, we evaluated two surgical techniques in terms of bladder injury due to obturator reflex in patients that underwent TUR for non-muscle invasive bladder cancer (NMIBC). MATERIAL AND METHODS: 93 patients who underwent TUR for bladder cancer were analyzed. Fifty patients underwent monopolar resection and 43 patients underwent plasmakinetic resection. Standard TUR were performed with conventional Storz monopolar resection using a U-shaped cutting loop, 120V cutting/80 V coagulation settings, 5% mannitol fluid was used for irrigation. For bipolar resection, an Olympus ESG-400 plasmakinetic loop bipolar device using a U-shaped cutting loop, 160V cutting/80V coagulation settings and normal saline for irrigation was used. RESULTS: In the monopolar resection group; obturator reflex was seen in 4 (8%) patients. Bladder perforation caused by the obturator reflex was seen in 4 (8%) patients, but hemorrhage and other major complications were not seen in this group. In the bipolar resection group; obturator reflex was seen in 15 (34%) patients. Bladder perforation caused by the obturator reflex was seen in 10 (23%) patients. CONCLUSIONS: Bipolar transurethral resection of bladder tumor was not superior to monopolar resection with respect to obturator reflex and bladder perforation. We conclude that we do not yet have enough experience concerning the long-term complications and major complications associated with bipolar resection of bladder cancer. PMID- 26568868 TI - CyberKnife-based prostate cancer patient radioablation - early results of irradiation in 200 patients. AB - INTRODUCTION: Prostrate cancer (PC) is one of the most common malignancies and is frequently treated with an 8-week course of radiotherapy. CyberKnife (CK) based radioablation enables completion of therapy within 5-9 days. The aim of this study is an evaluation of the effectiveness and tolerance of CyberKnife-based radioablation in prostate cancer patients. MATERIAL AND METHODS: 200 PC patients (94 low risk [LR], 106 intermediate risk [IR]) underwent CK irradiation every other day (fraction dose [fd] 7.25 Gy, total dose [TD] 36.25 Gy, time 9 days). PSA varied from 1.1 to 19.5 (median 7.7) and T stage from T1c to T2c. The percentage of patients with Androgen Deprivation Therapy (ADT), GI (gastrointestinal) and GU (genitourinary) toxicity (EORTC/RTOG scale), and PSA were checked at 1, 4 and 8 months, and thereafter every 6 months - up to a total of 26 months - post-treatment. RESULTS: The percentage of patients without ADT increased from 47.5% to 94.1% after 26 months. The maximum percentage of acute G3 adverse effects was 0.6% for GI, 1% for GU and G2 - 2.1% for GI and 8.5% for GU. No late G3 toxicity was observed. The maximum percentage of late G2 toxicity was 0.7% for GI and 3.4% for GU. Median PSA decreased from 7.7 to 0.1 ng/ml during FU. One patient relapsed and was treated with salvage brachytherapy. CONCLUSIONS: We conclude that CK-based radioablation in low and intermediate risk PC patients is an effective treatment modality enabling OTT reduction and presents a very low percentage of adverse effects. PMID- 26568869 TI - Optimizing the formation of vesicourethral anastomosis and reduction of procedure time. A two-year experience with a modified technique for endoscopic running vesicourethral anastomosis. AB - INTRODUCTION: Creation of a watertight vesicourethral anastomosis is a challenging and time-consuming procedure. In an attempt to simplify this critical step of radical prostatectomy we have developed a laparoscopic running single suture technique and presented preliminary results previously. Here we report our two-year experience with the Chlosta's single running suture technique. MATERIAL AND METHODS: Between January 2013 and June 2014, 60 consecutive patients underwent laparoscopic radical prostatectomy with a running vesicourethral anastomosis using our modified technique for clinically localized prostate cancer. Analyses of the patients' data from a prospectively maintained database with respect to perioperative characteristics, morbidity and urinary continence was performed. RESULTS: The mean anastomotic time was 10.2 min. There was no clinically significant anastomotic leakage observed. Only 3 patients developed perioperative morbidity, but none of them was classified as major. Bladder neck contracture occurred in only one man and it was managed endoscopically. Overall continence rates at 3, 6, 12, and 18 months were 73%, 85%, 96.7%, and 95%, respectively, and 76.8%, 89.3%, 96.4%, and 96.4%, respectively when analysis was limited to those without adjuvant radiotherapy. CONCLUSIONS: Obtained results confirm our initial observation from the preliminary report and support the use of our single running suture for the vesicourethral anastomosis in LRP. PMID- 26568870 TI - Biochemical recurrence risk factors in surgically treated high and very high-risk prostate tumors. AB - INTRODUCTION: High and very high-risk prostate cancers are tumors that display great variation in their progression, making their behaviour and consequent prognosis difficult to predict. We analyse preoperative and postoperative risk factors that could influence biochemical recurrence of these tumors. MATERIAL AND METHODS: We carried out univariate and multivariate analyses in an attempt to establish statistically significant preoperative (age, rectal examination, PSA, biopsy Gleason score, uni/bilateral tumor, affected cylinder percentage) and postoperative (pT stage, pN lymph node affectation, Gleason score, positive surgical margins, percentage of tumor affectation, perineural infiltration) risk factors, as well as their relationship with biochemical recurrence (PSA >0.2 ng/mL). RESULTS: We analysed 276 patients with high and very high-risk prostate cancer that were treated with laparoscopic radical prostatectomy (LRP) between 2003-2007, with a mean follow-up of 84 months. Incidence of biochemical recurrence is 37.3%. Preoperative factors with the greatest impact on recurrence are suspicious rectal exam (OR 2.2) and the bilateralism of the tumor in the biopsy (OR 1.8). Among the postoperative factors, the presence of a LRP positive surgical margins (OR 3.4) showed the greatest impact, followed by the first grade of the Gleason score (OR 3.3). CONCLUSIONS: The factor with the greatest influence on biochemical recurrence when it comes to surgery and high and very high-risk prostate cancer is the presence of a positive margin, followed by the Gleason score. Preoperative factors (PSA, biopsy Gleason score, rectal examination, number of affected cylinders) offered no guidance concerning the incidence of BCR. PMID- 26568871 TI - Sniffing out prostate cancer: a new clinical opportunity. PMID- 26568872 TI - Modified technique of cavoatrial tumor thrombectomy without cardiopulmonary by pass and hypothermic circulatory arrest: a preliminary report. AB - INTRODUCTION: Traditionally, tumor thrombi extending into the right atrium have been managed by open surgery with sternotomy, cardiopulmonary bypass circulation and hypothermic circulatory arrest, and are associated with significant morbidity and mortality rates. Here, we evaluate the results of cavoatrial thrombectomy using our own, Foley catheter assisted-technique, obviating the need for thoracotomy, extracorporeal circulation, and/or hypothermic circulatory arrest. MATERIAL AND METHODS: Between June 2013 and January 2015, 4 consecutive patients underwent cavoatrial thrombectomy performed with our own, Foley catheter assisted technique, via Chevron incision, with no need for extracorporeal circulation or hypothermy for renal cell carcinoma with tumor thrombus extending into the right atrium. Analyses of patients' data from a prospectively maintained database with respect to perioperative characteristics, morbidity and mortality were performed. RESULTS: The total mean duration of surgery was 255 minutes. The mean time of total IVC (inferior vena cava) occlusion was 90 seconds. The average blood loss volume, timed from the beginning of cavotomy incision until its closure, was 1200 ml. The total mean intraoperative blood loss was 3,150 ml. There was no perioperative death. Postoperative complications included one transient acute kidney injury requiring one-off hemodialysis and one re-operation due to bleeding. The follow-up time ranged between 12 to 17 months. None of the patients developed disease recurrence. All patients were still alive at the time of study completion. CONCLUSIONS: Obtained results support the validity of our own, Foley catheter assisted technique, without cardiopulmonary bypass and hypothermic circulatory arrest for the treatment of renal cell carcinoma with tumor thrombus extending into the right atrium. PMID- 26568873 TI - The minimal access technique for cavoatrial renal cancer thrombectomy - should it be used in all cases? PMID- 26568874 TI - AUTHOR'S REPLY. PMID- 26568875 TI - Laparoscopic nephrectomy - Pfannenstiel or expanded port site specimen extraction: a systematic review and meta-analysis. AB - INTRODUCTION: To anaylse the current evidence regarding the safety, feasibility and advantages of intact specimen extraction via various extraction sites after conventional laparoscopic nephrectomy (LN). MATERIAL AND METHODS: A comprehensive literature search was performed identifying studies evaluating outcomes from Pfannenstiel (PFN) versus extended port site (EPS) extraction sites, after conventional laparoscopic nephrectomy/nephroureterectomy (LRN/LNU) and donor nephrectomy (LDN). Outcome measures included procedure duration, incision length, duration of inpatient stay, analgesic requirements, complications and warm ischemia time (for donor nephrectomy cases). RESULTS: This systematic review of five comparative studies found no significant difference in morbidity, wound length, wound complications or opioid consumption across all studies. Inpatient stay (p = 0.03) and estimated blood loss (p = 0.03) were significantly less in favour of a PFN extraction site. When comparing radical nephrectomy cases alone, the PFN group had a shorter procedure time (NS), less estimated blood loss (p = 0.04), shorter inpatient stay (p <0.05), significantly less morphine use (p <0.006) and fewer wound complications. CONCLUSIONS: This review demonstrates the viability of retrieving a nephrectomy specimen/graft through a PFN incision in relation to the benefits of cosmesis and reduced pain. As reported in several trials, morbidity is not significantly increased and key outcome measures, such as duration of inpatient stay, pain scores, complications, analgesic requirements and time taken to return to normal activities, remain non-inferior. This study is limited by the small number of generally low quality studies available for analysis. Further well-constructed randomised controlled trials are needed to shed more light on this subject area. PMID- 26568876 TI - Macroscopic hematuria in patients on anticoagulation therapy. AB - INTRODUCTION: Visible hematuria is not rare in patients on anticoagulant therapy. There is no consensus regarding the diagnostic approach for them; some authors suggest restricted volume of diagnostic procedures because of the low number of urological etiology found. Some antibiotics have been reported to potentiate the effect of oral anticoagulants. MATERIAL AND METHODS: The study addresses the need for urological assessment of patients on anticoagulation therapy and the possible role of some drugs administrated simultaneously with an oral anticoagulant, for the onset of macroscopic hematuria. Patients hospitalized with hematuria, both with or without anticoagulation therapy, were investigated and followed up. RESULTS: The onset of hematuria depends on the monitoring of oral anticoagulation. INR (International Normalized Ratio) value corresponds with the probability of non-urological etiology, where INR>4 carries relatively low risk for urological and malignant etiology. Some antibiotics may influence the anticoagulation effect, so INR value may be elevated and hematuria may occur. CONCLUSIONS: Anticoagulation therapy should be administrated carefully and individually. The risk of urological etiology of hematuria is lower in patients on oral anticoagulants (especially when INR >4), however, it is not zero. PMID- 26568877 TI - Urolastic for the treatment of women with stress urinary incontinence: 24-month follow-up. AB - INTRODUCTION: To evaluate the efficacy and durability of Urolastic, a new urethral bulking agent in women with stress urinary incontinence (SUI), after a follow-up of 24-months. MATERIAL AND METHODS: A follow-up study of women with SUI who received a Urolastic injection and successfully passed the 12-month follow up. Assessment included the Stamey Grade, 1-h Pad weight test, and the International quality of life (I-QoL) score. RESULTS: Nineteen women who completed the 12-month follow-up were invited for the 24-month follow-up study. One patient did not respond to the correspondence. Four of the 18 patients who responded to the correspondence reported removal of the Urolastic implant at another facility, based on their desire. The explanation for this removal was painful intercourse (n = 1) or less than optimal dryness (n = 3). The overall objective improvement in continence status at 24-months was 66% compared to the 89% at the 12-month follow-up, while in addition the 1-h pad weight test showed >50% reduction in pad weight in 66% of patients compared to 84% at the 12-month follow-up. Adverse events reported were urinary tract infection (n = 1), local genital infection with erosion into the vagina (n = 1), painful intercourse (n = 2), and urgency (n = 4). CONCLUSIONS: Urolastic is comparable to other bulking agents in terms of durability, efficacy, and complications. PMID- 26568878 TI - Bulking agents for urinary incontinence: what, when and where? PMID- 26568879 TI - Current interventional management of male stress urinary incontinence following urological procedures. AB - INTRODUCTION: Despite improvements in surgical techniques and implementation of minimally invasive procedures, male stress urinary incontinence affects a substantial number of patients after prostatic surgery. In response to increasing demand of optimal treatment modality, new alternatives to artificial urinary sphincter have recently been introduced. This review summarises the therapeutic surgical options with their outcomes in management of postprostatectomy stress incontinence. MATERIAL AND METHODS: We performed a literature review by searching the PubMed, Web of Science and Embase databases for articles published from January 2000 until April 2015 based on clinical relevance. RESULTS: Artificial urinary sphincter is currently considered the "gold standard" treatment of male stress urinary incontinence. Although the new devices in this group have recently been investigated, the AMS 800 remains the only widely used implant. Male slings and adjustable continence devices, achieve the social continence rates up to 60%. Periurethral injections of bulking agents, have limited efficacy of male stress incontinence. Argus sling and ProACT are both associated with substantial explantation rates. Stem cell therapy is a promising option but still requires additional testing. CONCLUSIONS: The development of new alternatives to artificial urinary sphincter is constantly progressing. Although recently introduced minimally invasive treatment options have not yet surpassed the outcomes of the artificial urinary sphincter they should continue to be evaluated and compared against the gold standard. PMID- 26568880 TI - Effective radiation exposure evaluation during a one year follow-up of urolithiasis patients after extracorporeal shock wave lithotripsy. AB - INTRODUCTION: To determine and evaluate the effective radiation exposure during a one year follow-up of urolithiasis patients following the SWL (extracorporeal shock wave lithotripsy) treatment. MATERIAL AND METHODS: Total Effective Radiation Exposure (ERE) doses for each of the 129 patients: 44 kidney stone patients, 41 ureter stone patients, and 44 multiple stone location patients were calculated by adding up the radiation doses of each ionizing radiation session including images (IVU, KUB, CT) throughout a one year follow-up period following the SWL. RESULTS: Total mean ERE values for the kidney stone group was calculated as 15, 91 mSv (5.10-27.60), for the ureter group as 13.32 mSv (5.10-24.70), and in the multiple stone location group as 27.02 mSv (9.41-54.85). There was no statistically significant differences between the kidney and ureter groups in terms of the ERE dose values (p = 0.221) (p >0.05). In the comparison of the kidney and ureter stone groups with the multiple stone location group; however, there was a statistically significant difference (p = 0.000) (p <0.05). CONCLUSIONS: ERE doses should be a factor to be considered right at the initiation of any diagnostic and/or therapeutic procedure. Especially in the case of multiple stone locations, due to the high exposure to ionized radiation, different imaging modalities with low dose and/or totally without a dose should be employed in the diagnosis, treatment, and follow-up bearing the aim to optimize diagnosis while minimizing the radiation dose as much as possible. PMID- 26568881 TI - Value of preoperative stone scoring systems in predicting the results of percutaneous nephrolithotomy. AB - INTRODUCTION: Guy's Stone Score and S.T.O.N.E. Nephrolithometry nomograms have been introduced for systematic and quantitative assessment of kidney stones. The aim of this study was to reveal the value of two scorings systems, Guy and S.T.O.N.E, most frequently used for predicting postoperative stone-free status prior to Percutaneous Nephrolithotomy (PCNL), in the prediction of postoperative results of PCNL. MATERIAL AND METHODS: We retrospectively examined patients who underwent PCNL. Preoperative abdominopelvic computerized tomography images of these patients were reviewed and scored according to the Guy and S.T.O.N.E. systems. The relationship between the Guy and S.T.O.N.E. scores, and their postoperative stone-free status, complications based on Clavien system, operation time, fluoroscopy time and period of hospitalization was compared. RESULTS: We identified a total of 102 patients who underwent PCNL between 2010 and 2014, having met the inclusion criteria. The relationships between the total S.T.O.N.E score and Clavien score (p <0.001); time of operation (p = 0.012) and stone-free status (p <0.001); Guy stone score and Clavien score (p <0.001); and period of hospitalization (p <0.001) and time of operation (p <0.001) were found to be statistically significant. There was no statistically significant relationship between Guy score and stone-free status and no statistically significant relationship was found between fluoroscopy time and both stone scoring systems. CONCLUSIONS: Guy and S.T.O.N.E. scoring systems may be used as effective instruments particularly for predicting postoperative complications. PMID- 26568882 TI - Does ureteral stenting matter for stone size? A retrospective analyses of 1361 extracorporeal shock wave lithotripsy patients. AB - INTRODUCTION: The aim of our study was to determine the efficacy of ureteral stents for extracorporeal shock wave lithotripsy (SWL) treatment of pelvis renalis stones and to compare the results and complications in stented and non stented patients. MATERIAL AND METHODS: Between 1995 and 2011, 1361 patients with pelvis renalis stones were treated with SWL. Patients were subdivided into three groups according to stone burden: <=1 cm(2) (group 1; n = 514), 1.1 to 2 cm(2) (group 2; n = 530) and >2 cm(2) (group 3; n = 317). Each group was divided into subgroups of patients who did and did not undergo ureteral stent implantation before SWL treatment. The efficacy of treatment was evaluated by determining the effectiveness quotient (EQ). Statistical analysis was performed by chi-square, Fisher's exact and Mann-Whitney U tests. RESULTS: Of the 514, 530 and 317 patients in groups 1, 2 and 3 respectively, 30 (6%), 44 (8%) and 104 (33%) patients underwent auxiliary stent implantation. Steinstrasse rates did not differ significantly between stented and non-stented patients in each group. The EQ was calculated as 62%, 33% and 70% respectively in non-stented, stented and totally for group 1. This ratio calculated as 58%, 25% and 63% for group 2 and 62%, 26% and 47% for group 3. Stone-free rates were significantly higher for non stented than for stented patients in groups 2 and 3. CONCLUSIONS: Stone free rates are significantly higher in non-stented than in stented patients with pelvis renalis stones >1 cm(2), whereas steinstrasse rates are not affected. PMID- 26568883 TI - Varicocele as a source of male infertility - current treatment techniques. AB - To establish the extent of varicocele as the cause of infertility in men and compare the various techniques of treatment. We searched PubMed and the Cochrane Library database using varicocele, male infertility, varicocelectomy as keywords. Varicocele seems to be a growing problem considered to be one of the most common causes of male infertility in recent times. Nevertheless, its role remains unclear. The best treatment option seems to be microscopic surgery - the most effective and linked to rare surgical complications. But the greatest clinical problem remains the selection of patients to treat - recently it is believed that varicocelectomy is a possibly advisable option in patients with clinical varicocele and seminal parameter impairment [1]. More high-quality, multicenter, long-term randomized controlled trials (RCT's) are required to verify the findings. PMID- 26568884 TI - Fosfomycin tromethamine. Antibiotic of choice in the female patient: A multicenter study. AB - INTRODUCTION: The aim of this study was to evaluate oral single/multiple doses of Fosfomycin Trometamol with clinical and microbiological efficacy in:Asymptomatic bacteriuria in pregnancy.Endourological procedures.Lower urinary tract infections. MATERIAL AND METHODS: This prospective, uncontrolled, open label study was conducted in two tertiary hospitals over a period of three years. A total of 400 patients were included in the study. Group A (200 patients) with asymptomatic bacteriuria in pregnancy and Group B (200 Patients) with symptomatic lower urinary tract infections and with any day care endourological procedures were enrolled in our study. Efficacy end points like post- antibiotic urinalysis, microbiological efficacy and clinical improvement with adverse effects of the drug were evaluated. RESULTS: Of the 400 patients studied, 98% returned for follow-up. Out of the 304 urinary isolates in Table 2 (ASB and symptomatic LUTS) grown on urinary culture, majority of the isolates were Gram-negative Enterobacteriacae family. After oral single/multiple doses of fosfomycin, bacterial eradication, bacterial persistence, bacterial reinfection were 96.3%, 3.9%, 3.9% respectively (Figure 2). No isolates were grown in 8 cases (Table 2). However, on administration of the drug 23.5% patients noticed diarrhea (loose stools) followed by itching (19.7%) in genital area (Figure 1). CONCLUSIONS: Fosfomycin Trometamol is a bactericidal antibiotic with a broad spectrum activity against Gram-positive also Gram-negative bacteriae. It has an advantage of oral single /multiple doses, higher eradication rate of bacteria after 48 hours, excellent tolerability and safety in pregnancy and other female age groups. We recommend Fosfomycin Trometamol as the drug of choice particularly in patients with poor drug compliance and for minor day care endourological procedures. PMID- 26568885 TI - The standard of urological consultation of patients qualified for renal transplant - a review. AB - Urological consultation is an important step in the procedure of a patient's preparation before placing him/her on a waiting list for a renal transplant. Urological work-up aims to diagnose, treat, and optimize any preexisting urological disease. In the present paper we present the review of the literature together with the authors' conclusions based on literature and their experience. There is not enough data in current literature and urology manuals on the adequate sequence of the urological management with patients qualified for renal transplant and the literature needs an update. This study presents the crucial steps of the qualification and emphasizes the urge for a more standardized urological approach in patients qualified for a kidney transplantation. PMID- 26568886 TI - Urological evaluation prior to renal transplantation. PMID- 26568887 TI - Evolution in the treatment of the ureteropelvic junction obstruction syndrome. Laparoscopic versus open pyeloplasty. AB - INTRODUCTION: The treatment of ureteropelvic junction has evolved considerably over the past 20 years, resulting in new surgical techniques, but traditional open surgery remains the gold standard treatment. Currently, less invasive techniques are used for the treatment of ureteropelvic junction obstruction. The purpose of our study is to compare the surgical and functional results between laparoscopic and open pyeloplasty performed at our department during the last 12 years. MATERIAL AND METHODS: This is a retrospective review of 92 cases performed in a period of 12 years. Two groups were compared: 30 patients were treated with open surgery (OP) and 62 with a laparoscopic approach (LP). Demographics, clinical presentation, functionality of the affected kidney, presence of polar vessels, kidney stones, hospital stay, complications and functional results were statistically analyzed. RESULTS: The mean age was 42 years. The most common clinical presentation was kidney or ureteral pain: 60% (OP) vs. 52% (LP). The right side was affected in 59%; presence of crossing vessels was 47% (OP) vs. 58% (LP); presence of kidney stones was 20% (OP) vs. 19% (LP), with an average hospital stay of 5.86 days (OP) vs. 3.36 days (LP) p <0.05. Post-operative complications were observed in 3 (OP) vs. 5 (LP) patients, with a success rate comparable between groups. CONCLUSIONS: In our department, we recommend LP as the standard treatment for ureteropelvic junction obstruction because of the equal success rate compared to OP and the benefits of a minimally invasive surgery. PMID- 26568888 TI - Persistence and recurrence of vesicoureteric reflux in children after endoscopic therapy - implications of a risk-adapted follow-up. AB - INTRODUCTION: There is no well-defined follow-up scheme available to reliably detect persistent or recurrent vesicoureteric reflux (VUR) after endoscopic therapy (ET), but also to reduce postoperative invasive diagnostics in these children. Our aim was the evaluation of possible predictors of persistence and recurrence of VUR, in order to elaborate and test a risk-adapted follow-up regimen. MATERIAL AND METHODS: 92 patients (85/92%f, 7/8%m, age 2.99y) underwent direct isotope cystography (DIC) three months after ET. Persistent or recurrent VUR, scarring on dimercaptosuccinic acid (DMSA) scans and further fUTIs after therapy (follow-up 24.6 m) were documented and analysed. RESULTS: VUR persistence 3 months after ET was found in 11 (11.9%) patients; recurrent VUR in 4 (4.3%) patients. Scarring on preoperative DMSA and dilating VUR ( degrees III and degrees IV) were significantly associated with recurrent VUR. If only children with preoperative positive DMSA scan or dilating VUR would have undergone DIC, only 58/92 DICs (64%) would have been necessary. Only 45.5% of otherwise detected VURs would have been identified using this risk-adapted strategy. CONCLUSIONS: Limiting invasive follow-up diagnostics (VCUG) and, therewith, the radiation burden in a predefined group of patients at risk for persistence or recurrence of VUR is not recommended, due to the significant chance of missing persistent or new onset contralateral VUR. Therefore, we recommend a routine follow-up VCUG after ET. Further prospective scientific efforts to evaluate new, alternative factors influencing persistence and recurrence of VUR, in order to establish an effective follow-up strategy, are warranted. PMID- 26568889 TI - Mini-laparascopic dismembered pyeloplasty using only 3 mm instruments (3 mmML). PMID- 26568890 TI - Physicians Experience with and Expectations of the Safety and Tolerability of WHO Step III Opioids for Chronic (Low) Back Pain: Post Hoc Analysis of Data from a German Cross-Sectional Physician Survey. AB - Objective. To describe physicians' daily life experience with WHO-step III opioids in the treatment of chronic (low) back pain (CLBP). Methods. Post hoc analysis of data from a cross-sectional online survey with 4.283 Germany physicians. Results. With a reported median use in 17% of affected patients, WHO step III opioids play a minor role in treatment of CLBP in daily practice associated with a broad spectrum of positive and negative effects. If prescribed, potent opioids were reported to show clinically relevant effects (such as >=50% pain relief) in approximately 3 of 4 patients (median 72%). Analgesic effects reported are frequently related with adverse events (AEs). Only 20% of patients were reported to remain free of any AE. Most frequently reported AE was constipation (50%), also graded highest for AE-related daily life restrictions (median 46%). Specific AE countermeasures were reported to be necessary in approximately half of patients (median 45%); nevertheless AE-related premature discontinuation rates reported were high (median 22%). Fentanyl/morphine were the most/least prevalently prescribed potent opioids mentioned (median 20 versus 8%). Conclusion. Overall, use of WHO-step III opioids for CLBP is low. AEs, especially constipation, are commonly reported and interfere significantly with analgesic effects in daily practice. Nevertheless, beneficial effects outweigh related AEs in most patients with CLBP. PMID- 26568891 TI - Alterations of Regional Spontaneous Brain Activity and Gray Matter Volume in the Blind. AB - Visual deprivation can induce alterations of regional spontaneous brain activity (RSBA). However, the effects of onset age of blindness on the RSBA and the association between the alterations of RSBA and brain structure are still unclear in the blind. In this study, we performed resting-state functional and structural magnetic resonance imaging on 50 sighted controls and 91 blind subjects (20 congenitally blind, 27 early blind, and 44 late blind individuals). Compared with the sighted control, we identified increased RSBA in the blind in primary and high-level visual areas and decreased RSBA in brain regions which are ascribed to sensorimotor and salience networks. In contrast, blind subjects exhibited significantly decreased gray matter volume (GMV) in the visual areas, while they exhibited significantly increased GMV in the sensorimotor areas. Moreover, the onset age of blindness was negatively correlated with the GMV of visual areas in blind subjects, whereas it exerted complex influences on the RSBA. Finally, significant negative correlations were shown between RSBA and GMV values. Our results demonstrated system-dependent, inverse alterations in RSBA and GMV after visual deprivation. Furthermore, the onset age of blindness has different effects on the reorganizations in RSBA and GMV. PMID- 26568893 TI - Esthetic Rehabilitation of the Smile with No-Prep Porcelain Laminates and Partial Veneers. AB - Rehabilitation of patients with anterior conoid teeth may present a challenge for the clinician, especially when trying to mimic the nature with composite resins. This clinical report exemplifies how a patient with conoid upper lateral incisors was rehabilitated with minimally invasive adhesive restorations. Following diagnostic wax-up and cosmetic mock-up, no-prep veneers and ceramic fragments (partial veneers) were constructed with feldspathic porcelain. This restorative material presents excellent reproduction of the optical properties of the dental structure, especially at minimal thicknesses. In this paper, the details about the treatment are described. A very pleasing outcome was achieved, confirming that minimally invasive adhesive restorations are an excellent option for situations in which the dental elements are healthy, and can be modified exclusively by adding material and the patient does not want to suffer any wear on the teeth. PMID- 26568892 TI - Clinical Trial of Human Fetal Brain-Derived Neural Stem/Progenitor Cell Transplantation in Patients with Traumatic Cervical Spinal Cord Injury. AB - In a phase I/IIa open-label and nonrandomized controlled clinical trial, we sought to assess the safety and neurological effects of human neural stem/progenitor cells (hNSPCs) transplanted into the injured cord after traumatic cervical spinal cord injury (SCI). Of 19 treated subjects, 17 were sensorimotor complete and 2 were motor complete and sensory incomplete. hNSPCs derived from the fetal telencephalon were grown as neurospheres and transplanted into the cord. In the control group, who did not receive cell implantation but were otherwise closely matched with the transplantation group, 15 patients with traumatic cervical SCI were included. At 1 year after cell transplantation, there was no evidence of cord damage, syrinx or tumor formation, neurological deterioration, and exacerbating neuropathic pain or spasticity. The American Spinal Injury Association Impairment Scale (AIS) grade improved in 5 of 19 transplanted patients, 2 (A -> C), 1 (A -> B), and 2 (B -> D), whereas only one patient in the control group showed improvement (A -> B). Improvements included increased motor scores, recovery of motor levels, and responses to electrophysiological studies in the transplantation group. Therefore, the transplantation of hNSPCs into cervical SCI is safe and well-tolerated and is of modest neurological benefit up to 1 year after transplants. This trial is registered with Clinical Research Information Service (CRIS), Registration Number: KCT0000879. PMID- 26568894 TI - Adaptive Evolution Coupled with Retrotransposon Exaptation Allowed for the Generation of a Human-Protein-Specific Coding Gene That Promotes Cancer Cell Proliferation and Metastasis in Both Haematological Malignancies and Solid Tumours: The Extraordinary Case of MYEOV Gene. AB - The incidence of cancer in human is high as compared to chimpanzee. However previous analysis has documented that numerous human cancer-related genes are highly conserved in chimpanzee. Till date whether human genome includes species specific cancer-related genes that could potentially contribute to a higher cancer susceptibility remains obscure. This study focuses on MYEOV, an oncogene encoding for two protein isoforms, reported as causally involved in promoting cancer cell proliferation and metastasis in both haematological malignancies and solid tumours. First we document, via stringent in silico analysis, that MYEOV arose de novo in Catarrhini. We show that MYEOV short-isoform start codon was evolutionarily acquired after Catarrhini/Platyrrhini divergence. Throughout the course of Catarrhini evolution MYEOV acquired a gradually elongated translatable open reading frame (ORF), a gradually shortened translation-regulatory upstream ORF, and alternatively spliced mRNA variants. A point mutation introduced in human allowed for the acquisition of MYEOV long-isoform start codon. Second, we demonstrate the precious impact of exonized transposable elements on the creation of MYEOV gene structure. Third, we highlight that the initial part of MYEOV long isoform coding DNA sequence was under positive selection pressure during Catarrhini evolution. MYEOV represents a Primate Orphan Gene that acquired, via ORF expansion, a human-protein-specific coding potential. PMID- 26568895 TI - Patterns of Marital Relationship Change across the Transition from One Child to Two. AB - Patterns of marital change after the birth of a second child were explored in a sample of 229 married couples, starting in pregnancy, and at 1, 4, 8 and 12 months postpartum. Five trajectory patterns that reflected sudden, persistent decline (i.e., crisis), sudden, short-term decline (i.e., adjustment and adaptation), sudden, short-term gain (i.e., honeymoon effect), linear change, and no change were examined with dyadic, longitudinal data for husbands and wives. Six distinct latent classes emerged using growth mixture modeling: (a) wife decreasing positivity-husband honeymoon (44%), (b) wife increasing conflict husband adjustment and adaptation (34.5%), (c) wife honeymoon-discrepant spouse positivity (7.4%), (d) wife adjustment and adaptation (6.9%), (e) couple honeymoon with discrepant positivity and negativity (5.2%) and (f) husband adjustment and adaptation (1.7%). Classes were distinguished by individual vulnerabilities (i.e., depression, personality), stresses associated with the transition (i.e., unplanned pregnancy), and adaptive processes (i.e., marital communication, social support). Marital communication, parental depression, and social support emerged as important targets for intervention that can assist parents planning to have additional children. PMID- 26568896 TI - Titanium Dioxide Nanoparticles are not Cytotoxic or Clastogenic in Human Skin Cells. AB - The application of nanoparticle technology is rapidly expanding. The reduced dimensionality of nanoparticles can give rise to changes in chemical and physical properties, often resulting in altered toxicity. People are exposed dermally to titanium dioxide (TiO2) nanoparticles in industrial and residential settings. The general public is increasingly exposed to these nanoparticles as their use in cosmetics, sunscreens and lotions expands. The toxicity of TiO2 nanoparticles towards human skin cells is unclear and understudied. We used a human skin fibroblast cell line to investigate the cytotoxicity and clastogenicity of TiO2 nanoparticles after 24 h exposure. In a clonogenic survival assay, treatments of 10, 50 and 100 MUg/cm2 induced 97.8, 88.8 and 84.7% relative survival, respectively. Clastogenicity was assessed using a chromosomal aberration assay in order to determine whether TiO2 nanoparticles induced serious forms of DNA damage such as chromatid breaks, isochromatid lesions or chromatid exchanges. Treatments of 0, 10, 50 and 100 MUg/cm2 induced 3.3, 3.0, 3.0 and 2.7% metaphases with damage, respectively. No isochromatid lesions or chromatid exchanges were detected. These data show that TiO2 nanoparticles are not cytotoxic or clastogenic to human skin cells. PMID- 26568897 TI - Is a Cardio-Protective Diet Sustainable? A Review of the Synergies and Tensions Between Foods That Promote the Health of the Heart and the Planet. AB - There are many synergies between a diet that is healthy for the heart and one that is healthy for the planet, but there may also be tensions. We examined the Barilla Center for Food and Nutrition's double pyramid to describe the carbon, water, and ecological footprints of the components of a cardio-protective diet. Overall, fruits, vegetables, and whole grains all tend to have low carbon and water footprints, while nuts and olive oil have relatively higher water footprints and fish have a high ecological footprint. In order to increase the sustainability of a cardio-protective diet, consumers can choose nuts (e.g., walnuts) and oils (e.g., sunflower) with lower water footprints and sustainably produced fish. However, in order to increase consumption of these foods, parallel efforts should be implemented targeting consumer knowledge and incentives to make these foods more affordable. PMID- 26568899 TI - Psychosocial and Clinical Outcomes of a Cognitive Behavioral Therapy for Asians and Pacific Islanders with Type 2 Diabetes: A Randomized Clinical Trial. AB - Asian Americans and Pacific Islanders are twice as likely to be diagnosed with type 2 diabetes compared to Caucasians. The objective was to determine the effect of cognitive behavioral therapy on quality of life, general health perceptions, depressive symptoms, and glycemia in Asians and Pacific Islanders with type 2 diabetes. The design was a randomized controlled clinical trial comparing cognitive behavioral therapy to diabetes education and support for six weekly sessions. Participants were recruited from two endocrinology practices; 207 were enrolled. The cognitive behavioral therapy group was provided self-management tools which included biofeedback, breathing exercises, and stress relievers, while the diabetes education and support group included diabetes education and group discussions. Assessments of psychosocial and clinical outcomes were obtained before and after sessions and 12 months PostSession. Differences between the two groups were examined using linear mixed-effects models with linear contrasts. The cognitive behavioral therapy group had improved depressive symptom scores from PreSession to EndSession compared to the diabetes education and support group (P < .03), but the improvement did not extend to 12 months PostSession. Similar results were observed with misguided support scores in the Multidimensional Diabetes Questionnaire (P < .03) and susceptibility in health beliefs (P < .01), but no significant differences in HbA1c improvement were found between the two groups. Both interventions improved outcomes from baseline but were not sustained for 1 year. PMID- 26568898 TI - Whole-Blood Gene Expression Profiles in Large-Scale Epidemiological Studies: What Do They Tell? AB - In nutrigenomics, gene expression profiling is used to investigate transcriptional mechanisms associated with nutrients and diet. Blood samples collected in the framework of dietary interventions and epidemiological studies allow the use of humans as the model system, as opposed to using cell lines or animal models. Here, we review recent publications in the field of gene expression profiling, based on a systematic literature search focusing on studies from the last 5 years and including studies that investigated either single nutrients, foods, food groups, or dietary patterns. Findings highlight the role of inflammatory processes as key mediators of the association between diet and disease and point to the relevance of using blood as the target tissue in nutrigenomics. However, recurring challenges include study design issues, practical and statistical challenges, and biological interpretation of the results. Many of the published studies have small sample size, and given the nature of gene expression data, their conclusions have limited impact. These challenges should be addressed by future nutrigenomics studies in order to increase their relevance and validity. PMID- 26568900 TI - Levonorgestrel Intrauterine Device Use in Overweight and Obese Women. AB - The levonorgestrel intrauterine device (LNG-IUD) is a safe, effective, long acting, reversible contraceptive that reduces unintended pregnancy and decreases heavy menstrual bleeding. Many procedures such as IUD insertion are more challenging in overweight and obese women. The objective of this study was to describe LNG-IUD insertion, continuation, and complications in overweight and obese women in an ethnically diverse population in Hawai'i. A retrospective cohort study of women who had a LNG-IUD inserted at the University of Hawai'i, Department of Obstetrics and Gynecology Resident and Faculty practice sites between January 2009 and December 2010 was performed. A total of 149 women were followed. The most commonly reported races were Asian (32%), Native Hawaiian (26%), and non-Hawaiian Pacific Islander (20%). The mean BMI of the study population was 28.4 (standard deviation 7.2) with 37% classified as normal weight, 30% as overweight, and 33% as obese. Overall, 76% of women continued the LNG-IUD 12 months after insertion. No statistically significant difference emerged in 12-month IUD continuation between the BMI groups. Difficult (5%) and failed (3%) IUD insertions were rare for all BMI groups. IUD complications occurred in 9% of women and included expulsion and self-removal. In this diverse population, the majority of women continued to use the LNG-IUD one year after insertion with low rates of difficult insertions and complications. PMID- 26568901 TI - A Case of Wound Infection with Providencia rettgeri and Coincident Gout in a Patient from Guam. AB - Providencia rettgeri (P. rettgeri) is a ubiquitous organism that is infrequently associated with human disease. Here we report the isolation of this organism from a polymicrobial wound infection resulting from ruptured tophi on a 54-year-old male patient from Guam. We describe the identification and confirmation of this organism, and propose metabolic synergy as a possible mechanism of pathogenesis. To our knowledge, this is the first published report of a wound infection colonized by P. rettgeri from Guam, and the first report to speculate upon the role of bacterial synergy in P. rettgeri pathogenesis. PMID- 26568902 TI - Medical School Hotline: Liaison Committee on Medical Education Accreditation: Part II: The Graduation Objectives. PMID- 26568903 TI - Insights in Public Health: For the Love of Data! The Hawai'i Health Data Warehouse. AB - Data form the framework around which important public health decisions are made. Public health data are essential for surveillance and evaluating change. In Hawai'i, public health data come from a multitude of sources and agencies. The Hawai'i Health Data Warehouse (HHDW) was created to pull those data into a single location and to present results in a form that is easy for the public to access and utilize. In the years since its creation, HHDW has built a second consumer focused web site, Hawai'i Health Matters, and is now introducing new functionality on the original site that allows users to define their own enquiry. The newly adopted Indicator-Based Information System (IBIS) uses a web interface to perform real-time data analysis and display results. This gives users the power to examine health data by a wide range of demographic and socioeconomic dimensions, permitting them to pinpoint the data they need. PMID- 26568904 TI - The Daniel K. Inouye College of Pharmacy Scripts: Hepatitis C in 2015: Recent Advancements and Current Challenges. PMID- 26568906 TI - Treatment of Cryptosporidium: What We Know, Gaps, and the Way Forward. AB - Cryptosporidiosis is increasingly recognized as an important global health concern. While initially reported in immunocompromised such as AIDS patients, cryptosporidiosis has now been documented as a major cause of childhood diarrhea and an important factor in childhood malnutrition. Currently, nitazoxanide is the only proven anti-parasitic treatment for Cryptosporidium infections. However, it is not effective in severely immunocompromised patients and there is limited data in infants. Immune reconstitution or decreased immunosuppression is critical to therapy in AIDS and transplant patients. This limitation of treatment options presents a major public health challenge given the important burden of disease. Repurposing of drugs developed for other indications and development of inhibitors for novel targets offer hope for improved therapies, but none have advanced to clinical studies. PMID- 26568907 TI - Positive Narrative Group Psychotherapy: the use of traditional fairy tales to enhance psychological well-being and growth. AB - BACKGROUND: Oral narrative strategies have rarely been applied in the positive psychology domain. Traditional folk and fairy tales are concerned with several concepts that are now scientifically investigated by research on positive psychology, such as resilience, self-realization, personal growth and meaning in life. The aim of this pilot study was to apply a new narrative approach based on fairy tales (Marchen, tales of magic, rise tales) told, discussed, and written in a group context for the purpose of promoting psychological well-being and growth. METHODS: A group intervention consisting of 7 sessions was delivered to 21 women who reported adjustment disorder. The group was conducted by a folklorist and a clinical psychologist. Each session consisted of an introduction to a number of themes recurring in fairy tales as well as references to the social uses of narratives, followed by a discussion with the participants. In two concluding workshops, participants were asked to work as a group to write their own original fairy tale. Assessment pre- and post-intervention was performed with the Ryff Psychological Well-being Scale, the Kellner Symptom Questionnaire and 2 subscales of the Posttraumatic Growth Inventory (Appreciation of Life and personal strengths). RESULTS: Participants reported increased personal growth, self acceptance, and an enhanced sense of appreciation of life and personal strengths, together with decreased levels of anxiety. CONCLUSIONS: This pilot investigation suggests the feasibility and positive effect of a group intervention based on narrative strategies for promoting well-being and growth in stressed women. Considering its promising results, clinical implications and possible further applications are discussed. PMID- 26568908 TI - Relations of admiration and adoration with other emotions and well-being. AB - BACKGROUND: Admiration and adoration (also referred to as reverence or worship) have 2 received little empirical attention, although the two emotions theoretically have been related to individual and collective well-being. This research tested for associations of dispositional admiration and adoration with dimensions of psychological well-being and life satisfaction. METHODS: We developed a new measure of dispositional admiration and adoration and employed it in a questionnaire study with 342 participants. Additional measures included various emotion dispositions and dimensions of well-being. RESULTS: While admiration was linked to greater levels of personal growth and adoration to greater levels of purpose in life, the two emotions were unrelated to environmental mastery, self-acceptance, and life satisfaction. A multiple-step multiple mediator model revealed that counteractive positive and negative indirect effects of admiration and adoration on mastery, self-acceptance and life satisfaction were hidden beneath the nonsignificant total effects. Specifically, there were positive indirect effects of admiration and adoration via inspiration and gratitude and negative indirect effects via fascination and envy on well being. CONCLUSIONS: Taken together, the findings suggest that admiration and adoration bind people to ideals irrespective of their ability to move closer to them, thereby providing a potential source of satisfaction as well as frustration. PMID- 26568909 TI - Evaluation of the inner wellbeing model in Zambia. AB - BACKGROUND: Results of a recently published paper from members of the Wellbeing and Poverty Pathways Project team indicated that a seven-domain, intercorrelated factor model of economic confidence, agency/participation, social connections, close relationships, physical/mental health, competence/self-worth, and values/meaning as dimensions of inner wellbeing yielded optimal goodness-of-fit (compared to a single-factor model) among a large sample of individuals in rural India. The goal of the present study was to determine whether this model also provided optimal goodness-of-fit among a similarly large sample of individuals in rural Zambia. FINDINGS: A 35-item survey measuring each of the seven domains of inner wellbeing (5 items per domain) was administered to 344 individuals (140 men, 204 women). Results of confirmatory factor analyses indicated that the seven factor intercorrelated model not only was acceptable in itself but also yielded significantly better goodness-of-fit than did a one-factor model. Furthermore, 34 of the 35 items loaded significantly and positively on their hypothesised factors. CONCLUSIONS: Overall, results from the present paper - combined with results from the recently published paper by members of the Wellbeing and Poverty Pathways Project team - indicate that the seven-factor intercorrelated model can be generalised across India and Zambia. Implications for studies of wellbeing within (as well as outside) developing nations are discussed. PMID- 26568910 TI - Prostate cancer educational intervention among men in western Jamaica. AB - OBJECTIVE: To conduct and evaluate the impact of a theory-based health education intervention on awareness of prostate cancer and intention to screen among men in Western Jamaica and determine screening rates of men participating in the intervention at 6 months post-intervention. MATERIALS AND METHODS: 454 men utilizing various clinics and hospitals in Western Jamaica completed an interviewer-administered pretest survey on general prostate cancer knowledge and intention to screen. Upon completing the pretest, participants observed a prostate cancer health education intervention and immediately completed a posttest survey. RESULTS: Statistically significant improvements in the percentage of correct responses between the pretest and posttest were evident. (p < 0.05). Additionally, screening rates increased dramatically by 6 months post intervention with over 33% of men receiving a prostate exam after participating the in the educational intervention. CONCLUSION: The theory-based educational intervention increased participants' knowledge of prostate cancer, types of screening tests, frequency of screenings and risk factors and symptoms, and was effective in increasing screening rates among the men in Western Jamaica within 6 months post- intervention. This theory-based educational intervention may be replicated to promote awareness of prostate cancer and further increase screening rates in other areas of Jamaica and other developing countries. PMID- 26568911 TI - First International Workshopson Provocative Questions (PQ) in Cancer Research, October-November 2014, New Delhi, Bengaluru, and Thiruvananthapuram, India. AB - In 2011, the National Cancer Institute (NCI, USA) introduced the Provocative Questions (PQ) Initiative, a new approach allowing active researchers to define major unsolved or neglected problems in oncology unaddressed by existing funding. Last year, the U.S. NCI teamed up with the Indian Department of Biotechnology (DBT) to pilot the PQ approach in three cities in India. Workshop outcomes includedthe generation of fundable "PQs" (perplexing questions understudied by the international scientific community), as well as the identification of several non-PQ projects and research-related issues of importance to DBT and other Indian funding groups. The workshops clearly indicated the need to expand beyond crafting "PQs" when considering the best areas for research funding in international settings. Nonetheless, the first set of PQ workshops provided a forum to discuss key issues regarding cancer research in India, including the paucity of cancer research funding, and the lack of relevant human resource training and technology sharing platforms. Continued open debate between researchers, funders and policymakers will be essential to effectively strengthen the cancer research portfolio in India. PMID- 26568912 TI - The neural basis for insect pheromonal communication. AB - Insects rely on chemosensory signals to drive a multitude of behavioral decisions. From conspecific and mate recognition to aggression, the proper detection and processing of these chemical signals - termed pheromones - is crucial for insects' fitness. While the identities and physiological impacts of diverse insect pheromones have been known for many years, how these important molecules are perceived and processed by the nervous system to produce evolutionarily beneficial behaviors is still mostly unknown. Here we present an overview of the current state of research into the peripheral and central nervous system mechanisms that process and drive behavioral responses to diverse pheromonal cues. PMID- 26568913 TI - Pathogenesis of serous, extra-uterine Mullerian epithelial cancer and therapeutic implications. AB - Serous extra-uterine Mullerian tumors include lesions previously classified either as serous ovarian, fimbrial, or primary peritoneal tumors. They should be distinguished from intra-uterine (endometrial) serous tumors in spite of their common Mullerian differentiation lineage due to distinctive clinical-pathological parameters. Increased risk for these cancers is driven primarily by cell non autonomous hormonal factors associated with menstrual cycle progression, which can be accentuated by mutations in BRCA1/2. Additional factors, such as inflammatory conditions and others, may also contribute to elevated cancer risk in some individuals. The most consistent molecular alterations associated with serous extra-uterine Mullerian carcinomas, whether they arise in the context of familial predisposition or BRCA-independent hormonal factors, include severe aneuploidy superimposed on P53 mutations. Their near polyploid nature strongly suggests a role for mitotic errors associated with cytokinesis failure in their pathogenesis. A molecular mechanism is proposed involving a combination of both cell non-autonomous and cell autonomous factors in the development and progression of serous extra-uterine Mullerian tumors. Cell non-autonomous factors lead to increased cellular proliferation in extra-uterine serous Mullerian epithelium and contribute to the site-specificity of cancers associated with germline BRCA mutations. Cell autonomous factors in individuals with BRCA1 mutations lead to failure of cytokinesis following recovery from a cell cycle arrest at the mitotic spindle assembly checkpoint. In individuals with intact BRCA1/2 function, recovery from such arrest might be facilitated by CCNE1 amplification and ensuing centrosome duplication leading to increased microtubule anchoring, accounting for frequent amplification of this cyclin observed in tumors not associated with BRCA1/2 mutations. The cell non-autonomous factors provide an opportunity for using pharmacological means to control cancer incidence in individuals at elevated risk for these cancers such as BRCA1/2 mutation carriers, underscoring the importance of better understanding their determinants and downstream targets. The cell autonomous factors discussed here account for the molecular features of high-grade serous extra-uterine Mullerian carcinomas, which are regarded as a disease of chromosomes, and underscore the potential merit of targeting components of the spindle assembly checkpoint in their clinical management. PMID- 26568914 TI - Hepatitis delta virus: A fascinating and neglected pathogen. AB - Hepatitis delta virus (HDV) is the etiologic agent of the most severe form of virus hepatitis in humans. Sharing some structural and functional properties with plant viroids, the HDV RNA contains a single open reading frame coding for the only virus protein, the Delta antigen. A number of unique features, including ribozyme activity, RNA editing, rolling-circle RNA replication, and redirection for a RNA template of host DNA-dependent RNA polymerase II, make this small pathogen an excellent model to study virus-cell interactions and RNA biology. Treatment options for chronic hepatitis Delta are scarce and ineffective. The disease burden is perhaps largely underestimated making the search for new, specific drugs, targets, and treatment strategies an important public health challenge. In this review we address the main features of virus structure, replication, and interaction with the host. Virus pathogenicity and current treatment options are discussed in the light of recent developments. PMID- 26568917 TI - Human immunodeficiency virus/acquired immune deficiency syndrome: Using drug from mathematical perceptive. AB - Entry of acquired immune deficiency syndrome virus into the host immune cell involves the participation of various components of host and viral cell unit. These components may be categorized as attachment of the viral surface envelope protein subunit, gp120, to the CD4(+) receptor and chemokine coreceptors, CCR5 and CXCR4, present on T cell surface. The viral fusion protein, gp41, the second cleaved subunit of Env undergoes reconfiguration and the membrane fusion reaction itself. Since the CD4(+) T cell population is actively involved; the ultimate outcome of human immunodeficiency virus infection is total collapse of the host immune system. Mathematical modeling of the stages in viral membrane protein-host cell receptor-coreceptor interaction and the effect of antibody vaccine on the viral entry into the susceptible host cell has been carried out using as impulsive differential equations. We have studied the effect of antibody vaccination and determined analytically the threshold value of drug dosage and dosing interval for optimum levels of infection. We have also investigated the effect of perfect adherence of drug dose on the immune cell count in extreme cases and observed that systematic drug dosage of the immune cells leads to longer and improved lives. PMID- 26568918 TI - Rapid genotyping of human rotavirus using SYBR green real-time reverse transcription-polymerase chain reaction with melting curve analysis. AB - AIM: To develop a real-time reverse transcription-polymerase chain reaction (RT PCR) assay to genotype rotavirus (G and P) in Alberta from January 2012 to June 2013. METHODS: We developed and validated a different approach to perform rotavirus G and P genotyping using a two-step SYBR green RT-PCR (rt-gPCR) by selecting genotype-specific primers of published conventional RT nested PCR (cnRT PCR) assay and optimizing the amplification conditions. cDNA was first synthesized from total RNA with SuperScriptTM II reverse transcriptase kit followed by amplication step using monoplex SYBR green real-time PCR. After the PCR reaction, melting curve analysis was used to determine specific genotype. Sixteen samples previously genotyped using cnRT-PCR were tested using the new assay and the genotyping results were compared as sensitivity analysis. Assay specificity was evaluated by testing other gastroenteritis viruses with the new assay. The amplicon size of each available genotype was determined by gel electrophoresis and DNA sequences were obtained using Sanger-sequencing method. After validation and optimization, the new assay was used to genotype 122 pediatric clinical stool samples previously tested positive for rotavirus using electron microscopy between January 2012 and June 2013. RESULTS: The new rt-gPCR assay was validated and optimized. The assay detected G1 to G4, G9, G12 and P[4] and P[8] that were available as positive controls in our laboratory. A single and clear peak of melting curve was generated for each of specific G and P genotypes with a Tm ranging from 80 degrees C to 82 degrees C. The sensitivity of rt-gPCR was comparable to cnRT-PCR with 100% correlation of the 16 samples with known G and P genotypes. No cross reaction was found with other gastroenteritis viruses. Using the new rt-gPCR assay, genotypes were obtained for 121 of the 122 pediatric clinical samples tested positive for rotavirus: G1P[8] (42.6%), G2P[4] (4.9%), G3P[8] (10.7%), G9P[8] (10.7%), G9P[4] (6.6%), G12P[8] (23.0%), and unknown GP[8] (0.8%). For the first time, G12 rotavirus strains were found in Alberta and G12 was the second most common genotype during the study period. Gel electrophoresis of all the genotypes showed expected amplicon size for each genotype. The sequence data of the two G12 samples along with other genotypes were blasted in NCBI BLAST or analyzed with Rota C Genotyping tool (http://rotac.regatools.be/). All genotyping results were confirmed to be correct. CONCLUSION: rt-gPCR is a useful tool for the genotyping and characterization of rotavirus. Monitoring of rotavirus genotypes is important for the identification of emerging strains and ongoing evaluation of rotavirus vaccination programs. PMID- 26568915 TI - Update on hepatitis B and C virus diagnosis. AB - Viral hepatitis B and C virus (HBV and HCV) are responsible for the most of chronic liver disease worldwide and are transmitted by parenteral route, sexual and vertical transmission. One important measure to reduce the burden of these infections is the diagnosis of acute and chronic cases of HBV and HCV. In order to provide an effective diagnosis and monitoring of antiviral treatment, it is important to choose sensitive, rapid, inexpensive, and robust analytical methods. Primary diagnosis of HBV and HCV infection is made by using serological tests for detecting antigens and antibodies against these viruses. In order to confirm primary diagnosis, to quantify viral load, to determine genotypes and resistance mutants for antiviral treatment, qualitative and quantitative molecular tests are used. In this manuscript, we review the current serological and molecular methods for the diagnosis of hepatitis B and C. PMID- 26568916 TI - Hepatitis E virus infection: Epidemiology and treatment implications. AB - Hepatitis E virus (HEV) infection is now established as an emerging enteric viral hepatitis. Standard treatments in acute and chronic hepatitis E remain to be established. This study undertakes a review of the epidemiology, treatment implication and vaccine prevention from published literature. HEV infection is a worldwide public health problem and can cause acute and chronic hepatitis E. HEV genotypes 1 and 2 are primarily found in developing countries due to waterborne transmission, while the zoonotic potential of genotypes 3 and 4 affects mostly industrialized countries. An awareness of HEV transmission through blood donation, especially in the immunocompromised and solid organ transplant patients, merits an effective anti-viral therapy. There are currently no clear indications for the treatment of acute hepatitis E. Despite concerns for side effects, ribavirin monotherapy or in combination with pegylated interferon alpha for at least 3 mo appeared to show significant efficacy in the treatment of chronic hepatitis E. However, there are no available treatment options for specific patient population groups, such as women who are pregnant. Vaccination and screening of HEV in blood donors are currently a global priority in managing infection. New strategies for the treatment and control of hepatitis E are required for both acute and chronic infections, such as prophylactic use of medications, controlling large outbreaks, and finding acceptable antiviral therapy for pregnant women and other patient groups for whom the current options of treatment are not viable. PMID- 26568919 TI - Prevalence of adenovirus and rotavirus infection in immunocompromised patients with acute gastroenteritis in Portugal. AB - AIM: To characterize the prevalence of rotavirus (RV) and adenovirus (AdV) infections in immunocompromised patients with acute gastroenteritis. METHODS: The presence of RV and AdV (serotypes 40 and 41) was evaluated in 509 stool samples obtained between January 2009 and December 2010 from 200 immunocompromised patients (83 females and 117 males; median age 21 years old, range 0-72. The diagnosis of infection was performed as a routine procedure and the presence of RV and AdV (serotypes 40 and 41) was determined by immunochromatography using the RIDA((r)) Quick Rota-Adeno-Kombi kit (r-Biopharm, Darmstadt, Germany). The data analysis and description of seasonal frequencies were performed using computer software IBM((r)) SPSS((r)) (Statistical Package for Social Sciences) Statistics version 20.0 for Mac. The frequencies of infection were compared into different age and gender groups by chi(2) test. RESULTS: The study revealed 12.4% AdV positive samples and 0.8% RV positive samples, which correspond to a prevalence of 6.5% and 1.5%, respectively. AdV was more frequent between October 2009 and April 2010, while RV was identified in April 2010 and July 2010. The stool analysis revealed that from the 509 samples, 63 (12.4%) were positive for AdV and 4 (0.8%) positive for RV, which by resuming the information of each patient, lead to an overall prevalence of AdV and RV of 6.5% (13/200 patients) and 1.5% (3/200 patients), respectively. The stratification of the analysis regarding age groups showed a tendency to an increased prevalence of infection in paediatric patients between 0-10 years old. Considering the seasonal distribution of these infections, our study revealed that AdV infection was more frequent between October 2009 and April 2010, while RV infection was characterized by two distinct peaks (April 2010 and July 2010). CONCLUSION: The overall prevalence of AdV and RV infection in immunocompromised patients with acute gastroenteritis was 8% and AdV was the most prevalent agent. PMID- 26568920 TI - National nursing and midwifery legislation in countries of South-East Asia with high HIV burdens. AB - This paper analyses nursing and midwifery legislation in high HIV-burden countries of the World Health Organization (WHO) South-East Asia Region, with respect to global standards, and suggests areas that could be further examined to strengthen the nursing and midwifery professions and HIV service delivery. To provide universal access to HIV/AIDS prevention, care and treatment, sufficient numbers of competent human resources for health are required. Competence in this context means possession and use of requisite knowledge and skills to fulfil the role delineated in scopes of practice. Traditionally, the purpose of professional regulation has been to set standards that ensure the competence of practising health workers, such as nurses and midwives. One particularly powerful form of professional regulation is assessed here: national legislation in the form of nursing and midwifery acts. Five countries of the WHO South-East Asia Region account for more than 99% of the region's HIV burden: India, Indonesia, Myanmar, Nepal and Thailand. Online legislative archives were searched to obtain the most recent national nursing and midwifery legislation from these five countries. Indonesia was the only country included in this review without a national nursing and midwifery act. The national nursing and midwifery acts of India, Myanmar, Nepal and Thailand were all fairly comprehensive, containing between 15 and 20 of the 21 elements in the International Council of Nurses Model Nursing Act. Legislation in Myanmar and Thailand partially delineates nursing scopes of practice, thereby providing greater clarity concerning professional expectations. Continuing education was the only element not included in any of these four countries' legislation. Countries without a nursing and midwifery act may consider developing one, in order to facilitate professional regulation of training and practice. Countries considering reform to their existing nursing acts may benefit from comparing their legislation with that of other similarly situated countries and with global standards. Countries interested in improving the sustainability of scale-up for HIV services may benefit from a greater understanding of the manner in which nursing and midwifery is regulated, be it through continuing education, scopes of practice or other relevant requirements for training, registration and licensing. PMID- 26568921 TI - Checklists and Other Cognitive Aids For Emergency And Routine Anesthesia Care-A Survey on the Perception of Anesthesia Providers From a Large Academic US Institution. AB - BACKGROUND: The use of printed or electronic checklists and other cognitive aids has gained increasing interest from anesthesia providers and professional societies. While these aids are not currently considered standard of care, the perceptions of the clinician might have an impact on their adoption. OBJECTIVES: We conducted a comprehensive survey to study the current opinions of anesthesia provider on the use of checklists and other cognitive aids. PATIENTS AND METHODS: A questionnaire was developed by a departmental checklist focus group, which aimed to identify the perception of health care checklists in general as well as specific checklists for routine and crisis situations in anesthesia. Furthermore participants were asked regarding their perception of performing routine anesthesia and managing crisis situations without any cognitive aids. Using a web based system, the survey was administered to all anesthesia providers at a single large United States academic medical center (University of California San Francisco). Demographic information included professional status (faculty, anesthesia resident, or nurse anesthetists [certified registered nurse anesthetists; CRNA]) and years of clinical experience. RESULTS: 69% of 312 providers responded. 98% of the survey takers consider the procedural time-out (the widely used pre-incision operating room checklist) as important or very important. We found that many anesthesia providers acknowledged limitations in their ability to perform clinical tasks without any lapses, and a majority would use checklists and other cognitive aids if available. Their acceptances are especially high for crisis situations (87 - 97%, depending on years of experience) and routine care that providers do not perform often (76 - 91%). Printed or electronic aids for patient-care transition and shift hand-offs were also valued (61% and 58%). To prepare for and perform routine anesthesia care, 40% of providers claimed interest in using checklists, however, the interest differed significantly with clinical experience: While both the least and most experienced providers valued aids for routine anesthesia (54% and 50%), only 29% of providers with 2 - 10 years of anesthesia experience claimed interest in using them. Distraction from patient care and decreased efficiency were concerns expressed for the use of routine checklist (27% and 31%, respectively). The main factors found to support the successful implementation of checklists into clinical care are ease of use and thoughtful integration into the anesthesia workflow. CONCLUSIONS: Providers at our large academic institution generally embrace the concept of checklists and other cognitive aids. This was true for all providers for checklists for procedural time outs, anesthesia crisis situations and those for routine procedures that providers rarely perform. Only very experienced and very junior providers appreciated the use of checklists for routine care. There remains a discrepancy between these claims and provider's perception on their clinical competency based on memory alone. PMID- 26568922 TI - Implant therapy in oral and maxillofacial fields. PMID- 26568923 TI - Retrospective study on change in pharyngeal airway space and hyoid bone position after mandibular setback surgery. AB - OBJECTIVES: The purpose of this study was to evaluate changes in the pharyngeal airway space and hyoid bone position after mandibular setback surgery with bilateral sagittal split ramus osteotomy (BSSRO) and to analyze the correlation between the amount of mandibular setback and the amount of change in pharyngeal airway space or hyoid bone position. MATERIALS AND METHODS: From January 2010 to February 2013, a total of 30 patients who were diagnosed with skeletal class III malocclusion and underwent the same surgery (BSSRO) and fixation method in the Division of Oral and Maxillofacial Surgery, Department of Dentistry at the Ajou University School of Medicine (Suwon, Korea) were included in this study. Lateral cephalograms of the 30 patients were assessed preoperatively (T1), immediately postoperatively (T2), and 6 months postoperatively (T3) to investigate the significance of changes by time and the correlation between the amount of mandibular setback and the amount of change in the airway space and hyoid bone position. RESULTS: Three regions of the nasopharynx, oropharynx, and hypopharynx were measured and only the oropharynx showed a statistically significant decrease (P<0.01). A significant posterior and inferior displacement of the hyoid bone was found 6 months after surgery (P<0.01). Analysis of the correlation between the amount of mandibular setback and the amount of final change in the airway space and hyoid bone position with Pearson's correlation showed no significant correlation. CONCLUSION: In this study, the oropharynx significantly decreased after mandibular setback surgery, and changes in the surrounding structures were identified through posteroinferior movement of the hyoid bone during long-term follow-up. Therefore, postoperative obstructive sleep apnea should be considered in patients who plan to undergo mandibular setback surgery, and necessary modifications to the treatment plan should also be considered. PMID- 26568924 TI - Volumetric stability of autogenous bone graft with mandibular body bone: cone beam computed tomography and three-dimensional reconstruction analysis. AB - OBJECTIVES: The purpose of this study was to estimate the volumetric change of augmented autobone harvested from mandibular body cortical bone, using cone-beam computed tomography (CBCT) and three-dimensional reconstruction. In addition, the clinical success of dental implants placed 4 to 6 months after bone grafting was also evaluated. MATERIALS AND METHODS: Ninety-five patients (48 men and 47 women) aged 19 to 72 years were included in this study. A total of 128 graft sites were evaluated. The graft sites were divided into three parts: anterior and both posterior regions of one jaw. All patients included in the study were scheduled for an onlay graft and implantation using a two-stage procedure. The dental implants were inserted 4 to 6 months after the bone graft. Volumetric stability was evaluated by serial CBCT images. RESULTS: No major complications were observed for the donor sites. A total of 128 block bones were used to augment severely resorbed alveolar bone. Only 1 of the 128 bone grafts was resorbed by more than half, and that was due to infection. In total, the average amount of residual grafted bone after resorption at the recipient sites was 74.6%+/-8.4%. CONCLUSION: Volumetric stability of mandibular body autogenous block grafts is predictable. The procedure is satisfactory for patients who want dental implants regardless of atrophic alveolar bone. PMID- 26568925 TI - Analysis of time to failure of orthodontic mini-implants after insertion or loading. AB - OBJECTIVES: This study was performed to evaluate patterns of failure time after insertion, failure rate according to loading time after insertion, and the patterns of failure after loading. MATERIALS AND METHODS: A total of 331 mini implants were classified into the non-failure group (NFG) and failure group (FG), which was divided into failed group before loading (FGB) and failed group after loading (FGA). Orthodontic force was applied to both the NFG and FGA. Failed mini implants after insertion, ratio of FGA to NFG according to loading time after insertion, and failed mini-implants according to failed time after loading were analyzed. RESULTS: Percentages of failed mini-implants after insertion were 15.79%, 36.84%, 12.28%, and 10.53% at 4, 8, 12, and 16 weeks, respectively. Mini implant failure demonstrated a peak from 4 to 5 weeks after insertion. The failure rates according to loading time after insertion were 13.56%, 8.97%, 11.32%, and 5.00% at 4, 8, 12, and 16 weeks, respectively. Percentages of failed mini-implants after loading were 13.79%, 24.14%, 20.69%, and 6.9% at 4, 8, 12, and 16 weeks, respectively. CONCLUSION: Mini-implant stability is typically acquired 12 to 16 weeks after insertion, and immediate loading can cause failure of the mini-implant. Failure after loading was observed during the first 12 weeks. PMID- 26568926 TI - A clinical study of emergency room visits for oral and maxillofacial lacerations. AB - OBJECTIVES: This study investigated patients with oral and maxillofacial lacerations who visited the emergency room over a three-year period in an effort to determine the optimal treatment for these injuries. MATERIALS AND METHODS: This study examined 1,742 patients with oral and maxillofacial lacerations with 2,014 different laceration locations who visited the emergency room of Pusan National University Hospital (Busan, Korea) over three years, from January 2011 to December 2013. Patients were classified by sex, age, visit day, cause of injury, injury site, and the presence or absence of soft tissue and tooth injuries. RESULTS: The male to female ratio was 2.50:1. Patients under 10 years old were seen most frequently. Most emergency room visits were on weekends. Among intra-oral lacerations, the lip area was the most vulnerable site; among extra oral lacerations, the chin area was most frequently injured. The most frequent etiology was a slip down. Most lacerations occurred without bone fracture or tooth damage. CONCLUSION: Laceration may differ in large part as compared with the fracture. Therefore, it is necessary to continue collecting data on oral and maxillofacial lacerations to establish optimal emergency room diagnosis and treatment strategies. PMID- 26568927 TI - Analysis of glycosylated hemoglobin (HbA1c) level on maxillofacial fascial space infection in diabetic patients. AB - OBJECTIVES: This study was performed to evaluate the impact of glycosylated hemoglobin (HbA1c) level on characteristics and prognosis of maxillofacial fascial infection in diabetic patients. MATERIALS AND METHODS: We reviewed the medical records of 72 patients (35 patients with HbA1c lower than 7.0% and 37 patients with HbA1c higher than 7.0%) diagnosed with maxillofacial fascial space infection and hospitalized for treatment at the Department of Oral and Maxillofacial Surgery in Dankook University Hospital (Cheonan, Korea) from January 2005 to February 2014. We compared demographics, parameters of glucoregulation (HbA1c), laboratory parameters of inflammation (white blood cell [WBC], C-reactive protein [CRP] count), type and number of involved spaces, type and number of antibiotics, period of hospitalization, number of surgical operations, need for tracheostomy, complications, computed tomography (CT), and microorganisms between the two groups. RESULTS: Compared with the well-controlled diabetes mellitus (DM) group (HbA1c <7.0%), patients in the poorly-controlled (HbA1c >=7.0%) DM group had the following characteristics: longer hospitalization periods, higher values of laboratory parameters of inflammation (WBC, CRP count) at the time of admission, higher number of antibiotics prescribed, more frequent complications, frequent deep neck space involvement, and distinctive main causative microorganisms. As the HbA1c level increases, hospitalization periods and incidence of complications increase gradually. CONCLUSION: This retrospective study suggests that regulation of DM significantly impacts maxillofacial fascial infection. Poorly controlled DM with high HbA1c level negatively influences the prognosis of infection. PMID- 26568928 TI - Conservative condylectomy alone for the correction of mandibular asymmetry caused by osteochondroma of the mandibular condyle: a report of five cases. AB - We describe our experience with conservative condylectomy for the correction of facial asymmetry in five patients with osteochondroma of the mandibular condyle. All five patients presented with malocclusion and facial asymmetry, which are common clinical findings of osteochondroma involving the mandibular condyle. We performed conservative condylectomy without additional orthognathic surgery for all five patients, preserving the vertical height of the condylar process as much as possible. Following surgery, intermaxillary traction using a skeletal anchorage system with rubber elastics was performed on all patients to improve occlusion, and, when necessary, additional minimal orthodontic treatment was performed. The mean follow-up period was 42 months. At the last follow-up visit, all patients exhibited satisfactory facial symmetry and remodeling of the remaining condyle, with stable health and no signs of recurrence. In conclusion, conservative condylectomy alone, without subsequent orthognathic surgery, is adequate for the restoration of facial symmetry and the preservation of vertical condylar height in select patients with condylar osteochondroma. PMID- 26568929 TI - Aplastic anemia and dental implant rehabilitation: a clinical trial. AB - The purpose of this study was to investigate implant-supported restoration as a technique for restoring missing teeth in patients with aplastic anemia. Recurrent bleeding from wound sites leads to persistent release of iron in the tissue. Excessive iron in tissue is related to clinical findings, including fibrosis, poor wound healing, and high level of angiogenesis, which are possible etiological factors of reduced osseointegration. A 44-year-old female patient with aplastic anemia was treated with multiple endosseous implants throughout the mandible and in the posterior region of the maxilla. After 14 implants were placed, radiological and clinical parameters were assessed during the follow-up period. Marginal bone did not change significantly during the follow-up period. The fine trabecular bone in intimate contact and enclosing the implant fixture was sufficient for successful osseointegration. None of the 14 implants were associated with compilations during the seven-year experimental period. This study suggests that dental implant procedures are a safe and reliable treatment option for restoration of missing dentition in patients with aplastic anemia. PMID- 26568930 TI - Deep benign fibrous histiocytoma in the oral cavity: a case report. AB - Benign fibrous histiocytoma (FH) is a benign tumor composed of fibroblasts and histiocytes in varying proportions. This tumor is usually found in adult extremities but rarely occurs in deep soft tissues of the oral cavity. As it is difficult to diagnose with physical and radiologic exams, deep benign FH can only be diagnosed by histopathology. We report a case of a 36-year-old female patient who came to our department with painless swelling in the right buccal mucosa. This case report reviews the clinical, radiological, and histological aspects of this tumor. PMID- 26568931 TI - Primary oral soft tissue angiosarcoma of the cheek: a case report and literature review. AB - Angiosarcoma is a rare and aggressive malignant tumor that has a poor prognosis. It represents less than 1% of all malignancies occurring in the oral cavity and salivary glands. We present a 35-year-old male with angiosarcoma of the cheek following traumatic injury and a review of the current literature. PMID- 26568932 TI - Disappearance of a dental implant after migration into the maxillary sinus: an unusual case. AB - Migration of dental implants into the maxillary sinus is uncommon. However, poor bone quality and quantity in the posterior maxilla can increase the potential for this complication to arise during implant placement procedures. The aim of this report is to present a dental implant that migrated into the maxillary sinus and disappeared. A 53-year-old male patient was referred to us by his dentist after a dental implant migrated into his maxillary sinus. The displaced implant was discovered on a panoramic radiograph taken five days before his referral. Using computed tomography, we determined that the displaced dental implant was not in the antrum. There was also no sign of oroantral fistula. Because of the small size of the displaced implant, we think that the implant may have left the maxillary sinus via the ostium. PMID- 26568933 TI - Percutaneous self-injury to the femoral region caused by bur breakage during surgical extraction of a patient's impacted third molar. AB - Extraction of an impacted third molar is one of the most frequently performed techniques in oral and maxillofacial surgery. Surgeons can suffer numerous external injuries while extracting a tooth, with percutaneous injuries to the hand being the most commonly reported. In this article, we present a case involving a percutaneous injury of the surgeon's femoral region caused by breakage of the fissure bur connected to the handpiece during extraction of the third molar. We also propose precautions to prevent such injuries and steps to be undertaken when they occur. PMID- 26568934 TI - Autogenous tooth bone graft block for sinus augmentation with simultaneous implant installation: a technical note. AB - In cases of severe alveolar bone atrophy in the posterior maxillary area, which has only a thin sinus floor, the autogenous tooth bone graft block (ABTB) was used to wrap the implant to enhance its primary stability and osseointegration in the sinus. These cases with four years of clinical follow-up demonstrate the applicability of the ABTB in maxillary sinus membrane elevation to improve the outcomes of implant placement. PMID- 26568935 TI - Early Post Operative Enteral Versus Parenteral Feeding after Esophageal Cancer Surgery. AB - INTRODUCTION: The incidence of malnutrition in hospitalized patients is reported to be high. In particular, patients with esophageal cancer are prone to malnutrition, due to preoperative digestive system dysfunctions and short-term non-oral feeding postoperatively. Selection of an appropriate method for feeding in the postoperative period is important in these patients. MATERIALS AND METHODS: In this randomized clinical trial, 40 patients with esophageal cancer who had undergone esophagectomy between September 2008 and October 2009 were randomly assigned into either enteral feeding or parenteral feeding groups, with the same calorie intake in each group. The level of serum total protein, albumin, prealbumin, transferrin, C3, C4 and hs-C-reactive protein (hs-CRP), as well as the rate of surgical complications, restoration of bowel movements and cost was assessed in each group. RESULTS: Our results showed that there was no significant difference between the groups in terms of serum albumin, prealbumin or transferrin. However, C3 and C4 levels were significantly higher in the enteral feeding group compared with the parenteral group, while hs-CRP level was significantly lower in the enteral feeding group. Bowel movements were restored sooner and costs of treatment were lower in the enteral group. Postoperative complications did not differ significantly between the groups. There was one death in the parenteral group 10 days after surgery due to myocardial infarction. CONCLUSION: The results of our study showed that enteral feeding can be used effectively in the first days after surgery, with few early complications and similar nutritional outcomes compared with the parenteral method. Enteral feeding was associated with reduced inflammation and was associated with an improvement in immunological responses, quicker return of bowel movements, and reduced costs in comparison with parenteral feeding. PMID- 26568936 TI - An Island Flap Technique for Laryngeal Intracordal Mucous Retention Cysts. AB - INTRODUCTION: Mucous retention cysts are a subtype of intracordal vocal cysts that may occur spontaneously or may be associated with poor vocal hygiene, and which require optimal treatment. The objective of this study was to present a new laser-assisted microsurgery technique for treating intracordal mucous retention cysts and to describe the final outcomes. MATERIALS AND METHODS: In this prospective study, we assessed the pre-operative and post-operative acoustic analysis, maximum phonation time (MPT), and voice handicap index (VHI) of four patients with a diagnosis of mucous retention cyst. The island flap technique was applied to all patients without any complications. In this procedure, we favored the super-pulse mode using a 2-W power CO2 laser to remove the medial wall of the cyst, before clearing away the lateral wall margins of the cyst using repeat pulse mode and a 2-W power CO2 laser. Indeed, we maintained the underlying epithelium and lamina propria, including the island flap attached to the vocal ligament. RESULTS: There was a statistically significant improvement in the MPT (pre-op,11.05 s; post-op,15.85 s; P=0.002) and the VHI (pre-operative, 72/120; post-operative,27/120; P=0.001) in all patients. Moreover, jitter and shimmer were refined after surgery, but there was no statistically significant relationship between pre-operative and post-operative data (P=0.071) (P=0.622). In the follow-up period (median, 150 days), there was no report of recurrence or mucosal stiffness. CONCLUSION: The island flap procedure in association with CO2 laser microsurgery appears to be a safe and effective treatment option for intracordal mucous retention cysts, but needs further investigation to allow comparison with other methods. PMID- 26568937 TI - Effects of Oral Gabapentin, Local Bupivacaine and Intravenous Pethidine on Post Tonsillectomy Pain. AB - INTRODUCTION: Tonsillectomy is one of the most common surgeries performed worldwide. Post-operative pain arising from tonsillectomy is one of the earliest complications that can postpone oral nutrition and increase the hospitalization period. Administration of opioids via injection is usually preferred to relieve pain in these patients. However, the side effects of this approach prompted us to seek alternative treatments. In this study, the effectiveness of oral gabapentin is compared with an intravenous (IV) injection of pethidine and a local injection of bupivacaine in the control of pain after tonsillectomy. MATERIALS AND METHODS: This clinical trial was performed on 7-15 year-old patients who were candidates for tonsillectomy at Shahrekord Kashani hospital from 2012-2013. The patients were divided into three groups at random. Group 1 was give 20 mg/kg oral gabapentin 1 hour before anesthesia. In Group 2, 2.5 ml bupivacaine 0.25% was injected into each tonsil bed by a surgeon. In Group 3,1 mg/kg pethidine was injected intravenously after intubation. To assess post-operative pain, the Oucher scale was used in recovery as well as 3,6,12, and 24 hours after surgery. RESULTS: The pain score was lowest in the gabapentin group and highest in the bupivacaine group during the study. The pain score in the gabapentin group was significantly lower than that in the bupivacaine group (P<0.05). No statistically significant difference was found between the pain score of the Pethidine group and that of the Bupivacaine group (P>0.05). CONCLUSION: Gabapentin, with its antihyperalgesic properties and other unknown properties, is a convenient drug for controlling pain following tonsillectomy. PMID- 26568938 TI - Impact of Intravenous Tranexamic Acid on Hemorrhage During Endoscopic Sinus Surgery. AB - INTRODUCTION: Endoscopic sinus surgery is a common procedure performed by otolaryngologists. This study evaluated the efficacy of intravenous (IV) tranexamic acid (TA) on hemorrhage in patients undergoing elective endoscopic sinus surgery (ESS). MATERIALS AND METHODS: The present study was performed in 170 patients scheduled for ESS surgery under general anesthesia in order to examine the effects of IV TA on providing a bloodless surgical field and to evaluate the amount of bleeding. One hundred patients received intravenous TA and 70 patients received placebo. Intraoperative hemorrhage was estimated by the attending anesthesiologist at the end of surgery by accounting for loss of blood and irrigation fluid in a 25 mL-graded suction canister and nasopharyngeal packing (measured weight of packing on the electronic scale). Hemodynamic variables were monitored and coagulation profile was determined. RESULTS: A total of 170 patients (90 male [53%] and 80 female [47%]), mean age 30.54+/-4.14 years, were evaluated. There was a significantly lower bleeding volume in the TA group than in the placebo group (107.7+/-45.1 vs. 189.3+/-51 mL; P<0.001). There was no significant difference between pre- and postoperative hematocrit (38.81+/- 4.20 vs. 36.60+/- 3.35) or pre- and postoperative hemoglobin (12.51+/- 2.5 vs. 11.64+/ 1.9) levels in the TA group (P>0.05). Moreover, the difference between the TA and control groups regarding postoperative hematocrit (34.65+/-4.45 vs. 36.60+/-3.35) and hemoglobin (10.81+/-2.1vs. 11.64+/-1.9) levels was not significant (P>0.05). Vomiting and nausea in the control group was greater than in the control group, but the difference was not significant (P>0.05). We did not detect significant coagulation alterations in the TA group. CONCLUSION: TA significantly decreased hemorrhage without increasing side effects such as alteration in coagulation parameters, hemodynamic changes, and vomiting and nausea. Use of TA can avoid the need for antihypertensive agents to reduce blood loss in ESS. PMID- 26568939 TI - Sudden Sensorineural Hearing Loss; Prognostic Factors. AB - INTRODUCTION: Sudden sensorineural hearing loss (SSNHL) is a frightening and frustrating symptom for the patient as well as the physician. Prognosis is affected by multiple factors including duration of hearing loss, presence of associated vertigo and tinnitus, and co-morbidities such as hypertension and diabetes. MATERIALS AND METHODS: Forty subjects presenting to our department with features of sudden hearing loss were included in the study. Detailed otological history and examination, serial audiometric findings and course of disease were studied. RESULTS: Subjects presenting late (in older age), having associated vertigo, hypertension and diabetes had a significantly lower rate of recovery. CONCLUSION: Only 60-65% of patients experiencing SSNHL recover within a period of 1 month; this rate is further affected by presence of multiple prognostic indicators. PMID- 26568940 TI - Speech Intelligibility of Cochlear-Implanted and Normal-Hearing Children. AB - INTRODUCTION: Speech intelligibility, the ability to be understood verbally by listeners, is the gold standard for assessing the effectiveness of cochlear implantation. Thus, the goal of this study was to compare the speech intelligibility between normal-hearing and cochlear-implanted children using the Persian intelligibility test. MATERIALS AND METHODS: Twenty-six cochlear implanted children aged 48-95 months, who had been exposed to 95-100 speech therapy sessions, were compared with 40 normal-hearing children aged 48-84 months. The average post-implanted time was 14.53 months. Speech intelligibility was assessed using the Persian sentence speech intelligibility test. RESULTS: The mean score of the speech intelligibility test among cochlear-implanted children was 63.71% (standard deviation [SD], 1.06) compared with 100% intelligible among all normal-hearing children (P<0.000). No effects of age or gender on speech intelligibility were observed in these two groups at this range of ages (P>0.05). CONCLUSION: Speech intelligibility in the Persian language was poorer in cochlear implanted children in comparison with normal-hearing children. The differences in speech intelligibility between cochlear-implanted and normal-hearing children can be shown through the Persian sentence speech intelligibility test. PMID- 26568941 TI - Personality Traits in Patients with Subjective Idiopathic Tinnitus. AB - INTRODUCTION: Tinnitus is a common complaint in patients referred to otorhinolaryngology clinics and is a condition where one hears a sound without any distinguishable external acoustic source or electrical stimulus. About 3-30% of adults experience different degrees of tinnitus during their life. This study aims to ascertain and compare personality traits between patients with tinnitus and a control group. MATERIALS AND METHODS: In a case control study, 66 participants were assessed. The case group consisted of 33 patients who suffered from tinnitus for at least two months, in addition to 33 healthy volunteers who were selected among their family (preferably of the same age and sex). A standard demographic questionnaire and an Eyzenck personality questionnaire were filled for both groups. A tinnitus severity index (TSI) questionnaire was only filled for the case group. Data from each group was compared by Mann-Whitney U and Chi Square tests. SPSS V.18 was the selected software. RESULTS: Statistical analysis showed a meaningful difference in neuroticism (P=0.001) and extraversion (P=0.001) between the patients and the controls; however, there was no statistical difference between these groups regarding psychotism. CONCLUSION: Tinnitus can be associated with personality characteristics. This study showed that in patients with tinnitus, neuroticism increases and extraversion decreases. Considering the personality and psychotic traits observed in the patients with tinnitus, psychiatric consultation is recommended. PMID- 26568942 TI - Tracheobronchial Foreign-Bodies in Children; A 7 Year Retrospective Study. AB - INTRODUCTION: Foreign-body aspiration is still considered one of the most important diagnostic and therapeutic issues for physicians. Mortality rates and the prevalence of diseases caused by foreign bodies in the airway are higher in children because of the relatively narrow airway and immature protective mechanisms. The aim of this study was to study the pattern of foreign-body aspiration in the tracheobronchial tree as well as the success rate of rigid bronchoscopy in children admitted to the Amir-al-Momenin Hospital, Rasht during 2007-2014. MATERIALS AND METHODS: In this cross-sectional descriptive study, the required data were collected from the medical reports of all children under the age of 14 years with suspected foreign-body aspiration who were admitted and underwent explorative rigid bronchoscopy from 2007-2014. The data recorded in the checklists were analyzed using SPSS V16. RESULTS: Out of 103 children with suspected foreign-body aspiration, a foreign body was seen in 74 children (71.8%) during bronchoscopy. Among 74 patients with a confirmed aspiration, 73% (54) were males and 27% (20) were females (P=0.68). The average age of the subjects was 34.82+/-33.4 months; 66.2% were aged 1-3 years. The most common complaints (symptoms) of patients were non-productive cough (48.6%), wheezing (44.3%) and respiratory distress (18.6%). The most common physical examination findings were unilateral decreased pulmonary sound (62.3%), generalized wheezing (26.1%), and crackles (17.4%). Sixty-three patients had a suspected history of foreign-body aspiration. The most frequently aspirated foreign bodies were nuts (peanuts). In total, 52.7% of foreign bodies were lodged in the right bronchial tree. In 95.9% of cases, the foreign body was completely extracted by bronchoscope. The majority of cases were admitted more than 24 hours after the occurrence of aspiration, and pneumonia was the most common complication. CONCLUSION: Patient history, especially initial suspicion of aspiration, coughing, wheezing and respiratory distress, can be helpful in the diagnosis of foreign-body aspiration. PMID- 26568943 TI - Repeated Tracheostomy Tube Cuff Rupture Due to Tracheobronchopathia Osteochondroplastica: A Case Report. AB - INTRODUCTION: Tracheobronchopathia osteochondroplastica (TPO) is a rare benign disorder of the lower part of the trachea and the upper part of the main bronchi. CASE REPORT: A case of tracheobronchopathia osteochondroplastica (TPO) diagnosed at the time of intubation in an intensive care unit due to difficulty when advancing the endotracheal tube beyond the vocal cords, is reported. A problem was encountered which had not been reported previously in TPO: repeated cuff rupture at the time of surgical tracheostomy occurred possibly because of bony and cartilaginous tissue located in the tracheal wall. CONCLUSION: In addition to difficulty of intubation, TPO may cause tracheostomy tube cuff rupture, which could be explained due to bonny calcification in the tracheal wall. PMID- 26568944 TI - Atypical Isolated Infections of the Infratemporal Fossa: A Diagnostic Challenge. AB - INTRODUCTION: Atypical infratemporal fossa infections are rare and potentially fatal. CASE REPORT: A case of an aspergillosis localized in the infratemporal fossa and another case of tuberculosis of the infratemporal fossa originating from the maxillary sinus, is described. The first patient was immunocompromised and showed symptoms of facial numbness; whereas the other was an immunocompetent man who complained of trigeminal neuralgia type pain. It was difficult to differentiate between infection and tumour despite the utilization of computed tomography scans and magnetic resonance imaging. CONCLUSION: These cases illustrate the need for a high index of suspicion; in addition to endoscopic confirmation and histopathology to establish precise diagnosis and early intervention. PMID- 26568945 TI - A Rare Case of Aneurysmal Bone Cyst in the Paranasal Sinus. AB - INTRODUCTION: Aneurysmal Bone cysts (ABC) are extremely rare in the head and neck region and even rarer in sinuses. ABC is a benign multicystic mass that is locally-destructive and rapidly expandable. Hemorrhagic fluid content (like in this case) and septated appearance are the characteristic feature of ABC. Established treatment options for ABCs include sclerotherapy, embolization, radiotherapy, simple curettage, surgical excision, or a combination of methods. CASE REPORT: In this article, a 5 year-old boy with a recurrent nasal mass is presented. The patient was finally diagnosed with this rare entity: ABC of the paranasal sinuses. The patient was treated through complete surgical removal. CONCLUSION: ABC can be considered as a rare differential diagnosis of recurrent nasal hemorrhagic mass in a pediatric population. PMID- 26568946 TI - Solitary Fibrous Tumor of the Parotid Gland: A Case Report. AB - INTRODUCTION: Solitary fibrous tumor is a rare, mesenchymal neoplasm that has been reported in numerous sites. Occurrence in the parotid gland is exceedingly rare. CASE REPORT: A 53-year-old man with a 2 cm solitary fibrous tumor of the left parotid gland, that was observed clinically and operatively and thought to be a neoplasm arising from Stensen's duct, is described. A pre-operative CT scan demonstrated a well-circumscribed, solid, avidly-enhancing nodule superficial to the masseter muscle, deep to the platysma, and intimately associated with the parotid duct. Multiple fine needle aspirations yielded scant fibrous tissue and lymphocytes. A superficial parotidectomy was performed. The histopathological and immunohistochemical findings were in keeping with solitary fibrous tumor, fibrous variant, with a low mitotic rate and a peripherally-entrapped parotid duct surrounded by abundant periductal collagen and lymphocytes. At a 2-year follow up, there was no evidence of tumor recurrence or metastasis. CONCLUSION: Solitary fibrous tumor should be suspected in the context of a slow-growing, well circumscribed, solid, avidly-enhancing nodule of the parotid gland. Grossly intimate association with the parotid duct may reflect peripheral entrapment. Fine needle aspirations that predominantly yield collagen without spindle cell clusters should be correlated with clinical and radiological findings, as it is expected in tumor sampling of the fibrous variant. Although solitary fibrous tumor of the parotid gland usually exhibits benign behavior, it is best regarded as potentially malignant. Patient management and follow-up should be tailored to each individual and clinicopathological risk assessment of the recurrent/metastatic potential. PMID- 26568947 TI - WHAT WE HAVE LEARNED FROM EXERCISE AND LIFESTYLE TRIALS TO ALLEVIATE MOBILITY IMPAIRMENT IN OLDER ADULTS. AB - Enhancement of cardiovascular and muscular fitness through exercise and lifestyle interventions is critical to in alleviating mobility impairment in older adults. In this review article, we discuss the current knowledge-base surrounding mobility improvements in seniors following behavioral interventions that use lifestyle modifications involving physical activity and dietary interventions. PMID- 26568948 TI - RAISING AWARENESS ON THE URGENT NEED TO IMPLEMENT FRAILTY INTO CLINICAL PRACTICE. AB - Frailty has been linked to longer hospital stays and increased mortality in hospitalized patients. Frailty was found at the most common condition leading to death, followed by organ failure, cancer, other causes, advanced dementia, and sudden death. Yet despite evidence linking frailty to poor outcomes, frailty is not implemented clinically in most countries. Since many people are not identified as frail, they frequently are treated inappropriately in health care settings. Participants in the international conference on frailty emphasized the importance of raising awareness about frailty among geriatricians, general practitioners, and other primary care providers in order to implement frailty in clinical practice. The following recommendations were agreed upon: 1. Prioritize the identification of frail older persons in community settings, hospitals, and specialty clinics in order to ensure that people with frailty are treated appropriately and have access to interventional studies; 2. Build frailty clinics as a means of providing optimal management of frail elders; 3. Develop intervention programs incorporating physical and cognitive exercise, social support, and nutrition for people in the earliest stages of frailty in order to slow or reverse frailty; 4. Build stronger basic and clinical research programs in order to better understand the underlying causes of frailty, identify therapeutic targets, and develop new treatment strategies. PMID- 26568949 TI - MOBILITY AND FUNCTIONAL OUTCOMES FOR SARCOPENIA TRIALS. PMID- 26568950 TI - Measles may be a Risk Factor for Malignant Brain Tumors. AB - BACKGROUND: A possible risk factor for brain tumor might be measles, since late neurologic sequelae are part of measles pathology. Subacute sclerosing panencephalitis, a devastating neurologic illness, is prone to develop years after measles infection. METHODS: Because measles damage to the brain might increase the risk of brain tumor, we examined the relationship of measles incidence in 1960 and brain tumor incidence in 50 US States and the District of Columbia, 2004-2007. Data on number of cases of measles by state in 1960 are from the Morbidity and Mortality Weekly Report. In 1960 measles was a childhood illness. We calculated measles incidence by obtaining the population of each state from the 1960 US Census and then age adjusting our results to the cumulative percent of the state population under age 21, since this would have been the measles-infected group. Data on the percentage white population by state are from the US Census (www.census.gov). Age-adjusted incidence (to the 2000 US standard population) of brain tumors is from the Central Brain Tumor Registry of the United States 2011 report. RESULTS: There was a significant correlation between 1960 measles incidence and incidence of malignant brain tumors in persons 20 and older in 2004-2007 (r=0.321, p=0.026). Because glioblastoma is more frequent in whites and males, multivariate linear regression was performed with tumor incidence as the dependent variable, measles incidence, percent white population, and sex ratio by state as independent variables. Measles incidence was significantly correlated with malignant brain tumor incidence (beta=0.361, p<0.001) and independent of the effect of race (beta=0.734, p<0.001) and sex ratio m/f (beta=-0.478, p<0.001). There was no correlation of measles incidence with brain tumor incidence in persons younger than 20. CONCLUSION: Inflammation is a critical component of tumor development. The inflammation of measles-induced subacute sclerosing panencephalitis, even subclinical cases, could well promote tumor formation, since many tumors arise from sites of infection, chronic irritation and inflammation. PMID- 26568952 TI - Scattering Intensity and Directionality Probed Along Individual Zinc Oxide Nanorods with Precisely Controlled Light Polarization and Nanorod Orientation. AB - We elucidated the light-matter interaction of individual ZnO NRs with a monochromatic beam of linearly polarized light that scatters elastically from the ZnO NRs by performing forward scattering and back-aperture imaging in a dark field setting. We precisely controlled the electric field vector of the incident light and the NR orientation within the plane of light interaction during both modes of measurement, and spatially resolved the scattering response from different interaction points along the NR long axis. We then discerned, for the first time, the effects of light polarization, analyzer angle, and NR orientation on the intensity and directionality of the optical responses both qualitatively and quantitatively along the length of the single ZnO NRs. We identified distinctive scattering profiles from individual ZnO NRs subject to incident light polarization with controlled NR orientation from the forward dark-field scattering and back-aperture imaging modes. The fundamental light interaction behavior of ZnO NRs is likely to govern their functional outcomes in photonics, optoelectronics, and sensor devices. Hence, our efforts provided much needed insight into unique optical responses from individual 1D ZnO nanomaterials, which could be highly beneficial in developing next-generation optoelectronic systems and optical biodetectors with improved device efficiency and sensitivity. PMID- 26568951 TI - New Insights into the Pathogenesis of IgA Nephropathy. AB - BACKGROUND: IgA nephropathy, a frequent cause of end-stage renal disease, is an autoimmune disease wherein immune complexes consisting of IgA1 with galactose deficient O-glycans (autoantigen) and anti-glycan autoantibodies deposit in glomeruli and induce renal injury. Multiple genetic loci associated with disease risk have been identified. The prevalence of risk alleles varies geographically, highest in eastern Asia and northern Europe, fewer in other parts of Europe and North America, and the least in Africa. IgA nephropathy is diagnosed from pathological assessment of a renal biopsy specimen. Currently, therapy is not disease-targeted but rather is focused on maintaining control of blood pressure and proteinuria, ideally with suppression of angiotensin II. Possible additional approaches differ between countries. Disease-specific therapy as well as new tools for diagnosis, prognosis, and assessment of responses to therapy are needed. SUMMARY: Glycosylation pathways associated with aberrant O-glycosylation of IgA1 and, thus, production of autoantigen, have been identified. Furthermore, unique characteristics of the autoantibodies in IgA nephropathy have been uncovered. Many of these biochemical features are shared by patients with IgA nephropathy and Henoch-Schonlein purpura nephritis, suggesting that the two diseases may represent opposite ends of a spectrum of a disease process. Understanding the molecular mechanisms involved in formation of pathogenic IgA1 containing immune complexes will enable development of disease-specific therapies as well as diagnostic and prognostic biomarkers. KEY MESSAGES: IgA nephropathy is an autoimmune disease caused by glomerular deposition of nephritogenic circulating immune complexes consisting of galactose-deficient IgA1 (autoantigen) bound by anti-glycan autoantibodies. A better understanding of the multi-step process of pathogenesis of IgA nephropathy and the genetic and environmental contributing factors will lead to development of biomarkers to identify patients with progressive disease who would benefit from a future disease-specific therapy. PMID- 26568953 TI - Accelerating Smith-Waterman Alignment for Protein Database Search Using Frequency Distance Filtration Scheme Based on CPU-GPU Collaborative System. AB - The Smith-Waterman (SW) algorithm has been widely utilized for searching biological sequence databases in bioinformatics. Recently, several works have adopted the graphic card with Graphic Processing Units (GPUs) and their associated CUDA model to enhance the performance of SW computations. However, these works mainly focused on the protein database search by using the intertask parallelization technique, and only using the GPU capability to do the SW computations one by one. Hence, in this paper, we will propose an efficient SW alignment method, called CUDA-SWfr, for the protein database search by using the intratask parallelization technique based on a CPU-GPU collaborative system. Before doing the SW computations on GPU, a procedure is applied on CPU by using the frequency distance filtration scheme (FDFS) to eliminate the unnecessary alignments. The experimental results indicate that CUDA-SWfr runs 9.6 times and 96 times faster than the CPU-based SW method without and with FDFS, respectively. PMID- 26568954 TI - Personal Verification/Identification via Analysis of the Peripheral ECG Leads: Influence of the Personal Health Status on the Accuracy. AB - Traditional means for identity validation (PIN codes, passwords), and physiological and behavioral biometric characteristics (fingerprint, iris, and speech) are susceptible to hacker attacks and/or falsification. This paper presents a method for person verification/identification based on correlation of present-to-previous limb ECG leads: I (r I), II (r II), calculated from them first principal ECG component (r PCA), linear and nonlinear combinations between r I, r II, and r PCA. For the verification task, the one-to-one scenario is applied and threshold values for r I, r II, and r PCA and their combinations are derived. The identification task supposes one-to-many scenario and the tested subject is identified according to the maximal correlation with a previously recorded ECG in a database. The population based ECG-ILSA database of 540 patients (147 healthy subjects, 175 patients with cardiac diseases, and 218 with hypertension) has been considered. In addition a common reference PTB dataset (14 healthy individuals) with short time interval between the two acquisitions has been taken into account. The results on ECG-ILSA database were satisfactory with healthy people, and there was not a significant decrease in nonhealthy patients, demonstrating the robustness of the proposed method. With PTB database, the method provides an identification accuracy of 92.9% and a verification sensitivity and specificity of 100% and 89.9%. PMID- 26568955 TI - The Significance of Metastasectomy in Patients with Metastatic Renal Cell Carcinoma in the Era of Targeted Therapy. AB - OBJECTIVE: To investigate the efficacy of surgery in the treatment of metastatic renal cell carcinoma (mRCC) and to identify prognostic factors. METHODS: A single center retrospective study of 96 patients with mRCC from December 2004 to August 2013. RESULTS: The median follow-up time was 45 months. Thirty-one (32.3%) of the patients received complete resection of metastatic sites, 11 (11.5%) of the patients underwent incomplete resection of metastatic sites, and 54 (56.3%) of the patients received no surgery. In the univariate Kaplan-Meier analysis, the median overall survival times of the three groups were 52 months, 16 months, and 22 months, respectively (p < 0.001). The difference in the overall survival time was statistically significant between complete resection and no surgery groups (HR = 0.43, p = 0.009), while there was no significant difference between the incomplete metastasectomy and no surgery groups (HR = 1.80, p = 0.102). According to the multivariate Cox regression analysis, complete metastasectomy (HR = 0.49, p = 0.033), T stage > 3 (HR = 1.88, p = 0.015), disease free interval <12 months (HR = 2.34, p = 0.003), and multiorgan involvement (HR = 2.00, p = 0.011) were significant prognostic factors. CONCLUSION: In the era of targeted therapy, complete metastasectomy can improve overall survival. Complete metastasectomy, T stage > 3, disease free interval <12 months, and multiorgan involvement are independent prognostic factors. PMID- 26568956 TI - Verbal Aggression from Care Recipients as a Risk Factor among Nursing Staff: A Study on Burnout in the JD-R Model Perspective. AB - Among nursing staff, the risk of experiencing violence, especially verbal aggression, is particularly relevant. The present study, developed in the theoretical framework of the Job Demands-Resources model (JD-R), has two main aims: (a) to examine the association between verbal aggression and job burnout in both nurses and nurse's aides and (b) to assess whether job content, social resources, and organizational resources lessen the negative impact of verbal aggression on burnout in the two professional groups. The cross-sectional study uses a dataset that consists of 630 workers (522 nurses and 108 nurse's aides) employed in emergency and medical units. High associations were found between verbal aggression and job burnout in both professional groups. Moderated hierarchical regressions showed that, among nurses, only the job content level resources moderated the effects of the verbal aggression on job burnout. Among nurse's aides, the opposite was found. Some resources on the social and organizational levels but none of the job content level resources buffered the effects of verbal aggression on workers burnout. The study highlights the crucial role of different types of resources in protecting nursing staff from the detrimental effects of verbal aggression on job burnout. PMID- 26568957 TI - Computational Depth of Anesthesia via Multiple Vital Signs Based on Artificial Neural Networks. AB - This study evaluated the depth of anesthesia (DoA) index using artificial neural networks (ANN) which is performed as the modeling technique. Totally 63-patient data is addressed, for both modeling and testing of 17 and 46 patients, respectively. The empirical mode decomposition (EMD) is utilized to purify between the electroencephalography (EEG) signal and the noise. The filtered EEG signal is subsequently extracted to achieve a sample entropy index by every 5 second signal. Then, it is combined with other mean values of vital signs, that is, electromyography (EMG), heart rate (HR), pulse, systolic blood pressure (SBP), diastolic blood pressure (DBP), and signal quality index (SQI) to evaluate the DoA index as the input. The 5 doctor scores are averaged to obtain an output index. The mean absolute error (MAE) is utilized as the performance evaluation. 10-fold cross-validation is performed in order to generalize the model. The ANN model is compared with the bispectral index (BIS). The results show that the ANN is able to produce lower MAE than BIS. For the correlation coefficient, ANN also has higher value than BIS tested on the 46-patient testing data. Sensitivity analysis and cross-validation method are applied in advance. The results state that EMG has the most effecting parameter, significantly. PMID- 26568958 TI - Acoustic Coordinated Reset Neuromodulation in a Real Life Patient Population with Chronic Tonal Tinnitus. AB - PURPOSE: Primary tinnitus has a severe negative influence on the quality of life of a significant portion of the general population. Acoustic coordinated reset neuromodulation is designed to induce a long-lasting reduction of tinnitus symptoms. To test acoustic coordinated reset neuromodulation as a treatment for chronic, tonal tinnitus under real life conditions, an outpatient study "RESET Real Life" was commissioned by ANM GmbH. Herein we present the results of this study. METHODS: In a prospective, open-label, nonrandomized, noncontrolled multicenter clinical study with 200 chronic tinnitus patients, tinnitus questionnaire TBF-12 and Global Clinical Improvement-Impression Scale (CGI-I7) are used to study the safety and efficacy of acoustic coordinated reset neuromodulation. 189 patients completed the last 12-month visit, 11 patients dropped out (8 because of nontreatment related reasons; 2 because tinnitus did not change; and 1 because tinnitus got louder). RESULTS: Acoustic coordinated reset neuromodulation caused a statistically and clinically significant decrease in TBF-12 scores as well as in CGI-I7 after 12 months of therapy under real life conditions. There were no persistent adverse events reported that were related to the therapy. CONCLUSION: The field study "RESET Real Life" provides evidence for safety and efficacy of acoustic coordinated reset neuromodulation in a prospective, open-label, real life setting. PMID- 26568959 TI - Roles of Pyruvate, NADH, and Mitochondrial Complex I in Redox Balance and Imbalance in beta Cell Function and Dysfunction. AB - Pancreatic beta cells not only use glucose as an energy source, but also sense blood glucose levels for insulin secretion. While pyruvate and NADH metabolic pathways are known to be involved in regulating insulin secretion in response to glucose stimulation, the roles of many other components along the metabolic pathways remain poorly understood. Such is the case for mitochondrial complex I (NADH/ubiquinone oxidoreductase). It is known that normal complex I function is absolutely required for episodic insulin secretion after a meal, but the role of complex I in beta cells in the diabetic pancreas remains to be investigated. In this paper, we review the roles of pyruvate, NADH, and complex I in insulin secretion and hypothesize that complex I plays a crucial role in the pathogenesis of beta cell dysfunction in the diabetic pancreas. This hypothesis is based on the establishment that chronic hyperglycemia overloads complex I with NADH leading to enhanced complex I production of reactive oxygen species. As nearly all metabolic pathways are impaired in diabetes, understanding how complex I in the beta cells copes with elevated levels of NADH in the diabetic pancreas may provide potential therapeutic strategies for diabetes. PMID- 26568960 TI - Nonbilayer Phospholipid Arrangements Are Toll-Like Receptor-2/6 and TLR-4 Agonists and Trigger Inflammation in a Mouse Model Resembling Human Lupus. AB - Systemic lupus erythematosus is characterized by dysregulated activation of T and B cells and autoantibodies to nuclear antigens and, in some cases, lipid antigens. Liposomes with nonbilayer phospholipid arrangements induce a disease resembling human lupus in mice, including IgM and IgG antibodies against nonbilayer phospholipid arrangements. As the effect of these liposomes on the innate immune response is unknown and innate immune system activation is necessary for efficient antibody formation, we evaluated the effect of these liposomes on Toll-like receptor (TLR) signaling, cytokine production, proinflammatory gene expression, and T, NKT, dendritic, and B cells. Liposomes induce TLR-4- and, to a lesser extent, TLR-2/TLR-6-dependent signaling in TLR expressing human embryonic kidney (HEK) cells and bone marrow-derived macrophages. Mice with the lupus-like disease had increased serum concentrations of proinflammatory cytokines, C3a and C5a; they also had more TLR-4-expressing splenocytes, a higher expression of genes associated with TRIF-dependent TLR-4 signaling and complement activation, and a lower expression of apoptosis-related genes, compared to healthy mice. The percentage of NKT and the percentage and activation of dendritic and B2 cells were also increased. Thus, TLR-4 and TLR 2/TLR-6 activation by nonbilayer phospholipid arrangements triggers an inflammatory response that could contribute to autoantibody production and the generation of a lupus-like disease in mice. PMID- 26568961 TI - Evaluation of Humoral Immunity to Mycobacterium tuberculosis-Specific Antigens for Correlation with Clinical Status and Effective Vaccine Development. AB - Although tuberculosis remains a major global health problem, Bacille Calmette Guerin (BCG) is the only available vaccine. However, BCG has limited applications, and a more effective vaccine is needed. Cellular mediated immunity (CMI) is thought to be the most important immune response for protection against Mycobacterium tuberculosis (Mtb). However, the recent failure of a clinical trial for a booster BCG vaccine and increasing evidence of antibody-mediated immunity prompted us to evaluate humoral immunity to Mtb-specific antigens. Using Enzyme Linked ImmunoSpot and Enzyme-Linked ImmunoSorbent Assays, we observed less correlation of both CMI and IgG titers with patient clinical status, including serum concentration of C reactive protein. However, IgA titers against Mtb were significantly correlated with clinical status, suggesting that specific IgA antibodies protect against Mtb proliferation. In addition, in some cases, IgA antibody titers were significantly associated with the serum concentration of total albumin, which supports the idea that humoral immunity can be influenced by the nutritional status. Based on these observations, we propose that the induction of humoral immunity should be included as an option in TB vaccine development strategies. PMID- 26568962 TI - Applying the Concept of Peptide Uniqueness to Anti-Polio Vaccination. AB - BACKGROUND: Although rare, adverse events may associate with anti-poliovirus vaccination thus possibly hampering global polio eradication worldwide. OBJECTIVE: To design peptide-based anti-polio vaccines exempt from potential cross-reactivity risks and possibly able to reduce rare potential adverse events such as the postvaccine paralytic poliomyelitis due to the tendency of the poliovirus genome to mutate. METHODS: Proteins from poliovirus type 1, strain Mahoney, were analyzed for amino acid sequence identity to the human proteome at the pentapeptide level, searching for sequences that (1) have zero percent of identity to human proteins, (2) are potentially endowed with an immunologic potential, and (3) are highly conserved among poliovirus strains. RESULTS: Sequence analyses produced a set of consensus epitopic peptides potentially able to generate specific anti-polio immune responses exempt from cross-reactivity with the human host. CONCLUSION: Peptide sequences unique to poliovirus proteins and conserved among polio strains might help formulate a specific and universal anti-polio vaccine able to react with multiple viral strains and exempt from the burden of possible cross-reactions with human proteins. As an additional advantage, using a peptide-based vaccine instead of current anti-polio DNA vaccines would eliminate the rare post-polio poliomyelitis cases and other disabling symptoms that may appear following vaccination. PMID- 26568963 TI - New Insights about Treg and Th17 Cells in HIV Infection and Disease Progression. AB - Treg and Th17 cell subsets are characterized by the expression of specific transcriptional factors and chemokine receptor as well as by secretion of specific cytokine and chemokines. These subsets are important to the differentiation, expansion, homing capacity, and recruitment of several different immune cell populations to the site of infection. Whereas Treg cells maintain self-tolerance and control the activation and expansion of autoreactive CD4(+) T effector cells through an anti-inflammatory response, Th17 cells, in an exacerbated unregulated proinflammatory response, can promote autoimmunity. Despite such apparently opposite functions, Th17 and Treg cells share common characteristics, and their differentiation pathways are interconnected. Recent studies have revealed quite intricate relations between Treg and Th17 cells in HIV infection and progression to AIDS. Considering Treg cells, different subsets were already investigated in the context of HIV infection, indicating a fluctuation in the total number and frequency throughout the disease course. This review focuses on the recent findings regarding the role of regulatory T and Th17 cells in the context of HIV infection, highlighting the importance of the balance between these two subsets on disease progression. PMID- 26568965 TI - Automatic Generation of Validated Specific Epitope Sets. AB - Accurate measurement of B and T cell responses is a valuable tool to study autoimmunity, allergies, immunity to pathogens, and host-pathogen interactions and assist in the design and evaluation of T cell vaccines and immunotherapies. In this context, it is desirable to elucidate a method to select validated reference sets of epitopes to allow detection of T and B cells. However, the ever growing information contained in the Immune Epitope Database (IEDB) and the differences in quality and subjects studied between epitope assays make this task complicated. In this study, we develop a novel method to automatically select reference epitope sets according to a categorization system employed by the IEDB. From the sets generated, three epitope sets (EBV, mycobacteria and dengue) were experimentally validated by detection of T cell reactivity ex vivo from human donors. Furthermore, a web application that will potentially be implemented in the IEDB was created to allow users the capacity to generate customized epitope sets. PMID- 26568964 TI - Peptide-Based Treatment: A Promising Cancer Therapy. AB - Many new therapies are currently being used to treat cancer. Among these new methods, chemotherapy based on peptides has been of great interest due to the unique advantages of peptides, such as a low molecular weight, the ability to specifically target tumor cells, and low toxicity in normal tissues. In treating cancer, peptide-based chemotherapy can be mainly divided into three types, peptide-alone therapy, peptide vaccines, and peptide-conjugated nanomaterials. Peptide-alone therapy may specifically enhance the immune system's response to kill tumor cells. Peptide-based vaccines have been used in advanced cancers to improve patients' overall survival. Additionally, the combination of peptides with nanomaterials expands the therapeutic ability of peptides to treat cancer by enhancing drug delivery and sensitivity. In this review, we mainly focus on the new advances in the application of peptides in treating cancer in recent years, including diagnosis, treatment, and prognosis. PMID- 26568966 TI - Peripheral Blood Mononuclear Cell Gene Expression Remains Broadly Altered Years after Successful Interferon-Based Hepatitis C Virus Treatment. AB - BACKGROUND: Inflammatory gene expression in peripheral blood mononuclear cells (PBMCs) is altered in chronic Hepatitis C Virus (HCV) infection. Duration of changes after pegylated interferon- (peg-IFN-) based HCV treatment is unclear. METHODS: PBMC mRNA expression of 184 inflammatory response genes was analyzed (nCounter GX Human Inflammation Kit, Nanostring) from peg-IFN treatment nonresponders (NR, n = 18), sustained virologic responders (SVR, n = 22), and spontaneous clearers (SC, n = 15). Logistic regression was used for comparison. RESULTS: Median time from last treatment was 2 and 2.7 years in SVR and NR, respectively (p = NS). Mean mRNA counts were significantly different for 42 and 29 genes comparing SVR to SC patients and NR to SC, respectively, and no genes comparing SVR to NR. Differential expression of 24 genes was significantly different in both SVR and NR groups compared to SC. Among these 24 acute and chronic inflammatory cascade genes, significant upregulation was noted for proinflammatory transcription regulators Fos, CEBPB, and MyD88 in SVR and NR compared to SC. HDAC4 was significantly downregulated in SVR and NR compared to the SC group. CONCLUSIONS: PBMC inflammatory gene expression patterns in SVR resemble NR more than SC patients. A generalized inflammatory response persists in PBMCs long after successful peg-IFN treatment for HCV infection. PMID- 26568967 TI - CSF IgA NMDAR antibodies are potential biomarkers for teratomas in anti-NMDAR encephalitis. AB - OBJECTIVE: To evaluate the presence of immunoglobulin A (IgA) subtype of anti NMDA receptor (NMDAR) antibodies (IgA-NMDAR-Abs) in the CSF of patients with immunoglobulin G (IgG)-NMDAR-Ab encephalitis and to describe the potential association with a specific clinical pattern. METHODS: The retrospective analysis for the presence of IgA-NMDAR-Abs in 94 CSF samples from patients with anti-NMDAR encephalitis diagnosed between October 2007 and February 2014 was conducted at the French Reference Centre on Paraneoplastic Neurological Syndrome. This observational study compared 39 patients with both IgA- and IgG-NMDAR-Abs to 55 patients with only IgG-NMDAR-Abs. RESULTS: In the retrospective cohort, 41% of the patients with NMDAR-Ab encephalitis had both CSF IgG- and IgA-NMDAR-Abs. Approximately half of the IgA-NMDAR-Ab-positive patients (18/38, 49%) definitively possessed associated tumors, primarily ovarian teratomas (17/18, 94%), compared with only 5% (3/55) of the patients in the IgA-NMDAR-Ab-negative group (p < 0.001). In the adult female population at risk for ovarian teratoma, the detection of CSF IgA-NMDAR-Ab positivity showed 85% sensitivity, 70% specificity, a 57% positive predictive value, and a 90% negative predictive value for the diagnosis of ovarian teratoma. No other specific clinical features or clinical outcome were associated with CSF IgA-NMDAR-Ab positivity. CONCLUSION: These results suggest that in patients with IgG-NMDAR-Ab encephalitis, CSF IgA NMDAR-Abs could be used as a biological marker for the presence of an ovarian teratoma. PMID- 26568968 TI - Effect of vitamin D on MS activity by disease-modifying therapy class. AB - OBJECTIVE: To determine whether vitamin D status predicts disease activity in patients with multiple sclerosis (MS) taking interferon-beta (IFN), glatiramer acetate (GA), and fingolimod (FTY). METHODS: Participants (n = 324) with relapsing-remitting MS on IFN (96), GA (151), or FTY (77) were identified from the Comprehensive Longitudinal Investigation of MS at Brigham and Women's Hospital (CLIMB) Study at the Partners MS Center. FTY-treated participants were analyzed separately because of differences in selection. Serum vitamin 25(OH)D concentration was adjusted for season. We evaluated the relationship between 25(OH)D tertile and time to relapse or gadolinium-enhancing lesion using a Cox model adjusted for age, sex, and disease duration. RESULTS: Higher 25(OH)D was associated with longer time to the combined endpoint in the overall IFN/GA cohort (p for trend = 0.042; hazard ratio [HR] = 0.77) and in the IFN subgroup (HRIFN = 0.58; p IFN = 0.012), but not in GA-treated participants (p = 0.50; HR = 0.89). For gadolinium-enhancing lesions alone, there was a significant association observed in GA and IFN subgroups, although the effect was more pronounced on IFN (HRGA = 0.57; p GA = 0.039 vs HRIFN = 0.41; p IFN = 0.022). No significant associations were found for relapses. For FTY, higher 25(OH)D was associated with longer survival for the combined endpoint (HRFTY = 0.48; p FTY = 0.016) and for relapses (HRFTY = 0.50; p FTY = 0.046), but not for gadolinium-enhancing lesions. CONCLUSIONS: Disease activity generally improved with higher 25(OH)D, but this study raises the question of effect modification by treatment class. PMID- 26568969 TI - Cerebellar vermis hypermetabolism in opsoclonus myoclonus without onconeural antibodies. PMID- 26568970 TI - 7T MRI in natalizumab-associated PML and ongoing MS disease activity: A case study. AB - OBJECTIVE: To assess the ability of ultra-high-field MRI to distinguish early progressive multifocal leukoencephalopathy (PML) from multiple sclerosis (MS) lesions in a rare case of simultaneous presentation of natalizumab-associated PML and ongoing MS activity. METHODS: Advanced neuroimaging including 1.5T, 3T, and 7T MRI with a spatial resolution of up to 0.08 mm(3) was performed. RESULTS: 7T MRI differentiated between PML-related and MS-related brain damage in vivo. Ring enhancing MS plaques displayed a central vein, whereas confluent PML lesions were preceded by punctate or milky way-like T2 lesions. CONCLUSIONS: Given the importance of early diagnosis of treatment-associated PML, future systematic studies are warranted to assess the value of highly resolving MRI in differentiating between early PML- and MS-induced brain parenchymal lesions. PMID- 26568971 TI - Genetic Creutzfeldt-Jakob disease mimicking chronic inflammatory demyelinating polyneuropathy. PMID- 26568972 TI - Low frequencies of central memory CD4 T cells in progressive multifocal leukoencephalopathy. AB - OBJECTIVES: To assess alterations in the composition of peripheral immune cells in acute progressive multifocal leukoencephalopathy (PML). METHODS: Fresh blood samples from 5 patients with acute PML and 10 healthy controls were analyzed by flow cytometry for naive, central memory and effector memory CD4 and CD8 T cells, B lymphocytes, plasma cells, memory B cells, plasma blasts, and natural killer (NK) cells. The frequency of central memory CD4 T cells was determined longitudinally during the course of PML in 2 patients. RESULTS: The frequencies of naive, central memory and effector memory CD8 T cells, B cells, plasma cells, and NK cells were not altered in patients with PML. In contrast, the frequencies of naive CD4 T cells (p = 0.04) and central memory CD4 T cells (p < 0.00001) were reduced and the frequencies of effector memory CD4 T cells were increased (p = 0.01). Longitudinal analysis showed that this pattern was preserved in a patient with fatal PML outcome and restored in one patient who recovered from PML. CONCLUSIONS: These data indicate that PML is associated with reduced frequencies of peripheral central memory helper T cells but not with alterations in the frequencies of cytotoxic T cell populations, B lymphocytes, plasma cells, or NK cells. PMID- 26568973 TI - Data on individual PCR efficiency values as quality control for circulating miRNAs. AB - This data article contains data related to the research article entitled "Variability in microRNA recovery from plasma: Comparison of five commercial kits, doi:10.1016/j.ab.2015.07.018" Brunet-Vega (2015) [1]. PCR efficiency, along with RNA and cDNA quality, are the most important factors affecting the quality of qPCR results. Constant amplification efficiency in all compared samples is indispensable when relative quantification is used to measure changes in gene expression. An easy way to measure PCR efficiency, without the need of a standard curve, is LinRegPCR software. Individual PCR efficiency can be determined as a part of qPCR quality control. This is especially important when the initial RNA quantity is so low that cannot be accurately quantified, such as in circulating RNA extractions. This data article reports the Cqs and PCR efficiencies of 5 miRNAs quantified in RNA isolated from 4 patients with colorectal cancer (CRC) and 4 healthy donors using five commercially available kits. PMID- 26568974 TI - Survey of socio-economic and contextual factors of households' energy consumption. AB - We present a set of data relating to the investigation of the Tunisian Company of Electricity and Gas (STEG). The census is done on a sample of 3000 electrified households. The questionnaire is divided into three main sections: household socioeconomic status, contextual characteristics related to their housing and technical characteristics of equipments used. The objective of this survey is to achieve a reliable and detailed knowledge on the behavior of household energy consumption, particularly for energy saving behavior. This objective has recently been the subject of a research article Jridi et al. (2015) [2]. PMID- 26568975 TI - Topologies, structures and parameter files for lipid simulations in GROMACS with the OPLS-aa force field: DPPC, POPC, DOPC, PEPC, and cholesterol. AB - In this data article we provide topologies and force field parameters files for molecular dynamics simulations of lipids in the OPLS-aa force field using the GROMACS package. This is the first systematic parameterization of lipid molecules in this force field. Topologies are provided for four phosphatidylcholines: saturated DPPC, mono-cis unsaturated POPC and DOPC, and mono-trans unsaturated PEPC. Parameterization of the phosphatidylcholines was achieved in two steps: first, we supplemented the OPLS force field parameters for DPPC with new parameters for torsion angles and van der Waals parameters for the carbon and hydrogen atoms in the acyl chains, as well as new partial atomic charges and parameters for torsion angles in the phosphatidylcholine and glycerol moieties [1]. Next, we derived parameters for the cis and trans double bonds and the neighboring them single bonds [2]. Additionally, we provide GROMACS input files with parameters describing simulation conditions (md.mdp), which are strongly recommended to be used with these lipids models. The data are associated with the research article "Cis and trans unsaturated phosphatidylcholine bilayers: a molecular dynamics simulation study" [2] and provided as supporting materials. PMID- 26568976 TI - Data set for volumetric and pathological findings of epicardial adipose tissue. AB - This article contains the data regarding clinically-assessed visceral adipose tissue (VAT) area and epicardial adipose tissue (EAT) volume on computed tomography (CT) images and EAT pathology, represented by inflammation and neoangiogenesis, complementing the data reported by Kitagawa et al. [1]. In 45 patients scheduled for cardiac surgery, we studied CT images obtained prior to surgery and the numbers of CD68+ individual macrophages and CD31+ neovessels in EAT samples subsequently obtained during surgery. The data revealed a moderate correlation between VAT area and EAT volume, and a strong correlation between EAT macrophage infiltration and neoangiogenesis. PMID- 26568977 TI - The coordination of unprotonated peptide tertiary structure as a metric of pMHC TCR functional avidity. AB - The coordination difference between the unprotonated tertiary structures of a native (Tax) peptide and a number of its variants - all peptides presented by HLA A201 and bound to the human A6 T cell receptor-was discovered to constitute a metric of pMHC-TCR functional avidity. Moreover, increasing coordination deviations from the index were found to flag correspondingly weakening immunological outcomes of the variant peptides. The prognostic utility of the coordination difference of unprotonated tertiary structure was established to operate strictly on the peptide scale, seizing to be of relevance either to the immediate peptide environment (i.e. within the realm of peptide short range order, within 7 A of any peptide atom) or over the entirety of the pMHC-TCR complex. Additionally, the imprint of peptide immunological identity was expressed both by the total coordination as well as by its C-C partial. PMID- 26568978 TI - Pollen loads of eucalypt and other pollen types in birds in NW Spain. AB - Here we present the amount of pollen of eucalypt and pollen of other types for birds captured in two bird ringing stations for 14 months (March 2014 to April 2015) in NW Spain. Common and latin names of all birds species captured, together with the number of captured individuals (N), prevalence of eucalypt pollen (percentage of individuals with eucalypt pollen) and of pollen of other types and average pollen loads per individual for eucalypt and other pollen types is presented. See [1] for further information and discussion. PMID- 26568979 TI - Data from a cross-sectional study on Apolipoprotein E (APOE-epsilon4) and snoring/sleep apnea in non-demented older adults. AB - In the present data, we provide the details of the cross-sectional study, from the Washington Heights-Inwood Community Aging Project (WHICAP) that examined the association between Apolipoprotein E (APOE-epsilon4) and snoring/sleep apnea. A total of 1944 non-demented older adults constituted our sample. Sleep dysfunction was measured using sleep categories derived from the Medical Outcomes Study Sleep Scale. Stratified analyses were conducted in order to examine the association between APOE-epsilon4 and sleep variables by ethnic group. For further analyses and enhanced discussion, see "Examining the association between Apolipoprotein E (APOE) and self-reported sleep disturbances in non-demented older adults" by Tsapanou et al. (2015) [1]. PMID- 26568980 TI - Expression of biomarker genes of differentiation in D3 mouse embryonic stem cells after exposure to different embryotoxicant and non-embryotoxicant model chemicals. AB - There is a necessity to develop in vitro methods for testing embryotoxicity (Romero et al., 2015) [1]. We studied the progress of D3 mouse embryonic stem cells differentiation exposed to model embryotoxicants and non-embryotoxicants chemicals through the expression of biomarker genes. We studied a set of 16 different genes biomarkers of general cellular processes (Cdk1, Myc, Jun, Mixl, Cer and Wnt3), ectoderm formation (Nrcam, Nes, Shh and Pnpla6), mesoderm formation (Mesp1, Vegfa, Myo1e and Hdac7) and endoderm formation (Flk1 and Afp). We offer dose response in order to derive the concentration causing either 50% or 200% of expression of the biomarker gene. These records revealed to be a valuable end-point to predict in vitro the embryotoxicity of chemicals (Romero et al., 2015) [1]. PMID- 26568981 TI - Estimation of Symmetric Channels for Discrete Cosine Transform Type-I Multicarrier Systems: A Compressed Sensing Approach. AB - The problem of channel estimation for multicarrier communications is addressed. We focus on systems employing the Discrete Cosine Transform Type-I (DCT1) even at both the transmitter and the receiver, presenting an algorithm which achieves an accurate estimation of symmetric channel filters using only a small number of training symbols. The solution is obtained by using either matrix inversion or compressed sensing algorithms. We provide the theoretical results which guarantee the validity of the proposed technique for the DCT1. Numerical simulations illustrate the good behaviour of the proposed algorithm. PMID- 26568982 TI - Development of a Multiparametric Voxel-Based Magnetic Resonance Imaging Biomarker for Early Cancer Therapeutic Response Assessment. AB - Quantitative magnetic resonance imaging (MRI)-based biomarkers, which capture physiological and functional tumor processes, were evaluated as imaging surrogates of early tumor response following chemoradiotherapy in glioma patients. A multiparametric extension of a voxel-based analysis, referred as the parametric response map (PRM), was applied to quantitative MRI maps to test the predictive potential of this metric for detecting response. Fifty-six subjects with newly diagnosed high-grade gliomas treated with radiation and concurrent temozolomide were enrolled in a single-site prospective institutional review board-approved MRI study. Apparent diffusion coefficient (ADC) and relative cerebral blood volume (rCBV) maps were acquired before therapy and 3 weeks after therapy was initiated. Multiparametric PRM (mPRM) was applied to both physiological MRI maps and evaluated as an imaging biomarker of patient survival. For comparison, single-biomarker PRMs were also evaluated in this study. The simultaneous analysis of ADC and rCBV by the mPRM approach was found to improve the predictive potential for patient survival over single PRM measures. With an array of quantitative imaging parameters being evaluated as biomarkers of therapeutic response, mPRM shows promise as a new methodology for consolidating physiologically distinct imaging parameters into a single interpretable and quantitative metric. PMID- 26568983 TI - The Impact of Sources of Variability on Parametric Response Mapping of Lung CT Scans. AB - Parametric response mapping (PRM) of inspiration and expiration computed tomography (CT) images improves the radiological phenotyping of chronic obstructive pulmonary disease (COPD). PRM classifies individual voxels of lung parenchyma as normal, emphysematous, or nonemphysematous air trapping. In this study, bias and noise characteristics of the PRM methodology to CT and clinical procedures were evaluated to determine best practices for this quantitative technique. Twenty patients of varying COPD status with paired volumetric inspiration and expiration CT scans of the lungs were identified from the baseline COPD-Gene cohort. The impact of CT scanner manufacturer and reconstruction kernels were evaluated as potential sources of variability in PRM measurements along with simulations to quantify the impact of inspiration/expiration lung volume levels, misregistration, and image spacing on PRM measurements. Negligible variation in PRM metrics was observed when CT scanner type and reconstruction were consistent and inspiration/expiration lung volume levels were near target volumes. CT scanner Hounsfield unit drift occurred but remained difficult to ameliorate. Increasing levels of image misregistration and CT slice spacing were found to have a minor effect on PRM measurements. PRM derived values were found to be most sensitive to lung volume levels and mismatched reconstruction kernels. As with other quantitative imaging techniques, reliable PRM measurements are attainable when consistent clinical and CT protocols are implemented. PMID- 26568985 TI - Health care practitioners' opinions about traditional healing. AB - The World Health Organisation (WHO) has been encouraging governments to assume an active role in recruiting traditional healers to be part of primary health care. However, studies in many parts of the world have reported mixed results regarding health care practitioners' opinions of traditional healing. This study aimed to investigate South African-based western-trained health care practitioners' opinions about traditional African healing. Three hundred and nineteen health care practitioners participated in this study. Participants were conveniently sampled from state hospitals and clinics in two provinces in South Africa, namely Limpopo and Gauteng. The study used the Opinions of Traditional Healing Questionnaire for data collection. Results of the Kruskal-Wallis Test revealed a significant difference in opinions of traditional healing across the four categories of health care practitioners [Psychiatrists (n = 25), Physicians (n = 37), General nurses (n = 168) and Psychiatric nurses (n = 89)], X2 (3, n = 319) = 9.45, p = 0.024. The results revealed that health care practitioners working with psychiatric conditions had more positive opinions than general physicians and general nurses. By implication, if South Africa were to investigate the integration of traditional healers into primary health care, as the WHO proposes, psychiatric services and institutions would be the first logical contact for optimal integration. PMID- 26568984 TI - The Microbiome and Cancer: Is the 'Oncobiome' Mirage Real? AB - Investigations focused on the interplay between the human microbiome and cancer development, herein termed the 'oncobiome', have been growing at a rapid rate. However, these studies to date have primarily demonstrated associative relationships rather than causative ones. We pose the question of whether this emerging field of research is a 'mirage' without a clear picture, or truly represents a paradigm shift for cancer research. We propose the necessary steps needed to answer crucial questions and push the field forward to bring the mirage into a tangible reality. PMID- 26568986 TI - Two-dimensional Enrichment Analysis for Mining High-level Imaging Genetic Associations. AB - Enrichment analysis has been widely applied in the genome-wide association studies (GWAS), where gene sets corresponding to biological pathways are examined for significant associations with a phenotype to help increase statistical power and improve biological interpretation. In this work, we expand the scope of enrichment analysis into brain imaging genetics, an emerging field that studies how genetic variation influences brain structure and function measured by neuroimaging quantitative traits (QT). Given the high dimensionality of both imaging and genetic data, we propose to study Imaging Genetic Enrichment Analysis (IGEA), a new enrichment analysis paradigm that jointly considers meaningful gene sets (GS) and brain circuits (BC) and examines whether any given GS-BC pair is enriched in a list of gene-QT findings. Using gene expression data from Allen Human Brain Atlas and imaging genetics data from Alzheimer's Disease Neuroimaging Initiative as test beds, we present an IGEA framework and conduct a proof-of concept study. This empirical study identifies 12 significant high level two dimensional imaging genetics modules. Many of these modules are relevant to a variety of neurobiological pathways or neurodegenerative diseases, showing the promise of the proposal framework for providing insight into the mechanism of complex diseases. PMID- 26568987 TI - Parasitic diseases in humans transmitted by vectors. AB - Despite the considerable progress of medicine, parasitic diseases still pose a great threat to human health and life. Among parasitic diseases, those transmitted by vectors, mainly arthropods, play a particular role. These diseases occur most frequently in the poorest countries and affect a vast part of the human population. They include malaria, babesiosis, trypanosomiasis, leishmaniasis and filariasis. This study presents those vector-transmitted diseases that are responsible for the greatest incidence and mortality of people on a global scale. Attention is focused primarily on diseases transmitted by mosquitoes, flies, Hemiptera and ticks. PMID- 26568988 TI - Pine processionary caterpillar, Thaumetopoea pityocampa Denis and Schiffermuller, 1775 contact as a health risk for dogs. AB - Pine processionary, Thaumetopoea pityocampa Denis and Schiffermuller, 1775 is a moth that belongs to the order of insects Lepidoptera, and family Notodontidae. The larvae of pine processionary moth are the main pest of pines all over the world, but mainly in Mediterranean region. The contact with pine processionary caterpillar (lepidopterism) can produce a strong inflammatory reaction on skin and mucous membranes. Other findings include hyperthermia, tachypnoea, respiratory distress, cyanosis and tongue oedema, labial angioedema, ptyalism, bilateral submandibular lymphadenomegaly, conjunctivitis and severe tongue necrosis. Tough, few veterinary cases have been published. Also in Poland pine processionary moth (Thaumetopoea pinivora) is present, especially near the Baltic coast and can be a possible health risk for both humans and animals (especially dogs). The aim of this article is to increase knowledge about the clinical manifestations of pine processionary caterpillar contact, which may be useful for diagnosis of this dangerous disease. PMID- 26568989 TI - Analysis of study comprehensiveness for nematode fauna of hydrophilic birds in Ukrainian Polissya. AB - The fauna of helminths of hydrophilic birds was subject of many works in Ukraine. But the most of investigators dealt with helminth fauna of waterfowls in general. And only few works were dedicated to the parasitic nematodes. There are registered 81 species of helminths on Ukraine and 36 species of nematode of hydrophilic bird for Polissya (23 species for Belarus. 15 for Poland and 18 for Ukraine). As well it was compared lists of parts of Polissya between itself. The comprehension of the parasitic nematodes from different part of Polissya showed that 6 species of nematodes are common for whole Polissya: Eucoleus contortus, Amidostomum anseris, Echinuria uncinata, Porrocaecum crassum, Porrocaecum semiteres and Tetrameres fissispina. Further studies are necessary to increase our knowledge on biodiversity of the parasitic nematodes in waterfowls and clear up their taxonomic status. PMID- 26568990 TI - Consumption of sweetened beverages as a risk factor of colonization of oral cavity by fungi - eating habits of university students. AB - Foods rich in sugar are an excellent substrate for the microorganisms that inhabit the initial sections of the gastrointestinal tract, and one of the most commonly available sources of sugar is the sweetened drink. Students represent an interesting sub-population; the large number of classes and associated stress levels promote fixing of unhealthy behaviors, e.g. tendency to consume a lot of sweetened drinks, for example cola-type or energetic drinks. Aim of this study was to determine the relationship between the amount of sugar consumed in beverages and the prevalence of fungi in the oral cavity. The investigated material consisted of oral washings. Participants completed original questionnaire regarding beverages consumed. The relationship between the consumption of sweetened beverages and risk of the presence of fungi in the oral cavity was determined. Fungi were isolated from 68.1% of examined subjects. Seven species of the genus Candida were observed. Higher prevalence of fungi was seen in the oral cavity of subjects who declared consumption of beverages containing sugar. 37.8% of respondents were found to consume with beverages doses of sugar exceeding the recommended daily requirement. Significantly greater prevalence of oral cavity fungi was noted in those exceeding the recommended GDA (76.3%), compared to of those who were not (68.7%). There were positive correlations between occurrence of fungi and consumption of sweetened carbonated drinks or adding sugar to coffee and tea. The addition of sugar to coffee/tea and sugar consumption above the recommended daily amount significantly increases the risk of colonization of the oral cavity by fungi. Students, due to invalid nutritional habits especially excessive consumption of beverages containing large amounts of sugar, belong to a group with a predisposition to the occurrence of fungi in the oral cavity. PMID- 26568991 TI - Molecular detection of Ehrlichia canis, Hepatozoon canis and Babesia canis vogeli in stray dogs in Mahasarakham province, Thailand. AB - Canine tick borne diseases showing distribution worldwide have caused morbidity and mortality in dogs. This study observed the mainly tick borne pathogens described for dogs in Thailand, Ehrlichia canis, Hepatozoon canis and Babesia canis vogeli. From May to July 2014, blood samples were collected from 79 stray dogs from 7 districts of Mahasarakham province to molecular surveyed for 16s rRNA gene of E. canis and 18s rRNA gene of H. canis and B. canis vogeli. Twenty eight (35.44%) of stray dogs showed the infection with tick borne pathogens. The prevalence of E. canis infection was the highest with 21.5% (17/79). DNA of H. canis and B. canis vogeli were detected at the prevalence of 10.1% (8/79) and 6.3% (5/79), respectively. Co-infection between E. canis and B. canis vogeli were identified in 2 (2.5%) dogs. The results indicated that a wide range of tick borne pathogens are circulation in the canine population in Mahasarakham province. This study is the first report on prevalence of E. canis, H. canis and B. canis vogeli in stray dogs in Mahasarakham, a province in northern part of Thailand. This data providing is important to understand the prevalence of E. canis, H. canis and B. canis vogeli infection in stray dogs in this region, which will assist in the management of these blood parasite. PMID- 26568992 TI - Estimation of infection of internal parasites in horses from different type of farms. AB - Studies were carried out in year 2014 during the pasture period (from April to October) in Warmia and Mazury Region. Fecal samples were taken from cold- and warmblood horses from individual and agrotouristic farms with the different housing, feeding and pasture- care practices. Total of 512 horses were examined (320 mares, 170 geldings and 22 stallions). In the group of 185 horses from individual farms, 119 animals (64.3%) were infected with gastro-intestinal parasites. Among the 372 horses from agrotouristic farms 169 (51.7%) were infected with parasites. Most of the animals expelled the eggs of Cyathostominae. In some individuals occurred eggs of Strongylus spp., Parascaris equorum, Strongyloides westeri and tapeworm of Anoplocephala. The number of infected horses from agrotouristic farms was lower than from individual farms, probably due to more regular deworming (usually 2 times a year) and bigger care paid to cleaning pastures. PMID- 26568993 TI - Isolated primary orbital hydatid disease presenting as multiple cystic lesions: a rare cause of proptosis. AB - Echinococcal infection is a consequence of accidental ingestion of tapeworm eggs by humans. Liver scrutinises the initial haematogenous spread of portal blood and thus it is the most common organ involved. Isolated, primary involvement of other organs is a rarity. We describe a case of isolated orbital hydatid disease. To further add to the uniqueness of our case, two hydatid cysts were seen in our patient. The patient presented with unilateral proptosis with vision loss of the left eye since 6 months. Radiological imaging revealed two intraconal cystic lesions in the left eye. The chest radiography, abdominal sonogram and serology were negative for echinococcal disease. Surgical removal of the cysts was performed via lateral oribitotomy approach. Definitive diagnosis of Echinococcus was established on histopathology. The patient received post-operative albendazole therapy for 12 weeks. At 10 months' follow-up there was no recurrence or evidence of hydatid disease elsewhere. PMID- 26568994 TI - Cutaneous leishmaniasis mimicking granulomatous cheilitis and treated successfully with oral fluconazole in a boy. AB - Cutaneous leishmaniasis is a protozoan infectious disease and widespread in Mediterranean basin including Turkey. Lesions usually start with erythematous papules, gradually enlarges and afterwards it ulcerates. We present a 12-year-old boy with diffuse persistent lip swelling mimicking granulomatous cheilitis. Systemic glucantime was started. However, severe hypotension and bradycardia was developed after injection. Oral fluconazole was started and the lesion resolved completely. Cutaneous leishmaniasis can have varied clinical manifestations and should be suspected especially in endemic areas. Oral fluconazole seems to be safe and effective treatment modality in paediatric cases. PMID- 26568995 TI - Doctor Jacek Lachowicz DVM, PhD (1951-2015). PMID- 26568996 TI - [Multidisciplinary treatment in orthodontics]. PMID- 26568997 TI - [Dentistry in the Middle Ages in the low lands 10. "Vander siecheit der tonghe"]. PMID- 26568998 TI - [Combined orthodontic and restorative treatment]. AB - In patients with agenesis or enamel anomalies in anterior teeth combined orthodontic and restorative treatment is often necessary to achieve an optimal aesthetic result. How both can best be achieved, but also how to maintain the result, requires communication between the dentist and the orthodontist. The orthodontic treatment plan needs to be established in cooperation with the dentist who will carry out the restorative treatment while the patient is at a young age. Since with these young patients, who are still growing craniofacially and whose teeth are still developing, possible future restorative and/or orthodontic treatment, as well as the means of orthodontic retention, need to be included in the treatment plan. In cleft palate patients, it is also important that methods of orthodontic retention of maxillary arch width are given timely attention in the restorative treatment plan because it is especially vulnerable to relapse. PMID- 26568999 TI - [Orthodontic extrusion preliminary to implantology in the -aesthetic zone]. AB - The replacement of a missing tooth in the aesthetic zone by a dental implant is, in many respects, a challenge. In order to restore and maintain bone and soft tissue, various procedures are used varying from the immediate placement of a front tooth implant with minimal tissue grafts to an extensive treatment programme with bone grafting, possibly in combination with connective tissue grafts. Another treatment option is orthodontic extrusion. This procedure makes it possible for bone and soft tissue to be created both horizontally and vertically, as a result of which loss of vertical binding can be compensated and the primary stability of the implant can be guaranteed. The procedure for orthodontic extrusion is described on the basis of a case study. In an interdisciplinary treatment plan, orthodontic extrusion is a viable treatment alternative, which can make the immediate placement of a dental implant in the frontal region possible. PMID- 26569000 TI - [Autotransplants instead of implants? The secret of the periodontal ligament]. AB - Autotransplants are often applied in the Scandinavian countries. The indication for treatment concerns especially young patients for whom teeth with open apices are moved to areas with ageneses. The great advantage is the vital periodontal ligament, by means of which these teeth are able to grow along. In Rotterdam, during the past 11 years, transplants of teeth with fully developed apices have been carried out in cases with comparable indications. Over short and long periods of time, the results have been the same as those in the published findings in the literature. The fully developed apices appear to be just as successful as the open apices. The difference with the results in the research literature concerns the indications for transplantation in particular. These are not limited to the molar region. Within the same indication, the results are better by comparison with the implants, in both the transplants with open and with closed apices. On the basis of these results, autotransplants in dentistry have become an indication for every age group and when possible, a better treatment option than implants. PMID- 26569001 TI - [Mandibular advancement: bilateral sagittal split versus -distraction osteogenesis]. AB - In the 1990s intra-oral distraction osteogenesis (DO) became available as an alternative for bilateral sagittal splitosteotomy (BSSO) for advancement of the mandible. It was thought that DO would lead to more stability in the results and fewer neurosensory disturbances of the inferior alveolar nerve. However, there was no scientific evidence for this assumption. This article describes a number of recently published, prospective studies that demonstrate that BSSO is not inferior to DO with respect to stability and neurosensory disturbances of the inferior alveolar nerve. They also demonstrate that BSSO leads to less pain in patients and to lower total costs. It can be concluded that BSSO should be considered the standard therapy for mandibular advancement up to 10 mm in non syndromal patients. PMID- 26569002 TI - [Gingival recessions and orthodontics]. AB - Gingival recessions represent the most visible periodontal disease. The prevalence of gingival recessions is high. The root surface is literally exposed to negative influences such as erosion, abrasion, discoloration and decay. Moreover, gingival recessions can affect the quality of life by increased thermal sensitivity and reduced dento-gingival aesthetics. The aetiology of gingival recessions is complex and considered to be multifactorial. In order to prevent the development of gingival recessions during and after orthodontic treatment, several factors should be taken into account, among which maintenance of optimal oral hygiene and respect for the 'biological envelope' are decisive. Once gingival recessions have developed, orthodontic therapy can play a positive role in their treatment. PMID- 26569003 TI - [Gingival recessions and periodontal plastic surgery]. AB - Periodontal plastic surgery is defined as the set of surgical procedures that are performed to prevent or correct developmental disorders and anatomical, traumatic and pathological abnormalities of the gingiva, alveolar mucosa, and alveolar bone. Root coverage procedures fall under this term and have been applied for more than fifty years with varying degrees of success. There are several indications for the treatment of gingival recessions. When the treatment of choice - a conservative approach - offers no solace (any more), gingival recessions can be treated by applying periodontal plastic surgery. The goal of this surgery is complete recovery of the anatomical structures in the area of the recession. To this end several surgical techniques have been developed during the last decades. The choice of a particular technique depends on various factors, such as the number of defects, their size and the amount of keratinized gingiva around the defect. PMID- 26569004 TI - [Accelerated orthodontic treatment]. AB - An orthodontic treatment usually involves a long process which often represents an obstacle for patients. To overcome this problem, surgical techniques have been developed to support and accelerate the orthodontic treatment. Two systematic reviews of the literature on clinical research and animal experiments were carried out in order to draw reliable conclusions about the effectiveness of the various surgical techniques. A total of 18 clinical studies and 22 animal experimental studies were analysed. In both reviews of the literature, a study was made of whether the surgical techniques resulted in an accelerated rate of tooth movement and which complications may be observed. In addition, which biological mechanisms take place during surgically facilitated orthodontics was investigated. Both reviews reported accelerated tooth movement with minimal complications after surgical procedures in comparison to conventional orthodontics. An increase in catabolic and anabolic activities was observed. It has to be concluded that based on the quality of the current literature there is still insufficient information for general conclusions and that more standardised prospective research is necessary for a reliable conclusion about the optimal method of treatment. PMID- 26569005 TI - [Interdisciplinary orthodontic surgical treatment of children with cleft lip and palate from 9 to 20 years of age]. AB - Cleft lip and palate is a common congenital malformation with a prevalence of 1:600 newborns. Children with orofacial clefts are treated by an interdisciplinary team of specialists while parents and child play a key role in their own care process. The orthodontic and facial orthopedic treatment of a child with a cleft takes many years. Children often get bored of the long treatment and this can cause problems with compliance and oral hygiene. Therefore it is advisable to distinguish 5 well-defined stages in the orthodontic treatment and to attempt to have some 'orthodontics free' time in between. The 3 orthodontic treatment phases between the age of 9 and 20 years consist of orthodontic treatment concerning the closing of the cleft with a bone transplant, the treatment of the permanent dentition and, finally, a possible combined orthodontic surgical treatment at the end of the period of growth. Good interdisciplinary collaboration among the different dental disciplines is essential in this regard. PMID- 26569006 TI - Identifying the most important outcomes for systematic reviews of interventions for rhinosinusitis in adults: working with Patients, Public and Practitioners. AB - INTRODUCTION: Promoting the assessment of health interventions using outcomes that matter to patients and practitioners is a key principle of Cochrane. Cochrane UK therefore commissioned the OMIPP project: Outcomes that are Most Important for Patients, Public and Practitioners to identify the outcomes they felt most important and should be evaluated in Cochrane reviews of health interventions for Chronic Rhinosinusitis (CRS). METHODOLOGY: Using direct emailing, social media and printed cards, an online survey was distributed to a wide range of people involved in the care of patients with CRS. Patients and practitioners were asked to list the 3 outcomes from treatments most important to them. Responses were analysed through development of a thematic framework based on the data. RESULTS: Two hundred and thirty-five people completed the survey; 155 practitioners and 80 patients. Respondents provided 653 suggestions of important outcomes. 73% concerned symptoms of CRS, (nasal discharge or drip, facial pain, nasal blockage, headache, impaired sense of smell, congestion and breathing difficulties); 9% concerned quality of life, 4% reducing the need for further treatment and 4% side effects of treatment. Objective measurements of disease formed only 3% of responses. There was high level of agreement between patients and practitioners. Of 10 current Cochrane reviews on CRS, 9 include symptomatic outcomes identified by our survey as most important to patients and healthcare practitioners. CONCLUSIONS: We have identified outcomes that both patients and their doctors consider should be included in reviews evaluating treatments of rhinosinusitis. We recommend that primary outcomes in future reviews focus on symptom-based outcomes. The ability to extract these data from relevant trials is dependent upon their inclusion in trials, and so it is important that building on this work a core outcome set for rhinosinusitis research is developed. PMID- 26569007 TI - [Dopamine neurotransmission of peripheral blood lymphocytes is a potential biomarker of psychiatric and neurological disorders]. AB - Current literature on a role of dopamine in the development of mental and neurological disorders suggests that the discovery of endogenous dopamine in peripheral blood lymphocytes gave rise to a new line of research. Dopamine receptors are not only found on cells of the innate immune response (nonspecific), but also on cells of adaptive immune response (specific): T and B lymphocytes. These facts bring a new evidence of interrelationships between the peripheral immune system, neuroinflammation and neurodegeneration and suggest new ways for investigation of the pathogenesis of different mental and neurological disorders, in particular Parkinson's disease, Alzheimer's disease and schizophrenia. There is strong evidence that ligands of dopamine receptors can change the expression of coding genes both in central neurons and in peripheral cells. Thus, peripheral blood lymphocytes may prove a cellular tool to identify dopamine transmission disturbances in neuropsychiatric diseases, as well as to monitor the effects of pharmacological treatment. PMID- 26569008 TI - [Metastatic testicular melanoma. Case report]. AB - A 33 year-old male, who five years earlier was operated for a nodular melanoma in vertical growth phase of 1.5mm thick (Breslow), Clark II-III, presented to the Emergency department with a progressive increase of the left testicle. Ultrasound scan examination revealed a 2 x 2 cm solid mass in the left testis, with normal right testis.With the diagnosis of testicular neoplasm, we requested Alpha fetoprotein and beta HCG levels, and patient underwent radical orchiectomy. PMID- 26569009 TI - [RIGHT VARICOCELE AS FINDING OF RIGHT RENAL MASS]. AB - Abdominal and scrotal ultrasounds were requested and, in order of the findings watched they were complemented with an abdominal contrast enhanced CT scan (CECT). The CETC demonstrated a large right renal tumor sized 12 cm located in the upper pole of the right kidney, in contact with hepatic parenchyma (Figure 1). Renal vein and artery were not affected. Important peritumoral collateral circulation was noticed. Consequently to the large tumor size and extrinsic compression, there was dilatation of right spermatic vein. Both Collateral circulation and right spermatic dilated vein converged in the inguinal duct explaining the presence of right varicocele. The image was 3D reconstructed. PMID- 26569010 TI - [An antinociceptive effect of chondroprotectors: a myth or a reality?]. AB - Authors reviewed the literature on the efficacy of chondroprotectors in the treatment of chronic pain syndromes in comparison with placebo and other analgesics to discover the own antinociceptive effect of these drugs and mechanisms by which it occurs. Authors evaluated the results of various clinical studies on the effect of symptomatic slow-acting drugs for osteoarthritis (SYSADOA) on chronic pain syndrome in osteoarthritis and low back pain. We compared their effects with those of NSAIDs, celecoxib, or placebo. Assessment of pain and functional status was performed using WOMAC, VASandLeken's index as well as the Roland--Morrisquality of life questionnaire. The review of a number of clinical studies revealed a definite antinociceptive and anti-inflammatory effect of SYSADOA comparable with NSAIDs not only in the treatment of osteoarthritis, but also in chronic back pain, which is characterized by early onset and gradual development with a long-term retention of the result even after discontinuation of therapy. It has been shown that SYSADOA are able to reduce the level of inflammatory cytokines in the blood (IL-6, C-reactive protein) and to activate the production of anti-inflammatory cytokine IL-10 in the synovial membrane. It is shown that blocking of the effects of interleukin 1-beta and thereby inhibition of inflammatory enzymes like nitric oxide synthase and cyclooxygenase 2 is one of the points of glucosamine chondrocytes application. The data obtained in numerous studies that confirm the ability of SYSADOA to inhibit proinflammatory cytokines open the new perspectives for their use in the treatment of not only joint pain but also other chronic pain syndromes. PMID- 26569011 TI - Leiomyoma in a very rare location: Bladder. PMID- 26569012 TI - [Not Available]. PMID- 26569013 TI - Mantle cell lymphoma presenting as cardiac tamponade. PMID- 26569014 TI - Rapid evolution of intracranial myeloid sarcoma in 4 weeks: images in blood. PMID- 26569015 TI - Evolution of the violin: The law of effect in action. AB - As is true for most other human inventions, the origin of the violin is unknown. What is known is that this popular and versatile instrument has notably changed over the course of several hundred years. At issue is whether those evolutionary changes in the construction of the violin are the result of premeditated, intelligent design or whether they arose through a trial-and-error process. Recent scientific evidence favors the latter account. Our perspective piece puts these recent empirical findings into a comprehensive selectionist framework. According to this view, the many things we do and make--like violins--arise from a process of variation and selection which accords with the law of effect. Contrary to popular opinion, there is neither mystique nor romance in this process; it is as fundamental and ubiquitous as the law of natural selection. As with the law of natural selection in the evolution of organisms, there is staunch resistance to the role of the law of effect in the evolution of human inventions. We conclude our piece by considering several objections to our perspective. PMID- 26569016 TI - Transfer of dimensional associability in human contingency learning. AB - Several studies have demonstrated processing advantages for stimuli that were experienced to be reliable predictors of an outcome relative to other stimuli. The present study tested whether such increases in associability apply at the level of entire stimulus dimensions (as suggested by Sutherland & Mackintosh, 1971). In 4 experiments, participants had to learn associations between Gabor gratings and particular responses. In a first experiment, some gratings were more predictive of the response than other gratings, whereas in 3 subsequent experiments, one stimulus dimension (i.e., either the orientation or spatial frequency of the grating) was more predictive than the other dimension. In contrast to the learned predictiveness of individual gratings (Experiment 1), dimensional predictiveness did not affect the subsequent rate of learning (Experiments 2 and 3), suggesting changes in the associability of specific stimuli, but not of stimulus dimensions. Moreover, greater transfer of predictiveness was found in all experiments when particular stimulus values of the test discrimination did not lie between the previously relevant stimuli. In Experiment 4, an increased learning rate was found for discriminations along the previously predictive dimension compared with a dimension that was indicative of uncertainty, but again the transfer was more pronounced for specific stimuli that were compatible with the previously learned discrimination. Taken together, the results imply that a transfer of associability typically applies to individual stimuli and depends on how the transfer stimuli relate to those stimuli that individuals previously learned to attend. PMID- 26569017 TI - Blocking spatial navigation across environments that have a different shape. AB - According to the geometric module hypothesis, organisms encode a global representation of the space in which they navigate, and this representation is not prone to interference from other cues. A number of studies, however, have shown that both human and non-human animals can navigate on the basis of local geometric cues provided by the shape of an environment. According to the model of spatial learning proposed by Miller and Shettleworth (2007, 2008), geometric cues compete for associative strength in the same manner as non-geometric cues do. The experiments reported here were designed to test if humans learn about local geometric cues in a manner consistent with the Miller-Shettleworth model. Experiment 1 replicated previous findings that humans transfer navigational behavior, based on local geometric cues, from a rectangle-shaped environment to a kite-shaped environment, and vice versa. In Experiments 2 and 3, it was observed that learning about non-geometric cues blocked, and were blocked by, learning about local geometric cues. The reciprocal blocking observed is consistent with associative theories of spatial learning; however, it is difficult to explain the observed effects with theories of global-shape encoding in their current form. PMID- 26569018 TI - The effect of conditioned inhibition on the specific Pavlovian-instrumental transfer effect. AB - Four experiments examined the effect of Pavlovian conditioned inhibition on specific Pavlovian-instrumental transfer (PIT) in human participants. The task comprised an instrumental phase in which 2 responses (R1, R2) were each paired with 1 of 2 outcomes (O1, O2: R1->O1, R2->O2), and a Pavlovian phase, in which 2 conditioned stimuli (CSs), CS1 and CS2 each signaled 1 of the 2 outcomes (CS1 >O1, CS2->O2). In Experiments 1-2 a conditioned inhibitor, X, predicted the omission of 1 of the outcomes (e.g., CS1->O1, CS1X->nothing). In a subsequent test, performance of R1 and R2 was examined in the presence of CS1 and CS2. A specific PIT effect was observed: R1 was performed more than R2 during CS1, and R2 more than R1 during CS2. This PIT effect was significantly reduced by the presence of the inhibitor X in Experiment 1, in which the Pavlovian phase followed the instrumental phase, and in Experiment 2 in which it preceded it. No such effect was observed when X was presented in the absence of any expectation of the outcomes during the PIT test (Experiment 3a), or when X was trained as a signal for an alternative outcome (Experiment 3b). These results are consistent with the suggestion that the specific PIT effect occurs through a stimulus outcome-response (S-O-R) mechanism, according to which the CS evokes a representation of the outcome which in turn elicits the response (e.g., CS1->O1 >R1). The conditioned inhibitor suppresses performance of the response by suppressing activation of the outcome representation. PMID- 26569019 TI - Insights into membrane translocation of the cell-penetrating peptide pVEC from molecular dynamics calculations. AB - Discovery of cargo carrying cell-penetrating peptides has opened a new gate in the development of peptide-based drugs that can effectively target intracellular enzymes. Success in application and development of cell-penetrating peptides in drug design depends on understanding their translocation mechanisms. In this study, our aim was to examine the bacterial translocation mechanism of the cell penetrating pVEC peptide (LLIILRRRIRKQAHAHSK) using steered molecular dynamics (SMD) simulations. The significance of specific residues or regions for translocation was studied by performing SMD simulations on the alanine mutants and other variants of pVEC. Residue-based analysis showed that positively charged residues contribute to adsorption to the lipid bilayer and to electrostatic interactions with the lipid bilayer as peptides are translocated. Translocation takes place in three main stages; the insertion of the N-terminus into the bilayer, the inclusion of the whole peptide inside the membrane and the exit of the N-terminus from the bilayer. These three stages mirror the three regions on pVEC; namely, the hydrophobic N-terminus, the cationic midsection, and the hydrophilic C-terminus. The N-terminal truncated pVEC, I3A, L5A, R7A mutants and scramble-pVEC make weaker interactions with the lipids during translocation highlighting the contribution of the N-terminal residues and the sequence of the structural regions to the translocation mechanism. This study provides atomistic detail about the mechanism of pVEC peptide translocation and can guide future peptide-based drug design efforts. PMID- 26569020 TI - Psychological Basis of the Relationship Between the Rorschach Texture Response and Adult Attachment: The Mediational Role of the Accessibility of Tactile Knowledge. AB - This study clarifies the psychological basis for the linkage between adult attachment and the texture response on the Rorschach by examining the mediational role of the accessibility of tactile knowledge. Japanese undergraduate students (n = 35) completed the Rorschach Inkblot Method, the Experiences in Close Relationship Scale for General Objects (Nakao & Kato, 2004) and a lexical decision task designed to measure the accessibility of tactile knowledge. A mediation analysis revealed that the accessibility of tactile knowledge partially mediates the association between attachment anxiety and the texture response. These results suggest that our hypothetical model focusing on the response process provides a possible explanation of the relationship between the texture response and adult attachment. PMID- 26569021 TI - Unique Fe2P Nanoparticles Enveloped in Sandwichlike Graphited Carbon Sheets as Excellent Hydrogen Evolution Reaction Catalyst and Lithium-Ion Battery Anode. AB - The novel Fe2P nanoparticles encapsulated in sandwichlike graphited carbon envelope nanocomposite (Fe2P/GCS) that can be first applied in hydrogen evolution reaction (HER) as well as lithium-ion batteries (LIBs) has been designed and fabricated. The unique sandwiched Fe2P/GCS is characterized with several prominent merits, including large specific surface area, nanoporous structure, excellent electronic conductivity, enhanced structural integrity and so on. All of these endow the Fe2P/GCS with brilliant electrochemical performance. When used as a HER electrocatalyst in acidic media, the harvested Fe2P/GCS demonstrates low onset overpotential and Tafel slope as well as particularly outstanding durability. Moreover, as an anode material for LIBs, the sandwiched Fe2P/GCS presents high specific capacity and excellent cyclability and rate capability. As a consequence, the acquired Fe2P/GCS is a promising material for energy applications, especially HER and LIBs. PMID- 26569022 TI - Allosteric Modulation of Alpha7 Nicotinic Receptors: Mechanistic Insight through Metadynamics and Essential Dynamics. AB - Increasing attention has recently been devoted to allosteric modulators, as they can provide inherent advantages over classic receptor agonists. In the field of nicotinic receptors (nAChRs), the main advantage is that allosteric modulators can trigger pharmacological responses, limiting receptor desensitization. Most of the known allosteric ligands are "positive allosteric modulators" (PAMs), which increase both sensitivity to receptor agonists and current amplitude. Intriguingly, some allosteric modulators are also able to activate the alpha7 receptor (alpha7-nAChR) even in the absence of orthosteric agonists. These compounds have been named "ago-allosteric modulators" and GAT107 has been studied in depth because of its unique mechanism of action. We here investigate by molecular dynamics simulations, metadynamics, and essential dynamics the activation mechanism of alpha7-nAChR, in the presence of different nicotinic modulators. We determine the free energy profiles associated with the closed-to open motion of the loop C, and we highlight mechanistic differences observed in the presence of different modulators. In particular, we demonstrate that GAT107 triggers conformational motions and cross-talk similar to those observed when the alpha7-nACh receptor is in complex with both an agonist and an allosteric modulator. PMID- 26569024 TI - Use of Photosensitizers in Semisolid Formulations for Microbial Photodynamic Inactivation. AB - Semisolid formulations, such as gels, creams and ointments, have recently contributed to the progression of photodynamic therapy (PDT) and microbial photodynamic inactivation (PDI) in clinical applications. The most important challenges facing this field are the physicochemical properties of photosensitizers (PSs), optimal drug release profiles, and the photosensitivity of surrounding tissues. By further integration of nanotechnology with semisolid formulations, very promising pharmaceuticals have been generated against several dermatological diseases (PDT) and (antibiotic-resistant) pathogenic microorganisms (PDI). This review focuses on the different PSs and their associated semisolid formulations currently found in both the market and clinical trials that are used in PDT/PDI. Special emphasis is placed on the advantages that the semisolid formulations bring to drug delivery in PDI. Lastly, some potential considerations for improvement in this field are also discussed. PMID- 26569023 TI - Cholesterol-Dependent Conformational Exchange of the C-Terminal Domain of the Influenza A M2 Protein. AB - The C-terminal amphipathic helix of the influenza A M2 protein plays a critical cholesterol-dependent role in viral budding. To provide atomic-level detail on the impact cholesterol has on the conformation of M2 protein, we spin-labeled sites right before and within the C-terminal amphipathic helix of the M2 protein. We studied the spin-labeled M2 proteins in membranes both with and without cholesterol. We used a multipronged site-directed spin-label electron paramagnetic resonance (SDSL-EPR) approach and collected data on line shapes, relaxation rates, accessibility of sites to the membrane, and distances between symmetry-related sites within the tetrameric protein. We demonstrate that the C terminal amphipathic helix of M2 populates at least two conformations in POPC/POPG 4:1 bilayers. Furthermore, we show that the conformational state that becomes more populated in the presence of cholesterol is less dynamic, less membrane buried, and more tightly packed than the other state. Cholesterol dependent changes in M2 could be attributed to the changes cholesterol induces in bilayer properties and/or direct binding of cholesterol to the protein. We propose a model consistent with all of our experimental data that suggests that the predominant conformation we observe in the presence of cholesterol is relevant for the understanding of viral budding. PMID- 26569025 TI - Expressed Emotion in relatives of persons with dementia: a systematic review and meta-analysis. AB - OBJECTIVES: Expressed Emotion (EE) refers to a number of key aspects of interpersonal relationships which have been shown to relate to outcomes in relatives of people with health conditions. DESIGN: A systematic review and meta analysis of EE and outcomes in relatives of persons with dementia is reported. Potential research studies were identified via a search of three electronic databases; PsychINFO, MEDLINE and the Web of Science between 1960 and 2015. RESULTS: We reviewed 12 studies investigating correlations between EE and well being in relatives of patients with dementia. Factors hypothesised to influence EE including attributions, social support, coping strategies and relationship quality were also reviewed. CONCLUSION: High-EE relatives were found to have increased levels of burden (Z = 6.967, P < 0.001) and greater levels of depression (Z = 5.842, P < 0.001). Compared to low-EE relatives, high-EE relatives were more likely to attribute the patient's problems to factors that were personal to and controllable by the patient. Relatives with less social support, inefficient coping strategies and a poor relationship with the patients, were more likely to be classified as high-EE. PMID- 26569026 TI - alpha-Mannosidase I Protein Expression in Peripheral Blood Mononuclear Cells Is Upregulated During Hepatitis B Virus Infection. AB - Hepatitis B virus (HBV) has been reported to be recognized by dendritic cell specific ICAM-3-grabbing nonintegrin in the presence of the alpha-mannosidase I inhibitor kifunensine, whereas native HBV is not. The aim of our study was to determine whether changes in alpha-mannosidase I expression in peripheral blood mononuclear cells (PBMCs) occur in patients with HBV infection. Peripheral blood was collected from 90 HBV-infected patients (grouped into immune tolerance, chronic hepatitis B, or inactive carrier group based on their clinical states) and 30 healthy donors. Expression of the three alpha-mannosidase I subtypes, MAN1A1, MAN1A2, and MAN1C1, was measured using western blot analyses. Compared with the healthy controls, significant increases in the MAN1A1, MAN1A2, and MAN1C1 expression levels were observed in the three HBV-infected groups, among whom the immune tolerance group showed the largest increase. For the patients in the immune tolerance phase, the expression levels of both MAN1A1 and MAN1A2 were linearly and positively correlated with the hepatitis B e antigen (HBeAg) titer and HBV DNA level, although a positive correlation was only found between MAN1C1 expression and the HBeAg titer. These results indicate that increased alpha mannosidase I expression in PBMCs may play an important role in HBV immune escape and that its expression level is closely related to viral replication activity. PMID- 26569027 TI - Dietary (-)-epicatechin mitigates oxidative stress, NO metabolism alterations, and inflammation in renal cortex from fructose-fed rats. AB - High fructose consumption has been associated to deleterious metabolic conditions. In the kidney, high fructose causes renal alterations that contribute to the development of chronic kidney disease. Evidence suggests that dietary flavonoids have the ability to prevent/attenuate risk factors of chronic diseases. This work investigated the capacity of (-)-epicatechin to prevent the renal damage induced by high fructose consumption in rats. Male Sprague Dawley rats received 10% (w/v) fructose in the drinking water for 8 weeks, with or without supplementation with (-)-epicatechin (20mg/kg body weight/d) in the rat chow diet. Results showed that, in the presence of mild proteinuria, the renal cortex from fructose-fed rats exhibited fibrosis and decreases in nephrin, synaptopodin, and WT1, all indicators of podocyte function in association with: (i) increased markers of oxidative stress; (ii) modifications in the determinants of NO bioavailability, i.e., NO synthase (NOS) activity and expression; and (iii) development of a pro-inflammatory condition, manifested as NF-kappaB activation, and associated with high expression of TNFalpha, iNOS, and IL-6. Dietary supplementation with (-)-epicatechin prevented or ameliorated the adverse effects of high fructose consumption. These results suggest that (-)-epicatechin ingestion would benefit when renal alterations occur associated with inflammation or metabolic diseases. PMID- 26569028 TI - Sending your grandparents to university increases cognitive reserve: The Tasmanian Healthy Brain Project. AB - OBJECTIVE: Increasing an individual's level of cognitive reserve (CR) has been suggested as a nonpharmacological approach to reducing the risk for Alzheimer's disease. We examined changes in CR in older adults participating over 4 years in the Tasmanian Healthy Brain Project. METHOD: A sample of 459 healthy older adults between 50 and 79 years of age underwent a comprehensive annual assessment of current CR, neuropsychological function, and psychosocial factors over a 4-year period. The intervention group of 359 older adults (M = 59.61 years, SD = 6.67) having completed a minimum of 12 months part-time university study were compared against a control reference group of 100 adults (M = 62.49 years, SD = 6.24) who did not engage in further education. RESULTS: Growth mixture modeling demonstrated that 44.3% of the control sample showed no change in CR, whereas 92.5% of the further education participants displayed a significant linear increase in CR over the 4 years of the study. These results indicate that older adults engaging in high-level mental stimulation display an increase in CR over a 4-year period. CONCLUSION: Increasing mental activity in older adulthood may be a viable strategy to improve cognitive function and offset cognitive decline associated with normal aging. (PsycINFO Database Record PMID- 26569029 TI - The influence of sleep duration and sleep-related symptoms on baseline neurocognitive performance among male and female high school athletes. AB - Typically, the effects of sleep duration on cognition are examined in isolation. OBJECTIVE: This study examined the effects of restricted sleep and related symptoms on neurocognitive performance. METHOD: Baseline Immediate Post Concussion Assessment and Cognitive Testing (ImPACT) and postconcussion symptom scale (PCSS) were administered to athletes (N = 7,150) ages 14-17 (M = 15.26, SD = 1.09) prior to sport participation. Three groups of athletes were derived from total sleep duration: sleep restriction (<=5 hours), typical sleep (5.5-8.5 hours), and optimal sleep (>=9 hours). A MANCOVA (age and sex as covariates) was conducted to examine differences across ImPACT/PCSS. Follow-up MANOVA compared ImPACT/PCSS performance among symptomatic (e.g., trouble falling asleep, sleeping less than usual) adolescents from the sleep restriction group (n = 78) with asymptomatic optimal sleepers (n = 99). RESULTS: A dose-response effect of sleep duration on ImPACT performance and PCSS was replicated (Wilk's lambda = .98, F2,7145 = 17.25, p < .001, eta2 = .01). The symptomatic sleep restricted adolescents (n = 78) had poorer neurocognitive performance: verbal memory, F = 11.60, p = .001, visual memory, F = 6.57, p = .01, visual motor speed, F = 6.19, p = .01, and reaction time (RT), F = 5.21, p = .02, compared to demographically matched controls (n = 99). Girls in the sleep problem group performed worse on RT (p = .024). CONCLUSION: Examining the combination of sleep-related symptoms and reduced sleep duration effectively identified adolescents at risk for poor neurocognitive performance than sleep duration alone. (PsycINFO Database Record PMID- 26569030 TI - The mechanisms of far transfer from cognitive training: Review and hypothesis. AB - OBJECTIVE: General intelligence is important for success in daily life, fueling interest in developing cognitive training as an intervention to improve fluid ability (Gf). A major obstacle to the design of effective cognitive interventions has been the paucity of hypotheses bearing on mechanisms underlying transfer of cognitive training to Gf. Despite the large amounts of money and time currently being expended on cognitive training, there is little scientific agreement on how, or even whether, Gf can be heightened by such training. METHOD: We review the relevant strands of evidence on cognitive-training-related changes in (a) cortical mechanisms of distraction suppression, and (b) activation of the dorsal attention network (DAN). We hypothesize that training-related increases in control of attention are important for what is termed far transfer of cognitive training to untrained abilities, notably to Gf. RESULTS: We review the evidence that distraction suppression evident in behavior, neuronal firing, scalp electroencephalography, and hemodynamic change is important for protecting target processing during perception and also for protecting targets held in working memory. Importantly, attentional control also appears to be central to performance on Gf assessments. Consistent with this evidence, forms of cognitive training that increase ability to ignore distractions (e.g., working memory training and perceptual training) not only affect the DAN but also affect transfer to Gf. CONCLUSIONS: Our hypothesis is supported by existing evidence. However, to advance the field of cognitive training, it is necessary that competing hypotheses on mechanisms of far transfer of cognitive training be advanced and empirically tested. (PsycINFO Database Record PMID- 26569031 TI - Early language mediates the relations between preschool inattention and school age reading achievement. AB - OBJECTIVE: Early inattention is associated with later reading problems in children, but the mechanism by which this occurs is unclear. We investigated whether the negative relation between preschoolers' ADHD symptoms and 8-year-old reading achievement is directly related to the severity of inattention or is mediated by early language skills. METHOD: Children (n = 150; 76% boys) were evaluated at 3 time points: preschool (T1), mean (SD) age = 4.24 (.49) years; 1 year later (T2), mean (SD) age = 5.28 (.50) years; and during school age (T3), mean (SD) age = 8.61 (.31) years. At T1, parents' Kiddie-SADS responses were dimensionalized to reflect ADHD severity. Children completed the Language domain of the NEPSY (i.e., A Developmental Neuropsychological Assessment) at T1 and again at T2. At T3, children completed the Wechsler Individual Achievement Test, Second Edition Word Reading, Pseudoword Decoding, Reading Comprehension, and Spelling subtests, and their teachers completed ratings of Reading and Written Expression performance in school. The mediating effect of T2 Language on the relation between preschool Inattention and age 8 Reading was examined using the nonparametric bootstrapping procedure, while controlling for T1 Language. RESULTS: Language ability at T2 mediated the path from preschool inattention (but not hyperactivity/impulsivity) to 8-year-old reading achievement (both test scores and ratings) after controlling for preschoolers' language ability. CONCLUSIONS: Early attentional deficits may negatively impact school-age reading outcomes by compromising the development of language skills, which in turn imperils later reading achievement. Screening children with attentional problems for language impairment, as well as implementing early intervention for both attentional and language problems may be critical to promote reading achievement during school years. (PsycINFO Database Record PMID- 26569032 TI - Supplemental folic acid in pregnancy and maternal cancer risk. AB - BACKGROUND: There is evidence that increased intake of folate protects against the development of several types of cancer. Some studies have, however, raised concern about the safety of folate in relation to cancer risk. Here we examined the risk of maternal cancer after intake of supplemental folic acid in pregnancy. METHODS: This is a population-based cohort study comprising 429,004 women with data from the Medical Birth Registry of Norway, the Cancer Registry of Norway, and other national registries from 1999 to 2010. Altogether 3781 cancer cases were identified during follow-up (average 7 years). Cox proportional hazards regression models were used to estimate hazard ratios of maternal cancer according to folic acid use prior to and during one or two or more pregnancies as compared to no supplement use. RESULTS: Folic acid supplementation use had no overall effect on cancer risk in women using folic acid supplementation in one (HR 1.08; 95% CI 1.00-1.18) or two or more pregnancies (HR 1.06; 95% CI 0.91 1.22) (ptrend=0.12). Analyses of 13 cancer types revealed no associations between folic acid and cancer. CONCLUSION: Folic acid supplementation before and during pregnancy had no overall effect on maternal cancer risk. IMPACT: Folic acid substitution before and/or during pregnancy does not increase the short-term overall maternal cancer risk. PMID- 26569033 TI - Quantitative Dual-Energy Computed Tomography Supports a Vascular Etiology of Smoking-induced Inflammatory Lung Disease. AB - RATIONALE: Endothelial dysfunction is of interest in relation to smoking associated emphysema, a component of chronic obstructive pulmonary disease (COPD). We previously demonstrated that computed tomography (CT)-derived pulmonary blood flow (PBF) heterogeneity is greater in smokers with normal pulmonary function tests (PFTs) but who have visual evidence of centriacinar emphysema (CAE) on CT. OBJECTIVES: We introduced dual-energy CT (DECT) perfused blood volume (PBV) as a PBF surrogate to evaluate whether the CAE-associated increased PBF heterogeneity is reversible with sildenafil. METHODS: Seventeen PFT normal current smokers were divided into CAE-susceptible (SS; n = 10) and nonsusceptible (NS; n = 7) smokers, based on the presence or absence of CT detected CAE. DECT-PBV images were acquired before and 1 hour after administration of 20 mg oral sildenafil. Regional PBV and PBV coefficients of variation (CV), a measure of spatial blood flow heterogeneity, were determined, followed by quantitative assessment of the central arterial tree. MEASUREMENTS AND MAIN RESULTS: After sildenafil administration, regional PBV-CV decreased in SS subjects but did not decrease in NS subjects (P < 0.05), after adjusting for age and pack-years. Quantitative evaluation of the central pulmonary arteries revealed higher arterial volume and greater cross-sectional area (CSA) in the lower lobes of SS smokers, which suggested arterial enlargement in response to increased peripheral resistance. After sildenafil, arterial CSA decreased in SS smokers but did not decrease in NS smokers (P < 0.01). CONCLUSIONS: These results demonstrate that sildenafil restores peripheral perfusion and reduces central arterial enlargement in normal SS subjects with little effect in NS subjects, highlighting DECT-PBV as a biomarker of reversible endothelial dysfunction in smokers with CAE. PMID- 26569034 TI - Involvement of the monoamine system in antidepressant-like properties of 4-(1 phenyl-1h-pyrazol-4-ylmethyl)-piperazine-1-carboxylic acid ethyl ester. AB - AIMS: Piperazinic derivatives have therapeutic potential by acting as analgesic, antidepressant-like, anticonvulsant and antipsychotic in preclinical studies. In order to develop new drugs to treat mental disorders, we designed and synthesized the 4-(1-phenyl-1H-pyrazol-4-ylmethyl)-piperazine-1-carboxylic acid ethyl ester (PPMP), a new piperazine derivative with putative activities on central nervous system that seems to involve serotonergic system. MATERIALS AND METHODS: In order to investigate the antidepressant-like activity of PPMP, mice were treated acutely and tested in the forced swimming test (FST) and tail suspension test. Pretreatment with the 5-HT synthesis inhibitor p-chlorophenylalanine (PCPA, 100 mg/kg, i.p., 4 days), and the non-selective blocker of catecholamine synthesis alpha-methyl para-tyrosine (AMPT, 100 mg/kg, i.p.) were used to assay the involvement of serotonergic and catecholaminergic systems. "Ex vivo" monoamine oxidase (MAO) enzymatic assay and quantification of hippocampal level of brain derived neurotrophic factor (BDNF) were carried out. KEY FINDINGS: PPMP reduced the immobility time in both tests. PCPA or AMPT (100 mg/kg, i.p.) pretreatment blocked the effects of PPMP, thereby suggesting the involvement of serotonergic and catecholaminergic systems in the antidepressant-like effect of PPMP. PPMP did not inhibit the activity of MAO. Moreover, after 14 days of treatment, PPMP 15 mg/kg/day induced antidepressant-like effect and increased hippocampal level of BDNF. None of the treatments in this study altered the locomotor activity in the open field test. SIGNIFICANCE: In conclusion, PPMP demonstrates antidepressant like effect that involve both serotonergic and catecholaminergic systems without inhibition of MAO activity. PPMP administration increased the hippocampal levels of BDNF. PMID- 26569035 TI - Structure of amorphous Ag/Ge/S alloys: experimentally constrained density functional study. AB - Density functional/molecular dynamics simulations have been performed to determine structural and other properties of amorphous Ag/Ge/S and Ge/S alloys. In the former, the calculations have been combined with experimental data (x-ray and neutron diffraction, extended x-ray absorption fine structure). Ag/Ge/As alloys have high ionic conductivity and are among the most promising candidates for future memristor technology. We find excellent agreement between the experimental results and large-scale (500 atoms) simulations in Ag/Ge/S, and we compare and contrast the structures of Ge/S and Ag/Ge/S. The calculated electronic structures, vibrational densities of states, ionic mobilities, and cavity distributions of the amorphous materials are discussed and compared with data on crystalline phases where available. The high mobility of Ag in solid state electrolyte applications is related to the presence of cavities and can occur via jumps to a neighbouring vacant site. PMID- 26569036 TI - Normal cognitive conflict resolution in psychosis patients with and without schizophrenia. AB - Schizophrenia is thought to be associated with impairments of executive functions, among which conflict control functions play an important role. The available evidence, however, suggests that conflict control is intact in schizophrenia, despite being based on methods that have successfully unveiled conflict control problems in other disorders. Differences between schizophrenia patients and healthy controls in stimulus perception, selective attention, alertness, processing speed and reaction time variability may have been previously overlooked. By controlling for these potential confounders, the present experiments were aimed to be more rigorous tests of the hypothesis that psychosis and schizophrenia are associated with impairments of conflict control. To that end, 27 healthy controls and 53 recent-onset psychosis patients with (n = 27) and without schizophrenia (n = 26) with comparable age, intelligence, and education level, performed three iconic conflict control tasks: the Simon task, the Eriksen flanker task, and the Stroop task, all equipped with neutral trials, and analyzed for various potential confounders. They further performed a battery of standard neuropsychological tests. Schizophrenia patients showed no increased conflict effects in any of the 3 tasks for any alternative measures used. Nonschizophrenia patients only showed abnormally increased response competition in the Simon task. All patients nevertheless demonstrated impaired control of attention and verbal memory. These findings indicate that the type of conflict control engaged by conflict tasks is intact in recent-onset schizophrenia, suggesting that a major component of executive function is spared in schizophrenia. We discuss these findings in terms of proactive and reactive control. PMID- 26569038 TI - Older maternal age is associated with depression, anxiety, and stress symptoms in young adult female offspring. AB - The evidence regarding older parental age and incidence of mood disorder symptoms in offspring is limited, and that which exists is mixed. We sought to clarify these relationships by using data from the Western Australian Pregnancy Cohort (Raine) Study. The Raine Study provided comprehensive data from 2,900 pregnancies, resulting in 2,868 live born children. A total of 1,220 participants completed the short form of the Depression Anxiety Stress Scale (DASS-21) at the 20-year cohort follow-up. We used negative binomial regression analyses with log link and with adjustment for known perinatal risk factors to examine the extent to which maternal and paternal age at childbirth predicted continuous DASS-21 index scores. In the final multivariate models, a maternal age of 30-34 years was associated with significant increases in stress DASS-21 scores in female offspring relative to female offspring of 25- to 29-year-old mothers. A maternal age of 35 years and over was associated with increased scores on all DASS-21 scales in female offspring. Our results indicate that older maternal age is associated with depression, anxiety, and stress symptoms in young adult females. Further research into the mechanisms underpinning this relationship is needed. PMID- 26569037 TI - Longitudinal associations between social anxiety disorder and avoidant personality disorder: A twin study. AB - Social anxiety disorder (SAD) and avoidant personality disorder (AvPD) are frequently co-occurring psychiatric disorders with symptomatology related to fear of social situations. It is uncertain to what degree the 2 disorders reflect the same genetic and environmental risk factors. The current study addresses the stability and co-occurrence of SAD and AvPD, the factor structure of the diagnostic criteria, and genetic and environmental factors underlying the disorders at 2 time points. SAD and AvPD were assessed in 1,761 young adult female twins at baseline and 1,471 of these approximately 10 years later. Biometric models were fitted to dimensional representations of SAD and AvPD. SAD and AvPD were moderately and approximately equally stable from young to middle adulthood, with increasing co-occurrence driven by environmental factors. At the first wave, approximately 1 in 3 individuals with AvPD had SAD, increasing to 1 in 2 at follow-up. The diagnostic criteria for SAD and AvPD had a two-factor structure with low cross-loadings. The relationship between SAD and AvPD was best accounted for by a model with separate, although highly correlated (r = .76), and highly heritable (.66 and .71) risk factors for each disorder. Their genetic and environmental components correlated .84 and .59, respectively. The finding of partially distinct risk factors indicates qualitative differences in the etiology of SAD and AvPD. Genetic factors represented the strongest time-invariant influences, whereas environmental factors were most important at the specific points in time. PMID- 26569039 TI - A new biflavonoid from the whole herb of Lepisorus ussuriensis. AB - A new biflavonoid, 7-O-methylnaringenin-(4'->O->6")-scutellarein (1), together with 11 known compounds (2-12) were isolated from the whole herb of Lepisorus ussuriensis. The structure of compound 1 was elucidated by spectroscopic analyses. Amongst them, dihydroquercetin (6), diosmetin (9), baicalein (11) and 7,8-dihydroxyflavone (12) were reported from the family Polypodiaceae for the first time. Meanwhile, quercetin (7), diosmetin (9) and luteolin (10) inhibited TNF-alpha-induced NF-kappaB reporter gene expression on HeLa cells up to 30 and 100 MUM. PMID- 26569040 TI - Mode Specific Backscattering in a Quantum Point Contact. AB - We demonstrate a scanning gate grid measurement technique consisting in measuring the conductance of a quantum point contact (QPC) as a function of gate voltage at each tip position. Unlike conventional scanning gate experiments, it allows investigating QPC conductance plateaus affected by the tip at these positions. We compensate the capacitive coupling of the tip to the QPC and discover that interference fringes coexist with distorted QPC plateaus. We spatially resolve the mode structure for each plateau. PMID- 26569041 TI - Distribution of Fullerene Nanoparticles between Water and Solid Supported Lipid Membranes: Thermodynamics and Effects of Membrane Composition on Distribution. AB - The distribution coefficient (Klipw) of fullerene between solid supported lipid membranes (SSLMs) and water was examined using different lipid membrane compositions. Klipw of fullerene was significantly higher with a cationic lipid membrane compared to that with a zwitterionic or anionic lipid membrane, potentially due to the strong interactions between negative fullerene dispersions and positive lipid head groups. The higher Klipw for fullerene distribution to ternary lipid mixture membranes was attributed to an increase in the interfacial surface area of the lipid membrane resulting from phase separation. These results imply that lipid composition can be a critical factor that affects bioconcentration of fullerene. Distribution of fullerene into zwitterionic unsaturated lipid membranes was dominated by the entropy contribution (DeltaS) and the process was endothermic (DeltaH > 0). This result contrasts the partitioning thermodynamics of highly and moderately hydrophobic chemicals indicating that the lipid-water distribution mechanism of fullerene may be different from that of molecular level chemicals. Potential mechanisms for the distribution of fullerene that may explain these differences include adsorption on the lipid membrane surfaces and partitioning into the center of lipid membranes (i.e., absorption). PMID- 26569042 TI - Molecular Dynamics Simulations of the Initial Adsorption Stages of Fibrinogen on Mica and Graphite Surfaces. AB - Fibrinogen, a blood glycoprotein of vertebrates, plays an essential role in blood clotting by polymerizing into fibrin when activated. Upon adsorption on material surfaces, it also contributes to determine their biocompatibility and has been implicated in the onset of thrombosis and inflammation at medical implants. Here we present the first fully atomistic simulations of the initial stages of the adsorption process of fibrinogen on mica and graphite surfaces. The simulations reveal a weak adsorption on mica that allows frequent desorption and reorientation events. This adsorption is driven by electrostatic interactions between the protein and the silicate surface as well as the counterion layer. Preferred adsorption orientations for the globular regions of the protein are identified. The adsorption on graphite is found to be stronger with fewer reorientation and desorption events and shows the onset of denaturation of the protein. PMID- 26569043 TI - Amino Acid-Functionalized Dendritic Polyglycerol for Safe and Effective siRNA Delivery. AB - The development of safe and effective delivery vectors is a great challenge for the medicinal application of RNA interference (RNAi). In this study, we aimed to develop new synthetic transfection agents based on dendritic polyglycercol (dPG), which has shown great biocompatibility in several biomaterial applications. Histidine and aromatic amino acids were conjugated to the amine-terminated dPGs through amide bonds. We systematically tuned the amino acid combination, functionalization ratio, ligand density, and dPG core size to find optimal vectors. It was found that histidine-tryptophan-functionalized dPGs exhibited improved delivery efficiency and greatly reduced toxicity over simple amine terminated dPGs. Furthermore, the optimized vectors exhibited strong siRNA binding and high transfection efficiency in serum containing media. The results indicate that the current amino acid-functionalized dPG system is a promising candidate for in vivo siRNA delivery applications. PMID- 26569044 TI - Stiffness of hyaluronic acid gels containing liver extracellular matrix supports human hepatocyte function and alters cell morphology. AB - Tissue engineering and cell based liver therapies have utilized primary hepatocytes with limited success due to the failure of hepatocytes to maintain their phenotype in vitro. In order to overcome this challenge, hyaluronic acid (HA) cell culture substrates were formulated to closely mimic the composition and stiffness of the normal liver cellular microenvironment. The stiffness of the substrate was modulated by adjusting HA hydrogel crosslinking. Additionally, the repertoire of bioactive molecules within the HA substrate was bolstered by supplementation with normal liver extracellular matrix (ECM). Primary human hepatocyte viability and phenotype were determined over a narrow physiologically relevant range of substrate stiffnesses from 600 to 4600Pa in both the presence and absence of liver ECM. Cell attachment, viability, and organization of the actin cytoskeleton improved with increased stiffness up to 4600Pa. These differences were not evident in earlier time points or substrates containing only HA. However, gene expression for the hepatocyte markers hepatocyte nuclear factor 4 alpha (HNF4alpha) and albumin significantly decreased on the 4600Pa stiffness at day 7 indicating that cells may not have maintained their phenotype long-term at this stiffness. Function, as measured by albumin secretion, varied with both stiffness and time in culture and peaked at day 7 at the 1200Pa stiffness, slightly below the stiffness of normal liver ECM at 3000Pa. Overall, gel stiffness affected primary human hepatocyte cell adhesion, functional marker expression, and morphological characteristics dependent on both the presence of liver ECM in gel substrates and time in culture. PMID- 26569045 TI - Genital Cancers in Women: Foreword. PMID- 26569046 TI - Genital Cancers in Women: Uterine Cancer. AB - There are two main types of uterine cancer. Endometrial carcinoma, the most commonly diagnosed genital cancer in women, accounts for most cases (more than 95%) and sarcoma comprises the remainder. Endometrial cancer primarily occurs in postmenopausal women. Risk factors include exposure to high levels of endogenous estrogen (eg, obesity, nulliparity, late menopause) or exogenous estrogen (eg, hormone replacement therapy, tamoxifen) and pelvic radiation. Genetics are involved in a small percentage of cases, notably among women in families with hereditary nonpolyposis colorectal cancer (HNPCC). More than 80% of patients with endometrial cancers present with abnormal uterine bleeding. Endometrial biopsy and transvaginal ultrasound are the first-line tests to evaluate bleeding. If the endometrial lining is thickened on ultrasound, endometrial biopsy is indicated. If symptoms persist after negative biopsy results, or if biopsy results are inadequate, hysteroscopy is performed for tissue sampling. Most patients with endometrial cancer are diagnosed early, when cancer is confined to the uterus. Hysterectomy is the treatment of choice in such cases. Treatment of advanced disease involves radiotherapy and/or chemotherapy. Perimenopausal women should be informed that abnormal bleeding could be a sign of cancer and should be evaluated. However, no routine screening is recommended except for women with HNPCC. PMID- 26569047 TI - Genital Cancers in Women: Cervical Cancer. AB - In 2015 in the United States, it is estimated there will be approximately 12,900 new patients with cervical cancer and 4,100 will die of the disease. If diagnosed at a localized stage, the 5-year survival rate exceeds 90%. Human papillomavirus (HPV) infection is the main risk factor for cervical cancer. Current recommendations for cervical cancer screening include Papanicolaou (Pap) testing every 3 years for women ages 21 to 29 years. For women ages 30 to 65 years, an alternative is screening with Pap and HPV testing every 5 years. If screening results are abnormal, further evaluation can be guided by an algorithm. For a diagnosis of carcinoma in situ or grade 3 cervical intraepithelial neoplasia (CIN), treatment typically involves ablation or excision. Women with CIN 1 or CIN 2 that persists typically are treated with the same methods. For women diagnosed with early-stage invasive cancer, standard treatment is radical hysterectomy. More advanced cancers also are treated with surgery, but chemotherapy and/or radiation also may be used depending on cancer stage. Because most cervical cancer is caused by HPV, it is potentially preventable with HPV vaccination, which is recommended for females and males, ideally beginning at age 11 or 12 years. PMID- 26569048 TI - Genital Cancers in Women: Ovarian Cancer. AB - More than 20,000 US women are diagnosed with ovarian cancer each year. The average lifetime risk is 1.3%, but risk increases with BRCA1 or BRCA2 gene mutations (40% and 18% risk, respectively, by age 70 years) or hereditary nonpolyposis colorectal cancer syndrome (12% lifetime risk). Other risk factors include smoking, possibly past clomiphene use, and more years of ovulation. Symptoms are nonspecific. Abdominal pain is most common; others include pelvic pain, bloating, and early satiety. When ovarian cancer is suspected, evaluation should begin with transvaginal ultrasonography with Doppler studies. Cancer antigen 125 testing can be obtained, but levels are not elevated in all patients. Other biomarkers (eg, OVA1) and scoring systems can be used to help determine if cancer is present. When diagnosed early (stage I), the 5-year survival rate is 90% for epithelial ovarian cancer. However, most patients with epithelial ovarian cancer are diagnosed in stage III or later, with a 5-year survival rate of 17% to 39%. Treatment involves total abdominal hysterectomy and bilateral salpingo oophorectomy, with or without chemotherapy. Fertility-preserving options can be considered in some early-stage cancers, followed by more definitive surgical procedures. There is no evidence that routine screening is beneficial and it is associated with significant harms from unnecessary procedures. Women with genetic syndromes that increase risk should be considered for prophylactic bilateral salpingo-oophorectomy. PMID- 26569049 TI - Genital Cancers in Women: Vulvar Cancer. AB - Vulvar cancer is uncommon, accounting for 0.3% of all new US cancer diagnoses. The majority of cases are squamous cell carcinoma. Malignant melanoma is the second most common type. Other cases are related to chronic inflammatory skin disorders such as lichen sclerosus. Vulvar intraepithelial neoplasia (VIN) is a precursor to squamous cell vulvar cancer. It may be the usual type associated with human papillomavirus (HPV) infection, or the differentiated type often associated with chronic skin disorders. Risk factors for VIN are HPV infection, cigarette smoking, chronic skin disorders, and immunosuppression. Symptoms of vulvar cancer include pruritus, bleeding, skin color change, skin lesions, and dysuria. VIN and vulvar cancer are diagnosed by skin biopsy. Treatment of VIN includes wide local excision, via surgical removal or with laser or ultrasonic surgical aspiration procedures. Medical therapy with imiquimod also may be used. Prognosis is good with early detection; the 5-year survival rate for stage I cancer is greater than 85%. Advanced disease has a poor prognosis, with a 5-year survival rate in stage IV disease as low as 5%. Although screening for vulvar cancer is not recommended, clinicians should evaluate and biopsy any suspicious vulvar lesions. Current efforts at prevention are aimed at HPV vaccination. PMID- 26569050 TI - Pathophysiology of knee jerk reflex abnormalities in L5 root injury. AB - Although the knee jerk reflex is mediated by the L3 and L4 nerve roots, evidence exists that altered knee jerk expression may occur with exclusively L5 radiculopathy. The present study set out to identify the factors responsible for knee jerk reflex abnormalities in L5 monoradiculopathy. We analyzed clinical and electrophysiological data in 56 subjects affected by L5 monoradiculopathy. Seventeen patients (30.3%) showed an abnormal knee reflex. L5 patients with an abnormal knee reflex differed significantly, in severity of pretibial muscle damage, from those with a normal knee reflex. On the basis of evidence, in humans, of a specific spinal pathway linking the pretibial and quadriceps muscles, we infer that an impairment of the proprioceptive drive from the pretibial muscles to spinal premotor excitatory interneurons contacting quadriceps motor neurons is the main causative factor responsible for reducing knee jerk expression. This mechanism should be considered to avoid misinterpretation of knee jerk reflex changes in lumbar radiculopathies. PMID- 26569051 TI - Reversible formation of supramolecular polymer networks via orthogonal pillar[10]arene-based host-guest interactions and metal ion coordinations. AB - Supramolecular polymer networks, assembled via the combination of orthogonal terpyridine-Zn(2+), carbene-Ag(+), and pillar[10]arene/alkyl chain recognition motifs, exhibit dynamic properties responsive to various external stimuli. PMID- 26569052 TI - High density lipoprotein efficiently accepts surface but not internal oxidised lipids from oxidised low density lipoprotein. AB - OBJECTIVE: Oxidised low density lipoprotein (oxLDL) contributes to atherosclerosis, whereas high density lipoprotein (HDL) is known to be atheroprotective due, at least in part, to its ability to remove oxidised lipids from oxLDL. The molecular details of the lipid transfer process are not fully understood. We aimed to identify major oxidised lipid species of oxLDL and investigate their transfer upon co-incubation with HDL with varying levels of oxidation. APPROACH AND RESULTS: A total of 14 major species of oxidised phosphatidylcholine and oxidised cholesteryl ester from oxLDL were identified using an untargeted mass spectrometry approach. HDL obtained from pooled plasma of normolipidemic subjects (N=5) was oxidised under mild and heavy oxidative conditions. Non-oxidised (native) HDL and oxidised HDL were co-incubated with oxLDL, re-isolated and lipidomic analysis was performed. Lipoprotein surface lipids, oxidised phosphatidylcholines and oxidised cholesterols (7 ketocholesterol and 7beta-hydroxycholesterol), but not internal oxidised cholesteryl esters, were effectively transferred to native HDL. Saturated and monounsaturated lyso-phosphatidylcholines were also transferred from the oxLDL to native HDL. These processes were attenuated when HDL was oxidised under mild and heavy oxidative conditions. The impaired capacities were accompanied by an increase in a ratio of sphingomyelin to phosphatidylcholine and a reduction in phosphatidylserine content in oxidised HDL, both of which are potentially important regulators of the oxidised lipid transfer capacity of HDL. CONCLUSIONS: Our study has revealed the differential transfer efficiency of surface and internal oxidised lipids from oxLDL and their acceptance onto HDL. These capacities were modulated when HDL was itself oxidised. PMID- 26569053 TI - Angiopoietin-like protein 8 (betatrophin) is a stress-response protein that down regulates expression of adipocyte triglyceride lipase. AB - AIM: Atypical angiopoietin-like 8 (ANGPTL8), also known as betatrophin, is known to regulate lipid metabolism. However, its mechanism of action remains elusive. METHODS: HepG2, 3T3-L1, and NIT-1 cells were cultured in amino acid-complete MEM or histidine-free MEM to detect ANGPTL8 expression. The three cell types were treated with or without recombinant ANGPTL8 to investigate its role in lipid metabolism. Hydrodynamic tail vein gene delivery was also used to examine the role of ANGPTL8 in mice. RESULTS: ANGPTL8 is significantly up-regulated in amino acid-deprived cultured cells in vitro. The activation of ANGPTL8 gene transcription was mediated through the RAS/c-RAF/MAPK signaling pathway rather than the general GCN2/ATF4 pathways. ANGPTL8 activated the ERK signal transduction pathway in hepatocytes, adipocytes, and pancreatic beta-cells, up regulating early growth response transcription factor (Egr1) and down-regulating adipose triglyceride lipase (ATGL). CONCLUSION: ANGPTL8 is a stress-response protein that regulates fat metabolism by suppressing ATGL expression, revealing a mechanistic connection between ANGPTL8 and lipid homeostasis in mammalian cells. PMID- 26569054 TI - Effective Leveraging of Targeted Search Spaces for Improving Peptide Identification in Tandem Mass Spectrometry Based Proteomics. AB - In shotgun proteomics, peptides are typically identified using database searching, which involves scoring acquired tandem mass spectra against peptides derived from standard protein sequence databases such as Uniprot, Refseq, or Ensembl. In this strategy, the sensitivity of peptide identification is known to be affected by the size of the search space. Therefore, creating a targeted sequence database containing only peptides likely to be present in the analyzed sample can be a useful technique for improving the sensitivity of peptide identification. In this study, we describe how targeted peptide databases can be created based on the frequency of identification in the global proteome machine database (GPMDB), the largest publicly available repository of peptide and protein identification data. We demonstrate that targeted peptide databases can be easily integrated into existing proteome analysis workflows and describe a computational strategy for minimizing any loss of peptide identifications arising from potential search space incompleteness in the targeted search spaces. We demonstrate the performance of our workflow using several data sets of varying size and sample complexity. PMID- 26569055 TI - Laparoscopic Nerve-Sparing Radical Hysterectomy for Cervical Carcinoma: Emphasis on Nerve Content in Removed Cardinal Ligaments. AB - OBJECTIVE: To evaluate the histopathology of autonomic nerve removal within the cardinal ligaments (CLs), patients' postoperative urinary function, and the feasibility and safety of laparoscopic nerve-sparing radical hysterectomy (LNSRH) for treatment of early-stage cervical cancer. METHODS: Perioperative and postoperative parameters were compared between patients with biopsy-proven, early stage cervical carcinoma treated with LNSRH (n = 64) versus those treated with laparoscopic radical hysterectomy (LRH, n = 42) in a retrospective study. Nerves within CLs were identified by hematoxylin-eosin staining. Rates of the following complications were compared: bladder function, sexual dysfunction, and defecation problems. RESULTS: Duration of surgery, intraoperative blood loss, duration of hospitalization, and morbidity did not differ significantly between the LNSRH and LRH groups. Patients who underwent LNSRH had a significantly earlier return of bladder and bowel functions, with an average time to achieve residual urine of 50 mL or less of 10.22 days and a mean first defecation time of 3.58 days. Nerves were observed mainly in the CLs of the LRH group. Disease-free survival rate did not differ between the LNSRH (90.6%) and LRH (88.1%) groups (P = 0.643). CONCLUSIONS: The LNSRH is a safe, feasible, and easy procedure for trained laparoscopic surgeons. Patients who underwent LNSRH had a more satisfactory quality of life than patients who underwent LRH. PMID- 26569056 TI - Individualized Treatment of Patients With Early-Stage Epithelial Ovarian Cancer After Incomplete Initial Surgery. AB - OBJECTIVES: Incomplete initial surgery complicates subsequent management of early stage epithelial ovarian carcinoma (ESEOC). This study aimed to determine the most appropriate strategies for individualized treatment of these patients. METHODS: Medical records of ESEOC patients treated at our hospital between 2000 and 2011 were reviewed, and 246 patients initially treated by incomplete surgery were included. A scoring system was established to assess the quality of initial surgery (QOIS). RESULTS: Of 246 patients, 130 underwent restaging surgery and 116 received chemotherapy only. Follow-up duration ranged from 4 to 148 months (median, 72 months). The 5-year overall survival (OS) rates were 87.5% and 74.7% in the restaging and chemotherapy groups, respectively. Survival analysis showed significantly better recurrence-free survival (RFS) and OS in the restaging group (P = 0.043 and P = 0.029, respectively). Multivariate analysis showed that histologic grade was an independent predictor for RFS and OS in the restaging group (P = 0.035 and P = 0.038, respectively), and histologic grade (P = 0.005 and P = 0.015, respectively) and QOIS (P = 0.044 and P = 0.024, respectively) were independent predictors for RFS and OS in the chemotherapy group. Subgroup analysis showed that restaging surgery produced better RFS and OS than chemotherapy in patients with low QOIS and unfavorable histology (5-year RFS, 58.5% vs 33.4%, P = 0.007; 5-year OS, 82.2% vs 54.4%, P = 0.011), whereas the outcomes between the treatment options were comparable in patients with high QOIS or favorable histology. CONCLUSIONS: Our results support individualized treatment of ESEOC patients initially treated by incomplete surgery. Restaging surgery is recommended only for patients with low QOIS and unfavorable histology. PMID- 26569057 TI - Advances and Concepts in Cervical Cancer Trials: A Road Map for the Future. AB - OBJECTIVE: Cervical cancer is responsible for more than a quarter of a million deaths globally each year, mostly in developing countries, making therapeutic advances in all health care settings a top priority. The Gynecologic Cancer InterGroup (GCIG) is a worldwide collaboration of leading national research groups that develops and promotes multinational trials in gynecologic cancer. In recognition of the pressing need for action, the GCIG convened an international meeting with expert representation from the GCIG groups and selected large sites in low- and middle-income countries. METHODS: The focus was to develop a consensus on several concepts for future clinical trials, which would be developed and promoted by the GCIG and launched with major international participation. The first half of the meeting was devoted to a resume of the current state of the knowledge and identifying the gaps in need of new evidence, validating control arms for present and future clinical trials and identifying national and international barriers for studies of cervix cancers. The second half of the meeting was concerned with achieving consensus on a path forward. RESULTS AND CONCLUSIONS: There were 5 principal outcomes as follows: first, a proposal to expand fertility-preserving options with neoadjuvant chemotherapy; second, validation of the assessment of sentinel lymph nodes using minimally invasive surgery with an emphasis on identification and management of low-volume metastasis, such as isolated tumor cells and micrometastasis; third, evaluation of hypofractionation for palliative and curative radiation under the umbrella of the GCIG Cervix Cancer Research Network; fourth, adding to the advances in antiangiogenesis therapy in the setting of metastatic disease; and fifth, developing a maintenance study among women at high risk of relapse. The latter 2 systemic interventions could study PI3K (phosphatidylinositol-3-kinase) inhibitors, immunotherapy, anti-human papillomavirus approaches, or novel antiangiogenic agents/combinations. PMID- 26569058 TI - Predictive Factor of Conversion to Laparotomy in Minimally Invasive Surgical Staging for Endometrial Cancer. AB - OBJECTIVE: The aim of the study was to identify risk factors associated with laparotomy conversion during total laparoscopic hysterectomy for endometrial cancer. METHODS: This is a retrospective study examining endometrial cancer cases that underwent hysterectomy-based surgical staging initiated via conventional laparoscopic approach. Factors related to patient, tumor, and surgeon were examined to establish risk of laparotomy conversion using a multivariate logistic regression model. RESULTS: There were 251 cases identified including 30 cases (12.0%) of laparotomy conversion. The most common indication for laparotomy conversion was a large uterus (27.0%), followed by extensive adhesions (24.3%) and surgical complications (18.9%). Outcomes of cases resulting in laparotomy conversion include longer surgical time (333 vs 224 minutes, P < 0.001), larger blood loss (350 vs 100 mL, P < 0.001), longer hospital stay (4 vs 2 days, P < 0.001), and increased risk of hospital readmission (10% vs 1.4%, P = 0.024). In multivariate analysis, morbid obesity (odds ratio [OR], 4.51; P = 0.011), suboptimal pelvic examination or enlarged uterus during preoperative evaluation (OR, 3.55; P = 0.034), para-aortic lymphadenectomy (OR, 10.5; P = 0.001), uterine size 250 g or greater (OR, 3.49; P = 0.026), and extrauterine disease (OR, 4.68; P = 0.012) remained the independent predictors for laparotomy conversion. The following numbers of risk factors were significantly correlated with laparotomy conversion rate: none, 1.1%; single risk factor, 5.3% (OR, 5.00; P = 0.15); double risk factors, 21.7% (OR, 24.9; P = 0.002); and triple or more risk factors, 50% (OR, 90.0; P < 0.001). Ultrasonographic 3-dimensional volumes of 496 cm in preoperative uterine size correlate with actual uterine weight of 250 g (Y = 61.5 + 0.38X, P < 0.001). CONCLUSIONS: Laparotomy conversion significantly impacts outcomes of patients with endometrial cancer. In this setting, our predictive model for laparotomy conversion will be useful to guide the surgical management of endometrial cancer. PMID- 26569059 TI - Validation of the Predictive Value of Modeled Human Chorionic Gonadotrophin Residual Production in Low-Risk Gestational Trophoblastic Neoplasia Patients Treated in NRG Oncology/Gynecologic Oncology Group-174 Phase III Trial. AB - OBJECTIVES: In low-risk gestational trophoblastic neoplasia, chemotherapy effect is monitored and adjusted with serum human chorionic gonadotrophin (hCG) levels. Mathematical modeling of hCG kinetics may allow prediction of methotrexate (MTX) resistance, with production parameter "hCGres." This approach was evaluated using the GOG-174 (NRG Oncology/Gynecologic Oncology Group-174) trial database, in which weekly MTX (arm 1) was compared with dactinomycin (arm 2). METHODS: Database (210 patients, including 78 with resistance) was split into 2 sets. A 126-patient training set was initially used to estimate model parameters. Patient hCG kinetics from days 7 to 45 were fit to: [hCG(time)] = hCG7 * exp(-k * time) + hCGres, where hCGres is residual hCG tumor production, hCG7 is the initial hCG level, and k is the elimination rate constant. Receiver operating characteristic (ROC) analyses defined putative hCGRes predictor of resistance. An 84-patient test set was used to assess prediction validity. RESULTS: The hCGres was predictive of outcome in both arms, with no impact of treatment arm on unexplained variability of kinetic parameter estimates. The best hCGres cutoffs to discriminate resistant versus sensitive patients were 7.7 and 74.0 IU/L in arms 1 and 2, respectively. By combining them, 2 predictive groups were defined (ROC area under the curve, 0.82; sensitivity, 93.8%; specificity, 70.5%). The predictive value of hCGres-based groups regarding resistance was reproducible in test set (ROC area under the curve, 0.81; sensitivity, 88.9%; specificity, 73.1%). Both hCGres and treatment arm were associated with resistance by logistic regression analysis. CONCLUSIONS: The early predictive value of the modeled kinetic parameter hCGres regarding resistance seems promising in the GOG-174 study. This is the second positive evaluation of this approach. Prospective validation is warranted. PMID- 26569060 TI - Demographic Clinical and Prognostic Factors of Primary Ovarian Adenocarcinomas of Serous and Clear Cell Histology-A Comparative Study. AB - OBJECTIVE: To compare clinical demographic and prognostic factors as well as overall survival in a nationwide cohort of patients diagnosed with ovarian clear cell carcinoma (oCCC) and high grade ovarian serous adenocarcinoma (oSAC) during 2005 to 2013. MATERIALS AND METHODS: Population-based prospectively collected data on oCCC (n = 179) and oSAC (n = 2363) cases were obtained from the Danish Gynecological Cancer Database. chi, Fischer or Wilcoxon-Mann-Whitney, multivariate logistic regression, univariate Kaplan-Meier, and multivariate Cox regression tests were used. Statistical tests were 2-sided. P values less than 0.05 were considered statistically significant. RESULTS: The oCCC cases were significantly younger than oSAC cases. An inverse association between ever smoking and oCCC as compared to oSAC was observed and a significantly higher proportion of oCCC was found to be nulliparous (odds ratio, 0.62; 95% confidence interval, 0.37-0.92).Although more oSAC than oCCC cases diagnosed in stage III or IV were referred to neoadjuvant chemotherapy, a higher proportion of oCCC achieved complete cytoreduction at primary debulking surgery and/or had lymphadenectomy performed; overall survival were poorer among oCCC than oSAC cases in analyses restricted to stages III and IV (odds ratio, 1.87; 95% confidence interval, 1.35-2.61), whereas no difference between early stage oCCC and oSAC was observed. CONCLUSIONS: The study confirms that demographic features and risk factors differ between oCCC and oSAC cases. Furthermore, our findings confirm that advanced stages of oCCC have a poorer prognosis compared with oSAC probably because of the resistance toward adjuvant chemotherapy. The observed differences highlight the need for subtype-specific research and individualized treatment within ovarian cancer. PMID- 26569061 TI - Survey of Current Practice Patterns in the Treatment of Early-Stage Endometrial Cancer. AB - OBJECTIVES: Our aim was to assess current surgical practices and use of adjuvant therapy in the treatment of FIGO (International Federation of Gynecology and Obstetrics) stage I endometrioid endometrial cancer. METHODS: A 19-question survey was developed and sent to all Society of Gynecologic Oncologist members by e-mail. Data were collected anonymously using Internet-based survey software. Respondents were asked questions regarding preoperative evaluation, surgical approach, lymph node dissection (LND), and adjuvant therapy. RESULTS: A total of 1399 surveys were distributed, 320 (23%) members completed the survey. Ninety seven percent of respondents were gynecologic oncologists or fellows, and 87% treat 30 or more endometrial cancer patients yearly. Respondents were more likely to order preoperative tests such as computed tomography abdomen/pelvis and CA-125 for biopsy-proven grade 3 disease versus grade 1 (82% vs 29%). Robot-assisted laparoscopy was the preferred surgical approach (66%), followed by conventional laparoscopy (21%). Twenty-six percent of respondents perform LND in all cases. Forty-eight percent describe their LND as complete, to the level of the inferior mesenteric artery. Adjuvant therapy was recommended more often with increasing myometrial invasion, tumor grade, and lymphovascular space invasion. Vaginal brachytherapy was the most commonly recommended adjuvant therapy for stage IA. For stage IB, grade 3, positive lymphovascular space invasion disease, respondents were more likely to combine vaginal brachytherapy with external beam radiotherapy and/or chemotherapy. Older patients were more likely to have adjuvant therapy in earlier stages of disease than younger patients. CONCLUSIONS: Our findings demonstrate that respondents are individualizing care based on preoperative, intraoperative, and pathologic findings. As expected, adjuvant treatment is recommended for patients with higher stage and grade disease. Robot assisted hysterectomy and chemotherapy are now commonly used in the management of this disease. We anticipate that new trends will continue to emerge as results from additional studies become available. PMID- 26569062 TI - Should Systematic Infrarenal Para-aortic Dissection Be the Rule in the Pretherapeutic Staging of Primary or Recurrent Locally Advanced Cervix Cancer Patients With a Negative Preoperative Para-aortic PET Imaging? AB - BACKGROUND: Extended-field chemoradiation is the usual management of patients with locally advanced cervical cancer (LACC) and para-aortic node metastases (PA pN1). It is efficient but not without morbidity. Assessment of PA lymph node positivity by PA lymphadenectomy is the most accurate method to select the candidates for this treatment. Hence, to clarify the dissection pattern, we wanted to test the true incidence of isolated/skip node metastasis, above the level of the inferior mesenteric artery (IMA). MATERIALS AND METHODS: All patients with LACC and negative magnetic resonance imaging and positron emission tomography-computed tomography imaging at the PA level were offered a laparoscopic staging encompassing a diagnostic laparoscopy followed, if negative, by an extraperitoneal PA lymphadenectomy. All nodes were removed from both common iliac bifurcations up to the left renal vein. Node groups, below and above the IMA, were separately sent to the pathologist for definitive examination. RESULTS: From January 2010 to December 2013, 196 stage IB1 with pelvic pN1, IB2, to IVA LACC patients from 2 cancer centers who fulfilled the criteria were included in this institutional review board-approved study after informed consent. Thirty patients (15%) had PA pN1. Only 1 patient had positive nodes exclusively located above the IMA (3.3% of the pN1 group; 95% confidence interval, 0%-9.7%). Complications were observed in 15 (7.6%) of 196 patients. CONCLUSIONS: Given the very low rate of skip metastases above the IMA and the potential additional morbidity of a systematic extended dissection, a bilateral ilioinframesenteric dissection seems to be an acceptable pattern of PA lymphadenectomy in LACC patients. PMID- 26569063 TI - Evolution and Determinants of Health-Related Quality-of-Life in Kidney Transplant Patients Over the First 3 Years After Transplantation. AB - BACKGROUND: Health-related quality of life (HRQOL) usually improved after kidney transplantation; however, a non-negligible number of patients did not benefit from transplantation in HRQOL. The aims of this cohort study were to describe the evolution of HRQOL in kidney transplant recipients to search for subgroups with distinct time profiles and to investigate these determinants. METHODS: Three hundred thirty-seven adult patients were followed up from 1 to 36 months after kidney transplantation. Each patient completed repeated HRQOL assessments (median, 5; range, 2-9). K-means for longitudinal data was used to identify homogeneous clusters of HRQOL time profiles obtained for the mental and physical composite scores (MCS and PCS) and for the 8 dimensions of the short-form 36 scale. Covariates associated with these clusters were investigated using random forest analysis. Magnitude and shape of the HRQOL variations over time were investigated using linear regression mixed models. RESULTS: Two longitudinal clusters were identified for the time profiles of PCS and MCS. Patients classified in the higher cluster (ie, 60% of the population) exhibited a steady state HRQOL, similar on average to the general population, whereas in the lower cluster, PCS and MCS scores were significantly lower than in the general population. Muscular weakness in the first year after transplantation explained 19% of the interpatient variability of PCS 3 months after transplantation, whereas associated with anxiety, it explained 24% of interpatient MCS variability. CONCLUSIONS: This work suggests to promote (i) physical rehabilitation programs after transplantation to curb the muscular loss and (ii) systematic attention to the patient's anxiety. PMID- 26569064 TI - Cold Crystalloid Perfusion Provides Cardiac Preservation Superior to Cold Storage for Donation After Circulatory Death. AB - BACKGROUND: We previously showed that donation after circulatory death (DCD) canine hearts can be resuscitated if perfused with warm blood. However, clinical application of this technique is complex and difficult. We have developed a simplified system of cold crystalloid perfusion and compared it with standard cold storage for DCD heart preservation. METHODS: Anesthetized greyhounds underwent 30 minutes DCD by withdrawal of ventilation followed by assignment to either 4 hours of perfusion (n = 6) or cold storage (n = 7). Nonpreserved hearts (n = 5) served as a normal reference group. Perfusion hearts were reperfused with a protective solution then perfused for 4 hours with a novel oxygenated, nutrient containing solution at 20 mL/min at 4 degrees C to 10 degrees C. Cold storage hearts were flushed with St Thomas' cardioplegic solution and stored in ice. After preservation, the recovery of the hearts was assessed on a blood-perfused working heart rig. RESULTS: During preservation, perfusion hearts consumed oxygen (0.09 +/- 0.01 mL/100 g per minute) and showed decreasing lactate production in the perfusate (initial: 0.031 +/- 0.004 vs final: 0.007 +/- 0.002 mmol/min; P = 0.001). After preservation, compared to cold storage hearts, perfusion hearts had higher cardiac output (P = 0.004), LV dP/dt max (P = 0.003) and myocardial oxygen efficiency (P = 0.01), with lower blood perfusate lactate (P = 0.007). Hemodynamic values of perfused hearts reached 60% or more those in the normal reference group. CONCLUSIONS: Continuous cold crystalloid perfusion in a canine model of DCD: (1) facilitates aerobic metabolism and resuscitates the DCD heart, (2) provides functional and metabolic recovery superior to cold storage, (3) shows promise for improved clinical preservation of DCD and marginal donor hearts. PMID- 26569065 TI - Antithymocyte Globulins in Heart Transplantation: Rational Dosing for a Magic Potion. PMID- 26569066 TI - Early Measurement of Indocyanine Green Clearance Accurately Predicts Short-Term Outcomes After Liver Transplantation. AB - BACKGROUND: There are no accurate tools to predict short-term mortality or the need for early retransplantation after liver transplantation (LT). A noninvasive measurement of indocyanine green clearance, the plasma disappearance rate (PDR), has been associated with initial graft function. METHODS: We evaluated the ability of PDR to predict early mortality or retransplantation after LT. In this observational prospective study, 332 LT were analyzed. Donor, recipient, and intraoperative data were investigated. The ensuing score was prospectively evaluated in a validation cohort of 77 patients. RESULTS: Thirty-three patients reached the main endpoint. By multivariate analysis, the only independent predictors of the endpoint were PDR (odds ratio [OR], 0.85; 95% confidence interval, 0.79-0.92) and international normalized ratio (OR, 1.45; 95% confidence interval, 1.17-1.82). A risk score weighted by the OR was built using cutoff values of 2.2 or greater for international normalized ratio (1 point) and less than 10%/min for PDR (2 points). Four categories (0 to 3) were possible. The risk of early death or retransplantation was associated with the score (0, 4.4%; 1, 6.5%; 2, 12%; and 3, 50%; chi for trend, P < 0.001). The score was also associated with duration of mechanical ventilation and intensive care unit stay. The score had a good diagnostic performance in the validation cohort (sensitivity, 60%; specificity, 95.5%; positive predictive value, 66.7%; negative predictive value, 94.1%). CONCLUSIONS: A simple score obtained within the first day after LT predicts short-term survival and need for retransplantation and may prove useful when selecting diagnostic and therapeutic strategies. PMID- 26569067 TI - The Impact of Obesity on Allograft Failure After Kidney Transplantation: A Competing Risks Analysis. AB - BACKGROUND: The impact of pretransplant body mass index (BMI) on long-term allograft outcomes after kidney transplantation remains controversial. The conventional approach of using Kaplan-Meier method to calculate the cumulative risk of death-censored allograft failure may overestimate the risk of failure especially when competing failure risks are present. METHOD: A retrospective cohort of adult first-time kidney transplant recipients was drawn from the Organ Procurement and Transplantation Network database (2001 to 2009). Based on World Health Organization obesity classification, BMI was categorized as: less than 18.5, 18.5 to <25, 25 to < 30, 30 to < 35, 35 to <40 and >=40 kg/m. Both unadjusted and adjusted risk models were used to assess for risk of allograft failure in the presence of death as a competing event. RESULTS: A total of 108 654 recipients were studied. In both unadjusted and adjusted models, increasing BMI level was associated with increased risk of long-term allograft failure. In the adjusted model with BMI 18.5 to less than 25 as the reference, the subhazards ratios (SHRs) for BMI were: less than 18.5: SHR, 0.96; P = 0.41; 25 to less than 30: SHR, 1.05; P = 0.01; 30 to less than 35: SHR, 1.15; P = <0.001; 35 to less than 40: SHR, 1.21; P < 0.001; and greater than 40: SHR, 1.13; P = 0.002. CONCLUSIONS: Handling of death as a competing event demonstrates a graded, detrimental impact of increasing pretransplant BMI on the risk of graft failure after kidney transplantation in both unadjusted and adjusted models. Compared with previous studies, a lower BMI was not associated with an increased risk of graft loss in a competing risk model. PMID- 26569068 TI - The High-Risk Age Window After Pediatric Liver Transplantation: Modeling Allograft Loss Using Mathematical Tools. PMID- 26569069 TI - Donor-antigen Inoculation in the Testis Promotes Skin Allograft Acceptance Induced by Conventional Costimulatory Blockade via Induction of CD8 + CD122+ and CD4 + CD25+ Regulatory T Cells. AB - BACKGROUND: Immune responses are somewhat suppressed in immune privileged sites, including the testes, which provide a preexisting opportunity to prolong allograft survival. Previous studies have shown that intratesticular islet allografts enjoy extended survival even without any immunosuppression. However, it is unknown if testicular immune privilege can be exploited to prolong the survival of a solid allograft, including the skin, because it is impractical to implant a solid tissue in human testes. METHODS: To immunize recipient mice, splenocytes from BALB/c mice were injected into the testis of C57BL/6 recipients 1 week before skin transplantation. CD8 + CD122+ and CD4 + FoxP3+ regulatory T [Treg] cells were quantified by fluorescence-activated cell sorting. RESULTS: Although donor-antigen inoculation alone did not delay skin allograft rejection, it significantly extended the allograft survival when combined with CD40/CD40L or B7/CD28 costimulatory blockade and further induced long-term skin allograft acceptance when both costimulatory pathways were blocked. Similarly, donor antigen inoculation suppressed alloreactive T cell proliferation in draining lymph nodes of skin recipients in the presence of the same costimulatory blockade. Interestingly, donor-antigen inoculation via intratesticular injection increased CD8 + CD122+, but not CD4 + FoxP3+, Treg numbers after transplantation. However, both CD8 + CD122+ and CD4 + CD25+ Treg cells induced by donor-antigen inoculation and the costimulatory blockade were more potent in suppression than that induced without the inoculation. Depletion of CD8+ or CD25+ T cells largely abrogated long-term skin allograft survival induced by donor-antigen inoculation and the costimulatory blockade. CONCLUSIONS: Intratesticular inoculation with donor antigens promotes long-term skin allograft survival induced by conventional costimulatory blockade via the induction of both CD8 + CD122+ and CD4 + CD25+ Treg cells. PMID- 26569070 TI - The influence of gut microbiota on drug metabolism and toxicity. AB - INTRODUCTION: Gut microbiota plays critical roles in drug metabolism. The variation of gut microbiota contributes to the interindividual differences toward drug therapy including drug-induced toxicity and efficacy. Accordingly, the investigation and elucidation of gut microbial impacts on drug metabolism and toxicity will not only facilitate the way of personalized medicine, but also improve rational drug design. AREAS COVERED: This review provides an overview of the microbiota-host co-metabolism on drug metabolism and summarizes 30 clinical drugs that are co-metabolized by host and gut microbiota. Moreover, this review is specifically focused on elucidating the gut microbial modulation of some clinical drugs, in which the gut microbial influences on drug metabolism, drug induced toxicity and efficacy are discussed. EXPERT OPINION: The gut microbial contribution to drug metabolism and toxicity is increasingly recognized, but remains largely unexplored due to the extremely complex relationship between gut microbiota and host. The mechanistic elucidation of gut microbiota in drug metabolism is critical before any practical progress in drug design or personalized medicine could be made by modulating human gut microbiota. Analytical technique innovation is urgently required to strengthen our capability in recognizing microbial functions, including metagenomics, metabolomics and the integration of multidisciplinary knowledge. PMID- 26569071 TI - gammadelta T cell-based anticancer immunotherapy: progress and possibilities. PMID- 26569072 TI - Targeting IL-17 with ixekizumab in patients with psoriasis. AB - Psoriasis is a multifactorial chronic inflammatory skin disease of unknown etiology. Knowledge of the pathophysiology of psoriasis has evolved and identified IL-17 as a key pro-inflammatory mediator in psoriasis creating new medical avenues. Several agents targeting IL-17 or its receptor are in clinical trials for the treatment of moderate-to-severe psoriasis. This review focuses on the biological rationale and the results of clinical trials with ixekizumab, a humanized IgG4 monoclonal antibody. The currently available Phase I to III data indicate that ixekizumab is a well-tolerated promising drug, although long-term data of efficacy and safety are needed before ixekizumab and other IL-17 targeting therapeutics can find their place in clinical practice. PMID- 26569073 TI - Effects of Il-33/St2 pathway on alteration of iron and hematological parameters in acute inflammation. AB - AIM: The aim of this study was to examine the role of the IL-33/ST2 pathway in pathogenesis of acute inflammation by investigating its possible role in alteration of iron and hematological parameters in experimental model of acute inflammation. MATERIAL AND METHODS: Wild-type and ST2 knockout BALB/c mice were divided into four groups: wild-type control group, ST2-/- control group, wild type inflammatory group, and ST2-/- inflammatory group. Acute inflammation was induced by intramuscular injection of turpentine oil, while control groups were injected with saline. After 12h animals were anesthetized, and the treated tissue, blood and spleen were collected. Iron concentration in the treated tissue, hemoglobin blood concentration, mean corpuscular hemoglobin (MCH), hematocrit, erythrocyte, neutrophil and lymphocyte blood count, and erythrocytes percentage in spleen were determined. RESULTS: Iron concentration in the treated tissue was significantly higher in wild-type inflammatory group (WT-I) when compared to both, the wild-type control group (WT-C) and ST2-/- inflammatory group (KO-I). There was no significant difference in iron concentration between ST2-/- control group (KO-C) and the KO-I. MCH had significantly decreased in WT-I when compared to WT-C, while there was no significant difference between KO-C and KO-I. Hemoglobin blood concentration significantly increased in KO-I in comparison to KO-C, while it did not significantly differ between WT-I and KO-I. Erythrocyte count and hematocrit had significantly increased, while the percentage of erythrocytes in spleen decreased in both inflammatory groups when compared to their controls. Neutrophil count significantly decreased in WT-I, when compared to WT-C. Lymphocyte count decreased in both inflammatory groups when compared to their controls. CONCLUSION: Results of this study indicate that the IL-33/ST2 axis could have a role in the alteration of iron in acute inflammation, namely in an increase of iron concentration at the site of acute inflammation and a decrease of blood mean corpuscular hemoglobin. PMID- 26569074 TI - A study of the expression and localization of toll-like receptors 2 and 9 in different grades of cervical intraepithelial neoplasia and squamous cell carcinoma. AB - TLRs are important molecules of innate immune response, those play central role in host pathogen interaction and recognition through pathogen associated molecular patterns (PAMPs). Previous studies have indicated the role of TLRs in many human malignancy and cervical cancer in terms of viral recognition and inflammatory changes in-vivo. The objective of this study was to evaluate the expression and localization of toll-like receptor (TLR) 2 and TLR9 in preinvasive and invasive cervical cancer patients and to investigate its use as a probable diagnostic tool for better management cervical cancer. This single institution study includes individuals with normal, precancerous lesions, cervical intraepithelial neoplastic (CIN) and invasive squamous cell carcinoma (SCC) of the cervix. Upon confirmation by histopathology, fluorescence based immunohistochemistry was performed in all patients for TLR2 and TLR9, followed by semi-quantitative estimation of the staining intensity and grade of expression. The expression pattern of TLR2 and TLR9 does not vary greatly from normal to precancerous lesions, but a significant variation was observed in advance stages, i.e. squamous cell carcinoma of the uterine cervix. Additionally the expression increased marginally in higher grades. In spite of their low difference in expression along different stages of cervical cancer, both TLR2 and TLR9 could detect the disease at an advance stages as depicted by the receiver operator characteristics curve analysis. PMID- 26569075 TI - Laughing Gas in a Pediatric Emergency Department-Fun for All Participants: Vitamin B12 Status Among Medical Staff Working With Nitrous Oxide. AB - : The efficiency of nitrous oxide in an equimolar mixture with oxygen or in concentrations up to 70% is approved for short painful procedures. Evaluation of the vitamin B12 levels in anesthetic staff applying nitrous oxide showed reduced vitamin B12 plasma levels. This study examines the vitamin B12 status of medical staff working with nitrous oxide in a pediatric emergency department (ED). Medical staff of the ED at the University Children's Hospital Zurich participated. The vitamin B12 status was evaluated by measuring homocysteine, methylmalonic acid, vitamin B12, blood count, and the MTHFR C677T genotype. As a control group, medical personnel working in the "nitrous oxide-free" pediatric intensive care unit were recruited. RESULTS: The parameters for the vitamin B12 status of all participants were in the reference range, and there were no significant differences for the 2 groups. By trend, the ED staff showed higher vitamin B12 levels. The ED staff members were slightly older (P = 0.07) and had higher hemoglobin levels (P < 0.04) compared with the pediatric intensive care unit staff. CONCLUSIONS: The use of nitrous oxide (50%-70%) with a demand valve is safe for the vitamin B12 status of medical personnel in the ED. PMID- 26569076 TI - Non-accidental Trauma Work-up: Unusual Retinal Finding Leads to a Rare Diagnosis. AB - Lipoprotein lipase (LPL) deficiency is an autosomal recessive condition due to absent or decreased activity of LPL enzyme. The LPL deficiency is a rare condition that is mainly diagnosed in children, but there is no standard screening method at this time. In our report, we describe a 6-day-old male infant who was found to have hypertriglyceridemia after lipemia retinalis was diagnosed from a fundoscopic examination for nonaccidental trauma work-up. After dietary modification was done, his triglyceride levels decreased significantly, and there were no complications. When diagnosed later in life, recurrent pancreatitis can be a significant complication. PMID- 26569077 TI - Point-of-Care Ultrasound to Diagnose Infantile Parotid Hemangioma. AB - Soft tissue masses are common in the pediatric population and may represent a broad range of conditions. Point-of-care ultrasound can be used for rapid visualization and assessment of soft tissue masses in the emergency setting. We report a case of a pediatric head and neck mass in which point-of-care ultrasound was used to identify an infantile parotid hemangioma. PMID- 26569078 TI - Is Level of Serum Ischemia-Modified Albumin A Useful Biomarker in Carbon Monoxide Poisoning Cases? AB - OBJECTIVES: Ischemia-modified albumin (IMA) is an emerging diagnostic biomarker for many ischemic conditions. The study was conducted to investigate whether there is a change in IMA levels in carbon monoxide poisoning and, if so, the clinical relevance of IMA levels. METHODS: This study was performed between October 2013 and April 2014 to compare levels of serum IMA drawn at the time of admission to the emergency department in 49 patients poisoned with carbon monoxide and 37 healthy controls. Serum IMA, blood carboxyhemoglobin, and lactate levels were analyzed. RESULTS: Ischemia-modified albumin levels of patients with carbon monoxide poisoning were higher than those of controls. In patient group, however, there was no correlation between serum IMA and carboxyhemoglobin levels (r = -0.244, P > 0.05), whereas a negative correlation was detected between serum IMA and lactate levels (r = -0.334, P < 0.05). After all, a positive correlation was present between carboxyhemoglobin and lactate levels (r = 0.399, P < 0.05). CONCLUSIONS: Results from this preliminary study suggest that IMA might have diagnostic value in carbon monoxide poisoning and may be a parameter to be used clinically together with carboxyhemoglobin levels in terms of reflecting tissue hypoxia. In addition, IMA may be a criterion, especially in delayed cases where carboxyhemoglobin level may be normal in deciding hyperbaric oxygen treatment. To clarify this issue, further studies with larger population are needed. PMID- 26569079 TI - Parental Language and Return Visits to the Emergency Department After Discharge. AB - OBJECTIVE: Return visits to the emergency department (ED) are used as a marker of quality of care. Limited English proficiency, along with other demographic and disease-specific factors, has been associated with increased risk of return visit, but the relationship between language, short-term return visits, and overall ED use has not been well characterized. METHODS: This is a planned secondary analysis of a prospective cohort examining the ED discharge process for English- or Spanish-speaking parents of children aged 2 months to 2 years with fever and/or respiratory illness. At 1 year after the index visit, a standardized chart review was performed. The primary outcome was the number of ED visits within 72 hours of the index visit. Multivariable logistic regression was used to examine the relative importance of predictor variables and adjust for confounders. RESULTS: There were 202 parents eligible for inclusion, of whom 23% were Spanish speaking. In addition, 6.9% of the sample had a return visit within 72 hours. After adjustment for confounders, Spanish language was associated with return visit within 72 hours (odds ratio, 3.49; 95% confidence interval, 1.02 11.90) but decreased risk of a second visit within the year (odds ratio, 0.28; 95% confidence interval, 0.12-0.66). CONCLUSION: Spanish-speaking parents are at an increased risk of 72-hour return ED visit but do not seem to be at increased risk of ED use during the year after their ED visit. PMID- 26569080 TI - [Erratum for: Contralateral Recession of the Inferior Oblique Muscle in Graves' Disease Patients with Mild M. rectus inferior fibrosis]. PMID- 26569081 TI - Evidence of superconductivity-induced phonon spectra renormalization in alkali doped iron selenides. AB - Polarized Raman scattering spectra of superconducting K(x)Fe(2-y)Se2 and non superconducting K0.8Fe1.8Co0.2Se2 single crystals were measured in the temperature range from 10 K up to 300 K. Two Raman active modes from the I4/mmm phase and seven from the I4/m phase are observed in the frequency range from 150 to 325 cm(-1) in both compounds, suggesting that the K0.8Fe1.8Co0.2Se2 single crystal also has a two-phase nature. The temperature dependence of the Raman mode energy is analyzed in terms of lattice thermal expansion and phonon-phonon interaction. The temperature dependence of the Raman mode linewidth is dominated by temperature-induced anharmonic effects. It is shown that the change in Raman mode energy with temperature is dominantly driven by thermal expansion of the crystal lattice. An abrupt change of the A1g mode energy near T(C) was observed in K(x)Fe(2-y) Se2, whereas it is absent in non-superconducting K0.8Fe1.8Co0.2Se2. Phonon energy hardening at low temperatures in the superconducting sample is a consequence of superconductivity-induced redistribution of the electronic states below the critical temperature. PMID- 26569082 TI - Excluded volume contribution to cosolvent-mediated modulation of macromolecular folding and binding reactions. AB - Water-miscible cosolvents may stabilize or destabilize proteins, nucleic acids, and their complexes or may exert no influence. The mode of action of a specific cosolvent is determined by the interplay between the excluded volume effect and direct solute-cosolvent interactions. Excluded volume refers to the steric exclusion of water and cosolvent molecules from the space occupied by solute, an event accompanied by a decrease in translational entropy. In thermodynamic terms, the excluded volume effect is modeled by creating a cavity which is sufficiently large to accommodate the solute and which is inaccessible to surrounding molecules of water and cosolvent(s). An understanding of the relationship between the energetic contributions of cavity formation and direct solute-cosolvent interactions is required for elucidating the molecular origins of the stabilizing or destabilizing influence of specific cosolvents. In this work, we employed the concepts of scaled particle theory to compute changes in free energy of cavity formation, ??GC, accompanying the ligand-protein binding, protein dimerization, protein folding, and DNA duplex formation events. The computations were performed as a function of the concentration of methanol, urea, ethanol, ethylene glycol, and glycine betaine. Resulting data were used in conjunction with a previously developed statistical thermodynamic algorithm to estimate the excluded volume contribution to changes in preferential hydration, ?Gamma21, and interaction, ?Gamma23, parameters and m-values associated with the reactions under study. The excluded volume contributions to ?Gamma21, ?Gamma23, and m-values are very significant ranging from 30 to 70% correlating with the size of the cosolvent molecule. Our results suggest that a pair of "fully excluded cosolvents" with negligible solute-solvent interactions may differ significantly with respect to their excluded volume contributions to ?Gamma21, ?Gamma23, and m-values thereby differently influencing the equilibrium of the reaction being sampled. This notion has implications for understanding the long-standing observation that, in osmotic stress studies, various osmolytes may produce significantly distinct estimates of hydration/dehydration for the same reaction. PMID- 26569083 TI - Ablation of ischemic ventricular tachycardia: evidence, techniques, results, and future directions. AB - PURPOSE OF REVIEW: This article summarizes current understanding of the arrhythmia substrate and effect of catheter ablation for infarct-related ventricular tachycardia, focusing on recent findings. RECENT FINDINGS: Clinical studies support the use of catheter ablation earlier in the course of ischemic disease with moderate success in reducing arrhythmia recurrence and shocks from implantable defibrillators, although mortality remains unchanged. Ablation can be lifesaving for patients presenting with electrical storm. Advanced mapping systems with image integration facilitate identification of potential substrate, and several different approaches to manage hemodynamically unstable ventricular tachycardia have emerged. Novel ablation techniques that allow deeper lesion formation are in development. SUMMARY: Catheter ablation is an important therapeutic option for preventing or reducing episodes of ventricular tachycardia in patients with ischemic cardiomyopathy. Present technologies allow successful ablation in the majority of patients, even when the arrhythmia is hemodynamically unstable. Failure of the procedure is often because of anatomic challenges that will hopefully be addressed with technological progress. PMID- 26569084 TI - Brugada syndrome: diagnosis, risk stratification, and management. AB - PURPOSE OF REVIEW: Asymptomatic patients with Brugada syndrome (BrS) have a small, but not trivial, risk of cardiac events. Their risk stratification and its impact on their management are controversial. The review focuses on the clinical aspects of BrS with special emphasis on the asymptomatic patient. RECENT FINDINGS: Emerging data suggest that drug and fever-induced type I Brugada patterns are more common than previously appreciated. Although preliminary, these data may imply that asymptomatic patients with induced Brugada pattern are at an even lower risk than currently estimated.The latest data regarding induced ventricular arrhythmias during electrophysiological studies support its use as an indication for an implantable cardioverter defibrillator; however, this issue remains highly controversial.Several new risk markers, such as presence of the Brugada pattern in infero-lateral leads or the concomitant finding of an early repolarization pattern, have recently been proposed. SUMMARY: Most asymptomatic BrS patients are at low risk of cardiac events. The presence of new risk markers in this population may prompt consideration of primary prevention measures; however, data supporting this approach are still limited. PMID- 26569085 TI - Pediatric pulmonary hypertension: diagnosis and management. AB - PURPOSE OF REVIEW: The article is intended to provide an overview of the most current modalities for the diagnosis and management of pulmonary hypertension in the pediatric population. RECENT FINDINGS: The WHO has recently updated the classification for pulmonary hypertension to include an expanded range of pediatric disease cohorts. We continue to gain knowledge of traditional pulmonary hypertension therapies (phosphodiesterase inhibitors, endothelin-receptor antagonists, and prostanoids) and remain optimistic that new therapeutic modalities [cyclic guanosine monophosphate (cGMP) stimulators, oral prostacyclins, and gene therapy] will lead to improved outcomes in pediatric patients. SUMMARY: Pediatric pulmonary hypertension is a heterogeneous disorder that has the potential to improve in some cases as children grow throughout childhood. Utilization of dedicated multidisciplinary teams of medical providers is necessary to deliver the highest level of medical care to this complex patient population. Ongoing development of enhanced screening protocols, novel disease specific therapeutic targets, and comprehensive registries will hopefully lead to improved morbidity and mortality in the future. PMID- 26569086 TI - 2015 update on the diagnosis and management of arrhythmogenic right ventricular cardiomyopathy. AB - PURPOSE OF REVIEW: This review will discuss the recent advances in the diagnosis and management of arrhythmogenic right ventricular cardiomyopathy (ARVC). RECENT FINDINGS: Since the first detailed clinical description of the disease in 1982, we have learned much about the genetics, pathophysiology, diagnosis, and management of ARVC. We now appreciate that pathogenic mutations in desmosomal genes are the most common genetic finding. Although the right ventricle is mostly affected, left ventricular involvement is being increasingly recognized. Electrical instability precipitating sudden cardiac death often presents before structural abnormalities, and therefore early accurate diagnosis is of utmost importance. The broad spectrum of phenotypic variation, age-related penetrance, and lack of a definitive diagnostic test make the clinical diagnosis challenging. The diagnosis is made by fulfilling the 2010 Task Force criteria. Today, genetic testing and cardiac MRI play an important role in the diagnosis. Implantable cardioverter defibrillator implantation is the only lifesaving therapy available today for a subset of patients. In patients with recurrent ventricular arrhythmias, epicardial catheter ablation has demonstrated improved outcomes compared with endocardial ablation. Exercise restriction may delay the progression of disease. SUMMARY: ARVC is predominantly associated with mutations in desmosomal genes with incomplete penetrance and variable expressivity. Ventricular electrical instability is the hallmark of ARVC, often occurring before structural abnormalities. Goals in the evaluation and management of ARVC are early diagnosis, risk stratification for sudden cardiac death, minimizing ventricular arrhythmias, and delaying the progression of disease. PMID- 26569087 TI - Recognition and management of arrhythmias in adult congenital heart disease. AB - PURPOSE OF REVIEW: Adults with congenital heart disease now outnumber children with these syndromes in developed countries. This has seen a surge in the care required for these patients, and the development of an entirely new realm of cardiology. Arrhythmia is one of the most common causes of morbidity and mortality in this group, and this review highlights current approaches to recognition and management. RECENT FINDINGS: Atrial arrhythmias are especially common in this group of patients, while pacemaker or implantable cardioverter defibrillator implantation and cardiac ablation are also frequently necessary. The presentation and management of these entities present salient differences for the clinician--for both acute and chronic care--and more recently a national societal consensus statement has attempted to encapsulate the best approach. Without any level of evidence A, all recommendations are based on data derived from nonrandomized studies or only expert/consensus opinion. This review is aimed at providing current opinion on optimum clinical care in this arena in lieu of this publication and the more novel corroborative clinical studies. SUMMARY: Recognition and appropriate management of arrhythmia in adults with congenital heart disease frequently differ from those patients with a normal heart or acquired heart disease. Early diagnosis and proper treatment are essential in this complex patient category. PMID- 26569088 TI - Radiation safety and ergonomics in the electrophysiology laboratory: update on recent advances. AB - PURPOSE OF REVIEW: Risks associated with exposure to ionizing radiation in patients undergoing electrophysiology procedures and interventional cardiac electrophysiologists performing these procedures are a serious concern. Strategies to reduce radiation exposure are of obvious importance. In addition, interventional cardiac electrophysiologists have to perform procedures wearing heavy lead protection for prolonged periods, making them prone to cervical and lumbar spinal injuries. RECENT FINDINGS: Recently developed technologies, such as low-exposure radiographic imaging, novel radiographic imaging protection systems, nonfluoroscopic mapping systems using image integration, and remote catheter manipulation systems have been successful in reducing ionizing radiation exposure in the electrophysiology laboratory. The efficacy and safety of these technologies are being evaluated in clinical trials. In addition, economic analyses are being performed to evaluate these novel systems. The use of nonweight-bearing radiation protection devices and ergonomic design of the electrophysiology laboratory aim to reduce the incidence of occupational injuries in interventional cardiac electrophysiologists. SUMMARY: There is need for ongoing development and evaluation of new technologies to minimize exposure to ionizing radiation during electrophysiologic procedures. In addition, ergonomic planning of the electrophysiology laboratory and training of interventional cardiac electrophysiologists are crucial to occupational injury prevention. PMID- 26569089 TI - Anticoagulation in atrial fibrillation and chronic heart failure: the risk and drug of choice. AB - PURPOSE OF REVIEW: This review seeks to provide an evidence-based update on the issue of atrial fibrillation and chronic heart failure with an emphasis on anticoagulation and the expanding use of the novel oral anticoagulants (NOACs). RECENT FINDINGS: There is an increasing appreciation of the important reciprocal relationship between atrial fibrillation and heart failure and the negative prognostic impact that each condition has on the other. There are now four NOACs approved for stroke prevention in atrial fibrillation. There are increasing data to support their use in atrial fibrillation with heart failure, including in patients with nonmechanical or rheumatic valvular disease, and to facilitate direct current cardioversion. The choice of NOAC is heavily dependent on individual patient characteristics. SUMMARY: The use of and indications for NOACs for patients with heart failure and atrial fibrillation are rapidly increasing. PMID- 26569090 TI - Tangeretin derivative, 5-acetyloxy-6,7,8,4'-tetramethoxyflavone induces G2/M arrest, apoptosis and autophagy in human non-small cell lung cancer cells in vitro and in vivo. AB - Tangeretin, a major phytochemicals in tangerine peels--an important Chinese herb, has been found to have anti-carcinogenic properties. To improve bioavailability and increase potency of tangeretin, its derivative, 5-acetyloxy-6,7,8,4' tetramethoxyflavone (5-AcTMF), has been synthesized and shown potent inhibition of proliferation activity against human breast and leukemia cancer cell lines. In this study, we have further investigated the anticancer effects of 5-AcTMF on CL1 5 non-small cell lung cancer cells (NSCLC) both in vitro and in vivo and demonstrated that 5-AcTMF effectively inhibited cancer cell proliferation, induced G2/M-phase arrest associated with cdc2 and CDC25c and increased in the apoptotic cells associated with caspase activation, down regulation of Bcl-2, XIAP and Survivn, inducing release of cytochrome c into the cytosol and disruption of mitochondrial membrane potential. We also found that 5-AcTMF treatment of CL1-5 activated autophagy, indicated by triggered autophagosome formation and increased LC3-II levels and formation of LC3 puncta. Moreover, we also found that 5-AcTMF lowered phophoatidylinositol 3-kinase/AKT/mTOR signaling pathway. Over-expression of AKT by AKT cDNA transfection decreased 5-AcTMF mediated apoptosis and autophagy, supporting the induction of apoptosis and autophagy by inhibition of AKT pathway. In an animal study, 5-AcTMF effectively delayed tumor growth in a nude mouse model of CL1-5 xenografts without observed adverse effect. Immunohistochemistry Analysis indicated that 5-AcTMF induced CL1 5 cell apoptosis and autophagy in vivo. Taken together, these data demonstrate that 5-AcTMF is a novel small molecule agent that can inhibit NSCLC cell proliferation, and induce G(2)/M phase arrest and via the mitochondrial apoptotic pathway and autophagy. PMID- 26569091 TI - The safety and feasibility of probiotics in children and adolescents undergoing hematopoietic cell transplantation. AB - Hematopoietic cell transplantation (HCT) has become a standard treatment for many adult and pediatric conditions. Emerging evidence suggests that perturbations in the microbiota diversity increase recipients' susceptibilities to gut-mediated conditions such as diarrhea, infection and acute GvHD. Probiotics preserve the microbiota and may minimize the risk of developing a gut-mediated condition; however, their safety has not been evaluated in the setting of HCT. We evaluated the safety and feasibility of the probiotic, Lactobacillus plantarum (LBP), in children and adolescents undergoing allogeneic HCT. Participants received once daily supplementation with LBP beginning on day -8 or -7 and continued until day +14. Outcomes were compliance with daily administration and incidence of LBP bacteremia. Administration of LBP was feasible with 97% (30/31, 95% confidence interval (CI) 83-100%) of children receiving at least 50% of the probiotic dose (median 97%; range 50-100%). We did not observe any case of LBP bacteremia (0% (0/30) with 95% CI 0-12%). There were not any unexpected adverse events related to LBP. Our study provides preliminary evidence that administration of LBP is safe and feasible in children and adolescents undergoing HCT. Future steps include the conduct of an approved randomized, controlled trial through Children's Oncology Group. PMID- 26569092 TI - A reappraisal of ICU and long-term outcome of allogeneic hematopoietic stem cell transplantation patients and reassessment of prognosis factors: results of a 5 year cohort study (2009-2013). AB - Epidemiology and prognosis of complications related to allogeneic hematopoietic stem cell transplant (HSCT) recipients requiring admission to intensive care unit (ICU) have not been reassessed precisely in the past few years. We performed a retrospective single-center study on 318 consecutive HSCT patients (2009-2013), analyzing outcome and factors prognostic of ICU admission. Among these patients, 73 were admitted to the ICU. In all, 32 patients (40.3%) died in ICU, 46 at hospital discharge (63%) and 61 (83.6%) 1 year later. Survivors had a significantly lower sequential organ failure assessment (SOFA) score, serum lactate and bilirubin upon ICU admission. Catecholamine support, mechanical ventilation (MV) and/or renal replacement therapy during ICU stay, a delayed organ support and an active graft versus host disease (GvHD) significantly worsen the outcome. By multivariate analysis, the worsening of SOFA score from days 1 to 3, the need for MV and the occurrence of an active GvHD were predictive of mortality. In conclusion, the incidence of HSCT-related complications requiring an admission to an ICU was at 22%, with an ICU mortality rate of 44%, and 84% 1 year later. A degradation of SOFA score at day 3 of ICU, need of MV and occurrence of an active GvHD are main predictive factors of mortality. PMID- 26569095 TI - Facilitation of the Lesioned Motor Cortex During Tonic Contraction of the Unaffected Limb Corresponds to Motor Status After Stroke. AB - BACKGROUND AND PURPOSE: Contraction of the muscles of the unaffected hand is associated with enhanced activation of lesioned motor cortex (ie, crossed facilitation) in some individuals after stroke. However, the association between crossed facilitation and motor function status remains unclear. We investigated whether existence of crossed facilitation corresponds to motor status of the affected upper limb after stroke. METHODS: Data were collected from 58 participants with unilateral stroke. The Fugl-Meyer assessment of upper extremity (FMA-UE) was used to evaluate motor status. Motor-evoked potentials (MEPs) were elicited from the abductor pollicis brevis (ABP) of the affected side under 3 conditions: rest, tonic contraction of the ABP of the unaffected side, or tonic contraction of the tibialis anterior of the unaffected side. RESULTS: In 28 of the 58 participants, MEPs could be elicited from the affected ABP at rest; these participants also exhibited crossed facilitation during contraction on the unaffected side. Participants with MEPs at rest exhibited higher FMA-UE scores (53.04 +/- 2.59) compared with participants with absent MEP (19.83 +/- 1.60; Z = 6.21). Seven participants with no MEPs at rest had MEPs with crossed facilitation; their FMA-UE scores were higher compared with the 23 who had no ABP MEP under any condition (Z = -2.66). FMA-UE scores were positively correlated with the amount of crossed facilitation during the APB task (r = 0.68) and the tibialis anterior task (r = 0.54). DISCUSSION AND CONCLUSIONS: In some participants, MEPs in the affected hand muscle were enhanced by tonic contraction of the muscles on the unaffected side even if no MEP could be evoked at rest. The degree of crossed facilitation in the affected hand muscle was correlated with the level of motor function of the affected upper limb, and the FMA-UE score could classify the presence/absence of crossed facilitation.Video abstract available for more insights from the authors (Supplemental Digital Content 1, http://links.lww.com/JNPT/A117). PMID- 26569093 TI - Thiotepa-based high-dose therapy for autologous stem cell transplantation in lymphoma: a retrospective study from the EBMT. AB - Clinical information about thiotepa-based autologous stem cell transplantation (auto-SCT) outside the primary central nervous system lymphoma (PCNSL) field is sparse. In this registry-based retrospective study, we evaluated potential risks and benefits of thiotepa-based preparative regimens compared with BEAM (carmustine, etoposide, cytarabine, melphalan) in auto-SCT for diffuse large B cell lymphoma (DLBCL, excluding PCNSL), follicular lymphoma (FL) or Hodgkin lymphoma (HL). A total of 14 544 patients (589 thiotepa and 13 955 BEAM) met the eligibility criteria, and 535 thiotepa- and 1031 BEAM-treated patients were matched in a 1:2 ratio for final comparison. No significant differences between thiotepa and BEAM groups for any survival end point were identified in the whole sample or disease entity subsets. For a more detailed analysis, 47 TEAM (thiotepa, etoposide, cytarabine, melphalan)-treated patients were compared with 75 matched BEAM patients with additional collection of toxicity data. Again, there were no significant differences between the two groups for any survival end point. In addition, the frequency of common infectious and non-infectious complications including secondary malignancies was comparable between TEAM and BEAM. These results indicate that thiotepa-based high-dose therapy might be a valuable alternative to BEAM in DLBCL, HL and FL. Further evaluation by prospective clinical trials is warranted. PMID- 26569096 TI - Lack of glutathione peroxidase-1 facilitates a pro-inflammatory and activated vascular endothelium. AB - A critical early event in the pathogenesis of atherosclerosis is vascular inflammation leading to endothelial dysfunction (ED). Reactive oxygen species and inflammation are inextricably linked and declining antioxidant defense is implicated in ED. We have previously shown that Glutathione peroxidase-1 (GPx1) is a crucial antioxidant enzyme in the protection against diabetes-associated atherosclerosis. In this study we aimed to investigate mechanisms by which lack of GPx1 affects pro-inflammatory mediators in primary aortic endothelial cells (PAECs) isolated from GPx1 knockout (GPx1 KO) mice. Herein, we demonstrate that lack of GPx1 prolonged TNF-alpha induced phosphorylation of P38, ERK and JNK, all of which was reversed upon treatment with the GPx1 mimetic, ebselen. In addition, Akt phosphorylation was reduced in GPx1 KO PAECs, which correlated with decreased nitric oxide (NO) bioavailability as compared to WT PAECs. Furthermore, IkappaB degradation was prolonged in GPx1 KO PAECS suggesting an augmentation of NF kappaB activity. In addition, the expression of vascular cell adhesion molecule (VCAM-1) was significantly increased in GPx1 KO PAECs and aortas. Static and dynamic flow adhesion assays showed significantly increased adhesion of fluorescently labeled leukocytes to GPx1 KO PAECS and aortas respectively, which were significantly reduced by ebselen treatment. Our results suggest that GPx1 plays a critical role in regulating pro-inflammatory pathways, including MAPK and NF-kappaB, and down-stream mediators such as VCAM-1, in vascular endothelial cells. Lack of GPx1, via effects on p-AKT also affects signaling to eNOS-derived NO. We speculate based on these results that declining antioxidant defenses as seen in cardiovascular diseases, by failing to regulate these pro-inflammatory pathways, facilitates an inflammatory and activated endothelium leading to ED and atherogenesis. PMID- 26569097 TI - Correction: Estimation of Instantaneous Gas Exchange in Flow-Through Respirometry Systems: A Modern Revision of Bartholomew's Z-Transform Method. PMID- 26569099 TI - Distinction between coordination and phosphine ligand oxidation: interactions of di- and triphosphines with Pn(3+) (Pn = P, As, Sb, Bi). AB - Reactions of polydentate phosphines with sources of Pn(3+) (Pn = P, As, Sb, Bi) yield complexes of Pn(1+) (Pn = P, As) or Pn(3+) (Pn = Sb, Bi) acceptors. The distinction between coordination of a phosphine center to Pn and oxidation of a phosphine ligand is dependent on Pn. The first structurally verified triphosphine complexes of Sb(III) and Bi(III) acceptors are reported. PMID- 26569098 TI - Clinical-Genetic Associations in the Prospective Huntington at Risk Observational Study (PHAROS): Implications for Clinical Trials. AB - IMPORTANCE: Identifying measures that are associated with the cytosine-adenine guanine (CAG) expansion in individuals before diagnosis of Huntington disease (HD) has implications for designing clinical trials. OBJECTIVE: To identify the earliest features associated with the motor diagnosis of HD in the Prospective Huntington at Risk Observational Study (PHAROS). DESIGN, SETTING, AND PARTICIPANTS: A prospective, multicenter, longitudinal cohort study was conducted at 43 US and Canadian Huntington Study Group research sites from July 9, 1999, through December 17, 2009. Participants included 983 unaffected adults at risk for HD who had chosen to remain unaware of their mutation status. Baseline comparability between CAG expansion (>=37 repeats) and nonexpansion (<37 repeats) groups was assessed. All participants and investigators were blinded to individual CAG analysis. A repeated-measures analysis adjusting for age and sex was used to assess the divergence of the linear trend between the expanded and nonexpanded groups. Data were analyzed from April 27, 2010, to September 3, 2013. EXPOSURE: Huntington disease mutation status in individuals with CAG expansion vs without CAG expansion. MAIN OUTCOMES AND MEASURES: Unified Huntington's Disease Rating Scale motor (score range, 0-124; higher scores indicate greater impairment), cognitive (symbol digits modality is the total number of correct responses in 90 seconds; lower scores indicate greater impairment), behavioral (score range, 0-176; higher scores indicate greater behavioral symptoms), and functional (Total Functional Capacity score range, 0-13; lower scores indicate reduced functional ability) domains were assessed at baseline and every 9 months up to a maximum of 10 years. RESULTS: Among the 983 research participants at risk for HD in the longitudinal cohort, 345 (35.1%) carried the CAG expansion and 638 (64.9%) did not. The mean (SD) duration of follow-up was 5.8 (3.0) years. At baseline, participants with expansions had more impaired motor (3.0 [4.2] vs 1.9 [2.8]; P < .001), cognitive (P < .05 for all measures except Verbal Fluency, P = .52), and behavioral domain scores (9.4 [11.4] vs 6.5 [8.5]; P < .001) but not significantly different measures of functional capacity (12.9 [0.3] vs 13.0 [0.2]; P = .23). With findings reported as mean slope (95% CI), in the longitudinal analyses, participants with CAG expansions showed significant worsening in motor (0.84 [0.73 to 0.95] vs 0.03 [-0.05 to 0.11]), cognitive ( 0.54 [-0.67 to -0.40] vs 0.22 [0.12 to 0.32]), and functional (-0.08 [-0.09 to 0.06] vs -0.01 [-0.02 to 0]) measures compared with those without expansion (P < .001 for all); behavioral domain scores did not diverge significantly between groups. CONCLUSIONS AND RELEVANCE: Using these prospectively accrued clinical data, relatively large treatment effects would be required to mount a randomized, placebo-controlled clinical trial involving premanifest HD individuals who carry the CAG expansion. PMID- 26569100 TI - Assessment of the Utility of Whole Genome Sequencing of Measles Virus in the Characterisation of Outbreaks. AB - BACKGROUND: Measles is a highly infectious disease caused by measles virus (MeV). Despite the availability of a safe and cost-effective vaccine, measles is one of the world-leading causes of death in young children. Within Europe, there is a target for eliminating endemic measles in 2015, with molecular epidemiology required on 80% of cases for inclusion/exclusion of outbreak transmission chains. Currently, MeV is genotyped on the basis of a 450 nucleotide region of the nucleoprotein gene (N-450) and the hemagglutinin gene (H). However, this is not sufficiently informative for distinguishing endemic from imported MeV. We have developed an amplicon-based method for obtaining whole genome sequences (WGS) using NGS or Sanger methodologies from cell culture isolates or oral fluid specimens, and have sequenced over 60 samples, including 42 from the 2012 outbreak in the UK. RESULTS: Overall, NGS coverage was over 90% for approximately 71% of the samples tested. Analysis of 32 WGS excluding 3' and 5' termini (WGS-t) obtained from the outbreak indicates that the single nucleotide difference found between the two major groups of N-450 sequences detected during the outbreak is most likely a result of stochastic viral mutation during endemic transmission rather than of multiple importation events: earlier strains appear to have evolved into two distinct strain clusters in 2013, one containing strains with both outbreak-associated N-450 sequences. Additionally, phylogenetic analysis of each genomic region of MeV for the strains in this study suggests that the most information is acquired from the non-coding region located between the matrix and fusion protein genes (M/F NCR) and the N-450 genotyping sequence, an observation supported by entropy analysis across genotypes. CONCLUSIONS: We suggest that both M/F NCR and WGS-t could be used to complement the information from classical epidemiology and N-450 sequencing to address specific questions in the context of measles elimination. PMID- 26569101 TI - Basal Metabolic Rate of Adolescent Modern Pentathlon Athletes: Agreement between Indirect Calorimetry and Predictive Equations and the Correlation with Body Parameters. AB - PURPOSE: The accurate estimative of energy needs is crucial for an optimal physical performance among athletes and the basal metabolic rate (BMR) equations often are not well adjusted for adolescent athletes requiring the use of specific methods, such as the golden standard indirect calorimetry (IC). Therefore, we had the aim to analyse the agreement between the BMR of adolescents pentathletes measured by IC and estimated by commonly used predictive equations. METHODS: Twenty-eight athletes (17 males and 11 females) were evaluated for BMR, using IC and the predictive equations Harris and Benedict (HB), Cunningham (CUN), Henry and Rees (HR) and FAO/WHO/UNU (FAO). Body composition was obtained using DXA and sexual maturity data were retrieved through validated questionnaires. The correlations among anthropometric variables an IC were analysed by T-student test and ICC, while the agreement between IC and the predictive equations was analysed according to Bland and Altman and by survival-agreement plotting. RESULTS: The whole sample average BMR measured by IC was significantly different from the estimated by FAO (p<0.05). Adjusting data by gender FAO and HR equations were statistically different from IC (p <0.05) among males, while female differed only for the HR equation (p <0.05). CONCLUSION: The FAO equation underestimated athletes' BMR when compared with IC (T Test). When compared to the golden standard IC, using Bland and Altman, ICC and Survival-Agreement, the equations underestimated the energy needs of adolescent pentathlon athletes up to 300kcal/day. Therefore, they should be used with caution when estimating individual energy requirements in such populations. PMID- 26569102 TI - A Chemical Screening Approach to Identify Novel Key Mediators of Erythroid Enucleation. AB - Erythroid enucleation is critical for terminal differentiation of red blood cells, and involves extrusion of the nucleus by orthochromatic erythroblasts to produce reticulocytes. Due to the difficulty of synchronizing erythroblasts, the molecular mechanisms underlying the enucleation process remain poorly understood. To elucidate the cellular program governing enucleation, we utilized a novel chemical screening approach whereby orthochromatic cells primed for enucleation were enriched ex vivo and subjected to a functional drug screen using a 324 compound library consisting of structurally diverse, medicinally active and cell permeable drugs. Using this approach, we have confirmed the role of HDACs, proteasomal regulators and MAPK in erythroid enucleation and introduce a new role for Cyclin-dependent kinases, in particular CDK9, in this process. Importantly, we demonstrate that when coupled with imaging analysis, this approach provides a powerful means to identify and characterize rate limiting steps involved in the erythroid enucleation process. PMID- 26569103 TI - Kinetics of Anti-Phlebotomus perniciosus Saliva Antibodies in Experimentally Bitten Mice and Rabbits. AB - BACKGROUND: Sand flies are hematophagous arthropods that act as vectors of Leishmania parasites. When hosts are bitten they develop cellular and humoral responses against sand fly saliva. A positive correlation has been observed between the number of bites and antibody levels indicating that anti-saliva antibody response can be used as marker of exposure to sand flies. Little is known about kinetics of antibodies against Phlebotomus perniciosus salivary gland homogenate (SGH) or recombinant salivary proteins (rSP). This work focused on the study of anti-P. perniciosus saliva antibodies in sera of mice and rabbits that were experimentally exposed to the bites of uninfected sand flies. METHODOLOGY/PRINCIPAL FINDINGS: Anti-saliva antibodies were evaluated by ELISA and Western blot. In addition, antibody levels against two P. perniciosus rSP, apyrase rSP01B and D7 related protein rSP04 were determined in mice sera. Anti saliva antibody levels increased along the immunizations and correlated with the number of sand fly bites. Anti-SGH antibody levels were detected in sera of mice five weeks after exposure, and persisted for at least three months. Anti-apyrase rSP01B antibodies followed similar kinetic responses than anti-SGH antibodies while rSP04 showed a delayed response and exhibited a greater variability among sera of immunized mice. In rabbits, anti-saliva antibodies appeared after the second week of exposure and IgG antibodies persisted at high levels, even 7 months post-exposure. CONCLUSIONS/SIGNIFICANCE: Our results contributed to increase the knowledge on the type of immune response P. perniciosus saliva and individual proteins elicited highlighting the use of rSP01B as an epidemiological marker of exposure. Anti-saliva kinetics in sera of experimentally bitten rabbits were studied for the first time. Results with rabbit model provided useful information for a better understanding of the anti-saliva antibody levels found in wild leporids in the human leishmaniasis focus in the Madrid region, Spain. PMID- 26569104 TI - Autologous Plasma Rich in Growth Factors Eyedrops in Refractory Cases of Ocular Surface Disorders. AB - PURPOSE: Preliminary information about the safety and efficacy of plasma rich in growth factors (PRGF) eyedrops in the treatment of refractory cases of diverse ocular surface disorders (OSDs) is presented here. MATERIAL AND METHODS: This retrospective cohort study included cases with OSDs refractory to previous treatment with conventional treatments or autologous serum or cyclosporine, and treated with PRGF eyedrops. The signs and symptoms of ocular surface disorders [using the ocular surface disease index (OSDI), best-corrected visual acuity (BCVA), visual analog scale (VAS) frequency and VAS severity] were evaluated before and after treatment with PRGF. A safety assessment was also performed reporting all adverse events or complications. RESULTS: Forty-one patients with a total of 80 treated eyes were evaluated. Statistically significant reductions in the OSDI scale (39.27%), VAS frequency (38.9%) and VAS severity (40.3%), and a significant improvement in BCVA (54.86%) were all observed (p < 0.05). The results were stratified according to the identified potential effect modifiers. There were only two adverse events (eye redness and eyelid inflammation), which were reported as mild and resolved in a few days. CONCLUSIONS: PRGF eyedrops could be a safe and effective treatment option for refractory cases of OSDs. When treating patients the possible influence on the results of some clinical variables must be taken into account. PMID- 26569105 TI - Demineralized Dentin Matrix Induces Odontoblastic Differentiation of Dental Pulp Stem Cells. AB - The aim of this study was to investigate the effect of demineralized dentin matrix (DDM) on dental pulp stem cells (DPSCs) and the potential of complexes with DPSCs and DDM for mineralized tissue formation. Stem cells derived from the dental pulp of healthy pigs aged 18 months were isolated and cultured. DPSCs were incubated with alpha-minimum essential medium treated with DDM extract at 1 mg/ml (DDM1) or 10 mg/ml (DDM10). The concentrations of 3 growth factors in DDM extract was measured by enzyme-linked immunosorbent assay. Adhesion of DPSCs on DDM and hydroxyapatite-tricalcium phosphate (HA-TCP) surfaces was observed using scanning electron microscopy. Cell proliferation was evaluated with cell counting kit-8 and migration by Transwell migration assays. Odontoblastic differentiation was assessed by alkaline phosphatase (ALP) and alizarin red staining, ALP activity and real-time polymerase chain reaction analysis of markers of ALP, runt-related transcription factor 2, type I collagen, dentin matrix acidic phosphoprotein-1, osteonectin and dentin sialophosphoprotein (DSPP). Finally, DPSCs were combined with DDM and placed subcutaneously in nude mice for 12 weeks; DPSCs combined with HA-TCP and DDM alone served as controls. DDM could promote DPSC adhesion, migration and odontoblastic differentiation. Mineralized tissue formation was observed with the DPSC and DDM combination and the DPSC and HA-TCP combination. The mineralized tissue of the DPSC + DDM combination stained positive for DSPP, similar to the dentin tissue. These results indicate that DDM induces DPSC odontoblastic differentiation, suggesting applications for dentin regeneration. PMID- 26569106 TI - Plasma Membrane Abundance of Human Aquaporin 5 Is Dynamically Regulated by Multiple Pathways. AB - Aquaporin membrane protein channels mediate cellular water flow. Human aquaporin 5 (AQP5) is highly expressed in the respiratory system and secretory glands where it facilitates the osmotically-driven generation of pulmonary secretions, saliva, sweat and tears. Dysfunctional trafficking of AQP5 has been implicated in several human disease states, including Sjogren's syndrome, bronchitis and cystic fibrosis. In order to investigate how the plasma membrane expression levels of AQP5 are regulated, we studied real-time translocation of GFP-tagged AQP5 in HEK293 cells. We show that AQP5 plasma membrane abundance in transfected HEK293 cells is rapidly and reversibly regulated by at least three independent mechanisms involving phosphorylation at Ser156, protein kinase A activity and extracellular tonicity. The crystal structure of a Ser156 phosphomimetic mutant indicates that its involvement in regulating AQP5 membrane abundance is not mediated by a conformational change of the carboxy-terminus. We suggest that together these pathways regulate cellular water flow. PMID- 26569107 TI - Bonding, Bridging, and Linking Social Capital and Self-Rated Health among Chinese Adults: Use of the Anchoring Vignettes Technique. AB - Three main opposing camps exist over how social capital relates to population health, namely the social support perspective, the inequality thesis, and the political economy approach. The distinction among bonding, bridging, and linking social capital probably helps close the debates between these three camps, which is rarely investigated in existing literatures. Moreover, although self-rated health is a frequently used health indicator in studies on the relationship between social capital and health, the interpersonal incomparability of this measure has been largely neglected. This study has two main objectives. Firstly, we aim to investigate the relationship between bonding, bridging, and linking social capital and self-rated health among Chinese adults. Secondly, we aim to improve the interpersonal comparability in self-rated health measurement. We use data from a nationally representative survey in China. Self-rated health was adjusted using the anchoring vignettes technique to improve comparability. Two level ordinal logistic regression was performed to model the association between social capital and self-rated health at both individual and community levels. The interaction between residence and social capital was included to examine urban/rural disparities in the relationship. We found that most social capital indicators had a significant relationship with adjusted self-rated health of Chinese adults, but the relationships were mixed. Individual-level bonding, linking social capital, and community-level bridging social capital were positively related with health. Significant urban/rural disparities appeared in the association between community-level bonding, linking social capital, and adjusted self-rated health. For example, people living in communities with higher bonding social capital tended to report poorer adjusted self-rated health in urban areas, but the opposite tendency held for rural areas. Furthermore, the comparison between multivariate analyses results before and after the anchoring vignettes adjustment showed that the relationship between community-level social capital and self-rated health might be distorted if comparability problems are not addressed. In conclusion, the framework of bonding, bridging, and linking social capital helps us better understand the mechanism between social capital and self-rated health. Cultural and socioeconomic factors should be considered when designing health intervention policies using social capital. Moreover, we recommend that more studies improve the comparability of self-rated health by using the anchoring vignettes technique. PMID- 26569108 TI - Strategic Grassland Bird Conservation throughout the Annual Cycle: Linking Policy Alternatives, Landowner Decisions, and Biological Population Outcomes. AB - Grassland bird habitat has declined substantially in the United States. Remaining grasslands are increasingly fragmented, mostly privately owned, and vary greatly in terms of habitat quality and protection status. A coordinated strategic response for grassland bird conservation is difficult, largely due to the scope and complexity of the problem, further compounded by biological, sociological, and economic uncertainties. We describe the results from a collaborative Structured Decision Making (SDM) workshop focused on linking social and economic drivers of landscape change to grassland bird population outcomes. We identified and evaluated alternative strategies for grassland bird conservation using a series of rapid prototype models. We modeled change in grassland and agriculture cover in hypothetical landscapes resulting from different landowner decisions in response to alternative socio-economic conservation policy decisions. Resulting changes in land cover at all three stages of the annual cycle (breeding, wintering, and migration) were used to estimate changes in grassland bird populations. Our results suggest that successful grassland bird conservation may depend upon linkages with ecosystem services on working agricultural lands and grassland-based marketing campaigns to engage the public. With further development, spatial models that link landowner decisions with biological outcomes can be essential tools for making conservation policy decisions. A coordinated non-traditional partnership will likely be necessary to clearly understand and systematically respond to the many conservation challenges facing grassland birds. PMID- 26569109 TI - Recommendations on Quality Control and Quality Assurance in Cervical Cytology. AB - OBJECTIVE: We aimed to critically evaluate the importance of quality control (QC) and quality assurance (QA) strategies in the routine work of uterine cervix cytology. STUDY DESIGN: We revised all the main principles of QC and QA that are already being implemented worldwide and then discussed the positive aspects and limitations of these as well as proposing alternatives when pertinent. RESULTS: A literature review was introduced after highlighting the main historical revisions, and then a critical evaluation of the principal innovations in screening programmes was conducted, with recommendations being postulated. CONCLUSIONS: Based on the analysed data, QC and QA are two essential arms that support the quality of a screening programme. PMID- 26569110 TI - MICB Allele Genotyping on Microarrays by Improving the Specificity of Extension Primers. AB - Major histocompatibility complex (MHC) class I chain-related gene B (MICB) encodes a ligand for activating NKG2D that expressed in natural killer cells, gammadelta T cells, and alphabeta CD8+ T cells, which is associated with autoimmune diseases, cancer, and infectious diseases. Here, we have established a system for genotyping MICB alleles using allele-specific primer extension (ASPE) on microarrays. Thirty-six high quality, allele-specific extension primers were evaluated using strict and reliable cut-off values using mean fluorescence intensity (MFI), whereby an MFI >30,000 represented a positive signal and an MFI <10,000 represented a negative signal. Eight allele-specific extension primers were found to be false positives, five of which were improved by adjusting their length, and three of which were optimized by refractory modification. The MICB alleles (*002:01, *003, *005:02/*010, *005:03, *008, *009N, *018, and *024) present in the quality control panel could be exactly defined by 22 allele specific extension primers. MICB genotypes that were identified by ASPE on microarrays were in full concordance with those identified by PCR-sequence-based typing. In conclusion, we have developed a method for genotyping MICB alleles using ASPE on microarrays; which can be applicable for large-scale single nucleotide polymorphism typing studies of population and disease associations. PMID- 26569111 TI - Reducing Antibiotic Use for Young Children with Intussusception following Successful Air Enema Reduction. AB - China introduced a new policy regarding the management of antibiotic use. We evaluated the reasonableness of antibiotic use among children suffering from intussusception before and after policy. A retrospective study was conducted involving 234 young children with intussusception who were treated between January 1, 2011 and December 30, 2013. Demographics and detailed antibiotics regimens were collected. chi2 test was used to evaluate differences between the phase I (preintervention, n = 68) and phase II (postintervention, n = 166). We determined that the overall antibiotic use rate following successful air enema reduction was 41% (97/234), which decreased from 99% (67/68) in phase I to 18% (30/166) in phase II. In phase I, prophylactic antibiotic usage reached up to 84% (56/67). The quantity of aztreonam for injection accounted for 63% (45/71), and cefamandole nafate for injection accounted for 25% (18/71). In phases II, prophylactic antibiotic usage were reduced to 13% (4/30). The quantity of aztreonam for injection was decreased to 12% (4/33) and cefamandole nafate for injection was 3% (1/33). Antibiotics' options were more diverse. In conclusion, policy intervention was effective in addressing some aspects of antibacterial drug usage among young children with intussusception. However, excessive drug use remains a public health problem. The guidelines for the antibiotic management of intussusception for children must be established in China. PMID- 26569112 TI - Increased Feeding Speed Is Associated with Higher Subsequent Sympathetic Activity in Dogs. AB - Although the domestication process has altered the feeding behavior of dogs, some breeds still demonstrate a remarkable ability to gorge, and will eat exceptionally large quantities of food whenever it is available. Lesions in the ventromedial hypothalamus increase appetite and lead to obesity, suggesting that the autonomic nervous system plays an important role in feeding. Focusing on the autonomic activities closely involved in food intake, we investigated sympathetic activities before and after feeding in dogs. The subjects were 56 healthy dogs of 21 different breeds (29 males and 27 females). Based on feeding habits, the 56 dogs were divided into three groups: Fast (n = 19), Slow (n = 24) and Leftover (n = 13). The feeding speed and the amount of food per mouthful of the Fast dogs were significantly greater than those of the Slow and the Leftover dogs. The plasma norepinephrine level in dogs of the Fast group was significantly increased after feeding, while those in the Slow and Leftover groups were significantly decreased after feeding, compared with the pre-feeding concentrations. The low frequency/high frequency ratio of heart rate variability is a good indicator of sympathetic activity and was also significantly higher in the Fast group than in the other groups. Delayed feeding using automatic feeding equipment decreased the plasma norepinephrine concentration and low frequency/high frequency ratio observed after feeding in dogs of the Fast group. In conclusion, dogs eating rapidly with less chewing, which indicates increased sympathetic activity during feeding, may benefit from delayed feeding. The slow eating may activate the parasympathetic nervous system after feeding, which could enhance the activity of the digestive system. PMID- 26569113 TI - An Event Related Potentials Study of the Effects of Age, Load and Maintenance Duration on Working Memory Recognition. AB - Age-related decline in cognitive capacities has been attributed to a generalized slowing of processing speed and a reduction in working memory (WM) capacity. Nevertheless, it is unclear how age affects visuospatial WM recognition and its underlying brain electrical activity. Whether age modulates the effects of memory load or information maintenance duration, which determine the limits of WM, remains also elusive. In this exploratory study, performance in a delayed match to sample task declined with age, particularly in conditions with high memory load. Event related potentials analysis revealed longer N2 and P300 latencies in old than in young adults during WM recognition, which may reflect slowing of stimulus evaluation and classification processes, respectively. Although there were no differences between groups in N2 or P300 amplitudes, the latter was more homogeneously distributed in old than in young adults, which may indicate an age related increased reliance in frontal vs parietal resources during WM recognition. This was further supported by an age-related reduced posterior cingulate activation and increased superior frontal gyrus activation revealed through standardized low resolution electromagnetic tomography. Memory load and maintenance duration effects on brain activity were similar in both age groups. These behavioral and electrophysiological results add evidence in support of age related decline in WM recognition theories, with a slowing of processing speed that may be limited to stimulus evaluation and categorization processes--with no effects on perceptual processes--and a posterior to anterior shift in the recruitment of neural resources. PMID- 26569115 TI - Diagnostic Magnetic Resonance Imaging of Atherosclerosis in Apolipoprotein E Knockout Mouse Model Using Macrophage-Targeted Gadolinium-Containing Synthetic Lipopeptide Nanoparticles. AB - Cardiovascular disease is the leading cause of death in Western cultures. The vast majority of cardiovascular events, including stroke and myocardial infarction, result from the rupture of vulnerable atherosclerotic plaques, which are characterized by high and active macrophage content. Current imaging modalities including magnetic resonance imaging (MRI) aim to characterize anatomic and structural features of plaques rather than their content. Previously, we reported that macrophage-targeted delivery of gadolinium (Gd) based contrast agent (GBCA-HDL) using high density lipoproteins (HDL)-like particles significantly enhances the detection of plaques in an apolipoprotein (apo) E knockout (KO) mouse model, with an atherosclerotic wall/muscle normalized enhancement ratio (NER) of 120% achieved. These particles are comprised of lipids and synthetic peptide fragments of the major protein of HDL, apo A-I, that contain a naturally occurring modification which targets the particles to macrophages. Targeted delivery minimizes the Gd dose and thus reduces the adverse effects of Gd. The aims of the current study were to test whether varying the GBCA-HDL particle shape and composition can further enhance atherosclerotic plaque MRI and control organ clearance of these agents. We show that the optimized GBCA-HDL particles are efficiently delivered intracellularly to and uptaken by both J774 macrophages in vitro and more importantly, by intraplaque macrophages in vivo, as evidenced by NER up to 160% and higher. This suggests high diagnostic power of our GBCA-HDL particles in the detection of vulnerable atherosclerotic plaques. Further, in contrast to discoidal, spherical GBCA-HDL exhibit hepatic clearance, which could further diminish adverse renal effects of Gd. Finally, activated macrophages are reliable indicators of any inflamed tissues and are implicated in other areas of unmet clinical need such as rheumatoid arthritis, sepsis and cancer, suggesting the expanded diagnostic and prognostic use of this method. PMID- 26569116 TI - Falling with Style: Bats Perform Complex Aerial Rotations by Adjusting Wing Inertia. AB - The remarkable maneuverability of flying animals results from precise movements of their highly specialized wings. Bats have evolved an impressive capacity to control their flight, in large part due to their ability to modulate wing shape, area, and angle of attack through many independently controlled joints. Bat wings, however, also contain many bones and relatively large muscles, and thus the ratio of bats' wing mass to their body mass is larger than it is for all other extant flyers. Although the inertia in bat wings would typically be associated with decreased aerial maneuverability, we show that bat maneuvers challenge this notion. We use a model-based tracking algorithm to measure the wing and body kinematics of bats performing complex aerial rotations. Using a minimal model of a bat with only six degrees of kinematic freedom, we show that bats can perform body rolls by selectively retracting one wing during the flapping cycle. We also show that this maneuver does not rely on aerodynamic forces, and furthermore that a fruit fly, with nearly massless wings, would not exhibit this effect. Similar results are shown for a pitching maneuver. Finally, we combine high-resolution kinematics of wing and body movements during landing and falling maneuvers with a 52-degree-of-freedom dynamical model of a bat to show that modulation of wing inertia plays the dominant role in reorienting the bat during landing and falling maneuvers, with minimal contribution from aerodynamic forces. Bats can, therefore, use their wings as multifunctional organs, capable of sophisticated aerodynamic and inertial dynamics not previously observed in other flying animals. This may also have implications for the control of aerial robotic vehicles. PMID- 26569114 TI - Genome-Wide Association Study of Staphylococcus aureus Carriage in a Community Based Sample of Mexican-Americans in Starr County, Texas. AB - Staphylococcus aureus is the number one cause of hospital-acquired infections. Understanding host pathogen interactions is paramount to the development of more effective treatment and prevention strategies. Therefore, whole exome sequence and chip-based genotype data were used to conduct rare variant and genome-wide association analyses in a Mexican-American cohort from Starr County, Texas to identify genes and variants associated with S. aureus nasal carriage. Unlike most studies of S. aureus that are based on hospitalized populations, this study used a representative community sample. Two nasal swabs were collected from participants (n = 858) 11-17 days apart between October 2009 and December 2013, screened for the presence of S. aureus, and then classified as either persistent, intermittent, or non-carriers. The chip-based and exome sequence-based single variant association analyses identified 1 genome-wide significant region (KAT2B) for intermittent and 11 regions suggestively associated with persistent or intermittent S. aureus carriage. We also report top findings from gene-based burden analyses of rare functional variation. Notably, we observed marked differences between signals associated with persistent and intermittent carriage. In single variant analyses of persistent carriage, 7 of 9 genes in suggestively associated regions and all 5 top gene-based findings are associated with cell growth or tight junction integrity or are structural constituents of the cytoskeleton, suggesting that variation in genes associated with persistent carriage impact cellular integrity and morphology. PMID- 26569118 TI - NGF Modulates trkANGFR/p75NTR in alphaSMA-Expressing Conjunctival Fibroblasts from Human Ocular Cicatricial Pemphigoid (OCP). AB - OBJECTIVE: In a previous study, we reported the upregulation of Nerve Growth Factor (NGF) and trkANGFR expression in Ocular Cicatricial Pemphigoid (OCP), an inflammatory and remodeling eye disease. Herein, we hypothesize a potential NGF driven mechanism on fibroblasts (FBs) during OCP remodeling events. To verify, human derived OCP-FBs were isolated and characterized either at baseline or after NGF exposure. MATERIALS AND METHODS: Conjunctival biopsies were obtained from 7 patients having OCP and 6 control subjects (cataract surgery). Both conjunctivas and primary FB cultures were characterised for alphaSMA, NGF and trkANGFR/p75NTR expression. Subcultures were exposed to NGF and evaluated for alphaSMA, NGF, trkANGFR/p75NTR expression as well as TGFbeta1/IL4 release. For analysis, early and advanced subgroups were defined according to clinical parameters. RESULTS: OCP-conjunctivas showed alphaSMA-expressing FBs and high NGF levels. Advanced OCP FBs showed higher alphaSMA expression associated with higher p75NTR and lower trkANGFR expression, as compared to early counterparts. alphaSMA expression was in keeping with disease severity and correlated to p75NTR. NGF exposure did not affect trkANGFR levels in early OCP-FBs while decreased both alphaSMA/p75NTR expression and TGFbeta1/IL4 release. These effects were not observed in advanced OCP-FBs. CONCLUSIONS: Taken together, these data are suggestive for a NGF/p75NTR task in the potential modulation of OCP fibrosis and encourages further studies to fully understand the underlying mechanism occurring in fibrosis. NGF/p75NTR might be viewed as a potential therapeutic target. PMID- 26569117 TI - Comparative Genomics of NAC Transcriptional Factors in Angiosperms: Implications for the Adaptation and Diversification of Flowering Plants. AB - NAC proteins constitute one of the largest groups of plant-specific transcription factors and are known to play essential roles in various developmental processes. They are also important in plant responses to stresses such as drought, soil salinity, cold, and heat, which adversely affect growth. The current knowledge regarding the distribution of NAC proteins in plant lineages comes from relatively small samplings from the available data. In the present study, we broadened the number of plant species containing the NAC family origin and evolution to shed new light on the evolutionary history of this family in angiosperms. A comparative genome analysis was performed on 24 land plant species, and NAC ortholog groups were identified by means of bidirectional BLAST hits. Large NAC gene families are found in those species that have experienced more whole-genome duplication events, pointing to an expansion of the NAC family with divergent functions in flowering plants. A total of 3,187 NAC transcription factors that clustered into six major groups were used in the phylogenetic analysis. Many orthologous groups were found in the monocot and eudicot lineages, but only five orthologous groups were found between P. patens and each representative taxa of flowering plants. These groups were called basal orthologous groups and likely expanded into more recent taxa to cope with their environmental needs. This analysis on the angiosperm NAC family represents an effort to grasp the evolutionary and functional diversity within this gene family while providing a basis for further functional research on vascular plant gene families. PMID- 26569119 TI - Spatial Scaling of Environmental Variables Improves Species-Habitat Models of Fishes in a Small, Sand-Bed Lowland River. AB - Habitat suitability and the distinct mobility of species depict fundamental keys for explaining and understanding the distribution of river fishes. In recent years, comprehensive data on river hydromorphology has been mapped at spatial scales down to 100 m, potentially serving high resolution species-habitat models, e.g., for fish. However, the relative importance of specific hydromorphological and in-stream habitat variables and their spatial scales of influence is poorly understood. Applying boosted regression trees, we developed species-habitat models for 13 fish species in a sand-bed lowland river based on river morphological and in-stream habitat data. First, we calculated mean values for the predictor variables in five distance classes (from the sampling site up to 4000 m up- and downstream) to identify the spatial scale that best predicts the presence of fish species. Second, we compared the suitability of measured variables and assessment scores related to natural reference conditions. Third, we identified variables which best explained the presence of fish species. The mean model quality (AUC = 0.78, area under the receiver operating characteristic curve) significantly increased when information on the habitat conditions up- and downstream of a sampling site (maximum AUC at 2500 m distance class, +0.049) and topological variables (e.g., stream order) were included (AUC = +0.014). Both measured and assessed variables were similarly well suited to predict species' presence. Stream order variables and measured cross section features (e.g., width, depth, velocity) were best-suited predictors. In addition, measured channel-bed characteristics (e.g., substrate types) and assessed longitudinal channel features (e.g., naturalness of river planform) were also good predictors. These findings demonstrate (i) the applicability of high resolution river morphological and instream-habitat data (measured and assessed variables) to predict fish presence, (ii) the importance of considering habitat at spatial scales larger than the sampling site, and (iii) that the importance of (river morphological) habitat characteristics differs depending on the spatial scale. PMID- 26569120 TI - Analytical Sensitivity Comparison between Singleplex Real-Time PCR and a Multiplex PCR Platform for Detecting Respiratory Viruses. AB - Multiplex PCR methods are attractive to clinical laboratories wanting to broaden their detection of respiratory viral pathogens in clinical specimens. However, multiplexed assays must be well optimized to retain or improve upon the analytic sensitivity of their singleplex counterparts. In this experiment, the lower limit of detection (LOD) of singleplex real-time PCR assays targeting respiratory viruses is compared to an equivalent panel on a multiplex PCR platform, the GenMark eSensor RVP. LODs were measured for each singleplex real-time PCR assay and expressed as the lowest copy number detected 95-100% of the time, depending on the assay. The GenMark eSensor RVP LODs were obtained by converting the TCID50/mL concentrations reported in the package insert to copies/MUL using qPCR. Analytical sensitivity between the two methods varied from 1.2-1280.8 copies/MUL (0.08-3.11 log differences) for all 12 assays compared. Assays targeting influenza A/H3N2, influenza A/H1N1pdm09, influenza B, and human parainfluenza 1 and 2 were most comparable (1.2-8.4 copies/MUL, <1 log difference). Largest differences in LOD were demonstrated for assays targeting adenovirus group E, respiratory syncytial virus subtype A, and a generic assay for all influenza A viruses regardless of subtype (319.4-1280.8 copies/MUL, 2.50-3.11 log difference). The multiplex PCR platform, the GenMark eSensor RVP, demonstrated improved analytical sensitivity for detecting influenza A/H3 viruses, influenza B virus, human parainfluenza virus 2, and human rhinovirus (1.6-94.8 copies/MUL, 0.20-1.98 logs). Broader detection of influenza A/H3 viruses was demonstrated by the GenMark eSensor RVP. The relationship between TCID50/mL concentrations and the corresponding copy number related to various ATCC cultures is also reported. PMID- 26569121 TI - The thermodynamics of protein interactions with essential first row transition metals. AB - BACKGROUND: The binding of metal ions to proteins is a crucial process required for their catalytic activity, structural stability and/or functional regulation. Isothermal titration calorimetry provides a wealth of fundamental information which when combined with structural data allow for a much deeper understanding of the underlying molecular mechanism. SCOPE OF REVIEW: A rigorous understanding of any molecular interaction requires in part an in-depth quantification of its thermodynamic properties. Here, we provide an overview of recent studies that have used ITC to quantify the interaction of essential first row transition metals with relevant proteins and highlight major findings from these thermodynamic studies. GENERAL SIGNIFICANCE: The thermodynamic characterization of metal ion-protein interactions is one important step to understanding the role that metal ions play in living systems. Such characterization has important implications not only to elucidating proteins' structure-function relationships and biological properties but also in the biotechnology sector, medicine and drug design particularly since a number of metal ions are involved in several neurodegenerative diseases. MAJOR CONCLUSIONS: Isothermal titration calorimetry measurements can provide complete thermodynamic profiles of any molecular interaction through the simultaneous determination of the reaction binding stoichiometry, binding affinity as well as the enthalpic and entropic contributions to the free energy change thus enabling a more in-depth understanding of the nature of these interactions. PMID- 26569122 TI - Serum Levels of sRAGE Are Associated with Body Measurements, but Not Glycemic Parameters in Patients with Prediabetes. AB - BACKGROUND: Our aim was to assess serum levels of the soluble receptor for advanced glycation end products (sRAGE) and to examine their association with anthropometric and metabolic parameters in patients with prediabetes and obese controls. METHODS: The two study groups were composed of 42 patients with prediabetes and diabetic neuropathy and 42 age-, gender-, body weight (BW)-, and body mass index (BMI)-matched obese adults as the control group. Prediabetes was diagnosed by the following criteria issued by the American Diabetes Association: impaired fasting glucose [fasting plasma glucose (FPG) level of 100-125 mg/dL], impaired glucose tolerance (2 hr plasma glucose level of 140-199 mg/dL after a 75 grams oral glucose challenge), or a glycated hemoglobin (HbA1C) level of 5.7% 6.4%. RESULTS: There were no differences between the groups in terms of age, gender distribution, BW, or BMI. Despite these similarities, patients with prediabetes had higher FPG, HbA1c, and 2-hr postchallenge glucose levels, higher systolic and diastolic blood pressure, and larger waist and hip circumferences compared with the obese controls. Lipid measurements, complete blood counts, kidney and liver function tests, high-sensitivity C-reactive protein, and sRAGE levels were similar between the two groups. We found significant negative correlations between sRAGE levels and BW, BMI, waist and hip circumferences, waist-to-hip ratios, and low-density lipoprotein (LDL) cholesterol levels. There were no significant correlations with other parameters, including demographic, metabolic, and blood pressure measurements. CONCLUSIONS: In contrast to glycemic parameters, serum levels of sRAGE were negatively correlated with body measurements indicative of obesity in the prediabetic state. In addition, the negative correlation with LDL cholesterol levels suggests that sRAGE has a more robust association with metabolic syndrome than with prediabetes. PMID- 26569123 TI - Structural genomic changes underlie alternative reproductive strategies in the ruff (Philomachus pugnax). AB - The ruff is a Palearctic wader with a spectacular lekking behavior where highly ornamented males compete for females. This bird has one of the most remarkable mating systems in the animal kingdom, comprising three different male morphs (independents, satellites and faeders) that differ in behavior, plumage color and body size. Remarkably, the satellite and faeder morphs are controlled by dominant alleles. Here we have used whole-genome sequencing and resolved the enigma of how such complex phenotypic differences can have a simple genetic basis. The Satellite and Faeder alleles are both associated with a 4.5-Mb inversion that occurred about 3.8 million years ago. We propose an evolutionary scenario where the Satellite chromosome arose by a rare recombination event about 500,000 years ago. The ruff mating system is the result of an evolutionary process in which multiple genetic changes contributing to phenotypic differences between morphs have accumulated within the inverted region. PMID- 26569124 TI - Domestication selected for deceleration of the circadian clock in cultivated tomato. AB - The circadian clock is a critical regulator of plant physiology and development, controlling key agricultural traits in crop plants. In addition, natural variation in circadian rhythms is important for local adaptation. However, quantitative modulation of circadian rhythms due to artificial selection has not yet been reported. Here we show that the circadian clock of cultivated tomato (Solanum lycopersicum) has slowed during domestication. Allelic variation of the tomato homolog of the Arabidopsis gene EID1 is responsible for a phase delay. Notably, the genomic region harboring EID1 shows signatures of a selective sweep. We find that the EID1 allele in cultivated tomatoes enhances plant performance specifically under long day photoperiods, suggesting that humans selected slower circadian rhythms to adapt the cultivated species to the long summer days it encountered as it was moved away from the equator. PMID- 26569126 TI - The contribution of rare variation to prostate cancer heritability. AB - We report targeted sequencing of 63 known prostate cancer risk regions in a multi ancestry study of 9,237 men and use the data to explore the contribution of low frequency variation to disease risk. We show that SNPs with minor allele frequencies (MAFs) of 0.1-1% explain a substantial fraction of prostate cancer risk in men of African ancestry. We estimate that these SNPs account for 0.12 (standard error (s.e.) = 0.05) of variance in risk (~42% of the variance contributed by SNPs with MAF of 0.1-50%). This contribution is much larger than the fraction of neutral variation due to SNPs in this class, implying that natural selection has driven down the frequency of many prostate cancer risk alleles; we estimate the coupling between selection and allelic effects at 0.48 (95% confidence interval [0.19, 0.78]) under the Eyre-Walker model. Our results indicate that rare variants make a disproportionate contribution to genetic risk for prostate cancer and suggest the possibility that rare variants may also have an outsize effect on other common traits. PMID- 26569125 TI - A supergene determines highly divergent male reproductive morphs in the ruff. AB - Three strikingly different alternative male mating morphs (aggressive 'independents', semicooperative 'satellites' and female-mimic 'faeders') coexist as a balanced polymorphism in the ruff, Philomachus pugnax, a lek-breeding wading bird. Major differences in body size, ornamentation, and aggressive and mating behaviors are inherited as an autosomal polymorphism. We show that development into satellites and faeders is determined by a supergene consisting of divergent alternative, dominant and non-recombining haplotypes of an inversion on chromosome 11, which contains 125 predicted genes. Independents are homozygous for the ancestral sequence. One breakpoint of the inversion disrupts the essential CENP-N gene (encoding centromere protein N), and pedigree analysis confirms the lethality of homozygosity for the inversion. We describe new differences in behavior, testis size and steroid metabolism among morphs and identify polymorphic genes within the inversion that are likely to contribute to the differences among morphs in reproductive traits. PMID- 26569128 TI - Integrating the switching, inhibition, and updating model of executive function with the Cattell-Horn-Carroll model. AB - Executive function is an important concept in neuropsychological and cognitive research, and is often viewed as central to effective clinical assessment of cognition. However, the construct validity of executive function tests is controversial. The switching, inhibition, and updating model is the most empirically supported and replicated factor model of executive function (Miyake et al., 2000). To evaluate the relation between executive function constructs and nonexplicitly executive cognitive constructs, we used confirmatory factor reanalysis guided by the comprehensive Cattell-Horn-Carroll (CHC) model of cognitive abilities. Data from 7 of the best studies supporting the executive function model were reanalyzed, contrasting executive function models and CHC models. Where possible, we examined the effect of specifying executive function factors in addition to the CHC factors. The results suggested that little evidence is available to support updating as a separate factor from general memory factors; that inhibition does not separate from general speed; and that switching is supported as a narrow factor under general speed, but with a more restricted definition than some clinicians and researchers have conceptualized. The replicated executive function factor structure was integrated with the larger body of research on individual difference in cognition, as represented by the CHC model. PMID- 26569127 TI - Antibiotic Overuse and Paronychia: A Teachable Moment. PMID- 26569129 TI - A dynamic model of reasoning and memory. AB - Previous models of category-based induction have neglected how the process of induction unfolds over time. We conceive of induction as a dynamic process and provide the first fine-grained examination of the distribution of response times observed in inductive reasoning. We used these data to develop and empirically test the first major quantitative modeling scheme that simultaneously accounts for inductive decisions and their time course. The model assumes that knowledge of similarity relations among novel test probes and items stored in memory drive an accumulation-to-bound sequential sampling process: Test probes with high similarity to studied exemplars are more likely to trigger a generalization response, and more rapidly, than items with low exemplar similarity. We contrast data and model predictions for inductive decisions with a recognition memory task using a common stimulus set. Hierarchical Bayesian analyses across 2 experiments demonstrated that inductive reasoning and recognition memory primarily differ in the threshold to trigger a decision: Observers required less evidence to make a property generalization judgment (induction) than an identity statement about a previously studied item (recognition). Experiment 1 and a condition emphasizing decision speed in Experiment 2 also found evidence that inductive decisions use lower quality similarity-based information than recognition. The findings suggest that induction might represent a less cautious form of recognition. We conclude that sequential sampling models grounded in exemplar-based similarity, combined with hierarchical Bayesian analysis, provide a more fine-grained and informative analysis of the processes involved in inductive reasoning than is possible solely through examination of choice data. PMID- 26569130 TI - Self-esteem modulates amygdala-ventrolateral prefrontal cortex connectivity in response to mortality threats. AB - Reminders of death often elicit defensive responses in individuals, especially among those with low self-esteem. Although empirical evidence indicates that self esteem serves as a buffer against mortality threats, the precise neural mechanism underlying this effect remains unknown. We used functional magnetic resonance imaging (fMRI) to test the hypothesis that self-esteem modulates neural responses to death-related stimuli, especially functional connectivity within the limbic frontal circuitry, thereby affecting subsequent defensive reactions. As predicted, individuals with high self-esteem subjected to a mortality threat exhibited increased amygdala-ventrolateral prefrontal cortex (VLPFC) connectivity during the processing of death-related stimuli compared with individuals who have low self-esteem. Further analysis revealed that stronger functional connectivity between the amygdala and the VLPFC predicted a subsequent decline in responding defensively to those who threaten one's beliefs. These results suggest that the amygdala-VLPFC interaction, which is modulated by self-esteem, can reduce the defensiveness caused by death-related stimuli, thereby providing a neural explanation for why individuals with high self-esteem exhibit less defensive reactions to mortality threats. PMID- 26569131 TI - Do discourse global coherence and cumulated information impact on sentence syntactic processing? An event-related brain potentials study. AB - The present study aimed at exploring how two main primarily semantic factors of discourse comprehension, namely global coherence and amount of information cumulated across a passage, may impact on the sentential syntactic processing. This was measured in two event-related brain potentials (ERP) to grammatical (morphosyntactic) violations: anterior negativities (LAN) and posterior positivities (P600). Global coherence did not yield any significant effects on either ERP component, although it appeared advantageous to the detection of morphosyntactic errors. Anterior negativities were also unaffected by the amount of cumulated information. Accordingly, it seems that first-pass syntactic processes are unaffected by these discourse variables. In contrast, the first portion of the P600 was significantly modulated (increased) by the latter factor. This probably reflects bigger efforts to combine sentential information during situations highly demanding for working memory. Our results would suggest that processes involved in global discourse coherence appear relatively independent of the on-line syntactic and combinatorial mechanisms reflected in the LAN and the P600 components of the ERPs. PMID- 26569132 TI - Possible involvement of basic FGF in the upregulation of PDGFRbeta in pericytes after ischemic stroke. AB - Central nervous system (CNS) pericytes have been recognized as an indispensable component of the neurovascular unit. The expression of platelet-derived growth factor receptor beta (PDGFRbeta) is markedly increased in CNS pericytes after brain ischemia. It has been elucidated that PDGFRbeta, expressed in pericytes and pericyte-derived fibroblast-like cells, plays important roles in the maintenance of the blood-brain barrier (BBB) and in the repair process in infarct areas. The aim of this study was to uncover how the PDGFRbeta expression is regulated in pericytes after brain ischemia. We found that basic fibroblast growth factor (bFGF), but neither hypoxia at 1% O2 nor acidification at pH 6.5, significantly upregulated the PDGFRbeta expression in human cultured CNS pericytes. SU5402, an inhibitor of FGF receptor (FGFR), and inhibitors of its downstream effectors Akt and Erk abolished the bFGF-induced upregulation of PDGFRbeta. On the other hand, acidification significantly upregulated the expression of bFGF, while hypoxia upregulated the expression of FGFR1 in the pericytes. The expression of bFGF and FGFR1 was markedly induced in the ischemic hemisphere after ischemic insult in a middle cerebral artery occlusion stroke model. Immunofluorescent double labeling demonstrated that the expression of bFGF and FGFR1 was co-localized with PDGFRbeta-positive cells in peri-infarct areas. Moreover, treatment with bFGF enhanced cell growth and the PDGF-BB-induced migratory activity of cultured pericytes, which were significantly suppressed by SU5402 or Sunitinib, an inhibitor of PDGFR. These data suggested that increased bFGF upregulates the expression of PDGFRbeta and may enhance PDGFRbeta-mediated pericyte functions after brain ischemia. PMID- 26569133 TI - A practical scale for Multi-Faceted Organizational Health Climate Assessment. AB - The current study sought to develop a practical scale to measure 3 facets of workplace health climate from the employee perspective as an important component of a healthy organization. The goal was to create a short, usable yet comprehensive scale that organizations and occupational health professionals could use to determine if workplace health interventions were needed. The proposed Multi-faceted Organizational Health Climate Assessment (MOHCA) scale assesses facets that correspond to 3 organizational levels: (a) workgroup, (b) supervisor, and (c) organization. Ten items were developed and tested on 2 distinct samples, 1 cross-organization and 1 within-organization. Exploratory and confirmatory factor analyses yielded a 9-item, hierarchical 3-factor structure. Tests confirmed MOHCA has convergent validity with related constructs, such as perceived organizational support and supervisor support, as well as discriminant validity with safety climate. Lastly, criterion-related validity was found between MOHCA and health-related outcomes. The multi-faceted nature of MOHCA provides a scale that has face validity and can be easily translated into practice, offering a means for diagnosing the shortcomings of an organization or workgroup's health climate to better plan health and well-being interventions. PMID- 26569134 TI - A concise, content valid, gender invariant measure of workplace incivility. AB - The authors present a short, valid, gender invariant measure of workplace incivility that should have a high degree of utility in a variety of research designs, especially those concerned with reducing participant burden such as experience sampling and multiwave longitudinal designs. Given ongoing concerns about the psychometric properties of workplace mistreatment constructs, they validated a 4-item measure of experienced incivility based on series of 3 independent field studies (N = 2,636). In addition to retaining items on the basis of employee rated conceptual alignment (i.e., judgmental criteria) with a standard incivility definition (i.e., ambiguous intent to harm), items were also chosen based on external criteria in terms of their ability to explain incremental variance in outcomes of interest (e.g., role overload, interpersonal deviance). Items with large systematic relationships with other mistreatment constructs (i.e., abusive supervision, supervisor undermining) were excluded. In turn, the authors demonstrated that the 4-item measure is gender invariant, a critical issue that has received limited attention in the literature to date. They also experimentally investigated the effect of recall window (2 weeks, 1 month, 1 year) and found a differential pattern of effect sizes for various outcomes of interest. A fourth independent field study was conducted as a practical application of the measure within a longitudinal framework. An autoregressive model examining experienced incivility and counterproductive work behaviors was tested. Data was collected from a sample of 278 respondents at 3 time points with 1 month between assessments. Implications of these findings are discussed. (PsycINFO Database Record PMID- 26569135 TI - The benefits of bad economies: Business cycles and time-based work-life conflict. AB - Recent management research has indicated the importance of family, sleep, and recreation as nonwork activities of employees. Drawing from entrainment theory, we develop an expanded model of work-life conflict to contend that macrolevel business cycles influence the amount of time employees spend on both work and nonwork activities. Focusing solely on working adults, we test this model in a large nationally representative dataset from the Bureau of Labor Statistics that spans an 8-year period, which includes the "Great Recession" from 2007 through 2009. We find that during economic booms, employees work more and therefore spend less time with family, sleeping, and recreating. In contrast, in recessionary economies, employees spend less time working and therefore more time with family, sleeping, and recreating. Thus, we extend the theory on time-based work-to-family conflict, showing that there are potential personal and relational benefits for employees in recessionary economies. PMID- 26569136 TI - Predicting Binding Poses and Affinities in the CSAR 2013-2014 Docking Exercises Using the Knowledge-Based Convex-PL Potential. AB - The 2013-2014 CSAR docking exercise was the opportunity to assess the performance of the novel knowledge-based potential we are developing, named Convex-PL. The data used to derive the potential consists only of structural information from protein-ligand interfaces found in the PDBBind database. As expected, our potential proved to be very efficient in the near-native pose detection exercises, where we correctly predicted two near-native poses in the 2013 exercise and also ranked 22 near-native poses first and 2 second in the 2014 exercise. Somewhat more surprisingly, we obtained a fair performance in some of the CSAR affinity ranking exercises, where the Spearman correlation coefficients between our predictions and the experiments are greater than 0.5 for several protein-ligand sets. Nonetheless, affinity prediction exercises turned out to be a challenge, and significant progress in the development of our method is needed before we can successfully predict binding constants. PMID- 26569137 TI - Size-Dependent Brittle-to-Ductile Transition in Silica Glass Nanofibers. AB - Silica (SiO2) glass, an essential material in human civilization, possesses excellent formability near its glass-transition temperature (Tg > 1100 degrees C). However, bulk SiO2 glass is very brittle at room temperature. Here we show a surprising brittle-to-ductile transition of SiO2 glass nanofibers at room temperature as its diameter reduces below 18 nm, accompanied by ultrahigh fracture strength. Large tensile plastic elongation up to 18% can be achieved at low strain rate. The unexpected ductility is due to a free surface affected zone in the nanofibers, with enhanced ionic mobility compared to the bulk that improves ductility by producing more bond-switching events per irreversible bond loss under tensile stress. Our discovery is fundamentally important for understanding the damage tolerance of small-scale amorphous structures. PMID- 26569138 TI - Strain-modulated Ge superlattices. AB - We present a numerical study of the electronic and optical properties of a model single-element superlattice made of a periodic sequence of relaxed and strained regions of a germanium crystal, realized by means of an externally applied strain. We adopt the tight-binding model to evaluate the strain-driven modifications of the band structure and the optical properties. Superlattice band gaps, spatial confinement of near-gap valence and conduction states, and analysis of their symmetry character, have been obtained for different superlattice periodicities and strain intensities. Our results indicate that, for suitable choices of spatial periodicity and strain values, type-I and direct-gap superlattices, with strong dipole matrix elements, can be realized. Conceptually, we demonstrate that Ge single-element strained superlattices could be active materials for novel Si-compatible optical devices. PMID- 26569139 TI - A Comparison of Some Approximate Confidence Intervals for a Single Proportion for Clustered Binary Outcome Data. AB - Interval estimation of the proportion parameter in the analysis of binary outcome data arising in cluster studies is often an important problem in many biomedical applications. In this paper, we propose two approaches based on the profile likelihood and Wilson score. We compare them with two existing methods recommended for complex survey data and some other methods that are simple extensions of well-known methods such as the likelihood, the generalized estimating equation of Zeger and Liang and the ratio estimator approach of Rao and Scott. An extensive simulation study is conducted for a variety of parameter combinations for the purposes of evaluating and comparing the performance of these methods in terms of coverage and expected lengths. Applications to biomedical data are used to illustrate the proposed methods. PMID- 26569140 TI - Constructing a group distribution from individual distributions. AB - A group distribution is a synthesis of a set of individual distributions. To be adequate, a method for creating group distributions should not introduce characteristics that are not present in the individual distributions and preserve those that are present. A method occasionally used is quantile averaging (sometimes called vincentizations), applied generally to response time distributions. However, it is shown here using quantile-quantile plots on empirical response times that this method is inadequate. As shown by Thomas and Ross (1980, Journal of Mathematical Psychology), to solve this problem, quantile averaging can be generalised using an appropriate nonlinear transformation of the data. Here we argue that the correct transformation is the log transform of response times to which the base response time has been removed. Equivalently, the geometric mean of the quantiles can be used. We first propose 4 estimates of the base response times. We next examine empirical data in a same-different task, in a redundant-attribute target detection task and in a visual search task. The results show that this approach is appropriate to construct group distributions. It can be used to aggregate distributions over multiple participants, over multiple sessions of training for a given participant, or both. (PsycINFO Database Record PMID- 26569141 TI - Competitive retrieval is not a prerequisite for forgetting in the retrieval practice paradigm. AB - Retrieving information from memory can lead to forgetting of other, related information. The inhibition account of this retrieval-induced forgetting effect predicts that this form of forgetting occurs when competition arises between the practiced information and the related information, leading to inhibition of the related information. In the standard retrieval practice paradigm, a retrieval practice task is used in which participants retrieve the items based on a category-plus-stem cue (e.g., FRUIT-or___). In the current experiment, participants instead generated the target based on a cue in which the first 2 letters of the target were transposed (e.g., FRUIT-roange). This noncompetitive task also induced forgetting of unpracticed items from practiced categories. This finding is inconsistent with the inhibition account, which asserts that the forgetting effect depends on competitive retrieval. We argue that interference based accounts of forgetting and the context-based account of retrieval-induced forgetting can account for this result. (PsycINFO Database Record PMID- 26569142 TI - Imidazole as a Small Molecule Analogue in Two-Component Signal Transduction. AB - In two-component signal transduction systems (TCSs), responses to stimuli are mediated through phosphotransfer between protein components. Canonical TCSs use His -> Asp phosphotransfer in which phosphoryl groups are transferred from a conserved His on a sensory histidine kinase (HK) to a conserved Asp on a response regulator (RR). RRs contain the catalytic core of His -> Asp phosphotransfer, evidenced by the ability of RRs to autophosphorylate with small molecule analogues of phospho-His proteins. Phosphorelays are a more complex variation of TCSs that additionally utilize Asp -> His phosphotransfer through the use of an additional component, the histidine-containing phosphotransfer domain (Hpt), which reacts with RRs both as phosphodonors and phosphoacceptors. Here we show that imidazole has features of a rudimentary Hpt. Imidazole acted as a nucleophile and attacked phosphorylated RRs (RR-P) to produce monophosphoimidazole (MPI) and unphosphorylated RR. Phosphotransfer from RR-P to imidazole required the intact RR active site, indicating that the RR provided the core catalytic machinery for Asp -> His phosphotransfer. Imidazole functioned in an artificial phosphorelay to transfer phosphoryl groups between unrelated RRs. The X-ray crystal structure of an activated RR.imidazole complex showed imidazole oriented in the RR active site similarly to the His of an Hpt. Imidazole interacted with RR nonconserved active site residues, which influenced the relative reactivity of RR-P with imidazole versus water. Rate constants for reaction of imidazole or MPI with chimeric RRs suggested that the RR active site contributes to the kinetic preferences exhibited by the YPD1 Hpt. PMID- 26569143 TI - Characterization of Electrical Current-Generation Capabilities from Thermophilic Bacterium Thermoanaerobacter pseudethanolicus Using Xylose, Glucose, Cellobiose, or Acetate with Fixed Anode Potentials. AB - Thermoanaerobacter pseudethanolicus 39E (ATCC 33223), a thermophilic, Fe(III) reducing, and fermentative bacterium, was evaluated for its ability to produce current from four electron donors-xylose, glucose, cellobiose, and acetate-with a fixed anode potential (+ 0.042 V vs SHE) in a microbial electrochemical cell (MXC). Under thermophilic conditions (60 degrees C), T. pseudethanolicus produced high current densities from xylose (5.8 +/- 2.4 A m(-2)), glucose (4.3 +/- 1.9 A m(-2)), and cellobiose (5.2 +/- 1.6 A m(-2)). It produced insignificant current when grown with acetate, but consumed the acetate produced from sugar fermentation to produce electrical current. Low-scan cyclic voltammetry (LSCV) revealed a sigmoidal response with a midpoint potential of -0.17 V vs SHE. Coulombic efficiency (CE) varied by electron donor, with xylose at 34.8% +/- 0.7%, glucose at 65.3% +/- 1.0%, and cellobiose at 27.7% +/- 1.5%. Anode respiration was sustained over a pH range of 5.4-8.3, with higher current densities observed at higher pH values. Scanning electron microscopy showed a well-developed biofilm of T. pseudethanolicus on the anode, and confocal laser scanning microscopy demonstrated a maximum biofilm thickness (Lf) greater than ~150 MUm for the glucose-fed biofilm. PMID- 26569144 TI - Covalent Attachment of Ferrocene to Silicon Microwire Arrays. AB - A fully integrated, freestanding device for photoelectrochemical fuel generation will likely require covalent attachment of catalysts to the surface of the photoelectrodes. Ferrocene has been utilized in the past as a model system for molecular catalyst integration on planar silicon; however, the surface structure of high-aspect ratio silicon microwires envisioned for a potential device presents potential challenges with respect to stability, characterization, and mass transport. Attachment of vinylferrocene to Cl-terminated surfaces of silicon microwires was performed thermally. By varying the reaction time, solutions of vinylferrocene in di-n-butyl ether were employed to control the extent of functionalization. X-ray photoelectron spectroscopy (XPS) and electrochemistry were used to estimate the density and surface coverage of the silicon microwire arrays with ferrocenyl groups, which could be controllably varied from 1.23 * 10( 11) to 4.60 * 10(-10) mol cm(-2) or 1 to 30% of a monolayer. Subsequent backfill of the remaining Si-Cl sites with methyl groups produced ferrocenyl-terminated surfaces that showed unchanged cyclic volammograms following two months in air, under ambient conditions, and repeated electrochemical cycling. PMID- 26569145 TI - Poly(N,N-dimethylaminoethyl methacrylate) Brushes: pH-Dependent Switching Kinetics of a Surface-Grafted Thermoresponsive Polyelectrolyte. AB - The temperature-dependent switching behavior of poly(N,N-dimethylaminoethyl methacrylate) brushes in alkaline, neutral, and acidic solutions is examined. A novel microscopic laser temperature-jump technique is employed in order to study characteristic thermodynamic and kinetic parameters. Static laser micromanipulation experiments allow one to determine the temperature-dependent variation of the swelling ratio. The data reveal a strong shift of the volume phase transition of the polymer brushes to higher temperatures when going from pH = 10 to pH = 4. Dynamic laser micromanipulation experiments offer a temporal resolution on a submillisecond time scale and provide a means to determine the intrinsic rate constants. Both the swelling and the deswelling rates strongly decrease in acidic solutions. Complementary experiments using in situ atomic force microscopy show an increased polymer layer thickness at these conditions. The data are discussed on the basis of pH-dependent structural changes of the polymer brushes including protonation of the amine groups and conformational rearrangements. Generally, repulsive electrostatic interactions and steric effects are assumed to hamper and slow down temperature-induced switching in acidic solutions. This imposes significant restrictions for smart polymer surfaces, sensors, and devices requiring fast response times. PMID- 26569146 TI - Rheological and molecular weight comparisons of approved hyaluronic acid products - preliminary standards for establishing class III medical device equivalence. AB - Hyaluronic acid of various molecular weights has been in use for the treatment of osteoarthritis knee pain for decades. Worldwide, these products are regulated as either as drugs or devices and in some countries as both. In the US, this class of products is regulated as Class III medical devices, which places specific regulatory requirements on developers of these materials under a Pre-Market Approval process, typically requiring data from prospective randomized controlled clinical studies. In 1984 pharmaceutical manufacturers became able to file an Abbreviated New Drug Application for approval of a generic drug, thus establishing standards for demonstrating equivalence to an existing chemical entity. Recently, the first biosimilar, or 'generic biologic', was approved. Biosimilars are biological products that are approved by the FDA because they are 'highly similar' to a reference product, and have been shown to have no clinically meaningful differences from the reference product. For devices, Class II medical devices have a pathway for declaring equivalence to an existing product by filing a 510 k application for FDA clearance. However, until recently no equivalent regulatory pathway was available to Class III devices. In this paper, we consider the critical mechanical performance parameters for intra articular hyaluronic products to demonstrate indistinguishable characteristics. Analogous to the aforementioned pathways that allow for a demonstration of equivalence, we examine these parameters for an existing, marketed device and compare molecular weight and rheological properties of multiple batches of a similar product. We propose that this establishes a scientific rationale for establishing Class III medical device equivalence. PMID- 26569147 TI - Evaluation of the Gibbs Free Energy Changes and Melting Temperatures of DNA/DNA Duplexes Using Hybridization Enthalpy Calculated by Molecular Dynamics Simulation. AB - A molecular dynamics simulation approach was applied for the prediction of the thermal stability of oligonucleotide duplexes. It was shown that the enthalpy of the DNA/DNA complex formation could be calculated using this approach. We have studied the influence of various simulation parameters on the secondary structure and the hybridization enthalpy value of Dickerson-Drew dodecamer. The optimal simulation parameters for the most reliable prediction of the enthalpy values were determined. The thermodynamic parameters (enthalpy and entropy changes) of a duplex formation were obtained experimentally for 305 oligonucleotides of various lengths and GC-content. The resulting database was studied with molecular dynamics (MD) simulation using the optimized simulation parameters. Gibbs free energy changes and the melting temperatures were evaluated using the experimental correlation between enthalpy and entropy changes of the duplex formation and the enthalpy values calculated by the MD simulation. The average errors in the predictions of enthalpy, the Gibbs free energy change, and the melting temperature of oligonucleotide complexes were 11%, 10%, and 4.4 degrees C, respectively. We have shown that the molecular dynamics simulation gives a possibility to calculate the thermal stability of native DNA/DNA complexes a priori with an unexpectedly high accuracy. PMID- 26569148 TI - Influencing College Student Drinking Intentions With Social Norms and Self-Schema Matched Messages: Differences Between Low and High Self-Monitors. AB - College students were exposed to either a self-schema matched message (emphasizing how binge drinking is inconsistent with personal values) or a social norms message (highlighting the true normative drinking behavior of peers). As predicted, low self-monitors intended to drink significantly less alcohol if they received the self-schema matched message versus the social norms message, and high self-monitors intended to drink less if they received the social norms message versus a self-schema message. While previous research supports both techniques for marketing responsible college student drinking, the current results suggest that each method may be especially effective for certain audiences. PMID- 26569149 TI - Effects of rotigotine on daytime symptoms in patients with primary restless legs syndrome: a randomized, placebo-controlled study. AB - OBJECTIVE: This 12 week double-blind, placebo-controlled study (ClinicalTrials.gov: NCT01569464) was conducted to evaluate the effects of rotigotine transdermal patch on daytime symptoms in patients with idiopathic restless legs syndrome (RLS). METHODS: Adult patients with moderate-to-severe RLS were randomized to rotigotine (optimal dose: 1-3 mg/24 h) or placebo. A modified four-assessment version (4:00 pm, 6:00 pm, 8:00 pm, and 10:00 pm) of the Multiple Suggested Immobilization Test (m-SIT) was performed at baseline and end of 4 week maintenance (EoM). Primary study outcomes were change from baseline to EoM in International Restless Legs Syndrome Rating Scale (IRLS) and in average of means for the m-SIT Discomfort Scale (m-SIT-DS) (combined average of mean values from each of the individual assessments). Secondary outcomes included average of means of Periodic Limb Movement during Wakefulness Index (PLMWI; PLM/hour) for the combination of m-SIT. RESULTS: A total of 150 patients were randomized and 137 (rotigotine: 92/101 [91.1%]; placebo: 45/49 [91.8%]) completed maintenance. All 150 randomized patients were assessed for efficacy. At EoM, mean change in IRLS was -14.9 +/- 9.3 with rotigotine vs. -12.7 +/- 7.6 with placebo (ANCOVA, LS mean treatment difference [95% CI]: -0.27 [-2.96, 2.42]; p = 0.8451). Changes in average of means of m-SIT-DS values of each individual SIT were comparable with rotigotine (-2.68 +/- 2.31) vs. placebo (-2.62 +/- 2.61) (ANCOVA, LS mean treatment difference [95% CI]: 0.07 [-0.61, 0.75]; p = 0.8336) and comparable reductions in PLMWI were observed in both treatment groups (8.34 [-8.50, 25.17]; p = 0.3290). Rotigotine was generally well tolerated. Application site reactions (rotigotine: 20 patients [19.8%]; placebo: 4 [8.2%]) and nausea (16 [15.8%]; 3 [6.1%]) were the most common AEs. CONCLUSIONS: Rotigotine was beneficial in improving overall RLS symptom severity (assessed by IRLS) and RLS symptom severity at various times of the day (m-SIT-DS); however, superiority to placebo was not established. PMID- 26569150 TI - Proton Magnetic Resonance Spectroscopy in Social Anxiety Disorder. AB - In the present study, 24 nonmedicated patients with social anxiety disorder (SAD) were compared with 24 healthy control subjects to assess metabolite levels in the anterior cingulate, insula, caudate, and putamen using proton magnetic resonance spectroscopy. The ratio of N-acetylaspartate (NAA)/creatine (Cr) was significantly higher in patients with SAD than in healthy control subjects in the anterior cingulate and insula. NAA/Cr ratios in the insula correlated positively with the Liebowitz Social Anxiety Scale total scores in patients with SAD. Our results support the significance and biochemical involvement of the anterior cingulate and insula in the pathophysiology of SAD. PMID- 26569151 TI - Corpus Callosum Pathology as a Potential Surrogate Marker of Cognitive Impairment in Diffuse Axonal Injury. AB - Diffuse axonal injury is a major form of traumatic brain injury. Neuropsychological assessments and high-resolution structural MRI were conducted using T1-weighted and diffusion tensor imaging. This study included 10 patients with diffuse axonal injury (all men, mean age 30.8+/-10.5 years) and 12 age- and sex-matched normal control participants. Patients with diffuse axonal injury had widespread volume reductions and lower fractional anisotropy in the corpus callosum (CC) compared with controls. Furthermore, cognitive processing speed was associated with reductions in white matter volume and fractional anisotropy in the CC. These findings suggest that CC pathology may be a potential surrogate marker of the cognitive deficits in these patients. PMID- 26569152 TI - Anxiety and Depressive Symptoms Are Associated With Worse Performance on Objective Cognitive Tests in MS. AB - Cognitive impairment, anxiety, and depressive symptoms are common in multiple sclerosis (MS) and are known to interact in non-MS populations. This retrospective chart review examined this relationship in a relapsing-remitting MS population. A significant difference on measures of processing speed/working memory and visual-spatial memory was found in MS patients with anxiety compared with nonanxious MS patients, while a significant difference was found on measures of processing speed, visual-spatial memory and executive function in MS patients with depressive symptoms compared with those without. Further research is needed to determine the causal relationship between anxiety and depressive symptoms and cognitive impairment. PMID- 26569153 TI - Procalcitonin testing to guide antibiotic therapy for the treatment of sepsis in intensive care settings and for suspected bacterial infection in emergency department settings: a systematic review and cost-effectiveness analysis. AB - BACKGROUND: Determination of the presence or absence of bacterial infection is important to guide appropriate therapy and reduce antibiotic exposure. Procalcitonin (PCT) is an inflammatory marker that has been suggested as a marker for bacterial infection. OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of adding PCT testing to the information used to guide antibiotic therapy in adults and children (1) with confirmed or highly suspected sepsis in intensive care and (2) presenting to the emergency department (ED) with suspected bacterial infection. METHODS: Twelve databases were searched to June 2014. Randomised controlled trials were assessed for quality using the Cochrane Risk of Bias tool. Summary relative risks (RRs) and weighted mean differences (WMDs) were estimated using random-effects models. Heterogeneity was assessed visually using forest plots and statistically using the I (2) and Q statistics and investigated through subgroup analysis. The cost-effectiveness of PCT testing in addition to current clinical practice was compared with current clinical practice using a decision tree with a 6 months' time horizon. RESULTS: Eighteen studies (36 reports) were included in the systematic review. PCT algorithms were associated with reduced antibiotic duration [WMD -3.19 days, 95% confidence interval (CI) -5.44 to -0.95 days, I (2) = 95.2%; four studies], hospital stay (WMD -3.85 days, 95% CI -6.78 to -0.92 days, I (2) = 75.2%; four studies) and a trend towards reduced intensive care unit (ICU) stay (WMD -2.03 days, 95% CI 4.19 to 0.13 days, I (2) = 81.0%; four studies). There were no differences for adverse clinical outcomes. PCT algorithms were associated with a reduction in the proportion of adults (RR 0.77, 95% CI 0.68 to 0.87; seven studies) and children (RR 0.86, 95% CI 0.80 to 0.93) receiving antibiotics, reduced antibiotic duration (two studies). There were no differences for adverse clinical outcomes. All but one of the studies in the ED were conducted in people presenting with respiratory symptoms. Cost-effectiveness: the base-case analyses indicated that PCT testing was cost-saving for (1) adults with confirmed or highly suspected sepsis in an ICU setting; (2) adults with suspected bacterial infection presenting to the ED; and (3) children with suspected bacterial infection presenting to the ED. Cost savings ranged from L368 to L3268. Moreover, PCT-guided treatment resulted in a small quality-adjusted life-year (QALY) gain (ranging between < 0.001 and 0.005). Cost-effectiveness acceptability curves showed that PCT-guided treatment has a probability of >= 84% of being cost-effective for all settings and populations considered (at willingness-to-pay thresholds of L20,000 and L30,000 per QALY). CONCLUSIONS: The limited available data suggest that PCT testing may be effective and cost-effective when used to guide discontinuation of antibiotics in adults being treated for suspected or confirmed sepsis in ICU settings and initiation of antibiotics in adults presenting to the ED with respiratory symptoms and suspected bacterial infection. However, it is not clear that observed costs and effects are directly attributable to PCT testing, are generalisable outside people presenting with respiratory symptoms (for the ED setting) and would be reproducible in the UK NHS. Further studies are needed to assess the effectiveness of adding PCT algorithms to the information used to guide antibiotic treatment in children with suspected or confirmed sepsis in ICU settings. Additional research is needed to examine whether the outcomes presented in this report are fully generalisable to the UK. STUDY REGISTRATION: This study is registered as PROSPERO CRD42014010822. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 26569154 TI - Amphiphilic Polymerizable Porphyrins Conjugated to a Polyglycerol Dendron Moiety as Functional Surfactants for Multifunctional Polymer Particles. AB - An amphiphilic polyglycerol dendron (PGD) conjugated porphyrin (PGP) bearing a polymerizable group was successfully synthesized. The PGP was used as an effective surfactant in emulsion and microsuspension polymerization systems to prepare styrene and methacrylate polymer particles, and the use of PGP provided the simple polymer particles with fluorescence derived from the metalloporphyrin and high colloidal stability due to the PGD. Furthermore, based on confocal laser scanning microscopy, we observed that the particles spontaneously formed a core shell morphology with the PGP localized in the shell region during the polymerization and demonstrated drug loading in the shell region using rhodamine B as a model drug. The results indicate that the use of the functional surfactant PGP led to the preparation of multifunctional polymer particles from simple monomer species, and the resulting particles possessed high colloidal stability, fluorescence, and drug loading capability. PMID- 26569155 TI - Advances in pharmacotherapy for treating endometriosis. AB - INTRODUCTION: Endometriosis is an estrogen-dependent chronic disease requiring long-term therapy. Therefore, the choice of medical treatment should be based on efficacy, preference of patients, incidence and severity of adverse effects and cost. AREAS COVERED: This review briefly summarizes the currently available medical treatment for endometriosis. The treatments most recently proposed for endometriosis will be described in detail, including gonadotropin-releasing hormone (GnRH) antagonists, aromatase inhibitors (AIs) and the flexible extended combined oral contraceptive. EXPERT OPINION: The oral contraceptive pill and progestogens allow for the treatment of the majority of patients with endometriosis. The flexible extended dosing regimen, containing drospirenone and ethinylestradiol, may be particularly useful in patients suffering severe dysmenorrhea and improving the adherence and compliance with treatment. GnRH agonists may be used in patients resistant to first-line therapy; up to now, limited data are available on the use of GnRH antagonist (such as elagolix) in patients with endometriosis. AIs should be regarded as experimental therapies and used only in patients with symptoms resistant to other therapies; however, the use of these drugs is limited by the possibility to administer the treatment for short-term periods only (6 months) and, similarly to GnRH antagonists, by the high incidence of adverse effects, requiring the use of add-back therapy. PMID- 26569156 TI - Role and Clinical Significance of Plasma N-Terminal Brain Natriuretic Peptide Measurement in Children with Brain Edema. AB - OBJECTIVE: Brain natriuretic peptide (BNP) is a potent natriuretic and vasodilator factor. BNP plasma concentrations were found to be elevated in patients with brain edema. The purpose of the present study is to evaluate the relationship between plasma NT-proBNP concentration and the presence of brain edema in patients with intracranial pathology. MATERIALS AND METHODS: The plasma NT-proBNP levels of 50 patients and 25 healthy subjects were measured. The NT proBNP levels of the patient group were measured during admission and after 7 days of treatment. RESULTS: NT-proBNP plasma concentrations were found to be significantly higher in the patient group with brain edema than in the control group (p < 0.005). There were no significant differences in the NT-proBNP plasma concentrations between patients with intracranial pathology without brain edema and the control group (p > 0.005). NT-proBNP plasma concentrations were found to be significantly higher in patients with brain edema as compared with patients without brain edema before treatment (p < 0.005). CONCLUSION: These results suggest that excessive secretion of plasma NT-proBNP is related to brain edema. Plasma NT-proBNP levels may serve as a marker to guide the early-diagnostic and therapeutic management in children with brain edema. Further studies are required to evaluate the role of BNP in brain edema pathophysiology. PMID- 26569157 TI - From Genetics to Genomics: A Short Introduction for Pediatric Neurologists. AB - It is estimated that in humans approximately 50% of all 22500 genes are needed for the development and maintenance of the nervous system. The introduction of high-throughput technology in genetic analysis has therefore major implications, not only for the investigation of specific disease entities but also for the diagnostic workup of single individuals with neurologic disorders of genetic origin. A short primer for clinicians is presented, addressing aspects of current developments in medical genomics. Significant findings of the last years are exemplified in an educational manner to provide a basic understanding of disease mechanisms that were unraveled by recent genomic analysis. PMID- 26569158 TI - Wallenberg Syndrome: An Exceptional Cause of Acute Vertigo in Children. AB - The assessment of acute vertigo in childhood is often challenging, but fortunately a central cause is rarely identified. We present the case of a 7-year old boy who developed, after a mild head trauma, a rotary vertigo associated with nausea and vomiting. A posttraumatic peripheral vestibular dysfunction was first suspected but not confirmed by an otoneurological evaluation. When subtle neurological signs were elicited, a brain magnetic resonance imaging was promptly requested. This showed a small infarct on the lateral posterior left part of the medulla oblongata of the brainstem, typical of Wallenberg syndrome. Vascular imaging was normal and no defined etiology was found. The child was started on prophylactic acetylsalicylic acid. The rapid disappearance of vertigo was noted. On follow-up at 6 months, there has been no recurrence and neurological examination was fully normal. Our case extends the differential diagnosis of acute vertigo in childhood that rarely includes the possibility of a brainstem infarct whose recognition through appropriate clinical examination is nevertheless capital for appropriate investigations and management. PMID- 26569159 TI - Severe and Progressive Fetal Ventriculomegaly Leading to the Diagnosis of Periventricular Nodular Heterotopias with Good Outcome. AB - Severe fetal ventriculomegaly is generally associated with poor prognosis in terms of survival and neurodevelopment outcome. As such, many parents opt to terminate the pregnancy independently of a known etiology. We report here the case of a female fetus with severe progressive ventriculomegaly due to the unexpected presence of bilateral nodular periventricular heterotopias visualized on MRI of a fetal brain. Reaching a structural diagnosis was perceived as a relief for the parents and the pregnancy was continued. Neurodevelopment assessment at 3 years of age is normal with no epilepsy. PMID- 26569160 TI - Predicted energetics and properties of rare-earth ferrites films grown on cubic (111)- and hexagonal (0001)-oriented substrates. AB - First-principles calculations are performed to compare the energetics of several phases, including hexagonal polar P6(3)cm and perovskite non-polar Pbnm-like states, of epitaxial RFeO3 films (with R = Ce, Pr, Nd, Sm, Gd, Tb, Dy, Ho, Er and Lu) grown on different cubic (1 1 1)- and hexagonal (0 0 0 1)-oriented substrates. The P63cm phase is found to be the ground state for large enough in plane lattice parameters in all investigated RFeO3 films, and its polarization is tunable by the amount of epitaxial strain. Series of available substrates allowing the growth of hexagonal polar RFeO3 films, as well as other phenomena of fundamental and technological importance (e.g. different ground states and coexistence between several phases) are also predicted. PMID- 26569162 TI - Abstracts of Presentations at the 2015 APS Annual Meeting. PMID- 26569163 TI - Abstracts of Special Session Presentations at the 2015 APS Annual Meeting. PMID- 26569165 TI - Green tea beverages enriched with catechins with a galloyl moiety reduce body fat in moderately obese adults: a randomized double-blind placebo-controlled trial. AB - Objective To determine whether ingesting a green tea beverage enriched with catechins with a galloyl moiety during a meal reduces body fat in moderately obese adults. Design Randomized double-blind placebo-controlled study. Subjects A total of 126 obese subjects (25 <= body mass index < 30 kg m(-2)) were randomly assigned to a group receiving green tea beverages without catechins (placebo), or a group receiving green tea beverages with a low or high content of catechins with a galloyl moiety. Each subject ingested 500 mL bottled green tea beverages containing 25, 180, or 279.5 mg green tea catechins (0, 149.5, or 246.5 mg catechins with a galloyl moiety, respectively), at mealtimes for 12 weeks; the subjects were instructed to ingest the beverage during the meal that had the highest fat content on that day. Methods Anthropometric measurements and blood chemistry analysis were performed during the run-in period; at weeks 0, 4, 8, and 12 of the intake period; and at the end of the withdrawal period. Abdominal fat area was measured by computed tomography at weeks 0, 8, and 12 of the intake period and at the end of the withdrawal period. Results Both the low- and high dose groups exhibited significant reductions in visceral and subcutaneous fat areas compared to the control group at 12 weeks post-intervention. Conclusion Ingestion of a green tea beverage enriched with catechins with a galloyl moiety during a high-fat meal reduces body fat in moderately obese adults. PMID- 26569161 TI - Role of volume-regulated and calcium-activated anion channels in cell volume homeostasis, cancer and drug resistance. AB - Volume-regulated channels for anions (VRAC) / organic osmolytes (VSOAC) play essential roles in cell volume regulation and other cellular functions, e.g. proliferation, cell migration and apoptosis. LRRC8A, which belongs to the leucine rich-repeat containing protein family, was recently shown to be an essential component of both VRAC and VSOAC. Reduced VRAC and VSOAC activities are seen in drug resistant cancer cells. ANO1 is a calcium-activated chloride channel expressed on the plasma membrane of e.g., secretory epithelia. ANO1 is amplified and highly expressed in a large number of carcinomas. The gene, encoding for ANO1, maps to a region on chromosome 11 (11q13) that is frequently amplified in cancer cells. Knockdown of ANO1 impairs cell proliferation and cell migration in several cancer cells. Below we summarize the basic biophysical properties of VRAC, VSOAC and ANO1 and their most important cellular functions as well as their role in cancer and drug resistance. PMID- 26569166 TI - Synthesis, structure and bonding of hexaphenyl thorium(IV): observation of a non octahedral structure. AB - We report herein the synthesis of the first structurally characterized homoleptic actinide aryl complexes, [Li(DME)3]2[Th(C6H5)6] (1) and [Li(THF)(12-crown 4)]2[Th(C6H5)6] (2), which feature an anion possessing a regular octahedral (1) or a severely distorted octahedral (2) geometry. The solid-state structure of 2 suggests the presence of pseudo-agostic ortho C-H...Th interactions, which arise from sigma(C-H) -> Th(5f) donation. The non-octahedral structure is also favoured in solution at low temperatures. PMID- 26569167 TI - Morbidity and Mortality after High-dose Transfusion. AB - BACKGROUND: It is well recognized that increased transfusion volumes are associated with increased morbidity and mortality, but dose-response relations between high- and very-high-dose transfusion and clinical outcomes have not been described previously. In this study, the authors assessed (1) the dose-response relation over a wide range of transfusion volumes for morbidity and mortality and (2) other clinical predictors of adverse outcomes. METHODS: The authors retrospectively analyzed electronic medical records for 272,592 medical and surgical patients (excluding those with hematologic malignancies), 3,523 of whom received transfusion (10 or greater erythrocyte units throughout the hospital stay), to create dose-response curves for transfusion volumes and in-hospital morbidity and mortality. Prehospital comorbidities were assessed in a risk adjusted manner to identify the correlation with clinical outcomes. RESULTS: For patients receiving high- or very-high-dose transfusion, infections and thrombotic events were four to five times more prevalent than renal, respiratory, and ischemic events. Mortality increased linearly over the entire dose range, with a 10% increase for each 10 units of erythrocytes transfused and 50% mortality after 50 erythrocyte units. Independent predictors of mortality were transfusion dose (odds ratio [OR], 1.037; 95% CI, 1.029 to 1.044), the Charlson comorbidity index (OR, 1.209; 95% CI, 1.141 to 1.276), and a history of congestive heart failure (OR, 1.482; 95% CI, 1.062 to 2.063). CONCLUSIONS: Patients receiving high- or very-high-dose transfusion are at especially high risk for hospital-acquired infections and thrombotic events. Mortality increased linearly over the entire dose range and exceeded 50% after 50 erythrocyte units. PMID- 26569168 TI - Uncovering the History of Operating Room Attire through Photographs. AB - BACKGROUND: Although early proponents for each of the four basic articles of operating room clothing--gowns, caps, masks, and gloves--can be identified, it is unclear from historical commentaries when each article achieved general acceptance and was consistently worn by surgeons and by anesthesia providers. METHODS: Historical photographs were identified from the Web sites of the National Library of Medicine, Google, and the archives of the Wood Library-Museum of Anesthesiology for the 11 decades 1860 to 1970. The presence or absence of each article of clothing was then determined for the surgical and anesthesia providers depicted. RESULTS: Over 1,000 photographs were identified and examined. Photographs were then eliminated for repetition, lack of available dating, questionable dating, and poor quality. In 338 remaining photographs that met inclusion criteria, 640 surgical providers and 219 anesthesia providers were depicted and used in the analysis. Statistical definitions for historical terms general acceptance and routine use were proposed. The probability that a surgeon was wearing nonstreet clothes (gown) was 0.66 (95% CI, 0.22 to 0.93) in 1863. The years (95% lower bound to 95% upper bound) associated with a 0.5 probability for wearing cap, gloves, and mask were 1900 (1896 to 1904), 1907 (1903 to 1910), and 1916 (1913 to 1919), respectively. The years associated with a 0.5 probability that an anesthesia provider would be wearing nonstreet clothes (gown), cap, and mask were 1883 (1863 to 1889), 1905 (1900 to 1911), and 1932 (1929 to 1937), respectively. CONCLUSION: Timelines for the adoption of each basic article of surgical attire by surgeons and anesthesia providers were determined by analysis of historical operating room photographs from 1863 to 1969. PMID- 26569169 TI - Severity of Myasthenia Gravis Influences the Relationship between Train-of-four Ratio and Twitch Tension and Run-down of Rat Endplate Potentials. AB - BACKGROUND: Train-of-four ratio (TOFR) is often used to evaluate muscle relaxation caused by neuromuscular-blocking agents (NMBAs). However, it is unknown whether TOFR reliably correlates with the first twitch tension (T1) in patients with myasthenia gravis (MG). By using rat models of experimental autoimmune MG (EAMG), the authors verified the hypothesis that the severity of MG influences the relationship between TOFR and T1. METHODS: EAMG rats were divided into sham, moderate MG, and severe MG groups. Isometric twitch tension of the hemidiaphragm was elicited by phrenic nerve stimulation with and without use of the NMBA rocuronium to measure TOFR and T1, and run-down of endplate potentials was estimated in the three groups. Changes around the neuromuscular junction in EAMG rats were investigated by observation of electron micrographs. RESULTS: With similar attenuation of T1, TOFR was significantly (n = 6) different among the three groups in the presence of 50% inhibitory concentrations of rocuronium (IC50). Run-down in the sham group was significantly (n = 8) greater with exposure to IC50, whereas that in the severe MG group was statistically insignificant. Width of the primary synaptic cleft in the severe MG group was significantly (n = 80) greater than that in the other groups. CONCLUSIONS: Severity of MG influences the relationship between TOFR and T1, together with changes in run-down of endplate potentials and those around the neuromuscular junction in rats. TOFR may, therefore, not be an accurate indicator of recovery from NMBAs in MG patients. PMID- 26569171 TI - Impact of Recruitment on Static and Dynamic Lung Strain in Acute Respiratory Distress Syndrome. AB - BACKGROUND: Lung strain, defined as the ratio between end-inspiratory volume and functional residual capacity, is a marker of the mechanical load during ventilation. However, changes in lung volumes in response to pressures may occur in injured lungs and modify strain values. The objective of this study was to clarify the role of recruitment in strain measurements. METHODS: Six oleic acid injured pigs were ventilated at positive end-expiratory pressure (PEEP) 0 and 10 cm H2O before and after a recruitment maneuver (PEEP = 20 cm H2O). Lung volumes were measured by helium dilution and inductance plethysmography. In addition, six patients with moderate-to-severe acute respiratory distress syndrome were ventilated with three strategies (peak inspiratory pressure/PEEP: 20/8, 32/8, and 32/20 cm H2O). Lung volumes were measured in computed tomography slices acquired at end-expiration and end-inspiration. From both series, recruited volume and lung strain (total, dynamic, and static) were computed. RESULTS: In the animal model, recruitment caused a significant decrease in dynamic strain (from [mean +/ SD] 0.4 +/- 0.12 to 0.25 +/- 0.07, P < 0.01), while increasing the static component. In patients, total strain remained constant for the three ventilatory settings (0.35 +/- 0.1, 0.37 +/- 0.11, and 0.32 +/- 0.1, respectively). Increases in tidal volume had no significant effects. Increasing PEEP constantly decreased dynamic strain (0.35 +/- 0.1, 0.32 +/- 0.1, and 0.04+0.03, P < 0.05) and increased static strain (0, 0.06 +/- 0.06, and 0.28 +/- 0.11, P < 0.05). The changes in dynamic and total strain among patients were correlated to the amount of recruited volume. An analysis restricted to the changes in normally aerated lung yielded similar results. CONCLUSION: Recruitment causes a shift from dynamic to static strain in early acute respiratory distress syndrome. PMID- 26569172 TI - In Vitro Comparative Effect of Carbetocin and Oxytocin in Pregnant Human Myometrium with and without Oxytocin Pretreatment. AB - BACKGROUND: The purpose of this study was to compare in vitro contractile effects of oxytocin and carbetocin on human term pregnant myometrium with and without oxytocin pretreatment. METHODS: This laboratory investigation was conducted on myometrial samples from women undergoing elective cesarean deliveries. The samples were dissected into four strips and suspended in individual organ bath chambers containing physiologic salt solution. After equilibration, they were pretreated with oxytocin 10 M (experimental group) or physiologic salt solution (control group) for 2 h and then subjected to dose-response testing with increasing concentrations of oxytocin or carbetocin (10 to 10 M). The amplitude, frequency, motility index (amplitude * frequency), and area under the curve of contractions were recorded and analyzed during the equilibration and dose response periods. Comparisons were made between oxytocin-induced and carbetocin induced contractions in control and oxytocin-pretreated groups. Motility index was the primary outcome measure. RESULTS: Sixty-three experiments were performed (carbetocin, n = 31; oxytocin, n = 32) on samples from 18 women. The motility index of contractions (?g.contractions/10 min) produced by oxytocin was significantly higher than carbetocin in both control (regression-estimated difference, 0.857; 95% CI, 0.290 to 1.425; P = 0.003) and oxytocin-pretreated (0.813; 0.328 to 1.299; P = 0.001) groups. The motility index was significantly lower in oxytocin-pretreated groups than their respective controls for both oxytocin (-1.040; -1.998 to -0.082; P = 0.03) and carbetocin (-0.996; -1.392 to 0.560; P < 0.001). CONCLUSIONS: In vitro contractions produced by oxytocin are superior to carbetocin in human myometrium with or without oxytocin pretreatment. Oxytocin pretreatment results in attenuation of contractions induced by both oxytocin and carbetocin. PMID- 26569173 TI - A Cysteine Substitution Probes beta3H267 Interactions with Propofol and Other Potent Anesthetics in alpha1beta3gamma2L gamma-Aminobutyric Acid Type A Receptors. AB - BACKGROUND: Anesthetic contact residues in gamma-aminobutyric acid type A (GABAA) receptors have been identified using photolabels, including two propofol derivatives. O-propofol diazirine labels H267 in beta3 and alpha1beta3 receptors, whereas m-azi-propofol labels other residues in intersubunit clefts of alpha1beta3. Neither label has been studied in alphabetagamma receptors, the most common isoform in mammalian brain. In alphabetagamma receptors, other anesthetic derivatives photolabel m-azi-propofol-labeled residues, but not betaH267. The authors' structural homology model of alpha1beta3gamma2L receptors suggests that beta3H267 may abut some of these sites. METHODS: Substituted cysteine modification-protection was used to test beta3H267C interactions with four potent anesthetics: propofol, etomidate, alphaxalone, and R-5-allyl-1-methyl-5-(m trifluoromethyl-diazirinylphenyl) barbituric acid (mTFD-MPAB). The authors expressed alpha1beta3gamma2L or alpha1beta3H267Cgamma2L GABAA receptors in Xenopus oocytes. The authors used voltage clamp electrophysiology to assess receptor sensitivity to gamma-aminobutyric acid (GABA) and anesthetics and to compare p-chloromercuribenzenesulfonate modification rates with GABA versus GABA plus anesthetics. RESULTS: Enhancement of low GABA (eliciting 5% of maximum) responses by equihypnotic concentrations of all four anesthetics was similar in alpha1beta3gamma2L and alpha1beta3H267Cgamma2L receptors (n > 3). Direct activation of alpha1beta3H267Cgamma2L receptors, but not alpha1beta3gamma2L, by mTFD-MPAB and propofol was significantly greater than the other anesthetics. Modification of beta3H267C by p-chloromercuribenzenesulfonate (n > 4) was rapid and accelerated by GABA. Only mTFD-MPAB slowed beta3H267C modification (approximately twofold; P = 0.011). CONCLUSIONS: beta3H267 in alpha1beta3gamma2L GABAA receptors contacts mTFD-MPAB, but not propofol. The study results suggest that beta3H267 is near the periphery of one or both transmembrane intersubunit (alpha+/beta- and gamma+/beta-) pockets where both mTFD-MPAB and propofol bind. PMID- 26569175 TI - Thymic Function Is Most Severely Impaired in Chronic HIV-1 Infection, but Individuals With Faster Disease Progression During Early HIV-1 Infection Expressed Lower Levels of RTEs. AB - In HIV disease course, the decline of peripheral CD4 T-cell count correlates with rapid disease progression. The supply of peripheral naive T cells by the thymus requires precursor T-cell proliferation within the thymus. In the setting of HIV 1 infection, when both naive and memory T cells are progressively depleted, the contribution of thymic dysfunction in CD4 depletion needs to be studied. Previous research has shown that thymic function may also be impaired in HIV-1 infection. However, it is inconclusive regarding whether this impairment occurred at the early time or during the chronic phase. In addition, the relationship between thymic dysfunction and disease progression remains unknown. In this study, we examined the thymic function in 65 HIV-infected individuals. Among them, 17 were in acute phase, 15 were in early chronic phase, 15 were in chronic phase with no ART (antiretroviral therapy), and 18 were on ART. We also included 11 uninfected individuals as controls. We measured the peripheral blood levels of T-cell receptor rearrangement excision circles and PTK7 and CD31 expressions for the frequency of circulating recent thymic emigrants. We observed that the 2 indicators of thymic function, sj/beta-TREC and PTK7, seemed to be lower in the chronic infection group than those in the acute and early chronic groups. Both indicators returned to the normal level after ART. However, after 1-year follow up of patients with early HIV-1 infection, rapid progressors (n = 4) had lower PTK7 and CD31 expressions than chronic progressors (n = 6). PMID- 26569174 TI - Worldwide Genetic Features of HIV-1 Env alpha4beta7 Binding Motif: The Local Dissemination Impact of the LDI Tripeptide. AB - BACKGROUND: HIV-1 gp120 binds to integrin alpha4beta7, a homing receptor of lymphocytes to gut-associated lymphoid tissues. This interaction is mediated by the LDI/V tripeptide encoded in the V2-loop. This tripeptide mimics similar motifs in mucosal addressin cellular adhesion molecule (MAdCAM) and vascular CAM (VCAM), the natural ligands of alpha4beta7. In this study, we explored the association of V2-loop LDI/V mimotopes with transmission routes and patterns of disease progression in HIV-infected adult and pediatric patients. HIV-1 env sequences available in the Los Alamos HIV Sequence database were included in the analyses. METHODS: HIV-1 V2-loop sequences generated from infected adults and infants from South and Southeast Brazil, and also retrieved from the Los Alamos database, were assessed for alpha4beta7 binding tripeptide composition. Chi Square/Fisher Exact test and Mann Whitney U test were used for tripeptide comparisons. Shannon entropy was assessed for conservancy of the alpha4beta7 tripeptide mimotope. RESULTS: We observed no association between the tripeptide composition or conservation and virus transmission route or disease progression. However, LDI was linked to successful epidemic dissemination of HIV-1 subtype C in South America, and further to other expanding non-B subtypes in Europe and Asia. In Africa, subtypes showing increased LDV prevalence evidenced an ongoing process of selection toward LDI expansion, an observation also extended to subtype B in the Americas and Western Europe. CONCLUSIONS: The V2-loop LDI mimotope was conserved in HIV-1C from South America and other expanding subtypes across the globe, which suggests that LDI may promote successful dissemination of HIV at local geographic levels by means of increased transmission fitness. PMID- 26569176 TI - Gene Expression in HIV-Associated Neurocognitive Disorders: A Meta-Analysis. AB - OBJECTIVES: To identify differentially expressed (DE) genes in HIV-associated neurocognitive disorders (HAND) patients in comparison with HIV-infected patients without HAND and controls. DESIGN: A meta-analysis of publicly available gene expression data from HIV postmortem brain tissue studies. METHODS: We selected studies using clearly defined inclusion and exclusion criteria. Within study data preprocessing and individual analyses were performed for each brain region. The following meta-analytic methods were applied: combining P values, combining effect sizes with and without a permutation method. The DE genes were defined with a false discovery rate less than 5% using Benjamini-Hochberg method. RESULTS: Our meta-analysis on 3 studies encompasses analyses of over 48 postmortem brains [25 HAND, 7 HIV encephalitis (HIVE), 8 HIV-infected patients, and 8 controls]. Overall, 411 genes in white matter were DE in HAND with HIVE patients when comparing with controls. Of these, 94 genes were significantly expressed in all statistical methods. These 94 genes participate in significant pathways such as immune system, interferon response, or antigen presentation. Sixty-six of the 94 genes were significantly upregulated with log2 intensities greater than 2-fold. Strong examples of the highly upregulated genes were PSMB8 AS1, APOL6, TRIM69, PSME1, CTSB, HLA-E, GPNMB, UBE2L6, PSME2, NET1, CAPG, B2M, RPL38, GBP1, and PLSCR1. Only BTN3A2 was expressed in HAND with HIVE patients as compared with HAND patients without HIVE. CONCLUSION: A number of genes were DE in our meta-analysis that were not identified in the individual analyses. The meta-analytic approach has increased statistical power for identifying DE genes in HAND. PMID- 26569177 TI - Disparities and Trends in Viral Suppression During a Transition to a "Test and Treat" Approach to the HIV Epidemic, San Francisco, 2008-2012. AB - BACKGROUND: In 2010, 2 years before national recommendations to provide antiretroviral therapy for HIV-infected persons regardless of CD4 count, the San Francisco Department of Public Health (SFDPH) implemented a "test and treat" strategy that expanded HIV testing and offered antiretroviral therapy to persons at all publicly funded HIV clinics. We used the SFDPH registry of HIV-infected persons to measure trends in the time to viral suppression of persons suppressed. METHODS: The Kaplan-Meier product limit method was used to assess trends in time from HIV diagnosis to viral suppression (HIV RNA <200 copies/mL) among persons diagnosed from 2008 to 2012. The annual proportion of persons living with HIV who were virally suppressed was measured for the years 2008 to 2012. Independent predictors of viral suppression were determined using proportional hazards regression for newly diagnosed cases and Poisson regression for living cases. RESULTS: Of the 2349 persons newly diagnosed, the median time from diagnosis to suppression decreased from 13 months in 2008 to 5 months in 2012 (P < 0.0001). Among the 11,787 persons living with HIV, the annual proportion suppressed increased from 69% in 2008 to 78% in 2012. African Americans, persons who inject drugs, persons without private insurance, and persons with nadir CD4 counts above 350 cells per cubic millimeter, were less likely to be virally suppressed. DISCUSSION: We found a decrease in time and overall population-level increases in viral suppression under a test and treat strategy and highlight sociodemographic disparities that may hamper the full benefit of this approach. PMID- 26569178 TI - Soluble CD163 But Not Soluble CD14 Is Associated With Cytomegalovirus Immunoglobulin G Antibody Levels in Virologically Suppressed HIV+ Individuals. PMID- 26569179 TI - Strengthening the "Viral Failure Pathway": Clinical Decision and Outcomes of Patients With Confirmed Viral Failure in a Large HIV Care Clinic in Uganda. PMID- 26569180 TI - Authors' Reply: Evidence-Based Programming of HIV Care and Support: Is the Psychosocial "Optional"? PMID- 26569182 TI - What do we know about the cost-effectiveness of HIV preexposure prophylaxis, and is it affordable? AB - PURPOSE OF REVIEW: The WHO recommends preexposure prophylaxis (PrEP) in populations at substantial risk of HIV. Despite a number of randomized controlled trials demonstrating its efficacy, and several ongoing implementation projects, PrEP is currently only available in a few countries. Modelling studies can provide useful insights into the long-term impact of introducing PrEP in different subgroups of the population. The review summarizes studies that either evaluated the cost-effectiveness or the cost of introducing PrEP, focusing on seven published in the last year. RECENT FINDINGS: These studies used a number of different types of models and investigated the introduction of PrEP in different settings. Among men having sex with men (MSM) in North America, PrEP ranged from being cost-saving (while benefiting population health) to costing US $160,000/quality-adjusted life-year gained. Among heterosexual sero-different couples, it varied from around US $5000 to US $10,000/disability-adjusted life year averted, when PrEP was used until 6 or 12 months after the HIV-positive partner had initiated antiretroviral therapy (ART) in, respectively, Uganda and South Africa. SUMMARY: Future cost-effectiveness studies of PrEP should consider the HIV incidence, the level of uptake, the effect of its introduction on alternative prevention approaches, and the budget impact of rolling it out. PMID- 26569183 TI - What people want from sex and preexposure prophylaxis. AB - PURPOSE OF REVIEW: As demand for preexposure prophylaxis (PrEP) increases, we are learning more about what people want from sex and PrEP. RECENT FINDINGS: PrEP demand has reached a tipping point in the USA and is increasing rapidly. Although the primary benefit of PrEP use is biological, to reduce risk of HIV infection, PrEP users often express an alternative set of social and emotional benefits that are provided by PrEP. These collateral benefits of PrEP have salience, affect, and are experienced in the present, which are compelling drivers of human behavior. PrEP use has been associated with feeling safe during sex, usually in contrast to ruminations related to fear of HIV or intimate partner violence or control. PrEP can create empowerment, or agency, defined as the capacity and autonomy to act on one's own behalf, because it provides control over one's vulnerability to HIV and relief to women and men who may otherwise worry about whether their partners will use a condom, take antiretroviral therapy, or disclose their HIV status accurately. Planning for sexual and social goals in calm moments is also empowering. These highly desired collateral benefits of PrEP could be undermined, or eliminated, if PrEP is implemented in ways that are coercive or that foment fear of sexual risk compensation, drug resistance, toxicity, or moral judgment. SUMMARY: Current PrEP implementation provides direct and indirect benefits that are highly desired. PMID- 26569185 TI - Sternoclavicular Reconstruction in the Young Active Patient: Risk Factor Analysis and Clinical Outcomes at Short-Term Follow-up. AB - OBJECTIVE: To determine the functional outcomes in young, active individuals after sternoclavicular (SC) joint reconstruction. DESIGN: Level IV, case series. SETTING: United States military hospitals, 2008-2012. PATIENTS/PARTICIPANTS: Retrospective review of all consecutive patients from the Military Health System Management Analysis and Reporting Tool was performed. Patients who underwent other open-shoulder procedures (eg, acromioclavicular joint reconstruction), those of nonmilitary or retired status, and patients with under 12-month minimum follow-up without medical separation were excluded from further analysis. INTERVENTION: Open reconstruction of SC joint dislocation. MAIN OUTCOME MEASURES: Primary outcomes of interest were clinical failure and medical separation due to persistent shoulder girdle dysfunction. Demographic data, surgical technique, outcomes, complications, and occupational military outcomes were recorded. RESULTS: Fourteen patients, with an average age of 26 years, experienced 8 anterior (57.1%) and 6 posterior (42.9%) SC joint dislocations. Four patients (28.6%) presented with dysphagia or dyspnea, and 10 patients (71.4%) had a missed diagnosis with an average of 13 months until diagnosis. Twelve of 14 (85.7%) patients underwent figure-of-eight tendon reconstruction, and 10 (71.4%) were able to return to full active military duty at an average 26.8 +/- 12.9 months follow-up. There were 6 complications in 5 patients (35.7%), whereas 2 (14.3%) reported persistent instability and 2 (14.3%) required reoperation. CONCLUSIONS: SC joint dislocations are rare injuries that are frequently missed on clinical presentation in this study. However, acute or delayed surgical reconstruction may afford predictable rates of return to function in young active military service members. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 26569184 TI - Does the OTA Open Fracture Classification Predict the Need for Limb Amputation? A Retrospective Observational Cohort Study on 512 Patients. AB - BACKGROUND: Few studies have examined the utility of the Orthopaedic Trauma Association Open Fracture Classification (OTA-OFC) compared to the traditional Gustilo-Anderson classification for prediction of treatment outcomes in patients with open fractures. QUESTIONS/OBJECTIVES:: (1) How do the Gustilo-Anderson classification and OTA-OFC systems compare in accuracy of predicting limb amputation, infection, and need for soft tissue coverage? (2) Is there an OTA-OFC summative threshold score that may guide the discussion and decision-making with regard to limb salvage or amputation? DESIGN: Retrospective observational cohort study; Level IV evidence. SETTING: Level I trauma center and urban safety-net institution. PATIENTS/PARTICIPANTS: Consecutive adult patients with open long bone fractures who underwent operative treatment between January 1, 2007 and December 31, 2012. MAIN OUTCOME AND MEASUREMENTS: Postoperative complications of infection, early limb amputation, and requirement for soft-tissue procedures. RESULTS: The study cohort comprised 512 patients with mean age 49.6 +/- 14.9 years. Nineteen patients (3.7%) underwent amputation. The Gustilo-Anderson classification demonstrated no correlations with any of the primary outcome measures, while OTA-OFC summative scores significantly varied between all outcome comparison groups. The skin injury component of the OTA-OFC was an independent predictor of limb amputation (OR, 5.44; 95% CI, 2.37-12.47), and an OTA-OFC summative score of >=10 best correlated with need for amputation (P < 0.001). Sensitivity and specificity of the reported model were 79% and 94%, respectively. CONCLUSIONS: Our results should be interpreted with caution due to the retrospective nature of our study. Based on our data, the OTA-OFC is superior to the Gustilo-Anderson classification system for prediction of postoperative complications and treatment outcomes in patients with open long bone fractures. A summative threshold score of 10 seems to identify increased odds of successful limb salvage. PMID- 26569186 TI - The Walking Speed Questionnaire: Assessing Walking Speed in a Self-reported Format. AB - OBJECTIVES: The literature increasingly demonstrates the importance of gait speed (GS) in the frailty assessment of patients aged 60 years and older. Conventional GS measurement, however, maybe contraindicated in settings such as trauma where the patient is temporarily immobilized. We devised a Walking Speed Questionnaire (WSQ) to allow assessment of preinjury baseline GS, in meters per second, in a self-reported manner, to overcome the inability to directly test the patients' walking speed. DESIGN: Four questions comprise the WSQ, and were derived using previously published questionnaires and expert opinion of 6 physician researchers. SETTING: Four ambulatory clinics. PARTICIPANTS: Ambulating individuals aged 60-95 (mean age, 73.2 +/- 8.1 years, 86.1% female, n = 101). INTERVENTION: Participants completed the WSQ and underwent GS measurement for comparison. ANALYSIS: WSQ score correlation to true GS, receiver operating characteristics, and validation statistics were performed. RESULTS: All 4 questions of the WSQ independently predicted true GS significantly (P < 0.001). The WSQ sufficiently predicted true GS with r = 0.696 and rho = 0.717. CONCLUSIONS: The WSQ is an effective tool for assessing baseline walking speed in patients aged 60 years and older in a self-reported manner. It permits gait screening in health care environments where conventional GS testing is contraindicated due to temporary immobilization and maybe used to provide baseline targets for goal-oriented post-trauma care. Given its ability to capture GS in patients who are unable to ambulate, it may open doors for frailty research in previously unattainable populations. LEVEL OF EVIDENCE: Diagnostic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 26569187 TI - Current Opinions on Fracture Follow-up: A Survey of OTA Members Regarding Standards of Care and Implications for Clinical Research. AB - OBJECTIVES: To determine current practice standards among Orthopaedic Trauma Association surgeons for postoperative fracture follow-up and to investigate the implications of these standards on clinical research. DESIGN: Survey. SETTING: Web-based survey. PARTICIPANTS: One hundred eighty-four orthopaedic trauma surgeons. METHODS: A web-based questionnaire was distributed to Orthopaedic Trauma Association members to identify standard postoperative radiographic and clinical follow-up duration. Assuming uneventful, complete fracture healing at 3 months, data were collected for 3 generic fracture types (diaphyseal, extra articular metaphyseal, and intra-articular) and 3 specific fractures (femoral shaft, intertrochanteric, and tibial plateau). Suggested follow-up for clinical research was also investigated. RESULTS: For extra-articular fractures, standard radiographic and clinical follow-up were considered to be 6 months or less by greater than 70% of respondents. For intra-articular fractures, standard radiographic and clinical follow-up was considered to be 6 months or less by greater than 39% of respondents. The most common responses for radiographic follow-up were 3 months for extra-articular fractures (33%) and 12 months for intra-articular fractures (34%). The most common responses for clinical follow-up were 6 months for extra-articular fractures (37%) and 12 months for intra articular fractures (35%). The majority (55%) indicated that follow-up to clinical and radiographic healing or the establishment of a nonunion should be the minimum follow-up for clinical fracture studies and 66% recommended follow-up to at least 1 year for functional outcome studies. CONCLUSIONS: Most surgeons follow-up patients with lower extremity extra-articular fractures (with uneventful healing) radiographically for 3-6 months and clinically for 6 months and slightly longer for intra-articular fractures. Many surgeons cease radiographic and clinical follow-up by 6 months. Therefore, retrospective fracture healing studies can only reasonably expect follow-up for 6 months. Publication requirements for longer follow-up of fracture-related studies would likely eliminated retrospective studies from consideration. Most surgeons support obtaining at least 1-year follow-up for clinical studies that include functional outcome. LEVEL OF EVIDENCE: Therapeutic Level V. See Instructions for Authors for a complete description of levels of evidence. PMID- 26569188 TI - Clinical and Molecular Epidemiology of Childhood Invasive Nontypeable Haemophilus influenzae Disease in England and Wales. AB - INTRODUCTION: In countries with established Haemophilus influenzae type b (Hib) immunization programs, nontypeable H. influenzae (NTHi) is now responsible for nearly all invasive H. influenzae cases across all age groups. METHODS: Public Health England (PHE) conducts enhanced national surveillance of invasive H. influenzae disease in England and Wales. Invasive NTHi isolates submitted to Public Health England from children of ages 1 month to 10 years during 2003-2010 were characterized by multilocus sequence typing (MLST). Detailed clinical information was obtained for all laboratory-confirmed cases of invasive NTHi disease in children during 2009-2013. RESULTS: In England and Wales, there were 7797 cases of invasive H. influenzae disease diagnosed during 2000-2013 and 1585 (20%) occurred in children aged 1 month to 10 years, where NTHi was responsible for 31-51 cases (incidence, 0.53-0.92/100,000) annually. Detailed clinical follow up of 214 confirmed NTHi cases diagnosed in this age-group during 2009-2013 revealed that 52% (n = 111) occurred in <2-year-old and 52% (n=110) had comorbidity. Bacteremic pneumonia was the most common clinical presentation (n = 99, 46%), 16% (n = 34) required intensive care and 11% (n = 23) died. Characterization by biotyping and MLST of 316 NTHi strains from children with invasive disease during 2003-2010 revealed a genetically heterogeneous population (155 MLSTs) with diverse biotypes and no association with comorbidity status, clinical disease or outcome. CONCLUSIONS: The high level of genetic diversity in invasive NTHi strains highlights the difficulties in developing an effective vaccine against this pathogen. PMID- 26569181 TI - Risk Factors for HCV Reinfection or Transmission in HIV-HCV Coinfected MSM (ANRS VESPA2 French National Survey). PMID- 26569189 TI - Who Can Have Parenteral Antibiotics at Home?: A Prospective Observational Study in Children with Moderate/Severe Cellulitis. AB - BACKGROUND: The benefits of treating children at home or in an ambulatory setting have been well documented. We aimed to describe the characteristics and evaluate the outcomes of children with moderate/severe cellulitis treated at home with intravenous (IV) ceftriaxone via direct referral from the Emergency Department to a hospital-in-the-home (HITH) program. METHODS: Patients aged 3 months to 18 years with moderate/severe cellulitis referred from a tertiary pediatric Emergency Department to HITH from September 2012 to January 2014 were prospectively identified. Data collection included demographics, clinical features, microbiological characteristics and outcomes. To ensure home treatment did not result in inferior outcomes, these patients were retrospectively compared with patients who were hospitalized for IV flucloxacillin, the standard-of-care over the same period. The primary outcome was home treatment failure necessitating hospital admission. Secondary outcomes included antibiotic changes, complications, length of stay and cost. RESULTS: Forty-one (28%) patients were treated on HITH and 103 (72%) were hospitalized. Compared with hospitalized patients, HITH patients were older (P < 0.01) and less likely to have periorbital cellulitis (P = 0.01) or fever (P = 0.04). There were no treatment failures under HITH care. The rate of antibiotic changes was similar in both groups (5% vs. 7%, P = 0.67), as was IV antibiotic duration (2.3 vs. 2.5 days, P = 0.23). CONCLUSION: Older children with moderate/severe limb cellulitis without systemic symptoms can be treated at home. To ascertain if this practice can be applied more widely, a comparative prospective, ideally randomized, study is needed. PMID- 26569190 TI - Chest Radiographic Findings and Outcomes of Pneumonia Among Children in Botswana. AB - BACKGROUND: Chest radiography is increasingly used to diagnose pneumonia in low income and middle-income countries. Few studies examined whether chest radiographic findings predict outcomes of children with clinically suspected pneumonia in these settings. METHODS: This is a hospital-based, prospective cohort study of children 1-23 months of age meeting clinical criteria for pneumonia in Botswana. Chest radiographs were reviewed by 2 pediatric radiologists to generate a consensus interpretation using standardized World Health Organization criteria. We assessed whether final chest radiograph classification was associated with our primary outcome, treatment failure at 48 hours, and secondary outcomes. RESULTS: From April 2012 to November 2014, we enrolled 249 children with evaluable chest radiographs. Median age was 6.1 months, and 58% were male. Chest radiograph classifications were primary endpoint pneumonia (35%), other infiltrate/abnormality (42%) or no significant pathology (22%). The prevalence of endpoint consolidation was higher in children with HIV infection (P = 0.0005), whereas endpoint pleural effusions were more frequent among children with moderate or severe malnutrition (P = 0.0003). Ninety-one (37%) children failed treatment, and 12 (4.8%) children died. Primary endpoint pneumonia was associated with an increased risk of treatment failure at 48 hours (P = 0.002), a requirement for more days of respiratory support (P = 0.002) and a longer length of stay (P = 0.0003) compared with no significant pathology. Primary endpoint pneumonia also predicted a higher risk of treatment failure than other infiltrate/abnormality (P = 0.004). CONCLUSIONS: Chest radiograph provides useful prognostic information for children meeting clinical criteria for pneumonia in Botswana. These findings highlight the potential benefit of expanded global access to diagnostic radiology services. PMID- 26569191 TI - Risk Factors for Sporadic Infection With Campylobacter Spp. Among Children in Israel: A Case-control Study. AB - BACKGROUND: Campylobacter spp. has been identified as one of the leading causes of bacterial gastroenteritis in the world. In recent years, an increase in the incidence of campylobacteriosis in several countries, including Israel, was demonstrated. The incidence rate of campylobacteriosis in Israel increased from 22.3 per 100,000 in 1997 to 77.4 per 100,000 in 2009. The aim of this study was to explore risk factors for sporadic infection with Campylobacter among young children in Israel. METHODS: A matched case-control study was performed to investigate risk factors for sporadic Campylobacter infection among 113 affected children of 1-5 years of age and 113 age-matched, gender-matched and neighborhood matched controls. Information about exposure to potential risk factors was obtained via telephone interview and was evaluated by conditional logistic regression analysis. RESULTS: In the multivariable model, for each additional chicken meal consumed during the week before the onset of illness, the odds for Campylobacter infection increased by 32% [adjusted matched odds ratios (aMOR): 1.32; 95% confidence interval (CI): 1.01-1.72; P = 0.04], whereas consumption of fruits and vegetables decreased the odds for Campylobacter infection by 97% (aMOR: 0.03; 95% CI: 0.00-0.28; P < 0.01), and for each additional child living in the household, the odds for infection decreased by 48% (aMOR: 0.52; 95% CI: 0.33-0.83; P < 0.01). Using diaper increased the odds for campylobacteriosis (aMOR: 7.36; 95% CI: 1.66-32.70; P < 0.01). CONCLUSIONS: Interventions that focus on proper handling of chicken and chicken products, hand washing and encouraging consumption of fruits and vegetables could help in controlling Campylobacter infections. PMID- 26569192 TI - Markers of Protection in Children and Adolescents Six to Fourteen Years After Primary Hepatitis B Vaccination in Real Life: A Pilot Study. AB - BACKGROUND: Not many data are available on long-term immunity against hepatitis B (HB) for children vaccinated under real-life conditions. METHODS: Two hundred and thirty-two children and adolescents vaccinated 6-14 years earlier in pediatric practices were examined for conditions of vaccination and markers of protection as anti-HBs, anamnestic response to a booster dose and cell-mediated immunity. RESULTS: Fifty-six percent of the participants were vaccinated according to the German vaccination recommendations (group 1). In 44.0% (group 2), these recommendations were not followed. Anti-HBs concentrations of >=10 IU/L were found in 53.1% of group 1 and 45.1% of group 2 participants. A booster dose resulted in 91 of 99 participants in having an anamnestic response, in 3 (5.9%) of group 1 and 5 (10.4%) of group 2 anti-HBs remained below 10 IU/L. In group 1, postbooster anti-HBs concentration was inversely correlated with time since the last vaccination. Cellular immune responses were seen in only 5% of revaccinated individuals before the booster, increasing to 30% thereafter. CONCLUSIONS: Under real-life conditions about half of vaccinees have lost protecting antibodies 6-14 years after vaccination in infancy, but in approximately 90% of them, immune memory was demonstrated. However, as memory may wane, revaccination at a time when boostability is still present might be considered. PMID- 26569193 TI - Pneumococcal Mastoiditis in Children Before and After the Introduction of Conjugate Pneumococcal Vaccines. AB - OBJECTIVES: To determine whether serotype distribution and antibiotic resistance of Streptococcus pneumoniae acute mastoiditis (AM) in children have changed in the post pneumococcal conjugate vaccines (PCVs) era. METHODS: Medical records of pneumococcal AM cases, in a tertiary pediatric hospital were reviewed from January 1999 to December 2014. S. pneumoniae isolates were serotyped using the quellung reaction and tested for antibiotic susceptibility by E-test and for macrolide resistance genes by polymerase chain reaction. RESULTS: Among 334 children with AM, S. pneumoniae was isolated from 89 (26.6%) with median age 22 months (interquartile range: 12-30 months). S. pneumoniae was recovered from ear fluid (58%), mastoid specimens (35.2%) and blood (6.8%). Resistance to penicillin, erythromycin and clindamycin was 12.4%, 49.4% and 18%, respectively. Distribution of pneumococcal serotypes before (1999-2005), after the introduction of PCV7 (2006-2010) and after PCV13 (2011-2014) was found: for the PCV7 serotypes 81%, 25% and 0% (P < 0.0001), for PCV13 additional serotypes 16.3%, 70.8% and 63.6% (P < 0.0001) and for non-PCV serotypes 2.3%, 4.1% and 36.3% (P = 0.0002), respectively. Significant increase was detected for the serotype 19A after PCV7, and this trend was not changed after PCV13 (2.3%, 50% and 50%, respectively; P < 0.0001). A significant proportion of resistant isolates to penicillin (54.5%) and erythromycin (34.8%) was identified as 19A. CONCLUSIONS: After the introduction of PCV7, a significant increase of serotype 19A and replacement of PCVs serotypes was identified. After PCV13, the overall proportion of pneumococcal mastoiditis and the incidence of serotype 19A were not significantly declined. A significant proportion of resistant isolates to penicillin and erythromycin is attributed to serotype 19A. PMID- 26569194 TI - Clinical Characteristics of Carbapenem-resistant Klebsiella pneumoniae Infections in Ill and Colonized Children in Colombia. AB - BACKGROUND: Multidrug-resistant Gram-negative infections represent a growing problem and a serious global threat. Data in children are scarce. Klebsiella pneumoniae carbapenemases (KPC) are the most common mechanism of resistance this organism has developed. We report the clinical characteristics and outcomes from a cohort of children infected or colonized with carbapenem-resistant K. pneumoniae (CRKp) at a tertiary care center in Medellin, Colombia. METHODS: We performed a retrospective chart review of all pediatric cases from whom CRKp isolates were obtained from 2008 to 2013. Clinical characteristics and outcomes were recorded. RESULTS: A total of 34 infected children (median age, 22.8 months) with 43 episodes and 55 colonized patients (median age, 33 months) were identified. All patients had at least 1 risk factor previously related with multidrug-resistant Gram-negative infections (premorbid conditions, previous exposure to antibiotics, prolonged length of stay and use of indwelling devices). Urinary tract infections, abdominal infections and bacteremia were the most common clinical presentations. Overall mortality was 38%, and it was lower when a meropenem-containing regimen was used. Colistin was the most used antibiotic either alone or in combination and was associated with 8.8% of nephrotoxicity. CONCLUSION: CRKp infections have high mortality in children and usually occur in children with comorbidities, prolonged hospital stay and prior antibiotic exposure. Combined therapy with meropenem-containing regimens seems to be the best option in severely ill children. PMID- 26569195 TI - Cardiac Dysfunction Among Ugandan HIV-infected Children on Antiretroviral Therapy. AB - BACKGROUND: Despite effective antiretroviral therapy (ART), HIV-infected children on treatment have been observed to have cardiac abnormalities. We sought to determine the prevalence, types and factors associated with cardiac abnormalities among HIV-infected Ugandan children on combination ART. METHODS: We carried out a cross-sectional study from July 2012 to January 2013, at Joint Clinical Research Centre among HIV-infected children aged 1-18 years. Cardiac abnormalities were assessed using electrocardiography and echocardiography. CD4 counts, viral load and complete blood count were performed at enrollment. The prevalence of cardiac abnormalities was determined using simple proportions with the associated factors ascertained using logistic regression. RESULTS: Among 285 children recruited, the median (interquartile range) age was 9 (6-13) years, 54% were female; 72% were on first line combination ART. Their mean (+/-SD) CD4 count was 1092 (+/-868.7) cells/mm; median (interquartile range) viral load was 20 (20-76) copies/mL. Ninety-four percent had adherence to ART of more than 95%. Cardiac abnormalities were detected in 39 (13.7%) children. The most common abnormalities by electrocardiography and echocardiography were nonspecific T wave changes (4.6%) and pericardial disease (thickened pericardium with or without pericardial effusion; 2.8%), respectively. No factor assessed was found to be significantly associated occurrence of cardiac dysfunction. CONCLUSIONS: The prevalence of cardiac dysfunction among the HIV-infected children on ART was 13.7%, which was high, with nonspecific T wave changes and pericardial disease being the most frequent abnormalities observed. No factor assessed was found to be associated with cardiac dysfunction. PMID- 26569196 TI - Extremely Randomized Machine Learning Methods for Compound Activity Prediction. AB - Speed, a relatively low requirement for computational resources and high effectiveness of the evaluation of the bioactivity of compounds have caused a rapid growth of interest in the application of machine learning methods to virtual screening tasks. However, due to the growth of the amount of data also in cheminformatics and related fields, the aim of research has shifted not only towards the development of algorithms of high predictive power but also towards the simplification of previously existing methods to obtain results more quickly. In the study, we tested two approaches belonging to the group of so-called 'extremely randomized methods'-Extreme Entropy Machine and Extremely Randomized Trees-for their ability to properly identify compounds that have activity towards particular protein targets. These methods were compared with their 'non-extreme' competitors, i.e., Support Vector Machine and Random Forest. The extreme approaches were not only found out to improve the efficiency of the classification of bioactive compounds, but they were also proved to be less computationally complex, requiring fewer steps to perform an optimization procedure. PMID- 26569197 TI - Design and Synthesis of New 2-Aryl-4,5-Dihydro-thiazole Analogues: In Vitro Antibacterial Activities and Preliminary Mechanism of Action. AB - Sixty 2-aryl-4,5-dihydrothiazoles were designed and synthesized in yields ranging from 64% to 89% from cysteine and substituted-benzonitriles via a novel metal- and catalyst-free method. The structures of the title compounds were confirmed mainly by NMR spectral data analysis. Antibacterial activity assays showed that the compounds (S)-2-(2'-hydroxyphenyl)-4-hydroxy-methyl- 4,5-dihydrothiazole (7h) and (R)-2-(2'-hydroxyphenyl)-4-hydroxymethyl-4,5-dihydro-thiazole (7h') exhibited significant inhibition against Ralstonia solanacearum, Pseudomonas syringae pv. actinidiae, Bacillus subtilis and Bacillus cereus, with minimum inhibitory concentrations (MICs) ranging from 3.91 to 31.24 MUg.mL(-1). The effect of substituents showed that not only electron-withdrawing groups, but also electron donating groups could abolish the antibacterial activities unless a 2'-hydroxy group was introduced on the 2-aryl substituent of the 4,5-dihydrothiazole analogues. The results of scanning electron microscope (SEM) and fatty acid exposure experiments indicated that these antibacterial compounds influence fatty acid synthesis in the tested bacteria. PMID- 26569198 TI - Molecular Differentiated Initiator Reactivity in the Synthesis of Poly(caprolactone)-Based Hydrophobic Homopolymer and Amphiphilic Core Corona Star Polymers. AB - Macromolecules that possess three-dimensional, branched molecular structures are of great interest because they exhibit significantly differentiated application performance compared to conventional linear (straight chain) polymers. This paper reports the synthesis of 3- and 4-arm star branched polymers via ring opening polymerisation (ROP) utilising multi-functional hydroxyl initiators and Sn(Oct)2 as precatalyst. The structures produced include mono-functional hydrophobic and multi-functional amphiphilic core corona stars. The characteristics of the synthetic process were shown to be principally dependent upon the physical/dielectric properties of the initiators used. ROP's using initiators that were more available to become directly involved with the Sn(Oct)2 in the "in situ" formation of the true catalytic species were observed to require shorter reaction times. Use of microwave heating (MWH) in homopolymer star synthesis reduced reaction times compared to conventional heating (CH) equivalents, this was attributed to an increased rate of "in-situ" catalyst formation. However, in amphiphilic core corona star formation, the MWH polymerisations exhibited slower propagation rates than CH equivalents. This was attributed to macro-structuring within the reaction medium, which reduced the potential for reaction. It was concluded that CH experiments were less affected by this macro-structuring because it was disrupted by the thermal currents/gradients caused by the conductive/convective heating mechanisms. These gradients are much reduced/absent with MWH because it selectively heats specific species simultaneously throughout the entire volume of the reaction medium. These partitioning problems were overcome by introducing additional quantities of the species that had been determined to selectively heat. PMID- 26569200 TI - New Sulphated Flavonoids from Wissadula periplocifolia (L.) C. Presl (Malvaceae). AB - Wissadula periplocifolia (L.) C. Presl (Malvaceae) is commonly used in Brazil to treat bee stings and as an antiseptic. The antioxidant properties of its extracts have been previously demonstrated, thus justifying a phytochemical investigation for its bioactive phenolic constituents. This has yielded five new sulphated flavonoids: 8-O-sulphate isoscutellarein (yannin) (1a); 4'-O-methyl-7-O-sulphate isoscutellarein (beltraonin) (1b); 7-O-sulphate acacetin (wissadulin) (2a); 4'-O methyl-8-O-sulphate isoscutellarein (caicoine) (2b) and 3'-O-methyl-8-O-sulphate hypolaetin (pedroin) (3b) along with the known flavonoids 7,4'-di-O-methyl-8-O sulphate isoscutellarein (4), acacetin, apigenin, isoscutellarein, 4'-O-methyl isoscutellarein, 7,4'-di-O-methylisoscutellarein, astragalin and tiliroside. The compounds were isolated by column chromatography and identified by NMR (1H, (13)C, HMQC, HMBC and COSY) and LC-HRMS. A cell based assay was carried out to evaluate the preliminary cytotoxic properties of the flavonoids against UVW glioma and PC-3M prostate cancer cells as well as non-tumour cell lines. The obtained results showed that acacetin, tiliroside, a mixture of acacetin + apigenin and the sulphated flavonoids 2a + 2b exhibited inhibitory activity against at least one of the cell lines tested. Among the tested flavonoids acacetin and tiliroside showed lower IC50 values, presenting promising antitumor effects. PMID- 26569199 TI - Membrane Disintegration Caused by the Steroid Saponin Digitonin Is Related to the Presence of Cholesterol. AB - In the present investigation we studied the molecular mechanisms of the monodesmosidic saponin digitonin on natural and artificial membranes. We measured the hemolytic activity of digitonin on red blood cells (RBCs). Also different lipid membrane models (large unilamellar vesicles, LUVs, and giant unilamellar vesicles, GUVs) in the presence and absence of cholesterol were employed. The stability and permeability of the different vesicle systems were studied by using calcein release assay, GUVs membrane permeability assay using confocal microscopy (CM) and fluorescence correlation spectroscopy (FCS) and vesicle size measurement by dynamic light scattering (DLS). The results support the essential role of cholesterol in explaining how digitonin can disintegrate biological and artificial membranes. Digitonin induces membrane permeability or causes membrane rupturing only in the presence of cholesterol in an all-or-none mechanism. This effect depends on the concentrations of both digitonin and cholesterol. At low concentrations, digitonin induces membrane permeability while keeping the membrane intact. When digitonin is combined with other drugs, a synergistic potentiation can be observed because it facilitates their uptake. PMID- 26569201 TI - Glycosylated Metal Phthalocyanines. AB - In the first part; the syntheses of mono-; di-; and tetra-glycosylated phthalonitriles is described; which are the most used starting materials for the preparation of the corresponding glycosylated metal (mostly zinc) phthalocyanines. In the second section; the preparation of symmetric and unsymmetric mono-; tetra-; and octa- glycosylated zinc phthalocyanines are reviewed; in which the sugar is attached to the phthalocyanine macrocycle; either anomerically or via another one of its OH-groups. PMID- 26569202 TI - Synthesis of Novel beta-Keto-Enol Derivatives Tethered Pyrazole, Pyridine and Furan as New Potential Antifungal and Anti-Breast Cancer Agents. AB - Recently, a new generation of highly promising inhibitors bearing beta-keto-enol functionality has emerged. Reported herein is the first synthesis and use of novel designed drugs based on the beta-keto-enol group embedded with heterocyclic moieties such as pyrazole, pyridine, and furan, prepared in a one-step procedure by mixed Claisen condensation. All the newly synthesized compounds were characterized by FT-IR, 1H-NMR, (13)C-NMR, ESI/LC-MS, elemental analysis, and evaluated for their in vitro antiproliferative activity against breast cancer (MDA-MB241) human cell lines and fungal strains (Fusarium oxysporum f.sp albedinis FAO). Three of the synthesized compounds showed potent activity against fungal strains with IC50 values in the range of 0.055-0.092 uM. The results revealed that these compounds showed better IC50 values while compared with positive controls. PMID- 26569203 TI - Isomerization of Internal Alkynes to Iridium(III) Allene Complexes via C-H Bond Activation: Expanded Substrate Scope, and Progress towards a Catalytic Methodology. AB - The synthesis of a series of allene complexes (POCOP)Ir(eta2-RC=(.)=CR') 1b-4b (POCOP = 2,6-bis(di-tert-butylphosphonito)benzene) via isomerization of internal alkynes is reported. We have demonstrated that the application of this methodology is viable for the isomerization of a wide variety of alkyne substrates. Deuterium labeling experiments support our proposed mechanism. The structures of the allene complexes 1b-4b were determined using spectroscopic data analysis. Additionally, the solid-state molecular structure of complex 2b was determined using single crystal X-ray diffraction studies and it confirmed the assignment of an iridium-bound allene isomerization product. The rates of isomerization were measured using NMR techniques over a range of temperatures to allow determination of thermodynamic parameters. Finally, we report a preliminary step towards developing a catalytic methodology; the allene may be liberated from the metal center by exposure of the complex to an atmosphere of carbon monoxide. PMID- 26569204 TI - Functional Analysis of the Isopentenyl Diphosphate Isomerase of Salvia miltiorrhiza via Color Complementation and RNA Interference. AB - Isopentenyl diphosphate isomerase (IPI) catalyzes the isomerization between the common terpene precursor substances isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) during the terpenoid biosynthesis process. In this study, tissue expression analysis revealed that the expression level of the Salvia miltiorrhiza IPI1 gene (SmIPI1) was higher in the leaves than in the roots and stems. Furthermore, color complementation and RNA interference methods were used to verify the function of the SmIPI1 gene from two aspects. A recombinant SmIPI1 plasmid was successfully constructed and transferred into engineered E. coli for validating the function of SmIPI1 through the color difference in comparison to the control group; the observed color difference indicated that SmIPI1 served in promoting the accumulation of lycopene. Transformant hairy root lines with RNA interference of SmIPI1 were successfully constructed mediated by Agrobacterium rhizogenes ACCC 10060. RNA interference hairy roots had a severe phenotype characterized by withering, deformity or even death. The mRNA expression level of SmIPI1 in the RSi3 root line was only 8.4% of that of the wild type. Furthermore the tanshinone content was too low to be detected in the RNA interference lines. These results suggest that SmIPI1 plays a critical role in terpenoid metabolic pathways. Addition of an exogenous SmIPI1 gene promoted metabolic flow toward the biosynthesis of carotenoids in E. coli, and SmIPI1 interference in S. miltiorrhiza hairy roots may cause interruption of the 2-C methyl-D-erythritol-4-phosphate metabolic pathway. PMID- 26569205 TI - Genetic Authentication of Gardenia jasminoides Ellis var. grandiflora Nakai by Improved RAPD-Derived DNA Markers. AB - The evergreen shrub, Gardenia jasminoides Ellis var. grandiflora Nakai is one of the most popular garden-plants, with significant ornamental importance. Here, we have cloned improved random amplified polymorphic DNA (RAPD) derived fragments into T-vector, and developed sequence-characterized amplified region (SCAR) markers. These markers have been deposited in GenBank database with the accession numbers KP641310, KP641311, KP641312 and KP641313 respectively. The BLAST search of database confirmed the novelty of these markers. The four SCAR markers, namely ZZH11, ZZH31, ZZH41 and ZZH51 can specifically recognize the genetic materials of G. jasminoides from other plant species. Moreover, SCAR marker ZZH31 can be used to distinguish G. jasminoides Ellis var. grandiflora Nakai from other G. jasminoides on the market. Together, this study has developed four stably molecular SCAR markers by improved RAPD-derived DNA markers for the genetic identification and authentication, and for ecological conservation of medicinal and ornamental plant G. jasminoides. PMID- 26569206 TI - Auraptene Acts as an Anti-Inflammatory Agent in the Mouse Brain. AB - The anti-inflammatory activity of auraptene (AUR), a citrus coumarin, in peripheral tissues is well-known, and we previously demonstrated that AUR exerts anti-inflammatory effects in the ischemic brain; the treatment of mice with AUR for eight days immediately after ischemic surgery suppressed demise and neuronal cell death in the hippocampus, possibly through its anti-inflammatory effects in the brain. We suggested that these effects were at least partly mediated by the suppression of inflammatory mediators derived from astrocytes. The present study showed that (1) AUR, as a pretreatment for five days before and another three days after ischemic surgery, suppressed microglial activation, cyclooxygenase (COX)-2 expression in astrocytes, and COX-2 mRNA expression in the hippocampus; (2) AUR suppressed the lipopolysaccharide-induced expression of COX-2 mRNA and the mRNA of pro-inflammatory cytokines in cultured astrocytes; (3) AUR was still detectable in the brain 60 min after its intraperitoneal administration. These results support our previous suggestion that AUR directly exerts anti inflammatory effects on the brain. PMID- 26569207 TI - Role of the Red Ginseng in Defense against the Environmental Heat Stress in Sprague Dawley Rats. AB - Global temperature change causes heat stress related disorders in humans. A constituent of red ginseng has been known the beneficial effect on the resistance to many diseases. However, the mechanism of red ginseng (RG) against heat stress still remains unclear. To determine the effect of RG on heat stress, we examined the effect of the RG on the gene expression profiles in rats subjected to environmental heat stress. We evaluated the transcripts associated with hepatic lipid accumulation and oxidative stress in rats subjected to heat stress. We also analyzed the reactive oxygen species (ROS) contents. Our results suggested RG inhibited heat stress mediated altering mRNA expressions include HSPA1, DEAF1, HMGCR, and FMO1. We also determined RG attenuated fat accumulation in the liver by altering C/EBPbeta expression. RG promoted to repress the heat stress mediated hepatic cell death by inhibiting of Bcl-2 expression in rats subjected to heat stress. Moreover, RG administered group during heat stress dramatically decreased the malondialdehyde (MDA) contents and ROS associated genes compared with the control group. Thus, we suggest that RG might influence inhibitory effect on environmental heat stress induced abnormal conditions in humans. PMID- 26569208 TI - Molecular Cloning, Expression Pattern and Genotypic Effects on Glucoraphanin Biosynthetic Related Genes in Chinese Kale (Brassica oleracea var. alboglabra Bailey). AB - Glucoraphanin is a plant secondary metabolite that is involved in plant defense and imparts health-promoting properties to cruciferous vegetables. In this study, three genes involved in glucoraphanin metabolism, branched-chain aminotransferase 4 (BCAT4), methylthioalkylmalate synthase 1 (MAM1) and dihomomethionine N hydroxylase (CYP79F1), were cloned from Chinese kale (Brassica oleracea var. alboglabra Bailey). Sequence homology and phylogenetic analysis identified these genes and confirmed the evolutionary status of Chinese kale. The transcript levels of BCAT4, MAM1 and CYP79F1 were higher in cotyledon, leaf and stem compared with flower and silique. BCAT4, MAM1 and CYP79F1 were expressed throughout leaf development with lower transcript levels during the younger stages. Glucoraphanin content varied extensively among different varieties, which ranged from 0.25 to 2.73 umol.g(-1) DW (dry weight). Expression levels of BCAT4 and MAM1 were high at vegetative-reproductive transition phase, while CYP79F1 was expressed high at reproductive phase. BCAT4, MAM1 and CYP79F1 were expressed significantly high in genotypes with high glucoraphanin content. All the results provided a better understanding of the roles of BCAT4, MAM1 and CYP79F1 in the glucoraphanin biosynthesis of Chinese kale. PMID- 26569209 TI - Evaluation of the Cytotoxicity of alpha-Cyclodextrin Derivatives on the Caco-2 Cell Line and Human Erythrocytes. AB - Cyclodextrins, even the 6-membered alpha-cyclodextrin, are approved in the various pharmacopoeias as pharmaceutical excipients for solubilizing and stabilizing drugs as well as for controlling drug release. Recently alpha cyclodextrin has also been marketed as health food with beneficial effects on blood lipid profiles. However, the concentration of alpha-cyclodextrin used may be very high in these cases, and its toxic attributes have to be seriously considered. The objective of this study was to investigate the cytotoxicity of various, differently substituted alpha-cyclodextrin derivatives and determine relationship between the structures and cytotoxicity. Three different methods were used, viability tests (MTT assay and Real Time Cell Electronic Sensing on Caco-2 cells) as well as hemolysis test on human red blood cells. The effect of alpha-cyclodextrin derivatives resulted in concentration-dependent cytotoxicity, so the IC50 values have been determined. Based on our evaluation, the Real Time Cell Electronic Sensing method is the most accurate for describing the time and concentration dependency of the observed toxic effects. Regarding the cytotoxicity on Caco-2 cells, phosphatidylcholine extraction may play a main role in the mechanism. Our results should provide help in selecting those alpha cyclodextrin derivatives which have the potential of being used safely in medical formulations. PMID- 26569210 TI - beta-Cyclodextrin-Propyl Sulfonic Acid Catalysed One-Pot Synthesis of 1,2,4,5 Tetrasubstituted Imidazoles as Local Anesthetic Agents. AB - Some functionalized 1,2,4,5-tetrasubstituted imidazole derivatives were synthesized using a one-pot, four component reaction involving 1,2-diketones, aryl aldehydes, ammonium acetate and substituted aromatic amines. The synthesis has been efficiently carried out in a solvent free medium using beta-cyclodextrin propyl sulfonic acid as a catalyst to afford the target compounds in excellent yields. The local anesthetic effect of these derivatives was assessed in comparison to lidocaine as a standard using a rabbit corneal and mouse tail anesthesia model. The three most potent promising compounds were subjected to a rat sciatic nerve block assay where they showed considerable local anesthetic activity, along with minimal toxicity. Among the tested analogues, 4-(1-benzyl 4,5-diphenyl-1H-imidazol-2-yl)-N,N-dimethylaniline (5g) was identified as most potent analogue with minimal toxicity. It was further characterized by a more favourable therapeutic index than the standard. PMID- 26569211 TI - Derinat Protects Skin against Ultraviolet-B (UVB)-Induced Cellular Damage. AB - Ultraviolet-B (UVB) is one of the most cytotoxic and mutagenic stresses that contribute to skin damage and aging through increasing intracellular Ca(2+) and reactive oxygen species (ROS). Derinat (sodium deoxyribonucleate) has been utilized as an immunomodulator for the treatment of ROS-associated diseases in clinics. However, the molecular mechanism by which Derinat protects skin cells from UVB-induced damage is poorly understood. Here, we show that Derinat significantly attenuated UVB-induced intracellular ROS production and decreased DNA damage in primary skin cells. Furthermore, Derinat reduced intracellular ROS, cyclooxygenase-2 (COX-2) expression and DNA damage in the skin of the BALB/c-nu mice exposed to UVB for seven days in vivo. Importantly, Derinat blocked the transient receptor potential canonical (TRPC) channels (TRPCs), as demonstrated by calcium imaging. Together, our results indicate that Derinat acts as a TRPCs blocker to reduce intracellular ROS production and DNA damage upon UVB irradiation. This mechanism provides a potential new application of Derinat for the protection against UVB-induced skin damage and aging. PMID- 26569212 TI - Cytotoxic Activities, SAR and Anti-Invasion Effects of Butylphthalide Derivatives on Human Hepatocellular Carcinoma SMMC7721 Cells. AB - A series of butylphthalide derivatives (BPDs) 1-8 were isolated from the extract of the dried rhizome of Ligusticum chuanxiong Hort. (Umbelliferae). The cytotoxic activities of BPDs 1-8 were evaluated using a panel of human cancer cell lines. In addition, the SAR analysis and potential anti-invasion activities were investigated. The sp2 carbons at C-7 and C-7a appeared to be essential for the cytotoxic activities of BPDs. BPDs 5 and 6 remarkably inhibited the migration and invasion of cancer cells. The anti-invasion activity of dimer 6 was demonstrated to be significantly higher than monomer 5. PMID- 26569213 TI - Enhancement of Palmarumycin C12 and C13 Production by the Endophytic Fungus Berkleasmium sp. Dzf12 in an Aqueous-Organic Solvent System. AB - The endophytic fungus Berkleasmium sp. Dzf12, isolated from Dioscorea zingiberensis, was found to produce palmarumycins C12 and C13 which possess a great variety of biological activities. Seven biocompatible water-immiscible organic solvents including n-dodecane, n-hexadecane, 1-hexadecene, liquid paraffin, dibutyl phthalate, butyl oleate and oleic acid were evaluated to improve palmarumycins C12 and C13 production in suspension culture of Berkleasmium sp. Dzf12. Among the chosen solvents both butyl oleate and liquid paraffin were the most effective to improve palmarumycins C12 and C13 production. The addition of dibutyl phthalate, butyl oleate and oleic acid to the cultures of Berkleasmium sp. Dzf12 significantly enhanced palmarumycin C12 production by adsorbing palmarumycin C12 into the organic phase. When butyl oleate was fed at 5% (v/v) in medium at the beginning of fermentation (day 0), the highest palmarumycin C12 yield (191.6 mg/L) was achieved, about a 34.87-fold increase in comparison with the control (5.3 mg/L). n-Dodecane, 1-hexadecene and liquid paraffin had a great influence on the production of palmarumycin C13. When liquid paraffin was added at 10% (v/v) in medium on day 3 of fermentation, the palmarumycin C13 yield reached a maximum value (134.1 mg/L), which was 4.35-fold that of the control (30.8 mg/L). Application of the aqueous-organic solvent system should be a simple and efficient process strategy for enhancing palmarumycin C12 and C13 production in liquid cultures of the endophytic fungus Berkleasmium sp. Dzf12. PMID- 26569214 TI - Triterpenoids from the Herbs of Salicornia bigelovii. AB - A new nortriterpene saponin, 3-O-beta-d-glucuronopyranosyl-30-norolean-12,20(29) dien-23- oxo-28-oic acid, namely bigelovii D (11), was isolated from the hydroalcoholic extract of herbs of Salicornia bigelovii along with 10 known saponins (1-10). Their chemical structures were identified on the basis of spectroscopic analyses including two-dimensional NMR and a comparison with literature data. Some of these compounds showed potent antifungal activities in vitro. Compounds 3, 4, 5, 6, 7, 10 and 11 demonstrated potent inhibitory activities against Colletotrichum gloeosporioides and compound 11 displayed broad spectrum inhibitory activity against Alternaria alternata, A. solani, Botrytis cinerea, C. gloeosporioides, Fusarium graminearum, F. verticilloides, Thanatephorus cucumeris and Sclerotinia sclerotiorum, with EC50 values ranging from 13.6 to 36.3 MUg/mL. PMID- 26569215 TI - Direct Aminolysis of Ethoxycarbonylmethyl 1,4-Dihydropyridine-3-carboxylates. AB - The ethoxycarbonylmethyl esters of 1,4-dihydropyridines were directly converted into carbamoylmethyl esters in the presence of 1,5,7-triazabicyclo[4.4.0]dec-5 ene (TBD) in good to excellent yields under mild conditions. The use of TBD is crucial for the successful aminolysis of ethoxycarbonylmethyl ester of 1,4 dihydropyridines with secondary amines as without it the reaction does not proceed at all. The aminolysis reaction proceeded regioselectively, as the alkyl ester conjugated with the 1,4-dihydropyridine cycle was not involved in the reaction. Screening of other N-containing bases, such as triethylamine (TEA), pyridine, 4-(N,N-dimethylamino)pyridine (DMAP), 1,8-diazabicyclo[5.4.0]undec-7 ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), imidazole, tetramethyl guanidine (TMG) and 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD) as catalysts revealed no activity in the studied reaction. PMID- 26569216 TI - alpha-Linolenic Acid, A Nutraceutical with Pleiotropic Properties That Targets Endogenous Neuroprotective Pathways to Protect against Organophosphate Nerve Agent-Induced Neuropathology. AB - alpha-Linolenic acid (ALA) is a nutraceutical found in vegetable products such as flax and walnuts. The pleiotropic properties of ALA target endogenous neuroprotective and neurorestorative pathways in brain and involve the transcription factor nuclear factor kappa B (NF-kappaB), brain-derived neurotrophic factor (BDNF), a major neuroprotective protein in brain, and downstream signaling pathways likely mediated via activation of TrkB, the cognate receptor of BDNF. In this review, we discuss possible mechanisms of ALA efficacy against the highly toxic OP nerve agent soman. Organophosphate (OP) nerve agents are highly toxic chemical warfare agents and a threat to military and civilian populations. Once considered only for battlefield use, these agents are now used by terrorists to inflict mass casualties. OP nerve agents inhibit the critical enzyme acetylcholinesterase (AChE) that rapidly leads to a cholinergic crisis involving multiple organs. Status epilepticus results from the excessive accumulation of synaptic acetylcholine which in turn leads to the overactivation of muscarinic receptors; prolonged seizures cause the neuropathology and long term consequences in survivors. Current countermeasures mitigate symptoms and signs as well as reduce brain damage, but must be given within minutes after exposure to OP nerve agents supporting interest in newer and more effective therapies. The pleiotropic properties of ALA result in a coordinated molecular and cellular program to restore neuronal networks and improve cognitive function in soman-exposed animals. Collectively, ALA should be brought to the clinic to treat the long-term consequences of nerve agents in survivors. ALA may be an effective therapy for other acute and chronic neurodegenerative disorders. PMID- 26569217 TI - Mobilization of Copper ions by Flavonoids in Human Peripheral Lymphocytes Leads to Oxidative DNA Breakage: A Structure Activity Study. AB - Epidemiological studies have linked dietary consumption of plant polyphenols with lower incidence of various cancers. In particular, flavonoids (present in onion, tomato and other plant sources) induce apoptosis and cytotoxicity in cancer cells. These can therefore be used as lead compounds for the synthesis of novel anticancer drugs with greater bioavailability. In the present study, we examined the chemical basis of cytotoxicity of flavonoids by studying the structure activity relationship of myricetin (MN), fisetin (FN), quercetin (QN), kaempferol (KL) and galangin (GN). Using single cell alkaline gel electrophoresis (comet assay), we established the relative efficiency of cellular DNA breakage as MN > FN > QN > KL > GN. Also, we determined that the cellular DNA breakage was the result of mobilization of chromatin-bound copper ions and the generation of reactive oxygen species. The relative DNA binding affinity order was further confirmed using molecular docking and thermodynamic studies through the interaction of flavonoids with calf thymus DNA. Our results suggest that novel anti-cancer molecules should have ortho-dihydroxy groups in B-ring and hydroxyl groups at positions 3 and 5 in the A-ring system. Additional hydroxyl groups at other positions further enhance the cellular cytotoxicity of the flavonoids. PMID- 26569218 TI - Numerical Analysis of Hydrodynamic Flow in Microfluidic Biochip for Single-Cell Trapping Application. AB - Single-cell analysis has become the interest of a wide range of biological and biomedical engineering research. It could provide precise information on individual cells, leading to important knowledge regarding human diseases. To perform single-cell analysis, it is crucial to isolate the individual cells before further manipulation is carried out. Recently, microfluidic biochips have been widely used for cell trapping and single cell analysis, such as mechanical and electrical detection. This work focuses on developing a finite element simulation model of single-cell trapping system for any types of cells or particles based on the hydrodynamic flow resistance (Rh) manipulations in the main channel and trap channel to achieve successful trapping. Analysis is carried out using finite element ABAQUS-FEATM software. A guideline to design and optimize single-cell trapping model is proposed and the example of a thorough optimization analysis is carried out using a yeast cell model. The results show the finite element model is able to trap a single cell inside the fluidic environment. Fluid's velocity profile and streamline plots for successful and unsuccessful single yeast cell trapping are presented according to the hydrodynamic concept. The single-cell trapping model can be a significant important guideline in designing a new chip for biomedical applications. PMID- 26569219 TI - Global Profiling of Various Metabolites in Platycodon grandiflorum by UPLC QTOF/MS. AB - In this study, a method of metabolite profiling based on UPLC-QTOF/MS was developed to analyze Platycodon grandiflorum. In the optimal UPLC, various metabolites, including major platycosides, were separated well in 15 min. The metabolite extraction protocols were also optimized by selecting a solvent for use in the study, the ratio of solvent to sample and sonication time. This method was used to profile two different parts of P. grandiflorum, i.e., the roots of P. grandiflorum (PR) and the stems and leaves of P. grandiflorum (PS), in the positive and negative ion modes. As a result, PR and PS showed qualitatively and quantitatively different metabolite profiles. Furthermore, their metabolite compositions differed according to individual plant samples. These results indicate that the UPLC-QTOF/MS-based profiling method is a good tool to analyze various metabolites in P. grandiflorum. This metabolomics approach can also be applied to evaluate the overall quality of P. grandiflorum, as well as to discriminate the cultivars for the medicinal plant industry. PMID- 26569220 TI - The Function of Autophagy in Neurodegenerative Diseases. AB - Macroautophagy, hereafter referred to as autophagy, is a bulk degradation process performed by lysosomes in which aggregated and altered proteins as well as dysfunctional organelles are decomposed. Autophagy is a basic cellular process that maintains homeostasis and is crucial for postmitotic neurons. Thus, impaired autophagic processes in neurons lead to improper homeostasis and neurodegeneration. Recent studies have suggested that impairments of the autophagic process are associated with several neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and static encephalopathy of childhood with neurodegeneration in adulthood. In this review, we focus on the recent findings regarding the autophagic process and the involvement of autophagy in neurodegenerative diseases. PMID- 26569221 TI - Effect of Human Adipose Tissue Mesenchymal Stem Cells on the Regeneration of Ovine Articular Cartilage. AB - Cell therapy is a promising approach to improve cartilage healing. Adipose tissue is an abundant and readily accessible cell source. Previous studies have demonstrated good cartilage repair results with adipose tissue mesenchymal stem cells in small animal experiments. This study aimed to examine these cells in a large animal model. Thirty knees of adult sheep were randomly allocated to three treatment groups: CELLS (scaffold seeded with human adipose tissue mesenchymal stem cells), SCAFFOLD (scaffold without cells), or EMPTY (untreated lesions). A partial thickness defect was created in the medial femoral condyle. After six months, the knees were examined according to an adaptation of the International Cartilage Repair Society (ICRS 1) score, in addition to a new Partial Thickness Model scale and the ICRS macroscopic score. All of the animals completed the follow-up period. The CELLS group presented with the highest ICRS 1 score (8.3 +/ 3.1), followed by the SCAFFOLD group (5.6 +/- 2.2) and the EMPTY group (5.2 +/- 2.4) (p = 0.033). Other scores were not significantly different. These results suggest that human adipose tissue mesenchymal stem cells promoted satisfactory cartilage repair in the ovine model. PMID- 26569222 TI - Single-Cell Isolation and Gene Analysis: Pitfalls and Possibilities. AB - During the last two decades single-cell analysis (SCA) has revealed extensive phenotypic differences within homogenous cell populations. These phenotypic differences are reflected in the stochastic nature of gene regulation, which is often masked by qualitatively and quantitatively averaging in whole tissue analyses. The ability to isolate transcripts and investigate how genes are regulated at the single cell level requires highly sensitive and refined methods. This paper reviews different strategies currently used for SCA, including harvesting, reverse transcription, and amplification of the RNA, followed by methods for transcript quantification. The review provides the historical background to SCA, discusses limitations, and current and future possibilities in this exciting field of research. PMID- 26569223 TI - Augmenting the Activity of Monoterpenoid Phenols against Fungal Pathogens Using 2 Hydroxy-4-methoxybenzaldehyde that Target Cell Wall Integrity. AB - Disruption of cell wall integrity system should be an effective strategy for control of fungal pathogens. To augment the cell wall disruption efficacy of monoterpenoid phenols (carvacrol, thymol), antimycotic potency of benzaldehyde derivatives that can serve as chemosensitizing agents were evaluated against strains of Saccharomyces cerevisiae wild type (WT), slt2Delta and bck1Delta (mutants of the mitogen-activated protein kinase (MAPK) and MAPK kinase kinase, respectively, in the cell wall integrity pathway). Among fourteen compounds investigated, slt2Delta and bck1Delta showed higher susceptibility to nine benzaldehydes, compared to WT. Differential antimycotic activity of screened compounds indicated "structure-activity relationship" for targeting the cell wall integrity, where 2-hydroxy-4-methoxybenzaldehyde (2H4M) exhibited the highest antimycotic potency. The efficacy of 2H4M as an effective chemosensitizer to monoterpenoid phenols (viz., 2H4M + carvacrol or thymol) was assessed in yeasts or filamentous fungi (Aspergillus, Penicillium) according to European Committee on Antimicrobial Susceptibility Testing or Clinical Laboratory Standards Institute M38-A protocols, respectively. Synergistic chemosensitization greatly lowers minimum inhibitory or fungicidal concentrations of the co-administered compounds. 2H4M also overcame the tolerance of two MAPK mutants (sakADelta, mpkCDelta) of Aspergillus fumigatus to fludioxonil (phenylpyrrole fungicide). Collectively, 2H4M possesses chemosensitizing capability to magnify the efficacy of monoterpenoid phenols, which improves target-based (viz., cell wall disruption) antifungal intervention. PMID- 26569224 TI - Identification of Arsenic Direct-Binding Proteins in Acute Promyelocytic Leukaemia Cells. AB - The identification of arsenic direct-binding proteins is essential for determining the mechanism by which arsenic trioxide achieves its chemotherapeutic effects. At least two cysteines close together in the amino acid sequence are crucial to the binding of arsenic and essential to the identification of arsenic binding proteins. In the present study, arsenic binding proteins were pulled down with streptavidin and identified using a liquid chromatograph-mass spectrometer (LC-MS/MS). More than 40 arsenic-binding proteins were separated, and redox related proteins, glutathione S-transferase P1 (GSTP1), heat shock 70 kDa protein 9 (HSPA9) and pyruvate kinase M2 (PKM2), were further studied using binding assays in vitro. Notably, PKM2 has a high affinity for arsenic. In contrast to PKM2, GSTP1and HSPA9 did not combine with arsenic directly in vitro. These observations suggest that arsenic-mediated acute promyelocytic leukaemia (APL) suppressive effects involve PKM2. In summary, we identified several arsenic binding proteins in APL cells and investigated the therapeutic mechanisms of arsenic trioxide for APL. Further investigation into specific signal pathways by which PKM2 mediates APL developments may lead to a better understanding of arsenic effects on APL. PMID- 26569226 TI - Silencing of Kv1.5 Gene Inhibits Proliferation and Induces Apoptosis of Osteosarcoma Cells. AB - Kv1.5 (also known as KCNA5) is a protein encoded by the KCNA5 gene, which belongs to the voltage-gated potassium channel, shaker-related subfamily. Recently, a number of studies have suggested that Kv1.5 is overexpressed in numerous cancers and plays crucial roles in cancer development. However, until now, the expression and functions of Kv1.5 in osteosarcoma are still unclear. To characterize the potential biological functions of Kv1.5 in osteosarcoma, herein, we examined the expression levels of Kv1.5 in osteosarcoma cells and tissues using quantitative real-time polymerase chain reaction (qRT-PCR), western blot, and immunohistochemistry assays. Four short hairpin RNAs (shRNAs) targeting Kv1.5 were designed and homologous recombination technology was used to construct pGeneSil-Kv1.5 vectors. In addition, the vectors were transfected into osteosarcoma MG63 cells and Kv1.5 mRNA level was measured by qRT-PCR and the Kv1.5 protein level was examined by western blot. We also examined the effects of Kv1.5 silencing on proliferation, cell cycle and apoptosis of the osteosarcoma cells using CCK-8, colony formation, flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays. Our results showed that Kv1.5 was aberrantly expressed in osteosarcoma and that the synthesized shRNA targeting Kv1.5 reduced Kv1.5 mRNA and protein expression effectively. Silencing Kv1.5 expression in the osteosarcoma cells significantly inhibited the proliferation of osteosarcoma cells, induced cell cycle arrest at G0/G1 phase, and induced cell apoptosis through up-regulation of p21, p27, Bax, Bcl-XL and caspase-3 and down regulation of cyclins A, cyclins D1, cyclins E, Bcl-2 and Bik. In summary, our results indicate that Kv1.5 silencing could suppress osteosarcoma progression through multiple signaling pathways and suggest that Kv1.5 may be a novel target for osteosarcoma therapeutics. PMID- 26569227 TI - Calpain 3 Expression Pattern during Gastrocnemius Muscle Atrophy and Regeneration Following Sciatic Nerve Injury in Rats. AB - Calpain 3 (CAPN3), also known as p94, is a skeletal muscle-specific member of the calpain family that is involved in muscular dystrophy; however, the roles of CAPN3 in muscular atrophy and regeneration are yet to be understood. In the present study, we attempted to explain the effect of CAPN3 in muscle atrophy by evaluating CAPN3 expression in rat gastrocnemius muscle following reversible sciatic nerve injury. After nerve injury, the wet weight ratio and cross sectional area (CSA) of gastrocnemius muscle were decreased gradually from 1-14 days and then recovery from 14-28 days. The active form of CAPN3 (~62 kDa) protein decreased slightly on day 3 and then increased from day 7 to 14 before a decrease from day 14 to 28. The result of linear correlation analysis showed that expression of the active CAPN3 protein level was negatively correlated with muscle wet weight ratio. CAPN3 knockdown by short interfering RNA (siRNA) injection improved muscle recovery on days 7 and 14 after injury as compared to that observed with control siRNA treatment. Depletion of CAPN3 gene expression could promote myoblast differentiation in L6 cells. Based on these findings, we conclude that the expression pattern of the active CAPN3 protein is linked to muscle atrophy and regeneration following denervation: its upregulation during early stages may promote satellite cell renewal by inhibiting differentiation, whereas in later stages, CAPN3 expression may be downregulated to stimulate myogenic differentiation and enhance recovery. These results provide a novel mechanistic insight into the role of CAPN3 protein in muscle regeneration after peripheral nerve injury. PMID- 26569229 TI - Alteration of the Donor/Acceptor Spectrum of the (S)-Amine Transaminase from Vibrio fluvialis. AB - To alter the amine donor/acceptor spectrum of an (S)-selective amine transaminase (ATA), a library based on the Vibrio fluvialis ATA targeting four residues close to the active site (L56, W57, R415 and L417) was created. A 3DM-derived alignment comprising fold class I pyridoxal-5'-phosphate (PLP)-dependent enzymes allowed identification of positions, which were assumed to determine substrate specificity. These positions were targeted for mutagenesis with a focused alphabet of hydrophobic amino acids to convert an amine:alpha-keto acid transferase into an amine:aldehyde transferase. Screening of 1200 variants revealed three hits, which showed a shifted amine donor/acceptor spectrum towards aliphatic aldehydes (mainly pentanal), as well as an altered pH profile. Interestingly, all three hits, although found independently, contained the same mutation R415L and additional W57F and L417V substitutions. PMID- 26569225 TI - Therapeutic Implications for Overcoming Radiation Resistance in Cancer Therapy. AB - Ionizing radiation (IR), such as X-rays and gamma (gamma)-rays, mediates various forms of cancer cell death such as apoptosis, necrosis, autophagy, mitotic catastrophe, and senescence. Among them, apoptosis and mitotic catastrophe are the main mechanisms of IR action. DNA damage and genomic instability contribute to IR-induced cancer cell death. Although IR therapy may be curative in a number of cancer types, the resistance of cancer cells to radiation remains a major therapeutic problem. In this review, we describe the morphological and molecular aspects of various IR-induced types of cell death. We also discuss cytogenetic variations representative of IR-induced DNA damage and genomic instability. Most importantly, we focus on several pathways and their associated marker proteins responsible for cancer resistance and its therapeutic implications in terms of cancer cell death of various types and characteristics. Finally, we propose radiation-sensitization strategies, such as the modification of fractionation, inflammation, and hypoxia and the combined treatment, that can counteract the resistance of tumors to IR. PMID- 26569228 TI - Exploring Different Strategies for Efficient Delivery of Colorectal Cancer Therapy. AB - Colorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer death in the world. Currently available chemotherapy of CRC usually delivers the drug to both normal as well as cancerous tissues, thus leading to numerous undesirable effects. Much emphasis is being laid on the development of effective drug delivery systems for achieving selective delivery of the active moiety at the anticipated site of action with minimized unwanted side effects. Researchers have employed various techniques (dependent on pH, time, pressure and/or bacteria) for targeting drugs directly to the colonic region. On the other hand, systemic drug delivery strategies to specific molecular targets (such as FGFR, EGFR, CD44, EpCAM, CA IX, PPARgamma and COX-2) overexpressed by cancerous cells have also been shown to be effective. This review aims to put forth an overview of drug delivery technologies that have been, and may be developed, for the treatment of CRC. PMID- 26569230 TI - Molecular Effects of Irradiation (Cobalt-60) on the Control of Panonychus citri (Acari: Tetranychidae). AB - The effective dose of irradiation to control pest mites in quarantine has been studied extensively, but the molecular mechanisms underlying the effects of the irradiation on mites are largely unknown. In this study, exposure to 400 Gy of gamma rays had significant (p < 0.05) effects on the adult survival, fecundity and egg viability of Panonychus citri. The irradiation caused the degradation of the DNA of P. citri adults and damaged the plasma membrane system of the egg, which led to condensed nucleoli and gathered yolk. Additionally, the transcriptomes and gene expression profiles between irradiated and non-irradiated mites were compared, and three digital gene expression libraries were assembled and analyzed. The differentially expressed genes were putatively involved in apoptosis, cell death and the cell cycle. Finally, the expression profiles of some related genes were studied using quantitative real-time PCR. Our study provides valuable information on the changes in the transcriptome of irradiated P. citri, which will facilitate a better understanding of the molecular mechanisms that cause the sterility induced by irradiation. PMID- 26569231 TI - CpLEA5, the Late Embryogenesis Abundant Protein Gene from Chimonanthus praecox, Possesses Low Temperature and Osmotic Resistances in Prokaryote and Eukaryotes. AB - Plants synthesize and accumulate a series of stress-resistance proteins to protect normal physiological activities under adverse conditions. Chimonanthus praecox which blooms in freezing weather accumulates late embryogenesis abundant proteins (LEAs) in flowers, but C. praecox LEAs are little reported. Here, we report a group of five LEA genes of C. praecox (CpLEA5, KT727031). Prokaryotic expressed CpLEA5 was employed in Escherichia coli to investigate bioactivities and membrane permeability at low-temperature. In comparison with the vacant strains, CpLEA5-containing strains survived in a 20% higher rate; and the degree of cell membrane damage in CpLEA5-containing strains was 55% of that of the vacant strains according to a conductivity test, revealing the low-temperature resistance of CpLEA5 in bacteria. CpLEA5 was also expressed in Pichia pastoris. Interestingly, besides low-temperature resistance, CpLEA5 conferred high resistance to salt and alkali in CpLEA5 overexpressing yeast. The CpLEA5 gene was transferred into Arabidopsis thaliana to also demonstrate CpLEA5 actions in plants. As expected, the transgenic lines were more resistant against low temperature and drought while compared with the wild type. Taken together, CpLEA5 conferred resistances to several conditions in prokaryote and eukaryotes could have great value as a genetic technology to enhance osmotic stress and low temperature tolerance. PMID- 26569232 TI - Morphological Characters and Transcriptome Profiles Associated with Black Skin and Red Skin in Crimson Snapper (Lutjanus erythropterus). AB - In this study, morphology observation and illumina sequencing were performed on two different coloration skins of crimson snapper (Lutjanus erythropterus), the black zone and the red zone. Three types of chromatophores, melanophores, iridophores and xanthophores, were organized in the skins. The main differences between the two colorations were in the amount and distribution of the three chromatophores. After comparing the two transcriptomes, 9200 unigenes with significantly different expressions (ratio change >= 2 and q-value <= 0.05) were found, of which 5972 were up-regulated in black skin and 3228 were up-regulated in red skin. Through the function annotation, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of the differentially transcribed genes, we excavated a number of uncharacterized candidate pigment genes as well as found the conserved genes affecting pigmentation in crimson snapper. The patterns of expression of 14 pigment genes were confirmed by the Quantitative real-time PCR analysis between the two color skins. Overall, this study shows a global survey of the morphological characters and transcriptome analysis of the different coloration skins in crimson snapper, and provides valuable cellular and genetic information to uncover the mechanism of the formation of pigment patterns in snappers. PMID- 26569233 TI - Immunoregulatory Cell Depletion Improves the Efficacy of Photodynamic Therapy Generated Cancer Vaccines. AB - Photodynamic therapy (PDT)-generated cancer vaccine represents an attractive potential application of PDT, therapeutic modality destroying targeted lesions by localized photooxidative stress. Since immunoregulatory cell activity has become recognized as a major obstacle to effective cancer immunotherapy, the present study examined their participation in the therapeutic effect of PDT cancer vaccine. Following protocols from previous studies, mouse with squamous cell carcinoma SCCVII tumors were vaccinated by SCCVII cells treated by PDT and response monitored by tumor size measurement. The effects of low-dose cyclophosphamide (50 mg/kg) and all-trans retinoic acid (ATRA) on the numbers of Tregs and myeloid-derived suppressor cells (MDSCs) were determined by antibody staining followed by flow cytometry, while their impact on PDT vaccine therapy was evaluated by monitoring changes in tumor responses. Cyclophosphamide effectively reduced the numbers of Tregs, which became elevated following PDT vaccine treatment, and this resulted in an increase in the vaccine's effectiveness. A similar benefit for the therapy outcome with PDT vaccine was attained by ATRA treatment. The activities of Tregs and MDSCs thus have a critical impact on therapy outcome with PDT vaccine and reducing their numbers substantially improves the vaccine's effectiveness. PMID- 26569235 TI - A PPO Promoter from Betalain-Producing Red Swiss Chard, Directs Petiole- and Root Preferential Expression of Foreign Gene in Anthocyanins-Producing Plants. AB - A 1670 bp 5'-flanking region of the polyphenol oxidase (PPO) gene was isolated from red Swiss chard, a betalain-producing plant. This region, named promoter BvcPPOP, and its 5'-truncated versions were fused with the GUS gene and introduced into Arabidopsis, an anthocyanins-producing plant. GUS histochemical staining and quantitative analysis of transgenic plants at the vegetative and reproductive stages showed that BvcPPOP could direct GUS gene expression in vegetative organs with root- and petiole-preference, but not in reproductive organs including inflorescences shoot, inflorescences leaf, flower, pod and seed. This promoter was regulated by developmental stages in its driving strength, but not in expression pattern. It was also regulated by the abiotic stressors tested, positively by salicylic acid (SA) and methyl jasmonate (MeJA) but negatively by abscisic acid (ABA), gibberellin (GA), NaCl and OH(-). Its four 5'-truncated versions varied in the driving strength, but not obviously in expression pattern, and even the shortest version (-225 to +22) retained the root- and petiole- preference. This promoter is, to our knowledge, the first PPO promoter cloned and functionally elucidated from the betalain-producing plant, and thus provides not only a useful tool for expressing gene(s) of agricultural interest in vegetative organs, but also a clue to clarify the function of metabolism-specific PPO in betalain biosynthesis. PMID- 26569234 TI - Sildenafil Protects against Myocardial Ischemia-Reperfusion Injury Following Cardiac Arrest in a Porcine Model: Possible Role of the Renin-Angiotensin System. AB - Sildenafil, a phosphodiesterase-5 inhibitor sold as Viagra, is a cardioprotector against myocardial ischemia/reperfusion (I/R) injury. Our study explored whether sildenafil protects against I/R-induced damage in a porcine cardiac arrest and resuscitation (CAR) model via modulating the renin-angiotensin system. Male pigs were randomly divided to three groups: Sham group, Saline group, and sildenafil (0.5 mg/kg) group. Thirty min after drug infusion, ventricular fibrillation (8 min) and cardiopulmonary resuscitation (up to 30 min) was conducted in these animals. We found that sildenafil ameliorated the reduced cardiac function and improved the 24-h survival rate in this model. Sildenafil partly attenuated the increases of plasma angiotensin II (Ang II) and Ang (1-7) levels after CAR. Sildenafil also decreased apoptosis and Ang II expression in myocardium. The increases of expression of angiotensin-converting-enzyme (ACE), ACE2, Ang II type 1 receptor (AT1R), and the Ang (1-7) receptor Mas in myocardial tissue were enhanced after CAR. Sildenafil suppressed AT1R up-regulation, but had no effect on ACE, ACE2, and Mas expression. Sildenafil further boosted the upregulation of endothelial nitric oxide synthase (eNOS), cyclic guanosine monophosphate (cGMP) and inducible nitric oxide synthase(iNOS). Collectively, our results suggest that cardioprotection of sildenafil in CAR model is accompanied by an inhibition of Ang II-AT1R axis activation. PMID- 26569236 TI - Online Measurement of Real-Time Cytotoxic Responses Induced by Multi-Component Matrices, such as Natural Products, through Electric Cell-Substrate Impedance Sensing (ECIS). AB - Natural products are complex matrices of compounds that are prone to interfere with the label-dependent methods that are typically used for cytotoxicity screenings. Here, we developed a label-free Electric Cell-substrate Impedance Sensing (ECIS)-based cytotoxicity assay that can be applied in the assessment of the cytotoxicity of natural extracts. The conditions to measure the impedance using ECIS were first optimized in mice immortalized hypothalamic neurons GT1-7 cells. The performance of four natural extracts when tested using three conventional cytotoxicity assays in GT1-7 cells, was studied. Betula pendula (silver birch tree) was found to interfere with all of the cytotoxicity assays in which labels were applied. The silver birch extract was also proven to be cytotoxic and, thus, served as a proof-of-concept for the use of ECIS. The extract was fractionated and the ECIS method permitted the distinction of specific kinetic patterns of cytotoxicity on the fractions as well as the extract's pure constituents. This study offers evidence that ECIS is an excellent tool for real-time monitoring of the cytotoxicity of complex extracts that are difficult to work with using conventional (label-based) assays. Altogether, it offers a very suitable cytotoxicity-screening assay making the work with natural products less challenging within the drug discovery workflow. PMID- 26569237 TI - Benzene-Induced Aberrant miRNA Expression Profile in Hematopoietic Progenitor Cells in C57BL/6 Mice. AB - Benzene is a common environmental pollutant that causes hematological alterations. MicroRNAs (miRNAs) may play a role in benzene-induced hematotoxicity. In this study, C57BL/6 mice showed significant hematotoxicity after exposure to 150 mg/kg benzene for 4 weeks. Benzene exposure decreased not only the number of cells in peripheral blood but also hematopoietic progenitor cells in the bone marrow. Meanwhile, RNA from Lin(-) cells sorted from the bone marrow was applied to aberrant miRNA expression profile using Illumina sequencing. We found that 5 miRNAs were overexpressed and 45 miRNAs were downregulated in the benzene exposure group. Sequencing results were confirmed through qRT-PCR. Furthermore, we also identified five miRNAs which significantly altered in Lin(-)c-Kit+ cells obtained from benzene-exposed mice, including mmu miR-34a-5p; mmu-miR-342-3p; mmu-miR-100-5p; mmu-miR-181a-5p; and mmu-miR-196b-5p. In summary, we successfully established a classical animal model to induce significant hematotoxicity by benzene injection. Benzene exposure may cause severe hematotoxicity not only to blood cells in peripheral circulation but also to hematopoietic cells in bone marrow. Benzene exposure also alters miRNA expression in hematopoietic progenitor cells. This study suggests that benzene induces alteration in hematopoiesis and hematopoiesis-associated miRNAs. PMID- 26569238 TI - A Comparative Study on Two Cationic Porphycenes: Photophysical and Antimicrobial Photoinactivation Evaluation. AB - Over the last decades, the number of pathogenic multi-resistant microorganisms has grown dramatically, which has stimulated the search for novel strategies to combat antimicrobial resistance. Antimicrobial photodynamic therapy (aPDT) is one of the promising alternatives to conventional treatments based on antibiotics. Here, we present a comparative study of two aryl tricationic porphycenes where photoinactivation efficiency against model pathogenic microorganisms is correlated to the photophysical behavior of the porphycene derivatives. Moreover, the extent of photosensitizer cell binding to bacteria has been assessed by flow cytometry in experiments with, or without, removing the unbound porphycene from the incubation medium. Results show that the peripheral substituent change do not significantly affect the overall behavior for both tricationic compounds neither in terms of photokilling efficiency, nor in terms of binding. PMID- 26569240 TI - The Mine Locomotive Wireless Network Strategy Based on Successive Interference Cancellation. AB - We consider a wireless network strategy based on successive interference cancellation (SIC) for mine locomotives. We firstly build the original mathematical model for the strategy which is a non-convex model. Then, we examine this model intensively, and figure out that there are certain regulations embedded in it. Based on these findings, we are able to reformulate the model into a new form and design a simple algorithm which can assign each locomotive with a proper transmitting scheme during the whole schedule procedure. Simulation results show that the outcomes obtained through this algorithm are improved by around 50% compared with those that do not apply the SIC technique. PMID- 26569239 TI - A Graphene-Based Biosensing Platform Based on Regulated Release of an Aptameric DNA Biosensor. AB - A novel biosensing platform was developed by integrating an aptamer-based DNA biosensor with graphene oxide (GO) for rapid and facile detection of adenosine triphosphate (ATP, as a model target). The DNA biosensor, which is locked by GO, is designed to contain two sensing modules that include recognition site for ATP and self-replication track that yields the nicking domain for Nt.BbvCI. By taking advantage of the different binding affinity of single-stranded DNA, double stranded DNA and aptamer-target complex toward GO, the DNA biosensor could be efficiently released from GO in the presence of target with the help of a complementary DNA strand (CPDNA) that partially hybridizes to the DNA biosensor. Then, the polymerization/nicking enzyme synergetic isothermal amplification could be triggered, leading to the synthesis of massive DNA amplicons, thus achieving an enhanced sensitivity with a wide linear dynamic response range of four orders of magnitude and good selectivity. This biosensing strategy expands the applications of GO-DNA nanobiointerfaces in biological sensing, showing great potential in fundamental research and biomedical diagnosis. PMID- 26569241 TI - Real-Valued Covariance Vector Sparsity-Inducing DOA Estimation for Monostatic MIMO Radar. AB - In this paper, a real-valued covariance vector sparsity-inducing method for direction of arrival (DOA) estimation is proposed in monostatic multiple-input multiple-output (MIMO) radar. Exploiting the special configuration of monostatic MIMO radar, low-dimensional real-valued received data can be obtained by using the reduced-dimensional transformation and unitary transformation technique. Then, based on the Khatri-Rao product, a real-valued sparse representation framework of the covariance vector is formulated to estimate DOA. Compared to the existing sparsity-inducing DOA estimation methods, the proposed method provides better angle estimation performance and lower computational complexity. Simulation results verify the effectiveness and advantage of the proposed method. PMID- 26569242 TI - Prototyping a GNSS-Based Passive Radar for UAVs: An Instrument to Classify the Water Content Feature of Lands. AB - Global Navigation Satellite Systems (GNSS) broadcast signals for positioning and navigation, which can be also employed for remote sensing applications. Indeed, the satellites of any GNSS can be seen as synchronized sources of electromagnetic radiation, and specific processing of the signals reflected back from the ground can be used to estimate the geophysical properties of the Earth's surface. Several experiments have successfully demonstrated GNSS-reflectometry (GNSS-R), whereas new applications are continuously emerging and are presently under development, either from static or dynamic platforms. GNSS-R can be implemented at a low cost, primarily if small devices are mounted on-board unmanned aerial vehicles (UAVs), which today can be equipped with several types of sensors for environmental monitoring. So far, many instruments for GNSS-R have followed the GNSS bistatic radar architecture and consisted of custom GNSS receivers, often requiring a personal computer and bulky systems to store large amounts of data. This paper presents the development of a GNSS-based sensor for UAVs and small manned aircraft, used to classify lands according to their soil water content. The paper provides details on the design of the major hardware and software components, as well as the description of the results obtained through field tests. PMID- 26569243 TI - The Node Deployment of Intelligent Sensor Networks Based on the Spatial Difference of Farmland Soil. AB - Considering that agricultural production is characterized by vast areas, scattered fields and long crop growth cycles, intelligent wireless sensor networks (WSNs) are suitable for monitoring crop growth information. Cost and coverage are the most key indexes for WSN applications. The differences in crop conditions are influenced by the spatial distribution of soil nutrients. If the nutrients are distributed evenly, the crop conditions are expected to be approximately uniform with little difference; on the contrary, there will be great differences in crop conditions. In accordance with the differences in the spatial distribution of soil information in farmland, fuzzy c-means clustering was applied to divide the farmland into several areas, where the soil fertility of each area is nearly uniform. Then the crop growth information in the area could be monitored with complete coverage by deploying a sensor node there, which could greatly decrease the deployed sensor nodes. Moreover, in order to accurately judge the optimal cluster number of fuzzy c-means clustering, a discriminant function for Normalized Intra-Cluster Coefficient of Variation (NICCV) was established. The sensitivity analysis indicates that NICCV is insensitive to the fuzzy weighting exponent, but it shows a strong sensitivity to the number of clusters. PMID- 26569244 TI - Magnetic Sensors Based on Amorphous Ferromagnetic Materials: A Review. AB - Currently there are many types of sensors that are used in lots of applications. Among these, magnetic sensors are a good alternative for the detection and measurement of different phenomena because they are a "simple" and readily available technology. For the construction of such devices there are many magnetic materials available, although amorphous ferromagnetic materials are the most suitable. The existence in the market of these materials allows the production of different kinds of sensors, without requiring expensive manufacture investments for the magnetic cores. Furthermore, these are not fragile materials that require special care, favouring the construction of solid and reliable devices. Another important feature is that these sensors can be developed without electric contact between the measuring device and the sensor, making them especially fit for use in harsh environments. In this review we will look at the main types of developed magnetic sensors. This work presents the state of the art of magnetic sensors based on amorphous ferromagnetic materials used in modern technology: security devices, weapon detection, magnetic maps, car industry, credit cards, etc. PMID- 26569245 TI - Analysis of the Sensitivity of K-Type Molecular Sieve-Deposited MWNTs for the Detection of SF6 Decomposition Gases under Partial Discharge. AB - Sulfur hexafluoride (SF6) is widely utilized in gas-insulated switchgear (GIS). However, part of SF6 decomposes into different components under partial discharge (PD) conditions. Previous research has shown that the gas responses of intrinsic and 4 A-type molecular sieve-deposited multi-wall carbon nanotubes (MWNTs) to SOF2 and SO2F2, two important decomposition components of SF6, are not obvious. In this study, a K-type molecular sieve-deposited MWNTs sensor was developed. Its gas response characteristics and the influence of the mixture ratios of gases on the gas-sensing properties were studied. The results showed that, for sensors with gas mixture ratios of 5:1, 10:1, and 20:1, the resistance change rate increased by nearly 13.0% after SOF2 adsorption, almost 10 times that of MWNTs sensors, while the sensors' resistance change rate with a mixture ratio of 10:1 reached 17.3% after SO2F2 adsorption, nearly nine times that of intrinsic MWNT sensors. Besides, a good linear relationship was observed between concentration of decomposition components and the resistance change rate of sensors. PMID- 26569246 TI - Application of Novel Lateral Tire Force Sensors to Vehicle Parameter Estimation of Electric Vehicles. AB - This article presents methods for estimating lateral vehicle velocity and tire cornering stiffness, which are key parameters in vehicle dynamics control, using lateral tire force measurements. Lateral tire forces acting on each tire are directly measured by load-sensing hub bearings that were invented and further developed by NSK Ltd. For estimating the lateral vehicle velocity, tire force models considering lateral load transfer effects are used, and a recursive least square algorithm is adapted to identify the lateral vehicle velocity as an unknown parameter. Using the estimated lateral vehicle velocity, tire cornering stiffness, which is an important tire parameter dominating the vehicle's cornering responses, is estimated. For the practical implementation, the cornering stiffness estimation algorithm based on a simple bicycle model is developed and discussed. Finally, proposed estimation algorithms were evaluated using experimental test data. PMID- 26569247 TI - Optimization Algorithm for Kalman Filter Exploiting the Numerical Characteristics of SINS/GPS Integrated Navigation Systems. AB - Aiming at addressing the problem of high computational cost of the traditional Kalman filter in SINS/GPS, a practical optimization algorithm with offline derivation and parallel processing methods based on the numerical characteristics of the system is presented in this paper. The algorithm exploits the sparseness and/or symmetry of matrices to simplify the computational procedure. Thus plenty of invalid operations can be avoided by offline derivation using a block matrix technique. For enhanced efficiency, a new parallel computational mechanism is established by subdividing and restructuring calculation processes after analyzing the extracted "useful" data. As a result, the algorithm saves about 90% of the CPU processing time and 66% of the memory usage needed in a classical Kalman filter. Meanwhile, the method as a numerical approach needs no precise loss transformation/approximation of system modules and the accuracy suffers little in comparison with the filter before computational optimization. Furthermore, since no complicated matrix theories are needed, the algorithm can be easily transplanted into other modified filters as a secondary optimization method to achieve further efficiency. PMID- 26569248 TI - An Electrochemical NO2 Sensor Based on Ionic Liquid: Influence of the Morphology of the Polymer Electrolyte on Sensor Sensitivity. AB - A systematic study was carried out to investigate the effect of ionic liquid in solid polymer electrolyte (SPE) and its layer morphology on the characteristics of an electrochemical amperometric nitrogen dioxide sensor. Five different ionic liquids were immobilized into a solid polymer electrolyte and key sensor parameters (sensitivity, response/recovery times, hysteresis and limit of detection) were characterized. The study revealed that the sensor based on 1 ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([EMIM][N(Tf)2]) showed the best sensitivity, fast response/recovery times, and low sensor response hysteresis. The working electrode, deposited from water-based carbon nanotube ink, was prepared by aerosol-jet printing technology. It was observed that the thermal treatment and crystallinity of poly(vinylidene fluoride) (PVDF) in the solid polymer electrolyte influenced the sensitivity. Picture analysis of the morphology of the SPE layer based on [EMIM][N(Tf)2] ionic liquid treated under different conditions suggests that the sensor sensitivity strongly depends on the fractal dimension of PVDF spherical objects in SPE. Their deformation, e.g., due to crowding, leads to a decrease in sensor sensitivity. PMID- 26569249 TI - Wearable Goniometer and Accelerometer Sensory Fusion for Knee Joint Angle Measurement in Daily Life. AB - Human motion analysis is crucial for a wide range of applications and disciplines. The development and validation of low cost and unobtrusive sensing systems for ambulatory motion detection is still an open issue. Inertial measurement systems and e-textile sensors are emerging as potential technologies for daily life situations. We developed and conducted a preliminary evaluation of an innovative sensing concept that combines e-textiles and tri-axial accelerometers for ambulatory human motion analysis. Our sensory fusion method is based on a Kalman filter technique and combines the outputs of textile electrogoniometers and accelerometers without making any assumptions regarding the initial accelerometer position and orientation. We used our technique to measure the flexion-extension angle of the knee in different motion tasks (monopodalic flexions and walking at different velocities). The estimation technique was benchmarked against a commercial measurement system based on inertial measurement units and performed reliably for all of the various tasks (mean and standard deviation of the root mean square error of 1:96 and 0:96, respectively). In addition, the method showed a notable improvement in angular estimation compared to the estimation derived by the textile goniometer and accelerometer considered separately. In future work, we will extend this method to more complex and multi-degree of freedom joints. PMID- 26569250 TI - In Vivo Pattern Classification of Ingestive Behavior in Ruminants Using FBG Sensors and Machine Learning. AB - Pattern classification of ingestive behavior in grazing animals has extreme importance in studies related to animal nutrition, growth and health. In this paper, a system to classify chewing patterns of ruminants in in vivo experiments is developed. The proposal is based on data collected by optical fiber Bragg grating sensors (FBG) that are processed by machine learning techniques. The FBG sensors measure the biomechanical strain during jaw movements, and a decision tree is responsible for the classification of the associated chewing pattern. In this study, patterns associated with food intake of dietary supplement, hay and ryegrass were considered. Additionally, two other important events for ingestive behavior were monitored: rumination and idleness. Experimental results show that the proposed approach for pattern classification is capable of differentiating the five patterns involved in the chewing process with an overall accuracy of 94%. PMID- 26569251 TI - Flight Test Result for the Ground-Based Radio Navigation System Sensor with an Unmanned Air Vehicle. AB - The Ground-based Radio Navigation System (GRNS) is an alternative/backup navigation system based on time synchronized pseudolites. It has been studied for some years due to the potential vulnerability issue of satellite navigation systems (e.g., GPS or Galileo). In the framework of our study, a periodic pulsed sequence was used instead of the randomized pulse sequence recommended as the RTCM (radio technical commission for maritime services) SC (special committee) 104 pseudolite signal, as a randomized pulse sequence with a long dwell time is not suitable for applications requiring high dynamics. This paper introduces a mathematical model of the post-correlation output in a navigation sensor, showing that the aliasing caused by the additional frequency term of a periodic pulsed signal leads to a false lock (i.e., Doppler frequency bias) during the signal acquisition process or in the carrier tracking loop of the navigation sensor. We suggest algorithms to resolve the frequency false lock issue in this paper, relying on the use of a multi-correlator. A flight test with an unmanned helicopter was conducted to verify the implemented navigation sensor. The results of this analysis show that there were no false locks during the flight test and that outliers stem from bad dilution of precision (DOP) or fluctuations in the received signal quality. PMID- 26569252 TI - Performance Evaluation of a Multichannel All-In-One Phantom Dosimeter for Dose Measurement of Diagnostic X-ray Beam. AB - We developed a multichannel all-in-one phantom dosimeter system composed of nine sensing probes, a chest phantom, an image intensifier, and a complementary metal oxide semiconductor (CMOS) image sensor to measure the dose distribution of an X ray beam used in radiation diagnosis. Nine sensing probes of the phantom dosimeter were fabricated identically by connecting a plastic scintillating fiber (PSF) to a plastic optical fiber (POF). To measure the planar dose distribution on a chest phantom according to exposure parameters used in clinical practice, we divided the top of the chest phantom into nine equal parts virtually and then installed the nine sensing probes at each center of the nine equal parts on the top of the chest phantom as measuring points. Each scintillation signal generated in the nine sensing probes was transmitted through the POFs and then intensified by the image intensifier because the scintillation signal normally has a very low light intensity. Real-time scintillation images (RSIs) containing the intensified scintillation signals were taken by the CMOS image sensor with a single lens optical system and displayed through a software program. Under variation of the exposure parameters, we measured RSIs containing dose information using the multichannel all-in-one phantom dosimeter and compared the results with the absorbed doses obtained by using a semiconductor dosimeter (SCD). From the experimental results of this study, the light intensities of nine regions of interest (ROI) in the RSI measured by the phantom dosimeter were similar to the dose distribution obtained using the SCD. In conclusion, we demonstrated that the planar dose distribution including the entrance surface dose (ESD) can be easily measured by using the proposed phantom dosimeter system. PMID- 26569253 TI - Acetone Sensing Properties of a Gas Sensor Composed of Carbon Nanotubes Doped With Iron Oxide Nanopowder. AB - Iron oxide (Fe2O3) nanopowder was prepared by a precipitation method and then mixed with different proportions of carbon nanotubes. The composite materials were characterized by X-ray powder diffraction, Fourier transform infrared spectroscopy and scanning electron microscopy. A fabricated heater-type gas sensor was compared with a pure Fe2O3 gas sensor under the influence of acetone. The effects of the amount of doping, the sintering temperature, and the operating temperature on the response of the sensor and the response recovery time were analyzed. Experiments show that doping of carbon nanotubes with iron oxide effectively improves the response of the resulting gas sensors to acetone gas. It also reduces the operating temperature and shortens the response recovery time of the sensor. The response of the sensor in an acetone gas concentration of 80 ppm was enhanced, with good repeatability. PMID- 26569254 TI - Maximizing Information Diffusion in the Cyber-physical Integrated Network. AB - Nowadays, our living environment has been embedded with smart objects, such as smart sensors, smart watches and smart phones. They make cyberspace and physical space integrated by their abundant abilities of sensing, communication and computation, forming a cyber-physical integrated network. In order to maximize information diffusion in such a network, a group of objects are selected as the forwarding points. To optimize the selection, a minimum connected dominating set (CDS) strategy is adopted. However, existing approaches focus on minimizing the size of the CDS, neglecting an important factor: the weight of links. In this paper, we propose a distributed maximizing the probability of information diffusion (DMPID) algorithm in the cyber-physical integrated network. Unlike previous approaches that only consider the size of CDS selection, DMPID also considers the information spread probability that depends on the weight of links. To weaken the effects of excessively-weighted links, we also present an optimization strategy that can properly balance the two factors. The results of extensive simulation show that DMPID can nearly double the information diffusion probability, while keeping a reasonable size of selection with low overhead in different distributed networks. PMID- 26569255 TI - High-Temperature SAW Wireless Strain Sensor with Langasite. AB - Two Surface acoustic wave (SAW) resonators were fabricated on langasite substrates with Euler angle of (0 degrees , 138.5 degrees , 117 degrees ) and (0 degrees , 138.5 degrees , 27 degrees ). A dipole antenna was bonded to the prepared SAW resonator to form a wireless sensor. The characteristics of the SAW sensors were measured by wireless frequency domain interrogation methods from 20 degrees C to 600 degrees C. Different temperature behaviors of the sensors were observed. Strain sensing was achieved using a cantilever configuration. The sensors were measured under applied strain from 20 degrees C to 500 degrees C. The shift of the resonance frequency contributed merely by strain is extracted from the combined effects of temperature and strain. Both the strain factors of the two SAW sensors increase with rising ambient temperature, and the SAW sensor deposited on (0 degrees , 138.5 degrees , 117 degrees ) cut is more sensitive to applied strain. The measurement errors of the two sensors are also discussed. The relative errors of the two sensors are between 0.63% and 2.09%. Even at 500 degrees C, the hysteresis errors of the two sensors are less than 5%. PMID- 26569257 TI - Reusable EGaIn-Injected Substrate-Integrated-Waveguide Resonator for Wireless Sensor Applications. AB - The proposed structure in this research is constructed on substrate integrated waveguide (SIW) technology and has a mechanism that produces 16 different and distinct resonant frequencies between 2.45 and 3.05 GHz by perturbing a fundamental TE10 mode. It is a unique method for producing multiple resonances in a radio frequency planar structure without any extra circuitry or passive elements is developed. The proposed SIW structure has four vertical fluidic holes (channels); injecting eutectic gallium indium (EGaIn), also known commonly as liquid metal (LM), into these vertical channels produces different resonant frequencies. Either a channel is empty, or it is filled with LM. In total, the combination of different frequencies produced from four vertical channels is 16. PMID- 26569256 TI - Modelling the Size Effects on the Mechanical Properties of Micro/Nano Structures. AB - Experiments on micro- and nano-mechanical systems (M/NEMS) have shown that their behavior under bending loads departs in many cases from the classical predictions using Euler-Bernoulli theory and Hooke's law. This anomalous response has usually been seen as a dependence of the material properties on the size of the structure, in particular thickness. A theoretical model that allows for quantitative understanding and prediction of this size effect is important for the design of M/NEMS. In this paper, we summarize and analyze the five theories that can be found in the literature: Grain Boundary Theory (GBT), Surface Stress Theory (SST), Residual Stress Theory (RST), Couple Stress Theory (CST) and Surface Elasticity Theory (SET). By comparing these theories with experimental data we propose a simplified model combination of CST and SET that properly fits all considered cases, therefore delivering a simple (two parameters) model that can be used to predict the mechanical properties at the nanoscale. PMID- 26569258 TI - Development of an Automatic Identification System Autonomous Positioning System. AB - In order to overcome the vulnerability of the global navigation satellite system (GNSS) and provide robust position, navigation and time (PNT) information in marine navigation, the autonomous positioning system based on ranging-mode Automatic Identification System (AIS) is presented in the paper. The principle of the AIS autonomous positioning system (AAPS) is investigated, including the position algorithm, the signal measurement technique, the geometric dilution of precision, the time synchronization technique and the additional secondary factor correction technique. In order to validate the proposed AAPS, a verification system has been established in the Xinghai sea region of Dalian (China). Static and dynamic positioning experiments are performed. The original function of the AIS in the AAPS is not influenced. The experimental results show that the positioning precision of the AAPS is better than 10 m in the area with good geometric dilution of precision (GDOP) by the additional secondary factor correction technology. This is the most economical solution for a land-based positioning system to complement the GNSS for the navigation safety of vessels sailing along coasts. PMID- 26569259 TI - Performance Analysis of the Ironless Inductive Position Sensor in the Large Hadron Collider Collimators Environment. AB - The Ironless Inductive Position Sensor (I2PS) has been introduced as a valid alternative to Linear Variable Differential Transformers (LVDTs) when external magnetic fields are present. Potential applications of this linear position sensor can be found in critical systems such as nuclear plants, tokamaks, satellites and particle accelerators. This paper analyzes the performance of the I2PS in the harsh environment of the collimators of the Large Hadron Collider (LHC), where position uncertainties of less than 20 um are demanded in the presence of nuclear radiation and external magnetic fields. The I2PS has been targeted for installation for LHC Run 2, in order to solve the magnetic interference problem which standard LVDTs are experiencing. The paper describes in detail the chain of systems which belong to the new I2PS measurement task, their impact on the sensor performance and their possible further optimization. The I2PS performance is analyzed evaluating the position uncertainty (on 30 s), the magnetic immunity and the long-term stability (on 7 days). These three indicators are assessed from data acquired during the LHC operation in 2015 and compared with those of LVDTs. PMID- 26569260 TI - A Novel Scheme for an Energy Efficient Internet of Things Based on Wireless Sensor Networks. AB - One of the emerging networking standards that gap between the physical world and the cyber one is the Internet of Things. In the Internet of Things, smart objects communicate with each other, data are gathered and certain requests of users are satisfied by different queried data. The development of energy efficient schemes for the IoT is a challenging issue as the IoT becomes more complex due to its large scale the current techniques of wireless sensor networks cannot be applied directly to the IoT. To achieve the green networked IoT, this paper addresses energy efficiency issues by proposing a novel deployment scheme. This scheme, introduces: (1) a hierarchical network design; (2) a model for the energy efficient IoT; (3) a minimum energy consumption transmission algorithm to implement the optimal model. The simulation results show that the new scheme is more energy efficient and flexible than traditional WSN schemes and consequently it can be implemented for efficient communication in the IoT. PMID- 26569261 TI - Development of a High Irradiance LED Configuration for Small Field of View Motion Estimation of Fertilizer Particles. AB - Better characterization of the fertilizer spreading process, especially the fertilizer pattern distribution on the ground, requires an accurate measurement of individual particle properties and dynamics. Both 2D and 3D high speed imaging techniques have been developed for this purpose. To maximize the accuracy of the predictions, a specific illumination level is required. This paper describes the development of a high irradiance LED system for high speed motion estimation of fertilizer particles. A spectral sensitivity factor was used to select the optimal LED in relation to the used camera from a range of commercially available high power LEDs. A multiple objective genetic algorithm was used to find the optimal configuration of LEDs resulting in the most homogeneous irradiance in the target area. Simulations were carried out for different lenses and number of LEDs. The chosen configuration resulted in an average irradiance level of 452 W/m2 with coefficient of variation less than 2%. The algorithm proved superior and more flexible to other approaches reported in the literature and can be used for various other applications. PMID- 26569262 TI - HAGR-D: A Novel Approach for Gesture Recognition with Depth Maps. AB - The hand is an important part of the body used to express information through gestures, and its movements can be used in dynamic gesture recognition systems based on computer vision with practical applications, such as medical, games and sign language. Although depth sensors have led to great progress in gesture recognition, hand gesture recognition still is an open problem because of its complexity, which is due to the large number of small articulations in a hand. This paper proposes a novel approach for hand gesture recognition with depth maps generated by the Microsoft Kinect Sensor (Microsoft, Redmond, WA, USA) using a variation of the CIPBR (convex invariant position based on RANSAC) algorithm and a hybrid classifier composed of dynamic time warping (DTW) and Hidden Markov models (HMM), called the hybrid approach for gesture recognition with depth maps (HAGR-D). The experiments show that the proposed model overcomes other algorithms presented in the literature in hand gesture recognition tasks, achieving a classification rate of 97.49% in the MSRGesture3D dataset and 98.43% in the RPPDI dynamic gesture dataset. PMID- 26569263 TI - Recent Developments of Magnetoresistive Sensors for Industrial Applications. AB - The research and development in the field of magnetoresistive sensors has played an important role in the last few decades. Here, the authors give an introduction to the fundamentals of the anisotropic magnetoresistive (AMR) and the giant magnetoresistive (GMR) effect as well as an overview of various types of sensors in industrial applications. In addition, the authors present their recent work in this field, ranging from sensor systems fabricated on traditional substrate materials like silicon (Si), over new fabrication techniques for magnetoresistive sensors on flexible substrates for special applications, e.g., a flexible write head for component integrated data storage, micro-stamping of sensors on arbitrary surfaces or three dimensional sensing under extreme conditions (restricted mounting space in motor air gap, high temperatures during geothermal drilling). PMID- 26569264 TI - Using a Novel Wireless-Networked Decentralized Control Scheme under Unpredictable Environmental Conditions. AB - The direction of sunshine or the installation sites of environmental control facilities in the greenhouse result in different temperature and humidity levels in the various zones of the greenhouse, and thus, the production quality of crop is inconsistent. This study proposed a wireless-networked decentralized fuzzy control scheme to regulate the environmental parameters of various culture zones within a greenhouse. The proposed scheme can create different environmental conditions for cultivating different crops in various zones and achieve diversification or standardization of crop production. A star-type wireless sensor network is utilized to communicate with each sensing node, actuator node, and control node in various zones within the greenhouse. The fuzzy rule-based inference system is used to regulate the environmental parameters for temperature and humidity based on real-time data of plant growth response provided by a growth stage selector. The growth stage selector defines the control ranges of temperature and humidity of the various culture zones according to the leaf area of the plant, the number of leaves, and the cumulative amount of light. The experimental results show that the proposed scheme is stable and robust and provides basis for future greenhouse applications. PMID- 26569265 TI - The Marine-Derived Kinase Inhibitor Fascaplysin Exerts Anti-Thrombotic Activity. AB - BACKGROUND: The marine-derived kinase inhibitor fascaplysin down-regulates the PI3K pathway in cancer cells. Since this pathway also plays an essential role in platelet signaling, we herein investigated the effect of fascaplysin on thrombosis. METHODS: Fascaplysin effects on platelet activation, platelet aggregation and platelet-leukocyte aggregates (PLA) formation were analyzed by flow cytometry. Mouse dorsal skinfold chambers were used to determine in vivo the effect of fascaplysin on photochemically induced thrombus formation and tail-vein bleeding time. RESULTS: Pre-treatment of platelets with fascaplysin reduced the activation of glycoprotein (GP)IIb/IIIa after protease-activated receptor-1 activating peptide (PAR-1-AP), adenosine diphosphate (ADP) and phorbol-12 myristate-13-acetate (PMA) stimulation, but did not markedly affect the expression of P-selectin. This was associated with a decreased platelet aggregation. Fascaplysin also decreased PLA formation after PMA but not PAR-1-AP and ADP stimulation. This may be explained by an increased expression of CD11b on leukocytes in PAR-1-AP- and ADP-treated whole blood. In the dorsal skinfold chamber model of photochemically induced thrombus formation, fascaplysin-treated mice revealed a significantly extended complete vessel occlusion time when compared to controls. Furthermore, fascaplysin increased the tail-vein bleeding time. CONCLUSION: Fascaplysin exerts anti-thrombotic activity, which represents a novel mode of action in the pleiotropic activity spectrum of this compound. PMID- 26569266 TI - Biomedical and Clinical Importance of Mussel-Inspired Polymers and Materials. AB - The substance secreted by mussels, also known as nature's glue, is a type of liquid protein that hardens rapidly into a solid water-resistant adhesive material. While in seawater or saline conditions, mussels can adhere to all types of surfaces, sustaining its bonds via mussel adhesive proteins (MAPs), a group of proteins containing 3,4-dihydroxyphenylalanine (DOPA) and catecholic amino acid. Several aspects of this adhesion process have inspired the development of various types of synthetic materials for biomedical applications. Further, there is an urgent need to utilize biologically inspired strategies to develop new biocompatible materials for medical applications. Consequently, many researchers have recently reported bio-inspired techniques and materials that show results similar to or better than those shown by MAPs for a range of medical applications. However, the susceptibility to oxidation of 3,4 dihydroxyphenylalanine poses major challenges with regard to the practical translation of mussel adhesion. In this review, various strategies are discussed to provide an option for DOPA/metal ion chelation and to compensate for the limitations imposed by facile 3,4-dihydroxyphenylalanine autoxidation. We discuss the anti-proliferative, anti-inflammatory, anti-microbial activity, and adhesive behaviors of mussel bio-products and mussel-inspired materials (MIMs) that make them attractive for synthetic adaptation. The development of biologically inspired adhesive interfaces, bioactive mussel products, MIMs, and arising areas of research leading to biomedical applications are considered in this review. PMID- 26569267 TI - Production of a Novel Fucoidanase for the Green Synthesis of Gold Nanoparticles by Streptomyces sp. and Its Cytotoxic Effect on HeLa Cells. AB - Marine actinobacteria-produced fucoidanases have received considerable attention as one of the major research topics in recent years, particularly for the medical exploitation of fucoidans and their degradation products. The present study describes the optimization and production of a novel fucoidanase for the green synthesis of gold nanoparticles and its biological applications. The production of fucoidanase was optimized using Streptomyces sp. The medium components were selected in accordance with the Plackett-Burman design and were further optimized via response surface methodology. The fucoidanase was statistically optimized with the most significant factors, namely wheat bran 3.3441 g/L, kelp powder 0.7041 g/L, and NaCl 0.8807 g/L, respectively. The biosynthesized gold nanoparticles were determined by UV-vis spectroscopy and were further characterized by X-ray diffraction analysis, Fourier transform infrared spectroscopy, field emission scanning electron microscopy, energy dispersive X ray analysis, and high-resolution transmission electron microscopy. Furthermore, the biosynthesized gold nanoparticles exhibited a dose-dependent cytotoxicity against HeLa cells and the inhibitory concentration (IC50) was found to be 350 ug/mL at 24 h and 250 ug/mL at 48 h. Therefore, the production of novel fucoidanase for the green synthesis of gold nanoparticles has comparatively rapid, less expensive and wide application to anticancer therapy in modern medicine. PMID- 26569268 TI - Seaweeds as Preventive Agents for Cardiovascular Diseases: From Nutrients to Functional Foods. AB - Being naturally enriched in key nutrients and in various health-promoting compounds, seaweeds represent promising candidates for the design of functional foods. Soluble dietary fibers, peptides, phlorotannins, lipids and minerals are macroalgae's major compounds that can hold potential in high-value food products derived from macroalgae, including those directed to the cardiovascular-health promotion. This manuscript revises available reported data focusing the role of diet supplementation of macroalgae, or extracts enriched in bioactive compounds from macroalgae origin, in targeting modifiable markers of cardiovascular diseases (CVDs), like dyslipidemia, oxidative stress, vascular inflammation, hypertension, hypercoagulability and activation of the sympathetic and renin angiotensin systems, among others. At last, the review also describes several products that have been formulated with the use of whole macroalgae or extracts, along with their claimed cardiovascular-associated benefits. PMID- 26569270 TI - Spatially Explicit Landscape-Level Ecological Risks Induced by Land Use and Land Cover Change in a National Ecologically Representative Region in China. AB - Land use and land cover change is driven by multiple influential factors from environmental and social dimensions in a land system. Land use practices of human decision-makers modify the landscape of the land system, possibly leading to landscape fragmentation, biodiversity loss, or environmental pollution-severe environmental or ecological impacts. While landscape-level ecological risk assessment supports the evaluation of these impacts, investigations on how these ecological risks induced by land use practices change over space and time in response to alternative policy intervention remain inadequate. In this article, we conducted spatially explicit landscape ecological risk analysis in Ezhou City, China. Our study area is a national ecologically representative region experiencing drastic land use and land cover change, and is regulated by multiple policies represented by farmland protection, ecological conservation, and urban development. We employed landscape metrics to consider the influence of potential landscape-level disturbance for the evaluation of landscape ecological risks. Using spatiotemporal simulation, we designed scenarios to examine spatiotemporal patterns in landscape ecological risks in response to policy intervention. Our study demonstrated that spatially explicit landscape ecological risk analysis combined with simulation-driven scenario analysis is of particular importance for guiding the sustainable development of ecologically vulnerable land systems. PMID- 26569269 TI - Polyphenol-Rich Fraction of Ecklonia cava Improves Nonalcoholic Fatty Liver Disease in High Fat Diet-Fed Mice. AB - Ecklonia cava (E. cava; CA) is an edible brown alga with beneficial effects in diabetes via regulation of various metabolic processes such as lipogenesis, lipolysis, inflammation, and the antioxidant defense system in liver and adipose tissue. We investigated the effect of the polyphenol-rich fraction of E. cava produced from Gijang (G-CA) on nonalcoholic fatty liver disease (NAFLD) in high fat diet (HFD)-fed mice. C57BL6 mice were fed a HFD for six weeks and then the HFD group was administered 300 mg/kg of G-CA extracts by oral intubation for 10 weeks. Body weight, fat mass, and serum biochemical parameters were reduced by G CA extract treatment. MRI/MRS analysis showed that liver fat and liver volume in HFD-induced obese mice were reduced by G-CA extract treatment. Further, we analyzed hepatic gene expression related to inflammation and lipid metabolism. The mRNA expression levels of inflammatory cytokines and hepatic lipogenesis related genes were decreased in G-CA-treated HFD mice. The mRNA expression levels of cholesterol 7 alpha-hydroxylase 1 (CYP7A1), the key enzyme in bile acid synthesis, were dramatically increased by G-CA treatment in HFD mice. We suggest that G-CA treatment ameliorated hepatic steatosis by inhibiting inflammation and improving lipid metabolism. PMID- 26569271 TI - Physiological and Psychological Effects of a Walk in Urban Parks in Fall. AB - In recent times, attention has been focused on the role of urban green spaces in promoting human health and well-being. However, there is a lack of evidence-based research on the physiological effects of walking in urban green areas. This study aimed to clarify the physiological and psychological effects of walking in urban parks during fall. Twenty-three males (mean age 22.3 +/- 1.2 years) were instructed to walk predetermined 15-min courses in an urban park and in a nearby city area (control). Heart rate and heart rate variability were measured to assess physiological responses, and the semantic differential method, Profile of Mood States, and State-Trait Anxiety Inventory were used to measure psychological responses. We observed that walking in an urban park resulted in a significantly lower heart rate, higher parasympathetic nerve activity, and lower sympathetic nerve activity than walking through the city area. In subjective evaluations, participants were more "comfortable," "natural," "relaxed," and "vigorous" after a walk in the urban park. Furthermore, they exhibited significantly lower levels of negative emotions and anxiety. These findings provide scientific evidence for the physiological and psychological relaxation effects of walking in urban parks during fall. PMID- 26569272 TI - Variation in the Effect of Particulate Matter on Pulmonary Function in Schoolchildren in Western Japan and Its Relation with Interleukin-8. AB - This study aimed to investigate the effects of particulate matter (PM) on pulmonary function in schoolchildren, as well as the relationships of these effects with interleukin-8. Morning peak expiratory flow (PEF) was measured daily in 399 children during April-May 2012, and in 384 of these children during March May 2013. PEF's association with the daily levels of suspended particulate matter (SPM) and PM < 2.5 mm (PM2.5) was estimated using a linear mixed model. Interleukin-8 promoter activity was assessed in THP-G8 cells stimulated by fallen PM collected at Tottori University Hospital during four periods (two in 2012 and two in 2013). An increase of 14.0 mg/m3 in SPM led to PEF changes of -2.16 L/min in 2012 and -0.81 L/min in 2013, respectively. An increment of 10.7 mg/m3 in PM2.5 was associated with PEF changes of -2.58 L/min in 2012 and -0.55 L/min in 2013, respectively. These associations were only significant in 2012. Interleukin 8 promoter activity was significantly higher in both periods of 2012 than in 2013. There was a significant association between pulmonary function in schoolchildren and daily levels of SPM and PM2.5, but this association may differ depending on the PM's ability to elicit interleukin-8 production. PMID- 26569273 TI - Factors Associated with the Competencies of Public Health Workers in Township Hospitals: A Cross-Sectional Survey in Chongqing Municipality, China. AB - PURPOSE: This study aimed to explore the competencies of public health workers (PHWs) of township hospitals in Chongqing Municipality (China), and determine the related impact factors of the competencies of PHWs; METHODS: A cross-sectional research was conducted on 314 PHWs from 27 township hospitals in three districts in Chongqing Municipality (China), from June to August 2014. A self-assessment questionnaire was established on the basis of literature reviews and a competency dictionary. The differences in competencies among the three districts were determined by adopting the chi-square test, t-test, analysis of variance (ANOVA) method, and the impact factors of the competencies of PHWs were determined by adopting stepwise regression analysis. RESULTS: (1) RESULTS of the demographic characteristics of PHWs in three sample districts of Chongqing Municipality showed that a significant difference in age of PHWs (p = 0.021 < 0.05) and the majors of PHWs (p = 0.045 < 0.05); (2) In terms of the self-evaluation competency results of PHWs in township hospitals, seven among the 11 aspects were found to have significant differences in the three districts by the ANOVA test; (3) By adopting the t-test and ANOVA method, results of the relationship between the characteristics of PHWs and their competency scores showed that significant differences were found in the economic level (p = 0.000 < 0.05), age (p = 0.000 < 0.05), years of working (p = 0.000 < 0.05) and title of PHWs (p = 0.000 < 0.05); (4) Stepwise regression analysis was used to determine the impact factors of the competencies of PHWs in township hospitals, including the economic level (p = 0.000 < 0.001), years of working (p = 0.000 < 0.001), title (p = 0.001 < 0.005), and public health major (p = 0.007 < 0.01). CONCLUSIONS: The competencies of the township hospital staff in Chongqing Municipality (China), are generally insufficient, therefore, regulating the medical education and training skills of PHWs is crucial to improve the competencies of PHWs in the township hospitals of Chongqing Municipality. The results of this study can be mirrored in other areas of China. PMID- 26569274 TI - Perceived Relevance of Educative Information on Public (Skin) Health: Results of a Representative, Population-Based Telephone Survey. AB - Individual skin health attitudes are influenced by various factors, including public education campaigns, mass media, family, and friends. Evidence-based, educative information materials assist communication and decision-making in doctor-patient interactions. The present study aims at assessing the prevailing use of skin health information material and sources and their impact on skin health knowledge, motives to tan, and sun protection. We conducted a questionnaire survey among a representative sample of Austrian residents. Print media and television were perceived as the two most relevant sources for skin health information, whereas the source physician was ranked third. Picking the information source physician increased participants' skin health knowledge (p = 0.025) and sun-protective behavior (p < 0.001). The study results highlight the demand for targeted health messages to attain lifestyle changes towards photo protective habits. Providing resources that encourage pro-active counseling in every-day doctor-patient communication could increase skin health knowledge and sun-protective behavior, and thus, curb the rise in skin cancer incidence rates. PMID- 26569275 TI - Associations between Carotid Artery Plaque Score, Carotid Hemodynamics and Coronary Heart Disease. AB - BACKGROUND: The carotid artery plaque score (PS) is an independent predictor of Coronary Heart Disease (CHD). This study aims to evaluate the combination of PS and carotid hemodynamics to predict CHD. METHODS: A total of 476 patients who underwent carotid ultrasonography and coronary angiography were divided into two groups depending on the presence of CHD. PS, carotid intima-media thickness, and carotid blood flow were measured. Receiver operating characteristic curve analysis was performed to establish the best prediction model for CHD presence. RESULTS: Age, sex, carotid intima-media thickness of internal carotid artery and carotid bifurcation, PS, peak systolic velocity (PSA) of right internal carotid artery (RICA), and most resistance index data were significantly related with the presence of CHD. The area under the curve for a collective model, which included factors of the PS, carotid hemodynamics and age, was significantly higher than the other model. Age, PS, and PSA of RICA were significant contributors for predicting CHD presence. CONCLUSIONS: The model of PS and PSA of RICA has greater predictive value for CHD than PS alone. Adding age to PS and PSA of RICA further improves predictive value over PS alone. PMID- 26569276 TI - Arsenic and Other Metals' Presence in Biomarkers of Cambodians in Arsenic Contaminated Areas. AB - Chemical analyses of metal (Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Mo, Ba, and Pb) concentrations in hair, nails, and urine of Cambodians in arsenic-contaminated areas who consumed groundwater daily showed elevated levels in these biomarkers for most metals of toxicological interest. The levels of metals in biomarkers corresponded to their levels in groundwater, especially for As, whose concentrations exceeded the WHO guidelines for drinking water. About 75.6% of hair samples from the population in this study contained As levels higher than the normal level in unexposed individuals (1 mg.kg(-1)). Most of the population (83.3%) showed As urinary levels exceeding the normal (<50 ng.mg(-1)). These results indicate the possibility of arsenicosis symptoms in residents of the areas studied. Among the three biomarkers tested, hair has shown to be a reliable indicator of metal exposures. The levels of As (r2 = 0.633), Ba (r2 = 0.646), Fe (r2 = 0.595), and Mo (r2 = 0.555) in hair were strongly positively associated with the levels of those metals in groundwater. In addition, significant weak correlations (p < 0.01) were found between levels of exposure to As and As concentrations in both nails (r2 = 0.544) and urine (r2 = 0.243). PMID- 26569277 TI - Exposure to Air Ions in Indoor Environments: Experimental Study with Healthy Adults. AB - Since the beginning of the 20th century there has been a scientific debate about the potential effects of air ions on biological tissues, wellbeing and health. Effects on the cardiovascular and respiratory system as well as on mental health have been described. In recent years, there has been a renewed interest in this topic. In an experimental indoor setting we conducted a double-blind cross-over trial to determine if higher levels of air ions, generated by a special wall paint, affect cognitive performance, wellbeing, lung function, and cardiovascular function. Twenty healthy non-smoking volunteers (10 female, 10 male) participated in the study. Levels of air ions, volatile organic compounds and indoor climate factors were determined by standardized measurement procedures. Air ions affected the autonomous nervous system (in terms of an increase of sympathetic activity accompanied by a small decrease of vagal efferent activity): In the test room with higher levels of air ions (2194/cm3 vs. 1038/cm3) a significantly higher low to high frequency ratio of the electrocardiography (ECG) beat-to-beat interval spectrogram was found. Furthermore, six of nine subtests of a cognitive performance test were solved better, three of them statistically significant (verbal factor, reasoning, and perceptual speed), in the room with higher ion concentration. There was no influence of air ions on lung function and on wellbeing. Our results indicate slightly activating and cognitive performance enhancing effects of a short-term exposure to higher indoor air ion concentrations. PMID- 26569278 TI - Kinetics and Mechanisms of Phosphorus Adsorption in Soils from Diverse Ecological Zones in the Source Area of a Drinking-Water Reservoir. AB - On-site soils are increasingly used in the treatment and restoration of ecosystems to harmonize with the local landscape and minimize costs. Eight natural soils from diverse ecological zones in the source area of a drinking water reservoir in central China are used as adsorbents for the uptake of phosphorus from aqueous solutions. The X-ray fluorescence (XRF) spectrometric and BET (Brunauer-Emmett-Teller) tests and the Scanning Electron Microscopy (SEM) and Fourier Transform Infrared (FTIR) spectral analyses are carried out to investigate the soils' chemical properties and their potential changes with adsorbed phosphorous from aqueous solutions. The intra-particle diffusion, pseudo first-order, and pseudo-second-order kinetic models describe the adsorption kinetic processes. Our results indicate that the adsorption processes of phosphorus in soils occurred in three stages and that the rate-controlling steps are not solely dependent on intra-particle diffusion. A quantitative comparison of two kinetics models based on their linear and non-linear representations, and using the chi-square (chi2) test and the coefficient of determination (r2), indicates that the adsorptive properties of the soils are best described by the non-linear pseudo-second-order kinetic model. The adsorption characteristics of aqueous phosphorous are determined along with the essential kinetic parameters. PMID- 26569279 TI - Social and Physical Environments and Self-Rated Health in Urban and Rural Communities in Korea. AB - This study evaluated the associations between social and physical environments and self-rated health (SRH) for urban and rural Korean adults, using data from the Korean Community Health Survey (KCHS) of 199,790 participants (115,454 urban and 84,336 rural). The main dependent variable was SRH, while the primary independent variables were social and physical characteristics. Urban residents reported better SRH than did rural residents. Five social environmental variables (trust of neighbors, residence in the area for over 20 years, exchanging help with neighbors, friend and fellowship activities, contact with relatives and neighbors over five times per month) were more prevalent among rural residents. Satisfaction with physical environment was more common among rural residents, but satisfaction with traffic and healthcare facilities was more common among urban areas. After adjusting for relevant factors, positive associations between SRH and trust of neighbors, exchanging help with neighbors, participation in social activities or organizations, and physical environment existed in both rural and urban populations. Also, in both areas, there was no demonstrated association between SRH and years of residence or frequency of contact with relatives. Our findings suggest the existence of an association between social and physical factors and perceived health status among the general population of Korea. PMID- 26569280 TI - Green Space Attachment and Health: A Comparative Study in Two Urban Neighborhoods. AB - The positive relationships between urban green space and health have been well documented. Little is known, however, about the role of residents' emotional attachment to local green spaces in these relationships, and how attachment to green spaces and health may be promoted by the availability of accessible and usable green spaces. The present research aimed to examine the links between self reported health, attachment to green space, and the availability of accessible and usable green spaces. Data were collected via paper-mailed surveys in two neighborhoods (n = 223) of a medium-sized Dutch city in the Netherlands. These neighborhoods differ in the perceived and objectively measured accessibility and usability of green spaces, but are matched in the physically available amount of urban green space, as well as in demographic and socio-economic status, and housing conditions. Four dimensions of green space attachment were identified through confirmatory factor analysis: place dependence, affective attachment, place identity and social bonding. The results show greater attachment to local green space and better self-reported mental health in the neighborhood with higher availability of accessible and usable green spaces. The two neighborhoods did not differ, however, in physical and general health. Structural Equation Modelling confirmed the neighborhood differences in green space attachment and mental health, and also revealed a positive path from green space attachment to mental health. These findings convey the message that we should make green places, instead of green spaces. PMID- 26569281 TI - Different Choices of Drinking Water Source and Different Health Risks in a Rural Population Living Near a Lead/Zinc Mine in Chenzhou City, Southern China. AB - This study aimed to describe the households' choices of drinking water sources, and evaluate the risk of human exposure to heavy metals via different drinking water sources in Chenzhou City of Hunan Province, Southern China. A cross sectional face-to-face survey of 192 householders in MaTian and ZhuDui village was conducted. The concentrations of heavy metals in their drinking water sources were analyzed. Carcinogenic and non-carcinogenic risk assessment was performed according to the method recommended by the United States Environmental Protection Agency. In total, 52.60% of the households used hand-pressed well water, and 34.89% used barreled water for drinking. In total, 6.67% of the water samples exceeded the Chinese drinking water standards. The total health risk of five metals is 5.20 * 10(-9)~3.62 * 10(-5). The total health risk of five metals was at acceptable levels for drinking water sources. However, the total risk of using hand-pressed well water's highest value is 6961 times higher than the risk of using tap water. Household income level was significantly associated with drinking water choices. Arsenic (As) and lead (Pb) are priority controlled pollutants in this region. Using safe drinking water (tap water, barreled water and so on) can remarkably reduce the risk of ingesting heavy metals. PMID- 26569282 TI - Association between Self-Rated Health and the Ethnic Composition of the Residential Environment of Six Ethnic Groups in Amsterdam. AB - BACKGROUND: Studies on the association between health and neighborhood ethnic composition yielded inconsistent results, possibly due to methodological limitations. We assessed these associations at different spatial scales and for different measures of ethnic composition. METHODS: We obtained health survey data of 4673 respondents of Dutch, Surinamese, Moroccan, Turkish other non-Western and other Western origin. Neighborhood ethnic composition was measured for buffers varying from 50-1000 m. Associations with self-rated health were measured using logistic multilevel regression analysis, with control for socioeconomic position at the individual and area level. RESULTS: Overall ethnic heterogeneity was not related to health for any ethnic group. The presence of other Surinamese was associated with poor self-rated health among Surinamese respondents. The presence of Moroccans or Turks was associated with poor health among some groups. The presence of Dutch was associated with better self-rated health among Surinamese and Turks. In most cases, these associations were stronger at lower spatial scales. We found no other associations. CONCLUSIONS: In Amsterdam, self-rated health was not associated with ethnic heterogeneity in general, but may be related to the presence of specific ethnic groups. Policies regarding social and ethnic mixing should pay special attention to the co-residence of groups with problematic interrelations. PMID- 26569283 TI - An Enhanced K-Means Algorithm for Water Quality Analysis of The Haihe River in China. AB - The increase and the complexity of data caused by the uncertain environment is today's reality. In order to identify water quality effectively and reliably, this paper presents a modified fast clustering algorithm for water quality analysis. The algorithm has adopted a varying weights K-means cluster algorithm to analyze water monitoring data. The varying weights scheme was the best weighting indicator selected by a modified indicator weight self-adjustment algorithm based on K-means, which is named MIWAS-K-means. The new clustering algorithm avoids the margin of the iteration not being calculated in some cases. With the fast clustering analysis, we can identify the quality of water samples. The algorithm is applied in water quality analysis of the Haihe River (China) data obtained by the monitoring network over a period of eight years (2006-2013) with four indicators at seven different sites (2078 samples). Both the theoretical and simulated results demonstrate that the algorithm is efficient and reliable for water quality analysis of the Haihe River. In addition, the algorithm can be applied to more complex data matrices with high dimensionality. PMID- 26569284 TI - Death Rates among Detained Immigrants in the United States. AB - The United States system of immigrant detention centers has been the subject of considerable scrutiny with respect to health care of detainees. We sought to characterize the rates and types of deaths that have occurred within this system between the years 2003-2015. We analyzed a file of detainee deaths released by the U.S. Department of Homeland Security as part of a freedom of information request. Between 2003 and 2015, 150 deaths were recorded. During this time period, the annual rate of death among detainees dropped dramatically, whether measured by annual admissions or by person years of exposure. The most common causes of death were cardiovascular, cancer and suicide. More research is needed to adequately account for the contributors to these declining rates of death in immigration detention settings. PMID- 26569285 TI - Genomic Mining Reveals Deep Evolutionary Relationships between Bornaviruses and Bats. AB - Bats globally harbor viruses in order Mononegavirales, such as lyssaviruses and henipaviruses; however, little is known about their relationships with bornaviruses. Previous studies showed that viral fossils of bornaviral origin are embedded in the genomes of several mammalian species such as primates, indicative of an ancient origin of exogenous bornaviruses. In this study, we mined the available 10 bat genomes and recreated a clear evolutionary relationship of endogenous bornaviral elements and bats. Comparative genomics showed that endogenization of bornaviral elements frequently occurred in vesper bats, harboring EBLLs (endogenous bornavirus-like L elements) in their genomes. Molecular dating uncovered a continuous bornavirus-bat interaction spanning 70 million years. We conclude that better understanding of modern exogenous bornaviral circulation in bat populations is warranted. PMID- 26569286 TI - Potential for Co-Infection of a Mosquito-Specific Flavivirus, Nhumirim Virus, to Block West Nile Virus Transmission in Mosquitoes. AB - Nhumirim virus (NHUV) is an insect-specific virus that phylogenetically affiliates with dual-host mosquito-borne flaviviruses. Previous in vitro co infection experiments demonstrated prior or concurrent infection of Aedes albopictus C6/36 mosquito cells with NHUV resulted in a 10,000-fold reduction in viral production of West Nile virus (WNV). This interference between WNV and NHUV was observed herein in an additional Ae. albopictus mosquito cell line, C7-10. A WNV 2K peptide (V9M) mutant capable of superinfection with a pre-established WNV infection demonstrated a comparable level of interference from NHUV as the parental WNV strain in C6/36 and C7-10 cells. Culex quinquefasciatus and Culex pipiens mosquitoes intrathoracically inoculated with NHUV and WNV, or solely with WNV as a control, were allowed to extrinsically incubate the viruses up to nine and 14 days, respectively, and transmissibility and replication of WNV was determined. The proportion of Cx. quinquefasciatus mosquitoes capable of transmitting WNV was significantly lower for the WNV/NHUV group than the WNV control at seven and nine days post inoculation (dpi), while no differences were observed in the Cx. pipiens inoculation group. By dpi nine, a 40% reduction in transmissibility in mosquitoes from the dual inoculation group was observed compared to the WNV-only control. These data indicate the potential that infection of some Culex spp. vectors with NHUV could serve as a barrier for efficient transmissibility of flaviviruses associated with human disease. PMID- 26569287 TI - Cleavage of the HPV16 Minor Capsid Protein L2 during Virion Morphogenesis Ablates the Requirement for Cellular Furin during De Novo Infection. AB - Infections by high-risk human papillomaviruses (HPV) are the causative agents for the development of cervical cancer. As with other non-enveloped viruses, HPVs are taken up by the cell through endocytosis following primary attachment to the host cell. Through studies using recombinant pseudovirus particles (PsV), many host cellular proteins have been implicated in the process. The proprotein convertase furin has been demonstrated to cleave the minor capsid protein, L2, post attachment to host cells and is required for infectious entry by HPV16 PsV. In contrast, using biochemical inhibition by a furin inhibitor and furin-negative cells, we show that tissue-derived HPV16 native virus (NV) initiates infection independent of cellular furin. We show that HPV16 L2 is cleaved during virion morphogenesis in differentiated tissue. In addition, HPV45 is also not dependent on cellular furin, but two other alpha papillomaviruses, HPV18 and HPV31, are dependent on the activity of cellular furin for infection. PMID- 26569288 TI - Meningitis Caused by Toscana Virus Is Associated with Strong Antiviral Response in the CNS and Altered Frequency of Blood Antigen-Presenting Cells. AB - Toscana virus (TOSV) is a Phlebotomus-transmitted RNA virus and a frequent cause of human meningitis and meningoencephalitis in Southern Europe during the summer season. While evidence for TOSV-related central nervous system (CNS) cases is increasing, little is known about the host defenses against TOSV. We evaluated innate immune response to TOSV by analyzing frequency and activation of blood antigen-presenting cells (APCs) and cytokine levels in plasma and cerebrospinal fluid (CSF) from patients with TOSV neuroinvasive infection and controls. An altered frequency of different blood APC subsets was observed in TOSV-infected patients, with signs of monocytic deactivation. Nevertheless, a proper or even increased responsiveness of toll-like receptor 3 and 7/8 was observed in blood APCs of these patients as compared to healthy controls. Systemic levels of cytokines remained low in TOSV-infected patients, while levels of anti inflammatory and antiviral mediators were significantly higher in CSF from TOSV infected patients as compared to patients with other infectious and noninfectious neurological diseases. Thus, the early host response to TOSV appears effective for viral clearance, by proper response to TLR3 and TLR7/8 agonists in peripheral blood and by a strong and selective antiviral and anti-inflammatory response in the CNS. PMID- 26569289 TI - Detection and Characterization of a Novel Reassortant Mammalian Orthoreovirus in Bats in Europe. AB - A renewed interest in mammalian orthoreoviruses (MRVs) has emerged since new viruses related to bat MRV type 3, detected in Europe, were identified in humans and pigs with gastroenteritis. This study reports the isolation and characterization of a novel reassortant MRV from the lesser horseshoe bat (Rhinolophus hipposideros). The isolate, here designated BatMRV1-IT2011, was first identified by electron microscopy and confirmed using PCR and virus neutralization tests. The full genome sequence was obtained by next-generation sequencing. Molecular and antigenic characterizations revealed that BatMRV1 IT2011 belonged to serotype 1, which had not previously been identified in bats. Phylogenetic and recombination detection program analyses suggested that BatMRV1 IT2011 was a reassortant strain containing an S1 genome segment similar to those of MRV T1/bovine/Maryland/Clone23/59 and C/bovine/ Indiana/MRV00304/2014, while other segments were more similar to MRVs of different hosts, origins and serotypes. The presence of neutralizing antibodies against MRVs has also been investigated in animals (dogs, pigs, bovines and horses). Preliminary results suggested that MRVs are widespread in animals and that infections containing multiple serotypes, including MRVs of serotype 1 with an S1 gene similar to BatMRV1-IT2011, are common. This paper extends the current knowledge of MRVs and stresses the importance to continue and improve MRV surveillance in bats and other mammals through the development and standardization of specific diagnostic tools. PMID- 26569290 TI - In Vitro Evolution of Bovine Foamy Virus Variants with Enhanced Cell-Free Virus Titers and Transmission. AB - Virus transmission is essential for spreading viral infections and is a highly coordinated process which occurs by cell-free transmission or cell-cell contact. The transmission of Bovine Foamy Virus (BFV) is highly cell-associated, with undetectable cell-free transmission. However, BFV particle budding can be induced by overexpression of wild-type (wt) BFV Gag and Env or artificial retargeting of Gag to the plasma membrane via myristoylation membrane targeting signals, closely resembling observations in other foamy viruses. Thus, the particle release machinery of wt BFV appears to be an excellent model system to study viral adaption to cell-free transmission by in vitro selection and evolution. Using selection for BFV variants with high cell-free infectivity in bovine and non bovine cells, infectivity dramatically increased from almost no infectious units to about 105-106 FFU (fluorescent focus forming units)/mL in both cell types. Importantly, the selected BFV variants with high titer (HT) cell-free infectivity could still transmit via cell-cell contacts and were neutralized by serum from naturally infected cows. These selected HT-BFV variants will shed light into virus transmission and potential routes of intervention in the spread of viral infections. It will also allow the improvement or development of new promising approaches for antiretroviral therapies. PMID- 26569291 TI - Psoralen Inactivation of Viruses: A Process for the Safe Manipulation of Viral Antigen and Nucleic Acid. AB - High consequence human pathogenic viruses must be handled at biosafety level 2, 3 or 4 and must be rendered non-infectious before they can be utilized for molecular or immunological applications at lower biosafety levels. Here we evaluate psoralen-inactivated Arena-, Bunya-, Corona-, Filo-, Flavi- and Orthomyxoviruses for their suitability as antigen in immunological processes and as template for reverse transcription PCR and sequencing. The method of virus inactivation using a psoralen molecule appears to have broad applicability to RNA viruses and to leave both the particle and RNA of the treated virus intact, while rendering the virus non-infectious. PMID- 26569292 TI - Inverse Correlation between Vitamin D and C-Reactive Protein in Newborns. AB - Some studies suggested that adequate vitamin D might reduce inflammation in adults. However, little is known about this association in early life. We aimed to determine the relationship between cord blood 25-hydroxyvitamin D (25(OH)D) and C-reactive protein (CRP) in neonates. Cord blood levels of 25(OH)D and CRP were measured in 1491 neonates in Hefei, China. Potential confounders including maternal sociodemographic characteristics, perinatal health status, lifestyle, and birth outcomes were prospectively collected. The average values of cord blood 25(OH)D and CRP were 39.43 nmol/L (SD = 20.35) and 6.71 mg/L (SD = 3.07), respectively. Stratified by 25(OH)D levels, per 10 nmol/L increase in 25(OH)D, CRP decreased by 1.42 mg/L (95% CI: 0.90, 1.95) among neonates with 25(OH)D <25.0 nmol/L, and decreased by 0.49 mg/L (95% CI: 0.17, 0.80) among neonates with 25(OH)D between 25.0 nmol/L and 49.9 nmol/L, after adjusting for potential confounders. However, no significant association between 25(OH)D and CRP was observed among neonates with 25(OH)D >=50 nmol/L. Cord blood 25(OH)D and CRP levels showed a significant seasonal trend with lower 25(OH)D and higher CRP during winter-spring than summer-autumn. Stratified by season, a significant linear association of 25(OH)D with CRP was observed in neonates born in winter spring (adjusted beta = -0.11, 95% CI: -0.13, -0.10), but not summer-autumn. Among neonates born in winter-spring, neonates with 25(OH)D <25 nmol/L had higher risk of CRP >=10 mg/L (adjusted OR = 3.06, 95% CI: 2.00, 4.69), compared to neonates with 25(OH)D >=25 nmol/L. Neonates with vitamin D deficiency had higher risk of exposure to elevated inflammation at birth. PMID- 26569294 TI - A Multi-Center Assessment of Nutrient Levels and Foods Provided by Hospital Patient Menus. AB - Diets of high nutritional quality can aid in the prevention and management of malnutrition in hospitalized patients. This study evaluated the nutritional quality of hospital patient menus. At three large acute care hospitals in Ontario, Canada, 84 standard menus were evaluated, which included regular and carbohydrate-controlled diets and 3000 mg and 2000 mg sodium diets. Mean levels of calories, macronutrients and vitamins and minerals provided were calculated. Comparisons were made with the Dietary Reference Intakes (DRI) and Canada's Food Guide (CFG) recommendations. Calorie levels ranged from 1281 to 3007 kcal, with 45% of menus below 1600 kcal. Protein ranged from 49 to 159 g (0.9-1.1 g/kg/day). Energy and protein levels were highest in carbohydrate-controlled menus. All regular and carbohydrate-controlled menus provided macronutrients within the Acceptable Macronutrient Distribution Ranges. The proportion of regular diet menus meeting the DRIs: 0% for fiber; 7% for calcium; 57% for vitamin C; and 100% for iron. Compared to CFG recommended servings, 35% met vegetables and fruit and milk and alternatives, 11% met grain products and 8% met meat and alternatives. These data support the need for frequent monitoring and evaluation of menus, food procurement and menu planning policies and for sufficient resources to ensure menu quality. PMID- 26569296 TI - Lentil and Kale: Complementary Nutrient-Rich Whole Food Sources to Combat Micronutrient and Calorie Malnutrition. AB - Lentil (Lens culinaris Medik.) is a nutritious food and a staple for millions of people. Not only are lentils a good source of energy, they also contain a range of micronutrients and prebiotic carbohydrates. Kale (Brassica oleracea v. acephala) has been considered as a health food, but its full range of benefits and composition has not been extensively studied. Recent studies suggest that foods are enrich in prebiotic carbohydrates and dietary fiber that can potentially reduce risks of non-communicable diseases, including obesity, cancer, heart disease, and diabetes. Lentil and kale added to a cereal-based diet would enhance intakes of essential minerals and vitamins to combat micronutrient malnutrition. This review provides an overview of lentil and kale as a complementary nutrient-rich whole food source to combat global malnutrition and calorie issues. In addition, prebiotic carbohydrate profiles and the genetic potential of these crops for further micronutrient enrichment are briefly discussed with respect to developing sustainable and nutritious food systems. PMID- 26569297 TI - Comparison of Various Databases for Estimation of Dietary Polyphenol Intake in the Population of Polish Adults. AB - The primary aim of the study was to estimate the consumption of polyphenols in a population of 6661 subjects aged between 20 and 74 years representing a cross section of the Polish society, and the second objective was to compare the intakes of flavonoids calculated on the basis of the two commonly used databases. Daily food consumption data were collected in 2003-2005 using a single 24-hour dietary recall. Intake of total polyphenols was estimated using an online Phenol Explorer database, and flavonoid intake was determined using following data sources: the United States Department of Agriculture (USDA) database combined of flavonoid and isoflavone databases, and the Phenol-Explorer database. Total polyphenol intake, which was calculated with the Phenol-Explorer database, was 989 mg/day with the major contributions of phenolic acids 556 mg/day and flavonoids 403.5 mg/day. The flavonoid intake calculated on the basis of the USDA databases was 525 mg/day. This study found that tea is the primary source of polyphenols and flavonoids for the studied population, including mainly flavanols, while coffee is the most important contributor of phenolic acids, mostly hydroxycinnamic acids. Our study also demonstrated that flavonoid intakes estimated according to various databases may substantially differ. Further work should be undertaken to expand polyphenol databases to better reflect their food contents. PMID- 26569293 TI - Cell Systems to Investigate the Impact of Polyphenols on Cardiovascular Health. AB - Polyphenols are a diverse group of micronutrients from plant origin that may serve as antioxidants and that contribute to human health in general. More specifically, many research groups have investigated their protective effect against cardiovascular diseases in several animal studies and human trials. Yet, because of the excessive processing of the polyphenol structure by human cells and the residing intestinal microbial community, which results in a large variability between the test subjects, the exact mechanisms of their protective effects are still under investigation. To this end, simplified cell culture systems have been used to decrease the inter-individual variability in mechanistic studies. In this review, we will discuss the different cell culture models that have been used so far for polyphenol research in the context of cardiovascular diseases. We will also review the current trends in cell culture research, including co-culture methodologies. Finally, we will discuss the potential of these advanced models to screen for cardiovascular effects of the large pool of bioactive polyphenols present in foods and their metabolites. PMID- 26569295 TI - Pomegranate Peel Extract Prevents Bone Loss in a Preclinical Model of Osteoporosis and Stimulates Osteoblastic Differentiation in Vitro. AB - The nutritional benefits of pomegranate have attracted great scientific interest. The pomegranate, including the pomegranate peel, has been used worldwide for many years as a fruit with medicinal activity, mostly antioxidant properties. Among chronic diseases, osteoporosis, which is associated with bone remodelling impairment leading to progressive bone loss, could eventually benefit from antioxidant compounds because of the involvement of oxidative stress in the pathogenesis of osteopenia. In this study, with in vivo and ex vivo experiments, we investigated whether the consumption of pomegranate peel extract (PGPE) could limit the process of osteopenia. We demonstrated that in ovariectomized (OVX) C57BL/6J mice, PGPE consumption was able to significantly prevent the decrease in bone mineral density (-31.9%; p < 0.001 vs. OVX mice) and bone microarchitecture impairment. Moreover, the exposure of RAW264.7 cells to serum harvested from mice that had been given a PGPE-enriched diet elicited reduced osteoclast differentiation and bone resorption, as shown by the inhibition of the major osteoclast markers. In addition, PGPE appeared to substantially stimulate osteoblastic MC3T3-E1 alkaline phosphatase (ALP) activity at day 7, mineralization at day 21 and the transcription level of osteogenic markers. PGPE may be effective in preventing the bone loss associated with ovariectomy in mice, and offers a promising alternative for the nutritional management of this disease. PMID- 26569298 TI - Association of Dietary Vitamin A and beta-Carotene Intake with the Risk of Lung Cancer: A Meta-Analysis of 19 Publications. AB - Whether dietary beta-carotene and vitamin A intake protect against lung cancer risk is not clear. Therefore, we performed this meta-analysis to investigate the association between them. The related articles were searched using the databases PubMed and the Web of Knowledge up to May 2015. We used the random-effect model to estimate the relative risk (RR) and their 95% CI. Small-study effect was assessed using Egger's test. In total, 19 studies comprising 10,261 lung cancer cases met the inclusion criteria. The pooled RR and their 95% CI was 0.855 (0.739 0.989) for higher category of dietary vitamin A intake and lung cancer risk, especially among Asian populations and in the cohort studies. Evidence from 18 studies suggested that higher category of dietary beta-carotene intake could reduce lung cancer risk (0.768 (0.675-0.874)).The associations were also significant in American and Asian populations. In conclusions, higher category of dietary beta-carotene and vitamin A intakes could reduce the risk of lung cancer. However, the dose-response analysis was not performed due to the limited data in each individual study. Due to this limitation, further studies with detailed dose, cases and person-years for beta-carotene and vitamin A of each category are wanted to assess this dose-response association. PMID- 26569299 TI - Celiac Disease Genomic, Environmental, Microbiome, and Metabolomic (CDGEMM) Study Design: Approach to the Future of Personalized Prevention of Celiac Disease. AB - In the past it was believed that genetic predisposition and exposure to gluten were necessary and sufficient to develop celiac disease (CD). Recent studies however suggest that loss of gluten tolerance can occur at any time in life as a consequence of other environmental stimuli. Many environmental factors known to influence the composition of the intestinal microbiota are also suggested to play a role in the development of CD. These include birthing delivery mode, infant feeding, and antibiotic use. To date no large-scale longitudinal studies have defined if and how gut microbiota composition and metabolomic profiles may influence the loss of gluten tolerance and subsequent onset of CD in genetically susceptible individuals. Here we describe a prospective, multicenter, longitudinal study of infants at risk for CD which will employ a blend of basic and applied studies to yield fundamental insights into the role of the gut microbiome as an additional factor that may play a key role in early steps involved in the onset of autoimmune disease. PMID- 26569301 TI - Consumers' Exposure to Nutrition and Health Claims on Pre-Packed Foods: Use of Sales Weighting for Assessing the Food Supply in Slovenia. AB - Insights into the use of health-related information on foods are important for planning studies about the effects of such information on the consumer's understanding, purchasing, and consumption of foods, and also support further food policy decisions. We tested the use of sales data for weighting consumers' exposure to health-related labeling information in the Slovenian food supply. Food labeling data were collected from 6342 pre-packed foods available in four different food stores in Slovenia. Consumers' exposure was calculated as the percentage of available food products with particular food information in the food category. In addition, 12-month sales data were used to calculate sales weighted exposure as a percentage of sold food products with certain food information in the food category. The consumer's in-store and sales-weighted exposure to nutrition claims was 37% and 45%, respectively. Exposure to health claims was much lower (13%, 11% when sales-weighted). Health claims were mainly found in the form of general non-specific claims or function claims, while children's development and reduction of disease risk claims were present on only 0.1% and 0.2% of the investigated foods, respectively. Sales data were found very useful for establishing a reliable estimation of consumers' exposure to information provided on food labels. The high penetration of health-related information on food labels indicates that careful regulation of this area is appropriate. Further studies should focus on assessing the nutritional quality of foods labeled with nutrition and health claims, and understanding the importance of such labeling techniques for consumers' food preferences and choices. PMID- 26569300 TI - Ameliorating Effect of Akebia quinata Fruit Extracts on Skin Aging Induced by Advanced Glycation End Products. AB - The accumulation of free radicals and advanced glycation end products (AGEs) in the skin plays a very important role in skin aging. Both are known to interact with each other. Therefore, natural compounds or extracts that possess both antioxidant and antiglycation activities might have great antiageing potential. Akebia quinata fruit extract (AQFE) has been used to treat urinary tract inflammatory disease in traditional Korean and Chinese medicines. In the present study, AQFE was demonstrated to possess antioxidant and antiglycation activity. AQFE protects human dermal fibroblasts (HDFs) from oxidative stress and inhibits cellular senescence induced by oxidative stress. We also found that AQFE inhibits glycation reaction between BSA and glucose. The antiglycation activity of AQFE was dose-dependent. In addition, the antiglycation activity of AQFE was confirmed in a human skin explant model. AQFE reduced CML expression and stimulated fibrillin-1 expression in comparison to the methyglyoxal treatment. In addition, the possibility of the extract as an anti-skin aging agent has also been clinically validated. Our analysis of the crow's feet wrinkle showed that there was a decrease in the depth of deep furrows in RI treated with AQFE cream over an eight-week period. The overall results suggest that AQFE may work as an anti-skin aging agent by preventing oxidative stress and other complications associated with AGEs formation. PMID- 26569302 TI - Dietary Patterns during Pregnancy Are Associated with Risk of Gestational Diabetes Mellitus. AB - Maternal dietary patterns before and during pregnancy play important roles in the development of gestational diabetes mellitus (GDM). We aimed to identify dietary patterns during pregnancy that are associated with GDM risk in pregnant U.S. women. From a 24 h dietary recall of 253 pregnant women (16-41 years) included in the National Health and Nutrition Examination Survey (NHANES) 2003-2012, food items were aggregated into 28 food groups based on Food Patterns Equivalents Database. Three dietary patterns were identified by reduced rank regression with responses including prepregnancy body mass index (BMI), dietary fiber, and ratio of poly- and monounsaturated fatty acids to saturated fatty acid: "high refined grains, fats, oils and fruit juice", "high nuts, seeds, fat and soybean; low milk and cheese", and "high added sugar and organ meats; low fruits, vegetables and seafood". GDM was diagnosed using fasting plasma glucose levels >=5.1 mmol/L for gestation <24 weeks. Multivariable logistic regression models were used to estimate adjusted odds ratio (AOR) and 95% confidence intervals (CIs) for GDM, after controlling for maternal age, race/ethnicity, education, family poverty income ratio, marital status, prepregnancy BMI, gestational weight gain, energy intake, physical activity, and log-transformed C-reactive protein (CRP). All statistical analyses accounted for the appropriate survey design and sample weights of the NHANES. Of 249 pregnant women, 34 pregnant women (14%) had GDM. Multivariable AOR (95% CIs) of GDM for comparisons between the highest vs. lowest tertiles were 4.9 (1.4-17.0) for "high refined grains, fats, oils and fruit juice" pattern, 7.5 (1.8-32.3) for "high nuts, seeds, fat and soybean; low milk and cheese" pattern, and 22.3 (3.9-127.4) for "high added sugar and organ meats; low fruits, vegetables and seafood" pattern after controlling for maternal sociodemographic variables, prepregnancy BMI, gestational weight gain, energy intake and log-transformed CRP. These findings suggest that dietary patterns during pregnancy are associated with risk of GDM after controlling for potential confounders. The observed connection between a high consumption of refined grains, fat, added sugars and low intake of fruits and vegetables during pregnancy with higher odds for GDM, are consistent with general health benefits of healthy diets, but warrants further research to understand underlying pathophysiology of GDM associated with dietary behaviors during pregnancy. PMID- 26569303 TI - A Priori and a Posteriori Dietary Patterns during Pregnancy and Gestational Weight Gain: The Generation R Study. AB - Abnormal gestational weight gain (GWG) is associated with adverse pregnancy outcomes. We examined whether dietary patterns are associated with GWG. Participants included 3374 pregnant women from a population-based cohort in the Netherlands. Dietary intake during pregnancy was assessed with food-frequency questionnaires. Three a posteriori-derived dietary patterns were identified using principal component analysis: a "Vegetable, oil and fish", a "Nuts, high-fiber cereals and soy", and a "Margarine, sugar and snacks" pattern. The a priori defined dietary pattern was based on national dietary recommendations. Weight was repeatedly measured around 13, 20 and 30 weeks of pregnancy; pre-pregnancy and maximum weight were self-reported. Normal weight women with high adherence to the "Vegetable, oil and fish" pattern had higher early-pregnancy GWG than those with low adherence (43 g/week (95% CI 16; 69) for highest vs. lowest quartile (Q)). Adherence to the "Margarine, sugar and snacks" pattern was associated with a higher prevalence of excessive GWG (OR 1.45 (95% CI 1.06; 1.99) Q4 vs. Q1). Normal weight women with higher scores on the "Nuts, high-fiber cereals and soy" pattern had more moderate GWG than women with lower scores (-0.01 (95% CI -0.02; 0.00) per SD). The a priori-defined pattern was not associated with GWG. To conclude, specific dietary patterns may play a role in early pregnancy but are not consistently associated with GWG. PMID- 26569304 TI - The mutation Glu151Asp in the B-component of the Bacillus cereus non-hemolytic enterotoxin (Nhe) leads to a diverging reactivity in antibody-based detection systems. AB - The ability of Bacillus cereus to cause foodborne toxicoinfections leads to increasing concerns regarding consumer protection. For the diarrhea-associated enterotoxins, the assessment of the non-hemolytic enterotoxin B (NheB) titer determined by a sandwich enzyme immunoassay (EIA) correlates best with in vitro cytotoxicity. In general, the regulation of enterotoxin expression of B. cereus is a coordinately-regulated process influenced by environmental, and probably also by host factors. As long as these factors are not completely understood, the currently-applied diagnostic procedures are based on indirect approaches to assess the potential virulence of an isolate. To date, sandwich EIA results serve as a surrogate marker to categorize isolates as either potentially low or highly toxic. Here, we report on a single amino acid exchange in the NheB sequence leading to an underestimation of the cytotoxic potential in a limited number of strains. During the screening of a large panel of B. cereus isolates, six showed uncommon features with low sandwich EIA titers despite high cytotoxicity. Sequence analysis revealed the point-mutation (Glu)151(Asp) in the potential binding region of the capture antibody. Application of this antibody also results in low titers in an indirect EIA format and shows variable detection intensities in Western-immunoblots. A commercially-available assay based on a lateral flow device detects all strains correctly as NheB producers in a qualitative manner. In conclusion, isolates showing low NheB titers should additionally be assayed in an indirect EIA or for their in vitro cytotoxicity to ensure a correct classification as either low or highly toxic. PMID- 26569305 TI - Delay of the onset of puberty in female rats by prepubertal exposure to T-2 toxin. AB - Growing evidence has revealed the deleterious influence of environmental and food contaminants on puberty onset and development in both animals and children, provoking an increasing health concern. T-2 toxin, a naturally-produced Type A trichothecene mycotoxin which is frequently found in cereal grains and products intended for human and animal consumption, has been shown to impair the reproduction and development in animals. Nevertheless, whether this trichothecene mycotoxin can disturb the onset of puberty in females remains unclear. To clarify this point, infantile female rats were given a daily intragastric administration of vehicle or 187.5 MUg/kg body weight of T-2 toxin for five consecutive days from postnatal day 15 to 19, and the effects on puberty onset were evaluated in the present study. The results revealed that the days of vaginal opening, first dioestrus, and first estrus in regular estrous cycle were delayed following prepubertal exposure to T-2 toxin. The relative weights of reproductive organs uterus, ovaries, and vagina, and the incidence of corpora lutea were all diminished in T-2 toxin-treated rats. Serum levels of gonadotropins luteinizing hormone, follicle-stimulating hormone, and estradiol were also reduced by T-2 toxin treatment. The mRNA expressions of hypothalamic gonadotropin-releasing hormone (GnRH) and pituitary GnRH receptor displayed significant reductions following exposure to T-2 toxin, which were consistent with the changes of serum gonadotropins, delayed reproductive organ development, and delayed vaginal opening. In conclusion, the present study reveals that prepubertal exposure to T 2 toxin delays the onset of puberty in immature female rats, probably by the mechanism of disturbance of hypothalamic-pituitary-gonadal (HPG) axis function. Considering the vulnerability of developmental children to food contaminants and the relative high level of dietary intake of T-2 toxin in children, we think the findings of the present study provide valuable information for the health risk assessment in children. PMID- 26569306 TI - The effects of low doses of two Fusarium toxins, zearalenone and deoxynivalenol, on the pig jejunum. A light and electron microscopic study. AB - Immature gilts were administered per os with zearalenone (ZEN) at 40 MUg/kg BW (group Z, n = 9), deoxynivalenol (DON) at 12 MUg/kg BW (group D, n = 9), a mixture of ZEN and DON (group M, n = 9) or a placebo (group C, n = 9) over a period of six weeks. The pigs were sacrificed after one, three, or six weeks of the treatment (12 pigs per each time-point). Histological investigations revealed an increase in the mucosal thickness and the crypt depth as well as a decrease in the ratio of the villus height to the crypt depth in groups D and M after six weeks of exposure to the mycotoxins. The number of goblet cells in the villus epithelium was elevated in groups Z and M after one week and in group D after three weeks. The administration of ZEN increased the lymphocyte number in the villus epithelium after 1 week and the plasma cell quantity in the lamina propria after one, three, and six weeks of the experiment. DON treatment resulted in an increase in the lymphocyte number in the villus epithelium and the lamina propria after six weeks, and in the plasma cell quantity in the lamina propria after one, three, and six weeks of exposure. In group M, lymphocyte counts in the epithelium and the lamina propria increased significantly after six weeks. Neither mycotoxin induced significant adverse changes in the ultrastructure of the mucosal epithelium and the lamina propria or in the intestinal barrier permeability. Our results indicate that immune cells are the principal target of low doses of ZEN and DON. PMID- 26569307 TI - Metabolism of deoxynivalenol and deepoxy-deoxynivalenol in broiler chickens, pullets, roosters and turkeys. AB - Recently, deoxynivalenol-3-sulfate (DON-3-sulfate) was proposed as a major DON metabolite in poultry. In the present work, the first LC-MS/MS based method for determination of DON-3-sulfate, deepoxy-DON-3-sulfate (DOM-3-sulfate), DON, DOM, DON sulfonates 1, 2, 3, and DOM sulfonate 2 in excreta samples of chickens and turkeys was developed and validated. To this end, DOM-3-sulfate was chemically synthesized and characterized by NMR and LC-HR-MS/MS measurements. Application of the method to excreta and chyme samples of four feeding trials with turkeys, chickens, pullets, and roosters confirmed DON-3-sulfate as the major DON metabolite in all poultry species studied. Analogously to DON-3-sulfate, DOM-3 sulfate was formed after oral administration of DOM both in turkeys and in chickens. In addition, pullets and roosters metabolized DON into DOM-3-sulfate. In vitro transcription/translation assays revealed DOM-3-sulfate to be 2000 times less toxic on the ribosome than DON. Biological recoveries of DON and DOM orally administered to broiler chickens, turkeys, and pullets were 74%-106% (chickens), 51%-72% (roosters), and 131%-151% (pullets). In pullets, DON-3-sulfate concentrations increased from jejunum chyme samples to excreta samples by a factor of 60. This result, put into context with earlier studies, indicates fast and efficient absorption of DON between crop and jejunum, conversion to DON-3 sulfate in intestinal mucosa, liver, and possibly kidney, and rapid elimination into excreta via bile and urine. PMID- 26569308 TI - Meta-Analysis of DNA Tumor-Viral Integration Site Selection Indicates a Role for Repeats, Gene Expression and Epigenetics. AB - Oncoviruses cause tremendous global cancer burden. For several DNA tumor viruses, human genome integration is consistently associated with cancer development. However, genomic features associated with tumor viral integration are poorly understood. We sought to define genomic determinants for 1897 loci prone to hosting human papillomavirus (HPV), hepatitis B virus (HBV) or Merkel cell polyomavirus (MCPyV). These were compared to HIV, whose enzyme-mediated integration is well understood. A comprehensive catalog of integration sites was constructed from the literature and experimentally-determined HPV integration sites. Features were scored in eight categories (genes, expression, open chromatin, histone modifications, methylation, protein binding, chromatin segmentation and repeats) and compared to random loci. Random forest models determined loci classification and feature selection. HPV and HBV integrants were not fragile site associated. MCPyV preferred integration near sensory perception genes. Unique signatures of integration-associated predictive genomic features were detected. Importantly, repeats, actively-transcribed regions and histone modifications were common tumor viral integration signatures. PMID- 26569309 TI - Tumor Volumes and Prognosis in Laryngeal Cancer. AB - Tumor staging systems for laryngeal cancer (LC) have been developed to assist in estimating prognosis after treatment and comparing treatment results across institutions. While the laryngeal TNM system has been shown to have prognostic information, varying cure rates in the literature have suggested concern about the accuracy and effectiveness of the T-classification in particular. To test the hypothesis that tumor volumes are more useful than T classification, we conducted a retrospective review of 78 patients with laryngeal cancer treated with radiation therapy at our institution. Using multivariable analysis, we demonstrate the significant prognostic value of anatomic volumes in patients with previously untreated laryngeal cancer. In this cohort, primary tumor volume (GTVP), composite nodal volumes (GTVN) and composite total volume (GTVP + GTVN = GTVC) had prognostic value in both univariate and multivariate cox model analysis. Interestingly, when anatomic volumes were measured from CT scans after a single cycle of induction chemotherapy, all significant prognosticating value for measured anatomic volumes was lost. Given the literature findings and the results of this study, the authors advocate the use of tumor anatomic volumes calculated from pretreatment scans to supplement the TNM staging system in subjects with untreated laryngeal cancer. The study found that tumor volume assessment after induction chemotherapy is not of prognostic significance. PMID- 26569310 TI - Differences in Redox Regulatory Systems in Human Lung and Liver Tumors Suggest Different Avenues for Therapy. AB - A common characteristic of many cancer cells is that they suffer from oxidative stress. They, therefore, require effective redox regulatory systems to combat the higher levels of reactive oxygen species that accompany accelerated growth compared to the normal cells of origin. An elevated dependence on these systems in cancers suggests that targeting these systems may provide an avenue for retarding the malignancy process. Herein, we examined the redox regulatory systems in human liver and lung cancers by comparing human lung adenocarcinoma and liver carcinoma to their respective surrounding normal tissues. Significant differences were found in the two major redox systems, the thioredoxin and glutathione systems. Thioredoxin reductase 1 levels were elevated in both malignancies, but thioredoxin was highly upregulated in lung tumor and only slightly upregulated in liver tumor, while peroxiredoxin 1 was highly elevated in lung tumor, but downregulated in liver tumor. There were also major differences within the glutathione system between the malignancies and their normal tissues. The data suggest a greater dependence of liver on either the thioredoxin or glutathione system to drive the malignancy, while lung cancer appeared to depend primarily on the thioredoxin system. PMID- 26569311 TI - Super Enhancers in Cancers, Complex Disease, and Developmental Disorders. AB - Recently, unique areas of transcriptional regulation termed super-enhancers have been identified and implicated in human disease. Defined by their magnitude of size, transcription factor density, and binding of transcriptional machinery, super-enhancers have been associated with genes driving cell differentiation. While their functions are not completely understood, it is clear that these regions driving high-level transcription are susceptible to perturbation, and trait-associated single nucleotide polymorphisms (SNPs) occur within super enhancers of disease-relevant cell types. Here we review evidence for super enhancer involvement in cancers, complex diseases, and developmental disorders and discuss interactions between super-enhancers and cofactors/chromatin regulators. PMID- 26569312 TI - Identification of Differentially Expressed IGFBP5-Related Genes in Breast Cancer Tumor Tissues Using cDNA Microarray Experiments. AB - IGFBP5 is an important regulatory protein in breast cancer progression. We tried to identify differentially expressed genes (DEGs) between breast tumor tissues with IGFBP5 overexpression and their adjacent normal tissues. In this study, thirty-eight breast cancer and adjacent normal breast tissue samples were used to determine IGFBP5 expression by qPCR. cDNA microarrays were applied to the highest IGFBP5 overexpressed tumor samples compared to their adjacent normal breast tissue. Microarray analysis revealed that a total of 186 genes were differentially expressed in breast cancer compared with normal breast tissues. Of the 186 genes, 169 genes were downregulated and 17 genes were upregulated in the tumor samples. KEGG pathway analyses showed that protein digestion and absorption, focal adhesion, salivary secretion, drug metabolism-cytochrome P450, and phenylalanine metabolism pathways are involved. Among these DEGs, the prominent top two genes (MMP11 and COL1A1) which potentially correlated with IGFBP5 were selected for validation using real time RT-qPCR. Only COL1A1 expression showed a consistent upregulation with IGFBP5 expression and COL1A1 and MMP11 were significantly positively correlated. We concluded that the discovery of coordinately expressed genes related with IGFBP5 might contribute to understanding of the molecular mechanism of the function of IGFBP5 in breast cancer. Further functional studies on DEGs and association with IGFBP5 may identify novel biomarkers for clinical applications in breast cancer. PMID- 26569313 TI - Starvation-Survival in Haloarchaea. AB - Recent studies claiming to revive ancient microorganisms trapped in fluid inclusions in halite have warranted an investigation of long-term microbial persistence. While starvation-survival is widely reported for bacteria, it is less well known for halophilic archaea-microorganisms likely to be trapped in ancient salt crystals. To better understand microbial survival in fluid inclusions in ancient evaporites, laboratory experiments were designed to simulate growth of halophilic archaea under media-rich conditions, complete nutrient deprivation, and a controlled substrate condition (glycerol-rich) and record their responses. Haloarchaea used for this work included Hbt. salinarum and isolate DV582A-1 (genus Haloterrigena) sub-cultured from 34 kyear Death Valley salt. Hbt. salinarum and DV582A-1 reacted to nutrient limitation with morphological and population changes. Starved populations increased and most cells converted from rods to small cocci within 56 days of nutrient deprivation. The exact timing of starvation adaptations and the physical transformations differed between species, populations of the same species, and cells of the same population. This is the first study to report the timing of starvation strategies for Hbt. salinarum and DV582A-1. The morphological states in these experiments may allow differentiation between cells trapped with adequate nutrients (represented here by early stages in nutrient-rich media) from cells trapped without nutrients (represented here by experimental starvation) in ancient salt. The hypothesis that glycerol, leaked from Dunaliella, provides nutrients for the survival of haloarchaea trapped in fluid inclusions in ancient halite, is also tested. Hbt. salinarum and DV582A-1 were exposed to a mixture of lysed and intact Dunaliella for 56 days. The ability of these organisms to utilize glycerol from Dunaliella cells was assessed by documenting population growth, cell length, and cell morphology. Hbt. salinarum and DV582A-1 experienced size reductions and shape transitions from rods to cocci. In the short-term, these trends more closely resembled the response of these organisms to starvation conditions than to nutrient-rich media. Results from this experiment reproduced the physical state of cells (small cocci) in ancient halite where prokaryotes co-exist with single-celled algae. We conclude that glycerol is not the limiting factor in the survival of haloarchaea for thousands of years in fluid inclusions in halite. PMID- 26569315 TI - Mating Success, Longevity, and Fertility of Diabrotica virgifera virgifera LeConte (Chrysomelidae: Coleoptera) in Relation to Body Size and Cry3Bb1 Resistant and Cry3Bb1-Susceptible Genotypes. AB - Insect resistance to population control methodologies is a widespread problem. The development of effective resistance management programs is often dependent on detailed knowledge regarding the biology of individual species and changes in that biology associated with resistance evolution. This study examined the reproductive behavior and biology of western corn rootworm beetles of known body size from lines resistant and susceptible to the Cry3Bb1 protein toxin expressed in transgenic Bacillus thuringiensis maize. In crosses between, and within, the resistant and susceptible genotypes, no differences occurred in mating frequency, copulation duration, courtship duration, or fertility; however, females mated with resistant males showed reduced longevity. Body size did not vary with genotype. Larger males and females were not more likely to mate than smaller males and females, but larger females laid more eggs. Moderately strong, positive correlation occurred between the body sizes of successfully mated males and females; however, weak correlation also existed for pairs that did not mate. Our study provided only limited evidence for fitness costs associated with the Cry3Bb1-resistant genotype that might reduce the persistence in populations of the resistant genotype but provided additional evidence for size-based, assortative mating, which could favor the persistence of resistant genotypes affecting body size. PMID- 26569314 TI - Non-Standard Genetic Codes Define New Concepts for Protein Engineering. AB - The essential feature of the genetic code is the strict one-to-one correspondence between codons and amino acids. The canonical code consists of three stop codons and 61 sense codons that encode 20% of the amino acid repertoire observed in nature. It was originally designated as immutable and universal due to its conservation in most organisms, but sequencing of genes from the human mitochondrial genomes revealed deviations in codon assignments. Since then, alternative codes have been reported in both nuclear and mitochondrial genomes and genetic code engineering has become an important research field. Here, we review the most recent concepts arising from the study of natural non-standard genetic codes with special emphasis on codon re-assignment strategies that are relevant to engineering genetic code in the laboratory. Recent tools for synthetic biology and current attempts to engineer new codes for incorporation of non-standard amino acids are also reviewed in this article. PMID- 26569317 TI - Wildlife in U.S. Cities: Managing Unwanted Animals. AB - Conflicts between people and wild animals in cities are undoubtedly as old as urban living itself. In the United States it is only of late, however, that many of the species now found in cities have come to live there. The increasing kind and number of human-wildlife conflicts in urbanizing environments makes it a priority that effective and humane means of conflict resolution be found. The urban public wants conflicts with wildlife resolved humanely, but needs to know what the alternative management approaches are, and what ethical standards should guide their use. This paper examines contemporary urban wildlife control in the United States with a focus on the moral concerns this raises. Much of the future for urban wildlife will depend on reform in governance, but much as well will depend on cultural changes that promote greater respect and understanding for wild animals and the biotic communities of which they and we are both a part. PMID- 26569316 TI - Disruptions of Host Immunity and Inflammation by Giardia Duodenalis: Potential Consequences for Co-Infections in the Gastro-Intestinal Tract. AB - Giardia duodenalis (syn. G. intestinalis, or G. lamblia) is a leading cause of waterborne diarrheal disease that infects hundreds of millions of people annually. Research on Giardia has greatly expanded within the last few years, and our understanding of the pathophysiology and immunology on this parasite is ever increasing. At peak infection, Giardia trophozoites induce pathophysiological responses that culminate in the development of diarrheal disease. However, human data has suggested that the intestinal mucosa of Giardia-infected individuals is devoid of signs of overt intestinal inflammation, an observation that is reproduced in animal models. Thus, our understanding of host inflammatory responses to the parasite remain incompletely understood and human studies and experimental data have produced conflicting results. It is now also apparent that certain Giardia infections contain mechanisms capable of modulating their host's immune responses. As the oral route of Giardia infection is shared with many other gastrointestinal (GI) pathogens, co-infections may often occur, especially in places with poor sanitation and/or improper treatment of drinking water. Moreover, Giardia infections may modulate host immune responses and have been found to protect against the development of diarrheal disease in developing countries. The following review summarizes our current understanding of the immunomodulatory mechanisms of Giardia infections and their consequences for the host, and highlights areas for future research. Potential implications of these immunomodulatory effects during GI co-infection are also discussed. PMID- 26569319 TI - Development of a Safety Management Web Tool for Horse Stables. AB - Managing a horse stable involves risks, which can have serious consequences for the stable, employees, clients, visitors and horses. Existing industrial or farm production risk management tools are not directly applicable to horse stables and they need to be adapted for use by managers of different types of stables. As a part of the InnoEquine project, an innovative web tool, InnoHorse, was developed to support horse stable managers in business, safety, pasture and manure management. A literature review, empirical horse stable case studies, expert panel workshops and stakeholder interviews were carried out to support the design. The InnoHorse web tool includes a safety section containing a horse stable safety map, stable safety checklists, and examples of good practices in stable safety, horse handling and rescue planning. This new horse stable safety management tool can also help in organizing work processes in horse stables in general. PMID- 26569318 TI - Digital Dermatitis in Cattle: Current Bacterial and Immunological Findings. AB - Globally; digital dermatitis is a leading form of lameness observed in production dairy cattle. While the precise etiology remains to be determined; the disease is clearly associated with infection by numerous species of treponemes; in addition to other anaerobic bacteria. The goal of this review article is to provide an overview of the current literature; focusing on discussion of the polybacterial nature of the digital dermatitis disease complex and host immune response. Several phylotypes of treponemes have been identified; some of which correlate with location in the lesion and some with stages of lesion development. Local innate immune responses may contribute to the proliferative, inflammatory conditions that perpetuate digital dermatitis lesions. While serum antibody is produced to bacterial antigens in the lesions, little is known about cellular based immunity. Studies are still required to delineate the pathogenic traits of treponemes associated with digital dermatitis; and other host factors that mediate pathology and protection of digital dermatitis lesions. PMID- 26569320 TI - Emotional Meta-Memories: A Review. AB - Emotional meta-memory can be defined as the knowledge people have about the strategies and monitoring processes that they can use to remember their emotionally charged memories. Although meta-memory per se has been studied in many cognitive laboratories for many years, fewer studies have explicitly focused on meta-memory for emotionally charged or valenced information. In this brief review, we analyzed a series of behavioral and neuroimaging studies that used different meta-memory tasks with valenced information in order to foster new research in this direction, especially in terms of commonalities/peculiarities of the emotion and meta-memory interaction. In addition, results further support meta-cognitive models that take emotional factors into account when defining meta memory per se. PMID- 26569322 TI - Renin-Angiotensin-Aldosterone System Blockade in Diabetic Nephropathy. Present Evidences. AB - Diabetic Kidney Disease (DKD) is the leading cause of chronic kidney disease in developed countries and its prevalence has increased dramatically in the past few decades. These patients are at an increased risk for premature death, cardiovascular disease, and other severe illnesses that result in frequent hospitalizations and increased health-care utilization. Although much progress has been made in slowing the progression of diabetic nephropathy, renal dysfunction and the development of end-stage renal disease remain major concerns in diabetes. Dysregulation of the renin-angiotensin-aldosterone system (RAAS) results in progressive renal damage. RAAS blockade is the cornerstone of treatment of DKD, with proven efficacy in many arenas. The theoretically attractive option of combining these medications that target different points in the pathway, potentially offering a more complete RAAS blockade, has also been tested in clinical trials, but long-term outcomes were disappointing. This review examines the "state of play" for RAAS blockade in DKD, dual blockade of various combinations, and a perspective on its benefits and potential risks. PMID- 26569323 TI - Polish Scientists in Fish Immunology: A Short History. AB - This review describes the role played by Polish scientists in the field of fish immunology and vaccination starting around 1900. In the early days, most publications were dealing with a description of relevant cells and organs in fish. Functional studies (phagocytosis, antibody response) came later starting in the late 1930s. Detailed papers on fish vaccination were published from 1970 onwards. Another important development was the unraveling of neuro-endocrine immune interactions in the 1970s until today. Around 1980, it became more and more clear how important immunomodulation (stimulation or suppression by environmental factors, food components, drugs) was for fish health. The most recent findings are focusing on the discovery of genetic factors, signaling molecules, and receptors, which play a crucial role in the immune response. It can be concluded, that Polish scientists made considerable contributions to our present understanding of fish immunity and to applications in aquaculture worldwide. PMID- 26569321 TI - Live-Attenuated Bacterial Vectors: Tools for Vaccine and Therapeutic Agent Delivery. AB - Genetically attenuated microorganisms, including pathogenic and commensal bacteria, can be engineered to carry and deliver heterologous antigens to elicit host immunity against both the vector as well as the pathogen from which the donor gene is derived. These live attenuated bacterial vectors have been given much attention due to their capacity to induce a broad range of immune responses including localized mucosal, as well as systemic humoral and/or cell-mediated immunity. In addition, the unique tumor-homing characteristics of these bacterial vectors has also been exploited for alternative anti-tumor vaccines and therapies. In such approach, tumor-associated antigen, immunostimulatory molecules, anti-tumor drugs, or nucleotides (DNA or RNA) are delivered. Different potential vectors are appropriate for specific applications, depending on their pathogenic routes. In this review, we survey and summarize the main features of the different types of live bacterial vectors and discussed the clinical applications in the field of vaccinology. In addition, different approaches for using live attenuated bacterial vectors for anti-cancer therapy is discussed, and some promising pre-clinical and clinical studies in this field are outlined. PMID- 26569324 TI - Teleost Chemokines and Their Receptors. AB - Chemokines are a superfamily of cytokines that appeared about 650 million years ago, at the emergence of vertebrates, and are responsible for regulating cell migration under both inflammatory and physiological conditions. The first teleost chemokine gene was reported in rainbow trout in 1998. Since then, numerous chemokine genes have been identified in diverse fish species evidencing the great differences that exist among fish and mammalian chemokines, and within the different fish species, as a consequence of extensive intrachromosomal gene duplications and different infectious experiences. Subsequently, it has only been possible to establish clear homologies with mammalian chemokines in the case of some chemokines with well-conserved homeostatic roles, whereas the functionality of other chemokine genes will have to be independently addressed in each species. Despite this, functional studies have only been undertaken for a few of these chemokine genes. In this review, we describe the current state of knowledge of chemokine biology in teleost fish. We have mainly focused on those species for which more research efforts have been made in this subject, specially zebrafish (Danio rerio), rainbow trout (Oncorhynchus mykiss) and catfish (Ictalurus punctatus), outlining which genes have been identified thus far, highlighting the most important aspects of their expression regulation and addressing any known aspects of their biological role in immunity. Finally, we summarise what is known about the chemokine receptors in teleosts and provide some analysis using recently available data to help characterise them more clearly. PMID- 26569325 TI - Comparative Lipidomics of Caenorhabditis elegans Metabolic Disease Models by SWATH Non-Targeted Tandem Mass Spectrometry. AB - Tandem mass spectrometry (MS/MS) with Sequential Window Acquisition of all Theoretical (SWATH) mass spectra generates a comprehensive archive of lipid species within an extract for retrospective, quantitative MS/MS analysis. Here we apply this new technology in Caenorhabditis elegans (C. elegans) to identify potential lipid mediators and pathways. The DAF-1 type I TGF-beta and DAF-2 insulin receptors transmit endocrine signals that couple metabolic status to fertility and lifespan. Mutations in daf-1 and daf-2 reduce prostaglandin endoperoxide synthase (i.e., Cox)-independent prostaglandin synthesis, increase triacylglyceride storage, and alter transcription of numerous lipid metabolism genes. However, the extent to which DAF-1 and DAF-2 signaling modulate lipid metabolism and the underlying mechanisms are not well understood. MS/MSALL with SWATH analysis across the groups identified significant changes in numerous lipids, including specific triacylglycerols, diacylglycerols, and phosphatidylinositols. Examples are provided, using retrospective neutral loss and precursor ion scans as well as MS/MS spectra, to help identify annotated lipids and search libraries for lipids of interest. As proof of principle, we used comparative lipidomics to investigate the prostaglandin metabolism pathway. SWATH data support an unanticipated model: Cox-independent prostaglandin synthesis may involve lysophosphatidylcholine and other lyso glycerophospholipids. This study showcases the power of comprehensive, retrospectively searchable lipid archives as a systems approach for biological discovery in genetic animal models. PMID- 26569326 TI - RNase P-Mediated Sequence-Specific Cleavage of RNA by Engineered External Guide Sequences. AB - The RNA cleavage activity of RNase P can be employed to decrease the levels of specific RNAs and to study their function or even to eradicate pathogens. Two different technologies have been developed to use RNase P as a tool for RNA knockdown. In one of these, an external guide sequence, which mimics a tRNA precursor, a well-known natural RNase P substrate, is used to target an RNA molecule for cleavage by endogenous RNase P. Alternatively, a guide sequence can be attached to M1 RNA, the (catalytic) RNase P RNA subunit of Escherichia coli. The guide sequence is specific for an RNA target, which is subsequently cleaved by the bacterial M1 RNA moiety. These approaches are applicable in both bacteria and eukaryotes. In this review, we will discuss the two technologies in which RNase P is used to reduce RNA expression levels. PMID- 26569327 TI - Expression and Function of CD44 in Epithelial Ovarian Carcinoma. AB - CD44, a cell surface glycoprotein, has been increasingly implicated in the pathogenesis and progression of epithelial ovarian cancer, the deadliest gynecologic malignancy in women. Here, we review recent reports on the expression and function of CD44 in epithelial ovarian carcinoma. Further functional data for CD44 in peritoneal adhesion and metastatic progression and its association with stem cells is highlighted. Recent studies utilizing CD44 for therapeutic targeting are also discussed. PMID- 26569328 TI - Computational Studies of Glutamate Transporters. AB - Glutamate is the major excitatory neurotransmitter in the human brain whose binding to receptors on neurons excites them while excess glutamate are removed from synapses via transporter proteins. Determination of the crystal structures of bacterial aspartate transporters has paved the way for computational investigation of their function and dynamics at the molecular level. Here, we review molecular dynamics and free energy calculation methods used in these computational studies and discuss the recent applications to glutamate transporters. The focus of the review is on the insights gained on the transport mechanism through computational methods, which otherwise is not directly accessible by experimental probes. Recent efforts to model the mammalian glutamate and other amino acid transporters, whose crystal structures have not been solved yet, are included in the review. PMID- 26569329 TI - Transcriptional Activation of Inflammatory Genes: Mechanistic Insight into Selectivity and Diversity. AB - Acute inflammation, an integral part of host defence and immunity, is a highly conserved cellular response to pathogens and other harmful stimuli. An inflammatory stimulation triggers transcriptional activation of selective pro inflammatory genes that carry out specific functions such as anti-microbial activity or tissue healing. Based on the nature of inflammatory stimuli, an extensive exploitation of selective transcriptional activations of pro inflammatory genes is performed by the host to ensure a defined inflammatory response. Inflammatory signal transductions are initiated by the recognition of inflammatory stimuli by transmembrane receptors, followed by the transmission of the signals to the nucleus for differential gene activations. The differential transcriptional activation of pro-inflammatory genes is precisely controlled by the selective binding of transcription factors to the promoters of these genes. Among a number of transcription factors identified to date, NF-kappaB still remains the most prominent and studied factor for its diverse range of selective transcriptional activities. Differential transcriptional activities of NF-kappaB are dictated by post-translational modifications, specificities in dimer formation, and variability in activation kinetics. Apart from the differential functions of transcription factors, the transcriptional activation of selective pro-inflammatory genes is also governed by chromatin structures, epigenetic markers, and other regulators as the field is continuously expanding. PMID- 26569332 TI - Inconsistencies in Risk Analyses for Ambient Air Pollutant Regulations. AB - This article describes inconsistencies between health risk analyses that the U.S. Environmental Protection Agency (EPA) uses to support its decisions on primary National Ambient Air Quality Standards (NAAQS), and in the associated Regulatory Impact Analyses (RIAs) that accompany each NAAQS rulemaking. Quantitative risk estimates are prepared during the NAAQS-setting deliberations using inputs derived from statistical associations between measured pollutant concentrations and health effects. The resulting risk estimates are not directly used to set a NAAQS, but incorporated into a broader evidence-based rationale for the standard that is intended to demonstrate conformity with the statutory requirement that primary NAAQS protect the public health with a margin of safety. In a separate process, EPA staff rely on the same risk calculations to prepare estimates of the benefits of the rule that are reported in its RIA for the standard. Although NAAQS rules and their RIAs are released simultaneously, the rationales used to set the NAAQS have become inconsistent with their RIAs' estimates of benefits, with very large fractions of RIAs' risk-reduction estimates being attributed to populations living in areas that will already be attaining the respective NAAQS. This article explains the source of this inconsistency and provides a quantitative example based on the 2012 revision of the fine particulate matter (PM2.5 ) primary NAAQS. This article also demonstrates how this inconsistency is amplified when criteria pollutant co-benefits are calculated in RIAs for non NAAQS rules, using quantitative examples from the 2011 Mercury and Air Toxics Standards and the currently proposed Clean Power Plan. PMID- 26569330 TI - Overview of Glutamatergic Dysregulation in Central Pathologies. AB - As the major excitatory neurotransmitter in the mammalian central nervous system, glutamate plays a key role in many central pathologies, including gliomas, psychiatric, neurodevelopmental, and neurodegenerative disorders. Post-mortem and serological studies have implicated glutamatergic dysregulation in these pathologies, and pharmacological modulation of glutamate receptors and transporters has provided further validation for the involvement of glutamate. Furthermore, efforts from genetic, in vitro, and animal studies are actively elucidating the specific glutamatergic mechanisms that contribute to the aetiology of central pathologies. However, details regarding specific mechanisms remain sparse and progress in effectively modulating glutamate to alleviate symptoms or inhibit disease states has been relatively slow. In this report, we review what is currently known about glutamate signalling in central pathologies. We also discuss glutamate's mediating role in comorbidities, specifically cancer induced bone pain and depression. PMID- 26569331 TI - Immune Mechanisms Linking Obesity and Preeclampsia. AB - Preeclampsia (PE) is characterized by hypertension occurring after the twentieth week of pregnancy. It is a significant contributor to maternal and perinatal morbidity and mortality in developing countries and its pervasiveness is increasing within developed countries including the USA. However, the mechanisms mediating the pathogenesis of this maternal disorder and its rising prevalence are far from clear. A major theory with strong experimental evidence is that placental ischemia, resulting from inappropriate remodeling and widening of the maternal spiral arteries, stimulates the release of soluble factors from the ischemic placenta causing maternal endothelial dysfunction and hypertension. Aberrant maternal immune responses and inflammation have been implicated in each of these stages in the cascade leading to PE. Regarding the increased prevalence of this disease, it is becoming increasingly evident from epidemiological data that obesity, which is a state of chronic inflammation in itself, increases the risk for PE. Although the specific mechanisms whereby obesity increases the rate of PE are unclear, there are strong candidates including activated macrophages and natural killer cells within the uterus and placenta and activation in the periphery of T helper cells producing cytokines including TNF-alpha, IL-6 and IL 17 and the anti-angiogenic factor sFlt-1 and B cells producing the agonistic autoantibodies to the angiotensin type 1 receptor (AT1-aa). This review will focus on the immune mechanisms that have been implicated in the pathogenesis of hypertension in PE with an emphasis on the potential importance of inflammatory factors in the increased risk of developing PE in obese pregnancies. PMID- 26569334 TI - Impacts of pavement types on in-vehicle noise and human health. AB - Noise is a major source of pollution that can affect the human physiology and living environment. According to the World Health Organization (WHO), an exposure for longer than 24 hours to noise levels above 70 dB(A) may damage human hearing sensitivity, induce adverse health effects, and cause anxiety to residents nearby roadways. Pavement type with different roughness is one of the associated sources that may contribute to in-vehicle noise. Most previous studies have focused on the impact of pavement type on the surrounding acoustic environment of roadways, and given little attention to in-vehicle noise levels. This paper explores the impacts of different pavement types on in-vehicle noise levels and the associated adverse health effects. An old concrete pavement and a pavement with a thin asphalt overlay were chosen as the test beds. The in-vehicle noise caused by the asphalt and concrete pavements were measured, as well as the drivers' corresponding heart rates and reported riding comfort. Results show that the overall in-vehicle sound levels are higher than 70 dB(A) even at midnight. The newly overlaid asphalt pavement reduced in-vehicle noise at a driving speed of 96.5 km/hr by approximately 6 dB(A). Further, on the concrete pavement with higher roughness, driver heart rates were significantly higher than on the asphalt pavement. Drivers reported feeling more comfortable when driving on asphalt than on concrete pavement. Further tests on more drivers with different demographic characteristics, along highways with complicated configurations, and an examination of more factors contributing to in-vehicle noise are recommended, in addition to measuring additional physical symptoms of both drivers and passengers. IMPLICATIONS: While there have been many previous noise-related studies, few have addressed in-vehicle noise. Most studies have focused on the noise that residents have complained about, such as neighborhood traffic noise. As yet, there have been no complaints by drivers that their own in-vehicle noise is too loud. Nevertheless, it is a fact that in-vehicle noise can also result in adverse health effects if it exceeds 85 dB(A). Results of this study show that in vehicle noise was strongly associated with pavement type and roughness; also, driver heart rate patterns presented statistically significant differences on different types of pavement with different roughness. PMID- 26569335 TI - Dimethyltin Dichloride Catalyzed Regioselective Alkylation of cis-1,2-Diols at Room Temperature. AB - Here, we have developed a mild and general method for the regioselective installation of benzyl, allyl, para-methoxybenzyl and naphthyl groups on cis-1,2 diols. The optimized method operates at room temperature using dimethyltin dichloride as catalyst and silver oxide as an additive. The present method works well with both sugars (such as mono- and disaccharides) and nonsugars (such as inositols, propan-1,2-diol, 1,2-cycloalkanediols and anhydroerythritol) and also provides comparatively better functional group compatibility. PMID- 26569336 TI - Automatic imitation? Imitative compatibility affects responses at high perceptual load. AB - Imitation involves matching the visual representation of another's action onto the observer's own motor program for that action. However, there has been some debate regarding the extent to which imitation is "automatic"-that is, occurs without attention. Participants performed a perceptual load task in which images of finger movements were presented as distractors. Responses to target letter stimuli were performed via finger movements that could be imitatively compatible (requiring the same finger movement) or incompatible with the distractor movements: In this common stimulus-response compatibility manipulation, the stimulus set comprises images of the response movements, producing an imitative compatibility effect. Attention to the distractor movements was manipulated by altering perceptual load through increasing the number of nontarget letter stimuli. If imitation requires attention, then at high perceptual load, imitative compatibility should not affect response times. In contrast, imitative compatibility influenced response times at high perceptual load, demonstrating that distractor movements were processed. However, the compatibility effect was reversed, suggesting that longer response times at high perceptual load tap into an inhibitory stage of distractor movement processing. A follow-up experiment manipulating temporal delay between targets and distractor movements supported this explanation. Further experiments confirmed that nonmovement distractor stimuli in the same configuration produced standard perceptual load effects and that results were not solely due to effector compatibility. These data suggest that imitation can occur without attention. (PsycINFO Database Record PMID- 26569337 TI - Categorical perception for red and brown. AB - Recent studies suggest that the widely accepted evidence in support of categorical perception of color may be a confound of effects due to low-level sensory mechanisms that are unrelated to color categories. To reveal genuine category effects, we investigated the category boundary least prone to spurious effects of low-level mechanisms: the boundary between red and brown. We tested for low-level sensory and high-level cognitive effects of categories on color discrimination, while carefully controlling potential factors of color vision that are not related to color categories. First, we established the red-brown boundary through a naming task and measured just-noticeable differences (JNDs) for colors across the boundary. If low-level sensitivity to color differences was categorical, JNDs should decrease toward the boundary. However, this was not the case. Second, we measured performance in terms of response times and error rates in a speeded discrimination task with color pairs that were equalized in discriminability based on the empirical JNDs. There was a boost of performance (lower response times and error rates) for identifying color differences in equally discriminable color pairs, when the colors crossed the boundary. Given the particularity of the red-brown boundary, these results prove that the observed effects were due to color categories rather than low-level visual mechanisms. These findings support the idea that category effects are due to a shift of attention to the linguistic distinction between categories, rather than being a pure product of perception. These category effects do not depend on the hemispheric lateralization of language. (PsycINFO Database Record PMID- 26569338 TI - Fractional-order information in the visual control of lateral locomotor interception. AB - Previous work on locomotor interception of a target moving in the transverse plane has suggested that interception is achieved by maintaining the target's bearing angle (often inadvertently confused and/or confounded with the target heading angle) at a constant value. However, dynamics-based model simulations testing the veracity of the underlying control strategy of nulling the rate of change in the bearing angle have been restricted to limited conditions of target motion, and only a few alternatives have been considered. Exploring a wide range of target motion characteristics with straight and curving ball trajectories in a virtual reality setting, we examined how soccer goalkeepers moved along the goal line to intercept long-range shots on goal, a situation in which interception is naturally constrained to movement along a single dimension. Analyses of the movement patterns suggested reliance on combinations of optical position and velocity for straight trajectories and optical velocity and acceleration for curving trajectories. As an alternative to combining such standard integer-order derivatives, we demonstrate with a simple dynamical model that nulling a single informational variable of a self-tuned fractional (rather than integer) order efficiently captures the timing and patterning of the observed interception behaviors. This new perspective could fundamentally change the conception of what perceptual systems may actually provide, both in humans and in other animals. (PsycINFO Database Record PMID- 26569340 TI - DDX17 (P72), a Sox2 binding partner, promotes stem-like features conferred by Sox2 in a small cell population in estrogen receptor-positive breast cancer. AB - We have previously demonstrated the existence of two phenotypically distinct cell subsets in estrogen receptor (ER)-positive breast cancer (BC) based on their differential response to a Sox2 reporter (SRR2), with reporter responsive (RR) cells being more tumorigenic and stem-like than reporter unresponsive (RU) cells. To delineate the molecular mechanisms underlying this phenotypic dichotomy, we tested our hypothesis that Sox2, which is a key regulator of the RR phenotype, is under the control of its binding partners. In this study, we focused on DDX17, known to be a transcription co-activator and found to be a Sox2 binding partner by liquid chromatography-mass spectrometry. Using immunoprecipitation, we confirmed the binding between DDX17 and Sox2, although this interaction was largely restricted to RR cells. While DDX17 was found in both the cytoplasm and nuclei in RU cells, it is confined to the nuclei in RR cells. siRNA knockdown of DDX17 in RR cells substantially decreased the Sox2-SRR2 binding and significantly decreased the SRR2 reporter activity without affecting the protein level of Sox2. Using ChIP-PCR, DDX17 knockdown also significantly decreased the binding of Sox2 to genomic SRR2, as well as 3 of its specific gene targets including MUC15, CCND1 and CD133. Correlating with these findings, siRNA knockdown of DDX17 significantly reduced soft agar colony formation and mammosphere formation in RR cells but not RU cells. To conclude, DDX17 is a Sox2-binding protein in ER positive BC. In RR but not RU cells, DDX17 enhances the tumorigenic and stem-like features of Sox2 by promoting its binding to its target genes. PMID- 26569333 TI - Obesity, Oxidative Stress, Adipose Tissue Dysfunction, and the Associated Health Risks: Causes and Therapeutic Strategies. AB - Obesity is gaining acceptance as a serious primary health burden that impairs the quality of life because of its associated complications, including diabetes, cardiovascular diseases, cancer, asthma, sleep disorders, hepatic dysfunction, renal dysfunction, and infertility. It is a complex metabolic disorder with a multifactorial origin. Growing evidence suggests that oxidative stress plays a role as the critical factor linking obesity with its associated complications. Obesity per se can induce systemic oxidative stress through various biochemical mechanisms, such as superoxide generation from NADPH oxidases, oxidative phosphorylation, glyceraldehyde auto-oxidation, protein kinase C activation, and polyol and hexosamine pathways. Other factors that also contribute to oxidative stress in obesity include hyperleptinemia, low antioxidant defense, chronic inflammation, and postprandial reactive oxygen species generation. In addition, recent studies suggest that adipose tissue plays a critical role in regulating the pathophysiological mechanisms of obesity and its related co-morbidities. To establish an adequate platform for the prevention of obesity and its associated health risks, understanding the factors that contribute to the cause of obesity is necessary. The most current list of obesity determinants includes genetic factors, dietary intake, physical activity, environmental and socioeconomic factors, eating disorders, and societal influences. On the basis of the currently identified predominant determinants of obesity, a broad range of strategies have been recommended to reduce the prevalence of obesity, such as regular physical activity, ad libitum food intake limiting to certain micronutrients, increased dietary intake of fruits and vegetables, and meal replacements. This review aims to highlight recent findings regarding the role of oxidative stress in the pathogenesis of obesity and its associated risk factors, the role of dysfunctional adipose tissue in development of these risk factors, and potential strategies to regulate body weight loss/gain for better health benefits. PMID- 26569339 TI - Toll-like receptor-3 mediates HIV-1 transactivation via NFkappaB and JNK pathways and histone acetylation, but prolonged activation suppresses Tat and HIV-1 replication. AB - TLR3 has been implicated in the pathogenesis of several viral infections, including SIV- and HIV-1-induced inflammation and AIDS. However the molecular mechanisms of these TLR3-mediated effects are not known, and it is not known whether HIV interacts with cellular TLR3 to affect disease process. Here we investigate the effects of TLR3 ligands on HIV-1 transactivation using both primary human macrophages and cells containing integrated copies of the HIV-1 promoter. We demonstrate that TLR3 activation induced upregulation of transcription factors such as c-Jun, CCAAT/enhancer-binding protein alpha (CEBPA), signal transducer and activator of transcription (STAT)-1, STAT-2, RELB, and nuclear factor kappa-B1 (NFkappaB1), most of which are known to regulate the HIV promoter activity. We also demonstrate that TLR3 activation increased HIV-1 transactivation via the c-Jun N-terminal kinase (JNK) and NFkappaB pathways. This was associated with epigenetic modifications, including decreased histone deacetylase activity, increased histone acetyl transferase (HAT) activity, and increased acetylation of histones H3 and H4 at lysine residues in the nucleosome 0 and nucleosome-1 of the HIV-1 promoter. However, prolonged TLR3 activation decreased HIV-1 transactivation, decreased HAT activity and Tat transcription, and suppressed viral replication. Overall, data suggests that TLR3 can act as viral sensor to mediate viral transactivation, cellular signaling, innate immune response, and inflammation in HIV-infected humans. Our study provides novel insights into the molecular basis for these TLR3-mediated effects. PMID- 26569341 TI - Echocardiography in PICU: when the heart sees what is invisible to the eye. AB - OBJECTIVE: Echocardiography has become an indispensable bedside diagnostic tool in the realm of pediatric intensive care units (PICU). It has proven to be an influential factor in the formula of clinical decision-making. This study aimed to delineate the impact of echocardiography on the management of critically ill pediatric patients in the PICU at Sultan Qaboos University Hospital, Oman. METHOD: This was a retrospective cohort study conducted in a five-bed PICU. Patients admitted to the PICU from January of 2011 to December of 2012 were reviewed. Those who have undergone bedside echocardiography during their ICU stay were recruited. Electronic patient record was used as data source. RESULTS: Over a-24-month period, 424 patients were admitted in this PICU. One hundred and one clinically indicated transthoracic echocardiograms were performed. 81.8% of these presented new findings (n=82) that significantly impacted the clinical decision of patient management, namely, alteration in drug therapy and procedure, whereas no difference in the management was yielded in the remaining 17.8% of the studied cases. CONCLUSIONS: Echocardiography had a significant impact on the management of PICU patients. Such salutary effect was consequently reflected on the outcome. Pediatric intensivists are encouraged to acquire such bedside skill. PMID- 26569342 TI - A Robust Highly Aligned DNA Nanowire Array-Enabled Lithography for Graphene Nanoribbon Transistors. AB - Because of its excellent charge carrier mobility at the Dirac point, graphene possesses exceptional properties for high-performance devices. Of particular interest is the potential use of graphene nanoribbons or graphene nanomesh for field-effect transistors. Herein, highly aligned DNA nanowire arrays were crafted by flow-assisted self-assembly of a drop of DNA aqueous solution on a flat polymer substrate. Subsequently, they were exploited as "ink" and transfer printed on chemical vapor deposited (CVD)-grown graphene substrate. The oriented DNA nanowires served as the lithographic resist for selective removal of graphene, forming highly aligned graphene nanoribbons. Intriguingly, these graphene nanoribbons can be readily produced over a large area (i.e., millimeter scale) with a high degree of feature-size controllability and a low level of defects, rendering the fabrication of flexible two terminal devices and field effect transistors. PMID- 26569344 TI - Sensing Gram-negative bacteria: a phylogenetic perspective. AB - Gram-negative bacteria represent a major group of pathogens that infect all eukaryotes from plants to mammals. Gram-negative microbe-associated molecular patterns include lipopolysaccharides and peptidoglycans, major immunostimulatory determinants across phyla. Recent advances have furthered our understanding of Gram-negative detection beyond the well-defined pattern recognition receptors such as TLR4. A B-type lectin receptor for LPS and Lysine-motif containing receptors for peptidoglycans were recently added to the plant arsenal. Caspases join the ranks of mammalian cytosolic immune detectors by binding LPS, and make TLR4 redundant for septic shock. Fascinating bacterial evasion mechanisms lure the host into tolerance or promote inter-bacterial competition. Our review aims to cover recent advances on bacterial messages and host decoding systems across phyla, and highlight evolutionarily recurrent strategies. PMID- 26569343 TI - Dissecting vectorial capacity for mosquito-borne viruses. AB - The inter-relationship between mosquitoes and the viruses they transmit is complex. While previously understood barriers to infection and transmission remain valid, additional factors have been uncovered that suggest an 'arms race' between mosquito and virus. These include the mosquito microbiota and interplay between mosquito and viral genetics. Following an infectious blood meal, the mosquito mounts an immune and transcriptional response, leading to altered expression of multiple genes. These complex interactions, specific to vector and virus genotypes, combine with external influences, particularly temperature, to determine vector competence. The mosquito's response to the infecting agent may have consequences in terms of longevity, feeding behavior and/or fecundity. These factors, together with population density and the frequency of host contact determine vectorial capacity. PMID- 26569345 TI - Diagnostic and prognostic potential of circulating cell-free genomic and mitochondrial DNA fragments in clear cell renal cell carcinoma patients. AB - BACKGROUND: There is inconsistent information about the clinical usefulness of circulating cell-free DNA (cfDNA) in plasma from clear cell renal cell cancer (RCC) patients. This is attributed to preanalytical, analytical, and clinical factors that were considered as far as possible in this study. METHODS: cfDNA was extracted from EDTA plasma of healthy people (n=40), non-metastatic (n=145) and metastatic (n=84) RCC patients using the QIAamp Circulating Nucleic Acid Kit. Genomic and mitochondrial cfDNA concentrations were determined using qPCR of different cfDNA fragments (67-306bp). Their diagnostic and prognostic potential was estimated using receiver operating characteristics (ROC) and Cox regression analyses. RESULTS: The 67bp and 180bp genomic cfDNA fragments did not differ between the three study groups while the 306bp fragment was lower in RCC patients than in controls. The mitochondrial cfDNA was higher in metastatic than in non metastatic patients and controls. The cfDNA integrity indices decreased from controls to metastatic patients. Models built by logistic regression and Cox regression resulted in area under the ROC curves >0.75 and concordance indices of >0.800 in predicting recurrence-free survival and overall survival. CONCLUSION: The study suggests that combinations of cfDNA markers have promising diagnostic and prognostic potential in RCC patients and are worth for further validation in future prospective multicenter studies. PMID- 26569346 TI - Predictive value of serum caspase-cleaved cytokeratin-18 concentrations after acute intracerebral hemorrhage. AB - BACKGROUND: Caspase-cleaved Cytokeratin-18 (CCCK-18) is released during apoptosis. Serum CCCK-18 concentrations are associated with prognosis of some critical illness. We investigated the potential relationships between serum CCCK 18 concentrations and disease severity and long-term clinical outcomes after intracerebral hemorrhage. METHODS: Serum CCCK-18 concentrations were determined in a total of 102 patients and 102 controls. Multivariate models were used to predict high concentration of CCCK-18 and 6-month clinical outcomes. The predictive values were evaluated based on areas under receiver operating curve. RESULTS: Compared with controls, serum CCCK-18 concentrations were increased in patients (245.8+/-108.3U/l vs. 23.6+/-18.1U/l, P<0.001). National Institute of Health Stroke Scale scores [odds ratio (OR), 1.164; 95% confidence interval (CI), 1.027-1.320; P=0.003] and hematoma volumes (OR, 1.079; 95% CI, 1.018-1.205; P=0.008) were independent predictors of high concentration of CCCK-18. CCCK-18 was identified as an independent predictor of 6-month mortality (OR, 1.019; 95% CI, 1.010-1.038; P=0.013) and 6-month unfavorable outcome (OR, 1.017; 95% CI, 1.008-1.029; P=0.032) and possessed high predictive values. CONCLUSION: Increased serum CCCK-18 concentrations are associated with disease severity and clinical outcomes, suggesting that CCCK represent a novel prognostic predictive biomarker after intracerebral hemorrhage. PMID- 26569347 TI - Model analysis of effect of canagliflozin (Invokana), a sodium-glucose cotransporter 2 inhibitor, to alter plasma 1,5-anhydroglucitol. AB - BACKGROUND: Renal reabsorption of 1,5-anhydroglucitol (AG) is competitively inhibited by elevated glucose and leads to depleted plasma AG in diabetes. Plasma AG recovery in diabetes normally correlates with improved glycemic control. However, use of sodium-glucose co-transporter 2 (SGLT2) inhibitors (e.g., canagliflozin) to treat diabetes by inhibition of renal glucose reabsorption can negate this correlation, via an indirect effect (increase of renal filtrate glucose concentration) to inhibit AG reabsorption by sodium-glucose co transporter 4 (SGLT4). Conversely, then, AG measurement might be useful as an independent marker for SGLT2 inhibitor activity. METHODS: Using an AG mass balance model, we analyzed literature data on plasma AG before and after initiation of canagliflozin therapy (CT) to quantitatively characterize the effect of CT on AG reabsorption. RESULTS: According to model calculations, modest decreases (<5%) in fractional reabsorption of AG account for the drastic decrease in [AG] observed during CT. Decreases are predicted to be rapid (t1/2<3days) after CT initiation. CONCLUSION: CT negates the usual premise of AG measurement (that [AG] should increase with improved glycemic control). However, according to model calculations, a substantial and likely rapid effect of CT on [AG] means that AG measurement might provide an early marker for CT activity. PMID- 26569348 TI - Monitoring the Progression of Structure-Activity Relationship Information during Lead Optimization. AB - Lead optimization (LO) in medicinal chemistry is largely driven by hypotheses and depends on the ingenuity, experience, and intuition of medicinal chemists, focusing on the key question of which compound should be made next. It is essentially impossible to predict whether an LO project might ultimately be successful, and it is also very difficult to estimate when a sufficient number of compounds has been evaluated to judge the odds of a project. Given the subjective nature of LO decisions and the inherent optimism of project teams, very few attempts have been made to systematically evaluate project progression. Herein, we introduce a computational framework to follow the evolution of structure activity relationship (SAR) information over a time course. The approach is based on the use of SAR matrix data structures as a diagnostic tool and enables graphical analysis of SAR redundancy and project progression. This framework should help the process of making decisions in close-in analogue work. PMID- 26569349 TI - Interactive retinal blood flow analysis of the macular region. AB - The study of retinal hemodynamics plays an important role to understand the onset and progression of diabetic retinopathy. In this work, we developed an interactive retinal analysis tool to quantitatively measure the blood flow velocity (BFV) and blood flow rate (BFR) in the macular region using the Retinal Function Imager (RFI). By employing a high definition stroboscopic fundus camera, the RFI device is able to assess retinal blood flow characteristics in vivo. However, the measurements of BFV using a user-guided vessel segmentation tool may induce significant inter-observer differences and BFR is not provided in the built-in software. In this work, we have developed an interactive tool to assess the retinal BFV and BFR in the macular region. Optical coherence tomography data was registered with the RFI image to locate the fovea accurately. The boundaries of the vessels were delineated on a motion contrast enhanced image and BFV was computed by maximizing the cross-correlation of pixel intensities in a ratio video. Furthermore, we were able to calculate the BFR in absolute values (MUl/s). Experiments were conducted on 122 vessels from 5 healthy and 5 mild non proliferative diabetic retinopathy (NPDR) subjects. The Pearson's correlation of the vessel diameter measurements between our method and manual labeling on 40 vessels was 0.984. The intraclass correlation (ICC) of BFV between our proposed method and built-in software was 0.924 and 0.830 for vessels from healthy and NPDR subjects, respectively. The coefficient of variation between repeated sessions was reduced significantly from 22.5% to 15.9% in our proposed method (p<0.001). PMID- 26569350 TI - Immunostained plaque assay for detection and titration of rabies virus infectivity. AB - The fluorescent antibody test (FAT) is the most commonly used method for detection of the rabies virus (RV). The plaque assay can only be applied to fixed RVs, and cannot be used for street RVs. In this study, plaque formation allowing the determination of both fixed and street RVs was achieved using the immune plaque assay. The immune plaque assay carried out using both fixed and street RVs showed the formation of clear and countable plaques after immunostaining with anti-RV P monoclonal antibody and HRP-conjugated anti-mouse IgG. Plaque size increased with incubation time, and the plaque morphology differed according to viral strain. Fixed RVs had the dot-shaped regular plaque morphology and street RVs had the small irregular-shape plaque morphology. In addition, no significant differences were observed between the growth kinetics of the KGH strain when the virus was titrated using the FAT and the immune plaque assay. It allowed the successful detection and quantification of both street and fixed RVs through the production of clear, countable plaques, making it easy to obtain objective results. The assay is an applicable tool for the detection of RVs in various investigations, including virus neutralizing antibody testing, cell-to-cell spread, and viral drug sensitivity testing. PMID- 26569351 TI - Development of a new vector using Soybean yellow common mosaic virus for gene function study or heterologous protein expression in soybeans. AB - A new vector using Soybean yellow common mosaic virus (SYCMV) was constructed for gene function study or heterologous protein expression in soybeans. The in vitro transcript with a 5' cap analog m7GpppG from an SYCMV full-length infectious vector driven by a T7 promoter infected soybeans (pSYCMVT7-full). The symptoms observed in the soybeans infected with either the sap from SYCMV-infected leaves or pSYCMVT7-full were indistinguishable, suggesting that the vector exhibits equivalent biological activity as the virus itself. To utilize the vector further, a DNA-based vector driven by the Cauliflower mosaic virus (CaMV) 35S promoter was constructed. The complete sequence of the SYCMV genome was inserted into a binary vector flanked by a CaMV 35S promoter at the 5' terminus of the SYCMV genome and a cis-cleaving ribozyme sequence followed by a nopaline synthase terminator at the 3' terminus of the SYCMV genome (pSYCMV-full). The SYCMV derived vector was tested for use as a virus-induced gene silencing (VIGS) vector for the functional analysis of soybean genes. VIGS constructs containing either a fragment of the Phytoene desaturase (PDS) gene (pSYCMV-PDS1) or a fragment of the small subunit of ribulose-1,5-bisphosphate carboxylase/oxygenase (RbcS) gene (pSYCMV-RbcS2) were constructed. Plants infiltrated with each vector using the Agrobacterium-mediated inoculation method exhibited distinct symptoms, such as photo-bleaching in plants infiltrated with pSYCMV-PDS1 and yellow or pale green coloring in plants infiltrated with pSYCMV-RbcS2. In addition, down-regulation of the transcripts of the two target genes was confirmed via northern blot analysis. Particle bombardment and direct plasmid DNA rubbing were also confirmed as alternative inoculation methods. To determine if the SYCMV vector can be used for the expression of heterologous proteins in soybean plants, the vector encoding amino acids 135-160 of VP1 of Foot-and-mouth disease virus (FMDV) serotype O1 Campos (O1C) was constructed (pSYCMV-FMDV). Plants infiltrated with pSYCMV-FMDV were only detected via western blotting using the O1C antibody. Based on these results, we propose that the SYCMV-derived vector can be used for gene function study or expression of useful heterologous proteins in soybeans. PMID- 26569352 TI - Dual nucleotide specificity determinants of an infection aborting anticodon nuclease. AB - The anticodon nuclease (ACNase) PrrC is silenced by a DNA restriction modification (RM) protein and activated by a phage T4-encoded restriction inhibitor. The activation is driven by GTP hydrolysis while dTTP, which accumulates during the infection, stabilizes the active form. We show here, first, that the ABC-ATPase N-domains of PrrC can accommodate the two nucleotides simultaneously. Second, mutating a sequence motif that distinguishes the N-domain of PrrC from typical ABC-ATPases implicates three residues in the specificity for dTTP. Third, failure to bind dTTP or its deprivation hastened the centrifugal sedimentation of PrrC, possibly due to exposed sticky PrrC surfaces. Fourth, dTTP inhibited the GTPase activity of PrrC, probably by preventing GDP from leaving. These observations, correlated with relevant traits of a related ACNase, further suggest that PrrC utilizes GTP at canonical ABC-ATPase sites and binds dTTP to distinct sites exposed upon disruption of the ACNase-silencing interaction with the RM partner. PMID- 26569353 TI - RXRalpha transcriptional inhibitors from the stems of Calophyllum membranaceum. AB - Bioassay-guided fractionation of the 60% ethanol extract of the stems of Calophyllum membranaceum using the RXRalpha transcription activation assay led to the isolation of two new chromanones, calopolyanic acid methyl ester (1) and isopinetoric acid methyl ester (2), two new xanthones, calophylixanthones A-B (3 4), and one new C-glycoside, calophymembranside C (5), along with 13 known compounds. Their structures were elucidated on the basis of extensive spectroscopic data. Compounds 5, 11 and 18 showed transcriptional inhibitory activity of RXRalpha with 50% inhibitory concentration (IC50) values of 29.95 +/- 1.08, 31.06 +/- 9.02, and 25.88 +/- 1.62 MUM, respectively. PMID- 26569354 TI - Extending the RENO model: Clinical and ethical applications. AB - The RENO Model, first published during 2004, described a science-based framework of responsible gambling principles for a range of industry operators, health service providers, community and consumer groups, and governments. These strategic principles serve as a guide for the adoption and implementation of responsible gambling and harm-minimization initiatives. This article extends the RENO Model core principles by describing how to apply these strategies to clinical practice. This discussion examines the central tenets of the model and includes a review of (a) the ethical principles that should guide the development, implementation, and practice of RENO Model responsible gambling activities; (b) a brief consideration of the various perspectives that influence the treatment of gambling-related problems; and (c) a discussion of key applied elements of responsible gambling programs. This article advances the argument that, to maximize positive outcomes and to avoid unintended harms, clinicians should apply science-based principles to rigorously evaluate the efficacy and impact of their clinical practice activities. (PsycINFO Database Record PMID- 26569355 TI - Emergency shelter care utilization in child welfare: Who goes to shelter care? How long do they stay? AB - Emergency shelter care for children entering foster care is widely used as a temporary first placement, despite its contraindications. However, little research has examined predictors of utilization (e.g., entry into care, length of stay in care). A sample of 123 children (ages 6-13) entering foster care was studied to explore the variables associated with an initial placement in shelter care versus kinship care and variables associated with children staying less than 30 days in the shelter versus 30 days or longer. After applying a classification tree analysis (CTA via Optimal Data Analysis), results indicated that variables across the child's ecology--specifically the microsystem, mesosystem, and exosystem--were associated with increased emergency shelter utilization, including older age, entering as a dependency case, more relatives and fictive kin with barriers to involvement in the child's life, and the child welfare agency serving the child. These results suggest that although emergency shelter care utilization may be determined by a complex interaction of variables across the child's ecology, policy and programmatic attention to some of these risk factors might be effective in limiting utilization so that children can enter care with a more long-term, family-based placement. PMID- 26569356 TI - Spin-orbit-induced gap modification in buckled honeycomb XBi and XBi3 (X = B, Al, Ga, and In) sheets. AB - The band structure and stability of XBi and XBi3 (X = B, Al, Ga, and In) single sheets are predicted using first-principles calculations. It is demonstrated that the band gap values of these new classes of two-dimensional (2D) materials depend on both the spin-orbit coupling (SOC) and type of group-III elements in these hetero-sheets. Thus, topological properties can be achieved, allowing for viable applications based on coherent spin transport at room temperature. The spin-orbit effects are proved to be essential to explain the tunability by group-III atoms. A clear effect of including SOC in the calculations is lifting the spin degeneracy of the bands at the Gamma point of the Brillouin zone. The nature of the band gaps, direct or indirect, is also tuned by SOC, and by the appropriate X element involved. It is observed that, in the case of XBi single sheets, band inversions naturally occur for GaBi and InBi, which exhibit band gap values around 172 meV. This indicates that these 2D materials are potential candidates for topological insulators. On the contrary, a similar type of band inversion, as obtained for the XBi, was not observed in the XBi3 band structure. In general, the calculations, taking into account SOC, reveal that some of these buckled sheets exhibit sizable gaps, making them suitable for applications in room temperature spintronic devices. PMID- 26569357 TI - Impact of statin non-adherence on in-stent restenosis following bare-metal stent implantation. PMID- 26569358 TI - Exercise promotes cardiac-specific fibroblast growth factor 21 expression. PMID- 26569359 TI - Placental growth factor 2--A potential therapeutic strategy for chronic myocardial ischemia. AB - OBJECTIVES: We investigated whether sustained infusion of recombinant human placental growth factor-2 (rhPlGF-2) improves myocardial perfusion and left ventricular (LV) function in a porcine model of ischemic cardiomyopathy (ICM). METHODS: We induced myocardial ischemia using a flow-limiting stent in the LAD. Four weeks later, we randomized pigs with confirmed myocardial dysfunction to blinded rhPlGF-2 administration (PlGF2, 15 MUg/kg/day, 14 days) or PBS (CON). At 8 weeks, we measured hemodynamics, contractile function and regional perfusion at rest and during stress using MRI and microspheres. We evaluated neovascularization post mortem. RESULTS: RhPlGF-2 administration increased PlGF serum levels more than 63-fold (83 3 +/- 361 versus 11 +/- 5 pg/ml CON, P<0.05) without adverse effects. After 4weeks, rhPlGF-2 significantly enhanced perfusion in the ischemic region at rest (0.83 +/- 0.32 versus 0.58 +/- 0.21 ml/min/g CON, P<0.05) and during hyperemia (1.50 +/- 0.50 versus 1.02 +/- 0.46 ml/min/g CON, P<0.05). Consequently, regional contractile function in rhPlGF-2-treated pigs improved at rest (37 +/- 15% versus 23 +/- 9% CON, P<0.05) and during high dose dobutamine stress (53 +/- 31% versus 27 +/- 16% CON, P<0.05). Enhanced perfusion translated into a greater improvement in LV ejection fraction and in preload recruitable stroke work in rhPlGF-2-treated animals than in CON (52 +/- 11 versus 41 +/- 9%, and 76 +/- 24 versus 41 +/- 21 mmHg, respectively, P<0.05 for both), which was associated with significantly greater vascular density in the ischemic region. CONCLUSIONS: In chronic ICM, systemic rhPlGF-2 administration significantly enhances regional myocardial perfusion, contractile function at rest and during stress, and induces a prominent recovery of global cardiac function. PlGF-2 protein infusion is safe and may represent a promising therapy in chronic ICM. PMID- 26569360 TI - Heart block after herpes zoster reactivation. PMID- 26569361 TI - Paclitaxel-coated balloon exerts late vessel healing and enlargement: A documented phenomenon with optical coherence tomography analysis. PMID- 26569362 TI - Light-to-moderate drinking and incident heart failure--the Norwegian HUNT study. AB - BACKGROUND: We analyzed the association between light-to-moderate alcohol intake and the risk of heart failure (HF). METHODS AND RESULTS: We studied 60,665 individuals free of HF who provided information on alcohol consumption in a population-based cohort study conducted in 1995-97 in Norway. Sociodemographic factors, cardiovascular risk factors and common chronic disorders were assessed by questionnaires and/or by a clinical examination. The cohort was followed for a first HF event for an average of 11.2 +/- 3.0 years. Mean alcohol consumption was 2.95 +/- 4.5 g/day; 1588 HF cases occurred during follow-up. The quantity of alcohol consumption was inversely associated with incident HF in this low drinking population. The risk was lowest for consumption over three but less than six drinks/week; the multivariate hazard ratio when comparing this category to non-drinkers was 0.67 (95% CI: 0.50-0.92). Among problem drinkers based on CAGE questionnaires, total consumption showed no favorable association with HF, even when overall consumption was otherwise moderate. Excluding former drinkers and controlling for common chronic diseases had minimal effect on these associations. Frequent alcohol consumption, i.e. more than five times/month, was associated with the lowest HF risk; the adjusted hazard ratio comparing this group to alcohol intake less than once/month was 0.83 (95% CI: 0.68-1.03). We found no evidence for a differential effect according to beverage type, nor that the competing risks of death from other causes modified the association. CONCLUSIONS: Frequent light-to-moderate alcohol consumption without problem drinking was associated with a lower HF risk in this population characterized by a low average alcohol intake. PMID- 26569363 TI - Prognostic significance of exercise capacity and resting heart rate: Comparison between atrial fibrillation and sinus rhythm. PMID- 26569364 TI - MicroRNAs relate to early worsening of renal function in patients with acute heart failure. AB - BACKGROUND: Deregulation of microRNAs (miRNAs) may be involved in the pathogenesis of heart failure (HF) and renal disease. Our aim is to describe miRNA levels related to early worsening renal function in acute HF patients. METHOD AND RESULTS: We studied the association between 12 circulating miRNAs and Worsening Renal Function (WRF; defined as an increase in the serum creatinine level of 0.3mg per deciliter or more from admission to day 3), absolute change in creatinine and Neutrophil Gelatinase Associated Lipocalin (NGAL) from admission to day 3 in 98 patients hospitalized for acute HF. At baseline, circulating levels of all miRNAs were lower in patients with WRF, with statistically significant decreased levels of miR-199a-3p, miR-423-3p, and miR-let-7i-5p (p value<0.05). The increase in creatinine during the first 3 days of hospitalization was significantly associated with lower levels of miR-199a-3p, miR-27a-3p, miR-652-3p, miR-423-5p, and miR-let-7i-5p, while the increase in NGAL was significantly associated with lower levels of miR-18a-5p, miR-106a-5p, miR 223-3p, miR-199a-3p and miR-423-3p. MiR-199a-3p was the strongest predictor of WRF, with an Odds Ratio of 1.48 (1.061-2.065; p-value=0.021) and a C-index of 0.701. CONCLUSIONS: Our results show that the levels of circulating miRNAs at hospital admission for acute HF were consistently lower in patients who developed worsening of renal function. MiR-199a-3p was the best predictor of WRF in these patients. PMID- 26569365 TI - In systemic sclerosis prolonged QTc interval is associated with reduced exercise tolerance. PMID- 26569366 TI - Hypertrophic cardiomyopathy: The heart of the matter by looking into the matter of the heart. PMID- 26569367 TI - Diabetes, statins and FH. PMID- 26569369 TI - Appropriateness of cardiac stress test use among primary care physicians and cardiologists in the United States. PMID- 26569368 TI - Management of acute massive pulmonary embolism: Is surgical embolectomy inferior to thrombolysis? AB - BACKGROUND: Although current guidelines for pulmonary embolism (PE) treatment recommend surgical embolectomy when thrombolysis is contraindicated or has failed, their clinical outcomes rarely have been compared directly. METHODS: After excluding patients aged under 18 years and those with submassive or non massive PE, 45 consecutive patients (median age, 68 years; 62% female; 31% experienced cardiac arrest before PE treatment onset; 33% had cancer diagnosis history; and 29% received extracorporeal membrane oxygenation [ECMO]) who underwent only thrombolysis (TL group; n=19) or surgical embolectomy (SE group; n=26, including 4 who had failed thrombolysis) for acute massive PE from 2000 to 2013 at Samsung Medical Center were enrolled to assess cardiac mortality as primary outcome. RESULTS: Median follow-up duration was 17.2 months. In the SE group, significantly higher proportions of patients had recent surgery and ECMO. Overall 30-day all-cause mortality rate was 24% (n=11), without significant difference between the SE (15%) and TL (37%) groups (P=0.098); however, cardiac mortality rate was significantly higher in the TL than SE group (Log rank P=0.023). TL was an independent multivariate predictor of cardiac death (P=0.03). CONCLUSION: In this small retrospective single center experience, surgical embolectomy is associated with lower cardiac mortality risk than thrombolysis, which might render it first-line treatment option for acute massive PE for patients without life-limiting comorbidities. PMID- 26569370 TI - NanoLuc Complementation Reporter Optimized for Accurate Measurement of Protein Interactions in Cells. AB - Protein-fragment complementation assays (PCAs) are widely used for investigating protein interactions. However, the fragments used are structurally compromised and have not been optimized nor thoroughly characterized for accurately assessing these interactions. We took advantage of the small size and bright luminescence of NanoLuc to engineer a new complementation reporter (NanoBiT). By design, the NanoBiT subunits (i.e., 1.3 kDa peptide, 18 kDa polypeptide) weakly associate so that their assembly into a luminescent complex is dictated by the interaction characteristics of the target proteins onto which they are appended. To ascertain their general suitability for measuring interaction affinities and kinetics, we determined that their intrinsic affinity (KD = 190 MUM) and association constants (kon = 500 M(-1) s(-1), koff = 0.2 s(-1)) are outside of the ranges typical for protein interactions. The accuracy of NanoBiT was verified under defined biochemical conditions using the previously characterized interaction between SME 1 beta-lactamase and a set of inhibitor binding proteins. In cells, NanoBiT fusions to FRB/FKBP produced luminescence consistent with the linear characteristics of NanoLuc. Response dynamics, evaluated using both protein kinase A and beta-arrestin-2, were rapid, reversible, and robust to temperature (21-37 degrees C). Finally, NanoBiT provided a means to measure pharmacology of kinase inhibitors known to induce the interaction between BRAF and CRAF. Our results demonstrate that the intrinsic properties of NanoBiT allow accurate representation of protein interactions and that the reporter responds reliably and dynamically in cells. PMID- 26569371 TI - Molecular Basis of Hydroperoxide Specificity in Peroxiredoxins: The Case of AhpE from Mycobacterium tuberculosis. AB - Peroxiredoxins (Prxs) constitute a ubiquitous family of Cys-dependent peroxidases that play essential roles in reducing hydrogen peroxide, peroxynitrite, and organic hydroperoxides in almost all organisms. Members of the Prx subfamilies show differential oxidizing substrate specificities that await explanations at a molecular level. Among them, alkyl hydroperoxide reductases E (AhpE) is a novel subfamily comprising Mycobacterium tuberculosis AhpE and AhpE-like proteins expressed in some bacteria and archaea. We previously reported that MtAhpE reacts ~10(4) times faster with an arachidonic acid derived hydroperoxide than with hydrogen peroxide, and suggested that this surprisingly high reactivity was related to the presence of a hydrophobic groove at the dimer interface evidenced in the crystallography structure of the enzyme. In this contribution we experimentally confirmed the existence of an exposed hydrophobic patch in MtAhpE. We found that fatty acid hydroperoxide reduction by the enzyme showed positive activation entropy that importantly contributed to catalysis. Computational dynamics indicated that interactions of fatty acid-derived hydroperoxides with the enzyme properly accommodated them inside the active site and modifies enzyme's dynamics. The computed reaction free energy profile obtained via QM/MM simulations is consistent with a greater reactivity in comparison with hydrogen peroxide. This study represents new insights on the understanding of the molecular basis that determines oxidizing substrate selectivity in the peroxiredoxin family, which has not been investigated at an atomic level so far. PMID- 26569372 TI - PdCu Nanoalloy Electrocatalysts in Oxygen Reduction Reaction: Role of Composition and Phase State in Catalytic Synergy. AB - The catalytic synergy of nanoalloy catalysts depends on the nanoscale size, composition, phase state, and surface properties. This report describes findings of an investigation of their roles in the enhancement of electrocatalytic activity of PdCu alloy nanoparticle catalysts for oxygen reduction reaction (ORR). Pd(n)Cu(100-n) nanoalloys with controlled composition and subtle differences in size and phase state were synthesized by two different wet chemical methods. Detailed electrochemical characterization was performed to determine the surface properties and the catalytic activities. The atomic-scale structures of these catalysts were also characterized by high-energy synchrotron X-ray diffraction coupled with atomic pair distribution function analysis. The electrocatalytic activity and stability were shown to depend on the size, composition, and phase structure. With Pd(n)Cu(100-n) catalysts from both methods, a maximum ORR activity was revealed at Pd/Cu ratio close to 50:50. Structurally, Pd50Cu50 nanoalloys feature a mixed phase consisting of chemically ordered (body-centered cubic type) and disordered (face-centered cubic type) domains. The phase-segregated structure is shown to change to a single phase upon electrochemical potential cycling in ORR condition. While the surface Cu dissolution occurred in PdCu catalysts from the two different synthesis methods, the PdCu with a single-phase character is found to exhibit a tendency of a much greater dissolution than that with the phase segregation. Analysis of the results, along theoretical modeling based on density functional theory calculation, has provided new insights for the correlation between the electrocatalytic activity and the catalyst structures. PMID- 26569373 TI - Insights into the Spin-State Transitions in [Fe(tpy)2]2+: Importance of the Terpyridine Rocking Motion. AB - Iron(II) polypyridine complexes have the potential for numerous applications on a global scale, such as sensitizers, sensors, and molecular memory. The excited state properties of these systems, particularly the intersystem crossing (ISC) rates, are sensitive to the choice of ligands and can be significantly altered depending on the coordination environment. We employ density functional theory and Smolyak's sparse grid interpolation algorithm to construct potential energy surfaces (PESs) for the photophysically relevant states ((1)A, (3,5)MC, and (1,3)MLCT) of the [Fe(tpy)2](2+) (tpy = 2,2':6',2"-terpyridine) complex, with the goal of obtaining a deeper understanding of the ground- and excited-state electronic structure of this system. The three dimensions that define our adiabatic PESs consist of equatorial and axial metal-ligand bond length distortions and a terpyridine ligand "rocking angle", which has not previously been investigated. The intersection crossing seams and minimum energy crossing points (MECPs) between surfaces are also determined. Overall, we find that the PESs of all electronic excited states investigated are characterized by low energy valleys along the tpy rocking-angle coordinate. This results in the presence of large low-energy areas around the MECPs on the intersection seams of different electronic states and indicates that inclusion of this third coordinate is crucial for an adequate description of the PESs and surface crossing seams of the [Fe(tpy)2](2+) complex. Finally, we suggest that tuning the energetics of the tpy ligand rocking motion could provide a way to control the ISC process in this complex. PMID- 26569374 TI - Metal-Organic Frameworks (MOFs) as Sandwich Coating Cushion for Silicon Anode in Lithium Ion Batteries. AB - A novel metal-organic framework (MOF) sandwich coating method (denoted as MOF-SC) is developed for hybrid Li ion battery electrode preparation, in which the MOF films are casted on the surface of a silicon layer and sandwiched between the active silicon and the separator. The obtained electrodes show improved cycling performance. The areal capacity of the cheap and readily available microsized Si treated with MOF-SC can reach 1700 MUAh cm(-2) at 265 MUA cm(-2) and maintain at 850 MUAh cm(-2) after 50 cycles. Beyond the above, the commercial nanosized Si treated by MOF-SC also shows greatly enhanced areal capacity and outstanding cycle stability, 600 MUAh cm(-2) for 100 cycles without any apparent fading. By virtue of the novel structure prepared by the MOFs, this new MOF-SC structure serves as an efficient protection cushion for the drastic volume change of silicon during charge/discharge cycles. Furthermore, this MOF layer, with large pore volume and high surface area, can adsorb electrolyte and allow faster diffusion of Li(+) as evidenced by decreased impedance and improved rate performance. PMID- 26569375 TI - Controlling in Vitro Insulin Amyloidosis with Stable Peptide Conjugates: A Combined Experimental and Computational Study. AB - Insulin aggregation, to afford amyloidogenic polypeptide fibrils, is an energetically driven, well-studied phenomenon, which presents interesting biological ramifications. These aggregates are also known to form around insulin injection sites and in diabetic patients suffering from Parkinson's disease. Such occurrences force considerable reduction in hormone activity and are often responsible for necrotic deposits in diabetic patients. Changes in physicochemical environment, such as pH, temperature, ionic strength, and mechanical agitation, affect insulin fibrillation, which also presents intrigue from the structural viewpoint. Several reports have tried to unravel underlying mechanisms concerning the aggregation process taking into account a three aromatic amino acid patch Phe(B24)-Phe(B25)-Tyr(B26) located in the C-terminal part of the B chain, identified as a key site for human insulin-receptor interaction. The present study describes design and inhibitory effects of novel peptide conjugates toward fibrillation of insulin as investigated by thioflavin T assay, circular dichroism, and AFM. Possible interaction of insulin with peptide based fibrillation inhibitors reveals an important role of hydrophobic interactions in the inhibition process. Molecular dynamics simulation studies demonstrate that inhibitor D4 interacts with insulin residues from the helix and the C-terminal extended segment of chain B. These studies present a novel approach for the discovery of stable, peptide-based ligands as novel antiamyloidogenic agents for insulin aggregation. PMID- 26569376 TI - A social network typology and sexual risk-taking among men who have sex with men in Cape Town and Port Elizabeth, South Africa. AB - Despite the high prevalence of HIV among men who have sex with men in South Africa, very little is known about their lived realities, including their social and sexual networks. Given the influence of social network structure on sexual risk behaviours, a better understanding of the social contexts of men who have sex with men is essential for informing the design of HIV programming and messaging. This study explored social network connectivity, an understudied network attribute, examining self-reported connectivity between friends, family and sex partners. Data were collected in Cape Town and Port Elizabeth, South Africa, from 78 men who have sex with men who participated in in-depth interviews that included a social network mapping component. Five social network types emerged from the content analysis of these social network maps based on the level of connectivity between family, friends and sex partners, and ranged from disconnected to densely connected networks. The ways in which participants reported sexual risk-taking differed across the five network types, revealing diversity in social network profiles. HIV programming and messaging for this population can greatly benefit from recognising the diversity in lived realities and social connections between men who have sex with men. PMID- 26569378 TI - Banning Tobacco Sales at the Retail Pharmacy: Natural Evolution of Drug Store As Responsible Health Provider Or Effective Marketing Strategy? AB - CVS Health has taken a strategic marketing move by banning tobacco sales. They risk losing customers who buy medications and cigarettes at their drugstores. They estimate they will lose 2 billion dollars by banning cigarette sales. CVS Health believes they will benefit from being regarded as health care partner by insurers and banning cigarette sales is an important step in being recognized as such. The Affordable Care Act expanded access to pharmacy-based medical clinics, increased affordability of medications, and expanded the clinical role of pharmacists. CVS Health is positioning itself to take advantage of these changes. PMID- 26569377 TI - Treatment of Obstructive Sleep Apnea. Prospects for Personalized Combined Modality Therapy. AB - Obstructive sleep apnea (OSA) is a common sleep disorder with serious associated morbidities. Although several treatment options are currently available, variable efficacy and adherence result in many patients either not being treated or receiving inadequate treatment long term. Personalized treatment based on relevant patient characteristics may improve adherence to treatment and long-term clinical outcomes. Four key traits of upper airway anatomy and neuromuscular control interact to varying degrees within individuals to cause OSA. These are: (1) the pharyngeal critical closing pressure, (2) the stability of ventilator chemoreflex feedback control (loop gain), (3) the negative intraesophageal pressure that triggers arousal (arousal threshold), and (4) the level of stimulus required to activated upper airway dilator muscles (upper airway recruitment threshold). Simplified diagnostic methods are being developed to assess these pathophysiological traits, potentially allowing prediction of which treatment would best suit each patient. In contrast to current practice of using various treatment modes alone, model predictions and pilot clinical trials show improved outcomes by combining several treatments targeted to each patient's pathophysiology profile. These developments could theoretically improve efficacy and adherence to treatment and in turn reduce the social and economic health burden of OSA and the associated life-threatening morbidities. This article reviews OSA pathophysiology and identifies currently available and investigational treatments that may be combined in the future to optimize therapy based on individual profiles of key patient pathophysiological traits. PMID- 26569379 TI - The ABCs of the US Broad Spectrum Antimicrobials Program: Antibiotics, Biosecurity, and Congress. AB - Antibiotic resistance has been increasing at an alarming rate in the United States and globally for decades, but the problem has only recently gained broad attention at the highest levels of the US government. More and more patients are dying of infections that do not respond to antibiotics that are currently available. Meanwhile, the antibacterial product pipeline remains fragile in part because of a lack of commercial interest from pharmaceutical companies. The Biomedical Advanced Research and Development Authority (BARDA) Broad Spectrum Antimicrobials (BSA) program leads the US government's effort to bridge this gap by advancing new antibacterials through late stages of clinical development. Other commentators have described in detail BARDA's structure, process, and role in antibacterial development. This commentary offers a public policy perspective on the emerging politics of antibiotic resistance in the context of US biosecurity politics and medical countermeasure (MCM) development. It identifies promising developments and difficult challenges that together will ultimately determine whether BARDA can become a global leader for antibiotic development. PMID- 26569380 TI - Microbiota depletion promotes browning of white adipose tissue and reduces obesity. AB - Brown adipose tissue (BAT) promotes a lean and healthy phenotype and improves insulin sensitivity. In response to cold or exercise, brown fat cells also emerge in the white adipose tissue (WAT; also known as beige cells), a process known as browning. Here we show that the development of functional beige fat in the inguinal subcutaneous adipose tissue (ingSAT) and perigonadal visceral adipose tissue (pgVAT) is promoted by the depletion of microbiota either by means of antibiotic treatment or in germ-free mice. This leads to improved glucose tolerance and insulin sensitivity and decreased white fat and adipocyte size in lean mice, obese leptin-deficient (ob/ob) mice and high-fat diet (HFD)-fed mice. Such metabolic improvements are mediated by eosinophil infiltration, enhanced type 2 cytokine signaling and M2 macrophage polarization in the subcutaneous white fat depots of microbiota-depleted animals. The metabolic phenotype and the browning of the subcutaneous fat are impaired by the suppression of type 2 cytokine signaling, and they are reversed by recolonization of the antibiotic treated or germ-free mice with microbes. These results provide insight into the microbiota-fat signaling axis and beige-fat development in health and metabolic disease. PMID- 26569381 TI - Dystrophin expression in muscle stem cells regulates their polarity and asymmetric division. AB - Dystrophin is expressed in differentiated myofibers, in which it is required for sarcolemmal integrity, and loss-of-function mutations in the gene that encodes it result in Duchenne muscular dystrophy (DMD), a disease characterized by progressive and severe skeletal muscle degeneration. Here we found that dystrophin is also highly expressed in activated muscle stem cells (also known as satellite cells), in which it associates with the serine-threonine kinase Mark2 (also known as Par1b), an important regulator of cell polarity. In the absence of dystrophin, expression of Mark2 protein is downregulated, resulting in the inability to localize the cell polarity regulator Pard3 to the opposite side of the cell. Consequently, the number of asymmetric divisions is strikingly reduced in dystrophin-deficient satellite cells, which also display a loss of polarity, abnormal division patterns (including centrosome amplification), impaired mitotic spindle orientation and prolonged cell divisions. Altogether, these intrinsic defects strongly reduce the generation of myogenic progenitors that are needed for proper muscle regeneration. Therefore, we conclude that dystrophin has an essential role in the regulation of satellite cell polarity and asymmetric division. Our findings indicate that muscle wasting in DMD not only is caused by myofiber fragility, but also is exacerbated by impaired regeneration owing to intrinsic satellite cell dysfunction. PMID- 26569383 TI - Letter in response to: External validation of the paracetamol-aminotransferase multiplication product to predict hepatotoxicity from paracetamol overdose. PMID- 26569384 TI - The role of performance validity tests in the assessment of cognitive functioning after military concussion: A replication and extension. AB - The current investigation is a replication and extension of a previously published study by Cooper, Vanderploeg, Armistead-Jehle, Lewis, and Bowles (2014) demonstrating that performance validity test scores accounted for more variance in cognitive testing among service members with a history of concussion than did demographic variables, etiology of and time since injury, and symptom severity. The present study included a sample of 142 active-duty service members evaluated following a suspected or confirmed history of mild traumatic brain injury. Participants completed a battery of neuropsychological measures that included scales of performance and symptom validity (specifically the Medical Symptom Validity Test, Nonverbal Medical Symptom Validity Test, and Personality Assessment Inventory). Among the factors considered in the current study, performance validity test results accounted for the most variance in cognitive test scores, above demographic, concussion history, symptom validity, and psychological distress variables. Performance validity test results were modestly related to symptom validity as measured by the Personality Assessment Inventory Negative Impression Management scale. In sum, the current results replicated the original Cooper et al. study and highlight the importance of including performance validity tests as part of neurocognitive evaluation, even in clinical contexts, within this population. PMID- 26569382 TI - Targeting megakaryocytic-induced fibrosis in myeloproliferative neoplasms by AURKA inhibition. AB - Primary myelofibrosis (PMF) is characterized by bone marrow fibrosis, myeloproliferation, extramedullary hematopoiesis, splenomegaly and leukemic progression. Moreover, the bone marrow and spleens of individuals with PMF contain large numbers of atypical megakaryocytes that are postulated to contribute to fibrosis through the release of cytokines, including transforming growth factor (TGF)-beta. Although the Janus kinase inhibitor ruxolitinib provides symptomatic relief, it does not reduce the mutant allele burden or substantially reverse fibrosis. Here we show through pharmacologic and genetic studies that aurora kinase A (AURKA) represents a new therapeutic target in PMF. Treatment with MLN8237, a selective AURKA inhibitor, promoted polyploidization and differentiation of megakaryocytes with PMF-associated mutations and had potent antifibrotic and antitumor activity in vivo in mouse models of PMF. Moreover, heterozygous deletion of Aurka was sufficient to ameliorate fibrosis and other PMF features in vivo. Our data suggest that megakaryocytes drive fibrosis in PMF and that targeting them with AURKA inhibitors has the potential to provide therapeutic benefit. PMID- 26569385 TI - Functional characteristics of the growth factor receptor family and some ligands in the oropharyngeal cavity of the Chukar partridge (Alectoris chukar). AB - 1. The aim of the present study is to describe, immunohistochemically, the expression and cell type localisation of growth factor receptors and some of their ligands in the oropharyngeal organs of the Chukar partridge. 2. The tissue samples from 10 healthy adult partridges were dissected under ether anaesthesia and then embedded in paraffin following routine histological procedures. The immunoreaction for receptors and ligands of the epidermal growth factor receptor (EGFR)/ligand system was localised in the cell membrane, nucleus and cytoplasm of the luminal and glandular epithelial cells, stromal and striated muscle cells, and vascular endothelial and smooth muscle cells. 3. Variations were observed in the avian oropharyngeal organs. The immunostaining for the erbB1/HER1 (human epidermal growth factor receptor 1) and the EGF (epidermal growth factor) and AREG (Amphiregulin) ligands in the luminal epithelial cells was higher than in the glandular epithelial, stromal and striated muscle cells. However, the immunostaining for erbB3/HER3 (human epidermal growth factor receptor 3) and erbB4/HER4 (human epidermal growth factor receptor 4) were similar in the luminal epithelium, stromal and striated muscle cells. 4. Growth factor receptors and some of their ligands were localised in different cell types in the oropharyngeal organs. We suggest that erbB/HERs (human epidermal growth factor receptors) and their ligands play an important role in proliferation, differentiation, growth, survival and migration of the cells. PMID- 26569386 TI - Addressing the Needs of Children in a Time of Health Reform via Medicaid, CHIP, or Subsidized Markets. PMID- 26569388 TI - Young Women's Perceptions of the Relationship in Fifty Shades of Grey. AB - OBJECTIVE: Millions of women are interacting with Fifty Shades of Grey-a best selling novel and film. Yet, to date, no social science study has been undertaken to examine women's perceptions of the Fifty Shades relationship narrative in its film adaptation-what they deem appealing, what they deem unappealing, and what they would welcome or resist in their own relationship. In the present study, we used focus groups to examine women's perceptions of the relationship patterns in the Fifty Shades of Grey film. METHODS: Focus groups were conducted with 35 young adult women (randomly sampled from the registrar's office of a large Midwestern university) immediately after watching the Fifty Shades film with the study team at a local theater within two days of the film's release. Seven semistructured questions concentrating on reactions to the relationship patterns between Christian Grey and Anastasia Steele depicted in the Fifty Shades film were asked, including general reactions, appealing and unappealing characteristics, romantic and dangerous elements, and aspects that participants would tolerate (or not tolerate) in their own relationships. RESULTS: While participants assessed parts of the relationship between Christian and Anastasia as exciting and romantic, they consistently indicated an unappealing lack of health in the relationship. Participants expressed grave concerns over Christian's stalking, controlling, manipulative, and emotionally abusive behavior, anger in sexual interactions, and neglect of Anastasia's needs. At the same time, they sympathized with and rationalized Christian's behaviors as a function of his personality, needs, and abilities. A small contingent implicated Anastasia in the unhealthy relationship process, whereas a broader majority of participants highlighted the challenges with trying to "speak up" in an unhealthy relationship like Christian and Anastasia's. When asked where participants would draw the line in their own relationship, participants indicated they would welcome the adventure and gifts, but would not tolerate being controlled and stalked, having their needs neglected, and having a partner who expressed anger in sexual interactions. CONCLUSIONS: Our findings point to the value of using popular culture, including the Fifty Shades narrative, to actively engage young women in productive conversation about characteristics of relationship health and un-health. Similar approaches could be used to engage young women in safe, relatable conversations about healthy and unhealthy relationships, including the warning signs of abuse. As a broader impact, our study contributes to an understanding of how young women interact with and make sense of relationships depicted in popular culture. PMID- 26569387 TI - Association Between Olfactory Dysfunction and Amnestic Mild Cognitive Impairment and Alzheimer Disease Dementia. AB - IMPORTANCE: To increase the opportunity to delay or prevent mild cognitive impairment (MCI) or Alzheimer disease (AD) dementia, markers of early detection are essential. Olfactory impairment may be an important clinical marker and predictor of these conditions and may help identify persons at increased risk. OBJECTIVE: To examine associations of impaired olfaction with incident MCI subtypes and progression from MCI subtypes to AD dementia. DESIGN, SETTING, AND PARTICIPANTS: Participants enrolled in the population-based, prospective Mayo Clinic Study of Aging between 2004 and 2010 were clinically evaluated at baseline and every 15 months through 2014. Participants (N = 1630) were classified as having normal cognition, MCI (amnestic MCI [aMCI] and nonamnestic MCI [naMCI]), and dementia. We administered the Brief Smell Identification Test (B-SIT) to assess olfactory function. MAIN OUTCOMES AND MEASURES: Mild cognitive impairment, AD dementia, and longitudinal change in cognitive performance measures. RESULTS: Of the 1630 participants who were cognitively normal at the time of the smell test, 33 died before follow-up and 167 were lost to follow-up. Among the 1430 cognitively normal participants included, the mean (SD) age was 79.5 (5.3) years, 49.4% were men, the mean duration of education was 14.3 years, and 25.4% were APOE epsilon4 carriers. Over a mean 3.5 years of follow-up, there were 250 incident cases of MCI among 1430 cognitively normal participants. We observed an association between decreasing olfactory identification, as measured by a decrease in the number of correct responses in B-SIT score, and an increased risk of aMCI. Compared with the upper B-SIT quartile (quartile [Q] 4, best scores), hazard ratios (HRs) (95% CI) were 1.12 (0.65-1.92) for Q3 (P = .68); 1.95 (1.25 3.03) for Q2 (P = .003); and 2.18 (1.36-3.51) for Q1 (P = .001) (worst scores; P for trend <.001) after adjustment for sex and education, with age as the time scale. There was no association with naMCI. There were 64 incident dementia cases among 221 prevalent MCI cases. The B-SIT score also predicted progression from aMCI to AD dementia, with a significant dose-response with worsening B-SIT quartiles. Compared with Q4, HR (95% CI) estimates were 3.02 (1.06-8.57) for Q3 (P = .04); 3.63 (1.19-11.10) for Q2 (P = .02); and 5.20 (1.90-14.20) for Q1 (P = .001). After adjusting for key predictors of MCI risk, B-SIT (as a continuous measure) remained a significant predictor of MCI (HR, 1.10 [95% CI, 1.04-1.16]; P < .001) and improved the model concordance. CONCLUSIONS AND RELEVANCE: Olfactory impairment is associated with incident aMCI and progression from aMCI to AD dementia. These findings are consistent with previous studies that have reported associations of olfactory impairment with cognitive impairment in late life and suggest that olfactory tests have potential utility for screening for MCI and MCI that is likely to progress. PMID- 26569389 TI - Adhesive Small Bowel Obstruction: Predictive Factors of Lack of Response in Conservative Management with Gastrografin. AB - BACKGROUND: Gastrografin represents a useful tool in the diagnosis and management of adhesive small bowel obstruction (ASBO). The aim of this study is to identify variables with negative influence in nonoperative management with gastrografin. METHODS: From August 2008 to March 2013, 223 consecutive patients with 235 episodes of ASBO were included and received gastrografin. A protocol for prospective data collection was developed. In order to explore factors related to the failure of nonoperative treatment, univariate and multivariate analysis were performed. RESULTS: One hundred and ninety eight episodes responded to nonoperative treatment (84.2% of success) and 33 patients (15.8%) required surgical intervention. Only 3 patients of the gastrografin cohort with contrast in colon, required surgery. Predictive factors of failure of nonoperative management with gastrografin were patients aged above 65 (p = 0.01; OR 1.791, 95% CI 1.41-2.19), with a history of 2 or more previous laparotomies (p = 0.03; OR 2.91, 95% CI 2.19-3.71), and who had undergone previous abdominal surgery due to ASBO (p = 0.002; OR 1.381, 95% CI 1.10-1.79). CONCLUSION: Patient age, the number of previous laparotomies, and the fact that previous abdominal surgery was conducted due to ASBO are indicative of unsuccessful management with gastrografin. PMID- 26569390 TI - Autologous Internal Limiting Membrane Fragment Transplantation for Large, Chronic, and Refractory Macular Holes. AB - OBJECTIVE: To evaluate a technique of autologous internal limiting membrane (ILM) fragment transplantation for the treatment of large, chronic, and/or refractory macular holes (MH). DESIGN: This was a 6-month prospective interventional case series. METHOD: Ten eyes of 10 patients with MH underwent pars plana vitretomy (PPV) and ILM peeling followed by transplantation of an autologous ILM fragment to the MH. Six patients had primary MH with an internal diameter greater than 500 um and a duration of more than 18 months, including 1 patient with nonproliferative diabetic retinopathy previously treated with panretinal photocoagulation. Four eyes with MH had previously been submitted to PPV (i.e. 1 for retinal detachment and 3 to attempt to close large MH). One of the latter also displayed juxtapapillary choroidal neovascularization due to age-related macular degeneration. The primary and secondary outcomes were MH closure and improvement of the best corrected visual acuity (BCVA), respectively. RESULTS: Complete MH closure was achieved in all cases. A statistically significant improvement in the average BCVA was observed after 6 months of follow-up (p = 0.018; paired t test). The BCVA improved in 8 eyes (80%), and in 6 of those eyes it improved by >= 15 letters. In 1 patient, the BCVA remained unchanged after the surgery, but the visual field reportedly improved. One patient experienced a slight worsening (0.16 logMAR). Two cases developed atrophy of the retinal pigment epithelium despite MH closure and BCVA improvement. CONCLUSION: Treatment with autologous ILM fragment transplantation seems to be an efficient alternative for large, chronic, and refractory MH. PMID- 26569391 TI - Tensions between the conduct of randomised controlled trials in health promotion research and the role of autonomy in human health and well being. AB - The goal of developing increasingly effective interventions to change health related behaviours, which is an inevitable result of the use of the scientific method, conflicts with respect for the autonomy and dignity of the individual. This paper recommends a new direction for the field of health promotion based on building people's capacity to exercise autonomy, in the ethically relevant meaning of the term, and thereby promote a more comprehensive understanding of the goals of the field, a state of health that includes the irreducible ethical dimension signified by human dignity. PMID- 26569392 TI - Persistent Postural-Perceptual Dizziness: A Matter of Higher, Central Dysfunction? AB - OBJECTIVE: Persistent postural-perceptual dizziness (PPPD) is the most common vestibular disorder in the age group between 30 and 50 years. It is considered to be based on a multisensory maladjustment involving alterations of sensory response pattern including vestibular, visual and motion stimuli. Previous data supported a link between vestibular and pain mechanism. The aim of the study was to investigate whether other sensory inputs such as pain stimuli might be altered in terms of a more widespread central perception dysfunction in this disorder. METHODS: Nociceptive blink reflex was measured in 27 patients with PPPD and compared with 27 healthy, age and gender matched controls. The habituation of the R2 component of the blink reflex was evaluated as the percentage area-under-the curve (AUC) decrease in ten consecutive blocks of five averaged rectified responses. Additionally, clinical characteristics were evaluated. RESULTS: In patients with PPPD a lack of habituation was observed compared to healthy controls. Relative AUC decreased between the first and the tenth block by 19.48% in PPPD patients and by 31.63% (p = 0.035) in healthy controls. There was no correlation between clinical data (course of disease, comorbid depression, medication, trigger factors) or electrophysiological data (perception threshold, pain threshold, stimulus intensity) and habituation pattern. No trigeminal sensitization in terms of facilitation of absolute values could be detected. CONCLUSION: Our study results supports the hypothesis of the multisensory dimension of impaired sensory processing in patients with PPPD extends beyond vestibular/visual motion stimuli and reflexive postural/oculomotor control mechanisms to other sensory inputs such as pain perception in terms of a more generalized disturbed habituation pattern. PMID- 26569393 TI - Oxidative Balance Score and Chronic Kidney Disease. AB - BACKGROUND: The oxidative balance score (OBS) is a composite estimate of the overall pro- and antioxidant exposure status in an individual. The aim of this study was to determine the association between OBS and renal disease. METHODS: Using the Reasons for Geographic and Racial Differences in Stroke cohort study, OBS was calculated by combining 13 a priori-defined pro- and antioxidant factors by using baseline dietary and lifestyle assessment. OBS was divided into quartiles (Q1-Q4) with the lowest quartile, Q1 (predominance of pro-oxidants), as the reference. Multivariable logistic regression and Cox proportional hazards models were used to estimate adjusted ORs for albuminuria defined as urine albumin/creatinine ratio (ACR)>30 mg/g, macroalbuminuria defined as ACR>300 mg/g and chronic kidney disease (CKD) defined as estimated glomerular filtration rate<60 ml/min/1.73 m2 according to the Chronic Kidney Disease Epidemiology Collaboration and hazards ratios for end-stage renal disease (ESRD), respectively. RESULTS: Of the 19,461 participants analyzed, 12.9% had albuminuria and 10.1% had CKD at baseline; over a median follow-up of 3.5 years (range 2.14 4.32 years), 0.46% developed ESRD. Higher OBS quartiles were associated with lower prevalence of CKD (OR vs. Q1: Q2=0.93 [95% CI 0.80-1.08]; Q3=0.90 [95% CI 0.77-1.04] and Q4=0.79 [95% CI 0.67-0.92], p for trend<.01). The associations between OBS and albuminuria (p for trend 0.31) and incident ESRD (p for trend 0.56) were not significant in the fully adjusted models. CONCLUSIONS: These findings suggest that higher OBS is associated with lower prevalence of CKD. Lack of association with ESRD incidence in the multivariable analyses indicates that temporal relation between OBS and renal damage remains unclear. PMID- 26569394 TI - CCK Response Deficiency in Synphilin-1 Transgenic Mice. AB - Previously, we have identified a novel role for the cytoplasmic protein, synphilin-1(SP1), in the controls of food intake and body weight in both mice and Drosophila. Ubiquitous overexpression of human SP1 in brain neurons in transgenic mice results in hyperphagia expressed as an increase in meal size. However, the mechanisms underlying this action of SP1 remain to be determined. Here we investigate a potential role for altered gut feedback signaling in the effects of SP1 on food intake. We examined responses to peripheral administration of cholecytokinin (CCK), amylin, and the glucagon like peptide-1 (GLP-1) receptor agonist, exendin-4. Intraperitoneal administration of CCK at doses ranging from 1 10 nmol/kg significantly reduced glucose intake in wild type (WT) mice, but failed to affect intake in SP1 transgenic mice. Moreover, there was a significant attenuation of CCK-induced c-Fos expression in the dorsal vagal complex in SP1 transgenic mice. In contrast, WT and SP1 transgenic mice were similarly responsive to both amylin and exendin-4 treatment. These studies demonstrate that SP1 results in a CCK response deficiency that may contribute to the increased meal size and overall hyperphagia in synphillin-1 transgenic mice. PMID- 26569396 TI - Low Level Laser Therapy Reduces the Development of Lung Inflammation Induced by Formaldehyde Exposure. AB - Lung diseases constitute an important public health problem and its growing level of concern has led to efforts for the development of new therapies, particularly for the control of lung inflammation. Low Level Laser Therapy (LLLT) has been highlighted as a non-invasive therapy with few side effects, but its mechanisms need to be better understood and explored. Considering that pollution causes several harmful effects on human health, including lung inflammation, in this study, we have used formaldehyde (FA), an environmental and occupational pollutant, for the induction of neutrophilic lung inflammation. Our objective was to investigate the local and systemic effects of LLLT after FA exposure. Male Wistar rats were exposed to FA (1%) or vehicle (distillated water) during 3 consecutive days and treated or not with LLLT (1 and 5 hours after each FA exposure). Non-manipulated rats were used as control. 24 h after the last FA exposure, we analyzed the local and systemic effects of LLLT. The treatment with LLLT reduced the development of neutrophilic lung inflammation induced by FA, as observed by the reduced number of leukocytes, mast cells degranulated, and a decreased myeloperoxidase activity in the lung. Moreover, LLLT also reduced the microvascular lung permeability in the parenchyma and the intrapulmonary bronchi. Alterations on the profile of inflammatory cytokines were evidenced by the reduced levels of IL-6 and TNF-alpha and the elevated levels of IL-10 in the lung. Together, our results showed that LLLT abolishes FA-induced neutrophilic lung inflammation by a reduction of the inflammatory cytokines and mast cell degranulation. This study may provide important information about the mechanisms of LLLT in lung inflammation induced by a pollutant. PMID- 26569398 TI - Correction: Binge Ethanol and MDMA Combination Exacerbates Toxic Cardiac Effects by Inducing Cellular Stress. PMID- 26569395 TI - High-Throughput Amplicon-Based Copy Number Detection of 11 Genes in Formalin Fixed Paraffin-Embedded Ovarian Tumour Samples by MLPA-Seq. AB - Whilst next generation sequencing can report point mutations in fixed tissue tumour samples reliably, the accurate determination of copy number is more challenging. The conventional Multiplex Ligation-dependent Probe Amplification (MLPA) assay is an effective tool for measurement of gene dosage, but is restricted to around 50 targets due to size resolution of the MLPA probes. By switching from a size-resolved format, to a sequence-resolved format we developed a scalable, high-throughput, quantitative assay. MLPA-seq is capable of detecting deletions, duplications, and amplifications in as little as 5ng of genomic DNA, including from formalin-fixed paraffin-embedded (FFPE) tumour samples. We show that this method can detect BRCA1, BRCA2, ERBB2 and CCNE1 copy number changes in DNA extracted from snap-frozen and FFPE tumour tissue, with 100% sensitivity and >99.5% specificity. PMID- 26569397 TI - Imaging Tumor Necrosis with Ferumoxytol. AB - OBJECTIVE: Ultra-small superparamagnetic iron oxide nanoparticles (USPIO) are promising contrast agents for magnetic resonance imaging (MRI). USPIO mediated proton relaxation rate enhancement is strongly dependent on compartmentalization of the agent and can vary depending on their intracellular or extracellular location in the tumor microenvironment. We compared the T1- and T2-enhancement pattern of intracellular and extracellular USPIO in mouse models of cancer and pilot data from patients. A better understanding of these MR signal effects will enable non-invasive characterizations of the composition of the tumor microenvironment. MATERIALS AND METHODS: Six 4T1 and six MMTV-PyMT mammary tumors were grown in mice and imaged with ferumoxytol-enhanced MRI. R1 relaxation rates were calculated for different tumor types and different tumor areas and compared with histology. The transendothelial leakage rate of ferumoxytol was obtained by our measured relaxivity of ferumoxytol and compared between different tumor types, using a t-test. Additionally, 3 patients with malignant sarcomas were imaged with ferumoxytol-enhanced MRI. T1- and T2-enhancement patterns were compared with histopathology in a descriptive manner as a proof of concept for clinical translation of our observations. RESULTS: 4T1 tumors showed central areas of high signal on T1 and low signal on T2 weighted MR images, which corresponded to extracellular nanoparticles in a necrotic core on histopathology. MMTV-PyMT tumors showed little change on T1 but decreased signal on T2 weighted images, which correlated to compartmentalized nanoparticles in tumor associated macrophages. Only 4T1 tumors demonstrated significantly increased R1 relaxation rates of the tumor core compared to the tumor periphery (p<0.001). Transendothelial USPIO leakage was significantly higher for 4T1 tumors (3.4+/ 0.9x10-3 mL/min/100cm3) compared to MMTV-PyMT tumors (1.0+/-0.9x10-3 mL/min/100 cm3). Likewise, ferumoxytol imaging in patients showed similar findings with high T1 signal in areas of tumor necrosis and low signal in areas of intracellularly compartmentalized iron. CONCLUSION: Differential T1- and T2-enhancement patterns of USPIO in tumors enable conclusions about their intracellular and extracellular location. This information can be used to characterize the composition of the tumor microenvironment. PMID- 26569399 TI - Changes in Carboxy Methylation and Tyrosine Phosphorylation of Protein Phosphatase PP2A Are Associated with Epididymal Sperm Maturation and Motility. AB - Mammalian sperm contain the serine/threonine phosphatases PP1gamma2 and PP2A. The role of sperm PP1gamma2 is relatively well studied. Here we confirm the presence of PP2A in sperm and show that it undergoes marked changes in methylation (leucine 309), tyrosine phosphorylation (tyrosine 307) and catalytic activity during epididymal sperm maturation. Spermatozoa isolated from proximal caput, distal caput and caudal regions of the epididymis contain equal immuno-reactive amounts of PP2A. Using demethyl sensitive antibodies we show that PP2A is methylated at its carboxy terminus in sperm from the distal caput and caudal regions but not in sperm from the proximal caput region of the epididymis. The methylation status of PP2A was confirmed by isolation of PP2A with microcystin agarose followed by alkali treatment, which causes hydrolysis of protein carboxy methyl esters. Tyrosine phosphorylation of sperm PP2A varied inversely with methylation. That is, PP2A was tyrosine phosphorylated when it was demethylated but not when methylated. PP2A demethylation and its reciprocal tyrosine phosphorylation were also affected by treatment of sperm with L-homocysteine and adenosine, which are known to elevate intracellular S-adenosylhomocysteine, a feedback inhibitor of methyltransferases. Catalytic activity of PP2A declined during epididymal sperm maturation. Inhibition of PP2A by okadaic acid or by incubation of caudal epididymal spermatozoa with L-homocysteine and adenosine resulted in increase of sperm motility parameters including percent motility, velocity, and lateral head amplitude. Demethylation or pharmacological inhibition of PP2A also leads to an increase in phosphorylation of glycogen synthase kinase 3 (GSK3). Our results show for the first time that changes in PP2A activity due to methylation and tyrosine phosphorylation occur in sperm and that these changes may play an important role in the regulation of sperm function. PMID- 26569400 TI - The Season for Peace: Reconciliation in a Despotic Species (Lemur catta). AB - However despotic a social group may be, managing conflicts of interest is crucial to preserve group living benefits, mainly based on cooperation. In despotic groups, post-conflict management via reconciliation (the first post-conflict reunion between former opponents) can occur, even if conciliatory rates are considerably different. Lemur catta is defined as a despotic species because groups are characterized by a strict linear hierarchy maintained by the adult females (the dominant sex) mainly via aggression. Reconciliation was reported in one out of four captive groups of L. catta. Here we investigate which variables influence the occurrence of reconciliation in these despotic groups. We analyzed 2339 Post Conflict (PC)-Matched Control (MC) observation pairs, collected on eight groups (five in the Berenty forest, Madagascar; three hosted at the Pistoia Zoo, Italy). Since L. catta is characterized by steep female dominance but shows female-female coalitionary support, we expected to confirm the presence of reconciliation in the study species. Consistently, we found reconciliation in one captive group and two wild groups, thus providing the first evidence of the presence of this phenomenon in wild L. catta. Moreover, because this species is a seasonal breeder (with mating occurring once a year), we expected seasonal fluctuations in reconciliation levels. Via a GLMM analysis using data from all wild groups and on a captive group followed for more than one year, we found that season (but not rank; individuals' identity, sex, and age; or group identity) significantly affected individual reconciliation rates, and such rates were lowest during the mating period. Thus, reconciliation can be present in groups in which dominants strongly influence and limit social relationships (steep dominance hierarchy) except when the advantages of intra-group cooperation are overcome by competition, as occurs in seasonal breeders when reproduction is at stake. We conclude that in despotic social groups in which coalitions are observed, the right question is not if but when reconciliation can be present. PMID- 26569401 TI - NopC Is a Rhizobium-Specific Type 3 Secretion System Effector Secreted by Sinorhizobium (Ensifer) fredii HH103. AB - Sinorhizobium (Ensifer) fredii HH103 is a broad host-range nitrogen-fixing bacterium able to nodulate many legumes, including soybean. In several rhizobia, root nodulation is influenced by proteins secreted through the type 3 secretion system (T3SS). This specialized secretion apparatus is a common virulence mechanism of many plant and animal pathogenic bacteria that delivers proteins, called effectors, directly into the eukaryotic host cells where they interfere with signal transduction pathways and promote infection by suppressing host defenses. In rhizobia, secreted proteins, called nodulation outer proteins (Nops), are involved in host-range determination and symbiotic efficiency. S. fredii HH103 secretes at least eight Nops through the T3SS. Interestingly, there are Rhizobium-specific Nops, such as NopC, which do not have homologues in pathogenic bacteria. In this work we studied the S. fredii HH103 nopC gene and confirmed that its expression was regulated in a flavonoid-, NodD1- and TtsI dependent manner. Besides, in vivo bioluminescent studies indicated that the S. fredii HH103 T3SS was expressed in young soybean nodules and adenylate cyclase assays confirmed that NopC was delivered directly into soybean root cells by means of the T3SS machinery. Finally, nodulation assays showed that NopC exerted a positive effect on symbiosis with Glycine max cv. Williams 82 and Vigna unguiculata. All these results indicate that NopC can be considered a Rhizobium specific effector secreted by S. fredii HH103. PMID- 26569402 TI - Laboratory Assay of Brood Care for Quantitative Analyses of Individual Differences in Honey Bee (Apis mellifera) Affiliative Behavior. AB - Care of offspring is a form of affiliative behavior that is fundamental to studies of animal social behavior. Insects do not figure prominently in this topic because Drosophila melanogaster and other traditional models show little if any paternal or maternal care. However, the eusocial honey bee exhibits cooperative brood care with larvae receiving intense and continuous care from their adult sisters, but this behavior has not been well studied because a robust quantitative assay does not exist. We present a new laboratory assay that enables quantification of group or individual honey bee brood "nursing behavior" toward a queen larva. In addition to validating the assay, we used it to examine the influence of the age of the larva and the genetic background of the adult bees on nursing performance. This new assay also can be used in the future for mechanistic analyses of eusociality and comparative analyses of affilative behavior with other animals. PMID- 26569403 TI - Comparative Genomic and Phylogenomic Analyses Reveal a Conserved Core Genome Shared by Estuarine and Oceanic Cyanopodoviruses. AB - Podoviruses are among the major viral groups that infect marine picocyanobacteria Prochlorococcus and Synechococcus. Here, we reported the genome sequences of five Synechococcus podoviruses isolated from the estuarine environment, and performed comparative genomic and phylogenomic analyses based on a total of 20 cyanopodovirus genomes. The genomes of all the known marine cyanopodoviruses are highly syntenic. A pan-genome of 349 clustered orthologous groups was determined, among which 15 were core genes. These core genes make up nearly half of each genome in length, reflecting the high level of genome conservation among this cyanophage type. The whole genome phylogenies based on concatenated core genes and gene content were highly consistent and confirmed the separation of two discrete marine cyanopodovirus clusters MPP-A and MPP-B. The genomes within cluster MPP-B grouped into subclusters mainly corresponding to Prochlorococcus or Synechococcus host types. Auxiliary metabolic genes tend to occur in a specific phylogenetic group of these cyanopodoviruses. All the MPP-B phages analyzed here encode the photosynthesis gene psbA, which are absent in all the MPP-A genomes thus far. Interestingly, all the MPP-B and two MPP-A Synechococcus podoviruses encode the thymidylate synthase gene thyX, while at the same genome locus all the MPP-B Prochlorococcus podoviruses encode the transaldolase gene talC. Both genes are hypothesized to have the potential to facilitate the biosynthesis of deoxynucleotide for phage replication. Inheritance of specific functional genes could be important to the evolution and ecological fitness of certain cyanophage genotypes. Our analyses demonstrate that cyanopodoviruses of estuarine and oceanic origins share a conserved core genome and suggest that accessory genes may be related to environmental adaptation. PMID- 26569404 TI - Is there a causal link between psychological disorders and functional gastrointestinal disorders? AB - Psychological disorders, most notably anxiety and depressive disorders, somatization and catastrophizing, often precede or exacerbate functional gastrointestinal disorder (FGID) symptoms and correlate with symptom severity and health outcomes. Mounting evidence shows that psychological distress alters gut immunity, in particular mast cell activation, leading to a potentiation of sensory nerves and aberrant visceral pain perception. On the other hand, psychological stressors modulate the processing of incoming sensory signals by the brain, thereby contributing to FGID symptom development. A better understanding of the molecular mechanisms underlying stress-induced changes in the immune system or brain processing is crucial for the development of novel beneficial therapeutic strategies. PMID- 26569405 TI - Identification of New Antifungal Compounds Targeting Thioredoxin Reductase of Paracoccidioides Genus. AB - The prevalence of invasive fungal infections worldwide has increased in the last decades. The development of specific drugs targeting pathogenic fungi without producing collateral damage to mammalian cells is a daunting pharmacological challenge. Indeed, many of the toxicities and drug interactions observed with contemporary antifungal therapies can be attributed to "nonselective" interactions with enzymes or cell membrane systems found in mammalian host cells. A computer-aided screening strategy against the TRR1 protein of Paracoccidioides lutzii is presented here. Initially, a bank of commercially available compounds from Life Chemicals provider was docked to model by virtual screening simulations. The small molecules that interact with the model were ranked and, among the best hits, twelve compounds out of 3,000 commercially-available candidates were selected. These molecules were synthesized for validation and in vitro antifungal activity assays for Paracoccidioides lutzii and P. brasiliensis were performed. From 12 molecules tested, 3 harbor inhibitory activity in antifungal assays against the two pathogenic fungi. Corroborating these findings, the molecules have inhibitory activity against the purified recombinant enzyme TRR1 in biochemical assays. Therefore, a rational combination of molecular modeling simulations and virtual screening of new drugs has provided a cost effective solution to an early-stage medicinal challenge. These results provide a promising technique to the development of new and innovative drugs. PMID- 26569407 TI - Retraction. Rare Orbitocranial Tumour in an Adult. PMID- 26569408 TI - How Bats Land Upside Down. AB - A new study reveals that bats use the inertia of their unusually heavy wings rather than their aerodynamic properties-to help them perform acrobatic maneuvers like landing upside down to roost. Read the Research Article. PMID- 26569406 TI - The Bulk of Autotaxin Activity Is Dispensable for Adult Mouse Life. AB - Autotaxin (ATX, Enpp2) is a secreted lysophospholipase D catalysing the production of lysophosphatidic acid, a pleiotropic growth factor-like lysophospholipid. Increased ATX expression has been detected in a number of chronic inflammatory diseases and different types of cancer, while genetic interventions have proven a role for ATX in disease pathogenesis. Therefore, ATX has emerged as a potential drug target and a large number of ATX inhibitors have been developed exhibiting promising therapeutic potential. However, the embryonic lethality of ATX null mice and the ubiquitous expression of ATX and LPA receptors in adult life question the suitability of ATX as a drug target. Here we show that inducible, ubiquitous genetic deletion of ATX in adult mice, as well as long-term potent pharmacologic inhibition, are well tolerated, alleviating potential toxicity concerns of ATX therapeutic targeting. PMID- 26569410 TI - Social Work Leadership as Ambassadors of Health Care Reform: Developing and Implementing a Health Home Program Within a Large Urban Health System. AB - Beginning in 2011, The Mount Sinai Hospital participated in the New York State Department of Health Medicaid Health Home (HH) program, evolving into what is now the Mount Sinai Health Home (MSHH). The lead HH designation required social work leadership to develop and implement this initiative within a large health system, consisting of five New York City area hospitals. Additionally, strategic partnerships with sub-contracted, community based organizations and Medicaid Managed Care Organizations (MCOs) were essential to the HH's success, and were facilitated by inter- and intra-organization collaboration. This article provides an overview of the HH model and discusses the process by which MSHH was formed, the integral role of social work in its development and success, challenges and lessons learned, and recommendations for the development of the profession's future workforce. The authors intend to leave the reader with a model of social work leadership within the current environment of health care reform, and to exemplify social work care coordination and engagement of a hard to reach patient population. PMID- 26569409 TI - Hepatocyte-Specific Arid1a Deficiency Initiates Mouse Steatohepatitis and Hepatocellular Carcinoma. AB - ARID1A, encoding a subunit of chromatin remodeling SWI/SNF complexes, has recently been considered as a new type of tumor suppressor gene for its somatic mutations frequently found in various human tumors, including hepatocellular carcinoma (HCC). However, the role and mechanism of inactivated ARID1A mutations in tumorigenesis remain unclear. To investigate the role of ARID1A inactivation in HCC pathogenesis, we generated hepatocyte-specific Arid1a knockout (Arid1aLKO) mice by crossing mice carrying loxP-flanked Arid1a exon 8 alleles (Arid1af/f) with albumin promoter-Cre transgenic mice. Significantly, the hepatocyte-specific Arid1a deficiency results in mouse steatohepatitis and HCC development. In Arid1aLKO mice, we found that innate immune cells, including F4/80+ macrophages and CD11c+ neutrophil cells, infiltrate into the liver parenchyma, accompanied by the increased tumor necrosis factor (TNF)-alpha and interleukin (IL)-6, and activation of STAT3 and NF-kappaB pathways. In conclusion, hepatocyte-specific Arid1a deficiency could lead to mouse steatohepatitis and HCC development. This study provides an alternative mechanism by which Arid1a deficiency contributes to HCC tumorigenesis. PMID- 26569411 TI - Relations of Distinct Psychopathic Personality Traits with Anxiety and Fear: Findings from Offenders and Non-Offenders. AB - Early descriptions of psychopathy emphasise fearlessness and a lack of nervousness or anxiety as key characteristics of the disorder. However, conflicting evidence suggests that anxiety may be positively correlated with some aspects of the psychopathy construct. This position may seem somewhat paradoxical when considered alongside impaired processing of fear related stimuli in psychopathic personality. The aim of the current paper was to examine the distinct relations of callous, egocentric, and antisocial psychopathic traits with measures of anxiety and social anxiety in samples of non-offenders (Study 1) and violent offenders (Study 2). In Study 2 we also used an emotion recognition task to examine fearful face recognition. In Studies 1 and 2 we showed distinct and opposite significant relationships of egocentric and antisocial psychopathic traits with trait anxiety. Thus, while trait anxiety was negatively predicted by egocentric traits, it was predicted in a positive direction by antisocial traits in both samples. In Study 2 we found that callous traits were predictive of greater impairments in fearful face recognition. These findings suggest that anxiety and fear are distinguishable constructs in relation to psychopathic personality traits, and are discussed in terms of potentially separable mechanisms for these two constructs. PMID- 26569413 TI - From Fishing to Fish Processing: Separation of Fish from Crustaceans in the Norway Lobster-Directed Multispecies Trawl Fishery Improves Seafood Quality. AB - Fishing gears have negative impacts on seafood quality, especially on fish in the mixed trawl fishery targeting Norway lobster (Nephrops norvegicus). In this fishery, which is worth about ?80 millions in Denmark alone, the quality of fish can be significantly improved by simple gear changes. A trawl codend divided into an upper and lower codend was designed to separate fish from Norway lobster during the fishing process by encourage fish to swim into the upper codend by using a frame at the entrance of the lower codend. Separate codends for fish and Norway lobster in the same gear provide the opportunity to selectively reduce small low-value fish, which will reduce catch weight and sorting time onboard the vessel. For this horizontally divided test codend and a standard codend, in which the catch was mixed, quality assessments were performed on the same batches of fish during three steps of the value chain: i) aboard the fishing vessel; ii) at the Fishermen's Collection Central, and iii) in the production plant. Four species of fish and fillets from fish caught in the upper codend of the test codend were of significantly better quality for several of the assessed parameters compared with those caught in the standard codend: i) newly caught fish showed significantly less scale loss and discolourations and had significantly better texture; ii) landed fish had significantly better skin appearance and texture and significantly fewer discolourations; and iii) fillets showed significantly fewer blood spots and had significantly better texture. There were no differences in injuries for newly caught fish or gaping and bruises for fillets between the test and standard codends. The decrease in catch-related damages in the test codend is explained by little contact between fish and animals with hard or spiny surfaces due to successful separation of fish and Norway lobster into the upper and lower codends, respectively, and by lower catch weight in the upper codend of the test codend compared with the standard codend. The decrease in damages may also improve quality indirectly by inflicting less stress to the fish and subsequently give better texture, which offers advantages such as pre-rigor filleting and fresher products for the market. Significant improvements in fish quality can potentially increase the catch value in nationally important fisheries. PMID- 26569412 TI - Linking Ventilation Heterogeneity Quantified via Hyperpolarized 3He MRI to Dynamic Lung Mechanics and Airway Hyperresponsiveness. AB - Advancements in hyperpolarized helium-3 MRI (HP 3He-MRI) have introduced the ability to render and quantify ventilation patterns throughout the anatomic regions of the lung. The goal of this study was to establish how ventilation heterogeneity relates to the dynamic changes in mechanical lung function and airway hyperresponsiveness in asthmatic subjects. In four healthy and nine mild to-moderate asthmatic subjects, we measured dynamic lung resistance and lung elastance from 0.1 to 8 Hz via a broadband ventilation waveform technique. We quantified ventilation heterogeneity using a recently developed coefficient of variation method from HP 3He-MRI imaging. Dynamic lung mechanics and imaging were performed at baseline, post-challenge, and after a series of five deep inspirations. AHR was measured via the concentration of agonist that elicits a 20% decrease in the subject's forced expiratory volume in one second compared to baseline (PC20) dose. The ventilation coefficient of variation was correlated to low-frequency lung resistance (R = 0.647, P < 0.0001), the difference between high and low frequency lung resistance (R = 0.668, P < 0.0001), and low-frequency lung elastance (R = 0.547, P = 0.0003). In asthmatic subjects with PC20 values <25 mg/mL, the coefficient of variation at baseline exhibited a strong negative trend (R = -0.798, P = 0.02) to PC20 dose. Our findings were consistent with the notion of peripheral rather than central involvement of ventilation heterogeneity. Also, the degree of AHR appears to be dependent on the degree to which baseline airway constriction creates baseline ventilation heterogeneity. HP 3He-MRI imaging may be a powerful predictor of the degree of AHR and in tracking the efficacy of therapy. PMID- 26569415 TI - Interplay between 3d-3d and 3d-4f interactions at the origin of the magnetic ordering in the Ba2LnFeO5 oxides. AB - A new family of oxides in which 3d-3d and 3d-4f interactions are of comparable strength has been synthesized and characterized both from structural and physical viewpoints. These compounds of formulation Ba2LnFeO5 (Ln = Sm, Eu, Gd, Dy, Ho, Er, Yb) are isotypic to the perovskite derivative Ba2YFeO5. They exhibit an original structure consisting of isolated FeO4 tetrahedra linked via LnO6 (or YO6) octahedra. Magnetic and calorimetric measurements show that all these compounds exhibit a unique, antiferromagnetic transition involving both the 3d and 4f ions. The antiferromagnetic properties of the Ln = Y phase (non-magnetic Y(3+)) and of the Ln = Eu (non-magnetic ground state multiplet of Eu(3+)) are ascribed to super-super exchange Fe-O-O-Fe interactions, leading to the lowest T(N) (5.5 K for Y and 4.6 K for Eu). The introduction of a magnetic lanthanide, i.e. Ln = Sm, Gd, Dy, Ho, Er, Yb, in the octahedral sites, leads to larger T(N) values (up to 9.8 K for Ln = Yb). It is found that several mechanisms must be taken into account to explain the complex evolution of the magnetic properties along the Ba2LnFeO5 series. In particular, the super-exchange Ln-O-Fe, as well as the on-site Ln(3+) magnetocrystalline anisotropy, are suggested to play crucial roles. This Ba2LnFeO5 series offers a rare opportunity to investigate experimentally a situation where the 3d-3d and 3d-4f interactions co-operate on an equal footing to trigger a unique long-range magnetic ordering in insulating oxides. PMID- 26569416 TI - Expression of Glutamate Transporters in Alcohol Withdrawal. AB - INTRODUCTION: The study aimed to investigate the expression of glutamate transporters during withdrawal in the alcohol-dependent patients. METHOD: The study consisted of 20 male inpatient alcoholics during the withdrawal period and 20 healthy controls. Expressions of glutamate transporters, namely the excitatory amino acid transporter 2 (EAAT2) and EAAT3, in white blood cells were measured with the real-time polymerase chain reaction (RT-PCR) method in early (first day) and late (28(th) day) withdrawal in alcoholic patients and once in the controls. RESULTS: EAAT2 and EAAT3 expressions in the patients during both early and late withdrawal were higher than those of the controls. There was no difference in the EAAT2 and EAAT3 levels of the patients between early and late abstinence. DISCUSSION: The study revealed an upregulation of glutamate transporters EAAT2 and EAAT3 during early and late withdrawal in patients with alcohol withdrawal. PMID- 26569414 TI - A Novel, Open Access Method to Assess Sleep Duration Using a Wrist-Worn Accelerometer. AB - Wrist-worn accelerometers are increasingly being used for the assessment of physical activity in population studies, but little is known about their value for sleep assessment. We developed a novel method of assessing sleep duration using data from 4,094 Whitehall II Study (United Kingdom, 2012-2013) participants aged 60-83 who wore the accelerometer for 9 consecutive days, filled in a sleep log and reported sleep duration via questionnaire. Our sleep detection algorithm defined (nocturnal) sleep as a period of sustained inactivity, itself detected as the absence of change in arm angle greater than 5 degrees for 5 minutes or more, during a period recorded as sleep by the participant in their sleep log. The resulting estimate of sleep duration had a moderate (but similar to previous findings) agreement with questionnaire based measures for time in bed, defined as the difference between sleep onset and waking time (kappa = 0.32, 95%CI:0.29,0.34) and total sleep duration (kappa = 0.39, 0.36,0.42). This estimate was lower for time in bed for women, depressed participants, those reporting more insomnia symptoms, and on weekend days. No such group differences were found for total sleep duration. Our algorithm was validated against data from a polysomnography study on 28 persons which found a longer time window and lower angle threshold to have better sensitivity to wakefulness, while the reverse was true for sensitivity to sleep. The novelty of our method is the use of a generic algorithm that will allow comparison between studies rather than a "count" based, device specific method. PMID- 26569417 TI - Sexual Dysfunction Related to Drugs: a Critical Review. Part V: alpha-Blocker and 5-ARI Drugs. AB - Sexual dysfunction is a potential side effect of BPH (benign prostatic hyperplasia) and LUTS (lower urinary tract symptoms) drugs: this article is a critical review of the current literature. Many studies have been published on this topic. Methodological flaws limit the conclusions of these studies, mainly because of the lack of diagnostic criteria for ejaculatory and sexual desire dysfunction. Few of these studies are RCTs. The alpha-blocker (also called alpha1 adrenergic antagonist, alpha-adrenoceptor antagonist, alpha-blocker or AB) and 5 ARI (also called 5alpha-reductase inhibitor or testosterone-5-alpha reductase inhibitor) drugs can in particular cause erectile dysfunction, ejaculatory disorders and reduction of sexual desire. The sexual side effect profile of these drugs is different. Among the alpha-blockers, silodosin appears have the highest incidence of ejaculatory disorders. Persistent sexual side effects after discontinuation of finasteride has recently been reported, however further studies are needed to clarify the true incidence and the significance of this finding. It is desirable that future studies include validated tools to assess and diagnose sexual dysfunction induced by these medications, especially for ejaculation and sexual desire disorders. Only a small amount of research has intentionally set out to investigate sexual dysfunction caused by alpha-blocker and 5-ARI drugs: studies to specifically assess sexual dysfunction induced by these drugs are needed. Further studies are also needed to assess in the long term the role of combined therapy of phosphodiesterase type 5 inhibitors and alpha-blockers or 5-ARIs in treating LUTS/BPH. METHODS: This study was conducted in 2014 using the paper and electronic resources of the library of the "Azienda Provinciale per i Servizi Sanitari (APSS)" in Trento, Italy (http://atoz.ebsco.com/Titles/2793). The library has access to a wide range of databases including DYNAMED, MEDLINE Full Text, CINAHL Plus Full Text, The Cochrane Library, Micromedex healthcare series, BMJ Clinical Evidence. The full list of available journals can be viewed at http://atoz.ebsco.com/Titles/2793, or at the APSS web site (http://www.apss.tn.it). In completing this review, a literature search was conducted using the key words "benign prostatic hyperplasia drugs", "lower urinary tract symptoms drugs", "alpha-blockers", "5-ARIs", "sexual dysfunction", "sexual side effects", "treatment-emergent sexual dysfunction", "phosphodiesterase type 5 (PDE5) inhibitors". All resulting listed articles were reviewed. Studies published between 2002 and December 2014 were included in the review. We included all studies that explicitly reported data on sexual dysfunction during treatment with alpha-blockers and 5-ARIs. We also reviewed studies that have evaluated the use of phosphodiesterase type 5 (PDE5) inhibitors in combination with these drugs. The purpose was to identify possible intervention strategies for sexual dysfunction related to these drugs. PMID- 26569419 TI - Individual differences in moral judgment competence are related to activity of the prefrontal cortex when attributing blame to evil intention. AB - The weighing of intentions and consequences is inconsistent in adult's moral judgments, and this is particularly prominent when assigning blame to the immoral intentions in the absence of negative outcomes. The current study extends previous research by examining how individual differences in moral judgment competence are reflected in the cortical network when making judgments about immoral intentions. Twenty-four participants were scanned, using functional magnetic resonance imaging, while making judgments about three kinds of moral scenarios: a neutral condition, an immoral intention condition, and an immoral condition. The result showed that comparing with making judgments about the other two conditions, making judgments about the immoral intentions takes longer time and was associated with significantly elevated activity in the dorsolateral prefrontal cortex and the ventrolateral prefrontal cortex. Additionally, moral judgment competence scores were inversely correlated with activity in the right dorsolateral prefrontal cortex when assigning blame to the immoral intentions. Greater activity in the right dorsolateral prefrontal cortex in participants with lower moral judgment competence possibly reflected increased recruitment of cognitive resource applied to control impulsive response and integrate competitive information in making judgments about the immoral intention. PMID- 26569420 TI - Phenolic-rich lychee (Litchi chinensis Sonn.) pulp extracts offer hepatoprotection against restraint stress-induced liver injury in mice by modulating mitochondrial dysfunction. AB - The pulp from lychee, a tropical to subtropical fruit, contains large quantities of phenolic compounds and exhibits antioxidant activities both in vitro and in vivo. In the present study, we investigated the mechanisms underlying the hepatoprotective effects of lychee pulp phenolics (LPPs) against restraint stress induced liver injury in mice. After 18 h of restraint stress, increased levels of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities were observed. High levels of thiobarbituric acid reactive substances (TBARS) were also found. Restraint stress causes liver damage, which was protected against by LPP pretreatment at a dosage of 200 mg (kg d)(-1) for 21 consecutive days. This treatment remarkably decreased the serum ALT, AST and TBARS levels, elevated the liver glutathione (GSH) content, and the activities of glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT). Furthermore, respiratory chain complex and Na(+)-K(+)-ATPase activities were enhanced in liver mitochondria, while mitochondrial membrane potential levels and reactive oxygen species (ROS) production decreased. Thus, treatment with LPPs ameliorated restraint stress-induced liver mitochondrial dysfunction. These results suggest that LPPs protect the liver against restraint stress-induced damage by scavenging free radicals and modulating mitochondrial dysfunction. Thus, lychee pulp may be a functional biofactor to mitigate oxidative stress. PMID- 26569421 TI - Total syntheses of (+/-)-spiroindimicins B and C enabled by a late-stage Schollkopf-Magnus-Barton-Zard (SMBZ) reaction. AB - The spiroindimicins are a family of structurally unprecedented alkaloids isolated from the deep-sea-derived marine actinomycete Streptomyces sp. SCSIO 03032. The total syntheses of (+/-)-spiroindimicins B and C are disclosed, the first of any member of this family. Central to the successful strategy was installing the spirocentre using a mild intramolecular Heck reaction, the assembly of a pentacyclic spirobisindole by Fischer indolization and a late-stage Schollkopf Magnus-Barton-Zard (SMBZ) reaction to construct the trisubstituted pyrrole. PMID- 26569422 TI - Genomic architecture of lung cancers. AB - PURPOSE OF REVIEW: Lung cancer remains the most frequent cancer worldwide and the leading cause of cancer death in most countries. The molecular characteristics of lung tumors play an important role in clinical decisions, which ultimately affect patients' survival. This review aims to summarize the most recent genomic discoveries made on lung cancer. RECENT FINDINGS: A relatively comprehensive molecular characterization has been achieved for the three major types of lung cancer: adenocarcinoma, squamous-cell carcinoma, and small-cell carcinoma. Little is still known about large-cell neuroendocrine carcinoma and carcinoid tumors. A major finding has been the nonnegligible inter and intratumor heterogeneity of lung cancer and their impact in the clinical management of this disease. SUMMARY: The high load of mutations, the frequent inactivation of major tumor suppressor genes, and the huge heterogeneity of lung cancer tumors may complicate long lasting therapeutic responses. The development of strategies for the early detection of lung cancer might translate into an increase of the number of surgical resectable tumors, and therefore contribute to improve the survival rate of these patients. PMID- 26569423 TI - MicroRNA networks in pulmonary arterial hypertension: share mechanisms with cancer? AB - PURPOSE OF REVIEW: Pulmonary arterial hypertension (PAH) is a rare disease with poor prognosis and no therapeutics. PAH is characterized by severe remodeling of precapillary pulmonary arteries, leading to increased vascular resistance, pulmonary hypertension compensatory right ventricular hypertrophy, then heart failure and death. PAH pathogenesis shares similarities with carcinogenesis such as excessive cell proliferation, apoptosis resistance, metabolic shifts, or phenotypic transition. Although PAH is not a cancer, comparison of analogous mechanisms between PAH and cancer led to the concept of a cancer-like disease to emerge. MicroRNAs (miRNAs) are small noncoding RNAs involved in the regulation of posttranscriptional gene expression. miRNA dysregulations have been reported as promoter of the development of various diseases including cancers. RECENT FINDINGS: Recent studies revealed that miRNA dysregulations also occur in PAH pathogenesis. In PAH, different miRNAs have been implicated to be the main features of PAH pathophysiology (in pulmonary inflammation, vascular remodeling, angiogenesis, and right heart hypertrophy). SUMMARY: The review summarizes the implication of miRNA dysregulation in PAH development and discusses the similarities and differences with those observed in cancers. PMID- 26569424 TI - Follicular cell thyroid neoplasia: insights from genomics and The Cancer Genome Atlas research network. AB - PURPOSE OF REVIEW: The present review is focused on the recently published study on the genomics of papillary thyroid carcinoma performed by The Cancer Genome Atlas Research Network and its implications for the follicular variant of papillary carcinoma. RECENT FINDINGS: The Cancer Genome Atlas study of papillary thyroid carcinoma comprehensively examined the cancer genome of nearly 500 primary tumors. Using a highly integrated bioinformatic analysis, papillary carcinoma was shown at the genomic level to consist of two highly distinct classes that reflected both tumor histology and underlying genotype. Tumors with true papillary architecture were dominated by BRAF(V600E) mutations and RET kinase fusions and were designated as BRAF(V600E)-like. Tumors with follicular architecture were conversely dominated by RAS mutations and were designated as RAS-like. Given the strong genotype:phenotype correlation known to be present in thyroid cancer, the separation of BRAF(V600E)-like and RAS-like tumors has profound implications for its classification, especially the follicular variant of papillary carcinoma. SUMMARY: The recent genomic characterization of papillary thyroid carcinoma is challenging the established pathological classification of thyroid cancer with significance for the care of patients. PMID- 26569425 TI - Precision medicine ethics: selected issues and developments in next-generation sequencing, clinical oncology, and ethics. AB - PURPOSE OF REVIEW: In early 2015 the National Institutes of Health launched a new, national Precision Medicine Initiative with the primary goal of rapidly improving the prevention, diagnosis, and treatment of cancers. The first-stage emphasis on oncology presents unique opportunities for clinical oncology to influence how the ethical challenges of precision medicine are to be articulated and addressed. Thus, a review of recent developments in connection with the Initiative, in particular on core ethics issues in clinical genomics, is a useful starting point. RECENT FINDINGS: Unique ethical issues arise in precision medicine because of the enormous amounts of data generated by clinical whole genome or whole-exome sequencing and the extent of current uncertainties with respect to data interpretations and disease associations. Among the most ethically challenging issues for clinicians are complicated informed consent processes, returning results - particularly secondary and incidental findings-and privacy and confidentiality. SUMMARY: The first tests of precision medicine ethics in practice will be in clinical oncology, providing a rare opportunity to shape the agenda and integrate practical ethics considerations. These efforts can benefit from pre-existing research ethics analyses and recommendations from clinical and translational genetics research. PMID- 26569426 TI - How to Put Your Best Self Forward in Plastic Surgery Residency Interviews. PMID- 26569427 TI - The Effect of Anesthetic Choice (Sevoflurane Versus Desflurane) and Neuromuscular Management on Speed of Airway Reflex Recovery. AB - BACKGROUND: Nonintubated patients receiving sevoflurane have slower protective airway reflex recovery after anesthesia compared with patients receiving desflurane. We asked whether this difference would remain significant among intubated patients receiving rocuronium or whether the impact of variable neuromuscular recovery would predominate and thus minimize differences between anesthetics. METHODS: After obtaining written informed consent, patients were randomly assigned to receive sevoflurane (n = 41) or desflurane (n = 40), with neuromuscular monitoring by quantitative train-of-four (TOF) method using accelerometry. Intubation was facilitated by administration of 1 mg/kg rocuronium. Neuromuscular block was produced, with the goal of maintaining 10% to 15% of baseline function. After surgery, neostigmine 70 ug/kg + glycopyrrolate 14 ug/kg was administered. When TOF ratio reached >= 0.7, anesthetic was discontinued and fresh gas flow was raised to 15 L/m. The time of first response to command was noted, after which patients were given a 20-mL water swallowing test at 2, 6, 14, 22, 30, and 60 minutes. The following average time intervals were compared between the 2 intervention groups: anesthetic discontinuation to first response to command (T1); first response to command to first successful passing of swallow test (T2); and anesthetic discontinuation to first successful passing of swallow test (T3). We also compared the rates of successful swallow tests at 2 minutes after first response to command in the 2 groups, first categorizing as failures all those who were unable to take the test at 2 minutes, and then excluding 10 patients unable to take the test at this time for reasons other than somnolence (n = 10). RESULTS: Patients receiving desflurane passed the swallowing test at shorter time intervals after first response to command than did patients receiving sevoflurane (Wilcoxon-Mann-Whitney odds = 1.60; 95% confidence interval [CI], 1.01-2.69; P = 0.054). Two minutes after the first response to command, among all 81 patients, the chance of passing the swallowing test was higher after desflurane compared with sevoflurane anesthesia (relative risk = 1.6; 95% CI, 1.0-2.5; P = 0.04). Of the 71 patients (as above), we observed a significantly higher chance of passing at 2 minutes after first response to command (relative risk = 1.8; 95% CI, 1.2-2.7; P = 0.006) in patients receiving desflurane (25/33) compared with those receiving sevoflurane (16/38). In 18 of 81 and 16 of 71 patients, the neuromuscular monitoring and reversal protocols were not followed (neostigmine underdosed, extubation at TOF <0.7, or reliance on tactile as opposed to quantitative TOF measurement). In both the total cohort and the subset of 71, neuromuscular protocol adherence increased the chance of passing the swallow test, independent of anesthetic assignment in multivariable logistic regression (P = 0.02 and P = 0.006, respectively), demonstrating significant effect on airway reflex recovery independent of chosen anesthetic. CONCLUSIONS: Compared with sevoflurane, desflurane allowed faster recovery of airway reflexes after anesthesia in intubated patients. Clinical management of neuromuscular block, including full reversal and the use of quantitative TOF, affects airway reflex recovery-an effect that may be at least as profound as the choice of potent inhaled anesthetic. PMID- 26569428 TI - The proportion of distal fibula Salter-Harris type I epiphyseal fracture in the paediatric population with acute ankle injury: a prospective MRI study. AB - Ankle injuries are common among the paediatric population. There are few prospective studies utilizing MRI to diagnose a clinically suspected Salter Harris type I of the distal fibula (SH1FDF). The aim of this study was to examine the proportion of clinically suspected SH1FDF in children. All paediatric patients with ankle injury, seen at the emergency room from September 2012 to May 2013 at a single institution, underwent a standardized clinical examination, and their radiographs were obtained if found necessary. All images and data were recorded prospectively and patients suspected of having SH1FDF were referred for MRI of the ankle joint. Out of 391 paediatric patients seen at the emergency room with ankle injury, 38 patients had a clinical suspicion of SH1FDF. A total of 31 patients, 18 male and 13 female, with a mean age of 10 +/- 2.86 years, were included in the study. Only seven patients were excluded from the study. MRI was obtained on an average of 6.9 +/- 2.87 days. None of the included patients had evidence of SH1FDF on MRI. Our study and review of the literature verifies the high false-positive rate of clinically suspected SH1FDF. Most children had ligamentous lesions, bone contusion or joint effusion, rather than SH1FDF. PMID- 26569429 TI - A solitary unilobed osteochondroma of the hamate: a case report. AB - Solitary osteochondromas originating from the carpal bones are very uncommon; when they occur, they usually arise from the scaphoid or capitate. We report a solitary, unilobed osteochondroma arising from the hamate that was excised, with no evidence of recurrence at the 3-year follow-up. PMID- 26569430 TI - Two cases of macrodactyly of the foot: relevance in pediatric orthopedics. AB - Congenital enlargement of one or several digits of the foot, known as macrodactyly, is a rare malformation. Macrodactyly impedes foot development and affects function and gait. Here, we describe a surgical technique used to correct macrodactyly in two pediatric patients. We performed amputation of the enlarged phalanx and debulking of the soft tissues to construct a normal-sized digit. This precise technique involves a simple surgical plan that preserves the metatarsus and cuneiform and does not result in a wide plantapedis. Both patients subsequently showed improved gait and were able to wear normal shoes. PMID- 26569431 TI - The fate of lateral femoral cutaneous nerve after surgical reduction of developmental dysplasia of the hip: preliminary results. AB - This study aimed to determine the fate of the lateral femoral cutaneous nerve (LFCN) after anterior reduction of the hip with or without pelvic or proximal femoral osteotomy for acetabular dysplasia. Using the antidromic technique, recording the response using standard electromyography equipment, evaluation was made of the LFCN in 36 hips of 24 patients (18 female and six male). The response was absent in six patients (25%) and nine patients (37.5%) had a somatosensory evoked potential latency greater than 40 ms. There was no relationship between somatosensory evoked potential latency or absent response with the type of incision or procedure (P=0.229 and 0.794, respectively). LFCN injury after anterior open reduction of the hip has an unexpectedly high incidence in the young paediatric age group. Exposure of the nerve during surgery can negatively affect the nerve nutrition leading to neuropraxia. PMID- 26569432 TI - Dendritic cells in brain diseases. PMID- 26569433 TI - Intramolecular Conjugate Additions with Heterocyclic Olefins. AB - The intramolecular reactions of olefinic N-heterocycles have been studied. In triflic acid-promoted reactions, conjugate addition is observed with pyrazine-, 2 pyrimidine-, and 2-quinoxaline-based olefins and a phenyl group nucleophile. Markovnikov addition is observed with pyridine and 5-quinoxaline-based olefins. These results are in accordance with previous observations relating the type of addition-conjugate or Markovnikov-to the positions of olefinic substituents of the N-heterocycle. PMID- 26569434 TI - The timing of verb selection in Japanese sentence production. AB - Many influential models of sentence production (e.g., Bock & Levelt, 1994; Kempen & Hoenkamp, 1987; Levelt, 1989) emphasize the central role of verbs in structural encoding, and thus predict that verbs should be selected early in sentence formulation, possibly even before the phonological encoding of the first constituent (Ferreira, 2000). However, the most direct experimental test of this hypothesis (Schriefers, Teruel, & Meinshausen, 1998) found no evidence for advance verb selection in verb-final (subject-verb and subject-object-verb) utterances in German. The current study, based on a multiword picture-word interference task (Meyer, 1996; Schriefers et al., 1998), demonstrates that in Japanese, a strongly verb-final language, verbs are indeed planned in advance, but selectively before object noun articulation and not before subject noun articulation. This contrasting pattern of advance verb selection may reconcile the motivation for advance verb selection in structural encoding while explaining the previous failures to demonstrate it. Potential mechanisms that might underlie this contrasting pattern of advance verb selection are discussed. (PsycINFO Database Record PMID- 26569435 TI - Incidental learning of rewarded associations bolsters learning on an associative task. AB - Reward has been shown to change behavior as a result of incentive learning (by motivating the individual to increase their effort) and instrumental learning (by increasing the frequency of a particular behavior). However, Palminteri et al. (2011) demonstrated that reward can also improve the incidental learning of a motor skill even when participants are unaware of the relationship between the reward and the motor act. Nonetheless, it remains unknown whether these effects of reward are the indirect results of manipulations of top-down factors. To identify the locus of the benefit associated with rewarded incidental learning, we used a chord-learning task (Seibel, 1963) in which the correct performance of some chords was consistently rewarded with points necessary to complete the block whereas the correct performance of other chords was not rewarded. Following training, participants performed a transfer phase without reward and then answered a questionnaire to assess explicit awareness about the rewards. Experiment 1 revealed that rewarded chords were performed more quickly than unrewarded chords, and there was little awareness about the relationship between chords and reward. Experiment 2 obtained similar findings with simplified responses to show that the advantage for rewarded stimulus combinations reflected more efficient binding of stimulus-response (S-R) associations, rather than a response bias for rewarded associations or improved motor learning. These results indicate that rewards can be used to significantly improve the learning of S-R associations without directly manipulating top-down factors. (PsycINFO Database Record PMID- 26569436 TI - Reasoning and memory: People make varied use of the information available in working memory. AB - Working memory (WM) is used for storing information in a highly accessible state so that other mental processes, such as reasoning, can use that information. Some WM tasks require that participants not only store information, but also reason about that information to perform optimally on the task. In this study, we used visual WM tasks that had both storage and reasoning components to determine both how ideally people are able to reason about information in WM and if there is a relationship between information storage and reasoning. We developed novel psychological process models of the tasks that allowed us to estimate for each participant both how much information they had in WM and how efficiently they reasoned about that information. Our estimates of information use showed that participants are not all ideal information users or minimal information users, but rather that there are individual differences in the thoroughness of information use in our WM tasks. However, we found that our participants tended to be more ideal than minimal. One implication of this work is that to accurately estimate the amount of information in WM, it is important to also estimate how efficiently that information is used. This new analysis contributes to the theoretical premise that human rationality may be bounded by the complexity of task demands. (PsycINFO Database Record PMID- 26569437 TI - Consider the alternative: The effects of causal knowledge on representing and using alternative hypotheses in judgments under uncertainty. AB - Four experiments examined the locus of impact of causal knowledge on consideration of alternative hypotheses in judgments under uncertainty. Two possible loci were examined; overcoming neglect of the alternative when developing a representation of a judgment problem and improving utilization of statistics associated with the alternative hypothesis. In Experiment 1, participants could search for information about the various components of Bayes's rule in a diagnostic problem. A majority failed to spontaneously search for information about an alternative hypothesis, but this bias was reduced when a specific alternative hypothesis was mentioned before search. No change in search patterns was found when a generic alternative cause was mentioned. Experiments 2a and 2b broadly replicated these patterns when participants rated or made binary judgments about the relevance of each of the Bayesian components. In contrast, Experiment 3 showed that when participants were given the likelihood of the data given a focal hypothesis p(D|H) and an alternative hypothesis p(D|!H), they gave estimates of p(H|D) that were consistent with Bayesian principles. Additional causal knowledge had relatively little impact on such judgments. These results show that causal knowledge primarily affects neglect of the alternative hypothesis at the initial stage of problem representation. (PsycINFO Database Record PMID- 26569438 TI - Association Between DSCR1 Variations and Congenital Heart Disease Susceptibility. AB - BACKGROUND The objective of this study was aimed to detect the association of Down syndrome critical region 1 (DSCR1) gene polymorphisms (rs149048873 and rs143081213) and congenital heart disease (CHD) susceptibility. MATERIAL AND METHODS This case-control study included 102 CHD patients and 113 healthy controls. Cases and controls were matched in age and gender. Genotypes of DSCR1 gene polymorphisms were detected by TaqMan method in cases and controls. Hardy Weinberg equilibrium (HWE) examination was performed by PLINK 1.0 software. Chi square test was utilized to assess the distribution of the genotypes and the alleles. Relative risk of CHD was presented by odds ratios (ORs) with 95% confidence intervals (CIs). All of the calculations were implemented using SPSS 18.0. RESULTS Variant genotype distribution of rs149048873 and rs143081213 mutations were higher in cases than in controls, but the differences were not statistically obvious (P>0.05). Additionally, frequencies of mutant allele of the two polymorphisms were also significantly different in case and control groups (P>0.05). CONCLUSIONS No significant associations existed between DSCR1 gene rs149048873 and rs143081213 polymorphisms and CHD susceptibility. PMID- 26569439 TI - Transition-Metal-Free Oxidative Aliphatic C-H Azidation. AB - The first example of a practical and selective azidation of unactivated aliphatic C-H bonds with easily handled sulfonyl azides as azide source without the use of transition metals has been explored. This method is operationally simple, scalable, and applicable to late-stage azidation of natural products and derivatives, which make it a valuable method for the synthesis of organic azides. PMID- 26569440 TI - The influence of bexarotene, a selective agonist of the retinoid receptor X (RXR), and tazarotene, a selective agonist of the retinoid acid receptor (RAR), on bone metabolism in rats. AB - PURPOSE: The purpose of this study was to investigate the influence of selective agonists of the retinoid receptor X (RXR) and the retinoid acid receptor (RAR) on bone metabolism in rats. METHODS: Thirty six male Wistar rats were divided into three groups: receiving bexarotene, or tazarotene, or to control group. Serum biochemical markers of bone turnover (osteocalcin - OC, tartrate resistant acid phosphatase 5 - TRACP5b and osteoprotegerin - OPG) and mechanical properties of bones were analyzed. RESULTS: There was a significant decrease in the femur index value in groups receiving tazarotene and bexarotene on Day 14 (8% and 20% respectively, p=0.0039). On Day 28, 14 days after discontinuation of tazarotene and bexarotene, the difference in femur indexes was still significant (4% for T1 6 and B1-6, p=0.0270). In the bexarotene group an increase in mean plasma osteocalcin level and mean plasma TRACP5b level was detected. In the tazarotene group the mean osteocalcin level remained unchanged and the mean plasma TRACP5b level decreased. An increased yield stress was detected in groups receiving retinoids comparing to controls after 14 days of tazarotene and bexarotene administration. CONCLUSION: Although bexarotene and tazarotene administration caused decrease in the femur index, mechanisms responsible for that effect seem to be different. Our results suggest that bexaroten increases bone turnover. On the contrary, tazaroten seems to have inhibitory effect on bone turnover. A counter influence of selective RAR and RXR agonists on the bone turnover might be the reason for inconsistency in results from published research concerning the influence of retinoids on bone metabolism. PMID- 26569441 TI - Polypyrrole and graphene quantum dots @ Prussian Blue hybrid film on graphite felt electrodes: Application for amperometric determination of l-cysteine. AB - A novel polypyrrole (PPy) and graphene quantum dots (GQDs) @ Prussian Blue (PB) nanocomposite has been grafted on a graphite felt (GF) substrate (PPy/GQDs@PB/GF), and has been proven to be an efficient electrochemical sensor for the determination of l-cysteine (l-cys). GQDs, which were fabricated by carbonization of citric acid and adsorbed on GF surface ultrasonically, played an important role for promoting the synthesis process of PB via a spontaneous redox reaction between Fe(3+) and [Fe(CN)6](3-). The PPy film has been electro polymerized to improve the electrochemical stability of the PPy/GQDs@PB/GF electrode. The as-prepared electrode was characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), infrared spectroscopy (IR), X-ray diffraction (XRD) and electrochemical methods. It exhibited an excellent activity for the electrocatalytic oxidation of l-cys, with a detection sensitivity equal to 0.41 Amol(-1) L for a concentration range of 0.2-50 MUmolL( 1), and equal to 0.15 Amol(-1) L for a concentration range of 50-1000 MUmolL(-1). A low detection limit of 0.15 MUmolL(-1), as well as a remarkable long-time stability and a negligible sensitivity to interfering analytes, were also ascertained. PMID- 26569442 TI - A novel platform for high sensitivity determination of PbP2a based on gold nanoparticles composited graphitized mesoporous carbon and doxorubicin loaded hollow gold nanospheres. AB - Gold nanoparticles composite graphitized mesoporous carbon nanoparticles (GMCs@AuNPs) biocomposite with the signal amplification capability was successfully synthesized for use in an immunoassay for penicillin binding protein 2 a (PbP2a). The polyamidoamine (PAMAM) dendrimers were first electrodeposited onto the Au electrode can greatly increase the amount of the captured antibodies. Protein A was used to properly orientate immobilized antibody against PbP2a, which strongly improved specificity of the antigen-antibody binding. Hollow gold nanospheres (HGNPs) as effective nanocarriers have been synthesized by sacrificial galvanic replacement of cobalt nanoparticles capable of encapsulating doxorubicin (Dox). The obtained HGNPs@Dox bionanocomposite was used for further loading of detection antibody (Ab2) to form the HGNPs@Dox@Ab2 bioconjugate. Then, the differential pulse voltammetric signals related to the concentration of PbP2a for Dox could be detected, and the immunosensor exhibited a detection limit as low as 0.65 pg mL(-1) (at an S/N ratio of 3). The proposed method with an excellent differentiation ability showed high sensitivity and specificity. The morphologies and electrochemistry properties of the composites were investigated by scanning electron microscopy, electrochemical characterization, UV-visible absorption spectroscopy, fluorescence spectrophotometer and Malvern laser particle size analyzer, respectively. In addition, the basic approach described here would be applicable towards developing biodetection assays against other important targets. Moreover, the bioconjugate of HGNPs@Dox is also a promising pattern to delivery Dox in vivo for anticancer therapy. PMID- 26569443 TI - Polyethylene glycol (PEG) gel arrays for differentiating oligopeptide fragments and on-chip protease assays. AB - Polyethylene glycol (PEG) hydrogel is permeable to biomolecules, but its permeability depends on the molecular weight of monomers and the concentration of monomer solutions. In this study, we show that PEG hydrogel made from 20% to 30% of PEG700 monomer is permeable to amino acids yet impermeable to oligopeptides. Because of its unique permeability, the gel can be used to detect protease by separating amino acids from oligopeptides when proteases cleave the oligopeptides and release amino acids. Based on this principle, an UV crosslinked gel array is fabricated on a chip for simultaneous detection of protease in up to 40 samples with only 1 ul of volume required for each sample. As a proof of concept, the on chip protease assays are used to detect trypsin in buffer and serum. The detection limits are 1.2 nM in buffer and 17.7 nM in serum, which are comparable to conventional protease assays. Moreover, because only 1 ul of liquid is required, as little as 1.2 fmol of trypsin can be detected by using the on-chip assay. The protease assay also shows good specificity for trypsin and chymotrypsin. The gel array chip could be a useful miniaturized platform for high throughput detection of different proteases and screening of their inhibitors. PMID- 26569444 TI - Imprinting of molecular recognition sites combined with pi-donor-acceptor interactions using bis-aniline-crosslinked Au-CdSe/ZnS nanoparticles array on electrodes: Development of electrochemiluminescence sensor for the ultrasensitive and selective detection of 2-methyl-4-chlorophenoxyacetic acid. AB - A novel strategy is reported for the fabrication of bis-aniline-crosslinked Au nanoparticles (NPs)-CdSe/ZnS quantum dots (QDs) array composite by facil one-step co-electropolymerization of thioaniline-functionalized AuNPs and thioaniline functionalized CdSe/ZnS QDs onto thioaniline-functionalized Au elctrodes (AuE). Stable and enhanced cathodic electrochemiluminescence (ECL) of CdSe/ZnS QDs is observed on the modified electrode in neutral solution, suggesting promising applications in ECL sensing. An advanced ECL sensor is explored for detection of 2-methyl-4-chlorophenoxyacetic acid (MCPA) which quenches the ECL signal through electron-transfer pathway. The sensitive determination of MCPA with limit of detection (LOD) of 2.2 nmolL(-1) (S/N=3) is achieved by pi-donor-acceptor interactions between MCPA and the bis-aniline bridging units. Impressively, the imprinting of molecular recognition sites into the bis-aniline-crosslinked AuNPs CdSe/ZnS QDs array yields a functionalized electrode with an extremely sensitive response to MCPA in a linear range of 10 pmolL(-1)-50 MUmolL(-1) with a LOD of 4.3 pmolL(-1 ()S/N=3). The proposed ECL sensor with high sensitivity, good selectivity, reproducibility and stability has been successfully applied for the determination of MCPA in real samples with satisfactory recoveries. In this study, ECL sensor combined the merits of QDs-ECL and molecularly imprinting technology is reported for the first time. The developed ECL sensor holds great promise for the fabrication of QDs-based ECL sensors with improved sensitivity and furthermore opens the door to wide applications of QDs-based ECL in food safety and environmental monitoring. PMID- 26569445 TI - Real-time direct electrochemical sensing of ascorbic acid over rat liver tissues using RuO2 nanowires on electrospun TiO2 nanofibers. AB - This paper reports that the high electrocatalytic activity of RuO2 nanowires grown on electrospun TiO2 nanofibers for the oxidation of l-ascorbic acid (AA); and the application of these materials for direct selective sensing of AA in complex samples. Compared to bare glassy carbon (GC) electrode, RuO2 nanowires on TiO2 nanofibers-loaded GC electrode facilitates the oxidation of AA most drastically among the tested species: AA, 4-acetamidophenol (AP), dopamine (DA), uric acid (UA), and glucose. The amperometric response of RuO2 nanowires on TiO2 nanofibers at the applied potential of 0.018 V (vs. SCE) exhibits high sensitivity (268.2 +/- 3.7 MUAmM(-1)cm(-2), n=5), low detection limit (<1.8 MUM), great linearity, reasonable stability, and exclusive selectivity over AP, DA, glucose and UA at their physiological levels. In differential pulse voltammetry, it is verified that the potential resolution of RuO2 nanowires on TiO2 nanofibers is able to differentiate AA, DA, UA, and AP one from the others. In addition, as prepared RuO2 nanowires on TiO2 nanofibers are successfully applied for direct and selective AA measurements in commercial vitamin samples and for the real-time direct analysis of AA generated from living rat liver tissue in vitro. PMID- 26569446 TI - Towards autonomous lab-on-a-chip devices for cell phone biosensing. AB - Modern cell phones are a ubiquitous resource with a residual capacity to accommodate chemical sensing and biosensing capabilities. From the different approaches explored to capitalize on such resource, the use of autonomous disposable lab-on-a-chip (LOC) devices-conceived as only accessories to complement cell phones-underscores the possibility to entirely retain cell phones' ubiquity for distributed biosensing. The technology and principles exploited for autonomous LOC devices are here selected and reviewed focusing on their potential to serve cell phone readout configurations. Together with this requirement, the central aspects of cell phones' resources that determine their potential for analytical detection are examined. The conversion of these LOC concepts into universal architectures that are readable on unaccessorized phones is discussed within this context. PMID- 26569447 TI - IUD services among primary care practices in New York City. AB - OBJECTIVE: Intrauterine devices (IUDs) are one of the most effective forms of reversible contraception and can reduce unintended pregnancy rates. We explored practice characteristics associated with IUD services across a network of primary care practices in New York City during 2010-2013. STUDY DESIGN: Data were extracted from electronic health records (EHRs) for 253 primary care practices participating in an EHR quality improvement program in New York City. We used diagnostic and procedure codes to count IUD insertions and removals among females aged 10-49 years during 2010-2013. Logistic regression models predicted the likelihood of IUD insertion, removal or no activity for 2013, based on practice characteristics. We stratified trends in IUD services over time by practice type and specialty. RESULTS: From 2010 to 2013, the proportion of practices that inserted IUDs increased slightly from 4.7% to 6.3% (p=0.17), and the proportion removing IUDs increased from 8.3% to 12.3% (p<0.01). More than 60% of obstetricians/gynecologists and midwives performed insertions or removals each year; fewer than 10% of internal medicine and pediatric providers did so. Community health centers had higher odds of performing removals than independent practices (adjusted odds ratio=10.24, 95% confidence interval: 3.37-31.17). Practices seeing >66% female patients had higher odds of performing both insertions and removals. CONCLUSIONS: From 2010 to 2013, IUD services increased but remained low among primary care practices in this network. Provider training and system readiness programs should include independent primary care practices, which rarely provide IUDs, to ensure that women can receive IUDs or IUD service referrals in the primary care setting. IMPLICATIONS: Much of primary care in the United States takes place in independent practices with one or two providers. Our study of a major urban area found that these types of practices are much less likely to offer IUD services than community health centers. Ensuring that small practices know where to refer women for IUD insertion and removal services is warranted to ensure women's access to IUDs. PMID- 26569448 TI - What makes a likely abortion provider? Evidence from a nationwide survey of final year students at Ghana's public midwifery training colleges. AB - BACKGROUND: Even in countries where the abortion law is technically liberal, the full application of the law has been delayed due to resistance on the part of providers to offer services. Ghana has a liberal law, allowing abortions for a wide range of indications. The current study sought to investigate factors associated with midwifery students' reported likelihood to provide abortion services. METHODS: Final-year students at 15 public midwifery training colleges participated in a computer-based survey. Demographic and attitudinal variables were tested against the outcome variable, likely to provide comprehensive abortion care (CAC) services, and those variables found to have a significant association in bivariate analysis were entered into a multivariate model. Marginal effects were assessed after the final logistic regression was conducted. RESULTS: A total of 853 out of 929 eligible students enrolled in the 15 public midwifery schools took the survey, for a response rate of 91.8%. In multivariate regression analysis, the factors significantly associated with reported likeliness to provide CAC services were having had an unplanned pregnancy, currently using contraception, feeling adequately prepared, agreeing it is a good thing women can get a legal abortion and having been exposed to multiple forms of education around surgical abortion. DISCUSSION: Midwifery students at Ghana's public midwifery training colleges report that they are likely to provide CAC. Ensuring that midwives-in-training are well trained in abortion services, as well as encouraging empathy in these students, may increase the number of providers of safe abortion care in Ghana. PMID- 26569449 TI - Synchronized Desorption Electrospray Ionization Mass Spectrometry Imaging. AB - Desorption electrospray ionization (DESI) has emerged as a powerful technique for mass spectral analysis and imaging under ambient conditions. Synchronization of DESI (sDESI) with the ion injection period (IT)of low-duty cycle mass spectrometers has been previously shown to improve sensitivity and reduce the amount of sample depleted during the acquisition of each spectrum (viz. MS scan time). In this report, we describe the development and characterization of an sDESI mass spectrometry imaging source (sDESI-MSI). Our results show that synchronization of DESI with the IT of an LTQ Orbitrap-XL mass spectrometer improves spatial resolution by factors of ~4-6. In addition, under certain experimental conditions, synchronization was essential to acquire distinct MS images of low-intensity endogenous FAs (< 5% relative intensity) in fingermarks at high sampling frequencies (step sizes <= 75 MUm). The magnitudes of these improvements in performance depend on the properties of the microdroplet spray, sample, and surface. Simulations that model analyte movement during desorption and the "washing effect" replicate the experimental results with the washing parameter having the greatest impact on performance. Thus, synchronization improves spatial resolution and sensitivity by decreasing the percentage of the total MS scan time that analytes are influenced by the "washing effect". Generally, synchronization of DESI with IT improves performance and expands the range of analytes, surfaces, and experimental conditions amenable to DESI-MSI, especially for analytes that are weakly attached to a surface. PMID- 26569450 TI - Multiple phase transitions in Pauli-limited iron-based superconductors. AB - Specific heat measurements have been successfully used to probe unconventional superconducting phases in one-band heavy-fermion and organic superconductors. We extend the method to study successive phase transitions in multi-band materials such as iron-based superconductors. The signatures are multiple peaks in the specific heat, at low temperatures and high magnetic field, which can lead to the experimental verification of unconventional superconducting states with non-zero total momentum. PMID- 26569451 TI - Acute effects of varying intensities of treadmill walking exercise on inhibitory control in persons with multiple sclerosis: A pilot investigation. AB - INTRODUCTION: Exercise training represents a promising approach for managing cognitive impairment in persons with multiple sclerosis (MS). There is preliminary evidence that treadmill walking might be the modality of exercise that exerts the greatest beneficial effects on inhibitory control in fully ambulatory persons with MS. However, the dose-dependent effects of varying intensities of treadmill walking exercise on this cognitive function are unknown. Such an investigation is critical for better delineating the optimal exercise stimulus (or stimuli) for improving inhibitory control in MS. METHODS: The present study compared the acute effects of light, moderate, and vigorous intensity treadmill walking exercise on inhibitory control (i.e., interference control) relative to quiet rest in 24 fully-ambulatory persons with MS, using a within-subjects, repeated-measures experimental design. Participants completed four experimental conditions that consisted of 20min of light, moderate, and vigorous intensity treadmill walking exercise, and quiet rest in a randomized, counterbalanced order. Participants underwent a modified flanker task as a measure of inhibitory control immediately prior to and following each condition. RESULTS: Repeated-measures ANOVAs indicated large, statistically significant reductions in the cost of interfering stimuli on reaction time, but not accuracy, on the modified flanker task for light, moderate, and vigorous intensity exercise compared with quiet rest (F(3,69)=4.27, p=.01, etap(2)=.16). There were no differences in magnitude of reduction across the three exercise intensities. CONCLUSIONS: The present results support light, moderate, and vigorous intensity treadmill walking as exercise stimuli that might particularly benefit interference control of reaction time. This represents the next step in delineating the optimal exercise stimuli for improving this cognitive function in fully-ambulatory persons with MS, and perhaps is important for informing a subsequent longitudinal exercise training intervention. PMID- 26569452 TI - Oxidative costs of reproduction: Oxidative stress in mice fed standard and low antioxidant diets. AB - Lactation is one of the most energetically expensive behaviours, and trade-offs may exist between the energy devoted to it and somatic maintenance, including protection against oxidative damage. However, conflicting data exist for the effects of reproduction on oxidative stress. In the wild, a positive relationship is often observed, but in laboratory studies oxidative damage is often lower in lactating than in non-breeding animals. We hypothesised that this discrepancy may exist because during lactation food intake increases many-fold resulting in a large increase in the intake of dietary antioxidants which are typically high in laboratory rodent chow where they are added as a preservative. We supplied lactating and non-breeding control mice with either a standard or low antioxidant diet and studied how this affected the activity of endogenous antioxidants (catalase, superoxide dismutase; SOD, and glutathione peroxidise; GPx) and oxidative damage to proteins (protein carbonyls, PC) in liver and brain tissue. The low antioxidant diet did not significantly affect activities of antioxidant enzymes in brain or liver, and generally did not result in increased protein damage, except in livers of control mice on low antioxidant diet. Catalase activity, but not GPx or SOD, was decreased in both control and lactating mice on the low antioxidant diet. Lactating mice had significantly reduced oxidative damage to both liver and brain compared to control mice, independent of the diet they were given. In conclusion, antioxidant content of the diet did not affect oxidative stress in control or reproductive mice, and cannot explain the previously observed reduction in oxidative stress in lactating mammals studied in the laboratory. The reduced oxidative stress in the livers of lactating mice even under low antioxidant diet treatment was consistent with the 'shielding' hypothesis. PMID- 26569453 TI - Riboflavin acetate induces apoptosis in squamous carcinoma cells after photodynamic therapy. AB - Several research efforts have been focused on finding newer and more efficient photosensitizers for photodynamic therapy (PDT). Although, it was demonstrated that riboflavin is an efficient photosensitizer for PDT, the effect of its ester derivate, riboflavin 2',3',4',5'-tetraacetate (RFTA), which has higher cellular uptake, has not been well defined. To evaluate the cell death generated by applying RFTA as the photosensitizer in PDT in a human cancer cell line of squamous carcinoma (SCC-13), these cells were incubated with riboflavin and its ester derivate, RFTA followed by irradiation with different blue light doses. Cell viability was evaluated using neutral red uptake assay and cell death was evaluated using transmission electron microscopy, TUNEL assay and annexin V PE/7AAD double staining. The expression of caspase-3, Bax, Bcl-2, ERK 1/2 and p38(MAPK) was evaluated by Western blotting and generation of intracellular ROS and changes in anion superoxide levels were analyzed using 2',7' dichlorofluorescein-diacetate and dihydroethidium dye, respectively. RFTA-PDT generated a decrease in cancer cell viability in a light dose-response. Treated SCC-13 cells exhibited chromatin condensation, formation of apoptotic bodies, increases in TUNEL-positive cells, phosphatidylserine externalization and decreased procaspase-3 and Bcl-2 protein expression and increment of ERK 1/2 phosphorylation. Moreover, trolox abolished the effect of PDT on cell viability linking the increase in intracellular ROS levels with the cell death observed, whereas that the pre-treatment with MEK inhibitor did not induce changes in SCC 13 cell survival. These findings demonstrate the effects of RFTA in triggering apoptosis induced by ROS (?O2(-)) production after visible light irradiation of squamous carcinoma cells. PMID- 26569454 TI - Chlorin e6-mediated photodynamic effect diminishes therapeutic potential of 5-aza 2'-deoxycytidine-based whole-tumour-cell vaccine in mice bearing squamous cell carcinoma SCCVII. AB - After years of setbacks, therapeutic cancer vaccines have become an alternative treatment option. Among the diversity of targeted tumour associated antigens (TAA), cancer-testis antigens (CTAs) are promising targets for cancer immunotherapy because they are highly immunogenic; meanwhile, they are expressed in human tumours of different histological origin but not in adult somatic tissues. Epigenetic modifications, such as DNA methylation, regulate CTAs expression both in normal and cancer cells. 5-Aza-2'-deoxycytidine (5-AZA-CdR), a DNA hypomethylating drug, induces the expression of CTAs in neoplastic cells. In these studies, we used 5-AZA-CdR-mediated up-regulation of CTAs and chlorin e6 mediated photodynamic effect in the production of a whole-tumour-cell vaccine against murine squamous cell carcinoma SCCVII in C3H/HeN mice. The results show that 5-AZA-CdR can be used to elevate levels of diverse CTAs in SCCVII cells. The 5-AZA-CdR-based vaccine, combined with the systemic administration of 5-AZA-CdR, delayed tumour growth. However, the treatment had no effect on survival in mice, most likely because of the toxicity of systemic treatment with 5-AZA-CdR. The photodynamic effect diminished therapeutic potential of 5-AZA-CdR-based vaccine. Chemo-immunotherapy with 5-AZA-CdR and therapeutic cancer vaccines may be an alternative approach to cancer therapy. However, further studies are needed to optimize treatment and vaccine preparation protocols. PMID- 26569455 TI - Personality and ectoparasitic mites (Hemipteroseius adleri) in firebugs (Pyrrhocoris apterus). AB - Individuals of the same species often consistently differ in their behaviour across time and context. These stable differences are usually termed 'animal personality'. Parasitism is known to significantly influence the evolution of animal personality at least in part because more explorative individuals may meet parasites more frequently than less explorative ones. Previously, we have demonstrated that consistent individual differences (i.e. boldness, activity, exploration) can be measured in firebugs. As continuation, we examined here the relationship between firebug personality traits and their ectoparasitic mite loads in a wild population. We showed that bugs that behaved in a more explorative way have more mites and we also found a marginally significant interaction between sex, boldness and activity: bolder and more active female firebugs were more infected. In addition, we experimentally tested whether an artificial infection causes any alteration in the bug's behaviour and whether there is any relationship between firebug personality and immune response. This treatment did not induce any alteration in bugs' personality. We found that bugs become more explorative but less active when repeating the experiment, but at the same time all personality traits (boldness, activity and exploration) were repeatable. Furthermore, firebugs with a stronger immune response behaved more boldly but also less actively. PMID- 26569456 TI - Scaling like behaviour of resistivity observed in LaNiO3 thin films grown on SrTiO3 substrate by pulsed laser deposition. AB - We discuss the origin of the temperature dependence of resistivity rho observed in highly oriented LaNiO3 thin films grown on SrTiO3 substrate by a pulsed laser deposition technique. All the experimental data are found to collapse into a single universal curve rho(T, d) ? [T/T(sf)(d)]3/2 for the entire temperature interval (20K4 g in 24 h, exceeding the recommended daily dose. RESULTS: One hundred eighteen surveys were completed (response rate 100%, 56% females). Forty-one (35% of total) participants took >4 g within the 24-h scenario period. About 24% (10/42) of the standard packaging group, 37% (13/35) of the standard packaging + pre-existing warning label group and 48% (19/40) of the SP + large customized warning label group ingested >4 g of paracetamol. There were no significant differences between the three groups (p > 0.05). CONCLUSION: In this small, simulated dental pain scenario, use of customized warning labels did not reduce the likelihood of supratherapeutic misadventure. PMID- 26569471 TI - Dietary supplementation with sodium bicarbonate improves calcium absorption and eggshell quality of laying hens during peak production. AB - The advantage of supplemental sodium bicarbonate (NaHCO3) on eggshell quality in laying hens changes with age. Besides increasing calcium (Ca) secretion in the eggshell gland, it may improve Ca absorption in the intestine or kidney. Hy-Line Brown layers (n = 384), 25 weeks of age, were allocated to two treatment groups in two experiments, each of which included 4 replicates of 24 hens. Hens were fed a basal diet (control) or the basal diet containing 3 g NaHCO3 g/kg for 50 or 20 weeks in Experiment 1 or 2, respectively. A 24-h continuous lighting regimen was used to allow hens to consume the dietary supplements during the period of active eggshell formation. In Experiment 1, particularly from 25 to 50 weeks of age, and in Experiment 2, NaHCO3 supplementation favoured hen-d egg production at the expense of lower egg weight. The increased eggshell thickness should have nothing to do with the additional eggshell formation, because of the unchanged egg mass and daily eggshell calcification. At 35 weeks of age in both experiments, NaHCO3 supplementation increased duodenal expression of calbindin-d28k (CaBP-D28k) protein, contributing to higher Ca retention and balance. From 50 to 75 weeks of age in Experiment 1, the hens had little response to NaHCO3 supplementation and showed a negative trend on eggshell thickness and strength. It is concluded that dietary supplementation with 3 g NaHCO3 g/kg improves Ca absorption and eggshell quality of laying hens during the peak but not late production period, with the introduction of continuous lighting. PMID- 26569472 TI - YouTube Video as Health Literacy Tool: A Test of Body Image Campaign Effectiveness. AB - This study examined the effectiveness of four media campaigns about disordered eating behaviors. It investigated possible factors that affected females' perceived effectiveness of four campaign videos. Results indicated that health campaign about a celebrity's struggle with extreme thinness proved to be the least effective of four campaign videos, whereas the video presenting solid facts about the dangers of extreme dieting was perceived as the most effective campaign. Self-discrepancy was not a significant predictor to females' perceived effectiveness of campaign videos. Similarly, the frequency of Internet usage was proved as a weak predictor of their perceived effectiveness. These findings and the possible rationale for the lack of support with regard to the correlates of campaign effectiveness were also discussed. PMID- 26569473 TI - Fundamental limits of material toughening in molecularly confined polymers. AB - The exceptional mechanical properties of polymer nanocomposites are achieved through intimate mixing of the polymer and inorganic phases, which leads to spatial confinement of the polymer phase. In this study we probe the mechanical and fracture properties of polymers in the extreme limits of molecular confinement, where a stiff inorganic phase confines the polymer chains to dimensions far smaller than their bulk radius of gyration. We show that polymers confined at molecular length scales dissipate energy through a confinement induced molecular bridging mechanism that is distinct from existing entanglement based theories of polymer deformation and fracture. We demonstrate that the toughening is controlled by the molecular size and the degree of confinement, but is ultimately limited by the strength of individual molecules. PMID- 26569474 TI - A magnetic protein biocompass. AB - The notion that animals can detect the Earth's magnetic field was once ridiculed, but is now well established. Yet the biological nature of such magnetosensing phenomenon remains unknown. Here, we report a putative magnetic receptor (Drosophila CG8198, here named MagR) and a multimeric magnetosensing rod-like protein complex, identified by theoretical postulation and genome-wide screening, and validated with cellular, biochemical, structural and biophysical methods. The magnetosensing complex consists of the identified putative magnetoreceptor and known magnetoreception-related photoreceptor cryptochromes (Cry), has the attributes of both Cry- and iron-based systems, and exhibits spontaneous alignment in magnetic fields, including that of the Earth. Such a protein complex may form the basis of magnetoreception in animals, and may lead to applications across multiple fields. PMID- 26569475 TI - Spatially orthogonal chemical functionalization of a hierarchical pore network for catalytic cascade reactions. AB - The chemical functionality within porous architectures dictates their performance as heterogeneous catalysts; however, synthetic routes to control the spatial distribution of individual functions within porous solids are limited. Here we report the fabrication of spatially orthogonal bifunctional porous catalysts, through the stepwise template removal and chemical functionalization of an interconnected silica framework. Selective removal of polystyrene nanosphere templates from a lyotropic liquid crystal-templated silica sol-gel matrix, followed by extraction of the liquid crystal template, affords a hierarchical macroporous-mesoporous architecture. Decoupling of the individual template extractions allows independent functionalization of macropore and mesopore networks on the basis of chemical and/or size specificity. Spatial compartmentalization of, and directed molecular transport between, chemical functionalities affords control over the reaction sequence in catalytic cascades; herein illustrated by the Pd/Pt-catalysed oxidation of cinnamyl alcohol to cinnamic acid. We anticipate that our methodology will prompt further design of multifunctional materials comprising spatially compartmentalized functions. PMID- 26569476 TI - Thermodynamics of the hybrid interaction of hydrogen with palladium nanoparticles. AB - Palladium-hydrogen is a prototypical metal-hydrogen system. It is therefore not at all surprising that a lot of attention has been devoted to the absorption and desorption of hydrogen in nanosized palladium particles. Several seminal articles on the interaction of H with Pd nanocubes and nanoparticles have recently been published. Although each article provides for the first time detailed data on specific aspects of hydrogen in nanoparticles, they individually do not contain enough information to draw firm conclusions about the involved mechanisms. Here, we show that the large body of data available so far in literature exhibits general patterns that lead to unambiguous conclusions about the processes involved in H absorption and desorption in Pd nanoparticles. On the basis of a remarkably robust scaling law for the hysteresis in absorption-desorption isotherms, we show that hydrogen absorption in palladium nanoparticles is consistent with a coherent interface model and is thus clearly different from bulk Pd behaviour. However, H desorption occurs fully coherently only for small nanoparticles (typically smaller than 50 nm) at temperatures sufficiently close to the critical temperature. For larger particles it is partially incoherent, as in bulk, where dilute alpha-PdHx and high concentration beta-PdHx phases coexist. PMID- 26569478 TI - The Effect of Apatinib on the Metabolism of Carvedilol Both in vitro and in vivo. AB - BACKGROUND: In light of the growing number of cancer survivors, the incidence of cardiovascular complications in these patients had also increased, while the effect of apatinib on the pharmacokinetic of cardioprotective drug (carvedilol) in rats or human is still unknown. The present work was to study the impact of apatinib on the metabolism of carvedilol both in vitro and vivo. METHODS: A specific and sensitive ultra-performance liquid-chromatography tandem mass spectrometry method was applied to determine the concentration of carvedilol and its metabolites (4'-hydroxyphenyl carvedilol [4'-HPC], 5'-hydroxyphenyl carvedilol [5'-HPC] and o-desmethyl carvedilol [o-DMC]). RESULTS: The inhibition ratios in human liver microsomes were 10.28, 10.89 and 5.94% for 4'-HPC, 5'-HPC and o-DMC, respectively, while in rat liver microsomes, they were 3.22, 1.58 and 1.81%, respectively. The data in vitro of rat microsomes were consistent with the data in vivo that the inhibition of 4'-HPC and 5'-HPC formation was higher than the control group. CONCLUSION: Our study showed that apatinib could significantly inhibit the formation of carvedilol metabolites both in human and rat liver microsomes. It is recommended that the effect of apatinib on the metabolism of carvedilol should be noted and carvedilol plasma concentration should be monitored. PMID- 26569480 TI - Antioxidants Therapy for Patients with Chronic Kidney Disease: A Question of Balance. PMID- 26569479 TI - Evolution of Diffusion-Weighted Magnetic Resonance Imaging Signal Abnormality in Sporadic Creutzfeldt-Jakob Disease, With Histopathological Correlation. AB - IMPORTANCE: Prion diseases represent the archetype of brain diseases caused by protein misfolding, with the most common subtype being sporadic Creutzfeldt-Jakob disease (sCJD), a rapidly progressive dementia. Diffusion-weighted imaging (DWI) has emerged as the most sensitive magnetic resonance imaging (MRI) sequence for the diagnosis of sCJD, but few studies have assessed the evolution of MRI signal as the disease progresses. OBJECTIVES: To assess the natural history of the MRI signal abnormalities on DWI in sCJD to improve our understanding of the pathogenesis and to investigate the potential of DWI as a biomarker of disease progression, with histopathological correlation. DESIGN, SETTING, AND PARTICIPANTS: Gray matter involvement on DWI was assessed among 37 patients with sCJD in 26 cortical and 5 subcortical subdivisions per hemisphere using a semiquantitative scoring system of 0 to 2 at baseline and follow-up. A total brain score was calculated as the summed scores in the individual regions. In 7 patients, serial mean diffusivity measurements were obtained. Age at baseline MRI, disease duration, atrophy, codon 129 methionine valine polymorphism, Medical Research Council Rating Scale score, and histopathological findings were documented. The study setting was the National Prion Clinic, London, England. All participants had a probable or definite diagnosis of sCJD and had at least 2 MRI studies performed during the course of their illness. The study dates were October 1, 2008 to April 1, 2012. The dates of our analysis were January 19 to April 20, 2012. MAIN OUTCOMES AND MEASURES: Correlation of regional and total brain scores with disease duration. RESULTS: Among the 37 patients with sCJD in this study there was a significant increase in the number of regions demonstrating signal abnormality during the study period, with 59 of 62 regions showing increased signal intensity (SI) at follow-up, most substantially in the caudate and putamen (P < .001 for both). The increase in the mean (SD) total brain score from 30.2 (17.3) at baseline to 40.5 (20.6) at follow-up (P = .001) correlated with disease duration (r = 0.47, P = .003 at baseline and r = 0.35, P = .03 at follow-up), and the left frontal SI correlated with the degree of spongiosis (r = 0.64, P = .047). Decreased mean diffusivity in the left caudate at follow-up was seen (P < .001). Eight patients demonstrated decreased SI in cortical regions, including the left inferior temporal gyrus and the right lingual gyrus. CONCLUSIONS AND RELEVANCE: Magnetic resonance images in sCJD show increased extent and degree of SI on DWI that correlates with disease duration and the degree of spongiosis. Although cortical SI may fluctuate, increased basal ganglia SI is a consistent finding and is due to restricted diffusion. Diffusion weighted imaging in the basal ganglia may provide a noninvasive biomarker in future therapeutic trials. PMID- 26569481 TI - An Electropolymerized Crystalline Film Incorporating Axially-Bound Metalloporphycenes: Remarkable Reversibility, Reproducibility, and Coloration Efficiency of Ruthenium(II/III)-Based Electrochromism. AB - Oxidative electropolymeization of an axially bound, bithiophene-pyridine complex of ruthenium(III)-porphycene [Ru(TPrPc) (btp)2]PF6 (1) gives a submicrometer thick, polymeric film on an ITO electrode with a crystalline morphology. The polymeric film, the first example of axially linked multimetalloporphycene coordination arrays, exhibits highly stable and reproducible electrochromic response with high electrochromic efficiency upon electrochemical control over the metal-centered electron transfer process (Ru(II)/Ru(III)). PMID- 26569482 TI - Statistical Mechanics of the Human Placenta: A Stationary State of a Near Equilibrium System in a Linear Regime. AB - All near-equilibrium systems under linear regime evolve to stationary states in which there is constant entropy production rate. In an open chemical system that exchanges matter and energy with the exterior, we can identify both the energy and entropy flows associated with the exchange of matter and energy. This can be achieved by applying statistical mechanics (SM), which links the microscopic properties of a system to its bulk properties. In the case of contractile tissues such as human placenta, Huxley's equations offer a phenomenological formalism for applying SM. SM was investigated in human placental stem villi (PSV) (n = 40). PSV were stimulated by means of KCl exposure (n = 20) and tetanic electrical stimulation (n = 20). This made it possible to determine statistical entropy (S), internal energy (E), affinity (A), thermodynamic force (A / T) (T: temperature), thermodynamic flow (v) and entropy production rate (A / T x v). We found that PSV operated near equilibrium, i.e., A ?? 2500 J/mol and in a stationary linear regime, i.e., (A / T) varied linearly with v. As v was dramatically low, entropy production rate which quantified irreversibility of chemical processes appeared to be the lowest ever observed in any contractile system. PMID- 26569483 TI - Complementary Effects of Host Defense Peptides Piscidin 1 and Piscidin 3 on DNA and Lipid Membranes: Biophysical Insights into Contrasting Biological Activities. AB - Piscidins were the first antimicrobial peptides discovered in the mast cells of vertebrates. While two family members, piscidin 1 (p1) and piscidin 3 (p3), have highly similar sequences and alpha-helical structures when bound to model membranes, p1 generally exhibits stronger antimicrobial and hemolytic activity than p3 for reasons that remain elusive. In this study, we combine activity assays and biophysical methods to investigate the mechanisms underlying the cellular function and differing biological potencies of these peptides, and report findings spanning three major facets. First, added to Gram-positive (Bacillus megaterium) and Gram-negative (Escherichia coli) bacteria at sublethal concentrations and imaged by confocal microscopy, both p1 and p3 translocate across cell membranes and colocalize with nucleoids. In E. coli, translocation is accompanied by nonlethal permeabilization that features more pronounced leakage for p1. Second, p1 is also more disruptive than p3 to bacterial model membranes, as quantified by a dye-leakage assay and (2)H solid-state NMR-monitored lipid acyl chain order parameters. Oriented CD studies in the same bilayers show that, beyond a critical peptide concentration, both peptides transition from a surface bound state to a tilted orientation. Third, gel retardation experiments and CD monitored titrations on isolated DNA demonstrate that both peptides bind DNA but p3 has stronger condensing effects. Notably, solid-state NMR reveals that the peptides are alpha-helical when bound to DNA. Overall, these studies identify two polyreactive piscidin isoforms that bind phosphate-containing targets in a poised amphipathic alpha-helical conformation, disrupt bacterial membranes, and access the intracellular constituents of target cells. Remarkably, the two isoforms have complementary effects; p1 is more membrane active, while p3 has stronger DNA condensing effects. Subtle differences in their physicochemical properties are highlighted to help explain their contrasting activities. PMID- 26569484 TI - Chronic Mild Cold Conditioning Modulates the Expression of Hypothalamic Neuropeptide and Intermediary Metabolic-Related Genes and Improves Growth Performances in Young Chicks. AB - BACKGROUND: Low environmental temperatures are among the most challenging stressors in poultry industries. Although landmark studies using acute severe cold exposure have been conducted, still the molecular mechanisms underlying cold stress responses in birds are not completely defined. In the present study we determine the effect of chronic mild cold conditioning (CMCC) on growth performances and on the expression of key metabolic-related genes in three metabolically important tissues: brain (main site for feed intake control), liver (main site for lipogenesis) and muscle (main site for thermogenesis). METHODS: 80 one-day old male broiler chicks were divided into two weight-matched groups and maintained in two different temperature floor pen rooms (40 birds/room). The temperature of control room was 32 degrees C, while the cold room temperature started at 26.7 degrees C and gradually reduced every day (1 degrees C/day) to reach 19.7 degrees C at the seventh day of the experiment. At day 7, growth performances were recorded (from all birds) and blood samples and tissues were collected (n = 10). The rest of birds were maintained at the same standard environmental condition for two more weeks and growth performances were measured. RESULTS: Although feed intake remained unchanged, body weight gain was significantly increased in CMCC compared to the control chicks resulting in a significant low feed conversion ratio (FCR). Circulating cholesterol and creatine kinase levels were higher in CMCC chicks compared to the control group (P<0.05). CMCC significantly decreased the expression of both the hypothalamic orexigenic neuropeptide Y (NPY) and anorexigenic cocaine and amphetamine regulated transcript (CART) in chick brain which may explain the similar feed intake between the two groups. Compared to the control condition, CMCC increased the mRNA abundance of AMPKalpha1/alpha2 and decreased mTOR gene expression (P<0.05), the master energy and nutrient sensors, respectively. It also significantly decreased the expression of fatty acid synthase (FAS) gene in chick brain compared to the control. Although their roles are still unknown in avian species, adiponectin (Adpn) and its related receptors (AdipoR1 and 2) were down regulated in the brain of CMCC compared to control chicks (P<0.05). In the liver, CMCC significantly down regulated the expression of lipogenic genes namely FAS, acetyl CoA carboxylase alpha (ACCalpha) and malic enzyme (ME) and their related transcription factors sterol regulatory element binding protein 1/2 (SREBP-1 and 2). Hepatic mTOR mRNA levels and phosphorylated mTOR at Ser2448 were down regulated (P<0.05), however phosphorylated ACCalphaSer79 (inactivation) was up regulated (P<0.05) in CMCC compared to control chicks, indicating that CMCC switch hepatic catabolism on and inhibits hepatic lipogenesis. In the muscle however, CMCC significantly up regulated the expression of carnitine palmitoyltransferase 1 (CPT-1) gene and the mRNA and phosphorylated protein levels of mTOR compared to the control chicks, indicating that CMCC enhanced muscle fatty acid beta-oxidation. CONCLUSIONS: In conclusion, this is the first report indicating that CMCC may regulate AMPK-mTOR expression in a tissue specific manner and identifying AMPK-mTOR as a potential molecular signature that controls cellular fatty acid utilization (inhibition of hepatic lipogenesis and induction of muscle fatty acid beta-oxidation) to enhance growth performance during mild cold acclimation. PMID- 26569485 TI - Salivary Heparanase Level Is a Potential Biomarker to Diagnose and Prognose the Malignant Salivary Gland Tumor. AB - BACKGROUND: Upregulation of heparanase has been reported in an increasing number of human cancer tissues. However, the level of salivary heparanase and its clinical significance in patients with salivary gland tumors remain unclear. METHODS: Salivary heparanase levels in patients with salivary gland tumors were detected using enzyme-linked immunosorbent assays (ELISAs) and the clinical significance was evaluated by analyzing the correlations among salivary heparanase levels, clinicopathological parameters, and clinical outcomes. RESULTS: The levels of salivary heparanase were significantly higher in patients with malignant salivary gland tumors than in benign tumors and normal controls (P<0.0001). High salivary heparanase levels were positively correlated with increased lymph node metastasis (P = 0.0235) and poorer tumor node metastasis stage (TNM) (P = 0.0183). Survival analyses revealed that high salivary heparanase levels were associated with worse overall survival (P = 0.0023) and disease-free survival (DFS) (P = 0.0025). CONCLUSIONS: The study shows that salivary heparanase levels, as detected by the ELISAs, can be used to diagnose and provide an accurate prognosis for malignant salivary gland tumors. Salivary heparanase level was an independent predictor in patients with malignant salivary gland tumors. PMID- 26569486 TI - Integral Histogram with Random Projection for Pedestrian Detection. AB - In this paper, we give a systematic study to report several deep insights into the HOG, one of the most widely used features in the modern computer vision and image processing applications. We first show that, its magnitudes of gradient can be randomly projected with random matrix. To handle over-fitting, an integral histogram based on the differences of randomly selected blocks is proposed. The experiments show that both the random projection and integral histogram outperform the HOG feature obviously. Finally, the two ideas are combined into a new descriptor termed IHRP, which outperforms the HOG feature with less dimensions and higher speed. PMID- 26569487 TI - Costs and Cost Effectiveness of Three Approaches for Cervical Cancer Screening among HIV-Positive Women in Johannesburg, South Africa. AB - BACKGROUND: South Africa has high rates of HIV and HPV and high incidence and mortality from cervical cancer. However, cervical cancer is largely preventable when early screening and treatment are available. We estimate the costs and cost effectiveness of conventional cytology (Pap), visual inspection with acetic acid (VIA) and HPV DNA testing for detecting cases of CIN2+ among HIV-infected women currently taking antiretroviral treatment at a public HIV clinic in Johannesburg, South Africa. METHODS: Method effectiveness was derived from a validation study completed at the clinic. Costs were estimated from the provider perspective using micro-costing between June 2013-April 2014. Capital costs were annualized using a discount rate of 3%. Two different service volume scenarios were considered. Threshold analysis was used to explore the potential for reducing the cost of HPV DNA testing. RESULTS: VIA was least costly in both scenarios. In the higher volume scenario, the average cost per procedure was US$ 3.67 for VIA, US$ 8.17 for Pap and US$ 54.34 for HPV DNA. Colposcopic biopsies cost on average US$ 67.71 per procedure. VIA was least sensitive but most cost-effective at US$ 17.05 per true CIN2+ case detected. The cost per case detected for Pap testing was US$ 130.63 using a conventional definition for positive results and US$ 187.52 using a more conservative definition. HPV DNA testing was US$ 320.09 per case detected. Colposcopic biopsy costs largely drove the total and per case costs. A 71% reduction in HPV DNA screening costs would make it competitive with the conservative Pap definition. CONCLUSIONS: Women need access to services which meet their needs and address the burden of cervical dysplasia and cancer in this region. Although most cost-effective, VIA may require more frequent screening due to low sensitivity, an important consideration for an HIV-positive population with increased risk for disease progression. PMID- 26569489 TI - Correction: Novel Functions and Regulation of Cryptic Cellobiose Operons in Escherichia coli. PMID- 26569488 TI - Nitrogen Limited Red and Green Leaf Lettuce Accumulate Flavonoid Glycosides, Caffeic Acid Derivatives, and Sucrose while Losing Chlorophylls, Beta-Carotene and Xanthophylls. AB - Reduction of nitrogen application in crop production is desirable for ecological and health-related reasons. Interestingly, nitrogen deficiency can lead to enhanced concentrations of polyphenols in plants. The reason for this is still under discussion. The plants' response to low nitrogen concentration can interact with other factors, for example radiation intensity. We cultivated red and green leaf lettuce hydroponically in a Mediterranean greenhouse, supplying three different levels of nitrogen (12 mM, 3 mM, 0.75 mM), either in full or reduced ( 50%) radiation intensity. In both red and green lettuce, we found clear effects of the nitrogen treatments on growth characteristics, phenolic and photosynthetic compounds, nitrogen, nitrate and carbon concentration of the plants. Interestingly, the concentrations of all main flavonoid glycosides, caffeic acid derivatives, and sucrose increased with decreasing nitrogen concentration, whereas those of chlorophylls, beta-carotene, neoxanthin, lactucaxanthin, all trans- and cis-violaxanthin decreased. The constitutive concentrations of polyphenols were lower in the green cultivar, but their relative increase was more pronounced than in the red cultivar. The constitutive concentrations of chlorophylls, beta-carotene, neoxanthin, all trans- and cis-violaxanthin were similar in red and green lettuce and with decreasing nitrogen concentration they declined to a similar extent in both cultivars. We only detected little influence of the radiation treatments, e.g. on anthocyanin concentration, and hardly any interaction between radiation and nitrogen concentration. Our results imply a greater physiological plasticity of green compared to the red lettuce regarding its phenolic compounds. They support the photoprotection theory regarding anthocyanins as well as the theory that the deamination activity of phenylalanine ammonia-lyase drives phenylpropanoid synthesis. PMID- 26569490 TI - Two New Potential Barcodes to Discriminate Dalbergia Species. AB - DNA barcoding enables precise identification of species from analysis of unique DNA sequence of a target gene. The present study was undertaken to develop barcodes for different species of the genus Dalbergia, an economically important timber plant and is widely distributed in the tropics. Ten Dalbergia species selected from the Western Ghats of India were evaluated using three regions in the plastid genome (matK, rbcL, trnH-psbA), a nuclear transcribed spacer (nrITS) and their combinations, in order to discriminate them at species level. Five criteria: (i) inter and intraspecific distances, (ii) Neighbor Joining (NJ) trees, (iii) Best Match (BM) and Best Close Match (BCM), (iv) character based rank test and (v) Wilcoxon signed rank test were used for species discrimination. Among the evaluated loci, rbcL had the highest success rate for amplification and sequencing (97.6%), followed by matK (97.0%), trnH-psbA (94.7%) and nrITS (80.5%). The inter and intraspecific distances, along with Wilcoxon signed rank test, indicated a higher divergence for nrITS. The BM and BCM approaches revealed the highest rate of correct species identification (100%) with matK, matK+rbcL and matK+trnH-psb loci. These three loci, along with nrITS, were further supported by character based identification method. Considering the overall performance of these loci and their ranking with different approaches, we suggest matK and matK+rbcL as the most suitable barcodes to unambiguously differentiate Dalbergia species. These findings will potentially be helpful in delineating the various species of Dalbergia genus, as well as other related genera. PMID- 26569493 TI - Correction: Repressive LTR Nucleosome Positioning by the BAF Complex Is Required for HIV Latency. AB - [This corrects the article DOI: 10.1371/journal.pbio.1001206.]. PMID- 26569492 TI - Combination of Insecticide Treated Nets and Indoor Residual Spraying in Northern Tanzania Provides Additional Reduction in Vector Population Density and Malaria Transmission Rates Compared to Insecticide Treated Nets Alone: A Randomised Control Trial. AB - Indoor residual spraying (IRS) combined with insecticide treated nets (ITN) has been implemented together in several sub-Saharan countries with inconclusive evidence that the combined intervention provides added benefit. The impact on malaria transmission was evaluated in a cluster randomised trial comparing two rounds of IRS with bendiocarb plus universal coverage ITNs, with ITNs alone in northern Tanzania. From April 2011 to December 2012, eight houses in 20 clusters per study arm were sampled monthly for one night with CDC light trap collections. Anopheles gambiae s.l. were identified to species using real time PCR Taq Man and tested for the presence of Plasmodium falciparum circumsporozoite protein. ITN and IRS coverage was estimated from household surveys. IRS coverage was more than 85% in two rounds of spraying in January and April 2012. Household coverage with at least one ITN per house was 94.7% after the universal coverage net campaign in the baseline year and the proportion of household with all sleeping places covered by LLIN was 50.1% decreasing to 39.1% by the end of the intervention year. An.gambiae s.s. comprised 80% and An.arabiensis 18.3% of the anopheline collection in the baseline year. Mean An.gambiae s.l. density in the ITN+IRS arm was reduced by 84% (95%CI: 56%-94%, p = 0.001) relative to the ITN arm. In the stratum of clusters categorised as high anopheline density at baseline EIR was lower in the ITN+IRS arm compared to the ITN arm (0.5 versus 5.4 per house per month, Incidence Rate Ratio: 0.10, 95%CI: 0.01-0.66, p-value for interaction <0.001). This trial provides conclusive evidence that combining carbamate IRS and ITNs produces major reduction in Anopheles density and entomological inoculation rate compared to ITN alone in an area of moderate coverage of LLIN and high pyrethroid resistance in An.gambiae s.s. PMID- 26569491 TI - Work Disability among Employees with Diabetes: Latent Class Analysis of Risk Factors in Three Prospective Cohort Studies. AB - BACKGROUND: Studies of work disability in diabetes have examined diabetes as a homogeneous disease. We sought to identify subgroups among persons with diabetes based on potential risk factors for work disability. METHODS: Participants were 2,445 employees with diabetes from three prospective cohorts (the Finnish Public Sector study, the GAZEL study, and the Whitehall II study). Work disability was ascertained via linkage to registers of sickness absence and disability pensions during a follow-up of 4 years. Study-specific latent class analysis was used to identify subgroups according to prevalent comorbid disease and health-risk behaviours. Study-specific associations with work disability at follow-up were pooled using fixed-effects meta-analysis. RESULTS: Separate latent class analyses for men and women in each cohort supported a two-class solution with one subgroup (total n = 1,086; 44.4%) having high prevalence of chronic somatic diseases, psychological symptoms, obesity, physical inactivity and abstinence from alcohol and the other subgroup (total n = 1,359; 55.6%) low prevalence of these factors. In the adjusted meta-analyses, participants in the 'high-risk' group had more work disability days (pooled rate ratio = 1.66, 95% CI 1.38-1.99) and more work disability episodes (pooled rate ratio = 1.33, 95% CI 1.21-1.46). These associations were similar in men and women, younger and older participants, and across occupational groups. CONCLUSIONS: Diabetes is not a homogeneous disease in terms of work disability risk. Approximately half of people with diabetes are assigned to a subgroup characterised by clustering of comorbid health conditions, obesity, physical inactivity, abstinence of alcohol, and associated high risk of work disability; the other half to a subgroup characterised by a more favourable risk profile. PMID- 26569494 TI - Gender Specific Association of Serum Leptin and Insulinemic Indices with Nonalcoholic Fatty Liver Disease in Prediabetic Subjects. AB - Adipose tissue-derived hormone leptin plays a functional role in glucose tolerance through its effects on insulin secretion and insulin sensitivity which also represent the risk factors for nonalcoholic fatty liver disease (NAFLD). The present study explored the gender specific association of serum leptin and insulinemic indices with NAFLD in Bangladeshi prediabetic subjects. Under a cross sectional analytical design a total of 110 ultrasound examined prediabetic subjects, aged 25-68 years consisting of 57.3% male (55.6% non NAFLD and 44.4% NAFLD) and 42.7% female (57.4% non NAFLD and 42.6% NAFLD), were investigated. Insulin secretory function (HOMA%B) and insulin sensitivity (HOMA%S) were calculated from homeostasis model assessment (HOMA). Serum leptin showed significant positive correlation with fasting insulin (r = 0.530, P = 0.004), postprandial insulin (r = 0.384, P = 0.042) and HOMA-IR (r = 0.541, P = 0.003) as well as significant negative correlation with HOMA%S (r = -0.388, P = 0.046) and HOMA%B (r = -0.356, P = 0.039) in male prediabetic subjects with NAFLD. In multiple linear regression analysis, log transformed leptin showed significant positive association with HOMA-IR (beta = 0.706, P <0.001) after adjusting the effects of body mass index (BMI), triglyceride (TG) and HOMA%B in male subjects with NAFLD. In binary logistic regression analysis, only log leptin [OR 1.29 95% (C.I) (1.11-1.51), P = 0.001] in male subjects as well as HOMA%B [OR 0.94 95% (C.I) (0.89-0.98), P = 0.012], HOMA-IR [OR 3.30 95% (C.I) (0.99-10.95), P = 0.049] and log leptin [OR 1.10 95% (C.I) (1.01-1.20), P = 0.026] in female subjects were found to be independent determinants of NAFLD after adjusting the BMI and TG. Serum leptin seems to have an association with NAFLD both in male and female prediabetic subjects and this association in turn, is mediated by insulin secretory dysfunction and insulin resistance among these subjects. PMID- 26569495 TI - Medium-term follow-up of 92 femoral component revisions using a third-generation cementing technique. AB - BACKGROUND AND PURPOSE: Very little has been published on the outcome of femoral cemented revisions using a third-generation cementing technique. We report the medium-term outcome of a consecutive series of patients treated in this way. PATIENTS AND METHODS: This study included 92 consecutive cemented femoral revisions performed in our department with a third-generation cementing technique and without instrumented bone impaction grafting between 1996 and 2007. The average age of the patients at revision was 66 (25-92) years. None of the patients were lost to follow-up. At review in December 2013, 55 patients were still alive and had a non-re-revised femoral revision component in situ after a mean follow-up of 11 (5-17) years. RESULTS: The mean preoperative Harris hip score was 50, and improved to 73 at final follow-up. 2 patients died shortly after the revision surgery. 1 stem was re-revised for aseptic loosening; this was also the only case with radiolucent lines in all 7 Gruen zones. A femoral reoperation was performed in 19 hips during follow-up, and in 14 of these 19 reoperations the femoral component was re-revised. Survivorship at 10 years, with femoral re-revision for any reason as the endpoint, was 86% (95% CI: 77-92). However, excluding 8 patients with reinfections after septic index revisions and 1 with hematogenous spread of infection from the survival analysis, the adjusted survival for re-revision for any reason at 10 years was 92% (95% CI: 83-96). With re-revision for aseptic loosening as endpoint, the survival at 10 years was 99% (CI: 90-100). INTERPRETATION: Femoral component revision with a third-generation cemented stem results in acceptable survival after medium-term follow-up. We recommend the use of this technique in femoral revisions with limited loss of bone stock. PMID- 26569496 TI - TOR-dependent post-transcriptional regulation of autophagy. AB - Regulation of autophagy is required to maintain cellular equilibrium and prevent disease. While extensive study of post-translational mechanisms has yielded important insights into autophagy induction, less is known about post transcriptional mechanisms that could potentiate homeostatic control. In our study, we showed that the RNA-binding protein, Dhh1 in Saccharomyces cerevisiae and Vad1 in the pathogenic yeast Cryptococcus neoformans is involved in recruitment and degradation of key autophagy mRNAs. In addition, phosphorylation of the decapping protein Dcp2 by the target of rapamycin (TOR), facilitates decapping and degradation of autophagy-related mRNAs, resulting in repression of autophagy under nutrient-replete conditions. The post-transcriptional regulatory process is conserved in both mouse and human cells and plays a role in autophagy related modulation of the inflammasome product IL1B. These results were then applied to provide mechanistic insight into autoimmunity of a patient with a PIK3CD/p110delta gain-of-function mutation. These results thus identify an important new post-transcriptional mechanism of autophagy regulation that is highly conserved between yeast and mammals. PMID- 26569497 TI - Quality of Health Insurance Coverage and Access to Care for Children in Low Income Families. AB - IMPORTANCE: An increasing diversity of children's health coverage options under the US Patient Protection and Affordable Care Act, together with uncertainty regarding reauthorization of the Children's Health Insurance Program (CHIP) beyond 2017, merits renewed attention on the quality of these options for children. OBJECTIVE: To compare health care access, quality, and cost outcomes by insurance type (Medicaid, CHIP, private, and uninsured) for children in households with low to moderate incomes. DESIGN, SETTING, AND PARTICIPANTS: A repeated cross-sectional analysis was conducted using data from the 2003, 2007, and 2011-2012 US National Surveys of Children's Health, comprising 80,655 children 17 years or younger, weighted to 67 million children nationally, with household incomes between 100% and 300% of the federal poverty level. Multivariable logistic regression models compared caregiver-reported outcomes across insurance types. Analysis was conducted between July 14, 2014, and May 6, 2015. EXPOSURES: Insurance type was ascertained using a caregiver-reported measure of insurance status and each household's poverty status (percentage of the federal poverty level). MAIN OUTCOMES AND MEASURES: Caregiver-reported outcomes related to access to primary and specialty care, unmet needs, out-of pocket costs, care coordination, and satisfaction with care. RESULTS: Among the 80,655 children, 51,123 (57.3%) had private insurance, 11,853 (13.6%) had Medicaid, 9554 (18.4%) had CHIP, and 8125 (10.8%) were uninsured. In a multivariable logistic regression model (with results reported as adjusted probabilities [95% CIs]), children insured by Medicaid and CHIP were significantly more likely to receive a preventive medical (Medicaid, 88% [86% 89%]; P < .01; CHIP, 88% [87%-89%]; P < .01) and dental (Medicaid, 80% [78%-81%]; P < .01; CHIP, 77% [76%-79%]; P < .01) visits than were privately insured children (medical, 83% [82%-84%]; dental, 73% [72%-74%]). Children with all insurance types experienced challenges in access to specialty care, with caregivers of children insured by CHIP reporting the highest rates of difficulty accessing specialty care (28% [24%-32%]), problems obtaining a referral (23% [18% 29%]), and frustration obtaining health care services (26% [23%-28%]). These challenges were also magnified for privately insured children with special health care needs, whose caregivers reported significantly greater problems accessing specialty care (29% [26%-33%]) and frustration obtaining health care services (36% [32%-41%]) than did caregivers of children insured by Medicaid, and a lower likelihood of insurance always meeting the child's needs (63% [60%-67%]) than children insured by Medicaid or CHIP. Caregivers of privately insured children were also significantly more likely to experience out-of-pocket costs (77% [75% 78%]) than were caregivers of children insured by Medicaid (26% [23%-28%]; P < .01) or CHIP (38% [35%-40%]; P < .01). CONCLUSIONS AND RELEVANCE: This examination of caregiver experiences across insurance types revealed important differences that can help guide future policymaking regarding coverage for families with low to moderate incomes. PMID- 26569498 TI - Virtual reality and neuropsychological assessment: The reliability of a virtual kitchen to assess daily-life activities in victims of traumatic brain injury. AB - Traumatic brain injury (TBI) causes impairments affecting instrumental activities of daily living (IADL). However, few studies have considered virtual reality as an ecologically valid tool for the assessment of IADL in patients who have sustained a TBI. The main objective of the present study was to examine the use of the Nonimmersive Virtual Coffee Task (NI-VCT) for IADL assessment in patients with TBI. We analyzed the performance of 19 adults suffering from TBI and 19 healthy controls (HCs) in the real and virtual tasks of making coffee with a coffee machine, as well as in global IQ and executive functions. Patients performed worse than HCs on both real and virtual tasks and on all tests of executive functions. Correlation analyses revealed that NI-VCT scores were related to scores on the real task. Moreover, regression analyses demonstrated that performance on NI-VCT matched real-task performance. Our results support the idea that the virtual kitchen is a valid tool for IADL assessment in patients who have sustained a TBI. PMID- 26569499 TI - A New Comparative-Genomics Approach for Defining Phenotype-Specific Indicators Reveals Specific Genetic Markers in Predatory Bacteria. AB - Predatory bacteria seek and consume other live bacteria. Although belonging to taxonomically diverse groups, relatively few bacterial predator species are known. Consequently, it is difficult to assess the impact of predation within the bacterial realm. As no genetic signatures distinguishing them from non-predatory bacteria are known, genomic resources cannot be exploited to uncover novel predators. In order to identify genes specific to predatory bacteria, we developed a bioinformatic tool called DiffGene. This tool automatically identifies marker genes that are specific to phenotypic or taxonomic groups, by mapping the complete gene content of all available fully-sequenced genomes for the presence/absence of each gene in each genome. A putative 'predator region' of ~60 amino acids in the tryptophan 2,3-dioxygenase (TDO) protein was found to probably be a predator-specific marker. This region is found in all known obligate predator and a few facultative predator genomes, and is absent from most facultative predators and all non-predatory bacteria. We designed PCR primers that uniquely amplify a ~180bp-long sequence within the predators' TDO gene, and validated them in monocultures as well as in metagenetic analysis of environmental wastewater samples. This marker, in addition to its usage in predator identification and phylogenetics, may finally permit reliable enumeration and cataloguing of predatory bacteria from environmental samples, as well as uncovering novel predators. PMID- 26569500 TI - Combined Analysis of Plasma Amphiregulin and Heregulin Predicts Response to Cetuximab in Metastatic Colorectal Cancer. AB - BACKGROUND: Amphiregulin, a ligand of the epidermal growth factor receptor (EGFR), is associated with the efficacy of cetuximab, an antibody against EGFR, as treatment for colorectal cancer (CRC). In contrast, the HER3 ligand heregulin correlates with cetuximab resistance. In this study, we evaluated how the combined levels of circulating amphiregulin and heregulin affect clinical outcomes in patients who receive cetuximab as therapy against advanced CRC. METHODS: Plasma levels of amphiregulin and heregulin were measured by enzyme linked immunosorbent assay in 50 patients with CRC in a training cohort, and in 10 patients in a validation cohort. The combined expression was then assessed with clinical outcome after receiver operating characteristics analysis. RESULTS: Overall response rate was 26%, and median progression-free survival was 110 days in the training cohort. Patients with high amphiregulin and low heregulin had significantly higher objective response rate at 58% and significantly longer progression-free survival of 216 days. This result was confirmed in the validation cohort. CONCLUSION: A subgroup of CRC patients with high amphiregulin and low heregulin respond to cetuximab therapy better than other patients. PMID- 26569501 TI - The Chronic Care for Wet Age Related Macular Degeneration (CHARMED) Study: A Randomized Controlled Trial. AB - BACKGROUND: In real life, outcomes in wet age related macular degeneration (W AMD) continue to fall behind the results from randomized controlled trials. The aim of this trial was to assess if outcomes can be improved by an intervention in healthcare organization following recommendations of the Chronic Care Model (CCM). METHODS: Multi-centered randomized controlled clinical trial. The multifaceted intervention consisted in reorganization of care (delivery by trained chronic care coaches, using reminder systems, performing structured follow-up, empowering patients in self-monitoring and giving decision-support). In the control usual care was continued. Main outcome measures were changes in ETDRS visual acuity, optical coherence tomography (OCT) macular retinal thickness and quality of life (NEI VFQ-25 questionnaire). RESULTS: 169 consecutive patients in Swiss ophthalmology centers were included. Mean ETDRS baseline visual acuity of eyes with W-AMD was 57.8 (+/- 18.7). After 12 months, the between-group difference in mean change of ETDRS visual acuity was -4.8 (95%CI: -10.8 to +1.2, p = 0.15); difference in mean change of OCT was +14.0 (95% CI -39.6 to 67.6, p = 0.60); difference in mean change of NEI VFQ-25 composite score mean change was +2.1(95%CI: -1.3 to +5.5, p = 0.19). CONCLUSIONS: The intervention aiming at improving chronic care was not associated with favorable outcomes within 12 months. Other approaches need to be tested to close the evidence-performance gap in W-AMD. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN32507927. PMID- 26569502 TI - A Decrease in Ambient Temperature Induces Post-Mitotic Enlargement of Palisade Cells in North American Lake Cress. AB - In order to maintain organs and structures at their appropriate sizes, multicellular organisms orchestrate cell proliferation and post-mitotic cell expansion during morphogenesis. Recent studies using Arabidopsis leaves have shown that compensation, which is defined as post-mitotic cell expansion induced by a decrease in the number of cells during lateral organ development, is one example of such orchestration. Some of the basic molecular mechanisms underlying compensation have been revealed by genetic and chimeric analyses. However, to date, compensation had been observed only in mutants, transgenics, and gamma-ray treated plants, and it was unclear whether it occurs in plants under natural conditions. Here, we illustrate that a shift in ambient temperature could induce compensation in Rorippa aquatica (Brassicaceae), a semi-aquatic plant found in North America. The results suggest that compensation is a universal phenomenon among angiosperms and that the mechanism underlying compensation is shared, in part, between Arabidopsis and R. aquatica. PMID- 26569503 TI - Living Shorelines: Coastal Resilience with a Blue Carbon Benefit. AB - Living shorelines are a type of estuarine shoreline erosion control that incorporates native vegetation and preserves native habitats. Because they provide the ecosystem services associated with natural coastal wetlands while also increasing shoreline resilience, living shorelines are part of the natural and hybrid infrastructure approach to coastal resiliency. Marshes created as living shorelines are typically narrow (< 30 m) fringing marshes with sandy substrates that are well flushed by tides. These characteristics distinguish living shorelines from the larger meadow marshes in which most of the current knowledge about created marshes was developed. The value of living shorelines for providing both erosion control and habitat for estuarine organisms has been documented but their capacity for carbon sequestration has not. We measured carbon sequestration rates in living shorelines and sandy transplanted Spartina alterniflora marshes in the Newport River Estuary, North Carolina. The marshes sampled here range in age from 12 to 38 years and represent a continuum of soil development. Carbon sequestration rates ranged from 58 to 283 g C m-2 yr-1 and decreased with marsh age. The pattern of lower sequestration rates in older marshes is hypothesized to be the result of a relative enrichment of labile organic matter in younger sites and illustrates the importance of choosing mature marshes for determination of long-term carbon sequestration potential. The data presented here are within the range of published carbon sequestration rates for S. alterniflora marshes and suggest that wide-scale use of the living shoreline approach to shoreline management may come with a substantial carbon benefit. PMID- 26569504 TI - Navigating the ethics of cross-cultural health promotion research. AB - Health promotion researchers must consider the ethics of their research, and are usually required to abide by a set of ethical requirements stipulated by governing bodies (such as the Australian National Health and Medical Research Council) and human research ethics committees (HRECs). These requirements address both deontological (rule-based) and consequence-based issues. However, at times there can be a disconnect between the requirements of deontological issues and the cultural sensitivity required when research is set in cultural contexts and settings etic to the HREC. This poses a challenge for health promotion researchers who must negotiate between meeting both the requirements of the HREC and the needs of the community with whom the research is being conducted. Drawing on two case studies, this paper discusses examples from cross-cultural health promotion research in Australian and international settings where disconnect arose and negotiation was required to appropriately meet the needs of all parties. The examples relate to issues of participant recruitment and informed consent, participants under the Australian legal age of consent, participant withdrawal when this seemingly occurs in an ad hoc rather than a formal manner and reciprocity. Although these approaches are context specific, they highlight issues for consideration to advance more culturally appropriate practice in research ethics and suggest ways a stronger anthropological lens can be applied to research ethics to overcome these challenges. PMID- 26569505 TI - Altered Memory T-Cell Responses to Bacillus Calmette-Guerin and Tetanus Toxoid Vaccination and Altered Cytokine Responses to Polyclonal Stimulation in HIV Exposed Uninfected Kenyan Infants. AB - Implementation of successful prevention of mother-to-child transmission of HIV strategies has resulted in an increased population of HIV-exposed uninfected (HEU) infants. HEU infants have higher rates of morbidity and mortality than HIV unexposed (HU) infants. Numerous factors may contribute to poor health in HEU infants including immunological alterations. The present study assessed T-cell phenotype and function in HEU infants with a focus on memory Th1 responses to vaccination. We compared cross-sectionally selected parameters at 3 and 12 months of age in HIV-exposed (n = 42) and HU (n = 28) Kenyan infants. We measured ex vivo activated and bulk memory CD4 and CD8 T-cells and regulatory T-cells by flow cytometry. In addition, we measured the magnitude, quality and memory phenotype of antigen-specific T-cell responses to Bacillus Calmette-Guerin and Tetanus Toxoid vaccine antigens, and the magnitude and quality of the T cell response following polyclonal stimulation with staphylococcal enterotoxin B. Finally, the influence of maternal disease markers on the immunological parameters measured was assessed in HEU infants. Few perturbations were detected in ex vivo T-cell subsets, though amongst HEU infants maternal HIV viral load positively correlated with CD8 T cell immune activation at 12 months. Conversely, we observed age dependent differences in the magnitude and polyfunctionality of IL-2 and TNF alpha responses to vaccine antigens particularly in Th1 cells. These changes mirrored those seen following polyclonal stimulation, where at 3 months, cytokine responses were higher in HEU infants compared to HU infants, and at 12 months, HEU infant cytokine responses were consistently lower than those seen in HU infants. Finally, reduced effector memory Th1 responses to vaccine antigens were observed in HEU infants at 3 and 12 months and higher central memory Th1 responses to M. tuberculosis antigens were observed at 3 months only. Long-term monitoring of vaccine efficacy and T-cell immunity in this vulnerable population is warranted. PMID- 26569507 TI - Metal speciation in sediments and soils associated with acid-mine drainage in Mount Morgan (Queensland, Australia). AB - This study investigated the influence of acid-mine drainage (AMD) from the historic gold and copper mine in Mount Morgan, Queensland (Australia) on Dee River sediments and adjacent agricultural soils during pre- and post-acid flows and the speciation of metals in these sediments and soils. This was done to assess the potential bioavailability of the metals and to provide baseline information for parallel research on the potential of the metals to enter agricultural produce. Sediments at site 5 (20 km downstream of the mine site) contained Cd, Cu, and Zn levels of 4.8, 2631, and 602 mg kg-1, respectively, during low flow, and 2.6, 1835, and 756 mg kg-1, respectively, post high or acid flow. Sediments at site 8A in the floodplain area (about 60 km downstream of the mine), showed Cd, Cu, and Zn levels of 0.6, 294, and 159 mg kg-1, respectively, during low flow and 1.5, 689, and 295 mg kg-1, respectively, post high (acid) flow. Sediment cores (18-cm long) from site 8A gave ratios of Cd, Cu and S concentration in the top slice (0-6 cm from riverbed surface) to their concentration in the deeper slice (12-18 cm) of 36, 9 and 40, respectively, indicating historical AMD contamination. Lead was not a serious AMD contaminant as its level varied less than two-fold within the core in all cases. Sulfur levels were consistently high (mean = 10267 mg kg-1) in the entire 12-cm core from site 7B and were about 10 times the surface (0-6 cm) levels from the other sites, suggesting possible geogenic S sources at this site. Mean Cu level was 1783 mg kg-1 (range = 368-2510) in soils from the Dee River floodplain. BCR sequential extraction showed very similar average distribution of metals in the four fractions (F1 to F4) in sediments (from sites 5, 7B and 8A) and in the floodplain soils (site Dee P2). The sums of the acid-soluble (F1) and reducible (F2) fractions relative to the total metal content were Cd = 58%, Cu = 58%, Pb = 47% and Zn = 67% in sediments, and Cd = 67%, Cu = 63%, Pb = 47% and Zn = 58% in soils. Cu levels in these two most labile fractions alone exceeded the Australian sediment trigger value by an average factor of 9 (range = 3-23) in sediments, and the ecological investigation level for soils by an average factor of 12. The study demonstrated that AMD contamination spanned at least 80 km of the Dee River downstream of the mine and 30-cm depth of the riverbed and floodplains, with at least 50% of the total metal (particularly Cd, Cu and Zn) in the sediments and floodplain soils being potentially bioavailable to aquatic life and to the agricultural produce in the area. PMID- 26569506 TI - A Natural Product from Polygonum cuspidatum Sieb. Et Zucc. Promotes Tat-Dependent HIV Latency Reversal through Triggering P-TEFb's Release from 7SK snRNP. AB - The latent reservoirs of HIV represent a major impediment to eradication of HIV/AIDS. To overcome this problem, agents that can activate latent HIV proviruses have been actively sought after, as they can potentially be used in combination with the highly active antiretroviral therapy (HAART) to eliminate the latent reservoirs. Although several chemical compounds have been shown to activate latency, they are of limited use due to high toxicity and poor clinical outcomes. In an attempt to identify natural products as effective latency activators from traditional Chinese medicinal herbs that have long been widely used in human population, we have isolated procyanidin C-13,3',3"-tri-O-gallate (named as REJ-C1G3) from Polygonum cuspidatum Sieb. et Zucc., that can activate HIV in latently infected Jurkat T cells. REJ-C1G3 preferentially stimulates HIV transcription in a process that depends on the viral encoded Tat protein and acts synergistically with prostratin (an activator of the NF-kappaB pathway) or JQ1 (an inhibitor of Brd4) to activate HIV latency. Our mechanistic analyses further show that REJ-C1G3 accomplishes these tasks by inducing the release of P-TEFb, a host cofactor essential for Tat-activation of HIV transcription, from the cellular P-TEFb reservoir 7SK snRNP. PMID- 26569508 TI - Misprescribing controlled substances: An evaluation of a professional development program. AB - BACKGROUND: Controlled prescription drug (CPD) abuse has reached epidemic proportions in the United States. Most physicians attending a 3-day continuing medical education (CME) professional development program (PDP) lack training in identifying risk and in managing patients who misuse CPDs. To address this issue, the authors conducted an evaluation of a PDP that trains physicians on proper prescribing, identifying substance abuse, utilizing screening, brief intervention, and referral to treatment (SBIRT), and implementing motivational interviewing (MI). METHODS: The authors conducted a program evaluation to assess the efficacy and impact of the PDP on physicians' knowledge and prescribing behaviors. RESULTS: Participants (N = 174) were typically middle-aged (average age of 53 years), male (89%), and physicians (82%) and other health care professionals (18%). Many physicians practice in solo primary care settings (46%). Course evaluations were completed by n = 155 (89%) participants who rated the course and presenters highly (mean 4.8/5 respectively). Physicians' knowledge scores on pre/post assessments increased significantly: pretest (M = 58.7, SD = 13.12) and posttest (M = 78.28, SD = 9.83) (t(173) = 20.06, P <= .0001, 95% confidence interval, CI: [-21.51, -17.65]). Almost half of the participants, n = 83/174 (48%), completed the follow-up survey, and 93% agreed/strongly agreed (A/SA) they made professional practice changes. Of participants practicing with an active DEA (Drug Enforcement Administration) registration (n = 57), most agreed/strongly agreed they implemented changes to align their practices with current guidelines (89%), used CPD more appropriately (87%), implemented office policies on prescribing (81%), identified and referred more substance abuse patients to treatment (80%), shared new information/experience from course with other 25 health professionals (93%), and felt the course positively impacted their behaviors personally and professionally (90% and 96%, respectively). CONCLUSIONS: This is the first known study evaluating a PDP in this population. Results demonstrated participant satisfaction and improvement in prescribers' knowledge and self-reported prescribing behaviors. However, further study is needed to assess actual clinical practice changes, direct impact on patient outcomes, and rates of recidivism. PMID- 26569509 TI - Valrubicin in refractory non-muscle invasive bladder cancer. AB - The most effective intravesical regimen for the treatment of non-muscle invasive bladder cancer (NMIBC) refractory to Bacillus Calmette-Guerin (BCG) has still not been identified or optimized to minimize recurrence-free survival and prevent progression reliably and consistently. Valrubicin, however, is a cytotoxic chemotherapeutic agent that is used as an intravesical agent for BCG-refractory carcinoma in situ (CIS) of the urinary bladder in patients for whom immediate cystectomy would be associated with unacceptable morbidity or mortality. Here we analyze the literature regarding the treatment of non-muscle invasive urothelial malignancies with intravesical valrubicin for refractory bladder cancer, present our opinion on its current clinical impact and speculate on how its utilization will evolve in the near future. PMID- 26569510 TI - First principles calculations on nitrogen reactivity on tungsten surfaces. AB - Using the spin-polarized gradient-corrected density functional theory we investigate the adsorption and dissociation of nitrogen molecule and hydrogen nitride radicals on two model surfaces of tungsten, W{1 0 0} and W{1 1 0}. The goal of the investigations is to predict the number and nature of the nitrogenized moieties that could be found on a tungsten surface after nitrogen seeded hydrogen (deuterium) plasma discharge. The surfaces are considered clean or saturated in hydrogen or nitrogen atoms as they are expected to be after nitrogen seeded hydrogen plasma irradiation. We find that the radicals NH, NH2 and NH3 are dissociated by the catalytic action of the metallic surfaces if they are animated with an initial kinetic energy of less than 2.5 eV. The products of the reaction are a nitrogen atom incorporated into the metal surface and an adsorbed proton. The general conclusion is that nitrogen reduces hydrogen retention on the surface and more generally that the nitrided surfaces should be less reactive than the clean tungsten even if the two surfaces we consider behave quite differently. PMID- 26569512 TI - Characterization of polysaccharide fractions in mulberry fruit and assessment of their antioxidant and hypoglycemic activities in vitro. AB - The present study aimed to characterize and investigate the polysaccharide fractions of mulberry fruit, and their antioxidant and hypoglycemic activities. Mulberry fruit polysaccharides (MFP) were extracted by using hot water as the solvent and fractioned by using a DEAE-Sepharose fast-flow column. In total four eluents of water (MFP-1), 0.1 M NaCl (MFP-2), 0.2 M NaCl (MFP-3) and 0.3 M NaCl (MFP-4) were fractionated. Arabinose, galactose, glucose, xylose and mannose were the main components present in MFP-1, while MFP-2 and MFP-3 were composed of arabinose and galactose, and MFP-4 of arabinose, galactose and glucose. High performance gel permeation chromatography (HP-GPC) analysis indicated a narrower molecular weight distribution in the MFP-1 fraction. Scanning electron microscopy (SEM) exhibited a smooth surface for MFP-1 and MFP-3 fractions, whereas MFP-2 and MFP-4 have pore openings and flocculent fibers on a smooth surface. Tertiary structure analyses indicated that none of the fractions had a triple-helical conformation. On the whole, MFP-3 and MFP-4 showed better antioxidant activity and inhibitory effects on alpha-amylase and alpha-glucosidase compared to MFP-1 and MFP-2. These results show significant potential for the antioxidant and hypoglycemic activities of MFP-3 and MFP-4 indicating the need for their further exploration as potential antidiabetic agents. PMID- 26569513 TI - Utility of rotational thromboelastometry for the diagnosis of asymptomatic hyperfibrinolysis secondary to anaphylaxis. AB - We present a case of hyperfibrinolysis induced by oxaliplatin-derived anaphylactic shock, which was diagnosed with rotational thromboelastometry (ROTEM). A 57-year-old male patient underwent a second course of oxaliplatin (126 mg/m/course)-based chemotherapy for stage IV metastatic rectal cancer. Two minutes after the infusion of oxaliplatin, the patient lost consciousness and developed generalized urticarial lesions, followed by hemodynamic instability and respiratory insufficiency. He was diagnosed anaphylactic shock and transported to emergency department (ED) after intramuscular injection of 0.2 mg of adrenaline, an intravenous injection of 100 mg of hydrocortisone, and 500 mg of methylprednisolone. After arriving in the ED, the patient remained in shock and early resuscitation with administration of 5 mg of D-chlorpheniramine maleate and 20 mg of famotidine was performed. He recovered from his state of shock 30 min after the resuscitation. ROTEM findings showed fulminant hyperfibrinolysis with minimal changes in standard coagulation tests (SCTs) and no remarkable coagulopathy. Seven hours after the attack, he became asymptomatic and follow-up ROTEM revealed values within normal limits with the exception of sustained slight abnormalities of SCTs. He was discharged the next day without any signs of spontaneous bleeding and has continued his outpatient chemotherapy uneventfully. A review of the literature on anaphylaxis-induced hyperfibrinolysis and a discussion of the mechanism between anaphylactic shock and hyperfibrinolysis were performed. Although administration of tissue-type plasminogen activator can play a vital role in anaphylactic shock-induced hyperfibrinolysis, early effective resuscitation is imperative to prevent severe hemorrhagic complications. Therefore, ROTEM is a useful tool that can detect these dynamic changes faster and more accurately than SCTs. PMID- 26569514 TI - Severe jaundice due to intrahepatic cholestasis after initiating anticoagulation with rivaroxaban. AB - Rivaroxaban, a highly selective direct factor Xa inhibitor, is a new oral anticoagulant approved by the US Food and Drug Administration in November 2011 for stroke prophylaxis in patients with nonvalvular atrial fibrillation. Because of its efficacy and once-a-day dosing, it is commonly preferred in patients with nonvalvular atrial fibrillation and intolerance to warfarin in clinical practice. However, it can result in some adverse effects such as bleeding, rashes and liver injury. Here, we described a very rare adverse reaction of rivaroxaban, jaundice due to intrahepatic cholestasis, appeared in a 71-year-old male patient after taking rivaroxaban. PMID- 26569515 TI - Association between platelet indices and first trimester miscarriage. AB - We aimed to measure the effect of several potential risk factors on first trimester miscarriage. A total of 169 cases were included in the present study. Patients were selected from women who had first trimester miscarriage (n = 78) and controls were selected from the women who had given birth at term (> 37 weeks of gestation) to healthy infants (n = 91). Compared with the control group, in the miscarriage group gestational age (8.9 +/- 2.8 weeks and 8.1 +/- 2.2 weeks, respectively, P = 0.032), mean platelet volume (MPV) (8.8 +/- 1 and 9.5 +/- 1.1 fl, respectively, P < 0.001), plateletcrit (0.209 +/- 0.03% and 0.241 +/- 0.05%, respectively, P < 0.001), and platelet/lymphocyte ratio (128 +/- 37 and 145 +/- 60, respectively, P = 0.027) were significantly higher. Multivariate analysis showed that first trimester miscarriage development ratio was 1.909 times higher when MPV value was over 9.1 fl (P < 0.001); 9.147 times higher when plateletcrit value was over 0.219% (P = 0.022). Receiver operating characteristic analysis was performed to determine diagnostic MPV and plateletcrit values for first trimester miscarriage. MPV value greater than 9.1 fl determined miscarriage with 60% sensitivity and 65% specificity, while plateletcrit value greater than 0.219% determined miscarriage with 64.5% sensitivity and 64.7% specificity. MPV and plateletcrit values were strongly associated with first trimester miscarriage. Platelet indices can be used for prediction of fetal loss. PMID- 26569516 TI - The impact of ruxolitinib on thrombosis in patients with polycythemia vera and myelofibrosis: a meta-analysis. AB - The Food and Drug Administration approval of ruxolitinib for treatment of myelofibrosis and polycythemia vera has changed the management of patients with myeloproliferative neoplasms. Yet the impact of this therapy on risk of thrombosis, a major cause of morbidity and mortality among these patients, remains unknown. The aim of this study was to evaluate the impact of ruxolitinib on the risk of thrombosis among patients with polycythemia vera or myelofibrosis. Following identification of randomized controlled trials comparing ruxolitinib to standard care or placebo, rates of thrombosis, including venous and arterial thrombosis, were analyzed using fixed effects models. Rates of thrombosis were significantly lower among patients treated with ruxolitinib [risk ratio 0.45, 95% confidence interval (CI) 0.23-0.88]. Subgroup analysis of venous and arterial thrombosis demonstrated similar risk ratios, which did not reach statistical significance (risk ratio 0.46, 95% CI 0.14-1.48 and RR 0.42, 95% CI 0.18-1.01, respectively). In conclusion, our analysis suggests that JAK2 inhibition with ruxolitinib decreases the risk of arterial and/or venous thrombosis in patients with polycythemia vera or myelofibrosis. These findings will require confirmation in a prospective study. PMID- 26569517 TI - On the formation of pyridine in the interstellar medium. AB - Nitrogen-substituted polycyclic aromatic hydrocarbons (NPAHs) have been proposed to play a key role in the astrochemical evolution of the interstellar medium, but the formation mechanism of even their simplest building block - the aromatic pyridine molecule - has remained elusive for decades. Here we reveal a potential pathway to a facile pyridine (C5H5N) synthesis via the reaction of the cyano vinyl (C2H2CN) radical with vinyl cyanide (C2H3CN) in high temperature environments simulating conditions in carbon-rich circumstellar envelopes of Asymptotic Giant Branch (AGB) stars like IRC+10216. Since this reaction is barrier-less, pyridine can also be synthesized via this bimolecular reaction in cold molecular clouds such as in TMC-1. The synchronized aromatization of precursors readily available in the interstellar medium leading to nitrogen incorporation into the aromatic rings would open up a novel route to pyridine derivatives such as vitamin B3 and pyrimidine bases as detected in carbonaceous chondrites like Murchison. PMID- 26569518 TI - Genetics of Early and Normal Menopause. AB - Menopause is defined as the permanent cessation of ovulation and hence menstruation due to ovarian failure. The median age of menopause is 51 years. However, early menopause might occur at 40 years of age while late menopause might happen as late as 62 years of age. Premature menopause is defined as the cessation of ovulation prior to the age of 40 years, a condition generally referred to as primary ovarian insufficiency (POI). Menopause is also a highly heritable condition. Genetic variants are known to contribute to ~50% of the variation in age at menopause. Several genetic studies have tried to unravel this genetic background making use of different genetic techniques in population studies as well as in animal models. Genome-wide linkage studies have identified only a limited amount of genetic variants that seem to be associated with menopause. Population-based studies as well as animal research into the genetic background of POI have identified several genetic variants that seem to be associated with POI. However, a lot of these studies suffer from methodological flaws because results are generally not replicated in different independent samples and most of these studies are underpowered. Hence, results are conflicting. Recent genome-wide association studies (GWAS) have identified several genetic variants that are associated with menopause and POI. Genes seem to be involved in DNA repair and maintenance as well as in immune function. Biological as well as epidemiological data seem to indicate that reproductive performance, age at menopause, and longevity are interlinked through common genetic factors involved in DNA repair and maintenance. In case these systems fail, cell death and accelerated aging occur. Consequently, it seems that the aging of the soma, as a result of dysfunctional DNA repair, is responsible for failure to reproduce and the subsequent occurrence of menopause. Hence, reproductive performance constitutes a good predictor for general health in later life. PMID- 26569519 TI - The Fate of Iliopsoas Muscle in the Long-term Follow-up After Open Reduction of Developmental Dysplasia of the Hip by Medial Approach. Part 1: MRI Evaluation. AB - BACKGROUND: There has been little information about the long-term status of the iliopsoas, which is the main flexor of the hip, after iliopsoas tenotomy in the treatment of developmental dysplasia of the hip (DDH). The aim of this study was to assess the status of the iliopsoas muscle and other flexors and extensors of the hip in long-term follow-up with magnetic resonance imaging after complete iliopsoas tenotomy in patients with unilateral DDH treated with open reduction with a medial approach. METHODS: The study included 20 patients who underwent open reduction with a medial approach for unilateral DDH and had long-term follow up. Magnetic resonance imaging assessment of iliopsoas, rectus femoris, tensor fasia lata, sartorius, and gluteus maximus muscles was applied and the muscles of the hip that was operated on were compared with the unoperated hip. In addition, the iliopsoas muscle was examined for reattachment and the effect of reattachment was evaluated. RESULTS: The mean age at the time of operation was 10.53+/-3.61 months (range, 5 to 18 mo), and mean follow-up was 16.65+/-2.16 years (range, 13 to 20 y). Spontaneous reattachment of the iliopsoas was observed in 18 patients (90%), either in the lesser trochanter (65%) or the superior part of it (25%). There was no significant difference between the hips that were operated on and those that were not with regard to the mean cross-sectional areas (CSA) of the tensor fascia lata, rectus femoris, sartorius, and gluteus maximus muscles. The CSA of the tensor fascia lata, rectus femoris, sartorius, and gluteus maximus muscles showed no significant difference (P>0.05); however, CSA of iliopsoas muscle was significantly reduced in the operated hip (P<0.001). CONCLUSIONS: Although the iliopsoas tendon was atrophied after complete iliopsoas tenotomy, it was reattached in 90% of the patients spontaneously in long-term follow-up. There was no statistically significant compensatory hypertrophy in any muscles in response to iliopsoas atrophy. LEVEL OF EVIDENCE: Level IV-Therapeutic. PMID- 26569520 TI - Unthreaded Fixation of Slipped Capital Femoral Epiphysis Leads to Continued Growth of the Femoral Neck. AB - BACKGROUND: The optimal treatment for slipped capital femoral epiphysis (SCFE) remains controversial. In Sweden, the standard treatment is unthreaded fixation over the physis, with the purpose to permit continued growth of the femoral neck. The aim of the present study was to verify and quantify longitudinal growth of the femoral neck after in situ pinning with the Hansson hook-pin. METHODS: We performed a retrospective study of 54 patients treated with the Hansson hook-pin for SCFE between 2001 and 2009. The immediate postoperative radiograph and the radiograph after physeal closure (mean interval, 34 mo) were analyzed. Because the smooth Hansson hook-pin only has a grip fixation in the epiphysis, the femoral neck growth was determined as the difference in nail protrusion from the lateral cortex between the 2 radiographs. The femoral neck offset was also measured in all radiographs. RESULTS: Significant longitudinal growth occurred both in the slipped and the prophylactically treated contralateral hip by mean 7.1 mm (P<0.001) and 10.0 mm (P<0.001), respectively. There was no difference in growth between genders and no correlation between the amount of longitudinal growth and slip severity (range, 4.0 to 71,6 degrees; mean 27.3 degrees). Young patients (less than 11 y) grew more than older patients (more than 14 y), 12.1 vs. 4.2 mm, P=0.002. The femoral offset increased by mean 16% from mean 30.0 to 35.2 mm (P<0.001). The longitudinal growth of the femoral neck correlated with the increase in femoral offset (R=0.51, P<0.001). CONCLUSIONS: Unthreaded fixation of SCFE with the Hansson hook-pin allows continued growth of the femoral neck. The remaining growth enables the patient to achieve an almost anatomic offset of the hip. This is essential to optimize the abduction forces that stabilize the pelvis during gait. Future studies need to establish whether the longitudinal growth also results in improved remodelling of the proximal femur. LEVEL OF EVIDENCE: Level III-retrospective comparative study. PMID- 26569521 TI - A review of preoperative manoeuvres for prophylaxis of endophthalmitis in intraocular surgery: topical application of antibiotics, disinfectants, or both? AB - PURPOSE OF REVIEW: Postoperative endophthalmitis is an ophthalmic surgeon's most feared complication, as it portends a high probability of visual loss. The purpose of this article is to review the literature on the subject of preoperative measures used for prevention of postoperative endophthalmitis and to determine the effectiveness of these measures. RECENT FINDINGS: The present reviewed literature regarding topical prophylaxis of endophthalmitis in cataract surgery. SUMMARY: There is strong evidence for the use of povidone-iodine preoperatively for prophylaxis of postoperative endophthalmitis in ocular surgery; the evidence for topical antibiotics is not as compelling. PMID- 26569522 TI - High myopia and cataract surgery. AB - PURPOSE OF REVIEW: Cataract surgery in high myopes is challenging. Using third generation intraocular lens (IOL) formulas, without adjustments, hyperopic refractive outcomes are common. We discuss these issues, focusing on the various lens formulas and transformations that have improved postoperative accuracy. RECENT FINDINGS: Axial length measurement error has been largely overcome by the use of optical interferometry. Despite this, consistent hyperopic errors are still reported. We reviewed the postoperative refraction results compared with the predicted refractions using: standard formulas (Holladay 1, SRK/T, Hoffer Q, and Haigis) with manufacturers' optical lens constants, the User Group for Laser Interference Biometry (ULIB) constants, manufacturers' constants with axial length adjustment method, and fourth-generation IOL formulas (Barrett Universal II, Holladay 2, and Olsen). SUMMARY: Improved predictive results is obtained with the Barrett Universal II (software constants), Haigis (ULIB), SRK/T, Holladay 2 (software constants), and Olsen (software constants) formulas in eyes with axial lengths greater than 26.0 mm and IOL powers greater than 6.0 D. In eyes with axial lengths greater than 26.0 mm and IOL less than 6.0 D, the Barrett Universal II formula (software constants) and the Haigis (axial length adjusted) and Holladay 1 formulas (axial length-adjusted) should be used. PMID- 26569523 TI - Intraocular lens alignment methods. AB - PURPOSE OF REVIEW: This article reviews current concepts in intraocular lens alignment strategies to maximize intraocular lens (IOL) positioning. RECENT FINDINGS: A variety of strategies has been developed to maximize toric IOL position, including preoperative calculators to determine the appropriate IOL power and orientation, intraoperative alignment devices, and postoperative software to determine if IOL rotation would be beneficial for refractive outcomes. SUMMARY: The combination of using multiple toric IOL calculators and intraoperative alignment devices has improved toric IOL outcomes. The relationship of the posterior corneal power and its effect on outcomes remains to be fully elucidated. Postoperative IOL rotation may be necessary even when the IOL is aligned as planned because of surgically induced astigmatism. PMID- 26569524 TI - The location of incision in cataract surgery and its impact on induced astigmatism. AB - PURPOSE OF REVIEW: The purpose of the present study is a systematic review of previous studies on choosing the best incision site for the correction of astigmatism in cataract surgery and assessing the amount of surgically induced astigmatism (SIA) with each approach. RECENT FINDINGS: Regardless of astigmatism axis, studies show that using an on-axis incision is associated with favorable results for 0.5-1.0 diopter (D) of astigmatism. In cases with more than 1.0 D astigmatism, paired on-axis incisions can be appreciably efficient in astigmatism correction and cause at least 1.5 D SIA. Considering the amount of SIA, a temporal incision is the best approach when the patient has minimal amounts of corneal astigmatism preoperatively. At higher levels of astigmatism, if no other astigmatism correction method is used simultaneously, the temporal incision is used less frequently; however, since it is associated with the least SIA, it is still the choice site when another correction method is used. SUMMARY: The temporal incisions in cataract surgery are associated with little SIA and are appropriate choices for mild preoperative astigmatism. At higher levels of preoperative astigmatism, superior incisions are associated with better results when combined methods are not applied. PMID- 26569525 TI - The impact of cataract surgery on cognitive function in an aging population. AB - PURPOSE OF REVIEW: To review the relationship between cognitive function and cataract surgery, as it is rarely addressed, and yet is becoming increasingly important as the number of elderly people in the world continues to rise. RECENT FINDINGS: From US Census and international data, it is expected that the predicted proportion of people over 65 years of age in a number of countries will increase drastically over a half century. Therefore, the percentage of patients with cataracts and cognitive impairment, which are both age-related diseases, will be expected to rise as well. Although there are many papers reporting on the association between visual impairments and cognitive impairments, there is a relative dearth of research supporting the hypothesis that cataract surgery can improve cognitive function in patients with cognitive impairment. This reflects some inherent problems with most cognitive tests, which include both vision dependent and vision-independent items. There may also be an element of learning from repeated cognitive tests, which may falsely elevate test scores. SUMMARY: There is an increase in reports supporting the hypothesis that cataract surgery can improve cognition; however, there is still insufficient evidence for cognitive improvement after cataract surgery. As this is a growing area of research, we expect more studies to shed light on this relationship. PMID- 26569526 TI - Mechanisms and management of dry eye in cataract surgery patients. AB - PURPOSE OF REVIEW: To provide a summary of the mechanisms that may cause dry eye after cataract surgery and discuss available and upcoming treatment modalities. RECENT FINDINGS: Development or worsening of dry eye symptoms after cataract surgery is multifactorial with corneal nerve transection, inflammation, goblet cell loss, and meibomian gland dysfunction commonly cited as underlying disorders. With increasing awareness of the prevalence of dry eye disease, current surgical techniques are being analyzed for their contribution to the issue. Although many classic interventions, such as artificial tears and anti inflammatory drops, remain first-line treatment options, they may not adequately address abnormalities of the tear film. The trend has been to create new drugs and technologies that target meibomian gland deficiencies and restore goblet cell numbers. SUMMARY: Therapy for postoperative dry eye symptoms should be determined based on symptom severity and which underlying cause is most prominent at a given time. Patients with high-level risk factors for dry eye should be evaluated preoperatively to determine whether they have preexisting dry eye disease or if they are susceptible to developing disease after surgery. PMID- 26569527 TI - Glaucoma and cataract surgery: two roads merging into one. AB - PURPOSE OF REVIEW: To discuss the increasing utilization of cataract extraction in the management of glaucoma and to highlight advances in surgical care that can promote synergistic treatment of these comorbid conditions. RECENT FINDINGS: Recent years have demonstrated significant advances in the management of glaucoma through the use of novel microinvasive glaucoma devices. Furthermore, an increased understanding of the role of cataract surgery in the treatment of various glaucomas warrants review. Nevertheless, cataract surgery in the glaucoma patient warrants specific preoperative, intraoperative, and postoperative planning to optimize visual function and quality of life while mitigating potential risk factors for adverse events. SUMMARY: Although the challenges of performing cataract extraction on glaucoma patients exist, the potential benefit to these patients is substantial. With attention to pre- and perioperative surgical planning and intraoperative technique, as well as with awareness and potential utilization of novel devices and treatment strategies, cataract extraction offers a unique platform for anatomical and functional improvement in this increasingly common cohort of patients. PMID- 26569528 TI - Carbon footprint and cost-effectiveness of cataract surgery. AB - PURPOSE OF REVIEW: This article raises awareness about the cost-effectiveness and carbon footprint of various cataract surgery techniques, comparing their relative carbon emissions and expenses: manual small-incision cataract surgery (MSICS), phacoemulsification, and femtosecond laser-assisted cataract surgery. RECENT FINDINGS: As the most commonly performed surgical procedure worldwide, cataract surgery contributes significantly to global climate change. The carbon footprint of a single phacoemulsification cataract surgery is estimated to be comparable to that of a typical person's life for 1 week. Phacoemulsification has been estimated to be between 1.4 and 4.7 times more expensive than MSICS; however, given the lower degree of postoperative astigmatism and other potential complications, phacoemulsification may still be preferable to MSICS in relatively resource-rich settings requiring high levels of visual function. Limited data are currently available regarding the environmental and financial impact of femtosecond laser-assisted cataract surgery; however, in its current form, it appears to be the least cost-effective option. SUMMARY: Cataract surgery has a high value to patients. The relative environmental impact and cost of different types of cataract surgery should be considered as this treatment becomes even more broadly available globally and as new technologies are developed and implemented. PMID- 26569529 TI - Cataract surgery: a procedure to us, an experience to the patient. PMID- 26569530 TI - Optical coherence tomography platforms and parameters for glaucoma diagnosis and progression. AB - PURPOSE OF REVIEW: Optical coherence tomography (OCT) aids in the diagnosis and long-term monitoring of various ocular diseases, including glaucoma. Initially, the retinal nerve fiber layer was the only OCT structural parameter used in glaucoma. Subsequent research has resulted in more retinal and optic nerve head parameters. In addition, OCT is being investigated for its ability to assess ocular hemodynamics. This review summarizes these spectral domain-optical coherence tomography (SDOCT) parameters in the context of glaucoma. RECENT FINDINGS: Several new SDOCT retinal nerve fiber layer, optic nerve head, and macular parameters with good glaucoma diagnostic ability have been added to existing ones recently. The combination of SDOCT and Doppler or angiography has also resulted in hemodynamic parameters that may prove to be useful in the functional assessment in glaucoma. SUMMARY: OCT technology is advancing not only as a tool for structural assessment, but also as a multimodality tool to assess both structure and function to enhance our understanding of glaucoma, and ultimately clinical decisions. PMID- 26569531 TI - Treatment of ocular hypertension: is it cost effective? AB - PURPOSE OF REVIEW: The review evaluates the past 18-month literature related to cost-effectiveness of treating ocular hypertension (OHT) and give an opinion of the state of research. RECENT FINDINGS: Three studies question the value of intensive monitoring in OHT and glaucoma. One study suggests that implementing Ocular Hypertension Treatment Study - European Glaucoma Prevention Study (OHTS EGPS) risk prediction in every day practice overestimates the risk of open-angle glaucoma. While two models suggest that treating all intraocular pressures above 21 mmHg would be cost-saving (but disagree on the impact of this strategy on conversion to glaucoma), another study in turn suggests than we could safely reduce medications in almost half of the patients. Two studies suggest that effective early treatment could decrease follow-up costs in OHT and one modeling study suggests that using laser in preference to medication would be cost effective in glaucoma. SUMMARY: The results of this time-limited review are confusing as they challenge many current beliefs to continue to do more than what we are currently doing. We have a huge gap in understating whether we are currently doing the 'right' things in our every day practices. PMID- 26569532 TI - Intra- and inter-observer reliability of quantitative analysis of the infra patellar fat pad and comparison between fat- and non-fat-suppressed imaging--Data from the osteoarthritis initiative. AB - The infra-patellar fat pad (IPFP), as intra-articular adipose tissue represents a potential source of pro-inflammatory cytokines and its size has been suggested to be associated with osteoarthritis (OA) of the knee. This study examines inter- and intra-observer reliability of fat-suppressed (fs) and non-fat-suppressed (nfs) MR imaging for determination of IPFP morphological measurements as novel biomarkers. The IPFP of nine right knees of healthy Osteoarthritis Initiative participants was segmented by five readers, using fs and nfs baseline sagittal MRIs. The intra-observer reliability was determined from baseline and 1-year follow-up images. All segmentations were quality controlled (QC) by an expert reader. Reliability was expressed as root mean square coefficient of variation (RMS CV%). After QC, the inter-observer reliability for fs (nfs) imaging was 2.0% (1.1%) for IPFP volume, 2.1%/2.5% (1.6%/1.8%) for anterior/posterior surface areas, 1.8% (1.8%) for depth, and 2.1% (2.4%) for maximum sagittal area. The intra-observer reliability was 3.1% (5.0%) for volume, 2.3%/2.8% (2.5%/2.9%) for anterior/posterior surfaces, 1.9% (3.5%) for depth, and 3.3% (4.5%) for maximum sagittal area. IPFP volume from nfs images was systematically greater (+7.3%) than from fs images, but highly correlated (r=0.98). The results suggest that quantitative measurements of IPFP morphology can be performed with satisfactory reliability when expert QC is implemented. The IPFP is more clearly depicted in nfs images, and there is a small systematic off-set versus analysis from fs images. However, the high linear relationship between fs and nfs imaging suggests that fs images can be used to analyze IPFP morphology, when nfs images are not available. PMID- 26569533 TI - Postsurgical Depressive Symptoms and Proinflammatory Cytokine Elevations in Women Undergoing Primary Treatment for Breast Cancer. AB - OBJECTIVE: Depression and inflammation may independently promote breast cancer (BCa) disease progression and poorer clinical outcomes. Depression has been associated with increased levels of inflammatory markers in medically healthy individuals and patients with cancer. However, inconsistencies in study time frames complicate interpretation of results within specific cancer types. This study examined relationships between depressive symptoms and inflammation in women with early-stage BCa before beginning adjuvant treatment. METHODS: Women with Stage 0-III BCa were recruited approximately 4 to 8 weeks after surgery. Depressive symptoms were assessed using the Hamilton Rating Scale for Depression, and blood samples were collected to quantify circulating levels of interleukin (IL)-1beta, IL-6, and tumor necrosis factor alpha (TNF-alpha) by enzyme-linked immunosorbent assay. Analyses of covariance were used to test for group differences (elevated versus low depressive symptoms) in levels of cytokines. Multiple regression analyses were used to examine relationships between continuous severity of depressive symptoms and levels of cytokines adjusting for relevant biobehavioral covariates. RESULTS: Thirty-six (40%) of 89 patients showed elevated levels of depressive symptoms and, in adjusted models, had marginally higher levels of IL-1beta (mean [M] = 14.49 [95% confidence interval {CI} = 6.11-32.65] versus M = 4.68 [95% CI = 1.96-9.86] and IL-6 [M = 88.74 {95% CI = 33.28-233.96} versus M = 61.52 {95% CI = 27.44-136.40}]) significantly higher levels of TNF-alpha (M = 17.07 [95% CI = 8.27-34.32] versus M = 6.94 [95% CI = 3.58-12.80]) than did women with low depressive symptoms. Across the spectrum of depressive symptoms, greater magnitude of depressive symptoms was related to greater levels of IL-1beta (beta = 0.06, p = .006, R = 0.25) and TNF alpha (beta = 0.06, p = .003, R = 0.27). CONCLUSIONS: Postsurgery and preadjuvant treatment for early-stage BCa, depressive symptoms covary with elevated levels of multiple proinflammatory cytokines. Findings have implications for psychosocial and biological interventions concurrently focusing on depression and inflammation. TRIAL REGISTRATION: NCT01422551. PMID- 26569534 TI - Flow-Mediated Dilation and Neurocognition: Systematic Review and Future Directions. AB - BACKGROUND: Previous literature indicates that flow-mediated dilation (FMD) is associated with impaired cognition among patients with stroke. The relationship between FMD and cognition in individuals without cerebrovascular disease has yet to be systematically reviewed. METHODS: The literature was searched using MEDLINE. Exclusion criteria were as follows: focus on neurological disease (e.g., stroke), animal studies, no quantitative measure of endothelial function or cognition, newborn studies, articles with no original data, and articles that are irrelevant to the topic of interest. Neurocognitive tests were categorized in the following domains: executive function, memory (general, working, episodic/semantic, verbal, visual), global cognitive function, information processing speed, language, psychomotor speed, and visual-spatial ability. RESULTS: The search yielded 700 articles, of which 10 articles, consisting of 2791 participants, met the criteria for inclusion. Most studies conclude that impaired FMD is associated with poorer neuropsychological functioning, particularly in executive functioning (effect sizes: r = 0.07-0.58) and working memory tasks (effect sizes: r = 0.19-0.39). No association was found between other subdomains of memory and FMD. Visual spatial tasks, information processing speed, language tasks, and global cognition were not associated with FMD overall; however fewer studies examined these domains. CONCLUSIONS: Even in the absence of cerebrovascular disease, there are links between cognition, particularly executive tasks, and vascular function. Public health implications include the potential value of examining FMD as a predictor of cognitive decline, as well as the potential value of improving cognition through pharmacological and behavioral interventions that improve vascular function. Future studies incorporating neuroimaging measures of cerebral blood flow are warranted. PMID- 26569535 TI - The Role of Nitric Oxide in the Antidepressant Actions of 5-Aminoimidazole-4 Carboxamide-1-beta-D-Ribofuranoside in Insulin-Resistant Mice. AB - OBJECTIVE: Depression and Type 2 diabetes mellitus are interrelated conditions, but the underlying neurobiology is insufficiently understood. The current study compared the effects of a pharmacological manipulation with 5-aminoimidazole-4 carboxamide-1-beta-D-ribofuranoside (AICAR) that targets neurobiological processes by adenosine 5'-monophosphate-activated protein kinase activation versus exercise on depression-like behavior and nitric oxide (NO)-related measures. METHODS: A mouse model of a depression-like and insulin-resistant state, induced by the co-treatment of high-fat diet and corticosterone administration, was used to examine the antidepressant action of AICAR and exercise. RESULTS: Data showed that AICAR was a putative antidepressant in the depression-like and insulin-resistant mice (total ambulatory distance in the open field test was 5120.69 +/- 167.47 cm, mobility duration in the forced swim test was 17.61 +/- 1.54 seconds, latency to feed in the novelty suppressed feeding test was 255.67 +/- 37.80 seconds; all p values < .05). Furthermore, the antidepressant actions of AICAR required endothelial nitric oxide synthase activity with increased NO production in the prefrontal cortex, whereas corticosterone-induced expression of neuronal nitric oxide synthase and NO production may increase the risk of depression. In contrast to the traditional antidepressants such as ketamine and imipramine, AICAR interfered with the effects of insulin in skeletal muscle in the context of high-fat diet, consistent with the potential antidepressant effects of AICAR. Exercise also resulted in activation of adenosine 5'-monophosphate-activated protein kinase, nitric oxide synthase, and NO production (all p values < .01), which in turn may be implicated in the antidepressant effects of exercise. CONCLUSIONS: These findings suggest that NO is an essential signal mediating the antidepressant actions of AICAR. Ultimately, the concurrent effects of AICAR on brain insulin action and mitochondrial function suggest a potential of neural insulin resistance, which may contribute to our understanding of the comorbidity of depression and Type 2 diabetes. PMID- 26569537 TI - Risk of Coronary Heart Disease in Men With Poor Emotional Control: A Prospective Study. AB - OBJECTIVE: Many psychosocial factors have been associated with coronary heart disease (CHD), including hostility, anger, and depression. We tested the hypothesis that these factors may have their basis in emotion regulation abilities. Our aim was to determine whether poor emotional control predicted long term risk of CHD. METHODS: This Swedish national study includes 46,393 men who were conscripted for military service in 1969 and 1970. The men were aged 18 to 20 years at the time of conscription. Psychologists used a brief semistructured interview to retrospectively assess the conscripts' level of emotional control in childhood and adolescence. The outcome measure was a first fatal or nonfatal event of CHD. We calculated hazard ratios (HRs) and 95% confidence intervals (CIs) for poor and adequate versus good emotional control. RESULTS: After 38 years of follow-up (1971-2009), 2456 incident cases of CHD had occurred. Poor emotional control increased the risk of CHD (HR = 1.31, 95% CI = 1.18-1.45), adjusting for childhood socioeconomic position, anxiety, depression, and parental history of CHD. Further adjustment for life-style-related factors, for example, smoking and body mass index, attenuated the HR to 1.08 (95% CI = 0.97-1.21). In stratified analyses, the fully adjusted association between poor emotional control with CHD remained significantly elevated among men with a parental history of CHD (HR = 1.49, 95% CI = 1.11-2.01, p interaction = .037). CONCLUSIONS: In the overall study population, poor emotional control had no direct effect on CHD beyond life-style-related factors. However, in men with a parental history of CHD, poor emotional control in adolescence remained significantly predictive of long-term CHD risk even when adjusting for life-style related factors. PMID- 26569536 TI - Intraindividual Cortisol Variability and Psychological Functioning in Caregivers of Hematopoietic Stem Cell Transplant Patients. AB - OBJECTIVE: Caregiving for allogeneic hematopoietic stem cell transplant (Allo HSCT) patients carries a significant psychological burden, yet it remains unclear whether Allo-HSCT caregivers demonstrate disruptions to stress systems, such as the hypothalamic-pituitary-adrenal axis. Greater intraindividual cortisol variability (ICV) has been observed in psychiatric disorders; however, there is a knowledge gap evaluating ICV in caregivers. We predicted that greater ICV would be related to poorer mental health in Allo-HSCT caregivers. METHODS: Allo-HSCT caregivers (n = 140) collected saliva for 3 consecutive days at 4 time points/d. Psychological variables included sleep quality and a summary composite score of overall mental health. RESULTS: Regression analyses demonstrated that greater ICV was significantly related to poorer overall mental health (beta = 0.25, p = .009), whereas poorer sleep did not reach significance (beta = 0.16, p = .069). No significant relationships emerged for the cortisol area under the curve, diurnal decline, or awakening response. CONCLUSIONS: Results extend prior work examining ICV as a unique marker that is possibly more sensitive than other widely applied measures of hypothalamic-pituitary-adrenal axis dysregulation to a distressed population of caregivers. PMID- 26569538 TI - Endogenous Cortisol Exposure and Declarative Verbal Memory: A Longitudinal Study of Healthy Older Adults. AB - OBJECTIVE: Exposure to endogenous cortisol is associated with hippocampal degeneration and may contribute to problems with declarative memory, but effects of persistent versus phasic cortisol elevations have not been established. The present longitudinal investigation examined persistent individual differences and phasic changes in cortisol as they related to verbal memory, executive functions, and subjective cognitive function. METHODS: Older adults (n = 132, aged 60-93 years) were followed up for up to 5 years. They were assessed annually for verbal memory and every 6 months for executive functions, subjective cognitive function, and cortisol area under the curve (averaged over 3 days). RESULTS: In multilevel models, persistently but not phasically higher cortisol was associated with worse verbal memory in both learning (t(181) = 2.99, p = .003) and recall (t(280) = 3.10, p = .002). This effect withstood adjustment for stress, depression, metabolic health, and age. There was evidence for attenuated primacy in learning with higher persistent cortisol. Phasic increases in cortisol were not associated with changes in memory, and cortisol was not related to executive functions or subjective cognitive function. CONCLUSIONS: Higher secretion of cortisol may, over time, contribute to memory dysfunction in older adults. PMID- 26569539 TI - A 15-Year Follow-Up Study of Sense of Humor and Causes of Mortality: The Nord Trondelag Health Study. AB - BACKGROUND: Associations between the sense of humor and survival in relation to specific diseases has so far never been studied. METHODS: We conducted a 15-year follow-up study of 53,556 participants in the population-based Nord-Trondelag Health Study, Norway. Cognitive, social, and affective components of the sense of humor were obtained, and associations with all-cause mortality, mortality due to cardiovascular diseases (CVD), infections, cancer, and chronic obstructive pulmonary diseases were estimated by hazard ratios (HRs). RESULTS: After multivariate adjustments, high scores on the cognitive component of the sense of humor were significantly associated with lower all-cause mortality in women (HR = 0.52, 95% confidence interval [CI] = 0.33-0.81), but not in men (HR = 0.88, 95% CI = 0.59-1.32). Mortality due to CVD was significantly lower in women with high scores on the cognitive component (HR = 0.27, 95% CI = 0.15-0.47), and so was mortality due to infections both in men (HR = 0.26, 95% CI = 0.09-0.74) and women (HR = 0.17, 95% CI = 0.04-0.76). The social and affective components of the sense of humor were not associated with mortality. In the total population, the positive association between the cognitive component of sense of humor and survival was present until the age of 85 years. CONCLUSIONS: The cognitive component of the sense of humor is positively associated with survival from mortality related to CVD and infections in women and with infection-related mortality in men. The findings indicate that sense of humor is a health protecting cognitive coping resource. PMID- 26569540 TI - Psychiatric Disorders and Weight Change in a Prospective Study of Bariatric Surgery Patients: A 3-Year Follow-Up. AB - OBJECTIVES: To document changes in Axis I psychiatric disorders after bariatric surgery and examine their relationship with postsurgery weight loss. METHODS: As part of a three-site substudy of the Longitudinal Assessment of Bariatric Surgery Research Consortium, 199 patients completed the Structured Clinical Interview for DSM-IV before Roux-en-Y gastric bypass or laparoscopic adjustable gastric band. At 2 or 3 years after surgery, 165 (83%) patients completed a follow-up assessment (presurgery median body mass index = 44.8 kg/m, median age = 46 years, 92.7% white, 81.1% female). Linear-mixed modeling was used to test change in prevalence of psychiatric disorders over time, report remission and incidence, and examine associations between psychiatric disorders and weight loss. RESULTS: Compared with status presurgery, the prevalence of any Axis I psychiatric disorder was significantly lower at 2 and 3 years after surgery (30.2% versus 16.8% [p = .003] and 18.4% [p = .012], respectively). Adjusting for site, age, sex, race, presurgery body mass index, and surgical procedure, presurgery mood, anxiety, eating or substance use disorders (lifetime or current) were not related to weight change, nor were postsurgery mood or anxiety disorders (p for all > .05). However, having a postsurgery eating disorder was independently associated with less weight loss at 2 or 3 years (beta = 6.7%, p = .035). CONCLUSIONS: Bariatric surgery was associated with decreases in psychiatric disorders through 3 years after surgery. Postsurgical eating disorders were associated with less weight loss after surgery, adding to the literature suggesting that disordered eating after surgery is related to suboptimal weight loss. PMID- 26569541 TI - The Psychosocial Context of Financial Stress: Implications for Inflammation and Psychological Health. AB - OBJECTIVE: Psychological distress may contribute to chronic activation of acute phase inflammation. The current study investigated how financial stressors influence psychosocial functioning and inflammation. This study examined a) the direct relations between financial stress and inflammation; b) whether the relationships between financial stress and inflammation are mediated in part by negative interpersonal events, psychological distress, and psychological well being; and c) whether social standing in one's community moderates the relations between financial stress and psychological distress, psychological well-being, and markers of inflammation (interleukin-6 [IL-6] and C-reactive protein). METHODS: Stressful financial and interpersonal events over the previous year, perceived social status, indices of psychological well-being and distress, and levels of IL-6 and C-reactive protein were assessed in a community sample of 680 middle-aged adults (ages 40-65 years). RESULTS: Structural equation modeling analyses revealed significant relations among financial stress, interpersonal stress, and psychological distress and well-being, and complex relationships between these variables and inflammatory markers. Psychological well-being mediated the association between financial stress and IL-6 ([mediation] ab = 0.012, standard error [SE] = 0.006, p = .048). Furthermore, individuals with higher perceived social standing within their communities exhibited a stronger relation between negative financial events and both interpersonal stressors (interaction B = 0.067, SE = 0.017, p < .001) and C-reactive protein (interaction B = 0.051, SE = 0.026, p = .050). CONCLUSIONS: Financial stress demonstrates complex relations with inflammation, due partly to psychological well-being and social perceptions. Findings are discussed with regard to the social context of stress and physiological factors pertinent to stress adaptation and inflammation. PMID- 26569542 TI - Well-Being and Chronic Disease Incidence: The English Longitudinal Study of Ageing. AB - BACKGROUND: Previous research suggests that greater well-being may protect against onset of chronic disease. However, it is unclear whether this association is similar across different types of disease. METHOD: We used Cox proportional hazards regression to examine the prospective relationship between well-being (measured using the CASP-19 quality of life questionnaire) and incidence of arthritis, cancer, stroke, diabetes, myocardial infarction, and chronic lung disease over 8 years. The sample consisted of 8182 participants 50 years or older from the English Longitudinal Study of Ageing. RESULTS: After adjustments for established risk factors, a standard deviation increase in CASP-19 score was associated with a decrease in arthritis risk (hazard ratio [HR] = 0.89, 95% confidence interval [CI] = 0.83-0.96) and, in those younger than 65 years, a decrease in diabetes risk (HR = 0.82, 95% CI = 0.70-0.95) and chronic lung disease risk (HR = 0.80, 95% CI = 0.66-0.97). Higher CASP-19 scores were associated with reduced risk for stroke and myocardial infarction; however, these associations were no longer significant after adjustments for established risk factors. No association was observed for cancer incidence. An age interaction was observed for diabetes, myocardial infarction, and chronic lung disease, with a stronger association between CASP-19 score and disease incidence at younger ages. CONCLUSIONS: The extent of association between well-being and incident disease risk is not consistent across different chronic diseases. Future studies should examine the cause of this variation. PMID- 26569544 TI - Partners' Similarity in Differentiation of Self is Associated With Higher Sexual Desire: A Quantitative Dyadic Study. AB - The relationship between sexual desire and differentiation of self in couples has been frequently discussed in clinical literature but lacks empirical support. This exploratory study investigates the associations between individual and dyadic levels of sexual desire, differentiation of self, and couple satisfaction. Similarities and discrepancies in sexual desire and differentiation of self between partners were especially targeted. Partners were expected to have a lower discrepancy of differentiation of self than unrelated individuals (Bowen's similarity hypothesis). Partners' discrepancy in differentiation of self was expected to be negatively associated with sexual desire, and higher levels of sexual desire and differentiation in the dyad were expected be positively associated with couple satisfaction. Results suggest that partners' similarity regarding differentiation of self predicted individual sexual desire. Other findings suggest that couple satisfaction was positively associated with both sexual desire and differentiation of self. Limitations and clinical implications are discussed. PMID- 26569545 TI - The Effects of Acupuncture on Cerebral Blood Flow in Post-Stroke Patients: A Randomized Controlled Trial. AB - BACKGROUND/OBJECTIVE: Stroke is a major cause of disability and death in the Western world. Studies have shown a direct relationship between specific mental and motor activity and changes in cerebral blood flow. Acupuncture is often used in post-stroke patients, but there is a lack of sham-controlled studies evaluating the effects of acupuncture on cerebral blood flow following a stroke. This pilot concept-assessment study sought to evaluate the effects of true acupuncture on cerebral blood flow velocity compared with sham acupuncture and lay a foundation for future work in this field. METHODS: Seventeen inpatients (age range, 44-79 years) 1-3 months post-stroke were allocated to acupuncture at true acupuncture (TA) points or at sham acupuncture (SA) points. The treatment was 20 minutes long. Transcranial Doppler ultrasonography was used to measure mean flow velocity (MFV) and peak flow velocity (PFV) at both healthy and damaged hemispheres before (T0), in the middle of (T15), and 5 minutes after (T25) treatment. Blood pressure was measured at T0 and T25. RESULTS: A statistically significant (p < 0.04) MFV increase in both hemispheres was found during and after TA; this increase was higher than that seen with SA (p < 0.035). Acupuncture had no significant effect on PFV. Systolic blood pressure significantly decreased after acupuncture (p < 0.005) in a similar manner for both TA and SA. National Institutes of Health Stroke Scale score was negatively correlated with MFV at T15 (r = -0.825; p < 0.05). CONCLUSION: This pilot study showed a significant influence on cerebral blood flow velocity by TA. This study lays a foundation for larger-scale studies that may prove acupuncture to be a useful tool for cerebral blood flow enhancement during post-stroke rehabilitation. PMID- 26569546 TI - A devolved model for public involvement in the field of mental health research: case study learning. AB - BACKGROUND: Patient and public involvement in all aspects of research is espoused and there is a continued interest in understanding its wider impact. Existing investigations have identified both beneficial outcomes and remaining issues. This paper presents the impact of public involvement in one case study led by a mental health charity conducted as part of a larger research project. The case study used a devolved model of working, contracting with service user-led organizations to maximize the benefits of local knowledge on the implementation of personalized budgets, support recruitment and local user-led organizations. OBJECTIVE: To understand the processes and impact of public involvement in a devolved model of working with user-led organizations. DESIGN: Multiple data collection methods were employed throughout 2012. These included interviews with the researchers (n = 10) and research partners (n = 5), observation of two case study meetings and the review of key case study documentation. Analysis was conducted in NVivo10 using a coding framework developed following a literature review. FINDINGS: Five key themes emerged from the data; Devolved model, Nature of involvement, Enabling factors, Implementation challenges and Impact. While there were some challenges of implementing the devolved model it is clear that our findings add to the growing understanding of the positive benefits research partners can bring to complex research. CONCLUSIONS: A devolved model can support the involvement of user-led organizations in research if there is a clear understanding of the underpinning philosophy and support mechanisms are in place. PMID- 26569547 TI - Toward Singlet-Triplet Bistable Nonalternant Kekule Hydrocarbons: Azulene-to Naphthalene Rearrangement. AB - Recent developments of open-shell singlet diradicaloids motivated the search for stable singlet-triplet bistable nonalternant polycyclic hydrocarbons. During the synthesis of this type of molecule, such as the dibenzo-cyclohepta[def]fluorene 3, an unexpected azulene-to-naphthalene rearrangement was observed at room temperature, which resulted in new nonalternant hydrocarbons 8a/8b with a closed shell singlet ground state. These studies provided insight into the unique chemistry of azulene and challenges for the synthesis of singlet-triplet bistable polycyclic hydrocarbons. PMID- 26569548 TI - Reprint of "Pharmacological study of the light/dark preference test in zebrafish (Danio rerio): Waterborne administration". AB - Anxiety is a complex disorder; thus, its mechanisms remain unclear. Zebrafish (Danio rerio) are a promising pharmacological model for anxiety research. Light/dark preference test is a behaviorally validated measure of anxiety in zebrafish; however, it requires pharmacological validation. We sought to evaluate the sensitivity of the light/dark preference test in adult zebrafish by immersing them in drug solutions containing clonazepam, buspirone, imipramine, fluoxetine, paroxetine, haloperidol, risperidone, propranolol, or ethanol. The time spent in the dark environment, the latency time to first crossing, and the number of midline crossings were analyzed. Intermediate concentrations of clonazepam administered for 600s decreased the time spent in the dark and increased locomotor activity. Buspirone reduced motor activity. Imipramine and fluoxetine increased time spent in the dark and the first latency, and decreased the number of alternations. Paroxetine did not alter the time in the dark; however, it increased the first latency time and decreased locomotor activity. Haloperidol decreased the time spent in the dark at low concentrations. Risperidone and propranolol did not change any parameters. Ethanol reduced the time spent in the dark and increased the number of crossings at intermediate concentrations. These results corroborate the previous work using intraperitoneal drug administration in zebrafish and rodents, suggesting that water drug delivery in zebrafish can effectively be used as an animal anxiety model. PMID- 26569549 TI - Reprint of "Caffeine protects against memory loss induced by high and non anxiolytic dose of cannabidiol in adult zebrafish (Danio rerio)". AB - Cannabidiol (CBD) has been investigated in a wide spectrum of clinical approaches due to its psychopharmacological properties. CBD has low affinity for cannabinoid neuroreceptors and agonistic properties to 5-HT receptors. An interaction between cannabinoid and purinergic receptor systems has been proposed. The purpose of this study is to evaluate CBD properties on memory behavioral and locomotor parameters and the effects of pre-treatment of adenosine receptor blockers on CBD impacts on memory using adult zebrafish. CBD (0.1, 0.5, 5, and 10mg/kg) was tested in the avoidance inhibitory paradigm and anxiety task. We analyzed the effect of a long-term caffeine pre-treatment (~20mg/L - four months). Also, acute block of adenosine receptors was performed in co-administration with CBD exposure in the memory assessment. CBD promoted an inverted U-shaped dose-response curve in the anxiety task; in the memory assessment, CBD in the dose of 5mg/Kg promoted the strongest effects without interfering with social and aggressive behavior. Caffeine treatment was able to prevent CBD (5mg/kg) effects on memory when CBD was given after the training session. CBD effects on memory were partially prevented by co-treatment with a specific A2A adenosine receptor antagonist when given prior to or after the training session, while CBD effects after the training session were fully prevented by adenosine A1 receptor antagonist. These results indicated that zebrafish have responses to CBD anxiolytic properties that are comparable to other animal models, and high doses changed memory retention in a way dependent on adenosine. PMID- 26569551 TI - Clinical practice guidelines in hypertension: a review. AB - The aim of this study is the methodological evaluation of Clinical Practice Guidelines (CPG) in hypertension. This is the first in a series of review articles, analysis, assessment in methodology and content of clinical practice guidelines in Cardiology. Of all clinical practice guidelines, three were selected and the Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument was used to assess each guide. The guidelines obtained the lowest score in the domain of applicability (mean 43.8%); while the highest score was for clarity of presentation (mean 81.5%). The lowest percentage was found in the applicability domain (European guideline) and the highest of all scores was found in two domains: scope and purpose, and clarity of presentation (Canadian guideline). Assessing the quality of the clinical practice guidelines analyzed, the Canadian is one with the best scores obtained by applying the AGREE II instrument, and it is advised to be used without modifications. PMID- 26569550 TI - Thrombin-induced reactive oxygen species generation in platelets: A novel role for protease-activated receptor 4 and GPIbalpha. AB - BACKGROUND: Platelets are essential for maintaining haemostasis and play a key role in the pathogenesis of cardiovascular disease. Upon ligation of platelet receptors through subendothelial matrix proteins, intracellular reactive oxygen species (ROS) are generated, further amplifying the platelet activation response. Thrombin, a potent platelet activator, can signal through GPIbalpha and protease activated receptor (PAR) 1 and PAR4 on human platelets, and recently has been implicated in the generation of ROS. While ROS are known to have key roles in intra-platelet signalling and subsequent platelet activation, the precise receptors and signalling pathways involved in thrombin-induced ROS generation have yet to be fully elucidated. OBJECTIVE: To investigate the relative contribution of platelet GPIbalpha and PARs to thrombin-induced reactive oxygen species (ROS) generation. METHODS AND RESULTS: Highly specific antagonists targeting PAR1 and PAR4, and the GPIbalpha-cleaving enzyme, Naja kaouthia (Nk) protease, were used in quantitative flow cytometry assays of thrombin-induced ROS production. Antagonists of PAR4 but not PAR1, inhibited thrombin-derived ROS generation. Removal of the GPIbalpha ligand binding region attenuated PAR4 induced and completely inhibited thrombin-induced ROS formation. Similarly, PAR4 deficiency in mice abolished thrombin-induced ROS generation. Additionally, GPIbalpha and PAR4-dependent ROS formation were shown to be mediated through focal adhesion kinase (FAK) and NADPH oxidase 1 (NOX1) proteins. CONCLUSIONS: Both GPIbalpha and PAR4 are required for thrombin-induced ROS formation, suggesting a novel functional cooperation between GPIbalpha and PAR4. Our study identifies a novel role for PAR4 in mediating thrombin-induced ROS production that was not shared by PAR1. This suggests an independent signalling pathway in platelet activation that may be targeted therapeutically. PMID- 26569552 TI - N-Heterocyclic Carbene-Catalyzed Diastereoselective Vinylogous Michael Addition Reaction of gamma-Substituted Deconjugated Butenolides. AB - An efficient N-heterocyclic carbene (NHC)-catalyzed vinylogous Michael addition of deconjugated butenolides was developed. In the presence of 5 mol % of the NHC catalyst, both gamma-alkyl- and aryl-substituted deconjugated butenolides undergo vinylogous Michael addition with various alpha, beta-unsaturated ketones, esters, or nitriles to afford gamma,gamma-disubstituted butenolides containing adjacent quaternary and tertiary carbon centers in good to excellent yields with excellent diastereoselectivities. In this process, the free carbene is assumed to act as a strong Bronsted base to promote the conjugate addition. PMID- 26569553 TI - How older adults use cognition in sentence-final word recognition. AB - This study examined the effects of executive control and working memory on older adults' sentence-final word recognition. The question we addressed was the importance of executive functions to this process and how it is modulated by the predictability of the speech material. To this end, we tested 173 neurologically intact adult native English speakers aged 55-84 years. Participants were given a sentence-final word recognition test in which sentential context was manipulated and sentences were presented in different levels of babble, and multiple tests of executive functioning assessing inhibition, shifting, and efficient access to long-term memory, as well as working memory. Using a generalized linear mixed model, we found that better inhibition was associated with higher accuracy in word recognition, while increased age and greater hearing loss were associated with poorer performance. Findings are discussed in the framework of semantic control and are interpreted as supporting a theoretical view of executive control which emphasizes functional diversity among executive components. PMID- 26569554 TI - Evaluation of radioactive environmental hazards in Area-3, Northern Palmyrides, Central Syria using airborne spectrometric gamma technique. AB - Airborne spectrometric gamma data are used in this paper to estimate the degree of radioactive hazard on humanity in Area-3, Northern Palmyrides, Central Syria. Exposure Rate (ER), Absorbed Dose Rate (ADR), Annual Effective Dose Rate (AEDR), and Heat Production (HP) of the eleven radiometric units included in the established lithological scored map in the study area have been computed to evaluate the radiation background influence in humans. The results obtained indicate that a human body in Area-3 is subjected to radiation hazards in the acceptable limits for long duration exposure. The highest radiogenetic heat production values in Area-3 correspond to the phosphatic locations characterized by relatively high values of uranium and thorium. PMID- 26569555 TI - Truncated RASSF7 promotes centrosomal defects and cell death. AB - RASSF7 protein localises to the centrosome and plays a key role in mitosis. Its expression is also increased in a range of tumour types. However, little is known about the molecular basis of RASSF7's function and it is not clear if it acts as an oncogene in the cancers where its levels are elevated. Here, we carry out the first analysis of the domains of rassf7, focusing on which of them are responsible for its localisation to the centrosome. Constructs were generated to allow the expression of a series of truncated versions of rassf7 and the level of centrosomal localisation shown by each protein quantified. This analysis was carried out in Xenopus embryos which are a tractable system where rassf7 localisation can easily be studied. Our data shows that the coiled-coil domain of rassf7 is required and sufficient to direct its centrosomal localisation. The RA domain did not appear to have a role in mediating localisation. Surprisingly, removal of the extreme C-terminus of the protein caused rassf7 to accumulate at the centrosome and drive centrosome defects, including accumulation of the centrosomal protein gamma-tubulin and an amplification of the number of gamma tubulin foci. These effects required the centrosomal localisation mediated by the coiled-coil domain. Later in development cells expressing this truncated rassf7 protein underwent cell death. Finally, analysis of a database of tumour sequences identified a mutation in RASSF7 which would cause a similar C-terminal truncation of the protein. Based on our data this truncated protein might drive centrosomal defects and we propose the hypothesis that truncated RASSF7 could act as an oncogene in a small subset of tumours where it is mutated in this way. PMID- 26569556 TI - Comprehensive analysis of Hox gene expression in the amphipod crustacean Parhyale hawaiensis. AB - Hox genes play crucial roles in establishing regional identity along the anterior posterior axis in bilaterian animals, and have been implicated in generating morphological diversity throughout evolution. Here we report the identification, expression, and initial genomic characterization of the complete set of Hox genes from the amphipod crustacean Parhyale hawaiensis. Parhyale is an emerging model system that is amenable to experimental manipulations and evolutionary comparisons among the arthropods. Our analyses indicate that the Parhyale genome contains a single copy of each canonical Hox gene with the exception of fushi tarazu, and preliminary mapping suggests that at least some of these genes are clustered together in the genome. With few exceptions, Parhyale Hox genes exhibit both temporal and spatial colinearity, and expression boundaries correlate with morphological differences between segments and their associated appendages. This work represents the most comprehensive analysis of Hox gene expression in a crustacean to date, and provides a foundation for functional studies aimed at elucidating the role of Hox genes in arthropod development and evolution. PMID- 26569557 TI - Novel Fluorometric Method for the Determination of Production Rate and Steady State Concentration of Photochemically Generated Superoxide Radical in Seawater Using 3',6'-(Diphenylphosphinyl)fluorescein. AB - Superoxide radical (O2(*-)) is an important reactive oxygen species in seawater. Measurements of its production rates and steady-state concentrations generated by photochemical processes have been a Herculean task over the years. In this study, a probe - 3'6'-(diphenylphosphinyl)fluorescein (PF-1) - was used to trap photochemically generated O2(*-) in seawater, thereby yielding fluorescein. The fluorescein produced was measured by an isocratic fluorescence HPLC at excitation/emission wavelengths of 490/513 nm, respectively. The reaction rate constant of PF-1 with O2(*-) (kPF-1) was pH-dependent: (3.2-23.5) * 10(7) M(-1) s(-1) at pHTOT 7.65-8.50. By applying appropriate equations, both the production rate and the steady-state concentration of O2(*-) generated by photochemical reactions in the seawater were quantified. Under the optimized experimental conditions, fluorescein standards (3-50 nM) exhibited linearity in the seawater by HPLC. The photoformation of fluorescein, due to the reaction of PF-1 with the O2(*-) photochemically produced in the seawater, was linear within the 20 min irradiation. The detection limit of the fluorescein photoformation rate was 0.03 pM s(-1), defined as 3sigma of the lowest standard fluorescein concentration per 20 min irradiation. Using this value, the yield of fluorescein, and the fraction of O2(*-) that reacted with PF-1 in the seawater, the detection limit of the O2(* ) photoformation rate was 1.78 pM s(-1). Superoxide measurements using the proposed method were relatively unaffected by the potential interfering species in seawater. Application of the proposed method to ten (10) seawater samples from the Seto Inland Sea, Japan, resulted in measured O2(*-) photoformation rates of 3.1-8.5 nM s(-1), with steady-state concentrations ranging (0.06-0.3) * 10(-10) M. The method is simple, requires no technical sample preparation, and can be used to analyze a large number of samples. PMID- 26569558 TI - Distinguishing between realistic and fantastical figures in Iran. AB - Children in the United States come to distinguish historical from fictional story figures between the ages of 3 and 5 years, guided by the plausibility of the story events surrounding the figure (Corriveau, Kim, Schwalen, & Harris, 2009; Woolley & Cox, 2007). However, U.S. children vary in their reactions to stories that include fantastical events. Secular children with no religious education think of such stories and their protagonists as fictional, whereas children who have had a religious education are more prone to think of them as historically true. In the current studies, we asked if a sample of children in Iran who are regularly exposed to religious narratives in their daily lives resemble religious children in the United States. As expected, Iranian 5- and 6-year-olds systematically categorized figures in realistic stories as real, but they were also prone to think of figures in fantastical stories as real. We suggest that children's willingness to conceive of figures in fantastical stories as real is explained by their exposure to religious narratives alleging that miracles have actually happened. PMID- 26569559 TI - The impact of malnutrition on intelligence at 3 and 11 years of age: The mediating role of temperament. AB - Previous work has shown that malnutrition has deleterious effects on both IQ and aspects of temperament. It is hypothesized that while malnutrition bears a direct relation to IQ, aspects of temperament are also involved in a mediating role so that they produce indirect associations between malnutrition and IQ. The study examines the association of 3 indices of malnutrition-stunting, anemia and wasting-to Verbal IQ (VIQ) and Performance IQ (PIQ) and temperament in 1,376 3 year-old and 11-year-old children in Mauritius. Two dimensions of temperament were extracted from ratings of behavior and were labeled as Uninhibited (UI) and Task Orientation (TO). At age 3 stunting had direct relations to Verbal IQ and Performance IQ and also indirect relations via the mediating effect of temperament (UI but not TO). In the case of anemia there were no direct relations to VIQ or PIQ but both temperament meditators were involved in indirect relations. For wasting, indirect but not direct relations were observed. When age 11 cognitive performance was examined, there were direct relations to stunting and anemia and indirect relations via UI, but not TO. The relations between malnutrition and IQ were graded and linear showing that it is not only when malnutrition is defined by its severest levels that it has an effect on cognitive performance. It is suggested that malnutrition affects those brain structures and functions that are involved in both cognitive behavior and temperament. PMID- 26569560 TI - Infants, mothers, and dyadic contributions to stability and prediction of social stress response at 6 months. AB - The study of infants' interactive style and social stress response to repeated stress exposures is of great interest for developmental and clinical psychologists. Stable maternal and dyadic behavior is critical to sustain infants' development of an adaptive social stress response, but the association between infants' interactive style and social stress response has received scant attention in previous literature. In the present article, overtime stability of infant, maternal, and dyadic behaviors was measured across 2 social stress (i.e., Face-to-Face Still-Face, FFSF) exposures, separated by 15 days. Moreover, infant, maternal, and dyadic behaviors were simultaneously assessed as predictors of infants' social stress to both FFSF exposures. Eighty-one mother-infant dyads underwent the FFSF twice, at 6 months (Exposure 1: the first social stress) and at 6 months and 15 days (Exposure 2: repeated social stress). Infant and mother behavior and dyadic synchrony were microanalytically coded. Overall, individual behavioral stability emerged between FFSF exposures. Infants' response to the first stress was predicted by infant behavior during Exposure 1 Play. Infants' response to the repeated social stress was predicted by infants' response to the first exposure to the Still-Face and by infants' behavior and dyadic synchrony during Exposure 2 Play. Findings reveal stability for individual, but not for dyadic, behavior between 2 social stress exposures at 6 months. Infants' response to repeated social stress was predicted by infants' earlier stress response, infants' own behavior in play, and dyadic synchrony. No predictive effects of maternal behavior were found. Insights for research and clinical work are discussed. PMID- 26569561 TI - Passing on: Personal attributes associated with midlife expressions of intended legacies. AB - Expressions of the intent to leave behind something when we die can contain elements of both selflessness and selfishness. In this paper, we identify 3 different types of expressed legacy (personal, broader, and composite), and distinguish between them by examining their correlates (generativity, narcissism, and community involvement), as well as differences in expressed legacies for midlife African Americans and European Americans. Quantitative and qualitative data from surveys and interviews were drawn from the Foley Longitudinal Study of Adulthood (FLSA; N = 138; aged 55-58). We examined the contributions of generativity, narcissism, community involvement, and SES to each legacy, as well as the comparative levels of common significant predictors for each legacy, and the comparative likelihood of expressing particular legacies by race. Quantitative analyses showed that a different constellation of correlates predicted each legacy. Additionally, African Americans were more likely than European Americans to express legacies that indicated community involvement. Qualitative analyses showed that legacy groups (and races) also differed in open ended responses encompassing personal concerns, talents, and goals. These findings highlight some of the mechanisms and correlates of how the intent to leave a legacy can provide meaning and purpose for midlife African Americans and European Americans. Results are discussed in light of previous research concerning how legacies are transmitted, and potential differences in cultural roots and meaning for African Americans and European Americans. PMID- 26569562 TI - Children's causal inferences from conflicting testimony and observations. AB - Preschoolers use both direct observation of statistical data and informant testimony to learn causal relationships. Can children integrate information from these sources, especially when source reliability is uncertain? We investigate how children handle a conflict between what they hear and what they see. In Experiment 1, 4-year-olds were introduced to a machine and 2 blocks by a knowledgeable informant who claimed to know which block was better at activating the machine, or by a naive informant who guessed. Children then observed probabilistic evidence contradicting the informant and were asked to identify the block that worked better. Next, the informant claimed to know which of 2 novel blocks was a better activator, and children chose 1 block to try themselves. After observing conflicting data, children were more likely to say the informant's block was better when the informant was knowledgeable than when she was naive. Children also used the statistical data to evaluate the informant's reliability and were less likely to try the novel block she endorsed than children in a baseline group who did not observe data. In Experiment 2, children saw conflicting deterministic data; the majority chose the block that consistently activated the machine as better than the endorsed block. Children's causal inferences varied with the confidence of the informant and strength of the statistical data, and informed their future trust in the informant. Children consider the strength of both social and physical causal cues even when they disagree and integrate information from these sources in a rational way. PMID- 26569563 TI - Development of sensitivity to audiovisual temporal asynchrony during midchildhood. AB - Temporal proximity is one of the key factors determining whether events in different modalities are integrated into a unified percept. Sensitivity to audiovisual temporal asynchrony has been studied in adults in great detail. However, how such sensitivity matures during childhood is poorly understood. We examined perception of audiovisual temporal asynchrony in 7- to 8-year-olds, 10- to 11-year-olds, and adults by using a simultaneity judgment task (SJT). Additionally, we evaluated whether nonverbal intelligence, verbal ability, attention skills, or age influenced children's performance. On each trial, participants saw an explosion-shaped figure and heard a 2-kHz pure tone. These occurred at the following stimulus onset asynchronies (SOAs): 0, 100, 200, 300, 400, and 500 ms. In half of all trials, the visual stimulus appeared first (VA condition), and in the other half, the auditory stimulus appeared first (AV condition). Both groups of children were significantly more likely than adults to perceive asynchronous events as synchronous at all SOAs exceeding 100 ms, in both VA and AV conditions. Furthermore, only adults exhibited a significant shortening of reaction time (RT) at long SOAs compared to medium SOAs. Sensitivities to the VA and AV temporal asynchronies showed different developmental trajectories, with 10- to 11-year-olds outperforming 7- to 8-year-olds at the 300- to 500-ms SOAs, but only in the AV condition. Lastly, age was the only predictor of children's performance on the SJT. These results provide an important baseline against which children with developmental disorders associated with impaired audiovisual temporal function-such as autism, specific language impairment, and dyslexia-may be compared. PMID- 26569564 TI - Thriving while engaging in risk? Examining trajectories of adaptive functioning, delinquency, and substance use in a nationally representative sample of U.S. adolescents. AB - Recent advances in positive youth development theory and research explicate complex associations between adaptive functioning and risk behavior, acknowledging that high levels of both co-occur in the lives of some adolescents. However, evidence on nuanced overlapping developmental trajectories of adaptive functioning and risk has been limited to 1 sample of youth and a single conceptualization of adaptive functioning. We build on prior work by utilizing a nationally representative sample of U.S. adolescents (N = 1,665) followed from 7th grade until after high school and using a measure of adaptive functioning that was validated in a secondary sample of older adolescents (N = 93). In using dual trajectory growth mixture modeling to investigate links between developmental trajectories of adaptive functioning and delinquency and substance use, respectively, results provided evidence of heterogeneity in the overlap between adaptive functioning and risk trajectories. Males were more likely to be in the highest adaptive functioning group as well as the most at-risk delinquency class. The magnitude of negative associations between adaptive functioning and both risk behaviors decreased at Wave 3, indicating a decoupling of adaptive functioning and risk as youth aged. These findings converge in underscoring the need to generate a cohesive theory that specifies factors that promote adaptive functioning and risk in concert. PMID- 26569565 TI - Lost in search: (Mal-)adaptation to probabilistic decision environments in children and adults. AB - Adaptive decision making in probabilistic environments requires individuals to use probabilities as weights in predecisional information searches and/or when making subsequent choices. Within a child-friendly computerized environment (Mousekids), we tracked 205 children's (105 children 5-6 years of age and 100 children 9-10 years of age) and 103 adults' (age range: 21-22 years) search behaviors and decisions under different probability dispersions (.17; .33, .83 vs. .50, .67, .83) and constraint conditions (instructions to limit search: yes vs. no). All age groups limited their depth of search when instructed to do so and when probability dispersion was high (range: .17-.83). Unlike adults, children failed to use probabilities as weights for their searches, which were largely not systematic. When examining choices, however, elementary school children (unlike preschoolers) systematically used probabilities as weights in their decisions. This suggests that an intuitive understanding of probabilities and the capacity to use them as weights during integration is not a sufficient condition for applying simple selective search strategies that place one's focus on weight distributions. PMID- 26569566 TI - You get what you get and you don't throw a fit!: Emotion socialization and child physiology jointly predict early prosocial development. AB - Prosocial behavior in early childhood is a precursor to later adaptive social functioning. This investigation leveraged mother-reported, physiological, and observational data to examine children's prosocial development from age 2 to age 4 (N = 125). Maternal emotion socialization (ES) strategies and children's parasympathetic regulation have each been implicated in prosocial behavior, but are rarely examined together or prospectively. Given the transactional nature of parent-child relationships, the effects of maternal ES strategies on children's prosocial behavior are likely moderated by children's individual differences in parasympathetic regulation. As expected, mothers' reported use of problem-focused ES strategies predicted prosocial behavior at age 4. Additionally, children who showed parasympathetic reactivity consistent with more effective emotion regulation during a lab-based disappointment task were rated as more prosocial at age 4. Several interactions with maternal ES strategies emerged. Children's parasympathetic regulation moderated the relations between observed physical comfort or cognitive reframing and prosocial behavior. Observed distraction (either behavioral or cognitive) moderated the link between mothers' reported use of problem-focused ES strategies and children's prosocial behavior. Findings suggest that children's emerging prosocial behavior is shaped by the interactive contributions of interpersonal maternal ES as well as intrapersonal intrinsic physiological regulation. (PsycINFO Database Record PMID- 26569568 TI - Entanglement discrimination in multi-rail electron-hole currents. AB - We propose a quantum-Hall interferometer that integrates an electron-hole entangler with an analyzer working as an entanglement witness by implementing a multi-rail encoding. The witness has the ability to discriminate (and quantify) spatial-mode and occupancy entanglement. This represents a feasible alternative to limited approaches based on the violation of Bell-like inequalities. PMID- 26569567 TI - A longitudinal examination of perceived discrimination and depressive symptoms in ethnic minority youth: The roles of attributional style, positive ethnic/racial affect, and emotional reactivity. AB - Although perceived ethnic/racial discrimination is well established as a risk factor for depressive symptoms in ethnic minority youth, few studies have examined their longitudinal relationship over time. This study examined whether a negative attributional style, positive ethnic/racial affect, and emotional reactivity moderated the longitudinal relationship of perceived peer or adult discrimination and depressive symptoms in a sample of African American and Latino high school students (n = 155). African American and Latino youth who experienced increases in perceived peer discrimination also reported greater depressive symptoms over time, but positive ethnic/racial affect buffered the longitudinal association. Emotional reactivity also served as a significant moderator but only of the baseline association between perceived peer discrimination and depressive symptoms. Thus, perceived ethnic/racial discrimination appears to play a significant role in the development of depressive symptoms for ethnic minority youth, especially those who start high school with lower levels of positive ethnic/racial affect. PMID- 26569570 TI - Bayesian model reduction and empirical Bayes for group (DCM) studies. AB - This technical note describes some Bayesian procedures for the analysis of group studies that use nonlinear models at the first (within-subject) level - e.g., dynamic causal models - and linear models at subsequent (between-subject) levels. Its focus is on using Bayesian model reduction to finesse the inversion of multiple models of a single dataset or a single (hierarchical or empirical Bayes) model of multiple datasets. These applications of Bayesian model reduction allow one to consider parametric random effects and make inferences about group effects very efficiently (in a few seconds). We provide the relatively straightforward theoretical background to these procedures and illustrate their application using a worked example. This example uses a simulated mismatch negativity study of schizophrenia. We illustrate the robustness of Bayesian model reduction to violations of the (commonly used) Laplace assumption in dynamic causal modelling and show how its recursive application can facilitate both classical and Bayesian inference about group differences. Finally, we consider the application of these empirical Bayesian procedures to classification and prediction. PMID- 26569571 TI - Exercise Training in Group 2 Pulmonary Hypertension: Which Intensity and What Modality. AB - Pulmonary hypertension (PH) due to left-sided heart disease (LSHD) is a common and disconcerting occurrence. For example, both heart failure (HF) with preserved and reduced ejection fraction (HFpEF and HFrEF) often lead to PH as a consequence of a chronic elevation in left atrial filling pressure. A wealth of literature demonstrates the value of exercise training (ET) in patients with LSHD, which is particularly robust in patients with HFrEF and growing in patients with HFpEF. While the effects of ET have not been specifically explored in the LSHD-PH phenotype (i.e., composite pathophysiologic characteristics of patients in this advanced disease state), the overall body of evidence supports clinical application in this subgroup. Moderate intensity aerobic ET significantly improves peak oxygen consumption, quality of life and prognosis in patients with HF. Resistance ET significantly improves muscle strength and endurance in patients with HF, which further enhance functional capacity. When warranted, inspiratory muscle training and neuromuscular electrical stimulation are becoming recognized as important components of a comprehensive rehabilitation program. This review will provide a detailed account of ET programing considerations in patients with LSHD with a particular focus on those concomitantly diagnosed with PH. PMID- 26569572 TI - Biotin-mediated epigenetic modifications: Potential defense against the carcinogenicity of benzo[a]pyrene. AB - Environmental pollution and an unhealthy lifestyle result in direct exposure to dangerous chemicals that can modify endogenous pathways and induce malignant transformation of human cells. Although the molecular mechanisms of tumorigenesis are still not well understood, epigenetic alteration may be associated with exogenous chemical-induced carcinogenicity. Given the association between nutrition and cancer, nutrient supplementation may reduce aberrant epigenetic modifications induced by chemicals, thus decreasing carcinogenesis. This paper provides an overview of the epigenetic events caused by benzo[a]pyrene, a procarcinogenic and environmental pollutant, and biotin, an essential water soluble vitamin, and investigates potential connections between them. This paper also discusses the potential inhibitory effect of biotin-related epigenetic modifications on the carcinogenicity of benzo[a]pyrene. The effect of nutritional supplementation on tumorigenesis involving epigenetic modifications is also discussed. PMID- 26569573 TI - Analysis of miRNA expression profiling in mouse spleen affected by acute Toxoplasma gondii infection. AB - Toxoplasma gondii is a worldwide prevalent pathogen that infects most of the warm blood vertebrates. To investigate the regulation network of splenic miRNAs altered by acute infection with T. gondii, we herein investigated the changes of miRNA profile in mouse spleen via next generation sequencing and bioinformatics analysis. A total of 379 miRNAs was identified, 131 miRNAs of them were differentially expressed (including 97 upregulated and 34 downregulated miRNAs). 48 differentially expressed miRNAs had validated targets in the miRWalk2.0 database. Gene Ontology (GO) enrichment analysis revealed that the validated targets of differently expressed miRNAs were significantly enriched in gene transcription regulation. It suggested that T. gondii can modulate host gene expression through targeting to trans-regulation factors. The genes involved in apoptosis or anti-apoptosis were both targeted by differentially expressed miRNAs. The change of power balance between the miRNAs targeting host apoptosis genes and those regulating host anti-apoptosis genes contributes to the fate of host apoptosis process. Twelve pathways were significantly enriched in KEGG analysis with most of them being cancer related, including pathways in cancer, pancreatic cancer, colorectal cancer, axon guidance, MAPK signaling pathway, focal adhesion, chronic myeloid leukemia, renal cell carcinoma, prostate cancer, glioma, regulation of actin cytoskeleton, and Wnt signaling pathway. Our study showed a changed miRNA regulation network in mouse spleen infected by T. gondii. These findings will be helpful for better understanding of miRNA regulation network in host-T. gondii interaction, revealing the relationship among T. gondii infection, gene regulation, apoptosis and cancer process alterations in infected spleen. PMID- 26569574 TI - Inelastic neutron scattering study of the lattice dynamics in the clathrate compound BaGe5. AB - We report inelastic neutron scattering (INS) measurements on the polycrystalline oP60-type clathrate BaGe5, whose crystal structure is related to the type-I clathrate Ba8Ge43?3 and to the cP124-clathrate Ba6Ge25. Our results show that BaGe5 exhibits a similar phonon density of states (PDOS) in the energy range 0-40 meV with respect to Ba8Ge43?3. The low-energy region of the PDOS spectrum (0-10 meV) consists of two peaks at 4.1 and 6.2 meV likely related to Ba-weighted modes. Compared to Ba8Ge43?3, the low-energy region of the phonon spectrum of BaGe5 shows a more complex structure, likely reflecting the presence of three distinct crystallographic sites for Ba. The specific heat data of BaGe5, reexamined in light of the INS results, indicate that the Ba-weighted modes dominate the low-temperature behavior of Cp. PMID- 26569575 TI - Soft Anisotropic Conductors as Electric Vias for Ga-Based Liquid Metal Circuits. AB - We introduce a method for sealing liquid metal (LM) circuits with soft anisotropic conductors that prevent leaking, while simultaneously allowing for electrical contact with skin and surface mounted electronics. These films are composed of polydimethylsiloxane (PDMS) embedded with vertically aligned columns of ferromagnetic Ag-Ni microparticles. The microparticles are magnetically aligned and support electrical conductivity only through the thickness (z-axis) of the elastomer film. Measurements on 10-40% (by wt) composites show moderate volumetric resistivity (as low as rho = 0.03 Omega/m) through the thickness and no conductivity between adjacent traces. Functionality is demonstrated with several illustrative applications related to tactile sensing and electronics hardware integration. PMID- 26569576 TI - Short-Term Outcomes for Opiate and Crack Users Accessing Treatment: The Effects of Criminal Justice Referral and Crack Use. AB - BACKGROUND/AIMS: The English drug treatment population doubled in size between 1998 and 2008, increasingly characterised by crack cocaine use and criminal justice system (CJS) referral. We assessed short-term (median 3.5 month) behaviour changes following participation in drug treatment and the moderating effect of CJS referral/crack use. METHODS: Opiate and/or crack cocaine users (n = 1,267) were recruited from 342 agencies. Outcome effects were assessed via interaction term regression, clustered at participant level, controlling for client characteristics. Treatment retention effects were tested via Cox proportional hazard models. RESULTS: Statistically significant improvements in health, drug use and offensive behaviour were observed (e.g. heroin use from 87 to 51%, acquisitive offending from 47 to 23%). Referral route was not associated with variation in outcomes. Crack use at baseline was associated with a greater chance of non-fatal overdose at follow-up (p = 0.035, 95% CI 1.08-8.20) but a greater reduction in offending income (p = 0.002, 95% CI L104-L419). CONCLUSION: Despite changes in the English drug treatment population, equivalent short-term improvements in client behaviour were observed a decade earlier. Outcomes for CJS referred clients were comparable to non-CJS. Crack use at treatment entry offered some scope for greater improvements in offending but may be a barrier to cessation of mortality-associated risky behaviour. PMID- 26569577 TI - Associations between gender-based violence and personality disorders in U.S. women. AB - Gender-based violence (GBV) is prevalent and associated with deleterious outcomes including posttraumatic stress disorder, depression, and substance use disorders. Despite substantial comorbidity between these conditions and personality disorders (PDs), few, if any, studies have examined associations between lifetime exposure to GBV and risk for a range of PDs in nationally representative U.S. SAMPLES: The current study addressed this gap in the literature by examining adjusted odds ratios (aORs) and population attributable fractions (PAFs) of 10 PDs by lifetime GBV exposure. Participants were 20,089 women who participated in wave 2 (2004-2005) of the National Epidemiologic Survey of Alcohol and Related Conditions. Lifetime GBV and PD were reported by 25% and 20% of women, respectively. Logistic regressions indicated that women with GBV had 3.5 times the odds of lifetime PD; aORs ranged from 2.3 to 6.3 for Schizoid and Borderline PD, respectively. GBV was associated with 38% of all PD cases, and women who had experienced all 3 GBV types had 8.5 times the odds of PD compared to nonvictims. Preventing GBV, particularly multitype GBV, may be critical to reducing the burden of PDs. Clinicians working with GBV victims should consider assessing PDs and providing treatment targeting multiple outcomes. PMID- 26569578 TI - Electronic Structure of Fullerene Acceptors in Organic Bulk-Heterojunctions: A Combined EPR and DFT Study. AB - Organic photovoltaic (OPV) devices are a promising alternative energy source. Attempts to improve their performance have focused on the optimization of electron-donating polymers, while electron-accepting fullerenes have received less attention. Here, we report an electronic structure study of the widely used soluble fullerene derivatives PC61BM and PC71BM in their singly reduced state, that are generated in the polymer:fullerene blends upon light-induced charge separation. Density functional theory (DFT) calculations characterize the electronic structures of the fullerene radical anions through spin density distributions and magnetic resonance parameters. The good agreement of the calculated magnetic resonance parameters with those determined experimentally by advanced electron paramagnetic resonance (EPR) allows the validation of the DFT calculations. Thus, for the first time, the complete set of magnetic resonance parameters including directions of the principal g-tensor axes were determined. For both molecules, no spin density is present on the PCBM side chain, and the axis of the largest g-value lies along the PCBM molecular axis. While the spin density distribution is largely uniform for PC61BM, it is not evenly distributed for PC71BM. PMID- 26569579 TI - Visible Surface Plasmon Modes in Single Bi2Te3 Nanoplate. AB - Searching for new plasmonic building blocks which offer tunability and design flexibility beyond noble metals is crucial for advancing the field of plasmonics. Herein, we report that solution-synthesized hexagonal Bi2Te3 nanoplates, in the absence of grating configurations, can exhibit multiple plasmon modes covering the entire visible range, as observed by transmission electron microscopy (TEM) based electron energy-loss spectroscopy (EELS) and cathodoluminescence (CL) spectroscopy. Moreover, different plasmon modes are observed in the center and edge of the single Bi2Te3 nanoplate and a breathing mode is discovered for the first time in a non-noble metal. Theoretical calculations show that the plasmons observed in the visible range are mainly due to strong spin-orbit coupling induced metallic surface states of Bi2Te3. The versatility of shape- and size engineered Bi2Te3 nanocrystals suggests exciting possibilities in plasmonics enabled technology. PMID- 26569580 TI - Establishing an Academic-Industrial Stratified Medicine Consortium: Psoriasis Stratification to Optimize Relevant Therapy. PMID- 26569583 TI - Chromatin Modifications and Mast Cell Migration in UV-Induced Immunosuppression, an Epigenetic Piece of The Puzzle. AB - The migration of dermal mast cells to skin-draining lymph nodes is a key step in UV-induced immunosuppression. Examining the effects of platelet-activating factor (PAF), a phospholipid mediator secreted by keratinocytes following UV exposure, on mast cells, Damiani et al. demonstrate that increased expression of CXCR4 is associated with increased histone acetylation at the promoter of this chemokine receptor gene. PMID- 26569584 TI - Mutational Heterogeneity in Melanoma: An Inconvenient Truth. AB - Identification of oncogenic BRAF mutations in primary and metastatic melanomas supports a linear model of clonal evolution in cancer. Some mutational studies, however, have failed to identify BRAF mutations in metastatic tumors from patients with BRAFmutant primary melanomas. Using a combination of methods, Riveiro-Falkenbach et al. (2015) assert that technical issues, and not clonal heterogeneity, may explain prior discordant mutational results. PMID- 26569585 TI - Beyond Red Hair and Sunburns: Uncovering the Molecular Mechanisms of MC1R Signaling and Repair of UV-Induced DNA Damage. AB - Scientists at the University of Kentucky are unraveling the details of DNA-damage repair in the melanocyte, with an eye towards finding druggable targets for melanoma prevention. Jarret et al., (2015, this issue) report in this issue three new assays that can yield mechanistic information about nucleotide excision repair (NER) stimulated by cAMP-dependent signaling downstream of the melanocortin-1 receptor (MC1R). PMID- 26569586 TI - Melanocyte Regeneration in Vitiligo Requires WNT beneath their Wings. AB - Melanocytes in patients with vitiligo possess intrinsic abnormalities that contribute to its pathogenesis. Regazzetti et al. report that CXCL10 expression reflects subtle inflammation in normal-appearing skin but not in stable depigmented lesions, supporting the hypothesis that melanocytes themselves initiate autoimmune inflammation prior to clinically evident disease. In addition, they find that oxidative stress in melanocytes impairs WNT signaling and that targeting this pathway induces melanoblast differentiation. Thus, activating the WNT pathway may serve as an adjunctive strategy to support repigmentation in patients with vitiligo. PMID- 26569587 TI - Microenvironment-Driven Resistance to BRAF Inhibition Comes of Age. AB - Increasingly comprehensive observations indicate that the tumor microenvironment contributes to drug resistance toward small molecule inhibitors. Fedorenko et al. describe a role for fibroblasts in creating a favorable niche for melanoma cell survival if treated with the BRAF inhibitor vemurafenib. TGF-beta released by vemurafenib-treated melanoma cells stimulated fibroblasts for increased alpha smooth muscle actin, neuregulin (NRG), and fibronectin expression. Off-target effects of vemurafenib led to paradoxical secretion of hepatocyte growth factor (HGF) by fibroblasts. Combined inhibition of BRAF/MET/HER kinases was insufficient to reverse the protective effect of the fibroblasts, whereas reversal was achieved by combined BRAF/PI3K inhibition. A thorough understanding of the complex spatiotemporal interactions in tumor microenvironments holds promise for improved targeting using combination therapies in patients with melanoma. PMID- 26569591 TI - Cells to Surgery Quiz: December 2015. Answers: 1. e. 2. d. 3. a. PMID- 26569592 TI - December 2015 Snapshot Dx Quiz: Linking Science to Patient Care. Answers: 1. c. 2. c. 3. e. PMID- 26569593 TI - Humanized Mice in Dermatology Research. PMID- 26569596 TI - Searching for Improved Photoreleasing Abilities of Organic Molecules. AB - Photoremovable protecting groups (PPGs) are chemical auxiliaries that provide spatial and temporal control over the release of various molecules: bioagents (neurotransmitters and cell-signaling molecules, Ca(2+) ions), acids, bases, oxidants, insecticides, pheromones, fragrances, etc. A major challenge for the improvement of PPGs lies in the development of organic chromophores that release the desired bioagents upon continuous irradiation at wavelengths above 650 nm, that is, in the tissue-transparent window. Understanding of the photorelease reaction mechanisms, investigated by laser flash photolysis and rationalized with the aid of quantum chemical calculations, allows for achieving this goal. In particular, simple Huckel calculations provide useful guidelines for designing new PPGs, because both the lowest excited singlet and triplet states of conjugated systems can be reasonably well described by a single electronic configuration formed by promotion of a single electron from the highest occupied molecular orbital (HOMO) to the lowest unoccupied MO (LUMO) of the ground state configuration. Here we show that Huckel calculations permit rapid identification of common features in the nodal properties of the frontier orbitals of various chromophores that can be classified into distinct chromophore families. If the electronic excitation involves a substantial electron density transfer to an sp(2) carbon atom at which HOMO and LUMO are nearly disjoint, for example, by virtue of symmetry, favorable photoheterolysis can be expected when the corresponding atom carries a leaving group at the alpha-position. We show examples of photoheterolytic reactions that indicate that the efficiency of photoheterolysis diminishes for chromophores absorbing in the NIR region. We provide a rationale for more efficient photoheterolytic reactions occurring via the triplet state, and we demonstrate the advantages of this mechanistic pathway. Analogies in the structure-reactivity relationships of PPGs can therefore lead to new strategies for the development of more efficient NIR-absorbing photoremovable protecting groups. PMID- 26569594 TI - Insights into the molecular evolution of Dengue virus type 4 in Puerto Rico over two decades of emergence. AB - Dengue has emerged globally as a major human health problem since the 1950s and is now the most important arboviral disease of humans, infecting nearly 400 million people annually. While some cases are asymptomatic, others can develop a febrile illness (dengue fever) or even progress to severe and fatal dengue. Dengue is caused by any of 4 closely related but distinct viruses, known as Dengue virus serotype 1 to 4 (DENV-1 to DENV-4) which are maintained in endemic transmission to humans in large urban centers of the tropics by Aedes mosquitoes. Since the early 1960s, Puerto Rico, a major metropolitan center in the Caribbean, has experienced increasingly larger and clinically more severe epidemics following the introduction of all four dengue serotypes. The first dengue hemorrhagic fever epidemic in 1986, and a particularly severe outbreak in 1998 were dominated by novel DENV-4 strains that evolved in Puerto Rico, replacing earlier strains and spreading throughout the region. Sequence characterization of 54 complete DENV-4 genomes and their comparative evolution against 74 previously published viral sequences from the region over several decades shows that DENV-4 strains from these periods were genetically distinct based on unique changes in the envelope and non-structural genes. Their replacement of earlier strains in Puerto Rico progressed rapidly, suggesting that strong natural selection played a role in their fixation. This study confirms that DENVs evolve through rapid lineage turnover driven in part by natural selection and genetic drift. PMID- 26569595 TI - Elimination of HCV via a non-ISG-mediated mechanism by vaniprevir and BMS-788329 combination therapy in human hepatocyte chimeric mice. AB - We previously reported that interferon (IFN)-free direct-acting antiviral combination treatment succeeded in eradicating genotype 1b hepatitis C virus (HCV) in human hepatocyte chimeric mice. In this study, we examined the effect of vaniprevir (MK7009, NS3/4A protease inhibitor) and BMS-788329 (NS5A inhibitor) combination treatment on HCV genotype 1b and the expression of IFN-stimulated genes (ISGs) using a subgenomic replicon system and the same animal model. Combination treatment with vaniprevir and BMS-788329 significantly reduced HCV replication compared to vaniprevir monotherapy in HCV replicon cells (Huh7/Rep Feo cells). HCV genotype 1b-infected human hepatocyte chimeric mice were treated with vaniprevir alone or in combination with BMS-788329 for four weeks. Vaniprevir monotherapy reduced serum HCV RNA titers in mice, but viral breakthrough was observed in mice with high HCV titers. Ultra-deep sequence analysis revealed a predominant replacement by drug-resistant substitutions at 168 in HCV NS3 region in these mice. Conversely, in mice with low HCV titers, HCV was eradicated by vaniprevir monotherapy without viral breakthrough. In contrast to monotherapy, combination treatment with vaniprevir and BMS-788329 succeeded in completely eradicating HCV regardless of serum viral titer. IFN-alpha treatment significantly increased ISG expression; however, vaniprevir and BMS-788329 combination treatment caused no increase in ISG expression both in cultured cells and in mouse livers. Therefore, combination treatment with vaniprevir and BMS 788329 eliminated HCV via a non-ISG-mediated mechanism. This oral treatment might offer an alternative DAA combination therapy for patients with chronic hepatitis C. PMID- 26569597 TI - Metabolic Interaction Potential between Clopidogrel and Sulfonylurea Antidiabetic Agents: Effects on Clopidogrel Bioactivation. AB - BACKGROUND: Patients with diabetes have increased rates of cardiovascular events, and concomitant use of antidiabetic agents and clopidogrel may increase the risk for drug interactions. This study was undertaken to investigate the interaction potential between sulfonylurea drugs and clopidogrel, with an emphasis on key steps in the clopidogrel bioactivation processes. METHODS: Inhibition of clopidogrel metabolism by sulfonylureas was evaluated by monitoring the formation of clopidogrel carboxylic acid and 2-oxo-clopidogrel in human liver microsomes (HLM), human intestinal microsomes and recombinant human enzymes. CYP2C9-based interaction was investigated for both 2-oxo-clopidogrel and glimepiride using HLM and the recombinant CYP2C9 system. RESULTS: For the formation of clopidogrel carboxylic acid (the deactivation step) and 2-oxo-clopidogrel (the first step of bioactivation) in human microsomes, the inhibition potency of the 3 sulfonylurea drugs tested followed the order of glimepiride > glipizide > gliclazide. For the metabolism of 2-oxo-clopidogrel (the second step of bioactivation), glimepiride demonstrated a relatively strong inhibition against CYP2C9 activity (IC50 12.7 MUmol/l). In addition, 2-oxo-clopidogrel displayed a moderate inhibitory effect toward the CYP2C9-mediated metabolism of glimepiride. CONCLUSION: The moderate inhibition observed for clopidogrel bioactivation may not present a significant risk for drug-drug interactions between sulfonylureas and clopidogrel. While these findings bode well for multidrug therapies involving sulfonylureas and clopidogrel, clinical investigations are needed to define the clinical risk and benefit for combining these agents for the management of cardiovascular events in diabetic patients. PMID- 26569598 TI - Quantitative characterization of genetic parts and circuits for plant synthetic biology. AB - Plant synthetic biology promises immense technological benefits, including the potential development of a sustainable bio-based economy through the predictive design of synthetic gene circuits. Such circuits are built from quantitatively characterized genetic parts; however, this characterization is a significant obstacle in work with plants because of the time required for stable transformation. We describe a method for rapid quantitative characterization of genetic plant parts using transient expression in protoplasts and dual luciferase outputs. We observed experimental variability in transient-expression assays and developed a mathematical model to describe, as well as statistical normalization methods to account for, this variability, which allowed us to extract quantitative parameters. We characterized >120 synthetic parts in Arabidopsis and validated our method by comparing transient expression with expression in stably transformed plants. We also tested >100 synthetic parts in sorghum (Sorghum bicolor) protoplasts, and the results showed that our method works in diverse plant groups. Our approach enables the construction of tunable gene circuits in complex eukaryotic organisms. PMID- 26569600 TI - Impact of Poverty and Health Care Insurance on Arteriovenous Fistula Use among Incident Hemodialysis Patients. AB - BACKGROUND: The impact of socioeconomic factors on arteriovenous fistula (AVF) creation in hemodialysis (HD) patients is not well understood. We assessed the association of area and individual-level indicators of poverty and health care insurance on AVF use among incident end-stage renal disease (ESRD) patients initiated on HD. METHODS: In this retrospective cohort study using the United States Renal Data System database, we identified 669,206 patients initiated on maintenance HD from January 1, 2007 through December 31, 2012. We assessed the Medicare-Medicaid dual-eligibility status as an indicator of individual-level poverty and ZIP code-level median household income (MHI) data obtained from the 2010 United States Census. We conducted logistic regression of AVF use at start of dialysis as the outcome variable. RESULTS: The proportions of dual-eligible and non-dual-eligible patients who initiated HD with an AVF were 12.53 and 16.17%, respectively (p<0.001). Dual eligibility was associated with significantly lower likelihood of AVF use upon initiation of HD (adjusted odds ratio (aOR) 0.91; 95% CI 0.90-0.93). Patients in the lowest area-level MHI quintile had an aOR of 0.97 (95% CI 0.95-0.99) compared to those in higher quintile levels. However, dual eligibility and area-level MHI were not significant in patients with Veterans Affairs (VA) coverage. CONCLUSIONS: Individual- and area-level measures of poverty were independently associated with a lower likelihood of AVF use at the start of HD, the only exception being patients with VA health care benefits. Efforts to improve incident AVF use may require focusing on pre-ESRD care to be successful. PMID- 26569599 TI - Parmbsc1: a refined force field for DNA simulations. AB - We present parmbsc1, a force field for DNA atomistic simulation, which has been parameterized from high-level quantum mechanical data and tested for nearly 100 systems (representing a total simulation time of ~ 140 MUs) covering most of DNA structural space. Parmbsc1 provides high-quality results in diverse systems. Parameters and trajectories are available at http://mmb.irbbarcelona.org/ParmBSC1/. PMID- 26569601 TI - Development of separation technology for the removal of radium-223 from decayed thorium-227 in drug formulations. Material screening and method development. AB - Targeted thorium conjugates are currently being investigated as a new class of alpha-radiopharmaceuticals. The natural decay of thorium-227 ((227)Th) results in the ingrowth of radium-223 ((223)Ra). Consideration must, therefore, be given to define acceptable limits of (223)Ra in the drug product at the time of dose administration. By effective sequestration of (223)Ra, we aim to improve the radiochemical purity and extend the effective user window of drug products containing (227)Th. (223)Ra is the first progeny of (227)Th and the only one with a long half-life (days). We have, therefore, focused on the removal of this specific species since the progenies of (223)Ra will have a very limited lifetime in the formulation once (223)Ra is removed. In this study, we investigated a multitude of materials for their ability to reduce the (223)Ra level by: (1) passive diffusion or (2) by cartridge filtration on gravity columns. In addition, we probe the compatibility of these materials in the presence of antibody trastuzumab to assess the level of protein binding and estimate the quenching of radiolysis by binding of radionuclides. A screening matrix of organic and inorganic materials was established, i.e. strontium and calcium alginate gel beads, distearoyl phosphatidylglycerol (DSPG) liposomes, ceramic hydroxyapatite, Zeolite UOP type 4A and cation exchange resins AG50W-X8 and SOURCE 30S. First, passive diffusional uptake of (223)Ra by suspended materials present in the formulation was measured as a decrease in sample radioactivity after separation. Second, selected materials were packed on gravity columns in order to evaluate the efficiency of column separation versus diffusional adsorption. The retention of (223)Ra and (227)Th were characterized by measuring the radioactivity in the eluate and on the columns. Finally, the compatibility between trastuzumab, as a selected model antibody, and suspensions of the binding materials was analyzed during storage of the drug product in the presence of adsorbent. The formation of H2O2 was evaluated to measure the influence of radionuclide binding material on radiolysis in the formulation. All the materials bound (223)Ra by passive diffusional uptake ranging from 31% to 95% with DSPG liposomes demonstrating superiority at 95% efficiency. All materials suitable for assessment by gravity column filtration bound (223)Ra almost quantitatively (~100%) and with minimal variation (relative standard deviation <1%). The uptake was significantly higher compared to passive diffusional uptake. Alginate gel beads, ceramic hydroxyapatite and SOURCE 30S reduced the antibody concentration in solution to 40-50% while the Zeolite UOP type 4A, AG50W-X8 resin and DSPG liposomes showed <=10% reduction of antibody concentration. Ceramic hydroxyapatite significantly reduced H2O2 formed by radionuclide initiated radiolysis. PMID- 26569603 TI - The Elastic Behaviour of Sintered Metallic Fibre Networks: A Finite Element Study by Beam Theory. AB - BACKGROUND: The finite element method has complimented research in the field of network mechanics in the past years in numerous studies about various materials. Numerical predictions and the planning efficiency of experimental procedures are two of the motivational aspects for these numerical studies. The widespread availability of high performance computing facilities has been the enabler for the simulation of sufficiently large systems. OBJECTIVES AND MOTIVATION: In the present study, finite element models were built for sintered, metallic fibre networks and validated by previously published experimental stiffness measurements. The validated models were the basis for predictions about so far unknown properties. MATERIALS AND METHODS: The finite element models were built by transferring previously published skeletons of fibre networks into finite element models. Beam theory was applied as simplification method. RESULTS AND CONCLUSIONS: The obtained material stiffness isn't a constant but rather a function of variables such as sample size and boundary conditions. Beam theory offers an efficient finite element method for the simulated fibre networks. The experimental results can be approximated by the simulated systems. Two worthwhile aspects for future work will be the influence of size and shape and the mechanical interaction with matrix materials. PMID- 26569602 TI - Differential Neural Processing during Motor Imagery of Daily Activities in Chronic Low Back Pain Patients. AB - Chronic low back pain (chronic LBP) is both debilitating for patients but also a major burden on the health care system. Previous studies reported various maladaptive structural and functional changes among chronic LBP patients on spine and supraspinal levels including behavioral alterations. However, evidence for cortical reorganization in the sensorimotor system of chronic LBP patients is scarce. Motor Imagery (MI) is suitable for investigating the cortical sensorimotor network as it serves as a proxy for motor execution. Our aim was to investigate differential MI-driven cortical processing in chronic LBP compared to healthy controls (HC) by means of functional magnetic resonance imaging (fMRI). Twenty-nine subjects (15 chronic LBP patients, 14 HC) were included in the current study. MI stimuli consisted of randomly presented video clips showing every-day activities involving different whole-body movements as well as walking on even ground and walking downstairs and upstairs. Guided by the video clips, subjects had to perform MI of these activities, subsequently rating the vividness of their MI performance. Brain activity analysis revealed that chronic LBP patients exhibited significantly reduced activity compared to HC subjects in MI related brain regions, namely the left supplementary motor area and right superior temporal sulcus. Furthermore, psycho-physiological-interaction analysis yielded significantly enhanced functional connectivity (FC) between various MI associated brain regions in chronic LBP patients indicating diffuse and non specific changes in FC. Current results demonstrate initial findings about differences in MI-driven cortical processing in chronic LBP pointing towards reorganization processes in the sensorimotor network. PMID- 26569604 TI - Scenario-Led Habitat Modelling of Land Use Change Impacts on Key Species. AB - Accurate predictions of the impacts of future land use change on species of conservation concern can help to inform policy-makers and improve conservation measures. If predictions are spatially explicit, predicted consequences of likely land use changes could be accessible to land managers at a scale relevant to their working landscape. We introduce a method, based on open source software, which integrates habitat suitability modelling with scenario-building, and illustrate its use by investigating the effects of alternative land use change scenarios on landscape suitability for black grouse Tetrao tetrix. Expert opinion was used to construct five near-future (twenty years) scenarios for the 800 km2 study site in upland Scotland. For each scenario, the cover of different land use types was altered by 5-30% from 20 random starting locations and changes in habitat suitability assessed by projecting a MaxEnt suitability model onto each simulated landscape. A scenario converting grazed land to moorland and open forestry was the most beneficial for black grouse, and 'increased grazing' (the opposite conversion) the most detrimental. Positioning of new landscape blocks was shown to be important in some situations. Increasing the area of open-canopy forestry caused a proportional decrease in suitability, but suitability gains for the 'reduced grazing' scenario were nonlinear. 'Scenario-led' landscape simulation models can be applied in assessments of the impacts of land use change both on individual species and also on diversity and community measures, or ecosystem services. A next step would be to include landscape configuration more explicitly in the simulation models, both to make them more realistic, and to examine the effects of habitat placement more thoroughly. In this example, the recommended policy would be incentives on grazing reduction to benefit black grouse. PMID- 26569605 TI - Site-Specific MicroRNA Expression May Lead to Different Subtypes in Ulcerative Colitis. AB - BACKGROUND AND AIM: Ulcerative Colitis (UC) is a type of inflammatory bowel disease, considered as an important disease of gastrointestinal tract having a huge impact on the health of the patient. Prolonged inflammation of colon in UC patients increases the risk of developing colorectal cancer. MiRNA are reported as a connecting link between inflammation and cancer. Differential miRNA expression is reported in Crohn's disease (CD) patients involving various regions of the gastrointestinal tract. The current study was performed to dissect out the site specific miRNA expression in the colon biopsy samples of UC patients from Northern India. METHODS: Biopsy samples were collected from UC patients and healthy controls from Rectosigmoid Area (RS) and Ascending Colon (AC). MiRNA expression was compared between patients with RS and AC using a microarray platform. Differential expression was further validated by Real Time PCR analysis. Demographic and pathological data of UC -associated CRC patients was collected from the hospital database and analyzed for assessing the site of cancer. RESULTS: Upon analysis of data generated on a microarray platform and qRT PCR revealed that the expression of six miRNAs hsa-miR-146b-5p, hsa-miR-335-3p, hsa-miR-342-3p, hsa-miR-644b-3p, hsa-miR-491-3p, hsa-miR-4732-3p were downregulated in patients where RS was involved as compared to AC. The expression of hsa-miR-141-3p was upregulated in patients where RS region was involved as compared to AC. Analysis of the registered UC patient's database from the hospital revealed that the site of CRC was predomimnantly the rectosigmoid region of the colon in most of the cases. CONCLUSION: This is the first study to show the differential expression of miRNA involving different sites of colon in UC patients. Taking our data and previous reports into consideration, we propose that differential miRNA expression during UC perhaps contribute in the development of UC-associated CRC at the rectosigmoid area. PMID- 26569606 TI - How Distance Affects Semantic Integration in Discourse: Evidence from Event Related Potentials. AB - Event-related potentials were used to investigate whether semantic integration in discourse is influenced by the number of intervening sentences between the endpoints of integration. Readers read discourses in which the last sentence contained a critical word that was either congruent or incongruent with the information introduced in the first sentence. Furthermore, for the short discourses, the first and last sentence were intervened by only one sentence while for the long discourses, they were intervened by three sentences. We found that the incongruent words elicited an N400 effect for both the short and long discourses. However, a P600 effect was only observed for the long discourses, but not for the short ones. These results suggest that although readers can successfully integrate upcoming words into the existing discourse representation, the effort required for this integration process is modulated by the number of intervening sentences. Thus, discourse distance as measured by the number of intervening sentences should be taken as an important factor for semantic integration in discourse. PMID- 26569607 TI - Loss of Cellular Sialidases Does Not Affect the Sialylation Status of the Prion Protein but Increases the Amounts of Its Proteolytic Fragment C1. AB - The central molecular event underlying prion diseases involves conformational change of the cellular form of the prion protein (PrPC), which is a sialoglycoprotein, into the disease-associated, transmissible form denoted PrPSc. Recent studies revealed a correlation between the sialylation status of PrPSc and incubation time to disease and introduced a new hypothesis that progression of prion diseases could be controlled or reversed by altering the sialylation level of PrPC. Of the four known mammalian sialidases, the enzymes that cleave off sialic acid residues, only NEU1, NEU3 and NEU4 are expressed in the brain. To test whether cellular sialidases control the steady-state sialylation level of PrPC and to identify the putative sialidase responsible for desialylating PrPC, we analyzed brain-derived PrPC from knockout mice deficient in Neu1, Neu3, Neu4, or from Neu3/Neu4 double knockouts. Surprisingly, no differences in the sialylation of PrPC or its proteolytic product C1 were noticed in any of the knockout mice tested as compared to the age-matched controls. However, significantly higher amounts of the C1 fragment relative to full-length PrPC were detected in the brains of Neu1 knockout mice as compared to WT mice or to the other knockout mice. Additional experiments revealed that in neuroblastoma cell line the sialylation pattern of C1 could be changed by an inhibitor of sialylatransferases. In summary, this study suggests that targeting cellular sialidases is apparently not the correct strategy for altering the sialylation levels of PrPC, whereas modulating the activity of sialylatransferases might offer a more promising approach. Our findings also suggest that catabolism of PrPC involves its alpha-cleavage followed by desialylation of the resulting C1 fragments by NEU1 and consequent fast degradation of the desialylated products. PMID- 26569608 TI - The Virtual Teacher (VT) Paradigm: Learning New Patterns of Interpersonal Coordination Using the Human Dynamic Clamp. AB - The Virtual Teacher paradigm, a version of the Human Dynamic Clamp (HDC), is introduced into studies of learning patterns of inter-personal coordination. Combining mathematical modeling and experimentation, we investigate how the HDC may be used as a Virtual Teacher (VT) to help humans co-produce and internalize new inter-personal coordination pattern(s). Human learners produced rhythmic finger movements whilst observing a computer-driven avatar, animated by dynamic equations stemming from the well-established Haken-Kelso-Bunz (1985) and Schoner Kelso (1988) models of coordination. We demonstrate that the VT is successful in shifting the pattern co-produced by the VT-human system toward any value (Experiment 1) and that the VT can help humans learn unstable relative phasing patterns (Experiment 2). Using transfer entropy, we find that information flow from one partner to the other increases when VT-human coordination loses stability. This suggests that variable joint performance may actually facilitate interaction, and in the long run learning. VT appears to be a promising tool for exploring basic learning processes involved in social interaction, unraveling the dynamics of information flow between interacting partners, and providing possible rehabilitation opportunities. PMID- 26569609 TI - The Minor Allele of rs7574865 in the STAT4 Gene Is Associated with Increased mRNA and Protein Expression. AB - OBJECTIVE: The T allele of rs7574865 in STAT4 confers risk of developing autoimmune disorders. However, its functional significance remains unclear. Here we analyze how rs7574865 affects the transcription of STAT4 and its protein expression. METHODS: We studied 201 patients (80% female; median age, 54 years; median disease duration, 5.4 months) from PEARL study. Demographic, clinical, laboratory and therapeutic data were collected at each visit. IL-6 serum levels were measured by enzyme immune assay. The rs7574865 was genotyped using TaqMan probes. The expression levels of STAT4 mRNA were determined at 182 visits from 69 patients using quantitative real-time polymerase chain reaction. STAT4 protein was assessed by western blot in 62 samples from 34 patients. To determine the effect of different variables on the expression of STAT4 mRNA and protein, we performed multivariate longitudinal analyses using generalized linear models. RESULTS: After adjustment for age, disease activity and glucocorticoid dose as confounders, the presence of at least one copy of the T allele of rs7574865 was significantly associated with higher levels of STAT4 mRNA. Similarly, TT patients showed significantly higher levels of STAT4 protein than GG patients. IL-6 induced STAT4 and STAT5 phosphorylation in peripheral blood lymphocytes. Patients carrying at least one T allele of rs7574865 displayed lower levels of serum IL-6 compared to GG homozygous; by contrast the production of C-reactive protein was similar in both populations. CONCLUSION: Our data suggest that the presence of the rs7574865 T allele enhances STAT4 mRNA transcription and protein expression. It may enhance the signaling of molecules depending on the STAT4 pathway. PMID- 26569610 TI - Fast Fragmentation of Networks Using Module-Based Attacks. AB - In the multidisciplinary field of Network Science, optimization of procedures for efficiently breaking complex networks is attracting much attention from a practical point of view. In this contribution, we present a module-based method to efficiently fragment complex networks. The procedure firstly identifies topological communities through which the network can be represented using a well established heuristic algorithm of community finding. Then only the nodes that participate of inter-community links are removed in descending order of their betweenness centrality. We illustrate the method by applying it to a variety of examples in the social, infrastructure, and biological fields. It is shown that the module-based approach always outperforms targeted attacks to vertices based on node degree or betweenness centrality rankings, with gains in efficiency strongly related to the modularity of the network. Remarkably, in the US power grid case, by deleting 3% of the nodes, the proposed method breaks the original network in fragments which are twenty times smaller in size than the fragments left by betweenness-based attack. PMID- 26569611 TI - Retraction: The RNA-Binding Protein KSRP Promotes Decay of beta-Catenin mRNA and Is Inactivated by PI3K-AKT Signaling. PMID- 26569612 TI - Correction: Development of Self-Management Indicators for Chronic Hepatitis B Patients on Antiviral Therapy: Results of a Chinese Delphi Panel Survey. PMID- 26569614 TI - Cytoprotective potential of tiron and methyl palmitate against acetaminophen induced acute liver injury. AB - Acute liver injury is a debilitating disorder associated with loss of synthetic and detoxifying functions of the liver. This investigation was designed to assess cytoprotective efficacy of daily oral tiron (300 mg/kg) and daily oral methyl palmitate (300 mg/kg) against acetaminophen-induced acute liver injury. Rats were orally pretreated with either tiron or methyl palmitate at doses (300 mg/kg) for 7 days prior to oral acetaminophen (3 g/kg). Biochemical assay of markers of hepatotoxicity indices and oxidative stress was undertaken. Expression of inflammatory cytokine IL-6 was also evaluated. Histopathological examination of liver specimens was carried out as well. Both methyl palmitate and tiron significantly reversed the acetaminophen-induced elevation of biochemical markers (ALT, AST, and ALP) with restoration of SOD levels. Serum albumin levels and GSH liver contents increased, but in a nonsignificant manner. Moreover, methyl palmitate and tiron significantly decreased the level of serum LDH and serum IL-6 levels. Histopathology revealed that tiron markedly reduced the extent of acetaminophen-induced necrosis and methyl palmitate moderately decreased the necrosis in liver tissue. Methyl palmitate (300 mg/kg) and tiron (300 mg/kg) demonstrated promising hepatoprotective effects against acetaminophen-induced acute liver injury via modulation of inflammatory response and alleviation of the oxidative stress, allowing the preservation of hepatic functions. PMID- 26569613 TI - The Epidemiology of Invasive Haemophilus influenzae Non-Serotype B Disease in Ontario, Canada from 2004 to 2013. AB - BACKGROUND: Since the widespread use of Haemophilus influenzae (Hi) type b (Hib) vaccines among children aged <5 years, an increase in invasive non-Hib disease incidence has been reported internationally. We sought to describe the epidemiology of invasive non-Hib disease in Ontario, Canada (population ~13.5 million). METHODS: Confirmed invasive non-Hib cases (non-typeable [NTHi] and serotypes a, c, d, e, and f) were obtained from the provincial laboratory data system from 2004-2013. Data were deterministically linked to the provincial reportable disease system to provide further case information. Antibiotic resistance data were analysed separately from 2010-2014. Descriptive analyses included incidence rates, age group, serotype, site of specimen collection and resistance patterns; ethnicity data were not available. Temporal trends were evaluated by Poisson regression and p-values <0.05 were considered significant. RESULTS: A total of 1307 cases of invasive non-Hib disease were included, increasing from 0.67 cases to 1.60 cases /100,000 from 2004 to 2013. Significant increases in the incidence of NTHi (0.50 to 1.28 cases/100 000 population), Hia (0.02 to 0.08 cases/100, 000) and Hif (0.13 to 0.18 cases/100, 000 population) were seen. Among persons aged 40-64 years, 3 Hi strains significantly increased over time; NTHi (0.22 to 0.99 cases/100, 000), Hia (0.00 to 0.06 cases/100, 000) and Hif (0.05 to 0.21 cases/100, 000). Among persons aged 65-84 years, there was a significant increase of NTHi (1.62 to 3.14 cases/100, 000) and Hia (0.00 to 0.34 cases/100, 000). Among persons aged 85+ years, only NTHi significantly increased from 4.89 to 10.28 cases/100, 000). Antimicrobial resistance (AMR) to ampicillin and clarithromycin was seen in greater than 25% of isolates but AMR did not increase over the duration of this study. CONCLUSIONS: The incidence of invasive non-Hib disease has increased over time; NTHi, Hif and Hia are emerging pathogens, and should be monitored. PMID- 26569615 TI - Modified Release and Improved Stability of Unstable BCS II Drug by Using Cyclodextrin Complex as Carrier To Remotely Load Drug into Niosomes. AB - In answering to the challenge of enzymatic unstability of Biopharmaceutics Classification System (BCS) class II drugs, an effective remote loading strategy was developed to successfully incorporate the drug-cyclodextrin (CD) complex into niosomes to modify the release and stability of a drug candidate, pseudolaric acid B (PAB). Judged by binding constants, and combined solubilization effects of pH and CD complexation on PAB at different pH, the complex internalization driven by a transmembrane pH gradient (from 2.0 to 7.4) and the dynamic shifting of PAB CD complexation equilibrium at this gradient were introduced. The transfer of PAB CD complex into the internal aqueous phase of niosomes at 60 degrees C was primarily verified by synchrotron radiation Fourier transform infrared spectroscopy. The remote loading samples behaved as retarded release at pH 5.8, 6.8, and 7.4, for which the stability of PAB in rat plasma was significantly enhanced (about 8.1-fold), in comparison with niosomes prepared by the passive and lipid bilayer loading of PAB. The drug-carrier interaction based release modeling was further fitted, and the convection rate constant (ks) and free energy difference between free and bound states (DeltaG) indicated the strongest PAB-carrier interactions in remote loading niosomes. The remote loading strategy also reduced the CD-cholesterol interaction and provided better physical stability of the system. In conclusion, the remote loading of drug-CD complex into niosomes provides advantages to modify the release and enhance the stability of unstable BCS class II drug. PMID- 26569616 TI - Increased migration of uncemented acetabular cups in female total hip arthroplasty patients with low systemic bone mineral density. A 2-year RSA and 8 year radiographic follow-up study of 34 patients. AB - BACKGROUND AND PURPOSE: Low bone mineral density (BMD) may jeopardize the initial component stability and delay osseointegration of uncemented acetabular cups in total hip arthroplasty (THA). We measured the migration of uncemented cups in women with low or normal BMD. PATIENTS AND METHODS: We used radiostereometric analysis (RSA) to measure the migration of hydroxyapatite-coated titanium alloy cups with alumina-on-alumina bearings in THA of 34 female patients with a median age of 64 (41-78) years. 10 patients had normal BMD and 24 patients had low systemic BMD (T-score <= -1) based on dual-energy X-ray absorptiometry (DXA). Cup migration was followed with RSA for 2 years. Radiographic follow-up was done at a median of 8 (2-10) years. RESULTS: Patients with normal BMD did not show a statistically significant cup migration after the settling period of 3 months, while patients with low BMD had a continuous proximal migration between 3 and 12 months (p = 0.03). These differences in cup migration persisted at 24 months. Based on the perceived risk of cup revision, 14 of the 24 cases were "at risk" (proximal translation of 0.2 to 1.0 mm) in the low-BMD group and 2 of the 10 cases were "at risk" in the normal-BMD group (odds ratio (OR) = 8.0, 95% CI: 1.3 48). The radiographic follow-up showed no radiolucent lines or osteolysis. 2 cups have been revised for fractures of the ceramic bearings, but none for loosening. INTERPRETATION: Low BMD contributed to cup migration beyond the settling period of 3 months, but the migrating cups appeared to osseointegrate eventually. PMID- 26569617 TI - The McDonaldization of Medicine. PMID- 26569618 TI - International Trade Modelling Using Open Flow Networks: A Flow-Distance Based Analysis. AB - This paper models and analyzes international trade flows using open flow networks (OFNs) with the approaches of flow distances, which provide a novel perspective and effective tools for the study of international trade. We discuss the establishment of OFNs of international trade from two coupled viewpoints: the viewpoint of trading commodity flow and that of money flow. Based on the novel model with flow distance approaches, meaningful insights are gained. First, by introducing the concepts of trade trophic levels and niches, countries' roles and positions in the global supply chains (or value-added chains) can be evaluated quantitatively. We find that the distributions of trading "trophic levels" have the similar clustering pattern for different types of commodities, and summarize some regularities between money flow and commodity flow viewpoints. Second, we find that active and competitive countries trade a wide spectrum of products, while inactive and underdeveloped countries trade a limited variety of products. Besides, some abnormal countries import many types of goods, which the vast majority of countries do not need to import. Third, harmonic node centrality is proposed and we find the phenomenon of centrality stratification. All the results illustrate the usefulness of the model of OFNs with its network approaches for investigating international trade flows. PMID- 26569619 TI - Unifying Inference of Meso-Scale Structures in Networks. AB - Networks are among the most prevalent formal representations in scientific studies, employed to depict interactions between objects such as molecules, neuronal clusters, or social groups. Studies performed at meso-scale that involve grouping of objects based on their distinctive interaction patterns form one of the main lines of investigation in network science. In a social network, for instance, meso-scale structures can correspond to isolated social groupings or groups of individuals that serve as a communication core. Currently, the research on different meso-scale structures such as community and core-periphery structures has been conducted via independent approaches, which precludes the possibility of an algorithmic design that can handle multiple meso-scale structures and deciding which structure explains the observed data better. In this study, we propose a unified formulation for the algorithmic detection and analysis of different meso-scale structures. This facilitates the investigation of hybrid structures that capture the interplay between multiple meso-scale structures and statistical comparison of competing structures, all of which have been hitherto unavailable. We demonstrate the applicability of the methodology in analyzing the human brain network, by determining the dominant organizational structure (communities) of the brain, as well as its auxiliary characteristics (core-periphery). PMID- 26569620 TI - Granule Associated Serine Proteases of Hematopoietic Cells - An Analysis of Their Appearance and Diversification during Vertebrate Evolution. AB - Serine proteases are among the most abundant granule constituents of several hematopoietic cell lineages including mast cells, neutrophils, cytotoxic T cells and NK cells. These proteases are stored in their active form in the cytoplasmic granules and in mammals are encoded from four different chromosomal loci: the chymase locus, the met-ase locus, the T cell tryptase and the mast cell tryptase locus. In order to study their appearance during vertebrate evolution we have performed a bioinformatic analysis of related genes and gene loci from a large panel of metazoan animals from sea urchins to placental mammals for three of these loci: the chymase, met-ase and granzyme A/K loci. Genes related to mammalian granzymes A and K were the most well conserved and could be traced as far back to cartilaginous fish. Here, the granzyme A and K genes were found in essentially the same chromosomal location from sharks to humans. However in sharks, no genes clearly identifiable as members of the chymase or met-ase loci were found. A selection of these genes seemed to appear with bony fish, but sometimes in other loci. Genes related to mammalian met-ase locus genes were found in bony fish. Here, the most well conserved member was complement factor D. However, genes distantly related to the neutrophil proteases were also identified in this locus in several bony fish species, indicating that this locus is also old and appeared at the base of bony fish. In fish, a few of the chymase locus related genes were found in a locus with bordering genes other than the mammalian chymase locus and some were found in the fish met-ase locus. This indicates that a convergent evolution rather than divergent evolution has resulted in chymase locus-related genes in bony fish. PMID- 26569621 TI - Abnormal Protein Glycosylation and Activated PI3K/Akt/mTOR Pathway: Role in Bladder Cancer Prognosis and Targeted Therapeutics. AB - Muscle invasive bladder cancer (MIBC, stage >=T2) is generally associated with poor prognosis, constituting the second most common cause of death among genitourinary tumours. Due to high molecular heterogeneity significant variations in the natural history and disease outcome have been observed. This has also delayed the introduction of personalized therapeutics, making advanced stage bladder cancer almost an orphan disease in terms of treatment. Altered protein glycosylation translated by the expression of the sialyl-Tn antigen (STn) and its precursor Tn as well as the activation of the PI3K/Akt/mTOR pathway are cancer associated events that may hold potential for patient stratification and guided therapy. Therefore, a retrospective design, 96 bladder tumours of different stages (Ta, T1-T4) was screened for STn and phosphorylated forms of Akt (pAkt), mTOR (pmTOR), S6 (pS6) and PTEN, related with the activation of the PI3K/Akt/mTOR pathway. In our series the expression of Tn was residual and was not linked to stage or outcome, while STn was statically higher in MIBC when compared to non muscle invasive tumours (p = 0.001) and associated decreased cancer-specific survival (log rank p = 0.024). Conversely, PI3K/Akt/mTOR pathway intermediates showed an equal distribution between non-muscle invasive bladder cancer (NMIBC) and MIBC and did not associate with cancer-specif survival (CSS) in any of these groups. However, the overexpression of pAKT, pmTOR and/or pS6 allowed discriminating STn-positive advanced stage bladder tumours facing worst CSS (p = 0.027). Furthermore, multivariate Cox regression analysis revealed that overexpression of PI3K/Akt/mTOR pathway proteins in STn+ MIBC was independently associated with approximately 6-fold risk of death by cancer (p = 0.039). Mice bearing advanced stage chemically-induced bladder tumours mimicking the histological and molecular nature of human tumours were then administrated with mTOR-pathway inhibitor sirolimus (rapamycin). This decreased the number of invasive lesions and, concomitantly, the expression of STn and also pS6, the downstream effector of the PI3K/Akt/mTOR pathway. In conclusion, STn was found to be marker of poor prognosis in bladder cancer and, in combination with PI3K/Akt/mTOR pathway evaluation, holds potential to improve the stratification of stage disease. Animal experiments suggest that mTOR pathway inhibition could be a potential therapeutic approach for this specific subtype of MIBC. PMID- 26569622 TI - Decrease in Sphingomyelin (d18:1/16:0) in Stem Villi and Phosphatidylcholine (16:0/20:4) in Terminal Villi of Human Term Placentas with Pathohistological Maternal Malperfusion. AB - Placental villi play pivotal roles in feto-maternal transportation and phospholipids constitute a major part of the villous membrane. We have been developing and optimizing an imaging system based on a matrix-assisted laser desorption/ionization (MALDI)-based mass spectrometer, which provides clear two dimensional molecular distribution patterns using highly sensitive mass spectrometry from mixtures of ions generated on tissue surfaces. We recently applied this technology to normal human uncomplicated term placentas and detected the specific distribution of sphingomyelin (SM) (d18:1/16:0) in stem villi and phosphatidylcholine (PC) (16:0/20:4) in terminal villi. In the present study, we applied this technology to nine placentas with maternal or fetal complications, and determined whether a relationship existed between these specific distribution patterns of phospholipid molecules and the six representative pathological findings of placentas, i.e., villitis of unknown etiology (VUE), thrombus, atherosis, chorioamnionitis (CAM), immature terminal villi, and multiple branched terminal villi. In two placentas with the first and second largest total number of positive pathological findings, i.e., five and three positive findings, the specific distribution of SM (d18:1/16:0) in stem villi and PC (16:0/20:4) in terminal villi disappeared. The common pathological findings in these two placentas were atherosis, immature terminal villi, and multiple branched terminal villi, suggesting the possible involvement of the underperfusion of maternal blood into the intervillous space. On the other hand, the number of pathological findings were two or less in the seven other placentas, in which no specific relationships were observed between the differential expression patterns of these two phospholipids in stem and terminal villi and the pathological findings of the placentas; however, the specific distribution pattern of SM (d18:1/16:0) in stem villi disappeared in four placentas, while that of PC (16:0/20:4) in terminal villi was preserved. These results suggested that the absence of the specific distribution of PC (16:0/20:4) in terminal villi, possibly in combination with the absence of SM (d18:1/16:0) in stem villi, was linked to placental morphological changes in response to maternal underperfusion of the placenta. PMID- 26569623 TI - Zebrafish Egg Infection Model for Studying Candida albicans Adhesion Factors. AB - Disseminated candidiasis is associated with 30-40% mortality in severely immunocompromised patients. Among the causal agents, Candida albicans is the dominant one. Various animal models have been developed for investigating gene functions in C. albicans. Zebrafish injection models have increasingly been applied in elucidating C. albicans pathogenesis because of the conserved immunity, prolific fecundity of the zebrafish and the low costs of care systems. In this study, we established a simple, noninvasive zebrafish egg bath infection model, defined its optimal conditions, and evaluated the model with various C. albicans mutant strains. The deletion of SAP6 did not have significant effect on the virulence. By contrast, the deletion of BCR1, CPH1, EFG1, or TEC1 significantly reduced the virulence under current conditions. Furthermore, all embryos survived when co-incubated with bcr1/bcr1, cph1/cph1 efg1/efg1, efg1/efg1, or tec1/tec1 mutant cells. The results indicated that our novel zebrafish model is time-saving and cost effective. PMID- 26569624 TI - Melatonin Supplementation for Children With Atopic Dermatitis and Sleep Disturbance: A Randomized Clinical Trial. AB - IMPORTANCE: Sleep disturbance is common in children with atopic dermatitis (AD), but effective clinical management for this problem is lacking. Reduced levels of nocturnal melatonin were found to be associated with sleep disturbance and increased disease severity in children with AD. Melatonin also has sleep-inducing and anti-inflammatory properties and therefore might be useful for the management of AD. OBJECTIVE: To evaluate the effectiveness of melatonin supplementation for improving the sleep disturbance and severity of disease in children with AD. DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial used a double blind, placebo-controlled crossover design to study 73 children and adolescents aged 1 to 18 years with physician-diagnosed AD involving at least 5% of the total body surface area. The study was conducted at the pediatric department of a large tertiary care hospital in Taiwan from August 1, 2012, through January 31, 2013. Forty-eight children were randomized 1:1 to melatonin or placebo treatment, and 38 of these (79%) completed the cross-over period of the trial. Final follow-up occurred on April 13, 2013, and data were analyzed from January 27 to April 25, 2014. Analyses were based on intention to treat. INTERVENTIONS: Melatonin, 3 mg/d, or placebo for 4 weeks followed by a 2-week washout period and then crossover to the alternate treatment for 4 weeks. MAIN OUTCOMES AND MEASURES: The primary outcome was AD severity evaluated using the Scoring Atopic Dermatitis (SCORAD) index, with scores ranging from 0 to 103 and greater scores indicating worse symptoms. Secondary outcomes included sleep variables measured by actigraphy, subjective change in sleep and dermatitis, sleep variables measured by polysomnography, nocturnal urinary levels of 6-sulfatoxymelatonin, and serum IgE levels. RESULTS: After melatonin treatment among the 48 children included in the study, the SCORAD index decreased by 9.1 compared with after placebo (95% CI, -13.7 to -4.6; P < .001), from a mean (SD) of 49.1 (24.3) to 40.2 (20.9). Moreover, the sleep-onset latency shortened by 21.4 minutes after melatonin treatment compared with after placebo (95% CI, -38.6 to -4.2; P = .02). The improvement in the SCORAD index did not correlate significantly with the change in sleep-onset latency (r = -0.04; P = .85). No patient withdrew owing to adverse events, and no adverse event was reported throughout the study. CONCLUSIONS AND RELEVANCE: Melatonin supplementation is a safe and effective way to improve the sleep-onset latency and disease severity in children with AD. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01638234. PMID- 26569625 TI - Learning and serial effects on verbal memory in mild cognitive impairment. AB - The objective of this study was to examine different patterns of learning and episodic memory in 3 mild cognitive impairment (MCI) groups and a control group by administering the California Verbal Learning Test (CVLT) and using serial position effect as a principal variable. The study sample included 3 groups of patients with MCI (n = 90) divided into single-domain amnestic, multiple-domain amnestic, and multiple-domain nonamnestic MCI and a group of healthy controls (n = 60). We compared the performance of each group on several CVLT measures used in previous research, and we included a new measure that provides specific information about the serial effect. Data showed a similar pattern of learning and memory impairment in both amnestic MCI groups (i.e., no differences between the multiple-domain and single-domain subtypes); the recency effect was significantly higher in both amnestic MCI groups than in all other groups, and the primacy effect was only lower in the multiple-domain amnestic MCI subtype. Verbal learning and memory profiles of patients with amnestic MCI were very similar, independent of the presence of deficits in cognitive domains other than episodic memory. Results are discussed in light of the unitary-store model of memory. PMID- 26569627 TI - Management Of Fever And Suspected Infection In Pediatric Patients With Central Venous Catheters. AB - The use of indwelling central venous catheters is essential for pediatric patients who require hemodialysis, parenteral nutrition, chemotherapy, or other medications. Fever is a common chief complaint in the emergency department, and fever in a patient with a central venous catheter may be related to a common cause of fever, or it may be due to a catheter-associated bloodstream infection. Catheter-associated bloodstream infections may also lead to additional complications such as sepsis, septic shock, or septic complications including suppurative thrombophlebitis, endocarditis, osteomyelitis, septic emboli, and abscesses. Early resuscitation as well as timely and appropriate antibiotic therapy have been shown to improve outcomes. This issue focuses on the approach to fever in pediatric patients with central venous catheters and the management and disposition of patients with possible catheter-associated bloodstream infections. PMID- 26569626 TI - Autophagy regulates T lymphocyte proliferation through selective degradation of the cell-cycle inhibitor CDKN1B/p27Kip1. AB - The highly conserved cellular degradation pathway, macroautophagy, regulates the homeostasis of organelles and promotes the survival of T lymphocytes. Previous results indicate that Atg3-, Atg5-, or Pik3c3/Vps34-deficient T cells cannot proliferate efficiently. Here we demonstrate that the proliferation of Atg7 deficient T cells is defective. By using an adoptive transfer and Listeria monocytogenes (LM) mouse infection model, we found that the primary immune response against LM is intrinsically impaired in autophagy-deficient CD8(+) T cells because the cell population cannot expand after infection. Autophagy deficient T cells fail to enter into S-phase after TCR stimulation. The major negative regulator of the cell cycle in T lymphocytes, CDKN1B, is accumulated in autophagy-deficient naive T cells and CDKN1B cannot be degraded after TCR stimulation. Furthermore, our results indicate that genetic deletion of one allele of CDKN1B in autophagy-deficient T cells restores proliferative capability and the cells can enter into S-phase after TCR stimulation. Finally, we found that natural CDKN1B forms polymers and is physiologically associated with the autophagy receptor protein SQSTM1/p62 (sequestosome 1). Collectively, autophagy is required for maintaining the expression level of CDKN1B in naive T cells and selectively degrades CDKN1B after TCR stimulation. PMID- 26569628 TI - Surgical outcome of encapsulated brain abscess in superficial non-eloquent area: A systematic review. AB - OBJECTIVE: To investigate surgical (aspiration and resection) outcome of encapsulated brain abscess in superficial non-eloquent area. METHODS: We searched Pubmed, Embase and Cochrane Library from the foundation of the database till December 2013. Two researchers screened literatures independently, assessed the quality of the included studies and extracted the data. Revman 5.2.8 was used to do meta-analysis. RESULTS: A total of five studies were included, all retrospective cohort studies. Eighty-four cases were in the abscess aspiration group and 124 cases were in the abscess resection group. Meta-analysis showed that the abscess resection group had lower rate of postoperative residual abscess, lower re-operation rate, higher rate of improvement in neurological status within 1 month after surgery, their OR (95% Confidence Interval (CI)) were 0.12 (0.04, 0.34), 0.07 (0.02, 0.20), 7.9 (3.20, 19.51) respectively; the abscess resection group had shorter duration of post-operative antibiotics and average length of hospital stay; Standard Mean Difference (SMD) (95% CI) were -0.84 ( 1.27, -0.41), -1.01 (-1.54, -0.49), respectively. There was no statistically significant difference in the rate of improvement in neurological status at 3 months post-operative and the mortality. CONCLUSIONS: Current evidences suggest that for encapsulated brain abscess in superficial non-eloquent area, abscess resection compared to abscess aspiration had lower post-operative residual abscess rate; lower re-operation rate; higher rate of improvement in neurological status within 1 month after surgery, shorter duration of post-operative antibiotics and average length of hospital stay. There was no statistically significant difference in the rate of improvement in neurological status at 3 months post-operative and the mortality. PMID- 26569629 TI - In Memoriam: William M. "Bill" Beckner (1932-2015). PMID- 26569630 TI - Are Dieting and Dietary Inadequacy a Second Hit in the Association with Polycystic Ovary Syndrome Severity? AB - BACKGROUND: The composition of the diet is of increasing importance for the development and maturation of the ovarian follicles. In Polycystic Ovary Syndrome (PCOS) healthy dietary interventions improve the clinical spectrum. We hypothesized that dieting and diet inadequacy in the reproductive life course is associated with impaired programming of ovarian follicles and contributes to the severity of the PCOS phenotype. METHODS AND FINDINGS: To determine associations between the use of a self-initiated diet and diet inadequacy and the severity of the PCOS phenotype, we performed an explorative nested case control study embedded in a periconception cohort of 1,251 patients visiting the preconception outpatient clinic. 218 patients with PCOS and 799 subfertile controls were selected from the cohort and self-administered questionnaires, anthropometric measurements and blood samples were obtained. The Preconception Dietary Risk Score (PDR score), based on the Dutch dietary guidelines, was used to determine diet inadequacy in all women. The PDR score was negatively associated to cobalamin, serum and red blood cell folate and positively to tHcy. PCOS patients (19.9%), in particular the hyperandrogenic (HA) phenotype (22.5%) reported more often the use of a self-initiated diet than controls (13.1%; p = 0.023). The use of an inadequate diet was also significantly higher in PCOS than in controls (PDR score 3.7 vs 3.5; p = 0.017) and every point increase was associated with a more than 1.3 fold higher risk of the HA phenotype (adjusted OR 1.351, 95% CI 1.09 1.68). Diet inadequacy was independently associated with the anti-Mullerian Hormone (AMH) concentration (beta 0.084; p = 0.044; 95% CI 0.002 to 0.165) and free androgen index (beta 0.128; p = 0.013; 95% CI 0.028 to 0.229) in PCOS patients. CONCLUSIONS: The use of a self-initiated diet and diet inadequacy is associated with PCOS, in particular with the severe HA phenotype. This novel finding substantiated by the association between diet inadequacy and AMH needs further investigation. PMID- 26569632 TI - To what extent can mutual shifting of folded carbonaceous walls in slit-like pores affect their adsorption properties? AB - We have performed systematic Monte Carlo studies on the influence of shifting the walls in slit-like systems constructed from folded graphene sheets on their adsorption properties. Specifically, we have analysed the effect on the mechanism of argon adsorption (T = 87 K) and on adsorption and separation of three binary gas mixtures: CO2/N2, CO2/CH4 and CH4/N2 (T = 298 K). The effects of the changes in interlayer distance were also determined. We show that folding of the walls significantly improves the adsorption and separation properties in comparison to ideal slit-like systems. Moreover, we demonstrate that mutual shift of sheets (for small interlayer distances) causes the appearance of small pores between opposite bulges. This causes an increase in vapour adsorption at low pressures. Due to overlapping of interactions with opposite walls causing an increase in adsorption energy, the mutual shift of sheets is also connected with the rise in efficiency of mixture separation. The effects connected with sheet orientation vanish as the interlayer distance increases. PMID- 26569631 TI - Screening and evaluation of hepatitis C virus infection in pregnant women on opioid maintenance therapy: A retrospective cohort study. AB - BACKGROUND: The purpose of this study was to describe the delivery of prenatal care services to women with opioid use disorder (OUD) on opioid maintenance therapy at high risk for hepatitis C virus (HCV) infection. METHODS: We conducted a retrospective cohort evaluation of 791 pregnant women with OUD from 2009 to 2012. HCV screening was defined as documentation of (a) an anti-HCV antibody test or (b) a provider discussion regarding a known HCV diagnosis during pregnancy. Multivariate logistic regression was used to identify predictors of HCV screening during pregnancy. RESULTS: Among 791 pregnant women with OUD, 611 (77.2%) were screened for HCV infection and 369/611 (60.4%) were HCV positive. In multivariable analysis, patients who were married (odds ratio [OR] = 0.52; 95% confidence interval [CI] = 0.29, 0.91), used buprenorphine (OR = 0.45; 95% CI = 0.28, 0.71), and were cared for by private practice providers (OR = 0.29; 95% CI = 0.19, 0.45) were significantly less likely to be screened. In contrast, patients who used benzodiazepines (OR = 1.72; 95% CI = 1.02, 2.92), intravenous (IV) opioids (OR = 6.15; 95% CI = 3.96, 9.56), had legal problems (OR = 2.23; 95% CI = 1.12, 4.45), had children not in their custody (OR = 1.81; 95% CI = 1.01, 3.24), and who had a partner with substance abuse history (OR = 2.38; 95% CI = 1.23, 4.59) were significantly more likely to be screened. Of 369 HCV-positive patients, a new diagnosis of HCV was made during pregnancy for 108 (29.3%) patients. Only 94 (25.5%) had HCV viral load testing, 61 (16.5%) had HCV genotype testing, and 38 (10.4%) received an immunization for hepatitis A. Although 285 (77.2%) patients were referred to hepatology, only 71 (24.9%) attended the consultation. Finally, only 6 (1.6%) patients received HCV treatment 1 year following delivery. CONCLUSIONS: Prenatal care approaches to HCV infection remain inconsistent, and the majority of patients diagnosed with HCV infection during pregnancy do not receive treatment after delivery. PMID- 26569633 TI - Homosexuality and Mental Health. PMID- 26569634 TI - A critical view of transgender health care in Germany: Psychopathologizing gender identity - Symptom of 'disordered' psychiatric/psychological diagnostics? AB - After explaining the essential trans* terminology, I offer a short historical overview of the way health care has dealt with the subject of gender, trans* and health in different times. In the third section, I compare the world's most important diagnostic manuals, namely the International statistical classification of diseases and related health problems (ICD) and the Diagnostic and statistical manual of mental disorders (DSM), i.e. their criteria for 'gender identity disorders' (ICD-10) and 'gender dysphoria' (DSM-5). The fourth section branch out the factors which influence every diagnostic conception - of no matter whom - in the health care system. The last section discusses the implications resulting from this diagnostic dilemma for the health situation of gender nonconforming people. PMID- 26569635 TI - Chinese attitudes towards sexual minorities in Hong Kong: Implications for mental health. AB - Intolerant attitudes and sexual prejudice against sexual minorities (lesbian, gay, bisexual, and questioning/queer-LGBQ) has been a long-standing global concern. In this article, Chinese attitudes towards sexual minorities are examined with reference to the cultural context in Hong Kong, a place where the East has intermingled with the West for over a century. Chinese sexuality manifested in Hong Kong is a mix of Confucian ideology and Christian thought. Traditional Confucian values of xiao (filial piety) and conventional religious thoughts of Christianity together influence Chinese attitudes towards sexual minorities. Though many governmental policies have been put in place and numerous laws have been enacted to protect the human rights of underprivileged and disadvantaged groups over the past few decades, sexual minorities are frequently being excluded from most of these protections. In Hong Kong, sexual prejudice exists not only among the general public, but also among educators and mental health professionals. Thus, Chinese sexual minorities experience sexual prejudice and minority stress in Hong Kong under unique cultural circumstances. This calls for inclusive policies and an embracing attitude towards sexual minorities so their mental health will not suffer. PMID- 26569636 TI - Influence of hydraulic retention time and plant species on performance of mesocosm subsurface constructed wetlands during municipal wastewater treatment in super-arid areas. AB - A constructed wetland (CW) in arid areas requires special knowledge given the particular climatic conditions. Among other aspects, the Hydraulic Retention Time (HRT) and plant species may be two important design parameters in hyper- and super-arid areas. Therefore, the study aimed to evaluate the influence of both variables in the application of CW in super-arid areas. Two HRT, 3.5 d and 7 d, and plant species classified by their origin: (a) native, Festuca Orthopylla, Cortaderia atacamensis and Schoenoplectus americanus, and (b) foreign, Cyperus papyrus, were evaluated in four Mesocosm Constructed Wetlands (MCW) operated in a super-arid area. The results showed that the HRT significantly increased (alpha < 0.05) in more than 10% the removal efficiency of nitrogen and phosphorus forms (TN, NH4+-N, TP, PO4-3-P). These results were the same for the two groups of plants assessed. Moreover, Cyperus papyrus significantly increased (alpha < 0.05) above 30% the removal efficiency, but only for nitrogen and phosphorus forms. MCW with this plant species showed a water loss above 25% and significantly increased (alpha < 0.05) the Electrical Conductivity (EC) of effluents. MCW planted with Schoenoplectus americanus showed water losses of around 25% for the both HRT evaluated, and its influence was not significant (alpha > 0.05) on the EC of the effluents. These results suggest that Schoenoplectus americanus would be an ideal candidate species for use in CW with subsurface flow in super-arid areas, with HRT varying between 3.5 d and 7 d. PMID- 26569638 TI - A microfluidic dual gradient generator for conducting cell-based drug combination assays. AB - We present a microfluidic chip that generates linear concentration gradients of multiple solutes that are orthogonally-aligned to each other. The kinetics of gradient formation was characterized using a fluorescent tracer matching the molecular weight of small inhibitory drugs. Live-cell signalling and motility experiments were conducted to demonstrate the potential uses and advantages of the device. A431 epidermoid carcinoma cells, where EGF induces apoptosis in a concentration-dependent manner, were simultaneously exposed to gradients of MEK inhibitor and EGF receptor (EGFR) inhibitor. By monitoring live caspase activation in the entire chip, we were able to quickly assess the combinatorial interaction between MEK and EGFR pathways, which otherwise would require costly and time consuming titration experiments. We also characterized the motility and morphology of MDA-MB-231 breast cancer cells exposed to orthogonal gradients of EGF and EGFR inhibitor. The microfluidic chip not only permitted the quantitative analysis of a population of cells exposed to drug combinations, but also enabled the morphological characterization of individual cells. In summary, our microfluidic device, capable of establishing concentration gradients of multiple compounds over a group of cells, facilitates and accelerates in vitro cell biology experiments, such as those required for cell-based drug combination assays. PMID- 26569639 TI - Excited-state dynamics of guanosine in aqueous solution revealed by time-resolved photoelectron spectroscopy: experiment and theory. AB - Time-resolved photoelectron spectroscopy is performed on aqueous guanosine solution to study its excited-state relaxation dynamics. Experimental results are complemented by surface hopping dynamic simulations and evaluation of the excited state ionization energy by Koopmans' theorem. Two alternative models for the relaxation dynamics are discussed. The experimentally observed excited-state lifetime is about 2.5 ps if the molecule is excited at 266 nm and about 1.1 ps if the molecule is excited at 238 nm. The experimental probe photon energy dependence of the photoelectron kinetic energy distribution suggests that the probe step is not vertical and involves a doubly-excited autoionizing state. PMID- 26569641 TI - Plus ca change, plus c'est la meme chose [The More Things Change, the More They Stay the Same]. PMID- 26569642 TI - Analgesic Access for Acute Abdominal Pain in the Emergency Department Among Racial/Ethnic Minority Patients: A Nationwide Examination. AB - BACKGROUND: Prior studies of acute abdominal pain provide conflicting data regarding the presence of racial/ethnic disparities in the emergency department (ED). OBJECTIVE: To evaluate race/ethnicity-based differences in ED analgesic pain management among a national sample of adult patients with acute abdominal pain based on a uniform definition. RESEARCH DESIGN/SUBJECTS/MEASURES: The 2006 2010 CDC-NHAMCS data were retrospectively queried for patients 18 years and above presenting with a primary diagnosis of nontraumatic acute abdominal pain as defined by the American Association for the Surgery of Trauma. Independent predictors of analgesic/narcotic-specific analgesic receipt were determined. Risk adjusted multivariable analyses were then performed to determine associations between race/ethnicity and analgesic receipt. Stratified analyses considered risk adjusted differences by the level of patient-reported pain on presentation. Secondary outcomes included: prolonged ED-LOS (>6 h), ED wait time, number of diagnostic tests, and subsequent inpatient admission. RESULTS: A total of 6710 ED visits were included: 61.2% (n=4106) non-Hispanic white, 20.1% (n=1352) non Hispanic black, 14.0% (n=939) Hispanic, and 4.7% (n=313) other racial/ethnic group patients. Relative to non-Hispanic white patients, non-Hispanic black patients and patients of other races/ethnicities had 22%-30% lower risk-adjusted odds of analgesic receipt [OR (95% CI)=0.78 (0.67-0.90); 0.70 (0.56-0.88)]. They had 17%-30% lower risk-adjusted odds of narcotic analgesic receipt (P<0.05). Associations persisted for patients with moderate-severe pain but were insignificant for mild pain presentations. When stratified by the proportion of minority patients treated and the proportion of patients reporting severe pain, discrepancies in analgesic receipt were concentrated in hospitals treating the largest percentages of both. CONCLUSIONS: Analysis of 5 years of CDC-NHAMCS data corroborates the presence of racial/ethnic disparities in ED management of pain on a national scale. On the basis of a uniform definition, the results establish the need for concerted quality-improvement efforts to ensure that all patients, regardless of race/ethnicity, receive optimal access to pain relief. PMID- 26569643 TI - Organizational Factors Affecting the Likelihood of Cancer Screening Among VA Patients. AB - BACKGROUND: Preventive service delivery, including cancer screenings, continues to pose a challenge to quality improvement efforts. Although many studies have focused on person-level characteristics associated with screening, less is known about organizational influences on cancer screening. OBJECTIVES: This study aims to understand the association between organizational factors and adherence to cancer screenings. METHODS: This study employed a cross-sectional design using organizational-level, patient-level, and area-level data. Dependent variables included breast, cervical, and colorectal cancer screening. Organizational factors describing resource sufficiency were constructed using factor analyses from a survey of 250 Veterans Affairs primary care directors. We conducted random effects logistic regression analyses, modeling cancer screening as a function of organizational factors, controlling for patient-level and area-level factors. RESULTS: Overall, 87% of the patients received mammograms, 92% received cervical and 78% had colorectal screening. Quality improvement orientation increased the odds of cervical [odds ratio (OR): 1.27; 95% confidence interval (CI), 1.03-1.57] and colorectal cancer screening (OR: 1.10; 95% CI, 1.00-1.20). Authority in determining primary care components increased the odds of mammography screening (OR: 1.23; 95% CI, 1.03-1.51). Sufficiency in clinical staffing increased the odds of mammography and cervical cancer screenings. Several patient-level factors, serving as control variables, were associated with achievement of screenings. CONCLUSIONS: Resource sufficiency led to increased odds of screening possibly because they promote excellence in patient care by conveying organizational goals and facilitate goal achievement with resources. Complementary to patient-level factors, our findings identified organizational processes associated with better performance, which offer concrete strategies in which facilities can evaluate their capabilities to implement best practices to foster and sustain a culture of quality care. PMID- 26569644 TI - Antibiotic Use in Cold and Flu Season and Prescribing Quality: A Retrospective Cohort Study. AB - BACKGROUND: Excessive antibiotic use in cold and flu season is costly and contributes to antibiotic resistance. The study objective was to develop an index of excessive antibiotic use in cold and flu season and determine its correlation with other indicators of prescribing quality. METHODS AND FINDINGS: We included Medicare beneficiaries in the 40% random sample denominator file continuously enrolled in fee-for-service benefits for 2010 or 2011 (7,961,201 person-years) and extracted data on prescription fills for oral antibiotics that treat respiratory pathogens. We collapsed the data to the state level so they could be merged with monthly flu activity data from the Centers for Disease Control and Prevention. Linear regression, adjusted for state-specific mean antibiotic use and demographic characteristics, was used to estimate how antibiotic prescribing responded to state-specific flu activity. Flu-activity associated antibiotic use varied substantially across states-lowest in Vermont and Connecticut, highest in Mississippi and Florida. There was a robust positive correlation between flu activity associated prescribing and use of medications that often cause adverse events in the elderly (0.755; P<0.001), whereas there was a strong negative correlation with beta-blocker use after a myocardial infarction (-0.413; P=0.003). CONCLUSIONS: Adjusted flu-activity associated antibiotic use was positively correlated with prescribing high-risk medications to the elderly and negatively correlated with beta-blocker use after myocardial infarction. These findings suggest that excessive antibiotic use reflects low-quality prescribing. They imply that practice and policy solutions should go beyond narrow, antibiotic specific, approaches to encourage evidence-based prescribing for the elderly Medicare population. PMID- 26569645 TI - Synthesis of Mixed alpha/beta2,2-Peptides by Site-Selective Ring-Opening of Cyclic Quaternary Sulfamidates. AB - A method for site- and stereoselective peptide modification using a cyclic sulfamidate scaffold containing peptides is described. A peptide synthesis strategy allowing the rapid generation of mixed alpha/beta-peptides incorporating a sulfamidate residue, derived from 2-methylisoserine, has been generalized. The unique electrophilic nature of this scaffold for nucleophilic substitution at a quaternary center with total inversion of its configuration, which was demonstrated computationally, allows for site-selective conjugation with various nucleophiles, such as anomeric thiocarbohydrates and pyridines. This strategy provides rapid access to complex thioglyco-alpha/beta-conjugates and charged alpha/beta-peptides. PMID- 26569646 TI - [Periodontitis determining the onset and progression of Huntington's disease: review of the literature]. AB - Huntington's disease is a neurodegenerative disorder caused by the expansion of a CAG triplet in the huntingtin gene. It presents with physical, cognitive and psychiatric impairment at different ages in the adult, and has a fatal prognosis. Other than the number of triplet repetitions, there seem to be other factors that explain the onset of this disease at an earlier age. It is well known that neuroinflammation has a key role in neurodegenerative disorders; Huntington's disease is not an exception to that rule. Neuroinflammation exacerbates neuronal damage produced by mutation, by initiating aberrant activation of microglia cell, as well as astrocyte and dendritic cell dysfunction; also compromising the blood brain barrier and activating the complement cascade. The latter as a direct and indirect effect of the mutation and other stimuli such as chronic infections. In this study, periodontitis is presented as a model of chronic oral infection and a systemic inflammation source. We hypothesize the potential role of periodontitis in Huntington's disease, and the mechanisms by which it contributes to the early onset and progress of the disease. We considered experimental studies, systematic reviews, meta-analyses, published in both Spanish and English, obtained from the PubMed and SciELO databases. There are various mechanisms that generate brain inflammation in these patients; mechanisms of innate immunity being especially prominent. Chronic oral-dental infections, such as periodontal disease, may be an exacerbating factor that adds to the neuroinflammation of Huntington'?s disease. PMID- 26569647 TI - Prevention and consequences of vitamin D deficiency in pregnant and lactating women and children: A symposium to prioritise vitamin D on the global agenda. AB - The Department of Nutrition for Health and Development of the World Health Organization (WHO) in collaboration with the Executive Committee of the 18th Vitamin D Workshop (VDW), organised a joint symposium on the prevention and consequences of vitamin D deficiency in pregnant women and children, convening experts on vitamin D, clinicians and policy-makers. The overall aim was to identify priority areas for research and to discuss the need for global options for policy, with a focus on the prevention of rickets in infants and children and vitamin D deficiency in pregnant women. The scope and purpose were: (i) to present the WHO research strategy for health, addressing vitamin D-related public health problems and the process for the development of evidence-informed guidelines in general and how vitamin D interventions in diverse populations could be prioritised; (ii) to provide an overview of vitamin D status in children and pregnant and lactating women across the world; (iii) to review the health risks associated with vitamin D deficiency in children and in pregnant women and their offspring; (iv) to understand the aetiology of vitamin D deficiency in pregnant women and children; (v) to identify and interpret biomarkers to assess vitamin D status and to consider possible clinical and biochemical screening tools for determining the prevalence of nutritional rickets in at risk groups or communities; and (vi) to provide an overview of policies and recommendations on vitamin D across the world. The format of the symposium was a composite of comprehensive scientific presentations and a panel debate with international experts on WHO guidelines, nutritional rickets, nutritional policy and consequences of vitamin D deficiency during pregnancy. This paper summarizes the content and outcomes of the panel debate. PMID- 26569648 TI - [Results of Surgical and Conservative Treatment for Enterocutaneous Fistulas. Is there an Indication for Conservative Treatment?]. AB - INTRODUCTION: The manifestation of enterocutaneous fistulas is varied. They can range from controlled secretion via the abdominal wall to septic disease. The disease is categorised into low-, moderate- and high-output fistulas. Often the only option is surgical treatment. Occasionally, there is spontaneous healing under conservative treatment. The aim of this study was to work out a possible subgroup of patients who benefit from conservative treatment. Material und Methods: Ninety-nine patients were treated for enterocutaneous fistulas from 1 January 1995 to 31 December 2005. Seventy patients underwent surgery, 29 patients were treated conservatively. All data was collected prospectively using an admission form and was analysed retrospectively. Conservative treatment consisted of fasting with parenteral nutrition, while fistulas in the surgical group were treated by suture repair or resection. Additive treatments such as vacuum dressings or TNF-alpha medication for patients with Crohn's disease were not performed. RESULTS: In our study we achieved a total cure rate of 69%, with an average hospital stay of 38 days. Surgical treatment led to significantly better results compared with conservative treatment (83 vs. 34%). Mortality in the surgical group was distinctly, but not significantly reduced at 7%, compared with 14% in the conservative group. The fistulas that healed after conservative treatment were low-output fistulas only. CONCLUSION: Enterocutaneous fistulas are diseases associated with long hospital stays and, therefore, expensive treatment. Low-output fistulas may heal spontaneously. The best results are achieved by surgical treatment. More recent treatments such as vacuum therapy and TNF-alpha medication for patients with Crohn's disease are promising approaches. In the future, many of these will have to be combined with surgical treatment. PMID- 26569650 TI - Is High Sexual Desire a Facet of Male Hypersexuality? Results from an Online Study. AB - Despite a growing number of studies, hypersexuality remains controversial and empirically elusive. Using a group comparison approach, this study revisited the claim that hypersexuality cannot be reliably distinguished from high sexual desire. An online survey, advertised as focusing on pornography use and sexual health, was carried out in 2014 among 1,998 Croatian men aged 18 to 60 years (Mage = 34.7, SD = 9.83). Membership in the hypersexuality group (HYP; n = 57) was determined using the Hypersexual Disorder Screening Inventory and the Hypersexual Behavior Consequences Scale. The highest values on two indicators of sexual desire/interest set membership in the high sexual desire group (HSD; n = 70). The overlap between the groups was negligible (n = 4). Compared to the rest of the sample, men in the HYP group had significantly higher odds of being single, not exclusively heterosexual, religious, depressed, prone to sexual boredom, experiencing substance abuse consequences, holding negative attitudes toward pornography use, and evaluating one's sexual morality more negatively. In contrast, the HSD group differed from controls only in reporting more positive attitudes toward pornography use. The study findings point to a distinct phenomenology of HSD and HYP in men. Clinical implications of the findings are briefly discussed. PMID- 26569649 TI - Vitamin D Levels and Markers of Inflammation and Metabolism in HIV-Infected Individuals on Suppressive Antiretroviral Therapy. AB - Data on vitamin D insufficiency as a cause of inflammation and metabolic dysfunction in HIV-infected individuals are conflicting. We examined the relationships between levels of 25-hydroxyvitamin D [25(OH)D] and biomarkers of inflammation and metabolism in stored blood samples from a prospective trial of vitamin D repletion. Blood samples from HIV-infected individuals on antiretroviral therapy (ART) with HIV-1 RNA <200 copies/ml enrolled in a prospective study were analyzed for 25(OH)D levels, a broad panel of cytokines, highly sensitive C-reactive protein, D-dimer, adiponectin, leptin, and insulin. Correlations between markers and 25(OH)D levels were determined. The Wilcoxon Rank Sum test was used to compare markers between individuals 25(OH)D insufficient and sufficient at baseline and before and after repletion among those who were insufficient and repleted to >=30 ng/ml after 12 weeks. Of 106 subjects with stored plasma [66 with 25(OH)D <30 ng/ml and 40 >= 30 ng/ml], the median age was 50, the CD4 count was 515 cells/mm(3), 94% were male, and the median baseline 25(OH)D was 27 ng/ml. Higher 25(OH)D levels were associated with lower tumor necrosis factor (TNF)-alpha (r = -0.20, p = 0.04) and higher adiponectin levels (r = 0.30, p = 0.002). Following successful repletion to 25(OH)D >=30 ng/ml there were no significant changes in inflammatory or metabolic parameters. Our study found associations between low 25(OH)D levels and TNF-alpha and adiponectin. Repletion did not result in changes in markers of inflammation or metabolism. These data support continued study of the relationship between vitamin D, inflammation, and metabolism in treated HIV infection. PMID- 26569651 TI - Atrial Fibrillation Emergency Department Observation Protocol. PMID- 26569652 TI - Performance of the EDACS-accelerated Diagnostic Pathway in a Cohort of US Patients with Acute Chest Pain. AB - BACKGROUND: The Emergency Department Assessment of Chest pain Score-Accelerated Diagnostic Protocol (EDACS-ADP) is a decision aid designed to safely identify emergency department (ED) patients with chest pain for early discharge. Derivation and validation studies in Australasia have demonstrated high sensitivity (99%-100%) for major adverse cardiac events (MACE). OBJECTIVES: To validate the EDACS-ADP in a cohort of US ED patients with symptoms suspicious for acute coronary syndrome (ACS). METHODS: A secondary analysis of participants enrolled in the HEART Pathway Randomized Controlled Trial was conducted. This single-site trial enrolled 282 ED patients>=21 years old with symptoms concerning for ACS, inclusive of all cardiac risk levels. Each patient was classified as low risk or at risk by the EDACS-ADP based on EDACS, electrocardiogram, and serial troponins. Potential early discharge rate and sensitivity for MACE at 30 days, defined as cardiac death, myocardial infarction (MI), or coronary revascularization were calculated. RESULTS: MACE occurred in 17/282 (6.0%) participants, including no deaths, 16/282 (5.6%) with MI, and 1/282 (0.4%) with coronary revascularization without MI. The EDACS-ADP identified 188/282 patients [66.7%, 95% confidence interval (CI): 60.8%-72.1%] as low risk. Of these, 2/188 (1.1%, 95% CI: 0.1%-3.9%) had MACE at 30 days. EDACS-ADP was 88.2% (95% CI: 63.6% 98.5%) sensitive for MACE, identifying 15/17 patients. Of the 2 patients identified as low risk with MACE, 1 had MI and 1 had coronary revascularization without MI. CONCLUSIONS: Within a US cohort of ED patients with symptoms concerning for ACS, sensitivity for MACE was 88.2%. We are unable to validate the EDACS-ADP as sufficiently sensitive for clinical use. PMID- 26569653 TI - Feasibility of a Tablet Computer System to Collect Patient-reported Symptom Severity in Patients Undergoing Diagnostic Coronary Angiography. AB - BACKGROUND: Percutaneous coronary intervention is the most commonly performed revascularization modality for chronic stable angina, but does not improve survival or reduce major adverse cardiovascular event. Percutaneous coronary intervention in this population is performed primarily for symptomatic benefit; therefore, symptom reduction is an important marker of quality. Patient-reported outcome measures (PROMs) have been developed for chest pain and dyspnea which are valid and responsive to treatment; however, they are not widely used in routine care. We present a model for use of PROMs in routine care. METHODS: Partners Health System funded a tablet computer software platform to collect PROMs and include them in the medical record. We implemented this platform in the catheterization laboratory at Massachusetts General Hospital, targeting patients presenting for coronary angiography. Patients are assessed using the SAQ-7, the Rose dyspnea scale, the PHQ-2, and the PROMIS-10. We used a phased implementation, with the final program including preprocedure measurement, presentation of data to clinical providers, and follow up using an email platform. RESULTS: We successfully captured measures from 474 patients, 53.5% of outpatient visits. Key success factors included high-level leadership support and resources, a user-friendly interface for patients and staff, easily interpretable measures, and clinical relevance. CONCLUSIONS: We have demonstrated that routine capture of patient-reported symptom severity is technically feasible in a real world care environment. We share our experiences to provide others with a model for similar programs, and to accelerate implementation nationwide by helping others avoid pitfalls. We believe expansion of similar programs nationally may lead to more robust quality infrastructure. PMID- 26569654 TI - Significance of an Indeterminate Troponin I in Patients Evaluated for Chest Pain in an Emergency Department Observation Unit. AB - BACKGROUND: Previous studies have suggested that patients with an indeterminate troponin I (TnI) in the emergency department (ED) are significantly more likely to be diagnosed with acute myocardial infarction (MI). The role of the ED observation unit (EDOU) in the evaluation of these patients is unclear. OBJECTIVE: We sought to determine the risk of MI and revascularization in chest pain patients with an indeterminate TnI in the ED, who were placed in an EDOU. METHODS: We performed a prospective evaluation with 30-day follow-up for all chest pain patients placed in the University of Utah EDOU between June 1, 2009 and May 31, 2012. The EDOU excludes patients with a positive TnI, significant electrocardiogram changes, or active chest pain; however, the EDOU is utilized for further evaluation of patients who have an initial indeterminate TnI (0.06 ng/mL-0.49 ng/mL) with serial TnI measurements, cardiology consult, and potential provocative testing. We identified all patients who had an indeterminate TnI on initial testing in the ED. Primary outcomes were MI, revascularization with cardiac stent or coronary artery bypass graft, and death. RESULTS: We evaluated 1276 chest pain patients in the EDOU over the 3-year study period (average age: 54.1 years, 54% female). Fifty-eight patients (4.5%) had an initial indeterminate TnI. There were no deaths or adverse outcomes in the EDOU among those with an indeterminate TnI, and none of these patients developed a positive TnI during their hospital stay or 30-day follow-up. Patients with an indeterminate TnI had a higher rate of inpatient admission from the EDOU (24.1% vs. 10.3%; P=0.001). Among those with an indeterminate TnI, 8.6% underwent revascularization, while the rate of revascularization or MI was 2.9% among those who did not have an initial indeterminate TnI (P=0.032). CONCLUSION: Patients evaluated in our EDOU for chest pain with an initial indeterminate TnI did not develop subsequent MI. However, these patients had an increased rate of revascularization and inpatient admission compared with controls. While our experience suggests that patients with an indeterminate TnI may be safely evaluated in an observation setting, EDOUs which treat only low-risk chest pain patients may wish to recommend inpatient admission for this patient group. PMID- 26569655 TI - Lost to Follow-up and Withdrawal of Consent in Contemporary Global Cardiovascular Randomized Clinical Trials. AB - BACKGROUND: High rates of lost to follow-up (LTFU) and withdrawal of consent (WDC) may introduce uncertainty around the validity of the results of clinical trials. We sought to better understand published proportions of LTFU and WDC in large contemporary cardiovascular clinical trials. METHODS: Large (>5000 randomized subjects) cardiovascular clinical trials published between 2007 and 2012 in N Engl J Med were systematically reviewed. Data regarding LTFU and WDC were extracted from the primary manuscripts and supplementary online material. RESULTS: Twenty-five published randomized trials were identified. Trials ranged in size from 5518 to 26449 subjects. All trials reported LTFU with 15 separately reporting WDC. The duration of follow-up ranged from 30 days to 6.2 years. The number of subjects LTFU ranged from 8 to 905, and the median proportion of subjects LTFU was 0.23% (interquartile range: 0.12%-0.58%). Individual LTFU proportions varied 300-fold, from 0.03% to 9.7%. Proportions of WDC ranged from 0.02% to 8.3%-a 400-fold difference-with a median of 1.1% (interquartile range: 0.2%-2.6%). WDC occurred more frequently than LTFU in all but 2 studies. CONCLUSION: Contemporary cardiovascular clinical trials typically have low proportions of LTFU or WDC, but some trials have approximately 10% of subjects with LTFU or WDC. WDC occurred more frequently than LTFU but was only reported in 60% of the trials. These results emphasize the need to standardize reporting of LTFU and WDC as important trial metrics of quality and to develop strategies to minimize their occurrence. PMID- 26569656 TI - Inter-rater Reliability of the Diamond & Forrester Score in Emergency Department Chest Pain Observation Unit Patients. AB - BACKGROUND: Cardiology consensus guidelines recommend use of the Diamond & Forrester (D&F) score in augmenting the decision to pursue stress testing. We have recently shown that it may have value in safely reducing stress utilization in an emergency department chest pain unit (CPU). However, full application necessitates demonstration of a good inter-rater reliability of the D&F score in the CPU setting. We hypothesized that D&F pretest probability would have good inter-rater reliability in CPU patients. METHODS: This was a chart review of randomly selected patients from a previously collected prospective observational trial of admitted CPU patients in a large-volume academic urban emergency department. Inclusion criteria were: age>18 years, American Heart Association low/intermediate risk, nondynamic electrocardiograms, and normal initial troponin I. Exclusion criteria were: age>75 years with coronary artery disease. A D&F score for likelihood of coronary artery disease was calculated on each patient by 2 trained chart abstractors using a standardized data abstraction instrument. Abstractors were trained to specifically categorize presenting symptoms as fitting 1 of 3 types of chest pain symptoms: nonanginal, atypical, or anginal based on previously published prespecified criteria. Approximately 20% of charts in a CPU registry were abstracted by 2 chart abstractors who were blind to each other's categorization, the patient outcomes, and the study hypothesis. The primary outcome was the kappa statistic for agreement between the 2 raters. RESULTS: The charts of 705 random patients were reviewed. The mean age was 55.1+/ 11.8 years, 52% were female. Forty four percentage of patients received stress testing, and 2.4% of patients had acute coronary syndrome. The mean D&F score was 39+/-24. There was good inter-rater agreement of chest pain characteristics (kappa=0.77, 95% confidence interval, 0.72-0.81; P<0.01). CONCLUSION: This study supports the use of the D&F score as a reliable indicator of pretest probability in CPU patients by demonstrating that there is good inter-rater reliability. Prospective validation is necessary at the point of patient assessment, in conjunction with application of the D&F score to augment stress utilization decision making. PMID- 26569657 TI - Addition of B-Type Natriuretic Peptide to Existing Clinical Risk Scores Enhances Identification of Patients at Risk for Atrial Fibrillation Recurrence After Pulmonary Vein Isolation. AB - INTRODUCTION: Predicting which patients will be free from atrial fibrillation (AF) after pulmonary vein isolation (PVI) remains challenging. Clinical risk prediction scores show modest ability to identify patients at risk for AF recurrence after PVI. B-type natriuretic peptide (BNP) is associated with risk for incident and recurrent AF but is not currently included in existing AF risk scores. We sought to evaluate the incremental benefit of adding preoperative BNP to existing risk scores for predicting AF recurrence during the 6 months after PVI. METHODS: One hundred sixty-one patients with paroxysmal or persistent AF underwent an index PVI procedure between 2010 and 2013; 77 patients (48%) had late AF recurrence after PVI (>3 months post-PVI) over the 6-month follow-up period. RESULTS: A BNP greater than or equal to 100 pg/dL (P=0.01) and AF recurrence within 3 months after PVI (P<0.001) were associated with late AF recurrence in multivariate analyses. Addition of BNP to existing clinical risk scores significantly improved the areas under the curve for each score, with an integrated discrimination improvement of 0.08 (P=0.001) and a net reclassification improvement of 60% (P=0.001) for all risk scores. CONCLUSIONS: Circulating BNP levels are independently associated with late AF recurrence after PVI. Inclusion of BNP significantly improves the discriminative ability of CHADS2, CHA2DS2-VASc, R2CHADS2, and the HATCH score in predicting clinically significant, late AF recurrence after PVI and should be incorporated in decision making algorithms for management of AF. B-R2CHADS2 is the best score model for prediction of late AF recurrence. PMID- 26569660 TI - 45th Critical Care Congress, February 20-24, 2016, Orlando, Florida . PMID- 26570981 TI - Polarizability of Six-Helix Bundle and Triangle DNA Origami and Their Escape Characteristics from a Dielectrophoretic Trap. AB - DNA nanoassemblies, such as DNA origamis, hold promise in biosensing, drug delivery, nanoelectronic circuits, and biological computing, which require suitable methods for migration and precision positioning. Insulator-based dielectrophoresis (iDEP) has been demonstrated as a powerful migration and trapping tool for MUm- and nm-sized colloids as well as DNA origamis. However, little is known about the polarizability of origami species, which is responsible for their dielectrophoretic migration. Here, we report the experimentally determined polarizabilities of the six-helix bundle origami (6HxB) and triangle origami by measuring the migration times through a potential landscape exhibiting dielectrophoretic barriers. The resulting migration times correlate to the depth of the dielectrophoretic potential barrier and the escape characteristics of the origami according to an adapted Kramer's rate model, allowing their polarizabilities to be determined. We found that the 6HxB polarizability is larger than that of the triangle origami, which correlates with the variations in charge density of both origamis. Further, we discuss the orientation of both origami species in the dielectrophoretic trap and discuss the influence of diffusion during the escape process. Our study provides detailed insight into the factors contributing to the migration through dielectrophoretic potential landscapes, which can be exploited for applications with DNA and other nanoassemblies based on dielectrophoresis. PMID- 26569658 TI - Sofosbuvir and Velpatasvir for HCV in Patients with Decompensated Cirrhosis. AB - BACKGROUND: As the population that is infected with the hepatitis C virus (HCV) ages, the number of patients with decompensated cirrhosis is expected to increase. METHODS: We conducted a phase 3, open-label study involving both previously treated and previously untreated patients infected with HCV genotypes 1 through 6 who had decompensated cirrhosis (classified as Child-Pugh-Turcotte class B). Patients were randomly assigned in a 1:1:1 ratio to receive the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir once daily for 12 weeks, sofosbuvir-velpatasvir plus ribavirin for 12 weeks, or sofosbuvir-velpatasvir for 24 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. RESULTS: Of the 267 patients who received treatment, 78% had HCV genotype 1, 4% genotype 2, 15% genotype 3, 3% genotype 4, and less than 1% genotype 6; no patients had genotype 5. Overall rates of sustained virologic response were 83% (95% confidence interval [CI], 74 to 90) among patients who received 12 weeks of sofosbuvir velpatasvir, 94% (95% CI, 87 to 98) among those who received 12 weeks of sofosbuvir-velpatasvir plus ribavirin, and 86% (95% CI, 77 to 92) among those who received 24 weeks of sofosbuvir-velpatasvir. Post hoc analysis did not detect any significant differences in rates of sustained virologic response among the three study groups. Serious adverse events occurred in 19% of patients who received 12 weeks of sofosbuvir-velpatasvir, 16% of those who received 12 weeks of sofosbuvir velpatasvir plus ribavirin, and 18% of those who received 24 weeks of sofosbuvir velpatasvir. The most common adverse events were fatigue (29%), nausea (23%), and headache (22%) in all patients and anemia (31%) in the patients receiving ribavirin. CONCLUSIONS: Treatment with sofosbuvir-velpatasvir with or without ribavirin for 12 weeks and with sofosbuvir-velpatasvir for 24 weeks resulted in high rates of sustained virologic response in patients with HCV infection and decompensated cirrhosis. (Funded by Gilead Sciences; ASTRAL-4 ClinicalTrials.gov number, NCT02201901.). PMID- 26570982 TI - Pressure-induced stiffness of Au nanoparticles to 71 GPa under quasi-hydrostatic loading. AB - The compressibility of nanocrystalline gold (n-Au, 20 nm) has been studied by x ray total scattering using high-energy monochromatic x-rays in the diamond anvil cell under quasi-hydrostatic conditions up to 71 GPa. The bulk modulus, K0, of the n-Au obtained from fitting to a Vinet equation of state is ~196(3) GPa, which is about 17% higher than for the corresponding bulk materials (K0: 167 GPa). At low pressures (<7 GPa), the compression behavior of n-Au shows little difference from that of bulk Au. With increasing pressure, the compressive behavior of n-Au gradually deviates from the equation of state (EOS) of bulk gold. Analysis of the pair distribution function, peak broadening and Rietveld refinement reveals that the microstructure of n-Au is nearly a single-grain/domain at ambient conditions, but undergoes substantial pressure-induced reduction in grain size until 10 GPa. The results indicate that the nature of the internal microstructure in n-Au is associated with the observed EOS difference from bulk Au at high pressure. Full pattern analysis confirms that significant changes in grain size, stacking faults, grain orientation and texture occur in n-Au at high pressure. We have observed direct experimental evidence of a transition in compressional mechanism for n-Au at ~20 GPa, i.e. from a deformation dominated by nucleation and motion of lattice dislocations (dislocation-mediated) to a prominent grain boundary mediated response to external pressure. The internal microstructure inside the nanoparticle (nanocrystallinity) plays a critical role for the macro-mechanical properties of nano-Au. PMID- 26570983 TI - Role of Loop-Clamping Side Chains in Catalysis by Triosephosphate Isomerase. AB - The side chains of Y208 and S211 from loop 7 of triosephosphate isomerase (TIM) form hydrogen bonds to backbone amides and carbonyls from loop 6 to stabilize the caged enzyme-substrate complex. The effect of seven mutations [Y208T, Y208S, Y208A, Y208F, S211G, S211A, Y208T/S211G] on the kinetic parameters for TIM catalyzed reactions of the whole substrates dihydroxyacetone phosphate and d glyceraldehyde 3-phosphate [(k(cat)/K(m))(GAP) and (k(cat)/K(m))DHAP] and of the substrate pieces glycolaldehyde and phosphite dianion (k(cat)/K(HPi)K(GA)) are reported. The linear logarithmic correlation between these kinetic parameters, with slope of 1.04 +/- 0.03, shows that most mutations of TIM result in an identical change in the activation barriers for the catalyzed reactions of whole substrate and substrate pieces, so that the transition states for these reactions are stabilized by similar interactions with the protein catalyst. The second linear logarithmic correlation [slope = 0.53 +/- 0.16] between k(cat) for isomerization of GAP and K(d)(?) for phosphite dianion binding to the transition state for wildtype and many mutant TIM-catalyzed reactions of substrate pieces shows that ca. 50% of the wildtype TIM dianion binding energy, eliminated by these mutations, is expressed at the wildtype Michaelis complex, and ca. 50% is only expressed at the wildtype transition state. Negative deviations from this correlation are observed when the mutation results in a decrease in enzyme reactivity at the catalytic site. The main effect of Y208T, Y208S, and Y208A mutations is to cause a reduction in the total intrinsic dianion binding energy, but the effect of Y208F extends to the catalytic site. PMID- 26570984 TI - Oleanolic acid acetate inhibits rheumatoid arthritis by modulating T cell immune responses and matrix-degrading enzymes. AB - Rheumatoid arthritis (RA) is a chronic autoimmune disease associated with a combination of synovium joint inflammation, synovium hyperplasia, and destruction of cartilage and bone. Oleanolic acid acetate (OAA), a compound isolated from Vigna angularis, has been known to possess pharmacological activities, including anti-inflammation and anti-bone destruction. In this study, we investigated the effects of OAA on RA and the underlying mechanisms of action by using a type-II collagen-induced arthritis (CIA) mouse model and tumor necrosis factor (TNF) alpha-stimulated RA synovial fibroblasts. Oral administration of OAA decreased the clinical arthritis symptoms, paw thickness, histologic and radiologic changes, and serum total and anti-type II collagen IgG, IgG1, and IgG2a levels. OAA administration reduced Th1/Th17 phenotype CD4(+) T lymphocyte expansions and inflammatory cytokine productions in T cell activated draining lymph nodes and spleen. OAA reduced the expression and production of inflammatory mediators, such as cytokines and matrix metalloproteinase (MMP)-1/3, in the ankle joint tissue and RA synovial fibroblasts by down-regulating Akt, mitogen-activated protein kinases, and nuclear factor-kappaB. Our results clearly support that OAA plays a therapeutic role in RA pathogenesis by modulating helper T cell immune responses and matrix-degrading enzymes. The immunosuppressive effects of OAA were comparable to dexamethasone and ketoprofen. We provide evidences that OAA could be a potential therapeutic candidate for RA. PMID- 26570985 TI - Nano-curcumin prepared via supercritical: Improved anti-bacterial, anti-oxidant and anti-cancer efficacy. AB - Curcumin (CM) possesses multiple biological activities. However, poor water solubility and low bioavailability limit its application in biomedical fields. CM nanoparticles (NPs) (230-240nm) were prepared by solution-enhanced dispersion via supercritical CO2 (SEDS) (22-22.5MPa pressure, 31-32.5 degrees C temperature) and its biological functions were evaluated in this study. The Minimum inhibitory concentration of CM NPs against S. aureus (~250MUg/mL) was lower than CM-DMSO (~500MUg/mL). Meanwhile, CM NPs showed effective anti-oxidant ability at a concentration raging from 125 to 2000MUg/mL. CM NPs showed time-dependent intracellular internalization ability, resulting in an enhanced anti-cancer effect on colorectal cancer cells (HCT116), and the mechanism could be explained by cell cycle arrest in G2/M phase associated with inducing apoptotic cells. Moreover, CM NPs exhibited reduced cytotoxicity on normal cells (NCM460) compared to CM-DMSO and 5-Fu. In conclusion, CM NPs prepared via SEDS showed potentials in biomedical applications. PMID- 26570986 TI - Supercritical CO2 foamed polycaprolactone scaffolds for controlled delivery of 5 fluorouracil, nicotinamide and triflusal. AB - The manufacture of porous polycaprolactone (PCL) scaffolds containing three different drugs, namely 5-fluorouracil, nicotinamide and triflusal, was investigated in this work with the aim of obtaining bioactive systems with controlled drug delivery capabilities. The scaffolds were prepared by means of a supercritical CO2 (scCO2) foaming technique by optimizing the drug loading process. This was achieved by dissolving the drugs in organic solvents miscible with scCO2 and by mixing these drug/solvent solutions with PCL powder. The as prepared mixtures were further compressed to eliminate air bubbles and finally processed by the scCO2 foaming technique. ScCO2 saturation and foaming conditions were optimized to create the porosity within the samples and to allow for the concomitant removal of the organic solvents. Physical and chemical properties of porous scaffolds, as well as drug content and delivery profiles, were studied by HPLC. The results of this study demonstrated that the composition of the starting PCL/drug/solvent mixtures affected polymer crystallization, scaffold morphology and pore structure features. Furthermore, it was found that drug loading efficiency depended on both initial solution composition and drug solubility in scCO2. Nevertheless, in the case of highly scCO2-soluble drugs, such as triflusal, loading efficiency was improved by adding a proper amount of free drug inside of the pressure vessel. The drug delivery study indicated that release profiles depended mainly upon scaffolds composition and pore structure features. PMID- 26570987 TI - GX1-mediated anionic liposomes carrying adenoviral vectors for enhanced inhibition of gastric cancer vascular endothelial cells. AB - Gastric cancer is a highly lethal malignancy and its 5-year survival rate remains depressed in spite of multiple treatment options. Targeting drug delivery to tumor vasculature may be a promising strategy for gastric cancer therapy, for it can block the nutrition source of tumor and inhibit the metastasis and invasion in a certain extent. In present study, we have prepared the drug-targeting delivery system of peptide GX1-mediated anionic liposomes carrying adenoviral vectors (GX1-Ad5-AL), in which the tumor suppressor gene of PTEN was integrated into DNA of Ad5 and the GX1 peptide could play targeting role to vascular of gastric cancer. The inhibition ability of GX1-Ad5-AL to human gastric cancer cell lines (SGC-7901) and human umbilical vein endothelial cells (HUVEC) was evaluated by MTT assay. Further, the cell migration assay was carried out in transwell inserts and the cells uptaking of GX1-Ad5-AL was detected by confocal laser scanning microscopy. The experimental results indicated that the average cell proliferation inhibition rates resulted from the drug delivery system of GX1-Ad5 AL in SGC-7901 and HUVEC were 68.36% and 64.13%, respectively which were higher than that resulted from GX1 or Ad5-AL. Meanwhile, results of cell migration experiment demonstrated that GX1-Ad5-AL could significantly suppress the migration of gastric cancer cell of SGC-7901. Moreover, both the imaging from confocal laser scanning microscopy and the quantitative analysis of fluorescence intensity showed that, GX1-Ad5-AL was more easily uptaken by SGC-7901 cells, as compared to Ad5-AL. Therefore, the formulation of GX1-Ad5-AL was effective for enhancing the inhibition effect and suppressing the migration of gastric cancer vascular endothelial cells. PMID- 26570988 TI - HPLC analysis as a tool for assessing targeted liposome composition. AB - Functionalized phospholipids are indispensable materials for the design of targeted liposomes. Control over the quality and quantity of phospholipids is thereby key in the successful development and manufacture of such formulations. This was also the case for a complex liposomal preparation composed of 1,2 dioleoyl-sn-glycero-3-phosphocholine (DOPC), Cholesterol (CHO), 1,2-distearoyl-sn glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (DSPE-PEG2000). To this end, an RP-HPLC method was developed. Detection was done via evaporative light scattering (ELS) for liposomal components. The method was validated for linearity, precision, accuracy, sensitivity and robustness. The liposomal compounds had a non-linear quadratic response in the concentration range of 0.012 0.42 mg/ml with a correlation coefficient greater than 0.99 with an accuracy of method confirmed 95-105% of the theoretical concentration. Furthermore, degradation products from the liposomal formulation could be identified. The presented method was successfully implemented as a control tool during the preparation of functionalized liposomes. It underlined the benefit of HPLC analysis of phospholipids during liposome preparation as an easy and rapid control method for the functionalized lipid at each preparation step as well as for the quantification of all components. PMID- 26570989 TI - Enhanced Electrorheological Performance of Nb-Doped TiO2 Microspheres Based Suspensions and Their Behavior Characteristics in Low-Frequency Dielectric Spectroscopy. AB - Titanium dioxide and Nb-doped titanium dioxide microspheres with the same size were fabricated by a simple sol-gel method, and the formation mechanism of Nb doped titanium dioxide microspheres was proposed. Titanium dioxide and Nb-doped titanium dioxide microspheres were adopted as dispersed materials for electrorheological (ER) fluids to investigate the influence of the charge increase introduced by Nb doping on the ER activity. The results showed that Nb doping could effectively enhance the ER performance. Combining with the analysis of dielectric spectroscopy, it was found that the interface polarization of Nb doped TiO2 ER fluid was larger than that of TiO2 ER fluid, which might be caused by more surface charges in Nb-TiO2 microspheres due to Nb(5+) doping and resulting in enhancement of electric field force and strengthening of fibrous structure. In addition, by comparing and analyzing the permittivity curves of Nb TiO2/LDPE solid composite and Nb-TiO2/silicone-oil fluid composite, it could be concluded that the enhancement of permittivity at low frequency resulted from the increase of the order degree of dispersed particles in ER fluid rather than from the quasi-dc (QDC) behavior. Moreover, the absolute value of slope of permittivity curves (K) at 0.01 Hz could be utilized as the standard for judging the ability to maintain the chainlike structure. The relationships between polarizability of dispersed particles, dielectric spectrum, parameter K, and ER properties were discussed in detail. PMID- 26570991 TI - Coherent gigahertz phonons in Ge2Sb2Te5 phase-change materials. AB - Using ~40 fs ultrashort laser pulses, we investigate the picosecond acoustic response from a prototypical phase change material, thin Ge2Sb2Te5 (GST) films with various thicknesses. After excitation with a 1.53 eV-energy pulse with a fluence of ~5 mJ cm(-2), the time-resolved reflectivity change exhibits transient electronic response, followed by a combination of exponential-like strain and coherent acoustic phonons in the gigahertz (GHz) frequency range. The time-domain shape of the coherent acoustic pulse is well reproduced by the use of the strain model by Thomsen et al 1986 (Phys. Rev. B 34 4129). We found that the decay rate (the inverse of the relaxation time) of the acoustic phonon both in the amorphous and in the crystalline phases decreases as the film thickness increases. The thickness dependence of the acoustic phonon decay is well modeled based on both phonon-defect scattering and acoustic phonon attenuation at the GST/Si interface, and it is revealed that those scattering and attenuation are larger in crystalline GST films than those in amorphous GST films. PMID- 26570993 TI - Correction to "Mutual Exclusion of Urea and Trimethylamine N-Oxide from Amino Acids in Mixed Solvent Environment". PMID- 26570992 TI - Determining menstrual phase in human biobehavioral research: A review with recommendations. AB - Given the volume and importance of research focusing on menstrual phase, a review of the strategies being used to identify menstrual phase and recommendations that will promote methodological uniformity in the field is needed. We conducted a literature review via Ovid Medline and PsycINFO. Our goal was to review methods used to identify menstrual phase and subphases in biobehavioral research studies with women who had physiologically natural menstrual cycles. Therefore, we excluded articles that focused on any of the following: use of exogenous hormones, the postpartum period, menstrual-related problems (e.g., polycystic ovarian syndrome, endometriosis), and infertility/anovulation. We also excluded articles on either younger (<18 years old) or older (>45 years old) study samples. We initially identified a total of 1,809 articles. After our exclusionary criteria were applied, 146 articles remained, within which our review identified 6 different methods used to identify menstrual phase and subphases. The most common method used was self-report of onset of menses (145/146 articles) followed by urine luteinizing hormone testing (50/146 articles) and measurement of hormones (estradiol and/or progesterone) in blood samples (49/146 articles). Overall, we found a lack of consistency in the methodology used to determine menstrual phase and subphases. We provide several options to improve accuracy of phase identification, as well as to minimize costs and burden. Adoption of these recommendations will decrease misclassification within individual studies, facilitate cross-study comparisons, and enhance the reproducibility of results. PMID- 26570994 TI - Omega-3 Levels and Nicotine Dependence: A Cross-Sectional Study and Clinical Trial. AB - BACKGROUND: High oxidative stress, which is caused by smoking, can alter omega-3 fatty acid concentrations. Since omega-3 fatty acids play a role in dopaminergic neurotransmission related to dependence, it is important to understand their effects on nicotine dependence. METHODS: This research comprised 2 studies. The first one consisted of a cross-sectional evaluation, in which the levels of the most important omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), were compared between smokers and non-smokers in a sample of 171 individuals; of them, 120 were smokers and 51 were non-smokers. The other study was a clinical, double-blind, randomized, placebo controlled, in which 63 smokers received daily treatment with capsules of fish oil (a source of omega-3/3 g/day) or mineral oil (used as placebo, also 3 g/day), taken 3 times a day for 90 days. Each fish oil capsules contained approximately 210.99 mg EPA and 129.84 mg of DHA. The outcome was evaluated by means of psychometric and biological measures as well as self-reports of tobacco use. The evaluations were carried out at the beginning of treatment and once a month thereafter (total of 4 times). OUTCOMES: The omega-3 fatty acid lipid profile showed that smokers present lower concentrations of DHA. After treatment, the omega-3 group showed a significant reduction in their levels of dependence. INTERPRETATION: Smokers showed lower peripheral levels of omega-3, and treatment with the most important omega-3 fatty acids brought about a reduction in nicotine dependence. PMID- 26570995 TI - Direct Conversion of Free Space Millimeter Waves to Optical Domain by Plasmonic Modulator Antenna. AB - A scheme for the direct conversion of millimeter and THz waves to optical signals is introduced. The compact device consists of a plasmonic phase modulator that is seamlessly cointegrated with an antenna. Neither high-speed electronics nor electronic amplification is required to drive the modulator. A built-in enhancement of the electric field by a factor of 35,000 enables the direct conversion of millimeter-wave signals to the optical domain. This high enhancement is obtained via a resonant antenna that is directly coupled to an optical field by means of a plasmonic modulator. The suggested concept provides a simple and cost-efficient alternative solution to conventional schemes where millimeter-wave signals are first converted to the electrical domain before being up-converted to the optical domain. PMID- 26570996 TI - Effect of the Surface Charge of Artificial Chaperones on the Refolding of Thermally Denatured Lysozymes. AB - Artificial chaperones are of great interest in fighting protein misfolding and aggregation for the protection of protein bioactivity. A comprehensive understanding of the interaction between artificial chaperones and proteins is critical for the effective utilization of these materials in biomedicine. In this work, we fabricated three kinds of artificial chaperones with different surface charges based on mixed-shell polymeric micelles (MSPMs), and investigated their protective effect for lysozymes under thermal stress. It was found that MSPMs with different surface charges showed distinct chaperone-like behavior, and the neutral MSPM with PEG shell and PMEO2MA hydrophobic domain at high temperature is superior to the negatively and positively charged one, because of the excessive electrostatic interactions between the protein and charged MSPMs. The results may benefit to optimize this kind of artificial chaperone with enhanced properties and expand their application in the future. PMID- 26570997 TI - A perisinusoidal niche for extramedullary haematopoiesis in the spleen. AB - Haematopoietic stresses mobilize haematopoietic stem cells (HSCs) from the bone marrow to the spleen and induce extramedullary haematopoiesis (EMH). However, the cellular nature of the EMH niche is unknown. Here we assessed the sources of the key niche factors, SCF (also known as KITL) and CXCL12, in the mouse spleen after EMH induction by myeloablation, blood loss, or pregnancy. In each case, Scf was expressed by endothelial cells and Tcf21(+) stromal cells, primarily around sinusoids in the red pulp, while Cxcl12 was expressed by a subset of Tcf21(+) stromal cells. EMH induction markedly expanded the Scf-expressing endothelial cells and stromal cells by inducing proliferation. Most splenic HSCs were adjacent to Tcf21(+) stromal cells in red pulp. Conditional deletion of Scf from spleen endothelial cells, or of Scf or Cxcl12 from Tcf21+ stromal cells, severely reduced spleen EMH and reduced blood cell counts without affecting bone marrow haematopoiesis. Endothelial cells and Tcf21(+) stromal cells thus create a perisinusoidal EMH niche in the spleen, which is necessary for the physiological response to diverse haematopoietic stresses. PMID- 26570998 TI - Pharmacogenomic agreement between two cancer cell line data sets. AB - Large cancer cell line collections broadly capture the genomic diversity of human cancers and provide valuable insight into anti-cancer drug response. Here we show substantial agreement and biological consilience between drug sensitivity measurements and their associated genomic predictors from two publicly available large-scale pharmacogenomics resources: The Cancer Cell Line Encyclopedia and the Genomics of Drug Sensitivity in Cancer databases. PMID- 26570999 TI - Ubiquitous time variability of integrated stellar populations. AB - Long-period variable stars arise in the final stages of the asymptotic giant branch phase of stellar evolution. They have periods of up to about 1,000 days and amplitudes that can exceed a factor of three in the I-band flux. These stars pulsate predominantly in their fundamental mode, which is a function of mass and radius, and so the pulsation periods are sensitive to the age of the underlying stellar population. The overall number of long-period variables in a population is directly related to their lifetimes, which is difficult to predict from first principles because of uncertainties associated with stellar mass-loss and convective mixing. The time variability of these stars has not previously been taken into account when modelling the spectral energy distributions of galaxies. Here we construct time-dependent stellar population models that include the effects of long-period variable stars, and report the ubiquitous detection of this expected 'pixel shimmer' in the massive metal-rich galaxy M87. The pixel light curves display a variety of behaviours. The observed variation of 0.1 to 1 per cent is very well matched to the predictions of our models. The data provide a strong constraint on the properties of variable stars in an old and metal-rich stellar population, and we infer that the lifetime of long-period variables in M87 is shorter by approximately 30 per cent compared to predictions from the latest stellar evolution models. PMID- 26571001 TI - UV and solar photo-degradation of naproxen: TiO2 catalyst effect, reaction kinetics, products identification and toxicity assessment. AB - Direct photolysis and TiO2-photocatalytic degradation of naproxen (NPX) in aqueous solution were studied using a UV lamp and solar irradiation. The degradation of NPX was found to be in accordance with pseudo-first order kinetics, the photocatalytic process being more efficient than photolysis. The NPX removal by photolysis (pHinitial 6.5) was 83% after 3h, with 11% of chemical oxygen demand (COD) reduction, whereas the TiO2-UV process led to higher removals of both NPX (98%) and COD (25%). The apparent pseudo-first-order rate constant (kapp) for NPX degradation by photolysis ranged from 0.0050 min(-1) at pH 3.5 to 0.0095 min(-1) at pH 6.5, while it was estimated to be 0.0063 min(-1) under acidic conditions in photocatalysis, increasing by 4-fold at pH 6.5. Ultra High Performance Liquid chromatography (UHPLC) coupled with a triple quadrupole detector and also a hybrid mass spectrometer which combines the linear ion trap triple quadrupole (LTQ) and OrbiTrap mass analyser, were used to identify NPX degradation products. The main intermediates detected were 1-(6-methoxynaphtalene 2-yl) ethylhydroperoxide, 2-ethyl-6-methoxynaphthalene, 1-(6-methoxynaphtalen-2 yl) ethanol, 1-(6-methoxynaphtalen-2-yl) ethanone and malic acid. Solar photocatalysis of NPX showed COD removals of 33% and 65% after 3 and 4h of treatment, respectively, and some reduction of acute toxicity, evaluated by the exposure of Eisenia andrei to OECD soils spiked with NPX-treated solutions. PMID- 26571002 TI - Extraction of dye from aqueous solution in rotating packed bed. AB - The influence of centrifugal acceleration on mass transfer rates in liquid-liquid extraction was investigated experimentally in rotating packed bed (RPB) contactor. The extraction of methyl red using xylene was studied in the equipment. The effect of rotational speed (300-900rpm), flow rate of the aqueous (4.17-20.8*10(-6)m(3)/s), and organic phase (0.83-2.5*10(-6)m(3)/s) on the mass transfer performance was examined. The maximum stage efficiency attained was ~0.98 at aqueous to organic flow rate ratio of 10. The results suggest that contactor volume required to carry out a given separation can be reduced by an order of magnitude with RPB in comparison to conventional extractors. PMID- 26571003 TI - Single-Molecule Tribology: Force Microscopy Manipulation of a Porphyrin Derivative on a Copper Surface. AB - The low-temperature mechanical response of a single porphyrin molecule attached to the apex of an atomic force microscope (AFM) tip during vertical and lateral manipulations is studied. We find that approach-retraction cycles as well as surface scanning with the terminated tip result in atomic-scale friction patterns induced by the internal reorientations of the molecule. With a joint experimental and computational effort, we identify the dicyanophenyl side groups of the molecule interacting with the surface as the dominant factor determining the observed frictional behavior. To this end, we developed a generalized Prandtl Tomlinson model parametrized using density functional theory calculations that includes the internal degrees of freedom of the side group with respect to the core and its interactions with the underlying surface. We demonstrate that the friction pattern results from the variations of the bond length and bond angles between the dicyanophenyl side group and the porphyrin backbone as well as those of the CN group facing the surface during the lateral and vertical motion of the AFM tip. PMID- 26571000 TI - Nanogels: An overview of properties, biomedical applications and obstacles to clinical translation. AB - Nanogels have emerged as a versatile hydrophilic platform for encapsulation of guest molecules with a capability to respond to external stimuli that can be used for a multitude of applications. These are soft materials capable of holding small molecular therapeutics, biomacromolecules, and inorganic nanoparticles within their crosslinked networks, which allows them to find applications for therapy as well as imaging of a variety of disease conditions. Their stimuli responsive behavior can be easily controlled by selection of constituent polymer and crosslinker components to achieve a desired response at the site of action, which imparts nanogels the ability to participate actively in the intended function of the carrier system rather than being passive carriers of their cargo. These properties not only enhance the functionality of the carrier system but also help in overcoming many of the challenges associated with the delivery of cargo molecules, and this review aims to highlight the distinct and unique capabilities of nanogels as carrier systems for the delivery of an array of cargo molecules over other nanomaterials. Despite their obvious usefulness, nanogels are still not a commonplace occurrence in clinical practice. We have also made an attempt to highlight some of the major challenges that need to be overcome to advance nanogels further in the field of biomedical applications. PMID- 26571005 TI - Quantum metrology: The sensitive side of a spin. PMID- 26571004 TI - Field-induced conductance switching by charge-state alternation in organometallic single-molecule junctions. AB - Charge transport through single molecules can be influenced by the charge and spin states of redox-active metal centres placed in the transport pathway. These intrinsic properties are usually manipulated by varying the molecule's electrochemical and magnetic environment, a procedure that requires complex setups with multiple terminals. Here we show that oxidation and reduction of organometallic compounds containing either Fe, Ru or Mo centres can solely be triggered by the electric field applied to a two-terminal molecular junction. Whereas all compounds exhibit bias-dependent hysteresis, the Mo-containing compound additionally shows an abrupt voltage-induced conductance switching, yielding high-to-low current ratios exceeding 1,000 at bias voltages of less than 1.0 V. Density functional theory calculations identify a localized, redox-active molecular orbital that is weakly coupled to the electrodes and closely aligned with the Fermi energy of the leads because of the spin-polarized ground state unique to the Mo centre. This situation provides an additional slow and incoherent hopping channel for transport, triggering a transient charging effect in the entire molecule with a strong hysteresis and large high-to-low current ratios. PMID- 26571006 TI - Bell's inequality violation with spins in silicon. AB - Bell's theorem proves the existence of entangled quantum states with no classical counterpart. An experimental violation of Bell's inequality demands simultaneously high fidelities in the preparation, manipulation and measurement of multipartite quantum entangled states, and provides a single-number benchmark for the performance of devices that use such states for quantum computing. We demonstrate a Bell/ Clauser-Horne-Shimony-Holt inequality violation with Bell signals up to 2.70(9), using the electron and the nuclear spins of a single phosphorus atom embedded in a silicon nanoelectronic device. Two-qubit state tomography reveals that our prepared states match the target maximally entangled Bell states with >96% fidelity. These experiments demonstrate complete control of the two-qubit Hilbert space of a phosphorus atom and highlight the important function of the nuclear qubit to expand the computational basis and maximize the readout fidelity. PMID- 26571007 TI - Optimized quantum sensing with a single electron spin using real-time adaptive measurements. AB - Quantum sensors based on single solid-state spins promise a unique combination of sensitivity and spatial resolution. The key challenge in sensing is to achieve minimum estimation uncertainty within a given time and with high dynamic range. Adaptive strategies have been proposed to achieve optimal performance, but their implementation in solid-state systems has been hindered by the demanding experimental requirements. Here, we realize adaptive d.c. sensing by combining single-shot readout of an electron spin in diamond with fast feedback. By adapting the spin readout basis in real time based on previous outcomes, we demonstrate a sensitivity in Ramsey interferometry surpassing the standard measurement limit. Furthermore, we find by simulations and experiments that adaptive protocols offer a distinctive advantage over the best known non-adaptive protocols when overhead and limited estimation time are taken into account. Using an optimized adaptive protocol we achieve a magnetic field sensitivity of 6.1 +/- 1.7 nT Hz(-1/2) over a wide range of 1.78 mT. These results open up a new class of experiments for solid-state sensors in which real-time knowledge of the measurement history is exploited to obtain optimal performance. PMID- 26571008 TI - A flexoelectric microelectromechanical system on silicon. AB - Flexoelectricity allows a dielectric material to polarize in response to a mechanical bending moment and, conversely, to bend in response to an electric field. Compared with piezoelectricity, flexoelectricity is a weak effect of little practical significance in bulk materials. However, the roles can be reversed at the nanoscale. Here, we demonstrate that flexoelectricity is a viable route to lead-free microelectromechanical and nanoelectromechanical systems. Specifically, we have fabricated a silicon-compatible thin-film cantilever actuator with a single flexoelectrically active layer of strontium titanate with a figure of merit (curvature divided by electric field) of 3.33 MV(-1), comparable to that of state-of-the-art piezoelectric bimorph cantilevers. PMID- 26571009 TI - Lipid-based nanocarrier for quercetin delivery: system characterization and molecular interactions studies. AB - The flavonoid quercetin (QU) is a naturally occurring compound with several biological activities. However, the oral bioavailability of this compound is very low due to the high pre-systemic metabolism in the colon and liver and its low water solubility. In this context, the development of QU-loaded nanocarriers (NEs) is a promising approach to improve the drug oral bioavailability. This study investigates the variation of the concentration of 12-hydroxystearic acid polyethylene glycol copolymer, lecithin and castor oil (CO) as to increase the amount of QU encapsulated while maintaining physicochemical characteristics described in previous studies. To better understand the ability to load and release the drug, we investigated the molecular interactions between QU and NE. Lipid-based NEs were prepared using CO as oily phase and PEG 660-stearate and lecithin as surfactants. Hot solvent diffusion and phase inversion temperature were methods employed to produce NEs. The QU-NEs were investigated for physicochemical characteristics and in vitro drug release. Molecular interactions between QU and the NEs were monitored through the complementary infrared (Fourier transform infrared) and NMR. The results revealed that it was possible to incorporate higher amounts of QU in a lipid-based NE with a reduced size (20 nm). The system developed allow a sustained release of QU probably due to the shell formed by the surfactants around the NE and the flavonoid ordering effect in the emulsion hydrophobic regions, which may reduce the system permeability. PMID- 26571010 TI - The Small Molecule Indirubin-3'-Oxime Inhibits Protein Kinase R: Antiapoptotic and Antioxidant Effect in Rat Cardiac Myocytes. AB - Double-stranded, RNA-dependent protein kinase R (PKR) is a serine/threonine protein kinase activated by various stress signals. It plays an important role in inflammation, insulin sensitivity and glucose homeostasis. Increased PKR activity has been observed in obese humans as well as in obese diabetic mice. Indirubin-3' oxime (I3O) is an effective inhibitor of cyclin-dependent kinases and glycogen synthase kinase 3-beta. However, the effects of I3O on PKR activity/expression in cultured rat cardiomyocytes have not been reported. We investigated whether I3O attenuates the effects of high glucose on PKR, oxidative stress and apoptotic gene markers. Quantitative PCR and western blotting were used to measure protein and mRNA, respectively. High glucose treatment caused significant increase in the PKR protein/mRNA expression, which was attenuated by co-treatment with I3O. High glucose-treated, cultured cardiomyocytes developed a significant increase in mRNA expression for c-Jun-N-terminal kinase, caspase-3 and NF-KB, which were all attenuated by pretreatment with I3O. There was also a significant increase in reactive oxygen species generation in high glucose-treated, cultured cardiomyocytes, which was attenuated by pretreatment with I3O. In conclusion, I3O may have a preventive role against the deleterious effects of high glucose in the heart. PMID- 26571011 TI - Determination of urinary 5-hydroxyindoleacetic acid by combining DMU-SPE using carbon coated TiO2 nanotubes and LC-MS/MS. AB - BACKGROUND: In this article, carbon coated titanium dioxide nanotubes (TiO2-NT@C) are employed for the determination of 5-hydroxyindole-3-acetic acid in urine by LC-MS/MS. RESULTS: All the variables involved in the extraction have been studied and optimized in depth. The method has been analytically characterized on the basis of its linearity, accuracy, sensitivity and precision. The LOD is 155.8 MUg/l while the repeatability and the reproducibility, expressed as RSD, are better than 5.42 and 5.25%, respectively. The obtained relative recovery is 115%. CONCLUSION: TiO2-NT@C permit the efficient extraction of 5-hydroxyindole-3-acetic acid from complex biological samples such as urine allowing its sensitive determination by LC-MS/MS. PMID- 26571012 TI - A Randomised Crossover Trial: The Effect of Inulin on Glucose Homeostasis in Subtypes of Prediabetes. AB - BACKGROUND: Fermentable carbohydrates (FCHO) have been shown to improve insulin sensitivity in normoglycaemic and insulin-resistant subjects. However, there are no data on subjects with prediabetes. We aimed to investigate the effect of the FCHO inulin, on glucose homeostasis in subjects with prediabetes. METHODS: In a double-blind and placebo-controlled crossover study, 40 volunteers with prediabetes were randomly allocated to take 30 g/day of inulin or cellulose for 2 weeks in a crossover trial, following a 4-week dose-escalation run-in. Fasting insulin and glucose were measured for all subjects. Fifteen of the 40 subjects also underwent a meal tolerance test to assess insulin sensitivity, free fatty acids and glucagon-like peptide-1 concentrations. A subanalysis was carried out to examine any differences between the prediabetes subtypes. RESULTS: Inulin was associated with a significant increase in (0-30 min)incremental AUC (iAUC) for insulin (treatment: p < 0.04) and (0-60 min)iAUC for insulin (treatment: p < 0.04) compared to control. There was a significant reduction in insulin resistance measured by the homeostatic model assessment in the isolated-impaired fasting glucose (p < 0.05) but not in the isolated-impaired glucose tolerance groups (p = 0.59). CONCLUSION: The FCHO, inulin, may have unique metabolic effects that are of particular benefit to people at risk of diabetes, which warrant further investigation. PMID- 26571014 TI - A Changing Number of Alternative States in the Boreal Biome: Reproducibility Risks of Replacing Remote Sensing Products. AB - Publicly available remote sensing products have boosted science in many ways. The openness of these data sources suggests high reproducibility. However, as we show here, results may be specific to versions of the data products that can become unavailable as new versions are posted. We focus on remotely-sensed tree cover. Recent studies have used this public resource to detect multi-modality in tree cover in the tropical and boreal biomes. Such patterns suggest alternative stable states separated by critical tipping points. This has important implications for the potential response of these ecosystems to global climate change. For the boreal region, four distinct ecosystem states (i.e., treeless, sparse and dense woodland, and boreal forest) were previously identified by using the Collection 3 data of MODIS Vegetation Continuous Fields (VCF). Since then, the MODIS VCF product has been updated to Collection 5; and a Landsat VCF product of global tree cover at a fine spatial resolution of 30 meters has been developed. Here we compare these different remote-sensing products of tree cover to show that identification of alternative stable states in the boreal biome partly depends on the data source used. The updated MODIS data and the newer Landsat data consistently demonstrate three distinct modes around similar tree-cover values. Our analysis suggests that the boreal region has three modes: one sparsely vegetated state (treeless), one distinct 'savanna-like' state and one forest state, which could be alternative stable states. Our analysis illustrates that qualitative outcomes of studies may change fundamentally as new versions of remote sensing products are used. Scientific reproducibility thus requires that old versions remain publicly available. PMID- 26571013 TI - Essential Role of GATA2 in the Negative Regulation of Type 2 Deiodinase Gene by Liganded Thyroid Hormone Receptor beta2 in Thyrotroph. AB - The inhibition of thyrotropin (thyroid stimulating hormone; TSH) by thyroid hormone (T3) and its receptor (TR) is the central mechanism of the hypothalamus pituitary-thyroid axis. Two transcription factors, GATA2 and Pit-1, determine thyrotroph differentiation and maintain the expression of the beta subunit of TSH (TSHbeta). We previously reported that T3-dependent repression of the TSHbeta gene is mediated by GATA2 but not by the reported negative T3-responsive element (nTRE). In thyrotrophs, T3 also represses mRNA of the type-2 deiodinase (D2) gene, where no nTRE has been identified. Here, the human D2 promoter fused to the CAT or modified Renilla luciferase gene was co-transfected with Pit-1 and/or GATA2 expression plasmids into cell lines including CV1 and thyrotroph-derived TalphaT1. GATA2 but not Pit-1 activated the D2 promoter. Two GATA responsive elements (GATA-REs) were identified close to cAMP responsive element. The protein kinase A activator, forskolin, synergistically enhanced GATA2-dependent activity. Gel-shift and chromatin immunoprecipitation assays with TalphaT1 cells indicated that GATA2 binds to these GATA-REs. T3 repressed the GATA2-induced activity of the D2 promoter in the presence of the pituitary-specific TR, TRbeta2. The inhibition by T3-bound TRbeta2 was dominant over the synergism between GATA2 and forskolin. The D2 promoter is also stimulated by GATA4, the major GATA in cardiomyocytes, and this activity was repressed by T3 in the presence of TRalpha1. These data indicate that the GATA-induced activity of the D2 promoter is suppressed by T3-bound TRs via a tethering mechanism, as in the case of the TSHbeta gene. PMID- 26571015 TI - Single Pathogen Challenge with Agents of the Bovine Respiratory Disease Complex. AB - Bovine respiratory disease complex (BRDC) is an important cause of mortality and morbidity in cattle; costing the dairy and beef industries millions of dollars annually, despite the use of vaccines and antibiotics. BRDC is caused by one or more of several viruses (bovine respiratory syncytial virus, bovine herpes type 1 also known as infectious bovine rhinotracheitis, and bovine viral diarrhea virus), which predispose animals to infection with one or more bacteria. These include: Pasteurella multocida, Mannheimia haemolytica, Mycoplasma bovis, and Histophilus somni. Some cattle appear to be more resistant to BRDC than others. We hypothesize that appropriate immune responses to these pathogens are subject to genetic control. To determine which genes are involved in the immune response to each of these pathogens it was first necessary to experimentally induce infection separately with each pathogen to document clinical and pathological responses in animals from which tissues were harvested for subsequent RNA sequencing. Herein these infections and animal responses are described. PMID- 26571017 TI - Octaiodoporphyrin. AB - Interaction of 3,4-diiodopyrrole with 4-trifluoromethylbenzaldeyde under carefully optimized, Lindsey-type conditions at -10 degrees C has led to the synthesis of the first beta-octaiodoporphyrin, H2[I8TpCF3PP]. The free ligand readily yielded Ni, Cu, and Zn complexes, which all proved amenable to single crystal X-ray structure analyses. The zinc complex Zn[I8TpCF3PP] exhibits the most saddled porphyrin core for any simple porphyrin known to date and a dramatically red-shifted optical spectrum with a Soret maximum at 495 nm. PMID- 26571016 TI - A Long-Term High-Fat/High-Sucrose Diet Promotes Kidney Lipid Deposition and Causes Apoptosis and Glomerular Hypertrophy in Bama Minipigs. AB - Metabolic syndrome can induce chronic renal injury in humans. In the present study, Bama minipigs were fed a high-fat/high-sucrose diet (HFHSD) for 23 months, which caused them to develop the pathological characteristics of metabolic syndrome, including obesity, hyperinsulinemia, and hyperlipidemia, and resulted in kidney tissue damage. In the HFHSD group, the ratio of the glomus areas to the glomerulus area and the glomerular density inside the renal cortex both decreased. Lipid deposition in the renal tubules was detected in the HFHSD group, and up-regulated expression levels of SREBP-1, FABP3 and LEPR promoted lipid deposition. The decreased levels of SOD, T-AOC and GSH-PX indicated that the antioxidant capacity of the renal tissues was diminished in the HFHSD group compared with MDA, which increased. The renal tissue in the HFHSD group exhibited clear signs of inflammation as well as significantly elevated expression of key genes associated with inflammation, including tumor necrosis factor-alpha (TNF alpha) and macrophage migration inhibitory factor (MIF), compared with the control group. The tubular epithelial cells in the HFHSD group displayed significantly greater numbers of apoptotic cells, and the expression of proliferating cell nuclear antigen (PCNA) in the renal tubules decreased. Caspase 3 expression increased significantly, and the transcription factor nuclear factor kappaB (NF-kappaB) was activated and translocated into the nucleus. In conclusion, long-term HFHSDs cause metabolic syndrome and chronic renal tissue injury in Bama minipigs. These findings provide a foundation for further studies investigating metabolic syndrome and nephropathy. PMID- 26571018 TI - High Dietary Sodium Intake Assessed by Estimated 24-h Urinary Sodium Excretion Is Associated with NAFLD and Hepatic Fibrosis. AB - BACKGROUND: Although high sodium intake is associated with obesity and hypertension, few studies have investigated the relationship between sodium intake and non-alcoholic fatty liver disease (NAFLD). We evaluated the association between sodium intake assessed by estimated 24-h urinary sodium excretion and NAFLD in healthy Koreans. METHODS: We analyzed data from 27,433 participants in the Korea National Health and Nutrition Examination Surveys (2008 2010). The total amount of sodium excretion in 24-h urine was estimated using Tanaka's equations from spot urine specimens. Subjects were defined as having NAFLD when they had high scores in previously validated NAFLD prediction models such as the hepatic steatosis index (HSI) and fatty liver index (FLI). BARD scores and FIB-4 were used to define advanced fibrosis in subjects with NAFLD. RESULTS: The participants were classified into three groups according to estimated 24-h urinary excretion tertiles. The prevalence of NAFLD as assessed by both FLI and HSI was significantly higher in the highest estimated 24-h urinary sodium excretion tertile group. Even after adjustment for confounding factors including body fat and hypertension, the association between higher estimated 24 h urinary sodium excretion and NAFLD remained significant (Odds ratios (OR) 1.39, 95% confidence interval (CI) 1.26-1.55, in HSI; OR 1.75, CI 1.39-2.20, in FLI, both P < 0.001). Further, subjects with hepatic fibrosis as assessed by BARD score and FIB-4 in NAFLD patients had higher estimated 24-h urinary sodium values. CONCLUSIONS: High sodium intake was independently associated with an increased risk of NAFLD and advanced liver fibrosis. PMID- 26571019 TI - Curcumin and folic acid abrogated methotrexate induced vascular endothelial dysfunction. AB - Methotrexate, an antifolate drug widely used in rheumatoid arthritis, psoriasis, and cancer, is known to cause vascular endothelial dysfunction by causing hyperhomocysteinemia, direct injury to endothelium or by increasing the oxidative stress (raising levels of 7,8-dihydrobiopterin). Curcumin is a naturally occurring polyphenol with strong antioxidant and anti-inflammatory action and therapeutic spectra similar to that of methotrexate. This study was performed to evaluate the effects of curcumin on methotrexate induced vascular endothelial dysfunction and also compare its effect with that produced by folic acid (0.072 MUg.g(-1).day(-1), p.o., 2 weeks) per se and in combination. Male Wistar rats were exposed to methotrexate (0.35 mg.kg(-1).day(-1), i.p.) for 2 weeks to induce endothelial dysfunction. Methotrexate exposure led to shedding of endothelium, decreased vascular reactivity, increased oxidative stress, decreased serum nitrite levels, and increase in aortic collagen deposition. Curcumin (200 mg.kg( 1).day(-1) and 400 mg.kg(-1).day(-1), p.o.) for 4 weeks prevented the increase in oxidative stress, decrease in serum nitrite, aortic collagen deposition, and also vascular reactivity. The effects were comparable with those produced by folic acid therapy. The study shows that curcumin, when concomitantly administered with methotrexate, abrogated its vascular side effects by preventing an increase in oxidative stress and abating any reduction in physiological nitric oxide levels. PMID- 26571020 TI - Functional Significance of Labellum Pattern Variation in a Sexually Deceptive Orchid (Ophrys heldreichii): Evidence of Individual Signature Learning Effects. AB - Mimicking female insects to attract male pollinators is an important strategy in sexually deceptive orchids of the genus Ophrys, and some species possess flowers with conspicuous labellum patterns. The function of the variation of the patterns remains unresolved, with suggestions that these enhance pollinator communication. We investigated the possible function of the labellum pattern in Ophrys heldreichii, an orchid species in which the conspicuous and complex labellum pattern contrasts with a dark background. The orchid is pollinated exclusively by males of the solitary bee, Eucera berlandi. Comparisons of labellum patterns revealed that patterns within inflorescences are more similar than those of other conspecific plants. Field observations showed that the males approach at a great speed and directly land on flowers, but after an unsuccessful copulation attempt, bees hover close and visually scan the labellum pattern for up to a minute. Learning experiments conducted with honeybees as an accessible model of bee vision demonstrated that labellum patterns of different plants can be reliably learnt; in contrast, patterns of flowers from the same inflorescence could not be discriminated. These results support the hypothesis that variable labellum patterns in O. heldreichii are involved in flower-pollinator communication which would likely help these plants to avoid geitonogamy. PMID- 26571022 TI - Dapagliflozin combination therapy in type 2 diabetes mellitus. AB - Type 2 diabetes mellitus (T2DM) is a progressive disease, and most patients ultimately require two or more antidiabetes drugs in addition to lifestyle changes to achieve and maintain glycemic control. Current consensus statements and guidelines recommend metformin as first-line pharmacotherapy for the treatment of T2DM in most patients. When glycemic control cannot be maintained with metformin alone, the sequential, stepwise addition of other agents is recommended. Agents such as thiazolidinediones or sulfonylureas have typically been added to metformin therapy. Although effective in reducing glycated hemoglobin, these drugs are often associated with adverse effects, most notably weight gain, and in the case of sulfonylureas, hypoglycemia. Sodium-glucose cotransporter 2 inhibitors, such as dapagliflozin, are the newest class of antidiabetes drugs approved for the treatment of T2DM. Dapagliflozin effectively improves glycemic control by increasing the renal excretion of excess glucose. In clinical trials, dapagliflozin has been well tolerated and has additional benefits of weight loss, low risk of hypoglycemia and reduction in blood pressure. This review discusses the clinical evidence and rationale for the use of dapagliflozin as add-on therapy in T2DM. The results suggest that dapagliflozin add-on therapy is a promising new treatment option for a wide range of patients with T2DM. Results from an ongoing cardiovascular outcomes trial are needed to establish the long-term safety of dapagliflozin. PMID- 26571021 TI - Head-to-Head Comparison of Soluble vs. Qbeta VLP Circumsporozoite Protein Vaccines Reveals Selective Enhancement of NANP Repeat Responses. AB - Circumsporozoite protein (CSP) of Plasmodium falciparum is a promising malaria vaccine target. RTS,S, the most advanced malaria vaccine candidate consists of the central NANP repeat and carboxy-terminal region of CSP displayed on a hepatitis B virus-like particle (VLP). To build upon the success of RTS,S, we produced a near full-length Plasmodium falciparum CSP that also includes the conserved amino-terminal region of CSP. We recently showed that this soluble CSP, combined with a synthetic Toll-like-receptor-4 (TLR4) agonist in stable oil-in water emulsion (GLA/SE), induces a potent and protective immune response in mice against transgenic parasite challenge. Here we have investigated whether the immunogenicity of soluble CSP could be further augmented by presentation on a VLP. Bacteriophage Qbeta VLPs can be readily produced in E.coli, they have a diameter of 25 nm and contain packaged E. coli RNA which serves as a built in adjuvant through the activation of TLR7/8. CSP was chemically conjugated to Qbeta and the CSP-Qbeta vaccine immunogenicity and efficacy were compared to adjuvanted soluble CSP in the C57Bl/6 mouse model. When formulated with adjuvants lacking a TLR4 agonist (Alum, SE and Montanide) the Qbeta-CSP induced higher anti-NANP repeat titers, higher levels of cytophilic IgG2b/c antibodies and a trend towards higher protection against transgenic parasite challenge as compared to soluble CSP formulated in the same adjuvant. The VLP and soluble CSP immunogenicity difference was most pronounced at low antigen dose, and within the CSP molecule, the titers against the NANP repeats were preferentially enhanced by Qbeta presentation. While a TLR4 agonist enhanced the immunogenicity of soluble CSP to levels comparable to the VLP vaccine, the TLR4 agonist did not further improve the immunogenicity of the Qbeta-CSP vaccine. The data presented here pave the way for further improvement in the Qbeta conjugation chemistry and evaluation of both the Qbeta-CSP and soluble CSP vaccines in the non-human primate model. PMID- 26571023 TI - Effects of Lifestyle Modification on Telomerase Gene Expression in Hypertensive Patients: A Pilot Trial of Stress Reduction and Health Education Programs in African Americans. AB - BACKGROUND: African Americans suffer from disproportionately high rates of hypertension and cardiovascular disease. Psychosocial stress, lifestyle and telomere dysfunction contribute to the pathogenesis of hypertension and cardiovascular disease. This study evaluated effects of stress reduction and lifestyle modification on blood pressure, telomerase gene expression and lifestyle factors in African Americans. METHODS: Forty-eight African American men and women with stage I hypertension who participated in a larger randomized controlled trial volunteered for this substudy. These subjects participated in either stress reduction with the Transcendental Meditation technique and a basic health education course (SR) or an extensive health education program (EHE) for 16 weeks. Primary outcomes were telomerase gene expression (hTERT and hTR) and clinic blood pressure. Secondary outcomes included lifestyle-related factors. Data were analyzed for within-group and between-group changes. RESULTS: Both groups showed increases in the two measures of telomerase gene expression, hTR mRNA levels (SR: p< 0.001; EHE: p< 0.001) and hTERT mRNA levels (SR: p = 0.055; EHE: p< 0.002). However, no statistically significant between-group changes were observed. Both groups showed reductions in systolic BP. Adjusted changes were SR = -5.7 mm Hg, p< 0.01; EHE = -9.0 mm Hg, p < 0.001 with no statistically significant difference between group difference. There was a significant reduction in diastolic BP in the EHE group (-5.3 mm Hg, p< 0.001) but not in SR ( 1.2 mm Hg, p = 0.42); the between-group difference was significant (p = 0.04). The EHE group showed a greater number of changes in lifestyle behaviors. CONCLUSION: In this pilot trial, both stress reduction (Transcendental Meditation technique plus health education) and extensive health education groups demonstrated increased telomerase gene expression and reduced BP. The association between increased telomerase gene expression and reduced BP observed in this high risk population suggest hypotheses that telomerase gene expression may either be a biomarker for reduced BP or a mechanism by which stress reduction and lifestyle modification reduces BP. TRIAL REGISTRATION: ClinicalTrials.gov NCT00681200. PMID- 26571025 TI - Risks Associated With Catheters. PMID- 26571024 TI - ICAM1 Is a Potential Cancer Stem Cell Marker of Esophageal Squamous Cell Carcinoma. AB - Esophageal squamous cell carcinoma (ESCC) accounts for about 90% of esophageal cancer diagnosed in Asian countries, with its incidence on the rise. Cancer stem cell (CSC; also known as tumor-initiating cells, TIC) is inherently resistant to cytotoxic chemotherapy and radiation and associates with poor prognosis and therapy failure. Targeting therapy against cancer stem cell has emerged as a potential therapeutic approach to develop effective regimens. However, the suitable CSC marker of ESCC for identification and targeting is still limited. In this study, we screened the novel CSC membrane protein markers using two distinct stemness characteristics of cancer cell lines by a comparative approach. After the validation of RT-PCR, qPCR and western blot analyses, intercellular adhesion molecule 1 (ICAM1) was identified as a potential CSC marker of ESCC. ICAM1 promotes cancer cell migration, invasion as well as increasing mesenchymal marker expression and attenuating epithelial marker expression. In addition, ICAM1 contributes to CSC properties, including sphere formation, drug resistance, and tumorigenesis in mouse xenotransplantation model. Based on the analysis of ICAM1 regulated proteins, we speculated that ICAM1 regulates CSC properties partly through an ICAM1-PTTG1IP-p53-DNMT1 pathway. Moreover, we observed that ICAM1 and CD44 could have a compensation effect on maintaining the stemness characteristics of ESCC, suggesting that the combination of multi-targeting therapies should be under serious consideration to acquire a more potent therapeutic effect on CSC of ESCC. PMID- 26571026 TI - Inferring the Clonal Structure of Viral Populations from Time Series Sequencing. AB - RNA virus populations will undergo processes of mutation and selection resulting in a mixed population of viral particles. High throughput sequencing of a viral population subsequently contains a mixed signal of the underlying clones. We would like to identify the underlying evolutionary structures. We utilize two sources of information to attempt this; within segment linkage information, and mutation prevalence. We demonstrate that clone haplotypes, their prevalence, and maximum parsimony reticulate evolutionary structures can be identified, although the solutions may not be unique, even for complete sets of information. This is applied to a chain of influenza infection, where we infer evolutionary structures, including reassortment, and demonstrate some of the difficulties of interpretation that arise from deep sequencing due to artifacts such as template switching during PCR amplification. PMID- 26571027 TI - Correction: Antibodies to S. aureus LukS-PV Attenuated Subunit Vaccine Neutralize a Broad Spectrum of Canonical and Non-Canonical Bicomponent Leukotoxin Pairs. PMID- 26571028 TI - Epidemiology and Heritability of Major Depressive Disorder, Stratified by Age of Onset, Sex, and Illness Course in Generation Scotland: Scottish Family Health Study (GS:SFHS). AB - The heritability of Major Depressive Disorder (MDD) has been estimated at 37% based largely on twin studies that rely on contested assumptions. More recently, the heritability of MDD has been estimated on large populations from registries such as the Swedish, Finnish, and Chinese cohorts. Family-based designs utilise a number of different relationships and provide an alternative means of estimating heritability. Generation Scotland: Scottish Family Health Study (GS:SFHS) is a large (n = 20,198), family-based population study designed to identify the genetic determinants of common diseases, including Major Depressive Disorder. Two thousand seven hundred and six individuals were SCID diagnosed with MDD, 13.5% of the cohort, from which we inferred a population prevalence of 12.2% (95% credible interval: 11.4% to 13.1%). Increased risk of MDD was associated with being female, unemployed due to a disability, current smokers, former drinkers, and living in areas of greater social deprivation. The heritability of MDD in GS:SFHS was between 28% and 44%, estimated from a pedigree model. The genetic correlation of MDD between sexes, age of onset, and illness course were examined and showed strong genetic correlations. The genetic correlation between males and females with MDD was 0.75 (0.43 to 0.99); between earlier (<= age 40) and later (> age 40) onset was 0.85 (0.66 to 0.98); and between single and recurrent episodic illness course was 0.87 (0.72 to 0.98). We found that the heritability of recurrent MDD illness course was significantly greater than the heritability of single MDD illness course. The study confirms a moderate genetic contribution to depression, with a small contribution of the common family environment (variance proportion = 0.07, CI: 0.01 to 0.15), and supports the relationship of MDD with previously identified risk factors. This study did not find robust support for genetic differences in MDD due to sex, age of onset, or illness course. However, we found an intriguing difference in heritability between recurrent and single MDD illness course. These findings establish GS:SFHS as a valuable cohort for the genetic investigation of MDD. PMID- 26571029 TI - Non-Alcoholic Fatty Liver Disease as a Predictor of Atrial Fibrillation in Middle Aged Population (OPERA Study). AB - Non-alcoholic fatty liver disease (NAFLD) and atrial fibrillation (AF) are widespread diseases and have multiple common risk factors and comorbidities. No studies of association between ultrasonography-diagnosed NAFLD and AF exist in other than diabetic population. The goal of this prospective study was to study the value of NAFLD as a predictor of atrial fibrillation. This study had 958 subjects from the OPERA (Oulu Project Elucidating Risk of Atherosclerosis) cohort, and the mean follow-up time was 16.3 years. NAFLD was diagnosed if the subject had fatty liver in ultrasonography and no excess alcohol intake. AF was followed in the National Registers. In this study 249 subjects (26.0%) had NAFLD and 37 (14.9%) of these had AF whereas only 56 (7.9%) of those without NAFLD experienced AF during the follow-up time (p = 0.001). In the multiple Cox regression analysis including potential confounders (age, sex, study group, diabetes, body mass index (BMI), waist circumference, alcohol consumption, smoking, serum alanine aminotransferase concentration (ALT), systolic blood pressure, quick index, left ventricular mass index, left atrial diameter, coronary artery disease (CAD), atrial natriuretic peptide (ANP) and high sensitive C-reactive protein (hs-CRP)), NAFLD remained as an independent predictor of AF (Adjusted OR, 1.88 (95% Confidence interval (CI) 1.03-3.45)). In conclusion, our data shows that NAFLD is independently associated with the risk of AF. PMID- 26571030 TI - Transforming Growth Factor TGFbeta Increases Levels of Microtubule-Associated Protein MAP1S and Autophagy Flux in Pancreatic Ductal Adenocarcinomas. AB - BACKGROUND AND AIM: Autophagy is a cellular process to regulate the turnover of misfolded/aggregated proteins or dysfunctional organelles such as damaged mitochondria. Microtubule-associated protein MAP1S (originally named C19ORF5) is a widely-distributed homologue of neuronal-specific MAP1A and MAP1B with which autophagy marker light chain 3 (LC3) was originally co-purified. MAP1S bridges autophagic components with microtubules and mitochondria through LC3 and positively regulates autophagy flux from autophagosomal biogenesis to degradation. The MAP1S-mediated autophagy suppresses tumorigenesis as suggested in a mouse liver cancer model and in prostate cancer patients. The TGFbeta signaling pathway plays a central role in pancreatic tumorigenesis, and high levels of TGFbeta suggest a tumor suppressive function and predict a better survival for some patients with resectable pancreatic ductal adenocarcinoma. In this study, we try to understand the relationship between TGFbeta and MAP1S mediated autophagy in pancreatic ductal adenocarcinoma. METHODS: We collected the tumor and its adjacent normal tissues from 33 randomly selected patients of pancreatic ductal adenocarcinomas to test the association between TGFbeta and autophagy markers MAP1S and LC3. Then we tested the cause and effect relation between TGFbeta and autophagy markers in cultured pancreatic cancer cell lines. RESULTS: Here we show that levels of TGFbeta and autophagy markers MAP1S and LC3 are dramatically elevated in tumor tissues from patients with pancreatic ductal adenocarcinomas. TGFbeta increases levels of MAP1S protein and enhances autophagy flux. CONCLUSION: TGFbeta may suppress the development of pancreatic ductal adenocarcinomas by enhancing MAP1S-mediated autophagy. PMID- 26571031 TI - Active Contours Driven by Multi-Feature Gaussian Distribution Fitting Energy with Application to Vessel Segmentation. AB - Active contour models are of great importance for image segmentation and can extract smooth and closed boundary contours of the desired objects with promising results. However, they cannot work well in the presence of intensity inhomogeneity. Hence, a novel region-based active contour model is proposed by taking image intensities and 'vesselness values' from local phase-based vesselness enhancement into account simultaneously to define a novel multi feature Gaussian distribution fitting energy in this paper. This energy is then incorporated into a level set formulation with a regularization term for accurate segmentations. Experimental results based on publicly available STructured Analysis of the Retina (STARE) demonstrate our model is more accurate than some existing typical methods and can successfully segment most small vessels with varying width. PMID- 26571033 TI - Aneuploidy triggers a TFEB-mediated lysosomal stress response. AB - Aneuploidy, defined as an alteration in chromosome number that is not a multiple of the haploid complement, severely affects cellular physiology. Changes in chromosome number lead to imbalances in cellular protein composition, thus disrupting cellular processes and causing proteins to misfold and aggregate. We recently reported that in mammalian cells protein aggregates are readily encapsulated within autophagosomes but are not degraded by lysosomes. This leads to a lysosomal stress response in which the transcription factor TFEB induces expression of factors needed for macroautophagy-mediated protein degradation. Our studies uncover lysosomal degradation defects as a feature of the aneuploid state, and a role for the transcription factor TFEB in the response thereto. PMID- 26571032 TI - Implementing a Trauma-Informed Approach in Pediatric Health Care Networks. AB - Pediatric health care networks serve millions of children each year. Pediatric illness and injury are among the most common potentially emotionally traumatic experiences for children and their families. In addition, millions of children who present for medical care (including well visits) have been exposed to prior traumatic events, such as violence or natural disasters. Given the daily challenges of working in pediatric health care networks, medical professionals and support staff can experience trauma symptoms related to their work. The application of a trauma-informed approach to medical care has the potential to mitigate these negative consequences. Trauma-informed care minimizes the potential for medical care to become traumatic or trigger trauma reactions, addresses distress, provides emotional support for the entire family, encourages positive coping, and provides anticipatory guidance regarding the recovery process. When used in conjunction with family-centered practices, trauma-informed approaches enhance the quality of care for patients and their families and the well-being of medical professionals and support staff. Barriers to routine integration of trauma-informed approaches into pediatric medicine include a lack of available training and unclear best-practice guidelines. This article highlights the importance of implementing a trauma-informed approach and offers a framework for training pediatric health care networks in trauma-informed care practices. PMID- 26571034 TI - Performance of psychiatric diagnostic groups on measures and strategies of verbal fluency. AB - Analysis of cognitive deficits in people with psychiatric disorders can increase our understanding of those disorders. Here we contrast the performance of 5 diagnostic groups (n = 120; schizophrenia, mild-to-moderate and moderate-to severe depression, panic disorder, and healthy controls) on word and letter fluency tasks using 3 scoring systems (Abwender, Swan, Bowerman, & Connolly, 2001 ; Raskin, Silwinski, & Brood, 1992 ; Troyer, Moscovitch, & Winocur, 1997 ) that differ in complexity to determine what system best differentiates diagnostic groups. The 3 scoring methods differ in the range of cognitive strategies assessed and how strategies are defined. Groups with schizophrenia and major depression were hypothesized to show greater deficits in fluency than groups with panic disorder and healthy controls. Results showed that the group with schizophrenia had the lowest level of fluency regardless of scoring method, with the group with severe major depression also showing deficits. The healthy control and panic disorder groups, and unexpectedly, the mild-to-moderate depression group showed few, if any, deficits. The scoring method proposed by Abwender et al. ( 2001 ) proved to be most comprehensive and sensitive to group differences. PMID- 26571035 TI - Universal Linear Fit Identification: A Method Independent of Data, Outliers and Noise Distribution Model and Free of Missing or Removed Data Imputation. AB - Data processing requires a robust linear fit identification method. In this paper, we introduce a non-parametric robust linear fit identification method for time series. The method uses an indicator 2/n to identify linear fit, where n is number of terms in a series. The ratio Rmax of amax - amin and Sn - amin*n and that of Rmin of amax - amin and amax*n - Sn are always equal to 2/n, where amax is the maximum element, amin is the minimum element and Sn is the sum of all elements. If any series expected to follow y = c consists of data that do not agree with y = c form, Rmax > 2/n and Rmin > 2/n imply that the maximum and minimum elements, respectively, do not agree with linear fit. We define threshold values for outliers and noise detection as 2/n * (1 + k1) and 2/n * (1 + k2), respectively, where k1 > k2 and 0 <= k1 <= n/2 - 1. Given this relation and transformation technique, which transforms data into the form y = c, we show that removing all data that do not agree with linear fit is possible. Furthermore, the method is independent of the number of data points, missing data, removed data points and nature of distribution (Gaussian or non-Gaussian) of outliers, noise and clean data. These are major advantages over the existing linear fit methods. Since having a perfect linear relation between two variables in the real world is impossible, we used artificial data sets with extreme conditions to verify the method. The method detects the correct linear fit when the percentage of data agreeing with linear fit is less than 50%, and the deviation of data that do not agree with linear fit is very small, of the order of +/-10-4%. The method results in incorrect detections only when numerical accuracy is insufficient in the calculation process. PMID- 26571036 TI - Performing Isometric Force Control in Combination with a Cognitive Task: A Multidimensional Assessment. AB - INTRODUCTION: We used a multidimensional approach to study isometric force control in single and dual-task conditions. METHODS: Multiple measures of performance, efficiency, variability, and structural interference were calculated at low and higher force levels under single (force maintenance) and dual-task (force maintenance and reaction time) conditions. RESULTS: Reaction time and signal-to-noise ratio were larger in the dual-task conditions. They were also greater for the higher force condition, while sample entropy was lower. Perturbation analyses revealed smaller relative amplitude of downward perturbations for the higher force level. DISCUSSION: Attentional effort and efficiency are positively related when force level increases, and inversely related to entropy. These relations were presumably mediated by attentional investment. Behavioral perturbations show that attentional resources and structural interference models are not mutually exclusive to account for dual task situation. Overall, the present study highlights the interest of a multidimensional assessment of force control. PMID- 26571037 TI - A comparison of equivolume, equiosmolar solutions of hypertonic saline and mannitol for brain relaxation during elective supratentorial craniotomy. AB - BACKGROUND: Hyperosmolar solutions have been used in neurosurgery to reduce brain volume and facilitate surgical exposure. The purpose of this study was to compare the effects of equivolume, equiosmolar solutions of mannitol and hypertonic saline (HS) on brain relaxation, intensive care unit (ICU) and hospital stay, postoperative outcomes and incidence of side-effects in patients undergoing elective supratentorial craniotomy. METHODS: In a randomised, prospective, double blind study, 60 patients undergoing elective supratentorial craniotomy were randomised 1:1 to receive 3 ml/kg of either 20% mannitol or 3% HS. The primary outcome was the surgical condition of the brain assessed by the neurosurgeon using a 4-point scale after opening the dura (1 = relaxed, 2 = satisfactory, 3 = firm and 4 = bulging). Secondary outcomes were electrolytes, blood gases, plasma osmolality and haemodynamic variables measured at 0 min, 30 min, 2 h and 6 h after infusion. Also, predefined postoperative complications, length of ICU and hospital stay were recorded. Appropriate statistical tests were used for comparison; p < 0.05 was considered significant. RESULTS: There was no difference in brain relaxation [mannitol, 1(1-3) versus HS, 1(1.4) points; p = 0.55]. Patients with brain midline shift showed a worse response to hyperosmolar solutions than those without midline shift: 37% versus 8%, respectively; OR = 6.6 (95% CI, 1.54-28.83); p = 0.006. Plasma osmolality increased during the study period (6 h) in both the groups (p < 0.05 compared with baseline). No significant differences in postoperative complications or length of ICU and hospital stay were observed between the groups. CONCLUSIONS: Single doses of 3 ml/kg of 20% mannitol and 3% HS are safe and effective for intraoperative brain debulking during elective supratentorial craniotomy, but less effective in patients with pre-existing mass effect and midline shift. PMID- 26571040 TI - British Society of Breast Radiology Annual Scientific Meeting 2015. PMID- 26571039 TI - Electromyographic analysis of thigh muscles during track cycling on a velodrome. AB - We aimed to investigate neuromuscular activation of thigh muscles during track cycling at various speeds. Eight male competitive cyclists volunteered to participate in this study. Surface electromyography of the vastus lateralis, biceps femoris and adductor magnus muscles of the bilateral legs was recorded during track cycling on velodromes with a 250-m track. The participants were instructed to maintain three different lap times: 20, 18 and 16 s. The average rectified value (ARV) was calculated from the sampled surface electromyography. Significantly higher ARVs were observed in the right compared to left leg for the biceps femoris muscle during both straight and curved sections at 18- and 16-s lap times (P < 0.05). In the biceps femoris muscle, significant changes in ARVs during the recovery phase with an increase in speed were seen in the right leg only (P < 0.05). There were no significant differences in ARVs between the straight and curved sections for all three muscles (P > 0.05). From our findings, it was suggested that during track cycling on a velodrome the laterality of the biceps femoris muscle activity is a key strategy to regulate the speed, and fixed neuromuscular strategies are adopted between straight and curved sections for thigh muscles. PMID- 26571038 TI - The Protective Role of Interleukin-33 in Myocardial Ischemia and Reperfusion Is Associated with Decreased HMGB1 Expression and Up-Regulation of the P38 MAPK Signaling Pathway. AB - Interleukin-33 (IL-33) plays a protective role in myocardial ischemia and reperfusion (I/R) injury, but the underlying mechanism was not fully elucidated. The present study was designed to investigate whether IL-33 protects against myocardial I/R injury by regulating both P38 mitogen-activated-protein kinase (P38 MAPK), which is involved in one of the downstream signaling pathways of IL 33, and high mobility group box protein 1 (HMGB1), a late pro-inflammatory cytokine. Myocardial I/R injury increased the level of IL-33 and its induced receptor (sST) in myocardial tissue. Compared with the I/R group, the IL-33 group had significantly lower cardiac injury (lower serum creatine kinase (CK), lactate dehydrogenase (LDH), and cTnI levels and myocardial infarct size), a suppressed inflammatory response in myocardial tissue (lower expression of HMGB1, IL-6, TNF alpha and INF-gamma) and less myocardial apoptosis (much higher Bcl-2/Bax ratio and lower cleaved caspase-3 expression). Moreover, IL-33 activated the P38 MAPK signaling pathway (up-regulating P-P38 expression) in myocardial tissue, and SB230580 partially attenuated the anti-inflammatory and anti-apoptosis effects of IL-33. These findings indicated that IL-33 protects against myocardial I/R injury by inhibiting inflammatory responses and myocardial apoptosis, which may be associated with the HMGB1 and P38 MAPK signaling pathways. PMID- 26571041 TI - Investigation of the magnetic dipole field at the atomic scale in quasi-one dimensional paramagnetic conductor Li0.9Mo6O17. AB - We report magnetic dipole field investigation at the atomic scale in a single crystal of quasi-one-dimensional (Q1D) paramagnetic conductor Li0.9Mo6O17, using a paramagnetic electron model and (7)Li-NMR spectroscopy measurements with an externally applied magnetic field B 0 = 9 T. We find that the magnetic dipole field component ([Formula: see text]) parallel to B 0 at the Li site from the Mo electrons has no lattice axial symmetry; it is small around the middle between the lattice a and c axes in the ac-plane with the minimum at the field orientation angle [Formula: see text], while the [Formula: see text] maximum is at [Formula: see text] when B 0 is applied perpendicular to b ([Formula: see text]), where [Formula: see text] represents the direction of [Formula: see text]. Further estimation indicates that [Formula: see text] has a maximum value of 0.35 G at B 0 = 9 T. By minimizing the potential magnetic contributions to the NMR spectra satellites with the NMR spectroscopy measurements at the direction where the value of the magnetic dipole field component [Formula: see text] is ~0, the behavior of the electron charge statics is exhibited. This work demonstrates that the magnetic dipole field of the Mo electrons is the dominant source of the local magnetic fields at the Li site, and suggests that the unknown metal-'insulator' crossover at low temperatures is not a charge effect. The work also reveals valuable local electric and magnetic field information for further NMR investigation as recently suggested (2012 Phys. Rev. B 85 235128) regarding the unusual properties of the material. PMID- 26571042 TI - A Beacon Transmission Power Control Algorithm Based on Wireless Channel Load Forecasting in VANETs. AB - In a vehicular ad hoc network (VANET), the periodic exchange of single-hop status information broadcasts (beacon frames) produces channel loading, which causes channel congestion and induces information conflict problems. To guarantee fairness in beacon transmissions from each node and maximum network connectivity, adjustment of the beacon transmission power is an effective method for reducing and preventing channel congestion. In this study, the primary factors that influence wireless channel loading are selected to construct the KF-BCLF, which is a channel load forecasting algorithm based on a recursive Kalman filter and employs multiple regression equation. By pre-adjusting the transmission power based on the forecasted channel load, the channel load was kept within a predefined range; therefore, channel congestion was prevented. Based on this method, the CLF-BTPC, which is a transmission power control algorithm, is proposed. To verify KF-BCLF algorithm, a traffic survey method that involved the collection of floating car data along a major traffic road in Changchun City is employed. By comparing this forecast with the measured channel loads, the proposed KF-BCLF algorithm was proven to be effective. In addition, the CLF-BTPC algorithm is verified by simulating a section of eight-lane highway and a signal controlled urban intersection. The results of the two verification process indicate that this distributed CLF-BTPC algorithm can effectively control channel load, prevent channel congestion, and enhance the stability and robustness of wireless beacon transmission in a vehicular network. PMID- 26571043 TI - Mercury in Eisenia fetida and soil in the vicinity of a natural gas treatment plant in northern Croatia. AB - In the last two decades (1990-2012), as part of a mercury monitoring programme, earthworms and soils have been collected from four locations in the vicinity of a natural gas production and treatment plant near the village of Molve, Croatia. The aim of this study was to determine the concentration of mercury in the collected samples, monitor its changes over a longer period of time and determine the bioaccumulation of total mercury in earthworms (Eisenia fetida) from the soil. Total mercury concentrations in earthworms from the surroundings of four boreholes (Molve 9-12) ranged within 0.195-1.050, 0.129-1.0, 0.229-1.236 and 0.223-0.799 MUg g-1 dry weight, while total mercury concentrations in different soil types at the same locations within 0.055-0.350, 0.035-0.250, 0.031-0.240 and 0.071-0.475 MUg Hg g-1 of soil. The calculated mercury bioaccumulation factor ranged between 0.9 and 17.5. Mercury levels in soil and earthworms, as a tool for soil pollution assessment, suggested low mercury exposure and risks for human health in the monitored area. PMID- 26571044 TI - Effectiveness and safety of cyclosporine in pediatric plaque psoriasis: A multicentric retrospective analysis. AB - BACKGROUND: Cyclosporine (CysA) is effective for psoriasis in adult patients but little data exist about its efficacy and safety in childhood and adolescence psoriasis. OBJECTIVES: To assess the effectiveness and safety of CysA for childhood and adolescence psoriasis. METHODS: Retrospective analysis of a group of children and adolescents (age < 17 years) with plaque psoriasis treated with CysA at several Italian dermatology clinics. RESULTS: Our study population consisted of 38 patients. The median age at the start of treatment was 12.3 years. Therapy duration varied from one to 36 months. The median maintenance dosage per day was 3.2 mg/kg (range 2-5 mg/kg). Fifteen patients (39,4%) achieved a complete clearance or a good improvement of their psoriasis defined by an improvement from baseline of >=75% in the psoriasis area and severity index (PASI) at week 16. Eight patients (21.05%) discontinued the treatment due to laboratory anomalies or adverse events. Serious events were not recorded. CONCLUSIONS: In this case series, CysA was effective and well-tolerated treatment in a significant quote of children. CysA, when carefully monitored, may represent a therapeutic alternative to the currently used systemic immunosuppressive agents for severe childhood psoriasis. PMID- 26571045 TI - Structural specifics of light-induced metastable states in copper(II)-nitroxide molecular magnets. AB - Although light-induced magnetostructural switching in copper(II)-nitroxide molecular magnets Cu(hfac)2L(R) has been known for several years, structural characterization of metastable photoinduced states has not yet been accomplished due to significant technical demands. In this work we apply, for the first time, variable-temperature FTIR spectroscopy with photoexcitation to investigate the structural specifics of light-induced states in the Cu(hfac)2L(R) family represented by (i) Cu(hfac)2L(Me) comprising two-spin copper(II)-nitroxide clusters, and (ii) Cu(hfac)2L(Pr) comprising three-spin nitroxide-copper(II) nitroxide clusters. The light-induced state of Cu(hfac)2L(Me) manifests the same set of vibrational bands as the corresponding thermally-induced state, implying their similar structures. For the second compound Cu(hfac)2L(Pr), the coordination environment of copper(II) is similar in light- and thermally-induced states, but distinct differences are found for packing of the peripheral n-propyl substituent of nitroxide. Thus, generally the structures of the corresponding thermally- and light-induced states in molecular magnets Cu(hfac)2L(R) might differ, and FTIR spectroscopy provides a useful approach for revealing and elucidating such differences. PMID- 26571047 TI - Magnetic properties of C-N planar structures: d(0) ferromagnetism and half metallicity. AB - We investigate, from first principles calculations, the magnetic properties of planar carbon nitride structures with the lowest formation energies within twenty eight distinct stoichiometries and porosities. Surprisingly, we find that 3/4 of the low-energy carbon nitride structures present energetically favorable magnetic phases, and that more than 3/10 are ferromagnetic. This suggests that d(0) magnetism is a usual feature in this class of materials. Notably, within the energetically favorable ferromagnetic structures, we find that two structures have very high stabilization energies for ferromagnetic order, one having the highest predicted so far for this class of materials. We also find that several structures are half-metals, and one structure is half-zero-gap semiconductor (semicondutor in one spin channel, and graphene-like in the other channel). PMID- 26571048 TI - Sequential Multicomponent Reactions and a Cu-Mediated Rearrangement: Diastereoselective Synthesis of Tricyclic Ketones. AB - A novel Cu-mediated rearrangement reaction based on bisamides containing a thiazolidine substructure opens the possibility for diastereoselective synthesis toward a tricyclic annulated and bridged heterocyclic system. The required precursors are easily synthesizable by a two-step synthetic pathway using the concept of sequential multicomponent reactions, i.e. the Asinger and Ugi reactions. Due to this synthesis strategy, a number of unique tricyclic heterocycles, characterized by high diversity, are synthesized in an effective manner. PMID- 26571049 TI - Are Locked Plates Needed for Split Depression Tibial Plateau Fractures? AB - Displaced tibial plateau fractures often require surgical treatment and plate and screw constructs are the most common method of fixation. There has been increased usage of locking plate technology for both complex and simple fracture patterns without any evidence demonstrating their advantage. The purpose of this study was to compare the clinical use of locked versus nonlocked plating for repair of displaced Schatzker type-II (OTA Type 41B) tibial plateau fractures. Seventy seven consecutive patients treated operatively with one of two types of plate and screw constructs in a nonrandomized fashion for Schatzker type II tibial plateau fractures and they were prospectively followed over a 5-year period. A total of 35 (45.5%) patients were treated using a locked plate and screw construct and 42 (54.5%) patients were treated with a nonlocked plate and screw construct. All patients received the same pre- and postoperative care and there was no difference in plate morphology and length between cohorts. Clinical outcomes were assessed using Short Musculoskeletal Functional Assessment (SMFA) scores, Visual Analogue Score for pain, and knee ranges of motion. Radiographic outcome was assessed with plain radiographs at all follow-up points. Implant costs for both types of constructs were calculated from hospital purchasing records. Patients were assessed at a mean period of 18.5 months (range: 12-72 months). There was no difference in demographic factors, physical examination parameters, radiographic outcomes, and SMFA scores between cohorts. In terms of cost, the cost of locked construct was $905 more than the nonlocked construct. Based on clinical outcomes and cost per implant, we found no evidence to support the routine use of locked plating for simple split depression fractures of the lateral tibial plateau. The use of standard nonlocked, precontoured implants provides adequate fixation for these fracture patterns. PMID- 26571050 TI - Total Limb Rotation after Unilateral Total Knee Arthroplasty: Side-to-Side Discrepancy. AB - Total limb rotation, an important anatomical feature of the lower limb, is defined as any rotation of the lower limb on its longitudinal axis. The aim of the present study was to evaluate the discrepancies of rotational profiles of total limb between nonoperated and operated limb following unilateral total knee arthroplasty. We conducted an analysis of the computed tomography (CT) data from 32 patients undergoing primary unilateral total knee arthroplasty. Using these CT scan, rotational profiles of total limb, such as femoral neck anteversion angle expressed as femoral torsion angle (FTA), tibial torsion angle (TTA), knee joint rotation angle (KJRA), and total limb rotation (TLR) were measured. There were significant discrepancies of FTA and KJRA between operated and nonoperated limb following unilateral total knee arthroplasty. The mean difference of operated and nonoperated side for FTA and KJRA were -6.51 +/- 11.88 degrees (p = 0.0041) and 6.83 +/- 5.04 degrees (p < 0.001), respectively. However, there were no significant discrepancies of TLR, TTA. These results are due to the compensation effect of KJRA. However, excessive external rotation of the femoral component beyond the compensation effect of prosthetic knee joint can lead to a total limb rotational discrepancy in patient undergoing unilateral total knee arthroplasty. PMID- 26571046 TI - Re-membering the body: applications of computational neuroscience to the top-down control of regeneration of limbs and other complex organs. AB - A major goal of regenerative medicine and bioengineering is the regeneration of complex organs, such as limbs, and the capability to create artificial constructs (so-called biobots) with defined morphologies and robust self-repair capabilities. Developmental biology presents remarkable examples of systems that self-assemble and regenerate complex structures toward their correct shape despite significant perturbations. A fundamental challenge is to translate progress in molecular genetics into control of large-scale organismal anatomy, and the field is still searching for an appropriate theoretical paradigm for facilitating control of pattern homeostasis. However, computational neuroscience provides many examples in which cell networks - brains - store memories (e.g., of geometric configurations, rules, and patterns) and coordinate their activity towards proximal and distant goals. In this Perspective, we propose that programming large-scale morphogenesis requires exploiting the information processing by which cellular structures work toward specific shapes. In non neural cells, as in the brain, bioelectric signaling implements information processing, decision-making, and memory in regulating pattern and its remodeling. Thus, approaches used in computational neuroscience to understand goal-seeking neural systems offer a toolbox of techniques to model and control regenerative pattern formation. Here, we review recent data on developmental bioelectricity as a regulator of patterning, and propose that target morphology could be encoded within tissues as a kind of memory, using the same molecular mechanisms and algorithms so successfully exploited by the brain. We highlight the next steps of an unconventional research program, which may allow top-down control of growth and form for numerous applications in regenerative medicine and synthetic bioengineering. PMID- 26571051 TI - Time-resolved neuroimaging of visual short term memory consolidation by post perceptual attention shifts. AB - Post-perceptual cues can enhance visual short term memory encoding even after the offset of the visual stimulus. However, both the mechanisms by which the sensory stimulus characteristics are buffered as well as the mechanisms by which post perceptual selective attention enhances short term memory encoding remain unclear. We analyzed late post-perceptual event-related potentials (ERPs) in visual change detection tasks (100ms stimulus duration) by high-resolution ERP analysis to elucidate these mechanisms. The effects of early and late auditory post-cues (300ms or 850ms after visual stimulus onset) as well as the effects of a visual interference stimulus were examined in 27 healthy right-handed adults. Focusing attention with post-perceptual cues at both latencies significantly improved memory performance, i.e. sensory stimulus characteristics were available for up to 850ms after stimulus presentation. Passive watching of the visual stimuli without auditory cue presentation evoked a slow negative wave (N700) over occipito-temporal visual areas. N700 was strongly reduced by a visual interference stimulus which impeded memory maintenance. In contrast, contralateral delay activity (CDA) still developed in this condition after the application of auditory post-cues and was thereby dissociated from N700. CDA and N700 seem to represent two different processes involved in short term memory encoding. While N700 could reflect visual post processing by automatic attention attraction, CDA may reflect the top-down process of searching selectively for the required information through post-perceptual attention. PMID- 26571052 TI - Impact and relevance of the journal: Publishing in English and large number of unique visits. PMID- 26571053 TI - Schema Therapy in Sex Therapy: A Theoretical Conceptualization. AB - Schema therapy is an integrative approach of psychotherapy developed by Jeffrey E. Young. Its aim is to help clients explore and understand their deep emotional needs and meet them in a healthy manner. It is suitable for complex pathologies, such as comorbidities and personality disorders. In sex therapy, schema therapy can serve as a method for a deep, evidence-based, integrative conceptualization of a client's difficulties and needs. However, its principles have never been demonstrated in sex therapy. In this paper, we briefly review schema therapy and introduce schema domains. We bring a case study of a couple undergoing sex therapy from the cognitive-behavioral perspective. We then return to the same case study, in order to demonstrate the usefulness of a schema therapy conceptualization. PMID- 26571054 TI - Can Peripheral Bronchopleural Fistula Demonstrated on Computed Tomography be Treated Conservatively? A Retrospective Analysis. AB - PURPOSE: Peripheral bronchopleural fistulas (BPF) are communications between a peripheral bronchus or the lung parenchyma and the pleural space. Although reported cases with peripheral BPF might have typical symptoms, we postulate that there may be BPF patients without typical symptoms who are diagnosed on computed tomography (CT) for the first time. MATERIALS AND METHODS: We searched retrospectively for how frequently BPF is found on CT in cases with known or suspected empyema or hydropneumothorax. Also, we examined the clinical charts to ascertain if a diagnosis of BPF was suspected in the CT reports or clinically, and to determine the outcome of each case. RESULTS: Thirteen thoracic cavities of 12 patients were included in this study. Of these, BPF was suspected clinically in only 1. Mention in the CT report about the presence of BPF was found in 2 cases. An apparent finding of BPF on CT was found in 7 of 13 (53%) thoracic cavities of 6 cases. The outcomes were that 1 patient died 1 month later due to multiple organ failure, and 1 patient was discharged subsequently after CT. In the other 10 cases, there was no exacerbation of the symptom regardless of definite evidence of BPF on CT. CONCLUSIONS: In conclusion, when there is hydropneumothorax on CT, it is important for radiologists to diligently search for findings of peripheral BPF and to document it. However, a reference about the need for a surgical approach for BPF may not be required. PMID- 26571055 TI - Magnetic Resonance Imaging Findings in Kallmann Syndrome: 14 Cases and Review of the Literature. AB - PURPOSE: We sought to characterize the magnetic resonance imaging (MRI) findings in patients with Kallmann syndrome (KS). MATERIALS AND METHODS: Fourteen patients with KS and a comparison group of 20 matched people with normal MRI were analyzed with optimized voxel-based morphometry. Coronal T1- and T2-weighted images from the anterior margin of the frontal sinus to the hypothalamus were obtained. The olfactory sulci, bulbs, and bundles were assessed as normal, hypoplastic, or absent. The pituitary gland was also evaluated. RESULTS: Four of the 14 patients came from 1 family. Ten patients had low levels of GnRH and gonadal hormone, 11 had hyposmia, and 3 had anosmia. On MRI, the olfactory bulbs (OBs) and bundles were absent bilaterally in 8 patients. Two patients exhibited absence of the OBs and bundles on the left and hypoplasia on the right. Four patients displayed bilateral hypoplastic OBs and bundles. The olfactory sulci were absent in 5 and hypoplastic in 9 of these patients. The anterior pituitary was hypoplastic in 6 patients. CONCLUSIONS: Kallmann syndrome has distinctive features on MRI. Magnetic resonance imaging may aid in the diagnosis of KS in patients with ambiguous clinical findings. PMID- 26571056 TI - Do Left- and Right-Handed People Have Similar Iron Deposition in the Basal Ganglia? AB - OBJECTIVES: This study aimed to investigate whether right-, left-, or mixed handed people differ in terms of iron deposition using susceptibility weighted imaging in healthy subjects. MATERIALS AND METHODS: A total of 87 people (right handed, 51 subjects; left-handed, 19 subjects; mixed-handed, 17 subjects) aged 20 to 40 years participated. All underwent magnetic resonance examination, including conventional and susceptibility weighted imaging sequences. Phase images were used to quantify iron deposition in the head of the caudate nucleus and lenticular nucleus. The radian angle value was calculated and compared between the 3 (right-, left-, or mixed-handed) groups. RESULTS: There was no significant difference in the radian angle values between left-, right-, or mixed-handed people for either the right or left side of the caudate nucleus head. However, the amount of iron deposition in the left lenticular nucleus was significantly higher for right-handed than for the left-handed subjects (P < 0.001) and significantly higher for mixed-handed than for left-handed subjects (P = 0.006). In addition, the amount of iron deposition in the right lenticular nucleus was significantly lower for left-handed than for right-handed subjects (P < 0.001). CONCLUSIONS: The results revealed no significant differences in iron deposition in the head of the caudate nucleus. However, there was a significant difference in iron deposition in the lenticular nucleus between left- and right-handed subjects and between left- and mixed-handed subjects. PMID- 26571057 TI - Optimal Contrast of Cerebral Dual-Energy Computed Tomography Angiography in Patients With Spontaneous Subarachnoid Hemorrhage. AB - OBJECTIVE: The aim of this study was to investigate the image quality of cerebral dual-energy computed tomography (CT) angiography using a nonlinear image blending technique as compared with the conventional linear blending method in patients with spontaneous subarachnoid hemorrhage (SAH). METHODS: A retrospective review of 30 consecutive spontaneous SAH patients who underwent a dual-source, dual energy (80 kV and Sn140 kV mode) cerebral CT angiography was performed with permission from hospital ethical committee. Optimized images using nonlinear blending method were generated and compared with the 0.6 linear blending images by evaluating cerebral artery enhancement, attenuation of SAH, image noise, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR), respectively. Two neuroradiologists independently assessed subjective vessel visualization per segment using a 5-point scale. RESULTS: The nonlinear blending images showed higher cerebral artery enhancement (307.24 +/- 58.04 Hounsfield unit [HU]), lower attenuation of SAH (67.07 +/- 6.79 HU), and image noise (7.18 +/- 1.20 HU), thus achieving better SNR (43.92 +/- 11.14) and CNR (34.34 +/- 10.25), compared with those of linear blending images (235.47 +/- 46.45 HU for cerebral artery enhancement, 70.00 +/- 6.41 HU for attenuation of SAH, 8.39 +/- 1.25 HU for image noise, 28.86 +/- 8.43 for SNR, and 20.37 +/- 7.74 for CNR) (all P < 0.01). The segmental scorings of the nonlinear blending image (31.6% segments with a score of 5, 57.4% segments with a score of 4, 11% segments with a score of 3) ranged significantly higher than those of linear blending images (11.5% segments with a score of 5, 77.5% segments with a score of 4, 11% segments with a score of 3) (P < 0.01). The interobserver agreement was good (kappa = 0.762), and intraobserver agreement was excellent for both observers (kappa = 0.844 and 0.858, respectively). CONCLUSIONS: The nonlinear image blending technique improved vessel visualization of cerebral dual-energy CT angiography by optimizing contrast enhancement in spontaneous SAH patients. PMID- 26571058 TI - Association of Gluteus Medius and Minimus Muscle Atrophy and Fall-Related Hip Fracture in Older Individuals Using Computed Tomography. AB - PURPOSE: The aim of this study was to determine an association between fall related hip and/or pelvic fractures and gluteus medius and minimus atrophy. METHODS: Retrospective review of 64 patients with fall-related hip/pelvic fractures and 96 age- and sex-stratified controls was performed. Gluteus medius, gluteus minimus, tensor fascia lata, and iliopsoas atrophy was scored using a standard scale. Statistical analysis was performed. RESULTS: There is a significant difference (P < 0.0001) in gluteus medius and minimus atrophy in the fracture versus control groups. Presence of gluteus atrophy was predictive of fall-related fracture (odds ratio, 2.15; 95% confidence interval, 1.08-4.31). There is no significant difference in tensor fascia lata (P = 0.47) or iliopsoas (P = 0.15) atrophy between the 2 groups. Gluteus atrophy increased with age (r = 0.41, P < 0.0001). In unilateral fractures, there is a significant difference (P = 0.0002) in ipsilateral versus contralateral gluteus medius atrophy. CONCLUSIONS: Gluteus medius and minimus muscle atrophy is greater in fall-related hip/pelvic fractures, which may predispose the elderly to falls. PMID- 26571059 TI - Effect of Low-Osmolar Intravenous Contrast on Renal Length. AB - OBJECTIVE: The purpose was to study the effect of low-osmolar nonionic contrast on renal length. MATERIAL AND METHODS: This study included 56 patients (4-phase renal computed tomography [CT] and 4-phase CT urogram [CTU], 19 patients each; split-phase CTU, 18 patients). Three radiologists created the best off-axis plane and renal lengths measured on a postprocessing workstation. Two-way analysis of variance with Bonferroni corrections was performed along with single-sample t tests. RESULTS: Four-phase renal CT and CTU average differences from unenhanced phases were 0.30/0.16 mm (corticomedullary), 0.88/1.33 mm (nephrographic), and 2.17/2.22 mm (delayed). The nephrographic and delayed phases were significantly different from their unenhanced phase (P < 0.01). Nonsignificant differences between the corticomedullary phase and the unenhanced phase were observed (P = 0.217, 4-phase renal CT; P = 0.232, 4-phase CTU). The split-phase CTU average difference in the enhanced phase was 1.36 mm (P < 0.001). CONCLUSION: Renal length increases 1 to 2 mm with low-osmolar nonionic contrast. PMID- 26571060 TI - Dural Thickening of the Internal Auditory Canal in Patients With Spontaneous Intracranial Hypotension Syndrome. AB - OBJECTIVE: This study aimed to assess the utility of dural thickening of the internal auditory canal (IAC) in patients with spontaneous intracranial hypotension (SIH) syndrome and determined the sensitivity and specificity of this image finding. METHODS: Magnetic resonance images were evaluated for 22 cases of definite SIH and 16 cases of unlikely SIH. On contrast-enhanced magnetic resonance imaging, pachymeningeal enhancement and dural thickening of the IAC were assessed. RESULTS: Pachymeningeal enhancement was observed in 21 of 22 patients in the definite SIH group and 1 of 16 patients in the unlikely SIH group (sensitivity, 95.5%; specificity, 93.8%). Dural thickening of the IAC was observed in 15 of 22 patients in the definite SIH group and 0 of 16 patients in the unlikely SIH group (sensitivity, 68.2%; specificity, 100%). CONCLUSIONS: Dural thickening of the IAC showed 100% specificity for SIH syndrome and can increase the accuracy of diagnosis of SIH syndrome. PMID- 26571061 TI - High-Resolution Computed Tomography in the Diagnosis of Diffuse Parenchymal Lung Diseases: Is it Possible to Improve Radiologist's Performance? AB - OBJECTIVE: The aims of this study were to assess the concordance between high resolution computed tomography (HRCT) diagnostic hypotheses (DH) and final diagnosis in patients with diffuse lung disease and to evaluate whether clinical data or the radiologist's degree of certainty influence concordance. METHODS: Concordances between first and any one of radiologists' DH and final diagnosis were assessed before and after access to clinical data, with study of importance of degree of certainty in the DH formulated. RESULTS: Concordances of HRCT DH and final diagnosis were 48% and 76%, respectively, considering first or any of the DH without access to clinical data. Accessing clinical data improved concordance especially for hypersensitivity pneumonitis. Diagnostic hypotheses formulated with high degree of confidence were correct in 69% of cases. CONCLUSIONS: First HRCT DH was concordant with final diagnosis in approximately half of cases, increasing to approximately 75% when considering any 1 of the 3 DH. Radiologists' knowledge of clinical data or increased degree of certainty improved concordance of HRCT DH and the final diagnosis. PMID- 26571062 TI - Leukocytes Enhance Inflammatory and Catabolic Degenerative Changes in the Intervertebral Disc After Endplate Fracture In Vitro Without Infiltrating the Disc. AB - STUDY DESIGN: An established rabbit intervertebral disc (IVD)/endplate explant fracture model was extended with physiologic post-traumatic dynamic loading (PTDL) and coculturing of peripheral blood mononuclear cells (PBMCs). OBJECTIVE: The aim of this study was to quantify the effects of PTDL and of cocultured PBMCs on post-traumatic disc degeneration (DD) and to determine whether PTDL facilitates homing of PBMC to fractured IVD/endplates. SUMMARY OF BACKGROUND DATA: DD is associated with endplate fracture. In vivo studies suggest a key role of immune cells in the pathogenesis of DD. However, the complexity of in vivo systems impedes the investigation of single factors governing the pathogenesis. METHODS: Seventy-two IVD/endplate specimens were divided into 4 groups. In group A, endplate fractures were induced with a high-velocity axial load and exposed to PTDL in coculture with PBMCs for 14 days. Group A was compared with 3 control groups, with single-factor removal, in order to assess the relative contribution of PTDL (group B), PBMCs (group C), and endplate fracture (group D) to the biological response of the IVD. Disc gene transcription and serum nitric oxide (NO) serum concentration were measured to investigate differences in anabolism, catabolism, and inflammatory response between the groups. Changes in matrix composition and disc structure were assessed histologically. RESULTS: PBMCs did not home to fractured IVDs, with or without PTDL. Group A compared with group D showed an enhanced transcription of anabolic, catabolic, and pro-inflammatory genes during the entire experiment, and an increased NO concentration for the first 3 days. Changes typical for DD were also found in histological sections. Group A compared with group C showed significant increases in catabolic and pro inflammatory gene transcription after at least 7 days. No differences were found between groups A and B. CONCLUSION: Trauma induces degenerative changes; PTDL neither aggravates nor ameliorates this response. Although PBMCs do not infiltrate the disc, they aggravate the degenerative changes. LEVEL OF EVIDENCE: N/A. PMID- 26571063 TI - An Updated Meta-Analysis Comparing Artificial Cervical Disc Arthroplasty (CDA) Versus Anterior Cervical Discectomy and Fusion (ACDF) for the Treatment of Cervical Degenerative Disc Disease (CDDD). AB - STUDY DESIGN: A meta-analysis of published randomized controlled Trials (RCTs). OBJECTIVE: The aim of this study was to compare the efficacy and safety of cervical disc arthroplasty (CDA) with anterior cervical discectomy and fusion (ACDF) for the treatment of one-level cervical degenerative disc disease (CDDD). SUMMARY OF BACKGROUND DATA: ACDF has been widely performed for the treatment of CDDD. However, the loss of motion at the operated level has been hypothesized to accelerated adjacent-level disc degeneration. CDA is designed to avoid the side effect of fusion. However, it is still uncertain whether CDA is more effective and safer than ACDF. METHODS: We performed a meta-analysis of published RCTs to examine whether there was a superior clinical effects of CDA than ACDF. A PubMed database search through October 2014 was performed for relevant studies. We included RCTs that reported relevant data in the treatment of one-level CDDD, which were suitable for detailed extraction of data. RESULTS: We identified 18 RCTs eligible for analysis. The results of the meta-analysis indicated longer operative times, more blood loss, lower neck and arm pain scores reported on a visual analog scale (VAS), better neurological success, greater motion at the operated level, fewer secondary surgical procedures in the CDA group than in the ACDF group (P < 0.05). The 2 groups had similar lengths of hospital stay, Neck Disability Index scores, and rates of adverse events (P > 0.05). CONCLUSIONS: Findings of the present meta-analysis indicated that CDA was an effective and safe surgical procedure for the treatment of one-level CDDD, and CDA was found to be more superior than ACDF in terms of VAS neck and arm pain, neurological success, range of motion at the operated level, and secondary surgical procedures. LEVEL OF EVIDENCE: 1. PMID- 26571064 TI - "Lovely Pie in the Sky Plans": A Qualitative Study of Clinicians' Perspectives on Guidelines for Managing Low Back Pain in Primary Care in England. AB - STUDY DESIGN: A qualitative study in south-west England primary care. OBJECTIVE: To clarify the decision-making processes that result in the delivery of particular treatments to patients with low back pain (LBP) in primary care and to examine clinicians' perspectives on the English National Institute for Health and Care Excellence (NICE) clinical guidelines for managing LBP in primary care. SUMMARY OF BACKGROUND DATA: Merely publishing clinical guidelines is known to be insufficient to ensure their implementation. Gaining an in-depth understanding of clinicians' perspectives on specific clinical guidelines can suggest ways to improve the relevance of guidelines for clinical practice. METHODS: We conducted semi-structured interviews with 53 purposively sampled clinicians. Participants were 16 general practitioners (GPs), 10 chiropractors, 8 acupuncturists, 8 physiotherapists, 7 osteopaths, and 4 nurses, from the public sector (20), private sector (21), or both (12). We used thematic analysis. RESULTS: Official guidelines comprised just 1 of many inputs to clinical decision-making. Clinicians drew on personal experience and inter-professional networks and were constrained by organizational factors when deciding which treatment to prescribe, refer for, or deliver to an individual patient with LBP. Some found the guideline terminology-"non-specific LBP"-unfamiliar and of limited relevance to practice. They were frustrated by disparities between recommendations in the guidelines and the real-world situation of short consultation times, difficult-to-access specialist services, and sparse commissioning of guideline-recommended treatments. CONCLUSION: The NICE guidelines for managing LBP in primary care are one, relatively peripheral, influence on clinical decision-making among GPs, chiropractors, acupuncturists, physiotherapists, osteopaths, and nurses. When revised, these guidelines could be made more clinically relevant by: ensuring that guideline terminology reflects clinical practice terminology; dispelling the image of guidelines as rigid and prohibiting patient-centered care; providing opportunities for clinicians to engage in experiential learning about guideline recommended complementary therapies; and commissioning guideline-recommended treatments for public sector patients. LEVEL OF EVIDENCE: N/A. PMID- 26571065 TI - Online Curves: A Quality Analysis of Scoliosis Videos on YouTube. AB - STUDY DESIGN: A cross-sectional study. OBJECTIVE: The aim of this study was to evaluate the quality of online scoliosis information available on the video sharing site YouTube. SUMMARY OF BACKGROUND DATA: The Internet is an increasingly utilized resource for accessing information about a variety of heath conditions. YouTube is a video sharing platform used to both seek and distribute information. METHODS: A search for "scoliosis" was carried out using YouTube's search engine and data were collected on the first 50 videos returned. A JAMA score to determine currency, authorship, source and disclosure, and scoliosis-specific score that measures the amount of information on the diagnosis and treatment options (as devised by Mathur et al in 2005; scored 0-32) was recorded for each video to measure quality objectively. In addition, the number of views, number of comments, and feedback positivity was documented for each. Data analysis was conducted using R 3.1.4/R Studio 0.98 with control for the age of each video in analysis models. RESULTS: The average number of views per video was 71,152 with an average length of 7 minutes 32 seconds. Thirty-six percent of the videos fell under the authorship category of personal experience. The average JAMA score was 1.32/4 and average scoliosis specific score was 5.38/32. There was a positive correlation between JAMA score and number of views (P = 0.003). However, in contrast, there was a negative correlation between scoliosis-specific score and number of views (P = 0.01). CONCLUSIONS: Online health information has historically been poor and our study shows that in an environment like YouTube that lacks a peer review process, the quality of scoliosis information is low. Further work is needed to determine whether accessing information on YouTube can play a role in patient care other than simple education pertaining to the disease and its management. LEVEL OF EVIDENCE: 3. PMID- 26571067 TI - A novel initiation codon mutation of PAX9 in a family with oligodontia. AB - OBJECTIVE: Recent studies have attributed non-syndromic tooth agenesis to mutations in several genes, including MSX1, PAX9, AXIN2, WNT10A and EDA. In this study, mutation of PAX9gene was investigated in a four-generation Chinese family with oligodontia. DESIGN: Genomic DNA was isolated from the blood samples of all the available family members. Candidate genes MSX1 and PAX9 were amplified using polymerase chain reaction and then directly sequenced. RESULTS: A novel initiation codon mutation was identified; it consisted of a heterozygous c.2T>G mutation in the PAX9 gene which changed the ATG initiation codon to AGG. Restriction-enzyme analysis was performed to verify this mutation, which was segregated amongst the members with the oligodontia phenotype. CONCLUSIONS: Our results demonstrate a new initiation codon mutation in the PAX9 gene. This mutation probably caused the oligodontia in the investigated Chinese family through haplo-insufficiency. PMID- 26571068 TI - The impact of indoor residual spraying of deltamethrin on dengue vector populations in the Peruvian Amazon. AB - Dengue is an important public health problem in the Amazon area of Peru, resulting in significant morbidity each year. As in other areas of the world, ultra-low volume (ULV) application of insecticides is the main strategy to reduce adult populations of the dengue vector Aedes aegypti, despite growing evidence of its limitations as a single control method. This study investigated the efficacy of deltamethrin S.C. applied through indoor residual spraying (IRS) of dwellings in reducing A. aegypti populations. The residual effect of the insecticide was tested by monthly bioassays on the three most common indoor surfaces found in the Amazon area: painted wood, unpainted wood and brick. The results showed that in an area with moderate levels of A. aegypti infestation, IRS dramatically reduced all immature indices the first week after deltamethrin IRS application and the adult index from 18.5 to 3.1, four weeks after intervention (p<0.05). Even though housing conditions facilitated reinfestation with A. aegypti (100% of the houses have open roof eaves, 31.5% lack sewage systems, and 60.4% collected rain in open containers), indices remained low compared to baseline 16 weeks after insecticide application. Bioassays showed that deltamethrin S.C. caused mortalities >80% 8 weeks after application on all types of surfaces. The residual effect of the insecticide was greater on brick than on wooden walls (p<0.05). Our results demonstrate that IRS can have both an immediate and sustained effect on reducing adult and immature A. aegypti populations and should be considered as an adult mosquito control strategy by dengue vector control programs. PMID- 26571066 TI - Sofosbuvir and Velpatasvir for HCV Genotype 1, 2, 4, 5, and 6 Infection. AB - BACKGROUND: A simple treatment regimen that is effective in a broad range of patients who are chronically infected with the hepatitis C virus (HCV) remains an unmet medical need. METHODS: We conducted a phase 3, double-blind, placebo controlled study involving untreated and previously treated patients with chronic HCV genotype 1, 2, 4, 5, or 6 infection, including those with compensated cirrhosis. Patients with HCV genotype 1, 2, 4, or 6 were randomly assigned in a 5:1 ratio to receive the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir in a once-daily, fixed-dose combination tablet or matching placebo for 12 weeks. Because of the low prevalence of genotype 5 in the study regions, patients with genotype 5 did not undergo randomization but were assigned to the sofosbuvir-velpatasvir group. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. RESULTS: Of the 624 patients who received treatment with sofosbuvir-velpatasvir, 34% had HCV genotype 1a, 19% genotype 1b, 17% genotype 2, 19% genotype 4, 6% genotype 5, and 7% genotype 6. A total of 8% of patients were black, 19% had cirrhosis, and 32% had been previously treated for HCV. The rate of sustained virologic response among patients receiving sofosbuvir-velpatasvir was 99% (95% confidence interval, 98 to >99). Two patients receiving sofosbuvir-velpatasvir, both with HCV genotype 1, had a virologic relapse. None of the 116 patients receiving placebo had a sustained virologic response. Serious adverse events were reported in 15 patients (2%) in the sofosbuvir-velpatasvir group and none in the placebo group. CONCLUSIONS: Once-daily sofosbuvir-velpatasvir for 12 weeks provided high rates of sustained virologic response among both previously treated and untreated patients infected with HCV genotype 1, 2, 4, 5, or 6, including those with compensated cirrhosis. (Funded by Gilead Sciences; ClinicalTrials.gov number, NCT02201940.). PMID- 26571069 TI - The role of GlcNAc-PI-de-N-acetylase gene by gene knockout through homologous recombination and its consequences on survival, growth and infectivity of Leishmania major in in vitro and in vivo conditions. AB - At present, there are no efficacious vaccines or effective drugs against leishmaniasis; therefore new and innovative control methods are urgently required. One way to achieve this important goal is through using reverse genetic engineering to evaluate important enzymes, proteins and macromolecules. One of the most important enzymes for Glycosylphosphatidylinositol (GPI) biosynthetic pathways is GlcNAc-PI-de-N-acetylase (GPI12). The molecular constructs were cloned in Escherichia coli strain Top 10 and confirmed by molecular methods and were transfected by electroporation into Leishmania major. We demonstrated that two alleles of the GPI12 gene in L. major were successfully removed and enabling the generation of a null mutant, which supports the idea that GPI12 is not an essential gene for the growth and survival of Leishmania and the homozygous knockouts of Leishmania are able to survive. We were able to produce a mutant parasite that caused no damaged to the host. Further investigations are essential to check the safety profile in laboratory animals. PMID- 26571070 TI - Transcriptome profiling of the cysticercus stage of the laboratory model Taenia crassiceps, strain ORF. AB - Neurocysticercosis (NC) is a serious public health problem mainly in developing countries. NC caused by the cysticercus stage from cestode Taenia solium is considered by the WHO and ITFDE as a potentially eradicable disease. Definitive diagnosis of NC is challenging because of the unspecific clinical manifestations such as the non-definitive evidence presented by neuroimaging (in most cases) and the lack of definitive serological test. Taenia crassiceps (ORF strain) is a cestode closely related to T. solium and it has frequently been used as a source of antigens for immunodiagnostics. A murine model to study host immune response to infection has also been established by using T. crassiceps. Despite the extensive use of T. crassiceps for research, molecular information for this cestode is scarce in public databases. With the aim of providing more extensive information on T. crassiceps biology, an RNA-seq experiment and subsequent bioinformatic transcriptome processing of this cestode parasite mRNA in its cysticercus stage were carried out. A total of 227,082 read/ESTs were sequenced using the 454-GS FLX Titanium technology and assembled into 10,787 contigs. This transcriptome dataset represents new and valuable molecular information of the cestode T. crassiceps (ORF). This information will substantially improve public information and will help to achieve a better understanding of the biology of T. crassiceps and to identify target proteins for serodiagnosis and vaccination. PMID- 26571071 TI - Toxocariasis-associated cardiac diseases--A systematic review of the literature. AB - Toxocariasis, caused by Toxocara canis or Toxocara catis, is a worldwide occurring parasitic disease, reaching high prevalences especially in tropical and subtropical countries. The clinical presentation can range from asymptomatic seropositivity to life threatenting disease, depending on the organ system involved. Cardiac involvement, one of the possible manifestations of human Toxocara spp. infection, is rarely reported in case reports. As far as we know, no systematic reviews of clinical presentations have been published till now and no clear recommendations regarding the treatment of Toxocara spp. infection involving the heart exist. In a systematic review of the literature, 24 published cases of Toxocara spp. infection involving the heart were identified. The cardiac entities described included myocarditis, pericarditis, and Loeffler's endocarditis. The clinical presentation ranged from asymptomatic or mild disease to life threatening myocarditis/pericarditis with heart failure or cardiac tamponade, leading to death. In most cases, the diagnosis was based on a combination of clinical, laboratory and radiological findings. Only in three of the nine cases in which histological analysis was performed (either pre- or post mortem), granulomas or remnants of the parasite were detected. In the other six cases, findings were non-specific; the damage of the heart was equally caused by direct invasion of the larvae and by immunological reactions, either caused by the systemic hypereosinophilia or by the presence of the larvae in the tissue. The treatment regimen described mostly consisted of anthelmintic drugs in combination with corticosteroids. Even though dosage and duration of treatment varied widely, ranging from days to months, most patients were treated successfully. Cardiac involvement in Toxocara spp. infection is a rare but potentially life-threatening complication of a very common disease. The therapeutic regimens vary widely especially with regard to the duration of therapy, however, the combination of an anthelmintic drug and a corticosteroid appears to be a valuable option. For the daily clinical work, tissue manifestation by parasites should be considered in cases of unspecific organ manifestations, (i.e. heart, lungs, liver), accompanied by fever and eosinophilia with or without allergic skin rashes. PMID- 26571072 TI - A disembodied man: A case of somatopsychic depersonalization in schizotypal disorder. AB - In the general concept of self-disturbances in schizophrenia and schizophrenia spectrum disorders, somatopsychic depersonalization (SPD) occupies a special place as it constitutes a syndrome that comprises feelings of detachment from one's own body and mental processes. However, apart from clinical descriptions, to date the pathophysiology of SPD is not fully understood due to the rareness of the syndrome and a lack of experimental studies. In a case study of one patient with schizotypal disorder, we applied a multimodal approach to understanding the SPD phenomena. The patient's clinical profile was identified as disruption of implicit bodily function, accompanied by depressive symptoms. On a neuropsychological level, the patient exhibited impairment in executive functioning, intact tactile perception and kinesthetic praxis. Behavioral tests revealed an altered sense of time but unimpaired self-agency. Furthermore, the patient exhibited a lack of empathy and he had autistic traits, although with a sufficient ability to verbalize his feelings. On the neurobiological level using an active and passive touch paradigm during functional magnetic resonance imaging (fMRI), we found a hyperconnectivity of the default-mode network and salience network and a hypoconnectivity of the central executive brain networks in the performance of the touch task as well as intact perceptual touch processing emerging from the direct comparisons of the touch conditions. Our data provide evidence for the important role of altered large-brain network functioning in SPD that corresponds to the specific behavioral and neurocognitive phenomena. PMID- 26571073 TI - The temporal characteristics of seizures in neonatal hypoxic ischemic encephalopathy treated with hypothermia. AB - PURPOSE: The characteristics of electrographic seizures in newborns with hypoxic ischaemic encephalopathy (HIE) treated with therapeutic hypothermia (TH) are poorly described. This retrospective, observational study provides reference data on the characteristics of seizures and their evolution over time in newborns with HIE receiving whole-body TH. METHOD: The cohort under analysis included 23 infants with HIE and seizures defined by multi-channel EEG recordings. Clinical presentation, details of TH and antiepileptic drugs used were recorded. Time from first to last-recorded electrographic seizure (seizure period) was calculated. Temporal characteristics of seizures - total burden, duration, number, burden in minutes per hour, distribution of burden over time (temporal evolution), time from seizure onset to maximum seizure burden (Tmsb), T1, and time from Tmsb to seizure offset, T2 - were analysed. RESULTS: The median age at electrographic seizure onset was 13.1h (IQR: 11.4 to 22.0). Tmsb was reached at a median age of 19.4 hours (IQR: 12.2 to 29.7). Median seizure period was 16.5h (IQR: 7.0 to 49.7), median number of seizures per hour was 1.9 (IQR: 1.0 to 3.3). The seizure burden was 4.0 min/h (IQR: 2.0 to 7.0). There was no consistent pattern in the temporal evolution of seizures in neonates treated with TH. The skewness was neither positive nor negative (p-value=0.15), there was no difference between the duration of T1 and T2 (p-value=0.09) and no difference in the seizure burden between T1 and T2 (p=0.09). There was an association between Tmsb and Phenobarbital (PB) administration (r=0.76, p-value<0.001). CONCLUSION: There is no consistent temporal evolution of seizure burden in neonates treated with TH. Seizures are diffuse, and their characteristics are variable. PMID- 26571074 TI - The journey of integrins and partners in a complex interactions landscape studied by super-resolution microscopy and single protein tracking. AB - Cells adjust their adhesive and cytoskeletal organizations according to changes in the biochemical and physical nature of their surroundings. In return, by adhering and generating forces on the extracellular matrix (ECM) cells organize their microenvironment. Integrin-dependent focal adhesions (FAs) are the converging zones integrating biochemical and biomechanical signals arising from the ECM and the actin cytoskeleton. Thus, integrin-mediated adhesion and mechanotransduction, the conversion of mechanical forces into biochemical signals, are involved in critical cellular functions such as migration, proliferation and differentiation, and their deregulation contributes to pathologies including cancer. A challenging problem is to decipher how stochastic protein movements and interactions lead to formation of dynamic architecture such as integrin-dependent adhesive structures. In this review, we will describe recent advances made possible by super-resolution microscopies and single molecule tracking approaches that provided new understanding on the organization and the dynamics of integrins and intracellular regulators at the nanoscale in living cells. PMID- 26571075 TI - Lipid droplets and associated proteins in sebocytes. AB - Mammalian skin is characterized by the presence of sebaceous glands (SGs), which develop with the hair follicle and whose predominant cell type is the sebocyte. Sebocytes are epithelial cells that progressively accumulate lipids and eventually release their content (sebum) by holocrine secretion as cells disrupt. In addition to thermoregulatory and pheromonal actions, numerous additional functions have been demonstrated or postulated for sebum, including antimicrobial and antioxidant activities. The SG has also been involved in the pathogenesis of skin diseases as acne vulgaris and some forms of alopecia. Although lipid accumulation culminating in cell disruption and content release is the hallmark of sebocyte differentiation, only a surprisingly low number of studies have so far focused on sebocyte lipid droplets and their associated proteins. PMID- 26571076 TI - Novel Amino-pyrazole Ureas with Potent In Vitro and In Vivo Antileishmanial Activity. AB - Visceral leishmaniasis is a severe parasitic disease that is one of the most neglected tropical diseases. Treatment options are limited, and there is an urgent need for new therapeutic agents. Following an HTS campaign and hit optimization, a novel series of amino-pyrazole ureas has been identified with potent in vitro antileishmanial activity. Furthermore, compound 26 shows high levels of in vivo efficacy (>90%) against Leishmania infantum, thus demonstrating proof of concept for this series. PMID- 26571077 TI - When bad moods may not be so bad: Valuing negative affect is associated with weakened affect-health links. AB - Bad moods are considered "bad" not only because they may be aversive experiences in and of themselves, but also because they are associated with poorer psychosocial functioning and health. We propose that people differ in their negative affect valuation (NAV; the extent to which negative affective states are valued as pleasant, useful/helpful, appropriate, and meaningful experiences) and that affect-health links are moderated by NAV. These predictions were tested in a life span sample of 365 participants ranging from 14-88 years of age using reports of momentary negative affect and physical well-being (via experience sampling) and assessments of NAV and psychosocial and physical functioning (via computer-assisted personal interviews and behavioral measures of hand grip strength). Our study demonstrated that the more individuals valued negative affect, the less pronounced (and sometimes even nonexistent) were the associations between everyday experiences of negative affect and a variety of indicators of poorer psychosocial functioning (i.e., emotional health problems, social integration) and physical health (i.e., number of health conditions, health complaints, hand grip strength, momentary physical well-being). Exploratory analyses revealed that valuing positive affect was not associated with the analogous moderating effects as NAV. These findings suggest that it may be particularly important to consider NAV in models of affect-health links. PMID- 26571078 TI - Anxiety, emotional distraction, and attentional control in the Stroop task. AB - Using a Stroop task, we investigated the effect of task-irrelevant emotional distractors on attentional proactive control and its interaction with trait anxiety. On the basis of recent findings showing opposed neural responses in the dorsal-executive versus the ventral-emotional systems in response to emotional distractors and of the attentional control theory (Eysenck, Derakshan, Santos, & Calvo, 2007), we hypothesized that negative distractors will result in a reduction of proactive task control in the executive system, especially for high trait-anxious individuals. Using a computational model of the Stroop task, we derive 2 specific behavioral predictions of reduced proactive task control: increased Stroop interference and reversed Stroop facilitation. Twenty-five high- and 25 low-trait-anxious participants completed a Stroop task in which the target stimuli were preceded by brief (neutral vs. aversive) emotional distractors. While no effects of picture valence on proactive control was found in the low anxious group, the predicted signatures of reduced proactive control were observed in the high-anxiety group. These results indicate that trait anxiety influences the interaction between irrelevant emotional stimuli and proactive control. PMID- 26571079 TI - Tumor Acidity-Sensitive Polymeric Vector for Active Targeted siRNA Delivery. AB - Although surface PEGylation of siRNA vectors is effective for preventing protein adsorption and thereby helps these vectors to evade the reticuloendothelial system (RES) in vivo, it also suppresses the cellular uptake of these vectors by target cells. This dilemma could be overcome by employing stimuli-responsive shell-detachable nanovectors to achieve enhanced cellular internalization while maintaining prolonged blood circulation. Among the possible stimuli, dysregulated pH in tumor (pHe) is the most universal and practical. However, the design of pHe sensitive system is problematic because of the subtle differences between the pHe and pH in other tissues. Here, a simple acid-sensitive bridged copolymer is developed and used for tumor-targeted systemic delivery of siRNA. After forming the micelleplex delivery system, the corresponding nanoparticles (Dm-NP) might undergo several modifications as follows: (i) a poly(ethylene glycol) (PEG) corona, which is stable in the circulatory system and protects nanovectors from RES clearance; (ii) a pHe responsive linkage breakage, which induces PEG detachment at tumor sites and thereby facilitates cell targeting; and (iii) a cell-penetration peptide, which is exposed upon the removal of PEG and further enhances cellular uptake. Thus, Dm-NP achieved both prolonged circulation and effective accumulation in tumor cells and resulted in the safe and enhanced inhibition of non-small cell lung cancer growth. PMID- 26571080 TI - Formation Pathways and Trade-Offs between Haloacetamides and Haloacetaldehydes during Combined Chlorination and Chloramination of Lignin Phenols and Natural Waters. AB - In vitro bioassays have indicated that haloacetamides and haloacetaldehydes exhibit the highest cytotoxicity among DBP classes. Previous research has focused on their potential formation from the chlorination or chloramination of aliphatic compounds, particularly nonaromatic amino acids, and acetaldehyde. The present work found that acetaldehyde served as a relatively poor precursor for trichloroacetaldehyde and dichloroacetamide, generally the most prevalent of the haloacetaldehydes and haloacetamides, during chlorination or chlorination/chloramination. Using phenolic model compounds, particularly 4 hydroxybenzoic acid, as models for structures in humic substances, we found significantly higher formation of trichloroacetaldehyde and dichloroacetamide from prechlorination followed by chloramination. Evaluation of the stoichiometry of chlorine reactions with 4-hydroxybenzoic acid and several intermediates indicated that seven successive Cl[+1] transfers, faster with chlorination than chloramination, can form 2,3,5,5,6-pentachloro-6-hydroxy-cyclohexa-2-ene-1,4 dione via chlorophenol and chlorobenzoquinone intermediates. Formation of 2,3,5,5,6-pentachloro-6-hydroxy-cyclohexa-2-ene-1,4-dione may serve as a key branching point, with chloramines promoting the formation of dichloroacetamide and chlorination promoting the formation of trichloroacetaldehyde. The behavior of 4-hydroxybenzoic acid with respect to yields of dichloroacetamide and trichloroacetaldehyde during chlorination followed by chloramination was similar to the behavior observed for model humic acids and several surface waters, suggesting that phenolic structures in natural waters may serve as the predominant, and common pool of precursors for haloacetamides and haloacetaldehydes. Experiments with natural waters indicated that the branching point is reached over prechlorine exposures (100-500 mg-min/L) relevant to drinking water utilities using chlorine as a primary disinfectant and chloramines for maintenance of a distribution system residual. PMID- 26571081 TI - Modeling and Treatment of Radiation Cystitis. AB - Radiation cystitis (RC) is a debilitating condition that, if not managed at an early stage, can have a major impact on the quality of life of a patient and can lead to severe hemorrhaging and even death. Current treatments are focused on arresting bladder hemorrhaging, but none are able to relieve other urological symptoms associated with cystitis. There is a strong need for in-depth studies using preclinical RC models to better understand the underlying disease progression and to test novel therapies. Here we review the most commonly used therapies for RC, novel treatment strategies, and the preclinical models used to date. PMID- 26571082 TI - Calcified Renal Mass. AB - A 56-year-old male was referred to our urology clinic for a renal mass. This was initially identified incidentally on a plain film radiograph of the lumbar spine as a spherical abdominal mass. Treatment with nephrectomy confirmed it as a cystic clear-cell renal cell carcinoma. PMID- 26571083 TI - ZrO2 Nanofiber as a Versatile Tool for Protein Analysis. AB - Phosphorylation is one of the most important post-translational modifications in proteins. Their essential roles in the regulation of cellular processes and alteration of protein-protein interaction networks have been actively studied. However, phosphorylated proteins are present at low abundance in cells, and ionization of the modified peptides is often suppressed by the more abundant species in mass spectrometry. Effective enrichment techniques are needed to remove the unmodified peptides and concentrate the phosphorylated ones before their identification and quantification. Herein, we prepared ZrO2 nanofibers by electrospinning, a straightforward and easy fabrication technique, and applied them to enrich phosphorylated peptides and proteins. The fibers showed good size homogeneity and porosity and could specifically bind to the phosphorylated peptides and proteins, allowing their separation from the unmodified analogues when present in either simple protein digests or highly complex cell lysates. The enrichment performance was superior to that of the commercially available nanoparticles. Moreover, modifying the solution pH could lead to selective adsorption of proteins with different pI values, suggesting the fibers' potential applicability in charge-based protein fractionation. Our results support that the electrospun ZrO2 nanofibers can serve as a versatile tool for protein analysis with great ease in preparation and handling. PMID- 26571084 TI - Anti-inflammatory properties of Morus bombycis Koidzumi via inhibiting IFN-beta signaling and NLRP3 inflammasome activation. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Morus bombycis Koidzumi (M. bombycis, Moraceae) has been used in Asian countries as a traditional medicine for the treatment of hypertension, diabetes, and inflammation-related disorders. AIM OF STUDY: Although its anti-inflammatory actions have been partly documented, scientific evidence involving its molecular mechanisms related to inflammasome activation signaling pathways remains unknown. MATERIALS AND METHODS: Lipopolysaccharide stimulated RAW 264.7 cells and bone marrow-derived murine macrophages were used to study the in vitro effect of methanolic extract of M. bombycis (MB) on inflammatory responses. A monosodium urate crystal (MSU)-induced peritonitis murine model was used to study the in vivo effects. RESULTS: MB attenuated the production of nitric oxide and interleukin-6, through the regulation of the interferon-beta receptor signaling pathway. MB also inhibited IL-1beta secretion via attenuation of NLRP3 inflammasome activation. Furthermore, MB inhibited MSU induced peritonitis in the in vivo murine model. CONCLUSIONS: This study provides the key molecular mechanisms involved in the anti-inflammatory effects of M. bombycis, substantiating the traditional claims of its use in the treatment of inflammation-related disorders. PMID- 26571085 TI - DXXK exerts anti-inflammatory effects by inhibiting the lipopolysaccharide induced NF-kappaB/COX-2 signalling pathway and the expression of inflammatory mediators. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Diao Xin Xue Kang (DXXK) is the active pharmaceutical ingredient of the traditional Chinese medicinal product DXXK capsules, which have been approved for the treatment of cardiovascular disease and have been widely used clinically in China for many years with distinct curative effects. In March 2012, DXXK capsules were approved in the Netherlands, making them the first traditional herbal medicinal product (THMP) made outside of Europe. AIM: To assess the anti-inflammatory effects of DXXK and the underlying mechanisms at the cellular and molecular levels. MATERIALS AND METHODS: In this study, lipopolysaccharide (LPS) was used to induce inflammation in RAW 264.7 cells. The sulphorhodamine B (SRB) assay was used to study the effect of DXXK on the proliferation of RAW 264.7 cells. Gene expression levels of cyclooxygenase 1 (COX-1), COX-2, tumour necrosis factor-alpha (TNF-alpha), IL-1beta and IL-6 were assessed by reverse transcription polymerase chain reaction (RT-PCR), while COX-2 protein levels were evaluated using western blotting. The levels of PGE2 in the culture media were detected by enzyme-linked immunosorbent assay (ELISA), while TNF-alpha, IL-1beta and IL-6 levels were detected using a Milliplex Map Mouse Cytokine Panel system. The activation and nuclear translocation of nuclear transcription factor kappaB (NF-kappaB) were studied using western blotting. In vivo studies in mice were carried out using the carrageenan-air pouch models of inflammation. In exudates, leucocytes were counted, total protein was determined using the Bradford assay, nitric oxide(NO) levels were assessed using the Griess reagent, and PGE2 and TNF-alpha levels were quantified by ELISA. RESULTS: The SRB assay showed that at the doses used in this study (10, 20 and 40 MUg/mL), DXXK did not affect the proliferation of RAW 264.7 cells. DXXK (10, 20 and 40 MUg/mL) inhibited LPS-induced PGE2 production by down-regulating the expression of COX-2, without influencing COX-1 expression. We also demonstrated that DXXK reduced the expression of pro-inflammatory cytokines, including TNF-alpha, IL-1beta and IL-6, at both the gene and protein levels. Furthermore, DXXK inhibited LPS-induced NF kappaB activation and nuclear translocation by suppressing the phosphorylation of IkappaB. Consistent with the in vitro results, the in vivo studies demonstrated that DXXK reduced leucocyte counts as well as total protein, NO, PGE2 and TNF alpha levels in the exudates of mice with carrageenan-air pouch inflammation. CONCLUSIONS: The current study revealed that DXXK has a significant anti inflammatory effect that may be attributed to its inhibitory effect on the NF kappaB/COX-2 pathway and associated inflammatory mediators, including PGE2, NO, TNF-alpha, IL-1beta and IL-6. The current study provides additional evidence of the effects of DXXK in inflammation. Based on the combination of our results and previously reported data, we propose that DXXK has multiple pharmacological effects that could be harnessed to treat systemic diseases. PMID- 26571086 TI - Inhibitory activities of some traditional Chinese herbs against testosterone 5alpha-reductase and effects of Cacumen platycladi on hair re-growth in testosterone-treated mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Many traditional Chinese medicines (TCM) have been used for hundreds of years for hair blackening and hair nourishing, and now many of them are commonly used in Chinese herbal shampoo to nourish the hair and promote hair growth. AIMS OF THE STUDY: The present study was performed to screen 5alpha-reductase (5alphaR) inhibitors from traditional Chinese medicines, evaluate its hair growth promoting activity in vivo, and further investigate its effects on androgen metabolism and the expression of 5alphaR II in hair follicles. MATERIALS AND METHODS: Nine TCM which were dried, ground and extracted by maceration with 75% ethanol or distilled water were used for screening 5alphaR inhibitors, and enzymes were extracted from the rat epididymis. The leaves of Platycladus orientalis (L.) Franco was used to evaluate the in vivo anti androgenic activity. Skin color was observed daily and the hair re-growth was assessed by assigning the hair growth score. The longitudinal sections of hair follicles were used for observing follicle morphology, classifying of distinct stages of hair follicle morphogenesis and calculate the average score. The transverse sections were used for determination of hair follicle counts. Testosterone (T), Dihydrotestosterone (DHT) and Estradiol (E2) levels in serum and skin tissue were detected by ELISA kits. The immunofluorescence assay was used to detect the influence of CP-ext on 5alphaR expression in dorsal skin. RESULTS: We found the extract of Ganoderma lucidum (GL-ext), Polygonum multiflori (PM-ext), Cacumen platycladi (CP-ext) and Cynomorium songaricum (CS-ext) showed stronger 5alphaR inhibitory activity. CP-ext (5mg and 2mg/mouse/day) could significantly shorten the time of the dorsal skin darkening and got longhaired (P<0.01), and showed high hair re-growth promoting activity. Furthermore the histological data of hair follicles in each group showed that CP-ext could promote the growth of hair follicle and slowed down hair follicles enter the telogen. What's more CP-ext significantly reduced DHT levels and down-regulated the expression of 5alphaRIIin skin (P<0.01). CONCLUSIONS: GL-ext, PM-ext, CP-ext and CS-ext showed strong 5alphaR inhibitory activity. CP-ext possesses high hair growth promoting activity in the in vivo androgen-sensitive mouse model via inhibiting the 5alphaR activity, decreasing the DHT levels and in turn suppressing the expression of 5alphaR. Our study may contribute to the development of a new generation of herbal supplements with clearer material basis of pharmacodynamic for treating androgenic alopecia (AGA). PMID- 26571087 TI - Lingzhilactones from Ganoderma lingzhi ameliorate adriamycin-induced nephropathy in mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Several Ganoderma fungi are well-known for their medical uses to treat cancer, insomnia and kidney disease in East Asia. Triperpenoids and polysaccharides have been considered for a long time to be the major active components of the genus Ganoderma. The present study is to examine the effects of lingzhilactones from G. lingzhi on adriamycin-induced nephropathy in mice. MATERIALS AND METHODS: A combination of various chromatography led to the isolation of lingzhilactones A-C, their structures were identified by spectroscopic and computational methods. The intracellular reactive oxygen species (ROS) was detected with the carboxymethyl-H2-dichlorofluorescein diacetate fluoroprobe. The fibrotic markers were analyzed by real-time RT-PCR and Western blot analyses. Detection of SEAP was conducted with the chemiluminescent. Urine albumin was measured using an ELISA assay. Histology and immunohistochemical staining was used to assess fibrotic lesions in mice. RESULTS: Three new lingzhilactones A-C (1-3) containing a fused lactone moiety were isolated from G. lingzhi. We found that 2 could inhibit ROS generation in a dose-dependent manner, inhibit mRNA expression of collagen IV, fibronectin, IL-6 and increase expression of Nrf2 in rat tubular epithelial cells. Furthermore, we found that 2 could reduce urinary albumin levels, abrogate myofibroblastic activation and inhibit the phosphorylation of Smad3 in adriamycin-induced mice. CONCLUSIONS: The in vitro and in vivo results suggested that lingzhilactone B could protect against renal injuries by increasing the activities of antioxidants and inhibiting inflammation. The inhibition of Smad3 phosphorylation suggested that this substance displays in vivo antifibrotic activity by a mechanism that is dependent on disruption of Smad3. These results promote understanding of the traditional usage of G. lingzhi and provide promising findings which may be beneficial for anti-kidney disease drug design. PMID- 26571088 TI - Gastroprotective effects and antimicrobial activity of Lithraea molleoides and isolated compounds against Helicobacter pylori. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Lithraea molleoides (Vell.) Engl. (Anacardiaceae) is a medicinal plant traditionally used in South America to treat various ailments, including diseases of the digestive system. AIM OF THE STUDY: To evaluate the in vivo antiulcer and antimicrobial activities against Helicobacter pylori of L. molleoides and its isolated compounds. MATERIALS AND METHODS: Methanolic extract 250 and 500 mg/kg, (LmE 250 and LmE 500, respectively) and infusions, 10 g and 20 g en 100mL (LmI 10 and LmI 20, respectively) of L. molleoides was evaluated for antiulcer activity against 0.6N HCl, 0.2N NaOH, 200mg/kg acetilsalicilic acid and absolute ethanol-induced gastric ulcers in rats. The degree of erosion in the glandular part of the stomach was assessed from a scoring system. Acute toxicity in mice was also evaluated. The antiulcer effect of the isolated compounds (catechol, mannitol, rutin, gallic acid, ferulic acid and caffeic acid, 100mg/kg) was evaluated against absolute ethanol-induced gastric ulcers in rats. The anti-Helicobacter pylori activity of L. molleoides and isolated compounds was performed using broth dilution methods. RESULTS: The LmE 250, LmE 500, LmI 10 and LmI 20 produced significant inhibition on the ulcer index in 0.6N HCl, 0.2N NaOH, 200mg/kg acetilsalicilic acid and absolute ethanol- induced gastric ulcers in rats. The isolated compounds, catechol, mannitol, rutin, ferulic acid and caffeic acid were active in absolute ethanol- induced gastric ulcers in rats. L. molleoides and different compounds showed antimicrobial activity in all strains tested. The lowest MIC value (0. 5 MUg/mL) was obtained with catechol in six of eleven strains assayed. No signs of toxicity were observed with doses up to 2g/kg in an acute toxicity assay. CONCLUSION: These findings indicate that L. molleoides displays potential antiulcerogenic and antimicrobial activities and the identification of active principles could support the use of this plant for the treatment of digestive affections. PMID- 26571089 TI - Li-Gan-Shi-Liu-Ba-Wei-San improves non-alcoholic fatty liver disease through enhancing lipid oxidation and alleviating oxidation stress. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Mongolian medicine is an important constituent of traditional Chinese medicine. Its representative prescription, Li-Gan-Shi-Liu-Ba Wei-San (LGSLBWS), is widely used for long-term treatment of chronic liver disease and nonalcoholic fatty liver disease (NAFLD). AIM OF THE STUDY: This study explored the effects and mechanism of LGSLBWS on NAFLD. MATERIALS AND METHODS: NAFLD rat model was established with high-fat diet. The effects of LGSLBWS on lipid metabolism, liver function, and hepatic morphology were observed in NAFLD rats. Superoxide dismutase (SOD) and malondialdehyde (MDA) contents in the liver, as well as the expression levels of peroxisome proliferator-activated receptor (PPAR)alpha, PPARbeta, inhibitor of nuclear factor kappaB alpha(IkappaBalpha), and inducible nitric oxide synthase (iNOS) were all detected. Finally, the effects of LGSLBWS on fatty acid oxidation, PPARalpha, PPARbeta, IkappaBalpha, and iNOS were determined in HepG2 cells. RESULTS: LGSLBWS significantly reduced the fat deposition in the liver and the serum aspartate aminotransferase levels in NAFLD rats. Serum triglyceride and free fatty acid levels were reduced by LGSLBWS. Total cholesterol and triglyceride contents in the liver were also downregulated. SOD and MDA levels were increased and decreased by LGSLBWS, respectively. LGSLBWS can significantly promote fatty acid oxidation of HepG2 cells. Upregulation of PPARalpha, PPARbeta, and IkappaBalpha and downregulation of iNOS by LGSLBWS were both observed in the NAFLD model and HepG2 cells. CONCLUSIONS: LGSLBWS can significantly improve NAFLD by enhancing fatty acid oxidation and alleviating oxidative stress. PMID- 26571090 TI - Pesticide residues in leafy vegetables, stalk and stem vegetables from South Korea: a long-term study on safety and health risk assessment. AB - South Korea has a unique food culture. South Koreans enjoy wrapping meat and eating or making kimchi (traditionally fermented Korean food) and eating using raw leafy vegetables, stalk and stem vegetables. Therefore, there is a high chance of being exposed to pesticide residues of vegetables. The objective of this study was to investigate pesticide residues in leafy vegetables, stalk and stem vegetables from South Korea. A total of 8496 samples were mainly collected from Gwangju and Jeonnam area (the largest production region of leafy vegetables, stalk and stem vegetables) in South Korea from 2010 to 2014. A total of 230 pesticides were used for multi-residue analysis of pesticides. Among 8496 samples, 61 different pesticides (1029 times) were detected in 890 samples, of which 118 samples (1.4%) exceeded the Korea maximum residue limits (MRLs). Samples exceeding the MRLs were mostly found in leafy vegetables (brassica lee ssp. namai, leafy lettuce, spinach, perilla leaves, crown daisy, marsh mallow, aster scaber, pimpinella brachycarpa) and Chinese chive. Procymidone, dimethomorph and azoxystrobin were the most frequently found pesticides. A risk assessment of pesticides exceeding the MRLs was evaluated by calculating the estimated daily intake (EDI) and the acceptable daily intake (ADI). The ratio of EDI to ADI was 0.003-30.4%. PMID- 26571091 TI - Microgravity-driven remodeling of the proteome reveals insights into molecular mechanisms and signal networks involved in response to the space flight environment. AB - Space is a hostile environment characterized by high vacuum, extreme temperatures, meteoroids, space debris, ionospheric plasma, microgravity and space radiation, which all represent risks for human health. A deep understanding of the biological consequences of exposure to the space environment is required to design efficient countermeasures to minimize their negative impact on human health. Recently, proteomic approaches have received a significant amount of attention in the effort to further study microgravity-induced physiological changes. In this review, we summarize the current knowledge about the effects of microgravity on microorganisms (in particular Cupriavidus metallidurans CH34, Bacillus cereus and Rhodospirillum rubrum S1H), plants (whole plants, organs, and cell cultures), mammalian cells (endothelial cells, bone cells, chondrocytes, muscle cells, thyroid cancer cells, immune system cells) and animals (invertebrates, vertebrates and mammals). Herein, we describe their proteome's response to microgravity, focusing on proteomic discoveries and their future potential applications in space research. BIOLOGICAL SIGNIFICANCE: Space experiments and operational flight experience have identified detrimental effects on human health and performance because of exposure to weightlessness, even when currently available countermeasures are implemented. Many experimental tools and methods have been developed to study microgravity induced physiological changes. Recently, genomic and proteomic approaches have received a significant amount of attention. This review summarizes the recent research studies of the proteome response to microgravity inmicroorganisms, plants, mammalians cells and animals. Current proteomic tools allow large-scale, high-throughput analyses for the detection, identification, and functional investigation of all proteomes. Understanding gene and/or protein expression is the key to unlocking the mechanisms behind microgravity-induced problems and to finding effective countermeasures to spaceflight-induced alterations but also for the study of diseases on earth. Future perspectives are also highlighted. PMID- 26571092 TI - Deciphering the groove binding modes of tau-fluvalinate and flumethrin with calf thymus DNA. AB - Tau-fluvalinate (TFL) and flumethrin (FL), widely used in agriculture and a class of synthetic pyrethroid pesticides with a similar structure, may cause a potential security risk. Herein, the modes of binding in vitro of TFL and FL with calf thymus DNA (ctDNA) were characterized by fluorescence, UV-vis absorption, circular dichroism (CD) and Fourier transform infrared (FT-IR) spectroscopy with the aid of viscosity measurements, melting analyses and molecular docking studies. The fluorescence titration indicated that both TFL and FL bound to ctDNA forming complexes through hydrogen bonding and van der Waals forces. The binding constants of TFL and FL with ctDNA were in the range of 10(4)Lmol(-1), and FL exhibited a higher binding propensity than TFL. The iodide quenching effect, single/double-stranded DNA effects, and ctDNA melting and viscosity measurements demonstrated that the binding of both TFL and FL to ctDNA was groove mode. The FT IR analyses suggested the A-T region of the minor groove of ctDNA as the preferential binding for TFL and FL, which was confirmed by the displacement assays with Hoechst 33258 probe, and the molecular docking visualized the specific binding. The changes in CD spectra indicated that both FL and TFL induced the perturbation on the base stacking and helicity of B-DNA, but the disturbance caused by FL was more obvious. Gel electrophoresis analyses indicated that both TFL and FL did not cause significant DNA cleavage. This study provides novel insights into the binding properties of TFL/FL with ctDNA and its toxic mechanisms. PMID- 26571093 TI - The mechanism for the nonlinear optical properties in La9Na3B8O27, La2Na3B3O9 and La2CaB10O19: ab initio studies. AB - The nonlinear optical (NLO) properties in La9Na3B8O27, La2Na3B3O9 and La2CaB10O19 are investigated using a plane-wave pseudopotential method. Based on the first principles electronic band structures, the birefringence and second harmonic generation (SHG) coefficients for the three crystals are determined. The calculated values match well with the experimental results. In order to elucidate the microscopic origins of the NLO performances in these crystals, a real-space atom-cutting method is adopted to calculate the contribution from the respective ions and groups. It is revealed that the La cations have covalent interactions with the neighbor O ions so as to form the La-O groups. The La-O bond covalency, combined with the distortion of La-O groups, makes the large contribution to the overall SHG coefficients in addition to the B-O groups, as also intuitively demonstrated by a SHG-density analysis. PMID- 26571094 TI - Learning from those we serve: Piloting a culture competence intervention co developed by university faculty and persons in recovery. AB - OBJECTIVE: This article describes the development and piloting of a bilevel intervention codeveloped by persons in recovery from mental illness and addiction and university faculty with expertise in cultural competence to improve the cultural competence of a community mental health center in the northeastern United States. METHOD: Two faculty and 5 persons in recovery met for 6 months to develop the bilevel training intervention. They discussed experiences of culturally responsive care and developed experiential activities and case examples for the 2-day training. Forty-five community mental health service providers attended the 2-day training. Trainees' self-reported awareness, knowledge, and skills in cultural competence were measured pre and post training and analyzed with repeated measure t tests. Next, faculty and persons in recovery provided follow-up training and helped to establish an infrastructure supported to support the agency cultural competence plan. One hundred twenty-five providers completed the Organizational Multicultural Competence Survey and between-subjects t tests measured increases in organizational cultural competence. RESULTS: Significant increases were found in providers' multicultural knowledge, awareness, and skills. Qualitative responses demonstrated the contribution of the experiences of persons in recovery to the training. Ratings of the organizational level cultural competence intervention showed significant improvements in the agency's cultural competence policies (e.g., implementation of strategies to hire and retain a diverse workforce). CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: These data suggest that bilevel interventions codeveloped by persons in recovery and researchers may be effective in increasing provider and organizational-level cultural competence. Future research should evaluate the effect of these interventions on consumers and health outcomes. PMID- 26571095 TI - Photoconductivity of CdTe Nanocrystal-Based Thin Films: Te(2-) Ligands Lead To Charge Carrier Diffusion Lengths Over 2 MUm. AB - We report on photoconductivity of films of CdTe nanocrystals (NCs) using time resolved microwave photoconductivity (TRMC). Spherical and tetrapodal CdTe NCs with tunable size-dependent properties are studied as a function of surface ligand (including inorganic molecular chalcogenide species) and annealing temperature. Relatively high carrier mobility is measured for films of sintered tetrapod NCs (4 cm(2)/(V s)). Our TRMC findings show that Te(2-) capped CdTe NCs show a marked improvement in carrier mobility (11 cm(2)/(V s)), indicating that NC surface termination can be altered to play a crucial role in charge-carrier mobility even after the NC solids are sintered into bulk films. PMID- 26571096 TI - Edge and Surface Plasmons in Graphene Nanoribbons. AB - We report on nano-infrared (IR) imaging studies of confined plasmon modes inside patterned graphene nanoribbons (GNRs) fabricated with high-quality chemical-vapor deposited (CVD) graphene on Al2O3 substrates. The confined geometry of these ribbons leads to distinct mode patterns and strong field enhancement, both of which evolve systematically with the ribbon width. In addition, spectroscopic nanoimaging in the mid-infrared range 850-1450 cm(-1) allowed us to evaluate the effect of the substrate phonons on the plasmon damping. Furthermore, we observed edge plasmons: peculiar one-dimensional modes propagating strictly along the edges of our patterned graphene nanostructures. PMID- 26571097 TI - Effectiveness and Tolerability of THC/CBD Oromucosal Spray for Multiple Sclerosis Spasticity in Italy: First Data from a Large Observational Study. AB - BACKGROUND: The prospective, non-interventional Mobility Improvement (MOVE) 2 study was designed to provide real life data on clinical outcomes of patients with treatment-resistant multiple sclerosis (MS) spasticity receiving routine treatment with tetrahydrocannabinol (THC):cannabidiol (CBD) oromucosal spray (Sativex(r)), subsequent to its approval in European countries. METHODS: This interim analysis reports on MOVE 2 patients from Italy. RESULTS: Interim data from 322 patients (58.3% female; mean age 51.1 +/- 10.2 years) were analyzed. From baseline to month 3 of treatment (Visit 3), the mean 0-10 Numerical Rating Scale (NRS) score decreased by -19.1% (-1.6 points, p < 0.0001) and the mean modified Ashworth score decreased from 2.6 to 2.3 points (p < 0.0001). At Visit 3, 24.6% of 203 patients with available data were clinically relevant responders (>=30% improvement from baseline NRS score; p < 0.001 vs. baseline). The mean reported dose of THC:CBD oromucosal spray was 6.1 +/- 2.5 sprays/day at Visit 1 (1 month) and 5.1 +/- 2.6 sprays/day at Visit 3 (range 1-12 sprays/day at both timepoints). Forty-one (13.1%) patients reported at least one adverse event (AE), which included 3 serious AEs (1 unrelated). AEs with an incidence >=1% were dizziness (5.6%), confusion (2.5%), nausea (1.25%) and somnolence (1.25%). CONCLUSION: In everyday clinical practice in Italy, THC:CBD oromucosal spray provided symptomatic relief of MS spasticity with good tolerability in a relevant number of previously resistant patients. PMID- 26571098 TI - Evolution of translation machinery in recoded bacteria enables multi-site incorporation of nonstandard amino acids. AB - Expansion of the genetic code with nonstandard amino acids (nsAAs) has enabled biosynthesis of proteins with diverse new chemistries. However, this technology has been largely restricted to proteins containing a single or few nsAA instances. Here we describe an in vivo evolution approach in a genomically recoded Escherichia coli strain for the selection of orthogonal translation systems capable of multi-site nsAA incorporation. We evolved chromosomal aminoacyl-tRNA synthetases (aaRSs) with up to 25-fold increased protein production for p-acetyl-L-phenylalanine and p-azido-L-phenylalanine (pAzF). We also evolved aaRSs with tunable specificities for 14 nsAAs, including an enzyme that efficiently charges pAzF while excluding 237 other nsAAs. These variants enabled production of elastin-like-polypeptides with 30 nsAA residues at high yields (~50 mg/L) and high accuracy of incorporation (>95%). This approach to aaRS evolution should accelerate and expand our ability to produce functionalized proteins and sequence-defined polymers with diverse chemistries. PMID- 26571099 TI - Affinity regression predicts the recognition code of nucleic acid-binding proteins. AB - Predicting the affinity profiles of nucleic acid-binding proteins directly from the protein sequence is a challenging problem. We present a statistical approach for learning the recognition code of a family of transcription factors or RNA binding proteins (RBPs) from high-throughput binding data. Our method, called affinity regression, trains on protein binding microarray (PBM) or RNAcompete data to learn an interaction model between proteins and nucleic acids using only protein domain and probe sequences as inputs. When trained on mouse homeodomain PBM profiles, our model correctly identifies residues that confer DNA-binding specificity and accurately predicts binding motifs for an independent set of divergent homeodomains. Similarly, when trained on RNAcompete profiles for diverse RBPs, our model correctly predicts the binding affinities of held-out proteins and identifies key RNA-binding residues, despite the high level of sequence divergence across RBPs. We expect that the method will be broadly applicable to modeling and predicting paired macromolecular interactions in settings where high-throughput affinity data are available. PMID- 26571100 TI - Safeguarding CRISPR-Cas9 gene drives in yeast. AB - RNA-guided gene drives capable of spreading genomic alterations made in laboratory organisms through wild populations could be used to address environmental and public health problems. However, the possibility of unintended genome editing occurring through the escape of strains from laboratories, coupled with the prospect of unanticipated ecological change, demands caution. We report the efficacy of CRISPR-Cas9 gene drive systems in wild and laboratory strains of the yeast Saccharomyces cerevisiae. Furthermore, we address concerns surrounding accidental genome editing by developing and validating methods of molecular confinement that minimize the risk of unwanted genome editing. We also present a drive system capable of overwriting the changes introduced by an earlier gene drive. These molecular safeguards should enable the development of safe CRISPR gene drives for diverse organisms. PMID- 26571101 TI - Comprehensive analysis of protein glycosylation by solid-phase extraction of N linked glycans and glycosite-containing peptides. AB - Comprehensive characterization of protein glycosylation is critical for understanding the structure and function of glycoproteins. However, due to the complexity and heterogeneity of glycoprotein conformations, current glycoprotein analyses focus mainly on either the de-glycosylated glycosylation site (glycosite)-containing peptides or the released glycans. Here, we describe a chemoenzymatic method called solid phase extraction of N-linked glycans and glycosite-containing peptides (NGAG) for the comprehensive characterization of glycoproteins that is able to determine glycan heterogeneity for individual glycosites in addition to providing information about the total N-linked glycan, glycosite-containing peptide and glycoprotein content of complex samples. The NGAG method can also be applied to quantitatively detect glycoprotein alterations in total and site-specific glycan occupancies. PMID- 26571103 TI - Association of dimensional psychological health measures with telomere length in male war veterans. AB - BACKGROUND: Several psychiatric disorders may be characterized by peripheral telomere shortening. However, it is unclear whether telomere shortening is associated with these psychiatric disorders per se or, rather, with underlying dimensional parameters that are often, but not necessarily, associated with them. We explored the association between dimensional psychopathological measures and telomere length (TL) in granulocytes among veterans independent of psychiatric diagnosis. METHODS: Seventy-six combat-exposed male veterans (41 psychiatrically healthy, 18 with Posttraumatic Stress Disorder [PTSD] and 17 with concomitant PTSD and Major Depressive Disorder [MDD]) had TL assayed. Assessments included Clinician-Administered PTSD Scale (CAPS), Beck Depression Inventory-II (BDI-II), Early Trauma Inventory (ETI), Symptom Checklist-90-R Global Severity Index (SCL 90-GSI), Perceived Stress Scale (PSS) and Positive and Negative Affect Schedule (PANAS). Correlations were corrected for age, BMI, antidepressants and ethnicity. RESULTS: Across subjects, TL was negatively correlated with early trauma (p<0.001), global psychopathological severity (p=0.044) and perceived stress (p=0.019), positively correlated with positive affect (p=0.026), not significantly correlated with symptom severity of PTSD, depression or negative affect. Across these dimensions, early trauma and positive affect were associated with TL after excluding subjects with somatic illnesses. LIMITATIONS: The study was cross-sectional with a moderate sample size and only male combat-exposed subjects. CONCLUSIONS: These preliminary findings suggest that early trauma, severity of perceived stress and general psychopathological symptoms are more closely associated with shorter TL than is the severity of core diagnostic symptoms of PTSD or MDD, whereas positive affect is associated with longer TL. Larger-scale studies should assess TL associated with specific psychiatric dimensions, apart from only categorical psychiatric diagnoses, to develop more specific biologically-relevant endophenotypes. PMID- 26571102 TI - Cortical abnormalities and association with symptom dimensions across the depressive spectrum. AB - BACKGROUND: Few studies have investigated the relationship between structural brain abnormalities and dimensions of depressive symptomatology. METHODS: In the current study, we examined the relationship between cortical structural abnormalities and specific behavioral dimensions relevant to depression in a sample of unmedicated patients with major depressive disorder (MDD, n=57) and demographically similar healthy control volunteers (HC, n=29). All subjects underwent diagnostic assessment with the SCID, MRI at 3T, and dimensional assessments using the visual analog scales (VAS). Cortical regions were extracted for each subject, and group comparisons of cortical volume (CV), surface area (SA), and cortical thickness (CT) were performed controlling for multiple comparisons using a bootstrapping technique. Regions demonstrating group differences were analyzed for correlation with specific dimensions assessments. RESULTS: As compared with HC, MDD subjects exhibited reduced CV within the left supramarginal gyrus, right ventrolateral prefrontal cortex (VLPFC), entorhinal cortex, parahippocampal gyrus, fusiform gyrus and pericalcarine; reduced SA in the right VLPFC, cuneus, and left temporal pole; and reduced CT in the right rostral anterior cingulate cortex (rACC) (all p's<0.05, corrected). The largest effect occurred within the right VLPFC for CV and SA (MDD= 60 ml/min/1.73 m2 (determined using the Chronic Kidney Disease Epidemiology (CKD-EPI) Collaboration equation). Tubular proteinuria was defined by urine protein to creatinine ratio (uPCR) >=200 mg/g and albumin to protein ratio (uAPR) <0.4. RESULTS: Twenty per cent of patients had persistence of tubular proteinuria: TDF continuation was the main factor associated with this persistence [OR 9.0; 95%CI: 1.9-41.4; p = 0.01]. Among the 23 patients who discontinued TDF, uPCR returned below the threshold of 200 mg/g in 11 patients. Overall, eGFR decreased with a mean rate of decline of 3.8 ml/min/1.73m2/year. The decline in eGFR was lesser after discontinuation of TDF (5.8 ml/min/1.73m2/year during TDF exposure versus 3 ml/min/1.73m2/year after TDF discontinuation; p = 0.01). CONCLUSIONS: The continuation of TDF was the main factor associated with the persistence of proteinuria. Moreover, proteinuria was normalized in only half of the patients who discontinued TDF. The clinical significance of TDF-related low level of proteinuria as a factor associated with renal disease progression and bone loss remains poorly understood. PMID- 26571118 TI - Identifying Pelagic Habitat Hotspots of Neon Flying Squid in the Temperate Waters of the Central North Pacific. AB - We identified the pelagic habitat hotspots of the neon flying squid (Ommastrephes bartramii) in the central North Pacific from May to July and characterized the spatial patterns of squid aggregations in relation to oceanographic features such as mesoscale oceanic eddies and the Transition Zone Chlorophyll-a Front (TZCF). The data used for the habitat model construction and analyses were squid fishery information, remotely-sensed and numerical model-derived environmental data from May to July 1999-2010. Squid habitat hotspots were deduced from the monthly Maximum Entropy (MaxEnt) models and were identified as regions of persistent high suitable habitat across the 12-year period. The distribution of predicted squid habitat hotspots in central North Pacific revealed interesting spatial and temporal patterns likely linked with the presence and dynamics of oceanographic features in squid's putative foraging grounds from late spring to summer. From May to June, the inferred patches of squid habitat hotspots developed within the Kuroshio-Oyashio transition zone (KOTZ; 37-40 degrees N) and further expanded north towards the subarctic frontal zone (SAFZ; 40-44 degrees N) in July. The squid habitat hotspots within the KOTZ and areas west of the dateline (160 degrees W-180 degrees ) were likely influenced and associated with the highly dynamic and transient oceanic eddies and could possibly account for lower squid suitable habitat persistence obtained from these regions. However, predicted squid habitat hotspots located in regions east of the dateline (180 degrees -160 degrees W) from June to July, showed predominantly higher squid habitat persistence presumably due to their proximity to the mean position of the seasonally-shifting TZCF and consequent utilization of the highly productive waters of the SAFZ. PMID- 26571119 TI - All-Trans Retinoic Acid-Induced Deficiency of the Wnt/beta-Catenin Pathway Enhances Hepatic Carcinoma Stem Cell Differentiation. AB - Retinoic acid (RA) is an important biological signal that directly differentiates cells during embryonic development and tumorigenesis. However, the molecular mechanism of RA-mediated differentiation in hepatic cancer stem cells (hCSCs) is not well understood. In this study, we found that mRNA expressions of RA biosynthesis-related dehydrogenases were highly expressed in hepatocellular carcinoma. All-trans retinoic acid (ATRA) differentiated hCSCs through inhibiting the function of beta-catenin in vitro. ATRA also inhibited the function of PI3K AKT and enhanced GSK-3beta-dependent degradation of phosphorylated beta-catenin. Furthermore, ATRA and beta-catenin silencing both increased hCSC sensitivity to docetaxel treatment. Our results suggest that targeting beta-catenin will provide extra benefits for ATRA-mediated treatment of hepatic cancer patients. PMID- 26571121 TI - Optimizing Delivery of Preexposure Prophylaxis--The Next Frontier. PMID- 26571120 TI - Impaired Glucose Tolerance or Newly Diagnosed Diabetes Mellitus Diagnosed during Admission Adversely Affects Prognosis after Myocardial Infarction: An Observational Study. AB - OBJECTIVE: To investigate the prognostic effect of newly diagnosed diabetes mellitus (NDM) and impaired glucose tolerance (IGT) post myocardial infarction (MI). RESEARCH DESIGN AND METHODS: Retrospective cohort study of 768 patients without preexisting diabetes mellitus post-MI at one centre in Yorkshire between November 2005 and October 2008. Patients were categorised as normal glucose tolerance (NGT n = 337), IGT (n = 279) and NDM (n = 152) on pre- discharge oral glucose tolerance test (OGTT). Primary end-point was the first occurrence of major adverse cardiovascular events (MACE) including cardiovascular death, non fatal MI, severe heart failure (HF) or non-haemorrhagic stroke. Secondary end points were all cause mortality and individual components of MACE. RESULTS: Prevalence of NGT, impaired fasting glucose (IFG), IGT and NDM changed from 90%, 6%, 0% and 4% on fasting plasma glucose (FPG) to 43%, 1%, 36% and 20% respectively after OGTT. 102 deaths from all causes (79 as first events of which 46 were cardiovascular), 95 non fatal MI, 18 HF and 9 non haemorrhagic strokes occurred during 47.2 +/- 9.4 months follow up. Event free survival was lower in IGT and NDM groups. IGT (HR 1.54, 95% CI: 1.06-2.24, p = 0.024) and NDM (HR 2.15, 95% CI: 1.42-3.24, p = 0.003) independently predicted MACE free survival. IGT and NDM also independently predicted incidence of MACE. NDM but not IGT increased the risk of secondary end-points. CONCLUSION: Presence of IGT and NDM in patients presenting post-MI, identified using OGTT, is associated with increased incidence of MACE and is associated with adverse outcomes despite adequate secondary prevention. PMID- 26571122 TI - The Fate of Marine Bacterial Exopolysaccharide in Natural Marine Microbial Communities. AB - Most marine bacteria produce exopolysaccharides (EPS), and bacterial EPS represent an important source of dissolved organic carbon in marine ecosystems. It was proposed that bacterial EPS rich in uronic acid is resistant to mineralization by microbes and thus has a long residence time in global oceans. To confirm this hypothesis, bacterial EPS rich in galacturonic acid was isolated from Alteromonas sp. JL2810. The EPS was used to amend natural seawater to investigate the bioavailability of this EPS by native populations, in the presence and absence of ammonium and phosphate amendment. The data indicated that the bacterial EPS could not be completely consumed during the cultivation period and that the bioavailability of EPS was not only determined by its intrinsic properties, but was also determined by other factors such as the availability of inorganic nutrients. During the experiment, the humic-like component of fluorescent dissolved organic matter (FDOM) was freshly produced. Bacterial community structure analysis indicated that the class Flavobacteria of the phylum Bacteroidetes was the major contributor for the utilization of EPS. This report is the first to indicate that Flavobacteria are a major contributor to bacterial EPS degradation. The fraction of EPS that could not be completely utilized and the FDOM (e.g., humic acid-like substances) produced de novo may be refractory and may contribute to the carbon storage in the oceans. PMID- 26571123 TI - A Novel Procedure for Rapid Imaging of Adult Mouse Brains with MicroCT Using Iodine-Based Contrast. AB - High-resolution Magnetic Resonance Imaging (MRI) has been the primary modality for obtaining 3D cross-sectional anatomical information in animals for soft tissue, particularly brain. However, costs associated with MRI can be considerably high for large phenotypic screens for gross differences in the structure of the brain due to pathology and/or experimental manipulations. MicroCT (mCT), especially benchtop mCT, is becoming a common laboratory equipment with throughput rates equal or faster than any form of high-resolution MRI at lower costs. Here we explore adapting previously developed contrast based mCT to image adult mouse brains in-situ. We show that 2% weight per volume (w/v) iodine potassium iodide solution can be successfully used to image adult mouse brains within 48 hours post-mortem when a structural support matrix is used. We demonstrate that hydrogel can be effectively used as a perfusant which limits the tissue shrinkage due to iodine. PMID- 26571124 TI - Regulation of Heart Rate in Drosophila via Fragile X Mental Retardation Protein. AB - RNA binding proteins play a pivotal role in post-transcriptional gene expression regulation, however little is understood about their role in cardiac function. The Fragile X (FraX) family of RNA binding proteins is most commonly studied in the context of neurological disorders, as mutations in Fragile X Mental Retardation 1 (FMR1) are the leading cause of inherited mental retardation. More recently, alterations in the levels of Fragile X Related 1 protein, FXR1, the predominant FraX member expressed in vertebrate striated muscle, have been linked to structural and functional defects in mice and zebrafish models. FraX proteins are established regulators of translation and are known to regulate specific targets in different tissues. To decipher the direct role of FraX proteins in the heart in vivo, we turned to Drosophila, which harbors a sole, functionally conserved and ubiquitously expressed FraX protein, dFmr1. Using classical loss of function alleles as well as muscle specific RNAi knockdown, we show that Drosophila FMRP, dFmr1, is required for proper heart rate during development. Functional analyses in the context of cardiac-specific dFmr1 knockdown by RNAi demonstrate that dFmr1 is required cell autonomously in cardiac cells for regulating heart rate. Interestingly, these functional defects are not accompanied by any obvious structural abnormalities, suggesting that dFmr1 may regulate a different repertoire of targets in Drosophila than in vertebrates. Taken together, our findings support the hypothesis that dFmr1 protein is essential for proper cardiac function and establish the fly as a new model for studying the role(s) of FraX proteins in the heart. PMID- 26571125 TI - Convergent Evolution During Local Adaptation to Patchy Landscapes. AB - Species often encounter, and adapt to, many patches of similar environmental conditions across their range. Such adaptation can occur through convergent evolution if different alleles arise in different patches, or through the spread of shared alleles by migration acting to synchronize adaptation across the species. The tension between the two reflects the constraint imposed on evolution by the underlying genetic architecture versus how effectively selection and geographic isolation act to inhibit the geographic spread of locally adapted alleles. This paper studies the balance between these two routes to adaptation in a model of continuous environments with patchy selection pressures. We address the following questions: How long does it take for a novel allele to appear in a patch where it is locally adapted through mutation? Or, through migration from another, already adapted patch? Which is more likely to occur, as a function of distance between the patches? What population genetic signal is left by the spread of migrant alleles? To answer these questions we examine the family structure underlying migration-selection equilibrium surrounding an already adapted patch, treating those rare families that reach new patches as spatial branching processes. A main result is that patches further apart than a critical distance will likely evolve independent locally adapted alleles; this distance is proportional to the spatial scale of selection ([Formula: see text], where sigma is the dispersal distance and sm is the selective disadvantage of these alleles between patches), and depends linearly on log(sm/MU), where MU is the mutation rate. This provides a way to understand the role of geographic separation between patches in promoting convergent adaptation and the genomic signals it leaves behind. We illustrate these ideas using the convergent evolution of cryptic coloration in the rock pocket mouse, Chaetodipus intermedius, as an empirical example. PMID- 26571126 TI - Measurement Is Essential for Improving Diagnosis and Reducing Diagnostic Error: A Report From the Institute of Medicine. PMID- 26571127 TI - Correction: Therapeutic Potential of Stem Cells from Human Exfoliated Deciduous Teeth in Models of Acute Kidney Injury. PMID- 26571129 TI - Function from within: Autophagy induction by HPSE/heparanase--new possibilities for intervention. AB - HPSE (heparanase) is the predominant enzyme in mammals capable of cleaving heparan sulfate, an activity highly implicated in cellular invasion and tumor metastasis. HPSE expression is induced in many types of cancer and increased HPSE levels are most often associated with increased tumor metastasis and reduced patient survival post operation. In addition, HPSE induction is associated with progression of the primary tumors but the mechanism(s) underlying tumor expansion by HPSE have not been sufficiently resolved. Our results establish a role for heparanase in modulating autophagy in normal and malignant cells, thereby conferring growth advantages as well as resistance to chemotherapy. PMID- 26571128 TI - Association of Maternal Vitamin D Status with Glucose Tolerance and Caesarean Section in a Multi-Ethnic Asian Cohort: The Growing Up in Singapore Towards Healthy Outcomes Study. AB - OBJECTIVE: Epidemiological studies relating maternal 25-hydroxyvitamin D (25OHD) with gestational diabetes mellitus (GDM) and mode of delivery have shown controversial results. We examined if maternal 25OHD status was associated with plasma glucose concentrations, risks of GDM and caesarean section in the Growing Up in Singapore Towards healthy Outcomes (GUSTO) study. METHODS: Plasma 25OHD concentrations, fasting glucose (FG) and 2-hour postprandial glucose (2HPPG) concentrations were measured in 940 women from a Singapore mother-offspring cohort study at 26-28 weeks' gestation. 25OHD inadequacy and adequacy were defined based on concentrations of 25OHD <=75nmol/l and >75nmol/l respectively. Mode of delivery was obtained from hospital records. Multiple linear regression was performed to examine the association between 25OHD status and glucose concentrations, while multiple logistic regression was performed to examine the association of 25OHD status with risks of GDM and caesarean section. RESULTS: In total, 388 (41.3%) women had 25OHD inadequacy. Of these, 131 (33.8%), 155 (39.9%) and 102 (26.3%) were Chinese, Malay and Indian respectively. After adjustment for confounders, maternal 25OHD inadequacy was associated with higher FG concentrations (beta = 0.08mmol/l, 95% Confidence Interval (CI) = 0.01, 0.14), but not 2HPPG concentrations and risk of GDM. A trend between 25OHD inadequacy and higher likelihood of emergency caesarean section (Odds Ratio (OR) = 1.39, 95% CI = 0.95, 2.05) was observed. On stratification by ethnicity, the association with higher FG concentrations was significant in Malay women (beta = 0.19mmol/l, 95% CI = 0.04, 0.33), while risk of emergency caesarean section was greater in Chinese (OR = 1.90, 95% CI = 1.06, 3.43) and Indian women (OR = 2.41, 95% CI = 1.01, 5.73). CONCLUSIONS: 25OHD inadequacy is prevalent in pregnant Singaporean women, particularly among the Malay and Indian women. This is associated with higher FG concentrations in Malay women, and increased risk of emergency caesarean section in Chinese and Indian women. PMID- 26571130 TI - Differentiating cognitive functions of poststroke patients with specific brain lesions: A preliminary study on the clinical utility of Cognistat-P. AB - The Cognistat is widely used to measure the cognitive profile of neurological patients. This study aimed to further obtain evidence on the construct and discriminative validity of the Putonghua version of the Cognistat (Cognistat-P) on poststroke patients with specific brain lesions. Cognistat-P was administered to poststroke patients (n = 98), as well as healthy elderly (n = 40) and adult (n = 34) participants as the control groups. Poststroke patients were further categorized into 4 lesion groups using standard brain slice templates. Exploratory factory analysis reflected a 2-factor structure for the Cognistat-P that resembles that for the original English version. The Construction, Similarities, and Judgment subtests were found to differentiate patients with frontal or parietal lesions from those with subcortical lesions (p < .01, R(2) = .48). The Construction subtest, tapping the "fluid" ability, was the most useful for differentiating patients with parietal lesions from those with subcortical lesions. The Similarities subtest together with the Construction subtest was the most useful for differentiating patients with frontal lesions from those with subcortical lesions. This study established the validity of the Cognistat-P for differentiating poststroke patients with specific brain lesions. Future studies should replicate the results on a larger sample size and test the clinical significance of the Cognistat-P profiles. PMID- 26571131 TI - Protective Role of the Interleukin 33 rs3939286 Gene Polymorphism in the Development of Subclinical Atherosclerosis in Rheumatoid Arthritis Patients. AB - OBJECTIVES: To determine whether the interleukin-33 (IL-33)-interleukin-1 receptor like 1 (IL-1RL1) signaling pathway is implicated in the risk of subclinical atherosclerosis in patients with rheumatoid arthritis (RA). METHODS: A total of 576 Spanish RA patients from Northern Spain were genotyped for 6 well known IL33-IL1RL1 polymorphisms (IL33 rs3939286, IL33 rs7025417, IL33 rs7044343, IL1RL1 rs2058660, IL1RL1 rs2310173 and IL1RL1 rs13015714) by TaqMan genotyping assay. The presence of subclinical atherosclerosis was determined by the assessment of carotid intima-media thickness (cIMT) by carotid ultrasound (US). RESULTS: RA patients carrying the TT genotype of the IL33 rs3939286 polymorphism had lower cIMT values than those homozygous for the CC genotype (mean +/- standard deviation (SD): 0.71 +/- 0.14 mm versus 0.76 +/- 0.16 mm, respectively) while patients carrying the CT genotype had intermediate cIMT values (mean +/- SD: 0.73 +/- 0.17 mm). Moreover, RA patients carrying the mutant allele T of the IL33 rs3939286 polymorphism exhibited significantly lower cIMT values than those carrying the wild allele C (mean +/- SD: 0.72 +/- 0.16 mm versus 0.75 +/- 0.18 mm respectively; p = 0.04). The association of both genotype and allele frequencies of IL33 rs3939286 and cIMT levels remained statistically significant after adjustment for sex, age at the time of US study, follow-up and center (p = 0.006 and p = 0.0023, respectively), evidencing that the potential effect conferred by IL33 rs3939286 may be independent of confounder factors. No association with other IL33-IL1RL1 genetic variants was observed. CONCLUSIONS: In conclusion, our results may suggest a potential protective effect of the IL33 rs3939286 allele T in the risk of subclinical atherosclerosis in patients with RA. PMID- 26571132 TI - FRPR-4 Is a G-Protein Coupled Neuropeptide Receptor That Regulates Behavioral Quiescence and Posture in Caenorhabditis elegans. AB - Neuropeptides signal through G-protein coupled receptors (GPCRs) to regulate a broad array of animal behaviors and physiological processes. The Caenorhabditis elegans genome encodes approximately 100 predicted neuropeptide receptor GPCRs, but in vivo roles for only a few have been identified. We describe here a role for the GPCR FRPR-4 in the regulation of behavioral quiescence and locomotive posture. FRPR-4 is activated in cell culture by several neuropeptides with an amidated isoleucine-arginine-phenylalanine (IRF) motif or an amidated valine arginine-phenylalanine (VRF) motif at their carboxy termini, including those encoded by the gene flp-13. Loss of frpr-4 function results in a minor feeding quiescence defect after heat-induced cellular stress. Overexpression of frpr-4 induces quiescence of locomotion and feeding as well as an exaggerated body bend posture. The exaggerated body bend posture requires the gene flp-13. While frpr-4 is expressed broadly, selective overexpression of frpr-4 in the proprioceptive DVA neurons results in exaggerated body bends that require flp-13 in the ALA neuron. Our results suggest that FLP-13 and other neuropeptides signal through FRPR-4 and other receptors to regulate locomotion posture and behavioral quiescence. PMID- 26571133 TI - The Distribution of the Asymptotic Number of Citations to Sets of Publications by a Researcher or from an Academic Department Are Consistent with a Discrete Lognormal Model. AB - How to quantify the impact of a researcher's or an institution's body of work is a matter of increasing importance to scientists, funding agencies, and hiring committees. The use of bibliometric indicators, such as the h-index or the Journal Impact Factor, have become widespread despite their known limitations. We argue that most existing bibliometric indicators are inconsistent, biased, and, worst of all, susceptible to manipulation. Here, we pursue a principled approach to the development of an indicator to quantify the scientific impact of both individual researchers and research institutions grounded on the functional form of the distribution of the asymptotic number of citations. We validate our approach using the publication records of 1,283 researchers from seven scientific and engineering disciplines and the chemistry departments at the 106 U.S. research institutions classified as "very high research activity". Our approach has three distinct advantages. First, it accurately captures the overall scientific impact of researchers at all career stages, as measured by asymptotic citation counts. Second, unlike other measures, our indicator is resistant to manipulation and rewards publication quality over quantity. Third, our approach captures the time-evolution of the scientific impact of research institutions. PMID- 26571134 TI - Pineal parenchymal tumours of intermediate differentiation - An evidence-based review of a new pathological entity. AB - Pineal region lesions are uncommon, and pineal parenchymal tumours (PPT) account for 20-30% of tumours in this area of which pineocytomas (PCs) and pineoblastomas (PBs) are more prevalent. In 2007, the World Health Organisation (WHO) reclassified PPT from two subgroups (PC and PB) into four, including pineal parenchymal tumours of intermediate differentiation (PPTID). PPTID have been further divided into low- and high-grade lesions (WHO II and III), but due to their rarity have proven difficult lesions to diagnose and a paucity of literature means their optimal treatment options are a challenge to define. This article is a review of the literature of PPTID highlighting diagnostic criteria, a discussion on the role of surgery and radiotherapy, including treatment paradigms and reported outcomes for these problematic neoplasms. PMID- 26571135 TI - Study on Market Stability and Price Limit of Chinese Stock Index Futures Market: An Agent-Based Modeling Perspective. AB - This paper explores a method of managing the risk of the stock index futures market and the cross-market through analyzing the effectiveness of price limits on the Chinese Stock Index 300 futures market. We adopt a cross-market artificial financial market (include the stock market and the stock index futures market) as a platform on which to simulate the operation of the CSI 300 futures market by changing the settings of price limits. After comparing the market stability under different price limits by appropriate liquidity and volatility indicators, we find that enhancing price limits or removing price limits both play a negative impact on market stability. In contrast, a positive impact exists on market stability if the existing price limit is maintained (increase of limit by10%, down by 10%) or it is broadened to a proper extent. Our study provides reasonable advice for a price limit setting and risk management for CSI 300 futures. PMID- 26571136 TI - The health-enhancing efficacy of Zumba(r) fitness: An 8-week randomised controlled study. AB - The purpose of this study was to gain a holistic understanding of the efficacy of Zumba(r) fitness in a community-recruited cohort of overweight and physically inactive women by evaluating (i) its physiological effects on cardiovascular risk factors and inflammatory biomarkers and (ii) its mental health-enhancing effects on factors of health-related quality of life (HRQoL). Participants were randomly assigned to either engagement in one to two 1 h classes of Zumba(r) fitness weekly (intervention group; n = 10) or maintenance of habitual activity (control group; n = 10). Laboratory assessments were conducted pre- (week 0) and post intervention (week 8) with anthropometric, physiological, inflammatory and HRQoL data collected. In the intervention group, maximal oxygen uptake significantly increased (P < 0.05; partial eta(2) = 0.56) by 3.1 mL . kg(-1) . min(-1), per cent body fat significantly decreased (P < 0.05; partial eta(2) = 0.42) by -1.2%, and interleukin-6 and white blood cell (WBC) count both significantly decreased (P < 0.01) by -0.4 pg . mL(-1) (partial eta(2) = 0.96) and -2.1 * 10(9) cells . L(-1) (partial eta(2) = 0.87), respectively. Large magnitude enhancements were observed in the HRQoL factors of physical functioning, general health, energy/fatigue and emotional well-being. When interpreted in a community-based physical activity and psychosocial health promotion context, our data suggest that Zumba(r) fitness is indeed an efficacious health-enhancing activity for adults. PMID- 26571138 TI - Low-dimensional ScO2 with tunable electronic and magnetic properties: first principles studies. AB - Transition metal dichalcogenides (TMDs) have attracted extensive attention due to their appealing properties for device applications. In this work, we explored the structure stability, electronic structure and magnetism of low-dimensional scandium dioxides, ScO2, by using the first-principles calculations. The results demonstrate that bulk ScO2, monolayers and nanoribbons (NRs) are thermodynamically stable, implying a high possibility of fabricating ScO2 nanocrystals in experiments. Despite the metallic characteristics of bulk ScO2, low-dimensional ScO2 possesses various electronic behaviors that can be further modulated by crystal structure and dimensionality. The results also show that the ground states of ScO2 monolayers and NRs are ferromagnetic (FM) with about 1 MU B per ScO2 formula. Our studies expand a new realm in low-dimensional TMDs, with tunable electronic and magnetic properties. PMID- 26571137 TI - Insulin Sensitivity in Adipose and Skeletal Muscle Tissue of Dairy Cows in Response to Dietary Energy Level and 2,4-Thiazolidinedione (TZD). AB - The effects of dietary energy level and 2,4-thiazolidinedione (TZD) injection on feed intake, body fatness, blood biomarkers and TZD concentrations, genes related to insulin sensitivity in adipose tissue (AT) and skeletal muscle, and peroxisome proliferator-activated receptor gamma (PPARG) protein in subcutaneous AT (SAT) were evaluated in Holstein cows. Fourteen nonpregnant nonlactating cows were fed a control low-energy (CON, 1.30 Mcal/kg) diet to meet 100% of estimated nutrient requirements for 3 weeks, after which half of the cows were assigned to a higher energy diet (OVE, 1.60 Mcal/kg) and half of the cows continued on CON for 6 weeks. All cows received an intravenous injection of TZD starting 2 weeks after initiation of dietary treatments and for an additional 2 weeks, which served as the washout period. Cows fed OVE had greater energy intake and body mass than CON, and TZD had no effect during the administration period. The OVE cows had greater TZD clearance rate than CON cows. The lower concentration of nonesterified fatty acids (NEFA) and greater concentration of insulin in blood of OVE cows before TZD injection indicated positive energy balance and higher insulin sensitivity. Administration of TZD increased blood concentrations of glucose, insulin, and beta-hydroxybutyrate (BHBA) at 2 to 4 weeks after diet initiation, while the concentration of NEFA and adiponectin (ADIPOQ) remained unchanged during TZD. The TZD upregulated the mRNA expression of PPARG and its targets FASN and SREBF1 in SAT, but also SUMO1 and UBC9 which encode sumoylation proteins known to down-regulate PPARG expression and curtail adipogenesis. Therefore, a post-translational response to control PPARG gene expression in SAT could be a counteregulatory mechanism to restrain adipogenesis. The OVE cows had greater expression of the insulin sensitivity-related genes IRS1, SLC2A4, INSR, SCD, INSIG1, DGAT2, and ADIPOQ in SAT. In skeletal muscle, where PPARA and its targets orchestrate carbohydrate metabolism and fatty acid oxidation, the OVE cows had greater glyceroneogenesis (higher mRNA expression of PC and PCK1), whereas CON cows had greater glucose transport (SLC2A4). Administration of TZD increased triacylglycerol concentration and altered expression of carbohydrate- and fatty acid oxidation-related genes in skeletal muscle. Results indicate that overfeeding did not affect insulin sensitivity in nonpregnant, nonlactating dairy cows. The bovine PPARG receptor appears TZD-responsive, with its activation potentially leading to greater adipogenesis and lipogenesis in SAT, while differentially regulating glucose homeostasis and fatty acid oxidation in skeletal muscle. Targeting PPARG via dietary nutraceuticals while avoiding excessive fat deposition might improve insulin sensitivity in dairy cows during times such as the peripartal period when the onset of lactation naturally decreases systemic insulin release and sensitivity in tissues such as AT. PMID- 26571139 TI - miRge - A Multiplexed Method of Processing Small RNA-Seq Data to Determine MicroRNA Entropy. AB - Small RNA RNA-seq for microRNAs (miRNAs) is a rapidly developing field where opportunities still exist to create better bioinformatics tools to process these large datasets and generate new, useful analyses. We built miRge to be a fast, smart small RNA-seq solution to process samples in a highly multiplexed fashion. miRge employs a Bayesian alignment approach, whereby reads are sequentially aligned against customized mature miRNA, hairpin miRNA, noncoding RNA and mRNA sequence libraries. miRNAs are summarized at the level of raw reads in addition to reads per million (RPM). Reads for all other RNA species (tRNA, rRNA, snoRNA, mRNA) are provided, which is useful for identifying potential contaminants and optimizing small RNA purification strategies. miRge was designed to optimally identify miRNA isomiRs and employs an entropy based statistical measurement to identify differential production of isomiRs. This allowed us to identify decreasing entropy in isomiRs as stem cells mature into retinal pigment epithelial cells. Conversely, we show that pancreatic tumor miRNAs have similar entropy to matched normal pancreatic tissues. In a head-to-head comparison with other miRNA analysis tools (miRExpress 2.0, sRNAbench, omiRAs, miRDeep2, Chimira, UEA small RNA Workbench), miRge was faster (4 to 32-fold) and was among the top two methods in maximally aligning miRNAs reads per sample. Moreover, miRge has no inherent limits to its multiplexing. miRge was capable of simultaneously analyzing 100 small RNA-Seq samples in 52 minutes, providing an integrated analysis of miRNA expression across all samples. As miRge was designed for analysis of single as well as multiple samples, miRge is an ideal tool for high and low-throughput users. miRge is freely available at http://atlas.pathology.jhu.edu/baras/miRge.html. PMID- 26571140 TI - Leaching and antimicrobial properties of silver nanoparticles loaded onto natural zeolite clinoptilolite by ion exchange and wet impregnation. AB - This study aimed to compare the leaching and antimicrobial properties of silver that was loaded onto the natural zeolite clinoptilolite by ion exchange and wet impregnation. Silver ions were reduced using sodium borohydride (NaBH4). The leaching of silver from the prepared silver-clinoptilolite (Ag-EHC) nanocomposite samples and their antimicrobial activity on Escherichia coli Epi 300 were investigated. It was observed that the percentage of silver loaded onto EHC depended on the loading procedure and the concentration of silver precursor used. Up to 87% of silver was loaded onto EHC by wet impregnation. The size of synthesized silver nanoparticles varied between 8.71-72.67 nm and 7.93-73.91 nm when silver was loaded by ion exchange and wet impregnation, respectively. The antimicrobial activity of the prepared nanocomposite samples was related to the concentration of silver precursor used, the leaching rate and the size of silver nanoparticles obtained after reduction. However, only in the case of the nanocomposite sample (Ag-WEHC) obtained after loading 43.80 +/- 1.90 ug of Ag per gram zeolite through wet impregnation was the leaching rate lower than 0.1 mg L-1 limit recommended by WHO, with an acceptable microbial killing effect. PMID- 26571141 TI - Ceruloplasmin and antioxidative enzymes in pre-eclampsia. AB - OBJECTIVE: To evaluate diagnostic value of ceruloplasmin together with other enzymatic and nonenzymatic antioxidants (superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and uric acid) and to evaluate the level of oxidative stress in patients with pre-eclampsia (PE) and compare it with normal pregnancy. METHODS: In this prospective study, antioxidative markers were investigated in two groups of pregnant women: patients with pre-eclampsia (n = 32) and the healthy pregnant women (n = 60). The following antioxidative markers and enzymes were evaluated: serum ceruloplasmin levels, uric acid, superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). RESULTS: Serum levels of ceruloplasmin, uric acid and SOD were significantly higher in the PE group compared to the control group. Serum levels of GSH-Px were not significantly higher in the PE group compared to the control group. Serum ceruloplasmin and serum uric acid have the best diagnostic accuracy for oxidative stress in PE and are more accurate compared to antioxidative enzymes -SOD and specially more accurate than GSH-Px. CONCLUSIONS: Serum ceruloplasmin level may have significant role as the markers of oxidative stress in pre-eclampsia especially when used in combination with uric acid levels. PMID- 26571142 TI - Two Rh(III)-substituted polyoxoniobates and their base-induced transformation: [H2RhNb9O28](6-) and [Rh2(OH)4Nb10O30](8-). AB - Two new rhodium-substituted polyoxoniobates, [H2RhNb9O28](6-) (RhNb9) and [Rh2(OH)4Nb10O30](8-) (Rh2Nb10) are reported. The two distinct Rh(III) substituted niobate clusters behave differently when the pH is raised with TMAOH: the Rh2Nb10 is stable until pH ~ 12.7, but RhNb9 dissociates to form RhNb5 and RhNb10, similar to some of our other metal-substituted niobates, such as the MNb9 ions (M = Cr or Mn), which transform to MNb10 when the solution pH is raised. PMID- 26571144 TI - Synthesis of hollow cobalt oxide nanopowders by a salt-assisted spray pyrolysis process applying nanoscale Kirkendall diffusion and their electrochemical properties. AB - A new concept for preparing hollow metal oxide nanopowders by salt-assisted spray pyrolysis applying nanoscale Kirkendall diffusion is introduced. The composite powders of metal oxide and indecomposable metal salt are prepared by spray pyrolysis. Post-treatment under a reducing atmosphere and subsequent washing using distilled water produce aggregation-free metal nanopowders. The metal nanopowders are then transformed into metal oxide hollow nanopowders by nanoscale Kirkendall diffusion. Co3O4 hollow nanopowders are prepared as first target materials. A cobalt oxide-NaCl composite powder prepared by spray pyrolysis transforms into several Co3O4 hollow nanopowders by several treatment processes. The discharge capacities of the Co3O4 nanopowders with filled and hollow structures at a current density of 1 A g(-1) for the 150th cycle are 605 and 775 mA h g(-1), respectively. The hollow structure formed by nanoscale Kirkendall diffusion improves the lithium-ion storage properties of Co3O4 nanopowders. PMID- 26571143 TI - Recent advances in the biosynthesis of unusual polyketide synthase substrates. AB - This highlight provides an overview of recent advances in understanding the diversity of polyketide synthase (PKS) substrate building blocks. Substrates functioning as starter units and extender units contribute significantly to the chemical complexity and structural diversity exhibited by this class of natural products. This article complements and extends upon the current comprehensive reviews that have been published on these two topics (Moore and Hertweck, Nat. Prod. Rep., 2002, 19, 70; Chan et al., Nat. Prod. Rep., 2009, 1, 90; Wilson and Moore, Nat. Prod. Rep., 2012, 29, 72). PMID- 26571145 TI - P2Y12 Reaction Units: Effect on Hemorrhagic and Thromboembolic Complications in Patients With Cerebral Aneurysms Treated With the Pipeline Embolization Device. AB - BACKGROUND: The main concern with the use of the pipeline embolization device (PED) in treating cerebral aneurysms is the risk of hemorrhagic and thromboembolic complications. OBJECTIVE: To investigate if P2Y12 reaction unit (PRU) values are associated with hemorrhagic and thromboembolic complications after treatment with the PED and to find an optimal range of preprocedural PRU values. METHODS: Two hundred thirty-one patients with 248 cerebral aneurysms treated with the PED were retrospectively identified. Patients were started on dual-antiplatelet treatment at least 10 days before the intervention. PRU values were checked. Univariate and multivariate logistic regression were performed. Youden Indices were calculated to determine cutoffs for optimal PRU values. RESULTS: Mean patient age was 57 years. Mean last preprocedural PRU was 132 (range: 1-382). The combined rate of major hemorrhagic complications (4%) and major thromboembolic complications (5.6%) was 9.6%. Analysis using Youden indices suggested an optimal PRU range of 70 to 150 with higher odds of complications outside this range (P = .01, odds ratio [OR] = 3 [1.2-7.5]). PRU <60 was a significant predictor of hemorrhagic complications (P = .04, OR = 2.45 [1.01 5.9]) and PRU >240 was a significant predictor of any thromboembolic complication (P = .04, OR = 3.6 [1.04-12]) and cerebral thromboembolic complications (P = .02, OR = 4 [1.2-14]). CONCLUSION: Target preoperative PRU values should be between 60 and 240 and ideally between 70 and 150. Values below this range and above it carry higher odds of hemorrhagic and thromboembolic complications, respectively. PMID- 26571147 TI - Chiral Phosphine Oxide-Sc(OTf)3 Complex Catalyzed Enantioselective Bromoaminocyclization of 2-Benzofuranylmethyl N-Tosylcarbamates. Approach to a Novel Class of Optically Active Spiro Compounds. AB - An efficient enantioselective bromoaminocyclization of 2-benzofuranylmethyl N tosylcarbamates catalyzed by a chiral phosphine oxide-Sc(OTf)(3) complex is described. A wide variety of optically active spiro benzofuran oxazolidinones can be obtained with high enantioselectivities. PMID- 26571146 TI - Zonisamide Enhances Neurite Elongation of Primary Motor Neurons and Facilitates Peripheral Nerve Regeneration In Vitro and in a Mouse Model. AB - No clinically applicable drug is currently available to enhance neurite elongation after nerve injury. To identify a clinically applicable drug, we screened pre-approved drugs for neurite elongation in the motor neuron-like NSC34 cells. We found that zonisamide, an anti-epileptic and anti-Parkinson's disease drug, promoted neurite elongation in cultured primary motor neurons and NSC34 cells in a concentration-dependent manner. The neurite-scratch assay revealed that zonisamide enhanced neurite regeneration. Zonisamide was also protective against oxidative stress-induced cell death of primary motor neurons. Zonisamide induced mRNA expression of nerve growth factors (BDNF, NGF, and neurotrophin 4/5), and their receptors (tropomyosin receptor kinase A and B). In a mouse model of sciatic nerve autograft, intragastric administration of zonisamide for 1 week increased the size of axons distal to the transected site 3.9-fold. Zonisamide also improved the sciatic function index, a marker for motor function of hindlimbs after sciatic nerve autograft, from 6 weeks after surgery. At 8 weeks after surgery, zonisamide was protective against denervation-induced muscle degeneration in tibialis anterior, and increased gene expression of Chrne, Colq, and Rapsn, which are specifically expressed at the neuromuscular junction. We propose that zonisamide is a potential therapeutic agent for peripheral nerve injuries as well as for neuropathies due to other etiologies. PMID- 26571148 TI - A Novel Method for Assessing Cardiac Output With the Use of Oxygen Circulation Time. AB - BACKGROUND: We investigated whether a simple breath hold would yield dynamic oxygen (O2) saturation change and whether the derived circulation time would be useful in assessing cardiac function. METHODS AND RESULTS: Patients undergoing right heart catheterization for clinical indications (n = 48), including heart failure (HF; n = 24), were prospectively recruited. Each subject was instructed to hold their breath for 20-40 seconds. Lung to finger circulation time (LFCT), defined as the time from the point of rebreathing to nadir O2 desaturation, was correlated with cardiac output. Among 48 subjects recruited, 37 manifested >=3% O2 desaturation allowing for an LFCT measurement. Mean LFCT was 38.5 +/- 17.5 seconds (range 18.9-94.7 s). LFCT in patients with a clinical diagnosis of HF was significantly longer than those without (45.9 +/- 19.9 s vs 31.5 +/- 11.5 s; P = .01). Overall, the LFCT was inversely correlated with cardiac output (Fick: r = 0.56; P < .001 [n = 37]; thermodilution: r = -0.6; P = .001 [n = 27]). CONCLUSIONS: LFCT is prolonged in low cardiac output. LFCT is a novel method that may be useful to noninvasively assess cardiac function in HF. PMID- 26571150 TI - Electrophilic trifluoromethylation of carbonyl compounds and their nitrogen derivatives under copper catalysis. AB - Recent advances in electrophilic trifluoromethylation reactions of carbonyl compounds and their usual surrogates are highlighted with particular focus on copper-catalysed (or mediated) C-CF3 bond forming reactions. Ketones and aldehydes (notably via their enol ether and enamine derivatives) enable electrophilic trifluoromethylation at the alpha-carbon of the carbonyl compounds, whereas aldehyde N,N-disubstituted hydrazones undergo electrophilic attack of the cationic or radical CF3 species at the azomethine carbon, thus providing an umpolung alternative to nucleophilic trifluoromethylation of carbonyl compounds. A reversal in reactivity is also observed for conjugated systems. While alpha,beta-unsaturated ketones regioselectively incorporate the CF3 moiety at the alpha-position of the enones, trifluoromethylation occurs preferentially at the olefinic beta-carbon of the corresponding hydrazones. PMID- 26571149 TI - Prognostic Value of Galectin-3 for Adverse Outcomes in Chronic Heart Failure. AB - BACKGROUND: Clinical studies have suggested the prognostic value of galectin-3, a marker of fibrosis, in chronic heart failure. However, the specific role of galectin-3, compared with established biomarkers, remains uncertain. METHODS AND RESULTS: The Penn Heart Failure Study was an ambulatory heart failure cohort that included 1385 participants with reduced (1141), preserved (106), and recovered (138) left ventricular ejection fraction (LVEF). Cox regression models determined the association between galectin-3 and risk of all-cause mortality, cardiac transplantation, or placement of a ventricular assist device. Receiver operating characteristic curves compared the prognostic accuracy of galectin-3, high sensitivity soluble Toll-like receptor 2 (ST2), troponin I, and B-type natriuretic peptide (BNP) at 1 and 5 years. Higher galectin-3 levels were associated with an increased risk of adverse events (adjusted hazard ratio of 1.96 for each doubling in galectin-3; P < .001). This association was most pronounced among participants with preserved LVEF (adjusted hazard ratio 3.30; P < .001). At 5 years, galectin-3 was the most accurate discriminator of risk among participants with preserved LVEF (area under the curve 0.782; P = .81 vs high sensitivity ST2; P = .029 vs troponin I; P = .35 vs BNP). BNP was most accurate among participants with reduced and recovered LVEF (areas under the curves 0.716 and 0.728, respectively). CONCLUSIONS: Galectin-3 could have prognostic value for long-term events among patients with heart failure and preserved ejection fraction. PMID- 26571152 TI - About clinical trials: methodological and bioethical considerations. PMID- 26571151 TI - HIV-1 CRF01_AE and Subtype B Transmission Networks Crossover: A New AE/B Recombinant Identified in Japan. AB - The major circulating HIV-1 strains in Japan have been subtype B (B) followed by CRF01_AE (AE) in newly diagnosed HIV/AIDS cases. These two subtypes have distinct epidemiological characteristics; B predominates in men who have sex with men, while AE is observed mostly in heterosexuals engaging in high-risk sex. However, transmission networks of these two high-risk populations appear to be crossing over and diffusing. Here we report the emergence of previously unidentified HIV-1 AE/B recombinants in Japan. We initially identified 13 cases with discordant subtyping results with AE (gag MA)/B (pol PR-RT)/AE (env C2V3) by molecular phylogenetic analysis of 1,070 cases who visited Nagoya Medical Center from 1997 to 2012. Genetic characterization of full-length sequences demonstrated that they shared an identical recombinant structure, and was designated as CRF69_01B by the Los Alamos HIV National Laboratory. By reviewing gag, pol, and env sequences collected in the Japanese Drug Resistance HIV-1 Surveillance Network, we found five other CRF69_01B probable cases from different areas in Japan, suggesting that the strain is transmitted widely throughout the country. The time of the most recent common ancestor analyses estimated that CRF69_01B emerged between 1991 and 1995, soon after AE was introduced from neighboring countries in the mid 1990s. Understanding the current epidemic strains is important for the diagnosis and treatment of HIV/AIDS, as well as for the development of globally effective HIV vaccines. PMID- 26571153 TI - Alleviative effect of myricetin on ochratoxin A-induced oxidative stress in rat renal cortex: histological and biochemical study. AB - Ochratoxins (OTA) are secondary metabolites of Aspergillus and Penicillium. The detoxification of OTA has been of major interest due to its widespread threat to human health. We aimed to investigate the possible alleviative effect of myricetin (MYR) against OTA-induced damage in renal cortex of rats. Thirty adult male albino rats were randomized into five equal groups: control (untreated), vehicle control (0.5 ml corn oil/day including dimethylsulfoxide [DMSO]), MYR (100 mg MYR/kg b.w./day in distilled water), OTA (0.5 mg OTA/kg b.w./day; dissolved in 10% DMSO and then corn oil) and OTA + MYR group (received OTA and MYR at similar doses). All treatments were given by oral gavage for 2 weeks. At the end of the experiment, renal cortices were processed for light and electron microscope examinations. Immunohistochemical staining for localization of proliferating cell nuclear antigen (PCNA), p53 and transforming growth factor beta 1 (TGF-beta1) was carried out. Biochemical analysis of tissue glutathione peroxidase (GPX), catalase (CAT) and superoxide dismutase (SOD) were determined to evaluate oxidative stress. OTA administration induced deleterious renal injury evidenced by the structural and ultra-structural changes. Immunohistochemical expression of p53, PCNA and TGF-beta1 were significantly up regulated compared with control. Alterations in antioxidant parameters supported that oxidative stress was one of the mechanisms involved in OTA toxicity. On the contrary, co administration of MRY partially ameliorated OTA-induced renal injury. We suggest the potential effectiveness of MYR to counteract OTA-induced toxic oxidative stress on the renal cortex. PMID- 26571154 TI - The Evaluation of Donor Site Pain After Harvest of Tricortical Anterior Iliac Crest Bone Graft for Spinal Surgery: A Prospective Study. AB - STUDY DESIGN: A prospective cohort. OBJECTIVE: The aim of this study was to prospectively observe donor site pain, health-related quality-of-life outcomes, and complications following harvest of tricortical anterior iliac crest bone graft (AICBG) for anterior cervical discectomy and fusion (ACDF). SUMMARY OF BACKGROUND DATA: Persistent donor site pain from the anterior iliac crest has been reported to range between 2% and 40%. This morbidity has led surgeons to consider interbody alternatives for ACDF, which carry additional costs. METHODS: We prospectively enrolled 50 patients from 2 tertiary care centers over the course of 1 year observing complications and patient-reported outcomes. Patients filled out SF-12 and numeric rating scale (NRS) for pain in the arm, neck, and donor site pre-operatively and at 1 week, 2 weeks, 6 weeks, 3 to 6 months, and 1 year postoperatively. Outcomes were compared with a control group undergoing ACDF with allograft or Polyether ether ketone cages at 1 year. RESULTS: The mean +/- SD donor site pain at 1 week was 5.6 +/- 2.8 but decreased to 2.2 +/- 2.4 at 6 weeks and 1.1 +/- 1.8 at 1 year (P < 0.001). Including the 3 patients who were lost to follow-up, 10% of patients may have experienced persistent moderate or worse pain at 1 year. Linear regression analysis demonstrated that preoperative opioid use was an independent risk factor for increased donor site pain at 1 and 2 weeks (P < 0.05). There were no differences in outcomes at 1 year compared with the nonautograft group. There were 2 (4%) minor wound complications, both treated successfully with oral antibiotics. CONCLUSION: Tricortical AICBG for ACDF is not associated with major complications and only 4% of patients (potentially, maximum of 10%) experienced moderate, persistent donor site pain at 1 year. There is no difference in health-related outcomes between patients who have autograft with those who did not at 1 year. Preoperative opioid use is associated with increased donor site pain within the first 2 weeks postoperatively but not in the long term. At 6 weeks postoperatively, patients can expect the majority of their donor site pain to be resolved. LEVEL OF EVIDENCE: 2. PMID- 26571155 TI - Cost-Effectiveness of Surgical Versus Conservative Treatment for Thoracolumbar Burst Fractures. AB - STUDY DESIGN: Historical, register-based cohort study following 85 patients in the course of a time frame extending from 2 years before to 2 years after trauma occurrence. OBJECTIVE: To investigate the cost-effectiveness of surgery versus conservative management for thoracolumbar burst fractures. SUMMARY OF BACKGROUND DATA: Despite the prevalence of thoracolumbar burst fractures, consensus has still not been reached in terms of their clinical management and whereas from a health policy point of view, efficient use of resources is equally important, literature pertaining to this aspect is limited. METHODS: Consecutive patients who were admitted to a university clinic between 2004 and 2008 because of CT verified AO type A3 fractures (T11-L2), age 18 to 65 years Patients with neurological compromise, osteoporosis, or malignancy were not included. The cost parameter defined primary and secondary health-care use (2010 &OV0556;) and the effect parameter was based on three alternative measures of pain medication: morphine milligram and defined daily doses (DDD) of narcotic and nonnarcotic analgesics. For cost-effectiveness analysis, we employed a difference-in difference approach, including control for treatment selection (age, sex, and fracture type). Nonparametric bootstrapping was used to estimate conventional 95% confidence intervals of mean estimates. RESULTS: When taking into consideration all health-care consumption, surgical management was observed to cost an additional &OV0556;10,734 (4215; 15,144) as compared with conservative management. The differences on morphine at 527(-3031; 6,016) milligram, narcotic analgesics at -8(-176; 127) DDD, and nonnarcotic analgesics at -3(-72; 58) DDD were all insignificant The probability for surgery being cost-effective did not exceed 50% for any value of willingness to pay for effect. CONCLUSION: Surgical management does not seem to be a cost-effective strategy as compared with conservative management for traumatic thoracolumbar burst fractures without neurological deficits. In addition, higher-volume studies examining the clinical effect of alternative management strategies would be valuable. LEVEL OF EVIDENCE: 3. PMID- 26571156 TI - Greater Cervical Muscle Fat Infiltration Evaluated by Magnetic Resonance Imaging is Associated With Poor Postural Stability in Patients With Cervical Spondylotic Radiculopathy. AB - STUDY DESIGN: A population-based, cross-sectional study. OBJECTIVE: The aim of this study was to quantitatively evaluate the relationship between static postural stability and fat infiltration within cervical multifidus muscle in patients with cervical spondylotic radiculopathy (CSR). SUMMARY OF BACKGROUND DATA: CSR causes denervation by compression of nerve roots. This denervation is detected by fatty infiltration or results in fatty infiltration within muscles. Proprioceptive information in cervical multifidus muscle plays an important role in coordinated movement of postural stability; however, there have been few studies evaluating the relationship between postural stability and fat infiltration within cervical multifidus muscle among CSR patients. METHODS: Sixteen CSR patients with C6 injuries and 25 age-matched healthy controls underwent magnetic resonance images to examine bilateral cervical multifidus muscle. For evaluation of fat within muscle, a muscle fat index (MFI) was calculated by using both measurement of cervical multifidus muscle and intermuscular fat. Participants' postural stability at upright position with eyes opened and eyes-closed for 60 seconds was examined by a platform. Two parameters, the total length and the area of the center of pressure (COP), were used for evaluation. RESULTS: The CSR group showed significantly poorer postural stability than the control group (eyes-opened the total length; P < 0.05, eyes-closed the total length; P < 0.05, eyes-closed the area; P < 0.05). There were significant group differences at C4, C5, and C6 MFI (P < 0.05). In the CSR group, a correlation analysis demonstrated that the age, C4, C5, and C6 MFI values were significantly associated with the eyes-closed the total length of the COP (P < 0.05). CONCLUSIONS: Fat infiltration within muscle could lead to inhibition of normal activity of musculature. The present study suggests that fat within cervical multifidus muscle could directly cause postural instability in static standing, even though the proprioceptive information has normal lower limbs. PMID- 26571157 TI - Impact of Cervical Sagittal Alignment Parameters on Neck Disability. AB - STUDY DESIGN: Retrospective cross-sectional study. OBJECTIVE: Determine if pre operative cervical alignment serves as an independent predictor of pre-operative disability as measured by the neck disability index (NDI). SUMMARY OF BACKGROUND DATA: There is growing interest in the relationship between cervical sagittal alignment and clinical outcomes. While prior studies have shown that C2-C7 sagittal vertical axis (SVA) correlates with worse NDI scores in post-operative patients, no studies to date have examined the impact of cervical sagittal parameters on pre-operative disability in patients indicated for surgery. METHODS: Patients with pre-operative standing cervical radiographs, no prior cervical spine procedures and a pre-operative NDI score were identified. Measurements were made by two observers at two different time points. Parameters measured were: Occiput-C2 angle, C1-C2 angle, C2-C7 angle (CL), T1 slope (TS), TS minus CL (TS-CL), C2-C7 SVA, and C1-C7 SVA. Intra- and inter-observer reliability was calculated. Subgroup analyses of myelopathy vs. radiculopathy and deformity vs. no deformity was performed. A multivariate linear regression was performed. RESULTS: Ninety patients were included. Indications included cervical myelopathy (n = 63), cervical radiculopathy (n = 25), cervical stenosis (n = 9), and others (n = 5). CL averaged -13.7 +/- 14.9 degrees. TS averaged 30.7 +/- 10.4 degrees and C2-C7 SVA averaged 28.8 +/- 13.2 mm. Intra- and inter-observer reliability was good to excellent (ICC > 0.8). Increasing CL (r = 0.277, P = 0.009), increasing TS (r = -0.273, P = 0.011) and increasing TS-CL (r = -0.301, P = 0.005) were correlated with decreasing NDI. CL, TS and TS-CL were also strongly correlated with each other (r > 0.65, P < 0.001 for all bivariate correlations). A multivariate regression adjusting for age and indication showed TS-CL (P = 0.040) and C2-C7 SVA (P = 0.015) were independent predictors of NDI. CONCLUSION: Increasing CL, increasing TS and increasing TS-CL are correlated with decreasing pre-operative NDI. Low TS-CL and high C2-C7 SVA are independent predictors of high pre-operative NDI. LEVEL OF EVIDENCE: 4. PMID- 26571158 TI - Biomechanical Comparison of Sacral Fixation Characteristics of Standard S1 Pedicle Screw Fixation versus a Novel Constrained S1-Dual-Screw Anchorage in the S1-Pedicle and S1-Alar Bone. AB - STUDY DESIGN: Biomechanical Laboratory Study. OBJECTIVE: Analysis of the biomechanical characteristics of a novel sacral constrained dual-screw fixation device (S1-PALA), combining a S1-pedicle screw and a S1-ala screw, compared to a standard bicortical S1-pedicle screw (S1-PS) fixation. SUMMARY OF BACKGROUND DATA: Instrumented fusions to the sacrum are biomechanically challenging and plagued by a high risk of nonunion when S1-PS is used as the sole means of fixation. Thus, lumbopelvic fixation is increasingly selected instead, although associated with a reasonable number of instrumentation-related complications. METHODS: Around 30 fresh-frozen human sacral bones were harvested and embedded after CT scans. Instrumentation was conducted in alternating order with bicortical 7.0 mm S1-PS and with the S1-PALA including a S1-PS screw and a S1-ala screw, of 7.0 and 6.0 mm diameter, respectively. Specimens were subjected to cyclic loading with increasing loads (25-250 N) until a maximum of 2000 cycles or displacement >2 mm occurred. All implant sacral units (ISUs) were subject to coaxial pullout tests. Failure load, number of ISUs surpassing 2000 cycles, number of cycles, and loads at failure were recorded and compared. RESULTS: Donors' age averaged 77 +/- 14.2 years, and BMD was 115 +/- 64.8 mgCA-HA/ml. Total working length of screws implanted was 90 +/- 8.6 mm in the S1-PALA group and 46 +/- 5 mm in the S1-PS group (P = 0.0002). In the S1-PALA group, displacement >2 mm occurred after 845 +/- 325 cycles at 149 +/- 41 N compared to 512 +/- 281 cycles at 106 +/- 36 N in the S1-PS group (P = 0.004; P = 0.002). In coaxial pull-out testing, failure load was 2118.1 +/- 1166 N at a displacement of 2.5 +/- 1 mm in the S1-PALA group compared to 1375.6 +/- 750.1 N at a displacement of 1.6 +/- 0.5 mm in the S1-PS group (P = 0.0007; P = 0.0003). CONCLUSION: The novel sacral constrained dual-screw anchorage (S1-PALA) significantly improved holding strength after cyclic loading compared to S1-PS. The S1-PALA demonstrated mechanical potential as a useful adjunct in the armamentarium of lumbosacral fixations indicated in cases that need advanced construct stability, but where instrumentation to the ilium or distal dissection to S2 should be avoided. LEVEL OF EVIDENCE: N/A. PMID- 26571159 TI - Slump Test: Effect of Contralateral Knee Extension on Response Sensations in Asymptomatic Subjects and Cadaver Study. AB - STUDY DESIGN: Part 1: A randomized, single-blind study on the effect of contralateral knee extension on sensations produced by the slump test (ST) in asymptomatic subjects. Part 2: A cadaver study simulating the nerve root behavior of part 1. OBJECTIVE: Part 1: Test if contralateral knee extension consistently reduces normal stretch sensations with the ST.Part 2: Ascertain in cadavers an explanation for the results. SUMMARY OF BACKGROUND DATA: In asymptomatic subjects, contralateral knee extension reduces stretch sensations with the ST. In sciatica patients, contralateral SLR also can temporarily reduce sciatica. We studied this methodically in asymptomatic subjects before considering a clinical population. METHODS: Part 1: Sixty-one asymptomatic subjects were tested in control (ST), sham, or intervention (contralateral ST) groups and their sensation response intensity compared.Part 2: Caudal tension was applied to the L5 nerve root of 3 cadavers and tension behavior of the contralateral neural tissue recorded visually. RESULTS: Part 1: Reduction of stretch sensations occurred in the intervention group but not in control and sham groups (P <= 0.001).Part 2: Tension in the contralateral lumbar nerve roots and dura reduced in a manner consistent with the responses in the intervention (contralateral ST) group. CONCLUSION: Part 1: In asymptomatic subjects, normal thigh stretch sensations with the ST reduced consistently with the contralateral ST, showing that this is normal and may now be compared with patients with sciatica.Part 2: Contralateral reduction in lumbar neural tension with unilateral application of tension producing movements also occurred in cadavers, supporting the proposed explanatory hypothesis. PMID- 26571160 TI - Low Intensity Pulsed Ultrasound Promotes the Extracellular Matrix Synthesis of Degenerative Human Nucleus Pulposus Cells Through FAK/PI3K/Akt Pathway. AB - STUDY DESIGN: In vitro experimental study. OBJECTIVE: To investigate the effect of low-intensity pulsed ultrasound (LIPUS) on the extracellular matrix (ECM) synthesis of degenerative human nucleus pulposus cells and explore the molecular mechanism. SUMMARY OF BACKGROUND DATA: LIPUS has been used successfully for bone fracture healing and been proved to be effective in stimulating ECM metabolism in animal intervertebral disc cells. However, whether LIPUS also exerts an anabolic effect on degenerative human nucleus pulposus cells and the possible molecular mechanism is still unclear. METHODS: The degenerative human nucleus pulposus cells were cultured in calcium alginate beads. In the LIPUS group, cells were exposed to an average temporal intensity of 30 mW/cm2 and a frequency of 1.5 MHz of LIPUS 20 minutes daily for 1 week. The control group was cultured in the same way but without LIPUS stimulation. The LY294002 group was stimulated by LIPUS and treated with LY294002 simultaneously. The expression of aggrecan, collagen-II, Sox9, tissue inhibitor of metalloproteinase-,1 and matrix metalloproteinase-3 were evaluated by Enzyme-Linked Immunosorbent Assay, Western blot or RT-PCR. Expression of signaling proteins involved in FAK/PI3K/Akt pathway was studied by Western blot analysis. RESULTS: LIPUS significantly upregulated expression of aggrecan, collagen-II, Sox9, and tissue inhibitor of metalloproteinase-1 compared with control group, but inhibited secretion of matrix metalloproteinase-3. The study further demonstrated that the upregulation of aggrecan, collagen-II, and Sox9 was related to the activation of focal adhesion kinase (FAK)//PI3K/Akt pathway caused by LIPUS. Moreover, inhibition of PI3K/Akt significantly suppressed the special biological effect activated by LIPUS. CONCLUSION: LIPUS promotes the ECM synthesis of degenerative human nucleus pulposus cells through activation of FAK/PI3K/Akt pathway. LEVEL OF EVIDENCE: N/A. PMID- 26571161 TI - Pedicle Screw Fixation Under Nonaxial Loads: A Cadaveric Study. AB - STUDY DESIGN: An experimental study of pedicle screw fixation in human cadaveric vertebrae. OBJECTIVE: The aim of this study was to experimentally characterize pedicle screw fixation under nonaxial loading and to analyze the effect of the surgeons' screw and placement choices on the fixation risk of failure. SUMMARY OF BACKGROUND DATA: Pedicle screw fixation performance is traditionally characterized with axial pullout tests, which do not fully represent the various tridimensional loads sustained by the screws during correction maneuvers of severe spinal deformities. Previous studies have analyzed the biomechanics of nonaxial loads on pedicle screws, but their effects on the screw loosening mechanisms are still not well understood. METHODS: A design of experiment (DOE) approach was used to evaluate 2 screw thread designs (single-lead and dual-lead threads), 2 insertion trajectories in the transverse and sagittal planes, and 2 loading directions (lateral and cranial). Pedicle screws were inserted in both pedicles of 12 cadaveric lumbar vertebrae for a total of 24 tests. Four sinewave loading cycles (0-400 N) were applied, orthogonally to the screw axis, at the screw head. The resulting forces, displacements, and rotations of the screws were recorded. RESULTS: In comparison to the other cycles, the first loading cycle revealed important permanent deformation of the bone (mean permanent displacement of the screw head of 0.79 mm), which gradually accumulated over the following cycles to 1.75 mm on average (plowing effect). The cranial loading direction caused significantly lower (P < 0.05) bone deformation than lateral loading. The dual-lead screw had a significantly higher (P < 0.05) initial stiffness than the single-lead thread screw. CONCLUSIONS: Nonaxial loads induce screw plowing that lead to bone compacting and subsequent screw loosening or even bone failure, thus reducing the pedicle screw fixation strength. Lateral loads induce greater bone deformation and risks of failure than cranial loads. LEVEL OF EVIDENCE: N/A. PMID- 26571162 TI - Patient Factors That Influence Decision Making: Randomization Versus Observational Nonoperative Versus Observational Operative Treatment for Adult Symptomatic Lumbar Scoliosis. AB - STUDY DESIGN: A prospective study with randomized and observational cohorts. OBJECTIVE: The aim of this study was to determine baseline variables affecting adult symptomatic lumbar scoliosis (ASLS) decision making to participate in randomization (RAND), observational nonsurgical (OBS-NS), or observational surgical (OBS-S) cohorts. SUMMARY OF BACKGROUND DATA: Multiple factors play a key role in a patient's decision to be randomized or to choose an OBS-NS or OBS-S course for ASLS. Studies evaluating these factors are limited. METHODS: Eligible candidates (patients with ASLS and no prior spinal fusion deformity surgery) from 9 centers participated in a RAND, OBS-NS, or OBS-S cohort study. Baseline variables (demographics, socioeconomics, patient-reported outcomes [PROs], Functional Treadmill Test, radiographs) were analyzed. RESULTS: Two hundred ninety-five patients were enrolled: 67 RAND, 115 OBS-NS, 113 OBS-S. Subanalysis of older patients (60-80 years) found 54% of OBS-NS had college degrees compared with 82% of RAND and 71% of OBS-S (P = 0.010). Patients deciding to be part of a RAND cohort have similar clinical characteristics to the OBS-S cohort. OBS-S had more symptomatic spinal stenosis (57% vs. 39%, P = 0.029) and worse scores than OBS-NS on the basis of PROs (Back Pain Numerical Rating Scale [NRS 6.3 vs. 5.5, P = 0.007]; Scoliosis Research Society [SRS] Pain [2.8 vs. 3.0, P = 0.018], Function [3.1 vs. 3.4, P = 0.019] and Self-Image [2.7 vs. 3.1, P = 0.002]; Oswestry Disability Index (ODI) [36.9 vs. 31.8, P = 0.029]; post-Treadmill back [5.8 vs. 4.4, P = 0.002] and leg [4.3 vs. 3.1, P = 0.037] pain NRS and larger lumbar coronal Cobb angles (56.5 degrees vs. 48.8 degrees, P < 0.001). RAND had more baseline motor deficits (10.4% vs. 1.7%, P = 0.036) and worse scores than OBS-NS on the basis of ODI (38.8 vs. 31.8, P = 0.006), SRS Function [3.1 vs. 3.4, P = 0.034], and Self-Image [2.7 vs. 3.1, P = 0.007]. CONCLUSION: Patients with worse PROs, more back pain, more back and leg pain with ambulation, and larger lumbar Cobb angles are more inclined to select surgical over nonsurgical management. PMID- 26571163 TI - Patients' and Physiotherapists' Views on Triggers for Low Back Pain. AB - STUDY DESIGN: A cross-sectional survey. OBJECTIVE: The aim of this study was to compare patients' and physiotherapists' views on triggers for low back pain (LBP) and to identify any novel factors not previously reported. SUMMARY OF BACKGROUND DATA: Most research on risk factors for LBP is guided by the views of clinicians and researchers, not patients. Consequently, potentially valuable information about risk factors for LBP is not available from those suffering the condition. This study aimed to compare patients' and physiotherapists' views on triggers for LBP and to identify any novel factors not previously reported. METHODS: One hundred two physiotherapists and 999 patients with a sudden, acute episode of LBP participated in this study. Participating physiotherapists were asked to nominate the most likely short-term risk factors to trigger a LBP episode. Similarly, patients were asked what they thought had triggered their onset of LBP. Responses were coded into risk factor categories and subcategories by 2 independent researchers. Endorsement of each category was compared using the Pearson Chi square statistic. RESULTS: Both patients and physiotherapists endorsed biomechanical risk factors as the most important risk factor category (87.7% and 89.4%, respectively) and had similar levels of endorsement for 3 of the top 5 subcategories (lifting, bending, and prolonged sitting). There were significant differences in endorsement of awkward postures (13.4% vs 1.2%; P < 0.001) sports injuries (15.9% vs 4.7%; P < 0.001), physical trauma (3.4% vs 9.2%; P < 0.001), and unaccustomed activity (2.3% vs 7.3%; P < 0.001) by patients and physiotherapists, respectively. CONCLUSION: Overall, patients' and physiotherapists' views were remarkably similar. Both patients and physiotherapists endorsed lifting as the most important trigger for LBP and agreed on 3 of the top 5 (lifting, bending, and prolonged sitting). No new risk factors were suggested by patients. LEVEL OF EVIDENCE: 2. PMID- 26571164 TI - Delayed Postoperative Neurologic Deficits in Spinal Deformity Surgery. AB - STUDY DESIGN: A cross-sectional survey of surgeon members of the Scoliosis Research Society (SRS). OBJECTIVE: This study sought to characterize the incidence, clinical presentation, diagnostic workup, treatment, and neurologic prognosis following delayed postoperative neurologic deficit (DPND) in patients undergoing spinal deformity surgery. SUMMARY OF BACKGROUND DATA: DPND is a potentially devastating condition following spinal surgery, characterized by the development of a neurological deficit within hours or days of the surgical procedure. To date, only case reports and small case series have been published on the topic. METHODS: We developed a survey to characterize DPND following spinal deformity surgery. This survey was distributed to surgeon members of the SRS through email and standard mail. The overall response rate was 38% (352/929). RESULTS: Our results suggest an estimated DPND incidence of 1 of 9910 cases (0.01%). Eighty-one surgeons (23%) experienced at least 1 DPND in the past 10 years (92 total cases). Most common diagnoses were scoliosis (69%), kyphosis (23%), and spondylolisthesis (14%); 20% were revision surgeries. The number of hours to deficit onset was as follows: 1 to 12 (36%), 13 to 24 (27%), 25 to 48 (27%), more than 48 (10%). The most commonly cited sources of injury included ischemic injury (38%) and cord compression (15%). Forty-one percent experienced complete neurologic recovery, 26% partial, and 33% no recovery. Twenty-one percent of patients achieved final neurologic status within 1 week, 38% by 1 month, and 73% by 6 months. Patients with compression-related DPND had a significantly greater likelihood of experiencing some neurologic recovery (>=1 ASIA Grade) than ischemia-related DPND (86% versus 51%, P = 0.049). CONCLUSIONS: DPND occurs at an estimated incidence of 0.01%. Sixty-three percent of DPND cases occurred within the first 24 hours and 90% within 48 hours. Complete (41%) or partial (26%) neurologic recovery may be expected, especially in compression related DPND, emphasizing the need for perioperative vigilance, prompt recognition, and early intervention. LEVEL OF EVIDENCE: 4. PMID- 26571165 TI - Calculation of the Target Lumbar Lordosis Angle for Restoring an Optimal Pelvic Tilt in Elderly Patients With Adult Spinal Deformity. AB - STUDY DESIGN: This investigation consisted of a cross-sectional study and a retrospective multicenter case series. OBJECTIVE: This investigation sought to identify the ideal lumbar lordosis (LL) angle for restoring an optimal pelvic tilt (PT) in patients with adult spinal deformity (ASD). SUMMARY OF BACKGROUND DATA: To achieve successful corrective fusion in ASD patients with sagittal imbalance, it is essential to correct the sagittal spinal alignment and obtain a suitable pelvic inclination. We determined the LL angle that would restore the optimal PT following ASD surgery. METHODS: The cross-sectional study included 184 elderly volunteers (mean age 64 years) with an Oswestry Disability Index score less than 20%. The relationship between PT or LL and the pelvic incidence (PI) in normal individuals was investigated. The second study included 116 ASD patients (mean age 66 years) who underwent thoracolumbar corrective fusion at 1 of 4 spine centers. The postoperative PT values were calculated using the parameters measured. On the basis of these studies, an ideal LL angle was determined. RESULTS: In the cross-sectional study, the linear regression equation for the optimal PT as a function of PI was "optimal PT = 0.47 * PI - 7.5." In the second study, the postoperative PT was determined as a function of PI and corrected LL, using the equation "postoperative PT = 0.7 * PI - 0.5 * corrected LL + 8.1." The target LL angle was determined by mathematically equalizing the PTs of these 2 equations: "target LL = 0.45 * PI + 31.8." CONCLUSION: The ideal LL angle can be determined using the equation "LL = 0.45 * PI + 31.8," which can be used as a reference during surgical planning in ASD cases. LEVEL OF EVIDENCE: 4. PMID- 26571166 TI - Unilateral Acute Angle-Closure Glaucoma After Lumbar Spine Surgery: A Case Report and Systematic Review of the Literature. AB - STUDY DESIGN: A case report and literature review is presented of a patient that developed acute angle-closure glaucoma (AACG) after undergoing spine surgery in the prone position. OBJECTIVES: To report a case of AACG after undergoing spine surgery in the prone position and describe potential causes and implications for future care. SUMMARY OF BACKGROUND DATA: Visual loss is a devastating complication after spine surgery and is most often due to ischemic optic neuropathy. Although far less common, three cases of AACG have previously been reported, all of which were bilateral. Mydriatric agents and prone positioning were hypothesized as precipitating factors as both are known to increase intraocular pressure. In contrast to other visual loss diseases after spine surgery, AACG is amenable to treatment if recognized and treated early; however, its diagnosis is often complicated by patients presenting days after surgery. We report the case of a 65-year-old male who underwent multilevel revision spine surgery in the prone position and developed unilateral AACG after discharge on postoperative day 5. METHODS: The case report is described. A literature review was performed using PubMed and keywords. The resulting articles were evaluated and references checked for additional cases. RESULTS: The case herein resulted in no vision loss after the AACG was treated with laser iridotomy. The patient had a history of ocular issues in the affected side, highlighting the potential role anatomy plays in the development of AACG following spine surgery. Three reports of AACG were found after the literature review was performed. CONCLUSION: Although it is not practical to screen all patients through ophthalmologic referral, there may be a role for targeted preoperative screening of patients with risk factors for AACG. LEVEL OF EVIDENCE: 5. PMID- 26571167 TI - Comparison of Ocular Radiation Exposure Utilizing Three Types of Leaded Glasses. AB - STUDY DESIGN: Anthropomorphic phantoms were used to measure radiation exposure to the surgeon phantom's eye. Groups analyzed were: Group 1-no glasses (None); Group 2-leaded lenses without lead sides (WOLS); Group 3-leaded lenses with lead sides (WLS); and Group 4-sport wraparound leaded glasses (Sport). Glasses were 0.75 mm lead equivalent. OBJECTIVE: To evaluate the efficacy of three types of leaded eyeglasses at reducing radiation exposure to the lens during typical views of minimally invasive spine surgery. SUMMARY OF BACKGROUND DATA: Minimally invasive spine surgery relies upon fluoroscopic x-ray. Ocular radiation exposure is associated with cataract formation. Leaded glasses can reduce ocular radiation exposure. METHODS: Fifteen individual 20-second exposures with the fluoroscopic C arm in the anteroposterior (AP) and lateral positions, with phantom head positioned at 0, 45, and 90 degrees to the fluoroscope were performed. Radiation was measured using a solid-state dosimeter. Student t test was used to calculate significance. RESULTS: All glasses (WOLS, WLS, and Sport) had significant reductions in ocular radiation versus no glasses, at all individual head positions (P <= 1.31 * 10). Sport had significantly lower ocular radiation dose than WLS at all head positions except at 90 degrees AP (P = 0.001). WOLS had significantly lower ocular radiation dose than Sport in three out of six cases including phantom head at 0 degrees AP (P = 0.0003), 90 degrees AP (P = 4.46 * 10), and 90 degrees lateral (P = 7.38 * 10). WOLS had significantly lower radiation dosage at all head positions than WLS except at 45 degrees AP (P = 0.303). All glasses resulted in a significant reduction in total radiation dose from all head positions over no glasses (P <= 8.37 * 10). CONCLUSION: We demonstrate a significant reduction in ocular radiation exposure with all three types of leaded glasses. Lead glasses, WOLS and Sport, were the most effective at reducing ocular radiation. LEVEL OF EVIDENCE: 3. PMID- 26571168 TI - Treatment of Extreme Tuberculous Kyphosis Using Spinal Osteotomy and Halo-Pelvic Traction: A Case Report. AB - STUDY DESIGN: A case report of treatment of extreme tuberculous kyphosis using spinal osteotomy and halopelvic traction. OBJECTIVE: The aim of this study was to describe the process and outcome of treatment of a case with extreme tuberculous kyphosis using spine osteotomy and halo-pelvic traction. SUMMARY OF BACKGROUND DATA: Spinal tuberculosis causes destruction, deformity, and paraplegia. Long standing kyphosis may progress with growth in children, and produces respiratory insufficiency, and neurologic deficit. Surgery may help to prevent or reverse the neurological deterioration, while improving pulmonary function in cases with significant spinal deformity. METHODS: Review of records and radiographs. RESULTS: A 24-year-old female with tuberculous angular kyphosis presented with bilateral lower extremities paresis and dyspnea. The vertebral bodies from T3 to T9 were severely destructed, with a Cobb's angle of 180 degrees on radiographs. The total duration of distraction using halopelvic apparatus kept 10 months. During the duration of traction, the patient underwent a posterior release surgery because flexibility of the kyphosis was not sufficient. Pedicle subtraction osteotomy and pedicle screw fixation were performed to achieve final correction when the Cobb's angle decreased to about 80 degrees . After the whole treatment of halopelvic traction and spine ostetomy, the patient's height increased nearly 30 cm, whereas the angular kyphosis was corrected to a Cobb's angle of 30 degrees . The patient had no complication and neurological deterioration during the treatment. Correction angle and good sagittal balance were well maintained in the duration of 2 years' follow-up. CONCLUSION: The halo pelvic apparatus produces high corrective forces applied over a long period, and it provides a slow and safe correction of deformity. In cases of extreme kyphotic deformity, halopelvic traction is an appropriate technique, while avoiding many serious complications from a rapid, one-stage correction. LEVEL OF EVIDENCE: N/A. PMID- 26571169 TI - Impact of Lumbar Fusion on Health Care Resource Utilization. AB - STUDY DESIGN: A longitudinal cohort. OBJECTIVE: The aim of this study was to determine the extent of health care resource utilization decrease 2 years after lumbar spinal fusion. SUMMARY OF BACKGROUND DATA: Despite the assumption that surgery will minimize the need for ongoing nonsurgical treatment, the impact of lumbar fusion on subsequent health care resource utilization has not been effectively studied. METHODS: Patients who had continuous coverage by a major insurer during the year before decompression and posterolateral instrumented spinal fusion, and the 2 and a half years following were identified. All charges processed during this time-period were collected. Charges associated with the index surgery, the 90-day postoperative period, and those unrelated to spinal care were excluded. Associations with Oswestry Disability Index (ODI) score improvement at 2 years after surgery and health care resource utilization were determined. RESULTS: Sixty-six patients were included in the analysis. The mean age was 59 years and 39% were males. There was a decrease in health care utilization costs 1 year after surgery ($3267.59) compared with pre-op ($4246.32), but this was not statistically significant (P = 0.197). There was a statistically significant decrease in costs during the second year after surgery ($1420.97) compared with either pre-op (P = 0.000) or 1-year costs (P = 0.001). No statistically significant correlations could be found between change in ODI scores and costs incurred at either year post-op. CONCLUSION: Health care utilization decreased at 1 year and significantly at 2 years after lumbar fusion. However, there was no correlation between use of nonsurgical resources and clinical outcome based on ODI scores. This raises the question as to whether these resources were used in a rational manner. This cooperative study between a major insurer and a tertiary spine center provides improved insight into the cost profile of lumbar fusion surgery. Further study is needed to determine whether ongoing post-op treatment is necessary or simply established practice. LEVEL OF EVIDENCE: 2. PMID- 26571170 TI - Antimicrobial Effect of Polymer-Based Silver Nanoparticle Coated Pedicle Screws: Experimental Research on Biofilm Inhibition in Rabbits. AB - STUDY DESIGN: Antimicrobial effect of a novel silver-impregnated pedicle screw in rabbits. OBJECTIVE: A novel spine implant model was designed to study the antimicrobial effect of a modified Titanium (Ti) pedicle screws with methicillin resistant Staphylococcus aureus (MRSA) in multiple surgical sites in the lumbar spine of a rabbit. SUMMARY OF BACKGROUND DATA: Infection in spinal implant is of great concern. Anti-infection strategies must be tested in relevant animal models that will lead to appropriate clinical studies. METHODS: Fourteen New Zealand white rabbits were divided into 2 groups: group 1: infected unmodified Ti screw group (n = 6), and group 2: infected polyethylene glycol grafted, polypropylene based silver nanoparticle (PP-g-PEG-Ag) covered Ti screw group (n = 6), and 2 rabbits as sterile (sham-operated and control) group. In all groups, left L4 right L6 vertebra levels were exposed and screws were drilled to transverse processes after contamination of burr holes and surrounding tissue with 0.1 mL of 10 colony forming units (CFU) MRSA solutions in groups 1 and 2. After 21 days, samples were collected and infection was analyzed via light and scanning electron microscopy and culturing. Silver nanoparticles (Ag-NP) on the screws and tissues were assayed pre and postoperatively. RESULTS: The bacterial colony count for modified-Ti screw group was lower than for unmodified Ti screw (17.2 versus 200 x 10(3) CFU/mL, P = 0.029) with less biofilm formation. There was no difference in duration of surgery among groups and within the surgical sites. Ag-NPs were detected on the screw surface postoperatively. CONCLUSION: This novel experimental design of implantation in rabbits is easy to apply and resembles human stabilization technique. Modified Ti screws were shown to have antimicrobial effect especially inhibiting the biofilm formation. This anchored Ag NPs that remained after 21st day of implantation shows that it is resistant to tapping forces of the screw. PMID- 26571171 TI - Cadaveric Analysis of Posterior Pharyngoesophageal Wall Thickness: Implications for Anterior Cervical Spine Surgery. AB - STUDY DESIGN: A cadaveric study. OBJECTIVE: To investigate possible variations of posterior pharyngoesophageal (PE) wall thickness in the horizontal plane and their implications for anterior spine surgery. SUMMARY OF BACKGROUND DATA: Lower cervical levels (C5-7) are most commonly involved in cases of PE injury, and PE wall thickness could be one of the proposed reasons for the high incidence of PE injuries at these levels. The purpose of this study was to document thickness variations of the posterior PE wall at different cervical spine levels, because the study could provide valuable anatomical information that could reduce iatrogenic injuries caused by retractors or instrumentation. METHODS: Thirteen formaldehyde-fixed cadaveric specimens were included in current study. PE specimens were harvested from epiglottis to suprasternal notch within 2 months of formaldehyde fixation and sectioned axially. Four slices corresponding to the superior and inferior borders of thyroid cartilage, cricoid cartilage, and 2 cm below cricoid cartilage were sectioned. Posterior PE wall thickness was measured at three zones as follows: median, lateral, and paramedian. Posterior PE wall thicknesses were measured by a pathologist. RESULTS: Based on one-way ANOVA, posterior PE wall thickness showed several significantly different variations depending on cervical level and horizontal plane. PE walls were thinnest at the level of cricoid cartilage (P < 0.05). This difference was more pronounced in the median zone, because of thickness variations in the muscular layer (P < 0.001). CONCLUSION: The posterior PE wall was thinnest in the median zone at the cricoid cartilage level. Variations in muscle layer thickness caused PE wall thickness differences. The smaller wall thickness at the level of the cricoids cartilage and in the midline zone may place it at higher risk of injury, and special care should be taken during dissection, retraction, and instrument placement. LEVEL OF EVIDENCE: 3. PMID- 26571172 TI - Association Between the Plasma Levels of Mediators of Inflammation With Pain and Disability in the Elderly With Acute Low Back Pain: Data From the Back Complaints in the Elders (BACE)-Brazil Study. AB - STUDY DESIGN: Cross-sectional study with subsample of elderly women with acute low back pain (LBP), from Back Complaints in the Elders-Brazil (BACE-Brazil) OBJECTIVE: To investigate the association between plasma levels of mediators of inflammation (interleukin-1 beta (IL-1beta), IL-6, tumor necrosis factor alpha (TNF-alpha), and soluble TNF receptor 1 (sTNF-R1)) with pain and disability experienced by elderly women with acute LBP. SUMMARY OF BACKGROUND DATA: Among the elderly, LBP is a complaint of great importance and can lead to disability. Inflammatory cytokines are elevated in painful conditions, and may promote pain. METHODS: We included 155 community-dwelling elderly women (age >= 65 yr), who presented with a new (acute) episode of LBP. Enzyme-linked immunosorbent assays were used to measure TNF-alpha, sTNF-R1, IL-1beta, and IL-6. Disability was assessed using the Roland Morris Disability Questionnaire; pain was assessed using the McGill Pain Questionnaire. Linear regression models were fit with each pain and disability outcome as dependent variables: Present Pain Intensity; Qualities of pain; Severity of pain in the last week; LBP frequency and disability. RESULTS: Depressive symptoms and IL-6 were associated and explained 20.9% of "qualities of pain" variability. TNF-alpha, sTNFR1, education, body mass index, and depressive symptoms explained 8.4% of "Severity of pain in the past week" variability. TNF-alpha, education, BMI, depressive symptoms, present pain intensity, qualities of pain, and LBP frequency explained 48.6% of "disability." No associations between inflammatory cytokines and "present pain intensity" and "LBP frequency" were found. CONCLUSION: Our results demonstrate associations between inflammatory markers (TNF-alpha and sTNFR1) and pain severity, IL-6 was associated with the qualities of pain, and TNF-alpha was also associated with disability. These inflammatory mediators represent new markers to be considered in the assessment and treatment of elderly patients with LBP. LEVEL OF EVIDENCE: 5. PMID- 26571173 TI - Dedicated Spine Measurement Software Quantifies Key Spino-Pelvic Parameters More Reliably Than Traditional Picture Archiving and Communication Systems Tools. AB - STUDY DESIGN: Measurement reliability study of adult spinal deformity (ASD) patient radiographs using intraclass correlation coefficients (ICC) and variance. OBJECTIVE: The aim of the study was to compare picture archiving and communication systems (PACS) to dedicated spine measurement software (SMS). SUMMARY OF BACKGROUND DATA: Accurate radiographic measurement of sagittal alignment is essential for evaluating ASD. PACS measurements often necessitate rudimentary techniques and estimations of anatomic landmarks and angles. Though SMS has been studied and validated, no studies directly compare PACS to SMS. METHODS: Eleven independent observers (7 spine surgeons, 4 researchers) digitally measured 20 ASD radiographs for pelvic incidence (PI), pelvic tilt (PT), lumbar lordosis (LL), PI-LL, thoracic kyphosis (TK), and sagittal vertical axis (SVA). Round 1 used PACS basic line/angle tools; Round 2 used a validated SMS that automatically calculates spino-pelvic parameters from 6 user-identified landmarks. Means, coefficient of variance (CV), and intraclass correlation coefficients (ICC) were analyzed. RESULTS: PACS measurements were significantly greater than SMS (PI, PT, PI-LL: P < 0.0001), though within clinical and measurement margins of error. Excluding TK, the variations in measurement (CV) were significantly greater for PACS (14-34%) vs. SMS (11-23%). Reliability was greater in SMS than PACS for PI, PT, PI-LL, LL, and SVA. The greatest differences in intraclass correlation coefficients (ICC) between PACS and SMS were in PI (PACS: 0.647; SMS: 0.810) and PI-LL (PACS: 0.921; SMS: 0.970). Among surgeons, the differences between PACS and SMS were augmented, and SMS had higher intraclass correlation coefficients (ICC) than PACS for all parameters (mean intraclass correlation coefficients [ICC] 0.931 vs. 0.861). Among surgeons, PI had the lowest reliability ( PACS: 0.505; SMS: 0.752) and SVA had the highest ( PACS: 0.985; SMS: 0.994). CONCLUSION: SMS provides significantly more reliable measurements than PACS, especially among surgeons. Consistent use of SMS in the evaluation and surgical planning of ASD patients appears necessary given the significant differences in values, variance, and reliability between PACS and SMS. PMID- 26571174 TI - The Health Impact of Symptomatic Adult Spinal Deformity: Comparison of Deformity Types to United States Population Norms and Chronic Diseases. AB - STUDY DESIGN: A retrospective analysis of a prospective, multicenter database. OBJECTIVE: The aim of this study was to evaluate the health impact of symptomatic adult spinal deformity (SASD) by comparing Standard Form Version 2 (SF-36) scores for SASD with United States normative and chronic disease values. SUMMARY OF BACKGROUND DATA: Recent data have identified radiographic parameters correlating with poor health-related quality of life for SASD. Disability comparisons between SASD patients and patients with chronic diseases may provide further insight to the disease burden caused by SASD. METHODS: Consecutive SASD patients, with no history of spine surgery, were enrolled into a multicenter database and evaluated for type and severity of spinal deformity. Baseline SF-36 physical component summary (PCS) and mental component summary (MCS) values for SASD patients were compared with reported U.S. normative and chronic disease SF-36 scores. SF-36 scores were reported as normative-based scores (NBS) and evaluated for minimally clinical important difference (MCID). RESULTS: Between 2008 and 2011, 497 SASD patients were prospectively enrolled and evaluated. Mean PCS for all SASD was lower than U.S. total population (ASD = 40.9; US = 50; P < 0.05). Generational decline in PCS for SASD patients with no other reported comorbidities was more rapid than U.S. norms (P < 0.05). PCS worsened with lumbar scoliosis and increasing sagittal vertical axis (SVA). PCS scores for patients with isolated thoracic scoliosis were similar to values reported by individuals with chronic back pain (45.5 vs 45.7, respectively; P > 0.05), whereas patients with lumbar scoliosis combined with severe sagittal malalignment (SVA >10 cm) demonstrated worse PCS scores than values reported by patients with limited use of arms and legs (24.7 vs 29.1, respectively; P < 0.05). CONCLUSIONS: SASD is a heterogeneous condition that, depending upon the type and severity of the deformity, can have a debilitating impact on health often exceeding the disability of more recognized chronic diseases. Health care providers must be aware of the types of SASD that correlate with disability to facilitate appropriate diagnosis, treatment, and research efforts. LEVEL OF EVIDENCE: 3. PMID- 26571175 TI - MicroRNA-221 Regulates Hypertrophy of Ligamentum Flavum in Lumbar Spinal Stenosis by Targeting TIMP-2. AB - STUDY DESIGN: A study of lumbar ligamentum flavum (LF). OBJECTIVE: The aim of this study was to identify LF hypertrophy related microRNAs (miRNAs) expression profile and to investigate the role of miRNAs in the development of LF hypertrophy in lumbar spinal stenosis (LSS). SUMMARY OF BACKGROUND DATA: Although histologic and biologic literature on LF hypertrophy is available, the pathomechanism is still unknown. Accumulating evidence suggests that microRNAs (miRNAs) participate in many physiologic processes, including cell proliferation, differentiation, and fibrosis, but the role of specific miRNAs involved in LF hypertrophy remains elusive. METHODS: An initial screening of LF tissues miRNA expression by miRNA microarray was performed using samples from 10 patients and 10 controls, respectively. Subsequently, differential expression was validated using qRT-PCR. Then, functional analysis of the miRNAs in regulating collagens I and III expression was carried out. Western blotting and luciferase reporter assay were also used to detect the target gene. In addition, the thickness of the LF at the level of the facet joint was measured on axial T1-weighted magnetic resonance images. RESULTS: We identified 18 miRNAs that were differentially expressed in patients compared with controls. Following qRT-PCR confirmation, miR 221 was significantly lower in LF tissues of patients than controls. The LF was significantly thicker in patients than that in controls. Bioinformatics target prediction identified tissue inhibitors of matrix metalloproteinase (TIMP)-2 as a putative target of miR-221. Furthermore, luciferase reporter assays demonstrated that miR-221 directly targets TIMP-2 and affects the protein expression of TIMP-2 in fibroblasts isolated from LF. Of note, miR-221 mimic reduced mRNA and protein expression of collagens I and collagen III in fibroblasts isolated from LF. CONCLUSION: The downregulation of miR-221 might contribute to LF hypertrophy by promoting collagens I and III expression via the induction of TIMP-2. Our study also underscores the potential of miR-221 as a novel therapeutic target in LSS. LEVEL OF EVIDENCE: 3. PMID- 26571176 TI - Use of Recombinant Human Bone Morphogenetic Protein-2 in the Treatment of Degenerative Spondylolisthesis. AB - STUDY DESIGN: A questionnaire survey. OBJECTIVE: To report the current use of recombinant human bone morphogenetic protein-2 (rhBMP-2) in lumbar fusion procedures for the treatment of degenerative spondylolisthesis (DS), and identify associated factors including fusion technique, surgeon location, surgeon specialty, or surgeon practice model. SUMMARY OF BACKGROUND DATA: The prevalence of rhBMP-2 use in fusions increased dramatically from 0.7% in 2002 to 24.7% in 2006, however more recent studies have identified significant complications with its use. Furthermore, an independent review of the industry-sponsored trial data has demonstrated no significant difference in fusion rates or clinical results with the use of rhBMP-2 compared with iliac-crest autograft. METHODS: In July 2014, a survey was sent requesting information on the usage of rhBMP-2 in the treatment of DS. Determinants included the fusion technique, geographic location, specialty, and associated practice models. No funding was received for this work. RESULTS: Overall, 7.8% +/- 2.0% of surgeons reported using rhBMP-2 when performing an open L4-L5 posterolateral fusion for DS; 6.2% +/- 1.8% reported using rhBMP-2 for an open L4-L5 interbody fusion, and 12.1% +/- 2.5% reported using rhBMP-2 for a L4-L5 minimally invasive (MIS) interbody fusion. The variables that were statistically associated with the use of rhBMP-2 were North America surgeons (P < 0.0001) and the type of procedure (P = 0.0005). CONCLUSION: Compared with historical data, there has been a dramatic decrease in the number of surgeons using rhBMP-2 in lumbar fusion procedures for the treatment of DS. Currently, rhBMP-2 is more commonly used by surgeons in North America and those performing MIS interbody fusions. LEVEL OF EVIDENCE: N/A. PMID- 26571177 TI - Clinical Relevance of the SRS-Schwab Classification for Degenerative Lumbar Scoliosis. AB - STUDY DESIGN: Retrospective cohort study. OBJECTIVE: The aim of this study was to evaluate the clinical relevance of the SRS-Schwab classification for degenerative lumbar scoliosis (DLS). SUMMARY OF BACKGROUND DATA: The SRS-Schwab classification has been presented and validated as a useful tool for adult spinal deformity (ASD). This classification includes various types of ASD (degenerative de novo scoliosis or adult form of idiopathic scoliosis). However, DLS has different clinical characteristics and pathophysiology compared with other forms of ASD. METHODS: In this retrospective cohort study, 216 (146 conservatively treated and 70 surgically treated) DLS patients were enrolled. The average patient age was 72.1 +/- 7.4 years. Clinical parameters for disability were measured using Oswestry disability index (ODI) and back and leg pain numerical rating scale. Radiographic parameters included SRS-Schwab sagittal modifiers (pelvic tilt [PT]; sagittal vertical axis [SVA];pelvic incidence-lumbar lordosis [PI-LL]), T1 pelvic angle, and coronal parameters (Cobb's angle [CA]; coronal imbalance [CI]; coronal deviation distance [CDD]; tilting angle [TA]). Correlations between clinical parameters and radiographic parameters were assessed and surgical rates along the SRS-Schwab sagittal modifiers were evaluated. RESULTS: Only PI-LL as a sagittal radiographic parameter showed a weak correlation with clinical parameters (r = 0.137-0.176) (P < 0.05). Coronal parameters such as CA, CI, CDD, and TA also showed weak correlation with clinical parameters (r = 0.137-0.202) (P < 0.05). Multiple regression analysis identified CA, CI, CDD, and PI-LL to be correlated with clinical parameters. On analysis for clinical outcomes (surgical rates and patient self-reported disability) along the grades of the SRS-Schwab sagittal modifiers, PT and SVA were not related to higher surgical rates or disability. CONCLUSION: Even though some radiological parameters showed statistically significant results, correlation between radiological and clinical parameters was weak. Not only deformity but also other clinical factors should be considered when evaluating DLS. LEVEL OF EVIDENCE: 4. PMID- 26571178 TI - Identifying Spinal Injury Patterns in Underbody Blast to Develop Mechanistic Hypotheses. AB - STUDY DESIGN: A retrospective case series of UK victims of blast injury. OBJECTIVE: To identify the injury patterns in the spine caused by under-vehicle blast, and attempt to derive the mechanism of those injuries. SUMMARY OF BACKGROUND DATA: The Improvised Explosive Device has been a feature of recent conflicts with frequent attacks on vehicles, leading to devastating injuries. Vehicle design has evolved to reduce the risk of injury to occupants in underbody blast, where the device detonates beneath the vehicle. The mechanism of spinal injury in such attacks is not well understood; understanding the injury mechanism is necessary to produce evidence-based mitigation strategies. METHODS: A Joint Theatre Trauma Registry search identified UK victims of blast between 2008 and 2013. Each victim had their initial scan reviewed to classify spinal fractures. RESULTS: Seventy-eight victims were identified, of whom 53 were survivors. There were a total of 284 fractures, including 101 thoracolumbar vertebral body fractures and 39 cervical spine fractures. Most thoracolumbar fractures were wedge compression injuries. Most cervical spine fractures were compression extension injuries.The most common thoracic and lumbar body fractures in this group suggest a flexed posture at the time of injury. Most cervical spine fractures were in extension, which might be compatible with the head having struck another object. CONCLUSION: Modifying the seated posture might reduce the risk of thoracolumbar injury, or allow the resulting injury patterns to be controlled. Cervical spine injuries might be mitigated by changing vehicle design to protect the head. LEVEL OF EVIDENCE: N/A. PMID- 26571179 TI - Patient-Reported Outcome Instruments in Spine Surgery. AB - STUDY DESIGN: A critical review of the current literature. OBJECTIVE: The purpose of this study was to determine frequency, trends, and methods of utilization of spine-related PROIs over the last 10 years. SUMMARY OF BACKGROUND DATA: Patient reported outcome instruments (PROIs) have become the gold standard to assess the efficacy of various medical and surgical treatments. Currently, however, there is an expansive range of PROIs without a clear consensus or guideline addressing which PROIs should be used for a particular diagnosis or surgical intervention. METHODS: A PubMed search was conducted from 2004 to 2013 of 5 orthopedic journals (The Journal of Bone and Joint Surgery, The Bone and Joint Journal, The Spine Journal, The European Spine Journal, and Spine) that publish spine articles, chosen on the basis of readership and impact factor. Journal abstracts were inspected for spine surgery and inclusion of at least 1 PROI. All articles containing PROIs and investigating a surgical intervention with a level of evidence (LOE) 1 to 4 were included for analysis. Article title, LOE, journal, and chosen PROI were recorded for selected articles. RESULTS: Out of 19,736 articles published in our selected time frame, 1,079 utilized PROIs. Most studies were LOE 4 (32.7%). Nearly half (48.9%) of all articles addressed degenerative thoracolumbar conditions. In total, there were 206 unique PROIs in the studies chosen for inclusion. The top 6 instruments utilized were the (1) visual analog scale, (2) Oswestry disability index, (3) Short Form-36, (4) Japanese Orthopaedic Association Outcome Questionnaire, (5) Neck Disability Index, and (6) Scoliosis Research Society-22. CONCLUSION: The breadth of PROIs in spine surgery is extensive. Although there are preferred patient-reported outcome measures, a consensus or guideline addressing which instruments should be used for a particular diagnosis or procedure may be warranted. LEVEL OF EVIDENCE: 4. PMID- 26571180 TI - Age-Related and Degenerative Changes in the Osseous Anatomy, Alignment, and Range of Motion of the Cervical Spine: A Comparative Study of Radiographic Data From 1016 Patients With Cervical Spondylotic Myelopathy and 1230 Asymptomatic Subjects. AB - STUDY DESIGN: A prospective comparative study. OBJECTIVE: This study aimed to establish cervical spine morphometry, alignment, and range of motion (ROM) and to clarify the impact of these age-related and degenerative changes. SUMMARY OF BACKGROUND DATA: There are no studies that have evaluated differences in the results of cervical spine radiographs between a large series of cervical spondylotic myelopathy (CSM) patients and healthy subjects. METHODS: We enrolled 1016 consecutive CSM patients who underwent laminoplasty. CSM patients were also divided based on each decade of life between the fourth and ninth decades. We also enrolled a total of 1230 healthy volunteers as asymptomatic subjects in this study. There were at least 100 men and 100 women in each decade of life between the third and eighth decades. Cervical sagittal alignment on neutral and flexion extension views was measured by the Cobb method at C2-7. ROM was assessed by measuring the difference in alignment between flexion and extension. RESULTS: Cervical lordosis in the neutral position increased gradually with age in both groups. CSM patients showed significantly smaller lordotic angles compared with those shown by asymptomatic subjects within each decade. The total ROM decreased with increasing age in both groups. The total ROM of females was larger than males. The ROM of CSM patients was significantly smaller than asymptomatic subjects. The flexion ROM did not change with aging in either group. There was no significant difference in the flexion ROM between males and females in the two groups. However, the extension ROM decreased gradually in both groups. The extension ROM of CSM patients was significantly smaller than asymptomatic subjects. CONCLUSION: Age-related and degenerative changes in the cervical spine, alignment, and ROM in each decade of life were established between CSM patients and asymptomatic subjects. PMID- 26571181 TI - The 'alligator mouth' or 'reflective intubation' manoeuvre? Describing and modifying the same useful technique for difficult intubation. PMID- 26571182 TI - Automatic Thoughts During Sexual Activity, Distressing Sexual Symptoms, and Sexual Orientation: Findings from a Web Survey. AB - Studies with heterosexual samples have supported the role of cognitions on sexual functioning in men and women. However, there is no research on the impact of automatic thoughts on sexual functioning in sexual-minority samples. Therefore, the current study aimed to analyze the differences in automatic thoughts during sexual activity between gay and heterosexual men, and lesbian and heterosexual women, with and without distressing sexual symptoms, in order to establish similarities and differences between samples. A web survey was completed by 156 men and 168 women. A group of men and women with distressing sexual symptoms (78 men and 84 women) and a group without distressing sexual symptoms (78 men and 84 women) equally distributed in terms of sexual orientation and matched for sociodemographic variables were constituted. Participants answered a sociodemographic questionnaire, a questionnaire about sexual symptoms, and an automatic thoughts measure. Main findings suggested that men and women with distressing sexual symptoms reported significantly more negative automatic thoughts and fewer erotic thoughts during sexual activity, regardless of sexual orientation. Overall, current findings were consistent with previous research with heterosexual samples, suggesting a similar pattern in heterosexual samples, and gay men and lesbian women samples. PMID- 26571183 TI - Acute Thrombotic Occlusion of the Left Brachial Artery After Intra-Arterial Administration of Amiodarone. AB - OBJECTIVE: To report a case of intra-arterial amiodarone injection in a hemodynamically unstable patient leading to acute vessel occlusion and a subsequent compartment syndrome. DESIGN: Case report. SETTING: Prehospital setting, emergency department and ICU of a university hospital. PATIENT: A 58 year-old woman presenting with a ventricular tachycardia of 190 beats/min was administered amiodarone through an accidently placed arterial access in the left cubital fossa. Quickly, the woman developed clinical signs of an acute arterial occlusion. INTERVENTIONS: Immediate left brachial artery angiography with subsequent thrombectomy was performed. MEASUREMENTS AND MAIN RESULTS: A thrombotic occlusion at the injection side was found, which was immediately recanalized by thrombus aspiration. In addition to anticoagulation and an adenosine diphosphate-antagonist an adjunct therapy with vasodilators and gpIIb/IIIa inhibitors was given and repetitive duplex sonography confirmed arterial flow. However, despite restoration of blood flow the patient developed a severe compartment syndrome of the arm and had to receive multistep surgical interventions. CONCLUSIONS: This is the first report of an acute thrombotic vessel occlusion leading to a compartment syndrome upon accidental intra-arterial injection of amiodarone in an emergency setting. In the hemodynamically unstable patient healthcare providers should be aware of arterial miscanulation and its consequences. Upon intra-arterial injection, a direct antithrombotic and vasodilative therapy should be administered via the initially misplaced arterial access, which may include a gpIIb/IIIa inhibitor. PMID- 26571184 TI - Sequential N-Terminal Pro-B-Type Natriuretic Peptide and High-Sensitivity Cardiac Troponin Measurements During Albumin Replacement in Patients With Severe Sepsis or Septic Shock. AB - OBJECTIVES: Myocardial dysfunction is a frequent complication in patients with severe sepsis and can worsen the prognosis. We investigated whether circulating biomarkers related to myocardial function and injury predicted outcome and were associated with albumin replacement. DESIGN: A multicenter, randomized clinical trial about albumin replacement in severe sepsis or septic shock (the Albumin Italian Outcome Sepsis trial). SETTING: Forty ICUs in Italy. PATIENTS: Nine hundred and ninety-five patients with severe sepsis or septic shock. INTERVENTIONS: Randomization to albumin and crystalloid solutions or crystalloid solutions alone. MEASUREMENTS AND MAIN RESULTS: Plasma concentrations of N- terminal pro-B-type natriuretic peptide and high-sensitivity cardiac troponin T were measured 1, 2, and 7 days after enrollment. We tested the relationship of single marker measurements or changes over time with clinical events, organ dysfunctions, albumin replacement, and ICU or 90-day mortality in the overall population and after stratification by shock. N-terminal pro-B-type natriuretic peptide levels were abnormal in 97.4% of the patients and high-sensitivity cardiac troponin T in 84.5%, with higher concentrations in those with shock. After extensive adjustments, N-terminal pro-B-type natriuretic peptide concentrations predicted ICU or 90-day mortality, better than high-sensitivity cardiac troponin T. Early changes in N-terminal pro-B-type natriuretic peptide or high-sensitivity cardiac troponin T concentrations were independently associated with subsequent mortality in patients with shock. Patients given albumin had significantly higher N-terminal pro-B-type natriuretic peptide levels; in addition, early rise in N-terminal pro-B-type natriuretic peptide was associated with a better outcome in this subgroup. CONCLUSIONS: Circulating N-terminal pro-B type natriuretic peptide and high-sensitivity cardiac troponin T are frequently elevated in severe sepsis or septic shock and have relevant prognostic value, which may be important in monitoring the clinical efficacy of supporting therapy. PMID- 26571185 TI - Association Between Index Hospitalization and Hospital Readmission in Sepsis Survivors. AB - OBJECTIVES: Hospital readmission is common after sepsis, yet the relationship between the index admission and readmission remains poorly understood. We sought to examine the relationship between infection during the index acute care hospitalization and readmission and to identify potentially modifiable factors during the index sepsis hospitalization associated with readmission. DESIGN: In a retrospective cohort study, we evaluated 444 sepsis survivors at risk of an unplanned hospital readmission in 2012. The primary outcome was 30-day unplanned hospital readmission. SETTING: Three hospitals within an academic healthcare system. SUBJECTS: Four hundred forty-four sepsis survivors. MEASUREMENTS AND MAIN RESULTS: Of 444 sepsis survivors, 23.4% (95% CI, 19.6-27.6%) experienced an unplanned 30-day readmission compared with 10.1% (95% CI, 9.6-10.7%) among 11,364 nonsepsis survivors over the same time period. The most common cause for readmission after sepsis was infection (69.2%, 72 of 104). Among infection related readmissions, 51.4% were categorized as recurrent/unresolved. Patients with sepsis present on their index admission who also developed a hospital acquired infection ("second hit") were nearly twice as likely to have an unplanned 30-day readmission compared with those who presented with sepsis at admission and did not develop a hospital-acquired infection or those who presented without infection and then developed hospital-acquired sepsis (38.6% vs 22.2% vs 20.0%, p = 0.04). Infection-related hospital readmissions, specifically, were more likely in patients with a "second hit" and patients receiving a longer duration of antibiotics. The use of total parenteral nutrition (p = 0.03), longer duration of antibiotics (p = 0.047), prior hospitalizations, and lower discharge hemoglobin (p = 0.04) were independently associated with hospital readmission. CONCLUSIONS: We confirmed that the majority of unplanned hospital readmissions after sepsis are due to an infection. We found that patients with sepsis at admission who developed a hospital-acquired infection, and those who received a longer duration of antibiotics, appear to be high-risk groups for unplanned, all cause 30-day readmissions and infection-related 30-day readmissions. PMID- 26571186 TI - Significance of Prior Digestive Colonization With Extended-Spectrum beta Lactamase-Producing Enterobacteriaceae in Patients With Ventilator-Associated Pneumonia. AB - OBJECTIVES: Ventilator-associated pneumonia is frequent in ICUs. Extended spectrum beta-lactamase-producing Enterobacteriaceae are difficult-to-treat pathogens likely to cause ventilator-associated pneumonia. We sought to assess the interest of screening for extended-spectrum beta-lactamase-producing Enterobacteriaceae rectal carriage as a way to predict their involvement in ventilator-associated pneumonia. DESIGN: A retrospective cohort study of patients with suspected ventilator-associated pneumonia in a medical ICU was conducted. PATIENTS: Every patient admitted between January 2006 and August 2013 was eligible if subjected to mechanical ventilation for more than 48 hours. Each patient with suspected ventilator-associated pneumonia was included in the cohort. Active surveillance culture for extended-spectrum beta-lactamase producing Enterobacteriaceae detection was routinely performed in all patients at admission and then weekly throughout the study period. Extended-spectrum beta lactamase colonization was defined by the isolation of at least one extended spectrum beta-lactamase-producing Enterobacteriaceae from rectal swab culture. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 587 patients with suspected ventilator-associated pneumonia, 40 (6.8%) were colonized with extended spectrum beta-lactamase-producing Enterobacteriaceae prior to the development of pneumonia. Over the study period, 20 patients (3.4%) had ventilator-associated pneumonia caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae; of whom, 17 were previously detected as being colonized with extended-spectrum beta-lactamase-producing Enterobacteriaceae. Sensitivity and specificity of prior extended-spectrum beta-lactamase-producing Enterobacteriaceae colonization as a predictor of extended-spectrum beta lactamase-producing Enterobacteriaceae involvement in ventilator-associated pneumonia were 85.0% and 95.7%, respectively. The positive and negative predictive values were 41.5% and 99.4%, respectively. The positive likelihood ratio was 19.8. CONCLUSIONS: Screening for extended-spectrum beta-lactamase producing Enterobacteriaceae digestive colonization by weekly active surveillance cultures could reliably exclude the risk of the involvement of such pathogens in patients with ventilator-associated pneumonia in low-prevalence area. PMID- 26571187 TI - Fluid Responsiveness and the Six Guiding Principles of Fluid Resuscitation. PMID- 26571188 TI - Hospital Costs Of Extracorporeal Life Support Therapy. AB - OBJECTIVES: To conduct an exploration of the hospital costs of extracorporeal life support therapy. Extracorporeal life support seems an efficient therapy for acute, potentially reversible cardiac or respiratory failure, when conventional therapy has been inadequate, or as bridge to transplant, but unfortunately, no evidence in randomized controlled trials is delivered yet. DESIGN: Single-center retrospective exploratory cohort cost study. The study is performed from a hospital perspective with a time horizon of patients' complete hospital admission in which they received extracorporeal life support. SETTING: ICU of a university teaching hospital in The Netherlands. PATIENTS: All 67 consecutive adult patients who were admitted to the ICU of the University Medical Center Groningen in the period 2010-2013 and received extracorporeal life support treatment. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: The bottom-up microcosting method was used except when stated otherwise. Medical costs were estimated by multiplying every registered healthcare consumption with unit prices. Unit prices were largely based on Dutch reference prices. For each patient, the personnel costs and material costs were assessed in detail. The costs of extracorporeal life support were differentiated in costs of procedures and costs of daily surcharge of therapy. Procedure-related costs were subdivided in costs of devices and disposables, costs of additional human resources, and surgery hours. The mean total hospital costs were ? 106.263 (? 83.841 to ? 126.266) per patient ($145,580). On average, 52% of the total costs arose from hospital nursing days and 11% of direct procedure-related extracorporeal life support costs. Surgery and diagnostics represented a vast amount of the remaining costs. CONCLUSIONS: This large and detailed economic evaluation of hospital costs of extracorporeal life support therapy in the Netherlands showed that mean total hospital cost of extracorporeal life support treatment is ? 106.263 per patient. The majority of the costs are composed of nursing days. PMID- 26571189 TI - Determinants of Citation Impact in Large Clinical Trials in Critical Care: The Role of Investigator-Led Clinical Trials Groups. AB - OBJECTIVES: Randomized clinical trials provide the best evidence of treatment effectiveness; factors determining their impact are unknown. We sought to determine the influence of funding (industry vs nonindustry), research (comparative effectiveness vs technology evaluation), and organizational models (investigator-led trials group vs others) on the impact of large trials in critical care medicine. DATA SOURCES: We searched MEDLINE for randomized clinical trials published between 1990 and 2012 in five critical care, five general interest, and one pediatrics journal. Impact was evaluated as annual citation rates measured using the ISI Web of Knowledge database. STUDY SELECTION: Eligible trials enrolled at least 100 critically ill adults, children, or neonates, evaluated an intervention that was applied during the ICU stay, and reported mortality and/or length of ICU or hospital stay. DATA EXTRACTION: Two reviewers identified eligible studies, and two separate reviewers extracted data. DATA SYNTHESIS: We identified 391 randomized clinical trials, recruiting 208,154 subjects. Funding source--industry versus peer review versus mixed--did not impact citation rates. Comparative effectiveness studies made up 52.5% of the reports and were cited more frequently than studies evaluating novel technologies (median, 15.6 vs 10.3 citations/yr; p = 0.002). Trials conducted by investigator led trials groups (n = 45) were cited a median of 45.7 (interquartile range [IQR], 17.3-86.2) times per year, significantly more often (p < 0.0001) than multicenter trials conducted by ad hoc groups (n = 89; median, 19 [IQR, 8.7 30.4]) or industry (n = 85; median, 12.3 [IQR, 5.4-24.1]), and more than single center trials (n = 116; median, 6.8 [IQR, 3.5-12.8]) or small ad hoc trials involving two to five centers (n = 59; median, 11.0 [IQR, 4.5-22.4]). Although only 11.5% of all trials included, randomized clinical trials from investigator led research consortia accounted for nine of the 16 studies cited more than 100 times per year and 23.4% of all citations; their costs were substantially less than the typical costs of industry-run trials.. CONCLUSIONS: Clinical trials conducted by investigator-led research groups are significantly more frequently cited than industry-led trials in critical care medicine. In addition, costs appear to be substantially lower with investigator-led trials. Support for and expansion of this model of research can ensure that critical care research is clinically relevant and practice changing. PMID- 26571190 TI - Relationship Between ICU Length of Stay and Long-Term Mortality for Elderly ICU Survivors. AB - OBJECTIVES: To evaluate the association between length of ICU stay and 1-year mortality for elderly patients who survived to hospital discharge in the United States. DESIGN: Retrospective cohort study of a random sample of Medicare beneficiaries who survived to hospital discharge, with 1- and 3-year follow-up, stratified by the number of days of intensive care and with additional stratification based on receipt of mechanical ventilation. INTERVENTIONS: None. PATIENTS: The cohort included 34,696 Medicare beneficiaries older than 65 years who received intensive care and survived to hospital discharge in 2005. MEASUREMENTS AND MAIN RESULTS: Among 34,696 patients who survived to hospital discharge, the mean ICU length of stay was 3.4 days (+/- 4.5 d). Patients (88.9%) were in the ICU for 1-6 days, representing 58.6% of ICU bed-days. Patients (1.3%) were in the ICU for 21 or more days, but these patients used 11.6% of bed-days. The percentage of mechanically ventilated patients increased with increasing length of stay (6.3% for 1-6 d in the ICU and 71.3% for >= 21 d). One-year mortality was 26.6%, ranging from 19.4% for patients in the ICU for 1 day, up to 57.8% for patients in the ICU for 21 or more days. For each day beyond 7 days in the ICU, there was an increased odds of death by 1 year of 1.04 (95% CI, 1.03 1.05) irrespective of the need for mechanical ventilation. CONCLUSIONS: Increasing ICU length of stay is associated with higher 1-year mortality for both mechanically ventilated and non-mechanically ventilated patients. No specific cutoff was associated with a clear plateau or sharp increase in long-term risk. PMID- 26571191 TI - Finding NEMO in preeclampsia. AB - BACKGROUND: The mechanism of preeclampsia and its way of inheritance are still a mystery. Biochemical and immunochemical studies reveal a substantial increase in tumor necrosis factor alpha, interleukin-1 beta, and interleukin-6 concentrations in the blood of women with preeclampsia. The level of these factors is regulated by nuclear facxtor-kappa B, whose activation in a classical pathway requires inhibitory kappa B kinase gamma (known as NEMO or IKBKG). Moreover, NEMO can schedule between cytoplasma and the nucleus. In the nucleus, IKBKG interacts with other proteins, and thus, it is implicated in the regulation of different gene expressions, which are related to cell cycle progression, proliferation, differentiation, and apoptosis. OBJECTIVE: This is the first study investigating the association between the level of NEMO gene expression and the presence of preeclampsia. We tested the hypothesis that the simultaneous increase in NEMO gene expression both in the mother and her fetus may be responsible for the preeclampsia development. Moreover, the relationships between clinical risk factors of preeclampsia and the levels of NEMO gene expression in blood, umbilical cord blood, and placentas were investigated. STUDY DESIGN: A total of 91 women (43 preeclamptic women and 48 controls) and their children were examined. Real-time reverse transcription-polymerase chain reaction was used to assess the amount total NEMO messenger ribonucleic acid (mRNA) content and the mRNA level of each NEMO transcript from exons 1A, 1B, and 1C in maternal blood, umbilical cord blood, and placentas. Univariate analyses and correlation tests were performed to examine the association between NEMO gene expression and preeclampsia. RESULTS: Newborn weight and height, maternal platelet number, and gestational age (week of delivery) were lower in the group of women with preeclampsia than controls. NEMO gene expression level was found to be almost 7 times higher in the group of women with preeclampsia than healthy controls. The correlation analysis found that a simultaneous increase in the expression level of total NEMO mRNA in maternal blood and the mRNA for total NEMO (Rs = 0.311, P < .05), transcripts 1A (Rs = 0.463, P < .01), 1B (Rs = 0.454, P < .01), and 1C (Rs = 0.563, P < .001) in fetal blood was observed in preeclamptic pregnancies. In addition, the mRNA levels for total NEMO and transcripts 1A, 1B, and 1C were lower in placentas derived from pregnancies complicated by preeclampsia. CONCLUSION: Simultaneous increase of NEMO gene expression in maternal and fetal blood seems to be relevant for preeclampsia development. The results of our study also suggest that a decreased NEMO gene expression level in preeclamptic placentas may be the main reason for their intensified apoptosis. PMID- 26571192 TI - Cyanohydrin as an Anchoring Group for Potent and Selective Inhibitors of Enterovirus 71 3C Protease. AB - Cyanohydrin derivatives as enterovirus 71 (EV71) 3C protease (3C(pro)) inhibitors have been synthesized and assayed for their biochemical and antiviral activities. Compared with the reported inhibitors, cyanohydrins (1S,2S,2'S,5S)-16 and (1R,2S,2'S,5S)-16 exhibited significantly improved activity and attractive selectivity profiles against other proteases, which were a result of the specific interactions between the cyanohydrin moiety and the catalytic site of 3C(pro). Cyanohydrin as an anchoring group with high selectivity and excellent inhibitory activity represents a useful choice for cysteine protease inhibitors. PMID- 26571193 TI - Role of pedunculopontine cholinergic neurons in the vulnerability of nigral dopaminergic neurons in Parkinson's disease. AB - Pedunculopontine nucleus (PPN) cholinergic neurons, which exert excitatory nicotinic control over substantia nigra dopaminergic neurons, degenerate in Parkinson's disease (PD). This finding and other studies showing that nicotine, the preferential agonist of nicotinic acetylcholine receptors, is neuroprotective in experimental models of PD suggest that a deficit in PPN excitatory cholinergic inputs might contribute to the death of nigral dopaminergic neurons in PD. To explore this possibility, we used lesion paradigms of dopaminergic and/or cholinergic systems in rats and monkeys. Consistent with our hypothesis, we observed that stereotaxic lesioning of PPN cholinergic neurons with diphtheria toxin coupled to urotensin II resulted in a significant loss of nigral dopaminergic neurons in rats and induced morphological changes in these neurons in macaques. Unexpectedly, a lesion of dopaminergic neurons induced by unilateral striatal injection of 6-hydroxydopamine (6-OHDA) in rats, or by repeated systemic injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in macaques, led to a 29% and 7% loss of PPN cholinergic neurons, respectively. Lastly, when the PPN cholinergic lesion was performed in rats in which the dopaminergic lesion induced by 6-OHDA was in progress, loss of cholinergic neurons was more drastic than when each neurotransmitter system was lesioned separately. Thus, our results suggest that strong PPN cholinergic and dopaminergic interactions may be an important mechanism in the pathophysiology of PD. PMID- 26571194 TI - Distinct roles of cortical and pallidal beta and gamma frequencies in hemiparkinsonian and dyskinetic rats. AB - Enhanced beta band (betaB) activity, which is suppressed by levodopa (LD) treatment, has been demonstrated within the basal ganglia (BG) of Parkinson's disease (PD) patients. However, some data suggest that Parkinsonian symptoms are not directly related to this brain frequency and therefore, its causative role remains questionable. A less explored phenomenon is the link between the gamma band (gammaB) and PD phenomenology. Here, we monitored the development of the oscillatory activity during chronic LD depletion and LD treatment in Parkinsonian and levodopa-induced dyskinesia (LID) in rats. We found a significant and bilateral power increase in the high betaB frequencies (20-30 Hz) within the first 10 days after 6-hydroxydopamine (6-OHDA) lesion, which was in accordance with a significant depletion of dopaminergic fibers in the striatum. We also observed a clear-cut gammaB increase during LD treatment. The development of LID was characterized by a slight increase in the cumulative power of betaB accompanied by a large augmentation in the gammaB frequency (60-80 Hz). This latter effect reached a plateau in the frontal cortex bilaterally and the left globus pallidus after the second week of LD treatment. Our data suggest that the betaB parallels the emergence of Parkinsonian signs and can be taken as a predictive sign of DA depletion, matching TH-staining reduction. On the other hand, the gammaB is strictly correlated to the development of LID. LD treatment had an opposite effect on betaB and gammaB, respectively. PMID- 26571195 TI - Coping responses moderate prospective associations between marital conflict and youth adjustment. AB - Children's engaged coping responses to family conflict were examined as moderators of the prospective association between marital conflict in middle childhood and internalizing and externalizing symptoms in adolescence. Youth and their mothers participated in 4 waves of data collection (1-year intervals from Time 1 [T1] to Time 3 [T3]; 5-year interval between T3 and Time 4 [T4]). The final analytic sample included 304 participants (51% boys; 66% European American, 34% African American). Participants were approximately 8 and 16 years old at T1 and T4, respectively. A multi-informant, longitudinal design was used to address study aims. Mothers reported on marital conflict (T1 to T3) and externalizing problems (T1 to T4); youth reported on coping responses to family conflict (T3) and internalizing symptoms (T1 to T4). Primary (e.g., problem solving) and secondary (e.g., cognitive reappraisal) engaged coping were computed as proportion scores (out of all coping responses). Toward identifying unique effects, path models controlled for internalizing when predicting externalizing symptoms, and vice versa. Primary and secondary engaged coping emerged as moderators. In the context of marital conflict, higher levels of secondary engaged coping protected against, whereas lower levels of secondary engaged coping increased risk for, externalizing problems. Conversely, lower levels of primary and secondary engaged coping protected against, whereas higher levels of primary and secondary engaged coping increased risk for, internalizing symptoms in the context of marital conflict. Findings contribute to the small literature on the moderating role of coping in the context of marital conflict, providing further insight into the prediction of unique externalizing and internalizing symptoms. (PsycINFO Database Record PMID- 26571196 TI - The salience and severity of relationship problems among low-income couples. AB - Developing programs to support low-income married couples requires an accurate understanding of the challenges they face. To address this question, we assessed the salience and severity of relationship problems by asking 862 Black, White, and Latino newlywed spouses (N = 431 couples) living in low-income neighborhoods to (a) free list their 3 biggest sources of disagreement in the marriage, and (b) rate the severity of the problems appearing on a standard relationship problem inventory. Comparing the 2 sources of information revealed that, although relational problems (e.g., communication and moods) were rated as severe on the inventory, challenges external to the relationship (e.g., children) were more salient in the free listing task. The pattern of results is robust across couples of varying race/ethnicity, parental status, and income levels. We conclude that efforts to strengthen marriages among low-income couples may be more effective if they address not only relational problems, but also couples' external stresses by providing assistance with child care, finances, or job training. PMID- 26571197 TI - Relationship types among adolescent parents participating in a home-visiting program: A latent-transition analysis. AB - Young parents (less than 25 years of age) have been shown to have especially low rates of father involvement and union stability. However, research has also shown that parenting experiences of young fathers may not be uniform. There is a need for more research that assesses both the multidimensionality of relationship typologies and their temporality. Using a large longitudinal sample of low income, young mothers enrolled in a randomized control study of a home-visitation program (n = 704; 61% program, 39% control), we evaluated how mother-father relationship dynamics changed over time. Ten mother-reported indicators of relationships (e.g., coresidence, marital status, types of father support) were used to conduct a latent-class analysis of relationship types. A 4-class solution was identified at each time point: Single Parent, Supportive Nonresident Partner, Supportive Resident Partner, and Questioning/Ambivalent Coupling. Latent transition analyses were used to evaluate stability of relationships across 2 years. At each transition, a large proportion of women moved from one relationship class to another, indicating heterogeneity in relationship dynamics of adolescent parents. Results revealed the potential of a home-visiting program targeted at young parents to favorably promote more stable and supportive mother father relationships and coparenting arrangements. PMID- 26571198 TI - Occurrence and Profile Characteristics of the Pesticide Imidacloprid, Preservative Parabens, and Their Metabolites in Human Urine from Rural and Urban China. AB - Knowledge of human exposure to imidacloprid, the most extensively used insecticide, and para-hydroxybenzoic acid esters (parabens), the most extensively used preservative, is insufficient. In this study, 295 urine samples collected from subjects in rural and urban areas in China were analyzed for imidacloprid and four parabens (namely, methyl paraben, ethyl paraben, propyl paraben, and butyl paraben) as well as their major metabolites (namely, 6-chloronicotinic acid (6-ClNA) and para-hydroxybenzoic acid (p-HB)). Imidacloprid was detected in 100% of the urine samples from rural Chinese subjects and 95% of the urine samples from urban Chinese subjects. Concentrations of urinary imidacloprid detected in rural Chinese subjects (geometric mean (GM) = 0.18 ng/mL) were slightly higher than those detected in urban Chinese subjects (GM = 0.15 ng/mL) when the effect of pesticide spraying was excluded. However, concentrations of urinary imidacloprid detected in rural adults increased significantly in the subsequent days of pesticide spraying (GM = 0.62 ng/mL), which could return to the normal levels within 3 days. In contrast, concentrations of urinary parabens detected in rural Chinese subjects (GM = 6.90 ng/mL) were lower than that in urban Chinese subjects (GM = 30.5 ng/mL). In addition, the metabolism characteristics of imidacloprid to 6-ClNA and parabens to p-HB were discussed preliminarily. PMID- 26571199 TI - Electroless Functionalization of Silver Films by Its Molecular Doping. AB - We present a methodology which by far extends the potential applications of thin conductive silver films achieved by an electroless molecular doping process of the metal with any of the endless functional molecules that the large library of organic molecules offer. The resulting metallic films within which the molecule is entrapped--molecule@Ag--carry both the classical chemical and physical properties of silver films, as well as the function of the entrapped molecule. Raman measurements of the organic molecules from within the silver films provide the first spectroscopic observations from within silver, and clearly show that entrapment, a three-dimensional process, and adsorption, a two-dimensional process, on silver films are distinctly different processes. Three organic molecules, the cationic Neutral red, the anionic Congo red, and the antibacterial agent chlorhexidine digluconate (CH), were used to demonstrate the generality of this method for various types of molecules. We studied the sensitivity of the film conductivity to the type of the molecule entrapped within the film, to its concentration, and to temperature. Dual functionality was demonstrated with CH@Ag films, which are both conductive and have prolonged and high antibacterial activity, a combination of properties that has been unknown so far. PMID- 26571200 TI - Lymphopenia and its association with survival in patients with locally advanced cervical cancer. AB - OBJECTIVE: To evaluate the association between lymphopenia and survival in women with cervical cancer treated with primary chemoradiation. METHODS: A single institution, retrospective analysis of patients with stage IB2-IVA cervical cancer who received upfront chemoradiation from 1998 to 2013 was performed. Complete blood counts from pre-treatment to 36 months post-treatment were analyzed. Lymphopenia and known prognostic factors were evaluated for an association with progression-free (PFS) and overall survival (OS). RESULTS: Seventy-one patients met study criteria for whom 47 (66%) had a documented total lymphocyte count (TLC) two months after initiating chemoradiation. FIGO stage distribution was 6% Stage I, 46% Stage II, 45% Stage III and 3% Stage IV. Pre treatment TLC was abnormal (<1000 cells/mm3) in 15% of patients. The mean reduction in TLC was 70% two months after initiating chemoradiation. Severe post treatment lymphopenia (TLC <500 cells/mm3) was observed in 53% of patients; they experienced inferior median OS (21.2 vs. 45.0 months, P=0.03) and similar 25th percentile PFS (6.3 vs. 7.7 months, P=0.06) compared to patients without severe lymphopenia. Multivariate analysis demonstrated pre-treatment TLC >=1000 cells/mm3 and post-treatment TLC >500 cells/mm3 had a 77% (HR: 0.23; 95% CI 0.05 1.03; P=0.053) and 58% decrease in hazards of death (HR: 0.42; 95%CI 0.12-1.46; P=0.17) respectively. CONCLUSION: More than half of cervical cancer patients treated with chemoradiation experienced severe and prolonged lymphopenia. Although statistical significance was not reached, the findings suggest that pre- and post-treatment lymphopenia may be associated with decreased survival. Further research is warranted, given that lymphopenia could be a reversible prognostic factor. PMID- 26571201 TI - Sulforaphane induces Nrf2 target genes and attenuates inflammatory gene expression in microglia from brain of young adult and aged mice. AB - Increased neuroinflammation and oxidative stress resulting from heightened microglial activation are associated with age-related cognitive impairment. The objectives of this study were to examine the effects of the bioactive sulforaphane (SFN) on the nuclear factor E2-related factor 2 (Nrf2) pathway in BV2 microglia and primary microglia, and to evaluate proinflammatory cytokine expression in lipopolysaccharide (LPS)-stimulated primary microglia from adult and aged mice. BV2 microglia and primary microglia isolated from young adult and aged mice were treated with SFN and LPS. Changes in Nrf2 activity, expression of Nrf2 target genes, and levels of proinflammatory markers were assessed by quantitative PCR and immunoassay. SFN increased Nrf2 DNA-binding activity and upregulated Nrf2 target genes in BV2 microglia, while reducing LPS-induced interleukin (IL-)1beta, IL-6, and inducible nitric oxide synthase (iNOS). In primary microglia from adult and aged mice, SFN increased expression of Nrf2 target genes and attenuated IL-1beta, IL-6, and iNOS induced by LPS. These data indicate that SFN is a potential beneficial supplement that may be useful for reducing microglial mediated neuroinflammation and oxidative stress associated with aging. PMID- 26571202 TI - Arterial stiffness is associated with age-related differences in cerebrovascular conductance. AB - To determine if arterial stiffness is associated with age-related differences in cerebrovascular conductance and reactivity, twenty-eight apparently healthy sedentary young (25+/-1 years; n=15) and older (67+/-1 years; n=13) adults were studied. Brachial-ankle pulse wave velocity (baPWV) was measured as an index of arterial stiffness. Cerebrovascular reactivity was determined by measuring changes in mean blood velocity in the middle cerebral artery under normocapnic, hypocapnic and hypercapnic conditions. Mean baPWV was greater (p<0.05) in older compared with young adults. At baseline, mean cerebral blood flow velocity and cerebrovascular conductance index were lower (p<0.05) in older compared with young adults under normocapnic, hypocapnic and hypercapnic conditions. There were no significant group differences in cerebrovascular reactivity when they were adjusted for stimuli (i.e., end-tidal CO2 concentrations) in most perturbation conditions except for the normocapnia to hypercapnia condition. baPWV was negatively associated with cerebrovascular conductance index at all conditions (all p<0.05). We concluded that arterial stiffness was associated with age related differences in cerebrovascular conductance and that there were no apparent age-associated differences in cerebrovascular reactivity. PMID- 26571203 TI - Tubal ectopic pregnancy. AB - INTRODUCTION: Approximately 1/100 pregnancies are ectopic, with the conceptus usually implanting in the fallopian tube. Some ectopic pregnancies resolve spontaneously, but others continue to grow and can lead to rupture of the tube. Risks are higher in women who smoke or have damage to the fallopian tubes due to pelvic infections, surgery, or previous ectopic pregnancy. METHODS AND OUTCOMES: We conducted a systematic overview aiming to answer the following clinical question: What are the effects of treatments for unruptured tubal ectopic pregnancy on subsequent fertility? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2014 (Clinical Evidence overviews are updated periodically; please check our website for the most up-to date version of this overview). RESULTS: At this update, searching of electronic databases retrieved nine studies. After deduplication and removal of conference abstracts, nine records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of six studies and the further review of three full publications. Of the three full articles evaluated, no systematic reviews and one RCT were added at this update. We performed a GRADE evaluation for three PICO combinations. CONCLUSIONS: In this systematic overview we present information relating to the effectiveness and safety of the following interventions for unruptured tubal ectopic pregnancy on subsequent fertility: expectant management, methotrexate, salpingotomy, and salpingectomy. PMID- 26571204 TI - Stoichiometrically Controlled Immobilization of Multiple Enzymes on Magnetic Nanoparticles by the Magnetosome Display System for Efficient Cellulose Hydrolysis. AB - The immobilization of multiple cellulase complexes receiving attention for use in the efficient hydrolysis of celluloses. In this study, the magnetosome display system was employed for the preparation of systems mimicking natural multiple cellulase complexes (cellulosomes) on magnetic nanoparticles (MNPs). Initially, two fluorescent proteins, namely, green fluorescent protein and mCherry, were immobilized on MNPs. Fluorescence analysis revealed the close proximity of two different proteins on the MNPs. Enzyme-linked immunosorbent assay analysis showed that stoichiometrically equivalent amounts of the proteins were immobilized on the MNPs. Next, endoglucanase (EG) and beta-glucosidase (BG) were immobilized on MNPs to give EG/BG-MNPs. The resulting MNPs were applied for the hydrolysis of celluloses, with rapid hydrolysis of carboxymethyl cellulose being observed. Furthermore, the fusion of the cellulose-binding domain to EG/BG-MNPs promoted improved hydrolysis activity against the insoluble cellulose. We could therefore conclude that the magnetosome display system can expand the possibilities of mimicking natural cellulosome organization on MNPs. PMID- 26571206 TI - Re-visiting crash-speed relationships: A new perspective in crash modelling. AB - Although speed is considered to be one of the main crash contributory factors, research findings are inconsistent. Independent of the robustness of their statistical approaches, crash frequency models typically employ crash data that are aggregated using spatial criteria (e.g., crash counts by link termed as a link-based approach). In this approach, the variability in crashes between links is explained by highly aggregated average measures that may be inappropriate, especially for time-varying variables such as speed and volume. This paper re examines crash-speed relationships by creating a new crash data aggregation approach that enables improved representation of the road conditions just before crash occurrences. Crashes are aggregated according to the similarity of their pre-crash traffic and geometric conditions, forming an alternative crash count dataset termed as a condition-based approach. Crash-speed relationships are separately developed and compared for both approaches by employing the annual crashes that occurred on the Strategic Road Network of England in 2012. The datasets are modelled by injury severity using multivariate Poisson lognormal regression, with multivariate spatial effects for the link-based model, using a full Bayesian inference approach. The results of the condition-based approach show that high speeds trigger crash frequency. The outcome of the link-based model is the opposite; suggesting that the speed-crash relationship is negative regardless of crash severity. The differences between the results imply that data aggregation is a crucial, yet so far overlooked, methodological element of crash data analyses that may have direct impact on the modelling outcomes. PMID- 26571207 TI - Spin dynamics in Na(4-x)Ir3O8 (x = 0.3 and 0.7) investigated by 23Na NMR and MUSR. AB - We report (23)Na nuclear magnetic resonance (NMR) and zero-field (ZF) and longitudinal-field (LF) muon spin relaxation (MUSR) measurements of the depleted hyperkagome compounds Na(4-x)Ir3O8 (x = 0.3 and 0.7), which undergo an insulator-semimetal transition as a function of x. The (23)Na spin-lattice relaxation rates, T1(-1), follow a T(2.5) power law behavior at accessible temperatures of T = 120-350 K. A substantial temperature dependence of T1(-1) indicates the presence of gapped excitations at elevated temperatures through the transition to a semimetallic phase. ZF-MUSR results reveal that hole-doping leads to a melting of quasi-static order to a dynamically fluctuating state. The very slow muon depolarization rate which varies hardly with temperature indicates that spins are close to an itinerant limit in the largest doping x = 0.7. The dynamic relaxation rates extracted from the LF-MUSR spectra show a three dimensional diffusive transport. Our combined NMR and MUSR results suggest the occurrence of intriguing spin and charge excitations across the insulator semimetal transition. PMID- 26571205 TI - Immunomodulation as a neuroprotective and therapeutic strategy for Parkinson's disease. AB - While immune control is associated with nigrostriatal neuroprotection for Parkinson's disease, direct cause and effect relationships have not yet been realized, and modulating the immune system for therapeutic gain has been openly debated. Here, we review how innate and adaptive immunity affect disease pathobiology, and how each could be harnessed for treatment. The overarching idea is to employ immunopharmacologics as neuroprotective strategies for disease. The aim of the current work is to review disease-modifying treatments that are currently being developed as neuroprotective strategies for PD in experimental animal models and for human disease translation. The long-term goal of this research is to effectively harness the immune system to slow or prevent PD pathobiology. PMID- 26571208 TI - Differences in sensitivity to deviance partly explain ideological divides in social policy support. AB - We propose that political differences in social policy support may be partly driven by the tendency for conservatives to show greater sensitivity to deviance than liberals, even among targets lacking social or functional relevance. In 3 studies, participants were shown geometric figures and were asked to identify the extent to which they were "triangles" (or circles, squares, etc.). More conservative participants reported greater differentiation between perfect and imperfect shapes than more liberal participants, indicating greater sensitivity to deviance. Moreover, shape differentiation partly accounted for the relationship between political ideology and social policy, partially mediating the link between conservatism and harsher punishment of wrongdoers (Studies 1 and 4), less support for public aid for disadvantaged groups (Study 2), and less financial backing for policies that benefit marginalized groups in society (Study 3). This effect was specific to policies that targeted deviant groups (Study 3) and who were not too highly deviant (Study 4). Results suggest that, in addition to commonly cited affective and motivational reactions to deviant actors, political differences in social policy may also be driven by conservatives' greater cognitive propensity to distinguish deviance. (PsycINFO Database Record PMID- 26571209 TI - Optically Resolving the Dynamic Walking of a Plasmonic Walker Couple. AB - Deterministic placement and dynamic manipulation of individual plasmonic nanoparticles with nanoscale precision feature an important step toward active nanoplasmonic devices with prescribed levels of performance and functionalities at optical frequencies. In this Letter, we demonstrate a plasmonic walker couple system, in which two gold nanorod walkers can independently or simultaneously perform stepwise walking powered by DNA hybridization along the same DNA origami track. We utilize optical spectroscopy to resolve such dynamic walking with nanoscale steps well below the optical diffraction limit. We also show that the number of walkers and the optical response of the system can be correlated. Our studies exemplify the power of plasmonics, when integrated with DNA nanotechnology for realization of advanced artificial nanomachinery with tailored optical functionalities. PMID- 26571210 TI - Synthesis of Hollow Nanotubes of Zn2SiO4 or SiO2: Mechanistic Understanding and Uranium Adsorption Behavior. AB - We report a facile synthesis of Zn2SiO4 nanotubes using a two-step process consisting of a wet-chemical synthesis of core-shell ZnO@SiO2 nanorods followed by thermal annealing. While annealing in air leads to the formation of hollow Zn2SiO4, annealing under reducing atmosphere leads to the formation of SiO2 nanotubes. We rationalize the formation of the silicate phase at temperatures much lower than the temperatures reported in the literature based on the porous nature of the silica shell on the ZnO nanorods. We present results from in situ transmission electron microscopy experiments to clearly show void nucleation at the interface between ZnO and the silica shell and the growth of the silicate phase by the Kirkendall effect. The porous nature of the silica shell is also responsible for the etching of the ZnO leading to the formation of silica nanotubes under reducing conditions. Both the hollow silica and silicate nanotubes exhibit good uranium sorption at different ranges of pH making them possible candidates for nuclear waste management. PMID- 26571211 TI - The leukodystrophy protein FAM126A (hyccin) regulates PtdIns(4)P synthesis at the plasma membrane. AB - Genetic defects in myelin formation and maintenance cause leukodystrophies, a group of white matter diseases whose mechanistic underpinnings are poorly understood. Hypomyelination and congenital cataract (HCC), one of these disorders, is caused by mutations in FAM126A, a gene of unknown function. We show that FAM126A, also known as hyccin, regulates the synthesis of phosphatidylinositol 4-phosphate (PtdIns(4)P), a determinant of plasma membrane identity. HCC patient fibroblasts exhibit reduced PtdIns(4)P levels. FAM126A is an intrinsic component of the plasma membrane phosphatidylinositol 4-kinase complex that comprises PI4KIIIalpha and its adaptors TTC7 and EFR3 (refs 5,7). A FAM126A-TTC7 co-crystal structure reveals an all-alpha-helical heterodimer with a large protein-protein interface and a conserved surface that may mediate binding to PI4KIIIalpha. Absence of FAM126A, the predominant FAM126 isoform in oligodendrocytes, destabilizes the PI4KIIIalpha complex in mouse brain and patient fibroblasts. We propose that HCC pathogenesis involves defects in PtdIns(4)P production in oligodendrocytes, whose specialized function requires massive plasma membrane expansion and thus generation of PtdIns(4)P and downstream phosphoinositides. Our results point to a role for FAM126A in supporting myelination, an important process in development and also following acute exacerbations in multiple sclerosis. PMID- 26571213 TI - Factors Associated With Emotional Satisfaction During First Anal Intercourse in a Sample of YMSM. AB - We sought to determine, in a sample of 2,813 HIV seronegative young men who had sex with other men age 18-24, whether physical satisfaction would explain emotional satisfaction during first anal intercourse and whether emotional satisfaction would impact having sex with a partner a second time. Emotional satisfaction was explained mostly by physical satisfaction during the event, but partner type also had direct impact on emotional satisfaction. Our findings suggest that first anal intercourse experiences in young men are both emotionally and physically satisfying and may impact subsequent sexual behavior and partner decision-making. PMID- 26571214 TI - Effects of ammonia stress in the Amazon river shrimp Macrobrachium amazonicum (Decapoda, Palaemonidae). AB - We evaluate the effects of total ammonia nitrogen-N (TAN) exposure for 72h on (Na(+),K(+))- and V(H(+))-ATPase activities and on their subunit expressions in gills of the diadromous freshwater shrimp Macrobrachium amazonicum. Specific (Na(+),K(+))- and V(H(+))-ATPase activities increased roughly 1.5- to 2-fold, respectively, after exposure to 2.0mmolL(-1) TAN. Quantitative RT-PCR analyses revealed a 2.5-fold increase in V(H(+))-ATPase B subunit mRNA expression while (Na(+),K(+))-ATPase alpha-subunit expression was unchanged. Immunohistochemical analyses of the gill lamellae located the (Na(+),K(+))-ATPase throughout the intralamellar septal cells, independently of TAN concentration, while the V(H(+)) ATPase was located in both the apical pillar cell flanges and pillar cell bodies. Systemic stress parameters like total hemocyte count decreased by 30% after exposure to 2.0mmolL(-1) TAN, accompanied by increased activities of the oxidative stress enzymes superoxide dismutase, glutathione reductase and glucose 6-phosphate dehydrogenase in the gills. The stress responses of M. amazonicum to elevated TAN include increases in gill (Na(+),K(+))- and V(H(+))-ATPase activities that are accompanied by changes in oxidative stress enzyme activities, immune system effects and an increase in gill V(H(+))-ATPase gene expression. These findings likely underpin physiological effects in a crustacean like M. amazonicum that exploits multiple ecosystems during its life cycle, as well as under culture conditions that may significantly impact shrimp production by the aquaculture industry. PMID- 26571212 TI - The metabolome regulates the epigenetic landscape during naive-to-primed human embryonic stem cell transition. AB - For nearly a century developmental biologists have recognized that cells from embryos can differ in their potential to differentiate into distinct cell types. Recently, it has been recognized that embryonic stem cells derived from both mice and humans exhibit two stable yet epigenetically distinct states of pluripotency: naive and primed. We now show that nicotinamide N-methyltransferase (NNMT) and the metabolic state regulate pluripotency in human embryonic stem cells (hESCs). Specifically, in naive hESCs, NNMT and its enzymatic product 1-methylnicotinamide are highly upregulated, and NNMT is required for low S-adenosyl methionine (SAM) levels and the H3K27me3 repressive state. NNMT consumes SAM in naive cells, making it unavailable for histone methylation that represses Wnt and activates the HIF pathway in primed hESCs. These data support the hypothesis that the metabolome regulates the epigenetic landscape of the earliest steps in human development. PMID- 26571215 TI - Breast Cancer Induced by X-Ray Mammography Screening? A Review Based on Recent Understanding of Low-Dose Radiobiology. AB - Screening mammography offers the possibility of discovering malignant diseases at an early stage, which is consequently treated early, thereby reducing the mortality rate. However, ionizing radiation as used in low-dose X-ray mammography may be associated with a risk of radiation-induced carcinogenesis. In the context of the harmful effects of ionizing radiation, this article reviewed novel radiobiological data and provided a simulation of the relative incidence of radiation-induced breast cancer due to screening against a background baseline incidence in a population of 100,000 individuals. The use of modern digital mammographic technology was assumed, giving rise to a glandular dose of 2.5 mGy from a 2-view per breast image. Assuming no latency time, this led to a ratio of induced incidence rate over baseline incidence rate of about 1.60/00 for biennial screening in women aged 50-74 years, although it cannot be excluded that the dose and dose rate effectiveness factor values relying on new radiobiological insights may lower this number to about 0.70/00. This carcinogenic risk is considered small in relation to the potential beneficial effects of screening, especially as latency time was not taken into consideration. However, individuals who are known to be carriers of risk-increasing genetic variations and/or have an inherited disposition of breast cancer should avoid ionizing radiation as much as possible and should be referred to ultrasound or magnetic resonance imaging. In addition, a significant, but difficult to quantify, risk of cancer is present for individuals who suffer from hypersusceptibility to ionizing radiation. PMID- 26571216 TI - Paternal calorie restriction prior to conception alters anxiety-like behavior of the adult rat progeny. AB - The maternal environment influences a broad range of phenotypic outcomes for offspring, with anxiety-like behavior being particularly susceptible to maternal environmental perturbations. Much less is known regarding paternal environmental influences. To investigate this, adult male rats were exposed to 25% calorie restriction (CR) or glucocorticoid elevation (CORT; 200 MUg/ml of corticosterone in drinking water) for ~ 6 weeks prior to breeding. Elevated plus maze (EPM), open field (OF), predator odor (cat urine), and acoustic startle/pre-pulse inhibition (AS/PPI) were characterised in the adult male offspring. Plasma concentrations of corticotrophin-releasing hormone (CRF), adrenocorticotropin hormone (ACTH), and serum leptin were characterised in both sires and offspring. Maternal care received by litters was additionally observed. Expectedly, CR and CORT treatment attenuated weight gain, whilst only CR induced anxiolytic behavior in the EPM. The adult offspring sired by CR males also demonstrated a reduction in weight gain, food intake and serum leptin levels when compared to controls. Moreover, CR offspring demonstrated an anxiolytic-like profile in the EPM and OF, enhanced habituation to the AS pulse, reduced PPI, but no alteration to predator odor induced defensiveness compared to control. CORT offspring failed to demonstrate any behavioral differences from controls, however, exhibited a trend towards reduced ACTH and leptin concentration. Collectively, the results indicate that a reduction in calories in males prior to conception can affect the behavior of adult offspring. The phenotypic transmission of CR experiences from fathers to the progeny could potentially be mediated epigenetically. The role of glucocorticoid elevation and maternal care are also discussed. PMID- 26571217 TI - Molecularly Imprinted Polymer Arrays as Synthetic Protein Chips Prepared by Transcription-type Molecular Imprinting by Use of Protein-Immobilized Dots as Stamps. AB - Molecularly imprinted polymer (MIP) arrays were demonstrated for the recognition of proteins. They were prepared via transcription-type molecular imprinting where patterned dots composed of biotinylated nanoparticles were first immobilized on a glass substrate followed by the immobilization of versatile biotinylated proteins via avidin-biotin interactions, yielding a multiple protein-immobilized stamp as a mold that could be transcribed. MIPs were prepared between the stamp and a methacrylated glass substrate, and after the stamp was peeled off, MIP dots were able to be prepared on the methacrylated glass substrate according to the positions of the immobilized proteins on the stamp. We confirmed that the prepared MIP array showed the expected selective binding toward the corresponding template proteins by conducting competitive binding assays using the fluorescently labeled proteins as corresponding competitors. The binding behaviors were consistent with those obtained by a surface plasmon resonance sensing system. We believe that the proposed platform involving the easily handled nanoparticle-based protein stamps for the preparation of MIP arrays can provide a new type of pattern recognition-based protein chip, which can be adopted as a substitute for the use of conventional protein arrays in various research and industrial fields in the life sciences. PMID- 26571218 TI - Brain injury in the international multicenter randomized SafeBoosC phase II feasibility trial: cranial ultrasound and magnetic resonance imaging assessments. AB - BACKGROUND: Abnormal cerebral perfusion during the first days of life in preterm infants is associated with higher grades of intraventricular hemorrhages and lower developmental score. In SafeBoosC II, we obtained a significant reduction of cerebral hypoxia by monitoring cerebral oxygenation in combination with a treatment guideline. Here, we describe (i) difference in brain injury between groups, (ii) feasibility of serial cranial ultrasound (cUS) and magnetic resonance imaging (MRI), (iii) local and central cUS assessment. METHODS: Hundred and sixty-six extremely preterm infants were included. cUS was scheduled for day 1, 4, 7, 14, and 35 and at term-equivalent age (TEA). cUS was assessed locally (unblinded) and centrally (blinded). MRI at TEA was assessed centrally (blinded). Brain injury classification: no, mild/moderate, or severe. RESULTS: Severe brain injury did not differ significantly between groups: cUS (experimental 10/80, control 18/77, P = 0.32) and MRI (5/46 vs. 3/38, P = 0.72). Kappa values for local and central readers were moderate-to-good for severe and poor-to-moderate for mild/moderate injuries. At TEA, cUS and MRI were assessed in 72 and 64%, respectively. CONCLUSION: There was no difference in severe brain injury between groups. Acquiring cUS and MRI according the standard operating procedures must be improved for future trials. Whether monitoring cerebral oxygenation during the first 72 h of life prevents brain injury should be evaluated in larger multicenter trials. PMID- 26571219 TI - Primary distal renal tubular acidosis: novel findings in patients studied by next generation sequencing. AB - BACKGROUND: Primary distal renal tubular acidosis (DRTA) is a rare disease caused by loss-of-function mutations in at least three genes (ATP6V0A4, ATP6V1B1, and SLC4A1) involved in urinary distal acidification. The next-generation sequencing (NGS) technique facilitates the search for mutations in DRTA patients and helps to characterize the genetic and clinical spectrum of the disease. METHODS: Ten DRTA patients were studied. They had normal serum anion gap (AG), metabolic acidosis with simultaneous positive urinary AG, and inability to maximally acidify the urine. The exons of the three genes were sequenced in two pools by ultrasequencing. Putative mutations were confirmed by corresponding Sanger sequencing of each exon. RESULTS: We found 13 mutations in nine patients. ATP6V0A4: Intron16+2insA; p.R807Q; p.Q276fs; p.P395fs; Intron7-2T>C. ATP6V1B1: p.I386fs; p.R394Q. SLC4A1: p.V245M; p.R589C; p.R589H; p.G609A. One case was a compound heterozygous with a known mutation in ATP6V1B1 (p.G609R) and a pathogenic variation at SLC4A1 (p.E508K). One patient was negative for mutations. CONCLUSION: This study evidences that NGS is labor and cost effective for the analysis of DRTA genes. Our results show for the first time SLC4A1 gene mutations in Spanish patients and disclose that compound heterozygosity at two different genes can be responsible for DRTA. PMID- 26571220 TI - Metabolomic and proteomic analysis of serum from preterm infants with necrotising entercolitis and late-onset sepsis. AB - BACKGROUND: Necrotising enterocolitis (NEC) and late-onset sepsis (LOS) are the leading causes of death among preterm infants in the developed world. This study aimed to explore the serum proteome and metabolome longitudinally in preterm infants with NEC or LOS, matched to controls. METHODS: Nineteen patients (10 cases, 9 controls) were included. A sample 14 d prior to and following, as well as at disease diagnosis, was included for cases. Controls had serum matched at diagnosis for corresponding case. All samples (n = 39) underwent shotgun proteomic analysis, and 37 samples also underwent metabolomics analysis using ultra performance liquid chromatography-tandem mass spectrometry. RESULTS: The proteomic and metabolomic profiles of serum were comparable between all infants. Eight proteins were associated with NEC and four proteins were associated with LOS. C-reactive protein was increased in all NEC patients at diagnosis. CONCLUSION: No single protein or metabolite was detected in all NEC or LOS cases which was absent from controls; however, several proteins were identified which were associated with disease status. The differing expression of these proteins between diseased infants potentially relates to differing pathophysiology of disease. Thus, it is unlikely a single biomarker exists for NEC and/or LOS. PMID- 26571221 TI - Prenatal exposure to bisphenol-A is associated with Toll-like receptor-induced cytokine suppression in neonates. AB - BACKGROUND: Despite widespread human exposure to biphenol A (BPA), limited studies exist on the association of BPA with adverse health outcomes in young children. This study aims to investigate the effect of prenatal exposure to BPA on toll-like receptor-induced cytokine responses in neonates and its association with infectious diseases later in life. METHODS: Cord bloods were collected from 275 full-term neonates. Production of TNF-alpha, IL-6, and IL-10 were evaluated after stimulating mononuclear cells with toll-like receptor ligands (TLR1-4 and 7 8). Serum BPA concentrations were analyzed by enzyme-linked immunosorbent assay. Bacteria from nasopharyngeal specimens were identified with multiplex PCR and culture method. RESULT: Result showed significant association between cord BPA concentration and TLR3- and TLR4-stimulated TNF-alpha response (P = 0.001) and that of TLR78-stimulated IL-6 response (P = 0.03). Clinical analysis did not show prenatal BPA exposure to be correlated with infection or bacterial colonization during the first year of life. CONCLUSION: This is the first cohort study that indicated prenatal BPA exposure to play a part in TLR-related innate immune response of neonatal infants. However, despite an altered immune homeostasis, result did not show such exposure to be associated with increased risk of infection during early infancy. PMID- 26571222 TI - A novel method for assessing cerebral autoregulation in preterm infants using transfer function analysis. AB - BACKGROUND: Autoregulatory dysfunction is an important contributor to brain injury in premature infants, particularly intraventricular hemorrhage (IVH). The autoregulatory system acts as a filter that dampens the systemic blood flow to follow a normal cerebral perfusion profile. METHODS: Simultaneous arterial blood pressure and cerebral near-infrared spectroscopy (NIRS) data were collected from infants born before 28 wk estimated gestational age. The resulting data were preprocessed and then divided into nonoverlapping 20-min epochs. The transfer function estimate was calculated to determine dampening ability. RESULTS: Sixty two infants were prospectively recruited with a mean estimated gestational age of 25.4 +/- 1.3 wk and birth weight of 832 +/- 199 g. 67% were male, 24/62 had IVH, 17/62 received dopamine, 47/62 had antenatal steroid exposure, and 22/62 received fentanyl.Advancing estimated gestational age and birth weight z-score predicted stronger dampening while African-American race and IVH of any grade predicted weaker dampening. CONCLUSION: This preliminary report suggests an impairment in dampening ability associated with immaturity, decreased birth weight z-score, and African-American race. Decreased dampening is also associated with IVH, although these results cannot distinguish between decreased dampening as an antecedent or sequela of IVH. These observations should be studied in a larger sample. PMID- 26571223 TI - Post-weaning high-fat diet accelerates kidney injury, but not hypertension programmed by maternal diabetes. AB - BACKGROUND: The aim of this study was to establish the underlying mechanisms by which a post-weaning high-fat diet (HFD) accelerates the perinatal programming of kidney injury occurring in the offspring of diabetic mothers. METHODS: Male mice, offspring of nondiabetic and diabetic dams were fed with normal diet (ND) or HFD from 4 to 20 wk of age. Rat renal proximal tubular cells were used in vitro. RESULTS: On ND, the offspring of dams with severe maternal diabetes had an intrauterine growth restriction (IUGR) phenotype and developed mild hypertension and evidence of kidney injury in adulthood. Exposing the IUGR offspring to HFD resulted in rapid weight gain, catch-up growth, and later to profound kidney injury with activation of renal TGFbeta1 and collagen type IV expression, increased oxidative stress, and enhanced renal lipid deposition, but not systemic hypertension. Given our data, we speculate that HFD or free fatty acids may accelerate the process of perinatal programming of kidney injury, via increased CD36 and fatty acid-binding protein 4 expression, which may target reactive oxygen species, nuclear factor-kappa B, and TGFbeta1 signaling in vivo and in vitro. CONCLUSION: Early postnatal exposure to overnutrition with a HFD increases the risk of development of kidney injury, but not hypertension, in IUGR offspring of dams with maternal diabetes. PMID- 26571224 TI - Ontogeny of plasma proteins, albumin and binding of diazepam, cyclosporine, and deltamethrin. AB - BACKGROUND: To characterize the ontogeny of plasma albumin and total proteins, due to the lack of a comprehensive pediatric database. Secondly, to establish the magnitude and duration of maturational changes in binding of highly-bound drugs/chemicals. METHODS: Anonymized plasma samples from 296 donors were pooled in 6 age brackets from birth to adolescence. Total protein and albumin levels were measured in each age group, as was the age-dependency of plasma binding of diazepam (DZP), cyclosporine (CYC), and deltamethrin (DLM), a pyrethroid insecticide. RESULTS: Plasma levels of albumin and total proteins steadily increased for the first 1-3 y of life. Unbound DZP and CYC fractions were elevated three- to fourfold in neonates, but decreased to adult levels after 1 and 3 y, respectively. Unbound DLM levels exceeded those in adults for just 1 mo. CONCLUSION: Neonates and infants under 1-3 y may be at risk from increased amounts of free drug, when given standard doses of some highly-bound drugs. Pyrethroid insecticides might be anticipated to pose increased risk for 1 mo. PMID- 26571225 TI - The effect of hematocrit on in vitro bilirubin photoalteration. AB - BACKGROUND: Phototherapy using light in the spectral range of 410-500 nm, which overlaps the absorption of bilirubin, is the common treatment for neonatal hyperbilirubinemia. Hemoglobin (Hb) absorbs light strongly throughout this same range and thus can compete with bilirubin for this light and consequently reduce the efficacy of phototherapy. Here, we determined the effect of hematocrit (Hct) on in vitro bilirubin photoalteration using narrow-band blue (450 nm) light emitting diodes (LEDs). METHODS: Suspensions with Hcts from 0 to 80% and 16 +/- 1 mg/dl bilirubin were prepared by mixing red blood cells (RBCs), bilirubin (30 mg/dl) in 4% human serum albumin, and normal saline. Aliquots of each suspension were exposed to blue light at equal irradiances. Before and after 60 min of exposure, bilirubin levels in supernatants (n = 46) were measured using a diazo dye method. RESULTS: Bilirubin photoalteration steeply decreased by ~60% as Hct increased from 0 to 10%. Over the clinically relevant range of 30-70% Hct, the decrease was significant, but less drastic, exhibiting a quasi-linear dependence on Hct. CONCLUSION: Bilirubin photoalteration under blue light in vitro is significantly reduced as Hct increases. Clinical studies are warranted to confirm these in vitro observations that Hct can affect the efficacy of phototherapy. PMID- 26571226 TI - Validating bifidobacterial species and subspecies identity in commercial probiotic products. AB - BACKGROUND: The ingestion of probiotics to attempt to improve health is increasingly common; however, quality control of some commercial products can be limited. Clinical practice is shifting toward the routine use of probiotics to aid in prevention of necrotizing enterocolitis in premature infants, and probiotic administration to term infants is increasingly common to treat colic and/or prevent atopic disease. Since bifidobacteria dominate the feces of healthy breast-fed infants, they are often included in infant-targeted probiotics. METHODS: We evaluated 16 probiotic products to determine how well their label claims describe the species of detectable bifidobacteria in the product. Recently developed DNA-based methods were used as a primary means of identification, and were confirmed using culture-based techniques. RESULTS: We found that the contents of many bifidobacterial probiotic products differ from the ingredient list, sometimes at a subspecies level. Only 1 of the 16 probiotics perfectly matched its bifidobacterial label claims in all samples tested, and both pill-to pill and lot-to-lot variation were observed. CONCLUSION: Given the known differences between various bifidobacterial species and subspecies in metabolic capacity and colonization abilities, the prevalence of misidentified bifidobacteria in these products is cause for concern for those involved in clinical trials and consumers of probiotic products. PMID- 26571228 TI - Quantitative determination of the antidepressant vortioxetine and its major human metabolite in plasma. AB - BACKGROUND: Vortioxetine is a novel antidepressant that has been developed in a joint partnership between H. Lundbeck A/S and the Takeda Pharmaceutical Company, Ltd. RESULTS: A number of bioanalytical methods have been developed in order to support the nonclinical and clinical development of the drug. Method performance, long-term stability, urine analysis, unspecific binding and metabolites analysis are presented and discussed. CONCLUSION: Two different method applications for the quantification of vortioxetine and its major human metabolite in human plasma, an isocratic cation exchange HPLC-MS/MS method utilizing C8-SPE sample extracts and a reversed-phase UPLC-MS/MS method with gradient elution of protein precipitated sample extracts, have been validated according to current regulatory standards and applied in support to a large number of nonclinical as well as clinical studies. PMID- 26571229 TI - Role of Radical Species in Salicylaldiminato Ni(II) Mediated Polymer Chain Growth: A Case Study for the Migratory Insertion Polymerization of Ethylene in the Presence of Methyl Methacrylate. AB - To date, an inconclusive and partially contradictive picture exists on the behavior of neutral Ni(II) insertion polymerization catalysts toward methyl methacrylate (MMA). We shed light on this issue by a combination of comprehensive mechanistic NMR and EPR studies, isolation of a key Ni(I) intermediate, and pressure reactor studies with ethylene and MMA, followed by detailed polymer analysis. An interlocking mechanistic picture of an insertion and a free radical polymerization is revealed. Both polymerizations run simultaneously (25 bar ethylene, neat MMA, 70 degrees C); however, the chain growth cycles are independent of each other, and therefore exclusively a physical mixture of homo PE and homo-PMMA is obtained. A Ni-C bond cleavage was excluded as a free radical source. Rather a homolytic P-C bond cleavage in the labile aryl phosphine ligand and the reaction of low-valent Ni(0/I) species with specific iodo substituted N^O (Ar-I) ligands were shown to initiate radical MMA polymerizations. Several reductive elimination decomposition pathways of catalyst precursor or active intermediates were shown to form low-valent Ni species. One of those pathways is a bimolecular reductive coupling via intermediate (N^O)Ni(I) formation. These intermediate Ni(I) species can be prevented from ultimate decomposition by capturing with organic radical sources, forming insertion polymerization active [(N^O)Ni(II)-R] species and prolonging the ethylene polymerization activity. PMID- 26571227 TI - Bilastine: a new antihistamine with an optimal benefit-to-risk ratio for safety during driving. AB - INTRODUCTION: Rational selection of a second-generation H1-antihistamine requires efficacy and safety considerations, particularly regarding central nervous system (CNS) effects (cognitive and psychomotor function), potential for driving impairment, minimal sedative effects and a lack of interactions. This review evaluates the key safety features of the non-sedating antihistamine, bilastine, during driving and in preventing road traffic accidents. AREAS COVERED: Among the second-generation H1-antihistamines, sedative effects which can affect cognitive and psychomotor performance, and possibly driving ability, may not be similar. Bilastine is absorbed rapidly, undergoes no hepatic metabolism or cytochrome P450 interaction (minimal drug-drug interaction potential), and is a substrate for P glycoprotein (limiting CNS entry). Positron emission tomography showed that, compared with other second-generation H1-antihistamines, bilastine has the lowest cerebral histamine H1-receptor occupancy. Bilastine 20 mg once daily (therapeutic dose) is non-sedating, does not enhance the effects of alcohol or CNS sedatives, does not impair driving performance and has at least similar efficacy as other second-generation H1-antihistamines in the treatment of allergic rhinoconjunctivitis and urticaria. EXPERT OPINION: Current evidence shows that bilastine has an optimal benefit-to-risk ratio, meeting all conditions for contributing to safety in drivers who need antihistamines, and hence for being considered as an antihistamine of choice for drivers. PMID- 26571230 TI - 2-Furaldehyde diethyl acetal from tender coconut water (Cocos nucifera) attenuates biofilm formation and quorum sensing-mediated virulence of Chromobacterium violaceum and Pseudomonas aeruginosa. AB - The aim of this study was to evaluate the anti-biofilm and quorum sensing inhibitory (QSI) potential of tender coconut water (TCW) against Chromobacterium violaceum and Pseudomonas aeruginosa. TCW significantly inhibited the QS regulated violacein, virulence factors and biofilm production without affecting their growth. qRT-PCR analysis revealed the down-regulation of autoinducer synthase, transcriptional regulator and virulence genes. Mass-spectrometric analysis of a petroleum ether extract of the TCW hydrolyte revealed that 2 furaldehyde diethyl acetal (2FDA) and palmitic acid (PA) are the major compounds. In vitro bioassays confirmed the ability of 2FDA to inhibit the biofilm formation and virulence factors. In addition, the combination of PA with 2FDA resulted in potent inhibition of biofilm formation and virulence factors. The results obtained strongly suggest that TCW can be exploited as a base for designing a novel antipathogenic drug formulation to treat biofilm mediated infections caused by P. aeruginosa. PMID- 26571231 TI - Aplastic Anemia in Two Patients with Sex Chromosome Aneuploidies. AB - Sex chromosome aneuploidies range in incidence from rather common to exceedingly rare and have a variable phenotype. We report 2 patients with sex chromosome aneuploidies who developed severe aplastic anemia requiring treatment. The first patient had tetrasomy X (48,XXXX) and presented at 9 years of age, and the second patient had trisomy X (47,XXX) and presented at 5 years of age. Although aplastic anemia has been associated with other chromosomal abnormalities, sex chromosome abnormalities have not been traditionally considered a risk factor for this condition. A review of the literature reveals that at least one other patient with a sex chromosome aneuploidy (45,X) has suffered from aplastic anemia and that other autosomal chromosomal anomalies have been described. Despite the uncommon nature of each condition, it is possible that the apparent association is coincidental. A better understanding of the genetic causes of aplastic anemia remains important. PMID- 26571232 TI - Elastography for Predicting and Localizing Nodal Metastases during Endobronchial Ultrasound. AB - BACKGROUND: Elastography is a relatively new technology that can generate images reflective of tissue stiffness (elasticity). Neoplastic tissue is usually stiffer than normal structures. OBJECTIVES: The aim of this study was to evaluate the feasibility and utility of elastography when combined with convex-probe endobronchial ultrasound (CP-EBUS) for predicting and localizing metastatic lymph nodes during endobronchial ultrasound with transbronchial needle aspiration (EBUS TBNA). METHODS: Consecutive results of endobronchial elastography of lymph nodes performed using EBUS- TBNA were prospectively collected and retrospectively analyzed. Elastography images were acquired as JPEG images and also recorded as video clips. Stiff area ratios [(stiff areas as blue pixels) / (lymph node areas as region of interest pixels)] for each lymph node determined by elastography were collated with the results of pathological diagnosis. We also performed elastography of surgically resected lymph nodes and compared image findings with pathological sections. RESULTS: We evaluated 49 lymph nodes in 21 patients by CP EBUS. There were 16 metastatic nodes (10 lung cancer metastases and 6 metastases from extrathoracic malignancies). Mean stiff area ratios were significantly greater for metastatic lymph nodes (0.478) than for benign nodes (0.216; p = 0.0002). Using a cutoff value of 0.311 for stiff area ratios, the sensitivity and specificity for predicting metastatic disease were 0.81 and 0.85, respectively. The stiff area was histologically compatible with metastatic distribution in surgically resected lymph nodes. CONCLUSIONS: Endobronchial elastography is feasible for lymph nodes when combined with CP-EBUS. Stiff area ratios are useful for predicting metastatic lymph nodes, which may be an efficient guide for TBNA. PMID- 26571233 TI - Self-Reported Hindering Health Complaints of Community-Dwelling Older Persons: A Cross-Sectional Study. AB - PURPOSE: Proactive care for community-dwelling older persons targeting self reported hindering health complaints might prevent a decline in function. We investigated the spectrum of self-reported hindering complaints of community dwelling older persons, the association with functional outcomes, and help seeking behavior for these complaints. METHODS: Within the ISCOPE trial, participants (aged >=75 years) received the ISCOPE screening questionnaire, including the open-ended question "At the moment, which health complaints limit you the most in your day-to-day life?". After coding the answers with the ICPC-1 NL, we examined the prevalence and the association between the number and type of complaints and functional outcomes (Groningen Activities Restriction Scale, quality of life measured on Cantril's Ladder, Mini-Mental State Examination, Geriatric Depression Scale-15, and De Jong Gierveld Loneliness Scale). Electronic patient registers were searched for the most reported complaints. RESULTS: 7285 participants (median age: 81.0 years [IQR 77.8-85.3], 38.6% males) reported 13,524 hindering complaints (median 1, range 0-18); 32.7% reported no complaints. Participants mostly reported problems with walking/standing (22.1%), pain (20.8%) or weakness/tiredness (8.5%). These complaints were mentioned in the electronic patient registers in 28.3%, 91.3% and 55.5%, respectively. Higher numbers of hindering complaints were related to poorer scores on the number of domains with problems, Cantril's Ladder for quality of life, Groningen Activities Restriction Scale, Geriatric Depression Scale, and De Jong Gierveld Loneliness Scale. Self reported weakness, problems with walking/standing, visual limitations, cognitive problems, dyspnea and back complaints were associated with poorer scores on the number of domains with problems, Groningen Activities Restriction Scale, MMSE or Geriatric Depression Scale. CONCLUSION: One third of the participants reported no hindering complaints. Problems with walking/standing, pain, and weakness/tiredness were most reported, but not always found in electronic patient registers. A higher number of, and specific self-reported hindering complaints, were associated with poorer scores on functional outcomes. It may be helpful for general practitioners to ask about these complaints and their influence on daily life. PMID- 26571234 TI - Medical Directive for Urinary Catheter Removal by Nurses on General Medical Wards. PMID- 26571235 TI - Food Web Topology in High Mountain Lakes. AB - Although diversity and limnology of alpine lake systems are well studied, their food web structure and properties have rarely been addressed. Here, the topological food webs of three high mountain lakes in Central Spain were examined. We first addressed the pelagic networks of the lakes, and then we explored how food web topology changed when benthic biota was included to establish complete trophic networks. We conducted a literature search to compare our alpine lacustrine food webs and their structural metrics with those of 18 published lentic webs using a meta-analytic approach. The comparison revealed that the food webs in alpine lakes are relatively simple, in terms of structural network properties (linkage density and connectance), in comparison with lowland lakes, but no great differences were found among pelagic networks. The studied high mountain food webs were dominated by a high proportion of omnivores and species at intermediate trophic levels. Omnivores can exploit resources at multiple trophic levels, and this characteristic might reduce competition among interacting species. Accordingly, the trophic overlap, measured as trophic similarity, was very low in all three systems. Thus, these alpine networks are characterized by many omnivorous consumers with numerous prey species and few consumers with a single or few prey and with low competitive interactions among species. The present study emphasizes the ecological significance of omnivores in high mountain lakes as promoters of network stability and as central players in energy flow pathways via food partitioning and enabling energy mobility among trophic levels. PMID- 26571236 TI - Isolation and Characterization of Circulating Tumor Cells in Squamous Cell Carcinoma of the Lung Using a Non-EpCAM-Based Capture Method. AB - INTRODUCTION: The exclusion of circulating tumor cells (CTCs) that have lost epithelial antigens during the epithelial-to-mesenchymal transition (EMT) process by using Epithelial Cell Adhesion Molecule (EpCAM) based capture methods is still a matter of debate. In this study, cells obtained after depletion procedure from blood samples of squamous cell lung cancer (SQCLC) patients were identified based on morphology and characterized with the combination of FISH assessment and immunophenotypic profile. MATERIALS AND METHODS: Five mL blood samples, collected from 55 advanced SQCLC patients, were analyzed by a non-EpCAM-based capture method. After depletion of leukocytes and erythroid cells, the negative fraction was characterized by both FISH using a fibroblast growth factor receptor 1 (FGFR1) probe and by immunocytochemistry. Thirty healthy donors were also tested. RESULTS: Based on morphology (nuclear dimension >=10 MUm, shape and hypercromatic aspect) suspicious circulating cells clearly distinguishable from contaminant leukocytes were observed in 49/55 (89%) SQCLC patients. Thirty-four of the 44 (77%) samples evaluable for FGFR1 FISH showed >= 6 FGFR1 gene copy number on average per cell. Vimentin expression involved 43% (18/42) of pooled circulating SQCLC cells, whereas only 29% (14/48) were EpCAM positive. Confocal microscopy confirmed the localization of FGFR1 probe in suspicious circulating cells. Suspicious circulating elements were also observed in healthy donors and did not show any epithelial associated antigens. A significantly lower number of suspicious circulating cells in healthy donors compared to SQCLC patients was found. CONCLUSIONS: Among the heterogeneous cell population isolated by depletion procedure, the coexistence of cells with epithelial and/or mesenchymal phenotype suggests that EMT may participate to transendothelial invasion and migration of tumor cells in advanced SQCLC. The finding of cells with neither EpCAM or EMT phenotype, retrieved after non-EpCAM-based systems, underlines the presence of suspicious elements in the blood of both SQCLC patients and healthy donors. Further phenotyping and molecular analyses are necessary to fully characterize these circulating elements. PMID- 26571237 TI - Glutathione S-Transferase Gene Polymorphisms and Treatment Outcome in Cervical Cancer Patients under Concomitant Chemoradiation. AB - PURPOSE: Cisplatin based concomitant chemoradiation (CRT) is the standard treatment for locally advanced cervical cancer (CC). Glutathione S-transferase (GST), a phase II antioxidant enzyme is induced by oxidative stress generated by drugs and reactive oxidants. The present study was undertaken to evaluate the association of GSTM1, T1 and P1 polymorphisms with the outcome of CRT treatment in CC patients. METHODS: A total of 227 cervical cancer patients with stages IIB IIIB treated with the same chemoradiotherapy regimen were enrolled and genotyped for GSTM1, T1 and P1 gene polymorphisms by multiplex polymerase chain reaction (mPCR) and PCR-restriction fragment length polymorphism (PCR-RFLP). Overall survival was evaluated using Kaplan-Meier survival function and Cox proportional hazards model. All data were analyzed using SPSS (version 21.0). RESULTS: Stratified analysis showed that GSTM1 null (M1-) genotype was associated with a significantly better survival among patients with stage IIB cervical cancer (log rank P = 0.004) than cases with stage IIIA/IIIB. Death and recurrence were significantly higher in patients with GSTM1 present genotype (M1+) (P = 0.037 and P = 0.003 respectively) and those with M1- showed reduced hazard of death with an adjusted hazard ratio 'HR' of 0.47 (95% CI, 0.269-0.802, P = 0.006). Women with M1- genotype as well as in combination with GSTT1 null (T1-), GSTP1 (AG+GG) and GSTT1 null/GSTP1 (AG+GG) showed better survival and also reduced risk of death (HR = 0.31, P = 0.016; HR = 0.45, P = 0.013; HR = 0.31, P = 0.02 respectively). CONCLUSIONS: To the best of our knowledge, this is the first study to correlate the association of GSTM1, T1 and P1 gene polymorphisms with treatment outcome of CRT treated CC patients. Our results suggested that individuals with GSTM1 null genotype and in combination with GSTT1 null and GSTP1 (AG+GG) had a survival advantage. Such genetic studies may provide prognostic information in CRT treated CC patients. PMID- 26571238 TI - A Comprehensive MicroRNA Expression Profile Related to Hypoxia Adaptation in the Tibetan Pig. AB - Tibetan pigs live between 2500 and 4300 m above sea level on the Tibetan Plateau, and are better adapted to hypoxia than lowland pigs. MicroRNAs (miRNAs) are involved in a wide variety of cellular processes; however, their regulatory role in hypoxia adaptation remains unclear. In this study, miRNA-seq was used to identify differentially expressed miRNAs (DE miRNAs) in the cardiac muscle of Tibetan and Yorkshire pigs, which were both raised in high elevation environments. We obtained 108 M clean reads and 372 unique miRNAs, which included 210 known porcine miRNAs, 136 conserved in other mammals, and 26 novel pre miRNAs. In addition, 20 DE miRNAs, including 10 up-regulated and 10 down regulated miRNAs, were also found after comparison between Tibetan and Yorkshire pigs. We predicted miRNA targets based on differential expression and abundance in the two populations. Furthermore, the results of a Kyoto Encyclopedia of Genes and Genomes pathway analysis suggested that DE miRNAs in Tibetan and Yorkshire pigs are involved in hypoxia-related signaling pathways such as the mitogen activated protein kinase, which is the mechanistic target of rapamycin, and the vascular endothelial growth factor, as well as cancer-related signaling pathways. Five DE miRNAs were randomly selected to validate the results of miRNA-seq using real-time polymerase chain reaction, and the results corresponded to those from the miRNA-seq, confirming that deep-sequencing methods are feasible and efficient. In our study, we identified various previously unknown hypoxia-related miRNAs in pigs, and the data obtained suggest that hypoxia-related miRNA expression patterns are significantly altered in the Tibetan pig compared to other species. Therefore, DE miRNAs may play an important role in organisms that have adapted to hypoxic environments. PMID- 26571242 TI - Celebrating the ACP centennial: from the Annals archive--acute coronary syndromes. PMID- 26571241 TI - Accuracy of peripheral thermometers for estimating temperature: a systematic review and meta-analysis. AB - BACKGROUND: Body temperature is commonly used to screen patients for infectious diseases, establish diagnoses, monitor therapy, and guide management decisions. PURPOSE: To determine the accuracy of peripheral thermometers for estimating core body temperature in adults and children. DATA SOURCES: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and CINAHL Plus from inception to July 2015. STUDY SELECTION: Prospective studies comparing the accuracy of peripheral (tympanic membrane, temporal artery, axillary, or oral) thermometers with central (pulmonary artery catheter, urinary bladder, esophageal, or rectal) thermometers. DATA EXTRACTION: 2 reviewers extracted data on study characteristics, methods, and outcomes and assessed the quality of individual studies. DATA SYNTHESIS: 75 studies (8682 patients) were included. Most studies were at high or unclear risk of patient selection bias (74%) or index test bias (67%). Compared with central thermometers, peripheral thermometers had pooled 95% limits of agreement (random effects meta-analysis) outside the predefined clinically acceptable range (+/- 0.5 degrees C), especially among patients with fever (-1.44 degrees C to 1.46 degrees C for adults; -1.49 degrees C to 0.43 degrees C for children) and hypothermia (-2.07 degrees C to 1.90 degrees C for adults; no data for children). For detection of fever (bivariate random-effects meta-analysis), sensitivity was low (64% [95% CI, 55% to 72%]; I2 = 95.7%; P < 0.001) but specificity was high (96% [CI, 93% to 97%]; I2 = 96.3%; P < 0.001). Only 1 study reported sensitivity and specificity for the detection of hypothermia. LIMITATIONS: High-quality data for some temperature measurement techniques are limited. Pooled data are associated with interstudy heterogeneity that is not fully explained by stratified and metaregression analyses. CONCLUSION: Peripheral thermometers do not have clinically acceptable accuracy and should not be used when accurate measurement of body temperature will influence clinical decisions. PRIMARY FUNDING SOURCE: None. PMID- 26571243 TI - What adoption gave me. PMID- 26571245 TI - Effect of allowing choice of diet on weight loss. PMID- 26571246 TI - Effect of allowing choice of diet on weight loss--in response. PMID- 26571247 TI - Letters. PMID- 26571248 TI - Letters--in response. PMID- 26571249 TI - On-demand delivery of influenza vaccination. PMID- 26571251 TI - Web Exclusives. The consult guys - a case of hypertension: overcoming resistance requires change. PMID- 26571252 TI - ACP Journal Club: the Richmond Agitation Sedation Scale was accurate for detecting delirium in older patients in the ED. PMID- 26571253 TI - ACP Journal Club: ACC/AHA guidelines determining statin eligibility better predicted CVD than ATP-III guidelines. PMID- 26571254 TI - ACP Journal Club: the CKD-EPI equation for eGFR predicted adverse outcomes after PCI better than other equations. PMID- 26571255 TI - ACP Journal Club: in hospitalized patients, the Hospital-patient One-year Mortality Risk score predicted 1-year mortality. PMID- 26571256 TI - ACP Journal Club: a balance retraining exercise program reduced injurious falls in at-risk older community-dwelling women. PMID- 26571257 TI - ACP Journal Club: review: screening identifies women having intimate partner violence but effects are unclear. PMID- 26571258 TI - ACP Journal Club: review: in older patients with AF or acute VTE, some DOACs reduce thrombotic events and major bleeding. PMID- 26571259 TI - ACP Journal Club: in AF requiring warfarin interruption, no bridging was noninferior to anticoagulation bridging for thromboembolism. PMID- 26571260 TI - ACP Journal Club: after treating unprovoked PE with VKAs for 6 months, warfarin for 18 more months reduced a composite of VTE or major bleeding. PMID- 26571261 TI - ACP Journal Club: in uncontrolled hypertension, a pharmacist-prescribing intervention reduced blood pressure at 6 months. PMID- 26571262 TI - ACP Journal Club: optimized extracorporeal shock-wave therapy improved pain and functioning in chronic plantar fasciitis. PMID- 26571263 TI - ACP Journal Club: adding CT to screening for occult cancer did not increase diagnosis of cancer from screening in unprovoked VTE. PMID- 26571264 TI - Insights into Kinetics of Agitation-Induced Aggregation of Hen Lysozyme under Heat and Acidic Conditions from Various Spectroscopic Methods. AB - Protein misfolding and amyloid formation are an underlying pathological hallmark in a number of prevalent diseases of protein aggregation ranging from Alzheimer's and Parkinson's diseases to systemic lysozyme amyloidosis. In this context, we have used complementary spectroscopic methods to undertake a systematic study of the self-assembly of hen egg-white lysozyme under agitation during a prolonged heating in acidic pH. The kinetics of lysozyme aggregation, monitored by Thioflavin T fluorescence, dynamic light scattering and the quenching of tryptophan fluorescence by acrylamide, is described by a sigmoid curve typical of a nucleation-dependent polymerization process. Nevertheless, we observe significant differences between the values deduced for the kinetic parameters (lag time and aggregation rate). The fibrillation process of lysozyme, as assessed by the attenuated total reflection-Fourier transform infrared spectroscopy, is accompanied by an increase in the beta-sheet conformation at the expense of the alpha-helical conformation but the time-dependent variation of the content of these secondary structures does not evolve as a gradual transition. Moreover, the tryptophan fluorescence-monitored kinetics of lysozyme aggregation is described by three phases in which the temporal decrease of the tryptophan fluorescence quantum yield is of quasilinear nature. Finally, the generated lysozyme fibrils exhibit a typical amyloid morphology with various lengths (observed by atomic force microscopy) and contain exclusively the full-length protein (analyzed by highly performance liquid chromatography). Compared to the data obtained by other groups for the formation of lysozyme fibrils in acidic pH without agitation, this work provides new insights into the structural changes (local, secondary, oligomeric/fibrillar structures) undergone by the lysozyme during the agitation-induced formation of fibrils. PMID- 26571265 TI - Insights into the Activity and Substrate Binding of Xylella fastidiosa Polygalacturonase by Modification of a Unique QMK Amino Acid Motif Using Protein Chimeras. AB - Polygalacturonases (EC 3.2.1.15) catalyze the random hydrolysis of 1, 4-alpha-D galactosiduronic linkages in pectate and other galacturonans. Xylella fastidiosa possesses a single polygalacturonase gene, pglA (PD1485), and X. fastidiosa mutants deficient in the production of polygalacturonase are non-pathogenic and show a compromised ability to systemically infect grapevines. These results suggested that grapevines expressing sufficient amounts of an inhibitor of X. fastidiosa polygalacturonase might be protected from disease. Previous work in our laboratory and others have tried without success to produce soluble active X. fastidiosa polygalacturonase for use in inhibition assays. In this study, we created two enzymatically active X. fastidiosa / A. vitis polygalacturonase chimeras, AX1A and AX2A to explore the functionality of X. fastidiosa polygalacturonase in vitro. The AX1A chimera was constructed to specifically test if recombinant chimeric protein, produced in Escherichia coli, is soluble and if the X. fastidiosa polygalacturonase catalytic amino acids are able to hydrolyze polygalacturonic acid. The AX2A chimera was constructed to evaluate the ability of a unique QMK motif of X. fastidiosa polygalacturonase, most polygalacturonases have a R(I/L)K motif, to bind to and allow the hydrolysis of polygalacturonic acid. Furthermore, the AX2A chimera was also used to explore what effect modification of the QMK motif of X. fastidiosa polygalacturonase to a conserved RIK motif has on enzymatic activity. These experiments showed that both the AX1A and AX2A polygalacturonase chimeras were soluble and able to hydrolyze the polygalacturonic acid substrate. Additionally, the modification of the QMK motif to the conserved RIK motif eliminated hydrolytic activity, suggesting that the QMK motif is important for the activity of X. fastidiosa polygalacturonase. This result suggests X. fastidiosa polygalacturonase may preferentially hydrolyze a different pectic substrate or, alternatively, it has a different mechanism of substrate binding than other polygalacturonases characterized to date. PMID- 26571266 TI - Aggressive Bimodal Communication in Domestic Dogs, Canis familiaris. AB - Evidence of animal multimodal signalling is widespread and compelling. Dogs' aggressive vocalisations (growls and barks) have been extensively studied, but without any consideration of the simultaneously produced visual displays. In this study we aimed to categorize dogs' bimodal aggressive signals according to the redundant/non-redundant classification framework. We presented dogs with unimodal (audio or visual) or bimodal (audio-visual) stimuli and measured their gazing and motor behaviours. Responses did not qualitatively differ between the bimodal and two unimodal contexts, indicating that acoustic and visual signals provide redundant information. We could not further classify the signal as 'equivalent' or 'enhancing' as we found evidence for both subcategories. We discuss our findings in relation to the complex signal framework, and propose several hypotheses for this signal's function. PMID- 26571267 TI - Usefulness of the rivermead postconcussion symptoms questionnaire and the trail making test for outcome prediction in patients with mild traumatic brain injury. AB - The aim of the study was to determine if the Rivermead Postconcussion Symptoms Questionnaire (RPQ) is a better tool for outcome prediction than an objective neuropsychological assessment following mild traumatic brain injury (mTBI). The study included 47 patients with mTBI referred to an outpatient rehabilitation clinic. The RPQ and a brief neuropsychological battery were performed in the first few days following the trauma. The outcome measure used was the Mayo Portland Adaptability Inventory-4 (MPAI-4) which was completed within the first 3 months. The only variable associated with results on the MPAI-4 was the RPQ score (p < .001). The predictive outcome model including age, education, and the results of the Trail-Making Test-Parts A and B (TMT) had a pseudo-R(2) of .02. When the RPQ score was added, the pseudo-R(2) climbed to .19. This model indicates that the usefulness of the RPQ score and the TMT in predicting moderate to-severe limitations, while controlling for confounders, is substantial as suggested by a significant increase in the model chi-square value, delta (1df) = 6.517, p < .001. The RPQ and the TMT provide clinicians with a brief and reliable tool for predicting outcome functioning and can help target the need for further intervention and rehabilitation following mTBI. PMID- 26571268 TI - Bee Venom Alleviates Motor Deficits and Modulates the Transfer of Cortical Information through the Basal Ganglia in Rat Models of Parkinson's Disease. AB - Recent evidence points to a neuroprotective action of bee venom on nigral dopamine neurons in animal models of Parkinson's disease (PD). Here we examined whether bee venom also displays a symptomatic action by acting on the pathological functioning of the basal ganglia in rat PD models. Bee venom effects were assessed by combining motor behavior analyses and in vivo electrophysiological recordings in the substantia nigra pars reticulata (SNr, basal ganglia output structure) in pharmacological (neuroleptic treatment) and lesional (unilateral intranigral 6-hydroxydopamine injection) PD models. In the hemi-parkinsonian 6-hydroxydopamine lesion model, subchronic bee venom treatment significantly alleviates contralateral forelimb akinesia and apomorphine-induced rotations. Moreover, a single injection of bee venom reverses haloperidol-induced catalepsy, a pharmacological model reminiscent of parkinsonian akinetic deficit. This effect is mimicked by apamin, a blocker of small conductance Ca2+-activated K+ (SK) channels, and blocked by CyPPA, a positive modulator of these channels, suggesting the involvement of SK channels in the bee venom antiparkinsonian action. In vivo electrophysiological recordings in the substantia nigra pars reticulata (basal ganglia output structure) showed no significant effect of BV on the mean neuronal discharge frequency or pathological bursting activity. In contrast, analyses of the neuronal responses evoked by motor cortex stimulation show that bee venom reverses the 6-OHDA- and neuroleptic-induced biases in the influence exerted by the direct inhibitory and indirect excitatory striatonigral circuits. These data provide the first evidence for a beneficial action of bee venom on the pathological functioning of the cortico-basal ganglia circuits underlying motor PD symptoms with potential relevance to the symptomatic treatment of this disease. PMID- 26571269 TI - Validation of qPCR Methods for the Detection of Mycobacterium in New World Animal Reservoirs. AB - Zoonotic pathogens that cause leprosy (Mycobacterium leprae) and tuberculosis (Mycobacterium tuberculosis complex, MTBC) continue to impact modern human populations. Therefore, methods able to survey mycobacterial infection in potential animal hosts are necessary for proper evaluation of human exposure threats. Here we tested for mycobacterial-specific single- and multi-copy loci using qPCR. In a trial study in which armadillos were artificially infected with M. leprae, these techniques were specific and sensitive to pathogen detection, while more traditional ELISAs were only specific. These assays were then employed in a case study to detect M. leprae as well as MTBC in wild marmosets. All marmosets were negative for M. leprae DNA, but 14 were positive for the mycobacterial rpoB gene assay. Targeted capture and sequencing of rpoB and other MTBC genes validated the presence of mycobacterial DNA in these samples and revealed that qPCR is useful for identifying mycobacterial-infected animal hosts. PMID- 26571270 TI - Non-Human Primates Harbor Diverse Mammalian and Avian Astroviruses Including Those Associated with Human Infections. AB - Astroviruses (AstVs) are positive sense, single-stranded RNA viruses transmitted to a wide range of hosts via the fecal-oral route. The number of AstV-infected animal hosts has rapidly expanded in recent years with many more likely to be discovered because of the advances in viral surveillance and next generation sequencing. Yet no study to date has identified human AstV genotypes in animals, although diverse AstV genotypes similar to animal-origin viruses have been found in children with diarrhea and in one instance of encephalitis. Here we provide important new evidence that non-human primates (NHP) can harbor a wide variety of mammalian and avian AstV genotypes, including those only associated with human infection. Serological analyses confirmed that >25% of the NHP tested had antibodies to human AstVs. Further, we identified a recombinant AstV with parental relationships to known human AstVs. Phylogenetic analysis suggests AstVs in NHP are on average evolutionarily much closer to AstVs from other animals than are AstVs from bats, a frequently proposed reservoir. Our studies not only demonstrate that human astroviruses can be detected in NHP but also suggest that NHP are unique in their ability to support diverse AstV genotypes, further challenging the paradigm that astrovirus infection is species-specific. PMID- 26571272 TI - James Hill of Dumfries: First modern neurosurgical procedures. AB - James Hill (1703-1776) was a surgeon from Dumfries in Scotland who can lay claim to being the first to treat head injury patients in a thoroughly modern manner. He was highly regarded in his lifetime and for a century afterwards but has subsequently been forgotten. He had the lowest surgical mortality for trepanation of any surgeon of his time. He uniquely presented his results after a lengthy follow-up of many years. His management of cranial fractures was advanced. He did not use the trepan for fissures as others did and his conservative management of depressed fractures was based on biological rather than mechanical notions. He had an instinct for the management of raised intracranial pressure (ICP) unique in his day even though he could not have understood it in modern terms. He operated on head injuries only if there was a disturbance of consciousness. He was aware of the importance of cerebral pulsation and was alone in recording it in a majority of operated patients. He was ready to open the dura when necessary and did so six times. He introduced non-compressive bandaging over skull defects after surgery. In three cases he shaved off brain hernias which resulted in marked clinical improvement. He not only understood that an injury or disease on one side caused a deficit on the other side but uniquely encompassed this knowledge in his treatment planning. In view of these many insights and achievements, he deserves to be considered as the first surgeon whose neurosurgical management is recognisably close to modern practice. PMID- 26571271 TI - Genome-Wide Locations of Potential Epimutations Associated with Environmentally Induced Epigenetic Transgenerational Inheritance of Disease Using a Sequential Machine Learning Prediction Approach. AB - Environmentally induced epigenetic transgenerational inheritance of disease and phenotypic variation involves germline transmitted epimutations. The primary epimutations identified involve altered differential DNA methylation regions (DMRs). Different environmental toxicants have been shown to promote exposure (i.e., toxicant) specific signatures of germline epimutations. Analysis of genomic features associated with these epimutations identified low-density CpG regions (<3 CpG / 100bp) termed CpG deserts and a number of unique DNA sequence motifs. The rat genome was annotated for these and additional relevant features. The objective of the current study was to use a machine learning computational approach to predict all potential epimutations in the genome. A number of previously identified sperm epimutations were used as training sets. A novel machine learning approach using a sequential combination of Active Learning and Imbalance Class Learner analysis was developed. The transgenerational sperm epimutation analysis identified approximately 50K individual sites with a 1 kb mean size and 3,233 regions that had a minimum of three adjacent sites with a mean size of 3.5 kb. A select number of the most relevant genomic features were identified with the low density CpG deserts being a critical genomic feature of the features selected. A similar independent analysis with transgenerational somatic cell epimutation training sets identified a smaller number of 1,503 regions of genome-wide predicted sites and differences in genomic feature contributions. The predicted genome-wide germline (sperm) epimutations were found to be distinct from the predicted somatic cell epimutations. Validation of the genome-wide germline predicted sites used two recently identified transgenerational sperm epimutation signature sets from the pesticides dichlorodiphenyltrichloroethane (DDT) and methoxychlor (MXC) exposure lineage F3 generation. Analysis of this positive validation data set showed a 100% prediction accuracy for all the DDT-MXC sperm epimutations. Observations further elucidate the genomic features associated with transgenerational germline epimutations and identify a genome-wide set of potential epimutations that can be used to facilitate identification of epigenetic diagnostics for ancestral environmental exposures and disease susceptibility. PMID- 26571273 TI - Seasonal Variation in Mortality, Medical Care Expenditure and Institutionalization in Older People: Evidence from a Dutch Cohort of Older Health Insurance Clients. AB - BACKGROUND: The mortality rates of older people changes with the seasons. However, it has not been properly investigated whether the seasons affect medical care expenditure (MCE) and institutionalization. Seasonal variation in MCE is plausible, as MCE rises exponentially before death. It is therefore important to investigate the impact of the seasons on MCE both mediated and unmediated by mortality. METHODS: Data on mortality, MCE and institutionalization from people aged 65 and older in a region in the Netherlands from July 2007 through 2010 were retrieved from a regional health care insurer and were linked with data from the Netherlands Institute for Social Research, and Statistics Netherlands (n = 61,495). The Seasonal and Trend decomposition using Loess (STL) method was used to divide mortality rates, MCE, and institutionalization rates into a long-term trend, seasonal variation, and remaining variation. For every season we calculated the 95% confidence interval compared to the long-term trend using Welch's t-test. RESULTS: The mortality rates of older people differ significantly between the seasons, and are 21% higher in the winter compared to the summer. MCE rises with 13% from the summer to the winter; this seasonal difference is higher for the non-deceased than for the deceased group (14% vs. 6%). Seasonal variation in mortality is more pronounced in men and people in residential care. Seasonal variation in MCE is more pronounced in women. Institutionalization rates are significantly higher in the winter, but the other seasons show no significant impact. CONCLUSIONS: Seasonal changes affect mortality and the level of MCE of older people; institutionalization rates peak in the winter. Seasonal variation in MCE exists independently from patterns in mortality. Seasonal variation in mortality is similar for both institutionalized and community-dwelling elderly. Policy-makers, epidemiologists and health economists are urged to acknowledge and include the impact of the seasons in future policy and research. PMID- 26571274 TI - The Influence of Arm Swelling Duration on Shoulder Pathology in Breast Cancer Patients with Lymphedema. AB - PURPOSE: To evaluate the pathological effect of the duration of arm swelling on the shoulder pathology in patients with breast cancer-related lymphedema. METHODS: Forty seven breast cancer patients with unilateral arm lymphedema were assessed. The duration of the arm swelling and shoulder pain were recorded. Ultrasound examination of the shoulder joint was performed in all patients to detect any lesions. RESULTS: Abnormalities were detected by ultrasound in 41/47 (87.2%) study participants. Subacromial subdeltoid bursal thickening was found in 26/47 (55.3%) participants, distension of the biceps brachii tendon sheath was found in 14/47 (29.8%) and a supraspinatus tendon tear was found in 13/47 (27.7%). Patients with a supraspinatus tendon tear were found to have a significantly longer duration of lymphedema (1310 days vs. 398 days, p = 0.032). CONCLUSIONS: The duration of arm lymphedema has a progressive pathological effect on rotator cuff. Clinicians should adopt an early management approach of shoulder pain in patients with breast cancer-related lymphedema. PMID- 26571276 TI - EDITORIAL. PMID- 26571275 TI - CentiServer: A Comprehensive Resource, Web-Based Application and R Package for Centrality Analysis. AB - Various disciplines are trying to solve one of the most noteworthy queries and broadly used concepts in biology, essentiality. Centrality is a primary index and a promising method for identifying essential nodes, particularly in biological networks. The newly created CentiServer is a comprehensive online resource that provides over 110 definitions of different centrality indices, their computational methods, and algorithms in the form of an encyclopedia. In addition, CentiServer allows users to calculate 55 centralities with the help of an interactive web-based application tool and provides a numerical result as a comma separated value (csv) file format or a mapped graphical format as a graph modeling language (GML) file. The standalone version of this application has been developed in the form of an R package. The web-based application (CentiServer) and R package (centiserve) are freely available at http://www.centiserver.org/. PMID- 26571277 TI - Impact of breastfeeding or bottle-feeding on surgical wound dehiscence after cleft lip repair in infants: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this systematic review is to examine the impact of breastfeeding or bottle-feeding on surgical wound dehiscence after cleft lip repair in infants. BACKGROUND: Immediately after cleft lip repair in infants, breastfeeding and bottle-feeding are generally restricted. Alternative feeding methods such as spoon-feeding are recommended to avoid placing tension on the surgical wound. However, some studies have reported that alternative feeding methods are a source of stress to the infant and cause them to cry incessantly, resulting in postoperative weight loss. This suggests that these alternative feeding methods may have an unfavorable impact on surgical wound healing. However, a consensus on this topic has not been reached. The objective of this systematic review is to examine the impact of breastfeeding or bottle-feeding on surgical wound dehiscence after cleft lip repair in infants.Cleft lip and/or palate is a craniofacial anomaly and one of the most common birth defects. The incidence of cleft lip and/or palate differs among races, ethnic groups and geographical areas. The prevalence of cleft lip and/or palate is highest in South American countries (Bolivia: 22.94 per 10,000 live births; Paraguay: 14.90 per 10,000 live births), followed by Asian countries (China: 13.60 per 10,000 live births; Japan: 16.04 per 10,000 live births). The prevalence is lowest in African countries (3.54 per 10,000 live births). The overall worldwide prevalence is 7.9 per 10,000 births.A cleft lip and/or a cleft palate can occur separately, although they are more likely to occur together early in pregnancy. These anomalies can be surgically repaired. Without proper treatment, patients have aesthetic and functional problems, such as feeding disorders, otitis media and speech difficulties.Patients with cleft lip and/or palate usually undergo a combination of surgical procedures, speech therapy and orthodontic treatment from infancy to young adulthood. Comprehensive treatment is provided with thoughtful consideration of the balance between intervention and growth. Cleft lip repair is carried out first in comprehensive treatment regimens. The aim of cleft lip repair is to create contrast between the lip and external nose and provide good muscular continuity across the cleft without any scarring. It is usually performed from three to six months of age. Surgery is delayed until this age to allow for growth of the lip structure and assessment of the patient for the presence of comorbidities. The ability of newborn patients with cleft lip and/or palate to drink milk is important for proper growth and development.For cleft lip and/or palate patients in the newborn developmental stage, feeding can be an area of great concern and anxiety for their parents. One study found that 32% of newborn patients with cleft lip and/or palate had poor feeding skills. Feeding difficulties lead to poor growth and development in early infancy and increase the burden of care. Therefore, it is important for new parents to learn appropriate feeding techniques. Infants with cleft lip can generally drink milk from the breast through various ways of feeding. In contrast, infants with both cleft lip and palate have difficulty sucking the nipple because of weak intraoral negative pressure, and specially designed nipples are generally used. Although such infants suckle with weakened pressure, these nipples enable them to drink milk by lightly pushing them through their lip. However, after cleft lip repair, infants with cleft lip and/or palate are forced to change their feeding methods (even infants who have managed to drink milk before the repair).Breastfeeding and bottle-feeding are generally restricted immediately after cleft lip repair. Alternative feeding methods such as the use of a spoon, cup or syringe are recommended to avoid placing tension on the surgical incision. The use of a very soft nipple of sufficient size is recommended to provide a dripping milk flow, thus avoiding tension on the operative site. Some authors have recommended that patients with cleft lip and/or palate be spoon-fed for a certain period of time after cleft lip repair to avoid tension on the surgical site. However, management of the surgical site after surgical repair of cleft lip and/or palate varies among countries and healthcare centers. Little evidence-based research is available to guide healthcare staff members through the many treatment protocols for cleft lip and/or palate. No consensus about feeding methods after cleft lip repair has been reached.The above mentioned alternative feeding methods might influence the process of surgical wound healing. Minimizing crying has been considered to be the most important factor in avoiding tension on the surgical wound. In one study, however, 21.7% of infants who were given milk by a spoon on the first day after cleft lip repair resisted feeding by crying and/or moving the head laterally, while all infants fed by the nipple that had been used preoperatively accepted feeding without a major observable response. In another study, infants who were breastfed or bottle-fed after the repair were reportedly more relaxed than spoon-fed or syringe-fed infants. Changes in feeding methods seem to stress the infants and cause them to cry, which places tension on the wound.These alternative feeding methods may also have other impacts on surgical wound healing. One study reported that infants took longer to drink milk using alternative feeding methods than when using traditional feeding methods after the surgery. A systematic review suggested that alternative feeding methods were associated with less postoperative weight gain in patients than traditional feeding methods. Postoperative nutritional intake also influences wound healing. A long duration of feeding milk coupled with weight loss after the surgery suggests unnecessary energy consumption associated with the alternative feeding methods. Wound healing may consequently be inhibited or delayed.Wound healing complications after surgery include wound infection, dehiscence and proliferative scarring. Surgical wound dehiscence has been regarded as a typical complication after cleft lip and/or palate repair, followed by pyrexia. In one case series, post-surgical complications were found in 11 of 2100 infants who underwent surgical cleft lip and/or palate repair during a seven-year period. Wound dehiscence results from tissue failure rather than improper suturing technique. Therefore, alternative feeding methods are recommended to avoid placing tension on the surgical wound. However, no strong evidence has been presented to show that breastfeeding or bottle-feeding after cleft lip repair may cause surgical wound dehiscence among infants with cleft lip.Our initial search failed to find any systematic review examining the impact of breastfeeding or bottle-feeding on surgical wound dehiscence after cleft lip repair using the Cochrane Library, the JBI Database of Systematic Reviews and Implementation Reports, and other bibliographic databases, including MEDLINE and CINAHL. The proposed systematic review will contribute to the understanding of this topic and identify areas for further research. If breastfeeding or bottle-feeding is recommended immediately after cleft lip repair, the patients will experience less stress and crying, placing less tension on the wound than with alternative feeding methods. Breastfeeding or bottle-feeding will result in more weight gain, facilitating wound healing. PMID- 26571278 TI - The experiences of acute non-surgical pain of children who present to a healthcare facility for treatment: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The qualitative objective of this systematic review is to identify and synthesize the best available evidence on experiences of acute non-surgical pain, including pain management, of children (between four to 18 years) when they present to a healthcare facility for treatment.The specific objectives are to identify: BACKGROUND: The International Association for the Study of Pain defines pain as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage". The pain experience is multifaceted and complex, extending beyond the physiological interpretation of a noxious stimulus, encompassing other dimensions, including; psychological, cognitive, sociocultural, affective and emotional factors. Pain can be described as chronic (persisting for three months or more) or acute (a time limited response to a noxious stimuli). Over the past 50 years clinical research has made revolutionary contributions to better understanding pediatric pain. The once pervasive erroneous notion that infants do not experience pain the same way as adults has been firmly dispelled. We now know that nervous system structures associated with the physiological interpretation of pain are functional as early as fetal development. Despite this critical knowledge and the growing global commitment to improving pediatric pain management in clinical practice, evidence repeatedly suggests that pain management remains suboptimal and inconsistent, a phenomenon commonly referred to as oligoanalgesia. Research evidence has linked poorly managed pain in the pediatric population to negative behavioral and physiological consequences later in life. Effective pain management is therefore a priority area for health care professionals. Improved understanding of children's experiences of acute non surgical pain may lead to improved pain management and a reduction in oligoanalgesia.In the 1970s and 1980s, studies began exploring the subjective experiences of pediatric pain and discovered children's abilities to articulate their pain experiences, and to link causes and consequences of their pain. Developmental trends or age related patterns with regards to children's expressions and experiences of pain were identified. Recent studies have also recognized apparent trends in children's understanding and expressions of pain; these follow an age and cognitive development trajectory in line with Piaget's theories of development.For many children psychosocial aspects of pain, including emotions like fear, stress and anxiety, are often more unpleasant than the painful experience itself. Emotional responses such as distress and anxiety are commonly associated with the anticipation of pain, can exacerbate and intensify the pain experience, and can significantly lower a child's pain threshold. One study utilized an observational pain assessment tool to explore children's pain experiences. The findings indicated that children who underwent "non-painful" procedures (such as restraint) had equal, and in some cases higher, pain scores than those who underwent painful procedures (such as intravenous cannulation).Several studies exploring pediatric pain within health care settings (including, but not limited to, general practitioners, hospitals, emergency departments and outpatient clinics) have adopted quantitative methods, some examined parents' perspectives, and others explored nurses' perceptions. While results of such studies have added to the existing body of knowledge that supports the need to focus on improving pediatric pain management, it has been suggested that failing to ask children directly risks not capturing subjective experiences of pain from the children's perspectives in their entirety. Seeking the children's perspectives could provide a more reliable and adequate means of gaining insight into their needs and expectations when they are in pain.A single centered study in Singapore used semi-structured face-to-face interviews (n=15) to explore children's experiences of pain management postoperatively. While the children, aged between six and 12 years, identified the role of analgesia in managing their pain, they also placed significant emphasis on the role of parents and health care professionals in implementing non-pharmacological interventions in pain management. These results are relevant as they provide insights into how children experience and express pain, and their expectations of health care professionals in managing their pain. These findings draw attention to effective pain management approaches when caring for children. Similarly, a UK study adopted a cross sectional descriptive design using the draw and write technique aimed at investigating children's views on what helped when they were in pain. The children (n=71) were aged between four and 16 years. Findings revealed that children viewed themselves as active agents in pain management, while also placing significant emphasis on the importance of parents and nurses in managing their pain. In both studies, children valued nurses for social interactions, such as kindness and humor, rather than the provision of clinical care, including analgesia administration. Adjunct therapies such as distraction, visualization and music have also been shown to be effective in managing the pain experience in children.Not only do these findings demonstrate the complexity of the pain experience for the child, they also support the notion that improved pain management may come from research that is designed to better understand the entire pain experience from the child's perspective. While there are systematic reviews on interventions for managing children's pain, and one explored children's experiences in the postoperative context, none have considered children's experiences of acute non-surgical pain when they present for treatment. This qualitative systematic review aims to identify and synthesize results of studies exploring children's experiences of pain and pain management. PMID- 26571279 TI - The effectiveness of mindfulness based programs in reducing stress experienced by nurses in adult hospital settings: a systematic review of quantitative evidence protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this review is to identify the effectiveness of mindfulness based programs in reducing stress experienced by nurses in adult hospitalized patient care settings. BACKGROUND: Nursing professionals face extraordinary stressors in the medical environment. Many of these stressors have always been inherent to the profession: long work hours, dealing with pain, loss and emotional suffering, caring for dying patients and providing support to families. Recently nurses have been experiencing increased stress related to other factors such as staffing shortages, increasingly complex patients, corporate financial constraints and the increased need for knowledge of ever-changing technology. Stress affects high-level cognitive functions, specifically attention and memory, and this increases the already high stakes for nurses. Nurses are required to cope with very difficult situations that require accurate, timely decisions that affect human lives on a daily basis.Lapses in attention increase the risk of serious consequences such as medication errors, failure to recognize life-threatening signs and symptoms, and other essential patient safety issues. Research has also shown that the stress inherent to health care occupations can lead to depression, reduced job satisfaction, psychological distress and disruptions to personal relationships. These outcomes of stress are factors that create scenarios for risk of patient harm.There are three main effects of stress on nurses: burnout, depression and lateral violence. Burnout has been defined as a syndrome of depersonalization, emotional exhaustion, and a sense of low personal accomplishment, and the occurrence of burnout has been closely linked to perceived stress. Shimizu, Mizoue, Mishima and Nagata state that nurses experience considerable job stress which has been a major factor in the high rates of burnout that has been recorded among nurses. Zangaro and Soeken share this opinion and state that work related stress is largely contributing to the current nursing shortage. They report that work stress leads to a much higher turnover, especially during the first year after graduation, lowering retention rates in general.In a study conducted in Pennsylvania, researchers found that while 43% of the nurses who reported high levels of burnout indicated their intent to leave their current position, only 11% of nurses who were not burned out intended to leave in the following 12 months. In the same study patient-to nurse ratios were significantly associated with emotional exhaustion and burnout. An increase of one patient per nurse assignment to a hospital's staffing level increased burnout by 23%.Depression can be defined as a mood disorder that causes a persistent feeling of sadness and loss of interest. Wang found that high levels of work stress were associated with higher risk of mood and anxiety disorders. In Canada one out of every 10 nurses have shown depressive symptoms; compared to the average of 5.1% of the nurses' counterparts who do not work in healthcare. High incidences of depression and depressive symptoms were also reported in studies among Chinese nurses (38%) and Taiwanese nurses (27.7%). In the Taiwanese study the occurrence of depression was significantly and positively correlated to job stress experienced by the nurses (p<0.001).In a multivariate logistic regression, Ohler, Kerr and Forbes also found that job stress was significantly correlated to depression in nurses. The researchers reported that nurses who experienced a higher degree of job stress were 80% more likely to have suffered a major depressive episode in the previous year. A further finding in this study revealed that 75% of the participants also suffered from at least one chronic disease revealing a strong association between depression and other major health issues.A stressful working environment, such as a hospital, could potentially lead to lateral violence among nurses. Lateral violence is a serious occupational health concern among nurses as evidenced by extensive research and literature available on the topic. The impact of lateral violence has been well studied and documented over the past three decades. Griffin and Clark state that lateral violence is a form of bullying grounded in the theoretical framework of the oppression theory. The bullying behaviors occur among members of an oppressed group as a result of feeling powerless and having a perceived lack of control in their workplace. Griffin identified the ten most common forms of lateral violence among nurses as "non-verbal innuendo, verbal affront, undermining activities, withholding information, sabotage, infighting, scape-goating, backstabbing, failure to respect privacy, and broken confidences". Nurse-to-nurse lateral violence leads to negative workplace relationships and disrupts team performance, creating an environment where poor patient outcomes, burnout and high staff turnover rates are prevalent.Work-related stressors have been indicated as a potential cause of lateral violence. According to the Effort Reward Imbalance model (ERI) developed by Siegrist, work stress develops when an imbalance exists between the effort individuals put into their jobs and the rewards they receive in return. The ERI model has been widely used in occupational health settings based on its predictive power for adverse health and well-being outcomes. The model claims that both high efforts with low rewards could lead to negative emotions in the exposed employees. Vegchel, van Jonge, de Bosma & Schaufeli state that, according to the ERI model, occupational rewards mostly consist of money, esteem and job security or career opportunities. A survey conducted by Reineck & Furino indicated that registered nurses had a very high regard for the intrinsic rewards of their profession but that they identified workplace relationships and stress issues as some of the most important contributors to their frustration and exhaustion. Hauge, Skogstad & Einarsen state that work-related stress further increases the potential for lateral violence as it creates a negative environment for both the target and the perpetrator.Mindfulness based programs have proven to be a promising intervention in reducing stress experienced by nurses. Mindfulness was originally defined by Jon Kabat-Zinn in 1979 as "paying attention on purpose, in the present moment, and nonjudgmentally, to the unfolding of experience moment to moment". The Mindfulness Based Stress Reduction (MBSR) program is an educationally based program that focuses on training in the contemplative practice of mindfulness. It is an eight-week program where participants meet weekly for two-and-a-half hours and join a one-day long retreat for six hours. The program incorporates a combination of mindfulness meditation, body awareness and yoga to help increase mindfulness in participants. The practice is meant to facilitate relaxation in the body and calming of the mind by focusing on present moment awareness. The program has proven to be effective in reducing stress, improving quality of life and increasing self-compassion in healthcare professionals.Researchers have demonstrated that mindfulness interventions can effectively reduce stress, anxiety and depression in both clinical and non clinical populations. In a meta-analysis of seven studies conducted with healthy participants from the general public, the reviewers reported a significant reduction in stress when the treatment and control groups were compared. However, there have been limited studies to date that focused specifically on the effectiveness of mindfulness programs to reduce stress experienced by nurses.In addition to stress reduction, mindfulness based interventions can also enhance nurses' capacity for focused attention and concentration by increasing present moment awareness. Mindfulness techniques can be applied in everyday situations as well as stressful situations. According to Kabat-Zinn, work-related stress influences people differently based on their viewpoint and their interpretation of the situation. He states that individuals need to be able to see the whole picture, have perspective on the connectivity of all things and not operate on automatic pilot to effectively cope with stress. The goal of mindfulness meditation is to empower individuals to respond to situations consciously rather than automatically.Prior to the commencement of this systematic review, the Cochrane Library and JBI Database of Systematic Reviews and Implementation Reports were searched. No previous systematic reviews on the topic of reducing stress experienced by nurses through mindfulness programs were identified. Hence, the objective of this systematic review is to evaluate the best research evidence available pertaining to mindfulness-based programs and their effectiveness in reducing perceived stress among nurses. PMID- 26571280 TI - Changes in blood pressure among users of lay health worker or volunteer operated community-based blood pressure programs over time: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this review is to identify studies reporting on lay health worker- or volunteer-led community-based programs for blood pressure screening and cardiovascular awareness in order to determine if these programs contribute to changes in blood pressure among participants over time.The specific question for this review is: What are the changes in blood pressure among adult users of community-based blood pressure screening and awareness programs operated by lay health workers or volunteers as measured by the differences in systolic and diastolic blood pressure between the user's first visit to the program and their last visit to the program? BACKGROUND: Cardiovascular diseases, such as stroke and heart disease, are quickly becoming global diseases manifesting in countries and communities where they traditionally had not been widespread. The World Health Organization (WHO) has reported that "in the Asia/Pacific region, [cardiovascular disease] has become increasingly prevalent in recent decades, and now accounts for about one third of all deaths". One risk factor that can lead to cardiovascular disease is hypertension. Based on WHO data from 2008, hypertension is now a global problem affecting 27% of the population 25 years of age or older.The risk for cardiovascular disease also appears to be higher among people in urban areas. A recent United Nations population report indicates that in the next 40 years we could see an increase in the world's population by 2.3 billion people. The majority of these people will be residing in urban areas, particularly in developing nations. Between 2011 and 2050, "the population living in urban areas is projected to gain 2.6 billion, passing from 3.6 billion in 2011 to 6.3 billion in 2050". Population growth in urban areas is therefore not only projected to include the expected population growth but also expected to include a shift of rural population to urban centers and "most of the population growth expected in urban areas will be concentrated in the cities and towns of the less developed regions". This growth of urban areas has the potential to put enormous pressures on health care systems that are already struggling to cope with the rapid increase in diseases thought to be more prevalent in Western societies, such as cardiovascular diseases.Hypertension may be difficult to treat due to a number of factors. Globally, access to antihypertensive medications, hypertension screening, and access to medical care vary from one country to another. Lifestyle factors, such as salt and alcohol consumption, stress, smoking, body weight, and exercise, are risk factors for hypertension that may be influenced by culture, which can in turn support or hinder lifestyle decisions that could significantly affect blood pressure. Hypertension, however, is easy to detect. A trained person with access to a low cost sphygmomanometer can detect abnormal blood pressures quickly; however, access to trained personnel is not universally guaranteed. Globally - according to one model of skilled health care worker density and total requirement offered for discussion by the Global Health Workforce Alliance and WHO - there could currently be an estimated shortage of over seven million skilled health care workers (midwifes, nurses and physicians), as measured against a theoretical density of skilled health care workers to population. The shortage of skilled health care workers in this model could grow to over 12 million by 2035 if the assumptions of the model and population growth estimates are valid. Through rapid urbanization the potential for inequities in access to healthcare is also increased.Over the last few years, a number of community-based blood pressure screening and education initiatives have been established. These initiatives have been created either as part of research, as part of community outreach programs by publicly funded agencies, or as part of an outreach by not-for-profit organizations with a particular interest in reducing cardiovascular disease in specific hard-to-reach populations. Several systematic reviews have been conducted to assess different models for delivering services to people living with high blood pressure to assess community-based programs with a focus on cardiovascular disease, and to assess effectiveness of community health workers (CHW) in a variety of settings. These systematic reviews point to the importance of distinguishing between different categories of health care providers, their training and their roles in program delivery when assessing studies for possible inclusion in a systematic review.In a systematic review of studies from the US by Brownstein et al. focusing on the effectiveness of community health workers (CHWs) in the care of people with hypertension, this category of health care providers went under many different names. Community health workers in this review were defined as "any health workers who carried out functions related to health care deliver, were trained as part of an intervention, had no formal paraprofessional or professional designation, and had a relationship with the community being served". One of the findings from this review was the wide variety of formal training of the CHWs. In other parts of the world, a CHW might be defined differently. In their review of CHW-based programs focusing on children's health, Bhattacharyya, Winch, LeBan and Tien found that "in general CHWs are not paid salaries because the MOH (Ministry of Health) or donors do not consider salaries to be sustainable. Yet CHWs are often held accountable and supervised as if they were employees. Community health worker programs must recognize that CHWs are volunteers (emphasis in original), even if they receive small monetary or nonmonetary incentives. They are volunteering their time to serve the community". One Canadian model for delivering a cardiovascular awareness program designed to reach older adults through their primary care provider is based on volunteers with basic training to perform blood pressure measurements and cardiovascular health information.In a global review of a wide range of public health and health promotion initiatives operated by lay health workers from 2005, Lewin et al. identified over 40 different names or terms for a lay health worker. However, the definition of a lay health worker used by Lewin et al. is very similar to the definition of CHWs offered by Brownstein et al. Lewin et al.'s systematic review was the only study with a global focus that was located that reviewed studies of programs with a cardiovascular component using lay health workers. In this study, the sample size of studies focusing on lay health workers and cardiovascular disease was small (N=3) and the results from two of the studies were inconclusive to the point where the authors felt they could not pool the results.While a lay health worker may or may not receive some compensation for their work, volunteers in higher income areas of the world such as in North America typically do not receive any compensation. Volunteers, as observed by Bhattacharyya et al., are common in many parts of the world, and in some areas they provide delivery of programs and services that reach hundreds of thousands of individuals. One challenge for this systematic review will therefore be to isolate those programs that are delivered by lay health workers or volunteers who receive little or no compensation and programs where staff is paid. The importance of this distinction is on one hand related to cost - as observed by Bhattacharyya et al., many organizations responsible for delivery of community-based programs do not have funding for salaried staff. On the other hand there might be other factors in the relationship between a community being served by a program and the staff delivering the program. One such factor could be linked to the role of the person delivering the program as either a paid health care professional or an unpaid lay health worker or volunteer.Through this proposed JBI systematic review, the reviewers will focus on community-based blood pressure screening and health information programs delivered by either lay health workers or volunteers. Previous systematic reviews have indicated that programs focusing on blood pressure reduction delivered in a variety of settings and delivered by a variety of health care professionals might lower blood pressure among program participants over time. This systematic review will be limited to community-based programs rather than hospital or research facility-based programs, and to programs delivered by lay health workers or volunteers rather than programs delivered by paid community health workers, nurses or teams of health care providers under direction of a primary care provider. Compared to other recent systematic reviews which focused on studies with comparison groups and included few studies where lay health workers were involved, this systematic review will attempt to fill this gap in knowledge about programs delivered by lay health workers or volunteers by focusing on non-randomized controlled studies which report blood pressure changes over time in programs targeting the general population. Community-based programs might have a variety of designs with a number of different interventions, and where possible these designs and interventions will be identified and subgroup analysis conducted as appropriate. It is hoped that this systematic review can extend the work by Lewin et al. by identifying additional studies globally, focusing on programs delivered by lay health workers or volunteers but limited to studies reporting changes in blood pressure over time. Where possible, a meta-analysis of the changes in blood pressure over time among participants in these programs will be conducted. (ABSTRACT TRUNCATED) PMID- 26571281 TI - The experiences of persons living with HIV who participate in mind-body and energy therapies: a systematic review protocol of qualitative evidence. AB - REVIEW QUESTION/OBJECTIVE: The purpose of this systematic review is to explore the experiences and perceptions of persons living with HIV who participate in mind-body and energy therapies. The review will focus on the use of mind-body medicine and energy therapies that include meditation, prayer, mental healing, Tai Chi, yoga, art therapy, music therapy, dance therapy, Qigong, reiki, therapeutic touch, healing touch and electromagnetic therapy. These mind-body and energy therapies are selected categories because they do not involve options that might be contraindicated to an individual's current treatment regime. More specifically, the review questions are: BACKGROUND: Complementary and alternative medicine (CAM) is a popular adjunct to conventional medicine across global populations. Complementary generally refers to a non-mainstream approach together with conventional medicine whereas alternative refers to a non-mainstream approach in place of conventional medicine. Most people use non-mainstream approaches along with conventional treatments. The World Health Organization [WHO] defines CAM as distinct health-care practices that have not been assimilated into a country's mainstream health care system.The USA's National Center for Complementary and Integrative Health (NCCIH), formerly National Center for Complementary and Alternative Medicine (NCCAM), organizes CAM into five medical system categories: whole medical systems, mind-body medicine, biologically based practices, manipulative and body-based practices, and energy therapies. Whole medical systems include homeopathy, naturopathy, traditional Chinese medicine and Ayurveda. Mind-body medicine includes meditation, prayer, mental healing, Tai Chi, yoga, art therapy, music therapy and dance therapy. Biologically based practices include dietary supplements, herbal supplements and a few scientifically unproven therapies. Manipulative and body-based practices include massage and spinal manipulation such as chiropractic and osteopathic. Energy therapies include Qigong, reiki, therapeutic touch, healing touch and electromagnetic therapy.The NCCAM, the Alternative Medicine's Strategic Plan for 2011-2015 and the Healthy People 2020 envision a society in which all people have the opportunity to live long, healthy lives. In most countries, life expectancy has increased, but unfortunately, the incidence of chronic illnesses such as cardiovascular disease, cancer, hypertension, diabetes and depression continues to increase. Research findings indicate that the use of CAM is often greater among people living with a chronic or life threatening illness compared with the general population,Until the development of highly active antiretroviral medications (ARVs) in 1996, a diagnosis of human immunodeficiency virus (HIV) was considered to be a death sentence. The human immunodeficiency virus attacks the immune system and weakens a person's ability to combat infections and some types of cancer. Currently, there is no cure for HIV but because of lifesaving medications, the mortality rate has declined significantly. The disease is now considered a chronic illness and highly manageable. Effective treatment has resulted in approximately 35 million people worldwide still living with HIV at the end of 2012.Because HIV is no longer a death sentence but a chronic illness, there is a need to evaluate the experiences and perceptions of people using CAM, considering the prevalence of CAM use within this population. In the United States and Canada, the rate of CAM use among HIV positive persons is approximately 50% to 70%, whereas in Africa, rates of CAM use range from 36% to 68%. Popular forms of CAM among persons living with HIV include herbal or nutritional supplements, mind and body practices, and spiritual or religious healing. Worldwide, only a small percentage of persons who have access to ARVs refuse to take them and utilize CAM exclusively to treat their HIV infection.People living with HIV often report using CAM because they believe that these therapies will improve their overall health and well-being and provides them an opportunity to take some responsibility in managing their personal health, which includes medication side effects. However, the effect of CAM on an individual's physical health often cannot be measured physiologically, but may be felt or experienced.Understanding CAM use is essential so that health professionals will have the most accurate information about which integrative therapies may or may not be helpful for people living with HIV. As recommended by the Institute of Medicine report entitled, 'Integrative Medicine and Patient Centered Care', health professionals have a moral commitment to find innovative ways of obtaining evidence and expanding knowledge about diverse interpretations of health and healing. Research aimed at exploring patients' experiences and perceptions of mind-body and energy therapies is imperative so asto offer comprehensive care and promote shared decision making regarding complementary therapeutic options. PMID- 26571282 TI - Adherence to a standardized protocol for measuring grip strength and appropriate cut-off values in adults over 65 years with sarcopenia: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this review is to examine the use of grip strength analysis in well and unwell populations in adults 65 years and over as a tool to establish muscle strength in sarcopenia.More specifically, the main review question is:1. What protocol, if any, is most commonly used among older adults with sarcopenia and does this match the standardized protocol suggested in 2011 by Roberts et al.1?Secondary review questions are:2. What are the reported cut-off values being used to determine sarcopenia in older adults, with consideration for ethnic and gender variability?3. Is grip strength, as a tool to measure muscle strength, suitable for people with common comorbidities and geriatric syndromes, such as osteoarthritis, often associated with sarcopenia? BACKGROUND: Sarcopenia, a commonly used concept in geriatrics and gerontology, is characterized by a loss of muscle mass, muscle strength and/or physical functioning. Prevalence rates vary between 1-39% in community dwelling older populations and 14-33% in long-term care populations. Several epidemiological studies have shown the association of sarcopenia with adverse health outcomes such as falls, disability, hospitalization and mortality. Originally, sarcopenia refers to the loss of muscle mass with aging, which was later complemented with loss of muscle strength and physical functioning.In 2010, the European Working Group on Sarcopenia in Older People (EWGSOP) reported a consensus definition of sarcopenia, which included measurement of low muscle mass and low muscle function (strength or physical performance). This consensus definition can be used to identify sarcopenia patients in clinical practice and to select individuals for clinical trials. Well-designed clinical trials could ultimately lead to effective treatment and prevention strategies for sarcopenia. Since the publication of the consensus report, many studies have adopted this definition, which could potentially lead to better comparison of results between studies. On the other hand, within this definition there still is wide variability in measurement tools and use of cut-off values, which could actually hamper comparability between studies.To assess muscle strength, the EWGSOP has recommended grip strength measurement which is easy and inexpensive. A recent systematic review on the measurement properties of tools to assess sarcopenia concluded that grip strength measurement is a valid and reliable method. In a comprehensive review of the measurement of grip strength in clinical and epidemiological studies by Roberts et al., it was shown that there is wide variability in the choice of equipment and protocols for measuring grip strength. To enable comparison between studies, a standardized approach, incorporating more consistent measurement of grip strength is warranted. Based on the results of the review, a standardized approach was described including the utilization of the widely used Jamar hydraulic hand dynamometer, as was a clear assessment protocol. So far, it is unknown whether this approach has been adopted in studies investigating grip strength for sarcopenia. The primary aim of this current review is to identify whether studies are adhering to the suggested protocol, or whether a more common method is prevalent. The EWGSOP has suggested multiple cut-off values to define sarcopenia regarding muscle strength: an absolute cut-off score of 20 kilograms (kg) for women and 30 kg for men, and Body Mass Index (BMI) specific cut-off values for men and women. Alternatively, the Foundation for the National Institutes of Health (FNIH) Sarcopenia Study suggested cut-off points of 26kg for males and 16kg for females, based on the likelihood of mobility impairment. Similar values have also been suggested by Dodds et al., who generated grip strength reference values and calculated cut-off points 2.5 standard deviations below the mean from 12 United Kingdom (U.K)based epidemiology studies.Recently, Beaudart et al. showed that large differences in sarcopenia prevalence occur when both cut-off values are compared, especially in women. Additionally, prevalence has also shown to be dependent upon the tool used to assess muscle strength. Evidently, cut-off values are highly varied and may be selected for statistical, theoretical or practical reasons, and/or are based on the type and magnitude of association with clinical endpoints such as hospitalization, falls or mobility. Difficulties arise in promoting a clear-cut definition of sarcopenia with no consistent recommendation for cut-off values of grip strength available. It is therefore important to identify which grip strength cut-off values should be used for the identification of sarcopenia patients and how comorbidities such as osteoarthritis may affect such values. This review will aim to report on the cut off values used, the justification for and the considerations of comorbidities within the identified articles. Furthermore, a study has suggested that cut-off values may be different within Asian populations. Therefore, ethnicity will also be taken into account for variations in appropriate cut-off values.The overarching objective of this review is to provide insight into the current use of grip strength within the literature among older adults aged 65 and over and, subsequently, to provide commentary on the consistency of protocol and cut-off values reported for grip strength measures. This insight into current research practice will lead to well-considered recommendations concerning the measurement of grip strength in research and clinical practice. A preliminary search for sarcopenia revealed five systematic reviews in the Cochrane Library and two within the JBI Database of Systematic Reviews and Implementation Reports, but none that examine the protocol of grip strength measures. A single study was identified through a search of Medline [Via EBSCOhost] which examines the psychometric properties of common measures of muscle mass, strength and physical performance in sarcopenia, but it was not specific to grip strength measures, nor did it examine the used protocol within studies. A lack of research into this area warrants further research and the need for the conduct of this proposed review. PMID- 26571283 TI - Intermittent fasting interventions for the treatment of overweight and obesity in adults aged 18 years and over: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: Are intermittent fasting interventions an effective treatment for overweight and obesity in adults, when compared to usual care treatment (continuous daily energy restriction - reduced calorie diet) or no treatment (ad libitum diet)? BACKGROUND: Overweight and obesity (classified as Body Mass Index [BMI] of greater than or equal to 25 and 30 respectively) is a global public health concern, with more than 1.9 billion adults worldwide being overweight in 2014 (over 600 million of whom are obese), and resulting in more deaths than underweight. A raised BMI in adulthood is associated with an increased risk of developing a number of chronic diseases which include diabetes, cardiovascular disease, muscular skeletal disorders and some cancers. In addition to this substantial impact on individual health and well being, there are also significant wider costs, for example, in England the annual direct cost to the national health service for treating overweight, obesity and associated morbidity is estimated at over L5 billion pounds, with costs to the wider economy estimated at L27 billion. Therefore effective weight management is essential.As overweight and obesity results from an accumulation of excess body fat arising from an energy imbalance - consuming more energy (kcal) than is expended - the majority of weight management approaches center around behaviors to address this imbalance, i.e. reducing energy intake through caloric restriction and increasing energy expenditure through physical activity. However, the aetiology of overweight and obesity is highly complex, involving an interplay of biological, psychological, societal and environmental drivers. Consequently, effective weight management is challenging, and whilst there exists a plethora of available weight loss programs, not all are comprehensively evaluated and compared, and many weight loss attempts result in weight regain and poor long term results. It is therefore vitally important to review the effectiveness of all new approaches to support an evidence-based approach to weight management.Intermittent fasting (IF), also known as alternate day fasting (ADF), periodic fasting or intermittent energy restriction (IER) is a relatively new dietary approach to weight management that involves interspersing normal daily caloric intake with a short period of severe calorie restriction/fasting. In terms of the possible underlying biological benefits of intermittent fasting, there is some evidence, predominantly from animal studies, to demonstrate beneficial effects on weight loss and cardio-metabolic risk factors. Whilst the underpinning mechanistic evidence is limited, there is some evidence to suggest that the benefits may be explained mechanistically through fat utilization and nutritional stress. However current National Institute for Health and Care Excellence (NICE) guidance on the treatment of adult obesity does not recommend the routine use of very low calorie diets (VLCD) (defined as a hypocaloric diet of 800 or less kcal/day) for the treatment of adult obesity. The National Institute for Health and Care Excellence states that this approach should only be recommended if there is a clinical rationale for rapid weight loss and must be nutritionally complete, part of a multi-component weight management strategy, including ongoing support, and should be undertaken for a maximum of 12 weeks (followed continuously or intermittently). Furthermore, the British Dietetic Association raises concerns that rapid weight loss associated with fasting may largely be due to loss of water and glycogen rather than fat, and may result in fatigue, dizziness and low energy levels. Essentially IF involves the intermittent use of a VLCD, and there remain questions about the side effects of this approach, whether there is an optimal fasting pattern or calorie limit, and how sustainable it is for long term weight management.Intermittent fasting has recently gained much popularity following significant media attention. In the UK this dietary approach reached mainstream after a BBC Horizon documentary aired in August 2012, featured an IF approach called the 5:2 diet, which involves five days of regular eating patterns interchanged with two days of fasting (max 500kcal for women and 600kcal for men). However other IF patterns are used such as alternate day fasting. Despite the recent popularity of intermittent fasting and associated weight loss claims, the supporting evidence base in humans remains small and there is only one published systematic review examining the health benefits of this approach. However the aim of this review was to examine the impact of this intervention on wider health benefits (not specifically as a treatment approach for overweight and obesity), and did not provide a comprehensive methodology or meta-analysis of RCT data. This proposed review will hence address these gaps in the evidence base. PMID- 26571284 TI - The effectiveness of school-based family asthma educational programs on the quality of life and number of asthma exacerbations of children aged five to 18 years diagnosed with asthma: a systematic review protocol. AB - REVIEW OBJECTIVE: The objective of this review is to identify the best available quantitative evidence related to the effectiveness of school-based family asthma educational programs on the quality of life and number of asthma exacerbations of children aged five to18 years with a diagnosis of asthma. BACKGROUND: Asthma is a serious public health issue globally and nationally. The World Health Organization (WHO) Global Asthma Report 2014 estimates that 334 million people worldwide currently suffer from asthma. In the United States, asthma currently affects about 25 million people. Although asthma can occur at any age, it most often begins early in life, and is the most common non-communicable disease among children. Approximately 14% of the world's children have asthma. In the United States, 7.1 million children have asthma. Globally, the burden of asthma, measured by disability and premature death, is greatest in children approaching adolescence (ages 10-14). Asthma is also a serious economic concern in primary health care worldwide. In the United States, the estimated total cost of asthma to society was US$56 billion in 2007, or US$3259 per person. In 2008 asthma caused 10.5 million missed days from school and 14.2 missed days from work for caregivers. The estimated total cost of loss of productivity resulting from missed school or work days is US$3.8 billion per year, and premature death US$2.1 billion per year. Globally, asthma ranks 14 in terms of disability adjusted life years (DALYs), which are the number of years lost to ill health, disability or death attributed to asthma. According to a 2011 European study, the estimated total cost of asthma was ?19.3 billion among people aged 15 to 64 years. A study conducted in the Asia-Pacific region reported that the direct and indirect costs of asthma per person ranged from US$184 in Vietnam to US$1189in Hong Kong in 2000. A Canadian study showed that C$184 loss of productivity during one week was attributed to asthma in 2012. In Australia, AU$655 million was spent on asthma for 2008-09.Asthma is a chronic respiratory disease that affects millions of people of all ethnicities, ages and genders worldwide. The pathophysiology of asthma is multifaceted, and is characterized by restriction of airflow into and out of the lungs, airway inflammation with increased mucus production, and bronchial hyper-reactivity caused by exposure to environmental irritants and chemicals, often referred to as triggers, which in some cases are modifiable. Asthma triggers include respiratory infections, weather changes, stress, excitement, exercise and other physical activities, allergic hypersensitivity reactions, food additives, animal dander, dust mites, cockroaches, outdoor and indoor pollutants, certain medications and cigarette smoke. Asthma is characterized by recurrent, episodic, reversible symptoms often referred to as asthma exacerbations, or asthma attacks. Asthma symptoms include coughing, shortness of breath, chest tightness and wheezing that most frequently occur at night or in the early morning. Asthma symptoms vary in severity and frequency in affected individuals, and can occur several times a day or week. Asthma symptoms may be mild, moderate, or severe, and are classified according to presenting symptoms and quantitative measurements of lung function using a peak expiratory flow meter (PEF), or of forced expiratory volume in one second (FEV1). Asthma symptoms can be so severe that, if left untreated, death can occur.Exacerbations of asthma symptoms often result in school and work absenteeism, activity intolerance and emergency hospital visits for asthma. Nocturnal asthma exacerbations frequently cause sleeplessness, which may result in daytime fatigue. Asthma symptoms can interfere and disrupt activities of daily life, and can have an unfavorable impact on the quality of life for people with the disease, including children and their caregivers. For this review, quality of life represents how well the asthmatic child is able to manage symptoms of the disease and lead a normal healthy life. Caregiver refers to the primary person who takes care of a child with asthma. Family refers to the caregiver and the child.According to the United States Centers for Disease Control and Prevention (CDC), epidemiologists and clinical researchers concur that the burden of asthma is higher among children compared to adults. Asthma prevalence in children varies within and across countries. Asthma disparities also exist along ethnic and racial lines. The International Study of Asthma and Allergies in Childhood (ISAAC) quantified the prevalence of asthma symptoms of children from around the world. In the United States, non-Hispanic Black and Puerto Rican children have higher asthma prevalence compared to Caucasian children. Children from the Ivory Coast, Costa Rica and Wales have higher asthma prevalence compared to children from Kenya, Brazil and England respectively. Indigenous Australians, Aboriginal and Torres Strait Islander Australian children have a higher prevalence of asthma compared to non-Indigenous Australian children. The international prevalence of asthma prompted governments and communities to create initiatives and strategies to address this public health issue.The global burden of asthma led to the development of the Global Initiative for Asthma (GINA). Formed in 1993, in collaboration with theNational Heart, Lung, and Blood Institute, National Institutes of Health, United States of America and the WHO, GINA's goals include working with healthcare providers and public health officials worldwide to reduce asthma prevalence, morbidity and mortality. In an effort to increase public awareness of the global burden of asthma, GINA created World Asthma Day, which is held annually on the first Tuesday in May. The burden of asthma in the United States fostered the creation of the National Asthma Education and Prevention Program (NAEPP). This program is designed to raise awareness about asthma and the major public health concern it poses to society. In addition to conducting asthma prevention activities, NAEPP collaborates with other stakeholders to develop asthma educational programs for minority populations who are disproportionately affected by asthma. The program believes that adequate control of asthma, through modern treatment and educational programs, can be reinforced by the development of partnerships with caregivers, schools and healthcare providers. The NAEPP Expert Panel Report 3, Guidelines for the Diagnosis and Management of Asthma (EPR 3), has a provision that specifies that asthma education programs for children should include their caregivers. Caregivers' involvement is crucial for achieving the goals of asthma management in children, which supports the interest of GINA and NAEPP to include caregivers in school-based asthma education programs for children. The guidelines recommend education for asthma management should occur at all points of care, including schools. According to the EPR-3, schools are ideal locations to facilitate asthma education programs because they provide access to large numbers of children in an environment in which they are accustomed to learning. The long term effects of these approaches are improved healthcare practices, reduced mortality and morbidity, and reduced costs of asthma care.Although there is no cure for asthma, research evidence has demonstrated that asthma symptoms can be well-controlled with the appropriate medications, adherence to treatment, avoidance of asthma triggers, and education about disease management. Research studies that have investigated the effectiveness of school-based asthma education programs that have included caregivers have demonstrated beneficial effects of these programs on the quality of life and disease management of children with asthma, versus no school-based family asthma education programs.A randomized controlled trial (RCT) conducted by Clark et al. that included 835 children and their parents examined the effects of comprehensive school-based asthma education programs on symptoms, grades and school absences, and parents' asthma management practices. The interventions consisted of six components for children, their parents, classmates and school personnel. One of the six components included "Open Airways for Schools" disease management training for children, which also included handouts and homework for the parents. One of the five interventions for the parents included school fairs with asthma care questions and answers sessions to discuss the frequency and type of asthma symptoms of their children. Results of this study demonstrated that 24 months post intervention, children from the intervention groups had better disease management, which included improved control of daytime and nighttime symptoms, and reduced absences from school and work related to asthma exacerbations, compared to the children from the control group.In another study, Bruzzese et al. conducted a pilot RCT that included 24 families. Each family consisted of an asthmatic child and a caregiver. The study examined the effects of a two-month, school-based asthma education program. The interventions consisted of six interactive 75-minute group sessions for students, held once a week for six weeks, and five 90-minute group sessions for caregivers, held once a week. The student sessions were led by a developmental psychologist, and one of the lesson topics included prevention and management of asthma. The group sessions for caregivers were led by a clinical psychologist, and one of the lesson topics included asthma self-management of their children. The interventions resulted in positive short term changes in family relations and an overall improved health status for the children. (ABSTRACT TRUNCATED) PMID- 26571285 TI - The effectiveness of health literacy interventions on the informed consent process of health care users: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The aim of this systematic review is to establish the best available evidence of the effectiveness of health literacy interventions on the informed consent process for health care users. The specific review question is:What is the effectiveness of health literacy interventions on health care users' informed consent to health procedures processes? BACKGROUND: Informed consent is a fundamental principal in the health care context which nowadays includes the patient's capacity to judge and to be involved in the decision making concerning their care that ensures that the care received reflects their goals, preferences and values. The importance of obtaining a valid consent before any medical procedure is well-established. In a US court case in 1914, it was stated that it is the right of any adult with the capability of making decisions concerning his own body, and that any surgical operation without the patient's consent could be considered as an assault. In another US court case, the court stated that it is a doctor's duty to make a reasonable disclosure to his patient of the nature, probable consequences and dangers of the proposed treatment to the patient. The application of the doctrine of informed consent as a legal procedure may slightly differ from country to country or from state to state, and may have different forms even within the same country. For example in the UK, consent can be written, verbal or non-verbal/implied, and a written consent form is not the actual consent itself but merely serves as evidence that consent has been given. If the elements of voluntariness, appropriate information and capacity have not been satisfied, a signed informed consent form will not make the consent valid. Nowadays it is widely accepted that prior to the application of any medical procedure, its benefits, risks and alternatives must have been explained to the patient, and the competent patient should have voluntarily and understandingly consented. Hence, the informed consent refers both to the health professional's obligation of information disclosure to the patient and to the quality of the patient's understanding and decision making. In other words, it does not refer to the single moment of the agreement, but to the whole complex process of gaining information, deciding and consenting. Several factors may restrict informed consent, including the patient's competence, provision of limited information, ineffective communication between patients and professionals, the hospital environment itself and privacy problems.According to the World Health Organization (WHO), people are increasingly urged to make choices for themselves or for their family members in regards to health care use. However, at the same time, inadequate or problematic health literacy skills have been reported in approximately half of the adult population in eight European countries. "Health literacy is linked to literacy and entails people's knowledge, motivation and competences to access, understand, appraise and apply health information in order to make judgments and take decisions in everyday life concerning health care, disease prevention and health promotion to maintain or improve quality of life during the life course". There are many instruments measuring either health literacy in general or some dimensions of health literacy (e.g. numeracy), health literacy related to specific issues (e.g. nutrition, diabetes) or health literacy of specific populations (e.g. adolescents). The diversity of existing instruments, which includes diversity in terms of scoring and ranges, makes the comparison of the results of different studies difficult. Index thresholds and ranges for different levels of health literacy for most tools were set based either on that of other well established health literacy instruments used in the same study, or on experts' assessments of the required health literacy scores. Adequate health literacy could be considered as the capacity of successfully completing most tasks required to function in the health care setting.Low or inadequate health literacy has been found to have several adverse effects on health and health care use: reduced ability to take medications properly and to interpret labels and health messages, poorer overall health status and higher risk of mortality in seniors, increased emergency department and hospital use, and decreased use of preventive interventions.Most studies examining the relationship between health literacy and informed consent conclude that patients with low health literacy are less likely to participate in decision making concerning their health care. According to a recent literature review, health care users' literacy, together with other factors, were found to be important determinants of a patient's capacity to provide fully informed consent. According to this review, 21 to 86% of the patients were able to recall the potential risks and complications of their medical procedure. This percentage may be even lower because most of the included studies referred to self-reported recall, which may be a flawed measure. According to the literature, much of the written material related to the informed consent is too difficult for health care users to understand. In addition, in their study, McCarthy et al. observed that during consultations, physicians spoke and used significantly more complex language than their patients, which may result in inappropriate communication for the patients, mainly for those with limited literacy. The situations described above may raise a number of critical legal and ethical problems. Health professionals, who shape the conditions of interactions with the patient, are responsible for adapting appropriate interventions, such as communication approaches that take into account patients' health literacy. These interventions could have a major contribution to the improvement of the informed consent process.Sheridan et al. conducted a systematic review on interventions designed to reduce the effects of limited health literacy in general. Some of the outcomes of the included studies were comprehension and behavioral intent, outcomes which could be strongly related to the informed consent process. Without making any distinction of the studies referring to the informed consent process, they conclude that several health literacy interventions, for example, adding video to narrative, could improve an individual's comprehension. Schenker et al. conducted a systematic review on the interventions to improve patient comprehension of medical and surgical procedures, including articles published until 2008. One of their conclusions was that, in most studies, while particular attention is needed for interventions provided to patients with limited literacy, the literacy of the patients was not addressed or assessed.Since then, many articles on health literacy and informed consent have been published. According to a recent review on best practices and new models of health literacy for informed consent, which includes papers published from 2004 to 2014, over half of the collected articles were published since 2010. This review, which is limited to literature within the US and its territories, and does not focus on the evaluation of the recommended practices in the literature, concludes that different tactics for simplifying written documents and clarifying verbal exchanges, and the use of multimedia formats and computerized exchanges might ameliorate constraints to health literate communications required for informed consent.Studies have evaluated the effectiveness of health literacy interventions which aim to improve the informed consent process. Improvement of the informed consent process may refer not only to the patients' comprehension but also, for example, to the recall of the information provided, to their intention to ask for clarifications, or to their satisfaction with the procedure. Interventions described and tested in the literature focus on the improvement of the print material, the process (e.g. the communication of the appropriate information) or both. Davis et al. conducted a randomized controlled trial to compare two polio vaccine pamphlets written at a sixth grade level - an international standardized pamphlet and an easy-to-read pamphlet - for the comprehension and preference among parents. Although the parents in the intervention group (N=304) achieved significantly higher comprehension than the control group (N=306) (65% vs 60%, p<0.005), the authors concluded that simplifying written material increases appeal but not the comprehension to an adequate level without use of instructional graphics. Similarly, Lorenzen et al. found that a reader friendly informed consent document to surgical procedures was more commonly read by the health care users as compared to the original consent document; however, no difference was found in terms of the participants' capacity to describe the procedure in their own words. Kang et al. evaluated recall and comprehension of orthodontic informed consent among pairs of children and their parents (N=90) applying three different informed consent procedures. According to this study, a combination of improving the readability of consent materials and the informed consent process (audio and visual cues) led to better recall for the patients and better recall and comprehension for their parents compared to an improved readability form or the usual informed consent form. Smith et al. used a randomized controlled trial to compare a decision aid (booklet and DVD) specifically designed for adults with low literacy skills (N=357) with a standard information booklet (N=173) on screening for bowel cancer. They found that the proportion of participants making an informed choice was 22% higher in the intervention group than in the control group (34% vs 12%, P<0.001). Matsuyama et al. (ABSTRACT TRUNCATED) PMID- 26571286 TI - Feeding the critically ill obese patient: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this review is to identify effective enteral nutritional regimens targeting protein and calorie delivery for the critically ill obese patient on morbidity and mortality.More specifically, the review question is:In the critically ill obese patient, what is the optimal enteral protein and calorie target that improves mortality and morbidity? BACKGROUND: The World Health Organization (WHO) defines obesity as abnormal or excessive fat accumulation that may impair health, or, empirically, as a body mass index (BMI) >= 30 kg/m. Twenty-eight percent of the Australian population is obese with the prevalence rising to 44% in rural areas, and there is evidence that rates of obesity are increasing. The prevalence of obese patients in intensive care largely mirrors that of the general population. There is concern, however, that this may also be rising. A recently published multi-center nutritional study of critically ill patients reported a mean BMI of 29 in their sample, suggesting that just under 50% of their intensive care population is obese. It is inevitable, therefore, that the intensivist will care for the critically ill obese patient.Managing the critically ill obese patient is challenging, not least due to the co-morbid diseases frequently associated with obesity, including diabetes mellitus, cardiovascular disease, dyslipidaemia, sleep disordered breathing and respiratory insufficiency, hepatic steatohepatitis, chronic kidney disease and hypertension. There is also evidence that metabolic processes differ in the obese patient, particularly those with underlying insulin resistance, itself a marker of the metabolic syndrome, which may predispose to futile cycling, altered fuel utilization and protein catabolism. These issues are compounded by altered drug pharmacokinetics, and the additional logistical issues associated with prophylactic, therapeutic and diagnostic interventions.It is entirely plausible that the altered metabolic processes observed in the obese intensify and compound the metabolic changes that occur during critical illness. The early phases of critical illness are characterized by an increase in energy expenditure, resulting in a catabolic state driven by the stress response. Activation of the stress response involves up-regulation of the sympathetic nervous system and the release of pituitary hormones resulting in altered cortisol metabolism and elevated levels of endogenous catecholamines. These produce a range of metabolic disturbances including stress hyperglycemia, arising from both peripheral resistance to the effects of anabolic factors (predominantly insulin) and increased hepatic gluconeogenesis. Proteolysis is accelerated, releasing amino acids that are thought to be important in supporting tissue repair, immune defense and the synthesis of acute phase reactants. There is also altered mobilization of fuel stores, futile cycling, and evidence of altered lipoprotein metabolism. In the short term this is likely to be an adaptive response, but with time and ongoing inflammation this becomes maladaptive with a concomitant risk of protein-calorie malnutrition, immunosuppression and wasting of functional muscle tissue resulting from protein catabolism, and this is further compounded by disuse atrophy. Muscle atrophy and intensive care unit (ICU) acquired weakness is complex and poorly understood, but it is postulated that the provision of calories and sufficient protein to avoid a negative nitrogen balance mitigates this process. Avoiding lean muscle mass loss in the obese intuitively has substantial implications, given the larger mass that is required to be mobilized during their rehabilitation phase.There is, in addition, evolving evidence that hormones derived from both the gut and adipose tissue are also involved in the response to stress and critical illness, and that adipose tissue in particular is not a benign tissue bed, but rather should be considered an endocrine organ. Some of these hormones are thought to be pro-inflammatory and some anti-inflammatory; however both the net result and clinical significance of these are yet to be fully elucidated.The provision of adequate nutrition has become an integral component of supportive ICU care, but is complex. There is ongoing debate within critical care literature regarding the optimal route of delivery, the target dose, and the macronutrient components (proportion of protein and non-protein calories) of nutritional support. A number of studies have associated caloric deficit with morbidity and mortality, with the resultant assumption that prescribing sufficient calories to match energy expenditure will reduce morbidity and mortality, although the evidence base underpinning this assumption is limited to observational studies and small, randomized trials.There is research available that suggests hyper-caloric feeding or hyper-alimentation, particularly of carbohydrates, may result in increased morbidity including hyperglycemia, liver steatosis, respiratory insufficiency with prolonged duration of mechanical ventilation, re-feeding syndrome and immune suppression. But the results from studies of hypo-caloric and eucaloric feeding regimens in critically ill patients are conflicting, independent of the added metabolic complexities observed in the critically ill obese patient.Notwithstanding the debate regarding the dose and components of nutritional therapy, there is consensus that nutrition should be provided, preferably via the enteral route, and preferably initiated early in the ICU admission. The enteral route is preferred for a variety of reasons, not the least of which is cost. In addition there is evidence to suggest the enteral route is associated with the maintenance of gut integrity, a reduction in bacterial translocation and infection rates, a reduction in the incidence of stress ulceration, attenuation of oxidative stress, release of incretins and other entero-hormones, and modulation of systemic immune responses. Yet there is evidence that the initiation of enteral nutritional support for the obese critically ill patient is delayed, and that when delivered is at sub-optimal levels. The reasons for this remain obscure, but may be associated with the false assumption that every obese patient has nutritional reserves due to their adipose tissues, and can therefore withstand longer periods with no, or reduced nutritional support. In fact obesity does not necessarily protect from malnutrition, particularly protein and micronutrient malnutrition. It has been suggested by some authors that the malnutrition status of critically ill patients is a stronger predictor of mortality than BMI, and that once malnutrition status is controlled for, the apparent protective effects of obesity observed in several epidemiological studies dissipate. This would be consistent with the large body of evidence that associates malnutrition (BMI < 20 kg/m) with increased mortality, and has led some authors to postulate that the weight-mortality relationship is U-shaped. This has proven difficult to demonstrate, however, due to recognized confounding influences such as chronic co-morbidities, baseline nutritional status and the nature of the presenting critical illness.This has led to interest in nutritional regimens targeting alternative calorie and protein goals to protect the obese critically ill patient from complications arising from critical illness, and particularly protein catabolism. However, of the three major nutritional organizations, the American Society of Parenteral and Enteral Nutrition (ASPEN) is the only professional organization to make specific recommendations about providing enteral nutritional support to the critically ill obese patient, recommending a regimen targeting a hypo-caloric, high-protein goal. It is thought that this regimen, in which 60-70% of caloric requirements are provided promotes steady weight loss, while providing sufficient protein to achieve a neutral, or slightly positive, nitrogen balance, mitigating lean muscle mass loss, and allowing for wound healing. Targeting weight loss is proposed to improve insulin sensitivity, improve nursing care and reduce the risk of co morbidities, although how this occurs and whether it can occur over the relatively short time frame of an intensive care admission (days to weeks) remains unclear. Despite these recommendations observational data of international nutritional practice suggest that ICU patients are fed uniformly low levels of calories and protein across BMI groups.Supporting the critically ill obese patient will become an increasingly important skill in the intensivist's armamentarium, and enteral nutritional therapy forms a cornerstone of this support. Yet, neither the optimal total caloric goal nor the macronutrient components of a feeding regimen for the critically ill obese patient is evident. Although the suggestion that altering the macronutrient goals for this vulnerable group of patients appears to have a sound physiological basis, the level of evidence supporting this remains unclear, and there are no systematic reviews on this topic. The aim of this systematic review is to evaluate existing literature to determine the best available evidence describing a nutritional strategy that targets energy and protein delivery to reduce morbidity and mortality for the obese patient who is critically ill. PMID- 26571287 TI - Effectiveness of professional oral health care intervention on the oral health of residents with dementia in residential aged care facilities: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this review is to critically appraise and synthesize evidence on the effectiveness of professional oral health care intervention on the oral health of aged care residents with dementia.More specifically the objectives are to identify the efficacy of professional oral health care interventions on general oral health, the presence of plaque and the number of decayed or missing teeth. BACKGROUND: Dementia poses a significant challenge for health and social policy in Australia. The quality of life of individuals, their families and friends is impacted by dementia. Older people with dementia often have other health comorbidities resulting in the need for a higher level of care. From 2009 to 2010, 53% of permanent residents in Residential Aged Care Facilities (RACFs) had dementia on admission. Older Australians are retaining more of their natural teeth, therefore residents entering RACFs will have more of their natural teeth and require complex dental work than they did in previous generations. Data from the Australian Institute of Health and Welfare showed that more than half the residents in RACFs are now partially dentate with an average of 12 teeth each. Furthermore, coronal and root caries are significant problems, especially in older Australians who are cognitively impaired.Residents in aged care facilities frequently have poor oral health and hygiene with moderate to high levels of oral disease and overall dental neglect. This is reinforced by aged care staff who acknowledge that the demands of feeding, toileting and behavioral issues amongst residents often take precedence over oral health care regimens. Current literature shows that there is a general reluctance on the part of aged care staff to prioritize oral care due to limited knowledge as well as existing psychological barriers to working on another person's mouth. Although staff routinely deal with residents' urinary and faecal incontinence, deep psychological barriers exist when working on someone's mouth due to their own personal values of oral health or their views that residents should be looking after their own teeth or dentures. Furthermore, residents with behavioral issues associated with dementia frequently have their oral hygiene neglected as they may be resistant and violent towards receiving oral care from aged care staff. Studies have shown that residents with dementia will often refuse to open their mouth or partake in oral hygiene care by aged care staff. The aged care staff in return often do not pursue an oral care regimen for these "difficult" residents, perpetuating the cycle of oral neglect and resultant disease.Dental hygienists are qualified oral health professionals who are specifically trained to develop individualized oral health care plans and preventative programs to reduce oral health disease in the community. Residents with dementia in aged care facilities have the right to live their lives comfortably and free of oral discomfort or pain. A Victorian study conducted by Hopcraft et al. investigated the ability of a dental hygienist to undertake a dental examination/screening for residents in aged care facilities, to develop a preventative and periodontal treatment plan and to refer patients appropriately to a dentist. Results from this study demonstrated that there was an excellent agreement between the dentist and dental hygienist regarding the decision to refer residents to a dentist for treatment, demonstrating high sensitivity (99.6%) and high specificity (82.9%). Residents from 31 Victorian RACFs (n=510) were examined by a single experienced dental epidemiologist and one of four dental hygienists using a simple mouth mirror and probe. Hopcraft et al. concluded that hygienists should be utilized more widely in providing holistic oral health care to residents in aged care facilities.Recently, Lewis et al. discussed the need to develop models of care to improve access to dental care for frail and functionally dependent elderly people in aged care facilities, with the model of care involving dental hygienists/oral health therapists having merit.The concept of professional oral care involves an oral health professional such as a dental hygienist or oral health therapist supervising or assisting residents with their oral care. Oral care involves the mechanical removal of plaque and food debris using a toothbrush, interproximal brush and floss.In 2014, Morino et al. explored the efficacy of short term professional oral care from dental hygienists once a week after breakfast for one month. In this study, the dental hygienists did not perform dental scaling but brushed subjects' teeth using a toothbrush and interdental brush. Dental plaque scores decreased significantly (Fisher's two tailed tests, p<0.05) in the professional oral health intervention group. Interestingly, the positive effects of this short term intervention were sustained for the following three months (Wilcoxon test, p<0.05).A pilot study in Arkansas was conducted by Amerine et al. and utilized the dental hygienist as the "oral health champion" in the residential aged care facility using the Oral Health Assessment Tool (OHAT) and Geriatric Oral Health Assessment Index (GOHAI) scores to measure oral health. The results from this study showed improvements in three measured areas (tongue health, denture status and oral cleanliness) in the dental hygiene champion group. These findings suggest that the presence of a dental hygiene champion in long term care facilities may positively impact the oral health of residents requiring assistance with their oral care. However, the authors noted further research in this concept is required.Van Der Putten GJ et al. explored the effectiveness of a supervised implementation of an oral health care guideline in care homes. In each ward of the care homes, a nurse who acted as the ward oral health care organiser (WOO) was appointed. The dental hygienist and an investigator would attend the RACFs every six weeks to support them. The dental hygienist would train the WOO, and the WOO would train the ward nurses and nurse assistants. Participants were allocated into an intervention or a control group. The intervention group received supervised oral care. Statistically significant differences in mean dental and denture plaque scores at six months in both groups occurred (student t-test, p < 0.0001). This research study implemented an intervention using the train-the-trainer approach and although improvements in dental and denture plaque scores were seen in the six-month period, the long-term effects of this intervention are unknown. Further studies exploring the long-term effects of staff training on oral health education are needed as well as ongoing staff training in aged care facilities.A systematic review on oral health and aspiration pneumonia conducted by Vander Maarel-Wierink et al. has suggested that, in the frail elderly, the best intervention to reduce the incidence of aspiration pneumonia is brushing of teeth after each meal, cleaning dentures once a day, and receiving professional oral health care once a week.The need to advocate for a new model of geriatric dentistry is critical. A holistic multi-disciplinary approach to health care for residents entering aged care homes is imperative to achieve better oral health and comfort for residents, especially with Australia's ageing dentate population. A dental examination and assessment on admission to a RACF should be conducted by a Registered Nurse (RN), followed by an oral health professional such as a dentist, dental hygienist or oral health therapist. Current practice in the majority of Australian government funded nursing homes is that the RN or the Assistant in Nursing (AIN) conduct the oral health assessment as part of the aged care funding instrument (ACFI). Ongoing oral health care supported by an oral health professional is important throughout the individual's residency and eventual palliation whilst in an aged care facility.No systematic reviews conducted on the impact of professional oral care on the oral health of elderly people living in residential aged care facilities could be located, despite extensive searching of Medline, CINAHL, EMBASE, Web of Science, Cochrane Central Register of Trials and Dentistry & Oral Sciences Source (DOSS) databases. A JBI systematic review was conducted in 2004, titled, "Oral hygiene care for adults with dementia in residential aged care facilities"; however, this review examined the prevalence, incidence and increments of oral diseases; the use of assessment tools to evaluate oral health; preventative oral hygiene care strategies; and the provision of dental treatment and so had a different clinical focus. Twenty studies were included for analysis in the review conducted by Weening-Verbree et al, The studies in this review addressed oral health knowledge of aged care staff and mostly were conducted as an educational session delivered by dental hygienists or dentists.Overall, the current evidence available on interventions to improve oral health for residents living in aged care facilities is inadequate and should be explored further. PMID- 26571288 TI - Parents' experiences of transition when their infants are discharged from the Neonatal Intensive Care Unit: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this review is to identify, appraise and synthesize the best available studies exploring parents' experiences of transition when their infants are discharged from the Neonatal Intensive Care Unit (NICU).The review questions are: BACKGROUND: Giving birth to a premature or sick infant is a stressful event for parents. The parents' presence and participation in the care of the infant is fundamental to reduce this stress and to provide optimal care for both the premature or sick infant and family. A full term pregnancy is estimated to last between 37 and 40 weeks. Preterm infants born before 28 week (5.1%) are defined as extremely preterm, while those who are born between 28 to 31 weeks (10.3%) are defined as very preterm. The majority of the preterm (84.1%) are born between 32 to 37 week and may have significant medical problems requiring prolonged hospitalization.The prevalence of preterm birth is increasing worldwide. More than one in ten babies are born preterm annually. This is equal to 15 million preterm infants born globally and the second largest direct cause of deaths in children below five. The highest rates of preterm birth are in Sub-Saharan Africa and South Asia (more than 60%) and the lowest rates are in Northern Africa, Western Asia, Latin America and the Caribbean. The preterm birth rates in the developing countries vary widely and follow a different pattern than in high income countries.The preterm birth rate has increased between 1990 and 2010 with an average of 0.8% annually in almost all countries. Morbidity among critically ill newborn and preterm infants vary widely from no late effects to severe complications, such as visual or hearing impairment, chronic lung disease, growth failure in infancy and specific learning impairments, dyslexia and reduced academic achievement. Full term infants may also experience significant health problems requiring neonatal intensive care. The most common reasons for a full term infant to be admitted to a NICU after birth are temperature instability, hypoglycemia, respiratory distress, hyperbilirubinemia and neonatal mortality. Admission of a full term newborn infant from home within the first four weeks after birth is due to jaundice, dehydration, respiratory complications, feeding difficulties, urinary tract infection, diarrhea and meningitis.In the last two to three decades, technological advances in neonatalogy have improved the survival rates of critically ill and preterm infants.Two major issues have influenced the design of the NICU wards: i) the increased volume of preterm infants with extremely low gestational age who need neonatalogy assistance, and ii) the impact of the parents' presence in the NICU to support the infant's development.The health status of preterm babies can have a significant impact on the family wellbeing and function. The separation between the preterm infant and the parents is a threat to the attachment and bonding process. Worldwide, there has been a paradigm shift in the NICUs over the last decade, inviting parents to be admitted together with the infant or at least to spend most of the day together with their critical ill and preterm infant in the NICU. Parental involvement increases the performing of Kangaroo Mother Care during the admission in the NICU and increases parental preparedness for discharge to home. This change prepares the parents to take over tasks such as nurturing and feeding. The parents are the most important caregivers for the infant during the admission in the NICU and their co-admission increases the bonding and prepare the parents for the transition discharged to home.Family centered care (FCC) based on a partnership between families and professionals is described as essential in current research on neonatal care. Family centered care is facilitated by parental involvement, communication based on mutuality and respect, and unrestricted parental presence in the NICU. According to Mikkelsen and Frederiksen, the central attribute of FCC is partnership with the core value of mutuality and common goals.A NICU is a high tech setting where highly specialized professionals care for premature or critically ill infants. During the infants' hospitalization, the relationship between parents and nurses evolves through an interchange of roles and responsibilities. However, this collaboration is challenging due to a discrepancy between parents' and nurses' expectations of their roles.To facilitate parents' skin-to-skin contact and involvement in their infant's care, NICUs are now redesigned to facilitate parents' "24-hour" presence, also called "rooming-in". Seporo et al. describes several benefits with "rooming-in" the NICUs. Staying in the same room increases infants' and parents' possibility for "skin-to-skin care". This improves the infant's sleep time and temperature regulation, decreased crying and need for oxygen, increases parental confidence and positive infant-parent interaction. Parents' experience of "skin-to-skin care" and "rooming in" may help parents to be acquainted with their infant and thus prepare for the transition to home. However, despite these positive effects of rooming in, some negative effects, e.g. less sleep and lack of privacy, have been described by parents who have stayed with their child in a pediatric unit.The hospitalization may challenge the normal attachment process and parents' confidence as caregivers; parents' preparation for bringing the infant home is thus essential. The infant's discharge from the NICU is experienced as a moment of mixed feelings. Going home is a happy event, but at the same time it is combined with parental anxiety. Parents' pervasive uncertainty, medical concerns and adjustment to the new parental and partner-adjustment role are common concerns. To make parents confident and prepared for taking their infant home tailored information, guidance and hands-on experience caring for their infant before discharge is crucial.During the literature research we became aware of a systematic narrative review protocol by Parascandolo et al.'s concerning nurses', midwives', doctors' and parents' experiences of the preterm infants' discharge to home. The aim of our comprehensive review is to perform a metasynthesis on parents' perspectives and their experiences of transition from discharge from NICU to home. We will include qualitative primary studies to offer a deeper understanding of the parent perspective. PMID- 26571289 TI - The impact of knowledge on attitudes of emergency department staff towards patients with substance related presentations: a quantitative systematic review protocol. AB - CENTER CONDUCTING THE REVIEW: University of Manitoba and Queens Joanna Briggs Collaboration for Patient Safety: a Collaborating Center of the Joanna Briggs Institute REVIEW QUESTION/OBJECTIVE: The overall objective of this systematic review is to synthesize the available evidence on the relationship between new knowledge (gained through educational interventions about substance use/abuse) and health care providers' attitudes (measured by well validated instruments such as the Drug and Drug Problems Perceptions Questionnaire [DDPPQ], the Short Alcohol and Alcohol Problems Perception Questionnaire [SAAPPQ], etc.) towards patients with substance-related presentations to emergency departments.The specific review question is: Among emergency department staff, does the acquisition of knowledge (on educational interventions about substance use) impact attitudes in relation to their therapeutic role towards patients with substance-related presentations? BACKGROUND: Substance-related emergency department (ED) visits are common worldwide. Estimates of cases with alcohol involvement presenting to the ED range from 6% to 45%. Research conducted in the UK and Australia suggests that presentations related to illicit drug use are common and have increased in recent years.In 2012, an estimated six million Canadians met the criteria for substance use disorder; alcohol was the most common substance of abuse followed by cannabis and other drugs. The relationship between substance use and physical injury is well documented. The risk of mortality is increased by the side effects of substances on users involved in accidents and trauma. Not surprisingly, substance-related ED visits have been on the rise. Although only 3 to 10% of overall visits are typically related to a primary entrance complaint of drug or alcohol use or abuse, studies estimate that up to 35% of ED visits may be directly or indirectly substance related. These reasons may range from injury resulting from accidents or violence to substance related illnesses.Health care providers (i.e., typically medical and nursing staff) have often perceived substance using patients as a challenging group to manage and as adding to the workload of already busy staff. The challenges of providing care to this patient population may be attributed to: (1) the chaotic ED environment, (2) health care providers' lack of knowledge, experience or skill in identifying and addressing substance misuse, (3) health care providers' lack of support structures such as sufficient time, staff and resources in working with this population, (4) health care providers' negative attitudes towards this patient population, (5) unpleasant tasks (i.e. intoxicated patients who urinate on themselves) associated with care delivery to this patient population, (6) patients' aggressive or violent behavior, and (7) patients' lack of motivation to change.Health care providers' attitudes towards patients with substance use problems have been found to affect health care delivery. This is of concern given the research findings that suggest they generally hold negative attitudes towards this patient population. For instance, in their study of nurses' attitudes towards patients who use illicit drugs, Ford, Bammer and Becker found that only 15% of nurses gained satisfaction from caring for these patients and only 30% were motivated to care for this patient group. Researchers who have examined substance using patients' experiences accessing health care also point to the suboptimal attitudes of health care providers towards this patient population. In the Neale, Tompkins and Sheard study of the barriers encountered by injecting drug users when accessing health and social care services, injecting drug users reported that they were often treated poorly or differently from other patients (i.e. sent home prematurely, not given appropriate aftercare or discharge), and made them feel not worthy of receiving help. Although the evidence relating to health care providers' attitudes toward substance using patients comes primarily from studies conducted in mental health or primary care settings, researchers who have examined ED staff attitudes towards this patient population paint a similar picture. For instance, Camilli & Martin's review of ED nurses' attitudes toward intoxicated and psychiatric patients suggests that nurses are often frustrated when it comes to these patients as they are time consuming and offer repeat business to the ED. An ethnographic study of care delivery in an ED also points to the negative attitudes of ED staff towards this patient group. Henderson, Stacey and Dohan found that ED providers had interactions with substance using patients that may be considered excluding, rejecting or de-valuing, that is, in observations and interviews, providers often spoke of this patient population as abusing the system, overusing system resources, and not caring about their own health care. Other negative attitudes of ED staff towards substance using patients found in the literature pertain to: (1) being reluctant to ask patients about substance use, (2) believing little can be done in EDs to help these patients, (2) feeling angry or professionally dissatisfied when treating this patient group, (4) lacking a sense of responsibility for referring to specialist treatment, and (5) believing patients lack motivation to change following interaction with medical staff.Although there is considerable evidence that indicates health care providers hold negative attitudes towards substance using patients, there are also some studies that have found positive attitudes towards this patient population. For instance, in their study of physician attitudes toward injecting drug users, Ding et al. found that seeing more injecting drug users was associated with more positive attitudes towards this patient population. Similarly, Kelleher & Cotter's descriptive study of ED doctors' and nurses' knowledge and attitudes concerning substance use found that the ED doctors and nurses who participated in the study had positive attitudes with regards to working with substance using patients. In the majority of these studies, however, positive attitudes were reported when health care providers were professionals working in addiction services, had more experience caring for this patient population, or had more personal contact with substance using patients. But does knowledge about substance use impact attitudes towards patients with substance-related presentations?Providing education or experience based exercises may impact positively on attitudes towards substance using patients. Brief educational interventions, typically, informational sessions, either didactic or online, about alcohol and other drugs and how to assess and work with individuals using them, have been shown to have a positive impact on students' attitudes, knowledge and confidence relating to substance use and substance users. Whether ED staff attitudes towards patients with substance related presentations are similarly impacted by the knowledge acquired through educational interventions remains unknown. A full systematic review of the literature will answer this question. A systematic review that examines the impact of knowledge on attitudes of ED staff will inform the design of educational strategies with emergency department staff to improve attitudes towards this patient population.To confirm that no other systematic review has been published on this topic, a preliminary literature search was conducted. The following databases were searched and no current or planned review was found related to this topic: JBI Database of Systematic Reviews and Implementation Reports, Cochrane Database of Systematic Reviews, PROSPERO, CINAHL, PubMed, and Scopus. Grey literature was also searched; however, no systematic review addressing the impact of knowledge on attitudes of ED staff towards patients with substance-related presentations was located. PMID- 26571290 TI - Exploring conceptual and theoretical frameworks for nurse practitioner education: a scoping review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this review is to examine conceptual and/or theoretical frameworks that are relevant to nurse practitioner education.The specific review question is: What conceptual and/or theoretical frameworks are available that are relevant to the structuring of nurse practitioner education? BACKGROUND: The use of conceptual and theoretical frameworks to organize the educational curriculum of nursing programs is essential to protect and preserve the focus and clarity of nursing's distinct contribution to health care. Conceptual frameworks of nursing provide a means to look at nursing in relationship to external factors, thereby assigning meaning to the practice. Graduate level nursing education in the preparation of Nurse Practitioners (NPs) specifically and Advanced Practice Nurses (APNs) in general, is significantly compromised by the tendency to conceptualize the learning in these complex programs as being primarily related to skills-based tasks and competencies alone. According to Baumann, advanced nursing education must focus on the uniqueness of the NP position, in contrast to other health care professions. To do this, Baumann suggests using a conceptual nursing model and nursing theory as opposed to a strictly biomedical model. This allows NPs to interpret information in a way that differs from the strict biomedical model, providing opportunities for the NPs to be truly present in the lives of their patients.Canadian Nurse Practitioner (NP) practice competency documents are based primarily on the Canadian Nurses Association (CNA) Nurse Practitioner (NP) Core Competency Framework. This document defines the core set of entry-level competencies required for all NPs to practice in all Canadian jurisdictions, settings and client populations. The Core Competencies in the CNA NP Framework are organized within four main categories: professional role, responsibility and accountability; health assessment and diagnosis; therapeutic management; and health promotion and prevention of illness and injury. Although vital to the organization of provincial entry-level registration standards, this framework provides little direction to educational providers for curricula organization and philosophical perspectives.The Canadian Association of Schools of Nursing developed a national framework for NP education following a multi-phase consultation and literature and curriculum synthesis project. While the task force addressed the guiding principles and essential components of NP education along with contextual factors that impact on the delivery of curricula in Canadian jurisdictions, the philosophical approaches guiding and organizing the education were not addressed.A similar set of documents has been created in the United States by the National Organization of Nurse Practitioner Faculties (NONPF). These documents are organized by six population level foci (including the specialty of family/individual across the lifespan) and outline core competencies for entry to practice and registration and educational standards. The Core Competency documents provided by the NONPF are presented in the same manner as the CNA NP Framework and likewise, do not provide a guiding or organizing framework or philosophy for NP education.A full curriculum overhaul based on the NONPF competency requirements was performed at a university center in Oregon. The new curriculum was based on competencies that students must acquire, rather than learning objectives. While the NONPF Framework does provide an extensive list of entry-level requirements for NPs, the challenges faced by the institution as it aimed to incorporate the framework into the curriculum clearly provide evidence that these overarching frameworks need to include both a philosophical and organizational component to help guide educators.Conceptual frameworks are useful for establishing a congruent relationship between program curricula, objectives and content. Walker and Avant advance the utility of conceptual frameworks as providing the logic behind the interrelationships of terms and variables, and improving explanation and understanding. Gold, Haas & King assert that conceptual frameworks facilitate grounding of a nursing lens in the curricula of advanced practice nursing programs. It has been noted that newly practicing NPs have demonstrated an allegiance withmedical model thinking, second only in importance to wellness/health promotion considerations. Blasdell and colleagues surveyed 188 practicing NPs to investigate the relationship between education and the use of theory in clinical practice. Educated graduate NPs rated the importance of nursing theory to the NP practice role significantly higher than did diploma and baccalaureate degree NPs (4.05+/-2.06 versus 2.65+/-1.69, p<.001) but both groups rated the nursing models as less important for practice than a medical model approach.Huckabay highlighted the need for the use of a harmonized nursing model at the undergraduate level to ensure that students have a thorough understanding of what nursing is and what nursing care entails. At the graduate level, Huckabay suggested the use of multiple nursing models, depending on specialty. Regardless of the educational level, a conceptual framework used for education must enable nurse educators to have sufficient guidelines to construct a curriculum and determine what knowledge and skills are needed by the nursing students. Further, Furlong identified the need for Advanced Practice Nursing (APN) curriculae to be innovative and critically reflective, preparing students to be readily adaptable to challenges in the work place. Furlong suggests that to do this, the curriculum must rely upon an interdisciplinary framework to deliver content. Gold, Haas & King suggest that core curricula based on a medical model or a skill-related task list do not reflect the critical thinking of nurses, nor the uniqueness of the profession. Thus, conceptual models used for curricula development must: encompass the distinct nursing worldview, promote learning, and be efficient and comprehensive.Frameworks have been proposed and tested to guide the development and implementation of inter professional education (IPE) and collaborative practice curricula for NP and medical students. A qualitative assessment of a framework guided IPE module illustrated the benefit of improving the focus on role awareness in participating students. However, this particular curriculum was limited to a two-week period and not presented as a pervasive approach to the educational programs of each discipline.In education, an overarching philosophy can provide a road map for goal identification, teaching material development and the formulation of evaluation methods. For instance, when creating a curriculum that was a result of the collaboration of three different post-secondary institutions, the SHARE (students, humor, administrative support, resources, and educational technology) model was used. This model brings together resources, students and faculty, surrounding them with humor, which was viewed as a fundamental part of the process while the program was still in its early stages. According to the authors, the program has been widely successful and the reliance on humor as an underlying philosophy has enabled the students and faculty to deal with problems arising in the new program.Focusing on evaluation, Kapborg & Fischbein promoted the use of the Education Interaction Model. The model identifies how educational influences can interact with abilities of students and how the consequences of this interaction can be evaluated by observing changes in both students and programs. The authors argue that, while the educational interaction model is effective, it is not the only model that can be used to carry out evaluations. The authors stress that the model chosen to perform an evaluation should be based upon what or who is going to be evaluated.The standards outlined in the CNA NP framework are an essential part of organizing the education process for NPs and ensuring that NPs have acquired the necessary skills to practice in Canada as an NP. However, the framework is lacking philosophy and organization regarding NP education programs to ensure that the curriculum is preparing the NPs for the ever-changing work environment.An Australian survey of NP education documents from relevant universities as well as interviews with NPs and academic conveners from Australia and New Zealand found that, while NP educational programs need to have strong clinical and science based learning components, student directed and flexible learning models act to ensure the capability of NPs as they strive to adapt to practice situations. Capability, as an approach to the learning process, includes the flexibility to respond to the specific, self-identified learning needs of students. Knowing how to learn, having high self-efficacy, applying competencies to new tasks, collaborating with others, and being creative are all signs of a capable practitioner. Gardner et al. emphasized the need for a program that fosters both competent and capable NPs. In a follow-up study, using the same data, Gardner et al. confirmed that NPs viewed the attributes of a capable NP as imperative to practice. Thus, a framework for NP education must include both competency building elements, such as those currently found in the CNA NP framework and capability building elements which can be fostered through self directed learning.Similarly, Schaefer investigated the role of caring in nursing practice through a class for APN students in which the students reflected on their narratives of caring for patients. This qualitative study revealed that when APN students provide care by meeting the complex needs of suffering patients, the art and science of nursing combine. (ABSTRACT TRUNCATED) PMID- 26571291 TI - An exploration of adolescents' decisions to abstain or refrain from alcohol consumption in Australian social settings: a qualitative systematic review. AB - BACKGROUND: A significant number of Australian adolescents consume alcohol, with almost two thirds of them doing so at risky levels. This is continuing to increase despite recent National Health and Medical Research Council (NHMRC) guidelines stipulating that no alcohol is the safest option. Measures initiated to reduce and prevent alcohol consumption by adolescents have limited effectiveness. Consumption of alcohol by Australian adolescents is a national concern because of the deleterious effects of alcohol consumption on adolescents' social, physical and neurological development, as well as other short- and long term health risks, and the negative impact of alcohol-related violence and injury on the community. Understanding adolescents' decisions to abstain or refrain from alcohol consumption may provide valuable insights to assist in dealing with this significant social and health issue, more particularly about the mechanisms used by adolescents or their ability to make decisions about resisting or abstaining from alcohol consumption when exposed to alcohol in their social setting(s). OBJECTIVES: The review aimed to synthesize the best available qualitative evidence on the decisions made or mechanisms used by adolescents who abstain or refrain from consuming alcohol in any social setting where alcohol is available. INCLUSION CRITERIA: Adolescents aged between 14 and 19 years who reside in Australia.The phenomenon of interest was abstinence from or resistance to alcohol consumption when exposed to alcohol in social situations.This review considered studies that focused on qualitative data, including, but not limited to,designs such as phenomenology, grounded theory, action research and exploratory studies. SEARCH STRATEGY: A three-step search strategy was used. An initial search to identify keywords only was undertaken in Medline and CINAHL. This was followed by an expanded search using all identified keywords and index terms specific to each included database. The reference lists of included papers were then searched for any other relevant studies. METHODOLOGICAL QUALITY: No studies met the inclusion criteria sufficiently to progress to critical appraisal. DATA EXTRACTION: No studies progressed to data extraction. DATA SYNTHESIS: Data synthesis was not undertaken as no study met the inclusion criteria. RESULTS: Although a number of studies retrieved indicated they had qualitative elements to their studies, the qualitative data was not reported. CONCLUSIONS: Although a number of studies met some aspects of the inclusion criteria there was insufficient reporting of the phenomenon of interest. Due to the lack of studies meeting the inclusion criteria, no conclusions can be drawn for clinical practice. A lack of qualitative data on this topic has been identified. Thus there is a great need for qualitative research to understand and know more about what enables an adolescent to abstain or refrain from consumption in order to inform or formulate effective interventions, policies or plans to prevent or reduce the volume of alcohol consumed by Australian adolescents. PMID- 26571293 TI - Patients' involvement in improvement initiatives: a qualitative systematic review. AB - BACKGROUND: Over the last 20 years, quality improvement in health has become an important strategy in health services in many countries. With the emphasis on quality health care, there has been a shift in social paradigms towards including service users in their own health on different levels. There is growing evidence in literature on the positive impact on health outcomes where patients are active participants in their personal care. There is however less information available on the broader influence of users on improvement in systems. OBJECTIVES: The objective of this review was to identify the barriers and enablers to patients being involved in quality improvement efforts directed towards their own health care. INCLUSION CRITERIA: This review considered studies that included adults and children of any age experiencing any health problem.The review considered studies that explored patient or user participation in quality improvement and the factors enabling and hindering this processThe qualitative component of this review considered studies that focused on qualitative data, including, but not limited to, designs such as phenomenology, grounded theory, ethnography, action research and feminist research. Other texts such as opinion papers and reports were also considered. SEARCH STRATEGY: The search strategy aimed to find both published and unpublished studies. A three-step search strategy was utilized in this review. The searches using all identified keywords and index terms included the databases PubMed, PsycINFO, Medline, Scopus, EBSCOhost and CINAHL.Qualitative, text and opinion papers were considered for inclusion in this review.Closely related concepts like community involvement, family involvement, patients' involvement in their own care (for example, in the case of shared decision making), and patient centeredness in the context of a consultation were excluded. METHODOLOGICAL QUALITY: Qualitative and textual papers selected for retrieval were assessed by two independent reviewers for authenticity prior to inclusion in the review using the standardized critical appraisal instruments from the Joanna Briggs Institute. DATA EXTRACTION: Qualitative and textual data were extracted from papers included in the review using the standardized data extraction tool from the Joanna Briggs Institute. DATA SYNTHESIS: The above findings were pooled and through the identification of categories, a final meta synthesis was formulated. RESULTS: Two synthesized findings were created from the included papers. Firstly, there are barriers to patients' participation in quality improvement in health and in spite of policy support for user involvement in quality improvement, it is a difficult strategy to implement. The second synthesized finding was that there are enablers to patients' involvement in quality improvement: when patients are involved in quality improvement efforts in health care, there are innovative, often unexpected, outcomes at different levels of the process, and sustaining these efforts is possible with ongoing individual or group support.Five categories which supported the synthesized findings were created through the meta-aggregative process. CONCLUSIONS: There are enablers and barriers to involving patients in quality improvement in health care that need to be considered when planning such interventions.Relationships and roles will need to be very clear from the outset. A developmental approach needs to be considered where support and training is part of the project. Where patients are truly engaged in service improvement, unexpected innovation occurs.There are many more reports and opinion papers published regarding this topic than there are rigorous research studies. This leaves the field open to the development of good methodological studies related to quality improvement and in particular to the participation of patients. PMID- 26571292 TI - The effect of waterbirth on neonatal mortality and morbidity: a systematic review and meta-analysis. AB - BACKGROUND: Women have been giving birth in water in many centers across the globe; however, the practice remains controversial. Qualitative studies highlight the benefits that waterbirth confers on the laboring woman, though due to the nature of the intervention, it is not surprising that there are few randomized controlled trials available to inform practice. Much of the criticism directed at waterbirth focuses on the potential impact on the neonate. OBJECTIVES: The objective of this review was to systematically synthesize the best available evidence regarding the effect of waterbirth, compared to landbirth, on the mortality and morbidity of neonates born to low risk women. INCLUSION CRITERIA: This review considered studies that included low risk, well, pregnant women who labor and birth spontaneously, at term (37-42 weeks), with a single baby in a cephalic presentation. Low risk pregnancies are defined as pregnancies with an absence of co-morbidity or obstetric complication, such as maternal diabetes, previous cesarean section, high blood pressure or other illness. Women may be experiencing their first or subsequent pregnancy. The fetus must also be well and without any co-morbidity or complication.The intervention of interest is waterbirth. The comparator is landbirth. Women and their babies must be cared for by qualified maternity healthcare providers throughout their labor and birth. The birth setting must be clearly described but can include home, hospital or birth center, either freestanding or attached to a hospital.This review considered randomized controlled trials, quasi-experimental studies and observational prospective and retrospective cohort studies. SEARCH STRATEGY: A multi-step search strategy was utilized to find published and unpublished studies, in English between January 1999 and June 2014. METHODOLOGICAL QUALITY: The first author assessed the quality of all eligible studies. The three secondary authors independently assessed six studies each, followed by group discussion using the appropriate Joanna Briggs Institute appraisal checklist. DATA EXTRACTION: Data were extracted using a standardized extraction tool from Joanna Briggs Institute. DATA SYNTHESIS: Quantitative studies were pooled, where possible, for meta analysis using software provided by Cochrane. Effect sizes were expressed as odds ratio or relative risk, according to study design, and the 95% confidence intervals were calculated. Heterogeneity was assessed statistically using the standard Chi-square test. RESULTS: The meta-analyses of 12 studies showed that for the majority of outcomes measured in this review there is little difference between waterbirth and landbirth groups. Meta-analysis was not conducted for mortality within 24 days of birth. Heterogeneity was significant between studies for APGAR (Appearance, Pulse, Grimace, Activity, and Respiration). scores <=7 at one minute and admission to Special Care nursery. Sensitivity analysis for case control studies describing infection found results that were not statistically significant (OR 0.74, 95% CI 0.05-11.06). Results of meta-analysis were also not significant for studies describing resuscitation with oxygen (OR 1.12, 95% CI 0.14-8.79) and Respiratory Distress Syndrome (OR 0.81, 95% CI 0.44-1.49). Results comparing APGAR scores <=7 at five minutes for waterbirth and landbirth groups results for included RCTs demonstrated results that were not statistically significant (OR 6.4, 95% CI 0.63-64.71). However, results for included cohort studies describing APGAR scores <=7 at 5 minutes indicate neonates are less likely to have scores <=7 in the waterbirth group (OR 0.32, 95% 0.15-0.68). Data were not statistically significant for meta-analysis describing admission to NICU (OR 0.51, 95% CI 0.13-1.96) between water and landbirth groups. The differences in arterial (MD 0.02, 95% CI 0.01-0.02) and venous (MD 0.03, 95% CI 0.03-0.03) cord pH, while statistically significant, were clinically negligible. CONCLUSIONS: Analyses of data reporting on a variety of neonatal clinical outcomes comparing land with waterbirth do not suggest that outcomes are worse for babies born following waterbirth. Meta-analysis of results for five-minute APGAR scores <=7 should be treated with caution due to the different direction of results for meta-analysis of data from randomized controlled trials and cohort studies. Data measuring cord pH (an objective measure of neonatal wellbeing) were robust and showed no difference between groups. Overall this review was limited by heterogeneity between studies and meta-analysis could not be conducted on a number of outcomes. Waterbirth does not appear to be associated with adverse outcomes for the neonate in a population of low risk women. IMPLICATIONS FOR PRACTICE: There is no evidence to suggest that the practice of waterbirth in a low risk population is harmful to the neonate. IMPLICATIONS FOR RESEARCH: There is a paucity of high level evidence to guide practice in the area of waterbirth. It is unlikely that randomized controlled trials on waterbirth will be acceptable to childbearing women or maternity caregivers. Observational studies are a more appropriate choice for researchers in this field as they offer a more practical and ethical approach. PMID- 26571294 TI - The effectiveness of moisturizers in the management of burn scars following burn injury: a systematic review. AB - BACKGROUND: The common mantra with which patients often leave a burns unit is "moisturize and massage". Various products have been reported for use in practice including aqueous cream BP, bees wax and herbal oil creams, silicone based creams, paraffin/petroleum/mineral oil based products and aloe vera gels. Often combined with other scar management techniques such as pressure therapy, massage and contact media, moisturizers convey active properties of their own. To date no published review on the optimal moisturizer for burn scar management has been identified via searches of recognized databases. OBJECTIVES: The objective of this review was to identify and synthesize the best available evidence on the effectiveness of moisturizer use in the management of active burn scars following burn injury. More specifically, this review focused on the following questions: Does moisturizer use have an effect on scar outcomes following burn injury, including scar formation, skin breakdown, patient acceptance and water loss? What is the optimal base composition of moisturizers used in scar management for patients who have sustained a burn injury? INCLUSION CRITERIA: Types of participants: Patients of any age who have sustained a burn injury of any size, and have been admitted to a hospital or regional burn unit or burn centre for the management of their injury. Types of intervention(s)/phenomena of interest: Studies evaluating moisturizer applied to healed skin following burn injury were considered for inclusion. Moisturizer may have been compared to usual care as defined by the individual study, other interventions, or a different type of moisturizer. Studies comparing moisturizer and massage compared to moisturizer alone were excluded. Types of studies: This review primarily considered experimental study designs, including randomized and pseudo-randomized controlled trials. Types of outcomes: Primary outcomes for examination in this review included scar formation and skin breakdown, measured by objective tools or subjective scales. Secondary outcomes included product acceptance, patient compliance and transepidermal water loss. SEARCH STRATEGY: A search was conducted to identify published and unpublished studies via electronic databases. Reference lists of all papers selected for full text retrieval were then hand searched for potential additional citations. METHODOLOGICAL QUALITY: Articles meeting pre determined eligibility criteria for the review were assessed by two independent reviewers using standardized checklists from the Joanna Briggs Institute Meta Analysis of Statistics Assessment and Review Instrument. Corresponding authors were contacted where additional information was required; however this strategy did not yield additional information that altered study eligibility status. DATA COLLECTION: Data was extracted from the included paper using the standardized data extraction tool from the Joanna Briggs Institute Meta Analysis of Statistics Assessment and Review Instrument. DATA SYNTHESIS: Narrative synthesis of the included study was undertaken. RESULTS: One study, following a randomized controlled design, was eligible for inclusion in this review. This study investigated the effect of vitamin E cream versus a base moisturizing cream on outcomes including range of motion, scar thickness, cosmetic appearance and graft size. No significant differences between groups for all reported outcomes were observed. CONCLUSIONS: Despite the common practice involving moisturizers TRUNCATED AT 500 WORDS. PMID- 26571295 TI - Documentation of chemotherapy administration by nursing staff in inpatient and outpatient oncology/hematology settings: a best practice implementation project. AB - BACKGROUND: Documentation of chemotherapy administration by nursing staff is undertaken in a written and electronic form at the Canberra Hospital and has been identified as requiring improvement in both inpatient and outpatient settings. Safe prescribing, dispensing, administration and documentation are essential to patient safety, outcomes and quality of care, and to staff safety. Due to the limited available research and evidence on this topic, recommended safety standards for the safe administration of chemotherapy formed the framework for audit criteria and documentation requirements. OBJECTIVES: The aim of this evidence implementation project was to improve documentation of chemotherapy administration by nursing staff in inpatient and outpatient oncology/hematology units, thereby improving patient care and safety, as well as meeting the legal and educational responsibilities of the nursing staff. METHODS: This evidence implementation project used the JBI Practical Application of Clinical Evidence System and Getting Research into Practice audit and feedback tool. A baseline audit was conducted to assess current practice and identify areas requiring improvement, followed by reflection on results and design, and implementation of strategies for documentation improvement. Lastly, a follow-up audit was conducted to assess compliance and practice improvement. RESULTS: The baseline audit results highlighted areas of good current practice, areas requiring improvement and barriers to data collection and practice improvement. Strategies based on raising awareness of best practice guidelines, education and useful tools were developed and implemented. It was evident that the electronic documentation prompts used in the outpatient setting, compared to paper-based documentation in the inpatient setting, contributed to better compliance to documentation guidelines. The follow-up audit demonstrated improved practices across both the inpatient and outpatient settings. CONCLUSIONS: The aim of improving documentation after chemotherapy administration was achieved, yet there is still room for further improvement. Education will continue through training courses, communication at meetings and utilization of the tools developed. Future auditing is planned to ensure sustainability. PMID- 26571296 TI - A New Screen for Tuberculosis Drug Candidates Utilizing a Luciferase-Expressing Recombinant Mycobacterium bovis Bacillus Calmette-Gueren. AB - Tuberculosis (TB) is a serious infectious disease caused by a bacterial pathogen. Mortality from tuberculosis was estimated at 1.5 million deaths worldwide in 2013. Development of new TB drugs is needed to not only to shorten the medication period but also to treat multi-drug resistant and extensively drug-resistant TB. Mycobacterium tuberculosis (Mtb) grows slowly and only multiplies once or twice per day. Therefore, conventional drug screening takes more than 3 weeks. Additionally, a biosafety level-3 (BSL-3) facility is required. Thus, we developed a new screening method to identify TB drug candidates by utilizing luciferase-expressing recombinant Mycobacterium bovis bacillus Calmette-Gueren (rBCG). Using this method, we identified several candidates in 4 days in a non BSL-3 facility. We screened 10,080 individual crude extracts derived from Actinomyces and Streptomyces and identified 137 extracts which possessed suppressive activity to the luciferase of rBCG. Among them, 41 compounds inhibited the growth of both Mtb H37Rv and the extensively drug-resistant Mtb (XDR-Mtb) strains. We purified the active substance of the 1904-1 extract, which possessed strong activity toward rBCG, Mtb H37Rv, and XDR-Mtb but was harmless to the host eukaryotic cells. The MIC of this substance was 0.13 MUg/ml, 0.5 MUg/ml, and 2.0-7.5 MUg/ml against rBCG, H37Rv, and 2 XDR-strains, respectively. Its efficacy was specific to acid-fast bacterium except for the Mycobacterium avium intracellular complex. Mass spectrometry and nuclear magnetic resonance analyses revealed that the active substance of 1904-1 was cyclomarin A. To confirm the mode of action of the 1904-1-derived compound, resistant BCG clones were used. Whole genome DNA sequence analysis showed that these clones contained a mutation in the clpc gene which encodes caseinolytic protein, an essential component of an ATP-dependent proteinase, and the likely target of the active substance of 1904 1. Our method provides a rapid and convenient screen to identify an anti mycobacterial drug. PMID- 26571297 TI - Oligomerization of RNAIII-Inhibiting Peptide Inhibits Adherence and Biofilm Formation of Methicillin-Resistant Staphylococcus aureus In Vitro and In Vivo. AB - Biofilm formation enhances bacterial resistance and complicates treatment. Therefore, an innovative strategy is urgently needed for the treatment of Staphylococcus aureus biofilm infectious diseases. RNAIII-inhibiting peptide (RIP), as a quorum-sensing inhibitor, inhibits S. aureus biofilm formation. However, RIP possesses poor antibiofilm activity when used alone or at a low dose in vivo. The activity and stability of RIP can be enhanced by designing its derivatives through amino acid substitution, terminal modification, or oligomerization. Among the derivatives, 16P-AC significantly decreased the biofilm formation and adherence of methicillin-resistant S. aureus (MRSA) on polystyrene material by inhibiting the expression level of four biofilm formation related genes in vitro. Moreover, 16P-AC showed excellent protective effects by decreasing the bacterial titers in the urine, kidney, stent, and bladder, as well as by inhibiting intercellular adhesion on the implanted stent, in a rat urinary tract infection model induced by MRSA. This derivative also exhibited a relatively good stability in rat plasma. Therefore, 16P-AC is a potential drug candidate to treat biofilm-associated infections caused by MRSA. The present modification strategy is feasible to improve the metabolic stability and activity of RIP in vivo. PMID- 26571299 TI - Unusual borane addition to conjugated dienylphosphanes under frustrated Lewis pair conditions. AB - Dimesitylphosphinoisoprene 9a reacts with a series of R-B(C6F5)2 boron Lewis acids by isomerization and subsequent 1,4-P/B addition to give the heterocyclic phosphonium/borate zwitterionic products 13. Subsequent hydride abstraction from the isoprenyl derived methyl group by trityl cation proceeds with elimination of the R-B(C6F5)2 reagent to give the heterocyclic phosphonium system 20. PMID- 26571298 TI - Indirubin Increases CD4+CD25+Foxp3+ Regulatory T Cells to Prevent Immune Thrombocytopenia in Mice. AB - Indirubin, a traditional Chinese medicine, is used to treat autoimmune diseases in clinics. However, the effects of indirubin on the immunosuppressive CD4+CD25+Foxp3+ regulatory T cells (Treg) have not been addressed. Thus, we aimed to investigate the effects of indirubin on CD4+CD25+Treg cells in immune thrombocytopenia (ITP) CBA mice, which were established by immunization with Wistar rat platelets. 50 mg/kg indirubin treatment daily for 4 weeks significantly decreased anti-platelet antibody production and prevented the decrease of platelets caused by immunization in ITP mice. Consistently, indirubin significantly enhanced the percentage and cell number of CD4+CD25+Foxp3+Treg cells in the peripheral blood, spleen and lymph nodes. We also observed a significant increase of the frequency and cell number of CD4+CD25+Foxp3+Treg cells in the thymus upon indirubin treatment. Furthermore, CD4+CD25+Treg cells from indirubin-treated mice showed similar immunosuppression on T effector cells as compared to those from control mice. Altogether, indirubin ameliorates ITP by enhancing CD4+CD25+Foxp3+Treg cell level with preserving immunosuppressive function. PMID- 26571300 TI - Self-assembly of ABC triblock copolymers under 3D soft confinement: a Monte Carlo study. AB - Under three-dimensional (3D) soft confinement, block copolymers can self-assemble into unique nanostructures that cannot be fabricated in an un-confined space. Linear ABC triblock copolymers containing three chemically distinct polymer blocks possess relatively complex chain architecture, which can be a promising candidate for the 3D confined self-assembly. In the current study, the Monte Carlo technique was applied in a lattice model to study the self-assembly of ABC triblock copolymers under 3D soft confinement, which corresponds to the self assembly of block copolymers confined in emulsion droplets. We demonstrated how to create various nanostructures by tuning the symmetry of ABC triblock copolymers, the incompatibilities between different block types, and solvent properties. Besides common pupa-like and bud-like nanostructures, our simulations predicted various unique self-assembled nanostructures, including a striped pattern nanoparticle with intertwined A-cages and C-cages, a pyramid-like nanoparticle with four Janus B-C lamellae adhered onto its four surfaces, an ellipsoidal nanoparticle with a dumbbell-like A-core and two Janus B-C lamellae and a Janus B-C ring surrounding the A-core, a spherical nanoparticle with a A core and a helical Janus B-C stripe around the A-core, a cubic nanoparticle with a cube-shape A-core and six Janus B-C lamellae adhered onto the surfaces of the A cube, and a spherical nanoparticle with helical A, B and C structures, from the 3D confined self-assembly of ABC triblock copolymers. Moreover, the formation mechanisms of some typical nanostructures were also examined by the variations of the contact numbers with time and a series of snapshots at different Monte Carlo times. It is found that ABC triblock copolymers usually aggregate into a loose aggregate at first, and then the microphase separation between A, B and C blocks occurs, resulting in the formation of various nanostructures. PMID- 26571302 TI - Synthesis and Study of 7,12,17-Trioxa[11]helicene. AB - Synthesis of the title compound 7,12,17-trioxa[11]helicene, a large oxygen containing helicene, has been reported. The 11-membered heterohelicene was synthesized by a combination of two simple reactions involving oxidative coupling and dehydrative cyclization. The final helicene was characterized by single crystal X-ray diffraction, fluorescence spectroscopy, and differential scanning calorimetric analysis. PMID- 26571301 TI - The Incidence Characteristics of Second Primary Malignancy after Diagnosis of Primary Colon and Rectal Cancer: A Population Based Study. AB - BACKGROUND: With the expanding population of colorectal cancer (CRC) survivors in the United States, one concerning issue is the risk of developing second primary malignancies (SPMs) for these CRC survivors. The present study attempts to identify the incidence characteristics of SPMs after diagnosis of first primary colon cancer (CC) and rectal cancer (RC). METHODS: 189,890 CC and 83,802 RC cases were identified from Surveillance, Epidemiology and End Results Program (SEER) database. We performed rate analysis on incidence trend of SPMs in both CC and RC. Expected incidence rates were stratified by age, race and stage, calendar year of first CRC diagnosis and latency period since first CRC diagnosis. The standardized incidence ratios (SIRs), measure for estimating risk of SPMs, were calculated for CC and RC respectively. RESULTS: The trends of incidence of SPMs in both CC and RC were decreasing from 1992 to 2012. Both CC and RC survivors had higher risk of developing SPMs (SIRCC = 1.13; SIRRC = 1.05). For CC patients, the highest risks of SPM were cancers of small intestine (SIR = 4.03), colon (SIR = 1.87) and rectum (SIR = 1.80). For RC patients, the highest risks of SPMs were cancers of rectum (SIR = 2.88), small intestine (SIR = 2.16) and thyroid (SIR = 1.46). According to stratified analyses, we also identified incidence characteristics which were contributed to higher risk of developing SPMs, including the age between 20 and 40, American Indian/Alaska Native, localized stage, diagnosed at calendar year from 2002 to 2012 and the latency between 12 and 59 months. CONCLUSIONS: Both CC and RC survivors remain at higher risk of developing SPMs. The identification of incidence characteristics of SPMs is extremely essential for continuous cancer surveillance among CRC survivors. PMID- 26571303 TI - Feasibility and effectiveness of a brief, intensive phylogenetics workshop in a middle-income country. AB - There is an increasing role for bioinformatic and phylogenetic analysis in tropical medicine research. However, scientists working in low- and middle-income regions may lack access to training opportunities in these methods. To help address this gap, a 5-day intensive bioinformatics workshop was offered in Lima, Peru. The syllabus is presented here for others who want to develop similar programs. To assess knowledge gained, a 20-point knowledge questionnaire was administered to participants (21 participants) before and after the workshop, covering topics on sequence quality control, alignment/formatting, database retrieval, models of evolution, sequence statistics, tree building, and results interpretation. Evolution/tree-building methods represented the lowest scoring domain at baseline and after the workshop. There was a considerable median gain in total knowledge scores (increase of 30%, p<0.001) with gains as high as 55%. A 5-day workshop model was effective in improving the pathogen-applied bioinformatics knowledge of scientists working in a middle-income country setting. PMID- 26571304 TI - Chronic hepatitis B in pregnant women: is hepatitis B surface antigen quantification useful for viral load prediction? AB - BACKGROUND: New cases of hepatitis B virus (HBV) infection continue to occur worldwide. Most of these are due to mother-to-child transmission (MTCT), with maternal viraemia as the most important contributing factor. The hepatitis B surface antigen (HBsAg) level, which correlates positively with viral load, has been used for treatment monitoring in chronic hepatitis B. This study evaluated the usefulness of quantitative HBsAg for viral load prediction in HBsAg-positive pregnant women. METHODS: A total of 943 pregnant women in Makassar, Indonesia, were screened for HBsAg. Sixty-four women were HBsAg-positive and investigated. HBsAg level and hepatitis B e antigen (HBeAg)/hepatitis B e antibody (anti-HBe) status were determined serologically. Viral load was measured by real-time PCR. HBV DNA was sequenced and analysed for identification of genotype and basal core promoter (BCP)/precore (PC) mutations. RESULTS: Of 64 subjects, 12 (18.8%) were HBeAg-positive and 52 (81.3%) were HBeAg-negative. HBsAg and HBV DNA levels were significantly higher in the HBeAg-positive group (p<0.001). HBsAg and HBV DNA levels were positively correlated in the HBeAg-positive group (r = 0.659; p=0.02), but not in the HBeAg-negative group (r=0.194; p=0.168). Low HBsAg levels (<3.0 log10 IU/ml) corresponded with HBV DNA levels<6.0 log10 IU/ml (r=0.404; p=0.001), a recognized threshold for MTCT. Genotype C was more prevalent than genotype B, but not associated with HBsAg level, viral load, or HBeAg status. Two thirds of HBeAg-negative subjects with high HBV DNA levels harboured BCP (A1762T/G1764A) and/or PC (G1896A) variants. CONCLUSIONS: HBsAg levels provide a good viral load predictor in HBeAg-positive but not HBeAg-negative pregnant women. The HBeAg-negative group had a frequent occurrence of BCP/PC variants, which may have contributed to the lack of correlation observed. Samples with a low HBsAg level, which is associated with a low risk of MTCT, do not require HBV DNA measurement. PMID- 26571306 TI - The synthesis and biological evaluation of a kabiramide C fragment modified with a WH2 consensus actin-binding motif as a potential disruptor of the actin cytoskeleton. AB - The F-actin depolymerisation potency of a fragment of kabiramide C was increased when modified with a WH2 consensus actin-binding motif LKKV. Despite its low affinity for actin monomers, a shorter analogous fragment not bearing LKKV was identified as a potent inhibitor of actin polymerisation and a promoter of its depolymerisation, resulting in a loss of actin stress fibres in cells. PMID- 26571305 TI - Rhinovirus Detection in Symptomatic and Asymptomatic Children: Value of Host Transcriptome Analysis. AB - RATIONALE: Rhinoviruses (RVs) are a major cause of symptomatic respiratory tract infection in all age groups. However, RVs can frequently be detected in asymptomatic individuals. OBJECTIVES: To evaluate the ability of host transcriptional profiling to differentiate between symptomatic RV infection and incidental detection in children. METHODS: Previously healthy children younger than 2 years old (n = 151) were enrolled at four study sites and classified into four clinical groups: RV- healthy control subjects (n = 37), RV+ asymptomatic subjects (n = 14), RV+ outpatients (n = 30), and RV+ inpatients (n = 70). Host responses were analyzed using whole-blood RNA transcriptional profiles. MEASUREMENTS AND MAIN RESULTS: RV infection induced a robust transcriptional signature, which was validated in three independent cohorts and by quantitative real-time polymerase chain reaction with high prediction accuracy. The immune profile of symptomatic RV infection was characterized by overexpression of innate immunity and underexpression of adaptive immunity genes, whereas negligible changes were observed in asymptomatic RV+ subjects. Unsupervised hierarchical clustering identified two main clusters of subjects. The first included 93% of healthy control subjects and 100% of asymptomatic RV+ subjects, and the second comprised 98% of RV+ inpatients and 88% of RV+ outpatients. Genomic scores of healthy control subjects and asymptomatic RV+ children were similar and significantly lower than those of RV+ inpatients and outpatients (P < 0.0001). CONCLUSIONS: Symptomatic RV infection induced a robust and reproducible transcriptional signature, whereas identification of RV in asymptomatic children was not associated with significant systemic transcriptional immune responses. Transcriptional profiling represents a useful tool to discriminate between active infection and incidental virus detection. PMID- 26571307 TI - A Pronator Teres-sparing Volar Approach for Osteosynthesis of Midshaft Diaphyseal Radius Fractures. AB - Henry's approach is widely considered the "workhorse" for exposing the volar radius and has not really changed since his original description in 1945. We describe a pronator teres-sparing volar approach to the forearm, for osteosynthesis of midshaft diaphyseal radius fractures. We believe this approach is safe, simple, and reproducible, and has several practical and theoretical advantages over Henry's original description. PMID- 26571309 TI - A novel HSV-2 subunit vaccine induces GLA-dependent CD4 and CD8 T cell responses and protective immunity in mice and guinea pigs. AB - BACKGROUND/OBJECTIVES: There is currently no licensed prophylactic or therapeutic vaccine for HSV-2 infection. METHODS: We developed a novel preclinical vaccine candidate, G103, consisting of three recombinantly expressed HSV-2 proteins (gD and the UL19 and UL25 gene products) adjuvanted with the potent synthetic TLR4 agonist glucopyranosyl lipid A (GLA) formulated in stable emulsion. The vaccine was tested for immunogenicity and efficacy in pre-clinical models for preventative and therapeutic vaccination. RESULTS: Vaccination of mice with G103 elicited antigen-specific binding and neutralizing antibody responses, as well as robust CD4 and CD8 effector and memory T cells. The T cell responses were further boosted by subsequent challenge with live virus. Prophylactic immunization completely protected against lethal intravaginal HSV-2 infection in mice, with only transient replication of virus in the genital mucosa and sterilizing immunity in dorsal root ganglia. Supporting the use of G103 therapeutically, the vaccine expanded both CD4 and CD8 T cells induced in mice by previous infection with HSV-2. In the guinea pig model of recurrent HSV-2 infection, therapeutic immunization with G103 was approximately 50% effective in reducing the number of lesions per animal as well as the overall lesions score. CONCLUSIONS: Taken together, the data show that G103 is a viable candidate for development of a novel prophylactic and therapeutic HSV-2 vaccine. PMID- 26571310 TI - Reducing pain at the time of vaccination: WHO position paper, September 2015 Recommendations. AB - This article presents the World Health Organization's (WHO) recommendations for pain mitigation at the time of vaccination from the WHO position paper on reducing pain at the time of vaccination: WHO position paper-September 2015, recently published in the Weekly Epidemiological Record [1]. This position paper summarizes the evidence and integrates information pertaining to the reduction of pain, distress and fear during immunization across all age groups. In accordance with its mandate to provide guidance to Member States on health policy matters, WHO issues a series of regularly updated position papers on vaccines and combinations of vaccines against diseases that have an international public health impact, and on vaccination-related policy questions particularly concerning the use of vaccines in large-scale immunization programmes. They summarize essential background information and conclude with the current WHO position. This position paper addresses a cross-cutting issue which is relevant for all injectable vaccines and reflects the recommendations of WHO's Strategic Advisory Group of Experts (SAGE) on immunization. These recommendations were discussed by SAGE at its April 2015 meeting. The evidence presented at the meetings can be accessed at http://www.who.int/immunization/sage/previous/en/index.html. PMID- 26571308 TI - Alpha1a-Adrenoceptor Genetic Variant Triggers Vascular Smooth Muscle Cell Hyperproliferation and Agonist Induced Hypertrophy via EGFR Transactivation Pathway. AB - alpha1a Adrenergic receptors (alpha1aARs) are the predominant AR subtype in human vascular smooth muscle cells (SMCs). alpha1aARs in resistance vessels are crucial in the control of blood pressure, yet the impact of naturally occurring human alpha1aAR genetic variants in cardiovascular disorders remains poorly understood. To this end, we present novel findings demonstrating that 3D cultures of vascular SMCs expressing human alpha1aAR-247R (247R) genetic variant demonstrate significantly increased SMC contractility compared with cells expressing the alpha1aAR-WT (WT) receptor. Stable expression of 247R genetic variant also triggers MMP/EGFR-transactivation dependent serum- and agonist-independent (constitutive) hyperproliferation and agonist-dependent hypertrophy of SMCs. Agonist stimulation reduces contractility Using pathway-specific inhibitors we determined that the observed hyperproliferation of 247R-expressing cells is triggered via beta-arrestin1/Src/MMP-2/EGFR/ERK-dependent mechanism. MMP-2 specific siRNA inhibited 247R-triggered hyperproliferation indicating MMP-2 involvement in 247R-triggered hyperproliferation in SMCs. beta-arrestin1-specific shRNA also inhibited 247R-triggered hyperproliferation but did not affect hypertrophy in 247R-expressing SMCs, indicating that agonist-dependent hypertrophy is independent of beta-arrestin1. Our data reveal that in different cardiovascular cells the same human receptor genetic variant can activate alternative modulators of the same signaling pathway. Thus, our findings in SMCs demonstrate that depending on the type of cells expressing the same receptor (or receptor variant), different target-specific inhibitors could be used to modulate aberrant hyperproliferative or hypertrophic pathways in order to restore normal phenotype. PMID- 26571311 TI - Schistosomiasis vaccine candidate Sm14/GLA-SE: Phase 1 safety and immunogenicity clinical trial in healthy, male adults. AB - DESIGN: Safety and immunogenicity of a recombinant 14kDa, fatty acid-binding protein(FABP) from Schistosoma mansoni (rSm14) were evaluated through an open, non-placebo-controlled, dose-standardized trial, performed at a single research site. The vaccine was formulated with glucopyranosyl lipid A (GLA) adjuvant in an oil-in-water emulsion (SE) and investigated in 20 male volunteers from a non endemic area for schistosomiasis in the state of Rio de Janeiro, Brazil. Fifty microgram rSm14 with 10 MUg GLA-SE (rSm14/GLA-SE)/dose were given intramuscularly three times with 30-day intervals. Participants were assessed clinically, biochemically and immunologically for up to 120 days. METHODS: Participants were screened for inclusion by physical examination, haematology and blood chemistry; then followed to assess adverse events and immunogenicity. Sera were tested for IgG (total and isotypes) and IgE. T cell induction of cytokines IL-2, IL-5, IL 10, IFNgamma and TNFalpha was assessed by Milliplex kit and flow cytometry. RESULTS: The investigational product showed high tolerability; some self-limited, mild adverse events were observed during and after vaccine administration. Significant increases in Sm14-specific total IgG, IgG1 and IgG3 were observed 30 days after the first vaccination with specific IgG2 and IgG4 after 60 days. An increase in IgE antibodies was not observed at any time point. The IgG response was augmented after the second dose and 88% of all vaccinated subjects had developed high anti-Sm14 IgG titres 90 days after the first injection. From day 60 and onwards, there was an increase in CD4(+) T cells producing single cytokines, particularly TNFalpha and IL-2, with no significant increase of multi functional TH1 cells. CONCLUSION: Clinical trial data on tolerability and specific immune responses after vaccination of adult, male volunteers in a non endemic area for schistosomiasis with rSm14/GLA-SE, support this product as a safe, strongly immunogenic vaccine against schistosomiasis paving the way for follow-up Phase 2 trials. Study registration ID: NCT01154049 at http://www.clinicaltrials.gov. PMID- 26571312 TI - Role of Oxidative Stress in Male Reproductive Dysfunctions with Reference to Phthalate Compounds. AB - PURPOSE: A wide variety of environmental chemicals/xenobiotics including phthalates have been shown to cause oxidative stress targeting the endocrine system and cause reproductive anomalies. The present review describes various issues by oxidative stress causing male reproductive dysfunctions. Here in this review, the importance and role of phthalate compounds in male reproductive dysfunction has been well documented. MATERIALS AND METHODS: One class of environmental endocrine disruptors is phthalates. Phthalate compounds are mostly used as plasticizers, which increase the flexibility, durability, longevity, and etc. of the plastics. Large-scale use of plastic products in our daily life as well as thousands of workers engaged in the manufacture of plastic and plastic products and recycling plastic industry are potentially exposed to these chemicals. Further, general population as well as vulnerable groups i.e. children and pregnant women are also exposed to these chemicals. Phthalates are among wide variety of environmental toxicants capable of compromising male fertility by inducing a state of oxidative stress in the testes. They may also generate reactive oxygen species (ROS) that may affect various physiological and reproductive functions. RESULTS: The available data points out that phthalate compounds may also induce oxidative stress in the male reproductive organs mainly testis and epididymis. They impair spermatogenic process by inducing oxidative stress and apoptosis in germ cells or target sertoli cells and thereby hamper spermatogenesis. They also impair the Leydig cell function by inducing ROS, thereby decreasing the levels of steroidogenic enzymes. CONCLUSION: Thus in utero and postnatal exposure to phthalate compounds might lead to decreased sperm count and various other reproductive anomalies in the young male. PMID- 26571313 TI - Factors Influencing Complications of Percutaneous Nephrolithotomy: A Single Center Study. AB - PURPOSE: Percutaneous nephrolithotomy (PNL) is a minimally invasive procedure used for successful treatment of renal calculi. However, it is associated with various complications. We assessed the complications and their potential influencing factors in patients who had undergone PNL. MATERIALS AND METHODS: In total, 1750 patients who had undergone PNL from November 2003 to June 2011 were evaluated retrospectively. PNL complications and possible contributing risk factors (age, sex, serum creatinine level, previous operations, hydronephrosis, calculi size, localization, opacity, surgeon's experience, accessed calyxes, number of accesses, and costal entries) were determined. Receiver operating characteristic (ROC) analysis was used to investigate the cutoff values of the data. Ideal cutoff value was determined by Youden's J statistic. All the demographic and clinical variables were examined using backward stepwise logistical regression analysis. Continuous variables were categorized with logistic regression analysis according to the cutoff values. RESULTS: Complications occurred in 396 (24.4%) patients who had undergone PNL. Hemorrhage requiring blood transfusion occurred in 221 (12.6%) patients, hemorrhage requiring arterial embolization occurred in 7 (0.4%) patients, perirenal hematoma occurred in 17 (0.97%) patients, hemo-pneumothorax occurred in 32 (1.8%) patients, and colon perforation occurred in 4 (0.22%) patients. Three patients (0.06%) died of severe urosepsis, and one patient (0.02%) died of severe bleeding. The calculus size, localization, access site, number of accesses, presence of staghorn stones, surgeon's experience, and duration of the operation significantly affected the complication risk. CONCLUSION: Our retrospective evaluation of this large patient series reveals that, PNL is a very effective treatment modality for kidney stones. However, although rare, serious complications including death can occur. PMID- 26571314 TI - Core Length: An Alternative Method for Increasing Cancer Detection Rate in Patients with Prostate Cancer. AB - PURPOSE: We determine whether the lengths of benign and malignant cores affect cancer detection rates in patients with prostate cancer (PCa). MATERIALS AND METHODS: We evaluated retrospectively 512 patients in our clinic who had undergone 12 core transrectal ultrasound (TRUS)-guided prostate biopsies. The cores were divided into two groups: one with cancer (group 1) and one without cancer (group 2). We also classified Gleason scores as poorly differentiated (scores of 7-10) and moderately differentiated (scores of 5-6); these scores were compared with each other in terms of the core length. The core lengths of the groups were compared using a Student's t-test. A P value of less than .05 was considered to be statistically significant. RESULTS: Of the 512 patients, 76 (15%) had PCa. In total, we evaluated 912 cores of prostate biopsy samples from the 76 patients. Since 92 cores included insufficient tissue and rectal mucosa, we were not able to evaluate them. The remaining 820 cores were divided into two groups. Cancer was detected in 302 cores; 518 cores were benign in nature. The average core length in group 1 was 11.9 +/- 4.4 mm, and the average core length in group 2 was 11.1 +/- 5.1 mm (P = .015). The core lengths of poorly differentiated and moderately differentiated cancers were similar: 12.3 +/- 4.2 mm and 11.7 +/- 4.5 mm, respectively (P = .25). CONCLUSION: Increasing cancer detection rates in cores may be related to core length in TRUS-guided prostate biopsies in PCa patients. PMID- 26571315 TI - Diagnostic Yield and Complications Using a 20 Gauge Prostate Biopsy Needle versus a Standard 18 Gauge Needle: A Randomized Controlled Study. AB - PURPOSE: To compare and evaluate whether a 20 gauge (20G) biopsy needle maintains a similar detection rate as that of the commonly used 18G needle for transrectal ultrasound-guided prostate biopsy (TRUSPB) aimed at assessing prostate cancer (PCa) and decreasing pain and complications. MATERIALS AND METHODS: A total of 122 cases with indications of PCa were randomly allocated into two groups for this randomized controlled study. TRUSPB was performed randomly using either an 18G or 20G needle for core biopsies (62 cases with 18G and 60 cases with 20G). Detection rate, pain, and complications were assessed after the procedure. RESULTS: The cancer detection rate in the 18G group (40.3%) did not differ from that in the 20G group (35.0%). However, the number of patients with pain was significantly lower in 20G group (P < 0.05). The number of patients with self limiting hematuria decreased in both groups after the biopsy procedure (18G: 38 cases; 20G: 16 cases; P < .0001). Hematochezia occurred in 11 cases (9 cases [14.5%] in the 18G group; 2 cases [3.4%] in the 20G group). The number of patients with infection, dysuria, and urinary retention tended to be lower in 20G group. CONCLUSION: Use of a 20G needle for TRUSPB yielded a comparable cancer detection rate to that of an 18G needle and led to less local injury, pain, and complications. A larger and more sensitive study is needed to verify our results. PMID- 26571316 TI - Double Tension Adjustments with Novel Modification on Tension-Free Vaginal Tape. AB - OBJECTIVE: To evaluate the results of novel modifications on tension- free vaginal tape (TVT) for the treatment of women with stress urinary incontinence (SUI). MATERIALS AND METHODS: Sixteen female patients (average age 49.29 years, range: 31-78) who underwent anti-incontinence surgery to correct their SUI in the period between June 2010 and August 2014 were included in the study. In situ anterior vaginal wall sling was prepared, and monofilament polypropylene tape passed below the in situ-sling and standard TVT procedure was performed. Both ends of the mesh in the suprapubic region were labeled with Vicryl sutures and left outside the wound. The middle of the mesh in the vaginal region were labeled with similar suture and left outside the vagina. Foley catheter was removed on the third postoperative day. The average period of follow-up was 8 months (range: 5-17). RESULTS: All patients benefited from the surgery; 15 (94%) of them completely cured and one patient clinically improved. Urinary retention was observed in one patient where the tension of the tape was reduced using adjustment sutures. No vaginal mesh erosion was detected during the gynecological examination postoperatively. No significant post-voiding residue was detected after catheter removal. CONCLUSION: This technique gives feasible option to adjust the tension of the mesh in the early post-operative period in case of urinary retention. Presence of intervening in situ sling reduces the risk of vaginal erosions. Long-term success is expected because dislocation of the mid urethral sling is less likely. PMID- 26571317 TI - Comparison of Sexual Functions in Pregnant and Non-Pregnant Women. AB - PURPOSE: The physiology and anatomy of pregnant women change during pregnancy. Pregnancy is an anatomically and physiologically amended process experienced by women and as a result of these changes, sexual life of pregnant women alters during pregnancy. We aimed to compare sexual functions of pregnant and non pregnant women. MATERIALS AND METHODS: Sexually active 246 pregnant women were included into this cross-sectional controlled study. A total of 210 non-pregnant women were served as control. Both groups were compared in terms of age, gestational age, presence of urinary incontinence, body mass index, and obstetrical history. Sexual functions of the women were evaluated with Female Sexual Function Index (FSFI). Data were analyzed using chi-square, Mann-Whitney U, Fisher's Exact, Shapiro Wilk, Kruskal Wallis and Dunnett's tests where appropriate. The Pvalues < .05 were considered statistically significant. RESULTS: Mean age in both groups were comparable (P = .053). Median total FSFI scores in the pregnant women were significantly lower than those non-pregnant (18.9 vs. 22.7; P < .05). Additionally, the subgroup analyses of the FSFI scores were found that, total FSFI score is significantly lower in the pregnant group compared to non-pregnant group (P < .05). Furthermore, rate of sexual dysfunction in pregnant women was significantly higher than those non-pregnant women (91.08% vs. 67.61%, P = .0001). However, in pregnant women, no meaningful difference in rate of sexual dysfunction was found according to the trimesters (P = .632). Moreover, gravidity and parity exhibited negative impacts on the sexual functions. But number of abortions did not affect sexual function. CONCLUSION: These data demonstrate that pregnancy significantly diminishes sexual function in women. We believe that, couples need to be counseled regarding the impact of pregnancy on sexual functions. PMID- 26571318 TI - Re:Comparison of Sexual Functions in Pregnant and Non-Pregnant Women. PMID- 26571319 TI - Erectile Dysfunction Is Positively Correlated with Mean Platelet Volume and Platelet Count, but Not with Eosinophil Count in Peripheral Blood. AB - PURPOSE: Increased eosinophil count (EC), mean platelet volume (MPV), and platelet count (PC) are important in vascular disorders which are main factors resulting in endothelial dysfunction. We aimed to investigate the association between MPV, and EC, with erectile dysfunction (ED). MATERIALS AND METHODS: Two hundred thirty participants (130 patients with ED, and 100 healthy controls) were enrolled in this study. A detailed psychosexual history obtained, and physical, and laboratory examination were performed. International Index of Erectile Function (IIEF)-5 questionnaire was used to evaluate the erectile status objectively. IIEF-5 score was applied to all patients, and IIEF-5 score under 22 was considered as ED. The MPV, PC, and EC were compared between the two groups. RESULTS: The mean age of the patients with ED and control group was 55.62 +/- 8.90 years and 54.19 +/- 4.10 years, respectively. MPV and PC levels were significantly higher in ED group (8.51+/- 1.00 fL and 8.16 +/- 0.94 fL; 244.59 +/ 57.3 cells/uL and 230.17 +/- 48.44 cells/uL, respectively (P < .05). EC and white blood cell count were not significantly different between study and control groups. CONCLUSIONS: In our study a relationship was found between elevated MPV, and PC with ED. MPV and PC may be used as a biomarker in patients with ED. PMID- 26571320 TI - Re: Erectile Dysfunction Is Positively Correlated with Mean Platelet Volume and Platelet Count, But Not with Eosinophil Count in Peripheral Blood. PMID- 26571321 TI - 980-Nm Diode Laser Vaporization versus Transurethral Resection of the Prostate for Benign Prostatic Hyperplasia: Randomized Controlled Study. AB - PURPOSE: We compared the effectiveness and complications of 980-nm diode laser vaporization and transurethral resection of the prostate (TURP) in patients with benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: In total, 72 consecutive patients with BPH entered the study. All patients underwent general and urological evaluations. The primary outcome was improvement in the International Prostate Symptom Score (IPSS). The secondary outcomes were IPSS quality of life (QoL), maximum urinary flow rate (Qmax), residual volume, and complications. Patients were allocated randomly to the TURP and laser groups. The Ceralas HPD120, a diode laser system emitting at a wavelength of 980 nm, was used for photoselective vaporization of the prostate (PVP). TURP was performed with a monopolar 26 French resectoscope. Preoperative and operative parameters and surgical outcomes were compared. RESULTS: In total, 36 patients in each group underwent PVP and TURP. The mean age +/- standard deviation was 63.1 +/- 9.1 years and 64.7 +/- 10.2 years in the PVP and TURP groups, respectively. There were no statistically significant differences in age, prostate size, prostate specific antigen concentration, Qmax, preoperative IPSS, or preoperative Qmax between the two groups. The operation duration was also similar between the groups (P = .36). The catheterization time was 1.45 +/- 0.75 and 2.63 +/- 0.49 days in the PVP and TURP groups, respectively (P < .01). The PVP group had a shorter hospital stay than the TURP group. The 3-month postoperative Qmax increased to 9.90 +/- 3.61 and 6.59 +/- 6.06 mL/s from baseline in the TURP and PVP groups, respectively; there was no difference in the increases between the groups (P = .08). The IPSS and IPSS-QoL were significantly improved with the operation (P < .01), and this improvement was similar in both groups P = .3 and P = .8, respectively . The complication rate was also similar between the two groups. CONCLUSIONS: PVP with a diode laser is as safe and effective as TURP in the treatment of BPH, and the techniques have similar complication rates and functional results. PVP has the advantage of shorter hospitalization and catheter indwelling times and no need for discontinuation of anticoagulant therapy. PMID- 26571322 TI - Use of Lidocaine 2% Gel Does Not Reduce Pain during Flexible Cystoscopy and Is Not Cost-Effective. AB - PURPOSE: To compare the use of lubricant gel with lidocaine versus lubricant gel without anesthetic in flexible cystoscopy in terms of pain and tolerability. MATERIALS AND METHODS: In this observational non-randomized study, 72 patients were divided into two groups. Group 1 included 38 patients in whom lidocaine gel 2% was used and group 2 included 34 patients in whom lubricant gel without anesthetic was administered. The main variables analyzed were score in visual analogue scale (VAS) and score in Spanish Pain Questionnaire (SPQ). Student's t test and Chi-square test were used to compare differences between 2 groups. The P values < .05% were considered statistically significant. RESULTS: Mean age of patients in group 1 was 64.50 +/- 12.39 years and 67.79 +/- 10.87 years in group 2 (P = .23). The distribution according to sex was 29 men and 9 women in group 1 and 25 men and 9 women in group 2 (P = .78). The total VAS score was 2.21 +/- 2.05 in group 1 versus 1.59 +/- 1.61 in group 2 (P = .16). In the SPQ, the current intensity value was 1.82 +/- 0.86 in group 1 versus 1.53 +/- 0.74 in group 2 (P = .14), and the total intensity value was 1.92 +/- 1.86 in group 1 versus 1.03 +/- 1.75 in group 2 (P = .04). The cost of gel with lidocaine is 1.25 euro and gel without anesthetic 0.22 euro. CONCLUSION: The use of lidocaine gel does not produce benefit in terms of pain relief in flexible cystoscopy and also is costly. PMID- 26571323 TI - Effect of Preoperative Forced-Air Warming on Hypothermia in Elderly Patients Undergoing Transurethral Resection of the Prostate. AB - PURPOSE: Elderly patients under spinal anesthesia are vulnerable to hypothermia, leading to increased morbidity. The aim of this study was to investigate the effects of preoperative forced-air warming on perioperative hypothermia and shivering in elderly patients undergoing transurethral resection of the prostate (TURP) under spinal anesthesia. MATERIALS AND METHODS: Patients (> 65-year-old) scheduled for TURP under spinal anesthesia were randomly assigned to receive preoperative forced-air skin warming for 20 min (the pre-warmed group, n = 25) or not (control group, n = 25). Core temperatures were measured at 15-min intervals after spinal anesthesia, and intra- and post-operative shivering were also assessed. RESULTS: Incidences of intraoperative hypothermia (< 36 oC) in the pre warmed and control groups were not significantly different (10/25 [40%] vs. 15/24 [62.5%], P = .259). However, severities of hypothermia were significantly different (P = .019). No patient in the pre-warmed group showed moderate or profound hypothermia, whereas of patients in control group 21% and 13% did so, respectively. CONCLUSION: This study demonstrated that a brief period of preoperative forced-air warming did not completely prevent intraoperative hypothermia or shivering, but it could significantly reduce its severity in elderly male patients under spinal anesthesia. PMID- 26571324 TI - Benign Prostatic Hyperplasia Treatment with New Physiotherapeutic Device. AB - PURPOSE: Thermobalancing therapy, provided by Therapeutic Device, which contains a natural thermoelement, and is applied topically in the projection ofthe prostate,was aimed to improve blood circulation in the affected organ. We evaluated the effectiveness of new Therapeutic Device for the treatment of patients with benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: We performed a clinical non-randomized controlled trial before and after 6-month treatment. Therapeutic Device was administered to 124 patients with BPH as mono therapy. The dynamic of the patients' condition was assessed by the International Prostate Symptom Score (IPSS), ultrasound measurement of prostate volume (PV) and uroflowmetry. The control-group comprised 124 men who did not receive any treatment. The IPSS score, maximum flow rate (Qmax), and PV were compared between the groups. RESULTS: Baseline evaluation (pre-treatment) for both groups were comparable to each other with no clinically significant difference regarding age, IPSS score, Qmax and PV volume. Overall, thermobalancing therapy resulted in significant improvements from baseline to endpoint in IPSS (P = .001), IPSS storage and voiding subscores (both P = .001), and IPSS quality of life index (QoL) (P = .001) compared with control group. Moreover, comparison of parameters after 6 months treatment showed that thermobalancing therapy also improved the Qmax (P = .001), and PV (P = .001). CONCLUSION: Two years clinical trial demonstrated that thermobalancing therapy administered for 6 months provides a marked improvement in patients presenting with symptomatic BPH not only on lower urinary tract symptoms (LUTS) but also in QoL and Qmax. Thus urologists should be aware about thermobalancing therapy as a non-invasive physiotherapeutic treatment option for treatment of BPH. PMID- 26571325 TI - Ileo-Cavernosal Fistula after Radiotherapy: A Case Report and Review of the Literature. PMID- 26571326 TI - Behcet's Disease Detecting by Attacks of Recurrent Epididymo-Orchitis: Case Reports. PMID- 26571327 TI - Brunn's Cyst: A Rare Cause of Bladder Outlet Obstruction in a Young Man. PMID- 26571328 TI - The socioeconomic profile of a Barrett's oesophagus cohort assessed by the 2010 Index of Multiple Deprivation. AB - BACKGROUND: Several reports have described the relationship between socioeconomic status and oesophageal adenocarcinoma but only one with its precursor condition, Barrett's oesophagus. We therefore investigated such an association. PATIENTS: The majority (88%) of patients diagnosed with Barrett's at Rotherham District General Hospital between 28 April 1978 and 31 August 2012 consented to inclusion in the UK Barrett's Oesophagus Registry. Those residing within Rotherham form the basis of this study. METHODS: We assessed socioeconomic status using the Index of Multiple Deprivation 2010 scores which can be assigned to every English postcode. The scores for the whole of England were divided into five equal groups; those of the 6257 postcodes within Rotherham (including those of Barrett's patients) were compared against the national quintile relevant to their score. We examined the ratio of observed against expected numbers of Barrett's in each quintile before and since 2001, the median year of diagnosis. RESULTS: The study group comprised 1076 patients with Barrett's oesophagus. Before 2001 their distribution across the deprivation quintiles was similar to that expected. Since then it has changed significantly, with 37% more Barrett's patients than expected among the two least deprived quintiles, but 11% fewer than expected in the larger population comprising the two most deprived quintiles (P=0.0001). There was no significant difference in the distribution of sex (P=0.27), nor the mean age at diagnosis between the two time periods (P=0.92). CONCLUSION: Since 2001, there has been a major change in the distribution of Barrett's in relation to socioeconomic status, measured by the Index of Multiple Deprivation. PMID- 26571329 TI - Is intramedullary nailing superior to plating in patients with extraarticular fracture of the distal tibia? AB - Distal tibial metaphyseal fractures are generally produced by high-energy trauma such as car accidents and can cause severe disability due to pain and deformity. In the management of these fractures, there are multiple surgical alternatives, but it is uncertain which the best option is. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified six systematic reviews including three randomized trials. We combined the evidence using meta-analysis and generated a summary of findings table following the GRADE approach. We concluded it is not clear whether one surgical option is better than the other, because the certainty of the evidence is very low. Two ongoing randomized trials might help solving this uncertainty. PMID- 26571330 TI - Tuning a Lanthanide Complex To Be Responsive to the Environment in Solution. AB - The f-f emissions of lanthanide-ion complexes have predictable emission energies and many practical applications, but the emitting states are generally impervious to the surroundings. This investigation explores ligand- and metal-centered emission processes for a series of mixed-ligand complexes of composition M(X T)(NO3)3, where the metal ion is europium, gadolinium, terbium, or lutetium, and X-T denotes the tridentate ligand 2,2':6',2"-terpyridine (H-T), 4'-phenyl 2,2':6',2"-terpyridine (Ph-T), or 4'-pyrrolidin-N-yl-2,2':6',2"-terpyridine (pyrr T). The presence of the pyrrolidinyl substituent imparts intraligand charge transfer (ILCT) character to the ligand-based excited states and reduces the energy gap between the singlet and the triplet excited states. An enhanced rate of intersystem crossing results in a lutetium complex with a relatively small fluorescence quantum yield (0.15%) and a gadolinium complex with an impressive phosphorescence yield of 9.6% in deaerated solution. The Tb(pyrr-T)(NO3)3 system is unique because the relatively low-energy triplet ILCT state equilibrates with the emissive f-f state. The result is a truly remarkable f-f emission signal that is sensitive to the polarity of the local environment as well as the presence of dioxygen. PMID- 26571331 TI - Two New Species of the Family Syringophilidae (Prostigmata: Syringophilidae) Parasitising Bushshrikes (Passeriformes: Malaconotidae). AB - Two new species of quill mites of the subfamily Syringophilinae Lavoipierre (Acari: Prostigmata: Syringophilidae) are described from the Bushshrikes (Passeriformes: Malaconotidae) in the Afrotropical region: Neoaulonastus malaconotus n. sp. parasitizing Telophorus nigrifrons (Reichenow) (Malaconotidae) [type host] in Liberia and Kenya, Laniarius aethiopicus (Gmelin) in Somalia, Nilaus afer (Latham) in Kenya, and Syringophiloidus nkaii n. sp. from Nilaus afer in Kenya. PMID- 26571332 TI - Systematic Review of Chromium and Nickel Exposure During Pregnancy and Impact on Child Outcomes. AB - Some forms of chromium (Cr) and nickel (Ni) are toxic, especially with chronic elevated exposure, and certain forms such as hexavalent chromium or nickel carbonyl were labeled as carcinogens. Since both metals are naturally occurring, and used in industrial processes, individuals may be exposed through ingestion of contaminated food or water, inhalation, or dermal contact. This study focused on the impact of toxic forms of Cr and Ni during pregnancy and outcomes in newborn and young children. A systematic literature review following "The Navigation Guide" was applied, and 16 reports that satisfied the inclusion criteria were scored. Six papers studied birth weight, prematurity, or gestational age: one found an association between Ni and small for gestational age, while another linked Ni with low birth weight; however, four reported no marked associations. Of six studies that examined birth defects, three found no significant associations; one noted an association between Ni and neural tube defects; one showed an association between Ni and structural birth defects; and one reported a weak effect for Cr exposure and musculoskeletal defects. In the remaining four studies, weak associations were found for hexavalent Cr and neuroblastoma, Ni and autism spectrum disorder, Cr and Ni and DNA damage, and Cr and lymphocyte damage. Among the studies that were rated as good for execution and reliability, there was weak evidence of an association between Ni and autism spectrum disorder and small for gestational age, but no significant association between Cr and a child outcome. PMID- 26571333 TI - Removal of a wide range of emerging pollutants from wastewater treatment plant discharges by micro-grain activated carbon in fluidized bed as tertiary treatment at large pilot scale. AB - Among the solutions to reduce micropollutant discharges into the aquatic environment, activated carbon adsorption is a promising technique and a large scale pilot has been tested at the Seine Centre (240,000 m(3)/d - Paris, France) wastewater treatment plant (WWTP). While most of available works studied fixed bed or contact reactors with a separated separation step, this study assesses a new type of tertiary treatment based on a fluidized bed containing a high mass of activated carbon, continuously renewed. For the first time in the literature, micro-grain activated carbon (MUGAC) was studied. The aims were (1) to determine the performances of fluidized bed operating with MUCAG on both emerging micropollutants and conventional wastewater quality parameters, and (2) to compare its efficiency and applicability to wastewater to former results obtained with PAC. Thus, conventional wastewater quality parameters (n=11), pharmaceuticals and hormones (PPHs; n=62) and other emerging pollutants (n=57) have been monitored in MUGAC configuration during 13 campaigns. A significant correlation has been established between dissolved organic carbon (DOC), PPHs and UV absorbance at 254 nm (UV-254) removals. This confirms that UV-254 could be used as a tertiary treatment performance indicator to monitor the process. This parameter allowed identifying that the removals of UV-254 and DOC reach a plateau from a MUGAC retention time (SRT) of 90-100 days. The MUGAC configuration substantially improves the overall quality of the WWTP discharges by reducing biological (38-45%) and chemical oxygen demands (21-48%), DOC (13-44%) and UV-254 (22-48%). In addition, total suspended solids (TSS) are retained by the MUGAC bed and a biological activity (nitratation) leads to a total elimination of NO2(-). For micropollutants, PPHs have a good affinity for MUGAC and high (>60%) or very high (>80%) removals are observed for most of the quantified compounds (n=22/32), i.e. atenolol (92-97%), carbamazepine (80-94%), ciprofloxacin (75-95%), diclofenac (71-97%), oxazepam (74-91%) or sulfamethoxazole (56-83%). In addition, alkylphenols, artificial sweeteners, benzotriazole, bisphenol A, personal care products (triclocarban and parabens) and pesticides have removals lying in the 50 ->90% range. Overall, the fluidized bed of MUGAC allows obtaining performances comparable to PAC at the same activated carbon dose. Indeed, the average removal of the 13 PPHs found at a high occurrence (>75%) in WWTP discharges is similar at 20 g/m(3) of MUGAC (78-89%) and PAC (85-93%). In addition, this recycled MUGAC operation leads to several operational advantages (no FeCl3, reactivable, higher SRT, higher treated flow) and has a stronger impact on the overall wastewater quality compared to PAC. PMID- 26571334 TI - Clinical Decision Support for Nurses: A Fall Risk and Prevention Example. AB - Clinical decision support tools in electronic health records have demonstrated improvement with process measures and clinician performance, predominantly for providers. Clinical decision support tools could improve patient fall risk identification and prevention plans, a common concern for nursing. This quality improvement project used clinical decision support to improve the rate of nurse compliance with documented fall risk assessments and, for patients at high risk, fall prevention plans of care in 16 adult inpatient units. Preintervention and postintervention data were compared using quarterly audits, retrospective chart review, safety reports, and falls and falls-with-injury rates. Documentation of fall risk assessments on the 16 units improved significantly according to quarterly audit data (P = .05), whereas documentation of the plans of care did not. Retrospective chart review on two units indicated improvement for admission fall risk assessment (P = .05) and a decrease in the documentation of the shift plan of care (P = .01); one unit had a statistically significant decrease in documentation of plans of care on admission (P = .00). Examination of safety reports for patients who fell showed all patients before and after clinical decision support had fall risk assessments documented. Falls and falls with injury did not change significantly before and after clinical decision support intervention. PMID- 26571335 TI - Pilot Test of a Culturally Sensitive Hypertension Management Intervention Protocol for Older Chinese Immigrants: Chinese Medicine as Longevity Modality. AB - Hypertension control in older Chinese immigrants remains a significant health issue because of their unique cultural health practices to manage their hypertension. At present, there are limited culturally sensitive health education materials regarding hypertension management tailored for the older Chinese population available for and feasible to use. Because the San Francisco Bay Area has a large population of older Chinese immigrants, development of a culturally appropriate intervention is important to help this population achieve better blood pressure control. The focus of this study was to develop and test the feasibility of a culturally sensitive hypertension management intervention protocol, Chinese Medicine as Longevity Modality. This intervention protocol is implemented as a patient education health program delivered via video format in combination with an individual consultation provided by a nurse in the initial intervention, followed by four phone calls between the initial intervention and the second follow-up visit. The results of the study showed that the proposed intervention protocol was acceptable for the target population. PMID- 26571336 TI - Oxidation of NADH and ROS production by respiratory complex I. AB - Kinetic characteristics of the proton-pumping NADH:quinone reductases (respiratory complexes I) are reviewed. Unsolved problems of the redox-linked proton translocation activities are outlined. The parameters of complex I mediated superoxide/hydrogen peroxide generation are summarized, and the physiological significance of mitochondrial ROS production is discussed. This article is part of a Special Issue entitled Respiratory complex I, edited by Volker Zickermann and Ulrich Brandt. PMID- 26571337 TI - An unusual duodenal cyst: Brunner's glands cystadenoma. PMID- 26571338 TI - Analysis of Past and Present Synthetic Methodologies on Medicinal Chemistry: Where Have All the New Reactions Gone? AB - An analysis of chemical reactions used in current medicinal chemistry (2014), three decades ago (1984), and in natural product total synthesis has been conducted. The analysis revealed that of the current most frequently used synthetic reactions, none were discovered within the past 20 years and only two in the 1980s and 1990s (Suzuki-Miyaura and Buchwald-Hartwig). This suggests an inherent high bar of impact for new synthetic reactions in drug discovery. The most frequently used reactions were amide bond formation, Suzuki-Miyaura coupling, and SNAr reactions, most likely due to commercial availability of reagents, high chemoselectivity, and a pressure on delivery. We show that these practices result in overpopulation of certain types of molecular shapes to the exclusion of others using simple PMI plots. We hope that these results will help catalyze improvements in integration of new synthetic methodologies as well as new library design. PMID- 26571339 TI - Gender differences in psychopathy links to drug use. AB - Although the relationship between psychopathic personality traits and substance use has received some attention (Hart & Hare, 1989; Smith & Newman, 1990), gender differences have not been thoroughly assessed. The current study examined whether gender modified the relationship between 2 criminally relevant constructs, (a) psychopathy and its factors and (b) drug use. A sample of 318 participants with criminal histories and recent substance use was assessed for psychopathy using the Psychopathy Checklist: Screening Version and for illicit drug use using the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders. As expected, the impulsive-antisocial traits (Factor 2) of psychopathy were positively related to a number of drug use characteristics (symptoms, age of drug initiation, extent of drug experimentation), whereas the interpersonal affective traits (Factor 1) showed a negative relationship with drug abuse symptoms and a positive relationship with age of first use. In terms of gender differences, analyses revealed that women showed a stronger association between Factor 1 traits and later age of initiation compared to men, and that Factor 2, and the antisocial facet in particular, were more strongly related to drug abuse in women than men. These findings suggest that psychopathic traits serve as both protective (Factor 1) and risk (Factor 2) correlates of illicit drug use, and Factor 1 may be especially protective in terms of initiation of drug use among women. These conclusions add to the growing literature on potential routes to substance use and incarceration in women. PMID- 26571340 TI - Dissecting Proton Delocalization in an Enzyme's Hydrogen Bond Network with Unnatural Amino Acids. AB - Extended hydrogen bond networks are a common structural motif of enzymes. A recent analysis proposed quantum delocalization of protons as a feature present in the hydrogen bond network spanning a triad of tyrosines (Y(16), Y(32), and Y(57)) in the active site of ketosteroid isomerase (KSI), contributing to its unusual acidity and large isotope shift. In this study, we utilized amber suppression to substitute each tyrosine residue with 3-chlorotyrosine to test the delocalization model and the proton affinity balance in the triad. X-ray crystal structures of each variant demonstrated that the structure, notably the O-O distances within the triad, was unaffected by 3-chlorotyrosine substitutions. The changes in the cluster's acidity and the acidity's isotope dependence in these variants were assessed via UV-vis spectroscopy and the proton sharing pattern among individual residues with (13)C nuclear magnetic resonance. Our data show pKa detuning at each triad residue alters the proton delocalization behavior in the H-bond network. The extra stabilization energy necessary for the unusual acidity mainly comes from the strong interactions between Y(57) and Y(16). This is further enabled by Y(32), which maintains the right geometry and matched proton affinity in the triad. This study provides a rich picture of the energetics of the hydrogen bond network in enzymes for further model refinement. PMID- 26571341 TI - Long-Term Incubation Reveals Methanogenic Biodegradation of C5 and C6 iso-Alkanes in Oil Sands Tailings. AB - iso-Alkanes are major components of petroleum and have been considered recalcitrant to biodegradation under methanogenic conditions. However, indigenous microbes in oil sands tailings ponds exposed to solvents rich in 2-methylbutane, 2-methylpentane, 3-methylpentane, n-pentane, and n-hexane produce methane in situ. We incubated defined mixtures of iso- or n-alkanes with mature fine tailings from two tailings ponds of different ages historically exposed to different solvents: one, ~10 years old, receiving C5-C6 paraffins and the other, ~35 years old, receiving naphtha. A lengthy incubation (>6 years) revealed iso alkane biodegradation after lag phases of 900-1800 and ~280 days, respectively, before the onset of methanogenesis, although lag phases were shorter with n alkanes (~650-1675 and ~170 days, respectively). 2-Methylpentane and both n alkanes were completely depleted during ~2400 days of incubation, whereas 2 methylbutane and 3-methylpentane were partially depleted only during active degradation of 2-methylpentane, suggesting co-metabolism. In both cases, pyrotag sequencing of 16S rRNA genes showed codominance of Peptococcaceae with acetoclastic (Methanosaeta) and hydrogenotrophic (Methanoregula and Methanolinea) methanogens. These observations are important for predicting long-term greenhouse gas emissions from oil sands tailings ponds and extend the known range of hydrocarbons susceptible to methanogenic biodegradation in petroleum-impacted anaerobic environments. PMID- 26571342 TI - Electrodeposited Structurally Stable V2O5 Inverse Opal Networks as High Performance Thin Film Lithium Batteries. AB - High performance thin film lithium batteries using structurally stable electrodeposited V2O5 inverse opal (IO) networks as cathodes provide high capacity and outstanding cycling capability and also were demonstrated on transparent conducting oxide current collectors. The superior electrochemical performance of the inverse opal structures was evaluated through galvanostatic and potentiodynamic cycling, and the IO thin film battery offers increased capacity retention compared to micron-scale bulk particles from improved mechanical stability and electrical contact to stainless steel or transparent conducting current collectors from bottom-up electrodeposition growth. Li(+) is inserted into planar and IO structures at different potentials, and correlated to a preferential exposure of insertion sites of the IO network to the electrolyte. Additionally, potentiodynamic testing quantified the portion of the capacity stored as surface bound capacitive charge. Raman scattering and XRD characterization showed how the IO allows swelling into the pore volume rather than away from the current collector. V2O5 IO coin cells offer high initial capacities, but capacity fading can occur with limited electrolyte. Finally, we demonstrate that a V2O5 IO thin film battery prepared on a transparent conducting current collector with excess electrolyte exhibits high capacities (~200 mAh g( 1)) and outstanding capacity retention and rate capability. PMID- 26571343 TI - Sinigrin, a major glucosinolate from cruciferous vegetables restrains non enzymatic glycation of albumin. AB - Sinigrin is a major component of cruciferous vegetables such as cabbage, Brussels sprout, mustard greens and broccoli. The present study demonstrates the protective effects of sinigrin against the non-enzymatic glycation of albumin and lens crystallin based on fluorescence spectroscopy, circular dichroism and molecular interaction studies. Sinigrin was found to be a potent inhibitor for both the early (Amadori product) and advanced glycation end products (AGEs). In addition, the in vitro glycation studies of lens crystallin demonstrated the strong antiglycation activity of sinigrin. Computational studies using molecular docking approach revealed the interaction pattern of sinigrin with BSA and the binding affinity of sinigrin was found to be greater than the other potent natural inhibitors of glycation such as quercetin, apigenin, and curcumin. PMID- 26571344 TI - Role of the crystalline form of titanium dioxide nanoparticles: Rutile, and not anatase, induces toxic effects in Balb/3T3 mouse fibroblasts. AB - The wide use of titanium dioxide nanoparticles (TiO2 NPs) in industrial applications requires the investigation of their effects on human health. In this context, we investigated the effects of nanosized and bulk titania in two different crystalline forms (anatase and rutile) in vitro. By colony forming efficiency assay, a dose-dependent reduction of the clonogenic activity of Balb/3T3 mouse fibroblasts was detected in the presence of rutile, but not in the case of anatase NPs. Similarly, the cell transformation assay and the micronucleus test showed that rutile TiO2 NPs were able to induce type-III foci formation in Balb/3T3 cells and appeared to be slightly genotoxic, whereas anatase TiO2 NPs did not induce any significant neoplastic or genotoxic effect. Additionally, we investigated the interaction of TiO2 NPs with Balb/3T3 cells and quantified the in vitro uptake of titania using mass spectrometry. Results showed that the internalization was independent of the crystalline form of TiO2 NPs but size-dependent, as nano-titania were taken up more than their respective bulk materials. In conclusion, we demonstrated that the cytotoxic, neoplastic and genotoxic effects triggered in Balb/3T3 cells by TiO2 NPs depend on the crystalline form of the nanomaterial, whereas the internalization is regulated by the particle size. PMID- 26571345 TI - Iron intakes of Australian infants and toddlers: findings from the Melbourne Infant Feeding, Activity and Nutrition Trial (InFANT) Program. AB - Fe deficiency remains the most common nutritional deficiency worldwide and young children are at particular risk. Preventative food-based strategies require knowledge of current intakes, sources of Fe, and factors associated with low Fe intakes; yet few data are available for Australian children under 2 years. This study's objectives were to determine intakes and food sources of Fe for Australian infants and toddlers and identify non-dietary factors associated with Fe intake. Dietary, anthropometric and socio-demographic data from the Melbourne Infant Feeding, Activity and Nutrition Trial Program were analysed for 485 infants (mean age: 9.1 (sd 1.2) months) and 423 toddlers (mean age: 19.6 (sd 2.6) months) and their mothers. Dietary intakes were assessed via 24-h recalls over 3 non-consecutive days. Prevalence of inadequate Fe intake was estimated using the full probability approach. Associations between potential non-dietary predictors (sex, breast-feeding status, age when introduced to solid foods, maternal age, maternal education, maternal employment status and mother's country of birth) and Fe intakes were assessed using linear regression. Mean Fe intakes were 9.1 (sd 4.3) mg/d for infants and 6.6 (sd 2.4) mg/d for toddlers. Our results showed that 32.6 % of infants and 18.6 % of toddlers had inadequate Fe intake. Main food sources of Fe were Fe-fortified infant formula and cereals for infants and toddlers, respectively. Female sex and current breast-feeding were negatively associated with infant Fe intakes. Introduction to solid foods at or later than 6 months was negatively associated with Fe intake in toddlers. These data may facilitate food-based interventions to improve Australian children's Fe intake levels. PMID- 26571346 TI - Ordered DNA-Surfactant Hybrid Nanospheres Triggered by Magnetic Cationic Surfactants for Photon- and Magneto-Manipulated Drug Delivery and Release. AB - Here we construct for the first time ordered surfactant-DNA hybrid nanospheres of double-strand (ds) DNA and cationic surfactants with magnetic counterion, [FeCl3Br](-). The specificity of the magnetic cationic surfactants that can compact DNA at high concentrations makes it possible for building ordered nanospheres through aggregation, fusion, and coagulation. Cationic surfactants with conventional Br(-) cannot produce spheres under the same condition because they lose the DNA compaction ability. When a light-responsive magnetic cationic surfactant is used to produce nanospheres, a dual-controllable drug-delivery platform can be built simply by the applications of external magnetic force and alternative UV and visible light. These nanospheres obtain high drug absorption efficiency, slow release property, and good biocompatibility. There is potential for effective magnetic-field-based targeted drug delivery, followed by photocontrollable drug release. We deduce that our results might be of great interest for making new functional nucleic-acid-based nanomachines and be envisioned to find applications in nanotechnology and biochemistry. PMID- 26571347 TI - Infrared probe of spin-phonon coupling in antiferromagnetic honeycomb lattice compound Li2MnO3. AB - We investigated temperature-dependent infrared-active phonon modes of honeycomb Li2MnO3 which shows an antiferromagnetic transition at T(N) = 36 K. In the far infrared frequency region, we observed fourteen phonon modes. We obtained the temperature dependence of each phonon mode from the analysis of optical conductivity spectra by using the Lorentz and the Fano-type oscillator models. We found that the resonance frequencies of nine phonon modes showed an anomalous behavior near T(N) that should be attributed to the spin-phonon coupling. We calculated the magnitude of the spin-phonon coupling constant from the shift in the resonance frequencies of the phonon modes below T(N). Our results suggest that Li2MnO3 is weakly frustrated and that spin-phonon coupling plays a role in antiferromagnetic ordering. PMID- 26571348 TI - A 21-year longitudinal analysis of impact, coping, and appraisals following spinal cord injury. AB - OBJECTIVES: To examine mortality, psychological impact, coping strategies, and cognitive appraisals in a cohort of individuals with spinal cord injury from 12 weeks postinjury to >21 years post-hospital discharge. METHOD: This longitudinal, multiple-wave panel study accounted for 50.6% of Kennedy et al.'s (2000) original cohort. Twenty-two participants consented to take part in the current study, and data were collected from the COPE, Beck Depression Inventory, Functional Independence Measure, and a new measure of appraisal: Appraisals of DisAbility: Primary and Secondary Scale (ADAPSS). A further 22 individuals were deceased, giving a total sample of 44 for examining longitudinal factors in relation to mortality. RESULTS: The 22 deceased individuals were found to have significantly higher depression and anxiety at Week 12 than the 22 individuals who participated in the current study. There were significant increases in use of "positive" coping strategies and significant decreases in "negative" strategies. A significant regression model found coping strategies at Week 12 predicted 37% of variance in depression at 21-plus years. Depression and coping strategies at Week 12 were found to predict variance in cognitive appraisals at 21 years. CONCLUSIONS: The findings suggest that psychological factors, such as depression, and aspects of coping strategies may contribute to premature mortality. Further research is needed to develop interventions that focus on protective psychological factors to reduce mortality risk following SCI. Coping strategies in the early stages of rehabilitation are an important predictor of both long term psychological outcomes and appraisals, and this has clinical implications for psychological aspects of rehabilitation. PMID- 26571349 TI - Steady-State Density Functional Theory for Finite Bias Conductances. AB - In the framework of density functional theory, a formalism to describe electronic transport in the steady state is proposed which uses the density on the junction and the steady current as basic variables. We prove that, in a finite window around zero bias, there is a one-to-one map between the basic variables and both local potential on as well as bias across the junction. The resulting Kohn-Sham system features two exchange-correlation (xc) potentials, a local xc potential, and an xc contribution to the bias. For weakly coupled junctions the xc potentials exhibit steps in the density-current plane which are shown to be crucial to describe the Coulomb blockade diamonds. At small currents these steps emerge as the equilibrium xc discontinuity bifurcates. The formalism is applied to a model benzene junction, finding perfect agreement with the orthodox theory of Coulomb blockade. PMID- 26571350 TI - Fluorescent Detection of Tadalafil Based on Competitive Host-Guest Interaction Using p-Sulfonated Calix[6]arene Functionalized Graphene. AB - A competitive fluorescence method toward tadalafil detection has been developed based on host-guest recognition by selecting rhodamine B (RhB) and p-sulfonated calix[6]arene functionalized graphene (CX6-Gra) as the "reporter pair". Upon the presence of tadalafil to the performed CX6-Gra-RhB complex, the RhB molecules are displaced by tadalafil, leading to a "switch-on" fluorescence signal. The observed fluorescence signal can be used for quantitative detection of tadalafil ranging from 1.00 to 50.00 MUM with a detection limit of 0.32 MUM (S/N = 3). The inclusion complex of tadalafil and CX6 was studied by molecular docking and the results indicated that a 1:1 host-guest stoichiometry had the lowest DeltaG value of -7.18 kcal/mol. The docking studies demonstrated that the main forces including pi-pi interactions, electrostatic interactions, and hydrophobic interactions should be responsible for the formation of this inclusion compound. The mechanism of the competitive host-guest interaction was clarified. The binding constant (K) of the tadalafil/CX6 complex was more than 5 times greater than that of RhB/CX6. PMID- 26571353 TI - Beyond homogenization discourse: Reconsidering the cultural consequences of globalized medical education. AB - INTRODUCTION: Global medical education standards, largely designed in the West, have been promoted across national boundaries with limited regard for cultural differences. This review aims to identify discourses on cultural globalization in medical education literature from non-Western countries. METHODS: To explore the diversity of discourses related to globalization and culture in the field of medical education, the authors conducted a critical review of medical education research from non-Western countries published in Academic Medicine, Medical Education and Medical Teacher from 2006 to 2014. Key discourses about globalization and culture emerged from a preliminary analysis of this body of literature. A secondary analysis identified inductive sub-themes. RESULTS: Homogenization, polarization and hybridization emerged as key themes in the literature. These findings demonstrate the existence of discourses beyond Western led homogenization and the co-existence of globalization discourses ranging from homogenization to syncretism to resistance. CONCLUSIONS: This review calls attention to the existence of manifold discourses about globalization and culture in non-Western medical education contexts. In refocusing global medical education processes to avoid Western cultural imperialism, it will also be necessary to avoid the pitfalls of other globalization discourses. Moving beyond existing discourses, researchers and educators should work towards equitable, context sensitive and locally-driven approaches to global medical education. PMID- 26571351 TI - Allosteric regulation of G protein-coupled receptor activity by phospholipids. AB - Lipids are emerging as key regulators of membrane protein structure and activity. These effects can be attributed either to the modification of bilayer properties (thickness, curvature and surface tension) or to the binding of specific lipids to the protein surface. For G protein-coupled receptors (GPCRs), the effects of phospholipids on receptor structure and activity remain poorly understood. Here we reconstituted purified beta2-adrenergic receptor (beta2R) in high-density lipoparticles to systematically characterize the effect of biologically relevant phospholipids on receptor activity. We observed that the lipid headgroup type affected ligand binding (agonist and antagonist) and receptor activation. Specifically, phosphatidylgycerol markedly favored agonist binding and facilitated receptor activation, whereas phosphatidylethanolamine favored antagonist binding and stabilized the inactive state of the receptor. We then showed that these effects could be recapitulated with detergent-solubilized lipids, demonstrating that the functional modulation occurred in the absence of a bilayer. Our data suggest that phospholipids act as direct allosteric modulators of GPCR activity. PMID- 26571352 TI - Branched-chain amino acid catabolism fuels adipocyte differentiation and lipogenesis. AB - Adipose tissue plays important roles in regulating carbohydrate and lipid homeostasis, but less is known about the regulation of amino acid metabolism in adipocytes. Here we applied isotope tracing to pre-adipocytes and differentiated adipocytes to quantify the contributions of different substrates to tricarboxylic acid (TCA) metabolism and lipogenesis. In contrast to proliferating cells, which use glucose and glutamine for acetyl-coenzyme A (AcCoA) generation, differentiated adipocytes showed increased branched-chain amino acid (BCAA) catabolic flux such that leucine and isoleucine from medium and/or from protein catabolism accounted for as much as 30% of lipogenic AcCoA pools. Medium cobalamin deficiency caused methylmalonic acid accumulation and odd-chain fatty acid synthesis. Vitamin B12 supplementation reduced these metabolites and altered the balance of substrates entering mitochondria. Finally, inhibition of BCAA catabolism compromised adipogenesis. These results quantitatively highlight the contribution of BCAAs to adipocyte metabolism and suggest that BCAA catabolism has a functional role in adipocyte differentiation. PMID- 26571354 TI - Weight Change and All-Cause Mortality in Older Adults: A Meta-Analysis. AB - This meta-analysis of observational cohort studies examined the association between weight change (weight loss, weight gain, and weight fluctuation) and all cause mortality among older adults. We used Pub Med (MEDLINE), Web of Science, and Cochrane Library to identify prospective studies published in English from inception to November 2014. Seventeen prospective studies met the inclusion criteria and were included in this meta-analysis. Higher all-cause mortality risks were noted with weight change: weight loss (pooled RR, 1.67; 95% CI, 1.51 1.85; p < 0.001 for heterogeneity), weight gain (pooled RR, 1.21; 95% CI, 1.09 1.33; p = 0.03 for heterogeneity), and weight fluctuation (pooled RR, 1.53; 95% CI, 1.36-1.72; p = 0.43 for heterogeneity). Similar results were observed with stricter criteria for sensitivity analyses. None of the study characteristics had statistically significant effects on the pooled RR, except for study quality on weight loss. Weight change is associated with higher mortality risk among community-dwelling adults 60 years and older. PMID- 26571355 TI - Efficacy of Nutrition Education-Based Cooking Workshops in Community-Dwelling Adults Aged 50 Years and Older. AB - Nutrition interventions offer an opportunity to meet the nutritional needs of community-dwelling older adults. This retrospective qualitative observational study aimed to determine if nutrition education-based cooking workshops offered in Southern Quebec helped improve dietary habits and nutrition-related knowledge, autonomy, and confidence among older adults. Participants (n = 144) in an 8 session cooking workshop program completed pre- and post-workshop session questionnaires. Baseline nutritional risk (n = 116) and body mass index (n = 112) were assessed using the Elderly Nutrition Screening Questionnaire. Paired sample t-tests and McNemar analyses were performed to determine changes over time for knowledge, autonomy, confidence and dietary habits, and specific dietary behaviors, respectively. Pearson correlation tests were performed to assess associations between variables. Significant improvements were observed over time in knowledge, confidence, and desired dietary habits but not in autonomy. At the end of the intervention a greater proportion of participants reported always consuming recommended amounts of whole grains, fruits and vegetables, water, and milk or milk alternatives. A significant association was observed between confidence and dietary habits and between knowledge and confidence. Food skills interventions that link nutrition knowledge with cooking competence offer the opportunity to improve dietary habits among community-dwelling older adults. PMID- 26571356 TI - Estimation of Flavonoid Intake in Older Australians: Secondary Data Analysis of the Blue Mountains Eye Study. AB - Flavonoids, consumed in plant-based foods, have been linked to risk reduction of cancers, cardiovascular, and neurodegenerative diseases. The paucity of information on dietary sources and quantities of flavonoid intake in older adults limits interpretation of epidemiological studies that link flavonoid intake with health outcomes in this population. It was our aim to describe total flavonoid intake, including flavonoid subclasses, in older Australians and to identify rich and commonly consumed sources of flavonoids in this age group. Twelve days of weighed food record dietary data from a subsample of the Blue Mountains Eye Study baseline cohort study of older Australians (n = 79) was analyzed using the US Department of Agriculture flavonoid database. Mean intake of flavonoids was estimated to be 683 mg/day (SD = 507) of which flavan-3-ols contributed 92%, followed by flavonols (4%), flavanones (3%), and flavones (<1%). Black tea was the major flavonoid source, providing 89% of total flavonoid intake. No differences in intake between genders were identified. Dietary intake of flavonoids and flavonoid subclasses in older Australians is similar to the one other estimation of intake in Australian older adults and confirms the types of foods that contribute to flavonoid intake among this sample of older Australians. PMID- 26571357 TI - Beverage Consumption Patterns and Micronutrient and Caloric Intake from Beverages in Older Adults with Mild Cognitive Impairment. AB - The purpose of this study was to determine total water intake and patterns of beverage consumption, and its contribution to total daily micronutrients and calories in older adults with mild memory decline. A descriptive, cross-sectional study was used with 60 independent community-dwelling older adults (71.7 +/- 5.4 years) with mild cognitive impairment, who were mostly female, well-educated, and white. Three-day food records were analyzed using the Nutrition Data Systems for Research. Descriptive statistics were conducted for a summary of demographics, the average intakes of beverages, and the contribution of beverages to total calorie and micronutrient intakes. Total daily water intake was 53.6 +/- 26.7 fl oz and milk, plain water, and tea/coffee were beverages consumed most frequently. Beverage consumption contributed substantially to the intake of vitamin D (29.4%), calcium (26.4%), riboflavin (22.0%), magnesium (18.9%), and vitamin C (18.1%), but constituted only ~12.5% of total energy. These findings suggest that nutrient-dense beverages play a fundamental role in overall micronutrient intake, despite comprising a small component of daily caloric intake. Incorporating adequate amounts of such beverages in meals and snacks may help older adults meet their nutrient recommendations. PMID- 26571358 TI - The basic concept of the read-write genome: Mini-review on cell-mediated DNA modification. AB - The RW genome is a cell-modifiable DNA database encoding RNA and protein sequences. The data files are formatted by repetitive motifs for controlled replication, transmission, expression and repair. Cells have the biochemical natural genetic engineering (NGE) tools needed to make all types of changes to genome DNA. Mobile DNA elements serve as plug-in cassettes that can modify or reformat coding data. Cells regulate and target NGE activities by several well documented molecular mechanisms. Sequence databases show NGE has operated repeatedly in evolutionary history (e.g., domain swapping in proteins, network rewiring), while experimental studies and cancer cells provide real time examples of NGE action. Experimental tests are feasible to determine whether NGE activities operate in a demonstrably adaptive manner. PMID- 26571359 TI - Identification of stable and reactive metabolite(s) of nelfinavir in human liver microsomes and rCYP3A4. AB - The present study was performed to detect trace level stable and reactive metabolites of nelfinavir in human liver microsomes and rCYP3A4. Initially, chromatographic and MS parameters were optimized and fragmentation pattern of the drug was delineated. The structures of metabolites were then elucidated by comparison of their MS/MS fragmentation patterns with the drug. A total of thirty nine stable metabolites were formed, of which twelve were established to be monohydroxylated, eighteen dihydroxy, two dehydrogenated, and one each a diquinone, keto, carboxylic, N-deacylated, dealkylated, oxo and dehydro monohydroxyl metabolite. Previously, a biotransformation product with hydroxylation at tert-butyl group of nelfinavir is reported as an active metabolite of the drug. In our case, ortho-diquinone and N-oxide metabolites were detected, which are known to be reactive in nature. However, these metabolites did not show any interaction with nucleophiles, possibly due to steric hindrance at the site of interface. PMID- 26571360 TI - Correction to Quantifying Short-Lived Events in Multistate Ionic Channel Measurements. PMID- 26571362 TI - The safety of daclatasvir for the treatment of hepatitis C. AB - INTRODUCTION: The direct acting antiviral daclatasvir is an NS5A replication inhibitor active against the entire range of hepatitis C virus genotypes. It is a key step in establishing the goal of an all-oral, ribavirin-free, pan-genotypic regimen against hepatitis C. AREAS COVERED: We review current literature including published abstracts and manuscripts. Evidence was obtained through PubMed/Medline search using listed keywords and through review of published abstracts. EXPERT OPINION: Daclatasvir introduces a degree of pangenotypic potency currently lacking in other NS5A agents. Emerging literature suggests that daclatasvir in combination with other DAAs will represent a promising option in this difficult to treat populations including posttransplant, genotype 3 and HIV patients. PMID- 26571363 TI - Erratum. Correction to: Selective estrogen receptor modulators in clinical practice: a safety overview. PMID- 26571361 TI - Angiotensin II receptor blockade promotes repair of skeletal muscle through down regulation of aging-promoting C1q expression. AB - Disruption of angiotensin II type 1 (AT1) receptor prolonged life span in mice. Since aging-related decline in skeletal muscle function was retarded in Atgr1a(-/ ) mice, we examined the role of AT1 receptor in muscle regeneration after injury. Administration of AT1 receptor blocker irbesartan increased the size of regenerating myofibers, decreased fibrosis, and enhanced functional muscle recovery after cryoinjury. We recently reported that complement C1q, secreted by macrophages, activated Wnt/beta-catenin signaling and promoted aging-related decline in regenerative capacity of skeletal muscle. Notably, irbesartan induced M2 polarization of macrophages, but reduced C1q expression in cryoinjured muscles and in cultured macrophage cells. Irbesartan inhibited up-regulation of Axin2, a downstream gene of Wnt/beta-catenin pathway, in cryoinjured muscles. In addition, topical administration of C1q reversed beneficial effects of irbesartan on skeletal muscle regeneration after injury. These results suggest that AT1 receptor blockade improves muscle repair and regeneration through down-regulation of the aging-promoting C1q-Wnt/beta-catenin signaling pathway. PMID- 26571365 TI - 5th International Conference on Neurology and Epidemiology. Gold Coast, Australia, November 18-20, 2015: Abstracts. PMID- 26571364 TI - Development and validation of an ELISA for quantification of soluble IFN-beta receptor: assessment in multiple sclerosis. AB - AIM: The soluble isoform of the IFN-beta receptor (sIFNAR2) can bind IFN-beta and modulate its activity, although its role in autoimmune diseases remains unknown. METHODS: A recombinant human sIFNAR2 protein was cloned, expressed and purified after which we developed and validated an ELISA for its quantification in human serum. Serum sIFNAR2 were assessed in multiple sclerosis (MS) patients and healthy controls. RESULTS: The ELISA has a dynamic range of 3.9-250 ng/ml and a detection limit of 2.44 ng/ml. Serum sIFNAR2 were significantly lower in untreated-MS patients than in healthy controls. CONCLUSION: The ELISA is suitable for quantification of sIFNAR2 in serum and should facilitate the study of sIFNAR2 in neuroimmunological diseases such as MS. PMID- 26571366 TI - The effect of radiation-induced reactive oxygen species (ROS) on the structural and functional properties of yeast alcohol dehydrogenase (YADH). AB - PURPOSE: To determine the mechanism underlying oxidative modifications caused by radiation-induced reactive oxygen species (ROS) and elucidate their effect on the structure and function of yeast alcohol dehydrogenase (YADH), a zinc-containing protein. MATERIALS AND METHODS: YADH was exposed to water radiolysis products in an air atmosphere. YADH oxidation products were determined by spectrophotometric and spectrofluorimetric methods. The extent to which oxidative modifications affected enzyme activity was also studied. RESULTS: Water radiolysis products oxidized thiol groups leading to the release of zinc ions and the destruction of tryptophan and tyrosine residues. Those processes were accompanied by alterations in protein structure such as increased surface hydrophobicity, greater tryptophan accessibility to acrylamide, and changes in the secondary structure. Structural modifications were correlated with lower enzyme activity. CONCLUSION: During the process of functional and structural changes in YADH exposed to reactive oxygen species, a key part is the oxidation of cysteine residues attached to zinc and the release of zinc ions from the molecule. It may be assumed that ROS induce similar changes in many other zinc-containing proteins. PMID- 26571367 TI - Chemical composition of the pods of Albizia polyphylla. AB - In this study, we report for the first time the presence of alkaloids belonging to beta-carboline type in the pods of the endemic Albizia polyphylla from Madagascar. Three major alkaloids were isolated and structurally identified as: 1 methyl-beta-carboline, (+)-(R)-1-methyl-1,2,3,4-tetrahydro-beta-carboline and (-) (S)-1,2-dimethyl-1,2,3,4-tetrahydro-beta-carboline. PMID- 26571368 TI - Preexposure Prophylaxis Awareness and Use in a Population-Based Sample of Young Black Men Who Have Sex With Men. PMID- 26571369 TI - The Effects of Adjuvant Endocrine Treatment on Serum Leptin, Serum Adiponectin and Body Composition in Patients with Breast Cancer: The Izmir Oncology Group (IZOG) Study. AB - BACKGROUND: A limited number of studies have been conducted on the effects of hormonal therapy with tamoxifen (TMX) or aromatase inhibitors (AIs) on plasma levels of leptin and adiponectin, as well as body composition in breast cancer (BC) patients. Therefore, we aimed to analyze the relationship between adipocytokines and body composition as well as the effects of TMX and AIs on plasma adiponectin, leptin, leptin/adiponectin ratio (LAR) and body composition. METHODS: Patients were treated with either TMX or AI according to their menopausal status after adjuvant radiotherapy. Changes in body composition and serum leptin and adiponectin levels were evaluated. We recorded the type of hormonal therapy, BMI, waist/hip ratio (WHR), leptin and adiponectin levels at study entry, and after 6 and 12 months. RESULTS: From baseline to the 6- and 12 month follow-ups, there were statistically significant increases in WHR (p = 0.003), fat mass (p = 0.041), and serum leptin (p < 0.001) and adiponectin levels (p < 0.001). The changes in body composition and serum leptin and adiponectin levels were similar in TMX and AI groups. A statistically significant decrease was found in total body water and LAR (p < 0.001). Although weight and body fat percentage increased, such increases were not statistically significant. A positive correlation was found between baseline BMI and serum leptin levels. This correlation was maintained at 6 and 12 months. The negative correlation found between serum adiponectin levels at baseline and baseline BMI did not last throughout the study. CONCLUSION: In this study, increased leptin and adiponectin levels and a decreased LAR were found in both AI and TMX groups. These changes might have occurred through both mechanisms of hormonal therapy and body composition changes. Therefore, AIs and TMX may exert their protective effects for BC patients by decreasing LAR rather than affecting leptin or adiponectin alone. PMID- 26571370 TI - Hydronephrosis Predicts Successful Catheter Removal after Painful Urinary Retention - Preliminary Results of a Prospective Single Center Study. AB - INTRODUCTION: The study aims to identify candidates who can be managed conservatively after the first episode of spontaneous painful acute urinary retention (AUR). METHODS: A total of 20 patients with primary spontaneous painful AUR were prospectively included in the study. Twenty-four hours after AUR, the catheter was removed. When residual urinary volume was <100 ml, patients were referred without catheter, when residual urinary volume was >=100 ml, the catheter was replaced and removed again at day 4, 7 or 10 after AUR, respectively. Receiver operating characteristic curves, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated to assess predictors for successful catheter removal. RESULTS: Thirteen out of 20 (65%) patients had a successful catheter removal until day 10 after AUR. Among them 12 of 13 (93.2%) had a successful catheter removal until day 4 of AUR. Hydronephrosis urinary volume and Qmax at the time of AUR were significant numeric predictors for failure of successful catheter removal. In addition, we calculated a prediction model combing age + prostate volume + urinary volume + Qmax that highly predicts successful catheter removal (sensitivity 100%, specificity 69%, PPV 64%, NPV 100%). CONCLUSION: We found for the first time a significant association between hydronephrosis and successful catheter removal. Successful catheter removal until day 4 after AUR can safely be managed without immediate transurethral resection of the prostate. PMID- 26571371 TI - A Statistical Model for In Vivo Neuronal Dynamics. AB - Single neuron models have a long tradition in computational neuroscience. Detailed biophysical models such as the Hodgkin-Huxley model as well as simplified neuron models such as the class of integrate-and-fire models relate the input current to the membrane potential of the neuron. Those types of models have been extensively fitted to in vitro data where the input current is controlled. Those models are however of little use when it comes to characterize intracellular in vivo recordings since the input to the neuron is not known. Here we propose a novel single neuron model that characterizes the statistical properties of in vivo recordings. More specifically, we propose a stochastic process where the subthreshold membrane potential follows a Gaussian process and the spike emission intensity depends nonlinearly on the membrane potential as well as the spiking history. We first show that the model has a rich dynamical repertoire since it can capture arbitrary subthreshold autocovariance functions, firing-rate adaptations as well as arbitrary shapes of the action potential. We then show that this model can be efficiently fitted to data without overfitting. We finally show that this model can be used to characterize and therefore precisely compare various intracellular in vivo recordings from different animals and experimental conditions. PMID- 26571372 TI - Transcriptome Analysis and Development of SSR Molecular Markers in Glycyrrhiza uralensis Fisch. AB - Licorice is an important traditional Chinese medicine with clinical and industrial applications. Genetic resources of licorice are insufficient for analysis of molecular biology and genetic functions; as such, transcriptome sequencing must be conducted for functional characterization and development of molecular markers. In this study, transcriptome sequencing on the Illumina HiSeq 2500 sequencing platform generated a total of 5.41 Gb clean data. De novo assembly yielded a total of 46,641 unigenes. Comparison analysis using BLAST showed that the annotations of 29,614 unigenes were conserved. Further study revealed 773 genes related to biosynthesis of secondary metabolites of licorice, 40 genes involved in biosynthesis of the terpenoid backbone, and 16 genes associated with biosynthesis of glycyrrhizic acid. Analysis of unigenes larger than 1 Kb with a length of 11,702 nt presented 7,032 simple sequence repeats (SSR). Sixty-four of 69 randomly designed and synthesized SSR pairs were successfully amplified, 33 pairs of primers were polymorphism in in Glycyrrhiza uralensis Fisch., Glycyrrhiza inflata Bat., Glycyrrhiza glabra L. and Glycyrrhiza pallidiflora Maxim. This study not only presents the molecular biology data of licorice but also provides a basis for genetic diversity research and molecular marker-assisted breeding of licorice. PMID- 26571373 TI - Serotype Distribution, Antimicrobial Susceptibility, and Molecular Epidemiology of Streptococcus pneumoniae Isolated from Children in Shanghai, China. AB - OBJECTIVE: Streptococcus pneumoniae is a common pathogenic cause of pediatric infections. This study investigated the serotype distribution, antimicrobial susceptibility, and molecular epidemiology of pneumococci before the introduction of conjugate vaccines in Shanghai, China. METHODS: A total of 284 clinical pneumococcal isolates (270, 5, 4,3, and 2 of which were isolated from sputum, bronchoalveolar lavage fluid, blood, cerebral spinal fluid, and ear secretions, respectively) from children less than 14 years of age who had not been vaccinated with a conjugate vaccine, were collected between January and December in 2013. All isolates were serotyped by multiplex polymerase chain reaction or quellung reactions and antimicrobial susceptibility testing was performed using the broth microdilution method. The molecular epidemiology of S.pneumoniae was analyzed by multilocus sequence typing (MLST). RESULTS: Among the 284 pneumococcal isolates, 19F (33.5%), 19A (14.1%), 23F (12.0%), and 6A (8.8%) were the most common serotypes and the coverage rates of the 7-, 10-, and 13-valent pneumococcal conjugate vaccines (PCV7, PCV10, and PCV13) were 58.6%, 59.4% and 85.1%, respectively. Antimicrobial susceptibility showed that the prevalence rates of S.pneumoniae resistance to penicillin were 11.3% (32/284). Approximately 88.0% (250/284) of the isolates exhibited multi-drug resistance. MLST analysis revealed a high level of diversity, with 65 sequence types (STs) among 267 isolates. Specifically, the four predominant STs were ST271 (24.3%, 65/267), ST320 (11.2%, 30/267), ST81 (9.7%, 26/267), and ST3173 (5.2%, 14/267), which were mainly associated with serotypes 19F, 19A, 23F, and 6A, respectively. CONCLUSIONS: The prevalent serotypes among clinical isolates from children were 19F, 19A, 23F, and 6A and these isolates showed high resistance rates to beta-lactams and macrolides. The Taiwan19F-14 clone played a predominant role in the dissemination of pneumococcal isolates in Shanghai, China. Therefore, continued and regional surveillance on pneumococcal isolates may be necessary. PMID- 26571374 TI - Protective Behaviour of Citizens to Transport Accidents Involving Hazardous Materials: A Discrete Choice Experiment Applied to Populated Areas nearby Waterways. AB - BACKGROUND: To improve the information for and preparation of citizens at risk to hazardous material transport accidents, a first important step is to determine how different characteristics of hazardous material transport accidents will influence citizens' protective behaviour. However, quantitative studies investigating citizens' protective behaviour in case of hazardous material transport accidents are scarce. METHODS: A discrete choice experiment was conducted among subjects (19-64 years) living in the direct vicinity of a large waterway. Scenarios were described by three transport accident characteristics: odour perception, smoke/vapour perception, and the proportion of people in the environment that were leaving at their own discretion. Subjects were asked to consider each scenario as realistic and to choose the alternative that was most appealing to them: staying, seeking shelter, or escaping. A panel error component model was used to quantify how different transport accident characteristics influenced subjects' protective behaviour. RESULTS: The response was 44% (881/1,994). The predicted probability that a subject would stay ranged from 1% in case of a severe looking accident till 62% in case of a mild looking accident. All three transport accident characteristics proved to influence protective behaviour. Particularly a perception of strong ammonia or mercaptan odours and visible smoke/vapour close to citizens had the strongest positive influence on escaping. In general, 'escaping' was more preferred than 'seeking shelter', although stated preference heterogeneity among subjects for these protective behaviour options was substantial. Males were less willing to seek shelter than females, whereas elderly people were more willing to escape than younger people. CONCLUSION: Various characteristics of transport accident involving hazardous materials influence subjects' protective behaviour. The preference heterogeneity shows that information needs to be targeted differently depending on gender and age to prepare citizens properly. PMID- 26571376 TI - Cavitands Endow All-Dielectric Beads With Selectivity for Plasmon-Free Enhanced Raman Detection of Nepsilon-Methylated Lysine. AB - SiO2/TiO2 microbeads (T-rex) are promising materials for plasmon-free surface enhanced Raman scattering (SERS), offering several key advantages in biodiagnostics. In this paper we report the combination of T-rex beads with tetraphosphonate cavitands (Tiiii), which imparts selectivity toward Nepsilon methylated lysine. SERS experiments demonstrated the efficiency and selectivity of the T-rex-Tiiii assays in detecting methylated lysine hydrochloride (Nepsilon Me-Lys-Fmoc) from aqueous solutions, even in the presence of the parent Lys-Fmoc hydrochloride as interferent. The negative results obtained in control experiments using TSiiii ruled out any other form of surface recognition or preferential physisorption. MALDI-TOF analyses on the beads exposed to Nepsilon Me-Lys-Fmoc revealed the presence of the Tiiii*Nepsilon-Me-Lys-Fmoc complex. Raman analyses based on the intensity ratio of Nepsilon-Me-Lys-Fmoc and cavitand specific modes resulted in a dose-response plot, which allowed for estimating the concentration of Nepsilon-methylated lysine from initial solutions in the 1 * 10( 3) to 1 * 10(-5) M range. These results can set the basis for the development of new Raman assays for epigenetic diagnostics. PMID- 26571375 TI - Transcriptome Analysis of Cotton (Gossypium hirsutum L.) Genotypes That Are Susceptible, Resistant, and Hypersensitive to Reniform Nematode (Rotylenchulus reniformis). AB - Reniform nematode is a semi-endoparasitic nematode species causing significant yield loss in numerous crops, including cotton (Gossypium hirsutum L.). An RNA sequencing analysis was conducted to measure transcript abundance in reniform nematode susceptible (DP90 & SG747), resistant (BARBREN-713), and hypersensitive (LONREN-1) genotypes of cotton (Gossypium hirsutum L.) with and without reniform nematode infestation. Over 90 million trimmed high quality reads were assembled into 84,711 and 80, 353 transcripts using the G. arboreum and the G. raimondii genomes as references. Many transcripts were significantly differentially expressed between the three different genotypes both prior to and during nematode pathogenesis, including transcripts corresponding to the gene ontology categories of cell wall, hormone metabolism and signaling, redox reactions, secondary metabolism, transcriptional regulation, stress responses, and signaling. Further analysis revealed that a number of these differentially expressed transcripts mapped to the G. raimondii and/or the G. arboreum genomes within 1 megabase of quantitative trait loci that had previously been linked to reniform nematode resistance. Several resistance genes encoding proteins known to be strongly linked to pathogen perception and resistance, including LRR-like and NBS-LRR domain-containing proteins, were among the differentially expressed transcripts mapping near these quantitative trait loci. Further investigation is required to confirm a role for these transcripts in reniform nematode susceptibility, hypersensitivity, and/or resistance. This study presents the first systemic investigation of reniform nematode resistance-associated genes using different genotypes of cotton. The candidate reniform nematode resistance-associated genes identified in this study can serve as the basis for further functional analysis and aid in further development of reniform a nematode resistant cotton germplasm. PMID- 26571377 TI - An update on integrase inhibitors: new opportunities for a personalized therapy? The NEXTaim Project. AB - Thanks to the development of antiretroviral agents to control HIV replication, HIV infection has turned from a fatal disease into a treatable chronic infection. The present work collects the opinions of several experts on the efficacy and safety of recently approved second generation of integrase inhibitors and, in particular, on the role of this new class of drugs in antiretroviral therapy. The availability of new therapeutic options represents an opportunity to ameliorate the efficacy of cART in controlling HIV replication also within viral reservoirs. The personalization of the treatment driven mainly by the management of comorbidities, HIV-HCV co-infections and aging, will be easier with antiretroviral drugs without drug-drug interactions and with a better toxicity and tolerability profile. Future assessment of economic impact for the introduction of new innovative drugs in the field of antiretroviral therapy will likely need some degree of adjustment of the evaluation criteria of costs and benefit which are currently based almost exclusively on morbidity and mortality. PMID- 26571378 TI - Electrical enhancement of chlorhexidine efficacy against the periodontal pathogen Porphyromonas gingivalis within a biofilm. AB - Electric currents have been shown to promote the antimicrobial effectiveness of several biocides against microbial biofilms. Therefore, the objective of this work was to test the null hypothesis that low electric direct currents (DC) do not influence chlorhexidine (CHX) efficacy against the periodontal pathogen Porphyromonas gingivalis within a biofilm. A brain heart infusion medium inoculated with Streptococcus gordonii and P. gingivalis was perfused for 7 days in anaerobiosis through two modified Robbins devices (MRD) assembled in parallel. Biofilms grew on hydroxyapatite discs placed at the bottom of the MRD plugs, and were then treated for 10 min with either CHX or CHX/DC (1.5 mA or 10 mA). The bactericidal effect against biofilms was then evaluated by comparing the mean proportions of P. gingivalis killed. In the first series of experiments (CHX +/- 1.5mA), the proportions of P. gingivalis killed were 81.1% for biofilms undergoing CHX and 79.1% when they were additionally treated with 1.5mA (p>0.05). In the second series (CHX +/- 10mA), the viability of P.gingivalis was reduced by 87.3% with CHX and 98.9% when CHX was supplemented with 10mA (p<0.01). The null hypothesis was rejected, since a significant enhancement of the chlorhexidine 0.2% efficacy against P.gingivalis was observed when applying 10mA currents. PMID- 26571379 TI - Identification of Variants of Hepatitis C Virus (HCV) Entry Factors in Patients Highly Exposed to HCV but Remaining Uninfected: An ANRS Case-Control Study. AB - Hepatitis C virus (HCV) causes persistent infection in 75% of cases and is a major public health problem worldwide. More than 92% of intravenous drug users (IDU) infected by human immunodeficiency virus type 1 (HIV-1) are seropositive for HCV, and it is conceivable that some HIV-1-infected IDU who remain uninfected by HCV may be genetically resistant.Here we conducted a case-control study to identify mutations in HCV entry coreceptors in HIV-infected IDU who remained uninfected by HCV. We recruited 138 patients, comprising 22 HIV+ HCV- case IDU and 116 HIV+ HCV+ control IDU. We focused on coreceptors in which point mutations are known to abolish HCV infectivity in vitro. Our previous study of the Claudin 1 gene revealed no specific variants in the same case population. Here we performed direct genomic sequencing of the Claudin-6, Claudin-9, Occludin and Scavenger receptor-B1 (SCARB1) gene coding regions. Most HIV+ HCV- IDU had no mutations in HCV coreceptors. However, two HIV+ HCV- patients harbored a total of four specific mutations/variants of HCV entry factors that were not found in the HIV+ HCV+ controls. One case patient harbored heterozygous variants of both Claudin-6 and Occludin, and the other case patient harbored two heterozygous variants of SCARB1. This suggests that HCV resistance might involve complex genetic events and factors other than coreceptors, a situation similar to that reported for HIV-1 resistance. PMID- 26571380 TI - Sensitivity of Human Intrahepatic Cholangiocarcinoma Subtypes to Chemotherapeutics and Molecular Targeted Agents: A Study on Primary Cell Cultures. AB - We investigated the sensitivity of intrahepatic cholangiocarcinoma (IHCCA) subtypes to chemotherapeutics and molecular targeted agents. Primary cultures of mucin- and mixed-IHCCA were prepared from surgical specimens (N. 18 IHCCA patients) and evaluated for cell proliferation (MTS assay) and apoptosis (Caspase 3) after incubation (72 hours) with increasing concentrations of different drugs. In vivo, subcutaneous human tumor xenografts were evaluated. Primary cultures of mucin- and mixed-IHCCA were characterized by a different pattern of expression of cancer stem cell markers, and by a different drug sensitivity. Gemcitabine and the Gemcitabine-Cisplatin combination were more active in inhibiting cell proliferation in mixed-IHCCA while Cisplatin or Abraxane were more effective against mucin-IHCCA, where Abraxane also enhances apoptosis. 5-Fluoracil showed a slight inhibitory effect on cell proliferation that was more significant in mixed than mucin-IHCCA primary cultures and, induced apoptosis only in mucin-IHCCA. Among Hg inhibitors, LY2940680 and Vismodegib showed slight effects on proliferation of both IHCCA subtypes. The tyrosine kinase inhibitors, Imatinib Mesylate and Sorafenib showed significant inhibitory effects on proliferation of both mucin- and mixed-IHCCA. The MEK 1/2 inhibitor, Selumetinib, inhibited proliferation of only mucin-IHCCA while the aminopeptidase-N inhibitor, Bestatin was more active against mixed-IHCCA. The c-erbB2 blocking antibody was more active against mixed-IHCCA while, the Wnt inhibitor, LGK974, similarly inhibited proliferation of mucin- and mixed-IHCCA. Either mucin- or mixed-IHCCA showed high sensitivity to nanomolar concentrations of the dual PI3-kinase/mTOR inhibitor, NVP-BEZ235. In vivo, in subcutaneous xenografts, either NVP-BEZ235 or Abraxane, blocked tumor growth. In conclusion, mucin- and mixed-IHCCA are characterized by a different drug sensitivity. Cisplatin, Abraxane and the MEK 1/2 inhibitor, Selumetinib were more active against mucin-IHCCA while, Gemcitabine, Gemcitabine Cisplatin combination, the c-erbB2 blocking antibody and bestatin worked better against mixed-IHCCA. Remarkably, we identified a dual PI3-kinase/mTOR inhibitor that both in vitro and in vivo, exerts dramatic antiproliferative effects against both mucin- and mixed-IHCCA. PMID- 26571381 TI - GSE4, a Small Dyskerin- and GSE24.2-Related Peptide, Induces Telomerase Activity, Cell Proliferation and Reduces DNA Damage, Oxidative Stress and Cell Senescence in Dyskerin Mutant Cells. AB - Dyskeratosis congenita is an inherited disease caused by mutations in genes coding for telomeric components. It was previously reported that expression of a dyskerin-derived peptide, GSE24.2, increases telomerase activity, regulates gene expression and decreases DNA damage and oxidative stress in dyskeratosis congenita patient cells. The biological activity of short peptides derived from GSE24.2 was tested and one of them, GSE4, that probed to be active, was further characterized in this article. Expression of this eleven amino acids long peptide increased telomerase activity and reduced DNA damage, oxidative stress and cell senescence in dyskerin-mutated cells. GSE4 expression also activated c-myc and TERT promoters and increase of c-myc, TERT and TERC expression. The level of biological activity of GSE4 was similar to that obtained by GSE24.2 expression. Incorporation of a dyskerin nuclear localization signal to GSE24.2 did not change its activity on promoter regulation and DNA damage protection. However, incorporation of a signal that increases the rate of nucleolar localization impaired GSE24.2 activity. Incorporation of the dyskerin nuclear localization signal to GSE4 did not alter its biological activity. Mutation of the Aspartic Acid residue that is conserved in the pseudouridine synthase domain present in GSE4 did not impair its activity, except for the repression of c-myc promoter activity and the decrease of c-myc, TERT and TERC gene expression in dyskerin mutated cells. These results indicated that GSE4 could be of great therapeutic interest for treatment of dyskeratosis congenita patients. PMID- 26571382 TI - Association of PAX2 and Other Gene Mutations with the Clinical Manifestations of Renal Coloboma Syndrome. AB - BACKGROUND: Renal coloboma syndrome (RCS) is characterized by renal anomalies and optic nerve colobomas. PAX2 mutations contribute to RCS. However, approximately half of the patients with RCS have no mutation in PAX2 gene. METHODS: To investigate the incidence and effects of mutations of PAX2 and 25 candidate genes, patient genes were screened using next-generation sequence analysis, and candidate mutations were confirmed using Sanger sequencing. The correlation between mutations and clinical manifestation was evaluated. RESULT: Thirty patients, including 26 patients (two families of five and two, 19 sporadic cases) with RCS, and 4 optic nerve coloboma only control cases were evaluated in the present study. Six PAX2 mutations in 21 probands [28%; two in family cohorts (n = 5 and n = 2) and in 4 out of 19 patients with sporadic disease] including four novel mutations were confirmed using Sanger sequencing. Moreover, four other sequence variants (CHD7, SALL4, KIF26B, and SIX4) were also confirmed, including a potentially pathogenic novel KIF26B mutation. Kidney function and proteinuria were more severe in patients with PAX2 mutations than in those without the mutation. Moreover, the coloboma score was significantly higher in patients with PAX2 gene mutations. Three out of five patients with PAX2 mutations had focal segmental glomerulosclerosis (FSGS) diagnosed from kidney biopsies. CONCLUSION: The results of this study identify several new mutations of PAX2, and sequence variants in four additional genes, including a novel potentially pathogenic mutation in KIF26B, which may play a role in the pathogenesis of RCS. PMID- 26571383 TI - Termites Are Resistant to the Effects of Fire at Multiple Spatial Scales. AB - Termites play an important ecological role in many ecosystems, particularly in nutrient-poor arid and semi-arid environments. We examined the distribution and occurrence of termites in the fire-prone, semi-arid mallee region of south eastern Australia. In addition to periodic large wildfires, land managers use fire as a tool to achieve both asset protection and ecological outcomes in this region. Twelve taxa of termites were detected by using systematic searches and grids of cellulose baits at 560 sites, clustered in 28 landscapes selected to represent different fire mosaic patterns. There was no evidence of a significant relationship between the occurrence of termite species and time-since-fire at the site scale. Rather, the occurrence of species was related to habitat features such as the density of mallee trees and large logs (>10 cm diameter). Species richness was greater in chenopod mallee vegetation on heavier soils in swales, rather than Triodia mallee vegetation of the sandy dune slopes. At the landscape scale, there was little evidence that the frequency of occurrence of termite species was related to fire, and no evidence that habitat heterogeneity generated by fire influenced termite species richness. The most influential factor at the landscape scale was the environmental gradient represented by average annual rainfall. Although termites may be associated with flammable habitat components (e.g. dead wood), they appear to be buffered from the effects of fire by behavioural traits, including nesting underground, and the continued availability of dead wood after fire. There is no evidence to support the hypothesis that a fine-scale, diverse mosaic of post-fire age-classes will enhance the diversity of termites. Rather, termites appear to be resistant to the effects of fire at multiple spatial scales. PMID- 26571384 TI - Enhanced Jumping-Droplet Departure. AB - Water vapor condensation on superhydrophobic surfaces has received much attention in recent years because of its ability to shed water droplets at length scales 3 decades smaller than the capillary length (~1 mm) via coalescence-induced droplet jumping. Jumping-droplet condensation has been demonstrated to enhance heat transfer, anti-icing, and self-cleaning efficiency and is governed by the theoretical inertial-capillary scaled jumping speed (U). When two droplets coalesce, the experimentally measured jumping speed (Uexp) is fundamentally limited by the internal fluid dynamics during the coalescence process (Uexp < 0.23U). Here, we theoretically and experimentally demonstrate multidroplet (>2) coalescence as an avenue to break the two-droplet speed limit. Using side-view and top-view high-speed imaging to study more than 1000 jumping events on a copper oxide nanostructured superhydrophobic surface, we verify that droplet jumping occurs as a result of three fundamentally different mechanisms: (1) coalescence between two droplets, (2) coalescence among more than two droplets (multidroplet), and (3) coalescence between one or more droplets on the surface and a returning droplet that has already departed (multihop). We measured droplet jumping speeds for a wide range of droplet radii (5-50 MUm) and demonstrated that while the two-droplet capillary-to-inertial energy conversion mechanism is not identical to that of multidroplet jumping, speeds above the theoretical two droplet limit (>0.23U) can be achieved. However, we discovered that multihop coalescence resulted in drastically reduced jumping speeds (?0.23U) due to adverse momentum contributions from returning droplets. To quantify the impact of enhanced jumping speed on heat-transfer performance, we developed a condensation critical heat flux model to show that modest jumping speed enhancements of 50% using multidroplet jumping can enhance performance by up to 40%. Our results provide a starting point for the design of enhanced-performance jumping-droplet surfaces for industrial applications. PMID- 26571386 TI - Reversed-phase liquid chromatographic analysis of hydrophobic interaction between proanthocyanidins and a C8-alkyl compound in aqueous solution. AB - Structural and physicochemical properties of oligomeric flavan-3-ols (proanthocyanidins) in aqueous solution were investigated by spectrometric and reversed-phase (RP) HPLC analyses. Circular dichroism and fluorescence spectra of (-)-epicatechin (EC) oligomers linked through C-4 to C-8 interflavan bonds showed that EC oligomers larger than dimers formed a stable secondary structure in water. These EC oligomers are water-soluble hydrophilic compounds, whereas the oligomers were strongly retained by a C8-alkyl stationary phase under conventional RP-HPLC conditions. In a further C8-HPLC study, the hydrophobic interaction between EC oligomers and 1-octanesulfonic acid sodium salt (OSA Na) added to the mobile phase was quantitatively evaluated based on the relationship between the logarithm of the retention factor of the solute and the OSA Na concentration in the mobile phase. The strength values of the hydrophobic interaction of EC oligomers larger than dimers were the highest of 22 tested polyphenolic standards. PMID- 26571385 TI - Influence of Fatty Liver on the Severity and Clinical Outcome in Acute Pancreatitis. AB - Acute pancreatitis (AP) is a common disease in the department of gastroenterology with variable severity, from being mild and self-limited to severe and fatal. The early diagnosis and accurate prediction of AP severity are of great importance. Our primary observation showed that fatty liver (FL) was frequently detected in patients with AP. In this retrospective study, we aimed to evaluate the relation between FL and the severity and outcomes of AP. The medical records of 2671 patients with AP were reviewed retrospectively, and characteristics of AP patients were recorded. FL was assessed by abdominal CT scan, and AP patients were categorized by the occurrence of FL for the analysis. The variation of mortality, clinical severity and the appearance of CT were analyzed between the non-FL group and FL groups. Compared with patients without FL, an obviously higher rate of death and higher frequency of severe AP (SAP) and necrotizing AP (ANP) were observed in patients with FL, as well as the incidence of local complications and systemic complications. Taking obesity into consideration, a higher rate of death and more severe AP were found in patients with FL, no matter whether they were obese or not. Alcoholic fatty liver (AFL) and non-alcoholic fatty liver (NAFL) were also separated for comparison in this study; the incidence of ANP and the clinical severity had no significant difference between the AFL and NAFL groups. In conclusion, FL could influence the severity and clinical outcome and may play a prognostic role in AP. This study is of clinical significance, because few reports have been previously issued on FL and AP. PMID- 26571387 TI - Tumor Repression of VCaP Xenografts by a Pyrrole-Imidazole Polyamide. AB - Pyrrole-imidazole (Py-Im) polyamides are high affinity DNA-binding small molecules that can inhibit protein-DNA interactions. In VCaP cells, a human prostate cancer cell line overexpressing both AR and the TMPRSS2-ERG gene fusion, an androgen response element (ARE)-targeted Py-Im polyamide significantly downregulates AR driven gene expression. Polyamide exposure to VCaP cells reduced proliferation without causing DNA damage. Py-Im polyamide treatment also reduced tumor growth in a VCaP mouse xenograft model. In addition to the effects on AR regulated transcription, RNA-seq analysis revealed inhibition of topoisomerase DNA binding as a potential mechanism that contributes to the antitumor effects of polyamides in cell culture and in xenografts. These studies support the therapeutic potential of Py-Im polyamides to target multiple aspects of transcriptional regulation in prostate cancers without genotoxic stress. PMID- 26571388 TI - Physical Violence against General Practitioners and Nurses in Chinese Township Hospitals: A Cross-Sectional Survey. AB - PURPOSE: The purpose of this study is to identify risk factors of physical violence in Chinese township hospitals. METHODS: A cross-sectional survey was used in a sample of 442 general practitioners and 398 general nurses from 90 township hospitals located in Heilongjiang province, China (response rate = 84.8%). RESULTS: A total of 106 of the 840 (12.6%) respondents reported being physically attacked in their workplace in the previous 12 months. Most perpetrators were the patients' relatives (62.3%), followed by the patient (22.6%); 73.6% of perpetrators were aged between 20 and 40 years. Of the physical violence incidents, about 56.6% (n = 60) resulted in a physical injury, and 45.4% of respondents took two or three days of sick leave. Reporting workplace violence in hospitals to superiors or authorities was low (9.4%). Most respondents (62.8%) did not receive training on how to avoid workplace violence. Logistic regression analyses indicated that general nurses, aged 35 years or younger, and with a higher-level professional title were more likely to experience physical violence. Healthcare workers with direct physical contact (washing, turning, lifting) with patients had a higher risk of physical violence compared to other health care workers. Procedures for reporting workplace violence were a protective factor for physical violence; when in place, reporting after psychological violence (verbal abuse, bullying/mobbing, harassment, and threats) was more protective than waiting until an instance of physical violence (beating, kicking, slapping, stabbing, etc.). CONCLUSIONS: Physical violence in Chinese township hospitals is an occupational hazard of rural public health concern. Policies, procedures, and intervention strategies should be undertaken to manage this issue. PMID- 26571389 TI - Tumor Restrictive Suicide Gene Therapy for Glioma Controlled by the FOS Promoter. AB - Effective suicide gene delivery and expression are crucial to achieving successful effects in gene therapy. An ideal tumor-specific promoter expresses therapeutic genes in tumor cells with minimal normal tissue expression. We compared the activity of the FOS (FBJ murine osteosarcoma viral oncogene homolog) promoter with five alternative tumor-specific promoters in glioma cells and non malignant astrocytes. The FOS promoter caused significantly higher transcriptional activity in glioma cell lines than all alternative promoters with the exception of CMV. The FOS promoter showed 13.9%, 32.4%, and 70.8% of the transcriptional activity of CMV in three glioma cell lines (U87, U251, and U373). Importantly, however, the FOS promoter showed only 1.6% of the transcriptional activity of CMV in normal astrocytes. We also tested the biologic activity of recombinant adenovirus containing the suicide gene herpes simplex virus thymidine kinase (HSV-tk) driven by the FOS promoter, including selective killing efficacy in vitro and tumor inhibition rate in vivo. Adenoviral-mediated delivery of the HSV-tk gene controlled by the FOS promoter conferred a cytotoxic effect on human glioma cells in vitro and in vivo. This study suggests that use of the FOS-tk adenovirus system is a promising strategy for glioma-specific gene therapy but still much left for improvement. PMID- 26571390 TI - Identification and Characterization of Imipenem-Resistant Klebsiella pneumoniae and Susceptible Klebsiella variicola Isolates Obtained from the Same Patient. AB - Klebsiella variicola, a bacterium closely genetically related to Klebsiella pneumoniae, is commonly misidentified as K. pneumoniae by biochemical tests. To distinguish between the two bacteria, phylogenetic analysis of the rpoB gene and the identification of unique genes in both bacterial species by multiplex polymerase chain reaction (PCR) provide the means to reliably identify and genotype K. variicola. In recent years, K. variicola has been described both as the cause of an intrahospital outbreak in a pediatric hospital, which resulted in sepsis in inpatients, and as a frequent cause of bloodstream infections. In the present study, K. pneumoniae and K. variicola were isolated from a unique patient displaying different antimicrobial susceptibility phenotypes and different genotypes of virulence determinants. Eight clinical isolates were obtained at different time intervals; all during a 5-month period. The isolates were identified as K. pneumoniae by an automated identification system. The clinical (biochemical test) and molecular (multiplex-PCR and rpoB gene) characterization identified imipenem resistance in the first six K. pneumoniae ST258 isolates, which encode the SHV-12 cephalosporinase and KPC-3 carbapenemase genes. The two last remaining isolates corresponded to susceptible K. variicola. The bacterial species showed a specific profile of virulence-associated determinants, specifically the fimA, fimH, and ecpRAB fimbrial-encoding genes identified only in K. pneumoniae isolates. However, the entb (enterobactin), mrkD (fimbrial adhesin), uge (epimerase), ureA (urease), and wabG (transferase) genes were shared between both bacterial species. Recent studies attribute a higher mortality rate to K. variicola than to K. pneumonia. This work highlights the identification of K. pneumoniae and the closely related K. variicola isolated from the same patient. The value of distinguishing between these two bacterial species is in their clinical significance, their different phenotypes and genotypes, and the fact that they can be isolated from the same patient. PMID- 26571391 TI - Memory or amnesia: the dilemma of stem cell therapy in muscular dystrophies. AB - Muscular dystrophies are monogenetic diseases that are often characterized by the degeneration of both cardiac and skeletal muscle. Gene therapy to correct the mutated gene has shown promise in both animal models and clinical trials; however, current gene delivery strategies are limited to the introduction of the corrected gene into only one tissue. Strategies to target multiple striated muscle types would provide a much-needed improvement for the treatment of muscular dystrophies. In this issue of the JCI, Quattrocelli and colleagues demonstrate that induced pluripotent stem cells (iPSCs) with a myogenic propensity are able to engraft into both cardiac and skeletal muscles. The authors also identified a novel pool of mesodermal iPSC-derived progenitors (MiPs). Moreover, the authors show that these MiPs are amenable to gene correction and can restore function in murine dystrophic models. Together, the results of this study provide an important advance in improving gene delivery to treat patients with muscular dystrophy. PMID- 26571392 TI - Hirschsprung's disease, Down syndrome, and missing heritability: too much collagen slows migration. AB - Hirschsprung's disease (HSCR) causes functional intestinal obstruction due to the absence of the enteric nervous system (ENS) in the distal bowel and is usually diagnosed shortly after birth or during childhood. While several genetic and nongenetic factors have been linked to HSCR, the underlying mechanisms that prevent ENS precursors from colonizing distal bowel during fetal development are not completely understood in many affected children. In this issue of the JCI, Soret and colleagues identify a new mechanism that causes HSCR-like disease in mice and involves deposition of excess collagen VI in the intestine by migrating ENS precursors as they colonize fetal bowel. Remarkably, their findings may explain some of the so-called missing heritability of HSCR and suggest a mechanism for increased HSCR incidence in children with Down syndrome (trisomy 21). PMID- 26571393 TI - cAMP-independent effects of GLP-1 on beta cells. AB - The ability of glucose to stimulate insulin secretion from the pancreatic islets of Langerhans is enhanced by the intestinal hormone glucagon-like peptide 1 (GLP 1), which is secreted from the gut in response to nutrient ingestion. This action, called the incretin effect, accounts for as much as half of the postprandial insulin response and is exploited therapeutically for diabetes treatment through the use of incretin mimetic drugs and inhibitors of dipeptidyl peptidase 4, which degrades GLP-1. Despite a prominent role for incretin mimetics in diabetes treatment, several key questions remain about GLP-1-induced insulin secretion. Most studies have examined the effects of GLP-1 at concentrations several orders of magnitude higher than those found in vivo; therefore, one might question the physiological (and perhaps even pharmacological) relevance of pathways identified in these studies and whether other important mechanisms might have been obscured. In this issue of the JCI, Shigeto and colleagues demonstrate that physiological GLP-1 does indeed amplify the insulin secretory response. Intriguingly, while much of this response is PKA dependent, as might be expected, the use of picomolar GLP-1 reveals a new and important mechanism that contributes to GLP-1-induced insulin secretion. PMID- 26571394 TI - Old dog, new tricks: extracellular domain arginine methylation regulates EGFR function. AB - Conventional wisdom holds that methylation of RTKs should be restricted to intracellular sites. Alterations--such as deletion, mutation, and proteolytic cleavage events--to the extracellular ligand binding and dimer interface domains of the EGFR can induce EGFR dimer formation, leading to aberrant receptor activation and oncogenic activity. Recently, the extracellular domain of EGFR was also shown to be methylated, suggesting that posttranslational protein methylation events directed to the extracellular dimer interface provide another mechanism to regulate the EGFR activation state by modulating receptor dimerization. Critically, these methylation events abrogate response to conformation-specific therapeutic antibodies such as cetuximab. In this issue of the JCI, Liao et al. investigate the role of protein arginine methyltransferase I (PRMT1) in regulating EGFR function in colorectal cancer. The authors provide evidence that methylation of R198 and R200 within the dimer interface enhances growth factor ligand binding and cetuximab resistance through induction and stabilization of the active EGFR dimer conformation. Delineation of these and other subtleties involved in oncogenic RTK activation and their response to targeted therapies should facilitate the development of improved antibody-based treatments. PMID- 26571395 TI - Inflammation drives thrombosis after Salmonella infection via CLEC-2 on platelets. AB - Thrombosis is a common, life-threatening consequence of systemic infection; however, the underlying mechanisms that drive the formation of infection associated thrombi are poorly understood. Here, using a mouse model of systemic Salmonella Typhimurium infection, we determined that inflammation in tissues triggers thrombosis within vessels via ligation of C-type lectin-like receptor-2 (CLEC-2) on platelets by podoplanin exposed to the vasculature following breaching of the vessel wall. During infection, mice developed thrombi that persisted for weeks within the liver. Bacteria triggered but did not maintain this process, as thrombosis peaked at times when bacteremia was absent and bacteria in tissues were reduced by more than 90% from their peak levels. Thrombus development was triggered by an innate, TLR4-dependent inflammatory cascade that was independent of classical glycoprotein VI-mediated (GPVI mediated) platelet activation. After infection, IFN-gamma release enhanced the number of podoplanin-expressing monocytes and Kupffer cells in the hepatic parenchyma and perivascular sites and absence of TLR4, IFN-gamma, or depletion of monocytic-lineage cells or CLEC-2 on platelets markedly inhibited the process. Together, our data indicate that infection-driven thrombosis follows local inflammation and upregulation of podoplanin and platelet activation. The identification of this pathway offers potential therapeutic opportunities to control the devastating consequences of infection-driven thrombosis without increasing the risk of bleeding. PMID- 26571396 TI - Mitochondrial metabolism mediates oxidative stress and inflammation in fatty liver. AB - Mitochondria are critical for respiration in all tissues; however, in liver, these organelles also accommodate high-capacity anaplerotic/cataplerotic pathways that are essential to gluconeogenesis and other biosynthetic activities. During nonalcoholic fatty liver disease (NAFLD), mitochondria also produce ROS that damage hepatocytes, trigger inflammation, and contribute to insulin resistance. Here, we provide several lines of evidence indicating that induction of biosynthesis through hepatic anaplerotic/cataplerotic pathways is energetically backed by elevated oxidative metabolism and hence contributes to oxidative stress and inflammation during NAFLD. First, in murine livers, elevation of fatty acid delivery not only induced oxidative metabolism, but also amplified anaplerosis/cataplerosis and caused a proportional rise in oxidative stress and inflammation. Second, loss of anaplerosis/cataplerosis via genetic knockdown of phosphoenolpyruvate carboxykinase 1 (Pck1) prevented fatty acid-induced rise in oxidative flux, oxidative stress, and inflammation. Flux appeared to be regulated by redox state, energy charge, and metabolite concentration, which may also amplify antioxidant pathways. Third, preventing elevated oxidative metabolism with metformin also normalized hepatic anaplerosis/cataplerosis and reduced markers of inflammation. Finally, independent histological grades in human NAFLD biopsies were proportional to oxidative flux. Thus, hepatic oxidative stress and inflammation are associated with elevated oxidative metabolism during an obesogenic diet, and this link may be provoked by increased work through anabolic pathways. PMID- 26571397 TI - Helminth-induced arginase-1 exacerbates lung inflammation and disease severity in tuberculosis. AB - Parasitic helminth worms, such as Schistosoma mansoni, are endemic in regions with a high prevalence of tuberculosis (TB) among the population. Human studies suggest that helminth coinfections contribute to increased TB susceptibility and increased rates of TB reactivation. Prevailing models suggest that T helper type 2 (Th2) responses induced by helminth infection impair Th1 immune responses and thereby limit Mycobacterium tuberculosis (Mtb) control. Using a pulmonary mouse model of Mtb infection, we demonstrated that S. mansoni coinfection or immunization with S. mansoni egg antigens can reversibly impair Mtb-specific T cell responses without affecting macrophage-mediated Mtb control. Instead, S. mansoni infection resulted in accumulation of high arginase-1-expressing macrophages in the lung, which formed type 2 granulomas and exacerbated inflammation in Mtb-infected mice. Treatment of coinfected animals with an antihelminthic improved Mtb-specific Th1 responses and reduced disease severity. In a genetically diverse mouse population infected with Mtb, enhanced arginase-1 activity was associated with increased lung inflammation. Moreover, in patients with pulmonary TB, lung damage correlated with increased serum activity of arginase-1, which was elevated in TB patients coinfected with helminths. Together, our data indicate that helminth coinfection induces arginase-1 expressing type 2 granulomas, thereby increasing inflammation and TB disease severity. These results also provide insight into the mechanisms by which helminth coinfections drive increased susceptibility, disease progression, and severity in TB. PMID- 26571398 TI - Mesodermal iPSC-derived progenitor cells functionally regenerate cardiac and skeletal muscle. AB - Conditions such as muscular dystrophies (MDs) that affect both cardiac and skeletal muscles would benefit from therapeutic strategies that enable regeneration of both of these striated muscle types. Protocols have been developed to promote induced pluripotent stem cells (iPSCs) to differentiate toward cardiac or skeletal muscle; however, there are currently no strategies to simultaneously target both muscle types. Tissues exhibit specific epigenetic alterations; therefore, source-related lineage biases have the potential to improve iPSC-driven multilineage differentiation. Here, we determined that differential myogenic propensity influences the commitment of isogenic iPSCs and a specifically isolated pool of mesodermal iPSC-derived progenitors (MiPs) toward the striated muscle lineages. Differential myogenic propensity did not influence pluripotency, but did selectively enhance chimerism of MiP-derived tissue in both fetal and adult skeletal muscle. When injected into dystrophic mice, MiPs engrafted and repaired both skeletal and cardiac muscle, reducing functional defects. Similarly, engraftment into dystrophic mice of canine MiPs from dystrophic dogs that had undergone TALEN-mediated correction of the MD-associated mutation also resulted in functional striatal muscle regeneration. Moreover, human MiPs exhibited the same capacity for the dual differentiation observed in murine and canine MiPs. The findings of this study suggest that MiPs should be further explored for combined therapy of cardiac and skeletal muscles. PMID- 26571399 TI - A collagen VI-dependent pathogenic mechanism for Hirschsprung's disease. AB - Hirschsprung's disease (HSCR) is a severe congenital anomaly of the enteric nervous system (ENS) characterized by functional intestinal obstruction due to a lack of intrinsic innervation in the distal bowel. Distal innervation deficiency results from incomplete colonization of the bowel by enteric neural crest cells (eNCCs), the ENS precursors. Here, we report the generation of a mouse model for HSCR--named Holstein--that contains an untargeted transgenic insertion upstream of the collagen-6alpha4 (Col6a4) gene. This insertion induces eNCC-specific upregulation of Col6a4 expression that increases total collagen VI protein levels in the extracellular matrix (ECM) surrounding both the developing and the postnatal ENS. Increased collagen VI levels during development mainly result in slower migration of eNCCs. This appears to be due to the fact that collagen VI is a poor substratum for supporting eNCC migration and can even interfere with the migration-promoting effects of fibronectin. Importantly, for a majority of patients in a HSCR cohort, the myenteric ganglia from the ganglionated region are also specifically surrounded by abundant collagen VI microfibrils, an outcome accentuated by Down syndrome. Collectively, our data thus unveil a clinically relevant pathogenic mechanism for HSCR that involves cell-autonomous changes in ECM composition surrounding eNCCs. Moreover, as COL6A1 and COL6A2 are on human Chr.21q, this mechanism is highly relevant to the predisposition of patients with Down syndrome to HSCR. PMID- 26571400 TI - GLP-1 stimulates insulin secretion by PKC-dependent TRPM4 and TRPM5 activation. AB - Strategies aimed at mimicking or enhancing the action of the incretin hormone glucagon-like peptide 1 (GLP-1) therapeutically improve glucose-stimulated insulin secretion (GSIS); however, it is not clear whether GLP-1 directly drives insulin secretion in pancreatic islets. Here, we examined the mechanisms by which GLP-1 stimulates insulin secretion in mouse and human islets. We found that GLP-1 enhances GSIS at a half-maximal effective concentration of 0.4 pM. Moreover, we determined that GLP-1 activates PLC, which increases submembrane diacylglycerol and thereby activates PKC, resulting in membrane depolarization and increased action potential firing and subsequent stimulation of insulin secretion. The depolarizing effect of GLP-1 on electrical activity was mimicked by the PKC activator PMA, occurred without activation of PKA, and persisted in the presence of PKA inhibitors, the KATP channel blocker tolbutamide, and the L-type Ca(2+) channel blocker isradipine; however, depolarization was abolished by lowering extracellular Na(+). The PKC-dependent effect of GLP-1 on membrane potential and electrical activity was mediated by activation of Na(+)-permeable TRPM4 and TRPM5 channels by mobilization of intracellular Ca(2+) from thapsigargin-sensitive Ca(2+) stores. Concordantly, GLP-1 effects were negligible in Trpm4 or Trpm5 KO islets. These data provide important insight into the therapeutic action of GLP-1 and suggest that circulating levels of this hormone directly stimulate insulin secretion by beta cells. PMID- 26571401 TI - PRMT1-mediated methylation of the EGF receptor regulates signaling and cetuximab response. AB - Posttranslational modifications to the intracellular domain of the EGFR are known to regulate EGFR functions; however, modifications to the extracellular domain and their effects remain relatively unexplored. Here, we determined that methylation at R198 and R200 of the EGFR extracellular domain by protein arginine methyltransferase 1 (PRMT1) enhances binding to EGF and subsequent receptor dimerization and signaling activation. In a mouse orthotopic colorectal cancer xenograft model, expression of a methylation-defective EGFR reduced tumor growth. Moreover, increased EGFR methylation sustained signaling activation and cell proliferation in the presence of the therapeutic EGFR monoclonal antibody cetuximab. In colorectal cancer patients, EGFR methylation level also correlated with a higher recurrence rate after cetuximab treatment and reduced overall survival. Together, these data indicate that R198/R200 methylation of the EGFR plays an important role in regulating EGFR functionality and resistance to cetuximab treatment. PMID- 26571403 TI - Hydrothermal synthesis of oxygen functionalized S-P codoped g-C3N4 nanorods with outstanding visible light activity under anoxic conditions. AB - Extending the application of photocatalytic oxidation technology to the anoxic removal of organic pollutants that exist under some oxygen-free conditions is attractive but challenging. In this study, oxygen functionalized S-P codoped g C3N4 nanorods with outstanding visible light activity under anoxic conditions are synthesized using a hydrothermal post-treatment. S and P codoping inhibits the crystal growth of graphitic carbon nitride, enhances the SBET, decreases the band gap energy, and increases the separation efficiency of photogenerated electrons and holes, which increases the anoxic photocatalytic RhB degradation constant by approximately 6.5 times. Oxygen functionalization not only increases the adsorption ability of graphitic carbon nitride but also captures the photogenerated electrons to produce photogenerated holes for RhB degradation under anoxic conditions, leading to a doubling of the RhB degradation constant. This study provides new insight into the design and fabrication of anoxic photocatalysts. PMID- 26571402 TI - Motif mimetic of epsin perturbs tumor growth and metastasis. AB - Tumor angiogenesis is critical for cancer progression. In multiple murine models, endothelium-specific epsin deficiency abrogates tumor progression by shifting the balance of VEGFR2 signaling toward uncontrolled tumor angiogenesis, resulting in dysfunctional tumor vasculature. Here, we designed a tumor endothelium-targeting chimeric peptide (UPI) for the purpose of inhibiting endogenous tumor endothelial epsins by competitively binding activated VEGFR2. We determined that the UPI peptide specifically targets tumor endothelial VEGFR2 through an unconventional binding mechanism that is driven by unique residues present only in the epsin ubiquitin-interacting motif (UIM) and the VEGFR2 kinase domain. In murine models of neoangiogenesis, UPI peptide increased VEGF-driven angiogenesis and neovascularization but spared quiescent vascular beds. Further, in tumor-bearing mice, UPI peptide markedly impaired functional tumor angiogenesis, tumor growth, and metastasis, resulting in a notable increase in survival. Coadministration of UPI peptide with cytotoxic chemotherapeutics further sustained tumor inhibition. Equipped with localized tumor endothelium-specific targeting, our UPI peptide provides potential for an effective and alternative cancer therapy. PMID- 26571405 TI - Globular Glial Tauopathy Presenting as Semantic Variant Primary Progressive Aphasia. PMID- 26571406 TI - Can High-Resolution Computed Tomography Detect a Therapeutic Response to Medical Treatment in a Patient With Otosclerosis? PMID- 26571404 TI - Transcriptome Analysis of Kiwifruit (Actinidia chinensis) Bark in Response to Armoured Scale Insect (Hemiberlesia lataniae) Feeding. AB - The kiwifruit cultivar Actinidia chinensis 'Hort16A' is resistant to the polyphagous armoured scale insect pest Hemiberlesia lataniae (Hemiptera: Diaspididae). A cDNA microarray consisting of 17,512 unigenes selected from over 132,000 expressed sequence tags (ESTs) was used to measure the transcriptomic profile of the A. chinensis 'Hort16A' canes in response to a controlled infestation of H. lataniae. After 2 days, 272 transcripts were differentially expressed. After 7 days, 5,284 (30%) transcripts were differentially expressed. The transcripts were grouped into 22 major functional categories using MapMan software. After 7 days, transcripts associated with photosynthesis (photosystem II) were significantly down-regulated, while those associated with secondary metabolism were significantly up-regulated. A total of 643 transcripts associated with response to stress were differentially expressed. This included biotic stress-related transcripts orthologous with pathogenesis related proteins, the phenylpropanoid pathway, NBS-LRR (R) genes, and receptor-like kinase-leucine rich repeat signalling proteins. While transcriptional studies are not conclusive in their own right, results were suggestive of a defence response involving both ETI and PTI, with predominance of the SA signalling pathway. Exogenous application of an SA-mimic decreased H. lataniae growth on A. chinensis 'Hort16A' plants in two laboratory experiments. PMID- 26571407 TI - Teratoma of the Middle Ear With Cholesteatoma. PMID- 26571408 TI - Early Bimodal Stimulation Benefits Language Acquisition for Children With Cochlear Implants. AB - HYPOTHESIS: Adding a low-frequency acoustic signal to the cochlear implant (CI) signal (i.e., bimodal stimulation) for a period of time early in life improves language acquisition. BACKGROUND: Children must acquire sensitivity to the phonemic units of language to develop most language-related skills, including expressive vocabulary, working memory, and reading. Acquiring sensitivity to phonemic structure depends largely on having refined spectral (frequency) representations available in the signal, which does not happen with CIs alone. Combining the low-frequency acoustic signal available through hearing aids with the CI signal can enhance signal quality. A period with this bimodal stimulation has been shown to improve language skills in very young children. This study examined whether these benefits persist into childhood. METHODS: Data were examined for 48 children with CIs implanted under age 3 years, participating in a longitudinal study. All children wore hearing aids before receiving a CI, but upon receiving a first CI, 24 children had at least 1 year of bimodal stimulation (Bimodal group), and 24 children had only electric stimulation subsequent to implantation (CI-only group). Measures of phonemic awareness were obtained at second and fourth grades, along with measures of expressive vocabulary, working memory, and reading. RESULTS: Children in the Bimodal group generally performed better on measures of phonemic awareness, and that advantage was reflected in other language measures. CONCLUSIONS: Having even a brief period of time early in life with combined electric-acoustic input provides benefits to language learning into childhood, likely because of the enhancement in spectral representations provided. PMID- 26571409 TI - Bilateral Changes of Spontaneous Activity Within the Central Auditory Pathway Upon Chronic Unilateral Intracochlear Electrical Stimulation. AB - OBJECTIVES: In recent years, cochlear implants have been applied successfully for the treatment of unilateral hearing loss with quite surprising benefit. One reason for this successful treatment, including the relief from tinnitus, could be the normalization of spontaneous activity in the central auditory pathway because of the electrical stimulation. The present study, therefore, investigated at a cellular level, the effect of a unilateral chronic intracochlear stimulation on key structures of the central auditory pathway. DESIGN: Normal-hearing guinea pigs were mechanically single-sided deafened through a standard HiFocus1j electrode array (on a HiRes 90k cochlear implant) being inserted into the first turn of the cochlea. Four to five electrode contacts could be used for the stimulation. Six weeks after surgery, the speech processor (Auria) was fitted, based on tNRI values and mounted on the animal's back. The two experimental groups were stimulated 16 hours per day for 90 days, using a HiRes strategy based on different stimulation rates (low rate (275 pps/ch), high rate (5000 pps/ch)). The results were compared with those of unilateral deafened controls (implanted but not stimulated), as well as between the treatment groups. All animals experienced a standardized free field auditory environment. RESULTS: The low-rate group showed a significantly lower average spontaneous activity bilaterally in the dorsal cochlear nucleus and the medial geniculate body than the controls. However, there was no difference in the inferior colliculus and the primary auditory cortex. Spontaneous activity of the high-rate group was also reduced bilaterally in the dorsal cochlear nucleus and in the primary auditory cortex. No differences could be observed between the high-rate group and the controls in the contra-lateral inferior colliculus and medial geniculate body. The high-rate group showed bilaterally a higher activity in the CN and the MGB compared with the low-rate group, whereas in the IC and in the AC a trend for an opposite effect could be determined. CONCLUSIONS: Unilateral intracochlear electrical stimulation seems to facilitate the homeostasis of the network activity, since it decreases the spontaneous activity that is usually elevated upon deafferentiation. The electrical stimulation per se seems to be responsible for the bilateral changes described above, rather than the particular nature of the electrical stimulation (e.g., rate). The normalization effects of electrical stimulation found in the present study are of particular importance in cochlear implant recipients with single-sided deafness. PMID- 26571410 TI - Histopathologic Findings in Peripheral Vestibular System From Patients With Systemic Lupus Erythematosus: A Human Temporal Bone Study. AB - HYPOTHESIS: We hypothesized that a pathologic condition exists in vestibular hair cells in human temporal bones from patients with systemic lupus erythematosus (SLE). BACKGROUND: A significant association between sensorineural hearing loss and autoimmune disease has been reported. Patients with SLE also frequently have vestibular symptoms whose pathophysiologic mechanism is unclear. METHODS: We examined 15 temporal bone samples from 8 patients with SLE, along with 21 samples from 17 age-matched healthy control patients. The samples were serially sectioned in the horizontal plane and stained with hematoxylin and eosin. Using differential interference contrast microscopy, we counted the number of type I and type II hair cells in the saccular macula, the utricular macula, and the cristae of the three semicircular canals; then, we calculated the hair cell density (cells per 0.01 mm). RESULTS: The mean density of type I hair cells in our SLE group was significantly lower than in our control group in the saccular macula, in the utricular macula, and in the superior, lateral, and posterior semicircular canals. But in all five vestibular sensory epithelia, the mean density of type II hair cells did not significantly differ between our two groups. In our SLE group, the mean density of vestibular hair cells did not significantly correlate with the patient's age at death or with the duration of SLE. CONCLUSION: Type I hair cells in peripheral vestibular organs are affected in patients with SLE. Our findings could provide a pathologic basis for the difficulty with balance experienced by patients with SLE. PMID- 26571411 TI - Eustachian Tube Mucosal Inflammation Scale Validation Based on Digital Video Images. AB - BACKGROUND: The most common cause for Eustachian tube dilatory dysfunction is mucosal inflammation. The aim of this study was to validate a scale for Eustachian tube mucosal inflammation, based on digital video clips obtained during diagnostic rigid endoscopy. METHODS: A previously described four-step scale for grading the degree of inflammation of the mucosa of the Eustachian tube lumen was used for this validation study. A tutorial for use of the scale, including static images and 10 second video clips, was presented to 26 clinicians with various levels of experience. Each clinician then reviewed 35 short digital video samples of Eustachian tubes from patients and rated the degree of inflammation. A subset of the clinicians performed a second rating of the same video clips at a subsequent time. Statistical analysis of the ratings provided inter- and intrarater reliability scores. RESULTS: Twenty-six clinicians with various levels of experience rated a total of 35 videos. Thirteen clinicians rated the videos twice. The overall correlation coefficient for the rating of inflammation severity was relatively good (0.74, 95% confidence interval, 0.72 0.76). The intralevel correlation coefficient for intrarater reliability was high (0.86). For those who rated videos twice, the intralevel correlation coefficient improved after the first rating (0.73, to 0.76), but improvement was not statistically significant. CONCLUSION: The inflammation scale used for Eustachian tube mucosal inflammation is reliable and this scale can be used with a high level of consistency by clinicians with various levels of experience. PMID- 26571412 TI - Transcanal Endoscopic Management of Cerebrospinal Fluid Otorrhea Secondary to Congenital Inner Ear Malformations. AB - OBJECTIVE: To describe the feasibility of using a transcanal endoscopic approach for management of cerebrospinal leaks secondary to congenital inner ear malformations. PATIENTS: Two pediatric patients with congenital inner ear malformations and concurrent cerebrospinal fluid leakage. INTERVENTION: A stapedectomy was performed and the inner ear was packed with temporalis muscle using a transcanal endoscopic approach. MAIN OUTCOME MEASURE: Cessation of cerebrospinal fluid leakage from the inner ear to the middle ear. RESULTS: An otic capsule malformation with a modiolar defect as well as a defect in the stapes footplate was noted in both patients. Successful repair of cerebrospinal fluid otorrhea was achieved in both patients using a minimally invasive transcanal endoscopic approach. One patient developed postoperative meningitis that was successfully managed with antibiotics. CONCLUSIONS: Cerebrospinal fluid otorrhea from an inner ear malformation often presents as persistent clear otorrhea after tympanostomy tube placement or recurrent meningitis as was the case in the two patients in this series. A minimally invasive transcanal endoscopic approach is a viable alternative to manage this unique entity. PMID- 26571413 TI - Discovery of intermediate hosts for two species of blood flukes Cardicola orientalis and Cardicola forsteri (Trematoda: Aporocotylidae) infecting Pacific bluefin tuna in Japan. AB - Fish blood flukes (Aporocotylidae) are important pathogens of farmed finfish around the world. Among them, Cardicola spp. infecting farmed tuna are considered to be serious threats to tuna farming and have received tremendous attention. We conducted periodical samplings at a tuna farming site in Japan between January and May, 2015 to determine the life cycle of Cardicola spp. We collected over 4700 terebellid polychaetes from ropes, floats and frames of tuna culture cages and found nearly 400 infected worms. Sporocysts and cercariae found in Nicolea gracilibranchis were genetically identified as Cardicola orientalis by 28S and ITS2 ribosomal DNA sequences. This was the first discovery of the intermediate host for this parasite species. Infection prevalence and the abundance of N. gracilibranchis significantly varied between sampling points and the highest number of infected terebellids were collected from ropes. We also demonstrated morphologically and molecularly that asexual stages found in a single Amphitrite sp. (Terebellidae) and adult worms isolated from farmed juvenile tuna were Cardicola forsteri. This is the first report of C. forsteri in Pacific bluefin tuna (PBT) Thunnus orientalis in Japan. Our results demonstrated that all three species of Cardicola orientalis, C. forsteri and Cardicola opisthorchis exist in Japanese farmed PBTs and that they all use terebellid polychaetes as the intermediate hosts. PMID- 26571414 TI - Bioinformatic identification of cytochrome b5 homologues from the parasitic nematode Ascaris suum and the free-living nematode Caenorhabditis elegans highlights the crucial role of A. suum adult-specific secretory cytochrome b5 in parasitic adaptation. AB - We previously reported that adult Ascaris suum possesses NADH-metmyoglobin and NADH-methaemoglobin reductase systems that are located in the cells of the body wall and in the extracellular perienteric fluid, respectively, which helps them adapt to environmental hypoxia by recovering the differential functions of myoglobin and haemoglobin. A. suum cytochrome b5, an adult-specific secretory protein and an essential component of the NADH-metmyo (haemo) globin reductase system, has been extensively studied, and its unique nature has been determined. However, the relationship between A. suum cytochrome b5 and the canonical cytochrome b5 proteins, from the free-living nematode Caenorhabditis elegans is unclear. Here, we have characterised four cytochrome b5-like proteins from C. elegans (accession numbers: CAB01732, CCD68984, CAJ58492, and CAA98498) and three from A. suum (accession numbers: ADY48796, ADY46277, and ADY48338) and compared them with A. suum cytochrome b5 in silico. Bioinformatic and molecular analyses showed that CAA98498 from C. elegans is equivalent of A. suum cytochrome b5, which was not expressed as a mature mRNA. Further, the CAA98498 possessed no secretory signal peptide, which occurs in A. suum cytochrome b5 precursor. These results suggest that this free-living nematode does not need a haemoprotein such as the A. suum cytochrome b5 and highlight the crucial function of this A. suum adult-specific secretory cytochrome b5 in parasitic adaptation. PMID- 26571415 TI - Dynamic Bayesian Network Modeling of the Interplay between EGFR and Hedgehog Signaling. AB - Aberrant activation of sonic Hegdehog (SHH) signaling has been found to disrupt cellular differentiation in many human cancers and to increase proliferation. The SHH pathway is known to cross-talk with EGFR dependent signaling. Recent studies experimentally addressed this interplay in Daoy cells, which are presumable a model system for medulloblastoma, a highly malignant brain tumor that predominately occurs in children. Currently ongoing are several clinical trials for different solid cancers, which are designed to validate the clinical benefits of targeting the SHH in combination with other pathways. This has motivated us to investigate interactions between EGFR and SHH dependent signaling in greater depth. To our knowledge, there is no mathematical model describing the interplay between EGFR and SHH dependent signaling in medulloblastoma so far. Here we come up with a fully probabilistic approach using Dynamic Bayesian Networks (DBNs). To build our model, we made use of literature based knowledge describing SHH and EGFR signaling and integrated gene expression (Illumina) and cellular location dependent time series protein expression data (Reverse Phase Protein Arrays). We validated our model by sub-sampling training data and making Bayesian predictions on the left out test data. Our predictions focusing on key transcription factors and p70S6K, showed a high level of concordance with experimental data. Furthermore, the stability of our model was tested by a parametric bootstrap approach. Stable network features were in agreement with published data. Altogether we believe that our model improved our understanding of the interplay between two highly oncogenic signaling pathways in Daoy cells. This may open new perspectives for the future therapy of Hedghog/EGF-dependent solid tumors. PMID- 26571416 TI - Immuno-PET Imaging of HER3 in a Model in which HER3 Signaling Plays a Critical Role. AB - HER3 is overexpressed in various carcinomas including colorectal cancer (CRC), which is associated with poor prognosis, and is involved in the development of therapy resistance. Thus, an in vivo imaging technique is needed to evaluate the expression of HER3, an important therapeutic and diagnostic target. Here, we report successful HER3 PET imaging using a newly generated anti-human HER3 monoclonal antibody, Mab#58, and a mouse model of a HER3-overexpressing xenograft tumor. Furthermore, we assessed the role of HER3 signaling in CRC cancer tissue originated spheroid (CTOS) and applied HER3 imaging to detect endogenous HER3 in CTOS-derived xenografts. Cell binding assays of 89Zr-labeled Mab#58 using the HER3-overexpressing cell line HER3/RH7777 demonstrated that [89Zr]Mab#58 specifically bound to HER3/RH7777 cells (Kd = 2.7 nM). In vivo biodistribution study in mice bearing HER3/RH7777 and its parent cell xenografts showed that tumor accumulation of [89Zr]Mab#58 in HER3/RH7777 xenografts was significantly higher than that in the control from day 1 to day 4, tending to increase from day 1 to day 4 and reaching 12.2 +/- 4.5%ID/g. Radioactivity in other tissues, including the control xenograft, decreased or remained unchanged from day 1 to day 6. Positron emission tomography (PET) in the same model enabled clear visualization of HER3/RH7777 xenografts but not of RH7777 xenografts. CTOS growth assay and signaling assay revealed that CRC CTOS were dependent on HER3 signaling for their growth. In PET studies of mice bearing a CRC CTOS xenograft, the tumor was clearly visualized with [89Zr]Mab#58 but not with the 89Zr-labeled control antibody. Thus, tumor expression of HER3 was successfully visualized by PET with 89Zr-labeled anti-HER3 antibody in CTOS xenograft-bearing mice, a model that retains the properties of the patient tumor. Non-invasive targeting of HER3 by antibodies is feasible, and it is expected to be useful for cancer diagnosis and treatment. PMID- 26571417 TI - Improvement of Image Quality and Diagnostic Performance by an Innovative Motion Correction Algorithm for Prospectively ECG Triggered Coronary CT Angiography. AB - OBJECTIVE: To investigate the effect of a novel motion-correction algorithm (Snap short Freeze, SSF) on image quality and diagnostic accuracy in patients undergoing prospectively ECG-triggered CCTA without administering rate-lowering medications. MATERIALS AND METHODS: Forty-six consecutive patients suspected of CAD prospectively underwent CCTA using prospective ECG-triggering without rate control and invasive coronary angiography (ICA). Image quality, interpretability, and diagnostic performance of SSF were compared with conventional multisegment reconstruction without SSF, using ICA as the reference standard. RESULTS: All subjects (35 men, 57.6 +/- 8.9 years) successfully underwent ICA and CCTA. Mean heart rate was 68.8+/-8.4 (range: 50-88 beats/min) beats/min without rate controlling medications during CT scanning. Overall median image quality score (graded 1-4) was significantly increased from 3.0 to 4.0 by the new algorithm in comparison to conventional reconstruction. Overall interpretability was significantly improved, with a significant reduction in the number of non diagnostic segments (690 of 694, 99.4% vs 659 of 694, 94.9%; P<0.001). However, only the right coronary artery (RCA) showed a statistically significant difference (45 of 46, 97.8% vs 35 of 46, 76.1%; P = 0.004) on a per-vessel basis in this regard. Diagnostic accuracy for detecting >=50% stenosis was improved using the motion-correction algorithm on per-vessel [96.2% (177/184) vs 87.0% (160/184); P = 0.002] and per-segment [96.1% (667/694) vs 86.6% (601/694); P <0.001] levels, but there was not a statistically significant improvement on a per-patient level [97.8 (45/46) vs 89.1 (41/46); P = 0.203]. By artery analysis, diagnostic accuracy was improved only for the RCA [97.8% (45/46) vs 78.3% (36/46); P = 0.007]. CONCLUSION: The intracycle motion correction algorithm significantly improved image quality and diagnostic interpretability in patients undergoing CCTA with prospective ECG triggering and no rate control. PMID- 26571418 TI - Are prophylactic antibiotics useful in chronic obstructive pulmonary disease? AB - Bacterial infections are one of the main causes of chronic obstructive pulmonary disease exacerbation, so the use of prophylactic antibiotics, especially macrolides, has been proposed in these patients. However, it is unclear whether antibiotics use is worth the risk and cost. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified five systematic reviews including eight randomized trials. We combined the evidence using meta analysis and generated a summary of findings table following the GRADE approach. We concluded prophylactic antibiotics probably decrease exacerbations in chronic obstructive pulmonary disease, but have no effect on hospitalizations or mortality. PMID- 26571421 TI - Lowering Uric Acid With Allopurinol Improves Insulin Resistance and Systemic Inflammation in Asymptomatic Hyperuricemia. AB - BACKGROUND: Hyperuricemia is an independent predictor of impaired fasting glucose and type 2 diabetes, but whether it has a causal role in insulin resistance remains controversial. Here we tested the hypothesis that lowering uric acid in hyperuricemic nondiabetic subjects might improve insulin resistance. METHODS: Subjects with asymptomatic hyperuricemia (n = 73) were prospectively placed on allopurinol (n = 40) or control (n = 33) for 3 months. An additional control group consisted of 48 normouricemic subjects. Serum uric acid, fasting glucose, fasting insulin, HOMA-IR (homeostatic model assessment of insulin resistance), and high-sensitivity C-reactive protein were measured at baseline and at 3 months. RESULTS: Allopurinol-treated subjects showed a reduction in serum uric acid in association with improvement in fasting blood glucose, fasting insulin, and HOMA-IR index, as well as a reduction in serum high-sensitivity C-reactive protein. The number of subjects with impaired fasting glucose significantly decreased in the allopurinol group at 3 months compared with baseline (n = 8 [20%] vs n = 30 [75%], 3 months vs baseline, P < 0.001). In the hyperuricemic control group, only glucose decreased significantly and, in the normouricemic control, no end point changed. CONCLUSIONS: Allopurinol lowers uric acid and improves insulin resistance and systemic inflammation in asymptomatic hyperuricemia. Larger clinical trials are recommended to determine if lowering uric acid can help prevent type 2 diabetes. PMID- 26571423 TI - Strong contribution of pore morphology to the high-rate electrochemical performance of lithium-ion batteries. AB - The interconnected ordered pore channels facilitate faster permeation of Li(+) ions during the charge-discharge process than the isolated ordered pore channels, resulting in significantly enhanced capacities, better rate capabilities and more remarkable cycling stability. PMID- 26571424 TI - Dissecting the Genetic Architecture of Leaf Rust Resistance in Wheat by QTL Meta Analysis. AB - Leaf rust is an important disease that causes significant yield losses in wheat. Many studies have reported the identification of quantitative trait loci (QTL) controlling leaf rust resistance; therefore, QTL meta-analysis has become a useful tool for identifying consensus QTL and refining QTL positions among them. In this study, QTL meta-analysis was conducted using reported results on the number, position, and effects of QTL for leaf rust resistance in bread and durum wheat. Investigation of 14 leaf rust resistance traits from 19 studies involving 20 mapping populations and 33 different parental lines provided information for 144 unique QTL that were projected onto the Wheat Composite 2004 reference map. In total, 35 meta-QTL for leaf rust resistance traits were identified in 17 wheat chromosomes and 13 QTL remained as unique QTL. The results will facilitate further work on the cloning of QTL for pyramiding minor- and partial-effect resistance genes to develop varieties with durable resistance to leaf rust. PMID- 26571425 TI - Methodology for preservation of yeast-bound single chain fragment variable antibody affinity reagents. AB - Readily accessible affinity reagents are critical to the validation of biomarkers and to the development of new diagnostic tests. As alternatives to monoclonal antibodies, yeast-bound single chain fragment variable antibody (yeast-scFv) can be rapidly selected from yeast display libraries. An important characteristic for any diagnostic reagent is its stability or ability to store it. A lyophilization procedure that has extended the shelf life of yeast-scFv by a factor of >=10-fold relative to previous reports is reported. Real time stability for three yeast scFv clones to three distinct Entamoeba histolytica potential diagnostic antigen targets for one year at room temperature as well as at 37 degrees C and 45 degrees C. Retention of full binding activity and specificity of the yeast-scFv clones for their cognate antigens is shown by flow cytometry. Lyophilization can easily be carried out in batches and in single-use vials. PMID- 26571427 TI - Localization of genes encoding metallothionein-like protein (mt2 and smtb) in the brain of zebrafish. AB - Metallothionein (MT) is a small cysteine-rich heavy metal-binding protein involved in metal homeostasis, detoxification and free radical-scavenging. MT is ubiquitously expressed in several tissues, but its role in the central nervous system is not well understood. In this study, we identified two MT homologous genes (mt2 and smtb) in the zebrafish. Digoxigenin-in situ hybridization showed the expression of mt2 and smtb genes in the ventricular layers in the telencephalon, diencephalon, mesencephalon and rhombencephalon, most of which are cell proliferating regions in the brain of zebrafish. Cellular characteristics of MT genes expressing cells were examined by double-labelling with markers for neurons (HuC/D) and astrocytes (glial fibrillary acidic protein, GFAP and S100 protein) and cell proliferation marker (PCNA). mt2 and smtb mRNAs are expressed in neurons and not in astrocytes, and they were co-localized with PCNA. These results suggest that mt2 and smtb may play an important role in neurogenesis and neuroprotection. PMID- 26571428 TI - Drugs of abuse, cytostatic drugs and iodinated contrast media in tap water from the Madrid region (central Spain):A case study to analyse their occurrence and human health risk characterization. AB - This work analyses the presence of forty-eight emerging pollutants, including twenty-five drugs of abuse and metabolites, seventeen cytostatic drugs and six iodinated contrast media, in tap water from the Madrid Region. Analysis of the target compounds in the tap water was performed by means of (on-line or off-line) solid-phase extraction followed by analysis by liquid chromatography-tandem mass spectrometry. A preliminary human health risk characterization was undertaken for each individual compound and for different groups of compounds with a common mechanism of action found in tap water. The results of the study showed the presence of eight out of the twenty-five drugs of abuse and metabolites analysed, namely, the cocainics cocaine and benzoylecgonine, the amphetamine-type stimulants ephedrine, 3,4-methylenedioxymethamphetamine and methamphetamine, the opioid methadone and its metabolite 2-ethylene-1,5-dimethyl-3,3 diphenylpyrrolidine and, finally caffeine at concentrations ranging from 0.11 to 502 ng L(-1). Four out of the six analysed iodinated contrast media, namely, diatrizoate, iohexol, iomeprol and iopromide, were detected in at least one sample, with concentration values varying between 0.4 and 5 ng L(-1). Cytostatic compounds were not detected in any sample. Caffeine was the substance showing the highest concentrations, up to 502 ng L(-1), mainly in the drinking water sampling point located in Madrid city. Among the other drugs of abuse, the most abundant compounds were cocaine and benzoylecgonine, detected at concentrations ranging from 0.11 to 86 ng L(-1) and from 0.11 to 53 ng L(-1), respectively. Regarding iodinated contrast media, iohexol was the most ubiquitous and abundant compound, with a frequency of detection of 100% and concentrations from 0.5 to 5.0 ng L(-1) in basically the same range in all sampling points. Taking into account the results and types of treatment applied, ozonisation plus granular activated carbon filtration appears to be efficient in the removal of cocaine and benzoylecgonine. For the amphetamine-type stimulants, opioids and caffeine, ozonisation plus granular activated carbon filtration and ultrafiltration plus reverse osmosis showed higher removal efficiency than sand filtration. The human health risk characterization performed indicates that the lifetime consumption of the tap waters analysed has associated a negligible human health concern. PMID- 26571429 TI - Transvaginal Versus Transabdominal Placement of Synthetic Mesh at Time of Sacrocolpopexy. AB - OBJECTIVES: Our primary aim was to compare mesh-related complications at the time of total vaginal hysterectomy with laparoscopic sacrocolpopexy (TVH-LSC) versus laparoscopic placement of sacrocolpopexy mesh at time of laparoscopic supracervical hysterectomy (LSH-LSC). Our secondary aim was to compare operative time, intraoperative and postoperative complications, as well as subjective and objective success between these groups. METHODS: We performed a retrospective cohort study with prospective follow-up for patients with uterovaginal prolapse who underwent TVH-LSC or LSH-LSC from June 2008 to July 2012. We collected baseline demographics, mesh-related complications, intraoperative and postoperative complications, and pelvic organ prolapse quantification data. We contacted patients postoperatively for telephone interviews and to request a return to the office for repeat examination. RESULTS: One hundred eighty-two patients were included: 123 TVH-LSC and 59 LSH-LSC. There was no difference in the rate of mesh-related complications (1.6% [2/123]; 95% confidence interval, 0 3.86% vs 1.7% [1/59]; 95% confidence interval, 0-4.99%; P = 1.0). Median examination follow-up was similar between groups (9 (2-17) months TVH-LSC vs 9 (2 17) months LSH-LSC, P = 1.0).The TVH-LSC was associated with a significantly shorter operative time (256 +/- 53 vs 344 +/- 81 minutes; P < 0.01). There were no differences in intraoperative or postoperative complications or subjective and objective success between groups. CONCLUSIONS: There was no difference in mesh related complications between groups (1.6% TVH-LSC vs 1.7% LSH-LSC; P = 1.0). Vaginal mesh attachment during TVH-LSC decreased operative time by over 1 hour with no differences in intraoperative complications, reoperation for recurrent prolapse, and subjective or objective outcomes compared to LSH-LSC. PMID- 26571430 TI - Update on Urinary Tract Markers in Interstitial Cystitis/Bladder Pain Syndrome. AB - Interstitial cystitis (IC)/painful bladder syndrome/bladder pain syndrome (BPS) is a chronic hypersensory condition of unknown etiology. Moreover, the optimal modality for diagnosing IC remains disputed. Several urinary markers have been investigated that may have potential utility in the diagnosis or confirmation of IC/BPS. Thus, inflammatory mediators, proteoglycans, urinary hexosamines, proliferative factors, nitric oxide (NO), BK polyomavirus family, and urothelial proinflammatory gene analysis have been found to correlate with varying degrees with the clinical diagnosis or cystoscopic findings in patients with IC/BPS. The most promising urinary biomarker for IC/BPS is antiproliferative factor, a sialoglycopeptide that has demonstrated inhibitory effects on urothelial cell proliferation and a high sensitivity and specificity for IC/BPS symptoms and clinical findings. In this article, we review the urinary markers, possible future therapies for IC/BPS, and the clinical relevance and controversies regarding the diagnosis of IC/BPS. PMID- 26571431 TI - The Evaluation of Baseline Physical Function and Cognition in Women Undergoing Pelvic Floor Surgery. AB - OBJECTIVES: Physical and cognitive function impairments are associated with increased perioperative morbidity; however, limited data exist regarding these parameters in women planning pelvic floor surgery. Thus, our goal was to assess baseline physical function and cognition in patients scheduled for pelvic reconstructive surgery and to evaluate factors associated with preoperative upper and lower body function. METHODS: In a prospective study, we evaluated sociodemographics, body mass index, the Functional Comorbidity Index (FCI), Katz Activities of Daily Living (ADL), and Instrumental ADL (IADL). Physical function was evaluated with Timed Up and Go (TUG) test and dynamometers to assess handgrip and pinch strength. The Mini-Mental State Examination (MMSE) was used to evaluate cognitive impairment. RESULTS: Among 142 women in our study population, mean age was 58.4 +/- 13.9 years, comorbidities were low (mean FCI, 3.7 +/- 2.7) and independence level was high (mean ADL, 5.7 +/- 0.5; mean IADL, 7.8 +/- 0.8). Mean TUG test was 11.6 +/- 4.5 seconds, reflecting mildly impaired mobility. Maximum handgrip and pinch strength were 51.7 +/- 16.6 lb and 12.7 +/- 3.6 lb, respectively, which represent normal/above average scores. Age (P = 0.007), body mass index (P = 0.003), IADL (P = 0.003), and MMSE (P = 0.003) were significantly associated with TUG test scores in a multivariate linear regression analysis that adjusted for FCI. The mean MMSE mean score was 29.2 +/- 0.9; only 3.5% had mild cognitive impairment and 0.7% had moderate-severe impairment. CONCLUSIONS: Women undergoing elective pelvic reconstructive surgery had good physical and cognitive function. The simple TUG test was the most likely tool to identify patients with poorer physical function. PMID- 26571432 TI - Trends and Factors Influencing Inpatient Prolapse Surgical Costs and Length of Stay in the United States. AB - OBJECTIVE: This study aimed to assess trends and factors affecting inpatient hospital costs and length of stay (LOS) in surgical treatment of pelvic organ prolapse in the United States. METHODS: A retrospective cross-sectional study along with longitudinal trend analysis from the 2001 to 2011 National Inpatient Sample included subjects who underwent inpatient prolapse repairs. The primary outcomes were inpatient mean cost per admission and LOS. We compared unadjusted differences in primary outcomes for each patient and hospital characteristic using 2011 data with analysis of variance. Multivariable regression estimated proportional change in cost and LOS associated with each characteristic. RESULTS: Unadjusted analysis revealed increased LOS with age of 80 years or older, African American race, uninsured status, lower income, and lower surgical volume hospitals (<=75%) as well as increased costs in the West and public hospitals. On multivariable analyses, African Americans had 1.09 (95% confidence interval [CI], 1.05-1.13; P < 0.001) times longer LOS compared with Caucasians, and the uninsured had 1.15 (95% CI, 1.01-1.30; P = 0.032) times longer LOS compared with those privately insured. Comorbidities associated with 20% increase in LOS and costs were pulmonary circulation disorders, metastatic cancer, weight loss, coagulopathy, and electrolyte/fluid imbalance (P < 0.001). Congestive heart failure and blood loss/deficiency anemia lead to 20% longer LOS (P < 0.001). In 2001-2011, mean LOS declined from 2.42 days (95% CI, 2.37-2.47) to 1.79 days (95% CI, 1.71-1.87) (P < 0.001), whereas mean total cost increased from $6233 (95% CI, $5859-$6607) to $9035 (95% CI, $8632-$9438) (P < 0.001). CONCLUSIONS: Inpatient surgical costs for prolapse increased despite decreasing LOS. Some patient and hospital characteristics are associated with increased inpatient costs and LOS. PMID- 26571433 TI - Occult Stress Urinary Incontinence in Women With Pelvic Organ Prolapse: Is the One Step Surgical Approach a Risky Choice? AB - OBJECTIVES: Occult stress urinary incontinence (SUI, OSUI) is defined as the demonstration of SUI after pelvic organ prolapse (POP) reduction. The aim of this study was to evaluate the effectiveness and complication rates of the 1-step surgical approach for treating women with POP and OSUI. METHODS: Retrospective study of women with POP and OSUI who underwent a concomitant prolapse and midurethral sling procedure was conducted. Main outcome measures were absence of postoperative urodynamic stress incontinence (USI) and absence of postoperative SUI at 12 months. Secondary outcome measures included evaluation of objective and subjective parameters related to the lower urinary tract function and assessment of the quality of life. RESULTS: Of the 244 women, 205 women (84%) attended the 12-month postoperative follow-up visit and were included in the study. Overall, 87.8% (180/205) of the patients had absence of postoperative urodynamic stress incontinence, whereas 95.1% (195/205) did not report postoperative SUI. Evaluation of parameters related to the postoperative lower urinary tract dysfunction showed that (a) 43% of women with preexisting urgency symptoms continued to have urgency, (b) 16.7% of patients presented de novo urgency, (c) de novo detrusor overactivity occurred in 9.3% of patients, and (d) 4.9% of women with preoperative obstructive voiding symptoms continued to have obstructive voiding symptoms after combined surgery. King's Health Questionnaire data analysis showed a statistically significant improvement in all domains. CONCLUSIONS: This 1-step approach is both safe and effective and could be offered as a valid operative choice for those women who wish or should avoid a repeat surgical procedure for postoperative SUI. PMID- 26571434 TI - Body Image, Regret, and Satisfaction 24 Weeks After Colpocleisis: A Multicenter Study. AB - OBJECTIVE: To evaluate the impact of colpocleisis on body image, regret, satisfaction, and pelvic floor symptoms 24 weeks after surgery. METHODS: This was a prospective multicenter study conducted through the Society of Gynecologic Surgeons' Fellows' Pelvic Research Network with 7 sites across the United States. Women undergoing colpocleisis were enrolled. Outcomes assessed at 24 weeks included body image, regret, satisfaction, and pelvic floor symptoms. The Pelvic Floor Impact Questionnaire, Pelvic Floor Distress Inventory, the modified Body Image Scale, the Decision Regret Scale, and the Satisfaction with Decision Scale were administered. A sample size of 88 subjects was calculated for a significant change in the Body Image Scale. RESULTS: Ninety subjects were enrolled. Two did not undergo surgery, and 7 were deceased at the time of 24-week follow-up. Significant improvements in all pelvic floor symptoms were noted 6 weeks postoperatively, and 24-week data showed sustained improvement. In addition, mean and total body image scores showed lasting significant improvement when compared with preoperative scores (P < 0.001 and P < 0.001, respectively). Finally, patients continued to be satisfied with their decision to undergo surgery (mean [SD] 4.6, [0.6]) and had a very low level of regret regarding this decision (mean [SD], 1.5 [0.7]). CONCLUSIONS: Colpocleisis is a highly effective surgical treatment option for pelvic organ prolapse with improvements in both pelvic floor symptoms and body image. Furthermore, high satisfaction and low regret seen 24 weeks after surgery provide reassurance that colpocleisis is an excellent option for appropriate patients. PMID- 26571435 TI - Preoperative Prolapse Stage as Predictor of Failure of Sacrocolpopexy. AB - OBJECTIVES: Our aim was to determine if there was a correlation between the preoperative prolapse stage and postoperative recurrence of prolapse 1 year after sacrocolpopexy. Our null hypothesis is that the preoperative stage of prolapse does not increase the risk of recurrence. METHODS: This is a multicenter cohort study from 3 centers. We included subjects who underwent robotic-assisted sacrocolpopexy and completed a standardized 1-year follow-up from 2009-2014. All subjects underwent a complete preoperative evaluation and completed 12 months of follow-up with the pelvic organ prolapse quantification examination. We compared those subjects who met the definition of recurrence with those who did not, analyzing the following covariates: stage of prolapse using International Continence Society (ICS) definitions, individual pelvic organ prolapse quantification points, age, body mass index, race, exogenous estrogen use, menopause, smoking, vaginal parity, cesarean section, and performance of concomitant procedures. We defined recurrence as any prolapse beyond the hymen. RESULTS: We had 125 women from 3 centers who met our criteria, with 23.2% of them having recurrence at 1 year. We found that recurrence increased as the preoperative ICS stage of prolapse increased (P = <0.001 in the univariate model). In the multivariate model, using logistic regression, we found that the risk of recurrence of pelvic organ prolapse increased as the presurgery clinical stage increased with an odds ratio of 3.8 (95% confidence interval, 1.5-9) when controlling for age, menopausal status, and genital hiatus (P = 0.004). CONCLUSIONS: Much like a higher stage of disease in oncology, we found that increasing stage of prolapse preoperatively increased the risk of recurrence at 1 year after sacrocolpopexy. PMID- 26571436 TI - Intraoperative Ultrasound-Guided Removal of Retained Mini Sling Anchor Causing Vaginal Pain: A Case Report. AB - Since the introduction of the tension-free vaginal tape, the surgical management of female stress urinary incontinence has undergone a dramatic shift toward synthetic midurethral slings (MUSs). The evolution of the MUS has led to the development of the single incision mini sling (SIMS), a minimally invasive procedure that can be performed under local anesthesia. Complications arising after SIMS placement parallel those of the traditional MUS, including pelvic pain, dyspareunia, and mesh erosion. The patient in this case presented with persistent pelvic pain due to a retained SIMS anchor after having previously undergone SIMS placement and subsequent transvaginal exploration with mesh removal. We report the use of intraoperative ultrasound for identification and removal of the retained SIMS anchor. PMID- 26571437 TI - Perceptual discrimination in fear generalization: Mechanistic and clinical implications. AB - For almost a century, Pavlovian conditioning is the imperative experimental paradigm to investigate the development and generalization of fear. However, despite the rich research tradition, the conceptualization of fear generalization has remained somewhat ambiguous. In this selective review, we focus explicitly on some challenges with the current operationalization of fear generalization and their impact on the ability to make inferences on its clinical potential and underlying processes. The main conclusion is that, despite the strong evidence that learning influences perception, current research has largely neglected the role of perceptual discriminability and its plasticity in fear generalization. We propose an alternative operationalization of generalization, where the essence is that Pavlovian conditioning itself influences the breadth of fear generalization via learning-related changes in perceptual discriminability. Hence a conceptualization of fear generalization is incomplete without an in-depth analysis of processes of perceptual discriminability. Furthermore, this highlights perceptual learning and discriminability as important future targets for pre-clinical and clinical research. PMID- 26571438 TI - The natural compound nujiangexanthone A suppresses mast cell activation and allergic asthma. AB - Mast cells play an important role in allergic diseases such as asthma, allergic rhinitis and atopic dermatitis. The genus Garcinia of the family Guttiferae is well known as a prolific source of polycyclic polyprenylated acylphloroglucinols and bioactive prenylated xanthones, which exhibit various biological activities including antibacterial, antifungal, anti-inflammatory, antioxidant, and cytotoxic effects. Nujiangexanthone A (N7) is a novel compound isolated from the leaves of Garcinia nujiangensis. In this paper, we sought to determine the anti allergic and anti-inflammation activity of N7 in vivo and its mechanism in vitro. We found N7 suppressed IgE/Ag induced mast cell activiation, including degranulation and production of cytokines and eicosanoids, through inhibiting Src kinase activity and Syk dependent pathways. N7 inhibited histamine release, prostaglandin D2 and leukotriene C4 generation in mast cell dependent passive cutaneous anaphylaxis animal model. We also found N7 inhibited the IL-4, IL-5, IL 13 and IgE levels in ovalbumin-induced asthma model. Histological studies demonstrated that N7 substantially inhibited OVA-induced cellular infiltration and increased mucus production in the lung tissue. Our study reveals the anti allergic function of N7, thereby suggesting the utility of this compound as a possible novel agent for preventing mast cell-related immediate and delayed allergic diseases. PMID- 26571439 TI - Persistent Left Superior Vena Cava Demonstrated by First-Pass Radionuclide Angiography. AB - Persistent left superior vena cava (PLSVC) is a development variation of the embryonic thoracic venous system. It can be isolated or associated with congenital heart disease combined with shunting problems. Many image findings of PLSVC have been reported, but few mentioned findings in a first-pass radionuclide angiography. We report a case of PLSVC found incidentally in a first-pass radionuclide angiography with tracer injection through the left jugular vein. The right ventricular ejection fraction was underestimated. Injection via the right jugular or right cubital vein is recommended to obtain accurate ejection fractions in cases of PLSVC without shunting. PMID- 26571440 TI - "Cold" Spondylodiscitis on 18F-FDG PET/CT in a Patient With Myelofibrosis. AB - A 74-year-old man was evaluated by bone scan for possible rib fractures, which revealed a diffuse skeletal uptake secondary to myelofibrosis and focal midthoracic uptake. Chest CT and F-FDG PET/CT demonstrated pathological vertebral fractures of the midthoracic spine, which appeared as a cold defect on PET comparing to intense marrow uptake related to myelofibrosis and a lung nodule with a low uptake, later biopsy-proven as non-small cell lung carcinoma (NSCLC). MRI confirmed CT findings for the spine noting also an enhanced epidural collection. Biopsies did not reveal malignant cells. Final diagnosis was spondylodiscitis and a stage I NSCLC. PMID- 26571441 TI - Persistent Asymmetric Brain MIBG Activity Related to a Cerebrovascular Infarct. AB - A 13-year-old woman with a history of left malignant carotid body paraganglioma status postsurgical resection underwent 123I-MIBG scan for staging. The images demonstrated no definite evidence of MIBG-avid disease. However, there was asymmetric activity in the region of the brain with relatively less activity on the left compared with the contralateral right side on the head images, which was related to prior infarct revealed from the patient's history. This asymmetric MIBG activity persisted 8 years later. PMID- 26571442 TI - Bone Scintigraphic Findings in MRSA Osteomyelitis. AB - Methicillin-resistant Staphylococcus aureus osteomyelitis is a severe form of infection characterized by multifocal or multiple segmental osseous involvement and subperiosteal abscess formation with increased frequency of extraosseous complications including pyomyositis, septic thrombus, and septic arthritis. Bone scan showed long segment and/or multifocal involvement in 4 of 5 patients with areas of abnormal increased and decreased uptake. The clinical presentations included limp and/or pain. Joint involvement was seen in 4 cases. Bone scan abnormalities correlated well with MRI findings of severe and extensive bone disease, abscess formation, muscle, as well as joint and soft tissue involvement. PMID- 26571443 TI - Could 18F-FDG PET Be a Diagnostic Tool for Hemochromatosis? PMID- 26571444 TI - Incidental Detection of Urinary Leakage on FDG PET/CT Imaging for Staging of Gastric Cancer. AB - A 71-year-old woman presented to the emergency department with right flank pain and dysuria. An abdominal CT scan detected a gastric malignancy and hydronephrosis with urinary leakage of the right kidney. Percutaneous nephrostomy was performed on the right kidney. F-FDG PET/CT for staging the gastric malignancy revealed additional urinary leakage of the contralateral kidney. The interest in this case is the incidental detection of unexpected urinary leakage during an oncologic assessment with FDG PET/CT. PMID- 26571445 TI - 18F-FDG PET/CT Findings in Multicentric Reticulohistiocytosis. AB - Multicentric reticulohistiocytosis is a rare systemic inflammatory disease of unknown etiology characterized by the infiltration of histiocytes and multinucleated giant cells into multiple systems. The definitive diagnosis depends on biopsy of the affected tissues. Here, we report the F-FDG PET/CT findings of a 62-year-old man with multicentric reticulohistiocytosis. Increased FDG uptake was observed in cutaneomucosal papules, surrounding tissues of many joints, multiple muscles, and lymph nodes. PMID- 26571446 TI - Anthracofibrosis Manifesting as False-Positive Iodine Accumulation in a Patient With Recent History of Thyroid Carcinoma. AB - A 33-year-old Indonesian woman presented for follow-up after a recent history of papillary thyroid carcinoma treated with total thyroidectomy and radioiodine therapy. A 131I whole-body scintigraphy showed an elongated iodine accumulation in the right hemithorax. On suspicion of pulmonary metastasis, further diagnostics with 124I PET/CT showed thickening of the bronchial wall and retention of secretion in a middle lobe bronchus. Bronchoscopy and histology allowed a diagnosis of stenosing anthracofibrosis with chronic inflammatory changes. PMID- 26571447 TI - Rectal Carcinoma on 68Ga-PSMA PET/CT. AB - We report on a case of biopsy-proven and MRI-staged rectal carcinoma with avid prostate-specific membrane antigen (prostate-specific membrane antigen) uptake on Ga PET/CT as part of the workup for synchronous prostate cancer. This case adds to the growing number of observational reports on the presence of significant nonprostatic prostate-specific membrane antigen activity in malignant tumors and highlights the need for careful interpretation of unsuspected sites. PMID- 26571448 TI - Limbic Encephalitis Diagnosed With 18F-FDG PET/CT. AB - Limbic encephalitis is a subacute onset syndrome characterized by short-term memory impairment, confusion, temporal lobe epilepsy, hypothalamic dysfunction, and psychiatric symptoms. Common causes are autoimmune disorders or idiopathic disease, although it has been associated to tumors. We report the case of a woman arrived at the emergency department having had fluctuating impaired memory for 2 weeks. The first MRI was normal. It was decided to perform lumbar puncture and PET/CT to exclude viral origin or paraneoplastic syndrome. Typical abnormalities were found in the second MRI (1 month after previous); however, FDG PET is a useful tool that contributes to early detection. PMID- 26571449 TI - Precise Localization of Occult Gastrointestinal Hemorrhage Using Dynamic SPECT/CT. AB - Active but intermittent gastrointestinal (GI) bleeding can be readily detected with dynamic planar scintigraphic imaging. This is a case of a 48-year-old woman who presented from an outside institution with active GI bleeding on 99mTc labeled RBC (99mTc-RBC) scintigraphy, but the upper and lower GI evaluations failed to subsequently localize the site of persistent bleeding. Repeat 99mTc-RBC planar scintigraphy identified a focus of active extravasation in the right lower quadrant of the abdomen. Dynamic SPECT/CT imaging was immediately performed and further identified the ileocecal valve region as the precise site of active extravasation, which was confirmed at surgery. PMID- 26571450 TI - Scintigraphic Identification of Gastric Tissue in a Mediastinal Mass. AB - We present a Tc pertechnetate scintigraphy performed in a 64-year-old woman to investigate a mediastinal cystic mass in search of residual gastric mucosa after gastrectomy. She had a history of esophagectomy and gastric pull-up for esophageal cancer. Postoperative leakage necessitated ablation of the gastric pull-up and reconstruction using part of the colon. Oral realimentation resulted in mediastinal pain and brownish discharge within the trachea, raising the suspicion of residual gastric pouch. SPECT/CT demonstrated increased tracer uptake in the median part of the mediastinal cyst, and a biopsy confirmed the presence gastric mucosa. PMID- 26571451 TI - Omega 6 fatty acids for the primary prevention of cardiovascular disease. AB - BACKGROUND: Omega 6 plays a vital role in many physiological functions but there is controversy concerning its effect on cardiovascular disease (CVD) risk. There is conflicting evidence whether increasing or decreasing omega 6 intake results in beneficial effects. OBJECTIVES: The two primary objectives of this Cochrane review were to determine the effectiveness of:1. Increasing omega 6 (Linoleic acid (LA), Gamma-linolenic acid (GLA), Dihomo-gamma-linolenic acid (DGLA), Arachidonic acid (AA), or any combination) intake in place of saturated or monounsaturated fats or carbohydrates for the primary prevention of CVD.2. Decreasing omega 6 (LA, GLA, DGLA, AA, or any combination) intake in place of carbohydrates or protein (or both) for the primary prevention of CVD. SEARCH METHODS: We searched the following electronic databases up to 23 September 2014: the Cochrane Central Register of Controlled Trials (CENTRAL) on the Cochrane Library (Issue 8 of 12, 2014); MEDLINE (Ovid) (1946 to September week 2, 2014); EMBASE Classic and EMBASE (Ovid) (1947 to September 2014); Web of Science Core Collection (Thomson Reuters) (1990 to September 2014); Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment Database, and Health Economics Evaluations Database on the Cochrane Library (Issue 3 of 4, 2014). We searched trial registers and reference lists of reviews for further studies. We applied no language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCTs) of interventions stating an intention to increase or decrease omega 6 fatty acids, lasting at least six months, and including healthy adults or adults at high risk of CVD. The comparison group was given no advice, no supplementation, a placebo, a control diet, or continued with their usual diet. The outcomes of interest were CVD clinical events (all-cause mortality, cardiovascular mortality, non-fatal end points) and CVD risk factors (changes in blood pressure, changes in blood lipids, occurrence of type 2 diabetes). We excluded trials involving exercise or multifactorial interventions to avoid confounding. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, extracted the data, and assessed the risk of bias in the included trials. MAIN RESULTS: We included four RCTs (five papers) that randomised 660 participants. No ongoing trials were identified. All included trials had at least one domain with an unclear risk of bias. There were no RCTs of omega 6 intake reporting CVD clinical events. Three trials investigated the effect of increased omega 6 intake on lipid levels (total cholesterol, low density lipoprotein (LDL-cholesterol), and high density lipoprotein (HDL cholesterol)), two trials reported triglycerides, and two trials reported blood pressure (diastolic and systolic blood pressure). Two trials, one with two relevant intervention arms, investigated the effect of decreased omega 6 intake on blood pressure parameters and lipid levels (total cholesterol, LDL cholesterol, and HDL-cholesterol) and one trial reported triglycerides. Our analyses found no statistically significant effects of either increased or decreased omega 6 intake on CVD risk factors.Two studies were supported by funding from the UK Food Standards Agency and Medical Research Council. One study was supported by Lipid Nutrition, a commercial company in the Netherlands and the Dutch Ministry of Economic Affairs. The final study was supported by grants from the Finnish Food Research Foundation, Finnish Heart Research Foundation, Aarne and Aili Turnen Foundation, and the Research Council for Health, Academy of Finland. AUTHORS' CONCLUSIONS: We found no studies examining the effects of either increased or decreased omega 6 on our primary outcome CVD clinical endpoints and insufficient evidence to show an effect of increased or decreased omega 6 intake on CVD risk factors such as blood lipids and blood pressure. Very few trials were identified with a relatively small number of participants randomised. There is a need for larger well conducted RCTs assessing cardiovascular events as well as cardiovascular risk factors. PMID- 26571452 TI - Simultaneous quantification of acetaminophen and five acetaminophen metabolites in human plasma and urine by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry: Method validation and application to a neonatal pharmacokinetic study. AB - Drug metabolism plays a key role in acetaminophen (paracetamol)-induced hepatotoxicity, and quantification of acetaminophen metabolites provides critical information about factors influencing susceptibility to acetaminophen-induced hepatotoxicity in clinical and experimental settings. The aims of this study were to develop, validate, and apply high-performance liquid chromatography electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS) methods for simultaneous quantification of acetaminophen, acetaminophen-glucuronide, acetaminophen-sulfate, acetaminophen-glutathione, acetaminophen-cysteine, and acetaminophen-N-acetylcysteine in small volumes of human plasma and urine. In the reported procedures, acetaminophen-d4 and acetaminophen-d3-sulfate were utilized as internal standards (IS). Analytes and IS were recovered from human plasma (10MUL) by protein precipitation with acetonitrile. Human urine (10MUL) was prepared by fortification with IS followed only by sample dilution. Calibration concentration ranges were tailored to literature values for each analyte in each biological matrix. Prepared samples from plasma and urine were analyzed under the same HPLC-ESI-MS/MS conditions, and chromatographic separation was achieved through use of an Agilent Poroshell 120 EC-C18 column with a 20-min run time per injected sample. The analytes could be accurately and precisely quantified over 2.0-3.5 orders of magnitude. Across both matrices, mean intra- and inter-assay accuracies ranged from 85% to 112%, and intra- and inter-assay imprecision did not exceed 15%. Validation experiments included tests for specificity, recovery and ionization efficiency, inter-individual variability in matrix effects, stock solution stability, and sample stability under a variety of storage and handling conditions (room temperature, freezer, freeze-thaw, and post-preparative). The utility and suitability of the reported procedures were illustrated by analysis of pharmacokinetic samples collected from neonates receiving intravenous acetaminophen. PMID- 26571453 TI - Single-step microwave assisted headspace liquid-phase microextraction of trihalomethanes and haloketones in biological samples. AB - A single-step microwave assisted headspace liquid-phase microextraction (MA-HS LPME) method was developed for determination of trihalomethanes (THMs) and haloketones (HKs) in biological samples. In this method, a porous membrane envelope was filled with few microliters of extraction solvent and then placed inside the microwave extraction vial. A PTFE ring was designed to support the membrane envelope over a certain height inside the vial. An optimum amount of biological sample was placed in the vial equipped with magnetic stirrer. After that nitric acid was added to the vial for digestion of biological sample. The sample was digested and the volatile THMs and HKs were extracted at headspace in the solvent containing porous membrane. After simultaneous digestion and extraction, the extract was injected to gas chromatography/mass spectrometry for analysis. Factors affecting the extraction efficiency were optimized to achieve higher extraction performance. Quantification was carried out over a concentration range of 0.3-100ngg(-1) for brominated compounds while for the chlorinated ones linear range was between 0.5-100ngg(-1). Limit of detections (LODs) were ranged from 0.051 to 0.110ngg(-1) while limit of quantification (LOQ) were in the range of 0.175-0.351ngg(-1). The relative standard deviations (RSDs) of the calibrations were ranged between 1.1 and 6.8%. The MA-HS-LPME was applied for the determination of trace level THMs and HKs in fish tissue and green alga samples. PMID- 26571454 TI - Determination of a novel phosphodiesterase-4 inhibitor chlorbipram in mouse plasma and brain by UFLC-MS/MS: Application in pharmacokinetic studies after intravenous administration. AB - In this study, we evaluated a simple and sensitive method for determination of a novel phosphodiesterase-4 (PDE4) inhibitor, chlorbipram, in mouse plasma and brain using ultra-fast liquid chromatography-tandem mass spectrometry (UFLC MS/MS). Separation was achieved using an Acquity UPLC BEH C18 column (50mm*2.1mm, particle size 1.7MUm) with a gradient mobile phase consisting of water and methanol at a flow rate of 0.25ml/min. Detection was performed in the multiple reaction monitoring (MRM) mode using electrospray ionization (ESI) in the positive ion mode. The liquid-liquid extraction method with ethyl acetate was used for both pretreatment of plasma and brain homogenates. The calibration curves of chlorbipram showed good linearity over the concentration range of 0.5 200ng/ml (R(2)>0.994) for mouse plasma and over the range of 0.25-100ng/ml (R(2)>0.994) for mouse brain homogenate. The extraction recovery was in the range of 78.3-84.8% for chlorbipram and the internal standard (IS) ZXI14 in two different biological matrices. The intra- and inter-day precision values were less than 13.0% and the accuracy ranged from 97.8% to 106.0% for quality control samples. No noteworthy matrix effects and instability were observed for chlorbipram. This validated method was successfully applied to a pharmacokinetic study of chlorbipram in mice after intravenous administration. The results show that this novel drug crosses the blood-brain barrier and provides the basis for further studies on chlorbipram. PMID- 26571455 TI - Analysis of the chemical constituents and rats metabolites after oral administration of Nauclea officinalis by ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry. AB - Nauclea officinalis has long been used in China for the treatment of cold, fever, swelling of throat, pink eyes, and so on; however, the in vivo integrated metabolism of its multiple bioactive components remains unknown. In this paper, an ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS) method was established to identify chemical constituents in N. officinalis and metabolites in rat biological fluids after oral administration of N. officinalis. First, 40 chemical constituents in N. officinalis were detected within 19min by UPLC-QTOF/MS. Among them, 18 alkaloids and 7 phenolic acids and iridoids were identified or tentatively characterized. Secondly, 22 metabolites were identified after oral administration of N. officinalis extract, including 3, 9, 6 and 4 metabolites in the plasma, feces, urine and bile samples, respectively. Finally, the metabolic pathway was proposed, which were the hydroxylation, the hydroxylation of deglycosyation product of parent compound, the hydroxylation and dehydrogenation product of parent compound, and acetylation. Among these, hydroxylation was considered as the main metabolic processes. This work suggests that the integrative metabolism approach makes a useful template for drug metabolism research of traditional Chinese medicine (TCM). PMID- 26571456 TI - Predicting sleepiness during an awake craniotomy. AB - OBJECTIVE: An awake craniotomy is a safe neurological surgical technique that minimizes the risk of brain damage. During the course of this surgery, the patient is asked to perform motor or cognitive tasks, but some patients exhibit severe sleepiness. Thus, the present study investigated the predictive value of a patient's preoperative neuropsychological background in terms of sleepiness during an awake craniotomy. METHODS: Thirty-seven patients with brain tumor who underwent awake craniotomy were included in this study. Prior to craniotomy, the patient evaluated cognitive status, and during the surgery, each patient's performance and attitude toward cognitive tasks were recorded by neuropsychologists. RESULTS: The present findings showed that the construction and calculation abilities of the patients were moderately correlated with their sleepiness. CONCLUSION: These results indicate that the preoperative cognitive functioning of patients was related to their sleepiness during the awake craniotomy procedure and that the patients who exhibited sleepiness during an awake craniotomy had previously experienced reduced functioning in the parietal lobe. PMID- 26571457 TI - Late onset reversible cortical blindness following electrocution. AB - An elderly gentleman presented with acute onset of bilateral visual blurring and generalized headache after 1 week post electrocution injury. Clinically, the symptoms were attributed to cortical lesion. Magnetic resonance imaging (MRI) of brain revealed bilaterally symmetrical diffusion restriction in parietal and occipital areas. Treatment with intravenous steroids resulted in remarkable improvement in symptoms. Neurological injury secondary to electrocution is a well described entity having a variety of clinical presentation. We put forward our experience with this unique case presenting as post electrocution delayed onset of visual symptoms. Discussion and review of literature related to this clinical entity will also be presented. PMID- 26571458 TI - Post-traumatic neuroma due to closed nerve injury. Is recovery after peripheral nerve trauma related to ultrasonographic neuroma size? AB - OBJECTIVE: traumatic neuroma is a pathological condition of peripheral nervous system consisting of localized proliferation of injured nerve elements. The symptoms depend on the type of involved nerve (motor and/or sensitive) and on the site and the extension of the lesion. Ultrasound is the best tool to depict the morphology of nerve, especially in traumatic conditions. We present a study aimed to assess the correlation between the degree of nerve function and the ultrasound morphology of neuromas. PATIENTS AND METHODS: we retrospectively evaluated 18 patients with neuromas (not transected) occurred after a closed nerve trauma evaluated with clinical and ultrasound assessment. The clinical evaluation was related to the % of increase of cross sectional area as detected by nerve ultrasound respect to normal nerve. RESULTS: we observed that dimensions of neuromas are not related to function until neuroma have cross sectional area 5 times enlarged respect to normal nerve, in this case recovery never occurs. CONCLUSION: our study failed to clear detect a relation between cross sectional area enlargement of neuroma and nerve function, but showed a cut off beyond which prognosis is negative. This result provide some useful information for prognosis, nevertheless we believe that future perspective studies are needed to better understand the timing of developing neuromas and its evolution. PMID- 26571459 TI - The neuronal basis of fear generalization in humans. AB - Organisms tend to respond similarly to stimuli that are perceptually close to an event that predicts adversity, a phenomenon known as fear generalization. Greater dissimilarity yields weaker behavioral responses, forming a fear-tuning profile. The perceptual model of fear generalization assumes that behavioral fear tuning results from perceptual similarities, suggesting that brain responses should also exhibit the same fear-tuning profile. Using fMRI and a circular fear generalization procedure, we tested this prediction. In contrast with the perceptual model, insula responses showed less generalization than behavioral responses and encoded the aversive quality of the conditioned stimulus, as shown by high pattern similarity between the conditioned stimulus and the shock. Also inconsistent with the perceptual model, object-sensitive visual areas responded to ambiguity-related outcome uncertainty. Together these results indicate that fear generalization is not passively driven by perception, but is an active process integrating threat identification and ambiguity-based uncertainty to orchestrate a flexible, adaptive fear response. PMID- 26571460 TI - Canonical genetic signatures of the adult human brain. AB - The structure and function of the human brain are highly stereotyped, implying a conserved molecular program responsible for its development, cellular structure and function. We applied a correlation-based metric called differential stability to assess reproducibility of gene expression patterning across 132 structures in six individual brains, revealing mesoscale genetic organization. The genes with the highest differential stability are highly biologically relevant, with enrichment for brain-related annotations, disease associations, drug targets and literature citations. Using genes with high differential stability, we identified 32 anatomically diverse and reproducible gene expression signatures, which represent distinct cell types, intracellular components and/or associations with neurodevelopmental and neurodegenerative disorders. Genes in neuron-associated compared to non-neuronal networks showed higher preservation between human and mouse; however, many diversely patterned genes displayed marked shifts in regulation between species. Finally, highly consistent transcriptional architecture in neocortex is correlated with resting state functional connectivity, suggesting a link between conserved gene expression and functionally relevant circuitry. PMID- 26571462 TI - Key role of pancreatic stellate cells in pancreatic cancer. AB - Pancreatic stellate cells (PSCs) are responsible for producing the collagenous stroma in pancreatic cancer. Findings from the majority of in vitro and in vivo studies to date indicate that PSCs interact with cancer cells as well as with other cellular elements in the stroma including immune cells, endothelial cells and neuronal cells to set up a growth permissive microenvironment for pancreatic tumours. However, two recent studies reporting a protective effect of myofibroblasts in pancreatic cancer have served to remind researchers of the possibility that the role of PSCs in this disease may be context and time dependent, such that any possible early protective role of PSCs is subverted in later stages by the ability of cancer cells to turn PSCs into cancer-promoting aides. This concept is supported by the development in recent years of several novel therapeutic approaches targeting the stroma that have been successfully applied in pre-clinical settings to inhibit disease progression. A multi-pronged approach aimed at tumour cells as well as stromal elements may be the key to achieving better clinical outcomes in patients with pancreatic cancer. PMID- 26571463 TI - Advances in osteosarcoma stem cell research and opportunities for novel therapeutic targets. AB - Osteosarcoma is the most common type of bone cancer, especially in children and young adults. The primary treatment for osteosarcoma is a combination of surgery and chemotherapy, however prognoses remain poor due to chemoresistance and early metastases. Osteosarcoma stem cells appear to play central roles in tumor recurrence, metastases and chemoresistance via self-renewal and differentiation. Targeting these cells may provide a novel strategy in the treatment of osteosarcoma. This review summarizes current knowledge of this rare phenotype and recent advances in understanding the functions OSCs (osteosarcoma stem cells) in osteosarcoma, with the aim of improving therapies in the future. PMID- 26571464 TI - From Global to Local: Inequalities in Health and Healthcare. PMID- 26571465 TI - Canada's New Generic Pricing Policy: A Reasoned Approach to a Challenging Problem. AB - Alberta, quickly followed by other Canadian provinces, has introduced a new pricing model for generic drugs, in which prices are inversely related to the number of generic manufacturers of the drug. This paper examines the rationale for the new policy. PMID- 26571466 TI - Reimbursement of Drugs for Rare Diseases through the Public Healthcare System in Canada: Where Are We Now? AB - INTRODUCTION: Over the past 20 years, the number of therapies developed for rare diseases has rapidly increased. Often, these therapies represent the only active treatment for debilitating and/or life-threatening conditions. However, they create significant challenges for public and private payers. Because they target small patient populations, clinical evidence of efficacy/effectiveness is typically limited, while the cost per patient is high. In Canada, each province/territory establishes its own mechanisms for determining which drugs for rare diseases (DRDs) to provide. OBJECTIVES: To compare current mechanisms across provinces and territories, and explore their impact on access. METHODS: A systematic review of relevant published and unpublished documents was performed. Electronic bibliographic databases, the internet, and government websites were scanned using structured search strategies. Information was extracted independently by two researchers, and included aspects such as program type, condition/patient/therapy eligibility criteria, role of health technology assessment (HTA), decision options, ethical assumptions, and stakeholder input. It was validated through member-checking with provincial/territorial policy experts and tabulated to facilitate qualitative analyses. Impact on access was assessed through a cross-province/territory comparison of the coverage status of all non-cancer therapies reviewed by the Common Drug Review for indications affecting <1/2,000 Canadians using the Kappa statistic. Reasons for variations were explored using qualitative techniques. RESULTS: Each province/territory has formal and informal mechanisms through which such therapies may be accessed. In most cases, formal mechanisms constitute the centralized HTA processes that also apply to common therapies. While several provinces have established dedicated processes/programs, whether they have affected access is not clear. Despite broadly comparable approaches, there is less than perfect agreement on publicly funded DRDs across jurisdictions. CONCLUSIONS: Individual jurisdictions have developed different approaches to providing access to these therapies. However, as the number increases, a more systematic approach to decision-making may be needed. PMID- 26571467 TI - How Can Health System Efficiency Be Improved in Canada? AB - Improving value for money in the health system is an often-stated policy goal. This study is the first to systematically measure the efficiency of health regions in Canada in producing health gains with their available resources, and to identify the factors that are associated with increased efficiency. Based on the objective elicited from decision-makers that the health system should ensure access to care for Canadians when they need it, we measured the efficiency with which regions reduce causes of death that are amenable to healthcare interventions using a linear programming approach (data envelopment analysis). Variations in efficiency were explained in part by public health factors, such as the prevalence of obesity and smoking in the population; in part by characteristics of the population, such as their average income; and in part by managerial factors, such as hospital readmissions. PMID- 26571468 TI - Mix of Maternity Care Providers in Canada. AB - OBJECTIVE: To identify the factors influencing women's choice of maternity care providers in Canada. METHOD: Using the Maternity Experience Survey and a multinomial logit model, this paper examined the influence of various socio economic and demographic factors on the mix of maternity care providers, while controlling for maternal risk profiles. Additionally, provinces were interacted with maternal age to assess the extent to which regional variations in mix of maternity care providers is influenced by pregnant women's needs. RESULTS: Besides maternal risk factors, province of prenatal care and the place of residence were found to be statistically significant determinants of choice of maternity care providers. Analysis involving interaction terms indicated wide regional variations in the mix of providers by maternal age. CONCLUSIONS: The results suggest a wide provincial variation in the mix of maternity care providers. New provincial government initiatives are needed to enhance the supply and capacity of care providers. PMID- 26571461 TI - Mutations in NONO lead to syndromic intellectual disability and inhibitory synaptic defects. AB - The NONO protein has been characterized as an important transcriptional regulator in diverse cellular contexts. Here we show that loss of NONO function is a likely cause of human intellectual disability and that NONO-deficient mice have cognitive and affective deficits. Correspondingly, we find specific defects at inhibitory synapses, where NONO regulates synaptic transcription and gephyrin scaffold structure. Our data identify NONO as a possible neurodevelopmental disease gene and highlight the key role of the DBHS protein family in functional organization of GABAergic synapses. PMID- 26571469 TI - A Cost-Effectiveness Analysis of Low-Risk Deliveries: A Comparison of Midwives, Family Physicians and Obstetricians. AB - OBJECTIVE: To investigate the cost-effectiveness of in-hospital obstetrical care by obstetricians (OBs), family physicians (FPs) and midwives (MWs) for delivery of low-risk obstetrical patients. METHODS: Cost-effectiveness analysis from the Ministry of Health perspective using a retrospective cohort study. The time horizon was from hospital admission of a low-risk pregnant patient to the discharge of the mother and infant. Costing data included human resource, intervention and hospital case-mix costs. Interventions measured were induction or augmentation of labour with oxytocin, epidural use, forceps or vacuum delivery and caesarean section. The outcome measured was avoidance of transfer to a neonatal intensive care unit (NICU). Model results were tested using various types of sensitivity analyses. FINDINGS: The mean maternal age by provider groups was 29.7 for OBs, 29.8 for FPs and 31.2 for MWs - a statistically higher mean for the MW group. The MW deliveries had lower costs and better outcomes than FPs and OBs. FPs also dominated OB.s The differences in cost per delivery were small, but slightly lower in MW ($5,102) and FP ($5,116) than in OB ($5,188). Avoidance of transfer to an NICU was highest for MW at 94.0% (95% CI: 91.0-97.0), compared with 90.2% for FP (95% CI: 88.2-92.2) and 89.6% for OB (95% CI: 88.6-90.6). The cost-effectiveness of the MW group is diminished by increases in compensation, and the cost-effectiveness of the FP group is sensitive to changes in intervention rates and costs. CONCLUSIONS: The MW strategy was the most cost effective in this hospital setting. Given data limitations to further examine patient characteristics between groups, the overall conservative findings of this study support investments and better integration for MWs in the current system. PMID- 26571470 TI - The Untold Story of Being Designated an Alternate Level of Care Patient. AB - INTRODUCTION: Much of the research and policy reports on Alternate Level of Care (ALC) in Canada have focused on the impact ALC has on acute care services. To date, the experiences and opinions of those who must wait in hospital for alternate services have been largely absent from discussions. METHOD: A qualitative study was conducted with patients and families designated as ALC in one urban and two rural hospitals in Atlantic Canada. Data were analyzed using content analysis. RESULTS: Three themes emerged from the data: a perception of normalcy, being old but not sick and anticipating relocation to another facility. CONCLUSIONS: ALC is an important issue for patients and their families. Policy directives aimed at addressing the causes and impacts of ALC, identification and provision of appropriate supportive care in the community and sensitivity to the impact of ALC for individuals designated as ALC are needed. PMID- 26571472 TI - [The SCOT-HEART study]. PMID- 26571471 TI - Barriers to the Adoption of Safety-Engineered Needles Following a Regulatory Standard: Lessons Learned from Three Acute Care Hospitals. AB - BACKGROUND: A number of jurisdictions have introduced regulation to accelerate the adoption of safety-engineered needles (SENs). This study examined the transition to SENs in three acute care hospitals prior to and following the implementation of a regulatory standard in Ontario. This paper focuses on the ongoing barriers to the prevention of needlestick injuries among healthcare workers. METHODS: Information from document review and 30 informant interviews were used to prepare three case studies detailing each organization's implementation activities and outcomes. RESULTS: All three hospitals responded to the regulatory requirements with integrity and needlestick injuries declined. However, needlestick injuries continued to occur during the activation of safety devices, during procedures and during instrument disposal. The study documented substantial barriers to further progress in needlestick injury prevention. CONCLUSIONS: Healthcare organizations should focus on understanding their site specific challenges that contribute to ongoing injury risk to better understand issues related to product limitations, practice constraints and the work environment. PMID- 26571473 TI - [Should all patients with atrial fibrillation and CHA2DS2-VASc score 1 receive oral anticoagulation?]. PMID- 26571474 TI - [Betablockers in patients with heart failure and atrial fibrillation]. AB - A recent individual patient data meta-analysis has shown that beta-blockers reduce mortality in patients with heart failure and reduced left ventricular ejection fraction (HFrEF) who are in sinus rhythm but not in those who are in atrial fibrillation. Similar results applied also to cardiovascular death or first hospitalization for heart failure. The European Society of Cardiology guidelines recommend beta-blockers in patients with HFrEF regardless of baseline rhythm. However, despite improving symptoms, the prognostic benefits of beta blockers have now been questioned by these authors in patients with HFrEF and atrial fibrillation. In this review we comment the findings of this study. PMID- 26571475 TI - [What role for antiarrhythmic drugs today in patients with recurrent atrial fibrillation without relevant heart disease?]. AB - The efficacy of antiarrhythmic drugs (AADs) in the prevention of recurrent (paroxysmal or persistent) atrial fibrillation (AF) is rather low, since 1-year symptomatic recurrences are observed in ~50% of patients. New treatments have been suggested: upstream therapy does not appear to be effective in the prevention of AF recurrences, whereas catheter ablation has shown good results. Consistent data dealing with this procedure are available only in young patients, without relevant heart disease and with recurrent AF, refractory to AADs. In the present paper, an analysis of both systematic reviews of trials/meta-analyses and registries, which better express the real world, was carried out. The 1-year success rate of AF ablation in patients with the above mentioned characteristics was 70-80%. However, the 1-year single-procedure success rate, free of AADs, was only 47-57% in the trials and even lower in the real world (30-40%). The final success was increased by one or more repeated ablations, in 15-40% of patients, and by the use of AADs, ineffective before ablation, in ~40-50% of patients at 1 year and in ~60% at 2-year follow-up. AADs increased the success rate by ~15% in the trials and by a much higher percentage in the real world, even if not clearly definable. Considering that ~10-12% of patients have the first symptomatic recurrences only 1-2 years after ablation and others in the next years, AADs have still an important role in the management of patients with recurrent AF without relevant heart disease, not only as first-line treatment, but also in patients who underwent catheter ablation. Therefore, AF ablation appears to be more a supplementing procedure than a procedure alternative to AADs; in other words, the association ablation-AADs is more effective than AADs alone. PMID- 26571476 TI - [Innovative therapies for the treatment of refractory angina: the Reducer, a percutaneous device to narrow the coronary sinus]. AB - Refractory angina is a chronic condition characterized by the presence of disabling symptoms due to severe obstructive coronary artery disease that is not improved by a combination of medical therapy and percutaneous or surgical revascularization. Mortality rates associated with this condition are quite low in clinically stable patients on optimal medical therapy, but rehospitalization rates remain high. This mandates the need for new therapies targeting an improvement of symptoms in this population, taking into account also the potential impact in terms of healthcare and costs. The increase in coronary sinus pressure seems to reduce myocardial ischemia leading to a redistribution of blood flow to the ischemic territories. The coronary sinus Reducer is a percutaneous implantable device, made of a stainless steel hourglass-shaped stent, designed to achieve controlled narrowing of the coronary sinus and to increase its upstream pressure. In various studies, the Reducer was safely implanted percutaneously via the right jugular vein in patients with refractory angina who were not amenable to revascularization and was associated with an improvement in anginal symptoms and ischemia. These results support further evaluation of the Reducer as an alternative treatment for patients with chronic refractory angina who are not candidates for coronary revascularization. PMID- 26571477 TI - [Heart involvement in Anderson-Fabry disease: Italian recommendations for diagnostic, follow-up and therapeutic management]. AB - Anderson-Fabry disease is a rare X-linked lysosomal storage disorder caused by mutations of the GLA gene that encodes alpha-galactosidase A. It is characterized by a multisystemic involvement: the renal, neurological, heart, cochleovestibular and cutaneous systems are the most damaged. Morbidity and mortality of Anderson Fabry disease depend on renal insufficiency, heart failure and nervous system involvement. Left ventricular hypertrophy is the most common cardiac manifestation followed by conduction system disease, valve dysfunction, and arrhythmias. Mild to moderate left ventricular hypertrophy may simulate a non obstructive hypertrophic cardiomyopathy. Management of Anderson-Fabry disease starting from the diagnosis of cardiac involvement, the prevention of complications, the therapeutic aspects, up to appropriate clinical follow-up, requires a multidisciplinary approach. According to recent management guidelines, only few evidence-based data are available to guide the clinical and therapeutic approach to this rare disease. An Italian Board, composed by nephrologists, cardiologists, geneticists, pediatricians and neurologists has been established in order to approve by consensus a diagnostic and therapeutic management protocol. The authors report the results of this cardiologic management consensus. PMID- 26571478 TI - [The overuse of thromboprophylaxis in medical patients: main clinical aspects]. AB - BACKGROUND: Overuse of thromboprophylaxis is not an infrequent behavior in internal medicine. However, differently from underuse, overuse of thromboprophylaxis is rarely taken into account, and only few studies have addressed this issue. The purpose of our study was to try to understand the reasons behind this phenomenon. METHODS: Using data from the TEVERE study, we evaluated 279 patients hospitalized in 21 hospitals of the Lazio Region in Italy. Only patients who were negative to major risk scores as established in the scientific literature were included. We assessed the frequency of thromboprophylaxis in acutely ill medical patients hospitalized in emergency and internal medicine wards, and we performed a comparative analysis for each risk factor among patients who received or not received thromboprophylaxis. RESULTS: Forty-seven patients (16.5%) with negative risk scores were given thromboprophylaxis during hospitalization. On backward stepwise logistic regression analysis, severe infection (odds ratio [OR] 2.31; 95% confidence interval [CI] 1.25-4.35) and chronic venous insufficiency (OR 3.02; 95% CI 1.96 4.67) were found to be the strongest predictors of the use of thromboprophylactic treatment with heparin. The subgroup of patients who did not exhibit risk factors was also analyzed, and age was found to be the main factor in the decision-making process regarding heparin administration in the absence of other risk factors (74.9 +/- 11.8 vs 63.7 +/- 18.1, p=0.002). CONCLUSIONS: Our findings suggest that thromboprophylaxis is associated with considerable uncertainty, which results in its overuse. Further research is needed to better understand thromboembolic risk factors in hospitalized medical patients. PMID- 26571479 TI - [Heart and trauma: two representative cases of chest pain after high energy impact]. AB - Patients complaining of chest pain after a traumatic event represent a diagnostic challenge for the cardiologist. These patients can definitely escape from common diagnostic tests (particularly ECG and markers of myocardial lysis) that may guide the cardiologist, mostly because symptoms are attributed to the trauma itself. On the other hand, if blunt cardiac injury is suspected (involving coronary arteries, aorta, pulmonary trunk, pericardium, myocardium or valves), the selection of the most appropriate diagnostic and therapeutic tools (i.e. antithrombotic therapy) should also consider trauma involvement of other organs. We here describe two emblematic cases as examples of the challenges that diagnosis and treatment of cardiac injury can bring. PMID- 26571480 TI - [Isolated pulmonary valve endocarditis]. AB - We report a case of isolated pulmonary valve endocarditis evaluated with real time three-dimensional echocardiography in a previous intravenous drug user. Although right-sided infective endocarditis is common in this population, the involvement of the pulmonary valve without infection of the tricuspid valve is a rare condition. PMID- 26571481 TI - [Remarks on polyparametric assessment of sudden death risk for primary prevention ICD implantation in patients with left ventricular dysfunction of ischemic and non ischemic etiology. Italian Association of Hospital Cardiologists (ANMCO) Experts Position Paper]. AB - It is generally recognized that current guidelines, based on ejection fraction criteria, do not allow appropriate selection of patients for implantable cardioverter-defibrillator (ICD) therapy in the primary prevention of sudden death, thus hindering the optimal use of ICD in patients with left ventricular dysfunction of ischemic and nonischemic etiology. Ejection fraction alone has limitations in both sensitivity and specificity. Assessment of the risk for sudden death using a combination of multiple tests (ejection fraction associated with one or more different arrhythmic risk markers) could partially compensate for these limitations. In this position paper, the potential usefulness of a polyparametric assessment using some of the most investigated risk markers of sudden death is discussed, including late gadolinium enhancement cardiac magnetic resonance, programmed ventricular stimulation, T-wave alternans, autonomic tone, biomarkers, and genetic testing. PMID- 26571483 TI - Categories of Hospital-Associated Acute Kidney Injury: Time Course of Changes in Serum Creatinine Values. AB - Hospital-associated acute kidney injury (HA-AKI) is associated with increased inpatient mortality. Our objective was to categorize HA-AKI based on the timing of minimum and peak inpatient serum creatinine (sCr) and describe the association with inpatient mortality. MATERIALS AND METHODS: This study is a retrospective analysis of an administrative data set for adults admitted to a single medical center for over 4 years. Changes and timing of the minimum and peak sCr were used to define HA-AKI categories. RESULTS: Peak creatinine followed minimum creatinine for HA-AKI, and preceded the minimum value for transient HA-AKI (THA-AKI). A subset of patients developed HA-AKI after recovering from THA-AKI. Multivariable Cox regression analyses examined the association between these categories and 28 day inpatient mortality, adjusting for age, sex, race, Charlson comorbidity index, baseline kidney function, AKI recovery and renal replacement therapy. There were 50,601 patients included in the analyses, and 29,996 (59%) did not have AKI. There were 2,440 deaths; HA-AKI had a 2.24-fold (95% CI 1.99-2.51) increased risk, while THA-AKI group (12,101) had a 1.23-fold (95% CI 1.09-1.40) increased risk for inpatient mortality. THA-AKI patients who recovered and then developed HA-AKI had the same mortality risk as THA-AKI (1.27-fold [95% CI 1.07 1.51]) but longer hospitalization and less recovery from AKI. CONCLUSIONS: Risk of short-term inpatient mortality is associated with AKI, and this risk is attenuated with recovery of kidney function in the hospital. Systematic surveillance with repeated inpatient sCr values is needed to assess the short- and long-term consequences of HA-AKI. PMID- 26571484 TI - From Root Cause to Action Plan: How an Adverse Event Uncovered Deficiencies in Resident Knowledge of Sedation Policies and Practices. AB - Mild or moderate sedation for procedures frequently is administered outside the operating room by resident physicians with varying degrees of training. An adverse event at our institution involving procedural sedation prompted us to conduct a survey among resident physicians. This survey investigated resident knowledge and attitudes about sedatives and analgesics, in addition to knowledge of risk factors for sedation-related adverse events. The survey identified a range of knowledge deficiencies among resident physicians and a lack of awareness of institutional sedation policies. Identification of knowledge gaps facilitated an educational initiative that promoted training in the pharmacology of sedatives and analgesics, safe sedation practices, and institutional sedation policies. Additional interventions included updating our sedation policy and creation of an electronic order set to facilitate the safe prescription of sedatives. PMID- 26571482 TI - Preexposure Prophylaxis for HIV Infection Integrated With Municipal- and Community-Based Sexual Health Services. AB - IMPORTANCE: Several randomized clinical trials have demonstrated the efficacy of preexposure prophylaxis (PrEP) in preventing human immunodeficiency virus (HIV) acquisition. Little is known about adherence to the regimen, sexual practices, and overall effectiveness when PrEP is implemented in clinics that treat sexually transmitted infections (STIs) and community-based clinics serving men who have sex with men (MSM). OBJECTIVE: To assess PrEP adherence, sexual behaviors, and the incidence of STIs and HIV infection in a cohort of MSM and transgender women initiating PrEP in the United States. DESIGN, SETTING, AND PARTICIPANTS: Demonstration project conducted from October 1, 2012, through February 10, 2015 (last date of follow-up), among 557 MSM and transgender women in 2 STI clinics in San Francisco, California, and Miami, Florida, and a community health center in Washington, DC. Data were analyzed from December 18, 2014, through August 8, 2015. INTERVENTIONS: A combination of daily, oral tenofovir disoproxil fumarate and emtricitabine was provided free of charge for 48 weeks. All participants received HIV testing, brief client-centered counseling, and clinical monitoring. MAIN OUTCOMES AND MEASURES: Concentrations of tenofovir diphosphate in dried blood spot samples, self-reported numbers of anal sex partners and episodes of condomless receptive anal sex, and incidence of STI and HIV acquisition. RESULTS: Overall, 557 participants initiated PrEP, and 437 of these (78.5%) were retained through 48 weeks. Based on the findings from the 294 participants who underwent measurement of tenofovir diphosphate levels, 80.0% to 85.6% had protective levels (consistent with >=4 doses/wk) at follow-up visits. African American participants (56.8% of visits; P = .003) and those from the Miami site (65.1% of visits; P < .001) were less likely to have protective levels, whereas those with stable housing (86.8%; P = .02) and those reporting at least 2 condomless anal sex partners in the past 3 months (88.6%; P = .01) were more likely to have protective levels. The mean number of anal sex partners declined during follow-up from 10.9 to 9.3, whereas the proportion engaging in condomless receptive anal sex remained stable at 65.5% to 65.6%. Overall STI incidence was high (90 per 100 person-years) but did not increase over time. Two individuals became HIV infected during follow-up (HIV incidence, 0.43 [95% CI, 0.05-1.54] infections per 100 person-years); both had tenofovir diphosphate levels consistent with fewer than 2 doses/wk at seroconversion. CONCLUSIONS AND RELEVANCE: The incidence of HIV acquisition was extremely low despite a high incidence of STIs in a large US PrEP demonstration project. Adherence was higher among those participants who reported more risk behaviors. Interventions that address racial and geographic disparities and housing instability may increase the impact of PrEP. PMID- 26571485 TI - Early- and Middle-Term Surgical Outcomes in Patients with Heterotaxy Syndrome. AB - OBJECTIVES: Heterotaxy syndrome is a recognized risk factor for surgical cardiac interventions. We evaluated the early- and middle-term results of a surgical intervention for patients with heterotaxy syndrome. METHODS: A total of 42 patients with heterotaxy syndrome were enrolled (September 2008 to March 2015). Left and right atrial isomerism were identified in 26% (11 out of 42) and 74% of patients (31 out of 42), respectively. The median age of the patients at the time of surgery was 6.8 months (range: 5 days to 22.3 years). Biventricular repair was completed in 3 patients with left atrial isomerism. Seventeen out of 39 patients who were scheduled for single ventricular repair completed a modified Fontan procedure. RESULTS: The hospital mortality rate was 4.7% (2 out of 42). Another 5 deaths occurred in the remaining survivors following hospital discharge with a follow-up duration of 45.8 +/- 23.6 months (range: 13-111 months). The 1-year and 5-year survival rates were 88.1% (37/42) and 83.3% (35/42), respectively. Univariate analysis and multivariate analysis identified pulmonary venous obstruction and atrioventricular valve replacement as additional risk factors for mortality. CONCLUSIONS: Right ventricular bypass surgery remains the preferred palliative procedure for patients with heterotaxy syndrome. Based on the current results, the early- and middle-term outcomes are satisfactory. PMID- 26571486 TI - The Impact of Heterogeneous Thresholds on Social Contagion with Multiple Initiators. AB - The threshold model is a simple but classic model of contagion spreading in complex social systems. To capture the complex nature of social influencing we investigate numerically and analytically the transition in the behavior of threshold-limited cascades in the presence of multiple initiators as the distribution of thresholds is varied between the two extreme cases of identical thresholds and a uniform distribution. We accomplish this by employing a truncated normal distribution of the nodes' thresholds and observe a non monotonic change in the cascade size as we vary the standard deviation. Further, for a sufficiently large spread in the threshold distribution, the tipping-point behavior of the social influencing process disappears and is replaced by a smooth crossover governed by the size of initiator set. We demonstrate that for a given size of the initiator set, there is a specific variance of the threshold distribution for which an opinion spreads optimally. Furthermore, in the case of synthetic graphs we show that the spread asymptotically becomes independent of the system size, and that global cascades can arise just by the addition of a single node to the initiator set. PMID- 26571487 TI - Hypothetical Outcome Plots Outperform Error Bars and Violin Plots for Inferences about Reliability of Variable Ordering. AB - Many visual depictions of probability distributions, such as error bars, are difficult for users to accurately interpret. We present and study an alternative representation, Hypothetical Outcome Plots (HOPs), that animates a finite set of individual draws. In contrast to the statistical background required to interpret many static representations of distributions, HOPs require relatively little background knowledge to interpret. Instead, HOPs enables viewers to infer properties of the distribution using mental processes like counting and integration. We conducted an experiment comparing HOPs to error bars and violin plots. With HOPs, people made much more accurate judgments about plots of two and three quantities. Accuracy was similar with all three representations for most questions about distributions of a single quantity. PMID- 26571488 TI - Prebiotics Do Not Influence the Severity of Atopic Dermatitis in Infants: A Randomised Controlled Trial. AB - The objective was to evaluate the effects of a hypoallergenic (HA) formula supplemented with prebiotic galacto-oligosaccharides on the severity of atopic manifestations. A randomised clinical trial was conducted. The control group was infants, fed with hypoallergenic formula and without supplementation. The duration of the study was six months. The primary outcome of the study was a difference in the severity of atopic dermatitis measured using SCORAD (Scoring Atopic Dermatitis) criteria. Secondary outcomes were anthropometry (length, weight, and head circumference), together with the tolerance and incidence of infections. Both groups showed a decrease of average SCORAD values, but no statistically significant difference between the evaluated groups was observed. There were no statistically significant differences in anthropometry, or the tolerance or incidence of infections. Although there is no evidence, that consumption of a hypoallergenic infant formula enriched with prebiotic galacto oligosaccharides had any effect on SCORAD, it was safe and well tolerated. TRIAL REGISTRATION: www.clinicaltrials.gov NCT 02077088. PMID- 26571489 TI - Osteoprotegerin Induces Apoptosis of Osteoclasts and Osteoclast Precursor Cells via the Fas/Fas Ligand Pathway. AB - Osteoprotegerin (OPG) is known to inhibit differentiation and activation of osteoclasts (OCs) by functioning as a decoy receptor blocking interactions between RANK and RANKL. However, the exact role of OPG in the survival/apoptosis of OCs remains unclear. OPG caused increased rates of apoptosis of both OCs and osteoclast precursor cells (OPCs). The expression of Fas and activated caspase-8 was increased by both 20 ng/mL and 40 ng/mL of OPG, but was markedly decreased at 80 ng/mL. Interestingly, we noted that while levels of Fas ligand (FasL) increased with increasing doses of OPG, the soluble form of FasL in the supernatant decreased. The results of a co-immunoprecipitation assay suggested that the decrease of sFasL might be caused by the binding of OPG. This would block the inhibition of the apoptosis of OCs and OPCs. Furthermore, changes in expression levels of Bax/Bcl-2, cleaved-caspase-9, cleaved-caspased-3 and the translocation of cytochrome c, illustrated that OPG induced apoptosis of OCs and OPCs via the classic Fas/FasL apoptosis pathway, and was mediated by mitochondria. Altogether, our results demonstrate that OPG induces OCs and OPCs apoptosis partly by the Fas/FasL signaling pathway. PMID- 26571490 TI - Got Milk? Breastfeeding and Milk Analysis of a Mother on Chronic Hemodialysis. AB - PURPOSE: Women on dialysis rarely become pregnant. However, the overall rate of successful pregnancies is increasing in this patient population and breastfeeding becomes an option for mothers on dialysis. In this study we performed a systematic breast milk composition analysis of a mother on chronic hemodialysis (HD). METHODS: Specimens of breast milk and blood were collected in regular intervals before and after HD from a 39-year old woman starting on day 10 postpartum. Samples were analyzed for electrolytes, retention solutes, nutrients and other laboratory measurements. Breast milk samples from low-risk mothers matched for postpartum age were used as controls. RESULTS: Significantly higher levels of creatinine and urea were found in pre-HD breast milk when compared to post-HD. A similar post-dialytic decrease was only found for uric acid but not for any other investigated parameter. Conversely, sodium and chloride were significantly increased in post-HD samples. Compared to controls creatinine and urea were significantly higher in pre-HD samples while the difference remained only significant for post-HD creatinine. Phosphate was significantly lower in pre and post-HD breast milk when compared to controls, whereas calcium showed no significant differences. In terms of nutrient components glucose levels showed a strong trend for a decrease, whereas protein, triglycerides and cholesterol did not differ. Similarly, no significant differences were found in iron, potassium and magnesium content. CONCLUSION: To the best of our knowledge this is the first report on a breastfeeding mother on chronic dialysis. Although we found differences in creatinine, urea, sodium, chloride and phosphate, our general analysis showed high similarity of our patient's breast milk to samples from low risk control mothers. Significant variations in breast milk composition between pre- and post-HD samples suggest that breastfeeding might be preferably performed after dialysis treatment. In summary, our findings indicate that breastfeeding can be considered a viable option for newborns of mothers on dialysis. PMID- 26571491 TI - Quality of Life in Female Epispadias. PMID- 26571492 TI - Overall Quality of Life in Adult Biliary Atresia Survivors with or without Liver Transplantation: Results from a National Cohort. PMID- 26571493 TI - Vorinostat Enhances Cytotoxicity of SN-38 and Temozolomide in Ewing Sarcoma Cells and Activates STAT3/AKT/MAPK Pathways. AB - Histone deacetylase inhibitors (HDACi) have been evaluated in patients with Ewing sarcoma (EWS) but demonstrated limited activity. To better understand the potential for HDACi in EWS, we evaluated the combination of the HDACi vorinostat, with DNA damaging agents SN-38 (the active metabolite of irinotecan and topoisomerase 1 inhibitor) plus the alkylating agent temozolomide (ST). Drugs were evaluated in sequential and simultaneous combinations in two EWS cell lines. Results demonstrate that cell viability, DNA damage and reactive oxygen species (ROS) production are dependent on the sequence of drug administration. Enhanced cytotoxicity is exhibited in vitro in EWS cell lines treated with ST administered before vorinostat, which was modestly higher than concomitant treatment and superior to vorinostat administered before ST. Drug combinations downregulate cyclin D1 to induce G0/G1 arrest and promote apoptosis by cleavage of caspase-3 and PARP. When ST is administered before or concomitantly with vorinostat there is activation of STAT3, MAPK and the p53 pathway. In contrast, when vorinostat is administered before ST, there is DNA repair, increased AKT phosphorylation and reduced H2B acetylation. Inhibition of AKT using the small molecule inhibitor MK 2206 did not restore H2B acetylation. Combining ST with the dual ALK and IGF-1R inhibitor, AZD3463 simultaneously inhibited STAT3 and AKT to enhance the cytotoxic effects of ST and further reduce cell growth suggesting that STAT3 and AKT activation were in part mediated by ALK and IGF-1R signaling. In summary, potent antiproliferative and proapoptotic activity were demonstrated for ST induced DNA damage before or simultaneous with HDAC inhibition and cell death was mediated through the p53 pathway. These observations may aid in designing new protocols for treating pediatric patients with high-risk EWS. PMID- 26571494 TI - Interaction of Arabidopsis Trihelix-Domain Transcription Factors VFP3 and VFP5 with Agrobacterium Virulence Protein VirF. AB - Agrobacterium is a natural genetic engineer of plants that exports several virulence proteins into host cells in order to take advantage of the cell machinery to facilitate transformation and support bacterial growth. One of these effectors is the F-box protein VirF, which presumably uses the host ubiquitin/proteasome system (UPS) to uncoat the packaging proteins from the invading bacterial T-DNA. By analogy to several other bacterial effectors, VirF most likely has several functions in the host cell and, therefore, several interacting partners among host proteins. Here we identify one such interactor, an Arabidopsis trihelix-domain transcription factor VFP3, and further show that its very close homolog VFP5 also interacted with VirF. Interestingly, interactions of VirF with either VFP3 or VFP5 did not activate the host UPS, suggesting that VirF might play other UPS-independent roles in bacterial infection. To better understand the potential scope of VFP3 function, we used RNAi to reduce expression of the VFP3 gene. Transcriptome profiling of these VFP3 silenced plants using high-throughput cDNA sequencing (RNA-seq) revealed that VFP3 substantially affected plant gene expression; specifically, 1,118 genes representing approximately 5% of all expressed genes were significantly either up or down-regulated in the VFP3 RNAi line compared to wild-type Col-0 plants. Among the 507 up-regulated genes were genes implicated in the regulation of transcription, protein degradation, calcium signaling, and hormone metabolism, whereas the 611 down-regulated genes included those involved in redox regulation, light reactions of photosynthesis, and metabolism of lipids, amino acids, and cell wall. Overall, this pattern of changes in gene expression is characteristic of plants under stress. Thus, VFP3 likely plays an important role in controlling plant homeostasis. PMID- 26571495 TI - SS18-SSX, the Oncogenic Fusion Protein in Synovial Sarcoma, Is a Cellular Context Dependent Epigenetic Modifier. AB - The prevalence and specificity of unique fusion oncogenes are high in a number of soft tissue sarcomas (STSs). The close relationship between fusion genes and clinicopathological features suggests that a correlation may exist between the function of fusion proteins and cellular context of the cell-of-origin of each tumor. However, most STSs are origin-unknown tumors and this issue has not yet been investigated in detail. In the present study, we examined the effects of the cellular context on the function of the synovial sarcoma (SS)-specific fusion protein, SS18-SSX, using human pluripotent stem cells (hPSCs) containing the drug inducible SS18-SSX gene. We selected the neural crest cell (NCC) lineage for the first trial of this system, induced SS18-SSX at various differentiation stages from PSCs to NCC-derived mesenchymal stromal cells (MSCs), and compared its biological effects on each cell type. We found that the expression of FZD10, identified as an SS-specific gene, was induced by SS18-SSX at the PSC and NCC stages, but not at the MSC stage. This stage-specific induction of FZD10 correlated with stage-specific changes in histone marks associated with the FZD10 locus and also with the loss of the BAF47 protein, a member of the SWI/SNF chromatin-remodeling complex. Furthermore, the global gene expression profile of hPSC-derived NCCs was the closest to that of SS cell lines after the induction of SS18-SSX. These results clearly demonstrated that the cellular context is an important factor in the function of SS18-SSX as an epigenetic modifier. PMID- 26571496 TI - Lapatinib Plasma and Tumor Concentrations and Effects on HER Receptor Phosphorylation in Tumor. AB - PURPOSE: The paradigm shift in cancer treatment from cytotoxic drugs to tumor targeted therapies poses new challenges, including optimization of dose and schedule based on a biologically effective dose, rather than the historical maximum tolerated dose. Optimal dosing is currently determined using concentrations of tyrosine kinase inhibitors in plasma as a surrogate for tumor concentrations. To examine this plasma-tumor relationship, we explored the association between lapatinib levels in tumor and plasma in mice and humans, and those effects on phosphorylation of human epidermal growth factor receptors (HER) in human tumors. EXPERIMENTAL DESIGN: Mice bearing BT474 HER2+ human breast cancer xenografts were dosed once or twice daily (BID) with lapatinib. Drug concentrations were measured in blood, tumor, liver, and kidney. In a randomized phase I clinical trial, 28 treatment-naive female patients with early stage HER2+ breast cancer received lapatinib 1000 or 1500 mg once daily (QD) or 500 mg BID before evaluating steady-state lapatinib levels in plasma and tumor. RESULTS: In mice, lapatinib levels were 4-fold higher in tumor than blood with a 4-fold longer half-life. Tumor concentrations exceeded the in vitro IC90 (~ 900 nM or 500 ng/mL) for inhibition of HER2 phosphorylation throughout the 12-hour dosing interval. In patients, tumor levels were 6- and 10-fold higher with QD and BID dosing, respectively, compared to plasma trough levels. The relationship between tumor and plasma concentration was complex, indicating multiple determinants. HER receptor phosphorylation varied depending upon lapatinib tumor concentrations, suggestive of changes in the repertoire of HER homo- and heterodimers. CONCLUSION: Plasma lapatinib concentrations underestimated tumor drug levels, suggesting that optimal dosing should be focused on the site of action to avoid to inappropriate dose escalation. Larger clinical trials are required to determine optimal dose and schedule to achieve tumor concentrations that maximally inhibit HER receptors. TRIAL REGISTRATION: CLINICAL TRIAL REGISTRATION: NCT00359190. PMID- 26571497 TI - Simulating the Distribution of Individual Livestock Farms and Their Populations in the United States: An Example Using Domestic Swine (Sus scrofa domesticus) Farms. AB - Livestock distribution in the United States (U.S.) can only be mapped at a county level or worse resolution. We developed a spatial microsimulation model called the Farm Location and Agricultural Production Simulator (FLAPS) that simulated the distribution and populations of individual livestock farms throughout the conterminous U.S. Using domestic pigs (Sus scrofa domesticus) as an example species, we customized iterative proportional-fitting algorithms for the hierarchical structure of the U.S. Census of Agriculture and imputed unpublished state- or county-level livestock population totals that were redacted to ensure confidentiality. We used a weighted sampling design to collect data on the presence and absence of farms and used them to develop a national-scale distribution model that predicted the distribution of individual farms at a 100 m resolution. We implemented microsimulation algorithms that simulated the populations and locations of individual farms using output from our imputed Census of Agriculture dataset and distribution model. Approximately 19% of county level pig population totals were unpublished in the 2012 Census of Agriculture and needed to be imputed. Using aerial photography, we confirmed the presence or absence of livestock farms at 10,238 locations and found livestock farms were correlated with open areas, cropland, and roads, and also areas with cooler temperatures and gentler topography. The distribution of swine farms was highly variable, but cross-validation of our distribution model produced an area under the receiver-operating characteristics curve value of 0.78, which indicated good predictive performance. Verification analyses showed FLAPS accurately imputed and simulated Census of Agriculture data based on absolute percent difference values of < 0.01% at the state-to-national scale, 3.26% for the county-to-state scale, and 0.03% for the individual farm-to-county scale. Our output data have many applications for risk management of agricultural systems including epidemiological studies, food safety, biosecurity issues, emergency-response planning, and conflicts between livestock and other natural resources. PMID- 26571498 TI - TDP-43 Inhibits NF-kappaB Activity by Blocking p65 Nuclear Translocation. AB - TDP-43 (TAR DNA binding protein 43) is a heterogeneous nuclear ribonucleoprotein (hnRNP) that has been found to play an important role in neurodegenerative diseases. TDP-43's involvement in nuclear factor-kappaB pathways has been reported in both neurons and microglial cells. The NF-kappaB pathway targets hundreds of genes, many of which are involved in inflammation, immunity and cancer. p50/p65 (p50/RelA) heterodimers, as the major Rel complex in the NF kappaB family, are induced by diverse external physiological stimuli and modulate transcriptional activity in almost all cell types. Both p65 and TDP-43 translocation occur through the classic nuclear transportation system. In this study, we report that TDP-43 overexpression prevents TNF-alpha induced p65 nuclear translocation in a dose dependent manner, and that this further inhibits p65 transactivation activity. The inhibition by TDP-43 does not occur through preventing IkappaB degradation but probably by competing for the nuclear transporter-importin alpha3 (KPNA4). This competition is dependent on the presence of the nuclear localization signal (NLS) in TDP-43. Silencing TDP-43 using a specific siRNA also increased p65 nuclear localization upon TNF-alpha stimulation, suggesting that endogenous TDP-43 may be a default suppressor of the NF-kappaB pathway. Our results indicate that TDP-43 may play an important role in regulating the levels of NF-kappaB activity by controlling the nuclear translocation of p65. PMID- 26571499 TI - Galactomannan and Zymosan Block the Epinephrine-Induced Particle Transport in Tracheal Epithelium. AB - BACKGROUND: Ciliary beating by respiratory epithelial cells continuously purges pathogens from the lower airways. Here we investigated the effect of the fungal cell wall polysaccharides Galactomannan (GM) and Zymosan (Zym) on the adrenergic activated particle transport velocity (PTV) of tracheal epithelium. METHODS: Experiments were performed using tracheae isolated from male C57BL/6J mice. Transport velocity of the cilia bearing epithelial cells was measured by analysing recorded image sequences. Generation of reactive oxygen species (ROS) were determined using Amplex Red reagents. PCR experiments were performed on isolated tracheal epithelium to identify adrenergic receptor mRNA. RESULTS: The adrenergic receptors alpha1D, alpha2A, beta1 and beta2 have been identified in isolated tracheal epithelium. We found epinephrine responsible for an increase in PTV, which could only be reduced by selective beta-receptor-inhibition. In addition, either GM or Zym prevented the epinephrine induced PTV increase. Furthermore, we observed a strong ROS generation evoked by GM or Zym. However, epinephrine induced increase in PTV recovered in the presence of GM and Zym after application of ROS scavengers. CONCLUSION: Both GM or Zym trigger reversible ROS generation in tracheal tissue leading to inhibition of the beta-adrenergic increase in PTV. PMID- 26571500 TI - Abnormal Neural Responses to Emotional Stimuli but Not Go/NoGo and Stroop Tasks in Adults with a History of Childhood Nocturnal Enuresis. AB - BACKGROUND: Nocturnal enuresis (NE) is a common disorder in school-aged children. Previous studies have reported that children with NE exhibit structural, functional and neurochemical abnormalities in the brain, suggesting that children with NE may have cognitive problems. Additionally, children with NE have been shown to process emotions differently from control children. In fact, most cases of NE resolve with age. However, adults who had experienced NE during childhood may still have potential cognitive or emotion problems, and this possibility has not been thoroughly investigated. METHODOLOGY/PRINCIPAL FINDINGS: In this work, we used functional magnetic resonance imaging (fMRI) to evaluate brain functional changes in adults with a history of NE. Two groups, consisting of 21 adults with NE and 21 healthy controls, were scanned using fMRI. We did not observe a significant abnormality in activation during the Go/NoGo and Stroop tasks in adults with a history of NE compared with the control group. However, compared to healthy subjects, young adults with a history of NE mainly showed increased activation in the bilateral temporoparietal junctions, bilateral dorsolateral prefrontal cortex, and bilateral anterior cingulate cortex while looking at negative vs. neutral pictures. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that adults with a history of childhood NE have no obvious deficit in response inhibition or cognitive control but showed abnormal neural responses to emotional stimuli. PMID- 26571501 TI - A Simplified Method for Three-Dimensional (3-D) Ovarian Tissue Culture Yielding Oocytes Competent to Produce Full-Term Offspring in Mice. AB - In vitro growth of follicles is a promising technology to generate large quantities of competent oocytes from immature follicles and could expand the potential of assisted reproductive technologies (ART). Isolated follicle culture is currently the primary method used to develop and mature follicles in vitro. However, this procedure typically requires complicated, time-consuming procedures, as well as destruction of the normal ovarian microenvironment. Here we describe a simplified 3-D ovarian culture system that can be used to mature multilayered secondary follicles into antral follicles, generating developmentally competent oocytes in vitro. Ovaries recovered from mice at 14 days of age were cut into 8 pieces and placed onto a thick Matrigel drop (3-D culture) for 10 days of culture. As a control, ovarian pieces were cultured on a membrane filter without any Matrigel drop (Membrane culture). We also evaluated the effect of activin A treatment on follicle growth within the ovarian pieces with or without Matrigel support. Thus we tested four different culture conditions: C (Membrane/activin-), A (Membrane/activin+), M (Matrigel/activin-), and M+A (Matrigel/activin+). We found that the cultured follicles and oocytes steadily increased in size regardless of the culture condition used. However, antral cavity formation occurred only in the follicles grown in the 3-D culture system (M, M+A). Following ovarian tissue culture, full-grown GV oocytes were isolated from the larger follicles to evaluate their developmental competence by subjecting them to in vitro maturation (IVM) and in vitro fertilization (IVF). Maturation and fertilization rates were higher using oocytes grown in 3-D culture (M, M+A) than with those grown in membrane culture (C, A). In particular, activin A treatment further improved 3-D culture (M+A) success. Following IVF, two-cell embryos were transferred to recipients to generate full-term offspring. In summary, this simple and easy 3-D ovarian culture system using a Matrigel drop and activin A supplementation (M+A) provides optimal and convenient conditions to support growth of developmentally competent oocytes in vitro. PMID- 26571502 TI - Virological Characteristics of Acute Hepatitis B in Eastern India: Critical Differences with Chronic Infection. AB - Hepatitis B Virus (HBV) manifests high genetic variability and is classifiable into ten genotypes (A-J). HBV infection can lead to variable clinical outcomes, ranging from self-limiting acute hepatitis to active chronic hepatitis, cirrhosis and hepatocellular carcinoma. The present study characterizes HBV strains circulating among patients with acute (AHB) and chronic HBV infection (CHB). Among a total of 653 HBsAg positive cases, 40 manifested acute infection. After sequencing the surface(S), basal core promoter/pre-core(BCP/PC) and the X gene regions, phylogenetic tree was constructed using MEGA4 by neighbor-joining method. Statistical robustness was established with bootstrap analysis. Nucleotide diversity was determined by Shannon entropy per site using the Entropy program of the Los Alamos National Laboratories. Analyses of acute patients revealed that HBV/D2 is the major circulating sub-genotype and commonly associated with sexual promiscuity and the age group between15-30 years. Comparison of AHB and CHB patients revealed that HBeAg positivity, ALT levels and genotype D were significantly high in AHB, whereas CHB patients were predominantly male, had a high viral load, and were commonly associated with genotype C. The frequencies of mutations in the S, BCP/PC, and X gene were low in AHB as compared to CHB. Drug resistant mutations were not detectable in the polymerase gene of AHB. Average nucleotide diversity in AHB was considerably low as compared to CHB. Further, the highest average DeltaH (average difference in entropy between chronic and acute infection) was observed in the BCP/PC region implying that this region was most vulnerable to mutations upon HBV persistence, especially in case of genotype C. Additionally, among all substitutions, the A1762T and G1764A BCP mutations were the strongest indicators of chronicity. In conclusion, the study exhibits a general portrait of HBV strains circulating among acute hepatitis B patients in Eastern India and their intricate differences with chronic patients which should be useful from the clinical point of view. PMID- 26571503 TI - Does Fish Oil Have an Anti-Obesity Effect in Overweight/Obese Adults? A Meta Analysis of Randomized Controlled Trials. AB - CONTEXT: Accumulating evidence has suggested favorable effects of fish oil on weight loss in animal experiments; however, findings remain inconsistent in humans. OBJECTS: The meta-analysis was performed to investigate the influence of fish oil on some parameters of body composition in overweight/obese adults. DESIGN: Human randomized, placebo-controlled trials were identified by a systematic search of Embase, PubMed, the Cochrane Library, web of science and reference lists of related reviews and articles. The random-effects model was used to estimate the calculated results. RESULTS: In total, 21 studies with 30 study arms were included in this analysis. Calculated results of the meta analysis demonstrated that fish oil had no effect on reducing body weight (overall SMD = -0.07, 95% CI -0.21 to 0.07, P = 0.31) and BMI (overall SMD = 0.09, 95% CI -0.22 to 0.03, P = 0.14) whether alone or combined with life modification intervention in overweight/obese subjects. However, waist circumference was significantly reduced (SMD = -0.23, 95% CI -0.40 to -0.06, P = 0.008) in those with fish oil supplementation combined with life modification intervention. Waist hip ratio (WHR) was significantly reduced (overall SMD = 0.52 95% CI -0.76 to -0.27, P < 0.0005) in fish oil supplemented individuals with or without combination life modification intervention. CONCLUSION: Current evidence cannot support an exact anti-obesity role of n-3 polyunsaturated fatty acids (PUFAs) in overweight/obese subjects. However, these subjects may benefit from reducing abdominal fat with fish oil supplementation especially when combined with life modification intervention. Further large-scale and long-term clinical trials are needed to gain definite conclusions. PMID- 26571504 TI - The Deubiquitinating Enzyme UBPY Is Required for Lysosomal Biogenesis and Productive Autophagy in Drosophila. AB - Autophagy is a catabolic process that delivers cytoplasmic components to the lysosomes. Protein modification by ubiquitination is involved in this pathway: it regulates the stability of autophagy regulators such as BECLIN-1 and it also functions as a tag targeting specific substrates to autophagosomes. In order to identify deubiquitinating enzymes (DUBs) involved in autophagy, we have performed a genetic screen in the Drosophila larval fat body. This screen identified Uch L3, Usp45, Usp12 and Ubpy. In this paper, we show that Ubpy loss of function results in the accumulation of autophagosomes due to a blockade of the autophagy flux. Furthermore, analysis by electron and confocal microscopy of Ubpy-depleted fat body cells revealed altered lysosomal morphology, indicating that Ubpy inactivation affects lysosomal maintenance and/or biogenesis. Lastly, we have shown that shRNA mediated inactivation of UBPY in HeLa cells affects autophagy in a different way: in UBPY-depleted HeLa cells autophagy is deregulated. PMID- 26571506 TI - Estimation of Fluorescence Lifetimes Via Rotational Invariance Techniques. AB - Estimation of signal parameters via rotational invariance techniques is a classical algorithm widely used in array signal processing for direction-of arrival estimation of emitters. Inspired by this method, a new signal model and new fluorescence lifetime estimation via rotational invariance techniques (FLERIT) were developed for multiexponential fluorescence lifetime imaging (FLIM) experiments. The FLERIT only requires a few time bins of a histogram generated by a time-correlated single-photon counting FLIM system, greatly reducing the data throughput from the imager to the signal processing units. As a noniterative method, the FLERIT does not require initial conditions, prior information nor model selection that are usually required by widely used traditional fitting methods, including nonlinear least square methods or maximum-likelihood methods. Moreover, its simplicity means it is suitable for implementations in embedded systems for real-time applications. FLERIT was tested on synthesized and experimental fluorescent cell data showing the potentials to be widely applied in FLIM data analysis. PMID- 26571505 TI - SWI/SNF Subunits SMARCA4, SMARCD2 and DPF2 Collaborate in MLL-Rearranged Leukaemia Maintenance. AB - Alterations in chromatin structure caused by deregulated epigenetic mechanisms collaborate with underlying genetic lesions to promote cancer. SMARCA4/BRG1, a core component of the SWI/SNF ATP-dependent chromatin-remodelling complex, has been implicated by its mutational spectrum as exerting a tumour-suppressor function in many solid tumours; recently however, it has been reported to sustain leukaemogenic transformation in MLL-rearranged leukaemia in mice. Here we further explore the role of SMARCA4 and the two SWI/SNF subunits SMARCD2/BAF60B and DPF2/BAF45D in leukaemia. We observed the selective requirement for these proteins for leukaemic cell expansion and self-renewal in-vitro as well as in leukaemia. Gene expression profiling in human cells of each of these three factors suggests that they have overlapping functions in leukaemia. The gene expression changes induced by loss of the three proteins demonstrate that they are required for the expression of haematopoietic stem cell associated genes but in contrast to previous results obtained in mouse cells, the three proteins are not required for the expression of c-MYC regulated genes. PMID- 26571507 TI - Model-Based Design and Experimental Validation of Control Modules for Neuromodulation Devices. AB - GOAL: The goal of this paper is to propose a model-based control design framework, adapted to the development of control modules for medical devices. A particular example is presented in which instantaneous heart rate is regulated in real-time, by modulating, in an adaptive manner, the current delivered to the vagus nerve by a neuromodulator. METHODS: The proposed framework couples a control module, based on a classical PI controller, a mathematical model of the medical device, and a physiological model representing the cardiovascular responses to vagus nerve stimulation (VNS). In order to analyze and evaluate the behavior of the device, different control parameters are tested on a "virtual population," generated with the model, according to the Latin Hypercube sampling method. In particular, sensitivity analyses are applied for the identification of a domain of interest in the space of the control parameters. The obtained control parameter domain has been validated in an experimental evaluation on six sheep. RESULTS: A range of control parameters leading to accurate results was successfully estimated by the proposed model-based design method. Experimental evaluation of the control parameters inside such a domain led to the best compromise between accuracy and time response of the VNS control. CONCLUSION: The feasibility and usefulness of the proposed model-based design method were shown, leading to a functional, real-time closed-loop control of the VNS for the regulation of heart rate. PMID- 26571508 TI - Learning Recurrent Waveforms Within EEGs. AB - GOAL: We demonstrate an algorithm to automatically learn the time-limited waveforms associated with phasic events that repeatedly appear throughout an electroencephalogram. METHODS: To learn the phasic event waveforms we propose a multiscale modeling process that is based on existing shift-invariant dictionary learning algorithms. For each channel, waveforms at different temporal scales are learned based on the assumption that only a few waveforms occur in any window of the time-series, but the same waveforms reoccur throughout the signal. Once the waveforms are learned, the timing and amplitude of the phasic event occurrences are estimated using matching pursuit. To summarize the waveforms learned across multiple channels and subjects, we analyze their frequency content, their similarity to Gabor-Morlet wavelets, and perform shift-invariant k-means to cluster the waveforms. A prototype waveform from each cluster is then tested for differential spatial patterns between different motor imagery conditions. RESULTS: On multiple human EEG datasets, the learned waveforms capture key characteristics of signals they were trained to represent, with a consistency in waveform morphology and frequency content across multiple training sections and initializations. On multichannel datasets, the spatial amplitude patterns of the waveforms are also consistent and can be used to distinguish different modalities of motor imagery. CONCLUSION: We explored a methodology that can be used for modeling the recurrent waveforms in EEG traces. SIGNIFICANCE: The methodology automatically identifies the most frequent phasic event waveforms in EEG, which could then be used as features for automatic evaluation and comparison of EEG during sleep, pathology, or mentally engaging tasks. PMID- 26571509 TI - Less Invasive and Inotrope-Reduction Approach to Automated Closed-Loop Control of Hemodynamics in Decompensated Heart Failure. AB - We have been developing an automated cardiovascular drug infusion system for simultaneous control of arterial pressure (AP), cardiac output (CO), and left atrial pressure (PLA) in decompensated heart failure (HF). In our prototype system, CO and PLA were measured invasively through thoracotomy. Furthermore, the control logic inevitably required use of inotropes to improve hemodynamics, which was not in line with clinical HF guidelines. The goal of this study was to solve these problems and develop a clinically feasible system. We integrated to the system minimally invasive monitors of CO and pulmonary capillary wedge pressure (PCWP, surrogates for PLA) that we developed recently. We also redesigned the control logic to reduce the use of inotrope. We applied the newly developed system to nine dogs with decompensated HF. Once activated, our system started to control the infusion of vasodilator and diuretics in all the animals. Inotrope was not infused in three animals, and infused at minimal doses in six animals that were intolerant of vasodilator infusion alone. Within 50 min, our system controlled AP, CO, and PCWP to their respective targets accurately. Pulmonary artery catheterization confirmed optimization of hemodynamics (AP, from 98 +/- 4 to 74 +/- 11 mmHg; CO, from 2.2 +/- 0.5 to 2.9 +/- 0.3 L.min(-1).m(-2); PCWP, from 27.0 +/- 6.6 to 13.8 +/- 3.0 mmHg). In a minimally invasive setting while reducing the use of inotrope, our system succeeded in automatically optimizing the overall hemodynamics in canine models of HF. The present results pave the way for clinical application of our automated drug infusion system. PMID- 26571510 TI - An MEG-Compatible Electromagnetic-Tracking System for Monitoring Orofacial Kinematics. AB - We describe a novel motion-tracking system, called MASK (magnetoarticulography for the assessment of speech kinematics) designed to track detailed orofacial movements during magnetoencephalographic (MEG) measures of human brain activity. A three-dimensional electromagnetic-tracking method was employed using lightweight coils energized with high-frequency sinusoidal currents, creating magnetic dipoles that can be continuously localized by the MEG sensors. In addition to being compatible with commercial MEG devices, this system has advantages over optical or video methods in that it can record nonline-of-sight movements (e.g., tongue movements) and advantages over surface electromyographic recordings, which are prone to movement-related artifacts and signal crosstalk. Static and dynamic tracking accuracy was evaluated using calibration devices with fixed intercoil distances. MEG data were collected in two healthy adult volunteers to test feasibility of tracking movements during tongue and facial movement, and during overt speech. The MASK system was shown to have sufficient static and dynamic accuracy to track orofacial movements within the MEG helmet. We successfully acquired spatially precise kinematic information time-locked to brain activity with high temporal resolution. We demonstrated successful tracking of oromotor and speech movements together with brain activity using the MASK system. This novel technology will provide an innovative tool in support of research and clinical applications for individuals with speech and other oromotor disorders. PMID- 26571511 TI - Infinite Factorial Unbounded-State Hidden Markov Model. AB - There are many scenarios in artificial intelligence, signal processing or medicine, in which a temporal sequence consists of several unknown overlapping independent causes, and we are interested in accurately recovering those canonical causes. Factorial hidden Markov models (FHMMs) present the versatility to provide a good fit to these scenarios. However, in some scenarios, the number of causes or the number of states of the FHMM cannot be known or limited a priori. In this paper, we propose an infinite factorial unbounded-state hidden Markov model (IFUHMM), in which the number of parallel hidden Markovmodels (HMMs) and states in each HMM are potentially unbounded. We rely on a Bayesian nonparametric (BNP) prior over integer-valued matrices, in which the columns represent the Markov chains, the rows the time indexes, and the integers the state for each chain and time instant. First, we extend the existent infinite factorial binary-state HMM to allow for any number of states. Then, we modify this model to allow for an unbounded number of states and derive an MCMC-based inference algorithm that properly deals with the trade-off between the unbounded number of states and chains. We illustrate the performance of our proposed models in the power disaggregation problem. PMID- 26571512 TI - Variational Inference for Watson Mixture Model. AB - This paper addresses modelling data using the Watson distribution. The Watson distribution is one of the simplest distributions for analyzing axially symmetric data. This distribution has gained some attention in recent years due to its modeling capability. However, its Bayesian inference is fairly understudied due to difficulty in handling the normalization factor. Recent development of Markov chain Monte Carlo (MCMC) sampling methods can be applied for this purpose. However, these methods can be prohibitively slow for practical applications. A deterministic alternative is provided by variational methods that convert inference problems into optimization problems. In this paper, we present a variational inference for Watson mixture models. First, the variational framework is used to side-step the intractability arising from the coupling of latent states and parameters. Second, the variational free energy is further lower bounded in order to avoid intractable moment computation. The proposed approach provides a lower bound on the log marginal likelihood and retains distributional information over all parameters. Moreover, we show that it can regulate its own complexity by pruning unnecessary mixture components while avoiding over-fitting. We discuss potential applications of the modeling with Watson distributions in the problem of blind source separation, and clustering gene expression data sets. PMID- 26571513 TI - A Gamut-Mapping Framework for Color-Accurate Reproduction of HDR Images. AB - Few tone mapping operators (TMOs) take color management into consideration, limiting compression to luminance values only. This could lead to changes in image chroma and hues, which are typically managed with a post-processing step. However, current post-processing techniques for tone reproduction do not explicitly consider the target display gamut. Gamut mapping, on the other hand, deals with mapping images from one color gamut to another, usually smaller, gamut but has traditionally focused on smaller scale, chromatic changes. The authors present a combined gamut- and tone-management framework for color-accurate reproduction of high dynamic range images that can prevent hue and luminance shifts while taking gamut boundaries into consideration. Their approach is conceptually and computationally simple, parameter-free, and compatible with existing TMOs. PMID- 26571514 TI - Improving 3D Character Posing with a Gestural Interface. AB - The most time-consuming part of character animation is 3D character posing. Posing using a mouse is a slow and tedious task that involves sequences of selecting on-screen control handles and manipulating the handles to adjust character parameters, such as joint rotations and end effector positions. Thus, various 3D user interfaces have been proposed to make animating easier, but they typically provide less accuracy. The proposed interface combines a mouse with the Leap Motion device to provide 3D input. A usability study showed that users preferred the Leap Motion over a mouse as a 3D gestural input device. The Leap Motion drastically decreased the number of required operations and the task completion time, especially for novice users. PMID- 26571515 TI - A Natural Interface for Remote Operation of Underwater Robots. AB - Human-machine interfaces play a crucial role in intervention robotic systems operated in hazardous environments, such as deep sea conditions. This article introduces a user interface abstraction layer to enhance reconfigurability. It also describes a VR-based interface that utilizes immersive technologies to reduce user faults and mental fatigue. The goal is to show the user only the most relevant information about the current mission. PMID- 26571517 TI - A Decision-Support System for Sustainable Water Distribution System Planning. AB - An interactive decision-support system (DSS) can help experts prepare water resource management plans for decision makers and stakeholders. The design of the proposed prototype incorporates visualization techniques such as circle views, grid layout, small multiple maps, and node simplification to improve the data readability of water distribution systems. A case study with three urban water management and sanitary engineering experts revealed that the proposed DSS is satisfactory, efficient, and effective. PMID- 26571518 TI - Visualizing Volcanic Clouds in the Atmosphere and Their Impact on Air Traffic. AB - Volcanic eruptions are not only hazardous in the direct vicinity of a volcano, but they also affect the climate and air travel for great distances. This article sheds light on the Grimsvotn, Puyehue-Cordon Caulle, and Nabro eruptions in 2011. The authors study the agreement of the complementary satellite data, reconstruct sulfate aerosol and volcanic ash clouds, visualize endangered flight routes, minimize occlusion in particle trajectory visualizations, and focus on the main pathways of Nabro's sulfate aerosol into the stratosphere. The results here were developed for the 2014 IEEE Scientific Visualization Contest, which centers around the fusion of multiple satellite data modalities to reconstruct and assess the movement of volcanic ash and sulfate aerosol emissions. Using data from three volcanic eruptions that occurred in the span of approximately three weeks, the authors study the agreement of the complementary satellite data, reconstruct sulfate aerosol and volcanic ash clouds, visualize endangered flight routes, minimize occlusion in particle trajectory visualizations, and focus on the main pathways of sulfate aerosol into the stratosphere. This video provides animations of the reconstructed ash clouds. https://youtu.be/D9DvJ5AvZAs. PMID- 26571519 TI - A Sphere Phantom Approach to Measure Directional Modulation Transfer Functions for Tomosynthesis Imaging Systems. AB - We propose a sphere phantom approach to measure spatially varying directional modulation transfer functions (MTFs) for tomosynthesis imaging systems. Since the reconstructed tomosynthesis images contain significant artifacts, traditional background detrending techniques may not be effective to estimate the background trends accurately, which is essential to acquire sphere only data. A background detrending technique optimized for local volumes with different cone angles is presented. To measure directional MTFs, we calculate plane integrals of ideal sphere phantom and sphere only data. To minimize the effects of the high level of noise in tomosynthesis images, Richardson-Lucy deconvolution with Tikhonov-Miller is used to estimate directional plane spread function (PlSF). Then, directional MTFs are calculated by taking the modulus of the Fourier transform of the directional PlSFs. The measured directional MTFs are compared with the ideal directional MTFs calculated from a simulated point object. Our results show that the proposed method reliably measures directional MTFs along any desired directions, especially near low frequency regions. PMID- 26571520 TI - Excitation Waveform Design for Lamb Wave Pulse Compression. AB - Most ultrasonic guided wave methods focus on tone burst excitation to reduce the effect of dispersion so as to facilitate signal interpretation. However, the resolution of the output cannot attain a very high value because time duration of the excitation waveform cannot be very small. To overcome this limitation, a pulse compression technique is introduced to Lamb wave propagation to achieve a delta-like correlation so as to obtain a high resolution for inspection. Ideal delta-like correlation is impossible as only a finite frequency bandwidth can propagate. The primary purpose of this paper is to design a proper excitation waveform for Lamb wave pulse compression, which shortens the correlation as close as possible to a delta function. To achieve this purpose, the performance of some typical signals is discussed in pulse compression, which include linear chirp (L Chirp) signal, nonlinear chirp (NL-Chirp) signal, Barker code (BC), and Golay complementary code (GCC). In addition, how the excitation frequency range influences inspection resolution is investigated. A strategy for the frequency range determination is established subsequently. Finally, an experiment is carried out on an aluminum plate where these typical signals are used as excitations at different frequency ranges. The quantitative comparisons of the pulse compression responses validate the theoretical findings. By utilizing the experimental data, the improvement of pulse compression in resolution compared with tone burst excitation is also validated, and the robustness of the waveform design method to inaccuracies in the dispersion compensation is discussed as well. PMID- 26571521 TI - Tungsten Oxide Layers of High Acoustic Impedance for Fully Insulating Acoustic Reflectors. AB - Gravimetric sensors based on solidly mounted resonators require fully insulating acoustic reflectors to avoid parasitics when operating in liquid media. In this work, we propose a new high-acoustic impedance material, tungsten oxide ([Formula: see text]), for acoustic reflectors. We have optimized the sputtering conditions of [Formula: see text] to obtain nonconductive layers with mass density around [Formula: see text] and acoustic velocities for the shear and the longitudinal modes up to 2700 and 4500 m/s, respectively. Compared to other conventionally used high impedance layers, [Formula: see text] films display several manufacture advantages, such as high deposition rates, great reproducibility, and good adhesion to underlying substrates. We have demonstrated the applicability of [Formula: see text] in practical shear mode bulk acoustic wave resonators that display good performance in liquid environments. PMID- 26571522 TI - A Robotic Ultrasound Scanner for Automatic Vessel Tracking and Three-Dimensional Reconstruction of B-Mode Images. AB - Locating and evaluating the length and severity of a stenosis is very important for planning adequate treatment of peripheral arterial disease (PAD). Conventional ultrasound (US) examination cannot provide maps of entire lower limb arteries in 3-D. We propose a prototype 3D-US robotic system with B-mode images, which is nonionizing, noninvasive, and is able to track and reconstruct a continuous segment of the lower limb arterial tree between the groin and the knee. From an initialized cross-sectional view of the vessel, automatic tracking was conducted followed by 3D-US reconstructions evaluated using Hausdorff distance, cross-sectional area, and stenosis severity in comparison with 3-D reconstructions with computed tomography angiography (CTA). A mean Hausdorff distance of 0.97 +/- 0.46 mm was found in vitro for 3D-US compared with 3D-CTA vessel representations. To evaluate the stenosis severity in vitro, 3D-US reconstructions gave errors of 3%-6% when compared with designed dimensions of the phantom, which are comparable to 3D-CTA reconstructions, with 4%-13% errors. The in vivo system's feasibility to reconstruct a normal femoral artery segment of a volunteer was also investigated. These results encourage further ergonomic developments to increase the robot's capacity to represent lower limb vessels in the clinical context. PMID- 26571523 TI - The Parabolic Variance (PVAR): A Wavelet Variance Based on the Least-Square Fit. AB - This paper introduces the parabolic variance (PVAR), a wavelet variance similar to the Allan variance (AVAR), based on the linear regression (LR) of phase data. The companion article arXiv:1506.05009 [physics.ins-det] details the Omega frequency counter, which implements the LR estimate. The PVAR combines the advantages of AVAR and modified AVAR (MVAR). PVAR is good for long-term analysis because the wavelet spans over 2tau, the same as the AVAR wavelet, and good for short-term analysis because the response to white and flicker PM is 1/tau(3) and 1/tau(2), the same as the MVAR. After setting the theoretical framework, we study the degrees of freedom and the confidence interval for the most common noise types. Then, we focus on the detection of a weak noise process at the transition or corner-where a faster process rolls off. This new perspective raises the question of which variance detects the weak process with the shortest data record. Our simulations show that PVAR is a fortunate tradeoff. PVAR is superior to MVAR in all cases, exhibits the best ability to divide between fast noise phenomena (up to flicker FM), and is almost as good as AVAR for the detection of random walk and drift. PMID- 26571524 TI - Safety Assessment of Advanced Imaging Sequences II: Simulations. AB - An automatic approach for simulating the emitted pressure, intensity, and mechanical index (MI) of advanced ultrasound imaging sequences is presented. It is based on a linear simulation of pressure fields using Field II, and it is hypothesized that linear simulation can attain the needed accuracy for predicting MI and I(spta.3) as required by FDA. The method is performed on four different imaging schemes and compared to measurements conducted using the SARUS experimental scanner. The sequences include focused emissions with an F-number of 2 with 64 elements that generate highly nonlinear fields. The simulation time is between 0.67 and 2.8 ms per emission and imaging point, making it possible to simulate even complex emission sequences in less than 1 s for a single spatial position. The linear simulations yield a relative accuracy on MI between -12.1% and 52.3% and for I(spta.3) between -38.6% and 62.6%, when using the impulse response of the probe estimated from an independent measurement. The accuracy is increased to between -22% and 24.5% for MI and between -33.2% and 27.0% for I(spta.3), when using the pressure response measured at a single point to scale the simulation. The spatial distribution of MI and I(ta.3) closely matches that for the measurement, and simulations can, therefore, be used to select the region for measuring the intensities, resulting in a significant reduction in measurement time. It can validate emission sequences by showing symmetry of emitted pressure fields, focal position, and intensity distribution. PMID- 26571525 TI - F-k Domain Imaging for Synthetic Aperture Sequential Beamforming. AB - Spatial resolution in medical ultrasound images is a key component in image quality and an important factor for clinical diagnosis. In early systems, the lateral resolution was optimal in the focus but rapidly decreased outside the focal region. Improvements have been found in, e.g., dynamic-receive beamforming, in which the entire image is focused in receive, but this requires complex processing of element data and is not applicable for mechanical scanning of single-element images. This paper exploits the concept of two-stage beamforming based on virtual source-receivers, which reduces the front-end computational load while maintaining a similar data rate and frame rate compared to dynamic-receive beamforming. We introduce frequency-wavenumber domain data processing to obtain fast second-stage data processing while having similarly high lateral resolution as dynamic-receive beamforming and processing in time-space domain. The technique is very suitable in combination with emerging technologies such as application specific integrated circuits (ASICs), hand-held devices, and wireless data transfer. The suggested method consists of three steps. In the first step, single focused RF line data are shifted in time to relocate the focal point to a new origin t' = 0, z' = 0. This new origin is considered as an array of virtual source/receiver pairs, as has been suggested previously in literature. In the second step, the dataset is efficiently processed in the wavenumber-frequency domain to form an image that is in focus throughout its entire depth. In the third step, the data shift is undone to obtain a correct depth axis in the image. The method has been tested first with a single-element scanning system and second in a tissue-mimicking phantom using a linear array. In both setups, the method resulted in a -6-dB lateral point spread function (PSF) which was constant over the entire depth range, and similar to dynamic-receive beamforming and synthetic aperture sequential beamforming. The signal-to-noise ratio increased by 6 dB in both the near field and far field. These results show that the second-stage processing algorithm effectively produces a focused image over the entire depth range from a single-focused ultrasound field. PMID- 26571526 TI - Automatic 3D Segmentation and Quantification of Lenticulostriate Arteries from High-Resolution 7 Tesla MRA Images. AB - We propose a novel hybrid approach for automatic 3D segmentation and quantification of high-resolution 7 Tesla magnetic resonance angiography (MRA) images of the human cerebral vasculature. Our approach consists of two main steps. First, a 3D model-based approach is used to segment and quantify thick vessels and most parts of thin vessels. Second, remaining vessel gaps of the first step in low-contrast and noisy regions are completed using a 3D minimal path approach, which exploits directional information. We present two novel minimal path approaches. The first is an explicit approach based on energy minimization using probabilistic sampling, and the second is an implicit approach based on fast marching with anisotropic directional prior. We conducted an extensive evaluation with over 2300 3D synthetic images and 40 real 3D 7 Tesla MRA images. Quantitative and qualitative evaluation shows that our approach achieves superior results compared with a previous minimal path approach. Furthermore, our approach was successfully used in two clinical studies on stroke and vascular dementia. PMID- 26571527 TI - Multi-Scale Patch-Based Image Restoration. AB - Many image restoration algorithms in recent years are based on patch processing. The core idea is to decompose the target image into fully overlapping patches, restore each of them separately, and then merge the results by a plain averaging. This concept has been demonstrated to be highly effective, leading often times to the state-of-the-art results in denoising, inpainting, deblurring, segmentation, and other applications. While the above is indeed effective, this approach has one major flaw: the prior is imposed on intermediate (patch) results, rather than on the final outcome, and this is typically manifested by visual artifacts. The expected patch log likelihood (EPLL) method by Zoran and Weiss was conceived for addressing this very problem. Their algorithm imposes the prior on the patches of the final image, which in turn leads to an iterative restoration of diminishing effect. In this paper, we propose to further extend and improve the EPLL by considering a multi-scale prior. Our algorithm imposes the very same prior on different scale patches extracted from the target image. While all the treated patches are of the same size, their footprint in the destination image varies due to subsampling. Our scheme comes to alleviate another shortcoming existing in patch-based restoration algorithms--the fact that a local (patch-based) prior is serving as a model for a global stochastic phenomenon. We motivate the use of the multi-scale EPLL by restricting ourselves to the simple Gaussian case, comparing the aforementioned algorithms and showing a clear advantage to the proposed method. We then demonstrate our algorithm in the context of image denoising, deblurring, and super-resolution, showing an improvement in performance both visually and quantitatively. PMID- 26571528 TI - Detect2Rank: Combining Object Detectors Using Learning to Rank. AB - Object detection is an important research area in the field of computer vision. Many detection algorithms have been proposed. However, each object detector relies on specific assumptions of the object appearance and imaging conditions. As a consequence, no algorithm can be considered universal. With the large variety of object detectors, the subsequent question is how to select and combine them. In this paper, we propose a framework to learn how to combine object detectors. The proposed method uses (single) detectors like Deformable Part Models, Color Names and Ensemble of Exemplar-SVMs, and exploits their correlation by high-level contextual features to yield a combined detection list. Experiments on the PASCAL VOC07 and VOC10 data sets show that the proposed method significantly outperforms single object detectors, DPM (8.4%), CN (6.8%) and EES (17.0%) on VOC07 and DPM (6.5%), CN (5.5%) and EES (16.2%) on VOC10. We show with an experiment that there are no constraints on the type of the detector. The proposed method outperforms (2.4%) the state-of-the-art object detector (RCNN) on VOC07 when Regions with Convolutional Neural Network is combined with other detectors used in this paper. PMID- 26571529 TI - Building Hierarchical Representations for Oracle Character and Sketch Recognition. AB - In this paper, we study oracle character recognition and general sketch recognition. First, a data set of oracle characters, which are the oldest hieroglyphs in China yet remain a part of modern Chinese characters, is collected for analysis. Second, typical visual representations in shape- and sketch-related works are evaluated. We analyze the problems suffered when addressing these representations and determine several representation design criteria. Based on the analysis, we propose a novel hierarchical representation that combines a Gabor-related low-level representation and a sparse-encoder-related mid-level representation. Extensive experiments show the effectiveness of the proposed representation in both oracle character recognition and general sketch recognition. The proposed representation is also complementary to convolutional neural network (CNN)-based models. We introduce a solution to combine the proposed representation with CNN-based models, and achieve better performances over both approaches. This solution has beaten humans at recognizing general sketches. PMID- 26571530 TI - Massive Online Crowdsourced Study of Subjective and Objective Picture Quality. AB - Most publicly available image quality databases have been created under highly controlled conditions by introducing graded simulated distortions onto high quality photographs. However, images captured using typical real-world mobile camera devices are usually afflicted by complex mixtures of multiple distortions, which are not necessarily well-modeled by the synthetic distortions found in existing databases. The originators of existing legacy databases usually conducted human psychometric studies to obtain statistically meaningful sets of human opinion scores on images in a stringently controlled visual environment, resulting in small data collections relative to other kinds of image analysis databases. Toward overcoming these limitations, we designed and created a new database that we call the LIVE In the Wild Image Quality Challenge Database, which contains widely diverse authentic image distortions on a large number of images captured using a representative variety of modern mobile devices. We also designed and implemented a new online crowdsourcing system, which we have used to conduct a very large-scale, multi-month image quality assessment (IQA) subjective study. Our database consists of over 350 000 opinion scores on 1162 images evaluated by over 8100 unique human observers. Despite the lack of control over the experimental environments of the numerous study participants, we demonstrate excellent internal consistency of the subjective data set. We also evaluate several top-performing blind IQA algorithms on it and present insights on how the mixtures of distortions challenge both end users as well as automatic perceptual quality prediction models. The new database is available for public use at http://live.ece.utexas.edu/research/ChallengeDB/index.html. PMID- 26571531 TI - Fast Localization in Large-Scale Environments Using Supervised Indexing of Binary Features. AB - The essence of image-based localization lies in matching 2D key points in the query image and 3D points in the database. State-of-the-art methods mostly employ sophisticated key point detectors and feature descriptors, e.g., Difference of Gaussian (DoG) and Scale Invariant Feature Transform (SIFT), to ensure robust matching. While a high registration rate is attained, the registration speed is impeded by the expensive key point detection and the descriptor extraction. In this paper, we propose to use efficient key point detectors along with binary feature descriptors, since the extraction of such binary features is extremely fast. The naive usage of binary features, however, does not lend itself to significant speedup of localization, since existing indexing approaches, such as hierarchical clustering trees and locality sensitive hashing, are not efficient enough in indexing binary features and matching binary features turns out to be much slower than matching SIFT features. To overcome this, we propose a much more efficient indexing approach for approximate nearest neighbor search of binary features. This approach resorts to randomized trees that are constructed in a supervised training process by exploiting the label information derived from that multiple features correspond to a common 3D point. In the tree construction process, node tests are selected in a way such that trees have uniform leaf sizes and low error rates, which are two desired properties for efficient approximate nearest neighbor search. To further improve the search efficiency, a probabilistic priority search strategy is adopted. Apart from the label information, this strategy also uses non-binary pixel intensity differences available in descriptor extraction. By using the proposed indexing approach, matching binary features is no longer much slower but slightly faster than matching SIFT features. Consequently, the overall localization speed is significantly improved due to the much faster key point detection and descriptor extraction. It is empirically demonstrated that the localization speed is improved by an order of magnitude as compared with state-of-the-art methods, while comparable registration rate and localization accuracy are still maintained. PMID- 26571532 TI - Overview of the MPEG-CDVS Standard. AB - Compact descriptors for visual search (CDVS) is a recently completed standard from the ISO/IEC moving pictures experts group (MPEG). The primary goal of this standard is to provide a standardized bitstream syntax to enable interoperability in the context of image retrieval applications. Over the course of the standardization process, remarkable improvements were achieved in reducing the size of image feature data and in reducing the computation and memory footprint in the feature extraction process. This paper provides an overview of the technical features of the MPEG-CDVS standard and summarizes its evolution. PMID- 26571533 TI - Halftone Blending Between Smooth and Detail Screens to Improve Print Quality With Electrophotographic Printers. AB - In this paper, we consider a dual-mode process for the electrophotographic laser printer--a low-frequency halftoning for smooth regions and a high-frequency halftoning for detail regions. These regions are described by an object map that is extracted from the page description language version of the document. This manner of switching screens depending on the local content provides a stable halftone without artifacts in smooth areas and preserves the detail rendering in detail or texture areas. However, when switching between halftones with two different frequencies, jaggies may occur along the boundaries between areas halftoned with low- and high-frequency screens. To reduce the jaggies, our screens obey a harmonic relationship. In addition, we implement a blending process based on a transition region. We propose a nonlinear blending process in which at each pixel, we choose the maximum of the two weighted halftones, where the weights vary according to the position in the transition region. Moreover, we describe an online tone-mapping for the boundary blending process, based on an offline calibration procedure that effectively assures the desired tone values within the transition region. PMID- 26571534 TI - Seizure Suppression Efficacy of Closed-Loop Versus Open-Loop Deep Brain Stimulation in a Rodent Model of Epilepsy. AB - We assess and compare the effects of both closed-loop and open-loop neurostimulation of the rat hippocampus by means of a custom low-power programmable therapeutic neurostimulation device on the suppression of spontaneous seizures in a rodent model of epilepsy. Chronic seizures were induced by intraperitoneal kainic acid injection. Two bipolar electrodes were implanted into the CA1 regions of both hippocampi. The electrodes were connected to the custom-built programmable therapeutic neurostimulation device that can trigger an electrical stimulation either in a periodic manner or upon detection of the intracerebral electroencephalographic (icEEE) seizure onset. This device includes a microchip consisting of a 256-channel icEEG recording system and a 64-channel stimulator, and a programmable seizure detector implemented in a field programmable gate array (FPGA). The neurostimulator was used to evaluate seizure suppression efficacy in ten epileptic rats for a total of 240 subject-days (5760 subject-hours). For this purpose, all rats were randomly divided into two groups: the no-stimulation group and the stimulation group. The no-stimulation group did not receive stimulation. The stimulation group received, first, closed-loop stimulation and, next, open-loop stimulation. The no-stimulation and stimulation groups had a similar seizure frequency baseline, averaging five seizures per day. Closed-loop stimulation reduced seizure frequency by 90% and open-loop stimulation reduced seizure frequency by 17%, both in the stimulation group as compared to the no-stimulation group. PMID- 26571535 TI - Graphene-Based Glucose Sensors: A Brief Review. AB - Since the existence of graphene, a material only a single atomic layer thick, was demonstrated about a decade ago, it has caught the attention of researchers worldwide. This paper begins with a historical overview of graphene since its discovery, in 2004, and focuses on a citation-weighted review of graphene-based sensors developed for the detection of biological targets. Based on this statistical analysis, we categorize recent developments in graphene-based biosensors (GBBs) as optimized for detecting 1) proteins, 2) nucleic acids, 3) carbohydrates, or 4) compounds generated by metabolic processes. Existing detection methods employed by these sensors include electrical, electrochemical, and photonic approaches with respect to detecting labeled (or enzyme-assisted) and label-free (or enzyme-free) probe structures. Herein, we focus on graphene based glucose sensors because glucose-monitoring technology is extremely important in the management of diabetes and many practical examples of these carbohydrate sensors have been developed using the aforementioned detection methods. PMID- 26571536 TI - Investigating the Influence of HUVECs in the Formation of Glioblastoma Spheroids in High-Throughput Three-Dimensional Microwells. AB - Glioblastoma (GBM) is the most common form of primary brain tumor with a high infiltrative capacity, increased vascularity, and largely elusive tumor progression mechanism. The current GBM treatment methods do not increase the patient survival rate and studies using two-dimensional (2D) cell cultures and in vivo animal models to investigate GBM behavior and mechanism have limitations. Therefore, there is an increasing need for in vitro three-dimensional (3D) models that closely mimic in vivo microenvironment of the GBM tumors to understand the underlying mechanisms of the tumor progression. In this study we propose to use a 3D in vitro model to overcome these limitations, using poly (ethylene glycol) dimethyl acrylate (PEGDA) hydrogel-based microwells and co-culture GBM (U87) cells and endothelial cells (HUVEC) in the 3D microwells to provide a 3D in vitro simulation of the tumor microenvironment. Furthermore, we investigated the gene expression differences of co-cultures by quantitative real-time PCR. Our results suggested that the relative expression profiles of tumor angiogenesis markers, PECAM1/CD31, and VEGFR2, in co-cultures are consistent with in vivo GBM studies. Furthermore, we suggest that our microwell platform could provide robust and useful 3D co-culture models for high-throughput drug screening and treatment of the GBM. PMID- 26571538 TI - A Theoretical Foundation of Goal Representation Heuristic Dynamic Programming. AB - Goal representation heuristic dynamic programming (GrHDP) control design has been developed in recent years. The control performance of this design has been demonstrated in several case studies, and also showed applicable to industrial scale complex control problems. In this paper, we develop the theoretical analysis for the GrHDP design under certain conditions. It has been shown that the internal reinforcement signal is a bounded signal and the performance index can converge to its optimal value monotonically. The existence of the admissible control is also proved. Although the GrHDP control method has been investigated in many areas before, to the best of our knowledge, this is the first study of presenting the theoretical foundation of the internal reinforcement signal and how such an internal reinforcement signal can provide effective information to improve the control performance. Numerous simulation studies are used to validate the theoretical analysis and also demonstrate the effectiveness of the GrHDP design. PMID- 26571537 TI - Prediction the Substrate Specificities of Membrane Transport Proteins Based on Support Vector Machine and Hybrid Features. AB - Membrane transport proteins and their substrate specificities play crucial roles in a variety of cellular functions. Identifying the substrate specificities of membrane transport proteins is closely related to the protein-target interaction prediction, drug design, membrane recruitment, and dysregulation analysis. However, experimental methods to this aim are time consuming, labor intensive, and costly. Therefore, we proposed a novel method basing on support vector machine (SVM) to predict substrate specificities of membrane transport proteins by integrating features from position-specific score matrix (PSSM), PROFEAT, and Gene Ontology (GO). Finally, jackknife cross-validation tests were adopted on a benchmark and independent datasets to measure the performance of the proposed method. The overall accuracy of 96.16 and 80.45 percent were obtained for two datasets, which are higher (from 2.12 to 20.44 percent) than that by the state-of the-art tool. Comparison results indicate that the proposed model is more reliable and efficient for accurate prediction the substrate specificities of membrane transport proteins. PMID- 26571539 TI - Human-Centered Saliency Detection. AB - We introduce a new concept for detecting the saliency of 3-D shapes, that is, human-centered saliency (HCS) detection on the surface of shapes, whereby a given shape is analyzed not based on geometric or topological features directly obtained from the shape itself, but by studying how a human uses the object. Using virtual agents to simulate the ways in which humans interact with objects helps to understand shapes and detect their salient parts in relation to their functions. HCS detection is less affected by inconsistencies between the geometry or topology of the analyzed 3-D shapes. The potential benefit of the proposed method is that it is adaptable to variable shapes with the same semantics, as well as being robust against a geometrical and topological noise. Given a 3-D shape, its salient part is detected by automatically selecting a corresponding agent and making them interact with each other. Their adaption and alignment depend on an optimization framework and a training process. We demonstrate the detected salient parts for different types of objects together with the stability thereof. The salient parts can be used for important vision tasks, such as 3-D shape retrieval. PMID- 26571540 TI - Enhanced Logical Stochastic Resonance in Synthetic Genetic Networks. AB - In this brief, the concept of logical stochastic resonance is applied to implement the Set-Reset latch in a synthetic gene network derived from a bacteriophage lambda . Clear Set-Reset latch operation is obtained when the network is only subjected to periodic forcing. The correct probability of obtaining the desired logic operation first increases to unity and then decreases as the amplitude of the periodic forcing increases. In addition, the output logic operation can be easily morphed by tuning the frequency and the amplitude of the periodic forcing. At the same time, we indicate that adding moderate periodic forcing to the background Gaussian noise may increase the length of the optimal plateau of getting the desired logic operation in genetic regulatory network. We also point out that robust Set-Reset latch operation can be obtained using the interplay of periodic forcing and background noise when the noise strength is lower than what is required. PMID- 26571541 TI - Cosaliency Detection Based on Intrasaliency Prior Transfer and Deep Intersaliency Mining. AB - As an interesting and emerging topic, cosaliency detection aims at simultaneously extracting common salient objects in multiple related images. It differs from the conventional saliency detection paradigm in which saliency detection for each image is determined one by one independently without taking advantage of the homogeneity in the data pool of multiple related images. In this paper, we propose a novel cosaliency detection approach using deep learning models. Two new concepts, called intrasaliency prior transfer and deep intersaliency mining, are introduced and explored in the proposed work. For the intrasaliency prior transfer, we build a stacked denoising autoencoder (SDAE) to learn the saliency prior knowledge from auxiliary annotated data sets and then transfer the learned knowledge to estimate the intrasaliency for each image in cosaliency data sets. For the deep intersaliency mining, we formulate it by using the deep reconstruction residual obtained in the highest hidden layer of a self-trained SDAE. The obtained deep intersaliency can extract more intrinsic and general hidden patterns to discover the homogeneity of cosalient objects in terms of some higher level concepts. Finally, the cosaliency maps are generated by weighted integration of the proposed intrasaliency prior, deep intersaliency, and traditional shallow intersaliency. Comprehensive experiments over diverse publicly available benchmark data sets demonstrate consistent performance gains of the proposed method over the state-of-the-art cosaliency detection methods. PMID- 26571542 TI - Sequential Compact Code Learning for Unsupervised Image Hashing. AB - Effective hashing for large-scale image databases is a popular research area, attracting much attention in computer vision and visual information retrieval. Several recent methods attempt to learn either graph embedding or semantic coding for fast and accurate applications. In this paper, a novel unsupervised framework, termed evolutionary compact embedding (ECE), is introduced to automatically learn the task-specific binary hash codes. It can be regarded as an optimization algorithm that combines the genetic programming (GP) and a boosting trick. In our architecture, each bit of ECE is iteratively computed using a weak binary classification function, which is generated through GP evolving by jointly minimizing its empirical risk with the AdaBoost strategy on a training set. We address this as greedy optimization by embedding high-dimensional data points into a similarity-preserved Hamming space with a low dimension. We systematically evaluate ECE on two data sets, SIFT 1M and GIST 1M, showing the effectiveness and the accuracy of our method for a large-scale similarity search. PMID- 26571543 TI - A Survey on GPU-Based Implementation of Swarm Intelligence Algorithms. AB - Inspired by the collective behavior of natural swarm, swarm intelligence algorithms (SIAs) have been developed and widely used for solving optimization problems. When applied to complex problems, a large number of fitness function evaluations are needed to obtain an acceptable solution. To tackle this vital issue, graphical processing units (GPUs) have been used to accelerate the optimization procedure of SIAs. Thanks to their inherent parallelism, SIAs are very suitable for parallel implementation under the GPU platform which have achieved a great success in recent years. This paper presents a comprehensive review of GPU-based parallel SIAs in accordance with a newly proposed taxonomy. Critical concerns for the efficient parallel implementation of SIAs are also described in detail. Moreover, novel criteria are also proposed to evaluate and compare the parallel implementation and algorithm performance universally. The rationality and practicability of the proposed optimization methodology and criteria are verified by careful case study. Finally, our opinions and perspectives on the trends and prospects on the relatively new research domain are also presented for future development. PMID- 26571544 TI - Identifying Spatial Invasion of Pandemics on Metapopulation Networks Via Anatomizing Arrival History. AB - Spatial spread of infectious diseases among populations via the mobility of humans is highly stochastic and heterogeneous. Accurate forecast/mining of the spread process is often hard to be achieved by using statistical or mechanical models. Here we propose a new reverse problem, which aims to identify the stochastically spatial spread process itself from observable information regarding the arrival history of infectious cases in each subpopulation. We solved the problem by developing an efficient optimization algorithm based on dynamical programming, which comprises three procedures: 1) anatomizing the whole spread process among all subpopulations into disjoint componential patches; 2) inferring the most probable invasion pathways underlying each patch via maximum likelihood estimation; and 3) recovering the whole process by assembling the invasion pathways in each patch iteratively, without burdens in parameter calibrations and computer simulations. Based on the entropy theory, we introduced an identifiability measure to assess the difficulty level that an invasion pathway can be identified. Results on both artificial and empirical metapopulation networks show the robust performance in identifying actual invasion pathways driving pandemic spread. PMID- 26571545 TI - Semi-Supervised SVM With Extended Hidden Features. AB - Many traditional semi-supervised learning algorithms not only train on the labeled samples but also incorporate the unlabeled samples in the training sets through an automated labeling process such as manifold preserving. If some labeled samples are falsely labeled, the automated labeling process will generally propagate negative impact on the classifier in quite a serious manner. In order to avoid such an error propagating effect, the unlabeled samples should not be directly incorporated into the training sets during the automated labeling strategy. In this paper, a new semi-supervised support vector machine with extended hidden features (SSVM-EHF) is presented to address this issue. According to the maximum margin principle and the minimum integrated squared error between the probability distributions of the labeled and unlabeled samples, the dimensionality of the labeled and unlabeled samples is extended through an orthonormal transformation to generate the corresponding hidden features shared by the labeled and unlabeled samples. After doing so, the last step in the process of training of SSVM-EHF is done only on the labeled samples with their original and hidden features, and the unlabeled samples are no longer explicitly used. Experimental results confirm the effectiveness of the proposed method. PMID- 26571546 TI - Containment Control of Multiagent Systems With Dynamic Leaders Based on a $PI^{n}$ -Type Approach. AB - This paper studies the containment control of multiagent systems (MASs) with multiple dynamic leaders in both continuous-time domain and discrete-time domain. The leaders' motions are described by the n th-order polynomial trajectories. This setting makes practical sense because given some critical points, the leaders' trajectories are usually planned by the polynomial interpolations. In order to drive all followers into the convex hull spanned by the leaders, a PI n type containment algorithm is proposed ( P and I are short for proportional and integral, respectively; I n implies that the algorithm includes up to the n th order integral terms). It is theoretically proved that the PI n -type containment algorithm is able to solve the containment problem of MASs where the followers are described by any order integral dynamics. Compared to the previous results on the MASs with dynamic leaders, the distinguished features of this paper are that: 1) the containment problem is studied not only in the continuous-time domain but also in the discrete-time domain while most existing results only work in the continuous-time domain; 2) to deal with the leaders with the n th-order polynomial trajectories, existing results require the follower's dynamics to be the ( n+ 1)th-order integral while the followers considered in this paper can be described by any-order integral dynamics; 3) the "sign" function is not employed in the proposed algorithm, which avoids the chattering phenomenon; and 4) both disturbance and measurement noise are taken into account. Finally, some simulation examples are given to demonstrate the effectiveness of the proposed algorithm. PMID- 26571547 TI - Addiction. PMID- 26571548 TI - Medicare Program; Revisions to Payment Policies Under the Physician Fee Schedule and Other Revisions to Part B for CY 2016. Final rule with comment period. AB - This major final rule with comment period addresses changes to the physician fee schedule, and other Medicare Part B payment policies to ensure that our payment systems are updated to reflect changes in medical practice and the relative value of services, as well as changes in the statute. PMID- 26571549 TI - [Nucleocytoplasmic transport mediated by importin-beta family members]. PMID- 26571550 TI - [Functional Dynamics of Importin alpha family]. PMID- 26571551 TI - [Aging and the regulation of nucleo-cytoplasmic transport]. PMID- 26571552 TI - [Hikeshi: Nucleocytoplasmic protein transport under stress conditions]. PMID- 26571553 TI - [Nucleocytoplasmic transport systems in higher plants]. PMID- 26571554 TI - [Structural basis for assembly and disassembly of the CRM1 nuclear export complex and its application to drug development]. PMID- 26571555 TI - [Proteomic analyses reveal regulation of the nuclear pore complex by post translational modifications]. PMID- 26571556 TI - [Inner architecture of the nuclear pore complex and molecular mechanism of importin beta-dependent nuclear transport]. PMID- 26571557 TI - [Multidentate coating of maltooligosaccharides allows nuclear import of nanoparticles]. PMID- 26571558 TI - [Regulation of proper complex formation for nuclear RNA export]. PMID- 26571559 TI - [Formation and nuclear export of messenger ribonucleoprotein complexes]. PMID- 26571560 TI - [Initiation, development and potential of hydrogen medicine: Toward therapeutic and preventive applications of molecular hydrogen against a variety of diseases]. PMID- 26571561 TI - [The Ras-PI3K signaling is involved in the regulation of endocytosis and virus internalization]. PMID- 26571562 TI - [Expansion of the genetic alphabet of DNA toward xenobiology]. PMID- 26571563 TI - [Expansion of MAIT cells via reprogramming to pluripotency and redifferentiation]. PMID- 26571564 TI - [Regulatory mechanisms of phosphorylation signaling by various ubiquitin-related enzymes]. PMID- 26571565 TI - [A role of prostaglandin E2-mediated regulation of prefrontal dopaminergic activity under repeated social defeat stress]. PMID- 26571566 TI - [Identification of the old and new lipid mediator, 12-HHT and the role in skin wound healing]. PMID- 26571567 TI - [Nutritional regulation of cellular quiescence in animals]. PMID- 26571568 TI - [Molecular mechanisms for cortical area map formation and activity dependent dendrite formation]. PMID- 26571569 TI - [Structure, application, and evolution of copepod luciferases]. PMID- 26571570 TI - [Interaction between an Influenza A viral protein PB1-F2 and mitochondria]. PMID- 26571571 TI - [Foreword]. PMID- 26571572 TI - [Mechanisms of maintaining genomic and epigenomic integrities]. PMID- 26571573 TI - [The roles of FOXO1 in various metabolic organs]. PMID- 26571574 TI - [Obesity and liver cancer: the roles of gut microbiota and cellular senescence]. PMID- 26571575 TI - [Structure and function of Thrombomodulin, a molecule which expressed on the endothelial cell surface and acts as anti-thrombogenic and antiinflammatory in the closed circulatory system]. PMID- 26571576 TI - ["Actual-ideal" discrepancy in protein folding: protein aggregation and chaperones]. PMID- 26571577 TI - [Abnormal corticogenesis in Marinesco-Sjogren syndrome]. PMID- 26571578 TI - [Glycolipid biosynthesis and oxygenic photosynthesis in cyanobacteria]. PMID- 26571579 TI - [Regulatory mechanism for DNA mismatch repair endonuclease]. PMID- 26571580 TI - [A novel pathway to produce hydrogen sulfide]. PMID- 26571581 TI - [Visualization of neural activity related to instinct behavior in insect brains using a conserved immediate early gene, Hr38]. PMID- 26571582 TI - [3D fluorescence imaging using optical clearing agents]. PMID- 26571583 TI - [Regulation of cell proliferation and apoptosis by long noncoding RNA, ANRIL and PANDA]. PMID- 26571584 TI - [Biosynthesis of bacteriochlorophyll pigment absorbing near-infrared light and its application]. PMID- 26571585 TI - [The pathophysiological importance and therapeutic potential of NAD+ biosynthesis in age-related diseases]. PMID- 26571586 TI - [Regulation of neural stem cells in the developing and adult brain]. PMID- 26571587 TI - [Scaling of Dorsal-Ventral patterning by Embryo size]. PMID- 26571588 TI - [New insights into the regulation of anti-inflammatory regulator CYLD: Novel anti inflammatory strategy by up-regulating CYLD]. PMID- 26571590 TI - [Foreword]. PMID- 26571589 TI - [Phosphorylation of the transcriptional co-repressor complex by CK2 as a molecular switch]. PMID- 26571592 TI - [Functional discovery of functionally unknown proteins by mass spectrometry]. PMID- 26571591 TI - [Moonlighting proteins]. PMID- 26571593 TI - [Unprogrammed protein folding--the formation of amyloid fibrils]. PMID- 26571594 TI - [Mechanistic enzymology of serine palmitoyltransferase--Stereochemical reaction control revealed by the side reaction of mutant enzymes]. PMID- 26571595 TI - [Self-incompatibility in plants: RNA degradation and ubiquitination-mediated self /non-self-discrimination]. PMID- 26571596 TI - [Substrate activation/inhibition of flavin oxidases in low-level oxygen]. PMID- 26571597 TI - [Relationship between histamine and dopamine synthesizing enzymes]. PMID- 26571598 TI - [A multifunctional enzyme involved in the formation of L-pipecolic acid and L proline]. PMID- 26571599 TI - [Role of GABA-synthesizing enzyme, glutamate decarboxylase, at the expression sites]. PMID- 26571600 TI - [The mechanism of autoimmune disease by glycotope mimicry]. PMID- 26571601 TI - [The critical role of Menin for regulating T cell senescence]. PMID- 26571602 TI - [Sialoglycobiology of influenza--Molecular bases of the human adaptation of avian influenza viruses]. PMID- 26571603 TI - [Aire gene is a central player in the autoimmune disease]. PMID- 26571604 TI - [Suppression of tumor growth by the beta4-galactosyltransferase gene]. PMID- 26571605 TI - [Tipin solves a variety of DNA replication problems]. PMID- 26571606 TI - [Mechanism of brain-specific expression of a glycogene GnT-IX]. PMID- 26571607 TI - [Regulation of innate immune responses by long noncoding RNAs]. PMID- 26571608 TI - [The role of tyrosine phosphorylation of cancer stem cell marker CD133 in malignant tumor progression]. PMID- 26571609 TI - [Formation and roles of perineuronal extracellular matrices in the adult brain]. PMID- 26571610 TI - [Foreword]. PMID- 26571611 TI - [Dissecting microRNA biogenesis and microRNA-mediated regulation of gene network]. PMID- 26571612 TI - [Mechanisms of phospholipid scrambling on plasma membrane]. PMID- 26571613 TI - [Signaling mechanism for axonal guidance factors, semaphorins]. PMID- 26571614 TI - [Reconsideration of molecular mechanism of vitamin D action based on its metabolism]. PMID- 26571615 TI - [Production of Functional Classical Brown Adipocytes from Human Pluripotent Stem Cells]. PMID- 26571616 TI - [Biogenesis and quality control of the outer membrane of gram-negative bacteria]. PMID- 26571617 TI - [Structure and function of Type III-B CRISPR-Cmr complex from Thermus thermophilus]. PMID- 26571618 TI - [Significance of O-glycosylation in Notch signaling]. PMID- 26571619 TI - [DNA-mediated charge transfer and DNA photodamage by artificial nucleic acids]. PMID- 26571620 TI - [Functions of heparan sulfate proteoglycans at the Drosophia neuromuscular junction]. PMID- 26571621 TI - [Novel type III polyketide synthase CsyB from Aspergillus oryzae]. PMID- 26571622 TI - [Functional plasticity of bacterial ribosome: Experimental horizontal gene transfer of 16S rRNA genes in Escherichia coli]. PMID- 26571623 TI - [Frameshift mutations in the PQBP1 gene prevent its interaction with the splicing factor U5-15kD]. PMID- 26571624 TI - [Identification of a candidate therapeutic autophagy-inducing peptide]. PMID- 26571625 TI - [Beyond the cell cycle regulation: novel functions of cell cycle-related proteins in brain development]. PMID- 26571626 TI - [Classification of Disease Types in Uveitic Patients: Lessons from Epidemiologic]. PMID- 26571627 TI - [Diagnostic Criteria for Atrophic Age-related Macular Degeneration]. AB - Diagnostic criteria for dry age-related macular degeneration is described. Criteria include visual acuity, fundscopic findings, diagnostic image findings, exclusion criteria and classification of severity grades. Essential findings to make diagnosis as "geographic atrophy" are, 1) at least 250 MUm in diameter, 2) round/oval/cluster-like or geographic in shape, 3) sharp delineation, 4) hypopigmentation or depigmentation in retinal pigment epithelium, 5) choroidal vessels are more visible than in surrounding area. Severity grades were classified as mild, medium and severe by relation of geographic atrophy to the fovea and attendant findings. PMID- 26571628 TI - [Clinical Survey of Uveitis in Tokyo Medical and Dental University--Comparison between the Periods of 1998-2001 and 2007-2011]. AB - PURPOSE: To investigate a clinical survey of uveitis in Tokyo Medical and Dental University Hospital. SUBJECTS AND METHODS: The clinical records of patients with uveitis who were treated from October 1998 to December 2001 and from January 2007 to December 2011 were reviewed. The clinical results of both periods were compared. RESULTS: A total number of 455 patients (707 eyes) and 1091 patients (1716 eyes) were analyzed in this survey. The mean age of the first period was 45.4, and of the second 50.3 years old. The incidences of sarcoidosis (11.0%, 13.7%) and Vogt-Koyanagi-Harada disease (5.7%, 5.9%) were virtually unchanged in the two series. However, the incidence of Behcet's disease was higher in the first period (10.6%) than in the second (5.8%). The frequency of herpetic iritis (1.8%, 4.7%) and intraocular lymphoma (0.4%, 2.6%)showed apparent increase. Unclassified uveitis decreased from 55.6% to 47.5%. CONCLUSIONS: The etiologies of uveitis have changed with the progress of diagnostic techniques and the establishment of new disease concepts. PMID- 26571629 TI - [A Case of Metastatic Endophthalmitis Resulting from Liver Abscess Complicated with Pyogenic Ventriculitis via Optic Nerve]. AB - BACKGROUND: Intracranial extension of infection via the optic nerve is a rare but serious complication of bacterial endophthalmitis. CASE: A 79-year-old women was hospitalized complaining of right eyelid swelling, severe hyperemia and purulent conjunctival discharge in the right eye. Although the fundus was invisible due to cataract, right endophthalmitis of unknown origin was suggested by pus in the anterior chamber and brain computed tomography (CT) findings showing nasal scleral rupture and orbital cellulitis. Systemic examination revealed pyogenic liver abscess and percutaneous drainage of abscess disclosed Klebsiella pneumoniae, which was also isolated from conjunctival discharge. Because diffusion-weighted magnetic resonance imaging (MRI) findings demonstrated right optic neuritis and ventriculitis, enucleation of her right eye was performed based on the diagnosis of pyogenic ventriculitis via the optic nerve. Klebsiella pneumoniae was detected in both stumps of the transected right optic nerve. Despite intensive anti-bacterial treatment, she died of acute respiratory distress syndrome 46 days after hospitalization. CONCLUSION: Severe bacterial endophthalmitis may cause intracranial infection via the optic nerve. PMID- 26571630 TI - The Road To Antibiotic Stewardship. PMID- 26571631 TI - e-Prescribing Makes Its Debut In New York. PMID- 26571632 TI - 'White Collar' Overtime Eligibility May Broaden. PMID- 26571633 TI - Disruptive trends in Health Information Systems. PMID- 26571634 TI - HIMSS Venture+ Forum and HX360 Provide Industry View of Health Technology Innovation, Startup and Investment Activity; Advancing the New Model of Care. AB - Presented by HIMSS, the Venture+ Forum program and pitch competition provides a 360-degree view on health technology investing and today's top innovative companies. It features exciting 3-minute pitch presentations from emerging and growth-stage companies, investor panels and a networking reception. Recent Venture+ Forum winners include TowerView Health, Prima-Temp, ActuaiMeds and M3 Clinician. As an industry catalyst for health IT innovation and business-building resource for growing companies and emerging technology solutions, HIMSS has co developed with A VIA, a new initiative that addresses how emerging technologies, health system business model changes and investment will transform the delivery of care. HX360 engages senior healthcare leaders, innovation teams, investors and entrepreneurs around the vision of transforming healthcare delivery by leveraging technology, process and structure. PMID- 26571635 TI - Facilitating Virtual Health Management Using Medical Device Integration. AB - Data from connected medical devices (CMDS) provides an objective and rich source of information to augment patient care management and clinical decision making. A principal reason is measurements of patient properties made through bedside CMDs are not typically subject to errors associated with misinterpretation, incorrect recording, and incorrect time stamping. Furthermore, data from CMDs can be collected regularly, ensuring a dense and robust data record on a given patient. The ability to remotely manage and monitor patients is greatly facilitated by access to data, as measurements represent an objective source of information that facilitate clinical decision making. In my recent book, Connected Medical Devices: Integrating Patient Care Data in Healthcare System, I discuss the topic of medical device integration (MDI) in relation to implementing CMDs in healthcare settings as a guide to assist hospitals in this undertaking. The following discussion about MDI are the opening paragraphs from this text, followed by a discussion of MDI architectures. PMID- 26571636 TI - Hospitals will send an integrated nurse home with each discharge. AB - Hospitals must adapt to the rapidly changing environment of risk by changing the health behavior of their population. There is only one way to do this efficiently and at scale; send a nurse home with every patient at the time of discharge. That nurse can ensure adherence to medication and slowly, over time, transform personal behavior to evidence based levels ... basically taking their medication as prescribed, changing eating habits, increasing exercise, getting people to throw away their cigarettes, teaching them how to cope, improving their sleep and reducing their stress. But, this approach will require a nurse to basically "live" with the patient for prolonged periods of time, as bad health behaviors are quick to start but slow to change or end. The rapid developments in artificial intelligence and natural language understanding paired with cloud based computing and integrated with a variety of data sources has led to a new marketplace comprised of cognitive technologies that can emulate even the most creative, knowledgeable and effective nurse. Termed the Virtual Health Assistant, your patients can literally talk to these agents using normal conversational language. The possibility to send a nurse home with each patient to maintain adherence and prevent readmissions has arrived. The technology is available. Who will step forward to reap the rewards first? PMID- 26571637 TI - Rethinking online health information: How about personalization? AB - Dr. Howard Koh, Former Assistant Secretary of Health and Human Services (HHS explained, "While [health literacy] may not necessarily attract headlines, it is absolutely at the core of everything we do as health care ... professionals." Yet making health information that is searched for on the Internet accessible means not only reducingjargon but also reducing volume. Personalization is one answer that Medivizor, a start-up featured in Forbes, has developed to answer the need. Hospitals and providers partner with Medivizor to improve the health literacy of patients, enhancing engagement and collaborative decision-making. PMID- 26571638 TI - No turning back - prospects and challenges of eHealth. AB - eHealth is a term referring to tools and services using information and communication technologies (ICTs) that can improve healthcare in many ways, such as prevention, diagnosis, treatment, monitoring and management. The small 'e' in front of the eHealth (original abbreviation for "electronic health") has been given several meaning: 'e' also refers to efficiency, empowerment of patients, evidence-based health care, enabled cross-border communication, and equity access to services, for instance. Furthermore eHealth includes the attitude and commitment to networking and global way of thinking. The purpose of the article is to describe the many-sided eHealth, prospects and challenges, changes in roles of health care staff and patients, and to encourage discussion. PMID- 26571639 TI - If these walls could talk: utilizing health data from the home to reduce unnecessary readmissions. AB - In the post-Affordable Care Act landscape (ACA), comprehensive care management has become an essential component in the universal goal to reduce hospital readmissions and their associated costs. Utilizing real-time home health monitoring technologies, hospitals can transform transitional care from hospital to home while significantly improving long-term home care outcomes. To achieve the Institute for Healthcare Improvement's Triple Aim, we need widespread commitment and investment in home healthcare IT that connects clinicians, providers, and payers to patients with speed and accuracy. Technology that generates real-time actionable health care data from the home is an essential key to progress in this endeavor. PMID- 26571640 TI - Grasping the health horizon: toward a virtual, interoperable platform of health innovations. AB - The emergence of digital health, wearables, apps, telehealth and the proliferation of health services online are all indications that health is undergoing rapid innovation. Health innovation however has been traditionally slow, high cost and the commercialisation journey was not a guaranteed path to adoption outside the setting where it was developed whether in a hospital, university, clinic or lab. Most significant with this new explosion of health innovations is the sheer volume. The startup revolution, mobile health, personalised heath and globalisation of knowledge means that consumers are demanding innovations and are pulling health innovations through commercialisation with new modes of funding such as crowdsourcing and direct vendor purchases. Our Australian team initiated a project to use machine learning, data mining and classification techniques to bring together and analyse this expansion of heath innovations from all over the world. Following two years of data aggregation and quality analysis we present our findings which are applied to over 200,000 innovations from more than 25,000 organisations. Our findings have identified the dynamics and basis for a marketplace for health innovations that could assist innovators, health practitioners, consumers, investors and other health participants to research, evaluate and promote these innovations. PMID- 26571641 TI - Physician Collaboration - Now needed more than ever. AB - Driven by the changing reimbursement climate from volume to value-based, hospital systems must initiate technology and training to insure that communications between all HCPs involved with a given patient are coordinated and all test results and care plans are immediately available at every point of care in the system. Since the enactment of the Patient Protection and Affordable Care Act (PPACA), there has been intense pressure on hospitals and health systems to reduce costs. Many hospitals are responding by merging and buying doctors' practices, while some are beginning to offer their own health plans for the first time and setting up accountable care organizations that would provide coordinated high quality health care for large groups of patients. With new hospital mergers being announced weekly and more practices being added to hospital systems daily, the need to collaborate through virtual health initiatives is gaining strength. The addition of inexpensive secure telemedicine to the availability of an intelligent patient record form based on best practice guidelines will enable greater collaboration across the hospital system. This type of technology will increase revenues, cut costs, improve outcomes and increase patient and provider satisfaction. PMID- 26571642 TI - MASK-rhinitis, a single tool for integrated care pathways in allergic rhinitis. AB - Allergic rhinitis (AR) is among the most common diseases globally. MASK-rhinitis is a simple ICT tool to implement care pathways for allergic rhinitis from patients to health care providers using a common language and a clinical decision support system. This is based on the assessment of the control of allergic rhinitis by a visual analogue scale on and App and a tablet. MASK-rhinitis will allow (i) the patients to screen for allergic disease, (ii) the pharmacists, to guide them in the prescription of OTC medications and direct the uncontrolled patients to physicians, (iii) the primary care physician, to prescribe appropriate treatment and to follow-up with the patient according to the physician's instructions (CDSS) and assessment of control and (vi) the specialist and outpatient clinics in allergology, if there is failure to gain control by the primary physician. MASK-rhinitis will be important for establishing care pathways across the life cycle, stratify patients with severe uncontrolled rhinitis and to perform clinical trials. PMID- 26571643 TI - [Fractionation of dissolved organic carbon along soil profiles during the leaching process]. AB - Two distinct soil types in mid-subtropical China were selected for soil sampling at the depth of 0-10, 10-20, 20-40, 40-60, 60-80, 80-100 cm for soil cores preparation. Dissolved organic carbon (DOC) extracted from recently fallen litters of Castanopsis carlesii with ultrapure water was leached through such soil cores to investigate the fractionation and retention pattern when migrating along the soil layers. The results showed the leachates out of deeper soil cores had lower concentrations and were chemically simpler, the hydrophobic pools contributed to the majority of the retention, but the proportion of retained hydrophilic materials gradually increased with the increasing soil depth. The infrared spectrum suggested that the hydrophobic materials containing aromatic rings could be easily absorbed by soils, but alkanes and simple carbohydrates would transport into subsoils with soil solution. Proportional decrease in the highly sorptive DOC restricted C sorption by subsoils, and thus the adsorption occurred mainly in 0-40 cm soil layers, suggesting that the chemical nature of DOC had a greater influence on sorption capacity of the soils than soil physicochemical properties. The retention amounts of DOC by different soil types differed significantly, which were significantly positively correlated with the contents of clay, iron and aluminum oxides. PMID- 26571644 TI - [Effects of precipitation variation on growing seasonal dynamics of soil microbial biomass in broadleaved Korean pine mixed forest]. AB - Broadleaved Korean pine mixed forest is the zonal climax vegetation in Northeast China and it plays a significant role in maintaining the ecological security. Changbai Mountains is a suitable region to study the positive and negative feedback mechanisms of temperate forest for precipitation variation. This study analyzed responses of soil microbial biomass carbon (SMBC) and microbial biomass nitrogen (SMBN) to precipitation variation (+/- 30%) in original broadleaved Korean pine mixed forest of Changbai Mountains. The results showed that, during the growing seasons (from May to September), the averages of SMBC and SMBN were 879.09 and 100.03 mg . kg(-1), respectively. Moreover, both of these two parameters gradually decreased with the soil depth. The contents of SMBC and SMBN all increased with the increasing precipitation, and the changes of SMBC and SMBN in the 0-5 cm soil layer were stronger than in the 5-10 cm soil layer. The value of SMBC/SMBN declined with the increase of precipitation. The precipitation variation significantly influenced the means of SMBC and SMBN. Compared with precipitation reduction, precipitation enhancement affected the indices much significantly. Both SMBC and SMBN showed similar seasonal patterns, which were the lowest in May, and after that, they increased and then decreased and increased again, showing 1-2 peaks in the growing season. However, the value and occurring time of the peaks varied with the precipitation and soil layer, and the seasonal variations of SMBC and SMBN in the 0-5 cm soil layer were higher than in the 5-10 cm soil layer. SMBC and SMBN had significant positive correlation with organic matter and total nitrogen content. The variances of soil physical and chemical properties caused by precipitation variation were closely related with the difference in spatial-temporal patterns of the soil microbial biomass in the forest. In conclusion, the precipitation variations could cause the change of the soil microbial community structure and composition. PMID- 26571645 TI - [Spatial distribution pattern of soil nitrogen in Huanghuadianzi watershed and related affecting factors]. AB - This research was conducted in Huanghuadianzi watershed in Aohan, Chifeng, Inner Mongolia. Geostatistic was used to study the spatial distribution of soil nitrogen and their affecting factors. The results showed that the soil nitrogen contents in all layers distributed as an island shape, and the high value areas were mainly distributed in the northwest of the watershed as an obvious fertile island shape, while the low value areas were mainly distributed in the south of the watershed. Nitrogen was mainly concentrated in the surface soil, and its content decreased with the increase of soil depth. The soil nitrogen content at first increased then decreased with the altitude, decreased with the slope, and showed the order of shady slope>semi-shady slope>semi-sunny slope> sunny slope in different aspects. The average soil nitrogen contents in different land use types ranked as cropland >woodland > grassland. PMID- 26571646 TI - [Absorption and distribution of K, Na and Mg in Avicennia marina seedlings under cadmium stress]. AB - In this paper, mangrove seedlings Avicennia marina were treated with various contents of cadmium (0, 0.5, 5, 25, 50, 100, 150 mg . L(-1)). These seedlings were cultivated by man-made seawater with a salinity of 15 in sand for 90 days in a greenhouse. The absorption and distribution of elements contents (K, Na and Mg) under cadmium stress were investigated at 45th and 90th day, respectively. The results showed that the enrichment of cadmium in the different components of seedlings increased with the increasing cadmium stress level and exposure time. The cadmium contents in roots and cotyledons were relatively higher than in the other components, accounting for 66.9% and 16.3% of cadmium in the seedlings under the 150 mg . L(-1) cadmium stress, respectively. The fall of cotyledons could reduce the damage of cadmium stress to the whole seedlings. The Na contents increased in roots and stems and decreased in leaves and cotyledons after cadmium stress for 90 days. The K content decreased in roots and cotyledons, while had no significant change in stems and leaves. The Mg content in roots, stems, leaves and cotyledons of seedlings treated with cadmium for 90 days were lower than those of the control, and were negatively related to the cadmium content. PMID- 26571647 TI - [Effects of chilling stress on antioxidant system and ultrastructure of walnut cultivars]. AB - In order to reveal cold hardiness mechanisms and ascertain suitable cold hardiness biochemical indicators of walnut (Juglans regia) , three walnut cultivars ' Hartley' , 'Jinlong 1' and 'Jinlong 2' with strong to weak tolerance of chilling stress, were used to investigate variations of leaf antioxidant enzyme activity and superoxide anion (O2-.) content in one year-old branches under chilling stress at 1 degrees C in leaf-expansion period. The mesophyll cells ultrastructure of ' Hartley' and 'Jinlong 2' under chilling stress were also observed by transmission electron microscope. The results showed that the superoxide dismutase (SOD) and peroxidase (POD) enzyme activities were the strongest and O2-. content was the lowest in chilling-tolerant cultivar ' Hartley' under chilling stress among the three cultivars. The ultrastructure of the mesophyll cells was stable, and chilling injury symptoms of the leaves were not observed. In chilling-sensitive cultivar 'Jinlong 2' , the SOD, POD and catalase enzyme ( CAT) activities decreased sharply, and the O2-. content was kept at a high level under chilling stress. The ultrastructure of the mesophyll cells was injured obviously at 1 degrees C? for 72 hours. Most of chloroplasts were swollen, and grana lamella became thinner and fewer. A number of chloroplasts envelope and plasma membrane were damaged and became indistinct. At the same time, the edges of some of 'Jinlong 2' young leaves became water-soaked. It was concluded that the ultrastructure stability of mesophyll cells under chilling stress was closely related to walnut cold hardiness. SOD, POD enzyme activities and O2-. content in walnut leaves could be used as biochemical indicators of walnut cold hardiness in leaf-expansion period. There might be a correlation between the damage of cell membrane system and reactive oxygen accumulation under chilling stress. PMID- 26571648 TI - [Leaf morphology and photosynthetic characteristics of wild Ussurian pear in China]. AB - The wild Ussurian pear was the most important wild pear resource in northern China, belonging to the most hardiness species. Taking 48 accessions of wild Ussurian pear and 2 accessions of cultivated Ussurian pear as test materials, this paper studied the morphology of leaves, chlorophyll content, and photosynthetic characteristics. We compared the difference between the wild and cultivated Ussurian pear, analyzed the photosynthetic characteristics of wild Ussurian pear, clarified the interrelationships between the indices, and established significant linear equations of photosynthesis and water-related physiological indices. The results showed that the leaf morphological index, chlorophyll content and photosynthetic indices for cultivated Ussurian pear were significantly lower than their average values for wild Ussurian pear. The specific leaf area (SLA), leaf dry matter content ( LDMC) , and intercellular CO2 concentration had low coefficients of variation, and the other 8 indices had variation coefficient indices between 0.12-0.41. So, the level of diversity was high, indicating obvious difference in photosynthetic characteristic of wild pear resources in China. The photosynthetic indices were significantly correlated with chlorophyll composition (Chl a/b) and LDMC. The photosynthetic rate had significant exponential correlation with the intercellular CO2 concentration, transpiration rate, and stomatal conductance. The photosynthetic rate was mainly affected by stomatal limitation. The wild variety 'Jinzhoushanli' was selected as high photosynthetic genetic resource. PMID- 26571649 TI - [Effects of drip irrigation methods on the regulation between root and crown function of 'Cabernet Sauvignon' seedlings]. AB - The objective of this experiment was to study the effects of three irrigation methods, i.e., subsurface drip irrigation with a tank system (SDI) , plastic film mulched-drip irrigation (MDI), and conventional drip irrigation (DI) on the regulation between root and crown function of Vitis vinifera 'Cabernet Sauvignon' seedlings. The results showed that both the SDI and MDI systems promoted the growth of the grape seedlings compared with DI, with the SDI system promoting the root growth, and MDI system promoting the aboveground growth. Root area, root volume, and root activity and SOD enzyme activity in the SDI treatment were greater than those of MDI or DI treatment in the 20-60 cm soil layer. SDI treatment increased root penetration and physiological activity. Symptoms of drought stress appeared earlier in DI treatment than in either MDI or SDI treatment in the same watering schedule. Net photosynthetic rate (Pn) and stomatal conductance (g(s)) of leaves were higher in SDI and MDI treatments than in DI treatment. PhiPS II and qP at 12:00-14:00 were lower in the MDI treatment than in SDI treatment at 7 d after irrigation, suggesting that the degree of photoinhibition in the fluorescence process in MDI treatment was more than that in SDI treatment. The high biomass and physiological activity of roots in the 20 40 cm depth could increase both of total plant biomass and aboveground biomass. The regulation between root and crown function was better in SDI treatment than in MDI and DI treatments. Therefore, SDI could be used as an alternative technique of water-saving irrigation practices. PMID- 26571650 TI - [Effects of NO3- stress on cucumber seedling growth and magnesium absorbing under suboptimal temperature]. AB - The effects of NO3- stress on the growth and the magnesium absorption of cucumber seedlings were investigated after 1 and 14 d of suboptimal temperature [18 degrees C/12 degrees C (day/night)] treatment. The results indicated that the growth, net photosynthetic rate, transpiration rate, Fv/Fm and PhiPSII of cucumber seedlings were significantly inhibited by NO3- stress under suboptimal temperature. The magnesium content of cucumber seedlings was also significantly decreased compared with control treatment, especially in the IV treatment (suboptimal temperature +140 mmol . L(-1) NO3- + 1 mmol . L(-1) Mg2+), and the antagonistic impact of magnesium ion absorption on the absorption of potassium and calcium ion was observed. The magnesium deficiency symptom of cucumber seedlings could be partly alleviated by increasing the concentration of magnesium ion in the nutrient solution. PMID- 26571651 TI - [Effects of low magnesium on photosynthesis characteristics and antioxidant system in cucumber seedlings under low temperature]. AB - The effects of low magnesium (30% Mg) stress on photosynthesis characteristics and antioxidant system in 'Jinyou 3' cucumber ( Cucumis sativa) seedlings under low temperature (day/ night temperature was 12 degrees C/8 degrees C) were investigated, with Hoagland nutrient solution treatment as the control. The results showed that the 30% Mg treatment showed a significantly lower Mg content in leaves, compared with the control. However, no marked difference in roots between the 30% Mg treatment and the control was found. Low temperature significantly decreased the chlorophyll content, net photosynthetic rate (Pn), stomatal conductance (g(s)), and carboxylation efficiency (CE), while increased the intercelluar CO2 concentration (Ci). The 30% Mg treatment showed significantly lower chlorophyll content, Pn, g(s) and CE, compared with the control. No marked change was found in Ci between the 30% Mg treatment and the control. Low magnesium stress resulted in a more serious damage in chloroplast membrane under low temperature, and showed lower chloroplasts, grains and lamellas, while more and larger starch grains in cucumber seedlings. Low magnesium stress also led to an increase in MDA content, while a decrease in activities of superoxide dismutase (SOD) , peroxidase (POD) , catalase ( CAT) , ascorbate peroxidase (APX) and glutathione reductase (GR). These data suggested that magnesium deficiency caused by its hindered transportation under low temperature was the main reason for the chlorosis of cucumber leaves. The decrease in Pn was mainly caused by the non-stomatal limitation. Low magnesium stress increased the influence of low temperature on Pn, and the resulting decline in Pn was caused by the stomatal limitation. PMID- 26571652 TI - [Effects of temperature-shifted controlling on bolting and flowering of endive]. AB - Temperature sensitive periods and growth characteristics of endive under different temperatures were investigated in greenhouse by weekly reciprocal transferring experiment condition between warm (17 degrees C) and cold (average 10.5 degrees C) environment. The results indicated that difference in growth rate of endive was significant in cold and warm environments. There was no temperature sensitive period in endive, and it could feel outside temperature, thus, conducted vernalization induction in setting temperature range (2-17 degrees C). Meanwhile, low temperature favored the flower bud differentiation. Endives all completed flower bud differentiation and bloting either in warm or in cold environment. It took 24 days to complete flower bud differentiation in cold environment and 60 days in warm environment, and bolting was 7 days later in warm environment than in cold environment. From seeding to bolting, it took 111 days in warm environment and 104 days in cold environment, respectively. After flowering induction, the seeding bolting rate from warm environment to cold environment was obviously higher than that from cold to warm environment and higher temperature led to faster bolting in this period. PMID- 26571653 TI - [Effect of the same amount of faba bean fresh straw returning with different ratios of chemi- cal fertilizer on single cropping late rice]. AB - A field experiment was conducted on paddy soil derived from alluvial materials at Bihu Town, Lishui City, Zhejiang Province, China to explore the effects of combined application of faba bean fresh straw and different-rate chemical fertilizer on nutrient uptake, nutrient use efficiencies, and yields of single cropping late rice and to determine the optimal rate of chemical fertilizer under the condition of application of faba bean fresh straw at the rate of 15 t . hm( 2) (GM15) in 2012, April to December. The experiments consisted of 7 treatments: CK (no fertilizers) , CF (conventional chemical fertilizer rate) , and combined application of 15 t . hm(-2) of faba bean fresh straw and 0%, 20%, 40%, 60% and 80% of the conventional chemical fertilizer rate. The results showed that the highest total uptake amounts of N, P and K by the aboveground part were obtained from the treatments of GM15 + 60%CF and GM15 + 80% CF, but the highest nutrient agronomy use efficiencies of N, P and K in rice grains were obtained from the treatments of GM15 + 60% CF and GM15 + 40% CF. The agronomy use efficiencies and physiological use efficiencies of N, P, and K were significantly correlated with rice grain yields, thus they could be used for accurate comprehensive evaluation of fertilizer efficiencies of N, P, and K. Compared with no fertilizer treatment, the treatments of 100% CF and combined application of faba bean fresh straw and different-rate chemical fertilizer increased rice gain yields by 25.0% and 6.1% 29.2%, respectively. In the cropping system of faba bean-single cropping late rice, returning of 15 t . hm2 faba bean fresh straw to the paddy field did not result in the runt seedling of rice. From the point of improving fertilizer use efficiency and reducing environmental risk perspective, the optimum rate of chemical fertilizer was 60% of the conventional chemical fertilizer rate when 15 t . h(-2) of faba bean fresh straw was applied. PMID- 26571654 TI - [Comparison on submergence tolerance of different type rice at tillering stage in lower reaches of Yangtze River]. AB - The agronomic traits, physiological characteristics and yield traits of 9 rice varieties popularized in lower reaches of Yangtze River were investigated under submergence stress at the tillering stage. The differences of environmental adaptability to submergence stress for conventional japonica rice, indica hybrid rice and hybrid japonica rice, were also analyzed and compared. The results showed that the stem and the upper three leaves under submergence stress were elongated compared with the control. And the elongation of the different varieties was shown as, hybrid japonica rice > indica hybrid rice > conventional japonica rice. As to the numbers of tillers and green leaves, and the aboveground dry mass, the reduction of indica hybrid rice was all between hybrid japonica rice and conventional japonica rice. The damage of hybrid japonica was the lightest. The content of MDA in the leaves of conventional japonica rice increased, while the activities of SOD and CAT decreased. However, the performances of hybrid japonica rice and indica hybrid rice were opposite with conventional japonica rice. The yield loss of conventional japonica rice was significantly higher than those of the other types of rice. These results suggested that the submergence tolerance ability of hybrid japonica rice is superior to indica hybrid rice, and the submergence tolerance ability of conventional japonica rice is the weakest. PMID- 26571655 TI - [Effects of ridge and furrow rain harvesting with supplemental irrigation on winter wheat photosynthetic characteristics, yield and water use efficiency in Guanzhong irrigation district]. AB - A field experiment was conducted to determine the regulation of crop photosynthesis and output and water saving effect under ridge and furrow rain harvesting with supplemental irrigation in Guanzhong irrigation district. The experiment was set with 5 treatments with irrigation at returning green stage, and the widths of both ridge and furrow being 60 cm. T1, T2 and T3 were in the ridge and furrow rain harvesting planting pattern, with the irrigation volumes being 0, 375 and 750 m3 . hm(-2) respectively, T4 was flat planting with irrigation (border irrigation) of 750 m3 . hm(-2) and CK was flat planting without irrigation. Effects on winter wheat photosynthetic organs, photosynthetic rate, yield and water use efficiency, etc. were tested. The results showed that compared with T4, T1, T2 and T3 treatments increased the grain yield by 2.8%, 9.6% and 18.9%, improved the harvest index by 2.0% to 8.5%, advanced the flag leaf chlorophyll content by 41.9% to 64.4% significantly, and improved the 0-40 cm layer soil moisture content by 0.1%-4.6% during the whole growth period. Photosynthetic rates at the flowering and filling stages also increased by 22.3% to 54.2% and -4.3% to 67.2%, respectively. Total water use efficiencies (WUEy) were 17.9%, 10.4% and 15.4% higher than that of T4, and 69.3%, 58.6% and 65.7% higher than that of CK (P < 0.05), respectively, and enhanced precipitation utilization efficiency ( PUE ) by 94.3%-124.5% than CK. Leaf areas of T2 and T3 treatments at each growth stage were significantly higher than that of T4 and CK, irrigation water use efficiencies (IUE) were 119.1% and 18.8% higher than that of T4, respectively. Therefore, it was concluded that ridge and furrow rain harvesting cultivation could maintain higher grain yield than border irrigation without irrigation or with irrigation reduction by 50%. The utilization efficiency of irrigation water under the condition of irrigation reduction by 50% was improved significantly, and the ridge and furrow rain harvesting could significantly improve whole cropland water use efficiency in the year of less rainfall. PMID- 26571656 TI - [Effects of drought stress on performance of photosystem II in maize seedling stage]. AB - Maize cultivar Shandan 609 was used to determine the effects of drought stress on photosystem II, dry matter accumulation, protective enzyme activity and proline content at seedling stage in pot experiment. Two drought treatments (moderate drought and severe drought) were tested. The results showed that dry matter accumulation, leaf area and plant height of cultivar shaandan 609 decreased significantly with the increasing drought stress. The less grouped PS II units (L band > 0), severely damaged OEC (K-band > 0), and the inhibited acceptor side (psio significantly decreased) resulted in the overall dropped performance of PS II (PI(ABS)). Under the condition of moderate and severe drought stress, the activities of superoxide, peroxidase, catalase and proline content increased significantly, which were 1.3, 1.1, 1.2, 5.8 and 1.1, 3.3, 1.5, 15.0 times of control (CK), respectively. Those results indicated that damage of PS II acceptor and donor side under drought stress led to the decline of PS II performance, which was likely to cause the decline of dry mater accumulation of maize cultivar Shandan 609, while protective enzymes and proline as protective substance in plant played a positive role in drought resistance. PMID- 26571657 TI - [Effects of tillage at pre-planting of winter wheat and summer maize on leaf senescence of summer maize]. AB - This study explored the effects of different tillage treatments at pre-planting winter wheat and summer maize on leaf senescence physiological characteristics of summer maize in double cropping system. Zhengdan 958 was used as experimental material. Three tillage treatments, including rotary tillage before winter wheat seeding and no-tillage before summer maize seeding (RN), mold- board plow before winter wheat seeding and no-tillage before summer maize seeding (MN), and moldboard plow before winter wheat seeding and rotary tillage before summer maize seeding (MR), were designed to determine the effects of different tillage treatments on leaf area (LA) , leaf area reduction, photosynthetic pigments content, superoxide dismutase (SOD), catalase (CAT) and peroxidase (POD) activities and malondialdehyde (MDA) content in ear leaves of summer maize after tasselling (VT). LA of MN and MR were higher than that of RN from VT to 40 days after tasseling (VT + 40) and LA reduction of MR was the highest after VT + 40. As for MR, MN and NT, the photosynthetic pigments content got the maximum value at 20 days after tasselling (VT + 20) and then decreased, following the change of unimodal curve. At VT + 20, the contents of chlorophyll a in MR and MN were increased by 11.4% and 9.7%, the contents of chlorophyll b in MR and MN were increased by 14.9% and 15.9%, compared with RN. The soluble protein content in ear leaves decreased following the growth process in all treatments, and that of MR and MN remained 11.5% and 24.4% higher than that of RN from VT to VT + 40. SOD, CAT and POD activities of three treatments got the maximum values at VT + 20 and then decreased, following the change of unimodal curve. MDA content increased following the growth process in all treatments and that of RN always remained at high levels. Grain yields of MN and MR were 24.0% and 30.6% greater than that of RN, respectively. Grain yield of MR was 5.2% higher than that of MN. In conclusion, the ability of leaf senescence resistance of MN was improved, which was helpful to increase the yield of summer maize. PMID- 26571658 TI - [Degradation of lignocellulose in the corn straw by Bacillus amyloliquefaciens MN 8]. AB - Microbial degradation of lignocellulose is one of the key problems that need to be solved urgently in the process of utilizing biomass resource. Bacillus amyloliquefaciens MN-8 is our previously isolated bacterium capable of degrading lignin. To determine the capability of strain MN-8 to degrade lignocellulose of corn straw, B. amyloliquefaciens MN-8 was inoculated and fermented with solid state corn straw powder-MSM culture medium. The changes in the enzyme activity and degradation products of lignocellulose were monitored in the process of fermentation using the FTIR and GC/MS. The results showed that B. amyloliquefaciens MN-8 could produce lignin peroxidase, manganese peroxidase, cellulase and hemicellulase enzymes. The activities of all these enzymes reached the peak after being incubated for 10-16 days, and the highest enzyme activities were 55.0, 16.7, 45.4 and 60.5 U . g(-1), respectively. After 24 d of incubation, the degradation percentages of lignin, cellulose and hemicellulose were up to 42.9%, 40.6% and 27.1%, respectively. The spectroscopic data by FTIR indicated that the intensities of characteristic absorption peaks of lignin, cellulose and hemicellulose of the corn straw were decreased, indicating that the lignocellulose was degraded partly after being fermented by B. amyloliquefaciens MN-8. GC/MS analysis also demonstrated that strain MN-8 could degrade lignocellulose efficiently. It could depolymerize lignin into some monomeric compounds with retention of phenylpropane structure unit, such as amphetamine, benzene acetone and benzene propanoic acids, by the rupture of beta-O-4 bond connected between lignin monomer, and it further oxidized some monomer compounds into Calpha carbonyl compounds, such as 2-amino-1-benzeneacetone and 4-hydroxy 3,5-dimethoxy-acetophenone. The GC/MS analysis of the degradation products of cellulose and hemicellulose showed that there were not only monosaccharide compounds, such as glucose, mannose and galactose, but also some glycolysis products including formic acid, acetic acid, propionic acid, 1,1-ethanediol and 3 hydroxy butyric acid. Our results demonstrated that B. amyloliquefaciens MN-8 is capable of degrading lignocelluse of the corn straw effectively and the degradation capacity depends on the lignocellulase activity. PMID- 26571659 TI - [Effects of exogenous EBR and NO signal on antioxidant system and low response gene expression under cold stress on maize embryo]. AB - In this study, Xianyu 335, a maize hybrid, was used to investigate the effects of 24-Epibrassinolide (EBR, a synthetic BR) on antioxidant capacity and low temperature response gene expression in maize embryo germination under low temperature (LT) stress. The germination rate of maize seeds under LT stress was not affected by EBR, but the seed activity index and seedling growth were improved. EBR increased the activities of some antioxidative enzymes including SOD, POD, CAT and GR, and the contents of non-enzymatic antioxidants, such as GSH and proline, and induced the accumulation of nitric oxide (NO). NO scavenging c PTIO and NOS inhibitor L- NAME decreased but NO donor SNP increased the enzyme activities of CAT and POD, and the content of proline, indicating NO mediated the EBR-induced antioxidant capacity. The gene expression pattern analysis showed that the expression of P5CS1, CBF1, CBF3 and COR15a was induced by LT stress, and further increased by EBR treatment in maize embryo, while their expression was suppressed by c-PTIO and L-NAME, and improved by SNP, which implied LT-responsed genes were regulated by NO. These results demonstrated that NO was involved in the EBR-induced LT tolerance in maize embryo by modulating the antioxidative capacity and the expression of LT-responsive genes. PMID- 26571660 TI - [Influence of drought on leaf photosynthetic capacity and root growth of soybeans at grain filling stage]. AB - A drought-resistant soybean cultivar Jinda 70 and a drought-sensitive soybean cultivar Jindou 26 were taken as test materials. At the grain filling stage, the cultivars were subject to three water treatments including sufficient water supply, light drought stress, and severe drought stress by using pot experiments for research on influence of drought on leaf photosynthetic capacity and root growth of soybeans. The results showed that as the degree of drought stress was aggravated, all of the indices including leaf area, chlorophyll content, net photosynthetic rates (Pn), stomatal conductance (g(s)), transpiration rate (Tr), intercellular CO2 concentration (Ci), plant mass, plant height, seed yield, and harvest index in the two cultivars declined. The root length and root mass increased under light drought stress, and decreased under severe drought stress. Root-shoot ratio ascended as the degree of drought stress was aggravated. Under severe drought stress, the increase of root-shoot ratio of the drought-resistant soybean cultivar Jinda 70 was up to 135.7%, which was higher than the that (116.7%) of the drought-sensitive soybean cultivar Jindou 26. Simultaneously, leaf area and chlorophyll content in Jinda 70 were respectively 69.3% and 85.5% of those in the control, which were better than those of Jindou 26. g(s) and Pn of Jinda 70 respectively declined 67.9% and 77.9%, but still lower than those of Jindou 26. Therefore, the decline range of harvest index of Jinda 70 was 43.8%, which was lower than the range of 78.8% of Jindou 26. The Biplot revealed that under different dry treatments, there were significant positive correlations among the six indexes including leaf area, chlorophyll content, Pn, g(s), Tr, and Ci of the two cultivars. There were also significant positive correlations among the six indices including plant mass, plant height, root length, root mass, seed yield, and harvest index. Root-shoot ratio only had significant positive correlation with root mass and had significant negative correlations with other five indices. PMID- 26571661 TI - [Effects of sugarcane-soybean intercropping on cane yield, quality and economic benefit under low nitrogen condition]. AB - To explore the effects of sugarcane-soybean intercropping on cane yield, quality and economic benefit, three sugarcane cultivars (B8, ROC22 and GT21) planted under sugarcane monoculture and sugarcane-soybean intercropping with low nitrogen fertilization (urea application of 150 kg . hm(-2)). The field design was a split plot with the cropping pattern being the principal factor and the sugarcane cultivar being the secondary factor. The results showed that the millable stalks, stalk diameter, cane yield and sugar production were significantly affected by sugarcane-soybean intercropping while the cane quality wasn' t changed obviously. Compared with sugarcane monoculture, the stalk diameter, millable stalks, cane yield and sugar production in the intercropping system were increased by 5.1% 8.7%, 7.9%-31.0%, 9.0%-40.5% and 5.6%-39.5%, respectively. The total incomes of cane and soybean, and sugar and soybean were increased by 58900-79300 yuan . hm( 2) and 58300-77200 yuan . hm(-2), respectively. Among the three sugarcane cultivars in the sugarcane-soybean intercropping pattern, the economic benefit was the highest in ROC22, while the ratoon cane yields of GT21 and B8 were higher than that of ROC22. The results also indicated that sugarcane-soybean intercropping is an effective planting method to reduce nitrogen fertilizer application and increase economic income in sugarcane production. PMID- 26571662 TI - [Effects of calcium fertilizer application on peanut growth, physiological characteristics, yield and quality under drought stress]. AB - An experiment was carried out to study the effects of different rates of calcium application on peanut growth, physiological characteristics, yield and quality under drought stress at pegging stage and pod setting stage in pool cultivation with rainproof, using variety 606 as experimental material. The results showed that applying Ca fertilizer under drought stress could promote peanut growth, increase the chlorophyll content, leaf photosynthetic rate and the root vitality, increase the recovery ability of peanut during rewatering after drought stress, alleviate the impact of drought stress on peanut. Applying Ca fertilizer under drought stress increased pod and kernel yields because of the increase of kernel rate and pod number per plant. It also increased the fat and protein contents of peanut kernel, and improved peanut kernel quality under drought stress. It was suggested that 300 kg . hm(-2) Ca application is the best choice to alleviate the impact of drought stress on peanut. PMID- 26571663 TI - [Effects of phosphorus fertilizer on the root system and its relationship with the aboveground part of flue-cured tobacco]. AB - Using 'Yuyan 10' as the material, the effects of different phosphorus fertilizer application on root characteristics of tobacco, such as root dry mass and the difference of dry matter distribution and mineral nutrient accumulation between its above and underground parts were investigated. The results showed that the growth of flue-cured tobacco root system and the distribution of dry matter to the aboveground part were significantly promoted by phosphorus fertilizer application. The application of 30 kg P2O5 . hm(-2) led to the maximums of root dry mass, root volume, root activity and the minimum of root to shoot ratio. The maximum nutrient accumulation rates of root and leaf appeared 57-66 days after transplanting and 44-55 days after transplanting, respectively. Phosphorus could not only promote the mineral nutrition absorption of tobacco and the earlier appearance of maximum nutrient accumulation, but significantly promote the nutrient accumulation of the aboveground part. But, the positive effects described above would be weakened when the amount of phosphorus fertilizer was more than 30 kg P2O5 . hm(-2). Therefore, it's necessary to control the amount of phosphorus application to improve the quality of tobacco leaves. PMID- 26571664 TI - [Correlation between endogenous harmful components in mainstream cigarette smoke and chemical constituents in tobacco leaves]. AB - Correlation analysis between main chemical constituents of tobacco leaves and endogenous harmful components in mainstream cigarette smoke was conducted. Leaf stalk positions exhibited a high relation with endogenous harmful components and hazard index (H). Upper stalk position leaves had greater release of 1-butanone,4 (methylnitrosoamino)-1-(3-pyridinyl)-(NNK), B[a]P, HCN, NH3 and phenol in mainstream cigarette smoke, and a higher hazard index than middle position leaves except for crotonaldehyde, which had greater release from middle position leaves. Different endogenous harmful components in mainstream cigarette smoke presented complicated correlation with main chemical constituents in tobacco. The same type of leaf chemical constituents presented different correlations with various endogenous harmful components in mainstream cigarette smoke. Cigarette hazard index showed significantly positive correlations with contents of nicotine, protein, total nitrogen, major polyphenols and organic acids, while significantly negative correlation with potassium and carbonaceous substances, such as total sugars, reducing sugars and starch. The results suggested that properly increasing potassium content and decreasing nitrogenous constituents in cured tobacco leaf may reduce the cigarette hazard index. PMID- 26571665 TI - [Characteristics of the preferential flow and its response to irrigation amount in oasis cropland]. AB - Preferential flow is a physical process describing how water and solutes move aiong cer- tain pathways through soil profile. Studying the cropland preferential flow patterns and its influential factors could quantify the deep percolation, improve water and fertilizer use efficiency and reduce the risk of agrochemicals contaminating shallow groundwater in oasis cropland. The dye tracer exper- ments were carried out in field oasis cropland, using a brilliant blue FCF solution. The results showed that between ridge and furrow, the number of stained paths densities differed significantly at the 7.3-16.7 cm depth of the soil profiles, while the maximum dye depth had no significant differ- ence. The main influence factors of the maximum stained depth were the irrigation amount and the ant burrows. The maximum stained depth was (43.1 +/- 5.9) cm with the mean irrigation amount of 120 mm, however, the maximum stained depth was (68.3 +/- 7.6) cm with the irrigation amount of 55 mm under the influence of the ant burrows. Root played an important role in preferential flow, but only the fine roots (Phi <= 2 mm) were significantly related to the preferential flow in oasis cropland, while the coarse roots were not. In oasis cropland, the characteristics of the preferential flow were influenced by the irrigation amount, the furrow and ridge planting, the ant burrows and the roots, and the ant burrows were an uncertain factor which affected the maximum infiltration depth of the preferential flow. PMID- 26571666 TI - [Establishing a minimum data set of soil quality assessment for cold-waterlogged paddy field in Fujian Province, China]. AB - The yields of cold-waterlogged (CW) paddy fields widely spreading in Jiangnan mountainous areas are moderate or low but have a high potential to be increased. Based on data including 41 soil characteristics of 17 pairs of typical surface soils of cold-waterlogged paddy field and non cold-waterlogged (NCW) paddy field at a neighboring landscape unit in Fujian Province, various index differences of soil properties and causes between CW paddy field and NCW paddy field were systematically studied, and a minimum data set (MDS) of soil quality assessment for CW paddy field was established by principal component analysis. By pair analysis, soil characteristics of CW paddy field showed that the content of organic matter increased by 31.7%, but the microbial biomass C decreased by 37.8%, which belonged to active soil organic matter component. The content of ferrous iron (Fe2+) increased by 177.0%, but the available phosphorus (P) and potassium (K) decreased by 52.3% and 22.8%, respectively. Catalase and invertase activities increased by 58.3% and 22. 1%, but phosphatase, nitrate reductase activities and microflora decreased by 47. 8%, 66.6% and 29.8%-46.0%, respectively. The sand content increased about 8.0%, but the water immersed bulk density decreased by 25.8%. There were significant differences of indices for 28 of all 41 soil characteristics. Five principal components cumulatively exhibiting about 78.5% contribution were concluded from the 28 soil characteristics to reflect characteristics related to soil biochemistry, active organic nitrogen, reducing barriers, physical and chemical nutrients, respectively. Eventually, correlation analysis combined with expert experience method were applied to optimize MDS containing six factors for soil quality assessments, including C/N, bacteria, microbial biomass N, total reducing agents, physical sand and total P. PMID- 26571667 TI - [Influence of paddy rice-upland crop rotation of cold-waterlogged paddy field on crops produc- tion and soil characteristics]. AB - Two consecutive years (4-crop) experiments were conducted to study the influence of different paddy rice-upland crop rotation in cold-waterlogged paddy field on the growth of crops and soil characteristics. The result showed that compared with the rice-winter fallow (CK) pattern, the two-year average yield of paddy rice under four rotation modes, including rape-rice (R-R), spring corn-rice (C R), Chinese milk vetch-rice (M-R) and bean-rice (B-R), were increased by 5.3% 26.7%, with significant difference observed in C-R and R-R patterns. Except for M R pattern, the annual average total economic benefits were improved by 79.0% 392.4% in all rotation pattern compared with the CK, and the ration of output/input was enhanced by 0.06-0.72 unit, with the most significant effect found in the C-R pattern. Likewise, compared with the CK, the contents of chlorophyll and carotenoid, and net photosynthetic rate (Pn) of rice plant were all increased during the full-tillering stage of rice in all rotation patterns. The rusty lines and rusty spots of soils were more obvious compared with the CK during the rice harvest, particularly in R-R, C-R and B-R patterns. The ratio of water-stable soil macro aggregates of plough layer of soil (> 2 mm) decreased at different levels in all rotation patterns while the ratios of middle aggregate (0.25-2 mm, expect for M-R) and micro aggregate of soil (< 0.25 mm) were opposite. There was a decreasing trend for soil active reducing agents in all rotation patterns, whereas the available nutrient increased. The amounts of soil bacteria in C-R and B-R patterns, fungi in B-R rotation pattern, cellulose bacteria in R-R, C-R and B-R patterns and N-fixing bacteria in B-R pattern were improved by 285.7%-403.0%, 221.7%, 64.6-92.2% and 162.2%, respectively. Moreover, the differences in all microorganisms were significant. Thus, based on the experimental results of cold-waterlogged paddy field, it was concluded that changing from single cropping rice system to C-R, R-R and B-R rotation patterns had good effect in terms of improving total yield and economic benefits, and soil physical and chemical properties were improved. PMID- 26571668 TI - [Regional difference of NPK fertilizers application and environmental risk assessment in Jiangsu Province, China]. AB - It is of great importance to have a deep understanding of the spatial distribution of NPK fertilizers application and the potential threat to the ecological environment in Jiangsu Province, which is helpful for regulating the rational fertilization, strengthening the fertilizer use risk management and guidance, and preventing agricultural non-point pollution. Based on the environmental risk assessment model with consideration of different impacts of N, P, K fertilizers on environment, this paper researched the regional differentiation characteristic and environmental risk of intensity of NPK fertilizer usages in Jiangsu. Analystic hierarchy process ( AHP) was used to determine the weithts of N, P, K. The environmental safety thresholds of N, P, K were made according to the standard of 250 kg . hm(-2) for the construction of ecological counties sponsered by Chinese government and the proportion of 1:0.5:0.5 for N:P:K surposed by some developed countries. The results showed that the intensity of NPK fertilizer application currently presented a gradually increasing trend from south to north of Jiangsu, with the extremum ratio of 3.3, and the extremum ratios of nitrogen fertilizer, phosphorus fertilizer and potassium fertilizer were 3.3, 4.5 and 4.4, respectively. The average proportion of nitrogen fertilizer, phosphorus fertilizer and potassium fertilizer of 13 cities in Jiangsu was 1:0.39:0.26. Their proportion was relatively in equilibrium in southern Jiangsu, but the nutrient structure disorder was serious in northern Jiangsu. In Jiangsu, the environmental risk index of fertilization averaged at 0.69 and in the middle-range of environmental risk. The environmental risk index of fertilizer application in southern and central Jiangsu was respectively at the low and moderate levels, while that of cities in northern Jiangsu was at the moderate, serious or severe level. In Jiangsu, the regional difference of fertilizer application and environmental risk assessment were affected by many factors, including physical and economic conditions, government policy, management system, technology, and management methods. PMID- 26571669 TI - [Processes of earth road regolith erosion in loess area]. AB - Based on field investigation, the processes of earth road regolith erosion were studied under indoor simulated rainfall. Results showed that the runoff initiation time for both regolith and earth road surface erosion decreased with the increasing rainfall intensity and slope steepness. With the increase in regolith thickness, the initiation time for earth road surface erosion lagged for 2-5 min. When the regolith thickness was <= 0.5 cm, the runoff rate turned to be stable at 2 min after runoff generation, and the average runoff rate increased with the increasing rainfall intensity and decreased with the increasing slope steepness. When the regolith thickness was >= 1.0 cm, runoff rate turned to be stable at 3 min after runoff generation, and the average runoff rate increased linearly with the rainfall intensity but exhibited a gradually decreasing trend after the first increment with the increasing slope steepness. The critical point for regolith erosion decreased with the increasing rainfall intensity and slope steepness. With the regolith thickness of <= 0.5 cm, the erosion rate increased with the increasing rainfall intensity, with the erosion rate ranging from 24.5% to 434.4%, and the erosion rates for 8 degrees and 16 degrees slopes were 2.4 times as those for 2 degrees and 4 degrees slopes. With the regolith thickness of 1.0 cm, the erosion rate turned to be stable about 9 min after runoff generation and increased with the increasing rainfall intensity and slope. With the increasing slope steepness, the erosion form changed from sheet erosion to rill erosion and then to headward erosion. The average erosion amount over 10 min single rainfall for the regolith thickness of >= 1.0 cm was 1.3 times as that for the regolith thickness of <= 0.5 cm, while it was 2.7 times as that at the stage of regolith erosion alone. With the regolith thickness of <= 0.5 cm, the erosion amount had a significant correlation with rainfall intensity, and runoff volume with slope steepness. With the regolith thickness of >= 1.0 cm, both runoff and sediment yields in 10 min single rainfall had a significant correlation with rainfall intensity. The proportion of regolith erosion to the combined erosion increased with the increasing regolith thickness, while the road erosion was the main form at small regolith thickness. PMID- 26571670 TI - [Potential ecological risks assessment of heavy metals in the reservoir sediment of the western Haihe River basin]. AB - The reservoirs distributed in the western part of Haihe River basin play a key role in drinking water supply in the densely populated region. The potential ecological risk of heavy metals stored in the reservoir sediments has drawn more attention during recent decades. In this study, a total of 10 reservoirs in the western Haihe River basin were sampled. The sediment samples were assessed by the Hakanson potential ecological risk evaluation index. The sediments of upstream and downstream rivers were also sampled for comparative analysis with those of the reservoirs. The results indicated the concentration of Cd was significantly higher than the background value in this region, it was 1.67 times of the background value on average and the highest was 2.77 times. The concentration of Pb was higher than the background value for more than half of the reservoirs. The potential ecological risk was evaluated by the toxic coefficient. The ecological risk level was decreased in the order of Cd>As>Pb>Ni>Cu>Cr>Zn. The ecological risk of Cd in most reservoir sediments belonged to a moderate harm. Xidayang Reservior, which supplied the drinking water for Beijing and Baoding, had the highest level of Cd pollution. The ecological risk of Cd in the upstream and downstream rivers was significantly higher than that of the reservoirs. In addition, the ecological risks of Pb, Cu and Ni in the upstream rivers were also higher than the reservoirs. The difference of ecological risks of Zn and Cr was not significant between reservoirs and rivers. PMID- 26571671 TI - [Retrieval of crown closure of moso bamboo forest using unmanned aerial vehicle (UAV) remotely sensed imagery based on geometric-optical model]. AB - This research focused on the application of remotely sensed imagery from unmanned aerial vehicle (UAV) with high spatial resolution for the estimation of crown closure of moso bamboo forest based on the geometric-optical model, and analyzed the influence of unconstrained and fully constrained linear spectral mixture analysis (SMA) on the accuracy of the estimated results. The results demonstrated that the combination of UAV remotely sensed imagery and geometric-optical model could, to some degrees, achieve the estimation of crown closure. However, the different SMA methods led to significant differentiation in the estimation accuracy. Compared with unconstrained SMA, the fully constrained linear SMA method resulted in higher accuracy of the estimated values, with the coefficient of determination (R2) of 0.63 at 0.01 level, against the measured values acquired during the field survey. Root mean square error (RMSE) of approximate 0.04 was low, indicating that the usage of fully constrained linear SMA could bring about better results in crown closure estimation, which was closer to the actual condition in moso bamboo forest. PMID- 26571672 TI - [Landscape pattern change of Dongzhai Harbour mangrove, South China analyzed with a patch-based method and its driving forces]. AB - According to the interpreted results of three satellite images of Dongzhai Harbour obtained in 1988, 1998 and 2009, the changes of landscape pattern and the differences of its driving forces of mangrove forest in Dongzhai Harbour were analyzed with a patch-based method on spatial distribution dynamics. The results showed that the areas of mangrove forest in 1988, 1998 and 2009 were 1809.4, 1738.7 and 1608.2 hm2 respectively, which presented a trend of decrease with enhanced degree of landscape fragmentation. The transformations among different landscape types indicated that the mangrove, agricultural land and forest land were mainly changed into built-up land and aquaculture pond. The statistical results obtained from three different methods, i.e., accumulative counting, percentage counting and main transformation route counting, showed that natural factors were the main reason for the changes of patch number, responsible for 58.6%, 72.2% and 72.1% of patch number change, respectively, while the percentages of patch area change induced by human activities were 70.4%, 70.3% and 76.4%, respectively, indicating that human activities were the primary factors of the change of patch areas. PMID- 26571673 TI - [Coupling coordination evaluation method between eco-environment quality and economic development level in contiguous special poverty-stricken areas of China]. AB - It is one of the important strategies in the new period of national poverty alleviation and development to maintain the basic balance between the ecological environment and economic development, and to promote the coordinated sustainable development of economy and ecological environment. Taking six contiguous special poverty-stricken areas as the study areas, a coupling coordination evaluation method between eco-environment quality and economic development level in contiguous special poverty-stricken areas was explored in this paper. The region' s ecological poverty index system was proposed based on the natural attribute of ecological environment, and the ecological environment quality evaluation method was built up by using AHP weighting method, followed by the design of the coupling coordination evaluation method between the ecological environment indices and the county economic poverty comprehensive indices. The coupling coordination degrees were calculated and their spatial representation differentiations were analyzed respectively at district, province, city, and county scales. Results showed that approximately half of the counties in the study areas achieved the harmoniously coordinated development. However, the ecological environmental quality and the economic development in most counties could not be synchronized, where mountains, rivers and other geographic features existed roughly as a dividing line of the coordinated development types. The phenomena of dislocation between the ecological environment and economic development in state-level poor counties were more serious than those of local poor counties. PMID- 26571674 TI - [Interpolation of daily mean temperature by using geographically weighted regression-Kriging]. AB - Air temperature is the input variable of numerous models in agriculture, hydrology, climate, and ecology. Currently, in study areas where the terrain is complex, methods taking into account correlation between temperature and environment variables and autocorrelation of regression residual (e.g., regression Kriging, RK) are mainly adopted to interpolate the temperature. However, such methods are based on the global ordinary least squares (OLS) regression technique, without taking into account the spatial nonstationary relationship of environment variables. Geographically weighted regression-Kriging (GWRK) is a kind of method that takes into account spatial nonstationarity relationship of environment variables and spatial autocorrelation of regression residuals of environment variables. In this study, according to the results of correlation and stepwise regression analysis, RK1 (covariates only included altitude), GWRK1 (covariates only included altitude), RK2 (covariates included latitude, altitude and closest distance to the seaside) and GWRK2 (co-variates included altitude and closest distance to the seaside) were compared to predict the spatial distribution of mean daily air temperature on Hainan Island on December 18, 2013. The prediction accuracy was assessed using the maximum positive error, maximum negative error, mean absolute error and root mean squared error based on the 80 validation sites. The results showed that GWRK1's four assessment indices were all closest to 0. The fact that RK2 and GWRK2 were worse than RK1 and GWRK1 implied that correlation among covariates reduced model performance. PMID- 26571675 TI - [Landscape character assessment framework in rural area: A case study in Qiaokou, Chang-sha, China]. AB - Based on the concept and methods of landscape character assessment (LCA) in England, this paper applied a complete process of landscape character assessment with a case study in Qiaokou Town, which is located in a typical southern paddy fields area in Changsha City. We drew the landscape character map of Qiaokou Town through desk classification and field survey, identified and compared the key characters of each character area, and proposed suggestions on the improvement and stewardship of landscape characters. The results showed that Qiaokou could be divided into 2 landscape character types and 7 landscape character areas with the main differences in cropland and vegetation pattern as well as aesthetic characters. The case study indicated that LCA could be a critical tool to identify the characteristics in rural area, and provide helpful guidance to protect, restore and maintain the unique culture and characters of rural landscape, which is useful for targeted rural landscape development. In the future, we suggested that the assessment on the effects of landscape construction measures on the ecosystem services should be incorporated in LCA research as well. PMID- 26571676 TI - [Fish population structure in the fishway of Changzhou hydro-junction]. AB - The fishway of Changzhou hydro-junction, located in the main stream of Xijiang River, is the biggest fishway in China up to now. Efficiency assessment of the Changzhou fishway is important for fish resource and ecosystem protection of the Pearl River, and can provide basic data for design, construction and management of other fishways in China. A total of 40 fish species in the Changzhou fishway were sampled on 11 occasions from April to June during 2011-2014 by using blocking method. Migratory species such as marbled eel, eel, Fugu ocellatus and the four domestic fish ( black carp, grass carp, silver carp and bighead carp) appeared in the fishway. The dominant species included Pelteobagrus vachelli (29.1%), Spualiobarbus' curriculus (16.8%), Hemiculter leucisculus (14.7%), Pseudolaubuca sinensis (12.0%), Squalidus argentatus (10.8%), Anguilla japonica (7.3%) and Cirrhinus molitorella (2.7%). Species accumulation curve indicated that up to 61 species would be monitored in the fishway with increasing the sampling frequency, indicating its good passage efficiency. Fish diversity in the Changzhou fishway was significantly lower than that in the downstream in Xijiang River, and two dominant species in the downstream of the Changzhou Dam, Megalobrama hoffmanni and Mystus guttatus, were not monitored in the fishway in this study, revealing that attraction efficiency of the fishway was different for different fish species. The canonical correspondence analysis showed that dam water level was the most important factor for the fishway effectiveness, it was necessary to adjust the operation mode of the Changzhou dam to instigate more fish migration by the fishway. According to the present situation of fishery resources of the Pearl River, it was suggested to include four domestic fish, M. hoffmanni, S. curriculus and C. molitorella as target species of the Changzhou fishway, and consider more about ecological characteristics of these species. PMID- 26571677 TI - [Screening probiotic endophytic bacteria from medicinal plant flex cornuta and the phytopathogen-inhibiting effect]. AB - Culturable endophytic bacteria were isolated from medicinal plant Ilex cornuta by plate-spreading method, strains with strong inhibitory effect on phytopathogen were screened by confrontation culture and fermentation filtrate culture methods, and the morphological changes of phytopathogen hyphae treated with endophytic bacteria were examined by microscopy and micrograph. Their phylogenetic relationships were determined by homology analysis of the 16S rDNA sequences of PCR products and the taxonomic status of the selected strains was determined based on their morphology, physiology, biochemical test results and 16S rDNA sequence analysis. A total of 85 endophytic bacteria were isolated from the healthy roots, stems, leaves and fruits of I. cornuta, and 10 strains of them showed strong inhibitory effect on Alternaria alternata, Magnaporthe grisea, Fusarium oxysporum, and were preliminarily identified belonging to four genera and seven species. Three strains with the strongest inhibitory effect, GG78 (60.3%), GG31 (48.1%) and GG13 (61.0%) belonged to Enterobacter cloacae, Enterobacter ludwigii and Bacillus cereus, respectively. Microscopic analyses showed that the inhibited phytopathogen hyphae became deformed, distorted, and partially expanded forming plasma concentration and hair-like branch on the hyphae base. These morphological changes could be caused by the extracellular metabolic substances secreted by the endophytic bacteria, such as antibiotics, hydrolytic enzymes, alkaloids and so on. PMID- 26571678 TI - [Effects of copper stress on the function of arbuscular mycorrhizal fungi community]. AB - The functional differences of arbuscular mycorrhizal fungi (AMF) isolates from different sources have been extensively investigated in the last two decades. However, previous studies were mostly based on individual AMF species and the community level comparison was not addressed properly. Furthermore, many studies did not distinguish the difference between the effects of AMF source and community structure on their function, let alone concerned the significance of host plant. This study evaluated the effects of copper (Cu) stress on AMF community structure and compared the differences of AMF communities from Cu contaminated and uncontaminated substrates on performance of Zea mays through two short-term greenhouse pot culture experiments. The results showed that spore abundance and composition of AMF communities were changed dramatically under Cu stress compared with the control. The communities dominated by Rhizophagus intraradices and Claroideoglomus etunicatum from Cu contaminated soils conferred more benefits on Z. mays in terms of plant growth and physiological properties relative to that from control governed by Funneliformis mosseae. PMID- 26571679 TI - [Construction of an indicator system for evaluating the protection efficacy of national nature reserves in China: A case study on terrestrial vertebrates (excluding migratory birds)]. AB - The protection efficacy of nature reserves is a key element in achieving targets of biodiversity conservation. It is therefore very important to develop a scientific, systematic, and accurate index system for evaluating the protection efficacy of national nature reserves in China. Using methods of frequency statistics, expert consultation, analytic hierarchy process, and demonstration survey, we present a novel index system for evaluating the protection efficacy of Chinese national nature reserves for terrestrial vertebrates (excluding migratory birds) over a 10-year period. The indicator system included one target layer, two system layers, nine factor layers, and forty index layers. The system layer included ecological effectiveness evaluation (with a score of 60%) and management effectiveness evaluation (score of 40%). The ecological effectiveness evaluation was a comprehensive, dynamic evaluation of the target species, population, habitat, and ecological system. The management effectiveness evaluation was focused on the effectiveness of patrol and monitoring. The additional part aimed to analyze the impact of humans on the target species, population and nature resources of the nature reserve. This study combined the ecological effectiveness evaluation and the management effectiveness evaluation for the first time, highlighted the importance of time and space changes, distinguished the influence of natural factors from human factors, and integrated them into the evaluation results. By emphasizing quantifiable indicators, this evaluation index system could vastly assist the protection of nature reserves by improving management effectiveness, biodiversity conservation, and macroscopic decision-making. PMID- 26571680 TI - [Effects of earthworm on soil microbes and biological fertility: A review]. AB - Earthworms are considered as 'ecosystem engineers', as they affect soil microbial community and function by improving micro-habitat, increasing surface area of organic compound, feeding, and transporting microorganisms. Multi-scale cavities created through earthworm movements help improve soil porosity and aeration, thus supporting microbial growth and reproduction. Earthworms also break down complex organic compounds into microbe-accessible nutrients by means of feeding on, crushing, and mixing soil. This results in elevated mineralization and improvement of cycling of key soil nutrients including carbon, nitrogen, and phosphorus, overall enhancing the soil biological fertility. PMID- 26571681 TI - [Pothole ecosystem in mountain river: A review]. AB - The pothole is one of the special habitats in river ecosystems, which is simply structured, well-defined, food chain-short, and easily controlled, thus making it a model system in ecological, evolutionary and phenological studies. Here we first reviewed hydrological, chemical and physical characteristics of potholes, their biological community (biodiversity, environmental factors) as well as food chain (competition, predation and parasitism) in mountain rivers. The differences between pothole ecosystems and river ecosystems in hydrological characteristics, biological community and food-chain were analyzed. Hydrological, physical chemical, and ecological characteristics of potholes were largely unexplored in China. Finally, we suggested future directions and recommendations in pothole ecosystems. PMID- 26571682 TI - [Land use and land cover charnge (LUCC) and landscape service: Evaluation, mapping and modeling]. AB - Studies on ecosystem service from landscape scale aspect have received increasing attention from researchers all over the world. Compared with ecosystem scale, it should be more suitable to explore the influence of human activities on land use and land cover change (LUCC), and to interpret the mechanisms and processes of sustainable landscape dynamics on landscape scale. Based on comprehensive and systematic analysis of researches on landscape service, this paper firstly discussed basic concepts and classification of landscape service. Then, methods of evaluation, mapping and modeling of landscape service were analyzed and concluded. Finally, future trends for the research on landscape service were proposed. It was put forward that, exploring further connotation and classification system of landscape service, improving methods and quantitative indicators for evaluation, mapping and modelling of landscape service, carrying out long-term integrated researches on landscape pattern-process-service-scale relationships and enhancing the applications of theories and methods on landscape economics and landscape ecology are very important fields of the research on landscape service in future. PMID- 26571683 TI - [Current views on surface enhanced Raman spectroscopy in microbiology]. AB - Raman spectroscopy has generated many branches during the development for more than 90 years. Surface enhanced Raman spectroscopy (SERS) improves SNR by using the interaction between tested materials and the surface of rough metal, as to quickly get higher sensitivity and precision spectroscopy without sample pretreatment. This article describes the characteristic and classification of SERS, and updates the theory and clinical application of SERS. It also summarizes the present status and progress of SERS in various disciplines and illustrates the necessity and urgency of its research, which provides rationale for the application for SERS in microbiology. PMID- 26571684 TI - [Research progress in chondroitinase ABC]. AB - As the components of proteoglycans, glycosaminoglycans (GAGs) are linear polysaccharides consisting of hexose and uronic acid units linked by beta-1,3 glycosidic bond. GAGs mainly distribute in extracellular matrix and on cell surfaces. They guide many biological processes, such as proliferation of cells, transmission of signals and mediation of inflammation. Because of their large molecular weights, GAGs have limited biological functions in vitro. However, the appearance of chondroitinase ABC (ChSase ABC), which can lyse polysaccharides, solves the difficulties. Based on our work, we summarized the classification and the crystal structure of ChSase ABC, as well as other recent research progress on ChSase ABCs. The separation and purification methods of ChSase ABC and construction of engineering bacteria are illustrated. The stability and immobilization are also analyzed by taking account of the characterization of ChSase ABC. Finally, problems and future prospect of the ChSase ABC study are summarized. PMID- 26571685 TI - [Research progress in dextranase]. AB - Dextranase can degrade dextran polymer into low molecular weight polysaccharide. Dextranase and its hydrolysates are widely used in food, medicine and chemical industries. Studies on dextranase progresses rapidly in recent years. We reviewed literature reports combined with our study about the progress of dextranase and its potential applications in industry. In addition, we addressed hot topics and emphasized on the current research about dextranase, existing problems in domesticstudies and the future research needs needs. PMID- 26571686 TI - [Expression and adjuvant effects of the fusion peptide TBP5]. AB - Thymopentin (TP5) and bursopentin (BP5) are both immunopotentiators. To explore whether the TP5-BP5 fusion peptide (TBP5) has adjuvant activity or not, we cloned the TBP5 gene and confirmed that the TBP5 gene in a recombinant prokaryotic expression plasmid was successfully expressed in Escherichia coli BL21. TBP5 significantly promoted the proliferation of thymic and splenic lymphocytes of mice. The potential adjuvant activity of the TBP5 was examined in mice by coinjecting TBP5 and H9N2 avian influenza virus (AIV) inactivated vaccine. HI antibody titers, HA antibodies and cytokines levels (IL-4 and IFN-gamma) were determined. We found that TBP5 markedly elevated serum HI titers and HA antibody levels, induced the secretion of both IL-4 and IFN-gamma cytokines. Furthermore, virus challenge experiments confirmed that TBP5 contributed to inhibition replication of the virus [H9N2 AIV (A/chicken/Jiangsu/NJ07/05)] from mouse lungs. Altogether, these findings suggest that TBP5 may be an effective adjuvant for avian vaccine and that this study provides a reference for further research on new vaccine adjuvants. PMID- 26571687 TI - [Expression and characterization of a novel halohydrin dehalogenase from Tistrella mobilis KA081020-065]. AB - Halohydrin dehalogenase is of great significance for biodegradation of the chlorinated pollutants, and also serves as an important biocatalyst in the synthesis of chiral pharmaceutical intermediates. A putative halohydrin dehalogenase (HheTM) gene from Tistrella mobilis KA081020-065 was cloned and over expressed in Escherichia coli BL21 (DE3). The recombinant enzyme was purified by Ni-NTA column and characterized. Gel filtration and SDS-PAGE analysis showed that the native form of HheTM was a tetramer. It exhibited the highest activity at 50 degrees C. The nature and pH of the buffer had a great effect on its activity. The enzyme maintained high stability under the alkaline conditions and below 30 degrees C. HheTM catalyzed the transformation of ethyl(S)-4-chloro-3 hydroxybutyrate in the presence of cyanide, to give ethyl (R)-4-cyano-3 hydroxybutyrate, a key intermediate for the synthesis of atorvastatin. PMID- 26571688 TI - [Heterologous expression, purification and characterization of exo-inulinase from Kluyveromyces marxianus YX01]. AB - To improve the inulinase application in biotechnology, the characteristic of inulinase from Kluyveromyces marxianus YX01 was investigated. The inu gene of K. marxianus YX01 was transformed into Pichiapastoris GS115 host cells with molecular biology techniques. Then we achieved the heterologous expression of exo inulinase whose molecular mass was about 86.0 kDa by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Furthermore, six His-tag was added to the inulinase and a two-step method was applied in the purification of inulinase, including concentration via dialysis by polyethylene glycol 20 000 and metal Ni-NTA Agarose affinity adsorption. The purification factor of purified protein was 3.6 and the recovery rate of enzyme activity was 33.1%. We characterized the purified inulinase. The optimum temperature was 60 degrees C and pH was 4.62. When inulin and sucrose were used as substrates, the K(m) and V(max) values were 80.53 g/L vs 4.49 g/(L x min) and 183.10 g/L vs 20.20 g/(L x min), respectively. In addition, metal ions including Mn2+, Ca2+, Cu2+, Zn2+ and Fe2+ exhibited different degrees of inhibition on the enzyme activity, and Cu2+, Zn2+ and Fe2+ exhibited the most significant inhibition. Our findings might lay a good foundation for industrial application of inulinase. PMID- 26571689 TI - [Connection of hepcidin genes from two fish species and their expression in Pichia pastoris]. AB - Hepcidin are small cationic peptides with antibacterial activity expressed mainly in the liver of living organisms, and they play important roles in the host's immune response against microbial invasion and regulation of iron metabolism. Thus, they are considered to be good substitutes for traditional antibiotics. It is a good choice that the antimicrobial peptides are prepared by recombinant DNA expression. In the present study, two hepcidin mature peptide cDNAs from channel catfish (Ictalurus punctatus) (mCH) and tilapia (Oreochromis niloticus) (mTH) were connected by SOE-PCR in order to obtain more recombinant hepcidin with broad antimicrobial spectrum, and EcoR I and Not I sites were added to 5'- and 3'- ends of the fragment, respectively. The recombinant eukaryotic expression vector "pPIC9K-mCH-mTH" was successfully constructed, and transformed into Pichia pastoris GS115. The transformants containing multicopy gene insertion were selected by using different concentrations of G418 and other specific mediums, and identified by PCR for yeast genomic DNA. Expression was induced by adding 1% methanol at 30 degrees C for different times. Tricine-SDS-PAGE analysis demonstrated that the most appropriate expression time was 72 h, at which a high expression yield (77 mg/L) for the target protein was exhibited. The highly purified target protein was obtained from the fermentation supernatant by SP Sepharose cation exchange chromatography. Bacteriostatic activity assay demonstrated that the fermentation supernatant containing the target protein and purified recombinant target protein had bacteriostatic activities against gram positive and gram-negative bacterium. The present result provides the important initial value for industrial production of hepcidin antimicrobial peptide. PMID- 26571690 TI - [Construction of transgenic tobacco expressing tomato GGPS2 gene and analysis of its low light tolerance]. AB - To explore the influence of low light on the synthesis of carotenoids, chlorophyll and the adaptability of transgenic plants with tomato Solanum lycopersicon L. GGPS2 gene, we constructed a vector containing a GGPS2 gene with green fluorescent protein (GFP) as report gene under the control of a cauliflower mosaic virus 35S promoter and introduced it into tobacco Nicotiana tabacum L. cv. Wisconsin 38 by Agrobacterium tumefaciens-mediated transformation. PCR analysis of the DNA from kanamycin resistant tobacco indicated that the transgenic tobacco containing the nptII gene, SlaGGPS2 gene and without contamination of Agrobacterium. We also detected the root tip of kanamycin resistant tobacco showing characteristic fluorescence. The contents of carotenoid, chlorophyll and photosynthesis of transgenic tobacco increased in comparison with wild tobacco after low light treatment. In addition, leaf mass per unit area, total dry weight, ratio of root to shoot in transgenic tobacco were all higher than that of the wild tobacco, which proved that the transgenic tobacco could increase the accumulation of biomass and promote it transport to root. The transgenic tobacco with SlaGGPS2 gene can increase the contents of carotenoid, chlorophyll, enhance the photosynthetic rate, promote the biomass accumulation and its distribution to root. Hence, the transgenic tobacco with SlaGGPS2 gene had increased low light tolerance and the SlaGGPS2 gene maybe can be used in other crops. PMID- 26571691 TI - [Site-directed mutagenesis of human IL-29 and antineoplastic activity of the recombinant human IL-29 variant]. AB - To explore the anti-tumor proliferation activity of human interleukin-29 (hIL-29) variant and based on bioinformatics analyzed data of hIL-29, a mutant gene hIL 29(mut33,35) was amplified by site-directed mutagenesis and megaprimer PCR. The hIL-29(mut33,35) was inserted into an eukaryotic expression plasmid pPIC9K and successfully expressed in Pichia pastoris GS115. A recombinant variant protein (rhIL-29(mut33,35)) was purified from the ferment supernatant of the engineering GS115. To observe the antineoplastic activity of the variant rhIL-29(mut33,35), a CCK-8 reagent was used to detect the anti-proliferation effect. Results show that it has strong anti-proliferation effect when acted on liver cancer cell BEL7402, colon cancer cell HCT8 and gastric cancer cell SGC7901. The inhibition ratios of the three tumor cells were (30.99 +/- 1.58)%, (22.47 +/- 1.37)% and (32.05 +/- 2.02)%, respectively. In high dose group, the anti-proliferation effect of the rhIL-29(mut33,35) was stronger than that of wild type rhIL-29 (P < 0.01). This indicates the variant rhIL-29(mut33,35) has potential development value for medicine. PMID- 26571692 TI - [Prokaryotic expression of Hepatitis C Virus (HCV) NS3 protein and preparation of polyclonal antibody]. AB - To increase detection sensitivity and specificity on hepatitis C virus (HCV) is vital for prevention and controlling of the disease. To establish a more reliable detection method for HCV diagnosis, the full gene fragment of ns3 (non-structural protein of HCV) from recombinant plasmid of J6/JFH1 2a was amplified and then connected into the pET-28a prokaryotic expression vector, and the latter was subsequently transformed into Escherichia coli BL21 (DE3) to have the target protein expression. As a result, a protein with a molecular weight of 72 kDa was obtained and visualized in 10% SDS-PAGE. The purified NS3 protein was used as immunogen to inoculate BALB/c mice and the sera was collected after the fourth immunization. The antibody titer of serum is determined to be about 1:256000 with ELISA. Western blotting and indirect immunofluorescence analysis showed that the mouse polyclonal antibody could react specifically with the native NS3 protein in Huh 7.5.1 cells infected with HCV. These findings may provide basis for further preparation of monoclonal antibodies against NS3 and the development of related detection kit. PMID- 26571693 TI - [Expression and characterization of a bispecific antibody targeting TNF-alpha and ED-B containing fibronectin]. AB - To enhance the specificity of anti-TNF-alpha single chain Fv antibody (TNF-scFv) to inflamed site, we constructed a bispecific antibody BsDb that targets TNF alpha and ED-B-containing fibronectin (B-FN) by covalently linking TNF-scFv and the anti-ED-B scFv L19 at the gene level via a flexible peptide linker deriving from human serum albumin. BsDb was successfully secreted from Pichia pastoris as functional protein, identified by immunoblotting, and purified to homogeneity with affinity chromatography. BsDb retained the immunoreactivity of its original antibodies TNF-scFv and L19, and showed a marked gain in antigen-binding affinity and in TNF-alpha-neutralizing ability, when compared to TNF-scFv and L19 that were produced in Escherichia coli. In the adjuvant-induced arthritis (AIA) mice model, BsDb showed selective accumulation and retention in the inflamed paws but rapid clearance from blood, resulting in high arthritic paw to blood ratios. These data indicate that BsDb is endowed with high specificity to inflamed site and low toxicity to normal tissues and holds great potential for in vivo application for the targeted therapy of RA and other chronic inflammatory diseases. PMID- 26571694 TI - [Effects of elicitors on growth of adventitious roots and contents of secondary metabolites in Tripterygium wilfordii Hook. f]. AB - To study the effects of the extract of fungal elicitor, AgNO3, MeJA and yeast on the growth and content of secondary metabolites of adventitious roots in Tripterygium wilfordii. The above elicitors were supplemented to the medium, the growth and the content of secondary metabolites were measured. When the medium was supplemented with the elicitor Glomerella cingulata or Collectotrichum gloeosporioides, the content of triptolide was increased by 2.24 and 1.93-fold, the alkaloids content was increased by 2.02 and 2.07-fold, respectively. The optimal concentration of G. cingulata was 50 MUg/mL for accumulation of triptolide, alkaloids and for the growth of adventitious roots. AgNO3 inhibited the growth of adventitious roots and the accumulation of the alkaloids, whereas it (at 25 MUmol/L) increased the accumulation of triptolide by 1.71-fold compared to the control. The growth of adventitious roots, the contents of triptolide and alkaloids were increased 1.04, 1.64 and 2.12-folds, respectively when MeJA was at 50 MUmol/L. When the concentration of yeast reached 2 g/L, the content of triptolide increased 1.48-folds. This research demonstrated that supplementation of AgNO3 and yeast enhanced the biosynthesis of triptolide in adventitious roots and the synergism of G. cingulata and MeJA could promote the biosynthesis of both triptolide and alkaloids. PMID- 26571695 TI - [Improvement of natamycin production in an industrial strain by heterologous expression of the afsRS(cla) global regulatory genes]. AB - The afsRS(cla) global regulatory genes from Streptomyces clavuligerus activate the production of two antibiotics in Streptomyces lividans. In this study, we gained an increase of 38% in the production of natamycin (3.56 g/L) in an industrial strain Streptomyces gilvosporeus TZ1401 through the integration of pHL851 that bears the afsRS(cla) global regulatory genes into its genome. We discovered by quantitive real-time reverse transcription PCR (qRT-PCR) that the expression of 6 genes of the natamycin biosynthetic gene cluster were improved from 1.9 to 2.7 times. This suggests that afsRS(cla) improve the production of natamycin through increased transcription. This study provides a good example for applying afsRS(cla) in high yield breeding of industrial antibiotic producers. PMID- 26571696 TI - [Enhanced epsilon-poly-L-lysine production through pH regulation and organic nitrogen addition in fed-batch fermentation]. AB - During the production of epsilon-poly-L-lysine (epsilon-PL) in fed-batch fermentation, the decline of epsilon-PL synthesis often occurs at middle or late phase of the fermentation. To solve the problem, we adopted two strategies, namely pH shift and feeding yeast extract, to improve the productivity of epsilon PL. epsilon-PL productivity in fermentation by pH shift and feeding yeast extract achieved 4.62 g/(L x d) and 5.16 g/(L x d), which were increased by 27.3% and 42.2% compared with the control epsilon-PL fed-batch fermentation, respectively. Meanwhile, epsilon-PL production enhanced 36.95 g/L and 41.32 g/L in 192 h with these two strategies, increased by 27.4% and 42.48% compared to the control, respectively. epsilon-PL production could be improved at middle or late phase of fed-batch fermentation by pH shift or feeding yeast extract. PMID- 26571697 TI - [Hypertension: The Points of Management of Hypertension for All Physicians--Based on the JSH 2014 Hypertension Guidelines--Editorial: Characteristics and major revised points of JSH2014-difference from JSH2009]. PMID- 26571698 TI - [Hypertension: The Points of Management of Hypertension for All Physicians--Based on the JSH 2014 Hypertension Guidelines--Topics: I. Epidemiology of hypertension]. PMID- 26571699 TI - [Hypertension: The Points of Management of Hypertension for All Physicians--Based on the JSH 2014 Hypertension Guidelines--.Topics: II. Primary examinations for hypertensives]. PMID- 26571700 TI - [Hypertension: The Points of Management of Hypertension for All Physicians--Based on the JSH 2014 Hypertension Guidelines--.Topics; III. Key points of antihypertensive treatment-life-style modification and drug therapy]. PMID- 26571701 TI - [Hypertension: The Points of Management of Hypertensions--Based on the JSH 2014 Hypertension Guidelines--. Topics: IV. Treatment for hypertension associated with cerebrovascular disease/heart disease]. PMID- 26571702 TI - [Hypertension: The Points of Management of Hypertension for All Physicians--Based on the JSH 2014 Hypertension Guidelines--. Topics: V. Points of hypertension treatment for the patients complicated by kidney diseases and diabetes]. PMID- 26571703 TI - [Hypertension: The Points of Management of Hypertension for All Physicians--Based on the JSH 2014 Hypertension Guidelines--. Topics: VI. Pregnancy-induced hypertension]. PMID- 26571704 TI - [Hypertension: The Points of Management of Hypertension for All Physicians--Based on the JSH 2014 Hypertension Guidelines--. Topics: VII. Key points for the management of hypertension in the elderly]. PMID- 26571705 TI - [Hypertension: The Points of Management of Hypertension for all Physicians--Based on the JSH 2014 Hypertension Guidelines--. Topics: VIII. Diagnosis and treatment of secondary hypertension and resistant hypertension]. PMID- 26571706 TI - [Hypertension The Points of Management of Hypertension for All Physicians--Based on the JSH 2014 Hypertension Guidelines--. Topics: IX. Evaluation and management of hypertensive emergencies]. PMID- 26571707 TI - [Hypertension: The Points of Management of Hypertension for All Physicians--Based on the JSH 2014 Hypertension Guidelines--. Topics: X. Patients eligible for real denervation and PTRA--from the results of SYMPLICITY HTN-3 and CORAL trial]. PMID- 26571708 TI - [Case Report; Relapse of typhoid fever after confirming negative stool cultures]. PMID- 26571709 TI - [Case Report; A case of myositis occurring and getting worse during the treatment for NSIP]. PMID- 26571710 TI - [Case Report; An intestinal extranodal NK/T cell lymphoma mimicking Crohn's disease]. PMID- 26571711 TI - [Case Report; A case of cibenzoline abuse was diagnosed by its loading]. PMID- 26571712 TI - [The Cutting-edge of Medicine; Recent advances in biology and treatment of multiple myeloma]. PMID- 26571713 TI - [The Cutting-edge of Medicine; Frontiers in the pathogenesis and treatments for pulmonary alveolar proteinosis]. PMID- 26571714 TI - [The Cutting-edge of Medicine; Pre-clinical diagnosis of neurodegenerative diseases]. PMID- 26571715 TI - [How Does the Physician Interpret the Patient's Narrative as It Relates to the Physical Exam? Edema in the oldest-old subject]. PMID- 26571716 TI - [How Does the Physician Interpret the Patient's Narrative as It Relates to the Physical Exam?; The importance of skin eruption in diagnosis of systemic disease]. PMID- 26571717 TI - [Joint principles for the medical education of physicians as preparation for practice in the Patient-Centered Medical Home]. PMID- 26571718 TI - [The 42nd Scientific Meeting: Perspectives of Internal Medicine; Considerations to treatment and care of cancer by internists in the era of increasing cancer mortality; 1. Preface]. PMID- 26571719 TI - [The 42nd Scientific Meeting Perspectives of Internal Medicine; Considerations to treatment and care of cancer by internists in the era of increasing cancer mortality 2. Fruits of Basic Research on Cancer; 1) Cancer epidemiology--trends of cancer statistics based on cancer registry]. PMID- 26571720 TI - [The 42nd Scientific Meeting: Perspectives of Internal Medicine; Considerations to treatment and care of cancer by internists in the era of increasing cancer mortality; 2. Fruits of Basic Research on Cancer; 2) Clinical application of cancer genome analyses]. PMID- 26571721 TI - [The 42nd Scientific Meeting: Perspectives of Internal Medicine; Considerations to treatment and care of cancer by internists in the era of increasing cancer mortality; 2. Fruits of Basic Research on Cancer; 3) Cancer immunotherapy: the present and the future]. PMID- 26571722 TI - [The 42nd Scientific Meeting: Perspectives of Internal Medicine; Considerations to treatment and care of cancer by internists in the era of increasing cancer mortality; 3. Current Status of Diagnosis and Treatment of Cancer; 1) Recent diagnostic imaging for cancer]. PMID- 26571723 TI - [The 42nd Scientific Meeting: Perspectives of Internal Medicine: Considerations to treatment and care of cancer by internists in the era of increasing cancer mortality; 3. Current Status of Diagnosis and Treatment of Cancer; 2) Recent progress in the endoscopic diagnosis and intervention for gastrointestinal neoplasms]. PMID- 26571724 TI - [The 42nd Scientific Meeting: Perspectives of Internal Medicine; Considerations to treatment and care of cancer by internists in the era of increasing cancer mortality; 3. Current Status of Diagnosis and Treatment of Cancer; 3) Cancer biomarker and individualized therapy]. PMID- 26571725 TI - [The 42nd Scientific Meeting: Perspectives of Internal Medicine; Considerations to treatment and care of cancer by internists in the era of increasing cancer mortality; 4. Consideration for Cancer Care; 1) Medical cooperation--Role of clinic in cancer treatment]. PMID- 26571726 TI - [The 42nd Scientific Meeting: Perspectives of Internal Medicine; Considerations to treatment and care of cancer by internists in the era of increasing cancer mortality; 4. Consideration for Cancer Care; 2) What's next in palliative care?]. PMID- 26571727 TI - [The 42nd Scientific Meeting: Perspectives of Internal Medicine; Considerations to treatment and care of cancer by internists in the era of increasing cancer mortality; 4. Consideration for Cancer Care; 3) What we can do for society facing on cancer]. PMID- 26571728 TI - [The 42nd Scientific Meeting: Perspectives of Internal Medicine; Considerations to treatment and care of cancer by internists in the era of increasing cancer mortality; 5. Conclusion]. PMID- 26571729 TI - [Programs for Continuing Medical Education: A session; 1. Prevention of gastric cancer based on an understanding of the natural history of Helicobacter pylori associated gastritis]. PMID- 26571730 TI - [Programs for Continuing Medical Education: A session; 2. Recent concept of IgG4 related disease and autoimmune pancreatitis]. PMID- 26571731 TI - [Programs for Continuing Medical Education: A session; 3. Diagnosis and treatment for diabetes 2014]. PMID- 26571732 TI - [Programs for Continuing Medical Education: A session; 4. Diagnosis and novel therapies of refractory hypertension]. PMID- 26571733 TI - [Programs for Continuing Medical Education: A session; 5. Pathophysiology and treatment of headache]. PMID- 26571734 TI - [Programs for Continuing Medical Education: A session; 6. Advances in basic research and therapy of multiple sclerosis]. PMID- 26571735 TI - [Programs for Continuing Medical Education: A session; 7. Antiphospholipid syndrome: diagnosis and treatment]. PMID- 26571736 TI - [Programs for Continuing Medical Education: A session; 8. Recent advance in diagnosis and treatment of rheumatoid arthritis]. PMID- 26571737 TI - [Programs for Continuing Medical Education: A session; 9. Pitfall in geriatric emergency care]. PMID- 26571738 TI - [Programs for Continuing Medical Education: B session; 1. Current therapeutic opinion or atrial fibrillation]. PMID- 26571739 TI - [Programs for Continuing Medical Education: B session; 2. Non-vitamin K antagonist oral anticoagulants for atrial fibrillation]. PMID- 26571740 TI - [Programs for Continuing Medical Education: B session; 3. Diagnosis and therapy of interstitial pneumonias--Up to date]. PMID- 26571741 TI - [Programs for Continuing Medical Education: B session; 4. Sleep apnea syndrome diagnosis and treatment]. PMID- 26571742 TI - [Programs for Continuing Medical Education: B session; 5. Effect of medical cooperation on prevention of CKD aggravation]. PMID- 26571743 TI - [Programs for Continuing Medical Education: B session; 6. AKI (acute kidney injury): Aquiring new knowledge with cherishing old wisdom]. PMID- 26571744 TI - [Programs for Continuing Medical Education: B session; 7. Diagnosis and treatment of anemia]. PMID- 26571745 TI - [Programs for Continuing Medical Education: B session; 8. Spreading of antibiotic resistant bacteria in the community]. PMID- 26571746 TI - [Programs for Continuing Medical Education: B session; 9. Management of cancer pain]. PMID- 26571747 TI - [Case Report; A case of subacute fulminant hepatitis induced by methyldopa]. PMID- 26571748 TI - [Case Report; A case of the hepatogenic hydrothorax that art of pleurodesis succeeded by CPAP combination]. PMID- 26571749 TI - [The Cutting-edge of Medicine; Thyroid cancer and radiation]. PMID- 26571750 TI - [The Cutting-edge of Medicine; CKD and regenerative medicine]. PMID- 26571751 TI - [The Cutting-edge of Medicine: Pathophysiology and Management of thrombotic thrombocytopenic purpura]. PMID- 26571752 TI - [Improvement of Awareness and Diagnosis for Chronic Obstructive Pulmonary Disease (COPD) by General Physician. Editorial: A prospective view on COPD management by learning a lesson from the past]. PMID- 26571753 TI - [Improvement of Awareness and Diagnosis for Chronic Obstructive Pulmonary Disease (COPD) by General Physician. Topics: I. Epidemiology and prevention of COPD; with a focus on Health Japan 21 (the second)]. PMID- 26571754 TI - [Improvement of Awareness and Diagnosis for Chronic Obstructive Pulmonary Disease (COPD) by General Physician. Topics: II. Diagnosis of COPD in primary care physicians]. PMID- 26571755 TI - [Improvement of Awareness and Diagnosis for Chronic Obstructive Pulmonary Disease (COPD) by General Physician. Topics: III. Pathogenesis and Treatment of COPD; 1. Recent topics on pathogenesis of COPD]. PMID- 26571756 TI - [Improvement of Awareness and Diagnosis for Chronic Obstructive Pulmonary Disease (COPD) by General Physician. Topics: III. Pathogenesis and Treatment of COPD; 2. Asthma--COPD overlap syndrome (ACOS)]. PMID- 26571757 TI - [Improvement of Awareness and Diagnosis for Chronic Obstructive Pulmonary Disease (COPD) by General Physician. Topics: III. Pathogenesis and Treatment of COPD; 3. Comorbidity]. PMID- 26571759 TI - [Improvement of Awareness and Diagnosis for Chronic Obstructive Pulmonary Disease (COPD) by General Physician. Topics: III. Pathogenesis and Treatment of COPD; 5. COPD therapy]. PMID- 26571758 TI - [Improvement of Awareness and Diagnosis for Chronic Obstructive Pulmonary Disease (COPD) by General Physician. Topics: III. Pathogenesis and Treatment of COPD; 4. Exacerbation]. PMID- 26571760 TI - [Improvement of Awareness and Diagnosis for Chronic Obstructive Pulmonary Disease (COPD) by General Physician. Topics: III. Pathogenesis and Treatment of COPD; 6. Prognosis of COPD]. PMID- 26571761 TI - [Improvement of Awareness and Diagnosis for Chronic Obstructive Pulmonary Disease (COPD) by General Physician. Topics: IV. Pathology and the treatment of airway obstructive disease in the elderly]. PMID- 26571762 TI - [Discussion Meeting on COPD diagnosis and therapy by primary physician]. PMID- 26571763 TI - [Case Report; Juvenile cerebral infarction due to primary angiitis of the central nervous system]. PMID- 26571764 TI - [Case Report; Olmesartan associated enteropathy: A case of severe watery diarrhea with weight loss and acute renal failure]. PMID- 26571765 TI - [Case Report; Successful treatment with methotrexate and low-dose corticosteroids for recurrent cardiac sarcoidosis]. PMID- 26571766 TI - [The Cutting-edge of Medicine; Genetic alterations and their prognostic implications in acute myeloid leukemia]. PMID- 26571767 TI - [The Cutting-edge of Medicine; Disaster medical and internal medicine--Knowledge and activities in the event of a disaster, which is expected to physician]. PMID- 26571768 TI - [Patient-Centered Medical Home: Suggestions for the Health Care Delivery System Reform in Japan; The Patient-Centered Medical Home Neighbor. The Interface of the Patient-Centered Medical Home with Specialty/Subspecialty Practices]. PMID- 26571769 TI - [Report from the 10th Tohoku Chapter Educational Seminar: A case of intractable ascites with mediastinal lymphadenopathy]. PMID- 26571770 TI - [Discussion Meeting on the perspective of The Japanese Society of Internal Medicine and Japan Surgical Society]. PMID- 26571771 TI - [Gut Microbiota and Internal Diseases: Update Information. Editorial : Unexpected functions of the gut microbiota as a virtual organ]. PMID- 26571772 TI - [Gut Microbiota and Internal Diseases: Update Information. Topics: 1. The role of the gut microiota on inflammatory bowel disease (IBD)) and irritable bowel syndrome (IBS)]. PMID- 26571773 TI - [Gut Microbiota and Internal Diseases: Update Information. Topics: II. Fecal microbiota transplantation and its clinical application]. PMID- 26571774 TI - [Gut Microbiota and Internal Diseases: Update Information. Topics: III. NASH/NAFLD and gut microbiota]. PMID- 26571775 TI - [Gut Microbiota and Internal Diseases: Update Information. Topics: IV. Obesity, diabetes and gut microbiota]. PMID- 26571776 TI - [Gut Microbiota and Internal Diseases: Update Information. Topics: V. Gut Microbiota: Topics in Various Medical Fields; 1. Does intestinal flora promote atherosclerosis?]. PMID- 26571777 TI - [Gut Microbiota and Internal Diseases: Update Information. Topics: V. Gut Microbiota: Topics in Various Medical Fields; 2. Possible causal relationship of microbiota to rheumatoid arthritis and bronchial asthma]. PMID- 26571778 TI - [Gut Microbiota and Internal Diseases: Update Information. Topics: V. Gut Microbiota: Topics in Various Medical Fields; 3. Does the intestinal flora relate to nervous system disorders?]. PMID- 26571779 TI - [Gut Microbiota and Internal Diseases: Update Information. Topics: V. Gut Microbiota: Topics in Various Medical Fields; 4. Interactions between the host immune system and microbes]. PMID- 26571780 TI - [Gut Microbiota and Internal Diseases: Update Information. Topics: VI. Probiotics function and the clinical views]. PMID- 26571781 TI - [Case Report; A case of primary cardiac diffuse large B cell lymphoma with heart failure]. PMID- 26571782 TI - [Case Report; A case of pulmonary sclerosing hemangioma in a young male]. PMID- 26571783 TI - [Case Report; A severe Pseudomonas aeruginosa community-acquired pneumonia treated by veno-venous extracorporeal membrane oxygenation (ECMO)--a case report]. PMID- 26571784 TI - [Case Report; A case of IgA vasculitis during the course of severe acute pancreatitis]. PMID- 26571785 TI - [The Cutting-edge of Medicine; A recent trend of emerging infections: MERS and Avian influenza A (H7N9)]. PMID- 26571786 TI - [The Cutting-edge of Medicine; Clinical features of isolated cardiac sarcoidosis]. PMID- 26571787 TI - [The Cutting-edge of Medicine; Approach to gastric submucosal tumor]. PMID- 26571788 TI - [How Does the Physician Interpret the Patient's Narrative as It Relates to the Physical Exam?; A case of functional dyspepsia who started with nausea and vomiting, taking long period of time for the true diagnosis]. PMID- 26571789 TI - [Patient-Centered Medical Home: Suggestions for the Health Care Delivery System Reform in Japan; Introduction on the concept of Patient-Centered Medical Home (PCMH)]. PMID- 26571790 TI - [Patient-Centered Medical Home: Suggestions for the Health Care Delivery System Reform in Japan; Joint principles of the Patient-Centered Medical Home]. PMID- 26571791 TI - [Novel psychoactive substances: a worldwide problem that requires an adequate approach]. AB - The use of new psychoactive substances (NPSI is increasing worldwide. Each year the number of NPS which are found through seizures in Belgium rises. The prevalence in the general population is unknown. In the Belgian nightlife at least 7% has already consumed an NPS at least once. NPS are alternatives for traditional illicit drugs (cannabis, cocaine, ecstasy, ...) made legal by adding a small modification within the chemical structure. But these modified substances are often more dangerous because there is little known about the acute and chronic effects, which could lead quickly to overdosing. Current legislation in Belgium uses a nominative list. However, this procedure is not suited to respond fast enough to the dynamic nature of NPS. In 2014 a new legislation based on generic classification was introduced as a solution and should be in place in 2015 in Belgium to reduce the rising number of legal drugs. An important consequence of generic classification is that certain medicines and other useful compounds will be included by this new law, which is a problem for the pharmaceutical industry and pharmacy. I cooperation with the FAGG exceptions for these substances were made. PMID- 26571792 TI - [Ilicit drugs frequently used by drug addicts]. AB - Drugs stimulate the brain causing mental and physical effects. The effects of drugs can be stimulating, narcotic or mind-altering. This article briefly discusses some commonly used illicit drugs, namely heroin, cocaine, cannabis, ecstasy, amphetamines, LSD, psilocybin mushrooms and poppers. PMID- 26571793 TI - [Technology to improve adherence in community pharmacy: a literature review]. AB - INTRODUCTION: Drug-related problems are very common and they need some specific attention. Improper use of medication as well as poor adherence leads to side effects, interaction, increased healthcare costs,... AIM: What technologies can be used in community pharmacies to improve drug adherence? METHOD: Articles were found in scientific databases Pubmed, Embase and CINAHL using a fixed search strategy. RESULTS: In this review 21 studies were included. The different technologies were compared with each other. Reminders using sms or smartphone were the most effective. CONCLUSION: There are already plenty of reminder systems (SMS, Email, internet, smartphone) and practical tools (medication dispensers, MEMS) available in community pharmacies. A major hurdle is the lack of the infrastructure. There needs to be invested in systems were patients are confronted with their own drug use. PMID- 26571794 TI - [Drug shortages in the hospital: management, causes and budget impact]. AB - INTRODUCTION: Drug shortages have become an issue of growing interest for pharmacists. Both number and type of shortages have increased over the past decade and it is challenging to provide drug continuity. Aim To describe management and impact of drug shortages for the hospital pharmacy. To gain insight into the causes of shortages. METHODS: The management process for drug shortages was analysed for the hospital pharmacies of the Ghent University Hospital (GUH) and the Acute Care Hospital Sint-Lucas Ghent. Insights in possible causes were obtained by semi-structured interview with the Federation for Belgian Pharmacists (Association Pharmaceutique beIge (APB)), the Belgian association of the pharmaceutical industry (pharma.bel and the Federal Agency for Medicines and Health Products (FAMHPI. A database of 1329 drug shortages (Jan 2001-Feb 2014 of the GUH was used to define drug classes affected by shortages (mean shortage days per year, standard deviation (SDI), type of shortage [urgent/ important] %, total number (n)), formulation (parenteral:oral and duration of the shortages (median, interquartile range (IQR)). The total cost impact for the GUH pharmacy was estimated by calculating average, minimum and maximum time investment by the pharmacy team (Delphi-techniquel and by calculating the cost difference between original and alternative drug acquisition costs. Impact is presented as base case scenario (minimum as best and maximum as worst case scenario). RESULTS: The different management phases for the pharmacist are problem identification, preparation of solution and implementation. Communication and extensive administration are essential components. Causes are production related, next to distribution inequivalences, quota and European market flows. Shortages with anti infectious, cardiovascular and hormonal system drugs have the highest and constant proportion of drug shortage days, with recently appearance of other important drug classes such as anticancer therapy [2011 and further). The average number of drug shortage days in 2011-2013 is 8020 (SD 2142 compared to period 2001-2010 with on average 4633 days (SD 1731]. Fifty-four percent of the shortages is important for the direct hospital care and 22.9% needs urgent action. The proportion parenteral versus oral in the database is 3.3:1. Median duration of a shortage is 29 [IQR 11-65]1 days. The average excess cost of an equipotent dose of the alternative drug was 4.9 (SD 31.3) Euro. Total cost impact (gross salary and drug acquisition cost] for GUH pharmacy in 2013 is 117 281.4 Euro (best case: 88 345.06 and worst case: 151,208.2 Euro. CONCLUSION: The importance of the shortages and the diversification of the drug classes involved have an impact on the hospital pharmacy management. For the GUH this represents an important workload and an increased drug acquisition cost. Causes of shortages are production related but also distributional inequivalences and quota play an important role. PMID- 26571795 TI - [A new website with evidence-based pharmaceutical information]. AB - Aware of the difficult choices that health policy makers face and the desire to develop pharmaceutical care, the Pharmacy Practice Research Unit team from the CHU Sainte-Justine examined evidence about the role and the impact of pharmacists. This research took the form of a structured approach to review the evidence from the literature. A website was designed and programmed to ensure effective knowledge sharing (http://impactpharmacie.org). The site lists evidence of the role and impact of the pharmaceutical activities, in both inpatient and outpatient settings. The site lists twelve articles from Belgian literature for hospital and community practice. Four positive outcomes of pharmaceutical interventions were recorded. This site can help to foster reflection and action surrounding the development of clinical pharmacy in Belgium. PMID- 26571796 TI - [Information transmission to the community pharmacist after a patient's discharge from the hospital: setting up of a written medication discharge form, prospective evaluation of its impact, and survey of the information needs of the pharmacists]. AB - INTRODUCTION: Discharge from the hospital is a period at risk for the continuity of patient's medication (seamless pharmaceutical care). The community pharmacist is often the first health care professional seen by the patient after hospital discharge. The clinical pharmacist has potentially a key role in establishing an efficient information transfer from the hospital to the community pharmacy. OBJECTIVE: (1) To develop and, (2) to evaluate the impact of a structured discharge medication form prepared at hospital discharge by the clinical pharmacist and containing information items related to the medication regimen for the community pharmacist, and (3) to survey the information needs of the Belgian community pharmacists to ensure continuity of care after hospitalization. METHODS: (1) A structured discharge medication form has been developed based on a Literature review and on opinions expressed by community and clinical pharmacists, members of the Belgian Pharmaceutical Union (Association Pharmaceutique Belge) and an ethical committee. (2) A prospective study has been conducted with patients from geriatrics and orthopaedics wards of the University Hospital Dinant-Godinne returning home after hospital discharge with the discharge medication form to be given to their commuiity pharmacist; its use, the reasons for non-use, the perceived impact and the satisfaction of the community pharmacist have been assessed. (3) An on-line survey addressed to all Belgian community pharmacists evaluated their information needs. RESULTS: (1) The final version of the discharge medication form included key information items concerning the hospital, the patient, the discharge treatment (including the type of modifications made as compared to medications taken before admission), and on medication management at home. Some items were excluded because of Lack of perceived utility by pharmacists, confidentiality issues, and respect of patient's freedom of choice. (2) From the 71 medication forms given to patients, 48 were received by the community pharmacist. One quarter of respondents stated that they did not use the form, the main reason being that it was received after dispensing of the discharge treatment (n=6/11). The majority of the community pharmacists considered most of the information items as useful and the discharge medication form as being valuable for continuity of care. Requests for additional information were made (e.g., reason of admission and of treatment modifications, etc.). (3) The utility, benefits, and need for additional information items beyond what was included in the discharge medication form were highlighted by the respondents (n=309) of the national survey. Most of these respondents confirmed the value of the different information items included in the discharge medication form. CONCLUSION: The transmission of a structured medication form containing information about the medication regimen upon hospital discharge is of real interest and value for the community pharmacist because it goes beyond what is usually provided on a medical prescription. However, this discharge medication form should include more information items for effective pharmaceutical care. PMID- 26571797 TI - [Simeprevir (Olysio), oral administration]. PMID- 26571798 TI - [Sofosbuvir (Sovaldi), oral administration]. PMID- 26571799 TI - [Ingenol mebutate (Picato), dermal administration]. PMID- 26571800 TI - [Dynamics of osteogenesis associated with inoculation of autologous stromal cells from rat adipose tissue (experimental-morphological study)]. AB - Experiment was evaluated on 40 male Wistar rats. On the experimental model of mandible injury, bone autologous graft from tibia was placed on the surface of mandible (host bone). In the main experimental group, consisting of 20 animals, autologous rat adipose-derived stromal cells (ADSCs) were inoculated in space between autograph and host bones. ADSCs were not inoculated in the group of comparison. In experimental group with inoculated cells, the formation of a new fibroreticular bone structures in space between autograph and host bone was observed. These structures further underwent secondary reorganization and differentiation during the process of remodeling. As a result of the conducted study it was shown that in the experimental group by the day 180, statistically significant reduction of the area occupied by an immature fibroreticular bone took place. The reported phenomenon could be explained as a result of decline of the number of active cells in the population of inoculated ADSC, which is in consent with theory of limited cell division number due to telomeres shortening, described by Hayflick L. and Moorhead P.S. (1961). PMID- 26571801 TI - [Effect of the nerve growth factor mimetic GK-2 on post-resuscitation expression of neurotrophic factors]. AB - THE OBJECTIVE: to elucidate an influence of nerve growth factor mimetic GK-2 on the expression of neurotrophic factors and the process of neuronal death after ischemia-reperfusion. Materials and methods. Adult white male rats underwent cardiac arrest for 12 minutes, followed by resuscitation. 10 rats were injected GK-2 (Img/kg i/rho) at 30 minutes and 48 hours after resuscitation. 10 untreated animals received equivalent doses of saline. The control group consisted of sham operated animals (n = 10). On the 7th postoperative day the total density of hypoxia-sensitive cerebellar Purkinje cells was determined by morphometric analysis. Immunohistochemical study of proteins FGFb, NT4, BDNF was performed by indirect peroxidase-antiperoxidase method using primary polyclonal antibodies. The number of neurons with different expression levels of the neurotrophic factors was determined. RESULTS: In the post-resuscitation period the neuronal loss was detected in untreated animals. Namely NT4-negative, FGFb-negative and BDNF-negative cells died. GK-2 had no effect on the expression level of FGFb and NT4, however, promoted an increase in the expression level of BDNF. Initiating the expression of BDNF in neurons that were not previously producing this factor, GK-2 prevents the development of post-resuscitation neuronal death. Obtained facts lead to the conclusion that one of the mechanisms of neuroprotective action of nerve growth factor mimetic GK-2 is its ability to activate the expression of BDNF in nerve cells. PMID- 26571802 TI - [Dynamics of changes of p53-positive cells morphofunctional condition in the cerebral cortex of the temporal lobe in rats affected by carotid ischemia reperfusion]. AB - The influence of bilateral 20-minute carotid ischemia with reperfusion of various duration upon the activity of apoptotic processes in the neurons and glia cells of the cerebral cortex in the temporal lobe of rats has been studied. Bilateral carotid ischemia with one-hour reperjusion has been indicated to increase the location density of p53+-neurocytes in this region of the cerebral cortex, increases percentage and density of p53+-nerve cells and reduces the percentage and density of p53+-glia cells on the 12th day of the post-ischemic period. Ischemic-reperfusion lesion of the brain increases the concentration of p53 protein in glia cells of the cerebral cortex in the temporal region in the early ischemic-reperfusion period and reduces it in nerve and glia cells in the late one. PMID- 26571803 TI - [Influence of simulated microgravity on the threshold of pain sensitivity in humans with single dose of ketorolac]. AB - The data supporting the influence of simulated microgravity effects on pain sensitivity were obtained in the series of experiments involving human. In conditions of antiorthostatic hypokinesia (ANOH) and <> immersion revealed no reduction in pain sensitivity in the morning, which is typical for normal conditions. Ketorolac has no effect on pain sensitivity, when determining the pain threshold (PT) by method of thermoalgometry. However, the conditions of simulated microgravity substantially alter the pharmacokinetics of ketorolac, increasing the rate of absorption of the drug and reduce its relative bioavailability and retention time in the blood plasma. This may require changes in pain therapy schemes in space flight. PMID- 26571804 TI - [Analysis of tropalgin effects in an inflammation pain model in rats with different pain threshold]. AB - Individual pain sensitivity of male Wistar rats was determined in a tail-flick model after action of focused thermal ray (flick) on tail. Rats with latency less than 5 sec were qualified as high sensitive (HS) to pain, more than 10 sec as low sensitive (LS) to pain. Effects of a new nonopioid analgetic tropalgin 2 mg/kg (ED50) i.p. was studied in both groups of rats. Tropalgin was effective as an analgetic in aseptic inflammation model (formaldehyde test). The analgetic effects of tropalgin were same as after administration of methamizol sodium (50 mg/kg) or diclofenac sodium (7 mg/kg). Tropalgin did not change individual pain sensitivity in both HS and LS rats without inflammation. In HS to pain rats, the common time of pain behavioral reactions was decreased by 53% in an acute phase of pain and by 58% in a tonic phase of pain in inflammation pain model. In LS to pain rats, the time of leaking of inflamed paw was decreased by 42% in the first phase and by 66% in the second phase. We suggest that analgetic effect of tropalgin is connected with adenosine release in purinergic neurons that has been demonstrated earlier for drugs of tropin structure. PMID- 26571805 TI - [Atrial fibrillation and condition of vegetative nervous system: features of tactics and medical aid rendering at the pre-hospital stage]. AB - Comparative retrospective study of emergency action results for 1051 patients with atrial fibrillation attacks and their management tactics assessment at a pre hospital stage was done. It was found that occurrence of an attack of atrial fibrillation at a pre-hospital stage is accompanied expressed vegetative imbalance. Antiarrhythmic therapy using diazepam for atrial fibrillation promotes fast decrease of sympathicotonia at a pre-hospital stage and improves treatment efficacy in the first hour of observation of patients. PMID- 26571806 TI - [Effects of histone deacetylase inhibitor sodium valproate on the physical and behavioral development of 129SV mice]. AB - Sodium valproate is a widely used antiepileptic drug at high dosage levels, but it has been shown to produce a variety of toxic side-effects when used during perinatal period. These effects include increased risk of congenital anomalies and autism. For this reason, valproate is commonly employed in animal model of autism. Sodium valproate has multiple molecular targets including histone deacetylases. Therefore valproate can be utilized as a tool for the modulation of epigenetic modifications of the genome via inhibition of histone deacetylases. It is known that administration of sodium valproate at a dose of 50 mg/kg during early postnatal period leads to increase of the histone H3 acetylation level in the brain. The aim of the present study was to evaluate the effects of multiple valproate injections from 3rd to 6th postnatal day (50 mg/kg s.c.) on physical and sensorimotor development of 129Sv mice. The standard battery of tests was used. Our results show that valproate have no negative effect on physical development, sensorimotor function, and social behavior. The obtained results support the applicability of sodium valproate in our dosing schedule for further experimental modulation of histone acetulation level in the developing brain. PMID- 26571807 TI - [Systemic factors of acute pancreatitis advance]. AB - In experimental studies the sequence of vitals series lesion is established at various forms of acute experimental pancreatitis (edematous pancreatitis, a pancreatonecrosis). It is shown that one of the first in pathological process involves an intestine, then - a liver, further - kidneys. It is established that at acute pancreatitis the basis of a target organs lesion is membranodestruktivny process due to excess activity of lipids peroxidation processes and phospholipase systems which are registered not only in a blood plasma, but also in tissue structures of the studied organs - an intestine, a liver, kidneys (systemic distress damages of oxidative and phospholipase induced character) acts. PMID- 26571808 TI - [Taste perception during clinical symptom complex of gastroesophageal reflux disease]. AB - Taste perception is an important criterion for the state of the oral mucous membrane in patients with gastroesophageal reflux disease. The tongue, as an organ of taste, is characterized by serious changes in the functional state after injury with acid-containing substrates due to reflux. The specific features of taste perception and possibility for their correction were studied in 75 patients with this disorder. The type of changes in activity of tongue taste receptors and taste thresholds in patients before and after therapy were estimated by means of advanced gustometry and functional mobility technique. Specific changes in sensory function of the oral cavity were shown to be associated with acid aggression. Our results illustrate the possibility of taste correction in patients with gastroesophageal reflux disease. Taking into account some features of the general disease, it can be concluded that the introduction of Parodontax-F toothpaste and Emalan into combined therapy is accompanied by the improvement of taste perception. Correction of dysgeusia is an important criterion for the improvement of the quality of life of patients. PMID- 26571809 TI - [Effects of lithium carbonate nanosized particles on oxidant-antioxidant status in tumor tissue of hepatocarcinoma-29]. AB - Oxidant-antioxidant status in tumor tissue of male-mice CBA at spontaneous course of hepatocarcinoma-29 and after repeated injections of lithium carbonate nanosized particles was evaluated on changes of lipid peroxidation (LPO) products level reacted with 2-thiobarbituric acid (TBA) as indicator of oxidative stress and activity of superoxide dismutase (SOD) and catalase enzymes as indicators of antioxidant defense by spectrophotometer <> (Bio-Rad, USA). Tumor development after hepatocarcinoma-29 cells injection into muscle right leg changed the levels of LPO activity in two-phase manner. TBA-active products content were decreased in 2,4 times in comparison with the control indicates after invasion of tumor cells, it was raised in 2,1 times at excessive tumor growth and diminished at terminal stage. Catalase activity was significantly elevated, but SOD activity was reduced in tumor tissue samples at active growth of hepatocarcinoma. The repeated injections of lithium carbonate nanosized particles at hepatocarcinoma inhibited processes of lipid peroxidation in tumor tissue in 2,4 times, but didn't influence on activities of catalase and SOD. Thus the effects lithium carbonate nanosized particles injections referred on maintenance of balance between the oxidant and antioxidants may be of some help to limit the progression of precancerous condition toward malignancy and tumor growth. PMID- 26571810 TI - [Change lipid peroxidation as a mechanism of renal disease under heavy metals]. AB - Heavy metals are the most dangerous anthropogenic pollutants human environment. With an extensive range of pathological effects of heavy metals lead to the development of irreversible changes in the tissues of living organisms and systems. The main target organ destructive influence of metals are the kidneys, which is associated with the peculiarities of running these bodies physiological functions. There are many mechanisms allowing heavy metals to exercise their pathogenic effects on the body, the most significant of which is the mechanism of activation of free radical oxidation, due to the inherent heavy metals prooxidant activity. On this basis, the main objective of the pilot study was to investigate the influence of lipid peroxidation in the kidney function. To determine the functional state of the kidneys was performed to study the basic processes of urine formation, protein excretion and urine osmolarity. The intensity of lipid peroxidation was judged by the concentration of malondialdehyde and hydroperoxide in the blood of animals. Results of the study revealed that long-term administration of heavy metals in experimental animals leads to the development of a powerful oxidative stress, characterized by an increase in the content of lipid peroxidation products in the blood of animals. The paper found that the activation of lipid peroxidation in the conditions of long-term administration of heavy metals associated with the development of marked disorders of renal function. A strong antioxidant effect of melatonin in long-term poisoning with heavy metal salts reduces the activity of lipid peroxidation, which in turn weakens the pathological effects of xenobiotics on renal function. The findings suggest that the activation of heavy metals, lipid peroxidation is one of the mechanisms leading to the development of pathophysiological changes in the kidneys. PMID- 26571811 TI - [Effect of L-carnitine, afobazole and their combination with L-arginine on biochemical and histological indices of endothelial disfunction in cobalt intoxication in rats]. AB - The influence of L-carnitine and afobazole and their combination with L-arginine on biochemical and histological indices of endothelial dysfunction in rats with cobalt intoxication. The obtained data revealed biochemical markers of endothelial dysfunction. Found that-in rats with cobalt intoxication during treatment occurred inhibition of lipid peroxidation (LPO), reduced the concentration of malondialdehyde (MDA) in erythrocytes, activation of superoxide dismutase (SOD). This was accompanied by increased concentrations of nitric oxide (NO), the availability of the substrate L-arginine and possibly the expression of eNOS in the background of L-carnitine and afobazole. PMID- 26571812 TI - [SNAI1 and SNAI2 - transcriptional master-regulators of epithelial-mesenchimal transition]. AB - Epithelial-mesenchymal transition is a result of cellular epigenetic reprogramming. During this process differentiated epithelial cells lose specific markers of epithelial phenotype and gradually start displaying qualities of poorly differentiated mesenchymal cells, resistant to apoptosis and capable of local invasion. Despite their obvious importance for biology and medicine, many aspects of epithelial-mesenchymal transition, especially those related to its genetic regulation, remain poorly characterized. In this review we analyze molecular structure and mechanisms of regulation of two closely-related transcription factors SNAI1 and SNAI2, which play an important role in induction and progression of epithelial-mesenchymal transition during both normal development and carcinogenesis. Special attention is paid to the role of SNAI1 and SNAI2 and their active co-reeressors in initiation of epigenetic repression of epithelial differentiation marker genes. PMID- 26571813 TI - [Prospects for the use of cells possessing myogenic potential in the treatment of skeletal muscle diseases: a review of research. Part 1 - satellite cells]. AB - Musculoskeletal functions disorders may develop as a consequence of injuries and various types of congenital / acquired diseases, among which a special place belongs to muscular dystrophy. The technology with use of cells possessing myogenic potential is considered as one of the most promising approaches to solve the problem of effective restoration of skeletal muscles structure and function. In part I of the article the characteristic features, functions and phenotypic characteristics of satellite cells (SC) are reviewed as key factors of skeletal muscle tissue regeneration. Presented analysis of research results (preclinical and clinical) concerning therapeutic possibilities of technology using SC. In the second part of review will be presented data of the therapeutic use of stem cells of muscle and non-muscle origin for the treatment of skeletal muscles diseases. PMID- 26571814 TI - [Phenomena and signaling mechanisms of macrophage reprogramming]. AB - The process of changing the phenotype of macrophages is called <>. Reprogramming plays a central role in the immune response. Reprogrammed macrophages are characterized by four phenomena: the phenomenon of the gain response of macrophages on the reprogramming factor (direct gain), and the other factor (cross-gain); phenomenon of reciprocal suppression of alternative phenotypes; phenomenon of cascade activation for mechanisms of reprogramming and the phenomenon of positive and negative feedbacks. The formation of these phenomena provide the intracellular signaling pathways, such as INK-; PI3K/Akt-; Notch-; JAK/STAT-; TGF-beta-; TLR/NF-kappaB- and hypoxia-dependent signaling pathways. Analysis of the signaling mechanisms of reprogramming led to several conclusions: 1. There is a relative specialization of signaling pathways in macrophages reprogramming on action of different components of the microenvironment; 2. signaling pathways that are involved in reprogramming of macrophages can be divided in the way that program M1 phenotype and the way that program M2 phenotype; 3. Understanding the signaling pathways helps to explain the basic phenomena of reprogramming. Thus, the phenomenon of the gain response of reprogrammed macrophages is provided by convergence signaling pathways at specific protein; phenomenon of reciprocal suppression alternative macrophage phenotype is provided by that the formation of one phenotype is accompanied by increased synthesis of molecules that inhibit an alternative phenotype; at the heart of the phenomenon of cascade activation of signaling pathways is the ability one way to transmit signals over a different path and the basis for the phenomenon of positive and negative feedback is the ability to increase the synthesis of the activators and inhibitors of this pathway. 4. Signalling pathways that transmit the signal from the proinflammatory factors and programm proinflammatory M1 phenotype of macrophages are often branching, which, when activated, may increase the production of anti-inflammatory M2 cytokines; and vice versa. Since the violation reprogramming of macrophages plays an important role in the development of many diseases, understanding the signaling mechanisms of reprogramming, will assist in the selection of effective therapeutic targets to develop new ways of correction of impaired immunity. PMID- 26571815 TI - [Modeling of traumatic brain injury]. AB - Contemporary approaches to experimental traumatic brain injury modeling, the principles of functioning and techinical characteristics of appropriate equipment are reviewed. The methods describing traumatic brain injury modeling and assessment of brain structural and functional changes caused by the weight drop method are given. PMID- 26571816 TI - [Electrophysiological features (EEG) of ethanol withdrawal syndromes on isolated perfused rat brain]. AB - On isolated rat brains we studied native EEC and its derivates (mean EEC amplitude and power spectrums - Fourier transformation) during perfusion with ethanol (65 Mm/ L) and after its withdrawal. Previously rats were undergone ethanol burden for 6 days according to Majchrowicz procedures to get alcohol withdrawal syndrome. Duration perfusion without ethanol was 5, 10 and 20 min depending on the experimental schedule. Ethanol infusion between periods of withdrawal comprised 20 min. 55% of isolated brains shown epileptiform activity after 1-2 min of ethanol withdrawal but others manifested only increased mean amplitude and the power spectrums of EEC as well as an appearance of single or batch spikes. Differences between in vivo and in vitro conditions can be explained by the accelerated rate of ethanol elimination. The high positive correlation was obtained between EEC findings at the 5-th min of the first ethanol withdrawal and the same findings at the 5-th min of ethanol withdrawal in the second and the third episodes of ethanol withdrawal. Prolongation of withdrawal period more than 5th min caused brain death showing epileptiform activity. Isolated rat brain is the convenient subject to study pathogenesis of excitability of neurons and examination of drugs to treat alcohol withdrawal syndrome. PMID- 26571817 TI - [Pathophysiology as a bridge between medical theory and practice (information about VII Congress of International Society of Pathophysiologysts)]. PMID- 26571818 TI - [Intelligent distributed system of population cancer screening]. AB - This review summarizes data dedicated to improving the efficiency of screening of malignant tumors through the use of modern information and telecommunication technologies. It is showed that currently available software solutions in the field of medical imaging is not enough adapted for population screening. So far there is no single standard that defines checking algorithms of data processing at certain controlled conditions. The most expected result will be the organization of information centralized storage, sharing diagnostic data, providing broad access to them, automated analysis and selection of diagnostically significant results through the software. The basic requirements for the development of self-learning systems for intelligent processing array of heterogeneous data through the use of technologies of semantic networks are provided. PMID- 26571819 TI - [Lymphocyte receptors that regulate the immune-response--the key to the management of antitumor immunity]. AB - Tumor uses various mechanisms to "escape" from immune surveillance including the important role of dysregulation of interaction of signals from corresponding co stimulatory and co-inhibitory receptors (so-called "control points immunity"-- immune "checkpoints") modulating T-cell activation process. A creation of targeted drugs impacting on immune "checkpoints"" is a new promising trend in modern oncoimmunology. This review is devoted to a brief characterization of some receptors of immune competent cells (such as activation and inhibitor), which play a crucial role in the interaction of the immune system and tumors as well as targeted drugs acting on them for therapeutic purpose. PMID- 26571820 TI - [Metastatic brain lesion paradigm shift in radiation therapy]. AB - The development of methods of treatment using radiosurgery devices "Gamma Knife", "Cyber Knife" has significantly changed the results of treatment of patients with brain metastases, which allowed formulating new principles of treatment of this group of patients. Radiosurgical treatment by means of "Gamma Knife" and "Cyber Knife" provides stable reproducible results with local tumor control in the case of both single and multiple lesions. The optimal minimum dose is 18Gy. Indicators of local control were 90-94% for brain metastases from breast cancer and 81-98% for brain metastases from lung cancer. With respect to radioresistant brain metastases local tumor control after radiosurgical treatment was 73-90% for patients with melanoma and 83%-96% for patients with renal cell carcinoma. Currently there is a tendency of application of radiosurgical treatment of patients with multiple brain mertastases. Numerous studies show a high rate of local tumor control after radiosurgical treatment in this patient group. This review summarizes current literature data on radiosurgical treatment for brain metastases with an emphasis on survival, local control, distant metastasis, quality of life as well as the potential combinations of existing treatment methods. PMID- 26571821 TI - [Mechanisms of immune system contribution to efficiency of antitumor cytostatic therapy]. AB - Increasing the efficiency of antitumor therapy is one of major relevant tasks of oncology today. During recent years experimental evidence for active involvement of immune system in the regulation antitumor effects of cytostatic thereby has been obtained and theoretically justified. It was demonstrated that efficient cytostatic treatment is related to the cytotoxic activities of immune cells targeted against tumor cells. Such cytotoxic activities of immune cells are induced by radiotherapy or chemotherapy, where both innate and adaptive immune mechanisms are involved. However the disturbance in the functions of immune system can result in the impaired efficiency of cytostatic anti-tumor therapy. Cytotoxic agents can affect immune reactions by increasing the antigenic properties of tumor cells, facilitating their recognition of immune system, by stimulation of functional activation effector immune cells, elimination of immunosuppressive factors as well as systemic effects of antitumor therapy. A consideration of the crucial role of immune system in the providing of the efficiency of cytostatic antitumor therapy develops novel therapeutic approaches for treatment of malignant disorders based on balanced synergistic action of cytostatic agents and innovative immunomodulatory approaches. PMID- 26571822 TI - [Features of functional activity of dendritic cells in tumor growth]. AB - During recent years much data, accumulated on biology, function and role of dendritic cells (DC) in cancer development, in a new way allow assessing their role in disease process. Identification of features of DC functional state as well as their interaction and influence on the immune cells in tumor growth can be used as a basis for a new approach to cancer therapy enhancing standard therapy efficacy. The review analyzes different mechanisms of escaping of tumor cell from immune surveillance involving DC as one of the main participants of antitumor immune response. Also the prospects of using DC for vaccination are discussed. DC can be promising target for therapeutic strategies and also can be used for formation of antitumor response and cell therapy. PMID- 26571823 TI - [Acral lentiginous melanoma: the current state of the problem]. AB - This review is aimed at the analysis the current state of acral lentiginous melanoma. This tumor has rather aggressive course and is the main cause of death in skin cancer patients. In Russia the incidence of melanoma during the period 2000-2010 increased from 3.18 to 3.95 cases per 100000 of population. The average annual growth rate was 1.99% and the total growth rate was 21.81%. Although skin melanoma is a visual tumor, more than one third of patients visit oncologists at advanced stages of the disease. Primary melanoma with localizations on the skin of fingers, interdigital spaces, soles, palms and nail plates is especially difficult for early diagnostics. PMID- 26571824 TI - [Ozone therapy for radiation reactions and skin lesions after neutron therapy in patients with malignant tumors]. AB - The article discusses the problem of radiation complications from normal tissues in patients after therapy with fast neutrons of 6.3 MeV. The methods of treatment using ozone technologies in patients with radiation reactions and skin lesions on the areas of irradiation after neutron and neutron-photon therapy have been worked out. Ozone therapy showed its harmlessness and increased efficiency of complex treatment of these patients. PMID- 26571825 TI - [Obesity and characteristics of endometrial cancer: are there any changes over several decades?]. AB - It is shown that endometrial cancer features (including expression of the PTEN and HER-2/neu proteins) are connected dissimilarly with body mass index and with the belonging of the patients to the groups with standard, SO and metabolically healthy obesity, MHO. In the course of the last half-century an increases are discovered in the height and weight of the females with endometrial cancer that moves in the opposite direction with a reduction of the share of MHO cases among obese patients. This conclusion should be taken into account when one considers the means for contemporary prevention of both obesity and cancer of uterine body. PMID- 26571826 TI - [Anti-EGFR monoclonal antibodies in locally advanced head and neck squamous cell cancer]. AB - The article presents immediate results of neoadjuvant treatment of patients with locally advanced head and neck squamous cell cancer and an evaluation of the toxicity of cetuximab. Standard chemotherapy in combination with targeted therapy with cetuximab showed its high effectiveness and satisfactory tolerance. PMID- 26571827 TI - [Fast neutrons 6.3 MeV in the combined treatment of patients with local recurrence of breast cancer]. AB - The article is devoted to the problem of treatment of patients with locally advanced breast cancer recurrences as well as a study of neutron therapy influence on normal tissues and various critical organs. The use of fast neutrons of 6.3 MeV in these patients is often the only treatment option. A 6-year survival rate of patients without repeated signs of recurrent breast cancer after neutron and neutron-photon therapy is 92.2 +/- 5.7%. PMID- 26571828 TI - [Analysis of results of Gamma Knife radiosurgery for patients with melanoma brain metastases]. AB - The outcomes of Gamma Knife radiosurgery for 95 patients with melanoma brain metastases were studied. The majority of the patients (82%) presented multiple metastatic brain lesions. Local control was achieved in 94% of cases. The Kaplan Maier analyses of life expectancy revealed that median survival after radiosurgical treatment was 6.9 months. The median survival by RTOG RPA class was 18,3 months for class I; 6.9 months for class II and 3.9 months for class III. These results demonstrate that Gamma Knife radiosurgery provides a high level of local control for melanoma brain metastases and may increase the life expectancy. PMID- 26571829 TI - [Planning and implementation of conformal radiotherapy for patients with gynecologic neoplasms with urinary tract obstruction]. AB - Urinary tract pathology is one of the reasons limiting possibility of all kind of radical treatment followed by proper rehabilitation in patients with cancer of the female genital organs. 469 patients suffering from cancer of the female genital organs with urological obstructive complications were successfully treated by means of conformal external beam radiotherapy and brachytherapy for the period 2003-2012 after correction of urological pathology. A use of interventional technologies for urinary tract drainage that minimize the frequency of repeated invasive procedures to reduce the risk of remote infectious and functional urinal complications after radiotherapy is the most priority for the implementation of irradiation of any required volume in patients with cancer of the female genital organs. PMID- 26571830 TI - [Combined treatment in malignant tumors of the head and neck with reconstructive plastic surgery]. AB - The article is devoted to conservative and reconstructive-plastic surgical interventions using biocompatible implants accompanied by various types of radiotherapy and modern anticancer drugs that have allowed improving basic survival with maintaining a high level of quality of life. Our method of combined treatment for larynx, hypopharynx, oral cavity and oropharynx cancer of stage II III by chemoradotherapy shows high immediate effectiveness and allows achieving statistically significant increase of overall and disease-free survival in the remote period of observation. The use of NiTi implants provides reliable recovery of deleted structures, pressurization of the cranial cavity, reduces the duration of surgery, shortens the time of wound healing. PMID- 26571831 TI - [Laparoscopic surgery in treatment for colon cancer]. AB - There are presented results of treatment of 347 patients with colorectal cancer. Laparoscopic surgery had been planned for 92 (26.5%) patients (study group). In 79 (85.9%) patients surgery was performed completely by laparoscopy, 13 (14.1%) patients underwent conversion. In 255 (73.5%) patients surgery was carried out from an open access (control group). The authors showed the effectiveness of the use of minimally invasive techniques in treatment for colorectal cancer. PMID- 26571832 TI - [An evaluation of effectiveness of cytological method in diagnostics of breast tumors]. AB - This paper presents an analysis of the results of cytological diagnostics of breast tumors in 3415 patients who underwent tests in the Laboratory of Cytology for 2009-2013. In 1434 patients there were performed cytohistological correlations. Sensitivity of cytology was 99.1%, specificity--93.5%, predictive value of the positive test--98.5%, predictive value of the negative test--95.9%, accuracy--98%. Non-informative material was obtained in 13.5% of cases. The main factors that reduced effectiveness of cytological method were non-informative and little informative material and also difficulties in conducting of differential cytomorphological diagnostics. PMID- 26571833 TI - [Serum adipokines and their receptors in endometrial and colon cancer patients: relationship with tumor invasion and metastasis]. AB - The aim of the study was to investigate the serum adipokine levels and expression of adipokine receptors (AdipoR1, AdipoR2) in patients with endometrial and colon cancer in relation with the main clinical morphological parameters (tumor invasion, lymph node involvement). The study included 60 endometrial cancer patients with I-II Stage and 31 patients with colon cancer (T2-4N0-2M0). Serum adipokine levels, the level of soluble form of the leptin receptor (sOb-R) and AdipoR1 and AdipoR2 expression were evaluated with ELISA. In endometrial cancer serum leptin and adiponectin levels were associated not only with metabolic disorders but also with cervical invasion. In colon cancer serum leptin level was associated with lymph node involvement. The data obtained showed the potential implication of serum adipokines into tumor invasion and metastasis. In both sites intratumoral levels of AdipoR1 H AdipoR2 were not associated with the presence of metabolic syndrome. The AdipoR1 level was related with myometrial invasion. In colon cancer patients, AdipoR1 and AdipoR2 expressions were associated with lymph node involvement, and AdipoR1 expression was correlated with tumor size. The obtained results demonstrated involvement of adipose tissue hormones (leptin and adiponectin) and adiponectin receptors (AdipoR1 and AdipoR2) in tumor growth, invasion and lymphogenic metastasis. PMID- 26571834 TI - [Use of SPECT-CT for visualization of sentinel lymph nodes in breast cancer patients]. AB - This study was performed in order to determine individual variability of axillary sentinel lymph nodes (SLN) localization in patient with breast cancer (BC). Individual topography of axillary SLN was determined in 182 patients with early BC. All women were candidates for conservative surgical treatment with postoperative radiotherapy. SPECT-CT visualization of SLN started 120-240 min after intratumoral injection of 74-150MBq of 99mTc-radiocolloids. Distribution of axillary SLN was allocated to following subregions: central (C), pectoral (P), apical (AP), lateral (L), subscapular (SSc). SLN visualization by SPECT-CT was successful in 153 cases (84%). AP nodes were detected in 7 patients (5%). SLN were localized on thoracic wall in 34 cases (22%), in the intrapectoral region- in 3 (2%) women. According to axillary levels they were detected on level I--in 149 (97%), level II--15 (10%), level III-- (7.5%) cases. PMID- 26571835 TI - [Conformal radiotherapy in nasopharyngeal cancer patients]. AB - The paper is aimed at the determination of the efficiency of various technologies of conformal radiotherapy for patients with nasopharyngeal carcinoma. The study included 56 patients with squamous cell carcinoma of the nasopharynx treated with conformal radiotherapy. 3D-CRT was performed for 28 patients, IMRT--22 patients, RapidArc--6 patients. Dosimetric parameters were determined for planned volumes and organs at risk. TD on high-risk areas was 70Gy, intermediate-risk zones 60 66Gy and low-risk areas 50-56 Gy. There were determined session duration of exposure and the number of monitor units to evaluate the efficiency of treatment. Average (Dmean), maximum (Dmax) and the minimum (Dmin) dose for RapidArc, IMRT and 3D-CRT on PTV amounted to 70.2 Gy, 69.1 Gy and 70.7 Gy; 76.2 Gy, 76.1 Gy and 77Gr; 48.8, 54.4 and 46,6Gr respectively. Compared with IMRT and 3R-CRT RapidArc reduce Dmean in the brainstem and optic nerves by 14.1% and 23%; 12.2% and 25% respectively. The average number of MU (monitor unit) with RapidArc, IMRT and 3D CRT was 357, 1386 and 870. The average session time of irradiation was: with RapidArc, IMRT and 3D-CRT--300, 900 and 480 seconds. Compared with IMRT and 3D CRT average treatment time and the number of monitor units in RapidArc were reduced by 74%, 42% and 67%, 47%. Thus RapidArc and IMRT technologies allow getting a better dose distribution in the irradiated volume, compared with 3 D CRT on homogeneity and conformity. RapidArc technique reduces the pressure on the critical organs, diminishes exposure to the session and a number of MU. PMID- 26571836 TI - [Intraperitoneal chemotherapy--a method of improving treatment effectiveness in ovarian cancer]. AB - The study or antitumor effects of dioxadet, cisplatin, melphalan, paclitaxel, mitomycin C, cyclophosphamide and gemcitabine at intraperitoneal (i.p.) and intravenous (i.v.) administration as monochemotherapy and polychemotherapy in a rat model of ascitic ovarian cancer was carried out in 244 female Wistar rats. Ovarian cancer was transplanted i.p. at a number of 1 x 10(7) tumor cells. The drugs were administered once in 48 hours after ovarian cancer transplantation i.p. or i.v. for monotherapy--in maximum tolerated doses, for i.p. polychemotherapy--in half doses from maximum tolerated doses. Antitumor effects of the treatment were estimated in increase in median survival time (MST) compared to control rats who were administered saline i.p. At i.p. administration dioxadet, cisplatin and melphalan increased MST by 79%, 88% and 144%, respectively, while at i.v. administration these drugs didn't affect MST. Mitomycin C and paclitaxel had stronger antitumor action at i.v. administration increasing MST by 152% and 81%, respectively, while at i.p. administration these drugs increased MST by 35 and 45%, respectively. Combinations dioxadet + cisplatin, dioxadet + cyclophosphamide and dioxadet + paclitaxel at i.p. administration increased MST by 305%, 277% and 133%, respectively, and had additive antitumor action compared to mono-effects of these drugs. Gemcitabine and combination dioxadet + gemcitabine at i.p. administration didn't significantly affect survival of rats with ovarian cancer. Intraperitoneal monochemotherapy and polychemotherapy could be more effective in the treatment of peritoneal carcinomatosis from ovarian cancer compared to systemic administration of the drugs. PMID- 26571837 TI - [Age dynamics of angiogenesis markers in transgenic HER-2/neu (FBV/N) mammary adenocarcinoma-prone mice]. AB - Age-dependent angiogenesis intensity changes have been studied in transgenic HER 2/neu (FBV/N) mice characteristic of breast tumors' high incidence with hyperexpression of HER-2/neu. Concentration of vascular endothelial growth factor, insulin-dependent growth factor 1, nitrogen monoxide, tissue plasminogen activator and type 1 plasminogen activator inhibitor were assessed by means of immune-enzyme assay. The results testify to angiogenesis processes activation side by side with aging and growth of the tumors. Maximum manifestation of these disturbances (growth factors' blood concentrations increase and endotheliocytes' functional activity inhibition) has been revealed in 6-month-old mice during neoplasma maximum intensive and aggressive growth period. PMID- 26571838 TI - [Intraoperative intraperitoneal chemoperfusion treatment with cisplatin and dioxadet on a model of peritoneal carcinomatosis in ovarian cancer: safety and efficacy evaluation]. AB - A comparative study of safety and efficacy of normothermic and hyperthermic intraperitoneal chemoperfusion (IPEC and HIPEC) with cisplatin and dioxadet was carried out in 143 female Wistar rats. Ovarian cancer was inoculated intraperitoneally (i.p.). In 48 hours after ovarian cancer inoculation the drugs were administered i.p. or IPEC and HIPEC with the drugs were performed using maximum tolerated doses (MTD). Content of cisplatin was determined in the perfusate and blood plasma during HIPEC with the drug. The leukocyte count was measured using veterinary hematologic analyzer in peripheral blood of rats at different time points after HIPEC with dioxadet. Efficacy of the treatment was estimated in increase in median survival time (MST). During HIPEC cisplatin was accumulated in the abdominal cavity in a considerable amount with minimal systemic absorption. HIPEC with dioxadet didn't significantly affect the leukocyte count in peripheral blood while i.p. administration of dioxadet suppressed leukopoiesis. MST of rats after IPEC with cisplatin was 37.5 days which was significantly higher compared to MST after i.p. administration of cisplatin (19.5 days, p = 0.037). HIPEC with dioxadet was the most effective regimen of treatment with MST of rats reaching 49 days which was significantly higher compared to MST after HIPEC with cisplatin (25.5 days, p = 0.002). PMID- 26571839 TI - [Experience with the use of palonosetron (onicit) in patients with solid tumors receiving cytostatic therapy]. AB - Nausea and vomiting are among adverse effects of chemotherapy that significantly worsen quality of life of patients. 5-HT3 receptor antagonists have been used in recent decades to prevent and arrest these complications. Palonosetron is the most modern drug in this group. Palonosetron application during highly and moderately emetogenic chemotherapy showed its high effectiveness for nausea and vomiting prevention. PMID- 26571840 TI - [Results of complex treatment of patients with squamous cell carcinoma of the anal canal using advanced radiotherapy technologies]. AB - During recent decades radiotherapy is the basis, on which it is built a medical complex that is the first-line treatment of patients with squamous cell carcinoma of the anal canal. An increase of overall and disease-free survival and quality of life of patients with squamous cell carcinoma of the anal canal at the present stage of development of a comprehensive medical treatment is largely due to the improvement of technical equipment of radiotherapy departments of oncology clinics. The use of modem linear electron accelerators and systems of computer dosimetric planning to create a 3D program of isodose distribution, diagnostic devices (computed tomography and magnetic resonance imaging) as well as a number of other conditions permit accurate summarizing of proposed dose, reducing of absorbed dose to critical structures, diminishing unplanned interruptions in chemoradiotherapy course by means of modern technologies of conformal radiotherapy (3D CRT, IMRT, VMAT). The paper presents the preliminary results of a comprehensive medical treatment of 14 patients with squamous cell carcinoma of the anal canal. PMID- 26571841 TI - [Chemoradioresistance of the female reproductive system cancer--can local laser hyperthermia contribute to its overcoming?]. AB - There is presented the method of local laser hyperthermia on the domestic nanotechnological optic-fiber device LAZON-FT integrated into the program of brachytherapy for tumors of the female reproductive system. This is a universal radiosensibilizator that demonstrates the acceleration of tumor regression also during local and systemic chemotherapy--tumor regression at 50-705 in such conditions permits recommend it in locally advanced cervical and endometrial cancer as well as cancer of the vulva and vagina in the frames of combined use with brachytherapy and chemotherapy. PMID- 26571842 TI - [Analysis of results of drug therapy for symptomatic multiple myeloma]. AB - Drug therapy for symptomatic multiple myeloma is comparable for both sexes in its effectiveness and safety. A 3-year event-free survival is comparable in men and women; overall survival in men is lower than in women. PMID- 26571843 TI - [Minimally invasive surgery with therapeutic effect in cancer patients]. AB - During recent years ablative technologies have become very popular in tumor treatment. They are used in treatment for inoperable primary and metastatic tumors of the liver and the lung and also localized renal tumors of small sizes. The most studies on thermoablation in oncology are focused on the evaluation of tissue destruction and optimization of physical mechanisms, while potential mechanisms of immune response in thermoablation are still far from understanding. This study shows that with thermoablation of tumor within one month after the procedure the formation of a protective immune response is observed by increasing the content of activated T-helpers and cytotoxic T-lymphocytes. PMID- 26571845 TI - [Spindling in melanomas]. AB - The paper summarizes biological, morphological and clinical aspects of spindling in malignant melanomas. PMID- 26571844 TI - [Gefitinib therapy in advanced non-small cell lung cancer in patients with EGFR mutations: cost-effectiveness analysis]. AB - Therapy for advanced non-small cell lung cancer (NSCLC) is very complex clinical problem. The optimal choice of therapy demands not only the analysis of data on clinical effectiveness, but also an assessment of cost-effectiveness of the applied drugs. The current options for first- or second/third-line of lung cancer treatment are tirosine kinase inhibitors (TKI)--gefitinib, erlotinib and afatinib. According to the received results TKI first-line therapy for NSCLC in patients with EGFR mutations is not only clinically effective but also is economically acceptable from a position of the Russian budgetary health care. TKI second-line therapy for NSCLC patients who fail first-line therapy also provides improvement of the quality of life and prolonged time to progression. Comparable clinical effectiveness and safety of erlotinib and gefitinib in patients with EGFR mutations allows making drug choice on the basis of regional price characteristics. Afatinib is highly effective both in the first- and in the second/third-line of therapy in patients with the most frequent mutations (a deletion in exon 19 or a point mutation L858R in exon 21) but first-line therapy demands an increase of financial expenses caused by substantial increase of time to progression and duration of therapy. Thus TKI therapy of both the first-, and second/third-line of patients with NSCLC with EGFR mutations is characterized by acceptable cost-effectiveness. PMID- 26571846 TI - [Alexander Ivanovich Serebrov (to the 120th anniversary of his birth)]. PMID- 26571847 TI - Advocacy as an Expression of Charity. PMID- 26571848 TI - The Expanding Advocacy Agenda. AB - The ministry of advocacy has been an integral part of Catholic health care, beginning with the pioneering women religious who both cared for those in need and advocated for their health and welfare, as well as for the organizational structures to help them. PMID- 26571849 TI - Advocacy and the Catholic Health Ministry. PMID- 26571850 TI - Answering the Call To Meet Human Needs. PMID- 26571851 TI - Catholic Charities U.S.A. Providing a Voice for the Poor. AB - Think you know Catholic Charities? Look deeper--I bet you'll be surprised. People often tell me they know all about Catholic Charities' soup kitchens, coat drives, an annual Christmas fund-raiser. Some might mention local resume-writing classes or social enterprise endeavors like bake and furniture sales and other services for people struggling to lift themselves out of poverty. But only a few know that, as a movement, Catholic Charities has a dual mission and is committed to living out both components providing charity and seeking justice. PMID- 26571852 TI - Grassroots Advocacy for the Rural Poor. PMID- 26571853 TI - Environmental Advocacy. The Voices of Sacred Stories. PMID- 26571854 TI - Pediatric Toxic Stress. Changing the Game for Population Health. PMID- 26571855 TI - No-Fault Fund Model Can Help Preserve Birthing Services. PMID- 26571857 TI - Living Our Mission Through Our Investments. PMID- 26571856 TI - Caritas Internationalis. Service and Advocacy. PMID- 26571858 TI - Turning a Vision into Reality. PMID- 26571859 TI - Health reform. Refining Strategies & Vision. PMID- 26571860 TI - New Mission Leaders in Catholic Health Care. PMID- 26571861 TI - CONNECTING THE DOTS: MISSION AND ADVOCACY. PMID- 26571862 TI - PHARMACEUTICAL ACCESS FOR THE POOR. PMID- 26571863 TI - LOSS OF AN ECCLESIASTICAL OFFICE. PMID- 26571864 TI - BLESSING OF HOSPITAL ST. FRANCIS DE SALES. PMID- 26571865 TI - CELEBRATING A LEADER IN HEALTH CARE ETHICS. PMID- 26571866 TI - Prayer for Mission-Driven Advocacy. PMID- 26571867 TI - Connected Care Is Essential to Telemedicine's Success. PMID- 26571868 TI - Mercy Virtual: Connects with a New Model of Care. PMID- 26571869 TI - Technology Opens Promising Portals. PMID- 26571870 TI - Forging Rural Health Care Links. PMID- 26571871 TI - Mental Health Services Extend to Pipeline Towns. PMID- 26571872 TI - Rural Kentucky Gains More Access. PMID- 26571873 TI - At-Home Links Monitor Chronic Conditions. PMID- 26571874 TI - Dignity Health: Hope and Healing Through Telemedicine Dignity Health. PMID- 26571875 TI - Ministry Embraces Telehealth Care. PMID- 26571876 TI - Use Catholic Tradition To Guide Telehealth. PMID- 26571877 TI - BIOETHICS: Questions & Controversies. PMID- 26571878 TI - A Catholic Theology Of Employment-at-Will. PMID- 26571879 TI - DETAILS OF ENCOUNTER ARE KEY IN TELESPIRITUAL CARE. PMID- 26571880 TI - COMMUNITY BENEFIT AND POPULATION HEALTH MANAGEMENT. PMID- 26571881 TI - 'Touching the Flesh of Christ': CATHOLIC HEALTH CARE AND A CULTURE OF ENCOUNTER. PMID- 26571882 TI - REFLECT ON TRADITIONS IN THE NEW YEAR. PMID- 26571883 TI - Be Astonished, Tell About It. PMID- 26571884 TI - [The effect of the acupuncture intervention of dredging Governor Vessel and regulating mentality for the medication treatment of post-stroke depression]. AB - OBJECTIVE: To observe the differences in onset time and the overall efficacy of the acupuncture therapy of dredging Governor Vessel and regulating mentality combined with fluoxetine and the fluoxetine for post-stroke depression(PSD). METHODS: Sixty-three patients were randomly divided into an acupuncture intervention of dredging Governor Vessel and regulating mentality group(acupuncture and medication group, 33 cases) and a control group (medication group, 30 cases). In the medication group, 20 mg fluoxetine was used by oral administration, once a day at 7:00 in the morning, continuously for 4 weeks. In the acupuncture and medication group, based on the oral administration of fluoxetine, the acupuncture intervention of dredging Governor Vessel and regulating mentality was applied mainly at Baihui(GV 20), Fengfu(GV 16), Shenting(GV 24), Shuigou(GV 26), Dazhui(GV 14) and Shendao(GV 11), once a day, 6 times a week, continuously for 4 weeks. Twenty-four items in Hamilton Depression Scale(HAMD), modified Edinburgh Scandinavia Stroke Scale(MESSS) and activity of daily life scale(ADL, Barthel index, BI) were used before and after 2-week and 4 week treatment. The efficacy was compared between the two groups. RESULTS: After 2-week treatment, the HAMD score and the MESSS score in the acupuncture and medication group were obviously decreased and the BI score was apparently increased(all P<0. 01). In the medication group, however, the score of every scale was not statistically different from that before treatment(P'>0. 05). After 4-week treatment, HAMD scores and MESSS scores in the two groups were obviously decreased and the BI scores I were apparently increased(all P<0. 01). After 2 week and 4-week treatment, the HAMD scores and the MESSS scores in the acupuncture and medication group were lower than those in the medication group and the BI scores were higher than those in the medication group(P<0. 01, P<0. 05). The total effective rate of anti-depression (97. 0%, 32/33) the total effective rate of nerve function impairment(90. 9%, 30/33) and the total effective rate of daily life activity(97. 0% 32/33) in the acupuncture and medication group were better than 80. 0% (24/30), 80. 0%(24/30), 83. 3%(25/30) in the medication group(all P<0. 05). CONCLUSION: The acupuncture therapy of dredging Governor Vessel and regulating mentality could reduce the onset time of anti-depression medicine treatment of PSD and enhance the overall efficacy. Therefore, it enhances the clinical compliance. PMID- 26571885 TI - [The effect of floating-needle therapy combined with rehabilitation training for the hand function recovery of post-stroke patients]. AB - OBJECTIVE: To explore the improvement of hand motion function,spasm and self-care ability of daily life for stroke patients treated with floating-needle combined with rehabilitation training. METHODS: Eighty hand spasm patients of post-stroke within one year after stroke were randomly divided into an observation group and a control group, 40 cases in each one. In the two groups, rehabilitation was adopted for eight weeks,once a day,40 min one time. In the observation group, based on the above treatment and according to muscle fascia trigger point, 2~3 points in both the internal and external sides of forearm were treated with floating-needle. The positive or passive flexion and extension of wrist and knuckle till the relief of spasm hand was combined. The floating-needle therapy was given for eight weeks, on the first three days once a day and later once every other day. Modified Ashworth Scale(MAS), activity of daily life(ADL, Barthel index) scores and Fugl-Meyer(FMA) scores were used to assess the spasm hand degree,activity of daily life and hand motion function before and after 7 day, 14-day and 8-week treatment. RESULTS: After 7-day, 14-day and 8-week treatment, MAS scores were apparently lower than those before treatment in the two groups(all P<0. 05), and Barthel scores and FMA scores were obviously higher than those before-treatment(all P<0. 05). After 14-day and 8-week treatment, FMA scores in the observation group were markedly higher than those in the control group(both P<0. 05). CONCLUSION: Floating-needle therapy combined with rehabilitation training and simple rehabilitation training could both improve hand spasm degree, hand function and activity of daily life of post-stroke patients, but floating-needle therapy combined with rehabilitation training is superior to simple rehabilitation training for the improvement of hand function. PMID- 26571886 TI - [Case of koro]. PMID- 26571887 TI - [Impacts of the low-frequency electric stimulation at the acupoints on the content of plasma 5-HT and NE in the patients with post-stroke insomnia]. AB - OBJECTIVE: To compare the clinical efficacy on post-stroke insomnia between the low-frequency electric stimulation at the acupoints and the conventional western medication in the patients so as to explore the effect mechanism. METHODS: One hundred and twenty patients of post-stroke insomnia were randomized into a low frequency electric stimulation group, a medication group and a placebo group, 40 cases in each one. In the low-frequency electric stimulation group, the low frequency pulse electric apparatus was applied to stimulate Dazhui (GV 14) and Shenshu (BL 23), once every day. The treatment for 15 days made one session and 2 sessions were required. In the medication group, estazolam was taken orally, 1 mg each time; and in the placebo group, the starch capsules were taken, one capsule each time; in the two groups the treatment was adopted before sleep every night, continuously for 15 days as one session, and 2 sessions were required. The levels of plasma 5-hydroxytryptamine (5-HT) and norepinephrine (NE) were compared before and after treatment in the patients of the three groups and: the efficacy was compared. RESULTS: In the placebo group, 1 case was dropped out. The total effective rate was 95. 0% (38/40), 92. 5% (37/40) and 17. 9% (7/39) in the low frequency electric stimulation group, the medication group and the placebo group respectively. The effects in the low-frequency electric stimulation group and the medication group were better apparently than that in the placebo group (both P<0. 01). The effect was not different significantly between the low-frequency electric stimulation group and the medication group (P>0. 05). The levels of plasma 5-HT and NE were not different significantly between before and after treatment in the placebo group. The level of plasma 5-HT was increased (both P<0. 05) and thelevel of NE was decreased (both P<0. 05) as compared with that before treatment in the low-frequency electric stimulation group and the medication group. But the differences were not significant between the two groups (P>0. 05). CONCLUSION: The low-frequency electric stimlaton a the acupoints is safe and effective in the treatment of post-stroke insomnia, which is similar to oral medication of estazolam. The outcome of the increase of plasma 5-HT level and the decrease of plasma NE level is probably one of the effect mechanisms. PMID- 26571888 TI - [Acupuncture treatment of insomnia based on the spleen and stomach theory]. AB - OBJECTIVE: To observe the impact of acupuncture on the subjective symptom, sleep quality and sleep efficiency in the patients of insomnia differentiated as spleen deficiency or non-spleen deficiency in terms of the spleen and stomach theory. METHODS: Sixty patients with insomnia were divided into a spleen deficiency group and a non-spleen deficiency group, 30 cases in each one. In the two groups, acupuncture was applied at Sishencong (EX-HN1), Shenmen (HT 7), Sanyinjiao (SP 6), Zusanli (ST 36) and Tianshu (ST 25). The treatment was given once every other day, five times as one course, and two courses were required. The Athens Insomnia Scale (AIS) was used to observe the changes in the patients' subjective symptoms. The Pittsburgh sleep quality index (PSQI) was adopted to observe the changes of patients' sleep quality. The sleep efficiency was applied to observe the changes in sleep time. The clinical efficacy was determined. RESULTS: The total effective rate was both 80. 0% (24/30) after 5 and 10 treatments in the spleen deficiency group and was 76. 7% (23/30) and 80. 0% (24/30) respectively in the non-spleen deficiency group. The differences were not significant between the two groups (both P >0. 05). The AIS total scores and PSQI total scores were reduced apparently after 5 and 10 treatments as compared with those before treatment (all P<0. 01). The difference at each time point was not significant between the two groups (all P>0. 05). The sleep efficiency after 5 and 10 treatments was all improved as compared with that before the treatment in the two groups (all P<0. 01). CONCLUSION: Acupuncture based on the spleen and stomach theory achieves possibly the same clinical efficacy in the patients of insomnia differentiated as those with spleen deficiency and non-spleen deficiency. It relieves the subjective symptoms and improves the sleep quality and sleep efficiency in the patients. PMID- 26571889 TI - [Clinical study of cervical spondylotic radiculopathy treated with massage therapy combined with Magnetic sticking therapy at the auricular points and the cost comparison]. AB - OBJECTIVE: To compare the clinical efficacy on cervical spondylotic radiculopathy between the combined therapy of massage and magnetic-sticking at the auricular points and the simple massage therapy, and conduct the health economics evaluation. METHODS: Seventy-two patients of cervical spondylotic radiculopathy were randomized into a combined therapy group, and a simple massage group, 36 cases in each one. Finally, 35 cases and 34 cases were met the inclusive criteria in the corresponding groups separately. In the combined therapy group, the massage therapy and the magnetic sticking therapy at auricular points were combined in the treatment. Massage therapy was mainly applied to Fengchi (GB 20), Jianjing (GB 21), Jianwaishu (SI 14), Jianyu (LI 15) and Quchi (LI 11). The main auricular points for magnetic sticking pressure were Jingzhui (AH13), Gan (On12) Shen (CO10), Shenmen (TF4), Pizhixia (AT4). In the simple massage group, the simple massage therapy was given, the massage parts and methods were the same as those in the combined therapy group. The treatment was given once every two days, three times a week, for 4 weeks totally. The cervical spondylosis effect scale and the simplified McGill pain questionnaire were adopted to observe the improvements in the clinical symptoms, clinical examination, daily life movement, superficial muscular pain in the neck and the health economics cost in the patients of the two groups. The effect was evaluated in the two groups. RESULTS: The effective rate and the clinical curative rate in the combined therapy group were better than those in the control group [100. 0% (35/35) vs 85. 3% (29/34), 42. 9% (15/35) vs 17. 6% (6/34), both P<0. 05]. The scores of the spontaneous symptoms, clinical examnation, daily life movement and superficialmuscular pain in the neck were improved apparently after treatment as compared with those before treatment in the patients of the two groups (all P<0. 001). In terms of the improvements in the spontaneous symptoms, clinical examination total scores and superficial muscular pain in the' neck were more significant in the combined therapy group as compared with those in the simple massage group (P<0. 05, P<0. 01, P<0. 001). The cost at the unit effect in the combined therapy group was lower than that in the simple massage group (P<0. 05). CONCLUSION: Compared with the simple massage therapy, the massage therapy combined with magnetic sticking therapy at auricular points achieves the better effect and lower cost in health economics. PMID- 26571890 TI - [Clinical observation of breast hyperplasia treated with auricular point sticking therapy and Xiaopijian]. AB - OBJECTIVE: To observe the efficacy difference in the treatment of breast hyperplasia between the combined therapy of auricular point sticking and Xiaopijian and the simple application of Xiaopijian. METHODS: Ninety-one patients were randomized into an observation group (46 cases) and a control group (45 cases). In the observation group, the sticking therapy on the auricular points was applied in combination with the oral medication of Chinese herbal medicine, Xiaopijian. Auricular points included Ruxian, Neifenmi (CO18), Luanchan, Shenmen (TF4), Gan (CO2), Pi (CO13). The auricular point sticking therapy was applied once a week on the auricular points of one side alternatively. Xiaopijian was the self-prepared decoction. The main ingredients are radix bupleuri Bupleurum chinense, spica prunellae prunella vulgaris and radix peoniae alba Paeonia lactiflora, 30 mL each time, three times a day. In the control group, Xiaopijian was simply prescribed for oral administration, 30 mL each time, 3 times a day. The treatment was discontinued during menstruation in the two groups. The menstrual cycle of one month made one session of treatment. The treatments for 3 sessions were observed. The scores of symptoms and physical signs, including the degree of breast pain, hardness and size of breast masses as well as the scores of general and supplementary symptoms were compared before and after treatment in the patients of the two groups. The clinical efficacy was compared between the two groups. RESULTS: After treatment, the scores of symptoms and physical signs were reduced apparently as compared with those before treatment in the patients of the two groups (both P<0. 05). The score reduction in the observation group was much more than that in the control group (11.02+/-1. 78 vs 9.82+/-1. 53, P<0. 05). The total effective rate was 95.7% (44/46) in the observation group, higher apparently than 80. 0% (36/45, P<0. 05). CONCLUSION: The combined therapy of auricular point sticking and Xiaopijian achieves the superior efficacy on breast hyperplasia as compared with the simple application of Xiaopijian. PMID- 26571891 TI - [Efficacy on hemiplegic spasticity treated with plum blossom needle tapping therapy at the key points and Bobath therapy: a randomized controlled trial]. AB - OBJECTIVE: To evaluate the efficacy on hemiplegic spasticity after cerebral infarction treated with plum blossom needle tapping therapy at the key points and Bobath therapy. METHODS: Eighty patients were collected, in compliance with the inclusive criteria of hemiplegic spasticity after cerebral infarction, and randomized into an observation group and a control group, 40 cases in each one. In the control group, Bobath manipulation therapy was adopted to relieve spasticity and the treatment of 8 weeks was required. In the observation group, on the basis of the treatment as the control group, the tapping therapy with plum blossom needle was applied to the key points, named Jianyu (LI 15), Jianliao (LI 14), Jianzhen (SI 9), Hegu (LI 4), Chengfu (BL 36), Zusanli (ST 36), Xiyangguan (GB 33), etc. The treatment was given for 15 min each time, once a day. Before treatment, after 4 and 8 weeks of treatment, the Fugl-Meyer assessment (FMA) and Barthel index (BI) were adopted to evaluate the motor function of the extremity and the activity of daily life in the patients of the two groups separately. The modified Ashworth scale was used to evaluate the effect of anti-spasticity. RESULTS: In 4 and 8 weeks of treatment, FMA: scores and BI scores were all significantly increased as compared with those before treatment in the two groups: (both P<0. 05). The results in 8 weeks of treatment in the observation group were significantly better than those in the control group (all P<0. 05). In 4 and 8 weeks of treatment, the scores of spasticity state were improved as compared with those before treatment in the patients of the two groups (all P<0. 05). The result in 8 weeks of treatment in the observation group was significantly better than that in the control group (P<0. 05). In 8 weeks of treatment, the total effective rate of anti-spasticity was 90. 0% (36/40) in the observation group, better than 75. 0% (30/40) in the control group (P<0. 05). CONCLUSION: The tapping therapy with plum blossom needle at the key points combined with Bobath therapy effectively relieves hemiplegic spasticity in the patients of cerebral infarction and improves the motor function of extremity and the activity of daily life. PMID- 26571893 TI - [Characteristics of acupoints combination in the Evidence-based Guidelies of Clinical Practice]. AB - The evidence-based Guidelines of Clinical Practice with Acupuncture and Moxibustion are based on extesiv evidene of literature an compiled by eperience of experts, so the recommended acupoints present special thoughts and laws of compatibility. It is found the traditional acupoint combination methods predominate, such as distal-local acupoint combination, syndrome differentiation based acupoints combination and symptom-based acupoints combination, etc., and are combined with research achievements of modern medical science; PMID- 26571892 TI - [Law of the meridian abnormality based on the effectiveness of electroacupuncture for severe functional constipation]. AB - OBJECTIVE: To observe the law of the meridian abnormal changes and the correlation with acupuncture efficacy based on the effectiveness study of electroacupuncture (EA) in treatment of severe functional constipation. METHODS: Seventy patients of severe functional constipation were randomized into an EA group and a sham-EA group, 35 cases in each one. In the EA group, Tianshu (ST 25) and Fujie (SP 14) were punctured deeply and stimulated with EA (dense-disperse wave, 2Hz/15 Hz, 0. 1 to 1. 0 mA), and Shangjuxu (ST 37) was needled. In the sham EA group, the sites lateral to Tianshu (ST 25) and Fujie (SP 14) were punctured shallowly and stimulated with electricity. The site lateral to Shangjuxu (ST 37) was punctured shallowly. The treatment was given continuously for 8 weeks in the two groups, 5 times weekly in the first 2 weeks and 3 times weekly in the rest 6 weeks. WANG Juyi's meridian examination method was applied to detect the abnormalities of the spleen, stomach and large intestine meridians before treatment, and in 2, 4, 6 and 8 weeks among 70 patients separately. The frequency of complete spontaneous bowel movement (CSBM) every two weeks, meridian abnormal value and the relativity with CSBM change rate were compared in the patients between two groups. RESULTS: Regarding the increase of CSBM frequency, the effect started since the 2nd week in the EA group, with the treatment going on, CSBM frequency was increased apparently (all P<0. 05). In the sham-EA group, after 6 and 8-weeks of treatment, CSBM frequency was increased apparently as compared with that before treatment (all P<0. 05). The increase of CSBM frequency in the EA group was remarkably as compared with the sham-EA group at every time point (all P<0. 05). The abnormal value of the large intestine meridian in 2 weeks of treatment and the values of the stomach and spleen meridians and the relevant meridians in 4 weeks of treatment were all reduced apparently as compared with those in the baseline in the EA group (all P<0. 05). With the treatment time going on, the abnormal reflections on the large intestine and stomach meridians were reduced gradually (all P<0. 05), and the total change rate of abnormalities on the large intestine, stomach and spleen meridians presented the negative correlation with the total change rate of CSBM frequency (P<0. 01, P<0. 05). CONCLUSION: In the EA group, the efficacy on CSBM frequency in severe functional constipation is advantageous and stable as compared with the sham-EA group. Acupuncture at the relevant acupoints of the spleen, stomach and large intestine meridians achieves the definite regulation to the meridian abnormalities. It is discovered that the abnormal changes in the spleen, stomach PMID- 26571894 TI - [Fast acupuncture therapy combined with opposing needling on Daling (PC 7) for 45 cases of heel pain caused by lumbar spinal stenosis]. PMID- 26571895 TI - [Rediscussion on the relationshin between back-shu points and twelve meridians]. AB - In current theory, back-shu points are categorized into the bladder meridian of foot-taiyang, resulting in difficulties in interpretation and ineffective guide for clinical acupuncture. The development of acupuncture theory indicates that the relationship between back-shu points and corresponding meridians is established by manifestation and root cause of meridian, and enriched in Qianjin Yifang (A Supplement to Recipes Worth a Thousand Gold), but it has been categorized into the bladder meridian of foot-taiyang since Waitai Miyao Fang (Arcane Essentials from the Imperial Library) and its influences remain so far. After analysis on this academic development and basis of understanding, it is believed that the problems of back-shu points and twelve meridians are presented with how toselect existing theories; it is proposed that the academic value of relationship between back sha points and twelve meridians should be explored and promoted to establish the theory form and structure relationship. As a result, the theory can be completed to guide the clinical treatment. PMID- 26571896 TI - [Case of chronic diarrhea]. PMID- 26571897 TI - [Effects of acupuncture with different filiform needles on tissues, cells and collagenous fiber of fascia in acupoint area of rats]. AB - OBJECTIVE: To explore the effects of acupuncture with different filiform needles on structure of fascial connective tissues, cellular activity, arrangement and content of collagen fibers in acupoint area of rats. METHODS: A total of 32 SD rats were randomly divided into a blank group, a thin needle group, a medium needle group and a thick needle group, 8 rats in each one. Except for the blank group, rats in the remaining groups were treated with horizontal acupuncture at "Zhongwan" (CV 12) towards Conception Vessel with different filiform needles, and twirling mild reinforcing-reducing method was applied, once a day. Rats in the blank group were treated with identical anesthesia, grasping and fixation. After 3-day intervention, the fascial connective tissue of acupoint area was collected. HE staining, immumohistochemical staining of proliferating cell nuclear antigen (PCNA) and MASSON staining were adopted to observe the morphology of fascial connective tissues, expression of PCNA in cells and arrangement and expression of collagenous fiber. RESULTS: After acupuncture in each group, the consistency of morphology of fascial connective tissues and arrangement of collagenous fiber were changed; the expression of PCNA protein in the fascial connective tissue in each group was significantly increased (P<0. 01, P<0. 05). The area distribution of collagenous fiber were changed, and that in the thin needle group was insignificantly increased compared with that in the blank group (P>0. 05), and that in the medium needle group and thick needle group were reduced compared with that in the blank group (both P<0. 05). CONCLUSIONS: Acupuncture with different filiform needles can change the local tissue morphology of acupoints, strengthen cell activity and adjust the exyression of collagenous fiber protein, which may be one of the cellular biomechanics principles of the acupuncture therapy's "regulating meridians" effects. However, the stimulation is produced by different fifiform needles, and the complex relationships exist between cells and collagen fibers. PMID- 26571898 TI - [Effects of acupuncture at left and right Hegu (LI 4) for cerebral function laterality]. AB - OBJECTIVE: To explore the cerebral function laterality of acupuncture at left and right Hegu (LI 4) by using functional magnetic resonance imaging (fMRI) and provide objective evidences for side selection of Hegu (LI 4) in the clinical application. METHODS: Eighty healthy volunteers were randomly divided into a left acupoint group and a right-acupoint group, and they were treated with acupuncture at left Hegu (LI 4) and right Hegu (LI 4) respectively. After the arrival of qi, the task-state fMRI data in both groups was collected, and analysis of functional neuroimages (AFNI) software was used to perform intra-group and between-group comparisons. After acupuncture, acupuncture feelings were recorded and MGH acupuncture sensation scale (MASS) was recorded. RESULTS: The difference of MASS between the two groups was not significant (P>0. 05). The result of left-acupoint group showed an increased signal on right cerebral hemisphere, while the right acupoint group showed extensive signal changes in both cerebral hemispheres. The analysis between left-acupoint group and retroflex right-acupoint group showed differences in brain areas. CONCLUSIONS: The central effect of acupuncture at left and right Hegu (LI 4) is dissymmetry, indicating right hemisphere laterality. The right lobus insularis and cingulate gyrus may be the key regions in the acupuncture at Hegu (LI 4). PMID- 26571899 TI - [Impacts of the transcutaneous electrical acupoint stimulation on EC50 in the remifentanil inhibition of tracheal intubation response]. AB - OBJECTIVE: To explore the impacts on EC50 in the remifentanil inhibition of tracheal intubation response by the transcutaneous electrical acupoint stimulation (TEAS) at Hegu (LI 4) and Neiguan (PC 6). METHODS: Forty patients with selective surgery undergoing endotracheal intubation with intravenous general anesthesia were divided into I to II degree by the American Society of Anesthesiologists (ASA) and were randomized into an observation group and a control group, 20 cases in each one. Before general anesthesia induction, in the observation group, the transcutaneous electric stimulation was applied to bilateral Hegu (LI 4) and Neiguan (PC 6) for 30 min, with dense-disperse wave, 2 Hz/100 Hz in frequency; in the control group, the sham-stimulation was applied to the acupoints, with the lamp on, but without electric current output. Afterwards, the general anesthesia induction started. When the target concentration of propofol and remifentanil was stabilized at the preset value, the endotracheal intubation was conducted. Dixon sequential method was applied for the determination of ECs in remifentanil inhibition of tracheal intubation response. RESULTS: The level of EC50 in remifentanil inhibition of tracheal intubation response was 3. 46 ng/mL, 95% confidence interval was 2. 80 ng/ml to 4. 27ng/mL in the observation group; those were 4. 18 ng/mL and 3. 30 ng/mL to 5. 29 ng/mL in the control group separately. The differences were significant in comparison of the two groups (P<0. 01). CONCLUSION: TEAS apparently reduces EChe in the remifentanil inhibition of tracheal intubation response by around 17%as. PMID- 26571900 TI - [Treatment of insomnia with shujing massage therapy: a randomized controlled trial]. AB - OBJECTIVE: To compare the differences in the clinical efficacy on insomnia between shujing massage therapy and medication with estazolam. METHODS: Eighty patients of insomnia were randomized into a shujing mass age therapy group (40 cases) and a medication group (40 cases). In the shujing massage therapy group, the spreading massage manipulation was applied along the running course of the gallbladder meridian of foot-shaoyang on the temporal area. The pressing and kneading manipulation was done at Yangbai (GB 14), Benshen (GB 13), Toulinqi (GB 15), Zhengying (GB 17), Chengling (GB 18), Shuaigu (GB 8), and Fengchi (GB 20), etc, 1 min at each acupoint. In the medication group, 1 mg estazolam was taken orally half an hour before sleep. The treatment was given once every day in the two groups. After the continuous treatment for 1 month, every dimensional score and the total score in the Pittsburgh sleep quality index scale (PSQI) and the clinical efficacy were evaluated between the two groups. RESULTS: After the intervention, the each item score of PSQI was improved as compared with that before treatment in the patients of the two groups (all P<0. 05). The differences in sleep time and the time for falling into sleep were not significant between the two groups (both P>0. 05). In the shujing massage therapy group, the scores of sleep quality, sleep efficiency, sleep disturbance and daytime dysfunction, as well as the total score were all lower than those in the medication group (all P<0. 05). The total effective rate was 92. 1% (35/38) in the shujing massage group and was 84. 2% (32/38) in the medication group, indicating the significant difference (P<0. 05). CONCLUSION: Shujing massage therapy achieves the superior efficacy on insomnia compared with the oral administration of estazolam. PMID- 26571901 TI - [Innovation of characteristic medicinal cupping devices]. AB - OBJECTIVE: To compare the differences in the characteristic medicinal cupping therapy between the traditional cupping device and the innovated cupping device. METHODS: Fifty patients of neck and low back pain were selected. The self comparison was adopted. The cupping therapy was applied to the acupoints located on the left or right side with the traditional cupping device and the innovated cupping device. The cupping sites were centered at bilateral Quyuan (SI 13) and Dachangshu (BL 25). The cups were retained for 10 min. The traditional cupping device was the glass with smooth border, 100mL. The innovated cupping device was the vacuum-sucking cup. The operative time, medicinal leakage, comfort and cupping marks were observed for the two different cupping devices. RESULTS: The operative time with the innovated medicinal cupping device was shorter obviously compared with the traditional one at Quyuan (SI 13) and Dachangshu (BL 25, both P<0. 05). The comfort with the innovated medicinal cupping device was remarkably improved as compared with the traditional one at the two acupoints (both P<0. 05). The medicinal leakage was similar between the two different devices during the cupping operation (both P>0. 05). The cupping marks with the innovated medicinal cupping device were much deeper than those with the traditional one after cupping therapy. CONCLUSION: The innovated cupping device is more convenent and comfortable in operation during the characteristic medicinal cupping therapy. PMID- 26571902 TI - [FlU Zhonghua's clinical experience of Fu's subcutaneous needling for cervical spondylosis]. AB - Professor FU Zhonghua's unique clinical experience of Fu's subcutaneous needling (FSN) for cervical spondylosis (CS) is discussed in this paper, which is analyzed from the aspects of recognition of CS pathogenesis, treatment mechanism of FSN, advantage indications of FSN for CS and examples of medical cases. Professor FU introduced the theory of myofascial trigger points (MTrP) into the field of the management of CS. The site of neck MTrP should be carefully examined, and FSN needles for single use are used to sweep the affected area or subcutaneous layer of adjacent upper limb. This method can rapidly improve ischemia and hypoxia state of the relevant muscles and prompt the self-recovery of neck muscles. During FSN treatment, reperfusion approach is recommended to adopt to improve the qi and blood circulation and recovery of neck function. PMID- 26571903 TI - [TCM/aciipuncture therapy and medical insurance support in Switzerland]. AB - Based on the expeienes in th acdemic exchanges in Switzerland and relevant data, the development of TCM/acupuncture in Switzerland, Swiss medical insurance system and the acceptance to TCM/acupuncture were introduced in the paper. The case analysis was applied to explain the reimbursement, proportion and additional conditions of Obligatory Basic Insurance and Supplementary Alternative Insurance on TCM/acupuncture; Additionally, in the paper, the certification and registration from EMR, ASCA and NVS for the TCM physician were introduced, which is required to the recognition by insurance companies. All of these provide the guarantee for the positive development of TCM/acupuncture in Switzerland. PMID- 26571904 TI - [The understanding of Nei Jing theory of "the intersection of Weijin" of academician SHI Xuemin]. PMID- 26571905 TI - [Application of PBL method and LBL method in the teaching of Acupuncutre and Moxibustion]. AB - In order to improve teaching lever and explore teaching approach, the feasibility study on the combination of the problembased learning method CPBL) and the lecture-based learning method (LBL) was conducted in the teaching of Acupuncture and Moxibustion. The 2010 undergraduates in the major of clinical integrated Chinese and western medicine of five years were randomized into a PBL and LBL group and a LEL group. In the first semester, according to the basic teaching requirement, LBL was used to accomplish the teaching of basic theory. In the internship teaching section, the different teaching method was applied. In the PBL and LEL group, PEL was used, and in the LBL group, LBL was given. At the end of semester, the examination results of the theory learning and medical cases learning were evaluated. The questionnaire was summarized in the teachers and students. The final examination result of theory learning was not different significantly between the two groups (P >0. 05), but the result of medical cases learning in the PEL and LEL group was better than that in LEL group (84. 47+/-10. 72 vs 76. 00+/-9. 97, P<0. 05). The questionnaire for the students and teachers indicated that the result of PEL and LEL combined method was higher than that of LEL method (86. 27+/-8. 36 vs 56. 00+/-14. 59, P< 0. 01; 45. 89+/-3. 68 vs 36. 61+/-6. 41, P<0. 0l), indicating that the combined method of PBL and LEL is feasible in teaching of Acupuncture and Moxibustion and the teaching outcome is superior to the simple LBL, which provides the new approach to the teaching reform. PMID- 26571907 TI - [SHAO's five needling therapy from lung for 23 cases of chronic colitis]. PMID- 26571906 TI - [Report quality of randomized controlled trials of moxibustion for knee osteoarthritis based on CONSORT and STRICTOM]. AB - The report quality of randomized controlled trials (RCTs) of moxibustion for knee osteoarthritis (KOA) in China was evaluated by Consolidated Standards for Reporting of Trials (CONSORT) and Standards for Reporting Interventions in Controlled Trials of Moxibustion (STRICTOM). Computer and manual retrieval was used. Four databases of China National Knowledge Infrastructure (CNKD, China Biomedicine (CBM), VIP and WNFANG were searched in combination with manual retrieval for relevant journals to screen the literature that: met the inclusive criteria, and CONSORT and STRICTOM were used to assess the report quality. A total of 52 RCTs were included. It was found that unclear description of random methods, low use of blind methods, no allocation concealment, no sample size calculation, no intention-to-treat analysis,inadequate report of moxibustion details and no mention of practitioners background existed in the majority of the RCTs. Although the quality of RCTs of moxibustion for KOA was generally low, reducing the reliability and homogeneous comparability of the reports ,the quality of heat-sensitive moxibustion RCTs was high. It was believed that in order to improve the reliability and quality of RCTs of moxibustion, CONSORT and STRICTOM should be introduced into the RCT design of moxibustion and be strictly performed. PMID- 26571908 TI - [Rules of acupoints combination of ancient acupuncture for Xiaoke based on data mining technology]. AB - The rules of acupoints combination of ancient acupuncture for Xiaoke are mainly explored. By retrieval on ancient literature, the database of acupuncture and moxibustion for Xiaoke is established; based on the database, association analysis between acupoints and symptoms is performed. According to the association analysis in 5 databases of Xiaoke database, Xiaoke database of kidney deficiency, Xiaoke-database of dry mnouth and thirst, Xiaoke database of difficult urination, Xiaoke database of drinking addiction, the results are mainly characterized with symptom differentiation combination, distal-local combination, local combination and front-back combination, which can nourish yin and clear heat. It is believed that establishment of TCM ancient literature database and exploration of data mining technology is a potential research orientation. PMID- 26571909 TI - [Case of retrocollis spasmodic torticollis]. PMID- 26571910 TI - [Characteristics of acupoints selection of moxibustion for primary dysmenorrhea based on data mining technology]. AB - By using data mining technology, the characteristics of acupoints selection of modern moxibustion for primary dysmenorrhea (PD) were analyzed. The modern literature regarding moxibustion for PDl was coll6cted~ from a comprehensive retrieval in Chinese Biomedical Medicine (CBM), China National Knowledge Infrastructure (CNKI), VIP and PubMed. The prescription database of moxihustion was established, and the association rule4 method of data mining technology was adopted to analyze characteristics and rules of acupoints selection of modern moxibustion for PD. As a result, a total of 35 acupoints were involved with a total frequency of 399. The acupoints, with higher selected frequency included Guanyuan (CV 4, 90 times), Sanyinjiao (SP 6, 47 times), Shenque (CV 8, 43 times), Zhongji (CV 3, 3 times) and Qihai (CV 6, 28 tirmes); the ratio of yin-meridian acupoints to1 yang-meridian acupoints was approximately 341; the utilization of the specific acupoints accountedfor68. 6% (24/35); the crossing acupoints were used mostly (203 "times), featured with high acupoints selected, especially Guanyuan (CV 4), Sanyinjiao CSP 6) and Zhongji (CV 3); the front-mu points (130 times), he-sa points (19 times) and lower he-sea points (18 times) were frequently used. The results reveal thiat acupoints selection of moxibustion of PD focuses on the local acupoints and comnbination with the distal acupoints. The yin-meridian acupoints are preferred and the specific acupoints are the main part of the prescription. This conclusion can also be used to optimize the choosing of acupoints in clinic. PMID- 26571911 TI - [Case of Meige's syndrome]. PMID- 26571912 TI - [Condition and effectiveness evaluation of acupuncture for smoking cessation]. AB - The efectienes of acpuncture for smoking cessation was systematically evaluated in this paper. By using computer retrieval in Chinese national knowledge infrastructure (CNKI), WANFANG database, VIP database, PubMed, ScienceDirect and Springer, the randomized controlled trials (RCTs) regarding acupuncture for smoking cessation from January of 1983 to December of 2013 were collected; by using Table of Standardized Report Factors for Acupuncture RCTs, each inclusive RCT was evaluated; and by using RevMan 5. 2 software, the Meta-analysis was performed. Totally 24 RCTs were included, involving 3084 cases of smoking. The result of literature quality assessment showed that the average score was 25. 71 points without low-quality RCT which had a score of less than 16 points. The Meta analysis showed that acupuncture could significantly increase the short-time abstinence rate [RR=1. 48, 95% CI (1. 18,1. 84), Z=3. 47, P<0. 0005] and number of cigarettes smoked daily [RR=4. 35, 95% CI (2. 03, 6. 66), Z=3. 68, P<0. 001] and FTND [RR=2. 37, 95% CI (1. 88, 2. 86), Z= 9. 44, P<0. 00001], however, it could not increase the long-time abstinence rate [RR=1. 40, 95% Cl (0. 90, 2.17), Z=1. 49, P>0. 05]. Compared with other treatment, acupuncture has positive advantages on short-time abstinence rate, however, its effect on long-time abstinence rate needs to be verified by high-quality, large-sample and multi center RCT in the future. PMID- 26571913 TI - [Nerve root infiltration combined with multi-needling in rows acupunc ture for 60 cases of lumbar disc herniation]. PMID- 26571914 TI - [Discussing the nature of the qi and meridian from the perspectives of modern science]. PMID- 26571915 TI - [Current research situation and prospect of auricular acupuncture for epilepsy]. AB - Epilepsy is a group of chronic diseases characterized by recurrent and transient brain dysfunction induced by abrupt and intermittent abnormal discharge of neurons in the brain, which is difficult to be cured. Thee auricular concha are is he zone of visera in TCM auricular points, but also the innervating area of the auricular brach of the vagus nerve. Auricular acupuncture, as a special treatment, has superior therapeutic effect for epilepsy. In recent years, remarkable progress has been made in the theoretical basis and clinic application of auricular acupuncture for epilepsy, and the ear-vagus percutaneous electrical stimulation apparatus (auricular acupuncture apparatus) is developed for clinical trial researches. From the basic study to clinical research of auricular acupuncture for epilepsy, the epilepsy pathogenesis as well as the intervention pathway and clinical efficacy of auricular: experimental support and rich clinical experience for auricular acupuncture apparatus. PMID- 26571916 TI - The Board, the Journal...and clods..(the lump of earth type)! PMID- 26571917 TI - SADA position statement: Dental amalgam. PMID- 26571918 TI - Fifty years of South African Orthodontics celebrated in style!! PMID- 26571919 TI - Zuleika Nortje. 25 January 1964-15 August 2014. PMID- 26571920 TI - David Anderson. 18 October 1946-22 September 2014. PMID- 26571921 TI - Tony Garwood. 6 March 1950-1 September 2014. PMID- 26571922 TI - HIV-associated salivary gland enlargement: a clinical review. AB - Salivary gland disease is well established as an important HIV associated oral lesion. It manifests as salivary gland swelling involving one or both parotid glands with or without xerostomia. In the context of HIV, the swelling may be due to a wide spectrum of pathological conditions that include reactive or inflammatory disorders, acute and chronic infections, and neoplasms. This paper reviews the epidemiology, pathogenesis, clinical presentation, aspects of diagnosis and management of HIV associated salivary gland enlargement, in particular parotid gland enlargement, due to benign lymphoepithelial cysts (BLEC). Parotid gland enlargement is typically an early manifestation in the HIV positive patient and should alert healthcare professionals to the likelihood of HIV infection. FNAC of the parotid gland is required to confirm the diagnosis and instituting HAART forms an important part of the management. There is a shift away from surgery in the treatment of this essentially 'benign' condition. PMID- 26571923 TI - Reciprocating instruments in endodontics: a review of the literature. PMID- 26571924 TI - The value of three-dimensional imaging in the detection of a case of double pathology in the right maxilla of a patient. AB - A 14-year-old Black female was referred for management of an asymptomatic swelling in her right maxilla. The lesion measured 3cm across, was localised lateral to the right ala of the nose, felt bony hard in some areas and soft in others, and was continuous with the maxillary buccal plate. It occupied the right anterior vestibule but there was no palatal expansion. A panoramic radiograph showed a radiopaque lesion surrounded by a radiolucent periphery, but a lack of clarity prompted a computed tomographic scan. The latter revealed two separate lesions, one buccal and one palatal. The buccal lesion showed a well-defined radiolucency containing a radiopaque mass while the palatal lesion showed a small cystic area attached to the neck of an impacted tooth. Differential diagnoses of calcifying odontogenic cyst, adenomatoid odontogenic tumour or ameloblastic fibroodontoma and dentigerous cyst or odontogenic keratocyst were considered for the two lesions respectively. Enucleation of the buccal lesion and removal of the impacted tooth together with the overlying cyst presented no problem. Histologically the lesions were respectively diagnosed as a calcifying odontogenic cyst and a dentigerous cyst. Histological features are briefly described together with an historical review of the calcifying odontogenic cyst which has evoked much interest and controversy over the past five decades. PMID- 26571925 TI - Plunging ranula: an unusual multilocular presentation. AB - A 32-year-old male patient who was HIV positive presented at the Wits Oral Health Centre complaining of a large swelling of the left submandibular region of three years' duration. The swelling was nontender, soft and doughy on palpation and appeared to be crossing the midline. Bilateral submandibular and submental lymphadenopathy was present. Intraorally the lesion caused considerable elevation of the floor of the mouth and impaired the flow of saliva. Fluid from the lesion was aspirated and the patient sent for MRI examination. These images revealed a multilocular cystic lesion causing disruption of the mylohyold muscle. The aspirate consisted of a thick, bloody fluid which tested positive for salivary amylase. A provisional diagnosis of plunging ranula was made. The multilocular nature of the lesion seen on MRI prompted a more extensive surgical approach in order to prevent recurrence. Consequently the sublingual gland was removed via an intraoral approach while the multilocular cyst was dissected by means of a submandibular approach in order to effect complete removal. Microscopic examination of the submitted specimen confirmed the clinical diagnosis of a plunging ranula. PMID- 26571926 TI - Oral medicine case book 64: Some aspects of the pathophysiology of angioedema with special reference to the upper aerodigestive tract. AB - Angioedema refers to a localized oedematous swelling of subcutaneous or submucosal tissues, caused by dilatation and increased permeability of blood vessels, usually mediated either by histamine or by bradykinin. Deficiency or loss of functional activity of the complement component C1 esterase inhibitor (C1 INH) affects multiple systems, including the kallikrein-kinin, complement, coagulation and fibrinolytic pathways, and in the context of angioedema, the result is increased production and release of bradykinin and other vasoactive substances such as C3a. Owing to impairment of C1-INH, factors Xlla and kallikrein, by a positive feedback mechanism, bring about persistent activation of the kallikrein-kinin pathway with amplification of production of bradykinin, resulting in angioedema. Histamine can cause histaminergic angioedema. As the name implies, this oedema is caused by degranulation of mast cells/basophils as a result of an IgE-dependant allergic reaction to extracts of food, drugs, infectious agents, or to physical stimulation; or as the result of direct degranulation of mast cells/basophils independently of IgE, caused by releasing agents such as opiates, antibiotics or radiocontrast media. As dental, oral and maxillofacial operative procedures may trigger the development of angioederria in susceptible individuals, the dental practitioner should be familiar with its PMID- 26571927 TI - Maxillo-facial radiology case 125. PMID- 26571928 TI - Transcultural and language barriers to patient care. PMID- 26571929 TI - Partnerships--A Matter of Values. PMID- 26571930 TI - A Storm Rallies a Community And Its Partners. PMID- 26571931 TI - PARTNERS IN LOUISIANA. Missions of Care and Education Come Together. PMID- 26571932 TI - New Models Of Community Care. PMID- 26571933 TI - Pathways Model Aligns Care, Population Health. PMID- 26571934 TI - Determinants of Health Are the Building Blocks. PMID- 26571935 TI - 'Heath Partners' Are Venture's Cornerstones. PMID- 26571936 TI - A MODEL FOR VOLUNTEER CAREGIVING. Intergenerational Service Learning. PMID- 26571937 TI - Health Care Competitors Pull Together in Montana. PMID- 26571938 TI - Community Center Reflects Neighborhood Needs. PMID- 26571939 TI - Chaplains' Skills Support Whole-Person Care. PMID- 26571940 TI - A VISION FOR THE FUTURE: Maintaining Ministry and Identity. PMID- 26571941 TI - FIVE YEARS OF SPONSORSHIP: Ministerial Juridic Person Cultivates Community. PMID- 26571943 TI - HEA LTH CARE DELIVERY AND VALUE COMMITMENTS. PMID- 26571942 TI - NEEDS ASSESSMENTS SHOW THE IMPORTANCE OF PARTNERSHIPS. PMID- 26571944 TI - PUBLIC PRAYER IN A PLURALISTIC WORLD. 'How Catholic Should Our Prayer Be'? PMID- 26571945 TI - LONG-TERM TIES AID POPULATION HEALTH. PMID- 26571946 TI - Thinking of Global Aid as Population Health. PMID- 26571947 TI - Building Community Through Forgiveness and Celebration. PMID- 26571948 TI - Shortage of acute inpatient mental health. PMID- 26571949 TI - Welsh government launches plan to reduce suicide and self-harm. PMID- 26571950 TI - Quarter of local authorities 'ignore' looked after children's mental health. PMID- 26571951 TI - The changes the government is bringing to health and welfare benefits present challenges, but also opportunities. PMID- 26571952 TI - Breadwinners. PMID- 26571953 TI - Sporting chance. PMID- 26571954 TI - Expecting change. PMID- 26571955 TI - Welfare writes. PMID- 26571956 TI - Outside the box. PMID- 26571957 TI - The bigger picture. PMID- 26571958 TI - A child in mind. PMID- 26571959 TI - Personal wellbeing Network: From a research concept to practice development. PMID- 26571960 TI - Evidence Doctor's orders. PMID- 26571961 TI - Animal instincts. PMID- 26571962 TI - Getting back into work after experiencing mental illness can be difficult. PMID- 26571963 TI - Therapeutic alliances between service users and psychologists could be under threat from cuts. PMID- 26571965 TI - HOME COMFORTS. PMID- 26571964 TI - Outcomes of cognitive analytic therapy delivered by trainees. PMID- 26571966 TI - On the record. PMID- 26571967 TI - AHRA Member Survey Results: 2015. PMID- 26571968 TI - Regulatory Changes ahead for Medical Imaging. PMID- 26571970 TI - Value-Based Customer Service. PMID- 26571969 TI - Site Neutral Payments: An Overview. AB - A site neutral payment policy would entail CMS paying the same rate for the same healthcare service regardless of the location in which the service is provided. From the government's perspective, the reason behind this policy is potentially billions of dollars in savings. The rationale for using various payment systems is that there are different costs associated with providing healthcare services in different locations. Each payment system has a separate methodology for determining rates for services based on these costs. Hospitals may choose to prepare early for the inevitable through accurate cost reporting, shifting certain ancillary services to more appropriate outpatient, off site locations, and participating in the Medicare Shared Savings Program. PMID- 26571971 TI - The Organizational Impact of Presenteeism. AB - Presenteeism is defined as the act of going to work when sick. Occupations that have a high degree of human interaction, such as healthcare providers and educators, have been found to exhibit the highest rates of presenteeism. The incidence of presenteeism among physicians has been reported to be as high as 90%. Various reasons are given for choosing to work when sick including a commitment to patients, unwillingness to burden coworkers, competition, and the lack of a suitable replacement. The topic is important in the field of radiology given presenteeism has been shown to reduce worker productivity, increase the likelihood of patient errors, and result in negative long term health effects. Radiology managers can discourage presenteeism by changing attitudes toward the use of sick leave and through health promotion programs to encourage healthy lifestyles. PMID- 26571973 TI - What's in Your Gemba? PMID- 26571972 TI - Protocol to Clear Cervical Spine Injuries in Pediatric Trauma Patients. AB - In order to minimize the amount of ionizing radiation to which young trauma patients are subjected, a cervical spine clearance project was implemented. The aim was to increase the number of pediatric trauma patients clinically cleared and decrease the number of such patients undergoing cervical spine CT imaging when they met clinical clearance criteria. To accomplish the goals, a brief education program about the epidemiology of pediatric cervical spine injuries, radiation exposure risks, and safe and effective means available for cervical spine clearance to pediatric trauma providers was delivered. This was made possible through funds awarded by the AHRA & Toshiba Putting Patients First grant. Mean knowledge scores after the program increased significantly for all groups of providers. This study showed that after implementation of the cervical spine clinical clearance protocol, there was an increase of 35.7% in the number of patients who were clinically cleared based on the protocol's criteria. Additionally, a 24%. decrease was seen in the number of pediatric patients undergoing CT scans of the cervical spine when they met criteria for clinical clearance of the cervical spine. PMID- 26571974 TI - Process Improvement: Customer Service. AB - Utilizing the comment section of patient satisfaction surveys, Clark Memorial Hospital in Jeffersonville, IN went through a thoughtful process to arrive at an experience that patients said they wanted. Two Lean Six Sigma tools were used- the Voice of the Customer (VoC) and the Affinity Diagram. Even when using these tools, a facility will not be able to accomplish everything the patient may want. Guidelines were set and rules were established for the Process Improvement Team in order to lessen frustration, increase focus, and ultimately be successful. The project's success is driven by the team members carrying its message back to their areas. It's about ensuring that everyone is striving to improve the patients' experience by listening to what they say is being done right and what they say can be done better. And then acting on it. PMID- 26571976 TI - Translating Physiology for wider applications. PMID- 26571975 TI - The Good Old Days. PMID- 26571977 TI - Intra-class Correlation among Heart Rate Variability analysis softwares across different physiological postures. AB - Heart rate variability (HRV) is a simple technique which helps to assess the alterations in cardiac autonomic activity in healthy and diseased individuals. It is performed in various research centers using different hardwares and softwares. Hence, HRV reports generated from these centers cannot be compared unless their HRV data acquisition systems and the HRV analysis softwares correlate or agree with each other. In this study, Intra-class correlation coefficient test was done to see the extent of correlation among three HRV analysis softwares used by researchers in India, namely, (1). Kubios HRV version 2.0, Department of Physics, University of Kuopio, Finland, (2). HRV soft 1.1 Version, Autonomic Function Laboratory, Department of Physiology, All India Institute Of Medical Sciences (AIIMS), New Delhi and (3). Nevrokard aHRV 12.0.0. (Medistar Inc., Slovenia). Following standard guidelines, five minutes ECG data was acquired from twenty six healthy volunteers in supine, sitting and standing positions. The R-R intervals were computed from the ECG data and was subjected to short-term HRV analysis using the above three softwares. Statistical analysis revealed a highly significantly (p<0.001) perfect positive correlation (ICC values > 0.8) among the three softwares for both time domain and frequency domain parameters in the three different positions. Hence, it may be proposed that the interpretation of short term HRV reports generated by the three softwares, across laboratories, can be equated. PMID- 26571978 TI - Heart rate variability changes during stroop color and word test among genders. AB - Stress is the reaction of the body to a change that requires physical, mental or emotional adjustments. Individual differences in stress reactivity are a potentially important risk factor for gender-specific health problems in men and women. The Autonomic regulation of the cardiovascular system is most commonly affected by stress and is assessed by means of short term heart rate variability (HRV).The present study was undertaken to investigate the difference in the cardiovascular Autonomic Nervous System response to mental stress between the genders using HRV as tool. We compared the mean RR interval, Blood pressure and indices of HRV during the StroopColor Word Test (SCWT).Twenty five male (Age 19.52+/-0.714, BMI 22.73+/-2 kg/m2) and twenty five female subjects (Age 19.80+/ 0.65, BMI 22.39+/-1.9) performed SCWT for five minutes. Blood Pressure (SBP p<0.01, DBP p<0.042) & Mean HR (p<0.010) values showed statistically significant difference among the genders. HRV indices like LFms2 (p<0.051), HF nu (p<0.029) and LF/HF ratio (p<0.025, p<0.052) show statistically significant difference among the genders. The response by the cardiovascular system to a simple mental stressor exhibits difference among the genders. PMID- 26571979 TI - Evaluation of arterial stiffness in elderly with prehypertension. AB - Arterial stiffness is an independent marker of cardiovascular (CV) risk that increases with age. Hypertension is known to augment the age-related arterial stiffness. The influence of prehypertension on arterial stiffness in elderly is least studied. The present study was aimed to assess the age-associated arterial stiffness in the elderly subjects with prehypertension. A cross sectional study was conducted on elderly subjects aged 60-80 years with prehypertension (n=25) and age-matched normotensives (n=20). The arterial stiffness was assessed by measuring: (1) Pulse wave velocity between carotid-femoral (c-f PWV) and brachial ankle (baPWV) (2) Augmentation index (AIx) and (3) Arterial stiffness index (ASI) at brachial (bASI) and tibial artery (aASI). We found a significant increase in c f PWV (p<0.001), baPWV (p<0.001) and AIx@75 (p<0.001) in prehypertensives than normotensive elderly individuals. There was no significant difference in the ASI at brachial and tibial arteries. The significant predictor of c-f PWV and Alx@75 was SBP (beta=0.584, p=0.04; beta=0.700, p=0.019 respectively), and aASI was PP (beta=0.493, p=0.049). These findings show an augmentation of age-related arterial stiffness in elderly with prehypertension. PMID- 26571980 TI - Reflex hypertensive response induced by capsaicin involves endothelin-dependent mechanisms. AB - Capsaicin, a nociceptive agent produces triphasic pressure response in rats. The mechanisms underlying capsaicin-induced pressure responses are not clear. Therefore, the present study was undertaken to determine the mechanisms involved in capsaicin - induced pressure responses. The trachea, jugular vein and femoral artery were cannulated in anaesthetized rats. Capsaicin (10 ug/kg; i.v) - induced reflex changes in the blood pressure, respiratory excursions and ECG were recorded before/after vagotomy in the absence/presence of antagonists. Capsaicin produced the triphasic pressure response characterized by immediate fall, recovery (intermediate phase) and delayed progressive fall. After vagotomy, the immediate hypotension was abolished and the intermediate pressure response was potentiated as a hypertensive response while the delayed hypotensive response persisted. The time-matched heart rate changes (bradycardia) and respiratory changes (tachypnea in delayed phase) were abolished after vagotomy. Pretreatment with endothelin receptor antagonist (bosentan; 10 mg/kg) blocked the capsiaicn induced intermediate hypertensive response in vagotomised animals but not the delayed hypotension. Pretreatment with nitric oxide synthase (NOS) inhibitor (L NAME; 30 pg/kg), prostaglandin synthase inhibitor (indomethacin; 10 mg/kg) and kinin synthase inhibitor (aprotinin; 6000 KIU) did not block the delayed hypotensive response. These results demonstrate that capsaicin-induced intermediate hypertensive response involves endothelin-dependent mechanisms and the delayed hypotensive response is independent of nitrergic, prostaglandinergic or kininergic mechanisms. PMID- 26571981 TI - Cardiac hemodynamic profile and its correlates by Impedance plethysmography in normal individuals of Central India. AB - Evaluation of hemodynamic profile by impedance plethysmography (IPG) provides functional expression of cardiovascular performance with efficacy of treatment. Objective of this study was to establish normative hemodynamic parameters by IPG. In this cross-sectional study hemodynamic parameters including cardiac output (CO), Stroke volume (SV), left ventricular ejection time (LVET), impedance (Zo) Cardiac index (CI) and Stroke index (SI) of 50 normal individuals in mean age 38.9+/-15.2 years were evaluated. Mean CO and CI were 4.9+/-0.8L/min and 3.3+/ 0.7 L/min/m2 respectively. A negative linear co-relation of CI with increasing age and body fat mass was observed. Mean LVET was 336+/-33ms with a significant positive linear correlation (r = 0.46) with advancing age and body fat mass while a negative linear correlation with BSA. To conclude preliminary normative data of cardiac parameters using IPG, in subjects of central India of different age groups has been presented. PMID- 26571982 TI - Salt taste threshold and its relation to blood pressure in normotensive offspring of hypertensive parents amongst indian adolescents. AB - To study Salt Taste Threshold (STT) and its relation to Blood pressure (BP) in normotensive adolescents, age and BMI matched 60 subjects of 18-20 years were segregated on basis of family history of hypertension, documented risk factor for development of hypertension. Student's unpaired t-test showed that STT and BP values were significantly higher in Hypertensive offspring group than Control. Pearson Chi Square test with 60 mM Nacl as cut-off point showed highly significant association of STT in hypertensive offspring group. A significant positive correlation was found between STT and BP by Pearson correlation analysis. Family history of hypertension is strongly linked to reduced salt taste sensitivity. This reinforces rationale that both conditions may be genetically linked though causal relation cannot be established. STT can be used as significant marker to screen 'salt sensible' subjects that eventually will develop hypertension and can be advised healthy habits early or prophylactically treated. PMID- 26571983 TI - Effect of controlled deep breathing on psychomotor and higher mental functions in normal individuals. AB - OBJECTIVE: The present study was conducted to assess the effect of controlled deep breathing on psychomotor and higher mental functions. METHODS: 100 normal healthy subjects (52 females and 48 males, age range - 18 to 25 years) participated in the study. Each subject acted as his or her own control. Six weeks course of controlled deep breathing i.e. 5 seconds of maximal inhalation followed by 5 seconds of maximal exhalation, once a day for ten minutes, six days a week was arranged. (i) Letter cancellation test (ii) Rapid fire arithmetic deviation test and (iii) Playing card test were conducted before and after six weeks of controlled deep breathing practice for evaluating psychomotor and higher mental functions. RESULTS: No significant gender difference was observed on comparing baseline readings between female and male subjects. After six weeks of controlled deep breathing practice letter cancellation test time significantly reduced (P<0.001), rapid fire arithmetic deviation test and playing card test scores (P<0.001) significantly improved. Letter cancellation test score didn't show improvement. CONCLUSION: The results suggest that a short, simple breathing practice can be helpful in improving cognitive processes. PMID- 26571984 TI - Adherence To JNC-VII and WHO-ISH guidelines of antihypertensive medications prescribed to hypertensive patients with co-morbid conditions. AB - The present study aims at comparing the prescribing pattern of antihypertensive drugs in essential hypertension with specific co-morbid conditions with JNC-VII and WHO-ISH guidelines. Adult patients of both sex, who were attending medicine OPD of Shri Krishna Hospital, Karamsad, Gujarat since last 6 months and being prescribed antihypertensive drug/s for hypertension, were selected for the study. Hypertensive patients with co-morbities diabetes mellitus, ischemic heart diseases, congestive heart failure, and chronic renal diseases were included in the study. Adherence to JNC-VII guideline and WHO-ISH guidelines with respect to prescribing antihypertensive drugs in patients with diabetes mellitus were found to be 97% and 40.81% respectively, while it was found to be 72.27% to both the guidelines in patients with IHD. Similarly in cases of hypertension with CHF, adherence to prescribing antihypertensive were found to be 93.62% and 38.30% respectively, whereas for CKD patients, adherence to both guidelines was found to be same i.e. 33.33%. There is need of following such authentic guidelines in managing hypertension like chronic disease since these guidelines are based on various clinical trials and successful attainment of target BP in patients will be much easier by implementing them. PMID- 26571985 TI - Different anthropometric adiposity measures and their association with cardiovascular disease risk factors in middle aged women. AB - A cross sectional study of 136 women age group40-55 years was conducted to study which anthropometric measure had the strongest association with cardiovascular disease risk factors in middle aged women. In accordance with their BMI measurement subjects were divided into three groups namely: Normal weight (Group1) BMI 18.5-24.9 kg/m2, Overweight (Group2) - 25 kg/m2 - 29.9 kg/m2, Obese (Group3) - BMI > 30 kg/m2. Each group was further divided into premenopausal and postmenopausal women BMI, WHR, WHtR, SBP, DBP were recorded. TG, TC, HDL and FBS values were estimated. Results showed that both pre and post menopausal middle aged obese women with higher BMI, WHR and WHtR have more chances of having cardiovascular diseases. BMI, WHR and WHtR are theeasy and practical methods to diagnose obesity and together can be used as simple measures to predict cardiovascular risk factors in middle aged women. PMID- 26571986 TI - Association of ABO blood group and breast cancer in Jodhpur. AB - There is a large amount of evidence that the ABO blood group system may play a role in disease etiology. However, in relation to breast cancer, these findings are inconsistent and contradictory. Present study was conducted for analysis to access ABO blood groups potential role of in breast carcinoma. The study was conducted on 206 clinically diagnosed breast cancer patients from Radiotherapy Department of Mathura Das Mathur Hospital in Jodhpur, from September 2006 to December 2007. The standard agglutination test was used to determine the blood groups. Association of ABO blood groups and risk of breast cancers was found out with Odd Ratios (ORs) with 95% Confidence Interval (CI). In reference of proportion of breast cancer in blood group AB [OR 1 with 95% CI 0.476 to 2.103), the breast carcinoma in blood group A [OR 7.444 with 95% CI 4.098 to 13.5222) was found at 7.4 times at higher risk than in blood group 'AB'. Breast cancer was found minimum in blood group 'AB' and maximum in blood group 'A'. PMID- 26571987 TI - Holy basil (Ocimum sanctum Linn.) leaf extract enhances specific cognitive parameters in healthy adult volunteers: A placebo controlled study. AB - INTRODUCTION: Ocimum sanctum (OS), known as Holy basil, has been documented to possess neuroprotective, cognition-enhancing and stress relieving effects in animal models. However there is paucity of clinical studies to document these effects. MATERIALS AND METHODS: Effect of OS on parameters related to cognition and stress in humans was evaluated with administration of 300 milligram capsules of ethanolic leaf extracts of Ocimum sanctum (EtOS) or placebo per day, over 30 days. RESULTS: Intra-group comparison of Sternberg and Stroop test showed improvement in both the placebo and EtOS groups, however, the improvement stabilized after day 15 in the placebo group. Intergroup comparison revealed a significant improvement of the following cognitive parameters in the EtOS as compared to the placebo: reaction time (RT) and error rate (ER) of Sternberg test, RT of neutral task of Stroop, RT and ER of interference task of Stroop. The intra-group comparison of P300 latency, salivary cortisol, and State-Trait Anxiety Inventory showed improvement over time in the EtOS group alone, though the inter-group difference was significant in the P300 latency alone. There were no changes in heart rate (HR), AHR, or galvanic skin response (GSR) or AGSR. CONCLUSION: Ocimum sanctum leaf extract seems to have potential cognition enhancing properties in humans. PMID- 26571988 TI - Effect of peanut powder (Arachis hypogeae L., 1753) on zootechnic parameters and sex inversion in catfish Clarias gariepinus. AB - Benin is currently experiencing an overexploitation of piscatorial resources; this requires the research of endogenous means to increase the biomass of fish produced thanks to fish farming activities. The present study intends to improve the zootechnic performances and inverse the sex in catfish Clarias gariepinus. Therefore, 240 larvae obtained from artificial reproduction were used for this study. Three different feed were tested. The control feed (TO) was without peanut powder; contrary, the two experimental feeds were containing the powder at the rates of 10% (T1) and 20% (T2). The best growth of 94.51+/-27.14 g was recorded with the treatment T2 and 71.32+/-25.58 g from treatment T1 and finally 54.83+/ 22.19 g from the control group. The sex inversion rate varied from 50% in the control group to 66.13% in lot 1 then 80.13% in lot 2. However, survival rates were low and varied from 26.25% for T2, to 30% in TO then 42.5% in T1. This study permitted to get better results about the zootechnic parameters and the sex inversion in Clarias gariepinus at incorporation rates of 10% and 20% of peanut powder "Arachis hypogeae." PMID- 26571989 TI - Antioxidant effect of aqueous extract of sumac (Rhus coriaria L.) in the alloxan induced diabetic rats. AB - In this experimental study, 30 adult male Wistar rats divided into 5 groups (n=6). Experimental rats were treated with one intraperitoneal injection of 120 mg/kgbw Alloxan monohydrate alone or in combination with 28 days of oral administration with aqueous extract of Rhus coriaria (50, 100 and 250 mg/kgbw) while the control rats received normal saline. At the end of the study, blood glucose, malondialdehyde concentration and catalase activities of kidney and liver tissues were determined. Treatment with Rhus coriaria extract resulted in a significant reduction in blood glucose, and the liver and kidney tissue contents of malondialdehyde in comparison to diabetic group (P<0.05). Furthermore, diabetic group treated with extract showed a significant increase in catalase activities of the liver and kidney (P<0.05). The present study showed that Rhus coriaria could be effective in decreasing diabetic complication and this effect is attributed to the antioxidant activity of the plant. PMID- 26571990 TI - Role of Vitamin-D in the prevention and treatment of Alzheimer's disease. AB - Alzheimer's disease is the most common form of age related cognitive impairment. Aim of the present study was to see the effect of vitamin D on cognitive function in elderly. The study was conducted in Department of Physiology, King George's Medical University (KGMU). A total of 80 subjects were enrolled based on Mini Mental State Examination (MMSE) score < 24 and vitamin D deficiency. They were divided into two groups as Group A (case) and Group B (control), each group having 40 subjects. Intervention (Vitamin D supplementation) was given in Group A. The assessment of dementia was done by Mini Mental State Examination (MMSE) score. Every subject was clinically evaluated and estimation of vitamin D was done by direct ELISA kit. Gender, weight, height, BMI, residence and education were also similar between two groups. A significant (p=0.0001) change in MMSE score was observed in both Group A and Group B from baseline to 3 & 6 months and from 3 to 6 months, however, mean change was higher in Group A than Group B. In conclusion, vitamin D supplementation caused significant improvement in the cognitive performance in subjects with senile dementia. PMID- 26571991 TI - Bone density benefits with periodic fluid redistribution during diminished muscular activity in humans. AB - OBJECTIVE: Bone loss is an established reaction to diminished muscular activity (Hypokinesia; HK). It has been assumed that periodic fluid redistribution (PFR) could contribute to vascular volume. The fluid volume expansion would then increase tissue perfusion. We hypothesized that chronic PFR could contribute to or increase bone density during HK. Therefore we investigated the potential benefits of bone density with chronic PFR during HK. METHODS: Studies were conducted on 40 male volunteers. They were equally divided into four groups: active control subjects (ACS), hypokinetic subjects (HKS), periodic fluid redistribution control subjects (PFRCS) and periodic fluid redistribution hypokinetic subjects (PFRHS). The density of lumbar vertebrae (Ll-L4), ulna and radius, tarsal and metatarsal, tibia and fibula were measured during pre experimental period of 390 days and experimental period of 360 days. RESULTS: Density of lumbar vertebrae (L1 -L4), ulna and radius, tarsal and metatarsal, tibia and fibula increased (p<0.05) in the PFRHS group compared to the HKS group. Density of lumbar vertebrae (L1-L4), ulna and radius, tarsal and metatarsal, tibia and fibula decreased (p<0.05) in the HKS group compared to their pre experimental levels and the values in the other groups. In the PFRCS group lumbar vertebrae (L1-L4), ulna and radius, tarsal and metatarsal, tibia and fibula density were improve much less than in the PFRHS group. Bone density was not affected in the ACS group compared to their pre-experimental levels. CONCLUSION: The current study shows that bone density increases with chronic PFR suggesting potential benefits of bone density with chronic PFR during diminished muscular activity. PMID- 26571992 TI - Faculty perceptions of the strengths, weaknesses and future prospects of the current medical undergraduate experimental physiology curriculum in Gujarat, India. AB - Over the past several years, an opinion has emerged in India that the current practical curricula in medical schools fail to meet many of the objectives for which they were instituted. Hence, this study has assessed the perception of physiology faculty members regarding the current experimental physiology curriculum in one Indian state, Gujarat. The faculty were of the opinion that many of the topics currently taught in experimental physiology (amphibian nerve muscle and heart muscle experiments) were outdated and clinically irrelevant: Therefore, the faculty advocated that duration of teaching time devoted to some of these topics should be reduced and topics with clinical relevance should be introduced at the undergraduate level. The faculty also felt that more emphasis should be laid on highlighting the clinical aspect related to each concept taught in experimental physiology . Moreover, a majority of faculty members were in favour of replacing the current practice in Gujarat of teaching experimental physiology only by explanation of graphs obtained from experiments conducted in the previous years, with computer assisted learning in small groups. PMID- 26571993 TI - Test-retest reliability of a portable gas analysis system under free living conditions. AB - INTRODUCTION: K4b2 (COSMED Srl Italy) is a portable device that is considered valid and reliable for measuring oxygen uptake (VO2) and carbon dioxide production (VCO2) under laboratory conditions. OBJECTIVES: Evaluate the test retest reliability of K4b2 during walking, stair climbing and descending stairs under free living conditions. METHODS: Twelve participants completed two self selected comfortable paced walking tests and 20 participants completed two self selected comfortable paced stair climbing and descending tests. VO2 and VCO2 were measured during the tests using K4b2. RESULTS: ICCs for VO2 (ICC & 95% Cl: 0.91, 0.72-0.97) and VCO2 (0.91, 0.72-0.97) of walking demonstrated high reliability whereas reliability was moderate for stair climbing (VO2: 0.82, 0.6-0.93; VCO2: 0.73, 0.44 - 0.88) and low for descending stairs (VO2: 0.67, 0.33-0.85; VCO2: 0.51, 0.1-0.77). CONCLUSION: K4b2 is a highly reliable device for VO2 and VCO2 measurement during self-paced walking in free living environment. PMID- 26571994 TI - Silence in a Spiritual Master increases vagal tone during two meditative states: A single case study. PMID- 26571995 TI - The Bright Spotlight on Pro Football Concussions. PMID- 26571996 TI - Choosing the Best Confined Space Gas Detector. PMID- 26571997 TI - Creating a Step Change in Your BBS Process Through Big Data. PMID- 26571998 TI - Behavior-Based Safety Programs--Should They Be Implemented? PMID- 26571999 TI - When Overfamiliarity Becomes a Problem. PMID- 26572000 TI - Wireless Safety System Can Cut Costs and Protect Workers. PMID- 26572001 TI - Keeping an Eye on Your Vision Protection Program. PMID- 26572002 TI - Keeping Up to Date with Electrical Services. PMID- 26572003 TI - Air Sampling with Remote Control: Telematics for Personal Exposure Assessment. PMID- 26572004 TI - Besting Winter's Worst. PMID- 26572005 TI - Fire Extinguisher ABCs. PMID- 26572006 TI - Leading Through Difficult Times. PMID- 26572007 TI - Preventing Older Worker Slip-ups. PMID- 26572008 TI - George B Hart, MD, FACS. 29 January 1930--27 September 2014. PMID- 26572009 TI - [Soluble nitrogen and soluble phosphorus dynamics during foliar litter decomposition in winter in alinine forest streams]. AB - In order to understand the dynamic pattern of soluble nitrogen and soluble phosphorus in the headwater streams during the process of litter decomposition in winter, a field experiment using litterbag method was conducted in an alpine forest in Western Sichuan, China. The foliar litter of two dominant canopy trees (Sabina saltuaria, and Larix mastersiana) and two shrubs (Salix paraplesia and Rhododendron lapponicum) were selected. The litterbags were placed in a headwater stream, river, riparian zone and closed canopy, and sampled in different freezing thawing periods of winter (pre-freezing period, freezing period and thawing period). The results indicated that the soluble nitrogen content of foliar litter showed little changes over a whole winter decomposition regardless of species. In contrast, the soluble phosphorus content displayed the order as river < stream < riparian zone < closed canopy, and showed a decrease tendency in stream, river and riparian, although little changes under closed canopy over a whole winter decomposition. Correlation analysis suggested that the dynamics of soluble phosphorus content significantly correlated to the average temperature, positive accumulated temperature, negative accumulated temperature and flow velocity during the decomposition in winter. The dynamics of soluble nitrogen content only exhibited significant correlations with positive accumulated temperature. Additionally, litter quality (species) also controlled the dynamics of soluble nitrogen and soluble phosphorus content as litter decomposition proceeded. The results implied that soluble phosphorus could be more liable to loss in streams and rivers during litter decomposition compared with soluble nitrogen, which could further provide some new ideas in understanding nitrogen and phosphorus cycling in this alpine forest. PMID- 26572010 TI - [Community stability for spruce-fir forest at different succession stages in Changbai Mountains, Northeast China]. AB - Based on the analysis of three forest communities (polar-birch secondary forest, spruce-fir mixed forest, spruce-fir near pristine forest) in Changbai Mountains, a total of 22 factors of 5 indices, including the population regeneration, soil fertility (soil moisture and soli nutrient), woodland productivity and species diversity that reflected community characteristics were used to evaluate the stability of forest community succession at different stages by calculating subordinate function values of a model based on fuzzy mathematics. The results that the indices of population regeneration, soli nutrient, woodland productivity and species diversity were the highest in the spruce-fir mixed forest, and the indices of soil moisture were the highest in the spruce-fir near-pristine forest. The stability of three forest communities was in order of natural spruce-fir mixed forest > spruce-fir near pristine forest > polar-birch secondary forest. PMID- 26572011 TI - [Spatial point pattern analysis of Abies georgei var. smithii in forest of Sygera Mountains in southeast Tibet, China]. AB - In this study, based on a 4 hm2 stem-mapping plot, we analyzed spatial distributions of Abies georgei var. smithii, the dominant species in forest of Sygera Mountains in southeast Tibet, China. Pair-correlation function was used to characterize univariate spatial point patterns of three size classes of the population and bivariate spatial patterns between those and different sizes of dead wood. A. georgei var. smithii population was characterized by reverse J shaped DBH distribution, indicating an increasing population. Saplings of the population were spatially obviously aggregated at the small scales (0-7 m), and mid-sized trees and large-sized trees of the population were randomly or uniformly distributed. The aggregation intensities of A. georgei var. smithii decreased with the increasing diameter classes and spatial scales. Saplings and mid-sized trees were significantly and negatively associated with large-sized trees at the small scales (0-35 and 0-30 m), but the associations reversed at the large scales (45-100 and 80-100 m). In addition, with the increasing age difference between diameter classes of the population, the intensities of positive or negative correlations increased. Spatial associations between saplings and dead large-sized trees, and between mid-sized trees and dead large sized trees were negative at the small scales (0-34 and 5-27 m), but positive at the large scales (49-100 and 73-100 m). This suggested that released niche space due to dead large-sized trees is not enough to weaken their negative impacts on saplings. We concluded that self-thinning effect and Janzen-Connell hypothesis may be the main mechanisms for the spatial pattern formation of A. georgei var. smithii population. PMID- 26572012 TI - [Characteristics of surface energy fluxes over a sparse shrubland ecosystem in the farming-pastoral zone of the Loess Plateau, Northwest China]. AB - Based on the energy flux and meteorological data during 2011-2012 over a sparse shrubland ecosystem in the farming-pastoral zone of the Loess Plateau, this study investigated the diurnal and seasonal variations of the energy balance components, and discussed the responses of the latent and sensible heat fluxes to different intensities of rainfall events. In addition, we identified the major environmental controlling factors on latent and sensible heat fluxes via correlation analysis. The results showed that the diurnal and seasonal variations of net radiation (Rn), sensible heat flux (H), latent heat flux (LE) and soil heat flux (G) all showed single-peak curves. The annual mean values of Rn, H, LE and G were 78.19, 33.32, 24.91 and 2.65 W . m(-2), respectively. The ratios of energy budget components to net radiation were 43% (H/Rn), 32% (LE/Rn), and 3% (G/Rn), which indicated that sensible heat flux was the major form of energy loss at this site. In the growing season, the ratios of sensible heat flux and latent heat flux to net radiation were nearly the same (36%); while in the non-growing season, sensible heat flux accounted for 54% of net radiation. Latent heat flux increased sharply after heavy and weak rainfall events, while sensible heat flux decreased sharply at the same time. Continuous rainfall events would lead to fluctuations in latent and sensible heat fluxes. There were significant correlations between latent heat flux and net radiation, vapor pressure deficit and vegetation parameter, while remarkable correlations were found between sensible heat flux and net radiation, and air temperature gradient. PMID- 26572013 TI - [Impact of canopy structural characteristics on inner air temperature and relative humidity of Koelreuteria paniculata community in summer]. AB - To investigate the diurnal variation of the correlations between the cooling and humidifying effects and canopy structural characteristics of the Koelreuteria paniculata community, the measurements of air temperature, relative humidity, canopy density, leaf area index (LAI) and mean leaf angle (MLA) were performed on calm sunny summer days in the community in Beijing Olympic Forest Park, China. There were significant correlations between the canopy density, LAI and MLA, which affected the cooling and humidifying effects together. The cooling effect reached its maximum by 12:00, whereas the humidifying effect reached its peak at 10:00. Compared with the control open space site, the community appeared to lower the air temperature by 0.43 to 7.53 degrees C and to increase the relative humidity by 1%-22% during the daytime. However, the cooling and humidifying effects seem to be not effective during the night. The canopy density and LAI were better for determining the cooling and humidifying effects from 9:00 to 12:00. However, these effects were largely controlled only by the canopy density from 12:00 to 14:00 and were significantly correlated with the canopy density and LAI afterwards until 18:00. PMID- 26572014 TI - [Effects of fertilization method and nitrogen application rate on soil nitrogen vertical migration in a Populus xeuramericana cv. 'Guariento' plantation]. AB - A field experiment was conducted to investigate the effects of fertilization methods, i.e., drip (DF) and furrow fertilization (GF), and nitrogen (N) application rates (25, 50, 75 g N . plant(-1) . time(-1)) on the dynamics of soil N vertical migration in a Populus x euramericana cv. 'Guariento' plantation. The results showed that soil NH4(+)-N and NO3(-)-N contents decreased with the increasing soil depth under different fertilization methods and N application rates. In the DF treatment, soil NH4(+)-N and NO3(-)-N were mainly concentrated in the 0-40 cm soil layer, and their contents ascended firstly and then descended, reaching their maximum values at the 5th day (211.1 mg . kg(-1)) and 10th day (128.8 mg . kg(-1)) after fertilization, respectively. In the GF treatment, soil NH4(+)-N and NO3(-)-N were mainly concentrated in the 0-20 cm layer, and the content of soil NO3(-)-N rose gradually and reached its maximum at the 20th day (175.7 mg . kg(-1)) after fertilization, while the NH4(+)-N content did not change significantly after fertilization. Overall, N fertilizer had an effect within 20 days in the DF treatment, and more than 20 days in the GF treatment. In the DF treatment, the content and migration depth of soil NH4(+)-N and NO3(-)-N increased with the N application rate. In the GF treatment, the NO3( )-N content increased with the N application rate, but the NH4(+)-N content was not influenced. Under the DF treatment, the hydrolysis rate, nitrification rate and migration depth of urea were higher or larger than that under the GF treatment, and more N accumulated in deep soil as the N application rate increased. Considering the distribution characteristics of fine roots and soil N, DF would be a better fertilization method in P. xeuramericana cv. 'Guariento' plantation, since it could supply N to larger distribution area of fine roots. When the N application rate was 50 g . tree(-1) each time, nitrogen mainly distributed in the zone of fine roots and had no risk of deep leaching, consequently improving the fertilizer utilization efficiency. PMID- 26572015 TI - [Spatial interpolation of soil organic matter using regression Kriging and geographically weighted regression Kriging]. AB - Relative elevation and stream power index were selected as auxiliary variables based on correlation analysis for mapping soil organic matter. Geographically weighted regression Kriging (GWRK) and regression Kriging (RK) were used for spatial interpolation of soil organic matter and compared with ordinary Kriging (OK), which acts as a control. The results indicated that soil or- ganic matter was significantly positively correlated with relative elevation whilst it had a significantly negative correlation with stream power index. Semivariance analysis showed that both soil organic matter content and its residuals (including ordinary least square regression residual and GWR resi- dual) had strong spatial autocorrelation. Interpolation accuracies by different methods were esti- mated based on a data set of 98 validation samples. Results showed that the mean error (ME), mean absolute error (MAE) and root mean square error (RMSE) of RK were respectively 39.2%, 17.7% and 20.6% lower than the corresponding values of OK, with a relative-improvement (RI) of 20.63. GWRK showed a similar tendency, having its ME, MAE and RMSE to be respectively 60.6%, 23.7% and 27.6% lower than those of OK, with a RI of 59.79. Therefore, both RK and GWRK significantly improved the accuracy of OK interpolation of soil organic matter due to their in- corporation of auxiliary variables. In addition, GWRK performed obviously better than RK did in this study, and its improved performance should be attributed to the consideration of sample spatial locations. PMID- 26572016 TI - [Estimating forest canopy cover by combining spaceborne ICESat-GLAS waveforms and mul- tispectral Landsat-TM images]. AB - The spatial distribution of forest canopy cover is a critical indicator for evaluating the forest productivity and decomposition rates. With the Wangqing Forest Region in Jilin Province of China as the study area, this study first estimated the forest canopy cover using spaceborne LiDAR IC- ESat-GLAS waveforms and Landsat-TM multispectral images, respectively, and then GLAS data and TM images were combined to further estimate forest canopy cover by using multiple linear regression and BP neural network. The results showed that when the forest canopy cover was estimated with single data source, the determination coefficient of model was 0.762 for GLAS data and 0.598 for TM data. When the forest canopy cover was estimated by combining GLAS data and TM data, the determination coefficient of model was 0.841 for multiple linear regression, and the simulation precision was 0.851 for BP neural network. The study indicated that the combination of ICESat-GLAS data and Landsat-TM images could exploit the advantages of multi-source remote sensing data and improve the estimating accuracy of forest canopy cover, and it was expected to provide a promising way for spatially continuous mapping of forest canopy cover in future. PMID- 26572017 TI - [An object-based information extraction technology for dominant tree species group types]. AB - Information extraction for dominant tree group types is difficult in remote sensing image classification, howevers, the object-oriented classification method using high spatial resolution remote sensing data is a new method to realize the accurate type information extraction. In this paper, taking the Jiangle Forest Farm in Fujian Province as the research area, based on the Quickbird image data in 2013, the object-oriented method was adopted to identify the farmland, shrub herbaceous plant, young afforested land, Pinus massoniana, Cunninghamia lanceolata and broad-leave tree types. Three types of classification factors including spectral, texture, and different vegetation indices were used to establish a class hierarchy. According to the different levels, membership functions and the decision tree classification rules were adopted. The results showed that the method based on the object-oriented method by using texture, spectrum and the vegetation indices achieved the classification accuracy of 91.3%, which was increased by 5.7% compared with that by only using the texture and spectrum. PMID- 26572018 TI - [Further reduction of nitrogen fertilizer application in paddy field under green manuring of Taihu Area, China]. AB - This study focused on the nitrogen loss via runoff, change of nitrogen in different forms in surface water in paddy field, and grain yield, through further reduction of nitrogen fertilizer application rate under green manuring without basal dressing. Results showed that with 150 kg . hm(-2) inorganic N fertilizer input after return of green manure to soil, no basal dressing could not only sharply reduce N concentration in surface water and decrease 17.2% of N loss, but also increase 2.8% of grain yield in comparison with basal dressing. It was a worthwhile farming method that inorganic nitrogen fertilizer was not used for basal dressing but for topdressing after return of green ma- nure to soil in Taihu Area. However, the grain yield would decrease if the rate of topdressing nitro- gen was excessively reduced or increased. After all, it was feasible to realize harmonization of grain yield and environmental benefits in Taihu Area, with 133 kg . hm(-2) inorganic N fertilizer input after return of green manure to soil as well as no application of basal dressing, which could greatly reduce N fertilizer input and N loss as well as ensure rice yield. PMID- 26572019 TI - [Low-temperature response and cold tolerance at spike differentiation stage of winter wheat varieties sowed in spring]. AB - A total of 10 winter wheat varieties were imported from the middle and lower reaches of the Yangtze River region in China. Those varieties were sowed in spring in Xinding basin area of Shanxi Province, and the field trials were performed for two years (2013-2014). The traits and physiological characteristics under low temperature stress including grain yield, total content of chlorophyll, osmotic adjustment, membrane system, ion leakage rate, contents of soluble sugar and soluble protein were investigated, and the cold tolerance levels of the wheat varieties were assessed. The results showed that low temperature stress led to increases in wheat leaf ion leakage rate, soluble sugar and protein contents, but obvious reduction of chlorophyll content. According to principal component analysis and cold tolerance (D value) , Yumai 10, Yangmai 20, and Yunmai 42 were classed as cold sensitive wheat varieties. Yangmai 13, Yumai 12, and Ningmai 13 were classed as stronger cold-resistant wheat genotypes, and showed stability through two-year field trials, with the D values being 0.665-0.659, 0.493-0.495, and 0.471-0.583, respectively, while the D values for the controls Ning 2038 and Xinchun 30 were 0.368-0.397, and 0.328-0.330, respectively. The grain yields of the cold resistant wheat varieties were significantly higher than that of the other varieties tested. Therefore, Yangmai 13, Yumai 12 and Ningmai 13 could be imported and used as the cold tolerant wheat varieties for North Plain of China. PMID- 26572020 TI - [Effects of sub-low temperature and drought stress on characteristics of photosynthetic and fluorescence kinetics in tomato leaves]. AB - By using tomato as material potted in climatic chamber, the photosynthetic characteristics and allocation of energy and electron flow were studied under sub low temperature (8-15 degrees C) and drought (55%-65% of field moisture capacity) conditions. The results showed that the photosynthetic pigment content declined under sub-low temperature stress, but increased under drought stress. Both sub-low temperature stress and drought stress significantly decreased the intercellular CO2 concentration, stomatal conductance and photosynthetic rate, and increased the stomatal limita- tion, which further decreased or increased under simultaneous treatment of sub-low temperature and drought stress. The photorespiration significantly increased under separate treatment of sub-low temperature and drought stress, but decreased under simultaneous treatment. The stress declined the Fo, Fv/Fm and Fv'/Fm', which showed the damage of photosystem. It increased the distribution of energy to PS I and declined the photochemical efficiency, total electron flow and alternating electron flow. Thermal dissipation and the ratio of alternating electron flow were elevated to dissipate the excess energy. Compared with separate treatment of sub-low temperature and drought stress, the simultaneous treatment made thermal dissipation higher, but did not make alternating electrons flow further increase. PMID- 26572021 TI - [Effect of climatic mean value change on the evaluation result of rice delayed cold damage in Liaoning Province, Northeast China]. AB - The anomaly of mean temperature summation from May to September (DeltaT5-9) was commonly used to assess delayed cold damage of rice in Northeast China, but whether the change of statistics years for climatic mean value (SigmaT5-9) would affect the, evaluation results of Liaoning rice under cold damage needed to be further studied. By using the meteorological industry standard of the People's Republic of China "technical standard on rice cold damage evaluation" (QX/T 182- 2013) and the supplemental indices (DeltaT5-9), the index (SigmaT5-9) was calculated in four periods 1961-1990 (S1), 1971-2000 (S2), 1981-2010 (S3) and 1961-2010 (S4), and the spatial and temporal changes of cold damage in Liaoning Province were analyzed based on the ratio between cold damage stations and total stations (IOC) and the occurrence frequency. The results showed that the heat condition (Sigma T5-9) in rice growing season increased obviously and the spatial and temporal changes were significant from 1961 to 2010. The original meteorological index of rice cold damage was improved by using quadratic polynomial model. The identification results were similar between S2 and S4. The variation coefficient of IOC in S3 was lower than that of the other three. Compared with the typical rice yield reduction years, the evaluation results accorded better with the actual situation in evaluating the rice delayed cold damage in Liaoning during study period by using the S3 climate mean value. The results could provide evidence for accurately evaluating the variation of rice cold damage in spatial and temporal distribution in Liaoning Province under the background of global climate change. PMID- 26572022 TI - [Simulation of instantaneous light transmission in wheat/maize intercropping canopy in Hetao region, China]. AB - The leaf distribution in intercropping canopy is usually laterally and vertically heterogeneous, which makes continuous measurement of light interception very difficult. In order to quantify the light interception by wheat/maize intercropping during different growth stages, a geometrical model was developed in this study to simulate photosynthetically active radiation (PAR) transmission in this system. Measured PAR values in field experiments were used to validate the geometrical model. Results showed that the geometrical model efficiently simulated the PAR transmitted on soil surface under intercropping canopy. The determination coefficients of linear regression between estimated and measured values were 0.947 and 0.950 for 6:2 intercropping (I62) and 12:4 intercropping (I124), respectively. The values of PAR intercepted by I62 intercropping system in 2012 and 2013 were 1061.4 and 924.3 MJ . m(-2), respectively, which were the highest among all cropping systems. The radiation caption ratios (RCRs) of I62 and I124 relative to sole crops were 1.29 and 1.19 during 2012 growing season, and 1.21 and 1.16 during 2013 growing season, respectively. PMID- 26572023 TI - [Dimensional fractal of post-paddy wheat root architecture]. AB - To evaluate whether crop rooting system was directionally dependent, a field digitizer was used to measure post-paddy wheat root architectures. The acquired data was transferred to Pro-E, in which virtual root architecture was reconstructed and projected to a series of planes each separated in 10 degrees apart. Fractal dimension and fractal abundance of root projections in all the 18 planes were calculated, revealing a distinctive architectural distribution of wheat root in each direction. This strongly proved that post-paddy wheat root architecture was directionally dependent. From seedling to turning green stage, fractal dimension of the 18 projections fluctuated significantly, illustrating a dynamical root developing process in the period. At the jointing stage, however, fractal indices of wheat root architecture resumed its regularity in each dimension. This wheat root architecture recovered its dimensional distinctness. The proposed method was applicable for precision modeling field state root distribution in soil. PMID- 26572024 TI - [Effects of exogenous alpha-naphthaleneacetic aid on the antioxidation system in soybean leaves subjected to long-term drought stress during flowering]. AB - Two different drought tolerance soybean ( Glycine max) varieties (Nannong 99-6 and Kefeng 1) were used to study the effects of alpha-naphthaleneacetic acid (NAA) on the antioxidation system under long-term drought stress after flowering with pot experiment, which lasted for 110 days at Pailou Experiment Station, Nanjing Agricultural University, in 2012. The results showed that long-term stress decreased the shoot dry mass significantly, however, increased the level of reactive oxygen species (ROS) and malondialdehyde (MDA) content. It also obviously increased the activities of superoxide dismutase (SOD), peroxidase (POD), catalase (CAT) , ascorbate peroxidase (APX), monodehydroascorbate reductase (MDHAR), glutathione reductase (GR) and glutathione peroxidase (GPX). The contents of ascorbic acid (AsA) and glutathione (GSH), and the ratios of AsA/DHA (dehydroascorbic acid) and GSH/GSSG (L-glutathione oxidized) were obviously enhanced. Kefeng 1 showed a higher antioxidation ability than Nannong 99-6, and could consequently maintain lower ROS and MDA levels. NAA distinctly enhanced the activities of APX, POD, CAT, MDHAR, GPX, and ratios of AsA/DHA and GSH/GSSG, while decreased the levels of ROS and MDA. The AsA content and dehydroascorbate reductase (DHAR) activity were significantly increased in Kefeng 1. PMID- 26572025 TI - [Effects of plant density and nitrogen level on nitrogen uptake and utilization of winter wheat]. AB - A two-year (2011-2012 and 2012-2013) field experiment was conducted on one winter wheat cultivar supplied with two levels, of nitrogen (180 and 240 kg N . hm(-2)) under three plant densities (135 x 10(4), 270 x 10(4), and 405 x 10(4) plants . hm(-2)) . The 15N-labeled urea was injected into 20, 60 and 100 cm soil depths, respectively, aiming to investigate the effect of nitrogen and plant density and their interaction on the N uptake, utilization and nitrate nitrogen contents at different soil depths. The results showed that increasing the plant density from 135 x 10(4) to 405 x 10(4) plants . hm(-2) significantly increased the 15N uptake at depths of 20, 60 and 100 cm averagely by 1.86, 2.28 and 2.51 kg . hm(-2), respectively, and increased the above ground N uptake (AGN) , N uptake efficiency (UPE) averagely by 12.6% and 12.6%, respectively, but decreased the N utilization efficiency (UTE) by 5.4%. Compared to the N input of 240 kg N . hm(-2) the 180 kg N . hm(-2) significantly reduced the 15N uptake at depths of 20 and 60 cm averagely by 4. 11 and 1.21 kg . hm(-2), respectively, and significantly increased the 15N uptake at depths of 100 cm averagely by 1.02 kg . hm(-2). Reducing the N input decreased the AGN averagely by 13.5%, but significantly increased the UPE and UTE by 9.4% and 12.2%, respectively. Equivalent grain yield was observed among N input of 180 kg N . hm(-2) with plant density of 405 x 10(4) plants . hm(-2) and N input of 240 kg N . hm(-2) with plant densities of 270 x 10(4) and 405 x 10(4) plants . hm(-2). Increasing the plant density or reducing the N input could encourage the N uptake at deep soil profile and increased UPE and UTE by 13.4% and 11.9%, respectively. Meanwhile, both the nitrate nitrogen contents in 0-200 cm soil layers at maturity and the ratio of the nitrate nitrogen in 100-200 cm soil layers to that in -200 cm were significantly decreased. Therefore, properly decreasing the N input with increasing the plant density of winter wheat was efficient in absorbing N at deep soil, synergistically obtaining high grain yield, UPE and UTE, and reducing the pollution of residual soil nitrate. PMID- 26572026 TI - [Effects of irrigation amount and various fertigation methods on yield and quality of cucumber in greenhouse]. AB - Taking cucumber as experimental plant, an experiment was conducted to study the effects of irrigation amount and fertigation methods on growth, yield and quality of cucumber in greenhouse. The experiment had designed two irrigation levels, i.e. 100% ET0 (W1) and 75% ET0 (W2), and four fertigation fertilization ratios, i.e. 100%, 66.6%, 33.3% and 0% (Z100, Z66 , Z33, Z0) fertigation of a total amount of (360:180:540 kg . hm(-2)) (N:P2O5:K2O) by 8 times with the corresponding remainders (0%, 33.3%, 66.6% and 100%) were applied to soil as basic fertilization before the planting according to the recommended fertilization rate, and no fertilizer treatment was set up as the control (CK). Results showed that irrigation and fertilization levels had positive correlations with plant height, leaf areas, dry mass, yield and quality of cucumber. Yield at W1Z100 was the highest, reaching 67760 kg . hm(-2). W2 treatment increased the mean water use efficiency (WUE) by 9.4% compared to W1. W2Z100 treatment had the highest WUE, reaching 47.13 kg . m(-3). Yield at W2Z100 was only 3.4% lower than the maximum, but saved 25% of water. Yield and dry matter at Z100 were 15.3% and 16.8% higher than at Z0, respectively, the cucumber fruit vitamin C, soluble protein and soluble sugar contents were increased, and the water use efficiency was increased by 19.1%. W2Z100 treatment was the best treatment which could enable cucumber to obtain both the high-yield and the high-quality. PMID- 26572027 TI - [Effects of different LED light qualities on photosynthetic characteristics, fruit production and quality of strawberry]. AB - Taking 'Miaoxiang No.7' strawberry as material, full red light, full blue light, full yellow light, full white light, red/blue/yellow (7/2/1), red/blue (7/2) light generated by light emitting diode (LED) was applied to accurately modulate with white light generated as control. The indicators of photosynthetic and fluorescence parameters, pigment content, fruit production and quality, root activity were investigated. The effects of light quality under the light intensity (500 umol . m(-2) . s(-1)) on the photosynthetic characteristic, fruit production and quality of strawberry were studied. The results showed that the red light could increase photosynthetic parameters (Pn, Tr), while blue light had inhibitory effect. Intercellular CO2 concentration (Ci) and conductance (g(s)) were the highest under blue light. The fluorescence parameters were significantly affected by light quality, Fo, Fm and Phi PS II the highest under red light, but values of the maximal photochemical of PS II (Fv/Fm), Fv/Fo and Fm/Fo highest under red/blue/yellow (7/2/1). In addition, the soluble solids content and vitamin C were highest under red light, the blue light could increase protein and titratable acid, sugar-acid ratio was the highest under red/blue/yellow (7/2/1). Comprehensive analysis indicated that red/blue/yellow (7/2/1) was more beneficial to the increase of pigment contents of leaves, fruit production and some qualities of strawberry. PMID- 26572028 TI - [Effect of plant density on population yield and economic output value in maize soybean intercropping]. AB - The effects of plant density on population yield and economic output value in maize and soybean intercropping were studied with the design of the double saturated D-optimal regression. A mathematical model was developed, in which the densities of maize and soybean were independent variables, and population grain yield, dry matter accumulation and economic output value were dependent variables, respectively. The result showed that the plant density significantly affected the population grain yield, dry matter accumulation and economic output value, and the effects of density of maize on population indices were greater than those of density of soybean. Under the low level conditions of density, the population grain yield, dry matter accumulation and economic output value increased with the density of maize and soybean. The maximum population grain yield was 8101.31 kg . hm(-2) the optimized combination of 72023 plant maize . hm(-2) and 99924 plant soybean . hm(-2), while the maximum population dry matter accumulation was 15282.45 kg . hm(-2) with the optimized combination of 75000 plant maize . hm(-2) and 93372 plant soybean . hm(-2), and the maximum population economic output value was 23494.50 Yuan . hm(-2) with the optimized combination of 73758 plant maize . hm(-2) and 87597 plant soybean . hm(-2). The optimum combination of densities of maize and soybean calculated by computer were 58554 71547 plant . hm(-2) for maize and 82217-100303 plant . hm(-2) for soybean in order to obtain grain yield greater than 7500 kg . hm(-2), dry matter accumulation greater than 14250 kg . hm(-2) and economic output value greater 22500 yuan . hm(-2) under the condition of this experiment. PMID- 26572029 TI - [Physiological response of the distribution of non-structural carbohydrates to water stress in wheat]. AB - In this paper, the spring wheat (cv. Xihan No. 2) was taken as research material to investigate the dynamic changes of the non-structural carbohydrates (NSC) in flag leaves, stems and leaf sheaths and activities of carbon-metabolizing enzymes (SSS, GBSS) in grains during wheat development process under various water stresses by water stress and re-watering treatment methods. The results indicated that various water stresses had no significant effects on the sucrose contents in flag leaves, stems, leaf sheaths and other organs of wheat. With the increase of water stress, the content of starch in flag leaves was significantly increased within 12-18 d after flowering. Water stress shortened the starch accumulation period in stems and sheaths after flowering and inhibited the transformation and distribution of starch in wheat stems. The accumulation of starch in sheath also gradually increased, which was early terminated under moderate water stress. At the beginning of the water stress, the contents of NSC in vegetative organs were listed as: flag leaves > stems > leaf sheaths. With the increase of water stresses, the NSC contents in vegetative organs were listed as: stems > flag leaves > leaf sheaths. We could conclude that the changes in main NSC (sugar, starch) distribution and carbon-metabolism enzyme activities was a kind of physiological regulation response of wheat to water stresses. PMID- 26572030 TI - [Effects of different straw recycling and tillage methods on soil respiration and microbial activity]. AB - To explore the effects of different tillage methods and straw recycling on soil respiration and microbial activity in summer maize field during the winter wheat and summer maize double cropping system, substrate induced respiration method and CO2 release method were used to determine soil microbial biomass carbon, microbial activity, soil respiration, and microbial respiratory quotient. The experiment included 3 tillage methods during the winter wheat growing season, i.e., no-tillage, subsoiling and conventional tillage. Each tillage method was companied with 2 straw management patterns, i.e., straw recycling and no straw. The results indicated that the conservation tillage methods and straw recycling mainly affected 0-10 cm soil layer. Straw recycling could significantly improve the microbial biomass carbon and microbial activity, while decrease microbial respiratory quotient. Straw recycling could improve the soil respiration at both seedling stage and anthesis, however, it could reduce the soil respiration at filling stage, wax ripeness, and harvest stage. Under the same straw application, compared with conventional tillage, the soil respiration and microbial respiratory quotient in both subsoiling and no-tillage were reduced, while the microbial biomass carbon and microbial activity were increased. During the summer maize growing season, soil microbial biomass carbon and microbial activity were increased in straw returning with conservation tillage, while the respiratory quotient was reduced. In 0-10 cm soil layer, compared with conventional tillage, straw recycling with subsoiling and no-tillage significantly increased soil microbial biomass carbon by 95.8% and 74.3%, and increased soil microbial activity by 97.1% and 74.2%, respectively. PMID- 26572031 TI - [Regulation of biochar on matrix enzyme activities and microorganisms around cucumber roots under continuous cropping]. AB - The effects of addition of biochar on the matrix enzymes activity, microorganisms population and microbial community structure were evaluated under cucumber continuous cropping for 6 years (11 rotations). Cucumbers were grown in pots in greenhouse with 5% or 3% of medium (by mass) substituted with biochar. The control consisted of medium alone without biochar. The results showed that the activity of peroxidase was significantly improved to the level of the first rotation crop form 30 to 120 d after planting in both biochar treatments, with the effect of 5% biochar being more significant than that of 3% biochar. However, the neutral phosphatase activity was markedly reduced after biochar treatment. The addition of 5% biochar had significant regulation effect on the activities of invertase and urease from 30 to 90 d after planting, while the addition of 3% biochar had little effect. The populations of bacteria and actinomycetes were increased and the fungi population was reduced in both biochar treatments from 30 to 90 d after planting, and the effect of 5% biochar was more significant than that of 3% biochar. Meanwhile, the addition of biochar significantly increased the diversity of the bacterial community structure. In summary, biochar had obvious regulation effect on soil enzyme activity, microorganism quantity and microbial community in continuous cropping nutrition medium. PMID- 26572032 TI - [Effects of crop rotation and bio-organic manure on soil microbial characteristics of Chrysanthemum cropping system]. AB - We conducted a field experiment to evaluate the effects of rotation system and bio-organic manure on soil microbial characteristics of Chrysanthemum cropping system. Taking Chrysanthemum morifolium Ramat and wheat as experimental plants, treatments under Chrysanthemum continuous cropping system (M1), conventional Chrysanthemum-wheat rotation system (M2), and Chrysanthemum-wheat rotation system receiving bio-organic manure application of 200 kg . 667 m(-2) (M3) were designed. Soil chemical properties, soil microbial biomass carbon (MBC) and nitrogen (MBN), and the amounts of different types of soil microorganisms were determined. Results showed that compared with M1, treatments of M2 and M3 significantly increased soil pH, organic matter, available N, P, and K, MBC, MBN, and the amounts of bacteria, fungi and actinomycetes, but decreased the ratio of MBC/MBN, and the relative percentage of fungi in the total amount of microorganisms. Treatment of M3 had the highest contents of soil organic matter, available N, available P, available K, MBC, MBN, and the amounts of bacteria, fungi and actinomycetes, with the values being 15.62 g . kg(-1), 64.75 mg . kg( 1), 83.26 mg . kg(-1), 96.72 mg . kg(-1), 217.40 mg . kg(-1), 38.41 mg . kg(-1), 22.31 x 10(6) cfu . g(-1), 56.36 x 10(3) cfu . g(-1), 15.90 x 10(5) cfu . g(-1), respectively. We concluded that rational crop rotation and bio-organic manure application could weaken soil acidification, improve soil fertility and microbial community structure, increase the efficiency of nutrition supply, and have a positive effect on reducing the obstacles of continuous cropping. PMID- 26572033 TI - [Effects of tillage and straw returning on microorganism quantity, enzyme activities in soils and grain yield]. AB - A two-year field study with split plot design was conducted to investigate the effects of different soil tillage (conventional tillage, CT; deep tillage, DT; subsoil tillage, ST) and straw returning (all straw retention, AS; no straw returning, NS) on microorganism quantity, enzyme activities in soil and grain yield. The results showed that, deep or subsoil tillage and straw returning not only reduced the soil bulk density and promoted the content of organic carbon in soil, but increased the soil microbial quantity, soil enzyme activities and grain yield. Furthermore, such influences in maize season were greater than that in wheat season. Compared with CT+NS, DT+AS and ST+AS decreased the soil bulk density at 20-30 cm depth by 8.5% and 6.6%, increased the content of soil organic carbon by 14.8% and 12.4%, increased the microorganism quantity by 45.9% and 33.9%, increased the soil enzyme activities by 34.1% and 25.5%, increased the grain yield by 18.0% and 19.3%, respectively. No significant difference was observed between DT+AS and ST+AS. We concluded that retaining crop residue and deep or subsoil tillage improved soil microorganism quantity, enzyme activities and crop yield. PMID- 26572034 TI - [Topographical and pedological factors adapted to the growth of domestic truffles (Tuber indicum)]. AB - Topographical and pedological factors at 9 sites of Tuber indicum in Yunnan, Sichuan and Tibet were studied by using principal component analysis in order to determine the connection between truffle-growth with topographic factors and soil factors. Results showed that: 1) The 5 principal components selected from 15 topographical and pedological factors had a great cumulative contribution, up to 87.5%. Among the topographical factors, the slope position was the most important ecological factor affecting truffles growth. The higher the slope position was, the less conducive to truffles growth. In the middle and lower parts of the slope, T. indicum grew best. 2) As for the pedological factors, the bulk density, silt content, pH, total nitrogen content, exchangeable calcium and magnesium contents were the important factors restricting T. indicum growth. Under the condition of bulk density 0.65-0.82 g . cm(-3), silt content 30.0% and sand content about 55.0%, T. indicum grew well. Too high bulk density or clay content was not conducive to its growth. The soil with pH 6.40 or so, total nitrogen content of 2.29-3.70 g . kg(-1), exchangeable calcium content of 22.91-37.17 cmol . kg(-1) and exchangeable magnesium content of 1.85-2.59 cmol . kg(-1) were favorable for growth of T. indicum. 3) The comprehensive evaluation showed that the site at Shaoshang Village in Kunming, Yunnan and Jiangsegang Village in Linzhi Prefecture, Tibet had higher scores, which meant these two sites had the most favorable conditions for truffles growth. However, the site at Ershijiu liangzi Village in Panzhihua, Sichuan and the Mt. Wuding in Chuxiong Prefecture, Yunnan had lower scores, which meant these two sites were not fit for truffles growth regarding the topographical and soil conditions. PMID- 26572035 TI - [Effects of different salt and alkali stresses on ion distribution in Red globe/Beta grapevines]. AB - The potted Red globe/Beta grapevines were selected to irrigated with NaCl, Na2SO4, NaHCO3, NH4Cl, (NH4)2SO4. Hence, the ions which induced leaf etiolation were screened and the impacts of different salt and alkali on ion distribution in different organs of grapevines were investigated. It was found that NaHCO3 exerted the greatest effects on grapevines, leaf etiolation at 14 days after treatment. By contrast, NaCl and NH4Cl treatments induced leaf etiolation at 28 days after treatment. The Na+ content in all the detected organs were significantly increased under NaHCO3 and NaCl treatment, and Na+ content in root under NaHCO3 treatment was 6.4 times as that in control root. NaHCO3 and NaCl treatments significantly decreased K+ content in the organs with the exception of leaf. NaHCO3 treatment significantly decreased K/Na in different organs, which declined to 0.1 in root. By contrast, NaCl treatment significantly decreased K/Na in the detected organs with exception of stem. Besides, the transport of Ca2+, Mg2+, Fe2+ to aboveground organs was significantly decreased by NaHCO3 and NaCl treatments. K/Na ratio in the detected organs were decreased under NH4Cl, (NH4) 2SO4 and Na2SO4 treatments, especially under NH4 Cl treatment. Taken together, NaHCO3 was the primary factor resulting in leaf etiolation, followed by NaCl and NH4Cl, while (NH4) 2SO4 and Na2SO4 produced impacts. PMID- 26572036 TI - [Effects of long-term fertilization on bacterial and archaeal diversity and community structure within subtropical red paddy soils]. AB - Paddy soils not only function as an important sink for "missing carbon" but also play an important role in the production of greenhouse gases such as N2O and CH4. Dynamic changes in greenhouse gases in the atmosphere are closely related to microbially mediated carbon and nitrogen transformation processes occurring in soil. Using soil samples collected from a long-term fertilization experimental site in Taojiang County, subtropical China (established in 1986), we determined the effects of long-term (>25 years) non-fertilization (CK), chemical fertilization (NPK), and NPK combined with rice straw residues (NPKS) on soil bacterial and archaeal community structures. The 16S rRNA genotypes from the three differently treated soils were divided into 9 bacterial phylotypes, mainly including Proteobacteria, Acidobacteria, Chloroflexi, and archaea of Crenarchaeota and Euryarchaeota. The relative abundance of Proteobacteria, Acidobacteria and Crenarchaeota increased in the soils under NPK and NPKS treatments, with the increase being greater in the latter treatment. LUBSHUFF statistical analyses also demonstrated that there was significant difference among the microbial community compositions in CK-, NPK- and NPKS-treated soils. The abundance of bacterial and archaeal 16S rRNA genes ranged from 0.58 x 10(10) to 1.06 x 10(10) copies . g(-1) dry soil and from 1.16 x 10(6) to 1.72 x 10(6) copies . g(-1) dry soil, respectively. Application of fertilizers increased the bacterial and archaeal abundance and diversity in the treated soils, with NPKS > NPK. Long-term chemical and organic applications significantly affected the abundance, diversity and composition of bacterial and archaeal communities in paddy ecosystems. PMID- 26572037 TI - [Effects of GA, and CPPU on grape fruit adjacent leaf photosynthesis and fruit quality]. AB - Taken the grape cultivar 'Shine Muscat' as the material, the effect of the combination of GA3 and CPPU on the light-response curves in the fruit adjacent leaves and fruit quality were investigated two weeks after blossoming. The results showed that non-rectangular hyperbolic model was more suitable for grape fruit adjacent leaf light response curve-fitting. Pn and g(s) of fruit adjacent leaves among all treatments increased with the increasing light intensity under the combination treat-ments of 25 mg . L(-1) GA3 and 5, 10, 15, 20 mg . L(-1) CPPU, respectively, but Ci decreased. Fruit quality increased with the increasing CPPU concentration under the combination treatments of 25 mg . L(-1) GA3 and 5, 10, 15 mg . L(-1) CPPU, respectively. Grape fruit adjacent leaf photosynthesis under the 25 mg . L(-1) GA3 + 20 mg . L(-1) CPPU treatment was higher than the other treatments. The fruit quality under the 25 mg . L(-1) GA3 + 20 mg . L(-1) CPPU treatment was lower than the 25 mg . L(-1) GA3 + 15 mg . L(-1) CPPU treatment. It indicated that reasonable CPPU treatment concentration could improve fruit adjacent leaf photosynthetic ability and fruit quality. Too high concentration made the fruit quality lower instead. The 25 mg . L(-1) GA3 + 15 mg . L(-1) CPPU treatment was most appropriate in two weeks after blossoming. PMID- 26572038 TI - [Environmental efficiency evaluation under carbon emission constraint in Western China]. AB - This research used the SBM model based on undesirable outputs to measure the static environmental efficiency of Western China under carbon emission constraint from 2000 to 2012. The researchers also utilized the Malmquist index to further analyze the change tendency of environmental efficiency. Additionally, Tobit regression analysis was used to study the factors relevant to environmental efficiency. Practical solutions to improve environmental quality in Western China were put forward. The study showed that in Western China, environmental efficiency with carbon emission constraint was significantly lower than that without carbon emission constraint, and the difference could be described as an inverse U-shaped curve which increased at first and then decreased. Guang-xi and Inner Mongolia, the two provinces met the effective environmental efficiency levels all the time under carbon emission constraint. However, the five provinces of Guizhou, Gansu, Qinghai, Ningxia and Xinjiang did not. Furthermore, Ningxia had the lowest level of environmental efficiency, with a score between 0.281 0.386. Although the environmental efficiency of most provinces was currently at an ineffective level, the environmental efficiency quality was gradually improving at an average speed of 6.6%. Excessive CO2 emission and a large amount of energy consumption were the primary factors causing environmental inefficiency in Western China, and energy intensity had the most negative impact on the environmental efficiency. The increase of import and export trade reduced the environmental efficiency significantly in Western China, while the increase of foreign direct investment had a positive effect on its environmental efficiency. PMID- 26572039 TI - [Net anthropogenic nitrogen input to Huaihe River Basin, China during 1990-2010]. AB - Social economy in Huaihe River Basin had undergone enormous changes during 1990 2010. The grain yield had increased by 58%, from 64.14 million tons to 101.21 million tons, and the urbanization rate had increased by 22%, from 13% to 35%. Assessing the negative impacts of these high intensive human activities caused by rapid social development on terrestrial ecosystem would serve as a scientific basis for quantitative management of regional ecology. This paper estimated the spatial and temporal distribution of net anthropogenic nitrogen input (NANI) in Huaihe River Basin during 1990-2010. The results showed that there was an increasing trend in NANI in the period of 1990-2001, and after that this trend was slower. The NANI increased from approximately 17232 kg N . km(-2) . a(-1) in 1990 to a peak of 28771 kg N . km(-2) . a(-1) in 2003, and then declined to 26415 kg N . km(-2) . a(-1) in 2010. Chemical fertilizer and atmospheric deposition were the largest two sources of NANI, followed by food & feed import and biological nitrogen. Contributions from both chemical fertilizer and atmospheric deposition had been increasing continuously, respectively from 64% and 16% in 1990 to 77% and 19%. Our findings implied that the shift from fertilizer supported agriculture and fossil fuel-supported industry to sci-tech lead economic development is urgently needed. PMID- 26572040 TI - [Spatial-temporal evolution of urban thermal environment based on spatial statistical features]. AB - A new method which aims to determine the area of urban heat island (UHI) was proposed in this paper based on spatial statistical features by means of remote sensing and GIS spatial analysis tools, and was applied in the spatial-temporal evolution analysis of UHI in Hangzhou, China. The results showed that the area of UHI in Hangzhou increased 8.66 times from 1984 to 2010. During the 26 years, the spatial structure of UHI in Hangzhou had become more and more complex, and its spatial distribution changed from single-center to multi-center. Generally speaking, the change trend of thermal environment in Hangzhou was turning from low-temperature spatial equilibrium to high-temperature spatial equilibrium. The major cause for the development of UHI in Hangzhou was urban expansion as it showed in the results of dynamic change detection. This new method considered the spatial correlation of urban land surface temperature (LST), and reflected the global statistical features of LST. It was more objective and accurate than the conventional methods, and could provide more information, which would help us to resolve the problem of being lack of generality and comparability in the current research. PMID- 26572041 TI - [Evaluation of ecosystem service and emergy of Wanshan Waters in Zhuhai, Guangdong Province, China]. AB - The method for monetary value and emergy value analysis of ecosystem service was used in this paper to analyze the change in value of marine ecosystem service of Wanshan District, Zhuhai from 2007 to 2012. The result showed that the monetary value and emergy value of marine ecosystem service of Wanshan District, Zhuhai rose to 11512840000 yuan and 1.97 x 10(22) sej from 7721630000 yuan and 1.04 x 10(22) sej, respectively. Both monetary value and emergy value could forecast the change in the value of marine ecosystem service, but they reflected different value structures and ecological energy, which could be used to more objectively evaluate the ecosystem service. Ecological civilization development, as an inherent driving force to impel the development of marine ecosystem service structure, was important for rational exploitation of marine resources and optimization of marine ecosystem service. PMID- 26572042 TI - [Ecological security early-warning in Zhoushan Islands based on variable weight model]. AB - Ecological security early warning, as an important content of ecological security research, is of indicating significance in maintaining regional ecological security. Based on driving force, pressure, state, impact and response (D-P-S-I R) framework model, this paper took Zhoushan Islands in Zhejiang Province as an example to construct the ecological security early warning index system, test degrees of ecological security early warning of Zhoushan Islands from 2000 to 2012 by using the method of variable weight model, and forecast ecological security state of 2013-2018 by Markov prediction method. The results showed that the variable weight model could meet the study needs of ecological security early warning of Zhoushan Islands. There was a fluctuant rising ecological security early warning index from 0.286 to 0.484 in Zhoushan Islands between year 2000 and 2012, in which the security grade turned from "serious alert" into " medium alert" and the indicator light turned from "orange" to "yellow". The degree of ecological security warning was "medium alert" with the light of "yellow" for Zhoushan Islands from 2013 to 2018. These findings could provide a reference for ecological security maintenance of Zhoushan Islands. PMID- 26572043 TI - [Impact of artificial reef on community of macrobenthos in Jincheng area of Laizhou Bay, China]. AB - In order to evaluate the impact of artificial reef on the communities of macrobenthos, from 2009 to 2012, samples were collected in four seasons at the artificial reef area and the control area in Jincheng area of Laizhou Bay from 9 cruises. A total of 35 macrobenthos species (4 phyla, 30 families) were recorded in the two areas, with 30 species in the artificial reef area, and 27 species in the control area. Results suggested that the two macrobenthos communities with different species composition could be discriminated. One community was located in artificial reef area, the other outside the reef area. Planktophagous group was the most dissimilarity-contributing species. The species similarity (Jaccard) of the two areas increased from 37.5% in the first year to 58.6% in the second year. The biomass and abundance of macrobenthos in the artificial reef area respectively increased from 1.00 g . m(-2) and 540 ind . m(-2) in the first year to 1.55 g . m(-2) and 622 ind . m(-2) in the second year, which were both higher than those in the control area. Compared with the control area, the Shannon index and abundance index of the artificial reef area were increased, while the evenness index was decreased. The abundance biomass comparison (ABC) curve showed that the macrobenthos communities were more heavily disturbed in the second year than that in the first year after artificial reef set. It was considered that the macrobenthos community was unsteady at the early stage after artificial reef construction (1-2 years). The physical, chemical, biological and human activities were the main factors influencing macrobenthos community in Jincheng area of Laizhou Bay. PMID- 26572044 TI - [Enrichment of Cd2+ and Hg2+ in Phascolosoma esculenta and their effects]. AB - The accumulation of Cd2+ and Hg2+ in Phascolosoma esculenta and its effects on its growth and main nutrient components were investigated using atomic absorption spectrometer analysis and atomic fluorescence spectrometer examination. The results showed that within the experimental heavy metal concentrations, the amounts of Cd2+ and Hg2+ accumulated in the somatic muscles increased with increasing exposure time and reached their saturated levels at the end of the experiment. Exposure of higher heavy metal concentrations speeded up the accumulation of Cd2+ and Hg2+ and subsequently took less time to reach their saturated levels, which were greater than those of lower concentration groups. The rate of mass gain of P. esculenta decreased with increasing the heavy metal exposure concentrations. The combination exposure of Cd2+ and Hg2+ led to a significantly lower mass gain rate compared to those exposed to Cd2+ or Hg2+. The protein content of somatic muscles increased with the increase of exposure concentration and reached the maximum values at 0.05 and 0.02 mg . L(-1) for Cd2+ and Hg2+, respectively. After that, the protein content of somatic muscles began to decrease. The combined exposure of the two heavy metals showed similar effect trends but more significant impacts on the protein content of somatic muscles. The lipid content of somatic muscles decreased with increasing the concentration of Cd2+ or Hg2+ exposure, and the combination of Cd2+ and Hg2+ led to lower lipid content. PMID- 26572045 TI - [Interspecies diet relationship of Coreius from Yinbin reach of Yangtze River, China]. AB - This study investigated the diet compositions of Coreius heterodon and C. guichenoti in Yibin reach of Yangtze River from April to May, 2012 by carbon and nitrogen stable isotopes technique, and analyzed their diet relationship by the multivariate statistical technique, which covered the diet similarity index, overlap coefficient, and the influence of morphological differences in feeding organ between the two species on diet compositions. The results showed that, 1) the delta13C and delta15N of C. heterodon was from -21.15 per thousand to -20.31 per thousand and 9.67 per thousand to 10.21 per thousand, respectively, which indicated that the fish had an omnivorous possessing carnivorous preference. The delta13C and delta15N of C. guichenoti was from -23.30 per thousand to -21.18 per thousand and 7.40 per thousand to 9.21 per thousand, respectively, which had an omnivorous possessing phytophagous preference. There were some differences in the results between the stable isotopes and the traditional intestinal contents analysis. 2) The diet similarity index and the overlap coefficient was 78.7% and 55.6%, respectively. 3) The principal component analysis (PCA) result showed that the morphological characters of the feeding organs in the two fishes were different. In conclusion, the interspecies competition was not intense between the C. heterodon and C. guichenoti, and as the last investigation of the diet composition and food relationship of the two species before the impoundment of the Xiangjiaba Reservoir, the results could provide reference for analyzing the influence of impoundment on the fish trophic structure in Yibin reach of Yangtze River. PMID- 26572046 TI - [Heavy metal pollution characteristics and ecological risk analysis for soil in Phyllostachys praecox stands of Lin'an]. AB - An investigation was carried out in an attempt to reveal the characteristics of heavy metals contamination in the soils of Phyllostachys praecox forest in Lin' an. Based on the concentrations of Hg, As, Cu, Pb, Zn, Cd, Cr, Ni, Co and Mn in 160 topsoil samples, the pollution status and ecological risks of heavy metals in the soils were assessed by single factor pollution index, Nemerow integrated pollution index and Hankanson potential ecological risk index. The spatial variability of heavy metal concentrations in the soils closely related to the distribution of traffic, industrial and livestock pollution sources. The average concentrations of Hg, As, Cu, Pb, Zn, Cd, Cr, Ni, Co and Mn in the soils were 0.16, 7.41, 34.36, 87.98, 103.98, 0.26, 59.12, 29.56, 11.44 and 350.26 mg . kg( 1), respectively. Pb, Cd, Zn and Cu concentrations were as 2.89, 1.70, 1.12 and 1.12 times as the background values of soil in Zhejiang Province, respectively. But their concentrations were all lower than the threshold values of the National Environmental Quality Standard for Soil (GB 15618-1995). The average single factor pollution index revealed that the level of heavy metal pollution in the soils was in order of Pb>Cd>Cu= Zn>Hg>As>Ni>Co>Cr>Mn. Pb pollution was of moderate level while Cd, Cu and Zn pollutions were slight. There was no soil pollution caused by the other heavy metals. However, the Nemerow integrated pollution index showed that all the 160 soil samples were contaminated by heavy metals to a certain extent. Among total 160 soil samples, slight pollution level, moderate pollution level and heavy pollution level accounted for 55.6%, 29.4% and 15.0%, respectively. The average single factor potential ecological risk index (Er(i)) implied that the potential ecological risk related to Cd reached moderate level, while the others were of slight level. Furthermore, Cd and Hg showed higher potential ecological risk indices which reached up to 256.82 and 187.33 respectively, indicating Cd and Hg had a strong ecological risk and therefore might pose the most serious ecological risk in the soils of P. praecox standsin Lin' an. In addition, the integrated factor potential ecological risk analysis suggested a slight risk to local ecosystem originated from heavy metal contamination in the soils of P. praecox stands in Lin'an. PMID- 26572047 TI - [Research progress of cover crop in Chinese orchard]. AB - Grass growing in orchard is implemented in most fruit cultivation advanced countries, but only China carries out grass weeding. To effectively resolve the puzzle on harmful or beneficial effect on fruit production imparted by grass growing, and promote grass growing management in orchard in China, more and more domestic research was reported in recent years. Combined the results of our research and domestic related research, we reviewed the latest research progress about the effect of growing grass on soil, microclimate, fruit tree diseases and insect pests, tree growth and fruit quali- ty, etc. in this paper. We pointed out that grass growing in orchard must consider the local conditions, economic efficiency, the critical period, and the supporting technique. PMID- 26572048 TI - [Advances in low impact development technology for urban stormwater management]. AB - Low impact development ( LID), as an innovative technology for stormwater management, is effective to mitigate urban flooding and to detain pollutants. This paper systemically introduced the LID technology system, and summarized the reduction effects of three typical LID facilities (i.e. , bio-retention, green roof and permeable pavement) on stormwater runoff and main pollutants in recent literature, as well as research outcomes and experiences of LID technology on model simulation, cost-benefit analysis and management system. On this basis, we analyzed the problems and limitations of current LID technology studies. Finally, some suggestions about future research directions, appropriate design and scientific management were put forth. This work intended to provide scientific basis and suggestions for widespread use and standard setting of LID technology in China by referencing overseas studies. PMID- 26572049 TI - Clean-up of cereal extracts for gas chromatography-tandem quadrupole mass spectrometry pesticide residues analysis using primary secondary amine and C18. AB - The level of co-extracted matrix in wheat and oat extracts obtained by the QuEChERS method (EN 15662) is high and the occurrence of free fatty acids generates a major matrix peak in TIC chromatograms (rt. 13-22min). Matrix can compromise the analytical performance in pesticide analysis using GC-MS/MS. In order to reduce the amount and the effects of matrix we tested the effect of using six different amounts of primary secondary amine (PSA) (0, 25, 50, 100, 150 and 200mg/ml extract) with and without the addition of six different amounts of C18 (0, 25, 50, 100, 150 and 200mg/ml extract) in the dispersive solid phase extraction (dSPE) procedure. dSPE clean-up using 25mg/ml extract significantly reduced the major matrix peak observed for wheat extracts. Higher amounts of PSA reduced the analytical response for iprodione and malathion. For oat extract 50 150mg PSA/ml extract was needed to obtain equally low intensity of the matrix peak. For oat the analytical responses of the target pesticides generally increased with increasing amount of PSA. C18 had no significant effect on the intensity of the major matrix peaks and even resulted in lower analytical responses for several of the target pesticides. Based on the present study it is concluded that the optimal dSPE clean-up procedure employs 25mg PSA/ml extract for wheat and 150mg PSA/ml extract for oat. PMID- 26572050 TI - Analysis of iminosugars and other low molecular weight carbohydrates in Aglaonema sp. extracts by hydrophilic interaction liquid chromatography coupled to mass spectrometry. AB - A method by hydrophilic interaction liquid chromatography coupled to tandem mass spectrometry (HILIC-MS(2)) has been successfully developed for the simultaneous analysis of bioactive iminosugars and other low molecular weight carbohydrates in Aglaonema leaf extracts. Among other experimental chromatographic conditions, mobile phase eluents, additives and column temperature were evaluated in terms of retention time, resolution, peak width and symmetry provided for target carbohydrates. In general, narrow peaks (wh: 0.2-0.6min) with good symmetry (As: 0.9-1.3) and excellent resolution (Rs>1.8) were obtained for iminosugars using an acetonitrile:water gradient with 5mM ammonium acetate in both eluents at 55 degrees C. Tandem mass spectra were used to confirm the presence of previously detected iminosugars in Aglaonema extracts and to tentatively identify for the first time others such as miglitol isomer, glycosyl-miglitol isomers and glycosyl DMDP isomers. Concentration of total iminosugars varied from 1.35 to 2.84mgg(-1) in the extracts of the different Aglaonema samples analyzed. To the best of our knowledge, this is the first time that a HILIC-MS(2) method has been proposed for the simultaneous analysis of iminosugars and other low molecular weight carbohydrates of Aglaonema sp. extracts. PMID- 26572051 TI - Cloud-point extraction is compatible with liquid chromatography coupled to electrospray ionization mass spectrometry for the determination of bisoprolol in human plasma. AB - Cloud-point extraction (CPE) draws increasing interest in a number of analytical fields including bioanalysis, but combining CPE and LC-MS with electrospray ionization (ESI) in the determination of drugs in biological fluids such as plasma, serum or blood has not been reported so far. Bisoprolol was determined in human plasma by CPE using Trition X-114 as a surfactant and metoprolol as the internal standard. NaOH concentration, temperature and Trition X-114 concentration were optimized. All analyses were performed using liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). All validation experiments met international acceptance criteria and no significant matrix effect was observed. The compatibility of CPE and LC-ESI-MS/MS was confirmed using clinical plasma samples and appropriate statistical tests. The determination of bisoprolol concentration in human plasma in the range 1.0 70ngmL(-1) by the CPE method leads to the results which are equivalent to those obtained by the widely used liquid-liquid extraction method. The results revealed that a structural analogue may be an appropriate internal standard when CPE is used as the extraction technique. CPE offers significant practical advantages over the classical extraction methods, including a positive impact on the environment, therefore its wider application in future pharmacokinetic studies is justifiable. PMID- 26572052 TI - Retraction of "Hydrothermally Grown Upright-Standing Nanoporous Nanosheets of Iodine-Doped ZnO (ZnO:I) Nanocrystallites for a High-Efficiency Dye-Sensitized Solar Cell". PMID- 26572053 TI - Enterococcus faecalis attenuates osteogenesis through activation of p38 and ERK1/2 pathways in MC3T3-E1 cells. AB - AIM: To explore the role of Enterococcus faecalis in the proliferation, apoptosis and differentiation of osteoblasts. METHODOLOGY: Pre-osteoblastic MC3T3-E1 cells were treated with heat-killed E. faecalis ATCC 29212 and clinical E. faecalis P25RC strains, respectively. Cell proliferation, mineralized calcium deposition, alkaline phosphatase (ALP) activity and apoptosis were assessed at various time points. The expression levels of osteogenic-related genes including ALP, osteocalcin (OC), runt-related protein 2 (Runx2) and collagen type 1 (COL1) were also analysed throughout the duration of the experiment. Additionally, the involvement of mitogen-activated protein kinases (MAPKs) signalling pathways was analysed by Western blotting. In the presence of culture supernatant from E. faecalis-treated murine macrophages, apoptosis of MC3T3-E1 cells was detected with flow cytometry. Data were analysed using analysis of variance (anova), and P < 0.05 was considered significantly different. RESULTS: E. faecalis significantly inhibited proliferation (P < 0.05) and also significantly induced apoptosis of MC3T3-E1 cells (P < 0.05), whilst differentiation seemed to be unaffected after 7 days of E. faecalis treatment. However, osteogenic differentiation was significantly inhibited with 21-day E. faecalis treatment (P < 0.05). The p38 and ERK1/2 phosphorylation pathways associated with mineral deposition and apoptosis were significantly activated in MC3T3-E1 cells. The culture supernatants from E. faecalis-treated macrophages induced osteoblast apoptosis. CONCLUSIONS: E. faecalis exerted an inhibitory effect on osteogenesis in pre-osteoblastic MC3T3 E1 cells via phosphorylation of p38 and ERK1/2. PMID- 26572054 TI - [Application of robustness test for assessment of the measurement uncertainty at the end of development phase of a chromatographic method for quantification of water-soluble vitamins]. AB - OBJECTIVE: We propose in this work an efficient way to evaluate the measurement of uncertainty at the end of the development step of an analytical method, since this assessment provides an indication of the performance of the optimization process. METHOD: The estimation of the uncertainty is done through a robustness test by applying a Placquett-Burman design, investigating six parameters influencing the simultaneous chromatographic assay of five water-soluble vitamins. The estimated effects of the variation of each parameter are translated into standard uncertainty value at each concentration level. RESULTS: The values obtained of the relative uncertainty do not exceed the acceptance limit of 5%, showing that the procedure development was well done. In addition, a statistical comparison conducted to compare standard uncertainty after the development stage and those of the validation step indicates that the estimated uncertainty are equivalent. CONCLUSION: The results obtained show clearly the performance and capacity of the chromatographic method to simultaneously assay the five vitamins and suitability for use in routine application. PMID- 26572055 TI - The effect of memantine on sleep architecture and psychiatric symptoms in patients with Alzheimer's disease. AB - OBJECTIVE: Behavioural and psychological symptoms of dementia (BPSD) are commonly present in patients with Alzheimer's disease (AD). Disturbed sleep quality is also observed in AD patients. However, the effects of memantine on sleep architecture have not been investigated. The purpose of this study was to investigate the effects of memantine on polysomnography (PSG) variables and BPSD. METHODS: In total, 12 patients with AD (mean age: 79.0+/-4.1 years old) were enrolled in this study. The following tests were performed: the Neuropsychiatric Inventory for the assessment of BPSD, the Mini-Mental State Examination (MMSE) for cognitive function, and PSG for evaluation of sleep architecture. After baseline examinations, patients were treated with memantine according to a standard prescription protocol. After being treated with 20 mg/day of memantine for 4 weeks, examinations were carried out again. RESULTS: All subjects completed the trial. The mean MMSE and NPI scores were 22.6+/-3.4 and 13.8+/-12.9, respectively. Treatment with memantine significantly decreased the NPI score (5.8+/-4.3, p<0.01). There were significant decreases in the scores of subscales for anxiety (p=0.04) and irritability/lability (p=0.04). PSG demonstrated a longer total sleep time (TST) (p<0.01), increases in sleep efficiency (p<0.01) and time spent in stage II (% TST, p=0.02), and decreases in nocturnal awakening (p<0.01), the periodic limb movement index (p<0.01), and time spent in stage I (% TST, p=0.02). CONCLUSION: Memantine was effective for reducing fragmented sleep and improving BPSD, and was well tolerated. PMID- 26572056 TI - Ulipristal acetate for uterine fibroids: a systematic review and meta-analysis. AB - Ulipristal acetate (UA), a selective progesterone modulator, has been approved for short-term therapy for symptomatic fibroids. We decided to undertake a systematic review of the best available evidence and draw a more definitive conclusion regarding the efficacy of UA for the management of uterine fibroids. The outcomes included symptomatic relief, quality of life-related parameters, reduction in fibroid size, side effects and recurrence rate. We included four randomised controlled trials which consisted of three trials which compared UA with placebo, and one trial compared it with gonadotropin-releasing hormone analogues for symptomatic relief. The three trials comparing UA with placebo reported significant improvement in symptoms related to excessive uterine bleeding as evidenced by the attainment of amenorrhea or reduction in pictorial blood assessment chart. However, due to the heterogeneity of the available data, a meta-analysis was possible only for one the outcomes - attainment of amenorrhea which indicated improvement in symptoms [57.88 (19.81-169.16); p < 0.00001]. The improved quality of life parameters and reduction in fibroid size was noted in the UA group. With regards to adverse events, even though the three included studies reported increased non-physiological endometrial-related changes following UA, these changes reverted back to normal within 6 months. Short-term use of UA seems to be an effective and safe method of treating uterine fibroids. PMID- 26572057 TI - Biofilm-associated proteins: news from Acinetobacter. AB - BACKGROUND: A giant protein called BAP (biofilm-associated protein) plays a role in biofilm formation and adhesion to host cells in A. baumannii. Most of the protein is made by arrays of 80-110 aa modules featuring immunoglobulin-like (Ig like) motifs. RESULTS: The survey of 541 A. baumannii sequenced strains belonging to 108 STs (sequence types) revealed that BAP is highly polymorphic, distinguishable in three main types for changes both in the repetitive and the COOH region. Analyzing the different STs, we found that 29 % feature type-1, 40 % type-2 BAP, 11 % type-3 BAP, 20 % lack BAP. The type-3 variant is restricted to A. baumannii, type-1 and type-2 BAP have been identified also in other species of the Acinetobacter calcoaceticus-baumannii (ACB) complex. A. calcoaceticus and A. pittii also encode BAP-like proteins in which Ig-like repeats are replaced by long tracts of alternating serine and aspartic acid residues. We have identified in species of the ACB complex two additional proteins, BLP1 and BLP2 (BAP-like proteins 1 and 2) which feature Ig-like repeats, share with BAP a sequence motif at the NH2 terminus, and are similarly expressed in stationary growth phase. The knock-out of either BLP1 or BLP2 genes of the A. baumannii ST1 AYE strain severely affected biofilm formation, as measured by comparing biofilm biomass and thickness, and adherence to epithelial cells. BLP1 is missing in the majority of type-3 BAP strains. BLP2 is largely conserved, but is frequently missing in BAP negative cells. CONCLUSIONS: Multiple proteins sharing Ig-like repeats seem to be involved in biofilm formation. The uneven distribution of the different BAP types, BLP1, and BLP2 is highly indicative that alternative protein complexes involved in biofilm formation are assembled in different A. baumannii strains. PMID- 26572058 TI - Emergence of Two-Dimensional Massless Dirac Fermions, Chiral Pseudospins, and Berry's Phase in Potassium Doped Few-Layer Black Phosphorus. AB - Thin flakes of black phosphorus (BP) are a two-dimensional (2D) semiconductor whose energy gap is predicted being sensitive to the number of layers and external perturbations. Very recently, it was found that a simple method of potassium (K) doping on the surface of BP closes its band gap completely, producing a Dirac semimetal state with a linear band dispersion in the armchair direction and a quadratic one in the zigzag direction. Here, based on first principles density functional calculations, we predict that, beyond the critical K density of the gap closure, 2D massless Dirac Fermions (i.e., Dirac cones) emerge in K-doped few-layer BP, with linear band dispersions in all momentum directions, and the electronic states around Dirac points have chiral pseudospins and Berry's phase. These features are robust with respect to the spin-orbit interaction and may lead to graphene-like electronic transport properties with greater flexibility for potential device applications. PMID- 26572059 TI - The relationship between adherence to clinic appointments and year-one mortality for newly enrolled HIV infected patients at a regional referral hospital in Western Kenya, January 2011-December 2012. AB - This retrospective cohort analysis was conducted to describe the association between adherence to clinic appointments and mortality, one year after enrollment into HIV care. We examined appointment-adherence for newly enrolled patients between January 2011 and December 2012 at a regional referral hospital in western Kenya. The outcomes of interest were patient default, risk factors for repeat default, and year-one risk of death. Of 582 enrolled patients, 258 (44%) were defaulters. GEE revealed that once having been defaulters, patients were significantly more likely to repeatedly default (OR 1.4; 95% CI 1.12-1.77), especially the unemployed (OR 1.43; 95% CI 1.07-1.91), smokers (OR 2.22; 95% CI 1.31-3.76), and those with no known disclosure (OR 2.17; 95% CI 1.42-3.3). Nineteen patients (3%) died during the follow-up period. Cox proportional hazards revealed that the risk of death was significantly higher among defaulters (HR 3.12; 95% CI 1.2-8.0) and increased proportionally to the rate of patient default; HR was 4.05 (95% CI1.38-11.81) and 4.98 (95% CI 1.45-17.09) for a cumulative of 4-60 and >=60 days elapsed between all scheduled and actual clinic appointment dates, respectively. Risk factors for repeat default suggest a need to deliver targeted adherence programs. PMID- 26572060 TI - Strategies to reduce end-product inhibition in family 48 glycoside hydrolases. AB - Family 48 cellobiohydrolases are some of the most abundant glycoside hydrolases in nature. They are able to degrade cellulosic biomass and therefore serve as good enzyme candidates for biofuel production. Family 48 cellulases hydrolyze cellulose chains via a processive mechanism, and produce end products composed primarily of cellobiose as well as other cellooligomers (dp <= 4). The challenge of utilizing cellulases in biofuel production lies in their extremely slow turnover rate. A factor contributing to the low enzyme activity is suggested to be product binding to enzyme and the resulting performance inhibition. In this study, we quantitatively evaluated the product inhibitory effect of four family 48 glycoside hydrolases using molecular dynamics simulations and product expulsion free-energy calculations. We also suggested a series of single mutants of the four family 48 glycoside hydrolases with theoretically reduced level of product inhibition. The theoretical calculations provide a guide for future experimental studies designed to produce mutant cellulases with enhanced activity. PMID- 26572061 TI - CD4+ T Cell Tolerance to Tissue-Restricted Self Antigens Is Mediated by Antigen Specific Regulatory T Cells Rather Than Deletion. AB - Deletion of self-antigen-specific T cells during thymic development provides protection from autoimmunity. However, it is unclear how efficiently this occurs for tissue-restricted self antigens, or how immune tolerance is maintained for self-antigen-specific T cells that routinely escape deletion. Here we show that endogenous CD4+ T cells with specificity for a set of tissue-restricted self antigens were not deleted at all. For pancreatic self antigen, this resulted in an absence of steady-state tolerance, while for the lung and intestine, tolerance was maintained by the enhanced presence of thymically-derived antigen-specific Foxp3+ regulatory T (Treg) cells. Unlike deletional tolerance, Treg cell-mediated tolerance was broken by successive antigen challenges. These findings reveal that for some tissue-restricted self antigens, tolerance relies entirely on nondeletional mechanisms that are less durable than T cell deletion. This might explain why autoimmunity is often tissue-specific, and it offers a rationale for cancer vaccine strategies targeting tissue-restricted tumor antigens. PMID- 26572062 TI - Caspase-11 Requires the Pannexin-1 Channel and the Purinergic P2X7 Pore to Mediate Pyroptosis and Endotoxic Shock. AB - The noncanonical inflammasome induced by intracellular lipopolysaccharide (LPS) leads to caspase-11-dependent pyroptosis, which is critical for induction of endotoxic shock in mice. However, the signaling pathway downstream of caspase-11 is unknown. We found that cytosolic LPS stimulation induced caspase-11-dependent cleavage of the pannexin-1 channel followed up by ATP release, which in turn activated the purinergic P2X7 receptor to mediate cytotoxicity. In the absence of P2X7 or pannexin-1, pyroptosis induced by cytosolic LPS was abrogated. Cleavage of pannexin-1 required the catalytic activity of caspase-11 and was essential for ATP release and P2X7-mediated pyroptosis. Priming the caspase-11 pathway in vivo with LPS or Toll-like receptor-3 (TLR3) agonist resulted in high mortality in wild-type mice after secondary LPS challenge, but not in Casp11(-/-), Panx1(-/-), or P2x7(-/-) mice. These results reveal a critical role for pannexin-1 and P2X7 downstream of caspase-11 for pyroptosis and susceptibility to sepsis induced by the noncanonical inflammasome. PMID- 26572063 TI - Inflammasomes Coordinate Pyroptosis and Natural Killer Cell Cytotoxicity to Clear Infection by a Ubiquitous Environmental Bacterium. AB - Defective neutrophils in patients with chronic granulomatous disease (CGD) cause susceptibility to extracellular and intracellular infections. Microbes must first be ejected from intracellular niches to expose them to neutrophil attack, so we hypothesized that inflammasomes detect certain CGD pathogens upstream of neutrophil killing. Here, we identified one such ubiquitous environmental bacterium, Chromobacterium violaceum, whose extreme virulence was fully counteracted by the NLRC4 inflammasome. Caspase-1 protected via two parallel pathways that eliminated intracellular replication niches. Pyroptosis was the primary bacterial clearance mechanism in the spleen, but both pyroptosis and interleukin-18 (IL-18)-driven natural killer (NK) cell responses were required for liver defense. NK cells cleared hepatocyte replication niches via perforin dependent cytotoxicity, whereas interferon-gamma was not required. These insights suggested a therapeutic approach: exogenous IL-18 restored perforin-dependent cytotoxicity during infection by the inflammasome-evasive bacterium Listeria monocytogenes. Therefore, inflammasomes can trigger complementary programmed cell death mechanisms, directing sterilizing immunity against intracellular bacterial pathogens. PMID- 26572064 TI - Response to diet-induced obesity produces time-dependent induction and progression of metabolic osteoarthritis in rat knees. AB - Obesity, and corresponding chronic-low grade inflammation, is associated with the onset and progression of knee OA. The origin of this inflammation is poorly understood. Here, the effect of high fat, high sucrose (HFS) diet induced obesity (DIO) on local (synovial fluid), and systemic (serum) inflammation is evaluated after a 12-week obesity induction and a further 16-week adaptation period. For 12 weeks of obesity induction, n = 40 DIO male Sprague-Dawley rats consumed a HFS diet while the control group (n = 14) remained on chow. DIO rats were allocated to prone (DIO-P, top 33% based on weight change) or resistant (DIO-R, bottom 33%) groups at 12-weeks. Animals were euthanized at 12- and after an additional 16 weeks on diet (28-weeks). At sacrifice, body composition and knee joints were collected and assessed. Synovial fluid and sera were profiled using cytokine array analysis. At 12-weeks, DIO-P animals demonstrated increased Modified Mankin scores compared to DIO-R and chow (p = 0.026), and DIO-R had higher Mankin scores compared to chow (p = 0.049). While numerous systemic and limited synovial fluid inflammatory markers were increased at 12-weeks in DIO animals compared to chow, by 28-weeks there were limited systemic differences but marked increases in local synovial fluid inflammatory marker concentrations. Metabolic OA may manifest from an initial systemic inflammatory disturbance. Twelve weeks of obesity induction leads to a unique inflammatory profile and induction of metabolic OA which is altered after a further 16-weeks of obesity and HFS diet intake, suggesting that obesity is a dynamic, progressive process. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1010-1018, 2016. PMID- 26572065 TI - Piezoelectric tuning fork biosensors for the quantitative measurement of biomolecular interactions. AB - The quantitative measurement of biomolecular interactions is of great interest in molecular biology. Atomic force microscopy (AFM) has proved its capacity to act as a biosensor and determine the affinity between biomolecules of interest. Nevertheless, the detection scheme presents certain limitations when it comes to developing a compact biosensor. Recently, piezoelectric quartz tuning forks (QTFs) have been used as laser-free detection sensors for AFM. However, only a few studies along these lines have considered soft biological samples, and even fewer constitute quantified molecular recognition experiments. Here, we demonstrate the capacity of QTF probes to perform specific interaction measurements between biotin-streptavidin complexes in buffer solution. We propose in this paper a variant of dynamic force spectroscopy based on representing adhesion energies E (aJ) against pulling rates v (nm s(-1)). Our results are compared with conventional AFM measurements and show the great potential of these sensors in molecular interaction studies. PMID- 26572066 TI - The Sec1/Munc18 Protein Groove Plays a Conserved Role in Interaction with Sec9p/SNAP-25. AB - The Sec1/Munc18 (SM) proteins constitute a conserved family with essential functions in SNARE-mediated membrane fusion. Recently, a new protein-protein interaction site in Sec1p, designated the groove, was proposed. Here, we show that a sec1 groove mutant yeast strain, sec1(w24), displays temperature-sensitive growth and secretion defects. The yeast Sec1p and mammalian Munc18-1 grooves were shown to play an important role in the interaction with the SNAREs Sec9p and SNAP 25b, respectively. Incubation of SNAP-25b with the Munc18-1 groove mutant resulted in a lag in the kinetics of SNARE complex assembly in vitro when compared with wild-type Munc18-1. The SNARE regulator SRO7 was identified as a multicopy suppressor of sec1(w24) groove mutant and an intact Sec1p groove was required for the plasma membrane targeting of Sro7p-SNARE complexes. Simultaneous inactivation of Sec1p groove and SRO7 resulted in reduced levels of exocytic SNARE complexes. Our results identify the groove as a conserved interaction surface in SM proteins. The results indicate that this structural element is important for interactions with Sec9p/SNAP-25 and participates, in concert with Sro7p, in the initial steps of SNARE complex assembly. PMID- 26572067 TI - The influence of dexamethasone administered prenatally on cartilage of newborn spiny mouse (Acomys cahirinus) offspring. AB - Considering the negative effects of glucocorticoid treatment, especially during fetal development it is important to investigate effectors decreasing such disadvantages. The aim of this study was to investigate the effect of prenatally administered dexamethasone (Dex), a synthetic glucocorticoid, on the histomorphometry of the femur in the offspring of spiny mice. The study was performed on 24 pregnant spiny mice. The time of the experiment included the prenatal period between the 20th day of gestation until birth (pregnancy lasts on average of 36-38 days). The mice from the experimental group received dexamethasone per os in a dose of 125 mg/kg birth weight daily. At the end, the newborns from the experimental and control group were weighted and euthanized. Maternal Dex treatment resulted in a 17% decrease in birth weight in newborns. Dex administration significantly reduced the thickness of the hypertrophy zone of the growth plate by 34% and total thickness by 8,7%. In addition, Dex decreased the number of cells in the articular cartilage by 27% and significantly decreased their diameter by 5%. Dex also affected the structure and spatial distribution of thick and thin collagen fibers, lowering the proportion of thin fibers compared with the control group. Moreover, Dex treatment considerably lowered the amount of proteoglycans in articular and growth cartilages. Exposure to glucocorticoids in pregnant spiny mice affects cartilage development by accelerating maturity of collagen fibers and growth plate, presumably along with further disruption of longitudinal growth of long bones. PMID- 26572068 TI - A 96-week randomized trial of switching to entecavir in patients who achieved virological suppression on lamivudine therapy. AB - BACKGROUND AND AIM: There are limited data assessing whether patients who achieved virological suppression on lamivudine but remain hepatitis B "e" antigen positive should be switched to a more potent antiviral with a high genetic barrier to resistance or continue with lamivudine. We compared the safety and efficacy of switching with entecavir versus continuing lamivudine. METHODS: This was a Phase IV, randomized, open-label, prospective study in a tertiary care setting. Seventy-three chronic hepatitis B patients who achieved virological suppression on lamivudine (serum hepatitis B virus DNA < 60 International Unit (IU)/mL) were enrolled. Entecavir or lamivudine were administered orally for up to 96 weeks. Virologic and serologic responses were measured throughout the study. RESULTS: A significantly higher proportion of patients in the entecavir group achieved hepatitis B virus DNA < 60 IU/mL at Weeks 48 (100% [38/38] vs 62.8% [22/35]; P < 0.001) and 96 (97.4% [37/38] vs 57.1% [20/35]; P<0.001). A greater number of patients had virologic breakthrough (Week 96 cumulative incidence 42.9% vs 2.6%; P<0.001) and genotypic lamivudine resistance (28.6% [10/35] vs 0% [0/38]; P<0.001) in the lamivudine group. No serious adverse events or laboratory abnormalities were reported. CONCLUSIONS: Even after achieving virological suppression on lamivudine therapy, the risk of emergent lamivudine resistance increases over time. Switching to entecavir resulted in a maintained virologic response and superior serologic responses versus continued lamivudine therapy. This study supports a rationale for switching to entecavir in chronic hepatitis B patients with virological suppression on lamivudine. PMID- 26572070 TI - Public health research in the UK: the era of implementation. PMID- 26572069 TI - Combination of remote ischemic perconditioning and remote ischemic postconditioning fails to increase protection against myocardial ischemia/reperfusion injury, compared with either alone. AB - Remote ischemic perconditioning (RIPerC) and remote ischemic postconditioning (RIPostC) have been previously demonstrated to protect the myocardium against ischemia/reperfusion (IR) injury. However, their combined effects remain to be fully elucidated. In order to investigate this, the present study used an in vivo rat model to assess whether synergistic effects are produced when RIPerC is combined with RIPostC. The rats were randomly assigned to the following groups: Sham, IR, RIPerC, RIPostC and RIPerC + RIPostC groups. The IR model was established by performing 40 min of left coronary artery occlusion, followed by 2 h of reperfusion. RIPerC and RIPostC were induced via four cycles of 5 min occlusion and 5 min reperfusion of the hindlimbs, either during or subsequent to myocardial ischemia. On measurement of infarct sizes, compared with the IR group (49.45+/-6.59%), the infarct sizes were significantly reduced in the RIPerC (34.36+/-5.87%) and RIPostC (36.04+/-6.16%) groups (P<0.05). However, no further reduction in infarct size was observed in the RIPerC + RIPostC group (31.43+/ 5.43%; P>0.05), compared with the groups treated with either RIPerC or RIPostC alone. Activation of the reperfusion injury salvage kinase (RISK) Akt, extracellular signal-regulated kinase 1/2 and glycogen synthase kinase-3beta, and survivor activating factor enhancement (SAFE) signal transducer and activator of transcription-3 pathways were enhanced in the RIPerC, RIPostC and the RIPerC + RIPostC groups, compared with the IR group, with no difference among the three groups. Therefore, whereas RIPerC and RIPostC were equally effective in providing protection against myocardial IR injury, the combination of RIPerC and RIPostC failed to provide further protection than treatment with either alone. The cardioprotective effects were found to be associated with increased activation of the RISK and SAFE pathways. PMID- 26572071 TI - A distinct section of the Early Bronze Age society? Stable isotope investigations of burials in settlement pits and multiple inhumations of the Unetice culture in central Germany. AB - OBJECTIVES: Inhumations in so-called settlement pits and multiple interments are subordinate burial practices of the Early Bronze Age Unetice culture in central Germany (2200-1700/1650 BC). The majority of the Unetice population was entombed as single inhumations in rectangular grave pits with a normative position of the body. The goal of the study was to test archaeological hypotheses that the deviant burials may represent socially distinct or nonlocal individuals. MATERIALS AND METHODS: The study comprised up to two teeth and one bone each of 74 human individuals from eight sites and faunal comparative samples. The inhumations included regular, deviant burials in so-called settlement or storage pits, and multiple burials. We investigated radiogenic strontium isotope compositions of tooth enamel ((87) Sr/(86) Sr) and light stable isotope ratios of carbon and nitrogen of bone collagen (delta(13) C, delta(15) N) aiming at the disclosure of residential changes and dietary patterns. RESULTS: Site-specific strontium isotope data ranges mirror different geological properties including calcareous bedrock, loess, and glacial till. Independent from burial types, they disclose low portions of nonlocal individuals of up to some 20% at the individual sites. The light stable isotope ratios of burials in settlement pits and rectangular graves overlap widely and indicate highly similar dietary habits. DISCUSSION: The analytical results let to conclude that inhumations in settlement pits and multiple burials were two of the manifold burial practices of the Early Bronze Age. The selection criteria of the individuals for the different forms of inhumation remained undisclosed. PMID- 26572072 TI - Colonic transit: what is the impact of a diverting loop ileostomy? AB - BACKGROUND: Diverting loop ileostomy (DLI) is used following low anterior resections (LAR) or ultra-low anterior resections (ULAR) to reduce anastomotic leak (AL). Preoperative mechanical bowel preparation (MBP) is traditionally used with DLI. However, clearance of the left colon can be achieved with a fleet enema without the physiological compromise of MBP. We aimed to assess colonic transit following DLI in this context. METHODS: A prospective, observational study was performed with patients with rectal cancer undergoing LAR or ULAR in a tertiary colorectal unit with preoperative fleet enema. Radiopaque markers were inserted into the caecum following rectal resection and formation of a DLI with placement confirmed by image intensifier and endoscopy. X-rays were performed at days 1, 3, 5 and 14 post-operation with data collected prospectively. RESULTS: Ten patients (mean age 57, nine males) were enrolled. Mean time to functioning stoma was 1.9 days (range 1-3). There was no movement in the majority of markers in all patients at Day 5 post-operation. In all seven patients with Day 14 X-rays, the majority of markers remained in the right colon. Two patients had delayed AL, with markers found within the pelvis in both of these patients. CONCLUSIONS: This is the first study to assess colonic transit following DLI using fleet enema only, with results suggesting colonic motility is abolished in this setting. The use of a fleet enema without MBP may be sufficient prior to rectal resection surgery when DLI is employed. AL may actually increase colonic transit. Further research is warranted. PMID- 26572073 TI - Reply to H.J adams et al: "Is FDG-PET/CT a sensitive and specific method for the detection of extranodal involvement in diffuse large B-cell lymphoma?". PMID- 26572074 TI - Erratum: Structural isomerism in gold nanoparticles revealed by X-ray crystallography. PMID- 26572075 TI - MiR-181b promotes chemoresistance in breast cancer by regulating Bim expression. AB - MicroRNAs are emerging as critical regulators of the initiation and progression of multiple types of human cancers, including breast cancer. In the present study, the expression of miR-181b in breast cancer patient serum and breast cancer cell lines was evaluated. It was demonstrated that the miR-181b level was significantly upregulated in patient serum and breast cancer cell lines compared with that in normal controls. The results of in vitro 3H thymidine incorporation and Transwell migration assay indicated that miR-181b overexpression markedly promoted the proliferation and metastasis of breast cancer cells. These data suggest that miR-181b is a tumor promoter in breast cancer. Furthermore, miR-181b expression was found to be upregulated in doxorubicin (DOX)-resistant T-47D cells (T-47D-R) compared with that in the parental T-47D cells, and upregulation of miR 181b expression decreased the anticancer effect of DOX in the T-47D cells. Mechanistic studies demonstrated that the Bim gene, an essential initiator of apoptosis, was inhibited by miR-181b overexpression. We observed that knockdown of miR-181b by its specific inhibitors significantly re-sensitized the T-47D-R cells to the cytotoxicity of DOX. Importantly, we demonstrated that miR-181b inhibitors increased the level of Bim in the T-47D-R cells, resulting in the loss of mitochondrial membrane potential (MMP) and the activation of caspases caused by DOX. In summary, the results of the present study suggest that miR-181b functions as an oncogene during breast cancer development, and the miR-181b/Bim pathway may be a novel target used to overcome the chemoresistance in breast cancer. PMID- 26572076 TI - Overexpression of melanopsin in the retina restores visual function in Royal College of Surgeons rats. AB - Retinitis pigmentosa (RP) is a pathological condition leading to progressive visual decline resulting from continual loss of photoreceptor cells and outer nuclear layers of the retina. The aim of the present study was to explore whether melanopsin was able to restore retinal function and inhibit its degeneration by acting in a similar manner to channel rhodopsins. Royal College of Surgeons rats, which were used as an animal model of inherited retinal degeneration, were subjected to sub-retinal injection with melanopsin overexpression vector (AV-OPN4 GFP). Immunohistochemical and western blot analyses were used to detect the distribution and protein expression of melanopsin in the retina, revealing that melanopsin was gradually reduced with increasing age of the rats, which was due to loss of dendritic axons of intrinsically photosensitive retinal ganglion cells. Animals injected into both eyes were subjected to a behavioral open-field test, revealing that melanopsin overexpression reduced the loss of light sensitivity of the rats. In a flash electroretinography experiment, the b-wave and response to light flash stimuli at three and five weeks following injection with AV-OPN4-GFP were higher compared to those in eyes injected with AV-GFP (P<0.05). In conclusion, the present study showed that during retinal degeneration, the expression of melanopsin was significantly decreased, while vector-mediated overexpression of melanopsin delayed the loss of visual function in rats. PMID- 26572077 TI - Dual role of CD44 isoforms in ampullary adenocarcinoma: CD44s predicts poor prognosis in early cancer and CD44nu is an indicator for recurrence in advanced cancer. AB - BACKGROUND: Although postoperative adjuvant chemoradiotherapies prevent recurrence for some patients with ampullary cancer, the recurrence rate is as high as 29% in patients with stage I cancer. In an effort to identify predictors of recurrence in patients with ampullary adenocarcinoma, we investigated the clinical value of assessing standard and variant forms of CD44. METHODS: Immunohistochemistry staining and reverse-transcription polymerase chain reaction (RT-PCR) was used to detect standard and variant forms of CD44 in samples of ampullary adenocarcinoma. The cDNA microarray analysis comparing tumors with or without pancreatic invasion was undertaken and analyzed by Ingenuity Pathway Analysis. RESULTS: The standard CD44 (CD44s) isoform was detected in 76 of 98 patients with ampullary adenocarcinoma, and the negative or weak expression of CD44s was correlated with pancreatic invasion, lymphovascular invasion, advanced stage and bone metastasis. Moderate to dense expression of CD44s was correlated with shorter overall survival in patients with localized cancer (T1 or T2 disease, P=0.0268). The patients with advanced cancer (T3 or T4 disease) and moderate or dense CD44s expression had a trend toward better survival. Alternative splicing of CD44 was confirmed using RT-PCR, which revealed that the CD44nu3-10 isoform was only expressed in patients with cancer recurrence. Fold change of CD44nu6-10 was also increased. In addition, networks containing CD44, vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR), transforming growth factor-beta (TGF-beta), matrix metalloproteinase 2 (MMP2), AKT, extracellular signal-regulated protein kinase 1 and 2 (ERK1/2), p38 MAPK, activated protein 1 (AP1)' and CTNNB1 were constructed after comparing microarray data from patients with and without pancreatic invasion. CONCLUSIONS: Whereas CD44s functions as tumor-promoting oncoprotein in early localized ampullary adenocarcinoma, CD44 variants are expressed in advanced cancer and patients with recurrence. Regional invasiveness and distant metastasis of ampullary cancer is controlled by a complex interacting network. PMID- 26572078 TI - Acetaminophen for Chronic Pain: A Systematic Review on Efficacy. AB - Acetaminophen (paracetamol) is the most commonly used analgesic worldwide and recommended as first-line treatment in all pain conditions by WHO. We performed a systematic literature review to evaluate the efficacy of acetaminophen when used for chronic pain conditions. Applying three broad search strategies for acetaminophen use in chronic pain in both Embase and PubMed, 1551 hits were obtained. After cross-reference searches of both trials and 38 reviews, seven studies comparing acetaminophen in continuous dosing regimens of more than 2 weeks with placebo were included. The review was conducted according to the PRISMA guidelines. All studies were conducted in patients with hip- or knee osteoarthritis and six of seven studies had observation periods of less than 3 months. All included studies showed no or little efficacy with dubious clinical relevance. In conclusion, there is little evidence to support the efficacy of acetaminophen treatment in patients with chronic pain conditions. Assessment of continuous efficacy in the many patients using acetaminophen worldwide is recommended. PMID- 26572079 TI - Multifunctional Silica Nanoparticles for Covalent Immobilization of Highly Sensitive Proteins. AB - A convenient reverse micellar one-pot reaction yields multifunctional silica nanoparticles, which can be tailored to effectively suppress non-specific adsorption and, at the same time, enable efficient specific covalent immobilization of proteins. Using two highly sensitive proteins, it is demonstrated that the new particles provide a suitable microenvironment to maintain the protein's activity. PMID- 26572080 TI - A patient with severe haemophilia A and multiple arterial thromboses caused by large vessel vasculitis: a case report. PMID- 26572081 TI - Television viewing duration and blood pressure among 18-74-year-old adults. The French nutrition and health survey (ENNS, 2006-2007). AB - OBJECTIVES: To describe Blood Pressure (BP) according to the time spent viewing television and examine whether the associations between television viewing and systolic and diastolic BP differed depending on sex, age and BMI. DESIGN: The French health and nutrition survey (ENNS) was conducted in 2006-2007 on a multistage stratified random sample of 18-74-year-old adults. METHODS: Systolic (SBP) and diastolic BP (DBP) were assessed using three measurements. Among subjects without BP-lowering drugs and lifestyle measures, adjusted means of SBP and DBP were estimated for each television viewing category (<3h and >=3h). RESULTS: Among 2050 ENNS participants, 81.2% declared neither drug medication nor lifestyle change to lower BP. In women without BP-lowering measure, viewing television 3h/day or more increased significantly SBP and DBP adjusted means (+2mmHg) compared to women who spent less than 3h/day in front of the television. These associations were stronger in obese or 35-54-year-old women. In men, no relationship between DBP and television-viewing has been observed. Though, SBP was positively associated with television-viewing in non-overweight, 18-29 or 55 74 year-old men. CONCLUSIONS: These results show that the association between television viewing duration and BP must be evaluated differently between gender, age group and BMI category. PMID- 26572082 TI - Stones: Expelling stones with ultrasonic propulsion. PMID- 26572083 TI - Prostate cancer: Staying grounded - flightless-1 is a tumour suppressor. PMID- 26572084 TI - Sexual dysfunction: Magnetic control of stem cells: feasible for ED. PMID- 26572085 TI - Prostate cancer: Galeterone ARMORs up against CRPC. PMID- 26572086 TI - Meaning in life in psychotherapy: The perspective of experienced psychotherapists. AB - OBJECTIVE: Our goal was to explore the meaning experienced psychotherapists derive from providing psychotherapy, their beliefs about the role of meaning in life (MIL) in psychotherapy, how they worked with MIL with a client who explicitly presented concerns about MIL, and how they worked with a different client for whom MIL was a secondary and more implicit concern. METHOD: Thirteen experienced psychotherapists were interviewed and data were analyzed using consensual qualitative research. RESULTS: Therapists derived self-oriented meaning (e.g., feeling gratified, fulfilled, connected) and other-oriented meaning (helping others, making the world a better place) from providing psychotherapy. They believed that MIL is fundamental and underlies all human concerns, including those brought to therapy. In contrast to the clients who had implicit MIL concerns, clients who explicitly presented MIL concerns were reported to have more interpersonal problems and physical problems, but about the same amount of psychological distress and loss/grief. Therapists used insight oriented interventions, support, action-oriented interventions, and exploratory interventions to work with MIL with both types of clients, but used more exploratory interventions with implicit than explicit MIL clients. CONCLUSIONS: MIL is a salient topic for experienced, existentially oriented psychotherapists; they work with MIL extensively with some clients in psychotherapy. We recommend that therapists receive training to work with MIL in therapy, and that they pay attention to MIL concerns when they conduct psychotherapy. We also recommend additional research on MIL in psychotherapy. PMID- 26572087 TI - Gain-of-function p53 mutant with 21-bp deletion confers susceptibility to multidrug resistance in MCF-7 cells. AB - The majority of p53 mutations, which are responsible for gain of oncogenic function, are missense mutations in hotspot codons. However, in our previous study, we demonstrated that a deletion spanning codons 127-133 in the p53 gene (designated as del p53) was detected in doxorubicin-resistant MCF-7 cell lines following various induction processes. In the present study, we aimed to investigate the role of del p53 and its association with the proliferation, metastasis and drug resistance of MCF-7 cells. The MCF-7/del p53 cell line is a representative of the del p53 stably expressed clones which were constructed by transfection of the del p53-containing construct into MCF-7/wt cells. Markers of multidrug resistance (MDR), epithelial-mesenchymal transition (EMT) and stem cell like properties were examined in the MCF-7/del p53 cells. The results revealed that the MCF-7/del p53 cells expressed full-length p53 and del p53 mRNA and protein, as well as P-glycoprotein (P-gp). The MCF-7/del p53 cells acquired resistance to doxorubicin with increased P-gp efflux function. Using a transient expression assay, the mdr1 promoter was found to be significantly activated by external or integrated del p53 (P<0.001). The inhibition of nuclear factor (NF) kappaB by cyclosporine sensitized the MCF-7/del p53 cells to doxorubicin toxicity. In addition, the morphological characteristics of the MCF-7/del p53 and MCF-7/adr were similar. EMT was observed in the MCF-7/del p53 cells as demonstrated by the presence of the mesenchymal markers, Slug and vimentin, and the decrease in the epithelial marker, cadherin 1, type 1, E-cadherin (CDH1), as well as an enhanced migration ability (P<0.001). Furthermore, the number of cells expressing the cancer stem cell-like marker, CD44, increased, accompanied by mammosphere formation. Taken together, these findings indicate that the expression of del p53 in MCF-7/del p53 cells enables the cells to partially acquire doxorubicin resistance characteristics of the MCF-7/adr cells. Thus, del p53 may be an important factor in non-invasive MCF-7 cells, activating NF-kappaB signaling and the mdr1 promoter and partially attributing to EMT; the cells thus acquire stem cell-like properties, which facilitates drug resistance. Therefore, the 21-bp deletion of p53 may prove to be a therapeutic strategy with which to prevent cancer cells from acquiring resistance to drugs. PMID- 26572088 TI - PEG-Biscyanoacrylate Crosslinker for Octyl Cyanoacrylate Bioadhesive. AB - PEG400 (polyethylene glycol, MW 400) biscyanoacrylate is synthesized and copolymerized with 2-octyl cyanoacrylate for potential use as bioadhesive. PEG400 biscyanoacrylate is synthesized from the esterification of anthracenyl cyanoacrylic acid where the anthracene unit serves as vinyl-protecting group. Copolymerization increases the plasticity, mechanical strength, and resilience of the resulted polymer as determined by dynamic mechanical analysis. Peeling test confirms its superior bioadhesive properties. Surface morphology is characterized by SEM imaging. The formulations are cytocompatible and safe. This cyanoacrylate composition may provide improved bioadhesive cyanoacrylates. PMID- 26572089 TI - Novel approaches to biological therapy for psoriatic arthritis. AB - INTRODUCTION: Improved understanding of the immunopathogenic mechanisms in psoriatic arthritis (PsA) has led to the development of targeted biological therapies, which demonstrate superior clinical efficacy to traditional disease modifying antirheumatic drugs (DMARDs). There are currently 3 classes of biological agents that are approved for the treatment of psoriatic disease: tumor necrosis factor alpha inhibitors (TNFi), including etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol; ustekinumab, a monoclonal antibody (mAb) directed against interleukin (IL)-12 and IL-23; and secukinumab, a human anti-IL-17A mAb. Other agents are in development. Our growing experience with these medications has revolutionized the approach to disease management in PsA. AREAS COVERED: This article discusses the rationale for using biological therapies in PsA, highlighting clinical trial evidence that supports the use of these agents. We summarize novel treatment approaches using biological therapies in the management of PsA, including early intervention, targeted therapy, TNFi switching, combination therapy, and tapering or discontinuation of biological therapy. We conclude with a discussion of the importance comorbidities have on selection of therapy. EXPERT OPINION: The advent of highly effective biological therapies has revolutionized the management of patients with PsA. Growing experience with these agents has led to novel treatment approaches that may improve clinical outcomes for PsA patients. PMID- 26572090 TI - Cholinergic control of ventral surface chemoreceptors involves Gq/inositol 1,4,5 trisphosphate-mediated inhibition of KCNQ channels. AB - KEY POINTS: ACh is an important modulator of breathing, including at the level of the retrotrapezoid nucleus (RTN), where evidence suggests that ACh is essential for the maintenance of breathing. Despite this potentially important physiological role, little is known about the mechanisms responsible for the cholinergic control of RTN function. In the present study, we show at the cellular level that ACh increases RTN chemoreceptor activity by a CO2/H(+) independent mechanism involving M1/M3 receptor-mediated inositol 1,4,5 trisphosphate/Ca(+2) signalling and downstream inhibition of KCNQ channels. These results dispel the theory that ACh is required for RTN chemoreception by showing that ACh, similar to serotonin and other modulators, controls the activity of RTN chemoreceptors without interfering with the mechanisms by which these cells sense H(+). By identifying the mechanisms by which wake-on neurotransmitters such as ACh modulate RTN chemoreception, the results of the present study provide a framework for understanding the molecular basis of the sleep-wake state-dependent control of breathing. ABSTRACT: ACh has long been considered important for the CO2/H(+)-dependent drive to breathe produced by chemosensitive neurons in the retrotrapezoid nucleus (RTN). However, despite this potentially important physiological role, almost nothing is known about the mechanisms responsible for the cholinergic control of RTN function. In the present study, we used slice patch electrophysiology and pharmacological tools to characterize the effects of ACh on baseline activity and CO2/H(+)-sensitivity of RTN chemoreceptors, as well as to dissect the signalling pathway by which ACh activates these neurons. We found that ACh activates RTN chemoreceptors in a dose-dependent manner (EC50 = 1.2 MUm). The firing response of RTN chemoreceptors to ACh was mimicked by a muscarinic receptor agonist (oxotremorine; 1 MUm), and blunted by M1- (pirezenpine; 2 MUm) and M3- (diphenyl-acetoxy-N-methyl-piperidine; 100 nm) receptor blockers, but not by a nicotinic-receptor blocker (mecamylamine; 10 MUm). Furthermore, pirenzepine, diphenyl-acetoxy-N-methyl-piperidine and mecamylamine had no measurable effect on the CO2/H(+)-sensitivity of RTN chemoreceptors. The effects of ACh on RTN chemoreceptor activity were also blunted by inhibition of inositol 1,4,5-trisphosphate receptors with 2 aminoethoxydiphenyl borate (100 MUm), depletion of intracellular Ca(2+) stores with thapsigargin (10 MUm), inhibition of casein kinase 2 (4,5,6,7 tetrabromobenzotriazole; 10 MUm) and blockade of KCNQ channels (XE991; 10 MUm). These results show that ACh activates RTN chemoreceptors by a CO2/H(+) independent mechanism involving M1/M3 receptor-mediated inositol 1,4,5 trisphosphate/Ca(+2) signalling and downstream inhibition of KCNQ channels. Identifying the components of the signalling pathway coupling muscarinic receptor activation to changes in chemoreceptor activity may provide new potential therapeutic targets for the treatment of respiratory control disorders. PMID- 26572091 TI - N-terminally and C-terminally truncated forms of glucose-dependent insulinotropic polypeptide are high-affinity competitive antagonists of the human GIP receptor. AB - BACKGROUND AND PURPOSE: Glucose-dependent insulinotropic polypeptide (GIP) affects lipid, bone and glucose homeostasis. High-affinity ligands for the GIP receptor are needed to elucidate the physiological functions and pharmacological potential of GIP in vivo. GIP(1-30)NH2 is a naturally occurring truncation of GIP(1-42). Here, we have characterized eight N-terminal truncations of human GIP(1-30)NH2 . EXPERIMENTAL APPROACH: COS-7 cells were transiently transfected with human GIP receptors and assessed for cAMP accumulation upon ligand stimulation or competition binding with (125) I-labelled GIP(1-42), GIP(1-30)NH2 , GIP(2-30)NH2 or GIP(3-30)NH2 . KEY RESULTS: GIP(1-30)NH2 displaced (125) I GIP(1-42) as effectively as GIP(1-42) (Ki 0.75 nM), whereas the eight truncations displayed lower affinities (Ki 2.3-347 nM) with highest affinities for GIP(3 30)NH2 and GIP(5-30)NH2 (5-30)NH2 . Only GIP(1-30)NH2 (Emax 100% of GIP(1-42)) and GIP(2-30)NH2 (Emax 20%) were agonists. GIP(2- to 9-30)NH2 displayed antagonism (IC50 12-450 nM) and Schild plot analyses identified GIP(3-30)NH2 and GIP(5-30)NH2 as competitive antagonists (Ki 15 nM). GIP(3-30) NH2 was a 26-fold more potent antagonist than GIP(3-42). Binding studies with agonist ((125) I GIP(1-30)NH2 ), partial agonist ((125) I-GIP(2-30)NH2 ) and competitive antagonist ((125) I-GIP(3-30)NH2 ) revealed distinct receptor conformations for these three ligand classes. CONCLUSIONS AND IMPLICATIONS: The N-terminus is crucial for GIP agonist activity. Removal of the C-terminus of the endogenous GIP(3-42) creates another naturally occurring, more potent, antagonist GIP(3 30)NH2 , which like GIP(5-30)NH2 , was a high-affinity competitive antagonist. These peptides may be suitable tools for basic GIP research and future pharmacological interventions. PMID- 26572092 TI - Gene expression and immunochemical localization of major cytochrome P450 drug metabolizing enzymes in bovine nasal olfactory and respiratory mucosa. AB - Despite tremendous advancement in the characterization of nasal enzyme expression, knowledge of the role of the nasal mucosa in the metabolism of xenobiotics is still inadequate, primarily due to the limited availability of in vitro models for nasal metabolism screening studies. An extensive knowledge of the oxidative and conjugative metabolizing capacity of the cattle (Bos taurus) olfactory and respiratory mucosa can aid in efficient use of these tissues for pre-clinical investigations of the biotransformation and toxicity of therapeutic agents following nasal administration or inhalation. Cows are also exposed to a variety of airborne pollutants and pesticides during their lifetime, the metabolism of which can have profound toxicological and ecological consequences. The aim of the present study was to characterize cytochrome P450 (CYP) enzyme expression in the bovine nasal mucosa. Amplification of the specific genes through RT-PCR confirmed expression of several CYP enzymes in bovine hepatic and nasal tissues. The results demonstrate that bovine nasal olfactory and respiratory mucosal and liver tissues express similar populations, families, and distributions of CYP enzymes, as has been previously reported with other species, including humans. Bovine ex vivo tissues can serve as a readily available reference tissue to elucidate preclinical toxico-kinetic effects resulting from exposure to substances in the environment or following drug administration. PMID- 26572093 TI - Fit 5 Kids TV Reduction Program for Latino Preschoolers: A Cluster Randomized Controlled Trial. AB - INTRODUCTION: Reducing Latino preschoolers' TV viewing is needed to reduce their risk of obesity and other chronic diseases. This study's objective was to evaluate the Fit 5 Kids (F5K) TV reduction program's impact on Latino preschooler's TV viewing. STUDY DESIGN: Cluster RCT with randomization at the center level and N=160 participants. SETTING/PARTICIPANTS: Latino children aged 3 5 years and their parents were recruited from six Head Start centers in Houston TX in 2010-2012 with analyses in 2013-2014. INTERVENTION: F5K was culturally adapted for Latino preschoolers and the overall goal was to reduce TV viewing. Study staff taught F5K over 7-8 weeks during the regular Head Start day directly to intervention students. Control schools provided the usual Head Start curriculum, which did not specifically cover TV viewing. MAIN OUTCOME MEASURES: Individual-level outcomes were measured prior to (Time 1) and immediately following (Time 2) the intervention. The primary outcome, TV viewing (minutes/day), was measured by validated 7-day TV diaries (parent-reported). Sedentary time was measured by accelerometers. RESULTS: Per the adjusted repeated measures linear mixed effects model for TV viewing (minutes/day), intervention children decreased from 76.2 (9.9) at Time 1 to 52.1 (10.0) at Time 2, whereas control children remained about the same from 84.2 (10.5) at Time 1 to 85.4 (10.5) at Time 2. The relative difference from Time 1 to Time 2 was -25.3 (95% CI= -45.2, -5.4) minutes for intervention versus control children (N=160, p=0.01). In a similar adjusted model, there was a relative decrease in sedentary time (minutes/day) from Time 1 to Time 2 favoring the intervention children ( 9.5, 95% CI= -23.0, 4.1), although not significant at p<0.05. CONCLUSIONS: F5K reduced Latino preschoolers' TV viewing by >25 minutes daily. These findings have implications for prevention of obesity, related disorders, and health equity. TRIAL REGISTRATION: This study is registered at www.clinicaltrials.gov NCT01216306. PMID- 26572094 TI - Comparison of Lecture-Based Learning vs Discussion-Based Learning in Undergraduate Medical Students. AB - OBJECTIVE: To compare lecture-based learning (LBL) and discussion-based learning (DBL) by assessing immediate and long-term knowledge retention and application of practical knowledge in third- and fourth-year medical students. DESIGN: A prospective, randomized control trial was designed to study the effects of DBL. Medical students were randomly assigned to intervention (DBL) or control (LBL) groups. Both the groups were instructed regarding the management of gastroschisis. The control group received a PowerPoint presentation, whereas the intervention group was guided only by an objectives list and a gastroschisis model. Students were evaluated using a multiple-choice pretest (Pre-Test MC) immediately before the teaching session, a posttest (Post-Test MC) following the session, and a follow-up test (Follow-Up MC) at 3 months. A practical examination (PE), which tested simple skills and management decisions, was administered at the end of the clerkship (Initial PE) and at 3 months after clerkship (Follow-Up PE). Students were also given a self-evaluation immediately following the Post Test MC to gauge satisfaction and comfort level in the management of gastroschisis. SETTING: University of Iowa Hospitals and Clinics and the Carver College of Medicine, Iowa City, IA. PARTICIPANTS: A total of 49 third- and fourth year medical students who were enrolled in the general surgery clerkship were eligible for this study. Enrollment into the study was completely voluntary. Of the 49 eligible students, 36 students agreed to participate in the study, and 27 completed the study. RESULTS: Mean scores for the Pre-Test MC, Post-Test MC, and Follow-Up MC were similar between the control and intervention groups. In the control group, the Post-Test MC scores were significantly greater than Pre-Test MC scores (8.92 +/- 0.79 vs 4.00 +/- 1.04, p < 0.0001), whereas the Follow-Up MC scores were significantly lower than Post-Test MC scores (7.17 +/- 1.75 vs 8.92 +/- 0.79, p = 0.005). In the control group, the Follow-Up MC scores were significantly greater than Pre-Test MC scores (7.17 +/- 1.75 vs 4.00 +/- 1.04, p < 0.0001). Analysis of variance for all control group MC examinations had a p < 0.0001. In the intervention group, the Post-Test MC scores were significantly greater than Pre-Test MC scores (8.33 +/- 1.23 vs 4.60 +/- 1.55, p < 0.0001), whereas the Follow-Up MC scores were significantly lower than Post-Test MC scores (7.13 +/- 1.77 vs 8.33 +/- 1.23, p = 0.04). In the intervention group, the Follow Up MC scores were significantly greater than Pre-Test MC scores (7.13 +/- 1.77 vs 4.60 +/- 1.55, p = 0.0002). Analysis of variance for all intervention group MC examinations had a p < 0.0001. Mean scores for the Initial PE were significantly higher for the intervention group compared with the control group's score (7.47 +/- 1.68 vs 5.25 +/- 2.34, p = 0.008). Mean scores for the Follow-Up PE were significantly higher for the intervention group compared with the control group's score (7.87 +/- 1.77 vs 5.83 +/- 2.04, p = 0.005). A comparison of Initial PE vs Follow-Up PE was not significant in either group. Students in the intervention group were more comfortable in the immediate management of gastroschisis and placement of a silo and felt that the educational experience was more worthwhile than students in the control group did. CONCLUSIONS: After a single instructional session, there was a significant difference in the students' scores between the control and the intervention groups on both administrations of the PEs. There were no significant differences between the 2 groups in any administration of the MC examinations. This seems to suggest that DBL may lead to better practical knowledge and potentially improved long-term knowledge retention when compared with LBL. Students in the DBL group also felt more comfortable with the management of gastroschisis and were more satisfied with the educational session. PMID- 26572095 TI - Preparing Scientific Papers, Posters, and Slides. AB - Publications and presentations are important in academic medicine. The ability to present information in a standard fashion is critically important. Papers, posters, and slides must be prepared appropriately to maximize their chance of being accepted. The first step is to use word processing software correctly. English language usage must conform to standard scientific English usage. Abbreviations should be avoided as much as possible. Numerical data must be presented with the appropriate number of significant figures. The first step in preparing a paper is to decide the target journal. Papers should always be written in 12 point Times New Roman font, while slides and posters should be in Arial or Helvetica. The Results section must contain actual data with appropriate statistical analysis. Take great care to prepare figures and tables according to the journal's instructions. Posters must be prepared to allow easy reading at a distance of 2m. Use a white background and dark letters. The majority of the area of your poster should be Results, and there is no need to include the abstract or references on a poster. Slide presentations should be limited to about one slide for each minute of the talk. Avoid the use of animations and excessive use of color. Do not use abbreviations on slides. Following these simple guidelines will meet the requirements of most journals and allow your audience to appreciate the data on your posters and slides. PMID- 26572096 TI - Basic Surgical Skill Retention: Can Patriot Motion Tracking System Provide an Objective Measurement for it? AB - BACKGROUND: Knot tying is a fundamental skill that surgical trainees have to learn early on in their training. The aim of this study was to establish the predictive and concurrent validity of the Patriot as an assessment tool and determine the skill retention in first-year surgical trainees after 5 months of training. METHODS: First-year surgical trainees were recruited in their first month of the training program. Experts were invited to set the proficiency level. The subjects performed hand knot tying on a bench model. The skill was assessed at baseline in the first month of training and at 5 months. The assessment tools were the Patriot electromagnetic tracking system and Objective Structured Assessment of Technical Skills (OSATS). The trainees' scores were compared to the proficiency score. The data were analyzed using paired t-test and Pearson correlation analysis. RESULTS: A total of 14 first-year trainees participated in this study. The time taken to complete the task and the path length (PL) were significantly shorter (p = 0.007 and p = 0.0085, respectively) at 5 months. OSATS scoring showed a significant improvement (p = 0.0004). There was a significant correlation between PL and OSATS at baseline (r = -0.873) and at Month 5 (r = 0.774). In all, 50% of trainees reached the proficiency PL at baseline and at Month 5. Among them, 3 trainees improved their PL to reach proficiency and the other 3 trainees failed to reach proficiency. CONCLUSION: The parameters from the Patriot motion tracker demonstrated a significant correlation with the classical observational assessment tool and were capable of highlighting the skill retention in surgical trainees. Therefore, the automated scoring system has a significant role in the surgical training curriculum as an adjunct to the available assessment tool. PMID- 26572098 TI - Selective fluorescence functionalization of dye-doped polymerized structures fabricated by direct laser writing (DLW) lithography. AB - The continuous development of the vast arsenal of fabrication techniques is a pivotal factor in the breakthrough of nanotechnology. Although the broad interest is generally focused on the reduction of the dimensions of the fabricated structures, localized functionalization of the nanomaterials emerges as a key factor closely linked to their potential applications. In particular, fabrication of spatially selective fluorescence nanostructures is highly demanded in nanophotonics, as for example in three-dimensional (3D) optical data storage (ODS), where massive storage capacity and fast writing-reading processes are promised. We have developed an innovative method to control the location and intensity of the fluorescence signal in dye-doped photopolymerized structures fabricated with Direct Laser Writing (DLW) lithography. Well-defined fluorescent pixels (area = 0.24 MUm(2)) were written inside a polymer matrix with the help of a femtosecond pulsed laser (multiphoton absorption) via a thermally-induced di aggregation of a fluorescent dye. Moreover, we have accomplished a fine control of the fluorescence intensity which can increase the storage capacity of ODS systems fabricated with this approach. PMID- 26572097 TI - Enhanced renewal of regulatory T cells in relation to CD4(+) conventional T lymphocytes in the peripheral compartment. AB - CD4(+) Foxp3(+) regulatory T (Treg) cells are necessary for the maintenance of self-tolerance and T-cell homeostasis. This population is kept at stable frequencies in secondary lymphoid organs for the majority of the lifetime, despite permanent thymic emigration or in the face of thymic involution. Continuous competition is expected to occur between recently thymus-emigrated and resident Treg cells (either natural or post-thymically induced). In the present work, we analysed the renewal dynamics of Treg cells compared with CD4(+) Foxp3- conventional T cells (Tconv), using protocols of single or successive T-cell transfers into syngeneic euthymic or lymphopenic (nu/nu or RAG2(-/-)) mice, respectively. Our results show a higher turnover for Treg cells in the peripheral compartment, compared with Tconv cells, when B cell-sufficient euthymic or nude hosts are studied. This increased renewal within the Treg pool, shown by the greater replacement of resident Treg cells by donor counterparts, correlates with augmented rates of proliferation and is not modified following temporary environmental perturbations induced by inflammatory state or microbiota alterations. Notably, the preferential substitution of Treg lymphocytes was not observed in RAG2(-/-) hosts. We showed that limited B-cell replenishment in the RAG2(-/-) hosts decisively contributed to the altered peripheral T-cell homeostasis. Accordingly, weekly transfers of B cells to RAG2(-/-) hosts rescued the preferential substitution of Treg lymphocytes. Our study discloses a new aspect of T-cell homeostasis that depends on the presence of B lymphocytes to regulate the relative incorporation of recently arrived Treg and Tconv cells in the peripheral compartment. PMID- 26572099 TI - Occupational exposures and chronic kidney disease: Possible associations with endotoxin and ultrafine particles. AB - BACKGROUND: Chronic kidney disease (CKD) carries a high public health burden yet there is limited research on occupational factors, which are examined in this retrospective case-control study. METHODS: Newly diagnosed cases of CKD (n = 547) and controls (n = 508) from North Carolina provided detailed work histories in telephone interviews. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: There was heterogeneity in the association of CKD and agricultural work, with crop production associated with increased risk and work with livestock associated with decreased risk. Work with cutting/cooling/lubricating oils was associated with a reduced risk. CKD risk was increased for working in dusty conditions. CONCLUSIONS: CKD risk was reduced in subjects with occupational exposures previously reported to involve endotoxin exposure. Further, exposure to dusty conditions was consistently associated with increased risk of glomerulonephritis across industry, suggesting that research on CKD and ultrafine particulates is needed. PMID- 26572100 TI - MicroRNA-1915-3p prevents the apoptosis of lung cancer cells by downregulating DRG2 and PBX2. AB - Micro (mi)RNAs are short non-coding RNA molecules, which post-transcriptionally regulate gene expression and exert key roles in cell growth, differentiation and apoptosis. In the present study, the mechanism and the function of miR-1915-3p in the apoptotic regulation of lung cancer cell lines (NCI-H441 and NCI-H1650) were investigated. The expression analysis confirmed that the expression of miR-1915 3p was markedly decreased in the apoptotic cells. The overexpression of miR-1915 3p in the lung cancer cells prevented apoptosis induced by etoposide. Developmentally regulated GTP-binding protein 2 (DRG2) and pre-B cell leukemia homeobox 2 (PBX2) were identified as downstream targets of miR-1915-3p, which was shown to bind directly to the 3'-untranslated region of DRG2 and PBX2, subsequently lowering their mRNA and protein expression levels. Co-expression of miR-1915-3p and DRG2/PBX2 in the NCI-H441 and NCI-H1650 cells partly circumvented the effect of miR-1915-3p on apoptosis. The results in the present study revealed that miR-1915-3p functions as a silencer of apoptosis, which regulates lung cancer apoptosis via targeting DRG2/PBX2, and consequently this miRNA may be a putative therapeutic target in lung cancer. PMID- 26572101 TI - Optogenetic stimulation reveals distinct modulatory properties of thalamostriatal vs corticostriatal glutamatergic inputs to fast-spiking interneurons. AB - Parvalbumin-containing fast-spiking interneurons (FSIs) exert a powerful feed forward GABAergic inhibition on striatal medium spiny neurons (MSNs), playing a critical role in timing striatal output. However, how glutamatergic inputs modulate their firing activity is still unexplored. Here, by means of a combined optogenetic and electrophysiological approach, we provide evidence for a differential modulation of cortico- vs thalamo-striatal synaptic inputs to FSIs in transgenic mice carrying light-gated ion channels channelrhodopsin-2 (ChR2) in glutamatergic fibers. Corticostriatal synapses show a postsynaptic facilitation, whereas thalamostriatal synapses present a postsynaptic depression. Moreover, thalamostriatal synapses exhibit more prominent AMPA-mediated currents than corticostriatal synapses, and an increased release probability. Furthermore, during current-evoked firing activity, simultaneous corticostriatal stimulation increases bursting activity. Conversely, thalamostriatal fiber activation shifts the canonical burst-pause activity to a more prolonged, regular firing pattern. However, this change in firing pattern was accompanied by a significant rise in the frequency of membrane potential oscillations. Notably, the responses to thalamic stimulation were fully abolished by blocking metabotropic glutamate 1 (mGlu1) receptor subtype, whereas both acetylcholine and dopamine receptor antagonists were ineffective. Our findings demonstrate that cortical and thalamic glutamatergic input differently modulate FSIs firing activity through specific intrinsic and synaptic properties, exerting a powerful influence on striatal outputs. PMID- 26572102 TI - Outcome of patients on second line antiretroviral therapy under programmatic condition in India. AB - BACKGROUND: The National AIDS Control Organization of India has been providing free second line antiretroviral therapy (ART) since 2008. This observational study reports the survival and virologic suppression of patients on second-line ART under programmatic condition and type of mutations acquired by those failing therapy. METHODS: 170 patients initiated on second-line therapy between 2008 and 2012 were followed up till 2013. Viral Load (VL) was repeated at 6 months for all patients and at 12 months for those with VL >400 copies/ml at 6 months. Adequate virological response was defined as plasma HIV-1 VL <400 copies/ml and virological failure was defined as VL >1000 copies/ml. Genotyping was done in 16 patients with virological failure. RESULTS: Out of 170 patients, 110 (64.7 %) were alive and on therapy and 35 (20.5 %) expired. In the first year the occurrence of death was 13.7 /100 person years while between 1 and 5 year it was 3.88 /100 person years. In the first year, duration of immunological failure >12 months, weight <45 kg, WHO clinical stage 3 and 4 and WHO criteria CD4 count less than pretherapy baseline [hazard ratio HR 4.2. 15.8, 11.9 & 4.1 respectively] and beyond first year poor first and second line adherence and first line CD4 count < 200/MUL [HR 5.2,15.8, 3.3 respectively] had high risk of death. 119/152 (78.2 %) had adequate virological response and 27/152 (17.7 %) had virological failure. High viral load at baseline and poor second line adherence (Odds Ratio 3.4 & 2.8 respectively) had increased risk of virological failure. Among those genotyped, 50 % had major Protease Inhibitor mutation (M46I commonest) however 87.5 % were still susceptible to darunavir. CONCLUSIONS: Second line therapy has shown high early mortality but good virological suppression under programmatic conditions. PMID- 26572103 TI - Universal Quake Statistics: From Compressed Nanocrystals to Earthquakes. AB - Slowly-compressed single crystals, bulk metallic glasses (BMGs), rocks, granular materials, and the earth all deform via intermittent slips or "quakes". We find that although these systems span 12 decades in length scale, they all show the same scaling behavior for their slip size distributions and other statistical properties. Remarkably, the size distributions follow the same power law multiplied with the same exponential cutoff. The cutoff grows with applied force for materials spanning length scales from nanometers to kilometers. The tuneability of the cutoff with stress reflects "tuned critical" behavior, rather than self-organized criticality (SOC), which would imply stress-independence. A simple mean field model for avalanches of slipping weak spots explains the agreement across scales. It predicts the observed slip-size distributions and the observed stress-dependent cutoff function. The results enable extrapolations from one scale to another, and from one force to another, across different materials and structures, from nanocrystals to earthquakes. PMID- 26572105 TI - [Our Goal: To Keep Looking for Excellence in Colombian Psychiatry]. PMID- 26572104 TI - [Leukocytes as risk markers for cardiovascular disease in adolescents: association with birth characteristics, nutritional status and biochemical tests]. AB - OBJECTIVE: To evaluate the correlation between the number of leukocytes and cardiovascular risks associated with birth characteristics, nutritional status and biochemical tests. METHODS: Cross-sectional study developed with 475 adolescents, born between 1992 and 2001, in the municipality of Vicosa (MG). Maternal medical records were analyzed in the hospital units, and the following was recorded: birth weight and length, head circumference, chest circumference, Apgar score, gestational age. In adolescents, body mass index, skinfold thickness, body composition, blood count, biochemical tests and clinical variables were also assessed. The statistical analyses was carried out using Statistical Package for Social Sciences (SPSS) version 20.0 and Data Analysis and Statistical Software (STATA) with Kruskal-Wallis, Mann-Whitney, chi-square or Fisher's exact tests and Linear Regression. Significance level was set at alpha<0.05. The study was approved by the Research Ethics Committee of UFV for studies with human subjects. RESULTS: Weight and birth length, head and chest circumference were higher among boys. In adolescents, the number of leukocytes was higher in individuals with excess weight and body fat and high adiposity index, waist-to-height ratio and waist circumference. Only altered triglycerides showed differences between leukocyte medians. Regardless of the anthropometric variable of the final regression model, the stage of adolescence, number of platelets, eosinophils, monocytes and lymphocytes were associated with the increase in leukocytes. CONCLUSIONS: The birth variables were not associated with changes in leukocyte numbers, whereas the anthropometric variables were good indicators for a higher leukocyte count, regardless of the stage of adolescence and gender. PMID- 26572106 TI - [Cerebral Changes in the Morphometrics of HIV Patients]. AB - Cerebral atrophy is a common finding in patients infected with the Human Immunodeficiency Virus (HIV), particularly in patients with dementia. This disease shows neocortical compromise in late stages as well as compromise in the basal ganglia in early or asyntomatic phases. OBJECTIVE: Evaluate changes in total brain volume, caudate nucleus volume, nucleus accumbens volume, and fractional anisotropy of white matter tracts in HIV patients without neurodegenerative symptoms, in comparison with healthy subjects. METHODS: For segmentation and quantification purposes of the brain tissue, the brain and skull were extracted and the tissue was normalized according to total brain volume. From the tissue thus obtained, the caudate nucleus and nucleus accumbens volumes were segmented. The method of statistic spatial tractography was used for quantification and search of differences in the fractional anisotropy coefficient. RESULTS: The percentage of white matter volume with respect to brain volume was smaller in HIV patients (42.83+/-2.65 %) when compared with healthy subjects (43.56+/-1.60 %). The percentage of left nucleus accumbens volume in HIV patients was 0.0254+/-0.0073 % of the brain and 0.0351+/-0.0067 % in healthy subjects; (p<0.05). CONCLUSIONS: It was not evident A decrease in the volume of the gray matter parenchyma was not evident or significant, except in the left nucleus accumbens. Global but not regional changes were found in white matter tracts. PMID- 26572107 TI - [Self-esteem Level in Scholarized Adolescents of the Rural Area of Pereira, Colombia]. AB - OBJECTIVE: To assess the level of self-esteem of adolescents in a rural school of a district of Pereira. METHODS: Students were called upon to participate, 292 agreed to undergo the test, while 20 abstained. RESULTS: After a previous reliability test analysis, we found that 47.9% of students had low and very low self esteem. A multivariate model reported that self-esteem was reduced as age increased. CONCLUSIONS: The academic community and the family must work together in order to improve self-esteem among teenagers in general. PMID- 26572108 TI - [Infidelities: Learning from Therapeutic Conversations]. AB - INTRODUCTION: In this article the authors explore the different vicissitudes in the construction of the infidelity experience. OBJECTIVE: Increase knowledge concerning infidelity beyond existing topics in the literature. Deepen the understanding of infidelity towards a sort of complexity that includes contextual aspects of each couple. METHODS: A qualitative analysis of different cases of couples having experienced infidelity. CONCLUSIONS: Infidelity is a painful couple event requiring an individualized understanding of its construction process. PMID- 26572109 TI - [New Forms of Hysteria: Globalization, Market and the Comeback of Hysteria]. AB - INTRODUCTION: Hysterical disorder has had different interpretations and therapeutic approaches according to the different cultural contexts. In the Middle Ages, hysteria was conceived as devilish possessions whose symptoms became a sort of veracity certificate for the era's cultural pillar: the Bible. During Renaissance, hysteria obeys a new master: Science, dramatizing the neurological degenerative injuries to give reputation to physicians of the time. There is a kind of consensus: hysteria is an ever less observable disorder in consultation. It has practically disappeared in the North American Diagnosis Manual, DSM-IV. We wonder, has hysteria as such disappeared? Has it gotten new expressions? METHODS: Psychoanalytic review of hysteria, followed by a qualitative, historical and hermeneutic study. DEVELOPMENT: In these days of globalization, science is not the master anymore; instead, science is at the service of computing and market. The market biggest sellers are: depressive and anxious disorders, bulimia, anorexia, fibromyalgia, sexual drawbacks, somatoform disorders and extreme exhaustion disorder. Hysteria, raising bewilderment in modern medicine, comes back, cut up into pieces, in the form of these multiple disorders. Not only hysteria has not disappeared, but it has increased in consultation, almost perfect simulation of the disorders most promoted by capitalistic markets, granting power to the new master. Subsequently, its powerlessness is denounced, nothing alleviates said disorders. As Freud stated, the problem lies in the fact that this word does not have a receiver to decipher it. PMID- 26572110 TI - [Quality of Life of Teenage Mothers, University Students]. AB - INTRODUCTION: University education and motherhood are two aspects not generally associated, although their relationship determines a significant risk regarding the learning process of student-mothers. OBJECTIVE: To assess life quality as perceived by university- student mothers. METHODS: Comprehensive study of the phenomenological-hermeneutical type. Interviews and life stories of 34 students between 19 and 24, who were, or are teenager mothers, were used. A qualitative analysis was applied to triangulate the discourses so as to establish relationships between practice and the social phenomenon studied. RESULTS: The University as a social support network is negatively perceived; student mothers feel rejected and disregarded. Sometimes they feel alone and experience emotional emptiness. Additionally, physical health, stress and depression affect their emotional health; in general, they also experience eating and sleeping difficulties. When positively assumed, motherhood generates personal productivity leading to professional growth thus achieving a good working performance. CONCLUSIONS: The quality of life in student-mothers is strongly linked to the condition of their family relationships and the social support perceived in the university context. In terms of their personal productivity, emotional expression, health, and safety, they become dependent but can be strengthened with acceptance of the commitment implied by motherhood within their families and academic communities. Universities face a major challenge regarding this reality and the criteria to be followed to accompany the integral formation student mothers. PMID- 26572111 TI - [Psychoactive Drug Abuse in Adolescent Addicts of a Colombian Rehabilitation Foundation. Descriptive Study]. AB - OBJECTIVE: To describe the use of psychoactive substances (PAS) in addict population between 14 and 18 years of a foundation devoted to rehabilitation in the Department of Quindio, Colombia. METHODS: Quantitative-descriptive research. The VESPA (Epidemiological surveillance for psychoactive substance abuse) Forms of the people admitted to the institution between 2006 and 2009. RESULTS: During the study, 333 adolescents between 14 and 18 were attended. 75.4% were men, only 31.2% had primary education, 56% reported being unemployed, and 34.5% stated they were admitted at the foundation after legal indication. Upon admission, the PAS was: 44.2%, tobacco; 25.8%, marijuana; 18.0%, alcohol and 5.7% cocaine. The average starting age for men was 12.33, while for women was 11.96; reported substances showed the following starting averages: alcohol, 12.26 ys old; tobacco, 12.49 ys old; marijuana, 13.39 ys old; inhalants, 13.98 ys old; cocaine, 14.01 ys old; crack, 14.27 ys old; and heroin, 15 ys old. The average admission age to the institution was 15.7 ys old. CONCLUSIONS: Figures found highlight the need for greater and better prevention programs regarding PAS abuse in adolescents and children. PMID- 26572112 TI - [Upbringing and Sexuality in Children from Marginal Prostitute Women Downtown in Bogota]. AB - INTRODUCTION: Child upbringing of women engaged in prostitution has been little explored. METHODS: Child upbringing beliefs, attitudes and practices regarding sexuality in prostitutes' children and adolescents were explored downtown in Bogota. Analytical-interpretive research included in-depth interviews and a focus group. There were ten women between 28 and 56 years of age. Core issues were their subjectivity as mothers, sexual development challenges, upbringing social and cultural conditions. RESULTS: Structural, symbolic and economic violence are the main determinants of parenting. Sexual abuse and the possibility of pregnancy in their adolescent daughters are the most important concerns. CONCLUSIONS: In general, the participants share the same values and reproduce traditional ideals in gender and sexuality, which are transmitted and modeled from upbringing. PMID- 26572113 TI - [Age at Onset as a Marker of Subtypes of Manic-Depressive Illness]. AB - INTRODUCTION: Age at onset of bipolar disorder has been reported as a variable that may be associated with different clinical subtypes. OBJECTIVE: To identify patterns in the distributions of age at onset of bipolar disease and to determine whether age at onset is associated with specific clinical characteristics. METHODS: Admixture analysis was applied to identify bipolar disorder subtypes according to age at onset. The EMUN scale was used to evaluate clinical characteristics and principal components were estimated to evaluate the relationship between subtypes according to age at onset and symptoms in the acute in the acute phase, using multivariable analyses. RESULTS: According to age at onset, three distributions have been found: early onset: 17.7 years (S.D. 2.4); intermediate-onset: 23.9 years (S.D. 5.6); late onset: 42.8 years (S.D. 12.1). The late-onset group is antisocial, with depressive symptoms, thinking and language disorders, and socially disruptive behaviors. CONCLUSIONS: In patients having bipolar disorder, age at onset is antisocial with three groups having specific clinical characteristics. PMID- 26572114 TI - [Validity and Reliability of the KIDSCREEN-27 Life Quality Questionnaire, Parents' Version, in Medellin, Colombia]. AB - OBJECTIVE: Validate the KIDSCREEN-27 for parents in the metropolitan area of Medellin, Colombia, including the Social Acceptance (SA) subscale of KIDSCREEN 52, as it evaluates the effect of bullying in Life Quality of children. METHODS: The study population was made up by parents of children between 8 and 18, from Medellin and its metropolitan area. A sample of 1,150 parents was estimated according to the different psychometric properties to be measured. Construct validation was made by comparing the mean scores between groups of high and low socioeconomic conditions. The content validity and the measurement of reliability were verified by internal consistency and test-retest stability. The parent-child agreement was also measured. RESULTS: The internal consistency was adequate (Cronbach alpha 0,76-0,83). Parents of children with better socio-economic status had higher scores in all dimensions (p<0,05). Scores were higher among healthy children. Women had lower scores than men, while children registered higher scores than adolescents. The intraclass correlation coefficient for the reliability assessment was above 0.7 in all dimensions, except in School Environment-SE- (ICC 0,6-0,92). The parent-child agreement reached moderate and good levels (ICC 0,49-0,69). The exploratory factorial analysis, including social acceptance subscale, registered eight dimensions, four of which in agreement with the original questionnaire: Physical activity, SE, Social Support, and SA subscale. CONCLUSIONS: KIDSCREEN-27 for parents is a valid and reliable instrument to be used in the Colombian context. PMID- 26572115 TI - [Prevalence of Depressive and Anxious Symptomatology in 14-18 ys-old Students from a Private School in Medellin]. AB - OBJECTIVE: This study describes prevalence of depressive and anxious symptoms together with family, environmental and personal risk factors in a group of adolescents between 14 and 18 years of age in a private school of Medellin. METHODS: An analytic observational cross sectional study was performed in 152 adolescents, evaluating sociodemographic aspects and prevalence of depressive and anxious symptomatology, as established through BDI-II and BAI. RESULTS: Average age was 15.4 +/- 0.9 years old, with a 25% prevalence of anxiety symptoms and 25.7% of depressive symptoms. From the 38 (25%) students with BAI positive, 26 (68.4%) were BDI positive, and from the 39 (25.6%) students with BDI positive, 26 (66.7%) were BAI positive. CONCLUSIONS: the risk factors for anxiety and depressive symptomatology were: being a woman, being a victim of bullying and abuse. Having friends was the protective factors for depressive symptomatology. There was a statistical association between self-report of depressive and anxiety symptomatology; between the anxiety self-report and the depressive symptomatology; as well as between depressive and anxiety symptomatology and parents' perception of such symptoms. PMID- 26572116 TI - [Depression in Patients with Age-Related Macular Degeneration]. AB - Age-related macular degeneration is a cause for disability in the elderly since it greatly affects their quality of life and increases depression likelihood. This article discusses the negative effect depression has on patients with age related macular degeneration and summarizes the interventions available for decreasing their depression index. PMID- 26572117 TI - [Swan Song: The Advent of the Psychotic Nucleus]. AB - INTRODUCTION: Different forms of artistic expression, such as literature and cinema, constitute an inexhaustible source for the study of mental illness. The use of psychodynamic models may contribute to a better understanding of the spectrum between personality disorders and the psychosis spectrum, thus enriching the phenomenological approach in the psychiatric clinical practice. OBJECTIVE: To examine from psychodynamic standpoints the main character of the American film Black Swan, and the nature of her psychotic symptoms. METHODS: Reviewing of sources and relevant theoretical currents. RESULTS AND CONCLUSIONS: Analysis shows the usefulness of a psychodynamically- oriented dimensional model for understanding the so-called psychotic breaks as well as the applicability of psychoanalytic psychosis theories in general psychiatric practice, as they may provide a more flexible clinical approach, closer to the patient's subjective experience. PMID- 26572118 TI - [Neurophenomenology: Project for a Science of Past Experiences]. AB - INTRODUCTION: Since the middle of 20(th) Century, cognitive science has been recognized as the genuine convergence field for all scientific advances in human mind studies with the mechanisms enabling knowledge. Since then, it has become a multidisciplinary area where several research disciplines and actors have acquired citizenship, allowing new expectations on the scientific study of human uniqueness. OBJECTIVES: Critical assessment of the discussion that the discourse of theoretical biology has been assuming regarding the study of the cognitive phenomenon with special attention to the enactive project and, extensively, to the neuro-phenomenology of Francisco J. Varela. METHODS: Starting with a brief and synthesized history of cognitive science, we will establish the key principles for understanding the emergence of the enactive paradigm and the "embodied" turn influenced by continental phenomenology in the cognitive science, as well as the general guidelines of Neurophenomenology. CONCLUSIONS: The "hard problem" of consciousness still faces several types of reductionism relegating the cognitive issue to a kind of merely rational, individual, abstract and disembodied mechanism, thus strengthening the functionalist paradigm in mind philosophy. A solution to classic dichotomies in mind sciences must start rejecting such assumptions. PMID- 26572119 TI - [Factor Analysis: Principles to Evaluate Measurement Tools for Mental Health]. AB - The validation of a measurement tool in mental health is a complex process that usually starts by estimating reliability, to later approach its validity. Factor analysis is a way to know the number of dimensions, domains or factors of a measuring tool, generally related to the construct validity of the scale. The analysis could be exploratory or confirmatory, and helps in the selection of the items with better performance. For an acceptable factor analysis, it is necessary to follow some steps and recommendations, conduct some statistical tests, and rely on a proper sample of participants. PMID- 26572120 TI - [Psychotic Acute Episode and Rhabdomyolysis after Lovastatin Ingestion]. AB - INTRODUCTION: Statins are the most prescribed drugs worldwide given the benefit and security they offer. However, they can cause severe neurological, gastrointestinal, renal and muscular side effects. OBJECTIVE: To describe the clinical course of a female patient with adverse drug reaction to Lovastatin. METHODS: Case report and literature review. RESULTS: 52-year old woman with sudden psychosis and rhabdomyolysis secondary to Lovastatin and ending after the drug suspension. The causal relationship was corroborated with a score of 6 (probable ADR) on Naranjo's Scale. CONCLUSIONS: The simultaneous manifestation of psychosis and rhabdomiolysis represents an atypical and unique case following Lovastatin ingestion. PMID- 26572121 TI - [A case of Psychogenous Crisis, a Linking Psychiatric Pathology]. AB - Psychogenous seizures described by Charcot, are an entity that can be difficult to distinguish from epileptic seizures. 70% of these patients have an underlying psychiatric diagnosis. We describe the case of a female patient who was diagnosed with seizures for several years, poly-medicated, and included in the epilepsy surgery protocol for refractory patients. During the evaluation, a psychogenous origin was discovered for such crises. We analyzed the clinical criteria and laboratory tests that allow us to approach the differential diagnosis between both entities. PMID- 26572122 TI - [Schizophrenia and Liver Transplantation: Case Report]. AB - INTRODUCTION: Liver transplantation is a treatment available for many patients with liver cirrhosis who find in this treatment a way to improve life expectancy and quality of life. Paranoid schizophrenia affects 1% of the general population, produces psychotic symptoms, and runs a chronic course in some cases with significant deterioration in all areas of life. OBJECTIVE: To discuss the case of a patient with liver cirrhosis diagnosed with paranoid schizophrenia during the evaluation protocol for liver transplantation. METHOD: Case report. RESULTS: We report the case of a 47-year-old woman with liver cirrhosis whose only alternative to improve life expectancy and quality of life was access to liver transplantation. During routine evaluations the liaison psychiatrist observed first-order psychotic symptoms and documented a life story that confirmed the presence of paranoid schizophrenia. DISCUSSION AND CONCLUSIONS: Paranoid schizophrenia is a psychiatric disorder common in the general population that can be a part of the medical comorbidities of patients requiring liver transplantation and is not an absolute contraindication to its completion. We are unaware of similar cases of liver transplantation in patients with schizophrenia in our country. We believe this is a big step on the road to overcome the stigma that mental illness imposes on patients. PMID- 26572123 TI - Generation of a conditional lima1a allele in zebrafish using the FLEx switch technology. AB - Gene trapping has emerged as a valuable tool to create conditional alleles in various model organisms. Here we report the FLEx-based gene trap vector SAGFLEx that allows the generation of conditional mutations in zebrafish by gene-trap mutagenesis. The SAGFLEx gene-trap cassette comprises the rabbit beta-globin splice acceptor and the coding sequence of GFP, flanked by pairs of inversely oriented heterotypic target sites for the site-specific recombinases Cre and Flp. Insertion of the gene-trap cassette into endogenous genes can result in conditional mutations that are stably inverted by Cre and Flp, respectively. To test the functionality of this system we performed a pilot screen and analyzed the insertion of the gene-trap cassette into the lima1a gene locus. In this lima1a allele, GFP expression faithfully recapitulated the endogenous lima1a expression and resulted in a complete knockout of the gene in homozygosity. Application of either Cre or Flp was able to mediate the stable inversion of the gene trap cassette and showed the ability to conditionally rescue or reintroduce the gene inactivation. Combined with pharmacologically inducible site specific recombinases the SAGFLEx vector insertions will enable precise conditional knockout studies in a spatial- and temporal-controlled manner. PMID- 26572124 TI - The effects of zoledronate on the survival and function of human osteoblast-like cells. AB - BACKGROUND: Prolonged bisphosphonate treatment might suppress bone remodeling to the extent that normal bone repair is impaired. While this adverse side effect is usually ascribed to the negative effects of bisphosphonates on osteoclast survival and function, these effects on osteoblasts are still unclear. METHODS: In the current study, we hypothesized that zoledronate (ZOL) at the MUM level might present negative effects on osteoblast survival and function. In vitro analyses of proliferation, migration and differentiation were performed on human osteoblast-like cells. RESULTS: Our results revealed that ZOL treatment dose- and time-dependently induced apoptosis of osteoblasts after concentrations had reached 10 MUM (p < 0.001). The concentrations at which ZOL inhibited osteoblast migration by 50 % were between 10 and 15 MUM. Moreover, there was a dose dependent reduction in the extent of matrix mineralization, but without a concomitant inhibition of osteogenic differentiation in terms of secreted type I collagen and osteocalcin and of alkaline phosphatase activity per viable cell. Analyses of the expression of osteogenic genes confirmed that ZOL at the MUM level had no effects on osteogenic differentiation of osteoblasts. CONCLUSION: We concluded that ZOL at the MUM level affected osteoblast survival and migration, but did not affect differentiation. The pathophysiological implications of ZOL at the MUM level on skeletal disorders need to be investigated and clarified in the future researches. PMID- 26572125 TI - Barriers and facilitators to providing primary care-based weight management services in a patient centered medical home for Veterans: a qualitative study. AB - BACKGROUND: Obesity is highly prevalent among Veterans. In the United States, the Veterans Health Administration (VHA) offers a comprehensive weight management program called MOVE!. Yet, fewer than 10 % of eligible patients ever attend one MOVE! visit. The VHA has a patient-centered medical home (PCMH) model of primary care (PC) called Patient-Aligned Care Teams (PACT) at all Veterans Affairs (VA) Medical Centers. PACT teamlets conduct obesity screening, weight management counseling, and refer to MOVE!. As part of a needs assessment to improve delivery of weight management services, the purpose of this study was to assess PACT teamlet and MOVE! staff: 1) current attitudes and perceptions regarding obesity care; 2) obesity-related counseling practices 3) experiences with the MOVE! program; and 4) targets for interventions to improve implementation of obesity care in the PC setting. METHODS: We recruited 25 PACT teamlet members from a single VA study site-11 PC physicians, 5 registered nurses, 5 licensed practical nurses, 1 clerical assistant, and 3 MOVE! staff (2 dietitians, 1 psychologist) for individual interviews using a combination of convenience and snowball sampling. Audio recorded interviews were professionally transcribed and iteratively coded by two independent reviewers. The analytic process was guided by discourse analysis in order to discover how the participants perceived and provided weight management care and what specific attitudes affected their practices, all as bounded within the organization. RESULTS: Emerging themes included: 1) role perceptions, 2) anticipated outcomes of weight management counseling and programs, and 3) communication and information dissemination. Perceived role among PCPs was influenced by training, whereas personal experience with their own weight management impacted role perception among LPNs/RNs. Attitudes about whether or not they could impact patients' weight outcomes via counseling or referral to MOVE! varied. System-level communication about VHA priorities through electronic health records and time allocation influenced teams to prioritize referral to MOVE! over weight management counseling. CONCLUSION: We found a diversity of attitudes, and practices within PACT, and identified factors that can enhance the MOVE! program and inform interventions to improve weight management within primary care. Although findings are site-specific, many are supported in the literature and applicable to other VA and non-VA sites with PCMH models of care. PMID- 26572126 TI - Psychometric properties of the Dutch version of the Evidence-Based Practice Attitude Scale (EBPAS). AB - BACKGROUND: The Evidence-Based Practice Attitude Scale (EBPAS) was developed in the United States to assess attitudes of mental health and welfare professionals toward evidence-based interventions. Although the EBPAS has been translated in different languages and is being used in several countries, all research on the psychometric properties of the EBPAS within youth care has been carried out in the United States. The purpose of this study was to investigate the psychometric properties of the Dutch version of the EBPAS. METHODS: After translation into Dutch, the Dutch version of the EBPAS was examined in a diverse sample of 270 youth care professionals working in five institutions in the Netherlands. We examined the factor structure with both exploratory and confirmatory factor analyses and the internal consistency reliability. We also conducted multiple linear regression analyses to examine the association of EBPAS scores with professionals' characteristics. It was hypothesized that responses to the EBPAS items could be explained by one general factor plus four specific factors, good to excellent internal consistency reliability would be found, and EBPAS scores would vary by age, sex, and educational level. RESULTS: The exploratory factor analysis suggested a four-factor solution according to the hypothesized dimensions: Requirements, Appeal, Openness, and Divergence. Cronbach's alphas ranged from 0.67 to 0.89, and the overall scale alpha was 0.72. The confirmatory factor analyses confirmed the factor structure and suggested that the lower order EBPAS factors are indicators of a higher order construct. However, Divergence was not significantly correlated with any of the subscales or the total score. The confirmatory bifactor analysis endorsed that variance was explained both by a general attitude towards evidence-based interventions and by four specific factors. The regression analyses showed an association between EBPAS scores and youth care professionals' age, sex, and educational level. CONCLUSIONS: The present study provides strong support for a structure with a general factor plus four specific factors and internal consistency reliability of the Dutch version of the EBPAS in a diverse sample of youth care professionals. Hence, the factor structure and reliability of the original version of the EBPAS seem generalizable to the Dutch version of the EBPAS. PMID- 26572127 TI - Social inequality in morbidity, framed within the current economic crisis in Spain. AB - INTRODUCTION: Inspired by the 'Fundamental Cause Theory (FCT)' we explore social inequalities in preventable versus relatively less-preventable illnesses in Spain. The focus is on the education-health gradient, as education is one of the most important components of an individual's socioeconomic status (SES). Framed in the context of the recent economic crisis, we investigate the education gradient in depression, diabetes, and myocardial infarction (relatively highly preventable illnesses) and malignant tumors (less preventable), and whether this educational gradient varies across the regional-economic context and changes therein. METHODS: We use data from three waves of the Spanish National Health Survey (2003-2004, 2006-2007, and 2011-2012), and from the 2009-2010 wave of the European Health Survey in Spain, which results in a repeated cross-sectional design. Logistic multilevel regressions are performed with depression, diabetes, myocardial infarction, and malignant tumors as dependent variables. The multilevel design has three levels (the individual, period-regional, and regional level), which allows us to estimate both longitudinal and cross-sectional macro effects. The regional-economic context and changes therein are assessed using the real GDP growth rate and the low work intensity indicator. RESULTS: Education gradients in more-preventable illness are observed, while this is far less the case in our less-preventable disease group. Regional economic conditions seem to have a direct impact on depression among Spanish men (y-stand. OR = 1.04 [95 % CI: 1.01-1.07]). Diabetes is associated with cross-regional differences in low work intensity among men (y-stand. OR = 1.02 [95 % CI: 1.00-1.05]) and women (y stand. OR = 1.04 [95 % CI: 1.01-1.06]). Economic contraction increases the likelihood of having diabetes among men (y-stand. OR = 1.04 [95 % CI: 1.01 1.06]), and smaller decreases in the real GDP growth rate are associated with lower likelihood of myocardial infarction among women (y-stand. OR = 0.83 [95 % CI: 0.69-1.00]). Finally, there are interesting associations between the macroeconomic changes across the crisis period and the likelihood of suffering from myocardial infarction among lower educated groups, and the likelihood of having depression and diabetes among less-educated women. CONCLUSION: Our findings partially support the predictions of the FCT for Spain. The crisis effects on health emerge especially in the case of our more-preventable illnesses and among lower educated groups. Health inequalities in Spain could increase rapidly in the coming years due to the differential effects of recession on socioeconomic groups. PMID- 26572128 TI - Differential development of oil granulomas induced by pristane injection in galectin-3 deficient mice. AB - BACKGROUND: Galectin-3 is known to be a lectin that plays an important role in inflammatory processes, acting as pro-inflammatory mediator in activation and migration of neutrophils and macrophages, as well as in the phagocytic function of these cells. The injection of mineral oils into the peritoneal cavity of mice, such as 2, 6, 10, 14-tetramethylpentadecane (pristane), induce a chronic granulomatous inflammatory reaction which is rich in macrophages, B cells and peritoneal plasma cells known as oil granuloma. In addition, this inflammatory microenvironment provided by oil granulomas is also an important site of plasmacytoma induction, which are dependent on cytokine production and cellular mobilization. Here, we have analyzed the role of galectin-3 in inflammatory cells mobilization and organization after pristane injection characterizing granulomatous reaction through the formation of oil granulomas. RESULTS: In galectin-3 deficient mice (gal-3(-/-)), the mobilization of inflammatory cells, between peritoneal cavity and bone marrow, was responsible for the formation of disorganized oil granulomas, which presented scattered cells, large necrotic areas and low amounts of extracellular matrix. The production of inflammatory cytokines partially explained the distribution of cells through peritoneal cavity, since high levels of IL-6 in gal-3(-/-) mice led to drastically reduction of B1 cells. The previous pro-inflammatory status of these animals also explains the excess of cell death and disruption of oil granulomas architecture. CONCLUSIONS: Our data indicate, for the first time, that the disruption in the inflammatory cells migration in the absence of galectin-3 is a crucial event in the formation and organization of oil granulomas. PMID- 26572129 TI - Suicidal behaviors among Moroccan school students: prevalence and association with socio-demographic characteristics and psychoactive substances use: a cross sectional study. AB - BACKGROUND: Suicidal behavior is a major cause of injury and death worldwide, especially among adolescents and young adults. Few studies have tackled this issue in the Arab world. The present study investigated the prevalence and the risk factors of suicidal behaviors among Moroccan school students. METHODS: From April 2012 to November 2013, a cross-sectional study was conducted in the North Centre region of Morocco among students in public secondary schools selected using stratified cluster random sampling. The data were collected via anonymous self-administered questionnaires. The Mini International Neuropsychiatric Interview was used in its Moroccan Colloquial Arabic version to assess suicidality according to the DSM-IV criteria. RESULTS: A total of 3020 students (53 % boys) aged 11-23 years (average age = 16 +/- 2.1 years) were included in the study. The prevalence of suicide ideation, suicide planning and suicide attempts during the last month were 15.7, 6.3, and 6.5 % respectively. Univariate analyses demonstrated that suicidal behaviors followed different epidemiological patterns. According to the multivariate analyses, the risk factors for all suicidal behaviors among Moroccan school students were the female gender, middle school level, urban locations, low family income, parents' divorce, tobacco consumption and psychoactive substances (alcohol and cannabis) use. CONCLUSIONS: The intervention of preventive programs has become an emergency to overcome the issue of suicidality in Morocco. Further researches on adolescents' suicidal behaviors are suggested to update temporal data and assess the effectiveness of potential interventions. PMID- 26572130 TI - IL-6 signaling promotes DNA repair and prevents apoptosis in CD133+ stem-like cells of lung cancer after radiation. AB - BACKGROUND: Local tumor control by standard fractionated radiotherapy (RT) remains poor because of tumor resistance to radiation (radioresistance). It has been suggested that cancer stem cells (CSCs) are more radioresistant than non CSCs. In previous studies, we have shown IL-6 promotes self-renewal of CD133+ CSC like cells. In this study, we investigated whether IL-6 plays roles not only in promoting self-renewal of CD133+ cells after radiation, but also in conferring radioresistance of CD133+ cells in NSCLC. MATERIALS AND METHODS: To compare radiation sensitivity of CSCs and non-CSCs, CD133+ CSC-like and CD133- cell populations were isolated from two NSCLC cell lines, A549 and H157, by immunomagnetic separation and their sensitivities to ionizing radiation were investigated using the clonogenic survival assay. To further study the IL-6 effect on the radiosensitivity of CD133+ CSC-like cells, CD133+ cells were isolated from A549IL-6si/sc and H157IL-6si/sc cells whose intracellular IL-6 levels were manipulated via the lentiviral transduction with IL-6siRNA. Post irradiation DNA damage was analyzed by gamma-H2AX staining and Comet assay. Molecular mechanisms by which IL-6 regulates the molecules associated with DNA repair and anti-apoptosis after radiation were analyzed by Western blot and immunofluoresecence (IF) staining analyses. RESULTS: NSCLC CD133+ CSC-like cells were enriched upon radiation. Survival of NSCLC CD133+ cells after radiation was higher than that of CD133- cells. Survival of IL-6 expressing NSC LC CD133+ cells (sc) was higher than that of IL-6 knocked-down cells (IL-6si) after radiation. IL 6 played a role in protecting NSCLC CD133+ cells from radiation-induced DNA damage and apoptosis. CONCLUSIONS: IL-6 signaling promotes DNA repair while protecting CD133+ CSC-like cells from apoptotic death after radiation for lung cancer. A combined therapy of radiation and agents that inhibit IL-6 signaling (or its downstream signaling) is suggested to reduce CSC-mediated radioresistance in lung cancer. PMID- 26572132 TI - Datafish Multiphase Data Mining Technique to Match Multiple Mutually Inclusive Independent Variables in Large PACS Databases. AB - Retrospective data mining has tremendous potential in research but is time and labor intensive. Current data mining software contains many advanced search features but is limited in its ability to identify patients who meet multiple complex independent search criteria. Simple keyword and Boolean search techniques are ineffective when more complex searches are required, or when a search for multiple mutually inclusive variables becomes important. This is particularly true when trying to identify patients with a set of specific radiologic findings or proximity in time across multiple different imaging modalities. Another challenge that arises in retrospective data mining is that much variation still exists in how image findings are described in radiology reports. We present an algorithmic approach to solve this problem and describe a specific use case scenario in which we applied our technique to a real-world data set in order to identify patients who matched several independent variables in our institution's picture archiving and communication systems (PACS) database. PMID- 26572131 TI - Caffeine reduces hepatic lipid accumulation through regulation of lipogenesis and ER stress in zebrafish larvae. AB - BACKGROUND: Caffeine, the main component of coffee, has showed its protective effect on non-alcoholic fatty liver disease (NAFLD) in many studies. However, the hepatoprotection of caffeine and its mechanisms in zebrafish were unexplored. Thus, this study's intentions are to establish a NAFLD model of zebrafish larvae and to examine the role of caffeine on fatty liver with the model. RESULTS: Growth and the incidence of fatty liver of zebrafish larvae increased with the increased amount of feeding in a dose-dependent manner. The degree of hepatic steatosis of larvae also gradually aggravated with the increased quantity and duration of feeding. Triglyceride contents of zebrafish fed for 20 days significantly increased in model group (180 mg/d) compared with control group (30 mg/d) (P < 0.001). Significant decreases in body weight and hepatic steatosis rate were observed in 2.5, 5, 8 % caffeine treatment group compared with model group (P < 0.05). Hepatic lipid accumulation was also significantly reduced in caffeine treatment larvae. Moreover, caffeine treatment was associated with upregulation of lipid beta-oxidation gene ACO and downregulation of lipogenesis associated genes (SREBP1, ACC1, CD36 and UCP2), ER stress-associated genes (PERK, IRE1, ATF6 and BIP), the inflammatory cytokine genes (IL-1beta and TNF-alpha) and autophagy associated genes (ATG12 and Beclin-1). Protein expression of CHOP, BIP and IL-1beta remarkably reduced in caffeine treatment group compared with model group. CONCLUSIONS: We induced hepatoteatosis in zebrafish by overfeeding regimen and demonstrated caffeine have a role in suppression of hepatosteatosis by downregulation of genes associated with lipogenesis, ER stress, inflammatory response and enhancement of lipid oxidation, indicating zebrafish model may be used to identify putative pharmacological targets and to test novel drugs for human NAFLD treatment. PMID- 26572133 TI - Bilobate leaves of Bauhinia (Leguminosae, Caesalpinioideae, Cercideae) from the middle Miocene of Fujian Province, southeastern China and their biogeographic implications. AB - BACKGROUND: Morphological and molecular phylogenetic studies suggest that the pantropical genus Bauhinia L. s.l. (Bauhiniinae, Cercideae, Leguminosae) is paraphyletic and may as well be subdivided into nine genera, including Bauhinia L. s.s. and its allies. Their leaves are usually characteristic bilobate and are thus easily recognized in the fossil record. This provides the opportunity to understand the early evolution, diversification, and biogeographic history of orchid trees from an historical perspective under the framework of morphological and molecular studies. RESULTS: The taxonomy, distribution, and leaf architecture of Bauhinia and its allies across the world are summarized in detail, which formed the basis for classifying the bilobate leaf fossils and evaluating the fossil record and biogeography of Bauhinia. Two species of Bauhinia are described from the middle Miocene Fotan Group of Fujian Province, southeastern China. Bauhinia ungulatoides sp. nov. is characterized by shallowly to moderately bilobate, pulvinate leaves with shallowly cordate bases and acute apices on each lobe, as well as paracytic stomatal complexes. Bauhinia fotana F.M.B. Jacques et al. emend. possesses moderately bilobate, pulvinate leaves with moderately to deeply cordate bases and acute or slightly obtuse apices on each lobe. CONCLUSIONS: Bilobate leaf fossils Bauhinia ungulatoides and B. fotana together with other late Paleogene - early Neogene Chinese record of the genus suggest that Bauhinia had been diverse in South China by the late Paleogene. Their great similarities to some species from South America and South Asia respectively imply that Bauhinia might have undergone extensive dispersals and diversification during or before the Miocene. The fossil record, extant species diversity, as well as molecular phylogenetic analyses demonstrate that the Bauhiniinae might have originated in the Paleogene of low-latitudes along the eastern Tethys Seaway. They dispersed southwards into Africa, migrated from Eurasia to North America via the North Atlantic Land Bridge or floating islands during the Oligocene. Then the genus spread into South America probably via the Isthmus of Panama since the Miocene onward, and underwent regional extinctions in the Boreotropics of mid-high-latitudes during the Neogene climatic cooling. Hence, Bauhinia presently exhibits a pantropical intercontinental disjunct distribution. PMID- 26572134 TI - [Sonication in the diagnosis of periprosthetic infections : Significance and practical implementation]. AB - Endoprosthetic joint replacement is one of the most common and most successful operations in current medicine. With the increase in joint prosthesis implantations, the number of periprosthetic infections is also rising. Detection of the causative pathogen and its antimicrobial susceptibility is crucial for successful antibiotic therapy. For a reliable diagnosis, in addition to conventional microbiological methods (synovial fluid culture and intraoperative periprosthetic tissue samples), other methods of detecting biofilms are used. With sonication of the removed implant components, microorganisms are released from the implant surface and then detected qualitatively and quantitatively in the sonication fluid. The sonication is particularly useful for chronic, "low grade" infections in which a small number of bacteria are present and the biofilm adheres more strongly to the prosthesis surface. The sonication fluid is suitable for aerobic and anaerobic cultures, in addition to newer, culture-independent detection methods (e.g., molecular methods, mass spectrometry, microcalorimetry). In the article the significance, advantages and disadvantages, and the practical implementation of the sonication of implants are presented and critically discussed. PMID- 26572135 TI - A combined prediction strategy increases identification of peptides bound with high affinity and stability to porcine MHC class I molecules SLA-1*04:01, SLA 2*04:01, and SLA-3*04:01. AB - Affinity and stability of peptides bound by major histocompatibility complex (MHC) class I molecules are important factors in presentation of peptides to cytotoxic T lymphocytes (CTLs). In silico prediction methods of peptide-MHC binding followed by experimental analysis of peptide-MHC interactions constitute an attractive protocol to select target peptides from the vast pool of viral proteome peptides. We have earlier reported the peptide binding motif of the porcine MHC-I molecules SLA-1*04:01 and SLA-2*04:01, identified by an ELISA affinity-based positional scanning combinatorial peptide library (PSCPL) approach. Here, we report the peptide binding motif of SLA-3*04:01 and combine two prediction methods and analysis of both peptide binding affinity and stability of peptide-MHC complexes to improve rational peptide selection. Using a peptide prediction strategy combining PSCPL binding matrices and in silico prediction algorithms (NetMHCpan), peptide ligands from a repository of 8900 peptides were predicted for binding to SLA-1*04:01, SLA-2*04:01, and SLA-3*04:01 and validated by affinity and stability assays. From the pool of predicted peptides for SLA-1*04:01, SLA-2*04:01, and SLA-3*04:01, a total of 71, 28, and 38% were binders with affinities below 500 nM, respectively. Comparison of peptide-SLA binding affinity and complex stability showed that peptides of high affinity generally, but not always, produce complexes of high stability. In conclusion, we demonstrate how state-of-the-art prediction and in vitro immunology tools in combination can be used for accurate selection of peptides for MHC class I binding, hence providing an expansion of the field of peptide-MHC analysis also to include pigs as a livestock experimental model. PMID- 26572136 TI - Sex differences and endocrine regulation of auditory-evoked, neural responses in African clawed frogs (Xenopus). AB - Mating depends on the accurate detection of signals that convey species identity and reproductive state. In African clawed frogs, Xenopus, this information is conveyed by vocal signals that differ in temporal patterns and spectral features between sexes and across species. We characterized spectral sensitivity using auditory-evoked potentials (AEPs), commonly known as the auditory brainstem response, in males and females of four Xenopus species. In female X. amieti, X. petersii, and X. laevis, peripheral auditory sensitivity to their species own dyad-two, species-specific dominant frequencies in the male advertisement call-is enhanced relative to males. Males were most sensitive to lower frequencies including those in the male-directed release calls. Frequency sensitivity was influenced by endocrine state; ovariectomized females had male-like auditory tuning while dihydrotestosterone-treated, ovariectomized females maintained female-like tuning. Thus, adult, female Xenopus demonstrate an endocrine dependent sensitivity to the spectral features of conspecific male advertisement calls that could facilitate mating. Xenopus AEPs resemble those of other species in stimulus and level dependence, and in sensitivity to anesthetic (MS222). AEPs were correlated with body size and sex within some species. A frequency following response, probably encoded by the amphibian papilla, might facilitate dyad source localization via interaural time differences. PMID- 26572137 TI - Whole-exome sequencing identifies mutations of TBC1D1 encoding a Rab-GTPase activating protein in patients with congenital anomalies of the kidneys and urinary tract (CAKUT). AB - Congenital anomalies of the kidneys and urinary tract (CAKUT) are genetically highly heterogeneous leaving most cases unclear after mutational analysis of the around 30 causative genes known so far. Assuming that phenotypes frequently showing dominant inheritance, such as CAKUT, can be caused by de novo mutations, de novo analysis of whole-exome sequencing data was done on two patient-parent trios to identify novel CAKUT genes. In one case, we detected a heterozygous de novo frameshift variant in TBC1D1 encoding a Rab-GTPase-activating protein regulating glucose transporter GLUT4 translocation. Sequence analysis of 100 further CAKUT cases yielded three novel or rare inherited heterozygous TBC1D1 missense variants predicted to be pathogenic. TBC1D1 mutations affected Ser237 phosphorylation or protein stability and thereby act as hypomorphs. Tbc1d1 showed widespread expression in the developing murine urogenital system. A mild CAKUT spectrum phenotype, including anomalies observed in patients carrying TBC1D1 mutations, was found in kidneys of some Tbc1d1 (-/-) mice. Significantly reduced Glut4 levels were detected in kidneys of Tbc1d1 (-/-) mice and the dysplastic kidney of a TBC1D1 mutation carrier versus controls. TBC1D1 and SLC2A4 encoding GLUT4 were highly expressed in human fetal kidney. The patient with the truncating TBC1D1 mutation showed evidence for insulin resistance. These data demonstrate heterozygous deactivating TBC1D1 mutations in CAKUT patients with a similar renal and ureteral phenotype, and provide evidence that TBC1D1 mutations may contribute to CAKUT pathogenesis, possibly via a role in glucose homeostasis. PMID- 26572138 TI - Comparison of individual and pooled urine samples for estimating the presence and intensity of Schistosoma haematobium infections at the population level. AB - BACKGROUND: There is a lack of cost-effective diagnostic strategies to evaluate whether mass drug administration (MDA) programmes to control Schistosoma haematobium progress as anticipated. The purpose of this study is to provide a proof-of-principle for examination of pooled urine samples as a strategy for rapid assessment of presence and intensity of Schistosoma haematobium infections at the population level. METHODS: A total of 640 urine samples were collected from 520 school-aged children (520 at baseline and 120 at follow-up) during a clinical trial that was designed to assess the efficacy of praziquantel against Schistosoma haematobium infections in Ethiopia. Individual and pooled urine samples were screened using the filtration technique (volume of 10 ml urine) to determine the number of S. haematobium eggs in 10 ml of urine. Samples were pooled into pools of 5 (n = 128), 10 (n = 64) and 20 (n = 32) individual samples. The sensitivity, the probability of finding at least one egg in a pooled sample when the mean urine egg count (UEC) of the corresponding individual urine samples was not zero, was calculated for each pool size. UECs of a pooled examination strategy were compared with the mean UECs of the corresponding individual samples. RESULTS: The sensitivity of a pooled examination strategy was 50.6% for pools of 5, 68.6% for pools of 10 and 63.3% for pools of 20. The sensitivity of a pooled examination strategy increased as a function of increasing mean UEC of the corresponding individual urine samples. For each of the three pool sizes, there was a significant positive correlation between mean UECs of individual and those obtained in pooled samples (correlation coefficient: 0.81 - 0.93). Examination of pools of 5 provided significantly lower UECs compared to the individual examination strategy (3.9 eggs/10 ml urine versus 5.0 eggs/10 ml urine). For pools of 10 (4.4 eggs/10 ml) and 20 (4.2 eggs/10 ml), no significant difference in UECs was observed. CONCLUSIONS: Examination of pooled urine samples applying urine filtration holds promise for rapid assessment of intensity of S. haematobium infections, but may fail to detect presence of infections when endemicity is low. Further investigation is required to determine when and how pooling can be optimally implemented in monitoring of mass drug administration programmes. PMID- 26572139 TI - Education and mortality in Spain: a national study supports local findings. AB - OBJECTIVES: To estimate educational inequalities in mortality in Spain and in three Spanish areas: Madrid, Barcelona, and the Basque country. METHODS: A national prospective study was carried out including all persons aged 25-74 years living in Spain in 2001 and followed up for mortality over 7 years. The mortality rate ratio and difference from all causes and from leading causes of death were estimated for the entire Spanish population and for the above three geographical areas. RESULTS: With respect to people with the highest education, the mortality rate ratios in the entire population of Spain in people with the second highest, second lowest and lowest education were, respectively, 1.09, 1.10, 1.39 in women and 1.19, 1.27 and 1.54 in men. The mortality rate differences per 100,000 person years were, respectively, 24.8, 28.3, 108.2 in women and 116.7, 162.5 and 319.1 in men. These estimates were intermediate in magnitude compared to those seen in the three geographical areas. CONCLUSIONS: The results provide further evidence that educational inequalities in mortality are smaller in the south of Europe than in other European countries. PMID- 26572140 TI - An expeditious synthesis of blood-group antigens, ABO histo-blood group type II antigens and xenoantigen oligosaccharides with amino type spacer-arms. AB - Blood group oligosaccharides are one of the most clinically important antigen families and they may also act as secondary ligands for bacterial toxins from Escherichia coli and Vibrio cholerae. Herein we report the synthesis of spacered (sp = CH2CH2CH2NH2) glycosides of A antigen {alpha-D-GalNAc-(l->3)-[alpha-L-Fuc (l->2)]-beta-D-Gal-}, B antigen{alpha-D-Gal-(l->3)-[alpha-L-Fuc-(l->2)]-beta-D Gal-}, LewisX{alpha-D-Gal-(l->4)-[alpha-L-Fuc-(l->3)]-beta-D-GlcNAc-}, A type-II {alpha-D-GalNAc-(l->3)-[alpha-L-Fuc-(l->2)]-beta-D-Gal-(1->4)-beta-D-GlcNAc-}, B type-II {alpha-D-Gal-(l->3)-[alpha-L-Fuc-(l->2)]-beta-D-Gal-(1->4)-beta-D-GlcNAc }, H type-II{alpha-L-Fuc-(l->2)-beta-D-Gal-(1->4)-beta-D-GlcNAc-}, xenoantigen {alpha-D-Gal-(l->3)-beta-D-Gal-(1->4)-[alpha-L-Fuc-(l->2)]-beta-D-GlcNAc-} and Linear B Type II {alpha-D-Gal-(l->3)-beta-D-Gal-(1->4)-beta-D-GlcNAc-} useful for a range of biochemical investigations. This linker was chosen so as to facilitate the future conjugation of the antigens to proteins or other molecules. We also measured the affinities of some synthesized oligosaccharides against El Tor CTB strain from V. cholera. PMID- 26572141 TI - MRI Detection of Cerebral Infarction in Subarachnoid Hemorrhage. AB - OBJECTIVE: To investigate magnetic resonance imaging (MRI) detection of cerebral infarction (CI) in patients presenting with subarachnoid hemorrhage (SAH). BACKGROUND: CI is a well-known complication of SAH that is typically detected on computed tomography (CT). MRI has improved sensitivity for acute CI over CT, particularly with multiple, small, or asymptomatic lesions. METHODS: With IRB approval, 400 consecutive SAH patients admitted to our institution from August 2006 to March 2011 were retrospectively reviewed. Traumatic SAH and secondary SAH were excluded. Data were collected on demographics, cause of SAH, Hunt Hess and World Federation of Neurosurgical Societies grades, and neuroimaging results. MRIs were categorized by CI pattern as single cortical (SC), single deep (SD), multiple cortical (MC), multiple deep (MD), and multiple cortical and deep (MCD). RESULTS: Among 123 (30.8 %) SAH patients who underwent MRIs during their hospitalization, 64 (52 %) demonstrated acute CI. The mean time from hospital admission to MRI was 5.7 days (range 0-29 days). Among the 64 patients with MRI infarcts, MRI CI pattern was as follows: MC in 20 (31 %), MCD in 18 (28 %), SC in 16 (25 %), SD in 3 (5 %), MD in 2 (3 %), and 5 (8 %) did not have images available for review. Most infarcts detected on MRI (39/64 or 61 %) were not visible on CT. CONCLUSIONS: The use of MRI increases the detection of CI in SAH. Unlike CT studies, MRI-detected CI in SAH tends to involve multiple vascular territories. Studies that rely on CT may underestimate the burden of CI after SAH. PMID- 26572142 TI - Sensory source for stroop effects in persons after TBI: support from fNIRS-based investigation. PMID- 26572143 TI - Male brain ages faster: the age and gender dependence of subcortical volumes. AB - Effects of gender on grey matter (GM) volume differences in subcortical structures of the human brain have consistently been reported. Recent research evidence suggests that both gender and brain size influences volume distribution in subcortical areas independently. The goal of this study was to determine the effects of the interplay between brain size, gender and age contributing to volume differences of subcortical GM in the human brain. High-resolution T1 weighted images were acquired from 53 healthy males and 50 age-matched healthy females. Total GM volume was determined using voxel-based morphometry. We used model-based subcortical segmentation analysis to measure the volume of subcortical nuclei. Main effects of gender, brain volume and aging on subcortical structures were examined using multivariate analysis of variance. No significant difference was found in total brain volume between the two genders after correcting for total intracranial volume. Our analysis revealed significantly larger hippocampus volume for females. Additionally, GM volumes of the caudate nucleus, putamen and thalamus displayed a significant age-related decrease in males as compared to females. In contrast to this only the thalamic volume loss proved significant for females. Strikingly, GM volume decreases faster in males than in females emphasizing the interplay between aging and gender on subcortical structures. These findings might have important implications for the interpretation of the effects of unalterable factors (i.e. gender and age) in cross-sectional structural MRI studies. Furthermore, the volume distribution and changes of subcortical structures have been consistently related to several neuropsychiatric disorders (e.g. Parkinson's disease, attention deficit hyperactivity disorder, etc.). Understanding these changes might yield further insight in the course and prognosis of these disorders. PMID- 26572144 TI - A majority rule approach for region-of-interest-guided streamline fiber tractography. AB - Hand-drawn gray matter regions of interest (ROI) are often used to guide the estimation of white matter tractography, obtained from diffusion-weighted magnetic resonance imaging (DWI), in healthy and in patient populations. However, such ROIs are vulnerable to rater bias of the individual segmenting the ROIs, scan variability, and individual differences in neuroanatomy. In this report, a "majority rule" approach is introduced for ROI segmentation used to guide streamline tractography in white matter structures. DWI of one healthy participant was acquired in ten separate sessions using a 3 T scanner over the course of a month. Four raters identified ROIs within the left hemisphere [Cerebral Peduncle (CPED); Internal Capsule (IC); Hand Portion of the Motor Cortex, or Hand Bump, (HB)] using a group-established standard operating procedure for ROI definition to guide the estimation of streamline tracts within the corticospinal tract (CST). Each rater traced the ROIs twice for each scan session. The overlap of each rater's two ROIs was used to define a representative ROI for each rater. These ROIs were combined to create a "majority rules" ROI, in which the rule requires that each voxel is selected by at least three of four raters. Reproducibility for ROIs and CST segmentations were analyzed with the Dice Similarity Coefficient (DSC). Intra-rater reliability for each ROI was high (DSCs >= 0.83). Inter-rater reliability was moderate to adequate (DSC range 0.54 0.75; lowest for IC). Using intersected majority rules ROIs, the resulting CST showed improved overlap (DSC = 0.82) in the estimated streamline tracks for the ten sessions. Despite high intra-rater reliability, there was lower inter-rater reliability consistent with the expectation of rater bias. Employing the majority rules method improved reliability in the overlap of the CST. PMID- 26572145 TI - Label-aligned multi-task feature learning for multimodal classification of Alzheimer's disease and mild cognitive impairment. AB - Multimodal classification methods using different modalities of imaging and non imaging data have recently shown great advantages over traditional single modality-based ones for diagnosis and prognosis of Alzheimer's disease (AD), as well as its prodromal stage, i.e., mild cognitive impairment (MCI). However, to the best of our knowledge, most existing methods focus on mining the relationship across multiple modalities of the same subjects, while ignoring the potentially useful relationship across different subjects. Accordingly, in this paper, we propose a novel learning method for multimodal classification of AD/MCI, by fully exploring the relationships across both modalities and subjects. Specifically, our proposed method includes two subsequent components, i.e., label-aligned multi task feature selection and multimodal classification. In the first step, the feature selection learning from multiple modalities are treated as different learning tasks and a group sparsity regularizer is imposed to jointly select a subset of relevant features. Furthermore, to utilize the discriminative information among labeled subjects, a new label-aligned regularization term is added into the objective function of standard multi-task feature selection, where label-alignment means that all multi-modality subjects with the same class labels should be closer in the new feature-reduced space. In the second step, a multi kernel support vector machine (SVM) is adopted to fuse the selected features from multi-modality data for final classification. To validate our method, we perform experiments on the Alzheimer's Disease Neuroimaging Initiative (ADNI) database using baseline MRI and FDG-PET imaging data. The experimental results demonstrate that our proposed method achieves better classification performance compared with several state-of-the-art methods for multimodal classification of AD/MCI. PMID- 26572146 TI - Epigenetic inactivation of galanin and GALR1/2 is associated with early recurrence in head and neck cancer. AB - The aim of this study was to investigate the prognostic value of galanin (GAL) and galanin receptor (GALR) promoter hypermethylation in patients with head and neck squamous cell carcinoma (HNSCC). The methylation status of three genes-GAL, GALR1, and GALR2 was examined in HNSCC patient tumors using quantitative methylation-specific PCR (Q-MSP). To determine the prognostic value of GAL, GALR1 and GALR2 methylation status, their associations with various clinical characteristics and patient survival were assessed in HNSCC patient tumors (n = 142). Aberrant methylation of at least one gene was observed in 84 of the 142 (59.2 %) primary tumors analyzed. The methylation index, defined as the ratio between the number of methylated genes and the number of genes examined, was positively correlated with larger tumor size (P = 0.034) and disease recurrence (P < 0.001). In the multivariate logistic-regression analysis, methylation of both GAL and GALR1 exhibited the highest association with poor survival (hazard ratio, 6.83, P = 0.002). Moreover, among patients without lymph node metastasis, a multivariate analysis showed a significant trend for poor survival as the number of hypermethylated genes increased (log-rank test, P = 0.003). CpG hypermethylation is a likely mechanism of GAL and GALR1/2 gene inactivation, indicating that GAL and its receptors play a role in HNSCC tumorigenesis. As such, GAL and GALR1/2 methylation status may serve as an important biomarker for clinical outcome. PMID- 26572148 TI - Candida tropicalis Biofilms: Biomass, Metabolic Activity and Secreted Aspartyl Proteinase Production. AB - According to epidemiological data, Candida tropicalis has been related to urinary tract infections and haematological malignancy. Several virulence factors seem to be responsible for C. tropicalis infections, for example: their ability to adhere and to form biofilms onto different indwelling medical devices; their capacity to adhere, invade and damage host human tissues due to enzymes production such as proteinases. The main aim of this work was to study the behaviour of C. tropicalis biofilms of different ages (24-120 h) formed in artificial urine (AU) and their ability to express aspartyl proteinase (SAPT) genes. The reference strain C. tropicalis ATCC 750 and two C. tropicalis isolates from urine were used. Biofilms were evaluated in terms of culturable cells by colony-forming units enumeration; total biofilm biomass was evaluated using the crystal violet staining method; metabolic activity was evaluated by XTT assay; and SAPT gene expression was determined by real-time PCR. All strains of C. tropicalis were able to form biofilms in AU, although with differences between strains. Candida tropicalis biofilms showed a decrease in terms of the number of culturable cells from 48 to 72 h. Generally, SAPT3 was highly expressed. C. tropicalis strains assayed were able to form biofilms in the presence of AU although in a strain- and time-dependent way, and SAPT genes are expressed during C. tropicalis biofilm formation. PMID- 26572149 TI - The polymorphism in miR-25 attenuated the oncogenic function in gastric cancer. AB - miR-25 was identified as an essential oncogene by promoting the growth and metastasis through TOB1 in gastric cancer (GC). The function of the single nucleotide polymorphism (SNP) located in the mature region of miR-25 (rs41274221) has not been investigated. In this study, we aimed to explore the involvement of rs41274221 in miR-25 in gastric cancer. We found that SNP rs41274221 in miR-25 was participated in the occurrence of GC by acting as a tumor protective factor associating with the tumor growth and metastasis. Besides, further investigation found that upregulation of miR-25 with AA genotype could attenuate the proliferation and invasion of tumor cells caused by wild-type miR-25. The dual luciferase reporter assay also confirmed that miR-25 harbored the A allele which caused an incapacitation of binding at the TOB1. In conclusion, rs41274221 in miR 25 was a subgroup which may protect the patients from further growth and metastasis of gastric cancer and might serve as a novel biomarker for the disease. PMID- 26572150 TI - Cross-reacting material 197 reverses the resistance to paclitaxel in paclitaxel resistant human ovarian cancer. AB - Heparin-binding epidermal growth factor-like growth factor (HB-EGF) has been proven to be a promising chemotherapeutic target for ovarian cancer. Our previous studies have demonstrated that inhibition of HB-EGF by the special inhibitor, cross-reacting material 197 (CRM197), potently inhibits the anti-tumor activity in paclitaxel-resistant ovarian cancer. Here, we found that inhibition of HB-EGF by CRM197 significantly reverses the resistance to paclitaxel in paclitaxel resistant ovarian carcinoma cell line (A2780/Taxol). A2780/Taxol cells over expressed HB-EGF and epidermal growth factor receptor (EGFR) and CRM197 notably suppressed the expression of HB-EGF and EGFR. Experiments performed in vitro and in vivo further suggested that CRM197 markedly down-regulated the ATP-binding cassette sub-family B member 1 (ABCB1/MDR1) messenger RNA (mRNA) expression (P = 0.01), plasma membrane glycoprotein (P-gp) protein (P = 0.009), and P-gp-mediated efflux (P = 0.007) through inhibition of nuclear factor-kappaB (NF-kappaB) expression, which were classical chemoresistance-related targets with respect to paclitaxel therapy. Meanwhile, inhibition of HB-EGF enhanced caspase-3 activity to induce apoptosis via MDR1 inhibition in A2780/Taxol cells (P = 0.038). Collectively, HB-EGF is a molecular target for the resistance of ovarian cancer to paclitaxel and CRM197 as a HB-EGF-targeted agent might be a chemosensitizing agent for paclitaxel-resistant ovarian carcinoma. Our findings provide novel possible mechanisms for HB-EGF to be a target to restore the chemosensitivity to paclitaxel. PMID- 26572151 TI - Polymorphisms of tumor necrosis factor alpha in Middle Eastern population with colorectal cancer. AB - Tumor necrosis factor-alpha (TNF-alpha) contributes in inflammation and has been implicated in the development of colorectal cancer (CRC). Single nucleotide polymorphisms (SNPs) in TNF-alpha promoter could affect the risk of CRC by regulating TNF-alpha production. This is the first study to investigate TNF-alpha SNPs in a Middle Eastern population. In this study, we examined three SNPs in TNF alpha for association with CRC. One hundred CRC patients and 100 controls were genotyped for TNF-alpha -308, -238, and -857 using TaqMan allelic discrimination assay. The TNF-alpha -238 (G/A) genotype was significantly associated with high risk of CRC (p = 0.003552). The distribution of three genotypes of -238 G/A was significantly different between the controls and CRC patients even after Bonferroni's correction. The AA genotype of -238 G/A SNP was observed at considerably higher proportion (13 %) in CRCs compared to controls (1 %). Additionally, similar to genotypes, the allelic frequencies of -238 G/A were significantly different between the CRC cases and controls (odds ratios (OR) = 7.647, chi (2) = 18.50, p = 0.00002). The genotype frequencies of -308 and -857 were not notably different between the cases and controls. TNF-alpha -238A may be useful as a screening marker to identify individuals prior to their acquiring CRC in the Saudi population although, further validations in larger cohorts are needed. PMID- 26572152 TI - Identification of CTNNB1 mutations, CTNNB1 amplifications, and an Axin2 splice variant in juvenile angiofibromas. AB - Juvenile angiofibromas (JAs) are benign fibro-vascular tumors occurring nearly exclusively in adolescent males. Even less is known about this rare tumor entity, alterations affecting the Wnt-pathway seem to play a pivotal role in tumor biology as activating CTNNB1 mutations have been detected. However, the knowledge of Wnt-pathway changes is still limited. Therefore, we aimed to determine in JAs further insight into Wnt/beta-catenin pathway components. In our present study, genetic alterations of the Wnt-pathway members CTNNB1, APC, GSK3beta, and Axin2 detected by metaphase comparative genomic hybridization (CGH) were shown to result in elevated transcript levels in the majority of JA samples compared to nasal mucosa stroma (p < 0.001, p = 0.001, p = 0.046, and p = 0.006, respectively). Additionally, amplifications of CTNNB1 were validated by fluorescence in situ hybridization (FISH) and genomic qPCR. Moreover, our mutation analysis detected already known mutations as well as, to the best of our knowledge, mutations and an interstitial deletion of CTNNB1 not described in JAs before. Additionally, a so far unknown transcribed Axin2 splice variant was found, but no further Axin2 mutations. Taken together, our current study supports the importance of aberrant Wnt-signaling as a common event in JAs, most likely by the observed genetic alterations driven by mutations, interstitial deletions but also amplifications of CTNNB1 contributing to the stabilization of beta-catenin. PMID- 26572153 TI - miR-411 contributes the cell proliferation of lung cancer by targeting FOXO1. AB - Lung cancer is the leading cause of cancer deaths worldwide; the study of microRNAs gives new hope for lung cancer treatment. miR-411 has been demonstrated to be an independent prognostic factor for lung adenocarcinoma, but the role and regulatory mechanism are largely unknown. In the present study, we found miR-411 was overexpressed in the lung cancer cells; overexpression of miR-411 promoted anchorage-dependent and anchorage-independent growths of lung cancer, while miR 411 knockdown reduced this effect. Further study showed forkhead box O1 (FOXO1) was a target of miR-411. Overexpression of miR-411 suppressed the expression of FOXO1; the effect of suppression was abrogated when the mutation occurred in the 3'UTR of FOXO1. Knockdown of FOXO1 in cells which miR-411 was inhibited recapitulated the phenotype of miR-411 overexpression. Taken together, our study revealed miR-411 promoted cell proliferation of lung cancer by targeting tumor suppressor gene FOXO1 and miR-411 might be a potential target for lung cancer therapy. PMID- 26572154 TI - Autologous staged fat tissue transfer in post-traumatic lower extremity reconstruction. AB - Autologous fat tissue transfer for aesthetic reconstruction has been described in the literature for soft tissue damage as early as 1893. One area that has yet to be described is the role of fat grafting in post-traumatic lower extremity injuries. In this case report, we present a patient who had significant injury to her right lower extremity and presented for reconstruction. The patient is a 52 year-old female who presented to clinic after a right lower extremity traumatic injury that required multiple re-operations, which lead to dense scarring and volume loss along the extremity inferior to the knee joint. The patient received two staged autologous fat injections and reported positive outcomes. Our case report demonstrates the utility of fat transfer in reconstruction of the lower extremity in staged fashion. Further research in the refinement of this technique and patient follow-up will lead to better graft survival and reconstructive outcomes. PMID- 26572155 TI - Prevalence of anemia and malnutrition and their association in elderly nursing home residents. AB - PURPOSE: Malnutrition is one of the most important geriatric syndromes in the elderly. The aim of this study was to investigate the association between anemia and malnutrition in elderly nursing home residents. MATERIALS AND METHODS: Local nursing home residents over 60 years old in the Izmir were included in the study. Blood samples were taken from study participants for hemogram, iron, ferritin, total iron-binding capacity, vitamin B12 and folic acid analysis. WHO criteria were used to define anemia. Causes of anemia were classified as iron deficiency, vitamin B12 or folic acid deficiency, anemia of chronic disease or other hematologic causes. Anemia was defined as the dependent variable and malnutrition was defined as the independent variable. Correlation between MNA scores and Hb levels was determined using Pearson correlation analysis. The slope of causality between malnutrition and anemia was determined using the chi (2) test and logistic regression analysis. RESULTS: The study included 257 elderly nursing home residents with a mean age of 78.5 +/- 7.8 years. The overall prevalence of anemia was 54.9 %; 35.8 % of the study participants were at risk of malnutrition and 8.2 % were malnourished. Anemia risk was 2.12-fold higher in participants at risk of malnutrition and 5.05-fold higher in those with malnutrition. In the participants with malnutrition or malnutrition risk, the most common cause of anemia was anemia of chronic disease (57.1 and 46.5 %, respectively). CONCLUSION: The prevalence of anemia among elderly nursing home residents is high in Turkey. Malnutrition and malnutrition risk increase the incidence of anemia. PMID- 26572156 TI - Description and cohort characterization of the Longevity Study: learning from our elders. AB - The purpose of this article is to describe the Longevity Study: Learning From Our Elders, a research program on healthy aging that began in 2007 at the Center for Healthy Aging at Banner Sun Health Research Institute. As of June 2015, 1139 participants (age range of 50-110 years) completed baseline assessments with the majority living in the Sun Cities retirement communities northwest of Phoenix, Arizona but expanding throughout the state. The registry includes over 830 currently active participants with 450 aged 80 years and older, 188 aged 90 and older, and 27 centenarians. Data from in-person interviews at the Center for Healthy Aging in Sun City or in the participants' residences which includes sociodemographic, medical, cognitive, physical and psychosocial variables have been collected since the study's inception. This paper outlines some of the key demographic and clinical characteristics of the Longevity Study, its progress, and future directions. It also reflects on how exceptional aging individuals function psychosocially, cognitively and physically, particularly among individuals aged 85 and older. PMID- 26572158 TI - More than 400 pharmacists will be recruited to GP surgeries by next year. PMID- 26572157 TI - Meta-analysis of the rs2075650 polymorphism and risk of Alzheimer disease. AB - BACKGROUND: Several researchers have suggested that the rs2075650 polymorphism is significantly associated with an increased risk of developing Alzheimer disease (AD) in European. However, some others found inconsistent results in Asian (Chinese and Korean). We addressed the controversy through performing a meta analysis of the relationship between rs2075650 in TOMM40 (translocase of outer mitochondrial membrane 40 homologue) and Alzheimer disease. METHODS: We selected eight case-control studies involving 4290 cases of Alzheimer disease and 5556 healthy individuals. The association between the TOMM40 rs2075650 polymorphism and Alzheimer disease was examined by overall odds ratio (OR) with a 95 % confidence interval (CI). We used different genetic model analysis, sensitivity analysis, and assessments of bias in our meta-analysis. RESULTS: The pooled analysis showed the inconsistent results that TOMM40 rs2075650 polymorphism was associated with Alzheimer disease in European and Korean population in all genetic models, but there was no significant association between the TOMM40 rs2075650 polymorphism and Alzheimer disease risk in Chinese population. CONCLUSION: We conclude that rs2075650 in TOMM40 gene may increase the risk of Alzheimer disease. PMID- 26572159 TI - Two-year Test-Retest Reliability of ImPACT in High School Athletes. AB - This research evaluated the 2-year test-retest reliability of the Immediate Postconcussion Assessment and Cognitive Testing (ImPACT) neuropsychological battery, and clarified the need for biennial updated baseline testing of high school athletes. This study compared the baseline test scores of 212 non concussed athletes that were obtained in Grade 9 and again 2 years later when they were in Grade 11. Regression-based methods indicated that 4 of the 5 ImPACT scores were stable over 2 years, as they fell within the 80% and 95% confidence intervals (CIs). The results suggested that updating baseline testing for high school athletes after 2 years is not necessary. Further research into the consistency of computerized neuropsychological tests over 2 years with high school athletes is recommended. PMID- 26572160 TI - Quality of Life and School Absenteeism in Children With Chronic Illness. AB - OBJECTIVE: Children and adolescents with a chronic illness (CI) tend to demonstrate diminished physical and social functioning, which contribute to school attendance issues. We investigated the role of social and physical functioning in reducing school absenteeism in children participating in Mastering Each New Direction (MEND), a family-based psychosocial intervention for youths with CI. METHODS: Forty-eight children and adolescents with a CI (70.8% female, M age = 14.922, SD = 2.143) and their parent(s) completed a health-related quality of life (HRQOL) measure pre- and postintervention. Using multiple mediation, we examined whether parent- and child-rated physical and social HRQOL mediated the relationship between school attendance before and after MEND. Once the mediational model was not supported, we investigated whether HRQOL moderated the relationship between missed school days pre- and postintervention. RESULTS: Neither physical nor social functioning mediated or moderated the relationship between missed school days pre- and postintervention. Instead, higher parent rated physical functioning directly predicted decreased number of missed school days, while lower parent-rated social and child-rated physical functioning predicted increased missed school days. CONCLUSIONS: Parent-perceived HRQOL may have a direct effect on health-related behaviors such as school attendance. Future research should determine whether gains in parent-rated QOL are maintained in the long term and whether these continue to impact markers of functional well being. PMID- 26572161 TI - Heterologous expression of peptidyl-Lys metallopeptidase of Armillaria mellea and mutagenic analysis of the recombinant peptidase. AB - A method to express, purify and modify the Peptidyl-Lys metallopeptidase (LysN) ofArmillaria melleainPichia pastoriswas developed to enable functional studies of the protease. Based on prior work, we propose a mechanism of action of LysN. Catalytic residues were investigated by site-directed mutagenesis. As anticipated, these mutations resulted in significantly reduced catalytic rates. Additionally, based on molecular modelling eleven mutants were designed to have altered substrate specificity. The S1' binding pocket of LysN is quite narrow and lined with negative charge to specifically accommodate lysine. To allow for arginine specificity in S1', it was proposed to extend the S1' binding pocket by mutagenesis, however the resulting mutant did not show any activity with arginine in P1'. Two mutants, A101D and T105D, showed increased specificity towards arginine in subsites S2'-S4' compared to the wild type protease. We speculate that the increased specificity to result from the additional negative charge which attract and interact with positively charged residues better than the wild type. PMID- 26572162 TI - Impact of long-term stress in Takotsubo syndrome: Experience of patients. AB - BACKGROUND: The connection between stress and disease has been part of folk wisdom for a long time and has even made its way into our language with phrases such as 'scared to death' and 'a broken heart'. Takotsubo syndrome is a form of acute, reversible heart failure characterized by ballooning of the left ventricle. Post-menopausal women are primarily affected, but cases have been described in both sexes and at all ages. The complete pathophysiology is unknown, but the disease has been connected to psychological or physical stress and a surge in catecholamines. Despite the strong connection with stress, knowledge about the life of patients before the onset of Takotsubo syndrome is lacking. AIM: The aim of this study was to describe and interpret patients' narratives about long-term stress experienced before the onset of Takotsubo syndrome. METHOD: Nineteen people diagnosed with Takotsubo syndrome were interviewed. The narrative interviews were recorded and transcribed verbatim. The resulting texts were analysed using phenomenological hermeneutics. RESULTS: The analysis revealed that the interviewees lived under stressful circumstances, characterized by feeling burdened by responsibilities, injustice and uncertainty, long before the onset of Takotsubo syndrome. This long-term stress wore down the defences of the interviewees to the degree that their capacity was exhausted and the smallest stressor could 'tip them over the edge'. The findings indicated that the social structure of gender possibly contributed to the interviewees' condition. CONCLUSIONS: These findings indicated that long-term stressful circumstances may cause vulnerability to acute psychological or physical stressors and, subsequently, to the onset of Takotsubo syndrome. PMID- 26572164 TI - Surface charge-conversion polymeric nanoparticles for photodynamic treatment of urinary tract bacterial infections. AB - Urinary tract infections are typical bacterial infections which result in a number of economic burdens. With increasing antibiotic resistance, it is urgent that new approaches are explored that can eliminate pathogenic bacteria without inducing drug resistance. Antimicrobial photodynamic therapy (PDT) is a new promising tactic. It is a gentle in situ photochemical reaction in which a photosensitizer (PS) generates reactive oxygen species (ROS) under laser irradiation. In this work, we have demonstrated Chlorin e6 (Ce6) encapsulated charge-conversion polymeric nanoparticles (NPs) for efficiently targeting and killing pathogenic bacteria in a weakly acidic urinary tract infection environment. Owing to the surface charge conversion of NPs in an acidic environment, the NPs exhibited enhanced recognition for Gram-positive (ex. S. aureus) and Gram-negative (ex. E. coli) bacteria due to the charge interaction. Also, those NPs showed significant antibacterial efficacy in vitro with low cytotoxicity. The MIC value of NPs to E. coli is 17.91 MUg ml(-1), compared with the free Ce6 value of 29.85 MUg ml(-1). Finally, a mouse acute cystitis model was used to assess the photodynamic therapy effects in urinary tract infections. A significant decline (P < 0.05) in bacterial cells between NPs and free Ce6 occurred in urine after photodynamic therapy treatment. And the plated counting results revealed a remarkable bacterial cells drop (P < 0.05) in the sacrificed bladder tissue. Above all, this nanotechnology strategy opens a new door for the treatment of urinary tract infections with minimal side effects. PMID- 26572163 TI - Integrated genomics approach to identify biologically relevant alterations in fewer samples. AB - BACKGROUND: Several statistical tools have been developed to identify genes mutated at rates significantly higher than background, indicative of positive selection, involving large sample cohort studies. However, studies involving smaller sample sizes are inherently restrictive due to their limited statistical power to identify low frequency genetic variations. RESULTS: We performed an integrated characterization of copy number, mutation and expression analyses of four head and neck cancer cell lines - NT8e, OT9, AW13516 and AW8507 - by applying a filtering strategy to prioritize for genes affected by two or more alterations within or across the cell lines. Besides identifying TP53, PTEN, HRAS and MET as major altered HNSCC hallmark genes, this analysis uncovered 34 novel candidate genes altered. Of these, we find a heterozygous truncating mutation in Nuclear receptor binding protein, NRBP1 pseudokinase gene, identical to as reported in other cancers, is oncogenic when ectopically expressed in NIH-3 T3 cells. Knockdown of NRBP1 in an oral carcinoma cell line bearing NRBP1 mutation inhibit transformation and survival of the cells. CONCLUSIONS: In overall, we present the first comprehensive genomic characterization of four head and neck cancer cell lines established from Indian patients. We also demonstrate the ability of integrated analysis to uncover biologically important genetic variation in studies involving fewer or rare clinical specimens. PMID- 26572165 TI - Neuroprotective effects of lycopene pretreatment on transient global cerebral ischemia-reperfusion in rats: The role of the Nrf2/HO-1 signaling pathway. AB - The present study aimed to investigate the neuroprotective effect of lycopene in a mouse model of bilateral common carotid artery occlusion (BCCAO) and the role of the Nrf2/HO-1 signaling pathway. A total of 60 male C57BL/6 mice, aged 12 weeks and weighing 20-24 g, were used in the present study. The mice were randomly assigned to three groups: Control, BCCAO and BCCAO + lycopene. The neurological score was assessed 24, 48 or 72 h following BCCAO. Hematoxylin and eosin staining, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) were performed to detect neuronal death and survival. The production of glutathione (GSH) and reactive oxygen species were detected to investigate the oxidative stress. The expression levels of nuclear factor erythroid 2-related factor (Nrf2) and Heme oxygenase-1 (HO-1) were determined by western blotting. Lycopene significantly improved the neurological score in the BCCAO mice. It attenuated neuronal apoptosis, as indicated by TUNEL staining, and attenuated the oxidative stress induced by global ischemia. Lycopene increased the expression levels of Nrf2 and HO-1, indicating that the Nrf2/HO-1 signaling pathway may be involved in the neuroprotective effect of lycopene. The present study revealed that lycopene protects the brain from global ischemic injury, which is associated with its antiapoptotic effect and the activation of the Nrf2/HO-1 signaling pathway. PMID- 26572166 TI - YAP overexpression promotes the epithelial-mesenchymal transition and chemoresistance in pancreatic cancer cells. AB - The expression of Yes-associated protein (YAP) has been reported to be dysregulated in pancreatic cancer. However, its contributions to tumor formation and progression remain to be elucidated. The present study demonstrated that YAP overexpression promoted the epithelial-mesenchymal transition (EMT) in a manner associated with pancreatic cancer invasion in vitro. RNA interference-mediated silencing of YAP attenuated cell invasion in vitro. Mechanistically, the present study demonstrated that YAP overexpression fosters pancreatic cancer progression by inducing the EMT in pancreatic cancer cells by activating the AKT cascade, which can counteract the effect of gemcitabine. These data suggested that the YAP acts synergistically to promote pancreatic cancer progression by hyperactivation of AKT signaling. The present study revealed YAP as a potential therapeutic target for pancreatic cancer and a biomarker for predicting gemcitabine treatment response. PMID- 26572167 TI - MiR-218-5p inhibits the stem cell properties and invasive ability of the A2B5+CD133- subgroup of human glioma stem cells. AB - MicroRNAs (miRs) act as oncogenes or tumor-suppressor genes, and regulate the proliferation, apoptosis, invasion, differentiation, angiogenesis and behavior of glioma stem cells, which are important in glioma development and recurrence. The present study was performed to investigate the impact of miR-218-5p on stem cell properties and invasive ability of the A2B5+CD133- human glioma stem cell subgroup. qRT-PCR was used to detect miR-218-5p expression in non-cancerous brain and human glioma tissues, human glioma cell lines and human glioma stem cell lines. Lentivirus vectors encoding miR-218-5p and anti-miR-218-5p were constructed and stably transfected into A2B5+CD133- SHG-139s cells. Neurosphere formation Cell Counting Kit-8 (CCK-8) and Transwell assays, immunofluorescence and qRT-PCR analyses were used to explore the role of miR-218-5p in SHG-139s cells. qRT-PCR analysis showed that miR-218-5p expression was lower in human glioma tissues and cells than in non-cancerous brain tissues and normal human astrocyte cells, and lower in A2B5+CD133- (SHG-139s) cells than in CD133+ (SU2 and U87s) cells. The CCK-8 assay demonstrated that the growth curve was significantly inhibited in the miR-218-5p-SHG-139s cells compared to the miR control, blank and anti-miR-218-5p groups. The neurosphere formation assay indicated that upregulation of miR-218-5p expression inhibited SHG-139s neurosphere formation. Immunofluorescence staining and qRT-PCR showed that miR 218-5p reduced stem cell marker (A2B5, nestin, PLAGL2, ALDH1 and Sox2) expression compared with the controls; however, immunofluorescence staining analysis showed that upregulation of miR-218-5p expression led to no difference in CD133 expression. miR-218-5p reduced SHG-139s cell invasiveness in the Transwell assay and reduced MMP9 expression as detected in qRT-PCR and immunofluorescence analyses. All differences were statistically significant. miR-218-5p expression was lower in human glioma tissues, cells and the A2B5+CD133- human glioma stem cell subgroup. miR-218-5p may be a tumor-suppressor gene in glioma that functions by upregulating miR-218-5p expression, which inhibits the stem cell properties and invasive properties of SHG-139s cells. PMID- 26572168 TI - Training intensity modulates changes in PGC-1alpha and p53 protein content and mitochondrial respiration, but not markers of mitochondrial content in human skeletal muscle. AB - Exercise training has been associated with increased mitochondrial content and respiration. However, no study to date has compared in parallel how training at different intensities affects mitochondrial respiration and markers of mitochondrial biogenesis. Twenty-nine healthy men performed 4 wk (12 cycling sessions) of either sprint interval training [SIT; 4-10 * 30-s all-out bouts at ~200% of peak power output (WPeak)], high-intensity interval training (HIIT; 4-7 * 4-min intervals at ~90% WPeak), or sublactate threshold continuous training (STCT; 20-36 min at ~65% WPeak). The STCT and HIIT groups were matched for total work. Resting biopsy samples (vastus lateralis) were obtained before and after training. The maximal mitochondrial respiration in permeabilized muscle fibers increased significantly only after SIT (25%). Similarly, the protein content of peroxisome proliferator-activated receptor gamma coactivator (PGC)-1alpha, p53, and plant homeodomain finger-containing protein 20 (PHF20) increased only after SIT (60-90%). Conversely, citrate synthase activity, and the protein content of TFAM and subunits of the electron transport system complexes remained unchanged throughout. Our findings suggest that training intensity is an important factor that regulates training-induced changes in mitochondrial respiration and that there is an apparent dissociation between training-induced changes in mitochondrial respiration and mitochondrial content. Moreover, changes in the protein content of PGC-1alpha, p53, and PHF20 are more strongly associated with training-induced changes in mitochondrial respiration than mitochondrial content. PMID- 26572170 TI - Subcortical volume changes in dementia with Lewy bodies and Alzheimer's disease. A comparison with healthy aging. AB - BACKGROUND: Differentiating Alzheimer's disease (AD) and dementia with Lewy bodies (DLB), two of the commonest forms of dementia in older age, remains a diagnostic challenge. To assist with better understanding of the differences between the conditions during life, we assessed limbic and subcortical brain volumes in AD, DLB, and healthy older individuals using magnetic resonance imaging (MRI), with the hypothesis that when compared with controls, subcortical volumes would be reduced to a greater extent in DLB than in AD. METHODS: One hundred participants (35 healthy controls, 32 AD, and 33 DLB) underwent 3 Tesla T1 weighted MR scanning. Volumes were automatically segmented for each participant using FreeSurfer, then expressed as a percentage of their total intracranial volumes. Group effects were assessed using multivariate analysis of covariance, controlling for age and gender. RESULTS: Significant group effects were apparent among subcortical brain volumes (F 28,162 = 4.8, p < 0.001; Wilk's Lambda = 0.30, partial eta 2 = 0.45), while univariate tests showed differences in all volumetric measures (p AD, p < 0.008). CONCLUSIONS: For similar levels of dementia severity, DLB appears to have greater involvement of subcortical brain atrophy than AD. Further investigation of the subcortical brain structures in DLB is warranted to fully understand their neurobiological role in this disease. PMID- 26572169 TI - Next-generation sequencing of tyrosine kinase inhibitor-resistant non-small-cell lung cancers in patients harboring epidermal growth factor-activating mutations. AB - BACKGROUND: The aim of this study was to detect the epidermal growth factor receptor (EGFR)-activating mutations and other oncogene alterations in patients with non-small-cell lung cancers (NSCLC) who experienced a treatment failure in response to EGFR-tyrosine kinase inhibitors (TKIs) with a next generation sequencer. METHODS: Fifteen patients with advanced NSCLC previously treated with EGFR-TKIs were examined between August 2005 and October 2014. For each case, new biopsies were performed, followed by DNA sequencing on an Ion Torrent Personal Genome Machine (PGM) system using the Ion AmpliSeq Cancer Hotspot Panel version 2. RESULTS: All 15 patients were diagnosed with NSCLC harboring EGFR-activating mutations (seven cases of exon 19 deletion, seven cases of L858R in exon 21, and one case of L861Q in exon 21). Of the 15 cases, acquired T790M resistance mutations were detected in 9 (60.0%) patients. In addition, other mutations were identified outside of EGFR, including 13 cases (86.7%) exhibiting TP53 P72R mutations, 5 cases (33.3%) of KDR Q472H, and 2 cases (13.3%) of KIT M541L. CONCLUSIONS: Here, we showed that next-generation sequencing (NGS) is able to detect EGFR T790M mutations in cases not readily diagnosed by other conventional methods. Significant differences in the degree of EGFR T790M and other EGFR activating mutations may be indicative of the heterogeneity of disease phenotype evident within these patients. The co-existence of known oncogenic mutations within each of these patients may play a role in acquired EGFR-TKIs resistance, suggesting the need for alternative treatment strategies, with PCR-based NGS playing an important role in disease diagnosis. PMID- 26572171 TI - Anti-wrinkle effects of a tuna heart H2O fraction on Hs27 human fibroblasts. AB - With the increase in life expectancy, there is also growing interest in anti aging treatments and technologies. The development of anti-aging functional drugs for the skin, and foods from natural sources, may offer solutions to this global matter. Aging involves structural, functional and biochemical changes that occur throughout cells and bodily tissues; the amount of hormones secreted from of all human organs, including the skin, decreases over time. Matrix metalloproteinase (MMP) genes (MMP-1 and -8) play an important role in the aging of skin fibroblasts. For example, an increased MMP expression causes accelerated aging and the degradation of skin elasticity-related genes. In the present study, we examined the anti-wrinkle effects of tuna heart extract which are mediated through the inhibition of MMPs in skin cells. Generally, tuna contains high concentrations of selenium and antioxidants, which serve to remove free radicals, and is known to delay skin and body aging. In addition, unsaturated fatty acids in tuna help to maintain the natural glossy look of skin, and increase skin elasticity, providing moisture for dry skin. A recent study confirmed the various bio-effects of boiled tuna extract and muscle. However, bioactivity studies using tuna heart are limited. Thus, in the present study, we obtained extracts and fractions of tuna heart, and examined their effects on Hs27 human fibroblast proliferation using an MTS assay. In addition, we measured procollagen type 1 levels and elastase activity, and performed beta-galactosidase staining. We then measured the expression levels of phosphatidylinositol 3-kinase/Akt and MMP related genes by western blot analysis and RT-PCR. Our results revealed that tuna heart extract decreased MMP expression by upregulating tissue inhibitors of metalloproteinase-1 (TIMP-1) and decreasing elastase activity, thus exerting anti aging and anti-wrinkle effects by increasing collagen synthesis and promoting skin fibroblast proliferation. Thus, our data suggest that tuna heart (TH)-H2O fractions exert anti-wrinkle effects on Hs27 cells. PMID- 26572172 TI - N-acetylcysteine attenuates cigaret smoke-induced pulmonary exacerbation in a mouse model of emphysema. AB - OBJECTIVE: The purpose of this study was to investigate the effects of cigaret smoke (CS) on a mouse model of emphysema and examine the protective role of N acetylcysteine (NAC) in the CS-induced exacerbation of pulmonary damage in the mice. METHOD: Particulate matter (PM) in sidestream cigaret smoke aerosol was analyzed by a scanning mobility particle sizer spectrometer. A mouse model of emphysema was established by an injection of porcine pancreatic elastase (PPE) into the trachea. Mice with emphysema were then exposed to filtered air, or sidestream CS with intragastric administration of NAC or normal saline. Mouse body weight, survival, pulmonary tissue histology, total antioxidant capacity (T AOC) and malonaldehyde (MDA) contents in lung tissue, and inflammatory responses were examined. RESULTS: Particles with a size of <=346 nm constituted 99.06% of CS PM. Mice exhibited ruptured alveolar septal, alveolar fusion, significantly increased mean lining interval, and reduced mean alveolar number (all p < 0.05), 21 d after PPE injection. Exposure of mice with emphysema to CS exacerbated the pulmonary tissue damage, caused weight loss, significantly increased mortality, decreased T-AOC, elevated MDA contents in lung tissue, and increased interleukin (IL)-1beta levels in bronchoalveolar lavage (BAL) fluids (all p < 0.05). Administration of NAC attenuated those CS-induced adverse effects in the mice and increased anti-inflammatory factor IL-10 levels in BAL fluids significantly (all p < 0.05). CONCLUSIONS: Exposure of mice with emphysema to CS exacerbated the pulmonary damage, and NAC reduced the CS-mediated pulmonary damage by preventing oxidative damage and reducing inflammatory responses. PMID- 26572174 TI - Transoral versus transcervical approach to submandibular gland: techniques and outcomes. AB - OBJECTIVES: This study aims to evaluate the risks and benefits of the transoral approach for removal of the submandibular gland compared to the transcervical approach. PATIENTS AND METHODS: Twenty consecutive patients who underwent submandibular gland excision surgery via the transoral (6 males, 4 females; mean age 45.4 years) or transcervical (7 males, 3 females; mean age 44.1 years) approach between March 2009 and December 2014 were analyzed retrospectively. Age, surgical indications, complications, duration of hospitalization, and postoperative histopathological results were recorded and compared between two groups. RESULTS: Of 20 patients, 35% were previously treated with antibiotics. There were no significantly differences in demographic characteristics and postoperative histopathological results between the groups (p<0.05). Duration of hospitalization was statistically shorter in the patients operated via transoral approach (p<0.05). Relapsing sialoadenitis occurred in a patient who was operated by transoral approach due to the incomplete resection of the gland. CONCLUSION: The transoral approach for submandibular gland excision has several advantages over the transcervical approach in terms of cosmetic outcome, marginal mandibular nerve injury, and length of hospital stay. PMID- 26572173 TI - Physicians' information to patients and prescription of the emergency contraceptive pill according to their personal experience of using the method and perception of its mechanism of action. AB - OBJECTIVES: The aim of the study was to evaluate the association between physicians' understanding of the mechanism of action of the emergency contraceptive pill (ECP), their personal use of it, and their practice in informing their patients about the method and in prescribing it. METHODS: The study was carried out in a sample of 3337 obstetrician-gynaecologists who responded to a mailed questionnaire. Bivariate analysis was used to test the association between physicians' personal use of the ECP, their understanding of its mechanism of action, and their practice in informing their patients about the method and in prescribing it. Multiple Poisson regression analysis was carried out to identify variables independently associated with the two dependent variables. RESULTS: Multiple regression analysis showed that the percentage of physicians who had informed their patients about the ECP was significantly lower among those who had needed it themselves but had not used it and among those living in the northeast of Brazil. A significantly higher percentage of female than male physicians had provided information on the ECP. The percentage of physicians who had prescribed the ECP was significantly lower among those who had needed it themselves but had not used it and among those who believed that it caused a mini-abortion. The proportion of physicians who had ever-prescribed the ECP was greater among those who worked exclusively in private practice and among those who worked in a state capital. CONCLUSIONS: The misconception that emergency contraception could cause a mini-abortion was associated with its denial to potential users, while physicians' personal experience of needing to use it favoured the likelihood of their informing potential users about it and prescribing it. PMID- 26572175 TI - A novel method to prevent complications of nasal osteotomy: matress suture which traverses lateral walls and septum. AB - OBJECTIVES: This study aims to investigate long-term nasal wall stability and prevention of nasal osteotomy complications using thin osteotomes without a nasal splint. PATIENTS AND METHODS: Between March 2012 and August 2014, 16 male patients (mean age 24 years; range 18 to 42 years) who were admitted with the complaint of appearance of nose to our clinic and were diagnosed with nasal deformity were included in this study. Primary rhinoplasty was performed on 15 patients, while secondary rhinoplasty due to open roof deformity was applied in one patient. After hump resection, two holes were made cranially and caudally over the each nasal bone. The mattress suture was performed by passing these holes to stabilize the nasal bone in a desired position following osteotomy. With this technique, only adhesive tapes were applied postoperatively. No external nasal splint was used. RESULTS: The mean follow-up was nine (range, 7 to 13) months. None of the patients experienced open roof deformity, inverted V deformity, nasal bone collapses or wall irregularities. CONCLUSION: Our study results show that our technique is useful to reduce osteotomy complications and to reach the optimal cosmetic outcomes in rhinoplasty. PMID- 26572176 TI - [Sonoelastography, B-mode sonography, and color Doppler sonography findings of pleomorphic adenomas and Warthin tumors of parotid gland]. AB - OBJECTIVES: This study aims to investigate the sonoelastography (SE), B-mode sonography, and color Doppler sonography findings of the pleomorphic adenomas and Warthin tumors of the parotid gland. PATIENTS AND METHODS: A total of 84 parotid masses (23 pleomorphic adenomas, 25 Warthin tumors) in 72 patients (37 males, 35 females; mean age 59 years; range 30 to 79 years) were retrospectively analyzed. For each lesion, B-mode sonography, color Doppler sonography, and SE images were evaluated. Vascularity and elasticity scores of the tumors during color Doppler sonography and SE examinations were calculated by 4-scoring method. RESULTS: Lobulated contour and cystic areas were more common in the pleomorphic adenomas and Warthin tumors during the B-mode sonography examination (p<0.05). Peripheral vascularity was common in more than half of the pleomorphic adenoma patients, whereas central or mixed vascularity was seen in a large group of the Warthin tumor patients (p<0.05). The mean scores on color Doppler sonography examination were 1.13+/-0.81 for pleomorphic adenomas and 1.96+/-0.97 for Warthin tumors (p<0.05). The mean scores on SE examination were 2.69+/-0.70 for pleomorphic adenomas and 1.83+/-0.63 for Warthin tumors (p<0.05). Score 1 on SE examination was found in three of five Warthin tumor patients with peripheral vascularity on color Doppler sonography. CONCLUSION: B-mode, color Doppler and elastography examinations by sonography provide some helpful findings in the differentiation of pleomorphic adenomas and Warthin tumors. PMID- 26572177 TI - Vestibular-evoked myogenic potentials before and after dental implant surgery. AB - OBJECTIVES: This study aims to examine the effects of dental implant surgery on vestibular-evoked myogenic potential (VEMP) responses. PATIENTS AND METHODS: Between October 2012 and October 2014, a total of 60 consecutive patients undergoing dental implant surgery at Baskent University Hospital, Department of Otorhinolaryngology were included in the study. The control group consisted of 40 healthy subjects undergoing routine clinical examination. The VEMP response was evaluated at baseline, second and seventh days. Positional tests and Dix-Hallpike testing for vertigo were performed at baseline, second and seventh days. RESULTS: Hundred-eight dental implants were placed in 60 patients. There was no significant difference in the p1 and n1 latencies in the control group at baseline, second day, and seventh day (p>0.05). However, there was a significant increase at the second day for p1 latencies in the study group, compared to the baseline and seventh day (p=0.038). There was a significant increase at the second day for n1 compared to the baseline (p=0.016) and seventh day in the study group (p=0.005). There was a significant increase at the seventh day for n1 compared to the baseline in the study group (p=0.016). CONCLUSION: The present study revealed a significant difference in the cervical VEMP response on the second postoperative day for p1 and n1 latencies compared to the baseline and seventh postoperative day in dental implantation patients. Dental implant patients should be informed of such possible temporary problems as dizziness and vestibular problems. PMID- 26572178 TI - [Mean platelet volume play a role in disease severity in patients with obstructive sleep apnea syndrome?]. AB - OBJECTIVES: This study aims to show the effects of nasal continuous positive airway pressure (CPAP) treatment on platelet activation in patients with severe obstructive sleep apnea syndrome (OSAS). PATIENTS AND METHODS: Forty-six patients (29 males, 17 females; mean age 48.2+/-7.6 years; range 40 to 56 years) with severe OSAS with apnea/hypopnea index (AHI) >=30 were included in this study. Complete blood counts were analyzed and mean platelet volume (MPV) values were compared in patients before and after CPAP treatment at six months. RESULTS: The mean MPV values before CPAP were 8.9+/-1.3 (p<0.001), while the mean values were 7.7+/-1.1 (p<0.001) at six months after CPAP treatment in patients with severe OSAS. There was a statistically significant decrease in the MPV values after CPAP treatment. Patients' number of platelets which was measured six months after the CPAP treatment increased at a significant level compared to baseline (p<0.001). CONCLUSION: Continuous positive airway pressure treatment caused a significant decrease in the MPV values in patients with severe OSAS. As a negative acute phase reactant, MPV can be used as a marker to exert the cardioprotective effect of CPAP. PMID- 26572179 TI - Diagnosis and treatment of malignant lymphomas of parotid gland. AB - OBJECTIVES: This study aims to report surgical outcomes of primary parotid lymphomas and to discuss the histopathological subtypes, incidence rates, and clinical course. PATIENTS AND METHODS: Between January 2002 and December 2014, eight patients (2 males, 6 females; man age 46.6 years; range 25 to 60 years) who were diagnosed with primary parotid lymphoma and underwent parotidectomy were retrospectively analyzed. Demographic characteristics of the patients, histopathological subtypes, disease stage, and survival rates were recorded. RESULTS: The ratio of the patients diagnosed with lymphoma was 2.82% among all patients, while 18.1% of the malignancies were lymphomas. Fine needle aspiration biopsy was non-diagnostic. CD20-positive low-grade B-cell lymphoma was the most common histopathological subtype in 37.5% of the patients. CONCLUSION: Based on our study results, the fine needle aspiration biopsy is not helpful in the diagnosis of the lymphomas of the parotid gland. Although rarely seen, lymphomas of the parotid gland should be considered in the differential diagnosis. PMID- 26572180 TI - [The principles of differentiated thyroid cancer surgery and anesthesia in pregnancy: three case reports]. AB - Development of thyroid nodule during pregnancy is rare, however the cancer rate of this nodule is high. Herein, we present medical outcomes of three pregnant women who were operated with the diagnosis of differentiated thyroid carcinoma in the light of literature. As sonographic findings of three cases showed malignant characteristics, fine needle aspiration biopsy (FNAB) was performed. Cytological examination result was reported as papillary thyroid carcinoma (PTC). Surgery was performed in the second trimester in all cases. One case underwent total thyroidectomy with neck dissection at level III and VI and two cases underwent total thyroidectomy with neck dissection at level VI. Pathological examination result was also reported as PTC. Lymph node metastases in the dissected materials were detected. During the intraoperative and early postoperative period, no complications occurred and no findings of recurrence or residues were observed during one-year follow-up following surgery. In conclusion, as the first trimester has an increased risk of congenital malformations, elective surgery should be performed at the second trimester, if applicable. In pregnants with malignant sonographic features and PTC confirmed by FNAB, surgery can be applied safely by taking precautions during pre-/peri- and postoperative period. These patients should not be given premedication for anesthesia, should be properly positioned and teratogenic agents should be avoided. After surgery, mother and fetus should be monitored closely. PMID- 26572181 TI - [Lipoid proteinosis (Urbach-Wiethe's Disease)]. AB - A 25-year-old female patient was admitted to our outpatient clinic with postpartum hoarseness. Punch biopsy specimens obtained from the larynx and sublingual region revealed multi-folded squamous epithelium with a hyperkeratosis pattern and amorphous hyaline material aggregation. This aggregation was also remarkable around the vessels. Histochemical examination showed periodic acid schiff-positive staining of the basal membrane with negative staining with Congo red. Physical examination revealed papule-like itchy lesions in the whole body and hoarseness. Ophthalmological examination showed bilateral blepharitis. Tooth loss and yellowish papule formation in the oral mucosa were remarkable. The patient was diagnosed with lipoid proteinosis characterized by typical vocal cord involvement and conventional histopathological and clinical findings. PMID- 26572182 TI - [Aberrant parapharyngeal internal carotid artery: a case series]. AB - In this article, we report eight elderly cases who were diagnosed with aberrant internal carotid artery at the Department of Otorhinolaryngology and Head and Neck Surgery of Baskent University Ankara Hospital. Three cases had dysphagia, two cases had foreign body sensation in the throat, one case had increased tinnitus, and one case had complaints of aspiration which was not previously reported in the literature and chocking sensation. One patient was asymptomatic. Five cases had kink form of aberrant parapharyngeal internal carotid artery, one case had tortuosity and one case had both tortuosity and kink form. In one case, internal carotid artery was in form of 90 degrees angle in the right side and S shaped in the left side, which was not described in the classification. PMID- 26572183 TI - [Terminology and classification of condylar hyperplasia: Two case reports and review]. AB - Condylar hyperplasia is characterized by the growth of mandibular condyle. Its etiology and pathogenesis remain controversial. It often occurs unilaterally and leads to facial asymmetry and malocclusion. In the literature, it was also classified according to anomalies accompanied by the growth of other components of the mandible. Differential diagnosis of condylar hyperplasia usually includes tumors of temporomandibular joint. In this article, we discuss the term "condylar hyperplasia" and its classification considering two patients with condylar growth. PMID- 26572184 TI - Open versus robotic thyroidectomy: is it really a controversial choice? PMID- 26572215 TI - Using perceptual mapping methods to understand gender differences in perceived barriers and benefits of clinical research participation in urban minority HIV+ patients. AB - Minority participation in HIV clinical trials research is critical to understanding the impact of medications or behavioral interventions, but little is known about gender differences in perceptions of participation. We surveyed 50 minority HIV+ patients from an urban clinic to assess perceived risks/benefits of clinical trial research participation and used innovative marketing methods to analyze results. Perceptual mapping and vector message-modeling, a method that creates 3-D models representing how groups conceptualize elements, were used to assess how male and female participants could be motivated to participate. Results showed men farther away from participation and more concerned with HIV disclosure and experimentation than women. Men expressed distrust of the medical system, doubted HIV's origin, and knew less about research implementation. Women were closer to participation in both behavior and medical trials and perceived medication issues as more significant, including fear of losing medication stability, medications not working, being in the placebo group, and experiencing side effects. Vector modeling shows that messages would need to focus on different aspects of clinical research for men and women and that interventions aimed at minority HIV+ patients to encourage clinical trial participation would need to be targeted to their unique perceptions. Understanding gender perceptions of HIV clinical research has significant implications for targeting messages to increase minority participation. PMID- 26572216 TI - Identification of hub genes of pneumocyte senescence induced by thoracic irradiation using weighted gene co-expression network analysis. AB - Irradiation commonly causes pneumocyte senescence, which may lead to severe fatal lung injury characterized by pulmonary dysfunction and respiratory failure. However, the molecular mechanism underlying the induction of pneumocyte senescence by irradiation remains to be elucidated. In the present study, weighted gene co-expression network analysis (WGCNA) was used to screen for differentially expressed genes, and to identify the hub genes and gene modules, which may be critical for senescence. A total of 2,916 differentially expressed genes were identified between the senescence and non-senescence groups following thoracic irradiation. In total, 10 gene modules associated with cell senescence were detected, and six hub genes were identified, including B-cell scaffold protein with ankyrin repeats 1, translocase of outer mitochondrial membrane 70 homolog A, actin filament-associated protein 1, Cd84, Nuf2 and nuclear factor erythroid 2. These genes were markedly associated with cell proliferation, cell division and cell cycle arrest. The results of the present study demonstrated that WGCNA of microarray data may provide further insight into the molecular mechanism underlying pneumocyte senescence. PMID- 26572217 TI - Disrupting Acetyl-Lysine Recognition: Progress in the Development of Bromodomain Inhibitors. AB - Bromodomains, small protein modules that recognize acetylated lysine on histones, play a significant role in the epigenome, where they function as "readers" that ultimately determine the functional outcome of the post-translational modification. Because the initial discovery of selective BET inhibitors have helped define the role of that protein family in oncology and inflammation, BET bromodomains have continued to garner the most attention of any other bromodomain. More recently, non-BET bromodomain inhibitors that are potent and selective have been disclosed for ATAD2, CBP, BRD7/9, BRPF, BRPF/TRIM24, CECR2, SMARCA4, and BAZ2A/B. Such novel inhibitors can be used to probe the physiological function of these non-BET bromodomains and further understanding of their role in certain disease states. Here, we provide an update to the progress in identifying selective bromodomain inhibitors and their use as biological tools, as well as our perspective on the field. PMID- 26572219 TI - Visible-Light-Driven Photocatalytic Initiation of Radical Thiol-Ene Reactions Using Bismuth Oxide. AB - A nontoxic and inexpensive photocatalytic initiation of anti-Markovnikov hydrothiolation of olefins using visible light is reported. This method is characterized by low catalyst loading, thereby enabling a mild and selective method for radical initiation in thiol-ene reactions between a wide scope of olefins and thiols. PMID- 26572218 TI - Klenow Fragment Discriminates against the Incorporation of the Hyperoxidized dGTP Lesion Spiroiminodihydantoin into DNA. AB - Defining the biological consequences of oxidative DNA damage remains an important and ongoing area of investigation. At the foundation of understanding the repercussions of such damage is a molecular-level description of the action of DNA-processing enzymes, such as polymerases. In this work, we focus on a secondary, or hyperoxidized, oxidative lesion of dG that is formed by oxidation of the primary oxidative lesion, 2'-deoxy-8-oxo-7,8-dihydroguanosine (8-oxodG). In particular, we examine incorporation into DNA of the diastereomers of the hyperoxidized guanosine triphosphate lesion spiroiminodihydantoin-2' deoxynucleoside-5'-triphosphate (dSpTP). Using kinetic parameters, we describe the ability of the Klenow fragment of Escherichia coli DNA polymerase I lacking 3' -> 5' exonuclease activity (KF(-)) to utilize (S)-dSpTP and (R)-dSpTP as building blocks during replication. We find that both diastereomers act as covert lesions, similar to a Trojan horse: KF(-) incorporates the lesion dNTP opposite dC, which is a nonmutagenic event; however, during the subsequent replication, it is known that dSp is nearly 100% mutagenic. Nevertheless, using kpol/Kd to define the nucleotide incorporation specificity, we find that the extent of oxidation of the dGTP-derived lesion correlates with its ability to be incorporated into DNA. KF(-) has the highest specificity for incorporation of dGTP opposite dC. The selection factors for incorporating 8-oxodGTP, (S)-dSpTP, and (R)-dSpTP are 1700 , 64000-, and 850000-fold lower, respectively. Thus, KF(-) is rigorous in its discrimination against incorporation of the hyperoxidized lesion, and these results suggest that the specificity of cellular polymerases provides an effective mechanism to avoid incorporating dSpTP lesions into DNA from the nucleotide pool. PMID- 26572221 TI - Hydrogen storage in a chemical bond stabilized Co9S8-graphene layered structure. AB - With the high energy ball milling method, a Co9S8-decorated reduced graphene oxide (RGO) composite, which shows excellent hydrogen storage capacity, has been successfully fabricated with a well-organized layered structure. Moreover, the stabilized mechanism of the well-organized layered structure is investigated and attributed to the strong interactions between Co9S8 and defective RGO. The C-S bond interaction is identified and the hydrogen storage process is also studied with different analysis methods. Finally, an optimized Co9S8 to RGO weight ratio of 6:1 shows excellent electrochemical performances in terms of the excellent cycling stability and competitive hydrogen storage capacity of 4.86 wt%. PMID- 26572220 TI - Differential proteomic analysis of virus-enriched fractions obtained from plasma pools of patients with dengue fever or severe dengue. AB - BACKGROUND: Dengue is the most widespread mosquito-borne viral disease of public health concern. In some patients, endothelial cell and platelet dysfunction lead to life-threatening hemorrhagic dengue fever or dengue shock syndrome. Prognostication of disease severity is urgently required to improve patient management. The pathogenesis of severe dengue has not been fully elucidated, and the role of host proteins associated with viral particles has received little exploration. METHODS: The proteomes of virion-enriched fractions purified from plasma pools of patients with dengue fever or severe dengue were compared. Virions were purified by ultracentrifugation combined with a water-insoluble polyelectrolyte-based technique. Following in-gel hydrolysis, peptides were analyzed by nano-liquid chromatography coupled to ion trap mass spectrometry and identified using data libraries. RESULTS: Both dengue fever and severe dengue viral-enriched fractions contained identifiable viral envelope proteins and host cellular proteins. Canonical pathway analysis revealed the identified host proteins are mainly involved in the coagulation cascade, complement pathway or acute phase response signaling pathway. Some host proteins were over- or under represented in plasma from patients with severe dengue compared to patients with dengue fever. ELISAs were used to validate differential expression of a selection of identified host proteins in individual plasma samples of patients with dengue fever compared to patients with severe dengue. Among 22 host proteins tested, two could differentiate between dengue fever and severe dengue in two independent cohorts (olfactomedin-4: area under the curve (AUC), 0.958; and platelet factor 4: AUC, 0.836). CONCLUSION: A novel technique of virion-enrichment from plasma has allowed to identify two host proteins that have prognostic value for classifying patients with acute dengue who are more likely to develop a severe dengue. The impact of these host proteins on pathogenicity and disease outcome are discussed. PMID- 26572222 TI - Cancer of the penis associated with HIV: a report of three cases presenting at the CHU cocody, ivory coast. AB - BACKGROUND: We describe three cases of advanced penile cancer associated with HIV infection. CASE PRESENTATION: Advanced penile cancer associated with VIH infection were discovered in three patients aged respectively 47, 56 and 40. The prognosis was extremely poor. Two patients died without receiving any treatment and one patient was lost to follow-up after refusing all treatment proposed. CONCLUSION: There appears to be a link between HIV infection and penile cancer with concomitant HIV infection worsening the prognosis of the disease. PMID- 26572223 TI - Synthesis of beta-Cyclodextrin-Based Electrospun Nanofiber Membranes for Highly Efficient Adsorption and Separation of Methylene Blue. AB - Water-insoluble beta-cyclodextrin-based fibers were synthesized by electrospinining followed by thermal cross-linking. The fibers were characterized by field-emission scanning electron microscopic (FE-SEM) and Fourier transformed infrared spectrometer (FT-IR). The highly insoluble fraction obtained from different pH values (3-11) indicates successful cross-linking reactions and their usability in aqueous solution. After the cross-linking reaction, the fibers' tensile strength increases significantly and the BET surface area is 19.49 m(2)/g. The cross-linked fibers exhibited high adsorption capacity for cationic dye methylene blue (MB) with good recyclability. The adsorption performance can be fitted well with pseudo-second-order model and Langmuir isotherm model. The maximum adsorption capacity is 826.45 mg/g according to Langmuir fitting. Due to electrostatic repulsion, the fibers show weak adsorption toward negatively charged anionic dye methyl orange (MO). On the basis of the selective adsorption, the fiber membrane can separate the MB/MO mixture solution by dynamic filtration at a high flow rate of 150 mL/min. The fibers can maintain good fibrous morphology and high separation efficiency even after five filtration-regeneration cycles. The obtained results suggested potential applications of beta cyclodextrin-based electrospun fibers in the dye wastewater treatment field. PMID- 26572224 TI - Primary health care teams put to the test a cross-sectional study from Austria within the QUALICOPC project. AB - BACKGROUND: Multidisciplinary Primary Health Care Teams (PHCT) provide a comprehensive approach to address the social and health needs of communities. It was the aim of this analysis to assess the number of PHCT in Austria, a country with a weak PHC system, and to compare preventive activities, psychosocial care, and work satisfaction between GPs who work and those who do not work in PHCT. METHOD: Within the QUALICOPC study, data collection was performed between November 2011 and May 2012, utilizing a standardized questionnaire for GPs. A stratified sample of GPs from across Austria was invited. Statistical analyses included descriptive statistics and tests. RESULTS: Data from 171 GPs questionnaires were used for this analysis. Of these, 61.1 % (n = 113) had a mono disciplinary office, 26.3 % (n = 45) worked in an office consisting of GP, receptionist and one additional primary care profession, and 7.6 % (n = 13) worked in a larger PHCT. GPs that worked in larger PHCT were younger and more involved in psychosocial and preventive care. No differences were found with regard to work satisfaction or workload. CONCLUSIONS: This study gives insight into the structures of PHC in Austria. The results indicate a low number of PHCT; however, the overall return rate in our sample was low with more male GPs, more GPs from urban areas and more GPs working in offices together with other physicians than the national average. Younger GPs demonstrate a greater tendency to implement this primary care practice model in their practices, which seems to be associated with an emphasis in psychosocial and preventive care. If Austria is to increase the number of PHC teams, the country should embrace the work of young GPs and should offer relevant support for PHCT. Future developments could be guided by considering effective models of good practice and governmental support as in other countries. PMID- 26572225 TI - Traversing myths and mountains: addressing socioeconomic inequities in the promotion of nutrition and physical activity behaviours. AB - BACKGROUND: In developed countries, individuals experiencing socioeconomic disadvantage - whether a low education level, low income, low-status occupation, or living in a socioeconomically disadvantaged neighbourhood - are less likely than those more advantaged to engage in eating and physical activity behaviours conducive to optimal health. These socioeconomic inequities in nutrition and physical activity (and some sedentary) behaviours are graded, persistent, and evident across multiple populations and studies. They are concerning in that they mirror socioeconomic inequities in obesity and in health outcomes. Yet there remains a dearth of evidence of the most effective means of addressing these inequities. People experiencing disadvantage face multiple challenges to healthy behaviours that can appear insurmountable. With increasing recognition of the role of underlying structural and societal factors as determinants of nutrition and physical activity behaviours and inequities in these behaviours, and the limited success of behaviour change approaches in addressing these inequities, we might wonder whether there remains a role for behavioural scientists to tackle these challenges. DISCUSSION: This debate piece argues that behavioural scientists can play an important role in addressing socioeconomic inequities in nutrition, physical activity and sedentary behaviours, and that this will involve challenging myths and taking on new perspectives. There are successful models for doing so from which we can learn. Addressing socioeconomic inequities in eating, physical activity and sedentary behaviours is challenging. However, successful examples demonstrate that overcoming such challenges is possible, and provide guidance for doing so. Given the disproportionate burden of ill health carried by people experiencing socioeconomic disadvantage, all our nutrition and physical activity interventions, programs and policies should be designed to reach and positively impact these individuals at greatest need. PMID- 26572226 TI - Care seeking pathways of older adults with hip fracture in India: exploratory study protocol. AB - BACKGROUND: The incidence of hip fractures in older adults in India is likely to increase dramatically in the coming decades as a result of an aging population and increasing life expectancy. Currently, more than 600,000 adults over 60 years of age suffer a hip fracture annually in India. This paper outlines a protocol for a qualitative study investigating the care seeking behavior of older adults with hip fractures: to determine the processes in decision making, identify causes for delay in obtaining care, and identify potential barriers and facilitators to seeking appropriate care in time. METHODS AND DESIGN: The planned study will consider Odisha, an eastern state in India with limited health care facility, as a suitable case study. It is proposed to conduct 30 in-depth interviews in two administrative districts of Odisha. The participants will be patient and their carers in seven health facilities- four public hospitals, two private hospitals and one traditional bone-setting facility. The study relies on a purposive sampling strategy. Ethics permission will be sought from each participating institution and participants. The participants will be adults aged 50 years or older of both sexes arriving at the recruiting centers with a history of fall or injury, pain in the hip region and inability to walk and X-ray confirmed diagnosis of proximal femoral fracture and their primary carer. Trained qualitative research team will conduct these interviews. A thematic framework approach will be used to analyze the data using NVivo 9 software. The data collected from the interviews will be analysed to explore the cause of the hip fracture, events following the injury, the experiences of patients from the time of sustaining the injury, pain relief measures, decision to seek care, understanding of the urgency for treatment, causes for delay in receiving treatment, funding sources, cost liabilities for the family, financing mechanisms for out of pocket expenditure and the burden for caring. DISCUSSION: The findings of this study will provide an increased understanding of the care seeking behaviors of older adults with hip fracture, and inform contextually appropriate changes in healthcare program and policy aimed at improving health outcomes. PMID- 26572227 TI - Development of reverse-transcription loop-mediated isothermal amplification assay for rapid detection and differentiation of dengue virus serotypes 1-4. AB - BACKGROUND: Dengue virus (DENV), the most widely prevalent arbovirus, continues to be a threat to human health in the tropics and subtropics. Early and rapid detection of DENV infection during the acute phase of illness is crucial for proper clinical patient management and preventing the spread of infection. The aim of the current study was to develop a specific, sensitive, and robust reverse transcriptase loop-mediated isothermal amplification (RT-LAMP) assay for detection and differentiation of DENV1-4 serotypes. RESULTS: The method detection primers, which were designed to target the different DENV serotypes, were identified by inspection of multiple sequence alignments of the non-structural protein (NS) 2A of DENV1, NS4B of DENV2, NS4A of DENV3 and the 3' untranslated region of the NS protein of DENV4. No cross-reactions of the four serotypes were observed during the tests. The detection limits of the DENV1-4-specific RT-LAMP assays were approximately 10-copy templates per reaction. The RT-LAMP assays were ten-fold more sensitive than RT-PCR or real-time PCR. The diagnostic rate was 100% for clinical strains of DENV, and 98.9% of the DENV-infected patients whose samples were tested were detected by RT-LAMP. Importantly, no false-positives were detected with the new equipment and methodology that was used to avoid aerosol contamination of the samples. CONCLUSION: The RT-LAMP method used in our study is specific, sensitive, and suitable for further investigation as a useful alternative to the current methods used for clinical diagnosis of DENV1-4, especially in hospitals and laboratories that lack sophisticated diagnostic systems. PMID- 26572228 TI - Survey on examining prevalence of paternal anxiety and its risk factors in perinatal period in Hong Kong: a longitudinal study. AB - BACKGROUND: There is emerging evidence of the significance of paternal mental health problems among the expectant fathers during the antenatal and postnatal period. The present study aims at determining the prevalence of paternal perinatal anxiety and identifying its risk factors among the fathers. METHODS: A total of 622 expectant fathers were recruited in Hong Kong. The expectant fathers were assessed using standardized and validated psychological instruments on three time points including early pregnancy, late pregnancy and 6 week postnatal. Independent samples t-test, one way ANOVA, Pearson's correlation and multiple linear regression were used to examine the effect of hypothesized risk factors. Hierarchical multiple regression and mixed effect model were also conducted with potential confounding factors controlled for. RESULTS: Results showed that a significant proportion of expectant fathers experienced anxiety during the perinatal period. Low self-esteem and poor social support were found to be risk factors of paternal anxiety across pregnancy to postnatal period. Work-family conflict could significantly predict paternal anxiety in the pregnancy period. CONCLUSIONS: The present study points to the need for greater research and clinical attention to paternal anxiety, given that it is a highly prevalent problem and could be detrimental to their partner's well-being and children development. The present findings contributes to the theoretical understanding of the prevalence and risk factors of paternal perinatal anxiety and have implications for the design of effective identification, prevention, and interventions of these clinical problems. PMID- 26572229 TI - The expression level of the transcription factor Aryl hydrocarbon receptor nuclear translocator (ARNT) determines cellular survival after radiation treatment. AB - BACKGROUND: Tumour hypoxia promotes radioresistance and is associated with poor prognosis. The transcription factor Aryl hydrocarbon receptor nuclear translocator (ARNT), also designated as Hypoxia-inducible factor (HIF)-1beta, is part of the HIF pathway which mediates cellular adaptations to oxygen deprivation and facilitates tumour progression. The subunits HIF-1alpha and ARNT are key players within this pathway. HIF-1alpha is regulated in an oxygen-dependent manner whereas ARNT is considered to be constitutively expressed. However, there is mounting evidence that certain tumour cells are capable to elevate ARNT in hypoxia which suggests a survival benefit. Therefore the objective of this study was to elucidate effects of an altered ARNT expression level on the cellular response to radiation. METHODS: Different human cell lines (Hep3B, MCF-7, 786 Owt, 786-Ovhl, RCC4wt and RCC4vhl) originating from various tumour entities (Hepatocellular carcinoma, breast cancer and renal cell carcinoma respectively) were X-irradiated using a conventional linear accelerator. Knockdown of ARNT expression was achieved by transient siRNA transfection. Complementary experiments were performed by forced ARNT overexpression using appropriate plasmids. Presence/absence of ARNT protein was confirmed by Western blot analysis. Clonogenic survival assays were performed in order to determine cellular survival post irradiation. Statistical comparison of two groups was achieved by the unpaired t-test. RESULTS: The results of this study indicate that ARNT depletion renders tumour cells susceptible to radiation whereas overexpression of this transcription factor confers radioresistance. CONCLUSIONS: These findings provide evidence to consider ARNT as a drug target and as a predictive marker in clinical applications concerning the response to radiation. PMID- 26572230 TI - Activation of MEK2 is sufficient to induce skin papilloma formation in transgenic zebrafish. AB - BACKGROUND: Mutations in mitogen-activated protein kinase (MAPK) kinase 1 (MEK1) that occur during cell proliferation and tumor formation are well described. Information on the roles of MEK2 in these effects is still limited. We established a constitutive MEK2 transgenic zebrafish, Tg(krt14:MEK2S219D-GFP), to elucidate the role of MEK2 in skin tumor formation. RESULTS: We found that both constitutive MEK2 and MEK1 are able to phosphorylate the extracellular signal regulated kinase 1 (ERK1) protein. Transient expression of constitutive MEK2 and MEK1 in the zebrafish epidermis induced papillary formation at 48 h post fertilization, but no effects were observed due to the expression of MEK1, MEK2, or the dominant negative form of MEK2. The transgenic zebrafish, Tg(krt14:MEK2S219D-GFP), developed skin papillomas in the epidermis within 6 days post-fertilization (dpf). The phospho-ERK signal was detected in section of skin papillomas in an immunohistochemical experiment. Treatment with 50 MUM of the MEK inhibitor, U0126, had significantly decreased the skin papilloma formation in Tg(krt14:MEK2S219D-GFP) zebrafish by 6 dpf. In vitro and in vivo proliferation assay in COS-1 cells and in Tg(krt14:MEK2S219D-GFP) transgenic fish show significantly increased cell number and Ki-67 signaling. CONCLUSION: Our data indicate that MEK2 is sufficient to induce epidermal papilloma formation through MAPK signaling in zebrafish, and this transgenic model can be used as a new platform for drug screening. PMID- 26572231 TI - A larger critical shoulder angle requires more rotator cuff activity to preserve joint stability. AB - Shoulders with rotator cuff tears (RCT) tears are associated with significantly larger critical shoulder angles (CSA) (RCT CSA = 38.2 degrees ) than shoulders without RCT (CSA = 32.9 degrees ). We hypothesized that larger CSAs increase the ratio of glenohumeral joint shear to joint compression forces, requiring substantially increased compensatory supraspinatus loads to stabilize the arm in abduction. A previously established three dimensional (3D) finite element (FE) model was used. Two acromion shapes mimicked the mean CSA of 38.2 degrees found in patients with RCT and that of a normal CSA (32.9 degrees ). In a first step, the moment arms for each muscle segment were obtained for 21 different thoracohumeral abduction angles to simulate a quasi-static abduction in the scapular plane. In a second step, the muscle forces were calculated by minimizing the range of muscle stresses able to compensate an external joint moment caused by the arm weight. If the joint became unstable, additional force was applied by the rotator cuff muscles to restore joint stability. The model showed a higher joint shear to joint compressive force for the RCT CSA (38.2 degrees ) for thoracohumeral abduction angles between 40 degrees and 90 degrees with a peak difference of 23% at 50 degrees of abduction. To achieve stability in this case additional rotator cuff forces exceeding physiological values were required. Our results document that a higher CSA tends to destabilize the glenohumeral joint such that higher than normal supraspinatus forces are required to maintain modeled stability during active abduction. This lends strong support to the concept that a high CSA can induce supraspinatus (SSP) overload. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:961-968, 2016. PMID- 26572232 TI - Activation and dynamic expression of Notch signalling in dental pulp cells after injury in vitro and in vivo. AB - AIM: To investigate the expression pattern of Notch signalling in odontoblast like cells stimulated by lipopolysaccharide (LPS) in vitro, and in injured rat dental pulp in vivo. METHODOLOGY: Mouse odontoblast-like cells (MDPC-23) were exposed to LPS. Expression of Notch-related genes was detected by real-time PCR. A rat pulpitis model was established by mechanical injury and LPS plus mechanical injury was followed by the analysis of expression of Notch2 by immunohistochemical staining. One-way analysis of variance (anova) was performed to examine the effect of differing concentrations of LPS on cell proliferation, and least significant difference test was used for paired comparisons. For independent sample, t-test was performed to compare the expression of Notch signalling genes between LPS group and control group in vitro. RESULTS: The in vitro study revealed the proliferation of MDPC-23 cells on exposure to 10 ng mL-1 to 1 MUg mL-1 LPS. Expression of Notch1 and Notch2 was significantly higher in the LPS group than that in the control group on day 1 and day 3 (P ? 0.05). The levels of both Delta1 and Jagged1 were higher in the study group than in the control group on day 3 (P = 0.019 and P = 0.034) and day 5 (P ? 0.001 and P = 0.046), respectively. In addition, Hes1 levels were significantly higher in the study group than in the control group on day 5 (P = 0.005). The in vivo study demonstrated positive staining for Notch2, both in the mechanical injury (MI) group and in the LPS plus mechanical injury (LMI) group from day 3 to day 7, which showed very weak or absent staining on day 14, thereby demonstrating the dynamic nature of the change. CONCLUSIONS: Both in vitro and in vivo activation and dynamic expression of Notch signalling in dental pulp cells after injury were found. Notch signalling activation by LPS stimulation or mechanical injury showed a similar pattern in vivo. PMID- 26572233 TI - Safety and efficacy of ferumoxytol for the episodic treatment of iron deficiency anemia in patients with a history of unsatisfactory oral iron therapy: Results of a phase III, open-label, 6-month extension study. PMID- 26572234 TI - Long-term Intrinsic Rhythm Evaluation in Dogs with Atrioventricular Block. AB - BACKGROUND: Atrioventricular block (AVB) is a conduction abnormality along the atrioventricular node that, depending on etiology, may lead to different outcomes. OBJECTIVES: To evaluate variations of intrinsic rhythm (IR) in dogs that underwent pacemaker implantation (PMI). ANIMALS: Medical records of 92 dogs affected by 3rd degree atrioventricular block (3AVB), advanced 2nd degree AVB (2AVB), paroxysmal 3AVB, 2:1 2AVB, or 3AVB with atrial fibrillation (AF) were retrospectively reviewed. METHOD: The patient IR was documented with telemetry on the day of 1--(95% CI, 1-2), 33--(95% CI, 28-35), 105--(95%CI, 98-156), and 275 days (95%CI, 221-380) after PMI. According to AVB grade at different examinations, AVB was defined as progressed, regressed, or unchanged. RESULTS: In 48 dogs, 3AVB remained unchanged, whereas in 7 it regressed. Eight cases of 2AVB progressed, 3 regressed and 2 remained unchanged. Eight cases of paroxysmal 3AVB progressed and 3 remained unchanged. Four dogs affected by 2:1 2AVB progressed, 2 regressed, and 1 remained unchanged. All cases with 3AVB with AF remained unchanged. Regression occurred within 30 days after PMI, whereas progression was documented at any time. Variations in IR were associated with type of AVB (P < .03) and time of follow-up (P < .0001). CONCLUSIONS AND CLINICAL IMPORTANCE: The degree of AVB assessed at the time of PMI should not be considered definitive because more than one-third of the cases in this study either progressed or regressed. Additional studies would be necessary to elucidate possible causes for transient AVB in dogs. PMID- 26572235 TI - Structural Studies of Nicotinic Acetylcholine Receptors: Using Acetylcholine Binding Protein as a Structural Surrogate. AB - Nicotinic acetylcholine receptors (nAChRs) are members of the pentameric ligand gated ion channel superfamily that play important roles in the control of neurotransmitter release in the central and peripheral nervous system. These receptors are important therapeutic targets for the development of drugs against a number of mental health disorders and for marketed smoking cessation aids. Unfortunately, drug discovery has been hampered by difficulties in obtaining sufficiently selective compounds. Together with functional complexity of the receptors, this has made it difficult to obtain drugs with sufficiently high target to off-target affinity ratios. The recent and ongoing progress in structural studies holds promise to help understand structure-function relationships of nAChR drugs at the atomic level. This will undoubtedly lead to the design of more efficient drugs with fewer side effects. As a high-resolution structure of a nAChR is yet to be determined, structural studies are to a large extent based on acetylcholine-binding proteins (AChBPs) that despite low overall sequence identity display a high degree of conservation of overall structure and amino acids at the ligand-binding site. Further, AChBPs reproduce relative binding affinities of ligands at nAChRs. Over the past decade, AChBPs have been used extensively as models for nAChRs and have aided the understanding of drug receptor interactions at nAChRs significantly. PMID- 26572237 TI - Implant salvage in breast reconstruction with severe peri-prosthetic infection. AB - BACKGROUND: Although treatment of mild peri-prosthetic infection in implant-based breast reconstruction results in high rates of resolution, successful management of severe peri-prosthetic infection remains a significant challenge. METHODS: In this case series, a protocol utilizing a novel dressing - negative pressure wound therapy with instillation (NPWTi) - for the management of severe peri-prosthetic infection in breast reconstruction patients is described. This is an operative technique involving: (i) explantation of the breast prosthesis and application of the NPWTi dressing to the implant pocket; (ii) change of the NPWTi dressing; (iii) intraoperative fluid/tissue cultures; and (iv) reimplantation of the breast prosthesis when cultures yield no growth. RESULTS: This protocol was utilized in six cases of severe peri-prosthetic infection in five patients with immediate breast reconstruction for breast cancer or risk-reducing surgery. Cultures of fluid/tissue grew typical and/or unusual organisms. Only one case did not yield an organism. The hospital length of stay upon completion of the protocol ranged from 7-16 days (mean, 12 days). Successful implant salvage was achieved in five of six cases. The protocol was aborted in one case to allow for completion of adjuvant chemotherapy. CONCLUSIONS: Early findings from this case series suggest that in cases of severe peri-prosthetic infection this novel operative protocol may result in successful implant salvage for breast reconstruction patients. Further studies are needed to more fully elaborate the role of NPWTi to achieve implant salvage in challenging cases of peri-prosthetic infection. PMID- 26572238 TI - Removing the Blindfold: Cardiac MRI Prior to Repeat Ablation of Ventricular Tachycardia. PMID- 26572236 TI - Human Peroxin PEX3 Is Co-translationally Integrated into the ER and Exits the ER in Budding Vesicles. AB - The long-standing paradigm that all peroxisomal proteins are imported post translationally into pre-existing peroxisomes has been challenged by the detection of peroxisomal membrane proteins (PMPs) inside the endoplasmic reticulum (ER). In mammals, the mechanisms of ER entry and exit of PMPs are completely unknown. We show that the human PMP PEX3 inserts co-translationally into the mammalian ER via the Sec61 translocon. Photocrosslinking and fluorescence spectroscopy studies demonstrate that the N-terminal transmembrane segment (TMS) of ribosome-bound PEX3 is recognized by the signal recognition particle (SRP). Binding to SRP is a prerequisite for targeting of the PEX3 containing ribosome*nascent chain complex (RNC) to the translocon, where an ordered multistep pathway integrates the nascent chain into the membrane adjacent to translocon proteins Sec61alpha and TRAM. This insertion of PEX3 into the ER is physiologically relevant because PEX3 then exits the ER via budding vesicles in an ATP-dependent process. This study identifies early steps in human peroxisomal biogenesis by demonstrating sequential stages of PMP passage through the mammalian ER. PMID- 26572239 TI - Bright Light-Emitting Diodes Based on Organometal Halide Perovskite Nanoplatelets. AB - Bright light-emitting diodes based on solution-processable organometal halide perovskite nanoplatelets are demonstrated. The nanoplatelets created using a facile one-pot synthesis exhibit narrow-band emissions at 529 nm and quantum yield up to 85%. Using these nanoparticles as emitters, efficient electroluminescence is achieved with a brightness of 10 590 cd m(-2) . These ligand-capped nanoplatelets appear to be quite stable in moisture, allowing out of-glovebox device fabrication. PMID- 26572240 TI - Evaluation of a novel Surgicric(r) cricothyroidotomy device for emergency tracheal access in a porcine model. AB - A can't intubate, can't ventilate scenario can result in morbidity and death. Although a rare occurrence (1:50 000 general anaesthetics), it is crucial that anaesthetists maintain the skills necessary to perform cricothyroidotomy, and are well-equipped with appropriate tools. We undertook a bench study comparing a new device, Surgicric((r)) , with two established techniques; the Melker Emergency Cricothyroidotomy, and a surgical technique. Twenty-five anaesthetists performed simulated emergency cricothyroidotomy on a porcine model, with the primary outcome measure being insertion time. Secondary outcomes included success rate, tracheal trauma and ease of use. The surgical technique was fastest. The median (IQR [range]) was 81 (62-126 [37-300]) s, followed by the Melker 124 (100-217 [71 300]) s, and the Surgicric 127 (68-171 [43-300]), p = 0.003. The Surgicric device was the most traumatic, as evaluated by a blinded Ear, Nose and Throat surgeon. Subsequently, the authors contacted the device manufacturer, who has now modified the kit in the hope that its clinical application might be improved. Further studies are required to evaluate the revised model. PMID- 26572241 TI - Superparamagnetic iron oxide-enhanced MRI at 3 T for accurate axillary staging in breast cancer. AB - BACKGROUND: The aim of this study was to evaluate whether MRI at 3 T with superparamagnetic iron oxide (SPIO) enhancement is an accurate and useful method for detecting metastases in sentinel nodes identified by CT-lymphography (CT-LG) in patients with breast cancer. The results were compared with those obtained using CT-LG alone and diagnosing metastasis according to size criteria. METHODS: Patients with clinically node-negative breast cancer were included. Sentinel nodes identified by CT-LG were evaluated prospectively using SPIO-enhanced MRI at 3 T. Sentinel node size was measured on CT-LG, and a node larger than 5 mm in short-axis diameter was considered metastatic. Sentinel nodes localized by CT-LG were removed, and imaging results and histopathological findings were compared. RESULTS: Sentinel nodes were identified successfully by CT-LG in 69 (99 per cent) of 70 patients. All 19 patients with a finding of metastasis in sentinel nodes at pathology were also shown to have metastases on MRI. Forty-eight of 50 patients with non-metastatic sentinel nodes diagnosed at pathology were classified as having non-metastatic nodes on MRI. On a patient-by-patient basis, the sensitivity, specificity and accuracy of MRI for the diagnosis of sentinel node metastases were 100, 96 and 97 per cent; respective values for CT-LG were 79, 56 and 62 per cent. The specificity and accuracy of MRI were superior to those of CT LG (P < 0.001 and P = 0.002 respectively). CONCLUSION: SPIO-enhanced MRI at 3 T is useful for accurate diagnosis of metastatic sentinel nodes, indicating that sentinel node biopsy may be avoided in patients with breast cancer who have non metastatic sentinel nodes on imaging. PMID- 26572243 TI - Combined high molecular weight Kininogen and factor XI deficiency. PMID- 26572242 TI - Surveying the serologic proteome in a tissue-specific kras(G12D) knockin mouse model of pancreatic cancer. AB - We have applied a serologic proteomic workflow involving three complementary MS approaches to a tissue-specific Kras(G12D) -knockin mouse model of pancreatic cancer that consistently forms precancerous lesions by 4 months of age. The three proteomics applications were highly complementary and allowed us to survey the entire range of low to high molecular weight serologic proteins. Combined, we identified 121 (49?, 72?) unique and statistically relevant serologic biomarkers with 88% previously reported to be associated with cancer and 38% specifically correlated with pancreatic cancer. Four markers, lysozyme C2, cytokeratin 19, Serpina1A and Pcf11, were further verified by Western blotting. When applying systems analysis, the top-associated gene ontology functions were tied to wound healing, RXR signaling, growth, differentiation and innate immune activation through the JAK/STAT pathway. Upon further investigation of the apparent immune response using a multiplex cytokine screen, we found that IFN-gamma, VEGF and GM CSF were significantly increased in serum from the Kras(G12D) animals compared to littermate controls. By combining three complementary MS applications, we were able to survey the native intact peptidome and the global proteome in parallel, unveiling pathways that may be biologically relevant to promotion of pancreatic cancer progression and serologic markers of noninvasive early-stage neoplasia. PMID- 26572244 TI - Myocardial infarction induces structural and functional remodelling of the intrinsic cardiac nervous system. AB - KEY POINTS: Intrinsic cardiac (IC) neurons undergo differential morphological and phenotypic remodelling that reflects the site of myocardial infarction (MI). Afferent neural signals from the infarcted region to IC neurons are attenuated, while those from border and remote regions are preserved post-MI, giving rise to a 'neural sensory border zone'. Convergent IC local circuit (processing) neurons have enhanced transduction capacity following MI. Functional network connectivity within the intrinsic cardiac nervous system is reduced post-MI. MI reduces the response and alters the characteristics of IC neurons to ventricular pacing. ABSTRACT: Autonomic dysregulation following myocardial infarction (MI) is an important pathogenic event. The intrinsic cardiac nervous system (ICNS) is a neural network located on the heart that is critically involved in autonomic regulation. The aims of this study were to characterize structural and functional remodelling of the ICNS post-MI in a porcine model (control (n = 16) vs. healed anteroapical MI (n = 16)). In vivo microelectrode recordings of basal activity, as well as responses to afferent and efferent stimuli, were recorded from intrinsic cardiac neurons. From control 118 neurons and from MI animals 102 neurons were functionally classified as afferent, efferent, or convergent (receiving both afferent and efferent inputs). In control and MI, convergent neurons represented the largest subpopulation (47% and 48%, respectively) and had enhanced transduction capacity following MI. Efferent inputs to neurons were maintained post-MI. Afferent inputs were attenuated from the infarcted region (19% in control vs. 7% in MI; P = 0.03), creating a 'neural sensory border zone', or heterogeneity in afferent information. MI reduced transduction of changes in preload (54% in control vs. 41% in MI; P = 0.05). The overall functional network connectivity, or the ability of neurons to respond to independent pairs of stimuli, within the ICNS was reduced following MI. The neuronal response was differentially decreased to ventricular vs. atrial pacing post-MI (63% in control vs. 44% in MI to ventricular pacing; P < 0.01). MI induced morphological and phenotypic changes within the ICNS. The alteration of afferent neural signals, and remodelling of convergent neurons, represents a 'neural signature' of ischaemic heart disease. PMID- 26572246 TI - Periodontal treatment in a patient with generalized idiopathic dystonia. AB - Dystonia is a neurological disorder that can cause constant muscle contractions and motor limitations. This work reports a clinical case of periodontal treatment in a patient with generalized idiopathic dystonia. The intraoral clinical examination was focused on the presence of caries and periodontal diseases. The plaque index (PI), probing depth (PD), and bleeding on probing (BOP) were measured. Initially, oral hygiene instruction was provided using a soft conventional toothbrush and dental floss, but the clinical results achieved using these methods were inadequate. Alternative methods of plaque removal were offered, such as the use of a power toothbrush and a dental floss fork, which resulted in improvement in the PI, PD, and BOP and allowed the patient to undergo periodontal surgery for the restoration of subgingival caries. Our results suggested that generalized idiopathic dystonia leads to motor limitations that may cause difficulty with regard to plaque control, but adaptations of the methods used for oral hygiene may improve the oral health conditions in these patients. PMID- 26572245 TI - Complementing the inflammasome. AB - The innate immune system is an ancient surveillance system able to sense microbial invaders as well as aberrations in normal cell function. No longer viewed as a static and non-specific part of immunity, the innate immune system employs a plethora of specialized pattern recognition sensors to monitor and achieve homeostasis; these include the Toll-like receptors, the retinoic acid inducible gene-like receptors, the nucleotide-binding oligomerization domain receptors (NLRs), the C-type lectins and the complement system. In order to increase specificity and diversity, innate immunity uses homotypic and heterotypic associations among these different components. Multi-molecular assemblies are formed both on the cell surface and in the cytosol to respond to pathogen and danger signals. Diverse, but tailored, responses to a changing environment are orchestrated depending on the the nature of the challenge and the repertoire of interacting receptors and components available in the sensing cell. It is now emerging that innate immunity operates a system of 'checks and balances' where interaction among the sensors is key in maintaining normal cell function. Complement sits at the heart of this alarm system and it is becoming apparent that it is capable of interacting with all the other pathways to effect a tailored immune response. In this review, we will focus on complement interactions with NLRs, the so-called 'inflammasomes', describing the molecular mechanisms that have been revealed so far and discussing the circumstantial evidence that exists for these interactions in disease states. PMID- 26572247 TI - Fluorescent Probes Based on Rhodamine Hydrazides and Hydroxamates. AB - Rhodamine hydrazides and hydroxamates derived from hydrazines and hydroxylamines have been applied as fluorescent chemosensors. Reaction-based irreversible probes based on the specific chemical reactions of reactive target species have been developed and applied in bio-imaging studies. The strong chelation frames provided by the rhodamine hydrazides and hydroxamates have been utilized for the monitoring of metal ions, amino acids, and reactive acid derivatives. This Personal Account focuses on our perspective of developing fluorescent probes based on rhodamine hydrazides and hydroxamates. PMID- 26572249 TI - Inheritance and heritability of deltamethrin resistance under laboratory conditions of Triatoma infestans from Bolivia. AB - BACKGROUND: Over the last few decades, pyrethroid-resistant in Triatoma infestans populations have been reported, mainly on the border between Argentina and Bolivia. Understanding the genetic basis of inheritance mode and heritability of resistance to insecticides under laboratory conditions is crucial for vector management and monitoring of insecticide resistance. Currently, few studies have been performed to characterize the inheritance mode of resistance to pyrethroids in T. infestans; for this reason, the present study aims to characterize the inheritance and heritability of deltamethrin resistance in T. infestans populations from Bolivia with different toxicological profiles. METHODS: Experimental crosses were performed between a susceptible (S) colony and resistant (R) and reduced susceptibility (RS) colonies in both directions (? x ? and ? x ?), and inheritance mode was determined based on degree of dominance (DO) and effective dominance (D(ML)). In addition, realized heritability (h(2)) was estimated based on a resistant colony, and select pressure was performed for two generations based on the diagnostic dose (10 ng. i. a. /nymph). The F1 progeny of the experimental crosses and the selection were tested by a standard insecticide resistance bioassay. RESULTS: The result for DO and D(ML) (< 1) indicates that resistance is an incompletely dominant character, and inheritance is autosomal, not sex-linked. The LD50 for F1 of ?S x ?R and ?S x ?R was 0.74 and 3.97, respectively, which is indicative of dilution effect. In the resistant colony, after selection pressure, the value of h(2) was 0.37; thus, the LD50 value increased 2.25-fold (F2) and 26.83-fold (F3) compared with the parental colony. CONCLUSION: The inheritance mode of resistance of T. infestans to deltamethrin, is autosomal and an incompletely dominant character; this is a previously known process, confirmed in the present study on T. infestans populations from Bolivia. The lethal doses (LD50) increase from one generation to another rapidly after selection pressure with deltamethrin. This suggests that resistance is an additive and cumulative factor, mainly in highly structured populations with limited dispersal capacity, such as T. infestans. This phenomenon was demonstrated for the first time for T. infestans in the present study. These results are very important for vector control strategies in problematic areas where high resistance ratios of T. infestans have been reported. PMID- 26572248 TI - Identification of the meiotic toolkit in diatoms and exploration of meiosis specific SPO11 and RAD51 homologs in the sexual species Pseudo-nitzschia multistriata and Seminavis robusta. AB - BACKGROUND: Sexual reproduction is an obligate phase in the life cycle of most eukaryotes. Meiosis varies among organisms, which is reflected by the variability of the gene set associated to the process. Diatoms are unicellular organisms that belong to the stramenopile clade and have unique life cycles that can include a sexual phase. RESULTS: The exploration of five diatom genomes and one diatom transcriptome led to the identification of 42 genes potentially involved in meiosis. While these include the majority of known meiosis-related genes, several meiosis-specific genes, including DMC1, could not be identified. Furthermore, phylogenetic analyses supported gene identification and revealed ancestral loss and recent expansion in the RAD51 family in diatoms. The two sexual species Pseudo-nitzschia multistriata and Seminavis robusta were used to explore the expression of meiosis-related genes: RAD21, SPO11-2, RAD51-A, RAD51-B and RAD51-C were upregulated during meiosis, whereas other paralogs in these families showed no differential expression patterns, suggesting that they may play a role during vegetative divisions. An almost identical toolkit is shared among Pseudo nitzschia multiseries and Fragilariopsis cylindrus, as well as two species for which sex has not been observed, Phaeodactylum tricornutum and Thalassiosira pseudonana, suggesting that these two may retain a facultative sexual phase. CONCLUSIONS: Our results reveal the conserved meiotic toolkit in six diatom species and indicate that Stramenopiles share major modifications of canonical meiosis processes ancestral to eukaryotes, with important divergences in each Kingdom. PMID- 26572250 TI - Deep sequencing of the uterine immune response to bacteria during the equine oestrous cycle. AB - BACKGROUND: The steroid hormone environment in healthy horses seems to have a significant impact on the efficiency of their uterine immune response. The objective of this study was to characterize the changes in gene expression in the equine endometrium in response to the introduction of bacterial pathogens and the influence of steroid hormone concentrations on this expression. METHODS: Endometrial biopsies were collected from five horses before and 3 h after the inoculation of Escherichia coli once in oestrus (follicle >35 mm in diameter) and once in dioestrus (5 days after ovulation) and analysed using high-throughput RNA sequencing techniques (RNA-Seq). RESULTS: Comparison between time points revealed that 2422 genes were expressed at significantly higher levels and 2191 genes at significantly lower levels 3 h post inoculation in oestrus in comparison to pre inoculation levels. In dioestrus, the expression of 1476 genes was up-regulated and 383 genes were down-regulated post inoculation. Many immune related genes were found to be up-regulated after the introduction of E. coli. These include pathogen recognition receptors, particularly toll-like receptors TLR2 and 4 and NOD-like receptor NLRC5. In addition, several interleukins including IL1B, IL6, IL8 and IL1ra were significantly up-regulated. Genes for chemokines, including CCL 2, CXCL 6, 9, 10, 11 and 16 and those for antimicrobial peptides, including secretory phospholipase sPLA 2, lipocalin 2, lysozyme and equine beta-defensin 1, as well as the gene for tissue inhibitor for metalloproteinases TIMP-1 were also up-regulated post inoculation. CONCLUSION: The results of this study emphasize the complexity of an effective uterine immune response during acute endometritis and the tight balance between pro- and anti-inflammatory factors required for efficient elimination of bacteria. It is one of the first high-throughput analyses of the uterine inflammatory response in any species and several new potential targets for treatment of inflammatory diseases of the equine uterus have been identified. PMID- 26572251 TI - KiSS-1-mediated suppression of the invasive ability of human pancreatic carcinoma cells is not dependent on the level of KiSS-1 receptor GPR54. AB - The onset of local invasion and lymphatic metastasis in pancreatic cancer limits survival following surgical intervention and additional therapies. Reduced expression of KiSS-1 in pancreatic cancer is associated with cancer metastasis. Previous studies have indicated that kisspeptin, the KiSS-1 peptide, is able to bind to its receptor-GPR54 (hOT7T175) and suppress the migration of PANC-1 pancreatic cancer cells. Whether the metastatic suppression of KiSS-1 is dependent on the levels of GPR54 in pancreatic cancer cell lines remains unclear. Human BxPC-3 pancreatic carcinoma cells are highly differentiated without exhibiting metastasis, however PANC-1 pancreatic carcinoma cells are poorly differentiated and exhibit local and lymph node metastasis. Compared with primary cultured trophoblasts, BxPc-3 and PANC-1 cells were observed to express low levels of KiSS-1 mRNA and protein, measured using reverse transcription quantitative polymerase chain reaction and western blotting, respectively. However, greater mRNA and protein expression levels of GPR54 were observed in PANC-1 cells compared with BxPc-3 cells. An MTT assay was used to investigate the effect of KiSS-1 on BxPc-3 and PANC-1 cell proliferation. There were no significant differences in proliferation following transfection with KiSS-1 in BxPc-3 and PANC-1 cells compared with the controls (P>0.05). A Transwell assay with chambers coated with Matrigel was used to evaluate the in vitro invasive ability of BxPc-3 and PANC-1 cells, with the invasion index of BxPc-3 and PANC-1 cells significantly reduced following 48 h of KiSS-1 overexpression (P<0.05). The mRNA and protein expression levels of KiSS-1 were significantly increased in BxPc 3 and PANC-1 cells 48 h subsequent to transfection with KiSS-1 (P<0.05), while GPR54 expression was not altered (P>0.05). KiSS-1 is a metastasis suppressor gene of pancreatic cancer, and this suppression is not dependent on the expression levels of GPR54. Therefore, KiSS-1 is potentially a novel target for gene therapy. PMID- 26572252 TI - Mental healthcare for older adults in rural Greece. PMID- 26572253 TI - Mechanical tearing of graphene on an oxidizing metal surface. AB - Graphene, the thinnest possible anticorrosion and gas-permeation barrier, is poised to transform the protective coatings industry for a variety of surface applications. In this work, we have studied the structural changes of graphene when the underlying copper surface undergoes oxidation upon heating. Single-layer graphene directly grown on a copper surface by chemical vapour deposition was annealed under ambient atmosphere conditions up to 400 degrees C. The onset temperature of the surface oxidation of copper is found to be higher for graphene coated foils. Parallel arrays of graphene nanoripples are a ubiquitous feature of pristine graphene on copper, and we demonstrate that these form crucial sites for the onset of the oxidation of copper, particularly for ~0.3-0.4 MUm ripple widths. In these regions, the oxidation proceeds along the length of the nanoripples, resulting in the formation of parallel stripes of oxidized copper regions. We demonstrate from temperature-dependent Raman spectroscopy that the primary defect formation process in graphene involves boundary-type defects rather than vacancy or sp(3)-type defects. This observation is consistent with a mechanical tearing process that splits graphene into small polycrystalline domains. The size of these is estimated to be sub-50 nm. PMID- 26572254 TI - Self-Management of Anticoagulant Therapy in Mechanical Heart Valve Patients: A Matched Cohort Study. AB - BACKGROUND: Patient-self-management (PSM) of oral anticoagulant therapy with vitamin K antagonists for mechanical heart valves has demonstrated efficacy in randomized controlled trials. However, the effectiveness of PSM in clinical practice has only been investigated in small trials. Our aim was to evaluate the effectiveness of PSM of oral anticoagulant therapy in mechanical heart valve patients. METHODS: We conducted a matched cohort study: cases were patients with a mechanical heart valve performing PSM affiliated with Aarhus University Hospital or Aalborg University Hospital, Denmark, in the period 1996 to 2012 (n = 615). Prospectively registered patient data were obtained from databases at two hospitals, and cross linkage between these databases and national patient registries provided detailed information on comorbidities and events. Control patients were matched (on sex, date of birth, year of first valve surgery, and grouped valve position) in a ratio of 5:1 (n = 3,075) with patients receiving conventional management who were randomly selected within the match group. The effectiveness and safety was estimated using major bleeding and thromboembolic events and death as outcomes. RESULTS: We observed low event rates in the PSM group. After 5 years, PSM was associated with a lower risk of all-cause mortality compared with conventional management (adjusted hazard ratio of 0.49, 95% confidence interval: 0.34 to 0.71). The hazard ratios for thromboembolism and major bleeding were 0.91 (95% confidence interval: 0.66 to 1.24) and 0.83 (95% confidence interval: 0.56 to 1.22). CONCLUSIONS: Owing to superior clinical effectiveness, self-managed oral anticoagulant therapy may potentially improve the standard of care for patients with mechanical heart valves. PMID- 26572255 TI - Outcomes After Surgery in High-Risk Patients With Early Stage Lung Cancer. AB - BACKGROUND: Patients with early stage lung cancer considered high risk for surgery are increasingly being treated with nonsurgical therapies. However, consensus on the classification of high risk does not exist. We compared clinical outcomes of patients considered to be high risk with those of standard-risk patients, after lung cancer surgery. METHODS: A total of 490 patients from our institutional Society of Thoracic Surgeons data from 2009 to 2013 underwent resection for clinical stage I lung cancer. High-risk patients were identified by ACOSOG z4032/z4099 criteria: major: forced expiratory volume in 1 second (FEV1) 50% or less or diffusing capacity of lung for carbon monoxide (Dlco) 50% or less; and minor: (two of the following), age 75 years or more, FEV1 51% to 60%, or Dlco 51% to 60%. Demographics, perioperative outcomes, and survival between high-risk and standard-risk patients undergoing lobectomy and sublobar resection were compared. Univariate analysis was performed using the chi(2) test/Fisher's exact test and the t test/Mann-Whitney U test. Survival was studied using a Cox regression model to calculate hazard ratios, and Kaplan-Meier survival curves were drawn. RESULTS: In all, 180 patients (37%) were classified as high risk. These patients were older than standard-risk patients (70 years versus 65 years, respectively; p < 0.0001) and had worse FEV1 (57% versus 85%, p < 0.0001), and Dlco (47% versus 77%, p < 0.0001). High-risk patients also had more smoking pack years than standard-risk patients (46 versus 30, p < 0.0001) and a greater incidence of chronic obstructive pulmonary disease (72% versus 32%, p < 0.0001), and were more likely to undergo sublobar resection (32% versus 20%, p = 0.001). Length of stay was longer in the high-risk group (5 versus 4 days, p < 0.0001), but there was no difference in postoperative mortality (2% versus 1%, p = 0.53). Nodal upstaging occurred in 20% of high-risk patients and 21% of standard-risk patients (p = 0.79). Three-year survival was 59% for high-risk patients and 76% for standard-risk patients (p < 0.0001). CONCLUSIONS: Good clinical outcomes after surgery for early stage lung cancer can be achieved in patients classified as high risk. In our study, surgery led to upstaging in 20% of patients and acceptable 1-, 2-, and 3-year survival as compared with historical rates for nonsurgical therapies. This study suggests that empiric selection criteria may deny patients optimal oncologic therapy. PMID- 26572256 TI - An Isolated Congenital Left Ventricular Diverticulum with Mitral Valve Endocarditis. AB - Congenital left ventricular diverticulum is a rare cardiac malformation, which could result in rupture, thrombosis, congestive heart failure, infective endocarditis, ventricular arrhythmia and aortic insufficiency. Most authors propose that patients who are symptomatic and have a higher risk for major complications should undergo surgical treatment. We present a case of isolated congenital left ventricular diverticulum with mitral valve infective endocarditis and anomalous single coronary artery observed intra-operatively. The patient underwent successful surgical repair of the diverticulum by continuous suture of the internal opening inside the left ventricle. PMID- 26572257 TI - Reduction of apoptosis by proanthocyanidin-induced autophagy in the human gastric cancer cell line MGC-803. AB - Proanthocyanidins are flavonoids that are widely present in the skin and seeds of various plants, with the highest content in grape seeds. Many experiments have shown that proanthocyanidins have antitumor activity both in vivo and in vitro. Autophagy and apoptosis of tumor cells induced by drugs are two of the major causes of tumor cell death. However, reports on the effect of autophagy induced by drugs in tumor cells are not consistent and suggest that autophagy can have synergistic or antagonistic effects with apoptosis. This research was aimed at investigating whether proanthocyanidins induced autophagy and apoptosis in human gastric cancer cell line MGC-803 cells and to identify the mechanism of proanthocyanidins action to further determine the effect of proanthocyanidins induced autophagy on apoptosis. MTT assay was used to examine the proanthocyanidin cytotoxicity against human gastric cancer cell line MGC-803. Transmission electron microscopy and monodansylcadaverine (MDC) staining were used to detect autophagy. Annexin V APC/7-AAD double staining and Hoechst 33342/propidium iodide (PI) double staining were used to explore apoptosis. Western blotting was used to determine expression of proteins related to autophagy and apoptosis. Real-time quantitative PCR technology was used to determine the mRNA level of Beclin1 and BCL-2. The results showed that proanthocyanidins exhibit a significant inhibitory effect on the human gastric cancer cell line MGC-803 proliferation in vitro and simultaneously activate autophagy and apoptosis to promote cell death. Furthermore, when proanthocyanidin induced autophagy is inhibited, apoptosis increases significantly, proanthocyanidins can be used together with autophagy inhibitors to enhance cytotoxicity. PMID- 26572258 TI - Methylene blue exerts a neuroprotective effect against traumatic brain injury by promoting autophagy and inhibiting microglial activation. AB - Traumatic brain injury (TBI) leads to permanent neurological impairment, and methylene blue (MB) exerts central nervous system neuroprotective effects. However, only one previous study has investigated the effectiveness of MB in a controlled cortical impact injury model of TBI. In addition, the specific mechanisms underlying the effect of MB against TBI remain to be elucidated. Therefore, the present study investigated the neuroprotective effect of MB on TBI and the possible mechanisms involved. In a mouse model of TBI, the animals were randomly divided into sham, vehicle (normal saline) or MB groups. The treatment time-points were 24 and 72 h (acute phase of TBI), and 14 days (chronic phase of TBI) post-TBI. The brain water content (BWC), and levels of neuronal death, and autophagy were determined during the acute phase, and neurological deficit, injury volume and microglial activation were assessed at all time-points. The injured hemisphere BWC was significantly increased 24 h post-TBI, and this was attenuated following treatment with MB. There was a significantly higher number of surviving neurons in the MB group, compared with the Vehicle group at 24 and 72 h post-TBI. In the acute phase, the MB-treated animals exhibited significantly upregulated expression of Beclin 1 and increased LC3-II to LC3-I ratios, compared with the vehicle group, indicating an increased rate of autophagy. Neurological functional deficits, measured using the modified neurological severity score, were significantly lower in the acute phase in the MB-treated animals and cerebral lesion volumes in the MB-treated animals were significantly lower, compared with the other groups at all time-points. Microglia were activated 24 h after TBI, peaked at 72 h and persisted until 14 days after TBI. Although the number of Iba-1-positive cells in the vehicle and MB groups 24 h post-TBI were not significantly different, marked microglial inhibition was observed in the MB group 72 h and 14 days after -TBI. These results indicated that MB exerts a neuroprotective effect by increasing autophagy, decreasing brain edema and inhibiting microglial activation. PMID- 26572259 TI - [Occupational risk factors for lung cancer]. AB - OBJECTIVE: We aimed to review the literature regarding the dose-response relationship between occupational exposure to chemicals classified by the International Agency for Research on Cancer (IARC) as carcinogenic agents and the risk of some lung cancers and on any combined effect with tobacco exposure on lung cancer risk. METHODS: A literature search was performed in three databases as well as in the IARC monographs between January 1990 and April 2015. RESULTS: The literature is abundant for some carcinogens such as asbestos, crystalline silica and diesel exhaust fumes but is more sparse for many carcinogens and particularly any interaction with tobacco on lung cancer risk. CONCLUSION: Few data exist for most lung occupational carcinogens including their interaction with tobacco exposure. In the case of exposure to occupational carcinogens and co exposure to tobacco smoke, there is a dual primary prevention objective: the elimination of both occupational risk factors and tobacco smoke. PMID- 26572260 TI - [Euthanasia 2002-2014: The situation in Belgium]. AB - INTRODUCTION: Since 2002, Belgian law has authorized the practice of euthanasia under certain clear conditions. All cases have to be reported to the Assessment and Control Commission (ACC). To date, more than 9000 cases have been reported. AIM: To make a statement about the Belgian experience requires consideration of several different essential points: detailed data and information from the ACC reports, their analysis, consequences on medical practice, problems experienced, legal and medical perspectives, criticism and attacks. The concept of individual and institutional conscience is also considered. Euthanasia for minors has been permitted since March 2014 but, to date, no case has been reported. In the light of what has happened in Belgium, we propose to analyse the legal situation in France. MAIN POINTS AND CONCLUSIONS: The Belgian experience is much more than an example and shows that, in difficult and painful situations, it is possible to meet the expectations of patients experiencing intolerable suffering with great respect and without imposing dogmatically something they do not wish. PMID- 26572262 TI - Editorial. PMID- 26572261 TI - [Pneumocystis pneumonia in HIV-negative adults]. AB - In HIV-negative adults, Pneumocystis jirovecii pneumonia can be observed when immunodeficiency is present, especially in case of drug-induced immune suppression (steroids, chemotherapy, transplantation). Clinical, radiological, and biological presentations are different in HIV-positive and HIV-negative individuals with different immunodeficiency profiles. In HIV-negative patients, dyspnea occurs more quickly (median duration of 5 days to get a diagnosis), diagnosis is more difficult because of less Pneumocystis in bronchoalveolar lavage, and mortality is higher than in HIV-positive individuals. Lung CT-scan typically shows diffuse ground glass opacities, but peri-bronchovascular condensations or ground glass opacities clearly limited by interlobular septa can also be observed. Lymphopenia is common but CD4+ T-cells count is rarely performed. HIV-negative patients with Pneumocystis pneumonia are co-infected with bacteria, viruses or fungi in about 30% cases. Bronchoalveolar lavage is often more neutrophilic than in HIV-positive individuals. PCR and beta-D-glucan have good sensitivity but poor specificity to diagnose Pneumocystis pneumonia. Trimethoprim-sulfamethoxazole remains the first choice of treatment. Duration is 14 days in HIV-negative patients whereas it is typically of 21 days in HIV positive individuals. Adjunctive corticosteroids are of beneficial effect in HIV positive adult patients with substantial hypoxaemia but are not recommended in HIV-negative patients, as they could be deleterious in some individuals. PMID- 26572263 TI - [Integral Care Guide for Early Detection and Diagnosis of Depressive Episodes and Recurrent Depressive Disorder in Adults. Integral Attention of Adults with a Diagnosis of Depressive Episodes and Recurrent Depressive Disorder: Part I: Risk Factors, Screening, Suicide Risk Diagnosis and Assessment in Patients with a Depression Diagnosis]. AB - INTRODUCTION: Depression is an important cause of morbidity and disability in the world; however, it is under-diagnosed at all care levels. OBJECTIVE: The purpose here is to present recommendations based on the evidence gathered to answer a series of clinical questions concerning risk factors, screening, suicide risk diagnosis and evaluation in patients undergoing a depressive episode and recurrent depressive disorder. Emphasis has been made upon the approach used at the primary care level so as to grant adult diagnosed patients the health care guidelines based on the best and more updated evidence available thus achieving minimum quality standards. METHODOLOGY: A practical clinical guide was elaborated according to standards of the Methodological Guide of the Ministry of Social Protection. Recommendation from guides NICE90 and CANMAT were adopted and updated so as to answer the questions posed while de novo questions were developed. RESULTS: Recommendations 1-22 corresponding to screening, suicide risk and depression diagnosis were presented. The corresponding degree of recommendation is included. PMID- 26572264 TI - [Integral Care Guide for Early Detection and Diagnosis of Depressive Episodes and Recurrent Depressive Disorder in Adults. Integral Attention of Adults with a Diagnosis of Depressive Episodes and Recurrent Depressive Disorder: Part II: General Aspects of Treatment, Management of the Acute Phase, Continuation and Maintenance of Patients with a Depression Diagnosis]. AB - INTRODUCTION: This article presents recommendations based on evidence gathered to answer a series of clinical questions concerning the depressive episode and the recurrent depressive disorder, with emphasis on general treatment aspects, treatment in the acute phase and management of the continuation/maintenance, all intended to grant health care parameters based on the best and more updated available evidence for achieving minimum quality standards with adult patients thus diagnosed. METHODOLOGY: A practical clinical guide was elaborated according to standards of the Methodological Guide of the Ministry of Social Protection. Recommendation from NICE90 and CANMAT guides were adopted and updated so as to answer the questions posed while de novo questions were developed. RESULTS: Recommendations 5-22 corresponding to management of depression are presented. PMID- 26572265 TI - [Integral Care Guide for Early Detection and Diagnosis of Depressive Episodes and Recurrent Depressive Disorder in Adults. Integral Attention of Adults with a Diagnosis of Depressive Episodes and Recurrent Depressive Disorder: Part III: Treatment of Resistant Depression and Psychotic Depression, Occupational Therapy and Day Hospital Treatment]. AB - INTRODUCTION: This article presents recommendations based on the evidence gathered to answer a series of clinical questions concerning the depressive episode and the recurrent depressive disorder. Emphasis was given to general treatment issues of resistant depression and psychotic depression, occupational therapy and day hospital treatment so as to grant diagnosed adult patients the health care parameters based on the best and more updated evidence available and achieve minimum quality standards. METHODOLOGY: A practical clinical guide was elaborated according to standards of the Methodological Guide of the Ministry of Social Protection. Recommendation from NICE90 and CANMAT guides were adopted and updated so as to answer the questions posed while de novo questions were developed. RESULTS: Recommendations 23-25 corresponding to the management of depression are presented. PMID- 26572266 TI - [Clinical Practice Guide for Early Detection, Diagnosis and Treatment of the Acute Intoxication Phase in Patients with Alcohol Abuse or Dependence: Part I: Screening, Early Detection and Risk Factors in Patients with Alcohol Abuse or Dependence]. AB - INTRODUCTION: Worldwide, alcohol is the second most-used psychotropic substance and the third risk factor for early death and disability. Its noxious use is a world public health problem given its personal, labor, family, economic and social impact. 70 % of people under risk of having alcohol problems go undetected in medical practice, a fact that underlines the need for specific screening measures allowing early detection leading to timely treatment. This article presents evidence gathered by alcohol abuse and dependence screening as well as by risk factor identification and screening. It also presents evidence concerning withdrawal symptoms, delirium tremens and Wernicke's encephalopathy in order to promote early detection and timely treatment. METHODOLOGY: Systematic revision of the evidence available together with an evaluation of pertinent guidelines found in literature so as to decide whether to adopt or adapt the existing recommendation for each question or to develop de novo recommendations. For de novo recommendations as well as those adapted, it was carried out an evidence synthesis, together with evidence tables and formulation of recommendations based on the evidence. RESULTS: Evidence was found and recommendations were made for the pertinent screening and search of risk factors, in order to perform a diagnosis and carry out a timely management of alcohol abuse, dependence and ensuing complications: withdrawal syndrome, delirium tremens and Wernicke's encephalopathy. PMID- 26572267 TI - [Clinical Practice Guide for Early Detection, Diagnosis and Treatment of the Acute Intoxication Phase in Patients with Alcohol Abuse or Dependence: Part II: Evaluation and Management of Patients with Acute Alcohol Intoxication]. AB - INTRODUCTION: Worldwide, alcohol is the second most-used psychotropic substance and the third risk factor for early death and disability. Its noxious use is a world public health problem given its personal, labor, family, economic and social impact. The identification of acute alcohol intoxication is extremely important, as well as the alcohol withdrawal syndrome and its complications, such as delirium tremens and Wernicke's encephalopathy in order to grant a timely treatment for those patients. This article introduces the evidence found so as to face and treat these clinic manifestations. METHODOLOGY: Systematic revision of the evidence available together with an evaluation of pertinent guidelines found in literature so as to decide whether to adopt or adapt the existing recommendation for each question or to develop de novo recommendations. For de novo recommendations as well as those adapted, it was carried out an evidence synthesis, together with evidence tables and formulation of recommendations based on the evidence. RESULTS: Evidence was found and recommendations were made for the diagnosis and treatment of acute alcohol intoxication, withdrawal syndrome, delirium tremens and Wernicke's encephalopathy. PMID- 26572268 TI - [Implementation Plan for Two Clinical Practice Guides (CPGs) Contained in the Integral Care Guides (ICGs) of the General System of Social Health Care in Colombia: A) "Early Detection of Depressive Episode and Recurrent Depressive Disorder in Adults. Integral Attention of Adults with Diagnosis of Depressive Episode or Recurrent Depressive Disorder (CPG-Depression)". B) "Early Detection, Diagnosis and Treatment of the Acute Intoxication Phase In 18-Years-Old Patients with Alcohol Abuse or Dependence (CPG-Alcohol)"]. AB - INTRODUCTION: Clinical practice guides (CPGs) are systematically recommended, with the best clinical evidence available, to help physicians and patients in decision-making concerning the most adequate sanitary care as well as the selection of the best diagnostic and therapeutic options when facing a health problem or a clinical condition. After obtaining these recommendations, it is crucial to adopt them in daily clinical practice; the process through which this change is sought is known as implementation. This document contains recommendations for implementing CPGs in two psychiatric pathologies: 1) depressive episode and recurrent depressive disorder in adults, and 2) acute intoxication phase in cases of alcohol abuse or dependence. METHODOLOGY: The recommended implementation process is described; besides, barriers and facilitators found in the two guides, together with the list of management indicators and clinical outcomes, are identified for their monitoring within the General Health Social Security System of Colombia. CONCLUSION: CPGs contain recommendations with the best clinical evidence available. The challenge is achieving the adoption of such tool by users, being therefore necessary to follow the diffusion, dissemination and implementation plan, overcoming barriers and resorting to intrinsic and extrinsic facilitators for CPGs as well as performing monitoring with indicators described for measuring the implementation process (management indicators) and the effect of CPGs in clinical practice (indicators of clinical outcome.). PMID- 26572269 TI - [Predominant polarity in type-I bipolar patients: Study in an isolated population with a high prevalence of mood disorders]. AB - INTRODUCTION: Recent studies have shown that the predominant description of polarity has effects upon early detection and the timely beginning of treatment in patients with bipolar affective disorder (BAD). METHODOLOGY: Cross sectional cut and descriptive study in 101 BAD patients coming from a genetically isolated population from the Colombian Region of Antioquia. RESULTS: The study covered a population of 101 patients with type-I BAD diagnosis, out of which 57,4% met the criteria for maniac polarity (MP), 10,1% exhibited depressive polarity (DP) and 25,7% were classified with Indefinite Polarity (IP). In comparison, MP patients have a lower education level and less starting age, including a greater number of single people. The MP group showed the greatest prevalence of suicide and greater use of cannabinoids and cocaine. Within the DP group there was a strong tendency to cigarette and alcohol consumption. With respect to pharmaceutical drugs consumed by the study patients during their lives, antipsychotics were the most widely used group, followed by lithium and anti-convulsivants. There is high percentage of MP patients who have used antidepressants during their lives. CONCLUSION: The polarity of the first episode of the disease seems to be a valid predictive parameter concerning the polarity of subsequent episodes; therefore, it works indirectly as a valid predictor of the disease's course. PMID- 26572270 TI - [Would the Screening of Common Mental Disorders in Primary-Care Health Services Hyper-Frequent Patients Be Useful?]. AB - Hyper-frequentation in health services is a problem for patients, their families and the institutions. This study is aimed at determining the frequency and characteristics of common mental disorders in hyper-frequent patients showing vague symptoms and signs at a primary healthcare service during the year 2007 in the city of Cali (Colombia). METHODOLOGY: Cross sectional. The most frequent mental disorders in hyper-frequent patients were detected through a telephone interview which included several modules of the PRIME MD instrument. RESULTS: In general, healthcare service hyper-frequenters are working women, 38,7-year old in average. Basically, the consultation is due to cephalalgia but they also exhibit a high prevalence of common mental disorders (somatization, depression and anxiety) not easily diagnosed by physicians in primary care. Expenses for additional health activities generated by these patients are attributed basically to medical consultation and required procedures. CONCLUSION: Considering hyper frequenters in health care services as a risk group in terms of common mental disorders involves screening as an efficient strategy to prevent abuse in service use and to improve satisfaction with the attention received. PMID- 26572271 TI - [Reliability and Validity of the Scale for Homophobia in Medicine Students]. AB - INTRODUCTION: There are several scales to quantify homophobia in different populations. However, the reliability and validity of these instruments among Colombian students are unknown. Consequently, this work is intended to assess reliability (inner consistency) as well as the validity of the Scale for Homophobia in Medicine students from a private university in Bogota (Colombia). METHODOLOGY: Methodological study with 199 Medicine students from 1st to 5th semester that filled out the Homophobia Scale form, the general welfare questionnaire, the Attitude Towards Gays and Lesbians Scale (ATGL), WHO-5 (divergent validity) and the Francis Scale of Attitude Toward Christianity (nomologic validity). Pearson's correlations were computed, the Cronbach's alfa coefficient, the omega coefficient (construct's reliability) and confirmatory factorial analysis. RESULTS: The Scale for Homophobia showed an alpha Cronbach coefficient of 0,785, an omega coefficient of 0,790 and a Pearson correlation with the ATGL of 0,844; with WHO-5, -0,059; and a Francis Scale of Attitude Toward Christianity, 0,187. The Scale toward Homophobia exhibited a relevant factor of 44,7% of the total variance. CONCLUSIONS: The Scale for Homophobia showed acceptable reliability and validity. New studies should investigate the stability of the scale and the nomologic validity regarding other constructs. PMID- 26572272 TI - [Consistent Declarative Memory with Depressive Symptomatology]. AB - INTRODUCTION: Some studies have suggested that potentiated remembrance of negative events on people with depressive disorders seems to be an important factor in the etiology, course and maintenance of depression. OBJECTIVE: Evaluate the emotional memory in people with and without depressive symptomatology by means of an audio-visual test. METHODOLOGY: 73 university students were evaluated, male and female, between 18 and 40 years old, distributed in two groups: with depressive symptomatology (32) and without depressive symptomatology (40), using the Scale from the Center of Epidemiologic Studies for Depression (CES-D, English Abbreviation) and a cutting point of 20. RESULTS: There were not meaningful differences between free and voluntary recalls, with and without depressive symptomatology, in spite of the fact that both groups had granted a higher emotional value to the audio-visual test and that they had associated it with emotional sadness. CONCLUSION: People with depressive symptomatology did not exhibit the effect of mnemonic potentiation generally associated to the content of the emotional version of the test; therefore, the hypothesis of emotional consistency was not validated. PMID- 26572273 TI - [Critical Approach to Somatomorphic Disorders in Children]. AB - Somatomorphic disorders have common somatic manifestations without medical explanation, that can affect daily life. There are evaluation difficulties regarding symptom report or observation in children due to their age, parental influence and associated factors. The aim of this work is to acknowledge diagnosis difficulties and clinic tools to approach somatomorphic disorders in children. A systematic search in the information published for the last ten years was carried out. Historical evolution of the concept of somatization has generated difficulties to approach this issue. Some signs could indicate a somatomorphic disorder; however, there are very little evaluating tools for children. Currently, said tools are only based on lists of symptoms without fully answering to all questions. Somatomorphic disorders or somatic symptoms in children are still a gap to be closed. PMID- 26572274 TI - [Report of a case of penile self-amputation]. AB - INTRODUCTION: Motivated by a clinic case, this report introduces some issues related with genital self-amputation in terms of descriptions, epidemiological and clinical issues. METHODOLOGY: Case report describing a clinic case of genital self-amputation. The description is followed by a discussion based on the information available in the scientific literature. A man, 32 years old, with no history of mental disorder, who amputates his penis with a cutting object after quarreling with his mate for infidelity reasons. RESULTS: Several characteristics imply risk factors for genital self-mutilation, such as gender identity disorders, rejection to male genitals, guilt feelings related to sexual activity and a history of previous self-injuries. More common diagnoses include schizophrenia and affective disorders followed by disorders induced by psychoactive substances. CONCLUSION: Genital self-amputation is not a frequent situation and has been under-recorded; however, bearing in mind the high association with psychopathology and recurrence reported in worldwide literature, it is necessary to carry out a proper study and following up of patients exhibiting this conduct. PMID- 26572275 TI - [Not Available]. PMID- 26572276 TI - [Not Available]. PMID- 26572277 TI - Exogenous spermine inhibits the proliferation of human pulmonary artery smooth muscle cells caused by chemically-induced hypoxia via the suppression of the ERK1/2- and PI3K/AKT-associated pathways. AB - Pulmonary vascular remodeling is a significant pathological feature of hypoxia induced pulmonary hypertension (HPH), while pulmonary artery smooth muscle cell (PASMC) proliferation plays a leading role in pulmonary vascular remodeling. Spermine (Sp), a polyamine, plays a critical role in periodic cell proliferation and apoptosis. The present study was conducted to observe the association between hypoxia-induced PASMC proliferation and polyamine metabolism, and to explore the effects of exogenous Sp on PASMC poliferation and the related mechanisms. In the present study, PASMCs were cultured with cobalt chloride (CoCl2) to establish a hypoxia model, and Sp at various final concentrations (0.1, 1, 10 and 100 uM) was added to the medium of PASMCs 40 min prior to the induction of hypoxia. Cell proliferation was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay, cell counting kit-8 assay and 5-bromo-2' deoxyuridine (BrdU) incorporation assay. Cell cycle progression was determined by flow cytometry, and the protein expression levels of spermidine/spermine N1 acetyltransferase (SSAT; the key enzyme in the terminal degradation of polyamine), ornithine decarboxylase (ODC; the key enzyme of polyamine biosynthesis), cyclin D1 and p27 were measured by western blot analysis. The results revealed that the proliferation of the PASMCs cultured with CoCl2 at 50 uM for 24 h markedly increased. The expression of ODC was decreased and the expression of SSAT was increased in the cells under hypoxic conditions. Exogenous Sp at concentrations of 1 and 10 uM significantly inhibited hypoxia-induced PASMC proliferation, leading to cell cycle arrest at the G1/G0 phase. In addition, Sp decreased cyclin D1 expression, increased p27 expression, and suppressed the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT); however, the above-metioned parameters were not markedly affected by Sp at concentrations of 0.1 or 100 uM. These results suggest that hypoxia disrupts polyamine metabolism, and Sp at concentrations of 1 and 10 uM inhibits the increase in human PASMC proliferation caused by chemically-induced hypoxia via the suppression of the ERK1/2- and PI3K/AKT-associated pathways. This study thus offer new insight into the prevention and treatment of HPH. PMID- 26572278 TI - Realization of a vertical topological p-n junction in epitaxial Sb2Te3/Bi2Te3 heterostructures. AB - Three-dimensional (3D) topological insulators are a new state of quantum matter, which exhibits both a bulk band structure with an insulating energy gap as well as metallic spin-polarized Dirac fermion states when interfaced with a topologically trivial material. There have been various attempts to tune the Dirac point to a desired energetic position for exploring its unusual quantum properties. Here we show a direct experimental proof by angle-resolved photoemission of the realization of a vertical topological p-n junction made of a heterostructure of two different binary 3D TI materials Bi2Te3 and Sb2Te3 epitaxially grown on Si(111). We demonstrate that the chemical potential is tunable by about 200 meV when decreasing the upper Sb2Te3 layer thickness from 25 to 6 quintuple layers without applying any external bias. These results make it realistic to observe the topological exciton condensate and pave the way for exploring other exotic quantum phenomena in the near future. PMID- 26572279 TI - American tegumentary leishmaniasis: mRNA expression for Th1 and Treg mediators are predominant in patients with recent active disease. AB - Besides the Th1*Th2 paradigm, Treg and Th17 cytokines may play a role in the response to American tegumentary leishmaniasis. Considering the sensitivity and accuracy of qPCR and the lack of studies using this approach, we evaluated mRNA expression for IFN-gamma, TNF-alpha, IL-4, IL-10, IL-6, IL-17A, IL-22, TGF-beta, Foxp3 and RORC in peripheral blood mononuclear cells (PBMC) from patients with active disease, after stimulation with L. (V.) braziliensis soluble or insoluble fractions. Our results show that the antigens promoted specific mRNA expression related to the immune response in patients with ATL, and the insoluble fraction seems to stimulate the immune response in a higher intensity. The pro inflammatory response was also fueled by IFN-gamma and TNF-alpha, probably due to the active disease. IL-4, in certain way, seems to regulate this response along with IL-10 that may be produced by Treg cells, which are supposedly present in the patients' samples due the evidenced expression of Foxp3, in the presence of AgIns. In contrast, down-regulated RORC suggests that the significant levels of IL-6 expressed in response to AgSol were not able to induce an expressive Th17 profile along with TGF-beta, which might have predominantly contributed to the development of a regulatory profile in the active disease. PMID- 26572281 TI - How Many Patients would Benefit from Steering Technology for Deep Brain Stimulation? PMID- 26572280 TI - Transcranial Direct Current Brain Stimulation Increases Ability to Resist Smoking. AB - BACKGROUND: The ability to exert self-control over temptation is a fundamental component of smoking behavior change. Transcranial direct current stimulation (tDCS) of the dorsolateral prefrontal cortex (DLPFC) has been shown to modulate cognitive control circuits. Although prior studies show that stimulation reduces cigarette craving and self-reported smoking, effects on ability to resist smoking have not been investigated directly. OBJECTIVES: We assessed effects of a single 20-minute session of 1.0 mA anodal stimulation over the left DLPFC with cathodal stimulation over the right supra-orbital area (vs. sham stimulation) on ability to resist smoking in a validated smoking lapse paradigm. METHODS: Twenty-five participants completed two tDCS sessions (active and sham stimulation) in a within-subject, double-blind, randomized and counterbalanced order with a 2-week washout period. Following overnight abstinence, participants received tDCS in the presence of smoking related cues; they had the option to smoke at any time or receive $1 for every 5 minutes they abstained. After 50 minutes, they participated in a 1 hour ad libitum smoking session. Primary and secondary outcomes were time to first cigarette and cigarette consumption, respectively. RESULTS: In multiple regression models, active tDCS (compared to sham) significantly increased latency to smoke (p = 0.02) and decreased the total number of cigarettes smoked (p = 0.014) during the session. CONCLUSION: These findings suggest that acute anodal stimulation over the left DLPFC (with cathodal stimulation over the right supra-orbital area) can improve ability to resist smoking, supporting the therapeutic potential of tDCS for smoking cessation treatment. PMID- 26572282 TI - Synthesis and Biological Evaluation of Novel Bouchardatine Derivatives as Potential Adipogenesis/Lipogenesis Inhibitors for Antiobesity Treatment. AB - Our recent study has shown that the natural product bouchardatine (1) can reduce the triglyceride (TG) content in 3T3-L1 adipocytes (EC50 ~ 25 MUM). Here, we synthesized two series of compounds by introducing amine side chains at the 5 or 8 position of 1 and evaluated the lipid-lowering activity of derivatives. It was found that some of the compounds had significant lipid-lowering effects, and the most active compound 3d showed better activity (EC50 = 0.017 MUM) than 2 (EC50 = 0.086 MUM), a compound reported by us. Further, the mechanism studies revealed that 3d blocked TG accumulation via activation of the LKB1-AMPK signaling pathway, efficiently down-regulating the expression of key regulators of adipogenesis/lipogenesis. Cell uptake assay and confocal imaging of 3d in cells indicated that compound 3d had favorable cell permeability. Our results suggest that 3d may be a promising agent for the treatment of obesity and related metabolic disorders. PMID- 26572283 TI - Superresolution imaging with optical fluctuation using speckle patterns illumination. AB - Superresolution fluorescence microscopy possesses an important role for the study of processes in biological cells with subdiffraction resolution. Recently, superresolution methods employing the emission properties of fluorophores have rapidly evolved due to their technical simplicity and direct applicability to existing microscopes. However, the application of these methods has been limited to samples labeled with fluorophores that can exhibit intrinsic emission properties at a restricted timescale, especially stochastic blinking. Here, we present a superresolution method that can be performed using general fluorophores, regardless of this intrinsic property. Utilizing speckle patterns illumination, temporal emission fluctuation of fluorophores is induced and controlled, from which a superresolution image can be obtained exploiting its statistical property. Using this method, we demonstrate, theoretically and experimentally, the capability to produce subdiffraction resolution images. A spatial resolution of 500 nm, 300 nm and 140 nm with 0.4, 0.5 and 1.4 NA objective lenses respectively was achieved in various samples with an enhancement factor of 1.6 compared to conventional fluorescence microscopy. PMID- 26572314 TI - Unobtrusive ambulatory EEG using a smartphone and flexible printed electrodes around the ear. AB - This study presents first evidence that reliable EEG data can be recorded with a new cEEGrid electrode array, which consists of ten electrodes printed on flexible sheet and arranged in a c-shape to fit around the ear. Ten participants wore two cEEGrid systems for at least seven hours. Using a smartphone for stimulus delivery and signal acquisition, resting EEG and auditory oddball data were collected in the morning and in the afternoon six to seven hours apart. Analysis of resting EEG data confirmed well-known spectral differences between eyes open and eyes closed conditions. The ERP results confirmed the predicted condition effects with significantly larger P300 amplitudes for target compared to standard tones, and a high test-retest reliability of the P300 amplitude (r > = .74). Moreover, a linear classifier trained on data from the morning session revealed similar performance in classification accuracy for the morning and the afternoon sessions (both > 70%). These findings demonstrate the feasibility of concealed and comfortable brain activity acquisition over many hours. PMID- 26572315 TI - Synthesis of Vitamin K and Related Naphthoquinones via Demethoxycarbonylative Annulations and a Retro-Wittig Rearrangement. AB - Anionic annulations of 3-nucleofugal phthalides with alpha-alkyl(aryl)acrylates involving a demethoxycarbonylation provide a succinct synthesis of vitamin K and related naphthoquinones. Also reported is a new cascade reaction stemming from a Cope-retro-Wittig rearrangement. This cascade leads to direct formation of 1 hydroxy-4-prenyloxynaphthalene-2-carboxylates from the corresponding alpha-prenyl acrylate acceptors. PMID- 26572316 TI - Hypogonadotropic hypogonadism in a trisomy X carrier: phenotype description and genotype correlation. AB - We report on a 31-year old female who presented at genetic counseling for a small uterus, secondary amenorrhea and sterility. Gonadotropic hormone levels were low, suggesting a Hypogonadotropic Hypogonadism (HH) condition. Cytogenetic analysis demonstrated the presence of Trisomy X associated to an interstitial deletion of chromosome 4q13.2, resulting in the complete loss of a copy of the GNRHR gene. As GNRHR is known to be responsible for an autosomal recessive form of HH, we checked the status of the undeleted allele and we found the Q106R substitution. In conclusion, the results of our cytogenetic and molecular analyses have allowed us to clarify the etiology of the patient's condition. PMID- 26572317 TI - Hardy exotics species in temperate zone: can "warm water" crayfish invaders establish regardless of low temperatures? AB - The spreading of new crayfish species poses a serious risk for freshwater ecosystems; because they are omnivores they influence more than one level in the trophic chain and they represent a significant part of the benthic biomass. Both the environmental change through global warming and the expansion of the pet trade increase the possibilities of their spreading. We investigated the potential of four "warm water" highly invasive crayfish species to overwinter in the temperate zone, so as to predict whether these species pose a risk for European freshwaters. We used 15 specimens of each of the following species: the red swamp crayfish (Procambarus clarkii), the marbled crayfish (Procambarus fallax f. virginalis), the yabby (Cherax destructor), and the redclaw (Cherax quadricarinatus). Specimens were acclimatized and kept for 6.5 months at temperatures simulating the winter temperature regime of European temperate zone lentic ecosystems. We conclude that the red swamp crayfish, marbled crayfish and yabby have the ability to withstand low winter temperatures relevant for lentic habitats in the European temperate zone, making them a serious invasive threat to freshwater ecosystems. PMID- 26572319 TI - Therapeutic value of melatonin post-treatment on CCl4-induced fibrotic rat liver. AB - Melatonin is known for being beneficial in targeting liver diseases. This study aimed to investigate whether melatonin post-treatment is capable of rat carbon tetrachloride (CCl4)-induced liver fibrosis reduction. Thirty-two male Sprague Dawley rats were divided into 4 groups: normal; fibrosis with CCl4 injection (1 mL/kg) twice weekly for 8 weeks; phosphate-buffered saline (PBS); and melatonin (20 mg/kg) for a further 4 weeks on cessation of CCl4. At the beginning of week 13, liver tissue samples were used for hematoxylin-eosin (H&E), periodic acid Schiff (PAS), Masson's trichrome (MT), and Oil Red O staining, quantitative real time PCR (qRT-PCR) analysis of the matrix metalloproteinase-9 (MMP-9), MMP-13, transforming growth factor-beta1 (TGF-beta1), Bcl-2, and Bax genes as well as immunofluorescence (IF) of the first 3, and sera for measurement of aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, and hydroxyproline. Chronic administration of CCl4 followed by considerable increase in tissue disruption, macro- and micro-vesicles, collagen, lipid droplets (LDs), AST, ALT, hydroxyproline, TGF-beta1, and Bax, and decrease in glycogen depository, albumin, Bcl-2, MMP-9, and MMP-13; however, the pattern was reverse when it comes to melatonin treatment (for all p < 0.05). Our results reveal the beneficial aspects of melatonin in treatment of liver fibrosis probably via inhibition of TGF-beta1expression. PMID- 26572318 TI - Extended regimen combined oral contraception: A review of evolving concepts and acceptance by women and clinicians. AB - OBJECTIVES: The clinical utility of extended regimen combined oral contraceptives (COCs) is increasingly being recognised. Our objective was to understand the attitudes of women and clinicians about the use of these regimens. We present the rationale for extended regimen COCs from a historical perspective, and trace their evolution and growing popularity in light of their clinical benefits. We conclude by offering potential strategies for counselling women about extended regimen COC options. METHODS: We conducted a MEDLINE search to identify and summarise studies of extended regimen COCs, focusing on attitudes of women and clinicians regarding efficacy, safety/tolerability and fewer scheduled bleeding episodes and other potential benefits. RESULTS: The body of contemporary literature on extended regimen COCs suggests that their contraceptive efficacy is comparable to that of conventional 28-day (i.e., 21/7) regimens. For women seeking contraception that allows infrequent scheduled bleeding episodes, particularly those who suffer from hormone withdrawal symptoms and cyclical symptoms (e.g., headache, mood changes, dysmenorrhoea, heavy menstrual bleeding), extended regimen COCs are an effective and safe option. Although satisfaction with extended regimen COCs in clinical trials is high, misperceptions about continuous hormone use may still limit the widespread acceptance of this approach. CONCLUSIONS: Despite the widespread acceptance among clinicians of extended regimen COCs as an effective and safe contraceptive option, these regimens are underused, likely due to a lack of awareness about their availability and utility among women. Improved patient education and counselling regarding the safety and benefits of extended regimen COCs may help women make more informed contraceptive choices. PMID- 26572320 TI - Enhanced Structural and Magnetic Coupling in a Mesocrystal-Assisted Nanocomposite. AB - Benefiting from the advances made in well-controlled materials synthesis techniques, nanocomposites have drawn considerable attention due to their enthralling physics and functionalities. In this work, we report a new heteroepitaxial mesocrystal-perovskite nanocomposite, (NiFe2O4)0.33:(La0.67Ca0.33MnO3)0.67. Elaborate structural studies revealed that tiny NiFe2O4 nanocrystals aggregate into ordered octahedral mesocrystal arrays with {111} facets together with a concomitant structural phase transition of the La0.67Ca0.33MnO3 matrix upon postannealing process. Combined magnetic and X-ray absorption spectroscopic measurements show significant enhancement in the magnetic properties at room temperature due to the structural evolution of magnetic NiFe2O4 and the consequent magnetic coupling at the heterointerfaces mediating via well connected octahedrons of Mn-O6 in La0.67Ca0.33MnO3 and (Ni,Fe) O6 in NiFe2O4. This work demonstrates an approach to manipulate the exciting physical properties of material systems by integrating desired functionalities of the constituents via synthesis of a self-assembled mesocrystal embedded nanocomposite system. PMID- 26572321 TI - Evidence for Anaerobic Dechlorination of Dechlorane Plus in Sewage Sludge. AB - The environmental occurrence of dechlorination moieties from the high production volume flame retardant, Dechlorane Plus (DP), has largely been documented; however, the sources have yet to be well understood. In addition, few laboratory based studies exist which identify the cause for the occurrence of these chemicals in the environment or humans. Anaerobic dechlorination of the two DP isomers was investigated using a laboratory-simulated wastewater treatment plant (WWTP) environment where anaerobic digestion is used as part of the treatment regime. Known amounts of each isomer were added separately to sewage sludge which provided the electron-donating substrate and at prescribed time points in the incubation, a portion of the media was removed and analyzed for DP and any dechlorination metabolites. After 7 days, monohydrodechlorinated products were observed for both the syn- and anti-DP which were continued throughout the duration of our study (49 days) in an increasing manner giving a calculated formation rate of 0.48 +/- 0.09 and 0.79 +/- 0.12 pmols/day for syn- and anti-DP, respectively. Furthermore, we observed a second monohydrodechlorinated product only in the anti-DP isomer incubation medium. This strongly suggests that anti-DP is more susceptible to anaerobic degradation than the syn isomer. We also provide compelling evidence to the location of chlorine loss in the dechlorination DP analogues. Finally, the dechlorination DP moieties formed in our study matched the retention times and identification of those observed in surficial sediment located downstream of the WWTP. PMID- 26572322 TI - Nanofilms of hyaluronan/chitosan assembled layer-by-layer: An antibacterial surface for Xylella fastidiosa. AB - In this work, nanofilms of hyaluronan/chitosan (HA/CHI) assembled layer by layer were synthesized; their application as a potential antimicrobial material was demonstrated for the phytopathogen Xylella fastidiosa, a gram-negative bacterium, here used as a model. For the synthesis, the influence of pH and ionic strength of these natural polymer stem-solutions on final characteristics of the HA/CHI nanofilms was studied in detail. The antibacterial effect was evaluated using widefield fluorescence microscopy. These results were correlated with the chemical properties of the nanofilms, studied by FTIR and Raman spectroscopy, as well as with their morphology and surface properties characterized using SEM and AFM. The present findings can be extended to design and optimize HA/CHI nanofilms with enhanced antimicrobial behavior for other type of phytopathogenic gram negative bacteria species, such as Xanthomonas citri, Xanthomas campestri and Ralstonia solanacearum. PMID- 26572323 TI - Polymyxin B immobilized on cross-linked cellulose microspheres for endotoxin adsorption. AB - Cross-linked cellulose microspheres (CL-CMs) were successfully prepared by inverse crosslinking suspension method. NaOH/urea aqueous solution was used as solvent to dissolve cellulose at low temperature. The microspheres presented good spherical shape and monodispersity, which were applied to synthesize endotoxin adsorbent with polymyxin B (PMB) as ligand. The adsorbent showed good adsorption capability on endotoxin in physiologic saline solution and the maximum adsorption capacity was 3605 EU/g (1 EU=100 pg). It was worth noting that more than 70% of endotoxin could be effectively removed from the human plasma with the initial concentration of endotoxin ranged from 1 EU/mL to 5 EU/mL. The dynamic adsorption efficiency of endotoxin was 72.3% at the plasma perfusion rate of 300 mL/h with the endotoxin concentration of 4 EU/mL, while the variation of plasma protein before and after adsorption was only 8.9%. It suggests that the PMB immobilized CL-CMs have great potential application in clinical blood purification. PMID- 26572324 TI - Lamellar, micro-phase separated blends of methyl cellulose and dendritic polyethylene glycol, POSS-PEG. AB - Blends of methyl cellulose (MC) and liquid pegylated polyoctahedralsilsesquioxane (POSS-PEG) were prepared from non-gelled, aqueous solutions at room temperature (RT), which was below their gel temperatures (Tm). Lamellar, fibrillated films (pure MC) and increasingly micro-porous morphologies with increasing POSS-PEG content were formed, which had RT moduli between 1 and 5GPa. Evidence of distinct micro-phase separated MC and POSS-PEG domains was indicated by the persistence of the MC and POSS-PEG (at 77K) crystal structures in the X-ray diffraction data, and scanning transmission electron images. Mixing of MC and POSS-PEG in the interface region was indicated by suppression of crystallinity in the POSS-PEG, and increases/decreases in the glass transition temperatures (Tg) of POSS-PEG/MC in the blends compared with the pure components. These interface interactions may serve as cross-link sites between the micro-phase separated domains that permit incorporation of high amounts of POSS-PEG in the blends, prevent macro-phase separation and result in rubbery material properties (at high POSS-PEG content). Above Tg/Tm of POSS-PEG, the moduli of the blends increase with MC content as expected. However, below Tg/Tm of POSS-PEG, the moduli are greater for blends with high POSS-PEG content, suggesting that it behaves like semi-crystalline polyethylene oxide reinforced with silica (SiO1.5). PMID- 26572325 TI - Dithiocarbamate-modified starch derivatives with high heavy metal adsorption performance. AB - In this work, three types of dithiocarbamate (DTC)-modified starch derivatives including DTC starch (DTCS), DTC enzymolysis starch (DTCES) and DTC mesoporous starch (DTCMS) were developed, which showed the significant heavy metal adsorption performance. The adsorption ability of these three DTC modified starch derivatives followed the sequences: DTCMS>DTCES>DTCS. In single metal aqueous solutions, the uptake amount of heavy metal ions onto the modified starches obeyed the orders: Cu(II)>Ni(II)>Cr(VI)>Zn(II)>Pb(II). The adsorption mechanism was proved by the chelating between DTC groups and heavy metal ions through the pH effect measurements. A monolayer adsorption of Langmuir isotherm model for the adsorption of Cu(II) onto DTCMS was well fitted rather than the multilayer adsorption of Freundlich isotherm model. The adsorption kinetics of Cu(II) onto starch derivatives was found to be fit well with the pseudo-second-order model. Additionally, in the presence of EDTA, the adsorption ability and uptake amount of heavy metal ions onto these three DTC modified starch derivatives is identical with the results obtained in the absence of EDTA. PMID- 26572326 TI - Interactions at the mild steel acid solution interface in the presence of O fumaryl-chitosan: Electrochemical and surface studies. AB - The performance of synthesised O-fumaryl-chitosan (OFC) as corrosion inhibitor for mild steel in 1M HCl has been evaluated through various studies. The initial screening by weight loss method revealed the good inhibition efficiency by the inhibitor. Thermodynamic and kinetic parameters have been calculated and discussed. The mode of adsorption is physical in nature and it follows Langmuir adsorption isotherm. Electrochemical measurements supported the inhibition of mild steel by the fumaryl derivative of chitosan. Polarisation studies provided the information that the inhibition is of mixed type. The formation of inhibitor film is assured by surface morphological studies with Scanning electron microscopy (SEM) and Atomic force microscopy (AFM). The mechanism of inhibition is derived from the Fourier-transform infrared (FTIR) spectroscopy and zero charge potential measurement. The adsorbed film is characterised using FTIR and X ray diffraction studies (XRD). PMID- 26572327 TI - Silver/polysaccharide-based nanofibrous materials synthesized from green chemistry approach. AB - In this contribution a novel green chemistry approach for the synthesis of nanofibrous materials based on blends of carboxymethyl-cellulose (CMC)-silver nanoparticles (AgNPs) composite and polyvinyl-alcohol (PVA) is proposed. These nanofibrous materials were obtained from the electrospinning of blends of aqueous solutions of CMC-AgNPs composite and PVA, which were prepared at different CMC/PVA weight ratios in order to electrospin nanofibers applying a constant tension of 15kV. The synthesized materials were characterized by means of transmission electron microscopy, scanning electron microscopy; as well as Fourier-transform infrared, ultraviolet and Raman spectroscopic techniques. Experimental evidence suggests that the diameter of the nanofibers is thinner than any other reported in the literature regarding the electrospinning of CMC. This feature is related to the interactions of AgNPs with carboxyl functional groups of the CMC, which diminish those between the later and acetyl groups of PVA. PMID- 26572328 TI - Preparation of Aun quantum clusters with catalytic activity in beta-cyclodextrin polyurethane nanosponges. AB - Here we report the use of beta-cyclodextrin polyurethane nanosponges cross-linked with 1,6-hexamethylene diisocyanate as a template for the preparation of Aun quantum clusters, by the core-etching of glutathione-capped Au nanoparticles. The study of temporal evolution of the core-etching process using different Au concentrations indicated that formation of Aun clusters embedded in the nanosponge is favored by the use of lower Au concentrations, since it began at shorter times and lead to higher cluster loading. An estimation of the number of Au atoms based on the maximum photoluminescence wavelength suggested that, depending on the Au concentration and the core etching time, clusters with 11-15 atoms were formed. After excluding the possibility of an inclusion complex formation, evaluation of the catalytic activity of nanosponge-loaded Aun clusters toward the reduction of 4-nitrophenol has shown that the reaction is catalyzed by the Aun clusters with no induction time, following the Langmuir-Hinshelwood kinetic model. PMID- 26572329 TI - Development of starch based mucoadhesive vaginal drug delivery systems for application in veterinary medicine. AB - The aim of this study was to prepare and evaluate the mucoadhesive, biocompatible and biodegradable progesterone containing vaginal tablets based on modified starch copolymers for the estrus synchronization of ewes. Starch-graft poly(acrylic acid) copolymers (S-g-PAA) were synthesized and characterized. The vaginal tablets were fabricated with S-g-PAA and their equilibrium swelling degree (Qe) and matrix erosion (ME%) were determined in lactate buffer solution. In vitro, mucoadhesive properties of the tablets were investigated by using ewe vaginal mucosa and in vivo residence time were also investigated. In vitro and in vivo progesterone release profiles from the tablets were compared with two commercial products. Tablet formulation containing wheat starch based grafted copolymer (WS-g-PAA)gc indicated promising results and might be convenient as an alternative product to the commercial products in veterinary medicine. PMID- 26572330 TI - Alginate stabilized gold nanoparticle as multidrug carrier: Evaluation of cellular interactions and hemolytic potential. AB - This work delineates the synthesis of curcumin (Ccm) and methotrexate (MTX) conjugated biopolymer stabilized AuNPs (MP@Alg-Ccm AuNPs). The dual drug conjugated nano-vector was characterized by FTIR, (1)H NMR and UV-vis spectroscopic techniques. Hydrodynamic diameter and surface charge of the AuNPs were determined by DLS analysis and the spherical particles were visualized by TEM. MP@Alg-Ccm AuNPs exhibited improved cytotoxic potential against C6 glioma and MCF-7 cancer cell lines and was found to be highly hemocompatible. MP@Alg-Ccm AuNPs also exhibited active targeting efficiency against MCF-7 cancer cells due to the presence of "antifolate" drug MTX. Thus MP@Alg-Ccm AuNPs may find potential application in targeted combination chemotherapy for the treatment of cancer. The study is also interesting from the synthetic point of view because, here generation of AuNPs was done using "green chemical" alginate and dual drug conjugated AuNPs were created in two simple reaction steps using "green solvent" water. PMID- 26572331 TI - Multi-chamber electroosmosis using textile reinforced agar membranes--A promising concept for the future of hemodialysis. AB - Renal replacement therapy options are limited to hemodialysis and peritoneal dialysis (70% of US patients) or renal transplantation. Diffusion processes are the main physico-chemical principle behind hemodialysis. An alternative way to achieve liquid flow through membranes bases on the electroosmotic flow which is observed as electrokinetic phenomenon in porous membranes which bear surface charges. Agar consists of the non-ionic agarose and the negatively charged agaropectine thus an electroosmotic flux is observed in analytical electrophoresis. In this study the potential electroosmosis on textile reinforced agar membranes as separation method was investigated. Using a five-chamber electrolysis cell and an agar membrane/cellulose fabric composite an intensive electroosmotic flow of 1-2 ml cm(2) h(-1) at 100 mA cell current could be observed. The movement of cations in the negatively charged agar structure led to an intensive electroosmotic flux, which also transported uncharged molecules such as urea, glucose through the membrane. Separation of uncharged low molecular weight molecules is determined by the membrane characteristic. The transport of ions (K(+), PO4(3-), creatinine) and uncharged molecules (urea, glucose) in electroosmotic separation experiments was monitored using a pH 5.5 phosphate electrolyte with the aim to assess the overall transport processes in the electrochemical cell. The results demonstrate the potential of the method for filtration of biological fluids in the absence of external pressure or high shear rates. PMID- 26572332 TI - Modification of deoiled cumin dietary fiber with laccase and cellulase under high hydrostatic pressure. AB - In this study, we evaluated the effects of high hydrostatic pressure (HHP) and enzyme (laccase and cellulase) treatment on the structural, physicochemical, and functional properties and antioxidant activity of deoiled cumin dietary fiber (DF). HHP-enzyme treatment increased the contents of soluble dietary fiber (SDF) (30.37 g/100g), monosaccharides (except for glucose), uronic acids, and total polyphenol. HHP-enzyme treatment altered the honey-comb structure of DF and generated new polysaccharides. DF modified by HHP-enzyme treatment exhibited improved water retention capacity (10.02 g/g), water swelling capacity (11.19 mL/g), fat and glucose absorption capacities (10.44 g/g, 22.18-63.54 mmol/g), alpha-amylase activity inhibition ration (37.95%), and bile acid retardation index (48.85-52.58%). The antioxidant activity of DF was mainly correlated to total polyphenol content (R=0.8742). Therefore, DF modified by HHP-enzyme treatment from deoiled cumin could be used as a fiber-rich ingredient in functional foods. PMID- 26572333 TI - Green and facile fabrication of carbon aerogels from cellulose-based waste newspaper for solving organic pollution. AB - Carbon-based aerogel fabricated from waste biomass is a potential absorbent material for solving organic pollution. Herein, the lightweight, hydrophobic and porous carbon aerogels (CAs) have been synthesized through freezing-drying and post-pyrolysis by using waste newspaper as the only raw materials. The as prepared CAs exhibited a low density of 18.5 mg cm(-3) and excellent hydrophobicity with a water contact angle of 132 degrees and selective absorption for organic reagents. The absorption capacity of CA for organic compounds can be 29-51 times its own weight. Moreover, three methods (e.g., squeezing, combustion, and distillation) can be employed to recycle CA and harvest organic pollutants. Combined with waste biomass as raw materials, green and facile fabrication process, excellent hydrophobicity and oleophilicity, CA used as an absorbent material has great potential in application of organic pollutant solvents absorption and environmental protection. PMID- 26572334 TI - Carboxymethyl starch/montmorillonite composite microparticles: Properties and controlled release of isoproturon. AB - Preparation of novel high substituted carboxymethyl starch-based microparticles containing sodium montmorillonite (MMT) by crosslinking with Al(3+) was described. For preparing nanocomposite granules carboxymethyl starch (CMS) from native potato starch as well as CMS from amylopectin has been used. The hydrophilic CMS/MMT composite systems were used for herbicide, i.e. isoproturon encapsulation (ca. 75% encapsulation efficiency). The herbicide release rate from CMS/MMT composites in water was significantly reduced when compared to commercial isoproturon: 95% released after ca. 700 h and ca. 24h, respectively. Leaching in soil from composite systems was relatively slower than release in water. After a series of eight irrigations leached about 10% of isoproturon loaded. The CMS/MMT carriers could reduce the potential leaching of herbicide and beneficially reduce pollution of the environment. PMID- 26572335 TI - Properties of baked foams from citric acid modified cassava starch and native cassava starch blends. AB - Starch foams from native cassava starch (NS) and citric acid modified cassava starch (CNS) were prepared using baking processes with blend ratios of 80/20, 60/40, 50/50, 40/60 and 20/80. The density, thickness, morphology, thermal stability and water absorption of the NS, CNS and blended starch foams were determined. The ratio of the two starch components had a significant influence on the density and thickness of the blended starch foams. All blended starch foams showed good water resistance. Moreover, the morphology of the blended starch foam with the NS/CNS ratio of 50/50 showed a more ordered distribution of cell sizes with thicker cell walls than for the NS and CNS foams. The thermal stability of the blended starch foams was somewhat lower than the stability of the NS foam but not to the extent that it affected any potential practical applications. PMID- 26572336 TI - Hexagonal-shaped chondroitin sulfate self-assemblies have exalted anti-HSV-2 activity. AB - The initial step in mucosal infection by the herpes simplex virus type 2 (HSV-2) requires its binding to certain glycosaminoglycans naturally present on host cell membranes. We took advantage of this interaction to design biomimetic supramolecular hexagonal-shaped nanoassemblies composed of chondroitin sulfate having exalted anti-HSV-2 activity in comparison with native chondroitin sulfate. Nanoassemblies were formed by mixing hydrophobically-modified chondroitin sulfate with alpha-cyclodextrin in water. Optimization of alkyl chain length grafted on chondroitin sulfate and the ratio between hydrophobically-modified chondroitin sulfate and alpha-cyclodextrin showed that more cohesive and well-structured nanoassemblies were obtained using higher alpha-cyclodextrin concentration and longer alkyl chain lengths. A structure-activity relationship was found between anti-HSV-2 activity and the amphiphilic nature of hydrophobically-modified chondroitin sulfate. Also, antiviral activity of hexagonal nanoassemblies against HSV-2 was further improved in comparison with hydrophobically-modified chondroitin sulfate. This work suggests a new biomimetic formulation approach that can be extended to other heparan-sulfate-dependent viruses. PMID- 26572337 TI - Improve the flame retardancy of cellulose fibers by grafting zinc ion. AB - Zinc ion as the only flame retardant of cellulose fibers was successfully grafted onto cellulose fibers. Grafting maleic anhydride onto cellulose fibers via homogeneous acylation reaction between N,N-dimethyl formamide (DMF) as the first step. Then, graft zinc ion onto the formed cellulose fibers was conducted with zinc carbonate. The resulting copolymers were characterized by FTIR. Flame retardancy and thermal degradation of zinc-ion-modified cellulose fibers (cellulose-Zn fibers) was investigated by limiting oxygen index (LOI), cone calorimeter (CONE), XRD, TG and SEM. Zinc ion could effectively improve flame retardancy and thermal degradation when its content increases up to 4.96 wt%. PMID- 26572338 TI - Molecular and functional characteristics of purified gum from Australian chia seeds. AB - Chia seed gum (CSG) was extracted from the seed coat of Salvia hispanica, purified in the laboratory and its chemical composition and functional properties were investigated. CSG was found to comprise 93.8% carbohydrate consisting of xylose, glucose, arabinose, galactose, glucuronic acid and galacturonic acid as monosaccharide units. The presence of uronic acids was reflected in the anionic behavior of the CSG solution over a wide range of pH (>= 1.8). The solubility of CSG increased slightly with temperature and pH of the aqueous medium. CSG was able to resist pyrolytic decomposition at temperatures well in excess of 250 degrees C, and exhibited a high water holding capacity (23 times of its own weight). The surface activity and emulsifying properties of CSG were found to be either superior or comparable to other common gums and industrial polysaccharides indicating the potential of CSG as an effective thickener and stabilizer of processed foods. PMID- 26572339 TI - Bilayered (silica-chitosan) coatings for studying dye release in aqueous media: The role of chitosan properties. AB - Chitosan and bilayered--Rhodamine 6G impregnated silica-chitosan--coatings (300 3000 nm thick) were prepared and investigated as a model for controlled drug release. Properties of native, ionically (sodium triphosphate) and covalently (glutaraldehyde) cross-linked layers of chitosan in contact with aqueous phase (modeling human blood pH of ca. 7.3) were investigated. The cross-linking was confirmed by attenuated total reflection (ATR) Fourier transform infrared (FTIR), energy-dispersive spectroscopy (EDS) and solid state (13)C nuclear magnetic resonance (NMR) spectroscopy. The evolution of advancing water contact angles as a function of time was measured, and from the results restricted mobility of polymer segments in the interfacial layer of cross-linked chitosan coatings were assumed. Spectroscopic ellipsometry measurements showed that covalent cross linking leads to a lowered, while ionic cross-linking to an increased swelling degree of chitosan layers. Despite the swelling behavior both cross-linked chitosan layers showed significant retard effect on dye release from the bilayered coatings. PMID- 26572340 TI - Bioinspired composites from cross-linked galactoglucomannan and microfibrillated cellulose: Thermal, mechanical and oxygen barrier properties. AB - In this study, new wood-inspired films were developed from microfibrillated cellulose and galactoglucomannan-lignin networks isolated from chemothermomechanical pulping side streams and cross-linked using laccase enzymes. To the best of our knowledge, this is the first time that cross-linked galactoglucomannan-lignin networks have been used for the potential development of composite films inspired by woody-cell wall formation. Their capability as polymeric matrices was assessed based on thermal, structural, mechanical and oxygen permeability analyses. The addition of different amounts of microfibrillated cellulose as a reinforcing agent and glycerol as a plasticizer on the film performances was evaluated. In general, an increase in microfibrillated cellulose resulted in a film with better thermal, mechanical and oxygen barrier performance. However, the presence of glycerol decreased the thermal stability, stiffness and oxygen barrier properties of the films but improved their elongation. Therefore, depending on the application, the film properties can be tailored by adjusting the amounts of reinforcing agent and plasticizer in the film formulation. PMID- 26572341 TI - Three-dimensional cellulose sponge: Fabrication, characterization, biomimetic mineralization, and in vitro cell infiltration. AB - In this study, cellulose based scaffolds were produced by electrospinning of cellulose acetate (CA) solution followed by its saponification with NaOH/ethanol system for 24h. The resulting nonwoven cellulose mat was treated with sodium borohydride (SB) solution. In situ hydrolysis of SB solution into the pores of the membrane produced hydrogen gas resulting a three-dimensional (3D) cellulose sponge. SEM images demonstrated an open porous and loosely packed fibrous mesh compared to the tightly packed single-layered structure of the conventional electrospun membrane. 3D cellulose sponge showed admirable ability to nucleate bioactive calcium phosphate (Ca-P) crystals in simulated body fluid (SBF) solution. SEM-EDX and X-ray diffraction studies revealed that the minerals deposited on the nanofibers have the nonstoichiometric composition similar to that of hydroxyapatite, the mineralized component of the bone. 3D cellulose sponge exhibited the better cell infiltration, spreading and proliferation compared to 2D cellulose mat. Therefore, a facile fabrication of 3D cellulose sponge with improved mineralization represents an innovative strategy for the bone tissue engineering applications. PMID- 26572342 TI - Effect of organoclay on morphology and properties of linear low density polyethylene and Vietnamese cassava starch biobased blend. AB - Linear low density polyethylene (LLDPE)/thermal plastic starch (TPS) blend was studied to prepare the biobased nanocomposite material using organoclay nanofil15 (N15) modified by alkilammonium as the reinforced phase. The LLDPE/TPS blend and its nanocomposites were elaborated by melt mixing method at 160 degrees C for 7 min. And the compounded sample was filmed by blowing method at three different zones of temperature profile which are 160-170-165 degrees C. The good dispersion of clay in the polymer blend matrix is showed by X-ray diffraction (XRD) and transmission electronic microscopy (TEM), and a semi-exfoliated structure was obtained. The thermal and mechanical properties of materials are enhanced when N15 is added to the mixture. The effect of N15 on morphology and particles size of TPS phase is also investigated. The biodegradation test shows that more than 60% in weight of LLDPE/TPS film is degraded into CO2, H2O, methane and biomass after 5 months in compost soil. PMID- 26572343 TI - Synthesis and characterization of quaternized bacterial cellulose prepared in homogeneous aqueous solution. AB - In this work, bacterial cellulose (BC) was activated by ethylenediamine (EDA) and then dissolved in lithium chloride/N,N-dimethylacetamide (LiCl/DMAc) aqueous solutions. The resulting transparent solution was cast on a glass plate to prepare regenerated BC. Then cationic BC was prepared homogeneously by the reaction between regenerated BC and 3-chloro-2-hydroxypropyl-trimethyl ammonium chloride (CHPTAC) in a NaOH/urea aqueous solution. Structure and properties of the BC and its products were characterized by different techniques such as X-ray diffraction (XRD), Fourier transform spectroscopy (FT-IR), scanning electron microscopy (SEM) and thermo-gravimetric analysis (TGA). The results showed that there was no significant difference between the structures of BC, activated BC and regenerated BC. The effects of different temperature and molar ratio of CHPTAC to anhydroglucose unit (AGU) on the degree of substitution (DS) value were examined. The DS values of cationic BC ranged between 0.21 and 0.51. PMID- 26572344 TI - A procoagulant chemically sulfated mannan. AB - Disorders of hemostasis can produce innumerous problems. Polysaccharides have been studied both as anticoagulant and as procoagulant agents. A mannan with a main chain of alpha-(1 -> 6)-linked-Manp units, branched at O-2 mainly by side chains of 2-O-linked-alpha-Manp units was chemically sulfated, structurally characterized by NMR and GC-MS (methylation, desulfation and methylation with trideuterated iodomethane), and tested in vitro and in vivo on blood coagulation models. Chemical analyses indicate a high degree of substitution on the sulfated polysaccharide. This polymer acted as a procoagulant agent, increasing blood coagulation in normal and hemophilic plasma, activated platelet aggregation and also decreased ex vivo aPTT. Polymers such as the sulfated mannan could be a helpful source of hemostatic agents to prevent hemorrhagic states. PMID- 26572345 TI - Optimization extraction, characterization and antioxidant activities of pectic polysaccharide from tangerine peels. AB - Response surface methodology (RSM) was employed to optimize the microwave assisted extraction (MAE) process of pectic polysaccharide (TPPs) from tangerines peel. The optimal extraction conditions were as follows: microwave power 704 W, extraction temperature 52.2 degrees C, and extraction time 41.8 min Under these conditions, the experimental yield was 19.9 +/- 0.2%. The purified pectic polysaccharide TPPs-2-1 was successfully obtained by anion-exchange and gel filtration chromatography. TPPs-2-1, linked mainly by alpha-glycosidic bonds, consisted of galacturonic acid (GalA), arabinose (Ara), galactose (Gal), rhamnose (Rha), glucose (Glc) and mannose (Man) with the average molecular weight of 17.8 kDa, and had typical IR spectra characteristic of pectic polysaccharides. Antioxidant activities were investigated on the basis of ferric-reducing antioxidant power (FRAP), hydroxyl radical (OH), 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) and superoxide radical (O2(-)) scavenging assay. TPPs-2-1 exhibited significant antioxidant activity in a concentration-dependent manner and might be exploited as effective natural antioxidant applied in functional food and medicine. PMID- 26572346 TI - Using wastewater after lipid fermentation as substrate for bacterial cellulose production by Gluconacetobacter xylinus. AB - In this study, lipid fermentation wastewater (fermentation broth after separation with yeast biomass) with high Chemical Oxygen Demand (COD) value of 25,591 mg/L was used as substrate for bacterial cellulose (BC) production by Gluconacetobacter xylinus for the first time. After 5 days of fermentation, the highest BC yield (0.659 g/L) was obtained. Both monosaccharide and polysaccharides present in lipid fermentation wastewater could be utilized by G. xylinus simultaneously during fermentation. By this bioconversion, 30.0% of COD could be removed after 10 days of fermentation and the remaining wastewater could be used for further BC fermentation. The crystallinity of BC samples in lipid fermentation wastewater increased gradually during fermentation but overall the environment of lipid fermentation wastewater showed small influence on BC structure by comparison with that in traditional HS medium by using FE-SEM, FTIR, and XRD. By this work, the possibility of using lipid fermentation wastewater containing low value carbohydrate polymer (extracellular polysaccharides) for high value carbohydrate polymer (BC) production was proven. PMID- 26572347 TI - Effect of structural characteristics of corncob hemicelluloses fractionated by graded ethanol precipitation on furfural production. AB - In the present study, a graded ethanol precipitation technique was employed to obtain hemicelluloses from the alkali-extracted corncob liquid. The relationship between the structural characteristics of alkali-soluble corncob hemicelluloses and the production of furfural was investigated by a heterogeneous process in a biphasic system. Results showed that alkali-soluble corncob hemicelluloses mainly consisted of glucuronoarabinoxylans and L-arabino-(4-O-methylglucurono)-D-xylans, and the drying way had less influence on the sugar composition, molecular weights and the functional groups of hemicelluloses obtained by the different ethanol concentration precipitation except for the thermal property, the amorphous structure and the ability for the furfural production. Furthermore, alkali soluble corncob hemicelluloses with higher xylose content, lower branch degree, higher polydispersity and crystallinity contributed to the furfural production. A highest furfural yield of 45.41% with the xylose conversion efficiency of 99.06% and the furfural selectivity of 45.84% was obtained from the oven-dried hemicelluloses precipitated at the 30% (v/v) ethanol concentration. PMID- 26572348 TI - Evaluation of the effect of reprocessing on the structure and properties of low density polyethylene/thermoplastic starch blends. AB - The great quantity of synthetic plastic discarded inappropriately in the environment is forcing the search for materials that can be reprocessable and biodegradable. Blends between synthetic polymers and natural and biodegradable polymers can be good candidates of such novel materials because they can combine processability with biodegradation and the use of renewable raw materials. However, traditional polymers usually present high levels of recyclability and use the well-established recycling infrastructure that can eventually be affected by the introduction of systems containing natural polymers. Thus, this work aims to evaluate the effect of reprocessing (simulated here by multiple extrusions) on the structure and properties of a low density polyethylene/thermoplastic starch (LDPE/TPS) blend compared to LDPE. The results indicated that multiple extrusion steps led to a reduction in the average size of the starch-rich phases of LDPE/TPS blends and minor changes in the mechanical and rheological properties of the materials. Such results suggest that the LDPE/TPS blend presents similar reprocessability to the LDPE for the experimental conditions used. PMID- 26572349 TI - Amphiphilic graft copolymers with ethyl cellulose backbone: Synthesis, self assembly and tunable temperature-CO2 response. AB - Amphiphilic ethyl cellulose-graft-poly(N,N-dimethylaminoethyl methacrylate) (EC-g PDMAEMA) and ethyl cellulose-graft-poly(2-(2-methoxyethoxy)ethyl methacrylate-co N,N-dimethylaminoethyl methacrylate) (EC-g-P(MEO2MA-co-DMAEMA)) graft copolymers were easily synthesized by atom transfer radical polymerization (ATRP). The micelles self-assembled from the copolymer presented switchable temperature-CO2 dually responsive properties. The value of lower critical solution temperature (LCST) for the copolymer micelle solutions could be adjusted by CO2/Ar. Moreover, due to the alteration of the ratio of DMAEMA to MEO2MA, the LCST values of the micelle solutions decreased with the increase of MEO2MA in copolymer. The temperature-CO2 dually responsive properties of the copolymer were reversible and could be accomplished through altering the temperature and bubbling CO2/Ar. The hydrodynamic radius (Rh) of the copolymer micelles was also influenced by the ratio of DMAEMA to MEO2MA and the stimuli of temperature and CO2/Ar. As a drug release system, the copolymer micelles could achieve the control release of doxorubicin (DOX) by changing the temperature and alternatively bubbling CO2/Ar. PMID- 26572350 TI - Fluorescence study on the aggregation of collagen molecules in acid solution influenced by hydroxypropyl methylcellulose. AB - The effect of hydroxypropyl methylcellulose (HPMC) on the aggregation of collagen molecules with collagen concentrations of 0.25, 0.5 and 1.0mg/mL was studied by fluorescence techniques. On one hand, both the synchronous fluorescence spectra and fluorescence emission spectra showed that there was no change in the fluorescence intensity of collagen intrinsic fluorescence when 30% HPMC was added, while it decreased obviously when HPMC content >= 50%. From the two dimensional fluorescence correlation analysis, it was indicated that collagen molecules in 0.25 and 0.5mg/mL collagen solutions were more sensitive to HPMC than those in 1.0mg/mL collagen solution. On the other hand, the pyrene fluorescence and the fluorescence anisotropy measurements indicated that HPMC inhibited the collagen aggregation for 0.25 and 0.5mg/mL collagen, but promoted it for 1.0mg/mL collagen. The atomic force microscopy images further confirmed the effect of HPMC on collagen with different initial states. PMID- 26572351 TI - Tragacanth gum biopolymer as reducing and stabilizing agent in biosonosynthesis of urchin-like ZnO nanorod arrays: A low cytotoxic photocatalyst with antibacterial and antifungal properties. AB - Tragacanth, a natural gum, has been used for centuries as emulsifier, thickener, stabilizer and binder in various fields such as food, medical and cosmetic industries. In this study, Tragacanth gum was used as a clean and natural reducing and stabilizing agent for preparation of urchin-like ZnO nanorod arrays at low-temperature using ultrasonic irradiation. The morphology and structure of urchin-like ZnO nanorod arrays was investigated by XRD, FESEM images, EDX, UV-vis and FT-IR spectroscopy. The hexagonal zinc oxide nanorods were synthesized with the average diameter of 55-80 nm and length of 240 nm. The peak appeared in 447 cm(-1) in FTIR spectra and the peak around 362.3 nm in UV-vis spectra of ZnO nanorods confirmed the successful synthesis of ZnO nanorods. The urchin-like ZnO nanorod arrays indicated a good photocatalytic activity through degradation of methylene blue with 92.2% efficiency and rate constant of 0.0027 min(-1) at 120 min. Finally, the synthesized urchin-like ZnO nanorod arrays indicated 100% antibacterial activity against S. aureus and E. coli and 93% antifungal activity against C. albicans with a low cytotoxicity. PMID- 26572352 TI - Characterization of microstructure, viscoelasticity, heterogeneity and ergodicity in pectin-laponite-CTAB-calcium nanocomposite hydrogels. AB - In order to customize the viscoelastic properties of pectin gels, it is necessary to work on a composite platform. Herein, the gelation kinetics, and viscoelastic characterization of anionic polysaccharide pectin dispersion prepared in presence of nanoclay laponite are reported using dynamic light scattering and rheology measurements. The ratio Rg/Rh (Rg and Rh are radius of gyration and hydrodynamic radius respectively) determined from light scattering data revealed the presence of random coils of pectin chains inside the gel matrix. When nanoclay laponite was added to the pectin chains solution, two-phase separation was noticed instantaneously. Therefore, the surfactant cetyltrimethylammonium bromide [CTAB] was added to exfoliate the clay platelets in the dispersion, and also in its gel phase. The exfoliating agent cetyltrimethylammonium bromide ([CTAB]~ cmc/10) helped to enhance the homogeneity and stability of the pectin-clay sols and gels. The storage and loss moduli (G' and G") of the composite gel changed significantly as function of nanoclay laponite content for concentration up to 0.03% (w/v) causing the softening of the gels (gel strength reduced by close to 50%) compared to pectin-calcium gel. However, as the concentration of nanoclay laponite was maintained between 0.01% and 0.03% (w/v), the gel rigidity (G') recovered by 30% (35-45 Pa). The transition from ergodic to non-ergodic state occurred during sol-gel transition owing to the presence of the nanoclay laponite. The gelation time was not too different from the ergodicity breaking time. Thus, the presence of nanoclay laponite in such minute concentration is shown to cause considerable change in the thermo-physical property of the composite gels. This material property modulation will facilitate designing of soft gels having storage modulus continuously varying in the wide range of 10-70 Pa while keeping the gelation temperature mostly unaltered. PMID- 26572353 TI - Increased functional properties and thermal stability of flexible cellulose nanocrystal/ZnO films. AB - In this work we attempt to improve the functional properties and thermal stability of cellulose nanocrystal (CNC) films by means of eco-friendly materials and processes. Mechanically flexible films of closely packed CNCs with concentrations up to 5 wt.% of zinc oxide (ZnO) nanoparticles have been prepared by a simple, standard and environmentally friendly method using solely water. Results reveal that ultraviolet light is blocked by 98.5% at 1 wt.% ZnO while good transparency is maintained. A sharp hydrophobicity increase is observed with the addition of ZnO which would enhance the durability of films by decreasing the water diffusion through the material. The thermal degradation activation energy (E) presents an increase of 141%, denoting a high thermal stability of films, which would result beneficial for their potential application in the field of flexible electronics. Mechanical results demonstrate a high structural integrity of CNC/ZnO as a result of the occurring strong cellulosic inter- and intramolecular interactions within the closely packed CNC network. In overall, this work highlights the potential for environmentally friendly processing of sustainable nanostructured functional materials based on cellulose. PMID- 26572354 TI - Effects of ionic crosslinking on physical and mechanical properties of alginate mulching films. AB - The effect of different ionic crosslinking parameters on the thickness, radiometric profiles, and mechanical and water vapor permeation (WVP) properties of alginate mulching films was investigated. Crosslinking by Mn(2+), Zn(2+), and Ca(2+) (but not Al(3+)) increased the tensile strength and light transmission and decreased the WVP of the films. Among the films, those crosslinked by Ca(2+) had the greatest tensile strength and exhibited the highest elongation and light transmission. Furthermore, the WVP and light transmission decreased gradually with increasing Ca(2+) concentration, and the maximum tensile strength and elongation were obtained for 2% (w/v) of Ca(2+). However, the WVP of the films increased gradually with increasing crosslinking time, and the elongation saturated after 2 min. These results suggest that alginate films crosslinked by 2% (w/v) calcium chloride for 2 min had the best overall performance and therefore have the potential to be used as entirely biodegradable agricultural mulching films. PMID- 26572355 TI - Zinc chloride aqueous solution as a solvent for starch. AB - It is important to obtain starch-based homogeneous systems for starch modification. Regarding this, an important key point is to find cheap, low-cost and low-toxicity solvents to allow complete dissolution of starch and its easy regeneration. This study reveals that a ZnCl2 aqueous solution is a good non derivatizing solvent for starch at 50 degrees C, and can completely dissolve starch granules. The possible formation of a "zinc-starch complex" might account for the dissolution; and the degradation of starch, which was caused by the H(+) inZnCl2 aqueous solution, could not contribute to full dissolution. From polarized light microscopic observation combined with the solution turbidity results, it was found that the lowest ZnCl2 concentration for full dissolution was 29.6 wt.% at 50 degrees C, with the dissolving time being 4h. Using Fourier transform infrared (FTIR), solid state (13)C nuclear magnetic resonance (NMR), and X-ray diffraction (XRD), it was revealed that ZnCl2 solution had no chemical reaction with starch glucosides, but only weakened starch hydrogen bonding and converted the crystalline regions to amorphous regions. In addition, as shown by intrinsic viscosity and thermogravimetric analysis (TGA), ZnCl2 solution caused degradation of starch macromolecules, which was more serious with a higher concentration of ZnCl2 solution. PMID- 26572356 TI - Strategies for the production of high-content fructo-oligosaccharides through the removal of small saccharides by co-culture or successive fermentation with yeast. AB - Fructo-oligosaccharides (FOS) obtained by fermentation of sucrose may be purified at large-scale by continuous chromatography (Simulated Moving Bed: SMB). In order to improve the efficiency of the subsequent SMB purification, the optimization of the fermentative broth composition in salts and sugars was investigated. Fermentations conducted at reduced amount of salts, using Aureobasidium pullulans whole cells, yielded 0.63 +/- 0.03 g of FOS per gram of initial sucrose. Additionally, a microbial treatment was proposed to reduce the amount of small saccharides in the mixture. Two approaches were evaluated, namely a co-culture of A. pullulans with Saccharomyces cerevisiae; and a two-step fermentation in which FOS were first synthesized by A. pullulans and then the small saccharides were metabolized by S. cerevisiae. Assays were performed in 100mL shaken flasks and further scaled-up to a 3 L working volume bioreactor. Fermentations in two-step were found to be more efficient than the co-culture ones. FOS were obtained with a purity of 81.6 +/- 0.8% (w/w), on a dry weight basis, after the second-step fermentation with S. cerevisiae. The sucrose amount was reduced from 13.5 to 5.4% in total sugars, which suggests that FOS from this culture broth will be more efficiently separated by SMB. PMID- 26572357 TI - Synthesis of water dispersed nanoparticles from different polysaccharides and their application in drug release. AB - This work describes an original method to synthesize nanoparticles of starch (NPS), cellulose (NPC), and cellulose/hemicellulose (NPCH) from corn starch (S), microcrystalline cellulose (MCC) and hemp fibers (H), respectively. The synthesis is simply based on the treatment of the latter with trifluoroacetic acid. The resultant nanoparticles are easily dispersed in aqueous solutions. The size of these quasi-spherical particles, as measured by TEM and AFM, is less than 10nm. Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction analysis (XRD) of NPC revealed the loss of original cellulose crystallinity and formation of cellulose II structure after dispersion in water, while the structures of NPCH and NPS were found to be amorphous. Thermogravimetric analysis (TGA) results indicated that the resultant NPC and NPS undergo a two-step pyrolysis, whereas the unprocessed MCC and S undergo one-step pyrolysis. Curcumin was chosen as a model drug. As a model drug release system, NPS were found to release curcumin in a controlled way through a pH-dependent mechanism, with release capacity of about 43% and 65% of the original loaded curcumin under pH 7.4 and 1.2, respectively. PMID- 26572358 TI - Liquid-core nanocellulose-shell capsules with tunable oxygen permeability. AB - Encapsulation of oxygen sensitive components is important in several areas, including those in the food and pharmaceutical sectors, in order to improve shelf life (oxidation resistance). Neat nanocellulose films demonstrate outstanding oxygen barrier properties, and thus nanocellulose-based capsules are interesting from the perspective of enhanced protection from oxygen. Herein, two types of nanocellulose-based capsules with liquid hexadecane cores were successfully prepared; a primary nanocellulose polyurea-urethane capsule (diameter: 1.66 MUm) and a bigger aggregate capsule (diameter: 8.3 MUm) containing several primary capsules in a nanocellulose matrix. To quantify oxygen permeation through the capsule walls, an oxygen-sensitive spin probe was dissolved within the liquid hexadecane core, allowing non-invasive measurements (spin-probe oximetry, electron spin resonance, ESR) of the oxygen concentration within the core. It was observed that the oxygen uptake rate was significantly reduced for both capsule types compared to a neat hexadecane solution containing the spin-probe, i.e. the slope of the non-steady state part of the ESR-curve was approximately one-third and one-ninth for the primary nanocellulose capsule and aggregated capsule, respectively, compared to that for the hexadecane sample. The transport of oxygen was modeled mathematically and by fitting to the experimental data, the oxygen diffusion coefficients of the capsule wall was determined. These values were, however, lower than expected and one plausible reason for this was that the ESR technique underestimate the true oxygen uptake rate in the present systems at non steady conditions, when the overall diffusion of oxygen was very slow. PMID- 26572359 TI - Dual pH and temperature responsive hydrogels based on beta-cyclodextrin derivatives for atorvastatin delivery. AB - 2-Methylacrylic acid modified beta-cyclodextrin was copolymerized with 2 methylacrylic acid and N,N'-methylene diacrylamide to fabricate dual pH and temperature responsive hydrogels for the controlled release of atorvastatin. The swelling behaviors, pH and temperature responsive atorvastatin release profiles of the hydrogels were investigated. The results indicated that the hydrogel prepared in DMSO exhibited the best swelling rate, which was 51 for 10 min and 252 for 16 h when immersed in medium of buffer solution with pH=8.06. The media with low (pH <= 3.84) and high (pH >= 10.34) pH values would reduce the swelling rate of hydrogels. The swelling of the hydrogel was increased with increasing temperature from 30 degrees C to 45 degrees C. Atorvastatin was loaded in the hydrogel for drug release investigation. The cumulative release rate of atorvastatin was as high as 90.5% in pH=8.06 buffer solution. The solubility of atorvastatin was improved from 0.13 to 1.2mg/mL in the hydrogel. PMID- 26572360 TI - Investigation of gelling behavior of thiolated chitosan in alkaline condition and its application in stent coating. AB - The gelling behaviors of thiolated chitosan (TCS) in alkaline condition were investigated. Thioglycolic acid was conjugated onto chitosan backbone through amide bond formation. The variations of thiol group content were monitored in presence of H2O2 or different pH values (pH 7.0, 8.0, 9.0) in dialysis mode. Different from the decreasing thiol group content upon time in acidic condition, increasing amount of thiol groups was detected in alkaline pH during 120 min dialysis attributed to alkaline hydrolysis of intra-molecular disulfide bonds. The extent of which was larger at higher pH values. Higher degree of thiolation, thiomer concentration or pH values promoted gelation of TCS. Entanglement and coagulation of chitosan molecule chains and re-arrangement of disulfide bonds acted closely and dynamically in the gelation process. Disulfide bonds, especially inter-molecular type, are formed by synergetic effects of thiol/disulfide interchange and thiol/thiol oxidation reactions. TCS coated vascular stent displayed wave-like microstructure of parallel ridges and grooves, which favored HUVECs adhesion and proliferation. The biocompatibility, peculiar morphology and thiol moieties of TCS as stent coating material appear application potential for vascular stent. PMID- 26572361 TI - Stepwise ethanolic precipitation of sugar beet pectins from the acidic extract. AB - A stepwise ethanol-precipitation (SEP) procedure was developed for the purification of sugar beet pectins (SBP) from a pectin-containing aqueous extract. Five fractions of different chemical and molecular characteristics were produced by stepwise elevating the alcohol concentration of the precipitation medium from 50% to 80% v/v. Comparison of chemical and macromolecular features between the obtained fractions indirectly suggested that the ability of pectin to solubilize in the ethanol-water binary mixture depended greatly on the polymer structure. Fractions rich in neutral sugars were precipitated at relatively high ethanol concentrations, probably due to the enhanced interactions generated between pectin side chains and solvent molecules. Furthermore, the obtained fractions displayed different surface activities. Results obtained in this work indicate that the SEP procedure is more selective with respect to pectin structural features and surface properties than the one-step ethanolic precipitation. PMID- 26572362 TI - Electrospun cellulose acetate supported Ag@AgCl composites with facet-dependent photocatalytic properties on degradation of organic dyes under visible-light irradiation. AB - Electrospun cellulose acetate (CA) membrane was employed as a support that provided sites for AgCl crystals in situ growth. The Ag@AgCl crystals on electrospun CA composites with exposed {100} and {111} facets were fabricated at room temperature by a double diffusion technique. The crystal structure, morphology, composition, and absorption light ability of CA supported Ag@AgCl were characterized utilizing X-ray powder diffraction (XRD), scanning electron microscopy (SEM), attenuated total reflection-infrared intensity (ATR-IR), X-ray photoelectron spectroscopy measurements (XPS), energy dispersive spectrometer (EDS) and ultraviolet-visible (UV-vis) diffuse reflectance spectra, respectively. The photocatalytic activity of the catalysts was evaluated using methyl orange (MO) as a target. The CA supported cubic Ag@AgCl catalyst exhibited much higher catalytic activity than octahedral catalyst in terms of the degradation of MO under visible light. The 10mg CA based cubes could completely degrade MO (10 mg L(-1)) in 160 min. The photocatalyst still exhibited a good catalytic ability after three times. PMID- 26572363 TI - Adsorption properties of cross-linked cellulose-epichlorohydrin polymers in aqueous solution. AB - Cellulose was cross-linked with epichlorohydrin (EP) at variable levels (CLE-0.5, CLE-2 and CLE-4), where CLE-i denotes the cellulose to EP mole ratios. The cross linked products were characterized by TGA and FT-IR spectroscopy, pH at the point of zero charge (pHpzc), water swelling, and dye-adsorption methods employing two types of dyes [phenolphthalein (phth) and p-nitrophenol (PNP)]. The characterization methods provide evidence of cross-linking of cellulose in accordance with variations in surface area, PZC, available surface hydroxyl groups, and thermal stability when compared against pristine cellulose. The pHpzc of the sorbent materials was ~ 6.5 indicating a negative surface charge occurs above pHpzc. The cross-linked polymers possess greater swelling properties relative to pristine cellulose. Detailed adsorption studies were carried out at pH 9 for cellulose and CLE-i with five types single component carboxylate anions [2-hexyldecanoic acid (S1), trans-4-pentylcyclohexanecarboxylic acid (S2), 2 dicyclohexylacetic acid (S3), adamantane carboxylic acid (S4), and cyclohexane carboxylic acid (S5)] at 295 K. The uptake properties of PNP with cellulose and CLE-i were also compared at pH 5 and 9, respectively. CLE-2 had the highest uptake of PNP (Qm=1.22 * 10(-1)mmol/g, pH 9) and S1 (Qm=4.27 mg/g) while cellulose and CLE-4 had the strongest binding affinity (1.43 L/mmol and 5.90 * 10(-2)L/mg), respectively. Uptake of PNP by CLE-0.5 at pH 5 (Q m=5.30 * 10( 2)mmol/g) was higher than uptake at pH 9 (Qm=3.11 * 10(-2)mmol/g). Sorption of CLE-4 with S1, S2 and S3 showed that relative uptake of the surrogates had the following order: S3>S2>S1, where S2 had the strongest binding affinity to CLE-i. CLE-2 had the highest sorption capacity towards Si in an equimolar mixture with evidence of molecular selective uptake. At pH 9, low uptake was mainly related to electrostatic repulsion between the negatively charged sorbent surface and the carboxylate head groups of Si. PMID- 26572364 TI - Preparation of uniform starch microcapsules by premix membrane emulsion for controlled release of avermectin. AB - In recent years, starch microparticles have gained interest in many fields. However, low production, uncontrollable size, and varying size distribution hinder their practical application. Here, we adopt a premix membrane emulsification (PME) method to prepare starch microcapsules at high production rates. The process conditions were optimized to fabricate uniform microcapsules with controllable sizes and narrow size distribution (PDI<0.1). Through encapsulating avermectin (Av), a kind of water-insoluble pesticide, into the shell of the microcapsules in situ during the process, we developed a pesticide delivery system that enabled a controlled and consistent release of Av over a period of 2 weeks. Kinetic analysis indicated that the mechanisms of Av release involved non-Fickian and Case-II transport. The diameters (0.70-4.8 MUm) of the microcapsules and Av contents (16-47%) were adjusted to achieve suitable release profiles. The results will lay the foundation for further field experiments. PMID- 26572365 TI - Electron paramagnetic resonance study of hydrogen peroxide/ascorbic acid ratio as initiator redox pair in the inulin-gallic acid molecular grafting reaction. AB - Gallic acid (GA) was grafted onto inulin using the free radicals method, generated by the hydrogen peroxide/ascorbic acid (H2O2/AA) redox pair. Molar ratios of H2O2/AA at 9, 20, 39 and 49 were evaluated by Electron Paramagnetic Resonance in order to find the effect of the oxidation of the inulin and the efficiency in the inulin-gallic acid grafting (IGA). The highest concentration of the inulin macro-radical was obtained with H2O2/AA molar ratios of 20 and 49 with the removal of a hydrogen atom from a methyl group of the inulin fructose monomers. The highest grafting ratio (30.4 mg GA eq/g IGA) was obtained at 9 M of H2O2/AA. UV-Vis, FT-IR-ATR and XDR results confirmed a successful IGA grafting. The efficiency of the grafting reaction depends on the concentration of the macro radical, it depends on the molar ratio of H2O2/AA, being affected by simultaneous reactions between components of the mixture (H2O2, AA, inulin, GA and eventually atmospheric oxygen) as well. PMID- 26572366 TI - Mushroom heteropolysaccharides: A review on their sources, structure and biological effects. AB - Mushrooms have been largely studied not only by their d-glucans, but also because they present a class of more complex polymers: the heteropolysaccharides. Heteropolysaccharides show variability on their monosaccharide composition, anomeric configuration, linkage and branching type, besides some of these molecules can present natural methylated monosaccharides and also acid monosaccharides, which enhance the difficulty of the purification and characterization of their structure. As a result of such complexity, mushroom heteropolysaccharides can be considered an interesting source of molecules with medicinal and industrial applications. Consequently a plenty of new researches has been published in the past 12 years about the isolation, chemical characterization and biological activities of heteropolysaccharides from mushrooms, especially from Basidiomycetes. Therefore, this review intends to organize and classify the information described up to now about such polysaccharides obtained from different sources of mushroom-forming fungi, Basidiomycetes, Ascomycetes and Hybrid mushrooms, and provides a brief reflection on how the chemical studies have been carried out. PMID- 26572367 TI - Monosaccharide compositions of sulfated chitosans obtained by analysis of nitrous acid degraded and pyrazolone-labeled products. AB - Chemically sulfated chitosans are important biomaterials. However, a reliable analytical method for quality control over such compounds is still lacking. In this study, we prepared four different kinds of selectively sulfated chitosans and developed a novel method to analyze their monosaccharide compositions by HPLC. In this method, nitrous acid was used to generate 2, 5-hydro mannose (M), 3 O-sulfated M (M3), 6-O-sulfated M (M6), and 3, 6-O-disulfated M (M9) from the sulfated chitosans. PMP, that is 1-phenyl-3-methyl-5-pyrazolone with a UV absorbance at 245 nm, was used to label all the Ms quantitatively. The monosaccharide compositions for each sulfated chitosan were obtained by C18 HPLC separation and online UV detection of all PMP-labeled Ms. The identities of all Ms were confirmed by MS analysis with the help of standard Ms generated from a heparin pentasaccharide and chitosan. The overall results indicated that the newly developed method had advantages over (13)C NMR in defining the monosaccharide compositions of sulfated chitosans and was useful for quality control purpose. PMID- 26572368 TI - Inhibitory effect of xanthan gum and synergistic surfactant additives for mild steel corrosion in 1M HCl. AB - Natural polymer xanthan gum (XG) was investigated as eco friendly corrosion inhibitor for mild steel in 1M HCl at 30 degrees C, 40 degrees C, 50 degrees C and 60 degrees C, respectively. The inhibition studies were performed using gravimetric analysis, potentiodynamic polarization, electrochemical impedance spectroscopy (EIS), quantum chemical calculations, scanning electron microscopy (SEM), and UV-visible spectrophotometry. XG significantly reduces the corrosion rates of mild steel. The inhibition efficiency (IE) of the XG increased with increase in concentration, but decreased with temperature; the maximum IE of 74.24% was obtained at concentration of 1000 ppm at 30 degrees C. The inhibiting action of XG is synergistically enhanced on addition of very small amount of surfactants sodium dodecyl sulfate (SDS), cetyl pyridinium chloride (CPC) and Triton X-100 (TX). The effect of SDS is more pronounced than other surfactants. Potentiodynamic polarization studies confirm XG as a mixed type inhibitor. Results of weight loss measurements are in good agreement of the results of electrochemical measurements. The UV-visible spectroscopic results indicate the formation of complex between XG and Fe(2+) ions during corrosion reaction. Mechanism of inhibition was also investigated by calculating the thermodynamic and activation parameters like DeltaG(0), Ea, DeltaH and DeltaS. The adsorption of inhibitor on mild steel surface obeys Langmuir adsorption isotherm. SEM micrographs show a clearly different morphology in presence of XG and XG surfactant additives and confirmed the existence of an adsorbed protective film on the mild steel surface. PMID- 26572369 TI - Preparation and characterization of corn starch-beta-carotene composites. AB - Starch-beta-carotene composites were generated by drop-wise addition of ethanol comprising varying beta-carotene contents (5, 10, or 20mg) into starch pastes (1, 3, or 5% w/v) to improve water-dispersibility and stability of beta-carotene. The mean diameter of the composites was less than 900 nm, allowing particles to be homogeneously dispersed in aqueous media for over two weeks without sedimentation. X-ray diffraction and differential scanning calorimetry analysis confirmed the composite mainly consisted of Vh-amylose, amorphous starch matrices, and starch-beta-carotene ordered structures. Both amorphous matrices and Vh-amylose structures in the composite were readily digested within 20 min in vitro digestion, while highly ordered structures, which melted between 132 and 159 degrees C, exhibited inhibited and/or delayed enzymatic digestion. As more beta-carotene was incorporated into the composite, the beta-carotene content of the ordered structure was increased. Formation of starch-beta-carotene composites also appeared to enhance the stability of beta-carotene against chemical oxidation. PMID- 26572370 TI - Simultaneous bench scale production of dissolving grade pulp and valuable hemicelluloses from softwood kraft pulp by ionic liquid extraction. AB - Ionic liquid extraction of wood pulp has been highlighted as a highly potential new process for dissolving pulp production. Coproduction with a polymeric hemicellulose fraction was demonstrated in bench scale from softwood kraft pulp using extraction with the ionic liquid 1-ethyl-3-methylimidazolium acetate (EMIM OAc) and water. In total, the recovered pulp and hemicellulose fraction together yielded 95.5 wt.% of the pulp input. The extracted pulp had a remarkably high purity with an R18-value of 97.8%. The hemicellulose fraction consisted of galactoglucomannan, arabinoxylan and some cellulose and was precipitated from the ionic liquid-water mixture. After hydroxypropylation of the hemicellulose fraction, films were prepared and barrier and strength properties were compared to films from other polysaccharides. Reduced oxygen and water vapor permeation and good strength properties were demonstrated when compared to corresponding films from hydroxypropylated xylan from cold caustic extraction. The films have potential for applications in food packaging and edible films. PMID- 26572371 TI - Near-infrared chemical imaging and its correlation with the mechanical properties of chitosan-gelatin edible films. AB - Plasticizers influence the physical properties of edible films by their interaction with the film-forming polymers. Using near-infrared chemical imaging, it is possible to characterize the interaction between compounds through the analysis of their relative presence throughout the film (abundance) and their variability. These parameters and standard mechanical properties were used to characterize the interaction between gelatin, chitosan and several plasticizers, pure or in binary combinations. Triacetin showed the least interaction with the polymers, while polyethylene glycol 400 and glycerol showed high interaction with them. In addition, we observed that the tensile strength of the film was well correlated with the variability of gelatin and chitosan. PMID- 26572372 TI - A silver complex of hyaluronan-lipoate (SHLS12): Synthesis, characterization and biological properties. AB - In this study we present a novel silver complex of hyaluronan-lipoate (SHLS12) in a gel-state form. NMR analysis, conductometry and elemental analysis demonstrated stable non-covalent interactions between silver ions and the polysaccharide lipoate backbone, whereas rheological investigations confirmed its gel-like physical-chemical behavior. Biological studies showed the ability of SHLS12 to exert a straightforward activity against different bacterial strains grown in sessile/planktonic state. The biocompatibility was also proved toward two eukaryotic cell lines. By considering both its ability to preserve antibacterial properties when exposed to the serum protein BSA and its low susceptibility to be degraded by hyaluronidase enzyme, this novel complex may be considered as a promising biomaterial for future in vivo applications. PMID- 26572373 TI - Development of a fermented ice-cream as influenced by in situ exopolysaccharide production: Rheological, molecular, microstructural and sensory characterization. AB - This study aimed to investigate the role of in situ exopolysaccharide (EPS) production by EPS(+)Streptococcus thermophilus strains on physicochemical, rheological, molecular, microstructural and sensory properties of ice cream in order to develop a fermented and consequently functional ice-cream in which no stabilizers would be required in ice-cream production. For this purpose, the effect of EPS producing strains (control, strain 1, strain 2 and mixture) and fermentation conditions (fermentation temperature; 32, 37 and 42 degrees C and time; 2, 3 and 4h) on pH, S. thermophilus count, EPS amount, consistency coefficient (K), and apparent viscosity (eta50) were investigated and optimized using single and multiple response optimization tools of response surface methodology. Optimization analyses indicated that functional ice-cream should be fermented with strain 1 or strain mixture at 40-42 degrees C for 4h in order to produce the most viscous ice-cream with maximum EPS content. Optimization analysis results also revealed that strain specific conditions appeared to be more effective factor on in situ EPS production amount, K and eta50 parameters than did fermentation temperature and time. The rheological analysis of the ice cream produced by EPS(+) strains revealed its high viscous and pseudoplastic non Newtonian fluid behavior, which demonstrates potential of S. thermophilus EPS as thickening and gelling agent in dairy industry. FTIR analysis proved that the EPS in ice-cream corresponded to a typical EPS, as revealed by the presence of carboxyl, hydroxyl and amide groups with additional alpha-glycosidic linkages. SEM studies demonstrated that it had a web-like compact microstructure with pores in ice-cream, revealing its application possibility in dairy products to improve their rheological properties. PMID- 26572374 TI - Effect of different polyol-based plasticizers on thermal properties of polyvinyl alcohol:starch blends. AB - A series of gelatinized polyvinyl alcohol (PVA):starch blends were prepared with various polyol-based plasticizers in 5 wt%, 15 wt% and 25 wt% ratios via solution casting method. The obtained films were analyzed by Fourier transform infrared (FT-IR) spectroscopy, differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Remarkable changes have been observed in glass transition temperature (Tg) and thermal stability of the samples containing varying concentrations of different plasticizers and they have been discussed in detail with respect to the conducted thermal and chemical analyses. The observed order of Tg point depression of the samples containing 15 wt% plasticizer is 1,4 butanediol - 1,2,6-hexanetriol--pentaerythriyol--xylitol--mannitol, which is similar to the sequence of the thermal stability changes of the samples. PMID- 26572375 TI - Phase diagrams of hybrid carrageenans extracted from Ahnfeltiopsis devoniensis and Chondrus crispus. AB - NaCl and KCl phase diagrams of two kappa/iota-hybrid carrageenans (KI) are established, and the rheological properties of obtained solutions and gels are reported. KI were extracted from Ahnfeltiopsis devoniensis and Chondrus crispus seaweeds and showed different chemical composition, 48 mol% of kappa carrageenan (K) and 52 mol% of iota carrageenan (I), and 78 mol% of K and 22 mol% of I, respectively. Phase diagrams are systematically compared those of blends of commercial K and I (K+I) showing equivalent chemical compositions. Results confirm that KI clearly differ from mixtures of K and I. K+I form gels at lower polysaccharide concentration and ionic strength, and exhibit gel separation from a liquid phase when large amount (>0.1 mol/L) of KCl is used. In contrast, no syneresis was found in KI gels formed under similar conditions. Both KI and K+I gels are strain hardening, and show a concentration scaling of the elasticity with exponents ranging from 1.1 to 3.2 depending on the type of salt and ionic strength. The strain at break of KI gels does not show salt specificity and is similar to the strain at break of K+I gels in KCl under similar salt and polysaccharide concentrations. K+I gels in NaCl are more fragile than in KCl, thus showing salt specificity. PMID- 26572376 TI - Deconstruction of Nordic hardwood in switchable ionic liquids and acylation of the dissolved cellulose. AB - Nordic hardwood (Betula pendula) was fractionated in a batch autoclave equipped with a custom-made SpinChem((r)) rotating bed reactor, at 120 degrees C using CO2 and CS2-based switchable ionic liquids systems. Analyses of the non-dissolved wood after treatment showed that 64 wt% of hemicelluloses and 70 wt% of lignin were removed from the native wood. Long processing periods or successive short time treatments using fresh SILs further decreased the amount of hemicelluloses and lignin in the non-dissolved fraction to 12 and 15 wt%, respectively. The cellulose-rich fraction was partially dissolved in an organic superbase and an ionic liquid system for further derivatization. Homogeneous acylation of the dissolved cellulose in the presence or absence of catalyst resulted in cellulose acetates with variable degree of substitution (DS), depending on the treatment conditions. By varying the reaction conditions, the cellulose acetate with the desired DS could be obtained under mild conditions. PMID- 26572377 TI - Assessment of the bifidogenic effect of substituted xylo-oligosaccharides obtained from corn straw. AB - This work evaluates the bifidogenic potential of substituted xylo oligosaccharides (XOS) obtained from a lignocellulosic feedstock (corn straw). Autohydrolysis was used to selectively hydrolyse the xylan-rich hemicellulosic fraction and the soluble oligosaccharides were purified by gel filtration chromatography. Selected oligosaccharides fractions within the target ranges of polymerization degree (4-6 and 9-21, samples S1 and S2, respectively) were characterized and their bifidogenic potential was investigated by in vitro fermentations using human fecal inocula. Bacterial growth was assessed by fluorescent in situ hybridization (FISH). XOS consumption and short-chain fatty acids (SCFA) production were evaluated and compared with commercial oligosaccharides. Under the tested conditions, all the substrates were utilized by the microbiota, and fermentation resulted in increased bifidobacteria populations. Samples S1 and S2 increased bifidobacteria populations and the production profile of SCFA was similar for XOS samples and commercial oligosaccharides although XOS samples displayed the highest concentration of SCFA on longer fermentation times. PMID- 26572378 TI - Regioselective synthesis of cationic 6-deoxy-6-(N,N,N-trialkylammonio)curdlan derivatives. AB - Curdlan, a bioactive beta-1,3-glucan, is of intense interest for pharmaceutical and biomedical applications. Cationic derivatives of curdlan and other polysaccharides are especially attractive for their potential to interact in controlled fashion with proteins, among many other possible applications, but relatively few methods exist for their synthesis. Herein we report a regioselective method for preparation of cationic, water-soluble 6-(N,N,N trialkylammonio)-6-deoxycurdlan salts by reaction of 6-bromo-6-deoxycurdlan and its 2,4-O-diesters with trialkylamines. Dimethyl sulfoxide was identified as the optimal solvent for this nucleophilic displacement to produce cationic curdlan derivatives (80 degrees C, 24h), providing maximum degree of triethylammonium substitution (DS) of 0.89, exclusively at the C-6 position. 6-Bromo-6 deoxycurdlan was also reacted with heterocyclic amines such as pyridine and imidazole, providing ammonium-substituted curdlan derivatives with substantial DS (0.66 and 0.86, respectively). The new combination of regioselective Furuhata bromination and bromine displacement under optimized conditions with tertiary amines provides access to quaternized curdlan derivatives that possess high, permanent positive charge and are readily water-soluble, properties that indicate potential application promise including for mucoadhesion, permeation enhancement, and delivery of genes and anionic drugs. Regioselectivity and DS of those curdlan ammonium derivatives were quantified by means of (1)H NMR, (13)C NMR and FTIR spectroscopic methods and by elemental analysis. PMID- 26572379 TI - Preparation of highly charged cellulose nanofibrils using high-pressure homogenization coupled with strong acid hydrolysis pretreatments. AB - Cellulose nanofibrils (CNFs) are attracting much attention for the advantages of excellent mechanical strength, good optical transparency, and high surface area. An eco-friendly and energy-saving method was created in this work to produce highly negative charged CNFs using high-pressure mechanical defibrillation coupled with strong acid hydrolysis pretreatments. The morphological development, zeta potential, crystal structure, chemical composition and thermal degradation behavior of the resultant materials were evaluated by transmission electron microscopy (TEM), zeta potential analysis, X-ray diffraction (XRD), Fourier transform infrared spectrometry (FTIR), and thermogravimetric analysis (TGA). These CNFs were fully separated, surface-charged, and highly entangled. They showed a large fiber aspect ratio compared to traditional cellulose nanocrystrals that are produced by strong acid hydrolysis. Compared to hydrochloric acid hydrolysis, the CNFs produced by sulfuric acid pretreatments were completely defibrillated and presented stable suspensions (or gels) even at low fiber content. On the other hand, CNFs pretreated by hydrochloric acid hydrolysis trended to aggregate because of the absence of surface charge. The crystallinity index (CI) of CNFs decreased because of mechanical defibrillation, and then increased dramatically with increased sulfuric acid concentration and reaction time. FTIR analysis showed that the C-O-SO3 group was introduced on the surfaces of CNFs during sulfuric acid hydrolysis. These sulfate groups accelerated the thermal degradation of CNFs, which occurred at lower temperature than wood pulp, indicating that the thermal stability of sulfuric acid hydrolyzed CNFs was decreased. The temperature of the maximum decomposition rate (Tmax) and the maximum weight-loss rates (MWLRmax) were much lower than for wood pulp because of the retardant effect of sulfuric acid during the combustion of CNFs. By contrast, the CNFs treated with hydrochloric acid had better thermal stability, because no functional groups were introduced on the surface. PMID- 26572380 TI - Study on the sorption process of triclosan on cationic microfibrillated cellulose and its antibacterial activity. AB - Cationic microfibrillated cellulose (CMFC), as one kind of cellulose-based materials, is widely used in many fields. In this work, it was functionalized with a traditional antibacterial agent (triclosan, TCS). The sorption process of TCS onto CMFC was expressed by kinetic and isotherm models. The results showed that there was a high correlation coefficient (R(2)>0.9) in the pseudo-second order model and the isotherm models, indicating that CMFC had a good sorption capacity for TCS. The sorption type was chemisorption, and the reaction power was electrostatic interactions. The antibacterial activity of the assembled TCS/CMFC compound was tested by disk diffusion method, and it was found a higher antibacterial activity than CMFC alone (bigger inhibition zone diameters). Further, the functionalized TCS/CMFC compound was used in the fiber network during handsheets making, and it had a higher antibacterial rate than TCS alone (increase by 45.1% against Escherichia coli and by 54.8% against Staphylococcus aureus, respectively). PMID- 26572381 TI - Microcrystalline cellulose-carboxymethyl cellulose sodium as an effective dispersant for drug nanocrystals: A case study. AB - This study is aimed at seeking an alternative dispersant for spray drying of drug nanosuspensions. The ideal dispersant is not only able to prevent the agglomeration of drug nanocrystals in the suspension state, but also it is able to preserve redispersibility of drug nanocrystals after drying. An active pharmaceutical ingredient (API) was used as a model drug. API nanosuspensions were prepared by homogenization and converted into nanocrystals powder (API-NP) with microcrystalline cellulose-carboxymethyl cellulose sodium (MCCS) via spray drying. It was found that MCCS was able to prevent the aggregation of API-NP in the suspension state and the agglomeration during spray-drying process, possibility due to its high Zeta potential and steric barrier from network structure, and reduction of API size at nanoscale and incorporation into MCCS network structure did not affect the solid state of API as evidenced by DSC and XRD analysis. The spray-dried API-NP/MCCS powders exhibited excellent sphere shape performance, and could easily redispersed to API-NC suspensions state. Dissolution of the spray-dried API-NP was distinctly superior to those of the crude powder and physical mixture, respectively. Within 30 min, approximate 85.87% of API was dissolved from the API-NP/MCCS. MCCS was demonstrated to be an effective dispersant for spray-dried drug nanocrystals and preservation of the nanocrystals associated with excellent redispersibility. PMID- 26572382 TI - Equilibrium and kinetic models on the adsorption of Reactive Black 5 from aqueous solution using Eichhornia crassipes/chitosan composite. AB - New natural biopolymer composite was prepared using extracted cellulose from an environmentally problematic water hyacinth Eichhornia crassipes (EC). The extracted cellulose was functionalized by chitosan and TiO2 nanoparticles to form EC/Chitosan (EC/Cs) composite network. Surface characterization of EC/Cs natural biopolymer composite was examined by spectrum analysis FT-IR, specific surface area, micropore volume, pore width and SEM. Furthermore, the sorption experiments were carried out as a function of pH, various initial dye concentration and contact time. Experiment results showed that the EC/Cs composite have high ability to remove C.I. Reactive Black 5 from its dye-bath effluent. The equilibrium sorption evaluation of RB5 conformed and fitted well to Langmuir adsorption isotherm models and the maximum sorption capacity was 0.606 mg/g. The kinetic adsorption models followed pseudo-second order model and the dye intra particle diffusion may suggesting a chemical reaction mechanism. Further, it was obvious from the investigation that this composite could be applied as a promising low cost adsorbent for anionic dye removal from aqueous solutions. PMID- 26572383 TI - Characterization and biocompatibility of injectable microspheres-loaded hydrogel for methotrexate delivery. AB - Injectable thermosensitive hydrogels have widely been studied as drug delivery systems for their minimally invasive administration and localized drug release. However, burst drug release limits clinical applications of such hydrogels. A double-component injectable formulation (microspheres-loaded hydrogel, CMs-CS-HG) was thus fabricated to eliminate the limitation. Gelation temperature, gelation time, complex viscosity and syringeability tests for CMs-CS-HG demonstrated excellent injectability. After injection, the drug-loaded chitosan-based microspheres (CMs) were localized within the hydrogel, leading to localized drug release. Moreover, CMs-CS-HG had good hemocompatibility and histocompatibility, and had non-genotoxicity and non-cytotoxicity to Kunming mice. In addition, both in vitro and in vivo methotrexate (MTX) releasing efficiencies were evaluated, demonstrating long-term sustained MTX release from MTX-loaded CMs-CS-HG. These results showed the double-component CMs-CS-HG not only maintained good injectability and biocompatibility but also prolonged drug-releasing time in comparison with the single-component CS-HG or CMs, suggesting that CMs-CS-HG may be a promising drug delivery system. PMID- 26572384 TI - Regioselective sulfation of Artemisia sphaerocephala polysaccharide: Solution conformation and antioxidant activities in vitro. AB - Regioselective modification is an effective approach to synthesize polysaccharides with different structure features and improved properties. In this study, regioselective sulfation of Artemisia sphaerocephala polysaccharide (SRSASP) was prepared by using triphenylchloromethane (TrCl) as protecting precursor. The decrease in fractal dimension (df) values (1.56-2.04) of SRSASP was observed in size-exclusion chromatography combined with multi angle laser light scattering (SEC-MALLS) analysis. Compared to sample substituted at C-6, SRSASP showed a more expanded conformation of random coil, which was attributed to the breakup of hydrogen bonds and elastic contributions. Circular dichroism (CD), methylene blue (MB) and congo red (CR) spectrophotometric method and atomic force microscopy (AFM) results confirmed the conformational transition and stiffness of the chains after sulfation. SRSASP exhibited enhanced antioxidant activities in the DPPH, superoxide and hydroxyl radical scavenging assay. Sulfation at C-2 or C-3 was favorable for the chelation which might prevent the generation of hydroxyl radicals. It concluded that the degree of substitution and substitution position were the factors influencing biological activities of sulfated polysaccharides. PMID- 26572385 TI - Formulation of mucoadhesive gastric retentive drug delivery using thiolated xyloglucan. AB - Tamarind seed xyloglucan is a polymer reported to possess mucoadhesive property. In the present work, role of cysteine derivative of tamarind seed polysaccharide (thiomer) to enhance the mucoadhesion and its influence on drug permeation has been studied. The xyloglucan was first chemically modified to carboxymethyl derivative which was further converted to thiomer by conjugation with cysteine in presence of a coupling agent, EDAC. The matrix tablets of simvastatin prepared using thiomer demonstrated drug release retardation, increased mucoadhesion force and increased ex vivo permeation, the same were proportional to the increase in the amount of thiomer. The in vivo residence of thiomer placebo was more than 7h in rabbit. Pharmacokinetic evaluation in rabbits indicated higher AUC for the formulation with highest content of thiomer and level 'A' correlation could be established from the generated dissolution and bioavailability data. PMID- 26572386 TI - Preparation of novel stable antibacterial nanoparticles using hydroxyethylcellulose and application in paper. AB - Taking advantage of the self-assembly between the components, novel stable antibacterial nanoparticles were efficiently fabricated via a facile one-step co polymerization of acrylic acid (AA) and N,N'-methylenebisacrylamide (MBA) on a mixed aqueous solution of poly(hexamethylene guanidine hydrochloride) (PHMG) and hydroxyethylcellulose (HEC). The z-average hydrodynamic diameters of the nanoparticles ranged from 220 nm to 450 nm. The inner layer of the nanoparticles is composed of water-insoluble interpolymer complexes of PHMG and PAA networks, while the outer layer is composed of PHMG and HEC. The nanoparticles are stabilized by electrostatic interactions, hydrogen bonding interactions, and the chemical bonds. The nanoparticle solution remained stable in a wide pH range of 2.0-12.0 and at salt concentrations below 0.25 mol/L. The nanoparticles were incorporated into handsheets using a dipping treatment. The resulted handsheets exhibited excellent antimicrobial activities even after multiple water washing treatments. The nanoparticles are promising in fabricating paper, water-based coatings and textiles with permanent antibacterial activity. PMID- 26572387 TI - Conjugation of silica nanoparticles with cellulose acetate/polyethylene glycol 300 membrane for reverse osmosis using MgSO4 solution. AB - Thermally-induced phase separation (TIPS) method was used to synthesize polymer matrix (PM) membranes for reverse osmosis from cellulose acetate/polyethylene glycol (CA/PEG300) conjugated with silica nanoparticles (SNPs). Experimental data showed that the conjugation of SNPs changed the surface properties as dense and asymmetric composite structure. The results were explicitly determined by the permeability flux and salt rejection efficiency of the PM-SNPs membranes. The effect of SNPs conjugation on MgSO4 salt rejection was more significant in magnitude than on permeation flux i.e. 2.38 L/m(2)h. FTIR verified that SNPs were successfully conjugated on the surface of PM membrane. DSC of PM-SNPs shows an improved Tg from 76.2 to 101.8 degrees C for PM and PM-S4 respectively. Thermal stability of the PM-SNPs membranes was observed by TGA which was significantly enhanced with the conjugation of SNPs. The micrographs of SEM and AFM showed the morphological changes and increase in the valley and ridges on membrane surface. Experimental data showed that the PM-S4 (0.4 wt% SNPs) membrane has maximum salt rejection capacity and was selected as an optimal membrane. PMID- 26572388 TI - Optimization of selenylation modification for garlic polysaccharide based on immune-enhancing activity. AB - Garlic polysaccharide (GPS) was modified in selenylation respectively by nitric acid-sodium selenite (NA-SS), glacial acetic acid-selenous acid (GA-SA), glacial acetic acid-sodium selenite (GA-SS) and selenium oxychloride (SOC) methods each under nine modification conditions of L9(3(4)) orthogonal design and each to obtain nine selenizing GPSs (sGPSs). Their structures were identified, yields and selenium contents were determined, selenium yields were calculated, and the immune-enhancing activities of four sGPSs with higher selenium yields were compared taking unmodified GPS as control. The results showed that among four methods the selenylation efficiency of NA-SS method were the highest, the activity of sGPS5 was the strongest and significantly stronger than that of unmodified GPS. This indicates that selenylation modification can significantly enhance the immune-enhancing activity of GPS, NA-SS method is the best method and the optimal conditions are 0.8:1 weight ratio of sodium selenite to GPS, reaction temperature of 70 degrees C and reaction time of 10h. PMID- 26572389 TI - Composite chitosan hydrogels for extended release of hydrophobic drugs. AB - A composite chitosan hydrogel durable in physiological conditions intended for sustained release of hydrophobic drugs was investigated. The design is based on chitosan crosslinked with genipin with embedded biocompatible non-ionic microemulsion (ME). A prolonged release period of 48 h in water, and of 24h in phosphate buffer saline (PBS) of pH 7.4 was demonstrated for Nile red and curcumin. The differences in release patterns in water and PBS were attributed to distinct dissimilarities in the swelling behaviors; in water, the hydrogels swell enormously, while in PBS they expel water and shrink. The release mechanism dominating this system is complex due to intermolecular bonding between the oil droplets and the polymeric network, as confirmed by Fourier transform infrared spectroscopy (FTIR) experiments. This is the first time that oil in water microemulsions were introduced into a chitosan hydrogels for the creation of a hydrophobic drug delivery system. PMID- 26572390 TI - Amino-modified cellulose nanocrystals with adjustable hydrophobicity from combined regioselective oxidation and reductive amination. AB - The controlled revision of surface properties to alter the hydrophobic features of nanocellulose is a potential technique to obtain materials for many novel applications and to replace oil-based materials acting as amphiphilic polyelectrolytes, among others. In this study, linear amines with increasing chain length were used to adjust the hydrophobicity of amphiphilic cellulose nanocrystals (CNCs). Methyl-, ethyl-, n-propyl-, n-butyl-, n-pentylamine, and n hexylamine were introduced into a cellulose backbone using combined periodate oxidation and reductive amination in an aqueous environment. A high-pressure homogenizer was used to liberate a highly transparent (over 85% at visible light range) nanocrystal dispersion containing CNCs with a length of 73-131 nm and a width of 5-6 nm. All of the CNCs had similar charge density but the hydrophobicity, indicated by the contact angle measurement from the films, increased gradually from 64 degrees to 109 degrees as a function of amine chain length. Thus, this study demonstrated the fabrication of uniform, amphiphilic nanosized polyelectrolytes with modifiable hydrophobicity. PMID- 26572391 TI - Purification, characterization and hepatoprotective activities of mycelia zinc polysaccharides by Pleurotus djamor. AB - This study was designed to investigate the physicochemical properties (molecular weights, bond types and monosaccharide compositions), antioxidant activities, and hepatoprotective effects on carbon tetrachloride (CCl4)-induced acute liver damage of mycelia zinc polysaccharides (MZPSs) and its major fractions (MZPS-1, 2 and -3) separated from Pleurotus djamor. In vitro assays, the MZPS-3 demonstrated relatively strong antioxidant activities in dose-dependent manners. For in vivo hepatoprotective activities, administration of MZPS-3 at 800 mg/kg significantly decreased the levels of AST, ALT, MDA and LPO, remarkably increased the levels of TC, TG and ALB, and prominently restored the activities of SOD, GSH Px, CAT and T-AOC in serum/liver homogenate against CCl4-induced injures. Findings presented in this study clearly demonstrated that MZPSs, especially MZPS 3, might be suitable for functional foods and natural drugs in preventing the CCl4-induced acute liver damage. PMID- 26572392 TI - Amphiphilic photosensitive dextran-g-poly(o-nitrobenzyl acrylate) glycopolymers. AB - Among all photosensitive monomers reported in the literature, o-nitrobenzyl acrylate (NBA) was selected in this present study. Two strategies were compared to produce azido-terminated poly(o-nitrobenzyl acrylate) (PNBA) using controlled Single Electron Transfer-Living Radical Polymerization (SET-LRP). In a parallel way, dextran (Dex) was modified by the introduction of several alkynyl-terminated hydrophobic chains. Finally, an Huisgen-type Copper (I)-catalyzed Azide-Alkyne Cycloaddition (CuAAC) click-chemistry was carried out to produce amphiphilic Dex g-PNBA glycopolymers with different number and length of PNBA grafts. 2D DOSY (1)H NMR was used to prove the formation of such glycopolymers. Preliminary study on Dex-g-PNBA self-assembly was done by measuring the critical water content (CWC) above which Dex-g-PNBA started to auto-organize themselves to produce nano objects. Finally, under UV irradiation, PNBA grafts turn into poly(acrylic acid) ones giving light-sensitive properties to such amphiphilic Dex-g-PNBA. Such properties were evaluated and compared with those of PNBA. PMID- 26572393 TI - Colloidal chitin nanogels: A plethora of applications under one shell. AB - Chitin nanogels (CNGs) are a relatively new class of natural polymeric nanomaterials which have a large potential in the field of drug delivery and nanotherapeutics. These nanogels being very biocompatible are non-toxic when internalized by cells. In this review various properties, preparation techniques and applications of CNGs have been described. CNGs because of their nano-size possess certain unique properties which enable them to be used in a number of biomedical applications. CNGs are prepared by simple regeneration technique without using any cross-linkers. Various polymers, drugs and fluorescent dyes can be blended or incorporated or labelled with the chitin hydrogel network. Drugs and molecules encapsulated within CNGs can be used for targeted delivery, in vivo monitoring or even for therapeutic purposes. Here various applications of CNGs in the field of drug delivery, imaging, sensing and therapeutics have been discussed. PMID- 26572394 TI - Nano-porous nitrocellulose liquid bandage modulates cell and cytokine response and accelerates cutaneous wound healing in a mouse model. AB - Nitrocellulose liquid bandage (L-Bandage) is extensively used in hard-to-cover cuts and wounds management, owing to its flexibility, softness, transparency, and conformability. However, evidence supporting their mechanisms of action as wound dressing is scanty. This study introduces a novel nano-porous L-Bandage, and provides results from a mouse full-thickness wound model investigating its mechanism of action on wound healing. Different characteristics, such as porosity, mechanical properties and water vapor transmission rate (WVTR) were determined. The L-Bandage formed film had a porous network structure with mean diameter of 18 nm that could effectively prevent the bacterial invasion, and favorable properties of tensile strength, elongation, and WVTR. The L-Bandage treated wound exhibited accelerated healing, with reduced inflammations, enhanced wound re-epithelialization, contraction, granulation tissue formation, and rapid angiogenesis. Our data suggested that L-Bandage could serve as a promising wound dressing, because of its desirable properties for wound healing. PMID- 26572395 TI - Tragacanth gum-based nanogel as a superparamagnetic molecularly imprinted polymer for quercetin recognition and controlled release. AB - A highly selective magnetic molecularly imprinted polymer (MMIP) with core-shell structure has been synthesized by a sol-gel process composed of Tragacanth Gum (TG) crosslinker, Fe3O4/SiO2 nanoparticles, and N-vinyl imidazole(VI) functional monomer in the presence of template Quercetin (QC). Different techniques including scanning electron microscopy (SEM), SEM-energy dispersive spectroscopy (SEM-EDS), vibrating sample magnetometer (VSM), and transmission electron microscopy (TEM) were used to verify the successful synthesis of MIP on the surface of Fe3O4/SiO2 nanoparticles. The swelling behavior of MMIP, its recognition and selectivity for QC and structural analog, Catechin (CT), were tested and compared with magnetic non imprinted polymer (MNIP). MMIP adsorbs the template drug quickly and equilibrium could be reached in 2h. The mechanism for adsorption was found to follow the Langmuir model with the maximum capacity of 175.43 mg g(-1). The MMIP indicated excellent recognition and binding affinity toward QC, selectivity factor (E) relative to CT was 2.16. Finally, the MMIP was evaluated as a drug delivery device by performing in vitro release studies in PBS. PMID- 26572396 TI - Anticoagulant and FGF/FGFR signal activating activities of the heparinoid propylene glycol alginate sodium sulfate and its oligosaccharides. AB - Propylene glycol alginate sodium sulfate (PSS), prepared by chemical sulfation of alginate, has been used for treating cardiovascular diseases in China for nearly 30 years. In the current study, the PSS was hydrolyzed partially by an environment-friendly solid phase acid degradation method, and then separated by using a Bio-Gel P6 chromatographic column. Thirteen PSS oligosaccharide fractions were obtained and characterized by ESI-MS. The results of different coagulation assays showed that a high molecular weight and a higher degree of sulfation were essential for the anticoagulant activity of the PSS because the PSS oligosaccharides exhibited no detectable anticoagulant activity. In contrast, not only PSS but also certain oligosaccharides showed significant activities in stimulation of FGF1, 2, 7, 8, 9 or 10 induced cell proliferation in FGFR1c expressing BaF3 cells. Such properties made the PSS and its oligosaccharides promising compounds in the regulation of FGF-dependent development, treatment of cancer, and wound healing processes. PMID- 26572397 TI - Properties of a glycogen like polysaccharide produced by a mutant of Escherichia coli lacking glycogen synthase and maltodextrin phosphorylase. AB - Escherichia coli mutant TBP38 lacks glycogen synthase (GlgA) and maltodextrin phosphorylase (MalP). When grown on maltose in fed-batch fermentation TBP38 accumulated more than 50-fold higher glycogen-type polysaccharide than its parental strain. The polysaccharides were extracted at different growth stages and migrated as one peak in size-exclusion chromatography. TBP38 produced polysaccharides ranging 2.6 * 10(6)-4.6 * 10(6)Da. A ratio of short side-chains (DP ? 12) in the polysaccharides was greater than 50%, and number-average degree of polymerization varied from 9.8 to 8.4. The polysaccharides showed 70-290 times greater water-solubility than amylopectin. Km values using porcine and human pancreatic alpha-amylases with polysaccharides were 2- to 4-fold larger than that of amylopectin. kcat values were similar for both alpha-amylases. The TBP38 polysaccharides had 40-60% lower digestibility to amyloglucosidase than amylopectin. Intriguingly, the polysaccharides showed strong immunostimulating effects on mouse macrophage cell comparable to lipopolysaccharides. The lipopolysaccharide contamination levels were too low to account for this effect. PMID- 26572398 TI - Effects of reaction conditions on cellulose structures synthesized in vitro by bacterial cellulose synthases. AB - Cellulose was synthesized by cellulose synthases extracted from the Komagataeibacter xylinus (formerly known as Gluconacetobacter xylinus). The effects of temperature and centrifugation of the reaction solution on the synthesis products were investigated. Cellulose with number-average degree of polymerization (DPn) roughly in the range 60-80 and cellulose II crystal structure was produced under all conditions. The amount of cellulose varied with temperature and centrifugation, and the centrifugation at 2000 * g also slightly reduced the DPn. Cellulose production was maximal around the temperature 35 degrees C and without centrifugation. At higher temperatures and during centrifugation at 2000 * g the proteins started to denature, causing differences also in the morphology of the cellulosic aggregates, as seen with electron microscopy. These observations serve as a basis for discussions about the factors affecting the structure formation and chain length of in vitro synthesized cellulose. PMID- 26572399 TI - Does viscosity or structure govern the rate at which starch granules are digested? AB - The rates of in vitro digestion of incompletely or fully gelatinised potato and corn starch were measured at 37 degrees C over 20 min in a rheometer fitted with cup and vane geometry at shear rates of 0.1, 1 and 10 s(-1). Shear rate did not influence the rate of starch digestion provided it was close to physiological levels. However, rates of digestion were significantly reduced when shear rates were below the physiological range (0.1 s(-1)) or when gelatinisation was incomplete. At physiological shear rates the relationship between starch digestion and viscosity was sigmoid in form and following a short initial slow phase a rapid decline in viscosity occurred as starch was digested and the structural integrity of the granules was lost. Conversely, when shear rate was reduced below physiological levels or gelatinisation was incomplete, digestion was hindered, granule integrity was maintained and the relationship between starch and viscosity became linear. PMID- 26572400 TI - Nanofiller for the mechanical reinforcement of maltodextrins orodispersible films. AB - One of the most critical quality attributes of orodispersible films (ODFs) is related to the development of dosage forms with tensile properties suitable for the packaging and patient's handling. Aiming to develop a strategy to reinforce the tensile properties, the current work reported the feasibility to improve the tensile strength of maltodextrins (MDX) based ODFs by adding an amorphous water insoluble nanofiller, namely polyvinylacetate (PVAc). The possible interactions between components investigated by DSC and ATR-FTIR spectroscopy revealed that MDX and PVAc were immiscible; even if, the presence of plasticizers permitted the homogeneous dispersion of PVAc in the film until the 10% w/w concentration was reached. As a consequence, PVAc nanoparticles was found to be an effective reinforcing agent only at the concentrations of 3 and 5% w/w. In this optimal range, the tensile strength increased at least 1.5 fold and the elastic modulus increased at least 4 times. PMID- 26572401 TI - Cefazolin loaded chitosan nanoparticles to cure multi drug resistant Gram negative pathogens. AB - Antibiotic resistance against Gram-negative microbes is considered as an alarming phenomenon that needs to be addressed urgently to develop better therapeutic solutions. The aim of the present research work was to investigate and develop cefazolin loaded chitosan nanoparticles (CSNPs) as a potential tool against multidrug resistant pathogens. Empty and drug loaded CSNPs were prepared by ionic gelation method. It was observed by Scanning Electron Microscopy (SEM) and Atomic Force Microscopy (AFM) based studies that CSNPs were less than 100 nm in size and displayed homogeneity both in shape and size. Encapsulation of cefazolin has not increased the size of nano systems. Zeta sizer results revealed that both systems have positive zeta potential of more or less +50 mV, thus contributing towards a stable formulation. Encapsulation efficiency was directly proportional to the increase in the concentration of antibiotic (28-62%). Furthermore, growth kinetics study had demonstrated excellent antimicrobial potential of cefazolin loaded CSNPs against multi drug resistant Klebsiella pneumoniae, Pseudomonas aeroginosa and Extended Spectrum Beta Lactamase (ESBL) positive Escherichia coli. PMID- 26572402 TI - Formulation and in vivo evaluation of probiotics-encapsulated pellets with hydroxypropyl methylcellulose acetate succinate (HPMCAS). AB - The aim of this study was to formulate probiotics-encapsulated pellets with hydroxypropyl methylcellulose acetate succinate (HPMCAS) using a dry powder coating technique to improve the storage stability, acid resistance, and intestinal adherence of viable bacteria (Lactobacillus acidophilus and Bifidobacteria animalis ssp. Lactis). Dry coated pellet (DCP) loaded with probiotics was optimized with respect to the quantity of the HPMCAS, an enteric coating polymer (108 mg), and the kinds and amounts of plasticizer (triethyl citrate, 15.7 mg; acetylated monoglyceride, 6.8 mg), by evaluating the survival rate of the bacteria during preparation process and in an acidic medium. Dry coating process allows the whole survivals of living bacteria during preparation process. The DCP formulation exhibited markedly higher acid tolerability and storage stability compared to uncoated viable bacteria. In an in vivo mucosal adherence study in rats, a profound colonization of viable bacteria in the small and large intestine was observed in rats receiving DCP system (p<0.05) compared to rats receiving uncoated probiotics. Moreover, we found that the repeated DCP administration noticeably inhibited intestinal penetration of endotoxin, a potent inflammatory stimulant, from intestinal mucus. The novel DCP system may be an alternative approach for improving bacterial viability in the preparation process and in an acidic medium, and to promote mucosal colonization of probiotic bacteria in the human gut. PMID- 26572403 TI - Catalytic conversion of sugarcane bagasse to cellulosic ethanol: TiO2 coupled nanocellulose as an effective hydrolysis enhancer. AB - The present study deals with the production of cellulosic ethanol from bagasse using the synthesized TiO2 coupled nanocellulose (NC-TiO2) as catalyst. Aspergillus nidulans AJSU04 cellulase was used for the hydrolysis of bagasse. NC TiO2 at various concentrations was added to bagasse in order to enhance the yield of reducing sugars. Complex interaction between cellulase, bagasse, NC-TiO2 and the reaction environment is thoroughly studied. A mathematical model was developed to describe the hydrolysis reaction. Ethanol production from enzymatically hydrolyzed sugarcane bagasse catalyzed with NC-TiO2 was carried out using Saccharomyces cerevisiae ATCC 20602. The glucose release rates and ethanol concentrations were determined. Ethanol produced was found to be strongly dependent on pretreatment given, hydrolysis and fermentation conditions. The study confirmed the promising accessibility of NC-TiO2, for enhanced glucose production rates and improved ethanol yield. PMID- 26572404 TI - Bacterial polysaccharide levan as stabilizing, non-toxic and functional coating material for microelement-nanoparticles. AB - Levan, fructose-composed biopolymer of bacterial origin, has potential in biotechnology due to its prebiotic and immunostimulatory properties. In this study levan synthesized by levansucrase from Pseudomonas syringae was thoroughly characterized and used as multifunctional biocompatible coating material for microelement-nanoparticles (NPs) of selenium, iron and cobalt. Transmission electron microscopy (TEM), hydrodynamic size measurements (DLS) and X-ray photoelectron spectroscopy (XPS) showed the interaction of levan with NPs. Levan stabilized the dispersions of NPs, decreased their toxicity and had protective effect on human intestinal cells Caco-2. In addition, levan attached to cobalt NPs remained accessible as a substrate for the colon bacteria Bacteroides thetaiotaomicron. We suggest that the combination of levan and nutritionally important microelements in the form of NPs serves as a first step towards a novel "2 in 1" approach for food supplements to provide safe and efficient delivery of microelements for humans and support beneficial gut microbiota with nutritional oligosaccharides. PMID- 26572405 TI - (1)H NMR-based DS determination of barley starch sulfates prepared in 1-allyl-3 methylimidazolium chloride. AB - The use of natural resources in a development of products and materials is currently increasing. Starch is one of the investigated resources due to its bioavailability, biodegradability, safety and affordability. In this study, native barley starch was sulfated using a SO3-pyridine complex. The reaction was carried out for the first time using 1-allyl-3-methylimidazolium chloride ionic liquid, an excellent solvent for the starch modification. Reaction conditions (temperature, time and amount of the reagent) were studied using an experimental design. Starch sulfates with the degree of substitution (DS) 1.37 were obtained when the reaction was carried out at 40 degrees C for 75 min with 4:1 molar ratio of SO3-pyridine complex:anhydroglucose unit. The determination of DS was based on (1)H NMR instead of elemental analysis, which showed overestimated DS values in this study. Starch sulfates were analyzed with FTIR and HPLC, which showed that products contained small and large sulfated molecules. PMID- 26572406 TI - Structure and chain conformation of a neutral intracellular heteropolysaccharide from mycelium of Paecilomyces cicadae. AB - A neutral heteropolysaccharide (PCIPS2) was isolated and purified from mycelium of Paecilomyces cicadae, which was investigated to be mainly composed of D mannose, L-rhamnose, 3-O-methyl-D-galactose, D-glucose and D-galactose with a molar ratio of 47.9:3.1:6.4:0.9:0.8. It had a backbone of 1,4-linked alpha-L-Rhap residues and 1,6-linked alpha-D-Manp residues with branches at O-3 of alpha-D Manp residues. Its side chain was comprised of minor terminal beta-D-glucose and 1,4-linked alpha-3-O-Me-D-Galp residues terminated by alpha-D-galactose. Furthermore, its chain information on the values of weight-average molar mass (Mw), root mean square radius ([Formula: see text]), hydrodynamic radius (Rh) and intrinsic viscosity ([eta]) for PCIPS2 were analyzed to be 3.09 * 10(4)g/mol, 7.8 nm, 3.6 nm and 8.5 mL/g, respectively. The structural exponent alpha of 0.57 indicated that PCIPS2 existed as a flexible chain conformation with a coil-like structure in 0.1M NaNO3 at 25 degrees C. In terms of known theory for worm-like chains, the model parameters for PCIPS2 were as following: molar mass per unit contour length (ML) = 379 nm(-1), persistence length (q) = 0.74 nm and hydrodynamic diameter of cylinder (d) = 0.82 nm, which were further evidenced by atomic force microscopy (AFM). PMID- 26572407 TI - Two-step sequential cross-linking of sugar beet pectin for transforming zein nanoparticle-based Pickering emulsions to emulgels. AB - Nanosized (<100 nm) zein spheres were employed for fabrication of a series of fish O/W Pickering emulsions. Although surface tension measurement informed the high potency of zein particles for interfacial adsorption, the prepared emulsions destabilized shortly. Electrostatic deposition of sugar beet pectin onto zein particles interfacial layer at pH 4.0 increased significantly the emulsion stability which was attributed to enhanced steric and electrostatic repulsions based on zeta-potential measurements. Pectin enrichment also increased the viscosity of the continuous phase of emulsion. Injection of the oxidative enzyme laccase into the pectin-enriched emulsion to cross-link the feruloyl-bearing pectin molecules and the subsequent addition of CaCl2 to set ion-mediated cross linkages between carboxyl groups of pectin chains transformed Pickering emulsions to emulgels. The higher the pectin content, the shorter was the gelation time of emulsions. The obtained emulgels were self-standing and became harder along with increasing pectin content. PMID- 26572408 TI - EPR spectroscopy applied to the study of the TEMPO mediated oxidation of nanocellulose. AB - Two different methods of pH control were used in the synthesis of 2,2,6,6 tetramethylpiperidine-1-oxyl (TEMPO) oxidized cellulose nanocrystals (CNC) and the reaction kinetics and degree of oxidation were investigated. In method I the media pH was controlled by addition of NaOH solution. The effect of the oxidant concentration (sodium hypochloride, NaClO) on the final degree of oxidation and crystallinity of the samples was investigated. Conditions for obtaining an optimum balance between high crystallinity and degree of oxidation were selected from those results. In method II, pH was fixed by using a buffer solution. Electron spin resonance (ESR) spectroscopy offered direct information of the decay of TEMPO concentration under these conditions. The kinetics of the reaction was determined, finding a direct correlation between these results and those corresponding to the decay of the NaClO concentration and the advance of the CNC degree of oxidation. Differences found between the two methods were analyzed. PMID- 26572409 TI - Polysaccharides based superabsorbent hydrogel from Linseed: Dynamic swelling, stimuli responsive on-off switching and drug release. AB - Swelling properties of Linseed hydrogel (LSH) were studied in deionized water and different physiological pH values, i.e., 1.2, 6.8 and 7.4. Analysis of the kinetics drawn from swelling data has revealed that swelling of LSH followed second order kinetics. The results indicated that swelling of LSH is greatly affected by different concentration of salts. Stimuli responsive on-off switching of LSH was studied in water/normal saline, water/ethanol and basic/acidic environment and found reversible. LSH swells maximum in water and at pH 7.4 while deswells abruptly in ethanol and at pH 1.2. The elongated porous structures uniformly organized in layers were observed in FE-SEM. LSH was used as a sustained release material for tablet formulation of diclofenac sodium. Drug release study followed non-Fickian diffusion. LSH sustained the release of drug even better than a commercially available formulation of diclofenac sodium. PMID- 26572410 TI - Synthesis of alginate derivative via the Ugi reaction and its characterization. AB - In this research, the systematic evaluation of fundamental properties of the alginate derivative (Ugi-Alg) synthesized by the Ugi reaction is presented. The structure of Ugi-Alg with the degree of substitution of 23.24% was confirmed by FT-IR and (1)H NMR spectrometers. The X-ray diffraction (XRD) results indicate the amorphous structure and the crystal structure change of Ugi-Alg, which is possibly ascribed to the destruction of inter- and intra-molecular hydrogen bonding interactions during the Ugi reaction. From thermal gravimetric analysis (TGA) and fluorescence spectrophotometer, Ugi-Alg shows high thermal stability and good amphiphilic functionality with the critical aggregation concentration of 0.07 g/L in 0.15 mol/L aqueous NaCl solution. Transmission electron microscope (TEM) image and dynamic light scattering (DLS) reveal that stable Ugi-Alg self aggregated micelle with the average size of 162.3 nm and zeta potential at about 31.7 mV could form in the aqueous media, which presents tremendous potential in pharmacology and tissue engineering. PMID- 26572411 TI - Chitosan-based hydrogel implants enriched with calcium ions intended for peripheral nervous tissue regeneration. AB - A new method for fabrication of chitosan-based hydrogel implants intended for peripheral nervous tissue regeneration was developed. The method is based on an electrodeposition phenomenon from a solution of chitosan and organic acid. In order to increase the mechanical strength of the implant, the solution was enriched with hydroxyapatite. Hydroxyapatite served as a source of calcium ions too. The influence of the concentration of the polymer and the additive on chemical, mechanical as well as biological properties of the obtained implant was evaluated. The study showed great dependence of the initial solution composition mainly on the physicochemical properties of the resulting structure. Basic in vitro cytotoxic and pro-inflammatory assays showed biocompatibility of manufactured implants, therefore, animal experimentations may be considered. PMID- 26572412 TI - Investigation of the effect of magnetic particles on the Crystal Violet adsorption onto a novel nanocomposite based on kappa-carrageenan-g poly(methacrylic acid). AB - A novel nanocomposite hydrogel prepared by incorporating Fe3O4 magnetic nanoparticles into the kappa-carrageenan-g-poly (methacrylic acid) with in situ polymerization and was characterized by FT-IR, XRD, SEM, TEM and VSM. Synthesized nanocomposite was used to adsorb Crystal Violet (CV) (cationic dye) in aqueous solution in a batch system. The research studies showed that the adsorption of CV can be impressed as a function of contact time, initial concentration of CV, pH and molar ratio of kappa-carrageenan to poly(methacrylic acid). CV adsorption tests disclosed that it only takes 15 min to reach the equilibrium and adsorption capacity for this dye was 28.24 mg g(-1). Langmuir isotherm for equilibrium adsorption data was fitted well and the pseudo-second-order model can describe the adsorption kinetics. Thermodynamic parameters of DeltaG degrees , DeltaH degrees and DeltaS degrees showed the endothermic nature of adsorption and a spontaneous process. PMID- 26572413 TI - Heparin-functionalized Pluronic nanoparticles to enhance the antitumor efficacy of sorafenib in gastric cancers. AB - In this study, chitosan/heparin immobilized delivery system was developed for the delivery of sorafenib in gastric cancers. The SRF NP was nanosized with spherical outfit and present in the amorphous form. The SRF NP exhibited a sustained release of drug at pH 7.4 conditions and enhanced drug released at pH 5.5 conditions. Flow cytometer analysis showed that cellular uptake of NP increased two-fold after 4h of incubation compared to 1h incubation. The SRF NP showed superior anticancer effect compared to that of free SRF in BGC-823 cancer cells. SRF NP induced a remarkable apoptosis of cancer cells consistent with the cytotoxicity assay. Approximately, ~ 50% of cell fractions were observed in early apoptosis phase with ~ 15% of cells in the late apoptosis stage. Consistently, SRF NP exhibited a strong band for caspase-3 and P-53 than compared to free SRF in MGC-823 cancer cells. Importantly, SRF NP showed superior anticancer effect in xenograft tumor model making it a promising delivery vehicle in the treatment of gastric cancers. PMID- 26572414 TI - Receptor-mediated gene delivery into human mesenchymal stem cells using hyaluronic acid-shielded polyethylenimine/pDNA nanogels. AB - Polyethylenimine (PEI) has been used as a vehicle to deliver genes to cancer cells and somatic cells. In this study, cationic polymers of PEI were shielded with anionic polymers of hyaluronic acid (HA) to safely and effectively deliver genes into human mesenchymal stem cells (hMSCs). HA interacted with CD44 in the plasma membranes of hMSCs to facilitate the internalization of HA-shielded PEI/pDNA complexes. The HA-shielded PEI/pDNA nanogels were confirmed by size changes, zeta-potential, and gel retardation assays. HA-shielded nanogels were easily internalized by hMSCs, and this was reduced by pretreatment with a specific monoclonal antibody that blocked CD44. By shielding PEI/pDNA complexes with HA, nanogels were easily internalized to hMSCs when it did not blocked by anti-CD44. These shielded nanogels were also easily internalized by HeLa cells, and this was reduced by pretreatment with an anti-CD44 monoclonal antibody. Following internalization of the SOX9 gene, chondrogenesis of hMSCs was increased, as determined by RT-PCR, real-time quantitative PCR, and histological analyses. PMID- 26572415 TI - Characterization and immunoenhancement activities of Eucommia ulmoides polysaccharides. AB - The aim of this study is to investigate the physicochemical properties, monosaccharide composition and immunomodulatory effects of Eucommia ulmoides Oliv. polysaccharide. The average molecular weight (Mw) of EUPS was 11.4632 * 10(5)Da. The monosaccharide components of EUPS were glucose, fructose, mannose, fucose, galactose and arabinose with a relative mass of 36.6%, 16.6%, 14.2%, 15.7%, 9.5% and 7.4%, respectively. In in vitro experiments, EUPS (1.2-75 MUg/mL) treatment of dendritic cells (DC) increased their surface expression of MHC I/II, CD80, CD40, and CD86 and indicated that EUPS induced DC maturation. Furthermore, EUPS also significantly enhanced lymphocyte proliferation and significantly enhanced cytokine (IL-4 and IFN-gamma) production. In in vivo experiments, our data showed that EUPS could significantly enhance the FMDV-specific IgG, IgG1, IgG2a, and IgG2b antibody titers and T cell proliferation. Together, these results suggest that EUPS is a strong immunostimulant. PMID- 26572416 TI - Enhancing distributive mixing of immiscible polyethylene/thermoplastic starch blend through zeolite ZSM-5 compounding sequence. AB - The aim of this work was to explore the effect of zeolite ZSM-5 (ZSM5) incorporation sequence on the phase morphology, microstructure, and performance of polyethylene/thermoplastic starch (PE/TPS) films. Two processing sequences were used for preparing PE/TPS/ZSM5 composites at a weight ratio of PE to TPS of 70:30 and ZSM5 concentrations of 1-5 wt%: (i) melt compounding of PE with ZSM5 prior to melt blending with TPS (SI); and (ii) TPS was compounded with ZSM5 prior to blending with PE (SII). Distributive mixing and mechanical properties of PE/TPS blend were greatly enhanced when ZSM5 was incorporated via SII. These were caused by both the higher affinity between PE and ZSM5, compared to that of TPS and ZSM5, and the reduction of TPS viscosity after compounding with ZSM5, leading to migration of ZSM5 from TPS dispersed phase toward PE matrix and increase in breakup of TPS droplets during SII sequence. PMID- 26572417 TI - Effect of precipitated calcium carbonate--Cellulose nanofibrils composite filler on paper properties. AB - A new concept of composite filler was developed by using cellulose nanofibrils (CNF), precipitated calcium carbonate (PCC) and cationic starch (C-starch). In this study, cellulose nanofibrils were utilized in two different ways: a PCC-CNF composite filler and a papermaking additive in sheet forming. The aim was to elucidate their effects on flocculation, filler retention and the strength and optical properties of handsheets. The highest filler retention was obtained by using the PCC-CNF composite filler in paper sheets. The paper filled with the composite fillers had much higher bursting and tensile strengths than conventional PCC loading. It was also found that the paper prepared with PCC-CNF composite fillers became denser with increasing the filler content of paper. PMID- 26572418 TI - Anticoagulant and antithrombotic activities of modified xylofucan sulfate from the brown alga Punctaria plantaginea. AB - Selectively and totally sulfated (1 -> 3)-linked linear homofucans bearing ~ 20 monosaccharide residues on average have been prepared from the branched xylofucan sulfate isolated from the brown alga Punctaria plantaginea. Anticoagulant and antithrombotic properties of the parent biopolymer and its derivatives were assessed in vitro. Highly sulfated linear fucan derivatives were shown to inhibit clot formation in APTT assay and ristocetin induced platelets aggregation, while the partially sulfated analogs were inactive. In the experiments with purified proteins, fucan derivatives with degree of sulfation of ~ 2.0 were found to enhance thrombin and factor Xa inhibition by antithrombin III. The effect of sulfated fucans on thrombin inhibition, which was similar to those of heparinoid Clexane((r)) (enoxaparin) and of a fucoidan from the brown alga Saccharina latissima studied previously, can be explained by the multicenter interaction and formation of a ternary complex thrombin-antithrombin III-polysaccharide. The possibility of such complexation was confirmed by computer docking study. PMID- 26572419 TI - Extensional flow behavior of aqueous guar gum derivative solutions by capillary breakup elongational rheometry (CaBER). AB - The extensional rheological properties of aqueous ionic carboxymethyl hydroxypropyl guar gum (CMHPG) and non-ionic hydroxypropyl guar gum (HPG) solutions between the semi-dilute solution state and the concentrated network solution state were investigated by capillary breakup elongational rheometry (CaBER). Carboxymethylated guar gum derivatives show an instable filament formation in deionized water. The ratio of elongational relaxation time lambdaE over the shear relaxation time lambdaS follows a power law of lambdaE/lambdaS~(c . [eta])(-2). The difference of the relaxation times in shear and elongation can be related to the loss of entanglements and superstructures in elongational flows at higher strains. PMID- 26572420 TI - Cellulose nanofibrils extracted from the byproduct of cotton plant. AB - Cotton stalk bark, as the byproduct of cotton plant, was usually discarded and/or combusted, leading to waste of resources and environment pollution. How to efficiently utilize this kind of cellulosic materials is of significative to energy saving and environment protection. Herein, we report on the extraction of cellulose nanofibrils (CNF) from the cotton stalk bark for the first time by a combination of TEMPO-oxidation and mechanical disintegration method. The obtained CNF showed a yield more than 20 wt%. The morphologies, crystalline structures and thermal properties of CNF were extensively investigated by the transmission electron microscopy, scanning electron microscopy, synchrotron radiation wide angle X-ray scattering, Fourier transform infrared spectra and differential scanning calorimetry, respectively. The results showed that the final extracted CNF have similar polymorphs with their starting materials and a significantly increased crystallinity. This work will provide a new way to utilize the cotton stalk barks. PMID- 26572421 TI - A novel gellan-PVA nanofibrous scaffold for skin tissue regeneration: Fabrication and characterization. AB - In this investigation, we have introduced novel electrospun gellan based nanofibers as a hydrophilic scaffolding material for skin tissue regeneration. These nanofibers were fabricated using a blend mixture of gellan with polyvinyl alcohol (PVA). PVA reduced the repulsive force of resulting solution and lead to formation of uniform fibers with improved nanostructure. Field emission scanning electron microscopy (FESEM) confirmed the average diameter of nanofibers down to 50 nm. The infrared spectra (IR), differential scanning calorimetry (DSC) and X ray diffraction (XRD) analysis evaluated the crosslinking, thermal stability and highly crystalline nature of gellan-PVA nanofibers, respectively. Furthermore, the cell culture studies using human dermal fibroblast (3T3L1) cells established that these gellan based nanofibrous scaffold could induce improved cell adhesion and enhanced cell growth than conventionally proposed gellan based hydrogels and dry films. Importantly, the nanofibrous scaffold are biodegradable and could be potentially used as a temporary substrate/or biomedical graft to induce skin tissue regeneration. PMID- 26572422 TI - Surface fluid-swellable chitosan fiber as the wound dressing material. AB - The objective of this study was to develop a novel surface fluid-swellable chitosan (SFSC) fiber for potential wound dressing. The SFSC fiber was successfully prepared by surface modification of chitosan fiber with succinic anhydride, which was characterized by FTIR and solid-state (13)C NMR. The SFSC fiber exhibited better water absorption capacity (approx. 2980%) and stronger antibacterial activities (both above 90%) against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) than chitosan fiber (both below 75%). The cell viability was more than 90% after treated with the SFSC fiber extract, which demonstrated that SFSC fiber had low cytotoxicity towards mouse embryo fibroblasts (MEFs). The SFSC fiber could promote wound healing with advanced development of granulation tissue and epithelial coverage compared with the control (gauze-covered) group. The results indicated that SFSC fiber had great potential to be used as wound dressing material. PMID- 26572423 TI - Positive/negative surface charge of chitosan based nanogels and its potential influence on oral insulin delivery. AB - To develop insulin delivery system for the treatment of diabetes, two insulin loaded nanogels with opposite zeta potential (-15.94 +/- 0.449 mV for insulin:CMCS/CS-NGs(-) and +17.15 +/- 0.492 mV for insulin:CMCS/CS-NGs(+)) were obtained. Ex vivo results showed that the nanogels with opposite surface charge exhibited different adhesion and permeation in specific intestinal segments. There was no significant differences in adhesion and permeation in rat duodenum, but in rat jejunum, insulin:CMCS/CS-NGs(-) exhibited enhanced adhesion and permeation, which were about 3 folds (adhesion) and 1.7 folds (permeation) higher than insulin:CMCS/CS-NGs(+). These results demonstrated that the surface charge property of nanogels determined the absorption sites of CMCS/CS-NGs in small intestine. In vivo study, the blood glucose level in insulin:CMCS/CS-NGs(-) group had 3 mmol/L lower than insulin:CMCS/CS-NGs(+) group during 1h to 11h after the oral administration, which demonstrated that negative insulin:CMCS/CS-NGs had a better management of blood glucose than positive ones. PMID- 26572424 TI - Characterization of a novel purified polysaccharide from the flesh of Cipangopaludina chinensis. AB - The purpose of this paper was to investigate the characterization of a novel polysaccharide from the flesh of Cipangopaludina chinensis, named CCPSn. The results found CCPSn was a white powder, readily soluble in hot water and slightly soluble in water. CCPSn was a homopolysaccharide composed of D-glucose (D-Glc) with molecular weight of 91.1 kDa. Based on analysis of UV-visible, FT-IR, periodic acid oxidation, Smith degradation, methylation, GM-MS and NMR, the structure of CCPSn was elucidated as follows: the backbone was composed of (1 -> 3) linked alpha-D-Glc. The branches, consisting of a single (1 -> 3) linked alpha D-Glc units and terminal alpha-D-Glc-4-O-SO3(-), were attached to the main chain at C-4 positions. The degree of branching was calculated to be about 16.73%. The C-1 of terminal alpha-D-Glc-4-O-SO3(-) was linked to O-3 of (1 -> 3) linked alpha D-Glc in the branches. In addition, the results indicated CCPSn was a sulfated polysaccharide with the sulfate radical content of 9.12%. PMID- 26572425 TI - Synthesis, antioxidant and cathepsin D inhibition activity of quaternary ammonium chitosan derivatives. AB - Two (2-hydroxypropyl) trimethyl ammonium and/or imidazole-based quaternary ammonium chitosan derivatives (NHT-chitosan and Im-OHT-chitosan) were synthesized by using nucleophilic substitution reaction. These two synthesized chitosan derivatives were characterized by Fourier transform infrared spectroscopy, NMR spectra, and UV-visible spectra. The applications as antioxidant agents and cathepsin D inhibitors were further investigated. Both of quaternary ammonium chitosan derivatives exhibited good antioxidant activity upon scavenging against hydroxyl radical and hydrogen peroxide as well as the lipid peroxidation inhibition in the linoleic acid emulsion system. They also exhibited good inhibition activity of cathepsin D protease. NHT-chitosan and Im-OHT-chitosan are potential the natural, healthy and safe preservatives in food industry. PMID- 26572426 TI - Regenerated cellulose scaffolds: Preparation, characterization and toxicological evaluation. AB - Regenerated cellulose scaffolds (RCS) may be used as alloplastic materials for tissue repair. In this work, the RCS were obtained by viscose process and characterized by scanning electron microscopy (SEM), wide angle X-ray diffraction (WAXD), Fourier transform infrared spectroscopy (FTIR) and thermogravimetry analysis (TG). In vitro enzymatic degradation assay and toxicological assays were also evaluated. The physicochemical characterizations revealed the formation of a porous material with distinct thermal profile and crystallinity compared to pristine cellulose pulp. Enzymatic degradation assay revealed that lysozyme showed a mildest catalytic action when compared to cellulase, Tricoderma reesei (Tr). Nevertheless, both enzymes were efficient for degrading the RCS. RCS did not show cytotoxicity, mutagenic or genotoxic effects. The systematically characterization of this work suggests that RCS presented distinct features that make it a viable material for future studies related to the development of scaffolds for biological applications. PMID- 26572427 TI - Structural characterization and effect on anti-angiogenic activity of a fucoidan from Sargassum fusiforme. AB - A fucoidan FP08S2 was isolated from the boiling-water extract of Sargassum fusiforme, purified by CaCl2 precipitation and chromatography on DEAE-cellulose and Sephacryl S-300. FP08S2 contained fucose, xylose, galactose, mannose, glucuronic acid, and 20.8% sulfate. The sulfate groups were attached to diverse positions of fucose, xylose, mannose, and galactose residues. The backbone of FP08S2 consisted of alternate 1,2-linked alpha-D-Manp and 1,4-linked beta-D GlcpA. Sugar composition analysis and ESI-MS revealed that the oligosaccharides from branches contained fucose, xylose, galactose, glucuronic acid and sulfate. FP08S2 could significantly inhibit tube formation and migration of human microvascular endothelial cells (HMEC-1) dose-dependently. These results suggested that the fucoidan FP08S2 from brown seaweeds S. fusiforme could be a potent anti-angiogenic agent. PMID- 26572428 TI - Structural and physico-mechanical characterization of bio-cellulose produced by a cell-free system. AB - This study was aimed to characterize the structural and physico-mechanical properties of bio-cellulose produced through cell-free system. Fourier transform infrared spectrum illustrated exact matching of structural peaks with microbial cellulose, used as reference. Field-emission scanning electron microscopy revealed that fibrils of bio-cellulose were thicker and more compact than microbial cellulose. The specific positions of peaks in the X-ray diffraction and nuclear magnetic resonance spectra indicated that bio-cellulose possessed cellulose II polymorphic structure. Bio-cellulose presented superior physico mechanical properties than microbial cellulose. The water holding capacity of bio cellulose and microbial cellulose were found to be 188.6 +/- 5.41 and 167.4 +/- 4.32 times their dry-weights, respectively. Tensile strengths and degradation temperature of bio-cellulose were 17.63 MPa and 352 degrees C, respectively compared to 14.71 MPa and 327 degrees C of microbial cellulose. Overall, the results indicated successful synthesis and superior properties of bio-cellulose that advocate its effectiveness for various applications. PMID- 26572429 TI - Production, structural characterization and gel forming property of a new exopolysaccharide produced by Agrobacterium HX1126 using glycerol or d-mannitol as substrate. AB - A strain Agrobacterium HX1126 was isolated from soil sample near the canal in Wuxi. Glycerol was used as carbon source for the production of a new exopolysaccharide which was named PGHX. PGHX composed mainly of galactose, with lower amounts of arabinose and aminogalactose. It was found that this strain could use d-mannitol as carbon source to produce PGHX too. A method for the preparation of crude PGHX was proposed and the crude PGHX can be formed in a gel formation when 30 g/L was put into the boiling water for 10 min, with an achieved gel strength of 957 g/cm(2). The concentration of proteins in the crude product was considered to be an important parameter which directly influence the gel forming property. The highest production of PGHX (24.9 g/L) was obtained under the nitrogen depletion condition. The structure of the product was confirmed by NMR and FTIR. PMID- 26572430 TI - Modified sugar beet pectin induces apoptosis of colon cancer cells via an interaction with the neutral sugar side-chains. AB - Pectins extracted from a variety of sources and modified with heat and/or pH have previously been shown to exhibit activity towards several cancer cell lines. However, the structural basis for the anti-cancer activity of modified pectin requires clarification. Sugar beet and citrus pectin extracts have been compared. Pectin extracted from sugar beet pulp only weakly affected the viability of colon cancer cells. Alkali treatment increased the anti-cancer effect of sugar beet pectin via an induction of apoptosis. Alkali treatment decreased the degree of esterification (DE) and increased the ratio of rhamnogalacturonan I (RGI) to homogalacturonan. Low DE per se did not play a significant role in the anti cancer activity. However, the enzymatic removal of galactose and, to a lesser extent, arabinose from the pectin decreased the effect on cancer cells indicating that the neutral sugar-containing RGI regions are important for pectin bioactivity. PMID- 26572431 TI - Deep eutectic solvents as efficient solvent system for the extraction of kappa carrageenan from Kappaphycus alvarezii. AB - Three different deep eutectic solvents (DESs) prepared by the complexation of choline chloride with urea, ethylene glycol and glycerol along with their hydrated counterparts were used for the selective extraction of kappa-carrageenan from Kappaphycus alvarezii. Upon comparison of the quality of the polysaccharide with the one obtained using water as extraction media as well as the one extracted using widely practiced conventional method, it was found that, the physicochemical as well as rheological properties of kappa-carrageenan obtained using DESs as solvents was at par to the one obtained using conventional method and was superior in quality when compared to kappa-carrageenan obtained using water as solvent. Considering the tedious nature of the extraction method employed in conventional extraction process, the DESs can be considered as suitable alternative solvents for the facile extraction of the polysaccharide directly from the seaweed. However, among the hydrated and non-hydrated DESs, the hydrated ones were found to be more effective in comparison to their non-hydrated counterparts. PMID- 26572432 TI - Chitosan-coated poly(lactic-co-glycolic acid) perfluorooctyl bromide nanoparticles for cell labeling in (19)F magnetic resonance imaging. AB - Noninvasive therapeutic cell tracking methods in living animals are important for understanding cell function and fate in connection with cell therapy. Here we report a new particle system based on chitosan-coated poly(lactic-co-glycolic acid) perfluorooctyl bromide (PLGA PFOB) nanoparticles designed for (19)F magnetic resonance imaging (MRI) cell tracking. Chitosan was adsorbed onto the PLGA PFOB nanoparticles through electric interactions, which led to an increase in the hydrodynamic size and a surface charge proportional to the coating weight ratio. Confocal laser scanning microscopy, flow cytometry analysis and (19)F-MRI showed that to achieve the highest labeling efficiency in vitro, the optimal weight ratio of chitosan to the PLGA PFOB nanoparticles was 1:10 for human mesenchymal stem cells (hMSCs) and 1:100 for Raw 264.7 macrophages. In vivo(19)F MRI showed that (19)F labeled hMSCs remained at the injected site 24h after injection. Thus, this study validates that chitosan-coated PLGA PFOB nanoparticles have the potential to track cell migration in vivo. PMID- 26572433 TI - Structural investigation of cellulose nanocrystals extracted from chili leftover and their reinforcement in cariflex-IR rubber latex. AB - The morphology and chemical composition of chili fibres were investigated. Unusual low lignin content was found when compared to other annual plants. High aspect ratio cellulose nanocrystals (CNCs) were prepared from these fibres by an acid hydrolysis treatment. CNCs extracted from chili leftover were characterized using FT-IR, AFM, TGA and XRD to access their functional, structural, thermal and crystallinity properties, respectively. The length and diameter of the chili leftover CNC were 90-180 nm and 4-6 nm, respectively, resulting in an average aspect ratio of 26. This high aspect ratio ensures percolation at low filler content which in turn results in high thermal and mechanical properties of the nanocomposites. These CNCs were used to prepare nanocomposite films using the highly marketing commercial latex called Cariflex-Isoprene (IR) by casting/evaporation in order to investigate their reinforcing effect. The mechanical properties of nanocomposite films were investigated in both the linear and nonlinear range by DMA and tensile test, respectively, and their morphology was studied using scanning electron microscopy. PMID- 26572434 TI - Dynamic-mechanical and thermomechanical properties of cellulose nanofiber/polyester resin composites. AB - Composites of unsaturated polyester resin (UPR) and cellulose nanofibers (CNFs) obtained from dry cellulose waste of softwood (Pinus sp.) and hardwood (Eucalyptus sp.) were developed. The fiber properties and the influence of the CNFs in the dynamic-mechanical and thermomechanical properties of the composites were evaluated. CNFs with a diameter of 70-90 nm were obtained. Eucalyptus sp. has higher alpha-cellulose content than Pinus sp. fibers. The crystallinity of the cellulose pulps decreased after grinding. However, high values were still obtained. The chemical composition of the fibers was not significantly altered by the grinding process. Eucalyptus sp. CNF composites had water absorption close to the neat resin at 1 wt% filler. The dynamic-mechanical properties of Eucalyptus sp. CNFs were slightly increased and the thermal stability was improved. PMID- 26572435 TI - Biomineralization of calcium phosphate crystals on chitin nanofiber hydrogel for bone regeneration material. AB - We previously reported a chitin nanofiber hydrogel from squid pen beta-chitin by a simple NaOH treatment. In the present study, a calcium phosphate/chitin nanofiber hydrogel was prepared for bone tissue engineering. Calcium phosphate was mineralized on the hydrogel by incubation in a solution of diammonium hydrogen phosphate solution followed by calcium nitrate tetrahydrate. X-ray diffractometry and Fourier transform infrared spectroscopy showed the formation of calcium phosphate crystals. The morphology of the calcium phosphate crystals changed depending on the calcification time. After mineralization, the mechanical properties of the hydrogel improved due to the reinforcement effect of calcium phosphate crystal. In an animal experiment, calcium phosphate/chitin nanofiber hydrogel accelerated mineralization in subcutaneous tissues. Morphological osteoblasts were observed. PMID- 26572436 TI - Functionality of maize, wheat, teff and cassava starches with stearic acid and xanthan gum. AB - Consumer concerns to synthetic chemicals have led to strong preference for 'clean' label starches. Lipid and hydrocolloids are food friendly chemicals. This study determines the effects of stearic acid and xanthan gum alone and in combination on the functionality of maize, wheat, teff and cassava starches. An increase in viscosity was observed for all starches with stearic acid and xanthan gum compared to the controls with cassava having the least increase. A further increase in viscosity was observed for the cereal starches with combination of stearic acid and xanthan gum. Stearic acid reduced retrogradation, resulting in soft textured pastes. Combination of stearic acid and xanthan gum reduced the formation of type IIb amylose-lipid complexes, syneresis, and hysteresis in cereal starches compared to stearic acid alone. A combination of stearic acid and xanthan gum produce higher viscosity non-gelling starches and xanthan gum addition increases physical stability to freezing and better structural recovery after shear. PMID- 26572437 TI - Application of tetra-n-methylammonium hydroxide on cellulose dissolution and isolation from sugarcane bagasse. AB - Cellulose isolation, a promising way for lignocellulosic biomass utilization, is always restricted by the poor solubility of cellulose. In this paper, tetra-n methylammonium hydroxide (TMAH) was confirmed to be capable of readily dissolving/regenerating cellulose without chemical modification at room temperature. Meanwhile, cellulose isolation from lignocellulosic biomass by initially dissolving the biomass in TMAH followed by cellulose precipitation was proposed, and the isolated substance with average cellulose purity of 92.1 +/- 0.3% could be obtained throughout this process under the optimum conditions: temperature 52 degrees C, time 60 min, and loading ratio of TMAH/biomass (w/w) 7.2:1. Besides, high efficiency cellulose isolation (i.e. >70% cellulose purity) could be continuously remained during 4-round cycles by using the recycled TMAH solvent without distinct activity loss. PMID- 26572438 TI - Carboxymethylation of polysaccharide from Cyclocarya paliurus and their characterization and antioxidant properties evaluation. AB - In this study, three chemically carboxymethyl polysaccharides (CM-CPs) were derived from Cyclocarya paliurus polysaccharides. The physicochemical properties and antioxidant activity in vitro of carboxymethyl derivatives were determined. The results of degree of substitution and FT-IR analysis showed the carboxymethylation of polysaccharides were successful. Compared with unmodified polysaccharides, the contents of carbohydrate and protein were decreased while CM CP3 with highest DS value had more uronic acid. The carboxymethyl derivatives was mainly composed of Ara, Gal, Glc, Man, GalA, with a molecular weight (Mw) of 1.03 1.08 * 10(6)Da. Compared with the native polysaccharide, the CM-CP3 with highest DS and Mw exhibited the highest antioxidant activity in beta-carotene-linoleic acid assay. However, the superoxide radical and hydroxyl radical scavenging activity were decreased by CM-CPs. These results demonstrated appropriate carboxymethylation modification could enhance the potential of C. paliurus polysaccharide as oxidation inhibitor. PMID- 26572439 TI - Silkrose: A novel acidic polysaccharide from the silkmoth that can stimulate the innate immune response. AB - We have identified a novel acidic polysaccharide from silkmoth (Antheraea yamamai) pupae that activates the mammalian innate immune response. This bioactive polysaccharide was isolated using nitric oxide production in mouse RAW264 macrophages as an indicator of immunostimulatory activity. We named this polysaccharide "silkrose". It has a molecular weight of 3.15 * 10(5) and comprises nine monosaccharides. The expression profiles indicated that silkrose induced the expression of proinflammatory cytokines and interferon beta that exist downstream of MyD88-dependent and MyD88-indeptendent signaling pathways. Also, the inhibition of Toll-like receptor 4 (TLR4), which exists upstream of the signaling pathways, led to the suppression of NO production by silkrose. Furthermore, this polysaccharide promoted the activation of nuclear factor kappa B in RAW264 cells, indicating that it stimulates the induction of various cytokines in macrophages through the TLR4 signaling pathway. Our results thus suggest that silkrose activates the innate immune response to various pathogenic microorganisms and viral infections. PMID- 26572440 TI - One-pot synthesis of alpha,beta-unsaturated polyaldehyde of chondroitin sulfate. AB - Chondroitin sulfate (CS) was chemoselectively oxidized by Tempo/NaClO to C-6 aldehyde of a D-galactosamine subunit (GalNAc). The subsequent, spontaneous desulfatation of oxidized CS gave rise to alpha,beta-unsaturated aldehyde. A new derivative of CS was fully characterized and a degree of oxidation was determined by spectroscopic analysis. The optimization of reaction conditions showed a proportional degree of oxidation to an amount of sodium hypochlorite. The utility of alpha,beta-unsaturated aldehyde for crosslinking and conjugation was demonstrated by a seamless condensation with various N-nucleophiles. We also demonstrated pH-dependent release of biologically active agents from oxidized CS. A live-dead assay in the presence of alpha,beta-unsaturated aldehyde revealed unaffected viability of NIH 3T3 fibroblasts, which made this precursor promising for several biomedical applications including drug delivery and tissue engineering. PMID- 26572441 TI - Synthesis and characterization of starch-poly(methyl acrylate) graft copolymers using horseradish peroxidase. AB - Horseradish peroxidase (HRP)-mediated graft polymerization in the presence of hydrogen peroxide (H2O2) and acetylacetone (Acac) has been successfully applied to the synthesis of starch-poly(methyl acrylate) (PMA). The graft copolymer was characterized by Fourier transform infrared (FT-IR), elemental analysis, nuclear magnetic resonance ((1)H NMR and (13)C NMR), and differential scanning calorimetry (DSC). FT-IR, elemental analysis and NMR confirmed that methyl acrylate (MA) was grafted onto starch successfully. DSC results showed the graft reaction had changed the crystalline regions of the gelatinized starch. The effects of pH, MA content, HRP dosage, incubation temperature and time on grafting percentage (GP) and grafting efficiency (GE) were also investigated. The GP and GE under optimal conditions reached 30.21% and 45.13%, respectively. PMID- 26572442 TI - Preparation, characterization, and biocompatibility evaluation of poly(NE acryloyl-L-lysine)/hyaluronic acid interpenetrating network hydrogels. AB - In the present study, poly(NE-acryloyl-L-lysine)/hyaluronic acid (pLysAAm/HA) interpenetrating network (IPN) hydrogels were successfully fabricated through the combination of hydrazone bond crosslinking and photo-crosslinking reactions. The HA hydrogel network was first synthesized from 3,3'-dithiodipropionate hydrazide modified HA and polyethylene glycol dilevulinate by hydrazone bond crosslinking. The pLysAAm hydrogel network was prepared from NE-acryloyl-L-lysine and N,N' bis(acryloyl)-(L)-cystine by photo-crosslinking. The resultant pLysAAm/HA hydrogels had a good shape recovery property after loading and unloading for 1.5 cycles (up to 90%) and displayed a highly porous microstructure. Their compressive moduli were at least 5 times higher than that of HA hydrogels. The pLysAAm/HA hydrogels had an equilibrium swelling ratio of up to 37.9 and displayed a glutathione-responsive degradation behavior. The results from in vitro biocompatibility evaluation with pre-osteoblasts MC3T3-E1 cells revealed that the pLysAAm/HA hydrogels could support cell viability and proliferation. Hematoxylin and eosin staining indicated that the pLysAAm/HA hydrogels allowed cell and tissue infiltration, confirming their good in vivo biocompatibility. Therefore, the novel pLysAAm/HA IPN hydrogels have great potential for bone tissue engineering applications. PMID- 26572443 TI - Poly(vinyl alcohol) films reinforced with nanofibrillated cellulose (NFC) isolated from corn husk by high intensity ultrasonication. AB - This work was aimed at fabricating and characterizing poly(vinyl alcohol) films that were reinforced by nanofibrillated corn husk celluloses using a combination of chemical pretreatments and ultrasonication. The obtained nanofibrillated celluloses (NFCs) possessed a narrow width ranging from 50 to 250 nm and a high aspect ratio (394). The crystalline type of NFC was cellulose I type. Compared with the original corn husks, the NCF crystallinity and thermal stability increased due to the removal of the hemicelluloses and lignin. PVA films containing different NFC concentrations (0.5%, 1%, 3%, 5%, 7% and 9%, w/w, dry basis) were examined. The 1% PVA/NFC reinforced films exhibited a highly visible light transmittance of 80%, and its tensile strength and the tensile strain at break were increased by 1.47 and 1.80 times compared to that of the pure PVA film, respectively. The NFC with high aspect ratio and high crystallinity is beneficial to the improvement of the mechanical strength and thermal stability. PMID- 26572444 TI - Nanocrystalline cellulose-dispersed AKD emulsion for enhancing the mechanical and multiple barrier properties of surface-sized paper. AB - In this study, we employed nanocrystalline cellulose (NCC) as an efficient dispersant to perpare alkyl ketene dimer (AKD) emulsion. The particle size and zeta potential of AKD/NCC emulsion were measured, which were approximately 5 MUm and -50 mV, respectively. The surface-sized paper possessed multiple barriers properties. The air permeability of surface-sized paper was 0.29 MUm/Pas and the sizing degree reached 42 s when the amount of sizing was 12.58 g/m(2) with a 96.83% decrease and a 40.00%, increase, respectively. Furthermore, the mechanical properties were optimal when the amount of sizing was about 8 g/m(2). AKD/NCC emulsion acted as a good reinforcing agent in surface-sized paper. PMID- 26572445 TI - Carrot fiber (CF) composite films for antioxidant preservation: Particle size effect. AB - The effect of particle size (53, 105 and 210 MUm) of carrot fiber (CF) on their hydration properties and antioxidant capacity as well as on the performance of the CF-composite films developed with commercial low methoxyl pectin (LMP) was studied. It was determined that CF contained carotenoids and phenolics co extracted with polysaccharides (80%), rich in pectins (15%). CF showed antioxidant activity and produced homogeneous calcium-LMP-based composites. The 53-MUm-CF showed the lowest hydration capability and produced the least elastic and deformable composite film due probably to CF bridged by calcium-crosslinked LMP chains. Antioxidant activity associated to the loaded CF was found in composites. When L-(+)-ascorbic acid (AA) was also loaded, its hydrolytic stability increased with the decrease in CF-particle size, showing the lowest stability in the 0%-CF- and 210 MUm-CF-LMP films. Below ~ 250 MUm, the particle size determined the hydration properties of pectin-containing CF, affecting the microstructure and water mobility in composites. PMID- 26572446 TI - Antioxidant films based on cross-linked methyl cellulose and native Chilean berry for food packaging applications. AB - Development of antioxidant and antimicrobial active food packaging materials based on biodegradable polymer and natural plant extracts has numerous advantages as reduction of synthetic additives into the food, reduction of plastic waste, and food protection against microorganisms and oxidation reactions. In this way, active films based on methylcellulose (MC) and maqui (Aristotelia chilensis) berry fruit extract, as a source of antioxidants agents, were studied. On the other hand, due to the high water affinity of MC, this polymer was firstly cross linked with glutaraldehyde (GA) at different concentrations. The results showed that the addition of GA decreased water solubility, swelling, water vapor permeability of MC films, and the release of antioxidant substances from the active materials increased with the concentration of GA. Natural extract and active cross-linked films were characterized in order to obtain the optimal formulation with the highest antioxidant activity and the best physical properties for latter active food packaging application. PMID- 26572447 TI - Peptide-conjugated hyaluronic acid surface for the culture of human induced pluripotent stem cells under defined conditions. AB - Hyaluronic acid (HA) has been cross-linked to form hydrogel for potential applications in the self-renewal and differentiation of human pluripotent stem cells (hPSCs) for years. However, HA hydrogel with improved residence time and mechanical integrity that allows the survival of hPSCs under defined conditions is still much needed for clinical applications. In this study, HA was modified with methacrylate functional groups (MeHA) and cross-linked by photo-crosslinking method. After subsequent conjugation with adhesive peptide, these MeHA surfaces demonstrated performance in facilitating human induced pluripotent stem cells (hiPSCs) proliferation, and good pluripotency maintenance of hiPSCs under defined conditions. Moreover, MeHA films on glass-slides exhibited long residence time and mechanical stability throughout hiPSC culture. Our photo-crosslinkable MeHA possesses great value in accelerating the application of HA hydrogel in hiPSCs proliferation and differentiation with the conjugation of adhesive peptides. PMID- 26572448 TI - Exopolysaccharide from Trichoderma pseudokoningii induces the apoptosis of MCF-7 cells through an intrinsic mitochondrial pathway. AB - In this study, we reported the anticancer efficacy of exopolysaccharide (EPS) derived from Trichoderma pseudokoningii, on human breast cancer MCF-7 cells. Our results showed that EPS inhibited the proliferation of MCF-7 cells and induced lactic dehydrogenase release by inducing apoptosis and cell arrest at S phase. Further study revealed that EPS-induced apoptosis of MCF-7 cells was associated with alteration of nuclear morphology, disruption of mitochondrial membrane potential and accumulation of intracellular reactive oxygen species. Sequentially, EPS increased the activation of caspase-9 and caspase-3 in a dose dependent manner; however, caspase-8 remained intact. Western blot analysis revealed that EPS increased the ratio of Bax/Bcl-2 and promoted the release of cytochrome c into the cytoplasm. Taken together, these findings provided evidence that EPS induced the apoptosis of MCF-7 cells through an intrinsic mitochondrial apoptotic pathway and that EPS may therefore be considered as an effective adjuvant agent against human breast cancer. PMID- 26572449 TI - Digestibility and prebiotic properties of potato rhamnogalacturonan I polysaccharide and its galactose-rich oligosaccharides/oligomers. AB - Galactose-rich oligosaccharides/oligomers (oligo-RG I) were produced by the enzymatic treatment of potato galactan-rich rhamnogalacturonan I (RG I) with endo beta-1,4-galactanase and Depol 670L multi-enzymatic preparation. The digestibility study revealed that 81.6 and 79.3% of RG I and its corresponding oligomers remained unhydrolyzed, respectively. The prebiotic properties of RG I and its hydrolysates were investigated using a continuous culture system inoculated with immobilized fecal microbiota. Both RG I and oligo-RG I have stimulated the growth of Bifidobacterium spp. and Lactobacillus spp., with oligo RG I hydrolysates being more selectively fermented by these beneficial bacteria. Furthermore, none of RG I nor its hydrolysates increased the populations of Bacteroidetes and Clostridium leptum. Total amounts of short chain fatty acids, generated upon the fermentation of oligo-RG I, were higher than those obtained with its parent RG I and the positive control (fructooligosaccharides). The overall study contributes to the understandings of the prebiotic properties of potato RG I and its corresponding oligosaccharides/oligomers. PMID- 26572450 TI - Functional chitosan-stabilized nanoscale zero-valent iron used to remove acid fuchsine with the assistance of ultrasound. AB - Chitosan-stabilized nanoscale zero-valent iron (CS-nZVI) was prepared and used for the removal of acid fuchsine (AF) from aqueous solution with the assistance of ultrasound. More than 98.9% of AF was removed using CS-nZVI, aged CS-nZVI (exposed to air for 2 months), while only 14.6% removal efficiency was achieved after 15 min by chitosan alone with the assistance of ultrasound. Scanning electron microscopy (SEM) confirmed that chitosan polymers were arranged in a homocentric layered structure. Thus, the polymer can prevent the aggregation of nZVI and increase their anti-oxidation capacity. X-ray diffraction (XRD) also suggested that the chitosan used in synthesis may protect nZVI nanoparticles from air oxidation. Different factors impacting on the removal of AF using CS-nZVI showed that the reduction increased when dosage and temperature increased, but decreased when pH and initial concentration rose. Kinetic studies revealed that the removal of AF fitted well to the pseudo-first-order model. The apparent activation energy was 55.34 kJ/mol, indicating a chemically controlled reaction. Finally, the application of CS-nZVI in dyeing wastewater led to a removal efficiency of 99% of AF, while the reuse test confirmed that AF's removal efficiency declined from 99.6 to 39.3% after seven cycles. PMID- 26572451 TI - Primary structure and chain conformation of fucoidan extracted from sea cucumber Holothuria tubulosa. AB - Knowledge of the structure of polysaccharides is essential for understanding and controlling their functional properties. In this study, fucoidan was extracted from Holothuria tubulosa, a species of sea cucumber that has recently become commercially important. The primary structure of the H. tubulosa fucoidan was clarified using a combination of enzymatic degradation, methylation analysis, and NMR, and its chain conformation was further elucidated by utilizing high performance size exclusion chromatography combined with multiple angle laser light scattering and viscometry. The fucoidan was composed of a tetrafucose repeating unit [ -> 3-alpha-L-Fucp2(OSO3(-))-1 -> 3-alpha-L-Fucp2,4(OSO3(-))-1 -> 3-alpha-L-Fucp-1 -> 3-alpha-L-Fucp2(OSO3(-))-1 -> ]. Its sulfate content was determined to be 31.2 +/- 1.6% and the weight-average molecular mass was 1567.6 +/- 34.1 kDa. The molecule adapted a random coil conformation in 0.15M NaCl solution (pH 7.4) at 25 degrees C, with a root-mean-square radius of 63.9 +/- 1.8 nm and a hydrodynamic radius of 44.5 +/- 4.5 nm. This is the first report on the chain conformation of sea cucumber fucoidan. PMID- 26572452 TI - Potential of electrospun core-shell structured gelatin-chitosan nanofibers for biomedical applications. AB - Coaxial electrospinning is an upcoming technology that has emerged from the conventional electrospinning process in order to realize the production of nanofibers of less spinnable materials with potential applications. The present work focuses on the production of chitosan nanofibers in a benign route, using natural polymer as core template, mild solvent system and naturally derived cross linkers. Nanofibers with chitosan as shell are fabricated by coaxial electrospinning with highly spinnable gelatin as core using aqueous acetic acid as solvent. For maintaining the biocompatibility and structural integrity of the core-shell nanofibers, cross-linking is carried out using naturally derived cross linking agents, dextran aldehyde and sucrose aldehyde. The biological evaluation of gelatin/chitosan mat is carried out using human osteoblast like cells. The results show that the cross-linked core-shell nanofibers are excellent matrices for cell adhesion and proliferation. PMID- 26572453 TI - Design, preparation and characterization of ulvan based thermosensitive hydrogels. AB - The present study is focused on the exploitation and conversion of sulphated polysaccharides obtained from waste algal biomass into high value added material for biomedical applications. ulvan, a sulphated polysaccharide extracted from green seaweeds belonging to Ulva sp. was selected as a suitable material due to its chemical versatility and widely ascertained bioactivity. To date the present work represents the first successful attempt of preparation of ulvan-based hydrogels displaying thermogelling behaviour. ulvan was provided with thermogelling properties by grafting poly(N-isopropylacrylamide) chains onto its backbone as thermosensitive component. To this aim ulvan was properly modified with acryloyl groups to act as macroinitiator in the radical polymerization of N isopropylacrylamide, induced by UV irradiation through a "grafting from" method. The thermogelling properties of the copolymer were investigated by thermal and rheological analyses. Sol-gel transition of the copolymer was found to occur at 30-31 degrees C thus indicating the feasibility of ulvan for being used as in situ hydrogel forming systems for biomedical applications. PMID- 26572454 TI - A novel composite matrix based on polymeric micelle and hydrogel as a drug carrier for the controlled release of dual drugs. AB - In the present work, we present a system of hydrogel/micelle composite as dual drug release vehicle. The hydrogel is prepared from poly(ethyleneglycol) PEG and poly(vinyl alcohol) PVA. Polymeric micelles are enjoying high resurgence of interest in biomedical field as promising candidates for the stabilization and delivery of water insoluble drugs. This property was used to design and synthesize oleic acid-g-chitosan (OA-g-CS) copolymer micelles. Dual drugs, an analgesic, Tramadol (TMD) and an antibiotic, Cefixime trihydrate (CFX) were used as model drugs. The drug release behaviors of the micelle and PEG-PVA/micelle DDDS were studied as functions of pH and temperature. The release profiles were analyzed by a power law equation to reveal the release mechanism of drugs. The drug carrier vehicle was characterized and studies including swelling, effect of ionic strength, anti-oxidant, antimicrobial and in vitro drug release were carried out. The release of the two drugs was much more pronounced in the basic medium than in the acidic medium. PMID- 26572455 TI - Eco-friendly microwave-assisted green and rapid synthesis of well-stabilized gold and core-shell silver-gold nanoparticles. AB - Herein, we present a new approach for the synthesis of gold nanoparticles (AuNPs) individually and as bimetallic core-shell nanoparticles (AgNPs-AuNPs). The novelty of the approach is further maximized by using curdlan (CRD) biopolymer to perform the dual role of reducing and capping agents and microwave-aided technology for affecting the said nanoparticles with varying concentrations in addition to those affected by precursor concentrations. Thus, for preparation of AuNPs, curdlan was solubilized in alkali solution followed by an addition of tetrachloroauric acid (HAuCl4). The curdlan solution containing HAuCl4 was then subjected to microwave radiation for up to 10 min. The optimum conditions obtained with the synthesis of AuNPs were employed for preparation of core-shell silver-gold nanoparticles by replacing definite portion of HAuCl4 with an equivalent portion of silver nitrate (AgNO3). The portion of AgNO3 was added initially and allowed to be reduced by virtue of the dual role of curdlan under microwave radiation. The corresponding portion of HAuCl4 was then added and allowed to complete the reaction. Characterization of AuNPs and AgNPs-AuNPs core shell were made using UV-vis spectra, TEM, FTIR, XRD, zeta potential, and AFM analysis. Accordingly, strong peaks of the colloidal particles show surface plasmon resonance (SPR) at maximum wavelength of 540 nm, proving the formation of well-stabilized gold nanoparticles. TEM investigations reveal that the major size of AuNPs formed at different Au(+3)concentration lie below 20 nm with narrow size distribution. Whilst, the SPR bands of AgNPs-AuNPs core-shell differ than those obtained from original AgNPs (420 nm) and AuNPs (540 nm). Such shifting due to SPR of Au nanoshell deposited onto AgNPs core was significantly affected by the variation of bimetallic ratios applied. TEM micrographs show variation in contrast between dark silver core and the lighter gold shell. Increasing the ratio of silver ions leads to significant decrease in zeta potential of the formed bimetallic core-shell. FT-IR discloses the interaction between CRD and metal nanoparticles, which could be the question of reducing and stabilizing metal and bimetallic nanoparticles. XRD patterns assume insufficient difference for the AuNPs and AgNPs-AuNPs core-shell samples due to close lattice constants of Ag and Au. Based on AFM, AuNPs and AgNPs-AuNPs core-shell exhibited good monodispersity with spherical particles possessing different sizes in the studied samples. The average sizes of both metal and bimetallic core-shell were found to be 52 and 45 nm, respectively. PMID- 26572456 TI - Flexible fibers wet-spun from formic acid modified chitosan. AB - The rigidity and low strain of chitosan fibers hindered their broader utility for biomedical applications. In present work, formic acid was employed as an efficient modifier for chitosan to prepare flexible fibers wet-spun from the formic acid modified chitosan solution. The formation of amide linkages between chitosan and formic acid was confirmed by FTIR, (13)C NMR, (1)H NMR and XRD measurements. The degree of formylation evaluated by (1)H NMR spectra was varied from 14.1% to 37.2% as a function of the reaction temperature. The results of the mechanical properties showed that the as-spun fibers exhibited an enhanced ductility with a maximum elongation at break of 21.7% compared with that spun from the chitosan dissolved in diluted acetic acid. The novel flexible chitosan fibers were anticipated to be used as comfortable wound dressing and bandages in biomedical fields. PMID- 26572457 TI - Electrically conductive nano graphite-filled bacterial cellulose composites. AB - A unique three dimensional (3D) porous structured bacterial cellulose (BC) can act as a supporting material to deposit the nanofillers in order to create advanced BC-based functional nanomaterials for various technological applications. In this study, novel nanocomposites comprised of BC with exfoliated graphite nanoplatelets (xGnP) incorporated into the BC matrix were prepared using a simple particle impregnation strategy to enhance the thermal properties and electrical conductivity of the BC. The flake-shaped xGnP particles were well dispersed and formed a continuous network throughout the BC matrix. The temperature at 10% weight loss, thermal stability and residual ash content of the nanocomposites increased at higher xGnP loadings. The electrical conductivity of the composites increased with increasing xGnP loading (attaining values 0.75 S/cm with the addition of 2 wt.% of xGnP). The enhanced conductive and thermal properties of the BC-xGnP nanocomposites will broaden applications (biosensors, tissue engineering, etc.) of BC and xGnP. PMID- 26572458 TI - Improvement of antimicrobial activity of graphene oxide/bacterial cellulose nanocomposites through the electrostatic modification. AB - Graphene oxide (GO) has an attracting and ever-growing interest in various research fields for its fascinating nanostructures. In this study, bacterial cellulose (BC) was used as a matrix to synthesize GO-based materials by a mechanical mixing method. The modification of GO with PEI significantly improved the bonding force between GO nanofillers and BC matrix. The morphology of the nanocomposites had a significant effect on the mechanical properties, hydrophilic properties as well as the antibacterial activity. After the modification, the GO PEI/BC showed a strong antimicrobial effect on Saccharomyces cerevisiae due to the effective direct contacts between the nanofillers of the composites and the cell surfaces. This study demonstrates that the morphology of the nanocomposites has a great effect on physiochemical properties and the interactions between the microorganism and the nanocomposites. PMID- 26572459 TI - Association of Lactobacillus crispatus with fructo-oligosaccharides and ascorbic acid in hydroxypropyl methylcellulose vaginal insert. AB - The aim of this work was to develop a synbiotic vaginal insert containing the probiotic strain Lactobacillus crispatus BC5, the prebiotic substrate fructo oligosaccharide and the antioxidant agent ascorbic acid, for the prophylaxis and therapy of vaginal infections. Mucoadhesive in situ gelling vaginal inserts based on hydroxypropyl methylcellulose were prepared by freeze-drying, stored at +2-8 degrees C for 90 days and characterized in terms of technological and functional properties. Complete survival of L. crispatus BC5 was found immediately after insert preparation (96.08%) as well as after 90 days of storage (95.82%) in the vaginal inserts containing fructo-oligosaccharide, ascorbic acid and skimmed milk. Synbiotic inserts showed improved mucoadhesion ability (from three- to five fold) with respect to a standard formulation based on hydroxypropyl methylcellulose alone. Moreover, inserts allowed to modulate lactobacilli release in virtue of the different amounts of fructo-oligosaccharide. Finally, antimicrobial activity was exerted by L. crispatus BC5 released from the vaginal formulation. PMID- 26572460 TI - Solvent resistant chitosan/poly(ether-block-amide) composite membranes for pervaporation of n-methyl-2-pyrrolidone/water mixtures. AB - A novel composite barrier comprising of hydrophilic and solvent resistant chitosan (CS) membrane on porous solvent resistant poly(ether-block-amide) (PEBA 2533) substrate was synthesized for pervaporation (PV) based dehydration of the polar aprotic n-methyl-2-pyrolidone (NMP) green solvent. The composite barrier was crosslinked with tetraethyl orthosilicate (TEOS) to control swelling and enhance selectivity. Operating parameters such as feed water concentration, permeate pressure and membrane thickness were varied to assess membrane flux and selectivity. A two-dimensional finite element method (FEM) model was developed to predict the concentration profile within the membrane through computational fluid dynamics (CFD). On the basis of complete mixing experiments, a numerical simulation was performed to predict membrane area requirement and exit streams' compositions for commercial pervaporation units operated in plug flow mode. Both unmodified chitosan and tetraethyl orthosilicate crosslinked composite membranes successfully separated feed mixture containing 4.6 wt% water by exhibiting water fluxes of 0.024 and 0.019 kg/m(2)h, whereas the corresponding selectivities were found to be as high as 182 and 225, respectively. PMID- 26572461 TI - Kinetic investigation and lifetime prediction of Cs-NIPAM-MBA-based thermo responsive hydrogels. AB - This study attempted to clarify the influence of a cross-linker, N,N methylenebisacrylamide (MBA), and N-isopropylacrylamide (NIPAM) on the non isothermal kinetic degradation, solid state and lifetime of hydrogels using the Flynn-Wall-Ozawa (F-W-O), Kissinger, and Coats-Redfern (C-Red) methods. The series of dual-responsive Cs-PNIPAM-MBA microgels were synthesized by soapless emulsion free radical copolymerization in an aqueous medium at 70 degrees C. The thermal properties were investigated using thermogravimetric analysis (TG) and differential scanning calorimetry (DSC) under nitrogen atmosphere. The apparent activation energy using the chosen Flynn-Wall-Ozawa and Kissinger methods showed that they fitted each other. Meanwhile, the type of solid state mechanism was determined using the Coats-Redfern method proposed for F1 (pure Cs) and F2 (Cs PNIPAM-MBA hydrogel series) types, which comprise random nucleation with one nucleus reacting on individual particles, and random nucleation with two nuclei reacting on individual particles, respectively. On average, a higher Ea was attributed to the greater cross-linking density of the Cs hydrogel. PMID- 26572462 TI - Continuous flow adsorption of methylene blue by cellulose nanocrystal-alginate hydrogel beads in fixed bed columns. AB - The adsorption behavior of methylene blue by cellulose nanocrystal-alginate (CNC ALG) hydrogel beads in a fixed bed column was studied by varying the initial dye concentrations, bed depths and flow rates. An unusual phenomenon was observed in the early phase of the adsorption, and the phenomenon was elucidated by varying other critical design parameters, such as the flow direction, diameter of column and composition of adsorbent. The swelling and shrinkage of hydrogel beads during the adsorption was responsible for the anomalous concentration versus time profile of the adsorption process. The maximum adsorption capacity of the column was 255.5mg/g, which is in agreement with the batch study determined from the Langmuir adsorption isotherm. A comprehensive understanding on the adsorption mechanism of CNC-ALG hydrogel beads during the early stages of adsorption was derived from this study. PMID- 26572463 TI - Synthesis, characterization and hydrophobicity of silylated starch nanocrystal. AB - Starch nanocrystal (SNC) was silylated by hexadecyltrimethoxysilane (HDS) aiming to improve its hydrophobicity. HDS was firstly hydrolyzed in ethanol/water and then adsorbed onto SNC through hydrogen bonds, finally the long chain hydrocarbon was covalently linked to the surface of SNC through SiOC bonds which formed via the condensation reaction between hydroxyl and silanol groups. Due to the multilayer coverage of the hydrolyzed HDS, the long chain hydrocarbon crystalized on the surface of SNC and superimposed over the original A-type starch diffraction pattern. Both the hydrophobicity and hydrophobic stability were increased with the increase of the applied HDS. The contact angle of modified SNC increased from 43 degrees to 119 degrees as the applied HDS increased from 0% to 0.3% (v/v). The modification significantly improved its dispersibility in non polar solvents and a homogenous suspension could be formed in acetone and n hexane. PMID- 26572464 TI - Thermoresponsive cellulose ether and its flocculation behavior for organic dye removal. AB - A thermoresponsive polymer, 2-hydroxy-3-butoxypropyl hydroxyethyl cellulose (HBPEC), was prepared by grafting butyl glycidyl ether (BGE) onto hydroxyethyl cellulose (HEC). The lower critical solution temperature (LCST) and critical flocculation temperature (CFT) of HBPEC were varied by changing the molar substitution (MS) and salt concentrations. Transmission electron microscopy (TEM) images and fluorescence spectroscopy showed that HBPEC can assemble into micelles. Additionally, using Nile Red as a model dye, the performance of HBPEC for the removing Nile Red from aqueous solutions via cloud point extraction procedures was investigated in detail. The encapsulation behavior of dye in the aqueous solution of HBPEC was studied by fluorescence spectroscopy and fluorescence microscope. The experimental results indicated that 99.4% of dye was removed from the aqueous solutions, and the HBPEC was recycled and reused easily, Furthermore, the recycle efficiency (RE) and maximum loading capacity portrayed little loss with the number of cycles. PMID- 26572465 TI - Studies on methylcellulose/pectin/montmorillonite nanocomposite films and their application possibilities. AB - Films based on methylcellulose (MC) and pectin (PEC) of different ratios were prepared. MC/PEC (90:10) (MP10) gave the best results in terms of mechanical properties. Sodium montmorillonite (MMT) (1, 3 and 5 wt%) was incorporated in the MP10 matrix. The resulting films were characterized by X-ray diffraction and transmission electron microscopy, and it was found that nanocomposites were intercalated in nature. Mechanical studies established that addition of 3 wt% MMT gave best results in terms of mechanical properties. However, thermo-gravimetric and dynamic mechanical analysis proved that decomposition and glass transition temperature increased with increasing MMT concentration from 1 to 5 wt%. It was also observed that moisture absorption and water vapor permeability studies gave best result in the case of 3 wt% MMT. Optical clarity of the nanocomposite films was not much affected with loading of MMT. In vitro drug release studies showed that MC/PEC/MMT based films can be used for controlled transdermal drug delivery applications. PMID- 26572466 TI - Synthesis and characterization of a chitosan based nanocomposite injectable hydrogel. AB - The aim of the current study was to enhance the mechanical property of chitosan/beta-glycerophosphate disodium salt (CS/GP) injectable hydrogels. A novel nanocomposite injectable hydrogel was prepared by introducing attapulgite (ATP) nano particles into the CS/GP hydrogels. The mechanical properties of the composite hydrogels with two different water contents were characterized by tensile test, the results shown that the tensile strength and elongation at break of composite hydrogels both increased obviously with increasing of ATP content. And, in our testing range, the maximum values of tensile strength and elongation at break were both more than 5 times larger than that of neat CS/GP hydrogel. We discussed this enhancement effect in detail by Scanning electron microscope observations (SEM) and Fourier transform infrared spectroscopy testing (FT-IR). The SEM images of composite hydrogels shown quite different from the neat CS/GP hydrogel, where the pores were more tightly and with some uniform and smaller holes dispersed on the wall. FT-IR test results revealed that the introduction of ATP increased the cross-link density because of the hydrogen bonds formation between ATP nanoparticles and CS molecules. Also, we studied the impact of ATP introduction on gelation speed through tracking the dynamic process of the sol gel transition by means of rheological measurement, and the results shown that the reaction rate increased significantly with the increase of ATP concentration. PMID- 26572467 TI - Green route to modification of wood waste, cellulose and hemicellulose using reactive extrusion. AB - A large volume of wood waste is produced in timber processing industry which traditionally used in low value applications. Here, value addition to the wood waste (Sander dust) and cellulose, hemicellulose isolated thereof by functionalisation using cyclic anhydrides in a solvent-free and green reactive extrusion process is reported. The effect of extrusion temperature, catalyst and different weight ratios of Sander dust (SD):succinic anhydride (SA) on the esterification reaction is evaluated. The esterified products were characterised by the acid value, degree of substitution (DS), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), solid state (13)C NMR and thermo-gravimetric analysis (TGA). Under optimum extrusion conditions, mixed esters are formed, with highest acid value obtained for succinylation of cellulose (0.122 g/g at DS of 0.350) which is two times higher compared to succinylated SD (0.059 g/g at a weight gain of 0.452) and hemicellulose (0.043 g/g at DS of 0.290). The reactivity trend for individual anhydride was: (1) SA Cellulose>SD>hemicellulose; (2) maleic anhydride (MA)-SD>hemicellulose>cellulose and (3) dodecenyl succinic anhydride (DDSA)-SD ~ cellulose ? hemicellulose. The pendant free carboxyl groups generated through functionalisation of wood waste, cellulose and hemicellulose without the presence of polymeric carriers will allow more tailored or targeted modification of wood-plastic composites. PMID- 26572468 TI - Bioenhanced oral curcumin nanoparticles: Role of carbohydrates. AB - The paper discusses polysaccharide-adsorbed curcumin-Gantrez nanoparticles for bioenhancement of oral curcumin. Nanoparticles revealed no change in size over time in pH 1.2 and 7.4, and a rapid drug release in pH 1.2 and 7.4 medium containing surfactant. Without adsorbed polysaccharides, nanoparticles exhibited high Cmax (61.3 +/- 22.3 ng/mL), sustained plasma concentration up to 24h and 117% absolute bioavailability, attributed to bioadhesion. In contrast galactose polysaccharides arabinogalactan and kappa-carrageenan adsorbed nanoparticles exhibited rapid absorption with higher Cmax of 109.5 +/- 31.2 ng/mL and 92.3 +/- 21.2 ng/mL, respectively, but faster elimination and absolute bioavailability of greater than 25%. The glucose polysaccharide pullulan adsorbed nanoparticles exhibited significantly lower Cmax (39.7 +/- 20.6 ng/mL) and bioavailability (13%). Lower bioavailability of polysaccharide adsorbed nanoparticles was attributed to high metabolism of curcumin in the intestine as a result of faster gastric elimination and high intestinal localization. However polysaccharide adsorbed nanoparticles could play an important role in bioenhancement of drugs specifically those exhibiting good stability across the gastrointestinal tract. PMID- 26572469 TI - Synthesis of carbamoylethyl Cassia angustifolia seed gum in an aqueous medium. AB - The Cassia angustifolia seed gum (CAG), a galactomannan, isolated from the seeds of C. angustifolia was subjected to the carbamoylethylation which involved the reaction of CAG with acrylamide in an aqueous medium (water) in the presence of alkali (NaOH) as a catalyst. Alkali concentration, acrylamide concentration, liquor:gum ratio as well as reaction temperature and time were found to affect the extent of carbamoylethylation of CAG (expressed in terms of nitrogen content) and so, these were optimized. Degree of substitution (DS) and reaction efficiency was also determined. FTIR revealed the successful carbamoylethylation of CAG and rheological study conducted on 1 and 2% (w/w) solutions of the carbamoylethyl-CAG not only brought out the non-Newtonian pseudoplastic behaviour, but also high stability of carbamoylethyl-CAG solutions in comparison to solutions of the unmodified CAG. PMID- 26572470 TI - Structural characterization of an intestinal immune system-modulating arabino-3,6 galactan-like polysaccharide from the above-ground part of Astragalus membranaceus (Bunge). AB - Arabino-3,6-galactan (AMA-1-b-PS2), an intestinal immunomodulatory compound, was purified from the above-ground portion of Astragalus membranaceus (Bunge). Its structure was characterized using sequential enzymatic digestion with exo-alpha-L arabinofuranosidase (AFase) and exo-beta-D-(1 -> 3)-galactanase (GNase), producing small amounts of intermediate-sized and shorter oligosaccharide (AF-PS2 G2 and AF-PS2-G3) fractions, and a large GNase-resistant fraction (AF-PS2-G1). Simultaneous AFase and GNase digestion of the enzyme-resistant fraction produced two long fragments (AF3-PS2-G1-1-1 and AF3-PS2-G1-1-2). Products of GNase digestion of the upper fractions showed decreased intestinal immunomodulatory activity; the GNase-resistant fraction (AF-PS2-G1) retained significant activity. Sugar component, methylation, and FAB-MS analyses indicated that the oligosaccharides consisted of hexosyl tri- to hexa-decasaccharides and hexosyl di to hepta-saccharides mainly comprising 6-linked Gal(f) and Gal(p); some were partially mono- or di-arabinosylated. These oligosaccharide fractions were attached to the non-reducing terminus of the beta-D-(1 -> 3)-galactan backbone as side chains at position 6. AMA-1-b-PS2 likely modulates both the systemic and gastric mucosal immune systems. PMID- 26572471 TI - Neutral monosaccharide composition analysis of plant-derived oligo- and polysaccharides by high performance liquid chromatography. AB - A novel analytical method for neutral monosaccharide composition analysis of plant-derived oligo- and polysaccharides was developed using hydrophilic interaction liquid chromatography coupled to a charged aerosol detector. The effects of column type, additives, pH and column temperature on retention and separation were evaluated. Additionally, the method could distinguish potential impurities in samples, including chloride, sulfate and sodium, from sugars. The results of validation demonstrated that this method had good linearity (R(2) >= 0.9981), high precision (relative standard deviation <= 4.43%), and adequate accuracy (94.02-103.37% recovery) and sensitivity (detection limit: 15-40 ng). Finally, the monosaccharide compositions of the polysaccharide from Eclipta prostrasta L. and stachyose were successfully profiled through this method. This report represents the first time that all of these common monosaccharides could be well-separated and determined simultaneously by high performance liquid chromatography without additional derivatization. This newly developed method is convenient, efficient and reliable for monosaccharide analysis. PMID- 26572472 TI - Acid hydrolysis of cellulosic fibres: Comparison of bleached kraft pulp, dissolving pulps and cotton textile cellulose. AB - The behaviour of different cellulosic fibres during acid hydrolysis has been investigated and the levelling-off degree of polymerisation (LODP) has been determined. The study included a bleached kraft pulp (both never-dried and once dried) and two dissolving pulps (once-dried). Additionally, cotton cellulose from new cotton sheets and sheets discarded after long-time use was studied. Experimental results from the investigation, together with results found in literature, imply that ultrastructural differences between different fibres affect their susceptibility towards acid hydrolysis. Drying of a bleached kraft pulp was found to enhance the rate of acid hydrolysis and also result in a decrease in LODP. This implies that the susceptibility of cellulosic fibres towards acid hydrolysis is affected by drying-induced stresses in the cellulose chains. In cotton cellulose, it was found that use and laundering gave a substantial loss in the degree of polymerisation (DP), but that the LODP was only marginally affected. PMID- 26572473 TI - Preparation and characterization of carbon nanotubes/chitosan composite foam with enhanced elastic property. AB - Carbon nanotubes/chitosan (CNTs/CHI) composite foams with ordered lamellar structure were prepared by unidirectionally freezing a dispersion of CNTs in chitosan aqueous solution and subsequent freeze drying. The structure and thermal stability of the composite foams have been characterized by wide-angle X-ray diffraction, Fourier transform infrared spectroscopy, scanning electron microscopy, and thermogravimetry analysis. And their elastic behaviors were investigated by cyclic compression tests. The produced CNTs/CHI composite foams have better recoverability and improved elastic properties compared with the pure chitosan foams. Freezing rate, fraction of CNTs and density are the important factors affecting on the micro morphology, elasticity and mechanical strength of CNTs/CHI composite foams. Due to less ice dendrites and thicker lamellas being formed under low freezing rate, the CNTs/CHI composite foams prepared under low freezing rate (6 mm min(-1)) possesses better mechanical properties than those prepared under high freezing rate (10 cm min(-1)). With the increasing CNTs fraction, the recovery ability of CNTs/CHI composite increases and achieves the maximum at a critical point, and then decreases dramatically due to the inadequate chitosan matrix and aggregation of CNTs. The critical point herein appears at the CNTs fraction >= 0.5 and >= 0.3, respectively, for the samples with density of 0.02 and 0.01 g cm(-3). The CNTs/CHI composite foams with high density (0.02 g cm(-3)) possess better elasticity and mechanical strength than the ones with low density (0.01 g cm(-3)). PMID- 26572474 TI - Extended release and enhanced bioavailability of moxifloxacin conjugated with hydrophilic cellulose ethers. AB - Macromolecular prodrugs (MPDs) of moxifloxacin were fabricated based on hydroxypropylcellulose (HPC) and hydroxyethylcellulose (HEC). UV/Vis spectrophotometry was employed to determine covalently loaded drug content (DC) of each conjugate. The degree of substitution (DS) of moxifloxacin attained ranged from 0.27 to 0.38 (HPC) and 0.19 to 0.26 (HEC) per anhydroglucose unit (AGU), respectively. Transmission electron microscopic analyses showed that HPC moxifloxacin conjugates self-assembled into nanowires of ~ 30 nm diameters while HEC-moxifloxacin conjugates self-assembled into nanoparticles of 150-350 nm. In vitro drug release studies revealed that 15 and 49% moxifloxacin release occurred from the HPC-moxifloxacin conjugate after 6h at pH 1.2 and 7.4, respectively. Similarly, moxifloxacin release from HEC-moxifloxacin conjugates was 15 and 39% at pH 1.2 and 7.4, respectively. Bioavailability and pharmacokinetic studies in rabbits showed that both HPC- and HEC-conjugates exhibited significantly enhanced moxifloxacin plasma half-life, over 24h, confirming sustained release and enhanced bioavailability (AUC 2.0-2.1 times higher) of moxifloxacin. PMID- 26572475 TI - Rheological properties, gelling behavior and texture characteristics of polysaccharide from Enteromorpha prolifera. AB - Polysaccharide from Enteromorpha prolifera (PE) which is the most common green algae is gradually becoming an attractive candidate with novel functions by virtue of its unique chemical and physicochemical properties. The infrared spectrum (FT-IR) of PE confirmed that it is a distinctive, sulfated heteropolysaccharide. Dynamic rheology was systematically conducted to investigate the effect of concentration, temperature, pH, and electrolytes on PE. The flow behavior testing verified its pseudoplastic character. A closed hysteresis loop was obtained when the PE concentration reached 10 g/L. For the phase angel (tandelta) was always less than 1, the solid-like behavior of PE is also found at 10-14 g/L PE in the linear viscoelastic region (LVR). Furthermore, study on its potential gelling behavior showed that 16 g/L PE could form a gel and had well textural properties. The unique functional groups and characteristics of PE provided the possibility to apply into food industry. PMID- 26572476 TI - Phosphorylated cellulose triacetate-silica composite adsorbent for recovery of heavy metal ion. AB - Phosphorylated cellulose triacetate (CTA)/silica composite adsorbent was prepared by acid catalyzed sol-gel method using an inorganic precursor (3-aminopropyl triethoxysilane (APTEOS)). Reported composite adsorbent showed comparatively high adsorption capacity for Ni(II) in compare with different heavy metal ions (Cu(2+), Ni(2+), Cd(2+) and Pb(2+)). For Ni(II) adsorption, effect of time, temperature, pH, adsorbent dose and adsorbate concentration were investigated; different kinetic models were also evaluated. Thermodynamic parameters such as DeltaG degrees , DeltaH degrees and DeltaS degrees were also estimated and equilibrium adsorption obeyed Langmuir and Freundlich isotherms. Developed adsorbent exhibited about 78.8% Ni(II) adsorption at pH: 6 and a suitable candidate for the removal of Ni(II) ions from wastewater. Further, about 65.5% recovery of adsorbed Ni(II) using EDTA solution was demonstrated, which suggested effective recycling of the functionalized beads would enable it to be used in the treatment of contaminated water in industry. PMID- 26572477 TI - Synthesize of new fluorescent polymeric nanoparticle using modified cellulose nanowhisker through click reaction. AB - New biopolymeric nanoparticles consisting of cellulose nanowhisker (CNW) as support system and polyglycerol (PG) as surface modifying agent were prepared. PG was attached to the surface of CNW by click chemistry reaction. CdSe quantum dots then interact with the prepared system by noncovalent interaction. These new synthesized biopolymeric nanoparticles were characterized by spectroscopic measurement methods such as IR spectroscopy, UV-vis spectroscopy, NMR spectroscopy; scanning electron microscopy etc. due to the presence of hydrophilic polymerr at the surface of CNW, synthesized nanomaterials were water soluble, and have a large number of functional group for further modification. Also the presence of fluorescence quantum dots (QDS) caused fluorescence property of synthesized system. These new synthesized system has potential application to be used in different filed such as drug delivery, biomedical imaging etc. PMID- 26572478 TI - Understanding the influence of Tween 80 on pullulan fermentation by Aureobasidium pullulans CGMCC1234. AB - In this paper, several new perspectives concerned with the effect of Tween 80 promoting pullulan production were presented. With the presence of Tween 80, the maximum pullulan yield increased by 41% (53.04 g/L). Meanwhile, the carbon source was consumed faster and the broth viscosity was higher. The lower final pH suggested that Tween 80 could protect the integrity of the mycelia. The dispersed filaments were not easily entangled with each other and less pellets were formed in the Tween 80 culture broth. FT-IR spectrum analysis indicated that the evaluated sample structure was coincided with commercial pullulan. The molecular weight of sample significantly dropped comparing with the control. The above findings indicated that Tween 80 facilitated the uptake of nutrient from surroundings to the microorganism and the release of pullulan into the extracellular fluid. These results were useful in better understanding the regulation and optimization of efficient pullulan fermentation. PMID- 26572479 TI - Composite chitosan/alginate hydrogel for controlled release of deferoxamine: A system to potentially treat iron dysregulation diseases. AB - Recently, the potential application of deferoxamine (DFO) in several iron dysregulation diseases has been highlighted. However, DFO presents significant limitations in clinical use due to its poor absorption in the gut and very short plasma half-life. To overcome these problems, the feasibility of chitosan/alginate hydrogels as prolonged delivery systems of DFO was investigated. Hydrogel alone or co-formulated with poly(D,L-lactide-co-glycolide) microspheres were prepared and studied in vitro. The influence of the preparation methods on the performance of composite hydrogels on controlled DFO release was explored. Spray-dried microspheres based on poly(D,L-lactide-co-glycolide) were able to encapsulate DFO, a highly water soluble drug. Nevertheless, only the composite hydrogels managed to provide sustained drug release. The inclusion of microspheres into pre-formed chitosan/alginate hydrogel provided the most efficient delivery system; the drug released from microspheres is strongly entrapped in the hydrogel network and slowly released by diffusion. PMID- 26572480 TI - Determination of substitution positions in hyaluronic acid hydrogels using NMR and MS based methods. AB - In hydrogels of cross-linked polysaccharides, the total amount of cross-linker and the degree of cross-linking influence the properties of the hydrogel. The substitution position of the cross-linker on the polysaccharide is another parameter that can influence hydrogel properties; hence methods for detailed structural analysis of the substitution pattern are required. NMR and LC-MS methods were developed to determine the positions and amounts of substitution of 1,4-butanediol diglycidyl ether (BDDE) on hyaluronic acid (HA), and for the first time it is shown that BDDE can react with any of the four available hydroxyl groups of the HA disaccharide repeating unit. This was achieved by studying di-, tetra-, and hexasaccharides obtained from degradation of BDDE cross-linked HA hydrogel by chondroitinase. Furthermore, amount of linker substitution at each position was shown to be dependent on the size of the oligosaccharides. For the disaccharide, substitutions were predominantly at DeltaGlcA-OH2 and GlcNAc-OH6 while in the tetra- and hexasaccharides, it was mainly at the reducing end GlcNAc OH4. In the disaccharide there was no substitution at this position. Since chondroitinase is able to completely hydrolyse non-substituted HA into unsaturated disaccharides, these results indicate that the enzyme is prevented to cleave on the non-reducing side of an oligosaccharide substituted at the reducing end GlcNAc-OH4. The procedure can be adopted for the determination of substitution positions in other types of polymers. PMID- 26572481 TI - Structural characteristics of pectic polysaccharides and arabinogalactan proteins from Heracleum sosnowskyi Manden. AB - Polymers with different structures were isolated from the aboveground part of Heracleum sosnowskyi Manden. The sequential treatment of Heracleum with water, HCl solution, and (NH4)2C2O4 solution was observed to decrease the arabinogalactan proteins (AGP) content and increase the pectins content in the extracted polysaccharides. The linear region of the HSO-I polysaccharide having the highest yield was found to be composed mainly of partially methylesterified homogalacturonan fragments, whereas the branched region was made up of fragments of rhamnogalacturonan I whose core represents 1,2-alpha-L-rhamno-1,4-alpha-D galacturonan. The carbohydrate side chains of the branched region are linked to the alpha-L-Rhap core residues via the 1,4-glycosidic bond and consist chiefly of T-beta-D-Galp, 1,4-beta-D-Galp and 1,6-beta-D-Galp residues indicating the presence of the 1,4-beta-D-galactan. NMR spectroscopy revealed the carbohydrate moiety of the AGP molecule to consist mainly of 1,3- and 1,3,6-beta-D-Galp residues. The side chains comprised 1,6-beta-D-Galp, terminal 4-O-Me-beta-D GlcpA, and beta-D-Galp. PMID- 26572482 TI - Carrageenan and agaran structures from the red seaweed Gymnogongrus tenuis. AB - The galactan system biosynthesized by the red seaweed Gymnogongrus tenuis (Phyllophoraceae) is constituted by major amounts of kappa/iota-carrageenans, with predominance of iota-structures, which were isolated by extraction with hot water in high yield (~ 45%). A small amount of non-cyclized carrageenans mostly of the nu-type was also obtained. Besides, 12% of these galactans are agaran structures, which were present in major quantities in the room temperature water extracts, but they were also found in the hot water extract. They are constituted by 3-linked beta-D-galactose units partially substituted on C-6 with sulfate or single stubs of beta-D-xylose and 4-linked residues that comprise alpha-L galactose units partially sulfated or methoxylated on C-3 or sulfated on C-3 and C-6 and 3,6-anhydro-alpha-L-galactose. Related structural patterns were previously found for agarans synthesized by other carrageenophytes. Results presented here show that these agarans are low molecular weight molecules independent of the carrageenan structures, with strong interactions between them. PMID- 26572483 TI - Chitosan/silica coated carbon nanotubes composite proton exchange membranes for fuel cell applications. AB - Silica-coated carbon nanotubes (SCNTs), which were obtained by a simple sol-gel method, were utilized in preparation of chitosan/SCNTs (CS/SCNTs) composite membranes. The thermal and oxidative stability, morphology, mechanical properties, water uptake and proton conductivity of CS/SCNTs composite membranes were investigated. The insulated and hydrophilic silica layer coated on CNTs eliminates the risk of electronic short-circuiting and enhances the interaction between SCNTs and chitosan to ensure the homogenous dispersion of SCNTs, although the water uptake of CS/SCNTs membranes is reduced owing to the decrease of the effective number of the amino functional groups of chitosan. The CS/SCNTs composite membranes are superior to the pure CS membrane in thermal and oxidative stability, mechanical properties and proton conductivity. The results of this study suggest that CS/SCNTs composite membranes exhibit promising potential for practical application in proton exchange membranes. PMID- 26572484 TI - Prognostic factors and multidisciplinary treatment modalities for brain metastases from colorectal cancer: analysis of 93 patients. AB - BACKGROUND: The purpose of this study was to review patient characteristics and evaluate the potential factors affecting prognosis in cases of brain metastasis (BM) from colorectal cancer (CRC). METHODS: We retrospectively reviewed 93 cases of BM from CRC in our hospital. Patient demographics, neurologic symptoms, and location and number of BMs were recorded. Factors analyzed included: age; sex; Karnofsky performance score; number of BMs; presence of extracranial metastases; dimensions; location of tumors; treatment modalities. RESULTS: The overall 1- and 2-year survival rates were 27.7 and 9.9%. On multivariate analysis, the number of BMs, extracranial metastases and the initial treatment modalities were found to be independent prognostic factors for overall survival. Patients treated with surgical resection followed by WBRT or SRS had an improved prognosis relative to those treated with surgery alone (P=0.02 and P=0.02, respectively). No significance difference in survival rate was found between patients treated with SRS alone or SRS plus WBRT (P=0.11). CONCLUSIONS: Surgical resection of BMs from CRC in selected patients may help prolong survival. Additional radiotherapy following surgery is valuable in improving prognosis. Extracranial metastasis, multiple BM lesions and initial non operation can be considered as independent factors associated with poor prognosis. PMID- 26572485 TI - A considerable proportion of CRF01_AE strains in China originated from circulating intrasubtype recombinant forms (CIRF). AB - BACKGROUND: In this study, the prevalence of HIV-1 CRF01_AE intrasubtype recombinants in China is estimated and their contributions to the epidemic are explored. METHODS: Available HIV-1 complete genomes of CRF01_AE were retrieved from the HIV database. The two alignments were evaluated with RDP3. Recombinants were defined as cases in which the recombination signal was supported by at least 3 methods with P-values of <=0.05 after Bonferroni correction for multiple comparisons implemented in RDP3. Phylogenetic analysis was performed to further investigate the role of intrasubtype recombinants in epidemics. RESULTS: Here, 124 out of the 339 sequences from around the world (36.6 %) showed significant evidence of recombination. Here, 84 of these recombinants were from China, accounting for 54.9 % of local total sequences (84 out of 153). The results indicated non-negligible levels of intrasubtype recombination. Subsequent phylogenetic analysis indicated that a considerable proportion of CRF01_AE strains in China originated from circulating intrasubtype recombinant forms. Three large, well-supported intrasubtype recombinants clusters were identified here. Through a survey of risk factors and sampling cities and provinces, cluster I and cluster II were found to be prevalent primarily among men who have sex with men in major northern cities. Cluster III was prevalent among heterosexuals and intravenous drug users in southern and southwestern provinces. CONCLUSIONS: The current work highlighted the remarkable prevalence of intrasubtype recombination within the CRF01_AE epidemic and emphasized the value of intrasubtype recombinants, which came to circulate in the same manner as intersubtype recombinants. PMID- 26572486 TI - NGA- A Novel Hypothetical Drug Model: Combinatorial Approach to Multifactorial Alzheimer's Disease. AB - Alzheimer's disease (AD) is supposed to stanch from inappropriate waving in the brain sections related to memory and perception. The incidence of AD in distressed person associated with an upsurge in the accumulation of amyloid plaque-rich senile plaques and neurofibrillary tangles in the brain. We hypothesize that a combination therapy provides a new treatment for AD. We propose that an anti-AD drug, NGA, a combination of NSAIDS, Galanthamine and ACS 40 may be useful in preventing the formation of amyloid plaques from beta amyloid. Being a widespread incurable disease, the treatment for Alzheimer's has been at the forefront of the medical research work. We propose a novel drug-like NGA will allow for the effective control and treatment of the progression of AD by preventing acetylcholinesterase activity and reducing plaque formation that forms the distinctive symptom for the identification of the onset of AD. A combinatory use of NSAID with a natural neurotransmitter will allow for an efficient control of amyloid beta toxicity and will open doors for the treatment of a myriad of other neurodegenerative diseases. PMID- 26572487 TI - Mouse Resistin (mRetn): cloning, expression and purification in Escherichia coli and the potential regulative effects on murine bone marrow hematopoiesis. AB - BACKGROUND: Resistin (Retn) is a cytokine which has a controversial physiological role regarding its involvement with obesity and type II diabetes mellitus. Recently, murine Retn was found to be a possibly potential regulator of hematopoiesis in mice shown in the screening results of a set of gene chips which mapped the expression level of murine genes during regeneration of impaired bone marrow (BM) by 5-fluorouracil. RESULTS: Recombinant mice Retn was expressed in Escherichia coli and purified using ion exchange chromatography. Totally 11.4 mg rmRetn was obtained from 500 ml culture with endotoxin level less than 1.0 EU/ug. The purity of recombinant murine Resistin reached to at least 97.6% via SDS-PAGE analysis and HPLC. The protein possessed chemotaxis effects in the mouse aortic endothelial cells in vitro in transwell analysis. In vitro, rmRetn could up regulate the CFU number of mice BM and after rmRetn was administered, the cell number of murine bone marrow was significantly increased in vivo after chemotherapy. Finally, rmRetn was found able to protect mice from the chemotoxicity of 5-fluorouracil. CONCLUSIONS: The discovery demonstrated a new function of murine Retn and suggested that it could potentially accelerate bone marrow regeneration post chemotherapy. PMID- 26572488 TI - Combination of sorafenib and gadolinium chloride (GdCl3) attenuates dimethylnitrosamine(DMN)-induced liver fibrosis in rats. AB - BACKGROUND/AIMS: Liver sinusoidal endothelial cells (SECs), hepatic stellate cells (HSCs) and Kupffer cells (KCs) are involved in the development of liver fibrosis and represent a potential therapeutic target. The therapeutic effects on liver fibrosis of sorafenib, a multiple tyrosine kinase inhibitor, and gadolinium chloride (GdCl3), which depletes KCs, were evaluated in rats. METHODS: Liver fibrosis was induced in rats with dimethylnitrosamine, and the effects of sorafenib and/or GdCl3 in these rats were monitored. Interactions among ECs, HSCs and KCs were assessed by laser confocal microscopy. RESULTS: The combination of sorafenib and GdCl3, but not each agent alone, attenuated liver fibrosis and significantly reduced liver function and hydroxyproline (Hyp). Sorafenib significantly inhibited the expression of angiogenesis-associated cell markers and cytokines, including CD31, von Willebrand factor (vWF), and vascular endothelial growth factor, whereas GdCl3 suppressed macrophage-related cell markers and cytokines, including CD68, tumor necrosis factor-alpha, interleukin 1beta, and CCL2. Laser confocal microscopy showed that sorafenib inhibited vWF expression and GdCl3 reduced CD68 staining. Sorafenib plus GdCl3 suppressed the interactions of HSCs, ECs and KCs. CONCLUSION: Sorafenib plus GdCl3 can suppress collagen accumulation, suggesting that this combination may be a potential therapeutic strategy in the treatment of liver fibrosis. PMID- 26572489 TI - PDL regeneration via cell homing in delayed replantation of avulsed teeth. AB - BACKGROUND: This study was aimed to investigate whether regeneration of periodontal ligament (PDL) like tissue could be promoted by stromal cell-derived factor-1 (SDF1) and bone morphogenetic protein-7 (BMP7) induced cell homing in delayed replantation of avulsed teeth. METHODS: Canine mandibular premolar teeth were first extracted and air-dried for 2 h followed by complete detachment of their PDL tissues. The crown and pulp of the teeth were also removed. Twenty-four roots divided into two groups (n = 12/group) were used for the following in vivo transplantation. The roots of Group A were treated with 17 % EDTA for 24 h to achieve demineralization, and then coated with SDF1 and BMP7 supplemented collagen solution. The roots of Group B were similarly treated except being coated with a pristine collagen solution. The above roots were transplanted in the sockets that formed previously during tooth extraction. At 6 months' post operation, PDL-like tissue composed of spindle-shaped cells, capillaries and highly organized collagen fibers was observed in the interstitial space between the avulsed root surface and surrounding alveolar bone in Group A. The neo-fibers inserted deeply and perpendicularly into the cementum and adjacent bone. The periodontium-like characteristics of the neo-tissue was confirmed by immunohistochemical staining for collagen I, fibronectin and osteocalcin. RESULTS: A high incidence of PDL re-establishment as 42 % was achieved for samples of Group A. However, no PDL-like tissue was found but root ankylosis and replacement resorption as well as inflammatory resorption was observed in the replanted roots of Group B. CONCLUSIONS: It can be confirmed that avulsed teeth could be successfully rescued even in delayed transplantation to avoid dentoalveolar ankylosis or replacement resorption via the current developed cell homing method. PMID- 26572490 TI - Health care utilization and costs among medical-aid enrollees, the poor not enrolled in medical-aid, and the near poor in South Korea. AB - BACKGROUND: Although government has implemented medical-aid policy that provides assistance to the poor with almost free medical services, there are low-income people who do not receive necessary medical services in Korea. The aim of this study is to highlight the characteristics of Medical-Aid enrollees, the poor not enrolled in Medical-Aid, and the near poor and their utilization and costs for health care. METHODS: This study draws on the 2012 Korea Welfare Panel Study (KOWEPS), a nationally representative dataset. We divided people with income less than 120% of the minimum cost of living (MCL) into three groups (n = 2,784): the poor enrolled in Medical-Aid, the poor not enrolled in Medical-Aid (at or below 100% of MCL), and the near poor (100-120% of MCL). Using a cross-sectional design, this study provides an overview of health care utilization and costs of these three groups. RESULTS: The findings of the study suggest that significantly lower health care utilization was observed for the poor not enrolled in Medical Aid compared to those enrolled in Medical-Aid. On the other hand, two groups (the poor not enrolled in Medical-Aid, the near poor) had higher health care costs, percentage of medical expenses to income compared to Medical-Aid. CONCLUSION: Given the particularly low rate of the population enrolled in Medical-Aid, similarly economically vulnerable groups are more likely to face barriers to needed health services. Meeting the health needs of these groups is an important consideration. PMID- 26572491 TI - Investigating the temporal relationship between individual-level social capital and health in fragile families. AB - BACKGROUND: The potential for social capital to influence health outcomes has received significant attention, yet few studies have assessed the temporal ordering between the two. Even less attention has been paid to more vulnerable populations, such as low-income women with children. Our objective was to explore how different dimensions of social capital impact future health status among this population. METHODS: This study uses data from the Fragile Families and Child Well-Being (FFCWB) Study, which has followed a cohort of children and their families born in large U.S. cities between 1998 and 2000 to mostly minority, unmarried parents who tend to be at greater risk for falling into poverty. Four separate measures of social capital were constructed, which include measures of social support and trust, social participation, perceptions of neighborhood social cohesion, and perceptions of neighborhood social control. The temporal effect of social capital on self-reported health (SRH) is investigated using logistic regression and we hypothesize that higher levels of social capital are associated with higher levels of self-rated health. RESULTS: After controlling for socioeconomic and demographic factors related to social capital and self rated health, social support and trust, perceptions of neighborhood social cohesion and control at an earlier point in time were positively associated with higher levels of health four-years later. Social participation was not related to increased health. The empirical results appear robust. CONCLUSION: Higher levels of social capital are predictive of improved health over a four-year time frame. These results suggest that policy initiatives supporting increasing the social capital available and accessible by low-income, urban, minority women are viable for improving health. Such policies may have the potential to reduce socioeconomic health disparities. PMID- 26572494 TI - Data management, documentation and analysis systems in radiation oncology: a multi-institutional survey. AB - INTRODUCTION: Recently, information availability has become more elaborate and widespread, and treatment decisions are based on a multitude of factors. Gathering relevant data, also referred to as Big Data, is therefore critical for reaching the best patient care, and enhancing interdisciplinary and clinical research. Combining patient data from all involved systems is essential to prepare unstructured data for analyses. This demands special coordination in data management. Our study aims to characterize current developments in German speaking hospital departments and practices. We successfully conducted the survey with the members of the Deutsche Gesellschaft fur Radioonkologie (DEGRO). METHODS: A questionnaire was developed consisting of 17 questions related to data management, documentation and clinical trial analyses, reflecting the clinical topics such as basic patient information, imaging, follow-up information as well as connection of documentation tools with radiooncological treatment planning machines. RESULTS: A total of 44 institutions completed the online survey (University hospitals n = 17, hospitals n = 13, practices/institutes n = 14). University hospitals, community hospitals and private practices are equally equipped concerning IT infrastructure for clinical use. However, private practices have a low interest in research work. All respondents stated the biggest obstacles about introducing a documentation system into their unit lie in funding and support of the central IT departments. Only 27 % (12/44) of responsible persons are specialists for documentation and data management. CONCLUSION: Our study gives an understanding of the challenges and solutions we need to be looking at for medical data storage. In the future, inter-departmental cross-links will enable the radiation oncology community to generate large-scale analyses. PMID- 26572493 TI - Staphylococcus aureus isolates colonizing and infecting cirrhotic and liver transplantation patients: comparison of molecular typing and virulence factors. AB - BACKGROUND: S. aureus is an important agent of colonization and infection in liver transplant patients. It harbors several virulence factors that can increase its pathogenicity. However, studies of virulence and molecular typing of MRSA in cirrhotic and liver transplantation patients are scarce. RESULTS: Here we use SCCmec, PFGE, spa typing, MLST and virulence factors to characterize MRSA isolates in pre and post liver transplantation patients. Sixteen (13%) of 126 cirrhotic and 15 of the 64 liver-transplanted patients (23%) were colonized by MRSA (p=0.091). SCCmec types I, II and III that are generally associated with nosocomial infections were identified in 91% of the isolates. None of the isolates carried PVL, adhesion factors and fib gene. Only three MRSA colonized isolates carried tst gene and were characterized as SCCmec type I and t149. Ten spa types and five STs were identified; t002 and ST105 were the most frequent profiles. Spa types and ST1510 never described in Brazil and a new spa type t14789 were identified. Nineteen PFGE subtypes were found and grouped into nine types. There was a predominant cluster, which was related to the New York/Japanese epidemic clone and harboured SCCmec type II identified in both cirrhotic and post-transplantation patients. Based on SCCmec and virulence factors the MRSA isolates belonged to NY/Jpn clone seen be more similar to the USA100 MRSA isolates. CONCLUSIONS: Although without significance, liver transplantation was more frequently colonized by MRSA than cirrhotic patients. The most frequent SCCmec was type II, and the predominant cluster was related to the New York/Japanese clone. A new spa t14789, and ST1510 never reported in Brazil were identified. PMID- 26572495 TI - Transgenic expression of omega-3 PUFA synthesis genes improves zebrafish survival during Vibrio vulnificus infection. AB - BACKGROUND: Highly desaturated n-3 polyunsaturated fatty acids (PUFAs), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are synthesized by desaturases and elongase. They exert hepatoprotective effects to prevent alcoholic fatty liver syndrome or cholestatic liver injury. However, it is unclear how n-3 PUFAs improve immune function in liver. Vibrio vulnificus, a gram negative bacterial pathogen, causes high mortality of aquaculture fishes upon infection. Humans can become infected with V. vulnificus through open wounds or by eating raw seafood, and such infections may result in systemic septicemia. Moreover, patients with liver diseases are vulnerable to infection, and are more likely than healthy persons to present with liver inflammation following infection. This study quantified n-3 PUFAs and their anti-bacterial effects in Fadsd6 and Elvol5a transgenic zebrafish. RESULTS: Two transgenic zebrafish strains with strong liver specific expression of Fadsd6 and Elvol5a (driven by the zebrafish Fabp10 promoter) were established using the Tol2 system. Synthesis of n-3 PUFAs in these strains were increased by 2.5-fold as compared to wild type (Wt) fish. The survival rate in 24 h following challenge with V. vulnificus was 20 % in Wt, but 70 % in the transgenic strains. In addition, the bacteria counts in transgenic fish strains were significantly decreased. The expression levels of pro-inflammatory genes, such as TNF-alpha, IL-1beta, and NF-kappaB, were suppressed between 9 and 12 h after challenge. This study confirms the anti bacterial function of n-3 PUFAs in a transgenic zebrafish model. CONCLUSIONS: Fadsd6 and Elvol5a transgenic zebrafish are more resistant to V. vulnificus infection, and enhance survival by diminishing the attendant inflammatory response. PMID- 26572496 TI - Relationship of Height to Site-Specific Fracture Risk in Postmenopausal Women. AB - Height has been associated with increased risk of fracture of the neck of femur. However, information on the association of height with fractures at other sites is limited and conflicting. A total of 796,081 postmenopausal women, who reported on health and lifestyle factors including a history of previous fractures and osteoporosis, were followed for 8 years for incident fracture at various sites by record linkage to National Health Service hospital admission data. Adjusted relative risks of fracture at different sites per 10-cm increase in height were estimated using Cox regression. Numbers with site-specific fractures were: humerus (3036 cases), radius and/or ulna (1775), wrist (9684), neck of femur (5734), femur (not neck) (713), patella (649), tibia and/or fibula (1811), ankle (5523), and clavicle/spine/rib (2174). The risk of fracture of the neck of femur increased with increasing height (relative risk [RR] = 1.48 per 10-cm increase, 99% confidence interval [CI] 1.39-1.57) and the proportional increase in risk was significantly greater than for all other fracture sites (pheterogeneity < 0.001). For the other sites, fracture risk also increased with height (RR = 1.15 per 10 cm, CI 1.12-1.18), but there was only very weak evidence of a possible difference in risk between the sites (pheterogeneity = 0.03). In conclusion, taller women are at increased risk of fracture, especially of the neck of femur. PMID- 26572497 TI - Multiple Eruptive Pyogenic Granulomas Occurring in a Region of Scalded Skin. AB - We report a case of multiple eruptive pyogenic granulomas after scalding. A 4 year-old girl developed papules and nodules within the scalded areas after a hot soup burn. Although the occurrence of pyogenic granulomas after trauma to the skin is common, multiple lesions of pyogenic granuloma secondary to scalding are rare. PMID- 26572498 TI - Intense Chiral Optical Phenomena in Racemic Polymers by Cocrystallization With Chiral Guest Molecules: A Brief Overview. AB - This review is devoted to the chiral optical behavior of films of racemic polymers whose chirality is induced by cocrystallization with nonracemic (also temporary) guest molecules. We provide examples of macromolecular amplification of chirality, produced by molecular and supramolecular mechanisms, on industrially relevant polymers like poly(2,6-dimethyl-1,4-phenylene)oxide (PPO) and syndiotactic polystyrene (s-PS). PMID- 26572499 TI - Is FDG-PET/CT a sensitive and specific method for the detection of extranodal involvement in diffuse large B-cell lymphoma? PMID- 26572500 TI - Fabrication of Ruthenium Nanoparticles in Porous Organic Polymers: Towards Advanced Heterogeneous Catalytic Nanoreactors. AB - A novel strategy has been adopted for the construction of a copolymer of benzene benzylamine-1 (BBA-1), which is a porous organic polymer (POP) with a high BET surface area, through Friedel-Crafts alkylation of benzylamine and benzene by using formaldehyde dimethyl acetal as a cross-linker and anhydrous FeCl3 as a promoter. Ruthenium nanoparticles (Ru NPs) were successfully distributed in the interior cavities of polymers through NaBH4, ethylene glycol, and hydrothermal reduction routes, which delivered Ru-A, Ru-B, and Ru-C materials, respectively, and avoided aggregation of metal NPs. Homogeneous dispersion, the nanoconfinement effect of the polymer, and the oxidation state of Ru NPs were verified by employing TEM, energy-dispersive X-ray spectroscopy mapping, cross polarization magic-angle spinning (13)C NMR spectroscopy, and X-ray photoelectron spectroscopy analytical tools. These three new Ru-based POP materials exhibited excellent catalytic performance in the hydrogenation of nitroarenes at RT (with a reaction time of only ~ 30 min), with high conversion, selectivity, stability, and recyclability for several catalytic cycles, compared with other traditional materials, such as Ru@C, Ru@SiO2, and Ru@TiO2, but no clear agglomeration or loss of catalytic activity was observed. The high catalytic performance of the ruthenium-based POP materials is due to the synergetic effect of nanoconfinement and electron donation offered by the 3D POP network. DFT calculations showed that hydrogenation of nitrobenzene over the Ru (0001) catalyst surface through a direct reaction pathway is more favorable than that through an indirect reaction pathway. PMID- 26572501 TI - Dual-Loop Bi-Atrial Macroreentrant Atrial Tachycardia in a Patient With Modified Cox Maze IV: Where Is the Initial Ablation Target? PMID- 26572502 TI - ATR inhibition rewires cellular signaling networks induced by replication stress. AB - The slowing down or stalling of replication forks is commonly known as replication stress and arises from multiple causes such as DNA lesions, nucleotide depletion, RNA-DNA hybrids, and oncogene activation. The ataxia telangiectasia and Rad3-related kinase (ATR) plays an essential role in the cellular response to replication stress and inhibition of ATR has emerged as therapeutic strategy for the treatment of cancers that exhibit high levels of replication stress. However, the cellular signaling induced by replication stress and the substrate spectrum of ATR has not been systematically investigated. In this study, we employed quantitative MS-based proteomics to define the cellular signaling after nucleotide depletion-induced replication stress and replication fork collapse following ATR inhibition. We demonstrate that replication stress results in increased phosphorylation of a subset of proteins, many of which are involved in RNA splicing and transcription and have previously not been associated with the cellular replication stress response. Furthermore, our data reveal the ATR-dependent phosphorylation following replication stress and discover novel putative ATR target sites on MCM6, TOPBP1, RAD51AP1, and PSMD4. We establish that ATR inhibition rewires cellular signaling networks induced by replication stress and leads to the activation of the ATM-driven double-strand break repair signaling. PMID- 26572503 TI - Omeprazole and Semen Quality. AB - A number of studies have linked omeprazole, a commonly used acid reducer under the brand name Prilosec, with semen quality. This MiniReview systematically addresses and summarizes the effect of omeprazole on semen quality, and male infertility. We searched the MEDLINE electronic database for English-language articles using the keywords 'omeprazole' versus 'sperm' and 'testosterone' and the references from selected articles were reviewed, if relevant. In summary, omeprazole does not appear to change semen quality. This may be because, at least in part, it does not alter the basal levels of pituitary-gonadal hormones; in addition, it counteracts the damaging effect of reactive oxygen species. However, further research is still required to confirm this effect. PMID- 26572504 TI - Caring for pregnant women for whom transfusion is not an option. A national review to assist in patient care. AB - Postpartum haemorrhage (PPH) is the leading cause of maternal mortality and morbidity globally. Obstetric bleeding can be catastrophic and management is challenging, involving a coordinated multidisciplinary approach, which may include blood products. In settings where blood transfusion is not an option, either because of patient refusal (most commonly in Jehovah Witnesses) or because of unavailability of blood, management becomes even more challenging. Observational studies have demonstrated an association between refusal of blood products in major obstetric haemorrhage and increased morbidity and mortality. This review draws upon evidence in the literature, physiological principles and expert opinion for strategies and guidance to optimise the outcomes of pregnant women in whom blood transfusion is either refused or impossible. The importance of a multidisciplinary antenatal and perinatal management plan, including optimisation of haemoglobin and iron stores pre-delivery, blood loss minimisation, early haemorrhage control and postpartum anaemia treatment, is discussed. PMID- 26572505 TI - Volumetric optoacoustic imaging feedback during endovenous laser therapy - an ex vivo investigation. AB - Endovenous laser therapy (ELT) was introduced in clinical practice for treating incompetent veins about fifteen years ago. Despite the considerable clinical evidence collected so far, no rigorous guidelines are yet available regarding the optimal energy deposition protocols while incidence of recanalization, lack of vessel occlusion and collateral damage remains variable among patients. Online monitoring and feedback-based control over the lesion progression may improve clinical outcomes. Yet the currently employed monitoring tools, such as Doppler ultrasound, often do not provide sufficient contrast as well as three-dimensional imaging capacity for accurate lesion assessment during thermal treatments. Here we investigate on the utility of volumetric optoacoustic tomography for real-time monitoring of the ELT procedures. Experiments performed in subcutaneous veins of an ox foot model revealed the accurate spatio-temporal maps of the lesion progression and characteristics of the vessel wall. Optoacoustic images further correlated with the temperature elevation measured in the area adjacent to the coagulation spot and made it possible to track the position of the fiber tip during its pull back in real time and in all three dimensions. Overall, we showcase that volumetric optoacoustic tomography is a promising tool for providing online feedback during endovenous laser therapy. PMID- 26572506 TI - Enantioselective Total Synthesis of (-)-Martinellic Acid. AB - An enantioselective total synthesis of martinellic acid is described. The pyrroloquinoline alkaloid core is efficiently prepared from a quinoline, employing a method which relies on a newly developed Cu-catalyzed enantioselective alkynylation using the chiral imidazole-based biaryl P,N ligand StackPhos to establish the absolute stereochemistry. The remaining carbon atoms are then installed by means of a diastereoselective Pd-catalyzed decarboxylative allylation and the synthesis is completed after straightforward functional-group manipulation. This new synthetic method enables the most concise enantioselective synthesis of this important class of molecules to date. PMID- 26572507 TI - Pharmacokinetic profile of Optivate(r) (high-purity factor VIII/von Willebrand factor concentrate) in treating von Willebrand disease. PMID- 26572508 TI - Rotavirus-induced miR-142-5p elicits proviral milieu by targeting non-canonical transforming growth factor beta signalling and apoptosis in cells. AB - MicroRNA (miRNA) expression is significantly influenced by viral infection, because of either host antiviral defences or proviral factors resulting in the modulation of viral propagation. This study was undertaken to identify and analyse the significance of cellular miRNAs during rotavirus (SA11 or KU) infection. Sixteen differentially regulated miRNAs were identified during rotavirus infection of which hsa-miR-142-5p was up-regulated and validated by quantitative polymerase chain reaction. Exogenous expression of miR-142-5p inhibitor resulted in a significant reduction of viral titer indicating proviral role of miR-142-5p. Functional studies of hsa-miR-142-5p identified its role in transforming growth factor beta (TGFbeta) signalling as TGFbeta receptor 2 and SMAD3 were degraded during both hsa-miR-142-5p overexpression and rotavirus infection. TGFbeta is induced during rotavirus infection, which may promote apoptosis by activation of non-canonical pathways in HT29 cells. However, up regulated miR-142-5p resulted in the inhibition of TGFbeta-induced apoptosis suggesting its anti-apoptotic function. Rotavirus NSP5 was identified as a regulator of miR-142-5p expression. Concurrently, NSP5-HT29 cells showed inhibition of TGFbeta-induced apoptosis and epithelial to mesenchymal transition by blocking non-canonical pathways. Overall, the study identified proviral function of hsa-miR-142-5p during rotavirus infection. In addition, modulation of TGFbeta-induced non-canonical signalling in microsatellite stable colon cancer cells can be exploited for cancer therapeutics. PMID- 26572509 TI - Impact of delay between imaging and treatment in patients with potentially curable pancreatic cancer. AB - BACKGROUND: Locoregional pancreatic ductal adenocarcinoma (PDAC) may progress rapidly and/or disseminate despite having an early stage at diagnostic imaging. A prolonged interval from imaging to resection might represent a risk factor for encountering tumour progression at laparotomy. The aim of this study was to determine the therapeutic window for timely surgical intervention. METHODS: This observational cohort study included patients with histologically confirmed PDAC scheduled for resection with curative intent from 2008 to 2014. The impact of imaging-to-resection/reassessment (IR) interval, vascular involvement and tumour size on local tumour progression or presence of metastases at reimaging or laparotomy was evaluated using univariable and multivariable regression. Risk estimates were approximated using hazard ratios (HRs). RESULTS: Median IR interval was 42 days. Of 349 patients scheduled for resection, 82 had unresectable disease (resectability rate 76.5 per cent). The unresectability rate was zero when the IR interval was 22 days or shorter, and was lower for an IR interval of 32 days or less compared with longer waiting times (13 versus 26.2 per cent; HR 0.42, P = 0.021). It was also lower for tumours smaller than 30 mm than for larger tumours (13.9 versus 32.5 per cent; HR 0.34, P < 0.001). Tumours with no or minor vascular involvement showed decreased rates of unresectable disease (20.6 per cent versus 38 per cent when there was major or combined vascular involvement; HR 0.43, P = 0.007). However, this failed to reach statistical significance on multivariable analysis (P = 0.411), in contrast to IR interval (P = 0.028) and tumour size (P < 0.001). CONCLUSION: Operation within 32 days of diagnostic imaging reduced the risk of tumour progression to unresectable disease by half compared with a longer waiting time. The results of this study highlight the importance of efficient clinical PDAC management. PMID- 26572510 TI - Steroids in ARDS: to be or not to be. PMID- 26572511 TI - Diaphragmatic dysfunction in patients with ICU-acquired weakness and its impact on extubation failure. AB - PURPOSE: Diaphragm function is rarely studied in intensive care patients with unit-acquired weakness (ICUAW) in whom weaning from mechanical ventilation is challenging. The aim of the present study was to evaluate the diaphragm function and the outcome using a multimodal approach in ICUAW patients. METHODS: Patients were eligible if they were diagnosed for ICUAW [Medical Research Council (MRC) Score <48], mechanically ventilated for at least 48 h and were undergoing a spontaneous breathing trial. Diaphragm function was assessed using magnetic stimulation of the phrenic nerves (change in endotracheal tube pressure), maximal inspiratory pressure and ultrasonographically (thickening fraction). Diaphragmatic dysfunction was defined by a change in endotracheal tube pressure below 11 cmH2O. The endpoints were to describe the correlation between diaphragm function and ICUAW and its impact on extubation. RESULTS: Among 185 consecutive patients ventilated for more than 48 h, 40 (22 %) with a MRC score of 31 [20-36] were included. Diaphragm dysfunction was observed with ICUAW in 32 patients (80 %). Change in endotracheal tube pressure and MRC score were not correlated. Maximal inspiratory pressure was correlated with change in endotracheal tube pressure after magnetic stimulation of the phrenic nerves (r = 0.43; p = 0.005) and MRC score (r = 0.34; p = 0.02). Thickening fraction was less than 20 % in 70 % of the patients and was statistically correlated with change in endotracheal tube pressure (r = 0.4; p = 0.02) but not with MRC score. Half of the patients could be extubated without needing reintubation within 72 h. CONCLUSION: Diaphragm dysfunction is frequent in patients with ICU-acquired weakness (80 %) but poorly correlated with the ICU-acquired weakness MRC score. Half of the patients with ICU-acquired weakness were successfully extubated. Half of the patients who failed the weaning process died during the ICU stay. PMID- 26572512 TI - Giant craniopharyngiomas in children: short- and long-term implications. AB - OBJECT: Craniopharyngiomas (CPs) are histologically benign tumors, yet they may carry an unfavorable prognosis. "Giant" tumors are associated with worse prognosis. Our aim was to evaluate the impact of tumor's size on different short- and long-term clinical factors. METHODS: Between 2002 and 2012, a total of 36 consecutive CP patients less than 18 years of age and with at least 12 months of post-operative follow-up (FU) underwent a total of 54 operations for excision of CPs. Gross total resection (GTR) was the goal for all the first surgical resections. Twenty-seven patients were identified as eligible for inclusion in this study. Data were retrospectively collected by reviewing pertinent clinic/office notes and inpatient records as well as pre- and post-operative imaging. Long-term neurosurgical, ophthalmological, and endocrinological outcomes were obtained from records of the most recent FU office visit. Statistical analysis was performed to compare data from patients with tumors greater than or equal to 4.5 cm (nine patients) to those with smaller ones (<4.5 cm; 18 patients). RESULTS: Mean age at the time of surgery was 5.4 years (median 5 years, range 1.3-15.3 years) for patients in the large-tumor group (LTG) and 8.9 years (median 9.6 years, range 2.1-17.1 years) for the small-tumor group (STG). Average duration of follow-up was 82.1 and 105.4 months for LTG and STG patients, respectively. There was a noticeable difference in the rate of emergent surgeries between the two groups (33.3 vs. 5.5 % in the LTG and STG, respectively; p = 0.055) as well as in recurrent surgeries (RR = 3.76; CI = 95 %, 1.793-7.877) and radiotherapy (RR = 2, 95 % CI 0.775-5.154). Rates of residual tumor on both initial post-operative imaging and last FU imaging were significantly increased in LTG patients (44.5 vs. 27.7 % and 66.6 vs. 16.6 %; respectively). Progression free survivals (PFS) assessed at 2 and 5 years were 33.3 vs. 73.3 % (RR = 2.2, 95 % CI = 0.171-1.202) and 33.3 vs. 53.3 % (RR = 1.6, 95 % CI 0.221-1.765) in favor of smaller tumors. No difference in 2-, 5-, and 10-year overall survival was found. We found no significant difference in mean BMI at last follow-up between the two groups (23.83 +/- 4.86 and 27.33 +/- 8.09, respectively; p = 0.27), although significantly more patients in the LTG had shorter stature (mean height SDS -1.72 +/- 1.88 and -0.17 +/- 1.08 in LTG and STG patients, respectively; p = 0.027). CONCLUSION: Tumor's size has significant impact on the management of CP in children. It affects both short-term factors (initial symptoms, urgency of surgical resection, extent of resection, and perioperative morbidity) as well as long-term parameters (PFS, rate of adjuvant treatments/recurrent surgeries, and metabolic/endocrinal/ophthalmological and functional outcomes). We think that a proper, world-wide accepted definition of what is "large," "giant," or even "monstrous" CP should be established. This will enable carrying multi institutional studies on a larger group of patients, allowing further determining the importance of tumor's size in the management and outcome of craniopharyngiomas in children. PMID- 26572513 TI - Evolution of cerebellar tonsillar ischemia to cerebellar tonsillar cysts in the Chiari I malformation: radiological, surgical, and histological evidence. AB - BACKGROUND: Rare reports in the literature have documented the presence of a cyst at the tip of the cerebellar tonsil in patients with Chiari I malformation. The current study aimed to better elucidate these cysts and identify their etiology via a histological and radiologically analysis. PATIENTS AND METHODS: We prospectively reviewed all new Chiari I malformation (CM-I) patients who presented to our clinic during a 2-year period. This was a pediatric cohort made up of 340 children aged 3 to 18 years. Specifically, all patients were screened for ischemic or cystic lesions of the herniated cerebellar tonsils on MRI. RESULTS: Out of 340 patients, 2.9 % were found to have signal changes on MRI consistent with ischemia or cysts in the cerebellar tonsils. Of the 340 patients, 20 % underwent posterior fossa decompression. Of the 67 patients, cerebellar tonsillar ischemia was observed in 10.4 % and cerebellar tonsillar cysts were seen in 6 %. Four of the seven operative patients with cerebellar tonsillar ischemia and concomitant syringomyelia and three of these patients with tonsillar cysts concomitant syringomyelia and cerebellar tonsillar cysts underwent subpial dissection of some cerebellar tonsil to ensure that CSF egress from the fourth ventricle to the cervical subarachnoid space, and this transected tissue was also sent for histological analysis. Three of the four patients found to have intraoperative tonsillar cysts were noted to have tonsillar ischemic changes on preoperative imaging in this same region. For both ischemic and cystic cerebellar tonsils, histologically, the tissue demonstrated loss of Purkinje cells with concomitant Bergmann gliosis. The ischemic and cystic tissues were virtually the same, histologically. CONCLUSIONS: Based on our findings, cerebellar tonsillar ischemia and cysts in patients with CM-I can often be seen radiologically. Histologically, these ischemic and cystic tissues are the same. Moreover, we document patients where ischemic lesions progressed to cysts, radiologically. Taken together, cerebellar tonsillar ischemia and cysts are on a continuum and represent chronic compression of this herniated part of the cerebellum. PMID- 26572514 TI - Role of "major" and "minor" lambdoid arch sutures in posterior cranial fossa changes: mechanism of cerebellar tonsillar herniation in infants with multisutural craniosynostosis. AB - PURPOSE: This study aimed to explain the functional role of lambdoid arch sutures in the development of cerebellar tonsillar herniation. Posterior cranial fossa (PCF) changes were investigated in infants with premature synostosis of the major and minor sutures of the lambdoid arch without premature synostosis of the PCF synchondroses. METHODS: Morphometric and volumetric PCF measurements were performed on preoperative high-resolution CT studies in 12 infants with multisutural craniosynostosis involving the lambdoid arch and compared with those of 12 age-matched healthy subjects. RESULTS: All 12 patients had hypoplasia of PCF bone structures and normal volumes of the PCF and neural structures. PCF hypoplasia was related to exocciput length in infants with isolated involvement of major sutures, while it was related to posterior skull base hemifossae in infants with isolated involvement of minor lambdoid arch sutures. Foramen magnum AP diameter was reduced in babies with major suture involvement and tonsillar herniation, while foramen magnum AP and LL diameters were reduced in babies with minor suture involvement without tonsillar herniation. Right and left jugular foramen (JF) areas differed in all infants; however, the area of the smaller JF was significantly reduced only in infants with involvement of minor lambdoid arch sutures. CONCLUSION: Hypoplasia of PCF bone structures due to sutural synostosis of the lambdoid arch is a required predisposing but not sufficient factor for the development of cerebellar tonsillar herniation through the foramen magnum. Normal PCF volume and foramen magnum anatomy may partly explain the development of cerebellar tonsil herniation in infants with lambdoid arch synostosis. PMID- 26572515 TI - Modified concentric craniotomy for the removal of a huge calvarial metastatic tumor: technical note. AB - BACKGROUND: It is challenging for neurosurgeons to remove huge tumors involving the skull that may possibly invade the dura or intracranial neural tissue. In this situation, excision of the tumor may cause profound blood loss, unexpected opening of the dura, or neurological injury. We describe a technique of craniotomy in a pediatric patient to avoid surgical complications. METHODS: A 15 year-old boy had a huge metastatic calvarial Ewing's sarcoma. We removed the tumor successfully with modified concentric craniotomy. First, two oval burr holes are made on both sides of the tumor. The inner craniotomy uses the internal margin of the oval holes, while the outer cut uses the outer margins. The skull bone in between the two craniotomies is removed easily in two pieces and the dura surrounding the tumor can be exposed early in the procedure. In this way, the huge skull tumor can be removed en bloc under direct vision to avoid unwanted complications. Minimal blood and bone loss can be achieved. RESULTS: Blood transfusion was not necessary during the surgery. The patient did not have new neurological symptoms and signs after surgery. CONCLUSIONS: The goal of the modified concentric craniotomy is to develop an accessible margin of the dura surrounding the bulky tumor in the early phase of surgery. Blood and bone loss can be reduced significantly. PMID- 26572516 TI - Predicting dentists' decisions: a choice-based conjoint analysis of Medicaid participation. AB - OBJECTIVES: Private practice dentists are the major source of care for the dental safety net; however, the proportion of dentists who participate in state Medicaid programs is low, often due to poor perceptions of the program's administration and patient population. Using a discrete choice experiment and a series of hypothetical scenarios, this study evaluated trade-offs dentists make when deciding to accept Medicaid patients. METHODS: An online choice-based conjoint survey was sent to 272 general dentists in Iowa. Hypothetical scenarios presented factors at systematically varied levels. The primary determination was whether dentists would accept a new Medicaid patient in each scenario. Using an ecological model of behavior, determining factors were selected from the categories of policy, administration, community, and patient population to estimate dentists' relative preferences. RESULTS: 62 percent of general dentists responded to the survey. The probability of accepting a new Medicaid patient was highest (81 percent) when reimbursement rates were 85 percent of the dentist's fees, patients never missed appointments, claims were approved on first submission, and no other practices in the area accepted Medicaid. Although dentists preferred higher reimbursement rates, 56 percent would still accept a new Medicaid patient when reimbursement decreased to 55 percent if they were told that the patient would never miss appointments and claims would be approved on initial submission. CONCLUSIONS: This study revealed trade-offs that dentists make when deciding to participate in Medicaid. Findings indicate that states can potentially improve Medicaid participation without changing reimbursement rates by making improvements in claims processing and care coordination to reduce missed appointments. PMID- 26572517 TI - Why not nursing? A systematic review of factors influencing career choice among healthcare students. AB - BACKGROUND: A global shortage of healthcare professionals calls for effective recruitment and retention strategies. The nursing profession faces greater staffing shortages compared with other healthcare professions. Identifying these factors for choosing a career in health care is an important step in structuring future nursing recruitment strategies. AIM: This systematic review examined the motivations for choosing a career in health care, then compared them to factors that influence the choice to pursue a career in nursing. METHODS: A literature search of the CINAHL, PubMed, Web of Science and Scopus databases for articles published between 2002 and 2013 was conducted. The search included studies that focused on factors influencing career choice among undergraduate medicine, dentistry, pharmacy and nursing students. RESULTS: A total of 29 papers were included in the review. The themes and subthemes that emerged from this review included: (1) intrinsic factors, including a desire to help others and a personal interest in health care, (2) extrinsic factors, such as financial remuneration, job security, professional prestige and job autonomy, (3) socio-demographic factors such as gender and socio-economic status, and (4) interpersonal factors, encompassing the influence of family and other professional individuals. DISCUSSION: Healthcare professionals were generally motivated by intrinsic factors. However, public perceptions of nursing as a low-paying and low-status job have significantly hindered the participants' choice to pursue it as a career. CONCLUSION AND IMPLICATIONS FOR NURSING AND/OR HEALTH POLICY: Nursing institutions could provide more platforms to help school leavers better understand the nursing career. In turn, hospital administrators could invite parents to nursing career fairs, increase financial remuneration for nurses, and provide decision-making avenues aimed at recruiting and retaining more nurses. PMID- 26572518 TI - Bioreactors for lignocellulose conversion into fermentable sugars for production of high added value products. AB - Lignocellulosic biomasses derived from dedicated crops and agro-industrial residual materials are promising renewable resources for the production of fuels and other added value bioproducts. Due to the tolerance to a wide range of environments, the dedicated crops can be cultivated on marginal lands, avoiding conflict with food production and having beneficial effects on the environment. Besides, the agro-industrial residual materials represent an abundant, available, and cheap source of bioproducts that completely cut out the economical and environmental issues related to the cultivation of energy crops. Different processing steps like pretreatment, hydrolysis and microbial fermentation are needed to convert biomass into added value bioproducts. The reactor configuration, the operative conditions, and the operation mode of the conversion processes are crucial parameters for a high yield and productivity of the biomass bioconversion process. This review summarizes the last progresses in the bioreactor field, with main attention on the new configurations and the agitation systems, for conversion of dedicated energy crops (Arundo donax) and residual materials (corn stover, wheat straw, mesquite wood, agave bagasse, fruit and citrus peel wastes, sunflower seed hull, switchgrass, poplar sawdust, cogon grass, sugarcane bagasse, sunflower seed hull, and poplar wood) into sugars and ethanol. The main novelty of this review is its focus on reactor components and properties. PMID- 26572519 TI - Temporal-spatial variation of bacterial diversity in estuary sediments in the south of Zhejiang Province, China. AB - The winter and summer microbial community structure in sediment samples obtained from the estuaries of the wastewater-polluted River Ou (DO and XO), River Feiyun (DF and XF), and River Ao (DA and XA) in the south of Zhejiang Province in China was determined using 454 pyrosequencing. Sediment samples (DD and XD) were also correspondingly collected near the shore far from the estuaries for comparison. For the above sediments, 294,870 effective sequences were obtained to do the bacterial diversity and abundance determination. In total, 1924, 1517, 2071, 1956, 1995, 1800, 2261, and 2097 operational taxonomic units were obtained at 3 % distance cutoff in the DO, XO, DF, XF, DA, XA, DD, and XD sediments, respectively. Bacterial phylotype richness in DD was higher than the other sediments, and XO had the least richness. The most dominant class in the DA, DD, DF, DO, and XA sediments is Gammaproteobacteria. Deltaproteobacteria is the most dominant one in XD, XO, and XF. Circa 14.4 % sequences in XD were found to be affiliated with the Flavobacteriales order. Characterization of the estuarine sediment bacterial communities indicated that chemical pollution has the potential to decrease the natural variability that exists among estuary ecosystems. However, chemical pollutants did not cause clear bio-homogenization in these estuaries. PMID- 26572520 TI - Nutrient and media recycling in heterotrophic microalgae cultures. AB - In order for microalgae-based processes to reach commercial production for biofuels and high-value products such as omega-3 fatty acids, it is necessary that economic feasibility be demonstrated at the industrial scale. Therefore, process optimization is critical to ensure that the maximum yield can be achieved from the most efficient use of resources. This is particularly true for processes involving heterotrophic microalgae, which have not been studied as extensively as phototrophic microalgae. An area that has received significant conceptual praise, but little experimental validation, is that of nutrient recycling, where the waste materials from prior cultures and post-lipid extraction are reused for secondary fermentations. While the concept is very simple and could result in significant economic and environmental benefits, there are some underlying challenges that must be overcome before adoption of nutrient recycling is viable at commercial scale. Even more, adapting nutrient recycling for optimized heterotrophic cultures presents some added challenges that must be identified and addressed that have been largely unexplored to date. These challenges center on carbon and nitrogen recycling and the implications of using waste materials in conjunction with virgin nutrients for secondary cultures. The aim of this review is to provide a foundation for further understanding of nutrient recycling for microalgae cultivation. As such, we outline the current state of technology and practical challenges associated with nutrient recycling for heterotrophic microalgae on an industrial scale and give recommendations for future work. PMID- 26572521 TI - Fermentation and genomic analysis of acetone-uncoupled butanol production by Clostridium tetanomorphum. AB - In typical acetone-butanol-ethanol (ABE) fermentation, acetone is the main by product (50 % of butanol mass) of butanol production, resulting in a low yield of butanol. It is known that some Clostridium tetanomorphum strains are able to produce butanol without acetone in nature. Here, we described that C. tetanomorphum strain DSM665 can produce 4.16 g/L butanol and 4.98 g/L ethanol at pH 6.0, and 9.81 g/L butanol and 1.01 g/L ethanol when adding 1 mM methyl viologen. Butyrate and acetate could be reassimilated and no acetone was produced. Further analysis indicated that the activity of the acetate/butyrate:acetoacetyl-CoA transferase responsible for acetone production is lost in C. tetanomorphum DSM665. The genome of C. tetanomorphum DSM665 was sequenced and deposited in DDBJ, EMBL, and GenBank under the accession no. APJS00000000. Sequence analysis indicated that there are no typical genes (ctfA/B and adc) that are typically parts of an acetone synthesis pathway in C. tetanomorphum DSM665. This work provides new insights in the mechanism of clostridial butanol production and should prove useful for the design of a high butanol-producing strain. PMID- 26572522 TI - Optimization of Lactobacillus acidophilus cultivation using taro waste and evaluation of its biological activity. AB - In this study, taro waste (TW) was utilized for Lactobacillus acidophilus BCRC 14079 cultivation and the anti-tumor and immune-modulatory properties of heat killed cells (HKCs), cytoplasmic fraction (CF), and exopolysaccharide (EPS) were evaluated. The optimum liquefaction enzyme dosage, temperature, and time determined by Box-Behnken design response surface methodology (BBD-RSM) were 9 mL/L of alpha-amylase, 79.2 degrees C, and 5 h of reaction, respectively. The optimum temperature and reaction time for saccharification were determined as 60 degrees C and 3 h. The optimum medium, CGMY1 medium, constitutes of TW hydrolysate containing 37 g/L of glucose, 25 g/L of corn gluten meal (CGM), and 1 g/L of yeast extract (YE). Results of MTT assay showed that HKCs and EPS from CGM medium exhibited the highest anti-proliferative in HT-29 (IC50 of HKCs, 467.25 MUg/mL; EPS, 716.10 MUg/mL) and in Caco-2 cells (IC50 of EPS, 741.60 MUg/mL). Luciferase-based NF-KappaB and COX-2 systems indicated HKCs from CGM medium stimulated the highest expression of luciferin in both systems. The luciferase activities by using 100 and 500 MUg/mL of HKCs from CGM were 24.30- and 45.83 fold in NF-KappaB system and 11.54- and 4.93-fold in COX-2 system higher than the control. In conclusion, this study demonstrated the potential of TW medium for L. acidophilus cultivation and the production of non-viable probiotics with enhanced biological activities. PMID- 26572523 TI - Constitutive overexpression of asm18 increases the production and diversity of maytansinoids in Actinosynnema pretiosum. AB - Ansamitocins isolated from Actinosynnema pretiosum, potent antitumor compounds, belong to the family of maytansinoids, and the antibody-maytansinoid conjugates are currently under different phases of clinical trials. The clinical applications of ansamitocins have stimulated extensive studies to improve their production yields. In this study, we investigated the function of a pathway specific S treptomyces antibiotic regulatory protein (SARP) family regulator, Asm18, and observed that ectopic overexpression of the asm18 gene increased the production of N-demethyl-4,5-desepoxy-maytansinol (2) to 50 mg/L in the HGF052 + pJTU824-asm18 strain, an increase by 4.7-fold compared to that of the control strain HGF052 + pJTU824. Real-time PCR analysis showed that the overexpression of the asm18 gene selectively increased the transcription levels of the genes involved in the biosynthesis of the starter unit (asm43), polyketide assembly (asmA), post-PKS modification (asm21), as well as the transcription levels of the regulatory gene (asm8), which is a specific LAL-type activator in ansamitocin biosynthesis. With the increase of fermentation titre, seven ansamitocin analogs (1-7) including three new ones (1, 5, and 6) and maytansinol (7) were isolated from the HGF052 + pJTU824-asm18 strain. Our results not only pave the way for further improving the production of ansamitocin analogs but also indicate that the post-PKS modifications of ansamitocin biosynthesis are flexible, which brings a potential of producing maytansinol, the most fascinating intermediate for the synthesis of antibody-maytansinoid conjugates, by optimizing the HGF052 and/or HGF052 + pJTU824-asm18 strains. PMID- 26572524 TI - Hemorrhagic Complications in Laparoscopic Sleeve Gastrectomy. PMID- 26572525 TI - Minimising Haemorrhagic Complications with Bariatric Surgery. PMID- 26572527 TI - Similarities between a manuscript in Clin Oral Invest (published online 21 July 2015; DOI 10.1007/s00784-015-1530-4) and a former publication (J Investig Clin Dent 2010;1(2):126-32. doi: 10.1111/j.2041-1626.2010.00026.x.). PMID- 26572526 TI - Role of Percutaneous Glue Treatment After Persisting Leak After Laparoscopic Sleeve Gastrectomy. AB - BACKGROUND: Over the years, many treatment modes have been attempted for gastrocutaneous fistula (GCF) after laparoscopic sleeve gastrectomy (LSG). Minimally invasive techniques for GCF treatment include stent placement and radiological percutaneous glue treatment (GT). MATERIAL AND METHOD: Ten patients underwent a radiological acrylate mixed with contrast medium GT combined or not with other treatment strategies such as relaparoscopy, ultrasound, or computerized tomography scan (CT scan)-guided drain and endoscopic stent placement. RESULTS: Ten patients (mean age 47.1 years, range 64-29) were treated by percutaneous injection of glue after LSG leak. Body mass index (BMI) was 42.2 kg/m(2) +/- 6.7 at the time of LSG surgery. Mean time between LSG and leak diagnosis was 12 days (range 4-31 days). GT was only effective when performed after endoscopic stent placement (80 % resolution). With this regimen, five patients required a laparoscopic Roux limb placement. All fistulas eventually healed a mean of 75 days (range 29-293 days) after GCF diagnosis. CONCLUSIONS: Percutaneous glue treatment alone does not seem to provide adequate results. Stenting previous to the glue treatment allows for better results. PMID- 26572528 TI - An oral health survey of vulnerable older people in Belgium. AB - OBJECTIVES: The aim of this study was to gain insight in the oral health of persons aged 65 years or more. MATERIALS AND METHODS: Data were obtained from 652 vulnerable older persons (>=65) by means of a clinical oral examination. Additional demographic data were gathered including age, gender, residence, and care dependency. RESULTS: The mean age of the total study sample was 83 (7.7) years and 71 % was female. Nearly 33 % of the sample was living at home with support, and 67 % was residing in nursing homes. The number of occluding pairs was low and the proportion of edentulous people was highest among persons with the highest care dependency. The mean Decay-missing-filled teeth index (DMFT) was 20.3 (9.0). A prosthetic treatment need and inadequate oral hygiene levels were observed in 40 % and more than 60 % of the subjects, respectively. The highest treatment need was observed in the oldest age group and the highest mean dental plaque in older persons with the highest care dependency. CONCLUSIONS: The oral health in frail older people in Belgium is poor. The restorative and prosthetic treatment need is high and oral hygiene levels are problematic. Age, residence, and care dependency seemed to have some influence on oral health parameters. CLINICAL SIGNIFICANCE: In the long term, the most important future challenge of oral health care policies is to identify older adults before they begin to manifest such oral health deterioration. Regular dental visits should be strongly promoted by all (oral) health care workers during the lifespan of all persons including older adults. PMID- 26572529 TI - Chelating effect of citric acid is negligible for development of enamel erosions. AB - AIM: Citric acid (CA) is a component in beverages responsible for dental erosion. The aim of this study was to examine the influence of CA with different pH, titratable acid and buffer capacity (beta), and the impact of the chelating effect of CA on development of enamel erosions. MATERIAL AND METHODS: In a superfusion model, hydroxy apatite (HAp) dissolution of bovine enamel was measured in four experiments (EXP 1-4) with 27 experimental groups (n = 8 per group). The samples were superfused with different CA variations and respective controls. EXP-1: Dilution series of HCl (pH 2.15-3.02). EXP-2: Dilution series of natural CA (56-1.75 mmol l(-1); pH 2.15-3.02). EXP-3: CA solutions (56 and 14 mmol l(-1), beta: 39.7 and 10.2 mmol l(-1) pH(-1), respectively) with different titratable acidity at equal pH values. EXP-4: CA concentrations (56-1.75 mmol l( 1)) neutralized to pH 7. RESULTS: CA led to higher HAp-dissolution than HCl. With higher pH, the difference in HAp-dissolution rate between the two acids became increasingly smaller. At equal pH, HAp-dissolution was higher for the CA with the higher amount of titratable acid. However, no clear correlation between erosion and titratable acid or beta could be found. Only minimal amounts of HAp were dissolved by neutralized CA compared to CA with natural pH. CONCLUSION: Under the chosen conditions chelating effects of CA do not have a relevant influence of HAp dissolution of enamel. Moreover, amount of HAp-dissolution by CA is not attributed to a single factor alone. The interplay between the different parameters of CA seems to be responsible for its erosive potential. CLINICAL RELEVANCE: The erosive potential of solutions containing citric acid with unknown concentrations could not be predicted using a single parameter alone, and should at best determined in experimental set-ups. PMID- 26572530 TI - Changes in airway dimensions and hyoid bone position following class II correction with forsus fatigue resistant device. AB - OBJECTIVE: The objective of this study was to investigate the effects of fixed functional therapy on oropharyngeal airway dimensions and hyoid bone positions in Class II patients and make comparison with an untreated Class II group. MATERIALS AND METHODS: Eighteen patients (8 girls, 10 boys; mean age 13.62 +/- 1.92 years) who were treated with Forsus Fatique Resistant Device (FFRD) and 19 patients (11 girls, 8 boys; mean age 12.74 +/- 0.91 years) who served as control were enrolled. Cephalograms were used to assess linear, angular, and area measurements. Intragroup comparisons were made by paired t and Wilcoxon tests and intergroup comparisons were performed by independent t test. RESULTS: With respect to controls, FFRD group showed increased airway dimensions at soft palate (P < 0.05) and more forward positioning of the hyoid bone (P < 0.05). Dentoalveolar changes exhibited mesial movement of lower incisors and molars and reduction in overjet (P < 0.001) in FFRD group. CONCLUSIONS: Positive effects in oropharyngeal airway dimensions and increased values of hyoid bone displacement to a more forward position were found after fixed functional therapy. CLINICAL RELEVANCE: Treatment with fixed functional appliances is mostly based on mesial movement of mandibular dentition, which might influence changes in tongue posture. The present results might indicate that oropharyngeal airway dimensions may be affected by postural changes of the hyoid bone in consequence of dentoalveolar changes. Clinically, these may be considered especially in Class II cases with reduced airway dimensions. PMID- 26572531 TI - Restoration outcomes after restoring vital teeth with advanced caries lesions: a practice-based retrospective study. AB - OBJECTIVES: Maintaining pulpal vitality and achieving long-term restoration success are challenging when treating advanced caries lesions. We aimed at assessing success, survival, and influencing factors of treating advanced lesions in general dental practice. METHODS: Patient record databases from six practices in Germany were assessed. Permanent posterior teeth with lesions radiographically extending into inner dentin with sensible (vital) pulps were retrospectively evaluated. Outcome parameters were success (absence of re-treatment) and survival (absence of extraction). Mean success/survival times were estimated, and effect of treatment modifiers assessed using Lee, Wei, and Amato (LWA) regression. RESULTS: Two hundred thirty-two patients (308 teeth) were assessed. Lesions (93 %) included proximal surfaces. Eight teeth showed preoperative intermitting or provocation pain. Thirty four % of teeth experienced pulpal exposure during excavation. Mean follow-up time was 74 months. Mean success time was 130 months. Teeth (142/308) required re-interventions, mostly due to secondary caries and restorative or endodontic complications. Only 13 teeth required extraction (mean survival time 307 months). Hazard of failure was significantly reduced in younger patients (<40 years) (hazard ratio (HR) [95 % confidence interval (CI)] 0.57 [0.35/0.91]) and teeth without preoperative pain (0.39 [0.17/0.90]). Compared with teeth receiving amalgams, those restored using cements (2.44 [1.05/3.98]) or composites (1.64 [1.15/2.38]) had higher risk of failure. Hazard of extraction was higher in teeth with pulpal exposure (4.90 [1.36/17.7] or cement restorations (23.6 [5.56/100]). CONCLUSION: Teeth with advanced lesions had high risk of failure, while risk of extraction was low. CLINICAL RELEVANCE: Teeth treated for advanced lesions required re-treatment frequently but were retained long term. Age, pulpal exposure, and restoration type were associated with risk of failure or extraction. PMID- 26572532 TI - Circulating serum chemerin levels are elevated in lipodystrophy. AB - OBJECTIVE: Lipodystrophy (LD) is characterized by loss of adipose tissue, dysregulation of adipokines and severe metabolic complications. Regulation of the insulin resistance-inducing and proinflammatory adipokine chemerin has not been assessed in LD. Therefore, we determined chemerin serum levels in LD, chemerin mRNA expression in insulin-sensitive tissues of LD mice, as well as the impact of metreleptin treatment on circulating chemerin in LD patients. RESEARCH DESIGN AND METHODS: Serum chemerin, as well as clinical and biochemical parameters of glucose metabolism, lipid metabolism, and inflammation, was measured in 37 LD patients and 37 age-, gender- and body mass index-matched controls. Furthermore, chemerin mRNA expression was determined in LD mice and controls. Moreover, circulating chemerin was assessed at five different time points in 10 LD patients treated with metreleptin over 1 year. RESULTS: Median serum chemerin levels were significantly higher in 37 subjects with LD (234.3 MUg/l) as compared to controls (204.0 MUg/l) (P = 0.002). Multiple linear regression analysis showed that circulating chemerin was independently and positively associated with glycosylated haemoglobin A1c (HbA1c) and C-reactive protein (CRP). Chemerin mRNA expression was significantly increased 2.5-fold in visceral adipose tissue (VAT) and 5.3-fold in brown adipose tissue (BAT) of LD mice as compared to controls (P < 0.01). Circulating chemerin was not significantly altered by metreleptin treatment. CONCLUSIONS: Circulating levels of the adipokine chemerin are elevated in LD, as well as independently and positively associated with HbA1c and CRP. Increased chemerin might originate from VAT and BAT. PMID- 26572533 TI - Diagnostic Clinical, Electrodiagnostic and Muscle Pathology Features of Spinal and Bulbar Muscular Atrophy. AB - Kennedy's disease or spinal and bulbar muscular atrophy (SBMA) is a multi-system disorder affecting adult males, which is characterized by weakness of limbs and faciobulbar muscles primarily due to loss of lower motor neurons. Besides the obvious motor neuronopathy, additional findings in a substantial proportion of SBMA patients include sensory neuropathy and signs of androgen deficiency, such as poor sexual functioning and reduced fertility with gynaecomastia. The presence of elevated glucose, liver pathology or dyslipidaemia is less consistent features. We review the striking clinical, electrodiagnostic and muscle pathology features characteristic of Kennedy's disease, which has some peculiar and diagnostically useful features not observed in many other neuromuscular disorders. PMID- 26572534 TI - Attenuated Weight Gain with the Novel Analog of Olanzapine Linked to Sarcosinyl Moiety (PGW5) Compared to Olanzapine. AB - Olanzapine-induced weight gain is associated with atherosclerosis, hypertension, dyslipidemia, and diabetes. We synthesized a novel antipsychotic drug (PGW5) possessing an olanzapine moiety linked to sarcosine, a glycine transporter 1 inhibitor. In this study, we compared the metabolic effects of PGW5 and olanzapine in a female rat model of weight gain. Female rats were treated daily with oral olanzapine (4 mg/kg), PGW5 (25 mg/kg), or vehicle for 16 days. Behavioral tests were conducted on days 12-14. Biochemical analyses were performed at the end of the treatment. A significant increase in body weight was observed in the olanzapine-treated group, while the PGW5 group did not differ from the controls. The open field test showed hypo-locomotion in the olanzapine treated animals as compared to PGW5 and control groups. A significant increase in hypothalamic protein expression of the neuropeptide Y5 receptor and a decrease in pro-opiomelanocortin messenger ribonucleic acid (mRNA) levels were detected following PGW5 treatment, but not after olanzapine administration. PGW5 appears to possess minor metabolic effects compared with the parent compound olanzapine. The differential modulation of brain peptides associated with appetite regulation is possibly involved in the attenuation of metabolic effects by PGW5. PMID- 26572536 TI - All-Trans Retinoic Acid Induces Expression of a Novel Intergenic Long Noncoding RNA in Adult rat Primary Hippocampal Neurons. AB - Around 90% of the mammalian genome undergoes pervasive transcription into various types of small and long regulatory noncoding RNAs, whereas only ~ 1.5% codes for proteins. Long noncoding RNAs (lncRNAs) constitute diverse classes of sense- and antisense transcripts that are abundantly expressed in the mammalian central nervous system (CNS) in cell type- and developmental stage-specific manners. They are implicated in brain development, differentiation, neuronal plasticity, and other cognitive functions. Mammalian brain requires the vitamin A metabolite all trans retinoic acid (atRA) for its normal development, differentiation, and cell fate determination. However, its role in adult brain function is less understood. Here, we report atRA-mediated transcriptional upregulation of endogenous expression of a novel long intergenic noncoding RNA-rat brain expressed (LINC RBE) in cultured primary hippocampal neurons from adult rat. We have previously reported LINC-RBE as an intergenic, simple repeat sequence containing lncRNA highly expressed in the rat brain. This is a first-time report of involvement of atRA in transcriptional upregulation of lncRNA expression in rat hippocampal neurons. Therefore, it may be involved in regulation of brain function and disease. PMID- 26572535 TI - The Role of the Protein Quality Control System in SBMA. AB - Spinal and bulbar muscular atrophy (SBMA) or Kennedy's disease is an X-linked disease associated with the expansion of the CAG triplet repeat present in exon 1 of the androgen receptor (AR) gene. This results in the production of a mutant AR containing an elongated polyglutamine tract (polyQ) in its N-terminus. Interestingly, the ARpolyQ becomes toxic only after its activation by the natural androgenic ligands, possibly because of aberrant androgen-induced conformational changes of the ARpolyQ, which generate misfolded species. These misfolded ARpolyQ species must be cleared from motoneurons and muscle cells, and this process is mediated by the protein quality control (PQC) system. Experimental evidence suggested that failure of the PQC pathways occurs in disease, leading to ARpolyQ accumulation and toxicity in the target cells. In this review, we summarized the overall impact of mutant and misfolded ARpolyQ on the PQC system and described how molecular chaperones and the degradative pathways (ubiquitin-proteasome system (UPS), the autophagy-lysosome pathway (ALP), and the unfolded protein response (UPR), which activates the endoplasmic reticulum-associated degradation (ERAD)) are differentially affected in SBMA. We also extensively and critically reviewed several molecular and pharmacological approaches proposed to restore a global intracellular activity of the PQC system. Collectively, these data suggest that the fine and delicate equilibrium existing among the different players of the PQC system could be restored in a therapeutic perspective by the synergic/additive activities of compounds designed to tackle sequential or alternative steps of the intracellular defense mechanisms triggered against proteotoxic misfolded species. PMID- 26572537 TI - Clinical Trials in Spinal and Bulbar Muscular Atrophy-Past, Present, and Future. AB - Spinal and Bulbar Muscular Atrophy (SBMA), also known as Kennedy's disease, is a rare adult-onset lower motor neuron disorder with a classic X-linked inheritance pattern. It is caused by the abnormal expansion of the CAG-repeat tract in the androgen receptor gene. Despite important progress in the understanding of the molecular pathogenesis and the availability of a broad set of model organisms, successful translation of these insights into clinical interventions remains elusive. Here we review the available information on clinical trials in SBMA and discuss the challenges and pitfalls that impede therapy development. Two important factors are the variability of the complex neuro-endocrinological phenotype and the comparatively low incidence of the disease that renders recruitment for clinical trials demanding. We propose that these challenges can be and need to be overcome by fostering closer collaborations between clinical research centers, the patient communities and the industry and non-industry sponsors of clinical trials. PMID- 26572540 TI - To serve and to protect: the role of decidual innate immune cells on human pregnancy. AB - The maternal-fetal interface undergoes dynamic changes that promote successful development of the embryo/fetal allograft during pregnancy. This immune privilege of the conceptus is mediated through local and systemic cellular responses. In species in which endometrial decidualization accompanies pregnancy, unique immune cell niches are found. Many studies have addressed the enigmatic roles of uterine (u)NK cells as killers and helpers because they are frequently found in the uterine lining and decidua of normal and pathological pregnancies. Accumulating evidence indicates that uNK cells are induced and transformed by sensing signals within their microenvironment to both protect the mother from the fetal allograft and support the fetus during its development. Here, we review the mechanisms that modulate these functions of uNK cells during pregnancy. We suggest that uNK cells must be tightly regulated in order to serve these two roles and support a healthy pregnancy. PMID- 26572541 TI - Tyrosine hydroxylase immunoreactivity is common in the enteric nervous system in teleosts. AB - Tyrosine hydroxylase (TH) is the rate-limiting enzyme in the synthesis of catecholamines and TH immunoreactivity is indicative of cells synthesising either adrenaline/noradrenaline or dopamine. In this study, the distribution of TH immunoreactivity was examined in two distantly related teleost species, zebrafish (Danio rerio) and shorthorn sculpin (Myoxocephalus scorpius). In both species, TH immunoreactive nerve cell bodies and varicose nerve fibres were common in the myenteric plexus of the intestine. However, no TH-immunoreactive nerve cell bodies were seen in the sculpin stomach. The TH-immunoreactive nerve cell bodies seemed to constitute a larger proportion of the total enteric population in shorthorn sculpin (50 +/- 5 %, n = 3067 cells) compared with zebrafish (14 +/- 2 %, n = 10,163 cells). In contrast, in sculpin, the TH-immunoreactive cells were smaller than the average enteric nerve cell bodies, whereas in zebrafish, the relationship was the opposite. In developing zebrafish larvae, TH-immunoreactive nerve cell bodies were common (approx. 75 % of the total population) at 3 days post-fertilization (dpf), but decreased in numbers between 3 and 7 dpf. In conclusion, in contrast to previous studies, TH-immunoreactive intrinsic neurons are common in the fish gut. Their role and function need to be further characterized in order to understand the potential importance of this enteric subpopulation in controlling various gut functions. PMID- 26572539 TI - Impact of Chromogranin A deficiency on catecholamine storage, catecholamine granule morphology and chromaffin cell energy metabolism in vivo. AB - Chromogranin A (CgA) is a prohormone and granulogenic factor in neuroendocrine tissues with a regulated secretory pathway. The impact of CgA depletion on secretory granule formation has been previously demonstrated in cell culture. However, studies linking the structural effects of CgA deficiency with secretory performance and cell metabolism in the adrenomedullary chromaffin cells in vivo have not previously been reported. Adrenomedullary content of the secreted adrenal catecholamines norepinephrine (NE) and epinephrine (EPI) was decreased 30 40 % in Chga-KO mice. Quantification of NE and EPI-storing dense core (DC) vesicles (DCV) revealed decreased DCV numbers in chromaffin cells in Chga-KO mice. For both cell types, the DCV diameter in Chga-KO mice was less (100-200 nm) than in WT mice (200-350 nm). The volume density of the vesicle and vesicle number was also lower in Chga-KO mice. Chga-KO mice showed an ~47 % increase in DCV/DC ratio, implying vesicle swelling due to increased osmotically active free catecholamines. Upon challenge with 2 U/kg insulin, there was a diminution in adrenomedullary EPI, no change in NE and a very large increase in the EPI and NE precursor dopamine (DA), consistent with increased catecholamine biosynthesis during prolonged secretion. We found dilated mitochondrial cristae, endoplasmic reticulum and Golgi complex, as well as increased synaptic mitochondria, synaptic vesicles and glycogen granules in Chga-KO mice compared to WT mice, suggesting that decreased granulogenesis and catecholamine storage in CgA-deficient mouse adrenal medulla is compensated by increased VMAT-dependent catecholamine update into storage vesicles, at the expense of enhanced energy expenditure by the chromaffin cell. PMID- 26572542 TI - CXCL10/CXCR3 signaling mediates inhibitory action by interferon-gamma on CRF stimulated adrenocorticotropic hormone (ACTH) release. AB - Secretion of hormones by the anterior pituitary gland can be stimulated or inhibited by paracrine factors that are produced during inflammatory reactions. The inflammation cytokine interferon-gamma (IFN-gamma) is known to inhibit corticotropin-releasing factor (CRF)-stimulated adrenocorticotropin (ACTH) release but its signaling mechanism is not yet known. Using rat anterior pituitary, we previously demonstrated that the CXC chemokine ligand 10 (CXCL10), known as interferon-gamma (IFN-gamma) inducible protein 10 kDa, is expressed in dendritic cell-like S100beta protein-positive (DC-like S100beta-positive) cells and that its receptor CXCR3 is expressed in ACTH-producing cells. DC-like S100beta-positive cells are a subpopulation of folliculo-stellate cells in the anterior pituitary. In the present study, we examine whether CXCL10/CXCR3 signaling between DC-like S100beta-positive cells and ACTH-producing cells mediates inhibition of CRF-activated ACTH-release by IFN-gamma, using a CXCR3 antagonist in the primary pituitary cell culture. We found that IFN-gamma up regulated Cxcl10 expression via JAK/STAT signaling and proopiomelanocortin (Pomc) expression, while we reconfirmed that IFN-gamma inhibits CRF-stimulated ACTH release. Next, we used a CXCR3 agonist in primary culture to analyze whether CXCL10 induces Pomc-expression and ACTH-release using a CXCR3 agonist in the primary culture. The CXCR3 agonist significantly stimulated Pomc-expression and inhibited CRF-induced ACTH-release, while ACTH-release in the absence of CRF did not change. Thus, the present study leads us to an assumption that CXCL10/CXCR3 signaling mediates inhibition of the CRF-stimulated ACTH-release by IFN-gamma. Our findings bring us to an assumption that CXCL10 from DC-like S100beta-positive cells acts as a local modulator of ACTH-release during inflammation. PMID- 26572543 TI - Depression and anxiety as predictors of mortality among heart failure patients: systematic review and meta-analysis. AB - Several studies suggest that psychological factors are associated with negative outcomes and in particular higher mortality rates among heart failure (HF) patients. We aimed to evaluate the effect sizes of depression and anxiety on all cause mortality in HF patients. We conducted a systematic review according to the PRISMA methodology. We searched for studies on depression or anxiety effects on all-cause mortality among HF patients published up to June 2015. A number of 26 and 6 articles met inclusion criteria for depression (total 80,627 patients) and anxiety (total 17,214 patients), respectively. The effect estimates were pooled using random-effect meta-analysis. Depression has significant and moderately heterogeneous effect on all-cause mortality (HR = 1.57; 95%CI 1.30-1.89, p < 0.001); adjustment for confounders led to a similar effect estimate (HR = 1.40; 95%CI 1.22-1.60; p < 0.001). Larger studies and higher study prevalence of depression were associated with smaller effect size. The effect of anxiety on mortality outcome was small and not conclusive given the low number of studies (n = 6) (HR = 1.02; 95% CI 1.00-1.04, p < 0.05). This systematic review and meta analysis suggests that depression is an important and independent predictor of all-cause mortality among HF patients, while anxiety does not appear to have a strong effect. Further research is recommended toward the detection and treatment of depression. PMID- 26572544 TI - Health of Psychiatry Residents: Nutritional Status, Physical Activity, and Mental Health. AB - OBJECTIVE: This study aims to analyze mental health, nutritional status, and physical activity in psychiatry residents. METHODS: Sixty-two residents were invited and 59 participated (95.2% response). Depressive, anxious, and social phobic symptoms; alcohol use; and nicotine dependence were measured. Body mass index and lifestyle were also evaluated. RESULTS: Almost half of psychiatry residents were overweight or obese, and 61% reported a sedentary lifestyle. Furthermore, 33.9% of residents had high scores for anxiety; 30.5% for social phobia; and 19% for depression. In addition, 81.4% reported alcohol use, and 22% had harmful alcohol use. High scores for anxiety were associated with lower attention and worse relationship with preceptors, and high scores of depressive symptoms were related to a worse relationship with patients and preceptors. Anxiety was associated with depressive symptoms (p < 0.001) and social phobia (p = 0.006). CONCLUSION: The findings of this study highlight high rates of overweight/obesity, physical inactivity, and depressive and anxiety symptoms in psychiatric residents. PMID- 26572545 TI - Roles of Wnt Signaling in the Neurogenic Niche of the Adult Mouse Ventricular Subventricular Zone. AB - In many animal species, the production of new neurons (neurogenesis) occurs throughout life, in a specialized germinal region called the ventricular subventricular zone (V-SVZ). In this region, neural stem cells undergo self renewal and generate neural progenitor cells and new neurons. In the olfactory system, the new neurons migrate rostrally toward the olfactory bulb, where they differentiate into mature interneurons. V-SVZ-derived new neurons can also migrate toward sites of brain injury, where they contribute to neural regeneration. Recent studies indicate that two major branches of the Wnt signaling pathway, the Wnt/beta-catenin and Wnt/planar cell polarity pathways, play essential roles in various facets of adult neurogenesis. Here, we review the Wnt signaling-mediated regulation of adult neurogenesis in the V-SVZ under physiological and pathological conditions. PMID- 26572546 TI - Maternal vaccination against H1N1 influenza and offspring mortality: population based cohort study and sibling design. AB - STUDY QUESTION: What is the mortality in offspring of mothers who had influenza A(H1N1)pdm09 vaccination during pregnancy? METHODS: This was a prospective population based cohort study in seven healthcare regions in Sweden based on vaccinations taking place between 2 October 2009 and 26 November 2010. H1N1 vaccination data were linked with pregnancy and birth characteristics and offspring mortality data in 275,500 births (of which 1203 were stillbirths) from 137,886 mothers. Of these offspring, 41,183 had been exposed to vaccination with Pandemrix, a monovalent AS03 adjuvanted H1N1 influenza vaccine, during fetal life. A primary comparison group consisted of pregnancies of women who were not vaccinated during the same calendar period. In a second comparison, non-exposed siblings of infants prenatally exposed to vaccination were used as controls. Cox regression was used to estimate hazard ratios for stillbirth, early neonatal mortality (days 0-6 after birth), and subsequent mortality (beginning on day 7) in vaccinated versus non-vaccinated women, adjusting for mother's age at delivery, body mass index, parity, smoking, country of birth, and disposable income and for sex of offspring. STUDY ANSWER AND LIMITATIONS: The results of this study suggest that AS03 adjuvanted H1N1 vaccination during pregnancy does not affect the risk of stillbirth, early neonatal death, or later mortality in the offspring. During follow-up, 1172 stillbirths, 380 early neonatal deaths, and 706 deaths thereafter occurred. Compared with general population controls, this corresponded to adjusted hazard ratios of 0.83 (95% confidence interval 0.65 to 1.04) for stillbirth, 0.71 (0.44 to 1.14) for early neonatal death, and 0.97 (0.69 to 1.36) for later death. When siblings were used as controls, adjusted hazard ratios were 0.88 (0.59 to 1.30) for stillbirth, 0.82 (0.46 to 1.49) for early neonatal death, and 0.78 (0.52 to 1.19) for later death. Limitations of the study include lack of data on miscarriage before gestational week 22, inability to ascertain which mothers had pandemic flu during pregnancy, and lack of data on factors influencing the decision to vaccinate during pregnancy. WHAT THIS STUDY ADDS: H1N1 vaccination during pregnancy is not associated with adverse fetal outcome or offspring mortality, including when familial factors are taken into account. FUNDING, COMPETING INTERESTS, DATA SHARING: This project was supported by grants from the Swedish Research Council and the Swedish Council for Working Life and Social Research. NF was employed at the Swedish Medical Product Agency at the time of the study. PMID- 26572547 TI - The effects of entombment on water chemistry and bacterial assemblages in closed cryoconite holes on Antarctic glaciers. AB - Closed cryoconite holes (CCHs) are small aquatic ecosystems enclosed in glacier surface ice, and they collectively contribute substantial aquatic habitat to inland Antarctica. We examined the morphology, geochemistry and bacterial diversity of 57 CCHs, spread over seven sites, located on five glaciers, covering a range of latitudes, elevations and distance from open seawater. Isotopes confirmed glacial ice as the initial water source, with water chemistry evolving through freeze concentration and photosynthetic processes to have conductivities ranging from <0.005 to >4 mS cm(-1) and pH from <5 to >11. Nitrate concentrations were more elevated in inland, higher altitude sites. Bacterial communities were characterized by Automated Ribosomal Intergenic Spacer Analysis and high throughput sequencing. The dominant phyla were Cyanobacteria, Bacteroides, Proteobacteria and Actinobacteria. CCH bacterial communities predominantly grouped by geographic location, suggesting initial wind-borne inocula from local and regional sources play a role in structuring assemblages. However, multivariate multiple regression analysis indicated that internal CCH conditions also influenced community structure, particularly the ion content and pH of the liquid water. This highlights the importance of founder bacterial populations, isolation and water chemistry in the evolution of CCH bacterial communities. PMID- 26572548 TI - Design of Organic Transformations at Ambient Conditions: Our Sincere Efforts to the Cause of Green Chemistry Practice. AB - This account summarizes our recent efforts in designing a good number of important organic transformations leading to the synthesis of biologically relevant compounds at room temperature and pressure. Currently, the concept of green chemistry is globally acclaimed and has already advanced quite significantly to emerge as a distinct branch of chemical sciences. Among the principles of green chemistry, one principle is dedicated to the "design of energy efficiency" - that is, to develop synthetic strategies that require less or the minimum amount of energy to carry out a specific reaction with optimum productivity - and the most effective way to save energy is to develop strategies/protocols that are capable enough to carry out the transformations at ambient temperature! As part of on-going developments in green synthetic strategies, the design of reactions under ambient conditions coupled with other green aspects is, thus, an area of current interest. The concept of developing reaction strategies at room temperature and pressure is now an emerging field of research in organic chemistry and is progressing steadily. This account is aimed to offer an overview of our recent research works directly related to this particular field of interest, and highlights the green chemistry practice leading to carbon-carbon and carbon-heteroatom bond-forming reactions of topical significance. Green synthetic routes to a variety of biologically relevant organic molecules (heterocyclic, heteroaromatic, alicyclic, acyclic, etc.) at room temperature and pressure are discussed. PMID- 26572549 TI - Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) Promotes Angiogenesis and Ischemia-Induced Neovascularization Via NADPH Oxidase 4 (NOX4) and Nitric Oxide-Dependent Mechanisms. AB - BACKGROUND: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has the ability to inhibit angiogenesis by inducing endothelial cell death, as well as being able to promote pro-angiogenic activity in vitro. These seemingly opposite effects make its role in ischemic disease unclear. Using Trail(-/-) and wildtype mice, we sought to determine the role of TRAIL in angiogenesis and neovascularization following hindlimb ischemia. METHODS AND RESULTS: Reduced vascularization assessed by real-time 3-dimensional Vevo ultrasound imaging and CD31 staining was evident in Trail(-/-) mice after ischemia, and associated with reduced capillary formation and increased apoptosis. Notably, adenoviral TRAIL administration significantly improved limb perfusion, capillary density, and vascular smooth-muscle cell content in both Trail(-/-) and wildtype mice. Fibroblast growth factor-2, a potent angiogenic factor, increased TRAIL expression in human microvascular endothelial cell-1, with fibroblast growth factor-2-mediated proliferation, migration, and tubule formation inhibited with TRAIL siRNA. Both fibroblast growth factor-2 and TRAIL significantly increased NADPH oxidase 4 (NOX4) expression. TRAIL-inducible angiogenic activity in vitro was inhibited with siRNAs targeting NOX4, and consistent with this, NOX4 mRNA was reduced in 3-day ischemic hindlimbs of Trail(-/-) mice. Furthermore, TRAIL induced proliferation, migration, and tubule formation was blocked by scavenging H2O2, or by inhibiting nitric oxide synthase activity. Importantly, TRAIL inducible endothelial nitric oxide synthase phosphorylation at Ser-1177 and intracellular human microvascular endothelial cell-1 cell nitric oxide levels were NOX4 dependent. CONCLUSIONS: This is the first report demonstrating that TRAIL can promote angiogenesis following hindlimb ischemia in vivo. The angiogenic effect of TRAIL on human microvascular endothelial cell-1 cells is downstream of fibroblast growth factor-2, involving NOX4 and nitric oxide signaling. These data have significant therapeutic implications, such that TRAIL may improve the angiogenic response to ischemia and increase perfusion recovery in patients with cardiovascular disease and diabetes. PMID- 26572550 TI - Expression of HMGB1 in septic serum induces vascular endothelial hyperpermeability. AB - The aim of the present study was to investigate the effects of high mobility group protein B1 (HMGB1), which is expressed in the serum of patients with sepsis, on vascular endothelial permeability. Sera from patients with sepsis were used to treat endothelial cells (ECs), and the effect on endothelial permeability was evaluated using immunofluorescence. The morphologies of endothelial cytoskeletal actin and vascular endothelial (VE)-cadherin were assessed using laser scanning confocal microscopy. The protein expression levels of HMGB1, B cell lymphoma 2 (BCL-2) and BCL-2-associated X protein (BAX) were detected using western blotting. EC apoptosis was measured using flow cytometry. The results demonstrated that HMGB1 was significantly expressed in the serum 24 h following the onset of sepsis, and the expression levels peaked at 48 h, which were sustained until 96 h post-onset. Compared with the control group, treatment of the ECs with 20% septic serum in vitro significantly increased endothelial monolayer permeability (P<0.01), markedly induced transcellular filamentous (F) actin rearrangement with stress fiber formation, and resulted in the localization of VE-cadherin fragmentations at the cell borders with increased gaps between ECs. Furthermore, flow cytometry showed that the apoptotic rate of ECs was significantly increased following treatment with septic serum. In addition, the expression levels of BAX were significantly increased, whereas the expression levels of BCL-2 were significantly decreased. Pretreatment with an HMGBI inhibitor (ethyl pyruvate; 5 uM) 24 h prior to treatment with the septic serum attenuated the effects of septic serum treatment. Together, these findings suggested that treatment of ECs with sera from patients with sepsis may induce the loss of vascular endothelial monolayer integrity, elicit the formation of endothelial F-actin stress fibers and initiate VE-cadherin redistribution, which may be attributed to high levels of HMGB1 in the serum. This mechanism also appears to involve changes in the activation of BAX and BCL-2, resulting in EC apoptosis. PMID- 26572551 TI - Group and individual cognitive therapies in Alzheimer's disease: the ETNA3 randomized trial. AB - BACKGROUND: Although non-drug interventions are widely used in patients with Alzheimer's disease, few large scale randomized trials involving a long-term intervention and several cognitive-oriented approaches have been carried out. ETNA3 trial compares the effect of cognitive training, reminiscence therapy, and an individualized cognitive rehabilitation program in Alzheimer's disease to usual care. METHODS: This is a multicenter (40 French clinical sites) randomized, parallel-group trial, with a two-year follow-up comparing groups receiving standardized programs of cognitive training (group sessions), reminiscence therapy (group sessions), individualized cognitive rehabilitation program (individual sessions), and usual care (reference group). Six hundred fifty-three outpatients with Alzheimer's disease were recruited. The primary efficacy outcome was the rate of survival without moderately severe to severe dementia at two years. Secondary outcomes were cognitive impairment, functional disability, behavioral disturbance, apathy, quality of life, depression, caregiver's burden, and resource utilization. RESULTS: No impact on the primary efficacy measure was evidenced. For the two group interventions (i.e. cognitive training and reminiscence), none of the secondary outcomes differed from usual care. The larger effect was seen with individualized cognitive rehabilitation in which significantly lower functional disability and a six-month delay in institutionalization at two years were evidenced. CONCLUSIONS: These findings challenge current management practices of Alzheimer's patients. While cognitive oriented group therapies have gained popularity, this trial does not show improvement for the patients. The individualized cognitive rehabilitation intervention provided clinically significant results. Individual interventions should be considered to delay institutionalization in Alzheimer's disease. PMID- 26572552 TI - Targeted amplification for enhanced detection of biothreat agents by next generation sequencing. AB - BACKGROUND: Historically, identification of causal agents of disease has relied heavily on the ability to culture the organism in the laboratory and/or the use of pathogen-specific antibodies or sequence-based probes. However, these methods can be limiting: Even highly sensitive PCR-based assays must be continually updated due to signature degradation as new target strains and near neighbors are sequenced. Thus, there has been a need for assays that do not suffer as greatly from these limitations and/or biases. Recent advances in library preparation technologies for Next-Generation Sequencing (NGS) are focusing on the use of targeted amplification and targeted enrichment/capture to ensure that the most highly discriminating regions of the genomes of known targets (organism-unique regions and/or regions containing functionally important genes or phylogenetically-discriminating SNPs) will be sequenced, regardless of the complex sample background. RESULTS: In the present study, we have assessed the feasibility of targeted sequence enhancement via amplification to facilitate detection of a bacterial pathogen present in low copy numbers in a background of human genomic material. Our results indicate that the targeted amplification of signature regions can effectively identify pathogen genomic material present in as little as 10 copies per ml in a complex sample. Importantly, the correct species and strain calls could be made in amplified samples, while this was not possible in unamplified samples. CONCLUSIONS: The results presented here demonstrate the efficacy of a targeted amplification approach to biothreat detection, using multiple highly-discriminative amplicons per biothreat organism that provide redundancy in case of variation in some primer regions. Importantly, strain level discrimination was possible at levels of 10 genome equivalents. Similar results could be obtained through use of panels focused on the identification of amplicons targeted for specific genes or SNPs instead of, or in addition to, those targeted for specific organisms (ongoing gene-targeting work to be reported later). Note that without some form of targeted enhancement, the enormous background present in complex clinical and environmental samples makes it highly unlikely that sufficient coverage of key pathogen(s) present in the sample will be achieved with current NGS technology to guarantee that the most highly discriminating regions will be sequenced. PMID- 26572554 TI - Calculation of dose distribution in compressible breast tissues using finite element modeling, Monte Carlo simulation and thermoluminescence dosimeters. AB - Compression is a technique to immobilize the target or improve the dose distribution within the treatment volume during different irradiation techniques such as AccuBoost((r)) brachytherapy. However, there is no systematic method for determination of dose distribution for uncompressed tissue after irradiation under compression. In this study, the mechanical behavior of breast tissue between compressed and uncompressed states was investigated. With that, a novel method was developed to determine the dose distribution in uncompressed tissue after irradiation of compressed breast tissue. Dosimetry was performed using two different methods, namely, Monte Carlo simulations using the MCNP5 code and measurements using thermoluminescent dosimeters (TLD). The displacement of the breast elements was simulated using a finite element model and calculated using ABAQUS software. From these results, the 3D dose distribution in uncompressed tissue was determined. The geometry of the model was constructed from magnetic resonance images of six different women volunteers. The mechanical properties were modeled by using the Mooney-Rivlin hyperelastic material model. Experimental dosimetry was performed by placing the TLD chips into the polyvinyl alcohol breast equivalent phantom. The results determined that the nodal displacements, due to the gravitational force and the 60 Newton compression forces (with 43% contraction in the loading direction and 37% expansion in the orthogonal direction) were determined. Finally, a comparison of the experimental data and the simulated data showed agreement within 11.5% +/- 5.9%. PMID- 26572553 TI - High-throughput mRNA and miRNA profiling of epithelial-mesenchymal transition in MDCK cells. AB - BACKGROUND: Epithelial-mesenchymal transition (EMT) is an important process in embryonic development, especially during gastrulation and organ formation. Furthermore EMT is widely observed in pathological conditions, e.g., fibrosis, tumor progression and metastasis. Madin-Darby Canine Kidney (MDCK) cells are widely used for studies of EMT and epithelial plasticity. MDCK cells show an epithelial phenotype, while oncogenic Ras-transformed MDCK (MDCK-Ras) cells undergo EMT and show a mesenchymal phenotype. METHODS: RNA-Seq and miRNA-Seq analyses were performed on MDCK and MDCK-Ras cells. Data were validated by qRT PCR. Gene signature analyses were carried out to identify pathways and gene ontology terms. For selected miRNAs target prediction was performed. RESULTS: With RNA-Seq, mRNAs of approximately half of the genes known for dog were detected. These were screened for differential regulation during Ras-induced EMT. We went further and performed gene signature analyses and found Gene Ontology (GO) terms and pathways important for epithelial polarity and implicated in EMT. Among the identified pathways, TGFbeta1 emerged as a central signaling factor in many EMT related pathways and biological processes. With miRNA-Seq, approximately half of the known canine miRNAs were found expressed in MDCK and MDCK-Ras cells. Furthermore, among differentially expressed miRNAs, miRNAs that are known to be important regulators of EMT were detected and new candidates were predicted. New dog miRNAs were discovered after aligning our reads to that of other species in miRBase. Importantly, we could identify 25 completely novel miRNAs with a stable hairpin structure. Two of these novel miRNAs were differentially expressed. We validated the two novel miRNAs with the highest read counts by RT-qPCR. Target prediction of a particular novel miRNA highly expressed in mesenchymal MDCK-Ras cells revealed that it targets components of epithelial cell junctional complexes. Combining target prediction for the most upregulated miRNAs and validation of the targets in MDCK-Ras cells with pathway analysis allowed us to identify two novel pathways, e.g., JAK/STAT signaling and pancreatic cancer pathways. These pathways could not be detected solely by gene set enrichment analyses of RNA-Seq data. CONCLUSION: With deep sequencing data of mRNAs and miRNAs of MDCK cells and of Ras-induced EMT in MDCK cells, differentially regulated mRNAs and miRNAs are identified. Many of the identified genes are within pathways known to be involved in EMT. Novel differentially upregulated genes in MDCK cells are interferon stimulated genes and genes involved in Slit and Netrin signaling. New pathways not yet linked to these processes were identified. A central pathway in Ras induced EMT is TGFbeta signaling, which leads to differential regulation of many target genes, including miRNAs. With miRNA-Seq we identified miRNAs involved in either epithelial cell biology or EMT. Finally, we describe completely novel miRNAs and their target genes. PMID- 26572555 TI - Interleukin-2: Biology, Design and Application. AB - Interleukin-2 (IL-2) exerts crucial functions during immune homeostasis via its effects on regulatory T (Treg) cells, and the optimizing and fine-tuning of effector lymphocyte responses. Thus, somewhat paradoxically, low doses of recombinant IL-2 have been used for Treg cell-based immunosuppressive strategies against immune pathologies, while high-dose IL-2 has shown some success in stimulating anti-tumor immune responses. Recent studies of the functional, biophysical and structural characteristics of IL-2 have led to the generation of IL-2 formulations, including IL-2/mAb complexes and IL-2 variants (muteins) that selectively enhance IL-2's immune stimulatory versus inhibitory properties. Here, we review these findings, placing new mechanistic insights into improved next generation IL-2 formulations within the broader context of IL-2 biology. We conclude by integrating these findings into a framework for understanding IL-2 mediated selective immune modulation. PMID- 26572556 TI - Major differential gene regulation in Coxiella burnetii between in vivo and in vitro cultivation models. AB - BACKGROUND: Coxiella burnetii is the causative agent of the zoonotic disease Q fever. As it is an intracellular pathogen, infection by C. burnetii requires adaptation to its eukaryotic host and intracellular environment. The recently developed cell-free medium also allows the bacteria to propagate without host cells, maintaining its infection potential. The adaptation to different hosts or extracellular environments has been assumed to involve genome-wide modulation of C. burnetii gene expression. However, little is currently known about these adaptation events which are critical for understanding the intracellular survival of C. burnetii. RESULTS: We studied C. burnetii genome-wide transcriptional patterns in vivo (mice spleen) and in cell and cell-free in vitro culture models to examine its metabolic pathways and virulence associated gene expression patterns that are required to colonize and persist in different environments. Within each model, the gene expression profiles of the Dutch C. burnetii outbreak strain (602) and NM reference strains were largely similar. In contrast, modulation of gene-expression was strongly influenced by the cultivation method, indicating adaptation of the bacterium to available components. Genome-wide expression profiles of C. burnetii from in vitro cell culture were more similar to those seen for in vivo conditions, while gene expression profiles of cell-free culture were more distant to in vivo. Under in vivo conditions, significant alterations of genes involved in metabolism and virulence were identified. We observed that C. burnetii under in vivo conditions predominantly uses glucose as a carbon source (mostly for biosynthetic processes) and fatty acids for energy generation. C. burnetii experienced nutrient limitation and anaerobiosis as major stressors, while phosphate limitation was identified as an important signal for intracellular growth inside eukaryotic host cells. Finally, the in vivo environment significantly induced expression of several virulence genes, including those implicated in LPS synthesis, colonization, host component modulation and DNA repair mechanisms. CONCLUSION: Our study shows that C. burnetii, with its relative small genome, requires only a subset of core gene functions to survive under in vitro conditions, but requires the induction of full repertoire of genes for successful pathogenesis and thriving in harsh environments in vivo. PMID- 26572557 TI - 131I therapy mediated by sodium/iodide symporter combined with kringle 5 has a synergistic therapeutic effect on glioma. AB - Glioblastoma (GBM) is the most common and most aggressive primary brain tumor; the prognosis of patients with GBM remains poor. The sodium/iodide symporter (NIS) can be used to absorb several isotopes, such as 131I for nuclear medicine imaging and radionuclide therapy. Previously, we found that the early growth response-1 (Egr1) promoter had an 131I radiation positive feedback effect on the NIS gene. Kringle 5 (K5), a kringle domain of plasminogen, induced endothelial cell apoptosis. We investigated the effect of K5 combined with the 131I radiation positive feedback effect (Egr1-NIS) for treating malignant U87 glioma cells using a lentiviral vector. We successfully constructed a stable U87 glioma cell line, U87-K5-Egr1-NIS. The radio-inducible Egr1 promoter induced an 131I radiation positive feedback effect absorbed by NIS. Mediated by 131I, K5 increased glioma cell apoptosis; 131I radiation also increased endothelial cell sensitivity to K5 induced apoptosis. The combined therapy had a synergistic effect on the antitumor efficacy of glioma treatment, not only increasing tumor cell apoptosis but also significantly inhibiting tumor cell proliferation and reducing capillary density in U87 glioma tissues. PMID- 26572558 TI - Effects of maslinic acid on the proliferation and apoptosis of A549 lung cancer cells. AB - Maslinic acid (MA) is a pentacyclic triterpene acid that is present in numerous dietary plants. Although certain studies have demonstrated that MA has anti cancer properties in different cell types, the effect of MA on lung cancer cell proliferation and apoptosis and the potential underlying mechanisms remain to be elucidated. In the present study, A549 lung cancer cells were treated with different doses of MA and it was found that MA significantly inhibited A549 cell growth in a dose-dependent manner. In addition, Annexin V/propidium iodide flow cytometric analysis demonstrated that MA induced apoptosis of A549 cells. The present study also confirmed that MA induced apoptosis by observing morphological alterations. In addition, the effect of MA treatment on the levels of apoptosis associated proteins was examined. The results demonstrated that MA treatment suppressed the expression of caspase-3, -8 and -9, and increased the expression of cleaved caspase-3, -8 and -9 in a dose-dependent manner. The level of inhibitors of apoptosis (IAPs) and Smac, which are possible upstream factors of caspase proteins, were also examined. It was found that MA treatment increased the protein expression of Smac and decreased the protein levels of c-IAP1, c IAP2, X-linked inhibitor of apoptosis protein (XIAP) and Survivin in a dose dependent manner. These results suggested that MA inhibited proliferation and induced apoptosis of A549 cells through regulation of caspase cleavage as well as Smac, c-IAP1, c-IAP2, XIAP and Survivin. PMID- 26572559 TI - Mammogram Tribulations. PMID- 26572561 TI - Italian biophysics and SIBPA speed-up the pace towards the long and winding road of the interdisciplinary science. AB - This Special Issue of Biophysical Chemistry presents a selection of the contributions presented at the XXII National Congress of the Italian Society of Pure and Applied Biophysics (i.e., SIBPA, Societa Italiana di Biofisica Pura ed Applicata) held on September 2014 in Palermo, Italy. Topics cover all biophysical disciplines, from molecular to cellular, to integrative biophysics giving a comprehensive view of the inter- and multi-disciplinary approach of modern biophysics. SIBPA, which turned 40 in 2013, continues to grow and attract interest. PMID- 26572560 TI - A comparison of fluorescent Ca2+ indicators for imaging local Ca2+ signals in cultured cells. AB - Localized subcellular changes in Ca(2+) serve as important cellular signaling elements, regulating processes as diverse as neuronal excitability and gene expression. Studies of cellular Ca(2+) signaling have been greatly facilitated by the availability of fluorescent Ca(2+) indicators. The respective merits of different indicators to monitor bulk changes in cellular Ca(2+) levels have been widely evaluated, but a comprehensive comparison for their use in detecting and analyzing local, subcellular Ca(2+) signals is lacking. Here, we evaluated several fluorescent Ca(2+) indicators in the context of local Ca(2+) signals (puffs) evoked by inositol 1,4,5-trisphosphate (IP3) in cultured human neuroblastoma SH-SY5Y cells, using high-speed video-microscopy. Altogether, nine synthetic Ca(2+) dyes (Fluo-4, Fluo-8, Fluo-8 high affinity, Fluo-8 low affinity, Oregon Green BAPTA-1, Cal-520, Rhod-4, Asante Calcium Red, and X-Rhod-1) and three genetically-encoded Ca(2+)-indicators (GCaMP6-slow, -medium and -fast variants) were tested; criteria include the magnitude, kinetics, signal-to-noise ratio and detection efficiency of local Ca(2+) puffs. Among these, we conclude that Cal-520 is the optimal indicator for detecting and faithfully tracking local events; that Rhod-4 is the red-emitting indicator of choice; and that none of the GCaMP6 variants are well suited for imaging subcellular Ca(2+) signals. PMID- 26572562 TI - Sample size under the additive hazards model. AB - BACKGROUND: The additive hazards model can be easier to interpret and in some cases fits better than the proportional hazards model. However, sample size formulas for clinical trials with time to event outcomes are currently based on either the proportional hazards assumption or an assumption of constant hazards. AIMS: The goal is to provide sample size formulas for superiority and non inferiority trials assuming an additive hazards model but no specific distribution, along with evaluations of the performance of the formulas. METHODS: Formulas are presented that determine the required sample size for a given scenario under the additive hazards model. Simulations are conducted to ensure that the formulas attain the desired power. For illustration, the non-inferiority sample size formula is applied to the calculations in the SPORTIF III trial of stroke prevention in atrial fibrillation. CONCLUSION: Simulation results show that the sample size calculations lead to the correct power. Sample size is easily calculated using a tool that is available on the web at http://leemcdaniel.github.io/samplesize.html. PMID- 26572563 TI - Avoiding bias and incorrect confidence interval coverage in prescription drug labeling. AB - BACKGROUND: The primary purpose of prescription drug labeling is to give healthcare professionals the information needed to prescribe drugs appropriately. Therefore, labeling typically reports the effects that the treatment might be expected to have on several efficacy measures, including not only the primary endpoint used to establish effectiveness but also a number of key secondary endpoints that are important to practitioners and patients. METHODS: One possible regulatory approach to drug labeling is to include results on important secondary efficacy endpoints in labeling only if there is statistical evidence of a treatment effect and a clinically meaningful estimated effect. We evaluate the statistical consequences of this approach by deriving and discussing the potential bias in point estimates and deviation from nominal coverage in confidence intervals that are reported in labeling. RESULTS: Such an approach can lead to substantial conditional bias in point estimates (toward spuriously greater effects than the truth) and undercoverage in confidence intervals. CONCLUSION: These statistical properties may have important and undesirable regulatory and public health implications. We discuss an alternative approach to include results in labeling for a selected set of reliably ascertained, clinically important endpoints whether or not there is evidence of a treatment effect. PMID- 26572564 TI - [Comprehensive Assessment of Psychiatric Residents: An Addition to the Program Admission Process]. AB - The training of medical specialists is a long and complex process. Its purpose is to guarantee the society that they are the right professionals to meet the health needs of the population. The first step to ensure this objective is the admission process. In psychiatry this process, monitoring resident students and the criteria for each one are different in each country. Admission in Colombia is a heterogeneous process, not standardized, which varies greatly from one university to another, even between private and public universities. At the National University of Colombia, the admissions process is handled by the Admissions Office and includes: a written test for which you must obtain a minimum score, a resume rating and an interview. The Teaching Committee and the Department of Psychiatry considered the admission procedure in general to be good, but in need of refinement. Due to the experience of some teachers and given the current rules, a "comprehensive assessment" for master and doctoral students was required and in 1996 it was decided that this method of assessment for admission to a specialization in Psychiatry would serve to complement the admission process. The article describes the experience of the process and its outcomes, strengths and weaknesses. PMID- 26572565 TI - [Research and Post-graduate in Psychiatry]. AB - The research component and the acquisition of skills related to the generation of knowledge in the training of medical and surgical specialists in the country is an issue that has recently begun to be discussed. For over 50 years this training has included only the area of professionalism as a copy of an educational model from the mid-twentieth century. Currently the country requires specialists with critical and analytical skills to question their actions and knowledge and generate alternative clinical care to apply to the general population in the search of bettering their own welfare. This article is a review in which the current situation of the teaching of psychiatry and the inclusion of research in the academic processes of our medical specialties in the country are analyzed. PMID- 26572566 TI - [Conceptual Aspects of the Teaching Psychiatry in Colombia]. AB - INTRODUCTION: The teaching of Psychiatry in Colombia is the result of the accumulation of different conceptual streams dating back to early twentieth century and the beginning of Psychiatric study. By a way of different teaching methods, this knowledge was transferred from generation to generation to materialize into its current formation. METHODS: Different key moments are recognied in the history of Psychiatry throughout the world and the introduction of these trends in Colombia, and specifically its impact on teaching. RESULTS: The current structure derives from French elemens of organ-dynamic Psychiatry, both conceptual and clinical, likewise, it is formed from conception kraepeliana and biologic therapies introduced from the second quarter of the last century and the psychoanalytic trend introduced since 1950. CONCLUSION: The Psychiatric Departments of Colombia form prominently in Pychiatry and are skillful in managing mental illness, with basic knowledge of pathophysiology and psychopathology, as well as good training in psychopharmacology and psychotherapy. A limitation is evident in the formation of community mental health. PMID- 26572567 TI - [Transgressive Conducts in the Academic Environment]. AB - INTRODUCTION: This article presents a historical review, from an ethic standpoint, of the national legislation that rules the practice of Medicine in Colombia; ity also refers to the deontological code and the Colombian psychiatric code as well as to the commitment of the Health Faculty of the Universidad del Valle regarding ethical conducts. DEVELOPMENT: Ethics is introduced as an original innate faculty, resulting from cognitive development and learning while being also a manifestation of underlying biological processes or a result of the interaction of different models. The teaching-learning process is a situation in which teachers and students get together in order to acquire competences that are to be ethically expressed. Empirical studies have shown transgressive forms of behavior in teachers, students and academic administrators throughout the world; in addition, the mass media expose transgressions committed by other social groups such as politicians, financiers, clergymen, researchers, etc. CONCLUSIONS: Firstly proposed as a problem-solving strategy is the acceptance of the very existence of transgressions, followed by the conformation of a committee aimed at principle-identification for, subsequently, undertaking eductional and following up actions, while administering sanctions when necessary. The proposal for adopting problem-solving strategies for the Faculty of Health of the Universidad del Valle is also presented. PMID- 26572568 TI - [Perception of Psychiatry among Undergraduate Students of a School of Medicine]. AB - OBJECTIVE: Learn about perceptions and beliefs regarding psychiatry among undergraduate medicine students and compare their conceptions and appreciations concerning positive and negative aspects, before and after specific training in psychiatry. METHODS: Observational, cross-sectional study; qualitative and quantitative research with application of a survey for undergraduate medicine students of the Universidad de La Sabana, before and after a specific psychiatry course. 90 students answered the survey in two groups: one of them before the course, and the other one afterwards; RESULTS: 52,2% corresponded to semesters prior to the course of psychiatry; 25.5% expressed the purpose to specialize in Psychiatry before the course, and such percentage decreased to 13.4% after the course. Association was found between the purpose of not specializing in Psychiatry with the fact of having taken said course (Fisher's exact test, p=0,042). Most students would not specialize in psychiatry because they are interested in other areas. Before the course, students made emphasis on the biological aspects of mental disease. After the course, they also directed their attention to other factors. The two groups believe that the management of these patients is mainly pharmacological. The incurable character of mental illness was also highlighted together with the risk of getting ill and the stigma it entails. CONCLUSIONS: Psychiatry is perceived as a medical specialization with emphasis on pharmacological treatment. There is a low frequency of students interested in this area. The course of psychiatry is associated with reduction of this frequency and limits the variability of the psychiatric concept. PMID- 26572569 TI - [The Purpose of Medical Education: Proposal to Standardize a System of Credits for Medical Specializations Programs]. AB - This article analyzes the concept of an academic credit system and proposes a way to systematize medical specialization programs. The credit system is a way to recognize and standardize the total time that a student must devote to their training. Thus, a credit equal to a certain number of hours of classroom training and independent activities is proposed. An educational program is expressed in the number of credits needed for the whole training process to achieve the competencies expected. A review of the concept of competition in education is also performed. The introduction of the term and its relation to the need to measure performance in future professionals according to labor market needs is identified. A critical discussion about skills defining the different types of skills in the educational field is later discussed. Subsequently, the Colombian regulatory framework is presented concerning the powers, in particular, Decree 1295 of 2010, which defines one academic credit equal to 48 hours in a semester, of which 16 hours are classroom and 32 hours are independent study. A tor of the major milestones in the history of medical education is later made. The structure of credits and contact hours, independent of postgraduate psychiatry in the country is reviewed showing the heterogeneity in their approach. The proposal is presented, defining the types of classroom activities and how to calculate the hours of independent study by type of classroom activity. PMID- 26572570 TI - [Proposal for Recertification of Medical Specialties in Colombia]. AB - This article gives a brief overview of the aspects that justify implementing a recertification of doctors. After a description of this process in the countries where it has the most experience, the advantages of having a recertification process and the criticism of the system is also discussed. Finally, the creation of the Council on Accreditation and Recertification Colombian Medical Specialist professionals (CAMEC, in Spanish), as a product of the work of the Colombian Association of Scientific Societies, and also the draft decree of the national government is proposed in the creation of the Integrated System for Continuing Education and Continuing Professional Development in Health (SFCTHS, in Spanish). PMID- 26572571 TI - [The Biology of Learning]. AB - The effort to relate mental and biological functioning has fluctuated between two doctrines: 1) an attempt to explain mental functioning as a collective property of the brain and 2) as one relatied to other mental processes associated with specific regions of the brain. The article reviews the main theories developed over the last 200 years: phrenology, the psuedo study of the brain, mass action, cellular connectionism and distributed processing among others. In addition, approaches have emerged in recent years that allows for an understanding of the biological determinants and individual differences in complex mental processes through what is called cognitive neuroscience. Knowing the definition of neuroscience, the learning of memory, the ways in which learning occurs, the principles of the neural basis of memory and learning and its effects on brain function, among other things, allows us the basic understanding of the processes of memory and learning and is an important requirement to address the best manner to commit to the of training future specialists in Psychiatry. PMID- 26572572 TI - [Social Pertinence and the Post-Graduate in Psychiatry]. AB - The epidemiological behavior of the population stems from health-disease processes and different bio-psycho-social variables in whch they participate in. Demographic changes show change in the population pyramid and the high incidence of chronic diseases, including mental disorders and neurodegenerative diseases, which have led to a high demand for psychiatric care at different levels. The health system, with its deep crisis, and the lack of response of the education sector in human resource training show a lack of social responsibility with regards to Psychiatric specialty in the country. We have an educational process that ensures that medical graduates respond appropriately to people who require service. However, our graduate programs do not meet the health needs and the number of specialists are not qualified as specialists and do not meet the needs in this region. The high costs of mental health services (eg, consultation and medicines) and lack of access to these services are proof that Colombia does not have a timely and effective response to the epidemiological situation of mental illness. Solid, valid, and continous policies are needed to invole education and health sectors in order to provide solutions to this problem. PMID- 26572573 TI - [Virtual Patients and Medical Teaching]. AB - INTRODUCTION: Biomedical advancements have evolved to the point where teaching software may be implemented to represent real-life scenarios. DEVELOPMENT: Virtual Patients or VPs are software programs that simulate clinical scenarios allowing students to generate a diagnosis and make treatment decisions. In this article, advantages and disadvantages regarding the use of this state-of-the-art technology are discussed. CONCLUSIONS: VP is a useful technique for psychiatry students. PMID- 26572574 TI - [Clinical Simulation and Emotional Learning]. AB - INTRODUCTION: At present, the clinical simulation has been incorporated into medical school curriculum. It is considered that the simulation is useful to develop skills, and as such its diffusion. Within the acquisition of skills, meaningful learning is an essential emotional component for the student and this point is essential to optimize the results of the simulation experience. METHODS: Narrative description on the subject of simulation and the degree of "emotionality." DEVELOPMENT: The taxonomy is described for the types of clinical simulation fidelity and correlates it with the degree of emotionality required to achieve significant and lasting learning by students. CONCLUSION: It is essential to take into account the student's level of emotion in the learning process through simulation strategy. PMID- 26572575 TI - [Use of Simulated Pacients in Psychiatry]. AB - INTRODUCTION: Scientific advances and the complexity of human knowledge generate a constant need for creating new tools intended to facilitate learning in an agreeable and lasting form. Simulated patients are one of such tools in medical education. Standardized or simulated patients are actors or people vigorously trained to represent a medical history or, if possible, specific physical findings with the purpose of using such representations as an educational and evaluating supplement in clinic practice. The use of simulated patients has been very well received, particularly in the psychiatric field; however, its usefulness in areas such as psychotherapy or evaluation of residents remains questionable. METHODS: A search was made in PubMed with the MESH words ("Psychiatry/education" and "Patient Simulation"); a search was also made in LILACS and scholar Google using similar words. RESULTS: Simulated patients are widely used throughout the world in the psychiatry field and their usefulness as an academic tool for pre-graduate students is confirmed in most of the literature reviewed. One of the main benefits of the use of this kind of patients is the acquisition of specific abilities (e.g.: medical history recording); nevertheless, its efficacy in more complex experiences like psychotherapy or certification of psychiatry residents is questioned. CONCLUSIONS: Notwithstanding the controversy, most of the literature reviewed confirms the benefits and acceptance of this methodology in the formation of students and psychiatrists. PMID- 26572576 TI - [Effective Presentations in Medicine. The Art of Communication and Transmission: Ten Recommendations]. AB - To communicate effectively during a lecture or presentation it is necessary to follow simple rules, including the preparation of the conference with the audience in mind and with the definition of a specific message to leave the audience. The public's attention should be quickly captured and all subsequent actions should aim to keep it. The text must be accurate and sizes easily visible, the slides should provide good contrast with solid and simple backgrounds and should avoid excessive animations. At the close of the conference, the conclusions and question session offers the invaluable opportunity to reinforce the desired message. PMID- 26572577 TI - [Assessment in Medical Education]. AB - INTRODUCTION: The assessment of medical education is fundamental for proper feedback and evaulation of students. DEVELOPMENT: The overall purpose of the evaluation is numerically and formatively revised. The suggested evaluation processes is described taking into account the Miller competence pyramid as a tool for designing evaluations and concepts of validity and reproducibility in assessments. The utility of student and the teacher is also raised. CONCLUSIONS: The issue of assessment should leave the knowledge parameters that are usually used. PMID- 26572578 TI - [Education in Psychiatry]. PMID- 26572579 TI - [Assessment of an Evaluation System for Psychiatry Learning]. AB - Through the analysis of a teaching evaluation system for a Psychiatry course aimed at Medicine students, the author reviews the basic elements taken into account in a teaching assessment process. METHODS: Analysis was carried out of the assessment methods used as well as of the grades obtained by the students from four groups into which the they were divided. RESULTS: The selected assessment methods are appropriate to evaluate educational objectives; the contents are selected by means of a specification matrix; there is a high correlation coefficient between the grades obtained in previous academic periods and the ones obtained in the course, thus demonstrating the validity of the results (both considering the whole exam or just a part of it). Most of the students are on the right side of the grading curve, which means that the majority of them acquire the knowledge expected. CONCLUSIONS: The assessment system used in the Psychopathology course is fair, valid and reliable, specifically concerning the objective methods used, but the conceptual evaluation should be improved or, preferably, eliminated as a constituernt part of the evaluation system. PMID- 26572580 TI - The role of human metapneumovirus in the critically ill adult patient. AB - PURPOSE: The purpose of the study is to describe the role of human metapneumovirus (hMPV) infection in critical illness and acute respiratory distress syndrome (ARDS). MATERIALS AND METHODS: We collected clinical and demographic information from a retrospective chart review, comparing patients with and without an intensive care unit (ICU) admission. Among patients admitted to the ICU, we assessed whether hMPV was "unlikely," "possibly," or "likely" the reason for ICU admission, based on a prespecified definition, and whether the patient met criteria for ARDS. RESULTS: We identified 128 hospitalized adults with hMPV infection. Forty hospitalized patients (31%) with hMPV infection required admission to the ICU. Among patients cared for in the ICU, hMPV was "possibly" the reason for ICU admission in 55% of patients and "likely" the reason in 38%. Forty-eight percent of ICU patients met criteria for ARDS. Although most patients admitted to the ICU had significant comorbidities or were immunosuppressed, 6 patients requiring ICU admission had more minor comorbidities and no underlying immunosuppression. CONCLUSIONS: Although most patients hospitalized with hMPV had chronic cardiac or pulmonary disease, hMPV can also be associated serious respiratory illness and ARDS in adult patients without significant comorbidities or immunosuppression. PMID- 26572581 TI - Orexin A induces autophagy in HCT-116 human colon cancer cells through the ERK signaling pathway. AB - Orexins are a class of peptides which have a potent influence on a broad variety of cancer cells. Autophagy is closely associated with tumors; however, its function is not yet completely understood. In this study, we aimed to determine whether orexin A induces autophagy in HCT-116 human colon cancer cells and to elucidate the molecular mechanisms involved. For this purpose, HCT-116 cells were treated with orexin A, and cell viability was then measured by MTT assay, and apoptosis was determined by flow cytometry. The expression levels of autophagy related proteins were measured by western blot analysis. Quantitative analysis of autophagy following acridine orange (AO) staining was performed using fluorescence microscopy, and cellular morphology was observed under a transmission electron microscope. In addition, the HCT-116 cells were treated with the extracellular signal-regulated kinase (ERK) inhibitor, U0126, or the autophagy inhibitor, chloroquine, in combination with orexin A in order to examine the activation of ERK. We found that orexin A significantly inhibited the viability of the HCT-116 cells. Both autophagy and apoptosis were activated during the orexin A-induced death of HCT-116 cells. When the HCT-116 cells were treated with orexin A for 24 h, an accumulation of punctate microtubule associated protein-1 light chain 3 (LC3) and an increase in LC3-II protein levels were also detected, indicating the activation of autophagy. Moreover, orexin A upregulated ERK phosphorylation; however, U0126 or chloroquine abrogated ERK phosphorylation and decreased autophagy, compared to treatment with orexin A alone. Therefore, our findings demonstratedm that orexin A induced autophagy through the ERK pathway in HCT-116 human colon cancer cells. The inhibition of autophagy may thus prove to be an effective strategy for enhancing the antitumor potential of orexin A as a treatment for colon cancer. PMID- 26572582 TI - The antisymmetry of distortions. AB - Distortions are ubiquitous in nature. Under perturbations such as stresses, fields or other changes, a physical system reconfigures by following a path from one state to another; this path, often a collection of atomic trajectories, describes a distortion. Here we introduce an antisymmetry operation called distortion reversal that reverses a distortion pathway. The symmetry of a distortion pathway is then uniquely defined by a distortion group; it has the same form as a magnetic group that involves time reversal. Given its isomorphism to magnetic groups, distortion groups could have a commensurate impact in the study of distortions, as the magnetic groups have had in the study of magnetic structures. Distortion symmetry has important implications for a range of phenomena such as structural and electronic phase transitions, diffusion, molecular conformational changes, vibrations, reaction pathways and interface dynamics. PMID- 26572583 TI - Expression of FLNa in human melanoma cells regulates the function of integrin alpha1beta1 and phosphorylation and localisation of PKB/AKT/ERK1/2 kinases. AB - FLNa is a ubiquitous cytoskeletal protein that links transmembrane receptors, including integrins, to F-actin and functions as a signalling intermediate. We investigated FLNa's role in the function of integrin-type collagen receptors, EGF EGFR signalling and regulation of PKB/Akt and ERK1/2. Using FLNa-deficient M2 human melanoma cells, and same cells expressing EGFP-FLNa (M2F) or its Ig-like repeats 1-8+24, 8-15+24 and 16-24, we found that in M2F and M2 8-15+24 cells, EGF induced the increased phosphorylation of PKB/Akt and ERK1/2. In M2F cells EGF induced the localisation of these kinases to cell nucleus and lamellipodia, respectively, and the ERK1/2 phosphorylation-dependent co-immunoprecipitation of FLNa with ERK1/2. Only M2F and M2 8-15+24 cells adhered to and spread on type I collagen whereas on fibronectin all cells behaved similarly. alpha1beta1 and alpha2beta1 were the integrin-type collagen receptors expressed on these cells with primarily alpha1beta1 localising to focal contacts and affecting cell adhesion and migration in a manner dependent on FLNa or its Ig-like repeats 8-15. Our results suggest a role for FLNa repeats 8-15 in the alpha1-subunit-dependent regulation of integrin alpha1beta1 function, EGF-EGFR signalling to PKB/Akt and ERK1/2, identify ERK1/2 in EGF-induced FLNa-associated protein complexes, and show that the function of different integrins is subjected to differential regulation by FLNa. PMID- 26572584 TI - Surgical treatment of bronchiectasis: A review of 20 years of experience. AB - BACKGROUND: Bronchiectasis is defined as an abnormal and irreversible dilation and distortion of the bronchi, which has numerous causes. Surgical treatment of this disease is usually reserved for focal disease and when the medical treatment is no longer effective. We report our center experience and outcomes in bronchiectasis surgery during the last 20 years. METHODS: Between 1994 and 2014, sixty-nine patients underwent surgical resection for bronchiectasis. Patient demographics, presenting symptoms, indications for surgical treatment, type of lung resection, morbidity and mortality, as well as clinical follow-up and outcomes were analyzed. RESULTS: From the 69 patients included, 31 (44.9%) were male and 38 (55.1%) were female. Surgery was indicated because of unsuccessful medical therapy in 33 patients (47.8%), haemoptysis in 22 patients (31.9%), nondiagnostic lung mass in 9 patients (13.0%) and lung abscess in 5 patients (7.3%). The surgical procedures were lobectomy in 45 (65.2%) patients, pneumonectomy in 10 (14.5%) patients, bilobectomy in 8 (11.6%) patients, lobectomy plus segmentectomy in 3 (4.3%) patients and only segmentectomy in 3 (4.3%) patients. Morbidity rate was 14.5% and there was no perioperative mortality. The follow-up was possible in 60 patients, with an outcome reported as excellent in 44 (73.3%) patients, as improved in 11 (18.3%) and as unchanged in 5 (8.3%). CONCLUSION: Although the number of patients with bronchiectasis referred for surgical treatment has decreased, pulmonary resection still plays a significant role. Surgical resection of localized bronchiectasis is a safe procedure with proven improvement of quality of life for the majority of patients. PMID- 26572585 TI - Role of Integrin beta4 in Lung Endothelial Cell Inflammatory Responses to Mechanical Stress. AB - Simvastatin, an HMG-CoA reductase inhibitor, has lung vascular-protective effects that are associated with decreased agonist-induced integrin beta4 (ITGB4) tyrosine phosphorylation. Accordingly, we hypothesized that endothelial cell (EC) protection by simvastatin is dependent on these effects and sought to further characterize the functional role of ITGB4 as a mediator of EC protection in the setting of excessive mechanical stretch at levels relevant to ventilator-induced lung injury (VILI). Initially, early ITGB4 tyrosine phosphorylation was confirmed in human pulmonary artery EC subjected to excessive cyclic stretch (18% CS). EC overexpression of mutant ITGB4 with specific tyrosines mutated to phenylalanine (Y1440, Y1526 Y1640, or Y1422) resulted in significantly attenuated CS-induced cytokine expression (IL6, IL-8, MCP-1, and RANTES). In addition, EC overexpression of ITGB4 constructs with specific structural deletions also resulted in significantly attenuated CS-induced inflammatory cytokine expression compared to overexpression of wildtype ITGB4. Finally, mice expressing a mutant ITGB4 lacking a cytoplasmic signaling domain were found to have attenuated lung injury after VILI-challenge (VT = 40 ml/kg, 4 h). Our results provide mechanistic insights into the anti-inflammatory properties of statins and may ultimately lead to novel strategies targeted at ITGB4 signaling to treat VILI. PMID- 26572586 TI - The role of attention processes in facial affect recognition in schizophrenia. AB - INTRODUCTION: Studies investigating the involvement of attention processes in facial affect recognition (FAR) have been contradictory, with some suggesting a generalised cognitive deficit, whereas others a specialised deficit in affect recognition. Given the ubiquity of both attention and emotion perception deficits in schizophrenia, we examined whether specific attentional processes, in fact, mediate FAR. METHODS: Patients with schizophrenia (n = 38) and healthy controls (n = 24) performed tests assessing FAR and attention processes, specifically, visual attention (Trail Making Test A), sustained attention/inhibition (Rapid Visual Processing subtest; Cambridge Automated Neuropsychological Test Battery), and attention to details in facial features (AFF). AFF and FAR were assessed with newly devised experimental procedures. RESULTS: Hierarchical multiple regression analyses showed a similar pattern of association between attention processes and FAR in both participant groups with respect to all attention processes investigated, predicting FAR accuracy. Additionally, visual attention predicted accuracy in happiness, disgust and surprise, whereas AFF predicted accuracy in anger and fear. Regarding FAR processing speed, no attention process predicted participants' performance on correct responses; AFF response speed predicted participants' FAR response speed, but only on incorrect responses. DISCUSSION: The present findings highlight the role of attentional processes in emotion recognition, as deficits in the former were predictive of impairments in the latter. Furthermore, AFF appears to be involved in the discrimination of negatively valenced facial expressions. The lack of association between attentional processes and FAR processing speed, particularly regarding correct responses, might reflect the differential pattern of activation of cortical and subcortical structures involved in these cognitive processes. PMID- 26572587 TI - Combined use of spatial restraint stress and middle cerebral artery occlusion is a novel model of post-stroke depression in mice. AB - Post stroke depression (PSD) is one of the most common complications of ischemic stroke. At present, the underlying mechanisms are unclear, largely because there are no reliable, valid and reproducible animal models of PSD. Here we report a novel animal model of PSD that displays consistent and reliable clinical features of hemiplegic stroke. The animal model encompasses a combination of the middle cerebral artery occlusion (MCAO) and spatial restraint stress. We found that a 60 minute MCAO followed by spatial restraint stress for 2 h daily for 2 to 4 weeks from the fourth day after MCAO induced PSD-like depressive phenotypes in mice. Importantly, the mice showed exacerbated deficits of neurological functions and decreased body weights, which were accompanied with reduced levels of brain derived neurotrophic factor and neurotransmitters including serotonin and dopamine. In addition, we identified increased levels of serum cortisol in our PSD mice. Finally, we found that mice with PSD were responsive to the tri-cyclic antidepressant imipramine as evidenced by their attenuated depressive behaviors, increased body weights, recovered brain serotonin levels, and decreased serum cortisol levels. This mouse model replicates multiple features of human post stroke depression and thus provides a new model for the investigation of PSD. PMID- 26572588 TI - Direct intramuscular fetal or maternal antenatal corticosteroid therapy: short time effects on fetal behavior and oxygenation: a comparative study. AB - OBJECTIVE: To compare the effects of antenatal administration of corticosteroids used in two different regimens, on fetal biophysical profile (BPP), baseline fetal heart rate (BFHR), nonstress test (NST) and perinatal outcomes. STUDY DESIGN: We evaluated the effects of single direct intramuscular (i.m.) fetal dose of dexamethasone (4 mg/kg), or four doses of 6 mg dexamethasone given to the mother 12 hours apart on the parameters of fetal BPP 0-4 hours before and after antenatal contraction stress (ACST). We evaluated two groups of 41 fetuses in the 31st gestation week at risk of fetal hypoxia at the Department of Gynecology/Obstetrics, Clinical Center of Serbia in 2013. RESULTS: In fetal ACST group, we found significantly different changes in fetal breathing movement before (D0-f) and after therapy (D1-f), p = 0.019 (-11.75; -1.12), 95% confidence interval (CI), as well as in the maternal ACST group, p = 0.001; ( 11.75; -1.12), 95% CI. We found significant difference between BPP 0-m and BPP1-m in the maternal group, p = 0.000. Neonatal asphyxia occurred more often with the increased frequency of fetal breath movements after both ACST (p = 0.04 versus p = 0.07). CONCLUSION: Fetal ACST results in increased fetal breathing movements. Maternal ACST can result in changes to BPP. The increase in fetal breathing movements determinates neonatal asphyxia regardless of the ACST. PMID- 26572589 TI - MicroRNA-21 stimulates epithelial-to-mesenchymal transition and tumorigenesis in clear cell renal cells. AB - Clear cell renal cell carcinoma (ccRCC) metastasis may result from epithelial-to mesenchymal transition and mesenchymal stem cells that contribute to the development of the primary tumor. In this study, it was demonstrated that microRNA-21 (miR-21) acts as an oncogenic driver of ccRCC. ccRCC spheres were isolated and it was shown that they exhibited cancer stem cell-like properties, including the formation of self-renewing spheres. Spheres showed increased expression of stem cell-related transcription factors and epithelial-mesenchymal transition (EMT) markers. In addition, secondary sphere formation capacity was assessed after miR-21 transfection. miR-21 accelerated the formation of ccRCC spheres, which shared molecular characteristics with the spontaneous ccRCC spheres. It was demonstrated that miR-21 overexpression facilitates ccRCC sphere formation. Thus, a single miRNA may have an impact on the formation of highly tumorigenic cancer spheres in kidney cancer. PMID- 26572591 TI - Iron-based phosphate binders--a new element in management of hyperphosphatemia. AB - INTRODUCTION: Management of serum phosphorus in patients with chronic kidney disease remains a significant clinical challenge. A pivotal component of the clinical approach to maintaining serum phosphorus concentrations towards the normal range is the use of phosphate binding agents in addition to comprehensive dietary counseling. The available agents work similarly by capitalizing on a cation within the agent to bind negatively charged phosphorus, forming an insoluble complex and reducing ingested phosphorus absorption. Despite several effective options for phosphate binder therapies, patient adherence remains an issue, mainly due to adverse effect profiles and large daily pill burdens. AREAS COVERED: Two new iron-based phosphate binder therapies have recently become available in the United States, sucroferric oxyhydroxide and ferric citrate. These agents have both been shown to effectively reduce serum phosphorus comparably to widely used calcium-based binders and sevelamer salts. EXPERT OPINION: The two new iron-based binders differ substantially with regard to phosphate binding chemistry and iron absorption profiles. Their place in therapy is still evolving and the impact of pill burden, gastrointestinal adverse effect profiles, potential cost reduction of anemia therapies and physiologic effects of long-term iron exposure need to be further evaluated. PMID- 26572590 TI - Divalent metal-ion transporter 1 is decreased in intestinal epithelial cells and contributes to the anemia in inflammatory bowel disease. AB - Divalent metal-ion transporter 1 (DMT1) has been found to play an important role in the iron metabolism and hemogenesis. However, little is known about the potential role of DMT1 in the pathogenesis of anemia from patients with inflammatory bowel disease (IBD). Herein, we investigated expression of DMT1 in the intestinal mucosa by quantitative real-time polymerase chain reaction (qRT PCR) and immunohistochemistry, and found that DMT1 was significantly decreased in the inflamed mucosa of active IBD patients compared with that in those patients at remission stage and healthy controls. To further study the mechanism, we cultured HCT 116 cell line in vitro. Expression of DMT1 in HCT116 was demonstrated to be markedly decreased under stimulation with TNF for 24 and 48 h, while JNK inhibitor (JNK-IN-7) could significantly reverse the decrease. Interestingly, anti-TNF therapy successfully improved anemia in clinical responsive Crohn's disease patients, and DMT1 was found to be markedly up regulated in intestinal mucosa. Taken together, our studies demonstrate that decreased expression of DMT1 in intestinal mucosa leads to compromised absorption and transportation of iron and that blockade of TNF could rescue anemia and promote DMT1 expression in gut mucosa. This work provides a therapeutic approach in the management of anemia in IBD. PMID- 26572592 TI - Nanocellulose-based Translucent Diffuser for Optoelectronic Device Applications with Dramatic Improvement of Light Coupling. AB - Nanocellulose is a biogenerated and biorenewable organic material. Using a process based on 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)/NaClO/NaBr system, a highly translucent and light-diffusive film consisting of many layers of nanocellulose fibers and wood pulp microfibers was made. The film demonstrates a combination of large optical transmittance of ~90% and tunable diffuse transmission of up to ~78% across the visible and near-infrared spectra. The detailed characterizations of the film indicate the combination of high optical transmittance and haze is due to the film's large packing density and microstructured surface. The superior optical properties make the film a translucent light diffuser and applicable for improving the efficiencies of optoelectronic devices such as thin-film silicon solar cells and organic light emitting devices. PMID- 26572593 TI - Oligodendrogliomas: a short history of clinical developments. PMID- 26572594 TI - Removal of Persistent Organic Contaminants by Electrochemically Activated Sulfate. AB - Solutions of sulfate have often been used as background electrolytes in the electrochemical degradation of contaminants and have been generally considered inert even when high-oxidation-power anodes such as boron-doped diamond (BDD) were employed. This study examines the role of sulfate by comparing electro oxidation rates for seven persistent organic contaminants at BDD anodes in sulfate and inert nitrate anolytes. Sulfate yielded electro-oxidation rates 10-15 times higher for all target contaminants compared to the rates of nitrate anolyte. This electrochemical activation of sulfate was also observed at concentrations as low as 1.6 mM, which is relevant for many wastewaters. Electrolysis of diatrizoate in the presence of specific radical quenchers (tert butanol and methanol) had a similar effect on electro-oxidation rates, illustrating a possible role of the hydroxyl radical ((*)OH) in the anodic formation of sulfate radical (SO4(*-)) species. The addition of 0.55 mM persulfate increased the electro-oxidation rate of diatrizoate in nitrate from 0.94 to 9.97 h(-1), suggesting a nonradical activation of persulfate. Overall findings indicate the formation of strong sulfate-derived oxidant species at BDD anodes when polarized at high potentials. This may have positive implications in the electro-oxidation of wastewaters containing sulfate. For example, the energy required for the 10-fold removal of diatrizoate was decreased from 45.6 to 2.44 kWh m(-3) by switching from nitrate to sulfate anolyte. PMID- 26572596 TI - A degradable polydopamine coating based on disulfide-exchange reaction. AB - Although the programmed degradation of biocompatible films finds applications in various fields including biomedical and bionanotechnological areas, coating methods have generally been limited to be substrate-specific, not applicable to any kinds of substrates. In this paper, we report a dopamine derivative, which allows for both universal coating of various substrates and stimuli-responsive film degradation, inspired by mussel-adhesive proteins. Two dopamine moieties are linked together by the disulfide bond, the cleavage of which enables the programmed film degradation. Mechanistic analysis of the degradable films indicates that the initial cleavage of the disulfide linkage causes rapid uptake of water molecules, hydrating the films, which leads to rapid degradation. Our substrate-independent coating of degradable films provides an advanced tool for drug delivery systems, tissue engineering, and anti-fouling strategies. PMID- 26572597 TI - 6th Biannual ECOtoxicology MEeting (BECOME 2014) - Environmental emergencies: Ecotoxicology as a management tool. PMID- 26572598 TI - Welcome letter. PMID- 26572600 TI - Venue. PMID- 26572601 TI - Scientific Program. PMID- 26572602 TI - Retraction Note: Central macular thickness in patients with type 2 diabetes mellitus without clinical retinopathy. PMID- 26572603 TI - Spanish adaptation of the Quality of Life Index-Spinal Cord Injury version. AB - STUDY DESIGN: A cross-sectional, validation study. OBJECTIVES: To (a) develop the Spanish version of the Quality of Life Index-Spinal Cord Injury version (SV QLI/SCI) and (b) assess its psychometric characteristics among permanent wheelchair users and specifically among those with SCI. SETTING: Associations of wheelchair users in Mallorca (Spain). METHODS: Two forward and backward translations of the QLI/SCI into Spanish were carried out separately. Seventy seven subjects were randomly selected among the members of the associations. They completed the SV-QLI/SCI and validated instruments to measure depression and spinal pain upon recruitment and 14 days later. Assessments included comprehensibility, reproducibility, floor and ceiling effects and correlations between quality of life, pain and depression (Spearman's correlation coefficient). Analyses were repeated excluding data from subjects without SCI. RESULTS: Three items of the SV-QLI/SCI required rephrasing. Reproducibility was 'almost perfect' for the entire questionnaire and its 'Health and functioning' subscale, 'substantial' for the 'Social and economic' and 'Family' subscales and 'moderate' for the 'Psychological/spiritual' subscale. Floor effect was not observed, and only for the 'Family' subscale >3% of the subjects reached the maximum possible score. The correlation between quality of life and depression was the strongest (r=-0.628). Results were virtually identical in the subsample with SCI. CONCLUSION: These results support the use of the SV-QLI/SCI among Spanish-speaking wheelchair users. PMID- 26572604 TI - Characteristics of C6-7 myelopathy: assessment of clinical symptoms and electrophysiological findings. AB - STUDY DESIGN: This is a single-center retrospective study. OBJECTIVES: The objective of this study was to study the clinical symptoms and electrophysiological features of C6-7 myelopathy. SETTING: This study was conducted at the Department of Orthopedic surgery, Yamaguchi University Graduate school of medicine, Japan. METHODS: A total of 20 patients with cervical compressive myelopathy were determined by spinal cord-evoked potentials or a single level of obvious magnetic resonance imaging (MRI)-documented cervical spinal cord compression. Neurological examinations included manual muscle testing and investigation of deep tendon reflex, including Hoffmann sign, and of sensory disturbance areas. Motor-evoked potentials (MEPs), compound muscle action potentials (CMAPs) and F-wave were recorded from bilateral abductor digit minim and abductor halluces muscles. Central motor conduction time was calculated as follows: MEPs latency-(CMAPs latency+F latency-1)/2 (ms). RESULTS: Eighteen patients (90%) had negative Hoffmann sign. Eight patients (40%) had no sensory disturbance in the upper limbs and 8 patients (40%) had no muscle weakness in the upper limbs. We determined that patients had cervical myelopathy when their central motor conduction time measured in abductor digit minim was longer than 6.76 ms (+2 s.d.). Using this definition, the sensitivity for myelopathy was 42.8%. CONCLUSION: Patients with C6-7 myelopathy may lack clinical symptoms in their hands and central motor conduction time measured in abductor digit minim tended to be less prolonged, and it only showed symptoms in their lower limbs as gait disturbance. Surgeons should bear in mind the possibility of disorders of caudal C6-7 when they encounter patients with no or few symptoms in their hands and with leg weakness or numbness. PMID- 26572605 TI - Circadian variations in melatonin and cortisol in patients with cervical spinal cord injury. AB - PURPOSE: In cervical spinal cord injury (CSCI), afferent and efferent circuits that influence the basal production of melatonin and cortisol may be disrupted and hence disrupt the basal functions of human physiology. Therefore, the aim of this study was to assess circadian changes, if any, in serum cortisol and melatonin in patients with CSCI. METHODS: Serum levels of cortisol and melatonin were measured at 6-h intervals of the day (0600, 1200, 1800 and 0000 hours) in 22 CSCI patients, as well as 22 healthy controls. RESULTS: Significantly higher melatonin levels were observed in the patient group in morning hours, whereas a significantly lower level of melatonin was found during the night time in the patient group than in the control group. Moreover, significantly higher values were obtained in the evening and night time serum cortisol levels among the patients compared with controls. Further, when the mean values of cortisol throughout the day were tested among patient and control groups similar circadian rhythm was found. The only difference being that serum cortisol declined much more in controls in evening and night samples as compared with CSCI patients. CONCLUSION: We conclude that circadian variations exist in the circulating levels of serum cortisol and melatonin in patients with CSCI. Low levels of melatonin secretion during night may contribute to the pervasive sleep disruption and increased pain perception. PMID- 26572606 TI - Measuring activity limitation outcomes in youth with spinal cord injury. AB - STUDY DESIGN: A cross-sectional study. OBJECTIVES: The Pediatric Spinal Cord Injury Activity Measure (PEDI-SCI AM), which includes calibrated item banks (child and parent versions) for general mobility, daily routines, wheeled mobility and ambulation, can be administered using computerized adaptive tests (CATs) or short forms (SFs). The study objectives are as follows: (1) to examine the psychometric properties of the PEDI-SCI AM item banks and 10-item CATs; and (2) to develop and evaluate the psychometric properties of PEDI-SCI AM SFs. SETTING: US Shriners Hospitals for Children (California, Illinois and Pennsylvania). METHODS: Calibration data from a convenience sample of 381 children and adolescents with SCI and 322 parents or caregivers were used to examine PEDI-SCI AM item banks, 10-item CATs and SF scores. We calculated group reliability, internal consistency (Cronbach's alpha) and interclass coefficients (ICCs) to assess agreement between 10-item CATs, SFs and item banks. The percent of the sample with highest (ceiling) and lowest (floor) scores was also determined. An expert panel selected items for 14 SFs. RESULTS: PEDI-SCI item banks, 10-item CATs and SFs demonstrate acceptable group reliability (0.73-0.96) and internal consistency (0.77-0.98). ICC values show strong agreement with item banks for 10-item CATs (0.72-0.99) and SFs. Floor effects are minimal (<15%). Ceiling effects are minimal for children with tetraplegia but high in children with paraplegia for general mobility (13.41-26.05%) and daily activities (12.99 32.71%). CONCLUSIONS: The PEDI-SCI AM exhibited strong psychometric properties for children with tetraplegia. Replenishment of the general mobility and daily routine item banks is needed to reduce ceiling effects noted for youth with paraplegia. PMID- 26572607 TI - Healthcare decision-making in end stage renal disease-patient preferences and clinical correlates. AB - BACKGROUND: Medical decision-making is critical to patient survival and well being. Patients with end stage renal disease (ESRD) are faced with incrementally complex decision-making throughout their treatment journey. The extent to which patients seek involvement in the decision-making process and factors which influence these in ESRD need to be understood. METHODS: 535 ESRD patients were enrolled into the cross-sectional study arm and 30 patients who started dialysis were prospectively evaluated. Patients were enrolled into 3 groups- 'predialysis' (group A), 'in-centre' haemodialysis (HD) (group B) and self-care HD (93 % at home-group C) from across five tertiary UK renal centres. The Autonomy Preference Index (API) has been employed to study patient preferences for information seeking (IS) and decision-making (DM). Demographic, psychosocial and neuropsychometric assessments are considered for analyses. RESULTS: 458 complete responses were available. API items have high internal consistency in the study population (Cronbach's alpha > 0.70). Overall and across individual study groups, the scores for information-seeking and decision-making are significantly different indicating that although patients had a strong preference to be well informed, they were more neutral in their preference to participate in DM (p < 0.05). In the age, education and study group adjusted multiple linear regression analysis, lower age, female gender, marital status; higher API IS scores and white ethnicity background were significant predictors of preference for decision making. DM scores were subdivided into tertiles to identify variables associated with high (DM > 70: and low DM (<=30) scores. This shows association of higher DM scores with lower age, lower comorbidity index score, higher executive brain function, belonging in the self-caring cohort and being unemployed. In the prospectively studied cohort of predialysis patients, there was no change in decision-making preference scores after commencement of dialysis. CONCLUSION: ESRD patients prefer to receive information, but this does not always imply active involvement in decision-making. By understanding modifiable and non modifiable factors which affect patient preferences for involvement in healthcare decision-making, health professionals may acknowledge the need to accommodate individual patient preferences to the extent determined by the individual patient factors. PMID- 26572608 TI - Genetic testing and genomic analysis: a debate on ethical, social and legal issues in the Arab world with a focus on Qatar. AB - In 2013 both Saudi Arabia and Qatar launched genome projects with the aim of providing information for better diagnosis, treatment and prevention of diseases and, ultimately to realize personalized medicine by sequencing hundred thousands samples. These population based genome activities raise a series of relevant ethical, legal and social issues general, related to the specific population structure as well as to the Islamic perspective on genomic analysis and genetic testing. To contribute to the debate, the Authors after reviewing the existing literature and taking advantage of their professional experience in the field and in the geographic area, discuss and provide their opinions. In particular, the Authors focus on the impact of consanguinity on population structure and disease frequency in the Arab world, on genetic testing and genomic analysis (i.e. technical aspects, impact, etc.) and on their regulations. A comparison between the Islamic perspective and the ethical, social and legal issues raised in other population contexts is also carried. In conclusion, this opinion article with an up-to-date contribution to the discussion on the relevance and impact of genomic analysis and genetic testing in the Arab world, might help in producing specific national guidelines on genetic testing and genomic analysis and help accelerate the implementation and roll out of genome projects in Muslim countries and more specifically in Qatar, and other countries of the Gulf. PMID- 26572610 TI - Perceptions and plans for prevention of Ebola: results from a national survey. AB - BACKGROUND: Literature suggests that Americans may have higher levels of perceived threat to Ebola than are warranted. METHODS: We surveyed 1018 U.S. adults from a nationally representative Internet panel about their knowledge, perceived threat, and behavioral intentions during the 2014 Ebola outbreak. RESULTS: Eighty-six percent of respondents knew that Ebola could be transmitted through blood and bodily fluids. However, a large percentage had some inaccurate knowledge and 19 % believed Ebola would spread to the U.S. Respondents favored mandatory quarantine (63 %) and travel bans (55 %). Confidence in the ability of the media and government to accurately report on or prevent a U.S. epidemic was low. Fifty-two percent intended to engage in behaviors such as avoiding public transportation. DISCUSSION: Despite low perceived susceptibility, half intended to engage in behaviors to prevent transmission and large numbers favored policies not currently recommended by health officials. The extreme nature of Ebola virus likely motivated people to engage in behaviors and favor policies that were not necessary given the low risk of transmission in the U.S. CONCLUSIONS: Health officials should ensure the public has accurate information about Ebola and bolster confidence in the government's ability to control infectious diseases in case of a future outbreak in the U.S. PMID- 26572611 TI - Leveraging NMR and X-ray Data of the Free Ligands to Build Better Drugs Targeting Angiotensin II Type 1 G-Protein Coupled Receptor. AB - The angiotensin II type 1 receptor (AT1R) has been recently crystallized. A new era has emerged for the structure-based rational drug design and the synthesis of novel AT1R antagonists. In this critical review, the X-ray crystallographic data of commercially available AT1R antagonists in free form are analyzed and compared with the conformational analysis results obtained using a combination of NMR spectroscopy and Molecular Modeling. The same AT1R antagonists are docked and compared in terms of their interactions in their binding site using homology models and the crystallized AT1R receptor. Various aspects derived from these comparisons regarding rational drug design are outlined. PMID- 26572609 TI - Effects of protein-rich nutritional supplementation and bisphosphonates on body composition, handgrip strength and health-related quality of life after hip fracture: a 12-month randomized controlled study. AB - BACKGROUND: The catabolic state that follows hip fracture contributes to loss of muscle mass and strength, that is sarcopenia, which impacts functional ability and health-related quality of life. Measures to prevent such long-term postoperative consequences are of important concern. The aim of this study was to evaluate the combined effects of protein-rich nutritional supplementation and bisphosphonate on body composition, handgrip strength and health-related quality of life following hip fracture. METHODS: The study included 79 men and women with hip fracture, mean age 79 years (SD 9), without severe cognitive impairment, who were ambulatory and living independently before fracture. Patients were randomized postoperatively to receive liquid supplementation that provided 40 g of protein and 600 kcal daily for six months after the fracture, in addition to bisphosphonates once weekly for 12 months (group N, n = 26), or bisphosphonates alone once weekly for 12 months (group B, n = 28). All patients, including the controls (group C, n = 25) received calcium 1 g and vitamin D3 800 IU daily. Body composition as measured by dual-energy X-ray absorptiometry (DXA), handgrip strength (HGS) and health-related quality of life (HRQoL) were registered at baseline, six and 12 months postoperatively. RESULTS: There were no differences among the groups regarding change in fat-free mass index (FFMI), HGS, or HRQoL during the study year. Intra-group analyses showed improvement of HGS between baseline and six months in the N group (P = 0.04). HRQoL decreased during the first year in the C and B groups (P = 0.03 and P = 0.01, respectively) but not in the nutritional supplementation N group (P = 0.22). CONCLUSIONS: Protein-rich nutritional supplementation was unable to preserve FFMI more effectively than vitamin D and calcium alone, or combined with bisphosphonate, in this relatively healthy group of hip fracture patients. However, trends toward positive effects on both HGS and HRQoL were observed following nutritional supplementation. TRIAL REGISTRATION: Clinicaltrials.gov NCT01950169 (Date of registration 23 Sept 2013). PMID- 26572612 TI - Colchicine, Biologic Agents and More for the Treatment of Familial Mediterranean Fever. The Old, the New, and the Rare. AB - Familial Mediterranean Fever (FMF) is a rare autosomal recessive autoinflammatory disorder involving the innate immunity and affecting almost exclusively populations with Mediterranean origin. Clinical features include recurrent episodes of fever, leukocitosis, serositis (peritonitis or pleuritis, arthritis), myalgia or erysipelas-like skin lesions, lasting 12-72 hrs. The MEFV gene mutations on chromosome 16p13.3 encodes the abnormal pyrin (marenostrin), a protein expressed in granulocytes, monocytes, serosal and synovial fibroblasts and involved in the activation of caspase-1 and the processing and release of active pro-inflammatory IL-1beta. Since the first report in 1972, maintenance therapy with colchicine, a tricyclic neutral alkaloid, remains the mainstay of treatment in symptomatic FMF patients since it reduces the disease activity and prevents the development of secondary amyloidosis and renal damage. Adjunctive symptomatic therapy to colchicine includes nonsteroideal antinflammatory drugs and corticosteroids. In a small group of colchicine-intolerant or colchicine resistant FMF patients, alternative treatments must be considered. Evolving experiences have focussed on the potential effectiveness of biologic agents working as TNF-alpha inhibitors (etanercept, infliximab), IL-1 trap (Rilonacept), IL-1 inhibitors (Anakinra, Canakinumab) and IL-6 receptor antibody (Tocilizumab). Interferon-alpha and thalidomide have also been employed in FMF patients. Still, clinical trials are mainly uncontrolled and restricted to few cases, thus requiring definitive conclusions. Old, and new treatments are discussed in the rare FMF disease, with the concept that any ideal treatment has to stand the test of time. PMID- 26572613 TI - Macrocyclic trichothecenes as antifungal and anticancer compounds. AB - Trichothecenes are sesquiterpenoid metabolites produced by fungi and species of the plant genus Baccharis, family Asteraceae. They comprise a tricyclic core with an epoxide at C-12 and C-13 and can be grouped into non-macrocyclic and macrocyclic compounds. While many of these compounds are of concern in agriculture, the macrocyclic metabolites have been evaluated as antiviral, anti cancer, antimalarial and antifungal compounds. Some known cytotoxic responses on eukaryotic cells include inhibition of protein, DNA and RNA syntheses, interference with mitochondrial function, effects on cell division and membranes. These targets however have been elucidated essentially employing non-macrocyclic trichothecenes and only one or two closely related macrocyclic compounds. For several macrocyclic trichothecenes high selectivity against fungal species and against cancer cell lines have been reported suggesting that the macrocycle and its stereochemistry are of crucial importance regarding biological activity and selectivity. This review is focused on compounds belonging to the macrocyclic type, where a cyclic diester or triester ring binds to the trichothecane moiety at C-4 and C- 15 leading to natural products belonging to the groups of satratoxins, verrucarins, roridins, myrotoxins and baccharinoids. Their biological activities, cytotoxic mechanisms and structure-activity relationships (SAR) are discussed. From the reported data it becomes evident that even small changes in the molecules can lead to pronounced effects on biological activity or selectivity against cancer cells lines. Understanding the underlying mechanisms may help to design highly specific drugs for cancer therapy. PMID- 26572614 TI - Phosphodiesterase 4 (PDE4) Inhibitors in the Treatment of COPD: Promising Drug Candidates and Future Directions. AB - The PDE4 enzyme has been proven to be a versatile drug target for therapeutics to treat diverse disease conditions such as asthma, COPD, diabetes, Huntington's disease, and various other inflammatory disorders. The treatment of COPD is the most studied utility for PDE4 inhibitors due to their ability to inhibit inflammatory cell responses. Roflumilast is the only approved drug belonging to this class to treat COPD and has shown significant results in the treatment of asthmatic patients. This perspective highlights the pharmacological details of roflumilast and cilomilast. Moreover, efforts have been made to justify the superiority of roflumilast over cilomilast by detailed comparison of their pharmacological, pharmacokinetic, pharmacodynamic properties and structural features. Several other molecules, with promising PDE4 inhibitory activity have also been highlighted. Commonly associated side effects with this class of compounds, their management, and future direction towards the development of PDE4 inhibitors with improved therapeutic index are the focus of this perspective. More emphasis has been given towards the future development strategies to limit the side effects such as emesis and to achieve better benefit to risk ratio. PMID- 26572615 TI - Nr2f1b control venous specification and angiogenic patterning during zebrafish vascular development. AB - BACKGROUND: The specification of vein and the patterning of intersegmental vessels (ISV) controlled by transcription factor is not fully characterized. The orphan nuclear receptor Chicken ovalbumin upstream promoter transcription factor II (CoupTFII, a.k.a NR2F2) positively regulates vein identity in mice. In this study, we show that nr2f1b is important for vein and tip cell identity during zebrafish development. RESULTS: Nr2f1b mRNA is expressed in ventral lateral mesoderm at 15S stage and in vessels at 24 hpf consistent with a role in early vascular specification. Morpholino knockdown of nr2f1b results in a decrease in both vein cell number and expression of the vein specific marker flt4 and mrc1, suggested its role in venous specification. We also show loss of nr2f1b reduced ISV cell number and impairs ISV growth, which is likely due to the impairment of angiogenic cells migration and/or proliferation by time-lapse imaging. Consequently, nr2f1b morphants showed pericardial edema and circulation defects. Overexpression of nr2f1b under the fli promoter increases the number of venous cells and ISV endothelial cells indicated the function of nr2f1b is required and necessary for vascular development. We further showed that nr2f1b likely interact with Notch signalling. nr2f1b expression is increased in rbpsuh morphants and DAPT-treatment embryos suggested nr2f1b is negatively regulated by Notch activity. CONCLUSIONS: We show nr2f1b control venous specification and angiogenic patterning during zebrafish vascular development, which is mediated by Notch signalings. PMID- 26572616 TI - Nontypeable Haemophilus influenzae exploits the interaction between protein-E and vitronectin for the adherence and invasion to bronchial epithelial cells. AB - BACKGROUND: Nontypeable Haemophilus influenzae (NTHi) is one of the most common Gram-negative pathogens in otitis media and exacerbation of chronic obstructive pulmonary disease. NTHi has been reported to invade bronchial epithelial cells. This penetration enables NTHi to evade the host immune system and antibiotics, and it seems to be related to the intractable features of these diseases. However, the precise mechanism of the invasion has been unknown. We hypothesized that protein-E, an outer membrane protein of NTHi, plays a role in this penetration into bronchial epithelial cells. RESULTS: We utilized two NTHi strains. NTHi efficiently attached to plate-bound vitronectin (254-309/field at 1,000* magnification) and this attachment was blocked by pretreatment with protein-E peptide (PE84-108). The blockade of adhesion was dependent on the concentration of PE84-108. NTHi strains invaded bronchial epithelial cells and the intracellular bacteria were localized in early endosomes. Furthermore, intracellular invasion of NTHi was also blocked by PE84-108, but not by Arg-Gly Asp (RGD) peptide. Pretreatment with PE84-108 significantly prevented cells from being invaded by both NTHi strains, which was confirmed by fluorescent microscope observation. In addition, pretreatment with PE84-108 significantly reduced percentages of CFU after gentamicin treatment of cells per input CFU. CONCLUSIONS: These results suggest that NTHi does not directly bind to the cell surface, but binds to host vitronectin that is bound to the cell surface, via bacterial protein-E. Bacterial protein-E and host vitronectin play a role in the attachment to bronchial epithelial cells and is also involved in the subsequent intracellular invasion of NTHi. A novel vaccine or treatment strategy targeting the protein-E-vitronectin axis may prevent respiratory intracellular infection of NTHi and may lead to better clinical outcomes. PMID- 26572617 TI - Is shared decision-making vanishing at the end-of-life? A descriptive and qualitative study of advanced cancer patients' involvement in specific therapies decision-making. AB - BACKGROUND: Little is known about what is at stake at a subjective level for the oncologists and the advanced cancer patients when they face the question whether to continue, limit or stop specific therapies. We studied (1) the frequency of such questioning, and (2) subjective determinants of the decision-making process from the physicians' and the patients' perspectives. METHODS: (1) All hospitalized patients were screened during 1 week in oncology and/or hematology units of five institutions. We included those with advanced cancer for whom a questioning about the pursuit, the limitation or the withholding of specific therapies (QST) was raised. (2) Qualitative design was based on in-depth interviews. RESULTS: In conventional units, 12.8 % of cancer patients (26 out of 202) were concerned by a QST during the study period. Interviews were conducted with all physicians and 21 advanced cancer patients. The timing of this questioning occurred most frequently as physicians estimated life expectancy between 15 days and 3 months. Faced with the most frequent dilemma (uncertain risk-benefit balance), physicians showed different ways of involving patients. The first two were called the "no choice" models: 1) trying to resolve the dilemma via a technical answer or a "wait-and-see" posture, instead of involving the patients in the questioning and the thinking; and 2), giving a "last minute" choice to the patients, leaving to them the responsibility of the decision. In a third model, they engaged early in shared reflections and dialogue about uncertainties and limits with patients, proxies and care teams. These schematic trends influenced patients' attitudes towards uncertainty and limits, as they were influenced by these ones. Individual and systemic barriers to a shared questioning were pointed out by physicians and patients. CONCLUSIONS: This study indicate to what extent these difficult decisions are related to physicians' and patients' respective and mutually influenced abilities to deal with and share about uncertainties and limits, throughout the disease trajectory. These insights may help physicians, patients and policy makers to enrich their understanding of underestimated and sensitive key issues of the decision-making process. PMID- 26572618 TI - Socioeconomic hierarchy and health gradient in Europe: the role of income inequality and of social origins. AB - BACKGROUND: Health inequalities reflect multidimensional inequality (income, education, and other indicators of socioeconomic position) and vary across countries and welfare regimes. To which extent there is intergenerational transmission of health via parental socioeconomic status has rarely been investigated in comparative perspective. The study sought to explore if different measures of stratification produce the same health gradient and to which extent health gradients of income and of social origins vary with level of living and income inequality. METHODS: A total of 299,770 observations were available from 18 countries assessed in EU-SILC 2005 and 2011 data, which contain information on social origins. Income inequality (Gini) and level of living were calculated from EU-SILC. Logit rank transformation provided normalized inequalities and distributions of income and social origins up to the extremes of the distribution and was used to investigate net comparable health gradients in detail. Multilevel random-slope models were run to post-estimate best linear unbiased predictors (BLUPs) and related standard deviations of residual intercepts (median health) and slopes (income-health gradients) per country and survey year. RESULTS: Health gradients varied across different measures of stratification, with origins and income producing significant slopes after controls. Income inequality was associated with worse average health, but income inequality and steepness of the health gradient were only marginally associated. CONCLUSIONS: Linear health gradients suggest gains in health per rank of income and of origins even at the very extremes of the distribution. Intergenerational transmission of status gains in importance in countries with higher income inequality. Countries differ in the association of income inequality and income-related health gradient, and low income inequality may mask health problems of vulnerable individuals with low status. Not only income inequality, but other country characteristics such as familial orientation play a considerable role in explaining steepness of the health gradient. PMID- 26572619 TI - Transducing oxidative stress to death signals in neurons. AB - Accumulation of reactive oxygen species (ROS) has been associated with aging and neurodegenerative diseases. Nevertheless, how elevated ROS levels cause neurodegeneration is unclear. In this issue, Wakatsuki et al. (2015. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201506102) delineate how oxidative stress is transduced into death signals, leading to neuronal apoptosis and axonal degeneration. PMID- 26572620 TI - The interactome challenge. AB - The properties of living cells are mediated by a huge number of ever-changing interactions of their component macromolecules forming living machines; collectively, these are termed the interactome. Pathogenic alterations in interactomes mechanistically underlie diseases. Therefore, there exists an essential need for much better tools to reveal and dissect interactomes. This need is only now beginning to be met. PMID- 26572621 TI - The seipin complex Fld1/Ldb16 stabilizes ER-lipid droplet contact sites. AB - Lipid droplets (LDs) are storage organelles consisting of a neutral lipid core surrounded by a phospholipid monolayer and a set of LD-specific proteins. Most LD components are synthesized in the endoplasmic reticulum (ER), an organelle that is often physically connected with LDs. How LD identity is established while maintaining biochemical and physical connections with the ER is not known. Here, we show that the yeast seipin Fld1, in complex with the ER membrane protein Ldb16, prevents equilibration of ER and LD surface components by stabilizing the contact sites between the two organelles. In the absence of the Fld1/Ldb16 complex, assembly of LDs results in phospholipid packing defects leading to aberrant distribution of lipid-binding proteins and abnormal LDs. We propose that the Fld1/Ldb16 complex facilitates the establishment of LD identity by acting as a diffusion barrier at the ER-LD contact sites. PMID- 26572622 TI - Oxidative stress-dependent phosphorylation activates ZNRF1 to induce neuronal/axonal degeneration. AB - Oxidative stress is a well-known inducer of neuronal apoptosis and axonal degeneration. We previously showed that the E3 ubiquitin ligase ZNRF1 promotes Wallerian degeneration by degrading AKT to induce GSK3B activation. We now demonstrate that oxidative stress serves as an activator of the ubiquitin ligase activity of ZNRF1 by inducing epidermal growth factor receptor (EGFR)-mediated phosphorylation at the 103rd tyrosine residue and that the up-regulation of ZNRF1 activity by oxidative stress leads to neuronal apoptosis and Wallerian degeneration. We also show that nicotinamide adenine dinucleotide phosphate reduced oxidase activity is required for the EGFR-dependent phosphorylation induced activation of ZNRF1 and resultant AKT degradation via the ubiquitin proteasome system to induce Wallerian degeneration. These results indicate the pathophysiological significance of the EGFR-ZNRF1 pathway induced by oxidative stress in the regulation of neuronal apoptosis and Wallerian degeneration. A deeper understanding of the regulatory mechanism for ZNRF1 catalytic activity via phosphorylation will provide a potential therapeutic avenue for neurodegeneration. PMID- 26572623 TI - Forcible destruction of severely misfolded mammalian glycoproteins by the non glycoprotein ERAD pathway. AB - Glycoproteins and non-glycoproteins possessing unfolded/misfolded parts in their luminal regions are cleared from the endoplasmic reticulum (ER) by ER-associated degradation (ERAD)-L with distinct mechanisms. Two-step mannose trimming from Man9GlcNAc2 is crucial in the ERAD-L of glycoproteins. We recently showed that this process is initiated by EDEM2 and completed by EDEM3/EDEM1. Here, we constructed chicken and human cells simultaneously deficient in EDEM1/2/3 and analyzed the fates of four ERAD-L substrates containing three potential N glycosylation sites. We found that native but unstable or somewhat unfolded glycoproteins, such as ATF6alpha, ATF6alpha(C), CD3-delta-DeltaTM, and EMC1, were stabilized in EDEM1/2/3 triple knockout cells. In marked contrast, degradation of severely misfolded glycoproteins, such as null Hong Kong (NHK) and deletion or insertion mutants of ATF6alpha(C), CD3-delta-DeltaTM, and EMC1, was delayed only at early chase periods, but they were eventually degraded as in wild-type cells. Thus, higher eukaryotes are able to extract severely misfolded glycoproteins from glycoprotein ERAD and target them to the non-glycoprotein ERAD pathway to maintain the homeostasis of the ER. PMID- 26572624 TI - [Complex pain therapy: if the right hand does not know what the left hand does - A case report]. AB - In this case report difficulties in cancer pain therapy are highlighted which can make adequate pain relief difficult. In addition to compliance, the main factor in this case report related to the patient, organizational setting and technological developments in recent years have become increasingly important. The transfer in storing medical records from paper version to a digital file has already started, and due to increasing amounts of data is also without alternative, though there is a lack of compatibility of the available information technology (IT) systems in Austria as well as across the borders in Europe. This often impedes continuous care to cancer patients, because this patient population is often treated by physicians in different settings and various disciplines. In particular, changes in the analgesic regimen to optimize pain relief in an inpatient setting sometimes cause problems when the medicines have to be prescribed subsequently in a private practice.Based on the available literature, the need for electric data collection in the health system and close networking with general practitioners and other physicians working in private practice will be discussed especially with regards to the medication. This is not only sensible and necessary in order to increase transparency and traceability of medical prescriptions, but also to minimize medical errors and avert harm to the patient. PMID- 26572625 TI - Risk factors for congenital diaphragmatic hernia in the Bogota birth defects surveillance and follow-up program, Colombia. AB - PURPOSE: The mortality rate for congenital diaphragmatic hernia (CDH) remains high and prevention efforts are limited by the lack of known risk factors. The aim of this study was to determine prevalence, risk factors, and neonatal results associated with CDH on a surveillance system hospital-based in Bogota, Colombia. METHODS: The data used in this study were obtained from The Bogota Birth Defects Surveillance and Follow-up Program (BBDSFP), between January 2001 and December 2013. With 386,419 births, there were 81 cases of CDH. A case-control methodology was conducted with 48 of the total cases of CDH and 192 controls for association analysis. RESULTS: The prevalence of CDH was 2.1 per 10,000 births. In the case control analysis, risk factors found were maternal age >=35 years (OR, 33.53; 95 % CI, 7.02-160.11), infants with CDH were more likely to be born before 37 weeks of gestation (OR, 5.57; 95 % CI, 2.05-15.14), to weigh less than 2500 g at birth (OR, 9.05; 95 % CI, 3.51-23.32), and be small for gestational age (OR, 5.72; 95 % CI, 2.18-14.99) with a high rate of death before hospital discharge in the CDH population (CDH: 38 % vs BBDSFP: <1 %; p < 0.001). CONCLUSIONS: The prevalence of CDH calculated was similar to the one reported in the literature. CDH is strongly associated with a high rate of death before hospital discharge and the risk factors found were maternal age >=35 years, preterm birth, be small for gestational age, and have low weight at birth. These neonatal characteristics in developing countries would help to identify early CDH. Prevention efforts have been limited by the lack of known risk factors and established epidemiological profiles, especially in developing countries. PMID- 26572627 TI - Letter to the editor. PMID- 26572628 TI - Fluoroscopy-guided intervertebral disc biopsy with a coaxial drill system. AB - OBJECTIVES: Percutaneous biopsy of discitis-osteomyelitis is performed to isolate the causative microorganism and exclude alternative diagnoses. We compared drill assisted and manual fluoroscopy-guided intervertebral disc biopsies with respect to conscious sedation requirements and histologic quality of obtained specimens. MATERIALS AND METHODS: Medical records of all single-level, fluoroscopy-guided intervertebral disc biopsies supervised by one of two musculoskeletal radiologists between January 2010 and March 2015 were reviewed. Duration and cumulative medication doses required for each biopsy were recorded. Pathology reports were reviewed to determine whether the obtained specimens were adequate for histopathologic evaluation. Microbiology reports were reviewed to determine whether the causative organism was isolated from the biopsy specimen. RESULTS: During the study period, 21 drill-assisted and 20 manual biopsies were performed. The median duration of conscious sedation for drill-assisted biopsies was 30 min (range, 17-40 min) compared with 39 min (range, 20-90 min) for manual biopsies (p < 0.01). Drill-assisted biopsies also required lower median cumulative doses of intravenous midazolam [2 mg (range, 0-5 mg) vs. 3 mg (range, 0-9 mg); p = 0.02]. All drill-assisted biopsy specimens were adequate for histopathologic evaluation. One manual biopsy specimen (5 %; 1/20) was inadequate for histopathologic evaluation owing to crush artifact. The microbiology yields of drill-assisted and manual biopsies were comparable [14 % (3/21) vs. 20 % (4/20); p = 0.62]. CONCLUSIONS: Fluoroscopically-guided intervertebral disc biopsies performed with drill assistance require less conscious sedation compared with manual biopsies and yield specimens that are adequate for histopathologic evaluation. PMID- 26572629 TI - How sensitive and specific is 1.5 Tesla MRI for diagnosing injuries in patients with knee dislocation? AB - PURPOSE: The purpose of this study was to assess the sensitivity and specificity of 1.5 T magnetic resonance imaging (MRI) in diagnosing and identifying the specific injury pattern in patients with knee dislocation. The hypothesis was that the sensitivity and specificity are low in patients with posterolateral corner injury and/or PCL tear. METHODS: A retrospective study was performed on 38 patients (m:f = 29:9, mean age +/- SD 34.3 +/- 14.0) with traumatic knee dislocation, who underwent 1.5 T MRI prior to surgery. MRI scans were analysed by a musculoskeletal radiologist, and the presence and type of tears to ligaments, tendons and meniscus or bone were recorded. Comparison was made with the intraoperative findings from the surgical records using the same reporting scheme. The agreement between MRI and surgical findings was assessed using kappa statistics, and the sensitivity and specificity were calculated. RESULTS: In patients with knee dislocation, MRI was found to have low sensitivity (25-38 %) but high specificity (94-97 %) for diagnosing injury to the posterolateral corner. There was high sensitivity in the diagnosis of tears in the cruciate and collateral ligaments (97-100 %); the specificity, however, was lower (50-67 %). The diagnosis of meniscal injury showed low sensitivity (36-56 %) and moderate specificity (69-83 %). CONCLUSIONS: MRI is a sensitive measure of cruciate and collateral ligament injury in acute knee dislocation; however, it does not reliably diagnose injury to the posterolateral corner or meniscus, and therefore, a higher index of suspicion is required during arthroscopy to prevent misdiagnosis which could affect long-term clinical outcome. LEVEL OF EVIDENCE: Diagnostic study, Level II. PMID- 26572630 TI - Prevention and rehabilitation of paediatric anterior cruciate ligament injuries. AB - PURPOSE: To review the current knowledge on anterior cruciate ligament (ACL) injury prevention and ACL rehabilitation in individuals who have not yet reached musculoskeletal maturity. METHODS: This is a narrative review based on a targeted and systematic literature search for paediatric ACL injury risk factors, injury prevention and rehabilitation. RESULTS: The search strategies resulted in 119 hits on risk factor studies, 57 hits on prevention and 37 hits on rehabilitation. Modifiable risk factors for ACL injury are largely unknown in the paediatric population. ACL injury prevention using neuromuscular training is highly successful in the adolescent population, and existing injury prevention programmes are cost-effective. The efficacy of ACL injury prevention programmes in children is, however, investigated to a markedly lesser degree. Paediatric ACL injury rehabilitation is poorly described, although supervised active rehabilitation progressed through phases with functional milestones is generally encouraged. CONCLUSION: Although limited, current evidence supports implementation of injury prevention programmes in female football players from the age of 12. Supervised active rehabilitation where progression is guided by functional milestones is also advocated. Future identification of modifiable risk factors is needed to design prevention programmes for younger children. There is a need for international multicentre studies on treatment algorithms and rehabilitation to increase knowledge on the short- and long-term outcomes following existing algorithms. STUDY DESIGN: Narrative review, level III. PMID- 26572631 TI - Predictive factors for the progression of spontaneous osteonecrosis of the knee. AB - PURPOSE: To assess potentially predictive factors that were evaluated 1 year after the onset of symptoms in patients with spontaneous osteonecrosis of the knee (SONK) and to determine receiver operating characteristic (ROC) curve cut off values. METHODS: Within 1 year of symptom onset, patients with SONK-selected treatment options, mainly based on severity of pain, chose either conservative treatment (n = 27 knees) or operative treatment (n = 27 knees). Knee and whole leg radiographs, knee MRIs and bone mineral density scans of the lumbar spine, femoral neck and femoral condyles were obtained. The parameters measured were: (1) anatomical angle on whole-leg radiograph and (2) lesion size and medial meniscus extrusion on MRI. RESULTS: The anatomical angle and lesion size in the sagittal section (depth) on MRI were markedly larger in the operative treatment group than those in the conservative treatment group. The anatomical angle and depth on MRI of SONK at Stages 1-3 were significantly different between groups, with odds ratios (95 % confidence intervals) of 1.16 (1.18-2.34) and 1.11 (1.01 1.23). One year after symptom onset, ROC curve cut-off value for anatomical angle was 180 degrees and depth on MRI was 20 mm. CONCLUSION: An anatomical angle >180 degrees and depth >20 mm on MRI were predictive factors for a poorer prognosis 1 year after symptom onset in patients with SONK. Our results on radiographs and MRI provided a predictive prognosis for patients with SONK at the initial visit to their orthopaedic surgeons. LEVEL OF EVIDENCE: III. PMID- 26572632 TI - Single-leg drop landing movement strategies in participants with chronic ankle instability compared with lateral ankle sprain 'copers'. AB - PURPOSE: To compare the movement patterns and underlying energetics of individuals with chronic ankle instability (CAI) to ankle sprain 'copers' during a landing task. METHODS: Twenty-eight (age 23.2 +/- 4.9 years; body mass 75.5 +/- 13.9 kg; height 1.7 +/- 0.1 m) participants with CAI and 42 (age 22.7 +/- 1.7 years; body mass 73.4 +/- 11.3 kg; height 1.7 +/- 0.1 m) ankle sprain 'copers' were evaluated 1 year after incurring a first-time lateral ankle sprain injury. Kinematics and kinetics of the hip, knee and ankle joints from 200 ms pre-initial contact (IC) to 200 ms post-IC, in addition to the vertical component of the landing ground reaction force, were acquired during performance of a drop land task. RESULTS: The CAI group adopted a position of increased hip flexion during the landing descent on their involved limb. This coincided with a reduced post-IC flexor pattern at the hip and increased overall hip joint stiffness compared to copers (-0.01 +/- 0.05 vs. 0.02 +/- 0.05 degrees /Nm kg(-1), p = 0.03). CONCLUSIONS: Individuals with CAI display alterations in hip joint kinematics and energetics during a unipodal landing task compared to LAS 'copers'. These alterations may be responsible for the increased risk of injury experienced by individuals with CAI during landing manoeuvres. Thus, clinicians must recognise the potential for joints proximal to the affected ankle to contribute to impaired function following an acute lateral ankle sprain injury and to develop rehabilitation protocols accordingly. LEVEL OF EVIDENCE: Level III. PMID- 26572633 TI - Tourniquet-induced ischaemia during total knee arthroplasty results in higher proteolytic activities within vastus medialis cells: a randomized clinical trial. AB - PURPOSE: Recent data suggest diminished post-operative quadriceps muscle strength after tourniquet application during total knee arthroplasty (TKA). The metabolic effects of the commonly utilized intraoperative tourniquet with consecutive ischaemia on the skeletal muscle cells were unknown. Ubiquitin proteasome system represents one of the main pathways involved in muscle protein breakdown contributing to muscle atrophy. Therefore, the purpose of the present study was to quantify the acute effects of the tourniquet application during TKA on the (1) concentrations of free/conjugated ubiquitin, (2) total ubiquitin-protein ligase activity, (3) proteasome-dependent and (4) proteasome-independent peptidase activities in the cells of vastus medialis. METHODS: The randomized, controlled, monocentric trial included 34 patients scheduled to undergo primary TKA. Each patient was randomly assigned to the tourniquet (n = 17) or non-tourniquet group (n = 17) after receiving a written consent. Muscle biopsies of (5 * 5 * 5 mm) 125 mm3 were obtained from vastus medialis immediately after performing the surgical approach and exactly 60 min later. After preparation of the muscle tissue specimen, the concentrations of the free/conjugated ubiquitin (Ub) were measured by western blot analyses. The ubiquitination was determined as biotinylated Ub incorporated into the sum of the cytosolic proteins and expressed as total ubiquitin-protein ligase activity (tUbPL). The quantification of the proteasome dependent and proteasome-independent peptidase activities was performed with peptidase assays. RESULTS: Tourniquet application did not influence the concentration of the free/conjugated Ub. There were no differences in tUbPL activities between groups and time points. Tourniquet-induced ischaemia resulted in statistically significant higher proteasome-dependent (caspase-like p = 0.0034; chymotryptic-like p = 0.0013; tryptic-like p = 0.0036) and proteasome independent (caspase-like p = 0.03; chymotryptic-like p = 0.0001; tryptic-like p = 0.0062) peptidase activities. CONCLUSION: Tourniquet application did not affect the free/conjugated Ub as well as tUbPL significantly, emphasizing the sophisticated regulation of ubiquitination. The proteasome-dependent peptidase activities were significantly upregulated during tourniquet application, suggesting an increase in protein degradation, which in turn might explain the skeletal muscle atrophy occurring after TKA. These findings add further knowledge and should raise the awareness of surgeons about the effects of tourniquet induced ischaemia at the molecular level. Additional high-quality research may be warranted to examine the short- and long-term clinical significance of the present data. LEVEL OF EVIDENCE: I. PMID- 26572634 TI - Evaluation of the sealing function of the acetabular labrum: an in vitro biomechanical study. AB - PURPOSE: To quantitatively evaluate the biomechanical sealing function of an intact labrum and the effect of labral-chondral separation, cerclage suture labral repair, vertical mattress suture repair and partial labrectomy on distraction load and hip joint centre (HJC) displacement. METHODS: Eight fresh frozen cadaveric hips were tested using a navigation system for intra-operative kinematic analysis. A six-axis load cell was used to measure the manually applied force when performing the tests: hip pivoting movement and distraction. The HJC displacement that occurred during the distraction test has been evaluated in correspondence of seven different values of applied force. During the pivoting motion, the maximum value of HJC displacement was evaluated. Five different conditions were tested: labrum intact, labral-chondral separation, vertical mattress suture repair, cerclage suture repair, and partial labrectomy. RESULTS: With regard to HJC displacement using at fixed value of force, the paired sample t test underscored the statistically significant differences (p < 0.05) for each of the five tested conditions among themselves. Only the comparison of intact versus labral-chondral separation was not significantly different. During pivoting motion, a statistically significantly greater displacement was identified after labrectomy when compared with the cerclage suture repair (p = 0.03) and vertical mattress repair (p < 0.01) in medial-lateral direction. Along proximal-distal direction, a significant lower displacement after labrectomy was identified when compared to the cerclage suture repair (p = 0.03). Performing the pivoting motion at the extreme ranges of motion demonstrated a higher value of displacement after labrectomy when compared with all the previously tested conditions. CONCLUSIONS: These results suggest that labral repair is important in the function of the hip and that the vertical mattress suture technique may be better than the cerclage suture repair. PMID- 26572635 TI - Evaluating general allometric models: interspecific and intraspecific data tell different stories due to interspecific variation in stem tissue density and leaf size. AB - The ability of general scaling models to capture the central tendency or dispersion in biological data has been questioned. In fact, the appropriate domain of such models has never been clearly articulated and they have been supported and challenged using both interspecific and/or intraspecific data. Here, we evaluate several simplifying assumptions and predictions of two prominent scaling models: West, Brown and Enquist's fractal model (WBE) and a null model of geometric similarity (GEOM). Using data for 53 herbaceous angiosperm species from the Songnen Grasslands of Northern China, we compared both the interspecific and intraspecific scaling relationships for plant geometry and biomass partitioning. Specifically, we considered biomass investment in shoots and leaves as well as related several traits not commonly collected in plant allometric analyses: shoot volume, leaf number, and mean leaf mass. At the interspecific level, we find substantial variation in regression slopes, and the simplifying assumptions of WBE and predictions of both the WBE and GEOM models do not hold. In contrast, we find substantial support for the WBE model at the intraspecific level, and to a lesser extent for GEOM. The differences between our results at interspecific and intraspecific levels are due to the fact that leaf size and stem tissue density vary considerably across species in contrast to the simplifying assumptions of WBE. These results highlight the domain within which simplifying model assumptions might be most appropriate, and suggest allometric models may be useful points of departure within some species, growth forms or taxonomic groups. PMID- 26572636 TI - Enrichment scale determines herbivore control of primary producers. AB - Anthropogenic nutrient enrichment stimulates primary production and threatens natural communities worldwide. Herbivores may counteract deleterious effects of enrichment by increasing their consumption of primary producers. However, field tests of herbivore control are often done by adding nutrients at small (e.g., sub meter) scales, while enrichment in real systems often occurs at much larger scales (e.g., kilometers). Therefore, experimental results may be driven by processes that are not relevant at larger scales. Using a mathematical model, we show that herbivores can control primary producer biomass in experiments by concentrating their foraging in small enriched plots; however, at larger, realistic scales, the same mechanism may not lead to herbivore control of primary producers. Instead, other demographic mechanisms are required, but these are not examined in most field studies (and may not operate in many systems). This mismatch between experiments and natural processes suggests that many ecosystems may be less resilient to degradation via enrichment than previously believed. PMID- 26572637 TI - Systemic Proteasome Inhibition Induces Sustained Post-stroke Neurological Recovery and Neuroprotection via Mechanisms Involving Reversal of Peripheral Immunosuppression and Preservation of Blood-Brain-Barrier Integrity. AB - In view of its profound effect on cell survival and function, the modulation of the ubiquitin-proteasome-system has recently been shown to promote neurological recovery and brain remodeling after focal cerebral ischemia. Hitherto, local intracerebral delivery strategies were used, which can hardly be translated to human patients. We herein analyzed effects of systemic intraperitoneal delivery of the proteasome inhibitor BSc2118 on neurological recovery, brain injury, peripheral and cerebral immune responses, neurovascular integrity, as well as cerebral neurogenesis and angiogenesis in a mouse model of transient intraluminal middle cerebral artery occlusion. Systemic delivery of BSc2118 induced acute neuroprotection reflected by reduced infarct volume when delivered up to 9 h post stroke. The latter was associated with reduced brain edema and stabilization of blood-brain-barrier integrity, albeit cerebral proteasome activity was only mildly reduced. Neuronal survival persisted in the post-acute stroke phase up to 28 days post-stroke and was associated with improved neurological recovery when the proteasome inhibitor was continuously delivered over 7 days. Systemic proteasome inhibition prevented stroke-induced acute leukocytosis in peripheral blood and reversed the subsequent immunosuppression, namely, the reduction of blood lymphocyte and granulocyte counts. On the contrary, post-ischemic brain inflammation, cerebral HIF-1alpha abundance, cell proliferation, neurogenesis, and angiogenesis were not influenced by the proteasome inhibitor. The modulation of peripheral immune responses might thus represent an attractive target for the clinical translation of proteasome inhibitors. PMID- 26572638 TI - SCY1-Like 1-Binding Protein 1 (SCYL1BP1) Suppressed Sciatic Nerve Regeneration by Enhancing the RhoA Pathway. AB - SCY1-like 1-binding protein 1 (SCYL1BP1) is first identified as an interacting protein with SCYL1. Since SCYL1BP1 is a soluble protein with coiled-coil domains known to be relevant with transcriptional regulation, it has been found to activate the transcription of murine double minute 2 (MDM2) and participate in neurite outgrowth and regeneration. However, the role and mechanism of SCYL1BP1 in peripheral nerve system lesion and repair are still unknown. Here in vitro, our work demonstrated that SCYL1BP1 inhibited cAMP-induced primary Schwann cell differentiation and suppressed nerve growth factor-mediated neurite outgrowth in PC12 cells by enhancing the RhoA pathway. Furthermore, we found that pretreatment with a Rho kinase inhibitor Y-27632 resulted in partial rescue of Schwann cell differentiation and neurite outgrowth. In vivo experiments showed that SCYL1BP1 could also suppress nerve fiber regeneration. In conclusion, we speculated that SCYL1BP1 participated in Schwann cell (SC) differentiation and neurite outgrowth in the sciatic nerve after crush by regulating the RhoA pathway. PMID- 26572639 TI - Left-Right Axis Differentiation and Functional Lateralization: a Haplotype in the Methyltransferase Encoding Gene SETDB2 Might Mediate Handedness in Healthy Adults. AB - Handedness is a multifactorial trait, and genes contributing to the differentiation of the left-right axis during embryogenesis have been identified as a major gene group associated with this trait. The methyltransferase SETDB2 (SET domain, bifurcated 2) has been shown to regulate structural left-right asymmetry in the vertebrate central nervous system by suppressing fgf8 expression. Here, we investigated the relation of genetic variation in SETDB2-and its paralogue SETDB1-with different handedness phenotypes in 950 healthy adult participants. We identified a haplotype on SETDB2 for which homozygous individuals showed a significantly lower lateralization quotient for handedness than the rest of the cohort after correction for multiple comparisons. Moreover, direction of handedness was significantly associated with genetic variation in this haplotype. This effect was mainly, but not exclusively, driven by the sequence variation rs4942830, as individuals homozygous for the A allele of this single nucleotide polymorphism had a significantly lower lateralization quotient than individuals with at least one T allele. These findings further confirm a role of genetic pathways relevant for structural left-right axis differentiation for functional lateralization. Moreover, as the protein encoded by SETDB2 regulates gene expression epigenetically by histone H3 methylation, our findings highlight the importance of investigating the role of epigenetic modulations of gene expression in relation to handedness. PMID- 26572640 TI - Common Polymorphisms Within QPCT Gene Are Associated with the Susceptibility of Schizophrenia in a Han Chinese Population. AB - A recent genome-wide association study conducted in Caucasians has identified glutaminyl-peptide cyclotransferase (QPCT) gene as a susceptibility gene for schizophrenia, as its common single nucleotide polymorphism (SNP) rs2373000 was significantly associated with the risk of this disease. To date, this finding has not been validated in other populations or ethnic groups. The aim of this study was to investigate the association of common SNPs spanning QPCT gene with the susceptibility of schizophrenia in a Han Chinese population comprising 440 schizophrenia patients and 450 control subjects. A total of 6 tagSNPs including rs2373000 was selected and then genotyped in our sample. Although the relation between rs2373000 and the risk of schizophrenia was not successfully replicated, we showed for the first time that the minor allele (C) of rs3770752 was associated with a reduced risk of schizophrenia (odds ratio (OR) = 0.645; 95 % confidence interval (CI) 0.486-0.855; P corrected = 0.012) in our cohorts. Meanwhile, this allele seemed to modify the schizophrenia risk through a dominant manner (CC + CT vs. TT, OR = 0.625; 95 % CI 0.457-0.854; P corrected = 0.03). In addition, we found that the minor allele (T) of rs3770748 remarkably reduced the schizophrenia risk via a recessive manner (TT vs. TC + CC, OR = 0.618; 95 % CI: 0.449-0.851; P corrected = 0.03). Taken together, these findings demonstrate a significant association between common SNPs within QPCT gene and schizophrenia risk in a Han Chinese population, suggesting QPCT gene may represent a susceptibility gene for this disease. PMID- 26572641 TI - Transgenerational Inheritance of Paternal Neurobehavioral Phenotypes: Stress, Addiction, Ageing and Metabolism. AB - Epigenetic modulation is found to get involved in multiple neurobehavioral processes. It is believed that different types of environmental stimuli could alter the epigenome of the whole brain or related neural circuits, subsequently contributing to the long-lasting neural plasticity of certain behavioral phenotypes. While the maternal influence on the health of offsprings has been long recognized, recent findings highlight an alternative way for neurobehavioral phenotypes to be passed on to the next generation, i.e., through the male germ line. In this review, we focus specifically on the transgenerational modulation induced by environmental stress, drugs of abuse, and other physical or mental changes (e.g., ageing, metabolism, fear) in fathers, and recapitulate the underlying mechanisms potentially mediating the alterations in epigenome or gene expression of offsprings. Together, these findings suggest that the inheritance of phenotypic traits through male germ-line epigenome may represent the unique manner of adaptation during evolution. Hence, more attention should be paid to the paternal health, given its equivalently important role in affecting neurobehaviors of descendants. PMID- 26572642 TI - Mechanisms of Platelet-Derived Growth Factor-BB in Restoring HIV Tat-Cocaine Mediated Impairment of Neuronal Differentiation. AB - Diminished adult neurogenesis is known to play a key role in the pathogenesis of diverse neurodegenerative disorders such as HIV-associated neurological disorders (HAND). Cocaine, often abused by HIV-infected patients, has been suggested to worsen HIV-associated CNS disease. Mounting evidence also indicates that HIV infection can lead not only to neuronal dysfunction or loss, but can also negatively impact neurogenesis, resulting in generation of fewer adult neural progenitor cells (NPCs) in the dentate gyrus of the hippocampus, brain area critical for memory and learning. The crucial role of platelet-derived growth factor-BB (PDGF-BB) in providing tropic support for the neurons as well as in promoting NPC proliferation has been demonstrated by us previously. However, whether PDGF-BB regulates neuronal differentiation especially in the context of HAND and drug abuse remains poorly understood. In this study, we demonstrate that pretreatment of rat hippocampal NPCs with PDGF-BB restored neuronal differentiation that had been impaired by HIV Tat and cocaine. To further study the intracellular mechanism(s) involved in this process, we examined the role of transient receptor potential canonical (TRPC) channels in mediating neuronal differentiation in the presence of PDGF-BB. TRPC channels are Ca2+-permeable, nonselective cationic channels that elicit a variety of physiological functions. Parallel but distinct ERK, Akt signaling pathways with downstream activation of CREB were found to be critical for neuronal differentiation. Pharmacological blocking of TRPC channels resulted in suppression of PDGF-mediated differentiation and PDGF-BB-induced activation of ERK and Akt, culminating also to inhibition of PDGF-induced activation of CREB. Taken together, these findings underpin the role of TRPC channel as a novel target regulating cell differentiation mediated by PDGF-BB. This finding could have implications for development of therapeutic interventions aimed at restoration of Tat and cocaine mediated impairment of neurogenesis in drug abusing HAND patients. PMID- 26572643 TI - Multivariate Analysis of Effects of Asthmatic Patient Respiratory Profiles on the In Vitro Performance of a Reservoir Multidose and a Capsule-Based Dry Powder Inhaler. AB - PURPOSE: The aim of this work was to evaluate the effect of two different dry powder inhalers, of the NGI induction port and Alberta throat and of the actual inspiratory profiles of asthmatic patients on in-vitro drug inhalation performances. METHODS: The two devices considered were a reservoir multidose and a capsule-based inhaler. The formulation used to test the inhalers was a combination of formoterol fumarate and beclomethasone dipropionate. A breath simulator was used to mimic inhalatory patterns previously determined in vivo. A multivariate approach was adopted to estimate the significance of the effect of the investigated variables in the explored domain. RESULTS: Breath simulator was a useful tool to mimic in vitro the in vivo inspiratory profiles of asthmatic patients. The type of throat coupled with the impactor did not affect the aerodynamic distribution of the investigated formulation. However, the type of inhaler and inspiratory profiles affected the respirable dose of drugs. CONCLUSIONS: The multivariate statistical approach demonstrated that the multidose inhaler, released efficiently a high fine particle mass independently from the inspiratory profiles adopted. Differently, the single dose capsule inhaler, showed a significant decrease of fine particle mass of both drugs when the device was activated using the minimum inspiratory volume (592 mL). PMID- 26572644 TI - Pharmacologic Studies of a Prodrug of Mitomycin C in Pegylated Liposomes (Promitil((r))): High Stability in Plasma and Rapid Thiolytic Prodrug Activation in Tissues. AB - PURPOSE: Pegylated liposomal (PL) mitomycin C lipid-based prodrug (MLP) has recently entered clinical testing. We studied here the preclinical pharmacology of PL-MLP. METHODS: The stability, pharmacokinetics, biodistribution, and other pharmacologic parameters of PL-MLP were examined. Thiolytic cleavage of MLP and release of active mitomycin C (MMC) were studied using dithiothreitol (DTT), and by incubation with tissue homogenates. RESULTS: MLP was incorporated in the bilayer at 10% molar ratio with nearly 100% entrapment efficiency, resulting in a formulation with high plasma stability. In vitro, DTT induced cleavage of MLP with predictable kinetics, generating MMC and enhancing pharmacological activity. A long circulation half-life of MLP (10-15 h) was observed in rodents and minipigs. Free MMC is either extremely low or undetectable in plasma. However, urine from PL-MLP injected rats revealed delayed but significant excretion of MMC indicating in vivo activation of MLP. Studies in mice injected with H3 cholesterol radiolabeled PL-MLP demonstrated relatively greater tissue levels of H3-cholesterol than MLP. MLP levels were highest in tumor and spleen, and very low or undetectable in liver and lung. Rapid cleavage of MLP in various tissues, particularly in liver, was shown in ex-vivo experiments of PL-MLP with tissue homogenates. PL-MLP was less toxic in vivo than equivalent doses of MMC. Therapeutic studies in C26 mouse tumor models demonstrated dose-dependent improved efficacy of PL-MLP over MMC. CONCLUSIONS: Thiolytic activation of PL-MLP occurs in tissues but not in plasma. Liposomal delivery of MLP confers a favorable pharmacological profile and greater therapeutic index than MMC. PMID- 26572646 TI - Improving erythropoiesis: a compelling case for iron chelation in myelofibrosis. PMID- 26572645 TI - Cytomegalovirus latency and reactivation: recent insights into an age old problem. AB - Human cytomegalovirus (HCMV) infection remains a major cause of morbidity in patient populations. In certain clinical settings, it is the reactivation of the pre-existing latent infection in the host that poses the health risk. The prevailing view of HCMV latency was that the virus was essentially quiescent in myeloid progenitor cells and that terminal differentiation resulted in the initiation of the lytic lifecycle and reactivation of infectious virus. However, our understanding of HCMV latency and reactivation at the molecular level has been greatly enhanced through recent advancements in systems biology approaches to perform global analyses of both experimental and natural latency. These approaches, in concert with more classical reductionist experimentation, are furnishing researchers with new concepts in cytomegalovirus latency and suggest that latent infection is far more active than first thought. In this review, we will focus on new studies that suggest that distinct sites of cellular latency could exist in the human host, which, when coupled with recent observations that report different transcriptional programmes within cells of the myeloid lineage, argues for multiple latent phenotypes that could impact differently on the biology of this virus in vivo. Finally, we will also consider how the biology of the host cell where the latent infection persists further contributes to the concept of a spectrum of latent phenotypes in multiple cell types that can be exploited by the virus. PMID- 26572647 TI - mTOR is essential for corticosteroid effects on hippocampal AMPA receptor function and fear memory. AB - Glucocorticoid hormones, via activation of their receptors, promote memory consolidation, but the exact underlying mechanisms remain elusive. We examined how corticosterone regulates AMPA receptors (AMPARs), which are crucial for synaptic plasticity and memory formation. Combining a live imaging fluorescent recovery after photobleaching approach with the use of the pH-sensitive GFP-AMPAR tagging revealed that corticosterone enhances the AMPAR mobile fraction and increases synaptic trapping of AMPARs in hippocampal cells. In parallel, corticosterone-enhanced AMPAR-mediated synaptic transmission. Blocking the mammalian target of rapamycin (mTOR) pathway prevented the effects of corticosterone on both AMPAR trapping-but not on the mobile fraction-and synaptic transmission. Blocking the mTOR pathway also prevented the memory enhancing effects of corticosterone in a contextual fear-conditioning paradigm. We conclude that activation of the mTOR pathway is essential for the effects of corticosterone on synaptic trapping of AMPARs and, possibly as a consequence, fearful memory formation. PMID- 26572648 TI - The cannabinoid system in the retrosplenial cortex modulates fear memory consolidation, reconsolidation, and extinction. AB - Despite the fact that the cannabinoid receptor type 1 (CB1R) plays a pivotal role in emotional memory processing in different regions of the brain, its function in the retrosplenial cortex (RSC) remains unknown. Here, using contextual fear conditioning in rats, we showed that a post-training intra-RSC infusion of the CB1R antagonist AM251 impaired, and the agonist CP55940 improved, long-term memory consolidation. Additionally, a post-reactivation infusion of AM251 enhanced memory reconsolidation, while CP55940 had the opposite effect. Finally, AM251 blocked extinction, whereas CP55940 facilitated it and maintained memory extinguished over time. Altogether, our data strongly suggest that the cannabinoid system of the RSC modulates emotional memory. PMID- 26572649 TI - Compound stimulus extinction reduces spontaneous recovery in humans. AB - Fear-related behaviors are prone to relapse following extinction. We tested in humans a compound extinction design ("deepened extinction") shown in animal studies to reduce post-extinction fear recovery. Adult subjects underwent fear conditioning to a visual and an auditory conditioned stimulus (CSA and CSB, respectively) separately paired with an electric shock. The target CS (CSA) was extinguished alone followed by compound presentations of the extinguished CSA and nonextinguished CSB. Recovery of conditioned skin conductance responses to CSA was reduced 24 h after compound extinction, as compared with a group who received an equal number of extinction trials to the CSA alone. PMID- 26572650 TI - Repeated stimulation of cultured networks of rat cortical neurons induces parallel memory traces. AB - During systems consolidation, memories are spontaneously replayed favoring information transfer from hippocampus to neocortex. However, at present no empirically supported mechanism to accomplish a transfer of memory from hippocampal to extra-hippocampal sites has been offered. We used cultured neuronal networks on multielectrode arrays and small-scale computational models to study the effect of memory replay on the formation of memory traces. We show that input-deprived networks develop an activity<=>connectivity balance where dominant activity patterns support current connectivity. Electrical stimulation at one electrode disturbs this balance and induces connectivity changes. Intrinsic forces in recurrent networks lead to a new equilibrium with activity patterns that include the stimulus response. The new connectivity is no longer disrupted by this stimulus, indicating that networks memorize it. A different stimulus again induces connectivity changes upon first application but not subsequently, demonstrating the formation of a second memory trace. Returning to the first stimulus does not affect connectivity, indicating parallel storage of both traces. A computer model robustly reproduced experimental results, suggesting that spike-timing-dependent plasticity and short time depression suffice to store parallel memory traces, even in networks without particular circuitry constraints. PMID- 26572651 TI - Appetitive but not aversive olfactory conditioning modifies antennal movements in honeybees. AB - In honeybees, two olfactory conditioning protocols allow the study of appetitive and aversive Pavlovian associations. Appetitive conditioning of the proboscis extension response (PER) involves associating an odor, the conditioned stimulus (CS) with a sucrose solution, the unconditioned stimulus (US). Conversely, aversive conditioning of the sting extension response (SER) involves associating the odor CS with an electric or thermal shock US. Each protocol is based on the measure of a different behavioral response (proboscis versus sting) and both only provide binary responses (extension or not of the proboscis or sting). These limitations render the measure of the acquired valence of an odor CS difficult without testing the animals in a freely moving situation. Here, we studied the effects of both olfactory conditioning protocols on the movements of the antennae, which are crucial sensory organs for bees. As bees' antennae are highly mobile, we asked whether their movements in response to an odorant change following appetitive or aversive conditioning and if so, do odor-evoked antennal movements contain information about the acquired valence of the CS? We implemented a tracking system for harnessed bees' antennal movements based on a motion capture principle at a high frequency rate. We observed that differential appetitive conditioning had a strong effect on antennal movements. Bees responded to the reinforced odorant with a marked forward motion of the antennae and a strong velocity increase. Conversely, differential aversive conditioning had no associative effect on antennal movements. Rather than revealing the acquired valence of an odorant, antennal movements may represent a novel conditioned response taking place during appetitive conditioning and may provide a possible advantage to bees when foraging in natural situations. PMID- 26572652 TI - Identification of genes related to learning and memory in the brain transcriptome of the mollusc, Hermissenda crassicornis. AB - The sea slug Hermissenda crassicornis (Mollusca, Gastropoda, Nudibranchia) has been studied extensively in associative learning paradigms. However, lack of genetic information previously hindered molecular-level investigations. Here, the Hermissenda brain transcriptome was sequenced and assembled de novo, producing 165,743 total transcripts. Orthologs of 95 genes implicated in learning were identified. These included genes for a serotonin receptor and a GABA-B receptor subunit that had not been previously described in molluscs, as well as an adenylyl cyclase gene not previously described in gastropods. This study illustrates the Hermissenda transcriptome's potential as an important genetic tool in future learning and memory research. PMID- 26572653 TI - 16p11.2 Deletion mice display cognitive deficits in touchscreen learning and novelty recognition tasks. AB - Chromosomal 16p11.2 deletion syndrome frequently presents with intellectual disabilities, speech delays, and autism. Here we investigated the Dolmetsch line of 16p11.2 heterozygous (+/-) mice on a range of cognitive tasks with different neuroanatomical substrates. Robust novel object recognition deficits were replicated in two cohorts of 16p11.2+/- mice, confirming previous findings. A similarly robust deficit in object location memory was discovered in +/-, indicating impaired spatial novelty recognition. Generalizability of novelty recognition deficits in +/- mice extended to preference for social novelty. Robust learning deficits and cognitive inflexibility were detected using Bussey Saksida touchscreen operant chambers. During acquisition of pairwise visual discrimination, +/- mice required significantly more training trials to reach criterion than wild-type littermates (+/+), and made more errors and correction errors than +/+. In the reversal phase, all +/+ reached criterion, whereas most +/- failed to reach criterion by the 30-d cutoff. Contextual and cued fear conditioning were normal in +/-. These cognitive phenotypes may be relevant to some aspects of cognitive impairments in humans with 16p11.2 deletion, and support the use of 16p11.2+/- mice as a model system for discovering treatments for cognitive impairments in 16p11.2 deletion syndrome. PMID- 26572654 TI - Synergistic effect of ascorbic acid and collagen addition on the increase in type 2 collagen accumulation in cartilage-like MSC sheet. AB - Aiming to increase the content of type 2 collagen in scaffold-free cartilage-like cell sheets prepared using human bone marrow mesenchymal stem cells, the effect of several kinds of additives in a chondrogenic medium was investigated. Addition of ascorbic acid 2 phosphate (VCP) at a high concentration (250 ug/ml) and type 1 atelocollagen (5 ug/ml) increased the accumulation of type 2 collagen by fourfold and twofold, respectively. On the other hand, an antioxidant, glutathione showed no such effect. The synergistic effect of VCP and type 1 atelocollagen resulted in an eightfold increase in the accumulation level of type 2 collagen. Furthermore, the gene expression level of type 2 collagen increased and that of matrix metalloproteinase-13 (MMP-13) decreased to approximately one-third of the control. The increase in type 2 collagen accumulation in the scaffold-free cartilage-like cell sheet might be due to not only the enhancement of the synthesis but also the suppression of the degradation of type 2 collagen by MMP 13. PMID- 26572655 TI - Brief Report: Fast Mapping Predicts Differences in Concurrent and Later Language Abilities Among Children with ASD. AB - This study investigated whether the ability to learn word-object associations following minimal exposure (i.e., fast mapping) was associated with concurrent and later language abilities in children with ASD. Children who were poor learners at age 31/2 had significantly lower receptive language abilities than children who successfully learned the new words, both concurrently (n = 59) and 2 years later (n = 53), lending ecological validity to experimental fast-mapping tasks. Fast mapping comprehension at age 31/2 was associated with better language outcomes regardless of whether children had produced the new words. These findings highlight the importance of investigating processes of language learning in children with ASD. Understanding these processes will enable the development of maximally effective strategies for supporting word learning. PMID- 26572657 TI - Understanding Hong Kong Chinese Families' Experiences of an Autism/ASD Diagnosis. AB - Little is known about the experience of Chinese parents of children diagnosed with autism spectrum disorders (ASD) living in the Hong Kong Special Administrative Region. Seventy-five parents of children (aged 6 months-18 years) with ASD diagnoses completed the Family Quality of Life Scale. Forty-five parents from the original surveyed cohort, also participated in semi-structured interviews. Parents' perceptions of their child's disability were influenced both by their cultural background and by the limited and expensive, pre- and post diagnostic services available. Longer waiting times to diagnosis were associated with lower emotional well-being and perceived disability-related support. Clinicians are encouraged to become part of the support network for parents of children with ASD, to help parents to adjust to caring for their child. PMID- 26572656 TI - Body Constraints on Motor Simulation in Autism Spectrum Disorders. AB - Developmental data suggested that mental simulation skills become progressively dissociated from overt motor activity across development. Thus, efficient simulation is rather independent from current sensorimotor information. Here, we tested the impact of bodily (sensorimotor) information on simulation skills of adolescents with Autism Spectrum Disorders (ASD). Typically-developing (TD) and ASD participants judged laterality of hand images while keeping one arm flexed on chest or while holding both arms extended. Both groups were able to mentally simulate actions, but this ability was constrained by body posture more in ASD than in TD adolescents. The strong impact of actual body information on motor simulation implies that simulative skills are not fully effective in ASD individuals. PMID- 26572658 TI - Initiation and Generalization of Self-Instructional Skills in Adolescents with Autism and Intellectual Disability. AB - Self-instruction using videos or other supports on a mobile device is a pivotal skill and can increase independence for individuals with disabilities by decreasing a need for adult supports. This study evaluated the effects of progressive time delay (PTD) to teach four adolescents with autism and intellectual disability how to initiate self-instruction in the presence of a task direction for an untrained task. Participants were screened for imitating video models prior to the study and were taught to navigate to videos on an iPhone((r)) in history training. A multiple probe design across settings embedded in a multiple probe design across participants was used to evaluate the effects of PTD on initiation of self-instruction. All participants learned to self instruct. Two participants generalized self-instruction to two novel settings. Two participants required instruction in two settings before generalizing to the third. Three participants generalized self-instruction in the presence of a task direction from the researcher to a task direction from their classroom teacher in all three settings. One participant generalized to a task direction presented by the classroom teacher in one setting, but not in the other two. All participants maintained self-instruction behaviors assessed 1 week after all participants met criteria in all settings. Self-instruction using videos or other supports on a mobile device is a pivotal skill and can increase independence for individuals with disabilities by decreasing a need for adult supports. PMID- 26572659 TI - Real-World Executive Functions in Adults with Autism Spectrum Disorder: Profiles of Impairment and Associations with Adaptive Functioning and Co-morbid Anxiety and Depression. AB - Although executive functioning (EF) difficulties are well documented among children and adolescents with autism spectrum disorder (ASD), little is known about real-world measures of EF among adults with ASD. Therefore, this study examined parent-reported real-world EF problems among 35 adults with ASD without intellectual disability and their correlations with adaptive functioning and co morbid anxiety and depression symptomatology. A variable EF profile was found with prominent deficits occurring in flexibility and metacognition. Flexibility problems were associated with anxiety-related symptoms while metacognition difficulties were associated with depression symptoms and impaired adaptive functioning (though the metacognition-adaptive functioning relationship was moderated by ADHD symptoms). These persistent EF problems are predictors of broader functioning and therefore remain an important treatment target among adults with ASD. PMID- 26572660 TI - Trajectories, Long-Term Outcomes and Family Experiences of 76 Adults with Autism Spectrum Disorder. AB - The aim of this retrospective study was to retrace the trajectories and long-term outcomes of individuals with autism in France, and to explore the family experiences. Data obtained from parents enables us to follow the trajectories of 76 adults. Two-thirds of adults with severe autism had a very poor outcome. Those with moderate autism had a better outcome. In adulthood, the majority were in residential accommodation. None were living independently. The trajectories of people with Asperger syndrome or high-functioning autism were more positive since all of them attended school for a long time and some went to university. All of them had a good outcome but they remained dependent on aging parents who had few available supports. PMID- 26572661 TI - Methods for Individualized Determination of Methylmercury Elimination Rate and De Methylation Status in Humans Following Fish Consumption. AB - Methylmercury (MeHg) exposure via fish in the diet remains a priority public health concern. Individual variation in response to a given MeHg exposure and the biotransformation of MeHg that follows complicate our understanding of this issue. MeHg elimination from the human body occurs slowly (elimination rate (kel) approximately 0.01 day(-1) or approximately 70 days half-life [t1/2]) and is a major determinant of the Hg body burden resulting from fish consumption. The underlying mechanisms that control MeHg elimination from the human body remain poorly understood. We describe here improved methods to obtain a MeHg elimination rate via longitudinal Hg analysis in hair using laser ablation-inductively coupled plasma-mass spectrometry. We measured MeHg elimination rates in eight individuals following the consumption of 3 fish meals in two 75-day trials separated by a 4-month washout period. In addition, since MeHg biotransformation to inorganic Hg (I-Hg) is associated with Hg excretion, we speciated Hg in feces samples to estimate individual MeHg de-methylation status. We observed a wide range of MeHg elimination rates between individuals and within individuals over time (kel = 0.0163-0.0054 day(-1); estimated t1/2 = 42.5-128.3 days). The ratio of MeHg and I-Hg in feces also varied widely among individuals. While the %I-Hg in feces was likely influenced by dental amalgams, findings with subjects who lacked amalgams suggest that faster MeHg elimination is associated with a higher %I-Hg in feces indicating more complete de-methylation. We anticipate these methods will contribute to future investigations of genetic and dietary factors that influence MeHg disposition in people. PMID- 26572663 TI - In Vitro Developmental Neurotoxicity Following Chronic Exposure to 50 Hz Extremely Low-Frequency Electromagnetic Fields in Primary Rat Cortical Cultures. AB - Exposure to 50-60 Hz extremely low-frequency electromagnetic fields (ELF-EMFs) has increased considerably over the last decades. Several epidemiological studies suggested that ELF-EMF exposure is associated with adverse health effects, including neurotoxicity. However, these studies are debated as results are often contradictory and the possible underlying mechanisms are unknown. Since the developing nervous system is particularly vulnerable to insults, we investigate effects of chronic, developmental ELF-EMF exposure in vitro. Primary rat cortical neurons received 7 days developmental exposure to 50 Hz block-pulsed ELF-EMF (0 1000 MUT) to assess effects on cell viability (Alamar Blue/CFDA assay), calcium homeostasis (single cell fluorescence microscopy), neurite outgrowth (beta(III) Tubulin immunofluorescent staining), and spontaneous neuronal activity (multi electrode arrays). Our data demonstrate that cell viability is not affected by developmental ELF-EMF (0-1000 MUT) exposure. Depolarization- and glutamate-evoked increases in intracellular calcium concentration ([Ca(2+)]i) are slightly increased at 1 MUT, whereas both basal and stimulation-evoked [Ca(2+)]i show a modest inhibition at 1000 MUT. Subsequent morphological analysis indicated that neurite length is unaffected up to 100 MUT, but increased at 1000 MUT. However, neuronal activity appeared largely unaltered following chronic ELF-EMF exposure up to 1000 MUT. The effects of ELF-EMF exposure were small and largely restricted to the highest field strength (1000 MUT), ie, 10 000 times above background exposure and well above current residential exposure limits. Our combined data therefore indicate that chronic ELF-EMF exposure has only limited (developmental) neurotoxic potential in vitro. PMID- 26572662 TI - Ah Receptor Activation by Dioxin Disrupts Activin, BMP, and WNT Signals During the Early Differentiation of Mouse Embryonic Stem Cells and Inhibits Cardiomyocyte Functions. AB - The AHR is a ligand-activated transcription factor that mediates gene-environment interactions. Genome-wide expression profiling during differentiation of mouse ES cells into cardiomyocytes showed that AHR activation by 2,3,7,8 tetrachlorodibenzo-p-dioxin; Dioxin (TCDD), its prototypical ligand, disrupted the expression of multiple homeobox transcription factors and inhibited cardiomyocyte contractility. Here we treated ES cells with TCDD at daily differentiation intervals to investigate whether TCDD-induced loss of contractility had a developmental window of sensitivity. Surprisingly, contractility was an AHR-dependent TCDD target solely between differentiation days 0 and 3 during the period of panmesoderm development, when TCDD also disrupted expression of genes in the TGFbeta/BMP2/4 and wingless-type MMTV integration site (WNT)signaling pathways, suppressed the secretion of bone morphogenetic protein (BMP4), WNT3a, and WNT5a and elevated the secretion of Activin A, as determined by ELISA of the secreted proteins in the culture medium. Supplementing the culture medium with BMP4, WNT3a, or WNT5a during the first 3 days of differentiation successfully countered TCDD-induced impairment of contractility, while anti-WNT3a, or anti-WNT5a antibodies or continuous Noggin (a BMP4 antagonist) or Activin A treatment inhibited the contractile phenotype. In Ahr(+/+), but not in Ahr(-) (/) (-) ES cells, TCDD treatment significantly increased mitochondrial copy number, suggestive of mitochondrial stress and remodeling. Sustained AHR activation during ES cell differentiation appears to disrupt the expression of signals critical to the ontogeny of cardiac mesoderm and cause the loss of contractility in the resulting cardiomyocyte lineage. PMID- 26572664 TI - Role of IgA receptors in the pathogenesis of IgA nephropathy. AB - Immunoglobulin A nephropathy (IgAN) or Berger's disease is the most common form of primary glomerulonephritis in the world and one of the first causes of end stage renal failure. IgAN is characterized by the accumulation of immune complexes containing polymeric IgA1 in mesangial areas. The pathogenesis of this disease involves the deposition of polymeric and hypogalactosylated IgA1 (Gd IgA1) in the mesangium. Quantitative and structural changes of Gd-IgA1 play a key role in the development of the disease due to functional abnormalities of two IgA receptors: the FcalphaRI (CD89) expressed by blood myeloid cells and the transferrin receptor (CD71) on mesangial cells. Abnormal Gd-IgA1 induces release of soluble CD89, which participates in the formation of circulating IgA1 complexes. These complexes are trapped by CD71 that is overexpressed on mesangial cells in IgAN patients together with the crosslinking enzyme transglutaminase 2 allowing pathogenic IgA complex formation in situ and mesangial cell activation. A humanized mouse model expressing IgA1 and CD89 develops IgAN in a similar manner as patients. In this model, a food antigen, the gliadin, was shown to be crucial for circulating IgA1 complex formation and deposition, which could be prevented by a gluten-free diet. Identification of these new partners opens new therapeutic prospects for IgAN treatment. PMID- 26572665 TI - Association of reduced kidney function with cardiovascular disease and mortality in elderly patients: comparison between the new Berlin initiative study (BIS1) and the MDRD study equations. AB - BACKGROUND: New creatinine based equations for estimating glomerular proposed for aged subjects have not been assessed in their association of reduced eGFR with cardiovascular (CV) morbidity or all cause (AC) mortality. PATIENTS: All subjects >=70 years old (2998) who had been admitted to the hospital during a 12 month period were examined. METHODS: In a cohort study we applied the new Berlin Initiative Study (BIS1) equation. We compared the association of reduced eGFR estimated by BIS1 and MDRD equations, with cardiovascular (CV) disease and all cause (AC) mortality. RESULTS: eGFR was 57 +/- 17 mL/min/1.73 m2 by MDRD and 71 +/- 28 mL/min/1.73 m2 by BIS1 (P < 0.001). A diagnosis of CV disease was present in 947 patients. CV disease was associated with eGFR < 60 mL/min/1.73 m2 by both formulas: OR 1.179 (CI 1.001-1.390) for BIS1 and OR 1.440 (CI 1.223-1.696) for MDRD. In survival analysis a significant association of eGFR < 60 mL/min/1.73 m2 with AC mortality was found for both equations: MDRD (HR = 1.270, CI 1.111-1.453, P < 0.001), BIS1 (HR = 1.174, CI 1.031-1.338, P = 0.016). The analysis repeated with groups of age showed that the association of mortality with eGFRBIS1 < 60 mL/min/1.73 m2 was lost over 80 years. CONCLUSIONS: In patients >70, admitted to hospital, the implementation of the new BIS1 estimating equation does not modify the relationship, observed with the MDRD formula, of reduced GFR with CV disease or AC mortality. PMID- 26572666 TI - Neuronal Glutathione Content and Antioxidant Capacity can be Normalized In Situ by N-acetyl Cysteine Concentrations Attained in Human Cerebrospinal Fluid. AB - N-acetyl cysteine (NAC) supports the synthesis of glutathione (GSH), an essential substrate for fast, enzymatically catalyzed oxidant scavenging and protein repair processes. NAC is entering clinical trials for adrenoleukodystrophy, Parkinson's disease, schizophrenia, and other disorders in which oxidative stress may contribute to disease progression. However, these trials are hampered by uncertainty about the dose of NAC required to achieve biological effects in human brain. Here we describe an approach to this issue in which mice are used to establish the levels of NAC in cerebrospinal fluid (CSF) required to affect brain neurons. NAC dosing in humans can then be calibrated to achieve these NAC levels in human CSF. The mice were treated with NAC over a range of doses, followed by assessments of neuronal GSH levels and neuronal antioxidant capacity in ex vivo brain slices. Neuronal GSH levels and antioxidant capacity were augmented at NAC doses that produced peak CSF NAC concentrations of >=50 nM. Oral NAC administration to humans produced CSF concentrations of up to 10 MUM, thus demonstrating that oral NAC administration can surpass the levels required for biological activity in brain. Variations of this approach may similarly facilitate and rationalize drug dosing for other agents targeting central nervous system disorders. PMID- 26572667 TI - Dermoscopy for Identification of Basal Cell Carcinomas in Basal Cell Nevus Syndrome During Carbon Dioxide Laser Surgery. AB - Basal cell nevus syndrome (BCNS) is a rare autosomal dominant condition best known for the development of early and multiple basal cell carcinomas (BCCs). Because the condition requires lifetime surveillance for new cancers, an efficient method of identification and treatment is desirable, especially in children. Dermoscopy and carbon dioxide laser have previously been shown to be effective in the identification and treatment, respectively, of BCCs in BCNS. We present here a case illustrating that the use of these modalities in a single session provides patients with safe and effective treatment that is efficient, cosmetically acceptable, and minimally disruptive to their lives. PMID- 26572668 TI - Machine Learning in Medicine. AB - Spurred by advances in processing power, memory, storage, and an unprecedented wealth of data, computers are being asked to tackle increasingly complex learning tasks, often with astonishing success. Computers have now mastered a popular variant of poker, learned the laws of physics from experimental data, and become experts in video games - tasks that would have been deemed impossible not too long ago. In parallel, the number of companies centered on applying complex data analysis to varying industries has exploded, and it is thus unsurprising that some analytic companies are turning attention to problems in health care. The purpose of this review is to explore what problems in medicine might benefit from such learning approaches and use examples from the literature to introduce basic concepts in machine learning. It is important to note that seemingly large enough medical data sets and adequate learning algorithms have been available for many decades, and yet, although there are thousands of papers applying machine learning algorithms to medical data, very few have contributed meaningfully to clinical care. This lack of impact stands in stark contrast to the enormous relevance of machine learning to many other industries. Thus, part of my effort will be to identify what obstacles there may be to changing the practice of medicine through statistical learning approaches, and discuss how these might be overcome. PMID- 26572669 TI - Contrast-Induced Nephropathy. PMID- 26572670 TI - Utility of 18F-Fluorodeoxyglucose Positron Emission Tomography Computed Tomography in the Diagnosis and Management of Aortitis. PMID- 26572671 TI - Isolated Pulmonary Vasculitis. PMID- 26572672 TI - Letter by Coffey et al Regarding Article, "Temporal Trends in the Incidence and Prognosis of Aortic Stenosis: A Nationwide Study of the Swedish Population". PMID- 26572673 TI - Response to Letter Regarding Article "Temporal Trends in the Incidence and Prognosis of Aortic Stenosis: A Nationwide Study of the Swedish Population". PMID- 26572674 TI - Letter by de Araujo Goncalves et al Regarding Article, "Invasive Evaluation of Patients With Angina in the Absence of Obstructive Coronary Artery Disease". PMID- 26572675 TI - Letter by Sheikh et al Regarding Article, "Invasive Evaluation Of Patients With Angina in the Absence of Obstructive Coronary Artery Disease". PMID- 26572676 TI - Letter by Savas and Kalay Regarding Article, "Invasive Evaluation of Patients With Angina in the Absence of Obstructive Coronary Artery Disease". PMID- 26572677 TI - Response to Letters Regarding Article, "Invasive Evaluation of Patients With Angina in the Absence of Obstructive Coronary Artery Disease". PMID- 26572678 TI - Low-Level Cadmium Exposure Is Associated With Decreased Bone Mineral Density and Increased Risk of Incident Fractures in Elderly Men: The MrOS Sweden Study. AB - One risk factor for osteoporosis that has attracted increasing attention in recent years is exposure to cadmium. The aim of this study was to examine the associations between low-level cadmium exposure, from diet and smoking, and bone mineral density (BMD) and incident fractures in elderly men. The study population consisted of 936 men from the Swedish cohort of the Osteoporotic Fractures in Men (MrOS) study, aged 70 to 81 years at inclusion (years 2002 to 2004), with reliable data on cadmium in urine (U-Cd) analyzed using inductively coupled plasma mass spectrometry in baseline samples. The participants also answered a questionnaire on lifestyle factors and medical history. BMD was measured at baseline using dual-energy X-ray absorptiometry (DXA) in the total body, hip, and lumbar spine. During the follow-up period (until 2013), all new fractures were registered by date and type. Associations between BMD and U-Cd were assessed using multiple linear regression, and associations between incident fractures and baseline U-Cd were analyzed using Cox regression. In both cases, a number of potential confounders and other risk factors (eg, age, smoking, body mass index [BMI], and physical activity) were included in the models. We found significant negative associations between U-Cd and BMD, with lower BMD (4% to 8%) for all sites in the fourth quartile of U-Cd, using the first quartile as the reference. In addition, we found positive associations between U-Cd and incident fractures, especially nonvertebral osteoporosis fractures in the fourth quartile of U-Cd, with hazard ratios of 1.8 to 3.3 in the various models. U-Cd as a continuous variable was significantly associated with nonvertebral osteoporosis fractures (adjusted hazard ratio 1.3 to 1.4 per MUg Cd/g creatinine), also in never smokers, but not with the other fracture groups (all fractures, hip fractures, vertebral fractures, and other fractures). Our results indicate that even relatively low cadmium exposure through diet and smoking increases the risk of low BMD and osteoporosis-related fractures in elderly men. PMID- 26572680 TI - [Splitting into two lines: The historical development of the analytical and the gas ultracentrifuge]. AB - In a historical perspective the ultracentrifuge is often taken as perfect example of a research technology according to Shinn and Joerges (Shinn and Joerges 2000, 2002). Research technologies are defined by a generic device, its own metrology and the interstitiality of the historical actors connected with the device. In our paper we give a detailed analysis of the development of the ultracentrifuge and thereby reveal two different lines of development: analytical ultracentrifuges and gas ultra centrifuges used for isotope separation. Surprisingly, we could not find any interstitial and transversal connections for these two lines. The lines end up with two different devices based on two different technical concepts. Moreover, the great majority of the actors stick to one line. These results are in accordance withother authors, who developed the concept of research technologies further and tried to sharpen their definition. PMID- 26572681 TI - Transmembrane transporter expression regulated by the glucosylceramide pathway in Cryptococcus neoformans. AB - BACKGROUND: The sphingolipid glucosylceramide (GlcCer) and factors involved in the fungal GlcCer pathways were shown earlier to be an integral part of fungal virulence, especially in fungal replication at 37 degrees C, in neutral/alkaline pH and 5 % CO2 environments (e.g. alveolar spaces). Two mutants, ?gcs 1 lacking glucosylceramide synthase 1 gene (GCS1) which catalyzes the formation of sphingolipid GlcCer from the C9-methyl ceramide and ?smt1 lacking sphingolipid C9 methyltransferase gene (SMT1), which adds a methyl group to position nine of the sphingosine backbone of ceramide, of this pathway were attenuated in virulence and have a growth defect at the above-mentioned conditions. These mutants with either no or structurally modified GlcCer located on the cell-membrane have reduced membrane rigidity, which may have altered not only the physical location of membrane proteins but also their expression, as the pathogen's mode of adaptation to changing need. Importantly, pathogens are known to adapt themselves to the changing host environments by altering their patterns of gene expression. RESULTS: By transcriptional analysis of gene expression, we identified six genes whose expression was changed from their wild-type counterpart grown in the same conditions, i.e. they became either down regulated or up regulated in these two mutants. The microarray data was validated by real-time PCR, which confirmed their fold change in gene expression. All the six genes we identified, viz siderochrome-iron transporter (CNAG_02083), monosaccharide transporter (CNAG_05340), glucose transporter (CNAG_03772), membrane protein (CNAG_03912), membrane transport protein (CNAG_00539), and sugar transporter (CNAG_06963), are membrane-localized and have significantly altered gene expression levels. Therefore, we hypothesize that these genes function either independently or in tandem with a structurally modified cell wall/plasma membrane resulting from the modifications of the GlcCer pathway and thus possibly disrupt transmembrane signaling complex, which in turn contributes to cryptococcal osmotic, pH, ion homeostasis and its pathobiology. CONCLUSION: Six genes identified from gene expression microarrays by gene set enrichment analysis and validated by RT-PCR, are membrane located and associated with the growth defect at neutral-alkaline pH due to the absence and or presence of a structurally modified GlcCer. They may be involved in the transmembrane signaling network in Cryptococcus neoformans, and therefore the pathobiology of the fungus in these conditions. PMID- 26572683 TI - Real-time mid-infrared imaging of living microorganisms. AB - The speed and efficiency of quantum cascade laser-based mid-infrared microspectroscopy are demonstrated using two different model organisms as examples. For the slowly moving Amoeba proteus, a quantum cascade laser is tuned over the wavelength range of 7.6 um to 8.6 um (wavenumbers 1320 cm(-1) and 1160 cm(-1) , respectively). The recording of a hyperspectral image takes 11.3 s whereby an average signal-to-noise ratio of 29 is achieved. The limits of time resolution are tested by imaging the fast moving Caenorhabditis elegans at a discrete wavenumber of 1265 cm(-1) . Mid-infrared imaging is performed with the 640 * 480 pixel video graphics array (VGA) standard and at a full-frame time resolution of 0.02 s (i.e. well above the most common frame rate standards). An average signal-to-noise ratio of 16 is obtained. To the best of our knowledge, these findings constitute the first mid-infrared imaging of living organisms at VGA standard and video frame rate. PMID- 26572682 TI - Combined metabolome and transcriptome profiling provides new insights into diterpene biosynthesis in S. pomifera glandular trichomes. AB - BACKGROUND: Salvia diterpenes have been found to have health promoting properties. Among them, carnosic acid and carnosol, tanshinones and sclareol are well known for their cardiovascular, antitumor, antiinflammatory and antioxidant activities. However, many of these compounds are not available at a constant supply and developing biotechnological methods for their production could provide a sustainable alternative. The transcriptome of S.pomifera glandular trichomes was analysed aiming to identify genes that could be used in the engineering of synthetic microbial systems. RESULTS: In the present study, a thorough metabolite analysis of S. pomifera leaves led to the isolation and structure elucidation of carnosic acid-family metabolites including one new natural product. These labdane diterpenes seem to be synthesized through miltiradiene and ferruginol. Transcriptomic analysis of the glandular trichomes from the S. pomifera leaves revealed two genes likely involved in miltiradiene synthesis. Their products were identified and the corresponding enzymes were characterized as copalyl diphosphate synthase (SpCDS) and miltiradiene synthase (SpMilS). In addition, several CYP-encoding transcripts were identified providing a valuable resource for the identification of the biosynthetic mechanism responsible for the production of carnosic acid-family metabolites in S. pomifera. CONCLUSIONS: Our work has uncovered the key enzymes involved in miltiradiene biosynthesis in S. pomifera leaf glandular trichomes. The transcriptomic dataset obtained provides a valuable tool for the identification of the CYPs involved in the synthesis of carnosic acid-family metabolites. PMID- 26572684 TI - Transcriptome profiling reveals distinctive traits of retinol metabolism and neonatal parallels in the MRL/MpJ mouse. AB - BACKGROUND: The MRL/MpJ mouse is a laboratory inbred strain known for regenerative abilities which are manifested by scarless closure of ear pinna punch holes. Enhanced healing responses have been reported in other organs. A remarkable feature of the strain is that the adult MRL/MpJ mouse retains several embryonic biochemical characteristics, including increased expression of stem cell markers. RESULTS: We explored the transcriptome of the MRL/MpJ mouse in the heart, liver, spleen, bone marrow and ears. We used two reference strains, thus increasing the chances to discover the genes responsible for the exceptional properties of the regenerative strain. We revealed several distinctive characteristics of gene expression patterns in the MRL/MpJ mouse, including the repression of immune response genes, the up-regulation of those associated with retinol metabolism and PPAR signalling, as well as differences in expression of the genes engaged in wounding response. Another crucial finding is that the gene expression patterns in the adult MRL/MpJ mouse and murine neonates share a number of parallels, which are also related to immune and wounding response, PPAR pathway, and retinol metabolism. CONCLUSIONS: Our results indicate the significance of retinol signalling and neonatal transcriptomic relics as the distinguishing features of the MRL/MpJ mouse. The possibility that retinoids could act as key regulatory molecules in this regeneration model brings important implications for regenerative medicine. PMID- 26572685 TI - Stroke and recurrent haemorrhage associated with antithrombotic treatment after gastrointestinal bleeding in patients with atrial fibrillation: nationwide cohort study. AB - STUDY QUESTION: What are the risks of all cause mortality, thromboembolism, major bleeding, and recurrent gastrointestinal bleeding associated with restarting antithrombotic treatment after gastrointestinal bleeding in patients with atrial fibrillation? METHODS: This Danish cohort study (1996-2012) included all patients with atrial fibrillation discharged from hospital after gastrointestinal bleeding while receiving antithrombotic treatment. Restarted treatment regimens were single or combined antithrombotic drugs with oral anticoagulation and antiplatelets. Follow-up started 90 days after discharge to avoid confounding from use of previously prescribed drugs on discharge. Risks of all cause mortality, thromboembolism, major bleeding, and recurrent gastrointestinal bleeding were estimated with competing risks models and time dependent multiple Cox regression models. STUDY ANSWER AND LIMITATIONS: 4602 patients (mean age 78 years) were included. Within two years, 39.9% (95% confidence interval 38.4% to 41.3%, n=1745) of the patients had died, 12.0% (11.0% to 13.0%, n=526) had experienced thromboembolism, 17.7% (16.5% to 18.8%, n=788) major bleeding, and 12.1% (11.1% to 13.1%, n=546) recurrent gastrointestinal bleeding. 27.1% (n=924) of patients did not resume antithrombotic treatment. Compared with non-resumption of treatment, a reduced risk of all cause mortality was found in association with restart of oral anticoagulation (hazard ratio 0.39, 95% confidence interval 0.34 to 0.46), an antiplatelet agent (0.76, 0.68 to 0.86), and oral anticoagulation plus an antiplatelet agent (0.41, 0.32 to 0.52), and a reduced risk of thromboembolism was found in association with restart of oral anticoagulation (0.41, 0.31 to 0.54), an antiplatelet agent (0.76, 0.61 to 0.95), and oral anticoagulation plus an antiplatelet agent (0.54, 0.36 to 0.82). Restarting oral anticoagulation alone was the only regimen with an increased risk of major bleeding (1.37, 1.06 to 1.77) compared with non-resumption of treatment; however, the difference in risk of recurrent gastrointestinal bleeding was not significant between patients who restarted an antithrombotic treatment regimen and those who did not resume treatment. WHAT THIS STUDY ADDS: Among patients with atrial fibrillation who experience gastrointestinal bleeding while receiving antithrombotic treatment; subsequent restart of oral anticoagulation alone was associated with better outcomes for all cause mortality and thromboembolism compared with patients who did not resume treatment. This was despite an increased longitudinal associated risk of bleeding. FUNDING, COMPETING INTERESTS, DATA SHARING: This study was supported by a grant from Boehringer-Ingelheim. Competing interests are available in the full paper on bmj.com. The authors have no additional data to share. PMID- 26572686 TI - Open-label study of faldaprevir plus peginterferon and ribavirin in hepatitis C virus genotype 1-infected patients who failed placebo plus peginterferon and ribavirin. AB - Faldaprevir, a hepatitis C virus (HCV) NS3/4A protease inhibitor, was evaluated in HCV genotype 1-infected patients who failed peginterferon and ribavirin (PegIFN/RBV) treatment during one of three prior faldaprevir trials. Patients who received placebo plus PegIFN/RBV and had virological failure during a prior trial were enrolled and treated in two cohorts: prior relapsers (n = 43) and prior nonresponders (null responders, partial responders and patients with breakthrough; n = 75). Both cohorts received faldaprevir 240 mg once daily plus PegIFN/RBV for 24 weeks. Prior relapsers with early treatment success (ETS; HCV RNA <25 IU/mL detectable or undetectable at week 4 and <25 IU/mL undetectable at week 8) stopped treatment at week 24. Others received PegIFN/RBV through week 48. The primary efficacy endpoint was sustained virological response (HCV RNA <25 IU/mL undetectable) 12 weeks post treatment (SVR12). More prior nonresponders than prior relapsers had baseline HCV RNA >= 800,000 IU/mL (80% vs 58%) and a non CC IL28B genotype (91% vs 70%). Rates of SVR12 (95% CI) were 95.3% (89.1, 100.0) among prior relapsers and 54.7% (43.4, 65.9) among prior nonresponders; corresponding ETS rates were 97.7% and 65.3%. Adverse events led to faldaprevir discontinuations in 3% of patients. The most common Division of AIDS Grade >= 2 adverse events were anaemia (13%), nausea (10%) and hyperbilirubinaemia (9%). In conclusion, faldaprevir plus PegIFN/RBV achieved clinically meaningful SVR12 rates in patients who failed PegIFN/RBV in a prior trial, with response rates higher among prior relapsers than among prior nonresponders. The adverse event profile was consistent with the known safety profile of faldaprevir. PMID- 26572687 TI - Variability of Voriconazole Trough Levels in Haematological Patients: Influence of Comedications with cytochrome P450(CYP) Inhibitors and/or with CYP Inhibitors plus CYP Inducers. AB - Voriconazole plasma exposure greatly varies among haematological patients. The purpose of this study was to identify the magnitude of influence of comedications with CYP inhibitors and/or with CYP inhibitors plus CYP inducers on voriconazole trough level (Cmin ). Voriconazole Cmin was retrospectively assessed among haematological patients who underwent therapeutic drug monitoring (TDM). Univariate and multivariate linear mixed-effect regression analyses were performed to identify the independent predictors of normalized Cmin . Of the 83 included patients, 35 had comedications with CYP inhibitors (omeprazole or pantoprazole) and 21 with CYP inhibitors (omeprazole or pantoprazole) plus CYP inducers (methylprednisolone, dexamethasone, phenobarbital, rifampin or carbamazepine). Median Cmin value (n = 199) was 2.4 mg/L with a wide range of distribution (<0.2-13.5 mg/L). Median (IQR) normalized voriconazole Cmin value was significantly higher in the presence of CYP inhibitors (4.20 mg/L, 3.23-5.51 mg/L) than either in the absence of interacting cotreatments (2.55 mg/L, 1.54 3.47 mg/L) or in the presence of CYP inhibitors plus CYP inducers (2.16 mg/L, 1.19-3.09 mg/L). The presence of CYP inhibitors was highly significantly associated with Cmin >5.5 mg/L (OR: 23.22, 95% CI: 3.01-179.09, p = 0.003). No significant association emerged when CYP inhibitors were coadministered with CYP inducers (OR: 3.53, 95% CI: 0.36-34.95, p = 0.280). The amount of expected Cmin increase was significantly influenced by both the type and the dose of the administered proton pump inhibitor. The study highlights that the benefit from TDM of voriconazole may be maximal in those patients who are cotreated with CYP inhibitors and/or with CYP inhibitors plus CYP inducers, especially when receiving proton pump inhibitors (PPIs) at very high dosages intravenously. PMID- 26572688 TI - Synthesis of Alkynylated Benzo[a]naphtho[2,3-i]phenazine Derivatives. AB - Thermal condensation of 2,3-diamino-1,4-(bistriisopropylsilylethynyl)benzene, naphthalene,-anthracene, and -benzothiadiazole substrates with 1,2 naphthalenedione forms bent benzophenazine-type heteroarenes in a one-step reaction in good to excellent yields. The targets are investigated by UV/Vis spectroscopy, cyclic voltammetry, and single-crystal X-ray crystallography. The packing of the targets in the solid state follows either a herringbone or a brick wall motif. In the case of 8,13 bis(triisopropylsilylethynyl)dibenzo[a,i]phenazine, polymorphs with either packing result. PMID- 26572689 TI - The Electrochemical Characterization of Single Core-Shell Nanoparticles. AB - We report the direct solution-phase characterization of individual gold-core silver-shell nanoparticles through an electrochemical means, with selectivity achieved between the core and shell components based on their different redox activities. The electrochemically determined core-shell sizes are in excellent agreement with electron microscopy-based results, successfully demonstrating the electrochemical characterization of individual core-shell nanoparticles. PMID- 26572690 TI - Arabidopsis thaliana root cell wall proteomics: Increasing the proteome coverage using a combinatorial peptide ligand library and description of unexpected Hyp in peroxidase amino acid sequences. AB - Plant cell walls (CWs) contain a large proportion of polysaccharides (90-95% of CW mass) and proteins (5-10%) that play major roles in CW plasticity during development and in response to environmental cues. Here, we present CW proteomics data of Arabidopsis thaliana roots. Plants were cultivated in hydroponic conditions. CW protein (CWP) extracts were prepared and analyzed in two different ways in order to enlarge the coverage of the root CW proteome: proteins were analyzed either directly or following an affinity chromatography on a combinatorial peptide ligand library (CPLL) to reduce the concentration dynamic range. Proteins were identified by LC-MS/MS and bioinformatics. Altogether, 424 proteins having predicted signal peptides have been identified (CWPs). CPLL permitted to identify low-abundant CWPs never described before, thus enlarging the coverage of the root CW proteome. The number of oxidoreductases is particularly high and includes a large collection of class III peroxidases (CIII Prxs; 38 out of the 73 A. thaliana CIII Prxs). For the first time, hydroxyproline residues were localized at conserved positions in CIII Prx amino acid sequences. PMID- 26572692 TI - Effect of steam explosion-assisted extraction on phenolic acid profiles and antioxidant properties of wheat bran. AB - BACKGROUND: The majority of phenolic acids in wheat bran are bound to the cell walls. Hence, a high proportion of phenolic acids cannot be extracted with conventional extraction methods. This study aimed to investigate the efficiency of steam explosion pre-treatment in increasing the extractability of phenolic compounds from wheat bran. RESULTS: Bound phenolic acids (BPA) can be released by steam explosion-assisted extraction. Within the experimental range, soluble free phenolic acids (FPA) and soluble conjugated phenolic acids (CPA) increased gradually with residence time and temperature. After steam explosion at 215 degrees C for 120 s, the total FPA and CPA reached 6671.8 and 2578.6 ug GAE g(-1) bran, respectively, which was about 39-fold and seven-fold higher than that of the untreated sample. Ferulic acid, the major individual phenolic acids in bran, increased from 55.7 to 586.3 ug g(-1) for FPA, and from 44.9 to 1108.4 ug g(-1) for CPA. The antioxidant properties of FPA and CPA extracts were significantly improved after treated. Correlation analysis indicated that the antioxidant capacity was in close relationship with phenolic content in FPA and CPA. CONCLUSION: Steam explosion pre-treatment could be effectively used to release of BPA and enhance the antioxidant capacity of wheat bran. (c) 2015 Society of Chemical Industry. PMID- 26572691 TI - U-Insertion/Deletion mRNA-Editing Holoenzyme: Definition in Sight. AB - RNA editing is a process that alters DNA-encoded sequences and is distinct from splicing, 5' capping, and 3' additions. In 30 years since editing was discovered in mitochondria of trypanosomes, several functionally and evolutionarily unrelated mechanisms have been described in eukaryotes, archaea, and viruses. Editing events are predominantly post-transcriptional and include nucleoside insertions and deletions, and base substitutions and modifications. Here, we review the mechanism of uridine insertion/deletion mRNA editing in kinetoplastid protists typified by Trypanosoma brucei. This type of editing corrects frameshifts, introduces translation punctuation signals, and often adds hundreds of uridines to create protein-coding sequences. We focus on protein complexes responsible for editing reactions and their interactions with other elements of the mitochondrial gene expression pathway. PMID- 26572693 TI - Nurses' perceptions of the challenges related to the Omanization policy. AB - BACKGROUND: Human resource development has become a major concern in Oman since the inception of the 'Omanization' policy in 1988. The main goal of this policy was to replace the expatriate nursing workforce with similarly qualified local nurses to develop a sustainable workforce and achieve self-reliance. AIM: The aim of this study is to explore the nurses' perceptions of Omanization policy. METHODS: A qualitative research design was used and 16 Omani registered nurses and 26 student nurses were interviewed in depth. Transcribed data were analysed using content analysis. RESULTS: Two main themes emerged from the data: 'Challenges of sustaining the local nursing workforce' and 'Challenges of educational preparation for local nurses'. The participants agreed that Omanization benefited national development, social stability and ensuring local workforce. The challenges faced were cultural and work life balance, preparation of nurses and pace of replacement. CONCLUSION: The participants were concerned that the pace of replacement could leave behind a marked experience gap. A slow phased approach to Omanization of the nursing workforce was recommended by the participants. LIMITATIONS: Results obtained from this study reflect the perceptions and voices of student nurses and registered nurses only from the Institute of Nursing and Oman Ministry of Health. IMPLICATIONS FOR NURSING EDUCATION AND POLICY: A policy of this magnitude requires gradual establishment. The upgrading of the nursing education to degree level, continuous professional development, mentoring and role modeling of expert nurses should be established to prepare local nurses for the localization of the nursing workforce. PMID- 26572694 TI - Interferon-inducible GTPases in cell autonomous and innate immunity. AB - Detection and clearance of invading pathogens requires a coordinated response of the adaptive and innate immune system. Host cell, however, also features different mechanisms that restrict pathogen replication in a cell-intrinsic manner, collectively referred to as cell-autonomous immunity. In immune cells, the ability to unleash those mechanisms strongly depends on the activation state of the cell, which is controlled by cytokines or the detection of pathogen associated molecular patterns by pattern-recognition receptors. The interferon (IFN) class of cytokines is one of the strongest inducers of antimicrobial effector mechanisms and acts against viral, bacterial and parasitic intracellular pathogens. This has been linked to the upregulation of several hundreds of IFN stimulated genes, among them the so-called IFN-inducible GTPases. Two subfamilies of IFN-inducible GTPases, the immunity-related GTPases (IRGs) and the guanylate binding proteins (GBPs), have gained attention due to their exceptional ability to specifically target intracellular vacuolar pathogens and restrict their replication by destroying their vacuolar compartment. Their repertoire has recently been expanded to the regulation of inflammasome complexes, which are cytosolic multi-protein complexes that control an inflammatory cell death called pyroptosis and the release of cytokines like interleukin-1beta and interleukin 18. Here we discuss recent advances in understanding the function, the targeting and regulation of IRG and GBP proteins during microbial infections. PMID- 26572696 TI - High-performance computational analysis and peptide screening from databases of cyclotides from poaceae. AB - Cyclotides are a family of head-to-tail cyclized peptides containing three conserved disulfide bonds, in a structural scaffold also known as a cyclic cysteine knot. Due to the high degree of cysteine conservation, novel members from this peptide family can be identified in protein databases through a search through regular expression (REGEX). In this work, six novel cyclotide-like precursors from the Poaceae were identified from NCBI's non-redundant protein database by the use of REGEX. Two out of six sequences (named Zea mays L and M) showed an Asp residue in the C-terminal, which indicated that they could be cyclic. Gene expression in maize tissues was investigated, showing that the previously described cyclotide-like Z. mays J is expressed in the roots. According to molecular dynamics, the structure of Z. mays J seems to be stable, despite the putative absence of cyclization. As regards cyclotide evolution, it was hypothesized that this is an outcome from convergent evolution and/or horizontal gene transfer. The results showed that peptide screening from databases should be performed periodically in order to include novel sequences, which are deposited as the databases grow. Indeed, the advances in computational and experimental methods will together help to answer key questions and reach new horizons in defense-related peptide identification. PMID- 26572695 TI - Subcutaneous infusion of kisspeptin-54 stimulates gonadotrophin release in women and the response correlates with basal oestradiol levels. AB - BACKGROUND AND OBJECTIVE: Kisspeptin stimulates hypothalamic GnRH secretion resulting in gonadotrophin release and has potential as a future therapeutic. Chronic subcutaneous infusion of kisspeptin via a pump (similar to an insulin pump) may provide an alternative route of administration in the future. We investigated for the first time in humans, the gonadotrophin response to subcutaneous (SC) infusions of kisspeptin-54 in healthy women. Women are markedly more responsive to exogenous kisspeptin in the late follicular phase preovulation when oestradiol levels are naturally high. Therefore, we further investigated whether there was a correlation between baseline oestradiol levels and LH response to kisspeptin. DESIGN AND PATIENTS: A prospective, single-blinded placebo-controlled study. Healthy women (n = 4) received an 8-h SC infusion of kisspeptin-54 0.1, 0.3 or 1.0 nmol/kg/h or saline in the early follicular phase of 4 separate menstrual cycles. Gonadotrophins and oestradiol were measured every 10 min during the infusions. RESULTS: SC infusion of kisspeptin-54 increased LH and FSH. The LH response to SC infusion of kisspeptin-54 (0.3 and 1.0 nmol/kg/h) positively correlated with baseline oestradiol levels (P < 0.001). Further statistical analyses showed that in the 1.0 nmol/kg/h group, a 100pmol/l rise in baseline oestradiol was associated with a 1.0 IU/l increase in LH. CONCLUSIONS: Kisspeptin administered via a SC infusion could be a viable future therapeutic route of administration for patients with infertility. Baseline oestradiol levels may be an important determinant of the gonadotrophin response to kisspeptin treatment in women and should be taken into consideration when evaluating gonadotrophin response. PMID- 26572697 TI - Radiofrequency ablation as an alternative to hepatic resection for single small hepatocellular carcinomas. AB - BACKGROUND: This study aimed to investigate whether radiofrequency ablation (RFA) is an alternative to surgical resection for hepatocellular carcinoma (HCC) within the context of current guidelines. METHODS: This retrospective study included patients with normal portal pressure and serum bilirubin level who initially underwent liver resection or RFA for a single HCC of maximum size 3 cm. Between group differences in cumulative rates of survival and recurrence specific for HCC were analysed in the entire cohort and in a propensity score-matched cohort. RESULTS: A total of 604 patients were enrolled, 273 in the liver resection group and 331 in the RFA group. The 5- and 10-year HCC-specific survival rates for the resection and RFA groups were 87.6 versus 82.1 per cent and 59.0 versus 61.2 per cent respectively (P = 0.214), whereas overall 5- and 10-year recurrence-free survival rates for the corresponding groups were 60.6 versus 39.4 per cent and 37.5 versus 25.1 per cent respectively (P < 0.001). In the propensity score matched cohort (152 pairs), there were no differences in HCC-specific survival (hazard ratio (HR) 1.03 for RFA versus resection; P = 0.899), whereas recurrence free survival again differed between the treatment groups (HR 1.75; P < 0.001). RFA was independently associated with poorer outcomes in terms of treatment-site recurrence-free survival (adjusted HR 1.66; P = 0.026), but not non-treatment site recurrence-free survival (adjusted HR 1.15; P = 0.354). CONCLUSION: Although RFA carries a higher risk of treatment-site recurrence than hepatic resection, it provides comparable overall survival in patients with a single small HCC without portal hypertension or a raised bilirubin level. PMID- 26572698 TI - Impact of overnight traffic noise on sleep quality, sleepiness, and vigilant attention in long-haul truck drivers: Results of a pilot study. AB - This study aimed to evaluate the impact of traffic noise along the motorway on sleep quality, sleepiness, and vigilant attention in long-haul truck drivers. This was a randomized, crossover, within-subject controlled study. Healthy long haul truck drivers spent 6 consecutive nights in a real truck berth with full sleep laboratory equipment. During 3 nights, subjects were exposed to replayed traffic noise alongside motorways, whereas the other 3 nights were without traffic noise. Polysomnography was recorded during the nights and numerous sleepiness tests and vigilance examinations were performed during the following standardized working day. Outcome measures were compared between noisy and silent nights using the paired Wilcoxon test. Ten healthy long-haul truck drivers with a mean age of 36.3 +/- 7.3 years completed the study as planned. On noisy nights, subjects had greater latencies to the rapid eye movement (REM) phase (90 +/- 32 min vs 69 +/- 16 min, P = 0.074) and higher percentages of sleep stage 1 (13.7 +/ 5.5% vs 11.2 +/- 4.4%; P = 0.059). Subjects also rated their sleep quality as having been better during nights without noise (28.1 +/- 3.7 vs 30.3 +/- 6.2, P = 0.092). The impact of these differences on daytime sleepiness and vigilance was rather low; however, mean Karolinska Sleepiness Scale (KSS) scores measured during the course of the following day were higher on six out of eight occasions after noisy nights. The effects of overnight traffic noise on sleep quality are detectable but unlikely to have any major impact on the vigilant attention and driving performance of long haul-truck drivers with low nocturnal noise sensitivity. This might not be true for subgroups prone to sleeping disorders. PMID- 26572699 TI - Attitudes toward noise, perceived hearing symptoms, and reported use of hearing protection among college students: Influence of youth culture. AB - The purpose of this study was to assess the attitude toward noise, perceived hearing symptoms, noisy activities that were participated in, and factors associated with hearing protection use among college students. A 44-item online survey was completed by 2,151 college students (aged 17 years and above) to assess the attitudes toward noise, perceived hearing symptoms related to noise exposure, and use of hearing protection around noisy activities. Among the participants, 39.6% experienced at least one hearing symptom, with ear pain as the most frequently reported (22.5%). About 80% of the participants were involved in at least one noise activity, out of which 41% reported the use of hearing protection. A large majority of those with ear pain, hearing loss, permanent tinnitus, and noise sensitivity was involved in attending a sporting event, which was the most reported noisy activity. The highest reported hearing protection use was in the use of firearms, and the lowest in discos/ dances. The reported use of hearing protection is associated with having at least one hearing symptom but the relationship is stronger with tinnitus, hearing loss, and ear pain (chi2 = 30.5 43.5, P< 0.01) as compared to noise sensitivity (chi2 = 3.8, P= 0.03); it is also associated with anti-noise attitudes, particularly in youth social events. Universities and colleges have important roles in protecting young adults' hearing by integrating hearing conservation topic in the college curriculum, promoting hearing health by student health services, involving student groups in noise-induced hearing loss (NIHL) awareness and prevention, and establishing noise level limitations for all on-campus events. PMID- 26572700 TI - Association between polymorphism of interleukin-6 in the region -174G/C and tinnitus in the elderly with a history of occupational noise exposure. AB - Tinnitus is a symptom usually related to cochlear change that may arise from noise exposure and induces expression of proinflammatory cytokines including interleukin-6 (IL6). This study aimed to evaluate the association between the polymorphism of the IL6 gene in the region 174G/C and tinnitus in elderly with history of occupational noise exposure. SETTINGS AND DESIGN: This was a cross sectional study with a sample of 179 independent elderly individuals aged >60 years. Information on exposure to occupational noise was obtained by interviews. Audiological evaluation was performed using pure tone audiometry and genotyped through polymerase chain reaction by restriction fragment length polymorphism (PCR-RFLP). Data were analyzed using the chi-square test and the odds ratio (OR), with the significance level set at 5%. Among the study subjects, 24.6% were homozygous for the G allele, 39.7% were homozygous for the C allele, and 35.8% were heterozygous for IL6 (P > 0.05). Of these, 33.5% reported noise exposure history, with 42.5% having tinnitus. We found significant association between the genotype and allele frequencies of the IL6 -174 gene (rs1800795) and tinnitus among the elderly with history of exposure to occupational noise (P = 0.03). The elderly with the C allele were less likely to have tinnitus associated with history of exposure to occupational noise [OR = 0.167, confidence interval (CI) 95% 0.167-0.749; P = 0.004] when compared to those carrying the G allele. This study suggests that there is an association between polymorphisms in the IL6 gene at region - 174G/C and susceptibility to tinnitus. PMID- 26572701 TI - Hearing loss and tinnitus in rock musicians: A Norwegian survey. AB - Our focus in this study was to assess hearing thresholds and the prevalence and characteristics of tinnitus in a large group of rock musicians based in Norway. A further objective was to assess related factors such as exposure, instrument category, and the preventive effect of hearing protection. The study was a cross sectional survey of rock musicians selected at random from a defined cohort of musicians. A random control group was included for comparison. We recruited 111 active musicians from the Oslo region, and a control group of 40 nonmusicians from the student population at the University of TromsO. The subjects were investigated using clinical examination, pure tone audiometry, tympanometry, and a questionnaire. We observed a hearing loss in 37.8% of the rock musicians. Significantly poorer hearing thresholds were seen at most pure-tone frequencies in musicians than controls, with the most pronounced threshold shift at 6 kHz. The use of hearing protection, in particular custom-fitted earplugs, has a preventive effect but a minority of rock musicians apply them consistently. The degree of musical performance exposure was inversely related to the degree of hearing loss in our sample. Bass and guitar players had higher hearing thresholds than vocalists. We observed a 20% prevalence of chronic tinnitus but none of the affected musicians had severe tinnitus symptomatology. There was no statistical association between permanent tinnitus and hearing loss in our sample. We observed an increased prevalence of hearing loss and tinnitus in our sample of Norwegian rock musicians but the causal relationship between musical exposure and hearing loss or tinnitus is ambiguous. We recommend the use of hearing protection in rock musicians. PMID- 26572702 TI - Effects of noise and mental task performance upon changes in cerebral blood flow parameters. AB - The objectives of this paper were to determine whether traffic noise influences the parameters of cerebral blood flow (CBF) measured by functional transcranial Doppler sonography (fTCD) during the performance of mental tasks, and to see whether impact of noise on CBF changes with age. The study comprised 36 healthy volunteers, 22 women and 14 men, aged 25-49 years. The fTCD was performed using a fixed 2-MHz probe, aiming for an evaluation of mean velocity (MFV) and the pulsatility index (PI) in the middle cerebral artery (MCA) on both sides. Subsequently, fTCD was monitored: At rest; during performance of the Paced Auditory Serial Addition Test (PASAT); during exposure to traffic noise; and during concomitant exposure to noise and PASAT performance. MFV and PI were compared for particular conditions and correlated with age. During exposure to noise, flow parameters did not change significantly. PASAT performance in silence increased MFV and decreased PI in MCA on both sides. During PASAT performance, on exposure to noise, MCV and PI changed significantly only in the left MCA. However, values of MFV were significantly lower during noise than in silence. Correlations with age were noted for velocities in the right MCA during PASAT performance in silence and for PI on both sides during PASAT performed in noise conditions. Noise impairs the CBF during mental tasks. A comparison of changes in CBF parameters correlated with age suggests that the involvement of the nondominant hemisphere in managing with noise effects increases with age. PMID- 26572703 TI - Are the noise levels acceptable in a built environment like Hong Kong? AB - Governments all over the world have enacted environmental noise directives and noise control ordinances/acts to protect tranquility in residential areas. However, there is a lack of literature on the evaluation of whether the Acceptable Noise Levels (ANLs) stipulated in the directive/ordinance/act are actually achievable. The study aimed at measuring outdoor environmental noise levels in Hong Kong and identifying whether the measured noise levels are lower than the stipulated ANLs at 20 categories of residential areas. Data were gathered from a territory-wide noise survey. Outdoor noise measurements were conducted at 203 residential premises in urban areas, low-density residential areas, rural areas, and other areas. In total, 366 daytime hourly Leq outdoor noise levels, 362 nighttime hourly Leq outdoor noise levels, and 20 sets of daily, that is, 24 L(eq,1-)h outdoor noise levels were recorded. The mean daytime L(eq,1-h) values ranged 54.4-70.8 dBA, while the mean nighttime L(eq,1-h) values ranged 52.6-67.9 dBA. When the measured noise levels were compared with the stipulated ANLs, only three out of the 20 categories of areas had outdoor noise levels below ANLs during daytime. All other areas (and all areas during nighttime) were found to have outdoor noise levels at or above ANLs. PMID- 26572705 TI - MicroRNA-566 modulates vascular endothelial growth factor by targeting Von Hippel Landau in human glioblastoma in vitro and in vivo. AB - MicroRNAs (miRNAs) are able to function as either oncogenes or tumor suppressor genes in tumorigenesis, and have been proposed as novel targets for anticancer treatment. It has previously been suggested that miRNAs have important roles in the initiation and progression of glioblastoma; however, the effects of miR-566 in glioblastoma are currently unclear. The present study aimed to demonstrate that miR-566 can modulate vascular endothelial growth factor (VEGF) by targeting Von Hippel-Lindau (VHL) in glioblastoma in vitro and in vivo by inhibiting the expression of miR-566. Glioblastoma is a highly vascularized tumor, which exhibits increased expression of angiogenic factors, including VEGF, which are crucial in the process of glioblastoma angiogenesis. Existing research has demonstrated that VHL is a tumor suppressor gene that is associated with various tumors. In addition, VHL is able to regulate the expression of VEGF by promoting the degradation of hypoxia-inducible factor-1alpha via ubiquitination. It has been predicted, using bioinformatics, that the VHL gene is regulated by miR-566. Therefore, the present study hypothesized that miR-566 may regulate VEGF expression by targeting VHL during the angiogenic process of glioblastoma multiforme. The results of the present study demonstrated that inhibition of miR 566 expression increases the expression levels of VHL, decreases the expression levels of VEGF, and inhibits the invasive and migratory abilities of glioblastoma. In addition, VHL was identified as a functional target of miR-566. PMID- 26572704 TI - ARID1A gene mutation in ovarian and endometrial cancers (Review). AB - The AT-rich interacting domain-containing protein 1A gene (ARID1A) encodes ARID1A, a member of the SWI/SNF chromatin remodeling complex. Mutation of ARID1A induces changes in expression of multiple genes (CDKN1A, SMAD3, MLH1 and PIK3IP1) via chromatin remodeling dysfunction, contributes to carcinogenesis, and has been shown to cause transformation of cells in association with the PI3K/AKT pathway. Information on ARID1A has emerged from comprehensive genome-wide analyses with next-generation sequencers. ARID1A mutations have been found in various types of cancer and occur at high frequency in endometriosis-associated ovarian cancer, including clear cell adenocarcinoma and endometrioid adenocarcinoma, and also occur at endometrial cancer especially in endometrioid adenocarcinoma. It has also been suggested that ARID1A mutation occurs at the early stage of canceration from endometriosis to endometriosis-associated carcinoma in ovarian cancer and also from atypical endometrial hyperplasia to endometrioid adenocarcinoma in endometrial cancer. Therefore, development of a screening method that can detect mutations of ARID1A and activation of the PI3K/AKT pathway might enable early diagnosis of endometriosis-associated ovarian cancers and endometrial cancers. Important results may also emerge from a current clinical trial examining a multidrug regimen of temsirolimus, a small molecule inhibitor of the PI3K/AKT pathway, for treatment of advanced ovarian clear cell adenocarcinoma with ARID1A mutation and PI3K/AKT pathway activation. Also administration of sorafenib, a multikinase inhibitor, can inhibit cancer proliferation with PIK3CA mutation and resistance to mTOR inhibitors and GSK126, a molecular-targeted drug can inhibit proliferation of ARID1A-mutated ovarian clear cell adenocarcinoma cells by targeting and inhibiting EZH2. Further studies are needed to determine the mechanism of chromatin remodeling dysregulation initiated by ARID1A mutation, to develop methods for early diagnosis, to investigate new cancer therapy targeting ARID1A, and to examine the involvement of ARID1A mutations in development, survival and progression of cancer cells. PMID- 26572706 TI - Orgasmic Dysfunction After Robot-assisted Versus Open Radical Prostatectomy. AB - Several alterations of orgasmic function that occur after radical prostatectomy (RP) have never been assessed in robot-assisted RP (RARP) series. We sought to assess the prevalence and predictors of recovery from orgasm-associated incontinence (climacturia) and painful orgasm (PO) after RARP and open RP (ORP). Following surgery, sexually active patients who had undergone either RARP or ORP prospectively completed a 28-item questionnaire including sensitive issues regarding sexual function (eg, climacturia and PO). Rates of postoperative climacturia and PO were compared for RARP and ORP patients. Kaplan-Meier analysis was applied to assess estimated rates of recovery from either climacturia or PO after both procedures. Cox regression models tested predictors of recovery from those conditions. Overall, 221 (29.5%) of 749 patients reported climacturia, without differences between RARP and ORP. Conversely, PO was significantly more frequently reported after ORP than after RARP (46 [11.6%] vs 25 [7.1%] patients, respectively; p=0.04). At Kaplan-Meier analysis, recovery from climacturia over time was faster and greater after RARP than after ORP (8.5% vs 5%, respectively, at 24-mo assessment and 48% vs 15%, respectively, at 84-mo assessment; p<0.01). Conversely, no differences were found between groups in terms of postoperative recovery from PO. At multivariable analysis, only RARP achieved independent predictor status for recovery from climacturia after adjusting for other functional outcomes. Conversely, no variables were significantly associated with recovery from postoperative PO. PATIENT SUMMARY: Orgasmic modifications such as climacturia and painful orgasm (PO) are frequently reported after radical prostatectomy. Robotic surgery was associated with a lower rate of postoperative PO and with greater and faster recovery from climacturia. PMID- 26572707 TI - New Rates of Interventions to Manage Complications of Modern Prostate Cancer Treatment in Older Men. AB - BACKGROUND: Interventions to treat complications from prostate cancer (PCa) treatment are common and affect the course of a patient's life. OBJECTIVE: To examine rates of complications other than urinary incontinence and impotence for older patients treated for PCa. DESIGN, SETTING, AND PARTICIPANTS: Population based retrospective cohort study of patients aged 65-79 yr receiving radical prostatectomy or radiotherapy (RT) from 2001 to 2008 in the US Surveillance Epidemiology and End Results and Medicare linked databases. OUTCOME MEASURES AND STATISTICAL ANALYSIS: Complications were organised in three categories: urologic procedures, rectal-anal procedures, and major surgeries. We analysed the role of primary treatment on the number of complications using negative binomial regression. RESULTS AND LIMITATIONS: Among 60476 men, 14492 underwent primary surgery and 45984 underwent primary RT; 33418 (55%) experienced at least one complication (mean: 2.6 complications per patient). For both groups, complications peaked within 2 yr of treatment but continued at a steady rate for 10 yr. Patients treated with radiation had higher rates of urologic procedures (adjusted relative rate [aRR]: 1.25; 95% confidence interval [CI], 1.2-1.3; p<0.0001) and rectal-anal procedures (aRR: 1.4; 95% CI, 1.4-1.5; p<0.0001) but a lower rate of major surgeries (aRR: 0.9; 95% CI, 0.8-0.9; p<0.0001) compared with those having surgery. Because patients treated with RT were older and more comorbid, selection bias limits the strength of conclusions that can be drawn from this data. CONCLUSIONS: Complications are common following PCa cancer treatment and occur many years after treatment. The primary treatment is an important predictor of complication rates that may inform treatment decisions and long-term survivorship plans. PATIENT SUMMARY: We examined complications after prostate cancer treatment in a large American population. Patients treated with radiotherapy rather than surgery had higher rates of complications requiring urologic procedures and rectal-anal procedures but lower rates of open surgeries. However, we were only able to examine men aged >65 yr, and this, along with the observational study technique, means that these results may not apply to all patients and that factors beyond those that we could measure may have affected these results. PMID- 26572709 TI - [Violence and Mental Health]. PMID- 26572710 TI - [Dimensions of Empathy in Ex-Combatants of the Colombian Armed Conflict Using a Standardized Scale]. AB - INTRODUCTION: Empathy is one of the main concepts of in social neurosciences. It is defined as a trait with multiple dimensions allowing individuals to place themselves in the emotional states of others. Colombia has an irregular, internal and long-lasting armed conflict which has been increasing its cruelty levels. OBJECTIVES: to assess the empathy dimensions of 285 ex-combatants from the internal Colombian conflict, using the Interpersonal Reactivity Index(IRI) in Spanish. METHODOLOGY AND SUBJECTS: a sample of 285 male ex-combatants, 241 (84, 6%) males: 85,3% paramilitaries, and 14,7% guerillas. The 28 Item IRI questionnaires were administered. 3 exploratory factor analyses (EFA) were performed. Confirmatory factor analyses (CFA) were developed using structural equation procedures. RESULTS: The first EFA obtained 9 factors (KMO=0,74, variance 54,7% and internal consistency (IC): 0,22 - 0,63). The second EFA produced 20 items with burdens above 0,4 and showed a 6-factor structure (KMO=0,70, variance 50,3%, IC: 0,37 - 0,63). The third EFA forced the 4 original IRI dimensions (KMO=0,74, variance 33,77, IC: 0,44 - 0,77. CFAs showed goodness of adjustment indexes adequate for the three models. The 4-factor model obtained the lowest value, while the 6-factor model obtained the highest. The 4- factor model showed the best IC. CONCLUSION: The Spanish IRI administered to ex combatants of the Colombian conflict has possible structures of 4, 6 and 9 factors. The best adjustment was for the 6-fctor. The 4-factor model exhibited the best IC. PMID- 26572708 TI - The Early Effects of Rapid Androgen Deprivation on Human Prostate Cancer. AB - The androgen receptor (AR) is the dominant growth factor in prostate cancer (PCa). Therefore, understanding how ARs regulate the human transcriptome is of paramount importance. The early effects of castration on human PCa have not previously been studied 27 patients medically castrated with degarelix 7 d before radical prostatectomy. We used mass spectrometry, immunohistochemistry, and gene expression array (validated by reverse transcription-polymerase chain reaction) to compare resected tumour with matched, controlled, untreated PCa tissue. All patients had levels of serum androgen, with reduced levels of intraprostatic androgen at prostatectomy. We observed differential expression of known androgen regulated genes (TMPRSS2, KLK3, CAMKK2, FKBP5). We identified 749 genes downregulated and 908 genes upregulated following castration. AR regulation of alpha-methylacyl-CoA racemase expression and three other genes (FAM129A, RAB27A, and KIAA0101) was confirmed. Upregulation of oestrogen receptor 1 (ESR1) expression was observed in malignant epithelia and was associated with differential expression of ESR1-regulated genes and correlated with proliferation (Ki-67 expression). PATIENT SUMMARY: This first-in-man study defines the rapid gene expression changes taking place in prostate cancer (PCa) following castration. Expression levels of the genes that the androgen receptor regulates are predictive of treatment outcome. Upregulation of oestrogen receptor 1 is a mechanism by which PCa cells may survive despite castration. PMID- 26572711 TI - [Factors Related to the Disability Burden in People with Suicidal Attempts Attended in the Public Health Care Service Network of Santiago de Cali]. AB - INTRODUCTION: According to the World Health Organization (WHO), the aftermaths of suicide attempts are the sixth leading cause of poor health and disability in the world. OBJECT: Establish the level of disability and related factors in terms of restrictions regarding participation and activity limitations in cases of suicidal attempts attended by the Public Service Network Health of Santiago de Cali, from September 2009 to June 2010. METHODOLOGY: A cross-section, observational study was applied to 126 people between 15 and 65 who had attempted suicide and were treated at the Public Health Service in Santiago de Cali. A Spanish version of the Disability Assessment Scale of the World Health Organization RESULTS: 30 disability-adjusted life years (DALYs) were calculated together with a disability prevalence of 95.3%. 4.6% of the sample did not show disability while 41.27% had mild disability, 38.1%, moderate disability, and 15.87%, severe disability. Factors related with disability were: Age, occupation, presence of mental illness, current depressive symptoms, lethal methods, use of psychiatric drugs, activity limitations, participation restrictions and lack of religious practice. CONCLUSIONS: The prevalence of disability in people who have committed suicidal attempts treated at the public health services in Santiago de Cali, was 95.3%. The results are consistent with the study of global burden of disease that establishes a high score for mental disorders in suicidal attempts. The presence of a deficiency after the suicide attempt increases the burden of disability. PMID- 26572712 TI - [Socio-demographic Characterization of Psychosexual Development and Crime in Men Convicted of Sexual Crimes Imprisoned in the Manizales Penitentiary Center]. AB - This article introduces the socio-demographic characteristics of psychosexual development and sexual crimes in men deprived of liberty for such crimes who are doing time in a Manizales prison (Colombia) in 2011. It also describes the differences between abusers of individuals under 12 years of age or who are 12 years old, and abusers of individuals over that age. METHODOLOGY: This is a descriptive, retrospective study performed by simple random sampling. It consisted of semi-structured interviews in which socio-demographic characteristics, psychosexual development, characteristics of crime, and prevalence of mental disorders were analyzed in a sample of 80 inmates convicted of sexual offenses at the Medium-security Pentientiary center in the city of Manizales. Univariate and bivariate analysis were performed using the chi(2) test and the logistic regression analysis with variables showing statistical significance in the bivariate analysis. RESULTS: It was found that convicted sex offenders belong to lower socioeconomic levels, have low educational levels, and did not receive any sexual education. Such findings become more relevant when the crimes in questions are committed against 12-year-olders or children under this age. CONCLUSIONS: The lack of sexual education, low educational levels and lower socioeconomic levels are associated factors in the case of sexual offenses. It is important for society (particularly health-care institutions) to find additional measures for the criminalization of such behaviors in order to achieve a better control of the problem. PMID- 26572713 TI - [Assessment of Family Dynamics in Families with Children Diagnosed with Asthma]. AB - OBJECT: Determine from this research family functionality in asthmatic children between 7 and 12 years of age. METHODOLOGY: Cross-sectional study performed from July to September 2010 in six health-care institutions of the city of Medellin, Antioquia, Colombia. The study comprised 50 families having children diagnosed with asthma of whom 22 had uncontrolled asthma, while 28 other children had controlled asthma and served as comparison group. Family functionality was assessed by the Apgar family instrument and an M.D. family therapist while a pediatric pulmonologist made the asthma diagnosis and the clinical evaluation. Associations were explored through the odds ratio (OR) and confidence intervals (CI) 95%. RESULTS: Family dysfunction is a factor most commonly associated to families having children with uncontrolled asthma in comparison with those families without such patients (OR = 8.95; CI 95%; 2,4-32.3). The dysfunction is significantly greater in families having children with uncontrolled asthma. CONCLUSION: Given the frequency of family dysfunction in children with asthma, assessment of family functionality should be considered as part of a comprehensive approach to families with asthmatic children. PMID- 26572714 TI - [Predictors of Family Dysfunction among Adolescent Students]. AB - OBJECT: Determination of family dysfunction predictors in adolescent students of Cartagena, Colombia. METHODOLOGY: A cross-sectional analytical research was conducted by means of a probabilistic sample per conglomerate of high-school students. Participation of students between 13 and 17 years was requested. Family dysfunction was identified through the family APGAR scale. Predictors were adjusted by binary logistic regression. RESULTS: A total of 1,730 students agreed to participate, mean age was 14.7 years (SD=1.2), and 52.7% were girls. The family APGAR scale showed a Cronbach alpha of 0.78. A group of 896 students (51.8%) reported family dysfunction. Predictors of family dysfunction were: clinically significant depressive symptoms (OR=3.61; IC 95%: 2.31-5.63), low religiosity (OR=1.73; CI 95%: 1.41-2.13), non-nuclear family (OR=1.71, CI 95% 1.71-2.09) (OR=1.73, 95% CI 1.41-2.13), non-nuclear family (OR=1.71, 95%: CI 1.41 2.09), consumption of any illegal substance in their lives (OR=1.67, CI 95%: 1.15 2.13), residents of depressed neighborhoods (OR = 1.49; CI 95%: 1.19-1.87), and poor academic performance (OR=1.43; CI 95%: 1.15-1.76). CONCLUSIONS: Clinically significant depressive symptoms, low religiosity and non-nuclear family are the main predictors of family dysfunction among adolescent students in Cartagena, Colombia. The association is possibly bidirectional. PMID- 26572715 TI - [Care and Self-Care Among Families with a Person Suffering from Bipolar Disorder and Belonging to the Psychoeducational Group of the Psychiatry Department of the University of Antioquia, Colombia]. AB - OBJECTIVE: To analyze the families from the Psychoeducational Group of the Psychiatry Department of the University of Antioquia that have one member with bipolar disorder (BD) in order to identify their care-related practices. METHOD: A comprehensive research project using the phenomenological and hermeneutic method. Semi-structured interviews were conducted with twelve families. The data obtained were analyzed using the Atlas ti qualitative software. RESULTS: Two main categories emerged: 1. Care and family life course and 2. Care and self-care in relation to bipolar disorder. The first category manifests itself through practices such as: Taking care of the diseased person by being physically present, providing physical or emotional support, or by transferring care-related actions to other family members. Two main perspectives could be identified in the second category, namely: the caretaker's perspective and that of the person being taken care of. Two tendencies were found regarding the first one: taking care of others brings about transformations in the caretakers and taking care of others is tough. The second perspective has the same number of tendencies: self-care as poetics and taking care of oneself in order to go from the Diving Bell to the Butterfly. CONCLUSIONS: Taking care of others is a way of building humanity. Conducting research on care and self-care practices (i.e. the practices of both the caretaker and the person being taken care of) results in a more aesthetic way of providing care and a more aesthetic patient-caretaker dyad. PMID- 26572716 TI - [Limitations on Therapeutic Efforts: Much More than not Doing]. AB - The term LTE (Limitations on Therapeutic Efforts) refers to the withholding or withdrawing of medical treatment to a patient (either with or without capacity to decide) who does not clinically benefit from it. Although some countries already have legislation and official documents to formalize it, there are several reasons limiting the dissemination and acceptance of this proposal. One is the fact that physicians and health institutions consider this issue as the sole responsibility of patients; another reason is that physicians and the community in general believe the discussion refers just to elderly and terminal patients. It is necessary an academic approach on LTE from both, physicians and the community in general, to promote a sound ethical reflection so as to assist patients and their relatives in the hard task of becoming autonomous to decide and plan their futures. PMID- 26572717 TI - [Sex/Gender, Violence and Human Rights: Conceptual Perspectives for Approaching Gender-Based Violence against Women from the Health Sector]. AB - Based upon the public health sector perspective, this article explores conceptual approaches to address the issue of gender violence against women. OBJECT: To consider the election of an analysis framework regarding the phenomenon of violence against women in the health sector, in the light of the political implications of becoming a woman in the midst of a specific social order. METHODOLOGY: Expert review of scientific literature published on free-access data bases so as to identify the most commonly used interpretation frameworks with regard to the phenomenon of violence against women in order to explain its political implications according to a specific social order. CONCLUSIONS AND RESULTS: Becoming woman implies participation in social aspects from an inequity stemming from structural power. This is the reason why violence against women can never be considered away from its roots. i.e., a society that assigns to women social roles that imply diminished possibilities of access to the use of power through a sex/gender system which is binary, hierarchic and exclusive. In public health areas, the selection of interpretation frameworks that do not take into account the structural origin of violence against women contribute to their invisibilization and even to perpetuate it, independently from the conscience of the researcher on the basis of the political burden arising from the use of such frameworks to the detriment of others, or the intention of objectivity regarding frameworks with a heavy political burden that contribute to the maintenance of a sex/gender binary, hierarchic and excluding structure. PMID- 26572718 TI - [Autonomy, Trust and Medical Ethics in Onora O'Neill's Work]. AB - INTRODUCTION: Autonomy has become a key concept in bioethics. Onora O'neill is perhaps the most representative author and researcher in the philosophical and bioethical fields regrding the concept of autonomy. OBJECT: To review the concept of autonomy in Onora O'Neill's work so as to understand its relevance in current bioethics. METHOD: The concept of bioethics is reviewed in relation to three fundamental quesions: 1) Which are the main limitations of the individualistic conception of autonomy? 2) How to understand the relations between trust and autonomy together with their implications? and 3) Which are the implications of principled autonomy for aspects such as doctor-patient relationship and informed consent. The main works by O'Neill are reviewed, specifically regarding medical bioethics. RESULTS: O'neill's approach is original and relates Kantian autonomy to her own conceptions about trust, and both the individual and social levels of bioethics. CONCLUSIONS: The author has developed a Kantian non indvidualistic view of autonomy. Her conceptulization of trust and the crises this concept is currently undergoing complement and strengthen the concept of principled autonomy. The implications of O'Neill's concepts go beyond theoretical discussions and in her work she uses examples and analyzes circumstances which demonstrate the applicability of her proposals. O'Neill's work contributes to dealing with the challenges posed by the socio-political context of cost efficiency oriented health systems and of the so-called defensive medicine. PMID- 26572719 TI - [Report of Internal Consistency of the Scales in Research Published in the Colombian Journal of Psychiatry]. AB - OBJECT: Establishment of the frequency of reporting internal consistency of the scales in research published in the Colombian Journal of Psychiatry (CJP) between 2006 and 2010. METHOD: A descriptive study was carried out which computes the report of internal consistency (Cronbach alpha) of scales in research published as original papers in the CJP. Validation studies were excluded. RESULTS: A total of 114 articles were published and 30 of them were included in the analysis. Researchers applied 67 scales for measuring some variables and Cronbach alpha of 20 (29.8%) scales was reported in the participating population. CONCLUSIONS: In the CJP, few published studies that apply measuring scales for variables report internal consistency in the analyzed sample. It is necessary for authors to report the internal consistency of used scales in the study population to guarantee the validity of conclusions. PMID- 26572720 TI - [Atypical presentation of an induced hyperthyroidism]. AB - We present the case of a person with baseline Bipolar Affective Disorder, who starts receiving medical treatment for subclinical Hypothyroidism, during this time the patient develops Hyperthyroidism. During the course of the latter, the patient started to exhibit depressed mood symptoms and worsening of her baseline disorder. Typically there are depressive symptoms in hypothyroidism and manic symptoms in hyperthyroidism, there have been a few cases of depressive symptoms (depressed mood, asthenia and apathy) reported in patients with hyperthyroidism. Up till now it's a fact that Hyperthyroidism constitutes itself as a risk factor for developing or precipitating depressive states, thus increasing hospital readmissions, and another important fact is that of manifesting or worsening affective symptoms due to the influence of thyroid hormones. We also present the well-known relationship between thyroid malfunction and affective disorders. PMID- 26572721 TI - Effect of Rapid Maxillary Expansion on Voice. AB - OBJECTIVE: The purpose of this investigation is to evaluate the effect of rapid maxillary expansion (RME) on the fundamental frequency (F0) and formant frequencies F1-F4. STUDY DESIGN: Cross-sectional study. MATERIALS AND METHODS: A total of 14 consecutive patients between the ages of 9.6 years and 15 years with a constricted maxilla undergoing RME were included in this study. Measurements were made before (T1) and after treatment (T2). These included maxillary arch length, depth, width, and perimeter in addition to F0, habitual pitch, and formants F1, F2, F3, and F4 for the vowels /alpha/, /i/, /o/, and /u/. RESULTS: There was a significant difference in the mean of F1/alpha/ and F2/alpha/ before and after treatment (P value of 0.04 and 0.013, respectively). It is worth noting that F1/alpha/ decreased in 11 and F2/alpha/ decreased in 10 of the 14 subjects. CONCLUSION: The application of RME in the treatment of maxillary constriction leads to a significant lowering of the first and second formants for the vowel /alpha/ in most subjects. Subjects undergoing rapid maxillary application should be aware of the potential change in voice quality especially in case of professional voice users. PMID- 26572722 TI - Music therapy in patients with dementia and behavioral disturbance on an inpatient psychiatry unit: results from a pilot randomized controlled study. AB - The prevalence of dementia continues to grow worldwide due to an aging population and is projected to affect 65.7 million people by 2030 (World Health Organization, 2012). Behavioral and psychological symptoms of dementia (BPSD), including agitation, anxiety, aggression, depression, and psychosis, can occur in as much as 80% of the affected population, frequently necessitating psychiatric admission. Traditionally BPSD have been treated using pharmacological approaches. However, such medications could have serious adverse effects and additionally have limited efficacy in reducing such symptoms (Ballard et al., 2009). PMID- 26572723 TI - Current management of paratesticular rhabdomyosarcoma. AB - OBJECTIVES: Paratesticular rhabdomyosarcoma accounts for 7-10% of genitourinary rhabdomyosarcoma tumors and is the 3rd most common after RMS of the prostate and bladder. Though most (60%-80%) patients with paratesticular rhabdomysarcoma present with localized disease, assessment of systemic disease is vital. The treatment of paratesticular rhabdomyosarcoma has evolved over several decades; the current standard of care is multimodal treatment including surgery, chemotherapy, and radiation. We give insight into the evolution of treatment, present the oncologic outcomes of seminal studies, and summarize the current recommendations for the management of these patients. METHODS: A comprehensive search of the literature on the electronic databases PubMed was conducted for management of paratesticular rhabdomyosarcoma. Case reports were excluded, clinical trials from all the oncologic society were reviewed and relevant articles are included in the review. RESULTS: The treatment regimen is based on following principles: (1) local control of the primary site with radical orchiectomy and (2) assessment of local control and distant sites. Further treatment is directed according to disease stage, histology, and age of the patient. The goal of treatment is to achieve cure or maximum tumor control while minimizing toxicity. CONCLUSIONS: With the changing landscape in the management of paratesticular rhabomyosarcoma, significant improvement is evident in the oncologic outcomes. Further advance in genomic testing would lead us to tailor treatment based on individual risk factors and minimize long-term side effects. PMID- 26572724 TI - The effect of broader, directed antimicrobial prophylaxis including fungal coverage on perioperative infectious complications after radical cystectomy. AB - OBJECTIVES: Radical cystectomy (RC) with urinary diversion has a significant risk of infection. In an effort to decrease the rate of infectious complications, we instituted a broader, culture-based preoperative antimicrobial regimen, including fungal coverage, and studied its effect on infectious complications after RC. MATERIALS AND METHODS: In May 2013, antimicrobial prophylaxis for RC was changed at our institution after review of previous positive cultures. Ampicillin sulbactam 3g, gentamicin 4mg/kg, and fluconazole 400mg replaced cefoxitin. Patients undergoing RC from May 2011 to May 2014 were included. Before and after implementation of the new regimen, 30-day infectious complications (positive blood culture, urinary tract infection, wound infection, abscess, and pneumonia) and adverse events (Clostridium difficile, readmission, and mortality) were compared. Multivariate logistic regression was used to identify independent risk factors for infection while controlling for covariates. RESULTS: In total, 386 patients were studied (258 before the change and 128 after). The overall infection rate decreased with the new regimen (41% vs. 30%, P = 0.043) with improvements in wound (14% vs. 6%, P = 0.025) and fungal (10% vs. 3%, P = 0.021) infections. Median length of stay decreased from 8 (interquartile range [IQR]: 7 12) to 7 (IQR: 7-10) days (P = 0.008). On multivariate analysis, the new regimen decreased the risk of infections (odds ratio [OR] = 0.58, 95% CI [0.35-0.99], P = 0.044) whereas body mass index, operating room time, smoking, and total parenteral nutrition increased the risk (all P< 0.05). CONCLUSIONS: Risk factors for infection after RC include body mass index, operating room time, smoking, and total parenteral nutrition use. Changing from cefoxitin to broader, culture directed antimicrobial prophylaxis, based on institutional data to include antifungal coverage, decreased postoperative infections. PMID- 26572726 TI - Ultrafast response of monolayer molybdenum disulfide photodetectors. AB - The strong light emission and absorption exhibited by single atomic layer transitional metal dichalcogenides in the visible to near-infrared wavelength range make them attractive for optoelectronic applications. In this work, using two-pulse photovoltage correlation technique, we show that monolayer molybdenum disulfide photodetector can have intrinsic response times as short as 3 ps implying photodetection bandwidths as wide as 300 GHz. The fast photodetector response is a result of the short electron-hole and exciton lifetimes in this material. Recombination of photoexcited carriers in most two-dimensional metal dichalcogenides is dominated by nonradiative processes, most notable among which is Auger scattering. The fast response time, and the ease of fabrication of these devices, make them interesting for low-cost ultrafast optical communication links. PMID- 26572727 TI - Morphology and Vascular Layers of the Choroid in Stargardt Disease Analyzed Using Spectral-Domain Optical Coherence Tomography. PMID- 26572728 TI - Reply: To PMID 26164828. PMID- 26572729 TI - Early high flow nasal cannula therapy in bronchiolitis, a prospective randomised control trial (protocol): A Paediatric Acute Respiratory Intervention Study (PARIS). AB - BACKGROUND: Bronchiolitis imposes the largest health care burden on non-elective paediatric hospital admissions worldwide, with up to 15 % of cases requiring admission to intensive care. A number of previous studies have failed to show benefit of pharmaceutical treatment in respect to length of stay, reduction in PICU admission rates or intubation frequency. The early use of non-invasive respiratory support devices in less intensive scenarios to facilitate earlier respiratory support may have an impact on outcome by avoiding progression of the disease process. High Flow Nasal Cannula (HFNC) therapy has emerged as a new method to provide humidified air flow to deliver a non-invasive form of positive pressure support with titratable oxygen fraction. There is a lack of high-grade evidence on use of HFNC therapy in bronchiolitis. METHODS/DESIGN: Prospective multi-centre randomised trial comparing standard treatment (standard subnasal oxygen) and High Flow Nasal Cannula therapy in infants with bronchiolitis admitted to 17 hospitals emergency departments and wards in Australia and New Zealand, including 12 non-tertiary regional/metropolitan and 5 tertiary centres. The primary outcome is treatment failure; defined as meeting three out of four pre-specified failure criteria requiring escalation of treatment or higher level of care; i) heart rate remains unchanged or increased compared to admission/enrolment observations, ii) respiratory rate remains unchanged or increased compared to admission/enrolment observations, iii) oxygen requirement in HFNC therapy arm exceeds FiO2 >= 40 % to maintain SpO2 >= 92 % (or >=94 %) or oxygen requirement in standard subnasal oxygen therapy arm exceeds >2L/min to maintain SpO2 >= 92 % (or >=94 %), and iv) hospital internal Early Warning Tool calls for medical review and escalation of care. Secondary outcomes include transfer to tertiary institution, admission to intensive care, length of stay, length of oxygen treatment, need for non-invasive/invasive ventilation, intubation, adverse events, and cost. DISCUSSION: This large multicenter randomised trial will allow the definitive assessment of the efficacy of HFNC therapy as compared to standard subnasal oxygen in the treatment of bronchiolitis. TRIAL REGISTRATION: The trial is registered with the Australian and New Zealand Clinical Trials Registry ACTRN12613000388718 (registered on 10 April 2013). PMID- 26572730 TI - Structural connectivity in a paediatric case of anarchic hand syndrome. AB - BACKGROUND: "Anarchic hand" is a rare condition characterised by non-volitional, goal-directed movements of one arm. We report a case with analysis of structural and functional connectivity. CASE PRESENTATION: A 15 year old girl developed intermittent symptoms of intermanual conflict or anarchic hand as a result of traumatic brain injury during which she sustained a callosal bleed. Resting-state fMRI and DTI tractography were performed at a stage when symptoms had largely resolved. CONCLUSION: Structural connectivity between homologous superior frontal areas and functional connectivity between homologous posterior cingulate areas were significantly reduced, which may have contributed to causation. Tractography demonstrated new indirect connections between supplementary motor areas via the cerebellum, which we propose contributed to symptom resolution. PMID- 26572731 TI - Erratum: Meat, dairy and plant proteins alter bacterial composition of rat gut bacteria. PMID- 26572732 TI - Alterations in Circulating Immune Cells in Neovascular Age-Related Macular Degeneration. AB - Neovascular age-related macular degeneration (nAMD) is the leading cause of irreversible blindness in developed countries. Recent advances have highlighted the essential role of inflammation in the development of the disease. In addition to local retinal chronic inflammatory response, systemic immune alterations have also been observed in AMD patients. In this study we investigated the association between the frequency of circulating leukocyte populations and the prevalence as well as clinical presentations of nAMD. Leukocyte subsets of 103 nAMD patients (most of them were receiving anti-VEGF therapy prior to enrolment) and 26 controls were analysed by flow cytometry by relative cell size, granularity and surface markers. Circulating CD11b(+) cells and CD16(hi)HLA-DR(-) neutrophils were significantly increased (P = 0.015 and 0.009 respectively) in nAMD when compared to controls. The percentage of circulating CD4(+) T-cells was reduced in nAMD patients without subretinal fibrosis (P = 0.026) compared to patients with subretinal fibrosis. There was no correlation between the percentage of circulating leukocytes and the responsiveness to anti-VEGF therapy in nAMD patients. Our results suggest that higher levels of circulating CD11b(+) cells and neutrophils are associated with nAMD and that reduced levels of CD4(+) T cells are associated with the absence of subretinal fibrosis in nAMD. PMID- 26572733 TI - Gamma oscillations in V1 are correlated with GABA(A) receptor density: A multi modal MEG and Flumazenil-PET study. AB - High-frequency oscillations in the gamma-band reflect rhythmic synchronization of spike timing in active neural networks. The modulation of gamma oscillations is a widely established mechanism in a variety of neurobiological processes, yet its neurochemical basis is not fully understood. Modeling, in-vitro and in-vivo animal studies suggest that gamma oscillation properties depend on GABAergic inhibition. In humans, search for evidence linking total GABA concentration to gamma oscillations has led to promising -but also to partly diverging- observations. Here, we provide the first evidence of a direct relationship between the density of GABA(A) receptors and gamma oscillatory gamma responses in human primary visual cortex (V1). By combining Flumazenil-PET (to measure resting levels of GABA(A) receptor density) and MEG (to measure visually-induced gamma oscillations), we found that GABA(A) receptor densities correlated positively with the frequency and negatively with amplitude of visually-induced gamma oscillations in V1. Our findings demonstrate that gamma-band response profiles of primary visual cortex across healthy individuals are shaped by GABA(A)-receptor mediated inhibitory neurotransmission. These results bridge the gap with in-vitro and animal studies and may have future clinical implications given that altered GABAergic function, including dysregulation of GABA(A) receptors, has been related to psychiatric disorders including schizophrenia and depression. PMID- 26572734 TI - Quality of care in European home care programs using the second generation interRAI Home Care Quality Indicators (HCQIs). AB - BACKGROUND: Evaluating the quality of care provided to older individuals is a key step to ensure that needs are being met and to target interventions to improve care. To this aim, interRAI's second-generation home care quality indicators (HCQIs) were developed in 2013. This study assesses the quality of home care services in six European countries using these HCQIs as well as the two derived summary scales. METHODS: Data for this study were derived from the Aged in Home Care (AdHOC) study - a cohort study that examined different models of community care in European countries. The current study selected a sub-sample of the AdHOC cohort from six countries whose follow-up data were complete (Czech Republic, Denmark, Finland, Germany, Italy and the Netherlands). Data were collected from the interRAI Home Care instrument (RAI-HC) between 2000 and 2002. The 23 HCQIs of interest were determined according to previously established methodology, including risk adjustment. Two summary measures, the Clinical Balance Scale and Independence Quality Scale were also determined using established methodology. RESULTS: A total of 1,354 individuals from the AdHOC study were included in these analyses. Of the 23 HCQIs that were measured, the highest proportion of individuals experienced declines in Instrumental Activities of Daily Living (IADLs) (48.4 %). Of the clinical quality indicators, mood decline was the most prevalent (30.0 %), while no flu vaccination and being alone and distressed were the most prevalent procedural and social quality indicators, respectively (33.4 and 12.8 %). Scores on the two summary scales varied by country, but were concentrated around the median mark. CONCLUSIONS: The interRAI HCQIs can be used to determine the quality of home care services in Europe and identify areas for improvement. Our results suggest functional declines may prove the most beneficial targets for interventions. PMID- 26572735 TI - Pregnancy outcomes after failed cervical ripening with prostaglandin E2 followed by Foley balloon catheter. AB - OBJECTIVE: To study pregnancy outcomes of cervical ripening with Foley catheter, in women who failed to respond to prostaglandin-E2 (PGE2). METHODS: A retrospective cohort study of all patients with a singleton pregnancy, who underwent cervical ripening with vaginal PGE2, between 2013 and 2014, was performed. Patients who failed to respond to a total dose of 6-9 mg PGE2, defined as no change in Bishop score, underwent subsequent ripening with Foley catheter (non-responders group). Data were compared to patients who achieved sufficient response to a total dose of up to 9 mg PGE2 (responders group). RESULTS: Compared with the responders group (n = 813), patients in the non-responders group (n = 49) had higher rates of nulliparity (p < 0.001), pre-induction cervical dilation <=1 cm (p = 0.004), pre-induction cervical effacement <=50% (p = 0.01) and birth weight >4000 g (p = 0.02). A significantly higher cesarean delivery rate was observed in the non-responders group (51 versus 12.3%, p < 0.001). Failed ripening with PGE2 was found to be independently associated with cesarean delivery (aOR = 5.11, 95% CI = 2.72-9.62). CONCLUSIONS: The need for an additional cervical ripening method after failure with PGE2 is associated with a very high risk of cesarean delivery. This is particularly significant in nulliparous women, women carrying large fetuses, and women presenting with a low Bishop score. PMID- 26572737 TI - [Morning glory syndrome with Bergmeister papilla and retinal detachment]. PMID- 26572736 TI - Granulocyte transfusions in children and adults with hematological malignancies: benefits and controversies. AB - Bacterial and fungal infections continue to pose a major clinical challenge in patients with prolonged severe neutropenia after chemotherapy or hematopoietic stem cell transplantation (HSCT). With the advent of granulocyte colony stimulating factor (G-CSF) to mobilize neutrophils in healthy donors, granulocyte transfusions have been broadly used to prevent and/or treat life-threatening infections in patients with severe febrile neutropenia and/or neutrophil dysfunction. Although the results of randomized controlled trials are inconclusive, there are suggestions from pilot and retrospective studies that granulocyte transfusions may benefit selected categories of patients. We will critically appraise the evidence related to the use of therapeutic granulocyte transfusions in children and adults, highlighting current controversies in the field and discussing complementary approaches to modulate phagocyte function in the host. PMID- 26572738 TI - Screening and transport in 2D semiconductor systems at low temperatures. AB - Low temperature carrier transport properties in 2D semiconductor systems can be theoretically well-understood within RPA-Boltzmann theory as being limited by scattering from screened Coulomb disorder arising from random quenched charged impurities in the environment. In this work, we derive a number of analytical formula, supported by realistic numerical calculations, for the relevant density, mobility, and temperature range where 2D transport should manifest strong intrinsic (i.e., arising purely from electronic effects) metallic temperature dependence in different semiconductor materials arising entirely from the 2D screening properties, thus providing an explanation for why the strong temperature dependence of the 2D resistivity can only be observed in high-quality and low-disorder 2D samples and also why some high-quality 2D materials manifest much weaker metallicity than other materials. We also discuss effects of interaction and disorder on the 2D screening properties in this context as well as compare 2D and 3D screening functions to comment why such a strong intrinsic temperature dependence arising from screening cannot occur in 3D metallic carrier transport. Experimentally verifiable predictions are made about the quantitative magnitude of the maximum possible low-temperature metallicity in 2D systems and the scaling behavior of the temperature scale controlling the quantum to classical crossover. PMID- 26572739 TI - Does the social context of early alcohol use affect risky drinking in adolescents? Prospective cohort study. AB - BACKGROUND: There are limited longitudinal data on the associations between different social contexts of alcohol use and risky adolescent drinking. METHODS: Australian prospective longitudinal cohort of 1943 adolescents with 6 assessment waves at ages 14-17 years. Drinkers were asked where and how frequently they drank. Contexts were: at home with family, at home alone, at a party with friends, in a park/car, or at a bar/nightclub. The outcomes were prevalence and incidence of risky drinking (>=5 standard drinks (10g alcohol) on a day, past week) and very risky drinking (>20 standard drinks for males and >11 for females) in early (waves 1-2) and late (waves 3-6) adolescence. RESULTS: Forty-four percent (95 % CI: 41-46 %) reported past-week risky drinking on at least one wave during adolescence (waves 1-6). Drinking at a party was the most common repeated drinking context in early adolescence (28 %, 95 % CI 26-30 %); 15 % reported drinking repeatedly (3+ times) with their family in early adolescence (95 % CI: 14-17 %). For all contexts (including drinking with family), drinking 3+ times in a given context was associated with increased the risk of risky drinking in later adolescence. These effects remained apparent after adjustment for potential confounders (e.g. for drinking with family, adjusted RR 1.9; 95 % CI: 1.5-2.4). Similar patterns were observed for very risky drinking. CONCLUSIONS: Our results suggest that consumption with family does not protect against risky drinking. Furthermore, parents who wish to minimise high risk drinking by their adolescent children might also limit their children's opportunities to consume alcohol in unsupervised settings. PMID- 26572740 TI - Characteristics, disease burden and costs of COPD patients in the two years following initiation of long-acting bronchodilators in UK primary care. AB - BACKGROUND: To assess the symptomatic and cost burden among patients initiating long-acting bronchodilator (LABD) therapy and impact of adherence on healthcare resource use and costs. METHODS: This retrospective cohort study identified patients with COPD who were newly prescribed a LABD (long-acting muscarinic antagonist [LAMA], long-acting beta2-agonist [LABA], a combination of LABA+LAMA or combination of LABA with inhaled corticosteroid [ICS]/LABA) between January 1, 2009 and November 30, 2013 from the UK Clinical Practice Research Datalink. Health care resource use, costs and symptom burden up to 24 months after treatment initiation were estimated. Adherence in the follow-up period was assessed using the medication possession ratio (MPR >= 80%). RESULTS: The cohort comprised 8283 LABD initiators (16% LABA, 81% LAMA and 3% LABA+LAMA) and 9246 LABA+ICS initiators with generally similar baseline characteristics; prior exacerbation rate was higher in the LABA+ICS cohort. Less than half the patients (LAMA:42%; LABA:34% and LABA+ICS:34%) were adherent to their index medication. Among adherent patients, the total annual per patient cost of COPD was L3008 for LAMA initiators, L2783 for LABA initiators and L3376 for LABA+ICS initiators; primarily due to general practitioner interactions. Among patients with a Medical Research Council dyspnea score recorded during 24 months follow-up, a substantial proportion of adherent patients (LAMA: 41%; LABA: 45%; LABA+ICS 44%) had clinically significant dyspnoea (MRC >= 3). CONCLUSION: Cost and symptomatic burden of COPD was high among patients initiating maintenance treatment, including patients adherent with their initial treatment. General practitioner interactions were the primary driver of costs. Further, real world studies are required to address unmet needs and optimize treatment pathways to improve COPD symptom burden and outcomes. PMID- 26572741 TI - Profilin 1 with the amyotrophic lateral sclerosis associated mutation T109M displays unaltered actin binding and does not affect the actin cytoskeleton. AB - BACKGROUND: The recent identification of several mutations in PFN1, a protein involved in actin dynamics, strengthens the hypothesis that pathology of amyotrophic lateral sclerosis is linked to cytoskeletal defects. Impaired actin binding is a common denominator of several PFN1 mutations associated with amyotrophic lateral sclerosis, although further mechanisms may also contribute to the death of motor neurons. In this study we examine the actin binding properties of PFN1 carrying the causal T109M mutation and its effects on the actin cytoskeleton. METHODS: Actin binding of PFN1 T109M was examined by co immunoprecipitation experiments, a split luciferase complementation assay and a pulldown assay with recombinant PFN1. The actin cytoskeleton was investigated by fluorescence microscopy and by ultracentrifuge separation of globular and filamentous actin fractions followed by Western blotting. RESULTS: Using different technical approaches we show that PFN1 T109M displays unaltered actin binding. Furthermore we show that the actin cytoskeleton is not affected by PFN1 carrying the T109M mutation. CONCLUSION: Our data suggest that actin independent mechanisms contribute to the pathogenicity of PFN1 T109M and possibly other PFN1 mutations. PMID- 26572742 TI - Palliative care professionals' willingness to perform euthanasia or physician assisted suicide. AB - BACKGROUND: Euthanasia and physician assisted suicide (PAS) are highly debated upon particularly in the light of medical advancement and an aging society. Little is known about the professionals' willingness to perform these practices particularly among those engaged in the field of palliative care and pain management. Thus a study was performed among those professionals. METHODS: An anonymous questionnaire was handed out to all participants of a palliative care congress and a pain symposium in 2013. The questionnaire consisted of 8 questions regarding end of life decisions. Proposed patient vignettes were used. RESULTS: A total of 470 eligible questionnaires were returned, 198 by physicians, 272 by nurses. The response rate was 64 %. The majority of professionals were reluctant to perform euthanasia or PAS: 5.3 % of the respondents would be willing to perform euthanasia on a patient with a terminal illness if asked to do so. The reluctance grew in case of a patient with a non-terminal illness. The respondents were more willing to perform PAS than euthanasia. Nurses were more reluctant to take action as opposed to the physicians. The majority of the respondents would attempt to treat the patient's symptoms first before considering life-ending measures. As regards any decision making process the majority would consult with a colleague. CONCLUSIONS: This is the first German study to ask about the willingness of professionals to take action as regards euthanasia and PAS without biased phrasing. As opposed to the general acceptance that is respectively high, the actual willingness to perform life-ending measures is low. The German debate on physician assisted suicide and its possible legalization should also incorporate clarifications regarding the responsibility who should eventually perform these acts. PMID- 26572743 TI - General Approach for MOF-Derived Porous Spinel AFe2O4 Hollow Structures and Their Superior Lithium Storage Properties. AB - A general and simple approach for large-scale synthesis of porous hollow spinel AFe2O4 nanoarchitectures via metal organic framework self-sacrificial template strategy is proposed. By employing this method, we can successfully synthesize uniform NiFe2O4, ZnFe2O4, and CoFe2O4 hollow architectures that are hierarchically assembled by nanoparticles. When these hollow microcubes were tested as anode for lithium ion batteries, good rate capability and long-term cycling stability can be achieved. For example, high specific capacities of 636, 449, and 380 mA h g(-1) were depicted by NiFe2O4, ZnFe2O4, and CoFe2O4, respectively, at a high current density of 8.0 A g(-1). NiFe2O4 exhibits high specific capacities of 841 and 447 mA h g(-1) during the 100th cycle when it was tested at current densities of 1.0 and 5.0 A g(-1), respectively. Discharge capacities of 390 and 290 mA h g(-1) were delivered by the ZnFe2O4 and CoFe2O4, respectively, during the 100th cycle at 5.0 A g(-1). PMID- 26572744 TI - The spectrum of KIAA0196 variants, and characterization of a murine knockout: implications for the mutational mechanism in hereditary spastic paraplegia type SPG8. AB - BACKGROUND: The hereditary spastic paraplegias (HSPs) are rare neurodegenerative gait disorders which are genetically highly heterogeneous. For each single form, eventual consideration of therapeutic strategies requires an understanding of the mechanism by which mutations confer pathogenicity. SPG8 is a dominantly inherited HSP, and associated with rather early onset and rapid progression. A total of nine mutations in KIAA0196, which encodes the WASH regulatory complex (SHRC) member strumpellin, have been reported in SPG8 patients so far. Based on biochemical and cell biological approaches, they have been suggested to act via loss of function-mediated haploinsufficiency. METHODS: We generated a deletion based knockout allele for E430025E21Rik, i.e. the murine homologue of KIAA0196. The consequences on mRNA and protein levels were analyzed by qPCR and Western blotting, respectively. Motor performance was evaluated by the foot-base angle paradigm. Axon outgrowth and relevant organelle compartments were investigated in primary neuron cultures and primary fibroblast cultures, respectively. A homemade multiplex ligation-dependent probe amplification assay enabling identification of large inactivating KIAA0196 deletion alleles was applied to DNA from 240 HSP index patients. RESULTS: Homozygous but not heterozygous mice showed early embryonic lethality. No transcripts from the knockout allele were detected, and the previously suggested compensation by the wild-type allele upon heterozygosity was disproven. mRNA expression of genes encoding other SHRC members was unaltered, while there was evidence for reduced SHRC abundance at protein level. We did, however, neither observe HSP-related in vivo and ex vivo phenotypes, nor alterations affecting endosomal, lysosomal, or autophagic compartments. KIAA0196 copy number screening excluded large inactivating deletion mutations in HSP patients. The consequences of monoallelic KIAA0196/E430025E21Rik activation thus differ from those observed for dominant HSP genes for which a loss-of-function mechanism is well established. CONCLUSIONS: Our data do not support the current view that heterozygous loss of strumpellin/SHRC function leads to haploinsufficiency and, in turn, to HSP. The lethality of homozygous knockout mice, i.e. the effect of complete loss of function, also argues against a dominant negative effect of mutant on wild-type strumpellin in patients. Toxic gain-of-function represents a potential alternative explanation. Confirmation of this therapeutically relevant hypothesis in vivo, however, will require availability of appropriate knockin models. PMID- 26572745 TI - The Role of Levomilnacipran in the Management of Major Depressive Disorder: A Comprehensive Review. AB - Levomilnacipran, the more active enantiomer of the serotonin and norepinephrine reuptake inhibitor (SNRI) milnacipran, was recently approved in the US for the treatment of major depressive disorder (MDD). The drug was developed as an extended release (ER) capsule formulation to allow for once-daily administration, thereby improving patient adherence. This agent differs from other available SNRIs in having a greater potency for inhibition of norepinephrine relative to serotonin reuptake. The efficacy of levomilnacipran ER has been evaluated in seven randomised, double-blind clinical trials (one Phase II and four Phase III trials, and two long-term efficacy studies). These studies documented that levomilnacipran is generally more effective than placebo for the treatment of MDD in the short-term, whereas no firm evidence exists on long-term efficacy for relapse prevention. Preliminary evidence suggests that levomilnacipran ER may be effective in improving not only depressive symptoms but also symptoms related to functioning (social life, work, and family life). Short-and longer-term studies found that the rate of withdrawal from levomilnacipran therapy due to adverse events was rather low. Moreover the drug appeared to be generally well tolerated. The most common adverse effects included nausea, hyperhidrosis, constipation, tachycardia, palpitations, erectile dysfunction and ejaculation disorder. As hypertension or orthostatic hypotension may occur in a few patients, the cardiovascular safety of levomilnacipran needs to be more extensively investigated especially on long-term treatment. Additional active comparator trials evaluating efficacy, tolerability and cost-effectiveness are required to better define the role of levomilnacipran ER in the treatment of MDD in relation to currently available antidepressants including other SNRIs. PMID- 26572746 TI - Organic crystal-binding peptides: morphology control and one-pot formation of protein-displaying organic crystals. AB - Crystalline assemblies of fluorescent molecules have different functional properties than the constituent monomers, as well as unique optical characteristics that depend on the structure, size, and morphological homogeneity of the crystal particles. In this study, we selected peptides with affinity for the surface of perylene crystal particles by exposing a peptide-displaying phage library in aqueous solution to perylene crystals, eluting the surface-bound phages by means of acidic desorption or liquid-liquid extraction, and amplifying the obtained phages in Escherichia coli. One of the perylene-binding peptides, PeryBPb1: VQHNTKYSVVIR, selected by this biopanning procedure induced perylene molecules to form homogenous planar crystal nanoparticles by means of a poor solvent method, and fusion of the peptide to a fluorescent protein enabled one pot formation of protein-immobilized crystalline nanoparticles. The nanoparticles were well-dispersed in aqueous solution, and Forster resonance energy transfer from the perylene crystals to the fluorescent protein was observed. Our results show that the crystal-binding peptide could be used for simultaneous control of perylene crystal morphology and dispersion and protein immobilization on the crystals. PMID- 26572747 TI - Fenofibrate-induced massive regression of mutiple inflammatory hepatocellular adenoma. AB - Inflammatory hepatocellular adenomas (IHCA), which accounts for 40% to 50% of all hepatocellular adenomas are characterized by the activation of the IL6/JAK/STAT pathway. We herein report the case of a 52-year-old woman presenting with severe multiple typical IHCA that regressed dramatically on treatment with fenofibrate, a PPAR agonist known to prevent IL6-induced inflammation experimentally and in humans. Further similar observations are needed to ascertain the potential benefit of this therapeutic approach for large or unresectable IHCA. PMID- 26572748 TI - Erratum to: The mortality rates and the space-time patterns of John Snow's cholera epidemic map. PMID- 26572749 TI - Effects of nerve growth factor and basic fibroblast growth factor dual gene modification on rat bone marrow mesenchymal stem cell differentiation into neuron like cells in vitro. AB - Recent studies regarding regenerative medicine have focused on bone marrow mesenchymal stem cells (BMSCs), which have the potential to undergo neural differentiation, and may be transfected with specific genes. BMSCs can differentiate into neuron-like cells in certain neurotropic circumstances in vitro. Basic fibroblast growth factor (bFGF) and nerve growth factor (NGF) are often used to induce neural differentiation in BMSCs in vitro. However, previous studies regarding their combined actions are insufficient. The present study is the first, to the best of our knowledge, to thoroughly assess the enhancement of neural differentiation of BMSCs following transfection with bFGF and NGF. Sprague Dawley (SD) rat BMSCs were separated through whole bone marrow adherence, and were then passaged to the third generation. The cells were subsequently divided into five groups: The control group, which consisted of untransfected BMSCs; the plv-blank-transfected BMSCs group; the plv-bFGF-transfected BMSCs group; the plv NGF-transfected BMSCs group; and the plv-NGF-bFGF co-transfected BMSCs group. Cell neural differentiation was characterized in terms of stem cell molecular expression, and the neuronal morphology and expression of neural-like molecules was detected in each of the groups. A total of 72 h post-transfection, the expression levels of neuron-specific enolase, glial fibrillary acidic protein, and nestin protein, were higher in the co-transfected group, as compared with the other groups, the expression levels of beta-tubulin III were also increased in the co-transfected cells, thus suggesting the maturation of differentiated neuron like cells. Furthermore, higher neuronal proliferation was observed in the co transfected group, as compared with the other groups at passages 2, 4, 6 and 8. Western blotting demonstrated that the transfected groups exhibited a simultaneous increase in phosphorylation of the AKT and extracellular signal regulated kinases (ERK) signaling pathway. These results suggested that manipulation of the ERK and AKT signaling pathway may be associated with the differentiation of transfected BMSCs. PMID- 26572750 TI - Pharmacokinetic and pharmacodynamic evaluation of panitumumab in the treatment of colorectal cancer. AB - INTRODUCTION: Integration of targeted therapy and additional chemotherapy options has improved median overall survival (OS) in patients with unresectable metastatic colorectal cancer (mCRC). Cetuximab and panitumumab are examples of targeted therapies, specifically against the epidermal growth factor receptor (EGFR). This review focuses on Panitumumab, a fully human IgG2 monoclonal antibody, which inhibits key oncogenic downstream cell signalling pathways. Panitumumab and cetuximab have improved tumour response rate, progression-free survival, and OS in mCRC patients in whom the RAS (Rat Sarcoma) gene is of Wild Type (WT) status. AREAS COVERED: The EGFR signalling pathway and preclinical, Phase I and Phase II clinical studies on the pharmacokinetic, pharmacodynamic and safety evaluation of panitumumab are presented. Phase III studies utilising panitumumab in the first, second and third line setting in mCRC are also described. EXPERT OPINION: Panitumumab exhibits excellent pharmacokinetics and pharmacodynamics by way of uncomplicated dosing, non-existent drug interactions, minimal infusion reactions and manageable side effects, making it a suitable target for combination treatments. However, innate and acquired resistances are still obstacles. To overcome this, experimented strategies are ongoing, particularly in patients with Her-2 and BRAF gene alterations. Novel biomarkers to improve patient selection and second-generation targeted antibodies are in development. PMID- 26572751 TI - Partial deletion of the ROCK2 protein fails to reduce renal fibrosis in a unilateral ureteral obstruction model in mice. AB - Renal fibrosis is a well-known cause for the progression of chronic kidney disease. Rho/Rho-associated coiled-coil kinase (ROCK) signaling is involved in renal fibrotic processes. Non-selective ROCK1/2 inhibitors have been reported to reduce renal interstitial fibrosis in a rodent unilateral ureteral obstruction (UUO) model. To clarify the role and contribution of ROCK2 in renal fibrosis, the present study used ROCK2 heterozygous knockout (HKO) mice to assess collagen deposition and fibrosis-associated gene expression in the kidney of the UUO model. In the ROCK2 HKO mice, the expression level of ROCK2 in the normal kidney was half of that in the kidney of wild-type (WT) mice. The expression levels of ROCK1 in the ROCK2 HKO mice and WT mice were equivalent. Furthermore, in the ROCK2 HKO and the WT mice, the hydroxyproline content and the gene expression levels of collagen I and transforming growth factor-beta1 in the obstructed kidneys were augmented following UUO. By contrast, the mRNA expression of alpha smooth muscle actin decreased in the ROCK2 HKO mice, compared with that in the WT mice. The activity of ROCK in the obstructed kidneys, indicated by the phosphorylation of myosin phosphatase target subunit-1, which is a non-selective substrate of ROCK1 and ROCK2, was equivalent among the ROCK2 HKO and WT mice. In conclusion, no differences in renal interstitial fibrosis or UUO-induced ROCK activity were identified between the ROCK2 HKO and WT mice, indicating that the genetic partial disruption of ROCK2 is insufficient for protecting against renal fibrosis. PMID- 26572752 TI - Outcomes of Resected Colorectal Cancer Lung Metastases in Routine Clinical Practice: A Population-Based Study. AB - BACKGROUND: Previous reports on the outcome of surgery for colorectal cancer lung metastases (CRCLM) have come from high-volume centers. This report describes the outcomes achieved in the general population of Ontario. METHODS: All patients in Ontario who underwent resection of CRCLM between 1994 and 2009 were identified using the population-based Ontario Cancer Registry. Electronic treatment records identified surgical procedures and chemotherapy delivery. This report describes the volume of resections for CRCLM in relation to the incidence of colorectal cancer (CRC). Temporal trends in practice are described during three periods: 1994-1999, 2000-2004, and 2005-2009. Overall survival (OS) and cancer-specific survival (CSS) were measured from the time of lung resection. RESULTS: A total of 709 patients underwent resection of CRCLM. Between 1994 and 2009, surgical volume increased 190 %, from 1 resection for every 282 incident cases to 1 resection for every 97 incident cases (p < 0.001). The use surgery for CRCLM varied considerably between regions, from 1 resection per 95 incident cases to 1 resection per 212 incident cases (p = 0.021). Use of perioperative chemotherapy increased during study periods, from 22 % (28/130) to 34 % (73/217) to 40 % (146/362; p < 0.001). Utilization rates varied across geographic regions (range 21-59 %; p = 0.005). The OS rate was 40 % [95 % confidence interval (CI) 36-44 %] at 5 years and 27 % (95 % CI 23-31 %) at 10 years. The CSS rate was 42 % (95 % CI 38-46 %) at 5 years and 32 % (95 % CI 27-37 %) at 10 years. CONCLUSIONS: A proportion of patients with resected CRCLM will achieve long-term survival. Outcomes in routine practice are comparable with those reported for high-volume centers. The use of surgery varies considerably across Ontario. PMID- 26572753 TI - Routine Admission to Intensive Care Unit After Cytoreductive Surgery and Heated Intraperitoneal Chemotherapy: Not Always a Requirement. AB - BACKGROUND: Routine postoperative intensive care unit (ICU) observation of patients undergoing cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) is driven by historically reported morbidity and mortality data. The validity of this practice and the criteria for ICU admission have not been elucidated. METHODS: A prospectively maintained database of 1146 CRS/HIPEC procedures performed from December 1991 to 2014 was retrospectively analyzed. Patients with routine postoperative ICU admission were compared with patients sent directly to the surgical floor. To test the safety of non-ICU care practice, patients with less than 48 h ICU admission were compared with patients directly admitted to the floor. Demographics, primary tumor site, comorbidities, estimated blood loss (EBL), extent of CRS, Eastern Cooperative Oncology Group (ECOG) status, and overall survival were analyzed. RESULTS: Complete data were available for 1064 CRS/HIPEC procedures, of which 244 cases (22.93 %) did not require ICU admission. Multivariate logistic regression identified age [odds ratio (OR) 1.024; p = 0.02], EBL (OR 1.002; p < 0.0001), number of resected organs (OR 1.308; p = 0.01) and ECOG > 2 (OR 6.387; p = 0.003) as predictive variables of postoperative ICU admission. The cohort directly admitted to the floor demonstrated less minor grade I/II morbidity (29 vs. 47 %; p < 0.0001) and similar grade III/IV major morbidity (16.5 vs. 13.4 %; p = 0.3) than the patients admitted to the ICU for less than 48 h. CONCLUSIONS: ICU observation is not routinely required for all patients treated with CRS/HIPEC. Selective ICU admission based on ECOG status, nutritional status, age, EBL, and CRS extent is safe, with potential implications for hospitalization cost for these complex cases. PMID- 26572754 TI - The Role of Ki-67 and Pre-cytoreduction Parameters in Selecting Diffuse Malignant Peritoneal Mesothelioma (DMPM) Patients for Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC). AB - BACKGROUND: We conducted a prognostic analysis of preoperative parameters and Ki 67 determination to develop selection criteria for cytoreductive surgery (CRS) and HIPEC in patients with diffuse malignant peritoneal mesothelioma (DMPM). METHODS: DMPM patients treated with CRS and HIPEC at NCI of Milan participated in this study. Multivariate analysis was conducted using Cox proportional hazard model and conditional inference tree method to select independent predictors of overall survival (OS) from the followings pre-cytoreduction parameters: age, sex, ECOG performance status, Charlson comorbidity index, previous systemic chemotherapy, CA-125, histological subtype (epithelioid vs. biphasic/sarcomatoid), Ki-67 (determined with immunohistochemistry), and peritoneal cancer index (PCI). RESULTS: A total of 117 patients (male/female: 67/50) with median age of 60.5 (range 22-75) years were included. Eighty-three patients had ECOG performance status = 0, median Charlson comorbidity index was 4 (range 2-9), and 102 cases had epithelioid subtype. Median Ki-67 was 5 % (range 1 60). Ninety-four (80.3 %) cases were optimally cytoreduced. The Cox analysis identified Ki-67, PCI, and histological subtype as independent prognosticators of OS. Conditional inference tree method identified three prognostic subsets: (I) Ki 67 <= 9 %; (II) Ki-67 > 9 % and PCI <= 17; and (III) Ki-67 > 9 % and PCI > 17. The median OS for subsets I, II, and III were, 86.6, 63.2, and 10.3 months, respectively. CONCLUSIONS: Ki-67 is a powerful prognosticator that allows, along with PCI, and histological subtype, a good prediction of OS in patients with DMPM. Patients with Ki-67 > 9 % and PCI > 17 are unlikely to benefit from the procedure and should be considered for other treatment protocols. PMID- 26572755 TI - Computed Tomography-Based Limb Volume Measurements for Isolated Limb Infusion in Melanoma. AB - BACKGROUND: Despite advances in cross-sectional imaging, chemotherapeutic dosing for isolated limb infusion (ILI) in melanoma is currently calculated through cumbersome and potentially imprecise manual measurements. The primary objective of this study was to examine the feasibility of using computed tomography (CT) to calculate limb volume, its concordance with manual measurement, and its ability to predict clinical response and toxicity in patients undergoing ILI. METHODS: A retrospective analysis of all patients undergoing lower extremity ILI at Duke University Medical Center between 2003 and 2014 was performed. Data pertaining to manually measured limb volume, chemotherapeutic dosing, and patient outcome was obtained. CT-based measurements of limb volume were performed in all patients for whom imaging was available and subsequently compared with manually measured values. RESULTS: CT data were sufficient for measurement in 73 patients. The mean measurement time was 4.61 +/- 2.13 min. Although average CT-based measurements were 1.20 L higher in the case of lower limbs, they correlated well with those obtained manually (r (2) = 0.90). Unlike manual measurement, patients with complete responses to chemotherapy had smaller limb volumes than those with disease progression as measured by CT (9.3 vs. 10.7 L; p = .038). Patients suffering grade 3 and 4 toxicities also had statistically lower limb volumes as measured by CT than those who did not (p < .05). CONCLUSIONS: CT-based limb volume measurement is feasible for chemotherapy dosing in patients undergoing ILI for melanoma and has predictive value with respect to clinical response and toxicity. PMID- 26572756 TI - Efficacy of recreational football on bone health, body composition, and physical functioning in men with prostate cancer undergoing androgen deprivation therapy: 32-week follow-up of the FC prostate randomised controlled trial. AB - Androgen deprivation therapy (ADT) for prostate cancer (PCa) impairs musculoskeletal health. We evaluated the efficacy of 32-week football training on bone mineral density (BMD) and physical functioning in men undergoing ADT for PCa. Football training improved the femoral shaft and total hip BMD and physical functioning parameters compared to control. INTRODUCTION: ADT is a mainstay in PCa management. Side effects include decreased bone and muscle strength and increased fracture rates. The purpose of the present study was to evaluate the effects of 32 weeks of football training on BMD, bone turnover markers (BTMs), body composition, and physical functioning in men with PCa undergoing ADT. METHODS: Men receiving ADT >6 months (n = 57) were randomly allocated to a football training group (FTG) (n = 29) practising 2-3 times per week for 45-60 min or to a standard care control group (CON) (n = 28) for 32 weeks. Outcomes were total hip, femoral shaft, femoral neck and lumbar spine (L2-L4) BMD and systemic BTMs (procollagen type 1 amino-terminal propeptide, osteocalcin, C terminal telopeptide of type 1 collagen). Additionally, physical functioning (postural balance, jump height, repeated chair rise, stair climbing) was evaluated. RESULTS: Thirty-two-week follow-up measures were obtained for FTG (n = 21) and for CON (n = 20), respectively. Analysis of mean changes from baseline to 32 weeks showed significant differences between FTG and CON in right (0.015 g/cm(2)) and left (0.017 g/cm(2)) total hip and in right (0.018 g/cm(2)) and left (0.024 g/cm(2)) femoral shaft BMD, jump height (1.7 cm) and stair climbing (-0.21 s) all in favour of FTG (p < 0.05). No other significant between-group differences were observed. CONCLUSIONS: Compared to standard care, 32 weeks of football training improved BMD at clinically important femoral sites and parameters of physical functioning in men undergoing ADT for PCa. PMID- 26572757 TI - Timing of low bone mineral density and predictors of bone mineral density trajectory in children on long-term warfarin: a longitudinal study. AB - We studied bone mineral density (BMD) of children exposed to long-term warfarin. BMD Z-scores <= -2.0 were estimated to occur in less than one fifth of the patients after 10 years of warfarin exposure, and BMI and growth hormone deficiency predicted BMD changes over time. These predictors can help identify high-risk patients. INTRODUCTION: Children with chronic diseases are at increased risk of developing thrombosis, which may require long-term warfarin therapy. Warfarin could further jeopardize the bone health of a population already at risk for bone fragility. Our objective was to investigate the occurrence and timing of low bone mineral density (BMD) and the predictors that influence BMD trajectory in children receiving warfarin for >1 year. METHODS: We analyzed the results of an institutional protocol that includes dual-energy X-ray absorptiometry, with or without spinal X-rays and laboratory biomarkers, as required. RESULTS: Low BMD (age, sex, race, and height-for-age-Z-score adjusted BMD Z-score <= -2.0) was detected in 13 % (9/70) of the patients at some point during their follow-up; these patients were more likely to have complex underlying medical conditions and low body mass index (BMI) percentile. BMD Z-scores remained within normal range in 87 % of children. Survival analysis showed that the estimated 10-year abnormal BMD-free rate for the entire group was 81 % (95 % confidence interval [CI] 69 to 93 %). Trajectory analysis revealed that BMI percentiles at baseline and growth hormone deficiency (GHD) were associated with lower BMD Z-scores at the first assessment, whereas baseline BMI percentile was the only predictor of BMD Z-score over time. CONCLUSIONS: Our findings identified BMI and GHD as risk factors influencing BMD in children exposed to long-term warfarin, creating an opportunity for early detection and intervention in these patients. PMID- 26572758 TI - Serum carcinoembryonic antigen-related cell adhesion molecule 1 level in postmenopausal women: correlation with beta-catenin and bone mineral density. AB - Many epidemiological studies have shown that in some tumors carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) and beta-catenin appear to be related. However, it remains to be established whether CEACAM1 is related to beta catenin in osteoporosis. Here, we reveal that CEACAM1 might influence the canonical Wnt/beta-catenin pathway to modulate bone metabolism in postmenopausal osteoporosis. INTRODUCTION: The aim of this study is to assess the serum level of CEACAM1 in postmenopausal women and its correlation with beta-catenin and bone mineral density (BMD). METHODS: The BMD was measured at the lumbar spine (L1-L4) or the femoral neck using dual-energy X-ray absorptiometry (DXA). Serum CEACAM1, beta-catenin, receptor activator of nuclear factor kappa-B (RANKL), osteoprotegerin (OPG), beta-isomerized C-terminal crosslinking of type I collagen (beta-CTX), intact N-terminal propeptide of type I collagen (PINP), estradiol, and insulin were measured in 350 postmenopausal women. Patients were divided according to lumbar spine or femur neck T-scores into osteoporosis (group I), osteopenia (group II), and normal bone mineral density, the latter serving as control. RESULTS: Serum CEACAM1 levels were significantly lower in group I and II compared to those in control subjects (P < 0.001). Serum CEACAM1 levels correlated positively with beta-catenin and BMD, but correlated negatively to the ratio between RANKL and OPG. CONCLUSION: This study provides evidence that decreased serum CEACAM1 levels are related to low BMD in postmenopausal women, and that serum CEACAM1 levels correlated positively to beta-catenin. It suggests that CEACAM1 might influence the canonical Wnt/beta-catenin pathway to modulate bone metabolism. PMID- 26572759 TI - Interleukin-35 upregulates OPG and inhibits RANKL in mice with collagen-induced arthritis and fibroblast-like synoviocytes. AB - IL-35 is a novel anti-inflammatory cytokine, but the exact role of IL-35 in the progression of RA remains unclear, especially associated with osteoporosis and bone erosion. The present research has not been reported. Our purpose is to study how IL-35 affects RA bone destruction. INTRODUCTION: This study investigated the effect of interleukin-35 (IL-35) on OPG and RANKL expression in collagen-induced arthritis (CIA) in rats and in cultured fibroblast-like synoviocytes (FLS). METHODS: Thirty DBA/1J mice were randomly assigned to three groups (n = 10 per group): the control group, the CIA group, and the CIA + IL-35 group. Collagen induced arthritis was induced by immunization with collagen. IL-35 was intraperitoneally injected daily for 10 days, starting from the 24(th) day after immunization. FLS cells were isolated and cultured from CIA. The expression of IL 17, RANKL, and OPG was determined by RT-PCR and Western blot. Each experiment was repeated three times. RESULTS: CIA mice exhibited arthritis symptoms on day 24, followed by a rapid progression of arthritis. The expression of IL-17 and RANKL was increased and the expression of OPG was decreased in CIA mice compared with control mice. IL-35 treatment inhibited the development of arthritis in CIA mice, accompanied by a decrease in the expression of IL-17 and RANKL and an increase in the expression of OPG. Furthermore, IL-35 dose-dependently inhibited the expression of RANKL and increased the expression of OPG in cultured FLS cells. CONCLUSION: IL-35 inhibits RANKL expression and increases OPG expression in CIA mice. IL-35 may be used for treating rheumatoid arthritis. PMID- 26572760 TI - Aldehyde dehydrogenase isoform 1 (ALDH1) expression as a predictor of radiosensitivity in laryngeal cancer. AB - BACKGROUND: Aldehyde dehydrogenase isoform 1 (ALDH1) has been shown to be a marker of cancer stem cells (CSCs). These stem cells may be responsible for tumour perpetuation as well as local and distant invasion. Several studies have shown that CSCs are more chemoradiotherapy (CRT)-resistant and may be responsible for tumour recurrence. Other studies, in contrast, have found ALDH1 expression to be indicative of a better prognosis. METHODS: We retrospectively evaluated 84 patients diagnosed and treated for laryngeal cancer between 2006 and 2011. All patients underwent curative-intent radiotherapy or CRT at our institution. 57 of the 84 tumour samples contained sufficient material for ALDH1 assessment. RESULTS: ALDH1 expression was detected in 17.5 % (10/57) of the tissue samples. None of the tumours from stage I patients tested positive for ALDH1. The relapse rate in ALDH1 + patients was 10 versus 51.2 % for ALDH1-. No differences in overall survival were observed between the groups; however, disease-free survival was 90 % for the ALDH1 + group versus 48.9 % for ALDH1- patients (p = 0.034). CONCLUSION: The patients in this study with ALDH1 + tumours had better outcomes than their counterparts with ALDH1- tumours. This finding suggests that not all CSCs are resistant to conventional cancer treatments. It may also imply that new methods of correctly identifying these cells are needed. PMID- 26572761 TI - Renal background correction and measurement of split renal function: The challenge : Editorial Comment: EJNM-D-15-00322, M Donald Blaufox, MD, PhD. PMID- 26572762 TI - Tau imaging in neurodegenerative diseases. AB - Aggregated tau protein is a major neuropathological substrate central to the pathophysiology of neurodegenerative diseases such as Alzheimer's disease (AD), frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration and chronic traumatic encephalopathy. In AD, it has been shown that the density of hyperphosphorylated tau tangles correlates closely with neuronal dysfunction and cell death, unlike beta-amyloid. Until now, diagnostic and pathologic information about tau deposition has only been available from invasive techniques such as brain biopsy or autopsy. The recent development of selective in-vivo tau PET imaging ligands including [(18)F]THK523, [(18)F]THK5117, [(18)F]THK5105 and [(18)F]THK5351, [(18)F]AV1451(T807) and [(11)C]PBB3 has provided information about the role of tau in the early phases of neurodegenerative diseases, and provided support for diagnosis, prognosis, and imaging biomarkers to track disease progression. Moreover, the spatial and longitudinal relationship of tau distribution compared with beta - amyloid and other pathologies in these diseases can be mapped. In this review, we discuss the role of aggregated tau in tauopathies, the challenges posed in developing selective tau ligands as biomarkers, the state of development in tau tracers, and the new clinical information that has been uncovered, as well as the opportunities for improving diagnosis and designing clinical trials in the future. PMID- 26572763 TI - A "new/old method" for TSH stimulation: could a third way to prepare DTC patients for (131)I remnant ablation possibly exist? PMID- 26572764 TI - [Differential diagnosis of sternoclavicular arthritis]. AB - A 47-year-old male patient presented with a 6-month history of a painful swelling in the region of the right sternoclavicular joint together with fatigue. Initial investigations including X-rays of the sternoclavicular joint did not reveal any pathological conditions. Eventually, a CT scan revealed marked joint destruction, pulmonary condensation, and enlargement of the adrenal glands. Subsequent procedures, such as joint fluid aspiration and bronchoalveolar lavage, proved to be positive for Mycobacterium tuberculosis. After initiation of a standard combination therapy (four tuberculostatic drugs) the general condition of the patient stabilized and he was discharged from hospital after 4 weeks. PMID- 26572765 TI - Learning curve of self-taught laparoscopic liver surgeons in left lateral sectionectomy: results from an international multi-institutional analysis on 245 cases. AB - BACKGROUND: Laparoscopy was suggested as gold standard for left lateral sectionectomy (LLS), thanks to recognized benefits compared to open approach. Aim of this study was to define learning curve (LC) of laparoscopic LLS (LLLS) using operative time (OT) as tool to analyze outcome of procedures performed by four experienced surgeons. Reproducibility and safety of LC in LLLS among independent surgeons were also analyzed as essential features of "standard procedure" concept. METHODS: LLLS performed by four experienced surgeons was collected. Multivariate analysis was carried out to screen factors affecting OT. A cumulative LC was created calculating median OT. Skewness of OT was analyzed, and ROC curve was carried out to identify the cutoff for LC. The impact of LC on outcomes (morbidity and mortality, blood loss, conversions, surgical margins and length of stay) was determined. RESULTS: A total of 245 LLLSs were collected. Conversion rate was 1.2 %. Median OT was 141 min, blood loss 100 mL, morbidity 11.4 % and mortality 0.4 %. "Associated procedures" was the only independent factor affecting OT. The skewness of the OT was calculated, and the cutoff point for LC was determined after 15 LLLSs. LLLS performed during and after LC period had similar outcomes. CONCLUSION: LLLS is feasible with low morbidity, mortality and conversion rate. LC in LLLS is shorter compared to minor liver resections. Furthermore, it is reproducible and safe since it does not negatively affect clinical outcome. A reproducible, safe and short LC contributes to considering laparoscopy as the gold standard approach to perform LLS. PMID- 26572766 TI - Total endoscopic repair of unroofed coronary sinus syndrome via right mini thoracotomy. AB - Unroofed coronary sinus syndrome (URCS) is a rare congenital cardiac anomaly. Recently, cardiac surgery using a minimally invasive approach has become the preferred treatment, affording better cosmetic results and a more rapid post operative recovery than the traditional method. We report the case of a 54-year old male in whom partial URCS was treated via a totally endoscopic repair technique featuring right mini-thoracotomy. PMID- 26572767 TI - Pharmaceuticals May Disrupt Natural Chemical Information Flows and Species Interactions in Aquatic Systems: Ideas and Perspectives on a Hidden Global Change. AB - Pharmaceuticals consumption by humans and animals is increasing substantially, leading to unprecedented levels of these compounds in aquatic environments worldwide. Recent findings that concentrations reach levels that can directly have negative effects on organisms are important per se, but also sound an alarm for other potentially more pervasive effects that arise from the interconnected nature of ecological communities. Aquatic organisms use chemical cues to navigate numerous challenges, including the location of mates and food, and the avoidance of natural enemies. Low concentrations of pharmaceuticals can disrupt this "smellscape" of information leading to maladaptive responses. Furthermore, direct effects of pharmaceuticals on the traits and abundance of one species can cascade through a community, indirectly affecting other species. We review mechanisms by which pharmaceuticals in surface waters can disrupt natural chemical information flows and species interactions. Pharmaceuticals form a new class of chemical threats, which could have far-reaching implications for ecosystem functioning and conservation management. PMID- 26572769 TI - Invitation to the 17th international congress on photosynthesis research in 2016: photosynthesis in a changing world. AB - The 17th International Congress on Photosynthesis will be held from August 7 to 12, 2016 in Maastricht, The Netherlands. The congress will include an opening reception, 15 plenary lectures, 28 scientific symposia, many poster sessions, displays by scientific companies, excursions, congress dinner, social activities, and the first photosynthesis soccer world championship. See http://www.ps2016.com/ . The congress is organized as an official event of the International Society of Photosynthesis Research (see http://www.photosynthesisresearch.org/). PMID- 26572770 TI - Cardiac-Derived Extracellular Matrix Enhances Cardiogenic Properties of Human Cardiac Progenitor Cells. AB - The use of biomaterials has been demonstrated as a viable strategy to promote cell survival and cardiac repair. However, limitations on combinational cell biomaterial therapies exist, as cellular behavior is influenced by the microenvironment and physical characteristics of the material. Among the different scaffolds employed for cardiac tissue engineering, a myocardial matrix hydrogel has been shown to promote cardiogenesis in murine cardiac progenitor cells (mCPCs) in vitro. In this study, we investigated the influence of the hydrogel on Sca-1-like human fetal and adult CPCs (fCPCs and aCPCs) when encapsulated in three-dimensional (3D) material in vitro. fCPCs encapsulated in the myocardial matrix showed an increase in the gene expression level of cardiac markers GATA-4 and MLC2v and the vascular marker vascular endothelial growth factor receptor 2 (VEGFR2) after 4 days in culture, and a significant increase in GATA-4 up to 1 week. Increased gene expression levels of Nkx2.5, MEF2c, VEGFR2, and CD31 were also observed when aCPCs were cultured in the matrix compared to collagen. Cell survival was sustained in both hydrogels up to 1 week in culture with the myocardial matrix capable of enhancing the expression of the proliferation marker Ki-67 after 4 days in culture. When encapsulated CPCs were treated with H2O2, an improved survival of the cells cultured in the myocardial matrix was observed. Finally, we evaluated the use of the myocardial matrix as hydrogel for in vivo cell transplantation and demonstrated that the gelation properties of the hydrogel are not influenced by the cells. In summary, we showed that the myocardial matrix hydrogel promotes human CPC cardiogenic potential, proliferation, and survival and is a favorable hydrogel for 3D in vitro culture. Furthermore, we demonstrated the in vivo applicability of the matrix as a potential vehicle for cell transplantation. PMID- 26572771 TI - AAHFN Leadership Message. PMID- 26572772 TI - Comparison of different strategies for acute ST-segment elevation myocardial infarction with high thrombus burden in clinical practice: Symptom-free outcome at one year. AB - OBJECTIVE: The aim of this study was to evaluate the clinical effects of different strategies for preventing coronary microvascular obstruction in ST elevation myocardial infarction (STEMI) patients with a high thrombus-burden plaque. METHODS: Between January, 2007 and December, 2012, 354 patients suffering from STEMI with high thrombus-burden were enrolled and divided into three groups as the first group received a GP IIb/IIIa inhibitor, and the second group received a distal protective device, and the third group was treated with primary PCI alone. RESULTS: A high percentage of patients in the GP IIb/IIIa inhibitor (96.8% and 90.5%), distal protective device (99.3% and 87.6%) had better thirty day and one-year symptom-free outcomes when compared with PCI only group (91.6% and 65.6%) (P = 0.008 and P < 0.001; respectively). CONCLUSIONS: Treatment with intracoronary GP IIb/IIIa inhibitor injection or distal protection device to prevent coronary microvascular obstruction was demonstrated to increase the occurrences of thirty-day and one-year symptom-free outcomes; thus, these treatments can help decrease post-MI medical care costs. PMID- 26572773 TI - Development of a pain management algorithm for intensive care units. AB - OBJECTIVES: To develop a pain management algorithm for intensive care unit (ICU) patients and to evaluate the psychometric properties of the translated tools used in the algorithm. BACKGROUND: Many ICU patients experience pain. However, an evidence-based algorithm for pain management does not exist. METHODS: Literature review, expert panel, and pilot testing were used to develop the algorithm. The tools were evaluated for inter-rater reliability between two nurses. Discriminant validity was evaluated by comparing pain during turning and rest. RESULTS: An algorithm was developed. The Behavioral Pain Scale (BPS) and the Behavioral Pain Scale-Non Intubated (BPS-NI) discriminated between pain scores during turning and rest. Inter-rater reliability for the BPS varied from moderate (0.46) to very good (1.00). Inter-rater reliability for the BPS-NI varied from fair (0.21) to good (0.63). CONCLUSIONS: The content of the pain management algorithm is consistent with the latest clinical practice guideline recommendations. It may be a useful tool to improve pain assessment and management in adult ICU patients. PMID- 26572774 TI - An improved alkaline direct formate paper microfluidic fuel cell. AB - Paper-based microfluidic fuel cells (MFCs) are a potential replacement for traditional FCs and batteries due to their low cost, portability, and simplicity to operate. In MFCs, separate solutions of fuel and oxidant migrate through paper due to capillary action and laminar flow and, upon contact with each other and catalyst, produce electricity. In the present work, we describe an improved microfluidic paper-based direct formate FC (DFFC) employing formate and hydrogen peroxide as the anode fuel and cathode oxidant, respectively. The dimensions of the lateral column, current collectors, and cathode were optimized. A maximum power density of 2.53 mW/cm(2) was achieved with a DFFC of surface area 3.0 cm(2) , steel mesh as current collector, 5% carbon to paint mass ratio for cathode electrode and, 30% hydrogen peroxide. The longevity of the MFC's detailed herein is greater than eight hours with continuous flow of streams. In a series configuration, the MFCs generate sufficient energy to power light-emitting diodes and a handheld calculator. PMID- 26572775 TI - Infectious basophilia? PMID- 26572777 TI - Hematologic improvement with iron chelation therapy in acquired anemias. PMID- 26572776 TI - Prospective influenza vaccine safety surveillance using fresh data in the Sentinel System. AB - PURPOSE: To develop the infrastructure to conduct timely active surveillance for safety of influenza vaccines and other medical countermeasures in the Sentinel System (formerly the Mini-Sentinel Pilot), a Food and Drug Administration sponsored national surveillance system that typically relies on data that are mature, settled, and updated quarterly. METHODS: Three Data Partners provided their earliest available ("fresh") cumulative claims data on influenza vaccination and health outcomes 3-4 times on a staggered basis during the 2013 2014 influenza season, collectively producing 10 data updates. We monitored anaphylaxis in the entire population using a cohort design and seizures in children <=4 years of age using both a self-controlled risk interval design (primary) and a cohort design (secondary). After each data update, we conducted sequential analysis for inactivated (IIV) and live (LAIV) influenza vaccines using the Maximized Sequential Probability Ratio Test, adjusting for data-lag. RESULTS: Most of the 10 sequential analyses were conducted within 6 weeks of the last care-date in the cumulative dataset. A total of 6 682 336 doses of IIV and 782 125 doses of LAIV were captured. The primary analyses did not identify any statistical signals following IIV or LAIV. In secondary analysis, the risk of seizures was higher following concomitant IIV and PCV13 than historically after IIV in 6- to 23-month-olds (relative risk = 2.7), which requires further investigation. CONCLUSIONS: The Sentinel System can implement a sequential analysis system that uses fresh data for medical product safety surveillance. Active surveillance using sequential analysis of fresh data holds promise for detecting clinically significant health risks early. Limitations of employing fresh data for surveillance include cost and the need for careful scrutiny of signals. (c) 2015 The Authors. Pharmacoepidemiology and Drug Safety Published by John Wiley & Sons Ltd. PMID- 26572778 TI - Sun Exposure and Sun Protection at Primary Schools in The Netherlands: A Cross Sectional Study. AB - BACKGROUND: In The Netherlands, skin cancer incidence rates have dramatically increased during the last decades. Exposure to ultraviolet radiation is the most important environmental risk factor for developing skin cancer. AIMS: The present study aimed to determine the level of sun exposure and sun protection of children at Dutch primary schools. MATERIALS AND METHODS: Registered members of an Internet panel of a private research company with a child 6 to 12 years of age completed a standardized questionnaire on sun exposure, sun protection and sunburn for their child on school days during the spring and summer. RESULTS: A total of 1103 parents completed the questionnaire. Most parents reported that their child spent 31 minutes to 1 hour (39.7%) or 1 hour to 1.5 hours (26.1%) outside at school during the spring and summer, 29.3% reported that sunscreen is always or often applied to the skin of their child in the morning on school days, 37% reported that they always or often paid attention to sun protection when selecting their child's outfit, 19.3% of the parents stated that their child could not play in the shade outside at school, and 19.9% of the parents reported that their child had ever had a sunburn at school. DISCUSSION: With most children, this consistent and repetitive pattern of sun exposure at school will probably lead to damage of exposed skin, because sun protection is insufficiently achieved among children during school days in the spring and summer. CONCLUSIONS: Future school-based interventions are necessary to alert and change behavior of parents, children, and primary school teachers. PMID- 26572779 TI - Can a Computerized Simulator Assess Skill Level and Improvement in Performance of ERCP? AB - BACKGROUND: Endoscopic retrograde cholangiography (ERCP) is a challenging procedure with considerable risk. Computerized simulators are valuable in training for flexible endoscopy, but little data exist for their use in ERCP training. AIM: To determine a simulator's ability to assess the level of ERCP skill and its responsiveness over time to increasing trainee experience. MATERIALS AND METHODS: In this prospective parallel-arm cohort study, six novice gastroenterology fellows and four gastroenterology faculty with expertise in ERCP completed four simulated baseline cases and the same four cases at a later date. This study took place at a surgical skills center at an academic tertiary referral center. The primary outcome was the total time to complete the ERCP procedure. RESULTS: For the baseline session, experts had a shorter total procedure time than novices (444.0 vs. 616.9 s; least squares mean; p = 0.026). There was no significant difference between experts and novices in the difference of total procedure time between session 1 and session 2 (-200.3 vs. -164.4; least squares mean; p = 0.402). CONCLUSIONS: The simulator was able to differentiate experts from novices for the primary outcome of total procedure time. The simulator was not responsive to an increase in trainee experience over time. PMID- 26572780 TI - A Systematic Review of Esophageal MicroRNA Markers for Diagnosis and Monitoring of Barrett's Esophagus. AB - BACKGROUND: Esophageal epithelial microRNAs may be used to diagnose Barrett's esophagus (BE) and possibly monitor its progression to esophageal adenocarcinoma (EAC). AIMS: We reviewed studies that have investigated this to identify microRNAs with high biomarker potential for screening and disease monitoring in BE. METHODS: PubMed and EMBASE databases were searched for studies that quantified esophageal epithelial microRNAs. Publications reporting microRNA comparisons of normal, non-dysplastic BE, BE with high-grade dysplasia (HGD), and EAC tissues using both unbiased discovery and independent validation phases were reviewed. RESULTS: Eleven studies on microRNA expression differences between normal epithelium and non-dysplastic BE (seven studies), HGD (4) or EAC (7), or between non-dysplastic BE and HGD (3) or EAC (6) were identified, and the findings of their validation phase were analyzed. Increased miR-192, -194, and 215, and reduced miR-203 and -205 expression in BE compared to normal was noticed by all 4-6 of the seven studies that examined these microRNAs. In heterogeneity tests of the reported fold-change values, the I (2) statistics were 7.9-17.1 % (all P < 0.05). Elevated miR-192, -194, and -215, and diminished miR-203 and -205 levels were also noted for comparisons of HGD or EAC against normal. In contrast, a consistent microRNA expression difference was absent for the comparisons of HGD or EAC against BE. CONCLUSIONS: MicroRNAs miR-192, -194, -203, -205, and -215 are promising tissue biomarkers for diagnosing BE. Cross-sectional data suggest that microRNAs may have a limited role in separating BE from HGD/EAC epithelia but need further testing in longitudinal follow-up studies. PMID- 26572781 TI - Genetic Risk Scores Implicated in Adult Bone Fragility Associate With Pediatric Bone Density. AB - Using adult identified bone mineral density (BMD) loci, we calculated genetic risk scores (GRS) to determine if they were associated with changes in BMD during childhood. Longitudinal data from the Bone Mineral Density in Childhood Study were analyzed (N = 798, 54% female, all European ancestry). Participants had up to 6 annual dual energy X-ray scans, from which areal BMD (aBMD) Z-scores for the spine, total hip, and femoral neck were estimated, as well as total body less head bone mineral content (TBLH-BMC) Z-scores. Sixty-three single-nucleotide polymorphisms (SNPs) were genotyped, and the percentage of BMD-lowering alleles carried was calculated (overall adult GRS). Subtype GRS that include SNPs associated with fracture risk, pediatric BMD, WNT signaling, RANK-RANKL-OPG, and mesenchymal stem cell differentiation were also calculated. Linear mixed effects models were used to test associations between each GRS and bone Z-scores, and if any association differed by sex and/or chronological age. The overall adult, fracture, and WNT signaling GRS were associated with lower Z-scores (eg, spine aBMD Z-score: betaadult = -0.04, p = 3.4 * 10(-7) ; betafracture = -0.02, p = 8.9 * 10(-6) ; betaWNT = -0.01, p = 3.9 * 10(-4) ). The overall adult GRS was more strongly associated with lower Z-scores in females (p-interaction <= 0.05 for all sites). The fracture GRS was more strongly associated with lower Z-scores with increasing age (p-interaction <= 0.05 for all sites). The WNT GRS associations remained consistent for both sexes and all ages (p-interaction > 0.05 for all sites). The RANK-RANKL-OPG GRS was more strongly associated in females with increasing age (p-interaction < 0.05 for all sites). The mesenchymal stem cell GRS was associated with lower total hip and femoral neck Z-scores, in both boys and girls, across all ages. No associations were observed between the pediatric GRS and bone Z-scores. In conclusion, adult identified BMD loci associated with BMD and BMC in the pediatric setting, especially in females and in loci involved in fracture risk and WNT signaling. PMID- 26572783 TI - Erratum to: Evidence of an age-related correlation of ovarian reserve and FMR1 repeat number among women with "normal" CGG repeat status. PMID- 26572782 TI - Quantitative and qualitative trophectoderm grading allows for prediction of live birth and gender. AB - PURPOSE: Prolonged in vitro culture is thought to affect pre- and postnatal development of the embryo. This prospective study was set up to determine whether quality/size of inner cell mass (ICM) (from which the fetus ultimately develops) and trophectoderm (TE) (from which the placenta ultimately develops) is reflected in birth and placental weight, healthy live-birth rate, and gender after fresh and frozen single blastocyst transfer. METHODS: In 225 patients, qualitative scoring of blastocysts was done according to the criteria expansion, ICM, and TE appearance. In parallel, all three parameters were quantified semi-automatically. RESULTS: TE quality and cell number were the only parameters that predicted treatment outcome. In detail, pregnancies that continued on to a live birth could be distinguished from those pregnancies that aborted on the basis of TE grade and cell number. Male blastocysts had a 2.53 higher chance of showing TE of quality A compared to female ones. There was no correlation between the appearance of both cell lineages and birth or placental weight, respectively. CONCLUSIONS: The presented correlation of TE with outcome indicates that TE scoring could replace ICM scoring in terms of priority. This would automatically require a rethinking process in terms of blastocyst selection and cryopreservation strategy. PMID- 26572784 TI - Cherenkov luminescence measurements with digital silicon photomultipliers: a feasibility study. AB - BACKGROUND: A feasibility study was done to assess the capability of digital silicon photomultipliers to measure the Cherenkov luminescence emitted by a beta source. Cherenkov luminescence imaging (CLI) is possible with a charge coupled device (CCD) based technology, but a stand-alone technique for quantitative activity measurements based on Cherenkov luminescence has not yet been developed. Silicon photomultipliers (SiPMs) are photon counting devices with a fast impulse response and can potentially be used to quantify beta-emitting radiotracer distributions by CLI. METHODS: In this study, a Philips digital photon counting (PDPC) silicon photomultiplier detector was evaluated for measuring Cherenkov luminescence. The PDPC detector is a matrix of avalanche photodiodes, which were read one at a time in a dark count map (DCM) measurement mode (much like a CCD). This reduces the device active area but allows the information from a single avalanche photodiode to be preserved, which is not possible with analog SiPMs. An algorithm to reject the noisiest photodiodes and to correct the measured count rate for the dark current was developed. RESULTS: The results show that, in DCM mode and at (10-13) degrees C, the PDPC has a dynamic response to different levels of Cherenkov luminescence emitted by a beta source and transmitted through an opaque medium. This suggests the potential for this approach to provide quantitative activity measurements. Interestingly, the potential use of the PDPC in DCM mode for direct imaging of Cherenkov luminescence, as a opposed to a scalar measurement device, was also apparent. CONCLUSIONS: We showed that a PDPC tile in DCM mode is able to detect and image a beta source through its Cherenkov radiation emission. The detector's dynamic response to different levels of radiation suggests its potential quantitative capabilities, and the DCM mode allows imaging with a better spatial resolution than the conventional event triggered mode. Finally, the same acquisition procedure and data processing could be employed also for other low light levels applications, such as bioluminescence. PMID- 26572785 TI - The meningeal lymphatic system: a route for HIV brain migration? AB - Two innovative studies recently identified functional lymphatic structures in the meninges that may influence the development of HIV-associated neurological disorders (HAND). Until now, blood vessels were assumed to be the sole transport system by which HIV-infected monocytes entered the brain by bypassing a potentially hostile blood-brain barrier through inflammatory-mediated semi permeability. A cascade of specific chemokine signals promote monocyte migration from blood vessels to surrounding brain tissues via a well-supported endothelium, where the cells differentiate into tissue macrophages capable of productive HIV infection. Lymphatic vessels on the other hand are more loosely organized than blood vessels. They absorb interstitial fluid from bodily tissues where HIV may persist and exchange a variety of immune cells (CD4(+) T cells, monocytes, macrophages, and dendritic cells) with surrounding tissues through discontinuous endothelial junctions. We propose that the newly discovered meningeal lymphatics are key to HIV migration among viral reservoirs and brain tissue during periods of undetectable plasma viral loads due to suppressive combinational antiretroviral therapy, thus redefining the migration process in terms of a blood lymphatic transport system. PMID- 26572786 TI - Central nervous system penetration effectiveness of antiretroviral drugs and neuropsychological impairment in the Ontario HIV Treatment Network Cohort Study. AB - Since the introduction of combination antiretroviral therapy (cART), the incidence of severe HIV-associated neurocognitive impairment has declined significantly, whereas the prevalence of the milder forms has increased. Studies suggest that better distribution of cART drugs into the CNS may be important in reducing viral replication in the CNS and in reducing HIV-related brain injury. Correlates of neuropsychological (NP) performance were determined in 417 participants of the Ontario HIV Treatment Cohort Study (OCS). All participants were on three cART drugs for at least 90 days prior to assessment. Multiple logistic and linear regression methods were used. Most participants were Caucasian men with mean age of 47 years. About two thirds had a nadir CD4+ T-cell count below 200 cells/MUL and 92 % had an undetectable plasma HIV viral load. The median CNS penetration effectiveness (CPE) score was 7. Sixty percent of participants had neuropsychological impairment. Higher CPE values significantly correlated with lower prevalence of impairment in bivariate and multivariate analyses. In this cross-sectional analysis of HIV+ adults who had a low prevalence of comorbidities and were taking three-drug cART regimens, greater estimated distribution of cART drugs into the CNS was associated with better NP performance. PMID- 26572788 TI - Nurses' perspectives on nurse-coordinated prevention programmes in secondary prevention of cardiovascular disease: a pilot survey. AB - BACKGROUND: Secondary prevention of coronary artery disease (CAD) is increasingly provided by nurse-coordinated prevention programs (NCPP). Little is known about nurses' perspectives on these programs. AIM: To investigate nurses' perspectives/experiences in NCPPs in acute coronary syndrome patients. METHODS: Thirteen nurses from NCPPs in 11 medical centers in the RESPONSE trial completed an online survey containing 45 items evaluating 3 outcome categories: (1) conducting NCPP visits; (2) effects of NCPP interventions on risk profiles and (3) process of care. RESULTS: Nurses felt confident in counseling/motivating patients to reduce CAD risk. Interventions targeting LDL, blood pressure and medication adherence were reported as successful, corresponding with significant improvements of these risk factors. Improving weight, smoking and physical activity was reported as less effective. Screening for anxiety/depression was suggested as an improvement. CONCLUSIONS: Nurses acknowledge the importance and effectiveness of NCPPs, and correctly identify which components of the program are the most successful. Our study provides a basis for implementation and quality improvement for NCCPs. PMID- 26572789 TI - Impact of postoperative changes in sarcopenic factors on outcomes after hepatectomy for hepatocellular carcinoma. AB - BACKGROUND: We have reported that preoperative low skeletal muscle quality was an independent risk factor for poor outcomes after hepatectomy for hepatocellular carcinoma (HCC). However, postoperative changes of quality as well as quantity of skeletal muscle after hepatectomy for HCC and their impact on postoperative outcomes have not been fully investigated. METHODS: We retrospectively analyzed 241 patients undergoing primary hepatectomy for HCC between January 2007 and September 2012. The quality and quantity of skeletal muscle were evaluated by intramuscular adipose tissue content (IMAC) and the psoas muscle mass index (PMI) using computed tomography imaging at the umbilical level, respectively. We evaluated postoperative changes in IMAC and PMI in patients according to preoperative sarcopenia, sex, and surgical procedure. We also investigated the impact of DeltaIMAC and DeltaPMI on HCC recurrence in patients with preoperative normal IMAC. RESULTS: On multivariate analysis, indocyanine green retention test at 15 min >= 15% (odds ratio [OR] = 3.156; P = 0.041) and high DeltaIMAC at 6 months after hepatectomy (OR = 3.713; P = 0.024) were the risk factors for HCC recurrence in patients with preoperative normal IMAC. CONCLUSION: Postoperative depletion of skeletal muscle quality is closely involved with HCC recurrence after hepatectomy for HCC. PMID- 26572787 TI - The effects of cocaine on HIV transcription. AB - Illicit drug users are a high-risk population for infection with the human immunodeficiency virus (HIV). A strong correlation exists between prohibited drug use and an increased rate of HIV transmission. Cocaine stands out as one of the most frequently abused illicit drugs, and its use is correlated with HIV infection and disease progression. The central nervous system (CNS) is a common target for both drugs of abuse and HIV, and cocaine intake further accelerates neuronal injury in HIV patients. Although the high incidence of HIV infection in illicit drug abusers is primarily due to high-risk activities such as needle sharing and unprotected sex, several studies have demonstrated that cocaine enhances the rate of HIV gene expression and replication by activating various signal transduction pathways and downstream transcription factors. In order to generate mature HIV genomic transcript, HIV gene expression has to pass through both the initiation and elongation phases of transcription, which requires discrete transcription factors. In this review, we will provide a detailed analysis of the molecular mechanisms that regulate HIV transcription and discuss how cocaine modulates those mechanisms to upregulate HIV transcription and eventually HIV replication. PMID- 26572790 TI - [Gracilis tendon augmented reconstruction of the medial patellofemoral ligament with soft tissue fixation at the patellar insertion site]. AB - OBJECTIVE: Reconstruction of the medial patellofemoral ligament with autologous tendon augmentation and soft tissue fixation at the patellar insertion with resorbable suture material. INDICATIONS: Patellofemoral instability due to insufficiency of the medial passive stabilizers and dysplastic trochlea. CONTRAINDICATIONS: Primary traumatic dislocation of the patella without risk factors for patellar redislocation, severe osteoarthritis of the patellofemoral joint, infection. SURGICAL TECHNIQUE: Diagnostic arthroscopy to evaluate cartilage and shape of trochlea and to treat associated injuries. Harvesting of the gracilis tendon and arming with resorbable suture material. Transfer of the tendon through the medial capsule in the anatomical layer of the MPFL and weaving in u-shape through the capsule and periosteum near the patella. Soft tissue fixation with resorbable suture material. Anatomical reconstruction of the femoral insertion site. Femoral fixation with interference screw. POSTOPERATIVE TREATMENT: For 4 weeks, partial (20 kg) weight bearing with crutches; cast with physiotherapy (limited ROM extension, flexion 0-0-90 degrees ). Thereafter free range of motion and full weight bearing. RESULTS: 27 patients (age 12-45 years) with patellofemoral instability underwent reconstruction of the medial patellofemoral ligament. Clinical follow-up was assessed up to 12 months postoperatively. After 1 year, the Kujala and Flandry scores increased from preoperatively 72 points to 95 points and 65.7 points to 89.9 points, respectively. One redislocation was observed. Patient satisfaction was significantly increased at 6 months postoperatively. Reconstruction of the medial patellofemoral ligament shows good clinical results after 12 months. PMID- 26572791 TI - Isolated torsion of the fallopian tube in a menopausal woman and a pre-pubertal girl: two case reports. AB - INTRODUCTION: Isolated torsion of the fallopian tube without an ovarian abnormality is an uncommon event, with an incidence of approximately 1 in 1,500,000 females. Isolated torsion of the fallopian tube occurs mostly in reproductive-aged women, and is thus extremely rare in menopausal women and pre pubertal girls. CASE PRESENTATIONS: In case 1, 63-year-old Japanese woman presented with a 2-day history of acute lower abdominal pain. Menopause occurred at 53 years of age. Pelvic ultrasonography showed an enlarged mass (73 * 47 mm) on the right side of her uterus. An urgent laparoscopy was performed based on a presumptive diagnosis of right ovarian tumor torsion. During the laparoscopy, we noted a black, necrotic, solid tumor arising from the distal end of her right fimbria. Her right fallopian tube was twisted with the tumor, but her right ovary was normal and not involved. A laparoscopic tumorectomy with a right salpingectomy was performed. Her post-operative course was uneventful. In case 2, a 10-year-old Japanese girl presented with a 1-day history of lower abdominal pain associated with nausea and vomiting. Menarche had occurred 2 months earlier. A computed tomography and magnetic resonance imaging examination demonstrated a dilated tubal cystic mass with a normal uterus and bilateral ovaries. An urgent laparoscopy was performed based on a presumptive diagnosis of right fallopian tube torsion. During laparoscopy, her right fallopian tube was noted to be dark red, dilated, and twisted several times. Her right fimbria was necrotic-appearing and could not be preserved. Therefore, a laparoscopic right salpingectomy was performed. A histologic examination revealed ischemic changes with congestion of her right fallopian tube, which was consistent with tubal torsion. She had an uncomplicated post-operative course. CONCLUSION: We have presented two very rare cases of isolated fallopian tubal torsion. Radiologic interventions, such as computed tomography and magnetic resonance imaging, in addition to ultrasonography, are helpful diagnostic tools. Isolated torsion of the fallopian tube should be considered in the differential diagnosis of lower abdominal pain with a cystic mass and a normal ipsilateral ovary in all female patients, regardless of age. PMID- 26572792 TI - Genome-wide analysis and expression profiling of the PIN auxin transporter gene family in soybean (Glycine max). AB - BACKGROUND: The plant phytohormone auxin controls many aspects of plant growth and development, which largely depends on its uneven distribution in plant tissues. Transmembrane proteins of the PIN family are auxin efflux facilitators. They play a key role in polar auxin transport and are associated with auxin asymmetrical distribution in plants. PIN genes have been characterized in several plant species, while comprehensive analysis of this gene family in soybean has not been reported yet. RESULTS: In this study, twenty-three members of the PIN gene family were identified in the soybean genome through homology searches. Analysis of chromosome distribution and phylogenetic relationships of the soybean PIN genes indicated nine pairs of duplicated genes and a legume specific subfamily. Organ/tissue expression patterns and promoter activity assays of the soybean PINs suggested redundant functions for most duplicated genes and complementary and tissue-specific functions during development for non-duplicated genes. The soybean PIN genes were differentially regulated by various abiotic stresses and phytohormone stimuli, implying crosstalk between auxin and abiotic stress signaling pathways. This was further supported by the altered auxin distribution under these conditions as revealed by DR5::GUS transgenic soybean hairy root. Our data indicates that GmPIN9, a legume-specific PIN gene, which was responsive to several abiotic stresses, might play a role in auxin re distribution in soybean root under abiotic stress conditions. CONCLUSIONS: This study provided the first comprehensive analysis of the soybean PIN gene family. Information on phylogenetic relationships, gene structure, protein profiles and expression profiles of the soybean PIN genes in different tissues and under various abiotic stress treatments helps to identity candidates with potential roles in specific developmental processes and/or environmental stress conditions. Our study advances our understanding of plant responses to abiotic stresses and serves as a basis for uncovering the biological role of PIN genes in soybean development and adaption to adverse environments. PMID- 26572794 TI - What web browsing reveals about your health. AB - Advertisers can learn a lot from our digital footprints, including about our health. Timothy Libert and colleagues argue that we need to tighten restrictions on such data for marketing purposes while looking at their potential to improve health. PMID- 26572793 TI - Transcriptome-wide functional characterization reveals novel relationships among differentially expressed transcripts in developing soybean embryos. AB - BACKGROUND: Transcriptomics reveals the existence of transcripts of different coding potential and strand orientation. Alternative splicing (AS) can yield proteins with altered number and types of functional domains, suggesting the global occurrence of transcriptional and post-transcriptional events. Many biological processes, including seed maturation and desiccation, are regulated post-transcriptionally (e.g., by AS), leading to the production of more than one coding or noncoding sense transcript from a single locus. RESULTS: We present an integrated computational framework to predict isoform-specific functions of plant transcripts. This framework includes a novel plant-specific weighted support vector machine classifier called CodeWise, which predicts the coding potential of transcripts with over 96 % accuracy, and several other tools enabling global sequence similarity, functional domain, and co-expression network analyses. First, this framework was applied to all detected transcripts (103,106), out of which 13 % was predicted by CodeWise to be noncoding RNAs in developing soybean embryos. Second, to investigate the role of AS during soybean embryo development, a population of 2,938 alternatively spliced and differentially expressed splice variants was analyzed and mined with respect to timing of expression. Conserved domain analyses revealed that AS resulted in global changes in the number, types, and extent of truncation of functional domains in protein variants. Isoform specific co-expression network analysis using ArrayMining and clustering analyses revealed specific sub-networks and potential interactions among the components of selected signaling pathways related to seed maturation and the acquisition of desiccation tolerance. These signaling pathways involved abscisic acid- and FUSCA3-related transcripts, several of which were classified as noncoding and/or antisense transcripts and were co-expressed with corresponding coding transcripts. Noncoding and antisense transcripts likely play important regulatory roles in seed maturation- and desiccation-related signaling in soybean. CONCLUSIONS: This work demonstrates how our integrated framework can be implemented to make experimentally testable predictions regarding the coding potential, co-expression, co-regulation, and function of transcripts and proteins related to a biological process of interest. PMID- 26572795 TI - The Utility of Therapeutic Hypothermia for Post-Cardiac Arrest Syndrome Patients With an Initial Nonshockable Rhythm. AB - BACKGROUND: Therapeutic hypothermia (TH) attenuates reperfusion injury in comatose survivors of cardiac arrest. The utility of TH in patients with nonshockable initial rhythms has not been widely accepted. We sought to determine whether TH improved neurological outcome and survival in postarrest patients with nonshockable rhythms. METHODS AND RESULTS: We identified 519 patients after in- and out-of-hospital cardiac arrest with nonshockable initial rhythms from the Penn Alliance for Therapeutic Hypothermia (PATH) registry between 2000 and 2013. Propensity score matching was used. Patient and arrest characteristics used to estimate the propensity to receive TH were age, sex, location of arrest, witnessed arrest, and duration of arrest. To determine the association between TH and outcomes, we created 2 multivariable logistic models controlling for confounders. Of 201 propensity score-matched pairs, mean age was 63 +/- 17 years, 51% were male, and 60% had an initial rhythm of pulseless electric activity. Survival to hospital discharge was greater in patients who received TH (17.6% versus 28.9%; P < 0.01), as was a discharge Cerebral Performance Category of 1 to 2 (13.7% versus 21.4%; P = 0.04). In adjusted analyses, patients who received TH were more likely to survive (odds ratio, 2.8; 95% confidence interval, 1.6-4.7) and to have better neurological outcome (odds ratio, 3.5; 95% confidence interval, 1.8-6.6) than those that did not receive TH. CONCLUSIONS: Using propensity score matching, we found that patients with nonshockable initial rhythms treated with TH had better survival and neurological outcome at hospital discharge than those who did not receive TH. Our findings further support the use of TH in patients with initial nonshockable arrest rhythms. PMID- 26572797 TI - Health sociology from post-structuralism to the new materialisms. AB - The article reviews the impact of post-structuralism and postmodern social theory upon health sociology during the past 20 years. It then addresses the emergence of new materialist perspectives, which to an extent build upon insights of post structuralist concerning power, but mark a turn away from a textual or linguistic focus to address the range of materialities that affect health, illness and health care. I conclude by assessing the impact of these movements for health sociology. PMID- 26572796 TI - Association of Coffee Consumption With Total and Cause-Specific Mortality in 3 Large Prospective Cohorts. AB - BACKGROUND: The association between consumption of caffeinated and decaffeinated coffee and risk of mortality remains inconclusive. METHODS AND RESULTS: We examined the associations of consumption of total, caffeinated, and decaffeinated coffee with risk of subsequent total and cause-specific mortality among 74,890 women in the Nurses' Health Study (NHS), 93,054 women in the Nurses' Health Study II, and 40,557 men in the Health Professionals Follow-up Study. Coffee consumption was assessed at baseline using a semiquantitative food frequency questionnaire. During 4,690,072 person-years of follow-up, 19,524 women and 12,432 men died. Consumption of total, caffeinated, and decaffeinated coffee were nonlinearly associated with mortality. Compared with nondrinkers, coffee consumption of 1 to 5 cups per day was associated with lower risk of mortality, whereas coffee consumption of more than 5 cups per day was not associated with risk of mortality. However, when restricting to never smokers compared with nondrinkers, the hazard ratios (and 95% confidence intervals) of mortality were 0.94 (0.89-0.99) for 1.0 or less cup per day, 0.92 (0.87-0.97) for 1.1 to 3.0 cups per day, 0.85 (0.79-0.92) for 3.1 to 5.0 cup per day, and 0.88 (0.78-0.99) for more than 5.0 cup per day (P value for nonlinearity = 0.32; P value for trend < 0.001). Significant inverse associations were observed for caffeinated (P value for trend < 0.001) and decaffeinated coffee (P value for trend = 0.022). Significant inverse associations were observed between coffee consumption and deaths attributed to cardiovascular disease, neurologic diseases, and suicide. No significant association between coffee consumption and total cancer mortality was found. CONCLUSIONS: Higher consumption of total coffee, caffeinated coffee, and decaffeinated coffee was associated with lower risk of total mortality. PMID- 26572798 TI - Eighteen- to 30-year-olds more likely to link to hepatitis C virus care: an opportunity to decrease transmission. AB - Hepatitis C virus (HCV) infection incidence among 18- to 30-year-olds is increasing and guidelines recommend treatment of active injection drug users to limit transmission. We aimed to : measure linkage to HCV care among 18- to 30 year-olds and identify factors associated with linkage; compare linkage among 18- to 30-year-olds to that of patients >30 years. We used the electronic medical record at an urban safety net hospital to create a retrospective cohort with reactive HCV antibody between 2005 and 2010. We report seroprevalence and demographics of seropositive patients, and used multivariable logistic regression to identify factors associated with linkage to HCV care. We defined linkage as having evidence of HCV RNA testing after reactive antibody. Thirty two thousand four hundred and eighteen individuals were tested, including 8873 between 18 and 30 years. The seropositivity rate among those ages 18-30 was 10%. In multivariate analysis, among those 18-30, diagnosis location (Outpatient vs Inpatient/ED) (OR 1.78, 95% CI 1.28-2.49) and number of visits after diagnosis (OR 5.30, 95% CI 3.91-7.19) were associated with higher odds of linking to care. When we compared linkage in patients ages 18-30 to that among those older than 30, patients in the 18-30 years age group were more likely to link to HCV care than those in the older cohort even when controlling for gender, ethnicity, socioeconomic status, birthplace, diagnosis location and duration of follow-up. Eighteen- to 30-year olds are more likely to link to HCV care than their older counterparts. During the interferon-free treatment era, there is an opportunity to prevent further HCV transmission in this population. PMID- 26572799 TI - Benzylidene Acetal Protecting Group as Carboxylic Acid Surrogate: Synthesis of Functionalized Uronic Acids and Sugar Amino Acids. AB - Direct oxidation of the 4,6-O-benzylidene acetal protecting group to C-6 carboxylic acid has been developed that provides an easy access to a wide range of biologically important and synthetically challenging uronic acid and sugar amino acid derivatives in good yields. The RuCl3 -NaIO4 -mediated oxidative cleavage method eliminates protection and deprotection steps and the reaction takes place under mild conditions. The dual role of the benzylidene acetal, as a protecting group and source of carboxylic acid, was exploited in the efficient synthesis of six-carbon sialic acid analogues and disaccharides bearing uronic acids, including glycosaminoglycan analogues. PMID- 26572800 TI - Myostatin in relation to physical activity and dysglycaemia and its effect on energy metabolism in human skeletal muscle cells. AB - AIM: Some health benefits of exercise may be explained by an altered secretion of myokines. Because previous focus has been on upregulated myokines, we screened for downregulated myokines and identified myostatin. We studied the expression of myostatin in relation to exercise and dysglycaemia in skeletal muscle, adipose tissue and plasma. We further examined some effects of myostatin on energy metabolism in primary human muscle cells and Simpson-Golabi-Behmel syndrome (SGBS) adipocytes. METHODS: Sedentary men with or without dysglycaemia underwent a 45-min acute bicycle test before and after 12 weeks of combined endurance and strength training. Blood samples and biopsies from m. vastus lateralis and adipose tissue were collected. RESULTS: Myostatin mRNA expression was reduced in skeletal muscle after acute as well as long-term exercise and was even further downregulated by acute exercise on top of 12-week training. Furthermore, the expression of myostatin at baseline correlated negatively with insulin sensitivity. Myostatin expression in the adipose tissue increased after 12 weeks of training and correlated positively with insulin sensitivity markers. In cultured muscle cells but not in SGBS cells, myostatin promoted an insulin independent increase in glucose uptake. Furthermore, muscle cells incubated with myostatin had an enhanced rate of glucose oxidation and lactate production. CONCLUSION: Myostatin was differentially expressed in the muscle and adipose tissue in relation to physical activity and dysglycaemia. Recombinant myostatin increased the consumption of glucose in human skeletal muscle cells, suggesting a complex regulatory role of myostatin in skeletal muscle homeostasis. PMID- 26572801 TI - The diagnostic usefulness of capture assays for measuring global/specific extracellular micro-particles in plasma. AB - Capture assays were developed and validated for measuring the global pro coagulant activity of micro-particles (MPs, mainly originated from platelets), or specific extravascular cellular MPs (released from erythrocytes, leukocytes, monocytes, endothelial cells) as those exposing TF (MP-TF, mainly observed in patients with some cancers). Conversely to Flow Cytometry methods, these capture assays measure all coagulant activity associated with MPs, through thrombin generation (MP-Activity) or Factor Xa generation (MP-TF), and therefore they bring a complementary information, as they are more specific for the pro coagulant activity associated with MPs. Small particles (<0.40 u) exposing Phosphatidyl Serine (PS) exhibit a greater pro-coagulant surface than larger MPs (0.40 to >1.00 u), those preferentially measured with flow cytometry. Activity associated with MPs is a consequence of disease but can also be a cause contributing to pathological processes and development of thrombo-embolic events. In many diseases, flow cytometry and capture assays do not totally correlate, and have different associations with disease evolution. Optimized capture based assays are presented and discussed, along with their performance characteristics and some applications. They can be performed in any technically skillful hemostasis laboratory, using a thermostated ELISA equipment, or an incubator. Dynamic ranges for MP-Activity assay is from <0.1 nM to >2.5 nM Phospholipids, expressed as Phosphatidyl Serine (PS) equivalent, in the tested dilution. For MP TF the very sensitive bio-immunoassay reported allows measuring concentrations from <0.10 pg/ml (TF equivalent) to >5.00 pg/ml, in the assayed dilution. No measurable MP-TF was found in normals, although an important concentration was generated from whole blood treated with Lipo-Poly-Saccharides. Capture based assays are then highly useful in the laboratory setting for measuring the activities associated with pro-coagulant, or specific cellular MPs. PMID- 26572802 TI - Repositioning of drugs using open-access data portal DTome: A test case with probenecid (Review). AB - The one gene-one enzyme hypothesis, first introduced by Beadle and Tatum in the 1940s and based on their genetic analysis and observation of phenotype changes in Neurospora crassa challenged by various experimental conditions, has witnessed significant advances in recent decades. Much of our understanding of the association between genes and their phenotype expression has benefited from the completion of the human genome project, and has shown continual transformation guided by the effort directed at the annotation and characterization of human genes. Similarly, the idea of one drug-one primary disease indication that traditionally has been the benchmark for the labeling and usage of drugs has also undergone evident progressive refinements; in recent years the science and practice of pharmaceutical development has notable success in the strategy of drug repurposing. Drug repurposing is an innovative approach where, instead of de novo synthesis and discovery of new drugs with novel indications, drug candidates with the desired usage are identified by a process of re-profiling using an open source database or knowledge of known or failed drugs already in existence. In the present study, the repurposing drug strategy employing open-access data portal drug-target interactome (DTome) is applied to the uncovering of new clinical usage for probenecid. PMID- 26572803 TI - Recent advances: role of mycolactone in the pathogenesis and monitoring of Mycobacterium ulcerans infection/Buruli ulcer disease. AB - Infection of subcutaneous tissue with Mycobacterium ulcerans can lead to chronic skin ulceration known as Buruli ulcer. The pathogenesis of this neglected tropical disease is dependent on a lipid-like toxin, mycolactone, which diffuses through tissue away from the infecting organisms. Since its identification in 1999, this molecule has been intensely studied to elucidate its cytotoxic and immunosuppressive properties. Two recent major advances identifying the underlying molecular targets for mycolactone have been described. First, it can target scaffolding proteins (such as Wiskott Aldrich Syndrome Protein), which control actin dynamics in adherent cells and therefore lead to detachment and cell death by anoikis. Second, it prevents the co-translational translocation (and therefore production) of many proteins that pass through the endoplasmic reticulum for secretion or placement in cell membranes. These pleiotropic effects underpin the range of cell-specific functional defects in immune and other cells that contact mycolactone during infection. The dose and duration of mycolactone exposure for these different cells explains tissue necrosis and the paucity of immune cells in the ulcers. This review discusses recent advances in the field, revisits older findings in this context and highlights current developments in structure-function studies as well as methodology that make mycolactone a promising diagnostic biomarker. PMID- 26572804 TI - Stereocontrolled Synthesis of Vinyl Boronates and Vinyl Silanes via Atom Economical Ruthenium-Catalyzed Alkene-Alkyne Coupling. AB - The synthesis of vinyl boronates and vinyl silanes was achieved by employing a Ru catalyzed alkene-alkyne coupling reaction of allyl boronates or allyl silanes with various alkynes. The double bond geometry in the generated vinyl boronates can be remotely controlled by the juxtaposing boron- and silicon groups on the alkyne substrate. The synthetic utility of the coupling products has been demonstrated in a variety of synthetic transformations, including iterative cross coupling reactions, and a Chan-Lam-type allyloxylation followed by a Claisen rearrangement. A sequential one-pot alkene-alkyne-coupling/allylation-sequence with an aldehyde to deliver a highly complex alpha-silyl-beta-hydroxy olefin with a handle for further functionalization was also realized. PMID- 26572805 TI - Dynamic sensory description of Rioja Alavesa red wines made by different winemaking practices by using Temporal Dominance of Sensations. AB - BACKGROUND: Although sensory description of wines in scientific literature is very large, there is an evident lack of studies describing wines from a dynamic approach. The objective of this study was to describe the evolution of the sensations perceived in red wines from Rioja Alavesa by using Temporal Dominance of Sensations (TDS) and also to compare wines made with the two winemaking procedures used in Rioja Alavesa: carbonic maceration (CM) and destemming (DS). RESULTS: Ten sensory attributes were evaluated in eight wines (four CM and four DS wines) in triplicate by a panel of 16 trained assessors. Red/black berry and woody aromas were dominant firstly, whereas heat, astringent, bitter and pungent sensations were dominant later. CM wines showed higher dominance for woody, spicy, pungent and acid sensations and lower dominance for red/black berry aroma and astringency than DS wines. CONCLUSION: This study is the first to describe Rioja wines from a dynamic approach and it also provides information about the dynamic sensory differences between wines made by CM or by DS. In this sense, this work shows the usefulness of TDS to describe and differentiate wines and to provide additional information to the conventional static descriptive analysis. (c) 2015 Society of Chemical Industry. PMID- 26572806 TI - Mental Status in Patients Before and After Liver Transplantation. AB - BACKGROUND: In contrast to the well-described beneficial organic effects of liver transplantation (OLT) in patients with end-stage liver disease, changes in the mental status of patients after OLT remain poorly understood. The current study seeks to evaluate the influence of OLT on anxiety, depression, and dispositional optimism in patients with end-stage liver disease. MATERIAL AND METHODS: Questionnaires were sent to patients on the OLT waiting list and patients after OLT. Depression/anxiety and dispositional optimism were assessed using the HADS and LOT-R questionnaires, respectively. These findings were compared to results from the general population. RESULTS: The number of returned questionnaires was 292 of 940 (31.1%; 57 patients on the liver transplant waiting list: waiting group, 235 liver transplant recipients: OLT group). Both depression and anxiety scores were significantly higher in the waiting group when compared to the OLT group (p<0.05) and the general population (anxiety: p<0.001, depression: p<0.05), respectively. The OLT group was characterized by significantly higher anxiety scores (p<0.001) compared to the general population. Depression and summation scores did not differ (p>0.05). Dispositional optimism was higher in the OLT group compared to the waiting group (p<0.05) and to the general population (p<0.01). The waiting group had equal values as the general population (p>0.05). CONCLUSIONS: Besides beneficial effects on liver function, OLT appears to be associated with significant improvements in depression and anxiety and a more optimistic view of life. PMID- 26572807 TI - Tetramer formation of tumor suppressor protein p53: Structure, function, and applications. AB - Tetramer formation of p53 is essential for its tumor suppressor function. p53 not only acts as a tumor suppressor protein by inducing cell cycle arrest and apoptosis in response to genotoxic stress, but it also regulates other cellular processes, including autophagy, stem cell self-renewal, and reprogramming of differentiated cells into stem cells, immune system, and metastasis. More than 50% of human tumors have TP53 gene mutations, and most of them are missense mutations that presumably reduce tumor suppressor activity of p53. This review focuses on the role of the tetramerization (oligomerization), which is modulated by the protein concentration of p53, posttranslational modifications, and/or interactions with its binding proteins, in regulating the tumor suppressor function of p53. Functional control of p53 by stabilizing or inhibiting oligomer formation and its bio-applications are also discussed. (c) 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 598-612, 2016. PMID- 26572808 TI - Apoptosis-related protein-1 acts as a tumor suppressor in cholangiocarcinoma cells by inducing cell cycle arrest via downregulation of cyclin-dependent kinase subunits. AB - Cholangiocarcinoma, a malignancy arising from the biliary tract, is associated with high mortality due to the late diagnosis and lack of effective therapeutic approaches. Our knowledge of the molecular alterations during the carcinogenesis of cholangiocarcinoma is limited. Previous study suggests that apoptosis-related protein-1 (Apr-1) is involved in cancer cell proliferation and survival. In the present study, we first detected the expression pattern of Apr-1 in human cholangiocarcinoma tissues and the effects of forced Apr-1 expression on cell proliferation and cell cycle progression. Cell cycle gene array analysis was used to identify downstream molecules that were regulated by Apr-1, and their expression levels were further evaluated in human cholangiocarcinoma tissues. We showed that Apr-1 expression was downregulated in human cholangiocarcinoma tissues. Forced expression of Apr-1 inhibited cell proliferation of cholangiocarcinoma cell line QBC939 and induced G2/M phase arrest. Downregulation of cell cycle-related genes cyclin-dependent kinase (Cdk) 2, and cyclin-dependent kinase subunits (Cks) 1 and 2 was involved in Apr-1-induced cell cycle arrest. Furthermore, we found that Cdk2 and Cks1/2 expression levels were elevated in human cholangiocarcinoma tissues. Taken together, our data showed that Apr-1 plays a crucial role in cell proliferation by controlling cell cycle progression, implying a tumor-suppressor function of Apr-1 in cholangiocarcinoma carcinogenesis. Thus, the present study provides a rationale to further study the underlying mechanisms of Apr-1 downregulation in cholangiocarcinoma for exploring potential diagnostic and therapeutic targets. PMID- 26572809 TI - [The good news]. PMID- 26572810 TI - [Prevalence of Avoidable Potential Interactions Between Antidepressants and Other Drugs in Colombian Patients]. AB - OBJECTIVES: To determine the possible drugs interactions with antidepressive agents in data bases of patients in the Health Insurance System of Colombia. METHODS: From data bases of about 4 million users in Colombia, a systematic review of drugs dispensation statistics was made to identify drug interactions between antidepressive agents, cholinergic antagonists and tramadol in 2010. RESULTS: We identified 114,465 monthly users of antidepressive agents. Of these, 5776 (5.0%) received two, and 178 (0.2%) received three antidepressive agents simultaneously. The most frequent combination was fluoxetine+trazodone (n=3235; 56.9% of cases). About 1127 (1.0%) patients were prescribed a cholinergic antagonist simultaneously; 2523 (2.1%) users were dispensed tramadol at the same time, while raising the risk of serotonin syndrome. CONCLUSIONS: Drug interactions represent a potential risk that is often underestimated by physicians. Pharmacovigilance is a useful tool to optimize resources and prevent negative outcomes associated with medication. It is recommended that systematic search is made to enhance surveillance programs for the rational use of medicines in this country. PMID- 26572811 TI - [Psychosocial Factors and Burnout Syndrome Found in Workers in the Dough Processing Industry, Tepic, Mexico]. AB - INTRODUCTION: The workers in the dough processing industry are a population exposed to psychosocial risk factors due to the conditions in the workplace; therefore, they are likely to suffer from one of the consequences of chronic stress to which a worker is exposed daily: burnout syndrome. OBJETIVE: The aim of this study was to analyze the relationship between psychosocial factors and the burnout syndrome in workers in the dough processing industry in the city of Tepic, Mexico. MATERIAL AND METHODS: A cross-sectional and descriptive study was conducted in five companies from the dough processing industry. The total population consisted of 122 workers who were administered the scale of Psychosocial Factors Identification of the Mexican Social Security Institute and the Maslach Burnout Inventory scale, in order to gather information. RESULTS: The presence of adverse psychosocial factors was reported in 18.3%, and 79.8% with the syndrome. There were several variables that behaved as risk factors, specifically, the system of working with the emotional exhaustion. PMID- 26572812 TI - [Symptoms of Depression, Anxiety and Stress Among Dental Students: Prevalence and Related Factors]. AB - OBJECTIVES: To estimate the relationship between depressive symptoms, anxiety and stress and socio-demographic, academic and social factors among dental students. METHODS: A cross-sectional study was carried out on dental students from a university in Cartagena, selected by simple random sampling. Students answered a self-report anonymous questionnaire of 20 questions that included demographic characteristics, depression, anxiety and stress symptoms (DASS scale 21), family function (APGAR family) and other factors associated with the academic, economic and social context. Data were analyzed computing odds ratios by binomial logistic regression. RESULTS: The prevalence of symptoms of anxiety, depression and stress were 37.4%, 56.6% and 45.4%, respectively. Factors associated with depressive symptoms were lack of support from friends (OR=6.2; 95%CI, 2.6-14.5), family dysfunction (OR=3.6; 95%CI, 1.9-6.6) and economic hardship (OR=2.2; 95%CI, 1.2 3.9). The anxiety symptoms were associated with family dysfunction (OR=3.1; 95%CI, 1.8-5.3) and lack of support from friends (OR=2.1; 95%CI, 1.1-5.8). Also for symptoms of stress factors family dysfunction (OR=2.3; 95%CI, 1.4-4.1), income (OR=2.4; 95%CI, 1.2-4.9) and time to rest (OR=2.3; 95%CI, 1.4-4.0). CONCLUSIONS: Dental students report a high prevalence of symptoms of anxiety, depression and stress. Associated factors are economic resources, family function, lack of time for rest, and social support. PMID- 26572813 TI - [Analysis of Possible Sociodemographic and Occupational Risk Factors and the Prevalence of Professional Exhaustion Syndrome (Burnout) in Mexican Dentists]. AB - OBJECTIVES: To determine the prevalence of professional exhaustion syndrome (burnout) in dentists and to analyze possible sociodemographic and occupational risk factors . METHODS: An observational, descriptive and cross-sectional survey of 203 dental staff of the Metropolitan Zone of Guadalajara, Mexico, from the Mexican Social Security Institute, University of Guadalajara, and those in private practice. A self-reported identification form and the Maslach Burnout Inventory-Human Services Survey were used to gather data. Descriptive statistics and inferential analyzes were performed using SPSS 15.0 support and EpiInfo V6.1. RESULTS: There was an 88.3% response. Professional exhaustion syndrome (burnout) was detected in 52.2% of them. Significant differences were obtained depending on the employment contract. A negative correlation was observed between the subscales emotional exhaustion and depersonalization, and a positive one between the lack of personal accomplishment at work. CONCLUSIONS: Professional exhaustion syndrome (burnout) is common (52.2%) for dentists, their possible risk factors: working in a public institution, being male, over 40 years, without a regular partner, and with more than 15 years with a partner, not having children, being a specialist with 10 years or more in an institution and the current job, morning shift, permanent recruitment, and having another job. The involvement of emotional exhaustion behaves like the syndrome. Average levels of the subscales are generally near normal. A negative correlation was found between the subscales emotional exhaustion and depersonalization, and positive between the lack of personal fulfillment at work with the presence of the syndrome. This leads us to consider the need for preventive measures in the workplace and personnel, as well as intervention programs at an individual, social or organizational level to reduce the prevalence found. PMID- 26572814 TI - [Delirium in Patients Over 60 Years of Age in a Tertiary Level Public Hospital in the City of Pereira (Colombia): Under-Diagnosed and Under-Recorded]. AB - INTRODUCTION: Delirium is a common disorder in the hospitalized geriatric population and it has a great importance on the clinical outcome of inpatients; however, delirium is not diagnosed properly. OBJECTIVE: To clarify the state of delirium diagnosis and records in a tertiary level public hospital in the city of Pereira. METHODS: A cross-sectional descriptive study was performed by searching the clinical records of hospitalized patients older than 60 years 2010 and 2011, using the ICD-10 classification as a filter, and verifying the diagnostic criteria of DSM-IV in the clinical records. RESULTS: In the years 2010 and 2011, 5325 patients older than 60 years were hospitalized (19.3%). According to the official statistical records; 0.08% of them were reported with an unspecified diagnosis of delirium (F059). In the clinical records search 455 additional delirium patients were found using the same criteria (40.2%), of which 90.1% had delirium, and only 29.5% were classified with the code F059. CONCLUSIONS: The diagnoses and recording of delirium patients over 60 years old patients are underestimated, which is demonstrated by the incongruence of the data obtained from the official records and those obtained from the clinical records. This fact increases the risk and vulnerability of patients with undetected delirium or diagnosed but not reported delirium in hospital statistical sources. Liaison psychiatry is a necessity in third level health institutions, as well as a program of continued education for the health staff about prevention, diagnosis criteria and treatment of delirium. PMID- 26572815 TI - [Physical Exercise and Depression in the Elderly : A Systematic Review]. AB - BACKGROUND: The literature supports the benefits of exercise in people with depressive disorders, but there is controversy over these benefits in depressed elderly. OBJECTIVE: To determine the effect of different types of exercise on depression in older adults using a systematic review of clinical trials. DATA SOURCES: The Cochrane Library; PubMed-MEDLINE (1966-dic 2010); EMBASE (1980-dic 2010); LILACS (1986-dic 2010); SCIELO (1998-dic 2010); Register of Controlled Trials; manual search in other sources. METHODS: Clinical trials with people >60 years with diagnosis of depression were included, without restriction by year of publication, language and sex, with exercise intervention structures, controlled with usual care (medication, psychotherapy, electric shock therapy), placebo or non-intervention. Three independent reviewers conducted the search, applied inclusion and exclusion criteria, assessed methodological quality and extracted data; discrepancies were resolved by consensus. The primary outcome was the score for depressive symptoms. RESULTS: A total of 11 studies (n=7195) were identified. In general, exercise produces an improvement in depression in older adults with more evidence in the short-term (3 months) and strength training at high intensity. CONCLUSIONS: Exercise is beneficial for older persons with depression, but studies that support this are of low methodological quality and heterogeneous, which makes it necessary to develop clinical trials to clarify the magnitude of the effect and the levels at which it is beneficial. PMID- 26572816 TI - [Dysthymia in the Clinical Context]. AB - Dysthymia is defined as a chronic mood disorder that persists for at least two years in adults, and one year in adolescents and children. According to DSM IV TR, Dysthymia is classified into two subtypes: early-onset, when it begins before 21 years-old, and late onset Dysthymia, when it starts after this age. Before age 21, symptoms of conduct disorder, attention deficit disorder and hyperactivity with a few vegetative symptoms are usually present. It is important to distinguish it from other types of depression, as earlier as possible. This would allow providing these patients with the appropriate treatment to attenuate the impact of symptoms, such as poor awareness of self-mood, negative thinking, low self-esteem, and low energy for social and family activities, which progressively deteriorate their life quality. The etiology of Dysthymia is complex and multifactorial, given the various biological, psychological and social factors involved. Several hypotheses attempt to explain the etiology of Dysthymia, highlighting the genetic hypothesis, which also includes environmental factors, and an aminergic hypothesis suggesting a deficiency in serotonin, norepinephrine and dopamine in the central nervous system. From our point of view, dysthymia cannot be conceived as a simple mild depressive disorder. It is a distinct entity, characterized by a chronic depressive disorder which could persist throughout life, with important repercussions on the life quality of both patients and families. PMID- 26572817 TI - [Olfactory Reference Syndrome (ORS): Presentation of a Case]. AB - A 34 year old patient who was seen in the Harassment Psychiatry Unit after a series of medical visits to different specialties. The main reason for his harassment, exclusion and derision was due to his body odor. The reports issued by the other specialties ruled out any dermatological pathology, and any of the other conditions proposed by the patient. The psychiatric clinical interview, including the use of other evaluation and diagnostic techniques, suggested a differential diagnosis between a compulsive obsessive picture and mono symptomatic psychosis. PMID- 26572818 TI - [The Testimony. Contributions to the Construction of Historical Memory]. AB - INTRODUCTION AND OBJECTIVES: Testimony is a complex act that contributes significantly to the elaboration of mourning, both individually and on a collective level. This is the central idea that is discussed in the text, using as a basis, the results of research conducted as a pilot intervention in the year 2010 for Visible Victims Foundation, and was then replicated in four other regions. In 1998 the National Liberation Army attacked the pipeline OCENSA causing severe damage to the people of Machuca (Segovia, Antioquia). In 2010 the psychologist Ligia Rascovsky implemented an intervention strategy to support the construction of individual and collective memory among survivors of the attack, who, in addition to serious injuries, suffered physical and psychosocial after effects such as post-traumatic stress disorder (PTSD). The results of this work are used to understand the relevance of the testimony in the psychosocial recovery processes, which is a major challenge for Colombian society today. METHODS: The type of study was psychosocial intervention in 43 adults of both sexes, Machuca residents who were affected by the bombing, and agreed to voluntarily participate in designed workshops. The workshops followed experiential type techniques (psychodrama, psycho-fantasies, etc.), in which the purpose was to identify the damage by developing testimonial memory of what happened. RESULTS: The workshops express the emotions of grief, recognize the injustice of suffering, fight memory defense that justifies violence and raising awareness of human rights. It also facilitated the process of dignity, empowerment and security in personal and collective reconstruction. In expressing their memoirs thus, they could be free from fear and gain more confidence in themselves as individuals and as a social group, as seen in the formation of individual leadership. These results are the basis of the discussion presented. CONCLUSIONS: In this context it has been found that the testimonial narrative is an instrument of personal and social healing, as demonstrated in the workshops held with the inhabitants of Machuca, and made with a thousand other people in other locations. The testimony is essential to recognize the dignity and thus reconstruct individual memory from the collective memory. This work provides sufficient testimonial evidence to propose lines of work in the interests of psychosocial policy in order to combine the search for truth and reconstruction of collective memory, along with to the care of victims, and reparation and social reconciliation in Colombia. PMID- 26572819 TI - [The Natural Language Process and Its Relationship With Mental Health Research]. PMID- 26572820 TI - [Child Sex Abuse: An Area Omitted or Unnoticed in Colombia?]. PMID- 26572821 TI - The Good News. PMID- 26572822 TI - Protein substrates of the arginine methyltransferase Hmt1 identified by proteome arrays. AB - Arginine methylation on nonhistone proteins is associated with a number of cellular processes including RNA splicing, protein localization, and the formation of protein complexes. In this manuscript, Saccharomyces cerevisiae proteome arrays carrying 4228 proteins were used with an antimethylarginine antibody to first identify 88 putatively arginine-methylated proteins. By treating the arrays with recombinant arginine methyltransferase Hmt1, 42 proteins were found to be possible substrates of this enzyme. Analysis of the putative arginine-methylated proteins revealed that they were predominantly nuclear or nucleolar in localization, consistent with the localization of Hmt1. Many are involved in known methylarginine-associated functions, such as RNA processing and ribonucleoprotein complex biogenesis, yet others are of newer classes, namely RNA/DNA helicases and tRNA-associated proteins. Using ex vivo methylation and MS/MS, a set of 12 proteins (Brr1, Dia4, Hts1, Mpp10, Mrd1, Nug1, Prp43, Rpa43, Rrp43, Spp381, Utp4, and Npl3), including the RNA helicase Prp43 and tRNA ligases Dia4 and Hts1, were all validated as Hmt1 substrates. Interestingly, the majority of these also had human orthologs, or family members, that have been documented elsewhere to carry arginine methylation. These results confirm arginine methylation as a widespread modification and Hmt1 as the major arginine methyltransferase in the S. cerevisiae cell. PMID- 26572823 TI - Spirituality and spiritual care in Iran: nurses' perceptions and barriers. AB - AIM: This study aimed to explore the perception of Iranian nurses concerning spiritual care and to reveal any confronted barriers. BACKGROUND: Although the context of spiritual care is a substantial aspect of holistic care, the delivery of spiritual care has been problematic due to lack of nurses' understanding of this concept. INTRODUCTION: Nurses' perceptions of spirituality and spiritual care directly influence their performance as well as their relationships with patients. METHODS: This cross-sectional survey was conducted in 2013 with 259 nurses working in hospitals affiliated with Qazvin University of Medical Sciences, Iran. Data were collected using the Spirituality and Spiritual Care Rating Scale alongside qualitative open-ended questions. Descriptive and inferential statistics were used for the quantitative data and content analysis for the qualitative data. RESULTS: The overall average for spirituality and spiritual care was 2.84 (score range: 1-4), indicating a moderate mean score. A significant relationship was found between education level and spiritual care. The majority of participants believed that they did not receive enough training in this aspect of care. The main obstacles regarding delivering spiritual care included busy working schedules, insufficient knowledge regarding spiritual care, low motivation, diversity of patients' spiritual needs and feeling 'unqualified' to provide spiritual cares. DISCUSSION: Consistent with the previous studies, this study has demonstrated that nurses had low confidence to meet the spiritual needs of patients due to lack of knowledge and training in this regard. CONCLUSION: Iranian nurses' perception of spirituality and spiritual care is moderate, reflecting that they do not receive sufficient training regarding spiritual care. IMPLICATIONS FOR NURSING AND/OR HEALTH POLICY: Despite the attention focused on spiritual care in clinical settings in Iran, there remains a significant gap in terms of meeting the spiritual needs of patients in nursing practice. This finding assists nursing clinicians, educators and policy makers to more effectively approach spiritual care as a beneficial component of holistic care. It is proposed that more emphasis is placed on integrating spirituality content into educational programmes to enable more effective clinical delivery. In addition, it would be beneficial to implement more widespread cultural assessment in order to further benefit spiritual care practices. PMID- 26572824 TI - pH-sensitive Itaconic acid based polymeric hydrogels for dye removal applications. AB - A series of Itaconic Acid (IA) based pH-sensitive polymeric hydrogels were synthesized by condensation polymerization of Itaconic Acid (IA) with Ethylene Glycol (EG) in the presence of an acid medium resulted into pre-polymer. Further, pre-polymer were co-polymerized with Acrylic Acid (AA) through free radical polymerization using Potassium persulphate (KPS). The structural and surface morphological characterizations of the synthesized hydrogels were studied using FT-IR spectroscopy and Scanning Electron Microscope (SEM) respectively. The swelling and swelling equilibrium were performed at varies pH (4.0-10.0). Further, the effects of IA, EG and AA on swelling properties have also been investigated. Thermal stability of synthesized hydrogels have been investigated by TGA, DTA and DSC. The synthesized hydrogels have shown good ability to uptake a Cationic dye. The Methylene blue has been chosen as a model cationic dye. The results of dye removal using IA hydrogels found to have excellent dye removal capacity. Such kind of IA based hydrogels may be recommended for eco-friendly environmental application. viz., removal of dyes and metal ions and sewage water treatment, purification of water etc. PMID- 26572825 TI - UV Damage-Induced Phosphorylation of HBO1 Triggers CRL4DDB2-Mediated Degradation To Regulate Cell Proliferation. AB - Histone acetyltransferase binding to ORC-1 (HBO1) is a critically important histone acetyltransferase for forming the prereplicative complex (pre-RC) at the replication origin. Pre-RC formation is completed by loading of the MCM2-7 heterohexameric complex, which functions as a helicase in DNA replication. HBO1 recruited to the replication origin by CDT1 acetylates histone H4 to relax the chromatin conformation and facilitates loading of the MCM complex onto replication origins. However, the acetylation status and mechanism of regulation of histone H3 at replication origins remain elusive. HBO1 positively regulates cell proliferation under normal cell growth conditions. Whether HBO1 regulates proliferation in response to DNA damage is poorly understood. In this study, we demonstrated that HBO1 was degraded after DNA damage to suppress cell proliferation. Ser50 and Ser53 of HBO1 were phosphorylated in an ATM/ATR DNA damage sensor-dependent manner after UV treatment. ATM/ATR-dependently phosphorylated HBO1 preferentially interacted with DDB2 and was ubiquitylated by CRL4(DDB2). Replacement of endogenous HBO1 in Ser50/53Ala mutants maintained acetylation of histone H3K14 and impaired cell cycle regulation in response to UV irradiation. Our findings demonstrate that HBO1 is one of the targets in the DNA damage checkpoint. These results show that ubiquitin-dependent control of the HBO1 protein contributes to cell survival during UV irradiation. PMID- 26572826 TI - Adipocyte-Specific Hypoxia-Inducible Factor 2alpha Deficiency Exacerbates Obesity Induced Brown Adipose Tissue Dysfunction and Metabolic Dysregulation. AB - Angiogenesis is a central regulator for white (WAT) and brown (BAT) adipose tissue adaptation in the course of obesity. Here we show that deletion of hypoxia inducible factor 2alpha (HIF2alpha) in adipocytes (by using Fabp4-Cre transgenic mice) but not in myeloid or endothelial cells negatively impacted WAT angiogenesis and promoted WAT inflammation, WAT dysfunction, hepatosteatosis, and systemic insulin resistance in obesity. Importantly, adipocyte HIF2alpha regulated vascular endothelial growth factor (VEGF) expression and angiogenesis of obese BAT as well as its thermogenic function. Consistently, obese adipocyte specific HIF2alpha-deficient mice displayed BAT dysregulation, associated with reduced levels of uncoupling protein 1 (UCP1) and a dysfunctional thermogenic response to cold exposure. VEGF administration reversed WAT and BAT inflammation and BAT dysfunction in adipocyte HIF2alpha-deficient mice. Together, our findings show that adipocyte HIF2alpha is protective against maladaptation to obesity and metabolic dysregulation by promoting angiogenesis in both WAT and BAT and by counteracting obesity-mediated BAT dysfunction. PMID- 26572827 TI - Inhibition of Acid Sphingomyelinase Depletes Cellular Phosphatidylserine and Mislocalizes K-Ras from the Plasma Membrane. AB - K-Ras must localize to the plasma membrane for biological activity; thus, preventing plasma membrane interaction blocks K-Ras signal output. Here we show that inhibition of acid sphingomyelinase (ASM) mislocalizes both the K-Ras isoforms K-Ras4A and K-Ras4B from the plasma membrane to the endomembrane and inhibits their nanoclustering. We found that fendiline, a potent ASM inhibitor, reduces the phosphatidylserine (PtdSer) and cholesterol content of the inner plasma membrane. These lipid changes are causative because supplementation of fendiline-treated cells with exogenous PtdSer rapidly restores K-Ras4A and K Ras4B plasma membrane binding, nanoclustering, and signal output. Conversely, supplementation with exogenous cholesterol restores K-Ras4A but not K-Ras4B nanoclustering. These experiments reveal different operational pools of PtdSer on the plasma membrane. Inhibition of ASM elevates cellular sphingomyelin and reduces cellular ceramide levels. Concordantly, delivery of recombinant ASM or exogenous ceramide to fendiline-treated cells rapidly relocalizes K-Ras4B and PtdSer to the plasma membrane. K-Ras4B mislocalization is also recapitulated in ASM-deficient Neimann-Pick type A and B fibroblasts. This study identifies sphingomyelin metabolism as an indirect regulator of K-Ras4A and K-Ras4B signaling through the control of PtdSer plasma membrane content. It also demonstrates the critical and selective importance of PtdSer to K-Ras4A and K Ras4B plasma membrane binding and nanoscale spatial organization. PMID- 26572828 TI - The Mediator Subunit MED16 Transduces NRF2-Activating Signals into Antioxidant Gene Expression. AB - The KEAP1-NRF2 system plays a central role in cytoprotection. NRF2 is stabilized in response to electrophiles and activates transcription of antioxidant genes. Although robust induction of NRF2 target genes confers resistance to oxidative insults, how NRF2 triggers transcriptional activation after binding to DNA has not been elucidated. To decipher the molecular mechanisms underlying NRF2 dependent transcriptional activation, we purified the NRF2 nuclear protein complex and identified the Mediator subunits as NRF2 cofactors. Among them, MED16 directly associated with NRF2. Disruption of Med16 significantly attenuated the electrophile-induced expression of NRF2 target genes but did not affect hypoxia induced gene expression, suggesting a specific requirement for MED16 in NRF2 dependent transcription. Importantly, we found that 75% of NRF2-activated genes exhibited blunted inductions by electrophiles in Med16-deficient cells compared to wild-type cells, which strongly argues that MED16 is a major contributor supporting NRF2-dependent transcriptional activation. NRF2-dependent phosphorylation of the RNA polymerase II C-terminal domain was absent in Med16 deficient cells, suggesting that MED16 serves as a conduit to transmit NRF2 activating signals to RNA polymerase II. MED16 indeed turned out to be essential for cytoprotection against oxidative insults. Thus, the KEAP1-NRF2-MED16 axis has emerged as a new regulatory pathway mediating the antioxidant response through the robust activation of NRF2 target genes. PMID- 26572829 TI - JP-HHT phenotype in Danish patients with SMAD4 mutations. AB - Patients with germline mutations in SMAD4 can present symptoms of both juvenile polyposis syndrome (JPS) and hereditary hemorrhagic telangiectasia (HHT): the JP HHT syndrome. The complete phenotypic picture of this syndrome is only just emerging. We describe the clinical characteristics of 14 patients with SMAD4 mutations. The study was a retrospective, register-based study. SMAD4 mutations carriers were identified through the Danish HHT-registry, the genetic laboratories - and the genetic departments in Denmark. The medical files from relevant departments were reviewed and symptoms of HHT, JPS, aortopathy and family history were noted. We detected 14 patients with SMAD4 mutations. All patients had polyps removed and 11 of 14 fulfilled the diagnostic criteria for JPS. Eight patients were screened for HHT-symptoms and seven of these fulfilled the Curacao criteria. One patient had aortic root dilation. Our findings support that SMAD4 mutations carriers have symptoms of both HHT and JPS and that the frequency of PAVM and gastric involvement with polyps is higher than in patients with HHT or JPS not caused by a SMAD4 mutation. Out of eight patients screened for aortopathy, one had aortic root dilatation, highlighting the need for additional screening for aortopathy. PMID- 26572831 TI - Smith-Magenis syndrome in monozygotic twin fetuses presenting with discordant phenotypes and uteroplacental insufficiency. AB - Smith-Magenis syndrome (SMS) is a rare condition with multiple congenital malformations caused by the haploinsufficiency of RAI1 (deletion or mutation of RAI1). However, the correlation between genotype and phenotype is not well understood. The present study describes the prenatal diagnosis of monozygotic twins with a 17p11.2 deletion, which is indicative of SMS, who presented with discordant phenotypes and uteroplacental insufficiency. A high-resolution genome wide single nucleotide polymorphism array revealed a 3.7-Mb deletion in the 17p11.2 chromosome region. Accurate breakpoints of the deletion in these patients were used to identify correlations between SMS and the concomitant phenotypes, particularly uteroplacental insufficiency, which has rarely been investigated in SMS. In addition, no exonic mutations were identified in or affected known disease-associated loci that could explain the congenital anomalies, according to a model that accounts for the possibility of incomplete penetrance. Furthermore, a novel benign copy number variation (a duplication of 195 kb at 13q12.13) was identified but was unlikely to be clinically significant in the discordant phenotypes of the twins. The present study showed that multiple interacting genetic and environmental factors are involved in determining the variance of the SMS phenotype. PMID- 26572830 TI - Does the piezoelectric surgical technique produce fewer postoperative sequelae after lower third molar surgery than conventional rotary instruments? A systematic review and meta analysis. AB - A systematic review and meta-analysis was conducted to answer the clinical question "Does the piezoelectric surgical technique produce fewer postoperative sequelae after lower third molar surgery than conventional rotary instruments?" A systematic and electronic search of several databases with specific key words, a reference search, and a manual search were performed from respective dates of inception through November 2014. The inclusion criteria were clinical human studies, including randomized controlled trials (RCTs), controlled clinical trials (CCTs), and retrospective studies, with the aim of comparing the piezoelectric surgical osteotomy technique to the standard rotary instrument technique in lower third molar surgery. Postoperative sequelae (oedema, trismus, and pain), the total number of analgesics taken, and the duration of surgery were analyzed. A total of nine articles were included, six RCTs, two CCTs, and one retrospective study. Six studies had a low risk of bias and three had a moderate risk of bias. A statistically significant difference was found between piezoelectric surgery and conventional rotary instrument surgery for lower third molar extraction with regard to postoperative sequelae (oedema, trismus, and pain) and the total number of analgesics taken (P=0.0001, P=0.0001, P<0.00001, and P<0.0001, respectively). However, a statistically significant increased surgery time was required in the piezoelectric osteotomy group (P<0.00001). The results of the meta-analysis showed that piezoelectric surgery significantly reduced the occurrence of postoperative sequelae (oedema, trismus, and pain) and the total number of analgesics taken compared to the conventional rotary instrument technique in lower third molar surgery, but required a longer surgery time. PMID- 26572832 TI - Variability in penetrance of multiple endocrine neoplasia 2A with amino acid substitutions in RET codon 634. AB - OBJECTIVE: Controversy surrounds the importance of the different amino acids substituting for cysteine in REarranged during Transfection (RET) codon 634 for multiple endocrine neoplasia 2A (MEN 2A). This study aimed to clarify the relevance of these amino acid substitutions for the development of MEN 2A. DESIGN: Cross-sectional study at surgical referral centres in Germany. PATIENTS: Included were 184 carriers of RET mutations in codon 634. MEASUREMENTS: Arginine (79 carriers) and tyrosine (50 carriers) substitutions in codon 634 were compared with each other and, for the first time, gauged against a common reference standard comprising all other amino acid substitutions (phenylalanine, 35 carriers; serine, 12 carriers; glycine, 7 carriers; tryptophan, 1 carrier). RESULTS: Arginine substitutions in codon 634 were associated with higher penetrance of medullary thyroid cancer (MTC; 82% vs 62%; P = 0.010), any phaeochromocytoma (44% vs 15%, P < 0.001), bilateral phaeochromocytoma (32% vs 5%; P < 0.001) and primary hyperparathyroidism (18% vs 5%; P = 0.039) relative to the reference standard. The penetrance rates of any phaeochromocytoma (44% vs 26%; P = 0.041) and bilateral phaeochromocytoma (32% vs 14%; P = 0.035) were also higher with arginine than with tyrosine substitutions. Corrected for multiple testing, the associations of arginine with any phaeochromocytoma and bilateral phaeochromocytoma remained statistically significant. Progression of MTC, evidenced by largest primary tumour diameter, nodal status, distant metastasis and biochemical cure, did not differ by amino acid substitution. CONCLUSIONS: In codon 634, arginine substitutions for cysteine may cause slightly higher penetrance rates of MEN 2A which, overall, are too small to treat carriers differently. The mode of action by which arginine exerts these subtle effects warrants further research. PMID- 26572833 TI - Toward a harmonized approach for environmental assessment of human activities in the marine environment. AB - With a foreseen increase in maritime activities, and driven by new policies and conventions aiming at sustainable management of the marine ecosystem, spatial management at sea is of growing importance. Spatial management should ensure that the collective pressures caused by anthropogenic activities on the marine ecosystem are kept within acceptable levels. A multitude of approaches to environmental assessment are available to provide insight for sustainable management, and there is a need for a harmonized and integrated environmental assessment approach that can be used for different purposes and variable levels of detail. This article first provides an overview of the main types of environmental assessments: "environmental impact assessment" (EIA), "strategic environmental assessment" (SEA), "cumulative effect assessment" (CEA), and "environmental (or ecological) risk assessment" (ERA). Addressing the need for a conceptual "umbrella" for the fragmented approaches, a generic framework for environmental assessment is proposed: cumulative effects of offshore activities (CUMULEO). CUMULEO builds on the principle that activities cause pressures that may lead to adverse effects on the ecosystem. Basic elements and variables are defined that can be used consistently throughout sequential decision-making levels and diverse methodological implementations. This enables environmental assessment to start at a high strategic level (i.e., plan and/or program level), resulting in early environmental awareness and subsequently more informed, efficient, and focused project-level assessments, which has clear benefits for both industry and government. Its main strengths are simplicity, transparency, flexibility (allowing the use of both qualitative and quantitative data), and visualization, making it a powerful framework to support discussions with experts, stakeholders, and policymakers. Integr Environ Assess Manag 2016;12:632 642. (c) 2015 SETAC. PMID- 26572834 TI - A rapid dissolution procedure to aid initial nuclear forensics investigations of chemically refractory compounds and particles prior to gamma spectrometry. AB - A rapid and effective preparative procedure has been evaluated for the accurate determination of low-energy (40-200 keV) gamma-emitting radionuclides ((210)Pb, (234)Th, (226)Ra, (235)U) in uranium ores and uranium ore concentrates (UOCs) using high-resolution gamma ray spectrometry. The measurement of low-energy gamma photons is complicated in heterogeneous samples containing high-density mineral phases and in such situations activity concentrations will be underestimated. This is because attenuation corrections, calculated based on sample mean density, do not properly correct where dense grains are dispersed within a less dense matrix (analogous to a nugget effect). The current method overcomes these problems using a lithium tetraborate fusion that readily dissolves all components including high-density, self-attenuating minerals/compounds. This is the ideal method for dissolving complex, non-volatile components in soils, rocks, mineral concentrates, and other materials where density reduction is required. Lithium borate fusion avoids the need for theoretical efficiency corrections or measurement of matrix matched calibration standards. The resulting homogeneous quenched glass produced can be quickly dissolved in nitric acid producing low density solutions that can be counted by gamma spectrometry. The effectiveness of the technique is demonstrated using uranium-bearing Certified Reference Materials and provides accurate activity concentration determinations compared to the underestimated activity concentrations derived from direct measurements of a bulk sample. The procedure offers an effective solution for initial nuclear forensic studies where complex refractory minerals or matrices exist. It is also significantly faster, safer and simpler than alternative approaches. PMID- 26572835 TI - Review of the recent progress in photoresponsive molecularly imprinted polymers containing azobenzene chromophores. AB - Photoresponsive molecularly imprinted polymers (PMIPs) containing azobenzene have received wide research attention in recent years and made notable achievements. This article reviews the recent developments on PMIPs containing azobenzene. Topics include the following: (i) brief introduction of azobenzene, molecularly imprinted polymers, and PMIPs containing azobenzene; (ii) progress in functional monomers, cross-linkers, and polymerization conditions; (iii) preparation methods, properties, applications, as well as advantages and disadvantages of conventional PMIPs; (iv) substrate, preparation method, and applications of photoresponsive surface molecularly imprinted polymers; and (v) some perspectives for further development of PMIPs containing azobenzene. PMID- 26572836 TI - From sample treatment to biomarker discovery: A tutorial for untargeted metabolomics based on GC-(EI)-Q-MS. AB - This tutorial provides a comprehensive description of the GC-MS-based untargeted metabolomics workflow including: ethical approval requirement, sample collection and storage, equipment maintenance and setup, sample treatment, monitoring of analytical variability, data pre-processing including deconvolution by free software such as AMDIS, data processing, statistical analysis and validation, detection of outliers and biological interpretation of the results. For each stage tricks will be suggested, pitfalls will be highlighted and advice will be provided on how to get the best from this methodology and technique. In addition, a step-by-step procedure and an example of our in-house library have been included in the supplementary material to lead the user through the concepts described herein. As a case study, an interesting example from one of our experiments at CEMBIO Research Centre is described, presenting an example of the use of this ready-to use protocol for identification of a metabolite that was not previously included in Fiehn commercial target library. PMID- 26572837 TI - A novel approach for honey pollen profile assessment using an electronic tongue and chemometric tools. AB - Nowadays the main honey producing countries require accurate labeling of honey before commercialization, including floral classification. Traditionally, this classification is made by melissopalynology analysis, an accurate but time consuming task requiring laborious sample pre-treatment and high-skilled technicians. In this work the potential use of a potentiometric electronic tongue for pollinic assessment is evaluated, using monofloral and polyfloral honeys. The results showed that after splitting honeys according to color (white, amber and dark), the novel methodology enabled quantifying the relative percentage of the main pollens (Castanea sp., Echium sp., Erica sp., Eucaliptus sp., Lavandula sp., Prunus sp., Rubus sp. and Trifolium sp.). Multiple linear regression models were established for each type of pollen, based on the best sensors' sub-sets selected using the simulated annealing algorithm. To minimize the overfitting risk, a repeated K-fold cross-validation procedure was implemented, ensuring that at least 10-20% of the honeys were used for internal validation. With this approach, a minimum average determination coefficient of 0.91 +/- 0.15 was obtained. Also, the proposed technique enabled the correct classification of 92% and 100% of monofloral and polyfloral honeys, respectively. The quite satisfactory performance of the novel procedure for quantifying the relative pollen frequency may envisage its applicability for honey labeling and geographical origin identification. Nevertheless, this approach is not a full alternative to the traditional melissopalynologic analysis; it may be seen as a practical complementary tool for preliminary honey floral classification, leaving only problematic cases for pollinic evaluation. PMID- 26572838 TI - Facile synthesis of gallium ions immobilized and adenosine functionalized magnetic nanoparticles with high selectivity for multi-phosphopeptides. AB - Despite recent advances in phosphoproteome research, detection and characterization of multi-phosphopeptides have remained a challenge. Here we present a novel IMAC strategy for effective extracting multi-phosphopeptides from complex samples, through Ga(3+) chelation to the adenosine tri-phosphate (ATP) functionalized magnetic nanoparticles (Ga(3+)-ATP-MNPs). The high specificity of Ga(3+)-ATP-MNPs was demonstrated by efficient enriching multi-phosphopeptides from the digest mixture of beta-casein and BSA with molar ratio as low as 1:5000. Ga(3+)-ATP-MNPs were also successfully applied for the phosphoproteome analysis of rat liver mitochondria, resulting in the identification of 193 phosphopeptides with 331 phosphorylation sites from 158 phosphoproteins. In other words, 54.4% of the phosphopeptides trapped by Ga(3+)-ATP-MNPs were observed with more than one phosphorylated sites, resulting in significant improvement on the identification of peptides with multi-phosphorylated sites. The high specificity of Ga(3+)-ATP MNPs towards multi-phosphopeptides may be due to the synergistic effect of the strong hydrophilic surface functionalized by ATP and the proper chelating strength provided by Ga(3+). Moreover, the unique magnetic core of Ga(3+)-ATP MNPs also facilitates the isolation process and on-plate enrichment for direct MALDI MS analysis with limit of detection as low as 30 amol. This new affinity based protocol is expected to provide a powerful approach for characterizing multiple phosphorylation sites on proteins in complex and dilute analytes, which may be explored as complementary technique for improving the coverage of phosphoproteome. PMID- 26572839 TI - Cooling/heating-assisted headspace solid-phase microextraction of polycyclic aromatic hydrocarbons from contaminated soils. AB - A simple, low-cost, and effective cooling/heating-assisted headspace solid-phase microextraction (CHA-HS-SPME) device, capable of direct cooling the fiber to low temperatures and simultaneous heating the sample matrix to high temperatures, was fabricated and evaluated. It was able to cool down the commercial and handmade fibers for the effective tapping of volatile and semi-volatile species in the headspace of complex solid matrices, with minimal manipulation compared with conventional SPME. The CHA-HS-SPME system can create large temperature gaps (up to 200 degrees C) between the fiber and the sample matrix, because the cooling process is directly applied onto the fiber. Different effective experimental parameters for the fabrication of the CHA-HS-SPME device as well as for the extraction and determination of polycyclic aromatic hydrocarbons (PAHs) from solid samples were evaluated and optimized. The proposed device coupled to GC-FID was successfully applied for the extraction and determination of PAHs in contaminated soils without any sample pretreatment step. Good agreement was observed between the results obtained by the proposed CHA-HS-SPME-GC-FID method and those achieved by validated method. PMID- 26572840 TI - Analysis of aldehydes in human exhaled breath condensates by in-tube SPME-HPLC. AB - In this paper, polypyrrole/graphene (PPy/G) composite coating was prepared by a facile electrochemical polymerization strategy on the inner surface of a stainless steel (SS) tube. Based on the coating tube, a novel online in-tube solid-phase microextraction -high performance liquid chromatography (IT-SPME HPLC) was developed and applied for the extraction of aldehydes in the human exhaled breath condensates (EBC). The hybrid PPy/G nanocomposite exhibits remarkable chemical and mechanical stability, high selectivity, and satisfactory extraction performance toward aldehyde compounds. Moreover, the proposed online IT-SPME-HPLC method possesses numerous superiorities, such as time and cost saving, process simplicity, high precision and sensitivity. Some parameters related to extraction efficiency were optimized systematically. Under the optimal conditions, the recoveries of the aldehyde compounds at three spiked concentration levels varied in the range of 85%-117%. Good linearity was obtained with excellent correlation coefficients (R(2)) being larger than 0.994. The relative standard deviations (n = 5) of the method ranged from 1.8% to 11.3% and the limits of detection were between 2.3 and 3.3 nmol L(-1). The successful application of the proposed method in human EBC indicated that it is a promising approach for the determination of trace aldehyde metabolites in complex EBC samples. PMID- 26572841 TI - Development and characterization of a nanodendritic silver-based solid-phase extraction sorbent for selective enrichment of endocrine-disrupting chemicals in water and milk samples. AB - In this study, 4-[4-phenylazo-phenoxy] butyl-1-thiol (AzSH) functionalized nanodendritic silver (AzS@AgNDs) materials were prepared as a solid-phase extraction (SPE) sorbent for the selective extraction of estrogens. AzS@AgNDs possess an extremely large surface-to-volume ratio and a small average particle size. The performance of the material was evaluated by selective enrichment of hexestrol, diethylstilbestrol, dienestrol and bisphenol A in water and milk samples followed by rapid ultra-performance liquid chromatography-electrospray ionization mass spectrometry (UPLC-ESI-MS) analyses. The results exhibited that AzS@AgNDs had excellent adsorption capability for the targeted estrogens. The limits of detection of the four estrogens ranged from 0.1 to 5.0 pg/mL. The recoveries of the estrogens spiked into tap water were over the range of 83.6 105.3% with relative standard deviations of 2.8-6.0%. The results indicated the capability of this method for the rapid determination of estrogens in milk and other environmental water samples. In addition, this method would be useful for the determination of human exposure and health risk assessments trace level of endocrine-disrupting compounds (EDCs) in drinking water. PMID- 26572842 TI - Gold nanoparticles immobilized hydrophilic monoliths with variable functional modification for highly selective enrichment and on-line deglycosylation of glycopeptides. AB - The poly (glycidyl methacrylate-co-poly (ethylene glycol) diacrylate) monoliths modified with gold nanoparticles, with advantages of enhanced reactive sites, good hydrophilicity and facile modification, were prepared as the matrix, followed by variable functionalization with cysteine and PNGase F for glycopeptide enrichment and on-line deglycosylation respectively. By the cysteine functionalized monolithic column, glycopeptides could be efficiently and selectively enriched with good reproducibility based on hydrophilic interaction chromatography (HILIC). Furthermore, the enrichment was specially achieved in weak alkaline environment, with 10 mM NH4HCO3 as the elution buffer, compatible with deglycosylation conditions. Therefore, the glycopeptides could be on-line deglycosylated with high efficiency and throughput by directly coupling the PNGase F functionalized monolithic column with the enrichment column during elution without the requirement of buffer exchange and pH adjustment. By such a method, within only 70-min pretreatment, 196 N-linked glycopeptides, corresponding to 122 glycoproteins, could be identified from 5 MUg of human plasma with 14 high-abundant proteins removed, and the N-linked glycopeptides occupied 81% of all identified peptides, achieving to the best of our knowledge, the highest selectivity of HILIC-based methods. All the results demonstrated the high efficiency, selectivity and throughput of our proposed strategy for the large scale glycoproteome analysis. PMID- 26572843 TI - A label-free fluorescent probe based on DNA-templated silver nanoclusters and exonuclease III-assisted recycling amplification detection of nucleic acid. AB - A number of specific nucleic acids are closely related with many serious diseases, in the current research, a platform taking advantage of exonuclease III (Exo III) to realize double recycling amplification and label-free fluorescent DNA-templated silver nanoclusters (DNA-AgNCs) for detecting of nucleic acid had been developed. In this method, a molecular beacon (MB) with 3'-protruding termini and a single-stranded cytosine-rich (C-rich) probe were designed that coexist stably with Exo III. Once the target DNA appeared, portion of the MB could hybridize with target DNA and was digested by Exo III, which allowed the release of target DNA and a residual sequence. Subsequently, the residual sequence could trigger the Exo III to digest C-rich probe, and the DNA-AgNCs was not able to be synthesized because of the C-rich probe was destroyed; finally the fluorescent of solution was quenched. This assay enables to monitor human hemochromatosis gene (as a model) with high sensitivity, the detection limit is as low as 120 pM compared with other fluorescence DNA-AgNCs methods, this assay also exhibits superior specificity even against single base mismatch. The strategy is applied to detect human hemochromatosis gene in real human serum samples successfully. PMID- 26572844 TI - Two rhodamine lactam modulated lysosome-targetable fluorescence probes for sensitively and selectively monitoring subcellular organelle pH change. AB - Be a powerful technique for convenient detection of pH change in living cells, especially at subcellular level, fluorescent probes has attracted more and more attention. In this work, we designed and synthesized three rhodamine lactam modulated fluorescent probes RS1, RS2 and RS3, which all respond sensitively toward weak acidity (pH range 4-6) via the photophysical property in buffer solution without interference from the other metal ions, and they also show ideal pKa values and excellent reversibility. Particularly, by changing the lone pair electrons distribution of lactam-N atom with different conjugations, RS2 and RS3 exhibit high quantum yield, negligible cytotoxicity and excellent permeability. They are suitable to stain selectively lysosomes of tumor cells and monitor its pH changes sensitively via optical molecular imaging. The above findings suggest that the probes we designed could act as ideal and easy method for investigating the pivotal role of H(+) in lysosomes and are potential pH detectors in disease diagnosis through direct intracellular imaging. PMID- 26572845 TI - A colorimetric, ratiometric and water-soluble fluorescent probe for simultaneously sensing glutathione and cysteine/homocysteine. AB - A chlorinated coumarin-aldehyde was developed as a colorimetric and ratiometric fluorescent probe for distinguishing glutathione (GSH), cystenine (Cys) and homocysteine (Hcy). The GSH-induced substitution-cyclization and Cys/Hcy-induced substitution-rearrangement cascades lead to the corresponding thiol-coumarin iminium cation and amino-coumarin-aldehyde with distinct photophysical properties. The probe can be used to simultaneously detect GSH and Cys/Hcy by visual determination based on distinct different colors - red and pale-yellow in PBS buffer solution by two reaction sites. From the linear relationship of fluorescence intensity and biothiols concentrations, it was determined that the limits of detection for GSH, Hcy and Cys are 0.08, 0.09 and 0.18 MUM, respectively. Furthermore, the probe was successfully used in living cell imaging with low cell toxicity. PMID- 26572846 TI - Investigation of the kinetic process of solid phase microextraction in complex sample. AB - The presence of complex matrix in the aquatic system affects the environmental behavior of hydrophobic organic compounds (HOCs). In the current study, an automated solid-phase microextraction (SPME) desorption method was employed to study the effect of 2-hydroxypropyl-beta-cyclodextrin (beta-HPCD) on the kinetic process of 5 selected polyaromatic hydrocarbons (PAHs) desorbing from the fiber in aqueous sample. The results showed that the added beta-HPCD facilitated the desorption rates of PAHs from SPME fiber coating, and the enhancement effect can be predicted by a proposed theoretical model. Based on this model, the kinetic parameters of organic compounds desorbing from the SPME fiber can be determined, and the calculated results showed good agreement with the experimental data. In addition, the effect of temperature on the desorption kinetic was investigated. The results found that the SPME desorption time constant increased as the sampling temperature elevated, and followed the Arrhenius equation. Also, the temperature facilitated the desorption of HOCs from the bound matrix so that increased the lability degrees of the bound compounds. Finally, a calibration method based on the proposed theoretical model was developed and applied for the analysis of unknown sample. PMID- 26572847 TI - Influence of AIDS in collagen deposition and thickness of the bone marrow. AB - Bone marrow abnormalities are frequently observed in individuals with AIDS. Dysplasia, the most common abnormality, is found in more than 50% of patients infected with the HIV. The aim of this study was to assess trabecular thickness and collagen content as well as cellularity in the bone marrow of patients with AIDS. Sixty bone marrow samples were collected from the sternum of autopsied patients with or without AIDS (n = 30, each). Cellularity and trabecular thickness was assessed by performing hematoxylin-eosin staining; picrosirius staining was used to evaluate collagen content. Morphometric analyses were performed by using a Zeiss KS300 system (Kontron-Zeiss). Patients with AIDS showed a significant reduction in trabecular bone thickness and an increase in collagen deposition. No statistically significant differences were observed in cellularity between the 2 groups. Therefore, reduced thickness and increased collagen deposition were observed in the trabeculae of the bone marrow of patients with AIDS due to possible interaction between cytokines and bone marrow components. PMID- 26572848 TI - Exposure to prenatal consultation during pediatric surgery residency: Implications for training. AB - PURPOSE: Prenatal consultation is an important skill that should be learned during pediatric surgery training, but there are no formal guidelines for fellowship programs at this time. We sought to characterize the fellowship experience of recent pediatric surgery graduates and assess preparedness for providing prenatal consultation. METHODS: An anonymous online survey of pediatric surgery fellows graduating in 2012 and 2013 was performed. We asked respondents to describe participation in prenatal consultation and preparedness to perform consultation. We measured demographics and fellowship characteristics and tested associations between these variables and preparedness to perform prenatal consultation. RESULTS: A total of 49 out of 80 fellows responded to the survey (61% response rate). Most respondents (55%) saw five or fewer prenatal consults during fellowship, and 20% had not seen any prenatal consults. 47% said that fellowship could have better prepared them to perform prenatal consults. Fellows who saw more than 5 prenatal consults during fellowship (33% vs 77%, p=0.002) or described their fellowship as being structured to facilitate participation in prenatal consults (83% vs 27%, p<0.0001) were more likely to feel prepared. Stepwise logistic regression revealed that after adjusting for covariates, fellows graduating from programs that were 1) structured to facilitate participation in prenatal consults (OR 18, 95% CI 3.7-86.7), or 2) did NOT have an established fetal program (OR 5.5, 95% CI 1.1-27.8) were more likely to feel prepared. CONCLUSION: Exposure to prenatal consultation varies greatly across pediatric surgery fellowships, and many recent graduates do not feel prepared to perform prenatal consultation. The presence of an established fetal program did not necessarily translate into improved fellow training. Efforts should be made to standardize the approach to fellow education in this area and ensure that adequate guidance and resources are available to recently graduated pediatric surgeons. PMID- 26572849 TI - Factors associated with survival in pediatric adrenocortical carcinoma: An analysis of the National Cancer Data Base (NCDB). AB - PURPOSE: Adrenocortical carcinoma (ACC) is a rare tumor in children with important distinctions from the adult disease. We reviewed the National Cancer Data Base (NCDB) to determine factors associated with long-term survival. METHODS: The NCDB was queried for patients less than 18 years of age who were diagnosed with ACC between 1998 and 2011. Kaplan-Meier analysis was utilized to determine factors significantly associated with overall survival. RESULTS: A total of 111 patients were included (median age: 4 years, 69% female). ACC was more common in the youngest cohort, with 48% of cases occurring in children younger than the age of 3. Median tumor size was 9.5 cm (IQR: 6.5-13.0), and 87% of patients underwent some form of surgical resection. Among children with available data, 19 of 62 presented with metastases. Overall 1- and 3-year survival was 70% and 64%, respectively. Age, tumor size, extension of tumor into surrounding tissue, and metastatic disease were all found to be significantly associated with survival. Among patients who underwent a surgical procedure, margin status was also found to be significantly associated with survival. CONCLUSION: Age, tumor size, extension of tumor, metastatic disease, and margin status are significantly associated with long-term survival in children with adrenocortical carcinoma. PMID- 26572850 TI - Laparoscopic Nissen fundoplication in infants with hypoplastic left heart syndrome. AB - BACKGROUND/PURPOSE: Patients with hypoplastic left heart syndrome (HLHS) experience a higher risk for complications from gastroesophageal reflux, prompting frequent need for fundoplication. Patients between stage I and II palliation ("interstage") are at particularly high operative risk because of the parallel nature of their pulmonary and systemic blood flow. Laparoscopic approach for fundoplication is common for pediatric patients. However, its safety in interstage HLHS is relatively unknown. We examined the perioperative physiologic burden of a laparoscopic fundoplication in HLHS patients. METHODS: All patients who underwent open or laparoscopic fundoplication during the interstage period at our institution since 2006 were reviewed. Perioperative physiologic data, echocardiographic findings, survival, and complications were collected from the anesthetic record and patient chart. RESULTS: Nineteen patients with HLHS had laparoscopic fundoplication, 13 (68%) during the interstage period, compared to 64 performed by the open approach. Ten (77%) of 13 interstage patients had perioperative hemodynamic instability. Incidence of instability between open and laparoscopic groups was not different. One laparoscopic patient required ECMO support for shunt thrombosis. CONCLUSIONS: Despite a high incidence of hemodynamic instability, overall outcomes are consistent with those reported in the literature for this high-risk patient population. Laparoscopic approach for fundoplication during the interstage period appears to be a relatively safe option for these patients. PMID- 26572851 TI - Factors associated with peritoneal dialysis catheter complications in children. AB - BACKGROUND/PURPOSE: Peritoneal dialysis (PD) is a common method of renal replacement therapy for children. However, placement of PD catheters has risk, and some are never used. METHODS: We conducted a retrospective chart review of children with a PD catheter placed between 2000 and 2014. Logistic regression analyses were used to identify covariates associated with complications. RESULTS: We identified 175 children with PD catheters. 110 complications developed in 80 children (45.7%). Complications including unexpected return to the operating room and peritonitis increased as the length of time a catheter was in place increased. Children who weighed <12.4 kg had 3.2 times greater odds of developing a leak (95% CI 1.21-8.63, p=0.02). Twelve children never used their PD catheters, 9 with acute kidney injury (AKI) who recovered from their disease more quickly than expected. No covariate was associated with nonuse. CONCLUSIONS: Complications with PD catheters are common and increase the longer catheters are in place. Lower weight children are at greater risk of PD catheter leak. Decreased initial volumes of dialysate in smaller children may mitigate this risk. Nonuse may be reduced if dialysis is permitted the day of placement for children with AKI. PMID- 26572852 TI - Can we expect a favorable outcome after surgical treatment for an anorectal malformation? AB - BACKGROUND: The aim of this study was to retrospectively review the classification, surgical experience, and the functional outcome of anorectal malformations (ARMs) according the type of ARM. METHODS: A total of 311 children (M:F=200:111) who underwent surgical treatment for ARM between 1990 and 2011 were reviewed. Functional outcomes were evaluated using the Krickenbeck classification. The mean follow-up period was 112.2 +/- 76.7months (range: 36.8 414.9months). RESULTS: In the male patients, 90 (45%) had perineal fistulas, 60 (30%) had urethral fistulas, and 7 (3.5%) had rectovesical fistulas. There were 17 cases of ARM without a fistula (8.5%), and we could not determine the type of fistula in 26 boys (13%) because of follow-up losses and death. In the female patients, 34 (30.6%) had perineal fistulas, 71 (64%) had rectovestibular fistulas, and 2 (1.8%) had rectovaginal fistulas. Four patients did not have a fistula (3.6%). For 264 patients, we did anoplasty (121 cases), fistula transposition (14 cases), and posterior sagittal anorectoplasty (PSARP, 129 cases). We found that 224 (84.8%) patients showed voluntary bowel movements. The overall rate for constipation was 30.7% and for soiling was 6.5%. The continence outcome was good for 82.2% of children, fair for 2.7%, and poor for 15.2%. For rectovestibular fistulas, constipation was higher in the perineal operation group, but the continence outcome was similar. CONCLUSION: Through a review of 20years' experience, an accurate diagnosis based on the Krickenbeck classification and operations following the principles of PSARP are crucial to achieve a good functional outcome in children with an ARM. PMID- 26572854 TI - Assessing the costs of mobile voluntary counseling and testing at the work place versus facility based voluntary counseling and testing in Namibia. AB - INTRODUCTION: Bophelo! is a mobile voluntary counseling and testing (VCT) and wellness screening program operated by PharmAccess at workplaces in Namibia, funded from both public and private resources. Publicly funded fixed site New Start centers provide similar services in Namibia. At this time of this study, no comparative information on the cost effectiveness of mobile versus fixed site service provision was available in Namibia to inform future programming for scale up of VCT. The objectives of the study were to assess the costs of mobile VCT and wellness service delivery in Namibia and to compare the costs and effectiveness with fixed site VCT testing in Namibia. METHODS: The full direct costs of all resources used by the mobile and fixed site testing programs and data on people tested and outcomes were obtained from PharmAccess and New Start centers in Namibia. Data were also collected on the source of funding, both public donor funding and private funding through contributions from employers. The data were analyzed using Microsoft Excel to determine the average cost per person tested for HIV. RESULTS: In 2009, the average cost per person tested for HIV at the Bophelo! mobile clinic was an estimated US$60.59 (US$310,451 for the 5124 people tested). Private employer contributions to the testing costs reduced the public cost per person tested to US$37.76. The incremental cost per person associated with testing for conditions other than HIV infection was US$11.35, an increase of 18.7%, consisting of the costs of additional tests (US$8.62) and staff time (US$2.73). The cost of testing one person for HIV in 2009 at the New Start centers was estimated at US$58.21 (US$4,082,936 for the 70 143 people tested). CONCLUSIONS: Mobile clinics can provide cost-effective wellness testing services at the workplace and have the potential to mobilize local private funding sources. Providing wellness testing in addition to VCT can help address the growing issue of non-communicable diseases. PMID- 26572855 TI - Older prisoners: psychological distress and associations with mental health history, cognitive functioning, socio-demographic, and criminal justice factors. AB - BACKGROUND: The growth among older prisoner populations, including in Australia, necessitates an understanding of this group in order to generate effective management strategies. One particular concern is the mental well-being of older prisoners. This study aimed to determine the level of psychological distress among sentenced prisoners aged 50 years and older, to compare this level to that seen among younger prisoners and older people in the community, and to investigate which mental health history, cognitive functioning, socio demographic, and criminal justice characteristics were associated with psychological distress. METHODS: A cross-sectional survey of 173 older (M = 63 years) and 60 younger prisoners (M = 34 years) in two Australian jurisdictions was conducted. The Kessler Psychological Distress (K10) scale was administered with prisoners and additional data were collected from interviews and participant health and corrections files. K10 scores were compared to community norms using data from the Australian Health Survey. RESULTS: Average K10 scores of the older prisoners were significantly lower than the younger prisoners' (p = 0.04), though the effect size was small (r = 0.1). Significantly, higher distress levels were observed in comparison to the general population (p < 0.001), with older prisoners being three times more likely to display very high levels of distress (12.3% vs. 3.7%). Higher psychological distress scores among older prisoners were significantly associated with female gender (p = 0.002) and a history of mental health issues (p = 0.002). CONCLUSIONS: While the levels of distress seen among older prisoners were significantly lower than that of younger prisoners, their higher levels of distress in comparison to community norms demonstrate a need for correctional services to be attuned to the mental health of the expanding older prisoner population. PMID- 26572856 TI - Evaluation of the GROMOS 56ACARBO Force Field for the Calculation of Structural, Volumetric, and Dynamic Properties of Aqueous Glucose Systems. AB - Glucose is an important carbohydrate, relevant both for its biological functions and as a raw material for industrial processes. As a monomer of cellulose, the most abundant biopolymer, it is an alternative feedstock for fuels and chemicals in the biorefinery framework. Since glucose is often used and processed in aqueous solutions, it is important to understand the structural, volumetric, and dynamic properties of aqueous glucose solutions at varying concentrations. Molecular dynamics (MD) simulations are an effective means for computing the properties of liquid solutions, but the technique relies upon accurate intermolecular potential functions (i.e., "force fields"). Here we evaluate the accuracy of the recently developed GROMOS 56ACARBO glucose force field for its ability to model the density, viscosity, and self-diffusivity of aqueous glucose solutions as a function of concentration. We also compute different structural properties, including hydrogen bonds, radial and spatial distribution functions, and coordination numbers. The results show that the force field accurately models the density and viscosity of dilute solutions up to a glucose mole fraction of 0.1. At higher glucose concentrations, the force field overestimates the experimental density and viscosity. By analyzing the liquid structure, it is found that the glucose molecules tend to associate at higher concentrations, which leads to deviation from the experimental results. This suggests that, while the GROMOS 56ACARBO force field performs well for highly dilute glucose solutions (conditions under which it was developed), it is not appropriate for carrying out simulations of more concentrated glucose solutions. It is possible to obtain much more accurate densities and viscosities at high glucose concentrations by uniformly reducing the partial charges on glucose by 20%, which attenuates the self-association tendencies of glucose. PMID- 26572857 TI - Detection of early blight and late blight diseases on tomato leaves using hyperspectral imaging. AB - This study investigated the potential of using hyperspectral imaging for detecting different diseases on tomato leaves. One hundred and twenty healthy, one hundred and twenty early blight and seventy late blight diseased leaves were selected to obtain hyperspectral images covering spectral wavelengths from 380 to 1023 nm. An extreme learning machine (ELM) classifier model was established based on full wavelengths. Successive projections algorithm (SPA) was used to identify the most important wavelengths. Based on the five selected wavelengths (442, 508, 573, 696 and 715 nm), an ELM model was re-established. Then, eight texture features (mean, variance, homogeneity, contrast, dissimilarity, entropy, second moment and correlation) based on gray level co-occurrence matrix (GLCM) at the five effective wavelengths were extracted to establish detection models. Among the models which were established based on spectral information, all performed excellently with the overall classification accuracy ranging from 97.1% to 100% in testing sets. Among the eight texture features, dissimilarity, second moment and entropy carried most of the effective information with the classification accuracy of 71.8%, 70.9% and 69.9% in the ELM models. The results demonstrated that hyperspectral imaging has the potential as a non-invasive method to identify early blight and late blight diseases on tomato leaves. PMID- 26572859 TI - Current practice of neonatal resuscitation documentation in North America: a multi-center retrospective chart review. AB - BACKGROUND: To determine the comprehensiveness of neonatal resuscitation documentation and to determine the association of various patient, provider and institutional factors with completeness of neonatal documentation. METHODS: Multi center retrospective chart review of a sequential sample of very low birth weight infants born in 2013. The description of resuscitation in each infant's record was evaluated for the presence of 29 Resuscitation Data Items and assigned a Number of items documented per record. Covariates associated with this Assessment were identified. RESULTS: Charts of 263 infants were reviewed. The mean gestational age was 28.4 weeks, and the mean birth weight 1050 g. Of the infants, 69 % were singletons, and 74 % were delivered by Cesarean section. A mean of 13.2 (SD 3.5) of the 29 Resuscitation Data Items were registered for each birth. Items most frequently present were; review of obstetric history (98 %), Apgar scores (96 %), oxygen use (77 %), suctioning (71 %), and stimulation (62 %). In our model adjusted for measured covariates, the institution was significantly associated with documentation. CONCLUSIONS: Neonatal resuscitation documentation is not standardized and has significant variation. Variation in documentation was mostly dependent on institutional factors, not infant or provider characteristics. Understanding this variation may lead to efforts to standardize documentation of neonatal resuscitation. PMID- 26572858 TI - The trans-SNARE-regulating function of Munc18-1 is essential to synaptic exocytosis. AB - The fusion of neurotransmitter-filled synaptic vesicles with the plasma membrane requires two classes of molecules-SNAP receptor (SNARE) and Sec1/Munc18 (SM) protein. Reconstitution studies suggest that the SM protein Munc18-1 promotes the zippering of trans-SNARE complexes and accelerates the kinetics of SNARE dependent membrane fusion. However, the physiological role of this trans-SNARE regulating function in synaptic exocytosis remains to be established. Here we first demonstrate that two mutations in the vesicle-anchored v-SNARE selectively impair the ability of Munc18-1 to promote trans-SNARE zippering, whereas other known Munc18-1/SNARE-binding modes are unaffected. In cultured neurons, these v SNARE mutations strongly inhibit spontaneous as well as evoked neurotransmitter release, providing genetic evidence for the trans-SNARE-regulating function of Munc18-1 in synaptic exocytosis. Finally, we show that the trans-SNARE-regulating function of Munc18-1 is compromised by a mutation associated with Ohtahara Syndrome, a severe form of epilepsy. PMID- 26572860 TI - Patients' expectations of coming home with Very Early Supported Discharge and home rehabilitation after stroke - an interview study. AB - BACKGROUND: An Early Supported Discharge (ESD) and rehabilitation from a coordinated team in the home environment is recommended in several high-income countries for patients with mild to moderate symptoms after stroke. Returning home from the hospital takes place very early in Sweden today (12 days post stroke), thus the term Very Early Supported Discharge (VESD) is used in the current study. The aim of this study was to describe patients' expectations of coming home very early after stroke with support and rehabilitations at home. METHOD: This is an interview study nested within a randomized controlled trial; Gothenburg Very Early Supported Discharge (GOTVED), comparing VESD containing a home rehabilitation intervention from a coordinated team to conventional care after stroke. Ten participants (median age 69) with mild to moderate stroke symptoms (NHISS 0 to 8 points) were recruited from the intervention group in GOTVED. Interviews were conducted 0-5 days before discharge and the material was analyzed with qualitative content analysis. RESULTS: Four main categories containing 11 subcategories were found. The VESD team was expected to provide "Support towards independency", by helping the participants to manage and feel safe at home as well as to regain earlier abilities. The very early discharge gave rise to expectations of coming home to "A new and unknown situation", causing worries not to manage at home and to leave the safe environment at the ward. A fear to suffer a recurrent stroke when being out of reach of immediate professional help was also pronounced. In contrast to these feelings of insecurity and fear, "Returning to one's own setting" described the participants longing home, where they would become autonomous and capable people again. They expected this to facilitate recovery and rehabilitation. "A new everyday life" waited for the participants at home and this was expected to be challenging. Different strategies to deal with these challenges were described. CONCLUSIONS: The participants described mixed expectations such as insecurity and fear, and on the other hand, longing to come home. Moreover, they had a high degree of confidence in the expected support of the VESD team. The health professionals at the hospital may build on this trust to reduce the patients' insecurity for coming home. In addition, it may be beneficial to explore the patients' expectations thoroughly in front of discharge, as certain feelings and thoughts could complicate or support the home coming process. Thus, a greater attention on such expectations may facilitate the patient's transition from hospital to home after stroke. PMID- 26572861 TI - Characteristics and spread to the native population of HIV-1 non-B subtypes in two European countries with high migration rate. AB - BACKGROUND: Non-B subtypes account for at least 50 % of HIV-1 infections diagnosed in Belgium and Luxembourg. They are considered to be acquired through heterosexual contacts and infect primarily individuals of foreign origin. Information on the extent to which non-B subtypes spread to the local population is incomplete. METHODS: Pol and env gene sequences were collected from 410 non subtype B infections. Profound subtyping was performed using 5 subtyping tools and sequences of both pol and env. Demographic information, disease markers (viral load, CD4 count) and viral characteristics (co-receptor tropism) were compared between subtypes. Maximum likelihood phylogenetic trees were constructed and examined for clustering. RESULTS: The majority of non-B infections were diagnosed in patients originating from Africa (55.8 %), individuals born in Western Europe represented 30.5 %. Heterosexual transmission was the most frequently reported transmission route (79.9 %), MSM transmission accounted for 12.2 % and was significantly more frequently reported for Western Europeans (25.7 % versus 4.3 % for individuals originating from other regions; p < 0.001). Subtypes A and C and the circulating recombinant forms CRF01_AE and CRF02_AG were the most represented and were included in the comparative analysis. Native Western Europeans were underrepresented for subtype A (14.5 %) and overrepresented for CRF01_AE (38.6 %). The frequency of MSM transmission was the highest for CRF01_AE (18.2 %) and the lowest for subtype A (0 %). No differences in age, gender, viral load or CD4 count were observed. Prevalence of CXCR4-use differed between subtypes but largely depended on the tropism prediction algorithm applied. Indications for novel intersubtype recombinants were found in 20 patients (6.3 %). Phylogenetic analysis revealed only few and small clusters of local transmission but could document one cluster of CRF02_AG transmission among Belgian MSM. CONCLUSIONS: The extent to which non-B subtypes spread in the native Belgian-Luxembourg population is higher than expected, with 30.5 % of the non-B infections diagnosed in native Western Europeans. These infections resulted from hetero- as well as homosexual transmission. Introduction of non-B variants in the local high at risk population of MSM may lead to new sub-epidemics and/or increased genetic variability and is an evolution that needs to be closely monitored. PMID- 26572863 TI - Editor's perspectives - November 2015. PMID- 26572862 TI - MicroRNA regulation of unfolded protein response transcription factor XBP1 in the progression of cardiac hypertrophy and heart failure in vivo. AB - BACKGROUND: XBP1 is a key transcription factor of the unfolded protein response in mammalian cells, which is involved in several cardiovascular pathological progression including cardiac hypertrophy and myocardial infarction, but its expression trend, function and upstream regulate mechanism in the development of heart failure are unclear. In the present study, therefore, the potential role of miRNAs in the regulation of XBP1 expression in heart failure was examined. METHODS AND RESULTS: First, western blots showed that cardiac expression of ER stress marker XBP1 were induced in the early adaptive phase, but decreased in the maladaptive phase in hypertrophic and failing heart, while there was no obvious change of upstream ATF6 and IRE1 activity in this progression. Interestingly, we further found that XBP1 and its downstream target VEGF were attenuated by miR-30* and miR-214 in cardiomyocyte. Moreover, we found that miR-30* was significantly reduced in the early phase of cardiac hypertrophic animal model and in human failing hearts, while both miR-214 and miR-30* were increased in the maladaptive diseased heart, thereby contribute to impairment of cardiac XBP1 and VEGF expression. CONCLUSIONS: These results provide the first clear link between miRNAs and direct regulation of XBP1 in heart failure and reveal that miR-214 and miR-30* synergistically regulates cardiac VEGF expression and angiogenesis by targeting XBP1 in the progression from adaptive hypertrophy to heart failure. PMID- 26572864 TI - Signaled drug delivery and transport across the blood-brain barrier. AB - We use a mathematical model to describe the delivery of a drug to a specific region of the brain. The drug is carried by liposomes that can release their cargo by application of focused ultrasound (US). Thereupon, the drug is absorbed through the endothelial cells that line the brain capillaries and form the physiologically important blood-brain barrier (BBB). We present a compartmental model of a capillary that is able to capture the complex binding and transport processes the drug undergoes in the blood plasma and at the BBB. We apply this model to the delivery of levodopa (L-dopa, used to treat Parkinson's disease) and doxorubicin (an anticancer agent). The goal is to optimize the delivery of drug while at the same time minimizing possible side effects of the US. PMID- 26572866 TI - Bioreactor performance parameters for an industrially-promising methanotroph Methylomicrobium buryatense 5GB1. AB - BACKGROUND: Methane is a feedstock of interest for the future, both from natural gas and from renewable biogas sources. Methanotrophic bacteria have the potential to enable commercial methane bioconversion to value-added products such as fuels and chemicals. A strain of interest for such applications is Methylomicrobium buryatense 5GB1, due to its robust growth characteristics. However, to take advantage of the potential of this methanotroph, it is important to generate comprehensive bioreactor-based datasets for different growth conditions to compare bioprocess parameters. RESULTS: Datasets of growth parameters, gas utilization rates, and products (total biomass, extracted fatty acids, glycogen, excreted acids) were obtained for cultures of M. buryatense 5GB1 grown in continuous culture under methane limitation and O2 limitation conditions. Additionally, experiments were performed involving unrestricted batch growth conditions with both methane and methanol as substrate. All four growth conditions show significant differences. The most notable changes are the high glycogen content and high formate excretion for cells grown on methanol (batch), and high O2:CH4 utilization ratio for cells grown under methane limitation. CONCLUSIONS: The results presented here represent the most comprehensive published bioreactor datasets for a gamma-proteobacterial methanotroph. This information shows that metabolism by M. buryatense 5GB1 differs significantly for each of the four conditions tested. O2 limitation resulted in the lowest relative O2 demand and fed-batch growth on methane the highest. Future studies are needed to understand the metabolic basis of these differences. However, these results suggest that both batch and continuous culture conditions have specific advantages, depending on the product of interest. PMID- 26572865 TI - Hybrid STTR intervention for heterosexuals using anonymous HIV testing and confidential linkage to care: a single arm exploratory trial using respondent driven sampling. AB - BACKGROUND: An estimated 14 % of the 1.2 million individuals living with HIV in the U.S. are unaware of their status. Yet this modest proportion of individuals with undiagnosed HIV is linked to 44-66 % of all new infections. Thus innovative intervention approaches are needed to seek out and test those with undiagnosed HIV, and link them to HIV treatment with high retention, an approach referred to as "Seek, Test, Treat, and Retain" (STTR). The present protocol describes a creative "hybrid" STTR approach that uses anonymous HIV testing followed by confidential care linkage, focused on heterosexuals at high risk (HHR) for HIV, who do not test as frequently as, and are diagnosed later, than other risk groups. METHODS/DESIGN: This is a single-arm exploratory intervention efficacy trial. The study has two phases: one to seek out and test HHR, and another to link those found infected to HIV treatment in a timely fashion, with high retention. We will recruit African American/Black and Latino adult HHR who reside in urban locations with high poverty and HIV prevalence. Participants will be recruited with respondent-driven sampling, a peer recruitment method. The "Seek and Test" phase is comprised of a brief, convenient, single-session, anonymous HIV counseling and testing session. The "Treat and Retain" component will engage those newly diagnosed with HIV into a confidential research phase and use a set of procedures called care navigation to link them to HIV primary care. Participants will be followed for 6 months with objective assessment of outcomes (using medical records and biomarkers). DISCUSSION: Undiagnosed HIV infection is a major public health problem. While anonymous HIV testing is an important part of the HIV testing portfolio, it does not typically include linkage to care. The present study has potential to produce an innovative, brief, cost-effective, and replicable STTR intervention, and thereby reduce racial/ethnic disparities in HIV/AIDS. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02421159 , Registered April 15, 2015. PMID- 26572867 TI - Post-transcriptional regulation of SHANK3 expression by microRNAs related to multiple neuropsychiatric disorders. AB - BACKGROUND: Proper neuronal function requires tight control of gene dosage, and failure of this process underlies the pathogenesis of multiple neuropsychiatric disorders. The SHANK3 gene encoding core scaffolding proteins at glutamatergic postsynapse is a typical dosage-sensitive gene, both deletions and duplications of which are associated with Phelan-McDermid syndrome, autism spectrum disorders, bipolar disorder, intellectual disability, or schizophrenia. However, the regulatory mechanism of SHANK3 expression in neurons itself is poorly understood. RESULTS: Here we show post-transcriptional regulation of SHANK3 expression by three microRNAs (miRNAs), miR-7, miR-34a, and miR-504. Notably, the expression profiles of these miRNAs were previously shown to be altered in some neuropsychiatric disorders which are also associated with SHANK3 dosage changes. These miRNAs regulated the expression of SHANK3 and other genes encoding actin related proteins that interact with Shank3, through direct binding sites in the 3' untranslated region (UTR). Moreover, overexpression or inhibition of miR-7 and miR-504 affected the dendritic spines of the cultured hippocampal neurons in a Shank3-dependent manner. We further characterized miR-504 as it showed the most significant effect on both SHANK3 expression and dendritic spines among the three miRNAs. Lentivirus-mediated overexpression of miR-504, which mimics its reported expression change in postmortem brain tissues of bipolar disorder, decreased endogenous Shank3 protein in cultured hippocampal neurons. We also revealed that miR-504 is expressed in the cortical and hippocampal regions of human and mouse brains. CONCLUSIONS: Our study provides new insight into the miRNA-mediated regulation of SHANK3 expression, and its potential implication in multiple neuropsychiatric disorders associated with altered SHANK3 and miRNA expression profiles. PMID- 26572868 TI - Consistency of Use and Effectiveness of Household Water Treatment Practices Among Urban and Rural Populations Claiming to Treat Their Drinking Water at Home: A Case Study in Zambia. AB - Household water treatment (HWT) can improve drinking water quality and prevent disease, if used correctly and consistently. While international monitoring suggests that 1.8 billion people practice HWT, these estimates are based on household surveys that may overstate the level of consistent use and do not address microbiological effectiveness. We sought to examine how HWT is practiced among households identified as HWT users according to international monitoring standards. Case studies were conducted in urban and rural Zambia. After a baseline survey (urban: 203 households, rural: 276 households) to identify HWT users, 95 urban and 82 rural households were followed up for 6 weeks. Consistency of HWT reporting was low; only 72.6% of urban and 50.0% of rural households reported to be HWT users in the subsequent visit. Similarly, availability of treated water was low, only 23.3% and 4.2% of urban and rural households, respectively, had treated water on all visits. Drinking water was significantly worse than source water in both settings. Only 19.6% of urban and 2.4% of rural households had drinking water free of thermotolerant coliforms on all visits. Our findings raise questions about the value of the data gathered through the international monitoring of HWT practices as predictors of water quality in the home. PMID- 26572869 TI - Cholera Outbreak in Grande Comore: 1998-1999. AB - In 1998, a cholera epidemic in east Africa reached the Comoros Islands, an archipelago in the Mozambique Channel that had not reported a cholera case for more than 20 years. In just a little over 1 year (between January 1998 and March 1999), Grande Comore, the largest island in the Union of the Comoros, reported 7,851 cases of cholera, about 3% of the population. Using case reports and field observations during the medical response, we describe the epidemiology of the 1998-1999 cholera epidemic in Grande Comore. Outbreaks of infectious diseases on islands provide a unique opportunity to study transmission dynamics in a nearly closed population, and they may serve as stepping-stones for human pathogens to cross unpopulated expanses of ocean. PMID- 26572870 TI - Smartphone Microscopy of Parasite Eggs Accumulated into a Single Field of View. AB - A Nokia Lumia 1020 cellular phone (Microsoft Corp., Auckland, New Zealand) was configured to image the ova of Ascaris lumbricoides converged into a single field of view but on different focal planes. The phone was programmed to acquire images at different distances and, using public domain computer software, composite images were created that brought all the eggs into sharp focus. This proof of concept informs a framework for field-deployable, point of care monitoring of soil-transmitted helminths. PMID- 26572871 TI - Severe Dengue Fever Outbreak in Taiwan. AB - Dengue fever (DF) is a vector-borne disease caused by dengue viruses (DENVs). Epidemic dengue occurs intermittently in Taiwan. In 2014, Taiwan experienced its largest DF outbreak. There were 15,732 DF cases reported. There were a total of 136 dengue hemorrhagic fever (DHF) cases, of which 20 resulted in death. Most DF cases were reported in southern Taiwan. A total of 15,043 (96%) cases were from Kaohsiung, a modern city in southern Taiwan. This report reviews DF epidemics in Taiwan during 2005-2014. The correlation between DF and DHF along with temperature and precipitation were conjointly examined. We conclude that most dengue epidemics in Taiwan resulted from imported DF cases. Results indicate three main factors that may have been associated with this DF outbreak in Kaohsiung: an underground pipeline explosion combined with subsequent rainfall and higher temperature. These factors may have enhanced mosquito breeding activity, facilitating DENV transmission. PMID- 26572872 TI - Analysis of the Bacterial Diversity in Liver Abscess: Differences Between Pyogenic and Amebic Abscesses. AB - Several recent studies have demonstrated that virulence in Entamoeba histolytica is triggered in the presence of both pathogenic and nonpathogenic bacteria species using in vitro and in vivo experimental animal models. In this study, we examined samples aspirated from abscess material obtained from patients who were clinically diagnosed with amebic liver abscess (ALA) or pyogenic liver abscess (PLA). To determine the diversity of bacterial species in the abscesses, we performed partial 16S rRNA gene sequencing. In addition, the E. histolytica and Entamoeba dispar species were genotyped using tRNA-linked short tandem repeats as specific molecular markers. The association between clinical data and bacterial and parasite genotypes were examined through a correspondence analysis. The results showed the presence of numerous bacterial groups. These taxonomic groups constitute common members of the gut microbiota, although all of the detected bacterial species have a close phylogenetic relationship with bacterial pathogens. Furthermore, some patients clinically diagnosed with PLA and ALA were coinfected with E. dispar or E. histolytica, which suggests that the virulence of these parasites increased in the presence of bacteria. However, no specific bacterial groups were associated with this effect. Together, our results suggest a nonspecific mechanism of virulence modulation by bacteria in Entamoeba. PMID- 26572873 TI - Using remote, spatial techniques to select a random household sample in a dispersed, semi-nomadic pastoral community: utility for a longitudinal health and demographic surveillance system. AB - BACKGROUND: Obtaining a random household sample can be expensive and challenging. In a dispersed community of semi-nomadic households in rural Tanzania, this study aimed to test an alternative method utilizing freely available aerial imagery. METHODS: We pinned every single-standing structure or boma (compound) in Naitolia, Tanzania using a 'placemark' in Google Earth Pro (version 7.1.2.2041). Next, a local expert assisted in removing misclassified placemarks. A random sample was then selected using a random number generator. The random sample points were mapped and used by survey enumerators to navigate. RESULTS: We created a spatial sample frame and a random sample in 34.5 student working hours, 3 local expert hours and 1.5 academic working hours. Challenges included determining whether homes were occupied or abandoned, developing a protocol for placemark inclusion and quality issues with the aerial imagery itself. In the field, 175 sample points were visited and 170 of these (97%) were actual households. The primary advantages of this method were the: (a) ability to generate a robust random sample in a rural and remote area; (b) lack of reliance on existing, external population data sources; and (c) relatively low levels of funding and time required. CONCLUSIONS: This method to develop a spatial sample frame was efficient and cost-effective when compared to in-field generation of a household inventory or GPS tracking of households. Utilizing a local expert to review the sample frame prior to field testing greatly increased accuracy. Overall, this method is a promising alternative to expensive and possibly biased household inventories or in-field GPS data collection for all households. PMID- 26572874 TI - An apple plus a Brazil nut a day keeps the doctors away: antioxidant capacity of foods and their health benefits. AB - Antioxidant-rich foods scavenge free radicals and other reactive species, decreasing the risk of different non-communicable chronic diseases. The objective of this study was to review the content of total antioxidant capacity of commonly foods comparing with experimental data and to explore the health benefits due to foods with moderate to high TAC. The TAC was analytically measured using the "Total Antioxidant Capacity" (NX2332) test from Randox(r) (UK) by spectrometry at 600 nm. Brazil nut (Bertholletia excelsa), "guarana" (Paullinia cupana Kunth) powder, ready to drink boiled coffee (Coffea arabica L.), and milk chocolate (made from seeds of Theobroma cacao) had the highest TAC values, followed by collard greens (Brassica oleracea L.), beets (Beta vulgaris L.), apples (Malus domestica Borkh.), bananas (Musa paradisiaca), common beans (Phaseolus vulgaris), oranges (Citrus sinensis (L.) Osbeck), onions (Allium cepa L.), and lettuce (Lactuca sativa L.). Other foods also showed antioxidant capacity. The binomial antioxidant capacity of foods and health was extensively discussed according to science literature. Based on the high TAC content of Brazil nuts, guarana, coffee, chocolate, collard greens, apples, beets, beans, oranges, onions and other foods, their regular dietary intake is strongly recommended to reduce the risk of chronic non-communicable diseases. PMID- 26572875 TI - A new prognostic scale for the early prediction of ischemic stroke recovery mainly based on traditional Chinese medicine symptoms and NIHSS score: a retrospective cohort study. AB - BACKGROUND: Ischemic stroke (IS) is a common disease, often resulting in death or disability. Previous studies on prognosis of stroke mainly focused on the baseline condition or modern expensive tests. However, the change of clinical symptoms during acute stage is considerably neglected. In our study, we aim to develop a new prognostic scale to predict the 90-day outcome of IS patients. METHODS: In this retrospective cohort study, a secondary data analysis was performed on 489 patients extracted from 1046 patients of 4 hospitals. A new prognostic scale was constructed to predict the recovery of IS mainly based on the National Institutes of Health Stroke Scale (NIHSS) score, traditional Chinese Medicine (TCM) symptoms & signs and the changes during the first 3 days of patients in the 3 TCM hospitals. Receiver Operating Characteristic (ROC) curve was used to determine the cutoff point for prediction. In the end, the scale was used to test the outcome of IS patients in Xuanwu hospital. RESULTS: The new prognostic scale was composed of 8 items including age degree (OR = 3.32; 95 % CI: 1.72-6.42), history of diabetes mellitus (DM) (OR = 2.20; 95 % CI: 1.19 4.08), NIHSS score (OR = 3.08; 95 % CI: 2.16-4.40), anxiety (OR = 3.17; 95 % CI: 1.90-5.29) and irritability (OR = 4.61; 95 % CI: 1.36-15.63) on the 1st day of illness onset, change in NIHSS score (OR = 2.49; 95 % CI: 1.31-4.73), and circumrotating (OR = 7.80; 95 % CI: 1.98-30.64) and tinnitus (OR = 13.25; 95 % CI: 1.55-113.34) during the first 3 days of stroke onset. The total score of the scale was 16.5 and the cutoff point was 9.5, which means patients would have poor outcome at 90 days of stroke onset if the score was higher than 9.5. The new scale was validated on the data of Xuanwu hospital, and the value of its sensitivity, specificity and overall accuracy were 69.6 %, 83.3 % and 75.0 % respectively. CONCLUSIONS: The 8-item scale, mainly based on TCM symptoms, NIHSS score and their changes during the first 3 days, can predict the 90-day outcome for IS patients while it still needs to be further validated and optimized clinically. PMID- 26572876 TI - Sample storage conditions significantly influence faecal microbiome profiles. AB - Sequencing-based studies of the human faecal microbiota are increasingly common. Appropriate storage of sample material is essential to avoid the introduction of post-collection bias in microbial community composition. Rapid freezing to -80 degrees C is commonly considered to be best-practice. However, this is not feasible in many studies, particularly those involving sample collection in participants' homes. We determined the extent to which a range of stabilisation and storage strategies maintained the composition of faecal microbial community structure relative to freezing to -80 degrees C. Refrigeration at 4 degrees C, storage at ambient temperature, and the use of several common preservative buffers (RNAlater, OMNIgene.GUT, Tris-EDTA) were assessed relative to freezing. Following 72 hours of storage, faecal microbial composition was assessed by 16 S rRNA amplicon sequencing. Refrigeration was associated with no significant alteration in faecal microbiota diversity or composition. However, samples stored using other conditions showed substantial divergence compared to -80 degrees C control samples. Aside from refrigeration, the use of OMNIgene.GUT resulted in the least alteration, while the greatest change was seen in samples stored in Tris-EDTA buffer. The commercially available OMNIgene.GUT kit may provide an important alternative where refrigeration and cold chain transportation is not available. PMID- 26572877 TI - Oxygen Mass Transport in Stented Coronary Arteries. AB - Oxygen deficiency, known as hypoxia, in arterial walls has been linked to increased intimal hyperplasia, which is the main adverse biological process causing in-stent restenosis. Stent implantation has significant effects on the oxygen transport into the arterial wall. Elucidating these effects is critical to optimizing future stent designs. In this study the most advanced oxygen transport model developed to date was assessed in two test cases and used to compare three coronary stent designs. Additionally, the predicted results from four simplified blood oxygen transport models are compared in the two test cases. The advanced model showed good agreement with experimental measurements within the mass transfer boundary layer and at the luminal surface; however, more work is needed in predicting the oxygen transport within the arterial wall. Simplifying the oxygen transport model within the blood flow produces significant errors in predicting the oxygen transport in arteries. This study can be used as a guide for all future numerical studies in this area and the advanced model could provide a powerful tool in aiding design of stents and other cardiovascular devices. PMID- 26572878 TI - Is It Still an Emergency Department if It Can't Treat Children? PMID- 26572879 TI - Directional nanotopographic gradients: a high-throughput screening platform for cell contact guidance. AB - A novel approach was developed using PDMS-substrates with surface-aligned nanotopography gradients, varying unidirectional in amplitude and wavelength, for studying cell behavior with regard to adhesion and alignment. The gradients target more surface feature parameters simultaneously and provide more information with fewer experiments and are therefore vastly superior with respect to individual topography substrates. Cellular adhesion experiments on non gradient aligned nanowrinkled surfaces displayed a linear relationship of osteoblast cell adhesion with respect to topography aspect ratio. Additionally, an aspect ratio of 0.25 was found to be most efficient for cell alignment. Modification of the surface preparation method allowed us to develop an approach for creating surface nanotopography gradients which innovatively provided a superior data collection with fewer experiments showing that 1) low amplitude with small wavenumber is best for osteoblast cell adhesion 2) indeed higher aspect ratios are favorable for alignment however only with features between 80 180 nm in amplitude and 450-750 nm in wavelength with a clear transition between adhesion and alignment efficiency and 3) disproved a linear relationship of cell adhesion towards aspect ratio as was found for single feature substrate analysis. PMID- 26572880 TI - Ventilation monitoring for severe pediatric traumatic brain injury during interfacility transport. AB - BACKGROUND: Ventilation monitoring practice for intubated pediatric patients with severe traumatic brain injury (TBI) during interfacility transport (IFT) has not been well documented. We describe the difference of practices in ventilation monitoring during IFT from the perspective of a level I pediatric trauma center with an enormous catchment area. METHODS: Patients admitted between July 2008 and September 2013 at Winnipeg Health Science Center, Canada, were examined in this retrospective chart review. All patients with severe TBI were intubated in regional health centers and required transport to the level 1 trauma center. Injuries due to inflicted head trauma (<5 years of age), stroke, drowning, and asphyxia were excluded. Patient characteristics, injury data, ventilation monitoring, and transport metrics were obtained from a regional health center, and transport and trauma center charts. RESULTS: Thirty four patients were studied. Specialty transport teams utilized ventilation monitoring significantly more often (95 vs. 23 %; p < 0.001) than non-specialized ground transport. Specialty teams were more likely to obtain a blood gas prior to departure (74 vs. 0 %; p = 0.037) if end-tidal monitoring was used. Among unmonitored ground transport patients, mean transport time was 69.1 min. CONCLUSIONS: Non specialized ground IFT teams did not reliably monitor ventilation in intubated severe pediatric TBI patients. Blood gas monitoring was not a ubiquitous practice for either team. Optimal ventilation monitoring strategies for severe pediatric TBI may require both blood gas and end-tidal monitoring. PMID- 26572881 TI - Work-hour restrictions and orthopaedic resident education: a systematic review. AB - PURPOSE: The ACGME (US) and The European Working Time Directive (UK) placed work hour restrictions on medical trainees with the goal of improved patient safety. However, there has been concern over a potential decrease in medical education. Orthopaedic training is the focus of this study. We examined previously published subjective and objective data regarding education and work-hour restrictions and developed the questions: Do specific perceptions emerge within the subjective studies examined? Are there objective differences in educational measures before and after work-hour restrictions? Is there a difference between the subjective and objective data? METHODS: A systematic review was conducted via MedLine, regarding orthopaedic studies in the USA and UK, with reference to work-hour restrictions and education. RESULTS: Subjective survey studies demonstrate that residents and attending physicians have a negative response to work-hour restrictions because of the perceived impact on their overall education and operating room experience. Conversely, limited objective studies demonstrated no change in operative volume before or after implementation of restrictions. CONCLUSIONS: This review highlights the need for more objective studies on the educational implications of work-hour restrictions. Studies to date have not demonstrated a measurable difference based on case logs or training scores. Opinion-based surveys demonstrate an overall negative perception by both residents and attending physicians, on the impact of work-hour restrictions on orthopaedic education. Current published data is limited and stronger evidence based data are needed before definitive conclusions can be reached. PMID- 26572882 TI - Precision insertion of percutaneous sacroiliac screws using a novel augmented reality-based navigation system: a pilot study. AB - PURPOSE: Augmented reality (AR) enables superimposition of virtual images onto the real world. The aim of this study is to present a novel AR-based navigation system for sacroiliac screw insertion and to evaluate its feasibility and accuracy in cadaveric experiments. METHODS: Six cadavers with intact pelvises were employed in our study. They were CT scanned and the pelvis and vessels were segmented into 3D models. The ideal trajectory of the sacroiliac screw was planned and represented visually as a cylinder. For the intervention, the head mounted display created a real-time AR environment by superimposing the virtual 3D models onto the surgeon's field of view. The screws were drilled into the pelvis as guided by the trajectory represented by the cylinder. Following the intervention, a repeat CT scan was performed to evaluate the accuracy of the system, by assessing the screw positions and the deviations between the planned trajectories and inserted screws. RESULTS: Post-operative CT images showed that all 12 screws were correctly placed with no perforation. The mean deviation between the planned trajectories and the inserted screws was 2.7 +/- 1.2 mm at the bony entry point, 3.7 +/- 1.1 mm at the screw tip, and the mean angular deviation between the two trajectories was 2.9 degrees +/- 1.1 degrees . The mean deviation at the nerve root tunnels region on the sagittal plane was 3.6 +/- 1.0 mm. CONCLUSIONS: This study suggests an intuitive approach for guiding screw placement by way of AR-based navigation. This approach was feasible and accurate. It may serve as a valuable tool for assisting percutaneous sacroiliac screw insertion in live surgery. PMID- 26572883 TI - A comparison of percutaneous trephine excision and open surgery in the treatment of osteoid osteoma. AB - PURPOSE: The aim of this study was to compare CT-assisted percutaneous excision, which is a closed, economic method and a more cosmetic approach, and open surgery in the treatment of osteoid osteoma. MATERIALS AND METHODS: Fifty-three patients (12 female and 41 male patients) who had percutaneous excision (n = 24) and open surgery (n = 29) were evaluated retrospectively. The mean age was 16.6 years and the mean duration of follow-up was 53.5 months. During percutaneous excision, a trephine was advanced through the labeling wire and the site, including the nidus, was excised en-bloc and the incision walls were curetted. During the open surgery, the localization of the nidus was marked using c-arm X-ray and the nidus was accessed by lifting the cortical bone, layer-by-layer, using burr. The nidus was excised and its cavity curetted. RESULTS: The result was successful in 22 and a failure in three patients who had closed excision. The result was successful in 20 and a failure in nine patients who had open surgery. The mean duration of operation was 44.37 minutes in the percutaneous excision group and 80.6 minutes in the open surgery group. There was no difference in the pre-operative VAS values between the two groups, whereas the post-operative VAS values were statistically significantly different. There was also a statistically significant difference in the duration of the operation and the length of the hospital stay between the groups. CONCLUSION: Percutaneous excision with trephine is a more successful, effective, minimally invasive, safe and a better cosmetic approach in the treatment of osteoid osteoma. This method is also a cheap method that does not require expensive equipment. PMID- 26572885 TI - Does emergency surgical treatment allow good nerve recovery in humeral diaphyseal fractures associated with radial palsy? PMID- 26572884 TI - Displaced femoral shaft fractures treated by antegrade nailing with the assistance of an intramedullary reduction device. AB - PURPOSE: This study aims to assess the outcomes of displaced femoral shaft fractures (DFSFs) treated by antegrade nailing with the assistance of a newly invented intramedullary (IM) reduction device. METHODS: From December 2012 to August 2013, 43 adult patients with unilateral DFSFs, including 31 males and 12 females, were enrolled into this study. During the operation, the device was used to adjust the direction of guide wire to insert it into the medullary cavity of distal femur and used as a "joystick" to align the femoral shaft fractures before the insertion of IM nail. The operative time and fluoroscopy time were recorded. Follow-up was conducted to assess the fracture union and functional recovery of the affected limbs. RESULTS: The IM reduction device was used intra-operatively to advance the guide wire into the distal femoral medullary cavity successfully in all 43 cases, with a single attempt in 37 cases and two or three attempts in six cases. The average operative time and fluoroscopy time were 58.3 minutes (40 85 minutes) and 9.2 seconds (4.1-21.8 seconds), respectively. All fractures healed well on an average of 5.4 months post-operatively. No limb-length discrepancy or observable malalignment was noted at the follow ups. CONCLUSIONS: The IM reduction device can facilitate the insertion of a guide wire into the distal femoral medullary cavity in a closed and controllable manner, be used as a "joystick" to align the femoral shaft fracture, and subsequently facilitate IM nail insertion in the proper position. PMID- 26572886 TI - Assessment of fixation in cementless femoral revision of total hip arthroplasty: comparison of the Engh score versus radiolucent line measurement. AB - PURPOSE: To assess osseointegration and stability of a primary cementless femoral stem, many scoring systems have been developed, but none of them have taken into account only the radiolucent line. The purposes of this study were (1) to compare the results between the Engh score to assess osseointegration and stability of the cementless stem with results of a score called the O-SS score (osseointegration-secondary stability), which takes into account the radiolucent line, (2) to verify the relationship between these two scores and the functional results, and (3) to verify if there is a relationship between the O-SS score and secondary subsidence or a pedestal. METHODS: A clinical and radiological evaluation was performed in a group of 100 hip prosthesis revisions comparing the results obtained by Engh score and O-SS score for which reproducibility was analysed. RESULTS: Inter-observer reproducibility was estimated to be average at 0.5 and intra-observer reproducibility good at 0.7. The correlation with the Engh score was good at r = 0.59 (p < 0.0001). For the 80 cases assessed O-SS score as very good/good, Harris hip score was at 83.7 versus 78.25 for the 20 cases assessed as average/poor (p = 0.07). For the 73 cases with assessed Engh score as very good/good, this score was at 82.8 versus 82.14 for the 27 cases assessed as average/poor. No correlation between the O-SS score and secondary subsidence (p = 0.2) or pedestal (p = 0.2) was noticed. CONCLUSION: The evaluation of the clear radiolucent line alone, extent and location, is a sufficient condition to assess osseointegration and secondary stability of a cementless femoral stem. PMID- 26572887 TI - Accuracy of Low Dose Computed Tomography Scanogram for Measurement of Femoral Version after Locked Intramedullary Nailing. AB - PURPOSE: This prospective study was performed to compare the accuracy of femoral version measurements following repair of femoral shaft fractures using computed tomography (CT) scanograms with 10 % of the standard dose of ionizing radiation versus standard-dose scanograms. METHODS: CT scanogram protocols that used 90 and 10 % of the usual dose of ionizing radiation were developed. Ten patients with comminuted femoral shaft fractures repaired with either an intramedullary (IM) nail or plate were imaged with both high- and low-dose CT scanograms. Postoperative version of both femurs was measured and compared between the two dose scans using the Bonesetter application. This was a prospective blinded controlled study at a level 1 trauma centre. Statistical analysis was performed, including standard deviation (SD) and paired t test. Significance was set at p < 0.05. RESULTS: Comparison of femoral version measurements between the 90 and 10 % dose scanograms on the native and repaired sides were insignificant (p = 0.870 and p = 0.737, respectively). The difference between native and repaired femurs had an average error of 2.0 +/- 1.1 degrees for both the high- and low-dose scans and was insignificant (p = 0.742). CONCLUSIONS: Reducing the dose of ionizing radiation in a CT scanogram by 90 % has no significant effect on the accuracy of femoral version measurement. This simple change can significantly reduce patient radiation exposure while accurately measuring femoral version and length. PMID- 26572888 TI - Barbed sutures in total hip and knee arthroplasty: what is the evidence? A meta analysis. AB - INTRODUCTION: Newer methods of wound closure such as bidirectional barbed sutures hold the potential to reduce closure time and thus overall operating room costs during total joint arthroplasty (TJA), including total hip arthroplasty (THA) and total knee arthroplasty (TKA). However, it is unclear whether these sutures have similar clinical outcomes or whether they place the patient at risk of developing wound complications that may outweigh the time-saving benefits of these sutures. METHODS: A systematic review of the literature was performed to identify all level I trials that reported the use of barbed suture during TJA. We analyzed the efficacy, safety, major and minor complications, and overall cost related to barbed sutures. RESULTS: Four studies met our criteria, and included 588 patients who were randomized either to barbed suture closure (n = 290 TJAs, 268 TKAs, and 22 THAs) or to a matched conventional suture cohort (n = 298 TJAs, 279 TKAs, and 19 THA). In terms of time savings with wound closure, the barbed suture was 6.3 minutes faster than the conventional cohort (p < 0.05). The odds for developing a minor complication were nearly identical (odds ratio [OR] 1.04, p = 0.95) and for major complication was not significantly different (OR 2.94, p = 0.27). The overall mean savings including both THA and TKA was USD 298 per case. CONCLUSIONS: In randomized controlled trials, barbed sutures are consistently associated with shorter wound closure time, which also corresponds to cost savings, even when the higher cost of these sutures is taken into account. There was no significant difference in the odds of experiencing either minor or major complications between patients in whom barbed sutures versus standard sutures were used for wound closure. Current evidence supports continued use of these sutures. LEVEL OF EVIDENCE: Level I. PMID- 26572889 TI - Osteogenic progenitors in bone marrow aspirates have clinical potential for tibial non-unions healing in diabetic patients. AB - PURPOSE: There is a significantly higher incidence of delayed unions, non-unions, and increased healing time in diabetic patients compared with non-diabetic patients. Studies suggest that diabetics suffer from deficiencies of pancreatic stem/progenitor cells, and a clinically relevant question arises concerning the availability and functionality of progenitor cells obtained from bone marrow of diabetics for applications in bone repair. METHODS: We have evaluated the cellularity and frequency of osteogenic mesenchymal stem cells (MSCs) in bone marrow from 54 diabetic patients (12 with type 1 and 42 with type 2) with tibial non-unions. These patients were treated with bone marrow MSCs (BM-MSCs) delivered in an autologous bone marrow concentrate (BMC). Clinical outcomes and marrow cellularity were compared to 54 non-diabetic, matched patients with tibial non unions also treated with BMC. RESULTS: After adjusting for age and sex, no differences were identified with respect to bone marrow cellularity and MSC number among the diabetic and non-diabetic groups and both groups received approximately the same number of MSCs on average. BMC treatment promoted non union healing in 41 diabetic patients (76 %) and 49 non-diabetic patients (91 %), but the non-diabetic patients healed more quickly and produced a larger volume of callus. CONCLUSION: We recommend that diabetic patients be treated with an increased number of progenitor cells by increasing the bone marrow aspiration volume. We also anticipate a need to extend the time of casting and non-weight bearing for diabetic patients as compared with non-diabetic patients. PMID- 26572890 TI - Urine color as an indicator of urine concentration in pregnant and lactating women. AB - AIM: Urine concentration measured via osmolality (U OSM) and specific gravity (U SG) reflects the adequacy of daily fluid intake, which has important relationships to health in pregnant (PREG) and lactating (LACT) women. Urine color (U COL) may be a practical, surrogate marker for whole-body hydration status. PURPOSE: To determine whether U COL was a valid measure of urine concentration in PREG and LACT, and pair-matched non-pregnant, non-lactating control women (CON). METHODS: Eighteen PREG/LACT (age 31 +/- 1 years, pre pregnancy BMI 24.3 +/- 5.9 kg m-2) and eighteen CON (age 29 +/- 4 years, BMI 24.1 +/- 3.7 kg m-2) collected 24-h and single-urine samples on specified daily voids at five time points (15 +/- 2, 26 +/- 1, and 37 +/- 1 weeks gestation, 3 +/- 1 and 9 +/- 1 weeks postpartum during lactation; CON visits were separated by similar time intervals) for measurement of 24-h U OSM, U SG, and U COL and single sample U OSM and U COL. RESULTS: Twenty-four-hour U COL was significantly correlated with 24-h U OSM (r = 0.6085-0.8390, P < 0.0001) and 24-h U SG (r = 0.6213-0.8985, P < 0.0001) in all groups. A 24-h U COL >= 4 (AUC = 0.6848-0.9513, P < 0.05) and single-sample U COL >= 4 (AUC = 0.9094-0.9216, P < 0.0001) indicated 24-h U OSM >= 500 mOsm kg-1 (representing inadequate fluid intake) in PREG, LACT, and CON. CONCLUSIONS: Urine color was a valid marker of urine concentration in all groups. Thus, PREG, LACT, and CON can utilize U COL to monitor their daily fluid balance. Women who present with a U COL >= 4 likely have a U OSM >= 500 mOsm kg-1 and should increase fluid consumption to improve overall hydration status. PMID- 26572891 TI - The synergistic effect between the Mediterranean diet and GSTP1 or NAT2 SNPs decreases breast cancer risk in Greek-Cypriot women. AB - PURPOSE: Xenobiotic metabolism is related to the interplay between diet and breast cancer (BC) risk. This involves detoxification enzymes, which are polymorphic and metabolise various dietary metabolites. An important characteristic of this pathway is that chemoprotective micronutrients can act not only as substrates but also as inducers for these enzymes. We investigated whether functional GSTP1 (p.Ile105Val-rs1695), NAT2 (590G>A-rs1799930) SNPs and GSTM1 and GSTT1 deletion polymorphisms could modulate the effect of the Mediterranean diet (MD) on BC risk, in Greek-Cypriot women. METHODS: Genotyping was performed on women from the MASTOS case-control study of BC in Cyprus. A 32 item food-frequency questionnaire was used to obtain dietary intake information. A dietary pattern, which closely resembles the MD (high loadings of vegetables, fruit, legumes and fish), was previously derived with principal component analysis and was used as our dietary variable. RESULTS: GSTT1 null genotype increased BC risk compared with the homozygous non-null GSTT1 genotype (OR 1.21, 95 % CI 1.01-1.45). Increasing adherence to the MD reduced BC risk in women with at least one GSTP1 Ile allele (OR for Ile/Ile = 0.84, 95 % CI 0.74-0.95, for Ile/Val = 0.73, 95 % CI 0.62-0.85) or one NAT2 590G allele (OR for 590 GG = 0.73, 95 % CI 0.63-0.83, for 590 GA = 0.81, 95 % CI 0.70-0.94). p interaction values were not, however, statistically significant. CONCLUSION: The homozygous null GSTT1 genotype could be a risk allele for BC among Greek-Cypriot women. The anticarcinogenic effects of the high adherence to MD against BC risk could also be further enhanced when combined with the wild-type alleles of the detoxification GSTP1 or NAT2 SNPs. PMID- 26572892 TI - aHUS associated with C3 gene mutation: a case with numerous relapses and favorable 20-year outcome. AB - BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is frequently associated with gene mutations in complement-regulatory proteins and activators. Different complement C3 gene mutations have been associated with different outcomes in aHUS. CASE-DIAGNOSIS/TREATMENT: We report the case of a 21-year-old male with a C3 heterozygous gene mutation (p.Ile1157Thr) who developed aHUS at the age of 10 months and had six relapses, the last at the age of 14.5 years. Each relapse was characterized by an apparent predominance of hematological manifestations with milder renal involvement and was followed by complete recovery, with creatinine values and hematological parameters usually recovering after the 3rd to 6th day of hospitalization. The patient was treated with plasma infusion, apart from the initial and the last episode, when dialysis was needed. Twenty years after the onset, he retains normal renal function, with no proteinuria or hypertension. One similar case of highly recurrent aHUS carrying the same C3 mutation as our patient with recovery of renal function has been previously reported. CONCLUSIONS: We further support that aHUS associated with the p.Ile1157Thr C3 mutation may be highly recurrent, but with recovered renal function. The prevalent p.Ile1157Thr C3 gene mutation has variable disease manifestations and both severe and milder renal phenotypes have been found. PMID- 26572893 TI - Acute changes in fluid status affect the incidence, associative clinical outcomes, and urine biomarker performance in premature infants with acute kidney injury. AB - BACKGROUND: During the first postnatal weeks, infants have abrupt changes in fluid weight that alter serum creatinine (SCr) concentration, and possibly, the evaluation for acute kidney injury (AKI). METHODS: We performed a prospective study on 122 premature infants to determine how fluid adjustment (FA) to SCr alters the incidence of AKI, demographics, outcomes, and performance of candidate urine biomarkers. FA-SCr values were estimated using changes in total body water (TBW) from birth; FA-SCR = SCr * [TBW + (current wt. - BW)]/ TBW; where TBW = 0.8 * wt in kg). SCr-AKI and FA-SCr AKI were defined if values increased by >= 0.3 mg/dl from previous lowest value. RESULTS: AKI incidence was lower using the FA SCr vs. SCr definition [(23/122 (18.8 %) vs. (34/122 (27.9 %); p < 0.05)], with concordance in 105/122 (86 %) and discordance in 17/122 (14 %). Discordant subjects tended to have similar demographics and outcomes to those who were negative by both definitions. Candidate urine AKI biomarkers performed better under the FA-SCr than SCr definition, especially on day 4 and days 12-14. CONCLUSIONS: Adjusting SCr for acute change in fluid weight may help differentiate SCr rise from true change in renal function from acute concentration due to abrupt weight change. PMID- 26572894 TI - Smaller circuits for smaller patients: improving renal support therapy with AquadexTM. AB - BACKGROUND: Providing renal support for small children is very challenging using the machinery currently available in the United States. As the extracorporeal volume (ECV) relative to blood volume increases and the state of critical illness worsens, the chance for instability during continuous renal replacement therapy (CRRT) initiation also increases. CRRT machines with smaller ECV could reduce the risks and improve outcomes. METHODS: We present a case series of small children (n = 12) who received continuous venovenous hemofiltration (CVVH) via an AquadexTM machine (ECV = 33 ml) with 30 ml/kg/h of prereplacement fluids at Children's of Alabama between December 2013 and April 2015. We assessed in vitro fluid precision using the adapted continuous veno-venous hemofiltration (CVVH) system. RESULTS: We used 101 circuits over 261 days to provide CVVH for 12 children (median age 30 days; median weight 3.4 kg). Median CVVH duration was 14.5 days [interquartile range (IQR) = 10; 22.8 days]. Most circuits were routinely changed after 72 h. Five of 101 (5 %) initiations were associated with mild transient change in vital signs. Complications were infrequent (three transient cases of hypothermia, three puncture-site bleedings, one systemic bleed, and one right atrial thrombus). Most patients (7/12, 58 %) were discharged from the intensive care unit; six of them (50 %) were discharged home. CONCLUSIONS: CRRT machines with low ECV can enable clinicians to provide adequate, timely, safe, and efficient renal support to small, critically ill infants. PMID- 26572895 TI - Inhibition of hippocampal plasticity in rats performing contrafreeloading for water under repeated administrations of pramipexole. AB - RATIONALE: Compulsive symptoms develop in patients exposed to pramipexole (PPX), a dopaminergic agonist with high selectivity for the D3 receptor. Consistently, we demonstrated that PPX produces an exaggerated increase in contrafreeloading (CFL) for water, a repetitive and highly inflexible behavior that models core aspects of compulsive disorders. OBJECTIVES: Given the role of the hippocampus in behavioral flexibility, motivational control, and visuospatial working memory, we investigated the role of hippocampus in the expression of PPX-induced CFL. To this aim, rats were subjected to CFL under chronic PPX, and then examined for the electrophysiological, structural, and molecular properties of their hippocampus. METHODS: We measured long-term potentiation (LTP) at CA1 Schaffer collaterals, dendritic spine density in CA1 pyramidal neurons, and then glutamate release and expression of pre and postsynaptic proteins in hippocampal synaptosomes. The effects of PPX on hippocampal-dependent working memory were assessed through the novel object recognition (NOR) test. RESULTS: We found that PPX-treated rats showing CFL exhibited a significant decrease in hippocampal LTP and failed to exhibit the expected increase in hippocampal spine density. Glutamate release and PSD-95 expression were decreased, while pSYN expression was increased in hippocampal synaptosomes of PPX-treated rats showing CFL. Despite a general impairment of hippocampal synaptic function, working memory was unaffected by PPX treatment. CONCLUSIONS: Our findings demonstrate that chronic PPX affects synaptic function in the hippocampus, an area that is critically involved in the expression of flexible, goal-centered behaviors. We suggest that the hippocampus is a promising target in the pharmacotherapy of compulsive disorders. PMID- 26572897 TI - Global analysis of the effect of local climate on the hatchling output of leatherback turtles. AB - The most recent climate change projections show a global increase in temperatures along with precipitation changes throughout the 21(st) century. However, regional projections do not always match global projections and species with global distributions may exhibit varying regional susceptibility to climate change. Here we show the effect of local climatic conditions on the hatchling output of leatherback turtles (Dermochelys coriacea) at four nesting sites encompassing the Pacific, Atlantic and Indian Oceans. We found a heterogeneous effect of climate. Hatchling output increased with long-term precipitation in areas with dry climatic conditions (Playa Grande, Pacific Ocean and Sandy Point, Caribbean Sea), but the effect varied in areas where precipitation was high (Pacuare, Caribbean Sea) and was not detected at the temperate site (Maputaland, Indian Ocean). High air temperature reduced hatchling output only at the area experiencing seasonal droughts (Playa Grande). Climatic projections showed a drastic increase in air temperature and a mild decrease in precipitation at all sites by 2100. The most unfavorable conditions were projected for Sandy Point where hatching success has already declined over time along with precipitation levels. The heterogeneous effect of climate may lead to local extinctions of leatherback turtles in some areas but survival in others by 2100. PMID- 26572896 TI - Acute effects of cocaine and cannabis on reversal learning as a function of COMT and DRD2 genotype. AB - RATIONALE: Long-term cannabis and cocaine use has been associated with impairments in reversal learning. However, how acute cannabis and cocaine administration affect reversal learning in humans is not known. OBJECTIVE: In this study, we aimed to establish the acute effects of administration of cannabis and cocaine on valence-dependent reversal learning as a function of DRD2 Taq1A (rs1800497) and COMT Val108/158Met (rs4680) genotype. METHODS: A double-blind placebo-controlled randomized 3-way crossover design was used. Sixty-one regular poly-drug users completed a deterministic reversal learning task under the influence of cocaine, cannabis, and placebo that enabled assessment of both reward- and punishment-based reversal learning. RESULTS: Proportion correct on the reversal learning task was increased by cocaine, but decreased by cannabis. Effects of cocaine depended on the DRD2 genotype, as increases in proportion correct were seen only in the A1 carriers, and not in the A2/A2 homozygotes. COMT genotype did not modulate drug-induced effects on reversal learning. CONCLUSIONS: These data indicate that acute administration of cannabis and cocaine has opposite effects on reversal learning. The effects of cocaine, but not cannabis, depend on interindividual genetic differences in the dopamine D2 receptor gene. PMID- 26572898 TI - A Comprehensive Prevention Approach to Reducing Assault Offenses and Assault Injuries among Youth. AB - Since 2011, the CDC-funded Michigan Youth Violence Prevention Center (MI-YVPC), working with community partners, has implemented a comprehensive prevention approach to reducing youth violence in Flint, MI, based on public health principles. MI-YVPC employed an intervention strategy that capitalizes on existing community resources and application of evidence-based programs using a social-ecological approach to change. We evaluated the combined effect of six programs in reducing assaults and injury among 10-24 year olds in the intervention area relative to a matched comparison community. We used generalized linear mixed models to examine change in the intervention area counts of reported assault offenses and assault injury presentation relative to the comparison area over a period 6 years prior- and 30 months post-intervention. Results indicated that youth victimization and assault injuries fell in the intervention area subsequent to the initiation of the interventions and that these reductions were sustained over time. Our evaluation demonstrated that a comprehensive multi-level approach can be effective for reducing youth violence and injury. PMID- 26572899 TI - Comparison of the anti-inflammatory effect of dexamethasone and ketorolac in the extractions of third molars. AB - This double-blind, split-mouth, and randomized study was aimed to compare the efficacy of dexamethasone and ketorolac tromethamine, through the evaluation of pain, edema, and limitation of mouth opening. Thirty-four individuals aged 18-26 years, having bilateral mandibular third molars, in a similar position, were selected. Two different surgical procedures were performed on the same individual by the single surgeon. For an extraction, the individual received 1 capsule of 10 mg ketorolac tromethamine 1 h before surgery and every 8 h for 2 days. For the extraction of the contralateral side, the individual received 1 capsule of 8 mg dexamethasone 1 h before surgery and 1 placebo capsule every 8 h for 2 days. Sodium metamizol, 500 mg, was given as rescue medication in postoperative. Pain was assessed by the Visual Box Scale-11 points (BS-11) at 24 h postoperative. Edema (metric measurement) and the maximum mouth opening (interincisal) were recorded in the pre-operative, 24 h, 48 h, 72 h and 7 days postoperatively. The results showed that both therapeutic treatments used were effective in the postoperative, and there were no statistically significant differences between the groups for the pain and edema variables. However, for the limitation of mouth opening, 24 h and 7 days postoperatively, the dexamethasone group had a lower limitation of mouth opening, behaving better than the ketorolac for this variable in these periods. Due also to the higher margin of safety, the use of dexamethasone as a single dose becomes a more suitable alternative for use in routine surgical extractions of third molars. PMID- 26572900 TI - Microarray expression profiling and gene ontology analysis of long non-coding RNAs in spontaneously hypertensive rats and their potential roles in the pathogenesis of hypertension. AB - Long non-coding RNAs (lncRNAs) have been demonstrated to be significant in numerous biological processes. Hypertension is a form of cardiovascular disease with at least one billion cases worldwide. The present study sought to compare the differential expression profiles of lncRNAs in the renal cortex of spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto (WKY) rats. The ipsilateral renal cortex was obtained from 15-week-old SHRs and WKY rats whose blood pressures had been monitored. Total RNA was extracted using TRIzol, and lncRNAs and messenger RNAs were profiled by microarray and validated using fluorescent quantitative reverse transcription-polymerase chain reaction. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to predict the function of differentially expressed genes. Microarray analysis demonstrated that 145 lncRNAs were differentially expressed between SHRs and WKY rats. GO and KEGG pathway analysis indicated that these lncRNAs are involved in numerous biological processes. Thus, lncRNAs may contribute to the pathogenesis of hypertension. PMID- 26572901 TI - Highly cross-linked Cu/a-Si core-shell nanowires for ultra-long cycle life and high rate lithium batteries. AB - Seeking long cycle lifetime and high rate performance are still challenging aspects to promote the application of silicon-loaded lithium ion batteries (LIBs), where optimal structural and compositional design are critical to maximize a synergistic effect in composite core-shell nanowire anode structures. We here propose and demonstrate a high quality conformal coating of an amorphous Si (a-Si) thin film over a matrix of highly cross-linked CuO nanowires (NWs). The conformal a-Si coating can serve as both a high capacity storage medium and a high quality binder that joins crossing CuO NWs into a continuous network. And the CuO NWs can be reduced into highly conductive Cu cores in low temperature H2 annealing. In this way, we have demonstrated an excellent cycling stability that lasts more than 700 (or 1000) charge/discharge cycles at a current density of 3.6 A g(-1) (or 1 A g(-1)), with a high capacity retention rate of 80%. Remarkably, these Cu/a-Si core-shell anode structures can survive an extremely high charging current density of 64 A g(-1) for 25 runs, and then recover 75% initial capacity when returning to 1 A g(-1). We also present the first and straightforward experimental proof that these robust highly-cross-linked core-shell networks can preserve the structural integrity even after 1000 runs of cycling. All these results indicate a new and convenient strategy towards a high performance Si loaded battery application. PMID- 26572902 TI - Prevalence and predictors of human papillomavirus (HPV) vaccination among young women surviving childhood cancer. AB - PURPOSE: Human papillomavirus (HPV) is a sexually transmitted infection and the cause of cervical and other cancers. Vaccination is available to protect against genital HPV and is recommended for individuals aged 9-26 years. This study aimed to estimate the prevalence of HPV vaccination among childhood cancer survivors and to identify factors associated with vaccine outcomes. METHODS: Young adult females with (n = 114; M age = 21.18 years, SD = 2.48) and without (n = 98; M age = 20.65 years, SD = 2.29) a childhood cancer history completed surveys querying HPV vaccination initiation/completion, as well as sociodemographic, medical, and health belief factors. Multivariable logistic regression was used to calculate odds ratios (ORs) and 95 % confidence intervals (CIs) for vaccine outcomes. RESULTS: Among survivors, 38.6 % (44/114) and 26.3 % (30/114) initiated or completed vaccination compared to 44.9 % (44/98) and 28.6 % (28/98) among controls, respectively. In the combined survivor/control group, physician recommendation (OR = 11.24, 95 % CI 3.15-40.14) and familial HPV communication (OR = 7.28, 95 % CI 1.89-28.05) associated with vaccine initiation. Perceptions of vaccine benefit associated with vaccine completion (OR = 10.55, 95 % CI 1.59 69.92), whereas perceptions of HPV-related severity associated with non completion (OR = 0.14, 95 % CI 0.03-0.71). CONCLUSION: Despite their increased risk for HPV-related complication, a minority of childhood cancer survivors have initiated or completed HPV vaccination. Modifiable factors associated with vaccine outcomes were identified. IMPLICATIONS FOR CANCER SURVIVORS: HPV vaccination is a useful tool for cancer prevention in survivorship, and interventions to increase vaccine uptake are warranted. PMID- 26572903 TI - Patterns and predictors of survivorship clinic attendance in a population-based sample of pediatric and young adult childhood cancer survivors. AB - PURPOSE: Because many survivors do not receive recommended follow-up, we sought to characterize patterns and predictors of survivorship clinic attendance in a population-based sample of childhood cancer survivors. METHODS: Using the Connecticut Tumor Registry, we identified all patients diagnosed with cancer at age <= 18 years from March 1, 1998 to March 1, 2008, still in follow-up 5 years post-diagnosis, and living <100 miles from Yale. Survivorship clinic attendance, demographics, disease characteristics, and treatment exposures were ascertained. Vital status was confirmed with the National Death Index. The Kaplan-Meier curves and hazard ratios were calculated for survivorship clinic attendance. RESULTS: Four hundred eighty-nine eligible survivors currently 19.1 +/- 6.2 years old were diagnosed at a mean age of 9.1 +/- 5.8 years with leukemias/lymphomas (47.2 %), central nervous system tumors (16.4 %), sarcomas (11.2 %), thyroid cancers or melanomas (7.8 %), and other solid tumors (17.4 %). The 10-year post-diagnosis clinic attendance probability was 27.8 % (SE = 2.3) overall, and 36.9 % (SE = 4.4) and 40.8 % (SE = 3.8), in patients with radiation and anthracycline exposure, respectively. In adjusted analysis, patients with insurance (HR = 2.90; p < 0.01 for private and HR = 2.05; p = 0.02 for public assistance), treated with anthracyclines (HR = 3.05; p < 0.01), and treated with radiation (HR = 1.90; p < 0.01) were significantly more likely to attend clinic. CONCLUSIONS: The majority of childhood cancer survivors in our population-based sample had not attended survivorship clinic, even among those with high-risk exposures. Health care access, as measured by insurance status, was an important predictor of clinic attendance. IMPLICATIONS FOR CANCER SURVIVORS: More research is needed to clarify the link between insurance status and survivorship care to increase appropriate late effects surveillance in this population. PMID- 26572904 TI - Synthesis and biological evaluation of novel peptidomimetics as rhodesain inhibitors. AB - Novel rhodesain inhibitors were developed by combining an enantiomerically pure 3 bromoisoxazoline warhead with a 1,4-benzodiazepine scaffold as specific recognition moiety. All compounds were proven to inhibit rhodesain with Ki values in the low-micromolar range. Their activity towards rhodesain was found to be coupled to an in vitro antitrypanosomal activity, with IC50 values ranging from the mid-micromolar to a low-micromolar value for the most active rhodesain inhibitor (R,S,S)-3. All compounds showed a good selectivity against the target enzyme since all of them were proven to be poor inhibitors of human cathepsin L. PMID- 26572905 TI - Active and Passive Suicidal Ideation in Older Prisoners. AB - BACKGROUND: Older prisoners are the fastest growing incarcerated population with high suicide rates, yet limited information is available to inform best practices for their early risk detection and suicide prevention. AIMS: The present study sought to determine the current prevalence of and factors associated with active suicidal ideation (ASI) and passive suicidal ideation (PSI) in older prisoners, and to determine if ASI and PSI were similarly associated with depression and lifetime suicide attempt - markers of subsequent suicide. METHOD: ASI, PSI, current major depressive episode (MDE), lifetime suicide attempt, and participant characteristics were assessed during interviews with 124 prisoners aged 50 years and older. Participants were assigned to one of three mutually exclusive groups: no SI, PSI only, and ASI. RESULTS: Past alcohol dependence and fair/poor self rated health were associated with SI. Compared with those with no SI, older prisoners with PSI (10%) and ASI (11%) were more likely to have a lifetime suicide attempt and/or MDE. However, the likelihood of experiencing either MDE or a suicide attempt did not differ between those with ASI or PSI. CONCLUSIONS: Among older prisoners, PSI and ASI may be similarly associated with markers of subsequent suicide. PSI should not be considered inconsequential and may distinguish older prisoners with elevated suicide risk. PMID- 26572906 TI - The Effects of Significant International Sports Events on Hungarian Suicide Rates. AB - BACKGROUND: Several studies found a significant relationship between important sport events and suicidal behavior. AIMS: We set out to investigate whether there is a significant relationship between the raw suicide rate and the most important international sports events (Olympic Games, FIFA World Cup, UEFA European Championship) in such an achievement-oriented society as the Hungarian one, where these sport events receive great attention. METHOD: We examined suicide cases occurring over 15,706 days between January 1, 1970, and December 31, 2012 (43 years), separately for each gender. Because of the age-specific characteristics of suicide, the effects of these sport events were analyzed for the middle-aged (30-59 years old) and the elderly (over 60 years old) generations as well as for gender-specific population groups. The role of international sport events was examined with the help of time-series intervention analysis after cyclical and seasonal components were removed. Intervention analysis was based on the ARIMA model. RESULTS: Our results showed that only the Olympic Games had a significant effect in the middle-aged population. Neither in the older male nor in any of the female age groups was a relationship between suicide and Olympic Games detected. CONCLUSION: The Olympic Games seem to decrease the rate of suicide among middle aged men, slightly but significantly. PMID- 26572907 TI - General Practitioners' Accounts of Patients Who Have Self-Harmed: A Qualitative, Observational Study. AB - BACKGROUND: The relationship between self-harm and suicide is contested. Self harm is simultaneously understood to be largely nonsuicidal but to increase risk of future suicide. Little is known about how self-harm is conceptualized by general practitioners (GPs) and particularly how they assess the suicide risk of patients who have self-harmed. AIMS: The study aimed to explore how GPs respond to patients who had self-harmed. In this paper we analyze GPs' accounts of the relationship between self-harm, suicide, and suicide risk assessment. METHOD: Thirty semi-structured interviews were held with GPs working in different areas of Scotland. Verbatim transcripts were analyzed thematically. RESULTS: GPs provided diverse accounts of the relationship between self-harm and suicide. Some maintained that self-harm and suicide were distinct and that risk assessment was a matter of asking the right questions. Others suggested a complex inter relationship between self-harm and suicide; for these GPs, assessment was seen as more subjective. In part, these differences appeared to reflect the socioeconomic contexts in which the GPs worked. CONCLUSION: There are different conceptualizations of the relationship between self-harm, suicide, and the assessment of suicide risk among GPs. These need to be taken into account when planning training and service development. PMID- 26572908 TI - Self-Injury, Help-Seeking, and the Internet: Informing Online Service Provision for Young People. AB - BACKGROUND: Although increasing numbers of young people are seeking help online for self-injury, relatively little is known about their online help-seeking preferences. AIMS: To investigate the perspectives of young people who self injure regarding online services, with the aim of informing online service delivery. METHOD: A mixed-methods exploratory analysis regarding the perspectives of a subsample of young people who reported a history of self-injury and responded to questions regarding preferences for future online help-seeking (N = 457). The sample was identified as part of a larger study (N = 1,463) exploring self-injury and help-seeking. RESULTS: Seven themes emerged in relation to preferences for future online help-seeking: information, guidance, reduced isolation, online culture, facilitation of help-seeking, access, and privacy. Direct contact with a professional via instant messaging was the most highly endorsed form of online support. CONCLUSION: Young people expressed clear preferences regarding online services for self-injury, supporting the importance of consumer consultation in development of online services. PMID- 26572909 TI - Determination of unbound fraction of pazopanib in vitro and in cancer patients reveals albumin as the main binding site. AB - INTRODUCTION: Pazopanib exhibits wide inter-patient pharmacokinetic variability which may contribute to differences in treatment outcome. Unbound drug concentrations are believed to be more relevant to pharmacological responses than total concentrations. Thus it is desirable to evaluate pazopanib binding on plasma proteins and different factors potentially affecting this process. METHODS: An equilibrium dialysis method coupled with UPLC-MS/MS assay has been optimized and validated for the determination of pazopanib unbound fraction (fu%) in human plasma. Pazopanib binding in the plasma of healthy volunteers and in isolated protein solutions was investigated. The unbound fraction was determined for 24 cancer patients treated daily with pazopanib. RESULTS: We found that pazopanib was extensively bound in human plasma (>99.9 %) with a mean fu% value of 0.0106 +/- 0.0013 % at 40 MUg/mL. Protein binding was concentration independent over a clinically relevant range of concentrations. In isolated protein solutions, pazopanib at 40 MUg/mL was mainly bound to albumin (40 g/L) and to a lesser extent to alpha1-acid glycoprotein (1 g/L) and low density lipoproteins (1.2 g/L), with a mean fu% of 0.0073 +/- 0.0022 %, 0.992 +/- 0.44 % and 7.4 +/- 1.7 % respectively. Inter-patient variability (CV%) of fu% in cancer patients was limited (27.2 %). A correlation was observed between individual unbound fraction values and albuminemia. CONCLUSIONS: Pazopanib exhibits extensive binding to plasma proteins in human plasma. Variable albumin concentrations, frequently observed in cancer patients, may affect pazopanib unbound fraction with implications for inter-patient variability in drug efficacy and toxicity. PMID- 26572910 TI - Predicting the relative binding affinity of mineralocorticoid receptor antagonists by density functional methods. AB - In drug discovery, prediction of binding affinity ahead of synthesis to aid compound prioritization is still hampered by the low throughput of the more accurate methods and the lack of general pertinence of one method that fits all systems. Here we show the applicability of a method based on density functional theory using core fragments and a protein model with only the first shell residues surrounding the core, to predict relative binding affinity of a matched series of mineralocorticoid receptor (MR) antagonists. Antagonists of MR are used for treatment of chronic heart failure and hypertension. Marketed MR antagonists, spironolactone and eplerenone, are also believed to be highly efficacious in treatment of chronic kidney disease in diabetes patients, but is contra-indicated due to the increased risk for hyperkalemia. These findings and a significant unmet medical need among patients with chronic kidney disease continues to stimulate efforts in the discovery of new MR antagonist with maintained efficacy but low or no risk for hyperkalemia. Applied on a matched series of MR antagonists the quantum mechanical based method gave an R(2) = 0.76 for the experimental lipophilic ligand efficiency versus relative predicted binding affinity calculated with the M06-2X functional in gas phase and an R(2) = 0.64 for experimental binding affinity versus relative predicted binding affinity calculated with the M06-2X functional including an implicit solvation model. The quantum mechanical approach using core fragments was compared to free energy perturbation calculations using the full sized compound structures. PMID- 26572911 TI - Dynamics and structural determinants of ligand recognition of the 5-HT6 receptor. AB - In order to identify molecular models of the human 5-HT6 receptor suitable for virtual screening, homology modeling and membrane-embedded molecular dynamics simulations were performed. Structural requirements for robust enrichment were assessed by an unbiased chemometric analysis of enrichments from retrospective virtual screening studies. The two main structural features affecting enrichment are the outward movement of the second extracellular loop and the formation of a hydrophobic cavity deep in the binding site. These features appear transiently in the trajectories and furthermore the stretches of uniformly high enrichment may only last 4-10 ps. The formation of the inner hydrophobic cavity was also linked to the active-like to inactive-like transition of the receptor, especially the so called connector region. The best structural models provided significant and robust enrichment over three independent ligand sets. PMID- 26572912 TI - Evidence for zoonotic origins of Middle East respiratory syndrome coronavirus. AB - Middle East respiratory syndrome (MERS) is an emerging infectious disease, caused by Middle East respiratory syndrome coronavirus (MERS-CoV) and is considered to be a zoonosis. However, the natural reservoirs of MERS-CoV remain obscure, with bats and camels as the most suspected sources. In this article, we review the evidence supporting a bat/camel origin of human MERS-CoV infection and current knowledge on the modes of camel-to-human transmission of MERS-CoV. PMID- 26572913 TI - Multiple, Successful Pregnancies in Pompe Disease. AB - Pompe disease is an autosomal recessive lysosomal storage disease characterized in adult patients by slowly progressive limb-girdle muscle weakness and respiratory insufficiency. Data on pregnancy in women with Pompe disease, intrauterine development of the fetus and parturition are rare. Here we describe a twin pregnancy followed by a second pregnancy in a 38-year-old female patient with Pompe disease. We report the impact of pregnancy on muscle and respiratory functions as well as the neurological and endocrine systems and discuss the medical consequences for anaesthetic management at parturition. PMID- 26572914 TI - Dual-task backward compatibility effects are episodically mediated. AB - In dual-task performance, the backward compatibility effect (BCE; faster Task 1 reaction time when Task 1 and Task 2 responses are compatible) is thought to represent automatic activation of Task 2 response information in parallel with attended Task 1 performance. Work by Hommel and Eglau (Psychological Research, 66, 260-273, 2002) has suggested the BCE relies on stimulus-response learning in long-term memory. Subsequent work by Ellenbogen and Meiran (Memory and Cognition, 36, 968-978, 2008), however, proposed that the BCE is mediated by Task 2 rules held in working memory (WM) during Task 1 performance. The present study aimed to dissociate these two theoretical claims. In Experiment 1, we assessed the effects of prior single-task practice with Task 1 or Task 2 of a subsequent dual-task paradigm. Where the WM-mediated model predicts both BCE and overall reaction time improvement relative to prior task practice, an episodic learning model makes divergent predictions for BCE based on the context specificity of prior Task 2 learning. Results showed a close fit with episodic predictions and contradicted WM model predictions. Experiment 2 examined the finer grained timecourse of BCE over initial development, subsequent interference of this initial learning on BCE development with new conflicting Task 2 response mappings, and finally reestablishment of BCE in the original dual task. Data again showed close agreement with long-term learning predictions. We argue in favor of an episodic account of the BCE, and consider implications of WM and episodic mechanisms of automatic response activation on other aspects of dual-task performance. PMID- 26572915 TI - [Not Available]. PMID- 26572916 TI - Propofol protects against the neurotoxicity of 1-methyl-4-phenylpyridinium. AB - Parkinson's disease (PD) is a progressive and degenerative disorder of the central nervous system, characterized by the loss of dopaminergic neurons and muscular rigidity. Treatment with propofol (2,6-diisopropylphenol) has been observed to attenuate oxidative stress injury via inhibition of programmed cell death. Results from the present study indicate that propofol treatment attenuates 1-methyl-4-phenylpyridinium (MPP+)-induced oxidative stress, which was demonstrated by increased levels of reactive oxygen species, 4-hydroxy-2-nonenal and protein carbonyls. Furthermore, it was demonstrated that propofol may ameliorate MPP+-induced mitochondrial dysfunction by increasing the level of ATP and the mitochondrial membrane potential. MTT and lactate dehydrogenase assays indicated that propofol treatment reduces cell vulnerability to MPP+-induced insult. Propofol was also observed to prevent apoptotic signals by reducing the ratio of Bcl-2-associated X protein to B-cell lymphoma 2, reducing the expression level of cleaved caspase-3 and attenuating cytochrome c release. Thus, propofol may present as a novel therapeutic strategy for the treatment of PD. PMID- 26572917 TI - Acute trophoblastic pulmonary embolism during conservative treatment of placenta accreta: case report and review of literature. AB - BACKGROUND: Placenta accreta is a rare obstetric condition but can lead to life threatening complications that was mainly diagnosed in the third trimester. We present a case of acute trophoblastic pulmonary embolism (PE) during conservative treatment of placenta accreta. CASE PRESENTATION: A 24-year-old patient who delivered vaginally at 40(+4) weeks gestation. The placenta was retained despite the use of oxytocics and attempts of manual removal. Conservative management including uterine arteria embolism, hysteroscopic resection and mifepristone was used but failed and finally the patient died from acute trophoblastic PE and allergic shock when infusing povidone-iodine into her uterine cavity. CONCLUSION: Although conservative treatment of placenta accreta can retain reproductive potential and trophoblastic PE is rare, clinicians should consider hysterectomy when conservative treatment failed and infusion of povidone-iodine or other liquid into the cavity should be prohibited. PMID- 26572918 TI - Genomic mutational analysis of the impact of the classical strain improvement program on beta-lactam producing Penicillium chrysogenum. AB - BACKGROUND: Penicillium chrysogenum is a filamentous fungus that is employed as an industrial producer of beta-lactams. The high beta-lactam titers of current strains is the result of a classical strain improvement program (CSI) starting with a wild-type like strain more than six decades ago. This involved extensive mutagenesis and strain selection for improved beta-lactam titers and growth characteristics. However, the impact of the CSI on the secondary metabolism in general remains unknown. RESULTS: To examine the impact of CSI on secondary metabolism, a comparative genomic analysis of beta-lactam producing strains was carried out by genome sequencing of three P. chrysogenum strains that are part of a lineage of the CSI, i.e., strains NRRL1951, Wisconsin 54-1255, DS17690, and the derived penicillin biosynthesis cluster free strain DS68530. CSI has resulted in a wide spread of mutations, that statistically did not result in an over- or underrepresentation of specific gene classes. However, in this set of mutations, 8 out of 31 secondary metabolite genes (20 polyketide synthases and 11 non ribosomal peptide synthetases) were targeted with a corresponding and progressive loss in the production of a range of secondary metabolites unrelated to beta lactam production. Additionally, key Velvet complex proteins (LeaA and VelA) involved in global regulation of secondary metabolism have been repeatedly targeted for mutagenesis during CSI. Using comparative metabolic profiling, the polyketide synthetase gene cluster was identified that is responsible for sorbicillinoid biosynthesis, a group of yellow-colored metabolites that are abundantly produced by early production strains of P. chrysogenum. CONCLUSIONS: The classical industrial strain improvement of P. chrysogenum has had a broad mutagenic impact on metabolism and has resulted in silencing of specific secondary metabolite genes with the concomitant diversion of metabolism towards the production of beta-lactams. PMID- 26572919 TI - Financing Long-Term Services And Supports: Options Reflect Trade-Offs For Older Americans And Federal Spending. AB - About half of older Americans will need a high level of assistance with routine activities for a prolonged period of time. This help is commonly referred to as long-term services and supports (LTSS). Under current policies, these individuals will fund roughly half of their paid care out of pocket. Partly as a result of high costs and uncertainty, relatively few people purchase private long-term care insurance or save sufficiently to fully finance LTSS; many will eventually turn to Medicaid for help. To show how policy changes could expand insurance's role in financing these needs, we modeled several new insurance options. Specifically, we looked at a front-end-only benefit that provides coverage relatively early in the period of disability but caps benefits, a back-end benefit with no lifetime limit, and a combined comprehensive benefit. We modeled mandatory and voluntary versions of each option, and subsidized and unsubsidized versions of each voluntary option. We identified important differences among the alternatives, highlighting relevant trade-offs that policy makers can consider in evaluating proposals. If the primary goal is to significantly increase insurance coverage, the mandatory options would be more successful than the voluntary versions. If the major aim is to reduce Medicaid costs, the comprehensive and back-end mandatory options would be most beneficial. PMID- 26572920 TI - N-Glycosylation analysis of formalin fixed paraffin embedded samples by capillary electrophoresis. AB - In this study, N-linked glycans from intact, formalin treated and formalin fixed paraffin embedded (FFPE) standard glycoproteins, human serum and mouse tumor tissue samples were investigated in respect to their susceptibility for formaldehyde treatment mediated changes. FFPE samples were first deparaffinized, followed by solubilization in radioimmunoprecipitation assay buffer and treated with PNGase F for N-glycan release. The released glycans were labeled with a charged fluorophore and analyzed by capillary electrophoresis with laser induced fluorescent detection. No significant alterations were found in the N-glycome profile at any of the investigated complexation levels (i.e., glycoprotein, serum and tissue samples) of the study. These results suggest that FFPE samples can be readily used for global N-glycome analysis holding the promise to find novel carbohydrate biomarkers in prospective and retrospective studies. Exoglycosidase based carbohydrate sequencing was also applied to reveal some basic structural information about the N-linked carbohydrates of the mouse tumor tissue samples. PMID- 26572921 TI - The transcriptional landscape of insect galls: psyllid (Hemiptera) gall formation in Hawaiian Metrosideros polymorpha (Myrtaceae). AB - BACKGROUND: Recent studies show that galling Hymenoptera and Diptera are able to synthesize the plant hormone indole-3-acetic acid (auxin) from tryptophan and that plant response to insect-produced auxin is implicated in gall formation. We examined the leaf transcriptome of galled and ungalled leaves of individuals of the Hawaiian endemic plant Metrosideros polymorpha (Myrtaceae) subject to infestation by psyllid (Hemiptera) gall-makers in the genus Trioza (Triozidae). RESULTS: Transcript libraries were sequenced using Illumina technology and the reads assembled de novo into contigs. Functional identification of contigs followed a two-step procedure, first identifying contigs by comparison to the completely sequenced genome of the related Eucalyptus, followed by identifying the equivalent Arabidopsis gene using a pre-computed mapping between Eucalyptus and Arabidopsis genes. This allowed us to use the rich functional annotation of the Arabidopsis genome to assess the transcriptional landscape of galling in Metrosideros. Comparing galled and ungalled leaves, we find a highly significant enrichment of expressed genes with a gene ontology (GO) annotation to auxin response in the former. One gene consistently expressed in all galled trees examined but not detected in any libraries from ungalled leaves was the Metrosideros version of SMALL AUXIN UPREGULATED (SAUR) 67 which appears to be a marker for leaf-galling in Metrosideros. CONCLUSIONS: We conclude that an auxin response is involved in galling by Metrosideros psyllids. The possibility should therefore be considered that psyllids (like other insects examined) are able to synthesize auxin. PMID- 26572922 TI - Metal-Organic Frameworks Derived Porous Core/Shell Structured ZnO/ZnCo2O4/C Hybrids as Anodes for High-Performance Lithium-Ion Battery. AB - Metal-organic frameworks (MOFs) derived porous core/shell ZnO/ZnCo2O4/C hybrids with ZnO as a core and ZnCo2O4 as a shell are for the first time fabricated by using core/shell ZnCo-MOF precursors as reactant templates. The unique MOFs derived core/shell structured ZnO/ZnCo2O4/C hybrids are assembled from nanoparticles of ZnO and ZnCo2O4, with homogeneous carbon layers coated on the surface of the ZnCo2O4 shell. When acting as anode materials for lithium-ion batteries (LIBs), the MOFs-derived porous ZnO/ZnCo2O4/C anodes exhibit outstanding cycling stability, high Coulombic efficiency, and remarkable rate capability. The excellent electrochemical performance of the ZnO/ZnCo2O4/C LIB anodes can be attributed to the synergistic effect of the porous structure of the MOFs-derived core/shell ZnO/ZnCo2O4/C and homogeneous carbon layer coating on the surface of the ZnCo2O4 shells. The hierarchically porous core/shell structure offers abundant active sites, enhances the electrode/electrolyte contact area, provides abundant channels for electrolyte penetration, and also alleviates the structure decomposition induced by Li(+) insertion/extraction. The carbon layers effectively improve the conductivity of the hybrids and thus enhance the electron transfer rate, efficiently prevent ZnCo2O4 from aggregation and disintegration, and partially buffer the stress induced by the volume change during cycles. This strategy may shed light on designing new MOF-based hybrid electrodes for energy storage and conversion devices. PMID- 26572923 TI - How many paediatric referrals to an allergist could be managed by a general practitioner with special interest? AB - BACKGROUND: The concept of a general practitioner with special interest (GPwSI) was first proposed in the 2000 National Health Service Plan, as a way of providing specialized treatment closer to the patient's home and reducing hospital waiting times. Given the patchy and inadequate provision of paediatric allergy services in the UK, the introduction of GPwSIs might reduce pressure on existing specialist services. METHODS: A total of 100 consecutive referrals to a specialist paediatric allergy clinic were reviewed to assess what proportion could be managed by a GPwSI allergy service with a predefined range of facilities and expertise (accurate diagnosis and management of allergy; skin prick testing; provision of allergen avoidance advice; ability to assess suitability for desensitization). Each referral was reviewed independently by three allergy specialists. Cases were initially judged on the referral letter and then, to determine whether appropriate triage decisions could be made prospectively, cases were re-assessed with information summarized in the clinic letter. The proportion of referrals suitable for a GPwSI was calculated and their characteristics identified. RESULTS: At least 42% and up to 75% were suitable for management by a GPwSI in allergy based on unanimous and majority agreement, respectively. The appropriateness of 79% referrals could be identified based on the information in the referral letter. A total of 19% referrals were unsuitable for a GPwSI service because of complex or multisystem disease, need for specialist knowledge or facilities or patient's young age. CONCLUSIONS: At least two-fifths of paediatric allergy referrals to our hospital-based service could be dealt with in a GPwSI clinic, thereby diversifying the patient pathway, allowing specialist services to focus on complex cases and reducing waiting times for appointments. PMID- 26572925 TI - Doctors must ask carers before placing DNAR notices on files of mentally incapacitated patients. PMID- 26572924 TI - Lysosome biogenesis/scattering increases host cell susceptibility to invasion by Trypanosoma cruzi metacyclic forms and resistance to tissue culture trypomastigotes. AB - A fundamental question to be clarified concerning the host cell invasion by Trypanosoma cruzi is whether the insect-borne and mammalian-stage parasites use similar mechanisms for invasion. To address that question, we analysed the cell invasion capacity of metacyclic trypomastigotes (MT) and tissue culture trypomastigotes (TCT) under diverse conditions. Incubation of parasites for 1 h with HeLa cells in nutrient-deprived medium, a condition that triggered lysosome biogenesis and scattering, increased MT invasion and reduced TCT entry into cells. Sucrose-induced lysosome biogenesis increased HeLa cell susceptibility to MT and resistance to TCT. Treatment of cells with rapamycin, which inhibits mammalian target of rapamycin (mTOR), induced perinuclear lysosome accumulation and reduced MT invasion while augmenting TCT invasion. Metacylic trypomastigotes, but not TCT, induced mTOR dephosphorylation and the nuclear translocation of transcription factor EB (TFEB), a mTOR-associated lysosome biogenesis regulator. Lysosome biogenesis/scattering was stimulated upon HeLa cell interaction with MT but not with TCT. Recently, internalized MT, but not TCT, were surrounded by colocalized lysosome marker LAMP2 and mTOR. The recombinant gp82 protein, the MT specific surface molecule that mediates invasion, induced mTOR dephosphorylation, nuclear TFEB translocation and lysosome biogenesis/scattering. Taken together, our data clearly indicate that MT invasion is mainly lysosome-dependent, whereas TCT entry is predominantly lysosome-independent. PMID- 26572926 TI - Effective use of panobinostat in combination with other active agents in myeloma in a novel five-drug combination: Case report and interesting observations. PMID- 26572927 TI - Dietary Restriction-Induced Alterations in Bone Phenotype: Effects of Lifelong Versus Short-Term Caloric Restriction on Femoral and Vertebral Bone in C57BL/6 Mice. AB - Caloric restriction (CR) is a well-described dietary intervention that delays the onset of aging-associated biochemical and physiological changes, thereby extending the life span of rodents. The influence of CR on metabolism, strength, and morphology of bone has been controversially discussed in literature. Thus, the present study evaluated whether lifelong CR versus short-term late-onset dietary intervention differentially affects the development of senile osteoporosis in C57BL/6 mice. Two different dietary regimens with 40% food restriction were performed: lifelong CR starting in 4-week-old mice was maintained for 4, 20, or 74 weeks. In contrast, short-term late-onset CR lasting a period of 12 weeks was commenced at 48 or 68 weeks of age. Control mice were fed ad libitum (AL). Bone specimens were assessed using microcomputed tomography (MUCT, femur and lumbar vertebral body) and biomechanical testing (femur). Adverse effects of CR, including reduced cortical bone mineral density (Ct.BMD) and thickness (Ct.Th), were detected to some extent in senile mice (68+12w) but in particular in cortical bone of young growing mice (4+4w), associated with reduced femoral failure force (F). However, we observed a profound capacity of bone to compensate these deleterious changes of minor nutrition with increasing age presumably via reorganization of trabecular bone. Especially in lumbar vertebrae, lifelong CR lasting 20 or 74 weeks had beneficial effects on trabecular bone mineral density (Tb.BMD), bone volume fraction (BV/TV), and trabecular number (Tb.N). In parallel, lifelong CR groups showed reduced structure model index values compared to age-matched controls indicating a transformation of vertebral trabecular bone microarchitecture toward a platelike geometry. This effect was not visible in senile mice after short-term 12-week CR. In summary, CR has differential effects on cortical and trabecular bone dependent on bone localization and starting age. Our study underlines that bone compartments possess a lifelong capability to cope with changing nutritional influences. PMID- 26572928 TI - Morphofunctional structure of the lingual papillae in three species of South American Camelids: Alpaca, guanaco, and llama. AB - The aim of this study was to compare the anatomical and functional characteristics of the lingual papilla among the Camelidae. For this purpose, tongues of alpaca, guanaco, and llama were used. Numerous long and thin filiform papillae were located in the median groove and none were detected on the rest of the dorsal surface of the lingual apex in alpaca. Secondary papillae originated from the base of some filiform papillae on the ventral surface of alpaca tongue. The bases of some filiform papillae of the lateral surface of the lingual apex were inserted into conspicuous grooves in guanaco and tips of filiform papillae on the dorsal surface of the lingual body were ended by bifurcated apex. On the dorsal surface of the lingual apex of llama, there were no filiform papillae but there were numerous filiform papillae on both the lateral margins of the ventral surface of the lingual apex. Fungiform papillae were distributed randomly on dorsal lingual surface and ventral margins of the tongues of all camelid species. Lenticular papillae were located on the lingual torus and varied in size and topographical distribution for each species. Circumvallate papillae had irregular surfaces in llama and alpaca, and smooth surface in guanaco. In conclusion, llama and alpaca tongues were more similar to each other, and tongues of all camelid species displayed more similarities to those of Bactrian and dromedary camels in comparison with other herbivores and ruminants. PMID- 26572929 TI - Focus on the Top Ten Diagnoses Could Reduce Pediatric Dermatology Referrals. AB - There is a sense that many patients seen at referral centers could be managed at a primary health care level. The objective of the current study was to examine the range of diagnoses among consultations at the Red Cross Children's Hospital in Cape Town, South Africa, to help develop a strategy for targeted education of primary health care personnel. This was a retrospective review of data for children seen at a pediatric dermatology clinic from 2005 to 2010, recorded according to International Classification of Diseases coding and compared with published data from similar clinical settings. There were 13,253 clinic visits, with 4,789 patients seen (median age 4.8 yrs, range 2 days to 18.6 yrs). The top 10 diagnoses accounted for 88.5% of consultations (59.5% atopic eczema [AE], 7.1% seborrheic dermatitis [SD], 4.2% superficial mycoses, 3.1% molluscum contagiosum, 2.8% vitiligo, 2.7% viral warts, 2.4% prurigo or scabies, 2.3% psoriasis, 2.3% hemangioma, 2.1% impetigo). Disease prevalence was somewhat different during the first year of life (AE 43.7%, SD 18.6%, hemangiomas 13.4%). Inflammatory dermatoses (76.6%) were more prevalent than infections and infestations (14.5%). The disease spectrum was similar to that in developed countries, although AE prevalence was higher in this study (followed by London 36%, Greece 35%, and Hong Kong 33%) than in 19 published studies. The top 10 diagnoses accounted for more than 70% of diagnoses in 12 studies. The retrospective nature and setting at a specialist clinic increased bias and limited generalizability. Focused education on the optimal care of common diseases, especially AE, could reduce referrals, improve access, and allow specialists at tertiary centers more time to manage complex and uncommon dermatoses. PMID- 26572930 TI - Cellulose synthase gene expression profiling of Physcomitrella patens. AB - The cellulose synthase (CESA) gene family of seed plants comprises six clades that encode isoforms with conserved expression patterns and distinct functions in cellulose synthesis complex (CSC) formation and primary and secondary cell wall synthesis. In mosses, which have rosette CSCs like those of seed plants but lack lignified secondary cell walls, the CESA gene family diversified independently and includes no members of the six functionally distinct seed plant clades. There are seven CESA isoforms encoded in the genome of the moss Physcomitrella patens. However, only PpCESA5 has been characterised functionally, and little information is available on the expression of other PpCESA family members. We have profiled PpCESA expression through quantitative RT-PCR, analysis of promoter-reporter lines, and cluster analysis of public microarray data in an effort to identify expression and co-expression patterns that could help reveal the functions of PpCESA isoforms in protein complex formation and development of specific tissues. In contrast to the tissue-specific expression observed for seed plant CESAs, each of the PpCESAs was broadly expressed throughout most developing tissues. Although a few statistically significant differences in expression of PpCESAs were noted when some tissues and hormone treatments were compared, no strong co-expression patterns were observed. Along with CESA phylogenies and lack of single PpCESA mutant phenotypes reported elsewhere, broad overlapping expression of the PpCESAs indicates a high degree of inter-changeability and is consistent with a different pattern of functional specialisation in the evolution of the seed plant and moss CESA families. PMID- 26572931 TI - Important first encounter: Service user experience of pathways to care and early detection in first-episode psychosis. AB - BACKGROUND: Long duration of untreated psychosis is associated with poor clinical and functional outcomes. However, few systematic attempts have been made to reduce this delay and little is known of service users' experience of early detection efforts. AIM: We explored service users' experience of an early detection service and transition to specialized treatment service, including pathway to care, understanding of illness and barriers to adequate assessment and treatment. METHODS: In-depth interviews were conducted with 10 service users (median age 21, range 18-27, five males and five females) who were diagnosed with a first-episode non-affective psychosis and who were seen by an early detection team (TOP) and currently enrolled in a specialized early intervention service for this disorder (OPUS). RESULTS: Stigma and fear of the 'psychiatric system' were reported as significant barriers to help seeking, while family members were seen as a crucial support. Moreover, the impact of traumatic events on the experience and development of psychosis was highlighted. Finally, participants were relieved by the prospect of receiving help and the early detection team seemed to create a trusting relationship by offering a friendly, 'anti-stigmatized' space, where long-term symptomatology could be disclosed through accurate and validating questioning. CONCLUSIONS: Early detection services have two important functions. One is to make accurate assessments and referrals. The other is to instil hope and trust, and to facilitate further treatment by forming an early therapeutic alliance. The findings in this study provide important insights into the way in which early detection efforts and pathways to care are experienced by service users, with direct implications for improving psychiatric services. PMID- 26572932 TI - Maternal obesity and gestational weight gain are risk factors for infant death. AB - OBJECTIVE: Assessment of the joint and independent relationships of gestational weight gain and prepregnancy body mass index (BMI) on risk of infant mortality was performed. METHODS: This study used Pennsylvania linked birth-infant death records (2003-2011) from infants without anomalies born to mothers with prepregnancy BMI categorized as underweight (n = 58,973), normal weight (n = 610,118), overweight (n = 296,630), grade 1 obesity (n = 147,608), grade 2 obesity (n = 71,740), and grade 3 obesity (n = 47,277). Multivariable logistic regression models stratified by BMI category were used to estimate dose-response associations between z scores of gestational weight gain and infant death after confounder adjustment. RESULTS: Infant mortality risk was lowest among normal weight women and increased with rising BMI category. For all BMI groups except for grade 3 obesity, there were U-shaped associations between gestational weight gain and risk of infant death. Weight loss and very low weight gain among women with grades 1 and 2 obesity were associated with high risks of infant mortality. However, even when gestational weight gain in women with obesity was optimized, the predicted risk of infant death remained higher than that of normal-weight women. CONCLUSIONS: Interventions aimed at substantially reducing preconception weight among women with obesity and avoiding very low or very high gestational weight gain may reduce risk of infant death. PMID- 26572934 TI - Structural basis for the development of SARS 3CL protease inhibitors from a peptide mimic to an aza-decaline scaffold. AB - Design of inhibitors against severe acute respiratory syndrome (SARS) chymotrypsin-like protease (3CL(pro) ) is a potentially important approach to fight against SARS. We have developed several synthetic inhibitors by structure based drug design. In this report, we reveal two crystal structures of SARS 3CL(pro) complexed with two new inhibitors based on our previous work. These structures combined with six crystal structures complexed with a series of related ligands reported by us are collectively analyzed. To these eight complexes, the structural basis for inhibitor binding was analyzed by the COMBINE method, which is a chemometrical analysis optimized for the protein-ligand complex. The analysis revealed that the first two latent variables gave a cumulative contribution ratio of r(2) = 0.971. Interestingly, scores using the second latent variables for each complex were strongly correlated with root mean square deviations (RMSDs) of side-chain heavy atoms of Met(49) from those of the intact crystal structure of SARS-3CL(pro) (r = 0.77) enlarging the S2 pocket. The substantial contribution of this side chain (~10%) for the explanation of pIC50 s was dependent on stereochemistry and the chemical structure of the ligand adapted to the S2 pocket of the protease. Thus, starting from a substrate mimic inhibitor, a design for a central scaffold for a low molecular weight inhibitor was evaluated to develop a further potent inhibitor. (c) 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 391-403, 2016. PMID- 26572935 TI - Directly 2,12- and 2,8-Linked Zn(II) Porphyrin Oligomers: Synthesis, Optical Properties, and Coherence Lengths. AB - Directly 2,12- and 2,8-linked Zn(II) porphyrin oligomers were prepared from 2,12- and 2,8-diborylated Zn(II) porphyrin by a cross platinum-induced coupling with a 2-borylated Zn(II) porphyrin end unit followed by a triphenylphosphine (PPh3 ) mediated reductive elimination. Comparative studies on the steady-state absorption and fluorescence spectra and the fluorescence lifetimes led to a conclusion that the exciton in the S1 state is delocalized over approximately four and two Zn(II) porphyrin units for 2,12- and 2,8-linked Zn(II) porphyrin arrays, respectively. PMID- 26572936 TI - Autophosphorylation of alpha isoform of calcium/calmodulin-dependent kinase II regulates alcohol addiction-related behaviors. AB - The development of addiction is associated with a dysregulation of glutamatergic transmission in the brain reward circuit. alpha isoform of calcium/calmodulin dependent kinase II (alphaCaMKII) is one of the key proteins that regulates structural and functional plasticity of glutamatergic synapses. alphaCaMKII activity can be controlled by the autophosphorylation of threonine 286. The role of this autophosphorylation in the regulation of addiction-related behaviors has been proposed but is still poorly understood. Here, using alphaCaMKII autophosphorylation-deficient mutant mice (T286A), we show that, in comparison with wild-type animals, they are less resistant to high doses of alcohol and do not show psychostimulant response neither to alcohol injections nor during voluntary alcohol drinking. T286A mutants are also less prone to develop alcohol addiction-related behaviors including an increased motivation for alcohol, persistent alcohol seeking during withdrawal and alcohol consumption on relapse. Finally, we demonstrate that alphaCaMKII autophosphorylation regulates also alcohol-induced remodeling of glutamatergic synapses in the hippocampus and amygdala. In conclusion, our data suggest that alphaCaMKII autophosphorylation dependent remodeling of glutamatergic synapses is a plausible mechanism for the regulation of the alcohol addiction-related behaviors. PMID- 26572937 TI - Ventilation strategies for preventing oxidative stress-induced injury in preterm infants with respiratory disease: an update. AB - Reactive oxygen and nitrogen species are produced by several inflammatory and structural cells of the airways. The lungs of preterm newborns are susceptible to oxidative injury induced by both reactive oxygen and nitrogen species. Increased oxidative stress and imbalance in antioxidant enzymes may play a role in the pathogenesis of inflammatory pulmonary diseases. Preterm infants are frequently exposed to high oxygen concentrations, infections or inflammation; they have reduced antioxidant defense and high free iron levels which enhance toxic radical generation. Multiple ventilation strategies have been studied to reduce injury and improve outcomes in preterm infants. Using lung protective strategies, there is the need to reach a compromise between satisfaction of gas exchange and potential toxicities related to over-distension, derecruitment of lung units and high oxygen concentrations. In this review, the authors summarize scientific evidence concerning oxidative stress as it relates to resuscitation in the delivery room and to the strategies of ventilation. PMID- 26572938 TI - Gastrointestinal Bleeding Secondary to Calciphylaxis. AB - BACKGROUND Calciphylaxis is associated with a high mortality that approaches 80%. The diagnosis is usually made when obvious skin lesions (painful violaceous mottling of the skin) are present. However, visceral involvement is rare. We present a case of calciphylaxis leading to lower gastrointestinal (GI) bleeding and rectal ulceration of the GI mucosa. CASE REPORT A 66-year-old woman with past medical history of diabetes mellitus, hypertension, end-stage renal disease (ESRD), recently diagnosed ovarian cancer, and on hemodialysis (HD) presented with painful black necrotic eschar on both legs. The radiograph of the legs demonstrated extensive calcification of the lower extremity arteries. The hospital course was complicated with lower GI bleeding. A CT scan of the abdomen revealed severe circumferential calcification of the abdominal aorta, celiac artery, and superior and inferior mesenteric arteries and their branches. Colonoscopy revealed severe rectal necrosis. She was deemed to be a poor surgical candidate due to comorbidities and presence of extensive vascular calcifications. Recurrent episodes of profuse GI bleeding were managed conservatively with blood transfusion as needed. Following her diagnosis of calciphylaxis, supplementation with vitamin D and calcium containing phosphate binders was stopped. She was started on daily hemodialysis with low calcium dialysate bath as well as intravenous sodium thiosulphate. The clinical condition of the patient deteriorated. The patient died secondary to multiorgan failure. CONCLUSIONS Calciphylaxis leading to intestinal ischemia/perforation should be considered in the differential diagnosis in ESRD on HD presenting with abdominal pain or GI bleeding. PMID- 26572939 TI - Genome-wide identification of microRNAs responding to early stages of phosphate deficiency in maize. AB - Phosphorus (P) is an essential element involved in numerous biochemical reactions. In plants, stress responses, such as the expression of microRNAs (miRNAs), are induced to help them adapt to low phosphate (Pi) concentrations. In this study, deep sequencing was performed using the roots and leaves of maize seedlings grown under low Pi concentrations to identify miRNAs that are differentially expressed during the early stages of Pi deficiency. Eight small RNA libraries were constructed, and 159 known miRNAs representing 32 miRNA families and 10 novel miRNAs. Members of the miR396 family were extremely abundant. Further, 28 Pi-responsive miRNAs were identified (27 known and 1 novel) of which 8 and 7 were significantly expressed exclusively in leaf and root tissues, respectively. The analysis of Pi-responsive miRNAs target genes suggested that most target genes functioning as transcription factors were involved in root and leaf development. The expression profiles of selected Pi responsive miRNAs and target genes were confirmed by quantitative real-time polymerase chain reaction (qRT-PCR). Moreover, we discuss the significance of the differences in expression patterns of these miRNAs during the early and later stages of Pi starvation. This study provides useful information concerning the role of miRNAs in response to Pi starvation and will further our understanding of the mechanisms governing Pi homeostasis in maize. PMID- 26572940 TI - Histone deacetylase 4 increases progressive epithelial ovarian cancer cells via repression of p21 on fibrillar collagen matrices. AB - Histone deacetylase (HDAC) 4 is an emerging target in cancer therapeutics, but little is known about the function of HDAC4 in gynecologic malignancies. Therefore we investigated the mechanism of HDAC4 promoting the proliferation of epithelial ovarian cancer cells (OV). In this study, we observed that the proliferation of cells with HDAC4 inhibitor Trichostatin A (TSA) treatment was markedly decreased, Further, we showed that epithelial ovarian cancer tissues with stage III/IV had higher HDAC4 expression, compared to that with stage I/II. We examined first that the HDAC4 expression was increased in response to fibrillar collagen matrices. In addition, we found that HDAC4 was retained in the nucleus by regulation of PP1alpha, which regulated HDAC4 cellular fraction via phosphorylation of HDAC4. In addition, we found that HDAC4 bound to Sp1 in epithelial ovarian cancer cells. Finally, ovarian cancer cell line OVCAR3 was evaluated via gain/loss-of-function of HDAC4 by either overexpression of HDCA4 or knock-down of HDAC4 with shRNA. We examined both protein and mRNA of p21 by western blotting and qPCR. We performed analysis of colony formation in matrigel and migration by ECIS. Our results suggest that the accumulation of HDAC4 induced by fibrillar collagen matrices in the nucleus via co-localization of PP1alpha, leads to repression of the mRNA/protein of p21 and in turn promotes the proliferation and migration of epithelial ovarian cancer cells. PMID- 26572942 TI - Breakthrough Pain Associated with a Reduction in Serum Buprenorphine Concentration during Dialysis. AB - PURPOSE: To describe a case of breakthrough pain associated with a reduction in serum buprenorphine concentration during dialysis. METHODS: Pharmacokinetic sampling of total and free buprenorphine and norbuprenorphine in an 80 year old male undergoing haemodialysis three times per week who received 5760 ug oral and transdermal buprenorphine daily was performed. The patient's serum albumin concentration was 23g/l (reference range: 35-52 g/l). FINDINGS: Pharmacokinetic sampling revealed a free buprenorphine fraction of 32% (consistent with the hypoalbuminaemia), which was markedly reduced at the end of dialysis (free buprenorphine concentration 2.4 ug/l before vs. <0.1 ug/l after dialysis). IMPLICATIONS: Clinicians should be aware that some patients may require extra buprenorphine doses during dialysis to prevent significant falls in the concentration of active drug. PMID- 26572943 TI - [Commitment Must Be Shared]. PMID- 26572941 TI - Efficacy of Pramipexole for the Treatment of Primary Restless Leg Syndrome: A Systematic Review and Meta-analysis of Randomized Clinical Trials. AB - PURPOSE: The objective of this meta-analysis was to systematically evaluate the efficacy of pramipexole for the treatment of primary moderate-to-severe restless leg syndrome (RLS). METHODS: Databases of PubMed, OVID, ScienceDirect, SpringerLink, Thomson Reuters Web of Science, the Cochrane Library, the Wiley Online Library, ArticleFirst, CALIS, Study, CNKI, and WanFang were searched to identify randomized controlled trials (RCTs) investigating pramipexole for the treatment of primary moderate-to-severe RLS. A meta-analysis was then conducted to pool results. FINDINGS: Twelve RCTs involving 3286 participants were included in this study. The mean (SD) treatment duration was 11.12 (5.72) weeks/person. The meta-analysis found that the post-treatment change in the International Restless Leg Syndrome Study Group Rating Scale (IRLS) score of the pramipexole group was significantly superior to that of the placebo group (weighted mean difference [WMD] = -4.64; 95% CI, -5.95 to -3.33; n = 8). More patients in the pramipexole group reported at least a 50% reduction in the IRLS score after treatment (risk ratio [RR] = 1.57; 95% CI, 1.43 to 1.73; n = 8). In terms of the scores for the Clinical Global Impression of Improvement scale (RR = 1.48; 95% CI, 1.31 to 1.66; n = 11) and the Patient Global Impression scale (RR = 1.54; 95% CI, 1.31 to 1.81; n = 9), treatment outcomes of the pramipexole group were significantly superior to those of the placebo group. In terms of the change in quality of life (WMD = 5.39; 95% CI, 2.28 to 8.50; n = 4), the change in daytime tiredness (WMD = -0.61; 95% CI, -1.21 to -0.01; n = 4), the change in the number of periodic limb movements per hour of sleep (WMD = -35.95; 95% CI, -56.42 to 15.48; n = 3), and the change in the quality of sleep (WMD = 3.60; 95% CI, 1.69 to 5.50; n = 6), the treatment outcomes of the pramipexole group were significantly superior to those of the placebo group. IMPLICATIONS: This meta analysis study indicated that pramipexole could effectively improve the symptoms of patients with primary moderate-to-severe RLS, although the quality of evidence was relatively low. Future clinical trials focusing on the medium-term and long term treatment outcomes and using mainly objective indicators for evaluation are warranted. It is also necessary to pay close attention to augmentation during medication. PMID- 26572944 TI - [Risk Factors Associated With School Bullying in Local Authority Schools in Four Municipalities of Valle del Cauca, Colombia. Year 2009]. AB - OBJECTIVE: To determine the association between family and social relationships and School Bullying (SB) among peers in public education institutions in four municipalities of the department of Valle del Cauca, Colombia, during 2009. METHODS: A case-control study matched by sex and educational institution was carried out. The study population came from a secondary database provided by the Departof Health Secretaryhealth, which consisted of data gathered in a survey of schoolchildren enrolled in grades 6 to 11. The CISNEROS scale and the Family APGAR test were applied to measure outcome and exposure variables. A conditional logistic regression model was obtained to explain SB. RESULTS: It was found that schoolchildren living with a family where verbal and physical violence prevails, as well as in a hostile neighborhood, are more vulnerable to SB. The probability of being an SB victim is explained by: family dysfunction (OR=2.67; 95%CI, 1.05 6.82), verbal aggression at home (OR=2.81; 95%CI, 1.45-5.46), physical punishing parents (OR=2.53; 95%CI, 1.12-5.75), and neighbors who are physically aggressive to each other (OR=1.87; 95% CI, 1.00-3.56). CONCLUSIONS: The study confirmed that reported by Lopez, who suggested that victimization and school rejection in adolescence is related to factors outside the classroom, such as the quality of communication between parents and children. As regards family influence in the SB, Bowes indicates that a positive family atmosphere is significantly associated with the resilience of school victimization. Furthermore, being physically punished by parents generates low self-esteem in the schoolchild that leads to lack of self-protective attitudes to the attacks that occur within the school. PMID- 26572945 TI - [Use of Emerging Drugs in Medellin, Colombia]. AB - INTRODUCTION: The ongoing emergence of new synthetic substances that are used as drugs is a constant challenge to public health. Emerging drugs is the concept used in this research project to define the emergence of new psychoactive substances at a given time, a specific context and group, the reemergence of others that some epidemiologists considered had lost their prevalence, and the sudden prevalence of drugs that had low levels of consumption. METHOD: This research project was carried out using an empirical-analytical approach using a mixed methods study. The convenience sample was made up of 510 drug dependents institutionalized in treatment centers in Medellin in the year 2011. The examination was carried out related to the consumption of emerging drugs. An ad hoc tool was applied to all the drug users in order to identify which of the drugs of this study they considered to be emergent. Once the consumers were identified and selected based on the frequency of consumption, and the prevalence in the last year and last month, a semi-structured interview was carried out to find out details on the substances and their consumption characteristics. RESULTS: Based on the new drug consumers in Medellin, 82.2% were male and 17.8% female. As regards education levels, 58.2% were in high school, 26.8% hold higher technical or college degrees, and 1.4% had no schooling. Only 27.8% held a steady job, occasional employment, or were independent business owners, 40.7% were students and 8.9% were housewives. More than three-quarters (76.3%) were single, and 17.8% had a steady partner. The sample represented all social classes. Of all the emerging drugs found in this study, the prevalence of benzodiazepines stands out (flunitrazepam and clonazepam), life prevalence (LP), 97.5%; last year prevalence (LYP), 67.9%, and last month prevalence (LMP), 46.7%. These were followed by the synthetic drugs (LSD, Ecstasies, amphetamines, GHB, Vegetable Ecstasies, Phencyclidine; Methamphetamine, Ketamine, 2CB), with LP, 96.5%; LYP, 44.5%, and LMP, 23.5%. Then there was smokable cocaine (Crack and Free-Base), with LP, 80%, LYP, 52.1%, and LYP=31.7%. The opiate derivatives (heroine, morphine, opium, codeine, dextromethorphan, meperidine, fentanyl) had an LP, 61.4%; LYP, 26.7% and LMP, 16%. The consumption statistics of the hallucinogens such as mushrooms, scopolamine and "yague", had an LP, 73.5%; LYP, 23.2% and LMP, 12.2%. Finally, use of inhalants such as popper and dichloromethane (Dick) had an LP, 87.9%; LYP, 37.6% and LMP, 21.6%. CONCLUSION: These results are an alert to the need to track the development of these so called emergent drugs due to the risks they pose for public health. PMID- 26572946 TI - [Validation of the Schizophrenia Quality Of Life Scale (SQLS) to Measure Quality of Life in Patients Diagnosed With Schizophrenia in Colombia]. AB - OBJECTIVE: To validate the SQLS scale in Colombian patients diagnosed with schizophrenia. METHOD: The self-report scale was applied to 251 patients. Measures of test-retest reliability, internal consistency and correlation inter scales with the SF-12 were made by applying the scale 2 days later in 28 patients, and 30 days later in 38; 50 patients filled-out the SF-12 scale to determine the concurrent validity. RESULTS: Three domains were found with all of them having Cronbach's alphas >0.7. The three factors model did not show adequate fit indexes. Test-retest evaluation showed satisfactory correlation values (>0.86). Sensitivity to change did not shown significant differences between the repeated measures. As regards concurrent validity, acceptable correlation values were found only in SF-12 domains related to mental health and functioning. CONCLUSIONS: The SQLS has a factorial structure consistent with previous reports, adequate internal consistency and temporal stability. However, a more detailed examination of some of these items is required, considering that the measurement of the construct does not appear to be adequate. PMID- 26572947 TI - [Construction of an Institutional Declaration of Duties and Rights of Mentally Ill Patients]. AB - INTRODUCTION: A process of construction of institutional declaration of mental health patient's duties and rights is shown, highlighting that mentally ill people are considered particularly susceptible to the violation of their rights. Some aspects from historical, quality issues and law in Colombia are presented. Some declarations of rights were available, but they needed to be updated and adapted to the specific conditions of mental hospital health care. MATERIAL AND METHODS: Qualitative research, literature search, focus groups and consultation meetings of duties and rights with representatives of patients, families, residents of psychiatry, medicine students, and mental health workers. It sets out general principles and definitions, looking understandability of the Declaration by the different groups involved. RESULTS: The final document had users participation, this methodology is compatible with the regulations in Colombia, bioethical principles, quality issues and community participation. The final declaration was approved and integrated with corporate information. PMID- 26572948 TI - [Mental Health and Political Violence. Care of Psychiatric Patient or Acknowledge of the Micropolitics of the Subject]. AB - INTRODUCTION: Political violence is a global phenomenon, especially in low- to middle-income countries. This phenomenon increasingly involves civilians. This situation is a priority in collective health, as it produces multiple and complex effects on physical and mental health, and human and social ecosystems. The objective of this article is to present the main tendencies that coexist in research and practice on the understanding of the effects of political violence on mental health. The biomedical approach of psychiatric trauma and the wider perspective of social sciences, which incorporate the collective dimension of these effects, are also taken into account. METHODS: Review of research determines the relationship with political violence / collective violence and mental health in international databases and national documentation centers, academics and NGOs within the last decade of the twentieth century, and the first of this century under the headings of trauma, war, armed conflict and political violence. RESULTS: The limitations of general explanations of psychiatric trauma in understanding the complex effects of political violence on mental health are shown. The constructs that incorporate social and collective dimensions increase this comprehension of these effects and knowledge of mental health, both conceptually as methodologically. CONCLUSIONS: In a political violence context it urgent to change attitudes about mental health. It is a way to overcome the biomedical, individualistic, and short term epidemiology, and to remove medication from mental health. This means acknowledging that people who experience the effects of political violence effects are not sick. They are powerful people who can transform and produce the life they dream of. PMID- 26572949 TI - [Metabolic Syndrome and Bipolar Affective Disorder: A Review of the Literature]. AB - Bipolar disorder (BD) is a chronic psychiatric disorder that is found within the first ten causes of disability and premature mortality. The metabolic syndrome (MS) is a group of risk factors (RF) that predispose to cardiovascular disease (CV), diabetes and early mortality. Both diseases generate high costs to the health system. Major studies have shown that MS has a higher prevalence in patients with mental disorders compared to the general population. The incidence of MS in BD is multifactorial, and due to iatrogenic, genetic, economic, psychological, and behavioral causes related to the health system. The most common RF found is these patients was an increased abdominal circumference, and it was found that the risk of suffering this disease was greater in women and Hispanic patients. As regards the increase in RF to develop a CV in patients with BD, there have been several explanations based on the risky behavior of patients with mental illness, included tobacco abuse, physical inactivity and high calorie diets. An additional explanation described in literature is the view of BD as a multisystemic inflammatory illness, supported by the explanation that inflammation is a crucial element in atherosclerosis, endothelial dysfunction, platelet rupture, and thrombosis. The pathophysiology of MS and BD include factors such as adrenal, thyroid and sympathetic nervous system dysfunction, as well as poor lifestyle and medication common in these patients. This article attempts to give the reader an overall view of the information published in literature to date, as regards the association between BD and MS. PMID- 26572950 TI - [Schizotypical Disorder or Schizophrenia? Assessment of Penal Responsibility in a Patricide Case]. AB - Patricide is the murder of one of the parents. We report a case of a man who had committed two homicides, at different times, one of them being considered a parricide. He was referred for forensic psychiatric evaluation and later evaluated in a psychiatric assistance service. Psychiatric interview was carried out and the final psychiatric diagnosis was established based on the DSM-IV-TR criteria and retrospective analysis of forensic and clinical records. The court appointed forensic experts concluded that the patient suffered from schizotypical disorder, presenting cognitive and volitive impairment. He was found not guilty by reason of insanity. Later, in a second assessment, being in a psychiatric assistance service, the patient received a diagnosis of paranoid schizophrenia. The determination of criminal responsibility is essential to the proper disposition of convicted persons in any system of criminal law that protects human rights. PMID- 26572951 TI - [Standards in Medical Informatics: Fundamentals and Applications]. AB - The use of computers in medical practice has enabled novel forms of communication to be developed in health care. The optimization of communication processes is achieved through the use of standards to harmonize the exchange of information and provide a common language for all those involved. This article describes the concept of a standard applied to medical informatics and its importance in the development of various applications, such as computational representation of medical knowledge, disease classification and coding systems, medical literature searches and integration of biological and clinical sciences. PMID- 26572952 TI - Commitment Must Be Shared. PMID- 26572953 TI - Calibration plot for proteomics: A graphical tool to visually check the assumptions underlying FDR control in quantitative experiments. AB - In MS-based quantitative proteomics, the FDR control (i.e. the limitation of the number of proteins that are wrongly claimed as differentially abundant between several conditions) is a major postanalysis step. It is classically achieved thanks to a specific statistical procedure that computes the adjusted p-values of the putative differentially abundant proteins. Unfortunately, such adjustment is conservative only if the p-values are well-calibrated; the false discovery control being spuriously underestimated otherwise. However, well-calibration is a property that can be violated in some practical cases. To overcome this limitation, we propose a graphical method to straightforwardly and visually assess the p-value well-calibration, as well as the R codes to embed it in any pipeline. All MS data have been deposited in the ProteomeXchange with identifier PXD002370 (http://proteomecentral.proteomexchange.org/dataset/PXD002370). PMID- 26572954 TI - A novel CHST3 allele associated with spondyloepiphyseal dysplasia and hearing loss in Pakistani kindred. AB - Skeletal dysplasias (SDs) are highly heterogeneous disorders composed of 40 clinical sub-types that are part of 456 well-delineated syndromes in humans. Here, we enrolled consanguineous kindred from a remote area of Sindh province of Pakistan, with 14 affected individuals suffering with short stature, kyphoscoliosis, joint dislocations, clubfoot, heart valve anomalies and progressive bilateral mixed hearing loss. To identify pathogenic variants in this family, whole exome sequencing (WES) was performed in one affected and one normal individual, which revealed a novel transversion mutation (c.802G>T; p.Glu268*) in CHST3 associated with the phenotype. CHST3 encodes a chondroitin 6-O sulfotransferase-1 (C6ST-1) enzyme that is essential for the sulfation of proteoglycans found in cartilages. Previously, mutations in CHST3 have largely been reported in sporadic cases of SD, primarily with severe spinal abnormalities, joint dislocations, joint contractures, and clubfoot. Clinical and radiological examination of the affected individuals in this family provides new insights into phenotypic spectrum of CHST3 alleles and disease progression with age. PMID- 26572955 TI - Optical coherence tomography of the pulmonary arteries: A systematic review. AB - Optical coherence tomography (OCT) is an imaging technique extensively used for visualizing the coronary circulation, where it assists clinical decision-making. Along with the new interventional procedures being introduced for pulmonary vascular disease, there is an increasing need for intravascular imaging of the pulmonary arteries. Additionally, measurements of the wall thickness of the pulmonary arteries of patients with various types of pulmonary hypertension (PH) may provide relevant diagnostic and prognostic information. The aim of this review is to summarize all the available evidence on the use of OCT for imaging the pulmonary bed and to describe a simple protocol for OCT image acquisition. We conducted a systematic review of the literature using electronic reference databases through February 2015 (MEDLINE, Cochrane Library, Web of Knowledge, and references cited in other studies) and the search terms "optical coherence tomography," "pulmonary hypertension," and "pulmonary arteries." Studies in which OCT was used to image the pulmonary vessels were considered for inclusion. We identified 14 studies reporting OCT imaging data from the pulmonary arteries. OCT was able to identify intravascular thrombi in patients with chronic thromboembolic PH (CTEPH), and an increase in vessel wall thickness was found in most patients with PH, compared with the controls. OCT has also been reported to be useful for the selection of balloon size in the setting of balloon pulmonary angioplasty for CTEPH. The main limitations include lack of standardization, little data on outcomes, cost, and the technical limitations involved in visualizing small-diameter (<1mm) pulmonary vessels. OCT has become a potential tool for the in vivo study of vascular changes in the pulmonary arteries, and may provide additional information in the assessment of patients with PH. Prospective high-quality studies assessing the safety, validity, and clinical impact of OCT imaging for pulmonary vessels are warranted. PMID- 26572956 TI - Serum phosphate is an independent predictor of the total aortic calcification volume in non-hemodialysis patients undergoing cardiovascular surgery. AB - BACKGROUND: A high serum phosphate level is a well-known risk factor for vascular calcification (VC) in patients on hemodialysis (HD). However, the association between the serum phosphate level and VC in non-HD patients is unclear. Our aim was to assess the impact of serum phosphate level on aortic calcification (AC) volume in non-HD patients undergoing cardiovascular surgery. METHODS: A total of 117 patients who underwent thoracoabdominal computed tomography as a preoperative general evaluation before cardiovascular surgery were enrolled. The total AC volume was quantified using the volume-rendering method by extracting the area >=130HU within the entire aorta. The total AC volume index (AC-VI) was estimated as the total AC volume divided by the body surface area. RESULTS: In the 117 patients (64.7+/-13.1 years, 39% women), the median total AC-VI was 1.23mL/m(2). The mean estimated glomerular filtration rate (eGFR), adjusted serum calcium levels, and serum phosphate levels were 63.8+/-19.9mL/min/1.73m(2), 9.1+/ 0.4mg/dL, and 3.6+/-0.6mg/dL, respectively. When the patients were classified into four quartiles based on their total AC-VI value, the serum phosphate level showed a positive correlation with a probability of being in the highest AC-VI quartile (R(2)=0.0146, p=0.0383) whereas the adjusted serum calcium level did not show a significant correlation (R(2)=0.0040, p=0.2615). A similar relationship between the serum phosphate level, adjusted serum calcium level, and AC-VI was confirmed when the total AC-VI was divided into the thoracic AC-VI and abdominal AC-VI. Multivariate analysis indicated that the serum phosphate level was an independent positive predictor of higher total AC-VI quartiles (beta=0.8013, p=0.0160). CONCLUSIONS: An increase in serum phosphate level was associated with an increased AC burden in non-HD patients undergoing cardiovascular surgery. PMID- 26572957 TI - Left ventricular reverse remodeling with infantile dilated cardiomyopathy and pitfalls of carvedilol therapy. AB - BACKGROUND: The left ventricular reverse remodeling (LVRR) in idiopathic dilated cardiomyopathy (DCM) and the treatment with carvedilol in infants with severe heart failure remain poorly understood. METHODS: We reviewed the medical records of 5 infants around 12 months old referred to our hospital with severe heart failure due to DCM. Increased left ventricular fractional shortening (LVFS) by more than 10% and the percent of normal of left ventricular end-diastolic dimension (%LVDd) less than 120% were defined as LVRR in this study. RESULTS: DCM onset ranged from 8 to 16 months. Initial treatment of their acute heart failure was successful in all 5 but 4 patients relapsed despite the usual dose of carvedilol (induction 0.02-maintenance 0.4mg/kg/day), and developed worsening heart failure. Brain natriuretic peptide (BNP) levels which increased again after the acute treatment had fallen subsequent to discontinuing or decreasing carvedilol. Over 24 months, LVFS had increased from 11+/-2% (mean+/-SD) to 34+/ 5% (p<0.05), and %LVDd decreased from 149+/-27% to 108+/-11% (p<0.05). CONCLUSIONS: LVRR was found at 2 years after the onset of DCM. Usual dose induction of carvedilol therapy can sometimes worsen heart failure after successful initial conventional treatment for the acute heart failure in DCM. Close control of carvedilol treatment may determine the prognosis of infantile DCM around 12 months old. It is prudent to increase low-dose carvedilol slowly corresponding with the BNP level. PMID- 26572958 TI - Detection of Neisseria meningitidis in asymptomatic carriers in a university hospital from Brazil. AB - Asymptomatic meningococcus carriers in hospitals is a risk factor for acquiring meningococcal disease. Meningococcal carrier (MC) frequency was investigated in oropharyngeal swab samples collected from 200 staff members at a teaching hospital from Brazil. MC prevalence was 9% (95% CI 5-13%). Risk factors associated with MC were: mean age of 26.5 years, male gender, bar attendance frequency and number of persons/house. Of 18 isolated meningococcal strains, 14 were non-group able (NG), 3 corresponded to serogroup B and 1 to serogroup 29E. The frequency of serotypes and serosubtypes was heterogenous, with a slight predominance of serotypes 4 and 7 and serosubtypes P1.7 and P1.5. Most strains (n=13) were susceptible to the antimicrobials tested. The ctrA gene (PCR) was identified in 9 (64.3%) of the 14 NG strains, suggesting virulence in most of the NG isolated strains. Therefore, a constant surveillance of these asymptomatic carriers is required. PMID- 26572959 TI - Capsule expression in isolates of Streptococcus equi subsp. equi. PMID- 26572960 TI - Irradiation alters the differentiation potential of bone marrow mesenchymal stem cells. AB - Bone injury following radiotherapy has been confirmed by epidemiological and animal studies. However, the underlying mechanism remains to be elucidated and no preventive or curative solution has been identified for this bone loss. The present study aimed to investigate the irradiation-altered osteogenesis and adipogenesis of bone marrow mesenchymal stem cells (BMSCs). BMSCs were derived and exposed to gamma-irradiation at doses of 0, 0.25, 0.5, 1, 2, 5 and 10 Gy. Cell viability was assessed using a 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide assay, and clonal expansion in vitro was detected by colony forming unit assessment. The osteogenic differentiation ability was demonstrated by alkaline phosphatase (ALP) activity, ALP staining and mineralization alizarin red staining, and the adipogenic differentiation ability was determined using Oil O red staining. The osteogenesis-associated genes, RUNX2, ALP, osteocalcin (OCN) and adipogenesis-associated genes, PPAR-gamma and C/EBPalpha, were detected using reverse transcription-quantitative polymerase chain reaction analyses. The protein expression levels of RUNX2, ALP and PPAR-gamma were detected using western blotting. Compared with the control, significant decreases in the proliferation, ALP activity and mineralization ability of the BMSCs were observed in the gamma-irradiation group, with a high level of correlation with the exposure dose. However, no significant changes were observed in the area of Oil red O positive staining. The mRNA levels of RUNX2, ALP and OCN were decreased (P<0.05), however, no significant changes were observed in the levels of C/EBPalpha and PPAR-gamma. The protein expression levels of RUNX2 and ALP were decreased in the irradiated BMSCs, however, no significant difference was observed in the protein expression of PPAR-gamma. Irradiation inhibited the osteogenic and adipogenic ability of the BMSCs, and the osteogenic differentiation was decreased. The results of the present study provided evidence to assist in further elucidating radiotherapy-associated side effects on the skeleton. PMID- 26572962 TI - Estimating future dental services' demand and supply: a model for Northern Germany. AB - OBJECTIVES: To plan dental services, a spatial estimation of future demands and supply is required. We aimed at estimating demand and supply in 2030 in Northern Germany based on the expected local socio-demography and oral-health-related morbidity, and the predicted number of dentists and their working time. METHODS: All analyses were performed on zip-code level. Register data were used to determine the number of retiring dentists and to construct regression models for estimating the number of dentists moving into each zip-code area until 2030. Demand was modelled using projected demography and morbidities. Demand-supply ratios were evaluated and spatial analyses applied. Sensitivity analyses were employed to assess robustness of our findings. RESULTS: Compared with 2011, the population decreased (-7% to -11%) and aged (from mean 46 to 51 years) until 2030. Oral-health-related morbidity changed, leading to more periodontal and fewer prosthetic treatments needs, with the overall demand decreasing in all scenarios (-25% to -33%). In contrast, the overall number of dentists did only limitedly change, resulting in moderate decrease in the supplied service quantities (max. -22%). Thus, the demand-supply ratio increased in all but the worst case scenario, but was unequally distributed between spatial units, with several areas being over- and some being under- or none-serviced in 2030. CONCLUSIONS: Within the limitations of the underlying data and the required assumptions, this study expects an increasingly polarized ratio of dental services demand and supply in Northern Germany. Our estimation allows to assess the impact of different influence factors on demand or supply and to specifically identify potential challenges for workforce planning and regulation in different spatial units. PMID- 26572961 TI - Paternal uniparental disomy 11p15.5 in the pancreatic nodule of an infant with Costello syndrome: Shared mechanism for hyperinsulinemic hypoglycemia in neonates with Costello and Beckwith-Wiedemann syndrome and somatic loss of heterozygosity in Costello syndrome driving clonal expansion. AB - Costello syndrome (CS) entails a cancer predisposition and is caused by activating HRAS mutations, typically arising de novo in the paternal germline. Hypoglycemia is common in CS neonates. A previously reported individual with the rare HRAS p.Gln22Lys had hyperinsulinemic hypoglycemia. Autopsy showed a discrete pancreatic nodule. The morphologic and immunohistochemistry findings, including loss of p57(Kip2) protein, were identical to a focal lesion of congenital hyperinsulinism, however, no KCNJ11 or ABCC8 mutation was identified and germline derived DNA showed no alternation of the maternal or paternal 11p15 alleles. Here we report paternal uniparental disomy (pUPD) within the lesion, similar to the pUPD11p15.5 in Beckwith-Wiedemann syndrome (BWS). The similar extent of the pUPD suggests a similar mechanism driving hyperinsulinemia in both conditions. After coincidental somatic LOH and pUPD, the growth promoting effects of the paternally derived HRAS mutation, in combination with the increased function of the adjacent paternally expressed IGF2, may together result in clonal expansion. Although this somatic LOH within pancreatic tissue resulted in hyperinsulinism, similar LOH in mesenchymal cells may drive embryonal rhabdomyosarcoma (ERMS). Interestingly, biallelic IGF2 expression has been linked to rhabdomyosarcoma tumorigenesis and pUPD11 occurred in all 8 ERMS samples from CS individuals. Somatic KRAS and HRAS mutations occur with comparable frequency in isolated malignancies. Yet, the malignancy risk in CS is notably higher than in Noonan syndrome with a KRAS mutation. It is conceivable that HRAS co-localization with IGF2 and the combined effect of pUPD 11p15.5 on both genes contributes to the oncogenic potential. PMID- 26572963 TI - Serum IGF-1 is higher in patients with idiopathic normal pressure hydrocephalus than in the population. AB - BACKGROUND: Hypopituitarism has been reported in patients with idiopathic normal pressure hydrocephalus (iNPH), which could enhance characteristic symptoms like impaired wakefulness, gait, body balance, and subcortical cognitive deterioration. PURPOSE: To compare basal serum levels of pituitary and sex hormones and serum insulin-like growth factor-1 (S-IGF-1) in patients with iNPH and an age-matched control population, and to correlate the preoperative hormone levels with symptoms and signs pre-operatively and three months after surgery. METHODS: A cross-sectional case control design was used. Patients diagnosed with iNPH, n=108 (65 men and 43 women, mean age 72.3 years), were consecutively included during 2006-2011 at Sahlgrenska University Hospital, Gothenburg, Sweden. S-TSH, S-free T4, S-FSH, S-LH, S-prolactin, plasma ACTH, S-testosterone, S oestradiol and S-IGF-1 were examined. Symptoms and signs were scored using the iNPH scale score. Population controls, n=146, were recruited from the WHO MONICA project, Gothenburg in 2008. RESULTS: Men and women with iNPH had higher S-IGF-1 than controls (p<0.001). Women with iNPH had lower S-TSH (p=0.016) than controls, but the frequency of levothyroxine substitution was similar. Among men, a higher level of S-IGF-1 was associated with milder symptoms, while higher levels of S FSH and S-LH were associated with more severe symptoms. CONCLUSIONS: Patients with iNPH did not have lower levels of pituitary or sex hormones but presented with higher levels of S-IGF-1, compared with healthy, age-matched controls. Higher S-IGF-1 in men was related to milder mental and physical symptoms and signs. PMID- 26572964 TI - Uncovering Phosphorylation-Based Specificities through Functional Interaction Networks. AB - Protein kinases are an important class of enzymes involved in the phosphorylation of their targets, which regulate key cellular processes and are typically mediated by a specificity for certain residues around the target phospho-acceptor residue. While efforts have been made to identify such specificities, only ~30% of human kinases have a significant number of known binding sites. We describe a computational method that utilizes functional interaction data and phosphorylation data to predict specificities of kinases. We applied this method to human kinases to predict substrate preferences for 57% of all known kinases and show that we are able to reconstruct well-known specificities. We used an in vitro mass spectrometry approach to validate four understudied kinases and show that predicted models closely resemble true specificities. We show that this method can be applied to different organisms and can be extended to other phospho recognition domains. Applying this approach to different types of posttranslational modifications (PTMs) and binding domains could uncover specificities of understudied PTM recognition domains and provide significant insight into the mechanisms of signaling networks. PMID- 26572965 TI - Who attracts whom to rural general practice? Variation in temperament and character profiles of GP registrars across different vocational training pathways. AB - INTRODUCTION: The ongoing rural doctor workforce shortage continues to stimulate interest in new strategies to alleviate the situation. Alongside increasingly promising approaches is the notion that attracting and nurturing the 'right' individuals may be paramount to achieving long-term success in recruitment and retention. This study compares the patterns of demographic and temperament and character trait profiles of general practice registrars in training across three Australian vocational training pathways: the Australian College of Rural and Remote Medicine independent rural pathway, and the rural and general pathways of Australian general practice training. The aim is to describe the predominant personalities of existing trainees. At its foundation, this study strives to obtain more information about those individuals choosing rural practice, which may inform ways to enhance future recruitment and training into rural medicine. This rationale has been explored with medical students using intention as the dependent variable, but registrars are that much closer to their final career choice, and therefore may provide more practical and reliable indicators of the notion of who attracts whom into rural practice. METHODS: A cross-sectional design sampled four registrar training groups: one from the Australian College of Rural and Remote Medicine, one Australian general practice training rural only, and two Australian general practice training rural and general pathway regional training providers. Registrars (451) completed a questionnaire that gathered basic demographics and a personality trait profile using the Temperament and Character Inventory plus a measure of resilience. Statistical analysis explored the relationships between variables (multivariate analyses of variance) and compared levels of traits between registrar groups (analyses of variance). RESULTS: Registrars training via the Australian College of Rural and Remote Medicine pathway were more likely to be male, older, have a definite interest in or already practising in a rural area and were significantly (with moderate effect sizes) lower in levels of harm avoidance and higher in persistence, self directedness and resilience compared to the other training pathways. CONCLUSIONS: The implications of the data to the recruitment and training of general practice registrars goes further than identifying groups of individuals with similar temperament and character trait patterns. This sample is portrayed as relatively homogenous in light of their overall trait levels as compared to population norms. However, it is the combination of the levels of individual traits that suggests a profile that differs between registrars on a rural or general training path. Importantly the combination of trait levels that tend to differentiate registrars (low harm avoidance, high self-directedness and persistence) correlates strongly with high levels of resilience. Doctors and medical students benefit from a high level of resilience to cope with and manage the challenges of the profession and arguably more so in rural practice. Along with certain demographic characteristics, the combination and levels of temperament (stable) and character (developmental) traits support the notion of a mixture of personal traits that may be indicative of individuals best suited to rural and remote medicine. Further investigation is needed to determine whether individuals with a certain pattern of personal traits are attracted to rural practice training or whether the training itself, in part by exposure to rural life and rural medical practice, selects for those who are most suited to and will eventually choose to practice in a rural location. PMID- 26572966 TI - Two-dimensional airflow modeling underpredicts the wind velocity over dunes. AB - We investigate the average turbulent wind field over a barchan dune by means of Computational Fluid Dynamics. We find that the fractional speed-up ratio of the wind velocity over the three-dimensional barchan shape differs from the one obtained from two-dimensional calculations of the airflow over the longitudinal cut along the dune's symmetry axis - that is, over the equivalent transverse dune of same size. This finding suggests that the modeling of the airflow over the central slice of barchan dunes is insufficient for the purpose of the quantitative description of barchan dune dynamics as three-dimensional flow effects cannot be neglected. PMID- 26572967 TI - Communication and respect for people with dementia: student learning (CARDS) - the development and evaluation of a pilot of an education intervention for pre qualifying healthcare students. AB - BACKGROUND: Dementia is an international health priority and healthcare students need to be prepared to work with people living with dementia. There is a paucity of the literature describing appropriate educational interventions for pre qualifying healthcare students and even fewer that are evaluated. METHODS: Based on available evidence, an education program was developed aiming to increase students' knowledge and confidence in working with people with dementia (PWD). An introductory program (IP) of classroom sessions and workshops was followed by a volunteer care home experience (CHE) (4 * 3 h). Piloted with physiotherapy (IP n = 55; CHE n = 6) and nursing students (IP n = 20; CHE n = 7), using a survey design, knowledge, and perceived confidence for working with PWD were measured at four time points; baseline, after the IP, after the CHE, and six months later. The data were analyzed using paired t-tests or non-parametric equivalents. RESULTS: Knowledge scores increased after the IP (Time 1-2, p < 0.001, n = 48) and increases were retained after six months (Time 1-4, p < 0.001, n = 40). Perceived confidence increased at six months follow up (Time 1-4, p < 0.001, n = 40) with peaks after the IP (Time 1-2, p < 0.001, n = 47) and CHE (Time 2-3, p = 0.004, n = 13). Physiotherapy and nursing students did not differ on knowledge, but nursing students were more confident at baseline and after the IP. Prior experience equated with greater confidence but no more knowledge. CONCLUSIONS: Findings indicate that students' knowledge and confidence to work with PWD improves after this educational intervention, with confidence improving more when supplemented by experience. PMID- 26572968 TI - Effects of Mutations on the Reconfiguration Rate of alpha-Synuclein. AB - It is still poorly understood why alpha-synuclein, the intrinsically disordered protein involved in Parkinson's and other neurodegenerative diseases, is so prone to aggregation. Recent work has shown a correlation between the aggregation rate and the rate of diffusional reconfiguration by varying temperature and pH. Here we examine the effects of several point mutations in the sequence on the conformational ensemble and reconfiguration rate. We find that at lower temperatures the PD causing aggregation enhancing mutations slow down and aggregation reducing mutations drastically speed up intramolecular diffusion, as compared to the wild type sequence. However, at higher temperatures, one of three familial mutations that enhance aggregation slows intramolecular diffusion while non-natural mutations that inhibit aggregation speed up intramolecular diffusion. These results support the hypothesis that the first step of aggregation is kinetically controlled by reconfiguration in which the protein chain cannot reconfigure rapidly enough to escape oligomerization. Finally we provide physical and chemical insights into why small point mutations cause these dramatic changes in the conformational ensemble and dynamics. PMID- 26572969 TI - Transient misfolding dominates multidomain protein folding. AB - Neighbouring domains of multidomain proteins with homologous tandem repeats have divergent sequences, probably as a result of evolutionary pressure to avoid misfolding and aggregation, particularly at the high cellular protein concentrations. Here we combine microfluidic-mixing single-molecule kinetics, ensemble experiments and molecular simulations to investigate how misfolding between the immunoglobulin-like domains of titin is prevented. Surprisingly, we find that during refolding of tandem repeats, independent of sequence identity, more than half of all molecules transiently form a wide range of misfolded conformations. Simulations suggest that a large fraction of these misfolds resemble an intramolecular amyloid-like state reported in computational studies. However, for naturally occurring neighbours with low sequence identity, these transient misfolds disappear much more rapidly than for identical neighbours. We thus propose that evolutionary sequence divergence between domains is required to suppress the population of long-lived, potentially harmful misfolded states, whereas large populations of transient misfolded states appear to be tolerated. PMID- 26572970 TI - Variation in the association between socioeconomic status and breastfeeding practices by immigration status in Taiwan: a population based birth cohort study. AB - BACKGROUND: The relationship between socioeconomic status (SES) and breastfeeding has been extensively discussed in the literature. However, there is some evidence that this relationship can differ with immigration status. To date the majority of research investigating the relationships among SES, breastfeeding and immigration status has been conducted in Europe and the United States with a lack of similar research from Asia. Therefore, the aim of this study was to describe differences in breastfeeding practices between native-born Taiwanese mothers and immigrant mothers in Taiwan and to investigate any differences in the relationship between SES and breastfeeding practices by immigration status. METHODS: Data analyzed came from the Taiwan Birth Cohort Study, the first longitudinal study of babies in Taiwan with a nationally representative sample born in 2005. In the present study, we included 21,217 mothers or primary caregivers who completed interview surveys when their child was 6 months old. Socioeconomic status was measured by the education level of mothers and fathers, and the couple's monthly income. Data analysis involved multiple logistic regression. Control variables included residential area, mother's employment status, age of the father and mother, and sex of the infant. RESULTS: The proportion of immigrant mothers predominantly breastfeeding for 4 and for 6 months (Mainland Chinese mothers: 18.25 %, 36.29 %; Southeast Asian mothers: 10.71 %, 24.85 %) was significantly higher than that observed in their Taiwan born counterparts (7.03 %, 16.22 %). Analysis stratified by immigration status showed that a higher level of parental education was associated with a greater likelihood of predominantly breastfeeding in Taiwanese mothers. However, no statistically significant relationship was observed between education and predominantly breastfeeding in immigrant mothers. Higher monthly income was also significantly associated with a greater likelihood of predominantly breastfeeding in Taiwanese mothers. However, there was no significant linear relationship between monthly income and predominantly breastfeeding in immigrant women. CONCLUSION: The relationship between SES and breastfeeding is different in immigrant mothers and native-born Taiwanese mothers. Taiwanese policy should continue to encourage breastfeeding in immigrant mothers. However, greater attention should be placed on Taiwanese mothers from a low SES background. PMID- 26572971 TI - Merozoite surface protein-1 genetic diversity in Plasmodium malariae and Plasmodium brasilianum from Brazil. AB - BACKGROUND: The merozoite surface protein 1 (MSP1) gene encodes the major surface antigen of invasive forms of the Plasmodium erythrocytic stages and is considered a candidate vaccine antigen against malaria. Due to its polymorphisms, MSP1 is also useful for strain discrimination and consists of a good genetic marker. Sequence diversity in MSP1 has been analyzed in field isolates of three human parasites: P. falciparum, P. vivax, and P. ovale. However, the extent of variation in another human parasite, P. malariae, remains unknown. This parasite shows widespread, uneven distribution in tropical and subtropical regions throughout South America, Asia, and Africa. Interestingly, it is genetically indistinguishable from P. brasilianum, a parasite known to infect New World monkeys in Central and South America. METHODS: Specific fragments (1 to 5) covering 60 % of the MSP1 gene (mainly the putatively polymorphic regions), were amplified by PCR in isolates of P. malariae and P. brasilianum from different geographic origin and hosts. Sequencing of the PCR-amplified products or cloned PCR fragments was performed and the sequences were used to construct a phylogenetic tree by the maximum likelihood method. Data were computed to give insights into the evolutionary and phylogenetic relationships of these parasites. RESULTS: Except for fragment 4, sequences from all other fragments consisted of unpublished sequences. The most polymorphic gene region was fragment 2, and in samples where this region lacks polymorphism, all other regions are also identical. The low variability of the P. malariae msp1 sequences of these isolates and the identification of the same haplotype in those collected many years apart at different locations is compatible with a low transmission rate. We also found greater diversity among P. brasilianum isolates compared with P. malariae ones. Lastly, the sequences were segregated according to their geographic origins and hosts, showing a strong genetic and geographic structure. CONCLUSIONS: Our data show that there is a low level of sequence diversity and a possible absence of allelic dimorphism of MSP1 in these parasites as opposed to other Plasmodium species. P. brasilianum strains apparently show greater divergence in comparison to P. malariae, thus P. malariae could derive from P. brasilianum, as it has been proposed. PMID- 26572972 TI - Investigating parents/caregivers financial burden of care for children with non communicable diseases in Ghana. AB - BACKGROUND: The introduction of the Ghana national health insurance scheme (NHIS) has led to progressive and significant increase in utilization of health services. However, the financial burden of caring for children with non communicable diseases (NCDs) under the dispensation of the NHIS, especially during hospitalization, is less researched. This paper therefore sought to assess the financial burden parents/caregivers face in caring for children hospitalized with NCDs in Ghana, in the era of the Ghana NHIS. METHODS: We conducted a cross sectional survey of 225 parents or caregivers of children with NCDS hospitalized in three hospitals. Convenience sampling was used to select those whose children were discharged from hospital after hospitalization. Descriptive statistics such as frequencies and chi-square and logistic regression were used in data analysis. The main outcome variable was financial burden of care, proxied by cost of hospitalization. The independent variable included socio-economic and other indicators such as age, sex, income levels and financial difficulties faced by parents/caregivers. RESULTS: The study found that over 30 % of parents/caregivers spend more than Ghc50 (25$) as cost of treatment of children hospitalized with NCDs; and over 40 % of parents/caregivers also face financial difficulties in providing health care to their wards. It was also found that even though many children hospitalized with NCDs have been covered by the NHIS, and that the NHIS indeed, provides significant financial relief to parents in the care of children with NCDs, children who are insured still pay out-of-pocket for health care, in spite of their insurance status. It was also found that there is less support from relatives and friends in the care of children hospitalized with NCDs, thus exacerbating parents/caregivers financial burden of caring for the children. CONCLUSIONS: Even though health insurance has proven to be of significant relief to the financial burden of caring for children with NCDs, parents/caregivers still face significant financial burden in the care of their wards. Stakeholders in health care delivery should therefore ensure that all children with NCDs including those excluded from the NHIS should be covered by NHIS. A special effort focusing on identifying children with NCDs within the lower income groups, especially from rural areas, in order to exempt them from any form of payment for their health care is recommended. PMID- 26572973 TI - Screening assays for primary haemophagocytic lymphohistiocytosis in children presenting with suspected macrophage activation syndrome. AB - BACKGROUND: Primary haemophagocytic lymphohistiocytosis (HLH) screening assays are increasingly being performed in patients presenting with macrophage activation syndrome (MAS). The objective of this study was to describe their diagnostic and prognostic relevance in children who had presented to paediatric rheumatology and had undergone investigative work up for MAS. METHODS: Data was obtained retrospectively from an existing protein screening assay database and patient records. Assays included: intracellular expression of perforin in CD56+ Natural Killer (NK) cells; CD107a Granule Release Assay (GRA) in response to PHA in NK cells, or anti-CD3 stimulation of CD8 lymphocytes; in males Signal Lymphocyte Activating Molecule Associated Protein (SAP), and X-linked Inhibitor of Apoptosis Protein (XIAP) expression. All assays, requested by paediatric rheumatology, of children who had undergone investigative work up for MAS over a 5-year period (2007-2011) were included. RESULTS: Twenty-one patients (15 female), median age 6.5 years (range 0.6-16) with follow-up of 16 months (range 1 51), were retrospectively identified. At presentation, 3/21 (14 %) fulfilled HLH 2004 diagnostic criteria. At least one screening test result was available for all 21 patients; 7/21 (33 %) had at least one persistent screening test abnormality. Of this group 4/7 (57 %) died or required haematopoietic stem cell transplantation (HSCT), compared to 1/14 (7 %) with no screening test abnormality (p = 0.025). 3/21 (14 %) ultimately had a diagnosis of primary HLH (two confirmed genetically; XIAP, familial HLH type 3, and one confirmed clinically). Of the six patients with abnormal GRA 5/6 had negative routine genetic results. CONCLUSIONS: Screening for primary HLH is warranted for children whose first rheumatological presentation is with MAS, since overall 14 % had an eventual diagnosis of primary HLH. A persistently abnormal GRA in patients presenting with MAS defines a high risk group with poor outcome (mortality or HSCT), possibly due to as yet unidentified genetic cause. PMID- 26572974 TI - The Eukaryotic Translation Initiation Factor 4E (eIF4E) as a Therapeutic Target for Cancer. AB - Cancer cells depend on cap-dependent translation more than normal tissue. This explains the emergence of proteins involved in the cap-dependent translation as targets for potential anticancer drugs. Cap-dependent translation starts when eIF4E binds to mRNA cap domain. This review will present eIF4E's structure and functions. It will also expose the use of eIF4E as a therapeutic target in cancer. PMID- 26572975 TI - Antitumor Lipids--Structure, Functions, and Medical Applications. AB - Cell proliferation and metastasis are considered hallmarks of tumor progression. Therefore, efforts have been made to develop novel anticancer drugs that inhibit both the proliferation and the motility of tumor cells. Synthetic antitumor lipids (ATLs), which are chemically divided into two main classes, comprise (i) alkylphospholipids (APLs) and (ii) alkylphosphocholines (APCs). They represent a new entity of drugs with distinct antiproliferative properties in tumor cells. These compounds do not interfere with the DNA or mitotic spindle apparatus of the cell, instead, they incorporate into cell membranes, where they accumulate and interfere with lipid metabolism and lipid-dependent signaling pathways. Recently, it has been shown that the most commonly studied APLs inhibit proliferation by inducing apoptosis in malignant cells while leaving normal cells unaffected and are potent sensitizers of conventional chemo- and radiotherapy, as well as of electrical field therapy. APLs resist catabolic degradation to a large extent, therefore accumulate in the cell and interfere with lipid-dependent survival signaling pathways, notably PI3K-Akt and Raf-Erk1/2, and de novo phospholipid biosynthesis. They are internalized in the cell membrane via raft domains and cause downstream reactions as inhibition of cell growth and migration, cell cycle arrest, actin stress fibers collapse, and apoptosis. This review summarizes the in vitro, in vivo, and clinical trials of most common ATLs and their mode of action at molecular and biochemical levels. PMID- 26572976 TI - Telomere Repeat-Binding Factor 2 Is Responsible for the Telomere Attachment to the Nuclear Membrane. AB - Telomeres are nucleoprotein structures that specify ends of eukaryotic chromosomes. They enable complete DNA replication, protect chromosomes from end to-end fusions, and help organize chromatin structure. These functions are mediated by special telomeric proteins. TRF2 (telomeric repeat-binding factor 2) is an essential component of shelterin, a telomere-binding protein complex. TRF2 induces formation of a special structure of telomeric DNA, counteracts activation of double-strand break response pathway and ataxia telangiectasia mutated kinase pathway at telomeres. Some line of evidence implicates TRF2 in interactions with the nuclear envelope (NE). TRF2 is tightly bound to the nuclear membrane in frog oocytes nucleus, and it was found colocalized with NE or its remnants in mouse cells. Computer analysis of TRF2 amino acid sequence has shown that TRF2 possesses motifs, which resemble rod domain characteristic of intermediate filament proteins. These observations suggest that TRF2 is a good candidate for the attachment of telomeres to the NE in somatic cells. PMID- 26572977 TI - Alterations in Gene Expression in Depression: Prospects for Personalize Patient Treatment. AB - The number of people around the world suffering from depression has dramatically increased in last few decades. It has been predicted that by 2020 depression will become the second most common cause of disability. Furthermore, depression is often misdiagnosed and confused with other psychiatric disorders showing similar symptoms, i.e., anxiety and bipolar disorder, due to the fact that diagnosing is often carried out by medical workers who are not psychiatrically trained. These facts prompt us to prepare this review which focuses on alterations in gene expression in depression. We believe that an in-depth knowledge of molecular bases of behavior in depression and other mood disorders would be of a great benefit for the correct diagnosing of these disorders, as well as for prescribing a treatment that best suits each individual depending on expression alterations in depression-related genes. Therefore, the main aim of this review is to promote further translational research on the biochemistry of mood disorders and take the results further for the design of new targeted therapeutics that can be used for personalized treatment with minimal adverse effects. PMID- 26572978 TI - Evolution and Coevolution of PRC2 Genes in Vertebrates and Mammals. AB - Recruited by noncoding RNAs (ncRNAs) to specific genomic sites, polycomb repressive complexes 2 (PRC2) modify chromatin states in nearly all eukaryotes. The limited ncRNAs in Drosophila but abundant in mammals should have made PRC2 genes evolved significantly in Deuterostomia to adapt to the much increased ncRNAs. This study analyzes the evolution and coevolution of seven PRC2 genes in 29 Deuterostomia. These genes, previously assumed highly conserved, are found to have obtained multiple insertions in vertebrates and mammals and undergone significant positive selections in marsupials and prosimians, indicating adaptions to substantially increased lncRNAs (long noncoding RNAs) in mammals and in primates. Some insertions occur notably in homologous sequences of human nonsense-mediated decay (NMD) transcripts. Moreover, positive selections and signals of convergent evolution imply the independent increase of lncRNAs in mammals and in primates. Coevolutionary analysis reveals that patterns of interaction between PRC2 proteins have also much evolved from vertebrates to mammals, indicating adaptation at the protein complex level. The potential functions of mammalian-specific insertions and NMD transcripts deserve further experimental examination. PMID- 26572979 TI - Quartz-Crystal Microbalance (QCM) for Public Health: An Overview of Its Applications. AB - Nanobiotechnologies, from the convergence of nanotechnology and molecular biology and postgenomics medicine, play a major role in the field of public health. This overview summarizes the potentiality of piezoelectric sensors, and in particular, of quartz-crystal microbalance (QCM), a physical nanogram-sensitive device. QCM enables the rapid, real time, on-site detection of pathogens with an enormous burden in public health, such as influenza and other respiratory viruses, hepatitis B virus (HBV), and drug-resistant bacteria, among others. Further, it allows to detect food allergens, food-borne pathogens, such as Escherichia coli and Salmonella typhimurium, and food chemical contaminants, as well as water borne microorganisms and environmental contaminants. Moreover, QCM holds promises in early cancer detection and screening of new antiblastic drugs. Applications for monitoring biohazards, for assuring homeland security, and preventing bioterrorism are also discussed. PMID- 26572980 TI - Porous Alumina as a Promising Biomaterial for Public Health. AB - Porous aluminum is a nanostructured material characterized by unique properties, such as chemical stability, regular uniformity, dense hexagonal porous lattice with high aspect ratio nanopores, excellent mechanical strength, and biocompatibility. This overview examines how the structure and properties of porous alumina can be exploited in the field of public health. Porous alumina can be employed for fabricating membranes and filters for bioremediation, water ultrafiltration, and microfiltration/nanofiltration, being a promising technique for having clean and fresh water, which is essential for human health. Porous alumina-based nanobiosensor coated with specific antibodies or peptides seem to be a useful tool to detect and remove pathogens both in food and in water, as well as for environmental monitoring. Further, these applications, being low energy demanding and cost-effective, are particularly valuable in resource limited settings and contexts, and can be employed as point of use devices in developing countries, where there is an urgent need of hygiene and safety assurance. PMID- 26572981 TI - Human Papillomavirus Vaccine: State of the Art and Future Perspectives. AB - Human Papillomavirus (HPV) is a widely distributed and common virus, that causes benign lesions (such as warts and papillomas) but, if not cleared, can lead to malignant lesions as well, such as intraepithelial lesions and neoplasia. An extensive body of researches has demonstrated that E1 and E2 are involved in viral transcription and replication, E5, E6, and E7 act as oncoproteins, whilst L1 and L2 contribute to the formation of the capsid. However, this view has been recently challenged, since also E2 could play a role in HPV-induced carcinogenesis. Therefore, a complex picture is emerging, opening new ways and perspectives. The present article provides an overview of the biology of HPV, paying particular attention to its structural details and molecular mechanisms. The article also shows how this knowledge has been exploited for developing effective vaccines, both prophilactic/preventive and therapeutic ones. L1-based prophylactic vaccines, like Gardasil, Cervarix, and Gardasil 9, have been already licensed, whilst L2-based second generation preventive vaccines are still under clinical trials. New, highly immunogenic and effective vaccines can be further developed thanks to computer-aided design and bioinformatics/computational biology. The optimization of combinational therapies is another promising opportunity. PMID- 26572982 TI - SHOPIN: Semantic Homogeneity Optimization in Protein Interaction Networks. AB - Protein interaction networks (PINs) are argued to be the richest source of hidden knowledge of the intrinsic physical and/or functional meanings of the involved proteins. We propose a novel method for computational protein function prediction based on semantic homogeneity optimization in PIN (SHOPIN). The SHOPIN method creates graph representations of the PIN augmented by inclusion of the semantics of the proteins and their interacting contexts. Network wide semantic relationships, modeled using random walks, are used to map the augmented PIN graphs in a new semantic metric space. The method produces a hierarchical partitioning of the PIN optimal in terms of semantic homogeneity by iterative optimization of the ratio of between clusters dissimilarities and within clusters similarities in the new semantic metric space. Function prediction is done using cluster wide-hierarchy high function enrichment. Results validate the rationale of the SHOPIN method placing it right next to state-of-the-art approaches performance wise. PMID- 26572983 TI - The Sydney playground project--levelling the playing field: a cluster trial of a primary school-based intervention aiming to promote manageable risk-taking in children with disability. AB - BACKGROUND: Providing children and adults with opportunities to engage in manageable risk taking may be a stepping stone toward closing the gap in life conditions currently experienced by young people with disabilities. We aim to demonstrate the effectiveness of a simple, innovative program for 1) changing the way parents and teachers view manageable risk-taking for children with disabilities and 2) increasing the level of responsibility that children take for their own actions, as seen on the school playground. METHODS/DESIGN: We will employ a cluster repeated measures trial with six Sydney-area primary-school based programs for children with disabilities. The intervention comprises two arms. 1) Risk-reframing--teachers and parents will participate together in small group intervention sessions focusing on the benefits of manageable risk-taking; 2) Introduction of play materials--materials without a defined purpose and facilitative of social cooperation will be introduced to the school playground for children to use at all break times. A control period will be undertaken first for two school terms, followed by two terms of the intervention period. Outcome measures will include playground observations, The Coping Inventory, qualitative field notes, and The Tolerance of Risk in Play Scale. DISCUSSION: New national programs, such as Australia's National Disability Insurance Scheme, will place increasing demands on young people with disabilities to assume responsibility for difficult decisions regarding procuring services. Innovative approaches, commencing early in life, are required to prepare young people and their carers for this level of responsibility. This research offers innovative intervention strategies for promoting autonomy in children with disabilities and their carers. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registration Number ACTRN12614000549628 (registered 22/5/2014). PMID- 26572984 TI - Population genetic structure and natural selection of apical membrane antigen-1 in Plasmodium vivax Korean isolates. AB - BACKGROUND: Plasmodium vivax apical membrane antigen-1 (PvAMA-1) is a leading candidate antigen for blood stage malaria vaccine. However, antigenic variation is a major obstacle in the development of an effective vaccine based on this antigen. In this study, the genetic structure and the effect of natural selection of PvAMA-1 among Korean P. vivax isolates were analysed. METHODS: Blood samples were collected from 66 Korean patients with vivax malaria. The entire PvAMA-1 gene was amplified by polymerase chain reaction and cloned into a TA cloning vector. The PvAMA-1 sequence of each isolate was sequenced and the polymorphic characteristics and effect of natural selection were analysed using the DNASTAR, MEGA4, and DnaSP programs. RESULTS: Thirty haplotypes of PvAMA-1, which were further classified into seven different clusters, were identified in the 66 Korean P. vivax isolates. Domain II was highly conserved among the sequences, but substantial nucleotide diversity was observed in domains I and III. The difference between the rates of non-synonymous and synonymous mutations suggested that the gene has evolved under natural selection. No strong evidence indicating balancing or positive selection on PvAMA-1 was identified. Recombination may also play a role in the resulting genetic diversity of PvAMA-1. CONCLUSIONS: This study is the first comprehensive analysis of nucleotide diversity across the entire PvAMA-1 gene using a single population sample from Korea. Korean PvAMA-1 had limited genetic diversity compared to PvAMA-1 in global isolates. The overall pattern of genetic polymorphism of Korean PvAMA-1 differed from other global isolates and novel amino acid changes were also identified in Korean PvAMA-1. Evidences for natural selection and recombination event were observed, which is likely to play an important role in generating genetic diversity across the PvAMA 1. These results provide useful information for the understanding the population structure of P. vivax circulating in Korea and have important implications for the design of a vaccine incorporating PvAMA-1. PMID- 26572985 TI - Erratum: Concordance and limits between transcutaneous and arterial carbon dioxide pressure in emergency department patients with acute respiratory failure: a single-center, prospective, and observational study. AB - After publication of this article (Scand J Trauma Resusc Emerg Med 23:40, 2015), it came to light that an earlier version had been published in error. This erratum contains the correct version of the article, which incorporates revisions made in response to reviewer comments. Additionally, one of the authors was inadvertently omitted from the author list. This author, Justin Yan, has been included in the corrected author list above. BACKGROUND: Transcutaneous CO2 (PtCO2) is a continuous and non-invasive measure recommended by scientific societies in the management of respiratory distress. The objective of this study was to evaluate the correlation between PtCO2 and arterial partial pressure of CO2 (PaCO2) by arterial blood gas analysis in emergency patients with dyspnoea, and to determine the factors that interfere with this correlation. METHODS: From January to June 2014, all adult patients admitted to the RR with dyspnoea during business hours were included in the study if arterial blood gas measurements were indicated. A sensor measuring the PtCO2 was attached to the ear lobe of the patient before the gas analysis. Anamnesis, clinical and laboratory parameters were identified. RESULTS: Ninety patients with dyspnoea were included (104 pairs of measurements). The median (IQR) age was 79 years (69 - 85). The correlation between PtCO2 and PaCO2 was R(2) =.83 (p<.001) but became lower for values of PaCO2 above 60 mm Hg. The mean bias (+/- SD) between the two methods of measurement (Bland-Altman analysis) was -1.4 mm Hg (+/- 7.7) with limits of agreement from -16.4 to 13.7 mm Hg. In univariate analysis, PaO2 interfered with this correlation. After multivariate analysis, temperature (OR = 3.01; 95 % CIs [1.16, 7.80]) and PaO2 (OR = 1.22; 95 % CIs [1.02, 1.47]) significantly interfered with this correlation. CONCLUSIONS: There is a significant correlation between PaCO2 and PtCO2 values for patients admitted to the emergency department for acute respiratory failure. One limiting factor to routine use of PtCO2 measurements in the emergency department is the presence of hyperthermia. PMID- 26572987 TI - Pathologists and liability: an old medical story needing a new ending. PMID- 26572986 TI - The role of invertases in plant compensatory responses to simulated herbivory. AB - BACKGROUND: The ability of a plant to overcome animal-induced damage is referred to as compensation or tolerance and ranges from undercompensation (decreased fitness when damaged) to overcompensation (increased fitness when damaged). Although it is clear that genetic variation for compensation exists among plants, little is known about the specific genetic underpinnings leading to enhanced fitness. Our previous study identified the enzyme GLUCOSE-6-PHOSPHATE DEHYDROGENASE 1 (G6PD1) as a key regulator contributing to the phenomenon of overcompensation via its role in the oxidative pentose phosphate pathway (OPPP). Apart from G6PD1 we also identified an invertase gene which was up-regulated following damage and that potentially integrates with the OPPP. The invertase family of enzymes hydrolyze sucrose to glucose and fructose, whereby the glucose produced is shunted into the OPPP and presumably supports plant regrowth, development, and ultimately compensation. In the current study, we measured the relative expression of 12 invertase genes over the course of plant development in the Arabidopsis thaliana genotypes Columbia-4 and Landsberg erecta, which typically overcompensate and undercompensate, respectively, when damaged. We also compared the compensatory performances of a set of invertase knockout mutants to the Columbia-4 wild type. RESULTS: We report that Columbia-4 significantly up regulated 9 of 12 invertase genes when damaged relative to when undamaged, and ultimately overcompensated for fruit production. Landsberg erecta, in contrast, down-regulated two invertase genes following damage and suffered reduced fitness. Knockout mutants of two invertase genes both exhibited significant undercompensation for fruit production, exhibiting a complete reversal of the wild type Col-4's overcompensation. CONCLUSION: Collectively, these results confirm that invertases are essential for not only normal plant growth and development, but also plants' abilities to regrow and ultimately compensate for fitness following apical damage. PMID- 26572988 TI - Pathology consultation on human chorionic gonadotropin testing for pregnancy assessment. AB - OBJECTIVES: To provide clarity on the use of qualitative and quantitative human chorionic gonadotropin (hCG) tests for the assessment of pregnancy. METHODS: A case scenario and a brief review of the relevant literature describing clinical and analytical considerations regarding hCG testing are presented. RESULTS: In pregnancy, hCG is nearly always detectable in serum and urine within 16 days after ovulation. Serial hCG testing is valuable in the evaluation of suspected ectopic pregnancy. hCG assays vary in their analytical specificity, and qualitative tests may be less analytically sensitive than claimed. Erroneous hCG test results can occur for several reasons. CONCLUSIONS: hCG assays are reliable diagnostic tests for pregnancy assessment, but a clear understanding of their limitations is necessary for appropriate result interpretation. PMID- 26572989 TI - Nuclear grade plus proliferation grading system for invasive ductal carcinoma of the breast: validation in a tertiary referral hospital cohort. AB - OBJECTIVES: For patients with invasive breast cancer, management decisions are informed by tumor grade according to the Nottingham Grading System (NGS), either on its own or as part of the Nottingham Prognostic Index (NPI). A system retaining the nuclear grade element but substituting the two subjective components, mitosis count and tubule formation, of the NGS with a proliferation index based on Ki-67 (MIB-1) has been proposed (nuclear grade plus proliferation [N+P] grading). METHODS: We validated the prognostic value of this grading system on a population of 322 women. RESULTS: N+P grading resulted in more grade I tumors (47.9% vs 4.5%) and fewer grade II (32% vs 51.5%) and grade III (20.1% vs 44%) tumors compared with NGS. The NPI calculated based on N+P grade had a similar association with survival (P < .001; odds ratio, 1.729) as the NPI calculated on the basis of the NGS grade (P < .001; odds ratio, 1.668). CONCLUSIONS: The N+P system seems equivalent to the NGS system. PMID- 26572990 TI - The LAST guidelines in clinical practice: implementing recommendations for p16 use. AB - OBJECTIVES: To determine the impact of implementing p16 Lower Anogenital Squamous Terminology Standardization Project for HPV-Associated Lesions (LAST) guidelines, we compared p16 use and follow-up data before and after implementation of the guidelines. METHODS: We reviewed all cervical biopsy specimens diagnosed by two pathologists before and after implementation of the LAST guidelines and calculated the rate of and reason for p16 use across all biopsy specimens, high grade squamous intraepithelial lesion (HSIL) detection, and follow-up. RESULTS: In total, 1,829 and 1,623 cervical biopsy specimens were reviewed in periods A and B, respectively. Overall p16 use increased from 2.8% to 6.2% (P < .001). Recommendations 2 and 4 increased from 0.16% and 0% of all cervical biopsy specimens in period A to 1.4% and 1.9% in period B, respectively (P < .0001). p16+ HSIL increased from 1.4% to 2.3% (P < .05). The positive predictive value of p16+ HSIL increased from 48% to 76% (P < .05). CONCLUSIONS: Implementation of the p16 LAST guidelines resulted in a significant increase in p16 use and a significant increase in the positive predictive value of p16+ HSIL. PMID- 26572991 TI - Fine-needle aspiration diagnoses of noninvasive follicular variant of papillary thyroid carcinoma. AB - OBJECTIVES: Endocrine pathologists are reconsidering whether tumors characterized as noninvasive follicular variant of papillary thyroid carcinoma (NFVPTC) warrant a diagnosis of carcinoma. A change in terminology would affect cytology diagnoses; thus, our aim was to study the preceding fine-needle aspiration (FNA) diagnoses of this group of tumors. METHODS: We evaluated the FNA diagnoses of a primary cohort of 72 consecutively resected NFVPTCs and the cytologic and molecular features of an additional cohort of 39 tumors that included both NFVPTCs and classical papillary thyroid carcinomas (cPTCs). RESULTS: For our primary cohort, the preceding FNA diagnosis associated with the highest risk of malignancy was suspicious for PTC in nearly half (48.6%) of cases. In contrast to the majority of cPTCs, no NFVPTCs in our second cohort had papillae or pseudoinclusions on cytologic evaluation of the FNA specimens, and none harbored a BRAF V600E mutation. CONCLUSIONS: If NFVPTCs were no longer termed carcinomas, this would affect the rate of malignancy of FNA diagnostic categories. Cytologic and molecular features could aid in identifying NFVPTCs at the time of FNA diagnosis. PMID- 26572992 TI - Evaluation of paroxysmal nocturnal hemoglobinuria screening by flow cytometry through multicentric interlaboratory comparison in four countries. AB - OBJECTIVES: Paroxysmal nocturnal hemoglobinuria (PNH) is currently diagnosed by flow cytometry; although highly sensitive, its interpretation and reporting appear as critical as its technique. Thus, we developed a quality control scheme for the French-speaking region based on the international recommendations for PNH screening. METHODS: After a topical workshop, we proposed a 1-year, two-step survey program to any volunteering French-speaking clinical laboratory. The first survey consisted of sending raw data files to evaluate gating and the interpretation strategy of each center. The second stipulated sending fresh whole blood samples to evaluate the whole process and its practice. RESULTS: Forty-nine participants from voluntary centers returned results for each of the two successive surveys. On virtual survey, 27% reported false-positive PNH created by immature granulocytes, whereas the minor PNH clone was not detected by 9%. On fresh survey, 63% of centers used at least the same six-color combination (CD24, CD14, CD33, CD15, CD45, and fluorescent aerolysin), and nearly 70% of participants were able to perform a sensitivity test less than 0.1% on neutrophils. All participants detected the major PNH clone, yet 16% returned false-positive results for the non-PNH clone case. CONCLUSIONS: We succeeded in rallying numerous French-speaking clinical laboratories for both surveys and in harmonizing the technical practice by highlighting common pitfalls. PMID- 26572993 TI - The minimal carcinoma triple stain is superior to commercially available multiplex immunohistochemical stains: breast triple stain and LC/DC breast cocktail. AB - OBJECTIVES: The Minimal Carcinoma (MC) Triple Stain is a tri-chromogen multiplex immunostain (CK7, p63, and E-cadherin) helpful in classifying morphologically ambiguous and/or small carcinomas as either ductal or lobular and/or in situ or invasive. We compared the utility of this stain with two commercially available duplex/multiplex immunostains: Breast Triple Stain (BTS) (Clarient, Aliso Viejo, CA; CK5, p63, and CK8/18) and LC/DC Breast Cocktail (LCDC) (Biocare, Concord, CA; E-cadherin and p120). METHODS: Ninety-seven mammary carcinomas stained with the MC Triple Stain, BTS, and LCDC were compared. RESULTS: The MC Triple Stain, LCDC, and BTS were diagnostic in 90 (93%) of 97, 82 (85%) of 97, and 85 (88%) of 97 of cases, respectively. All stains showed decreased diagnostic utility due to variability in tissue integrity, quality of the staining, and/or ease of interpretation. In cases where all immunostains were interpretable, the MC Triple Stain yielded the most information. CONCLUSIONS: When technically sufficient, all three immunostains demonstrated relative strengths and weaknesses in their ability to provide diagnostic information with the highest consistency and ease of use. Many cases stained with LCDC were technically insufficient due to a suboptimal staining protocol provided by the company. Overall, the MC Triple Stain outperformed BTS and LCDC by more consistently providing more diagnostic information. The MC Triple Stain is a viable alternative to other multiplex immunostains in evaluating small foci of carcinoma, particularly when both the histologic type and extent of disease (in situ vs invasive) require clarification. PMID- 26572994 TI - Utility of direct immunofluorescence testing for IgA in patients with high and low clinical suspicion for dermatitis herpetiformis. AB - OBJECTIVES: The purpose of this study was to examine the utility of direct immunofluorescence (DIF) testing for the characteristic immunoglobulin A deposits of dermatitis herpetiformis (DH) in patients stratified into high and low clinical suspicion subgroups. METHODS: We retrospectively analyzed the results of H&E and DIF testing in 77 cases of suspected DH and separated them into high and low clinical suspicion subgroups based on clinical impression at the time of biopsy. RESULTS: The overall sensitivity and specificity of routine (H&E) histologic evaluation were 0.75 and 0.951, respectively. Although there were 13 cases of DH (of 36 total cases) in the high clinical suspicion subgroup, there were only three (of 41 total cases) in the low clinical suspicion subgroup. In the high clinical suspicion subgroup, the positive predictive value (PPV) was 0.9, and the negative predictive value (NPV) was 0.846. Alternatively, the PPV was 0.6 and the NPV was 1.0 for the low clinical suspicion subgroup. Histologic false negatives did occur, but all were in patients within the high clinical suspicion subgroup. CONCLUSIONS: It is anticipated that the NPV and PPV will vary due to differing clinical practice characteristics; however, in patients with a low clinical suspicion for DH, these data argue that it may be reasonable to first perform a biopsy for routine histologic evaluation before requesting DIF analysis. PMID- 26572995 TI - Drop-to-drop variation in the cellular components of fingerprick blood: implications for point-of-care diagnostic development. AB - OBJECTIVES: Blood obtained via fingerprick is commonly used in point-of-care assays, but few studies have assessed variability in parameters obtained from successive drops of fingerprick blood, which may cause problems for clinical decision making and for assessing accuracy of point-of-care tests. METHODS: We used a hematology analyzer to analyze the hemoglobin concentration, total WBC count, three-part WBC differential, and platelet count in six successive drops of blood collected from one fingerprick from each of 11 donors, and we used a hemoglobinometer to measure the hemoglobin concentration of 10 drops of fingerprick blood from each of 7 donors. RESULTS: The average percent coefficient of variation (CV) for successive drops of fingerprick blood was higher by up to 3.4 times for hemoglobin, 5.7 times for WBC count, 3 times for lymphocyte count, 7.7 times for granulocyte count, and 4 times for platelets than in venous controls measured using a hematology analyzer. The average percent CV for fingerprick blood was up to 5 times higher for hemoglobin than venous blood measured using a point-of-care hemoglobinometer. Fluctuations in blood parameters with increasing volume of fingerprick blood are within instrument variability for volumes equal to or greater than 60 to 100 MUL. CONCLUSIONS: These data suggest caution when using measurements from a single drop of fingerprick blood. PMID- 26572996 TI - The clinical laboratory service: medical practitioners' satisfaction in southern Ethiopia. AB - OBJECTIVES: To evaluate medical practitioners' satisfaction with the clinical laboratory services by health institution in southern Ethiopia. METHODS: A questionnaire-based cross-sectional survey was undertaken from June 2013 through April 2014, which involved 290 medical practitioners from 19 health institutions. RESULTS: The mean (SD) overall satisfaction score was 3.36 (0.87) of 5.0. For most of the specific service categories, the highest rating was "good." The highest mean (SD) score was for clarity and readability of results (4.09 [0.99] of 5.0), while the lowest was for blood bank service (1.72 [1.88] of 5.0). CONCLUSIONS: This study identified wide room for improvement by the services provided from clinical laboratories. Corrective actions for the less satisfied service categories and continuous monitoring of laboratory activities are essential for the development of quality in clinical laboratories of health institutions in southern Ethiopia. PMID- 26572997 TI - Accuracy and interobserver variability of the cytologic diagnosis of low-grade urothelial carcinoma in instrumented urinary tract cytology specimens. AB - OBJECTIVES: The aim of this study was to determine the accuracy of diagnosis and level of agreement of the cytologic diagnosis of low-grade urothelial carcinoma (LGUC) among experienced cytopathologists to help the development of the upcoming classification scheme ("The Paris System") of urinary cytology (UTCy). METHODS: Forty ThinPrep (Cytyc, Boxborough, MA) UTCy specimens (19 with corresponding biopsy specimens diagnosed as LGUC and 21 with negative biopsy and/or cystoscopy specimens) were blindly reviewed by six cytopathologists from three institutions and diagnosed as negative for malignancy (NM), atypical urothelial cells (AUCs), and LGUC. Interobserver agreement was measured with the weighted kappa statistic. Each observer's receiver operating characteristic (ROC) curves and the area under the ROC curve (AUROC) were calculated. RESULTS: Four to six reviewers diagnosed LGUC in five (26%) of 19 UTCy specimens, corresponding to a biopsy diagnosis of LGUC. Overall agreement was fair (kappa = 0.30). After collapsing AUC with NM, the reviewers' ranges of sensitivity, specificity, positive predictive value, and negative predictive value for LGUC were 21% to 53%, 81% to 95%, 71% to 90%, and 57% to 67%, respectively. AUROC varied from 0.66 to 0.74. CONCLUSIONS: We found that UTCy has a low sensitivity but relatively high specificity, resulting in poor to fair accuracy for the diagnosis of LGUC; the level of agreement between reviewers was only fair to moderate. PMID- 26572998 TI - Development of a BK virus real-time quantitative assay using the bioMerieux analyte-specific reagents in plasma specimens. AB - OBJECTIVES: Viral load testing for BK virus (BKV) has become the standard of care for diagnosing BKV infection and monitoring therapy in kidney transplant patients. However, there are currently no US Food and Drug Administration approved assays and no standardization among available tests. METHODS: This study evaluated the performance of the analyte-specific reagent (ASR) BKV primers r gene and probe r-gene reagents (bioMerieux, Marcy l'Etoile, France) soon to become available on the US market for accuracy, linearity, precision, analytical sensitivity, specificity, and correlation with the Qiagen (Germantown, MD) BKV ASR test using commercial material and patient plasma samples. RESULTS: The assay was linear from 204 to 3.92 million (2.31-6.6 log10) DNA copies/mL (coefficient of determination: R(2) =0.999). A dilution series demonstrated limits of detection and quantitation of 2.14 log10 and 2.30 log10 copies/mL (95% hit rate detection), respectively. Interrun precision was highly reproducible, with coefficients of variance ranging from 2.2% to 6.0%. A comparison of 34 matched samples showed a good agreement (R(2) = 0.87) between the bioMerieux BKV laboratory test and the Qiagen BKV ASR assay results, with an average negative bias (-0.28 log10 copies/mL). CONCLUSIONS: The laboratory-developed test with bioMerieux BKV reagents is a reliable and sensitive assay for BKV DNA quantitation compared with the Qiagen ASR test. PMID- 26572999 TI - Medical malpractice concerns and defensive medicine: a nationwide survey of breast pathologists. AB - OBJECTIVES: "Assurance behaviors" in medical practice involve providing additional services of marginal or no medical value to avoid adverse outcomes, deter patients from filing malpractice claims, or ensure that legal standards of care were met. The extent to which concerns about medical malpractice influence assurance behaviors of pathologists interpreting breast specimens is unknown. METHODS: Breast pathologists (n = 252) enrolled in a nationwide study completed an online survey of attitudes regarding malpractice and perceived alterations in interpretive behavior due to concerns of malpractice. Associations between pathologist characteristics and the impact of malpractice concerns on personal and colleagues' assurance behaviors were determined by chi(2) and logistic regression analysis. RESULTS: Most participants reported using one or more assurance behaviors due to concerns about medical malpractice for both their personal (88%) and colleagues' (88%) practices, including ordering additional stains, recommending additional surgical sampling, obtaining second reviews, or choosing the more severe diagnosis for borderline cases. Nervousness over breast pathology was positively associated with assurance behavior and remained statistically significant in a multivariable logistic regression model (odds ratio, 2.5; 95% confidence interval, 1.0-6.1; P = .043). CONCLUSIONS: Practicing US breast pathologists report exercising defensive medicine by using assurance behaviors due to malpractice concerns. PMID- 26573000 TI - Dual use of E-cadherin and D2-40 immunostaining in unusual meningioma subtypes. AB - OBJECTIVES: Meningiomas usually can be readily diagnosed on H&E alone, although occasionally immunohistochemistry (IHC) confirmation is desirable. Studies exploring the diagnostic utility of either podoplanin (D2-40) or E-cadherin IHC in meningiomas have conflicted, and no studies exist in which the two IHCs have been used in combination for diagnosis. METHODS: E-cadherin and D2-40 IHC was performed on 77 meningiomas (31 ordinary; eight microcystic; four rare myxoid; six metaplastic; six invasive of orbit, muscle, and/or soft tissue; two metastatic; six brain-invasive World Health Organization [WHO] grade II, nine non brain-invasive WHO grade II; and five anaplastic WHO grade III), with semi quantitative scoring on a three-tier scale (0, focal [1+], strong/diffuse [2+]). RESULTS: All meningiomas were either E-cadherin or D2-40 IHC+, with 69 of 77 showing dual immunostaining, most at the 2+ level. No downregulation of E cadherin IHC was found in invasive or high-grade meningiomas. CONCLUSIONS: Dual E cadherin/D2-40 IHC can supplement diagnosis of meningioma. PMID- 26573001 TI - High levels of regulatory T cells in blood are a poor prognostic factor in patients with diffuse large B-cell lymphoma. AB - OBJECTIVES: Host immunity likely plays a role in preventing progression of diffuse large B-cell lymphoma (DLBCL). Analysis of host immune cells may provide useful information for assessing prognosis or possibly clinical management. METHODS: Peripheral blood samples from 77 patients with DLBCL and 30 healthy volunteers were analyzed using flow cytometry immunophenotyping. CBC counts, T cell subsets, and dendritic cells (DCs) were detected, and the results were correlated with clinicopathologic characteristics. RESULTS: Compared with healthy volunteers, patients with DLBCL had significantly higher leukocyte and monocyte counts (P < .001); higher percentages of neutrophils (P < .001), "natural" regulatory T cells (Tregs; CD3+Foxp3+, P < .001), and immature DCs (CD83-CD1a+, P = .005); and lower percentages of lymphocytes (P < .001) and helper T cells (P = .038). In univariate analysis, high neutrophil counts (>=6,000/MUL, P = .014) and "induced" Tregs (CD4+CD25+, P = .026) were poor survival factors along with high International Prognostic Index scores (P < .001) and other high-risk clinical parameters. In multivariate analysis, high Tregs retained significance. Suppression of lymphocytes correlated with poor clinical factors; higher natural Tregs correlated with a lower CD4+/CD8+ ratio (P = .035) and more immature DCs (P = .055). CONCLUSIONS: Changes in blood immune cells occur in patients with DLBCL. The results also support a suppressive role of Tregs in adaptive immunity and correlate with poor-risk prognostic factors. PMID- 26573002 TI - The spectrum of histopathologic findings in cutaneous lesions in patients with Still disease. AB - OBJECTIVES: Still disease is a rare disorder characterized by seronegative arthralgias/arthritis, spiking fever, and either an evanescent salmon-colored rash or persistent papules and plaques. METHODS: We describe the clinical and biopsy findings in 10 patients with the evanescent rash of Still disease. RESULTS: Fourteen biopsy specimens were studied from seven women and three men with a mean age of 44.4 years. The skin lesions were typically erythematous macules, papules, or plaques with a median duration of 5 weeks. All patients had systemic symptoms, including fever and arthralgias. The infiltrate was predominantly lymphocytic in six biopsy specimens, approximately equal lymphocytic and neutrophilic in four biopsy specimens, and predominantly (although never exclusively) neutrophilic in four biopsy specimens. Other findings included focal vacuolar interface changes, neutrophilic eccrine hidradenitis, epidermal neutrophils, dermal mucin, and acanthosis associated with numerous upper epidermal dyskeratotic cells. CONCLUSIONS: It is important to be aware of the broad histologic spectrum that may be encountered in Still disease and to consider Still disease in the differential diagnosis of neutrophil-rich, lymphocyte-rich, and mixed inflammatory dermatoses. While the histologic findings seen in biopsy specimens of the evanescent rash are nonspecific, a distinctive variant also exists characterized by prominent epidermal apoptosis, especially involving the upper layers. PMID- 26573003 TI - Utility of estrogen receptor, progesterone receptor, and HER-2/neu analysis of multiple foci in multifocal ipsilateral invasive breast carcinoma. AB - OBJECTIVES: To determine the frequency of estrogen receptor (ER), progesterone receptor (PR), and HER-2/neu (HER2) testing multiple foci of ipsilateral invasive breast carcinoma at our institution and to evaluate resulting change in treatment recommendation. METHODS: We identified 165 consecutive cases of multifocal invasive breast cancer over a 10-year period (2005-2014). Clinicopathologic features and treatment recommendation were assessed by slide and chart review. RESULTS: Seventy (42.4%) of 165 patients had two or more foci tested. In the first 6 years (2005-2010), frequency of testing two or more foci was 31.6% and increased to 70.6% in 2014. Seven (10%) of 70 had a clinically significant difference in ER/PR and/or HER2 status, five (7.1%) with a difference in HER2, one (1.4%) in ER/PR, and one (1.4%) in both ER/PR and HER2. All cases with difference in status had different histology and/or the largest focus was the most positive one. CONCLUSIONS: Our findings support current recommendations to evaluate additional smaller tumor foci in multifocal invasive breast cancer if the focus is of different grade or histology. Additional features, including specific histology, grade, and ER, PR, and HER2 status of the largest focus, should also be considered when selecting cases for which testing of additional foci may be of benefit. PMID- 26573004 TI - Erratum to: miR-29b defines the pro-/anti-proliferative effects of S100A7 in breast cancer. PMID- 26573005 TI - Isolation and characterization of an antifungal compound 5-hydroxy-7,4' dimethoxyflavone from Combretum zeyheri. AB - BACKGROUND: Combretum zeyheri, belongs to the family Combretaceae and is one of the most popular herbal plants in tropical and subtropical countries. The leaves of Combretum zeyheri have been used as herbal medicine and have been reported to have pharmacological activity which includes anti-bacterial, anti-fungal, anticancer and antioxidant properties. The goal of this study was to isolate, identify and characterize compounds from C. zeyheri leaves which are responsible for its antifungal activity. METHODS: The preliminary isolation of C. zeyheri active compounds was carried out using chromatographic techniques which include sephadex gel column chromatography, silica gel column chromatography and thin layer chromatography (TLC). The isolated compounds were then investigated for their antifungal activity using broth dilution assay. The combined effect of the most potent compound and an antifungal drug miconazole was investigated using the checkerboard assay. Time-kill assays were conducted for the combinations using the colony counting method. The mechanism of action of 5-hydroxy-7,4' dimethoxyflavone as a potent antifungal agent was investigated by determining its inhibitory activity on Candida albicans drug efflux pumps using the ciprofloxacin assay. The ability of 5-hydroxy-7,4'-dimethoxyflavone to inhibit antioxidant enzymes as well as the biosynthesis of ergosterol were also investigated. RESULTS: A total of four pure compounds (A-D) were isolated from C. zeyheri leaf extract. Compound B (5-hydroxy-7,4'-dimethoxyflavone) was found to be active against Candida albicans using broth dilution method. This compound was also found to have synergistic activity on growth of C. albicans when combined with miconazole, completely inhibiting growth after only 4 hrs of incubation. Analysis of ergosterol content from Candida albicans showed a time-dependent decrease to 91 % and 63 % at 16 and 24 hrs respectively, in cells treated with 1/2 MIC of 5 hydroxy-7,4'-dimethoxyflavone. The compound 5-hydroxy-7,4'-dimethoxyflavone also showed inhibition of both the drug efflux pumps (with IC50 = 51.64 MUg/ml) and the antioxidant enzymes (at 5 MUM). CONCLUSION: The compound 5-hydroxy-7,4' dimethoxyflavone may be partly responsible for the reported antifungal activity of C. zeyheri, and may serve as a potential source of lead compounds that can be developed as antifungal phytomedicines. PMID- 26573006 TI - Chryseobacterium panacis sp. nov., isolated from ginseng soil. AB - A novel strain, DCY107(T), was isolated from soil collected from a ginseng field in Gochang, Republic of Korea. Strain DCY107(T) is Gram-negative, yellow pigmented, non-motile, non-flagellate, rod-shaped and aerobic. The strain was found to grow optimally at 25-30 degrees C and pH 6.5-7. Phylogenetically, strain DCY107(T) is closely related to Chryseobacterium polytrichastri DSM 26899(T) (98.49 % 16S rRNA gene sequence similarity), Chryseobacterium yeoncheonense JCM 18516(T) (97.78 %), Chryseobacterium aahli LMG 27338(T) (97.74 %), Chryseobacterium limigenitum LMG28734(T) (97.74 %), Chryseobacterium ginsenosidimutans JCM 16719(T) (97.47 %) and Chryseobacterium gregarium LMG 24052(T) (97.31 %). The DNA-DNA relatedness values between strain DCY107(T) and reference strains were found to be clearly below 70 %. The DNA G+C content of strain DCY107(T) was determined to be 34.2 mol%. The predominant quinone was identified menaquinone 6 (MK-6). The major polar lipids were identified as phosphatidylethanolamine and unidentified lipids: aminolipids AL1, AL2 and lipid L2. C16:00, iso-C15:00, iso-C15:02OH, iso-C17:03OH and summed feature 9 (iso C17:1 omega9c and/or C16:0 10-methyl) were identified as the major fatty acids present in strain DCY107(T). The results of physiological and biochemical tests allowed strain DCY107(T) to be differentiated phenotypically from other recognised species belonging to the genus Chryseobacterium. Therefore, it is suggested that the newly isolated organism represents a novel species, for which the name Chryseobacterium panacis sp. nov. is proposed, with the type strain designated as DCY107(T) (=CCTCC AB 2015195(T) = KCTC 42750(T)). PMID- 26573007 TI - Editorial: Challenging Organic Syntheses and Pharmacological Applications of Natural Products and their Derivatives. PMID- 26573008 TI - Highly-accurate metabolomic detection of early-stage ovarian cancer. AB - High performance mass spectrometry was employed to interrogate the serum metabolome of early-stage ovarian cancer (OC) patients and age-matched control women. The resulting spectral features were used to establish a linear support vector machine (SVM) model of sixteen diagnostic metabolites that are able to identify early-stage OC with 100% accuracy in our patient cohort. The results provide evidence for the importance of lipid and fatty acid metabolism in OC and serve as the foundation of a clinically significant diagnostic test. PMID- 26573010 TI - A comparison between adjustable single-incision sling and tension-free vaginal tape-obturator in treating stress urinary incontinence. AB - PURPOSE: To compare the subjective and objective cure rates, postoperative pain, postoperative complications, and postoperative quality of life of adjustable single-incision sling (Ajust(r)) versus tension-free vaginal tape-obturator (TVT OTM) in the treatment of female stress urinary incontinence (SUI). METHODS: Female patients with SUI (N = 368) were randomized to receive either Ajust(r) (N = 184) or TVT-OTM procedure (N = 184) between January 2012 and October 2013. Efficacy was evaluated using cure rate, postoperative complications, postoperative pain profile (using Visual Analogue Scale), Patient Global Impression of Improvement Scale, and International Consultation on Incontinence Questionnaire-Short Form. RESULTS: The patients from Ajust(r) and TVT-OTM groups had no statistically significant difference in subjective and objective cure rates (94.4 vs 90.7 %, P = 0.171; 97.2 vs 90.7 %, P = 0.195). Compared with the TVT-OTM group, patients in the Ajust(r) group had significantly less postoperative pain, shorter operative duration, and less intraoperative blood loss (all P values < 0.05). No significant difference in perioperative complications was observed between these two groups. Patients in Ajust(r) group had shorter recovery time (P < 0.001) compared to TVT-OTM group. The postoperative quality of life of patients in these two groups was significantly improved compared to baseline; however, no significant difference was observed in the average improvement of life between these two groups (P = 0.115). CONCLUSIONS: Ajust(r) procedure is simple, safe, and effective for the treatment of SUI. Compared with TVT-OTM, patients receiving Ajust(r) had less intraoperative blood loss, less postoperative pain, and shorter recovery time. PMID- 26573009 TI - Macromolecular Modelling and Docking Simulations for the Discovery of Selective GPER Ligands. AB - Estrogens influence multiple physiological processes and are implicated in many diseases as well. Cellular responses to estrogens are mainly mediated by the estrogen receptors (ER)alpha and ERbeta, which act as ligand-activated transcription factors. Recently, a member of the G protein-coupled receptor (GPCR) superfamily, namely GPER/GPR30, has been identified as a further mediator of estrogen signalling in different pathophysiological conditions, including cancer. Today, computational methods are commonly used in all areas of health science research. Among these methods, virtual ligand screening has become an established technique for hit discovery and optimization. The absence of an established three-dimensional structure of GPER promoted studies of structure based drug design in order to build reliable molecular models of this receptor. Here, we discuss the results obtained through the structure-based virtual ligand screening for GPER, which allowed the identification and synthesis of different selective agonist and antagonist moieties. These compounds led significant advances in our understanding of the GPER function at the cellular, tissue, and organismal levels. In particular, selective GPER ligands were critical toward the evaluation of the role elicited by this receptor in several pathophysiological conditions, including cancer. Considering that structure-based approaches are fundamental in drug discovery, future research breakthroughs with the aid of computer-aided molecular design and chemo-bioinformatics could generate a new class of drugs that, acting through GPER, would be useful in a variety of diseases as well as in innovative anticancer strategies. PMID- 26573011 TI - Does an increased cesarean section rate improve neonatal outcome in term pregnancies? AB - PURPOSE: To clarify whether an increased cesarean section rate improves the short term neonatal outcome in singleton term pregnancies with cephalic presentation. METHODS: A retrospective study of institutional data on the mode of delivery and neonatal outcome. The study included two cohorts: 1998-1999 (n = 7437) and 2004 2005 (n = 8505), since the institutional cesarean section rate increased sharply between these cohorts and has remained stable after the latter study period. RESULTS: The caesarean section rate almost doubled from 6.8 to 11.3 % (p < 0.001), during the study period. The rate of neonates suffering severe birth asphyxia remained low in both cohorts (0.4 vs. 0.6 %) and there were no significant differences in neonatal outcome (Apgar score <4 at 1 min and Apgar score <7 at 5 min, severe birth asphyxia, resuscitation or artificial ventilation) between the study periods. In the subgroup of neonates delivered vaginally, no significant differences were found in the above-mentioned neonatal outcomes between the cohorts. Apart from other outcomes admissions to neonatal intensive care unit increased significantly (p < 0.001) during the latter period (0.8 vs 1.6 %). CONCLUSIONS: Increasing cesarean section rate from a low to a moderate does not improve the short-term neonatal outcome in term singleton pregnancies. On the contrary neonatal intensive care unit admissions increased with increasing caesarean section rate. Furthermore it is possible to achieve good neonatal outcome with a low cesarean section rate. PMID- 26573012 TI - BMI and season are associated with vitamin D deficiency in women with impaired fertility: a two-centre analysis. AB - PURPOSE: Animal and human studies suggest that vitamin D regulates functions of the reproductive system. Vitamin D deficiency is prevalent in women of reproductive age. Vitamin D status has been associated with in vitro fertilisation outcome, features of polycystic ovarian syndrome (PCOS) and endometriosis. The aims of our study were to investigate the prevalence of vitamin D deficiency of infertile women living in central Germany, to identify risk factors for vitamin D deficiency and to specify seasonal variations of vitamin D status. METHODS: This was a retrospective cohort study at an academic tertiary care centre (N = 113) and an Outpatient Centre for Reproductive Medicine (N = 193) of women presenting for infertility treatment. The statistical evaluation was descriptive and explorative. Possible risk factors associated with an increased risk for vitamin D deficiency were assessed using multiple logistic regression models. Variables with p value less than 0.05 were further assessed in a multivariable logistic regression model. RESULTS: Overall, 98.2 % of patients at centre 1 and 81.3 % of women with impaired fertility at centre 2 had deficient or insufficient vitamin D levels. Overweight BMI and limited exposure to sun (winter, spring and autumn trimester) were associated with an increased risk of vitamin D deficiency. Vitamin D levels did not vary according to age or infertility associated disorders (e.g. endometriosis, PCOS). CONCLUSION: The rate of vitamin D deficiency among women with impaired fertility is alarming. Prospective studies are pressingly needed to confirm a causal relationship and to investigate the potential therapeutic benefits of vitamin D supplementation in this population. PMID- 26573013 TI - Outcome of fetuses with gastroschisis after modification of prenatal management strategies : Prenatal management and outcome of gastroschisis. AB - PURPOSE: To improve the outcome of fetuses with gastrochisis several studies evaluated prenatal predictors. But there are different guidelines established and therefore the prenatal care is not standardized. With our study we wanted to evaluate the outcome of fetuses with gastroschisis after modification of prenatal management strategies at the Department of Obstetrics and Gynecology of the University Hospital Munster. METHODS: In this explorative retrospective study of 39 fetuses with gastroschisis, we compare the clinical outcome between two management groups. In the first group (group 1, n = 14) prenatal indication for delivery was confirmed by a subjective evaluation of the small bowel diameter and the wall thickness without established cut-off values for these parameters. In the second group (group 2, n = 25) certain limits for the small bowel diameter (25 mm) and the wall thickness (2.5 mm) were used for fetal surveillance. RESULTS: Noticeable differences between the two groups regarding birth weight, weight centile, arterial pH, small bowel diameter, wall thickness, adverse bowel condition and re-operations could not be observed. In group 2, delivery was earlier (p = 0.011), and a lower rate of prenatal complications was observed (p = 0.016). CONCLUSION: To avoid adverse prenatal complications we recommend the observation of fetuses with gastroschisis by sonographic monitoring of the small bowel diameter and the wall thickness. PMID- 26573015 TI - [Evisceration of the small bowel through posterior perineum due to trauma in the elderly]. PMID- 26573014 TI - Graphene oxide and H2 production from bioelectrochemical graphite oxidation. AB - Graphene oxide (GO) is an emerging material for energy and environmental applications, but it has been primarily produced using chemical processes involving high energy consumption and hazardous chemicals. In this study, we reported a new bioelectrochemical method to produce GO from graphite under ambient conditions without chemical amendments, value-added organic compounds and high rate H2 were also produced. Compared with abiotic electrochemical electrolysis control, the microbial assisted graphite oxidation produced high rate of graphite oxide and graphene oxide (BEGO) sheets, CO2, and current at lower applied voltage. The resultant electrons are transferred to a biocathode, where H2 and organic compounds are produced by microbial reduction of protons and CO2, respectively, a process known as microbial electrosynthesis (MES). Pseudomonas is the dominant population on the anode, while abundant anaerobic solvent-producing bacteria Clostridium carboxidivorans is likely responsible for electrosynthesis on the cathode. Oxygen production through water electrolysis was not detected on the anode due to the presence of facultative and aerobic bacteria as O2 sinkers. This new method provides a sustainable route for producing graphene materials and renewable H2 at low cost, and it may stimulate a new area of research in MES. PMID- 26573016 TI - Erratum to: Traditional Chinese Medicine: Salvia miltiorrhiza Enhances Survival Rate of Autologous Adipose Tissue Transplantation in Rabbit Model. PMID- 26573017 TI - What determines positive, neutral, and negative impacts of Solidago canadensis invasion on native plant species richness? AB - Whether plant invasions pose a great threat to native plant diversity is still hotly debated due to conflicting findings. More importantly, we know little about the mechanisms of invasion impacts on native plant richness. We examined how Solidago canadensis invasion influenced native plants using data from 291 pairs of invaded and uninvaded plots covering an entire invaded range, and quantified the relative contributions of climate, recipient communities, and S. canadensis to invasion impacts. There were three types of invasion consequences for native plant species richness (i.e., positive, neutral, and negative impacts). Overall, the relative contributions of recipient communities, S. canadensis and climate to invasion impacts were 71.39%, 21.46% and 7.15%, respectively; furthermore, the roles of recipient communities, S. canadensis and climate were largely ascribed to plant diversity, density and cover, and precipitation. In terms of direct effects, invasion impacts were negatively linked to temperature and native plant communities, and positively to precipitation and soil microbes. Soil microbes were crucial in the network of indirect effects on invasion impacts. These findings suggest that the characteristics of recipient communities are the most important determinants of invasion impacts and that invasion impacts may be a continuum across an entire invaded range. PMID- 26573018 TI - MicroRNA-148b enhances proliferation and apoptosis in human renal cancer cells via directly targeting MAP3K9. AB - Increasing evidence revealed that miRNAs, the vital regulators of gene expression, are involved in various cellular processes, including cell growth, differentiation, apoptosis and progression. In addition, miRNAs act as oncogenes and/or tumor suppressors. The present study aimed to verify the potential roles of miR148b in human renal cancer cells. miR-148b was found to be downregulated in human renal cancel tissues and human renal cancer cell lines. Functional studies demonstrated that plasmid-mediated overexpression of miR-148b promoted cell proliferation, increased the S-phase population of the cell cycle and enhanced apoptosis in the 786-O and OS-RC-2 renal cancer cell lines, while it did not appear to affect the total number of viable cells according to a Cell Counting Kit-8 assay. Subsequently, a luciferase reporter assay verified that miR148b directly targeted mitogen-activated protein kinase (MAPK) kinase kinase 9 (MAP3K9), an upstream activator of MAPK kinase/c-Jun N-terminal kinase (JNK) signaling, suppressing the protein but not the mRNA levels. Furthermore, western blot analysis indicated that overexpression of miR148b in renal cancer cells inhibited MAPK/JNK signaling by decreasing the expression of phosphorylated (p)JNK. In addition, overexpression of MAP3K9 and pJNK was detected in clinical renal cell carcinoma specimens compared with that in their normal adjacent tissues. The present study therefore suggested that miR-148b exerts an oncogenic function by enhancing the proliferation and apoptosis of renal cancer cells by inhibiting the MAPK/JNK pathway. PMID- 26573020 TI - Aripiprazole long-acting injectable formulations for schizophrenia: aripiprazole monohydrate and aripiprazole lauroxil. AB - Aripiprazole monohydrate (AM) and aripiprazole lauroxil (AL) are two different long-acting injectable formulations of aripiprazole. AM 400 mg administered once monthly demonstrated efficacy in an acute, double-blind, placebo-controlled, randomized clinical trial, as well as in a double-blind, placebo-controlled, randomized-withdrawal maintenance study, and in two non-inferiority maintenance studies. AL is a prodrug of aripiprazole and available in 441 mg, 662 mg or 882 mg strengths. AL 441 mg and 882 mg administered once monthly demonstrated efficacy in an acute, double-blind, placebo-controlled, randomized clinical trial. The pharmacokinetic profile of AL also led to approval of dosing intervals of every 6 weeks for the 882 mg dose. The overall tolerability profiles of both products are consistent with what is known about oral aripiprazole. PMID- 26573019 TI - Using a retrospective pretest instead of a conventional pretest is replacing biases: a qualitative study of cognitive processes underlying responses to thentest items. AB - BACKGROUND: The thentest design aims to detect and control for recalibration response shift. This design assumes (1) more consistency in the content of the cognitive processes underlying patients' quality of life (QoL) between posttest and thentest assessments than between posttest and pretest assessments; and (2) consistency in the time frame and description of functioning referenced at pretest and thentest. Our objective is to utilize cognitive interviewing to qualitatively examine both assumptions. METHODS: We conducted think-aloud interviews with 24 patients with cancer prior to and after radiotherapy to elicit cognitive processes underlying their assessment of seven EORTC QLQ-C30 items at pretest, posttest and thentest. We used an analytic scheme based on the cognitive process models of Tourangeau et al. and Rapkin and Schwartz that yielded five cognitive processes. We subsequently used this input for quantitative analysis of count data. RESULTS: Contrary to expectation, the number of dissimilar cognitive processes between posttest and thentest was generally larger than between pretest and posttest across patients. Further, patients considered a range of time frames when answering the thentest questions. Moreover, patients' description at the thentest of their pretest functioning was often not similar to that which was noted at pretest. Items referring to trouble taking a short walk, overall health and QoL were most often violating the assumptions. CONCLUSIONS: Both assumptions underlying the thentest design appear not to be supported by the patients' cognitive processes. Replacing the conventional pretest-posttest design with the thentest design may simply be replacing one set of biases with another. PMID- 26573021 TI - Microcephaly-dystonia due to mutated PLEKHG2 with impaired actin polymerization. AB - Rearrangement of the actin cytoskeleton is controlled by RhoGTPases which are activated by RhoGEFs. We identified homozygosity for Arg204Trp mutation in the Rho guanidine exchange factor (RhoGEF) PLEKHG2 gene in five patients with profound mental retardation, dystonia, postnatal microcephaly, and distinct neuroimaging pattern. The activity of the mutant PLEKHG2 was significantly decreased, both in basal state and when Gbetagamma- or lysophosphatidic acid (LPA)-stimulated. SDF1a-stimulated actin polymerization was significantly impaired in patient cells, and this abnormality was duplicated in control cells when PLEKHG2 expression was downregulated. These results underscore the role of PLEKHG2 in actin polymerization and delineate the clinical and radiological findings in PLEKHG2 deficiency. PMID- 26573022 TI - Ceftobiprole medocaril in the treatment of hospital-acquired pneumonia. AB - Ceftobiprole medocaril is a fifth-generation cephalosporin approved in Europe as single-agent therapy for hospital-acquired pneumonia (HAP), excluding ventilator associated pneumonia (VAP). It is rapidly converted to the active metabolite ceftobiprole following intravenous administration. Ceftobiprole has a broad spectrum of activity, notably against methicillin-resistant Staphylococcus aureus, ampicillin-susceptible enterococci, penicillin-resistant pneumococci and Enterobacteriaceae not producing extended-spectrum beta-lactamase. Ceftobiprole is primarily excreted renally by glomerular filtration, with minimal propensity for interaction with co-administered drugs. Normal dose is ceftobiprole 500 mg, administered by 2-h intravenous infusion every 8 h, with dose adjustment according to renal function. In a pivotal Phase III trial in patients with HAP, ceftobiprole monotherapy was as efficacious as ceftazidime/linezolid for clinical and microbiological cure and was noninferior to ceftazidime/linezolid in the subgroup of patients with HAP excluding VAP. Ceftobiprole and ceftazidime/linezolid were similarly well tolerated. Ceftobiprole is an efficacious and well-tolerated option for empirical treatment of patients with HAP (excluding VAP). PMID- 26573023 TI - Evaluation of Total Antioxidant Capacity of Saliva in High School Students. AB - BACKGROUND & OBJECTIVE: Imbalance between oxidative stress and saliva antioxidants plays a major role in initiation and spread of dental caries. The aim of this study was to evaluate the total antioxidant capacity (TAC) of saliva in dental caries. METHODS: In this case-control study which employed high school students (14-18 years), the un-stimulated saliva samples of 60 students without dental caries (control group) and 60 students with dental caries (with at least 5 teeth levels of dental caries) were gathered. Each group comprised of males (half of cases) and females (half of cases). TAC of saliva was measured by Zellbio(r) (Netherlands) in terms of micmol/L. The data were analyzed using the SPSS software (ver. 17.0) and t-test with considering significance level at 0.05. RESULTS: TAC of saliva was significantly lower in cases with dental caries (0.256+/-0.106) compared to those without dental caries (0.396+/-0.077); P< 0.001. There was no statistically significant difference of TAC of saliva between males (0.319+/-0.119) and females (0.333+/-0.113) irrespective of dental caries (P=0.507). CONCLUSION: The results of the study indicated that there was a reverse association between dental caries and TAC of saliva. PMID- 26573024 TI - Effects of Letrozole-HMG and Clomiphene-HMG on Incidence of Luteinized Unruptured Follicle Syndrome in Infertile Women Undergoing Induction Ovulation and Intrauterine Insemination: A Randomised Trial. AB - BACKGROUND: Luteinized unruptured follicle (LUF) syndrome is considered a cause of ovulation failure and a subtle cause of infertility. Preovulatory injection of human chorionic gonadotropin (HCG) prevents or treats LUF syndrome, but it has also occurred after the induction of ovulation with clomiphene/HMG and HCG. This study was designed for evaluation and comparison of LUF incidence in eligible infertile women undergoing two stimulation protocols (clomiphene + HMG and letrozole + HMG) in addition to intrauterine insemination (IUI). Some related factors were compared between LUF and non-LUF cycles as secondary outcomes. METHODS: The study was designed as a prospective randomized controlled trial. Patients were randomized using a table of random numbers into two equal protocol groups. For group A, (n = 90) clomiphene citrate was administrated orally in doses of 100 mg/day, and group B (n = 90) orally received letrozole 5 mg/day from day 3 to 7 of the menstrual cycle. Then HMG 75IU/day was administered intramuscularly in both groups on day 8 of the menstrual cycle and the dose was adjusted on the basis of ovarian response. The optimum size of preovulatory follicles for the injection of HCG (10,000 IU) was considered 18-23 mm. The number and size of preovulatory follicles were assessed by vaginal ultrasound 12 h before HCG (D0). Endometrial thickness was measured as well. IUI was performed on all patients 38-40 h after HCG. The second ultrasound examination was performed to observe the evidence of oocyte releasing at the time of IUI (D1). If the follicles were unruptured, a third sonography was performed on day 7 after HCG (D7) to observe LUF syndrome. RESULTS: There was a significant difference between clomiphene-HMG and letrozole-HMG in LUF (p = 0.021) and pregnancy (p = 0.041). The complete LUF in letrozole-HMG was lower than the alternative group and the pregnancy rate was higher. The patients in the non-LUF group had higher midluteal progesterone and a thicker endometrium compared to LUF cycles (p = 0.039) and (p < 0.001). The results of our multivariate logistic regression indicate that size 18-19.9 mm leads to the complete LUF less than >=22 mm [AOR: 0.25, P = 0.005], and in size 20- 21.9 mm as well [AOR: 0.17, P = 0.002]. CONCLUSION: Letrozole, with lower incidences of LUF, is more effective than clomiphene citrate for the induction of ovulation in IUI cycles. In our study, we illustrated that larger follicles of >=22 mm diameter were associated with higher incidences of LUF. We recommend that further studies investigate and focus on the relationship between follicular size and/or full hormonal profiles and LUF. PMID- 26573025 TI - The Effectiveness of Mindfulness-Based Stress Reduction on Perceived Pain Intensity and Quality of Life in Patients With Chronic Headache. AB - The aim of this study was to determine the effectiveness of Mindfulness-Based Stress reduction (MBSR) on perceived pain intensity and quality of life in patients with chronic headache. Thus, forty patients based on the diagnosis of a neurologist and diagnostic criteria of the International Headache Society (IHS) for migraine and chronic tension-type headache were selected and randomly assigned to the intervention group and control group, respectively. The participants completed the Pain and quality of life (SF-36) questionnaire. The intervention group enrolled in an eight-week MBSR program that incorporated meditation and daily home practice, per week, session of 90-minutes. Results of covariance analysis with the elimination of the pre-test showed significantly improvement of pain and quality of life in the intervention group compared with the control group. The findings from this study revealed that MBSR can be used non-pharmacological intervention for improvement the quality of life and development of strategies to cope with pain in patients with chronic headache. And can be used in combination with other therapies such as pharmacotherapy. PMID- 26573026 TI - Risk Perception of HIV/AIDS and Low Self-Control Trait: Explaining Preventative Behaviors Among Iranian University Students. AB - BACKGROUND: In spite of developed countries there are progressive trend about HIV/AIDS and its' aspects of transmission in the low socio-economic societies. The aim of this was to explain the youth's behavior in adopting HIV/AIDS related preventive behaviors in a sample of Iranian university students by emphasizing on fear appeals approaches alongside examining the role of self-control trait for explaining adoption on danger or fear control processes based on Extended Parallel Process Model (EPPM). METHODS: A sample of 156 randomly selected university students in Jolfa, Iran was recruited in a predictive cross-sectional study by application of a researcher-designed questionnaire through self-report data collection manner. Sexual high risk behaviors, the EPPM variables, self control trait, and general self-efficacy were measured as theoretical framework. RESULTS: Findings indicated that 31.3% of participants were in the fear control process versus 68.7% in danger control about HIV/AIDS and also the presence of multi-sex partners and amphetamine consumption amongst the participants. Low self control trait and low perceived susceptibility significantly were related to having a history of multi-sex partners while high level of self-efficacy significantly increased the probability of condom use. CONCLUSION: Findings of the study were indicative of the protective role of high level of self-control, perceived susceptibility and self-efficacy factors on youth's high-risk behaviors and their preventative skills as well. PMID- 26573027 TI - The Association Between Postpartum Depression and Pica During Pregnancy. AB - INTRODUCTION & OBJECTIVES: Postpartum depression (PPD) is a common disorder and social debilitating that has adverse effects on the mother, child and family. Pica is an eating disorder characterized by persistent ingestion of substances that the consumer does not define as food. The aim of this study was to investigate the association of postpartum depression with pica during pregnancy. METHOD: This is case-control study was carried out in health centers in west Tehran. 152 depressed women (case group) and 148 non-depressed women (control group) were selected randomly from these health care centers. In addition to collecting demographic and pica data, the Edinburgh Depression Scale was used. The data was analyzed by both descriptive and analytic analyses such as chi squared and logistic regression in SPSS version 16. RESULT: In this study, there wasn't a significant association between PPD and pica during pregnancy (P=0.153, OR=2.043, CI=0.767, 5.438), but, postpartum depression has a significant association with type (clay) (P= 0.024) and duration (more than 2 months) (P= 0.023) of pica practice. CONCLUSIONS: In the present study, pregnancy pica was not important risk factor for PPD but there were similar risk factors such as iron supplementation during and postpartum pregnancy with pica and PPD. PMID- 26573028 TI - A Review on Noma: A Recent Update. AB - Noma is a gangrenous infection primarily affecting under developed countries. The aim of this paper was to review all recent articles on noma from January 2003 to August 2014 and briefly update the latest information related to the topic. A literature search was done on PUBMED using the keywords "noma/cancrum oris". Noma is commonly seen in malnourished children. There has been an increased incidence of noma in HIV patients. Apart from these, noma has also been reported in association with cyclic neutropenia, herpetic stomatitis, leukemia, Down's syndrome and Burkett's disease. Treatment of acute noma includes transfusion of blood and intravenous fluids, administration of antibiotics, putting the patient on a high protein diet and debridement of necrotic areas. Surgical phase is usually initiated 6 to 18 months after a period of quiescence. Although, the mortality rate associated with noma has reduced significantly with the advent of modern generation antibiotics, the functional, cosmetic and psychological challenges associated with the destruction of soft or hard tissues still remains a huge challenge. Adequate steps must be implemented by the government or medical professionals to prevent the disease and provide an early intervention. PMID- 26573029 TI - The Prevalence and Risk Factors of Gallstone Among Adults in South-East of Iran: A Population-Based Study. AB - OBJECTIVE: The present study aimed to evaluate the prevalence and possible risk factors of gallstone disease in the general population. PATIENTS & METHODS: This cross sectional study was carried out on a total of 1522 males and females aged >=30 years in Zahedan district, South-East of Iran. Data were collected by a validated questionnaire and gallstone diagnosis was assessed by an experienced radiologist using ultrasonography. Logistic regression model was used to identify the association between selected variables and gallstone disease. RESULTS: The overall prevalence of gallstone in participants was 2.4%. The risk of gallstone was 2.60 times higher in people age 45 and older than those aged 30 - 44 years (Odds Ratio = 2.60, 95% CI; 1.22 - 5.55). Females were 2.73 (95% CI; 1.34 - 5.56) times more likely to have disease compared to males as well. The risk in unmarried individuals was also three times higher than married ones (OR = 2.99: 95% CI 1.02 - 9.16). Additionally, daily physical activity reduced the risk of gallstone disease by 66% (95% CI; 0.18 - 0.86). CONCLUSION: In conclusion, increasing age and female gender were risk factors, whereas daily physical activity and marriage identified as protective factors in aetiology of gallstone disease. PMID- 26573030 TI - The Correlation Between Age and Bleeding Volume in Haemorrhagic Stroke Using Multi Slice CT at District Hospitals in Jakarta. AB - Haemorrhagic Stroke is a common disease in Indonesia. The best imaging modality for this disease is Multi Slice Computed Tomography Scanning (MSCT), as it may help strengthening the diagnosis as well as determining the brain bleeding volume. This study aimed to show correlation between bleeding volume of the brain and patient's age using cross-sectional approach. The 68 samples in this study were taken from secondary data from Head CT Scan of Haemorrhagic Stroke cases. Brain bleeding volume is the dependent variable, obtained through slice thickness of 5 mm and ABC/2 method with software measurement in MSCT Scan device. The independent variable of this study is the patient's age. The result of the study was the average brain's bleeding volume of 21.76 ml +/- 2.48 ml (range of 1.04 ml to 94.73 ml).The slice thickness using ABC/2 method, has a significant correlation with brain's bleeding volume in MSCT Scan examination, with correlation coefficient value r of 0.79. Brain bleeding volume in patients who have ages lower than 50 years and more or equal to 50 years were (18.93 +/- 3.26) ml and (23.53 +/- 3.47) ml respectively. There is no correlation between age and brain's bleeding volume in haemorrhagic stroke cases, with p value of 0.18, r = 0.19. PMID- 26573031 TI - Association Between Urinary Symptoms and Urinary Tract Infection in Patients With Multiple Sclerosis. AB - BACKGROUND & OBJECTIVE: Urinary dysfunctions occur in the majority of MS patients and these patients are at higher risks of developing UTI due to multiple reasons. We determined to study the association between different urinary symptoms and UTI in MS patients. MATERIAL & METHOD: Eighty seven MS patients that referred to our medical care center with an acute attack of the disease, from November 2012 to April 2014, were included in the study. Patients were classified into two groups based on their urine culture results: UTI positive and non-UTI patients. The prevalence of different types of urinary symptoms was then compared among the two groups. RESULT: The mean age of our patients was 36.8 years old. From the total 87 patients, 83 (95.4%) were female. Overall 56.3% of patients displayed urinary symptoms. The most prevalent urinary problems were urinary incontinence and frequency (25.3% and 24.1%, respectively). A positive urinary culture was seen in 71.3% of the patients. The prevalence of urinary problems was significantly higher in UTI patients in comparison to non-UTI patients (64.5% and 40% in UTI and non-UTI patients, respectively; p=0.036). Separately none of the different urinary symptoms displayed a significant difference between UTI and non-UTI patients (p>0.05). CONCLUSION: Not a single symptom can be diagnostic of UTI, but MS patient with urinary tract infections do present more urinary symptoms and this can be an indication for further urine analysis and screening measures for MS patients who display more urinary symptoms. PMID- 26573032 TI - Effect of the Prevalence of HIV/AIDS and the Life Expectancy Rate on Economic Growth in SSA Countries: Difference GMM Approach. AB - The productivity of countries around the globe is adversely affected by the health-related problems of their labour force. This study examined the effect of the prevalence of human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) and life expectancy on the economic growth of 33 Sub-Saharan African (SSA) countries over a period of 11 years (2002-2012). The study employed a dynamic panel approach as opposed to the static traditional approach utilised in the literature. The dynamic approach became eminent because of the fact that HIV/AIDS is a dynamic variable as its prevalence today depends on the previous years. The result revealed that HIV/AIDS is negatively correlated with economic growth in the region, with a coefficient of 0.014, and significant at the 1% level. That is, a 10% increase in HIV/AIDS prevalence leads to a 0.14% decrease in the GDP of the region. Tackling HIV/AIDS is therefore imperative to the developing Sub-Saharan African region and all hands must be on deck to end the menace globally. PMID- 26573033 TI - A Study of Couple Burnout in Infertile Couples. AB - INTRODUCTION: Infertility is a major crisis that can cause psychological problems and emotionally distressing experiences, and eventually affect a couples' relationship. The objective of this study is to investigate couple burnout in infertile couples who were undergoing treatmentat the Infertility Clinic of Yazd, Iran. METHOD: The present study is a cross-sectional descriptive one on 98 infertile couples referringto the Infertility Centerof Yazd, Iran, who were chosen on a simple random sampling basis. The measuring tools consisted of the Couple Burnout Measure (CBM) and a demographic questionnaire. The collected data were analyzed using SPSS 16 and the statistical tests of ANOVA and t-test.P values less than 0.05 were considered as significant. RESULTS: The results show that infertile women experience higher levels of couple burnout than their husbands (p<0.001). Also, a comparison of the scales of couple burnout- psychological burnout (p<0.01), somatic burnout (p<0.01), and emotional burnout (p<0.001)--between wives and husbands show that women are at greater risk. CONCLUSION: Infertile couples' emotional, mental, and sexual problems need to be addressed as part of the infertility treatment programs, and psychotherapists should be included in the medical team. PMID- 26573034 TI - The Effects of Balance Training on Static and Dynamic Postural Stability Indices After Acute ACL Reconstruction. AB - BACKGROUND: Proprioception and postural stability play an important role in knee movements. However, there are controversies about the overall recovery time of proprioception following knee surgery and onset of balance and neuromuscular training after ACL reconstruction. Therefore, it is necessary to evaluate the effect of balance training in early stage of knee rehabilitation after anterior cruciate ligament (ACL) reconstruction. The purpose of this study was to evaluate the effect of balance exercises on postural stability indices in subjects with anterior cruciate ligament (ACL) reconstruction. METHODS: The study was a controlled randomized trial study. Twenty four patients who had ACL reconstructed (balance training group) and twenty four healthy adults without any knee injury (control group) were recruited in the study. The balance exercises group performed balance exercises for 2 weeks. Before and after the interventions, overall, anteroposterior, and mediolateral stability indices were measured with a Biodex Balance System in bilateral and unilateral stance positions with the eyes open and closed. T-tests were used for statistical analysis (p<0.05). RESULTS: Results showed that amount of static stability indices did not change after training and there were not significant differences in static stability indices before and after balance training (p>0.05). Although amount of dynamic stability indices decreased, there were not significant differences in dynamic stability indices before and after balance training (p>0.05). Amount of dynamic stability indices were decreased in balance training group, however, there were not significant differences between groups (p>0.05). CONCLUSION: These results support that balance exercise could partially improved dynamic stability indices in early stage of ACL reconstruction rehabilitation. The results of this study suggest that balance exercises should be part of the rehabilitation program following ACL reconstruction. PMID- 26573035 TI - A Study of the Relationship Between Nurses' Professional Self-Concept and Professional Ethics in Hospitals Affiliated to Jahrom University of Medical Sciences, Iran. AB - BACKGROUND: Commitment to ethics usually results in nurses' better professional performance and advancement. Professional self-concept of nurses refers to their information and beliefs about their roles, values, and behaviors. The objective of this study is to analyze the relationship between nurses' professional self concept and professional ethics in hospitals affiliated to Jahrom University of Medical Sciences. METHODS: This cross sectional-analytical study was conducted in 2014. The 270 participants were practicing nurses and head-nurses at the teaching hospitals of Peimanieh and Motahari in Jahrom University of Medical Science. Sampling was based on sencus method. Data was collected using Cowin's Nurses' self-concept questionnaire (NSCQ) and the researcher-made questionnaire of professional ethics. RESULTS: The average of the sample's professional self concept score was 6.48+/-0.03 out of 8. The average of the sample's commitment to professional ethics score was 4.08+/-0.08 out of 5. Based on Pearson's correlation test, there is a significant relationship between professional ethics and professional self-concept (P=0.01, r=0.16). CONCLUSION: In view of the correlation between professional self-concept and professional ethics, it is recommended that nurses' self-concept, which can boost their commitment to ethics, be given more consideration. PMID- 26573036 TI - Association of Chlamydia pneumoniae Infection With Atherosclerotic Plaque Formation. AB - Atherosclerosis is a complex multifactorial disorder. Studies show that infectious microbial agents may play an important role in the development of atherosclerosis; however, these findings are conflicting. This study investigated the presence of Chlamydia pneumoniae DNA in atherosclerotic plaques of patients suffering from coronary artery disease. In a cross-sectional study, 85 patients (43 females and 42 males with mean age of 61+/-9.5, range 42-82 years) referred for coronary artery bypass grafting (CABG) and thoracic biopsy as the control groups were enrolled for this study. Standard questionnaires, including demographic and clinical evaluation were administered. Obtained specimens were processed and then nested polymerase chain reaction with primers for Pst1 fragment was carried out to detect Chlamydia pneumoniae DNA. Statistical analysis was done using the SPSS software. Of note, in 25 out of the 85 patients (29.4%), C. pneumoniae was detected within atherosclerotic plaques, whereas, 5 out of the 85 thoracic biopsy (5.9%) were positive for the presence of the mentioned bacteria in internal thoracic artery. There was a statistically significant association between atherosclerotic plaque (study group) and thoracic biopsy (control group) in terms of C. pneumoniae positivity (P= 0.0001). The findings of this study support the hypothesis that C. pneumoniae is associated with atherosclerosis. PMID- 26573037 TI - Controlled Blood Pressure in Iranian Patients: A Multi-Center Report. AB - We decided to determine the percentage of hypertensive patients whose blood pressure (BP) measurements were within recommended controlled range and to identify predictive factors for controlled BP. In this study carried out in 2014, 280 patients were included consecutively through sampling from both university and private medical centers/pharmacies in four Iranian cities. Demographic data as well as information about duration of HTN and prescribed medications, admission to emergency department (ED) because of HTN crisis, comorbidities, and control of HTN during the last 6 months by a healthcare provider were gathered. Adherence to anti-hypertensives was also determined using the validated Persian version of the 8-item Morisky Medication Adherence Scale (MMAS-8). Controlled BP was defined as systolic BP< 140 and diastolic BP< 90 mmHg in non-diabetics and < 130/80 mmHg in diabetics. Of 280 patients, 122 subjects (43.6%) had controlled BP. Among 55 diabetics, only two patients (3.6%) had controlled BP. Multiple logistic regression revealed the following variables as significant predictors of controlled BP: higher MMAS-8 score (adjusted odds ratio (OR)= 1.19, P= 0.03), fewer number of comorbid conditions (adjusted OR= 0.71, P = 0.03), having occupation as clerk/military personnel (adjusted OR= 1.03, P= 0.04), and not having history of ED admission during the last 6 months because of HTN crisis (adjusted OR= 2.11, P= 0.01). Considerable number of the studied patients had uncontrolled BP. Regarding the dramatic consequences of uncontrolled high BP in long term, it is advisable that careful attention by health care providers to the aforementioned factors could raise the likelihood of achieving controlled BP. PMID- 26573038 TI - The Association Between Pre-Diabetes With Body Mass Index and Marital Status in an Iranian Urban Population. AB - Pre-diabetes increased the development of diabetes mellitus (type 2). The aim of study was to determine the association of body weight, education and marital status with pre-diabetes in an Iranian urban population.A sample of 788 subjects (360 men and 428 women) between the ages 30-85 years participated in our study and anthropometric measurements, educational level and fasting blood sugar of participants were recorded. The t and Chi square tests were used for continuous and categorical variables. The association of age, BMI categories, educational level and marital status to pre-diabetes was assessed by estimating the odds ratio. A p-value <= 0.05 were considered significant. The analysis was done using SPSS version 11.5. Our study showed that pre-diabetic subjects were older and low educated than normoglycemic subjects. Mean BMI and educational level were associated to pre-diabetes only in women. The odds of being pre-diabetes also were higher in obese women than in normal BMI women. No relationship was found between education and marital status with pre-diabetes in both men and women. Based on our finding, it is possible that advancing age and obesity has increased in pre-diabetes. This highlights the importance of population based survey to monitor blood glucose for effective prevention and control. PMID- 26573039 TI - Hospital Workers Disaster Management and Hospital Nonstructural: A Study in Bandar Abbas, Iran. AB - INTRODUCTION: A devastating earthquake is inevitable in the long term and likely in the near future in Iran. The objective of the study was to assess the knowledge of hospital staff to disaster management system in hospital and to determine nonstructural safety assessment in Shahid Mohammadi hospital in Bandar Abbas city of Iran. This hospital is the main referral hospital in Hormozgan province with a capacity of about 450 beds and the highest patient admissions. METHODS: The cross-sectional study was conducted in 2013 on 200 healthcare workers at Shahid Mohammadi hospital, in the city of Bandar Abbas, Iran. This hospital is the main referral hospital in Hormozgan province and has a capacity of about 450 beds with highest numbers of patient admissions. Questionnaire and checklist used for assessing health workers knowledge and awareness towards disaster management and nonstructural safety this hospital. RESULTS: This study found that knowledge, awareness, and disaster preparedness of hospital staff need continual reinforcement to improve self efficacy for disaster management. Equipping health care facilities at the time of natural disasters, especially earthquakes are of great importance all over the world, especially in Iran. This requires the national strategies and planning for all health facilities. CONCLUSION: It seems due to limitations of hospital beds, insufficient of personnel, and medical equipment, health care providers paid greater attention to this issue. Since this hospital is the only educational public hospital in the province, it is essential to pay much attention to the risk management not only to this hospital but at the national level to health facilities. PMID- 26573040 TI - Implementing Perennial Kitchen Garden Model to Improve Diet Diversity in Melghat, India. AB - Lack of diet diversity causing micronutrient deficiency is common in developing countries and is gaining attention due to the hidden consequences of impaired physical and cognitive development. This paper describes the propagation of a sustainable perennial kitchen garden (KG) model to address household (HH) diet diversity in Melghat. Nutrient dense plants, comprising of minimum one tree (perennial) and one green leafy vegetable (GLV) were given to participating HHs along with qualitative interventions. Baseline survey was conducted in winter 2011 followed by seasonal surveys over 2 years to record changes in KG practices, dietary intake and childcare practices. Marked increase from 4% at baseline to 95% at endline was seen in the KG maintainance. Increased diversity was seen in all food categories other than cereals and pulses. Variety of GLVs consumed increased over the two winters as well as the 2 summers. However, no change in the quantity of GLV consumed was noted which was attributed to the duration of the study period being insufficient for the trees to grow and provide adequate leaves for consumption. Notably, livelihood component was not promoted and HHs were encouraged to harvest and distribute excess seeds to relatives and neighbours. The study generated huge demand from HHs within the intervention and neighbouring villages. It concludes that a well designed perennial KG along with imparting adequate knowledge can be a sustainable practice to increase diet diversity and GLV intake which would help address micronutrient deficiencies in the community. PMID- 26573041 TI - Comparison of GnRh Agonist Microdose Flare Up and GnRh Antagonist/Letrozole in Treatment of Poor Responder Patients in Intra Cytoplaspic Sperm Injection: Randomized Clinical Trial. AB - BACKGROUNDS: the prevalence of infertility is up to 10 to 15 % which 9 to 24 % of them are Poor Ovarian Responders (POR). This study was designed to compare two methods of GnRH Agonist Microdose Flareup (MF) and GnRH Antagonist/Letrozole (AL) in treatment of these patients. METHODS & MATERIALS: this randomized clinical trial study consisted of 123 patients. In the first step of treatment in both methods FSH, LH, estradiol, anderostandion, testestron in third day of menstruation period and the thickness of endometrium by Transvaginal sonography were evaluated. At the time of HCG injection the thickness of endometrium and follicles which were more than 14mm ware established and hormones were evaluated. Two weeks later serum betahCG and after 6 to 8 weeks Transvaginal sonography were applied to prove the pregnancy. RESULTS: there were 61 patients with mean age of 38.7+/-4.58 in MF group and 62 patients with mean age of 38.5+/-4.6 in AL group (P=0.80). At the time of hCG injection there were significant increase in the level of LH,estradiol, thickness of endometrium and follicles more than 14mm in MF patients (P<0.0001). The mean time of ovary stimulation in MF group was 10.72+/-1.5 and in AL was 8.45+/-1.2 (P<0.0001). The mean level of gonadotropin which were used was 80.6+/-20.1 in MF patients and 64.7+/-16.4 in AL group (P<0.0001). 18 % of MF group and 38.7% in AL group had no normal cycle of ovulation (OR: 2.87, 95% CI: 1.25-6.57, P=0.011). The mean numbers of oocyte and normal fetus in MF was 5.83+/-3.5 and 3.7+/-2.5 and in AL was 3+/-1.69 and 1.4+/ 1.33 (P<0.0001). The number of chemical pregnancy in MF group was 10 (16.4%) and in AL was 3 (4.8%) (OR:3.85, 95%CI:1.06-14.77, P=0.037). Clinical pregnancy in 10 patients (16.4%) of MF group and 3 (4.8%)in AL was reported. OR: 3.85, 95%CI: 1.06-14.77, P=0.037). CONCLUSION: this study showed that MF method of pregnancy leads to more positive results in pregnancy based on chemical and clinical evaluation in comparison with AL and is advised for poor responder patients. PMID- 26573042 TI - Comparison Between Effects of Home Based Cardiac Rehabilitation Programs Versus Usual Care on the Patients' Health Related Quality of Life After Coronary Artery Bypass Graft. AB - BACKGROUND & AIM: To compare home-based cardiac rehabilitation with usual care on the patients' Health Related Quality of Life (HRQoL) after coronary artery bypass graft in patients with coronary artery bypass graft (CABG) surgery. METHODS: In a randomized controlled clinical conducted from March 2013 to June 2013, 110 patients with CABG surgery were randomly assigned into two groups. While patients in group I, were received usual care and patients in group II, in addition to the usual care were received home-based cardiac rehabilitation programs. The 27-item MacNew Heart Disease HRQoL questionnaire was used to evaluate the patient's HRQoL under and over 2 months after intervention. RESULTS: At the time of 0, mean score of HRQoL was 67.86+/-7.5 and 64.76+/-8.4 in patients in group I and group II, respectively (P> 0.05). Although mean score of HRQoL in all patients in both groups increased two month after intervention, but this increase in patients in group II were higher than patients in group I (154.93+/-4.6 vs 134.20+/-8.2). This difference were statistically significant (P< 0.05). CONCLUSION: Quality of Life (QoL) can be considered as a quality indicator of health care systems. Results of present study showed that home-based cardiac rehabilitation program improved patients HRQoL after CABG surgery. PMID- 26573043 TI - Health Economics and Radium-223 (Xofigo(r)) in the Treatment of Metastatic Castration-Resistant Prostate Cancer (mCRPC): A Case History and a Systematic Review of the Literature. AB - OBJECTIVES: Prostate cancer (PC) is the most common cancer in Western countries. Recent advances in the treatment of metastatic castration resistant prostate cancer (mCRPC) have caused significant pressure on health care budgets. We aimed to exemplify this dilemma presenting an example, radium-223 (Xofigo(r)), and review the literature. METHODS: A 74-year-old man diagnosed with mCRPC was referred to our department in October 2014 for radium-223 therapy. We faced the following dilemma: is radium-223 standard therapy? Is it cost-effective? Medline was searched employing the following search criteria: "radium-223", "alpharadin", "Xofigo" and "prostate". Exclusion and inclusion criteria were applied. Guidelines and cost-effectiveness analyses were focused. We also searched the websites of ASCO, ESMO and ISPOR. The web was searched, using Yahoo and Google search engines, for Health Technology Assessments (HTAs). RESULTS: 181 publications were identified in the Medline database. Only four studies included the word "cost", three "economics" and none "budget" in heading or abstract. None of the publications were thorough of cost analysis (cost-effectiveness, cost utility, cost-minimizing or cost-of-illness analysis). Six HTAs and eight national guidelines were identified. The cost per quality adjusted life years was indicated ?80.000-94,000. HTAs concluded reimbursement being not recommendable or no ultimate statement could be made. One pointed towards a limited use with caution. CONCLUSION: Guidelines were based on data from randomized clinical trials (RCTs). Health economics was not considered when guidelines were made. Most HTAs concluded this therapy not cost-effective or there was insufficient data for final conclusions. Licensing and reimbursement processes should be run simultaneously. PMID- 26573044 TI - Scores of Brunei Lower Secondary School Students on Emotional Intelligence Variables: Exploring the Differences. AB - The survey compared the emotional intelligence of 254 (128 females) randomly selected Year 11 Brunei Cambridge General Certificate of Education (BCGCE) Ordinary Level students using the six subscales of the BarOn Emotional intelligence scale - youth version. Females scored significantly higher on the intrapersonal variable than males. However, males sored much higher on the positive impression subscale. In addition, students aged 16 scored significantly higher on the interpersonal scale than all others. However, the 15-year olds scored highest on the adaptability and positive impression scales than their peers. Furthermore, participants who reported that they were not so much satisfied with their personal life scored significantly higher on the interpersonal scale than their counterparts. Moreover, participants who consult friends when faced with problems scored significantly higher on the interpersonal variable while those who search the internet for solutions to problems scored higher than others on the adaptability scale. No significant differences were obtained on any subscale when participants were compared on the basis of their parents' marital status as well as the type of guardian they stayed / lived with. Implications of the findings are discussed and mixed-methods research was recommended. PMID- 26573045 TI - Use of Cyclosporine Therapy in Steroid Resistant Nephrotic Syndrome (SRNS): A Review. AB - A chronic, progressive disorder Steroid Resistant Nephrotic Syndrome (SRNS) accounts for 10-20% of all children with Nephrotic Syndrome. It is a heterogeneous disorder comprised of persistent edema, proteinuria, hypoalbuminemia and hyperlipidemia. Treatment for steroid-resistant nephrotic syndrome (SRNS) is challenging and children who suffer from SRNS require aggressive treatment to achieve remission. Calcineurin inhibitors have been used more in an empirical manner than on the basis of clear rationale. It was in 1984 when cyclosporine was first considered for the treatment of steroid resistant nephrotic syndrome. Cyclosporin is a calcineurin inhibitor that suppresses immune response by downregulating the transcription of various cytokine genes. Till now many studies have been conducted to determine dosages, duration of therapy, side effects and advantages of cyclosporine. Treatment of SRNS remains a difficult challenge in pediatric nephrology. Treatment should be individualized according to the underlying histopathology, and clinical and environmental conditions of the children. There is an urgent need to distinguish as soon as possible those patients who may benefit from prolonged immunosuppressive treatment from those who will not benefit from such treatment and who will just suffer from its major side effects. The emerging evidence that the majority of genetic forms of SRNS should receive symptomatic treatment only, should also be clinically tested and studies baring its significance should be evaluated in the future. PMID- 26573046 TI - Levothyroxine Dosage Requirement During Pregnancy in Well-Controlled Hypothyroid Women: A Longitudinal Study. AB - BACKGROUND: Untreated maternal hypothyroidism can have adverse effects on both the mother and fetus, but it can potentially be prevented by adequate levothyroxine replacement. This study was conducted to determine what percentage of hypothyroid pregnant women who were taking levothyroxine needed to adjust their medication dosage, and when and how much it should be increased. METHODS: In this longitudinal study, 81 well-controlled hypothyroid women (TSH<= 2.5 mIU/L) were monitored throughout pregnancy. Thyroid function tests were performed before conception, after the first missed menstrual period, in the second and third trimesters of pregnancy and one month after delivery. Levothyroxine dosage was adjusted according to TSH levels measured. RESULTS: Of the 81 pregnancies studied, the pregnancy outcomes were 74 full-term births, six abortions and one pre-term birth. The levothyroxine dosage needed to be increased in 84% (CI95%= 74 90) of the pregnancies (OR=5.2, CI95%= 2.9-9.4). Most levothyroxine dose adjustments were made in the first trimester of gestation. The levothyroxine requirement increased 50% (CI95%= 41-59) in the first trimester, 55% (CI95%= 45 64) in the second trimester and 62% (CI95%= 52-72) in the third trimester. Levothyroxine dosage was decreased for 6 cases (7.4%), and no adjustment was made for 7 women (8.6%). CONCLUSIONS: Increases in levothyroxine dosage administered in pregnancy appear to be indispensible in the majority of patients with well controlled hypothyroidism, especially in the first trimester. However, this change was not universal and levothyroxine dosage decreased in a few cases and remained unchanged in others. PMID- 26573048 TI - Knowledge, attitudes and perceptions among non blood donor female health care professionals. AB - INTRODUCTION: Blood donation is necessary in order to maintain an adequate supply of blood to patients who are suffering from any kind of disease or trauma, which requires them to have blood transfusion. Female non-blood donors are generally low in number. Therefore, this research was carried out to assess the main reasons behind the lack of blood donations made by females, and their knowledge, attitude and perceptions towards voluntary blood donation. METHODOLOGY: A cross sectional study was conducted on 664 female health professionals, who were selected by non-probability convenience sampling from two tertiary care hospitals. A pretested questionnaire was presented to the sample population, and the data was entered and analyzed on SPSS (V17). RESULTS: 94.6 % were aware with the fact that blood is screened for AIDS, Hepatitis B and C before transfusion. Moreover, 83.7% said that they will only donate blood if a family, relative or friend would need it and similarly 83.4% suggested that they would donate blood if blood donation camps are arranged in hospital premises. 81.8 % thought that blood donors can contract Hepatitis B after donation where as only 29.5% did not blood due already blood loss in menstrual cycle. CONCLUSION: The participants had adequate knowledge about the benefits of blood donation. The most important reason identified for not donating blood is the lack of facilities within the workplace or lack of approach by responsible authorities. The results of the study may help in minimizing the misconceptions of the participants about blood transfusion, which would increase their contribution towards blood donation. PMID- 26573047 TI - Effective Dose Radon 222 of the Tap Water in Children and Adults People; Minab City, Iran. AB - (222)Rn is a radioactive, odorless, and colorless element which has a half-life of 3.83 days. One of (222)Rn main resources are Groundwater (wells, springs, etc.). Hence, the use of groundwater with high concentration of (222)Rn can increase the risk of lung and stomach cancers. Concentration of (222)Rn in tap water of Minab city in two temperatures 5 and 15 oC was measured by radon meter model RTM1668-2. The effective dose was calculated by equations proposed by UNSCEAR. Geometric mean concentration of (222)Rn in drinking water was found to be 0.78+/-0.06 and 0.46+/-0.04 Bq/l at 5 and 15 C (p value<0.05), respectively. The effective doses were 0.006 and 0.003 mSv/y for adults, and 0.011 and 0.007 mSv/y for the children, respectively (p value<0.05). Besides, the effective dose for adult through inhaling (222)Rn at 5 and 15 C were estimated 0.0021 and 0.0012mSv/y, respectively. Geometric mean concentration in (222)Rn drinking water and effective dose received from drinking water and inhalation of (222)Rn is lower than WHO and EPA standard limits. Increasing temperature of drinking water will decrease the effective dose received. Annual Effective dose received from inhalation and consumption of (222)Rn in drinking water in children is more than adults. PMID- 26573049 TI - The Study of Prescribing Errors Among General Dentists. AB - INTRODUCTION: In dentistry, medicine often prescribed to relieve pain and remove infections .Therefore, wrong prescription can lead to a range of problems including lack of pain, antimicrobial treatment failure and the development of resistance to antibiotics. MATERIALS & METHODS: In this cross-sectional study, the aim was to evaluate the common errors in written prescriptions by general dentists in Kermanshah in 2014. Dentists received a questionnaire describing five hypothetical patient and the appropriate prescription for the patient in question was asked. Information about age, gender, work experience and the admission in university was collected. The frequency of errors in prescriptions was determined. Data by SPSS 20statistical software and using statistical t-test, chi square and Pearson correlation were analyzed (0.05> P). RESULTS: A total of 180 dentists (62.6% male and 37.4% female) with a mean age of 8.23 +/- 39.199 participated in this study. Prescription errors include the wrong in pharmaceutical form (11%), not having to write therapeutic dose (13%), writing wrong dose (14%), typos (15%), error prescription (23%) and writing wrong number of drugs (24%). The most frequent errors in the administration of antiviral drugs (31%) and later stages of antifungal drugs (30%), analgesics (23%) and antibiotics (16%) was observed. Males dentists compared with females dentists showed more frequent errors (P=0.046). Error frequency among dentists with a long work history (P>0.001) and the acceptance in the university except for the entrance examination (P=0.041) had a statistically significant relationship. CONCLUSION: This study showed that the written prescription by general dentists examined contained significant errors and improve prescribing through continuing education of dentists is essential. PMID- 26573050 TI - A New Horizon in Life: Experiences of Patients Receiving Chemotherapy. AB - INTRODUCTION: The treatment quality of diseases can affect the patient's experience. Due to its different complications among cancer patients, the experience of chemotherapy is unique. The present study was conducted to explore the lived experience among cancer patients who had received chemotherapy. METHODS: The study was conducted by a qualitative approach and a phenomenological method. In so doing, 12 cancer patients who had received chemotherapy were purposefully selected were interviewed using an in-depth method. After the required data were collected, they were analyzed by Tanner, Allen, Diekelmann method. RESULTS: Analysis of the collected data indicated that the experience of chemotherapy appeared as "a new horizon in life" for the patients. Secondary themes of the new horizon in life included rebirth, understanding of life values, dependence, and need. CONCLUSION: According to the results of the study, it was concluded that in addition to taking into providing mental-spiritual support and reducing the complications of the treatment, nurses in chemotherapy wards should pay attention to the experiences of the patients receiving chemotherapy and enhance hope and positive attitude among them. PMID- 26573051 TI - Epidemiological and Inducible Resistance in Coagulase Negative Staphylococci. AB - BACKGROUND & OBJECTIVES: Coagulase negative staphylococci (CNS) are potential pathogens with the increased use of implants in hospitals. Macrolide, lincosamide and streptogramin B (MLSB) are used in the treatment of staphylococcal infections. The aim of this study was to molecular detection of inducible clindamycin resistance and genetic pattern in CNS isolates and their transmission between hospitals. MATERIALS & METHODS: 110 CNS strains, isolated from hospitalized patients in the intensive care unit and infectious wards of Besat and Toohid hospitals, Sanandaj. Methicillin resistance was done by agar screen test and the resistance inducible Clindamycin by the D-Test. Multiplex PCR was performed, using primers specific for erm (A, B, C, and TR) genes. Diversity of strains was determined by ERIC-PCR technique based on the similarities between DNA fingerprints by using Jaccards coefficient in the SAHN program of the NTSYS pc software. RESULTS: Of the 110 isolates, 64(58.2%) were methicillin -resistant CNS (MRCNS), 48(43.6%) were resistant to erythromycin (ERCNS). Out of 48 Erythromycin-resistant strains 5 (10.4%) were iMLS B phenotypes that 4 isolates showed genes erm by Multiplex PCR. The ERIC-PCR profiles allowed typing of the 110 isolates into 90 ERIC-types which were grouped into fourteen main clusters (C1-C14). CONCLUSION: The results of this study also showed that most of CNS isolated produced different genomic fingerprint patterns, therefore, source of infection is differen t. PMID- 26573052 TI - Quality of Life for Elderly Residents in Nursing Homes. AB - BACKGROUND AND OBJECTIVES: More than 8% of Iran's populations are elderly. The greatest challenge in this generation is improvement of health and QoL.The main goal of this study was QoL for elderly residents in nursing homes over 65 years in Golestan Province - Iran. METHODS: This research was an analytical cross study. The population society includes the elderly over 65 years in Golestan Province - Iran. The sample size was calculated based on the correlation of 193 elderly men and women. Therefore, if the correlation is 2.0 or greater is statistically significant at 80% and 0.95 confidence. The needed data collected from two questionnaires Consumer product Safety Commission (CPSC) to assess the QOL of nursing homes and the SF-36 for health QOL the elderly indicators through interviews and observation. The reliability of the CPSC questionnaire was estimated using Cronbach's alpha with a coefficient of 0.838. The SF-36 questionnaire was validated with Cronbach's alpha with a coefficient of 0.95. To analyze data, ANOVA one-way test was used that after investigating homogenization of variances with Levin statistic, if homogenization reported P is rejected, the independent T-test was used to interpret it. RESULTS: Among QOL dimensions only General Health (GH) status showed a significant association with supporting organizations covering status (P = 0.01). The relationship between QOL with marital status in both genders was observed that the General Health (GH) (P = 0.001), Physical Functioning (PF) P = (0.007) Mobility Restricts (MR) P = (0.002), Emotional Problems (EP) (P = 0.001), vitality (V) (P = 0.001), Mental Health (MH) (P = 0.001) were significantly related. CONCLUSIONS: There was a significant relationship between the Physical Functioning (PF) mean and the mean of other QOL indicators in two groups of male and female (P = 0.007), also the safety of nursing homes just related respectively with residence variable (P = 0.01) and their employment (P = 0.031). PMID- 26573053 TI - Parents' Participation in the Sexuality Education of Their Children in Namibia: A Framework and an Educational Programme for Enhanced Action. AB - The purpose of the study was to empower rural parents to participate in the sexuality education of their children. The study was designed to be qualitative, explorative, descriptive and contextual in nature. It was performed in three phases. Phase 1 consisted of a situational analysis to explore and describe how parents provide sexuality education. Phase 2 consisted of the development of a conceptual framework that facilitated the development of an educational programme. In phase 3 the programme was implemented and evaluated, recommendations were made and conclusions drawn. The main findings revealed two themes: factors influencing parental participation in their children's sexuality education, and the need for parental participation in their children's sexuality education. This article is part of series of three article stems from a study on the topic of sexuality education empowerment programme of rural parents in Namibia. The three articles have the following titles: one: parent's participation in sexuality education of their children: a situational analysis; two: parent's participation in sexuality education of their children: a conceptual framework and an educational programme to enhance action, and three: parent's participation in sexuality education of their children: programme implementation and evaluation. The previous paper dealt with parent's participation in sexuality education of their children: a situational analysis: the results from the in-depth interviews and focus group discussions on sexuality education with children and parents were presented. This paper focuses on describing Phase 2 and 3, namely the process of devising a conceptual framework for the development of an educational programme to empower parents to participate in the sexuality education of their children. Discussions included a description of the conceptual framework, based on the researcher's paradigmatic assumptions, and the focus group and individual in-depth interviews results. The survey list suggested by Dickoff et al. (1968) consists of various elements which were employed in the conceptual framework, namely the context, agent, recipients, dynamics, procedure and a terminus. These elements were reflected in the "thinking map". PMID- 26573054 TI - Functional improvement after hip arthroscopy in cases of active paediatric hip joint tuberculosis: a retrospective comparative study vis-a-vis conservative management. AB - PURPOSE: Tuberculosis of the hip joint is a significant cause of preventable disability, especially in children. The aim of our study was to evaluate the functional results of hip arthroscopy done in a cohort of patients with hip joint tuberculosis and to compare them with the outcome of conservatively managed cases. METHODS: This was a retrospective cohort study in which we evaluated the records of 22 hip arthroscopies performed in known cases of tuberculosis of the hip joint in children less than 12 years of age. A note of the demographic and clinical parameters like age, duration of symptoms, stage of the disease, time period of follow-up, any complications during surgery, and pre- and post operative modified Harris hip score (MHHS) was made in all cases. We compared the results with an age-matched cohort of 44 children with hip joint tuberculosis who were treated non-operatively with anti-tuberculosis therapy and traction in the same tertiary care institute. RESULTS: The arthroscopic findings in our series included synovitis, chondral erosions of the femoral head and/or acetabulum, pannus formation over the femoral head and/or acetabulum, and labral tears. The various arthroscopic procedures which were done included joint lavage, synovectomy, labral debridement and cheilectomy. The mean follow-up was 45 months, with the minimum being 36 months. There was a statistically significant change in the mean MHHS after hip arthroscopic procedures (p < 0.001); the difference in the mean post- and pre-operative MHHS was independent of age, stage or duration of follow-up. There was a statistically significant difference (p < 0.05) between the magnitude of improvement in MHHS after hip arthroscopy and that after conservative management. CONCLUSIONS: Arthroscopy of the hip joint in children in cases of tuberculosis can serve as an emerging therapeutic modality. It is an effective and safe minimally invasive procedure, and helps in improving the functional outcome in early disease. PMID- 26573055 TI - A 2D Semiquinone Radical-Containing Microporous Magnet with Solvent-Induced Switching from Tc = 26 to 80 K. AB - The incorporation of tetraoxolene radical bridging ligands into a microporous magnetic solid is demonstrated. Metalation of the redox-active bridging ligand 2,5-dichloro-3,6-dihydroxy-1,4-benzoquinone (LH2) with Fe(II) affords the solid (Me2NH2)2[Fe2L3].2H2O.6DMF. Analysis of X-ray diffraction, Raman spectra, and Mossbauer spectra confirm the presence of Fe(III) centers with mixed-valence ligands of the form (L3)(8-) that result from a spontaneous electron transfer from Fe(II) to L(2-). Upon removal of DMF and H2O solvent molecules, the compound undergoes a slight structural distortion to give the desolvated phase (Me2NH2)2[Fe2L3], and a fit to N2 adsorption data of this activated compound gives a BET surface area of 885(105) m(2)/g. Dc magnetic susceptibility measurements reveal a spontaneous magnetization below 80 and 26 K for the solvated and the activated solids, respectively, with magnetic hysteresis up to 60 and 20 K. These results highlight the ability of redox-active tetraoxolene ligands to support the formation of a microporous magnet and provide the first example of a structurally characterized extended solid that contains tetraoxolene radical ligands. PMID- 26573056 TI - Outflow tract ventricular arrhythmia originating from the aortic cusps: our approach for challenging ablation. AB - BACKGROUND: Ablation of outflow flow ventricular arrhythmia (VA) originating from aortic cusps can be challenging. The aim of this study was to describe our approach for this ablation. METHODS: All patients with outflow VA suspected to originate from aortic cusps according to ECG or after failed ablation from right ventricular outflow tract (RVOT) underwent cardiac CT and radiofrequency ablation. CT image of aortic cusps and coronary arteries was integrated into electroanatomic mapping system by point (left main ostium)-based registration. Ablation was performed at the earliest activation site. RESULTS: Ten patients were included in this case cohort. The ablation catheter was easily maneuvered above and below the aortic valve after registration. Two patients who had previous failed ablation of RVOT focus had successful ablation at right coronary cusp (RCC) and at left coronary cusp (LCC). A patient who had previous failed ablations of RVOT and LCC focuses had successful ablation at RCC-LCC junction. A patient who had previous failed ablation at LCC had successful ablation at RCC LCC junction. Three patients had successful ablation at RCC-LCC junction, and one patient at LCC. One patient had successful ablation at anterior interventricular vein-great cardiac vein junction. One patient had successful ablation at non coronary cusp. During follow-up (12-30 months), one patient had recurrence of VA controlled by flecainide. The remaining patients were free of VA without medications. CONCLUSIONS: Catheter ablation of VA originating from aortic cusps is safe and effective. CT image integration into electroanatomic mapping system can be helpful in this challenging ablation. PMID- 26573057 TI - Individual differences in use of the recognition heuristic are stable across time, choice objects, domains, and presentation formats. AB - The recognition heuristic (RH) is a simple decision strategy that performs surprisingly well in many domains. According to the RH, people decide on the basis of recognition alone and ignore further knowledge when faced with a recognized and an unrecognized choice object. Previous research has revealed noteworthy individual differences in RH use, suggesting that people have preferences for using versus avoiding this strategy that might be causally linked to cognitive or personality traits. However, trying to explain differences in RH use in terms of traits presupposes temporal and cross-situational stability in use of the RH, an important prerequisite that has not been scrutinized so far. In a series of four experiments, we therefore assessed the stability in RH use across (1) time, (2) choice objects, (3) domains, and (4) presentation formats of the choice objects. In Experiment 1, participants worked on the same inference task and choice objects twice, separated by a delay of either one day or one week. Experiment 2 replicated Experiment 1 using two different object sets from the same domain, whereas Experiment 3 assessed the stability of RH use across two different domains. Finally, in Experiment 4 we investigated stability across verbal and pictorial presentation formats of the choice objects. For all measures of RH use proposed so far, we found strong evidence for both temporal and cross situational stability in use of the RH. Thus, RH use at least partly reflects a person-specific style of decision making whose determinants await further research. PMID- 26573058 TI - POINT: HER2-Targeted Combinations in Advanced HER2-Positive Breast Cancer. PMID- 26573059 TI - COUNTERPOINT: HER2-Targeted Combinations in Advanced HER2-Positive Breast Cancer. PMID- 26573060 TI - Current Standards and Novel Treatment Options for Metastatic Pancreatic Adenocarcinoma. AB - Pancreatic cancer is one of the most lethal solid tumors. The prognosis of metastatic pancreatic adenocarcinoma remains dismal, with a median survival of less than 1 year, due in large part to the fact that pancreatic adenocarcinoma is notoriously refractory to chemotherapy. However, there recently have been significant improvements in outcomes for patients with pancreatic adenocarcinoma: ongoing trials have shown promise, and these may lead to still further progress. Here we review the current treatment paradigms for metastatic disease, focusing on ways to ameliorate symptoms and lengthen survival. We then summarize recent advances in our understanding of the molecular and cellular aspects of pancreatic cancer. Finally, we outline new approaches currently under development for the treatment of metastatic disease, arising from our improved understanding of the genetic and nongenetic alterations within pancreatic cancer cells-and of interactions between cancer cells, the tumor microenvironment, and the immune system. PMID- 26573061 TI - Systemic Therapy of Pancreatic Cancer: Better Science, Faster Progress. PMID- 26573062 TI - Neoadjuvant Therapy for Early-Stage Breast Cancer: Current Practice, Controversies, and Future Directions. AB - Research in the fields of surgical, medical, and radiation oncology has changed the landscape of neoadjuvant therapy in breast cancer, yet many areas of controversy still exist. When considering whether a patient is a candidate for neoadjuvant therapy, ideally the initial assessment should be multidisciplinary in nature and should include clinical, radiographic, and pathologic evaluation. Optimization of systemic therapy is dependent upon identifying the patient's breast cancer subtype; the best approach may include targeted agents, as well as the determination of eligibility for enrollment into clinical trials that incorporate novel therapeutics or predictive biomarkers. This article will review a variety of surgical and radiation-based strategies for management of early stage breast cancer, including surgical options involving the breast and axilla, and the role of radiation based on response to systemic therapy. Key areas of controversy include the ideal systemic treatment for different breast cancer subtypes, the surgical and radiotherapeutic approaches for management of the axilla, and the role of pathologic response rates as a surrogate for survival in drug development. PMID- 26573063 TI - Neoadjuvant Therapy for Early-Stage Breast Cancer: A Model for Individualizing Outcomes and Tailoring Locoregional and Systemic Therapy. PMID- 26573064 TI - Neoadjuvant Therapy As a Platform for Drug Development: Current Controversies and Regulatory Perspectives. PMID- 26573065 TI - Don Dizon, MD, on Sexual Health After a Cancer Diagnosis, and the Disappointments of Precision Medicine. PMID- 26573066 TI - A Patient With Newly Diagnosed Metastatic Type 2 Papillary Renal Cell Carcinoma. PMID- 26573067 TI - Entrapment and traumatic neuropathies of the elbow and hand: An imaging approach. AB - Ultrasound and magnetic resonance imaging currently offer a detailed analysis of the peripheral nerves. Compressive and traumatic nerve injuries are the two main indications for imaging investigation of nerves with several publications describing the indications, technique and diagnostic capabilities of imaging signs. Investigation of entrapment neuropathies has three main goals, which are to confirm neuronal distress, search for the cause of nerve compression and exclude a differential diagnosis on the entire nerve. For traumatic nerve injuries, imaging, predominantly ultrasound, occasionally provides essential information for management including the type of nerve lesion, its exact site and local extension. PMID- 26573068 TI - Effect of vascular endothelial growth factor siRNA and wild-type p53 co expressing plasmid in MDA-MB-231 cells. AB - Breast cancer urgently requires improved therapeutic strategies. In the current study, a Pvp53 plasmid that co-expressed p53 and short-interfering RNA against vascular endothelial growth factor (si-VEGF) was developed to replace single plasmid transfections. Whether Pvp53 exhibited improved anti-tumor effects in breast cancer MDA-MB-231 cells was investigated in the present study. Pvp53 significantly reduced the Bcl-2/Bax ratio and increased the expression of cleaved caspase-3 and 8. Compared with p53 and si-VEGF single transfections, the Pvp53 co expression plasmid significantly increased the proportion of apoptotic cells and inhibited cell motility and proliferation. These results indicated that the Pvp53 co-expression plasmid has greater inhibitory effects on breast cancer MDA-MB-231 cells than single plasmids. PMID- 26573070 TI - Definition of Specificity in a Screening Trial. PMID- 26573069 TI - Time to Definitive Failure to the First Tyrosine Kinase Inhibitor in Localized GI Stromal Tumors Treated With Imatinib As an Adjuvant: A European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Intergroup Randomized Trial in Collaboration With the Australasian Gastro-Intestinal Trials Group, UNICANCER, French Sarcoma Group, Italian Sarcoma Group, and Spanish Group for Research on Sarcomas. AB - PURPOSE: In 2004, we started an intergroup randomized trial of adjuvant imatinib versus no further therapy after R0-R1 surgery patients with localized, high- or intermediate-risk GI stromal tumor (GIST). PATIENTS AND METHODS: Patients were randomly assigned to 2 years of imatinib 400 mg daily or no further therapy after surgery. The primary end point was overall survival; relapse-free survival (RFS), relapse-free interval, and toxicity were secondary end points. In 2009, given the concurrent improvement in prognosis of patients with advanced GIST, we changed the primary end point to imatinib failure-free survival (IFFS), with agreement of the independent data monitoring committee. We report on a planned interim analysis. RESULTS: A total of 908 patients were randomly assigned between December 2004 and October 2008: 454 to imatinib and 454 to observation. Of these, 835 patients were eligible. With a median follow-up of 4.7 years, 5-year IFFS was 87% in the imatinib arm versus 84% in the control arm (hazard ratio, 0.79; 98.5% CI, 0.50 to 1.25; P = .21); RFS was 84% versus 66% at 3 years and 69% versus 63% at 5 years (log-rank P < .001); and 5-year overall survival was 100% versus 99%, respectively. Among 528 patients with high-risk GIST by local pathologist, 5-year IFFS was 79% versus 73%; among 336 centrally reviewed high-risk patients, it was 77% versus 73%, respectively. CONCLUSION: This study confirms that adjuvant imatinib has an overt impact on RFS. No significant difference in IFFS was observed, although in the high-risk subgroup there was a trend in favor of the adjuvant arm. IFFS was conceived as a potential end point in the adjuvant setting because it is sensitive to secondary resistance, which is the main adverse prognostic factor in patients with advanced GIST. PMID- 26573071 TI - Reply to B. Jeremic et al. PMID- 26573072 TI - Metastatic Rhabdomyosarcoma: Still Room for Improvement. PMID- 26573073 TI - Pan Canadian Rash Trial: A Randomized Phase III Trial Evaluating the Impact of a Prophylactic Skin Treatment Regimen on Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor-Induced Skin Toxicities in Patients With Metastatic Lung Cancer. AB - PURPOSE: Erlotinib is an epidermal growth factor receptor inhibitor approved for patients with advanced non-small-cell lung cancer (NSCLC) whose epidermal growth factor receptor expression status is positive or unknown. Although it is efficacious, erlotinib can cause skin toxicity. This prospective, randomized phase III trial examined the effect of prophylactic treatment of erlotinib induced skin rash. PATIENTS AND METHODS: Patients receiving erlotinib in the second- or third-line setting for advanced NSCLC were randomly assigned to prophylactic minocycline (100 mg twice per day for 4 weeks), reactive treatment (after rash developed, per grade of rash), or no treatment unless severe (grade 3). Rash incidence and severity, time to maximal rash, time to resolution, and overall survival (OS) were compared among treatment groups. RESULTS: In all, 150 patients were randomly assigned, 50 to each of three treatment arms. The incidence of skin toxicity was 84% regardless of treatment arm. Prophylactic treatment with minocycline significantly lengthened the time to the most severe grade of rash. Grade 3 rash was significantly higher in the no-treatment arm. OS was not significantly different among treatment arms, but patients receiving prophylactic or reactive treatments had a longer OS (7.6 and 8 months, respectively) than those who received no rash treatment (6 months). Rash was not self-limiting. CONCLUSION: The incidence of all grades of rash did not differ statistically among the three arms, so the trial was negative. The incidence of grade 3 skin toxicities was reduced in patients who were treated with prophylactic minocycline or reactive treatment. Efficacy was not compromised. Prophylactic minocycline and reactive treatment are both acceptable options for the necessary treatment of erlotinib-induced rash in the second- or third-line setting of metastatic NSCLC. PMID- 26573074 TI - No Role For Trimodality Therapy and Consolidation Chemotherapy Compared With Concurrent Radiochemotherapy Alone in Stage III Non-Small-Cell Lung Cancer. PMID- 26573075 TI - Radiation Dose-Response Relationship for Risk of Coronary Heart Disease in Survivors of Hodgkin Lymphoma. AB - PURPOSE: Cardiovascular diseases are increasingly recognized as late effects of Hodgkin lymphoma (HL) treatment. The purpose of this study was to identify the risk factors for coronary heart disease (CHD) and to quantify the effects of radiation dose to the heart, chemotherapy, and other cardiovascular risk factors. PATIENTS AND METHODS: We conducted a nested case-control study in a cohort of 2,617 5-year HL survivors, treated between 1965 and 1995. Cases were patients diagnosed with CHD as their first cardiovascular event after HL. Detailed treatment information was collected from medical records of 325 cases and 1,204 matched controls. Radiation charts and simulation radiographs were used to estimate in-field heart volume and mean heart dose (MHD). A risk factor questionnaire was sent to patients still alive. RESULTS: The median interval between HL and CHD was 19.0 years. Risk of CHD increased linearly with increasing MHD (excess relative risk [ERR]) per Gray, 7.4%; 95% CI, 3.3% to 14.8%). This results in a 2.5-fold increased risk of CHD for patients receiving a MHD of 20 Gy from mediastinal radiotherapy, compared with patients not treated with mediastinal radiotherapy. ERRs seemed to decrease with each tertile of age at treatment (ERR/Gy(<27.5years), 20.0%; ERR/Gy(27.5-36.4years), 8.8%; ERR/Gy(36.5 50.9years), 4.2%; P(interaction) = .149). Having >= 1 classic CHD risk factor (diabetes mellitus, hypertension, or hypercholesterolemia) independently increased CHD risk (rate ratio, 1.5; 95% CI, 1.1 to 2.1). A high level of physical activity was associated with decreased CHD risk (rate ratio, 0.5; 95% CI, 0.3 to 0.8). CONCLUSION: The linear radiation dose-response relationship identified can be used to predict CHD risk for future HL patients and survivors. Appropriate early management of CHD risk factors and stimulation of physical activity may reduce CHD risk in HL survivors. PMID- 26573076 TI - Ovarian Cancer Early Detection Needs Better Imaging, Not Better Algorithms or Biomarkers. PMID- 26573077 TI - Preventing Ovarian Cancer. PMID- 26573078 TI - Upfront Genotyping of DPYD*2A to Individualize Fluoropyrimidine Therapy: A Safety and Cost Analysis. AB - PURPOSE: Fluoropyrimidines are frequently prescribed anticancer drugs. A polymorphism in the fluoropyrimidine metabolizing enzyme dihydropyrimidine dehydrogenase (DPD; ie, DPYD*2A) is strongly associated with fluoropyrimidine induced severe and life-threatening toxicity. This study determined the feasibility, safety, and cost of DPYD*2A genotype-guided dosing. PATIENTS AND METHODS: Patients intended to be treated with fluoropyrimidine-based chemotherapy were prospectively genotyped for DPYD*2A before start of therapy. Variant allele carriers received an initial dose reduction of >= 50% followed by dose titration based on tolerance. Toxicity was the primary end point and was compared with historical controls (ie, DPYD*2A variant allele carriers receiving standard dose described in literature) and with DPYD*2A wild-type patients treated with the standard dose in this study. Secondary end points included a model-based cost analysis, as well as pharmacokinetic and DPD enzyme activity analyses. RESULTS: A total of 2,038 patients were prospectively screened for DPYD*2A, of whom 22 (1.1%) were heterozygous polymorphic. DPYD*2A variant allele carriers were treated with a median dose-intensity of 48% (range, 17% to 91%). The risk of grade >= 3 toxicity was thereby significantly reduced from 73% (95% CI, 58% to 85%) in historical controls (n = 48) to 28% (95% CI, 10% to 53%) by genotype guided dosing (P < .001); drug-induced death was reduced from 10% to 0%. Adequate treatment of genotype-guided dosing was further demonstrated by a similar incidence of grade >= 3 toxicity compared with wild-type patients receiving the standard dose (23%; P = .64) and by similar systemic fluorouracil (active drug) exposure. Furthermore, average total treatment cost per patient was lower for screening (?2,772 [$3,767]) than for nonscreening (?2,817 [$3,828]), outweighing screening costs. CONCLUSION: DPYD*2A is strongly associated with fluoropyrimidine induced severe and life-threatening toxicity. DPYD*2A genotype-guided dosing results in adequate systemic drug exposure and significantly improves safety of fluoropyrimidine therapy for the individual patient. On a population level, upfront genotyping seemed cost saving. PMID- 26573079 TI - Reply to P.F. Pinsky, C.P. Crum, and M.W. McIntosh et al. PMID- 26573080 TI - Beautiful Imperfections. PMID- 26573081 TI - Challenges in Converting Acute Myeloid Leukemia (AML) Genomics Into AML Clinical Trials. PMID- 26573083 TI - [Diagnostic workup and therapy of infectious diarrhea. Current standards]. AB - Infectious diarrhea is very common; its severity ranges from uncomplicated, self limiting courses to potentially life-threatening disease. A rapid diagnostic workup providing detailed information on the suspected pathogen should be performed only in patients at risk, analyzing one single stool sample for Salmonella, Shigella, Campylobacter, and Norovirus. In the presence of risk factors, such as a history of antibiotic exposure within the last 3 months, testing for Clostridium difficile should be performed. Immunocompetent patients do not require specific antibiotic therapy. Exceptions exist in patients with severe comorbidities, immunodeficiency, fever/SIRS, and in patients with Shigella or C. difficile infection. Empirical antibiotic treatment should be considered in patients with fever and/or bloody diarrhea and in patients at risk. In patients with traveler's diarrhea, microbiological diagnosis is required only in patients with fever, bloody diarrhea, prolonged course of disease (more than 5 days), severe clinical course with hypotension or dehydration, and during outbreaks. In these patients one single fecal sample should be collected for stool cultures of Campylobacter, Shigella, and Salmonella, as well as microscopic examination for amoebiasis and Giardiasis. The main therapeutic measure for infectious diarrhea is sufficient oral rehydration. As in community-acquired diarrhea, azithromycin or ciprofloxacin are recommended-taking into account local antimicrobial resistance in the country of travel and possible side effects. PMID- 26573082 TI - Clinical Impact of Additional Cytogenetic Aberrations, cKIT and RAS Mutations, and Treatment Elements in Pediatric t(8;21)-AML: Results From an International Retrospective Study by the International Berlin-Frankfurt-Munster Study Group. AB - PURPOSE: This retrospective cohort study aimed to determine the predictive relevance of clinical characteristics, additional cytogenetic aberrations, and cKIT and RAS mutations, as well as to evaluate whether specific treatment elements were associated with outcomes in pediatric t(8;21)-positive patients with acute myeloid leukemia (AML). PATIENTS AND METHODS: Karyotypes of 916 pediatric patients with t(8;21)-AML were reviewed for the presence of additional cytogenetic aberrations, and 228 samples were screened for presence of cKIT and RAS mutations. Multivariable regression models were used to assess the relevance of anthracyclines, cytarabine, and etoposide during induction and overall treatment. End points were the probability of achieving complete remission, cumulative incidence of relapse (CIR), probability of event-free survival, and probability of overall survival. RESULTS: Of 838 patients included in final analyses, 92% achieved complete remission. The 5-year overall survival, event free survival, and CIR were 74%, 58%, and 26%, respectively. cKIT mutations and RAS mutations were not significantly associated with outcome. Patients with deletions of chromosome arm 9q [del(9q); n = 104] had a lower probability of complete remission (P = .01). Gain of chromosome 4 (+4; n = 21) was associated with inferior CIR and survival (P < .01). Anthracycline doses greater than 150 mg/m(2) and etoposide doses greater than 500 mg/m(2) in the first induction course and high-dose cytarabine 3 g/m(2) during induction were associated with better outcomes on various end points. Cumulative doses of cytarabine greater than 30 g/m(2) and etoposide greater than 1,500 mg/m(2) were associated with lower CIR rates and better probability of event-free survival. CONCLUSION: Pediatric patients with t(8;21)-AML and additional del(9q) or additional +4 might not be considered at good risk. Patients with t(8;21)-AML likely benefit from protocols that have high doses of anthracyclines, etoposide, and cytarabine during induction, as well as from protocols comprising cumulative high doses of cytarabine and etoposide. PMID- 26573084 TI - Routine screening for fetal limb abnormalities in the first trimester. AB - OBJECTIVE: We aim to determine the accuracy of first-trimester ultrasonography in detecting fetal limb abnormalities. METHODS: This is a retrospective study of all women undergoing fetal nuchal translucency (NT) assessment and detailed fetal anatomic survey in the first trimester at a single tertiary-care referral center in China. Fetal anatomy scans were repeated in the second trimester. Detection of fetal limb abnormalities was compared between first and second trimester anatomy scans and confirmed at delivery or at autopsy. RESULTS: Analyzed were 9438 fetuses from 9197 women (241 twin pairs). The incidence of fetal limb abnormalities was 0.38% (36/9438). Of these, 28 (77.8%) were diagnosed prenatally: 23 (63.9%) on first trimester scan and 5 (13.9%) on second trimester scan. Limb reduction defects (usually transverse limb deficiencies) were the most common limb defects identified in the first trimester (n = 12), followed by clubfoot (n = 4), skeletal dysplasia (n = 3), sirenomelia (n = 1), limb dysplasia (n = 1), malposition (n = 1), and syndactyly (n = 1). Nine fetuses with isolated limb abnormalities had normal NT, while 74.1% (20/27) of limb abnormalities that were associated with other abnormalities had increased NT. CONCLUSIONS: This study demonstrates that the majority of limb abnormalities detected prenatally [23/28 (82%)] can be identified in the first trimester, especially major limb defects; however, our numbers are small and still need larger cases for further investigation. PMID- 26573085 TI - Multiferroicity and Magnetoelectric Coupling in TbMnO3 Thin Films. AB - In this work, we report the growth and functional characterizations of multiferroic TbMnO3 thin films grown on Nb-doped SrTiO3 (001) substrates using pulsed laser deposition. By performing detailed magnetic and ferroelectric properties measurements, we demonstrate that the multiferroicity of spin origin known in the bulk crystals can be successfully transferred to TbMnO3 thin films. Meanwhile, anomalous magnetic transition and unusual magnetoelectric coupling related to Tb moments are observed, suggesting a modified magnetic configuration of Tb in the films as compared to the bulk counterpart. In addition, it is found that the magnetoelectric coupling enabled by Tb moments can even be seen far above the Tb spin ordering temperature, which provides a larger temperature range for the magnetoelectric control involving Tb moments. PMID- 26573086 TI - Effects of omalizumab on T lymphocyte function in inner-city children with asthma. PMID- 26573087 TI - Sex difference in age-related changes in knee extensor strength and power production during a 10-times-repeated sit-to-stand task in Japanese elderly. AB - BACKGROUND: For middle-aged and elderly women, age-related decline in an index representing power production during STS task (STS-PI), calculated by using an equation reported previously, has been shown to be greater than that in the force generation capability of lower extremity. Whether this is specific to women remains unclear. This study examined how the age-related changes in knee extensor strength and power production during STS differ between Japanese men and women aged 65 years or older. METHODS: The time taken for a 10-times-repeated STS test (STS time) and force developed during maximal voluntary isometric knee extension (KE-F) were determined in Japanese younger-old (262 men and 285 women) aged 65-74 years and older-old (96 men and 89 women) aged 75-90 years. STS-PI was calculated using the following equation: STS-PI = (body height - 0.4) * body mass * 10/STS time. RESULTS: KE-F and STS-PI were significantly greater in the younger-old than in the older-old group (p < 0.0001) and in men than in women (p < 0.0001). STS-PI and KE-F, expressed as the percentages of the mean value of the corresponding variable for the younger-old group (%STS-PI and %KE-F, respectively), were negatively correlated to chronological age in both men (r = -0.386 and r = 0.269, respectively, p < 0.0001) and women (r = -0.504 and r = -0.294, respectively, p < 0.0001). Regression slopes in the relationship between age and %KE-F were not significantly different between men (-1.521) and women (-1.618). However, regression slope in the relationship between age and %STS-PI was significantly steeper in women (-3.108) than in men (-2.170) (p < 0.05). In OOG, %KE-F had no significant effect of sex, but %STS-PI was significantly lower in women than in men (p < 0.001). CONCLUSIONS: In Japanese men and women aged 65 years or over, age-related loss in power production during STS is steeper in women than in men, with greater magnitude than that in knee extensor strength. This suggests a higher priority of improving power generation capability during whole-body movement such as STS in older women than in older men. PMID- 26573089 TI - Outcomes of unselected patients with metastatic clear-cell renal cell carcinoma treated with first-line pazopanib therapy followed by vascular endothelial growth factor receptor tyrosine kinase inhibitors or mammalian target of rapamycin inhibitors: a single institution experience. AB - OBJECTIVE: To explore the efficacy and safety of pazopanib in a 'real-world' setting in unselected patients, as data regarding unselected patients with metastatic clear-cell renal cell carcinoma (ccRCC) treated with first-line pazopanib are limited. PATIENTS AND METHODS: We reviewed records of patients with metastatic ccRCC treated with first-line pazopanib from 1 November 2009 through to 1 November 2012. Cox models were fitted to evaluate the association of progression-free survival (PFS) and overall survival (OS) with patient co variables. RESULTS: In all, 88 patients were identified; 74 were evaluable for response: two (3%) had a complete response, 27 (36%) a partial response, 36 (49%) had stable disease and nine (12%) had progressive disease. The median PFS was 13.7 months [95% confidence interval (CI) 8.7-18.3]. PFS was correlated with a Karnofsky Performance Status score of <80 [hazard ratio (HR) 3.26, P < 0.001] and serum lactate dehydrogenase of >1.5 * upper limit of normal (HR 3.25, P = 0.014). The median OS was 29.1 months (95% CI 20.2-not reached). The OS was correlated with brain metastasis (HR 2.55, P = 0.009), neutrophilia (HR 1.179, P = 0.018), and anaemia (HR 3.51, P < 0.001). There were no treatment-related deaths. In all, 53 patients received second-line therapy [vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKI) in 22 patients, mammalian target of rapamycin inhibitors (mTORi) in 22 patients, and other therapy in nine patients]; the median PFS was 8.6 months (95% CI 3.3-25.7) with VEGFR-TKI and 5 months (95% CI 3.5-15.2) with mTORi (P = 0.41); the median OS was 19.9 months (95% CI 12.9-not reached) and 14.2 months (95% CI 8.1-not reached), from initiation of second-line VEGFR-TKI or mTORi, respectively (P = 0.37). CONCLUSIONS: In this retrospective study, first-line pazopanib confirmed its efficacy in metastatic ccRCC. Trends for longer PFS and OS were seen with VEGFR TKI compared with mTORi after first-line pazopanib. PMID- 26573088 TI - High transcript abundance, RNA editing, and small RNAs in intergenic regions within the massive mitochondrial genome of the angiosperm Silene noctiflora. AB - BACKGROUND: Species within the angiosperm genus Silene contain the largest mitochondrial genomes ever identified. The enormity of these genomes (up to 11 Mb in size) appears to be the result of increased non-coding DNA, which represents >99 % of the genome content. These genomes are also fragmented into dozens of circular-mapping chromosomes, some of which contain no identifiable genes, raising questions about if and how these 'empty' chromosomes are maintained by selection. To assess the possibility that they contain novel and unannotated functional elements, we have performed RNA-seq to analyze the mitochondrial transcriptome of Silene noctiflora. RESULTS: We identified regions of high transcript abundance in almost every chromosome in the mitochondrial genome including those that lack any annotated genes. In some cases, these transcribed regions exhibited higher expression levels than some core mitochondrial protein coding genes. We also identified RNA editing sites throughout the genome, including 97 sites that were outside of protein-coding gene sequences and found in pseudogenes, introns, UTRs, and transcribed intergenic regions. Unlike in protein-coding sequences, however, most of these RNA editing sites were only edited at intermediate frequencies. Finally, analysis of mitochondrial small RNAs indicated that most were likely degradation products from longer transcripts, but we did identify candidates for functional small RNAs that mapped to intergenic regions and were not associated with longer RNA transcripts. CONCLUSIONS: Our findings demonstrate transcriptional activity in many localized regions within the extensive intergenic sequence content in the S. noctiflora mitochondrial genome, supporting the possibility that the genome contains previously unidentified functional elements. However, transcription by itself is not proof of functional importance, and we discuss evidence that some of the observed transcription and post-transcriptional modifications are non-adaptive. Therefore, further investigations are required to determine whether any of the identified transcribed regions have played a functional role in the proliferation and maintenance of the enormous non-coding regions in Silene mitochondrial genomes. PMID- 26573090 TI - Mutant calreticulin-expressing cells induce monocyte hyperreactivity through a paracrine mechanism. AB - Mutations in the calreticulin gene (CALR) were recently identified in approximately 70-80% of patients with JAK2-V617F-negative essential thrombocytosis and primary myelofibrosis. All frameshift mutations generate a recurring novel C-terminus. Here we provide evidence that mutant calreticulin does not accumulate efficiently in cells and is abnormally enriched in the nucleus and extracellular space compared to wildtype calreticulin. The main determinant of these findings is the loss of the calcium-binding and KDEL domains. Expression of type I mutant CALR in Ba/F3 cells confers minimal IL-3 independent growth. Interestingly, expression of type I and type II mutant CALR in a nonhematopoietic cell line does not directly activate JAK/STAT signaling compared to wildtype CALR and JAK2-V617F expression. These results led us to investigate paracrine mechanisms of JAK/STAT activation. Here we show that conditioned media from cells expressing type I mutant CALR exaggerate cytokine production from normal monocytes with or without treatment with a toll-like receptor agonist. These effects are not dependent on the novel C-terminus. These studies offer novel insights into the mechanism of JAK/STAT activation in patients with JAK2-V617F-negative essential thrombocytosis and primary myelofibrosis. PMID- 26573091 TI - Transient Canonical Wnt Stimulation Enriches Human Bone Marrow Mononuclear Cell Isolates for Osteoprogenitors. AB - Activation of the canonical Wnt signaling pathway is an attractive anabolic therapeutic strategy for bone. Emerging data suggest that activation of the Wnt signaling pathway promotes bone mineral accrual in osteoporotic patients. The effect of Wnt stimulation in fracture healing is less clear as Wnt signaling has both stimulatory and inhibitory effects on osteogenesis. Here, we tested the hypothesis that transient Wnt stimulation promotes the expansion and osteogenesis of a Wnt-responsive stem cell population present in human bone marrow. Bone marrow mononuclear cells (BMMNCs) were isolated from patients undergoing hip arthroplasty and exposed to Wnt3A protein. The effect of Wnt pathway stimulation was determined by measuring the frequency of stem cells within the BMMNC populations by fluorescence-activated cell sorting and colony forming unit fibroblast (CFU-F) assays, before determining their osteogenic capacity in in vitro differentiation experiments. We found that putative skeletal stem cells in BMMNC isolates exhibited elevated Wnt pathway activity compared with the population as whole. Wnt stimulation resulted in an increase in the frequency of skeletal stem cells marked by the STRO-1(bright) /Glycophorin A(-) phenotype. Osteogenesis was elevated in stromal cell populations arising from BMMNCs transiently stimulated by Wnt3A protein, but sustained stimulation inhibited osteogenesis in a concentration-dependent manner. These results demonstrate that Wnt stimulation could be used as a therapeutic approach by transient targeting of stem cell populations during early fracture healing, but that inappropriate stimulation may prevent osteogenesis. PMID- 26573092 TI - Molecular tools for studying the major malaria vector Anopheles funestus: improving the utility of the genome using a comparative poly(A) and Ribo-Zero RNAseq analysis. AB - BACKGROUND: Next-generation sequencing (NGS) offers great opportunities for studying the biology of insect vectors of disease. Prerequisites for successful analyses include high quality annotated genome assemblies and that techniques designed for use with model organisms be tested and optimised for use with these insects. We aimed to test and improve genomic tools for studying the major malaria vector Anopheles funestus. RESULTS: To guide future RNAseq transcriptomic studies of An. funestus, we compared two methods for enrichment of non-ribosomal RNA for analysis: enrichment of polyadenylated RNA and ribosomal RNA depletion using a kit designed to deplete human/rat/mouse rRNA. We found large differences between the two methods in the resulting transcriptomes, some of which is due to differential representation of polyadenylated and non-polyadenylated transcripts. We used the RNAseq data for validation and targeted manual editing of the draft An. funestus genome annotation, validating 62 % of annotated introns, manually improving the annotation of seven gene families involved in the detoxification of xenobiotics and integrated two published transcriptomic datasets with the recently published genome assembly. CONCLUSIONS: The mRNA enrichment method makes a substantial, replicable difference to the transcriptome composition, at least partly due to the representation of non-polyadenylated transcripts in the final transcriptome. Therefore, great care should be taken in comparing gene expression data among studies. Ribosomal RNA depletion of total RNA using a kit designed to deplete human/rat/mouse rRNA works in mosquitoes and, we argue, results in a truer representation of the transcriptome than poly(A) selection. The An. funestus genome annotation can be considerably improved with the help of these new RNAseq data and further guided manual gene editing efforts will be of great benefit to the Anopheles research community for studies of this insect's genome and transcriptome. PMID- 26573093 TI - Comparison of Childhood Vitiligo Presenting with or without Associated Halo Nevi. AB - BACKGROUND: Previous studies have characterized differences in vitiligo associated with halo nevi, but the features of vitiligo presenting with halo nevus in children have yet to be fully described. AIMS: We sought to provide an epidemiologic and clinical comparison of cases of childhood vitiligo presenting with or without associated halo nevi. MATERIALS AND METHODS: This was a retrospective chart review of children diagnosed with vitiligo in an academic pediatric dermatology practice from January 1990 to November 2014. The characteristics of children with vitiligo with or without associated halo nevi were compared. RESULTS: Halo nevi were identified in 55 (26%) of 208 children with vitiligo. Patients with halo nevi were significantly more likely to be male and develop vitiligo at a later age. Children with vitiligo associated with halo nevi were more likely to present with generalized vitiligo, defined according to the presence of bilateral macules. DISCUSSION: There was no significant association between groups in the percentage of body surface area with vitiligo or family history of vitiligo or autoimmune diseases. Patients with halo nevi were no more likely to develop new areas of vitiligo during the follow-up period, but there was a nonsignificant trend toward a higher rate of repigmentation in vitiligo associated with halo nevus. CONCLUSION: Halo nevi are a common finding in children with vitiligo. The presence of a halo nevus in a child with vitiligo is associated with generalized vitiligo. The presence of a halo nevus does not significantly alter the risk of disease progression and rate of treatment. PMID- 26573094 TI - The efficacy of extraembryonic stem cells in improving blood flow within animal models of lower limb ischaemia. AB - BACKGROUND: Stem cell (SC) administration is a potential therapeutic strategy to improve blood supply in patients with peripheral artery disease (PAD). The aim of this systematic review and meta-analysis was to investigate the efficacy of extraembryonic tissue-derived SC (ETSC) in improving blood flow within animal models of hindlimb ischaemia (HLI). METHODS: PubMed, ScienceDirect and Web of Science were searched to identify studies which investigated ETSCs within animal HLI models. A meta-analysis was performed focusing on the effect of ETSCs on limb blood flow assessed by laser Doppler imaging using a random effects model. Methodological quality was assessed using a newly devised quality assessment tool. RESULTS: Five studies investigating umbilical cord-derived SCs (three studies), placental SCs (one study), amnion and chorionic SCs (one study) were included. A meta-analysis suggested that administration of ETSCs improved the restoration of blood flow within the HLI models used. The methodological quality of the included studies was assessed as poor. Problems identified included lack of randomised design and blinding of outcome assessors; that the animal models did not incorporate recognised risk factors for human PAD or atherosclerosis; the models used did not have established chronic ischaemia as is the cases in most patients presenting with PAD; and the studies lacked a clear rationale for the dosage and frequency of SCs administered. CONCLUSIONS: The identified studies suggest that ETSCs improve recovery of limb blood supply within current animal HLI models. Improved study quality is, however, needed to provide support for the likelihood of translating these findings to patients with PAD. PMID- 26573095 TI - Seasonal and annual variations in the pollination efficiency of a pollinator community of Dictamnus albus L. AB - The interplay between insect and plant traits outlines the patterns of pollen transfer and the subsequent plant reproductive fitness. We studied the factors that affect the pollination efficiency of a pollinator community of Dictamnus albus L. by evaluating insect behaviour and morphological characteristics in relation to flowering phenology. In order to extrapolate the pollinator importance of single taxa and of the whole pollinator guild, we calculated an index distinguishing between potential (PPI) and realized (RPI) pollinator importance. Although the pollinator species spectrum appeared rather constant, we found high intra- and inter-annual variability of pollinator frequency and importance within the insect community. Flower visitation rate strictly depended on insect abundance and on the overlap between their flying period and flower blooming. All the pollinators visited flowers from the bottom to the top of the racemes, excluding intra-plant geitonogamous pollination, and most of them showed high pollen fidelity. Only medium large-sized bees could contact the upward bending stiles while feeding on nectar, highlighting a specialisation of the plant towards bigger pollinators. Moreover, we found evidence of functional specialisation, since all pollinators were restricted to a single taxonomic group (order: Hymenoptera; superfamily: Apoidea). Both the PPI and RPI indices indicate Habropoda tarsata as the most important pollinator of D. albus. Following hand cross-pollination experiments we revealed the presence of pollination limitation in 1 of the 3 years of field study. We discuss this result in relation to flowering abundance and to possible mismatches of phenological periods between plants and insects. PMID- 26573096 TI - Community-Driven Research Agenda to Reduce Health Disparities. AB - This paper describes how a new regional campus of an academic health center engaged in a community-based participatory research (CBPR) process to set a community-driven research agenda to address health disparities. The campus is situated among growing Marshallese and Hispanic populations that face significant health disparities. In 2013, with support from the Translational Research Institute, the University of Arkansas for Medical Sciences Northwest began building its research capacity in the region with the goal of developing a community-driven research agenda for the campus. While many researchers engage in some form of community-engaged research, using a CBPR process to set the research agenda for an entire campus is unique. Utilizing multiple levels of engagement, three research areas were chosen by the community: (1) chronic disease management and prevention; (2) obesity and physical activity; and (3) access to culturally appropriate healthcare. In only 18 months, the CBPR collaboration had dramatic results. Ten grants and five scholarly articles were collaboratively written and 25 community publications and presentations were disseminated. Nine research projects and health programs were initiated. In addition, many interprofessional educational and service learning objectives were aligned with the community driven agenda resulting in practical action to address the needs identified. PMID- 26573097 TI - It is time to take preconception health seriously. PMID- 26573098 TI - Using micro-sensor data to quantify macro kinematics of classical cross-country skiing during on-snow training. AB - Micro-sensors were used to quantify macro kinematics of classical cross-country skiing techniques and measure cycle rates and cycle lengths during on-snow training. Data were collected from seven national level participants skiing at two submaximal intensities while wearing a micro-sensor unit (MinimaxXTM). Algorithms were developed identifying double poling (DP), diagonal striding (DS), kick-double poling (KDP), tucking (Tuck), and turning (Turn). Technique duration (T-time), cycle rates, and cycle counts were compared to video-derived data to assess system accuracy. There was good reliability between micro-sensor and video calculated cycle rates for DP, DS, and KDP, with small mean differences (Mdiff% = -0.2 +/- 3.2, -1.5 +/- 2.2 and -1.4 +/- 6.2) and trivial to small effect sizes (ES = 0.20, 0.30 and 0.13). Very strong correlations were observed for DP, DS, and KDP for T-time (r = 0.87-0.99) and cycle count (r = 0.87-0.99), while mean values were under-reported by the micro-sensor. Incorrect Turn detection was a major factor in technique cycle misclassification. Data presented highlight the potential of automated ski technique classification in cross-country skiing research. With further refinement, this approach will allow many applied questions associated with pacing, fatigue, technique selection and power output during training and competition to be answered. PMID- 26573099 TI - Sonographic Evaluation of the Fetal Thymus Using the Thy-Box Technique Between 13 and 16 Weeks' Gestation. AB - OBJECTIVES: The purposes of this study were to assess the feasibility of fetal thymus measurement between 13 and 16 weeks' gestation, to evaluate the potential difference using color Doppler sonography with the thy-box technique, and to construct normal percentile ranges. METHODS: This retrospective study included 287 healthy singleton pregnancies. The fetal thymus was shown in an axial plane of the upper mediastinum. Color Doppler imaging was applied to outline the thy box: ie, the area between the brachiocephalic artery posteriorly and internal mammary arteries laterally. Measurements of the lateral and anteroposterior diameters of the thymus with and without color Doppler imaging were compared. RESULTS: The thymus was shown in 95% of the cases (273 of 287) between 13 and 16 weeks' gestation. The mean lateral thymus diameter +/- SD with color Doppler imaging (5.30 +/- 0.7 mm) was significantly longer in comparison to the measurement without color Doppler imaging (5.06 +/- 0.8 mm; P < .001), whereas the anteroposterior diameter was significantly shorter (3.19 +/- 0.9 versus 3.26 +/- 0.8 mm; P = .044). Normal percentiles of thymus measurements for gestational age were constructed. CONCLUSIONS: The fetal thymus can be clearly and accurately shown as early as 13 weeks' gestation by using the thy-box. Measurements with color Doppler imaging were significantly different from those without and hence are preferable, as color Doppler imaging can delineate the thymus borders more accurately. PMID- 26573100 TI - Transcranial Doppler Sonography in Pediatric Neurocritical Care: A Review of Clinical Applications and Case Illustrations in the Pediatric Intensive Care Unit. AB - Transcranial Doppler sonography is a noninvasive, real-time physiologic monitor that can detect altered cerebral hemodynamics during catastrophic brain injury. Recent data suggest that transcranial Doppler sonography may provide important information about cerebrovascular hemodynamics in children with traumatic brain injury, intracranial hypertension, vasospasm, stroke, cerebrovascular disorders, central nervous system infections, and brain death. Information derived from transcranial Doppler sonography in these disorders may elucidate underlying pathophysiologic characteristics, predict outcomes, monitor responses to treatment, and prompt a change in management. We review emerging applications for transcranial Doppler sonography in the pediatric intensive care unit with case illustrations from our own experience. PMID- 26573101 TI - Clinical Importance and Surgical Outcomes of Green Type III Cystocele in Women With Anterior Vaginal Prolapse. AB - OBJECTIVES: To explore the clinical importance and surgical outcomes of Green type III cystocele in women with anterior vaginal prolapse. METHODS: A database of 336 women with a Ba point higher than -3 cm on the Pelvic Organ Prolapse Quantification system was retrospectively reviewed. Investigated data comprised those obtained from a clinical interview, the Pelvic Organ Prolapse Quantification system, and sonography. Initially, the baseline data between women with (n = 126) and without (n = 210) Green type III cystocele on sonography were compared. Subsequently, 6-month postoperative data between women who had Green type III cystocele on sonography and underwent either anterior colporrhaphy (n = 25) or a Perigee procedure (n = 76) were compared. RESULTS: Women with Green type III cystocele had symptoms of voiding dysfunction more frequently, stress urinary incontinence less frequently, and more bulging (mean +/- SD, 2.7 +/- 1.2 versus 1.9 +/- 1.5 for women with versus without Green type III cystocele; P = .001), a greater likelihood of stage II or higher cystocele (86.5% versus 60.0% for women with versus without Green type III cystocele; P < .001), as well as more caudodorsal bladder neck and genitohiatal positions and a wider genital hiatus on sonography. Women with Green type III cystocele had a greater likelihood of stage 0 cystocele (64.0% versus 89.5% for anterior colporrhaphy versus Perigee; P< .001) and more ventral bladder neck positions after Perigee procedures. CONCLUSIONS: The presence of Green type III cystocele in women with anterior vaginal prolapse is associated with more functional impairments and anatomic defects. Despite comparable functional outcomes, Perigee procedures provide better anatomic outcomes for the anterior vagina in women with Green type III cystocele than anterior colporrhaphy does in the short term. PMID- 26573102 TI - Sonographic Quantification of Pronator Quadratus Activity During Gripping Effort. AB - OBJECTIVES: The aim of this study was to obtain quantitative data related to the activity of each head of the pronator quadratus based on dynamic sonographic parameters during gripping effort and to assess their relationships with grip and pronation strengths. METHODS: The forearms of 33 healthy volunteers were evaluated at 5 positions of axial rotation (full supination, 45 degrees supination, neutral, 45 degrees pronation, and full pronation). Echogenic intensity ratios and muscle thicknesses of each head of the pronator quadratus were measured from transverse cross-sectional sonograms obtained during maximal grip and release. Grip strengths and maximal isokinetic pronation torques at 90 degrees /s and 360 degrees /s were evaluated as strength parameters and correlated with sonographic measures. RESULTS: Echogenic intensity ratios of both heads significantly decreased during power grip (P <= .002). Changes in echogenic intensity ratios of the superficial head were greater when the forearm was pronated compared to supination (P < .001), whereas changes in echogenic intensity ratios of the deep head were constant at all forearm positions. Muscle thicknesses of the superficial head maximally increased at the neutral position during power grip (P < .001), whereas muscle thicknesses of the deep head did not change. There were significant negative correlations between grip strength and echogenic intensity ratios of both heads at all respective forearm positions (P <= .048). Pronation torque was significantly correlated with echogenic intensity ratios of the superficial head at all forearm positions and the deep head at 45 degrees and full pronation positions (P <= .034). CONCLUSIONS: The data revealed that the superficial head of the pronator quadratus more actively contracts when the forearm is in pronation, whereas the deep head constantly contracts at all positions. This study suggests that both heads of the pronator quadratus also play a role in grip strength, but the superficial head contributes more to pronation strength. PMID- 26573103 TI - Peptide nanospheres self-assembled from a modified beta-annulus peptide of Sesbania mosaic virus. AB - A novel beta-annulus peptide of Sesbania mosaic virus bearing an FKFE sequence at the C terminus was synthesized, and its self-assembling behavior in water was investigated. Dynamic light scattering and transmission electron microscopy showed that the beta-annulus peptide bearing an FKFE sequence self-assembled into approximately 30 nm nanospheres in water at pH 3.8, whereas the beta-annulus peptide without the FKFE sequence afforded only irregular aggregates. The peptide nanospheres possessed a definite critical aggregation concentration (CAC = 26 MUM), above which the size of nanospheres were nearly unaffected by the peptide concentration. The formation of peptide nanospheres was significantly affected by pH; the peptide did not form any assemblies at pH 2.2, whereas larger aggregates were formed at pH 6.4-11.6. (c) 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 470-475, 2016. PMID- 26573104 TI - US Supreme Court to hear challenge to restrictive Texas abortion law. PMID- 26573105 TI - Visible-Light/Photoredox-Mediated sp(3) C-H Functionalization and Coupling of Secondary Amines with Vinyl Azides in Flow Microreactors. AB - Structurally diverse imidazole derivatives were synthesized by a visible light/[Ru(bpy)3 ][(PF6 )2 ]-mediated coupling of vinyl azides and secondary amines in flow microreactors. This operationally simple and atom-economical protocol allows the formation of three new C-N bonds through the functionalization of sp(3) C-H bonds adjacent to the secondary nitrogen atom. In order to get mechanistic insight of the coupling reaction, several control experiments were carried out and discussed. PMID- 26573106 TI - Pacemaker lead vegetation sited between the right atrium and the right ventricle. PMID- 26573107 TI - Bilingual enhancements have no socioeconomic boundaries. AB - To understand how socioeconomic status (SES) and bilingualism simultaneously operate on cognitive and sensory function, we examined executive control, language skills, and neural processing of sound in adolescents who differed in language experience (i.e. English monolingual or Spanish-English bilingual) and level of maternal education (a proxy for SES). We hypothesized that experience communicating in two languages provides an enriched linguistic environment that can bolster neural precision in subcortical auditory processing which, in turn, enhances cognitive and linguistic function, regardless of the adolescent's socioeconomic standing. Consistent with this, we report that adolescent bilinguals of both low and high SES demonstrate more stable neural responses, stronger phonemic decoding skills, and heightened executive control, relative to their monolingual peers. These results support the argument that bilingualism can bolster cognitive and neural function in low-SES children and suggest that strengthened neural response consistency provides a biological mechanism through which these enhancements occur. PMID- 26573108 TI - Relation of Angiographic Thrombus Burden with Severity of Coronary Artery Disease in Patients with ST Segment Elevation Myocardial Infarction. AB - BACKGROUND We planned to investigate the relationship of thrombus burden with SYNTAX score in patients with ST elevation myocardial infarction (STEMI). MATERIAL AND METHODS We retrospectively enrolled 780 patients who underwent PPCI in our clinic due to STEMI. Clinical, laboratory, and demographic properties of the patients were recorded. Angiographic coronary thrombus burden was classified using thrombolysis in myocardial infarction (TIMI) thrombus grades. RESULTS Patients with high thrombus burden were older, with higher diabetes prevalence longer pain to balloon time, higher leukocyte count, higher admission troponin, and admission CK-MB concentrations. SYNTAX score was higher and myocardial perfusion grades were lower in patients with high thrombus burden. Multivariate logistic regression analysis revealed SYNTAX score as the strongest predictor of thrombus burden. ROC analysis demonstrated a sensitivity of 75.5%, specificity of 61.2%, and cut-off value of >14 (area under the curve (AUC): 0.702; 95% confidence interval [CI]: 0.773-0.874;P<0.001) for high thrombus burden. CONCLUSIONS SYNTAX score may have additional value in predicting higher thrombus burden besides being a marker of coronary artery disease severity and complexity. PMID- 26573109 TI - Activation of Tax protein by c-Jun-N-terminal kinase is not dependent on the presence or absence of the early growth response-1 gene product. AB - The Tax protein of human T cell leukemia virus type 1 plays a major role in the pathogenesis of adult T cell leukemia (ATL), an aggressive neoplasia of CD4+ T cells. In the present study, we investigated whether the EGR-1 pathway is involved in the regulation of Tax-induced JNK expression in human Jurkat T cells transfected to express the Tax protein in the presence or absence of PMA or ionomycin. Overexpression of EGR-1 in Jurkat cells transfected to express Tax, promoted the activation of several genes, with the most potent being those that contained AP-1 (Jun/c-Fos), whereas knockdown of endogenous EGR-1 by small interfering RNA (siRNA) somewhat reduced Tax-mediated JNK-1 transcription. Additionally, luciferase-based AP-1 and NF-kappaB reporter gene assays demonstrated that inhibition of EGR-1 expression by an siRNA did not affect the transcriptional activity of a consensus sequence of either AP-1 or NF-kappaB. On the other hand, the apoptosis assay, using all-trans retinoic acid (ATRA) as an inducer of apoptosis, confirmed that siRNA against EGR-1 failed to suppress ATRA induced apoptosis in Jurkat and Jurkat-Tax cells, as noted by the low levels of both DEVDase activity and DNA fragmentation, indicating that the induction of apoptosis by ATRA was Egr-1-independent. Finally, our data showed that activation of Tax by JNK-1 was not dependent on the EGR-1 cascade of events, suggesting that EGR-1 is important but not a determinant for the activity for Tax-induced proliferation of Jurkat cells. PMID- 26573110 TI - Involvement of cyclic-nucleotide response element-binding family members in the radiation response of Ramos B lymphoma cells. AB - The aim of the present study was to investigate the role of Cyclic-nucleotide Response Element-Binding (CREB) family members and related nuclear transcription factors in the radiation response of human B lymphoma cell lines (Daudi and Ramos). Unlike the more radiosensitive Daudi cells, Ramos cells demonstrated only a moderate increase in early apoptosis after 3-5 Gy irradiation doses, which was detected with Annexin V/PI staining. Moreover, a significant and dose-dependent G2/M phase accumulation was observed in the same cell line at 24 h after both ionizing radiation (IR) doses. Western blot analysis showed an early increase in CREB protein expression that was still present at 3 h and more evident after 3 Gy IR in Ramos cells, along with the dose-dependent upregulation of p53 and NF kappaB. These findings were consistent with real-time RT-PCR analysis that showed an early- and dose-dependent upregulation of NFKB1, IKBKB and XIAP gene expression. Unexpectedly, pre-treatment with SN50 did not increase cell death, but cell viability. Taken together, these findings let us hypothesise that the early induction and activation of NF-kappaB1 in Ramos cells could mediate necrotic cell death and be linked to other molecules belonging to CREB family and involved in the cell cycle regulation. PMID- 26573111 TI - Genetic analyses of oculocutaneous albinism types 2 and 4 with eight novel mutations. PMID- 26573112 TI - Morphology and function of the palatal dentition in Choristodera. AB - Choristoderes are a group of extinct freshwater reptiles that were distributed throughout Laurasia from the Middle Jurassic to the Miocene. They are inferred to have had a lifestyle similar to that of extant gavialid crocodiles, but they differed from crocodiles in retaining an extensive palatal dentition. All choristoderes had teeth on the vomers, palatines and pterygoids, and teeth are rarely present on the parasphenoid. Palatal teeth are conical, as in the marginal dentition, and form longitudinal and transverse rows. Detailed examination of different genera shows that the orientation of the palatal tooth crowns changes with their position on the palate, supporting the view that they are involved in intra-oral food transportation, presumably in combination with a fleshy tongue. Moreover, observed variation in palatal tooth shape and the width of palatal tooth batteries may provide additional clues about diet. The European Simoedosaurus lemoinei has sharper palatal teeth than its North American counterpart, S. dakotensis, suggesting a preference for softer prey - a conclusion consistent with the more gracile teeth and narrower snout. PMID- 26573114 TI - "When I Want to Cry I Can't": Inability to Cry Following SSRI Treatment. AB - INTRODUCTION: We describe seven cases of patients with an inability to cry after treatment with selective serotonin re-uptake inhibitor (SSRI) medication, even during sad or distressing situations that would have normally initiated a crying episode, in the light of the role of the serotonergic system in emotional expression. METHOD: Case series drawn from patients attended in a secondary care psychiatry service. RESULTS: While excessive crying without emotional distress has been previously reported in the literature, and is associated with reduced serotonin function, these reports suggest cases of the reverse dissociation, where emotional distress and an urge to cry was present, but crying was impaired. DISCUSSION: Although the case series presented here is new, these cases are consistent with the neuroscience of crying and their relationship with serotonergic function, and provide preliminary evidence for a double dissociation between subjective emotional experience and the behavioural expression of crying. This helps to further illuminate the neuroscience of emotional expression and suggests the possibility that the phenomenon is an under-recognised adverse effect of SSRI treatment. PMID- 26573115 TI - [Cortical Release Signs in Patients with Schizophrenia, Depressive Disorders, and Bipolar Affective Disorder]. AB - BACKGROUND AND OBJECTIVES: Determining the presence of cortical release signs associated with white matter damage, is a clinically easy method to perform. The objective of this study is to determine the presence of cortical release signs in patients with mental illnesses and cerebrovascular disease, as well as its clinical usefulness, given that it indicates cortical damage. MATERIAL AND METHODS: A review was made of cortical release signs in patients hospitalized in clinical psychiatry and general hospitals with bipolar affective disorder (40), depression (37), schizophrenia (33), cardiovascular disease (33) and dementia (37). RESULTS: The signs of cortical release do not have the same importance as cortical damage. For example, the glabellar reflex was found in all the groups, that of paratonia, particularly in the group with schizophrenia, and others signs in the group of patients with dementia. CONCLUSIONS: It is suggested that these signs imply subcortical white matter damage. The appearance of these signs shows the need for a follow up of patients diagnosed with bipolar affective disorder, depression and schizophrenia. PMID- 26573116 TI - Prevalence of Alcohol Problem Drinking Among the Indigenous Population in Colombia. AB - BACKGROUND: Some studies have reported a high prevalence of alcohol drinking problem among indigenous populations in Latin America. However, there is no available information on some of the variables associated with alcohol problem drinking. OBJECTIVE: To determine the prevalence and some factors associated with alcohol problem drinking among a sample of Colombian indigenous population in Bogota, Colombia. METHOD: A cross-sectional study was conducted using a Colombian indigenous population sample over 15 years old living in the community. Alcohol problem drinking was quantified with the Alcohol Use Disorders Identification Test (AUDIT) (Cut-off point of 8). Non conditional logistic regression was computed to adjust associated variables. RESULTS: A total of 184 subjects from the indigenous population participated in this research. The mean age was 32.0+/ 14.0 years and educated for 6.0+/-3.7 years. A total of 84 participants (45.7%) reported alcohol problem drinking. The AUDIT showed Cronbach alpha of 0.877. Male sex (OR=4.2; 95%CI, 2.2-7.6), and longer time living in Bogota (OR=1.8; 95%CI, 1.0-3.2) were associated with alcohol problem drinking. CONCLUSIONS: Almost 50% of the Colombian indigenous population living in Bogota meet criteria for alcohol problem drinking. Male gender and longer time living in Bogota are related to alcohol problem drinking. Further studies are needed to formally identify alcohol abuse or dependence. PMID- 26573117 TI - Cognitive and Executive Functions in Colombian School Children with Conduct Disorder: Sex Differences. AB - INTRODUCTION: Most of the studies that have examined cognitive and executive functions in conduct disorders (CD) have been conducted on institutionalized male adolescents. In this research the cognitive and executive functions of non institutionalized Colombian school children with CD were compared with normal school children, all between 6 and 12 years-old. MATERIALS AND METHODS: We used a case-control design. The cases were participants who met the diagnostic criteria for CD (n=39) and controls who did not meet these criteria (n=39), according to reports of a professional of the participants' institution, and a structured interview for childhood psychiatric syndromes. The two groups were selected from educational institutions, and there were no differences in age, school grade, or socioeconomic level. The IQ was reviewed, as well as the presence of other mental disorders, serious physical illnesses, and more serious neurological signs. The cognitive and executive functions were evaluated using a child neuropsychological test battery. RESULTS: We found that participants with CD had significantly lower scores in construction abilities, perceptual abilities (tactile, visual and auditory), differed in verbal memory, differed in visual memory, language (repetition, expression and understanding), meta-linguistic abilities, spatial abilities, visual and auditory attention, conceptual abilities, verbal and graphic fluency, and cognitive flexibility. The same differences were found between males, except in repetition, whereas girls showed fewer differences, thus the cognitive and executive performance was poorer in males with CD than in females, especially in verbal and linguistic-related functions. CONCLUSIONS: Children with CD could show generalized cognitive and executive deficits. These deficits seem to be more frequent in boys than in girls with CD. PMID- 26573118 TI - [Factors Associated with Suicide in Adolescents and Young People Self-Identified as Lesbian, Gay, and Bisexual: Current State of the Literature]. AB - INTRODUCTION: A framework within sexual and reproductive health is presented to understand the mental health issues of the population of lesbian, gay and bisexual (LGB) adolescents and young people. Different ways of understanding the nature of internalized homophobia were developed. On the other hand, in suicidology studies it is understood that the risk of suicide consists of the steps of ideation, planning and attempted suicide, and that there is an increased risk of suicide in the LGB population. Numerous factors have been associated with suicide risk in this population, one of the main internalized homophobia and other mental health problems. OBJECTIVES: By means of a literature review, to establish the possible relationship between internalized homophobia and ideation and attempted suicide in the LGB population, as well as to identify the mental health problems associated to suicide risk in sexually diverse communities. METHOD: Articles in English and Spanish, mainly within the last five years, were reviewed. They included articles in peer reviewed journals, and databases, such as Google Scholar, Redalyc, Byreme, Ovid, Science Direct, Taylor and Francis, MEDLINE, Scopus, PsycINFO, and Ebsco. RESULTS: It was found in the available literature that internalized homophobia is associated with suicide ideation and attempts in adults. A state of science of the major mental health problems associated with suicide risk in young LGB people reported contradictory findings. While some studies showed an association between depression, anxiety and distress and suicidal ideation and attempts, in others, the data do not allow such a conclusion. The theoretical framework presents the most important conceptualizations of suicide risk and emphasizes the social type. It identifies issues of suicide prevention, protective factors that contribute towards this, as well as elements of psychotherapy for LGB consultants. CONCLUSIONS: It concludes and discusses the importance of studying the sexually diverse as regards determining factors of mental health in Latin America, given the limited amount of literature found in the Spanish language, and myths of major disease that persist in many segments of the population. This review considers it necessary to overcome such contradictions, in order to inform the general population and avoid further stigmatization. PMID- 26573119 TI - [Genomic Advances in Eating Behavior Disorders]. AB - Eating behavior disorders are a public health issue. The etiology of these types of disorders is unknown, and they may have psychiatric, chemical and biological origins. The aim of this review is to present evidence that shows the contribution of genomic research in the study of eating behavior disorders. It also shows the considerable research that has been undertaken to identify the genes that may participate in the etiology of eating behavior disorders. PMID- 26573120 TI - Comments on the Use of Agomelatine in the Treatment of Depressive Disorder According to Clinical Guidelines in Colombia. PMID- 26573121 TI - [Reply to "Comments on the Use of Agomelatine in the Treatment of Depressive Disorder According to Clinical Guidelines in Colombia"]. PMID- 26573122 TI - The crisis in the Colombian healthcare system. PMID- 26573124 TI - Analysis of the effect of a novel therapeutic for type 2 diabetes on the proteome of a muscle cell line. AB - Elevated serum retinol-binding protein (RBP) concentration has been implicated in the development of insulin resistance and type 2 diabetes. Two series of small molecules have been designed to lower serum levels by reducing secretion of the transthyretin-RBP complex from the liver and enhancing RBP clearance through the kidney. These small molecules were seen to improve glucose and insulin tolerance tests and to reduce body weight gain in mice rendered diabetic through a high fat diet. A proteomics study was conducted to better understand the effects of these compounds in muscle cells, muscle being the primary site for energy expenditure. One lead compound, RTC-15, is seen to have a significant effect on proteins involved in fat and glucose metabolism. This could indicate that the compound is having a direct effect on muscle tissue to improve energy homeostasis as well as a whole body effect on circulating RBP levels. This newly characterized group of antidiabetic compounds may prove useful in the treatment and prevention of insulin resistance and obesity. PMID- 26573123 TI - A Test-Retest Reliability Study of the Whiplash Disability Questionnaire in Patients With Acute Whiplash-Associated Disorders. AB - OBJECTIVE: The purpose of this study was to determine the test-retest reliability and the Minimal Detectable Change (MDC) of the Whiplash Disability Questionnaire (WDQ) in individuals with acute whiplash-associated disorders (WADs). METHODS: We performed a test-retest reliability study. We included insurance claimants from Ontario who were at least 18 years of age, within 21 days of their motor vehicle collision and diagnosed as having acute WAD grades I to III. The WDQ, a 13-item questionnaire scored from 0 (no disability) to 130 (complete disability), was administered to all participants at baseline and by telephone 3 days later. We computed the intraclass correlation coefficient (model 2,1) and the MDC with 95% confidence intervals (CIs; MDC95). RESULTS: The mean (SD) age of the 66 participants was 41.6 (12.7) years and 71.2% were female. Twenty-nine percent had WAD I and 71.2% had WAD II. Time since injury ranged from 0 to 19 days. The mean (SD) baseline WDQ score was 49.3 (28.8) and 46.5 (29.8) 3 days later. The intraclass correlation coefficient for the WDQ total score was 0.89 (95% CI, 0.85 0.92) in the entire sample and 0.83 (95% CI, 0.69-0.93) for the 15 participants reporting no change in neck pain. The MDC95 of the WDQ was 21.4 (SD = 14.9) for participants reporting no change. CONCLUSION: The WDQ was reliable in individuals with acute WAD. There is 95% confidence that a change of approximately one-sixth of the total score is beyond the daily variation of a stable condition. This level of measurement error must be taken into consideration when interpreting change in WDQ scores. PMID- 26573125 TI - Vitamin D deficiency among subfertile women: case-control study. AB - OBJECTIVE: The objective of the study is to compare the dietary vitamin D and calcium intake among subfertile women (cases) versus pregnant women (controls) and to determine the vitamin D levels in the subfertile and pregnant women. The study design was an observational case-control study where a total of 181 (83 previously diagnosed subfertile cases from various causes and 98 pregnant controls) women of reproductive age. A validated questionnaire was used where it focused on key indicators evaluating vitamin D-related factors. Blood was withdrawn for the measurement of serum calcium, albumin and phosphate to exclude secondary causes that might affect vitamin D level. RESULTS: The prevalence of vitamin D deficiency was significantly higher in the subfertile group than controls (59.0% versus 40.4%; p < 0.01). Calcium supplements intake was significantly higher in controls than the subfertile group (64.6% versus 10.0%; p value < 0.001). Total dietary vitamin D intake (> 400 IU/day) was significantly higher in the controls than the subfertile group. CONCLUSION: Vitamin D deficiency is prevalent among subfertile women. Optimization of serum calcium and vitamin D levels is encouraged. PMID- 26573127 TI - Diagnostic value of CD10 and Bcl2 expression in distinguishing cutaneous basal cell carcinoma from squamous cell carcinoma and seborrheic keratosis. AB - The distinction between cutaneous basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and seborrheic keratosis (SK), which are common entities in clinical practice, can be difficult clinically and histologically. CD10 and Bcl2 antigens are important factors in tumor growth, survival and spread. The aim of the present study is to define the frequency of CD10 and Bcl2 expression in such cutaneous tumors and its relation to the clinicopathological characteristics as well as their possible diagnostic utility. CD10 and Bcl2 immunohistochemistry was performed on 30 BCC, 20 SCC and 15 SK. 93.3% of SK cases and 53.3% of BCC cases showed significant expression of CD10 in tumor cells when compared either with each other or with SCC cases (100% negative). Stromal CD10 expression was positive in 50% of BCC cases and 75% of SCC cases. Stromal CD10 expression was significantly higher in high risk BCC and BCC with infiltrating deep margins; furthermore, it showed a significant positive correlation with grade of SCC. A significant inverse correlation between CD10 expression in stromal and tumor cells of BCC was present. Bcl2 was significantly expressed in 93.3% of SK cases and 80% of BCC cases when compared with SCC cases (100% negative). It was found that for distinguishing BCC from SK, only CD10 expression in tumor cells provided a high diagnostic value with positive likelihood ratio (PLR) was 7.00. In addition, CD10 and Bcl2 expression in tumor cells could give convincing diagnostic value to distinguish SCC from SK (PLR=15.00 for each marker). Moreover, for differentiating BCC from SCC, only Bcl2 in the tumor cells could provide a high diagnostic value (PLR=5.5). In conclusion, CD10 and Bcl2 can help in differentiating cutaneous BCC from SK and SCC. The overexpression of CD10 in the stromal cells of SCC and some variants of BCC suggests the invasive properties of such tumors. PMID- 26573126 TI - Microfluidics-based optimization of neuroleukin-mediated regulation of articular chondrocyte proliferation. AB - Due to the low proliferative and migratory capacities of chondrocytes, cartilage repair remains a challenging clinical problem. Current therapeutic strategies for cartilage repair result in unsatisfactory outcomes. Autologous chondrocyte implantation (ACI) is a cell based therapy that relies on the in vitro expansion of healthy chondrocytes from the patient, during which proliferation-promoting factors are frequently used. Neuroleukin (NLK) is a multifunctional protein that possesses growth factor functions, and its expression has been associated with cartilage development and bone regeneration, however its direct role in chondrocyte proliferation remains to be fully elucidated. In the current study, the role of NLK in chondrocyte proliferation in vitro in addition to its potential to act as an exogenous factor during ACI was investigated. Furthermore, the concentration of NLK for in vitro chondrocyte culture was optimized using a microfluidic device. An NLK concentration of 12.85 ng/ml was observed to provide optimal conditions for the promotion of chondrocyte proliferation. Additionally, NLK stimulation resulted in an increase in type II collagen synthesis by chondrocytes, which is a cartilaginous secretion marker and associated with the phenotype of chondrocytes. Together these data suggest that NLK is able to promote cell proliferation and type II collagen synthesis during in vitro chondrocyte propagation, and thus may serve as an exogenous factor for ACI. PMID- 26573128 TI - NF45 inhibits cardiomyocyte apoptosis following myocardial ischemia-reperfusion injury. AB - Cardiomyocyte apoptosis, which occurs during ischemia and reperfusion injury, can cause irreversible damage to cardiac function. There is accumulating evidence that nuclear factor 45 (NF45) and regulatory pathways are important in understanding reparative processes in the myocardium. NF45 is a multifunctional regulator of gene expression that participates in the regulation of DNA break repair. Recently, NF45 has been proved to be associated with tumor cell apoptosis in various human malignancies. However, the underlying mechanism of NF45 regulating myocardial ischemia-reperfusion (I/R) injury remains unclear. In this study, western blot showed that NF45 expression decreased after myocardial I/R in vivo. Double immunofluorescent staining revealed that NF45, located in the nucleus of cardiomyocyes, was correlated with cardiomyocyte apoptosis. Furthermore, NF45 expression decreased in H9c2 cells after hypoxia-reoxygenation (H/R) treatment in vitro, which was in line with the results in vivo. Overexpression of NF45 in H9c2 cells reduced cell apoptosis, as evidenced by increased Bcl-2 level, as well as decreased cleaved caspase-3, p53 and p21 expression. The expression of NF45 was reduced by LY294002 (a PI3K/Akt inhibitor), but not SB203580 (a p38 inhibitor), suggesting that NF45 prevented H/R-induced H9c2 cell apoptosis via PI3K/Akt pathway. Our data may supply a novel molecular target for acute myocardial infarction (AMI) therapy. PMID- 26573129 TI - A new case of bent bone dysplasia--FGFR2 type and review of the literature. PMID- 26573130 TI - 2D EPID dose calibration for pretreatment quality control of conformal and IMRT fields: A simple and fast convolution approach. AB - PURPOSE: This work presents an original algorithm that converts the signal of an electronic portal imaging device (EPID) into absorbed dose in water at the depth of maximum. METHODS: The model includes a first image pre-processing step that accounts for the non-uniformity of the detector response but also for the perturbation of the signal due to backscatter radiation. Secondly, the image is converted into absorbed dose to water through a linear conversion function associated with a dose redistribution kernel. These two computation parameters were modelled by correlating the on-axis EPID signal with absorbed dose measurements obtained on square fields by using an ionization chamber placed in water at the depth of maximum dose. The accuracy of the algorithm was assessed by comparing the dose determined from the EPID signal with the dose derived by the treatment planning system (TPS) using the Upsilon-index. These comparisons were performed on 8 conformal radiotherapy treatment fields (3DCRT) and 18 modulated fields (IMRT). RESULTS: For a dose difference and a distance-to-agreement set to 3% of the maximum dose and 2 mm respectively, the mean percentage of points with a Upsilon-value less than or equal to 1 was 99.8% +/- 0.1% for 3DCRT fields and 96.8% +/- 2.7% for IMRT fields. Moreover, the mean gamma values were always less than 0.5 whatever the treatment technique. CONCLUSION: These results confirm that our algorithm is an accurate and suitable tool for clinical use in a context of IMRT quality assurance programmes. PMID- 26573131 TI - Association between subjective evaluation and physical parameters for radiographic images optimization. AB - PURPOSE: The purpose of this study was to develop a methodology to optimize computed radiographic techniques to image the skull, chest, and pelvis of a standard patient. METHODS: Optimization was performed by varying exposure levels with different tube voltages to generate images of an anthropomorphic phantom. Image quality was evaluated using visual grading analysis and measuring objective parameters such as the effective detective quantum efficiency and the contrast-to noise ratio. Objective and subjective evaluations were compared to obtain an optimized technique for each anatomic region. RESULTS: Gold standard techniques provided a significant reduction in X-ray doses compared to the techniques used in our radiology service, without compromising diagnostic accuracy. They were chosen as follows 102 kVp/1.6 mAs for skull; 81 kVp/4.5 mAs for pelvis and 90 kVp/3.2 mAs for chest. CONCLUSION: There is a range of acceptable techniques that produce adequate images for diagnosis in computed radiography systems. This aspect allows the optimization process to be focused on the patient dose without compromising diagnostic capabilities. This process should be performed through association of quantitative and qualitative parameters, such as effective detective quantum efficiency, contrast-to-noise ratio, and visual grading analysis. PMID- 26573132 TI - Short Communication: Limited HIV Pretreatment Drug Resistance Among Adults Attending Free Antiretroviral Therapy Clinic of Pune, India. AB - In India, the roll out of the free antiretroviral therapy (ART) program completed a decade of its initiation in 2014. The success of first-line ART is influenced by prevalence of HIV pretreatment drug resistance (PDR) in the population. In this cross-sectional study, we sought to determine the prevalence of PDR among adults attending the state-sponsored free ART clinic in Pune in western India. Fifty-two individuals eligible for ART as per national guidelines with median CD4 cell count of 253 cells/mm(3) (inter quartile range: 149-326) were recruited between January 2014 and April 2015. Population-based sequencing of partial pol gene sequences from plasma specimen revealed predominant HIV-1 subtype C infection (96.15%) and presence of single-drug resistance mutations against non nucleoside reverse transcriptase inhibitor in two sequences. The study supports the need for periodic surveillance, when offering PDR testing at individual level is not feasible. PMID- 26573133 TI - Oman's coral reefs: A unique ecosystem challenged by natural and man-related stresses and in need of conservation. AB - Oman contains diverse and abundant reef coral communities that extend along a coast that borders three environmentally distinct water bodies, with corals existing under unique and often stressful environmental conditions. In recent years Oman's reefs have undergone considerable change due to recurrent predatory starfish outbreaks, cyclone damage, harmful algal blooms, and other stressors. In this review we summarize current knowledge of the biology and status of corals in Oman, particularly in light of recent stressors and projected future threats, and examine current reef management practices. Oman's coral communities occur in marginal environmental conditions for reefs, and hence are quite vulnerable to anthropogenic effects. We recommend a focus on developing conservation-oriented coral research to guide proactive management and expansion of the number and size of designated protected areas in Oman, particularly those associated with critical coral habitat. PMID- 26573134 TI - Adaptability of free-floating green tide algae in the Yellow Sea to variable temperature and light intensity. AB - In this study, the influence of temperature and light intensity on the growth of seedlings and adults of four species of green tide algae (Ulvaprolifera, Ulvacompressa, Ulva flexuosa and Ulvalinza) from the Yellow Sea was evaluated. The results indicated that the specific growth rate (SGR) of seedlings was much higher than that of adults for the four species. The adaptability of U. prolifera is much wider: Adult daily SGRs were the highest among the four species at 15-20 degrees C with 10-600 MUmol . m(-2) . s(-1) and 25-30 degrees C with 200-600 MUmol . m(-2) . s(-1). SGRs were 1.5-3.5 times greater than the other three species at 15-25 degrees C with 200-600 MUmol . m(-2) . s(-1). These results indicate that U. prolifera has better tolerance to high temperature and light intensity than the other three species, which may in part explain why only U. prolifera undergoes large-scale outbreaks and floats to the Qingdao coast while the other three species decline and disappear at the early stage of blooming. PMID- 26573136 TI - A critical examination of the available data sources for estimating meat and protein consumption in the USA. AB - OBJECTIVE: To describe the methods, strengths and limitations of available data sources for estimating US meat and protein consumption in order to facilitate accurate interpretations and applications. DESIGN: We examined agricultural supply and dietary intake databases from the US Department of Agriculture (USDA), the US Department of Health and Human Services and the FAO to describe their methodology and to report the most recent estimates for meat and protein consumption. RESULTS: Together, loss-adjusted agricultural supply data and dietary recall data provide the best available estimates of US consumption; the most recent sources indicated that US citizens (ages 2 years and over) consume 4.4-5.9 oz (125.9-166.5 g) of total meat and 6.2-7.4 oz-eq (175.2-209.4 g-eq) from the USDA Protein Foods Group per day. Meat constitutes the majority of intake within the Protein Foods Group, and red meat and processed meat constitute the majority of total meat intake. Nutrient supply data indicate that total meat represents an estimated 43.1 % of the total protein available in the US food supply, but without any loss-adjusted nutrient data, per capita protein intake is best estimated by dietary recall data to be 79.9 g/d. CONCLUSIONS: In order to address public health concerns related to excess meat and/or protein consumption, practitioners, educators and researchers must appropriately use available data sources in order to accurately report consumption at the population level. Implications for comparing these estimates with various recommended intakes are discussed. PMID- 26573135 TI - Investigation of Pathogenic Genes in Chinese sporadic Hypertrophic Cardiomyopathy Patients by Whole Exome Sequencing. AB - Hypertrophic cardiomyopathy (HCM) is a cardiovascular disease with high heterogeneity. Limited knowledge concerning the genetic background of nearly 40% HCM cases indicates there is a clear need for further investigation to explore the genetic pathogenesis of the disease. In this study, we undertook a whole exome sequencing (WES) approach to identify novel candidate genes and mutations associated with HCM. The cohort consisted of 74 unrelated patients with sporadic HCM (sHCM) previously determined to be negative for mutations in eight sarcomere genes. The results showed that 7 of 74 patients (9.5%) had damaging mutations in 43 known HCM disease genes. Furthermore, after analysis combining the Transmission and De novo Association (TADA) program and the ToppGene program, 10 putative genes gained priority. A thorough review of public databases and related literature revealed that there is strong supporting evidence for most of the genes playing roles in various aspects of heart development. Findings from recent studies suggest that the putative and known disease genes converge on three functional pathways: sarcomere function, calcium signaling and metabolism pathway. This study illustrates the benefit of WES, in combination with rare variant analysis tools, in providing valuable insight into the genetic etiology of a heterogeneous sporadic disease. PMID- 26573137 TI - Community of practice and student interaction at an acute medical ward: An ethnographic study. AB - BACKGROUND: A deeper understanding is needed of the acute medical care setting as a learning environment for students. AIM: To explore workplace culture of an acute medical ward and students' interactions within this community. METHOD: An ethnographic design was applied. Medical and nurse students' interactions were observed and informal questioning performed. Field notes were transcribed and analysed qualitatively, inspired by Wengers' "Community of practice" theory. RESULTS: We identified four characteristics that regulated how students adapt and interact in the community of practice. Complex and stressful situations were stabilized by routines and carriers of culture. Variable composition and roles of community members were a part of the daily routine but did not seam obvious to students. Transitions through community boundaries were confusing especially for new students. Levels of importance and priority: Hierarchies and orders of priority were present as regulators of roles, routines and interactions, and of how staff approach different patient groups. CONCLUSION: The culture shaped a pattern for, and created prerequisites that challenged students' adaptation and created a space for learning. Students' task on arrival was to enter the semipermeable membrane of the community of practice and to understand and adapt to its culture, and try to become accepted. PMID- 26573138 TI - Evaluation of colostrum as an alternative biological sample for the diagnosis of human congenital toxoplasmosis. AB - BACKGROUND: Toxoplasmosis is a zoonosis caused by Toxoplasma gondii, an intracellular protozoan parasite able to infect a wide range of hosts, including humans. Congenital infection can cause severe damage to the fetus. Thus, it is important to detect antibodies against the parasite to confirm clinical manifestations. Considering that all immunoglobulin isotypes may be present in biological samples from newborns and their mothers, this study aimed to evaluate the ability to diagnose recent toxoplasmosis by using colostrum, as an alternative noninvasive way to obtain biological samples, as well as to determine correlation rates between antibodies from serum samples to detect IgG, IgM and IgA isotypes against T. gondii. METHODS: A total of 289 puerperal women from Clinical Hospital of Federal University of Uberlandia (mean age: 24.8 years, range: 14 - 43 years) took part in this study. Serum and colostrum samples from these patients were analyzed using ELISA and immunoblotting assays for soluble antigens from T. gondii. RESULTS: ELISA immunoassays with serum samples showed reactivity in 47.0, 6.9 and 2.8 % of samples to anti-T. gondii IgG, IgM and IgA, respectively, in comparison with colostrum samples, which showed reactivity in 46.0, 7.9 and 2.8 % of samples to the same isotypes. Also, significant correlation rates of anti-T. gondii antibody levels between serum and colostrum samples were observed. Interestingly, reactivity to IgM and/or IgA in colostrum and/or serum confirmed clinical manifestations of congenital toxoplasmosis in three newborns. Immunoblotting assays showed that it is possible to detect IgG, IgM and IgA antibodies against various antigens of T. gondii in serum and colostrum samples. IgG antibodies in serum and colostrum samples recognized more antigenic fractions than IgM and IgA antibodies. Serum IgG detected more antigenic fractions than IgG antibodies present in the colostrum of the same patient. In contrast, specific IgA present in colostrum recognized a higher number of antigens than IgA present in serum samples of the same patient. CONCLUSIONS: Overall, the results show that it is important to investigate the occurrence of congenital toxoplasmosis, even at puerperal period. Furthermore, this study demonstrates that T. gondii-specific IgG, IgM and IgA antibodies in serum and colostrum samples from puerperal women may be detected with a significant correlation, suggesting that colostrum may also be used as an alternative biological sample to efficiently diagnose recent human toxoplasmosis. PMID- 26573139 TI - Study of Preoperative Radiotherapy for Sarcomas of the Extremities with Intensity Modulation, Image-Guidance and Small Safety-margins (PREMISS). AB - BACKGROUND: The aim of the trial is to demonstrate that with the use of modern IMRT/IGRT and reduction of safety margins postoperative wound complications can be reduced. METHODS/ DESIGN: The trial is designed as a prospective, monocentric clinical phase II trial. The treatment is performed with helical IMRT on the Tomotherapy HiArt System(c) or with RapidArc(c) IMRT as available. All treatments are performed with 6 MV photons and daily online CT-based IGRT. A dose of 50 Gy in 2 Gy single fractions (5 fractions per week) is prescribed. Restaging including MRI of the primary tumor site as well as CT of the thorax/abdomen is planned 4 weeks after RT. PET-examinations or any other imaging can be performed as required clinically. In cases of R1 resection, brachytherapy is anticipated in the 2nd postoperative week. Brachytherapy catheters are implanted into the tumor bed depending on the size and location of the lesion. Surgery is planned 5-6 weeks after completion of neoadjuvant RT. All patients are seen for a first follow-up visit 2 weeks after wound healing is completed, thereafter every 3 months during the first 2 years. The endpoints of the study are evaluated in detail during the first (2 weeks) and second (3 months) follow-up. Functional outcome and QOL are documented prior to treatment and at year 1 and 2. Treatment response and efficacy will be scored according to the RECIST 1.1 criteria. A total patient number of 50 with an expected 20% rate of wound complications were calculated for the study, which translates into a 95% confidence interval of 10.0 33.7% for wound complication rate in a binomial distribution. DISCUSSION: The present study protocol prospectively evaluates the use of IMRT/IGRT for neoadjuvant RT in patients with soft tissue sarcomas of the extremity with the primary endpoint wound complications, which is the major concern with this treatment sequence. Besides complications rates, local control rates and survival rates, as well as QOL, functional outcome and treatment response parameters (imaging and pathology) are part of the protocol. The data of the present PREMISS study will enhance the current literature and support the hypothesis that neoadjuvant RT with IMRT/IGRT offers an excellent risk-benefit ratio in this patient population. TRIAL REGISTRATION: NCT01552239. PMID- 26573140 TI - Psycho-education for substance use and antisocial personality disorder: a randomized trial. AB - BACKGROUND: Antisocial personality disorder often co-exists with drug and alcohol use disorders. METHODS: This trial examined the effectiveness of offering psycho education for antisocial personality disorder in community substance use disorder treatment centers in Denmark. A total of 176 patients were randomly allocated to treatment as usual (TAU, n = 80) or TAU plus a psycho-educative program, Impulsive Lifestyle Counselling (ILC, n = 96) delivered by site clinicians (n = 39). Using follow-up interviews 3 and 9 months after randomization, we examined changes in drug and alcohol use (Addiction Severity Index Composite Scores), percent days abstinent (PDA) within last month, and aggression as measured with the Buss-Perry Aggression Questionnaire-Short Form and the Self-Report of Aggression and Social Behavior Measure. RESULTS: Overall engagement in psychological interventions was modest: 71 (76 %) of participants randomized to psycho-education attended at least one counselling session, and 21 (23 %) attended all six sessions. The Median number of sessions was 2. All patients reduced drug and alcohol problems at 9 months with small within-group effect sizes. Intention-to-treat analyses indicated significant differences between ILC and TAU in mean drugs composite score (p = .018) and in PDA (p = .041) at 3 months. Aggression declined in both groups, but no differences between ILC and TAU were observed in terms of alcohol problems or aggression at any follow-up. CONCLUSIONS: Moderate short-term improvements in substance use were associated with randomization to Impulsive Lifestyle Counselling. The findings support the usefulness of providing psycho-education to outpatients with antisocial personality disorder. TRIAL REGISTRATION: ISRCTN registry, ISRCTN67266318 , 17/7/2012. PMID- 26573142 TI - A measure of regularity for polygonal mosaics in biological systems. AB - BACKGROUND: The quantification of the spatial order of biological patterns or mosaics provides useful information as many properties are determined by the spatial distribution of their constituent elements. These are usually characterised by methods based on nearest neighbours distances, by the number of sides of cells, or by angles defined by the adjacent cells. METHODS: A measure of regularity in polygonal mosaics of different kinds in biological systems is proposed. It is based on the condition of eutacticity, expressed in terms of eutactic stars, which is closely related to regularity of polytopes. Thus it constitutes a natural measure of regularity. The proposed measure is tested with numerical and real data. Numerically is tested with a hexagonal lattice that is distorted progressively and with a non-periodic regular tiling. With real data, the distribution of oak trees in forests from three locations in the State of Queretaro, Mexico, and the spiral pattern of florets in a flowering plant are characterised. RESULTS: The proposed measure performs well and as expected while tested with a numerical experiment, as well as when applied to a known non periodic tiling of the plane. Concerning real data, the measure is sensitive to the degree of perturbation observed in the distribution of oak trees and detects high regularity in a phyllotactic pattern studied. CONCLUSIONS: The measure here proposed has a clear geometrical meaning, establishing what regularity means, and constitute an advantageous general purposes alternative to analyse spatial distributions, capable to indicate the degree of regularity of a mosaic or an array of points. PMID- 26573141 TI - Promoter Methylation Analysis Reveals That KCNA5 Ion Channel Silencing Supports Ewing Sarcoma Cell Proliferation. AB - Polycomb proteins are essential regulators of gene expression in stem cells and development. They function to reversibly repress gene transcription via posttranslational modification of histones and chromatin compaction. In many human cancers, genes that are repressed by polycomb in stem cells are subject to more stable silencing via DNA methylation of promoter CpG islands. Ewing sarcoma is an aggressive bone and soft-tissue tumor that is characterized by overexpression of polycomb proteins. This study investigates the DNA methylation status of polycomb target gene promoters in Ewing sarcoma tumors and cell lines and observes that the promoters of differentiation genes are frequent targets of CpG-island DNA methylation. In addition, the promoters of ion channel genes are highly differentially methylated in Ewing sarcoma compared with nonmalignant adult tissues. Ion channels regulate a variety of biologic processes, including proliferation, and dysfunction of these channels contributes to tumor pathogenesis. In particular, reduced expression of the voltage-gated Kv1.5 channel has been implicated in tumor progression. These data show that DNA methylation of the KCNA5 promoter contributes to stable epigenetic silencing of the Kv1.5 channel. This epigenetic repression is reversed by exposure to the DNA methylation inhibitor decitabine, which inhibits Ewing sarcoma cell proliferation through mechanisms that include restoration of the Kv1.5 channel function. IMPLICATIONS: This study demonstrates that promoters of ion channels are aberrantly methylated in Ewing sarcoma and that epigenetic silencing of KCNA5 contributes to tumor cell proliferation, thus providing further evidence of the importance of ion channel dysregulation to tumorigenesis. PMID- 26573143 TI - William Austin Sibley, MD (1925-2015). PMID- 26573144 TI - KContact, an enhanced intervention for contact between children in out-of-home care and their parents: protocol for a cluster randomised controlled trial. AB - BACKGROUND: When children are unable to safely live at home with their parents, contact between these children and their parents is considered, in most cases, important for maintaining children's sense of identity and relationships with their parents. However, the research evidence on contact is weak and provides little guidance on how to manage contact and when it is beneficial or potentially harmful. The evidence in relation to contact interventions with parents and their children who are to remain in long-term care is the most limited. A small number of studies have been identified where interventions which were therapeutic, child focused and with clear goals, particularly aimed at preparing and supporting parents, showed some promising results. This trial aims to build on the existing evidence by trialling an enhanced model of contact in multiple sites in Australia. METHODS/DESIGN: This study is a cluster randomised controlled trial of an enhanced contact intervention with children in long-term care who are having supervised contact with their parents. Intervention sites will implement the kContact intervention that increases the preparation and support provided to parents in relation to contact. Baseline and follow-up interviews are being conducted with parents, carers and agency workers at intervention and control sites. Follow-ups interviews will assess whether there has been an increase in children's emotional safety and a reduction in distress in response to contact visits with their parents (the primary outcome variable as measured using the Strength and Difficulties Questionnaire), improved relationships between children and their parents, improved parental ability to support contact, and fewer contact visits cancelled. DISCUSSION: By increasing the evidence base in this area, the study aims to better guide the management and supervision of contact visits in the out-of-home care context and improve outcomes for the children and their families. TRIAL REGISTRATION: Trial registered on 7 April 2015 with the Australian New Zealand Clinical Trials Registry ACTRN12615000313538. PMID- 26573145 TI - Contribution of fish farming ponds to the production of immature Anopheles spp. in a malaria-endemic Amazonian town. AB - BACKGROUND: In the past decade fish farming has become an important economic activity in the Occidental Brazilian Amazon, where the number of new fish farms is rapidly increasing. One of the primary concerns with this phenomenon is the contribution of fishponds to the maintenance and increase of the anopheline mosquito population, and the subsequent increase in human malaria burden. This study reports the results of a 2-year anopheline abundance survey in fishponds and natural water bodies in a malaria-endemic area in northwest Brazil. The objective of this study was to investigate the contribution of natural water bodies (rivers, streams, creeks, ponds, and puddles) and artificial fishponds as breeding sites for Anopheles spp. in Mancio Lima, Acre and to investigate the effect of limnological and environmental variables on Anopheles spp. larval abundance. METHODS: Natural water bodies and fishponds were sampled at eight different times over 2 years (early, mid and late rainy season, dry season) in the Amazonian town of Mancio Lima, Acre. Anopheline larvae were collected with an entomological dipper, and physical, chemical and ecological characteristics of each water body were measured. Management practices of fishpond owners were ascertained with a systematic questionnaire. RESULTS: Fishponds were four times more infested with anopheline larvae than natural water bodies. Electrical conductivity and the distance to the nearest house were both significant inverse predictors of larval abundance in natural water bodies. The density of larvae in fishponds raised with increasing border vegetation. Fishponds owned by different farmers varied in the extent of anopheline larval infestation but ponds owned by the same individual had similar infestation patterns over time. Commercial fishponds were 1.7-times more infested with anopheline larvae compared to fishponds for family use. CONCLUSIONS: These results suggest that fishponds are important breeding sites for anopheline larvae, and that adequate management activities, such as removal of border vegetation could reduce the abundance of mosquito larvae, most importantly Anopheles darlingi. PMID- 26573146 TI - Size-Dependent Melting Behavior of Colloidal In, Sn, and Bi Nanocrystals. AB - Colloidal nanocrystals are a technologically important class of nanostructures whose phase change properties have been largely unexplored. Here we report on the melting behavior of In, Sn, and Bi nanocrystals dispersed in a polymer matrix. This polymer matrix prevents the nanocrystals from coalescing with one another and enables previously unaccessed observations on the melting behavior of colloidal nanocrystals. We measure the melting temperature, melting enthalpy, and melting entropy of colloidal nanocrystals with diameters of approximately 10 to 20 nm. All of these properties decrease as nanocrystal size decreases, although the depression rate for melting temperature is comparatively slower than that of melting enthalpy and melting entropy. We also observe an elevated melting temperature during the initial melt-freeze cycle that we attribute to surface stabilization from the organic ligands on the nanocrystal surface. Broad endothermic melting valleys and very large supercoolings in our calorimetry data suggest that colloidal nanocrystals exhibit a significant amount of surface pre melting and low heterogeneous nucleation probabilities during freezing. PMID- 26573147 TI - Trauma team activation varies across Dutch emergency departments: a national survey. AB - BACKGROUND: Tiered trauma team response may contribute to efficient in-hospital trauma triage by reducing the amount of resources required and by improving health outcomes. This study evaluates current practice of trauma team activation (TTA) in Dutch emergency departments (EDs). METHODS: A survey was conducted among managers of all 102 EDs in the Netherlands, using a semi-structured online questionnaire. RESULTS: Seventy-two questionnaires were analysed. Most EDs use a one-team system (68 %). EDs with a tiered-response receive more multi trauma patients (p < 0.01) and have more trauma team alerts per year (p < 0.05) than one team EDs. The number of trauma team members varies from three to 16 professionals. The ED nurse usually receives the pre-notification (97 %), whereas the decision to activate a team is made by an ED nurse (46 %), ED physician (30 %), by multiple professionals (20 %) or other (4 %). Information in the pre notification mostly used for trauma team activation are Airway-Breathing Circulation (87 %), Glasgow Coma Score (90 %), and Revised Trauma Score (85 %) or Paediatric Trauma Score (86 %). However, this information is only available for 75 % of the patients or less. Only 56 % of the respondents were satisfied with their current in-hospital trauma triage system. CONCLUSIONS: Trauma team activation varies across Dutch EDs and there is room for improvement in the trauma triage system used, size of the teams and the professionals involved. More direct communication and more uniform criteria could be used to efficiently and safely activate a specific trauma team. Therefore, the implementation of a revised national consensus guideline is recommended. PMID- 26573148 TI - Mango (Mangifera indica L.) germplasm diversity based on single nucleotide polymorphisms derived from the transcriptome. AB - BACKGROUND: Germplasm collections are an important source for plant breeding, especially in fruit trees which have a long duration of juvenile period. Thus, efforts have been made to study the diversity of fruit tree collections. Even though mango is an economically important crop, most of the studies on diversity in mango collections have been conducted with a small number of genetic markers. RESULTS: We describe a de novo transcriptome assembly from mango cultivar 'Keitt'. Variation discovery was performed using Illumina resequencing of 'Keitt' and 'Tommy Atkins' cultivars identified 332,016 single-nucleotide polymorphisms (SNPs) and 1903 simple-sequence repeats (SSRs). Most of the SSRs (70.1%) were of trinucleotide with the preponderance of motif (GGA/AAG)n and only 23.5% were di nucleotide SSRs with the mostly of (AT/AT)n motif. Further investigation of the diversity in the Israeli mango collection was performed based on a subset of 293 SNPs. Those markers have divided the Israeli mango collection into two major groups: one group included mostly mango accessions from Southeast Asia (Malaysia, Thailand, Indonesia) and India and the other with mainly of Floridian and Israeli mango cultivars. The latter group was more polymorphic (FS=-0.1 on the average) and was more of an admixture than the former group. A slight population differentiation was detected (FST=0.03), suggesting that if the mango accessions of the western world apparently was originated from Southeast Asia, as has been previously suggested, the duration of cultivation was not long enough to develop a distinct genetic background. CONCLUSIONS: Whole-transcriptome reconstruction was used to significantly broaden the mango's genetic variation resources, i.e., SNPs and SSRs. The set of SNP markers described in this study is novel. A subset of SNPs was sampled to explore the Israeli mango collection and most of them were polymorphic in many mango accessions. Therefore, we believe that these SNPs will be valuable as they recapitulate and strengthen the history of mango diversity. PMID- 26573150 TI - Standardized handoff report form in clinical nursing education: An educational tool for patient safety and quality of care. AB - Effective change-of-shift handoff communication is a core competency in the generalist education of nurses. The use of a standardized handoff tool that fosters higher order thinking and clinical reasoning is fundamental in clinical education and nursing practice (AACN, 2008). A checklist that prompts students to implement evidence-based safety alerts will increase students' confidence and autonomy, prevent errors, promote patient safety, and successfully transform theoretical learning into competent practice. High-quality handoffs and contextualized post-conference debriefing using key items in the handoff form will help increase students' feelings of precision, accuracy, improve their self image, and enhance their sense of professional belonging. PMID- 26573149 TI - Efficient Generation of Mice with Consistent Transgene Expression by FEEST. AB - Transgenic mouse models are widely used in biomedical research; however, current techniques for producing transgenic mice are limited due to the unpredictable nature of transgene expression. Here, we report a novel, highly efficient technique for the generation of transgenic mice with single-copy integration of the transgene and guaranteed expression of the gene-of-interest (GOI). We refer to this technique as functionally enriched ES cell transgenics, or FEEST. ES cells harboring an inducible Cre gene enabled the efficient selection of transgenic ES cell clones using hygromycin before Cre-mediated recombination. Expression of the GOI was confirmed by assaying for the GFP after Cre recombination. As a proof-of-principle, we produced a transgenic mouse line containing Cre-activatable tTA (cl-tTA6). This tTA mouse model was able to induce tumor formation when crossed with a transgenic mouse line containing a doxycycline-inducible oncogene. We also showed that the cl-tTA6 mouse is a valuable tool for faithfully recapitulating the clinical course of tumor development. We showed that FEEST can be easily adapted for other genes by preparing a transgenic mouse model of conditionally activatable EGFR L858R. Thus, FEEST is a technique with the potential to generate transgenic mouse models at a genome-wide scale. PMID- 26573151 TI - The construction and evaluation of new educational software for nursing diagnoses: a randomized controlled trial. AB - BACKGROUND: Student nurses often have difficulties with diagnostic inferences. To achieve high accuracy nursing diagnoses, effective learning strategies are required. OBJECTIVE: To describe the construction and evaluation of new educational software called Wise Nurse, which was developed to increase the capacity of student nurses to identify nursing diagnoses (NDx) and to establish relationships between NDx, defining characteristics (DC), and related factors (RF). DESIGN: Randomized controlled trial. SETTING AND PARTICIPANTS: Participants were 2nd to 4th year student nurses from an undergraduate program at a university in Brazil. Of the 47 recruited students, 37 completed the survey. METHODS: Students were randomly assigned to test the software (experimental group) and to solve printed clinical cases (comparison group). A pretest and post-test were applied before and after the experiment. Statistical analyses of the students' performance in the tests were conducted. The primary outcome was the students' progress in solving questions and clinical cases regarding NDx. The System Usability Scale was used to measure the software's ease of use. RESULTS: No significant difference was found between the experimental and comparison groups before and after the experiment. The average students' performance in identifying RF and NDx was higher than in identifying DC. The post-test score was higher than the pretest score in both groups (P=0.022). The usability score was good (average score 83.75, N=20). CONCLUSION: The use of Wise Nurse supported an improvement in student diagnostic reasoning equivalent to that of the traditional NDx training, but the software stands out as an innovative teaching tool. PMID- 26573152 TI - Variant of PAI-2 gene is associated with coronary artery disease and recurrent coronary event risk in Chinese Han population. AB - BACKGROUND: Plasminogen activator inhibitor -2 (PAI-2) is an important molecular that plays a crucial role in vascular homeostasis and constitutes a critical response mechanism to cardiovascular injury, such as atherosclerosis, coronary artery disease (CAD). METHODS: The aim of the current study was to explore the association between the variants in PAI-2 gene and CAD and its prognoses. The three variants (rs8093048, rs9946657, rs9320032) of the PAI-2 gene were detected in 407 patients with CAD and 518 control subjects. All patients with CAD underwent one-year follow-up for major adverse cardiac events (MACE). RESULTS: The frequencies of the TT genotype and T allele of rs8093048 was significantly higher in CAD patients than that in control subjects (7.6% vs.3.5%, P = 0.003, 28.1 % vs.21.7%, P < 0.001, respectively). Multifactor logistic regression analysis showed that the TT genotype of rs8093048 was a risk factor for CAD (OR = 1.455, 95 % CI: 1.069-1.980, P = 0.017). In addition, the follow-up data showed that CAD patients with rs8093048 TT genotype had significantly higher rate of refractory angina and MACE than those with CC or CT genotype (P = 0.032, P = 0.009, respectively). Cox regression analysis showed that rs8093048 TT genotype was the risk factor for the MACE (Hazard ratio = 5.672, 95% CI = 1.992-16.152, P = 0.001). CONCLUSION: We firstly found that the variant of PAI-2 gene was associated with CAD and recurrent coronary event risk in Chinese Han population, in Xinjiang. PMID- 26573153 TI - A randomised controlled trial: can acupuncture reduce drug requirement during analgosedation with propofol and alfentanil for colonoscopy? A study protocol. AB - BACKGROUND: The number of colonoscopies tremendously increased in recent years and will further rise in the near future. Because of patients' growing expectation on comfort during medical procedures, it is not surprising that the demand for sedation also expands. Propofol in combination with alfentanil is known to provide excellent analgosedation, however, its use is associated with respiratory and cardiovascular depression. Acupuncture could be a technique to reduce drug requirement while providing the same level of sedation and analgesia. METHODS/DESIGN: The study will be performed as a single centre, randomised, placebo controlled trial. 153 patients scheduled for propofol/alfentanil sedation during colonoscopy will be randomly assigned to receive electroacupuncture (P6, ST36, LI4), sham acupuncture, or placebo acupuncture. Following endoscopy patients and gastroenterologists have to fill in questionnaires about their sedation experiences. Additionally, patients have to accomplish the Trieger test before and after the procedure. Patient monitoring includes time adapted HR, SpO2, ECG, NIBP, exCO2, OAA/S, and the Aldrete score. The primary outcome parameter is the dosage of propofol necessary for an adequate level of sedation to tolerate the procedure (OAA/S < 4). Effectiveness of sedation, classified by satisfaction levels measured by questionnaires is the secondary outcome parameter. DISCUSSION: Moderate to deep sedation using propofol is increasingly applied during colonoscopies with a high satisfaction level among patients despite well-known hemodynamic and respiratory side effects of this hypnotic agent. Acupuncture is known to attenuate gastrointestinal discomfort and pain. We hypothesize that the combination of conventional sedation techniques with acupuncture may result in equally satisfied patients with a lower risk of respiratory and hemodynamic events during colonoscopies. TRIAL REGISTRATION: This trial is registered in the Nederland's Trial Register NTR 4325 . The first patient was randomized on 13 February 2014. PMID- 26573154 TI - Critical Time Intervention for People Leaving Shelters in the Netherlands: Assessing Fidelity and Exploring Facilitators and Barriers. AB - International dissemination of evidence-based interventions calls for rigorous evaluation. As part of an evaluation of critical time intervention (CTI) for homeless people and abused women leaving Dutch shelters, this study assessed fidelity in two service delivery systems and explored factors influencing model adherence. Data collection entailed chart review (n = 70) and two focus groups with CTI workers (n = 11). The intervention obtained an overall score of three out of five (fairly implemented) for compliance fidelity and chart quality combined. Fidelity did not differ significantly between service systems, supporting its suitability for a range of populations. The eight themes that emerged from the focus groups as affecting model adherence provide guidance for future implementation efforts. PMID- 26573155 TI - Histopathologic ear findings of syphilis: a temporal bone study. AB - To the best of our knowledge, histopathologic studies of syphilitic ears have generally focused on hydropic changes; so far, no such studies have investigated peripheral vestibular otopathology using differential interference contrast microscopy, in patients with syphilis. For this study, we examined 13 human temporal bone samples from 8 patients with a history of syphilis. Using conventional light microscopy, we performed qualitative histopathologic assessment. In addition, using differential interference contrast microscopy, we performed type I and type II vestibular hair cell counts on each vestibular sense organ with minimal autolysis; in which the neuroepithelium was oriented perpendicular to the plane of section. We then compared vestibular hair cell densities (cells per 0.01 mm2 surface area) in the syphilis group vs. the control group. In the syphilis group, we observed precipitate in the endolymphatic or perilymphatic spaces in 1 (7.7 %) of the samples and endolymphatic hydrops in eight (61.5 %) of the samples. Hydrops involved the cochlea (four samples) and/or saccule (four samples). In addition, the syphilis group experienced a significant loss of type II vestibular hair cells in the maculae of the utricle and saccule, and in the cristae of the lateral and posterior semicircular canals, as compared with the control group (P < 0.05). PMID- 26573156 TI - Short, sharp shock public health campaign had limited impact on raising awareness of laryngeal cancer. AB - Laryngeal cancer has poorer outcomes if diagnosed at a later stage. Improving awareness could encourage earlier presentation and improve outcomes. This study aimed to evaluate a public engagement campaign targeted at raising awareness of laryngeal cancer. An epidemiological study identified high-risk populations in the region. A target population as well as a matched control population was selected. A cancer awareness survey combined with focus groups guided the design of a 3-month multimedia campaign. The survey was repeated post-campaign to evaluate the campaign effectiveness. The study identified populations with the highest rates of laryngeal cancer and late stage disease at presentation. The surveys performed revealed a limited effect of the multimedia campaign in raising awareness of the signs and symptoms of laryngeal cancer. Recall of the campaign also faded rapidly. This is the first public awareness campaign aimed at laryngeal cancer carried out in the UK. The results suggest that short-term campaigns have a limited effect and a more prolonged approach should be considered. PMID- 26573157 TI - Instrumentation of Flow-Through USP IV Dissolution Apparatus to Assess Poorly Soluble Basic Drug Products: a Technical Note. AB - Supersaturation and precipitation are common limitations encountered especially with poorly soluble basic drugs. The aims of this work were to explore the pattern of dissolution and precipitation of poorly soluble basic drugs using a United States Pharmacopoeia (USP) IV dissolution apparatus and to compare it to the widely used USP II dissolution apparatus. In order to investigate the influence of gastric emptying time on bioavailability, tables of two model drugs (dipyridamole 100 mg and cinnarizine 15 mg) were investigated and pH change from 1.2 to 6.8 were achieved after 10, 20 or 30 min using USP II or USP IV dissolution apparatuses. Using USP II, dipyridamole and cinnarizine concentrations dropped instantly as a result of drug precipitation with drug crystals evident in the dissolution vessel. At pH change times of 10, 20 and 30 min, the total amount of dissolved drug was dependent on pH change time. Using USP IV, at a flow rate of 8 ml/min, it was possible to have comparable release to agitation at 50 rpm using USP II suggesting that comparable hydrodynamic forces are possible. No drop in drug percentage occurs as the dissolved fraction was readily emptied from the flow cell, preventing drug accumulation in the dissolution medium. However, a negligible percentage of drug release took place following pH change. In conclusion, the use of the flow-through cell dissolution provided laminar flow, use of realistic fluid volumes and avoided precipitation of dissolved drug fraction in the gastric phase as it is discharged before pH change. PMID- 26573158 TI - Rat Palatability Study for Taste Assessment of Caffeine Citrate Formulation Prepared via Hot-Melt Extrusion Technology. AB - Developing a pediatric oral formulation with an age-appropriate dosage form and taste masking of naturally bitter active pharmaceutical ingredients (APIs) are key challenges for formulation scientists. Several techniques are used for taste masking of bitter APIs to improve formulation palatability; however, not all the techniques are applicable to pediatric dosage forms because of the limitations on the kind and concentration of the excipients that can be used. Hot-melt extrusion (HME) technology is used successfully for taste masking of bitter APIs and overcomes some of the limitations of the existing taste-masking techniques. Likewise, analytical taste assessment is an important quality control parameter evaluated by several in vivo and in vitro methods, such as the human taste panel, electrophysiological methods, electronic sensor, and animal preference tests to aid in selecting a taste-masked formulation. However, the most appropriate in vivo method to assess the taste-masking efficacy of pediatric formulations remains unknown because it is not known to what extent the human taste panel/electronic tongue can predict the palatability in the pediatric patients. The purpose of this study was to develop taste-masked caffeine citrate extrudates via HME and to demonstrate the wide applicability of a single bottle-test rat model to record and compare the volume consumed of the taste-masked solutions to that of the pure API. Thus, this rat model can be considered as a low-cost alternative taste-assessment method to the most commonly used expensive human taste panel/electronic tongue method for pediatric formulations. PMID- 26573159 TI - Efavirenz Self-Nano-Emulsifying Drug Delivery System: In Vitro and In Vivo Evaluation. AB - Self-emulsifying drug delivery system (SEDDS) is the isotropic and thermodynamically stable mixture of oil, surfactant, co-solvent/surfactant, and drug. It emulsifies spontaneously when introduced into an aqueous phase under a mild agitation. The current study was aimed to prepare SNEDDS to augment solubility, release rate, and oral bioavailability of BCS class II drug, efavirenz (EFV). A series of oil, surfactant, and co-surfactant was screened out by a ternary phase diagram to locate a better homogenous mixture. The prepared SNEDDS was evaluated regarding its appearance, mean droplet size, phase separation, in vitro drug release, and oral bioavailability. Among the screened oil, surfactant, and co-surfactant, Labrafil M 2125 CS, Tween 80, and Transcutol(r)P mixture exhibited superior solubilizing capacity, respectively. Optimized SNEDDS exhibits 98.39% drug release. SNEDDS dissolution behavior was attributed to oil/surfactant ratios and properties of the surfactant phase. It also demonstrates threefold increments in the area under curve (AUC) in comparison to neat EFV. Furthermore, the optimized SNEDDS does not show any vitrification during its 3-month storage. In the present study, better performance of SNEDDS is explained by various factors like (i) improved surface area of droplets, (ii) superior solubilization potential for hydrophobic drugs due to Labrafil M 2125 CS, and (iii) result of surfactant on mucosal permeability. This study demonstrated that SNEDDS may be an alternative approach for the poorly soluble drugs to improve their solubility and oral bioavailability. PMID- 26573161 TI - Congenital Scoliosis. AB - Congenital scoliosis is a lateral deformity of the spine with a disturbance of the sagittal profile caused by malformations of vertebra and ribs. Typically, early surgical intervention is the suggested treatment (before three-years-old) for young patients with congenital scoliosis. While a previous study was conducted in 2011 to investigate long-term studies supporting the necessity for this recommendation and no evidence was found , this current review, is an updated search for evidence published from 2011 through March 2015. This also failed to find any prospective or randomized controlled studies to support the hypothesis that spinal fusion surgery in patients with congenital scoliosis should be considered as evidence-based treatment. Contradictory results exist on the safety of hemivertebra resection and segmental fusion using pedicle screw fixation. When using the VEPTR (vertical expandable prosthetic titanium rib) device, studies show a high rate of complications exist. It is difficult to predict the final outcome for patients with congenital scoliosis. However, it is possible that many patients with congenital scoliosis may be able to avoid spinal surgery with the application of advanced bracing technology [5]. Therefore, it is only prudent to advocate for conservative management first before spinal surgery is considered. PMID- 26573160 TI - NRP1 is targeted by miR-130a and miR-130b, and is associated with multidrug resistance in epithelial ovarian cancer based on integrated gene network analysis. AB - Multidrug resistance (MDR) in epithelial ovarian cancer (EOC) remains a public health issue for women worldwide, and its molecular mechanisms remain to be fully elucidated. The present study aimed to predict the potential genes involved in MDR, and examine the mechanisms underlying MDR in EOC using bioinformatics techniques. In the present study, four public microarray datasets, including GSE41499, GSE33482, GSE15372 and GSE28739, available in Gene Expression Omnibus were downloaded, and 11 microRNAs (miRNA; miRs), including miR-130a, miR-214, let 7i, miR-125b, miR-376c, miR-199a, miR-93, miR-141, miR-130b, miR-193b* and miR 200c, from previously published reports in PubMed were used to perform a comprehensive bioinformatics analysis through gene expression analysis, signaling pathway analysis, literature co-occurrence and miRNA-mRNA interaction networks. The results demonstrated that the expression of neuropilin 1 (NRP1) was upregulated, thereby acting as the most important hub gene in the integrated gene network. NRP1 was targeted by miR-130a and miR-130b at the binding site of chromosome 10: 33466864-3466870, which was involved in the axon guidance signaling pathway. These results suggested that alteration of the gene expression levels of NRP1 expression may contribute to MDR in EOC. These data provide important information for further experimental investigations of the drug resistance-associated functions of NRP1 in EOC. PMID- 26573162 TI - Bracing Scoliosis - State of the Art. AB - : Spinal bracing is indicated in moderate to severe curves during growth. Brace effectiveness in halting progression of adolescent idiopathic scolisosis has been shown in a Cochrane review and in a randomized controlled trial (RCT). The outcome of brace treatment is dependent on the extent of in-brace correction and compliance. We have reviewed the literature on bracing to determine the types of brace that offer the best in-brace correction. MATERIALS AND METHODS: The literature has been searched for papers on bracing with documented in-brace corrections and long-term results . RESULTS: The in-brace percentage of correction of asymmetric braces is generally higher than that of the symmetric braces. According to the literature found in our search, long-term corrections are possible when starting treatment early, at an immature stage and with asymmetric braces of recent standards. CONCLUSIONS: Bracing today is supported by high quality evidence (Level I). Asymmetric braces have led to better corrections than that described for symmetric braces . An improvement of the average corrective effect has been described due to the latest CAD / CAM development. Long-term corrections are possible when starting brace treatment early, at an immature stage and with asymmetric braces of recent standards. PMID- 26573163 TI - Rehabilitation of Adolescents with Scoliosis During Growth - Preliminary Results Using a Novel Standardized Approach in Russia. (Methodology). AB - BACKGROUND: The aim of this study is to evaluate the effect of a Schroth Best Practice(r) program in an out-patient regimen on the signs of scoliosis in patients with adolescent idiopathic scoliosis (hereafter referred to as AIS). The second aim is to evaluate in-brace correction with the Gensingen Brace(r) in the first sample of patients with AIS. Both authors have undergone training in this special approach to scoliosis rehabilitation. The first author has undergone PT (physical therapy) and CAD-CAM (computer-aided design and manufacturing)bracing training, the second author PT training. MATERIALS AND METHODS: 23 patients with AIS, 19 girls and 4 boys, with an average age of 13.6 years, average Risser sign of 2.52 and an average Cobb angle of 36.9 degrees (20-88 degrees), underwent an out-patient Schroth Best Practice(r) program with an intensity of two days a week of 2 x 60 min sessions/day. The angle of trunk rotation (ATR) was measured before and after the course. Eleven of the patients were fit with Gensingen Braces(r). Braces were produced via CAD-CAM. In-brace correction was measured and compared with initial data. RESULTS: After an out-patient Schroth Best Practice(r) program ATR was reduced significantly from 9.58 degrees to 7.47 degrees in thoracic and from 8.9 to 6.6 degrees in lumbar. An average in-brace correction of 59% was achieved in CADCAM braces. DISCUSSION: The results achieved with out-patient rehabilitation in the investigations published previously are repeatable. The deformity of the trunk can be reduced significantly after out-patient rehabilitation according to Schroth Best Practice(r) standards. In-brace correction comparable with published results on CAD-CAM bracing can be achieved in braces according to Gensingen(r) standards after appropriate training. CONCLUSION: Out-patient rehabilitation following the Schroth Best Practice(r) standards seems to provide an improvement of signs of scoliosis patients in this study using a pre-/post prospective design. The results of the recent studies on Schroth Best Practice(r) program seem to be repeatable. Following appropriate training, the in-brace corrections achieved with the CAD / CAM technology can be compared to the in-brace corrections as published in recent literature. CAD / CAM allows for repeatable results globally. PMID- 26573164 TI - Observation and Early Intervention in Mild Idiopathic Scoliosis via Corrective Exercises in Growing Children. AB - Idiopathic scoliosis afflicts 2-3% of the population. For mild curvatures, observation is the treatment of choice. Though this passive "wait and see" approach has been used for many years, the practice is inconsistent among different countries. In Anglo-Saxon countries where scoliosis specific exercises are not practised, observation is indicated for curvatures below 25 degrees in growing children and adolescents. In countries, such as France, Germany, Italy and Poland where scoliosis specific corrective exercises are employed, only patients with no signs of maturity and with curvatures below 15 degrees are treated by observation. Patients with curvatures between 15 - 25 degrees are treated by scoliosis specific exercises. In view of the unpredictability of the progression of scoliosis curvatures in immature patients and the lack of knowledge of long term biomechanical repercussions of mild idiopathic scoliosis on lumbar spine and lower extremities, it is proposed that active intervention through scoliosis specific exercises rather than passive observation be employed in the treatment of mild adolescent idiopathic scoliosis. PMID- 26573165 TI - The Influence of Short-Term Scoliosis-Specific Exercise Rehabilitation on Pulmonary Function in Patients with AIS. AB - OBJECTIVE: To investigate the short-term outcomes of treatment utilizing an outpatient scoliosis- specific back school program in thirty-six patients with adolescent idiopathic scoliosis (AIS). BACKGROUND: Improved signs and symptoms of AIS have been reported in response to curve-patternspecific exercise therapy programs. Additional outcome studies are needed. METHODS/MATERIALS: Thirty-six patients with adolescent idiopathic scoliosis (AIS), 33 females and 3 males, completed a twenty-hour multimodal exercise program (Schroth Best Practice(r) - SBP) for five to seven days at Scoliosis 3DC(SM). Average age was 13.89 years and average Cobb angles were 36.92 degrees thoracic and 33.92 degrees lumbar. The sample was comprised of patients under treatment from August 2011 to February 2015 who never had scoliosis-related surgery and who were not undergoing brace treatment. SBP program components included physio-logic(r) exercises, mobilizations, activities of daily living (ADLs), 3-D Made Easy(r), and Schroth exercises. Forced vital capacity (FVC), forced expiratory volume in one second (FEV1), chest expansion (CE), and angle of trunk rotation (ATR) were clinical parameters used to evaluate results of this outpatient scoliosis-specific exercise program. RESULTS: Highly significant improvements were noted in FVC, FEV1, CE and Scoliometer(TM) readings. CONCLUSIONS: A short-term outpatient SBP program was found to have a positive influence on FVC, FEV1, ATR, and CE. We will present long-term results in a subsequent study. PMID- 26573166 TI - Postural Re-Education of Scoliosis - State of the Art (Mini-review). AB - A new development of correcting exercises has been derived from the original Schroth program in 2010 and the preliminary results have been published that year. Since then the program has been applied in some centers worldwide. As the original Schroth program was the only program so far to improve many signs and symptoms of scoliosis besides the angle of curvature (Cobb angle) it was interesting to look for the preliminary results of the recent development of scoliosis pattern specific corrective exercises derived from the original program, to see if similar effects can be achieved with this less complicated method. METHODS: A manual search in Pubmed was conducted, using the key words, Schroth, rehabilitation, and idiopathic scoliosis. Three papers have been found describing the short-term results of this new development today called Schroth Best Practice program (SBP). The papers were reviewed and analyzed with respect to the outcome parameters used. RESULTS: Outcome parameters were Angle of Trunk Rotation (ATR), Vital Capacity (VC), surface topography, electromyography, stabilometry and Cobb angle before and after a course of treatment. There was a significant improvement of all parameters after the application of this new program in all the three papers in the short- to mid-term. CONCLUSIONS: Scoliosis corrective exercises are supported by two randomized controlled trials (RCT) and should regularly be applied in mild scoliosis at risk for progression. Unspecific exercises such as Yoga, Dobomed cannot be regarded as effective as exercises using a well defined scoliosis pattern specific corrective routine. PMID- 26573167 TI - Evidence for Conservative Treatment of Adolescent Idiopathic Scoliosis - Update 2015 (Mini-Review). AB - Idiopathic scoliosis predominantly afflicts adolescents. Adolescents with mild curvatures do not generally have any symptoms. However spinal fusion is indicated when the deformity exceeds 45 degrees . Treatment is thus necessary to prevent and/or reduce the progression of curvatures to that below which surgery is indicated. Conservative treatment of adolescent idiopathic scoliosis includes observation, scoliosis-specific exercises (SSE) and bracing. There is increasing evidence suggesting that SSE and brace treatment can significantly limit the progression of spinal curvatures. In growing adolescents with curvatures more than 20 degrees , bracing is indicated and should be used in conjunction with SSE. The effectiveness of bracing varies according to the type of brace applied to the patient. In general rigid braces are preferable to soft flexible braces, as the latter falls short of halting curvatures progression. Also, preliminary evidence suggests that asymmetric braces which enable over-correction provide more correction when compared with symmetrical braces. Recently it has also been reported that high quality bracing can also reduce curvatures exceeding 45 degrees in over 70% of growing adolescents. This new knowledge might possibly increase the threshold of surgical indications to beyond 50 degrees or above in the near future. PMID- 26573168 TI - Glucose sensors based on electrospun nanofibers: a review. AB - The worldwide increase in the number of people suffering from diabetes has been the driving force for the development of glucose sensors. The recent past has devised various approaches to formulate glucose sensors using various nanostructure materials. This review presents a combined survey of these various approaches, with emphasis on the current progress in the use of electrospun nanofibers and their composites. Outstanding characteristics of electrospun nanofibers, including high surface area, porosity, flexibility, cost effectiveness, and portable nature, make them a good choice for sensor applications. Particularly, their nature of possessing a high surface area makes them the right fit for large immobilization sites, resulting in increased interaction with analytes. Thus, these electrospun nanofiber-based glucose sensors present a number of advantages, including increased life time, which is greatly needed for practical applications. Taking all these facts into consideration, we have highlighted the latest significant developments in the field of glucose sensors across diverse approaches. PMID- 26573169 TI - High mass accuracy assay for trimethylamine N-oxide using stable-isotope dilution with liquid chromatography coupled to orthogonal acceleration time of flight mass spectrometry with multiple reaction monitoring. AB - Trimethylamine N-oxide (TMAO) has attracted interest as circulating levels have reported prognostic value in patients with cardiovascular conditions, such as heart failure. With continual advances in accurate mass measurements, robust methods that can employ the capabilities of time of flight mass spectrometers would offer additional utility in the analysis of complex clinical samples. A Waters Acquity UPLC was coupled to a Waters Synapt G2-S high-resolution mass spectrometer. TMAO was measured in plasma by stable-isotope dilution-hydrophilic interaction liquid chromatography-time of flight mass spectrometry with multiple reaction monitoring (LC-ToF-MRM). Two transitions were monitored: m/z 76.1 to 58.066/59.073 and m/z 85.1 to 66.116/68.130. The method was assessed for linearity, lower limits of detection and quantitation, and reproducibility. A selected cohort of patients with systolic heart failure (SHF; n = 43) and healthy controls (n = 42) were measured to verify the assay is suitable for the analysis of clinical samples. Quantitative analysis of TMAO using LC-ToF-MRM enabled linearity to be established between 0.1 and 75 MUmol/L, with a lower limit of detection of 0.05 MUmol/L. Relative standard deviations reported an inter-day variation of <=20.8% and an intra-day variation of <=11.4% with an intra-study quality control variation of 2.7%. Run times were 2.5 min. Clinical application of the method reported that TMAO in SHF was elevated compared to that of healthy controls (p < 0.0005). LC-ToF-MRM offers a highly selective method for accurate mass measurement of TMAO with rapid and reproducible results. Applicability of the method was shown in a selected cohort of patient samples. PMID- 26573170 TI - Acellular reactivity of polymeric dendrimer nanoparticles as an indicator of oxidative stress in vitro. AB - The need for rapid and cost-effective pre-screening protocols of the toxicological response of the vast array of emerging nanoparticle types is apparent and the emerging consensus on the paradigm of oxidative stress by generation of intracellular reactive oxygen species as a primary source of the toxic response suggests the development of acellular assays to screen for nanoparticle surface reactivity. This study explores the potential of the monoamine oxidase A (MAO-A) enzyme-based assay with polymeric dendrimers as cofactors and serotonin as substrate, which generates H2O2, quantified by the conversion of the Carboxy-H2DCFDA dye to its fluorescent form. A range of generations of both PAMAM (poly(amidoamine)) (G4-G7) and PPI (poly(propylene imine)) (G0-G4) dendritic polymer nanoparticles are used as test particles to validate the quantitative nature of the assay response as a function of nanoparticle physico-chemical properties. The assay is well behaved as a function of dose over low dose ranges and the acellular reaction rate (ARR) is well correlated with the number of surface amino groups for the combined dendrimer series. For each series, the ARR is also well correlated with the previously documented cytotoxicity, although the correlation is substantially different for each series of dendrimers, pointing to the additional importance of cellular uptake rates in the determination of toxicity. PMID- 26573171 TI - Penetrable silica microspheres for immobilization of bovine serum albumin and their application to the study of the interaction between imatinib mesylate and protein by frontal affinity chromatography. AB - In the current study, novel featured silica, named penetrable silica, simultaneously containing macropores and mesopores, was immobilized with bovine serum albumin (BSA) via Schiff base method. The obtained BSA-SiO2 was employed as the high-performance liquid chromatographic (HPLC) stationary phase. Firstly, D- and L-tryptophan were used as probes to investigate the chiral separation ability of the BSA-SiO2 stationary phase. An excellent enantioseparation factor was obtained up to 4.3 with acceptable stability within at least 1 month. Next, the BSA-SiO2 stationary phase was applied to study the interaction between imatinib mesylate (IM) and BSA by frontal affinity chromatography. A single type of binding site was found for IM with the immobilized BSA, and the hydrogen-bonding and van der Waals interactions were expected to be contributing interactions based on the thermodynamic studies, and this was a spontaneous process. Compared to the traditional silica for HPLC stationary phase, the proposed penetrable silica microsphere possessed a larger capacity to bond more BSA, minimizing column overloading effects and enhancing enantioseparation ability. In addition, the lower running column back pressure and fast mass transfer were meaningful for the column stability and lifetime. It was a good substrate to immobilize biomolecules for fast chiral resolution and screening drug-protein interactions. PMID- 26573172 TI - Metabolic footprinting for investigation of antifungal properties of Lactobacillus paracasei. AB - Lactic acid bacteria with antifungal properties are applied for biopreservation of food. In order to further our understanding of their antifungal mechanism, there is an ongoing search for bioactive molecules. With a focus on the metabolites formed, bioassay-guided fractionation and comprehensive screening have identified compounds as antifungal. Although these are active, the compounds have been found in concentrations that are too low to account for the observed antifungal effect. It has been hypothesized that the formation of metabolites and consumption of nutrients during bacterial fermentations form the basis for the antifungal effect, i.e., the composition of the exometabolome. To build a more comprehensive view of the chemical changes induced by bacterial fermentation and the effects on mold growth, a strategy for correlating the exometabolomic profiles with mold growth was applied. The antifungal properties were assessed by measuring mold growth of two Penicillium strains on cell-free ferments of three strains of Lactobacillus paracasei pre-fermented in a chemically defined medium. Exometabolomic profiling was performed by reversed-phase liquid chromatography in combination with mass spectrometry in electrospray positive and negative modes. By multivariate data analysis, the three strains of Lb. paracasei were readily distinguished by the relative difference of their exometabolomes. The relative differences correlated with the relative growth of the two Penicillium strains. Metabolic footprinting proved to be a supplement to bioassay-guided fractionation for investigation of antifungal properties of bacterial ferments. Additionally, three previously identified and three novel antifungal metabolites from Lb. paracasei and their potential precursors were detected and assigned using the strategy. PMID- 26573173 TI - Dynamics of colloid accumulation under flow over porous obstacles. AB - The accumulation of colloidal particles to build dense structures from dilute suspensions may follow distinct routes. The mechanical, structural and geometrical properties of these structures depend on local hydrodynamics and colloidal interactions. Using model suspensions flowing into microfabricated porous obstacles, we investigate this interplay by tuning both the flow pattern and the ionic strength. We observe the formation of a large diversity of shapes, and demonstrate that growing structures in turn influence the local velocity pattern, favouring particle deposition either locally or over a wide front. We also show that these structures are labile, stabilised by the flow pushing on them, in low ionic strength conditions, or cohesive, in a gel-like state, at higher ionic strength. The interplay between aggregate cohesion and erosion thus selects preferential growth modes and therefore dictates the final shape of the structure. PMID- 26573174 TI - A Systematic Review of Patient-reported Outcomes in Randomized Controlled Trials of Unplanned General Surgery. AB - Unplanned general surgery represents a major workload and requires comprehensive evaluation with appropriate outcomes. This study aimed to summarize current reporting of patient-reported outcomes (PROs) in randomized clinical trials (RCTs) in unplanned general surgery. A systematic review identified RCTs reporting PROs in the commonest six areas of unplanned general surgery. Details of the PRO measures were examined using the CONSORT extension for PRO reporting in RCTs. Extracted information about each PRO domain included the reporting of baseline PROs, rationale for PRO selection and whether PRO findings were used in conjunction with clinical outcomes to inform treatment recommendations. The internal validity of included studies was assessed using the Cochrane risk of bias tool. 12,519 abstracts were screened and 20 RCTs containing data from 2037 patients included. Included studies used 14 separate PRO measures covering 35 different health domains. A visual analogue assessment of pain was most frequently reported (n = 13). Reporting of baseline PRO data was uncommon (11/35 PRO domains). The rationale for PRO data collection and a PRO-specific hypothesis were provided for 9 (25.7 %) and 5 (14.3 %) domains, respectively. Seventeen RCTs (85.0 %) used the PRO data alongside clinical outcomes to inform treatment recommendations. Of the 116 risk of bias assessments, 77 (66.0 %) were judged as high or unclear. There is a lack of well designed, and conducted RCTs in unplanned general surgery that include PROs. Future work to define relevant PROs and methods for optimal assessment are needed to inform health care decision making. PMID- 26573175 TI - High Rate of Organ/Space Surgical Site Infection After Hepatectomy with Preexisting Bilioenteric Anastomosis. AB - BACKGROUND: The clinical course of hepatectomy in patients with preexisting bilioenteric anastomosis (BEA) is poorly understood. The aim of this study was to evaluate the potential influence of preexisting BEA on organ/space surgical site infection (SSI) after hepatectomy. METHODS: We analyzed consecutive hepatectomies performed between March 2005 and January 2015. Patients' background, operative results, and complications were compared between hepatectomies with and without preexisting BEA. RESULTS: Twenty-two hepatectomies with preexisting BEA were identified among 1745 hepatectomies. The rate of organ/space SSI was much higher in hepatectomies with preexisting BEA than in those without preexisting BEA (40.9 vs. 6.4 %, P < 0.001). Multivariate analyses identified four variables as independent factors associated with organ/space SSI: liver-directed chemotherapy [odds ratio 5.06 (95 % confidence interval 2.29-10.54), P < 0.001], operative time >= 300 min [2.40 (1.30-4.54), P = 0.006], estimated blood loss >= 500 ml [2.34 (1.26-4.31), P < 0.001], and preexisting BEA [12.08 (4.54-31.32), P < 0.001]. A higher rate of organisms from intestinal flora was detected in organ/space SSI after hepatectomies with preexisting BEA (77.8 vs. 21.3 % without BEA, P = 0.002). Analysis of hepatectomies with preexisting BEA identified selection of antibiotics for prophylaxis as the sole risk factor for organ/space SSI (P = 0.049 for cefazolin versus other antibiotics targeting intestinal flora). CONCLUSIONS: Preexisting BEA is an independent risk factor for the development of organ/space SSI after hepatectomy. Antibiotics targeting intestinal flora are strongly recommended for prophylaxis of infectious complications. PMID- 26573176 TI - Treatment potential of the GLP-1 receptor agonists in type 2 diabetes mellitus: a review. AB - Over the last decade, the discovery of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) has increased the treatment options for patients with type 2 diabetes mellitus (T2DM). GLP-1 RAs mimic the effects of native GLP-1, which increases insulin secretion, inhibits glucagon secretion, increases satiety and slows gastric emptying. This review evaluates the phase III trials for all approved GLP 1 RAs and reports that all GLP-1 RAs decrease HbA1c, fasting plasma glucose, and lead to a reduction in body weight in the majority of trials. The most common adverse events are nausea and other gastrointestinal discomfort, while hypoglycaemia is rarely reported when GLP-1 RAs not are combined with sulfonylurea or insulin. Treatment options in the near future will include co formulations of basal insulin and a GLP-1 RA. PMID- 26573177 TI - Ref. Lu et al. Clothing resultant thermal insulation determined on a movable thermal manikin. Part I: effects of wind and body movement on total insulation. IJB. PMID- 26573178 TI - Management of Pseudomonas aeruginosa infection in cystic fibrosis patients using inhaled antibiotics with a focus on nebulized liposomal amikacin. AB - Pseudomonas aeruginosa (PsA) is a highly prevalent bacterial organism recovered from the lungs of cystic fibrosis (CF) patients and chronic PsA infection is linked to progressive pulmonary function decline. The eradication and treatment of this organism from CF airways is particularly challenging to CF care providers. Aerosolized antibiotics that target PsA help to slow down growth, maintain lung function and reduce the frequency of pulmonary exacerbations. In this review, we discuss the currently available inhaled antibiotics for management of PsA lung infections in CF patients, with a focus on liposomal amikacin for inhalation (LAI). LAI is a unique formulation of amikacin under development that enhances drug delivery and retention in CF airways via drug incorporation into neutral liposomes. Factors such as once-daily dosing, mucus and biofilm penetration and potentially prolonged off-drug periods make LAI a potentially attractive option to manage chronic PsA lung infections in CF patients. PMID- 26573179 TI - PON1 Q192R genetic variant and response to clopidogrel and prasugrel: pharmacokinetics, pharmacodynamics, and a meta-analysis of clinical outcomes. AB - Clopidogrel and prasugrel are antiplatelet therapies commonly used to treat patients with cardiovascular disease. They are both pro-drugs requiring biotransformation into active metabolites. It has been proposed that a genetic variant Q192R (rs662 A>G) in PON1 significantly alters the biotransformation of clopidogrel and affects clinical outcomes; however, this assertion has limited support. The relationship between this variant and clinical outcomes with prasugrel has not been studied. We genotyped PON1 Q192R in 275 healthy subjects treated with clopidogrel or prasugrel and 2922 patients with an ACS undergoing PCI randomized to treatment with clopidogrel or prasugrel in the TRITON-TIMI 38 trial. A meta-analysis was performed including 13 studies and 16,760 clopidogrel treated patients. Among clopidogrel-treated subjects, there were no associations between Q192R and active drug metabolite levels (P = 0.62) or change in platelet aggregation (P = 0.51). Consistent with these results, in clopidogrel-treated patients in TRITON-TIMI 38, there was no association between Q192R and the rates of CV death, myocardial infarction, or stroke (RR 11.2 %, QR 8.6 %, and QQ 9.3 %; P = 0.66) or stent thrombosis (RR 2.4 %, QR 0.7 %, and QQ 1.6 %, P = 0.30), with patients with the putative at-risk Q variant having numerically lower event rates. Likewise, among prasugrel-treated subjects, there were no associations between Q192R and active drug metabolite levels (P = 0.88), change in platelet aggregation (P = 0.97), or clinical outcomes (P = 0.72). In a meta-analysis, the Q variant was not significantly associated with MACE (QQ vs. RR 1.22, 95 % CI 0.84-1.76) or stent thrombosis (QQ vs. RR OR 1.36, 95 % CI 0.77-2.38). Furthermore, when restricted to the validation studies, the OR (95 % CI) for MACE and stent thrombosis were 0.99 (0.77-1.27) and 1.23 (0.74-2.03), respectively. In the present study, the Q192R genetic variant in PON1 was not associated with the pharmacologic or clinical response to clopidogrel, nor was it associated with the response to prasugrel. The meta-analysis reinforced a lack of a significant association between Q192R and cardiovascular outcomes in clopidogrel-treated patients. PMID- 26573180 TI - The impact of schistosomes and schistosomiasis on murine blood coagulation and fibrinolysis as determined by thromboelastography (TEG). AB - Schistosomes are parasitic platyhelminths that currently infect over 200 million people and cause the chronic debilitating disease schistosomiasis. While these large intravascular parasites can disturb blood flow, surprisingly they do not appear to provoke thrombus formation around them in vivo. In order to determine if the worms can alter their local environment to impede coagulation, we incubated adult worms (50 pairs) in murine blood (500 ul) for 1 h at 37 degrees C and, using thromboelastography (TEG), we compared the coagulation profile of the blood with control blood that never contained worms. Substantial differences were apparent between the two profiles. Blood that had been exposed to schistosomes clotted more slowly and yielded relatively poor, though stable, thrombi; all TEG measures of blood coagulation (R, K, alpha-angle, MA, G and TMA) differed significantly between conditions. No fibrinolysis (as determined by LY30 and LY60 values) was detected in either case. The observed TEG profile suggests that the worms are acting as local anti-coagulants. Blood recovered from schistosome-infected mice, however, does not behave in this way. At an early time point post infection (4-weeks), the TEG profile of infected murine blood is essentially the same as that of control blood. However at a later time point (7 weeks) infected murine blood clots significantly faster than control blood but these clots also break down faster. The R, K, alpha-angle, and TMA measures of coagulation are all significantly different between the control versus infected mice as are the LY30 and LY60 values. This profile is indicative of a hypercoagulable state with fibrinolysis and is akin to that seen in human patients with advanced schistosomiasis. PMID- 26573181 TI - Determining organisation-specific factors for developing health interventions in companies by a Delphi procedure: Organisational Mapping. AB - Companies, seen as social communities, are major health promotion contexts. However, health promotion in the work setting is often less successful than intended. An optimal adjustment to the organisational context is required. Knowledge of which organisation-specific factors are relevant to health promotion is scarce. A Delphi procedure is used to identify these factors. The aim is to contribute to more effective workplace health promotion. The identified factors are described and embedded into a practical methodology (Intervention Mapping). A systematic use of these factors (called 'Organisational Mapping') is likely to contribute to more effective health promotion in the work setting. PMID- 26573182 TI - Endocrine control of energy homeostasis. PMID- 26573183 TI - Electronic Conductivity, Ferrimagnetic Ordering, and Reductive Insertion Mediated by Organic Mixed-Valence in a Ferric Semiquinoid Metal-Organic Framework. AB - A three-dimensional network solid composed of Fe(III) centers and paramagnetic semiquinoid linkers, (NBu4)2Fe(III)2(dhbq)3 (dhbq(2-/3-) = 2,5 dioxidobenzoquinone/1,2-dioxido-4,5-semiquinone), is shown to exhibit a conductivity of 0.16 +/- 0.01 S/cm at 298 K, one of the highest values yet observed for a metal-organic framework (MOF). The origin of this electronic conductivity is determined to be ligand mixed-valency, which is characterized using a suite of spectroscopic techniques, slow-scan cyclic voltammetry, and variable-temperature conductivity and magnetic susceptibility measurements. Importantly, UV-vis-NIR diffuse reflectance measurements reveal the first observation of Robin-Day Class II/III mixed valency in a MOF. Pursuit of stoichiometric control over the ligand redox states resulted in synthesis of the reduced framework material Na0.9(NBu4)1.8Fe(III)2(dhbq)3. Differences in electronic conductivity and magnetic ordering temperature between the two compounds are investigated and correlated to the relative ratio of the two different ligand redox states. Overall, the transition metal-semiquinoid system is established as a particularly promising scaffold for achieving tunable long range electronic communication in MOFs. PMID- 26573184 TI - [Management of liver failure by a multidisciplinary team approach]. PMID- 26573185 TI - [Diagnosis of and multimodality therapy for hepatorenal syndrome]. PMID- 26573186 TI - [Diagnosis and multimodality therapy for non-alcoholic fatty liver disease]. PMID- 26573187 TI - [Perspectives on the multidisciplinary treatment approach for hepatocellular carcinoma]. PMID- 26573188 TI - [A randomized controlled trial on 240-week monotherapy with entecavir or adefovir in patients with chronic hepatitis B and cirrhosis]. AB - OBJECTIVE: To compare the efficacies ofentecavir and adefovir in patients with chronic hepatitis B (CHB) and cirrhosis when administered as monotherapies using a 240-week course. METHODS: Ninety patients diagnosed with CHB and cirrhosis (compensated or decompensated) were randomly divided into two treatment groups for administration of either entecavir (0.5 mg/day, oral; n =38) or adefovir (10 mg/day, oral; n =52) for 240 weeks. All participants underwent B-ultrasound and were tested for levels of HBV-DNA, alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen, creatinine, alpha-fetoprotein (AFP) and various serological markers of the hepatitis B virus at baseline and at treatment weeks 24, 48, 96, 144, 192, and 240. Instances of drug-related complications and adverse reactions were recorded. Patients who did not achieve complete virological response by treatment week 48 or who experienced virological breakthrough at any time during the study course were recorded and started on an appropriate combination therapy regimen. Statistical analyses were carried out using the t-test, chi-square test, and Cox regression modeling. RESULTS: The dropout rate in the entecavir group was 2.6% and in the adefovir group was 13.5%. At treatment week 240, significantly more patients in the entecavir group had undetectable serum HBV-DNA (91.9% vs. adefovir group: 57.8%; x2=10.362, P=0.001), a negative conversion rate of hepatitis B e antigen (HBeAg) (46.2% vs. adefovir group: 24%; x2=5.055, P=0.025), and rate of HBeAg seroconversion (23.1% vs. adefovir group: 8%, P=0.047).The entecavir group and the adefovir group showed no significant differences upon per-protocol analysis and intention-to-treat analysis, nor in the rates of hepatocellular carcinoma development (entecavir group: 8.1% vs. adefovir group: 6.7%; x2=0.000, P=1.000) or mortality (entecavir group: 8.1% vs. adefovir group: 4.4%; x2=0.051, P=0.821). The possibility of achieving undetectable serum HBV-DNA was 2.761 times higher in the entecavir group than in the adefovir group (95.0% CI: 1.630 to 4.679). The possibility of HBeAg seroconversion was 0.192 times higher for males than for females (95.0% CI: 0.046 to 0.806). CONCLUSION: Compared to adefovir, entecavir provides high efficiency and rapid viral suppression as a monotherapy for CHB patients when administered in a 240-week course. PMID- 26573189 TI - [Diagnostic value of FibroTest for liver fibrosis in patients with chronic hepatitis B]. AB - OBJECTIVE: To determine the diagnostic value of FibroTest (FT) for liver fibrosis in patients with chronic hepatitis B (CHB). METHODS: One hundred and forty-two patients with CHB were tested for the following five indicators: alpha2 microglobulin (a2-MG), haptoglobin (Hp), gamma-glutarnyl peptidase (GGT), total bilirubin (TBIL), and apolipoprotein A1 (ApoA1). The resultant data, along with the age and sex of the patients, were put into an algorithm to compute the final results of the FT. During the same period of FT, all of the CHB patients underwent liver stiffness measurement by FibroScan (FS) as well as liver biopsy. Considering the liver biopsy as the gold standard, we determined receiver operating characteristic (ROC) curves at different endpoints. Calculation of the area under the ROC curves (AUROC) was performed to evaluate the diagnostic importance of FT, FS towards the treatment of liver fibrosis in patients with CHB. RESULTS: Significant fibrosis (Scheuer score (S) more than or equal to 2) was predicted with an AUROC for FS, FT of 0.827 (0.753-0.900), 0.897 (0.844 0.949). Significant fibrosis (S more than or equal to 3) was predicted with an AUROC for FS, FT of 0.883 (0.818-0.949), 0.968 (0.932-1.00). Significant fibrosis (S=4) was predicted with an AUROC for FS, FT of 0.943 (0.893-0.993), 0.991 (0.973 1.00). CONCLUSION: s FT is a novel tool that can be used to assess the degree of fibrosis in patients with CHB. PMID- 26573190 TI - [Imaging features of factors related to blood supply from right inferior hepatic artery branches in hepatocellular carcinoma]. AB - OBJECTIVE: To analyze the angiographic features and factors related to the blood supply from right inferior phrenic artery (RIPA) branches in hepatocellular carcinoma (HCC). METHODS: Angiography images of blood supply from RIPA branches and clinical data from patients with HCC who had undergone tmnscatheter arterial chemoembolization in our hospital between 2009 and 2013 were collected for retrospective analysis. Angiographic features of the RIPA branches were assessed for correlation between treatment number, growth pattern, size, tumor location, and rates of blood supplying RIPA branches. Statistical analyses were carried out using chi-square test, t-test, Fisher's exact test and rank sum test. RESULTS: The 140 patients included in the analysis were grouped according to primary HCC (n=63; group A) and recurrent HCC (n=77; group B) and no statistically significant differences were found between the two groups for incidence of each nutrient branch or total number of nutrient branches. In group A, tumor size was associated with number of nutrient branches (P=0.047). There were 32 cases with HCC lesions in the bare area of the liver, and among those 26 of the cases were supplied by the posterior branch of RIPA. Each branch of RIPA showed greater firequency for particular blood supply areas; the anterior branch (n=55) and lateral branch (n=98) fed tumor lesions in segments 7 and 8, the posterior branch (n=98) fed tumor lesions in segments 6 and 7, and the supra-renal branch (n=10) fed tumor lesions in segment 6. The diaphragmatic branch always fed HCC partly located in segments 4 and 8 (n=17). Unique features were present on the digitally subtracted angiography (DSA) image for each nutrient branch and may be useful for distinguishing in clinical examination. CONCLUSION: Cases of primary HCC and recurrent HCC are not distinguishable by incidence of each nutrient branch or total numbers of the nutrient branches. However, tumor size is related to the number of RIPA nutrient branches, and each RIPA nutrient branch shows a dominant preference for certain blood supply areas, with unique features on DSA. PMID- 26573191 TI - [Regulatory role of serum miR-224 in invasiveness and metastasis of cholangiocarcinoma]. AB - OBJECTIVE: To investigate the expression profile of serum micro (mi)RNAs in cholangiocarcinoma (CCA) and investigate the regulatory contribution of miRNAs to the invasive and metastasis. METHODS: Microarray analysis was carried out using serum samples collected from 30 patients with CCA, bile duct cancer tissues and the corresponding normal tissues collected from 10 patients, and serum samples from 50 healthy volunteers. The miRNAs identified as dysregulated in CCA were verified by RT-PCR. Focused analysis on miR-224 was carried out using the human CCA cell lines HCCC-9810 and RBE to investigate the role of this miRNA in IL-6 expression (using IL-6 induction), cell growth, invasiveness and metastasis (using miR-224 mimic transfection). The one-way ANOVA test was used for statistical analysis. RESULTS: Forty-three miRNAs were dysregulated in CCA (vs. non-CCA, P<0.01), of which 22 were upregulated and 21 were downregulated. RT-PCR data showed that the miR-224 was significantly upregulated in serum as well as in cancer tissue from CCA patients. Induction of HCCC-9810 and RBE cells with IL-6 showed a time-dependent upregulation of miR-224. Furthermore, the HCCC-9810 and RBE cells transfected with miR-224 mimic showed enhanced cell growth, invasiveness and migratory ability. CONCLUSION: IL-6 may promote the invasive and metastatic properties of CCA through upregulated miR-224. Studies of the differentially expressed serum miRNAs in CCA may help to further elucidate the pathogenic processes of this disease and aid in the development of a novel and effective therapeutic strategy. PMID- 26573192 TI - [Body mass index is a risk factor for new-onset non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus]. AB - OBJECTIVE: To investigate the effect of body mass index (BMI) on new-onset non alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM). METHODS: Subjects with T2DM were recruited from the population of individuals attending the Affiliated General Hospital of North China University for routine health examination between 2006 and 2007 and offered participation in this community-based prospective cohort study. Enrollees were categorized into groups according to weight assessed by baseline BMI (underweight, normal, overweight, and obese groups). Cumulative incidence of NAFLD was compared between each group and the effect of baseline BMI on new-onset NAFLD was assessed by Cox regression analysis. RESULTS: The cumulative incidence of NAFLD increased in conjunction with increases in weight (low weight: 69%, normal weight: 73%, overweight: 90%, obese: 97%; P<0.01). Subjects in the overweight and obese groups showed an increased risk of NAFLD (relative risk (RR)=2.00, 95% CI: 1.76-2.29 and =2.87, 95% CI: 2.42-3.40; P<0.01), compared to those in the normal weight group. Moreover, after adjustment for baseline factors (e.g.age, sex) risk of NAFLD remained higher for the overweight and obese subjects (RR=1.73, 95% CI: 1.49-2.00 and =2.12, 95% CI: 1.73-2.60; P<0.01). CONCLUSION: Risk of NAFLD in T2DM patients increases in parallel to increase in weight assessed by BMI. BMI appeared to be an independent risk factor for NAFLD. PMID- 26573193 TI - [Relationship of socioeconomic status and non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus]. AB - OBJECTIVE: To explore the relationship between socioeconomic status (SES) and non alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM). METHODS: The medical records of Tianjin Third Central Hospital were retrospectively reviewed to identify patients who had been hospitalized for treatment of T2DM but without diagnosis of NAFLD between 2007 and 2012 and who had required a second hospitalization during this same period. Each patient was contacted by telephone for self-reporting of SES. Analysis was carried out with patients grouped according to SES (high vs. low) to determine association of SES with incidence of NAFLD at the second hospitalization; the relative risk (RR), attributable risk (AR) and attributable risk percent (ARP) were calculated. Furthermore, the correlation of SES with other clinical and socio-psychological variables was assessed. RESULTS: The patients in the high and low SES groups showed no significant differences at baseline. For development of NAFLD by the time of the second hospitalization, the low SES group had an RR of 2.19, an AR of 20.74%, and an ARP of 54.39%. Correlation analysis showed that SES was positively correlated with body mass index (r=-0.582) and levels of glycated hemoglobin (r= 0.421), fasting serum insulin (r=-0.570), insulin resistance (as assessed by the HOMA method) (r=-0.487), low-density lipopmtein (r=-0.396) and C-reactive protein (r=-0.353) (all P<0.05), and negatively correlated with high-density lipopmtein (r =0.539) and with the scores for physical functioning (r =0.241), general health (r=0.234), social functioning (r =0.286), emotional health (r=0.251), and mental health (r=0.215) (all P<0.05). CONCLUSION: SES is an influencing factor of NAFLD in patients with T2DM and is closely related to obesity, insulin resistance, lipid metabolic disorder, chronic inflammation and life quality in patients with NAFLD and T2DM. PMID- 26573194 TI - [Role of the Notch signaling pathway in development of acute liver failure in a mouse model]. AB - OBJECTIVE: To investigate the role of the Notch signaling pathway, and the underlying mechanism, in development of acute liver failure (ALF) in a mouse model. METHODS: For in vivo analysis of the role of Notch signaling in ALF, a mouse model of ALF was generated by intraperitoneal injection of 3.0 g/kg D galactosamine. Histological specimens were stained by hematoxylin-eosin, and then studied microscopically.Expression level of Jaggedl, Notchl, NICD, and Hes5 was measured by western blotting (for protein) and real time-PCR (for mRNA). The level of CD68 protein was detected by immunohistochemical staining. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), IL-10, high mobility group box 1 (HMGB1) chromatin protein, and lipopolysaccharide (LPS) were measured by standard methods. For in vitro analysis of the molecular mechanism, the RAW264.7 macrophage cell line was cultured with LPS in the absence or presence of the Notch inhibitor DAPT, and the intracellular levels of Notch1, NICD, and Hes5 were measured by western blotting and real time-PCR and the extracellular levels of IL-10 and HMGB1 were detected in the supematant. RESULTS: Compared with unmodeled (normal control) mice, the ALF modeled mice showed higher levels of serum ALT (848.40+/-94.83 U/L vs. 38.99+/-9.63 U/L), AST (911.49+/ 67.65 U/L vs. 55.28+/-7.50 U/L), HMGB1 (101.91+/-12.43 ug/L vs. 20.73+/-5.37 ug/L), 1L-10 (4 627.88+/-842.45 pg/mL vs. 1 064.92+/-238.46 pg/mL) and LPS (11.80+/-0.89 EU/mL vs. 0.58+/-0.12 EU/mL), as well as higher expression of Jagged1 (mRNA: 7.63+/-1.41 vs. 1.00+/-0.00; protein: 0.71+/-0.07 vs. 0.34+/ 0.07), Notch1 (mRNA: 7.10+/-0.66 vs. 1.00+/-0.00; protein: 0.66+/-0.11 vs. 0.27+/ 0.08), NICD (protein: 0.76+/-0.08 vs. 0.27+/-0.08), Hes5 (mRNA: 7.95+/-0.71 vs. 1.00+/-0.00; protein: 1.20+/-0.07 vs. 0.76+/-0.07), and CD68 (protein: 7 685.05+/ 417.34 vs. 2 294.01+/-392.93) (all P<0.01). In vitro, LPS increased the extracellular levels of HMGB1 (7.44+/-0.63 vs. 0.21+/-0.05), IL-10 (315.19+/ 79.13 vs. 59.19+/-23.30) and the intracellular expression of Notch1 (mRNA: 6.49+/ 0.73 vs. 1.00+/-0.00), NICD (protein: 0.65+/-0.10 vs. 0.23+/-0.07), and Hes5 (mRNA: 7.30+/-0.85 vs. 1.00+/-0.00; protein: 0.96+/-0.10 vs. 0.54+/-0.07) (all P<0.01). DAPT treatment led to a decrease above the index serum levels of HMGB1 (6.22+/-0.71) and IL-10 (252.06+/-57.63), and of expression of Notch 1 (mRNA: 3.20+/-0.68), NICD (protein: 0.42+/-0.05), and Hes5 (mRNA: 4.72+/-0.67; protein: 0.84+/-0.09) (P<0.01 or <0.05). CONCLUSION: The Notch signaling pathway may plan an important role in the development of ALF upon activation of the pathway in macrophages by LPS and leading to promoted secretion of HMGB 1 and IL-10, with a greater effect on the former. PMID- 26573196 TI - [Retrospective study on efficacy and safety of the sequential use of a non bioartificial liver support system in the treatment of acute fatty liver during pregnancy]. PMID- 26573195 TI - [Role of SREBP-1c in risk of liver disease associated with the triacylglycerol lipase PNPLA3 I148M variant]. AB - OBJECTIVE: To investigate the relationship between SREBP-1c and the risk of liver disease associated with the triacylglyceride lipase PNPLA3 I148M variant using a human hepatoma cell line model transfected with recombinant lentiviruses. METHODS: Huh7 cells were transfected with control lentivirus or lentivirus containing the PNPLA3 I148M variant (variant). The two cell groups were compared to assess differences in triglyceride content (using oil red O staining), levels of triglyceride and cholesterol (using automated biochemical analyzer), expression of SREBP-lc mRNA (using fluorescence quantitative PCR), and expression of SREBP-1c protein (using western blot. RESULTS: Cells expressing the PNPLA3 I148M variant showed higher triglyceride content (0.54+/-0.03 mmol/L vs. control cells: 0.23+/-0.02 mmol/L; t=22.58, P<0.001), cholesterol level (0.28+/-0.03 mmol/L vs. control cells: 0.13+/-0.02 mmol/L; t =11.83, P<0.001), SREBP-1cmRNA expression (13.59+/-0.60 vs. 11.81+/-0.82; [The abstract and text in the paper say variant increases, but the data shown says the higher value is in the control cells. Please correct to properly express the data.] P=0.001), and SREBP-1c protein expression. The level of SREBP-1c was positively correlated with serum triglyceride in the cells expressing the PNPLA3 I148M variant (r=0.912, P<0.01). CONCLUSION: The risk of liver disease associated with the PNPLA3 I148M variant, which increases lipogenesis, may involve SREBP-1c and a pathway that increases triglycerides. PMID- 26573197 TI - [Expression of cannabinoid receptors in hepatic stellate cells of patients with chronic hepatitis B and significance for progression of liver fibrosis]. PMID- 26573198 TI - [Antitumor activity of siRNAs targeting ALCAM in HepG2 liver cancer cells in vitro and in vivo]. PMID- 26573199 TI - [Apoptosis-stimulating protein of p53 (ASPP2) inhibits tumor growth]. PMID- 26573200 TI - [A case report of immune thrombocytopenia with drug induced liver disease]. PMID- 26573201 TI - [Brief introduction of 2015 international symposium: autoimmune diseases in the liver]. PMID- 26573202 TI - [Self-regulation of the renin-angiotensin system and liver fibrosis: clinical implications]. PMID- 26573203 TI - [Role of extracellular histones in liver failure]. PMID- 26573204 TI - [Clinical significance of abnormal Wnt signaling pathway expression in hepatitis and hepatocellular carcinoma]. PMID- 26573205 TI - Malignancy risk of anti-tumor necrosis factor alpha blockers: an overview of systematic reviews and meta-analyses. AB - The objective of the study is to systematically review the malignancy risk of anti-tumor necrosis factor alpha (anti-TNFalpha) agents. Databases of PubMed Medline, OVID EMBASE, and Cochrane Library were searched to identify published systematic reviews and meta-analyses of randomized control trials, observational studies, and case series that evaluated malignancy risk of anti-TNFalpha blockers. Search time duration was restricted from January 1st, 2000 to July 16th, 2015. Overview Quality Assessment Questionnaires were used to assess the quality of included reviews. Two methodology trained reviewers separately and repeatedly screened searched studies according to study selection criteria, collected data, and assessed quality. Totally, 42 reviews proved eligible with only one Cochrane review. Anti-TNFalpha antagonists were extensively used to treat various diseases; nevertheless, malignancy risks were most commonly described in patients with rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). In RA patients, no increased risks of breast cancer, lymphoma, and non-melanoma skin cancer were found, but if the use of anti-TNFalpha agents was associated with elevated risk of overall malignancy was still uncertainty. In IBD patients, the use of anti-TNFalpha inhibitors was not connected with enhanced risk of overall cancer. No increased cancer risk was found in other disease conditions. Twenty-nine reviews were rated as good quality, 12 as moderate, and one as poor. There are no sufficient evidences to draw the conclusion that anti TNFalpha blockers have relationship with increased malignancy risk. PMID- 26573206 TI - Rheumatic manifestations in inflammatory bowel diseases: a link between GI and rheumatology. AB - Musculoskeletal symptoms are the most frequent extra-intestinal manifestations of inflammatory bowel disease (IBD), ranging between 10 and 40 % of cases. Pathogenesis is still unclear, although several factors have been associated (genetic, environmental, and immunologic pathways). Rheumatic manifestations in IBD patients are heterogeneous, including axial and peripheral involvement, dactylitis, enthesitis, uveitis, as well as skin involvement. Currently, magnetic resonance imaging and ultrasonography are important tools for detecting early pathological changes in IBD patients with suspected rheumatic disease. New advances into the genetics and pathophysiology have provided more effective and targeted therapy for IBD patients with rheumatic manifestations. Given the high prevalence, awareness of the musculoskeletal symptoms is essential to avoid a misdiagnosis. Finally, an interdisciplinary approach of IBD patients, including rheumatologist and gastroenterologist, will improve the quality of life these patients. PMID- 26573207 TI - Growth and nutritional risk in children with developmental delay. AB - INTRODUCTION: Nutritional risk impacts outcome in developmental delay. The main objectives were to identify the incidence and factors contributing to growth faltering. METHODS: Clinical data review was completed for 500 patients with developmental delay accepted to an Early Intervention service. Data was collected using the standardised parent nutrition screening checklist prior to and at time of initial dietary assessment. Data was compared to nutritional assessment data, GOSH and FSAI dietary guidelines. Weight category was determined using RCPCH growth and BMI charts. Statistical analysis was conducted using Statistical Package for the Social Sciences version 20 (IBM Statistics 20.0). RESULTS: Nutritional risk was identified in 48.6 %. Weight categories were growth faltering (13.5 %), underweight (7.7 %), overweight (8.4 %) and obesity (4.3 %) at initial assessment. Growth faltering was correlated with age <1 year (p = 0.000) and with gestational age (p = 0.017) with highest rates identified in those born 32-36 weeks (3.6 %). Weight category was associated with introduction of solids pre 17 weeks recommendation (10.1 %), ANOVA demonstrating significance (P = 0.013). There was poor parental recognition of nutritional risk in 22.7 % of those assessed. Nutritional difficulties were common: 4.2 % were enterally fed, 7.7 % were on prescribed nutritional supplements, 29.1 % (n = 121) had feeding difficulties and 13.9 % (n = 58) had behavioural feeding difficulties. Iron intake did not meet the recommended intake in 20.9 % (n = 87), calcium in 4.5 % (n = 19). The prevalence of constipation was 21.6, 11.8 % of whom required medical management. CONCLUSIONS: Developmental delay predisposes to nutritional deficits which influence outcome. Screening, assessment and timely interventions are warranted to prevent poorer developmental outcomes. PMID- 26573208 TI - Cuticular Hydrocarbons as Potential Close Range Recognition Cues in Orchid Bees. AB - Male Neotropical orchid bees collect volatile chemicals from their environment and compose species-specific volatile signals, which are subsequently exposed during courtship display. These perfumes are hypothesized to serve as attractants and may play a role in female mate choice. Here, we investigated the potential of cuticular hydrocarbons as additional recognition cues. The cuticular hydrocarbons of males of 35 species belonging to four of the five extant euglossine bee genera consisted of aliphatic hydrocarbons ranging in chain lengths between 21 and 37 C atoms in distinct compositions, especially between sympatric species of similar coloring and size, for all but one case. Cleptoparasitic Exaerete spp. had divergent profiles, with major compounds predominantly constituted by longer hydrocarbon chains (>30 C-atoms), which may represent an adaptation to the parasitic life history ("chemical insignificance"). Phylogenetic comparative analyses imply that the chemical profiles exhibited by Exaerete spp. are evolutionarily divergent from the rest of the group. Female hydrocarbon profiles were not identical to male profiles in the investigated species, with either partial or complete separation between sexes in multivariate analyses. Sexually dimorphic hydrocarbon profiles are assumed to be the basis for sex recognition in a number of insects, and thus may supplement the acquired perfume phenotypes in chemical information transfer. Overall, cuticular hydrocarbons meet the requirements to function as intraspecific and intersexual close range recognition signals; behavioral experiments are needed to determine their potential involvement in mate recognition. PMID- 26573209 TI - NIM811 downregulates transforming growth factor-beta signal transduction in vivo and in vitro. AB - Liver fibrosis is the common histological feature of a number of chronic liver diseases, and leads to cirrhosis and hepatocellular carcinoma (HCC). It has been demonstrated that N-methyl-4-isoleucine cyclosporine (NIM811) attenuates CCl4 induced liver fibrosis and inflammation in rats. The present study investigated whether NIM811 downregulated transforming growth factor (TGF)-beta signaling in rats with CCl4-induced liver fibrosis and in HSC-T6 cells. Liver tissues were obtained from rats with CCl4-induced liver fibrosis, with or without NIM811 treatment. HSC-T6 cells were cultured with or without NIM811 for 18 h under serum free conditions. Expression of collagen I, alpha-smooth muscle actin (alpha-SMA), TGF-beta1, TGF-beta receptor I (TbetaR-I) and TGF-beta pathway downstream signaling molecules were measured by reverse transcription-quantitative polymerase chain reaction and/or western blotting. Collagen I and TGF-beta1 content in the cell supernatant was measured by ELISA. NIM811 profoundly inhibited collagen I, alpha-SMA, TGF-beta1 and TbetaR-I expression in the liver of CCl4-treated rats. Phosphorylation of Smad2, 3 and 1/5/8 was decreased in the liver of NIM811-treated groups, accompanied by increased In addition, Smad7 expression compared with the CCl4-treated rats. NIM811 inhibited collagen I, TGF beta1 and TbetaR-I expression in HSC-T6 cells. Smad1 mRNA and phospho-Smad1/5/8 protein levels decreased following NIM811 treatment, accompanied by increased Smad7 expression in HSC-T6 cells compared with normal controls. Furthermore, NIM811 also inhibited collagen I mRNA expression in the liver of rats with CCl4 induced liver fibrosis and in HSC-T6 cells. The results suggest that the antifibrotic effect of NIM811 was due to the inhibition of TGF-beta1 and its downstream signaling molecules. PMID- 26573211 TI - Modeling [(18)F]-FDG lymphoid tissue kinetics to characterize nonhuman primate immune response to Middle East respiratory syndrome-coronavirus aerosol challenge. AB - BACKGROUND: The pathogenesis and immune response to Middle East respiratory syndrome (MERS) caused by a recently discovered coronavirus, MERS-CoV, have not been fully characterized because a suitable animal model is currently not available. (18)F-Fluorodeoxyglucose ([(18)F]-FDG)-positron emission tomography/computed tomography (PET/CT) as a longitudinal noninvasive approach can be beneficial in providing biomarkers for host immune response. [(18)F]-FDG uptake is increased in activated immune cells in response to virus entry and can be localized by PET imaging. We used [(18)F]-FDG-PET/CT to investigate the host response developing in nonhuman primates after MERS-CoV exposure and applied kinetic modeling to monitor the influx rate constant (K i ) in responsive lymphoid tissue. METHODS: Multiple [(18)F]-FDG-PET and CT images were acquired on a PET/CT clinical scanner modified to operate in a biosafety level 4 environment prior to and up to 29 days after MERS-CoV aerosol exposure. Time activity curves of various lymphoid tissues were reconstructed to follow the [(18)F]-FDG uptake for approximately 60 min (3,600 s). Image-derived input function was used to calculate K i for lymphoid tissues by Patlak plot. RESULTS: Two-way repeated measures analysis of variance revealed alterations in K i that was associated with the time point (p < 0.001) after virus exposure and the location of lymphoid tissue (p = 0.0004). As revealed by a statistically significant interaction (p < 0.0001) between these two factors, the pattern of K i changes over time differed between three locations but not between subjects. A distinguished pattern of statistically significant elevation in K i was observed in mediastinal lymph nodes (LNs) that correlated to K i changes in axillary LNs. Changes in LNs K i were concurrent with elevations of monocytes in peripheral blood. CONCLUSIONS: [(18)F]-FDG-PET is able to detect subtle changes in host immune response to contain a subclinical virus infection. Full quantitative analysis is the preferred approach rather than semiquantitative analysis using standardized uptake value for detection of the immune response to the virus. PMID- 26573212 TI - Effects of UV-B and heavy metals on nitrogen and phosphorus metabolism in three cyanobacteria. AB - Cyanobacteria sp. (diazotrophic and planktonic) hold a major position in ecosystem, former one due to their intrinsic capability of N2-fixation and later because of mineralization of organic matter. Unfortunately, their exposure to variety of abiotic stresses is unavoidable. Comparative analysis of interactive effect of UV-B and heavy metals (Cd/Zn) on nitrogen and phosphorus metabolism of three cyanobacteria (Anabaena, Microcystis, Nostoc) revealed additive inhibition (chi(2) significant p < 0.05) of NH4(+) and PO4(3-) uptake whereas increase in nitrate uptake upon UV-B + heavy metal exposure. Glutamine synthetase and Alkaline phosphatase activity was reduced after all treatments whereas Nitrate reductase activity showed slight stimulation in UV-B and UV-B + heavy metals treatment. Combination of UV-B and metals seems more detrimental to the NH4(+), PO4(3-) uptake, GS and APA activity. A significant stimulation in NO3(-) uptake and NR activity following exposure to UV-B in all the three cyanobacteria suggests UV-B-induced structural change(s) in the enzyme/carriers. Metals seem to compete for the binding sites of the enzymes and carriers; as noticed for Anabaena and Microcystis showing change in Km while no change in the Km value of Nostoc suggests non-competitive nutrient uptake. Higher accumulation and more adverse effect on Na(+) and K(+) efflux proposes Cd as more toxic compared to Zn. PMID- 26573213 TI - The Effect of Exposed Facets of Ceria to the Nickel Species in Nickel-Ceria Catalysts and Their Performance in a NO + CO Reaction. AB - CeO2 rods with {110} facets and cubes with {100} facets were utilized as catalyst supports to probe the effect of crystallographic facets on the nickel species and the structure-dependent catalytic performance. Various analysis methods (ex and in situ XRD, TEM, Raman, XPS, TPR, TPD) were used to investigate the structural forms of the catalysts, and these results indicated that the deposition of nickel species resulted in the formation of two main active types of the catalyst components: NiO strongly or weakly interacted with the surface and Ni-Ce-O solid solution. Notably, the states and distribution ratio of nickel species were related to the shape of CeO2. It was found that CeO2 rods had more active sites to coordinate with nickel species to form a strong interaction with NiO on the surface and a more stable construction when compared to cubes. Furthermore, the nickel-ceria catalysts with rod shape were more active towards NO oxidation with complete conversion below 191 degrees C, but for cube shape, complete conversion occurred above 229 degrees C (e.g., for nickel loading of ~5%, the complete conversion temperature was 154 degrees C for the rod shape and 229 degrees C for the cube shape). On the basis of the analysis of the catalysts structure, the superior catalytic activity was due to a combination of surface structures of NiO (mainly strongly interacting with the surface) and nickel ions Ni(2+) in the Ni Ce-O bulk phase. PMID- 26573214 TI - Endoscopic resection of advanced and laterally spreading duodenal papillary tumors. AB - Historically, neoplasia of the duodenal papilla has been managed surgically, which may be associated with substantial morbidity and mortality. In the absence of invasive cancer, even lesions with extensive lateral duodenal wall involvement, or limited intraductal extension may be cured endoscopically with a superior safety profile. Endoscopic papillectomy is associated with greater risks of adverse events such as bleeding than resection elsewhere in the gastrointestinal tract. Additionally site-specific complications such as pancreatitis exist. A structured approach to lesion assessment, adherence to technical aspects of resection, endoscopic management of complications and post resection surveillance is required. Advances have been made in all facets of endoscopic papillary resection since its introduction in the 1980s; extending the boundaries of endoscopic cure, optimizing outcomes and enhancing patient safety. These will be the focus of the present review. PMID- 26573215 TI - A polymorphism-dependent T(1/2) shift of 100 K in a hysteretic spin-crossover complex related to differences in intermolecular weak CH...X hydrogen bonds (X = S vs. S and N). AB - A neutral mononuclear iron(II) complex with a 1,2,3-triazole-containing tetradentate ligand has been obtained as two solvent-free polymorphs. Both polymorphs show hysteretic spin crossover with a polymorphism-dependent T(1/2) shift of 100 K that spans room temperature due to differences in intermolecular weak CH...X hydrogen-bonding interactions (X = S vs. S and N). PMID- 26573216 TI - Trends in utilisation, perioperative outcomes, and costs of nephroureterectomies in the management of upper tract urothelial carcinoma: a 10-year population-based analysis. AB - OBJECTIVE: To perform a population-based study to evaluate contemporary utilisation trends, morbidity, and costs associated with nephroureterectomies (NUs), as contemporary data for NUs are largely derived from single academic institution series describing the experience of high-volume surgeons and it is unclear if the same favourable results occur at a national level. PATIENTS AND METHODS: Using the Premier Hospital Database, we captured patients undergoing a NU with diagnoses of renal pelvis or ureteric neoplasms from 2004 to 2013. We fitted regression models, adjusting for clustering by hospitals and survey weighting to evaluate 90-day postoperative complications, operating-room time (OT), prolonged length of stay (pLOS), and direct hospital costs among open (ONU), laparoscopic (LNU) and robotic (RNU) approaches. RESULTS: After applying sampling and propensity weights, we derived a final study cohort of 17 254 ONUs, 13 317 LNUs and 3774 RNUs for upper tract urothelial carcinoma (UTUC) in the USA between 2004 and 2013. During that period, minimally invasive NU (miNU) increased from 36% to 54%, while the total number of NUs decreased by nearly 20%. No differences were noted in perioperative outcomes between the three surgical approaches, including when the analysis was restricted to the highest-volume hospitals and highest-volume surgeons. The OT was longer for LNU and RNU (P < 0.001), while the pLOS rates were decreased (P < 0.001). Adjusted 90-day median direct hospital costs were higher for LNU and RNU (P < 0.001), which disappeared when adjusting for the highest-volume groups, except for RNUs performed by high volume surgeons. CONCLUSIONS: During this contemporary 10-year study, miNU has been replacing ONU for UTUC with a recent surge in RNU, along with a concurrent reduction in total NUs performed. Despite not being associated with a clinically significant improvement in perioperative outcomes, the costs for miNUs were consistently higher. However, higher hospital volumes suggest a potential cost containment strategy when performing miNUs. PMID- 26573218 TI - Transcranial Magnetic Stimulation for Parkinson's Disease. PMID- 26573217 TI - Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy. AB - OBJECTIVE: To continue evaluation of the long-term efficacy and safety of eteplirsen, a phosphorodiamidate morpholino oligomer designed to skip DMD exon 51 in patients with Duchenne muscular dystrophy (DMD). Three-year progression of eteplirsen-treated patients was compared to matched historical controls (HC). METHODS: Ambulatory DMD patients who were >=7 years old and amenable to exon 51 skipping were randomized to eteplirsen (30/50mg/kg) or placebo for 24 weeks. Thereafter, all received eteplirsen on an open-label basis. The primary functional assessment in this study was the 6-Minute Walk Test (6MWT). Respiratory muscle function was assessed by pulmonary function testing (PFT). Longitudinal natural history data were used for comparative analysis of 6MWT performance at baseline and months 12, 24, and 36. Patients were matched to the eteplirsen group based on age, corticosteroid use, and genotype. RESULTS: At 36 months, eteplirsen-treated patients (n = 12) demonstrated a statistically significant advantage of 151m (p < 0.01) on 6MWT and experienced a lower incidence of loss of ambulation in comparison to matched HC (n = 13) amenable to exon 51 skipping. PFT results remained relatively stable in eteplirsen-treated patients. Eteplirsen was well tolerated. Analysis of HC confirmed the previously observed change in disease trajectory at age 7 years, and more severe progression was observed in patients with mutations amenable to exon skipping than in those not amenable. The subset of patients amenable to exon 51 skipping showed a more severe disease course than those amenable to any exon skipping. INTERPRETATION: Over 3 years of follow-up, eteplirsen-treated patients showed a slower rate of decline in ambulation assessed by 6MWT compared to untreated matched HC. PMID- 26573219 TI - Local administration of Mitomycin-C-Treated peripheral blood mononuclear cells (PBMCs) prolongs allograft survival in vascularized composite allotransplantation. AB - BACKGROUND: VCA offers a potential treatment for extensive tissue defects. First results of systemic administration of Mitomycin C-treated PBMCs in VCA demonstrated a significant prolongation of allograft survival. The aim of this study is to evaluate if local administration of MMC-PBMCs prolongs allograft survival in allogeneic hind limb transplantations of the rat. METHODS: Sixty allogeneic hind limb transplantations in the rat were performed in six groups. Lewis rats (LEW) were used as hind limb donors and Brown-Norway rats (BN) as recipients. Animals in group A received donor-derived MMC-treated PBMCs locally (i.m.). Group B received no immunosuppressive therapy, group C received a standard immunosuppressive regime consisting of FK506 and Prednisolon, group D (BN to BN) comprised isograft transplantations without immunosuppressive treatment, group E received non-treated PBMCs (i.m.) and group F received phosphate buffered saline (PBS) without cells. The transplanted hind limbs were assessed for color, edema, skin, hair condition, and consistency of the thigh every 8 hours. RESULTS: Rejection in group A was delayed to an average of 7.2 +/- 0.6 days. Survival times were significantly prolonged (P < 0.01) compared to control groups B, E, and F (5.5 +/- 0.7, 5.8 +/- 0.7, and 5.7 +/- 0.5 days). Control groups C and D showed no signs of rejection. CONCLUSION: The findings of this study show that local administration of MMC-PBMCs has no side effects and significantly extends allograft survival. Further experiments with MMC-PBMCs treatments repeated at different time-points and being added to low dose immunosuppressive protocols need to be performed to improve experimental and eventually clinical outcome after VCA. (c) 2015 Wiley Periodicals, Inc. Microsurgery 36:417-425, 2016. PMID- 26573220 TI - Comparative efficacy of esomeprazole and omeprazole: Racemate to single enantiomer switch. AB - BACKGROUND: Both omeprazole and its S enantiomer (esomeprazole) have been available and used to treat symptoms of gastroesophageal reflux disease (GERD) and conditions associated with excessive stomach acid secretion for more than a decade. Controversy exists over improved efficacy of S enantiomer (esomeprazole) over parent racemate (omeprazole). However, a comparison of the clinical outcomes of these products may reveal the rationale for switching from the racemate to single enantiomer. Since enantiomers of omeprazole are equipotent, we compared the outcomes of equal doses of each product to see if both actually differ in their efficacy's or the reported superiority of S enantiomer is just a dose effect. METHODS: A web search was carried out for randomized controlled trials with head-to-head comparisons of omeprazole and S-omeprazole. The data were abstracted and after calculating the odd ratios (OR) for the outcomes reported in each study, the combined overall odd ratios (OR') were estimated. The random effect inverse variance method with omeprazole as the reference (OR" = 1) was used. RESULTS: Out of 1171 studies, 14 were deemed eligible. There was no significant difference in the therapeutic success between omeprazole and S omeprazole as a part of triple therapy for the treatment of H. pylori in both intention-to-treat (OR', 1.06; CI, 0.83, 1.36; p = 0.63) as well as per-protocol analysis (OR', 1.07; CI, 0.84, 1.36; p = 0.57). For the treatment of gastro oesophageal reflux disease, S-omeprazole was significantly but marginally superior to the racemate (OR', 1.18; CI, 1.01, 1.38; p = 0.04). The two products were equipotent in all metrics used to assess intragastric pH except for the % patients maintaining a 24 h gastric pH above 4 (1.57; CI, 1.04, 2.381; p = 0.03). CONCLUSION: The therapeutic benefit of chiral switch of omeprazole is questionable considering the substantially greater economic burden involved. PMID- 26573222 TI - Metabolic Remodeling of Cell-Surface Sialic Acids: Principles, Applications, and Recent Advances. AB - Cell-surface sialic acids are essential in mediating a variety of physiological and pathological processes. Sialic acid chemistry and biology remain challenging to investigate, demanding new tools for probing sialylation in living systems. The metabolic glycan labeling (MGL) strategy has emerged as an invaluable chemical biology tool that enables metabolic installation of useful functionalities into cell-surface sialoglycans by "hijacking" the sialic acid biosynthetic pathway. Here we review the principles of MGL and its applications in study and manipulation of sialic acid function, with an emphasis on recent advances. PMID- 26573221 TI - A comprehensive joint analysis of the long and short RNA transcriptomes of human erythrocytes. AB - BACKGROUND: Human erythrocytes are terminally differentiated, anucleate cells long thought to lack RNAs. However, previous studies have shown the persistence of many small-sized RNAs in erythrocytes. To comprehensively define the erythrocyte transcriptome, we used high-throughput sequencing to identify both short (18-24 nt) and long (>200 nt) RNAs in mature erythrocytes. RESULTS: Analysis of the short RNA transcriptome with miRDeep identified 287 known and 72 putative novel microRNAs. Unexpectedly, we also uncover an extensive repertoire of long erythrocyte RNAs that encode many proteins critical for erythrocyte differentiation and function. Additionally, the erythrocyte long RNA transcriptome is significantly enriched in the erythroid progenitor transcriptome. Joint analysis of both short and long RNAs identified several loci with co-expression of both microRNAs and long RNAs spanning microRNA precursor regions. Within the miR-144/451 locus previously implicated in erythroid development, we observed unique co-expression of several primate-specific noncoding RNAs, including a lncRNA, and miR-4732-5p/-3p. We show that miR-4732-3p targets both SMAD2 and SMAD4, two critical components of the TGF-beta pathway implicated in erythropoiesis. Furthermore, miR-4732-3p represses SMAD2/4 dependent TGF-beta signaling, thereby promoting cell proliferation during erythroid differentiation. CONCLUSIONS: Our study presents the most extensive profiling of erythrocyte RNAs to date, and describes primate-specific interactions between the key modulator miR-4732-3p and TGF-beta signaling during human erythropoiesis. PMID- 26573223 TI - Accrual Index: A Real-Time Measure of the Timeliness of Clinical Study Enrollment. AB - BACKGROUND: Achieving timely accrual into clinical research studies remains a challenge for clinical translational research. We developed an evaluation measure, the Accrual Index (AI), normalized for sample size and study duration, using data from the protocol and study management databases. We applied the AI retrospectively and prospectively to assess its utility. METHODS: Accrual Target, Projected Time to Accrual Completion (PTAC), Evaluable Subjects, Dates of Recruitment Initiation, Analysis, and Completion were defined. AI is (% Accrual Target accrued/% PTAC elapsed). Changes to recruitment practices were described, and data extracted from study management databases. RESULTS: December 2014 (or final) AI was analyzed for 101 studies initiating recruitment from 2007 to 2014. Median AI was >=1 for protocols initiating recruitment in 2011, 2013, and 2014. The AI varied widely for studies pre-2013. Studies with AI > 4 utilized convenience samples for recruitment. Data-justified PTAC was refined in 2013-2014 after which the AI range narrowed. Protocol characteristics were not associated with study AI. CONCLUSION: Protocol AI reflects the relative agreement between accrual feasibility assessment (PTAC), and accrual performance, and is affected by recruitment practices. The AI may be useful in managing accountability, modeling accrual, allocating recruitment resources, and testing innovations in recruitment practices. PMID- 26573225 TI - Abcg2-Labeled Cells Contribute to Different Cell Populations in the Embryonic and Adult Heart. AB - ATP-binding cassette transporter subfamily G member 2 (Abcg2)-expressing cardiac side population cells have been identified in the developing and adult heart, although the role they play in mammalian heart growth and regeneration remains unclear. In this study, we use genetic lineage tracing to follow the cell fate of Abcg2-expressing cells in the embryonic and adult heart. During cardiac embryogenesis, the Abcg2 lineage gives rise to multiple cardiovascular cell types, including cardiomyocytes, endothelial cells, and vascular smooth muscle cells. This capacity for Abcg2-expressing cells to contribute to cardiomyocytes decreases rapidly during the postnatal period. We further tested the role of the Abcg2 lineage following myocardial injury. One month following ischemia reperfusion injury, Abcg2-expressing cells contributed significantly to the endothelial cell lineage, however, there was no contribution to regenerated cardiomyocytes. Furthermore, consistent with previous results showing that Abcg2 plays an important cytoprotective role during oxidative stress, we show an increase in Abcg2 labeling of the vasculature, a decrease in the scar area, and a moderate improvement in cardiac function following myocardial injury. We have uncovered a difference in the capacity of Abcg2-expressing cells to generate the cardiovascular lineages during embryogenesis, postnatal growth, and cardiac regeneration. PMID- 26573226 TI - Five omic technologies are concordant in differentiating the biochemical characteristics of the berries of five grapevine (Vitis vinifera L.) cultivars. AB - BACKGROUND: Grape cultivars and wines are distinguishable by their color, flavor and aroma profiles. Omic analyses (transcripts, proteins and metabolites) are powerful tools for assessing biochemical differences in biological systems. RESULTS: Berry skins of red- (Cabernet Sauvignon, Merlot, Pinot Noir) and white skinned (Chardonnay, Semillon) wine grapes were harvested near optimum maturity ( degrees Brix-to-titratable acidity ratio) from the same experimental vineyard. The cultivars were exposed to a mild, seasonal water-deficit treatment from fruit set until harvest in 2011. Identical sample aliquots were analyzed for transcripts by grapevine whole-genome oligonucleotide microarray and RNAseq technologies, proteins by nano-liquid chromatography-mass spectroscopy, and metabolites by gas chromatography-mass spectroscopy and liquid chromatography mass spectroscopy. Principal components analysis of each of five Omic technologies showed similar results across cultivars in all Omic datasets. Comparison of the processed data of genes mapped in RNAseq and microarray data revealed a strong Pearson's correlation (0.80). The exclusion of probesets associated with genes with potential for cross-hybridization on the microarray improved the correlation to 0.93. The overall concordance of protein with transcript data was low with a Pearson's correlation of 0.27 and 0.24 for the RNAseq and microarray data, respectively. Integration of metabolite with protein and transcript data produced an expected model of phenylpropanoid biosynthesis, which distinguished red from white grapes, yet provided detail of individual cultivar differences. The mild water deficit treatment did not significantly alter the abundance of proteins or metabolites measured in the five cultivars, but did have a small effect on gene expression. CONCLUSIONS: The five Omic technologies were consistent in distinguishing cultivar variation. There was high concordance between transcriptomic technologies, but generally protein abundance did not correlate well with transcript abundance. The integration of multiple high-throughput Omic datasets revealed complex biochemical variation amongst five cultivars of an ancient and economically important crop species. PMID- 26573228 TI - LPS-induced TNF-alpha factor mediates pro-inflammatory and pro-fibrogenic pattern in non-alcoholic fatty liver disease. AB - Lipopolysaccharide (LPS) is currently considered one of the major players in non alcoholic fatty liver disease (NAFLD) pathogenesis and progression. Here, we aim to investigate the possible role of LPS-induced TNF-alpha factor (LITAF) in inducing a pro-inflammatory and pro-fibrogenic phenotype of non-alcoholic steatohepatitis (NASH).We found that children with NAFLD displayed, in different liver-resident cells, an increased expression of LITAF which correlated with histological traits of hepatic inflammation and fibrosis. Total and nuclear LITAF expression increased in mouse and human hepatic stellate cells (HSCs). Moreover, LPS induced LITAF-dependent transcription of IL-1beta, IL-6 and TNF-alpha in the clonal myofibroblastic HSC LX-2 cell line, and this effect was hampered by LITAF silencing. We showed, for the first time in HSCs, that LITAF recruitment to these cytokine promoters is LPS dependent. However, preventing LITAF nuclear translocation by p38MAPK inhibitor, the expression of IL-6 and TNF-alpha was significantly reduced with the aid of p65NF-A B, while IL-1beta transcription exclusively required LITAF expression/activity. Finally, IL-1beta levels in plasma mirrored those in the liver and correlated with LPS levels and LITAF positive HSCs in children with NASH.In conclusion, a more severe histological profile in paediatric NAFLD is associated with LITAF over-expression in HSCs, which in turn correlates with hepatic and circulating IL-1beta levels outlining a panel of potential biomarkers of NASH-related liver damage. The in vitro study highlights the role of LITAF as a key regulator of the LPS-induced pro inflammatory pattern in HSCs and suggests p38MAPK inhibitors as a possible therapeutic approach against hepatic inflammation in NASH. PMID- 26573229 TI - INPP4B is upregulated and functions as an oncogenic driver through SGK3 in a subset of melanomas. AB - Inositol polyphosphate 4-phosphatase type II (INPP4B) negatively regulates PI3K/Akt signalling and has a tumour suppressive role in some types of cancers. However, we have found that it is upregulated in a subset of melanomas. Here we report that INPP4B can function as an oncogenic driver through activation of serum- and glucocorticoid-regulated kinase 3 (SGK3) in melanoma. While INPP4B knockdown inhibited melanoma cell proliferation and retarded melanoma xenograft growth, overexpression of INPP4B enhanced melanoma cell and melanocyte proliferation and triggered anchorage-independent growth of melanocytes. Noticeably, INPP4B-mediated melanoma cell proliferation was not related to activation of Akt, but was mediated by SGK3. Upregulation of INPP4B in melanoma cells was associated with loss of miRNA (miR)-494 and/or miR-599 due to gene copy number reduction. Indeed, overexpression of miR-494 or miR-599 downregulated INPP4B, reduced SGK3 activation, and inhibited melanoma cell proliferation, whereas introduction of anti-miR-494 or anti-miR-599 upregulated INPP4B, enhanced SGK3 activation, and promoted melanoma cell proliferation. Collectively, these results identify upregulation of INPP4B as an oncogenic mechanism through activation of SGK3 in a subset of melanomas, with implications for targeting INPP4B and restoring miR-494 and miR-599 as novel approaches in the treatment of melanomas with high INPP4B expression. PMID- 26573230 TI - Transmembrane protein CD9 is glioblastoma biomarker, relevant for maintenance of glioblastoma stem cells. AB - The cancer stem cell model suggests that glioblastomas contain a subpopulation of stem-like tumor cells that reproduce themselves to sustain tumor growth. Targeting these cells thus represents a novel treatment strategy and therefore more specific markers that characterize glioblastoma stem cells need to be identified. In the present study, we performed transcriptomic analysis of glioblastoma tissues compared to normal brain tissues revealing sensible up regulation of CD9 gene. CD9 encodes the transmembrane protein tetraspanin which is involved in tumor cell invasion, apoptosis and resistance to chemotherapy. Using the public REMBRANDT database for brain tumors, we confirmed the prognostic value of CD9, whereby a more than two fold up-regulation correlates with shorter patient survival. We validated CD9 gene and protein expression showing selective up-regulation in glioblastoma stem cells isolated from primary biopsies and in primary organotypic glioblastoma spheroids as well as in U87-MG and U373 glioblastoma cell lines. In contrast, no or low CD9 gene expression was observed in normal human astrocytes, normal brain tissue and neural stem cells. CD9 silencing in three CD133+ glioblastoma cell lines (NCH644, NCH421k and NCH660h) led to decreased cell proliferation, survival, invasion, and self-renewal ability, and altered expression of the stem-cell markers CD133, nestin and SOX2. Moreover, CD9-silenced glioblastoma stem cells showed altered activation patterns of the Akt, MapK and Stat3 signaling transducers. Orthotopic xenotransplantation of CD9-silenced glioblastoma stem cells into nude rats promoted prolonged survival. Therefore, CD9 should be further evaluated as a target for glioblastoma treatment. PMID- 26573231 TI - Auranofin is a potent suppressor of osteosarcoma metastasis. AB - Osteosarcoma (OS) accounts for 56% of malignant bone cancers in children and adolescents. Patients with localized disease rarely develop metastasis; however, pulmonary metastasis occurs in approximately 50% of patients and leads to a 5 year survival rate of only 10-20%. Therefore, identifying the genes and pathways involved in metastasis, as new therapeutic targets, is crucial to improve long term survival of OS patients. Novel markers that define metastatic OS were identified using comparative transcriptomic analyses of two highly metastatic (C1 and C6) and two poorly metastatic clonal variants (C4 and C5) isolated from the metastatic OS cell line, KHOS. Using this approach, we determined that the metastatic phenotype correlated with overexpression of thioredoxin reductase 2 (TXNRD2) or vascular endothelial growth factor (VEGF). Validation in patient biopsies confirmed TXNRD2 and VEGF targets were highly expressed in 29-42% of metastatic OS patient biopsies, with no detectable expression in non-malignant bone or samples from OS patients with localised disease. Auranofin (AF) was used to selectively target and inhibit thioredoxin reductase (TrxR). At low doses, AF was able to inhibit TrxR activity without a significant effect on cell viability whereas at higher doses, AF could induce ROS-dependent apoptosis. AF treatment, in vivo, significantly reduced the development of pulmonary metastasis and we provide evidence that this effect may be due to an AF-dependent increase in cellular ROS. Thus, TXNRD2 may represent a novel druggable target that could be deployed to reduce the development of fatal pulmonary metastases in patients with OS. PMID- 26573232 TI - A genome-wide association study identifies WT1 variant with better response to 5 fluorouracil, pirarubicin and cyclophosphamide neoadjuvant chemotherapy in breast cancer patients. AB - Breast cancer is believed to result from the interplay of genetic and non-genetic risk factors, and individual genetic variation may influence the efficacy of chemotherapy. Here we conducted a genome-wide association study to identify single nucleotide polymorphisms (SNPs) associated with response to anthracycline- and taxane-based neoadjuvant chemotherapy in breast cancer patients. In the discovery stage, we divided 92 patients who received anthracycline-based neoadjuvant chemotherapy into 2 groups according to pathologic response and performed a genome-wide study using Affymetrix SNP6.0 genechip. Of 389,795 SNPs associated with pathologic complete response (pCR), we identified 2 SNPs, rs6044100 and rs1799937, that were significantly associated with pCR after neoadjuvant chemotherapy. In the validation stage, genotype analysis of samples from an independent cohort of 401 patients who received anthracycline-based neoadjuvant regimens and 467 patients who received taxane-based regimens was performed using sequencing analysis. We found that only SNP rs1799937, located in the WT1 gene, was associated with pCR after anthracycline-based neoadjuvant therapy (AA vs GG; odds ratio [OR], 2.81; 95% confidence interval [CI], 1.13 6.98; P < 0.05) but not after taxane-based neoadjuvant therapy (AA vs GG; OR, 0.85; 95% CI, 0.36-2.04; P = 0.72). These results suggest that WT1 may be a potential target of anthracycline-based neoadjuvant therapy for breast cancer. PMID- 26573233 TI - PD-1 blockade attenuates immunosuppressive myeloid cells due to inhibition of CD47/SIRPalpha axis in HPV negative head and neck squamous cell carcinoma. AB - Myeloid-derived suppressor cells (MDSCs) and tumor associated macrophages (TAMs) play key roles in the tumor immune suppressive network and tumor progression. However, precise roles of programmed death-1 (PD-1) in immunological functions of MDSCs and TAMs in head and neck squamous cell carcinoma (HNSCC) have not been clearly elucidated. In the present study, we show that PD-1 and PD-L1 levels were significantly higher in human HNSCC specimen than in normal oral mucosa. MDSCs and TAMs were characterized in mice and human HNSCC specimen, correlated well with PD-1 and PD-L1 expression. alphaPD-1 treatment was well tolerated and significantly reduced tumor growth in the HNSCC mouse model along with significant reduction in MDSCs and TAMs in immune organs and tumors. Molecular analysis suggests a reduction in the CD47/SIRPalpha pathway by PD-1 blockade, which regulates MDSCs, TAMs, dendritic cell as well as effector T cells. Hence, these data identify that PD-1/PD-L1 axis is significantly increased in human and mouse HNSCC. Adoptive alphaPD-1 immunotherapy may provide a novel therapeutic approach to modulate the micro- and macro-environment in HNSCC. PMID- 26573235 TI - 'First, do no harm': are disability assessments associated with adverse trends in mental health? A longitudinal ecological study. AB - BACKGROUND: In England between 2010 and 2013, just over one million recipients of the main out-of-work disability benefit had their eligibility reassessed using a new functional checklist-the Work Capability Assessment. Doctors and disability rights organisations have raised concerns that this has had an adverse effect on the mental health of claimants, but there are no population level studies exploring the health effects of this or similar policies. METHOD: We used multivariable regression to investigate whether variation in the trend in reassessments in each of 149 local authorities in England was associated with differences in local trends in suicides, self-reported mental health problems and antidepressant prescribing rates, while adjusting for baseline conditions and trends in other factors known to influence mental ill-health. RESULTS: Each additional 10,000 people reassessed in each area was associated with an additional 6 suicides (95% CI 2 to 9), 2700 cases of reported mental health problems (95% CI 548 to 4840), and the prescribing of an additional 7020 antidepressant items (95% CI 3930 to 10100). The reassessment process was associated with the greatest increases in these adverse mental health outcomes in the most deprived areas of the country, widening health inequalities. CONCLUSIONS: The programme of reassessing people on disability benefits using the Work Capability Assessment was independently associated with an increase in suicides, self-reported mental health problems and antidepressant prescribing. This policy may have had serious adverse consequences for mental health in England, which could outweigh any benefits that arise from moving people off disability benefits. PMID- 26573234 TI - Prognostic impact of concurrent MYC and BCL6 rearrangements and expression in de novo diffuse large B-cell lymphoma. AB - Double-hit B-cell lymphoma is a common designation for a group of tumors characterized by concurrent translocations of MYC and BCL2, BCL6, or other genes. The prognosis of concurrent MYC and BCL6 translocations is not well known. In this study, we assessed rearrangements and expression of MYC, BCL2 and BCL6 in 898 patients with de novo diffuse large B-cell lymphoma treated with standard chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab). Neither BCL6 translocation alone (more frequent in activated B-cell like diffuse large B-cell lymphoma) nor in combination with MYC translocation (observed in 2.0% of diffuse large B-cell lymphoma) predicted poorer survival in diffuse large B-cell lymphoma patients. Diffuse large B-cell lymphoma patients with MYC/BCL6 co-expression did have significantly poorer survival, however, MYC/BCL6 co-expression had no effect on prognosis in the absence of MYC/BCL2 co expression, and had no additive impact in MYC+/BCL2+ cases. The isolated MYC+/BCL6+/BCL2- subset, more frequent in germinal center B-cell like diffuse large B-cell lymphoma, had significantly better survival compared with the isolated MYC+/BCL2+/BCL6- subset (more frequent in activated B-cell like diffuse large B-cell lymphoma). In summary, diffuse large B-cell lymphoma patients with either MYC/BCL6 rearrangements or MYC/BCL6 co-expression did not always have poorer prognosis; MYC expression levels should be evaluated simultaneously; and double-hit B-cell lymphoma needs to be refined based on the specific genetic abnormalities present in these tumors. PMID- 26573236 TI - Six steps in quality intervention development (6SQuID). AB - Improving the effectiveness of public health interventions relies as much on the attention paid to their design and feasibility as to their evaluation. Yet, compared to the vast literature on how to evaluate interventions, there is little to guide researchers or practitioners on how best to develop such interventions in practical, logical, evidence based ways to maximise likely effectiveness. Existing models for the development of public health interventions tend to have a strong social-psychological, individual behaviour change orientation and some take years to implement. This paper presents a pragmatic guide to six essential Steps for Quality Intervention Development (6SQuID). The focus is on public health interventions but the model should have wider applicability. Once a problem has been identified as needing intervention, the process of designing an intervention can be broken down into six crucial steps: (1) defining and understanding the problem and its causes; (2) identifying which causal or contextual factors are modifiable: which have the greatest scope for change and who would benefit most; (3) deciding on the mechanisms of change; (4) clarifying how these will be delivered; (5) testing and adapting the intervention; and (6) collecting sufficient evidence of effectiveness to proceed to a rigorous evaluation. If each of these steps is carefully addressed, better use will be made of scarce public resources by avoiding the costly evaluation, or implementation, of unpromising interventions. PMID- 26573237 TI - Chemical synthesis of transmembrane peptide and its application for research on the transmembrane-juxtamembrane region of membrane protein. AB - Membrane proteins possess one or more hydrophobic regions that span the membrane and interact with the lipids that constitute the membrane. The interactions between the transmembrane (TM) region and lipids affect the structure and function of these membrane proteins. Molecular characterization of synthetic TM peptides in lipid bilayers helps to understand how the TM region participates in the formation of the structure and in the function of membrane proteins. The use of synthetic peptides enables site-specific labeling and modification and allows for designing of an artificial TM sequence. Research involving such samples has resulted in significant increase in the knowledge of the mechanisms that govern membrane biology. In this review, the chemical synthesis of TM peptides has been discussed. The preparation of synthetic TM peptides is still not trivial; however, the accumulated knowledge summarized here should provide a basis for preparing samples for spectroscopic analyses. The application of synthetic TM peptides for gaining insights into the mechanism of signal transduction by receptor tyrosine kinase (RTK) has also been discussed. RTK is a single TM protein and is one of the difficult targets in structural biology as crystallization of the full-length receptor has not been successful. This review describes the structural characterization of the synthetic TM-juxtamembrane sequence and proposes a possible scheme for the structural changes in this region for the activation of ErbBs, the epidermal growth factor receptor family. (c) 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 613-621, 2016. PMID- 26573238 TI - A Redox-Active Dinuclear Platinum Complex Exhibiting Multicolored Electrochromism and Luminescence. AB - A redox series of cyclometalated platinum complexes based on a dinuclear motif linked by acetamidato (aam) bridging ligands, [Pt2 (MU-aam)2 (ppy)2 ] (ppy(-) =2 phenylpyridinate ion), has been synthesized. The complexes in this series are easily oxidized and reduced by both electrochemical and chemical methods, and this is accompanied by multistep changes in their optical properties, that is, multiple color changes and luminescence. Isolation of the complexes and the structural determination of three oxidation states, +2, +2.33, and +3, have been achieved. The mixed-valent complex, with an average oxidation state of +2.33, forms a trimer based on the dinuclear motif. The mixed-valent complex has a characteristic color owing to intervalence transitions in the platinum chain. In contrast, the divalent complex exhibits strong red phosphorescence originating from a triplet metal-metal-to-ligand charge transfer ((3) MMLCT) state. This study demonstrates the unique chromic behavior of a redox-active and luminescent platinum complex. PMID- 26573239 TI - Thirty-six month clinical evaluation of a highly filled flowable composite for direct posterior restorations. AB - BACKGROUND: The aim of this randomized controlled study was to evaluate the clinical performance of a highly filled flowable composite compared to a conventional paste-type composite in direct posterior restorations after 36 months. METHODS: A total of 58 mid-size to extensive posterior composite restorations were randomly placed in 32 patients, mean age of 43.9 years (range 25-76), using either a conventional composite Estelite Sigma Quick (Conventional) or a highly filled flowable composite G-aenial Universal Flo with a two-step self etch adhesive. The restorations were evaluated after placement (baseline) and at 6, 12, 24 and 36 months according to the FDI criteria. RESULTS: At the 36-month follow-up, 42 restorations were evaluated in 21 patients. After 36 months, the difference between highly filled flowable and conventional restorations was not statistically significant with respect to all evaluation parameters (p < 0.05). No secondary caries was observed. CONCLUSIONS: The highly filled flowable composite showed a comparable clinical effectiveness as the conventional paste composite in posterior restorations over 36 months. PMID- 26573240 TI - Transitive inference of social dominance by human infants. AB - It is surprising that there are inconsistent findings of transitive inference (TI) in young infants given that non-linguistic species succeed on TI tests. To conclusively test for TI in infants, we developed a task within the social domain, with which infants are known to show sophistication. We familiarized 10- to 13-month-olds (M = 11.53 months) to a video of two dominance interactions between three puppets (bear > elephant; hippo > bear) consistent with a dominance hierarchy (hippo > bear > elephant; where '>' denotes greater dominance). Infants then viewed interactions between the two puppets that had not interacted during familiarization. These interactions were either congruent (hippo > elephant) or incongruent (elephant > hippo) with the inferred hierarchy. Consistent with TI, infants looked longer to incongruent than congruent displays. Control conditions ruled out the possibility that infants' expectations were based on stable behaviors specific to individual puppets rather than their inferred transitive dominance relations. We suggest that TI may be supported by phylogenetically ancient mechanisms of ordinal representation and visuospatial processing that come online early in human development. PMID- 26573241 TI - Epidemiology and Diagnosis of Pediatric Obstructive Sleep Apnea. PMID- 26573242 TI - Leveraging Social Science-Healthcare Collaborations to Improve Teamwork and Patient Safety. AB - Effective teamwork is critical to the provision of safe, effective healthcare. High functioning teams adapt to rapidly changing patient and environmental factors, preventing diagnostic and treatment errors. While the emphasis on teamwork and patient safety is relatively new, significant team-related foundational and implementation research exists in disciplines outside of healthcare. Social scientists, including, organizational psychologists, have expertise in the study of teams, multi-team units, and organizations. This article highlights guiding team science principles from the organizational psychology literature that can be applied to the study of teams in healthcare. The authors' goal is to provide some common language and understanding around teams and teamwork. Additionally, they hope to impart an appreciation for the potential synergy present within clinician-social scientist collaborations. PMID- 26573243 TI - Why Studying Human Behavior is a Critical Component of Patient Safety. AB - Since humans are an integral part of healthcare delivery, it is appropriate to understand how human nature and human error impact patient safety. A thorough understanding of the interactions between humans and the medical environment could help decrease errors that result in patient harm. This article describes some of our findings from a study that revealed unexpected behaviors which were documented on video during critical events (cardiac arrests) in a pediatric cardiac intensive care unit (CICU). We changed our training process for cardiac arrests as well as our nurse staffing in the CICU based upon results of our study. We believe that the lessons learned in our CICU are generalizable to both inpatient and ambulatory settings. We also emphasize the importance of collaborating with social scientists to rigorously study innate maladaptive patterns of human behavior to determine strategies to mitigate "human factors" during acute medical crises. PMID- 26573244 TI - Human Factors Science: Brief History and Applications to Healthcare. AB - This section will define the science of human factors, its origins, its impact on safety in other domains, and its impact and potential for impact on patient safety. PMID- 26573245 TI - Role of neutrophils in atherogenesis: an update. AB - BACKGROUND: The role of neutrophils in the beginning and the progression of the atherosclerotic process did not receive much attention until the last years. On the contrary, recent data, in both the experimental animals and humans, suggest important effects of these cells with possible clinical consequences. MATERIALS AND METHODS: This narrative review was based on the papers found on PubMed and MEDLINE up to July 2015. The search terms used were 'neutrophil, atherosclerosis' in combination with 'recruitment, chemokine, plaque destabilization and pathophysiology'. RESULTS: Different models demonstrate the presence and the actions of neutrophils in the early steps of the atherogenesis confirming the fundamental role of these cells in the response of the innate immune system to different pathogens (in this context the modified lipoproteins). However, also the late phases of the atherosclerotic process, in particular the destabilization of a mature plaque, seem to be modulated by the neutrophils, possibly through the interaction with recently discovered biological systems such as the endocannabinoids. CONCLUSIONS: The understanding of the mechanisms involved in the modulation exerted by neutrophils in atherosclerosis is pivotal in terms of the complete definition of the overall picture. This approach will certainly give us new targets and new pharmacological opportunities for the anti-inflammatory strategy of the cardiovascular prevention. PMID- 26573246 TI - Italian expert questions need for expanded vaccination schedule. PMID- 26573247 TI - Data-driven knowledge acquisition, validation, and transformation into HL7 Arden Syntax. AB - OBJECTIVE: The objective of this study is to help a team of physicians and knowledge engineers acquire clinical knowledge from existing practices datasets for treatment of head and neck cancer, to validate the knowledge against published guidelines, to create refined rules, and to incorporate these rules into clinical workflow for clinical decision support. METHODS AND MATERIALS: A team of physicians (clinical domain experts) and knowledge engineers adapt an approach for modeling existing treatment practices into final executable clinical models. For initial work, the oral cavity is selected as the candidate target area for the creation of rules covering a treatment plan for cancer. The final executable model is presented in HL7 Arden Syntax, which helps the clinical knowledge be shared among organizations. We use a data-driven knowledge acquisition approach based on analysis of real patient datasets to generate a predictive model (PM). The PM is converted into a refined-clinical knowledge model (R-CKM), which follows a rigorous validation process. The validation process uses a clinical knowledge model (CKM), which provides the basis for defining underlying validation criteria. The R-CKM is converted into a set of medical logic modules (MLMs) and is evaluated using real patient data from a hospital information system. RESULTS: We selected the oral cavity as the intended site for derivation of all related clinical rules for possible associated treatment plans. A team of physicians analyzed the National Comprehensive Cancer Network (NCCN) guidelines for the oral cavity and created a common CKM. Among the decision tree algorithms, chi-squared automatic interaction detection (CHAID) was applied to a refined dataset of 1229 patients to generate the PM. The PM was tested on a disjoint dataset of 739 patients, which gives 59.0% accuracy. Using a rigorous validation process, the R-CKM was created from the PM as the final model, after conforming to the CKM. The R-CKM was converted into four candidate MLMs, and was used to evaluate real data from 739 patients, yielding efficient performance with 53.0% accuracy. CONCLUSION: Data-driven knowledge acquisition and validation against published guidelines were used to help a team of physicians and knowledge engineers create executable clinical knowledge. The advantages of the R-CKM are twofold: it reflects real practices and conforms to standard guidelines, while providing optimal accuracy comparable to that of a PM. The proposed approach yields better insight into the steps of knowledge acquisition and enhances collaboration efforts of the team of physicians and knowledge engineers. PMID- 26573248 TI - Morphological analysis of the urethral muscle of the male pig with relevance to urinary continence and micturition. AB - To investigate whether the pig could be considered a suitable model to study lower urinary tract function and dysfunction, the pelvic urethra of 24 slaughtered male pigs were collected, and the associated muscles were macroscopically, histologically and histochemically analyzed. In cross-sections of the urethra, a muscular complex composed of an inner layer of smooth muscle and an outer layer of striated muscle that are not separated by fascial planes was observed. A tunica muscularis, composed of differently oriented smooth muscle bundles, is only evident in the proximal part of the pelvic urethra while, in the remaining part, it contributes to form the prostatic fibromuscular stroma. The striated urethral muscle surrounds the pelvic urethra in a horseshoe-like configuration with a dorsal longitudinal raphe, extending from the bladder neck to the central tendon of perineum. Proximally to the bladder, it is constituted of slow-twitch and fast-twitch myofibers of very small diameter, and embedded in an abundant collagen and elastic fiber net. Moving caudally it is gradually encircled and then completely substituted by larger and compact myofibers, principally presenting circular orientation and fast-twitch histochemical characteristics. So, like in humans, the cranial tract of the muscular system surrounding the pelvic urethra is principally composed of smooth musculature. The striated component cranially may have a role in blocking retrograde ejaculation, while the middle and caudal tracts may facilitate urine and semen flow, and seem especially concerned with the rapid and forceful urethral closure during active continence. Some differences in the morphology and structure between pigs and humans seem due to the different morphology of the 'secondary' sexual organs that develop from the urethral wall and to the different effect of gravity on the mechanics of the urinary system in quadruped and bipedal mammals. PMID- 26573250 TI - [Depression in Acute Coronary Syndromes: Application of the Beck Depression Inventory]. AB - BACKGROUND: Depression has been related to the occurrence of cardiovascular diseases, and also appears to increase the risk of death from coronary artery disease. The presence of depression after the occurrence of an acute coronary syndrome (ACS) and its relationship with socioeconomic factors has not been studied in Colombia. OBJECTIVE: To describe the frequency of depression and associated factors in patients hospitalized with an ACS. METHODS: A cross sectional study was carried out between April and May 2008 in three coronary care units in Santa Marta, Colombia. The presence of depression was evaluated with the Beck Depression Inventory (BDI). Depression was considered to be present if BDI was equal or greater than 10. The relationship between the presence of depression and demographic, clinic and laboratory characteristics was analyzed. RESULTS: A BDI score >=10 (any degree of depression) was seen in 21 (63.64%) of the patients. In 9 out of 10 (91.66%) patients without stable income had depression in contrast to 12 out of 23 (57.14%) with stable income (P=.037). Depression was found in in 8 of the 8 (100%) patients with electrocardiographic pathological T wave inversion, in contrast to 13 out of the 25 (52%) without changes in T wave (P=.014). Depression was detected in 17 of 22 (77.27%) patients who smoked cigarettes versus 4 of 11 (36.36%) of patients who have never smoked (P=.021). CONCLUSIONS: Depressive symptoms are significantly present in patients suffering an acute coronary syndrome. Unemployment, pathological T wave inversion, and smoking seem to be associated with the presence of depressive symptoms after an acute coronary event. PMID- 26573251 TI - [Factors Associated With the Temporary Abandonment of Treatment for Disorders Due to Substance Abuse in an Institution in Medellin, Colombia]. AB - OBJECTIVE: To determine the frequency and factors associated withtreatment drop out in patients from a Substance User Treatment Center in Medellin, Colombia. METHODS: A case-control study was conducted, with patients with an early treatment dropout as cases, and patients who completed the treatment as controls. Demographic data, substance use pattern, concomitant diseases, and the decision to initiate treatment were compared between cases and controls. RESULTS: The frequency of early drop-out was 59%, but a high proportion of this drop-out (47.5%) occurred in the transition period between the program stages. The variables associated with drop-out were: psychotic disorder (OR=0.32; 95% CI, 0.11-0.91), bipolar disorder (OR=0.31; 95% CI, 0.12-0.77), heroin as the principal substance compared to alcohol (OR=6.68; 95% CI, 1.52-29.4), decision to initiate the treatment by the family compared to personal decision (OR=3.02; 95% CI, 1.28-7.17), and previous treatments (OR=1.87; 95% CI, 1.02-3.44). CONCLUSIONS: The drop-out frequency is similar to those reported in other studies. Associated factors were found, which could be considered in order to plan strategies to improve the program results. PMID- 26573252 TI - [Procedural Motor Skills and Interference in the Academic Life Routine of a Group of Schoolchildren With Signs and Symptoms of ADHD]. AB - INTRODUCTION: There is a rising prevalence of attention deficit and hyperactivity disorder (ADHD) in educational institutions. Difficulties in academic development manifest as: slow information processing, difficulty in planning and working memory, difficulty staying focused, struggle selecting data or stimuli relevant to the implementation and completion of tasks. If adequate educational measures and specialized intervention are not established, the characteristics may affect instrumental learning. The aim of this study is to identify procedural motor skills that interfere with academic activities in a group of elementary school children, with signs and symptoms of ADHD. MATERIAL AND METHODS: Descriptive study including children from 2nd to 4th grade of elementary school in which teachers detected signs and symptoms of ADHD by using questionnaires and observing school behavior. Procedural motor skills were identified and it was evidenced which skills interfered in the execution of academic activities. RESULTS: The population that showed inattention and hyperactivity behaviors manifested behavioral problems, low academic performance, and in turn, greater difficulty in postural skills and skill related with organization of space and objects, which interfered with the activities of daily living academic routine, as expected. CONCLUSIONS: The assessment of procedural motor skills allowed to determine specific difficulties in routine activities, and to agree on intervention strategies in the classroom. PMID- 26573253 TI - [Intra-rater Reliability for the Questionnaire on Activity Limitations and Participation Restrictions of Children With ADHD]. AB - INTRODUCTION: Questionnaires for evaluating activity limitations and participation restrictions in children with ADHD (CLARP-TDAH) has recently been developed in Colombia, based on the suggestions made by the WHO from the International Classification of Functioning, Disability and Health (ICF), allowing clinical evaluation beyond an evaluation of the functionality and functioning of children in their family and school environments. Previous research with the questionnaire proved useful in the multidisciplinary approach of Colombian children with ADHD. This study determines the level of intra-rater reliability for questionnaires CLARP-TDAH Parents and Teachers. METHODS: The study included a non-random sample of 203 Colombian children attending school and diagnosed with ADHD. Intra-rater reliability and the reproducibility of the results was determined using the Kappa index. The informants were parents and teachers. RESULTS: Kappa values >0.7 were obtained for the intra-rater reliability of the questionnaire domains of CLARP-TDAH Parents, while for CLARP TDAH Teachers domains these values were >0.8. CONCLUSIONS: CLARP-TDAH questionnaires are a tool with a good level of intra-rater reliability, which allows a reliable assessment of activity limitations and participation restrictions in order to determine the level of functioning at home and school. PMID- 26573254 TI - [Fundamentals and Clinical Applications of Transcranial Magnetic Stimulation in Neuropsychiatry]. AB - Transcranial Magnetic Stimulation (TMS) is a non-invasive method for stimulation of brain that is based on the ability of a generated magnetic field to penetrate skull and brain meninges, inducing an electric current in the brain tissues that produces neuronal depolarization. TMS can be applied as single pulse of stimulation, pairs of stimuli separated by variable intervals to the same or different brain areas, or as trains of repetitive stimuli at various frequencies. Its mechanism of action is currently unknown. Repetitive TMS can modify the excitability of the cerebral cortex, and has been postulated as a diagnostic and therapeutic tool in the area of neuropsychiatry. The aim of this article is to review the knowledge of the TMS as regards its basic principles, pathophysiological mechanism, and its usefulness in clinical practice. PMID- 26573255 TI - [Mental Imagery: Neurophysiology and Implications in Psychiatry]. AB - OBJECTIVE: To provide an explanation about what mental imagery is and some implications in psychiatry. METHODS: This article is a narrative literature review. RESULTS: There are many terms in which imagery representations are described in different fields of research. They are defined as perceptions in the absence of an external stimulus, and can be created in any sensory modality. Their neurophysiological substrate is almost the same as the one activated during sensory perception. There is no unified theory about its function, but it is possibly the way that our brain uses and manipulates the information to respond to the environment. CONCLUSIONS: Mental imagery is an everyday phenomenon, and when it occurs in specific patterns it can be a sign of mental disorders. PMID- 26573256 TI - [Objective Assessment of Emotion Processing. Forensic Case Report]. AB - INTRODUCTION: The main objective of the emotions is to ensure the homeostasis, the survival and the well-being of the organism. OBJECTIVE: To demonstrate the usefulness of performing neurophysiological and neuropsychological assessments in patients, in order to demonstrate the significant role of the emotions in the execution of certain behaviours. METHODS: A forensic psychiatric interview was conducted. EEG in vigil state was registered, the generators of current density to theta band were calculated, and the emotions recognition test was performed. RESULTS: The results of the psychiatric interview demonstrated that fear was an important element in acting impulsively, and lack of foresight of the accused. A substantial decrease was demonstrated in the ability to understand the scope of the acts and the direction of the behaviour during the time the crime occurred. The EEG showed alterations in frontal regions, and the generators of current density were located in frontal-temporal regions and occipital associative areas. CONCLUSIONS: It is recommended to associate these studies with the forensic psychiatric assessment, in order to increase the objectivity of the diagnoses formulated by medical experts. PMID- 26573257 TI - [Intersubjectivity: Between Explanation and Understanding]. AB - The discussion on explanation and understanding has led to a division in the sciences, based on what is considered to be inherent to each of the domains. The task of the natural sciences would be the explanation, while that of the social sciences would be understanding or interpretation.There is a line of work that currently seeks to overcome the methodological dualism and to propose more interdisciplinary studies, such as the studies on emergence of the mental in the framework of intersubjective relationships. In particular, the concept of intersubjectivity defended by the phenomenology as an embodied practice, is being supported by the results of investigations carried out on the basis of the cognitive neuroscience and developmental psychology. Authors from different roots, such as J. Bruner and S. Gallagher propose considering these types of interdisciplinary collaboration as a possible way to integrate the traditions of the explanation and understanding. The purpose of this paper is to analyze to what extent this collaboration between phenomenology and sciences, particularly on the subject of understanding others and their relevance for the understanding of certain psychopathologies, has allowed to close the gap that had opened in the nineteenth century between these traditions. PMID- 26573258 TI - [Eugenics and Discrimination in Colombia: the Role of Medicine and Psychiatry in Immigration Policy at the Beginning of the 20th Century]. AB - With the Theory of Evolution, eugenics had its beginnings during the last decades of the 19th century. Academics discussed the results obtained from their observations, and progressively had influence on the promulgation of laws and norms related to ethnic hygiene and improvement of race. Such principles were the fundamentals to order eugenic and discriminatory laws. Colombia was not outside that discussion and developed immigration laws congruent to that thinking during the first half of the 20th century. PMID- 26573259 TI - The Importance of Continuing Education. PMID- 26573260 TI - Evolutionary implication of B-1 lineage cells from innate to adaptive immunity. AB - The paradigm that B cells mainly play a central role in adaptive immunity may have to be reevaluated because B-1 lineage cells have been found to exhibit innate-like functions, such as phagocytic and bactericidal activities. Therefore, the evolutionary connection of B-1 lineage cells between innate and adaptive immunities have received much attention. In this review, we summarized various innate-like characteristics of B-1 lineage cells, such as natural antibody production, antigen-presenting function in primary adaptive immunity, and T cell independent immune responses. These characteristics seem highly conserved between fish B cells and mammalian B-1 cells during vertebrate evolution. We proposed an evolutionary outline of B cells by comparing biological features, including morphology, phenotype, ontogeny, and functional activity between B-1 lineage cells and macrophages or B-2 cells. The B-1 lineage may be a transitional cell type between phagocytic cells (e.g., macrophages) and B-2 cells that functionally connects innate and adaptive immunities. Our discussion would contribute to the understanding on the origination of B cells specialized in adaptive immunity from innate immunity. The results might provide further insight into the evolution of the immune system as a whole. PMID- 26573261 TI - Hb F-Avellino [(G)gamma41(C7)Phe -> Leu; HBG2: c.124 T > C]: A New Hemoglobin Variant Observed In A Healthy Newborn. AB - Here we describe Hb F-Avellino [(G)gamma41(C7)Phe -> Leu; HBG2: c.124 T > C], a new hemoglobin (Hb) variant observed in a healthy newborn. The proband's hemolysate was found to be mildly unstable by the isopropanol test. The occurrence of the variant was assessed by both chromatographic and electrophoretic methods. DNA sequencing analysis of the (G)gamma gene showed a T to C transition at codon 41 (TTC > CTC) corresponding to the Phe -> Leu substitution. Normal functional properties have been hypothesized. PMID- 26573262 TI - Picking the right tool for the job--Phosphoproteomics of egg activation. AB - Eggs are the rarest cell in the human body, yet their study is essential for the fields of fertility, reproduction, and fetal health. Guo et al. (Proteomics 2015, 15, 4080-4095) use a "surrogate" animal to discover the phosphoproteomic pathways involved in egg activation. With datasets of several thousand phosphosites on 2500 different proteins, these investigators have defined new pathways, connections to pathways, and priorities in searches for how eggs are activated at fertilization. These results in a sea urchin are now transposable to mammals for testing on a per candidate strategy. PMID- 26573263 TI - SOX18 knockdown suppresses the proliferation and metastasis, and induces the apoptosis of osteosarcoma cells. AB - Sex determining region Y-box 18 (SOX18) has been found to be overexpressed in several types of tumor. However, the molecular mechanism underlying the biological function of SOX18 in osteosarcoma remains to be elucidated. The present study aimed to elucidate the roles of SOX18 in regulating the biological behavior of osteosarcoma cells. First, SOX18 mRNA expression was analyzed in osteosarcoma tissues using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The results demonstrated that the expression of SOX18 was elevated in osteosarcoma tissue, compared with normal bone tissue. In addition, the knockdown of SOX18 in U2OS or MG63 osteosarcoma cells inhibited cell proliferation and significantly increased the population of cells in the S-phase of the cell cycle, as measured by the CCK-8 assay and flow cytometric analysis, respectively. Additionally, suppression of the expression of SOX18 in the osteosarcoma cells significantly induced cell apoptosis as evaluated by annexin V/propidium iodide staining and flow cytometric analysis. The downregulation of SOX18 was found to significantly inhibit cell adhesion and invasion. The mRNA and protein expression levels of transforming growth factor-beta, platelet-derived growth factor (PDGF)-A, PDGF-B and RhoA were also reduced by SOX18 silencing, as assessed by RT-qPCR and western blot analysis, respectively. These results indicated that SOX18 may function as an oncogene, and may provide a novel and promising therapeutic strategy for osteosarcoma. PMID- 26573264 TI - Foveal hemorrhage in an immunocompetent patient with visceral leishmaniasis. AB - OBJECTIVE: To report a case of foveal and macular intraretinal hemorrhages in an immunocompetent male patient with visceral leishmaniasis. CASE REPORT: An immunocompetent, 42 year-old male, presented with progressive visual loss and metamorphopsia in his right eye. The fundus examination showed a foveal round yellow lesion and intraretinal hemorrhages in the macula. The patient was hospitalized with fever, anorexia, weight loss, hepatosplenomegaly, and progressive anemia. Laboratory studies were conducted and a positive test for leishmaniasis and hepatitis A was reported. Treatment was begun with amphotericin B 50mg/day up to a total dose of 1400mg. CONCLUSION: Bilateral retinal hemorrhages in an endemic country could suggest the diagnosis of visceral leishmaniasis. PMID- 26573265 TI - Correspondence to Vorselaars et al. thoracic aorta dilation in patients with hereditary hemorrhagic telangiectasia due to SMAD4 gene mutation. PMID- 26573266 TI - Implementation of an inter-agency transition model for youth with spina bifida. AB - BACKGROUND: To address gaps in transfer of care and transition support, a paediatric hospital and adult community health care centre partnered to implement an inter-agency transition model for youth with spina bifida. Our objective was to understand the enablers and challenges experienced in the implementation of the model. METHODS: Using a descriptive, qualitative design, we conducted semi structured interviews, in-person or over the phone, with 12 clinicians and nine key informants involved in implementing the spina bifida transition model. We recruited all 21 participants from an urban area of Ontario, Canada. RESULTS: Clinicians and key informants experienced several enablers and challenges in implementing the spina bifida transition model. Enablers included dedicated leadership, advocacy, funding, inter-agency partnerships, cross-appointed staff and gaps in co-ordinated care to connect youth to adult services. Challenges included gaps in the availability of adult specialty services, limited geographical catchment of adult services, limited engagement of front-line staff, gaps in communication and role clarity. CONCLUSIONS: Although the transition model has realized some initial successes, there are still many challenges to overcome in transferring youth with spina bifida to adult health care and transitioning to adulthood. PMID- 26573267 TI - [Randomised study of the relationship between the use of CPRmeter(r) device and the quality of chest compressions in a simulated cardiopulmonary resuscitation]. AB - OBJECTIVE: To determine whether the use of CPRmeter((r)) during the resuscitation manoeuvres, is related to a higher quality of external cardiac massage, as recommended by the International Liaison Committee on Resuscitation (ILCOR). To compare the quality obtained without the use or this, and whether there are differences related to anthropometric, demographic, professional and/or occupational factors. METHOD: Experimental, open trial performed with life support simulators in a stratified random sample of 88 health workers randomly distributed between groups A (without indications of the device) and B (with them). The homogeneity of their confounding variables was compared, as well as the compressions depth and compressions rate, the proportion of completed release, and distribution of the quality massage variable (according to criteria ILCOR) between the groups. The qualitative variables were analysed with the chi square test, and quantitative variables with the Student t-test or Mann-Whitney U test and the association between the variable quality massage variable, and use of the device with the odds ratio. RESULTS: Group A: mean depth 42.1mm (standard deviation 10.1), mean rate 121.3/min (21.6), percentage of complete release 71.2% (36.9). Group B: 51.2mm (5.9) 111.9/min (6.4), 92.9% (10.1) respectively. Odds ratio for quality massage regarding the use of the device was 5.170 (95% CI; 2.060-12.977). CONCLUSIONS: The use of CPRmeter((r)) device in simulated resuscitations is related to a higher quality of cardiac massage, improving the approach to the ILCOR recommendations, regardless of the characteristics of the participants. They were 83.8% more likely to achieve a quality massage using the device than without it. PMID- 26573268 TI - Differences in clinical characteristics and prognosis of Penicilliosis among HIV negative patients with or without underlying disease in Southern China: a retrospective study. AB - BACKGROUND: The incidence of Penicillium marneffei infection has recently increased. This fungus can cause fatal systemic mycosis in both immunocompetent and immunocompromised patients without HIV infection. METHODS: We retrospectively analysed Penicilliosis patients between January 1, 2003 and August 1, 2014 at the First Affiliated Hospital of Guangxi Medical University. HIV-negative patients with Penicilliosis were divided into two groups: patients with underlying disease (Group D) and patients without underlying disease (Group ND). HIV-positive patients were excluded. The relationships between overall survival and the study variables were assessed using univariate and multivariate analyses. RESULTS: During 11 years, Penicillium marneffei infection was diagnosed in 109 patients. Sixty-six (60.55 %) patients were HIV-positive and excluded from these cases. Forty-three patients were HIV-negative were enrolled. Among these patients, 18 (41.86 %) patients were in Group D, and 25 (58.14 %) were in Group ND. The most common underlying disease was diabetes. There were no statistically significant differences between the two groups in clinical characteristics, except for immune state and prognosis. Group ND had higher lymphocyte cell counts, CD4 cell counts, and CD4 T-cell percentages than Group D (P < 0.05). Patients in Group D had higher recurrence and mortality rates than Group ND (P < 0.05). In the univariate analysis, only underlying disease, CD4 cell percentage, and T lymphocyte cell percentage were significantly associated with overall survival. CONCLUSIONS: Penicillium marneffei can infect HIV-negative patients and can cause fatal systemic mycosis. There were no clear differences in clinical manifestations among HIV-negative patients with and without underlying disease. However, Penicillium marneffei in HIV-negative patients in with underlying diseases may cause immune function decline and a deficiency in T-cell-mediated immunity. Underlying disease, CD4 cell percentage, and T lymphocyte cell percentage may be potential risk factors affecting prognosis. Timely, effective, and longer courses of antifungal treatments are important in improving prognoses. PMID- 26573270 TI - Positive strategies men regularly use to prevent and manage depression: a national survey of Australian men. AB - BACKGROUND: Men are at greater risk than women of dying by suicide. One in eight will experience depression--a leading contributor to suicide--in their lifetime and men often delay seeking treatment. Previous research has focused on men's use of unhelpful coping strategies, with little emphasis on men's productive responses. The present study examines the positive strategies men use to prevent and manage depression. METHOD: A national online survey investigated Australian men's use of positive strategies, including 26 strategies specifically nominated by men in a previous qualitative study. Data were collected regarding frequency of use or openness to using untried strategies, depression risk, depression symptoms, demographic factors, and other strategies suggested by men. Multivariate regression analyses explored relationships between regular use of strategies and other variables. RESULTS: In total, 465 men aged between 18 and 74 years participated. The mean number of strategies used was 16.8 (SD 4.1) for preventing depression and 15.1 (SD 5.1) for management. The top five prevention strategies used regularly were eating healthily (54.2 %), keeping busy (50.1 %), exercising (44.9 %), humour (41.1 %) and helping others (35.7 %). The top five strategies used for management were taking time out (35.7 %), rewarding myself (35.1 %), keeping busy (35.1 %), exercising (33.3 %) and spending time with a pet (32.7 %). With untried strategies, a majority (58 %) were open to maintaining a relationship with a mentor, and nearly half were open to using meditation, mindfulness or gratitude exercises, seeing a health professional, or setting goals. In multivariate analyses, lower depression risk as measured by the Male Depression Risk Scale was associated with regular use of self-care, achievement based and cognitive strategies, while lower scores on the Patient Health Questionnaire-9 was associated with regular use of cognitive strategies. CONCLUSIONS: The results demonstrate that the men in the study currently use, and are open to using, a broad range of practical, social, emotional, cognitive and problem-solving strategies to maintain their mental health. This is significant for men in the community who may not be in contact with professional health services and would benefit from health messages promoting positive strategies as effective tools in the prevention and management of depression. PMID- 26573271 TI - A comparison of Plasmodium falciparum circumsporozoite protein-based slot blot and ELISA immuno-assays for oocyst detection in mosquito homogenates. AB - BACKGROUND: The infectivity of Plasmodium gametocytes is typically determined by microscopically examining the midguts of mosquitoes that have taken a blood meal containing potentially infectious parasites. Such assessments are required for the development and evaluation of transmission-reducing interventions (TRI), but are limited by subjectivity, technical complexity and throughput. The detection of circumsporozoite protein (CSP) by enzyme-linked immunosorbent assay (ELISA) and enhanced chemiluminescent slot-blot (ECL-SB) may be used as objective, scalable alternatives to microscopy for the determination of infection prevalence. METHODS: To compare the performance of the CSP ELISA and ECL-SB for the detection of mosquito infection, four groups of Anopheles stephensi mosquitoes were infected with cultured Plasmodium falciparum gametocytes. At day 8 post-infection (PI), parasite status was determined by microscopy for a sample of mosquitoes from each group. At days 8 and 10 PI, the parasite status of separate mosquito samples was analysed by both CSP ELISA and ECL-SB. RESULTS: When mosquito samples were analysed 8 days PI, the ECL-SB determined similar infection prevalence to microscopy; CSP ELISA lacked the sensitivity to detect CSP in all infected mosquitoes at this early time point. When mosquitoes were analysed 48 h later (10 days PI) both assays performed as well as microscopy for infection detection. CONCLUSIONS: Whilst microscopical examination of mosquito guts is of great value when quantification of parasite burden is required, ECL-SB and CSP ELISA are suitable alternatives at day 10 PI when infection prevalence is the desired endpoint, although CSP ELISA is not suitable at day 8 PI. These results are important to groups considering large-scale implementation of TRI. PMID- 26573272 TI - Proton beam therapy for a patient with large rhabdomyosarcoma of the body trunk. AB - BACKGROUND: We present the clinical course of a pediatric patient with large rhabdomyosarcoma of the body trunk who received proton beam therapy (PBT). CASE PRESENTATION: A 1-year-old girl was diagnosed with stage IV alveolar rhabdomyosarcoma in 2008. A large tumor was located in the central diaphragm and had infiltrated the liver and pericardium with peritoneal dissemination. Chemotherapy was immediately started with six courses of vincristine, actinomycin D and cyclophosphamide (VAC) firstly, and secondly followed by 2 courses of ifosfamide, carboplatin and etoposide (ICE), but a large tumor of 15 cm in size remained. The tumor was inoperable because of its location, and photon radiotherapy could not be performed due to limited liver tolerance. The patient was referred to our hospital and received PBT at a dose of 54 GyE in 30 fractions in June 2009. The tumor quickly responded and 95 % of volume reduction was achieved at the end of PBT. However, marginal recurrence in the caudal part of the irradiated field, where we reduced the proton dose because of the presence of the intestine, was detected in August 2010. The recurrent tumor size was less than 1 cm. Chemotherapy with VAC followed by topotecan and carboplatin (TC) was again tried, but the tumor size was stable. Repeated PBT was not possible because of limited intestinal tolerance; therefore, intraoperative radiotherapy was conducted with 20 Gy of electron beams in April 2011. The tumor was subsequently well controlled, but secondary myelodysplastic syndrome developed and the patient died of hemophagocytic syndrome after umbilical cord blood transplantation in May 2012. CONCLUSION: PBT was performed safely and effectively for a 1-year-old girl with alveolar rhabdomyosarcoma with liver and cardiac invasion that was resistant to surgery and chemotherapy. This case illustrates that PBT can be useful in cases that are difficult to treat with conventional radiotherapy. PMID- 26573269 TI - A systematic review of mental health outcome measures for young people aged 12 to 25 years. AB - BACKGROUND: Mental health outcome measures are used to monitor the quality and effectiveness of mental health services. There is also a growing expectation for implementation of routine measurement and measures being used by clinicians as a feedback monitoring system to improve client outcomes. The recent focus in Australia and elsewhere targeting mental health services to young people aged 12 25 years has meant that outcome measures relevant to this age range are now needed. This is a shift from the traditional divide of child and adolescent services versus adult services with a transitioning age at 18 years. This systematic review is the first to examine mental health outcome measures that are appropriate for the 12 to 25 year age range. METHODS: MEDLINE and PsychINFO databases were systematically searched to identify studies using mental health outcome measures with young people aged 12 to 25 years. The search strategy complied with the relevant sections of the PRISMA statement. RESULTS: A total of 184 published articles were identified, covering 29 different outcome measures. The measures were organised into domains that consisted of eight measures of cognition and emotion, nine functioning measures, six quality of life measures, and six multidimensional mental health measures. No measures were designed specifically for young people aged 12 to 25 years and only two had been used by clinicians as a feedback monitoring system. Five measures had been used across the whole 12 to 25 year age range, in a range of mental health settings and were deemed most appropriate for this age group. CONCLUSIONS: With changes to mental health service systems that increasingly focus on early intervention in adolescence and young adulthood, there is a need for outcome measures designed specifically for those aged 12 to 25 years. In particular, multidimensional measures that are clinically meaningful need to be developed to ensure quality and effectiveness in youth mental health. Additionally, outcome measures can be clinically useful when designed to be used within routine feedback monitoring systems. PMID- 26573274 TI - Corrigendum. PMID- 26573273 TI - Corrigendum. PMID- 26573275 TI - Anti-tumor activities of luteolin and silibinin in glioblastoma cells: overexpression of miR-7-1-3p augmented luteolin and silibinin to inhibit autophagy and induce apoptosis in glioblastoma in vivo. AB - Glioblastoma is the deadliest brain tumor in humans. High systemic toxicity of conventional chemotherapies prompted the search for natural compounds for controlling glioblastoma. The natural flavonoids luteolin (LUT) and silibinin (SIL) have anti-tumor activities. LUT inhibits autophagy, cell proliferation, metastasis, and angiogenesis and induces apoptosis; while SIL activates caspase-8 cascades to induce apoptosis. However, synergistic anti-tumor effects of LUT and SIL in glioblastoma remain unknown. Overexpression of tumor suppressor microRNA (miR) could enhance the anti-tumor effects of LUT and SIL. Here, we showed that 20 uM LUT and 50 uM SIL worked synergistically for inhibiting growth of two different human glioblastoma U87MG (wild-type p53) and T98G (mutant p53) cell lines and natural combination therapy was more effective than conventional chemotherapy (10 uM BCNU or 100 uM TMZ). Combination of LUT and SIL caused inhibition of growth of glioblastoma cells due to induction of significant amounts of apoptosis and complete inhibition of invasion and migration. Further, combination of LUT and SIL inhibited rapamycin (RAPA)-induced autophagy, a survival mechanism, with suppression of PKCalpha and promotion of apoptosis through down regulation of iNOS and significant increase in expression of the tumor suppressor miR-7-1-3p in glioblastoma cells. Our in vivo studies confirmed that overexpression of miR-7-1-3p augmented anti-tumor activities of LUT and SIL in RAPA pre-treated both U87MG and T98G tumors. In conclusion, our results clearly demonstrated that overexpression of miR-7-1-3p augmented the anti-tumor activities of LUT and SIL to inhibit autophagy and induce apoptosis for controlling growth of different human glioblastomas in vivo. PMID- 26573276 TI - Caspase-mediated cleavage of Beclin1 inhibits autophagy and promotes apoptosis induced by S1 in human ovarian cancer SKOV3 cells. AB - S1, a novel BH3 mimetic, can induce apoptosis dependent on Bax/Bak through inhibition of Bcl-2 in various tumors. S1 also induces autophagy through interrupting the interaction of Bcl-2 and Beclin1. Our results showed that S1 induces apoptosis in human ovarian cancer SKOV3 cells in a time- and dose dependent manner. Autophagy precedes apoptosis, in SKOV3 cells treated with S1 (6 MUmol/L), autophagy reached the maximum peak at 12 h after treatment and decreased to 24 h. In SKOV3 cells treated with different concentrations of S1 for 24 h, the highest level of autophagy was observed with 5 MUmol/L and decreased to 10 MUmol/L. Autophagy inhibitors 3-MA and CQ enhanced apoptosis induced by S1 in SKOV3 cells. However, overactivation of caspases in apoptosis induced by S1 may inhibit the autophagy-inducing function of Beclin1. Because the pan-caspase inhibitor Z-VAD recovered the autophagy-inducing function of Beclin1 through reduction of activated caspase-mediated cleavage of Beclin1. Furthermore, the Beclin1 cleavage products could further increase apoptosis induced by S1 in SKOV3 cells. This indicates that apoptosis induced by high doses and long exposure of S1 causes the overactivation of caspases and subsequent cleavage of Beclin1, and inhibits the protection of autophagy. Moreover, the cleaved product of Beclin1 further promotes apoptosis induced by S1 in SKOV3 cells. Our results suggest this may be a molecular mechanism for enhancing the sensitivity of cancer cells to apoptosis induced by small molecular compound targeting Bcl-2. PMID- 26573277 TI - Erythrophagocytosis in a cyclin D1 positive plasma cell myeloma with near tetraploid karyotypic abnormalities and cryptic MYC/IGH fusion. PMID- 26573278 TI - High-resolution copy number analysis of paired normal-tumor samples from diffuse large B cell lymphoma. AB - Copy number analysis can be useful for assessing prognosis in diffuse large B cell lymphoma (DLBCL). We analyzed copy number data from tumor samples of 60 patients diagnosed with DLBCL de novo and their matched normal samples. We detected 63 recurrent copy number alterations (CNAs), including 33 gains, 30 losses, and nine recurrent acquired copy number neutral loss of heterozygosity (CNN-LOH). Interestingly, 20 % of cases acquired CNN-LOH of 6p21 locus, which involves the HLA region. In normal cells, there were no CNAs but we observed CNN LOH involving some key lymphoma regions such as 6p21 and 9p24.1 (5 %) and 17p13.1 (2.5 %) in DLBCL patients. Furthermore, a model with some specific CNA was able to predict the subtype of DLBCL, 1p36.32 and 10q23.31 losses being restricted to germinal center B cell-like (GCB) DLBCL. In contrast, 8p23.3 losses and 11q24.3 gains were strongly associated with the non-GCB subtype. A poor prognosis was associated with biallelic inactivation of TP53 or 18p11.32 losses, while prognosis was better in cases carrying 11q24.3 gains. In summary, CNA abnormalities identify specific DLBCL groups, and we describe CNN-LOH in germline cells from DLBCL patients that are associated with genes that probably play a key role in DLBCL development. PMID- 26573279 TI - Longitudinal patterns of cancer patient reported outcomes in end of life care predict survival. AB - PURPOSE: Patients with advanced cancer typically demonstrate sharp deterioration in physical function and psychological status during the last months of life. This study evaluates the relationship between survival in patients with advanced cancer and longitudinal assessment of anxiety, depression, fatigue, pain interference, and/or physical function using the US National Institute of Health Patient Reported Outcomes Information System. METHODS: Mixed-effects models were used to evaluate patient-reported outcome trajectories over time among patients with advanced loco-regional or metastatic cancer receiving care in a hospital based palliative care clinic. Cox regression analysis was used to assess the statistical significance of differences in the probability of survival associated with patient-reported outcome scores. RESULTS: A total of 472 patients completed 1992 assessments during the 18-month study period. Longitudinal scores for fatigue, pain interference, and physical function demonstrated statistically significant non-linear trajectories. Scores for depression, fatigue, pain interference, and physical function were highly statistically significant predictors of survival (p < 0.01). Clinically meaningful differences in the probability of survival were demonstrated between patients with scores at the 25th vs. 75th percentiles, with absolute differences in survival at 6 and 12 months after assessment from 10 to 18 percentage points. CONCLUSIONS: Patient reported outcomes can be used to reliably estimate where patients are along the trajectory of deteriorating health status leading toward the end of life, and for identifying patients with declining symptoms in need of referral to palliative care or more aggressive symptom management. PMID- 26573280 TI - Out-of-pocket costs for cancer survivors between 5 and 10 years from diagnosis: an Italian population-based study. AB - PURPOSE: To illustrate the out-of-pocket (OOP) costs incurred by a population based group of patients from 5 to 10 years since their cancer diagnosis in a country with a nationwide public health system. METHODS: Interviews on OOP costs to a sample of 5-10 year prevalent cases randomly extracted from four population based cancer registries (CRs), two in the north and two in the south of Italy. The patients' general practitioners (GPs) gave assurance about the patient's physical and psychological condition for the interview. A zero-inflated negative binomial model was used to analyze OOP cost determinants. RESULTS: Two hundred six cancer patients were interviewed (48 % of the original sample). On average, a patient in the north spent ?69 monthly, against ?244 in the south. The main differences are for transport, room, and board (TRB) to reach the hospital and/or the cancer specialist (north ?0; south ?119). Everywhere, OOP costs without TRB costs were higher for patients with a low quality of life. CONCLUSIONS: Despite the limited participation, our study sample's characteristics are similar to those of the Italian cancer prevalence population, allowing us to generalize the results. The higher OOP costs in the south may be due to the scarcity of oncologic structures, obliging patients to seek assistance far from their residence. Implications for cancer survivors Cancer survivors need descriptive studies to show realistic data about their status. Future Italian and European descriptive studies on cancer survivorship should be based on population CRs and involve GPs in order to approach the patient at best. PMID- 26573281 TI - Impact of Cytochrome P450 2C19*2 and *3 on Clopidogrel Loading Dose in Saudi Patients with Acute Coronary Syndrome. AB - BACKGROUND: Emerging evidence shows that clopidogrel is greatly affected by nonfunctioning alleles measured by P2Y12 or platelet reactivity units (PRU). Cardiac events during short in-hospital stays have been inconclusively suggested as the main causes of discrepancies. OBJECTIVES: Evaluate the impact of CYP2C19 allele *2 and allele *3 on PRU and the potential clinical consequences of such interaction. To establish a rough estimation for the safe PRU limits for short inhospital stay following PCI. METHOD: A short-term experimental study was conducted with 90 patients who underwent coronary angioplasty with drug eluting stents at the Prince Sultan Cardiac Center, Buraidah. All the patients received an initial loading dose of 300 mg clopidogrel, followed by 75 mg daily. Blood samples were used for DNA extraction for cytochrome P450 (CYP) and realtime polymerase chain reaction (PCR) was used for genotyping. PRU and inhibition rate were tested by Verifynow(r). All in-hospital cardiac events were recorded until patients were discharged. RESULTS: Genotypes 1/1, 2/2, and 1/2 were expressed by 60, 28, and two patients (67, 32, and 3%), respectively. The PRU of the female patients was significantly higher than that of the male patients was (255.6 +/- 68.8 and 177.7 +/- 66.6, p = 0.000, respectively). There was no significant difference in PRUs (193 +/- 79 and 212 +/-55.4, respectively, p = 0.349), nor inhibition (17.9 +/- 18.80 and 13.88 +/- 11.5, p = 0.135) in wild and resistant variants, respectively. We only reported one cardiac in-thrombosis events. CONCLUSION: Genotype differences may not explain variations in the PRU of patients during short-term in-hospital stays. Although it is difficult to confirm, 117-267 units may be a safe PRU range for such patients, with emphasis on attaining higher PRU values in females. PMID- 26573282 TI - Genome characterization and phylogenetic analysis of a lineage IV peste des petits ruminants virus in southern China. AB - Since 2013, the second outbreak of peste des petits ruminants (PPR) caused by Peste des petits ruminants virus (PPRV) has spread over more than 20 provinces, municipalities, and autonomous regions in China, resulting in major economic losses for livestock industry. In 2014, we encountered a clinical PPR case on a goat farm in Guangdong province, southern China. The complete genome of this PPRV strain, named CH/GDDG/2014, was sequenced to determine its similarities and differences with other strains. The CH/GDDG/2014 genome comprised 15,954 nucleotides (six nucleotides more than classical PPRVs identified before 2013, but complying with the rule of six) with six open reading frames encoding nucleocapsid protein, phosphoprotein, matrix protein, fusion protein, hemagglutinin, and large polymerase protein, respectively. The whole-genome-based alignment analysis indicated that CH/GDDG/2014 had the most proximate consensus (99.8 %) to China/XJYL/2013 and the least consensus (87.2 %) to KN5/2011. The phylogenetic analysis showed that CH/GDDG/2014 was clustered in one branch (lineage IV) with other emerging strains during the second outbreak. This study is the first report describing the whole-genome sequence of PPRV in Guangdong province, southern China and also suggests the PPR outbreak may be closely related to illegal cross-regional importation of goats. PMID- 26573284 TI - The nature of delusion: psychologically explicable? psychologically inexplicable? philosophically explicable? Part 2. AB - The first part of this article dealt with the extant formulations of delusion, psychiatric and psychological, suggestions which, respectively, regard delusion as psychologically inexplicable or explicable. All this was subjected to critique. This second part puts forward informed philosophical thesis whereby delusion can be explained within the philosophical movement known as phenomenology and, in particular, Max Scheler's version of this. PMID- 26573283 TI - Complete genomic characterization and genetic diversity of four European genotype porcine reproductive and respiratory syndrome virus isolates from China in 2011. AB - Porcine reproductive and respiratory syndrome (PRRS) is an emerging disease that has caused serious economic losses to the swine industry worldwide. In 2011, a nation-wide surveillance program investigated the prevalence of PRRS viruses (PRRSV) in Chinese breeding swine farms, and four European genotype PRRSV (PRRSV Type 1) were successfully isolated. To explore the genetic diversity of PRRSV Type 1 in China, these 4 viral strains were subjected to genome sequencing and analysis. The four isolates shared 87.4-90.7 % nucleotide homology with the Lelystad strain (PRRSV-Type 1 stereotype strain). NSP2, ORF3, and ORF4 were the most variable regions and contained discontinuous deletions or insertions when compared to other PRRSV-Type 1 strains. All isolates fell into separate branches of the subtype 1 of PRRSV-Type 1 phylogenetic tree. This analysis of emerging PRRSV-Type 1 strains revealed previously unrecorded genetic diversity. Close attention should be paid to the prevention and control of this evolving virus. PMID- 26573285 TI - Fluorescein-N-Methylimidazole Conjugate as Cu(2+) Sensor in Mixed Aqueous Media Through Electron Transfer. AB - A new highly selective, chromogenic, and fluorogenic Cu(2+) chemosensor, fluorescein-N-methylimidazole conjugate 1, and another fluorescein-N-imidazole conjugate 2 were synthesized and investigated by UV-visible and fluorescence spectroscopy. The sensing of Cu(2+) quenches the emission band of 1 at lambdamax = 525 nm, with an association constant (K a = 1.0 x 10(7) M(-1)) and a stoichiometry of 1:1 in a buffered H2O: MeOH solution (4:1, pH = 7.4). The Cu(2+) detection limit for chemosensor 1 is 37 nM. The presence of the N-methyl group in 1 increased the Cu(2+) binding selectivity, resulting in a stronger binding constant and a broader pH working range (pH 5-10) in comparison to 2. The fluorescence in 1 and 2 is caused by electron transfer phenomenon from the imidazole nitrogen to fluorescein, which is readily inhibited by Cu(2+) binding. PMID- 26573287 TI - Immunohistochemical analysis of CD146 expression in canine skin tumours. AB - CD146, a cell adhesion molecule, is overexpressed in a variety of carcinomas, including melanoma, prostate cancer, epithelial ovarian cancer, and breast cancer. The level of expression is directly correlated with tumour progression and metastatic potential. The most commonly affected organ for both neoplastic and non-neoplastic tumours is the skin. The objective of this study is to investigate the immunohistochemical expression of CD146 in canine skin tumours of epidermal or follicular origin in 53 squamous cell carcinomas (SCCs), 9 squamous papillomas, 7 infundibular keratinizing acanthomas (IKA), 21 trichoepitheliomas, 13 trichoblastomas, and 3 pilomatricomas. Immunohistochemical results showed that SCCs (90.6%), squamous papilloma (33.3%), IKA (85.7%), trichoepithelioma (85.9%), trichoblastoma (30.8%) and pilomatricoma (100%), respectively, were positive for CD146. The significant expression of CD146 in SCCs supports its importance as a useful treatment target. CD146 could also be used in differentiation of trichoepithelioma and trichoblastoma. PMID- 26573286 TI - Eribulin upregulates miR-195 expression and downregulates Wnt3a expression in non basal-like type of triple-negative breast cancer cell MDA-MB-231. AB - Triple-negative breast cancer (TNBC), which does not show hormone sensitivity, is a poor prognosis disease without an established targeted treatment, so that establishing a therapeutic target for each subtype is desired. In addition, microRNA (miRNA), a non-cording RNA 19-25 nucleotide-longs in length, is known to be involved in regulating gene expression. We examined miRNA expression after exposure to eribulin, MDA-MB-231 cells, non-basal-like type of TNBC cell lines, and HCC1143 cells, basal-like type of TNBC cell lines. The activity of caspase-3 significantly increased compared to the control in MDA-MB-231, whereas no significant difference was observed in HCC1143. The expression level of 20-miRNAs significantly increased compared to the control in MDA-MB-231 after exposure to eribulin. The expression level of 6-miRNAs also significantly increased compared to the control in HCC1143. In these 2 cell types, miR-125b-1 and miR-195 were commonly expressed. While the expression level of miR-125b-1 decreased in both cells, the expression level of miR-195 increased in MDA-MB-231 and decreased in HCC1143. The expression level of miR-195 targeting Wnt3a significantly decreased compared to the control in MDA-MB-231, whereas it significantly increased in HCC1143. These results showed that exposure to eribulin highly increased the expression of miR-195 while it decreased the expression of Wnt3a in non-basal like type of TNBC. Some miRNAs are known to regulate other signaling pathways involved in human pathogenesis by regulating the Wnt signaling pathway, and miRNA can act as a tumor-suppressing gene; therefore, miR-195 may serve as a therapeutic target in non-basal-like type of TNBC. PMID- 26573288 TI - [In Process Citation]. AB - Today, lumbar disc disease is a very common disease, which will be often seen in both the family practice as well as in the consultations of orthopedics, neurology, rheumatology or neurosurgery. Furthermore, lumbar disc surgery is one of the most common spinal surgical procedures worldwide. But, for many centuries, physician had no clear understanding of the anatomical condition and the pathomechanism of this disease. Therefore, no rational treatment was available. The Hippocratic physicians knew the signs and symptoms of lumbar disc disease, which they then called "sciatica". But, they subsumed different disorders, like hip diseases under this term. In the mid-18th century, it was the Italian physician Domenico Felice Antonio Cotugno (1736-1822), who first brought clarity in the concept of radicular syndromes; he recognized, that the so-called "sciatica" could be of neurogenic origin. In 1742, a contemporary of Cotugno, the German Josias Weitbrecht (1702-1747) has to be credited for the first precise description of the intervertebral disc. Nearby a hundred years later, the German Hubert von Luschka (1820-1875) described for the first time a herniated disc in a pathologic specimen. With the landmark report of the New England Journal of Medicine in 1934, the two American surgeons, William Jason Mixter (1880-1958) and Joseph Seaton Barr (1901-1963), finally cleared the pathomechanism of lumbar disc disease. PMID- 26573289 TI - [Preface]. PMID- 26573290 TI - [Medication and bone metabolism: Clinical importance for fracture treatment]. AB - INTRODUCTION: The improvement and acceleration of fracture healing has been a component of medical practice since fractures have been treated. The aim is not only to fulfill the basic principles of fracture healing, such as reduction, retention, soft tissue coverage and infection prevention but also to reduce negative influences on fracture healing and promote positive factors. Nicotine, alcohol, diabetes and malnutrition can negatively affect fracture healing and should be appropriately controlled during fracture treatment; however, it is far more difficult to develop medicinal treatment strategies that lead to improvement and acceleration of fracture healing. AIM: This article provides an overview of pharmacological factors influencing fracture healing. In addition, substances frequently used in clinical practice will be evaluated in terms of the effects on fracture healing processes. MATERIAL AND METHODS: An extensive literature search was conducted in PubMed based on thematic keywords. The selection of studies and scientific publications focused mainly on results from clinical trials in order to provide practically relevant information. RESULTS: In this context, preclinical studies have identified several drugs that lead to the acceleration of fracture healing; however, only a very limited number of clinical trials have confirmed this positive effect. Most of these studies dealt with drugs developed for the treatment of osteoporosis, as osteoporotic fractures are common and a positive or negative influence of such drugs are of particular interest in this field. In the field of osteoporosis medication a certain degree of positive effect of parathyroid hormone 1-34 (PTH) on fracture healing has been shown in clinical trials. For other osteoporosis medications no negative influence on fracture healing in clinical settings has been reported; however, there seems to be a positive effect in terms of better implant fixation for patients receiving oral bisphosphonate therapy. DISCUSSION: Systemic medication to improve fracture healing will not be part of the clinical routine in the foreseeable future as the available data for already approved drugs and drugs under development do not currently justify routine administration. However, the currently known data should encourage the potential of known medications to be completely exhausted in fracture healing studies as well as novel therapy options in the sense of positive effects on fracture healing in order to improve patient care. PMID- 26573291 TI - [Sciatica. From stretch rack to microdiscectomy]. AB - In ancient times as well as in the Middle Ages treatment options for discogenic nerve compression syndrome were limited and usually not very specific because of low anatomical and pathophysiological knowledge. The stretch rack (scamnum Hippocratis) was particularly prominent but was widely used as a therapeutic device for very different spinal disorders. Since the beginning of the nineteenth century anatomical knowledge increased and the advances in the fields of asepsis, anesthesia and surgery resulted in an increase in surgical interventions on the spine. In 1908 the first successful lumbar discectomy was initiated and performed by the German neurologist Heinrich O. Oppenheim (1858-1919) and the surgeon Fedor Krause (1857-1937); however, neither recognized the true pathological condition of discogenic nerve compression syndrome. With the landmark report in the New England Journal of Medicine in 1934, the two American surgeons William Jason Mixter (1880-1958) and Joseph Seaton Barr (1901-1963) finally clarified the pathomechanism of lumbar disc herniation and furthermore, propagated discectomy as the standard therapy. Since then interventions on intervertebral discs rapidly increased and the treatment options for lumbar disc surgery quickly evolved. The surgical procedures changed over time and were continuously being refined. In the late 1960s the surgical microscope was introduced for spinal surgery by the work of the famous neurosurgeon Mahmut Gazi Yasargil and his colleague Wolfhard Caspar and so-called microdiscectomy was introduced. Besides open discectomy other interventional techniques were developed to overcome the side effects of surgical procedures. In 1964 the American orthopedic surgeon Lyman Smith (1912-1991) introduced chemonucleolysis, a minimally invasive technique consisting only of a cannula and the proteolytic enzyme chymopapain, which is injected into the disc compartment to dissolve the displaced disc material. In 1975 the Japanese orthopedic surgeon Sadahisa Hijikata described percutaneous discectomy for the first time, which was a further minimally invasive surgical technique. Further variants of minimally invasive surgical procedures, such as percutaneous laser discectomy in 1986 and percutaneous endoscopic microdiscectomy in 1997, were also introduced; however, open discectomy, especially microdiscectomy remains the therapeutic gold standard for lumbar disc herniation. PMID- 26573292 TI - Gene expression and functional annotation of human choroid plexus epithelium failure in Alzheimer's disease. AB - BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia. AD has a multifactorial disease etiology and is currently untreatable. Multiple genes and molecular mechanisms have been implicated in AD, including beta-amyloid deposition in the brain, neurofibrillary tangle accumulation of hyper phosphorylated Tau, synaptic failure, oxidative stress and inflammation. Relatively little is known about the role of the blood-brain barriers, especially the blood-cerebrospinal fluid barrier (BCSFB), in AD. The BCSFB is involved in cerebrospinal fluid (CSF) production, maintenance of brain homeostasis and neurodegenerative disorders. RESULTS: Using an Agilent platform with common reference design, we performed a large scale gene expression analysis and functional annotation of the Choroid Plexus Epithelium (CPE), which forms the BCSFB. We obtained 2 groups of freshly frozen Choroid Plexus (CP) of 7 human donor brains each, with and without AD: Braak stages (0-1) and (5-6). We cut CP cryo-sections and isolated RNA from cresyl-violet stained, laser dissected CPE cells. Gene expression results were analysed with T-tests (R) and the knowledge database Ingenuity. We found statistically significantly altered gene expression data sets, biological functions, canonical pathways, molecular networks and functionalities in AD-affected CPE. We observed specific cellular changes due to increased oxidative stress, such as the unfolded protein response, E1F2 and NRF2 signalling and the protein ubiquitin pathway. Most likely, the AD-affected BCSFB barrier becomes more permeable due to downregulation of CLDN5. Finally, our data also predicted down regulation of the glutathione mediated detoxification pathway and the urea cycle in the AD CPE, which suggest that the CPE sink action may be impaired. Remarkably, the expression of a number of genes known to be involved in AD, such as APP, PSEN1, PSEN2, TTR and CLU is moderate to high and remains stable in both healthy and affected CPE. Literature labelling of our new functional molecular networks confirmed multiple previous (molecular) observations in the AD literature and revealed many new ones. CONCLUSIONS: We conclude that CPE failure in AD exists. Combining our data with those of the literature, we propose the following chronological and overlapping chain of events: increased Abeta burden on CPE; increased oxidative stress in CPE; despite continuous high expression of TTR: decreased capability of CPE to process amyloid; (pro-) inflammatory and growth factor signalling by CPE; intracellular ubiquitin involvement, remodelling of CPE tight junctions and, finally, cellular atrophy. Our data corroborates the hypothesis that increased BCSFB permeability, especially loss of selective CLDN5 mediated paracellular transport, altered CSF production and CPE sink action, as well as loss of CPE mediated macrophage recruitment contribute to the pathogenesis of AD. PMID- 26573294 TI - Restarting antithrombotic drugs after gastrointestinal haemorrhage in people with atrial fibrillation. PMID- 26573293 TI - Doxazosin Treatment Attenuates Carbon Tetrachloride-Induced Liver Fibrosis in Hamsters through a Decrease in Transforming Growth Factor beta Secretion. AB - BACKGROUND/AIMS: The development of therapeutic strategies for the treatment of cirrhosis has become an important focus for basic and clinical researchers. Adrenergic receptor antagonists have been evaluated as antifibrotic drugs in rodent models of carbon tetrachloride (CCl4)-induced cirrhosis. The aim of the present study was to evaluate the effects of carvedilol and doxazosin on fibrosis/cirrhosis in a hamster animal model. METHODS: Cirrhotic-induced hamsters were treated by daily administration of carvedilol and doxazosin for 6 weeks. Hepatic function and histological evaluation were conducted by measuring biochemical markers, including total bilirubin, aspartate aminotransferase, alanine aminotransferase and albumin, and liver tissue slices. Additionally, transforming growth factor beta (TGF-beta) immunohistochemistry was analyzed. RESULTS: Biochemical markers revealed that hepatic function was restored after treatment with doxazosin and carvedilol. Histological evaluation showed a decrease in collagen type I deposits and TGF-beta-secreting cells. CONCLUSIONS: Taken together, these results suggest that the decrease in collagen type I following treatment with doxazosin or carvedilol is achieved by decreasing the profibrotic activities of TGF-beta via the blockage of alpha1- and beta adrenergic receptor. Consequently, a diminution of fibrotic tissue in the CCl4 induced model of cirrhosis is achieved. PMID- 26573295 TI - The G protein-coupled receptor P2RY8 and follicular dendritic cells promote germinal center confinement of B cells, whereas S1PR3 can contribute to their dissemination. AB - The orphan Galpha13-coupled receptor P2RY8 is mutated in human germinal center (GC)-derived lymphomas and was recently found to promote B cell association with GCs in a mouse model. Here we establish that P2RY8 promotes clustering of activated B cells within follicles in a follicular dendritic cell (FDC)-dependent manner. Although mice lack a P2RY8 orthologue, we show that mouse GC B cell clustering is also dependent on FDCs acting to support the function of a Galpha13 coupled receptor. Mutations in GNA13 and its downstream effector ARHGEF1 are associated with the development of disseminated GC-derived lymphomas. We find that egress of Gna13 mutant GC B cells from lymph nodes in the mouse depends on sphingosine-1-phosphate receptor-3. These findings provide evidence that FDCs promote GC confinement of both human and mouse GC B cells via Galpha13-dependent pathways, and they show that dissemination of Galpha13-deficient GC B cells additionally requires an egress-promoting receptor. PMID- 26573296 TI - Insulin-InsR signaling drives multipotent progenitor differentiation toward lymphoid lineages. AB - The lineage commitment of HSCs generates balanced myeloid and lymphoid populations in hematopoiesis. However, the underlying mechanisms that control this process remain largely unknown. Here, we show that insulin-insulin receptor (InsR) signaling is required for lineage commitment of multipotent progenitors (MPPs). Deletion of Insr in murine bone marrow causes skewed differentiation of MPPs to myeloid cells. mTOR acts as a downstream effector that modulates MPP differentiation. mTOR activates Stat3 by phosphorylation at serine 727 under insulin stimulation, which binds to the promoter of Ikaros, leading to its transcription priming. Our findings reveal that the insulin-InsR signaling drives MPP differentiation into lymphoid lineages in early lymphopoiesis, which is essential for maintaining a balanced immune system for an individual organism. PMID- 26573297 TI - Ethnicity and pathways to care during first episode psychosis: the role of cultural illness attributions. AB - BACKGROUND: Studies demonstrate ethnic variations in pathways to care during first episode psychosis (FEP). There are no extant studies, however, that have statistically examined the influence of culturally mediated illness attributions on these variations. METHODS: We conducted an observational study of 123 (45 White; 35 Black; 43 Asian) patients recruited over a two-year period from an Early Intervention Service (EIS) in Birmingham, UK. Sociodemographic factors (age; sex; education; country of birth; religious practice; marital status; living alone), duration of untreated psychosis (DUP), service contacts (general practitioner; emergency services; faith-based; compulsory detention; criminal justice) and illness attributions ("individual;" "natural;" "social;" "supernatural;" "no attribution") were assessed. RESULTS: Ethnic groups did not differ in DUP (p = 0.86). Asian patients were more likely to report supernatural illness attributions in comparison to White (Odds Ratio: 4.02; 95 % Confidence Intervals: 1.52, 10.62) and Black (OR: 3.48; 95 % CI: 1.25, 9.67) patients. In logistic regressions controlling for confounders and illness attributions, Black (OR: 14.00; 95 % CI: 1.30, 151.11) and Asian (OR: 13.29; 95 % CI: 1.26, 140.47) patients were more likely to consult faith-based institutions than White patients. Black patients were more likely to be compulsorily detained than White patients (OR: 4.56; 95 % CI: 1.40, 14.85). CONCLUSION: Illness attributions and sociodemographic confounders do not fully explain the ethnic tendency to seek out faith-based institutions. While Asian and Black patients are more likely to seek help from faith-based organisations, this does not appear to lead to a delay in contact with mental health services. PMID- 26573298 TI - The role of innate immune signaling in the pathogenesis of atopic dermatitis and consequences for treatments. AB - The skin is the largest organ at the interface between the environment and the host. Consequently, the skin plays a central role in mounting effective host defense. In addition to pathogens, the microbiota and the host immune system are in permanent contact and communication via the skin. Consequences of this permanent interaction are a unique and partly symbiotic relationship, a tight interdependence between these partners, and also a functional "setting the clock," in which, in the healthy steady state, an induction of protective responses to pathogens is guaranteed. At the same time, commensal microbes contribute to the alertness of the immune system and to the maintenance of immune tolerance. Atopic dermatitis (AD) is a chronic inflammatory skin disease based on a complex genetic trait with defects in cutaneous barrier, in stabilizing skin integrity. Most of AD patients develop deviated innate and adaptive immune responses. As a result, increased susceptibility to cutaneous infection is found in AD patients, and the interactions between these microbes and the skin participate in the development of chronic cutaneous inflammation. The role of the adaptive immune system was characterized in much detail, less though the contribution of innate immunity to AD pathogenesis. It is rather recent evidence that demonstrates a dominant role of components of the innate immune system not only for protecting from microbial invasion but also by orchestrating chronic skin inflammation. In this review we discuss the role of innate immune signaling and consecutive immune networks important for the pathogenesis and management of AD. PMID- 26573300 TI - Long-term outcomes after treatment for pedunculated-type T1 colorectal carcinoma: a multicenter retrospective cohort study. AB - BACKGROUND: The risk for lymph node metastasis and the prognostic significance of pedunculated-type T1 colorectal carcinomas (CRCs) require further study. We aimed to assess the validity of the 2014 Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines based on long-term outcomes of pedunculated-type T1 CRCs. METHODS: In this multicenter retrospective cohort study, we examined 176 patients who underwent resection endoscopically or surgically at 14 institutions between January 1990 and December 2010. Patients meeting the JSCCR curative criteria were defined as "endoscopically curable (e-curable)" and those who did not were "non-e-curable". We evaluated the prognosis of 116 patients (58 e curable, 58 non-e-curable) who were observed for >5 years after treatment. RESULTS: Overall incidence of lymph node metastasis was 5 % (4/81; 95 % confidence interval 1.4-12 %: three cases of submucosal invasion depth >=1000 MUm [stalk invasion] and lymphatic invasion, one case of head invasion and budding grade 2/3). There was no local or metastatic recurrence in the e-curable patients, but six of them died of another cause (observation period, 80 months). There was no local recurrence in the non-e-curable patients; however, distant metastasis was observed in one patient. Death due to the primary disease was not observed in non-e-curable patients, but six of them died of another cause (observation period, 72 months). CONCLUSIONS: Our data support the validity of the JSCCR curative criteria for pedunculated-type T1 CRCs. Endoscopic resection cannot be considered curative for pedunculated-type T1 CRC with head invasion alone. PMID- 26573301 TI - Tc-99m Radiolabeled Peptide p5 + 14 is an Effective Probe for SPECT Imaging of Systemic Amyloidosis. AB - PURPOSE: Systemic peripheral amyloidosis is a rare disease in which misfolded proteins deposit in various organs. We have previously developed I-124 labeled peptide p5 + 14 as a tracer for positron emission tomography imaging of amyloid in patients. In this report, we now document the labeling efficiency, bioactivity, and stability of Tc-99m labeled p5 + 14 for single-photon emission computed tomography (SPECT) imaging of amyloidosis, validated in a mouse model of systemic amyloidosis. PROCEDURES: Radiochemical yield, purity, and biological activity of [(99m)Tc]p5 + 14 were documented by instant thin-layer chromatography (ITLC), SDS-PAGE and a quantitative amyloid fibril pulldown assay. The efficacy and stability were documented in serum amyloid protein A (AA) amyloid-bearing or wild-type (WT) control mice imaged with SPECT/X-ray computed tomography (CT) at two time points. The uptake and retention of [(99m)Tc]p5 + 14 in hepatosplenic amyloid was evaluated using region of interest (ROI) and tissue counting measurements. RESULTS: Tc-99m p5 + 14 was produced with a radiochemical yield of 75 % with greater than 90 % purity and biological activity comparable to that of radioiodinated peptide. AA amyloid was visualized by SPECT/CT imaging with specific uptake seen in amyloid-laden organs at levels ~5 folds higher than in healthy mice. ROI analyses of decay-corrected SPECT/CT images showed <20 % loss of radiolabel from the 1 to 4 h imaging time points. Biodistribution data confirmed the specificity of the probe accumulation by amyloid-laden organs as compared to non-diseased tissues. CONCLUSION: [(99m)Tc]p5 + 14 is a specific and stable radiotracer for systemic amyloid in mice and may provide a convenient and inexpensive alternative to imaging of peripheral amyloidosis in patients. PMID- 26573299 TI - Update on psoriasis immunopathogenesis and targeted immunotherapy. AB - Over recent years, significant progress has been made in characterisation of the underlying pathogenic mechanisms in psoriasis, a common cutaneous disease that is associated with major systemic co-morbidity and reduced life expectancy. Basic science discoveries have informed the design of novel therapeutic approaches, many of which are now under evaluation in late-stage clinical trials. Here we describe the complex interplay between immune cell types and cytokine networks that acts within self-perpetuating feedback loops to drive cutaneous inflammation in psoriasis. Genetic studies have been pivotal in the construction of the disease model and more recently have uncovered a distinct aetiology for rare, pustular variants of psoriasis. The translation of mechanistic insights into potential advancements in clinical care will also be described, including several treatments that target the interleukin-23 (IL-23)/T17 immune axis. PMID- 26573302 TI - An Ethical Framework for Evaluating Experimental Technology. AB - How are we to appraise new technological developments that may bring revolutionary social changes? Currently this is often done by trying to predict or anticipate social consequences and to use these as a basis for moral and regulatory appraisal. Such an approach can, however, not deal with the uncertainties and unknowns that are inherent in social changes induced by technological development. An alternative approach is proposed that conceives of the introduction of new technologies into society as a social experiment. An ethical framework for the acceptability of such experiments is developed based on the bioethical principles for experiments with human subjects: non-maleficence, beneficence, respect for autonomy, and justice. This provides a handle for the moral and regulatory assessment of new technologies and their impact on society. PMID- 26573303 TI - Trouble in Paradise: Problems in Academic Research Co-authoring. AB - Scholars and policy-makers have expressed concerns about the crediting of coauthors in research publications. Most such problems fall into one of two categories, excluding deserving contributors or including undeserving ones. But our research shows that there is no consensus on "deserving" or on what type of contribution suffices for co-authorship award. Our study uses qualitative data, including interviews with 60 US academic science or engineering researchers in 14 disciplines in a set of geographically distributed research-intensive universities. We also employ data from 161 website posts provided by 93 study participants, again US academic scientists. We examine a variety of factors related to perceived unwarranted exclusion from co-author credit and unwarranted inclusion, providing an empirically-informed conceptual model to explain co author crediting outcomes. Determinants of outcomes include characteristics of disciplines and fields, institutional work culture, power dynamics and team specific norms and decision processes. PMID- 26573304 TI - Experience with genetic counseling: the adolescent perspective. AB - Adolescence is a complex period of development that involves creating a sense of identity, autonomy, relationships and values. This stage of adjustment can be complicated by having a genetic condition. Genetic counseling can play an important role in providing information and support to this patient population; however, resources and guidelines are currently limited. In order to appropriately establish genetic counseling approaches and resource development, we investigated the experiences and perspectives of adolescents with a genetic condition with respect to their genetic counseling interactions. Using a qualitative exploratory approach, eleven semi-structured interviews were conducted with adolescents diagnosed with a genetic condition who received genetic counseling between the ages of 12 and 18 years at The Hospital for Sick Children. Transcripts were analyzed thematically using qualitative content analysis, from which three major interrelated themes emerged: 1) understanding the genetic counselor's role; 2) increasing perceived personal control; and 3) adolescent-specific factors influencing adaptation to one's condition. Additionally, a list of suggested tools and strategies for genetic counseling practice were elucidated. Our findings can contribute to the development of an adolescent-focused framework to enhance emerging genetic counseling approaches for this patient population, and can also facilitate the transition process from pediatric to adult care within patient and family-centered contexts. PMID- 26573305 TI - Is disability pension a risk indicator for future need of psychiatric healthcare or suicidal behavior among MS patients- a nationwide register study in Sweden? AB - BACKGROUND: Mental disorders and suicidal behavior are common in patients with multiple sclerosis (MS), they also carry a higher risk of disability pension (DP). Our aim was to investigate if DP and other factors are associated with psychiatric disorders and suicidal behavior among MS patients, and whether DP is a stronger risk indicator among certain groups. METHOD: A prospective population based cohort study with six-year follow-up (2005-2010), including 11 346 MS patients who in 2004 were aged 16-64 and lived in Sweden. Incidence rate ratios (IRR) with 95 % confidence intervals (CI) were calculated. RESULTS: MS patients on DP had a modestly higher risk of requiring psychiatric healthcare, IRR: 1.36 (95 % CI: 1.18-1.58). MS patients with previous psychiatric healthcare had a higher IRR for both psychiatric healthcare and suicidal behavior; 2.32 (2.18 2.47) and 1.91 (1.59-2.30), respectively. DP moderated the association between sex and psychiatric healthcare, where women on DP displayed higher risk than men, X(2) 4.74 (p = 0.03). CONCLUSION: The findings suggest that losing one's role in work life aggravates rather than alleviates the burden of MS, as MS patients on DP seem to have a higher need for psychiatric healthcare, especially among women; which calls for extra awareness among clinicians. PMID- 26573306 TI - Challenges of diatom-based biological monitoring and assessment of streams in developing countries. AB - Stream biomonitoring tools are largely lacking for many developing countries, resulting in adoption of tools developed from other countries/regions. In many instances, however, the applicability of adopted tools to the new system has not been explicitly evaluated. The objective of this study was to test the applicability of foreign diatom-based water quality assessment indices to streams in Zimbabwe, with the view to highlight challenges being faced in diatom-based biological monitoring in this developing country. The study evaluated the relationship between measured water quality variables and diatom index scores and observed some degree of concordance between water quality variables and diatom index scores emphasising the importance of diatom indices in characterisation and monitoring of stream ecological conditions in developing countries. However, ecological requirements of some diatom species need to be clarified and incorporated in a diatom-based water quality assessment protocol unique to these regions. Resources should be channelled towards tackling challenges associated with diatom-based biological monitoring, principally taxonomic studies, training of skilled labour and acquiring and maintaining the necessary infrastructure. Meanwhile, simpler coarse taxonomy-based rapid bioassessment protocol, which is less time and resource consuming and requires less specialised manpower, can be developed for the country. PMID- 26573307 TI - Impact of a long-term fire retardant (Fire Trol 931) on the leaching of Ca, Mg, and K from a Mediterranean forest loamy soil. AB - The present laboratory study was conducted in pot soil taken from forest. The leaching of calcium (Ca), magnesium (Mg), and potassium (K) (plant macronutrients) due to the application of a nitrogen phosphate-based long-term fire retardant (LTFR) (Fire Trol 931) was investigated. The concentrations of Ca(2+), Mg(2+), and K(+) were measured in the resulting leachates from pots with forest soil and pine tree alone and in combination with fire. Magnesium is a minor component of Fire Trol 931. The leaching of Ca(2+), Mg(2+), and K(+) from treated soils with the retardant pots was significantly greater than that from control pots. The leaching of Mg(2+) was found to be of small percentage of the initially applied Mg quantities. Fire Trol 931 application resulted in the leaching of Ca(2+), Mg(2+), and K(+) from a typical Mediterranean forest soil in pots, following the application of simulated annual precipitation probably due to ammonium (one of the major retardant components) soil deposition that mobilizes base cations from the soil. It seems that LTFR application may result in chemical leaching from the soil to the drainage water. PMID- 26573308 TI - The legacy of lead (Pb) in fluvial bed sediments of an urban drainage basin, Oahu, Hawaii. AB - The study of fluvial bed sediments is essential for deciphering the impact of anthropogenic activities on water quality and drainage basin integrity. In this study, a systematic sampling design was employed to characterize the spatial variation of lead (Pb) concentrations in bed sediment of urban streams in the Palolo drainage basin, southeastern Oahu, Hawaii. Potentially bioavailable Pb was assessed with a dilute 0.5 N HCl extraction of the <63 MUm grain-size fraction from the upper bed sediment layer of 169 samples from Palolo, Pukele, and Waiomao streams. Contamination of bed sediments was associated with the direct transport of legacy Pb from the leaded gasoline era to stream channels via a dense network of storm drains linked to road surfaces throughout the basin. The Palolo Stream had the highest median Pb concentration (134 mg/kg), and the greatest road and storm drain densities, the greatest population, and the most vehicle numbers. Lower median Pb concentrations were associated with the less impacted Pukele Stream (24 mg/kg), and Waiomao Stream (7 mg/kg). The median Pb enrichment ratio values followed the sequence of Palolo (68) > Pukele (19) > Waiomao (8). Comparisons to sediment quality guidelines and potential toxicity estimates using a logistic regression model (LRM) indicated a significant potential risk of Palolo Stream bed sediments to bottom-dwelling organisms. PMID- 26573309 TI - Purifying capability, enzyme activity, and nitrification potentials in December in integrated vertical flow constructed wetland with earthworms and different substrates. AB - The response of purifying capability, enzyme activity, nitrification potentials, and total number of bacteria in the rhizosphere in December to wetland plants, substrates, and earthworms was investigated in integrated vertical flow constructed wetlands (IVFCW). The removal efficiency of total nitrogen (TN), NH4 N, chemical oxygen demand (COD), and total phosphorus (TP) was increased when earthworms were added into IVFCW. A significantly average removal efficiency of N in IVFCW that employed river sand as substrate and in IVFCW that employed a mixture of river sand and Qing sand as substrate was not found. However, the average removal efficiency of P was higher in IVFCW with a mixture of river sand and Qing sand as substrate than in IVFCW with river sand as substrate. Invertase activity in December was higher in IVFCW that used a mixture of river sand and Qing sand as substrate than in IVFCW which used only river sand as substrate. However, urease activity, nitrification potential, and total number of bacteria in December was higher in IVFCW that employed river sand as substrate than in IVFCW with a mixture of river sand and Qing sand as substrate. The addition of earthworms into the integrated vertical flow constructed wetland increased the above-ground biomass, enzyme activity (catalase, urease, and invertase), nitrification potentials, and total number of bacteria in December. The above ground biomass of wetland plants was significantly positively correlated with urease and nitrification potentials (p < 0.01). The addition of earthworms into IVFCW increased enzyme activity and nitrification potentials in December, which resulted in improving purifying capability. PMID- 26573310 TI - Chemical and sulfur isotopic composition of precipitation in Beijing, China. AB - China is experiencing serious acid rain contamination, with Beijing among the worst-hit areas. To understand the chemical feature and the origin of inorganic ions in precipitation of Beijing, 128 precipitation samples were collected and analyzed for major water-soluble ions and delta(34)S. The pH values ranged from 3.68 to 7.81 and showed a volume weighted average value (VWA) of 5.02, with a frequency of acid rain of 26.8 %. The VWA value of electrical conductivity (EC) was 68.6 MUS/cm, which was nearly 4 times higher than the background value of northern China. Ca(2+) represented the main cation; SO4 (2-) and NO3 (-) were the dominant anion in precipitation. Our study showed that SO4 (2-) and NO3 (-) originated from coal and fossil fuel combustion; Ca(2+), Mg(2+), and K(+) were from the continental sources. The delta(34)S value of SO4 (2-) in precipitation ranged from +2.1 to +12.80/00 with an average value of +4.70/00. The delta(34)S value showed a winter maximum and a summer minimum tendency, which was mainly associated with temperature-dependent isotope equilibrium fractionation as well as combustion of coal with relatively positive delta(34)S values in winter. Moreover, the delta(34)S values revealed that atmospheric sulfur in Beijing are mainly correlated to coal burning and traffic emission; coal combustion constituted a significant fraction of the SO4 (2-) in winter precipitation. PMID- 26573311 TI - Growth responses of Scots pine to climatic factors on reclaimed oil shale mined land. AB - Afforestation on reclaimed mining areas has high ecological and economic importance. However, ecosystems established on post-mining substrate can become vulnerable due to climate variability. We used tree-ring data and dendrochronological techniques to study the relationship between climate variables and annual growth of Scots pine (Pinus sylvestris L.) growing on reclaimed open cast oil shale mining areas in Northeast Estonia. Chronologies for trees of different age classes (50, 40, 30) were developed. Pearson's correlation analysis between radial growth indices and monthly climate variables revealed that precipitation in June-July and higher mean temperatures in spring season enhanced radial growth of pine plantations, while higher than average temperatures in summer months inhibited wood production. Sensitivity of radial increment to climatic factors on post-mining soils was not homogenous among the studied populations. Older trees growing on more developed soils were more sensitive to precipitation deficit in summer, while growth indices of two other stand groups (young and middle-aged) were highly correlated to temperature. High mean temperatures in August were negatively related to annual wood production in all trees, while trees in the youngest stands benefited from warmer temperatures in January. As a response to thinning, mean annual basal area increment increased up to 50 %. By managing tree competition in the closed-canopy stands, through the thinning activities, tree sensitivity and response to climate could be manipulated. PMID- 26573312 TI - Distributions, fluxes, and toxicities of heavy metals in sediment pore water from tributaries of the Ziya River system, northern China. AB - The distributions and mobilities of metals in pore water strongly influence the biogeochemical processes and bioavailabilities of metals at sediment-water interfaces. Heavy metal concentrations were measured in pore water samples from the Shaocun River (SR), the Wangyang River (WR), and the Xiao River (XR), tributaries of the Ziya River system, northern China. The aim was to assess heavy metal contamination in the system and the associated environmental risks. The mean Cd, Cr, Cu, Ni, Pb, and Zn concentrations in all three tributaries were 0.373, 57.1, 37.7, 20.4, 14.0, and 90.6 MUg/L, respectively. The calculated Cd, Cr, Cu, Ni, Pb, and Zn diffusion fluxes in the rivers were -0.427 to 0.469, -71.8 to 42.5, 3.16 to 86.6, 5.29 to 14.0, 7.24 to 19.0, and -204 to 21.9 MUg/(m(2) day), respectively, showing that the pore water was a source of most of the metals to the water column. Only Cu and Pb in the XR and Cu in the WR exceeded the final chronic value recommended by the US Environmental Protection Agency, but the metals in the WR sediment could have caused toxic effects. These results are likely to be useful to the authorities responsible for sustainable river management. PMID- 26573313 TI - Accumulation of Cd, Cu and Zn in shoots of maize (Zea mays L.) exposed to 0.8 or 20 nM Cd during vegetative growth and the relation with xylem sap composition. AB - This work focuses on the exposure of maize plants to nanomolar concentrations of Cd, which is relevant for agricultural soils cropped with food and feed plants. Maize plants were cultivated in nutrient solution at 0.8 or 20 nM Cd during the vegetative growth stages. No significant hormesis or toxic effects of Cd were observed on maize growth, but a decrease in the allocation of Cd to shoots between the 0.8 and 20 nM Cd exposures revealed that the plants already responded to these low concentrations of Cd according to a shoot Cd excluder strategy. The Cd, Cu and Zn concentrations in shoots decreased with time as the result of an early decrease in the root/shoot ratio and of a decrease in the coefficient of allocation to aboveground for Zn and Cd at 20 nM. As a consequence, shoots of young plants were richer in micronutrients Cu and Zn but also in toxic Cd. The rate of delivery of Cd, Cu and Zn from xylem sap was successfully used to predict the time course of concentrations of Cd, Cu and Zn in the shoot. However, it overestimated the actual concentrations of Cd in the shoot, presumably because the reallocation of this trace element from shoots back to roots was not taken into account. PMID- 26573314 TI - A study on toxic and essential elements in wheat grain from the Republic of Kazakhstan. AB - Little information is currently available about the content of different elements in wheat samples from the Republic of Kazakhstan. The concentrations of toxic (As, Cd, Cr, Hg, Pb, and U) and essential (Co, Cu, Fe, Mn, Ni, Se, and Zn) elements in 117 sampled wheat grains from the Republic of Kazakhstan were measured. The results indicated that the mean and maximum concentrations of most investigated elements (As, Cd, Co, Cr, Mn, Se, Pb, and U) were higher in samples collected from southern Kazakhstan. The mean and maximum concentrations of toxic elements such as As, Cd, Hg, and Pb did not exceed levels specified by European, FAO, or Kazakh legislation, although the hazard quotient (HQ) values for Co, Cu, Mn, and Zn were higher than 1 and the hazard index (HI) was higher than 1 for samples collected from all areas of Kazakhstan. This indicates that there should be concern about the potential hazards of the combination of toxic elements in Kazakh wheat. PMID- 26573315 TI - Utilization of rice husk silica as adsorbent for BTEX passive air sampler under high humidity condition. AB - Selective adsorbent of benzene, toluene, ethylbenzene, and xylenes (BTEX) was developed based on mesoporous silica materials, RH-MCM-41. It was synthesized from rice husk silica and modified by silane reagents. The silane reagents used in this study were trimethylchlorosilane (TMS), triisopropylchlorosilane (TIPS), and phenyldimethylchlorosilane (PDMS). Physiochemical properties of synthesized materials were characterized by small-angle X-ray diffraction (XRD), Fourier transformed infrared spectroscopy (FTIR), and surface area analysis. Materials packed in passive air sampler were tested for BTEX uptake capacity. The tests were carried out under an influence of relative humidity (25 to 99 %). Overall, RH-MCM-41 modified by TMS outperformed compared to those modified by other silane agents. The comparative BTEX adsorption on this material and commercial graphitized carbon black was reported. PMID- 26573316 TI - Gross parameters prediction of a granular-attached biomass reactor by means of multi-objective genetic-designed artificial neural networks: touristic pressure management case. AB - The Artificial Neural Networks by Multi-objective Genetic Algorithms (ANN-MOGA) model has been applied to gross parameters data of a Sequencing Batch Biofilter Granular Reactor (SBBGR) with the aim of providing an effective tool for predicting the fluctuations coming from touristic pressure. Six independent multivariate models, which were able to predict the dynamics of raw chemical oxygen demand (COD), soluble chemical oxygen demand (CODsol), total suspended solid (TSS), total nitrogen (TN), ammoniacal nitrogen (N-NH4 (+)) and total phosphorus (Ptot), were developed. The ANN-MOGA software application has shown to be suitable for addressing the SBBGR reactor modelling. The R (2) found are very good, with values equal to 0.94, 0.92, 0.88, 0.88, 0.98 and 0.91 for COD, CODsol, N-NH4 (+), TN, Ptot and TSS, respectively. A comparison was made between SBBGR and traditional activated sludge treatment plant modelling. The results showed the better performance of the ANN-MOGA application with respect to a wide selection of scientific literature cases. PMID- 26573317 TI - Effects of root exudates on the leachability, distribution, and bioavailability of phenanthrene and pyrene from mangrove sediments. AB - In this study, column leaching experiments were used to evaluate the leachability, distribution and bioavailability of phenanthrene and pyrene by root exudates from contaminated mangrove sediments. We observed that root exudates significantly promoted the release and enhanced the bioavailability of phenanthrene and pyrene from sediment columns. The concentration of phenanthrene and pyrene and cumulative content released from the analyzed sediment samples following root exudate rinsing decreased in the following order: citric acid > oxalic acid > malic acid. After elution, the total concentrations of phenanthrene and pyrene in sediment layers followed a descending order of bottom (9-12 cm) > middle (5-7 cm) > top (0-3 cm). Furthermore, a positive correlation between leachate pH values and PAH concentrations of the leachate was found. Consequently, the addition of root exudates can increase the leachability and bioavailability of phenanthrene and pyrene. PMID- 26573318 TI - Active and passive sampling for the assessment of hydrophilic organic contaminants in a river basin-ecotoxicological risk assessment. AB - This study presents a complementary approach for the evaluation of water quality in a river basin by employing active and passive sampling. Thirty-eight hydrophilic organic compounds (HpOCs) (organohalogen herbicides, organophosphorous pesticides, carbamate, triazine, urea, pharmaceuticals, phenols, and industrial chemicals) were studied in grab water samples and in passive samplers POCIS collected along Strymonas River, Northern Greece, at three sampling campaigns during the year 2013. Almost all the target compounds were detected at the periods of high rainfall intensity and/or low flow rate. The most frequently detected compounds were aminocarb, carbaryl, chlorfenviphos, chloropropham, 2,4-D, diflubenzuron, diuron, isoproturon, metolachlor, and salicylic acid. Bisphenol A and nonylphenol were also occasionally detected. The use of POCIS allowed the detection of more micropollutants than active sampling. Low discrepancy between the concentrations obtained from both samplings was observed, at least for compounds with >50 % detection frequency; thus, POCIS could be a valuable tool for the selection and monitoring of the most relevant HpOCs in the river basin. Results showed relatively low risk from the presence of HpOCs; however, the potential risk associated with micropollutants such as carbaryl, dinoseb, diuron, fenthion, isoproturon, metolachlor, nonylphenol, and salicylic acid should not be neglected. PMID- 26573319 TI - What Factors Influence the Success of Medial Gastrocnemius Flaps in the Treatment of Infected TKAs? AB - BACKGROUND: Soft tissue defects after TKA are a potentially devastating complication. Medial gastrocnemius flaps occasionally are used to provide soft tissue coverage, most commonly with a periprosthetic joint infection. QUESTIONS/PURPOSES: We asked: (1) What were the rates of persistent or recurrent infection, implant survivorship, flap-related complications, and reoperation for patients who underwent medial gastrocnemius flap reconstruction for soft tissue coverage after TKA? (2) What were the Knee Society clinical and functional scores for patients who underwent medial gastrocnemius flap reconstruction for soft tissue defects after TKA? (3) What were the risk factors for failure of medial gastrocnemius flap reconstruction after TKA, with failure defined as recurrent or new periprosthetic joint infection or inability to reimplant the TKA prosthesis? METHODS: Between 2003 and 2011, four surgeons at one institution performed 31 medial gastrocnemius flaps for soft tissue coverage over an infected TKA. Of those, 27 (87%) were available for followup at a minimum of 2 years (mean, 4 years; range, 2-6 years), although patients experiencing complications or treatment failures before two years were included. The study group consisted of 15 men and 12 women with a mean age of 61 years at the time of surgery (range, 36 86 years). The general indication for using a gastrocnemius flap in this setting was full-thickness soft tissue deficiency over the anterior knee during the course of treatment for concomitant deep infection. Six flaps were performed at prosthetic explantation and antibiotic spacer placement, eight at a spacer exchange, eight at second-stage TKA prosthesis reimplantation, and five at debridement with polyethylene exchange. The decision regarding when during staged treatment to place the flap was based solely on when the soft tissues were deemed insufficient, and not based on a belief that placement at one stage versus another was advantageous. Failure was defined as inability to undergo reimplantation of a TKA prosthesis or recurrence of periprosthetic joint infection. Patient and procedural characteristics were tested for association with failure. Survivorship was calculated by Cox proportional hazards modeling. Outcomes scores were drawn from a longitudinal institutional registry. RESULTS: Fourteen of 27 (52%) patients had a persistent or recurrent infection; survivorship of the TKA prosthesis at 4 years was 48% (95% CI, 31%-66%). Although there were no flap-related complications, 12 patients had a total of 19 reoperations during the study period. Overall, the mean (+/- SD) Knee Society knee (38 +/- 18 vs 65 +/- 20; p < 0.001) and function (20 +/- 22 vs 37 +/- 25; p = 0.002) scores were improved at most recent followup. No factors were identified as associated with failure when a Bonferroni correction was applied. CONCLUSIONS: Gastrocnemius flaps were used to address difficult soft tissue defects in this series, in the presence of deep infections; the high proportion of patients experiencing persistent or recurrent infections reflects the case complexity and not necessarily a problem with the flaps. However, this series highlights the need to continue to explore alternative approaches to managing this difficult clinical problem. Future studies should aim to establish an evidence-based reconstructive algorithm, focusing on host, wound, and timing characteristics that may maximize outcomes. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 26573320 TI - Editorial: Getting Evidence Into Practice--or Not: The Case of Viscosupplementation. PMID- 26573321 TI - Groin and Medial Thigh Pain in a 17-year-old Girl. PMID- 26573322 TI - Is Local Infiltration Analgesia Superior to Peripheral Nerve Blockade for Pain Management After THA: A Network Meta-analysis. AB - BACKGROUND: Local infiltration analgesia and peripheral nerve blocks are common methods for pain management in patients after THA but direct head-to-head, randomized controlled trials (RCTs) have not been performed. A network meta analysis allows indirect comparison of individual treatments relative to a common comparator; in this case placebo (or no intervention), epidural analgesia, and intrathecal morphine, yielding an estimate of comparative efficacy. QUESTIONS/PURPOSES: We asked, when compared with a placebo, (1) does use of local infiltration analgesia reduce patient pain scores and opioid consumption, (2) does use of peripheral nerve blocks reduce patient pain scores and opioid consumption, and (3) is local infiltration analgesia favored over peripheral nerve blocks for postoperative pain management after THA? METHODS: We searched six databases, from inception through June 30, 2014, to identify RCTs comparing local infiltration analgesia or peripheral nerve block use in patients after THA. A total of 35 RCTs at low risk of bias based on the recommended Cochrane Collaboration risk assessment tool were included in the network meta-analysis (2296 patients). Primary outcomes for this review were patient pain scores at rest and cumulative opioid consumption, both assessed at 24 hours after THA. Because of substantial heterogeneity (variation of outcomes between studies) across included trials, a random effect model for meta-analysis was used to estimate the weighted mean difference (WMD) and 95% CI. The gray literature was searched with the same inclusion criteria as published trials. Only one unpublished trial (published abstract) fulfilled our criteria and was included in this review. All other studies included in this systematic review were full published articles. Bayesian network meta-analysis included all RCTs that compared local infiltration analgesia or peripheral nerve blocks with placebo (or no intervention), epidural analgesia, and intrathecal morphine. RESULTS: Compared with placebo, local infiltration analgesia reduced patient pain scores (WMD, 0.61; 95% CI, -0.97 to -0.24; p = 0.001) and opioid consumption (WMD, -7.16 mg; 95% CI, -11.98 to -2.35; p = 0.004). Peripheral nerve blocks did not result in lower pain scores or reduced opioid consumption compared with placebo (WMD, 0.43; 95% CI, -0.99 to 0.12; p = 0.12 and WMD, -3.14 mg, 95% CI, -11.30 to 5.02; p = 0.45). However, network meta-analysis comparing local infiltration analgesia with peripheral nerve blocks through common comparators showed no differences between postoperative pain scores (WMD, -0.36; 95% CI, -1.06 to 0.31) and opioid consumption (WMD, -4.59 mg; 95% CI, -9.35 to 0.17), although rank-order analysis found local infiltration analgesia to be ranked first in more simulations than peripheral nerve blocks, suggesting that it may be more effective. CONCLUSIONS: Using the novel statistical network meta-analysis approach, we found no differences between local infiltration analgesia and peripheral nerve blocks in terms of analgesia or opioid consumption 24 hours after THA; there was a suggestion of a slight advantage to peripheral nerve blocks based on rank-order analysis, but the effect size in question is likely not large. Given the slight difference between interventions, clinicians may choose to focus on other factors such as cost and intervention-related complications when debating which analgesic treatment to use after THA. LEVEL OF EVIDENCE: Level I, therapeutic study. PMID- 26573323 TI - Outpatient treatment of alcohol use disorders among subjects 60+ years: design of a randomized clinical trial conducted in three countries (Elderly Study). AB - BACKGROUND: The proportion of 60+ years with excessive alcohol intake varies in western countries between 6-16 % among men and 2-7 % among women. Specific events related to aging (e.g. loss of job, physical and mental capacity, or spouse) may contribute to onset or continuation of alcohol use disorders (AUD). We present the rationale and design of a multisite, multinational AUD treatment study for subjects aged 60+ years. METHODS/DESIGN: 1,000 subjects seeking treatment for AUD according to DSM-5 in outpatient clinics in Denmark, Germany, and New Mexico (USA) are invited to participate in a RCT. Participants are randomly assigned to four sessions of Motivational Enhancement Treatment (MET) or to MET plus an add on with eight sessions based on the Community Reinforcement Approach (CRA), which include a new module targeting specific problems of older adults. A series of assessment instruments is applied, including the Form-90, Alcohol Dependence Scale, Penn Alcohol Craving Scale, Brief Symptom Inventory and WHO Quality of Life. Enrolment will be completed by April 2016 and data collection by April 2017. The primary outcome is the proportion in each group who are abstinent or have a controlled use of alcohol six months after treatment initiation. Controlled use is defined as maximum blood alcohol content not exceeding 0.05 % during the last month. Total abstinence is a secondary outcome, together with quality of life andcompliance with treatment. DISCUSSION: The study will provide new knowledge about brief treatment of AUD for older subjects. As the treatment is manualized and applied in routine treatment facilities, barriers for implementation in the health care system are relatively low. Finally, as the study is being conducted in three different countries it will also provide significant insight into the possible interaction of service system differences and related patient characteristics in predictionof treatment outcome. TRIAL REGISTRATION: Clinical Trials.gov NCT02084173 , March 7, 2014. PMID- 26573324 TI - A systematic review for the antidepressant effects of sleep deprivation with repetitive transcranial magnetic stimulation. AB - BACKGROUND: Sleep deprivation (SD) and repetitive transcranial magnetic stimulation (rTMS) have been commonly used to treat depression. Recent studies suggest that co-therapy with rTMS and SD may produce better therapeutic effects than either therapy alone. Therefore, this study was to review the current findings to determine if rTMS can augment the therapeutic effects of SD on depression. METHODS: Embase, JSTOR, Medline, PubMed, ScienceDirect, and the Cochrane Central Register of Controlled Trials were searched for clinical studies published between January 1985 and March 2015 using the search term "rTMS/repetitive transcranial magnetic stimulation AND sleep deprivation AND depress*". Only randomized and sham-controlled trials (RCTs) involving the combined use of rTMS and SD in depression patients were included in this systematic review. The scores of the Hamilton Rating Scale for Depression were extracted as primary outcome measures. RESULTS: Three RCTs with 72 patients that met the inclusion criteria were included for the systematic review. One of the trials reported skewed data and was described alone. The other two studies, which involved 30 patients in the experimental group (SD + active rTMS) and 22 patients in the control group (SD + sham rTMS), reported normally distributed data. The primary outcome measures showed different results among the three publications: two of which showed great difference between the experimental and the control subjects, and the other one showed non-significant antidepressant effect of rTMS on SD. In addition, two of the included studies reported secondary outcome measures with Clinical Global Impression Rating Scale and a self-reported well being scale which presented good improvement for the depressive patients in the experiment group when compared with the control. The follow-up assessments in two studies indicated maintained results with the immediate measurements. CONCLUSIONS: From this study, an overview of the publications concerning the combined use of rTMS and SD is presented, which provides a direction for future research of therapies for depression. More studies are needed to confirm whether there is an augmentative antidepressant effect of rTMS on SD. PMID- 26573326 TI - Desolvation-Driven 100-Fold Slow-down of Tunneling Relaxation Rate in Co(II) Dy(III) Single-Molecule Magnets through a Single-Crystal-to-Single-Crystal Process. AB - Single-molecule magnets (SMMs) are regarded as a class of promising materials for spintronic and ultrahigh-density storage devices. Tuning the magnetic dynamics of single-molecule magnets is a crucial challenge for chemists. Lanthanide ions are not only highly magnetically anisotropic but also highly sensitive to the changes in the coordination environments. We developed a feasible approach to understand parts of the magneto-structure correlations and propose to regulate the relaxation behaviors via rational design. A series of Co(II)-Dy(III)-Co(II) complexes were obtained using in situ synthesis; in this system of complexes, the relaxation dynamics can be greatly improved, accompanied with desolvation, via single-crystal to single-crystal transformation. The effective energy barrier can be increased from 293 cm(-1) (422 K) to 416 cm(-1) (600 K), and the tunneling relaxation time can be grown from 8.5 * 10(-4) s to 7.4 * 10(-2) s. These remarkable improvements are due to the change in the coordination environments of Dy(III) and Co(II). Ab initio calculations were performed to better understand the magnetic dynamics. PMID- 26573325 TI - Recurrent internal tandem duplications of BCOR in clear cell sarcoma of the kidney. AB - The X-linked BCL-6 co-repressor (BCOR) gene encodes a key constituent of a variant polycomb repressive complex (PRC) that is mutated or translocated in human cancers. Here we report on the identification of somatic internal tandem duplications (ITDs) clustering in the C terminus of BCOR in 23 of 27 (85%) pediatric clear cell sarcomas of the kidney (CCSK) from two independent cohorts. We profile CCSK tumours using a combination of whole-exome, transcriptome and targeted sequencing. Identical ITD mutations are found in primary and relapsed tumour pairs but not in adjacent normal kidney or blood. Mutant BCOR transcripts and proteins are markedly upregulated in ITD-positive tumours. Transcriptome analysis of ITD-positive CCSKs reveals enrichment for PRC2-regulated genes and similarity to undifferentiated sarcomas harbouring BCOR-CCNB3 fusions. The discovery of recurrent BCOR ITDs defines a major oncogenic event in this childhood sarcoma with significant implications for diagnostic and therapeutic approaches to this tumour. PMID- 26573327 TI - Best practice for arm recovery post stroke: an international application. AB - OBJECTIVE: To develop an evidence-based application ('app') for post-stroke upper extremity rehabilitation that can be used globally by therapists. PARTICIPANTS: Twenty-three experienced neurorehabilitation therapists, applied scientists and physicians, and 10 consultants dedicated to the provision of best practice to stroke survivors. DESIGN: This team evaluated the evidence to support the timely and appropriate provision of interventions and the most defensible outcome measures during a 4-year voluntary information gathering and assimilation effort, as a basis for the sequencing of an algorithm informed by the data and directed by changes in impairment and chronicity. OUTCOME MEASURES: The primary outcome was the formulation of a testable app that will be available for minimal user cost. The app is for a smartphone, and the comments of a focus group (audience at a World Confederation for Physical Therapy 2015 presentation, approximate n=175) during a 30-minute 'Questions and Answers' session were assessed. RESULTS: Analysis of documented, extensive input offered by the audience indicated a highly favourable disposition towards this novel tool, with provision of concrete suggestions prior to launching the final version. Suggestions centred on: inclusion of instructions; visuals and demonstrations; monitoring of adverse responses; availability of updates; autonomous use by patients; and potential to characterise practice. CONCLUSIONS: A simple, user-friendly app for decision making in the treatment of upper extremity impairments following stroke is feasible and welcomed. PMID- 26573328 TI - Aneuploidy causes premature differentiation of neural and intestinal stem cells. AB - Aneuploidy is associated with a variety of diseases such as cancer and microcephaly. Although many studies have addressed the consequences of a non euploid genome in cells, little is known about their overall consequences in tissue and organism development. Here we use two different mutant conditions to address the consequences of aneuploidy during tissue development and homeostasis in Drosophila. We show that aneuploidy causes brain size reduction due to a decrease in the number of proliferative neural stem cells (NSCs), but not through apoptosis. Instead, aneuploid NSCs present an extended G1 phase, which leads to cell cycle exit and premature differentiation. Moreover, we show that this response to aneuploidy is also present in adult intestinal stem cells but not in the wing disc. Our work highlights a neural and intestine stem cell-specific response to aneuploidy, which prevents their proliferation and expansion. PMID- 26573330 TI - Social disparities in dietary habits among women: Geographic Research on Wellbeing (GROW) Study. AB - OBJECTIVE: Relationships among race/ethnicity, individual socio-economic status (SES), neighbourhood SES and acculturation are complex. We sought to answer whether: (i) race/ethnicity, individual SES and neighbourhood SES have independent effects on women's fruit and vegetable consumption (FVC); (ii) SES modifies the effects of race/ethnicity on FVC; and (iii) nativity modifies the effect of Latina ethnicity on FVC. DESIGN: Cross-sectional surveys from the population-based Geographic Research on Wellbeing (GROW) Study were linked with census-tract level data. FVC was indicated by (i) consuming fruits and vegetables less often than daily (LOWFV) and (ii) not having fruits and vegetables in the home very often. Other variables included age, marital status, race/ethnicity, country of birth, educational attainment, family income and longitudinal neighbourhood poverty (based on latent class growth models). Weighted logistic regression models accounting for the complex sample design were constructed. SETTING: California, USA, 2012-2013. SUBJECTS: Women (n 2669). RESULTS: In adjusted models, race/ethnicity, education and income were independently associated with FVC, but not neighbourhood poverty. Women of colour, high-school graduates and women with incomes at 301-400 % of the federal poverty level were at higher odds of LOWFV compared with non-Hispanic Whites, college graduates and those with incomes >400 % of the federal poverty level. Little evidence for interactions between race/ethnicity and individual or neighbourhood SES was found; similar patterns were observed for immigrant and US-born Latinas. CONCLUSIONS: Addressing the dietary needs of lower-SES communities requires multilevel interventions that simultaneously provide culturally tailored nutrition education and address the physical and economic accessibility of culturally acceptable fruits and vegetables. PMID- 26573329 TI - Structural insights into the reaction mechanism of S-adenosyl-L-homocysteine hydrolase. AB - S-adenosyl-L-homocysteine hydrolase (SAH hydrolase or SAHH) is a highly conserved enzyme that catalyses the reversible hydrolysis of SAH to L-homocysteine (HCY) and adenosine (ADO). High-resolution crystal structures have been reported for bacterial and plant SAHHs, but not mammalian SAHHs. Here, we report the first high-resolution crystal structure of mammalian SAHH (mouse SAHH) in complex with a reaction product (ADO) and with two reaction intermediate analogues-3'-keto aristeromycin (3KA) and noraristeromycin (NRN)-at resolutions of 1.55, 1.55, and 1.65 A. Each of the three structures constitutes a structural snapshot of one of the last three steps of the five-step process of SAH hydrolysis by SAHH. In the NRN complex, a water molecule, which is an essential substrate for ADO formation, is structurally identified for the first time as the candidate donor in a Michael addition by SAHH to the 3'-keto-4',5'-didehydroadenosine reaction intermediate. The presence of the water molecule is consistent with the reaction mechanism proposed by Palmer &Abeles in 1979. These results provide insights into the reaction mechanism of the SAHH enzyme. PMID- 26573331 TI - [Spreading of protein misfolding: A new paradigm in neurology]. AB - Protein misfolding and spreading ("transconformation") are being better understood. Described in Prions diseases, this new paradigm in the field of neurodegenerative disorders and brain aging also implies sporadic inclusion myositis, type 2 diabetes, some cancers, sickle cell disease... Misfolding is transmitted from a protein or peptide to a normally folded one. Often associated with a stress of the endoplasmic reticulum, it may spread along the neurites, following anterograde or retrograde axonal transport. In the central nervous system, it occurs in a few cells and there is invasion of adjacent cells by cell to-cell spread. Three varieties of protein misfolding occur along neuroanatomical pathways. It can be a 'centripetal' process. The synucleinopathy of Parkinson disease has been carefully studied: the changes first occur in cardiac or enteric plexuses... and reach later on the mesencephalon and neocortex. Thus, skin biopsy might prove a diagnostic tool. Protein misfolding may also occur along 'centrifugal' pathways, from motor cortex to peripheral motor neurons. Examples are provided by SOD and pTDP-43 in Amyotrophic Lateral Sclerosis. Amyloid beta peptide in cerebral aging and Alzheimer's disease also spread from occipital cortex to the brainstem. Lastly, the propagation may remain 'central' for TDP-43 in behavioral variant frontotemporal dementia, following only pathways of the encephalic neural network. This has to be confirmed, however, since the spreading of some proteins (such as tau or Abeta peptides) has been considered central for a long time and has proved today to involve extracerebral tissues. The complex mechanisms of protein misfolding, still in analysis, include the involvement of chaperone proteins, the formation of very toxic labile proteins molecules (oligomers?), and provide a number of new therapeutic perspectives. PMID- 26573332 TI - [Geriatric particularities of Parkinson's disease: Clinical and therapeutic aspects]. AB - Parkinson's disease (PD) is a frequent and complex progressive neurological disorder that increases in incidence with age. Although historically PD has been characterized by the presence of progressive dopaminergic neuronal loss of the substantia nigra, the disease process also involves neurotransmitters other that dopamine and regions of the nervous system outside the basal ganglia. Its clinical presentation in elderly subjects differs from that in younger subjects, with more rapid progression, less frequent tremor, more pronounced axial signs, more frequent non-motor signs linked to concomitant degeneration of non dopaminergic systems, and more frequent associated lesions. Despite the high prevalence of PD in elderly subjects, few therapeutic trials have been conducted in geriatric patients. Nevertheless, to improve functional disability while ensuring drug tolerance, the principles of optimized and multidisciplinary clinical management have to be known. The aim of this review is to provide an update on clinical and therapeutic features of PD specifically observed in elderly subjects. PMID- 26573333 TI - [Acute disseminated encephalomyelitis in Tunisia: Report of a pediatric cohort]. AB - INTRODUCTION: Acute disseminated encephalomyelitis (ADEM) is an inflammatory, demyelinating disorder of the central nervous system whose clinical features, management and outcome are incompletely understood in Tunisian population. OBJECTIVE: To describe clinical, neuroimaging and laboratory features; treatment and outcome in a cohort of Tunisian children with ADEM. METHODS: We conducted a retrospective review of the medical records of all children attending the Department of Child and Adolescent Neurology (Tunis) with ADEM between 2005 and 2015. Clinical, neuroimaging and laboratory features, therapeutic data and outcome were analyzed. RESULTS: There were 15 children (7 males and 8 females). The mean age at onset was 6.9 years. Thirteen (86.6%) patients had a prodromal event. The onset of neurological symptoms occurred within 17.6 days (4-30). Limb weakness was the most common presenting symptom (53.3%). Extrapyramidal syndrome was noticed in 6 patients (40%). Initial MRI showed a deep gray matter involvement in 7 cases (46.6%). Gadolinium enhancement at acute stage was observed in only 2 patients (13%). Cerebrospinal fluid findings did not show intrathecal oligoclonal bands. The use of high-dose IV methylprednisolone followed by oral steroid taper was associated with rapid recovery. Additional treatment with intravenous immunoglobulin was necessary in 2 patients. Complete recovery was obtained in 11 patients (73.3%). A monophasic course was noticed in 14 cases. Only one patient (5%) developed multiple sclerosis. CONCLUSION: The high frequency of prodromal events and extrapyramidal syndrome in addition to the low rate of gadolinium enhancement at acute stage seem to be the main features in our patients. Larger ADEM multicenter cohort studies in Tunisia and North Africa could provide more detailed information about this entity. PMID- 26573334 TI - Cerebral venous thrombosis in a Caribbean population. AB - INTRODUCTION: Cerebral venous thrombosis (CVT) is a rare affliction characterized by a wide diversity in its clinical expression and etiologies. Data from black populations concerning CVT are limited. We examined the clinical, radiological, and etiological aspects as well as the outcome of CVT in Guadeloupe, a French Overseas Department in the Caribbean. METHODS: All patients hospitalized between 2000 and 2011 at the University Hospital of Pointe-a-Pitre and diagnosed with CVT were retrospectively studied. Forty-five patients, each having had a medical imaging confirming the diagnostic, were retained. RESULTS: The frequency of CVT in Guadeloupe was estimated at 15 to 20 per 100,0000 per year in our survey. Our patients were largely composed of young women (73.3%). The average patient age was 40 years (14 to 80), with an incidence peak for women in the 20 to 50 years age range. The onset was sub-acute in 69% of cases, where headaches represented 93% of initial symptoms. Thrombosis of the SLS (60%), and of the lateral sinuses (64.4%) were the most frequently encountered. We observed a majority of mild clinical forms with a good functional prognosis. The main etiological factors were oral estro-progestative contraception (40%), and a positive thrombophilia test (33.3%). The thrombophilia factors in Guadeloupe differed from those in Caucasian populations, with a higher frequency of protein S deficit. CONCLUSION: The clinical and radiological characters are similar to those described in classical studies. Our study suggests a higher incidence of CVT in Guadeloupe, compared to results from Western countries. Further investigation is necessary to better characterize the thrombo-embolic venous risk factors in the black population. Protein S deficit appears to be the most frequent cause of thrombophilia in our population. PMID- 26573335 TI - Generation of functional hippocampal neurons from self-organizing human embryonic stem cell-derived dorsomedial telencephalic tissue. AB - The developing dorsomedial telencephalon includes the medial pallium, which goes on to form the hippocampus. Generating a reliable source of human hippocampal tissue is an important step for cell-based research into hippocampus-related diseases. Here we show the generation of functional hippocampal granule- and pyramidal-like neurons from self-organizing dorsomedial telencephalic tissue using human embryonic stem cells (hESCs). First, we develop a hESC culture method that utilizes bone morphogenetic protein (BMP) and Wnt signalling to induce choroid plexus, the most dorsomedial portion of the telencephalon. Then, we find that titrating BMP and Wnt exposure allowed the self-organization of medial pallium tissues. Following long-term dissociation culture, these dorsomedial telencephalic tissues give rise to Zbtb20(+)/Prox1(+) granule neurons and Zbtb20(+)/KA1(+) pyramidal neurons, both of which were electrically functional with network formation. Thus, we have developed an in vitro model that recapitulates human hippocampus development, allowing the generation of functional hippocampal granule- and pyramidal-like neurons. PMID- 26573336 TI - Long-term maintenance of human induced pluripotent stem cells by automated cell culture system. AB - Pluripotent stem cells, such as embryonic stem cells and induced pluripotent stem (iPS) cells, are regarded as new sources for cell replacement therapy. These cells can unlimitedly expand under undifferentiated conditions and be differentiated into multiple cell types. Automated culture systems enable the large-scale production of cells. In addition to reducing the time and effort of researchers, an automated culture system improves the reproducibility of cell cultures. In the present study, we newly designed a fully automated cell culture system for human iPS maintenance. Using an automated culture system, hiPS cells maintained their undifferentiated state for 60 days. Automatically prepared hiPS cells had a potency of differentiation into three germ layer cells including dopaminergic neurons and pancreatic cells. PMID- 26573337 TI - Sodium sources in the Japanese diet: difference between generations and sexes. AB - OBJECTIVE: Globally, the Na consumption of most people exceeds the WHO recommendation. To be effective, salt reduction programmes require assessment of the dietary sources of Na. Due to methodological difficulties however, comprehensive assessments are rare. Here, we identified Na sources in the Japanese diet using a 4 d diet record that was specifically designed for Na source description. DESIGN: A cross-sectional study. SUBJECTS: Apparently healthy men (n 196) and women (n 196) aged 20-69 years. SETTING: The subjects were recruited from twenty-three of forty-seven prefectures in Japan. RESULTS: The proportion of discretionary Na intake in total Na intake was 52.3 % in men and 57.1 % in women, and was significantly lower in younger subjects. The two major food groups contributing to Na intake were seasonings such as salt or soya sauce (61.7 % of total Na intake in men, 62.9 % in women) and fish and shellfish (6.7 % in men, 6.6 % in women). The third major contributor differed between men and women (noodles in men, 4.9 %; bread in women, 5.0 %). Further, the contribution of each food group to total Na intake differed among age groups. CONCLUSIONS: While individual efforts to decrease Na intake remain important, population approaches to reducing Na content in processed foods are already equally important and will assume greater importance in the future even in Japan, an Asian country facing a rapid Westernization in dietary habits. PMID- 26573338 TI - Compared in vivo toxicity in mice of lung delivered biodegradable and non biodegradable nanoparticles. AB - To design nanoparticle (NP)-based drug delivery systems for pulmonary administration, biodegradable materials are considered safe, but their potential toxicity is poorly explored. We here explore the lung toxicity in mice of biodegradable nanoparticles (NPs) and compare it to the toxicity of non biodegradable ones. NP formulations of poly(d,l-lactide-co-glycolide) (PLGA) coated with chitosan (CS), poloxamer 188 (PF68) or poly(vinyl alcohol) (PVA), which renders 200 nm NPs of positive, negative or neutral surface charge respectively, were analyzed for their biodistribution by in vivo fluorescence imaging and their inflammatory potential after single lung nebulization in mice. After exposure, analysis of bronchoalveolar lavage (BAL) cell population, protein secretion and cytokine release as well as lung histology were carried out. The inflammatory response was compared to the one induced by non-biodegradable counterparts, namely, TiO2 of rutile and anatase crystal form and polystyrene (PS). PLGA NPs were mostly present in mice lungs, with little passage to other organs. An increase in neutrophil recruitment was observed in mice exposed to PS NPs 24 h after nebulization, which declined at 48 h. This result was supported by an increase in interleukin (IL)-6 and tumor necrosis factor alpha (TNFalpha) in BAL supernatant at 24 h. TiO2 anatase NPs were still present in lung cells 48 h after nebulization and induced the expression of pro-inflammatory cytokines and the recruitment of polymorphonuclear cells to BAL. In contrast, regardless of their surface charge, PLGA NPs did not induce significant changes in the inflammation markers analyzed. In conclusion, these results point out to a safe use of PLGA NPs regardless of their surface coating compared to non-biodegradable ones. PMID- 26573339 TI - Frustrated Solvation Structures Can Enhance Electron Transfer Rates. AB - Polar surfaces can interact strongly with nearby water molecules, leading to the formation of highly ordered interfacial hydration structures. This ordering can lead to frustration in the hydrogen bond network, and, in the presence of solutes, frustrated hydration structures. We study frustration in the hydration of cations when confined between sheets of the water oxidation catalyst manganese dioxide. Frustrated hydration structures are shown to have profound effects on ion-surface electron transfer through the enhancement of energy gap fluctuations beyond those expected from Marcus theory. These fluctuations are accompanied by a concomitant increase in the electron transfer rate in Marcus's normal regime. We demonstrate the generality of this phenomenon-enhancement of energy gap fluctuations due to frustration-by introducing a charge frustrated XY model, likening the hydration structure of confined cations to topological defects. Our findings shed light on recent experiments suggesting that water oxidation rates depend on the cation charge and Mn-oxidation state in these layered transition metal oxide materials. PMID- 26573341 TI - The influence of whispering gallery modes on the far field of ring lasers. AB - We introduce ring lasers with continuous pi-phase shifts in the second order distributed feedback grating. This configuration facilitates insights into the nature of the modal outcoupling in an optical cavity. The grating exploits the asymmetry of whispering gallery modes and induces a rotation of the far field pattern. We find that this rotation can be connected to the location of the mode relative to the grating. Furthermore, the direction of rotation depends on the radial order of the whispering gallery mode. This enables a distinct identification and characterization of the mode by simple analysis of the emission beam. PMID- 26573340 TI - Auditory sequence processing reveals evolutionarily conserved regions of frontal cortex in macaques and humans. AB - An evolutionary account of human language as a neurobiological system must distinguish between human-unique neurocognitive processes supporting language and evolutionarily conserved, domain-general processes that can be traced back to our primate ancestors. Neuroimaging studies across species may determine whether candidate neural processes are supported by homologous, functionally conserved brain areas or by different neurobiological substrates. Here we use functional magnetic resonance imaging in Rhesus macaques and humans to examine the brain regions involved in processing the ordering relationships between auditory nonsense words in rule-based sequences. We find that key regions in the human ventral frontal and opercular cortex have functional counterparts in the monkey brain. These regions are also known to be associated with initial stages of human syntactic processing. This study raises the possibility that certain ventral frontal neural systems, which play a significant role in language function in modern humans, originally evolved to support domain-general abilities involved in sequence processing. PMID- 26573342 TI - Nutritional predictors of successful chronic disease prevention for a community cohort in Central Australia. AB - OBJECTIVE: To investigate biomarkers of nutrition associated with chronic disease absence for an Aboriginal cohort. DESIGN: Screening for nutritional biomarkers was completed at baseline (1995). Evidence of chronic disease (diabetes, CVD, chronic kidney disease or hypertension) was sought from primary health-care clinics, hospitals and death records over 10 years of follow-up. Principal components analysis was used to group baseline nutritional biomarkers and logistic regression modelling used to investigate associations between the principal components and chronic disease absence. SETTING: Three Central Australian Aboriginal communities. SUBJECTS: Aboriginal people (n 444, 286 of whom were without chronic disease at baseline) aged 15-82 years. RESULTS: Principal components analysis grouped twelve nutritional biomarkers into four components: 'lipids'; 'adiposity'; 'dietary quality'; and 'habitus with inverse quality diet'. For the 286 individuals free of chronic disease at baseline, lower adiposity, lower lipids and better dietary quality components were each associated with the absence at follow-up of most chronic diseases examined, with the exception of chronic kidney disease. Low 'adiposity' component was associated with absence of diabetes, hypertension and CVD at follow-up. Low 'lipid' component was associated with absence of hypertension and CVD, and high 'dietary quality' component was associated with absence of CVD at follow-up. CONCLUSIONS: Lowering or maintenance of the factors related to 'adiposity' and 'lipids' to healthy thresholds and increasing access to a healthy diet appear useful targets for chronic disease prevention for Aboriginal people in Central Australia. PMID- 26573343 TI - Thioridazine in PLGA nanoparticles reduces toxicity and improves rifampicin therapy against mycobacterial infection in zebrafish. AB - Encapsulating antibiotics such as rifampicin in biodegradable nanoparticles provides several advantages compared to free drug administration, including reduced dosing due to localized targeting and sustained release. Consequently, these characteristics reduce systemic drug toxicity. However, new nanoformulations need to be tested in complex biological systems to fully characterize their potential for improved drug therapy. Tuberculosis, caused by infection with the bacterium Mycobacterium tuberculosis, requires lengthy and expensive treatment, and incomplete therapy contributes to an increasing incidence of drug resistance. Recent evidence suggests that standard therapy may be improved by combining antibiotics with bacterial efflux pump inhibitors, such as thioridazine. However, this drug is difficult to use clinically due to its toxicity. Here, we encapsulated thioridazine in poly(lactic-co-glycolic) acid nanoparticles and tested them alone and in combination with rifampicin nanoparticles, or free rifampicin in macrophages and in a zebrafish model of tuberculosis. Whereas free thioridazine was highly toxic in both cells and zebrafish embryos, after encapsulation in nanoparticles no toxicity was detected. When combined with rifampicin nanoparticles, the nanoparticles loaded with thioridazine gave a modest increase in killing of both Mycobacterium bovis BCG and M. tuberculosis in macrophages. In the zebrafish, the thioridazine nanoparticles showed a significant therapeutic effect in combination with rifampicin by enhancing embryo survival and reducing mycobacterial infection. Our results show that the zebrafish embryo is a highly sensitive indicator of drug toxicity and that thioridazine nanoparticle therapy can improve the antibacterial effect of rifampicin in vivo. PMID- 26573344 TI - Current paradigms in aortic arch repair: Striking the balance between open surgery and endovascular repair. PMID- 26573345 TI - "Lead from the front": Participative leadership. PMID- 26573346 TI - Pioneers paying it forward. PMID- 26573347 TI - Experience from the inaugural TSRA traveling fellowship award. PMID- 26573348 TI - Severe ischemic mitral regurgitation: Repair or replace? PMID- 26573349 TI - Cardiopulmonary bypass and the endothelial glycocalyx: Shedding new light. PMID- 26573350 TI - A call to arms against an enemy yet unknown. PMID- 26573351 TI - Lung cancer screening: Dollars and scents. PMID- 26573352 TI - Multiple arterial bypass grafting should be routine. AB - OBJECTIVE: We sought to estimate the reduction in deaths and the number of additional person-years of life that could potentially be gained by nationwide adoption of routine multiple arterial bypass grafting (MABG). METHODS: Propensity matching on 4883 patients undergoing primary, isolated coronary artery bypass grafting (CABG) using the left internal thoracic artery (LITA) from January 1995 to June 2011, resulted in 1023 matched pairs of LITA-radial artery and LITA saphenous vein patients. Kaplan-Meier estimated survivals were used to calculate the potential number of lives that could be saved based on a 20% and an 80% rate of MABG, compared with the national 10% rate, when applied to a hypothetical national sample of 200,000 similar patients. RESULTS: Our overall MABG rate was 40% with >80% rate for the past 3 years. Kaplan-Meier estimated 10-year survival was better for LITA-radial artery patients (83.1%) compared with LITA-saphenous vein patients (75.7%) (log rank test, P < .001). When compared with the current national 10% MABG rate, a 20% and an 80% MABG rate could potentially result in 1400 and 10,000 fewer annual deaths, respectively, among a hypothetical national cohort, yielding >9000 and >64,000 person-years of life over a 10-year period. CONCLUSIONS: An 80% rate of MABG has the potential to prevent more than 10,000 deaths annually and add >64,000 person-years of life over the course of 10 years. The use of a second arterial graft during CABG should be routine in the majority of patients undergoing CABG. PMID- 26573354 TI - Multiple arterial grafting: The cost of an inconvenience. PMID- 26573355 TI - Total aortic arch replacement: A comparative study of zone 0 hybrid arch exclusion versus traditional open repair. AB - OBJECTIVE: We attempted to identify predictors of adverse outcomes after traditional open and hybrid zone 0 total aortic arch replacement. METHODS: We performed multivariable analysis using 16 variables to identify predictors of adverse outcomes (mortality, permanent neurologic events, and permanent renal failure necessitating hemodialysis) in 319 consecutive patients who underwent total aortic arch replacement in the past 8.5 years and a subgroup analysis in 25 propensity-matched pairs. A total of 274 patients (85.9%) had traditional open repair, and 45 patients (14.1%) had hybrid zone 0 total arch exclusion. RESULTS: Operative mortality was 10.3% (n = 33): 11.1% (n = 5) in the hybrid group and 10.2% (n = 28) in the traditional group (P = .79). A total of 19 patients (5.9%) had permanent stroke (15 traditional [5.5%] vs 4 hybrid [8.9%]; P = .32), and 2 patients (both traditional) had permanent paraplegia (P = 1.00). The hybrid group had more total neurologic events (P = .051) but not more permanent strokes (P = .32). Prior cardiac disease unrelated to the aorta (P = .0033) and congestive heart failure (P = .0053) independently predicted permanent adverse outcome (operative mortality, permanent neurologic event, or permanent renal failure). Concomitant coronary artery bypass grafting independently predicted permanent stroke (P = .032), as did previous cerebrovascular disease (P = .032). In multivariable analysis, procedure type (hybrid or traditional) was not an independent predictor of stroke (P = .09). During a median follow-up of 4.5 years (95% confidence interval, 3.9-4.9), survival was 78.7%, with no intergroup difference (P = .14). CONCLUSIONS: Among contemporary cases, both traditional and hybrid total aortic arch replacement had acceptable results. Comparing these 2 different surgical treatment options is challenging, and an individualized approach offers the best results. Permanent adverse outcome was not significantly different between the 2 groups. Procedure type is not an independent predictor of permanent stroke. Prior cardiac disease, past or current smoking, and congestive heart failure predict adverse outcomes for total aortic arch replacement. PMID- 26573357 TI - Acute kidney injury after cardiac surgery: Et puis apres? PMID- 26573358 TI - This side up--Handle with care. PMID- 26573359 TI - Post-left ventricular assist device support right ventricular failure: Can it be predicted preoperatively, and should it be a contraindication to implantation? PMID- 26573360 TI - Is the era of the heart team coming? PMID- 26573361 TI - Ischemic mitral regurgitation: Repair the valve, reshape the ventricle, or both? PMID- 26573362 TI - Off-pump versus on-pump coronary artery bypass grafting: Who benefits? PMID- 26573363 TI - Off-pump on-pump debate: Caveat emptor. PMID- 26573364 TI - Giant cardiac fibroma leading to cardiac arrest: Surgical resection on the beating heart. PMID- 26573365 TI - Differential Isotope Labeling of Glycopeptides for Accurate Determination of Differences in Site-Specific Glycosylation. AB - We introduce a stable isotope labeling approach for glycopeptides that allows a specific glycosylation site in a protein to be quantitatively evaluated using mass spectrometry. Succinic anhydride is used to specifically label primary amino groups of the peptide portion of the glycopeptides. The heavy form (D4(13)C4) provides an 8 Da mass increment over the light natural form (H4(12)C4), allowing simultaneous analysis and direct comparison of two glycopeptide profiles in a single MS scan. We have optimized a protocol for an in-solution trypsin digestion, a one-pot labeling procedure, and a post-labeling solid-phase extraction to obtain purified and labeled glycopeptides. We provide the first demonstration of this approach by comparing IgG1 Fc glycopeptides from polyclonal IgG samples with respect to their galactosylation and sialylation patterns using MALDI MS and LC-ESI-MS. PMID- 26573366 TI - DNA damage induced by boron neutron capture therapy is partially repaired by DNA ligase IV. AB - Boron neutron capture therapy (BNCT) is a particle radiation therapy that involves the use of a thermal or epithermal neutron beam in combination with a boron ((10)B)-containing compound that specifically accumulates in tumor. (10)B captures neutrons and the resultant fission reaction produces an alpha ((4)He) particle and a recoiled lithium nucleus ((7)Li). These particles have the characteristics of high linear energy transfer (LET) radiation and therefore have marked biological effects. High-LET radiation is a potent inducer of DNA damage, specifically of DNA double-strand breaks (DSBs). The aim of the present study was to clarify the role of DNA ligase IV, a key player in the non-homologous end joining repair pathway, in the repair of BNCT-induced DSBs. We analyzed the cellular sensitivity of the mouse embryonic fibroblast cell lines Lig4-/- p53-/- and Lig4+/+ p53-/- to irradiation using a thermal neutron beam in the presence or absence of (10)B-para-boronophenylalanine (BPA). The Lig4-/- p53-/- cell line had a higher sensitivity than the Lig4+/+ p53-/-cell line to irradiation with the beam alone or the beam in combination with BPA. In BNCT (with BPA), both cell lines exhibited a reduction of the 50 % survival dose (D 50) by a factor of 1.4 compared with gamma-ray and neutron mixed beam (without BPA). Although it was found that (10)B uptake was higher in the Lig4+/+ p53-/- than in the Lig4-/- p53 /- cell line, the latter showed higher sensitivity than the former, even when compared at an equivalent (10)B concentration. These results indicate that BNCT induced DNA damage is partially repaired using DNA ligase IV. PMID- 26573367 TI - Direct visualization of dispersed lipid bicontinuous cubic phases by cryo electron tomography. AB - Bulk and dispersed cubic liquid crystalline phases (cubosomes), present in the body and in living cell membranes, are believed to play an essential role in biological phenomena. Moreover, their biocompatibility is attractive for nutrient or drug delivery system applications. Here the three-dimensional organization of dispersed cubic lipid self-assembled phases is fully revealed by cryo-electron tomography and compared with simulated structures. It is demonstrated that the interior is constituted of a perfect bicontinuous cubic phase, while the outside shows interlamellar attachments, which represent a transition state between the liquid crystalline interior phase and the outside vesicular structure. Therefore, compositional gradients within cubosomes are inferred, with a lipid bilayer separating at least one water channel set from the external aqueous phase. This is crucial to understand and enhance controlled release of target molecules and calls for a revision of postulated transport mechanisms from cubosomes to the aqueous phase. PMID- 26573368 TI - A randomised double-blind placebo-controlled trial investigating the behavioural effects of vitamin, mineral and n-3 fatty acid supplementation in typically developing adolescent schoolchildren. AB - Nutrient deficiencies have been implicated in anti-social behaviour in schoolchildren; hence, correcting them may improve sociability. We therefore tested the effects of vitamin, mineral and n-3 supplementation on behaviour in a 12-week double-blind randomised placebo-controlled trial in typically developing UK adolescents aged 13-16 years (n 196). Changes in erythrocyte n-3 and 6 fatty acids and some mineral and vitamin levels were measured and compared with behavioural changes, using Conners' teacher ratings and school disciplinary records. At baseline, the children's PUFA (n-3 and n-6), vitamin and mineral levels were low, but they improved significantly in the group treated with n-3, vitamins and minerals (P=0.0005). On the Conners disruptive behaviour scale, the group given the active supplements improved, whereas the placebo group worsened (F=5.555, d=0.35; P=0.02). The general level of disciplinary infringements was low, thus making it difficult to obtain improvements. However, throughout the school term school disciplinary infringements increased significantly (by 25 %; Bayes factor=115) in both the treated and untreated groups. However, when the subjects were split into high and low baseline infringements, the low subset increased their offences, whereas the high-misbehaviour subset appeared to improve after treatment. But it was not possible to determine whether this was merely a statistical artifact. Thus, when assessed using the validated and standardised Conners teacher tests (but less clearly when using school discipline records in a school where misbehaviour was infrequent), supplementary nutrition might have a protective effect against worsening behaviour. PMID- 26573369 TI - Should the scope of human mixture risk assessment span legislative/regulatory silos for chemicals? AB - Current chemicals regulation operates almost exclusively on a chemical-by chemical basis, however there is concern that this approach may not be sufficiently protective if two or more chemicals have the same toxic effect. Humans are indisputably exposed to more than one chemical at a time, for example to the multiple chemicals found in food, air and drinking water, and in household and consumer products, and in cosmetics. Assessment of cumulative risk to human health and/or the environment from multiple chemicals and routes can be done in a mixture risk assessment (MRA). Whilst there is a broad consensus on the basic science of mixture toxicology, the path to regulatory implementation of MRA within chemical risk assessment is less clear. In this discussion piece we pose an open question: should the scope of human MRA cross legislative remits or 'silos'? We define silos as, for instance, legislation that defines risk assessment practice for a subset of chemicals, usually on the basis of substance/product, media or process orientation. Currently any form of legal mandate for human MRA in the EU is limited to only a few pieces of legislation. We describe two lines of evidence, illustrated with selected examples, that are particularly pertinent to this question: 1) evidence that mixture effects have been shown for chemicals regulated in different silos and 2) evidence that humans are co-exposed to chemicals from different silos. We substantiate the position that, because there is no reason why chemicals allocated to specific regulatory silos would have non-overlapping risk profiles, then there is also no reason to expect that MRA limited only to chemicals within one silo can fully capture the risk that may be present to human consumers. Finally, we discuss possible options for implementation of MRA and we hope to prompt wider discussion of this issue. PMID- 26573370 TI - Evaluation of functional rhinoplasty using the Modified Cottle test in Asian patients. AB - CONCLUSION: MCT is a useful tool to pre-operatively determine whether internal nasal valve (INV) narrowing affects a nasal obstruction. Functional rhinoplasty seemed to produce better results than septoplasty in Asian patients with a nasal obstruction, due to INV narrowing. OBJECTIVE: This study compared pre-operative modified Cottle test (MCT) findings and post-operative clinical improvement according to surgical approach in an Asian population. METHODS: One-hundred and sixty-four patients who underwent septal surgery were enrolled. The clinical symptoms, radiological findings, and paranasal computed tomography (PNS CT) scan results were compared and analyzed between the MCT-positive and -negative groups, focusing on internal nasal valve narrowing. Post-operative clinical improvement were also compared based on whether septoplasty or functional rhinoplasty was performed. RESULTS: The MCT-positive group had significantly higher pre-operative visual analog scale scores for nasal obstruction and rhinorrhea than those in the negative group. The MCT-positive group had a significantly higher percentage of highly deviated septa on PNS CT and endoscopic findings than those in the MCT negative group. The functional rhinoplasty group had a significantly higher MCT conversion rate (positive to negative) and improvement in nasal obstruction than those in the septoplasty group. PMID- 26573371 TI - In response to 'Comment on: "Anthropometric parameters in relation to glycaemic status and lipid profile in a multi-ethnic sample in Italy" by Gualdi-Russo et al.'. PMID- 26573372 TI - Biocompatible fluorescent supramolecular nanofibrous hydrogel for long-term cell tracking and tumor imaging applications. AB - Biocompatible peptide-based supramolecular hydrogel has recently emerged as a new and promising system for biomedical applications. In this work, Rhodamine B is employed as a new capping group of self-assembling peptide, which not only provides the driving force for supramolecular nanofibrous hydrogel formation, but also endows the hydrogel with intrinsic fluroescence signal, allowing for various bioimaging applications. The fluorescent peptide nanofibrous hydrogel can be formed via disulfide bond reduction. After dilution of the hydrogel with aqueous solution, the fluorescent nanofiber suspension can be obtained. The resultant nanofibers are able to be internalized by the cancer cells and effectively track the HeLa cells for as long as 7 passages. Using a tumor-bearing mouse model, it is also demonstrated that the fluorescent supramolecular nanofibers can serve as an efficient probe for tumor imaging in a high-contrast manner. PMID- 26573373 TI - Proteomic Analysis of Lonicera japonica Thunb. Immature Flower Buds Using Combinatorial Peptide Ligand Libraries and Polyethylene Glycol Fractionation. AB - Lonicera japonica Thunb. flower is a well-known medicinal plant that has been widely used for the treatment of human disease. To explore the molecular mechanisms underlying the biological activities of L. japonica immature flower buds, a gel-free/label-free proteomic technique was used in combination with combinatorial peptide ligand libraries (CPLL) and polyethylene glycol (PEG) fractionation for the enrichment of low-abundance proteins and removal of high abundance proteins, respectively. A total of 177, 614, and 529 proteins were identified in crude protein extraction, CPLL fractions, and PEG fractions, respectively. Among the identified proteins, 283 and 239 proteins were specifically identified by the CPLL and PEG methods, respectively. In particular, proteins related to the oxidative pentose phosphate pathway, signaling, hormone metabolism, and transport were highly enriched by CPLL and PEG fractionation compared to crude protein extraction. A total of 28 secondary metabolism-related proteins and 25 metabolites were identified in L. japonica immature flower buds. To determine the specificity of the identified proteins and metabolites for L. japonica immature flower buds, Cerasus flower buds were used, which resulted in the abundance of hydroxymethylbutenyl 4-diphosphate synthase in L. japonica immature flower buds being 10-fold higher than that in Cerasus flower buds. These results suggest that proteins related to secondary metabolism might be responsible for the biological activities of L. japonica immature flower buds. PMID- 26573374 TI - Insight into 2alpha-Chloro-2'(2',6')-(Di)Halogenopicropodophyllotoxins Reacting with Carboxylic Acids Mediated by BF3.Et2O. AB - Stereospecific nucleophilic substitution at the C-4alpha position of 2alpha chloro-2'(2',6')-(di)halogenopicropodophyllotoxin derivatives with carboxylic acids mediated by BF3.Et2O was described. Interestingly, this stereoselective products were completely controlled by the reaction time. That is, if the reaction time was prolonged to 24.5-31 h, the resulting compounds were all transformed into the unusual C-ring aromatization products. Additionally, it demonstrated that BF3.Et2O and reaction temperature were the important factors for C-ring aromatization, and AlCl3 could be substituted for BF3.Et2O as a lewis acid for C-ring aromatization. Halogenation of E-ring of 2beta chloropodophyllotoxins with NCS or NBS also led to the same C-ring aromatization compounds. Especially compounds 5c, 6g and 7b exhibited insecticidal activity equal to that of toosendanin. PMID- 26573376 TI - Transgenerational epigenetic inheritance of diabetes risk as a consequence of early nutritional imbalances. AB - In today's world, there is an unprecedented rise in the prevalence of chronic metabolic diseases, including obesity, insulin resistance and type 2 diabetes (T2D). The pathogenesis of T2D includes both genetic and environmental factors, such as excessive energy intake and physical inactivity. It has recently been suggested that environmental factors experienced during early stages of development, including the intrauterine and neonatal periods, might play a major role in predisposing individuals to T2D. Furthermore, several studies have shown that such early environmental conditions might even contribute to disease risk in further generations. In this review, we summarise recent data describing how parental nutrition during development increases the risk of diabetes in the offspring. We also discuss the potential mechanisms underlying transgenerational inheritance of metabolic disease, with particular emphasis on epigenetic mechanisms. PMID- 26573375 TI - Genomic and transcriptomic evidence for scavenging of diverse organic compounds by widespread deep-sea archaea. AB - Microbial activity is one of the most important processes to mediate the flux of organic carbon from the ocean surface to the seafloor. However, little is known about the microorganisms that underpin this key step of the global carbon cycle in the deep oceans. Here we present genomic and transcriptomic evidence that five ubiquitous archaeal groups actively use proteins, carbohydrates, fatty acids and lipids as sources of carbon and energy at depths ranging from 800 to 4,950 m in hydrothermal vent plumes and pelagic background seawater across three different ocean basins. Genome-enabled metabolic reconstructions and gene expression patterns show that these marine archaea are motile heterotrophs with extensive mechanisms for scavenging organic matter. Our results shed light on the ecological and physiological properties of ubiquitous marine archaea and highlight their versatile metabolic strategies in deep oceans that might play a critical role in global carbon cycling. PMID- 26573377 TI - Improvement following total knee replacement surgery: Exploring preoperative symptoms and change in preoperative symptoms. AB - OBJECTIVE: To determine whether changes in preoperative osteoarthritis (OA) symptoms are associated with improvement after total knee replacement (TKR) and to identify predictors of clinically significant improvement. METHODS: Data on Osteoarthritis Initiative participants who were annually assessed and underwent TKR were included. T0 was the assessment prior to TKR while T-1 was the assessment prior to that. T+2 was the second assessment after TKR. We compiled data on the Western Ontario and McMaster Universities OA Index (WOMAC), OA related symptoms, and radiographic severity. We defined clinically significant improvement as improvement in WOMAC total score >= to the minimal important difference (MID) (0.5 SD of mean change) between T0 and T+2 and also considered other definitions of improvement. Logistic regression models were performed to evaluate the relationship between improvement and preoperative measures. RESULTS: Improved (n = 211) compared to unimproved (n = 58) patients had greater worsening of their WOMAC pain (p = 0.002) and disability (p < 0.001) from T-1 to T0. Preoperative measures as predictors of improvement included higher WOMAC disability (OR = 1.08, p < 0.001), presence of chronic OA symptoms in the surgical knee (OR = 5.77, p = 0.033), absence of OA-related symptoms in the contralateral knee (OR = 9.25, p < 0.001), exposure to frequent knee bending (OR = 3.46, p = 0.040), and having a Kellgren-Lawrence x-ray grade of >=2 in the contralateral knee (OR = 4.71, p = 0.010). CONCLUSIONS: More than 75% of participants had improvement after TKR. Improved patients were more likely to have escalation of OA pain and disability prior to surgery than unimproved patients. Other preoperative measures predicted improvement after TKR. PMID- 26573378 TI - MicroRNA-1246 promotes growth and metastasis of colorectal cancer cells involving CCNG2 reduction. AB - Colorectal cancer (CRC) is the third most common cancer type and the fourth leading cause of cancer-associated mortality worldwide. MicroRNA (miR)-1246 is involved in differentiation, invasion, metastasis and chemoresistance of certain types of tumor cells. CCNG2 encodes an unconventional cyclin homolog, cyclin G2 (CycG2), associated with growth inhibition, which correlated significantly with lymph node metastasis, clinical stage, histological grade and poor overall survival in numerous cancer types. To investigate the regulation of miR-1246 on CycG2 expression, and their effects on proliferation and metastasis of CRC, HCT 116 and LOVO cells were transfected with pre-miR-1246 anti-miR-1246 and their negative controls. It was demonstrated that the expression of miR-1246 was significantly increased in CRC tissues and cell lines, which was the opposite of CycG2. miR-1246 negatively regulated the expression of CycG2 in HCT-116 and LOVO CRC cells. CCNG2 is a direct target of miR-1246 in CRC cells. Overexpression of miR-1246 induced cell proliferation, migration and invasion, while knockdown of miR-1246 inhibited proliferation, migration and invasion in the CRC cells. Upregulation of miR-1246 mediated the malignant progression of CRC and is partly attributed to the downregulation of the expression of CycG2. Consequently, these findings provided a molecular basis for the role of miR-1246/CCNG2 in the progression of human CRC and suggested a novel target for the treatment of CRC. PMID- 26573379 TI - Prognostic predictors of sudden sensorineural hearing loss in defibrinogenation therapy. AB - CONCLUSIONS: Defibrinogenation therapy rather than corticosteroids therapy should be chosen for patients specifically with profound hearing loss and with initial high fibrinogen. OBJECTIVES: Corticosteroids therapy is the standard treatment for sudden sensorineural hearing loss (SSNHL) and prognostic factors by this therapy were reported. Defibrinogenation therapy is one of the treatment options for SSNHL. Aims of this study were to identify prognostic factors and correlative markers with hearing improvement in treating SSNHL by defibrinogenation therapy. METHODS: During the early phase of the study, consecutive 61 patients were treated by defibrinogenation therapy with batroxobin (50 units), whereas corticosteroids (500 mg/day of hydrocortisone tapered by 9 days) were used for consecutive 64 patients during the late phase. Blood data that could predict a complete recovery were identified. Coagulation/fibrinolysis markers correlated with hearing improvement by defibrinogenation therapy were investigated. RESULTS: Although there were no overall differences in hearing improvement between the two therapies, recovery rate in profound hearing loss patients was better in defibrinogenation therapy. In patients who showed complete recovery, serum fibrinogen level before treatment was significantly higher in the defibrinogenation group than the corticosteroid group. Responses of several fibrinolysis markers to defibrinogenation therapy evaluated by post-/pre-values were negatively correlated with hearing improvement. PMID- 26573381 TI - Observation of Fine Distribution of Minor Dopants in an Erbium-Doped Fiber Core using a Sample Thinning Technique for Field Emission Electron Probe Microanalysis. AB - To observe the fine distribution of minor aluminum and germanium dopants in the erbium-doped fiber (EDF) core of an optical amplifier, a sample thinning technique was applied for field emission electron probe microanalysis (FE-EPMA) together with wavelength-dispersive X-ray spectrometry. This technique significantly improved the spatial resolution without much degradation of the minimum detection limit for FE-EPMA. As such, this enabled us to observe the distribution of minor dopants in EDF. Moreover, we propose a very simple sample preparation to prevent electron-beam radiation damage, a problem involved with FE EPMA of low-conductivity materials such as SiO2 glass, which is the main component of EDF. PMID- 26573380 TI - Emergence of methadone as a street drug in St. Petersburg, Russia. AB - BACKGROUND: The syndemic of opioid addiction, HIV, hepatitis, tuberculosis, imprisonment, and overdose in Russia has been worsened by the illegality of opioid substitution therapy. As part of on-going serial studies, we sought to explore the influence of opioid availability on aspects of the syndemic as it has affected the city of St. Petersburg. METHODS: We employed a sequential approach in which quantitative data collection and statistical analysis were followed by a qualitative phase. Quantitative data were obtained in 2013-2014 from a respondent driven sample (RDS) of people who inject drugs (PWID). Individuals recruited by RDS were tested for antibodies to HIV and interviewed about drug use and injection practices, sociodemographics, health status, and access to medical care. Subsequently, we collected in-depth qualitative data on methadone use, knowledge, and market availability from PWID recruited at nine different locations within St. Petersburg. RESULTS: Analysis of interview data from the sample revealed the percentage of PWID injecting methadone in the 30 days prior to interview increased from 3.6% in 2010 to 53.3% in 2012-2013. Injection of only methadone, as compared to injecting only heroin or both drugs, was associated with less frequent injection and reduced HIV-related injected risk, especially a lower rate of injecting with a previously used syringe. In-depth questioning of methadone injectors corroborated the finding from serial quantitative surveys of PWID that methadone's black market availability is a recent phenomenon. Spatial analysis revealed widespread methadone availability but no concentration in any specific districts of the city. CONCLUSION: Despite the prohibition of substitution therapy and demonization of methadone, the drug has emerged to rival heroin as the most commonly available opioid in St. Petersburg. Ironically, its use is associated with reduced injection-related HIV risk even when its use is illegal. PMID- 26573382 TI - The distribution of blow fly (Diptera: Calliphoridae) larval lengths and its implications for estimating post mortem intervals. AB - The length or stage of development of blow fly (Diptera: Calliphoridae) larvae may be used to estimate a minimum postmortem interval, often by targeting the largest individuals of a species in the belief that they will be the oldest. However, natural variation in rate of development, and therefore length, implies that the size of the largest larva, as well as the number of larvae longer than any stated length, will be greater for larger cohorts. Length data from the blow flies Protophormia terraenovae and Lucilia sericata were collected from one field based and two laboratory-based experiments. The field cohorts contained considerably more individuals than have been used for reference data collection in the literature. Cohorts were shown to have an approximately normal distribution. Summary statistics were derived from the collected data allowing the quantification of errors in development time which arise when different sized cohorts are compared through their largest larvae. These errors may be considerable and can lead to overestimation of postmortem intervals when making comparisons with reference data collected from smaller cohorts. This source of error has hitherto been overlooked in forensic entomology. PMID- 26573383 TI - Enhancing the Liquid-Phase Exfoliation of Graphene in Organic Solvents upon Addition of n-Octylbenzene. AB - Due to a unique combination of electrical and thermal conductivity, mechanical stiffness, strength and elasticity, graphene became a rising star on the horizon of materials science. This two-dimensional material has found applications in many areas of science ranging from electronics to composites. Making use of different approaches, unfunctionalized and non-oxidized graphene sheets can be produced; among them an inexpensive and scalable method based on liquid-phase exfoliation of graphite (LPE) holds potential for applications in opto electronics and nanocomposites. Here we have used n-octylbenzene molecules as graphene dispersion-stabilizing agents during the graphite LPE process. We have demonstrated that by tuning the ratio between organic solvents such as N-methyl-2 pyrrolidinone or ortho-dichlorobenzene, and n-octylbenzene molecules, the concentration of exfoliated graphene can be enhanced by 230% as a result of the high affinity of the latter molecules for the basal plane of graphene. The LPE processed graphene dispersions were further deposited onto solid substrates by exploiting a new deposition technique called spin-controlled drop casting, which was shown to produce uniform highly conductive and transparent graphene films. PMID- 26573384 TI - Climate-driven environmental changes around 8,200 years ago favoured increases in cetacean strandings and Mediterranean hunter-gatherers exploited them. AB - Cetacean mass strandings occur regularly worldwide, yet the compounded effects of natural and anthropogenic factors often complicate our understanding of these phenomena. Evidence of past stranding episodes may, thus, be essential to establish the potential influence of climate change. Investigations on bones from the site of Grotta dell'Uzzo in North West Sicily (Italy) show that the rapid climate change around 8,200 years ago coincided with increased strandings in the Mediterranean Sea. Stable isotope analyses on collagen from a large sample of remains recovered at this cave indicate that Mesolithic hunter-gatherers relied little on marine resources. A human and a red fox dating to the 8.2-kyr-BP climatic event, however, acquired at least one third of their protein from cetaceans. Numerous carcasses should have been available annually, for at least a decade, to obtain these proportions of meat. Our findings imply that climate driven environmental changes, caused by global warming, may represent a serious threat to cetaceans in the near future. PMID- 26573385 TI - Are parasite richness and abundance linked to prey species richness and individual feeding preferences in fish hosts? AB - Variations in levels of parasitism among individuals in a population of hosts underpin the importance of parasites as an evolutionary or ecological force. Factors influencing parasite richness (number of parasite species) and load (abundance and biomass) at the individual host level ultimately form the basis of parasite infection patterns. In fish, diet range (number of prey taxa consumed) and prey selectivity (proportion of a particular prey taxon in the diet) have been shown to influence parasite infection levels. However, fish diet is most often characterized at the species or fish population level, thus ignoring variation among conspecific individuals and its potential effects on infection patterns among individuals. Here, we examined parasite infections and stomach contents of New Zealand freshwater fish at the individual level. We tested for potential links between the richness, abundance and biomass of helminth parasites and the diet range and prey selectivity of individual fish hosts. There was no obvious link between individual fish host diet and helminth infection levels. Our results were consistent across multiple fish host and parasite species and contrast with those of earlier studies in which fish diet and parasite infection were linked, hinting at a true disconnect between host diet and measures of parasite infections in our study systems. This absence of relationship between host diet and infection levels may be due to the relatively low richness of freshwater helminth parasites in New Zealand and high host-parasite specificity. PMID- 26573386 TI - Fennoscandian freshwater control on Greenland hydroclimate shifts at the onset of the Younger Dryas. AB - Sources and timing of freshwater forcing relative to hydroclimate shifts recorded in Greenland ice cores at the onset of Younger Dryas, ~12,800 years ago, remain speculative. Here we show that progressive Fennoscandian Ice Sheet (FIS) melting 13,100-12,880 years ago generates a hydroclimate dipole with drier-colder conditions in Northern Europe and wetter-warmer conditions in Greenland. FIS melting culminates 12,880 years ago synchronously with the start of Greenland Stadial 1 and a large-scale hydroclimate transition lasting ~180 years. Transient climate model simulations forced with FIS freshwater reproduce the initial hydroclimate dipole through sea-ice feedbacks in the Nordic Seas. The transition is attributed to the export of excess sea ice to the subpolar North Atlantic and a subsequent southward shift of the westerly winds. We suggest that North Atlantic hydroclimate sensitivity to FIS freshwater can explain the pace and sign of shifts recorded in Greenland at the climate transition into the Younger Dryas. PMID- 26573387 TI - Bromocriptine mitigated paliperidone metabolic and neuro-hormonal side effects and improved negative domain in a case of early onset schizophrenia. AB - We report a case of early onset schizophrenia that responded favourably to paliperidone but experienced hyperprolactinaemia, tremors, and weight gain, with impaired fasting glycaemia. Addition of bromocriptine helped with both hyperprolactinaemia and tremors, but also brought about euglycaemia and, strikingly, ameliorated negative symptoms. PMID- 26573388 TI - A regulatory circuit involving miR-143 and DNMT3a mediates vascular smooth muscle cell proliferation induced by homocysteine. AB - Accumulating evidence has suggested that homocysteine (Hcy) is an independent risk factor for atherosclerosis (AS). Hcy can promote vascular smooth muscle cell (VSMC) proliferation, which is pivotal in the pathogenesis and progression of AS. The aim of the present study was to investigate the epigenetic regulatory mechanism of microRNA (miR)-143-mediated VSMCs proliferation induced by Hcy. The results of a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphe-nyltetrazolium bromide assay revealed that VSMC proliferation was increased by 1.39-fold following treatment with 100 mM Hcy, compared with the control group. The levels of miR-143 were markedly downregulated in the Hcy group, compared with the control group, as determined using reverse transcription-quantitative polymerase chain reaction analysis. In addition, the level of miR-143 methylation was increased markedly in the VSMCs treated with Hcy, compared with the control, and was reduced following transfection with DNA methyltransferase (DNMT)3a small interfering RNA, determined using methylation-specific-PCR. The activities of DNMT3a luciferase were also altered accordingly in VSMCs transfected with pre-miR-143 and miR-143 inhibitor, respectively. In addition, the expression of miR-143 was observed to be inversely correlated with the mRNA and protein expression of DNMT3 in the VSMCs. Taken together, these findings suggest that DNMT3a is a direct target of miR-143, and that the upregulation of DNMT3 is responsible for the hypermethylation of miR-143 in Hcy-induced VSMC proliferation. PMID- 26573389 TI - Quality of life in the follow-up of uveal melanoma patients after enucleation in comparison to CyberKnife treatment. AB - PURPOSE: To compare quality of life (QoL) in patients with uveal melanoma after enucleation and stereotactic radiosurgery to that in an age-matched patient collective. METHODS: QoL was assessed in a cross-sectional survey and compared among 32 uveal melanoma patients after enucleation, 48 patients after stereotactic radiosurgery (CyberKnife((r)); Accuray((r)) Incorporated, Sunnyvale, CA, USA), and an age-matched control group of 35 patients, using the SF-12 Health Survey. Statistical analysis was performed with Fisher's exact test, Student's t test, one-way ANOVA analysis, Wilcoxon rank-sum (Mann-Whitney test), and ordered logistic regression for multivariate analysis. RESULTS: There was no significant difference in QoL between patients treated by stereotactic radiosurgery and the age-matched control group. After enucleation, patients presented significantly lower values in Physical Functioning (PF), Role Physical (RP), and Role Emotional (RE) compared to the radiosurgery and control group. To control for the overall QoL lowering effect of visual loss, the QoL of the patients who underwent enucleation was compared with the QoL of patients suffering severe functional loss after CyberKnife radiosurgery in a subgroup analysis, which showed no statistically significant difference. The number of comorbidities had a significant impact on QoL in multivariate analysis. CONCLUSIONS: Superior performance in PF, RP, and RE suggests that CyberKnife represents a suitable first-line therapy for uveal melanoma. In cases with painful amaurosis or vast tumor recurrence, enucleation can be performed with an acceptable QoL outcome. PMID- 26573390 TI - Anterior lens epithelium in intumescent white cataracts - scanning and transmission electron microscopy study. AB - PURPOSE: Our purpose was to study the structure of the lens epithelial cells (LECs) of intumescent white cataracts (IC) in comparison with nuclear cataracts (NC) in order to investigate possible structural reasons for development of IC. METHODS: The anterior lens capsule (aLC: basement membrane and associated LECs) were obtained from cataract surgery and prepared for scanning electron microscopy (SEM) and transmission electron microscopy (TEM). RESULTS: We observed by SEM that in IC, LEC swelling was pronounced with the clefts surrounding the groups of LECs. Another structural feature was spherical formations, that were observed on the apical side of LEC's, towards the fibre cell layer, both by SEM and TEM. Development of these structures, bulging out from the apical cell membrane of the LEC's and disrupting it, could be followed in steps towards the sphere formation. The degeneration of the lens epithelium and the structures of the aLC in IC similar to Morgagnian globules were also observed. None of these structural changes were observed in NC. CONCLUSIONS: We show by SEM and TEM that, in IC, LECs have pronounced structural features not observed in NC. This supports the hypothesis that the disturbed structure of LECs plays a role in water accumulation in the IC lens. We also suggest that, in IC, LECs produce bulging spheres that represent unique structures of degenerated material, extruded from the LEC. PMID- 26573391 TI - Bevacizumab treatment of macular edema in CRVO and BRVO: long-term follow-up (BERVOLT study: bevacizumab for RVO long-term follow-up). PMID- 26573392 TI - Why do people with chronic disease not contact consumer health organisations? A survey of general practice patients. AB - Aim Consumer health organisations (CHOs) are non-profit or voluntary sector organisations that promote and represent the interests of patients and carers affected by particular conditions. The purpose of this study was to examine, among patients with chronic disease, what differentiates those who contact CHOs from those who do not and what stops people from making contact. BACKGROUND: CHOs can enhance people's capacity to manage chronic disease by providing information, education and psychosocial support, but are under-utilised. Little is known about barriers to access. METHODS: Data were from a baseline telephone survey conducted as part of a randomised trial of an intervention to improve access to CHOs. Participants constituted a consecutive sample of 276 adults with diagnosed chronic disease recruited via 18 general practitioners in Brisbane, Australia. Quantitative survey items examined participants' use and perceptions of CHOs and a single open-ended question explored barriers to CHO use. Multiple logistic regression and thematic analysis were used. Findings Overall, 39% of participants had ever contacted a CHO for their health and 28% had contacted a CHO specifically focussed on their diagnosed chronic condition. Diabetes, poorer self reported physical health and greater health system contact were significantly associated with CHO contact. The view that 'my doctor does it all' was prevalent and, together with a belief that their health problems were 'not serious enough', was the primary reason patients did not make contact. CONCLUSION: Attitudinal and system-related barriers limit use of CHOs by those for whom they are designed. Developing referral pathways to CHOs and promoting awareness about what they offer is needed to improve access. PMID- 26573393 TI - Editorial overview: Catalysis and regulation. PMID- 26573394 TI - Selective interlayer ferromagnetic coupling between the Cu spins in YBa2Cu3O7-x grown on top of La0.7Ca0.3MnO3. AB - Studies to date on ferromagnet/d-wave superconductor heterostructures focus mainly on the effects at or near the interfaces while the response of bulk properties to heterostructuring is overlooked. Here we use resonant soft x-ray scattering spectroscopy to reveal a novel c-axis ferromagnetic coupling between the in-plane Cu spins in YBa2Cu3O7-x (YBCO) superconductor when it is grown on top of ferromagnetic La0.7Ca0.3MnO3 (LCMO) manganite layer. This coupling, present in both normal and superconducting states of YBCO, is sensitive to the interfacial termination such that it is only observed in bilayers with MnO2 but not with La0.7Ca0.3O interfacial termination. Such contrasting behaviors, we propose, are due to distinct energetic of CuO chain and CuO2 plane at the La0.7Ca0.3O and MnO2 terminated interfaces respectively, therefore influencing the transfer of spin-polarized electrons from manganite to cuprate differently. Our findings suggest that the superconducting/ferromagnetic bilayers with proper interfacial engineering can be good candidates for searching the theorized Fulde Ferrel-Larkin-Ovchinnikov (FFLO) state in cuprates and studying the competing quantum orders in highly correlated electron systems. PMID- 26573395 TI - Differences in the function and secretion of congenital aberrant fibrinogenemia between heterozygous gammaD320G (Okayama II) and gammaDeltaN319-DeltaD320 (Otsu I). AB - BACKGROUND: We encountered two patients with hypodysfibrinogenemia and designated them as Okayama II and Otsu I. Although the affected residue(s) in Okayama II and Otsu I overlapped, functionally determined fibrinogen levels and the ratio of functionally to immunologically determined plasma fibrinogen levels were markedly different. METHODS: DNA sequence and functional analyses were performed for purified plasma fibrinogen. A recombinant protein was synthesized in Chinese hamster ovary (CHO) cells to determine the secretion of variant fibrinogens. RESULTS: A heterozygous A>G in FGG, resulting in gamma320Asp>Gly for Okayama II, and a heterozygous deletion of AATGAT in FGG, resulting in the deletion of gammaAsn319 and gammaAsp320 (gammaDeltaN319-DeltaD320) for Otsu I, were obtained. SDS-PAGE and Coomassie staining revealed that the variant gamma-chain was not clear in Okayama II, but was clearly present in Otsu I. The lag period for the fibrin polymerization of Okayama II was slightly slower than that of the normal control, whereas Otsu I fibrinogen indicated no polymerization within 30 min. Both variant gamma-chains were synthesized in CHO cells and assembled into fibrinogen; however, the fibrinogen concentration ratio of the medium/cell lysate of gamma320Gly was six-fold lower than that of gammaDeltaN319-DeltaD320. CONCLUSIONS: We concluded that the plasma fibrinogen of Okayama II, constituted by a lower ratio of the variant gamma-chain, led to the almost normal functioning of fibrin polymerization. However, the plasma fibrinogen of Otsu I, with a higher ratio of the variant gamma-chain, led to marked reductions in fibrin polymerization. PMID- 26573396 TI - The lectin like domain of thrombomodulin is involved in the defence against pyelonephritis. AB - Pyelonephritis, a common complication of urinary tract infections, is frequently associated with kidney scarring and may lead to end-stage renal disease. During bacterial infections inflammatory and coagulation pathways and their mutual interaction are playing pivotal roles in the host response. Given that thrombomodulin (TM) is crucially involved in the interplay between coagulation and inflammation, we aimed to investigate the roles of its EGF and lectin-like domains in inflammation during acute pyelonephritis. Indeed, the EGF-like and the lectin-like domains of TM, are especially known to orchestrate inflammation and coagulation in different ways. Acute pyelonephritis was induced by intravesical inoculation of 1 * 10(8) CFU of uropathogenic Escherichia coli in two strains of TM transgenic mice. TM(pro/pro) mice carry a mutation in the EGF-like domain making them unable to activate protein C, an anticoagulant and anti-inflammatory protein. TM(LeD/LeD) mice lack the lectin-like domain of TM, which is critical for its anti-inflammatory and cytoprotective properties. Mice were sacrificed 24 and 48 h after inoculation. Bacterial loads, the immune response and the activation of coagulation were evaluated in the kidney and the bladder. TM(LeD/LeD) mice showed elevated bacterial load in bladder and kidneys compared to WT mice, whereas TM(pro/pro) had similar bacterial load as WT mice. TM(LeD/LeD) mice displayed a reduced local production of pro-inflammatory cytokines and neutrophil renal infiltration. Activation of coagulation was comparable in TM(LeD/LeD) and WT mice. From these data, we conclude that the lectin-like domain of thrombomodulin is critically involved in host defence against E. coli induced acute pyelonephritis. PMID- 26573397 TI - [Nutrition, let's communicate otherwise!]. PMID- 26573398 TI - [To be born and grow up in the prison universe]. PMID- 26573399 TI - [Woman and mother in prison, a difficult reality]. AB - Prison is a difficult and violent environment. Women prisoners are often in situations of frailty, social and emotional misery. Mothers who have a child under the age of 18 months are able to live with them in dedicated wings. However, although prison conditions have improved with time, discussion is needed around the development of alternatives to incarceration, such as electronic tagging. PMID- 26573400 TI - [The right to be a mother in prison]. AB - Since the beginning of the 21st century, legislation has been in place framing the rights of women prisoners. Pregnancy, motherhood and family life can be organised despite the complications and the difficulties. It is however preferable to favour alternative sentences, outside prison, in order to offer the child and the mother more suitable solutions. PMID- 26573401 TI - [Motherhood behind bars]. AB - Women represent a small fraction of the prison population. Major issues arise when a prisoner is both a woman and a mother. The psychological and support work is particularly important and must be aimed at both the women and their children. PMID- 26573402 TI - [Child health nurse in prison, a unique experience]. AB - A child health nurse from the mother and infant welfare protection service describes her work in prisons, with women prisoners and their children. A unique experience in which professionalism and emotion go hand in hand. Indeed, while prison is a place of detention, it can also be a place of care and support. PMID- 26573403 TI - ["I became a mother in prison."]. AB - When Jessica, a young female prisoner, discovered she was pregnant, she wanted a termination but the legal time limit had passed. Over the weeks, she felt her baby move and then became aware of all the love she could give it. The pregnancy followed by the birth of her son, transformed her. After seven months spent in a cell with him, came the long-awaited release. PMID- 26573404 TI - [The nurse consultation in a Swiss university paediatric emergency department]. AB - In Switzerland, overcrowding in tertiary emergency departments is a frequent problem, resulting in lengthy waiting times, lower satisfaction on the part of families and a risk for patient's safety. The setting up of a nurse consultation in a university paediatric emergency centre has helped to improve the quality of care in this context. PMID- 26573405 TI - [Singing as an aid in neonatology]. AB - Health professionals expect the beneficial effects of singing in neonatology, but remain reluctant to use it. The sensorimotor behaviour of newborns has been analysed when a professional or a mother sings. The results of a qualitative study show that singing before performing a care procedure can modify alertness by favouring interaction and have a positive impact on the behavioural assessment score. During the procedure, singing can help the baby's stability. A factor of well-being for the newborn, this practice could be developed on a wider scale. PMID- 26573406 TI - Perfusion Imaging of Tumefactive Demyelinating Lesions Compared to High Grade Gliomas. PMID- 26573407 TI - Photo-induced enhancement of the power factor of Cu2S thermoelectric films. AB - Element doping is commonly used to adjust the carrier concentrations in semiconductors such as thermoelectric materials. However, the doping process unavoidably brings in defects or distortions in crystal lattices, which further strongly affects the physical properties of the materials. In this work, high energy photons have been used to activate the carriers in Cu2S thermoelectric films. As a result, the carrier concentrations, and the respective electrical conductivity as well as Seebeck coefficient are further changed. The photon induced electrical transport properties are further analyzed utilizing a Parallel circuit model. Due to the realization of optimized carrier concentrations by photon activation, the power factor of Cu2S film is improved more than 900 times as compared with the dark data. As compared to the traditional doping process, the approach using photon activation can realize the tuning of carrier concentrations without affecting crystal lattice. This method provides an opportunity to investigate the intrinsic physical properties of semiconductor materials without involving traditional element doping process that usually brings in additional lattice defects or distortions. PMID- 26573409 TI - [Retracted] Blockade of 11beta-hydroxysteroid dehydrogenase type 1 enzyme inhibits experimental collagenase-induced osteoarthritis. AB - This manuscript has been retracted by the Editorial Board of Molecular Medicine Reports, following an investigation prompted by the authors of the article mentioned below and the Editor of the Journal, Inflammation. Fig. 1 in this manuscript was reproduced in its entirety from the following study: Gyurkovska V, Stefanova T, Dimitrova P, Danova S, Tropcheva R and Ivanovska N: Tyrosine kinase inhibitor tyrphostin AG490 retards chronic joint inflammation in mice. Inflammation 37: 995-1005, 2014. Every effort was made on the part of the publisher to contact the authors on the Molecular Medicine Reports paper, but were unable to do so. As a result, this article has been retracted by the Editorial Board of Molecular Medicine Reports. [The original article was published in Molecular Medicine Reports 11: 2071-2075, 2015 DOI: 10.3893/mmr.2014.2983]. PMID- 26573408 TI - Paracingulate sulcus morphology is associated with hallucinations in the human brain. AB - Hallucinations are common in psychiatric disorders, and are also experienced by many individuals who are not mentally ill. Here, in 153 participants, we investigate brain structural markers that predict the occurrence of hallucinations by comparing patients with schizophrenia who have experienced hallucinations against patients who have not, matched on a number of demographic and clinical variables. Using both newly validated visual classification techniques and automated, data-driven methods, hallucinations were associated with specific brain morphology differences in the paracingulate sulcus, a fold in the medial prefrontal cortex, with a 1 cm reduction in sulcal length increasing the likelihood of hallucinations by 19.9%, regardless of the sensory modality in which they were experienced. The findings suggest a specific morphological basis for a pervasive feature of typical and atypical human experience. PMID- 26573410 TI - Co-design and implementation research: challenges and solutions for ethics committees. AB - BACKGROUND: Implementation science research, especially when using participatory and co-design approaches, raises unique challenges for research ethics committees. Such challenges may be poorly addressed by approval and governance mechanisms that were developed for more traditional research approaches such as randomised controlled trials. DISCUSSION: Implementation science commonly involves the partnership of researchers and stakeholders, attempting to understand and encourage uptake of completed or piloted research. A co-creation approach involves collaboration between researchers and end users from the onset, in question framing, research design and delivery, and influencing strategy, with implementation and broader dissemination strategies part of its design from gestation. A defining feature of co-creation is its emergent and adaptive nature, making detailed pre-specification of interventions and outcome measures impossible. This methodology sits oddly with ethics committee protocols that require precise pre-definition of interventions, mode of delivery, outcome measurements, and the role of study participants. But the strict (and, some would say, inflexible) requirements of ethics committees were developed for a purpose - to protect participants from harm and help ensure the rigour and transparency of studies. We propose some guiding principles to help square this circle. First, ethics committees should acknowledge and celebrate the diversity of research approaches, both formally (through training) and informally (by promoting debate and discussion); without active support, their members may not understand or value participatory designs. Second, ground rules should be established for co design applications (e.g. how to judge when 'consultation' or 'engagement' becomes research) and communicated to committee members and stakeholders. Third, the benefits of power-sharing should be recognised and credit given to measures likely to support this important goal, especially in research with vulnerable communities. Co-design is considered best practice, for example, in research involving indigenous peoples in New Zealand, Australia and Canada. PMID- 26573411 TI - Equity in health care financing in Portugal: findings from the Household Budget Survey 2010/2011. AB - Equity in health care financing is recognised as a main goal in health policy. It implies that payments should be linked to capacity to pay and that households should be protected against catastrophic health expenditure (CHE). The risk of CHE is inversely related to the share of out-of-pocket payments (OOP) in total health expenditure. In Portugal, OOP represented 26% of total health expenditure in 2010 [one of the highest among Organisation for Economic Co-operation and Development (OECD) countries]. This study aims to identify the proportion of households with CHE in Portugal and the household factors associated with this outcome. Additionally, progressivity indices are calculated for OOP and private health insurance. Data were taken from the Portuguese Household Budget Survey 2010/2011. The prevalence of CHE is 2.1%, which is high for a developed country with a universal National Health Service. The main factor associated with CHE is the presence of at least one elderly person in households (when the risk quadruples). Payments are particularly regressive for medicines. Regarding the results by regions, the Kakwani index for total OOP is larger (negative) for the Centre and lower, not significant, for the Azores. Payments for voluntary health insurance are progressive. PMID- 26573412 TI - A Large Outbreak of Hepatitis C Virus Infections in a Hemodialysis Clinic. AB - BACKGROUND In November and December 2012, 6 patients at a hemodialysis clinic were given a diagnosis of new hepatitis C virus (HCV) infection. OBJECTIVE To investigate the outbreak to identify risk factors for transmission. METHODS A case patient was defined as a patient who was HCV-antibody negative on clinic admission but subsequently was found to be HCV-antibody positive from January 1, 2008, through April 30, 2013. Patient charts were reviewed to identify and describe case patients. The hypervariable region 1 of HCV from infected patients was tested to assess viral genetic relatedness. Infection control practices were evaluated via observations. A forensic chemiluminescent agent was used to identify blood contamination on environmental surfaces after cleaning. RESULTS Eighteen case patients were identified at the clinic from January 1, 2008, through April 30, 2013, resulting in an estimated 16.7% attack rate. Analysis of HCV quasispecies identified 4 separate clusters of transmission involving 11 case patients. The case patients and previously infected patients in each cluster were treated in neighboring dialysis stations during the same shift, or at the same dialysis station on 2 consecutive shifts. Lapses in infection control were identified. Visible and invisible blood was identified on multiple surfaces at the clinic. CONCLUSIONS Epidemiologic and laboratory data confirmed transmission of HCV among numerous patients at the dialysis clinic over 6 years. Infection control breaches were likely responsible. This outbreak highlights the importance of rigorous adherence to recommended infection control practices in dialysis settings. PMID- 26573413 TI - Why Bioresorbable Vascular Scaffold Should Be Approved for Marketing in the United States. PMID- 26573414 TI - Supra annular position of a transcatheter aortic valve prosthesis: from bed to bench. PMID- 26573415 TI - Novel, Synergistic Antifungal Combinations that Target Translation Fidelity. AB - There is an unmet need for new antifungal or fungicide treatments, as resistance to existing treatments grows. Combination treatments help to combat resistance. Here we develop a novel, effective target for combination antifungal therapy. Different aminoglycoside antibiotics combined with different sulphate-transport inhibitors produced strong, synergistic growth-inhibition of several fungi. Combinations decreased the respective MICs by >=8-fold. Synergy was suppressed in yeast mutants resistant to effects of sulphate-mimetics (like chromate or molybdate) on sulphate transport. By different mechanisms, aminoglycosides and inhibition of sulphate transport cause errors in mRNA translation. The mistranslation rate was stimulated up to 10-fold when the agents were used in combination, consistent with this being the mode of synergistic action. A range of undesirable fungi were susceptible to synergistic inhibition by the combinations, including the human pathogens Candida albicans, C. glabrata and Cryptococcus neoformans, the food spoilage organism Zygosaccharomyces bailii and the phytopathogens Rhizoctonia solani and Zymoseptoria tritici. There was some specificity as certain fungi were unaffected. There was no synergy against bacterial or mammalian cells. The results indicate that translation fidelity is a promising new target for combinatorial treatment of undesirable fungi, the combinations requiring substantially decreased doses of active components compared to each agent alone. PMID- 26573416 TI - Litomosoides sigmodontis: a jird urine metabolome study. AB - The neglected tropical disease onchocerciasis affects more than 35 million people worldwide with over 95% in Africa. Disease infection initiates from the filarial parasitic nematode Onchocerca volvulus, which is transmitted by the blackfly vector Simulium sp. carrying infectious L3 larvae. New treatments and diagnostics are required to eradicate this parasitic disease. Herein, we describe that a previously discovered biomarker for onchocerciasis, N-acetyltyramine-O glucuronide (NATOG) is also present in urine samples of jirds infected with the onchocerciasis model nematode Litomosoides sigmodontis. Increased NATOG values paralleled a progressing infection and demonstrated that quantification of NATOG in this rodent model can be utilized to track its infectivity. Moreover, our findings suggest how NATOG monitoring may be used for evaluating potential drug candidates. PMID- 26573417 TI - MicroRNA-101 induces apoptosis in cisplatin-resistant gastric cancer cells by targeting VEGF-C. AB - Deregulation of microRNAs (miRNAs) is known to be associated with drug resistance in human cancers. However, the precise role of miR-101 in the cisplatin (DPP) resistance of human gastric cancer cells has not been elucidated, yet. The present study revealed that miR-101 was markedly downregulated in gastric cancer cell lines compared to that in the normal gastric mucosa epithelial cell line GES1. Furthermore, a significant decrease in miR-101 levels, accompanied with an increased expression of vascular endothelial growth factor (VEGF)-C in DDP resistant SGC7901 gastric cancer cells (SGC7901/DDP) compared with those in native SGC7901 cells was observed. In addition, forced overexpression of miR-101 significantly inhibited cell proliferation, while enhancing cisplatin-induced apoptosis of SGC7901/DDP cells. A luciferase reporter assay confirmed that VEGF-C was a direct target of miR-101 in SGC7901/DDP cells. Forced overexpression of miR 101 in SGC7901/DDP cells reduced the expression of VEGF-C, while knockdown of miR 101 expression significantly enhanced VEGF-C expression in SGC7901/DDP cells. Finally, overexpression of VEGF-C inhibited DDP-induced apoptosis in SGC7901 cells. In conclusion, the results of the present study suggested that miR-101 inhibited the proliferation and promoted DDP-induced apoptosis of DDP-resistant gastric cancer cells, at least in part via targeting VEGF-C. PMID- 26573418 TI - The increased risk of active tuberculosis disease in patients with dermatomyositis - a nationwide retrospective cohort study. AB - The risk of active tuberculosis (TB) in patients with dermatomyositis (DM) is poorly understood. The cohort study aimed to investigate the association between DM and the risk of active TB disease. We conducted a population based study on 4,958 patients with newly diagnosed DM and 19,832 matched controls according to age, sex, and index date between 1998 and 2008. The hazard ratios (HRs) and cumulative incidences of active TB disease between DM patients and controls were analyzed. During the study period, a total of 85 (1.7%) DM patients developed active TB disease, which was significantly higher than that of non-DM patients (0.64%). The incidence rate of active TB disease was higher among DM patients than controls (incidence rate ratio 2.95; 95% confidence interval [CI], 2.24 to 3.88). The Cox regression model demonstrated significantly higher active TB disease rate among DM patients compared with controls (adjusted HR, 2.64; 95% CI, 1.97 to 3.54; p < 0.001) after adjusting for age, sex, and underlying medical disorders. The most significant risk factors for developing active TB included male sex, diabetes mellitus comorbidity, and use of corticosteroids and azathioprine in DM patients. In conclusion, DM patients are at a greater risk for active TB disease. PMID- 26573419 TI - Breast cancer: The importance of overdiagnosis in breast-cancer screening. PMID- 26573420 TI - Can FCR be curative in CLL? PMID- 26573421 TI - Molecular stratification and repair defects: revealing hidden treasures. PMID- 26573422 TI - Haematological cancer: ETV6 germline mutation - a risk for ALL. PMID- 26573423 TI - Allogeneic transplantation for CML in the TKI era: striking the right balance. AB - The management of chronic myeloid leukaemia (CML) has changed extensively over the past 15 years. Prior to the development of targeted therapies and in the absence of allogeneic haematopoetic stem-cell transplantation (HSCT), the median survival was 5-7 years. HSCT was quickly established as the standard of care for eligible patients through the 1980s and 1990s, when considerable advances were made in the optimization of conditioning regimens and supportive care. Exploiting a deeper understanding of the molecular basis of CML, the development of tyrosine kinase inhibitors (TKIs) in the late 1990s revolutionized the management of the disease. TKIs offer the prospect of long-term disease control with a simple oral therapy, and are the first-line treatment in the 21(st) century. The majority of patients treated with TKIs achieve excellent responses with sustained treatment, and some even continue to have undetectable or exceptionally low level disease upon TKI withdrawal; however, for an almost equal number of patients, an adequate response cannot be achieved with any of the currently available TKIs. For those patients who fail to respond adequately to TKIs, HSCT offers the best prospect of long-term survival. PMID- 26573424 TI - Cachexia in patients with oesophageal cancer. AB - Oesophageal cancer is a debilitating disease with a poor prognosis, and weight loss owing to malnutrition prevails in the majority of patients. Cachexia, a multifactorial syndrome characterized by the loss of fat and skeletal muscle mass and systemic inflammation arising from complex host-tumour interactions is a major contributor to malnutrition, which is a determinant of tolerance to treatment and survival. In patients with oesophageal cancer, cachexia is further compounded by eating difficulties owing to the stage and location of the tumour, and the effects of neoadjuvant therapy. Treatment with curative intent involves exceptionally extensive and invasive surgery, and the subsequent anatomical changes often lead to eating difficulties and severe postoperative malnutrition. Thus, screening for cachexia by means of percentage weight loss and BMI during the cancer trajectory and survivorship periods is imperative. Additionally, markers of inflammation (such as C-reactive protein), dysphagia and appetite loss should be assessed at diagnosis. Routine assessments of body composition are also necessary in patients with oesophageal cancer to enable assessment of skeletal muscle loss, which might be masked by sarcopenic obesity in these patients. A need exists for clinical trials examining the effectiveness of therapeutic and physical-activity-based interventions in mitigating muscle loss and counteracting cachexia in these patients. PMID- 26573426 TI - Agenesis of the corpus callosum. An autopsy study in fetuses. AB - Agenesis of the corpus callosum is currently diagnosed prenatally with ultrasound and MRI. While the diagnostic aspects of callosal defects are widely addressed, anatomo-histological data from fetal autopsies are sparse. Callosal defects were present in 50 fetal autopsies. Four distinct groups of complete, partial, hypoplastic, and mixed defects were determined by the gross and histologic details of the corpus callosum. These details helped to rule out other midline defects such as holoprosencephaly. Additional autopsy findings enabled specific diagnoses and suggested etiopathogeneses. Hypoplastic and mixed defects were associated with more abnormalities of the cerebral hemispheres and internal organs. The four groups did not differ according to gender, external dysmorphism, or cerebellar and brainstem anomalies. Defects were classified as syndromic (68 %), encephaloclastic (8 %), undetermined (14 %), or isolated (10 %) based on the autopsy findings. Isolated agenesis of the corpus callosum was diagnosed in only 10 % of the cases in this series, compared to higher numbers diagnosed by prenatal ultrasonography and MRI. Therefore, the autopsy, through its detailed, careful evaluation of external, as well as gross and histological internal features, can elucidate the etiopathogenesis of agenesis of the corpus callosum and suggest specific diagnoses which cannot be ascertained by prenatal imaging. PMID- 26573427 TI - Adhesion between highly stretchable materials. AB - Recently developed high-speed ionic devices require adherent laminates of stretchable and dissimilar materials, such as gels and elastomers. Adhesion between stretchable and dissimilar materials also plays important roles in medicine, stretchable electronics, and soft robots. Here we develop a method to characterize adhesion between materials capable of large, elastic deformation. We apply the method to measure the debond energy of elastomer-hydrogel bilayers. The debond energy between an acrylic elastomer and a polyacrylamide hydrogel is found to be about 0.5 J m(-2), independent of the thickness and the crosslink density of the hydrogel. This low debond energy, however, allows the bilayer to be adherent and highly stretchable, provided that the hydrogel is thin and compliant. Furthermore, we demonstrate that nanoparticles applied at the interface can improve adhesion between the elastomer and the hydrogel. PMID- 26573425 TI - RAS testing in metastatic colorectal cancer: advances in Europe. AB - Personalized medicine shows promise for maximizing efficacy and minimizing toxicity of anti-cancer treatment. KRAS exon 2 mutations are predictive of resistance to epidermal growth factor receptor-directed monoclonal antibodies in patients with metastatic colorectal cancer. Recent studies have shown that broader RAS testing (KRAS and NRAS) is needed to select patients for treatment. While Sanger sequencing is still used, approaches based on various methodologies are available. Few CE-approved kits, however, detect the full spectrum of RAS mutations. More recently, "next-generation" sequencing has been developed for research use, including parallel semiconductor sequencing and reversible termination. These techniques have high technical sensitivities for detecting mutations, although the ideal threshold is currently unknown. Finally, liquid biopsy has the potential to become an additional tool to assess tumor-derived DNA. For accurate and timely RAS testing, appropriate sampling and prompt delivery of material is critical. Processes to ensure efficient turnaround from sample request to RAS evaluation must be implemented so that patients receive the most appropriate treatment. Given the variety of methodologies, external quality assurance programs are important to ensure a high standard of RAS testing. Here, we review technical and practical aspects of RAS testing for pathologists working with metastatic colorectal cancer tumor samples. The extension of markers from KRAS to RAS testing is the new paradigm for biomarker testing in colorectal cancer. PMID- 26573428 TI - Stakeholder involvement in establishing a milk quality sub-index in dairy cow breeding goals: a Delphi approach. AB - The relative weighting on traits within breeding goals are generally determined by bio-economic models or profit functions. While such methods have generally delivered profitability gains to producers, and are being expanded to consider non-market values, current approaches generally do not consider the numerous and diverse stakeholders that affect, or are affected, by such tools. Based on principles of respondent anonymity, iteration, controlled feedback and statistical aggregation of feedback, a Delphi study was undertaken to gauge stakeholder opinion of the importance of detailed milk quality traits within an overall dairy breeding goal for profit, with the aim of assessing its suitability as a complementary, participatory approach to defining breeding goals. The questionnaires used over two survey rounds asked stakeholders: (a) their opinion on incorporating an explicit sub-index for milk quality into a national breeding goal; (b) the importance they would assign to a pre-determined list of milk quality traits and (c) the (relative) weighting they would give such a milk quality sub-index. Results from the survey highlighted a good degree of consensus among stakeholders on the issues raised. Similarly, revelation of the underlying assumptions and knowledge used by stakeholders to make their judgements illustrated their ability to consider a range of perspectives when evaluating traits, and to reconsider their answers based on the responses and rationales given by others, which demonstrated social learning. Finally, while the relative importance assigned by stakeholders in the Delphi survey (4% to 10%) and the results of calculations based on selection index theory of the relative emphasis that should be placed on milk quality to halt any deterioration (16%) are broadly in line, the difference indicates the benefit of considering more than one approach to determining breeding goals. This study thus illustrates the role of the Delphi technique, as a complementary approach to traditional approaches, to defining breeding goals. This has implications for how breeding goals will be defined and in determining who should be involved in the decision-making process. PMID- 26573429 TI - Smac mimetic-induced caspase-independent necroptosis requires RIP1 in breast cancer. AB - There is an urgent requirement for the development of novel targeted therapies to treat breast cancer, which is the most comment type of malignancy among women. The evasion of apoptosis is a hallmark of cancer, and is often due to the upregulation of inhibitor of apoptosis proteins (IAPs) in tumor cells. Second mitochondrial-derived activator of caspase/direct IAP-binding protein with low PI is a natural IAP antagonist, which is found in the mitochondrion; this protein has a motif, which binds to a surface groove on the baculovirus IAP repeat domains of the IAPs. In the present study, the effects of the LCL161 Smac mimetic, a small molecule IAP antagonist, on breast cell lines was examined. The results from MTT and colony formation assays demonstrated that LCL161 markedly inhibited the proliferation and induced the apoptosis of MDA-MB-231 and MCF-7 cell lines. As determined by western blotting, cIAP1 was degraded in the breast cancer cells, which occurred in an LCL161-dependent manner. Upon caspase activation, LCL161 treatment induced necroptosis, another form of programmed cell death. The downregulation of receptor-interacting protein kinase-1 via small interfering RNA protected the cells from LCL161-induced necroptosis. Taken together, the results of the present study showed that LCL161 can induce multiple forms of programmed cell death in breast cancer cells, and may thus offer promise as an anticancer agent in diverse genotypic backgrounds. PMID- 26573430 TI - New function of TSGA10 gene in angiogenesis and tumor metastasis: a response to a challengeable paradox. AB - Several studies have shown that testis-specific gene antigen (TSGA10) could be considered as a cancer testis antigen (CTA), except for one study which has identified it as a tumor suppressor gene. In order to exert its function, TSGA10 interacts closely with hypoxia inducible factor (HIF-1alpha) and since this interaction is still not completely defined, the exact role of TSGA10 in angiogenesis and invasion is also under question. The current study was conducted to investigate the function of TSGA10 gene and evaluate its potential effects on tumor angiogenesis and invasion. To do so, TSGA10 vector was designed for a stable transfection in HeLa cells, and then clonal selection was applied. The efficiency of transfection and the role of TSGA10 in abovementioned targets were evaluated by real-time PCR, western blot, zymography and ELISA tests in both normoxia and hypoxia. Invasion, migration and angiogenesis were assessed. Three dimensional model of TSGA10 protein was accurately built in which TSGA10 docked to 2 domains of HIF-1alpha. Increased expression of TSGA10 correlated with decreased HIF-1alpha transcriptional activity and inhibited angiogenesis and HeLa cells invasion in normoxia as well as hypoxia. Docking analysis indicated that binding affinity of TSGA10 with TAD-C (CBP) domain of HIF-1alpha would be stronger than that with PAS-B domain. Our findings showed that overexpression of TSGA10 would induce disruption of HIF-1alpha axis and exert potent inhibitory effects on tumor angiogenesis and metastasis. Therefore, TSGA10 could be considered as a potent therapeutic candidate, prognostic factor and a cancer management tool. PMID- 26573431 TI - No effect of escitalopram versus placebo on brain-derived neurotrophic factor in healthy individuals: a randomised trial. AB - OBJECTIVE: Brain-derived neurotrophic factor (BDNF) seems to play an important role in the course of depression including the response to antidepressants in patients with depression. We aimed to study the effect of an antidepressant intervention on peripheral BDNF in healthy individuals with a family history of depression. METHODS: We measured changes in BDNF messenger RNA (mRNA) expression and whole-blood BDNF levels in 80 healthy first-degree relatives of patients with depression randomly allocated to receive daily tablets of escitalopram 10 mg versus placebo for 4 weeks. RESULTS: We found no statistically significant difference between the escitalopram and the placebo group in the change in BDNF mRNA expression and whole-blood BDNF levels. Post hoc analyses showed a statistically significant negative correlation between plasma escitalopram concentration and change in whole-blood BDNF levels in the escitalopram-treated group. CONCLUSION: The results of this randomised trial suggest that escitalopram 10 mg has no effect on peripheral BDNF levels in healthy individuals. PMID- 26573432 TI - Introduction. PMID- 26573433 TI - Targeted Proteomics Enables Simultaneous Quantification of Folate Receptor Isoforms and Potential Isoform-based Diagnosis in Breast Cancer. AB - The distinct roles of protein isoforms in cancer are becoming increasingly evident. FRalpha and FRbeta, two major isoforms of the folate receptor family, generally have different cellular distribution and tissue specificity. However, the presence of FRbeta in breast tumors, where FRalpha is normally expressed, complicates this situation. Prior to applying any FR isoform-based diagnosis and therapeutics, it is essential to monitor the expression profile of FR isoforms in a more accurate manner. An LC-MS/MS-based targeted proteomics assay was developed and validated in this study because of the lack of suitable methodology for the simultaneous and specific measurement of highly homologous isoforms occurring at low concentrations. FRalpha and FRbeta monitoring was achieved by measuring their surrogate isoform-specific peptides. Five human breast cell lines, isolated macrophages and 60 matched pairs of breast tissue samples were subjected to the analysis. The results indicated that FRbeta was overexpressed in tumor-associated macrophages (TAMs) but not epithelial cells, in addition to an enhanced level of FRalpha in breast cancer cells and tissue samples. Moreover, the levels of the FR isoforms were evaluated according to the histology, histopathological features and molecular subtypes of breast cancer. Several positive associations with PR/ER and HER2 status and metastasis were revealed. PMID- 26573434 TI - Epidemiology of myasthenia gravis in Ontario, Canada. AB - Incidence and prevalence estimates in myasthenia gravis have varied widely. Recent studies based on administrative health data have large sample sizes but lack rigorous validation of MG cases, and have not examined the North American population. Our aim was to explore trends in MG incidence and prevalence for the years 1996-2013 in the province of Ontario, Canada (population 13.5 million). We employed a previously validated algorithm to identify MG cases. Linking with census data allowed for the calculation of crude- and age/sex-standardized incidence and prevalence rates for the years 1996-2013. The regional distribution of MG cases throughout the province was examined. Mean age at the first myasthenia gravis encounter was 60.2 +/- 17.1 years. In 2013, there were 3611 prevalent cases in Ontario, and the crude prevalence rate was 32.0/100,000 population. Age- and sex-standardized prevalence rates rose consistently over time from 16.3/100,000 (15.4-17.1) in 1996 to 26.3/100,000 (25.4-27.3) in 2013. Standardized incidence rates remained stable between 1996 (2.7/100,000; 95% CL 2.3-3.0) and 2013 (2.3/100,000; 2.1-2.6). Incidence was highest in younger women and older men, and geographic variation was evident throughout the province. In conclusion, this large epidemiological study shows rising myasthenia gravis prevalence with stable incidence over time, which is likely reflective of patients living longer, possibly due to improved disease treatment. Our findings provide accurate information on the Canadian epidemiology of myasthenia gravis and burden for health care resources planning for the province, respectively. PMID- 26573435 TI - Muscle imaging in muscle dystrophies produced by mutations in the EMD and LMNA genes. AB - Identifying the mutated gene that produces a particular muscle dystrophy is difficult because different genotypes may share a phenotype and vice versa. Muscle MRI is a useful tool to recognize patterns of muscle involvement in patients with muscle dystrophies and to guide the diagnosis process. The radiologic pattern of muscle involvement in patients with mutations in the EMD and LMNA genes has not been completely established. Our objective is to describe the pattern of muscle fatty infiltration in patients with mutations in the EMD and in the LMNA genes and to search for differences between the two genotypes that could be helpful to guide the genetic tests. We conducted a national multicenter study in 42 patients, 10 with mutations in the EMD gene and 32 with mutations in the LMNA gene. MRI or CT was used to study the muscles from trunk to legs. Patients had a similar pattern of fatty infiltration regardless of whether they had the mutation in the EMD or LMNA gene. The main muscles involved were the paravertebral, glutei, quadriceps, biceps, semitendinosus, semimembranosus, adductor major, soleus, and gastrocnemius. Involvement of peroneus muscle, which was more frequently affected in patients with mutations in the EMD gene, was useful to differentiate between the two genotypes. Muscle MRI/CT identifies a similar pattern of muscle fatty infiltration in patients with mutations in the EMD or the LMNA genes. The involvement of peroneus muscles could be useful to conduct genetic analysis in patients with an EDMD phenotype. PMID- 26573436 TI - Newly synthesized podophyllotoxin derivative, LJ12, induces apoptosis and mitotic catastrophe in non-small cell lung cancer cells in vitro. AB - Deoxypodophyllotoxin (DPT), an active compound isolated from a number of herbs and used in traditional medicine, has been reported to exhibit promising anti tumor activity. A newly synthesized derivative, N-(1-oxyl-4'-demethyl-4-deoxyp odophyllic)-L-methine-4'-piperazine carbamate (LJ12) may have improved antitumor activity and fewer side effects. The present study assessed the effect of LJ12 on cell viability, apoptosis, cell cycle distribution and mitotic catastrophe in A549 human lung cancer cells in vitro. The molecular mechanisms underlying the antitumor activity of LJ12 were also examined. The results demonstrated that LJ12 reduced A549 cell viability in a time- and dose-dependent manner, with a lower half maximal inhibitory concentration of ~0.1 uM, compared with another known DPT derivative, etoposide (10 uM). Flow cytometric analysis showed that LJ12 induced tumor cell arrest at the G2/M phase of the cell cycle. The present study also observed an expected concomitant decrease in the numbers of cells cells in the G0/G1 and S phases. LJ12 was found to upregulate the protein expression levels of Cdc2 and Cyclin B1. Furthermore, LJ12 induced tumor cell apoptosis and the protein expression of B cell lymphoma-2-associated X protein, caspase-3 and p53. The present study also observed the formation of giant, multinucleated cells, indicating that LJ12 induced mitotic catastrophe in the tumor cells. These results indicated that LJ12 has anti-non-small cell lung cancer activity in vitro. Further investigations aim to develop LJ12 as a therapeutic agent for the treatment of lung cancer. PMID- 26573437 TI - How should health service organizations respond to diversity? A content analysis of six approaches. AB - BACKGROUND: Health care organizations need to be responsive to the needs of increasingly diverse patient populations. We compared the contents of six publicly available approaches to organizational responsiveness to diversity. The central questions addressed in this paper are: what are the most consistently recommended issues for health care organizations to address in order to be responsive to the needs of diverse groups that differ from the majority population? How much consensus is there between various approaches? METHODS: We purposively sampled six approaches from the US, Australia and Europe and used qualitative textual analysis to categorize the content of each approach into domains (conceptually distinct topic areas) and, within each domain, into dimensions (operationalizations). The resulting classification framework was used for comparative analysis of the content of the six approaches. RESULTS: We identified seven domains that were represented in most or all approaches: organizational commitment, empirical evidence on inequalities and needs, a competent and diverse workforce, ensuring access for all users, ensuring responsiveness in care provision, fostering patient and community participation, and actively promoting responsiveness. Variations in the operationalization of these domains related to different scopes, contexts and types of diversity. For example, approaches that focus on ethnic diversity mostly provide recommendations to handle cultural and language differences; approaches that take an intersectional approach and broaden their target population to vulnerable groups in a more general sense also pay attention to factors such as socio-economic status and gender. CONCLUSIONS: Despite differences in labeling, there is a broad consensus about what health care organizations need to do in order to be responsive to patient diversity. This opens the way to full scale implementation of organizational responsiveness in healthcare and structured evaluation of its effectiveness in improving patient outcomes. PMID- 26573439 TI - Presentations at the annual meeting of the Finnish Society for Rheumatology, Tampere, 29-30 January 2015. PMID- 26573438 TI - Quantitative histology analysis of the ovarian tumour microenvironment. AB - Concerted efforts in genomic studies examining RNA transcription and DNA methylation patterns have revealed profound insights in prognostic ovarian cancer subtypes. On the other hand, abundant histology slides have been generated to date, yet their uses remain very limited and largely qualitative. Our goal is to develop automated histology analysis as an alternative subtyping technology for ovarian cancer that is cost-efficient and does not rely on DNA quality. We developed an automated system for scoring primary tumour sections of 91 late stage ovarian cancer to identify single cells. We demonstrated high accuracy of our system based on expert pathologists' scores (cancer = 97.1%, stromal = 89.1%) as well as compared to immunohistochemistry scoring (correlation = 0.87). The percentage of stromal cells in all cells is significantly associated with poor overall survival after controlling for clinical parameters including debulking status and age (multivariate analysis p = 0.0021, HR = 2.54, CI = 1.40-4.60) and progression-free survival (multivariate analysis p = 0.022, HR = 1.75, CI = 1.09 2.82). We demonstrate how automated image analysis enables objective quantification of microenvironmental composition of ovarian tumours. Our analysis reveals a strong effect of the tumour microenvironment on ovarian cancer progression and highlights the potential of therapeutic interventions that target the stromal compartment or cancer-stroma signalling in the stroma-high, late stage ovarian cancer subset. PMID- 26573443 TI - Task-specific preparatory neural activations in low-interference contexts. AB - How the brain prepares for forthcoming events is a pivotal question in human neuroscience. In the last years, several studies have suggested that expectations of perceiving upcoming stimuli engage relevant perceptual areas. Similarly, some experiments manipulating the task to be performed with targets have also found pre-activations in task-related brain areas. However, the usual configuration of this type of paradigms entails high levels of interference and/or working memory load, together with a small set of target stimuli. We designed a cued task paradigm in which interference was reduced to a minimum, as evidenced by behavioral indices of performance, and that included a high number of targets to avoid their anticipation. This was achieved using a large set of univalent target stimuli preceded by fully valid cues in a functional magnetic resonance imaging experiment. We found category-specific patterns of activity in which semantic cues engaged the left inferior frontal gyrus whereas spatial cues preactivated the right superior parietal lobe. Together with functional connectivity analyses, the activation maps showed the specific involvement of semantic and spatial processes upon the presentation of the cues that are coherent with previous literature. Our results thus suggest that even in contexts of low interference that prevent the anticipation of specific targets, our brain takes advantage of current information to deal with upcoming demands. PMID- 26573444 TI - Ductal carcinoma in situ (DCIS) treated by mastectomy, or local excision with or without radiotherapy: A monocentric, retrospective study of 608 women. AB - OBJECTIVES: Since mammographic screening programmes, the proportion of DCIS has dramatically increased. Adjuvant radiotherapy (RT) after local excision (LE) has become a solid option for DCIS since 4 randomised trials have proven a decrease in local relapse (LR), though failing to prove a benefit on mortality rate. DCIS is a heterogeneous disease and it is unclear whether all patients uniformly benefit from radiotherapy. We report a descriptive analysis including all types of treatment. MATERIALS AND METHODS: Our retrospective cohort describes 608 women treated for DCIS in our centre between 1983 and 2013. Mastectomy was recommended before 1992, or for multifocal or >3 cm DCIS. LE alone was an option for DCIS <=10 mm, with low or intermediate grade, and clear margins (>=2 mm). LE + RT was recommended for all other cases. RESULTS: The median follow-up time was 6.7 years. Treatment consisted in mastectomy for 252 women, LE + RT for 269 and LE for 86. The major prognosis factor for LR rate was the type of treatment: LE + RT or LE was associated with a higher LR-rate than those treated by mastectomy (HR respectively 2.06; 95%CI 1.33-3.19; p = 0.001 and 2.12; 95%CI 1.20-3.65; p = 0.007). In our selected population, women treated by LE + RT versus LE showed no significant differences in LR (HR 0.97; 95%CI 0.61-1.7; p = 0.91). The overall survival rate was 99.7% after ten years, with no differences between the treatment groups. CONCLUSION: Although retrospective, our monocentric study suggests that LE alone could be an option for DCIS with good prognosis factors. Confirmation by larger randomised studies is needed. PMID- 26573442 TI - Objectively measured physical activity of young Canadian children using accelerometry. AB - The objective of the study was to describe objectively measured physical activity (PA) and sedentary time of infants, toddlers, and preschoolers and determine the proportion meeting Canadian age-specific PA guidelines. Ninety children (47 girls, 43 boys; mean age 32 (range, 4-70) months) attending scheduled health supervision visits and in the TARGet Kids! (The Applied Research Group for Kids) cohort wore an Actical accelerometer for 7 days. Participants with 4 or more valid days were included in the analysis. Time, in mean minutes per day (min/day), spent sedentary and in light PA, moderate to vigorous PA (MVPA), and total PA was determined using published cut-points; age groups were compared using ANOVA. Twenty-three percent of children <18 months (n = 28) and 76% of children aged 18-59 months (n = 45) met the guideline of 180 min/day of total PA; 13% of children >=60 months (n = 17) met the guideline of 60 min/day of MVPA. Children <18 months spent more of their waking time per day engaged in sedentary behaviours (79%; ~7.3 h) compared with children aged 18-59 months (63%; ~6.6 h) and children >=60 months (58%; ~6.6 h). In conclusion, most children aged 18-59 months met the Canadian PA guidelines for children aged 0-4 years, whereas few younger than 18 months met the same guidelines. Only 13% of children >=5 years met their age-specific PA guidelines. Further research is needed to develop, test, and implement effective strategies to promote PA and reduce sedentary behaviour in very young children. PMID- 26573445 TI - A decade of offering a Healing Enhancement Program at an academic medical center. AB - An increased focus has been given to improving the patient experience in health care. This focus has included placing value in a patient-centric, holistic approach to patient care. In the past decade, the Healing Enhancement Program was developed at 1 large medical center to address this focus through implementation of such integrative medicine services as massage, acupuncture, and music therapy to holistically address the pain, anxiety, and tension that hospitalized patients often experience. We describe the development and growth of this program over the past decade. PMID- 26573446 TI - Providing acupuncture in a breast cancer and fatigue trial: The therapists' experience. AB - OBJECTIVE: To explore the experiences of therapists providing acupuncture in a trial context, to women with fatigue, following breast cancer treatment. METHODS: The focus groups were nested within a multi-site randomised control trial. Therapists (n = 15) involved in the trial were invited to participate in one of the focus groups, which took place in the north and south of England. The treatment protocol imposed constraints on dialogue to essential procedural conversation and stipulated needling times of 20 min. RESULTS: All 15 therapists (100%) participated. Whilst they reported learning more about fatigue and cancer, adhering to the trial protocol limited the holistic nature of their practice. Seeing improvements, despite the protocol, made some therapists question their practice, in terms of needling times and limiting dialogue. CONCLUSIONS: The study provided information about the therapists' perspective of working within a trial. This could have implications for providing acupuncture treatments more cost effectively and timely within clinical practice. PMID- 26573447 TI - A pilot randomized double-blind placebo-controlled trial on topical chamomile (Matricaria chamomilla L.) oil for severe carpal tunnel syndrome. AB - OBJECTIVE: To assess the effectiveness of standardized topical Chamomile (Matricaria chamomilla L.) oil in patients with severe carpal tunnel syndrome, as a complementary treatment. METHOD: A pilot randomized double-blind placebo controlled trial was conducted. Twenty six patients with documented severe carpal tunnel syndrome were treated in two parallel groups with a night splint plus topical chamomile oil or placebo. They were instructed to use their prescribed oil for 4 weeks, twice daily. Symptomatic and functional status of the patients and their electrodiagnostic parameters were evaluated when enrolled and after the trial period, as our outcome measures. RESULTS: A significant improvement of symptomatic and functional status of patients in the chamomile oil group was observed (p = 0.019 and 0.016, respectively) compared with those in the placebo group. However, electrodiagnostic parameters showed no significant changes between the two groups. CONCLUSION: Chamomile oil improved symptomatic and functional status of patients with severe carpal tunnel syndrome. PMID- 26573448 TI - Complementary and alternative therapies to relieve labor pain: A comparative study between music therapy and Hoku point ice massage. AB - BACKGROUND & AIM: Pain is a common experience for women during labor. In the present study, we compared the effect of two types of non-pharmacological pain relief methods "music therapy" and "Hoku point ice massage" on the severity of labor pain. METHODS: This prospective, randomized, controlled trial was conducted in Shahrekord, Iran, from September 2013 to June 2014. We randomly assigned 90 primiparous women who expected a normal childbirth into three groups: group "A" received music therapy, group "B" received Hoku point ice massage, and group "C" received usual labor care. At the beginning of the active phase (4 cm cervical dilation) and before and after each intervention (at dilations 4, 6, and 8 cm), the intensities of labor pain were measured using Visual Analogue Scale (VAS). RESULTS: At the beginning of the active phase, the mean VAS scores were 5.58 +/- 1.29, 5.42 +/- 1.31, and 6.13 +/- 1.37 in the women in groups "A," "B," and "C," respectively (P > 0.05). After the intervention, the mean pain scores were significantly lower at all of the time points in groups "A" and "B" than in group "C" women (P < 0.05). Although the pain scores showed a more decreasing trend after the intervention in group "A" than that in group "B," the difference between the two groups was not statistically significant (P > 0.05). CONCLUSIONS: Music therapy and Hoku point ice massage are easily available and inexpensive methods and have a similar effect in relieving labor pain. PMID- 26573449 TI - Knee arthritis pain is reduced and range of motion is increased following moderate pressure massage therapy. AB - BACKGROUND: The literature on massage therapy effects on knee pain suggests that pain was reduced based on self-report, but little is known about range of motion (ROM) effects. METHODS: Medical School staff and faculty who had knee arthritis pain were randomly assigned to a moderate pressure massage therapy or a waitlist control group (24 per group). Self-reports included the WOMAC (pain, stiffness and function) and the Pittsburgh Sleep Quality Index. ROM and ROM-related pain were assessed before and after the last sessions. RESULTS: The massage group showed an immediate post-massage increase in ROM and a decrease in ROM-associated pain. On the last versus the first day of the study, the massage group showed greater increases in ROM and decreases in ROM-related pain as well as less self reported pain and sleep disturbances than the waitlist control group. DISCUSSION: These data highlight the effectiveness of moderate pressure massage therapy for increasing ROM and lessening ROM-related pain and long-term pain and sleep disturbances. PMID- 26573451 TI - Claiming peaceful embodiment through yoga in the aftermath of trauma. AB - The purpose of this study was to describe the experiences of practicing yoga and its role within processes of healing for adult women with complex trauma histories. Using a hermeneutic phenomenological method, data were analyzed from interviews with 39 women. Results showed that the core meaning of participants' experience of healing through yoga is claiming peaceful embodiment. This is an ongoing process occurring on a continuum whereby women experienced improved connections with and sense of ownership and control over their bodies, emotions and thoughts, and a greater sense of well-being, calmness, and wholeness in their bodies and minds. A number of interconnected essential themes related to this core meaning were also identified, illuminating processes that supported claiming peaceful embodiment and capabilities that were enabled by being more peacefully embodied. Additional themes were identified highlighting factors that facilitated or impeded participants' engagement with yoga and their experiences of healing through yoga. PMID- 26573450 TI - Integrating complementary medicine literacy education into Australian medical curricula: Student-identified techniques and strategies for implementation. AB - Formal medical education about complementary medicine (CM) that comprises medicinal products/treatments is required due to possible CM interactions with conventional medicines; however, few guidelines exist on design and implementation of such education. This paper reports findings of a constructivist grounded theory method study that identified key strategies for integrating CM literacy education into medical curricula. Analysis of data from interviews with 30 medical students showed that students supported a longitudinal integrative and pluralistic approach to medicine. Awareness of common patient use, evidence, and information relevant to future clinical practice were identified as focus points needed for CM literacy education. Students advocated for interactive case-based, experiential and dialogical didactic techniques that are multiprofessional and student-centred. Suggested strategies provide key elements of CM literacy within research, field-based practice, and didactic teaching over the entirety of the curriculum. CM educational strategies should address CM knowledge deficits and ultimately respond to patients' needs. PMID- 26573452 TI - Acupressure for inducing labour for nulliparous women with post-dates pregnancy. AB - OBJECTIVE: To compare the efficacy of acupressure for induction of labour for nulliparous women with a post-dates pregnancy. DESIGN: A single-blind randomised trial. SETTING: Antenatal and labour ward of a UK district general hospital. PARTICIPANTS: One hundred and thirty two women requiring induction of labour with a post-dates pregnancy (>41 weeks gestation) with no significant medical, obstetric or fetal condition. METHOD: Acupressure: 20 intermittent presses to stimulate each pair of acupressure points; (Large Intestine 4, followed by Spleen 6) or 'Sham" treatment: 20 intermittent presses to the patella and then to the olecranon. MAIN OUTCOME MEASURES: Treatment-to-commencement of labour interval. SECONDARY OUTCOME MEASURES: Requirements for oxytocin, mode of delivery, duration of labour, requirement for pre-labour Caesarean section, presence of meconium, neonatal intensive care admission, 5 min Apgar scores, and evaluation of maternal satisfaction. RESULTS: There were no significant differences between the two groups in treatment-to-commencement of labour interval, requirements for oxytocin or mode of delivery. Fewer inductions of labour were required in the sham treatment group (p = 0.004 CI 1-35). The incidence of meconium-stained liquor, and neonatal outcomes were similar for both groups. CONCLUSIONS: Acupressure performed at 41 weeks gestation in nulliparous women does not appear to be effective for inducing labour for post-dates pregnancy. PMID- 26573453 TI - Kinesio taping or sham taping in knee osteoarthritis? A randomized, double-blind, sham-controlled trial. AB - PURPOSE: To compare effects of kinesio taping with sham taping at the end of 3 consecutive taping periods in knee osteoarthritis. METHODS: 41 patients diagnosed with knee osteoarthritis according to American College of Rheumatology were randomized to receive either KT or sham taping. Baseline evaluations included a visual analog scale (VAS) for activity and nocturnal pain, Lequesne index for functional assessment and Nottingham Health Profile (NHP) for the quality of life. Taping was applied every four days, three times, and all of the assessments were repeated at the end of the treatment period. RESULTS: In both groups VAS for activity pain, VAS for nocturnal pain, Lequesne index score, NHP score decreased significantly. NHP energy scores were different significantly between the groups in favor of sham taping at the end of the 12-day period. CONCLUSION: Our findings indicate inconclusive evidence of a beneficial effect of kinesio taping over sham taping in knee osteoarthritis. PMID- 26573454 TI - Effects of Quince syrup on clinical symptoms of children with symptomatic gastroesophageal reflux disease: A double-blind randomized controlled clinical trial. AB - OBJECTIVE: The aim of this study was to evaluate the efficacy of Quince syrup in pediatrics with symptomatic gastroesophageal reflux disease (GERD). METHOD: Participants (n = 80) were randomly assigned to the Quince group (0.6 cc/kg/day) or the Omeprazole group (1 cc/kg/day). Age specific questionnaires were used to assess the frequency and severity of the GERD symptoms. Mean of cumulative symptom score (CSS) at weeks 4 and 7 were compared with baseline. RESULTS: The mean CSS value was significantly decreased from baseline in each treatment group without statistically significant differences between them. Although the mean CSS value among infants and young children was slightly decreased in the Quince group at week seven, this value was increased among children aged 5-18 years in both treatment groups without significant differences. CONCLUSION: Despite the effectiveness of Quince syrup in reducing symptoms in all pediatrics age groups, no significant differences were observed in comparison with the control group. PMID- 26573455 TI - Effect of progressive relaxation exercises on fatigue and sleep quality in patients with chronic obstructive lung disease (COPD). AB - OBJECTIVE: This research was conducted to investigate the effect of Progressive Muscle Relaxation Technique on fatigue and sleep quality in patients with COPD. This research was performed as a single-group pretest/post-test pretrial model. METHODS: The study was conducted with 45 patients who met the research criteria and agreed to participate in the study. A Personal Information Form was used as a data collection tool, Fatigue Severity Scale was used for measuring fatigue, and the Pittsburgh Sleep Quality Index was used for evaluating the sleep quality. RESULTS: It was determined that PMRT decreased patients' fatigue level and improved their sleep quality, patients' fatigue level increased as their sleep quality decreased. CONCLUSION: Progressive relaxation exercises programs represent effective therapeutic intervention approaches for relieving COPD associated fatigue and sleep quality. PMRT programs will extend the scope of the rehabilitation nurses' work, as it is an important course of COPD patients' continuity nursing. PMID- 26573456 TI - Changes induced by music therapy to physiologic parameters in patients with dental anxiety. AB - INTRODUCTION: The aim of this study was to determine the effect of music therapy on patients suffering dental anxiety. In addition, a second objective was to determine the correlation between salivary cortisol and other physiologic parameters. METHODS: 34 patients were randomly assigned to the control group and the experimental group. For each patient was measured for salivary cortisol, stimulate salivary flow, blood pressure, heart rate, oxygen saturation and body temperature. Student t-test and Chi2 were applied to analyze significant differences between the studied variables before and after the unpleasant stimulation causes anxiety for dental treatment. RESULTS: Initially, both groups registered the same level of anxiety. In the second measurement, significant differences were registered in the salivary cortisol concentration, systolic and diastolic pressure, heart rate, body temperature and stimulated salivary flow for treated group with music therapy. CONCLUSION: Music therapy has a positive effect in control of dental anxiety. PMID- 26573458 TI - A comparative analysis of metal allergens associated with dental alloy prostheses and the expression of HLA-DR in gingival tissue. AB - The present study aimed to provide guidance for the selection of prosthodontic materials and the management of patients with a suspected metal allergy. This included a comparison of the sensitivity of patients to alloys used in prescribed metal-containing prostheses, and correlation analysis between metal allergy and accompanying clinical symptoms of sensitized patients using a patch test. The results from the patch test and metal component analyses were processed to reach a final diagnosis. In the present study, four dental alloys were assessed. Subsequent to polishing the surface of a metal restoration, the components were analyzed using an X-ray fluorescence microscopy and spectrometry. Immunohistochemical analysis, reverse transcription-polymerase chain reaction and western blotting were used to detect the expression levels of human leukocyte antigen (HLA)-DR in gingival tissues affected by alloy restoration, and in normal gingival tissue samples. Positive allergens identified in the patch test were consistent with the components of the metal prostheses. The prevalence of nickel (Ni) allergy was highest (22.8%), and women were significantly more allergic to palladium and Ni than men (P<0.05). The protein and gene expression levels of HLA DR in the Ni-chromium (Cr) prosthesis group were significantly higher, compared with those in the other groups (P<0.01); followed by cobalt-Cr alloy, gold alloy and titanium alloy. In conclusion, dentists require an understanding of the corrosion and allergy rates of prescribed alloys, in order to reduce the risk of allergic reactions. Patch testing for hypersensitive patients is recommended and caution is required when planning to use different alloys in the mouth. PMID- 26573457 TI - Transcription analysis of neonicotinoid resistance in Mediterranean (MED) populations of B. tabaci reveal novel cytochrome P450s, but no nAChR mutations associated with the phenotype. AB - BACKGROUND: Bemisia tabaci is one of the most damaging agricultural pests world wide. Although its control is based on insecticides, B. tabaci has developed resistance against almost all classes of insecticides, including neonicotinoids. RESULTS: We employed an RNA-seq approach to generate genome wide expression data and identify genes associated with neonicotinoid resistance in Mediterranean (MED) B. tabaci (Q1 biotype). Twelve libraries from insecticide resistant and susceptible whitefly populations were sequenced on an Illumina Next-generation sequencing platform, and genomic sequence information of approximately 73 Gbp was generated. A reference transcriptome was built by de novo assembly and functionally annotated. A total of 146 P450s, 18 GSTs and 23 CCEs enzymes (unigenes) potentially involved in the detoxification of xenobiotics were identified, along with 78 contigs encoding putative target proteins of six different insecticide classes. Ten unigenes encoding nicotinic Acetylcholine Receptors (nAChR), the target of neoinicotinoids, were identified and phylogenetically classified. No nAChR polymorphism potentially related with the resistant phenotypes, was observed among the studied strains. DE analysis revealed that among the 550 differentially (logFC > 1) over-transcribed unigenes, 52 detoxification enzymes were over expressed including unigenes with orthologues in P450s, GSTs, CCE and UDP-glucuronosyltransferases. Eight P450 unigenes belonging to clades CYP2, CYP3 and CYP4 were highly up-regulated (logFC > 2) including CYP6CM1, a gene already known to confer imidacloprid resistance in B. tabaci. Using quantitative qPCRs, a larger screening of field MED B. tabaci from Crete with known neonicotinoid phenotype was performed to associate expression levels of P450s with resistance levels. Expression levels of five P450s, including CYP6CM1, were found associated with neonicotinoid resistance. However, a significant correlation was found only in CYP303 and CYP6CX3, with imidacloprid and acetamiprid respectively. CONCLUSION: Our work has generated new toxicological data and genomic resources which will significantly enrich the available dataset and substantially facilitate the molecular studies in MED B. tabaci. No evidence of target site neonicotinoid resistance has been found. Eight P450 unigenes, including CYP6CM1, were found significantly over-expressed in resistant B. tabaci. This study suggests at least two novel P450s (CYP303 and CYP6CX3) as candidates for their functional characterization as detoxification mechanisms of neonicotinoid resistance in B. tabaci. PMID- 26573459 TI - Postdural disc herniation at L5/S1 level mimicking an extradural spinal tumor. AB - INTRODUCTION: Postdural disc herniation has been documented rarely and the pathogenesis is still unknown. The average age of postdural disc herniations is between 50 and 60 years, and the sites most frequently affected by postdural lumbar disc herniations are L3-L4 and L4-L5, only less than 10 % in L5-S1. Although magnetic resonance imaging (MRI) is a useful tool in the diagnosis of this disease, the postdural disc herniation is usually misdiagnosed as extradural spine tumor preoperatively. The definitive diagnosis is made during operation or according to the postoperative pathology. METHODS: In this article, we described here a 48-year-old male patient who presented with intermittent pain in the low back and frequent urination for 4 years as well as hypesthesia and pain of the left lower extremity for 1 month. RESULTS: A standard total laminectomy was performed and the histopathological diagnosis was consistent with a degenerated intervertebral disc. The patient presented significant relief of the pain and of the neurological symptoms, but no improvement of frequent urination, in the postoperative period. CONCLUSIONS: The diagnosis of postdural disc herniations is very difficult and mainly based on intraoperative and histopathological results. Early surgical intervention is important to relieve symptoms and prevent severe neurological deficits. PMID- 26573460 TI - Producing human ceramide-NS by metabolic engineering using yeast Saccharomyces cerevisiae. AB - Ceramide is one of the most important intercellular components responsible for the barrier and moisture retention functions of the skin. Because of the risks involved with using products of animal origin and the low productivity of plants, the availability of ceramides is currently limited. In this study, we successfully developed a system that produces sphingosine-containing human ceramide-NS in the yeast Saccharomyces cerevisiae by eliminating the genes for yeast sphingolipid hydroxylases (encoded by SUR2 and SCS7) and introducing the gene for a human sphingolipid desaturase (encoded by DES1). The inactivation of the ceramidase gene YDC1, overexpression of the inositol phosphosphingolipid phospholipase C gene ISC1, and endoplasmic reticulum localization of the DES1 gene product resulted in enhanced production of ceramide-NS. The engineered yeast strains can serve as hosts not only for providing a sustainable source of ceramide-NS but also for developing further systems to produce sphingosine containing sphingolipids. PMID- 26573461 TI - Cost effectiveness analysis of Year 2 of an elementary school-located influenza vaccination program-Results from a randomized controlled trial. AB - BACKGROUND: School-located vaccination against influenza (SLV-I) has the potential to improve current suboptimal influenza immunization coverage for U.S. school-aged children. However, little is known about SLV-I's cost-effectiveness. The objective of this study is to establish the cost-effectiveness of SLV-I based on a two-year community-based randomized controlled trial (Year 1: 2009-2010 vaccination season, an unusual H1N1 pandemic influenza season, and Year 2: 2010 2011, a more typical influenza season). METHODS: We performed a cost effectiveness analysis on a two-year randomized controlled trial of a Western New York SLV-I program. SLV-I clinics were offered in 21 intervention elementary schools (Year 1 n = 9,027; Year 2 n = 9,145 children) with standard-of-care (no SLV-I) in control schools (Year 1 n = 4,534 (10 schools); Year 2 n = 4,796 children (11 schools)). We estimated the cost-per-vaccinated child, by dividing the incremental cost of the intervention by the incremental effectiveness (i.e., the number of additionally vaccinated students in intervention schools compared to control schools). RESULTS: In Years 1 and 2, respectively, the effectiveness measure (proportion of children vaccinated) was 11.2 and 12.0 percentage points higher in intervention (40.7 % and 40.4 %) than control schools. In year 2, the cost-per-vaccinated child excluding vaccine purchase ($59.88 in 2010 US $) consisted of three component costs: (A) the school costs ($8.25); (B) the project coordination costs ($32.33); and (C) the vendor costs excluding vaccine purchase ($16.68), summed through Monte Carlo simulation. Compared to Year 1, the two component costs (A) and (C) decreased, while the component cost (B) increased in Year 2. The cost-per-vaccinated child, excluding vaccine purchase, was $59.73 (Year 1) and $59.88 (Year 2, statistically indistinguishable from Year 1), higher than the published cost of providing influenza vaccination in medical practices ($39.54). However, taking indirect costs (e.g., averted parental costs to visit medical practices) into account, vaccination was less costly in SLV-I ($23.96 in Year 1, $24.07 in Year 2) than in medical practices. CONCLUSIONS: Our two-year trial's findings reinforced the evidence to support SLV-I as a potentially favorable system to increase childhood influenza vaccination rates in a cost efficient way. Increased efficiencies in SLV-I are needed for a sustainable and scalable SLV-I program. PMID- 26573463 TI - A Place for BRAFV600E Mutation-specific Immunohistochemistry Alongside Cell-free DNA Mutation Detection in Melanoma. PMID- 26573462 TI - Senescence-Associated MCP-1 Secretion Is Dependent on a Decline in BMI1 in Human Mesenchymal Stromal Cells. AB - AIMS: Cellular senescence and its secretory phenotype (senescence-associated secretory phenotype [SASP]) develop after long-term expansion of mesenchymal stromal cells (MSCs). Further investigation of this phenotype is required to improve the therapeutic efficacy of MSC-based cell therapies. In this study, we show that positive feedback between SASP and inherent senescence processes plays a crucial role in the senescence of umbilical cord blood-derived MSCs (UCB-MSCs). RESULTS: We found that monocyte chemoattractant protein-1 (MCP-1) was secreted as a dominant component of the SASP during expansion of UCB-MSCs and reinforced senescence via its cognate receptor chemokine (c-c motif) receptor 2 (CCR2) by activating the ROS-p38-MAPK-p53/p21 signaling cascade in both an autocrine and paracrine manner. The activated p53 in turn increased MCP-1 secretion, completing a feed-forward loop that triggered the senescence program in UCB-MSCs. Accordingly, knockdown of CCR2 in UCB-MSCs significantly improved their therapeutic ability to alleviate airway inflammation in an experimental allergic asthma model. Moreover, BMI1, a polycomb protein, repressed the expression of MCP 1 by binding to its regulatory elements. The reduction in BMI1 levels during UCB MSC senescence altered the epigenetic status of MCP-1, including the loss of H2AK119Ub, and resulted in derepression of MCP-1. INNOVATION: Our results provide the first evidence supporting the existence of the SASP as a causative contributor to UCB-MSC senescence and reveal a so far unappreciated link between epigenetic regulation and SASP for maintaining a stable senescent phenotype. CONCLUSION: Senescence of UCB-MSCs is orchestrated by MCP-1, which is secreted as a major component of the SASP and is epigenetically regulated by BMI1. PMID- 26573464 TI - Hydrogen sulfide attenuates doxorubicin-induced cardiotoxicity by inhibiting the expression of peroxiredoxin III in H9c2 cells. AB - Doxorubicin (DOX) is a widely used chemotherapeutic agent, which can give rise to severe cardiotoxicity, limiting its clinical use. Preliminary evidence suggests that hydrogen sulfide (H2S) may exert protective effects on DOX-induced cardiotoxicity. Therefore, the aim of the present study was to investigate whether peroxiredoxin III is involved in the cardioprotection of H2S against DOX induced cardiotoxicity. The results demonstrated that DOX not only markedly induced injuries, including cytotoxicity and apoptosis, it also increased the expression levels of peroxiredoxin III. Notably, pretreatment with sodium hydrosulfide significantly attenuated the DOX-induced decrease in cell viability and increase in apoptosis, and also reversed the increased expression levels of peroxiredoxin III in H9c2 cardiomyocytes. In addition, pretreatment of the H9c2 cells with N-acetyl-L-cysteine, a scavenger of reactive oxygen species, prior to exposure to DOX markedly decreased the expression levels of peroxiredoxin III. In conclusion, the results of the present study suggested that exogenous H2S attenuates DOX-induced cardiotoxicity by inhibiting the expression of peroxiredoxin III in H9c2 cells. In the present study, the apoptosis of H9c2 cardiomyocytes was assessed using an methyl thiazolyl tetrazolium assay and Hoechst staining. The levels of Prx III and cystathionine-gamma-lyase were examined by western blotting. PMID- 26573465 TI - The Biosynthetic Basis of Cell Size Control. AB - Cell size is an important physiological trait that sets the scale of all biosynthetic processes. Although physiological studies have revealed that cells actively regulate their size, the molecular mechanisms underlying this regulation have remained unclear. Here we review recent progress in identifying the molecular mechanisms of cell size control. We focus on budding yeast, where cell growth dilutes a cell cycle inhibitor to couple growth and division. We discuss a new model for size control based on the titration of activator and inhibitor molecules whose synthesis rates are differentially dependent on cell size. PMID- 26573466 TI - [Psychiatry and Mental Health in the Framework of Act 1438 and Agreement 029]. PMID- 26573467 TI - [Psychopathological Profiles of Offspring of Subjects with Bipolar Disorder]. AB - INTRODUCTION: Bipolar Disorder (BD) has a high heritability and is more prevalent in first-degree relatives with family history. This makes the bipolar offspring (BO) an ideal study group to evaluate the natural history and the prodromal symptoms of this disorder. The main psychopathological findings for this group in various studies are described in this review. METHODS: Articles comparing the psychopathology of bipolar offspring to either the offspring of other psychiatric patients or the offspring of healthy controls were reviewed. RESULTS: The reviewed studies showed that the BO group had higher rates of affective disorders when compared to the offspring of other psychiatric patients or the offspring of healthy controls. The high prevalence of anxiety disorders, ADHD, and disruptive behavior disorders in this population suggest that such disorders could be considered prodromes of mood disorders. CONCLUSIONS: The group of BO had a significantly higher risk of developing a wide range of psychiatric disorders besides BD. More longitudinal studies are needed to characterize this population at risk for BD and to elucidate the risk factors in the progression of this disorder. PMID- 26573468 TI - [Factor Characterization Associated with Suicidal Behavior in 8(th) Grade Adolescent Students in Three Schools from Bogota (Colombia)]. AB - OBJECTIVE: To establish the probability for suicide risk and/or mental disorders, together with related factors among high school students in 3 schools in Bogota. METHODS: Cross sectional study of 309 adolescents. RESULTS: The average age was 13.83 +/- 0.9, female dominance (58.6%) and a 3(rd) socioeconomic stratum (68.3%). The suicidal risk behavioral probability and/or mental symptoms was 47.6%, 26.5% exhibited some suicide manifestations, 14.23% had experienced suicidal ideas in the last 3 months, 3.55% had had suicide attempts at least once in life, and 8.73% had suicidal ideas in the last 3 months with suicide attempts. The risk of suicidal behavior and/or mental disorders was explained jointly by depression (OR=27.9, 95% CI: 3.5-223. 1), low self-esteem (OR=11.8, 95% CI: 2.5 56.5), severe family dysfunction (OR=3.4, 95%CI 1.2-9.7), being female (OR=2.1, 95% CI: 1.2-3.8) and being 15 or older (OR=1.9, 95% CI: 0.967-3.9). Psychological abuse followed by physical mistreatment was associated with suicidal behavior and /or mental illness while good family relationships were associated to lower probability. CONCLUSION: Depression, low self-esteem, severe family dysfunction, female gender, older age (>=15) and domestic violence are risk factors associated with suicide and/or mental disorders in adolescents; good family relationships are associated with lower risk. PMID- 26573469 TI - [Analysis of the Structure of Acute Psychotic Disorder]. AB - INTRODUCTION: Schizophrenia is a clinically heterogeneous disorder. A multifactorial structure of this syndrome has been described in previous reports. The aim of this study was to evaluate what are the possible diagnostic categories in patients having acute psychotic symptoms, studying their clinical characteristics in a cross-sectional study. METHODS: An instrument for measuring psychotic symptoms was created using previous scales (SANS, SAPS, BPRS, EMUN, Zung depression scale). Using as criteria statistical indexes and redundance of items, the initial instrument having 101 items has been reduced to 57 items. 232 patients with acute psychotic symptoms, in most cases schizophrenia, attending Clinica Nuestra Senora de la Paz in Bogota and Hospital San Juan de Dios in Chia have been evaluated from April, 2008 to December, 2009. Multivariate statistical methods have been used for analyzing data. RESULTS: A six-factor structure has been found (Deficit, paranoid-aggressive, disorganized, depressive, bizarre delusions, hallucinations). Cluster analysis showed eight subtypes that can be described as: 1) bizarre delusions-hallucinations; 2) deterioration and disorganized behavior; 3) deterioration; 4) deterioration and paranoid-aggressive behavior; 5) bizarre delusions; 6) paranoia-anxiety- aggressiveness; 7) depressive symptoms and bizarre delusions; 8) paranoia and aggressiveness with depressive symptoms CONCLUSION: These subtypes allow a more exhaustive characterization that those included in standard classification schemes and should be validated in longitudinal studies. PMID- 26573470 TI - [Mental Health in the General Hospital: Results of the Patient Health Questionnaire (PHQ) in Four Hospital Services]. AB - INTRODUCTION: Few individuals have access to mental health services due in part to underdetection. As it is more likely to consult for medical conditions, primary care may be a useful gateway for early detection of mental health problems. OBJECTIVE: Detection of the frequency of mental health problems in four hospital services at the Fundacion Santa Fe de Bogota: Outpatient unit, hospitalization, emergency department, and primary care through a brief detection questionnaire, the Patient Health Questionnaire (PHQ). METHOD: Cross-sectional study of patients seen at the four services who answered a Demographic Data Questionnaire and the PHQ together with information gathered about current medical diagnosis, history of visits, and hospitalizations during the last year. RESULTS: 1094 patients seen at the four hospital services between September 2010 and May 2011 were selected at random. A mental health problem was detected in 36.7% of the total sample. Major depressive disorder (7.3%), alcohol abuse (14.4%), and any anxiety disorder (7.7%) showed the highest prevalence with the emergency department showing the highest frequency of detection. CONCLUSIONS: The usefulness of a brief detection questionnaire such as the PHQ in hospital settings is demonstrated and implications in the design of mental health programs in the general hospital are discussed. The need to replicate this study in other settings and to undertake further research is outlined. PMID- 26573471 TI - [Polymorphism in the Serotonin Transporter Gene (SLC6A4) and Emotional Bipolar Disorder in Two Regional Mental Health Centers from the Eje Cafetero (Colombia)]. AB - INTRODUCTION: The indel polymorphisms in the promoting region and the 2(nd) intron polymorphisms in the serotonin transporter gene (SLC6A4) have been associated to bipolar disorder 1 (BD1) in several population studies. The objective was to analyze the genotypic and allelic frequencies in both gene regions in a study of cases and controls with individuals from Risaralda and Quindio (Colombia) so as to establish possible associations to BD1, and compare results with previous and similar studies. METHODS: 133 patients and 120 controls were studied. L and S indel polymorphisms in the promoting region were analyzed by PCR, together with VNTR STin2.10 and STin 2.12 VNTRs polymorphisms in the 2(nd) intron of the SL-C6A4 gene RESULTS: Genotypic and allelic frequencies for the S and L polymorphisms were similar both in cases and controls. However, the LL genotype was significantly increased both in BD1 population (OR=1.89; CI95%=1.1-3.68), and when discriminated by gender. This particular genotype in general population is OR=2.22; IC95%=1.04-5.66 for women, and OR=1.62; IC 95%=0.71-4.39 for men. No significant genotypic and allelic differences were found for VNTR STin2.10 and STin 2.12. polymorphisms. CONCLUSIONS: No association was found between polymorphisms of 5-HTTLPR polymorphisms and the 2(nd) intron of the serotonin transporting gene in general patients with BD1, nor when compared by gender. Our results are similar to those reported for Caucasian populations and differ from those of Asian and Brazilian populations. PMID- 26573472 TI - [Validity and Reliability of Two Silhouette Scales to Asses the Body Image in Adolescent Students]. AB - OBJECTIVE: To determine the validity and reliability of the 13-figure images scale (13-CS) and Standard Figural Stimuli (SFS) for the evaluation of body images in adolescent students from Bucaramanga. METHODS: A probabilistic sample with 189 students was evaluated with the two scales. Two weeks later, the valuation together with the size, weight, percentage of body fat, SCOFF questionnaire and Rosenberg self-esteem valuation was repeated. RESULTS: The average age was 14.1 years; 62.7% were women. The correlation of the 13-CS and SFS with body fat index, weight and body fat percentage was 0.61, 0.74, 0.40 and 0.72, 0.55, 0.45 respectively. The correlation of dissatisfaction with body image according to the SCOFF and the Rosenberg scales was 0.43 and 0.26 with the 13-CS; 0.50 and -0.23 with the SFS. The reproducibility shows that perceived and ideal figure was 0.93 and 0.90 with the 13-CS; and 0.85 and 0.78 with the SFS. CONCLUSION: the concurrent validity of both scales was good. The reproducibility of the 13-CS was excellent while the SFS was good. PMID- 26573473 TI - [Psychosomatic Illness and Family Patterns of Children with Asthma]. AB - INTRODUCTION: Asthma is the most prevalent chronic illness in children and has been related to psychological aspects involved in its evolution. OBJECTIVE: To understand the types of relational patterns observed in families of children with this illness. METHOD: Qualitative analysis through intentional sample of children between the ages of 4 to 15 years with asthma and other mixed populations. RESULTS AND CONCLUSIONS: The analysis shows families with diffuse limits between its members, tendency towards amalgamation, high levels of anxiety, and the presence of parental and parental-offspring conflicts. PMID- 26573474 TI - [Development Inventory as a Diagnosis Tool in Children with Participation Difficulties in School Activities]. AB - INTRODUCTION: In recent years, evidence regarding acquisition of skills or critic behaviors for school performance has increased though there it is not conclusive in terms of the effectiveness in class participation. The purpose is to define the elements implicated in the acquisition of such skills or critical behaviors and describe them from the perspective of school activities involving participation. METHODS: Descriptive, observational study with a sample of 28 preschool and primary school students during September 2008 and March 2009 at a public institution in the city of Cali, Colombia. The procedure was the identification of child performance capabilities using Battell's developmental inventory to describe afterwards the repercussions on student's participation in school activities. RESULTS: 61.5% of the children show motor difficulties; 56% exhibit socio and personal difficulties, while 46.2% reveal adaptive difficulties. These areas are fundamental for school participation in the different activities. These children have not developed the ability for an integrated control of their muscles. They also exhibit difficulties regarding social interactions and regarding the skills necessary in the performance of daily activities. CONCLUSION: The results found in this study suggest the need to enhance the study on the relevance to develop motor, personal-social, and adaptive skills in cooperation with developmental professionals. It is necessary to know and learn strategies in cooperation with the developmental professionals. PMID- 26573475 TI - [Informed Consent and the Approval by Ethics Committees of Studies Involving the Use of Atypical Antipsychotics in the Management of Delirium]. AB - INTRODUCTION: Delirium is an acute alteration of consciousness and cognition. Atypical antipsychotics (AA) have recently become a main part of its treatment. Studies in this population generate a series of ethical dilemmas concerning the voluntary participation of patients and their state of vulnerability since their mental faculties are, by definition, compromised. OBJECTIVE: To assess whether studies with AA for the treatment of delirium obtained an approval by an ethics committee on human research (ECHR), if an informed consent (IC) was obtained, whether the IC was verbal or written, and who gave the approval to participate. METHOD: Systematic review of Medline for studies of delirium where quetiapine and olanzapine were the main treatment, assessing the existence of an ECHR approval and implementation of an IC. RESULTS: 11 studies were identified (6 of quetiapine and 5 of olanzapine). 5 had an ECHR approval. CONCLUSIONS: Most studies examining the treatment of delirium with quetiapine or olanzapine were not subject to approval by an ECHR and most of them did not obtain an IC from the patient's legal guardian. It is essential that future studies of antipsychotics and other drugs for the treatment of delirium have the protocol approved by an ECHR and a written IC signed by the patient's legal representative, since by definition delirium is a condition that compromises superior mental processes. PMID- 26573476 TI - [Clinical Applications of Peripheral Markers of Response in Antidepressant Treatment: Neurotrophins and Cytokines]. AB - INTRODUCTION: Explanatory theories of depression have advanced in recent decades from the monoaminergic hypothesis to neurogenesis alterations to the neurohormonal hypothesis that includes the dysfunction of the inflammatory response. Currently there is a growing interest in the development of biomarkers that can contribute to diagnosis and proper treatment. OBJECTIVES: To describe the role of neurotrophins such as brain-derived neurotrophic factor (BDNF) and cytokines in the pathophysiology of depressive disorder in addition to reviewing and analyzing evidence about their clinical application as biomarkers of antidepressant therapy. METHOD: Relevant data research in several databases. RESULTS AND CONCLUSIONS: In recent years evidence of alterations in neurogenesis mediated by the expression of BDNF in the hippocampus in the pathophysiology of depression has increased and there is ample evidence that BDNF is a marker of the diagnosis of depressive disorder and also of treatment effectiveness. There is little information about other neurotrophins. There has also been increased interest in relation to depression as an "inflammatory disease" and the link with cytokines in its pathogenesis. Evidence has been found for the usefulness of some cytokines especially IL-1 (interleukin 1), IL-6 (interleukin 6), and TNF (tumor necrosis factor) as biomarkers of antidepressant drug response in humans. PMID- 26573477 TI - [Conceptual Development in Cognitive Science. Part II]. AB - INTRODUCTION: Cognitive science has become the most influential paradigm on mental health in the late 20(th) and the early 21(st) centuries. In few years, the concepts, problem approaches and solutions proper to this science have significantly changed. METHOD: Introduction and discussion of the fundamental concepts of cognitive science divided in four stages: Start, Classic Cognitivism, Connectionism, and Embodying / Enacting. The 2(nd) Part of the paper discusses the above mentioned fourth stage and explores the clinical setting, especially in terms of cognitive psychotherapy. DEVELOPMENT AND CONCLUSIONS: The embodying/enacting stage highlights the role of the body including a set of determined evolutionary movements which provide a way of thinking and exploring the world. The performance of cognitive tasks is considered as a process that uses environmental resources that enhances mental skills and deploys them beyond the domestic sphere of the brain. On the other hand, body and mind are embedded in the world, thus giving rise to cognition when interacting, a process known as enacting. There is a close connection between perception and action, hence the interest in real-time interactions with the world rather than abstract reasoning. Regarding clinics, specifically the cognitive therapy, there is little conceptual discussion maybe due to good results from practice that may led us to consider that theoretical foundations are firm and not problem-raising. PMID- 26573478 TI - [Introduction to Exploratory Factor Analysis (EFA)]. AB - INTRODUCTION: Exploratory Factor Analysis (EFA) has become one of the most frequently used statistical techniques, especially in the medical and social sciences. Given its popularity, it is essential to understand the basic concepts necessary for its proper application and to take into consideration the main strengths and weaknesses of this technique. OBJECTIVE: To present in a clear and concise manner the main applications of this technique, to determine the basic requirements for its use providing a description step by step of its methodology, and to establish the elements that must be taken into account during its preparation in order to not incur in erroneous results and interpretations. METHODOLOGY: Narrative review. DEVELOPMENT: This review identifies the basic concepts and briefly describes the objectives, design, assumptions, and methodology to achieve factor derivation, global adjustment evaluation, and adequate interpretation of results. PMID- 26573479 TI - [Pregnancy Delusions and Pseudocyesis: Brief Approach]. AB - INTRODUCTION: Pregnancy delusions have usually been considered as symptoms of psychotic disorders in opposition to the hysterical and psychosomatic nature of pseudocyesis, though several authors have described some semiologic intersection between the two phenomena. METHOD: Introduction of four cases of patients with pregnancy delusions as well as review and discussion of relevant bibliography. RESULTS: In fact, there are symptoms shared by pregnancy delusions psychosis and pseudocyesis, without detriment of nosological differentiation between the two phenomena. There is certain confusion regarding conceptual and terminological issues that does not contribute to mark precise boundaries. CONCLUSION: A comprehensive and holistic approach for the study of pseudocyesis and pregnancy delusion is proposed. Maybe, these disorders are more frequently observed in Latin America. PMID- 26573480 TI - [Other Possible Clinical Applications of Drugs with 5HT2A effect in Liaison Psychiatry: Cases Report]. AB - INTRODUCTION: In liaison psychiatry it is possible to get an integral view of patient's treatment and needs, paying special attention to pharmacological interactions and contraindications. Some particular cases motivated the description, report and review about other possible applications of 5HT2A and 5HT3 antagonist, particularly Mirtazapine and Olanzapine, in hyperalgesia syndrome, tinnitus and Progressive Multifocal Leukoencephalopathy by JC virus. METHOD: Cases report. RESULTS: We describe 3 cases of patients in which Mirtazapine and Olanzapine were necessary not only to control psychiatric symptoms (affective / behavioral symptoms and insomnia) but to act as adjuvant therapy in axis III diseases. The use of any drug in psychiatry must take in to account the context of the patient, the presence of comorbidity, contraindications and pharmacological interactions so as to grant a positive outcome also promoting the multidisciplinary work between specialists. PMID- 26573482 TI - WIDDE: a Web-Interfaced next generation database for genetic diversity exploration, with a first application in cattle. AB - BACKGROUND: The advent and democratization of next generation sequencing and genotyping technologies lead to a huge amount of data for the characterization of population genetic diversity in model and non model-species. However, efficient storage, management, cross-analyzing and exploration of such dense genotyping datasets remain challenging. This is particularly true for the bovine species where many SNP datasets have been generated in various cattle populations with different genotyping tools. DESCRIPTION: We developed WIDDE, a Web-Interfaced Next Generation Database that stands as a generic tool applicable to a wide range of species and marker types ( http://widde.toulouse.inra.fr). As a first illustration, we hereby describe its first version dedicated to cattle biodiversity, which includes a large and evolving cattle genotyping dataset for over 750,000 SNPs available on 129 (89 public) different cattle populations representative of the world-wide bovine genetic diversity and on 7 outgroup bovid species. This version proposes an optional marker and individual filtering step, an export of genotyping data in different popular formats, and an exploration of genetic diversity through a principal component analysis. Users can also explore their own genotyping data together with data from WIDDE, assign their samples to WIDDE populations based on distance assignment method and supervised clustering, and estimate their ancestry composition relative to the populations represented in the database. CONCLUSION: The cattle version of WIDDE represents to our knowledge the first database dedicated to cattle biodiversity and SNP genotyping data that will be very useful for researchers interested in this field. As a generic tool applicable to a wide range of marker types, WIDDE is overall intended to the genetic diversity exploration of any species and will be extended to other species shortly. The structure makes it easy to include additional output formats and new tools dedicated to genetic diversity exploration. PMID- 26573481 TI - Structural basis of pyrimidine-pyrimidone (6-4) photoproduct recognition by UV DDB in the nucleosome. AB - UV-DDB, an initiation factor for the nucleotide excision repair pathway, recognizes 6-4PP lesions through a base flipping mechanism. As genomic DNA is almost entirely accommodated within nucleosomes, the flipping of the 6-4PP bases is supposed to be extremely difficult if the lesion occurs in a nucleosome, especially on the strand directly contacting the histone surface. Here we report that UV-DDB binds efficiently to nucleosomal 6-4PPs that are rotationally positioned on the solvent accessible or occluded surface. We determined the crystal structures of nucleosomes containing 6-4PPs in these rotational positions, and found that the 6-4PP DNA regions were flexibly disordered, especially in the strand exposed to the solvent. This characteristic of 6-4PP may facilitate UV-DDB binding to the damaged nucleosome. We present the first atomic resolution pictures of the detrimental DNA cross-links of neighboring pyrimidine bases within the nucleosome, and provide the mechanistic framework for lesion recognition by UV-DDB in chromatin. PMID- 26573483 TI - Development and Implementation Results of a Venous Thromboembolism Prophylaxis Guideline in a Tertiary Care Pediatric Hospital. AB - OBJECTIVES: Incidence of pediatric venous thromboembolism (VTE) is increasing due to increased survival of children with chronic diseases and use of interventions (eg, central venous lines), with VTE risk. Our objective was to create VTE prophylaxis guidelines with targeted identification of children at high risk to support appropriate mechanical and pharmacologic prophylaxis and integrate into the electronic medical record (EMR) as a hospital-wide quality improvement project. METHODS: Patients aged 12 to 17 years were included. We evaluated institutional data regarding VTE incidence and risk factors. We evaluated literature for populations at high risk for VTE. Guidelines were formulated, and an EMR tool to assess risk and support the guidelines was created and implemented. RESULTS: The EMR tool was used to screen 48% of qualified admissions for the first month and 81% in the final study month. On average, 69.1% of qualified admissions were screened monthly during the first 18 months of the program. No adverse events were reported due to pharmacologic prophylaxis. CONCLUSIONS: Many risk factors are common between children and adults and certain pediatric populations warrant prophylactic consideration. Pediatric VTE prophylaxis guidelines can be successfully implemented into the EMR to identify high-risk populations. Future studies should assess the long-term impact of implementation. PMID- 26573484 TI - A Comparison of Parents of Healthy Versus Sick Neonates: Is There a Difference in Readiness and/or Success in Quitting Smoking? AB - OBJECTIVES: Study objectives were to compare smoking cessation rates between parents in the newborn nursery (NBN) versus the NICU and compare acceptance of referral to the New York State Smoker's Quitline (NYSSQL) between the 2 units. Secondary aims were to identify opportunities for improved smoking cessation interventions with parents of newborns. METHODS: From January through December 2013, smoking parents/caregivers of infants in the NBN and NICU (n = 226) completed a 34-item questionnaire. For those who accepted electronic referral to the NYSSQL, participation/outcome data and questionnaire data were matched. Relationships were examined using the chi(2) test of independence. RESULTS: The majority of respondents had cut back (56%) or quit (36%) prenatally. Seventy-nine percent of NBN parents accepted referred to the NYSSQL versus 53% of NICU parents; odds ratio = 3.31 (1.48-7.40; P < .01). At 7- to 8-month follow-up (n = 35): 11 of 28 (NBN) versus 0 of 7 (NICU) quit, 11 of 28 (NBN) versus 5 of 7 (NICU) cut back, 6 of 28 (NBN) versus 2 of 7 (NICU) did not quit/cut back (P = .13). Significantly more mothers (80%; 16/20) compared with fathers (46%; 6/13) quit/cut back, 20% (4/20) of mothers versus 54% (7/13) of fathers did not quit/cut back (P = .04). Exclusive formula-feeding rates were higher in this cohort of smokers surveyed than in all parents of infants admitted to the NBN/NICU for the same year (45% vs 13%). CONCLUSIONS: In this study population, parents of healthy newborns were more receptive to quitline referrals than parents of infants admitted to the NICU. PMID- 26573485 TI - 2015 White Paper on recent issues in bioanalysis: focus on new technologies and biomarkers (Part 1 - small molecules by LCMS). AB - The 2015 9th Workshop on Recent Issues in Bioanalysis (9th WRIB) took place in Miami, Florida with participation of over 600 professionals from pharmaceutical and biopharmaceutical companies, biotechnology companies, contract research organizations and regulatory agencies worldwide. It is once again a 5-day week long event - a full immersion bioanalytical week - specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest in bioanalysis. The topics covered included both small and large molecules, and involved LCMS, hybrid LBA/LCMS, LBA approaches including the focus on biomarkers and immunogenicity. This 2015 White Paper encompasses recommendations that emerged from the extensive discussions held during the workshop, and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to advance scientific excellence, improve quality and deliver better regulatory compliance. Due to its length, the 2015 edition of this comprehensive White Paper has been divided into three parts. Part 1 covers the recommendations for small molecule bioanalysis using LCMS. Part 2 (hybrid LBA/LCMS and regulatory agencies' inputs) and Part 3 (large molecule bioanalysis using LBA, biomarkers and immunogenicity) will also be published in volume 7 of Bioanalysis, issues 23 and 24, respectively. PMID- 26573486 TI - Outcome after olecranon fracture repair: Does construct type matter? AB - PURPOSE: This study compares clinical and functional outcomes of patients with displaced olecranon fractures treated with either tension band wiring (TBW) or a hook plate construct. METHODS: We performed a retrospective review of olecranon fractures operatively treated with either TBW or plate fixation (PF) using a hook plate over a 7-year period. Patient demographics, injury information, and surgical management were recorded. Fractures were classified according to the Mayo system. Measured outcomes included range of elbow motion, time to union, and development of postoperative complications. Mayo Elbow Performance Index (MEPI) scores were obtained for all patients. All patients were followed for a minimum of 6 months. RESULTS: A total of 48 patients were included in this study, 23 treated with TBW and 25 treated with hook PF. Groups did not differ with respect to patient demographics, Mayo fracture type, or duration of follow-up. Patients undergoing PF had less terminal extension than TBW patients (-8.6 degrees +/- 7 degrees vs. -3.5 degrees +/- 9.3 degrees , p = 0.036) and a longer time to radiographic union (19 +/- 8 vs. 12 +/- 6 weeks, p = 0.001). There were no differences in rates of symptomatic hardware, MEPI scores, or other clinical outcomes. Two patients in each group required a second surgery. CONCLUSIONS: TBW and PF of olecranon fractures had similarly excellent functional outcomes in this study. Patients undergoing PF had a longer time to union and slightly worse extension at final follow-up. TBW remains an effective treatment for appropriately selected olecranon fractures and in this cohort outperformed plate osteosynthesis. PMID- 26573488 TI - Economic Evaluation of a Multifaceted Implementation Strategy for the Prevention of Hand Eczema Among Healthcare Workers in Comparison with a Control Group: The Hands4U Study. AB - The aim of this study was to evaluate the cost-effectiveness of a multifaceted implementation strategy for the prevention of hand eczema in comparison with a control group among healthcare workers. A total of 48 departments (n=1,649) were randomly allocated to the implementation strategy or the control group. Data on hand eczema and costs were collected at baseline and every 3 months. Cost effectiveness analyses were performed using linear multilevel analyses. The probability of the implementation strategy being cost-effective gradually increased with an increasing willingness-to-pay, to 0.84 at a ceiling ratio of ?590,000 per person with hand eczema prevented (societal perspective). The implementation strategy appeared to be not cost-effective in comparison with the control group (societal perspective), nor was it cost-beneficial to the employer. However, this study had some methodological problems which should be taken into account when interpreting the results. PMID- 26573487 TI - Models of care for musculoskeletal health: a cross-sectional qualitative study of Australian stakeholders' perspectives on relevance and standardised evaluation. AB - BACKGROUND: The prevalence and impact of musculoskeletal conditions are predicted to rapidly escalate in the coming decades. Effective strategies are required to minimise 'evidence-practice', 'burden-policy' and 'burden-service' gaps and optimise health system responsiveness for sustainable, best-practice healthcare. One mechanism by which evidence can be translated into practice and policy is through Models of Care (MoCs), which provide a blueprint for health services planning and delivery. While evidence supports the effectiveness of musculoskeletal MoCs for improving health outcomes and system efficiencies, no standardised national approach to evaluation in terms of their 'readiness' for implementation and 'success' after implementation, is yet available. Further, the value assigned to MoCs by end users is uncertain. This qualitative study aimed to explore end users' views on the relevance of musculoskeletal MoCs to their work and value of a standardised evaluation approach. METHODS: A cross-sectional qualitative study was undertaken. Subject matter experts (SMEs) with health, policy and administration and consumer backgrounds were drawn from three Australian states. A semi-structured interview schedule was developed and piloted to explore perceptions about musculoskeletal MoCs including: i) aspects important to their work (or life, for consumers) ii) usefulness of standardised evaluation frameworks to judge 'readiness' and 'success' and iii) challenges associated with standardised evaluation. Verbatim transcripts were analysed by two researchers using a grounded theory approach to derive key themes. RESULTS: Twenty-seven SMEs (n = 19; 70.4 % female) including five (18.5 %) consumers participated in the study. MoCs were perceived as critical for influencing and initiating changes to best-practice healthcare planning and delivery and providing practical guidance on how to implement and evaluate services. A 'readiness' evaluation framework assessing whether critical components across the health system had been considered prior to implementation was strongly supported, while 'success' was perceived as an already familiar evaluation concept. Perceived challenges associated with standardised evaluation included identifying, defining and measuring key 'readiness' and 'success' indicators; impacts of systems and context changes; cost; meaningful stakeholder consultation and developing a widely applicable framework. CONCLUSIONS: A standardised evaluation framework that includes a strong focus on 'readiness' is important to ensure successful and sustainable implementation of musculoskeletal MoCs. PMID- 26573489 TI - Cone-Beam CT with Fluoroscopic Overlay Versus Conventional CT Guidance for Percutaneous Abdominopelvic Abscess Drain Placement. AB - PURPOSE: To compare technical success and procedure time for percutaneous abscess drain placement with fluoroscopic cone-beam computed tomography (CT) and two-axis needle guidance versus conventional CT guidance. MATERIALS AND METHODS: A total of 85 consecutive patients undergoing abdominopelvic abscess drain placement guided by fluoroscopic cone-beam CT or conventional CT were retrospectively reviewed over a 2-year period. Forty-three patients underwent drain placement with cone-beam CT using XperGuide navigation and 42 underwent placement with conventional 64-slice CT. Patient characteristics, median abscess size (6.8 cm vs 7.8 cm; P = .14), and depth to abscess (7.2 cm vs 7.7 cm; P = .88) were similar between groups. RESULTS: Technical success rates were 98% (42 of 43) in the cone beam CT group and 100% (42 of 42) in the conventional CT group (P = .32), with a 10-F pigtail drainage catheter inserted in the majority of cases. There were no complications in either group. There was no significant difference in effective dose between groups (9.6 mSv vs 10.7 mSv; P = .30). Procedure times were significantly shorter in the cone-beam CT group (43 min vs 62 min; P = .02). In addition, during the study period, there was a gradual improvement in procedure time in the cone-beam CT group (50% reduction), whereas procedure time did not change for the conventional CT group. CONCLUSIONS: Cone-beam CT guidance appears to be equivalent to conventional CT guidance for drain placement into medium sized abdominopelvic collections, yielding similar technical success rates and radiation doses, with the additional benefit of reduced procedure times. PMID- 26573491 TI - [Revista Colombiana de Psiquiatria: Ten Years of Intense Work and Proposals for the Future]. PMID- 26573490 TI - Hepatitis B virus X protein upregulates DNA methyltransferase 3A/3B and enhances SOCS-1CpG island methylation. AB - The aim of the present study was to investigate the effect of hepatitis B virus X protein (HBx) on the expression of DNA methyltransferase (DNMT)3A/3B and suppressors of cytokine signaling-1 (SOCS-1), as well as promoter CpG island methylation of the SOCS-1 gene. Stable hepatocyte cell lines expressing the HBx gene (pcDNA-X/QSG7701) or an empty gene (pcDNA3.0/QSG7701) were established. Reverse transcription quantitative polymerase chain reaction (PCR) was used to detect the mRNA expression levels of DNMT3A/3B and SOCS-1. Immunohistochemistry was used to detect the protein expression of DNMT3A/3B. Methylation-specific PCR (MSP) was used to detect the methylation status of the SOCS-1 gene promoter. The mRNA and protein expression levels of DNMT3A/3B were significantly higher in the pcDNA-X/QSG7701-transfected cells, compared with those in the pcDNA3.0/QSG7701 or non-transfected QSG7701 cells (P<0.05), whereas the relative mRNA expression of SOCS-1 was significantly lower in the pcDNA-X/QSG7701 cells compared with the pcDNA3.0/QSG7701 and non-transfected QSG7701 cells (F=19.6; P<0.05). Western blot analysis showed that the protein expression of SOCS-1 was significantly lower in the pcDNA-X/QSG7701 cells, compared with the pcDNA3.0/QSG7701 or non-transfected QSG7701 cells (F=19.4; P<0.05). The results of the MSP analysis showed that SOCS 1 promoter region methylation was present only in the pcDNA-X/QSG7701 cells. The HBV-X gene upregulated the mRNA and protein expression levels of DNMT3A/3B, downregulated the expression of SOCS-1 and increased SOCS-1 gene promoter CpG island methylation. This may provide a potential explanation of the mechanism underlying HBx-associated hepatocellular carcinoma. PMID- 26573492 TI - [Association of Schizophrenia and its Clinical Implications with the NOS1AP Gene in the Colombian Population]. AB - INTRODUCTION: The nitric oxide synthase 1 adaptor protein (NOS1AP) gene is possibly implicated in schizophrenia etiopathogenesis. OBJECTIVE: To determine the association of NOS1AP gene variants with schizophrenia and the relationship of variants with the clinical dimensions of the disorder in the Colombian population. METHODOLOGY: It is a case-control study with 255 subjects per group. Markers within the NOS1AP gene were typified as well as other informative material of genetic origin so as to adjust by population stratification. A factorial analysis of the main components for each item in the Scales for Evaluating Negative Symptoms (SENS) together with the Scales for Evaluating Positive Symptoms (SEPS) to determine clinical dimensions. RESULTS: Association between the C/C genotype of the rs945713 marker with schizophrenia (OR = 1.79, 95% CI: 1.13 - 2.84) was found. The C/C genotype of the rs945713 was related to higher scores in the "affective flattening and alogia" dimension; and the A/A genotype of the rs4657181 marker was associated to lower scores in the same dimension. CONCLUSIONS: Significant associations of markers inside the NOS1AP gene with schizophrenia and the "affective flattening and alogia" clinical dimension were found. These results are consistent with previous studies and support the possibility that NOS1AP influences schizophrenia susceptibility. Furthermore, NOS1AP might be a modifier of schizophrenia clinical characteristics. PMID- 26573493 TI - [Alcohol Abuse and Associated Factors in Student Children and Adolescents]. AB - INTRODUCTION: Previous studies have confirmed high prevalence of alcohol abuse in adolescent students from Bucaramanga, Colombia. However, few studies on the associated factors have been carried out. OBJECTIVE: Assessment of prevalence of alcohol abuse and associated factors in student children and adolescents from Bucaramanga. METHODOLOGY: A random sample of adolescent students completed an anonymous questionnaire about the consumption of alcohol, illegal and legal substances, together with the CAGE questionnaire and a series of scales and questionnaires assessing risk factors for alcohol abuse. To adjust for confusing variables, a multivariate analysis was performed using a logistic regression model. RESULTS: 2916 students were surveyed with an average age between 10 and 22, and a mean of 14.4 years (SD 1.65), 51.1% were female, 36% were in the last two years of high school (10(th) and 11(th) grades), and 17.66% were in private schools. The alcohol abuse pattern as measured by the CAGE scale was 14.6% (95% CI, 13.3 - 16.0%). The associated factors were: age (OR: 1.15, 95% CI 1.04 - 1.27), having a smoking or consuming alcohol sibling (OR: 1.48, 95% CI, 1.01 - 1.17) antisocial behavior (OR 3.03, 95% CI, 2.12 - 4.32) and best friend who uses illicit substances (OR 1.71, 95% CI, 1.06 - 2.76), best friend who smokes or drinks alcohol (OR 2.01, 95% CI, 1.40 - 2.88). CONCLUSIONS: One out of 7 students showed a pattern of alcohol abuse. The associated factors were the influence of friends, family, age and antisocial behavior. PMID- 26573494 TI - [Creativity and Character Traits of University Students: Transversal Association Study]. AB - INTRODUCTION: This study was carried out to assess the relationship between character traits and creativity in a sample of students from a public university in Bogota. METHODOLOGY: A random sample of 157 students from the Universidad Nacional de Colombia. The two instruments used for measuring character traits and creativity were the International Personality Disorder Examination (IPDE) and the Abbreviated Torrance Test for Adults (ATTA). Additional information about gender, psychopathological antecedents, current academic period and academic average have been recorded. Robust regression methods have been used to analyze the relationship between creativity and character traits. RESULTS: Creativity and narcissistic traits were associated. In a multivariate model, other variables showing a relationship with creativity were found, i.e., male gender, mental illness family antecedents, number of academic periods completed, and a high academic average. CONCLUSIONS: Relationship between creativity and narcissistic traits had not been reported in previous. Longitudinal studies using more accurate scales should be undertaken to determine the validity of these findings. PMID- 26573495 TI - [Psychoactive Drug Use by Youth in a Post Armed-Conflict Region]. AB - INTRODUCTION: There are no studies in Colombia on the use of psychoactive substances (PAS) by post armed-conflict population to serve as guide for prevention programs and to account for the potential impact armed conflict may have upon this area. OBJECTIVE: To describe the use of PAS in young students in a post-conflict region. METHODOLOGY: A quantitative-descriptive study involving the totality of students of the township of Viota, Department of Cundinamarca, Colombia (1,304 participants). The World Health Survey for Schoolchildren was applied. RESULTS: Alcohol is the substance with the highest percentage of lifetime prevalence; during the last month, it was observed that the highest percentage of people start PAS use between the age of 8 and 13, while 42% of youngsters have experienced at least one drunkenness episode. It was found that 43.4% have been exposed to alcohol in their families while 35.1% were exposed to tobacco at school or in their neighborhoods. 84.5% stated their intention to continue consuming tobacco during the next year. CONCLUSIONS: Results show lower consumption percentages in comparison to school youngsters in Bogota, Colombia, which may indicate that the armed conflict has not increased consumption levels in this population. Based on the results, certain elements to be taken into account are proposed for the implementation of prevention programs with this population. PMID- 26573496 TI - [Preliminary Study on Cognitive Determinants Influencing Argentine Youngsters towards Intensive Alcohol Consumption or Binge Drinking]. AB - INTRODUCTION: The current alcohol consumption pattern among youngsters and adolescents, characterized by heavy drinking during a few hours, several days a week, or binge drinking (binge drinking, concentrated drinking or long-gulp drinking) is a reality in many countries, including Spain and Argentina. OBJECTIVE: To describe cognitive determinants in the behavior regarding excessive alcohol consumption (binge drinking) in 16-25 year subjects in Argentina. METHODOLOGY: An ad hoc survey was conducted to assess cognitive determinants influencing heavy alcohol consumption, according to I. Ajzen's guidelines. RESULTS: There are significant statistic differences between the group of heavy drinkers and the group that does not reach such level of consumption in relation to behavioral beliefs, and control beliefs. Both groups recognized consumption is noxious and not safe; no differences were observed concerning normative beliefs. CONCLUSIONS: There is a complex interaction mong attitudinal factors, motivational and behavior control factors. Instruments require greater sensitivity and further in-depth analysis is required regardomg short, middle and long consequences generated by binge drinking and its role as a positive or negative reinforment. PMID- 26573497 TI - [Risk of Eating Behavior Disorder among Medical Students in Colombia]. AB - INTRODUCTION: An important number of medical students are at Risk of suffering an Eating Behavior Disorder (REBD). However, research has been limited regarding associated variables in Colombian students. OBJECTIVE: To estimate the prevalence and related demographic and psychosocial variables associated to the REBD among medicine students in a university of Bogota, Colombia. METHODOLOGY: Transversal study. Demographic variables, academic performance, level of physical activity, daily cigarette smoking, and abuse of alcohol, personal health and observed stress were quantified. The SCOFF questionnaire was used to quantify REBD. Logistic regression was applied to adjust the associations. RESULTS: 289 students participated with an average age of 21.7 years (SD = 2.8), 63.7% were female students. It was observed that 82 students (28.4%) reported unsuccessful academic performance; 35 of them (12.1%), showed high level of physical activity; 39 (13.5%), reported daily cigarette smoking; 86 (29.8%), abused alcohol; 47 (16.3%), showed poor personal health; 23 (8.0%) high stress level observed; and 59 (20.4% 95% CI 15.8-25.0), REBD. High stress level observed (OR = 5.58; 95% CI 2.08-14.95), female (OR = 2.83; 95% CI 1.35-5.95) and alcohol abuse (OR = 2.18; 95% CI 1.10-4.11) were associated to REBD, after adjusting concerning personal health. CONCLUSIONS: Approximately one out of five medical students reports REBD in a private university of Bogota, Colombia reported REBD. High levels of stress observed, female gender and alcohol abuse are associated to REBD. Further research is necessary. PMID- 26573498 TI - [Study of Flexible Doses of Paliperidone ER in Pacients with Schizophrenia who Have Undergone Inefficient Treatment with other Antipsychotics]. AB - BACKGROUND: Extended-release (ER) paliperidone is an innovative atypical antipsychotic that allows minimal peak-to-through fluctuations with once-daily dosing. OBJECTIVE: To evaluate effectiveness, safety and tolerability of flexible, once-daily doses of paliperidone ER (3-12 mg/day) in patients with schizophrenia from Argentina and Colombia who had previously failed treatment with other antipsychotic agents. METHODS: The authors conducted a 6-month, open label, prospective and multicentric study. Effectiveness was assessed with Positive and Negative Syndrome Scale (PANSS) and Personal and Social Performance scale (PSP). Other measures of effectiveness, safety and tolerability, were also conducted. RESULTS: Paliperidone ER 3-12 mg/day improved Positive and Negative Syndrome Scale (PANSS) total scores (primary endpoint) from baseline to study end (p < 0,001). In the PANSS total score, the mean change from baseline (83, 9 units) to end point (53,7 units) was significant (p < 0,001). Flexible doses of paliperidone ER demonstrated a >=20% reduction in the PANSS total score (p<0.001) in almost two-thirds of patients. PSP mean change from baseline (52 units) to end point (85 units) was significant (p < 0,001). Secondary effectiveness assessments, as well as safety and tolerability measures, demonstrated favourable results throughout the study. CONCLUSIONS: Flexible doses of paliperidone ER over 6 months were effective, safe and well tolerated in patients with schizophrenia from Argentina and Colombia. PMID- 26573499 TI - [Clinical Characteristics of 276 Patients Treated with Electroconvulsive Therapy at a University Clinic in Medellin, Colombia]. AB - OBJECTIVE: To describe the socio-demographic and clinical characteristics of patients undergoing Electroconvulsive Therapy with Anesthesia and Relaxation (ECTAR) for 10 years in a university clinic. METHODOLOGY: Review of 276 medical records of patients who had undergone ECTAR between 1997 and 2007 at the Clinica Universitaria Bolivariana de Medellin, Colombia. Data was collected through an instrument designed for that purpose and then was analyzed. RESULTS: During 10 years, more than 2000 ECT procedures were performed; most of the patients were female 67.4%, between 15 and 86 years old. The first indication was a major depressive episode without psychotic symptoms (56.5%) almost half of the patients had a minor and temporary complication, and no major complications or deaths were reported. Pre-oxygenation, intravenous anesthesia and muscular relaxation were used in all procedures. CONCLUSIONS: The ECT used in a third-level hospital with participation of a trained, interdisciplinary team (psychiatrist, anesthesiologist, nursing assistants) and the use of the modified technique (oxygenation, monitoring, general anesthesia, and relaxation is safe for certain psychiatric pathologies disorders that have not responded to medication or when medication is counter-indicated. PMID- 26573500 TI - [Drug Abuse Comorbidity in Bipolar Disorder]. AB - INTRODUCTION: Drug use among patients with bipolar disorder is greater than the one observed in the general population; psychotic episodes are likely to occur after consumption. This has implications in the prevention, etiology, management, and treatment of the disease. Bipolar disorder pathology is likely to have positive response to pharmacological treatment. Therefore, identifying the strategies with better results to be applied in these patients is fundamental for psychiatrists and primary care physicians. OBJECTIVE: Review literature in order to determine the prevalence and characteristics of drug abuse in patients with bipolar disorder and establish the pharmacological strategies that have produced better results. METHODOLOGY: Literature review. RESULTS: A great variety of studies demonstrate the relationship between bipolar disorder and drug use disorder. These patients are hospitalized more frequently, have an earlier onset of the disease, and present a larger number of depressive episodes and suicide attempts which affect the course of the disease. The drug with better results in the treatment of these patients is Divalproate. Satisfactory results have been also obtained with other mood stabilizers such as carbamazepine, lamotrigine, and the antipsychotic aripiprazole. CONCLUSIONS: Substance abuse is present in a large number of patients with bipolar disorder. The Divalproate is the drug that has shown better results in the studies. PMID- 26573501 TI - [Prohibicion de fumar y sus implicaciones potenciales en cuidados de salud mental. Revision de la evidencia]. AB - Different publications have described a close relation between tobacco consumption and major psychiatric disorders. A great number of countries have enacted smoking bans in public or working places since the early 2000s; nonetheless, concerns remain over the exemption in some psychiatric settings regarding smoking bans. Admission of smokers to smoke-free units may lead to behavior deterioration, but some recent evidence refutes this argument. METHODS: Literature review. RESULTS: One of the earliest smoking bans was a 1.575 Mexican ecclesiastical council ban aimed at smoking prevention in churches. Several recent studies have documented health and economic benefits related to smoking bans. Over 83 countries now have introduced different sorts of regulations. There was no increase in aggression, seclusion or discharge against medical advice, neither increased use of PRN (as needed) medication following the ban. As part of the ban imposition, Nicotine Replacement Therapy- NRT was used by patients. Consistency, coordination and full staff support for the ban were seen as key success factors. Many patients continued smoking after discharge. CONCLUSIONS: Evidence shows that smoking has no place in psychiatric hospitals or facilities. The introduction of smoking bans in psychiatric settings is possible, but these bans must be conceived only as part of a much larger strategy, necessary to diminish smoking high rates among mental health populations. PMID- 26573502 TI - [From the Principle of Beneficence to the Principle of Autonomy. Assessment of Patients' Mental Competency in the General Hospital]. AB - INTRODUCTION: Refusing a medical procedure is a valid way of exercising every patient's right to autonomy. From the legal point of view, autonomy is based on the right to privacy. In recent decades the legal right to self-determination has gradually expanded and today patients in full possession of their mental faculties, have the moral and legal right to make their own decisions and these decisions take precedence over physician and family. Often liaison psychiatrists are called in to assess the mental competence of patients in the general hospital. OBJECTIVE: To determine the psychiatrist's role in evaluating these patients. DISCUSSION AND CONCLUSIONS: The assessment of a patient's ability to decide and self-determine is a common clinical problem in general hospitals. Evaluation of these patients requires a proper understanding of the philosophical, ethical, and legal issues that guide the appropriate treatment of these complex clinical problems. PMID- 26573503 TI - [The Psychotic Thinking of Patrick Bateman]. AB - INTRODUCTION: Literature is an inexhaustible source of study regarding mental illness which allows the academic exercise, whether dynamic oriented or not, that may help to understand the patient's inner world in the psychiatric clinical practice. OBJECTIVE: Freudian, Post-Freudian and analytical examination of the main character in the U.S.A. novel AMERICAN PSYCHO. METHODOLOGY: Review of sources and relevant theoretical currents. RESULTS AND CONCLUSIONS: Analysis highlights the official nosologic classification boundaries, for conditions where symptoms are scattered across the spectrum of personality disorders and psychosis spectrum; usefulness and applicability of psychoanalytic concepts in psychiatric practice are also pointed out, thus granting flexibility to the clinical approach in order to justify its use. PMID- 26573504 TI - [Etnography as an Integrative Method]. AB - INTRODUCTION: Ethnography is understood from three perspectives: approach, methodology and text. In the health field, ethnography can be used not only from the standpoint of the research process, but also from the very instances of medical consultation, diagnose and treatment. The pacient appreciates the fact of being heard and understood as a subject who has her/his own story and is involved in a particular culture related to her/his own status and to the effectsa caused by life experiences. METHODS: Analysis of the literature related to ethnography, participanting observation and an relationship between health and qualitative research. RESULTS: There is a diversity of opinions and attitudes about ethnography, its validity and usefulness as well as in considerations related to its method and the techniques that nourish it. Ethnography is an integrative approach that may resorty to multiple tools for collecting, analyzing and interpreting the data. Therefore, ethnography constitutes an option for the physician when performing individual assessment. CONCLUSIONS: Ethnography provides an opportunity to approach the reality of an individual or group of individuals in order to obtain information about the matter under investigation, its understanding and interpretation. PMID- 26573505 TI - [Factitious Disorder in Obstetrics: Case Report]. AB - INTRODUCTION: Munchhausen's syndrome is the best-studied type of factitious disorder with predominantly physical signs and symptoms. However, its clinical presentation during pregnancy is rare and literature on the subject is scarce. OBJECTIVE: To present a case of factitious disorder during pregnancy. METHOD: Review and analysis of a clinical case. RESULTS: The case of a 30-year-old woman six weeks pregnant who consults on multiple occasions with emesis and abdominal pain is discussed. Various different diagnoses were considered and pathologies such as acute intermittent porphyria, narcotic bowel syndrome, abdominal epilepsy, and esophageal spasm were discarded. The patient expressed her desire to terminate the pregnancy at week 21. The pregnancy was terminated after a medical panel concluded that there were both organic and mental conditions that placed the patient's health at risk. CONCLUSIONS: Factitious disorders are very complex and extremely challenging to the clinician especially during the initial phases. They are seldom suspected and rarely diagnosed even in hospital settings. Therefore it is of utmost importance to educate healthcare professionals in the detection of this disorder to ensure proper management and treatment. PMID- 26573506 TI - [Thalamic Stroke and Associated Behavior Disorders. Possibilities for Integral Management: Case Report]. AB - INTRODUCTION: Since ancient Greece, cerebrovascular accidents have been described with no variation. Even today, they are still a catastrophic event in the lives of patients with a high risk of disabling sequelae. METHODOLOGY: Case report of a 56-year male patient with thalamic ischemia. RESULTS: The intervention with integral strategies involving pharmacological management and cognitive interventions was decisive for the satisfactory evolution of the patient. CONCLUSIONS: The management of patients with cerebrovascular accidents cannot be limited to the emergency room. Pharmacological advances in programs and cognitive intervention methods provide intervention tools from the very beginning of the stroke thus reducing the impact of long-term sequelae, and consequently enabling a better reintegration of the patient to his family. PMID- 26573507 TI - [Shared Psychotic Disorder between Two Sisters]. AB - INTRODUCTION: The Shared Psychotic Disorder, also known as "folie a deux", is a mental disorder characterized by the development of psychiatric symptoms (psychotic symptoms) in an individual within the context of a close interpersonal relationship with another individual who has an established mental illness, usually with the presence of delusions. It is not considered a common disorder, its diagnosis is rare and it is a condition in which psychosocial factors are vital for its development. OBJECTIVE: To present the case of two sisters, the social consequences and difficulties in the intervention as well as ethical issues related to involuntary hospitalization. To perform a brief review of the topic so as to have a framework for the case. METHOD: Case report. CONCLUSIONS: This case makes evident the difficulty to achieve an adequate pharmacological and psychotherapeutic intervention because delusion symptoms can affect not only one but several family members. Furthermore, this case accounts both for individual risks inherent to the disease and for social risks involving third parties. PMID- 26573508 TI - Mitogen-activated protein kinase kinase 3 induces cell cycle arrest via p38 activation mediated Bmi-1 downregulation in hepatocellular carcinoma. AB - The underlying molecular pathogenesis of hepatocellular carcinoma (HCC) remains poorly understood. Mitogen-activated protein kinase kinase 3 (MKK3), has been reported as a novel tumor suppressor in breast cancer. However, its potential suppressive role in HCC has not been evaluated. In the current study, the biologic functions of MKK3 in HCC were investigated and a previously unreported cell cycle regulation mechanism was observed. MKK3 overexpression suppressed HepG2 and PLC-PRF-5 cell proliferation and induced cell cycle arrest in the two cell lines. In addition, MKK3 overexpression upregulated the cyclin-dependent kinase inhibitors, p16 INK4A and p15 INK4B in HCC cells. Their negative regulator, Bim-1, was downregulated following MKK3 overexpression. Moreover, MKK3 activated p38 in HCC cells and SB203580, a p38 inhibitor, reversed the tumor suppressive effect of MKK3. In conclusion, the results identify MKK3 as a tumor suppressor and highlighted the significance of p38 pathway aberration in HCC. PMID- 26573509 TI - Role of KRAS-LCS6 polymorphism in advanced NSCLC patients treated with erlotinib or docetaxel in second line treatment (TAILOR). AB - MicroRNAs were described to target mRNA and regulate the transcription of genes involved in processes de-regulated in tumorigenesis, such as proliferation, differentiation and survival. In particular, the miRNA let-7 has been suggested to regulate the expression of the KRAS gene, a common mutated gene in non-small cell lung cancer (NSCLC), through a let-7 complementary site (LCS) in 3'UTR of KRAS mRNA. We have reported the analysis performed on the role of the polymorphism located in the KRAS-LCS (rs61764370) which is involved in the disruption of the let-7 complementary site in NSCLC patients enrolled within the TAILOR trial, a randomised trial comparing erlotinib versus docetaxel in second line treatment. In our cohort of patients, KRAS-LCS6 polymorphism did not have any impact on both overall survival (OS) and progression free survival (PFS) and was not associated with any patient's baseline characteristics included in the study. Overall, patients had a better prognosis when treated with docetaxel instead of erlotinib for both OS and PFS. Considering KRAS-LCS6 status, the TG/GG patients had a benefit from docetaxel treatment (HR(docetaxel vs erlotinib) = 0.35, 95% CI 0.15-0.79, p = 0.011) compared with the TT patients (HR(docetaxel vs erlotinib) = 0.72, 95% CI 0.52-1.01, p = 0.056) in terms of PFS. PMID- 26573510 TI - Caveolae as a target to quench autoinduction of the metastatic phenotype in lung cancer. AB - PURPOSE: Mevalonate pathway inhibitors are potentially useful chemotherapeutic agents showing growth inhibition and pro-apoptotic effects in cancer cells. The effects of statins and bisphosphonates on cancer growth are attributed to a reduction in protein isoprenylation. Post-translational modification and activation of GTPase binding Ras superfamily permit the recruitment of these signal proteins to membranes where they mediate the cancer phenotype. Here, the effects of three inhibitors of the mevalonate pathway and one specific inhibitor of sterol regulatory element-binding proteins were studied in both an ER negative, Ras-inactive breast (MDA-MB-231) and lung adenocarcinoma (CaLu-1) cells in vitro. METHODS: Treated cells were subject to genome-wide gene expression profiling. A gene subset was established so that the epithelial to mesenchymal transition (EMT) could be observed and compared with signalling protein shifts. RESULTS: Within the subset, some genes normally up-regulated during EMT were asymmetrically reduced by a Delta-24 DHCR inhibitor in the lung cells. Signalling proteins associated with caveolae were down-regulated by this oxidoreductase inhibitor, while those associated with membrane rafts were up-regulated. CONCLUSIONS: This study decouples isoprenylation effects from cholesterol events per se. The data support a hypothesis that caveolae are abolished by Delta-24 DHCR intervention and it is revealed that these microdomains are vital EMT signalling structures for lung cells but not ER- and Ras-negative breast cells. When signalling by extracellular signals is quenched by removal of the hydrophilic conduit provided by caveolae, the transcriptome responds by moving the cellular identity towards quiescence. PMID- 26573511 TI - Radionuclide therapy using 131I-labeled anti-epidermal growth factor receptor targeted nanoparticles suppresses cancer cell growth caused by EGFR overexpression. AB - INTRODUCTION: Anti-epidermal growth factor receptor (EGFR)-targeted nanoparticles can be used to deliver a therapeutic and imaging agent to EGFR-overexpressing tumor cells. (131)I-labeled anti-EGFR nanoparticles derived from cetuximab were used as a tumor-targeting vehicle in radionuclide therapy. METHODS: This paper describes the construction of the anti-EGFR nanoparticle EGFR-BSA-PCL. This nanoparticle was characterized for EGFR-targeted binding and cellular uptake in EGFR-overexpressing cancer cells by using flow cytometry and confocal microscopy. Anti-EGFR and non-targeted nanoparticles were labeled with (131)I using the chloramine-T method. Analyses of cytotoxicity and targeted cell killing with (131)I were performed using the MTT assay. The time-dependent cellular uptake of (131)I-labeled anti-EGFR nanoparticles proved the slow-release effects of nanoparticles. A radioiodine therapy study was also performed in mice. RESULTS: The EGFR-targeted nanoparticle EGFR-BSA-PCL and the non-targeted nanoparticle BSA PCL were constructed; the effective diameters were approximately 100 nm. The results from flow cytometry and confocal microscopy revealed significant uptake of EGFR-BSA-PCL in EGFR-overexpressing tumor cells. Compared with EGFR-BSA-PCL, BSA-PCL could also bind to cells, but tumor cell retention was minimal and weak. In MTT assays, the EGFR-targeted radioactive nanoparticle (131)I-EGFR-BSA-PCL showed greater cytotoxicity and targeted cell killing than the non-targeted nanoparticle (131)I-BSA-PCL. The radioiodine uptake of both (131)I-labeled nanoparticles, (131)I-EGFR-BSA-PCL and (131)I-BSA-PCL, was rapid and reached maximal levels 4 h after incubation, but the (131)I uptake of (131)I-EGFR-BSA-PCL was higher than that of (131)I-BSA-PCL. On day 15, the average tumor volumes of the (131)I-EGFR-BSA-PCL and (131)I-BSA-PCL groups showed a slow growth relationship compared with that of the control group. CONCLUSION: The EGFR targeted nanoparticle EGFR-BSA-PCL demonstrated superior cellular binding and uptake compared with those of the control BSA-PCL. The EGFR-targeted radioactive nanoparticle (131)I-EGFR-BSA-PCL exhibited favorable intracellular retention of (131)I. Radionuclide therapy using (131)I-EGFR-BSA-PCL, which showed excellent targeted cell killing, suppressed cancer cell growth caused by EGFR overexpression. PMID- 26573514 TI - Advancing translation of biomarkers into regulatory science. PMID- 26573512 TI - Differential expression profiling of the early response to Ustilaginoidea virens between false smut resistant and susceptible rice varieties. AB - BACKGROUND: Rice false smut caused by Ustilaginoidea virens has recently become one of the most devastating rice diseases worldwide. Breeding and deployment of resistant varieties is considered as the most effective strategy to control this disease. However, little is known about the genes and molecular mechanisms underlying rice resistance against U. virens. RESULTS: To explore genetic basis of rice resistance to U. virens, differential expression profiles in resistant 'IR28' and susceptible 'LYP9' cultivars during early stages of U. virens infection were compared using RNA-Seq data. The analyses revealed that 748 genes were up-regulated only in the resistant variety and 438 genes showed opposite expression patterns between the two genotypes. The genes encoding receptor-like kinases and cytoplasmic kinases were highly enriched in this pool of oppositely expressed genes. Many pathogenesis-related (PR) and diterpene phytoalexin biosynthetic genes were specifically induced in the resistant variety. Interestingly, the RY repeat motif was significantly more abundant in the 5' regulatory regions of these differentially regulated PR genes. Several WRKY transcription factors were also differentially regulated in the two genotypes, which is consistent with our finding that the cis-regulatory W-boxes were abundant in the promoter regions of up-regulated genes in IR28. Furthermore, U. virens genes that are relevant to fungal reproduction and pathogenicity were found to be suppressed in the resistant cultivar. CONCLUSION: Our results indicate that rice resistance to false smut may be attributable to plant perception of pathogen-associated molecular patterns, activation of resistance signaling pathways, induced production of PR proteins and diterpene phytoalexins, and suppression of pathogenicity genes in U. virens as well. PMID- 26573513 TI - Clinical features of clear cell meningioma: a retrospective study of 36 cases among 10,529 patients in a single institution. AB - BACKGROUND: Clear cell meningioma (CCM) is a rare subtype of meningioma. We present the largest series of 36 CCMs and evaluate several prognostic factors of patient's clinical outcome. METHODS: Thirty-six patients with pathologically confirmed CCM among a total of 10,529 meningioma patients were retrospectively reviewed. RESULTS: CCM constituted 0.3 % of the intracranial meningiomas and 1.4 % of the intraspinal meningiomas. The male-to-female ratio (36 vs 64 %) for CCMs was similar to that for total meningiomas (28 vs 72 %) patients (chi-squared test, p = 0.3). The mean age at diagnosis of CCM patients (29.3 +/- 18.4 years) was significantly younger than that of total meningiomas (49.8 +/- 11.9 years) patients (t-test, p = 0). During the follow-up, 15 patients (42 %) suffered from tumor recurrence. The recurrence time ranged from 10 months to 12 years, with a median time of 29 months. Kaplan-Meier survival analysis showed that patients after total resection (Simpson grades I and II) had significantly longer progression-free survival (PFS) time than those after subtotal resection (Simpson grades III and IV) (log-rank test, p = 0.006). However, age (<=20 years or >20 years, p = 0.9), gender (p = 0.3), postoperative radiotherapy (p = 0.4), progesterone receptor staining (positivity or negativity, p = 0.2), and Ki-67 index (<=5 % or >5 %, p = 0.4) did not have significant effects on patients' PFS time. CONCLUSIONS: The proportion of CCM in spinal meningiomas is likely to be much larger than that in intracranial meningiomas. CCMs should be resected totally when possible to decrease the risk of recurrence or prolong patient's PFS time. PMID- 26573515 TI - Quantitative framework for ordered degradation of APC/C substrates. AB - BACKGROUND: During cell-cycle progression, substrates of a single master regulatory enzyme can be modified in a specific order. Here, we used experimental and computational approaches to dissect the quantitative mechanisms underlying the ordered degradation of the substrates of the ubiquitin ligase APC/C(Cdc20), a key regulator of chromosome segregation in mitosis. RESULTS: We show experimentally that the rate of catalysis varies with different substrates of APC/C(Cdc20). Using a computational model based on multi-step ubiquitination, we then show how changes in the interaction between a single substrate and APC/C(Cdc20) can alter the timing of degradation onset relative to APC/C(Cdc20) activation, while ensuring a fast degradation rate. Degradation timing and dynamics depend on substrate affinity for the enzyme as well as the catalytic rate at which the substrate is modified. When two substrates share the same pool of APC/C(Cdc20), their relative enzyme affinities and rates of catalysis influence the partitioning of APC/C(Cdc20) among substrates, resulting in substrate competition. Depending on how APC/C(Cdc20) is partitioned among its substrates, competition can have minor or major effects on the degradation of certain substrates. We show experimentally that increased expression of the early APC/C(Cdc20) substrate Clb5 does not delay the degradation of the later substrate securin, arguing against a role for competition with Clb5 in establishing securin degradation timing. CONCLUSIONS: The degradation timing of APC/C(Cdc20) substrates depends on the multi-step nature of ubiquitination, differences in substrate-APC/C(Cdc20) interactions, and competition among substrates. Our studies provide a conceptual framework for understanding how ordered modification can be established among substrates of the same regulatory enzyme, and facilitate our understanding of how precise temporal control is achieved by a small number of master regulators to ensure a successful cell division cycle. PMID- 26573516 TI - Molecular evidence of spotted fever group rickettsiae and Anaplasmataceae from ticks and stray dogs in Bangladesh. AB - Emerging tick-borne diseases (TBDs) are important foci for human and animal health worldwide. However, these diseases are sometimes over looked, especially in countries with limited resources to perform molecular-based surveys. The aim of this study was to detect and characterize spotted fever group (SFG) rickettsiae and Anaplasmataceae in Bangladesh, which are important tick-borne pathogens for humans and animals worldwide. A total of 50 canine blood samples, 15 ticks collected from dogs, and 154 ticks collected from cattle were screened for the presence of SFG rickettsiae and Anaplasmataceae using molecular-based methods such as PCR and real-time PCR. The sequence analysis of the amplified products detected two different genotypes of SFG rickettsiae in ticks from cattle. The genotype detected in Rhipicephalus microplus was closely related to Rickettsia monacensis, while the genotype detected in Haemaphysalis bispinosa was closely related to Rickettsia sp. found in Korea and Japan. Anaplasma bovis was detected in canine blood and ticks (Rhipicephalus sanguineus and H. bispinosa). Unexpectedly, the partial genome sequence of Wolbachia sp., presumably associated with the nematode Dirofilaria immitis, was identified in canine blood. The present study provides the first molecular evidence of SFG rickettsiae and A. bovis in Bangladesh, indicating the possible emergence of previously unrecognized TBDs in this country. PMID- 26573517 TI - Human parasitic protozoan infection to infertility: a systematic review. AB - Protozoan parasitic diseases are endemic in many countries worldwide, especially in developing countries, where infertility is a major burden. It has been reported that such infections may cause infertility through impairment in male and female reproductive systems. We searched Medline, PubMed, and Scopus databases and Google scholar to identify the potentially relevant studies on protozoan parasitic infections and their implications in human and animal model infertility. Literature described that some of the protozoan parasites such as Trichomonas vaginalis may cause deformities of the genital tract, cervical neoplasia, and tubal and atypical pelvic inflammations in women and also non gonoccocal urethritis, asthenozoospermia, and teratozoospermia in men. Toxopalasma gondii could cause endometritis, impaired folliculogenesis, ovarian and uterine atrophy, adrenal hypertrophy, vasculitis, and cessation of estrus cycling in female and also decrease in semen quality, concentration, and motility in male. Trypanosoma cruzi inhibits cell division in embryos and impairs normal implantation and development of placenta. Decrease in gestation rate, infection of hormone-producing glands, parasite invasion of the placenta, and overproduction of inflammatory cytokines in the oviducts and uterine horns are other possible mechanisms induced by Trypanosoma cruzi to infertility. Plasmodium spp. and Trypanosoma brucei spp. cause damage in pituitary gland, hormonal disorders, and decreased semen quality. Entamoeba histolytica infection leads to pelvic pain, salpingitis, tubo-ovarian abscess, and genital ulcers. Cutaneous and visceral leishmaniasis can induce genital lesion, testicular amyloidosis, inflammation of epididymis, prostatitis, and sperm abnormality in human and animals. In addition, some epidemiological studies have reported that rates of protozoan infections in infertile patients are higher than healthy controls. The current review indicates that protozoan parasitic infections may be an important cause of infertility. Given the widespread prevalence of parasitic protozoa diseases worldwide, we suggest further studies to better understanding of relationship between such infections and infertility. PMID- 26573518 TI - Characterization and mosquitocidal potential of neem cake-synthesized silver nanoparticles: genotoxicity and impact on predation efficiency of mosquito natural enemies. AB - Mosquitoes (Diptera: Culicidae) serve as important vectors for a wide number of parasites and pathogens of huge medical and veterinary importance. Aedes aegypti is a primary dengue vector in tropical and subtropical urban areas. There is an urgent need to develop eco-friendly mosquitocides. In this study, silver nanoparticles (AgNP) were biosynthesized using neem cake, a by-product of the neem oil extraction from the seed kernels of Azadirachta indica. AgNP were characterized using a variety of biophysical methods, including UV-vis spectrophotometry, FTIR, SEM, EDX, and XRD analyses. Furthermore, the neem cake extract and the biosynthesized AgNP were tested for acute toxicity against larvae and pupae of the dengue vector Ae. aegypti. LC50 values achieved by the neem cake extract ranged from 106.53 (larva I) to 235.36 ppm (pupa), while AgNP LC50 ranged from 3.969 (larva I) to 8.308 ppm (pupa). In standard laboratory conditions, the predation efficiency of a Carassius auratus per day was 7.9 (larva II) and 5.5 individuals (larva III). Post-treatment with sub-lethal doses of AgNP, the predation efficiency was boosted to 9.2 (larva II) and 8.1 individuals (larva III). The genotoxic effect of AgNP was studied on C. auratus using the comet assay and micronucleus frequency test. DNA damage was evaluated on peripheral erythrocytes sampled at different time intervals from the treatment; experiments showed no significant damages at doses below 12 ppm. Overall, this research pointed out that neem cake-fabricated AgNP are easy to produce, stable over time, and can be employed at low dosages to reduce populations of dengue vectors, with moderate detrimental effects on non-target mosquito natural enemies. PMID- 26573519 TI - Molecular diversity of avian schistosomes in Danish freshwater snails. AB - Avian schistosomes are widespread parasites of snails and waterfowl and may cause cercarial dermatitis (swimmer's itch) in humans, a disease that is frequently reported in European countries. These parasites are known to occur in Denmark, but here, we applied a new approach using molecular tools to identify the parasites at species level. In order to do that, 499 pulmonate freshwater snails (Radix sp., Lymnaea stagnalis, Stagnicola sp. and Planorbarius corneus) were sampled from 12 lakes, ponds, and marshes in the greater Copenhagen area. Avian schistosome cercariae were identified by microscopy and subjected to molecular investigation by sequencing and phylogenetic analysis of the 5.8S and ITS2 ribosomal DNA for species identification. Additionally, snail hosts belonging to the genus Radix were identified by sequencing and phylogenetic analysis of partial ITS2 ribosomal DNA. Three out of 499 snails shed different species of Trichobilharzia cercariae: Trichobilharzia szidati was isolated from L. stagnalis, Trichobilharzia franki from Radix auricularia and Trichobilharzia regenti from Radix peregra. In the light of the public health risk represented by bird schistosomes, these findings are of concern and, particularly, the presence of the potentially neuro-pathogenic species, T. regenti, in Danish freshwaters calls for attention. PMID- 26573520 TI - Multifunctional polyketide synthase genes identified by genomic survey of the symbiotic dinoflagellate, Symbiodinium minutum. AB - BACKGROUND: Dinoflagellates are unicellular marine and freshwater eukaryotes. They possess large nuclear genomes (1.5-245 gigabases) and produce structurally unique and biologically active polyketide secondary metabolites. Although polyketide biosynthesis is well studied in terrestrial and freshwater organisms, only recently have dinoflagellate polyketides been investigated. Transcriptomic analyses have characterized dinoflagellate polyketide synthase genes having single domains. The Genus Symbiodinium, with a comparatively small genome, is a group of major coral symbionts, and the S. minutum nuclear genome has been decoded. RESULTS: The present survey investigated the assembled S. minutum genome and identified 25 candidate polyketide synthase (PKS) genes that encode proteins with mono- and multifunctional domains. Predicted proteins retain functionally important amino acids in the catalytic ketosynthase (KS) domain. Molecular phylogenetic analyses of KS domains form a clade in which S. minutum domains cluster within the protist Type I PKS clade with those of other dinoflagellates and other eukaryotes. Single-domain PKS genes are likely expanded in dinoflagellate lineage. Two PKS genes of bacterial origin are found in the S. minutum genome. Interestingly, the largest enzyme is likely expressed as a hybrid non-ribosomal peptide synthetase-polyketide synthase (NRPS-PKS) assembly of 10,601 amino acids, containing NRPS and PKS modules and a thioesterase (TE) domain. We also found intron-rich genes with the minimal set of catalytic domains needed to produce polyketides. Ketosynthase (KS), acyltransferase (AT), and acyl carrier protein (ACP) along with other optional domains are present. Mapping of transcripts to the genome with the dinoflagellate-specific spliced leader sequence, supports expression of multifunctional PKS genes. Metabolite profiling of cultured S. minutum confirmed production of zooxanthellamide D, a polyhydroxy amide polyketide and other unknown polyketide secondary metabolites. CONCLUSION: This genomic survey demonstrates that S. minutum contains genes with the minimal set of catalytic domains needed to produce polyketides and provides evidence of the modular nature of Type I PKS, unlike monofunctional Type I PKS from other dinoflagellates. In addition, our study suggests that diversification of dinoflagellate PKS genes comprises dinoflagellate-specific PKS genes with single domains, multifunctional PKS genes with KS domains orthologous to those of other protists, and PKS genes of bacterial origin. PMID- 26573521 TI - Laboratory assessments in the course of Parkinson's disease: a clinician's perspective. AB - Physicians, caregivers and patients themselves must be alert to the onset of and changes in motor and non-motor features during the course of Parkinson's disease (PD). Parallel laboratory routine assessments are necessary because of the evolving impairment of the general health status of the individual. A number of potential biomarkers for the diagnosis of PD are currently under investigation, with diagnosis early in the disease course a particular goal, even before the onset of motor symptoms. The aim of this guideline article is to provide user friendly, clinical evidence-based recommendations for using laboratory pathological testing for the diagnosis and differential diagnosis of PD, for assessing its time course, and managing complications of long-term dopaminergic therapy and the disabling motor features that develop in the later stages of the disease. PMID- 26573522 TI - Small Molecule Copper and Its Relative Metabolites in Serum of Cerebral Ischemic Stroke Patients. AB - BACKGROUND: Copper is a strong pro-oxidant. The most important pro-oxidative form in serum is small molecule copper (SMC), which is copper that is loosely bound to small molecules, such as amino acids and polypeptides. The association between copper and atherosclerotic diseases has been confirmed, but that between SMC and cerebral ischemic stroke (CIS), one of the most principal manifestations and causes of death of atherosclerotic disease, is not yet clear. METHODS: We recruited 45 CIS patients and 25 age- and gender-matched healthy controls. We detected their serum levels of SMC, total copper, homocysteine (Hcy), and ceruloplasmin (CP), as well as urinary total copper, and analyzed the relationship of SMC with these aforementioned metabolites or compounds in CIS patients. RESULTS: SMC was 4.2 +/- .5 ug/L and 2.1 +/- .9 ug/L; total copper in sera was 1345.5 +/- 308.2 ug/L and 1180.3 +/- 134.0 ug/L; and total copper in urine was 27.6 +/- 9.3 ug/L and 18.8 +/- 8.1 ug/L in patients and controls, respectively (all P < .05). Serum CP activity in CIS patients was 59.92 +/- 12.11 U/L versus 37.76 +/- 5.71 U/L in controls (P = .0001). The concentration of SMC was positively correlated with CP activity, Hcy concentration in sera, and urinary total copper. CONCLUSION: The serum level of SMC and total copper is remarkably elevated, and SMC positively correlates with Hcy, CP activity, and urinary total copper in CIS patients. PMID- 26573523 TI - Lysine supplementation is not effective for the prevention or treatment of feline herpesvirus 1 infection in cats: a systematic review. AB - BACKGROUND: Feline herpesvirus 1 is a highly contagious virus that affects many cats. Virus infection presents with flu-like signs and irritation of ocular and nasal regions. While cats can recover from active infections without medical treatment, examination by a veterinarian is recommended. Lysine supplementation appears to be a popular intervention (recommended by > 90 % of veterinarians in cat hospitals). We investigated the scientific merit of lysine supplementation by systematically reviewing all relevant literature. METHODS: NCBI's PubMed database was used to search for published work on lysine and feline herpesvirus 1, as well as lysine and human herpesvirus 1. Seven studies on lysine and feline herpesvirus 1 (two in vitro studies and 5 studies with cats), and 10 publications on lysine and human herpesvirus 1 (three in vitro studies and 7 clinical trials) were included for qualitative analysis. RESULTS: There is evidence at multiple levels that lysine supplementation is not effective for the prevention or treatment of feline herpesvirus 1 infection in cats. Lysine does not have any antiviral properties, but is believed to act by lowering arginine levels. However, lysine does not antagonize arginine in cats, and evidence that low intracellular arginine concentrations would inhibit viral replication is lacking. Furthermore, lowering arginine levels is highly undesirable since cats cannot synthesize this amino acid themselves. Arginine deficiency will result in hyperammonemia, which may be fatal. In vitro studies with feline herpesvirus 1 showed that lysine has no effect on the replication kinetics of the virus. Finally, and most importantly, several clinical studies with cats have shown that lysine is not effective for the prevention or the treatment of feline herpesvirus 1 infection, and some even reported increased infection frequency and disease severity in cats receiving lysine supplementation. CONCLUSION: We recommend an immediate stop of lysine supplementation because of the complete lack of any scientific evidence for its efficacy. PMID- 26573525 TI - A natural reassortant and mutant serotype 3 reovirus from mink in China. AB - Mammalian orthoreoviruses (MRVs) are widespread and infect virtually all mammals. We report here the first case of a natural mutant and reassortant serotype 3 reovirus from mink in China, known as MRV3 SD-14. Whole-genome sequence analysis showed that the MRV3 SD-14 may have resulted from a reassortment involving MRVs that infected swine, humans and mink. Interestingly, the S1 segment, which encodes the viral attachment protein sigma1, which influences viral virulence and cell tropism in the host, had a stop codon mutation at amino acid 246. Surveillance of the virulence and evolution of MRVs in humans and other animals deserves more attention. PMID- 26573524 TI - Dormant non-culturable Mycobacterium tuberculosis retains stable low-abundant mRNA. AB - BACKGROUND: Dormant Mycobacterium tuberculosis bacilli are believed to play an important role in latent tuberculosis infection. Previously, we have demonstrated that cultivation of M. tuberculosis in K(+)-deficient medium resulted in generation of dormant cells. These bacilli were non-culturable on solid media (a key feature of dormant M. tuberculosis in vivo) and characterized by low metabolism and tolerance to anti-tuberculosis drugs. The dormant bacteria demonstrated a high potential to reactivation after K(+) reintroduction even after prolonged persistence under rifampicin. In this work, we studied the transcriptome and stability of transcripts in persisting dormant bacilli under arrest of mRNA de novo synthesis. RESULTS: RNA-seq-based analysis of the dormant non-culturable population obtained under rifampicin exposure revealed a 30-50 fold decrease of the total mRNA level, indicating global transcriptional repression. However, the analysis of persisting transcripts displayed a cohort of mRNA molecules coding for biosynthetic enzymes, proteins involved in adaptation and repair processes, detoxification, and control of transcription initiation. This 'dormant transcriptome' demonstrated considerable stability during M. tuberculosis persistence and mRNA de novo synthesis arrest. On the contrary, several small non-coding RNAs showed increased abundance on dormancy. Interestingly, M. tuberculosis entry into dormancy was accompanied by the cleavage of 23S ribosomal RNA at a specific point located outside the ribosome catalytic center. CONCLUSIONS: Dormant non-culturable M. tuberculosis bacilli are characterized by a global transcriptional repression. At the same time, the dormant bacilli retain low-abundant mRNAs, which are considerably stable during in vitro persistence, reflecting their readiness for translation upon early resuscitation steps. Increased abundance of non-coding RNAs on dormancy may indicate their role in the entry into and maintenance of M. tuberculosis dormant non-culturable state. PMID- 26573526 TI - Isolation and sequence analysis of the complete NS1 and VP2 genes of canine parvovirus from domestic dogs in 2013 and 2014 in China. AB - Canine parvovirus (CPV) can cause severe disease in animals and continuously generates new variant and recombinant strains in dogs that have a strong impact on sanitation. It is therefore necessary to investigate epidemic CPV strains to improve our understanding of CPV transmission and epidemic behavior. However, most studies have focused on the analysis of VP2, and therefore, information about recombination and relationships between strains is still lacking. Here, 14 strains of CPV were isolated from domestic dogs suspected of hosting CPV between 2013 and 2014 in China. The complete NS1 and VP2 genes were sequenced and analyzed. The results suggest that the new CPV-2a and new CPV-2b types are the prevalent strains in China. In addition to a few mutations (residues 19, 544, 545, 572 and 583 of NS1 and residues 267, 370, 377 and 440 of VP2) that were preserved during transmission, new mutations (residues 60, 630 of NS1, and residues 21, 310 of VP2) were found in the isolated strains. A phylogenetic tree based on VP2 sequences illustrated that the new CPV-2a and new CPV-2b strains from China form single clusters that are distinct from lineages from other countries. Moreover, recombination between the new CPV-2a and new CPV-2b types was also identified in the isolated strains. Due to differences in selection pressures or recombination, there were a small number of inconsistencies between the phylogenetic trees for VP2 and NS1, which indicated that phylogenetic relationships based on VP2 might not be representative of those based on NS1. The data indicated that mutations and recombination are constantly occurring along with the spread of CPV in China. PMID- 26573527 TI - Tailored expectant management in couples with unexplained infertility does not influence their experiences with the quality of fertility care. AB - STUDY QUESTION: Do couples who were eligible for tailored expectant management (TEM) and did not start treatment within 6 months after the fertility work-up, have different experiences with the quality of care than couples that were also eligible for TEM but started treatment right after the fertility work-up? SUMMARY ANSWER: Tailored expectant management of at least 6 months in couples with unexplained infertility is not associated with the experiences with quality of care or trust in their physician. WHAT IS KNOWN ALREADY: In couples with unexplained infertility and a good prognosis of natural conception within 1 year, expectant management for 6-12 months does not compromise ongoing birth rates and is equally as effective as starting medically assisted reproduction immediately. Therefore, TEM is recommended by various international clinical guidelines. Implementation of TEM is still not optimal because of existing barriers on both patient and professional level. An important barrier is the hesitance of professionals to counsel their patients for TEM because they fear that patients will be dissatisfied with care. However, if and how adherence to TEM actually affects the couples' experience with care is unknown. Experiences with the quality care can be measured by evaluating the patient-centredness of care and the patients' trust in their physician. STUDY DESIGN, SIZE, DURATION: This is a retrospective cross-sectional study. A survey with written questionnaires was performed among all couples who participated in the retrospective audit of guideline adherence on TEM in 25 Dutch clinics. PARTICIPANTS/MATERIALS, SETTING, METHODS: Couples were eligible to participate if they were diagnosed with unexplained infertility and had a good prognosis (>30%) of natural conception within 1 year based on the Hunault prediction model. We used patient's questionnaires to collect data on the couples' experience with the quality of care and possible confounders for their experiences other than having undergone TEM or not. Multilevel regression analyses were performed to investigate case-mix adjusted association of TEM with the patient-centredness of care (PCQ Infertility) and the patients' trust in their physician (Wake Forest Trust Scale). MAIN RESULTS AND THE ROLE OF CHANCE: Couples who adhered to TEM experienced the quality of care on the same level as couples who were exposed to early treatment, i.e. started fertility treatment within 6 months after fertility work-up. There were no associations between adherence to TEM and the patient centredness of care or the patients' trust in their physician. LIMITATIONS, REASONS FOR CAUTION: Because this study is retrospective, recall bias might occur. Furthermore, we were unable to measure the difference in experience with care over time. Therefore, our results have to be interpreted carefully. WIDER IMPLICATIONS OF THE FINDINGS: Prospective research on couples undergoing TEM have to be performed to provide more detailed insight in the patients' experiences with the decision making process and subsequently the expectant period. Tackling the barriers surrounding TEM, i.e. better counselling and more patient information material, could further improve patient experiences with the quality of care for couples who are advised TEM. STUDY FUNDING/COMPETING INTERESTS: Supported by Netherlands Organisation for Health Research and Development (ZonMW). ZonMW had no role in designing the study, data collection, analysis and interpretation of data or writing of the report. Competing interests: none. TRIAL REGISTRATION NUMBER: www.trialregister.nl NTR3405. PMID- 26573528 TI - A genetic risk score is associated with polycystic ovary syndrome-related traits. AB - STUDY QUESTION: Is a genetic risk score (GRS) associated with polycystic ovary syndrome (PCOS) and its related clinical features? SUMMARY ANSWER: The GRS calculated by genome-wide association studies (GWASs) was significantly associated with PCOS status and its related clinical features. WHAT IS KNOWN ALREADY: PCOS is a heterogeneous disorder and is characterized by oligomenorrhea, hyperandrogenism and polycystic ovary morphology. Although recent GWASs have identified multiple genes associated with PCOS, a comprehensive genetic risk study of these loci with PCOS and related traits (e.g. free testosterone, menstruation number/year and ovarian morphology) has not been performed. STUDY DESIGN, SIZE, DURATION: This study was designed as a cross-sectional case-control study. We recruited 862 women with PCOS and 860 controls. Women with PCOS were divided into four subgroups: (1) oligomenorrhea + hyperandrogenism + polycystic ovary, (2) oligomenorrhea + hyperandrogenism, (3) oligomenorrhea + polycystic ovary and (4) hyperandrogenism + polycystic ovary. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: Genomic DNA was genotyped for the PCOS susceptibility loci using the HumanOmni1-Quad v1 array. Venous blood was drawn in the early follicular phase to measure baseline metabolic and hormonal parameters. A GRS was calculated by summing the number of risk alleles from 11 single-nucleotide polymorphisms (SNPs) that were identified in previous GWASs on PCOS. A weighted GRS (wGRS) was calculated by multiplying the number of risk alleles for each SNP by its estimated effect (beta) obtained from the association analysis. MAIN RESULTS AND THE ROLE OF CHANCE: The GRS was higher in women with PCOS than in controls (8.8 versus 8.2, P < 0.01) and was significantly associated with PCOS after adjusting for age and BMI. An analysis of GRS quartiles (Q1 = 3-5, Q2 = 6 8, Q3 = 9-11, Q4 = 12-15) revealed that the subjects in the highest quartile showed a remarkable increased risk of PCOS compared with those in the lowest quartile (odds ratio = 6.28, P < 0.001). Free testosterone level, menstruation number per year, ovarian volume and ovarian follicle numbers were significantly associated with the GRS (in all cases, P < 0.01). The wGRS yielded similar results. LIMITATIONS, REASONS FOR CAUTION: We used 11 loci for the calculation of GRS, but a higher number of PCOS risk alleles was reported in previous studies. Therefore, further studies should assess the value of GRS including the additional SNPs related to PCOS. Although a GRS of >=12 was significantly associated with PCOS, the GRS showed a poor predictive value; therefore, the use of genetic information based on current GWAS data only may present problems. WIDER IMPLICATIONS OF THE FINDINGS: The GRS could be used to identify asymptomatic individuals among people at risk and stratify them into accurate risk categories for the purpose of individualizing treatment approaches, which could potentially improve health outcomes. STUDY FUNDING/COMPETING INTERESTS: None of the authors have any conflicts of interest to declare. No funding was obtained for the study. PMID- 26573529 TI - Urinary phthalate metabolites and ovarian reserve among women seeking infertility care. AB - STUDY QUESTION: Are urinary phthalate metabolites associated with reduced antral follicle growth among women in an infertility setting? SUMMARY ANSWER: Higher urinary concentrations of di(2-ethylhexyl) phthalate (DEHP) metabolites were associated with significant decreases in antral follicle count (AFC) among women seeking infertility care. WHAT IS KNOWN ALREADY: Experimental animal studies show that DEHP accelerates primordial follicle recruitment and inhibits antral follicle growth. Whether phthalates also reduce the growing antral follicle pool in humans remains unknown. STUDY DESIGN, SIZE, DURATION: We examined the association between urinary phthalate metabolites and AFC using prospective data from 215 females recruited between 2004 and 2012 in the Environment and Reproductive Health (EARTH) study. PARTICIPANTS/MATERIALS, SETTING, METHODS: We quantified the urinary concentrations of 11 phthalate metabolites. We estimated the geometric mean for all urine samples provided prior to unstimulated day 3 AFC assessment for each woman. We evaluated the association of AFC with ?DEHP (molar sum of four DEHP metabolites) and individual phthalate metabolites using Poisson regression, adjusting for age, BMI and smoking. MAIN RESULTS AND THE ROLE OF CHANCE: We observed significant decreases in mean AFC for all higher quartiles of ?DEHP as compared with the lowest quartile. Compared with women in the first quartile of ?DEHP, women in the second, third and fourth quartiles had a -24% (95% confidence interval (CI): -32%, -16%), -19% (95% CI: -27%, -9%), and -14% (95% CI: -23%, -5%) decrease in mean AFC. The absolute mean AFC in the first quartile was 14.2 follicles (95% CI: 13.2, 15.2) compared with 10.7 follicles (95% CI: 9.9, 11.6) in the second quartile. We observed similar trends among the four individual DEHP metabolites. There was no consistent change in AFC among the remaining phthalate metabolite concentrations evaluated. LIMITATIONS, REASONS FOR CAUTION: We demonstrated a negative association between DEHP and a well established marker of ovarian reserve among a subfertile population. However these findings may not be generalizable to women without fertility concerns, and we cannot rule out co-exposure to other chemicals. WIDER IMPLICATIONS OF THE FINDINGS: Environmental chemicals that inhibit the size of the growing antral follicle pool can impair fertility and reduce fecundity. This study suggests evidence in need of further investigation on the impact of phthalates on the human oocyte and follicular development. STUDY FUNDING/COMPETING INTERESTS: Work supported by grants ES009718, ES022955, ES000002, and T32ES007069 from the National Institute of Environmental Health Sciences (NIEHS) and grant T32 DK007703-16 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). C.M. was supported by a post-doctoral training award from the Canadian Institutes of Health Research. There are no competing interests to declare. PMID- 26573530 TI - Paracervical block as pain treatment during second-trimester medical termination of pregnancy: an RCT with bupivacaine versus sodium chloride. AB - STUDY QUESTION: Can paracervical block (PCB) administered before the onset of pain decrease women's pain experience during second-trimester medical termination of pregnancy (MToP)? SUMMARY ANSWER: There were no clinically significant differences between groups receiving PCB with bupivacaine or saline with regard to the highest and lowest pain intensity, morphine consumption or induction-to abortion interval. WHAT IS KNOWN ALREADY: The most common side effect of misoprostol is pain; nevertheless, there are sparse studies in pain and pain treatment during MToP, especially in second-trimester abortion. Pain reported in second-trimester medical abortion is often intense, and peaks when the fetal expulsion occurs. STUDY DESIGN, SIZE, DURATION: A double-blinded RCT was carried out from May 2012 until April 2015. A power calculation was based on a previous pilot study showing that the proportion of women with severe pain [visual analogue scale (VAS) >=7] was 63%. A clinically significant reduction was considered to yield 35% with severe pain, and with a power of 80% and significance level of 5% (two-sided) 112 women were needed. Accounting for a 20% drop-out rate, a total of 140 women were needed. The primary outcome, pain intensity measured as any VAS >=7, was analysed using a generalized estimating equations model. The level of significance was set to P < 0.05 two-sided. A computer generated randomization list with block size of 10 was used. The treatment allocation was placed in a sealed, opaque, envelope and picked consecutively. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 589 women attending a gynaecological clinic had a second-trimester abortion during the study period and 276 were invited to participate. A total of 113 women undergoing abortion from 13 weeks of gestation and above were recruited, of which 55 were randomly allocated to receive a PCB with bupivacaine and 58 a PCB with sodium chloride 1 h after the first dose of misoprostol. The full analysis set (FAS) population was defined as all randomized women that had at least one value for any of the outcomes (n = 102). The per-protocol (PP) population was defined as a subset of the FAS excluding patients with major protocol deviations or without a value for the primary outcome (n = 99). Pain was measured by VAS at misoprostol initiation (baseline) and repeated every 30 min until fetal expulsion. The primary outcome was the highest VAS pain intensity at any time point. MAIN RESULTS AND THE ROLE OF CHANCE: The highest pain intensity, did not show any differences at a cut-off of VAS >=7 [risk ratio (RR): 1.1; 95% confidence interval (CI): 0.9-1.5; P = 0.0.292]. In the PP analyses, there were 75% women in the bupivacaine group and 64% in the sodium chloride group with VAS >=7 (RR: 1.2; 95% CI: 0.9-1.5; P = 0.235). Most women did not experience pain at the misoprostol start, 19 women scored a VAS of >0, ranging from 1 to 4 with a mean of 1.8 and median of 2 (P = 1.000). Immediately prior to PCB, 61 women scored a VAS of >0, from 1 to 10 with a mean of 2.0 and median of 1 (P = 0.771). There was a 48% loss of VAS scores at the time of expulsion and the remaining scores did not differ between groups (RR: 1.5; 95% CI: 0.9-2.5). A subgroup analysis of primipara did not show any difference in highest pain intensity VAS >=7 (RR: 1.2; 95% CI: 0.9-1.6; P = 0.283). No statistically significant differences were observed between groups with regard to the highest and lowest (P = 553 and 0.182) pain intensity and morphine consumption (P = 0.772). Side effects were reported by 28 women (14 women in each group), with no differences between groups. Most common was nausea and vomiting in connection to morphine injection. LIMITATIONS, REASONS FOR CAUTION: Nearly 60% of the invited women did not want to participate in the study (fear of needles and fear of receiving the placebo) therefore women who tolerate pain may have been overrepresented in the study population. Data collection was stopped, in error, when 113 participants had been recruited. The loss to follow-up was, however, only 11 women (10%), which was lower than expected but intrinsically the study did not fully reach the intended number of women, which may have influenced the results. In addition, the obstetrical and gynaecological background of participating women differs. The participants were informed that they had a 50% chance of receiving a PCB with active substance, which could theoretically have affected their expectations and pain experience (placebo effect). The frequent attention at VAS scoring and the overall care provided may also have affected the participants in a positive way, and helped women to feel supported and more relaxed during the abortion. WIDER IMPLICATIONS OF THE FINDINGS: The highest pain intensity was severe (VAS: 7-10) among 65-75% of the participants, as reported for first-trimester medical abortion; however, the maximal pain scores remain high despite the PCB. There is, therefore, a clear need for more optimal pain treatment but only limited data exist on pain treatment during MToP over all gestational lengths. As PCB was well tolerated, did not cause any serious side effects and had no negative impact on the abortion process and efficacy, another approach may be worth exploring, namely PCB given on demand at the onset of painful contractions. STUDY FUNDING/COMPETING INTERESTS: The study was supported by grants from the Swedish Research Council (grant no: 2012-2844), ALF (Karolinska Institutet - Stockholm County Council, Agreement on Medical Research and Training) funding, the Karolinska Institutet, Stockholm South General Hospital, and Swedish Nurses in the Area of Pain - SSOS together with GlaxoSmithKline. None of the authors have any conflicts of interest. TRIAL REGISTRATION NUMBER: The trial was registered with ClinicalTrials.gov (identifier: NCT01617564) and The EudraCT (number: 2010-020780 21) and was approved by The Regional Ethical Review Board at Karolinska Institutet (dnr: 2007/1277-31/2 and 2010/410-31/1). TRIAL REGISTRATION DATE: Clinical trial registration was done in May 2012 before initiation of patient recruitment. DATE OF FIRST PATIENT'S ENROLMENT: 29 May 2012. PMID- 26573532 TI - DOCK8 Mutation Syndrome: A Diagnostic Challenge for Dermatologists. PMID- 26573531 TI - PHF11 expression and cellular distribution is regulated by the Toll-Like Receptor 3 Ligand Polyinosinic:Polycytidylic Acid in HaCaT keratinocytes. AB - BACKGROUND: Inflammatory skin diseases such as atopic dermatitis and psoriasis represent a complex interaction between the skin and infiltrating immune cells, resulting in damage to the skin barrier and increased inflammation. Polymorphisms in PHF11 have been associated with dermatitis and allergy and PHF11 regulates the transcription of T-cell cytokines as well as class switching to IgE in activated B-cells. The importance of skin barrier homeostasis in the context of inflammatory skin diseases, together with reports identifying PHF11 as an interferon-induced gene, have led us to examine its role in the innate immune response of keratinocytes. RESULTS: We developed a cell culture model that allowed us to analyze the effects of the double-stranded RNA analogue poly(I:C) on a confluent cell monolayer immediately after a 24-h treatment, as well as three days after withdrawal of treatment. Immediately after treatment with poly(I:C), PHF11, IL8, and interferon-dependent ISG15 RNA expression was increased. This was accompanied by nuclear localization of PHF11 as well the tight junction protein claudin-1. Knock-down of PHF11 resulted in increased interleukin-8 expression and secretion immediately following treatment with poly(I:C), as well as changes in the cellular distribution of membrane-bound and increased nuclear claudin-1 that was observed up to 3 days after the withdrawal of poly(I:C). This was associated with lower cell density and a decrease in the number of cells in the G1 phase of the cell cycle. CONCLUSIONS: In addition to a role for PHF11 in lymphocyte gene expression, we have now shown that PHF11 was part of the keratinocyte innate immune response by poly(I:C). As knock-down of PHF11 was associated with increased expression of the pro-inflammatory chemokine IL-8 and changes in the cellular distribution of claudin-1, a change normally associated with increased proliferation and migration, we suggest that PHF11 may contribute to epidermal recovery following infection or other damage. PMID- 26573533 TI - First molecular determination of herpesvirus from two mysticete species stranded in the Mediterranean Sea. AB - BACKGROUND: Herpesvirus can infect a wide range of animal species: mammals, birds, reptiles, fish, amphibians and bivalves. In marine mammals, several alpha- and gammaherpesvirus have been identified in some cetaceans and pinnipeds species. To date, however, this virus has not been detected in any member of the Balaenoptera genus. CASE PRESENTATION: Herpesvirus was determined by molecular methods in tissue samples from a male fin whale juvenile (Balaenoptera physalus) and a female common minke whale calf (Balaenoptera acutorostrata) stranded on the Mediterranean coast of the Region of Valencia (Spain). Samples of skin and penile mucosa from the fin whale and samples of skin, muscle and central nervous system tissue from the common minke whale tested positive for herpesvirus based on sequences of the DNA polymerase gene. Sequences from fin whale were identical and belonged to the Alphaherpesvirinae subfamily. Only members of the Gammaherpesvirinae subfamily were amplified from the common minke whale, and sequences from the muscle and central nervous system were identical. Sequences in GenBank most closely related to these novel sequences were viruses isolated from other cetacean species, consistent with previous observations that herpesviruses show similar phylogenetic branching as their hosts. CONCLUSIONS: To our knowledge, this is the first molecular determination of herpesvirus in the Balaenoptera genus. It shows that herpesvirus should be included in virological evaluation of these animals. PMID- 26573534 TI - A rapid, ideal, and eco-friendlier protocol for quantifying proline. AB - Proline, a stress marker, is routinely quantified by a protocol that essentially uses hazardous toluene. Negative impacts of toluene on human health prompted us to develop a reliable alternate protocol for proline quantification. Absorbance of the proline-ninhydrin condensation product formed by reaction of proline with ninhydrin at 100 degrees C in the reaction mixture was significantly higher than that recorded after its transfer to toluene, revealing that toluene lowers sensitivity of this assay. lambda max of the proline-ninhydrin complex in the reaction mixture and toluene were 508 and 513 nm, respectively. Ninhydrin in glacial acetic acid yielded higher quantity of the proline-ninhydrin condensation product compared to ninhydrin in mixture of glacial acetic acid and H3PO4, indicating negative impact of H3PO4 on proline quantification. Further, maximum yield of the proline-ninhydrin complex with ninhydrin in glacial acetic acid and ninhydrin in mixture of glacial acetic acid and H3PO4 was achieved within 30 and 60 min, respectively. This revealed that H3PO4 has negative impact on the reaction rate and quantity of the proline-ninhydrin complex formed. In brief, our proline quantification protocol involves reaction of a 1-ml proline sample with 2 ml of 1.25 % ninhydrin in glacial acetic acid at 100 degrees C for 30 min, followed by recording absorbance of the proline-ninhydrin condensation product in the reaction mixture itself at 508 nm. Amongst proline quantification protocols known till date, our protocol is the most simple, rapid, reliable, cost effective, and eco-friendlier. PMID- 26573535 TI - Alleviation of selenium toxicity in Brassica juncea L.: salicylic acid-mediated modulation in toxicity indicators, stress modulators, and sulfur-related gene transcripts. AB - The present work reveals the response of different doses of selenium (Se) and alleviating effect of salicylic acid (SA) on Se-stressed Brassica juncea seedlings. Selenium, a micronutrient, is essential for both humans and animals but is toxic at higher doses. Its beneficial role for the survival of plants, however, is still debatable. On the other hand, SA, a phenolic compound, is known to have specific responses under environmental stresses. Experiments were conducted using leaves of hydroponically grown seedlings of Pusa bold (PB) variety of B. juncea, treated with different concentrations of Se (50, 150, 300 MUM) for 24- and 96-h exposure times. Increasing Se concentrations inhibited growth and, caused lipid peroxidation, concomitantly increased stress modulators (proline, cysteine, SOD, CAT) along with sulfur-related gene transcripts (LAST, APS, APR, GR, OASL, MT-2, PCS) in Brassica seedlings. On the basis of the above studied parameters, maximum inhibition in growth was observed at 300 MUM Se after 96-h exposure time. Further, co-application of SA along with 300 MUM Se helped to mitigate Se stress, as shown by improved levels of growth parameters, toxicity indicators (chlorophyll, protein, MDA), stress modulators (proline, cysteine, SOD, and CAT), and expression of sulfur-related genes as compared to Se-treated seedlings alone. Altogether, this study revealed that Se + SA combinations improved seedling morphology and were effective in alleviation of Se stress in PB variety of B. juncea. PMID- 26573536 TI - Integrated role of ROS and Ca+2 in blue light-induced chloroplast avoidance movement in leaves of Hydrilla verticillata (L.f.) Royle. AB - Directional chloroplast photorelocation is a major physio-biochemical mechanism that allows these organelles to realign themselves intracellularly in response to the intensity of the incident light as an adaptive response. Signaling processes involved in blue light (BL)-dependent chloroplast movements were investigated in Hydrilla verticillata (L.f.) Royle leaves. Treatments with antagonists of actin filaments [2,3,5-triiodobenzoic acid (TIBA)] and microtubules (oryzalin) revealed that actin filaments, but not microtubules, play a pivotal role in chloroplast movement. Involvement of reactive oxygen species (ROS) in controlling chloroplast avoidance movement has been demonstrated, as exogenous H2O2 not only accelerated chloroplast avoidance but also could induce chloroplast avoidance even in weak blue light (WBL). Further support came from experiments with different ROS scavengers, i.e., dimethylthiourea (DMTU), KI, and CuCl2, which inhibited chloroplast avoidance, and from ROS localization using specific stains. Such avoidance was also partially inhibited by ZnCl2, an inhibitor of NADPH oxidase (NOX) as well as 3-(3,4-dichlorophenyl)-1,1-dimethylurea (DCMU), a photosynthetic electron transport chain (ETC) inhibitor at PS II. However, methyl viologen (MV), a PS I ETC inhibitor, rather accelerated avoidance response. Exogenous calcium (Ca+2) induced avoidance even in WBL while inhibited chloroplast accumulation partially. On the other hand, chloroplast movements (both accumulation and avoidance) were blocked by Ca+2 antagonists, La3+ (inhibitor of plasma membrane Ca+2 channel) and ethylene glycol-bis(2-aminoethylether)-N,N,N',N'-tetraacetic acid (EGTA, Ca+2 chelator) while LiCl that affects Ca+2 release from endosomal compartments did not show any effect. A model on integrated role of ROS and Ca+2 (influx from apolastic space) in actin-mediated chloroplast avoidance has been proposed. PMID- 26573537 TI - Deciphering the signaling mechanisms of the plant cell wall degradation machinery in Aspergillus oryzae. AB - BACKGROUND: The gene expression and secretion of fungal lignocellulolytic enzymes are tightly controlled at the transcription level using independent mechanisms to respond to distinct inducers from plant biomass. An advanced systems-level understanding of transcriptional regulatory networks is required to rationally engineer filamentous fungi for more efficient bioconversion of different types of biomass. RESULTS: In this study we focused on ten chemically defined inducers to drive expression of cellulases, hemicellulases and accessory enzymes in the model filamentous fungus Aspergillus oryzae and shed light on the complex network of transcriptional activators required. The chemical diversity analysis of the inducers, based on 186 chemical descriptors calculated from the structure, resulted into three clusters, however, the global, metabolic and extracellular protein transcription of the A. oryzae genome were only partially explained by the chemical similarity of the enzyme inducers. Genes encoding enzymes that have attracted considerable interest such as cellobiose dehydrogenases and copper dependent polysaccharide mono-oxygenases presented a substrate-specific induction. Several homology-model structures were derived using ab-initio multiple threading alignment in our effort to elucidate the interplay of transcription factors involved in regulating plant-deconstructing enzymes and metabolites. Systematic investigation of metabolite-protein interactions, using the 814 unique reactants involved in 2360 reactions in the genome scale metabolic network of A. oryzae, was performed through a two-step molecular docking against the binding pockets of the transcription factors AoXlnR and AoAmyR. A total of six metabolites viz., sulfite (H2SO3), sulfate (SLF), uroporphyrinogen III (UPGIII), ethanolamine phosphate (PETHM), D-glyceraldehyde 3-phosphate (T3P1) and taurine (TAUR) were found as strong binders, whereas the genes involved in the metabolic reactions that these metabolites appear were found to be significantly differentially expressed when comparing the inducers with glucose. CONCLUSIONS: Based on our observations, we believe that specific binding of sulfite to the regulator of the cellulase gene expression, AoXlnR, may be the molecular basis for the connection of sulfur metabolism and cellulase gene expression in filamentous fungi. Further characterization and manipulation of the regulatory network components identified in this study, will enable rational engineering of industrial strains for improved production of the sophisticated set of enzymes necessary to break-down chemically divergent plant biomass. PMID- 26573538 TI - Adolescents and parental caregivers as lay health advisers in a community-based risk reduction intervention for youth: baseline data from Teach One, Reach One. AB - The purpose of the current study is to describe the demographic, behavioral, and psychosocial characteristics of adolescent and caregiver lay health advisers (LHAs) participating in an intervention designed to reduce risk behaviors among rural African-American adolescents. Teach One, Reach One integrates constructs from the Theory of Planned Behavior and Social Cognitive Theory. It acknowledges that changing the sexual behaviors of African-American adolescents requires changing one's knowledge, attitudes, normative beliefs about the behavior of peers, and self-efficacy regarding adolescent sexual behavior, parent-teen communication about sex, and healthy dating relations among adolescents. Study participants completed baseline questionnaires assessing demographics and psychosocial determinants (knowledge, attitudes, perceived social norms, and self efficacy) of sexual behaviors. Sixty-two adolescent and caregiver dyads participated. Caregivers included biological parents, legal guardians, or other parental figures. Strengths and areas in need of improvement were determined using median splits. Few adolescents had initiated sex. Their strengths included high levels of open parent-teen communication; positive attitudes and normative beliefs regarding both sex communication and healthy dating relationships; and high knowledge and self-efficacy for healthy dating behaviors. Areas needing improvement included low knowledge, unfavorable attitudes, poor normative beliefs, and low self-efficacy regarding condom use. Caregiver strengths included positive attitudes, normative beliefs, and self-efficacy for sex communication; positive attitudes and self-efficacy for condom use; and low acceptance of couple violence. Areas needing improvement included low levels of actual communication about sex and low knowledge about effective communication strategies and condom use. The current study highlights the value of assessing baseline characteristics of LHAs prior to intervention implementation, as it enables a better understanding of the key characteristics necessary for planning and implementing interventions, as well as engaging in targeted training activities. PMID- 26573539 TI - Nitric oxide synthesis capacity, ambulatory blood pressure and end organ damage in a black and white population: the SABPA study. AB - Nitric oxide (NO) synthesis capacity is determined by the availability of substrate(s) such as L-arginine and the influence of nitric oxide synthase (NOS) inhibitors, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA). These factors may be important in black South Africans with a very high prevalence of hypertension. We compared ambulatory blood pressure (BP), markers of end organ damage and NO synthesis capacity markers [L-arginine, L homoarginine, L-citrulline, L-arginine:ADMA, ADMA, SDMA and dimethylarginine (DMA)], between black and white teachers (n = 390). Associations of nighttime BP and markers of end organ damage with NO synthesis capacity markers were also investigated. Although black men and women had higher BP and albumin-to creatinine ratio (ACR) (all p < 0.001), they also had higher L-arginine, L homoarginine, L-arginine:ADMA and lower SDMA and DMA levels (all p < 0.05). Only in white men ADMA concentrations associated positively with nighttime systolic blood pressure (R (2) = 0.20, beta = 0.26, p = 0.009), nighttime diastolic blood pressure (R (2) = 0.23, beta = 0.27, p = 0.007), carotid intima media thickness (cIMT) (R (2) = 0.36, beta = 0.22, p = 0.008) and ACR (R (2) = 0.14, beta = 0.32, p = 0.001). Our findings suggest that despite an adverse cardiovascular profile in blacks, their NO synthesis capacity profile seems favourable, and that other factors, such as NO inactivation, may prove to be more important. PMID- 26573540 TI - Simultaneous stable-isotope dilution GC-MS measurement of homoarginine, guanidinoacetate and their common precursor arginine in plasma and their interrelationships in healthy and diseased humans. AB - Low concentrations of L-homoarginine (hArg) in plasma or serum and urine have recently emerged as a novel cardiovascular risk factor. Previously, we reported gas chromatography-mass spectrometry (GC-MS) and GC-tandem MS (GC-MS/MS) methods for the quantitative determination of hArg and Arg in plasma, serum, urine and other biological samples. In these methods, plasma and serum are ultrafiltered by means of commercially available cartridges (10 kDa), and 10-uL ultrafiltrate aliquots are subjected to a two-step derivatization procedure, yielding the methyl ester tri(N-pentafluoropropionyl) derivatives. De novo prepared trideuteromethyl ester hArg (d3Me-hArg) was used as an internal standard. To make the hArg analysis in plasma more convenient, straightforward and cheaper we performed two key modifications: (1) precipitation of plasma proteins by methanol and (2) use of newly prepared and d3Me-hArg as the internal standard. The method was validated and used for the quantitative determination of hArg in human plasma by GC-MS after electron-capture negative-ion chemical ionization (ECNICI) using methane as the reactant gas. Intra-assay accuracy (recovery) and imprecision (relative standard deviation) were within generally accepted ranges (93-109 and 2.3-10 %, respectively). Furthermore, we extended the applicability of this method to guanidinoacetate (GAA). This is of particular importance because hArg and GAA are produced from Arg by the catalytic action of arginine:glycine amidinotransferase (AGAT) also known as glycine:arginine transamidinase (GATM). Using this method, we quantitated simultaneously hArg, Arg and GAA in the selected-ion monitoring mode in 10-uL aliquots of plasma. In plasma samples of 17 non-medicated healthy young men, the concentration of hArg, GAA and Arg was determined to be (mean +/- SD) 1.7 +/- 0.6, 2.6 +/- 0.8, 91 +/- 29 uM, respectively. The correlation between hArg and Arg was borderline (r = 0.47, P = 0.06). GAA strongly correlated with Arg (r = 0.82, P < 0.0001) but did not correlate with hArg (r = 0.17, P = 0.52). The plasma concentrations of hArg, GAA and Arg measured in 9 patients suffering from stroke or transitory ischemic attack were 1.8 +/- 0.6, 2.7 +/- 0.4 and 82 +/- 17 uM. The ratio values of the hArg, GAA and Arg concentrations measured after removal of plasma proteins by methanol precipitation or ultrafiltration were 0.94 +/- 0.1, 0.94 +/- 0.08, and 0.88 +/- 0.07, respectively. Simultaneous measurement of hArg and GAA in human plasma may allow assessment of AGAT activity in vivo with respect both to GAA and to hArg and their relationship in health, disease, nutrition and pharmacotherapy. PMID- 26573541 TI - beta-Hydroxy-beta-methylbutyrate, mitochondrial biogenesis, and skeletal muscle health. AB - The metabolic roles of mitochondria go far beyond serving exclusively as the major producer of ATP in tissues and cells. Evidence has shown that mitochondria may function as a key regulator of skeletal muscle fiber types and overall well being. Maintaining skeletal muscle mitochondrial content and function is important for sustaining health throughout the lifespan. Of great importance, beta-hydroxy-beta-methylbutyrate (HMB, a metabolite of L-leucine) has been proposed to enhance the protein deposition and efficiency of mitochondrial biogenesis in skeletal muscle, as well as muscle strength in both exercise and clinical settings. Specifically, dietary supplementation with HMB increases the gene expression of peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1alpha), which represents an upstream inducer of genes of mitochondrial metabolism, coordinates the expression of both nuclear- and mitochondrion-encoded genes in mitochondrial biogenesis. Additionally, PGC-1alpha plays a key role in the transformation of skeletal muscle fiber type, leading to a shift toward type I muscle fibers that are rich in mitochondria and have a high capacity for oxidative metabolism. As a nitrogen-free metabolite, HMB holds great promise to improve skeletal muscle mass and function, as well as whole-body health and well-being of animals and humans. PMID- 26573542 TI - Introduction: Meeting the Challenge of Lupus Nephritis. PMID- 26573544 TI - Neutrophils, Dendritic Cells, Toll-Like Receptors, and Interferon-alpha in Lupus Nephritis. AB - Finding better treatments for lupus nephritis requires an understanding of the pathogenesis of the causative systemic disease, how this leads to kidney disease, and how lupus nephritis progresses to end-stage kidney disease. Here, we provide a brief conceptual overview on the related pathomechanisms. As a main focus we discuss in detail the roles of neutrophils, dendritic cells, Toll-like receptors, and interferon-alpha in the pathogenesis of lupus nephritis by separately reviewing their roles in extrarenal systemic autoimmunity and in intrarenal inflammation and immunopathology. PMID- 26573543 TI - Genetics of Lupus Nephritis: Clinical Implications. AB - Systemic lupus erythematosus is a heterogeneous autoimmune disease marked by the presence of pathogenic autoantibodies, immune dysregulation, and chronic inflammation that may lead to increased morbidity and early mortality from end organ damage. More than half of all systemic lupus erythematosus patients will develop lupus nephritis. Genetic-association studies have identified more than 50 polymorphisms that contribute to lupus nephritis pathogenesis, including genetic variants associated with altered programmed cell death and defective immune clearance of programmed cell death debris. These variants may support the generation of autoantibody-containing immune complexes that contribute to lupus nephritis. Genetic variants associated with lupus nephritis also affect the initial phase of innate immunity and the amplifying, adaptive phase of the immune response. Finally, genetic variants associated with the kidney-specific effector response may influence end-organ damage and the progression to end-stage renal disease and death. This review discusses genetic insights of key pathogenic processes and pathways that may lead to lupus nephritis, as well as the clinical implications of these findings as they apply to recent advances in biologic therapies. PMID- 26573545 TI - Murine and Human Lupus Nephritis: Pathogenic Mechanisms and Theoretical Strategies for Therapy. AB - Lupus nephritis is one of the most serious manifestations of systemic lupus erythematosus, and represents one of the criteria implemented to classify systemic lupus erythematosus. Although studied for decades, no consensus has been reached related to the basic cellular, molecular, and immunologic mechanism(s) responsible for lupus nephritis. No causal treatments have been developed; therapy is approached mainly with nonspecific immunosuppressive medications. More detailed insight into disease mechanisms therefore is indispensable to develop new therapeutic strategies. In this review, contemporary knowledge on the pathogenic mechanisms of lupus nephritis is discussed based on recent data in murine and human lupus nephritis. Specific focus is given to the effect of anti double-stranded DNA/antinucleosome antibodies in the kidneys and whether they bind exposed chromatin fragments in glomeruli or whether they bind inherent glomerular structures by cross-recognition. Overall, the data presented here favor the exposed chromatin model because we did not find any indication to substantiate the anti-double-stranded DNA antibody cross-reacting model. At the end of this review we present data on why chromatin fragments are expressed in the glomeruli of patients with lupus nephritis, and discuss how this knowledge can be used to direct the development of future therapies. PMID- 26573546 TI - The Role of Anti-DNA Antibodies in the Development of Lupus Nephritis: A Complementary, or Alternative, Viewpoint? AB - Kidney disease, or lupus nephritis, is the organ involvement that is most closely associated with specific autoantibodies in patients with SLE. The concept of anti DNA antibodies being instrumental in the pathogenesis of lupus nephritis emerged ~50 years ago, and has been a topic of debate ever since. This article focuses on the description of the renal sub-cellular targets of nephritogenic autoantibodies and offers a counter-point opinion to the article by Pedersen et al. In addition, we provide an overview of some of the mechanisms by which anti-DNA antibodies bind to their renal targets and the pathogenic relevance to clinical nephritis. PMID- 26573547 TI - The Complement System in Lupus Nephritis. AB - The complement system is composed of a family of soluble and membrane-bound proteins that historically has been viewed as a key component of the innate immune system, with a primary role of providing a first-line defense against microorganisms. Although this role indeed is important, complement has many other physiological roles, including the following: (1) influencing appropriate immune responses, (2) disposing of waste in the circulation (immune complexes, cellular debris), and (3) contributing to damage of self-tissue through inflammatory pathways. These three roles are believed to be significant factors in the pathogenesis of systemic lupus erythematosus, particularly its renal manifestation (lupus nephritis), contributing both protective and damaging effects. In this review, we provide an overview of the human complement system and its functions, and discuss its intricate and seemingly contradictory roles in the pathogenesis of lupus nephritis. PMID- 26573549 TI - The Kidney Biopsy in Lupus Nephritis: Past, Present, and Future. AB - Since its incorporation into clinical practice in the 1950s, the percutaneous kidney biopsy has played an important role in advancing our understanding of lupus nephritis (LN). The biopsy findings have been used to classify and subgroup LN in order to obtain an accurate diagnosis and also to inform treatment decisions and predict prognosis. Several classifications schemes have been applied clinically however despite this evolution in histopathologic classification, our ability to predict treatment response and determine prognosis remains limited. In this review we will examine the evolving role of the kidney biopsy in the management of LN, including the potentially larger role the biopsy could play in the future. PMID- 26573550 TI - Antiphospholipid Syndrome and the Kidney. AB - The antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by a combination of arterial and/or venous thrombosis, pregnancy morbidity, and the persistent presence of circulating antiphospholipid antibodies (aPL). APS has been described as primary APS when it occurs in the absence of any features of other autoimmune disease, and as secondary in the presence of other autoimmune diseases, mainly systemic lupus erythematosus (SLE). There is a well known link between SLE and APS; 40% of SLE patients have aPL, and, in turn, some, but only a minority of patients with APS, eventually will develop features of SLE. Because SLE and APS can target the kidneys independently or at the same time, discriminating between inflammatory or thrombotic lesions is crucial in planning therapy. We provide an overview of the renal manifestations associated with the presence of aPL in patients with SLE, and discuss the impact of aPL in selected scenarios such as lupus nephritis, end-stage renal disease, and pregnancy. PMID- 26573548 TI - The Pathogenesis and Therapeutic Implications of Tubulointerstitial Inflammation in Human Lupus Nephritis. AB - Nephritis is a common complication of systemic lupus erythematosus for which current therapies often prove inadequate. Current lupus nephritis classification systems emphasize glomerular acuity and scarring. However, tubulointerstitial inflammation (TII) and scarring are much better predictors of progression to renal failure. It now is becoming clear that the immunologic features, and probable underlying mechanisms, are very different in lupus glomerulonephritis and TII at the time of biopsy. Although glomerulonephritis is a manifestation of systemic autoimmunity, TII is associated with local in situ adaptive immune cell networks predicted to amplify local inflammation and tissue damage. In addition, poorly defined networks of innate immune cells and effectors likely contribute to the severity of local inflammation. Defining these in situ immune mechanisms should lead to a better understanding of prognostically meaningful lupus nephritis subsets and show novel therapeutic opportunities. PMID- 26573551 TI - Pregnancy and Lupus Nephritis. AB - The management of lupus nephritis in pregnancy presents a diagnostic and therapeutic challenge for providers. Pregnancy creates a series of physiologic changes in the immune system and kidney that may result in an increased risk of disease flare and adverse maternal and fetal outcomes, such as preeclampsia, fetal loss, and preterm delivery. Conception should be delayed until disease is in remission to ensure the best pregnancy outcomes. Maternal disease activity and fetal well-being should be monitored closely by an interdisciplinary team, including obstetricians, rheumatologists, and nephrologists throughout pregnancy. Careful attention must be paid to the dosing and potential teratogenicity of medications. PMID- 26573552 TI - ESKD, Transplantation, and Dialysis in Lupus Nephritis. AB - Kidney disease resulting from systemic lupus erythematosus accounts for 1.9% of the end-stage kidney disease (ESKD) population in the United States. Systemic lupus erythematosus patients with lupus nephritis (LN) who progress to ESKD in the United States are mostly female (81%) and of African ancestry (49%), with a mean age of 41 years at initiation of renal replacement therapy (RRT). The incidence of ESKD in patients with LN steadily increased between 1982 and 1998 because RRT was offered more readily to LN patients in the United States. However, it appears to have plateaued in the early 2000s, and recently decreased, with approximately 3.26 incident cases per million patient-years during the biennium period of 2009 to 2010. When LN patients approach ESKD, patients and providers must choose among the RRT options available. The trend of the RRT used to support LN ESKD patients is not guided by the lower mortality seen with the use of kidney transplantation compared with dialysis (>85% versus 73% survival during 5 years of follow-up evaluation, respectively). Less than 4% of LN ESKD patients have pre-emptive kidney transplantation. Although the survival of LN ESKD patients who begin with hemodialysis and peritoneal dialysis are similar (77% versus 79% during 3 years of follow-up evaluation, respectively), more than 80% of patients begin with hemodialysis and less than 15% begin with peritoneal dialysis in the United States. PMID- 26573553 TI - Lessons Learned From the Clinical Trials of Novel Biologics and Small Molecules in Lupus Nephritis. AB - Systemic lupus erythematosus (SLE) is a ripe area for drug development. There are great unmet needs, especially for those with lupus nephritis, in which good responses occur only in the minority of treated patients. An expanded understanding of immunopathogenesis of SLE coupled with the availability of sophisticated bioengineering technologies has resulted in the ability to supply the lupus community with the reagents needed to perform clinical trials. However, drug development in SLE has proven to be particularly challenging. Only one drug, belimumab, has been approved for patients with SLE through the traditional route of randomized controlled trials. The basis for our failures is unknown, but most assuredly relates to trial design issues, confounding by background medicines, and the multiplicity of active biologic pathways in this disease. Off-label use of failed trial drugs such as mycophenolate mofetil and rituximab paradoxically has become routine in many parts of the world. Despite the obstacles, there currently is unprecedented clinical trial activity in lupus nephritis, which most likely will lead to at least one drug approval in years to come. PMID- 26573554 TI - Sesamin attenuates mast cell-mediated allergic responses by suppressing the activation of p38 and nuclear factor-kappaB. AB - Establishing therapeutic agents for the treatment of allergic diseases is an important focus of human health research. Sesamin, a lignan in sesame oil, exhibits a diverse range of pharmacological properties. However, to the best of our knowledge, the effect of sesamin on mast cell-mediated allergic responses has not yet been investigated. Thus, the aim of the present study was to investigate the effect of sesamin on mast cell-mediated allergic responses and the underlying mechanisms by which it produces this effect. In rats, oral administration of sesamin inhibited passive cutaneous anaphylaxis. Sesamin exposure attenuated immunoglobulin E-induced histamine release from rat peritoneal mast cells, which was indicated to be mediated by the modulation of intracellular calcium. In human mast cells, sesamin reduced the stimulatory effects of phorbol 12-myristate 13 acetate and calcium ionophore A23187 on the production and secretion of pro inflammatory cytokines, including tumor necrosis factor-alpha and interleukin-6. The inhibitory effect of sesamin on pro-inflammatory cytokine production was dependent on nuclear factor kappa-light-chain-enhancer of activated B cells (NF kappaB) and p38 mitogen-activated protein kinase (MAPK). The present study demonstrates that sesamin inhibits mast cell-derived inflammatory allergic reactions by blocking histamine release, and pro-inflammatory cytokine production and secretion. In addition, the findings indicate that the effect of sesamin is mediated by its effect on p38 MAPK/NF-kappaB signaling. Furthermore, the in vivo and in vitro anti-allergic effects of sesamin reported in the present study suggest that it is a promising therapeutic agent for the treatment of inflammatory allergic diseases. PMID- 26573555 TI - 3,5,4'-Tri-O-acetylresveratrol decreases seawater inhalation-induced acute lung injury by interfering with the NF-kappaB and i-NOS pathways. AB - Drowning is a cause of accidental mortality. However, survival may result in acute lung injury. The aim of the present study was to evaluate the effects of 3,5,4'-tri-O-acetylresveratrol (AC-Res) on acute lung injury (ALI) induced by seawater inhalation in rats. ALI models were established by the tracheal instillation of artificial seawater with or without 50 mg/kg AC-Res pretreatment for 7 days. Lung samples from different groups were harvested 4 h after the model was established. Histological changes, blood vessel permeability, inflammatory factor secretion and expression states of the nuclear factor-kappaB (NF-kappaB) and inducible NOS (i-NOS) pathway were assessed to evaluate seawater-induced lung injury and the protective effects of acetylated resveratrol. The results showed that seawater inspiration led to physiological structure changes and an increased permeability of blood vessels. In addition, seawater stimulation enhanced the expression levels of nitric oxide (NO), tumor necrosis factor alpha (TNF-alpha) and interleukin-1 beta (IL-1beta) secretion in vitro and in vivo. Notably, seawater inhalation increased NF-kappaB and i-NOS expression in lungs and cells. On the other hand, pretreatment of AC-Res inhibited the abnormal expression of the NF-kappaB and i-NOS pathways, followed by decreased NO, TNF-alpha and IL 1beta secretion, protein and cell content in bronchoalveolar lavage fluid (BALF) and Evans blue, protein and cell infiltration from blood vessels into lung tissues. The results therefore suggest that AC-Res attenuated seawater inhalation induced-ALI by interfering with the NF-kappaB and i-NOS pathways. PMID- 26573556 TI - Resilience and vulnerability: prolonged grief in the bereaved spouses of marital partners who died of AIDS. AB - Spousal bereavement is closely linked to prolonged grief, that is, significant adjustment symptoms that last for more than six months after the loss. This article focused on potential risk and protective factors that may influence bereavement outcomes. Participants in this study were surviving spouses of individuals who died of acquired immune deficiency syndrome (AIDS). These participants were themselves living with human immunodeficiency syndrome. In this cross-sectional study, 120 bereaved participants completed measures of grief, quality of dying and death of the deceased, negative conceptions of death resulting from AIDS, death attitudes, and personal resilience. The results showed that one-third (35.0%) of the bereaved participants reported grief levels above the prolonged grief cut-off scores, and can be categorized as the "prolonged grief" group. Although quality of dying and death was not associated with the intensity of grief, negative conceptions of death from AIDS, fear of death and resilience independently predicted grief symptoms in the regression models. Our findings provide insight into the grief process for the surviving spouse of AIDS victims in rural China. Since resilience is malleable, developing resilience interventions to enhance adjustment to bereavement may be a promising direction in grief counselling and therapies. PMID- 26573557 TI - Protective effects of the Tougu Xiaotong capsule on morphology and osteoprotegerin/nuclear factor-kappaB ligand expression in rabbits with knee osteoarthritis. AB - The imbalance of subchondral bone remodeling is a common pathological feature in the progression of osteoarthritis. In the current study, using a rabbit model of knee osteoarthritis, the effects of the Tougu Xiaotong capsule (TGXTC) on the cartilage and subchondral bone were investigated. In addition, osteoprotegerin (OPG), an inducer of bone formation, and receptor activator of nuclear factor kappaB ligand (RANKL), a regulator of bone resorption in the subchondral bone, were assessed, in order to further explore the protective role of TGXTC in subchondral bone remodeling. The rabbit model of knee osteoarthritis, which was induced by a modified version of Hulth's method, was treated with TGXTC or glucosamine hydrochloride for 4 or 8 weeks. Subsequently, the tibia and femur were harvested for observation of cartilage histology, and the subchondral bone was observed by scanning electron microscopy. The expression levels of OPG and RANKL at the gene and protein levels were determined by reverse transcription quantitative polymerase chain reaction and western blotting. TGXTC and glucosamine hydrochloride were identified to mitigate cartilage injury, reduce trabecular number and thickness and accelerate trabecular separation. It was additionally observed that the level of OPG mRNA and protein expression was reduced, and the RANKL mRNA and protein expression level was increased, in addition to the observation of a lower OPG/RANKL ratio in the TGXTC and hydrochloride groups. Taken together, these results suggest that TGXTC may mitigate cartilage injury and subchondral sclerosis, thus delaying the pathological development of osteoarthritis. This is suggested to be mediated partly through the reduction of OPG expression and increase of RANKL expression, which reduces the OPG/RANKL ratio, suppressing excessive bone formation. PMID- 26573558 TI - Resveratrol alleviates the cytotoxicity induced by the radiocontrast agent, ioxitalamate, by reducing the production of reactive oxygen species in HK-2 human renal proximal tubule epithelial cells in vitro. AB - Radiocontrast-induced nephropathy (RIN) is one of the leading causes of hospital acquired acute kidney injury (AKI). The clinical strategies currently available for the prevention of RIN are insufficient. In this study, we aimed to determine whether resveratrol, a polyphenol phytoalexin, can be used to prevent RIN. For this purpose, in vitro experiments were performed using a human renal proximal tubule epithelial cell line (HK-2 cells). Following treatment for 48 h, the highly toxic radiocontrast agent, ioxitalamate, exerted cytotoxic effects on the HK-2 cells in a concentration-dependent manner, as shown by MTT assay. The half maximal inhibitory concentration (IC50) was found to be approximately 30 mg/ml. Flow cytometry also revealed a marked increase in the number of apoptotic cells following exposure to ioxitalamate. In addition, the number of necrotic, but not necroptotic cells was increased. However, treatment with resveratrol (12.5 uM) for 48 h significantly alleviated ioxitalamate (30 mg/ml)-induced cytotoxicity, by reducing cytosolic DNA fragmentation, increasing the expression of the anti apoptotic protein, Bcl-2 (B-cell lymphoma 2), and survivin, activating caspase-3, preventing autophagic death and suppressing the production of reactive oxygen species (ROS). Resveratrol also suppressed the ioxitalamate-induced formation of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a biomarker of oxidative DNA damage. N acetylcysteine (NAC), a ROS scavenger commonly used to prevent RIN, also reduced ioxitalamate-induced cytotoxicity, but at a high concentration of 1 mM. Sirtuin (SIRT)1 and SIRT3 were not found to play a role in these effects. Overall, our findings suggest that resveratrol may prove to be an effective adjuvant therapy for the prevention of RIN. PMID- 26573559 TI - Behavioral and neuroimaging evidence for impaired executive function in "cognitively normal" older HIV-infected adults. AB - The increased prevalence of HIV among adults >50 years underscores the importance of improving our understanding of mechanisms causing HIV-associated neurocognitive disorders (HAND). Identifying novel and noninvasive diagnostic predictors of HAND prior to clinical manifestation is critical to ultimately identifying means of preventing progression to symptomatic HAND. Here, using a task-switching paradigm, in which subjects were cued (unpredictably) to perform a face-gender or a word-semantic task on superimposed face and word images, we examined the behavioral and neural profile of impaired cognitive control in older HIV + adults (N = 14, 9 HIV+). Functional magnetic resonance imaging (fMRI) and behavioral data were acquired while subjects were performing the face-gender or word-semantic task. We found that, despite comparable performance in standard neuropsychology tests that are designed to probe executive deficits, HIV-infected participants were significantly slower than uninfected controls in adapting to change in task demand, and the behavioral impairments can be quantitatively related to difference in fMRI signal at the dorsal anterior cingulate cortex (ACC). Due to the limited sample size of this hypothesis-generating study, we should take caution with these findings and future studies with a large and better matched sample size are needed. However, these rather novel findings in this study have a few important implications: first, the prevalence of cognitive impairments in HIV+ older adults might be even higher than previously proposed; second, ACC (in particularly its dorsal region) might be one of the key regions underlying cognitive impairments (in particularly executive functions) in HIV; and third, it might be beneficial to adopt paradigms developed and validated in cognitive neuroscience to study HAND, as these techniques might be more sensitive to some aspects of HIV-associated neurocognitive impairments than standard neuropsychology tests. PMID- 26573560 TI - FAM172A protein promotes the proliferation of human papillary thyroid carcinoma cells via the p38 mitogen-activated protein kinase pathway. AB - Family with sequence similarity 172, member A (FAM172A), was cloned from human aortic tissues and confirmed in our previous study in 2009, however, its functions remain to be fully elucidated. In our previous studies, the protein expression of FAM172A in human aortic smooth muscle cells was found to be upregulated by high glucose in a concentration- and time-dependent manner. Several reports have shown that insulin resistance is associated with papillary thyroid carcinoma (PTC). Thus, in the present study, the protein expression levels of FAM172A in human papillary thyroid carcinoma were investigated, and the effect of the FAM172A protein on the proliferation of IHH-4 human papillary thyroid carcinoma cells, and its potential molecular underlying mechanisms were examined. Immunohistochemistry and western blotting demonstrated that the protein expression of FAM172A in papillary thyroid carcinoma tissues was not only significantly higher than that in noncancerous tissues adjacent to the carcinoma tissues, but it was also markedly higher than that in normal thyroid and thyroid adenoma tissues. Overexpression of the FAM172A protein activated the p38 MAPK pathway, but not the PI3K and AMPK pathways, in the IHH-4 cells. In addition, overexpression of the FAM172A protein accelerated IHH-4 cell proliferation, compared with the control group, and the pro-proliferative effect of FAM172A protein on IHH4 cells was markedly attenuated by SB202190, an inhibitor of p38 MAPK. Taken together, these results suggest that the FAM172A protein is expressed at high levels in human PTC, which may promote cell proliferation via activation of the p38 MAPK signaling pathway, and be involved in the pathogenesis of PTC. PMID- 26573561 TI - Non-thermal dielectric-barrier discharge plasma damages human keratinocytes by inducing oxidative stress. AB - The aim of this study was to identify the mechanisms through which dielectric barrier discharge plasma damages human keratinocytes (HaCaT cells) through the induction of oxidative stress. For this purpose, the cells were exposed to surface dielectric-barrier discharge plasma in 70% oxygen and 30% argon. We noted that cell viability was decreased following exposure of the cells to plasma in a time-dependent manner, as shown by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay. The levels of intracellular reactive oxygen species (ROS) were determined using 2',7'-dichlorodihydrofluorescein diacetate and dihydroethidium was used to monitor superoxide anion production. Plasma induced the generation of ROS, including superoxide anions, hydrogen peroxide and hydroxyl radicals. N-acetyl cysteine, which is an antioxidant, prevented the decrease in cell viability caused by exposure to plasma. ROS generated by exposure to plasma resulted in damage to various cellular components, including lipid membrane peroxidation, DNA breaks and protein carbonylation, which was detected by measuring the levels of 8-isoprostane and diphenyl-1-pyrenylphosphine assay, comet assay and protein carbonyl formation. These results suggest that plasma exerts cytotoxic effects by causing oxidative stress-induced damage to cellular components. PMID- 26573562 TI - Algorithm for planning a double-jaw orthognathic surgery using a computer-aided surgical simulation (CASS) protocol. Part 1: planning sequence. AB - The success of craniomaxillofacial (CMF) surgery depends not only on the surgical techniques, but also on an accurate surgical plan. The adoption of computer-aided surgical simulation (CASS) has created a paradigm shift in surgical planning. However, planning an orthognathic operation using CASS differs fundamentally from planning using traditional methods. With this in mind, the Surgical Planning Laboratory of Houston Methodist Research Institute has developed a CASS protocol designed specifically for orthognathic surgery. The purpose of this article is to present an algorithm using virtual tools for planning a double-jaw orthognathic operation. This paper will serve as an operation manual for surgeons wanting to incorporate CASS into their clinical practice. PMID- 26573563 TI - Algorithm for planning a double-jaw orthognathic surgery using a computer-aided surgical simulation (CASS) protocol. Part 2: three-dimensional cephalometry. AB - Three-dimensional (3D) cephalometry is not as simple as just adding a 'third' dimension to a traditional two-dimensional cephalometric analysis. There are more complex issues in 3D analysis. These include how reference frames are created, how size, position, orientation and shape are measured, and how symmetry is assessed. The main purpose of this article is to present the geometric principles of 3D cephalometry. In addition, the Gateno-Xia cephalometric analysis is presented; this is the first 3D cephalometric analysis to observe these principles. PMID- 26573564 TI - Computer simulation in the daily practice of orthognathic surgery. AB - The availability of computers and advances in imaging, especially over the last 10 years, have allowed the adoption of three-dimensional (3D) imaging in the office setting. The affordability and ease of use of this modality has led to its widespread implementation in diagnosis and treatment planning, teaching, and follow-up care. 3D imaging is particularly useful when the deformities are complex and involve both function and aesthetics, such as those in the dentofacial area, and for orthognathic surgery. Computer imaging involves combining images obtained from different modalities to create a virtual record of an individual. In this article, the system is described and its use in the office demonstrated. Computer imaging with simulation, and more specifically patient specific anatomic records (PSAR), permit a more accurate analysis of the deformity as an aid to diagnosis and treatment planning. 3D imaging and computer simulation can be used effectively for the planning of office-based procedures. The technique can be used to perform virtual surgery and establish a definitive and objective treatment plan for correction of the facial deformity. In addition, patient education and follow-up can be facilitated. The end result is improved patient care and decreased expense. PMID- 26573565 TI - Orthodontic principles and guidelines for the surgery-first approach to orthognathic surgery. AB - The surgery-first approach has become a new paradigm in orthognathic surgery. With the surgery-first approach, most of the patient's teeth are in their original positions and have not undergone orthodontic treatment prior to the patient undergoing orthognathic surgery. A 'treatable' malocclusion should be attained following orthognathic surgery. Orthodontists must ensure that they can manage the 'treatable' malocclusion by actively participating in the patient's surgical plan. Therefore, orthodontic principles and guidelines must be established. Three-dimensional computed tomography should be used to construct the midfacial plane and then to assess discrepancies in the midfacial structures as well as yaw and roll of the bilateral facial structures. Orthognathic surgery should be performed to improve the alignment of such discrepancies to attain a skeletal class I relationship and to attain an aesthetically pleasing face. The surgery-first approach uses osteotomy to solve most of the skeletal and dental problems and to simplify postoperative orthodontic treatment by providing a treatable malocclusion for which mostly only anteroposterior orthodontic movement is required, with minimal transverse or vertical orthodontic movements. Numerous studies have documented the efficacy and long-term stability. Patients undergoing the surgery-first approach benefit from an immediate improvement in facial aesthetics, oral function, and self-confidence, with a shorter total treatment period. PMID- 26573566 TI - The surgery-first approach in orthognathic surgery: a retrospective study of 50 cases. AB - The surgery-first approach (SFA), without presurgical orthodontic treatment, has become favoured in the treatment of dentomaxillofacial deformities. This approach has been applied in our institution since 2012. The purpose of this study was to report our experience with the SFA for skeletal malocclusion. Fifty patients with skeletal malocclusions were enrolled in this study (11 bimaxillary protrusion, 27 skeletal class III malocclusion, and 12 facial asymmetry). After orthognathic orthodontic consultation, suitability for SFA was determined and a treatment plan drawn up. Patients then underwent orthognathic surgery, which included Le Fort I maxillary osteotomy, bilateral sagittal split ramus osteotomy, subapical osteotomy, and genioplasty. Postoperative orthodontic treatment was started after a healing period of 2 weeks. The mean postoperative orthodontic treatment duration was 14.9 months, which is shorter than that of traditional joint orthognathic-orthodontic treatment. In the bimaxillary protrusion group, this was about 19 months, which was longer than for the other groups. After joint orthognathic-orthodontic treatment, a good facial profile and ideal occlusion were achieved. With the advantages of earlier improvements in patient facial aesthetics and dental function, the reduction in difficulty and treatment duration of orthodontic management, and increasing patient acceptance, SFA is regarded as an ideal and valuable alternative for this potentially complicated procedure. PMID- 26573567 TI - Breast Cancer Virtual Special Issue. PMID- 26573568 TI - Deciphering mechanisms of drug sensitivity and resistance to Selective Inhibitor of Nuclear Export (SINE) compounds. AB - BACKGROUND: Exportin 1 (XPO1) is a well-characterized nuclear export protein whose expression is up-regulated in many types of cancers and functions to transport key tumor suppressor proteins (TSPs) from the nucleus. Karyopharm Therapeutics has developed a series of small-molecule Selective Inhibitor of Nuclear Export (SINE) compounds, which have been shown to block XPO1 function both in vitro and in vivo. The drug candidate, selinexor (KPT-330), is currently in Phase-II/IIb clinical trials for treatment of both hematologic and solid tumors. The present study sought to decipher the mechanisms that render cells either sensitive or resistant to treatment with SINE compounds, represented by KPT-185, an early analogue of KPT-330. METHODS: Using the human fibrosarcoma HT1080 cell line, resistance to SINE was acquired over a period of 10 months of constant incubation with increasing concentration of KPT-185. Cell viability was assayed by MTT. Immunofluorescence was used to compare nuclear export of TSPs. Fluorescence activated cell sorting (FACS), quantitative polymerase chain reaction (qPCR), and immunoblots were used to measure effects on cell cycle, gene expression, and cell death. RNA from naive and drug treated parental and resistant cells was analyzed by Affymetrix microarrays. RESULTS: Treatment of HT1080 cells with gradually increasing concentrations of SINE resulted in >100 fold decrease in sensitivity to SINE cytotoxicity. Resistant cells displayed prolonged cell cycle, reduced nuclear accumulation of TSPs, and similar changes in protein expression compared to parental cells, however the magnitude of the protein expression changes were more significant in parental cells. Microarray analyses comparing parental to resistant cells indicate that a number of key signaling pathways were altered in resistant cells including expression changes in genes involved in adhesion, apoptosis, and inflammation. While the patterns of changes in transcription following drug treatment are similar in parental and resistant cells, the extent of response was more robust in the parental cells. CONCLUSIONS: These results suggest that SINE resistance is conferred by alterations in signaling pathways downstream of XPO1 inhibition. Modulation of these pathways could potentially overcome the resistance to nuclear export inhibitors. PMID- 26573570 TI - Increased Surgical Site Infection Rates following Clindamycin Use in Head and Neck Free Tissue Transfer. AB - OBJECTIVE: The development of surgical site infections (SSIs) can put the viability of free tissue transfer reconstructions at risk, often resulting in considerable postoperative morbidity and prolonged hospitalization. Current antibiotic prophylactic guidelines suggest a first- or second-generation cephalosporin with metronidazole for clean-contaminated cases and recommend clindamycin as an alternative choice in penicillin-allergic patients. This study was designed to examine the rates of postoperative infection associated with prophylactic antibiotic regimens, including patients receiving clindamycin as an alternative due to penicillin allergy. STUDY DESIGN: Case series with chart review. SETTING: Tertiary academic medical center. SUBJECTS: Patients undergoing major ablative head and neck resection involving the pharynx and oral cavity reconstructed via free tissue transfer. METHODS: The sample included patients (n = 266) who underwent free tissue transfer involving the oral cavity and pharynx from 2009 to 2014. Data included demographic data, medical comorbidities, anatomic tumor subsite and surgical procedure, and prophylactic antibiotic regimen. SSI data were examined up to 30 days after the initial surgical procedure. Multivariate logistic regression analysis was performed to determine the overall risk for SSI. Culture data were also reviewed. RESULTS: The data indicated that clindamycin was associated with an approximate 4-fold increased risk for SSI (odds ratio, 3.784; 95% confidence interval: 1.367-10.470 [P = .010]) after controlling for possible confounding factors. CONCLUSION: For patients with a true penicillin allergy, we recommend broader gram-negative coverage with alternative antibiotics, such as cefuroxime, when undergoing free tissue transfer in the head and neck. PMID- 26573569 TI - A Boolean network model of human gonadal sex determination. AB - BACKGROUND: Gonadal sex determination (GSD) in humans is a complex biological process that takes place in early stages of embryonic development when the bipotential gonadal primordium (BGP) differentiates towards testes or ovaries. This decision is directed by one of two distinct pathways embedded in a GSD network activated in a population of coelomic epithelial cells, the Sertoli progenitor cells (SPC) and the granulosa progenitor cells (GPC). In males, the pathway is activated when the Sex-Determining Region Y (SRY) gene starts to be expressed, whereas in females the WNT4/ beta-catenin pathway promotes the differentiation of the GPCs towards ovaries. The interactions and dynamics of the elements that constitute the GSD network are poorly understood, thus our group is interested in inferring the general architecture of this network as well as modeling the dynamic behavior of a set of genes associated to this process under wild-type and mutant conditions. METHODS: We reconstructed the regulatory network of GSD with a set of genes directly associated with the process of differentiation from SPC and GPC towards Sertoli and granulosa cells, respectively. These genes are experimentally well-characterized and the effects of their deficiency have been clinically reported. We modeled this GSD network as a synchronous Boolean network model (BNM) and characterized its attractors under wild-type and mutant conditions. RESULTS: Three attractors with a clear biological meaning were found; one of them corresponding to the currently known gene expression pattern of Sertoli cells, the second correlating to the granulosa cells and, the third resembling a disgenetic gonad. CONCLUSIONS: The BNM of GSD that we present summarizes the experimental data on the pathways for Sertoli and granulosa establishment and sheds light on the overall behavior of a population of cells that differentiate within the developing gonad. With this model we propose a set of regulatory interactions needed to activate either the SRY or the WNT4/ beta-catenin pathway as well as their downstream targets, which are critical for further sex differentiation. In addition, we observed a pattern of altered regulatory interactions and their dynamics that lead to some disorders of sex development (DSD). PMID- 26573571 TI - Validation study of GRACE risk scores in indigenous and non-indigenous patients hospitalized with acute coronary syndrome. AB - BACKGROUND: Although cardiovascular disease is the major cause of premature death among Indigenous peoples in several advanced economies, no acute coronary syndrome (ACS) risk models have been validated in Indigenous populations. We tested the validity and calibration of three Global Registry of Acute Coronary Events (GRACE) scores among Aboriginal and non-Aboriginal Australians. METHODS: GRACE scores were calculated at admission or discharge using clinical data, with all-cause deaths obtained from data linkage. Scores for GRACE models were validated for; 1) in-hospital death, 2) death within 6 months from admission or 3) death within 6 months of discharge (this also for 1 and 5-years mortality). RESULTS: Aboriginal patient were younger (62 % aged <55 years versus 15 % non Aboriginal) and their median GRACE scores lower than non-Aboriginal patients, as was crude mortality at 6 months from admission (6 % vs 10 %) and at 1 and 5 years. After age stratification, risk scores for Aboriginal patients were equivalent or higher, especially among those aged <55 years. There was a trend to more deaths after discharge among Aboriginal patients in each age group, suggesting an age-related under-estimation of risk. The c-statistics for the three GRACE models within both groups were between 0.75 and 0.79. CONCLUSIONS: We demonstrated for the first time that while the discriminatory capacity of GRACE risk scores among Indigenous Australians is good, the models may need re calibrating to improve risk stratification in this and other Indigenous groups, where age of onset of coronary disease is much younger than among the original reference population. PMID- 26573572 TI - Short-and long-term effects of ischemic postconditioning in STEMI patients: a meta-analysis. AB - BACKGROUND: Compelling evidence from large randomized trials demonstrates the salutary effects of ischemic postconditioning on cardioprotection against ischemic/reperfusion injury. However, some studies appear negative findings. This study was designed to assess the short-and long-term effects of postconditioning (Poc) in studies including evolving ST-elevation myocardial infarction (STEMI). METHODS: Relevant studies were identified through an electronic literature search from the PubMed, Library of Congress, Embase, Cochrane Central Register of Controlled Trials, and ISI Web of Science. Studies published up to December 2014 were eligible for inclusion. Patients older than 18 years presenting within 12 h of the first STEMI and eligible for angioplasty were considered for the study. RESULTS: The 25 trials allocated 1136 patients to perform locational postconditioning cycles at the onset of reperfusion and 1153 patients to usual percutaneous coronary intervention (PCI). Ischemic postconditioning demonstrated a decrease in serum cardiac enzymes creatine kinase (CK) and CK-MB (P < 0.00001 and P =0.25, respectively) in the subgroup analysis based on direct stenting. Reduction in infarct size by imaging was showed during7 days after myocardial infarction (P =0.01), but not in the longterm (P = 0.08). The wall motion score index was improved in both the short term within 7 days (P = 0.009) and the long term over 6 months after receiving Poc (P = 0.02). All included studies were limited by the high risk of performance and publication bias. CONCLUSIONS: Ischemic postconditioning by brief interruptions of coronary blood flow at the onset of reperfusion after PCI appears to be superior to PCI alone in reducing myocardial injury and improving left ventricular function, especially in patients who have received direct stenting in PCI. PMID- 26573573 TI - Smoking and nasopharyngeal carcinoma mortality: a cohort study of 101,823 adults in Guangzhou, China. AB - BACKGROUND: Nasopharyngeal carcinoma (NPC), also known as Cantonese cancer, is rare worldwide, but has particularly high incidence in North Africa and Southeast Asia, especially in Guangdong, China, such as Guangzhou. Tobacco causes head and neck cancers, but nasopharyngeal carcinoma is not included as causally related to smoking in the 2014 United States Surgeon General's report. Prospective evidence remains limited. We used Guangzhou Occupational Cohort data to conduct the first and robust prospective study on smoking and NPC mortality in an NPC high-risk region. METHODS: Information on demographic characteristics and smoking status was collected through occupational health examinations in factories and driver examination stations from March 1988 to December 1992. Vital status and causes of deaths were retrieved until the end of 1999. Cox proportional hazard model was used to assess the association of smoking with NPC mortality. RESULTS: Of 101,823 subjects included for the present analysis, 34 NPC deaths occurred during the average 7.3 years of follow up. The mean age (standard deviation) of the subjects was 41 (5.7) years. Compared with never smokers, the hazard ratio (HR) of NPC mortality was 2.95 (95% confidence interval 1.01-8.68; p=0.048) for daily smokers and 4.03 (1.29-12.58; p=0.016) for smokers with more than 10 pack-years of cumulative consumption, after adjusting for age, sex, education, drinking status, occupation and cohort status and accounting for smoking-drinking interaction. The risk of NPC mortality increased significantly with cigarettes per day (p for trend=0.01) and number of pack-years (p for trend=0.02). CONCLUSIONS: In this first and largest cohort in a high NPC risk region, smoking was associated with higher NPC mortality. The findings have shown statistically significant dose response trend between smoking amount and smoking cumulative consumption and the risk of NPC mortality, but due to the small event number, further studies with larger sample size are needed to confirm the findings in the present study. Our results support that smoking is one of the risk factors likely to be causally associated with NPC mortality. PMID- 26573574 TI - Recombination elevates the effective evolutionary rate and facilitates the establishment of HIV-1 infection in infants after mother-to-child transmission. AB - BACKGROUND: Previous studies have demonstrated that single HIV-1 genotypes are commonly transmitted from mother to child, but such analyses primarily used single samples from mother and child. It is possible that in a single sample, obtained early after infection, only the most replication competent virus is detected even when other forms may have been transmitted. Such forms may have advantages later in infection, and may thus be detected in follow-up samples. Because HIV-1 frequently recombines, phylogenetic analyses that ignore recombination may miss transmission of multiple forms if they recombine after transmission. Moreover, recombination may facilitate adaptation, thus providing an advantage in establishing infection. The effect of recombination on viral evolution in HIV-1 infected children has not been well defined. RESULTS: We analyzed full-length env sequences after single genome amplification from the plasma of four subtype B HIV-1 infected women (11-67 env clones from 1 time point within a month prior to delivery) and their non-breastfed, intrapartum-infected children (3-6 longitudinal time points per child starting at the time of HIV-1 diagnosis). To address the potential beneficial or detrimental effects of recombination, we used a recently developed hierarchical recombination detection method based on the pairwise homoplasy index (PHI)-test. Recombination was observed in 9-67% of the maternal sequences and in 25-60% of the child sequences. In the child, recombination only occurred between variants that had evolved after transmission; taking recombination into account, we identified transmission of only 1 or 2 phylogenetic lineages from mother to child. Effective HIV-1 evolutionary rates of HIV-1 were initially high in the child and slowed over time (after 1000 days). Recombination was associated with elevated evolutionary rates. CONCLUSIONS: Our results confirm that 1-2 variants are typically transmitted from mothers to their newborns. They also demonstrate that early abundant recombination elevates the effective evolutionary rate, suggesting that recombination increases the rate of adaptation in HIV-1 evolution. PMID- 26573575 TI - Deaf, blind or deaf-blind: Is touch enhanced? AB - When someone looses one type of sensory input, s/he may compensate by using the sensory information conveyed by other senses. To verify whether loosing a sense or two has consequences on a spared sensory modality, namely touch, and whether these consequences depend on the type of sensory loss, we investigated the effects of deafness and blindness on temporal and spatial tactile tasks in deaf, blind and deaf-blind people. Deaf and deaf-blind people performed the spatial tactile task better than the temporal one, while blind and controls showed the opposite pattern. Deaf and deaf-blind participants were impaired in temporal discrimination as compared to controls, while deaf-blind individuals outperformed blind participants in the spatial tactile task. Overall, sensory-deprived participants did not show an enhanced tactile performance. We speculate that discriminative touch is not so relevant in humans, while social touch is. Probably, more complex tactile tasks would have revealed an increased performance in sensory-deprived people. PMID- 26573576 TI - Phase-dependent reversal of the crossed conditioning effect on the soleus Hoffmann reflex from cutaneous afferents during walking in humans. AB - We previously demonstrated that non-noxious electrical stimulation of the cutaneous nerve innervating the contralateral foot modified the excitability of the Hoffmann (H-) reflex in the soleus muscle (SOL) in a task-dependent manner during standing and walking in humans. To date, however, it remains unclear how the crossed conditioning effect on the SOL H-reflex from the contralateral foot is modified during the various phases of walking. We sought to answer this question in the present study. The SOL H-reflex was evoked in healthy volunteers by an electrical test stimulation (TS) of the right (ipsilateral) posterior tibial nerve at five different phases during treadmill walking (4 km/h). A non noxious electrical stimulation was delivered to the superficial peroneal nerve of the left (contralateral) ankle ~100 ms before the TS as a conditioning stimulation (CS). This CS significantly suppressed the H-reflex amplitude during the early stance phase, whereas the same CS significantly facilitated the H reflex amplitude during the late stance phase. The CS alone did not produce detectable changes in the full-wave rectified electromyogram of the SOL. This result indicates that presynaptic mechanisms driven by the activation of low threshold cutaneous afferents in the contralateral foot play a role in regulating the transmission between the Ia terminal and motoneurons in a phase-dependent manner. The modulation pattern of the crossed conditioning effect on the SOL H reflex may be functionally relevant for the left-right coordination of leg movements during bipedal walking. PMID- 26573577 TI - Novel sirolimus-eluting stent Prolim(r) with a biodegradable polymer in the all comers population: one year clinical results with quantitative coronary angiography and optical coherence tomography analysis. AB - BACKGROUND: The aim of this study was to assess the safety and the efficacy of the novel sirolimus-eluting Prolim(r) stent with a biodegradable polymer in the all-comers population. METHODS: We prospectively enrolled all patients with stable coronary artery disease or acute coronary syndrome treated with Prolim(r) stent between January and December 2013 in two interventional cardiology centers in Poland. Angiographic control was planned at 12 months, in which 15 % of patients (randomly chosen) underwent optical coherence tomography imaging. The primary end-point was the cumulative rate of cardiac death, myocardial infarction, and target lesion revascularization at 12 months. RESULTS: There were 204 patients enrolled, in whom 238 Prolim(r) stents were deployed (1.17 stent per patient). The mean age was 68 +/- 10 years and 32.8 % were females. The examined stent was implanted in 5.9 % in STEMI patients, in 21.6 % - in NSTE-ACS and in 72.5 % - in patients with stable coronary artery disease. The Prolim(r) stent was most frequently implanted in right coronary artery (38.2 %) followed by left anterior descending artery (34.0 %). The cumulative major adverse cardiovascular events rate at 12 months was 6.9 %, and the clinically-driven target lesion revascularization rate - 5.4 %. At 12 months in quantitative coronary angiography the late lumen loss was 0.21 +/- 0.18 mm, and in optical coherence tomography the mean neointima burden was 24.6 +/- 8.6 %. CONCLUSIONS: Sirolimus-eluting Prolim(r) stent with a biodegradable polymer is a feasible device with a very good safety profile and long-term clinical effectiveness. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT02545985 . PMID- 26573578 TI - Assessment of inpatient multimodal cardiac imaging appropriateness at large academic medical centers. AB - BACKGROUND: Responding to concerns regarding the growth of cardiac testing, the American College of Cardiology Foundation (ACCF) published Appropriate Use Criteria (AUC) for various cardiac imaging modalities. Single modality cardiac imaging appropriateness has been reported but there have been no studies assessing the appropriateness of multiple imaging modalities in an inpatient environment. METHODS: A retrospective study of the appropriateness of cardiac tests ordered by the inpatient General Internal Medicine (GIM) and Cardiology services at three Canadian academic hospitals was conducted over two one-month periods. Cardiac tests characterized were transthoracic echocardiography (TTE), transesophageal echocardiography (TEE), single-photon emission tomography myocardial perfusion imaging (SPECT), and diagnostic cardiac catheterization. RESULTS: Overall, 553 tests were assessed, of which 99.8% were classifiable by AUC. 91% of all studies were categorized as appropriate, 4% may be appropriate and 5% were rarely appropriate. There were high rates of appropriate use of all modalities by GIM and Cardiology throughout. Significantly more appropriate diagnostic catheterizations were ordered by Cardiology than GIM (93% vs. 82%, p = <0.01). Cardiology ordered more appropriate studies overall (94% vs. 88%, p = 0.03) but there was no difference in the rate of rarely appropriate studies (3% vs. 6%, p = 0.23). CONCLUSION: The ACCF AUC captured the vast majority of clinical scenarios for multiple cardiac imaging modalities in this multi-centered study on Cardiology and GIM inpatients in the acute care setting. The rate of appropriate ordering was high across all imaging modalities. We recommend further work towards improving appropriate utilization of cardiac imaging resources focus on the out-patient setting. PMID- 26573579 TI - Meaning in great ape communication: summarising the debate. AB - Does non-human great ape communication have meaning in the same way as human words (and some other human behaviours)? I recently argued that the answer to this question is most likely to be in the negative (Scott-Phillips in Anim Cogn 18(3):801-805, 2015a). Here, I (1) briefly respond to criticism of this view; (2) describe exactly what sort of empirical study could settle the matter; and (3) discuss what the best working hypotheses should be, in the absence of definitive empirical studies. PMID- 26573580 TI - Low-dose aspirin and survival from lung cancer: a population-based cohort study. AB - BACKGROUND: Preclinical evidence suggests that aspirin may inhibit lung cancer progression. In a large cohort of lung cancer patients, we investigated whether low-dose aspirin use was associated with a reduction in the risk of lung cancer specific mortality. METHODS: We identified lung cancer patients from English cancer registries diagnosed between 1998 to 2009 from the National Cancer Data Repository. Medication usage was obtained from linkages to the UK Clinical Practice Research Datalink and lung cancer-specific deaths were identified from Office of National Statistics mortality data. Hazard ratios (HR) and 95 % confidence intervals (CI) for the association between low-dose aspirin use (before and after diagnosis) and risk of lung cancer-specific mortality were calculated using Cox regression models. RESULTS: A total of 14,735 lung cancer patients were identified during the study period. In analysis of 3,635 lung cancer patients, there was no suggestion of an association between low-dose aspirin use after diagnosis and cancer-specific mortality (adjusted HR=0.96, 95% CI: 0.85, 1.09). Similarly, no association was evident for low-dose aspirin use before diagnosis and cancer-specific mortality (adjusted HR=1.00, 95% CI: 0.95, 1.05). Associations were comparable by duration of use and for all-cause mortality. CONCLUSION: Overall, we found little evidence of a protective association between low-dose aspirin use and cancer-specific mortality in a large population-based lung cancer cohort. PMID- 26573581 TI - "Once you join the streets you will have to do it": sexual practices of street children and youth in Uasin Gishu County, Kenya. AB - BACKGROUND: Adolescents living in HIV endemic settings face unique sexual health risks, and in the context of abject poverty, orphanhood, social marginalization, and discrimination, adolescents may be particularly at-risk of horizontal HIV transmission. Street-connected children and youth are a particularly vulnerable and marginalized population and therefore may be a key population at-risk. METHODS: We sought to describe the sexual behaviours of street-connected children and youth in order to comprehend their sexual practices and elucidate circumstances that put them at increased risk of contracting HIV utilizing qualitative methods from a sample of street-connected children and youth in Eldoret, Kenya. We recruited participants aged 11-24 years who had lived on the street for >= 3 months to participate in 25 in-depth interviews and 5 focus group discussions stratified by age and sex. RESULTS: In total we interviewed 65 street connected children and youth; 69 % were male with a median age of 18 years (IQR: 14-20.5 years). Participants identified both acceptable and unacceptable sexual acts that occur on the streets between males and females, between males, and between females. We grouped reasons for having sex into four categories based on common themes: pleasure, procreation, transactional, and forced. Transactional sex and multiple concurrent partnerships were frequently described by participants. Rape was endemic to street life for girls. CONCLUSION: These findings have important policy and programming implications, specifically for the government of Kenya's adolescent reproductive health policy, and highlight the need to target out-of-school youth. There is an urgent need for social protection to reduce transactional sex and interventions addressing the epidemic of sexual and gender-based violence. PMID- 26573583 TI - Pancreatic cancer takes its Toll. PMID- 26573582 TI - Arsenic Attenuates GLI Signaling, Increasing or Decreasing its Transcriptional Program in a Context-Dependent Manner. AB - The metalloid arsenic is a worldwide environmental toxicant, exposure to which is associated with many adverse outcomes. Arsenic is also an effective therapeutic agent in certain disease settings. Arsenic was recently shown to regulate the activity of the Hedgehog (HH) signal transduction pathway, and this regulation of HH signaling was proposed to be responsible for a subset of arsenic's biologic effects. Surprisingly, these separate reports proposed contradictory activities for arsenic, as either an agonist or antagonist of HH signaling. Here we provide in vitro and in vivo evidence that arsenic acts as a modulator of the activity of the HH effector protein glioma-associated oncogene family zinc finger (GLI), activating or inhibiting GLI activity in a context-dependent manner. This arsenic induced modulation of HH signaling is observed in cultured cells, patients with colorectal cancer who have received arsenic-based therapy, and a mouse colorectal cancer xenograft model. Our results show that arsenic activates GLI signaling when the intrinsic GLI activity is low but inhibits signaling in the presence of high-level GLI activity. Furthermore, we show that this modulation occurs downstream of primary cilia, evidenced by experiments in suppressor of fused homolog (SUFU) deficient cells. Combining our findings with previous reports, we present an inclusive model in which arsenic plays dual roles in GLI signaling modulation: when GLIs are primarily in their repressor form, arsenic antagonizes their repression capacity, leading to low-level GLI activation, but when GLIs are primarily in their activator form, arsenic attenuates their activity. PMID- 26573584 TI - Lending an 'ELPing hand to tumor initiation. PMID- 26573585 TI - Effective effector generation of CD8+ T cells and NK cells: A need for T-bet and ZEB-too. PMID- 26573586 TI - Cutting to the chase: How pathogenic mutations cause Alzheimer's. PMID- 26573587 TI - Angina at Low heart rate And Risk of imminent Myocardial infarction (the ALARM study): a prospective, observational proof-of-concept study. AB - BACKGROUND: Myocardial infarction (MI) is often preceded by unstable angina. Helping patients identify the onset of unstable angina rather than MI may result in earlier treatment and improve outcomes. Unstable angina is angina occurring at a lower-than-usual workload. Since heart rate (HR) is correlated with degree of exertion, we hypothesised that angina occurring at low HR is a warning signal for unstable angina and MI. METHODS: In this prospective study, 111 patients with acute coronary syndrome (ACS) or prognostically significant coronary disease were recruited. Each patient's HR was measured using a portable electrocardiogram (ECG) recorder after regular class III exercise on the Canadian Cardiovascular Society Angina Grading Scale and the cumulative moving average and three-sigma (standard deviation) range were calculated for each new measurement. The HR was subsequently measured at the beginning of angina; a HR lower than the preceding three-sigma ranges for class III or anginal HR was regarded as a 'warning signal'. The proportion of warning signals associated with ACS occurring in the following 2 weeks was compared with that for non-warning signals. RESULTS: Nine cases of ACS occurred in eight patients. Two cases were preceded by warning signals; a signal marked the onset of ACS in a third patient, and four patients failed to make anginal ECG recordings. There were 591 documented episodes of angina during the study and ECGs were available for 383 (64.8 %) of these of which 55 were warning signals. Of these warning signals, 4 occurred in the 2 weeks preceding ACS, compared with 4 of 328 non-warning signals (odds ratio, 6.4; 95 % confidence interval, 1.5-26.2; p = 0.01; positive predictive value, 7.3 %; negative predictive value, 98.8 %). CONCLUSIONS: Low HR angina may identify unstable angina and serve as an early warning for MI. In addition, angina that does not occur at a low heart rate indicates that ACS is very unlikely. PMID- 26573588 TI - A nanomolecular approach to decrease adhesion of biofouling-producing bacteria to graphene-coated material. AB - BACKGROUND: Biofouling, the colonization of artificial and natural surfaces by unwanted microorganisms, has an important economic impact on a wide range of industries. Low cost antifouling strategies are typically based on biocides which exhibit a negative environmental impact, affecting surrounding organisms related and not related to biofouling. Considering that the critical processes resulting in biofouling occur in the nanoscale/microscale dimensions, in this work we present a bionanotechnological approach to reduce adhesion of biofilm-producing bacteria Halomonas spp. CAM2 by introducing single layer graphene coatings. The use of this nanomaterial has been poorly explored for antifouling application. RESULTS: Our study revealed that graphene coatings modify material surface energy and electrostatic interaction between material and bacteria. Such nanoscale surface modification determine an important reduction over resulting bacterial adhesion and reduces the expression levels of genes related to adhesion when bacteria are in contact with graphene-coated material. CONCLUSIONS: Our results demonstrate that graphene coatings reduce considerably adhesion and expression levels of adhesion genes of biofilm-producing bacteria Halomonas spp. CAM2. Hydrophobic-hydrophilic interaction and repulsive electrostatic force dominate the interactions between Halomonas spp. CAM2 and material surface in saline media, impacting the final adhesion process. In addition no bactericide effect of graphene coatings was observed. The effect over biofilm formation is localized right at coated surface, in contrast to other antifouling techniques currently used, such as biocides. PMID- 26573589 TI - Aspirin resistance and other aspirin-related concerns. AB - Aspirin is a widely used medication and has become a cornerstone for treating cardiovascular disease. Aspirin can significantly reduce the incidence of cardiovascular ischemic events, recurrence and mortality, thereby improving the long-term prognosis of patients. However, there has been a staggering increase in the volume of literature addressing the issue of so-called "aspirin resistance" in recent years, and for some patients, it is difficult to avoid adverse reactions to aspirin. In this review, we present both the historical aspects of aspirin use and contemporary developments in its clinical use. PMID- 26573590 TI - Occurrence of neuropathies in patients with severe heart failure before and after heart transplantation. AB - Neuropathies may affect heart reinnervation and functional outcome after heart transplantation (HT). In this study, neurological evaluations, standard nerve conduction studies, and electromyography were performed in 32 HT candidates without a previous history of neuromuscular disorder. Ten patients underwent HT and were revaluated 3 months later. We found that before HT 10 (31.3%) patients had sensorimotor polyneuropathy (18.8%) or sensory polyneuropathy (12.5%). After HT, the percentage of patients with a neuromuscular disorder increased to 70%, most of them showing new or worsening neuropathies or neuromyopathies. The most sensitive abnormality that indicated neuromuscular involvement after HT was a reduction of the compound muscle action potential (CMAP) of the deep peroneal nerve. In conclusion, neuromuscular disorders are common in HT candidates, and they further increase in occurrence after HT. A reduction of the deep peroneal nerve CMAP amplitude after HT may help to identify patients who need a more detailed neurophysiological evaluation. The diagnosis of neuromuscular disorders before and after HT may contribute to the development of more accurate therapeutic and rehabilitative strategies for these patients. PMID- 26573591 TI - Correlated patterns of neuropsychological and behavioral symptoms in frontal variant of Alzheimer disease and behavioral variant frontotemporal dementia: a comparative case study. AB - Although the neuropathologic changes and diagnostic criteria for the neurodegenerative disorder Alzheimer's disease (AD) are well-established, the clinical symptoms vary largely. Symptomatically, frontal variant of AD (fv-AD) presents very similarly to behavioral variant frontotemporal dementia (bvFTD), which creates major challenges for differential diagnosis. Here, we report two patients who present with progressive cognitive impairment, early and prominent behavioral features, and significant frontotemporal lobe atrophy on magnetic resonance imaging, consistent with an initial diagnosis of probable bvFTD. However, multimodal functional neuroimaging revealed neuropathological data consistent with a diagnosis of probable AD for one patient (pathology distributed in the frontal lobes) and a diagnosis of probable bvFTD for the other patient (hypometabolism in the bilateral frontal lobes). In addition, the fv-AD patient presented with greater executive impairment and milder behavioral symptoms relative to the bvFTD patient. These cases highlight that recognition of these atypical syndromes using detailed neuropsychological tests, biomarkers, and multimodal neuroimaging will lead to greater accuracy in diagnosis and patient management. PMID- 26573592 TI - Increase of distal sensory action potential duration as a sensitive electrophysiological parameter in atypical case of acute inflammatory demyelinating polyneuropathy. PMID- 26573594 TI - Older adults with difficulty swallowing oral medicines: a systematic review of the literature. AB - PURPOSE: Difficulty swallowing oral medicines may arise due to swallowing disorders or due to patient self-reported difficulty in the absence of objective evidence of swallowing dysfunction. Medication use increases with age; therefore, difficulty swallowing medication may complicate medicine administration to older patients. Modifying oral medicines can impact on the safety, quality and efficacy of the medication. The objective of this systematic review is to critically appraise the evidence regarding the prevalence of difficulty swallowing oral medicines and the modification of oral medicines to overcome swallowing difficulties in the older cohort. METHODS: A systematic search of PubMed, EMBASE, MEDLINE, CINAHL, Scopus, Web of Science, The Cochrane Library, PsycINFO and ProQuest databases was conducted from database inception to November 2014. Studies investigating the prevalence of difficulty swallowing oral medicines or the modification of oral medicines were eligible for inclusion. A narrative analysis of the results was conducted. RESULTS: Five studies met the inclusion criteria. The results suggest that approximately 14 % of community-dwelling older patients experience difficulty swallowing medicines. Between one quarter and one third of occasions of medicine administration to older patients involve the modification of oral medicines. CONCLUSIONS: Difficulty swallowing oral medicines and the modification of medicines are reported as being common issues in the older cohort. However, evidence to support such contentions is limited. Future research should investigate the prevalence of medicine modification for older patients in all settings and identify what medicines are modified. This will allow targeting of interventions to optimise medicine administration to older patients. PMID- 26573593 TI - Induction of proto-oncogene BRF2 in breast cancer cells by the dietary soybean isoflavone daidzein. AB - BACKGROUND: BRF2 is a transcription factor required for synthesis of a small group of non-coding RNAs by RNA polymerase III. Overexpression of BRF2 can transform human mammary epithelial cells. In both breast and lung cancers, the BRF2 gene is amplified and overexpressed and may serve as an oncogenic driver. Furthermore, elevated BRF2 can be independently prognostic of unfavorable survival. Dietary soy isoflavones increase metastasis to lungs in a model of breast cancer and a recent study reported significantly increased cell proliferation in breast cancer patients who used soy supplementation. The soy isoflavone daidzein is a major food-derived phytoestrogen that is structurally similar to estrogen. The putative estrogenic effect of soy raises concern that high consumption of soy foods by breast cancer patients may increase tumor growth. METHODS: Expression of BRF2 RNA and protein was assayed in ER-positive or -negative human breast cancer cells after exposure to daidzein. We also measured mRNA stability, promoter methylation and response to the demethylating agent 5 azacytidine. In addition, expression was compared between mice fed diets enriched or deprived of isoflavones. RESULTS: We demonstrate that the soy isoflavone daidzein specifically stimulates expression of BRF2 in ER-positive breast cancer cells, as well as the related factor BRF1. Induction is accompanied by increased levels of non-coding RNAs that are regulated by BRF2 and BRF1. Daidzein treatment stabilizes BRF2 and BRF1 mRNAs and selectively decreases methylation of the BRF2 promoter. Functional significance of demethylation is supported by induction of BRF2 by the methyltransferase inhibitor 5-azacytidine. None of these effects are observed in an ER-negative breast cancer line, when tested in parallel with ER positive breast cancer cells. In vivo relevance is suggested by the significantly elevated levels of BRF2 mRNA detected in female mice fed a high-isoflavone commercial diet. In striking contrast, BRF2 and BRF1 mRNA levels are suppressed in matched male mice fed the same isoflavone-enriched diet. CONCLUSIONS: The BRF2 gene that is implicated in cancer can be induced in human breast cancer cells by the isoflavone daidzein, through promoter demethylation and/or mRNA stabilization. Dietary isoflavones may also induce BRF2 in female mice, whereas the converse occurs in males. PMID- 26573595 TI - Computerized tomography based tumor-thickness measurement is useful to predict postoperative pathological tumor thickness in oral tongue squamous cell carcinoma. AB - BACKGROUND: Tumor thickness has been shown in oral tongue squamous cell carcinoma (OTSCC) to be a predictor of cervical metastasis. The postoperative histological measurement is certainly the most accurate, but it would be of clinical interest to gain this information prior to treatment planning. This retrospective study aimed to compare the tumor thickness measurement between preoperative, CT scan, and surgical specimens . METHODS: We retrospectively included 116 OTSCC patients between 2001 and 2013. Thickness was measured on computer tomography imaging and again surgical specimens. RESULTS: The median age was 66 years. 62.8 % of patients were smokers with a mean of 31.4 pack-years. Positive nodal disease was reported in 41.2 %. Mean follow-up time was 33.1 months. The correlation between CT scan-based tumor thickness and surgical specimens based thickness was significant (Spearman rho = 0.755, P < 0.001). CONCLUSION: Tumor thickness assessed by CT scan may provide an accurate estimation of true thickness and can be used in treatment planning. PMID- 26573596 TI - The casposon-encoded Cas1 protein from Aciduliprofundum boonei is a DNA integrase that generates target site duplications. AB - Many archaea and bacteria have an adaptive immune system known as CRISPR which allows them to recognize and destroy foreign nucleic acid that they have previously encountered. Two CRISPR-associated proteins, Cas1 and Cas2, are required for the acquisition step of adaptation, in which fragments of foreign DNA are incorporated into the host CRISPR locus. Cas1 genes have also been found scattered in several archaeal and bacterial genomes, unassociated with CRISPR loci or other cas proteins. Rather, they are flanked by nearly identical inverted repeats and enclosed within direct repeats, suggesting that these genetic regions might be mobile elements ('casposons'). To investigate this possibility, we have characterized the in vitro activities of the putative Cas1 transposase ('casposase') from Aciduliprofundum boonei. The purified Cas1 casposase can integrate both short oligonucleotides with inverted repeat sequences and a 2.8 kb excised mini-casposon into target DNA. Casposon integration occurs without target specificity and generates 14-15 basepair target site duplications, consistent with those found in casposon host genomes. Thus, Cas1 casposases carry out similar biochemical reactions as the CRISPR Cas1-Cas2 complex but with opposite substrate specificities: casposases integrate specific sequences into random target sites, whereas CRISPR Cas1-Cas2 integrates essentially random sequences into a specific site in the CRISPR locus. PMID- 26573597 TI - The Immune Checkpoint Regulator PD-L1 Is Highly Expressed in Aggressive Primary Prostate Cancer. AB - PURPOSE: Therapies targeting the programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) pathway promote anti-tumor immunity and have shown promising results in various tumors. Preliminary data further indicate that immunohistochemically detected PD-L1 may be predictive for anti-PD-1 therapy. So far, no data are available on PD-L1 expression in primary prostate cancer. EXPERIMENTAL DESIGN: Following validation of a monoclonal antibody, immunohistochemical analysis of PD-L1 expression was performed in two independent, well-characterized cohorts of primary prostate cancer patients following radical prostatectomy (RP), and resulting data were correlated to clinicopathological parameters and outcome. RESULTS: In the training cohort (n= 209), 52.2% of cases expressed moderate to high PD-L1 levels, which positively correlated with proliferation (Ki-67,P< 0.001), Gleason score (P= 0.004), and androgen receptor (AR) expression (P< 0.001). Furthermore, PD-L1 positivity was prognostic for biochemical recurrence [BCR;P= 0.004; HR, 2.37; 95% confidence interval (CI), 1.32-4.25]. In the test cohort (n= 611), moderate to high PD-L1 expression was detected in 61.7% and remained prognostic for BCR in univariate Cox analysis (P= 0.011; HR, 1.49; 95% CI, 1.10-2.02). The correlation of Ki-67 and AR with PD-L1 expression was confirmed in the test cohort (P< 0.001). In multivariate Cox analysis of all patients, PD-L1 was corroborated as independently prognostic for BCR (P= 0.007; HR, 1.46; 95% CI, 1.11-1.92). CONCLUSIONS: We provide first evidence that expression of the therapy target PD L1 is not only highly prevalent in primary prostate cancer cells but is also an independent indicator of BCR, suggesting a biologic relevance in primary tumors. Further studies need to ascertain if PD-1/PD-L1-targeted therapy might be a treatment option for hormone-naive prostate cancers. PMID- 26573598 TI - Decreased Serum Thrombospondin-1 Levels in Pancreatic Cancer Patients Up to 24 Months Prior to Clinical Diagnosis: Association with Diabetes Mellitus. AB - PURPOSE: Identification of serum biomarkers enabling earlier diagnosis of pancreatic ductal adenocarcinoma (PDAC) could improve outcome. Serum protein profiles in patients with preclinical disease and at diagnosis were investigated. EXPERIMENTAL DESIGN: Serum from cases up to 4 years prior to PDAC diagnosis and controls (UKCTOCS,n= 174) were studied, alongside samples from patients diagnosed with PDAC, chronic pancreatitis, benign biliary disease, type 2 diabetes mellitus, and healthy subjects (n= 298). Isobaric tags for relative and absolute quantification (iTRAQ) enabled comparisons of pooled serum from a test set (n= 150). Validation was undertaken using multiple reaction monitoring (MRM) and/or Western blotting in all 472 human samples and samples from a KPC mouse model. RESULTS: iTRAQ identified thrombospondin-1 (TSP-1) as reduced preclinically and in diagnosed samples. MRM confirmed significant reduction in levels of TSP-1 up to 24 months prior to diagnosis. A combination of TSP-1 and CA19-9 gave an AUC of 0.86, significantly outperforming both markers alone (0.69 and 0.77, respectively;P< 0.01). TSP-1 was also decreased in PDAC patients compared with healthy controls (P< 0.05) and patients with benign biliary obstruction (P< 0.01). Low levels of TSP-1 correlated with poorer survival, preclinically (P< 0.05) and at clinical diagnosis (P< 0.02). In PDAC patients, reduced TSP-1 levels were more frequently observed in those with confirmed diabetes mellitus (P< 0.01). Significantly lower levels were also observed in PDAC patients with diabetes compared with individuals with type 2 diabetes mellitus (P= 0.01). CONCLUSIONS: Circulating TSP-1 levels decrease up to 24 months prior to diagnosis of PDAC and significantly enhance the diagnostic performance of CA19-9. The influence of diabetes mellitus on biomarker behavior should be considered in future studies. PMID- 26573599 TI - Circulating concentrations of endothelin-1 predict coronary heart disease in women but not in men: a longitudinal observational study in the Vara-Skovde Cohort. AB - BACKGROUND: The vasoconstricting peptide endothelin-1 has been proposed to be a marker of cardiovascular disease. Our aim was to investigate whether circulating endothelin-1 levels predict coronary heart disease (CHD) in Sweden. METHODS: In 2002-2005, 2816 adult participants (30-74 years) were randomly selected from two municipalities in south-western Sweden. Cardiovascular risk factors and endothelin-1 levels were assessed at baseline, and incident CHD was followed-up in all participants through 2011. After exclusion of 50 participants due to known CHD at baseline and 21 participants because of unsuccessful analysis of endothelin-1, 2745 participants were included in the study. In total, 72 CHD events (52 in men and 20 in women) were registered during the follow-up time. RESULTS: We showed that baseline circulating endothelin-1 levels were higher in women with incident CHD than in women without CHD (3.2 pg/ml, SE: 0.36 vs 2.4 pg/ml, SE: 0.03, p = 0.003) whereas this difference was not observed in men (2.3 pg/ml, SE: 0.16 vs 2.3 pg/ml, SE: 0.04, p = 0.828). An age-adjusted Cox proportional regression analysis showed an enhanced risk of CHD with increasing baseline endothelin-1 levels in women (hazard ratio (HR) = 1.51, 95 % CI = 1.1 2.1, p = 0.015) but not in men (HR = 0.98, 95 % CI = 0.8-1.2, p = 0.854). Furthermore, the predictive value of endothelin-1 for incident CHD in women was still significant after adjustments for age, HOMA-IR, apolipoprotein (apo)B/apoA1 and smoking (HR = 1.53, CI = 1.1-1.2, p = 0.024). CONCLUSION: Circulating endothelin-1 levels may predict CHD in women. PMID- 26573600 TI - Interpreting small treatment differences from quality of life data in cancer trials: an alternative measure of treatment benefit and effect size for the EORTC QLQ-C30. AB - BACKGROUND: The EORTC-QLQ-C30 is a widely used health related quality of life (HRQoL) questionnaire in lung cancer patients. Small HRQoL treatment effects are often reported as mean differences (MDs) between treatments, which are rarely justified or understood by patients and clinicians. An alternative approach using odds ratios (OR) for reporting effects is proposed. This may offer advantages including facilitating alignment between patient and clinician understanding of HRQoL effects. METHODS: Data from six CRUK sponsored randomized controlled lung cancer trials (2 small cell and 4 in non-small cell, in 2909 patients) were used to HRQoL effects. Results from Beta-Binomial (BB) standard mixed effects were compared. Preferences for ORs vs MDs were determined and Time to Deterioration (TD) was also compared. RESULTS: HRQoL effects using ORs offered coherent interpretations: MDs >0 resulted in ORs >1 and vice versa; effect sizes were classified as 'Trivial' if the OR was between 1 +/- 0.05 (i.e. 0.95 to 1.05); 'Small': for 1 +/- 0.1; 'Medium': 1 +/- 0.2 and 'Large': OR <0.8 or >1.20. Small HRQoL effects on the MD scale may translate to important treatment differences on the OR scale: for example, a worsening in symptoms (MD) by 2.6 points (p = 0.1314) would be a 17 % deterioration (p < 0.0001) with an OR. Hence important differences may be missed with MD; conversely, small ORs are unlikely to yield large MDs because methods based on OR model skewed data well. Initial evidence also suggests oncologists prefer ORs over MDs since interpretation is similar to hazard ratios. CONCLUSION: Reporting HRQoL benefits as MDs can be misleading. Estimates of HRQoL treatment effects in terms of ORs are preferred over MDs. Future analysis of QLQ-C30 and other HRQoL measures should consider reporting HRQoL treatment effects as ORs. PMID- 26573601 TI - Epstein-Barr virus positivity, not mismatch repair-deficiency, is a favorable risk factor for lymph node metastasis in submucosa-invasive early gastric cancer. AB - BACKGROUND: Epstein-Barr virus (EBV)-associated gastric cancer (GC) and microsatellite-instability-high GC are associated with a low prevalence of regional lymph node metastasis (LNM). To evaluate the feasibility of endoscopic treatment of EBV-associated and/or microsatellite-instability-high early GC (EGC), we analyzed the risk factors for LNM using a large series (n = 756) of submucosa-invasive (SM) EGC. METHODS: EBV-encoded RNA in situ hybridization (EBER ISH) and immunohistochemistry for four mismatch repair (MMR) proteins (MLH1, PMS2, MSH2, and MSH6) were performed. The clinicopathologic features and results of EBER ISH and immunohistochemistry were compared according to the LNM status. RESULTS: Among the cases, 146 EGCs (19.3 %) showed LNM. EBV negativity, larger tumor size (greater than 2 cm), deeper level of submucosal invasion, submucosal invasion depth greater than 500 um, presence of ulceration, and presence of lymphovascular invasion (LVI) were associated with LNM. However, the MMR deficiency was not correlated with LNM. On multivariate regression analysis, larger tumor size (greater than 2 cm; odds ratio 1.6, p = 0.030), deeper level of submucosal invasion (odds ratio 2.9, p = 0.001), LVI (odds ratio 7.4, p < 0.001), and EBV negativity (p = 0.020) were independent risk factors for LNM in SM EGCs. CONCLUSIONS: EBV positivity was a favorable risk factor for LNM in SM EGC. However, MMR deficiency was not associated with the status of LNM. Thus, we suggest that examination with EBER ISH could be considered for endoscopic resected specimens, especially in cases of SM EGC showing no LVI and clear resection margins. PMID- 26573602 TI - Molecular characterization and functional analysis of barley semi-dwarf mutant Riso no. 9265. AB - BACKGROUND: sdw1/denso is one of the most important and useful semi-dwarf genes in barley breeding. At least four sdw1/denso alleles have been reported and HvGA20ox 2 is considered as the candidate gene. Up to date, results of studies have not univocally proven the genetic relationship between sdw1/denso and HvGA20ox 2 . RESULTS: In the present study, a complete deletion of Morex_contig_40861 including both HvGA20ox 2 and Mloc_56463 genes was identified at the sdw1 locus from a semi-dwarf mutant Riso no. 9265. Expression of the genes encoding gibberellin biosynthesis (HvGA20ox 1 and HvGA3ox 2 ) were increased in the mutant compared to the wild type Bomi, while the expression of GA catabolic gene HvGA2ox 3 was decreased. Over-expression of HvGA20ox 2 could rescue the semi dwarf phenotype and increase GAs concentration. CONCLUSIONS: We confirmed that a GA biosynthetic enzyme HvGA20ox2, acted as GA 20-oxidase, is the functional gene for the sdw1/denso semi-dwarfism. Lose of HvGA20ox 2 is partially compensated by HvGA20ox 1 and further feedback is regulated by gibberellin. We also deduced that the sdw1/denso allele itself affects later heading owing to its reduced endogenous GAs concentration. PMID- 26573604 TI - Modeling Andersen's Syndrome in Human Induced Pluripotent Stem Cells. AB - Andersen's syndrome (AS) is a rare disorder characterized by a triad of symptoms: periodic paralysis, cardiac arrhythmia, and bone developmental defects. Most of the patients carry mutations on the inward rectifier potassium channel Kir2.1 encoded by the KCNJ2 gene. kcnj2 knockout mice are lethal at birth preventing, hence, thorough investigations of the physiological and pathophysiological events. We have generated induced pluripotent stem (iPS) cells from healthy as well as from AS patient muscular biopsies using the four-gene cassette required for cellular reprogramming (Oct4, Sox2, Klf4, and c-Myc). The generated AS-iPS cells exhibited the gold standard requirement for iPS cells: expression of genetics and surface pluripotent markers, strong alkaline phosphatase activity, self-renewal, and could be differentiated by the formation of embryoid bodies (EBs) into the three germ layers. Sequencing of the entire coding sequence of the KCNJ2 gene, in AS-iPS cells, revealed that the reprogramming process did not revert the Andersen's syndrome-associated mutation. Moreover, no difference was observed between control and AS-iPS cells in terms of pluripotent markers' expression, self-renewal, and three germ layer differentiation. Interestingly, expression of osteogenic markers are lower in EB-differentiated AS-iPS compared to control iPS cells. Our results showed that the Kir2.1 channel is not important for the reprogramming process and the early step of the development in vitro. However, the osteogenic machinery appears to be hastened in AS-iPS cells, strongly indicating that the generated AS-iPS cells could be a good model to better understand the AS pathophysiology. PMID- 26573603 TI - AXL is a potential therapeutic target in dedifferentiated and pleomorphic liposarcomas. AB - BACKGROUND: AXL is a well-characterized, protumorigenic receptor tyrosine kinase that is highly expressed and activated in numerous human carcinomas and sarcomas, including aggressive subtypes of liposarcoma. However, the role of AXL in the pathogenesis of well-differentiated (WDLPS), dedifferentiated (DDLPS), and pleomorphic liposarcoma (PLS) has not yet been determined. METHODS: Immunohistochemical analysis of AXL expression was conducted on two tissue microarrays containing patient WDLPS, DDLPS, and PLS samples. A panel of DDLPS and PLS cell lines were interrogated via western blot for AXL expression and activity and by ELISA for growth arrest-specific 6 (GAS6) production. AXL knockdown was achieved by siRNA or shRNA. The effects of AXL knockdown on cell proliferation, migration, and invasion were measured in vitro. In addition, AXL shRNA-containing DDLPS cells were assessed for their tumor-forming capacity in vivo. RESULTS: In this study, we determined that AXL is expressed in a subset of WDLPS, DDLPS, and PLS patient tumor samples. In addition, AXL and its ligand GAS6 are expressed in a panel of DDLPS and PLS cell lines. We show that the in vitro activation of AXL via stimulation with exogenous GAS6 resulted in a significant increase in cell proliferation, migration, and invasion in DDLPS and PLS cell lines. Transient knockdown of AXL resulted in attenuation of these protumorigenic phenotypes in vitro. Stable AXL knockdown not only decreased migratory and invasive characteristics of DDLPS and PLS cells in vitro but also significantly diminished tumorigenicity of two dedifferentiated liposarcoma xenograft models in vivo. CONCLUSIONS: Our results suggest that AXL signaling contributes to the aggressiveness of DDLPS and PLS, and that AXL is therefore a potential therapeutic target for treatment of these rare, yet devastating tumors. PMID- 26573605 TI - Erratum to: Neonatal brain MRI: how reliable is the radiologist's eye? PMID- 26573606 TI - Q-ball imaging models: comparison between high and low angular resolution diffusion-weighted MRI protocols for investigation of brain white matter integrity. AB - INTRODUCTION: Q-ball imaging (QBI) is one of the typical data models for quantifying white matter (WM) anisotropy in diffusion-weighted MRI (DwMRI) studies. Brain and spinal investigation by high angular resolution DwMRI (high angular resolution imaging (HARDI)) protocols exhibits higher angular resolution in diffusion imaging compared to low angular resolution models, although with longer acquisition times. We aimed to assess the difference between QBI-derived anisotropy values from high and low angular resolution DwMRI protocols and their potential advantages or shortcomings in neuroradiology. METHODS: Brain DwMRI data sets were acquired in seven healthy volunteers using both HARDI (b = 3000 s/mm(2), 54 gradient directions) and low angular resolution (b = 1000 s/mm(2), 32 gradient directions) acquisition schemes. For both sequences, tract of interest tractography and generalized fractional anisotropy (GFA) measures were extracted by using QBI model and were compared between the two data sets. RESULTS: QBI tractography and voxel-wise analyses showed that some WM tracts, such as corpus callosum, inferior longitudinal, and uncinate fasciculi, were reconstructed as one-dominant-direction fiber bundles with both acquisition schemes. In these WM tracts, mean percent different difference in GFA between the two data sets was less than 5%. Contrariwise, multidirectional fiber bundles, such as corticospinal tract and superior longitudinal fasciculus, were more accurately depicted by HARDI acquisition scheme. CONCLUSION: Our results suggest that the design of optimal DwMRI acquisition protocols for clinical investigation of WM anisotropy by QBI models should consider the specific brain target regions to be explored, inducing researchers to a trade-off choice between angular resolution and acquisition time. PMID- 26573607 TI - Estimation of cancer burden in Guangdong Province, China in 2009. AB - BACKGROUND: Surveying regional cancer incidence and mortality provides significant data that can assist in making health policy for local areas; however, the province- and region-based cancer burden in China is seldom reported. In this study, we estimated cancer incidence and mortality in Guangdong Province, China and presented basic information for making policies related to health resource allocation and disease control. METHODS: A log-linear model was used to calculate the sex-, age-, and registry-specific ratios of incidence to mortality (I/M) based on cancer registry data from Guangzhou, Zhongshan, and Sihui between 2004 and 2008. The cancer incidences in 2009 were then estimated according to representative I/M ratios and the mortality records from eight death surveillance sites in Guangdong Province. The cancer incidences in each city were estimated by the corresponding sex- and age-specific incidences from cancer registries or death surveillance sites in each area. Finally, the total and region-based cancer incidences and mortalities for the entire population of Guangdong Province were summarized. RESULTS: The estimated I/M ratios in Guangzhou (3.658), Zhongshan (2.153), and Sihui (1.527) were significantly different (P < 0.001), with an average I/M ratio of 2.446. Significant differences in the estimated I/M ratios were observed between distinct age groups and the three cancer registries. The estimated I/M ratio in females was significantly higher than that in males (2.864 vs. 2.027, P < 0.001). It was estimated that there were 163,376 new cancer cases (99,689 males and 63,687 females) in 2009; it was further estimated that 115,049 people (75,054 males and 39,995 females) died from cancer in Guangdong Province in 2009. The estimated crude and age-standardized rate of incidences (ASRI) in Guangdong Province were 231.34 and 246.87 per 100,000 males, respectively, and 156.98 and 163.57 per 100,000 females, respectively. The estimated crude and age-standardized rate of mortalities (ASRM) in Guangdong Province were 174.17 and 187.46 per 100,000 males, respectively, and 98.59 and 102.00 per 100,000 females, respectively. In comparison with the western area and the northern mountain area, higher ASRI and ASRM were recorded in the Pearl River Delta area and the eastern area in both males and females. CONCLUSIONS: Cancer imposes a heavy disease burden, and cancer patterns are unevenly distributed throughout Guangdong Province. More health resources should be allocated to cancer control, especially in the western and northern mountain areas. PMID- 26573608 TI - Ginkgetin exerts growth inhibitory and apoptotic effects on osteosarcoma cells through inhibition of STAT3 and activation of caspase-3/9. AB - Osteosarcoma is composed of tumor osteoblasts and bone-like tissues, with malignant tumors originating from osteogenesis organization. Osteosarcoma is a primary malignant bone tumor. Invasion and metastasis of osteosarcoma affect the prognosis of patients. However, effective therapeutic treatments remain to be identified. The aim of the present study was to investigate the possible inhibitory and apoptotic effects of ginkgetin in osteosarcoma cells. 3.3-(4,5 Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays were used to determine the effect ginkgetin exerted on the growth of osteosarcoma cells. Flow cytometry was used to determine cell apoptosis. STAT3 protein expression and activation of caspase-3/9 were measured using western blot analysis and the MTT and LDH assays, respectively. The results showed that ginkgetin inhibited cell growth and induced cell cytotoxicity in osteosarcoma cells in a dose-dependent manner. Treatment with ginkgetin significantly activated the apoptosis of osteosarcoma cells in a concentration dependent manner. The anticancer activity of ginkgetin significantly inhibited STAT3 and promoted caspase-3/9 activation in osteosarcoma cells. The findings demonstrated that ginkgetin exerts growth inhibitory and apoptotic effects on osteosarcoma cells through the inhibition of STAT3 and activation of caspase-3/9. PMID- 26573609 TI - Relationship between the A(8002)G intronic polymorphism of pre-pro-endothelin-1 gene and the endothelin-1 concentration among Tunisian coronary patients. AB - BACKGROUND: Acute coronary syndromes (ACS) are complex and polygenic diseases which are a real problem of public health. These syndromes require multidisciplinary studies to understand the pathogenesis mechanisms. Our study aims to evaluate the endothelin-1 (ET-1) serum concentration in Tunisian coronary compared to controls healthy, as well as the study of the impact of an intronic polymorphism A (8002) G of pre-pro-endothelin-1 Gene (inactive precursor of ET-1) on the change in serum endothelin-1 and in the susceptibility to Acute coronary syndrome (SCA). METHODS: Our samples were subdivided into coronary patients (157) and healthy subjects (142). The quantification of the ET-1 concentration was performed by high performance liquid chromatography, the identification of the different genotypes of the polymorphism A(8002)G was made by PCR-RFLP. The association between the ET-1 concentration and identified genotypes was realized by adapted software for descriptive statistics, Statistical Package for the Sociological Sciences (SPSS v 21.0). RESULTS: Our study showed that the concentration of ET-1 was significantly higher in patients compared to controls and that the mutated allele prevails in patients F (G) = 0.78 and there is a minority in controls F (G) = 0.3. Secondly the homozygous genotype GG is associated with higher concentrations of ET-1 in patients and controls, heterozygous genotype AG is associated with intermediaries' values and AA genotype is related to lower values. CONCLUSION: Although the polymorphism studied is an intronic polymorphism, it is involved in the change in serum concentration of ET-1 and is a candidate gene in susceptibility to SCA. Cardiovascular diseases are "polygenic" pathology and do not obey of the law for transmission of Mendel. PMID- 26573610 TI - Population preference values for health states in relapsed or refractory B precursor acute lymphoblastic leukemia in the United Kingdom. AB - BACKGROUND: To date, reliable and comprehensive health-related quality of life data for patients with relapsed or refractory B-precursor acute lymphoblastic leukemia (ALL) have not been collected in clinical trials of the disease, and no utility studies have been published. The purpose of this study was to define and validate health states experienced by adults with relapsed/refractory B-precursor ALL, and to assign utility values to these health states using time-trade off methodology. METHODS: This study was conducted in the UK in three phases. In the first phase, five health state descriptions were developed based on a recent clinical trial. The second phase validated the health state descriptions with clinicians and patients with experience of relapsed/refractory B-precursor ALL. The third phase involved prospective health state valuation using time-trade off methodology in a sample of the general public. The study was approved by the UK National Health Service Research Ethics Committee. RESULTS: In total, 123 participants were recruited and included in the final analysis; all participants gave written, informed consent. Complete remission was the most preferred health state (mean utility [SEM], 0.86 [0.01]), followed by complete remission with partial hematological recovery (with minimal risk of bleeding or developing infection) (0.75 [0.02]); aplastic bone marrow (0.59 [0.02]); partial remission (0.50 [0.03]); and progressive disease (0.30 [0.04]). CONCLUSIONS: This is the first study to report utility values for health states associated with relapsed/refractory B-precursor ALL. It was designed and conducted to align with NICE guidance on alternative methods for generating health state utility values when EQ-5D data are either unavailable or inappropriate. These utilities can be applied in future cost-effectiveness analyses of treatment for relapsed/refractory B-precursor ALL. PMID- 26573611 TI - Silencing of Gonad-Inhibiting Hormone Transcripts in Litopenaeus vannamei Females by use of the RNA Interference Technology. AB - The method usually employed to stimulate gonadal maturation and spawning of captive shrimp involves unilateral eyestalk ablation, which results in the removal of the endocrine complex responsible for gonad-inhibiting hormone (GIH) synthesis and release. In the present study, RNAi technology was used to inhibit transcripts of GIH in Litopenaeus vannamei females. The effect of gene silencing on gonad development was assessed by analyzing the expression of GIH and vitellogenin, respectively, in the eyestalk and ovaries of L. vannamei females, following ablation or injection with dsRNA-GIH, dsRNA-IGSF4D (non-related dsRNA), or saline solution. Histological analyses were performed to determine the stage of gonadal development and to assess the diameter of oocytes throughout the experimental procedure. Only oocytes at pre-vitellogenesis and primary vitellogenesis stages were identified in females injected with dsRNA-GIH, dsRNA IGSF4D, or saline solution. Oocytes at all developmental stages were observed in eyestalk-ablated females, with predominance of later stages, such as secondary vitellogenesis and mature oocytes. Despite achieving 64, 73, and 71% knockdown of eyestalk GIH mRNA levels by 15, 30, and 37 days post-injection (dpi), respectively, in dsRNA-GIH-injected females, the expected increase in ovary vitellogenin mRNA expression was only observed on the 37th dpi. This is the first report of the use of RNAi technology to develop an alternative method to eyestalk ablation in captive L. vannamei shrimps. PMID- 26573613 TI - Early effects of low dose bevacizumab treatment assessed by magnetic resonance imaging. AB - BACKGROUND: Antiangiogenic treatments have been shown to increase blood perfusion and oxygenation in some experimental tumors, and to reduce blood perfusion and induce hypoxia in others. The purpose of this preclinical study was to investigate the potential of dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) and diffusion weighted MRI (DW-MRI) in assessing early effects of low dose bevacizumab treatment, and to investigate intratumor heterogeneity in this effect. METHODS: A-07 and R-18 human melanoma xenografts, showing high and low expression of VEGF-A, respectively, were used as tumor models. Untreated and bevacizumab-treated tumors were subjected to DCE-MRI and DW-MRI before treatment, and twice during a 7-days treatment period. Tumor images of Ktrans (the volume transfer constant of Gd-DOTA) and ve (the fractional distribution volume of Gd DOTA) were produced by pharmacokinetic analysis of the DCE-MRI data, and tumor images of ADC (the apparent diffusion coefficient) were produced from DW-MRI data. RESULTS: Untreated A-07 tumors showed higher Ktrans, v e, and ADC values than untreated R-18 tumors. Untreated tumors showed radial heterogeneity in Ktrans, i.e., Ktrans was low in central tumor regions and increased gradually towards the tumor periphery. After the treatment, bevacizumab-treated A-07 tumors showed lower Ktrans values than untreated A-07 tumors. Peripherial tumor regions showed substantial reductions in Ktrans, whereas little or no effect was seen in central regions. Consequently, the treatment altered the radial heterogeneity in Ktrans. In R-18 tumors, significant changes in Ktrans were not observed. Treatment induced changes in tumor size, v e, and ADC were not seen in any of the tumor lines. CONCLUSIONS: Early effects of low dose bevacizumab treatment may be highly heterogeneous within tumors and can be detected with DCE-MRI. PMID- 26573612 TI - Functional analysis and transcriptional output of the Gottingen minipig genome. AB - BACKGROUND: In the past decade the Gottingen minipig has gained increasing recognition as animal model in pharmaceutical and safety research because it recapitulates many aspects of human physiology and metabolism. Genome-based comparison of drug targets together with quantitative tissue expression analysis allows rational prediction of pharmacology and cross-reactivity of human drugs in animal models thereby improving drug attrition which is an important challenge in the process of drug development. RESULTS: Here we present a new chromosome level based version of the Gottingen minipig genome together with a comparative transcriptional analysis of tissues with pharmaceutical relevance as basis for translational research. We relied on mapping and assembly of WGS (whole-genome shotgun sequencing) derived reads to the reference genome of the Duroc pig and predict 19,228 human orthologous protein-coding genes. Genome-based prediction of the sequence of human drug targets enables the prediction of drug cross reactivity based on conservation of binding sites. We further support the finding that the genome of Sus scrofa contains about ten-times less pseudogenized genes compared to other vertebrates. Among the functional human orthologs of these minipig pseudogenes we found HEPN1, a putative tumor suppressor gene. The genomes of Sus scrofa, the Tibetan boar, the African Bushpig, and the Warthog show sequence conservation of all inactivating HEPN1 mutations suggesting disruption before the evolutionary split of these pig species. We identify 133 Sus scrofa specific, conserved long non-coding RNAs (lncRNAs) in the minipig genome and show that these transcripts are highly conserved in the African pigs and the Tibetan boar suggesting functional significance. Using a new minipig specific microarray we show high conservation of gene expression signatures in 13 tissues with biomedical relevance between humans and adult minipigs. We underline this relationship for minipig and human liver where we could demonstrate similar expression levels for most phase I drug-metabolizing enzymes. Higher expression levels and metabolic activities were found for FMO1, AKR/CRs and for phase II drug metabolizing enzymes in minipig as compared to human. The variability of gene expression in equivalent human and minipig tissues is considerably higher in minipig organs, which is important for study design in case a human target belongs to this variable category in the minipig. The first analysis of gene expression in multiple tissues during development from young to adult shows that the majority of transcriptional programs are concluded four weeks after birth. This finding is in line with the advanced state of human postnatal organ development at comparative age categories and further supports the minipig as model for pediatric drug safety studies. CONCLUSIONS: Genome based assessment of sequence conservation combined with gene expression data in several tissues improves the translational value of the minipig for human drug development. The genome and gene expression data presented here are important resources for researchers using the minipig as model for biomedical research or commercial breeding. Potential impact of our data for comparative genomics, translational research, and experimental medicine are discussed. PMID- 26573614 TI - Frailty and Cognitive Impairment in ESRD: Brain-Body Connections. PMID- 26573615 TI - Frailty and Cognitive Function in Incident Hemodialysis Patients. AB - BACKGROUND AND OBJECTIVES: Patients of all ages undergoing hemodialysis (HD) have a high prevalence of cognitive impairment and worse cognitive function than healthy controls, and those with dementia are at high risk of death. Frailty has been associated with poor cognitive function in older adults without kidney disease. We hypothesized that frailty might also be associated with poor cognitive function in adults of all ages undergoing HD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: At HD initiation, 324 adults enrolled (November 2008 to July 2012) in a longitudinal cohort study (Predictors of Arrhythmic and Cardiovascular Risk in ESRD) were classified into three groups (frail, intermediately frail, and nonfrail) based on the Fried frailty phenotype. Global cognitive function (3MS) and speed/attention (Trail Making Tests A and B [TMTA and TMTB, respectively]) were assessed at cohort entry and 1-year follow-up. Associations between frailty and cognitive function (at cohort entry and 1-year follow-up) were evaluated in adjusted (for sex, age, race, body mass index, education, depression and comorbidity at baseline) linear (3MS, TMTA) and Tobit (TMTB) regression models. RESULTS: At cohort entry, the mean age was 54.8 years (SD 13.3), 56.5% were men, and 72.8% were black. The prevalence of frailty and intermediate frailty were 34.0% and 37.7%, respectively. The mean 3MS was 89.8 (SD 7.6), TMTA was 55.4 (SD 29), and TMTB was 161 (SD 83). Frailty was independently associated with lower cognitive function at cohort entry for all three measures (3MS: -2.4 points; 95% confidence interval [95% CI], -4.2 to -0.5; P=0.01; TMTA: 12.1 seconds; 95% CI, 4.7 to 19.4; P<0.001; and TMTB: 33.2 seconds; 95% CI, 9.9 to 56.4; P=0.01; all tests for trend, P<0.001) and with worse 3MS at 1-year follow-up (-2.8 points; 95% CI, -5.4 to -0.2; P=0.03). CONCLUSIONS: In adult incident HD patients, frailty is associated with worse cognitive function, particularly global cognitive function (3MS). PMID- 26573616 TI - Low-dose CT coronary angiography for assessment of coronary artery disease in patients with type 2 diabetes--a cross-sectional study. AB - BACKGROUND: Silent coronary artery disease (CAD) is prevalent in type 2 diabetes mellitus (T2DM). Although coronary computed tomography angiography (CCTA) over recent years has emerged a useful tool for assessing and diagnosing CAD it's role and applicability for patients with T2DM is still unclarified, in particular in asymptomatic patients. We aimed to assess the role of CCTA in detecting and characterizing CAD in patients with T2DM without cardiac symptoms when compared to gold standard invasive coronary angiography (ICA). METHODS: This was a cross sectional analysis of patients with T2DM without symptomatic CAD enrolled in the Asker and Baerum Cardiovascular Diabetes Study who, following clinical examination and laboratory assessment, underwent subsequently CCTA and ICA. RESULTS: In total 48 Caucasian patients with T2DM (36 men, age 64.0 +/- 7.3 years, diabetes duration 14.6 +/- 6.4 years, HbA1c 7.4 +/- 1.1 %, BMI 29.6 +/- 4.3 kg/m(2)) consented to, and underwent, both procedures (CCTA and ICA). The population was at intermediate cardiovascular risk (mean coronary artery calcium score 269, 75 % treated with antihypertensive therapy). ICA identified a prevalence of silent CAD at 17 % whereas CCTA 35 %. CCTA had a high sensitivity (100 %) and a high negative predictive value (100 %) for detection of patients with CAD when compared to ICA, but the positive predictive value was low (47 %). CONCLUSIONS: Low-dose CCTA is a reliable method for detection and exclusion of significant CAD in T2DM and thus may be a useful tool for the clinicians. However, a low positive predictive value may limit its usefulness as a screening tool for all CAD asymptomatic patients with T2DM. Further studies should assess the applicability for risk assessment beyond the evaluation of the vascular bed. PMID- 26573617 TI - High prevalence of oxacillinases in clinical multidrug-resistant Acinetobacter baumannii isolates from the Tshwane region, South Africa - an update. AB - BACKGROUND: Acinetobacter baumannii is an important hospital-acquired pathogen in healthcare facilities that frequently causes bacteraemia and ventilator associated pneumonia in intensive care units. Acinetobacter baumannii can be isolated from various sites in the hospital environment like medical equipment, bed linen, medical personnel and indwelling catheters. It is difficult to treat A. baumannii infections because of their highly resistant antimicrobial profiles. The purpose of this study was to determine the prevalence of beta-lactamase genes in multidrug-resistant (MDR) clinical A. baumannii isolates using Multiplex-PCR (M-PCR) assays. METHODS: One hundred MDR A. baumannii isolates were collected from the diagnostic division of the Department of Medical Microbiology after routine analysis of the submitted specimens. All collected isolates were identified and tested for susceptibility using the VITEK 2(r) system (bioMerieux, France). Six isolates were excluded from this study because the isolates were incorrectly identified as A. baumannii with the VITEK 2(r) system (bioMerieux, France). Molecular tests, namely M-PCR assays, pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) were performed. MLST analyses were performed on representative isolates from the four major pulsotypes (>=5 isolates with 80 % similarity) and selective isolates from each minor pulsotype. RESULTS: All the A. baumannii isolates showed 100 % resistance to ampicillin, amoxicillin, cefuroxime, cefuroximine axetil, cefoxitin, cefotaxime and nitrofurantoin. Seven percent of the isolates were resistant to amikacin. Two percent of the isolates were classified as having intermediate susceptibility to tigecycline. A. baumannii isolates showed an antibiotic resistance profile of 67 % and higher to antibiotics, such as ceftazidime, cefepime, imipenem, meropenem, gentamicin, ciprofloxacin and trimethoprim/sulfamethoxazole. None of the isolates were resistant to colistin. The M-PCR assays showed that 99 % of the isolates contained the OXA-51 gene and 77 % contained the OXA-23 gene. None of the isolates contained the GES, GIM, IMP, KPC, NDM, OXA-24, OXA-58, PER, SIM, SPM, VEB and VIM genes. Representative A. baumannii isolates were grouped into five existing sequence types (ST): ST106, ST258, ST339, ST502, ST758 and ST848. Isolates belonging to the pan-European clonal lineages I and II (EUI and EUII) were identified. CONCLUSION: The high prevalence of MDR A. baumannii isolates has a severe impact on available treatment choices and this in return impacts on treatment outcomes in the studied healthcare facilities. The most dominant ST among the collected isolates was ST758, member of the EUI group. The presence of the OXA-23 gene was not restricted to a specific ST. Continuous research and surveillance is necessary to monitor the circulating beta-lactamase genes in clinical settings to guide infection control policies in order to try and curb the spread of this bacterium. PMID- 26573618 TI - A survey on HIV-related health-seeking behaviors among transgender individuals in Jakarta, based on the theory of planned behavior. AB - BACKGROUND: Male-to-female transgender (waria) individuals are at high risk for HIV. This study aims at mapping the psychological determinants of four HIV related health-seeking behaviors. This knowledge can be used to develop effective interventions to prevent the spread of HIV/AIDS. METHODS: The study involved 209 waria from five districts in Jakarta, selected with a cluster sampling procedure. Cross-sectional data were gathered through structured interviews. The four examined behaviors are, visiting sexually transmitted infections (STIs) services regularly, adherence to STI treatment, taking an HIV test and picking up the result of HIV test. For all four behaviors, specific measures of the psychological determinants as defined by the Theory of Planned Behavior were developed: attitudes, subjective norms and perceived behavioral control (PBC). Logistic regression analyses were conducted with these three psychological measures as independent variables and the behaviors as dependent variables. RESULTS: Of the 209 waria, 20.6 % had never visited STI services in the last 6 months, while 56.5 % had visited the services once or twice, and 23 % had visited the service three or more times. A HIV test had been taken by 90.4 % of the waria, and of those, 64.6 % had picked up the results. About 85 % of the waria who did a HIV test had been tested for HIV one or two times in the last 6 months and 10 % had been tested three to four times. The variance in behaviors that was explained by the concepts defined in the Theory of Planned Behavior ranged from 15 to 70 %; PBC was the most powerful predictor. Furthermore, the results showed that in several cases the relationships of attitudes or subjective norms with the dependent variable were mediated by one or both other independent variables. CONCLUSIONS: The results regarding the prominent role of PBC suggest that interventions should increase waria's control over the behavior: Engaging in specific desired behaviors should be made easier for them. Besides, waria's attitudes and subjective norms should be addressed, by education, but possibly also by providing waria with a positive experience with the behavior, for example, by designing a professional and friendly health care system. PMID- 26573619 TI - EWS and FUS bind a subset of transcribed genes encoding proteins enriched in RNA regulatory functions. AB - BACKGROUND: FUS (TLS) and EWS (EWSR1) belong to the FET-protein family of RNA and DNA binding proteins. FUS and EWS are structurally and functionally related and participate in transcriptional regulation and RNA processing. FUS and EWS are identified in translocation generated cancer fusion proteins and involved in the human neurological diseases amyotrophic lateral sclerosis and fronto-temporal lobar degeneration. RESULTS: To determine the gene regulatory functions of FUS and EWS at the level of chromatin, we have performed chromatin immunoprecipitation followed by next generation sequencing (ChIP-seq). Our results show that FUS and EWS bind to a subset of actively transcribed genes, that binding often is downstream the poly(A)-signal, and that binding overlaps with RNA polymerase II. Functional examinations of selected target genes identified that FUS and EWS can regulate gene expression at different levels. Gene Ontology analyses showed that FUS and EWS target genes preferentially encode proteins involved in regulatory processes at the RNA level. CONCLUSIONS: The presented results yield new insights into gene interactions of EWS and FUS and have identified a set of FUS and EWS target genes involved in pathways at the RNA regulatory level with potential to mediate normal and disease-associated functions of the FUS and EWS proteins. PMID- 26573620 TI - Is there malaria transmission in urban settings in Colombia? AB - BACKGROUND: Colombia contributes a significant proportion of malaria cases in the Americas, which are predominantly rural. However, in the last 8 years ~ 10 % of the endemic municipalities have also reported urban and peri-urban malaria cases, a growing concern for health authorities. This study focused on the characterization of the officially reported urban malaria cases. METHODS: A descriptive retrospective study based on secondary information provided by the Colombian National Surveillance System-SIVIGILA for the 2008-2012 period was conducted. A total of 17 municipalities with consistent and persistent reports of urban and peri-urban malaria were selected for analysis, which included site of origin and of residence, age, gender and ethnicity of patients, health system affiliation, Plasmodium species and the presence of malaria vectors. RESULTS: A total of 18,113 malaria cases were reported from urban and peri-urban areas of 17 endemic municipalities. Almost 70 % of the reports originated in localities in the departments of Choco and Narino, located on the Pacific Coast where a predominantly Afro-Colombian population, of individuals of under 30 years of age, was the most affected (80.7 %), mainly with Plasmodium falciparum infections (52.1 %). Median annual parasite index (API) was 6.4 per 1000 inhabitants (3.4 in 2008; 10.8 in 2010 and 6.0 in 2012). Between 2011 and 2012 complicated cases (2.4 %) and malaria in pregnant women (1.4 %) were reported. Study areas reported the presence of at least seven Anopheles species considered malaria vectors. These analyses did not allow ascertaining the presumable origin of the recorded urban cases due to the lack of a consensus on a definition of urban, peri-urban and rural limits and the lack of proper verification of the geographical source of infection. CONCLUSIONS: The study indicates the probable presence of endemic, unstable and low-intensity malaria transmission in Colombian urban and peri-urban areas of a group of municipalities located mainly on the Pacific coast region and a few others in the eastern region. There is a need to unequivocally confirm the urban or peri-urban origin of the malaria cases reported and the transmission conditions, as well as to develop and implement new strategies for urban and peri urban malaria control and elimination. PMID- 26573621 TI - Is neutrophil gelatinase-associated lipocalin unaffected by convective continuous renal replacement therapy? Definitely ... maybe. PMID- 26573623 TI - Correction: S1-S3 counter charges in the voltage sensor module of a mammalian sodium channel regulate fast inactivation. PMID- 26573622 TI - Asymmetric protonation of EmrE. AB - The small multidrug resistance transporter EmrE is a homodimer that uses energy provided by the proton motive force to drive the efflux of drug substrates. The pKa values of its "active-site" residues--glutamate 14 (Glu14) from each subunit- must be poised around physiological pH values to efficiently couple proton import to drug export in vivo. To assess the protonation of EmrE, pH titrations were conducted with (1)H-(15)N TROSY-HSQC nuclear magnetic resonance (NMR) spectra. Analysis of these spectra indicates that the Glu14 residues have asymmetric pKa values of 7.0 +/- 0.1 and 8.2 +/- 0.3 at 45 degrees C and 6.8 +/- 0.1 and 8.5 +/- 0.2 at 25 degrees C. These pKa values are substantially increased compared with typical pKa values for solvent-exposed glutamates but are within the range of published Glu14 pKa values inferred from the pH dependence of substrate binding and transport assays. The active-site mutant, E14D-EmrE, has pKa values below the physiological pH range, consistent with its impaired transport activity. The NMR spectra demonstrate that the protonation states of the active-site Glu14 residues determine both the global structure and the rate of conformational exchange between inward- and outward-facing EmrE. Thus, the pKa values of the asymmetric active-site Glu14 residues are key for proper coupling of proton import to multidrug efflux. However, the results raise new questions regarding the coupling mechanism because they show that EmrE exists in a mixture of protonation states near neutral pH and can interconvert between inward- and outward-facing forms in multiple different protonation states. PMID- 26573625 TI - Perplexing new insight into the dynamics of the EmrE transporter. PMID- 26573624 TI - A general mechanism for drug promiscuity: Studies with amiodarone and other antiarrhythmics. AB - Amiodarone is a widely prescribed antiarrhythmic drug used to treat the most prevalent type of arrhythmia, atrial fibrillation (AF). At therapeutic concentrations, amiodarone alters the function of many diverse membrane proteins, which results in complex therapeutic and toxicity profiles. Other antiarrhythmics, such as dronedarone, similarly alter the function of multiple membrane proteins, suggesting that a multipronged mechanism may be beneficial for treating AF, but raising questions about how these antiarrhythmics regulate a diverse range of membrane proteins at similar concentrations. One possible mechanism is that these molecules regulate membrane protein function by altering the common environment provided by the host lipid bilayer. We took advantage of the gramicidin (gA) channels' sensitivity to changes in bilayer properties to determine whether commonly used antiarrhythmics--amiodarone, dronedarone, propranolol, and pindolol, whose pharmacological modes of action range from multi target to specific--perturb lipid bilayer properties at therapeutic concentrations. Using a gA-based fluorescence assay, we found that amiodarone and dronedarone are potent bilayer modifiers at therapeutic concentrations; propranolol alters bilayer properties only at supratherapeutic concentration, and pindolol has little effect. Using single-channel electrophysiology, we found that amiodarone and dronedarone, but not propranolol or pindolol, increase bilayer elasticity. The overlap between therapeutic and bilayer-altering concentrations, which is observed also using plasma membrane-like lipid mixtures, underscores the need to explore the role of the bilayer in therapeutic as well as toxic effects of antiarrhythmic agents. PMID- 26573626 TI - Understanding The Role of Mate Selection Processes in Couples' Pair-Bonding Behavior. AB - Couples are similar in their pair-bonding behavior, yet the reasons for this similarity are often unclear. A common explanation is phenotypic assortment, whereby individuals select partners with similar heritable characteristics. Alternatively, social homogamy, whereby individuals passively select partners with similar characteristic due to shared social backgrounds, is rarely considered. We examined whether phenotypic assortment and/or social homogamy can contribute to mate similarity using a twin-partner design. The sample came from the Twin and Offspring Study in Sweden, which included 876 male and female monozygotic and same-sex dizygotic twins plus their married or cohabitating partners. Results showed that variance in pair-bonding behavior was attributable to genetic and nonshared environmental factors. Furthermore, phenotypic assortment accounted for couple similarity in pair-bonding behavior. This suggests that individuals' genetically based characteristics are involved in their selection of mates with similar pair-bonding behavior. PMID- 26573627 TI - Recent Advances in Cerebellar Ischemic Stroke Syndromes Causing Vertigo and Hearing Loss. AB - Cerebellar ischemic stroke is one of the common causes of vascular vertigo. It usually accompanies other neurological symptoms or signs, but a small infarct in the cerebellum can present with vertigo without other localizing symptoms. Approximately 11 % of the patients with isolated cerebellar infarction simulated acute peripheral vestibulopathy, and most patients had an infarct in the territory of the medial branch of the posterior inferior cerebellar artery (PICA). A head impulse test can differentiate acute isolated vertigo associated with PICA territory cerebellar infarction from more benign disorders involving the inner ear. Acute hearing loss (AHL) of a vascular cause is mostly associated with cerebellar infarction in the territory of the anterior inferior cerebellar artery (AICA), but PICA territory cerebellar infarction rarely causes AHL. To date, at least eight subgroups of AICA territory infarction have been identified according to the pattern of neurotological presentations, among which the most common pattern of audiovestibular dysfunction is the combined loss of auditory and vestibular functions. Sometimes acute isolated audiovestibular loss can be the initial symptom of impending posterior circulation ischemic stroke (particularly within the territory of the AICA). Audiovestibular loss from cerebellar infarction has a good long-term outcome than previously thought. Approximately half of patients with superior cerebellar artery territory (SCA) cerebellar infarction experienced true vertigo, suggesting that the vertigo and nystagmus in the SCA territory cerebellar infarctions are more common than previously thought. In this article, recent findings on clinical features of vertigo and hearing loss from cerebellar ischemic stroke syndrome are summarized. PMID- 26573628 TI - Adult left-ventricular diverticulum and patent ductus arteriosus misdiagnosed as coronary artery disease with infarct aneurysm: a case report. AB - BACKGROUND: Left-ventricular diverticulum (LD) associated with patent ductus arteriosus (PDA) is extremely rare. We have not found any previous reports of the coexistence of these two malformations. Such an association presenting with chest pain mimicking an infarct aneurysm with angina or a takotsubo cardiomyopathy with chest pain is difficult to differentiate clinically. Here, we discuss several diseases characterized by left-ventricular apical protrusion with chest pain to familiarize clinicians with the differential diagnosis of these diseases. CASE PRESENTATION: A 58-year-old woman was referred to our hospital because of complaints of chest pain and dyspnoea, mainly on exertion. An electrocardiograph on admission showed a q-wave in lead I, a Q-wave in lead aVL, and an abnormal T wave in the limb leads and leads V4 to V6. A transthoracic echocardiograph revealed a PDA and a protrusion arising from the apex of the left ventricle. The diagnosis on admission was PDA and coronary artery disease with infarct aneurysm. To evaluate the source of the chest pain, further evaluations were performed. Coronary angiography showed no abnormal findings. Left ventriculography confirmed the presence of an apical contractile out-pouching. Based on these findings, we revised the diagnosis as LD associated with PDA. The patient underwent transcatheter occlusion of the PDA and was discharged 3 days later. Unexpectedly, transcatheter occlusion resolved the paroxysmal chest pain in this case. CONCLUSION: This is the first case report of LD combined with PDA. PDA should be considered in the list of differential diagnosis of chest pain. Several diseases characterized by left-ventricular apical protrusion with chest pain, such as LD, infarct aneurysm and takotsubo cardiomyopathy, can be misdiagnosed as one another. Therefore, it is important to familiarize clinicians with the differential diagnosis of these diseases. PMID- 26573629 TI - Evaluation of sensitivity and specificity of ELISA against Widal test for typhoid diagnosis in endemic population of Kathmandu. AB - BACKGROUND: Widal test, which has poor predictive outcomes in predominant typhoid population, is not standard enough to predict accurate diagnosis. This study aims to compare the diagnostic accuracy of Widal test to ELISA using blood culture as gold standard. METHODS: The blood samples were collected in Capital Hospital, Kathmandu, Nepal from febrile patients having >=48 h fever in 3 years study period for blood culture, Widal test and IgG-IgM ELISA. RESULTS: Amongst 1371 febrile cases, 237 were Salmonella typhi positive to blood culture and 71.4 % typhoid fever patient were of 46-60 years old with male to female ratio of 2:1. Blood culture confirmed patients had >=1:40 anti-TH and anti-TO titre in 45.56 % (n = 108) and 43.88 % (n = 104) patients respectively. The sensitivity and specificity of IgG (0.96 and 0.95) and IgM (0.95 and 0.94) at 95 % confidence level were significant compared to Widal anti-TH (0.72 and 0.58) and TO (0.80 and 0.51) test (p value, 0.038) at titre level >=1:200. Further the PPV of Widal TH and TO (0.38 and 0.23) was low compared to IgG and IgM ELISA (0.78 and 0.77) (p value, 0.045). CONCLUSION: Widal test is not sensitive enough for an endemic setting like Nepal and thus should be either replaced with more accurate test like ELISA or follow an alternative diagnostic methodology. PMID- 26573631 TI - Expansion of presoldier cuticle contributes to head elongation during soldier differentiation in termites. AB - In termites, the soldier caste possesses morphological features suitable for colony defence, despite some exceptions. Soldiers are differentiated via two moultings through a presoldier stage with dramatic morphogenesis. While a number of morphological modifications are known to occur during the presoldier moult, growth and morphogenesis seem to continue even after the moult. The present study, using the damp-wood termite Hodotermopsis sjostedti, carried out morphological and histological investigations on the developmental processes during the presoldier stage that is artificially induced by the application of a juvenile hormone analogue. Measurements of five body parameters indicated that head length significantly increased during the 14-day period after the presoldier moult, while it did not increase subsequently to the stationary moult (pseudergate moult as control). Histological observations also showed that the cuticular development played a role in the presoldier head elongation, suggesting that the soft and flexible presoldier cuticle contributed to the soldier morphogenesis in termites. PMID- 26573630 TI - Personalizing blood pressure management in septic shock. AB - This review examines the available evidence for targeting a specific mean arterial pressure (MAP) in sepsis resuscitation. The clinical data suggest that targeting an MAP of 65-70 mmHg in patients with septic shock who do not have chronic hypertension is a reasonable first approximation. Whereas in patients with chronic hypertension, targeting a higher MAP of 80-85 mmHg minimizes renal injury, but it comes with increased risk of arrhythmias. Importantly, MAP alone should not be used as a surrogate of organ perfusion pressure, especially under conditions in which intracranial, intra-abdominal or tissue pressures may be elevated. Organ-specific perfusion pressure targets include 50-70 mmHg for the brain based on trauma brain injury as a surrogate for sepsis, 65 mmHg for renal perfusion and >50 mmHg for hepato-splanchnic flow. Even at the same MAP, organs and regions within organs may have different perfusion pressure and pressure-flow relationships. Thus, once this initial MAP target is achieved, MAP should be titrated up or down based on the measures of organ function and tissue perfusion. PMID- 26573632 TI - Evaluating an online training module on protecting children from secondhand smoke exposure: impact on knowledge, confidence and self-reported practice of health and social care professionals. AB - BACKGROUND: Healthcare professionals report that a lack of training is the primary barrier to raising the issue of secondhand smoke (SHS). An open access online training module was therefore developed for those working with smoking families to deliver effective very brief advice on SHS. The current study aimed to evaluate the following: (1) does knowledge increase as a result of participating in the online training module, and (2) does the module impact on participant confidence and self-reported practice relating to SHS. METHODS: Those accessing the module were invited to participate in an evaluation to assess participants' knowledge about, and confidence in, delivering very brief advice on SHS. Change in knowledge was assessed via ten multiple choice questions and confidence was assessed by Likert scale responses to three statements. Data were collected across three time points: pre-training, post-training and after 3 months. Data were also collected at 3 months post module completion on self reported changes in practice and key learning points. RESULTS: Data at all three time points were available for 178 participants (~1 % of those who visited the module homepage over a 2 year period). Knowledge and confidence to deliver effective very brief advice for SHS significantly increased between the pre- and post-training assessments and was maintained at 3 months. Eighty-four percent self-reported that they perceived taking part in the training had led to positive changes in their clinical practice. CONCLUSIONS: There is potential for this module to be embedded within training programmes across health and social care professions, which may help to increase the knowledge and confidence of health and social care professionals to deliver very brief advice for SHS to smoking families. Future research needs to explore whether the smoking families who receive very brief advice for SHS are motivated to make changes to their home smoking behaviours and whether roll-out of this intervention would be cost effective. PMID- 26573634 TI - Effects of Soluble Phosphate on Phosphate-Solubilizing Characteristics and Expression of gcd Gene in Pseudomonas frederiksbergensis JW-SD2. AB - Phosphate-solubilizing bacteria have the ability of solubilizing mineral phosphate in soil and promoting growth of plants, but the activity of phosphate solubilization is influenced by exogenous soluble phosphate. In the present study, the effects of soluble phosphate on the activity of phosphate solubilization, acidification of media, growth, and organic acid secretion of phosphate-solubilizing bacterium Pseudomonas frederiksbergensis JW-SD2 were investigated under six levels of soluble phosphate conditions. The activity of phosphate solubilization decreased with the increase of soluble phosphate concentration, accompanying with the increase of media pH. However, the growth was promoted by adding soluble phosphate. Production of gluconic, tartaric, and oxalic acids by the strain was reduced with the increase of concentration of soluble phosphate, while acetic and pyruvic acids showed a remarkable increase. Gluconic acid predominantly produced by the strain at low levels of soluble phosphate showed that this acid was the most efficient organic acid in phosphate solubilization. Pyrroloquinoline quinone-glucose dehydrogenase gene gcd (pg5SD2) was cloned from the strain, and the expressions of pg5SD2 gene were repressed gradually with the increase of concentration of soluble phosphate. The soluble phosphate regulating the transcription of the gcd gene is speculated to underlie the regulation of the secretion of gluconic acid and subsequently the regulation of the activity of phosphate solubilization. Future research needs to consider a molecular engineering strategy to reduce the sensitivity of PSB strain to soluble phosphate via modification of the regulatory mechanism of gcd gene, which could improve the scope of PSB strains' application. PMID- 26573633 TI - Pain-related Somato Sensory Evoked Potentials: a potential new tool to improve the prognostic prediction of coma after cardiac arrest. AB - INTRODUCTION: Early prediction of a good outcome in comatose patients after cardiac arrest still remains an unsolved problem. The main aim of the present study was to examine the accuracy of middle-latency SSEP triggered by a painful electrical stimulation on median nerves to predict a favorable outcome. METHODS: No- and low-flow times, pupillary reflex, Glasgow motor score and biochemical data were evaluated at ICU admission. The following were considered within 72 h of cardiac arrest: highest creatinine value, hyperthermia occurrence, EEG, SSEP at low- (10 mA) and high-intensity (50 mA) stimulation, and blood pressure reactivity to 50 mA. Intensive care treatments were also considered. Data were compared to survival, consciousness recovery and 6-month CPC (Cerebral Performance Category). RESULTS: Pupillary reflex and EEG were statistically significant in predicting survival; the absence of blood pressure reactivity seems to predict brain death within 7 days of cardiac arrest. Middle- and short latency SSEP were statistically significant in predicting consciousness recovery, and middle-latency SSEP was statistically significant in predicting 6-month CPC outcome. The prognostic capability of 50 mA middle-latency-SSEP was demonstrated to occur earlier than that of EEG reactivity. CONCLUSIONS: Neurophysiological evaluation constitutes the key to early information about the neurological prognostication of postanoxic coma. In particular, the presence of 50 mA middle latency SSEP seems to be an early and reliable predictor of good neurological outcome, and its absence constitutes a marker of poor prognosis. Moreover, the absence 50 mA blood pressure reactivity seems to identify patients evolving towards the brain death. PMID- 26573635 TI - Genome sequence analysis of a flocculant-producing bacterium, Paenibacillus shenyangensis. AB - OBJECTIVE: To explore the metabolic process of Paenibacillus shenyangensis that is an efficient bioflocculant-producing bacterium. The biosynthesis mechanism of bioflocculation was used to enrich the genome of Paenibacillus shenyangensis and provide a basis for molecular genetics and functional genomics analyses. RESULTS: According to the analysis of de novo assembly, a total of 5,501,467 bp clean reads were generated, and were assembled into 92 contigs. 4800 unigenes were predicted of which 4393 were annotated showing a specific gene function in the NCBI-Nr database. 3423 genes were found in the database of cluster of orthologous groups. Among the 168 Kyoto Encyclopedia of Genes and Genomes database, cell growth and metabolism were the main biological processes, and a potential metabolic pathway was predicted from glucose to exopolysaccharide within the starch and sucrose metabolism pathway. CONCLUSION: By using the high-throughput sequencing technology, we provide a genome analysis of Paenibacillus shenyangensis that predicts the main metabolic processes and a potential pathway of exopolysaccharide biosynthesis. PMID- 26573636 TI - Comment on "Production of 2-butanol from crude glycerol by a genetically engineered Klebsiella pneumoniae strain [Oh et al., Biotechnol Lett (2014) 36:57 62]". PMID- 26573637 TI - Functional analysis of alcohol dehydrogenase (ADH) genes in Pichia pastoris. AB - OBJECTIVES: To characterize the genes responsible for ethanol utilization in Pichia pastoris. RESULTS: ADH3 (XM_002491337) and ADH (FN392323) genes were disrupted in P. pastoris. The ADH3 mutant strain, MK115 (Deltaadh3), lost its ability to grow on minimal ethanol media but produced ethanol in minimal glucose medium. ADH3p was responsible for 92 % of total Adh enzyme activity in glucose media. The double knockout strain MK117 (Deltaadh3Deltaadh) also produced ethanol. The Adh activities of X33 and MK116 (Deltaadh) strains were not different. Thus, the ADH gene does not play a role in ethanol metabolism. CONCLUSION: The PpADH3 is the only gene responsible for consumption of ethanol in P. pastoris. PMID- 26573638 TI - Prevalence, topographic and morphometric features of femoral cam-type deformity: changes in relation to age and gender. AB - Femoroacetabular impingement (FAI) syndrome is a frequent cause of pain and in recent years considered to be a precursor of premature hip osteoarthritis. The structural abnormalities which characterize FAI syndrome, such as the cam-type deformity, are associated with morphological alterations that may lead to hip osteoarthritis. The aim of this study was to determine the prevalence and topographic and morphometric features of the cam deformity in a series of 326 femur specimens obtained from a Mexican population, as well as changes in prevalence in relation to age and gender. The specimens were subdivided into groups according to gender and age. A standardized photograph of the proximal femur of each specimen was taken, and the photograph was used to determine the alpha angle using a computer program; the location of the lesion was determined by quadrant and the morphometric characteristics were determined by direct observation. The overall prevalence of cam deformities in the femur specimens was 29.8 % (97/326), with a prevalence by gender of 35.2 % (64/182) in men and 22.9 % (33/144) in women. The mean alpha angle was 54.6 degrees +/- 8.5 degrees in all of the osteological specimens and 65.6 degrees +/- 7.5 degrees in those specimens exhibiting a cam deformity. Cam deformities were found topographically in the anterior-superior quadrant of the femoral head-neck junction in 86.6 % (84/97) of the femurs. Deformities were found in 28.2 % of the right femurs and 31.3 % of the left femurs. The prevalence of cam deformity was higher in the femur specimens of young men and in those of middle-aged and older women. There were no significant differences in this deformity in relation to the alpha angle according to age and gender. PMID- 26573639 TI - A Study on the Secure User Profiling Structure and Procedure for Home Healthcare Systems. AB - Despite of various benefits such as a convenience and efficiency, home healthcare systems have some inherent security risks that may cause a serious leak on personal health information. This work presents a Secure User Profiling Structure which has the patient information including their health information. A patient and a hospital keep it at that same time, they share the updated data. While they share the data and communicate, the data can be leaked. To solve the security problems, a secure communication channel with a hash function and an One-Time Password between a client and a hospital should be established and to generate an input value to an OTP, it uses a dual hash-function. This work presents a dual hash function-based approach to generate the One-Time Password ensuring a secure communication channel with the secured key. In result, attackers are unable to decrypt the leaked information because of the secured key; in addition, the proposed method outperforms the existing methods in terms of computation cost. PMID- 26573640 TI - What is Your Risk of Contracting Alzheimer's Disease? A Telematics Tool Helps you to Predict it. AB - Alzheimer's disease (AD) is the most common dementia in developed countries. Between the identified risk factors, one of the most important is the age. Its prevalence reaches 24 % in men and 33 % in women over 85 years. Increase in life expectancy, making it a serious public health problem. Prevention of Alzheimer's disease represents a major challenge to health. Given that Alzheimer's disease is largely dependent on the genetics of each person and uninterrupted progress of the age, which is try to make people aware that there are other factors that can alter your chance of developing the Alzheimer disease and although currently not reduce, help is not increased in the near or distant future.The aim of this paper is to develop and evaluate a Web-Mobile application (Alzhe Alert) used to calculate the risk of Alzheimer's from a short questionnaire using a computer or mobile device, so that any user, without requiring computer skills, can access the website to estimate their risk of developing the disease in the coming years depending on their habits and daily basis activities. The users who have realized the questionnaire can to observe in a graph the result, and they will know which is at risk for Alzheimer's at present and over the next 50 years if they continue with the same habits and lifestyle. The objective is that the users can be aware of the risk they have different habits of life about their health. Currently, 243 users (84 women and 159 men) of white race have completed the questionnaire. 76 % of the users have got a risk below the average. PMID- 26573641 TI - Using RFID Positioning Technology to Construct an Automatic Rehabilitation Scheduling Mechanism. AB - Accurately and efficiently identifying the location of patients during the course of rehabilitation is an important issue. Wireless transmission technology can reach this goal. Tracking technologies such as RFID (Radio frequency identification) can support process improvement and improve efficiencies of rehabilitation. There are few published models or methods to solve the problem of positioning and apply this technology in the rehabilitation center. We propose a mechanism to enhance the accuracy of positioning technology and provide information about turns and obstacles on the path; and user-centered services based on location-aware to enhanced quality care in rehabilitation environment. This paper outlines the requirements and the role of RFID in assisting rehabilitation environment. A prototype RFID hospital support tool is established. It is designed to provide assistance for monitoring rehabilitation patients. It can simultaneously calculate the rehabilitant's location and the duration of treatment, and automatically record the rehabilitation course of the rehabilitant, so as to improve the management efficiency of the rehabilitation program. PMID- 26573642 TI - A Novel Framework for Medical Web Information Foraging Using Hybrid ACO and Tabu Search. AB - We present in this paper a novel approach based on multi-agent technology for Web information foraging. We proposed for this purpose an architecture in which we distinguish two important phases. The first one is a learning process for localizing the most relevant pages that might interest the user. This is performed on a fixed instance of the Web. The second takes into account the openness and dynamicity of the Web. It consists on an incremental learning starting from the result of the first phase and reshaping the outcomes taking into account the changes that undergoes the Web. The system was implemented using a colony of artificial ants hybridized with tabu search in order to achieve more effectiveness and efficiency. To validate our proposal, experiments were conducted on MedlinePlus, a real website dedicated for research in the domain of Health in contrast to other previous works where experiments were performed on web logs datasets. The main results are promising either for those related to strong Web regularities and for the response time, which is very short and hence complies the real time constraint. PMID- 26573643 TI - Improvement of the Prediction of Drugs Demand Using Spatial Data Mining Tools. AB - The continued availability of products at any store is the major issue in order to provide good customer service. If the store is a drugstore this matter reaches a greater importance, as out of stock of a drug when there is high demand causes problems and tensions in the healthcare system. There are numerous studies of the impact this issue has on patients. The lack of any drug in a pharmacy in certain seasons is very common, especially when some external factors proliferate favoring the occurrence of certain diseases. This study focuses on a particular drug consumed in the city of Jaen, southern Andalucia, Spain. Our goal is to determine in advance the Salbutamol demand. Advanced data mining techniques have been used with spatial variables. These last have a key role to generate an effective model. In this research we have used the attributes that are associated with Salbutamol demand and it has been generated a very accurate prediction model of 5.78% of mean absolute error. This is a very encouraging data considering that the consumption of this drug in Jaen varies 500% from one period to another. PMID- 26573644 TI - Synchronization Design and Error Analysis of Near-Infrared Cameras in Surgical Navigation. AB - The accuracy of optical tracking systems is important to scientists. With the improvements reported in this regard, such systems have been applied to an increasing number of operations. To enhance the accuracy of these systems further and to reduce the effect of synchronization and visual field errors, this study introduces a field-programmable gate array (FPGA)-based synchronization control method, a method for measuring synchronous errors, and an error distribution map in field of view. Synchronization control maximizes the parallel processing capability of FPGA, and synchronous error measurement can effectively detect the errors caused by synchronization in an optical tracking system. The distribution of positioning errors can be detected in field of view through the aforementioned error distribution map. Therefore, doctors can perform surgeries in areas with few positioning errors, and the accuracy of optical tracking systems is considerably improved. The system is analyzed and validated in this study through experiments that involve the proposed methods, which can eliminate positioning errors attributed to asynchronous cameras and different fields of view. PMID- 26573645 TI - Outcome Prediction in Clinical Treatment Processes. AB - Clinical outcome prediction, as strong implications for health service delivery of clinical treatment processes (CTPs), is important for both patients and healthcare providers. Prior studies typically use a priori knowledge, such as demographics or patient physical factors, to estimate clinical outcomes at early stages of CTPs (e.g., admission). They lack the ability to deal with temporal evolution of CTPs. In addition, most of the existing studies employ data mining or machine learning methods to generate a prediction model for a specific type of clinical outcome, however, a mathematical model that predicts multiple clinical outcomes simultaneously, has not yet been established. In this study, a hybrid approach is proposed to provide a continuous predictive monitoring service on multiple clinical outcomes. More specifically, a probabilistic topic model is applied to discover underlying treatment patterns of CTPs from electronic medical records. Then, the learned treatment patterns, as low-dimensional features of CTPs, are exploited for clinical outcome prediction across various stages of CTPs based on multi-label classification. The proposal is evaluated to predict three typical classes of clinical outcomes, i.e., length of stay, readmission time, and the type of discharge, using 3492 pieces of patients' medical records of the unstable angina CTP, extracted from a Chinese hospital. The stable model was characterized by 84.9% accuracy and 6.4% hamming-loss with 3 latent treatment patterns discovered from data, which outperforms the benchmark multi-label classification algorithms for clinical outcome prediction. Our study indicates the proposed approach can potentially improve the quality of clinical outcome prediction, and assist physicians to understand the patient conditions, treatment inventions, and clinical outcomes in an integrated view. PMID- 26573646 TI - Handheld Electronic Device Use by Pediatric Hospitalists on Family Centered Rounds. AB - Physicians increasingly use handheld electronic devices (HED) to assist in daily work activities. The objectives of our study were to describe the practice patterns of pediatric hospitalists in the use of HED during daily work activities and Family Centered Rounds (FCR). We also examined perceptions of pediatric hospitalists on benefits and barriers of these devices on trainee education and family/patient interactions. An anonymous cross-sectional survey was sent to the American Academy of Pediatrics' Section on Hospital Medicine Listserv between October-November 2012, to determine pediatric hospitalists usage and attitudes of HED on FCR. A total of 140 Listserv members responded. Seventy six percent reported using a HED in daily work activities. One-third claimed their institution has a policy on device use. Eighty one percent of respondents practice FCR at their institution. Only 34 % of those who practice FCR use a HED on FCR. Those who have used a HED on FCR responded "always" or "often" to the following questions: 48 % feel the use of these devices improves educational experiences for learners on FCR, and 49 % feel these devices improve patient/family educational opportunities on FCR. Over 75 % of pediatric hospitalists used a HED in their daily work activities. A majority is unaware or claims their institution has no policy on handheld device use. While most respondents practice FCR, only one-third used these devices on FCR despite the belief that these devices improve trainee and patient/family educational opportunities on FCR. PMID- 26573647 TI - The Use of Continuous Wavelet Transform Based on the Fast Fourier Transform in the Analysis of Multi-channel Electrogastrography Recordings. AB - This paper presents the analysis of multi-channel electrogastrographic (EGG) signals using the continuous wavelet transform based on the fast Fourier transform (CWTFT). The EGG analysis was based on the determination of the several signal parameters such as dominant frequency (DF), dominant power (DP) and index of normogastria (NI). The use of continuous wavelet transform (CWT) allows for better visible localization of the frequency components in the analyzed signals, than commonly used short-time Fourier transform (STFT). Such an analysis is possible by means of a variable width window, which corresponds to the scale time of observation (analysis). Wavelet analysis allows using long time windows when we need more precise low-frequency information, and shorter when we need high frequency information. Since the classic CWT transform requires considerable computing power and time, especially while applying it to the analysis of long signals, the authors used the CWT analysis based on the fast Fourier transform (FFT). The CWT was obtained using properties of the circular convolution to improve the speed of calculation. This method allows to obtain results for relatively long records of EGG in a fairly short time, much faster than using the classical methods based on running spectrum analysis (RSA). In this study authors indicate the possibility of a parametric analysis of EGG signals using continuous wavelet transform which is the completely new solution. The results obtained with the described method are shown in the example of an analysis of four-channel EGG recordings, performed for a non-caloric meal. PMID- 26573648 TI - The Effect of Screen Size on Mobile Phone User Comprehension of Health Information and Application Structure: An Experimental Approach. AB - This research analyzes the impact of mobile phone screen size on user comprehension of health information and application structure. Applying experimental approach, we asked randomly selected users to read content and conduct tasks on a commonly used diabetes mobile application using three different mobile phone screen sizes. We timed and tracked a number of parameters, including correctness, effectiveness of completing tasks, content ease of reading, clarity of information organization, and comprehension. The impact of screen size on user comprehension/retention, clarity of information organization, and reading time were mixed. It is assumed on first glance that mobile screen size would affect all qualities of information reading and comprehension, including clarity of displayed information organization, reading time and user comprehension/retention of displayed information, but actually the screen size, in this experimental research, did not have significant impact on user comprehension/retention of the content or on understanding the application structure. However, it did have significant impact on clarity of information organization and reading time. Participants with larger screen size took shorter time reading the content with a significant difference in the ease of reading. While there was no significant difference in the comprehension of information or the application structures, there were a higher task completion rate and a lower number of errors with the bigger screen size. Screen size does not directly affect user comprehension of health information. However, it does affect clarity of information organization, reading time and user's ability to recall information. PMID- 26573649 TI - A Secure ECC-based RFID Mutual Authentication Protocol to Enhance Patient Medication Safety. AB - Patient medication safety is an important issue in patient medication systems. In order to prevent medication errors, integrating Radio Frequency Identification (RFID) technology into automated patient medication systems is required in hospitals. Based on RFID technology, such systems can provide medical evidence for patients' prescriptions and medicine doses, etc. Due to the mutual authentication between the medication server and the tag, RFID authentication scheme is the best choice for automated patient medication systems. In this paper, we present a RFID mutual authentication scheme based on elliptic curve cryptography (ECC) to enhance patient medication safety. Our scheme can achieve security requirements and overcome various attacks existing in other schemes. In addition, our scheme has better performance in terms of computational cost and communication overhead. Therefore, the proposed scheme is well suitable for patient medication systems. PMID- 26573650 TI - Characterizing Awake and Anesthetized States Using a Dimensionality Reduction Method. AB - Distinguishing between awake and anesthetized states is one of the important problems in surgery. Vital signals contain valuable information that can be used in prediction of different levels of anesthesia. Some monitors based on electroencephalogram (EEG) such as the Bispectral (BIS) index have been proposed in recent years. This study proposes a new method for characterizing between awake and anesthetized states. We validated our method by obtaining data from 25 patients during the cardiac surgery that requires cardiopulmonary bypass. At first, some linear and non-linear features are extracted from EEG signals. Then a method called "LLE"(Locally Linear Embedding) is used to map high-dimensional features in a three-dimensional output space. Finally, low dimensional data are used as an input to a quadratic discriminant analyzer (QDA). The experimental results indicate that an overall accuracy of 88.4 % can be obtained using this method for classifying the EEG signal into conscious and unconscious states for all patients. Considering the reliability of this method, we can develop a new EEG monitoring system that could assist the anesthesiologists to estimate the depth of anesthesia accurately. PMID- 26573651 TI - Role of WhatsApp Messenger in the Laboratory Management System: A Boon to Communication. AB - The revolution of internet and specifically mobile internet has occurred at a blinding pace over the last decade. With the advent of smart phones, the hand held device has become much more than a medium of voice calling. Healthcare has been catching up with the digital revolution in the form of Hospital Information System and Laboratory Information System. However, the advent of instant messaging services, which are abundantly used by the youth, can be used to improve communication and coordination among the various stake holders in the healthcare sector. We have tried to look at the impact of using the WhatsApp messenger service in the laboratory management system, by forming multiple groups of the various subsections of the laboratory. A total of 35 members used this service for a period of 3 months and their response was taken on a scale of 1 to 10. There was significant improvement in the communication in the form of sharing photographic evidence, information about accidents, critical alerts, duty rosters, academic activities and getting directives from seniors. There was also some increase in the load of adding information to the application and disturbance in the routine activities; but the benefits far outweighed the minor hassles. We thereby suggest and foresee another communication revolution which will change the way information is shared in a healthcare sector, with hospital specific dedicated apps. PMID- 26573652 TI - The Importance of Interpolation in Computerized Growth Charting. AB - Computer growth charting is increasingly available for clinical and research applications. The LMS method is used to define the growth curves on the charts most commonly used in practice today. The data points for any given chart are at discrete points, and computer programs may simply round to the closest LMS data point when calculating growth centiles. We sought to determine whether applying an interpolation algorithm to the LMS data for commonly used growth charts may reduce the inherent errors which occur with rounding to the nearest data point. We developed a simple, easily implemented interpolation algorithm to use with LMS data. Using published growth charts, we compared predicted growth centiles using our interpolation algorithm versus a standard rounding approach. Using a test scenario of a patient at the 50th centile in weight, compared to using our interpolation algorithm, the method of simply rounding to the nearest data point resulted in maximal z-score errors in weight of the following: 2.02 standard deviations for the World Health Organization 0-to-23 month growth chart, 1.07 standard deviations for the Fenton preterm growth chart, 0.71 standard deviations for the Olsen preterm growth chart, and 0.11 standard deviations for the CDC 2-to 18 year growth chart. Failure to include an interpolation algorithm when designing computerizing growth charts can lead to large errors in centile and z score calculations. PMID- 26573653 TI - An Intelligent Phonocardiography for Automated Screening of Pediatric Heart Diseases. AB - This paper presents a robust device for automated screening of pediatric heart diseases based on our unique processing method in murmur characterization; the Arash-Band method. The present study modifies the Arash-Band method and employs output of the modified method in conjunction with the two other original techniques to extract indicative feature vectors for the screening. The extracted feature vectors are classified by using the support vector machine method. Results show that the proposed modifications significantly enhances performance of the Arash-Band in terms of the both accuracy and sensitivity as the corresponding effect sizes are sufficiently large. The proposed algorithm has been incorporated into an Android-based tablet to constitute an intelligent phonocardiogram with the automatic screening capability. In order to obtain confidence interval of the accuracy and sensitivity, an inferable statistical test is applied on our database containing the phonocardiogram signals recorded from 263 of the referrals to a hospital. The expected value of the accuracy/sensitivity is estimated to be 87.45 % / 87.29 % with a 95 % confidence interval of (80.19 % - 92.47 %) / (76.01 % - 95.78 %) exhibiting superior performance than a pediatric cardiologist who relies on conventional or even computer-assisted auscultation. PMID- 26573654 TI - A Review of Automatic Methods Based on Image Processing Techniques for Tuberculosis Detection from Microscopic Sputum Smear Images. AB - Tuberculosis (TB) is an infectious disease caused by the bacteria Mycobacterium tuberculosis. It primarily affects the lungs, but it can also affect other parts of the body. TB remains one of the leading causes of death in developing countries, and its recent resurgences in both developed and developing countries warrant global attention. The number of deaths due to TB is very high (as per the WHO report, 1.5 million died in 2013), although most are preventable if diagnosed early and treated. There are many tools for TB detection, but the most widely used one is sputum smear microscopy. It is done manually and is often time consuming; a laboratory technician is expected to spend at least 15 min per slide, limiting the number of slides that can be screened. Many countries, including India, have a dearth of properly trained technicians, and they often fail to detect TB cases due to the stress of a heavy workload. Automatic methods are generally considered as a solution to this problem. Attempts have been made to develop automatic approaches to identify TB bacteria from microscopic sputum smear images. In this paper, we provide a review of automatic methods based on image processing techniques published between 1998 and 2014. The review shows that the accuracy of algorithms for the automatic detection of TB increased significantly over the years and gladly acknowledges that commercial products based on published works also started appearing in the market. This review could be useful to researchers and practitioners working in the field of TB automation, providing a comprehensive and accessible overview of methods of this field of research. PMID- 26573655 TI - A Modular Framework for EEG Web Based Binary Brain Computer Interfaces to Recover Communication Abilities in Impaired People. AB - A Brain Computer Interface (BCI) allows communication for impaired people unable to express their intention with common channels. Electroencephalography (EEG) represents an effective tool to allow the implementation of a BCI. The present paper describes a modular framework for the implementation of the graphic interface for binary BCIs based on the selection of symbols in a table. The proposed system is also designed to reduce the time required for writing text. This is made by including a motivational tool, necessary to improve the quality of the collected signals, and by containing a predictive module based on the frequency of occurrence of letters in a language, and of words in a dictionary. The proposed framework is described in a top-down approach through its modules: signal acquisition, analysis, classification, communication, visualization, and predictive engine. The framework, being modular, can be easily modified to personalize the graphic interface to the needs of the subject who has to use the BCI and it can be integrated with different classification strategies, communication paradigms, and dictionaries/languages. The implementation of a scenario and some experimental results on healthy subjects are also reported and discussed: the modules of the proposed scenario can be used as a starting point for further developments, and application on severely disabled people under the guide of specialized personnel. PMID- 26573656 TI - Diagnosis of Brain Metastases from Lung Cancer Using a Modified Electromagnetism like Mechanism Algorithm. AB - Brain metastases are commonly found in patients that are diagnosed with primary malignancy on their lung. Lung cancer patients with brain metastasis tend to have a poor survivability, which is less than 6 months in median. Therefore, an early and effective detection system for such disease is needed to help prolong the patients' survivability and improved their quality of life. A modified electromagnetism-like mechanism (EM) algorithm, MEM-SVM, is proposed by combining EM algorithm with support vector machine (SVM) as the classifier and opposite sign test (OST) as the local search technique. The proposed method is applied to 44 UCI and IDA datasets, and 5 cancers microarray datasets as preliminary experiment. In addition, this method is tested on 4 lung cancer microarray public dataset. Further, we tested our method on a nationwide dataset of brain metastasis from lung cancer (BMLC) in Taiwan. Since the nature of real medical dataset to be highly imbalanced, the synthetic minority over-sampling technique (SMOTE) is utilized to handle this problem. The proposed method is compared against another 8 popular benchmark classifiers and feature selection methods. The performance evaluation is based on the accuracy and Kappa index. For the 44 UCI and IDA datasets and 5 cancer microarray datasets, a non-parametric statistical test confirmed that MEM-SVM outperformed the other methods. For the 4 lung cancer public microarray datasets, MEM-SVM still achieved the highest mean value for accuracy and Kappa index. Due to the imbalanced property on the real case of BMLC dataset, all methods achieve good accuracy without significance difference among the methods. However, on the balanced BMLC dataset, MEM-SVM appears to be the best method with higher accuracy and Kappa index. We successfully developed MEM-SVM to predict the occurrence of brain metastasis from lung cancer with the combination of SMOTE technique to handle the class imbalance properties. The results confirmed that MEM-SVM has good diagnosis power and can be applied as an alternative diagnosis tool in with other medical tests for the early detection of brain metastasis from lung cancer. PMID- 26573657 TI - Development of a Multi-Agent m-Health Application Based on Various Protocols for Chronic Disease Self-Management. AB - The purpose of this study was to develop and evaluate a mobile health application (Self-Management mobile Personal Health Record: "SmPHR") to ensure the interoperability of various personal health devices (PHDs) and electronic medical record systems (EMRs) for continuous self-management of chronic disease patients. The SmPHR was developed for Android 4.0.3, and implemented according to the optimized standard protocol for each interface of healthcare services adopted by the Continua Health Alliance (CHA). That is, the Personal Area Network (PAN) interface between the application and PHD implements ISO/IEEE 11073-20,601, 10,404, 10,407, 10,415, 10,417, and Bluetooth Health Device Profile (HDP), and EMRs with a wide area network (WAN) interface implement HL7 V2.6; the Health Record Network (HRN) interface implements Continuity of Care Document (CCD) and Continuity of Care Record (CCR). Also, for SmPHR, we evaluated the transmission error rate between the interface using four PHDs and personal health record systems (PHRs) from previous research, with 611 users and elderly people after receiving institutional review board (IRB) approval. In the evaluation, the PAN interface showed 15 (2.4 %) errors, and the WAN and HRN interface showed 13 (2.1 %) errors in a total of 611 transmission attempts. Also, we received opinions regarding SmPHR from 15 healthcare professionals who took part in the clinical trial. Thus, SmPHR can be provided as an interconnected PHR mobile health service to patients, allowing 'plug and play' of PHDs and EMRs through various standard protocols. PMID- 26573658 TI - Tracking social contact networks with online respondent-driven detection: who recruits whom? AB - BACKGROUND: Transmission of respiratory pathogens in a population depends on the contact network patterns of individuals. To accurately understand and explain epidemic behaviour information on contact networks is required, but only limited empirical data is available. Online respondent-driven detection can provide relevant epidemiological data on numbers of contact persons and dynamics of contacts between pairs of individuals. We aimed to analyse contact networks with respect to sociodemographic and geographical characteristics, vaccine-induced immunity and self-reported symptoms. METHODS: In 2014, volunteers from two large participatory surveillance panels in the Netherlands and Belgium were invited for a survey. Participants were asked to record numbers of contacts at different locations and self-reported influenza-like-illness symptoms, and to invite 4 individuals they had met face to face in the preceding 2 weeks. We calculated correlations between linked individuals to investigate mixing patterns. RESULTS: In total 1560 individuals completed the survey who reported in total 30591 contact persons; 488 recruiter-recruit pairs were analysed. Recruitment was assortative by age, education, household size, influenza vaccination status and sentiments, indicating that participants tended to recruit contact persons similar to themselves. We also found assortative recruitment by symptoms, reaffirming our objective of sampling contact persons whom a participant may infect or by whom a participant may get infected in case of an outbreak. Recruitment was random by sex and numbers of contact persons. Relationships between pairs were influenced by the spatial distribution of peer recruitment. CONCLUSIONS: Although complex mechanisms influence online peer recruitment, the observed statistical relationships reflected the observed contact network patterns in the general population relevant for the transmission of respiratory pathogens. This provides useful and innovative input for predictive epidemic models relying on network information. PMID- 26573661 TI - Innate Immune Cells May Prevent Metastasis. AB - Unlike classic monocytes, which can exacerbate metastasis upon recruitment to tumor sites, patrolling monocytes play a preemptive anticancer role by engulfing tumor cells and slowing their spread, particularly to the lung. PMID- 26573660 TI - [Transcranial direct current stimulation for depressive disorders]. AB - Major depressive disorders are one of the most prevalent psychiatric disorders worldwide but approximately 20-30 % of patients do not respond to standard guideline conform treatment. Recent neuroimaging studies in depressive patients revealed altered activation patterns in prefrontal brain areas and that successful cognitive behavioral therapy and psychopharmacological interventions are associated with a reversal of these neural alterations. Therefore, a direct modulation of prefrontal brain activation by non-invasive brain stimulation techniques, such as transcranial direct current stimulation (tDCS) seems to be a promising and innovative approach for the treatment of depressive disorders. In addition, recent neuropsychological findings indicated an augmentation of positive tDCS effects by simultaneous external activation of the stimulated brain area, for example by cognitive training tasks. Based on these findings, the possibility to augment cognitive-emotional learning processes during cognitive behavioral therapy by simultaneous tDCS to increase antidepressive therapeutic effects is discussed in this article. PMID- 26573662 TI - Avatars Identify Genetic Sources of Drug Response. AB - Using mouse avatars implanted with liver metastases of late-stage colorectal cancers, researchers uncovered mutations in five genes-ERBB2, EGFR, FGFR1, PDGFRA, and MAP2K1-that seem to promote cetuximab resistance. They also found that mutations in IRS2 may boost tumors' vulnerability to anti-EGFR therapy and tested specific therapies in the mice to gauge the drugs' effectiveness. PMID- 26573663 TI - Reactivation of occult hepatitis B virus infection in patients with rheumatic diseases: pathogenesis, risk assessment and prevention. AB - Over the past decade, reactivation of occult hepatitis B virus (HBV) infection has garnered much attention from rheumatologists owing to a number of reports which have indicated the potential risk of biologics in causing this previously ignored infectious complication. Hepatitis due to reactivation of occult HBV infection occurs only occasionally but with high mortality upon occurrence, placing us in a clinical dilemma "to address or not to address?" In this review, we discuss how biological and other immunosuppressive therapies increase the risk of developing reactivation of occult HBV infection and attempt to solve this clinical quandary. PMID- 26573665 TI - A fast method for calculating reliable event supports in tree reconciliations via Pareto optimality. AB - BACKGROUND: Given a gene and a species tree, reconciliation methods attempt to retrieve the macro-evolutionary events that best explain the discrepancies between the two tree topologies. The DTL parsimonious approach searches for a most parsimonious reconciliation between a gene tree and a (dated) species tree, considering four possible macro-evolutionary events (speciation, duplication, transfer, and loss) with specific costs. Unfortunately, many events are erroneously predicted due to errors in the input trees, inappropriate input cost values or because of the existence of several equally parsimonious scenarios. It is thus crucial to provide a measure of the reliability for predicted events. It has been recently proposed that the reliability of an event can be estimated via its frequency in the set of most parsimonious reconciliations obtained using a variety of reasonable input cost vectors. To compute such a support, a straightforward but time-consuming approach is to generate the costs slightly departing from the original ones, independently compute the set of all most parsimonious reconciliations for each vector, and combine these sets a posteriori. Another proposed approach uses Pareto-optimality to partition cost values into regions which induce reconciliations with the same number of DTL events. The support of an event is then defined as its frequency in the set of regions. However, often, the number of regions is not large enough to provide reliable supports. RESULTS: We present here a method to compute efficiently event supports via a polynomial-sized graph, which can represent all reconciliations for several different costs. Moreover, two methods are proposed to take into account alternative input costs: either explicitly providing an input cost range or allowing a tolerance for the over cost of a reconciliation. Our methods are faster than the region based method, substantially faster than the sampling-costs approach, and have a higher event-prediction accuracy on simulated data. CONCLUSIONS: We propose a new approach to improve the accuracy of event supports for parsimonious reconciliation methods to account for uncertainty in the input costs. Furthermore, because of their speed, our methods can be used on large gene families. Our algorithms are implemented in the ecceTERA program, freely available from http://mbb.univ-montp2.fr/MBB/. PMID- 26573664 TI - Lipid profile among girls with systemic lupus erythematosus. AB - The aim of the study was to describe biomarkers of lipid metabolism associated with increased cardiovascular risk and their correlation with disease variables and markers of inflammation in adolescent females with systemic lupus erythematosus (SLE). This cross-sectional controlled study evaluated 33 adolescent females with juvenile SLE and 33 healthy controls. Anthropometric data, SLE disease activity index (SLEDAI), medications, proteinuria, ultra sensitive C-reactive protein (us-CRP), lipid profile (total cholesterol, LDL-c, HDL-c and triglycerides), apolipoproteins A and B (Apo A-I and B), paraoxonase, and myeloperoxidase were evaluated. Median age of the patients and the median disease duration were 16.7 years and 54 months, respectively. SLEDAI scores above 4 were observed in 11 (33.3 %) patients. Moreover, 12 (36.4 %) patients were overweight, and 5 (15.2 %) had low height for age ratios. Dyslipidemia was observed in 13 (39.4 %) patients and in 7 (21.2 %) controls with a decrease in HDL-c concentrations in SLE patients even after adjustment for their nutritional status. In the group with SLE, us-CRP concentrations were inversely correlated with LDL-c/ApoB ratio (p = 0.031). After multivariate regression analysis, the SLE group showed lower concentration of Apo A-I and a decreased LDL-c/ApoB ratio. SLE adolescent females with low disease activity, with preserved kidney function and on low dose of corticosteroids, regardless of nutritional status and food intake, have proatherogenic lipid biomarkers, which may contribute to an increased atherosclerotic risk. PMID- 26573667 TI - Characteristics of a Novel Aerobic Denitrifying Bacterium, Enterobacter cloacae Strain HNR. AB - A novel aerobic denitrifier strain HNR, isolated from activated sludge, was identified as Enterobacter cloacae by16S rRNA sequencing analysis. Glucose was considered as the most favorable C-source for strain HNR. The logistic equation well described the bacterial growth, yielding a maximum growth rate (MUmax) of 0.283 h(-1) with an initial NO3 (-)-N concentration of 110 mg/L. Almost all NO3 ( )-N was removed aerobically within 30 h with an average removal rate of 4.58 mg N L(-1) h(-1). Nitrogen balance analysis revealed that proximately 70.8 % of NO3 ( )-N was removed as gas products and only 20.7 % was transformed into biomass. GC MS result indicates that N2 was the end product of aerobic denitrification. The enzyme activities of nitrate reductase and nitrite reductase, which are related to the process of aerobic denitrification, were 0.0688 and 0.0054 U/mg protein, respectively. Thus, the aerobic denitrification of reducing NO3 (-) to N2 by strain HNR was demonstrated. The optimal conditions for nitrate removal were C/N ratio 13, pH value 8, shaking speed 127 rpm and temperature 30 degrees C. These findings show that E. cloacae strain HNR has a potential application on wastewater treatment to achieve nitrate removal under aerobic conditions. PMID- 26573666 TI - AGEs Induce Apoptosis in Rat Osteoblast Cells by Activating the Caspase-3 Signaling Pathway Under a High-Glucose Environment In Vitro. AB - Advanced glycation end products (AGEs) accumulate under high-glucose conditions and affect the healing of bone damage through various pathways; however, the detail mechanisms underlying these changes are unknown. In this study, we investigated the effects of AGEs on the apoptosis of in vitro-cultured rat osteoblasts under high-glucose conditions and explored the underlying mechanisms of these effects. First, we cultured rat osteoblasts and determined the accumulation of AGEs in the culture medium under high-glucose conditions. Then, we cultured rat osteoblasts under a high glucose concentration (35 mM), a normal glucose concentration (5.5 mM), and a normal glucose concentration (5.5 mM) in the presence of AGEs. We examined the effects of high glucose and AGEs on the apoptosis of rat osteoblasts at different time points and further analyzed the activity and changes in the levels of procaspase-3, caspase-3, and the caspase-3 substrate poly ADP-ribose polymerase (PARP). Finally, we added sRAGE (soluble RAGE) (an AGE inhibitor) or DEVD (a caspase-3 inhibitor) to each culture group and examined apoptosis under each culture condition and the changes in the levels of procaspase-3, caspase-3, and its substrate PARP. The results showed that the high-glucose condition and the addition of AGEs increased the apoptosis of rat osteoblast cells and simultaneously increased the activity and quantity of caspase-3. These increases could be inhibited by the AGE inhibitor sRAGE or the caspase-3 inhibitor DEVD. The above results demonstrate that high-glucose conditions lead to the accumulation of AGEs and activation of the caspase-3 signaling pathway, resulting in the increased apoptosis of cultured rat osteoblast cells. PMID- 26573668 TI - [Improved prostate cancer treatment in certified centers : Is the strategic vision realistic?]. PMID- 26573669 TI - [Treatment quality of prostate cancer centers. Analysis of the 2014 annual report of the German Cancer Society]. AB - BACKGROUND: As of 31 December 2012, 92 departments of urology had been certified as a prostate cancer center by the German Cancer Society (DKG). In this paper, the treatment quality of these centers based on the annual 2014 DKG report shall be critically analyzed. BASIC DATA AND PATIENTS: In 2013, 19,558 primary cases of prostate cancer were registered. The mean number of primary cases per year was 159 (range 101-2089), whereby the minimum number of > 100 had been reached by all centers. The median number of radical prostatectomies decreased to 84 (range 35 2145); 6 of 88 centers did not fulfill the minimum number of 50 radical prostatectomies per year. Concerning radiotherapy or brachytherapy no minimal requirements exist. RESULTS: The number of operative revisions and wound infections including drainage of lymphoceles following radical prostatectomies and the relative number of nerve-sparing radical prostatectomies in low-risk patients with an IIEF > 22 are described. The requirement of < 10 % R1 resections was only fulfilled in 52 of 86 (60.5 %) centers; the median was 8.9 %. Data concerning treatment quality of external beam irradiation as well as data for potency and continence of all treatment modalities are completely lacking. CONCLUSION: The large number of registered prostate cancer cases offers the perfect opportunity to generate reliable benchmark data for all treatment modalities of prostate cancer. It is desirable that in the near future functional data such as continence and potency rates as well as prostate-specific antigen (PSA) recurrences of all treatment modalities will be reported. PMID- 26573670 TI - [Indicator analysis of prostate cancer centers certified by the German Cancer Society 2015]. AB - BACKGROUND: Since the first prostate cancer center was certified by the German Cancer Society (DKG) in 2008, there are currently 94 centers at 95 sites. During certification, data on the implementation of the requirements are collected. These data can be used for benchmarking purposes. OBJECTIVES: This paper describes the development and monitoring of indicators and presents a selection of recent results. MATERIALS AND METHODS: The descriptive results on 18,288 primary cases from 91 sites with complete data are presented. RESULTS: The prostate cancer center certification system has reached a plateau both in regard to the absolute number of centers and the total proportion of all primary cases treated in Germany. The implementation of the requirements is at a high level overall, although some centers have difficulties fulfilling selected key figures, e.g., the study quota requirement. CONCLUSION: The evaluation of current indicators documented good structural and process quality, which correspond for the most part to the target values for the total cohort. In the future, assessing medium and long-term outcome quality will be of greater importance, particularly with regard to patient-reported outcomes. PMID- 26573671 TI - [Systematic analysis of treatment results as a quality control instrument using the example of a large European center]. AB - BACKGROUND: Measurement of the quality of treatment has become increasingly important in hospitals. An easy and practical solution in data acquisition is the Patient-Reported Outcome Measurement (PROM). METHODS: In this article the historical development, general conditions, and difficulties of using the outcome measurement in our patients are describe. In addition, we illustrate the wide range of benefits due to our survey. Based on data from 2008-2013, the functional and oncological results of treatment in our clinic are shown. The main focus lies on the PROMs, e.g., urinary continence evaluated with the daily pad use, sexual function with the IIEF-5 questionnaire, and postoperative complications. CONCLUSIONS: A systematic and standardized outcome measurement may help to improve the quality of treatment, provides factual information for patients, and supports medical development. PMID- 26573672 TI - [Gap between postulated and real outcome quality of radical prostatectomy]. AB - BACKGROUND: Certified Prostate Centers proclaim congruent process and outcome quality results for treatment of prostate carcinoma. Therapy in accordance with the guidelines after presentation of the patient in an interdisciplinary conference and regular documented follow up are not in themselves a guarantee for good quality results (complication free, continence, erectile function, negative surgical margins, biochemical recurrence free), and are significantly influenced by factors not contained within the certification framework. DISCUSSION: An association between exceeding the minimum number of operations and quality assurance exists, if at all, only vaguely and on no account justifies the absolute numbers necessary for certification. Although good measuring instruments for a Pentafecta analysis are available, the gathering of quality results for a center are limited to questionnaires for functional quality results and in the non-differentiated request for a pT2R1 rate of under 10 % for oncological quality results. CONCLUSIONS: The reasons for this systematic ignoring of the for the patient so important quality results with a simultaneous excessive regard for standardizing organizational procedure processes are manifold. They comprise valid verifiability of process quality, the unclear effects of standardized treatment pathways on actual operation quality and the capitulation to statistical and patient determined problems with sufficient acquisition of comparable functional OP results. Whereas the outcome quality is more important than the process quality for patients with prostate carcinoma, the certified centers conduct themselves in exactly the opposite manner, thus creating a virtually insoluble dilemma. PMID- 26573673 TI - [Metastatic, hormone-naive prostate cancer interventional study : Multicenter, prospective, randomized study to evaluate the effect of standard drug therapy with or without radical prostatectomy in patients with limited bone metastasized prostate cancer (G-RAMPP - the AUO AP 75/13 study)]. PMID- 26573674 TI - [Priapism: Current diagnostics and therapy]. AB - Priapism is characterized by involuntary persistent penile erection after or independent of sexual stimulation. The diagnostic clarification, including patient history, physical findings, duplex ultrasonography and analysis of blood gases is decisive for the underlying pathophysiology and the appropriate therapeutic procedure. Non-hypoxic and non-acidotic blood gas parameters enable a conservative approach, hypoxic, hypercarbic and acidotic parameters may lead to fibrosis of the corpora cavernosa and, in turn, to a loss of penile function. Low flow or ischemic (veno-occlusive) priapism is an emergency situation and can lead to irreversible erectile dysfunction within 4 h. Treatment consists of blood aspiration and possibly intracavernosal injection of sympathomimetic drugs. A distal shunt is necessary in the case of treatment failure (in rare cases a proximal shunt). Management of recurrent priapism (stuttering) includes self injection of sympathomimetic drugs and preventive long-term administration of erection inhibitory and erection promoting substances. This concept still needs to be validated. High-flow or non-ischemic priapism does not necessitate immediate treatment measures and should be kept under observation. In cases of a detectable fistula selective artery embolization is often a successful option. PMID- 26573675 TI - [Not Available]. PMID- 26573679 TI - Ancestral and more recently acquired syntenic relationships of MADS-box genes uncovered by the Physcomitrella patens pseudochromosomal genome assembly. AB - KEY MESSAGE: The Physcomitrella pseudochromosomal genome assembly revealed previously invisible synteny enabling realisation of the full potential of shared synteny as a tool for probing evolution of this plant's MADS-box gene family. Assembly of the sequenced genome of Physcomitrella patens into 27 mega-scaffolds (pseudochromosomes) has confirmed the major predictions of our earlier model of expansion of the MADS-box gene family in the Physcomitrella lineage. Additionally, microsynteny has been conserved in the immediate vicinity of some recent duplicates of MADS-box genes. However, comparison of non-syntenic MIKC MADS-box genes and neighbouring genes indicates that chromosomal rearrangements and/or sequence degeneration have destroyed shared synteny over longer distances (macrosynteny) around MADS-box genes despite subsets comprising two or three MIKC genes having remained syntenic. In contrast, half of the type I MADS-box genes have been transposed creating new syntenic relations with MIKC genes. This implies that conservation of ancient ancestral synteny of MIKC genes and of more recently acquired synteny of type I and MIKC genes may be selectively advantageous. Our revised model predicts the birth rate of MIKC genes in Physcomitrella is higher than that of type I genes. However, this difference is attributable to an early tandem duplication and an early segmental duplication of MIKC genes prior to the two polyploidisations that account for most of the expansion of the MADS-box gene family in Physcomitrella. Furthermore, this early segmental duplication spawned two chromosomal lineages: one with a MIKC (C) gene, belonging to the PPM2 clade, in close proximity to one or a pair of MIKC* genes and another with a MIKC (C) gene, belonging to the PpMADS-S clade, characterised by greater separation from syntenic MIKC* genes. Our model has evolutionary implications for the Physcomitrella karyotype. PMID- 26573680 TI - MsZEP, a novel zeaxanthin epoxidase gene from alfalfa (Medicago sativa), confers drought and salt tolerance in transgenic tobacco. AB - KEY MESSAGE: The zeaxanthin epoxidase gene ( MsZEP ) was cloned and characterized from alfalfa and validated for its function of tolerance toward drought and salt stresses by heterologous expression in Nicotiana tabacum. Zeaxanthin epoxidase (ZEP) plays important roles in plant response to various environment stresses due to its functions in ABA biosynthetic and the xanthophyll cycle. To understand the expression characteristics and the biological functions of ZEP in alfalfa (Medicago sativa), a novel gene, designated as MsZEP (KM044311), was cloned, characterized and overexpressed in Nicotiana tabacum. The open reading frame of MsZEP contains 1992 bp nucleotides and encodes a 663-amino acid polypeptide. Amino acid sequence alignment indicated that deduced MsZEP protein was highly homologous to other plant ZEP sequences. Phylogenetic analysis showed that MsZEP was grouped into a branch with other legume plants. Real-time quantitative PCR revealed that MsZEP gene expression was clearly tissue-specific, and the expression levels were higher in green tissues (leaves and stems) than in roots. MsZEP expression decreased in shoots under drought, cold, heat and ABA treatment, while the expression levels in roots showed different trends. Besides, the results showed that nodules could up-regulate the MsZEP expression under non stressful conditions and in the earlier stage of different abiotic stress. Heterologous expression of the MsZEP gene in N. tabacum could confer tolerance to drought and salt stress by affecting various physiological pathways, ABA levels and stress-responsive genes expression. Taken together, these results suggested that the MsZEP gene may be involved in alfalfa responses to different abiotic stresses and nodules, and could enhance drought and salt tolerance of transgenic tobacco by heterologous expression. PMID- 26573681 TI - A new network representation of the metabolism to detect chemical transformation modules. AB - BACKGROUND: Metabolism is generally modeled by directed networks where nodes represent reactions and/or metabolites. In order to explore metabolic pathway conservation and divergence among organisms, previous studies were based on graph alignment to find similar pathways. Few years ago, the concept of chemical transformation modules, also called reaction modules, was introduced and correspond to sequences of chemical transformations which are conserved in metabolism. We propose here a novel graph representation of the metabolic network where reactions sharing a same chemical transformation type are grouped in Reaction Molecular Signatures (RMS). RESULTS: RMS were automatically computed for all reactions and encode changes in atoms and bonds. A reaction network containing all available metabolic knowledge was then reduced by an aggregation of reaction nodes and edges to obtain a RMS network. Paths in this network were explored and a substantial number of conserved chemical transformation modules was detected. Furthermore, this graph-based formalism allows us to define several path scores reflecting different biological conservation meanings. These scores are significantly higher for paths corresponding to known metabolic pathways and were used conjointly to build association rules that should predict metabolic pathway types like biosynthesis or degradation. CONCLUSIONS: This representation of metabolism in a RMS network offers new insights to capture relevant metabolic contexts. Furthermore, along with genomic context methods, it should improve the detection of gene clusters corresponding to new metabolic pathways. PMID- 26573682 TI - Reduction in respiratory motion artefacts on gadoxetate-enhanced MRI after training technicians to apply a simple and more patient-adapted breathing command. AB - OBJECTIVE: To investigate whether a trained group of technicians using a modified breathing command during gadoxetate-enhanced liver MRI reduces respiratory motion artefacts compared to non-trained technicians using a traditional breathing command. MATERIALS AND METHODS: The gadoxetate-enhanced liver MR images of 30 patients acquired using the traditional breathing command and the subsequent 30 patients after training the technicians to use a modified breathing command were analyzed. A subgroup of patients (n = 8) underwent scans both by trained and untrained technicians. Images obtained using the traditional and modified breathing command were compared for the presence of breathing artefacts [respiratory artefact-based image quality scores from 1 (best) to 5 (non diagnostic)]. RESULTS: There was a highly significant improvement in the arterial phase image quality scores in patients using the modified breathing command compared to the traditional one (P < 0.001). The percentage of patients with severe and extensive breathing artefacts in the arterial phase decreased from 33.3 % to 6.7 % after introducing the modified breathing command (P = 0.021). In the subgroup that underwent MRI using both breathing commands, arterial phase image quality improved significantly (P = 0.008) using the modified breathing command. CONCLUSION: Training technicians to use a modified breathing command significantly improved arterial phase image quality of gadoxetate-enhanced liver MRI. KEY POINTS: * A modified breathing command reduced respiratory artefacts on arterial-phase gadoxetate-enhanced MRI (P < 0.001). * The modified command decreased severe and extensive arterial-phase breathing artefacts (P = 0.021). * Training technicians to use a modified breathing command improved arterial-phase images. PMID- 26573683 TI - Parent-child inpatient treatment for children with behavioural and emotional disorders: a multilevel analysis of within-subjects effects. AB - BACKGROUND: The importance of parental involvement in child treatment is well established. Several child psychiatric clinics have, therefore, set up inpatient family units where children and parents are both actively involved in the treatment. Unfortunately, evidence supporting the benefits of these units is sparse. METHODS: We evaluated the effectiveness of inpatient treatment for families with severe parent-child interaction problems in a child psychiatric setting. Consecutive admissions to the parent-child ward (N = 66) were studied. A within-subjects design was used with four assessment points (baseline, admission, discharge, four-week follow-up). Outcome measures were 1) parent and teacher ratings of child behaviour, and 2) parent self-ratings of parenting practices, parental strains and parental mental health. Data were analyzed using multilevel modelling for longitudinal data (piecewise growth curve models). RESULTS: All parent-rated measures improved significantly during the four-week treatment period (d = 0.4 - 1.3). These improvements were significantly greater than those observed during the four-week pre-admission period. In addition, benefits were maintained during the four-week follow-up period. Only parents' self-efficacy in managing their child's behaviour showed continued improvement during follow-up. Teacher ratings of children's disruptive behaviour at school were stable during the pre-admission period and showed significant improvements at follow-up (d = 0.3 - 0.4). CONCLUSIONS: We conclude that parent-child inpatient treatment has positive effects on child and parent behaviour and mental health, and can therefore be recommended for children with behavioural and emotional disorders and severe parent-child interaction problems. PMID- 26573684 TI - misFinder: identify mis-assemblies in an unbiased manner using reference and paired-end reads. AB - BACKGROUND: Because of the short read length of high throughput sequencing data, assembly errors are introduced in genome assembly, which may have adverse impact to the downstream data analysis. Several tools have been developed to eliminate these errors by either 1) comparing the assembled sequences with some similar reference genome, or 2) analyzing paired-end reads aligned to the assembled sequences and determining inconsistent features alone mis-assembled sequences. However, the former approach cannot distinguish real structural variations between the target genome and the reference genome while the latter approach could have many false positive detections (correctly assembled sequence being considered as mis-assembled sequence). RESULTS: We present misFinder, a tool that aims to identify the assembly errors with high accuracy in an unbiased way and correct these errors at their mis-assembled positions to improve the assembly accuracy for downstream analysis. It combines the information of reference (or close related reference) genome and aligned paired-end reads to the assembled sequence. Assembly errors and correct assemblies corresponding to structural variations can be detected by comparing the genome reference and assembled sequence. Different types of assembly errors can then be distinguished from the mis-assembled sequence by analyzing the aligned paired-end reads using multiple features derived from coverage and consistence of insert distance to obtain high confident error calls. CONCLUSIONS: We tested the performance of misFinder on both simulated and real paired-end reads data, and misFinder gave accurate error calls with only very few miscalls. And, we further compared misFinder with QUAST and REAPR. misFinder outperformed QUAST and REAPR by 1) identified more true positive mis-assemblies with very few false positives and false negatives, and 2) distinguished the correct assemblies corresponding to structural variations from mis-assembled sequence. misFinder can be freely downloaded from https://github.com/hitbio/misFinder. PMID- 26573685 TI - Impact of mechanical mowing and chemical treatment on phytosociological, pedochemical and biological parameters in roadside soils and vegetation. AB - Many chemical and non-chemical strategies have been applied to control weeds in agricultural and industrial areas. Knowledge regarding the effects of these methods on roadside vegetation is still poor. A 2-year field experiment was performed along a road located near Livorno (Tuscany, central Italy). Eight plots/strips were identified, of which four were subjected to periodical mechanical mowing and the remaining four were treated with a chemical herbicide based on glyphosate (the producer's recommended rates were used for the selective control of broad-leaved weeds). Our results clearly showed that roadside soil and vegetation are a significant reservoir of anthropogenic activities which have a strong negative effect on several phytosociological, pedochemical and biological parameters. Compared with conventional mechanical mowing, chemical treatment induced (i) a significant increase in organic matter in the upper plot layers (+18%), and (ii) a marked reduction in weed height throughout the entire period of the experiment. Irrespectively of the kind of treatment, no significance differences were detected in terms of (i) biological quality of soil (the abundance and diversity of arthropod communities did not change), and (ii) plant elemental content (bulk concentrations of analysed trace elements had a good fit within ranges of occurrence in the "reference plant"). The glyphosate partially controlled broad-leaved weeds and this moderate efficacy is dependent upon the season/time of application. In conclusion, the rational and sustainable use of chemical herbicides may be a useful tool for the management of roadside vegetation. PMID- 26573686 TI - PHEDRE trial protocol - observational study of the prevalence of problematic use of Equimolar Mixture of Oxygen and Nitrous Oxide (EMONO) and analgesics in the French sickle-cell disease population. AB - BACKGROUND: The use of analgesics can lead to cases of drug abuse and dependence. It can also cause pseudo-addiction in patients suffering from pain. What is the actual situation in patients suffering from severe sickle-cell disease, exposed to acute pain during vaso-occlusive crises? Evaluation of the use of analgesics, on the basis of Diagnostic and Statistical Manual of Mental Disorders criteria for substance abuse and dependence, makes it possible to differentiate the symptoms occurring only in a context of pain, in the aim of managing the pain, and thus describing pseudo-addiction, from symptoms also occurring when there is no pain, and more in favour of true addiction. Currently there is no data available in France on this problem, and no studies have been carried out in children or adolescents with sickle-cell disease. The purpose of the study is to evaluate the prevalence of problematic use of equimolar mixture of oxygen and nitrous oxide and other analgesic drugs in a population of subjects with severe sickle-cell disease in France. METHODS/DESIGN: PHEDRE (Pharmacodependance Et DREpanocytose-drug dependence and sickle-cell disease) is an observational, descriptive and transversal study. Patients under the age of 26 with sickle-cell disease are included in the study by the doctors looking after them in sickle cell disease centres. The patients are then contacted by a trained researcher for a telephone interview, including an evaluation of the Diagnostic and Statistical Manual of Mental Disorders criteria for abuse and dependence to equimolar mixture of oxygen and nitrous oxide and for each of the analgesic drugs taken by the patient. The data are also completed using the subject's medical record. DISCUSSION: This study will make it possible to provide an initial quantitative and qualitative evaluation of problematic use of equimolar mixture of oxygen and nitrous oxide and analgesic drugs in the sickle-cell disease population. The results will be used firstly to provide additional data essential for monitoring the risk of overdose, abuse, dependence and misuse of these products, and to begin awareness-raising and to provide information for health care professionals, in order to significantly improve the management of sickle-cell disease-related pain. TRIAL REGISTRATION: Clinical Trials.gov ID: NCT02580565 registered 16 October 2015 Unique Protocol ID: RC14_0344. PMID- 26573687 TI - The origin and evolution of queen and fertility signals in Corbiculate bees. AB - BACKGROUND: In social Hymenoptera (ants, bees and wasps), various chemical compounds present on the cuticle have been shown to act as fertility signals. In addition, specific queen-characteristic hydrocarbons have been implicated as sterility-inducing queen signals in ants, wasps and bumblebees. In Corbiculate bees, however, the chemical nature of queen-characteristic and fertility-linked compounds appears to be more diverse than in ants and wasps. Moreover, it remains unknown how queen signals evolved across this group and how they might have been co-opted from fertility signals in solitary ancestors. RESULTS: Here, we perform a phylogenetic analysis of fertility-linked compounds across 16 species of solitary and eusocial bee species, comprising both literature data as well as new primary data from a key solitary outgroup species, the oil-collecting bee Centris analis, and the highly eusocial stingless bee Scaptotrigona depilis. Our results demonstrate the presence of fertility-linked compounds belonging to 12 different chemical classes. In addition, we find that some classes of compounds (linear and branched alkanes, alkenes, esters and fatty acids) were already present as fertility-linked signals in the solitary ancestors of Corbiculate bees, while others appear to be specific to certain species. CONCLUSION: Overall, our results suggest that queen signals in Corbiculate bees are likely derived from ancestral fertility-linked compounds present in solitary bees that lacked reproductive castes. These original fertility-linked cues or signals could have been produced either as a by-product of ovarian activation or could have served other communicative purposes, such as in mate recognition or the regulation of egg laying. PMID- 26573688 TI - Arsenic-induced genotoxicity in Nile tilapia (Orechromis niloticus); the role of Spirulina platensis extract. AB - Arsenic (As) is one of the most relevant environmental global single substance toxicants that have long been regarded as a carcinogenic and genotoxic potential. In this respect, we evaluated the cytogenetic effect of arsenic exposure in Nile tilapia (Oreochromis niloticus), in terms of erythrocyte alteration, apoptosis, and induction of micronuclei. Spirulina platensis (SP) is a filamentous cyanobacterium microalgae with potent dietary phytoantioxidant, anti inflammatory, and anti-cancerous properties supplementation. The protective role of Spirulina as supplementary feeds was studied in Nile tilapia (O. niloticus) against arsenic-induced cytogenotoxicity. Four groups were assigned as control group (no SP or As), As group (exposed to water-born As in the form of NaAsO2 at 7 ppm), SP1 (SP at 7.5% + As at the same level of exposure), and SP2 (SP at 10% + As at the same level of exposure). As-treated group had a significant increase in all cytogenetic analyses including erythrocyte alteration, apoptosis, and induction of micronuclei after 2 weeks with continuous increase in response after 3 weeks. The combined treatment of Spirulina at two different concentrations of 7.5 and 10% had significantly declined the induction of erythrocyte alteration, apoptosis, and micronuclei formation induced by arsenic intoxication. PMID- 26573689 TI - Modeling and estimating manganese concentrations in rural households in the mining district of Molango, Mexico. AB - Airborne manganese (Mn) is considered the most hazardous route of exposure since Mn particles can enter into the body through the lung and may access the brain directly through olfactory uptake, thereby bypassing homeostatic excretory mechanisms. Environmental indoor and outdoor manganese concentrations in PM2.5 were monitored in ten rural households from two communities of Hidalgo, Mexico, from 2006 to 2007. Indoor and outdoor air samples of PM2.5 were collected using MiniVol samplers, and Mn concentrations in the filters were measured using proton induced X-ray emission (PIXE). An adjusted generalized linear mixed model was applied and then used for estimating indoor concentrations in non-monitored households. Our monitoring results showed a higher daily average concentration of indoor PM2.5 vs. outdoor PM2.5 (46.4 vs. 36.2 MUg/m(3), respectively); however, manganese concentration in PM2.5 indoor and outdoor was 0.09 MUg/m(3) in both sceneries. Predictor variables of indoor Mn concentration were outdoor Mn concentration (64.5% increase per 0.1 MUg/m(3) change in Mn) and keeping the windows open (4.2% increase). Using these predictors, the average estimated indoor Mn concentration in PM2.5 was 0.07 MUg/m(3) (SD = 0.05). Our results confirm the direct effect of outdoor Mn levels, opening house windows, and the distance to the mining chimney in indoor Mn levels in houses. PMID- 26573690 TI - Prediction of municipal solid waste generation using nonlinear autoregressive network. AB - Most of the developing countries have solid waste management problems. Solid waste strategic planning requires accurate prediction of the quality and quantity of the generated waste. In developing countries, such as Malaysia, the solid waste generation rate is increasing rapidly, due to population growth and new consumption trends that characterize society. This paper proposes an artificial neural network (ANN) approach using feedforward nonlinear autoregressive network with exogenous inputs (NARX) to predict annual solid waste generation in relation to demographic and economic variables like population number, gross domestic product, electricity demand per capita and employment and unemployment numbers. In addition, variable selection procedures are also developed to select a significant explanatory variable. The model evaluation was performed using coefficient of determination (R(2)) and mean square error (MSE). The optimum model that produced the lowest testing MSE (2.46) and the highest R(2) (0.97) had three inputs (gross domestic product, population and employment), eight neurons and one lag in the hidden layer, and used Fletcher-Powell's conjugate gradient as the training algorithm. PMID- 26573691 TI - Empirical evidence about recovery and mental health. AB - BACKGROUND: Two discourses exist in mental health research and practice. The first focuses on the limitations associated with disability arising from mental disorder. The second focuses on the possibilities for living well with mental health problems. DISCUSSION: This article was prompted by a review to inform disability policy. We identify seven findings from this review: recovery is best judged by experts or using standardised assessment; few people with mental health problems recover; if a person no longer meets criteria for a mental illness, they are in remission; diagnosis is a robust basis for characterising groups and predicting need; treatment and other supports are important factors for improving outcome; the barriers to receiving effective treatment are availability, financing and client awareness; and the impact of mental illness, in particular schizophrenia, is entirely negative. We selectively review a wider range of evidence which challenge these findings, including the changing understanding of recovery, national mental health policies, systematic review methodology and undertainty, epidemiological evidence about recovery rates, reasoning biased due to assumptions about mental illness being an illness like any other, the contested nature of schizophrenia, the social construction of diagnoses, alternative explanations for psychosis experiences including the role of trauma, diagnostic over-shadowing, stigma, the technological paradigm, the treatment gap, social determinants of mental ill-health, the prevalence of voice-hearing in the general population, and the sometimes positive impact of psychosis experience in relation to perspective and purpose. CONCLUSION: We propose an alternative seven messages which are both empirically defensible and more helpful to mental health stakeholders: Recovery is best judged by the person living with the experience; Many people with mental health problems recover; If a person no longer meets criteria for a mental illness, they are not ill; Diagnosis is not a robust foundation; Treatment is one route among many to recovery; Some people choose not to use mental health services; and the impact of mental health problems is mixed. PMID- 26573692 TI - Karyotype differentiation in 19 species of river loach fishes (Nemacheilidae, Teleostei): extensive variability associated with rDNA and heterochromatin distribution and its phylogenetic and ecological interpretation. AB - BACKGROUND: Loaches of the family Nemacheilidae are one of the most speciose elements of Palearctic freshwater ichthyofauna and have undergone rapid ecological adaptations and colonizations. Their cytotaxonomy is largely unexplored; with the impact of cytogenetical changes on this evolutionary diversification still unknown. An extensive cytogenetical survey was performed in 19 nemacheilid species using both conventional (Giemsa staining, C- banding, Ag- and Chromomycin A3/DAPI stainings) and molecular (fluorescence in situ hybridization with 5S rDNA, 45S rDNA, and telomeric (TTAGGG)n probes) methods. A phylogenetic tree of the analysed specimens was constructed based on one mitochondrial (cytochrome b) and two nuclear (RAG1, IRBP) genes. RESULTS: Seventeen species showed karyotypes composed of 2n = 50 chromosomes but differentiated by fundamental chromosome number (NF = 68-90). Nemachilichthys ruppelli (2n = 38) and Schistura notostigma (2n = 44-48) displayed reduced 2n with an elevated number of large metacentric chromosomes. Only Schistura fasciolata showed morphologically differentiated sex chromosomes with a multiple system of the XY1Y2 type. Chromomycin A3 (CMA3)- fluorescence revealed interspecific heterogeneity in the distribution of GC-rich heterochromatin including its otherwise very rare association with 5S rDNA sites. The 45S rDNA sites were mostly located on a single chromosome pair contrasting markedly with a pattern of two (Barbatula barbatula, Nemacheilus binotatus, N. ruppelli) to 20 sites (Physoschistura sp.) of 5S rDNA. The cytogenetic changes did not follow the phylogenetic relationships between the samples. A high number of 5S rDNA sites was present in species with small effective population sizes. CONCLUSION: Despite a prevailing conservatism of 2n, Nemacheilidae exhibited a remarkable cytogenetic variability on microstructural level. We suggest an important role for pericentric inversions, tandem and centric fusions in nemacheilid karyotype differentiation. Short repetitive sequences, genetic drift, founder effect, as well as the involvement of transposable elements in the dispersion of ribosomal DNA sites, might also have played a role in evolutionary processes such as reproductive isolation. These remarkable dynamics of their genomes qualify river loaches as a model for the study of the cytogenetic background of major evolutionary processes such as radiation, endemism and colonization of a wide range of habitats. PMID- 26573693 TI - Development of a novel PTT assay for mutation detection in PALB2 large exons and PALB2 screening in medullary breast cancer. AB - Beyond BRCA1 and BRCA2 genes, PALB2 (Partner and localizer of BRCA2) emerges as the third breast cancer susceptibility gene due to its role in the same DNA repair pathway: homologous recombination. In most populations studied so far, PALB2 mutations are detected in 1-2% of BRCA negative female patients. PALB2 gene contains 13 exons; exons 4 and 5 consist 65% of the coding area. We developed a protein truncation test (PTT) for quick screening of truncating pathogenic mutations of these two large exons. Specific primers were de novo, in silico designed and the PTT-PCR products were translated in the presence of biotinylated lysine and detected colorimetrically. The assay was initially tested in 30 patients with hereditary breast cancer, negative for BRCA mutations and then, in 17 patients with the rare medullary breast cancer subtype. Small PALB2 exons were screened with high-resolution melting curve analysis (HRMA) and the large DNA rearrangements with multiplex ligation-dependent probe amplification (MLPA). Any alterations detected were verified by Sanger DNA Sequencing. The developed PTT methodology is highly specific for clinical significant mutations; positive control samples that produce truncated PALB2 peptides were correctly identified and the method was accurate when compared to DNA sequencing. We did not detect any deleterious PALB2 mutation in both groups of patients. HRMA and MLPA were also negative for all tested samples. However, our novel, fast and cost-effective PTT method for pathogenic mutation detection of the two large PALB2 exons can be applied in screening of a large number of breast cancer patients. PMID- 26573694 TI - Methoxy polyethylene glycol-epoetin beta for the treatment of anemia associated with chronic renal failure. AB - Since more than two decades erythropoiesis-stimulating agents are the main pillar for treatment of anemia associated with chronic kidney disease. Methoxy polyethylene glycol-epoetin beta (MPG-EPO), also called continuous erythropoietin receptor activator, is the longest acting erythropoiesis-stimulating agent currently available. MPG-EPO is characterized by an elimination half-life of approximately 137 h and offers extended dosing intervals up to 4 weeks. Numerous phase I/II studies and a comprehensive clinical phase III program demonstrated the feasibility of MPG-EPO therapy for anemia correction and maintenance of stable hemoglobin levels in adult chronic kidney disease patients. Due to patent disputes MPG-EPO was only available outside the US market so far. In view of a prevailing US market introduction, this review focuses on efficacy and safety data from pivotal trials, summarizes recent clinical research and finally tries to substantiate potential benefits associated with the use of this anti-anemic drug. PMID- 26573695 TI - Reply to letter: Transcranial magnetic stimulation for Parkinson's disease. PMID- 26573697 TI - How to effectively manage the event of bleeding complications when using anticoagulants. AB - Since affecting hemostasis, all the anticoagulant drugs carry a risk of bleeding. Minor bleeds may be managed without the need to reverse the anticoagulant effect, which is instead a key step to ensure efficacious hemostasis in major and life threatening bleeding. Drug withdrawal applies to all anticoagulants. Unfractionated heparin can be neutralized by protamine, which may partly neutralize low-molecular-weight heparins. There is no antidote for fondaparinux, and recombinant factor VIIa (rFVIIa) may be considered for critical bleeding. For vitamin K antagonists-induced major bleeding, rapid reversal with prothrombin complex concentrates (PCC) or plasma and intravenous vitamin K to confer lasting correction are recommended. PCC, activated PCC and rFVIIa are suggested for major bleeding related to new direct oral anticoagulants (DOAC), despite proper studies are lacking. Premarketing studies are ongoing on new antidotes (idarucizumab, andexanet, aripazine), which appear to be suitable for the treatment of DOAC induced life-threatening hemorrhage. PMID- 26573696 TI - Arginine Vasopressin and Arginine Vasopressin Receptor 1b Involved in Electroacupuncture-Attenuated Hypothalamic-Pituitary-Adrenal Axis Hyperactivity in Hepatectomy Rats. AB - OBJECTIVE: The study aims to know the effect of electroacupuncture (EA) in maintenance of the homeostasis of the neuroendocrine system in hepatectomy rats and the involvement of arginine vasopressin (AVP) signaling in hypothalamus after EA was observed. MATERIALS AND METHODS: Rats were randomly assigned to four groups, including the intact group, model group, sham-EA group, and EA group. EA was given during the perioperative period at the Zusanli (ST36) and Sanyinjiao (SP6) points after hepatectomy. The serum adrenocorticotropic hormone (ACTH) and corticosterone (CORT) levels were detected via radioimmunoassay. The expression of AVP, arginine vasopressin receptor 1a (AVPR1a), arginine vasopressin receptor 1b (AVPR1b), and glucocorticoid receptor (GR) was detected by Western blot after surgery. RESULTS: Compared with the intact group, the ACTH and CORT levels in the serum of model group were increased, whereas the ACTH and CORT levels were decreased in the EA group compared with the model group. Moreover, AVP and AVPR1b protein levels in the pituitary gland were increased in the model group and decreased in the EA group. Further, a distinct increase in the AVP and AVPR1a protein levels was observed in the model group, whereas they were significantly decreased in the EA group. Blockade of AVPR1b by nelivaptan reduced the increase of ACTH and CORT. D [Leu(4) , Lys(8) ] vasopressin can inhibit the effect of EA in rectification of the hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis. CONCLUSIONS: EA application at ST36 and SP6 can ameliorate the hyperactivity of the HPA axis via AVP signaling during the perioperative period. PMID- 26573698 TI - alpha7 nicotinic receptor agonists reduce levodopa-induced dyskinesias with severe nigrostriatal damage. AB - BACKGROUND: ABT-126 is a novel, safe, and well-tolerated alpha7 nicotinic receptor agonist in a Phase 2 Alzheimer's disease study. We tested the antidyskinetic effect of ABT-126 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treated squirrel monkeys with moderate and more severe nigrostriatal damage. METHODS: Monkeys (n = 21, set 1) were lesioned with 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine 1-2*. When parkinsonian, they were gavaged with levodopa (10 mg/kg)/carbidopa (2.5 mg/kg) twice daily and dyskinesias rated. They were then given nicotine in drinking water (n = 5), or treated with vehicle (n = 6) or ABT 126 (n = 10) twice daily orally 30 min before levodopa. Set 1 was then re lesioned 1 to 2 times for a total of 3 to 4 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine injections. The antidyskinetic effect of ABT-126, nicotine, and the beta2* nicotinic receptor agonist ABT-894 was re-assessed. Another group of monkeys (n = 23, set 2) were lesioned with 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine only 1* to 2*. They were treated with levodopa/carbidopa, administered the alpha7 agonist ABT-107 (n = 6), ABT-894 (n = 6), nicotine (n = 5), or vehicle (n = 6) and dyskinesias evaluated. All monkeys were euthanized and the dopamine transporter measured. RESULTS: With moderate nigrostriatal damage (1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine 1*-2*), ABT-126 dose-dependently decreased dyskinesias (~60%), with similar results seen with ABT-894 (~60%) or nicotine (~60%). With more severe damage (1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine 3-4*), ABT-126 and nicotine reduced dyskinesias, but ABT-894 did not. The dopamine transporter was 41% and 8.9% of control, with moderate and severe nigrostriatal damage, respectively. No drug modified parkinsonism. CONCLUSION: The novel alpha7 nicotinic receptor drug ABT-126 reduced dyskinesias in monkeys with both moderate and severe nigrostriatal damage. ABT-126 may be useful to reduce dyskinesias in both early- and later-stage Parkinson's disease. PMID- 26573699 TI - Implantable Colonic Electrical Stimulation Improves Gastrointestinal Transit and Defecation in a Canine Constipation Model. AB - OBJECTIVES: Colonic electrical stimulation (CES) may have a therapeutic potential for slow transit constipation (STC). This study aimed to evaluate the effects of implantable CES on gastrointestinal transit and defecation, and explore its mechanisms in a canine STC model. METHODS: Two pairs of electrodes were implanted in each of the proximal colon and rectosigmoid junction (RSJ). Parameters were individualized according to the symptoms of the stimulated dogs. In the STC model, gastrointestinal transit and defecation were assessed to evaluate the effects of double-site CES, and of double-site CES combined with atropine or N nitro-L-arginine (L-NNA) in a crossover design. RESULTS: Individualized parameters varied among the animals. The CES significantly shortened gastrointestinal transit time (GITT) and colonic transit time (CTT) compared with sham CES (p = 0.001 and p < 0.001, respectively). Compared with sham CES, the CES also exhibited significantly higher stool frequency and stool consistency score (p = 0.018 and p = 0.001, respectively). Co-treatment with atropine or L-NNA blocked the effects of CES on GITT, CTT, and stool consistency. The stool frequency increased by CES, however, only reduced by co-treatment with L-NNA. CONCLUSIONS: This double-site implantable CES can improve the gastrointestinal transit and defecation in a canine STC model, possibly by activating the cholinergic and nitrergic pathways. The CES mode used in this study may be proven feasible in treating STC. PMID- 26573700 TI - Recent advances in the exploration of the bile salt export pump (BSEP/ABCB11) function. AB - INTRODUCTION: The bile salt export pump (BSEP/ABCB11), residing in the apical membrane of hepatocyte, mediates the secretion of bile salts into the bile. A range of human diseases is associated with the malfunction of BSEP, including fatal hereditary liver disorders and mild cholestatic conditions. Manifestation of these diseases primarily depends on the mutation type; however, other factors such as hormonal changes and drug interactions can also trigger or influence the related diseases. AREAS COVERED: Here, we summarize the recent knowledge on BSEP by covering its transport properties, cellular localization, regulation and major mutations/polymorphisms, as well as the hereditary and acquired diseases associated with BSEP dysfunction. We discuss the different model expression systems employed to understand the function of the BSEP variants, their drug interactions and the contemporary therapeutic interventions. EXPERT OPINION: The limitations of the available model expression systems for BSEP result in controversial conclusions, and obstruct our deeper insight into BSEP deficiencies and BSEP-related drug interactions. The knowledge originating from different methodologies, such as clinical studies, molecular genetics, as well as in vitro and in silico modeling, should be integrated and harmonized. Increasing availability of robust molecular biological tools and our better understanding of the mechanism of BSEP deficiencies should make the personalized, mutation-based therapeutic interventions more attainable. PMID- 26573701 TI - Study of plasma-derived miRNAs mimic differences in Huntington's disease brain. AB - BACKGROUND: Biomarkers for Huntington's disease progression could accelerate therapeutic developments and improve patient care. Brain microRNAs relating to clinical features of Huntington's disease may represent a potential Huntington's disease biomarker in blood. OBJECTIVE: This study was undertaken to examine candidate microRNAs in plasma to determine whether changes observed in HD brains are detectable in peripheral samples. METHODS: Four microRNAs from 26 manifest Huntington's disease, four asymptomatic Huntington's disease gene carriers, and eight controls were quantified in plasma using reverse transcription quantitative polymerase chain reaction. Linear regression was used to assess microRNA levels across control, asymptomatic gene carriers, and manifest patients. RESULTS: miR 10b-5p (P = 0.0068) and miR-486-5p (P = 0.044) were elevated in Huntington's disease plasma. miR-10b-5p was decreased in asymptomatic gene carriers as compared with patients with Huntington's disease (P = 0.049), but no difference between asymptomatic gene carriers and healthy controls was observed (P = 0.24). CONCLUSIONS: These findings suggest that microRNA changes observed in Huntington's disease brain may be detectable in plasma and have potential clinical utility. PMID- 26573702 TI - Risk factors for intraoperative allogeneic blood transfusion during craniotomy for brain tumor removal in children. AB - BACKGROUND: Several clinical and surgical factors can influence the occurrence of allogeneic blood transfusion (ABT) during oncologic neurosurgery. OBJECTIVES: To identify the potential predictive factors of ABT during craniotomy for the removal of brain tumors in children and the potential impact of intraoperative ABT on early postoperative outcome. METHODS: A retrospective study was performed in all pediatric patients younger than 18 years who underwent craniotomy for brain tumor removal from December 2009 to December 2012 in our institution. Pre-, intra-, and postoperative data were collected from medical and stored electronic anesthesia records. The predictors of intraoperative ABT were determined using multivariate logistic regression. RESULTS: A total of 110 patients were included. Twenty-seven patients (25%) received intraoperative ABT with a volume of 16 +/- 8 ml.kg(-1) . On multivariate analysis, an age <4 years, a duration of surgery >270 min, and a preoperative hemoglobin <12.2 g.dl(-1) were independently associated with the need for intraoperative ABT. We did not show any significant difference concerning postoperative early outcome and length of stay between the transfused and non-transfused patients except for the duration of postoperative mechanical ventilation that was significantly higher in the transfused group (P = 0.04). CONCLUSION: In children, craniotomy for brain tumor removal is at risk of intraoperative ABT. An age <4 years, a duration of surgery >270 min, and a preoperative hemoglobin <12.2 g.dl(-1) are the main factors associated with intraoperative ABT during this surgery. PMID- 26573703 TI - Impact of Adiposity on Incident Hypertension Is Modified by Insulin Resistance in Adults: Longitudinal Observation From the Bogalusa Heart Study. AB - Adiposity and insulin resistance are closely associated with hypertension. This study aims to investigate whether the association between adiposity and hypertension is modified by insulin resistance. The cohort consisted of 1624 middle-aged normotensive black and white adults aged 18 to 43 years at baseline who followed for 16 years on average. Overweight/obesity at baseline was defined as body mass index (BMI) >=25, and insulin resistance was measured using homeostasis model assessment of insulin resistance. Prevalence of incident hypertension was compared between the insulin-sensitive adiposity and insulin resistant adiposity groups. The prevalence of incident hypertension was higher in the insulin-resistant adiposity than in the insulin-sensitive adiposity group (32.1% versus 22.1%, P<0.001). In multivariable logistic analyses, adjusted for baseline age, race, sex, follow-up years, and smoking, baseline insulin-resistant obesity was associated with incident hypertension (odds ratio, 1.9; P=0.008). Odds ratios did not differ between blacks and whites (P=0.238). Of note, the odds ratios of BMI associated with hypertension significantly increased with increasing quartiles of baseline homeostasis model assessment (odds ratio, 1.3, 1.1, 1.5, and 2.5 in quartiles I, II, III, and IV, respectively; P=0.006 for trend). Slopes of increasing follow-up blood pressure with baseline BMI, measured as regression coefficients (beta), were significantly greater in insulin resistant than in insulin-sensitive individuals (beta=0.74 versus beta=0.35 for systolic blood pressure, P=0.004 for difference; beta=0.51 versus beta=0.23 for diastolic blood pressure, P=0.001 for difference). These findings suggest that insulin resistance has a synergistic effect on the obesity-hypertension association in young adults, indicating that the role of adiposity in the development of hypertension is modified by insulin resistance. PMID- 26573704 TI - Clinical Management and Outcomes of Adrenal Hemorrhage Following Adrenal Vein Sampling in Primary Aldosteronism. AB - Aldosterone-producing adenoma and bilateral adrenal hyperplasia account for >90% of all primary aldosteronism cases. Distinguishing between bilateral and unilateral disease is of fundamental importance because it allows targeted therapy. Adrenal vein sampling (AVS) is the only reliable means to preoperatively differentiate between unilateral and bilateral subtypes. A rare but serious complication of AVS is an adrenal hemorrhage (AH). We retrospectively examined in detail 24 cases of AH during AVS in 6 different referral hypertension centers. AH more often affected the right adrenal (n=18) than the left (n=5, P<0.001); 1 bilateral. Median duration of experience of the radiologist in AVS at the time of AH was 5.0 years (0.6-7.8) and AH occurred with both highly experienced (>10 years) and less experienced radiologists. Of 9 patients who suffered AH in the gland contralateral to an aldosterone-producing adenoma and who underwent complete (n=6) or partial (n=3) unilateral adrenalectomy, only one required long term corticosteroid replacement for adrenal insufficiency. No reduction in blood pressure or biochemical resolution of primary aldosteronism occurred in any of those patients who experienced AH in the gland ipsilateral to an aldosterone producing adenoma (n=6) or who had bilateral adrenal hyperplasia (n=9). No patient required invasive treatments to control bleeding or blood transfusion. In conclusion, AH usually has a positive outcome causing either no or minor effects on adrenal function, and AVS should remain the best approach to primary aldosteronism subtype differentiation. PMID- 26573705 TI - Nrf2-Mediated Cardiac Maladaptive Remodeling and Dysfunction in a Setting of Autophagy Insufficiency. AB - Nuclear factor erythroid-2-related factor 2 (Nrf2) appears to exert either a protective or detrimental effect on the heart; however, the underlying mechanism remains poorly understood. Herein, we uncovered a novel mechanism for turning off the Nrf2-mediated cardioprotection and switching on Nrf2-mediated cardiac dysfunction. In a murine model of pressure overload-induced cardiac remodeling and dysfunction via transverse aortic arch constriction, knockout of Nrf2 enhanced myocardial necrosis and death rate during an initial stage of cardiac adaptation when myocardial autophagy function is intact. However, knockout of Nrf2 turned out to be cardioprotective throughout the later stage of cardiac maladaptive remodeling when myocardial autophagy function became insufficient. Transverse aortic arch constriction -induced activation of Nrf2 was dramatically enhanced in the heart with impaired autophagy, which is induced by cardiomyocyte specific knockout of autophagy-related gene (Atg)5. Notably, Nrf2 activation coincided with the upregulation of angiotensinogen (Agt) only in the autophagy impaired heart after transverse aortic arch constriction. Agt5 and Nrf2 gene loss of-function approaches in combination with Jak2 and Fyn kinase inhibitors revealed that suppression of autophagy inactivated Jak2 and Fyn and nuclear translocation of Fyn, while enhancing nuclear translocation of Nrf2 and Nrf2 driven Agt expression in cardiomyocytes. Taken together, these results indicate that the pathophysiological consequences of Nrf2 activation are closely linked with the functional integrity of myocardial autophagy during cardiac remodeling. When autophagy is intact, Nrf2 is required for cardiac adaptive responses; however, autophagy impairment most likely turns off Fyn-operated Nrf2 nuclear export thus activating Nrf2-driven Agt transcription, which exacerbates cardiac maladaptation leading to dysfunction. PMID- 26573706 TI - Association of Cross-Sectional and Longitudinal Change in Arterial Stiffness With Gene Expression in the Twins UK Cohort. AB - We investigated whether expression of genes previously implicated in arterial stiffening associates with cross-sectional and longitudinal measures of arterial stiffness. Women from the Twins UK cohort (n=470, aged 39-81 years) had gene expression in lymphoblastoid cell lines measured using an Illumina microarray. Arterial stiffness was measured by carotid-femoral pulse wave velocity and carotid distensibility. A subsample (n=121) of women had repeat vascular measures after a mean+/-SD follow-up of 4.3+/-1.4 years. Associations of arterial phenotypes with gene expression levels were examined for 52 genes identified from previous association studies. The gene transcript most closely associated with pulse wave velocity in cross-sectional analysis was ectonucleotide pyrophosphatase/phosphodiesterase (P=0.012). Pleiotropic genetic effects accounted for 14% of the phenotypic correlation between ectonucleotide pyrophosphatase/phosphodiesterase expression and pulse wave velocity. Progression of pulse wave velocity during the follow-up period best related to expression of ectonucleotide pyrophosphatase/phosphodiesterase (beta=0.19, P=0.008) and collagen type IV alpha 1 (beta=0.32, P<0.0001). Gene transcripts most closely related to change in carotid distensibility during the follow-up period were endothelial nitric oxide synthase (beta=-0.20, P=0.005), angiotensin-converting enzyme (beta=-0.15, P=0.035), and B-cell CLL/lymphoma11B (beta=0.18, P=0.010). Expression levels of angiotensin-converting enzyme also related to progression in carotid diameter (beta=0.21, P=0.012). Expression levels of ectonucleotide pyrophosphatase/phosphodiesterase, involved in arterial calcification, and collagen type IV alpha 1, involved in collagen formation, correlate with aortic stiffening. These genes may be functional mediators of arterial stiffening. PMID- 26573707 TI - Regulator of G-Protein Signaling 10 Negatively Regulates Cardiac Remodeling by Blocking Mitogen-Activated Protein Kinase-Extracellular Signal-Regulated Protein Kinase 1/2 Signaling. AB - Regulator of G-protein signaling 10 (RGS10) is an important member of the RGS family and produces biological effects in multiple organs. We used a genetic approach to study the role of RGS10 in the regulation of pathological cardiac hypertrophy and found that RGS10 can negatively influence pressure overload induced cardiac remodeling. RGS10 expression was markedly decreased in failing human hearts and hypertrophic murine hearts. The extent of aortic banding-induced cardiac hypertrophy, dysfunction, and fibrosis in RGS10-knockout mice was exacerbated, whereas the heart of transgenic mice with cardiac-specific RGS10 overexpression exhibited an alleviated response to pressure overload. Consistently, RGS10 also inhibited an angiotensin II-induced hypertrophic response in isolated cardiomyocytes. Mechanistically, cardiac remodeling improvement elicited by RGS10 was associated with the abrogation of mitogen activated protein kinase kinase 1/2-extracellular signal-regulated protein kinase 1/2 signaling. Furthermore, the inhibition of mitogen-activated protein kinase kinase-extracellular signal-regulated protein kinase 1/2 transduction abolished RGS10 deletion-induced hypertrophic aggravation. These findings place RGS10 and its downstream signaling mitogen-activated protein kinase kinase-extracellular signal-regulated protein kinase 1/2 as crucial regulators of pathological cardiac hypertrophy after pressure overload and identify this pathway as a potential therapeutic target to attenuate the pressure overload-driven cardiac remodeling. PMID- 26573708 TI - Genotype-Specific Steroid Profiles Associated With Aldosterone-Producing Adenomas. AB - Primary aldosteronism comprises 2 main subtypes: unilateral aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia. Somatic KCNJ5 mutations are found in APA at a prevalence of around 40% that drive and sustain aldosterone excess. Somatic APA mutations have been described in other genes (CACNA1D, ATP1A1, and ATP2B3) albeit at a lower frequency. Our objective was to identify genotype-specific steroid profiles in adrenal venous (AV) and peripheral venous (PV) plasma in patients with APAs. We measured the concentrations of 15 steroids in AV and PV plasma samples by liquid chromatography-tandem mass spectrometry from 79 patients with confirmed unilateral primary aldosteronism. AV sampling lateralization ratios of steroids normalized either to cortisol or to DHEA+androstenedione were also calculated. The hybrid steroid 18-oxocortisol exhibited 18- and 16-fold higher concentrations in lateralized AV and PV plasma, respectively, from APA with KCNJ5 mutations compared with all other APA combined together (P<0.001). Lateralization ratios for the KCNJ5 group were also generally higher. Strikingly, we demonstrate that a distinct steroid signature can differentiate APA genotype in AV and PV plasma. Notably, a 7-steroid fingerprint in PV plasma correctly classified 92% of the APA according to genotype. Prospective studies are necessary to translate these findings into clinical practice and determine if steroid fingerprinting could be of value to select patients with primary aldosteronism who are particularly suitable candidates for adrenal venous sampling because of a high probability of having an APA. PMID- 26573709 TI - Extreme Air Pollution Conditions Adversely Affect Blood Pressure and Insulin Resistance: The Air Pollution and Cardiometabolic Disease Study. AB - Mounting evidence supports that fine particulate matter adversely affects cardiometabolic diseases particularly in susceptible individuals; however, health effects induced by the extreme concentrations within megacities in Asia are not well described. We enrolled 65 nonsmoking adults with metabolic syndrome and insulin resistance in the Beijing metropolitan area into a panel study of 4 repeated visits across 4 seasons since 2012. Daily ambient fine particulate matter and personal black carbon levels ranged from 9.0 to 552.5 ug/m(3) and 0.2 to 24.5 ug/m(3), respectively, with extreme levels observed during January 2013. Cumulative fine particulate matter exposure windows across the prior 1 to 7 days were significantly associated with systolic blood pressure elevations ranging from 2.0 (95% confidence interval, 0.3-3.7) to 2.7 (0.6-4.8) mm Hg per SD increase (67.2 ug/m(3)), whereas cumulative black carbon exposure during the previous 2 to 5 days were significantly associated with ranges in elevations in diastolic blood pressure from 1.3 (0.0-2.5) to 1.7 (0.3-3.2) mm Hg per SD increase (3.6 ug/m(3)). Both black carbon and fine particulate matter were significantly associated with worsening insulin resistance (0.18 [0.01-0.36] and 0.22 [0.04-0.39] unit increase per SD increase of personal-level black carbon and 0.18 [0.02-0.34] and 0.22 [0.08-0.36] unit increase per SD increase of ambient fine particulate matter on lag days 4 and 5). These results provide important global public health warnings that air pollution may pose a risk to cardiometabolic health even at the extremely high concentrations faced by billions of people in the developing world today. PMID- 26573710 TI - Inhibition of Brain Mitogen-Activated Protein Kinase Signaling Reduces Central Endoplasmic Reticulum Stress and Inflammation and Sympathetic Nerve Activity in Heart Failure Rats. AB - Mitogen-activated protein kinase (MAPK) signaling and endoplasmic reticulum (ER) stress in the brain have been implicated in the pathophysiology of hypertension. This study determined whether ER stress occurs in subfornical organ and hypothalamic paraventricular nucleus in heart failure (HF) and how MAPK signaling interacts with ER stress and other inflammatory mediators. HF rats had significantly higher levels of the ER stress biomarkers (glucose-regulated protein 78, activating transcription factor 6, activating transcription factor 4, X-box binding protein 1, P58(IPK), and C/EBP homologous protein) in subfornical organ and paraventricular nucleus, which were attenuated by a 4-week intracerebroventricular infusion of inhibitors selective for p44/42 MAPK (PD98059), p38 MAPK (SB203580), or c-Jun N-terminal kinase (SP600125). HF rats also had higher mRNA levels of tumor necrosis factor-alpha, interleukin-1beta, cyclooxygenase-2, and nuclear factor-kappaB p65, and a lower mRNA level of IkappaB-alpha, in subfornical organ and paraventricular nucleus, compared with SHAM rats, and these indicators of increased inflammation were attenuated in the HF rats treated with the MAPK inhibitors. Plasma norepinephrine level was higher in HF rats than in SHAM rats but was reduced in the HF rats treated with PD98059 and SB203580. A 4-week intracerebroventricular infusion of PD98059 also improved some hemodynamic and anatomic indicators of left ventricular function in HF rats. These data demonstrate that ER stress increases in the subfornical organ and paraventricular nucleus of rats with ischemia-induced HF and that inhibition of brain MAPK signaling reduces brain ER stress and inflammation and decreases sympathetic excitation in HF. An interaction between MAPK signaling and ER stress in cardiovascular regions of the brain may contribute to the development of HF. PMID- 26573711 TI - Cytochrome P450 1B1 Contributes to the Development of Atherosclerosis and Hypertension in Apolipoprotein E-Deficient Mice. AB - Cytochrome P450 (CYP) 1B1 contributes to vascular smooth muscle cell growth and hypertension in male mice. This study was conducted to determine the contribution of CYP1B1 to the development of atherosclerosis and hypertension and associated pathogenesis in 8-week-old male apolipoprotein E-deficient (ApoE(-/ )/Cyp1b1(+/+)), and ApoE- and CYP1B1-deficient (ApoE(-/-)/Cyp1b1(-/-)) mice fed a normal or atherogenic diet for 12 weeks. A separate group of ApoE(-/ )/Cyp1b1(+/+) mice on an atherogenic diet was injected every third day with the CYP1B1 inhibitor, 2,3',4,5'-tetramethoxystilbene (300 MUg/kg), or its vehicle, dimethyl sulfoxide (30 MUL, IP); systolic blood pressure was measured by the tail cuff method. After 12 weeks, mice were euthanized, blood collected for lipid analysis, and aortas harvested for measuring lesions and remodeling, and for infiltration of inflammatory cells by histological and immunohistochemical analysis, respectively, and for reactive oxygen species production. Blood pressure, areas of lipids and collagen deposition, elastin breaks, infiltration of macrophages and T lymphocytes, reactive oxygen species generation in the aorta, and plasma lipid levels were increased in ApoE(-/-)/Cyp1b1(+/+) mice on an atherogenic diet; these changes were minimized in mice given 2,3',4,5' tetramethoxystilbene, and in ApoE(-/-)/Cyp1b1(-/-) mice on an atherogenic diet; absorption/production of lipids remained unaltered in these mice. These data suggest that aortic lesions, hypertension, and associated pathogenesis in ApoE(-/ )/Cyp1b1(+/+) mice on an atherogenic diet are most likely dependent on CYP1B1 generated oxidative stress and increased plasma lipid levels independent of blood pressure and absorption of lipids. CYP1B1 could serve as a novel target for developing drugs to treat atherosclerosis and hypertension caused by hypercholesterolemia. PMID- 26573712 TI - Growth Arrest-Specific 6 Exacerbates Pressure Overload-Induced Cardiac Hypertrophy. AB - Growth arrest-specific 6 (GAS6) is a member of the vitamin K-dependent protein family that is involved in the regulation of the cardiovascular system, including vascular remodeling, homeostasis, and atherosclerosis. However, there is still no study that systemically elucidates the role of GAS6 in cardiac hypertrophy. Here, we found that GAS6 was upregulated in human dilated cardiomyopathic hearts, hypertrophic murine hearts, and angiotensin II-treated cardiomyocytes. Next, we examined the influence of GAS6 expression in response to a cardiac stress by inducing chronic pressure overload with aortic banding in wild-type and GAS6 knockout mice or cardiac-specific GAS6 overexpressing mice. Under basal conditions, the GAS6-knockout mice had normal left ventricular structure and function but after aortic banding, the mice demonstrated less hypertrophy, fibrosis, and contractile dysfunction when compared with wild-type mice. Conversely, cardiac-specific overexpression of GAS6 exacerbated aortic banding induced cardiac hypertrophy, fibrosis, and dysfunction. Furthermore, we demonstrated that GAS6 activated the mitogen-activated protein kinase kinase 1/2 extracellular signal-regulated kinase 1/2 pathway during pressure overload induced cardiac hypertrophy, and the pharmacological mitogen-activated protein kinase kinase 1/2 inhibitor U0126 almost completely reversed GAS6 overexpression induced cardiac hypertrophy and fibrosis, resulting in improved cardiac function. Collectively, our data support the notion that GAS6 impairs ventricular adaptation to chronic pressure overload by activating mitogen-activated protein kinase kinase 1/2-extracellular signal-regulated kinase 1/2 signaling. Our findings suggest that strategies to reduce GAS6 activity in cardiac tissue may be a novel approach to attenuate the development of congestive heart failure. PMID- 26573714 TI - Are Hemodynamic Factors Involved in Cognitive Impairment? PMID- 26573713 TI - Cerebrovascular Damage Mediates Relations Between Aortic Stiffness and Memory. AB - Aortic stiffness is associated with cognitive decline. Here, we examined the association between carotid-femoral pulse wave velocity and cognitive function and investigated whether cerebrovascular remodeling and parenchymal small vessel disease damage mediate the relation. Analyses were based on 1820 (60% women) participants in the Age, Gene/Environment Susceptibility-Reykjavik Study. Multivariable linear regression models adjusted for vascular and demographic confounders showed that higher carotid-femoral pulse wave velocity was related to lower memory score (standardized beta: -0.071+/-0.023; P=0.002). Cerebrovascular resistance and white matter hyperintensities were each associated with carotid femoral pulse wave velocity and memory (P<0.05). Together, cerebrovascular resistance and white matter hyperintensities (total indirect effect: -0.029; 95% CI, -0.043 to -0.017) attenuated the direct relation between carotid-femoral pulse wave velocity and memory (direct effect: -0.042; 95% CI, -0.087 to 0.003; P=0.07) and explained ~41% of the observed effect. Our results suggest that in older adults, associations between aortic stiffness and memory are mediated by pathways that include cerebral microvascular remodeling and microvascular parenchymal damage. PMID- 26573715 TI - Hypertension Risk Subsequent to Gestational Dysglycemia Is Modified by Race/Ethnicity. AB - Gestational diabetes mellitus is associated with an increased risk of type 2 diabetes mellitus and hypertension. Additionally, gestational dysglycemia has been associated with an increased risk of type 2 diabetes mellitus but not yet associated with hypertension subsequent to pregnancy in long-term follow-up. Therefore, we set out to examine this relationship as well as the role of race/ethnicity in modifying this relationship. We analyzed a prospective observational cohort followed between 1998 and 2007. There were 17 655 women with self-reported race/ethnicity and full-term, live births. A 1-hour 50 g oral glucose-load test and a 3-hour 100 g oral glucose-tolerance test enabled third trimester stratification of women into 1 of 4 glucose-tolerance groups: (1) normal (n=15 056); (2) abnormal glucose-load test (n=1558); (3) abnormal glucose load and -tolerance tests (n=520); and (4) gestational diabetes mellitus (n=521). Women were then followed for a mean+/-standard deviation of 4.1+/-2.9 years after delivery for the development of hypertension. Although gestational diabetes mellitus was associated with an increased risk of hypertension after pregnancy (odds ratio [95% confidence interval]: 1.58 [1.02, 2.45]; P=0.04), dysglycemia defined by an abnormal glucose-load test predicted hypertension only among black women (4.52 [1.24, 16.52]; P=0.02). The risk of hypertension after pregnancy among dysglycemia groups not meeting criteria for gestational diabetes mellitus varied based on the race/ethnicity of the population. Further research on the implications of the intersection of race/ethnicity and gestational dysglycemia on subsequent hypertension is warranted. PMID- 26573716 TI - Regulators of G-Protein Signaling 10 and Heart Failure: The Importance of Negative Regulators of Heart Disease. PMID- 26573717 TI - Central Renin-Angiotensin System Activation and Inflammation Induced by High-Fat Diet Sensitize Angiotensin II-Elicited Hypertension. AB - Obesity has been shown to promote renin-angiotensin system activity and inflammation in the brain and to be accompanied by increased sympathetic activity and blood pressure. Our previous studies demonstrated that administration of a subpressor dose of angiotensin (Ang) II sensitizes subsequent Ang II-elicited hypertension. The present study tested whether high-fat diet (HFD) feeding also sensitizes the Ang II-elicited hypertensive response and whether HFD-induced sensitization is mediated by an increase in renin-angiotensin system activity and inflammatory mechanisms in the brain. HFD did not increase baseline blood pressure, but enhanced the hypertensive response to Ang II compared with a normal fat diet. The sensitization produced by the HFD was abolished by concomitant central infusions of either a tumor necrosis factor-alpha synthesis inhibitor, pentoxifylline, an Ang II type 1 receptor blocker, irbesartan, or an inhibitor of microglial activation, minocycline. Furthermore, central pretreatment with tumor necrosis factor-alpha mimicked the sensitizing action of a central subpressor dose of Ang II, whereas central pentoxifylline or minocycline abolished this Ang II-induced sensitization. Real-time quantitative reverse transcription-polymerase chain reaction analysis of lamina terminalis tissue indicated that HFD feeding, central tumor necrosis factor-alpha, or a central subpressor dose of Ang II upregulated mRNA expression of several components of the renin-angiotensin system and proinflammatory cytokines, whereas inhibition of Ang II type 1 receptor and of inflammation reversed these changes. The results suggest that HFD-induced sensitization of Ang II-elicited hypertension is mediated by upregulation of the brain renin-angiotensin system and of central proinflammatory cytokines. PMID- 26573718 TI - Evaluation of an 18-month commercial multidisciplinary obesity treatment programme. AB - The treatment of obesity is an often studied subject. Although reductions in weight and improvements in cardiometabolic risk factors are important aims of obesity treatment, improvements in quality of life and eating behaviour are also relevant outcomes. In this practice-based study, we evaluated an 18-month commercial multidisciplinary obesity treatment programme and report on treatment results for weight, cardiometabolic risk factors, eating behaviour and quality of life. From a local commercial obesity treatment centre, 426 subjects (65% female; 45.4 +/- 12.2 years; body mass index 40.0 +/- 6.6 kg m(-2)) were recruited. Measurements of body weight, height, body composition, waist circumference and blood pressure were scheduled at baseline and every 3 months, whereas fasting blood collections were scheduled at baseline and every 6 months. At the same time points, participants were asked to fill in questionnaires on dietary intake, eating behaviour and quality of life. After 18 months of treatment programme, average weight change [mean (95% confidence interval)] was -10.9 kg (-14.8 to 7.0; P < 0.001) for the completers (n = 181) and -10.8 kg (-14.2 to -7.4; P < 0.001) for the intention-to-treat population (n = 426). Waist circumference (mean +/- standard error of the mean) (-0.13 +/- 0.01 cm; P < 0.001), fat mass (-7.8 +/ 1.3 kg; P < 0.001) systolic (-11.4 +/- 2.0; P < 0.001) and diastolic (-7.0 +/- 1.3; P < 0.001) blood pressure, triglycerides (-0.4 +/- 0.1; P = 0.004) and plasma glucose (-0.6 +/- 0.2; P = 0.001) were significantly reduced. The PCS scale of the SF-36 and all three scales of the three-factor eating questionnaire improved significantly over the 18-month treatment period. All collected data in this study provide evidence that a multidisciplinary treatment programme based on lifestyle modification results in significant weight loss and improvements in cardiometabolic risk factors, quality of life and eating behaviour. PMID- 26573720 TI - Probing the roles of two tryptophans surrounding the unique zinc coordination site in lipase family I.5. AB - A unique zinc domain found in all of the identified members of the lipase family I.5 is surrounded by two conserved tryptophans (W61 and W212). In this study, we investigated the role of these hydrophobic residues in thermostability and thermoactivity of the lipase from Bacillus thermocatenulatus (BTL2) taken as the representative of the family. Circular dichroism spectroscopy revealed that the secondary structure of BTL2 is conserved by the tryptophan mutations (W61A, W212A, and W61A/W212A), and that W61 is located in a more rigid and less solvent exposed region than is W212. Thermal denaturation and optimal activity analyses pointed out that zinc induces thermostability and thermoactivity of BTL2, in which both tryptophans W61 and W212 play contributing roles. Molecular explanations describing the roles of these tryptophans were pursued by X-ray crystallography of the open form of the W61A mutant and molecular dynamics simulations which highlighted a critical function for W212 in zinc binding to the coordination site. This study reflects the potential use of hydrophobic amino acids in vicinity of metal coordination sites in lipase biocatalysts design. PMID- 26573719 TI - Rescue and evaluation of a recombinant PRRSV expressing porcine Interleukin-4. AB - BACKGROUND: The current vaccines for porcine reproductive and respiratory syndrome virus (PRRSV) have failed to provide broad protection against infection by various strains of PRRSV. Porcine Interleukin-4 (pIL-4) plays an important role in the regulation of the immune response and has been used previously as an immunological adjuvant. The objective of this study was to construct a recombinant PRRSV expressing pIL-4 and to evaluate the immune response of the recombinant virus in piglets. METHODS: The pIL-4 gene was inserted in the PRRSV (CH-1R strain) infectious clone by overlap PCR. Indirect immunofluorescence assay (IFA) and Western blotting were used to confirm the recombinant virus. The stability of the recombinant virus was assessed by DNA sequencing and IFA after 15 passages in vitro. Recombinant virus was injected into pigs and efficacy of immune protection was evaluated in comparison with the parental virus. RESULTS: The recombinant virus (CH-1R/pIL-4) was successfully rescued and shown to have similar growth kinetics as the parental virus. The recombinant virus was stable for 15 passages in cell culture. Pigs vaccinated with CH-1R/pIL-4 produced a similar humoral response to the response elicited by parental virus, but IL-4 level in the supernatant of PBMCs from pigs vaccinated with CH-1R/pIL-4 was significantly higher than the parent virus at 28 days post-immunization (DPI). Flow cytometric (FCM) analysis showed that the percentage of CD4(+)CD8(+) double positive T (DPT) cells in the CH-1R/pIL-4 vaccinated group was significantly higher than the parental virus at 3 and 7 Days Post-Challenge (DPC), and the IL-4 level in the blood significantly increased at 7 DPC. However, the viral load and histopathology did not show significant difference between the two groups. CONCLUSIONS: A recombinant PRRSV expressing porcine IL-4 was rescued and it remained genetically stable in vitro. The recombinant virus induced higher DPT ratios and IL-4 levels in the blood after HP-PRRSV challenge compared to the parental virus in piglets. However, it did not significantly improve protection efficacy of PRRSV vaccine. PMID- 26573721 TI - Vanadium(III)-L-cysteine protects cisplatin-induced nephropathy through activation of Nrf2/HO-1 pathway. AB - Cisplatin (CDDP) is one of the first-line anticancer drugs; however, the major limitation of CDDP therapy is development of nephrotoxicity (25-35% cases), whose precise mechanism mainly involves oxidative stress, inflammation and cell death. Therefore, in search of a potential chemoprotectant, an organovanadium complex, viz., vanadium(III)-L-cysteine (VC-III) was evaluated against CDDP-induced nephropathy in mice. CDDP was administered intraperitoneally (5 mg/kg b.w.) and VC-III was given by oral gavage (1 mg/kg b.w.) in concomitant and pre-treatment schedule. The results showed that VC-III administration reduced (p < 0.001) serum creatinine and blood urea nitrogen levels, suggesting amelioration of renal dysfunction. VC-III treatment also significantly (p < 0.001) prevented CDDP induced generation of reactive oxygen species, reactive nitrogen species, and onset of lipid peroxidation in kidney tissues of the experimental mice. In addition, VC-III also substantially (p < 0.001) restored CDDP-induced depleted activities of the renal antioxidant enzymes such as, superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase, and glutathione (reduced) level. Furthermore, histopathological study also confirmed the renoprotective efficacy of VC-III. Western blotting analysis appended by immunohistochemical data showed that VC-III treatment quite effectively reduced the expression of proinflammatory mediators such as, NFkappabeta, COX-2 and IL-6. VC-III administration also stimulated Nrf2-mediated antioxidant defense system by promotion of downstream antioxidant enzymes, such as HO-1. Moreover, treatment with VC-III significantly (p < 0.001) enhanced CDDP-mediated cytotoxicity in MCF 7 and NCI-H520 human cancer cell lines. Thus, VC-III can serve as a suitable chemoprotectant and increase the therapeutic window of CDDP in cancer patients. PMID- 26573722 TI - Complete genome analysis of a novel recombinant isolate of pepper veinal mottle virus from mainland China. AB - BACKGROUND: Pepper veinal mottle virus (PVMV) was well established in Africa, and also reported infecting pepper (Capsicum annuum L) in Taiwan and India. However, there is not available of PVMV in mainland China. Here, the first complete genome sequence of PVMV isolated from pepper in mainland China was reported. FINDING: The complete genomic sequence of isolate PVMV-HN isolated from pepper in mainland China is reported in this study. The genome of PVMV-HN is 9793 nucleotides (nt) excluding the poly (A) tail, shares 98-99 % nucleotide sequence identity with those two PVMV isolates from Ghana and Taiwan. Recombinant analysis showed that PVMV-HN probably represents a novel recombinant of PVMV. The phylogenetic relationship of PVMV-HN isolate to other PVMV isolates and other potyviruses based on genome or polyprotein sequence level and CP gene level, was also analyzed in this study. CONCLUSION: The current study will help to understand phylogenetic relationship of isolate PVMV-HN. PMID- 26573724 TI - Inter-relationship among renal arteriosclerosis, vascular function indexes, estimated renal function indexes and biochemical markers in patients with chronic kidney disease. PMID- 26573723 TI - Polyethylene glycol-mediated fusion of herpes simplex type 1 virions with the plasma membrane of cells that support endocytic entry. AB - BACKGROUND: Mouse B78 cells and Chinese hamster ovary (CHO) cells are important to the study of HSV-1 entry because both are resistant to infection at the level of viral entry. When provided with a gD-receptor such as nectin-1, these cells support HSV-1 entry by an endocytosis pathway. Treating some viruses bound to cells with the fusogen polyethylene glycol (PEG) mediates viral fusion with the cell surface but is insufficient to rescue viral entry. It is unclear whether PEG mediated fusion of HSV with the plasma membrane of B78 or CHO cells results in successful entry and infection. FINDINGS: Treating HSV-1 bound to B78 or CHO cells with PEG allowed viral entry as measured by virus-induced beta galactosidase activity. Based on the mechanism of PEG action, we propose that entry likely proceeds by direct fusion of HSV particles with the plasma membrane. Under the conditions tested, PEG-mediated infection of CHO cells progressed to the level of HSV late gene expression, while B78 cells supported HSV DNA replication. We tested whether proteolysis or acidification of cell-bound virions could trigger HSV fusion with the plasma membrane. Under the conditions tested, mildly acidic pH of 5-6 or the protease trypsin were not capable of triggering HSV-1 fusion as compared to PEG-treated cell-bound virions. CONCLUSIONS: B78 cells and CHO cells, which typically endocytose HSV prior to viral penetration, are capable of supporting HSV-1 entry via direct penetration. HSV capsids delivered directly to the cytosol at the periphery of these cells complete the entry process. B78 and CHO cells may be utilized to screen for factors that trigger entry as a consequence of fusion of virions with the cell surface, and PEG treatment can provide a necessary control. PMID- 26573725 TI - Secondary syphilis with pulmonary involvement. PMID- 26573727 TI - Stability strengths and weaknesses in protein structures detected by statistical potentials: Application to bovine seminal ribonuclease. AB - We present an in silico method to estimate the contribution of each residue in a protein to its overall stability using three database-derived statistical potentials that are based on inter-residue distances, backbone torsion angles and solvent accessibility, respectively. Residues that contribute very unfavorably to the folding free energy are defined as stability weaknesses, whereas residues that show a highly stabilizing contribution are called stability strengths. Strengths and/or weaknesses on residues that are in spatial contact are clustered into 3-dimensional (3D) stability patches. The identification and analysis of strength- and weakness-containing regions in a protein may reveal structural or functional characteristics, and/or interesting spots to introduce mutations. To illustrate the power of our method, we apply it to bovine seminal ribonuclease. This enzyme catalyzes the degradation of RNA strands, and has the peculiarity of undergoing 3D domain swapping in physiological conditions. The weaknesses and strengths were compared among the monomeric, dimeric and swapped dimeric forms. We identified weaknesses among the catalytic residues and a mixture of weaknesses and strengths among the substrate-binding residues in the three forms. In the regions involved in 3D swapping, we observed an accumulation of weaknesses in the monomer, which disappear in the dimer and especially in the swapped dimer. Moreover, monomeric homologous proteins were found to exhibit less weaknesses in these regions, whereas mutants known to favor unswapped dimerization appear stabilized in this form. Our method has several perspectives for functional annotation, rational prediction of targeted mutations, and mapping of stability changes upon conformational rearrangements. PMID- 26573726 TI - An ethnobotanical survey of medicinal plants used in the East Sepik province of Papua New Guinea. AB - BACKGROUND: Rapid modernization in the East Sepik (ES) Province of Papua New Guinea (PNG) is resulting in a decrease in individuals knowledgeable in medicinal plant use. Here we report a synthesis and comparison of traditional medicinal plant use from four ethnically distinct locations in the ES Province and furthermore compare them to two other previous reports of traditional plant use from different provinces of PNG. METHODS: This manuscript is based on an annotated combination of four Traditional Medicines (TM) survey reports generated by University of Papua New Guinea (UPNG) trainees. The surveys utilized a questionnaire titled "Information sheet on traditional herbal preparations and medicinal plants of PNG", administered in the context of the TM survey project which is supported by WHO, US NIH and PNG governmental health care initiatives and funding. Regional and transregional comparison of medicinal plant utilization was facilitated by using existing plant databases: the UPNG TM Database and the PNG Plant Database (PNG Plants) using Bayesian statistical analysis. RESULTS: Medicinal plant use between four distinct dialect study areas in the ES Province of PNG showed that only a small fraction of plants had shared use in each area, however usually utilizing different plant parts, being prepared differently and to treat different medical conditions. Several instances of previously unreported medicinal plants could be located. Medicinally under- and over-utilized plants were found both in the regional reports and in a transregional analysis, thus showing that these medicinal utilization frequencies differ between provinces. CONCLUSIONS: Documentation of consistent plant use argues for efficacy and is particularly important since established and effective herbal medicinal interventions are sorely needed in the rural areas of PNG, and unfortunately clinical validation for the same is often lacking. Despite the existence of a large corpus of medical annotation of plants for PNG, previously unknown medical uses of plants can be uncovered. Furthermore, comparisons of medicinal plant utilization is possible if databases are reformatted for consistencies that allow comparisons. A concerted effort in building easily comparable databases could dramatically facilitate ethnopharmacological analysis of the existing plant diversity. PMID- 26573728 TI - Conferring specificity in redox pathways by enzymatic thiol/disulfide exchange reactions. AB - Thiol-disulfide exchange reactions are highly reversible, displaying nucleophilic substitutions mechanism (S(N)2 type). For aliphatic, low molecular thiols, these reactions are slow, but can attain million times faster rates in enzymatic processes. Thioredoxin (Trx) proteins were the first enzymes described to accelerate thiol-disulfide exchange reactions and their high reactivity is related to the high nucleophilicity of the attacking thiol. Substrate specificity in Trx is achieved by several factors, including polar, hydrophobic, and topological interactions through a groove in the active site. Glutaredoxin (Grx) enzymes also contain the Trx fold, but they do not share amino acid sequence similarity with Trx. A conserved glutathione binding site is a typical feature of Grx that can reduce substrates by two mechanisms (mono and dithiol). The high reactivity of Grx enzymes is related to the very acid pK(a) values of reactive Cys that plays roles as good leaving groups. Therefore, although distinct oxidoreductases catalyze similar thiol-disulfide exchange reactions, their enzymatic mechanisms vary. PDI and DsbA are two other oxidoreductases, but they are involved in disulfide bond formation, instead of disulfide reduction, which is related to the oxidative environment where they are found. PDI enzymes and DsbC are endowed with disulfide isomerase activity, which is related with their tetra-domain architecture. As illustrative description of specificity in thiol disulfide exchange, redox aspects of transcription activation in bacteria, yeast, and mammals are presented in an evolutionary perspective. Therefore, thiol disulfide exchange reactions play important roles in conferring specificity to pathways, a required feature for signaling. PMID- 26573729 TI - The associations between peer victimization, psychological symptoms and quality of life in adolescents with acne vulgaris. PMID- 26573730 TI - Comparison of intradialytic changes in weight and fluid status. PMID- 26573731 TI - JQ1, an inhibitor of the epigenetic reader BRD4, suppresses the bidirectional MYC AP4 axis via multiple mechanisms. AB - Bromodomain and extra-terminal domain (BET) family proteins are representative epigenetic modulators that read acetylated lysine residues and transfer cellular signals. Recently, the BET protein inhibitor JQ1 was developed and has been extensively studied in many cancer cell types. We demonstrated that JQ1 effectively suppressed the MYC-AP4 axis and induced antitumorigenic effects by targeting a bidirectional positive loop between MYC and AP4 which was first proposed in the present study. MYC and AP4 are the direct targets of BRD4, as demonstrated by chromatin immunoprecipitation (ChIP) assay and BRD4 loss-of function experiments. Although inhibition of the MYC/MAC dimer suppressed AP4, the efficacy of suppression was not as effective as BRD4 inhibition. Notably, AP4 loss-of-function studies demonstrated that AP4 is a major critical target of JQ1 and that MYC is a novel downstream target of AP4, as demonstrated by AP4 binding to the MYC promoter. Taken together, our results suggest that the epigenetic reader BRD4 is a key mediator of the activated MYC-AP4 axis, which supports the possibility that targeting BET protein is a novel therapeutic strategy for MYC AP4 axis-activated cancers. PMID- 26573732 TI - Within-session communication patterns predict alcohol treatment outcomes. AB - BACKGROUND: Within-session client speech is theorized to be a key mechanism of behavior change in motivational interviewing (MI), a directional, client-centered approach to behavior change. Client change talk (CT: speech indicating movement toward changing a problematic health behavior) and sustain talk (ST: speech supporting continuing a problematic health behavior) have each shown relationships with outcomes. However, it may be the case that patterns of within session client speech, rather than counts of client speech, are important for producing change. METHODS: Recorded initial MI/MET psychotherapy sessions from Project MATCH had been previously rated using the Motivational Interviewing Sequential Code for Observing Process Exchange (MI-SCOPE), a mutually exclusive and exhaustive sequential coding system. From these existing data, session conditional probabilities for transitions of interest (the transition from CT to more CT, and the transition from reflections of CT to CT) were analyzed as empirical Bayes estimates of log-normalized odds ratios. RESULTS: CT frequencies and these log-normalized odds ratios were entered as independent variables into longitudinal generalized estimating equation (GEE) models predicting within treatment and post-treatment drinking. While all variables were significant predictors of within-treatment drinking, only the CT-CT transition emerged as a significant predictor of decreased drinking after treatment. CONCLUSIONS: The momentum of a client's speech about change during an MI session may be a better predictor of outcome than is a simple frequency count of it. Attending not only to the mere occurrence of CT, but also recognizing the importance of consecutive client statements of CT, may improve treatment outcomes. PMID- 26573733 TI - TLR vaccine adjuvants: closing the stable door before novel influenza strains bolt? PMID- 26573734 TI - Fabrication of Ultrafine Palladium Phosphide Nanoparticles as Highly Active Catalyst for Chemoselective Hydrogenation of Alkynes. AB - Monodisperse palladium phosphide nanoparticles (Pd-P NPs) with a smallest size ever reported of 3.9 nm were fabricated using cheap and stable triphenylphosphine as phosphorous source. After the deposition and calcination at 300 degrees C and 400 degrees C, the resulting Pd-P NPs increased in size to 4.0 nm and 4.8 nm, respectively. Notably, the latter NPs probably crystallized with a single phase of Pd3 P0.95, which acted as a highly active catalyst in semi- and stereoselective hydrogenation of alkynes. X-ray photoelectron spectroscopy analysis determined a positive shift of binding energy for Pd(3d) in Pd-P NPs compared to that in Pd on carbon. It indicated the electron flow from metal to phosphorus and the larger electron deficiency of Pd in Pd-P NPs, which suppressed palladium hydride formation and subsequently increased the selectivity. Thus, this result may also indicate the applications of Pd-P and other metal-P NPs in various selective hydrogenation reactions. PMID- 26573735 TI - The First Histidine Triad Motif of PhtD Is Critical for Zinc Homeostasis in Streptococcus pneumoniae. AB - Streptococcus pneumoniae is the world's foremost human pathogen. Acquisition of the first row transition metal ion zinc is essential for pneumococcal colonization and disease. Zinc is acquired via the ATP-binding cassette transporter AdcCB and two zinc-binding proteins, AdcA and AdcAII. We have previously shown that AdcAII is reliant upon the polyhistidine triad (Pht) proteins to aid in zinc recruitment. Pht proteins generally contain five histidine (His) triad motifs that are believed to facilitate zinc binding and therefore play a significant role in pneumococcal metal ion homeostasis. However, the importance and potential redundancy of these motifs have not been addressed. We examined the effects of mutating each of the five His triad motifs of PhtD. The combination of in vitro growth assays, active zinc uptake, and PhtD expression studies show that the His triad closest to the protein's amino terminus is the most important for zinc acquisition. Intriguingly, in vivo competitive infection studies investigating the amino- and carboxyl-terminal His triad mutants indicate that the motifs have similar importance in colonization. Collectively, our new insights into the contributions of the individual His triad motifs of PhtD, and by extension the other Pht proteins, highlight the crucial role of the first His triad site in zinc acquisition. This study also suggests that the Pht proteins likely play a role beyond zinc acquisition in pneumococcal virulence. PMID- 26573736 TI - Influence of IgG Subclass on Human Antimannan Antibody-Mediated Resistance to Hematogenously Disseminated Candidiasis in Mice. AB - Candida albicans is a yeast-like pathogen and can cause life-threatening systemic candidiasis. Its cell surface is enriched with mannan that is resistant to complement activation. Previously, we developed the recombinant human IgG1 antimannan antibody M1g1. M1g1 was found to promote complement activation and phagocytosis and protect mice from systemic candidiasis. Here, we evaluate the influence of IgG subclass on antimannan antibody-mediated protection. Three IgG subclass variants of M1g1 were constructed: M1g2, M1g3, and M1g4. The IgG subclass identity for each variant was confirmed with DNA sequence and subclass specific antibodies. These variants contain identical M1 Fabs and exhibited similar binding affinities for C. albicans yeast and purified mannan. Yeast cells and hyphae recovered from the kidney of antibody-treated mice with systemic candidiasis showed uniform binding of each variant, indicating constitutive expression of the M1 epitope and antibody opsonization in the kidney. All variants promoted deposition of both murine and human C3 onto the yeast cell surface, with M1g4 showing delayed activation, as determined by flow cytometry and immunofluorescence microscopy. M1g4-mediated complement activation was found to be associated with its M1 Fab that activates the alternative pathway in an Fc independent manner. Treatment with each subclass variant extended the survival of mice with systemic candidiasis (P < 0.001). However, treatment with M1g1, M1g3, or M1g4, but not with M1g2, also reduced the kidney fungal burden (P < 0.001). Thus, the role of human antimannan antibody in host resistance to systemic candidiasis is influenced by its IgG subclass. PMID- 26573737 TI - Host Genetic Variations and Sex Differences Potentiate Predisposition, Severity, and Outcomes of Group A Streptococcus-Mediated Necrotizing Soft Tissue Infections. AB - Host genetic variations play an important role in several pathogenic diseases, and we previously provided strong evidence that these genetic variations contribute significantly to differences in susceptibility and clinical outcomes of invasive group A Streptococcus (GAS) patients, including sepsis and necrotizing soft tissue infections (NSTIs). The goal of the present study was to investigate how genetic variations and sex differences among four commonly used mouse strains contribute to variation in severity, manifestations, and outcomes of NSTIs. DBA/2J mice were more susceptible to NSTIs than C57BL/6J, BALB/c, and CD-1 mice, as exhibited by significantly greater bacteremia, excessive dissemination to the spleen, and significantly higher mortality. Differences in the sex of the mice also contributed to differences in disease severity and outcomes: DBA/2J female mice were relatively resistant compared to their male counterparts. However, DBA/2J mice exhibited minimal weight loss and developed smaller lesions than did the aforementioned strains. Moreover, at 48 h after infection, compared with C57BL/6J mice, DBA/2J mice had increased bacteremia, excessive dissemination to the spleen, and excessive concentrations of inflammatory cytokines and chemokines. These results indicate that variations in the host genetic context as well as sex play a dominant role in determining the severity of and susceptibility to GAS NSTIs. PMID- 26573739 TI - Molecular dynamics simulations elucidate the mode of protein recognition by Skp1 and the F-box domain in the SCF complex. AB - Polyubiquitination of the target protein by a ubiquitin transferring machinery is key to various cellular processes. E3 ligase Skp1-Cul1-F-box (SCF) is one such complex which plays crucial role in substrate recognition and transfer of the ubiquitin molecule. Previous computational studies have focused on S-phase kinase associated protein 2 (Skp2), cullin, and RING-finger proteins of this complex, but the roles of the adapter protein Skp1 and F-box domain of Skp2 have not been determined. Using sub-microsecond molecular dynamics simulations of full-length Skp1, unbound Skp2, Skp2-Cks1 (Cks1: Cyclin-dependent kinases regulatory subunit 1), Skp1-Skp2, and Skp1-Skp2-Cks1 complexes, we have elucidated the function of Skp1 and the F-box domain of Skp2. We found that the L16 loop of Skp1, which was deleted in previous X-ray crystallography studies, can offer additional stability to the ternary complex via its interactions with the C-terminal tail of Skp2. Moreover, Skp1 helices H6, H7, and H8 display vivid conformational flexibility when not bound to Skp2, suggesting that these helices can recognize and lock the F-box proteins. Furthermore, we observed that the F-box domain could rotate (5 degrees -129 degrees ), and that the binding partner determined the degree of conformational flexibility. Finally, Skp1 and Skp2 were found to execute a domain motion in Skp1-Skp2 and Skp1-Skp2-Cks1 complexes that could decrease the distance between ubiquitination site of the substrate and the ubiquitin molecule by 3 nm. Thus, we propose that both the F-box domain of Skp2 and Skp1-Skp2 domain motions displaying preferential conformational control can together facilitate polyubiquitination of a wide variety of substrates. PMID- 26573738 TI - Neutralization of Clostridium difficile Toxin B Mediated by Engineered Lactobacilli That Produce Single-Domain Antibodies. AB - Clostridium difficile is the primary cause of nosocomial antibiotic-associated diarrhea in the Western world. The major virulence factors of C. difficile are two exotoxins, toxin A (TcdA) and toxin B (TcdB), which cause extensive colonic inflammation and epithelial damage manifested by episodes of diarrhea. In this study, we explored the basis for an oral antitoxin strategy based on engineered Lactobacillus strains expressing TcdB-neutralizing antibody fragments in the gastrointestinal tract. Variable domain of heavy chain-only (VHH) antibodies were raised in llamas by immunization with the complete TcdB toxin. Four unique VHH fragments neutralizing TcdB in vitro were isolated. When these VHH fragments were expressed in either secreted or cell wall-anchored form in Lactobacillus paracasei BL23, they were able to neutralize the cytotoxic effect of the toxin in an in vitro cell-based assay. Prophylactic treatment with a combination of two strains of engineered L. paracasei BL23 expressing two neutralizing anti-TcdB VHH fragments (VHH-B2 and VHH-G3) delayed killing in a hamster protection model where the animals were challenged with spores of a TcdA(-) TcdB(+) strain of C. difficile (P < 0.05). Half of the hamsters in the treated group survived until the termination of the experiment at day 5 and showed either no damage or limited inflammation of the colonic mucosa despite having been colonized with C. difficile for up to 4 days. The protective effect in the hamster model suggests that the strategy could be explored as a supplement to existing therapies for patients. PMID- 26573741 TI - Abstracts of the 17th Congress of the European Society for Organ Transplantation 13 - 16 September 2015, Brussels, Belgium. PMID- 26573740 TI - Electrospun polyvinyl alcohol-polyvinyl pyrrolidone nanofibrous membranes for interactive wound dressing application. AB - Cross-linked polyvinyl alcohol (PVA) and polyvinyl pyrrolidone (PVP) composite nanofibrous membranes have been prepared by electrospinning. Mechanical properties of the membranes improved significantly with PVP addition. PVP improved hydrophilicity and sustainable degradation of the membranes. Biocompatibility of the membranes was assessed by in vitro culture of native skin cells (L929 fibroblast and HaCaT keratinocytes). Tests showed sustained release of the antibiotic ciprofloxacin hydrochloride monohydrate by the membranes. Further, zone of inhibition study against Staphylococcus aureus growth demonstrated protective action against external pathogenic microbes. These studies show these simple PVA-PVP nanofibrous membranes are promising interactive antibiotic-eluting wound dressing materials. PMID- 26573742 TI - Eggs of Ephestia kuehniella and Ceratitis capitata, and motile stages of the astigmatid mites Tyrophagus putrescentiae and Carpoglyphus lactis as factitious foods for Orius spp. AB - Several factitious foods were assessed for rearing the anthocorid predators Orius thripoborus (Hesse) and Orius naivashae (Poppius) (Hemiptera: Anthocoridae) in the laboratory. Developmental and reproductive traits of both Orius species were examined when offered frozen eggs of the Mediterranean flour moth, Ephestia kuehniella Zeller, frozen processed eggs of the medfly, Ceratitis capitata Wiedemann, or mixed motile stages of the astigmatid mites Tyrophagus putrescentiae (Schrank) or Carpoglyphus lactis (L). Whereas C. lactis and T. putresecentiae proved to be an inferior food for rearing O. thripoborus and O. naivashae, eggs of C. capitata fully supported development and reproduction of both predators. Results on medfly eggs were similar or slightly inferior to those on E. kuehniella eggs, which is the standard food for culturing these anthocorid bugs. O. thripoborus could be maintained for 4 consecutive generations on C. capitata eggs indicating that processed medfly eggs can be a suitable and cheaper alternative to E. kuehniella eggs for prolonged rearing of these Orius spp. PMID- 26573743 TI - To eliminate tuberculosis, we must universally encourage treatment of its latent form - Reply. PMID- 26573744 TI - MiR-340 suppresses cell migration and invasion by targeting MYO10 in breast cancer. AB - Breast cancer is one of the most common malignant tumors among females, and can seriously affect the physical and mental health and even threaten the lives of women. Recently, research has demonstrated that microRNAs (miRNAs), as a new method of regulation, have been shown to have oncogenic and tumor-suppressive functions in human breast cancer. Detection of their expression may lead to the identification of novel markers for breast cancer. In the present study, we firstly detected miR-340 expression and found lower expression of miR-340 in 6 human breast cancer cell lines by using RT-qPCR. Then by using wound healing assay and Transwell migration and invasion experiments, we focused on the role of miR-340 in the regulation of tumor cell migration and invasion, exploring the relationship between them. The results revealed that induction of miR-340 expression was able to suppress tumor cell migration and invasion, whereas knockdown of miR-340 expression promoted breast cancer cell migration and invasion. At the gene level, MYO10 (myosin X), as a direct miR-340 target gene, mediated the cell migration and invasion. Finally, we verified our research further at the tissue specimen level and in animal experiments. In brief, miR-340 plays an important role in breast cancer progression. Thus, miR-340 may be further explored as a novel biomarker for breast cancer metastasis and prognosis, and potentially a therapeutic target. PMID- 26573746 TI - Nanoporous PtRu Alloys with Unique Catalytic Activity toward Hydrolytic Dehydrogenation of Ammonia Borane. AB - Nanoporous (NP) PtRu alloys with three different bimetallic components were straightforwardly fabricated by dealloying PtRuAl ternary alloys in hydrochloric acid. Selective etching of aluminum from source alloys generates bicontinuous network nanostructures with uniform size and structure. The as-made NP-PtRu alloys exhibit superior catalytic activity toward the hydrolytic dehydrogenation of ammonia borane (AB) than pure NP-Pt and NP-Ru owing to alloying platinum with ruthenium. The NP-Pt70 Ru30 alloy exhibits much higher specific activity toward hydrolytic dehydrogenation of AB than NP-Pt30 Ru70 and NP-Pt50 Ru50 . The hydrolysis activation energy of NP-Pt70 Ru30 was estimated to be about 38.9 kJ mol(-1) , which was lower than most of the reported activation energy values in the literature. In addition, recycling tests show that the NP-Pt70 Ru30 is still highly active in the hydrolysis of AB even after five runs, which indicates that NP-PtRu alloy accompanied by the network nanoarchitecture is beneficial to improve structural stability toward the dehydrogenation of AB. PMID- 26573745 TI - Improving appropriate polypharmacy for older people in primary care: selecting components of an evidence-based intervention to target prescribing and dispensing. AB - BACKGROUND: The use of multiple medicines (polypharmacy) is increasingly common in older people. Ensuring that patients receive the most appropriate combinations of medications (appropriate polypharmacy) is a significant challenge. The quality of evidence to support the effectiveness of interventions to improve appropriate polypharmacy is low. Systematic identification of mediators of behaviour change, using the Theoretical Domains Framework (TDF), provides a theoretically robust evidence base to inform intervention design. This study aimed to (1) identify key theoretical domains that were perceived to influence the prescribing and dispensing of appropriate polypharmacy to older patients by general practitioners (GPs) and community pharmacists, and (2) map domains to associated behaviour change techniques (BCTs) to include as components of an intervention to improve appropriate polypharmacy in older people in primary care. METHODS: Semi structured interviews were conducted with members of each healthcare professional (HCP) group using tailored topic guides based on TDF version 1 (12 domains). Questions covering each domain explored HCPs' perceptions of barriers and facilitators to ensuring the prescribing and dispensing of appropriate polypharmacy to older people. Interviews were audio-recorded and transcribed verbatim. Data analysis involved the framework method and content analysis. Key domains were identified and mapped to BCTs based on established methods and discussion within the research team. RESULTS: Thirty HCPs were interviewed (15 GPs, 15 pharmacists). Eight key domains were identified, perceived to influence prescribing and dispensing of appropriate polypharmacy: 'Skills', 'Beliefs about capabilities', 'Beliefs about consequences', 'Environmental context and resources', 'Memory, attention and decision processes', 'Social/professional role and identity', 'Social influences' and 'Behavioural regulation'. Following mapping, four BCTs were selected for inclusion in an intervention for GPs or pharmacists: 'Action planning', 'Prompts/cues', 'Modelling or demonstrating of behaviour' and 'Salience of consequences'. An additional BCT ('Social support or encouragement') was selected for inclusion in a community pharmacy-based intervention in order to address barriers relating to interprofessional working that were encountered by pharmacists. CONCLUSIONS: Selected BCTs will be operationalised in a theory-based intervention to improve appropriate polypharmacy for older people, to be delivered in GP practice and community pharmacy settings. Future research will involve development and feasibility testing of this intervention. PMID- 26573747 TI - A composite approach towards a complete model of the myosin rod. AB - Sarcomeric myosins have the remarkable ability to form regular bipolar thick filaments that, together with actin thin filaments, constitute the fundamental contractile unit of skeletal and cardiac muscle. This has been established for over 50 years and yet a molecular model for the thick filament has not been attained. In part this is due to the lack of a detailed molecular model for the coiled-coil that constitutes the myosin rod. The ability to self-assemble resides in the C-terminal section of myosin known as light meromyosin (LMM) which exhibits strong salt-dependent aggregation that has inhibited structural studies. Here we evaluate the feasibility of generating a complete model for the myosin rod by combining overlapping structures of five sections of coiled-coil covering 164 amino acid residues which constitute 20% of LMM. Each section contains ~ 7-9 heptads of myosin. The problem of aggregation was overcome by incorporating the globular folding domains, Gp7 and Xrcc4 which enhance crystallization. The effect of these domains on the stability and conformation of the myosin rod was examined through biophysical studies and overlapping structures. In addition, a computational approach was developed to combine the sections into a contiguous model. The structures were aligned, trimmed to form a contiguous model, and simulated for >700 ns to remove the discontinuities and achieve an equilibrated conformation that represents the native state. This experimental and computational strategy lays the foundation for building a model for the entire myosin rod. PMID- 26573749 TI - "Witchcraft, a fad or a racket?" Food allergy in historical perspective. PMID- 26573748 TI - Novel Association of miR-451 with the Incidence of TEVG Stenosis in a Murine Model. AB - The development of a tissue-engineered vascular graft (TEVG) holds great promise for advancing the field of cardiac surgery. Despite the successful translation of this technology, previous reports identify the primary mode of graft failure as stenosis secondary to intimal hyperplasia. MicroRNAs (miRNAs) regulate gene expression by interfering with mRNA function and recent research has suggested miRNA as a potential therapeutic target. The role of miRNAs in TEVGs during neotissue formation is currently unknown. In this study, we investigated if miRNAs regulate the inhibition of graft stenosis. Biodegradable PGA-P(LA/CL) scaffolds were implanted as inferior vena cava interposition grafts in a murine model (n = 14). Mice were sacrificed 14 days following implantation and TEVGs were harvested for histological analysis and miRNA profiling using Affymetrix miRNA arrays. Graft diameters were measured histologically, and the largest grafts (patent group) and smallest grafts (stenosed group) were profiled (n = 4 for each group). Cell population in each graft was analyzed with immunohistochemistry using antismooth muscle actin (SMA) and antimacrophage (F4/80) antibodies. The graft diameter was significantly greater in the patent group (0.63 +/- 0.06 mm) than in the stenosed group (0.17 +/- 0.06 mm) (p < 0.01). Cell proliferation was significantly greater in the stenosed grafts than in patent grafts (p < 0.01: SMA [187 +/- 11 vs. 77 +/- 8 cells] vs. p = 0.025: F4/80 [245 +/- 23 vs. 187 +/- 11 cells]). MiRNA array of 1416 genes showed that in stenosed grafts, mir-451, mir-338, and mir-466 were downregulated and mir-154 was upregulated. Mir-451 exhibited the greatest difference in expression between stenosed and patent grafts by -3.1-fold. Significant negative correlation was found between the expression of mir-451 and cell proliferation (SMA: r = -0.86, p = 0.003; F4/80: r = -0.89, p = 0.001). Our data, along with previous evidence that mir-451 regulates tumor suppressor genes, suggest that downregulation of mir 451 promotes acute proliferation of macrophages and smooth muscle cells, thereby inducing TEVG stenosis. Adequate expression of mir-451 may be critical for improving TEVG patency. PMID- 26573750 TI - A 63-year-old man with chronic spontaneous urticaria. PMID- 26573751 TI - Medical students talk openly about their mental health challenges. PMID- 26573752 TI - Optimism for restoration of refugee health care. PMID- 26573753 TI - Management of acne: Canadian clinical practice guideline. PMID- 26573754 TI - Intervention to improve the quality of antimicrobial prescribing for urinary tract infection: a cluster randomized trial. AB - BACKGROUND: Overuse of antimicrobial therapy in the community adds to the global spread of antimicrobial resistance, which is jeopardizing the treatment of common infections. METHODS: We designed a cluster randomized complex intervention to improve antimicrobial prescribing for urinary tract infection in Irish general practice. During a 3-month baseline period, all practices received a workshop to promote consultation coding for urinary tract infections. Practices in intervention arms A and B received a second workshop with information on antimicrobial prescribing guidelines and a practice audit report (baseline data). Practices in intervention arm B received additional evidence on delayed prescribing of antimicrobials for suspected urinary tract infection. A reminder integrated into the patient management software suggested first-line treatment and, for practices in arm B, delayed prescribing. Over the 6-month intervention, practices in arms A and B received monthly audit reports of antimicrobial prescribing. RESULTS: The proportion of antimicrobial prescribing according to guidelines for urinary tract infection increased in arms A and B relative to control (adjusted overall odds ratio [OR] 2.3, 95% confidence interval [CI] 1.7 to 3.2; arm A adjusted OR 2.7, 95% CI 1.8 to 4.1; arm B adjusted OR 2.0, 95% CI 1.3 to 3.0). An unintended increase in antimicrobial prescribing was observed in the intervention arms relative to control (arm A adjusted OR 2.2, 95% CI 1.2 to 4.0; arm B adjusted OR 1.4, 95% CI 0.9 to 2.1). Improvements in guideline-based prescribing were sustained at 5 months after the intervention. INTERPRETATION: A complex intervention, including audit reports and reminders, improved the quality of prescribing for urinary tract infection in Irish general practice. TRIAL REGISTRATION: ClinicalTrials.gov, no. NCT01913860. PMID- 26573755 TI - Arsenic and cadmium are contaminants of concern. PMID- 26573756 TI - Changing the antibiotic prescribing behaviour of clinicians in primary care. PMID- 26573757 TI - CMPA not an insurer, NB court told. PMID- 26573758 TI - Phonon-Assisted Anti-Stokes Lasing in ZnTe Nanoribbons. AB - Phonon-assisted anti-Stokes emission and its stimulated emission in polar semiconductor ZnTe are demonstrated via the annihilation of phonons as a result of strong exciton-phonon coupling. The findings are not only important for developing high-power radiation-balanced lasers, but are also promising for manufacturing ultraefficient solid-state laser coolers. PMID- 26573759 TI - Molecular and functional characterization of a candidate sex pheromone receptor OR1 in Spodoptera litura. AB - Olfaction is primarily mediated by highly specified olfactory receptors (ORs). Here, we cloned and identified an olfactory receptor, named SlituOR1 (Genbank no. JN835269), from Spodoptera litura and found evidence that it is a candidate pheromone receptor. It exhibited male-biased expression in the antennae, where it was localized at the base of sensilla trichoidea, the antennal sensilla mainly responsive to pheromones in moths. Conserved orthologues of this receptor, found among known pheromone receptors within the Lepidoptera, and SlituOR1 were placed among a clade of candidate pheromone receptors in a phylogeny tree of insect OR gene sequences. SlituOR1 showed differential expression in S. litura populations attracted to traps baited with different ratios of the two sex pheromone components (9Z,11E)-tetradecadienyl acetate (Z9E11-14:OAc) and (9Z,12E) tetradecadienyl acetate (Z9E12-14:OAc). Knocking down of SlituOR1 by RNA interference reduced the electroantennogram (EAG) response to Z9E11-14:OAc, and this result is consistent with the field trapping experiment. We infer that variation in transcription levels of olfactory receptors may modulate sex pheromone perception in male moths and could provide some of the flexibility required to maintain the functionality of communication with females when a population is adapting to a new niche and reproductive isolation becomes an advantage. PMID- 26573760 TI - To eliminate tuberculosis, we must universally encourage treatment of its latent form. PMID- 26573761 TI - MiR-106b~25 cluster regulates multidrug resistance in an ABC transporter independent manner via downregulation of EP300. AB - MicroRNA (miR)-106b~25 cluster regulates bypass of doxorubicin and gamma radiation induced senescence by downregulation of the E-cadherin transcriptional activator EP300. We asked whether upregulation of miR-106~25 cluster generates cells with a truly multidrug resistant (MDR) phenotype and whether this is due to upregulation of the ATP-binding cassette (ABC) transporter P-glycoprotein. We used minimally transformed mammary epithelial breast cancer cells (MTMECs) in which the miR-106b~25 cluster was experimentally upregulated by lentiviral transfection or in which hairpins targeting either EP300 or E-cadherin mRNAs have been expressed with lentiviruses. We find that overexpression of miR-106b~25 cluster led to the generation of MDR MTMECs (resistant to etoposide, colchicine and paclitaxel). Paclitaxel resistance was also studied after experimental downregulation of EP300 or E-cadherin. However none of these cells overexpressed P-glycoprotein or where able to efflux a fluorescent derivative of paclitaxel, making this phenotype drug-transporter independent. Paclitaxel treatment in MTMECs led to an increase in early apoptotic cells (Annexin V-positive), activation of caspase-9 and increase in the proportion of cells at the G2/M phase of the cell cycle. However, MTMEC overexpressing miR-106b~25 cluster, or with EP300 or E-cadherin downregulated, showed less activation of apoptosis, caspase-9 and caspase-3/-7 activities. Thus, miR-106b~25 cluster controls transporter independent MDR by apoptosis evasion via downregulation of EP300. PMID- 26573762 TI - Immunization against inhibin improves in vivo and in vitro embryo production. AB - The multiple ovulation and embryo transfer (MOET) technique has become an important breeding method in modern animal selection programs and a reproductive technique that can bypass ovarian dysfunction caused by heat stress to maintain reproductive performances in dairy cows. However, oocyte and embryo development often suffer from defects following repeated superovulation protocols. This phenomenon might be attributed to high levels of circulating inhibin, which is secreted by the supra-normal numbers of developing follicles during the process of superovulation. Through inhibin's negative impact on ovarian follicle development, high concentrations of inhibin might reduce oocyte quality and embryo developmental competence. Neutralizing endogenous inhibin bioactivities by active or passive immunizations against inhibin has been demonstrated to stimulate extra follicle development and induce multiple ovulations in both rodents and ruminants. Combined with conventional superovulatory protocols, immunization against inhibin further enhances follicle development and embryo yield. Furthermore, immunization against inhibin not only enhanced embryo quantity but also embryo quality in studies conducted in cows, sheep and water buffaloes. Similar beneficial effects on enhancing embryo development quality have been demonstrated in in vitro studies, where treatment with inhibin alpha subunit antibody enhances oocyte maturation and development of IVF or parthenogenically activated embryos. Thus, immunization against inhibin in combination with a conventional superovulation protocol can become a new technique to improve embryo production efficiency in vivo, as well as to develop a new oocyte IVM/IVF technique that can improve embryo IVP production efficiency. PMID- 26573763 TI - Cryopreservation of stallion spermatozoa using different cryoprotectants and combinations of cryoprotectants. AB - The present study investigates the effects of five cryoprotectants (CPAs) and cryoprotectant combinations on the post-thaw total motility, progressive motility, viability, mitochondrial membrane potential and acrosome integrity in stallion spermatozoa. In Experiment 1, the objective was to compare the impact of different concentrations (2.5%, 3.5% and 5%) of a single CPA, including glycerol (Gly), ethylene glycol (EG), dimethyl sulphoxide (DMSO), methyl formamide (MF), and dimethylformamide (DMF) for stallion spermatozoa cryopreservation. In Experiment 2, two or more CPAs were used to assess whether this improved post thaw spermatozoa quality. Gly, MF and DMF, were used to prepare seven combinations of freezing extender with different mixtures of cryoprotectant, and the 3.5% Gly, MF and DMF were used as a control group. The results show that post thaw total motility, progressive motility, viability, and mitochondrial membrane potential for all concentrations of EG and DMSO were less than the 3.5% and 5% Gly and MF and 2.5% and 3.5% DMF (P<0.05). Use of the 3.5% concentration resulted in the greater post-thaw total motility and progressive motility than the 2.5% and 5% concentrations for all CPAs. The results for the use of different combinations of cryoprotectant indicate there are differences in progressive motility and viability. The viability with the use of Gly(2/3)+MF(1/3) was 44.65% and was greater than the Gly(1/3)+MF(1/3)+DMF(1/3) (30.96%), MF(2/3)+DMF(1/3) (35.05%), Gly (32.21%) and MF(33.76%) (P<0.05). The progressive motility with the use of the MF(2/3)+Gly(1/3) combination was 36.0% and was greater than in the DMF (25.0%) and MF(2/3)+DMF(1/3) (22.7%) (P<0.05). These results suggest that using the appropriate cryoprotectant combination instead of a single cryoprotectant can improve horse spermatozoa cryopreservation. PMID- 26573764 TI - Is using an open-reservoir cardiopulmonary bypass circuit after 6 days on standby safe? AB - OBJECTIVES: To investigate the sterility and biocompatibility of a stored open reservoir cardiopulmonary bypass circuit maintained on standby. METHODS: A total of four cardiopulmonary bypass circuits were assembled, primed and left to recirculate. One unit was placed in a positive-pressure operating room and the other three were placed in the intensive care unit. The primed solutions, which employed Ringer's acetate, hydroxyethylated starch and hydrate steroid, were sampled after 0, 24, 48, 72, 96, 120 and 144 h in all cardiopulmonary bypass circuits to measure the bacteria count, endotoxin count and chemical substances within the primed solution. Chemical substances were detected by assessing the following: the total organic carbon by the combustion oxidation infrared spectrometry, and molecular weight spread by gel permeation chromatography. The environments were left unattended and were uncovered during the storage period to mimic the clinical scenario. RESULTS: There were no bacteria in any of the primed solutions, and only very minute concentrations of endotoxins were detected, both in the operating room and in the intensive care unit. The total organic carbon concentration was slightly more concentrated in the 144-h samples when compared with that in the 0-h samples. However, the molecular weight spread of the 0-h sample was identical to that in the 144-h sample. DISCUSSION: With regard to the presence of bacteria and endotoxins, we noted that the hardshell reservoirs in the cardiopulmonary bypass circuit were effectively sealed and not invaded by bacteria. With regard to the presence of chemical substances, we noted that an increase in total organic carbon concentration was caused by bedewing, and that there was no release of chemical substances such as a polymer-coating agent, or other molecular materials in the primed solution. CONCLUSIONS: There was no contamination or release of chemical substances in 6-day old cardiopulmonary bypass circuits maintained on standby, confirming that they are safe to use in terms of sterility and biocompatibility. PMID- 26573765 TI - Tissue Engineering for Pediatric Applications. AB - Severe birth defects occur in ~ 2-3% of live-born infants and are a leading cause of death in the young. Structural malformations can occur in just about any major organ system and often their causes are unknown. The pediatric population presents a unique set of opportunities to the field of tissue engineering and regenerative medicine (TERM). Infants and young children have significantly greater regenerative capacity than adults, which could be leveraged in TERM strategies. Children also arguably stand to benefit the most from TERM. Although the lack of growth potential and relatively short life span of synthetic materials may be suitable for adults, it is unacceptable for children. Furthermore, given that there is a particular scarcity of pediatric donor organs, the need for living functional tissue replacements that can grow with the child is quite evident. There is enormous potential for the TERM community to address the needs of the pediatric population. PMID- 26573766 TI - Evidence for the involvement of two heterodisulfide reductases in the energy conserving system of Methanomassiliicoccus luminyensis. AB - Methanomassiliicoccus luminyensis was isolated from the human gut, and requires H2 and methanol or methylamines to produce methane. The organism lacks cytochromes, indicating that it cannot couple membrane-bound electron transfer reactions with extrusion of H(+) or Na(+) ions using known methanogenic pathways. Furthermore, M. luminyensis contains a soluble hydrogenase/heterodisulfide reductase complex (MvhAGD/HdrABC) as found in obligate hydrogenotrophic methanogens, but the energy-conserving methyltransferase (MtrA-H) is absent. Thus, the question arises as to how this species synthesizes ATP. We present evidence that M. luminyensis uses two types of heterodisulfide reductases (HdrABC and HdrD) in a novel process for energy conservation. Quantitative RT-PCR studies revealed that genes encoding these heterodisulfide reductases showed high expression levels. Other genes with high transcript abundance were fpoA (part of the operon encoding the 'headless' F420 H2 dehydrogenase) and atpB (part of the operon encoding the A1 Ao ATP synthase). High activities of the soluble heterodisulfide reductase HdrABC and the hydrogenase MvhADG were found in the cytoplasm of M. luminyensis. Also, heterologously produced HdrD was able to reduce CoM-S-S-CoB using reduced methylviologen as an electron donor. We propose that membrane-bound electron transfer is based on conversion of two molecules of methanol and concurrent formation of two molecules of the heterodisulfide CoM-S-S CoB. First the HdrABC/MvhADG complex catalyzes the H2 -dependent reduction of CoM S-S-CoB and formation of reduced ferredoxin. In a second cycle, reduced ferredoxin is oxidized by the 'headless' F420 H2 dehydrogenase, thereby translocating up to 4 H(+) across the membrane, and electrons are channeled to HdrD for reduction of the second heterodisulfide. PMID- 26573767 TI - Ambipolar Organic Tri-Gate Transistor for Low-Power Complementary Electronics. AB - Ambipolar transistors typically suffer from large off-current inherently due to ambipolar conduction. Using a tri-gate transistor it is shown that it is possible to electrostatically switch ambipolar polymer transistors from ambipolar to unipolar mode. In unipolar mode, symmetric characteristics with an on/off current ratio of larger than 10(5) are obtained. This enables easy integration into low power complementary logic and volatile electronic memories. PMID- 26573768 TI - Curcumin induces autophagy, inhibits proliferation and invasion by downregulating AKT/mTOR signaling pathway in human melanoma cells. AB - Melanoma is the foremost malignant cutaneous cancer and it is extremely resistant to chemotherapy and radiotherapy. Curcumin is an active component of turmeric, the yellow spice derived from the rhizome of Curcuma longa, and is widely known for its anti-inflammatory and anti-cancerogenic properties. Several recent studies suggest that curcumin induces apoptosis by modulating multiple signaling pathways to exert its anticancer effect. In the present study, we investigated the effect of curcumin on the viability, invasion potential, cell cycle, autophagy and the AKT, mTOR, P70S6K proteins of AKT/mTOR signaling pathway in human melanoma A375 and C8161 cell lines in vitro and in an in vivo tumorigenesis model. Curcumin effectively inhibited the proliferation of melanoma cells in vitro and in vivo. It suppressed cell invasion, arrested the cancer cells at G2/M phase of the cell cycle, and induced autophagy. Furthermore, curcumin suppressed the activation of AKT, mTOR and P70S6K proteins. Curcumin, therefore, is a potent suppressor of cell viability and invasion, and simultaneously an inducer of autophagy in A375 and C8161 cells. Accordingly, curcumin could be a novel therapeutic candidate for the management of melanoma. PMID- 26573770 TI - Soft, Oxidative Stripping of Alkyl Thiolate Ligands from Hydroxyapatite-Supported Gold Nanoclusters for Oxidation Reactions. AB - A strategy for the mild deprotection of alkyl-thiolated (6-mercaptohexanoic acid, MHA, and 3-mercaptopropanoic acid, MPA) gold nanoclusters (Au NCs) supported on hydroxyapatite (HAP) has been developed by employing a peroxide (tert-butyl hydroperoxide, TBHP, or hydrogen peroxide, H2O2) as an oxidant. The thiol ligands on the supported Au NCs were removed after oxidation, and the size and integrity of the supported clusters were well-preserved. The bare gold clusters on HAP after removal of the ligands were catalytically effective for the epoxidation of styrene and the aerobic oxidation of benzyl alcohol. These two reactions were also investigated on calcined Au NCs that were supported on HAP for comparison, and the resulting Au NCs that were prepared by using this new strategy showed superior catalytic activity. PMID- 26573769 TI - Psychiatric gene discoveries shape evidence on ADHD's biology. AB - A strong motivation for undertaking psychiatric gene discovery studies is to provide novel insights into unknown biology. Although attention-deficit hyperactivity disorder (ADHD) is highly heritable, and large, rare copy number variants (CNVs) contribute to risk, little is known about its pathogenesis and it remains commonly misunderstood. We assembled and pooled five ADHD and control CNV data sets from the United Kingdom, Ireland, United States of America, Northern Europe and Canada. Our aim was to test for enrichment of neurodevelopmental gene sets, implicated by recent exome-sequencing studies of (a) schizophrenia and (b) autism as a means of testing the hypothesis that common pathogenic mechanisms underlie ADHD and these other neurodevelopmental disorders. We also undertook hypothesis-free testing of all biological pathways. We observed significant enrichment of individual genes previously found to harbour schizophrenia de novo non-synonymous single-nucleotide variants (SNVs; P=5.4 * 10(-4)) and targets of the Fragile X mental retardation protein (P=0.0018). No enrichment was observed for activity-regulated cytoskeleton-associated protein (P=0.23) or N-methyl-D aspartate receptor (P=0.74) post-synaptic signalling gene sets previously implicated in schizophrenia. Enrichment of ADHD CNV hits for genes impacted by autism de novo SNVs (P=0.019 for non-synonymous SNV genes) did not survive Bonferroni correction. Hypothesis-free testing yielded several highly significantly enriched biological pathways, including ion channel pathways. Enrichment findings were robust to multiple testing corrections and to sensitivity analyses that excluded the most significant sample. The findings reveal that CNVs in ADHD converge on biologically meaningful gene clusters, including ones now established as conferring risk of other neurodevelopmental disorders. PMID- 26573771 TI - Adult Human Mesenchymal Stem Cell Differentiation at the Cell Population and Single-Cell Levels Under Alternating Electric Current. AB - Mesenchymal stem cells, precursors that can differentiate into osteoblasts, chondrocytes, and adipocytes, have tremendous potential for derivation of cells with specific (e.g., osteogenic) phenotypes for tissue engineering and tissue regeneration applications. To date, the predominant strategy to achieve directed differentiation of MSCs into osteoblasts was to recapitulate the normal developmental ontogeny of osteoblasts using growth factors (e.g., bone morphogenetic proteins). In contrast, the effects of biophysical stimuli alone on such outcomes remain, at best, partially understood. This in vitro study examined and optimized the effects of alternating electric current alone on the differentiation of adult human mesenchymal stem cells (hMSCs) at the cell population and single-cell levels. hMSCs, cultured on flat, indium-tin-oxide coated glass in the absence of supplemented exogenous growth factors were exposed to alternating electric current (5-40 MUA, 5-10 Hz frequency, sinusoidal waveform), for 1-24 h daily for up to 21 consecutive days. Compared to results obtained from the respective controls, hMSC populations exposed to the alternating electric current alone (in the absence of exogenous growth factors) expressed genes at various stages of differentiation (specifically, TAZ, Runx-2, Osterix, Osteopontin, and Osteocalcin). Optimal osteogenic differentiation was achieved when hMSCs were exposed to a 10 MUA, 10 Hz alternating electric current for 6 h daily for up to 21 days. Exclusive osteodifferentiation was observed since genes for the chondrocyte (Collagen Type II) and adipocyte (FABP-4) lineages were not expressed under all conditions of the biophysical stimulus tested. Single cell mRNAs for 45 genes (indicative of hMSC differentiation) were monitored using Fluidigm Systems. Homogeneous expression of the early osteodifferentiation genes (specifically, TAZ and Runx-2) was observed in hMSCs exposed to the alternating electric current at 7 and 21 days. Heterogeneity for all other genes monitored was observed in hMSCs exposed to alternating electric current and in their respective controls. These results provide the first glimpse of gene expression in differentiating hMSCs at the cell population and single cell levels and represent novel approaches for stem cell differentiation pertinent to new tissue formation. PMID- 26573772 TI - Synaptic Metaplasticity Realized in Oxide Memristive Devices. AB - Metaplasticity, a higher order of synaptic plasticity, as well as a key issue in neuroscience, is realized with artificial synapses based on a WO3 thin film, and the activity-dependent metaplastic responses of the artificial synapses, such as spike-timing-dependent plasticity, are systematically investigated. This work has significant implications in neuromorphic computation. PMID- 26573773 TI - MALT1 cleaves the E3 ubiquitin ligase HOIL-1 in activated T cells, generating a dominant negative inhibitor of LUBAC-induced NF-kappaB signaling. AB - Human paracaspase 1 (PCASP1), better known as mucosa associated lymphoid tissue lymphoma translocation 1 (MALT1), plays a key role in immunity and inflammation by regulating gene expression in lymphocytes and other immune cell types. Deregulated MALT1 activity has been implicated in autoimmunity, immunodeficiency and certain types of lymphoma. As a scaffold MALT1 assembles downstream signaling proteins for nuclear factor-kappaB (NF-kappaB) activation, while its proteolytic activity further enhances NF-kappaB activation by cleaving NF-kappaB inhibitory proteins. MALT1 also processes and inactivates a number of mRNA destabilizing proteins, which further fine-tunes gene expression. MALT1 protease inhibitors are currently developed for therapeutic targeting. Here we show that T cell activation, as well as overexpression of the oncogenic fusion protein API2-MALT1, induces the MALT1-mediated cleavage of haem-oxidized IRP2 ubiquitin ligase 1 (HOIL-1). In addition, to acting as a K48-polyubiquitin specific E3 ubiquitin ligase for different substrates, HOIL-1 co-operates in a catalytic-independent manner with the E3 ubiquitin ligase HOIL-1L interacting protein (HOIP) as part of the linear ubiquitin chain assembly complex (LUBAC). Intriguingly, cleavage of HOIL-1 does not directly abolish its ability to support HOIP-induced NF-kappaB signaling, which is still mediated by the N-terminal cleavage fragment, but generates a C-terminal fragment with LUBAC inhibitory properties. We propose that MALT1-mediated HOIL-1 cleavage provides a gain-of-function mechanism that is involved in the negative feedback regulation of NF-kappaB signaling. PMID- 26573774 TI - Downregulation of Bmi-1 is associated with suppressed tumorigenesis and induced apoptosis in CD44+ nasopharyngeal carcinoma cancer stem-like cells. AB - Bmi-1 (B-cell-specific Moloney murine leukemia virus insertion site 1) is a member of the Polycomb group gene (PcG) family, which is involved in the proliferation, migration and tumorigenesis of several types of cancer stem cells (CSCs). However, its precise role and mechanism in CD44+ nasopharyngeal carcinoma (NPC) cancer stem-like cells (CSC-LCs) remain poorly understood. In our previous study, we successfully silenced Bmi-1 by short hairpin RNA (shRNA) in CD44+ NPC CSC-LCs and obtained stable Bmi-1 knockdown (KD) cell lines. In the present study, we tested the cell proliferation by CCK-8 assay and apoptosis by flow cytometry. Scratch wound healing assay, together with Transwell migration and invasion assays were used to measure the migration and invasion capacity. We further evaluated the tumorigenicity of CD44+ NPC CSC-LCs transfected with Bmi-1 shRNA in vivo. Based on our results, knockdown of Bmi-1 by shRNA resulted in the inhibition of tumor proliferation, migration and invasion in vitro, followed by cell apoptosis. In addition, our results preliminarily demonstrated that inhibition of Bmi-1 expression by shRNA increased tumor apoptosis through the p16INK4a-p14ARF-p53 pathway. Bmi-1 silencing in CD44+ NPC CSC-LCs also resulted in the failure to develop tumors in vivo. These results provide important insights into the role of Bmi-1 in the occurrence and development of NPC. Based on our findings, regulation of Bmi-1 in CD44+ NPC CSC-LCs may provide a potential molecular target for the therapy of NPC, and targeted silencing of Bmi-1 by shRNA may have clinical future implications in NPC therapy. PMID- 26573775 TI - Efficient Hole-Transporting Materials with Triazole Core for High-Efficiency Perovskite Solar Cells. AB - Efficient hole-transporting materials (HTMs), TAZ-[MeOTPA]2 and TAZ-[MeOTPATh]2 incorporating two electron-rich diphenylamino side arms, through direct linkage or thiophen bridges, respectively, on the C3- and C5-positions of a 4-phenyl 1,2,4-triazole core were synthesized. These synthetic HTMs with donor-acceptor type molecular structures exhibited effective intramolecular charge transfer for improving the hole-transporting properties. The structural modification of HTMs by thiophene bridging might increase intermolecular pi-pi stacking in the solid state and afford a better spectral response because of their increased pi conjugation length. Perovskite-based cells using TAZ-[MeOTPA]2 and TAZ [MeOTPATh]2 as HTMs afforded high power conversion efficiencies of 10.9 % and 14.4 %, respectively, showing a photovoltaic performance comparable to that obtained using spiro-OMeTAD. These synthetically simple and inexpensive HTMs hold promise for replacing the more expensive spiro-OMeTAD in high-efficiency perovskite solar cells. PMID- 26573776 TI - Lithographic Design of Overhanging Microdisk Arrays Toward Omniphobic Surfaces. AB - Omniphobic surfaces are created by designing an array of overhanging microdisks on a polymer film through two steps of photolithography. Two distinct edges and the large height of the microdisks relative to their separation ensure the formation of an air mat under the microdisks, providing an omniphobic property. Moreover, the freestanding omniphobic films are transparent and flexible, potentially serving as liquid-repellent surfaces in various applications. PMID- 26573777 TI - Antibiotic prescription evaluation in the rehabilitation ward of a geriatric hospital. AB - OBJECTIVES: We aimed to identify the indications for antibiotic prescriptions made to patients hospitalized in the rehabilitation ward of a geriatric hospital. Our final objective was to assess those prescriptions. PATIENTS AND METHODS: Medical experts performed a prospective study of all antibiotic treatments prescribed in the rehabilitation ward over a 4-month period based on Gyssens' algorithm and on the local guidelines for anti-infective drugs. Treatments were considered appropriate when the indication, choice of agent, duration, and dose were approved by the experts. They were however considered unnecessary when the indication was incorrect, and they were deemed inappropriate when the experts approved the indication but considered that treatment modalities were not optimal. We also reviewed the prescription re-evaluation made 48 to 72hours after treatment initiation. RESULTS: We reviewed 142 prescriptions. Treatments had mainly been prescribed for respiratory tract infections (81 infections), urinary tract infections (41), skin infections (15), or abdominal infections (8). A total of 27 prescriptions (19%) were considered unnecessary mainly because a urinary tract infection diagnosis had been wrongly made (21 prescriptions). Half of the prescriptions were considered inappropriate: 38 prescriptions had an inappropriate spectrum of activity and 32 had an inadequate treatment duration. A total of 67 prescriptions (47.2%) had been reassessed 48-72hours after treatment initiation. Overall, 25 prescriptions (17.6%) were considered appropriate and were reassessed 48-72hours after treatment initiation. CONCLUSIONS: We now have a better understanding of antibiotic prescription in a rehabilitation ward context. We identified several points that need to be improved: update and improvement of the local guidelines, better training for prescribers, and creation of a supporting document for the reassessment of the prescriptions 48-72hours after treatment initiation. PMID- 26573778 TI - The extended human PTPome: a growing tyrosine phosphatase family. AB - Tyr phosphatases are, by definition, enzymes that dephosphorylate phospho-Tyr (pTyr) from proteins. This activity is found in several structurally diverse protein families, including the protein Tyr phosphatase (PTP), arsenate reductase, rhodanese, haloacid dehalogenase (HAD) and His phosphatase (HP) families. Most of these families include members with substrate specificity for non-pTyr substrates, such as phospho-Ser/phospho-Thr, phosphoinositides, phosphorylated carbohydrates, mRNAs, or inorganic moieties. A Cys is essential for catalysis in PTPs, rhodanese and arsenate reductase enzymes, whereas this work is performed by an Asp in HAD phosphatases and by a His in HPs, via a catalytic mechanism shared by all of the different families. The category that contains most Tyr phosphatases is the PTP family, which, although it received its name from this activity, includes Ser, Thr, inositide, carbohydrate and RNA phosphatases, as well as some inactive pseudophosphatase proteins. Here, we propose an extended collection of human Tyr phosphatases, which we call the extended human PTPome. The addition of new members (SACs, paladin, INPP4s, TMEM55s, SSU72, and acid phosphatases) to the currently categorized PTP group of enzymes means that the extended human PTPome contains up to 125 proteins, of which ~ 40 are selective for pTyr. We set criteria to ascribe proteins to the extended PTPome, and summarize the more important features of the new PTPome members in the context of their phosphatase activity and their relationship with human disease. PMID- 26573779 TI - Microarray profiling of bone marrow long non-coding RNA expression in Chinese pediatric acute myeloid leukemia patients. AB - Long non-coding RNA (lncRNA) plays a role in gene transcription, protein expression and epigenetic regulation; and altered expression results in cancer development. Acute myeloid leukemia (AML) is rare in children; and thus, this study profiled lncRNA expression in bone marrow samples from pediatric AML patients. Arraystar Human LncRNA Array V3.0 was used to profile differentially expressed lncRNAs in three bone marrow samples obtained from each pediatric AML patient and normal controls. Quantitative polymerase chain reaction (qRT-PCR) was performed to confirm dysregulated lncRNA expressions in 22 AML bone marrow samples. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to construct the lncRNA-mRNA co-expression network. A total of 372 dysregulated lncRNAs (difference >=10-fold) were found in pediatric AML patients compared to normal controls. Fifty-one mRNA levels were significantly upregulated, while 85 mRNA levels were significantly downregulated by >10-fold in pediatric AML, compared to normal controls. GO terms and KEGG pathway annotation data revealed that cell cycle pathway-related genes were significantly associated with pediatric AML. As confirmed by qRT-PCR, expression of 24 of 97 lncRNA was altered in pediatric AML compared to normal controls. In pediatric AML, ENST00000435695 was the most upregulated lncRNA, while ENST00000415964 was the most downregulated lncRNA. Data from this study revealed dysregulated lncRNAs and mRNAs in pediatric AML versus normal controls that could form gene pathways to regulate cell cycle progression and immunoresponse. Further studies are required to determine whether these lncRNAs could serve as novel therapeutic targets and bbdiagnostic biomarkers in pediatric AML. PMID- 26573780 TI - The use of ultrasound in ocular diseases. PMID- 26573781 TI - Phosphodiesterase-5 inhibition improves macrocirculation and microcirculation during cardiopulmonary resuscitation. AB - AIM: This study is to clarify whether sildenafil, which is a selective inhibitor of the isoform 5 of the enzyme phosphodiesterase, improves macrocirculation or/and microcirculation during ventricular fibrillation (VF) and cardiopulmonary resuscitation (CPR) so as to improve outcomes of resuscitation. METHODS: Sixteen female pigs were used. After anesthesia, the abdominal cavity was opened to observe the mesenteric microcirculation. Following the guidelines, we determined microvascular flow index, perfused vessel density and proportion of perfused vessels both for large(diameter >20 MUm)and small (diameter <20 MUm) microvessels. Sildenafil (0.5 mg/kg) or saline was given at 30 minutes before inducing VF. After 8 min VF, 4 min CPR was started and then defibrillation was attempted. RESULTS: Compared with saline, sildenafil reduced the shocks and duration of CPR (all P < .05), and improved coronary perfusion pressure (CPP) during CPR and 24-hour survival (all P < .05). Sildenafil significantly improved microcirculatory parameters in large microvessel and decreased the lactic acid level during VF and CPR (all P < .05), but the differences in small microvessel were not significant (all P > .05). Microvascular flow index in both large and small microvessels were closely correlated to each other (r = 0.91, P < .01), and to CPP during CPR ([r = .88, P < .01] and [r = .70, P < .05], respectively). CONCLUSION: Sildenafil increases the success of resuscitation through improving macrocirculation and microcirculation during VF and CPR. There is a close relationship between microvascular flow and CPP during CPR. PMID- 26573782 TI - Medicaid beneficiaries who continue to use the ED: a focus on the Illinois Medical Home Network. AB - OBJECTIVES: Frequent, nonurgent emergency department use continues to plague the American health care system through ineffective disease management and unnecessary costs. In 2012, the Illinois Medical Home Network (MHN) was implemented to, in part, reduce an overreliance on already stressed emergency departments through better care coordination and access to primary care. The purpose of this study is to characterize MHN patients and compare them with non MHN patients for a preliminary understanding of MHN patients who visit the emergency department. Variables of interest include (1) frequency of emergency department use during the previous 12 months, (2) demographic characteristics, (3) acuity, (4) disposition, and (5) comorbidities. METHODS: We performed a retrospective data analysis of all emergency department visits at a large, urban academic medical center in 2013. Binary logistic regression analyses and analysis of variance were used to analyze data. RESULTS: Medical Home Network patients visited the emergency department more often than did non-MHN patients. Medical Home Network patients were more likely to be African American, Hispanic/Latino, female, and minors when compared with non-MHN patients. Greater proportions of MHN patients visiting the emergency department had asthma diagnoses. Medical Home Network patients possessed higher acuity but were more likely to be discharged from the emergency department compared with non-MHN patients. CONCLUSIONS: This research may assist with developing and evaluating intervention strategies targeting the reduction of health disparities through decreased use of emergency department services in these traditionally underserved populations. PMID- 26573783 TI - Bleeding sites in elderly trauma patients who required massive transfusion: a comparison with younger patients. AB - INTRODUCTION: Among elderly patients with severe trauma, the sites of massive hemorrhage and their clinical characteristics are not well understood. Therefore, we investigated the sites of massive hemorrhage in patients with severe trauma, and compared the results for younger and elderly patients. METHODS: A cohort of severe trauma patients (Injury Severity Score >=16) admitted from March 2007 to December 2014 was reviewed retrospectively. The inclusion criterion was massive bleeding, which was defined as bleeding that required the transfusion of >=10 red cell concentrate units within 24 hours of admission, or as cases of early death that occurred despite continuous blood transfusion and before the patient could receive >=10 red cell concentrate units within the first 24 hours after their admission. RESULTS: Eighty-four patients met our inclusion criterion. The younger group (<65 years old) included 40 patients (48%), whereas the older group (>=65 years old) included 44 patients (52%). The percentage of nondiagnosable cases at the primary survey (massive bleeding due to multisite damage caused by a bone fracture or contusion, retroperitoneal hematoma without a pelvic ring fracture and with stable pelvic ring fracture) was 14% in the younger group and 40% in the older group (odds ratio, 3.92; 95% confidence interval, 1.37-11.27, P = .017). CONCLUSIONS: Even if no abnormalities are observed at the primary survey of elderly patients with severe trauma, physicians should consider the possibility of massive bleeding. PMID- 26573784 TI - Effect of an electronic medical record alert for severe sepsis among ED patients. AB - BACKGROUND: Severe sepsis and septic shock are a major health concern worldwide. The objective of this study is to determine if Severe Sepsis Best Practice Alert (SS-BPA) implementation was associated with improved processes of care and clinical outcomes among patients with severe sepsis or septic shock presenting to the emergency department (ED). METHODS: This is a single-center, before-and-after observational study. The intervention group (n = 103) consisted of adult patients presenting to the ED with severe sepsis or septic shock during a 7-month period after implementation of the SS-BPA. The control group (n = 111) consisted of patients meeting the same criteria over a prior 7-month period. The SS-BPA primarily acts by automated, real-time, algorithm-based detection of severe sepsis or septic shock via the electronic medical record system. The primary outcome was in-hospital mortality. Secondary outcomes included hospital length of stay (LOS), time to antibiotic administration, and proportion of patients who received antibiotics within the target 60 minutes. RESULTS: Time to antibiotics was significantly reduced in the SS-BPA cohort (29 vs 61.5 minutes, P < .001). In addition, there was a higher proportion of patients who received antibiotics within 60 minutes (76.7 vs 48.6%; P < .001). On multivariable analysis, in hospital mortality was not significantly reduced in the intervention group (odds ratio, 0.64; 95% confidence interval, 0.26-1.57). Multivariable analysis of LOS indicated a significant reduction among patients in the SS-BPA cohort (geometric mean ratio, 0.66; 95% confidence interval, 0.53-0.82). CONCLUSION: Implementation of the SS-BPA for severe sepsis or septic shock among ED patients is associated with significantly improved timeliness of antibiotic administration and reduced hospital LOS. PMID- 26573785 TI - John Hardy is the UK's first Breakthrough Prize laureate. AB - John Hardy, Professor of Neuroscience at University College London and Editorial Board member of The FEBS Journal, has been awarded The Breakthrough Prize in Life Sciences in recognition of his work identifying mutations that cause amyloid build-up in the brain--research that has transformed the study of Alzheimer's disease and other major neurodegenerative diseases. PMID- 26573786 TI - Digitoxin and its synthetic analog MonoD have potent antiproliferative effects on lung cancer cells and potentiate the effects of hydroxyurea and paclitaxel. AB - Despite significant advances in the understanding of lung cancer biology, the prognosis of cancer patients remains poor. Part of the failure of anticancer therapy is due to intratumoral heterogeneity in these patients that limits the efficacy of single agents. Therefore, there is an urgent need for new anticancer drugs or drug combination regimens that possess increased activity against all cellular subtypes found within the tumor. In this study, we evaluated the in vitro antiproliferative activity of the cardiac glycosides (CGs) digitoxin and its synthetic analog MonoD on H460 lung cancer cells grown under different culture conditions. The CGs were tested alone in H460 cells under routine culture as well as in cells growing under short (24-72 h) and prolonged serum starvation (7 days) in order to evaluate the activity of drugs on cancer cells under varied degrees of proliferation. Our results showed that both CGs, and MonoD in particular, have potent antiproliferative activity at clinically relevant concentrations against cells in all the tested culture conditions. In contrast, paclitaxel, hydroxyurea and colchicine were only active in cells growing in routine culture conditions, and relatively inactive in serum-starved conditions. Importantly, both CGs were able to potentiate the effect of clinically relevant concentrations of hydroxyurea or paclitaxel in serum-starved conditions. When paclitaxel was used in combination with CGs, the highest antiproliferative effect was obtained when paclitaxel was administered first, followed by either digitoxin or MonoD. Our results indicate that CGs have potential clinical applications in translational oncology especially in combination with other drugs, and warrants further investigation of CGs in more advanced preclinical models of lung cancer. PMID- 26573787 TI - Reducing excess readmissions: promising effect of hospital readmissions reduction program in US hospitals. AB - OBJECTIVE: To evaluate the financial penalty effect of the Hospital Readmissions Reduction Program (HRRP) on 30-day inpatient readmissions for pneumonia (PN), acute myocardial infarction (AMI) and heart failure (HF) among hospitals identified as having excess readmissions. SETTING: Short-term, acute care hospitals in the USA. DESIGN: Secondary data analysis of publicly available HRRP Supplemental Data to examine the effect of HRRP on reducing excess hospital readmissions by utilizing repeated-measures analysis of variance models. PARTICIPANTS: A total of 3395 nonfederal, short-term acute care hospitals under the Inpatient Prospective Payment System that are subject to the HRRP program and that reported discharges data for PN, AMI and HF for the calculation of readmission ratios for the fiscal years 2013, 2014 and 2015. INTERVENTION: Implementation of the HRRP in October 2012 by the Centers for Medicare and Medicaid Services (CMS) to reduce Medicare payments to hospitals with excess readmissions. MAIN OUTCOME MEASURES: Thirty-day hospital readmission ratios for PN, AMI and HF. RESULTS: There was a significant decrease in excess readmissions for PN, AMI and HF between FY 2013 and FY 2015. The reduction in excess readmission ratios was 0.035 for PN (P < 0.001), 0.082 for AMI (P < 0.001) and 0.034 for HF (P < 0.001). The effect of HRRP on excess readmissions was greater for small hospitals, public hospitals and hospitals located in rural areas. CONCLUSIONS: HRRP to reduce payments to hospitals with excess readmissions had a significant effect on the inpatient readmissions for PN, AMI and HF in US Hospitals. PMID- 26573788 TI - A retrospective review of medical errors adjudicated in court between 2002 and 2012 in Spain. AB - OBJECTIVES: This paper describes verdicts in court involving injury-producing medical errors in Spain. DESIGN, SETTING AND PARTICIPANTS: A descriptive analysis of 1041 closed court verdicts from Spain between January 2002 and December 2012. It was determined whether a medical error had occurred, and among those with medical error (n = 270), characteristics and results of litigation were analyzed. Data on litigation were obtained from the Thomson Reuters Aranzadi Westlaw databases. MAIN OUTCOME MEASURES: All verdicts involving health system were reviewed and classified according to the presence of medical error. Among those, contributory factors, medical specialty involved, health impact (death, disability and severity) and results of litigation (resolution, time to verdict and economic compensations) were described. RESULTS: Medical errors were involved in 25.9% of court verdicts. The cause of medical error was a diagnosis-related problem in 25.1% and surgical treatment in 22.2%, and Obstetrics-Gynecology was the most frequent involved specialty (21%). Most of them were of high severity (59.4%), one-third (32%) caused death. The average time interval between the occurrence of the error and the verdict was 7.8 years. The average indemnity payment was ?239 505.24; the highest was psychiatry (?7 585 075.86) and the lowest was Emergency Medicine (?69 871.19). CONCLUSIONS: This study indicates that in Spain medical errors are common among verdicts involving the health system, most of them causing high-severity adverse outcomes. The interval between the medical error and the verdict is excessive, and there is a wide range of economic compensation. PMID- 26573789 TI - Patient safety's missing link: using clinical expertise to recognize, respond to and reduce risks at a population level. AB - INTRODUCTION: Although incident reporting systems are widespread in health care as a strategy to reduce harm to patients, the focus has been on reporting incidents rather than responding to them. Systems containing large numbers of incidents are uniquely placed to raise awareness of, and then characterize and respond to infrequent, but significant risks. The aim of this paper is to outline a framework for the surveillance of such risks, their systematic analysis, and for the development and dissemination of population-based preventive and corrective strategies using clinical and human factors expertise. REQUIREMENTS FOR A POPULATION-LEVEL RESPONSE: The framework outlines four system requirements: to report incidents; to aggregate them; to support and conduct a risk surveillance, review and response process; and to disseminate recommendations. Personnel requirements include a non-hierarchical multidisciplinary team comprising clinicians and subject-matter and human factors experts to provide interpretation and high-level judgement from a range of perspectives. The risk surveillance, review and response process includes searching of large incident and other databases for how and why things have gone wrong, narrative analysis by clinical experts, consultation with the health care sector, and development and pilot testing of corrective strategies. Criteria for deciding which incidents require a population-level response are outlined. DISCUSSION: The incremental cost of a population-based response function is modest compared with the 'reporting' element. Combining clinical and human factors expertise and a systematic approach underpins the creation of credible risk identification processes and the development of preventive and corrective strategies. PMID- 26573790 TI - Problems with the diagnosis of metastatic neuroendocrine neoplasms. Which diagnostic criteria should we use to determine tumor origin and help guide therapy? AB - Neuroendocrine neoplasms (NENs) can often present with metastatic disease before the primary tumor is discovered. Metastatic lesions are generally classified as well differentiated and poorly differentiated for prognostic and therapeutic purposes. In addition, for well-differentiated neuroendocrine tumors (WDNETs), pathologists are expected to determine the site of origin, if not already known, and grade the tumors. However, it is often difficult for pathologists to provide this information with certainty without knowing the site of tumor origin, as different criteria have been proposed by WHO for classification of gastrointestinal and pulmonary NENs. In this review, we will discuss the current classification and grading schema of NENs and their impact on clinical care, the differential diagnosis of NENs, the use of immunohistochemical stains that help identify tumor site of origin, and a proposed approach for the diagnosis and classification of metastatic NENs. PMID- 26573791 TI - Cardiovascular Drugs and Metformin Drug Dosage According to Renal Function in Non Institutionalized Elderly Patients. AB - Adaptation of drug dosage to kidney function is a common problem in general practice. The aim was to describe adaptation of cardiovascular drugs and metformin according to renal function and its association with mortality with regard to metformin in a cohort of elderly patients. This was an ancillary study to the S.AGES cohort made up of patients over 65 years of age managed by their general practitioner under real-life conditions and followed up prospectively for 3 years. The medications studied were digoxin, spironolactone and metformin. Adaptation of their daily dose according to renal function (eGFR according to CKD/EPI) was compared to that recommended in the summaries of product characteristics (SPCs) or international scientific societies (ISS). A total of 900 patients were included, including 588 on metformin. At baseline, dose adjustment according to renal function was 100% and 87.6% (95% CI: 82.6-92.6) for patients on digoxin and spironolactone respectively. For metformin, only 71.3% (95% CI: 67.6-74.9) or 78.1% (95% CI: 74.7-81.4) of patients had their dosage adapted at inclusion according to their renal function depending on whether the SPCs or ISS recommendations were considered. During the 3-year follow-up period, 42/588 patients died (none from lactic acidosis). At inclusion, a metformin dosage not adapted for renal function according to ISS was not associated with an increase in all-cause mortality (OR 1.7; 95% CI 0.6-5.0, p = 0.32). In conclusion, approximately one-quarter of elderly patients treated with metformin do not have their dosage adapted for renal function according to ISS although there is no increase in mortality after follow-up for 3 years. PMID- 26573792 TI - Disseminated Tumor Cells Persist in the Bone Marrow of Breast Cancer Patients through Sustained Activation of the Unfolded Protein Response. AB - Disseminated tumor cells (DTC), which share mesenchymal and epithelial properties, are considered to be metastasis-initiating cells in breast cancer. However, the mechanisms supporting DTC survival are poorly understood. DTC extravasation into the bone marrow may be encouraged by low oxygen concentrations that trigger metabolic and molecular alterations contributing to DTC survival. Here, we investigated how the unfolded protein response (UPR), an important cytoprotective program induced by hypoxia, affects the behavior of stressed cancer cells. DTC cell lines established from the bone marrow of patients with breast cancer (BC-M1), lung cancer, (LC-M1), and prostate cancer (PC-E1) were subjected to hypoxic and hypoglycemic conditions. BC-M1 and LC-M1 exhibiting mesenchymal and epithelial properties adapted readily to hypoxia and glucose starvation. Upregulation of UPR proteins, such as the glucose-regulated protein Grp78, induced the formation of filamentous networks, resulting in proliferative advantages and sustained survival under total glucose deprivation. High Grp78 expression correlated with mesenchymal attributes of breast and lung cancer cells and with poor differentiation in clinical samples of primary breast and lung carcinomas. In DTCs isolated from bone marrow specimens from breast cancer patients, Grp78-positive stress granules were observed, consistent with the likelihood these cells were exposed to acute cell stress. Overall, our findings provide the first evidence that the UPR is activated in DTC in the bone marrow from cancer patients, warranting further study of this cell stress pathway as a predictive biomarker for recurrent metastatic disease. PMID- 26573793 TI - Chemotherapy Induces Programmed Cell Death-Ligand 1 Overexpression via the Nuclear Factor-kappaB to Foster an Immunosuppressive Tumor Microenvironment in Ovarian Cancer. AB - Emerging evidence has highlighted the host immune system in modulating the patient response to chemotherapy, but the mechanism of this modulation remains unclear. The aim of this study was to analyze the effect of chemotherapy on antitumor immunity in the tumor microenvironment of ovarian cancer. Treatment of ovarian cancer cell lines with various chemotherapeutic agents resulted in upregulated expression of MHC class I and programmed cell death 1 ligand 1 (PD L1) in a NF-kappaB-dependent manner and suppression of antigen-specific T-cell function in vitro. In a mouse model of ovarian cancer, treatment with paclitaxel increased CD8(+) T-cell infiltration into the tumor site, upregulated PD-L1 expression, and activated NF-kappaB signaling. In particular, tumor-bearing mice treated with a combination of paclitaxel and a PD-L1/PD-1 signal blockade survived longer than mice treated with paclitaxel alone. In summary, we found that chemotherapy induces local immune suppression in ovarian cancer through NF kappaB-mediated PD-L1 upregulation. Thus, a combination of chemotherapy and immunotherapy targeting the PD-L1/PD-1 signaling axis may improve the antitumor response and offers a promising new treatment modality against ovarian cancer. PMID- 26573795 TI - Antibody-Dependent Phagocytosis of Tumor Cells by Macrophages: A Potent Effector Mechanism of Monoclonal Antibody Therapy of Cancer. AB - Nowadays, it is impossible to imagine modern cancer treatment without targeted therapies, such as mAbs, that bind to tumor-associated antigens. Subsequently, mAbs can use a wide range of effector functions that mostly engage the immune system. mAbs can bridge immune effector cells with tumor cells, which can result in antibody-dependent cytotoxicity. Increasing evidence, however, identified macrophages as prominent effector cells and induction of antibody-dependent cell phagocytosis as one of the primary mechanisms of action mediated by mAbs. Macrophages are extremely effective in eliminating tumor cells from the circulation. Several immunosuppressive mechanisms may, however, hamper their function, particularly in solid malignancies. In this review, we discuss the evolving insight of macrophages as effector cells in mAb therapy and address novel (co)therapeutic strategies that may be used to fully unleash their cytotoxic capacity for the treatment of cancer. PMID- 26573794 TI - Checkpoint Kinase 2 Negatively Regulates Androgen Sensitivity and Prostate Cancer Cell Growth. AB - Prostate cancer is the second leading cause of cancer death in American men, and curing metastatic disease remains a significant challenge. Nearly all patients with disseminated prostate cancer initially respond to androgen deprivation therapy (ADT), but virtually all patients will relapse and develop incurable castration-resistant prostate cancer (CRPC). A high-throughput RNAi screen to identify signaling pathways regulating prostate cancer cell growth led to our discovery that checkpoint kinase 2 (CHK2) knockdown dramatically increased prostate cancer growth and hypersensitized cells to low androgen levels. Mechanistic investigations revealed that the effects of CHK2 were dependent on the downstream signaling proteins CDC25C and CDK1. Moreover, CHK2 depletion increased androgen receptor (AR) transcriptional activity on androgen-regulated genes, substantiating the finding that CHK2 affects prostate cancer proliferation, partly, through the AR. Remarkably, we further show that CHK2 is a novel AR-repressed gene, suggestive of a negative feedback loop between CHK2 and AR. In addition, we provide evidence that CHK2 physically associates with the AR and that cell-cycle inhibition increased this association. Finally, IHC analysis of CHK2 in prostate cancer patient samples demonstrated a decrease in CHK2 expression in high-grade tumors. In conclusion, we propose that CHK2 is a negative regulator of androgen sensitivity and prostate cancer growth, and that CHK2 signaling is lost during prostate cancer progression to castration resistance. Thus, perturbing CHK2 signaling may offer a new therapeutic approach for sensitizing CRPC to ADT and radiation. PMID- 26573797 TI - p53: Protection against Tumor Growth beyond Effects on Cell Cycle and Apoptosis. AB - The tumor suppressor p53 has established functions in cancer. Specifically, it has been shown to cause cell-cycle arrest and apoptosis in response to DNA damage. It is also one of the most commonly mutated or silenced genes in cancer and for this reason has been extensively studied. Recently, the role of p53 has been shown to go beyond its effects on cell cycle and apoptosis, with effects on metabolism emerging as a key contributor to cancer growth in situations where p53 is lost. Beyond this, the role of p53 in the tumor microenvironment is poorly understood. The publication by Wang and colleagues demonstrates for the first time that p53 is a key negative regulator of aromatase and, hence, estrogen production in the breast tumor microenvironment. It goes further by demonstrating that an important regulator of aromatase, the obesity-associated and tumor derived factor prostaglandin E2, inhibits p53 in the breast adipose stroma. This review presents these findings in the context of established and emerging roles of p53 and discusses possible implications for the treatment of breast cancer. PMID- 26573796 TI - Obesity Contributes to Ovarian Cancer Metastatic Success through Increased Lipogenesis, Enhanced Vascularity, and Decreased Infiltration of M1 Macrophages. AB - Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancy, with high mortality attributable to widespread intraperitoneal metastases. Recent meta-analyses report an association between obesity, ovarian cancer incidence, and ovarian cancer survival, but the effect of obesity on metastasis has not been evaluated. The objective of this study was to use an integrative approach combining in vitro, ex vivo, and in vivo studies to test the hypothesis that obesity contributes to ovarian cancer metastatic success. Initial in vitro studies using three-dimensional mesomimetic cultures showed enhanced cell-cell adhesion to the lipid-loaded mesothelium. Furthermore, in an ex vivo colonization assay, ovarian cancer cells exhibited increased adhesion to mesothelial explants excised from mice modeling diet-induced obesity (DIO), in which they were fed a "Western" diet. Examination of mesothelial ultrastructure revealed a substantial increase in the density of microvilli in DIO mice. Moreover, enhanced intraperitoneal tumor burden was observed in overweight or obese animals in three distinct in vivo models. Further histologic analyses suggested that alterations in lipid regulatory factors, enhanced vascularity, and decreased M1/M2 macrophage ratios may account for the enhanced tumorigenicity. Together, these findings show that obesity potently affects ovarian cancer metastatic success, which likely contributes to the negative correlation between obesity and ovarian cancer survival. PMID- 26573798 TI - Hyperthermia Selectively Targets Human Papillomavirus in Cervical Tumors via p53 Dependent Apoptosis. AB - Human papillomavirus (HPV) is associated with cervical cancer, the third most common cancer in women. The high-risk HPV types 16 and 18 are found in over 70% of cervical cancers and produce the oncoprotein, early protein 6 (E6), which binds to p53 and mediates its ubiquitination and degradation. Targeting E6 has been shown to be a promising treatment option to eliminate HPV-positive tumor cells. In addition, combined hyperthermia with radiation is a very effective treatment strategy for cervical cancer. In this study, we examined the effect of hyperthermia on HPV-positive cells using cervical cancer cell lines infected with HPV 16 and 18, in vivo tumor models, and ex vivo-treated patient biopsies. Strikingly, we demonstrate that a clinically relevant hyperthermia temperature of 42 degrees C for 1 hour resulted in E6 degradation, thereby preventing the formation of the E6-p53 complex and enabling p53-dependent apoptosis and G2-phase arrest. Moreover, hyperthermia combined with p53 depletion restored both the cell cycle distribution and apoptosis to control levels. Collectively, our findings provide new insights into the treatment of HPV-positive cervical cancer and suggest that hyperthermia therapy could improve patient outcomes. PMID- 26573800 TI - Targeting a Plk1-Controlled Polarity Checkpoint in Therapy-Resistant Glioblastoma Propagating Cells. AB - The treatment of glioblastoma (GBM) remains challenging in part due to the presence of stem-like tumor-propagating cells that are resistant to standard therapies consisting of radiation and temozolomide. Among the novel and targeted agents under evaluation for the treatment of GBM are BRAF/MAPK inhibitors, but their effects on tumor-propagating cells are unclear. Here, we characterized the behaviors of CD133(+) tumor-propagating cells isolated from primary GBM cell lines. We show that CD133(+) cells exhibited decreased sensitivity to the antiproliferative effects of BRAF/MAPK inhibition compared to CD133(-) cells. Furthermore, CD133(+) cells exhibited an extended G2-M phase and increased polarized asymmetric cell divisions. At the molecular level, we observed that polo-like kinase (PLK) 1 activity was elevated in CD133(+) cells, prompting our investigation of BRAF/PLK1 combination treatment effects in an orthotopic GBM xenograft model. Combined inhibition of BRAF and PLK1 resulted in significantly greater antiproliferative and proapoptotic effects beyond those achieved by monotherapy (P < 0.05). We propose that PLK1 activity controls a polarity checkpoint and compensates for BRAF/MAPK inhibition in CD133(+) cells, suggesting the need for concurrent PLK1 inhibition to improve antitumor activity against a therapy-resistant cell compartment. PMID- 26573799 TI - An Effective Immuno-PET Imaging Method to Monitor CD8-Dependent Responses to Immunotherapy. AB - The rapidly advancing field of cancer immunotherapy is currently limited by the scarcity of noninvasive and quantitative technologies capable of monitoring the presence and abundance of CD8(+) T cells and other immune cell subsets. In this study, we describe the generation of (89)Zr-desferrioxamine-labeled anti-CD8 cys diabody ((89)Zr-malDFO-169 cDb) for noninvasive immuno-PET tracking of endogenous CD8(+) T cells. We demonstrate that anti-CD8 immuno-PET is a sensitive tool for detecting changes in systemic and tumor-infiltrating CD8 expression in preclinical syngeneic tumor immunotherapy models including antigen-specific adoptive T-cell transfer, agonistic antibody therapy (anti-CD137/4-1BB), and checkpoint blockade antibody therapy (anti-PD-L1). The ability of anti-CD8 immuno PET to provide whole body information regarding therapy-induced alterations of this dynamic T-cell population provides new opportunities to evaluate antitumor immune responses of immunotherapies currently being evaluated in the clinic. PMID- 26573801 TI - M-CSF and GM-CSF Receptor Signaling Differentially Regulate Monocyte Maturation and Macrophage Polarization in the Tumor Microenvironment. AB - Tumors contain a heterogeneous myeloid fraction comprised of discrete MHC-II(hi) and MHC-II(lo) tumor-associated macrophage (TAM) subpopulations that originate from Ly6C(hi) monocytes. However, the mechanisms regulating the abundance and phenotype of distinct TAM subsets remain unknown. Here, we investigated the role of macrophage colony-stimulating factor (M-CSF) in TAM differentiation and polarization in different mouse tumor models. We demonstrate that treatment of tumor-bearing mice with a blocking anti-M-CSFR monoclonal antibody resulted in a reduction of mature TAMs due to impaired recruitment, extravasation, proliferation, and maturation of their Ly6C(hi) monocytic precursors. M-CSFR signaling blockade shifted the MHC-II(lo)/MHC-II(hi) TAM balance in favor of the latter as observed by the preferential differentiation of Ly6C(hi) monocytes into MHC-II(hi) TAMs. In addition, the genetic and functional signatures of MHC-II(lo) TAMs were downregulated upon M-CSFR blockade, indicating that M-CSFR signaling shapes the MHC-II(lo) TAM phenotype. Conversely, granulocyte macrophage (GM)-CSFR had no effect on the mononuclear tumor infiltrate or relative abundance of TAM subsets. However, GM-CSFR signaling played an important role in fine-tuning the MHC-II(hi) phenotype. Overall, our data uncover the multifaceted and opposing roles of M-CSFR and GM-CSFR signaling in governing the phenotype of macrophage subsets in tumors, and provide new insight into the mechanism of action underlying M-CSFR blockade. PMID- 26573802 TI - miR-124 and Androgen Receptor Signaling Inhibitors Repress Prostate Cancer Growth by Downregulating Androgen Receptor Splice Variants, EZH2, and Src. AB - miR-124 targets the androgen receptor (AR) transcript, acting as a tumor suppressor to broadly limit the growth of prostate cancer. In this study, we unraveled the mechanisms through which miR-124 acts in this setting. miR-124 inhibited proliferation of prostate cancer cells in vitro and sensitized them to inhibitors of androgen receptor signaling. Notably, miR-124 could restore the apoptotic response of cells resistant to enzalutamide, a drug approved for the treatment of castration-resistant prostate cancer. We used xenograft models to examine the effects of miR-124 in vivo when complexed with polyethylenimine derived nanoparticles. Intravenous delivery of miR-124 was sufficient to inhibit tumor growth and to increase tumor cell apoptosis in combination with enzalutamide. Mechanistic investigations revealed that miR-124 directly downregulated AR splice variants AR-V4 and V7 along with EZH2 and Src, oncogenic targets that have been reported to contribute to prostate cancer progression and treatment resistance. Taken together, our results offer a preclinical rationale to evaluate miR-124 for cancer treatment. PMID- 26573803 TI - Heterogeneity of dN/dS Ratios at the Classical HLA Class I Genes over Divergence Time and Across the Allelic Phylogeny. AB - The classical class I HLA loci of humans show an excess of nonsynonymous with respect to synonymous substitutions at codons of the antigen recognition site (ARS), a hallmark of adaptive evolution. Additionally, high polymporphism, linkage disequilibrium, and disease associations suggest that one or more balancing selection regimes have acted upon these genes. However, several questions about these selective regimes remain open. First, it is unclear if stronger evidence for selection on deep timescales is due to changes in the intensity of selection over time or to a lack of power of most methods to detect selection on recent timescales. Another question concerns the functional entities which define the selected phenotype. While most analyses focus on selection acting on individual alleles, it is also plausible that phylogenetically defined groups of alleles ("lineages") are targets of selection. To address these questions, we analyzed how dN/dS (omega) varies with respect to divergence times between alleles and phylogenetic placement (position of branches). We find that omega for ARS codons of class I HLA genes increases with divergence time and is higher for inter-lineage branches. Throughout our analyses, we used non-selected codons to control for possible effects of inflation of omega associated to intra specific analysis, and showed that our results are not artifactual. Our findings indicate the importance of considering the timescale effect when analysing omega over a wide spectrum of divergences. Finally, our results support the divergent allele advantage model, whereby heterozygotes with more divergent alleles have higher fitness than those carrying similar alleles. PMID- 26573804 TI - Selection of Intracellularly Functional RNA Mimics of Green Fluorescent Protein Using Fluorescence-Activated Cell Sorting. AB - Fluorescence-activated cell sorting (FACS) was exploited to isolate Escherichia coli cells that were highly fluorescent due to the expression of RNA aptamers that induce fluorescence of 3,5-difluoro-4-hydroxybenzylidene imidazolinone. Two different aptamers, named ZT-26 and ZT-324, were identified by this method and compared to the fluorescence-signaling properties of Spinach, a previously reported RNA aptamer. Aptamer ZT-26 exhibits significantly enhanced fluorescence over Spinach only in vitro. However, aptamer ZT-324 is 36% brighter than Spinach when expressed in E. coli. The FACS-based selection strategy presented here is attractive for deriving fluorescent RNA aptamers that function in cells as it directly selects for cells with a high level of fluorescence due to the expression of the RNA aptamer. PMID- 26573805 TI - Cross-cultural adaptation, reliability and validity of the Spanish version of the Quality of Life in Adult Cancer Survivors (QLACS) questionnaire: application in a sample of short-term survivors. AB - BACKGROUND: The aim of this study was to validate the Quality of Life in Adult Cancer Survivors (QLACS) in short-term Spanish cancer survivor's patients. METHODS: Patients with breast, colorectal or prostate cancer that had finished their initial cancer treatment 3 years before the beginning of this study completed QLACS, WHOQOL, Short Form-36, Hospital Anxiety and Depression Scale, EORTC-QLQ-BR23 and EQ-5D. Cultural adaptation was made based on established guidelines. Reliability was evaluated using internal consistency and test-retest. Convergent validity was studied by mean of Pearson's correlation coefficient. Structural validity was determined by a second-order confirmatory factor analysis (CFA) and Rasch analysis was used to assess the unidimensionality of the Generic and Cancer-specific scales. RESULTS: Cronbach's alpha were above 0.7 in all domains and summary scales. Test-retest coefficients were 0.88 for Generic and 0.82 for Cancer-specific summary scales. QLACS generic summary scale was correlated with other generic criterion measures, SF-36 MCS (r = - 0.74) and EQ VAS (r = - 0.63). QLACS cancer-specific scale had lower values with the same constructs. CFA provided satisfactory fit indices in all cases. The RMSEA value was 0.061 and CFI and TLI values were 0.929 and 0.925, respectively. All factor loadings were higher than 0.40 and statistically significant (P < 0.001). Generic summary scale had eight misfitting items. In the remaining 20 items, the unidimensionality was supported. Cancer Specific summary scale showed four misfitting items, the remaining showed unidimensionality. CONCLUSIONS: The findings support the validity and reliability of QLACS questionnaire to be used in short-term cancer survivors. PMID- 26573806 TI - Stromal markers AKR1C1 and AKR1C2 are prognostic factors in primary human breast cancer. AB - BACKGROUND: Stromal fibroblasts influence tumor growth and progression. We evaluated two aldo-keto reductases, AKR1C1 and AKR1C2, in stromal fibroblasts and carcinoma cells as prognostic factors in primary human breast cancer. They are involved in intratumoral progesterone metabolism. METHODS: Immunohistochemistry was performed on tissue microarrays from 504 core biopsies from breast cancer patients. Primary endpoints were disease-free (DFS) and overall (OS) survival. RESULTS: AKR1C1 and AKR1C2 expression in fibroblasts and tumor cells correlated with favorable tumor characteristics, such as small tumor size and negative nodal status. In univariate analysis, AKR1C1 expression in carcinoma cells correlated positively with DFS und OS; AKR1C2 expression in both fibroblasts and tumor cells also showed a positive correlation with DFS and OS. In multivariate analysis, AKR1C1 expression in carcinoma cells was an independent prognostic marker. CONCLUSION: It can be assumed that our observations are due to the independent regulatory function of AKR1C1/2 in progesterone metabolism and therefore provide a basis for new hormone-based therapy options for breast cancer patients, independent of classic hormone receptor status. PMID- 26573807 TI - Neuropilin-2 induced by transforming growth factor-beta augments migration of hepatocellular carcinoma cells. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is the most common form of liver cancer and the third most lethal cancer worldwide. The epithelial to mesenchymal transition (EMT) describes the transformation of well-differentiated epithelial cells to a de-differentiated phenotype and plays a central role in the invasion and intrahepatic metastasis of HCC cells. Modulation of the transforming growth factor-beta (TGF-beta) signaling is known to induce various tumor-promoting and EMT-inducing pathways in HCC. The meta-analysis of a panel of EMT gene expression studies revealed that neuropilin 2 (NRP2) is significantly upregulated in cells that have undergone EMT induced by TGF-beta. In this study we assessed the functional role of NRP2 in epithelial and mesenchymal-like HCC cells and focused on the molecular interplay between NRP2 and TGF-beta/Smad signaling. METHODS: NRP2 expression was analyzed in human HCC cell lines and tissue arrays comprising 133 HCC samples. Cell migration was examined by wound healing and Transwell assays in the presence and absence of siRNA against NRP2. NRP2 and TGF-beta signaling were analyzed by Western blotting and confocal immunofluorescence microscopy. RESULTS: We show that NRP2 is particularly expressed in HCC cell lines with a dedifferentiated, mesenchymal-like phenotype. NRP2 expression is upregulated by the canonical TGF-beta/Smad signaling while NRP2 expression has no impact on TGF-beta signaling in HCC cells. Reduced expression of NRP2 by knock down or inhibition of TGF-beta signaling resulted in diminished cell migration independently of each other, suggesting that NRP2 fails to collaborate with TGF beta signaling in cell movement. In accordance with these data, elevated levels of NRP2 correlated with a higher tumor grade and less differentiation in a large collection of human HCC specimens. CONCLUSIONS: These data suggest that NRP2 associates with a less differentiated, mesenchymal-like HCC phenotype and that NRP2 plays an important role in tumor cell migration upon TGF-beta-dependent HCC progression. PMID- 26573808 TI - Association of estimated glomerular filtration rate with 24-h urinalysis and stone composition. AB - The aim of this study is to determine the association of estimated glomerular filtration rate (eGFR) with 24-h urine analysis and stone composition. We performed a retrospective review of 1060 stone formers with 24-h urinalysis, of which 499 had stone composition analysis available. Comparisons of baseline patient characteristics and urinary abnormalities across eGFR groups (<60, 60 89.9, >=90 mL/min/1.73 m(2)) were performed using Fisher's exact test for categorical data and analysis of variance for continuous variables. Analyses of 24-h urinalysis and stone composition across eGFR groups were performed using linear regression with eGFR groups as a continuous variable to evaluate trends. Of the 1060 patients in the study, 595 (56 %) were males. The mean age was 53.8 years. A total of 38 (4 %), 77 (7 %), and 945 (89 %) patients had eGFR <60, 60 89.9, and >=90 mL/min/1.73 m(2), respectively. Lower eGFR was associated with older age, lower body-mass index, and female gender (all P < 0.05). Lower eGFR was also associated with lower urinary volume, calcium, citrate, uric acid, sodium, magnesium, phosphorus, sulfate, and creatinine on both univariable and multivariable analyses, adjusted for demographics, comorbidities and medication use (all P < 0.05). The prevalence of hypocitraturia and hypomagnesuria was associated with decreased eGFR, while hypercalciuria, hyperoxaluria, hyperuricosuria and hyperphosphaturia were associated with higher eGFR (all P < 0.05). Stone composition was similar across eGFR groups (all P > 0.05). In conclusion, lower eGFR was associated with lower excretion of urinary elements in a routine 24-h urinalysis, but similar stone composition. PMID- 26573809 TI - Mobilizing social support networks to improve cancer screening: the COACH randomized controlled trial study design. AB - BACKGROUND: Disadvantaged populations face many barriers to cancer care, including limited support in navigating through the complexities of the healthcare system. Family members play an integral role in caring for patients and provide valuable care coordination; however, the effect of family navigators on adherence to cancer screening has not previously been evaluated. Training and evaluating trusted family members and other support persons may improve cancer outcomes for vulnerable patients. METHODS: Guided by principles of community based participatory research (CBPR), "Evaluating Coaches of Older Adults for Cancer Care and Healthy Behaviors (COACH)" is a community-based randomized controlled trial to assess the effectiveness of a trained participant-designated coach (support person or care giver) in navigating cancer-screening for older African American adults, 50-74 years old. Participants are randomly assigned as dyads (participant+coach pair) to receiving either printed educational materials only (PEM--control group) or educational materials plus coach training (COACH- intervention group). We defined a coach as family member, friend, or other lay support person designated by the older adult. The coach training is designed as a one-time, 35- to 40-minute training consisting of: 1) a didactic session that covers the role of the coach, basic facts about colorectal, breast and cervical cancers (including risk factors, signs and symptoms and screening modalities), engaging the healthcare provider in cancer screening, insurance coverage for screening, and related healthcare issues, 2) three video skits addressing misconceptions about and planning for cancer screening, and 3) an interactive role-play session with the trainer to reinforce and practice strategies for encouraging the participant to get screened. The primary study outcome is the difference in the proportion of participants completing at least one of the recommended screenings (for breast, cervix or colorectal cancer) between the control and intervention groups. DISCUSSION: Building on trusted patient contacts to encourage cancer screening, COACH is a highly sustainable intervention in a high-risk population. It has the potential to minimize the effect of mistrust of the medical establishment on screening behaviors by mobilizing participants' existing support networks. If effective, the intervention could have a high impact on health care disparities research across multiple diseases. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT01613430 ). Registered June 5, 2012. PMID- 26573810 TI - The bother of anal incontinence and St. Mark's Incontinence Score. AB - BACKGROUND: Patient self-report is important in the assessment of the impact of anal incontinence (AI) on quality of life. This study aimed to (1) determine the correlation between total St. Mark's Incontinence Score (SMIS) and a single-item visual analogue scale (VAS) for bother from AI, and (2) determine the correlation between individual components of SMIS and VAS. METHODS: This is a retrospective study conducted on a cohort of 516 women seen for symptoms of lower urinary tract and pelvic floor dysfunction between January 2013 and August 2014. If a woman responded "yes" to the question "Do you experience any leakage from the back passage/anus?" they were considered to have AI, and the SMIS was administered. They were also asked "How much are you bothered by these symptoms?" to assess bother from AI by VAS. Statistical analyses were performed using Spearman's correlation and Mann-Whitney U test. RESULTS: Eighty-four (16.3 %) women reported AI with a mean SMIS of 11 (SD +/- 5.11, range 2-24) and median bother of 5 (VAS 1 10). There was a fair correlation between VAS for the bother from AI and SMIS (Spearman's r = 0.523, p < 0.001). Fecal urgency, impact on lifestyle, and use of pad/plug were significantly associated with VAS (p = 0.05, p = 0.002 and p < 0.001, respectively). CONCLUSIONS: There is a fair, positive correlation between VAS for bother from AI and SMIS. Patients' bother from AI is strongly associated with its impact on lifestyle as quantified by individual SMIS components. PMID- 26573811 TI - Global audit on bowel perforations related to transanal irrigation. AB - PURPOSE: Transanal irrigation is increasingly used against chronic constipation and fecal incontinence in selected patients. The aims were to estimate the incidence of irrigation-related bowel perforation in patients using the Peristeen Anal Irrigation((r)) system, and to explore patient- and procedure-related factors associated with perforation. METHODS: External independent expert audit on the complete set of global vigilance data related to Peristeen Anal Irrigation from 2005 to 2013. RESULTS: In total, 49 reports of bowel perforation had been recorded. Based on sales figures, this corresponds to an average risk of bowel perforation of 6 per million procedures. The latest two-year data indicate a risk of 2 per million procedures. In 29 out of 43 evaluable cases (67 %), perforation happened within the first 8 weeks since start of treatment. After 8 weeks, long term use has an estimated risk of less than 2 per million procedures. Among patients with non-neurogenic bowel dysfunction, 11 out of 15 (73 %) had a history of pelvic organ surgery compared to 5 out of 26 (19 %) in neurogenic bowel dysfunction. In 11 of 46 (24 %) evaluable cases, burst of the rectal balloon was reported. CONCLUSION: Enema-induced perforation is a rare complication to transanal irrigation with Peristeen Anal Irrigation, which increases the benefit risk ratio in support of the further use of transanal irrigation. Increased risk is present during treatment initiation and in patients with prior pelvic organ surgery. Careful patient selection, patient evaluation and proper training of patients are critical to safe practice of this technique. PMID- 26573812 TI - Surgical Unit volume and 30-day reoperation rate following primary resection for colorectal cancer in the Veneto Region (Italy). AB - BACKGROUND: The aim of this study was to evaluate the impact of Surgical Unit volume on the 30-day reoperation rate in patients with CRC. METHODS: Data were extracted from the regional Hospital Discharge Dataset and included patients who underwent elective resection for primary CRC in the Veneto Region (2005-2013). The primary outcome measure was any unplanned reoperation performed within 30 days from the index surgery. Independent variables were: age, gender, comorbidity, previous abdominal surgery, site and year of the resection, open/laparoscopic approach and yearly Surgical Unit volume for colorectal resections as a whole, and in detail for colonic, rectal and laparoscopic resections. Multilevel multivariate regression analysis was used to evaluate the impact of variables on the outcome measure. RESULTS: During the study period, 21,797 elective primary colorectal resections were performed. The 30-day reoperation rate was 5.5% and was not associated with Surgical Unit volume. In multivariate multilevel analysis, a statistically significant association was found between 30-day reoperation rate and rectal resection volume (intermediate volume group OR 0.75; 95% CI 0.56-0.99) and laparoscopic approach (high-volume group OR 0.69; 95% CI 0.51-0.96). CONCLUSIONS: While Surgical Unit volume is not a predictor of 30-day reoperation after CRC resection, it is associated with an early return to the operating room for patients operated on for rectal cancer or with a laparoscopic approach. These findings suggest that quality improvement programmes or centralization of surgery may only be required for subgroups of CRC patients. PMID- 26573813 TI - Identification and characterization of microRNAs from in vitro-grown pear shoots infected with Apple stem grooving virus in response to high temperature using small RNA sequencing. AB - BACKGROUND: MicroRNAs (miRNAs) have functions in diverse biological processes such as growth, signal transduction, disease resistance, and stress responses in plants. Thermotherapy is an effective approach for elimination of viruses from fruit trees. However, the role of miRNAs in this process remains elusive. Previously, we showed that high temperature treatment reduces the titers of Apple stem grooving virus (ASGV) from the tips of in vitro-grown Pyrus pyrifolia plants. In this study, we identified high temperature-altered pear miRNAs using the next generation sequencing technology, and futher molecularly characterized miRNA-mediated regulaton of target gene expression in the meristem tip and base tissues of in vitro-grown, ASGV-infected pear shoots under different temperatures. RESULTS: Using in vitro-grown P. pyrifolia shoot meristem tips infected with ASGV, a total of 22,592,997 and 20,411,254 clean reads were obtained from Illumina high-throughput sequencing of small RNA libraries at 24 degrees C and 37 degrees C, respectively. We identified 149 conserved and 141 novel miRNAs. Seven conserved miRNAs and 77 novel miRNAs were differentially expressed at different temperatures. Target genes for differentially expressed known and novel miRNAs were predicted and functionally annotated. Gene Ontology (GO) analysis showed that high-ranking miRNA target genes were involved in metabolic processes, responses to stress, and signaling, indicating that these high temperature-responsive miRNAs have functions in diverse gene regulatory networks. Spatial expression patterns of the miRNAs and their target genes were found to be expressed in shoot tip and base tissues by qRT-PCR. In addition, high temperature reduced viral titers in the shoot meristem tip, while negatively regulated miRNA-mediated target genes related to resistance disease defense and hormone signal transduction pathway were up-regulated in the P. pyrifolia shoot tip in response to high temperature. These results suggested that miRNAs may have important functions in the high temperature-dependent decrease of ASGV titer in in vitro-grown pear shoots. CONCLUSIONS: This is the first report of miRNAs differentially expressed at 24 degrees C and 37 degrees C in the meristem tip of pear shoots infected with ASGV. The results of this study provide valuable information for further exploration of the function of high temperature-altered miRNAs in suppressing viral infections in pear and other fruit trees. PMID- 26573814 TI - High efficacy of two artemisinin-based combinations: artesunate + sulfadoxine pyrimethamine and artemether-lumefantrine for falciparum malaria in Yemen. AB - BACKGROUND: Artesunate + sulfadoxine-pyrimethamine (AS + SP) has been the first line treatment and artemether-lumefantrine (AL) the second-line treatment for uncomplicated falciparum malaria in Yemen since 2005. This paper reports the results of studies conducted to monitor therapeutic efficacy of these two drugs in sentinel sites in Yemen. METHODS: Eight therapeutic efficacy studies were conducted in six sentinel sites during the period 2009-2013 in Yemen. Five studies were for the evaluation of AS + SP (total of 465 patients) and three studies (total of 268 patients) for the evaluation of AL. The studies were done according to standard WHO protocol 2009 with 28-day follow-up. RESULTS: In the evaluation of AS + SP, the PCR-corrected cure rate was 98 % (95 % CI 92.2-99.5 %) in one site and 100 % in all of the other four sites. In the sites where AL was evaluated, the PCR-corrected cure rate was 100 % in all the sites. All patients were negative for asexual parasitaemia on day 3 in both the AS + SP and the AL groups. There was a higher rate of clearance of gametocytaemia in the AL-treated group when compared with the AS + SP groups from day 7 onwards. CONCLUSION: AS + SP remains the effective drug for uncomplicated falciparum malaria in Yemen. AL is also highly effective and can be an appropriate alternative to AS + SP for the treatment of falciparum malaria. AL demonstrated a higher efficacy in clearing microscopic gametocytaemia than AS + SP. TRIAL REGISTRATION: Trial registration number ACTRN12610000696099. PMID- 26573815 TI - Arrhythmia Detection in Pediatric Patients: ECG Quality and Diagnostic Yield of a Patient-Triggered Einthoven Lead-I Event Recorder (Zenicor EKG-2TM). AB - Symptoms that may be caused by arrhythmia are common in pediatric outpatient departments, though it remains challenging to reveal paroxysmal tachycardia. This investigation evaluated prospectively the quality and diagnostic yield of a newly available handheld patient-activated event recorder (ER) in children. In 226 children (pts) aged 0-17 years with or without congenital heart defects, pacemaker/ICDs or arrhythmia, a lead-I ER ECG was created. ER ECGs were recorded by pressing the patients' thumbs on the device and were analyzed in comparison with a lead-12 ECG, as gold standard. Event recording and data transmission were possible in all cases. ECG quality of the ER showed a high accordance in measuring heart rate (ICC = 0.962), duration of QRS complexes (kappa = 0.686), and PR interval (ICC = 0.750) (p < 0.001) although P wave detection remained challenging (p = 0.120). 36 % (n = 82) of the pts had heart rhythm disturbances. The ER yielded 92 % sensitivity in diagnosing supraventricular tachycardia plus 77 % sensitivity and 92 % specificity in identifying abnormal ECGs. In children, the application of the tested ER was suitable. ECGs of good quality could be performed and transmitted easily, and also complex arrhythmia analysis was possible. This ER is an excellent diagnostic device for the detection and exclusion of tachycardia in children. PMID- 26573816 TI - Pulmonary Hypertension in the Preterm Infant with Chronic Lung Disease can be Caused by Pulmonary Vein Stenosis: A Must-Know Entity. AB - Pulmonary hypertension (PHT) in the preterm infant is frequently due to chronic lung disease. Rarely, PHT can be caused by pulmonary vein (PV) stenosis that has been described to be associated with prematurity. This study is a retrospective analysis of all premature infants <37 weeks of gestation with PV stenosis and PHT in two French pediatric congenital cardiac centers from 1998 till 2015. Diagnosis, hemodynamics and outcome are described. Sixteen patients met the inclusion criteria. Median gestational age was 28 weeks (25 + 6-35) with a median birth weight of 842 g (585-1500). The majority of infants (87.5 %) had chronic lung disease and associated cardiac defects. Median age at diagnosis was 6.6 months (1.5-71). Fifty-six percentage (n = 9) had initially unilateral PV stenosis affecting in 89 % the left PV. Median initial invasive mean pulmonary artery pressure was 42 mmHg (25-70). Treatment options included surgical intervention (n = 6), interventional cardiac catheter (n = 3) and/or targeted therapy for pulmonary arterial hypertension (n = 5). In six patients, decision of nonintervention was taken. Global mortality was 44 %. All deaths occurred within 7 months after diagnosis regardless of chosen treatment option. Mean follow-up was 6 years (4.9 months-12 years). At last visit, all eight survivors were in stable clinical condition with five of them receiving targeted therapy for pulmonary arterial hypertension. PV stenosis is an unusual cause of PHT in the premature infant with chronic lung disease. Diagnosis is challenging since initial echocardiography can be normal and the disease is progressive. Treatment options are numerous, but prognosis remains guarded. PMID- 26573817 TI - Hartung-Knapp-Sidik-Jonkman approach and its modification for random-effects meta analysis with few studies. AB - BACKGROUND: Random-effects meta-analysis is commonly performed by first deriving an estimate of the between-study variation, the heterogeneity, and subsequently using this as the basis for combining results, i.e., for estimating the effect, the figure of primary interest. The heterogeneity variance estimate however is commonly associated with substantial uncertainty, especially in contexts where there are only few studies available, such as in small populations and rare diseases. METHODS: Confidence intervals and tests for the effect may be constructed via a simple normal approximation, or via a Student-t distribution, using the Hartung-Knapp-Sidik-Jonkman (HKSJ) approach, which additionally uses a refined estimator of variance of the effect estimator. The modified Knapp-Hartung method (mKH) applies an ad hoc correction and has been proposed to prevent counterintuitive effects and to yield more conservative inference. We performed a simulation study to investigate the behaviour of the standard HKSJ and modified mKH procedures in a range of circumstances, with a focus on the common case of meta-analysis based on only a few studies. RESULTS: The standard HKSJ procedure works well when the treatment effect estimates to be combined are of comparable precision, but nominal error levels are exceeded when standard errors vary considerably between studies (e.g. due to variations in study size). Application of the modification on the other hand yields more conservative results with error rates closer to the nominal level. Differences are most pronounced in the common case of few studies of varying size or precision. CONCLUSIONS: Use of the modified mKH procedure is recommended, especially when only a few studies contribute to the meta-analysis and the involved studies' precisions (standard errors) vary. PMID- 26573819 TI - Productivity losses attributable to headache, and their attempted recovery, in a heavy-manufacturing workforce in Turkey: implications for employers and politicians. AB - BACKGROUND: Headache disorders cause substantial productivity losses through absenteeism and impaired effectiveness at work (presenteeism). We had previously found these losses to be high in a mostly male, heavy-manufacturing workforce at Ford Otomotiv Sanayi AS (FO), in north-western Turkey. Here we aimed to confirm this finding in a year-long study to eliminate any effect of seasonal variation. The question then was how much of this lost productivity could be recovered by the effective provision of headache care. METHODS: We used the HALT-30 Index to estimate productivity losses, surveying FO's entire workforce (N = 7,200) during annual health-checks provided by the company's on-site health clinic. Then we established, and widely advertised, a headache clinic within the same health clinic, providing specialist care free for 15 months. Outcome measures were HALT 30, company sickness records and the HURT questionnaire. RESULTS: Usable data were collected from 5,916 employees (82.2 %; 5,485 males [92.7 %], 431 females [7.3 %]; mean age 32.5 +/- 5.4 years). One-month headache prevalence was 45.4 % (n = 2,688). Productivity losses were reported by 968 employees (16.4 %) and, per affected employee, increased from 0.23 to 7.56 days/month as headache frequency increased (P <0005). Employees reporting headache on >=15 days/month (n = 64; 1.1 %) accounted for 21.1 % of productivity losses, those with headache on 10-14 days (n = 104; 1.8 %) another 18.5 %. With increasing headache frequency, absenteeism/presenteeism ratio (overall 1:16) declined from about 1:4 to about 1:25 in those with headache on >=10 days/month. Headache frequency and lost productivity were higher in females than males (P <0.0005). Both absenteeism and presenteeism rates declined after age 34 years (P <0.0005). Only 344 employees with headache (12.8 %) requested appointments, and only 211 (7.8 %) actually consulted. Attendance was related to headache frequency (P <0.0005). Too few returned for follow-up to allow useful outcome assessment. CONCLUSION: The high productivity losses in this young mostly male workforce correlated with but were not wholly explained by headache frequency. A small minority of employees with high-frequency headache contributed highly disproportionately to the productivity losses. These should be the target of interventions aimed at productivity recovery. It is not clear what form such interventions should take: making headache care optimally available is not of itself sufficient. PMID- 26573818 TI - Mapping of genetic loci that modulate differential colonization by Escherichia coli O157:H7 TUV86-2 in advanced recombinant inbred BXD mice. AB - BACKGROUND: Shiga toxin (Stx)-producing E. coli (STEC) are responsible for foodborne outbreaks that can result in severe human disease. During an outbreak, differential disease outcomes are observed after infection with the same STEC strain. One question of particular interest is why some infected people resolve infection after hemorrhagic colitis whereas others progress to the hemolytic uremic syndrome (HUS). Host age and infection dose have been implicated; however, these parameters do not appear to fully account for all of the observed variation in disease severity. Therefore, we hypothesized that additional host genetic factors may play a role in progression to HUS. METHODS AND RESULTS: To mimic the genetic diversity in the human response to infection by STEC, we measured the capacity of an O157:H7 outbreak isolate to colonize mouse strains from the advanced recombinant inbred (ARI) BXD panel. We first infected the BXD parental strains C57BL/6 J (B6) and DBA/2 J (D2) with either 86-24 (Stx2a+) or TUV86-2, an Stx2a-negative isogenic mutant. Colonization levels were determined in an intact commensal flora (ICF) infection model. We found a significant difference in colonization levels between the parental B6 and D2 strains after infection with TUV86-2 but not with 86-24. This observation suggested that a host factor that may be masked by Stx2a affects O157:H7 colonization in some genetic backgrounds. We then determined the TUV86-2 colonization levels of 24 BXD strains in the ICF model. We identified several quantitative trait loci (QTL) associated with variation in colonization by correlation analyses. We found a highly significant QTL on proximal chromosome 9 (12.5-26.7 Mb) that strongly predicts variation in colonization levels and accounts for 15-20 % of variance. Linkage, polymorphism and co-citation analyses of the mapped region revealed 36 candidate genes within the QTL, and we identified five genes that are most likely responsible for the differential colonization. CONCLUSIONS: The identification of the QTL on chromosome 9 supports our hypothesis that individual genetic makeup affects the level of colonization after infection with STEC O157:H7. PMID- 26573820 TI - Zinc finger nuclease-based double-strand breaks attenuate malaria parasites and reveal rare microhomology-mediated end joining. AB - BACKGROUND: Genome editing of malaria parasites is key to the generation of live attenuated parasites used in experimental vaccination approaches. DNA repair in Plasmodium generally occurs only through homologous recombination. This has been used to generate transgenic parasites that lack one to three genes, leading to developmental arrest in the liver and allowing the host to launch a protective immune response. While effective in principle, this approach is not safe for use in humans as single surviving parasites can still cause disease. Here we use zinc finger nucleases to generate attenuated parasite lines lacking an entire chromosome arm, by a timed induction of a double-strand break. Rare surviving parasites also allow the investigation of unconventional DNA repair mechanisms in a rodent malaria parasite. RESULTS: A single, zinc-finger nuclease-induced DNA double-strand break results in the generation of attenuated parasite lines that show varying degrees of developmental arrest, protection efficacy in an immunisation regime and safety, depending on the timing of zinc-finger nuclease expression within the life cycle. We also identify DNA repair by microhomology mediated end joining with as little as four base pairs, resulting in surviving parasites and thus breakthrough infections. CONCLUSIONS: Malaria parasites can repair DNA double-strand breaks with surprisingly small mini-homology domains located across the break point. Timely expression of zinc-finger nucleases could be used to generate a new generation of attenuated parasite lines lacking hundreds of genes. PMID- 26573821 TI - Effect of microfabricated microgroove-surface devices on the morphology of mesenchymal stem cells. AB - The surface of a material that is in contact with cells is known to affect cell morphology and function. To develop an appropriate surface for tendon engineering, we used zigzag microgroove surfaces, which are similar to the tenocyte microenvironment. The purpose of this study was to investigate the effect of microgroove surfaces with different ridge angles (RAs), ridge lengths (RLs), ridge widths (RWs), and groove widths (GWs) on human bone marrow-derived mesenchymal stem cell (MSC) shape. Dishes with microgroove surfaces were fabricated using cyclic olefin polymer by injection-compression molding. The other parameters were fixed, and effects of different RAs (180 - 30 degrees ), RLs (5 - 500 MUm), RWs (5 - 500 MUm), and GWs (5 - 500 MUm) were examined. Changes in the zigzag shape of the cell due to different RAs, RLs, RWs, and GWs were observed by optical microscopy and scanning electron microscopy. Cytoskeletal changes were investigated using Phalloidin immunofluorescence staining. As observed by optical microscopy, MSCs changed to a zigzag shape in response to microgroove surfaces with different ridge and groove properties. . As observed by scanning electron microscopy, the cell shape changed at turns in the microgroove surface. Phalloidin immunofluorescence staining indicated that F actin, not only in cell filopodia but also inside the cell body, changed orientation to conform to the microgrooves. In conclusion, the use of zigzag microgroove surfaces microfabricated by injection-compression molding demonstrated the property of MSCs to alter their shapes to fit the surface. PMID- 26573822 TI - In memoriam: Yasuharu Nimura MD, PhD, 1923-2015. PMID- 26573823 TI - Validation of adult height prediction based on automated bone age determination in the Paris Longitudinal Study of healthy children. AB - BACKGROUND: An adult height prediction model based on automated determination of bone age was developed and validated in two studies from Zurich, Switzerland. Varied living conditions and genetic backgrounds might make the model less accurate. OBJECTIVE: To validate the adult height prediction model on children from another geographical location. MATERIALS AND METHODS: We included 51 boys and 58 girls from the Paris Longitudinal Study of children born 1953 to 1958. Radiographs were obtained once or twice a year in these children from birth to age 18. Bone age was determined using the BoneXpert method. Radiographs in children with bone age greater than 6 years were considered, in total 1,124 images. RESULTS: The root mean square deviation between the predicted and the observed adult height was 2.8 cm for boys in the bone age range 6-15 years and 3.1 cm for girls in the bone age range 6-13 years. The bias (the average signed difference) was zero, except for girls below bone age 12, where the predictions were 0.8 cm too low. CONCLUSION: The accuracy of the BoneXpert method in terms of root mean square error was as predicted by the model, i.e. in line with what was observed in the Zurich studies. PMID- 26573824 TI - Appendiceal diameter: CT versus sonographic measurements. AB - BACKGROUND: Ultrasound and CT are the dominant imaging modalities for assessment of suspected pediatric appendicitis, and the most commonly applied diagnostic criterion for both modalities is appendiceal diameter. The classically described cut-off diameter for the diagnosis of appendicitis is 6 mm when using either imaging modality. OBJECTIVE: To demonstrate the fallacy of using the same cut-off diameter for both CT and US in the diagnosis of appendicitis. MATERIALS AND METHODS: We conducted a retrospective review of patients younger than 18 years who underwent both US and CT of the appendix within 24 h. The shortest transverse dimension of the appendix was measured at the level of the proximal, mid and distal appendix on US and CT images. We compared mean absolute difference in appendiceal diameter between US and CT, using the paired t-test. RESULTS: We reviewed exams of 155 children (58.7% female) with a mean age of 11.3 +/- 4.2 years; 38 of the children (24.5%) were diagnosed with appendicitis. The average time interval between US and CT was 7.0 +/- 5.4 h. Mean appendiceal diameter measured by CT was significantly larger than that measured by US in cases without appendicitis (5.3 +/- 1.0 mm vs. 4.7 +/- 1.1 mm, P < 0.0001) and in cases with appendicitis (8.3 +/- 2.2 mm vs. 7.0 +/- 2.0 mm, P < 0.0001). Mean absolute diameter difference at any location along the appendix was 1.3-1.4 mm in normal appendices and 2 mm in cases of appendicitis. CONCLUSION: Measured appendiceal diameter differs between US and CT by 1-2 mm, calling into question use of the same diameter cut-off (6 mm) for both modalities for the diagnosis of appendicitis. PMID- 26573825 TI - Health system delay in treatment of multidrug resistant tuberculosis patients in Bangladesh. AB - BACKGROUND: Bangladesh is one of the 27 high burden countries for multidrug resistant tuberculosis listed by the World Health Organization. Delay in multidrug resistant tuberculosis treatment may allow progression of the disease and affect the attempts to curb transmission of drug resistant tuberculosis. The main objective of this study was to investigate the health system delay in multidrug resistant tuberculosis treatment in Bangladesh and to explore the factors related to the delay. METHODS: Information related to the delay was collected as part of a previously conducted case-control study. The current study restricts analysis to patients with multidrug resistant tuberculosis who were diagnosed using rapid diagnostic methods (Xpert MTB/RIF or the line probe assay). Information was collected by face-to-face interviews and through record reviews from all three Government hospitals providing multidrug resistant tuberculosis services, from September 2012 to April 2013. Multivariable regression analysis was performed using Bootstrap variance estimators. Definitions were as follows: Provider delay: time between visiting a provider for first consultation on MDR-TB related symptom to visiting a designated diagnostic centre for testing; Diagnostic delay: time from date of diagnostic sample provided to date of result; Treatment initiation delay: time between the date of diagnosis and date of treatment initiation; Health system delay: time between visiting a provider to start of treatment. Health system delay was derived by adding provider delay, diagnostic delay and treatment initiation delay. RESULTS: The 207 multidrug resistant tuberculosis patients experienced a health system delay of median 7.1 weeks. The health system delay consists of provider delay (median 4 weeks), diagnostic delay (median 5 days) and treatment initiation delay (median 10 days). Health system delay (Coefficient: 37.7; 95 %; CI 15.0-60.4; p 0.003) was associated with the visit to private practitioners for first consultation. CONCLUSIONS: Diagnosis time for multidrug resistant tuberculosis was fast using the rapid tests. However, some degree of delay was present in treatment initiation, after diagnosis. The most effective way to reduce health system delay would be through strategies such as engaging private practitioners in multidrug resistant tuberculosis control. PMID- 26573826 TI - Identification of alternative splicing events by RNA sequencing in early growth tomato fruits. AB - BACKGROUND: Alternative splicing (AS) regulates multiple biological processes including flowering, circadian and stress response in plant. Although accumulating evidences indicate that AS is developmentally regulated, how AS responds to developmental cues is not well understood. Early fruit growth mainly characterized by active cell division and cell expansion contributes to the formation of fruit morphology and quality traits. Transcriptome profiling has revealed the coordinated complex regulation of gene expression in the process. High throughput RNA sequencing (RNA-seq) technology is advancing the genome-wide analysis of AS events in plant species, but the landscape of AS in early growth fruit is still not available for tomato (Solanum lycopersicum), a model plant for fleshy fruit development study. RESULTS: Using RNA-seq, we surveyed the AS patterns in tomato seedlings, flowers and young developing fruits and found that 59.3 % of expressed multi-exon genes underwent AS in these tissues. The predominant type of AS events is intron retention, followed by alternative splice donor and acceptor, whereas exon skipping has the lowest frequency. Although the frequencies of AS events are similar among seedlings, flowers and early growth fruits, the fruits generated more splice variants per gene. Further comparison of gene expression in early growth fruits at 2, 5 and 10 days post anthesis revealed that 5206 multi-exon genes had at least one splice variants differentially expressed during early fruit development, whereas only 1059 out of them showed differential expression at gene level. We also identified 27 multi-exon genes showing differential splicing during early fruit growth. In addition, the study discovered 2507 new transcription regions (NTRs) unlinked to the annotated chromosomal regions, from where 956 putative protein coding transcripts and 1690 putative long non-coding RNAs were identified. CONCLUSIONS: Our genome-wide analysis of AS events reveals a distinctive AS pattern in early growth tomato fruits. The landscape of AS obtained in this study will facilitate future investigation on transcriptome complexity and AS regulation during early fruit growth in tomato. The newly found NTRs will also be useful for updating the tomato genome annotation. PMID- 26573828 TI - Dose impact of rectal gas on prostatic IMRT and VMAT. AB - PURPOSE: In this study, we compared the dose impact of the heterogeneity caused by rectal gas using two methods of treatment planning for intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy (VMAT). MATERIALS AND METHODS: In addition to the structure set used for the standard treatment plan, we created a structure set for evaluation for each patient. These sets were transferred to the same isocenter as the respective treatment plans for IMRT and VMAT that were to become the standard. Values were then recalculated. RESULTS: During the standard prostatic IMRT and VMAT treatment planning, all study participants met dose restrictions in place at our hospital. Dose restrictions were fulfilled in treatment plans for evaluation, excluding those with a clinical target volume (CTV) of V(100%) and planning target volume (PTV) of D95 when the rectum was excluded. However, in treatment plans for evaluation, IMRT was shown to have a higher concordance rate with standard treatment plans than VMAT. CONCLUSION: If rectal gas is present during either IMRT or VMAT, a dose decrease will occur in relation to CTV and PTV, suggesting that a plan does not eliminate adverse effects on organs at risk. PMID- 26573827 TI - Generalizing boundaries for triangular designs, and efficacy estimation at extended follow-ups. AB - BACKGROUND: Visceral leishmaniasis (VL) is a parasitic disease transmitted by sandflies and is fatal if left untreated. Phase II trials of new treatment regimens for VL are primarily carried out to evaluate safety and efficacy, while pharmacokinetic data are also important to inform future combination treatment regimens. The efficacy of VL treatments is evaluated at two time points, initial cure, when treatment is completed and definitive cure, commonly 6 months post end of treatment, to allow for slow response to treatment and detection of relapses. This paper investigates a generalization of the triangular design to impose a minimum sample size for pharmacokinetic or other analyses, and methods to estimate efficacy at extended follow-up accounting for the sequential design and changes in cure status during extended follow-up. METHODS: We provided R functions that generalize the triangular design to impose a minimum sample size before allowing stopping for efficacy. For estimation of efficacy at a second, extended, follow-up time, the performance of a shrinkage estimator (SHE), a probability tree estimator (PTE) and the maximum likelihood estimator (MLE) for estimation was assessed by simulation. RESULTS: The SHE and PTE are viable approaches to estimate an extended follow-up although the SHE performed better than the PTE: the bias and root mean square error were lower and coverage probabilities higher. CONCLUSIONS: Generalization of the triangular design is simple to implement for adaptations to meet requirements for pharmacokinetic analyses. Using the simple MLE approach to estimate efficacy at extended follow up will lead to biased results, generally over-estimating treatment success. The SHE is recommended in trials of two or more treatments. The PTE is an acceptable alternative for one-arm trials or where use of the SHE is not possible due to computational complexity. TRIAL REGISTRATION: NCT01067443 , February 2010. PMID- 26573829 TI - High levels at baseline of serum pyridinoline crosslinked carboxyterminal telopeptide of type I collagen are associated with worse prognosis for breast cancer patients. AB - It is speculated that adjuvant use of bisphosphonate reduces recurrence in breast cancer patients through suppression of bone resorption. To determine the prognostic impact of bone resorption markers, we investigated serum levels of the pyridinoline crosslinked carboxyterminal telopeptide of type I collagen (1CTP) and N-terminal crosslinking telopeptides of type I collagen (NTX). 1CTP and NTX were measured at baseline (before operation or neoadjuvant therapies) and afterward in 469 patients operated on breast cancer. The optimal cutoff value of 1CTP for relapse-free survival (RFS) was set at 3.6 ng/ml with an area under the receiver operating characteristics curve of 0.641 [95% confidence interval (CI) = 0.560-0.721; p = 0.0011]. However, we were unable to determine a significant cutoff value for NTX. RFS was significantly worse for 1CTP-high patients with than for those with low levels of 1CTP (p = 0.0002). Multivariate analysis with tumor size, lymph node metastasis, and nuclear grade showed that 1CTP was a significant independent prognostic factor (hazard ratio = 2.04, 95% CI = 1.13 3.68; p = 0.018). Worse prognosis for the subset with high 1CTP levels applied only to postmenopausal patients (p = 0.0002). RFS of 130 patients whose 1CTP changed from low at baseline to high at 6 months postoperatively showed RFS almost as poor as that for patients with high 1CTP throughout. These findings suggest that 1CTP may be useful not only for identifying patients with unfavorable prognosis, but also for selecting patients who may benefit from administration of bone-modifying agents in an adjuvant setting. PMID- 26573830 TI - Prospective assessment of the prognostic value of circulating tumor cells and their clusters in patients with advanced-stage breast cancer. AB - The enumeration of circulating tumor cells (CTCs) provides important prognostic values in patients with metastatic breast cancer. Recent studies indicate that individual CTCs form clusters and these CTC-clusters play an important role in tumor metastasis. We aimed to assess whether quantification of CTC-clusters provides additional prognostic value over quantification of individual CTCs alone. In 115 prospectively enrolled advanced-stage (III and IV) breast cancer patients, CTCs and CTC-clusters were counted in 7.5 ml whole blood using the CellSearch system at baseline before first-line therapy. The individual and joint effects of CTC and CTC cluster counts on patients' progression-free survival (PFS) were analyzed using Cox proportional hazards modeling. Of the 115 patients, 36 (31.3 %) had elevated baseline CTCs (>=5 CTCs/7.5 ml) and 20 (17.4 %) had CTC clusters (>=2 CTCs/7.5 ml). Patients with elevated CTCs and CTC-clusters both had worse PFS with a hazard ratio (HR) of 2.76 [95 % confidence interval (CI) 1.57 4.86, P log-rank = 0.0005] and 2.83 (1.48-5.39, P log-rank = 0.001), respectively. In joint analysis, compared with patients with <5 CTCs and without CTC-clusters, patients with elevated CTCs but without clusters, and patients with elevated CTCs and with clusters, had an increasing trend of progression risk, with an HR of 2.21 (1.02-4.78) and 3.32 (1.68-6.55), respectively (P log-rank = 0.0006, P trend = 0.0002). The additional prognostic value of CTC-clusters appeared to be more pronounced in patients with inflammatory breast cancer (IBC), the most aggressive form of breast cancer with the poorest survival. Baseline counts of both individual CTCs and CTC-clusters were associated with PFS in advanced-stage breast cancer patients. CTC-clusters might provide additional prognostic value compared with CTC enumeration alone, in patients with elevated CTCs. PMID- 26573831 TI - The High Diversity and Global Distribution of the Intracellular Bacterium Rickettsiella in the Polar Seabird Tick Ixodes uriae. AB - Obligate intracellular bacteria of the Rickettsiella genus are emerging as both widespread and biologically diverse in arthropods. Some Rickettsiella strains are highly virulent entomopathogenic agents, whereas others are maternally inherited endosymbionts exerting very subtle manipulations on host phenotype to promote their own spread. Recently, a variety of Rickettsiella strains have been reported from ticks, but their biology is entirely unknown. In the present study, we examined the incidence and diversity of Rickettsiella in 11 geographically distinct populations of the polar seabird tick Ixodes uriae. We found Rickettsiella in most tick populations with a prevalence ranging from 3 to 24 %. 16S ribosomal RNA (rRNA) and GroEL gene sequences revealed an unexpected diversity of Rickettsiella, with 12 genetically distinct Rickettsiella strains present in populations of I. uriae. Phylogenetic investigations further revealed that these Rickettsiella strains do not cluster within a tick-specific clade but rather exhibit distinct evolutionary origins demonstrating frequent horizontal transfers between distantly related arthropod species. Tick rearing further showed that Rickettsiella are present in eggs laid by infected females with no evidence of abortive development. Using this data set, we discuss the potential biological significance of Rickettsiella in seabird ticks. Most notably, we suggest that these organisms may not be pathogenic forms but rather use more subtle adaptive strategies to persist within tick populations. PMID- 26573832 TI - Expansion of Cultured Bacterial Diversity by Large-Scale Dilution-to-Extinction Culturing from a Single Seawater Sample. AB - High-throughput cultivation (HTC) based on a dilution-to-extinction method has been applied broadly to the cultivation of marine bacterial groups, which has often led to the repeated isolation of abundant lineages such as SAR11 and oligotrophic marine gammaproteobacteria (OMG). In this study, to expand the phylogenetic diversity of HTC isolates, we performed a large-scale HTC with a single surface seawater sample collected from the East Sea, the Western Pacific Ocean. Phylogenetic analyses of the 16S rRNA genes from 847 putative pure cultures demonstrated that some isolates were affiliated with not-yet-cultured clades, including the OPB35 and Puniceicoccaceae marine group of Verrucomicrobia and PS1 of Alphaproteobacteria. In addition, numerous strains were obtained from abundant clades, such as SAR11, marine Roseobacter clade, OMG (e.g., SAR92 and OM60), OM43, and SAR116, thereby increasing the size of available culture resources for representative marine bacterial groups. Comparison between the composition of HTC isolates and the bacterial community structure of the seawater sample used for HTC showed that diverse marine bacterial groups exhibited various growth capabilities under our HTC conditions. The growth response of many bacterial groups, however, was clearly different from that observed with conventional plating methods, as exemplified by numerous isolates of the SAR11 clade and Verrucomicrobia. This study showed that a large number of novel bacterial strains could be obtained by an extensive HTC from even a small number of samples. PMID- 26573833 TI - Yeasts Associated with Culex pipiens and Culex theileri Mosquito Larvae and the Effect of Selected Yeast Strains on the Ontogeny of Culex pipiens. AB - The success of mosquitoes in nature has been linked to their microbiota and bacteria in particular. Yet, knowledge on their symbioses with yeasts is lacking. To explore possible associations, culturable yeasts were isolated from wild larvae of Culex pipiens and Culex theileri. These yeasts were classified using restriction fragment length polymorphism (RFLP) analyses and identified by sequencing the D1/D2 region of the 26S rRNA gene. Representative strains of Candida, Cryptococcus, Galactomyces, Hannaella, Meyerozyma, Pichia, Rhodosporidium, Rhodotorula, Trichosporon and Wickerhamomyces were isolated. Our results provide, to our knowledge, the first records of the yeast microbiota from wild mosquito larvae and show that they may harbour potential clinically relevant yeast species, including the well-known opportunistic human pathogen Candida albicans. Also, diminished numbers of yeast isolates originating from adults, compared to larvae, support the hypothesis of microbial reduction/elimination during adult emergence and extend it to include yeasts. In addition, strains of Candida albicans, Candida glabrata, Candida pseudolambica, Cryptococcus gattii, Metschnikowia bicuspidata, Saccharomyces cerevisiae and Wickerhamomyces anomalus were tested as sole feed during a 21-day feeding experiment wherein cumulative larval growth, survival and pupation of Cx. pipiens were recorded. Although most yeasts supported larval growth in a similar manner to the positive control S. cerevisiae strain, the different yeast strains impacted differently on Culex pipiens ontogeny. Notably, survival and pupation of larvae were negatively impacted by a representative strain of the primary pathogen C. gattii - signifying some yeasts to be natural antagonists of mosquitoes. PMID- 26573834 TI - Costimulation Endows Immunotherapeutic CD8 T Cells with IL-36 Responsiveness during Aerobic Glycolysis. AB - CD134- and CD137-primed CD8 T cells mount powerful effector responses upon recall, but even without recall these dual-costimulated T cells respond to signal 3 cytokines such as IL-12. We searched for alternative signal 3 receptor pathways and found the IL-1 family member IL-36R. Although IL-36 alone did not stimulate effector CD8 T cells, in combination with IL-12, or more surprisingly IL-2, it induced striking and rapid TCR-independent IFN-gamma synthesis. To understand how signal 3 responses functioned in dual-costimulated T cells we showed that IL-2 induced IL-36R gene expression in a JAK/STAT-dependent manner. These data help delineate a sequential stimulation process where IL-2 conditioning must precede IL-36 for IFN-gamma synthesis. Importantly, this responsive state was transient and functioned only in effector T cells capable of aerobic glycolysis. Specifically, as the effector T cells metabolized glucose and consumed O2, they also retained potential to respond through IL-36R. This suggests that T cells use innate receptor pathways such as the IL-36R/axis when programmed for aerobic glycolysis. To explore a function for IL-36R in vivo, we showed that dual costimulation therapy reduced B16 melanoma tumor growth while increasing IL-36R gene expression. In summary, cytokine therapy to eliminate tumors may target effector T cells, even outside of TCR specificity, as long as the effectors are in the correct metabolic state. PMID- 26573836 TI - Characterization of Amphioxus IFN Regulatory Factor Family Reveals an Archaic Signaling Framework for Innate Immune Response. AB - The IFN regulatory factor (IRF) family encodes transcription factors that play important roles in immune defense, stress response, reproduction, development, and carcinogenesis. Although the origin of the IRF family has been dated back to multicellular organisms, invertebrate IRFs differ from vertebrate IRFs in genomic structure and gene synteny, and little is known about their functions. Through comparison of multiple amphioxus genomes, in this study we suggested that amphioxus contains nine IRF members, whose orthologs are supposed to be shared among three amphioxus species. As the orthologs to the vertebrate IRF1 and IRF4 subgroups, Branchiostoma belcheri tsingtauense (bbt)IRF1 and bbtIRF8 bind the IFN stimulated response element (ISRE) and were upregulated when amphioxus intestinal cells were stimulated with poly(I:C). As amphioxus-specific IRFs, both bbtIRF3 and bbtIRF7 bind ISRE. When activated, they can be phosphorylated by bbtTBK1 and then translocate into nucleus for target gene transcription. As transcriptional repressors, bbtIRF2 and bbtIRF4 can inhibit the transcriptional activities of bbtIRF1, 3, 7, and 8 by competing for the binding of ISRE. Interestingly, amphioxus IRF2, IRF8, and Rel were identified as target genes of bbtIRF1, bbtIRF7, and bbtIRF3, respectively, suggesting a dynamic feedback regulation among amphioxus IRF and NF-kappaB. Collectively, to our knowledge we present for the first time an archaic IRF signaling framework in a basal chordate, shedding new insights into the origin and evolution of vertebrate IFN-based antiviral networks. PMID- 26573835 TI - Activation of the Aryl Hydrocarbon Receptor by 10-Cl-BBQ Prevents Insulitis and Effector T Cell Development Independently of Foxp3+ Regulatory T Cells in Nonobese Diabetic Mice. AB - Aryl hydrocarbon receptor (AhR) activation by high-affinity ligands mediates immunosuppression in association with increased regulatory T cells (Tregs), making this transcription factor an attractive therapeutic target for autoimmune diseases. We recently discovered 10-chloro-7H-benzimidazo[2,1-a]benzo[de]iso quinolin-7-one (10-Cl-BBQ), a nanomolar affinity AhR ligand with immunosuppressive activity and favorable pharmacologic properties. In this study, we tested the consequences of AhR activation in the NOD model. Oral 10-Cl-BBQ treatment prevented islet infiltration without clinical toxicity, whereas AhR deficient NOD mice were not protected. Suppression of insulitis was associated with an increased frequency, but not total number, of Foxp3(+) Tregs in the pancreas and pancreatic lymph nodes. The requirement for Foxp3(+) cells in AhR induced suppression of insulitis was tested using NOD.Foxp3(DTR) mice, which show extensive islet infiltration upon treatment with diphtheria toxin. AhR activation prevented the development of insulitis caused by the depletion of Foxp3(+) cells, demonstrating that Foxp3(+) cells are not required for AhR-mediated suppression and furthermore that the AhR pathway is able to compensate for the absence of Foxp3(+) Tregs, countering current dogma. Concurrently, the development of disease-associated CD4(+)Nrp1(+)Foxp3(-)RORgammat(+) cells was inhibited by AhR activation. Taken together, 10-Cl-BBQ is an effective, nontoxic AhR ligand for the intervention of immune-mediated diseases that functions independently of Foxp3(+) Tregs to suppress pathogenic T cell development. PMID- 26573837 TI - Suboptimal Antigen Presentation Contributes to Virulence of Mycobacterium tuberculosis In Vivo. AB - Mycobacterium tuberculosis commonly causes persistent or chronic infection, despite the development of Ag-specific CD4 T cell responses. We hypothesized that M. tuberculosis evades elimination by CD4 T cell responses by manipulating MHC class II Ag presentation and CD4 T cell activation and tested this hypothesis by comparing activation of Ag85B-specific CD4 T cell responses to M. tuberculosis and M. bovis bacillus Calmette-Guerin (BCG) Pasteur in vivo and in vitro. We found that, although M. tuberculosis persists in lungs of immunocompetent mice, M. bovis BCG is cleared, and clearance is T cell dependent. We further discovered that M. tuberculosis-infected macrophages and dendritic cells activate Ag85B specific CD4 T cells less efficiently and less effectively than do BCG-infected cells, in vivo and in vitro, despite higher production and secretion of Ag85B by M. tuberculosis. During BCG infection, activation of Ag85B-specific CD4 T cells requires fewer infected dendritic cells and fewer Ag-producing bacteria than during M. tuberculosis infection. When dendritic cells containing equivalent numbers of M. tuberculosis or BCG were transferred to mice, BCG-infected cells activated proliferation of more Ag85B-specific CD4 T cells than did M. tuberculosis-infected cells. Differences in Ag85B-specific CD4 T cell activation were attributable to differential Ag presentation rather than differential expression of costimulatory or inhibitory molecules. These data indicate that suboptimal Ag presentation contributes to persistent infection and that limiting Ag presentation is a virulence property of M. tuberculosis. PMID- 26573838 TI - Adsorption of Pyrene onto the Agricultural By-Product: Corncob. AB - The adsorption behavior of pyrene on corncob was studied to provide a theoretical basis for the possible use of this material as an immobilized carrier for improving the bioremediation of PAH-contaminated soil. The results were as follows. Kinetic experiments showed that the adsorption processes obeyed a pseudo second-order model. The intraparticle diffusion of Weber-Morris model fitting showed that the film and intraparticle diffusions were the key rate-limiting processes, and the adsorption process mainly consisted of three steps: boundary layer diffusion and two intra-particle diffusions. Experimental adsorption data for pyrene were successfully described by the adsorption-partition equilibrium model. The maximum adsorption capacity at 25 degrees C was 214.8 MUg g(-1). The adsorption contribution decreased significantly when the Ce/Sw (the equilibrium concentration/solubility in water) was higher than 1. Adsorption decreased with increased temperature. Based on the above results, the corncob particles could be helpful in the bioremediation of pyrene-contaminated soil. PMID- 26573839 TI - Analysis of Insecticides in Dead Wild Birds in Korea from 2010 to 2013. AB - Wild birds are exposed to insecticides in a variety of ways, at different dose levels and via multiple routes, including ingestion of contaminated food items, and dermal, inhalation, preening, and embryonic exposure. Most poisoning by insecticides occurs as a result of misuse or accidental exposure, but intentional killing of unwanted animals also occurs. In this study, we investigated insecticides in the gastric contents of dead wild birds that were suspected to have died from insecticide poisoning based on necropsy. The wild birds were found dead in various regions and locations such as in mountains, and agricultural and urban areas. A total of 182 dead wild birds of 27 species were analyzed in this study, and insecticide residue levels were determined in 60.4% of the total samples analyzed. Monocrotophos and phosphamidon were the most common insecticides identified at rates of 50.0% and 30.7% of the insecticide-positive samples, respectively. Other insecticides identified in dead wild birds included organophosphorous, organochlorine and carbamate insecticides. However, there was limited evidence to conclusively establish the cause of death related to insecticides in this study. Nevertheless, considering the level of insecticide exposure, it is speculated that the exposure was mainly a result of accidental or intentional killing, and not from environmental residue. PMID- 26573840 TI - Dichotomizing partial compliance and increased participant burden in factorial designs: the performance of four noncompliance methods. AB - BACKGROUND: Noncompliance to treatment assignment is an inevitable occurrence in randomized clinical trials (RCTs). Intention to treat (ITT) is generally considered the best method for addressing noncompliance in RCTs. Alternatives to ITT exist, including per protocol (PP), as treated (AT), and instrumental variables (IV). These three methods define participant compliance dichotomously, but partial compliance is a common occurrence in RCTs. By defining a threshold, above which a participant is called a complier, PP, AT and IV can be used, but the resulting loss of information may affect their performance. Trials with factorial designs may experience higher rates of noncompliance due to the heavier burden that participants experience by being assigned to multiple experimental treatments. METHODS: Using simulations, we assessed the performance of ITT, PP, AT, and IV in both the partial compliance setting and in a 2-by-2 factorial design with increased participant burden for those randomized to both active treatments. RESULTS: The bias, mean squared error, and type I error rates of the IV method after dichotomizing partial compliance were heavily inflated. The performance of all four methods depended on the level of noncompliance present, with higher average noncompliance leading to poorer performance. PP and AT showed improved bias and power relative to ITT without inflating the type I error beyond acceptable limits. However, the PP and AT heavily inflated the type I error rates when participant compliance was affected by the participants' general health. CONCLUSIONS: There are consequences for dichotomizing compliance information to make it fit into well-known methods. The results suggest the need for a method of estimating treatment effects that can utilize partial compliance information. PMID- 26573841 TI - The diffusion of generics after patent expiry in Germany. AB - To identify the influences on the diffusion of generics after patent expiry, we analyzed 65 generic entries using prescription data of a large German sickness fund between 2007 and 2012 in a sales model. According to theory, several elements are responsible for technology diffusion: (1) time reflecting the rate of adaption within the social system, (2) communication channels, and (3) the degree of incremental innovation, e.g., the modifications of existing active ingredient's strength. We investigated diffusion in two ways: (1) generic market share (percentage of generic prescriptions of all prescriptions of a substance) and, (2) generic sales quantity (number of units sold) over time. We specified mixed regression models. Generic diffusion takes considerable time. An average generic market share of about 75 % was achieved not until 48 months. There was a positive effect of time since generic entry on generic market share (p < 0.001) and sales (p < 0.001). Variables describing the communication channels and the degree of innovation influenced generic market share (mostly p < 0.001), but not generic sales quantity. Market structure, e.g., the number of generic manufacturers (p < 0.001) and prices influenced both generic market share and sales. Imperfections in generic uptake through informational cascades seem to be largely present. Third-party payers could enhance means to promote generic diffusion to amplify savings through generic entry. PMID- 26573842 TI - Clinical, endoscopic, and pathologic characteristics of colorectal polyps in Indian children and adolescents. AB - OBJECTIVES: Colorectal polyps are among the common causes for rectal bleeding in children. We studied the clinical, colonoscopic, and histopathological features of colorectal polyps and polyposis syndrome in Indian children and adolescents. METHODS: Medical records of children and adolescents with colorectal polyps and polyposis syndrome were retrospectively reviewed from 2001 to 2014 at Department of Gastroenterology, in large tertiary care center of Mumbai. RESULTS: A total of 120 patients were found to have colonic polyps during study period. Mean age of presentation in children was 7.31 +/- 4.05 years (range 2 to 19 years), with male to-female ratio of 2.16:1. Rectal bleeding was presenting symptom in 95.8 % with mean duration of 12.6 +/- 15 months. Majority of polyps (77.5 %) were juvenile, and 97.2 % were located in left colon. Solitary polyps were seen in 76.6 %, multiple polyps in 11.6 %, juvenile polyposis syndrome in 6.6 %, familial adenomatous polyposis in 4.2 %, and Peutz-Jeghers syndrome in 0.8 % of the children. The polyposis syndrome group had higher age at presentation (p = 0.00006), greater likelihood of anemia, abdominal pain, and diarrhea (p = 0.0001, 0.0002, and 0.0051, respectively). Likelihood of adenomatous change in polyps was higher in polyposis syndrome group (p = 0.0003). Left colonic polyps were more common in non-polyposis group, whereas pan-colonic polyps were more common in polyposis syndrome group (p < 0.00001). CONCLUSION: Presence of anemia, abdominal pain, diarrhea, higher age at presentation (more than 10 years), and history of polypectomy are clinical indicators of polyposis syndrome. PMID- 26573843 TI - Demographic and clinicopathological profile of patients with chronic pancreatitis in a tertiary referral teaching hospital of West Bengal: Personal experience. AB - BACKGROUND: There is a paucity of data on the demographic and clinicopathological profiles of patients with chronic pancreatitis from the eastern part of India. This study documents the demographic and clinicopathological profiles of patients with chronic pancreatitis presenting to a general surgery unit of a tertiary referral hospital of Kolkata. METHODS: The records of 145 patients presenting with chronic pancreatitis over a 5-year period were scrutinized and their demographics, clinical profile, and complications and morphological changes of the pancreas are described. RESULTS: Of the 145 patients, more than 50% were under the age of 30 years. Males were affected more frequently than females (M/F = 3.8:1). While idiopathic pancreatitis was the most common form of chronic pancreatitis (41.4%), alcohol was found to be the most common etiology (37.9%). Pain was the most common presenting symptom (n = 143; 98.6%). Sixty-five subjects (45%) had diabetes of which 32 subjects were insulin-dependent. On contrast enhanced computed tomography, ductal dilatation was seen in 80 (55.17%) subjects, while ductal calculi and ductal dilatation in 54 cases (37.2%). Parenchymal calcification was seen in 45 patients of whom 40 patients (89%) were under the age of 30 years. Pseudocyst was the most common complication (n = 16) followed by biliary obstruction (n = 8) and portal hypertension (n = 4). Patients with alcoholic pancreatitis had significantly higher frequency of severe abdominal pain, diabetes, and local complications as compared to the other forms of pancreatitis in our study. CONCLUSION: Idiopathic pancreatitis was the most common form of chronic pancreatitis in this study, followed by alcoholic pancreatitis and then tropical pancreatitis. PMID- 26573844 TI - Effect of a 2-year home-based endurance training intervention on physiological function and PSA doubling time in prostate cancer patients. AB - AIM: Physical activity after prostate cancer diagnosis has been shown to reduce the risk of disease progression. Here, we aimed to evaluate the effect of a 2 year home-based endurance training intervention on body composition, biomarkers levels, and prostate-specific antigen (PSA) doubling time as a surrogate end point for progressing disease. METHODS: Out-clinic patients with either biochemical recurrence following radical prostatectomy or patients managed on active surveillance were randomized to either 24 months (3 times/week) of home based endurance training or usual care. Aerobic fitness, body composition, insulin sensitivity, and biomarkers were measured at 0, 6, and 24 months of intervention. PSA doubling time (PSADT) was calculated based on monthly PSA measurements. RESULTS: Twenty-five patients were enrolled, and 19 patients completed the study. PSADT increased in the training group from 28 to 76 months (p < 0.05) during the first 6 months and was correlated with changes in VO2max (p < 0.01, r (2) = 0.41). The training group lost 3.6 +/- 1.0 kg (p < 0.05) exclusively as fat mass, yet the changes in body composition were not associated with the increased PSADT. The training group showed significant improvements in plasma triglycerides, adiponectin, IGF-1, IGFBP-1, and fasting glucose levels, but no changes in insulin sensitivity (measured as Matsuda index), testosterone, cholesterols, fasting insulin, plasma TNF-alpha, IL-6, or leptin levels. The control group showed no changes in any of the evaluated parameters across the 2 year intervention. CONCLUSION: In this small randomized controlled trial, we found that improvements in fitness levels correlated with increasing PSADT, suggesting a link between training and disease progression. PMID- 26573846 TI - Prostate cancer risk among users of digoxin and other antiarrhythmic drugs in the Finnish Prostate Cancer Screening Trial. AB - PURPOSE: Long-term usage of the antiarrhythmic drug digoxin has been connected to lowered risk of prostate cancer. A recent study has suggested that beta-blockers might also have similar risk-decreasing effects. We evaluated the association between use of digoxin, beta-blocker sotalol, and other antiarrhythmic drugs and prostate cancer risk in a retrospective cohort study. METHODS: Our study population consisted of men in the Finnish Prostate Cancer Screening Trial during 1996-2012 (n = 78,615). During median follow-up of 12 years, 6,639 prostate cancer cases were diagnosed. The national prescription database was the source of the information of antiarrhythmic drug purchases. Data were analyzed using Cox regression method with medication use as a time-dependent variable. RESULTS: No association was found for overall prostate cancer risk with antiarrhythmic drug use (HR 1.05 95% CI 0.94-1.18). Neither sotalol (HR 0.97 95% CI 0.76-1.24) nor digoxin (HR 1.01 95% CI 0.87-1.16) users had a decreased risk of prostate cancer. Similar results were obtained for high-grade (Gleason 7-10) and metastatic prostate cancer. Nevertheless, the risk estimates for Gleason 7-10 prostate cancer tended to decrease by duration of digoxin use (p for trend = 0.052), suggesting that the drug may reduce the risk in long-term usage (HR 0.71, 95% CI 0.49-1.03). In analysis stratified by screening trial arm, the protective association against Gleason 7-10 disease was observed only in the screening arm (HR 0.31, 95% CI 0.12-0.84 for men who had used digoxin for 5 years or longer). CONCLUSION: Digoxin or other antiarrhythmic drugs are not associated with any clear decrease in prostate cancer risk. However, digoxin might have a benefit in long-term use by reducing risk of high-grade disease. Further research will be needed to evaluate possible effects on prostate cancer survival. PMID- 26573845 TI - Polycyclic aromatic hydrocarbons: determinants of residential carpet dust levels and risk of non-Hodgkin lymphoma. AB - PURPOSE: To investigate the risk of non-Hodgkin lymphoma (NHL) associated with residential carpet dust measurements of polycyclic aromatic hydrocarbons (PAHs). METHODS: We evaluated the relationship between residential carpet dust PAH concentrations (benz(a)anthracene, benzo(a)pyrene, benzo(b)fluoranthene, benzo(k)fluoranthene, chrysene, dibenz(a,h)anthracene, and indeno(1,2,3 c,d)pyrene, and their sum) and risk of NHL (676 cases, 511 controls) in the National Cancer Institute Surveillance Epidemiology and End Results multicenter case-control study. As a secondary aim, we investigated determinants of dust PAH concentrations. We computed odds ratios (OR) and 95 % confidence interval (CI) for associations between NHL and concentrations of individual and summed PAHs using unconditional logistic regression, adjusting for age, gender, and study center. Determinants of natural log-transformed PAHs were investigated using multivariate least-squares regression. RESULTS: We observed some elevated risks for NHL overall and B cell lymphoma subtypes in association with quartiles or tertiles of PAH concentrations, but without a monotonic trend, and there was no association comparing the highest quartile or tertile to the lowest. In contrast, risk of T cell lymphoma was significantly increased among participants with the highest tertile of summed PAHs (OR = 3.04; 95 % CI, 1.09-8.47) and benzo(k)fluoranthene (OR = 3.20; 95 % CI, 1.13-9.11) compared with the lowest tertile. Predictors of PAH dust concentrations in homes included ambient air PAH concentrations and the proportion of developed land within 2 km of a residence. Older age, more years of education, and white race were also predictive of higher levels in homes. CONCLUSION: Our results suggest a potential link between PAH exposure and risk of T cell lymphoma and demonstrate the importance of analyzing risk by NHL histologic type. PMID- 26573849 TI - Retraction Note: Does the hepatic branch of vagus mediate the secretion of glucagon-like peptide-1 during the Roux-en-Y gastric bypass surgery. PMID- 26573847 TI - Involuntary reflexive pelvic floor muscle training in addition to standard training versus standard training alone for women with stress urinary incontinence: study protocol for a randomized controlled trial. AB - BACKGROUND: Pelvic floor muscle training is effective and recommended as first line therapy for female patients with stress urinary incontinence. However, standard pelvic floor physiotherapy concentrates on voluntary contractions even though the situations provoking stress urinary incontinence (for example, sneezing, coughing, running) require involuntary fast reflexive pelvic floor muscle contractions. Training procedures for involuntary reflexive muscle contractions are widely implemented in rehabilitation and sports but not yet in pelvic floor rehabilitation. Therefore, the research group developed a training protocol including standard physiotherapy and in addition focused on involuntary reflexive pelvic floor muscle contractions. METHODS/DESIGN: The aim of the planned study is to compare this newly developed physiotherapy program (experimental group) and the standard physiotherapy program (control group) regarding their effect on stress urinary incontinence. The working hypothesis is that the experimental group focusing on involuntary reflexive muscle contractions will have a higher improvement of continence measured by the International Consultation on Incontinence Modular Questionnaire Urinary Incontinence (short form), and - regarding secondary and tertiary outcomes - higher pelvic floor muscle activity during stress urinary incontinence provoking activities, better pad-test results, higher quality of life scores (International Consultation on Incontinence Modular Questionnaire) and higher intravaginal muscle strength (digitally tested) from before to after the intervention phase. This study is designed as a prospective, triple-blinded (participant, investigator, outcome assessor), randomized controlled trial with two physiotherapy intervention groups with a 6-month follow-up including 48 stress urinary incontinent women per group. For both groups the intervention will last 16 weeks and will include 9 personal physiotherapy consultations and 78 short home training sessions (weeks 1-5 3x/week, 3x/day; weeks 6-16 3x/week, 1x/day). Thereafter both groups will continue with home training sessions (3x/week, 1x/day) until the 6-month follow up. To compare the primary outcome, International Consultation on Incontinence Modular Questionnaire (short form) between and within the two groups at ten time points (before intervention, physiotherapy sessions 2-9, after intervention) ANOVA models for longitudinal data will be applied. DISCUSSION: This study closes a gap, as involuntary reflexive pelvic floor muscle training has not yet been included in stress urinary incontinence physiotherapy, and if shown successful could be implemented in clinical practice immediately. TRIAL REGISTRATION: NCT02318251 ; 4 December 2014 First patient randomized: 11 March 2015. PMID- 26573850 TI - Surgery for Peptic Ulcer Disease in sub-Saharan Africa: Systematic Review of Published Data. AB - INTRODUCTION: Peptic ulcer disease is a significant cause of morbidity and mortality worldwide, with a significant burden in low- and middle-income countries. However, there is limited information regarding management of peptic ulcer disease in these countries. This study describes surgical interventions for peptic ulcer disease in sub-Saharan Africa. MATERIALS AND METHODS: A systematic review was performed using PubMed, EMBASE, and African Index Medicus for studies describing surgical management of peptic ulcer disease in sub-Saharan Africa. RESULTS: From 55 published reports, 6594 patients underwent surgery for peptic ulcer disease. Most ulcers (86%) were duodenal with the remainder gastric (14%). Thirty-five percent of operations were performed for perforation, 7% for bleeding, 30% for obstruction, and 28% for chronic disease. Common operations included vagotomy (60%) and primary repair (31%). The overall case fatality rate for peptic ulcer disease was 5.7% and varied with indication for operation: 13.6% for perforation, 11.5% for bleeding, 0.5% for obstruction, and 0.3% for chronic disease. CONCLUSION: Peptic ulcer disease remains a significant indication for surgery in sub-Saharan Africa. Recognizing the continued role of surgery for peptic ulcer disease in sub-Saharan Africa is important for strengthening surgical training programs and optimizing allocation of resources. PMID- 26573851 TI - The Worse Prognosis of Right-Sided Compared with Left-Sided Colon Cancers: a Systematic Review and Meta-analysis. AB - BACKGROUND: Right-sided colon cancers (RCC) and left-sided colon cancers (LCC) are of different embryological origins, and various differences exist between them. However, the survival difference has not been assessed. The aim of this meta-analysis was to quantify the prognostic differences between RCC and LCC. METHODS: Fifteen studies that compared the prognosis of colon cancer according to tumor location were identified. The effects of tumor location on survival outcome were assessed. RESULTS: Patients with RCC had a significantly worse prognosis than did those with LCC in overall survival (OS) (hazard ratio (HR) = 1.14, 95 % confidence interval (CI) 1.06-1.22, p < 0.01). Our subgroup analyses demonstrated significant prognostic differences in Western countries (HR = 1.15, 95 % CI 1.08 1.23, p < 0.01), a nationwide database (HR = 1.15, 95 % CI 1.05-1.27, p = 0.01), and a stage-adjusted analysis (HR = 1.14, 95 % CI 1.05-1.24, p < 0.01). CONCLUSIONS: These findings demonstrate that tumor location is associated with prognosis in colorectal cancer patients, and those with RCC have a significantly worse prognosis than those with LCC in terms of OS. RCC should be treated distinctively from LCC, and the establishment of standardized management for colon cancer by tumor location is needed. PMID- 26573853 TI - Is Training in a Primary Care Internal Medicine Residency Associated with a Career in Primary Care Medicine? PMID- 26573852 TI - Hepatic Hemodynamic Changes Following Stepwise Liver Resection. AB - AIM: Extended liver resection has increased during the last decades. However, hepatic hemodynamic changes after resection and the consequent complications like post hepatectomy liver failure are still a challenging issue. The aim of this study was to systematically evaluate the role of stepwise liver resection on hepatic hemodynamic changes. METHODS: To evaluate this effect we performed 25, 50, and 75 % sequential liver resections in 10 pigs. Before and after each resection, the hepatic artery flow and portal vein flow in relation to the remnant liver volume (RLV) as well as hepatic vascular pressures were measured and compared between the groups. RESULTS: Following sequential liver resection, the hepatic artery flow /100 g decreases and the portal vein flow increases up to 17 and 167 % following extended liver resection (75 %), respectively. Also, during stepwise liver resection, the portal vein pressure increases gradually up to 33 % following extended hepatectomy (75 %). CONCLUSION: Sequential decrease in the RLV decreases the hepatic artery flow /100 g and increases the portal vein flow /100 g and portal vein pressure. As the consequence, the liver goes under more poor-oxygenated blood supply and higher pressure. This may be one of the most important mechanisms of the post hepatectomy liver failure in case of extended liver resection. PMID- 26573854 TI - The thyroid gland and thyroid hormones in sheepshead minnow (Cyprinodon variegatus) during early development and metamorphosis. AB - The sheepshead minnow is widely used in ecotoxicological studies that only recently have begun to focus on disruption of the thyroid axis by xenobiotics and endocrine disrupting compounds. However, reference levels of the thyroid prohormone thyroxine (T4) and biologically active hormone 3,5,3'-triiodothyronine (T3) and their developmental patterns are unknown. This study set out to describe the ontogeny and morphology of the thyroid gland in sheepshead minnow, and to correlate these with whole-body concentrations of thyroid hormones during early development and metamorphosis. Eggs were collected by natural spawning in our laboratory. T4 and T3 were extracted from embryos, larvae and juveniles and an enzyme-linked immunoassay was used to measure whole-body hormone levels. Length and body mass, hatching success, gross morphology, thyroid hormone levels and histology were measured. The onset of metamorphosis at 12-day post-hatching coincided with surges in whole-body T4 and T3 concentrations. Thyroid follicles were first observed in pre-metamorphic larvae at hatching and were detected exclusively in the subpharyngeal region, surrounding the ventral aorta. Follicle size and thyrocyte epithelial cell heights varied during development, indicating fluctuations in thyroid hormone synthesis activity. The increase in the whole body T3/T4 ratio was indicative of an increase in outer ring deiodination activity. This study establishes a baseline for thyroid hormones in sheepshead minnows, which will be useful for the understanding of thyroid hormone functions and in future studies of thyroid toxicants in this species. PMID- 26573855 TI - The effect of hatching time on the bioenergetics of northern pike (Esox lucius) larvae from a single egg batch during the endogenous feeding period. AB - Size, caloric value and chemical composition were measured separately in the progeny of two northern pike (Esox lucius) females at 3-day intervals during the endogenous feeding period from hatching to final yolk resorption. Tissue, yolk and entire larvae were analysed separately in three groups of larvae that hatched at different times (between 88 and 106 degree-days post-fertilization). An integrated approach with the Gompertz model was used to compute the yolk conversion efficiency and time to maximum tissue size in early, mid and late hatched larvae. At hatching, unresorbed yolk of early hatched larvae contained more energy (39.20 J) and more protein (0.99 mg) compared to the yolk of larvae that hatched later (38.13 J and 0.92 mg protein for late hatched larvae, p < 0.05). In contrast, a significant reduction in tissue weight (-0.7 mg DW) and protein content (-0.5 mg) was found in early hatched larvae compared to those which hatched later (p < 0.05). Between days 9 and 12 post-hatching (108 and 144 degree-days post-hatching), close to the final yolk resorption, late hatched larvae stopped growing and their tissue began to be resorbed. This tissue resorption time was delayed in early hatched larvae which presented at the end of the experiment a greater tissue weight than late hatched ones. Yolk conversion efficiency in term of energy from hatching to complete yolk resorption stage was significantly higher for early and mid hatched larvae (51%) compared to late hatched ones (44%) (p = 0.004). Furthermore, the time to maximum tissue size was found to be negatively related to hatching time which implies that early hatched larvae take longer time to switch from one developmental stage to the next. The maximum tissue dry weight and energy content were found to be reached at approximately the same age post-fertilization for both early hatched and late hatched larvae, suggesting that the principal steps in a fish's lifespan are better correlated with time of fertilization than hatching time. PMID- 26573856 TI - Using cornstarch in microparticulate diets for larvicultured tropical gar (Atractosteus tropicus). AB - Aquaculture in Mexico has been developed by the cultivation of commercial species. In Tabasco, the cultivation of native species is mainly limited by the lack of nutrition studies to support its crop profitability. Among these species is the tropical gar (Atractosteus tropicus), which has great potential for cultivation. However, the nutritional value of carbohydrates in diets for this species which contribute to improved growth and survival, have not been evalulated,. Thus, in the present investigation, isoprotein and isolipid diets have been designed based on the substitution of cellulose by corn starch (D1: 0% starch-15% cellulose, D2: 7.5% starch-7.5% cellulose and D3: 15% starch-0% cellulose) and compared with a commercial trout diet (45% protein and 16% lipids). A total of 1800 larvae (0.008 +/- 0.002 g and 10.5 +/- LT 0.126 mm) were used, distributed in a recirculation system in order to evaluate growth and survival for 30 days. The results show higher growth and survival of 97% of larvae fed the D3 diet, while cannibalism in the species was mitigated. Major digestive enzyme activities occurred (acid protease, alkaline protease, trypsin, chymotrypsin, leucine aminopeptidase, carboxypeptidase A, lipase, alpha glucosidase and amylase) for larvae fed D3. It is concluded that the contribution of corn starch (15%) replacing cellulose in the diet improves growth and survival of this species. PMID- 26573857 TI - Morphological and histological changes in digestive tract development during starvation in the miiuy croaker. AB - A histological method was used to describe the ontogenetic development of the digestive tract of laboratory-reared miiuy croaker (Miichthys miiuy) and to evaluate the effects of short-term food deprivation on the morphology and histology of the digestive tract. Larvae and juveniles were maintained at 24 degrees C in a thermostatically controlled system. Three starvation experiments were conducted during different developmental stages: 1-7 days after hatching (dah; prior to benthic swimming); 26-35 dah (during settling); and 42-53 dah (after benthic swimming). According to the structural changes in the ontogenetic development of the digestive tract, three stages were observed. The first stage was from hatching to 3 dah; the digestive tract was undifferentiated in newly hatched larvae and then showed remarkable morphological changes and differentiation. During this period, larvae depended on endogenous nutrition. The second stage (4-20 dah) was a critical period in which larvae transitioned from endogenous feeding to exogenous feeding and the digestive tract fully differentiated into the buccopharynx, oesophagus, stomach, anterior intestine and posterior intestine. Goblet cells and vacuoles appeared in the digestive tract, and pharyngeal teeth and taste buds developed. During the third stage (20-36 dah), the gastric glands developed and the stomach differentiated into the fundic, cardiac and pyloric regions. At 25 dah, pyloric caeca developed and mucosal folds and spiral valves were clearly distinguishable. After 30 dah, the digestive tract did not undergo any noticeable differentiation, indicating the complete development of the digestive system. The wet weight and SGR (specific growth rate) of miiuy croaker larvae and juveniles greatly decreased when they were deprived of food, and compensatory growth was observed in re-feeding juveniles. The livers of starved larvae and juveniles were atrophied and dark coloured, the intestines were transparent and thin, and the stomach cubages were reduced. The histological effects of starvation were mainly evident in the degeneration of cells in digestive organs, as seen in the shrinkage and separation of cells and the loss of intercellular substances in the liver, pancreas, intestine and stomach. These changes became more severe with increased duration of starvation. In addition, the histological structure of the digestive tracts of starved larvae and juveniles partly recovered after re-feeding, and the effects of starvation on miiuy croaker were age dependent. PMID- 26573858 TI - Predictive characteristic of simple bone cyst treated with curettage and bone grafting. AB - BACKGROUND: The efficiency of treating simple bone cyst (SBC) is low. Depending on the choice of treatment, a positive response occurs in 20 to 80 % of cases. These rates are unacceptable, particularly considering they concern the treatment of benign lesions affecting children. Although cyst curettage is one of the first known ways of treating SBC, no precise qualification criteria exists for this procedure. The aim of our study is to identify which type of cyst may be most effectively treated using curettage with grafting. METHODS: A retrospective analysis was performed on 24 patients referred to our clinic for SBC treatment. To identify predictive factors, the group of patients who positively responded to treatment (Neer stages I and II, n = 14) were compared with the group in which recurrences occurred (Neer stages III and IV, n = 10). RESULTS: Significantly fewer patients with lesions located in the humerus (chi(2) = 9.351; p < 0.05) and without pathological facture at the time of diagnosis (p = 0.017) were found in the group with no recurrence. The following radiological parameters were found to vary significantly between groups: cyst area (z = 3.121; p < 0.01), cyst index (z = 2.213; p < 0.05) and cyst diameter ratio (z = 2.202; p < 0.05). In the group with no recurrences, the mean values of these parameters were found to be lower than in group with poor response to treatment. No statistically significant differences regarding age, sex or type of bone graft (p > 0.05) were found. Recurrences were experienced by 10 patients (41.7 %) during the 3-year period after surgery CONCLUSION: In the group treated with curettage, associations were identified between worse treatment results and the location in the humerus, pathological fractures at the time of diagnosis, large cyst area, large cyst index and large cyst diameter. PMID- 26573859 TI - Biomechanical risk factors associated with iliotibial band syndrome in runners: a systematic review. AB - BACKGROUND: Iliotibial band syndrome is the second most common running injury. A gradual increase in its occurrence has been noted over the past decade. This may be related to the increasing number of runners worldwide. Since the last systematic review, six additional papers have been published, providing an opportunity for this review to explore the previously identified proximal risk factors in more detail. The aim of this systematic review is thus to provide an up to date quantitative synthesis of the trunk, pelvis and lower limb biomechanical risk factors associated with Iliotibial band syndrome in runners and to provide an algorithm for future research and clinical guidance. METHODS: An electronic search was conducted of literature published up until April 2015. The critical appraisal tool for quantitative studies was used to evaluate methodological quality of eligible studies. Forest plots displayed biomechanical findings, mean differences and confidence intervals. Level of evidence and clinical impact were evaluated for each risk factor. A meta-analysis was conducted where possible. RESULT: Thirteen studies were included (prospective (n = 1), cross-sectional (n = 12)). Overall the methodological score of the studies was moderate. Female shod runners who went onto developing Iliotibial band syndrome presented with increased peak hip adduction and increased peak knee internal rotation during stance. Female shod runners with Iliotibial band syndrome presented with increased: peak knee internal rotation and peak trunk ipsilateral during stance. CONCLUSION: Findings indicate new quantitative evidence about the biomechanical risk factors associated with Iliotibial band syndrome in runners. Despite these findings, there are a number of limitations to this review including: the limited number of studies, small effect sizes and methodological shortcomings. This review has considered these shortcomings and has summarised the best available evidence to guide clinical decisions and plan future research on Iliotibial band syndrome aetiology and risk. PMID- 26573860 TI - Prediction of complications in a high-risk cohort of patients undergoing corrective arthrodesis of late stage Charcot deformity based on the PEDIS score. AB - BACKGROUND: All diabetic neuroosteoarthropathy (Charcot arthropathy) treatment concepts are focused on a long-term infection-free, ulcer-free, and plantigrade sufficiently stable foot in order to avoid amputation. Reconstructive arthrodesis techniques for severe deformities are associated with high postoperative complication rates. This study reports a detailed complication analysis and provides a strategy that may help detect patients at risk for a complicated postoperative course. METHODS: The study comprised 43 feet in 37 patients with severe non-plantigrade or unstable Charcot deformity, Eichenholtz stages II/III (Sanders and Frykberg types II-V), who underwent reconstructive arthrodesis of the mid- and/or hindfoot. Patients were retrospectively enrolled 4.5 years postoperatively (range 1.8-11.2 years). All patients showed at least two out of five positive Pinzur high-risk criteria (immuno-compromising illnesses, large bone deformity, longstanding ulcer overlying infected bone, regional osteopenia, obesity). Follow-up included a detailed clinical analysis and radiologic assessment with emphasis on complication analysis and evaluation in accordance to the PEDIS classification system. RESULTS: Significantly lower overall complication rates, as well as re-operation, reulceration and amputation counts were found for patients with a cumulative PEDIS count below 7. For PEDIS single criteria, significantly lower overall complication rates were found for patients without signs of occlusive peripheral artery disease, an ulcer extent <0.9 cm(2), ulcer depth including erosion and inflammation of the skin and subcutaneous tissues only. Soft-tissue complications affected 49 % of patients, hardware breakage 33 %, hardware loosening 19 %, non-union 18 % and amputation 21 %. Radiographs revealed a correct reconstruction and restoration of all foot axes postoperatively with partial recollapse at the lateral foot column; however, fixation strength for the medial column was maintained. CONCLUSIONS: Internal corrective arthrodesis for patients within the deformed stages of Charcot deformity can provide adequate reconstruction, as assessed by intraoperative radiographic measures, that exhibit superior long-term stability for the medial column. Despite a high risk patient population, a favourable outcome in terms of overall complication, re-ulceration, and amputation rates for patients/feet with a cumulative PEDIS count below 7 was found. The cut-off value of 7 may aid clinical decision-making during preoperative planning for Charcot deformity. PMID- 26573861 TI - Understanding the Microstructure and Macrostructure of Passages Among Chinese Elementary School Children. AB - Understanding the microstructure and macrostructure of passages is important for reading comprehension. What cognitive-linguistic skills may contribute to understanding these two levels of structures has rarely been investigated. The present study examined whether some word-level and text-level cognitive linguistic skills may contribute differently to the understanding of microstructure and macrostructure respectively. Seventy-nine Chinese elementary school children were tested on some cognitive-linguistic skills and literacy skills. It was found that word reading fluency and syntactic skills predicted significantly the understanding of microstructure of passages after controlling for age and IQ; while morphological awareness, syntactic skills, and discourse skills contributed significantly to understanding of macrostructure. These findings suggest that syntactic skills facilitate children's access of meaning from grammatical structures, which is a fundamental process in gaining text meaning at any level of reading comprehension. Discourse skills also allow readers to understand the cohesive interlinks within and between sentences and is important for a macro level of passage understanding. PMID- 26573862 TI - The Sociocultural Context of Mexican-Origin Pregnant Adolescents' Attitudes Toward Teen Pregnancy and Links to Future Outcomes. AB - Given the negative developmental risks associated with adolescent motherhood, it is important to examine the sociocultural context of adolescent mothers' lives to identify those most at risk for poor outcomes. Our goals were to identify profiles of Mexican-origin pregnant adolescents' cultural orientations and their attitudes toward teen pregnancy, and to investigate how these profiles were linked to adolescents' pregnancy intentions, family resources, and short-term family, educational, and parenting outcomes. With a sample of 205 Mexican-origin adolescent mothers, we identified three profiles based on cultural orientations and attitudes toward teen pregnancy: Bicultural-Moderate Attitudes, Acculturated Moderate Attitudes, and Enculturated-Low Attitudes. The results indicated that enculturated pregnant adolescents had the least favorable attitudes toward teen pregnancy, and the lowest levels of family income, pregnancy intentions, pregnancy support, and educational expectations compared to acculturated and bicultural pregnant adolescents; acculturated adolescents (with the highest family income and high levels of pregnancy support) had the highest levels of parenting efficacy 10 months postpartum. Our findings suggest that enculturated adolescent mothers (with less positive attitudes toward teen pregnancy) may benefit from educational support programs and enculturated and bicultural adolescent mothers (with moderately positive attitudes toward teen pregnancy) may benefit from programs to increase parenting efficacy. Such targeted interventions may, in turn, reduce the likelihood of adolescent mothers experiencing negative educational and parenting outcomes. PMID- 26573863 TI - Does Living Closer to a University Increase Educational Attainment? A Longitudinal Study of Aspirations, University Entry, and Elite University Enrolment of Australian Youth. AB - Geography remains a critical factor that shapes the development of aspirations, attainment, and choice in young people. We focus on the role of geography on university entry and aspirations due to the increasing requirement in society for a higher education qualification for access to prestigious positions in society. Using a large representative longitudinal database (N = 11,999; 50 % male; 27 % provincial or rural; 2 % Indigenous) of Australia youth we explore the association between distance to a university campus and the critical attainment outcomes of university entry and enrolment in an elite university as well as critical predictors of these outcomes in access to information resources (i.e., university outreach programs) and university aspirations. In doing so, we provide new insight into distance effects, and the extent that these are due to selection, cost, and community influence. Our findings suggest that distance is significantly associated with both university expectations and entrance, with an especially large impact upon young people from low socioeconomic backgrounds. However, we also find little evidence that distance is related to attending a university led information session. Our conclusion is that distance effects cannot be fully explained by selection in terms of academic achievement and socioeconomic status, and that anticipatory decisions and costs are the most likely drivers of the distance effect. PMID- 26573864 TI - Automated protein motif generation in the structure-based protein function prediction tool ProMOL. AB - ProMOL, a plugin for the PyMOL molecular graphics system, is a structure-based protein function prediction tool. ProMOL includes a set of routines for building motif templates that are used for screening query structures for enzyme active sites. Previously, each motif template was generated manually and required supervision in the optimization of parameters for sensitivity and selectivity. We developed an algorithm and workflow for the automation of motif building and testing routines in ProMOL. The algorithm uses a set of empirically derived parameters for optimization and requires little user intervention. The automated motif generation algorithm was first tested in a performance comparison with a set of manually generated motifs based on identical active sites from the same 112 PDB entries. The two sets of motifs were equally effective in identifying alignments with homologs and in rejecting alignments with unrelated structures. A second set of 296 active site motifs were generated automatically, based on Catalytic Site Atlas entries with literature citations, as an expansion of the library of existing manually generated motif templates. The new motif templates exhibited comparable performance to the existing ones in terms of hit rates against native structures, homologs with the same EC and Pfam designations, and randomly selected unrelated structures with a different EC designation at the first EC digit, as well as in terms of RMSD values obtained from local structural alignments of motifs and query structures. This research is supported by NIH grant GM078077. PMID- 26573866 TI - Management of opioid-induced constipation in pregnancy: a concise review with emphasis on the PAMORAs. AB - WHAT IS KNOWN AND OBJECTIVE: Opioid-induced constipation (OIC) is one of the most common opioid-induced adverse effects. Pregnancy also predisposes to bowel dysfunctions due to the associated endocrine changes. Pregnant women are thus at greater risk of OIC. We review the non-pharmacologic and pharmacologic treatment options as a guide for achieving a clinically optimal strategy for the management of OIC during pregnancy. METHODS: The published literature was searched for current therapeutic options, including non-pharmacologic dietary modifications, laxatives, and the peripherally acting mu-opioid receptor antagonists (PAMORAs). Each was assessed for efficacy and safety, particularly as they relate to pregnancy. RESULTS AND DISCUSSION: Non-pharmacologic approaches such as dietary change are generally safe, but generally insufficient when used alone to control OIC in pregnancy. Laxatives (bulking, osmotic, stimulant) can be effective, but have potential adverse effects that might be particularly troublesome during pregnancy (e.g. electrolyte disturbances, dehydration, abdominal pain, and pulmonary oedema or hypermagnesaemia in the extreme). PAMORAs, which attenuate OIC without affecting opioid-induced analgesia, have been associated with only minimal side effects during the clinical studies to date. WHAT IS NEW AND CONCLUSIONS: Conventional non-pharmacologic and pharmacologic options for the management of OIC in pregnancy are often suboptimal due to insufficient efficacy or adverse effects particularly troublesome during pregnancy. The PAMORA strategy appears to provide a safe and effective new option superior to conventional therapies for the management of OIC during pregnancy. PMID- 26573867 TI - Effect of smoking status on progression-free and overall survival in non-small cell lung cancer patients receiving erlotinib or gefitinib: a meta-analysis. AB - WHAT IS KNOWN AND OBJECTIVE: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) such as erlotinib or gefitinib are indicated for the treatment of non-small cell lung cancer (NSCLC). EGFR tyrosine kinase domain mutations have been reported to be associated with EGFR-TKI response in patients with NSCLC. Certain patient subgroups in which EGFR somatic mutations are more frequently observed are thought to derive more clinical benefit from EGFR-TKI therapy. We performed a systematic review and meta-analysis to summarize the evidence regarding the association of smoking status with overall survival (OS) and progression-free survival (PFS) in patients with NSCLC receiving EGFR-TKI therapy with erlotinib or gefitinib. METHODS: Eligible studies were selected by two independent reviewers using the inclusion and exclusion criteria predefined in the protocol. Eligible studies included those evaluating the association of smoking status with OS and PFS in patients with NSCLC receiving erlotinib or gefitinib. Non-clinical studies, case reports, non-peer-reviewed abstracts and non-relevant studies were excluded. RESULTS AND DISCUSSION: Data on OS and PFS in patients with NSCLC treated with EGFR-TKIs were available in nine and ten trials, respectively. The OS and PFS from both the treatment and control groups were not significantly different between never smokers and former or current smokers (OS: odds ratio [OR], 0.80; 95% confidence interval [CI], 0.63-1.09; PFS: OR, 0.75; 95% CI, 0.49-1.14), respectively. However, in comparison within each smoking group, EGFR-TKI treatment led to more favourable OS and PFS in never smokers (OS: OR, 0.55; 95% CI, 0.42-0.73; PFS: OR, 0.43; 95% CI, 0.33-0.54), compared with former or current smokers (OS: OR, 0.89; 95% CI, 0.80-0.97; PFS: OR, 0.73; 95% CI, 0.62-0.85). WHAT IS NEW AND CONCLUSION: Among patients with NSCLC receiving EGFR-TKI therapy with erlotinib or gefitinib, never smokers appear to show longer OS and PFS as compared to former or current smokers. However, this is based on indirect comparisons and more robust larger head-to-head trials are required for more robust inferences. PMID- 26573865 TI - Phenylalanine induces oxidative stress and decreases the viability of rat astrocytes: possible relevance for the pathophysiology of neurodegeneration in phenylketonuria. AB - The aim of this study was to investigate the effects of phenylalanine on oxidative stress and some metabolic parameters in astrocyte cultures from newborn Wistar rats. Astrocytes were cultured under four conditions: control (0.4 mM phenylalanine concentration in the Dulbecco's Modified Eagle Medium (DMEM) solution), Phe addition to achieve 0.5, 1.0 or 1.5 mM final phenylalanine concentrations. After 72 h the astrocytes were separated for the biochemical measurements. Overall measure of mitochondrial function by 3-(4,5-dimethylthiazol 2-yl)-2,5-diphenyltetrazolium bromide (MTT) and cell viability measured by lactate dehydrogenase (LDH) assays indicated that phenylalanine induced cell damage at the three concentrations tested. The alteration on the various parameters of oxidative stress indicated that phenylalanine was able to induce free radicals production. Therefore, our results strongly suggest that Phe at concentrations usually found in PKU induces oxidative stress and consequently cell death in astrocytes cultures. Considering the importance of the astrocytes for brain function, it is possible that these astrocytes alterations may contribute to the brain damage found in PKU patients. PMID- 26573868 TI - Prolonged use of fondaparinux for perioperative bridging: a case report of a patient with mechanical heart valve and heparin-induced thrombocytopenia. AB - WHAT IS KNOWN AND OBJECTIVES: Current guidelines provide no recommendations on perioperative bridging for patients after mechanical heart valve replacement (MHVR) who also have a history of heparin-induced thrombocytopenia (HIT). We present a successful case of prolonged bridging with fondaparinux in a 69-year old Chinese woman. CASE SUMMARY: The patient presented to our department with the aim for radical resection of oesophageal cancer. Fondaparinux has been administered alone at 2.5 mg subcutaneously once daily for 24 days during the interruption of warfarin perioperatively. There were no signs or symptoms of thromboembolic or bleeding throughout and after her hospitalization. WHAT IS NEW AND CONCLUSION: Fondaparinux may offer an option for management of the patients with MHVR who cannot use heparin products, but further clinical investigations are warranted. PMID- 26573869 TI - Glucose starvation induces mutation and lineage-dependent adaptive responses in a large collection of cancer cell lines. AB - Tolerance of glucose deprivation is an important factor for cancer proliferation, survival, migration and progression. To systematically understand adaptive responses under glucose starvation in cancers, we analyzed reverse phase protein array (RPPA) data of 115 protein antibodies across a panel of approximately 170 heterogeneous cancer cell lines, cultured under normal and low glucose conditions. In general, glucose starvation broadly altered levels of many of the proteins and phosphoproteins assessed across the cell lines. Many mTOR pathway components were selectively sensitive to glucose stress, although the change in their levels still varied greatly across the cell line set. Furthermore, lineage- and genotype-based classification of cancer cell lines revealed mutation-specific variation of protein expression and phosphorylation in response to glucose starvation. Decreased AKT phosphorylation (S473) was significantly associated with PTEN mutation under glucose starvation conditions in lung cancer cell lines. The present study (see TCPAportal.org for data resource) provides insight into adaptive responses to glucose deprivation under diverse cellular contexts. PMID- 26573870 TI - Hyponatraemia induced by terlipressin: a case report and literature review. AB - WHAT IS KNOWN AND OBJECTIVE: Terlipressin is widely used to treat variceal bleeding and hepatorenal syndrome. We report one case of stubborn hyponatraemia induced by long-term (up to 21 days) therapy with terlipressin and review the side effects of this agent. CASE SUMMARY: A 41-year-old man with variceal rebleeding experienced a course of stubborn hyponatraemia during a long-term (up to 21 days) therapy with terlipressin. The hyponatraemia could not be corrected until withdrawal of terlipressin. The adverse event is likely due to the stimulation of V1 receptors in the splanchnic area and V2 receptors in the collecting duct. WHAT IS NEW AND CONCLUSION: Given that this reaction has rarely been reported, we discuss the present case with a review of other similar cases. Serum sodium should be monitored intensively to avoid misdiagnosis whenever terlipressin treatment is employed for either gastrointestinal haemorrhage or hepatorenal syndrome. PMID- 26573871 TI - Inhibition of glutamine utilization sensitizes lung cancer cells to apigenin induced apoptosis resulting from metabolic and oxidative stress. AB - Recent studies have shown anticancer activity of apigenin by suppressing glucose transporter 1 (GLUT1) expression in cultured cancer cells; however, it is not clear whether apigenin can suppress glucose metabolism in lung cancer cells or sensitize them to inhibition of glutamine utilization-mediated apoptosis through metabolic and oxidative stress. We show that apigenin significantly decreases GLUT1 expression in mice. Furthermore, we demonstrate that apigenin induces growth retardation and apoptosis through metabolic and oxidative stress caused by suppression of glucose utilization in lung cancer cells. The underlying mechanisms were defined that the anticancer effects of apigenin were reversed by ectopic GLUT1 overexpression and galactose supplementation, through activation of pentose phosphate pathway-mediated NADPH generation. Importantly, we showed that severe metabolic stress using a glutaminase inhibitor, compound 968, was involved in the mechanism of sensitization by apigenin. Taken together, the combination of apigenin with inhibitors of glutamine metabolism may provide a promising therapeutic strategy for cancer treatment. PMID- 26573872 TI - Overexpression of Tyro3 and its implications on hepatocellular carcinoma progression. AB - While various tyrosine kinases have been associated with the pathogenesis of hepatocellular carcinoma (HCC), the identification of a dominant therapeutic target among them remains a challenge. Here, we investigated the role of Tyro3, a relatively uncharacterized member of the TAM (Tyro3, Axl and Mer) receptor family. The present study aimed to profile and identify potential association between Tyro3 expression in HCC and cancer phenotypes. RNAs obtained from 55 HCC patients were quantified for Tyro3 expression in both cancerous tissue and the adjacent normal tissue. Expression profile was correlated with clinical data. These observations were further substantiated with in vitro HCC cell culture investigations.Tyro3 was strongly upregulated (>2-fold elevation) in the tumor tissue of ~42% of the patients. It was shown that higher expression level of Tyro3 was associated with the key tumor marker AFP, and the tumor diameter and liver injury marker ALT. Subsequent cell culture models indicated high expression in various HCC cell lines, in particular Hep3B. Gene silencing of Tyro3 in Hep3B effectively reduced cell proliferation, ERK phosphorylation and cyclin D1 expression, indicating a key in maintaining the proliferative state of these cells. Notably, silencing also suppressed the transcriptional and translational expression of HCC tumor marker AFP. Overall, these data suggest that Tyro3 contributes significantly to tumor growth, aggressiveness and liver dysfunction. Inhibition of Tyro3 and its aberrant signaling in tumors with high expression could present new opportunities for HCC treatment. PMID- 26573873 TI - The neuroimmune guidance cue netrin-1 controls resolution programs and promotes liver regeneration. AB - Hepatic ischemia/reperfusion (I/R) is a major adverse reaction to liver transplantation, hemorrhagic shock, or resection. Recently, the anti-inflammatory properties of the axonal guidance cue netrin-1 were reported. Here, we demonstrate that netrin-1 also impacts the resolution of inflammation and promotes hepatic repair and regeneration during liver I/R injury. In initial studies, we investigated the induction of netrin-1 and its receptors in murine liver tissues after I/R injury. Hepatic I/R injury was performed in mice with a partial genetic netrin-1 deficiency (Ntn1(+/-) ) or wild-type C57BL/6 treated with exogenous netrin-1 to examine the endogenous and therapeutically administered impact of netrin-1. These investigations were corroborated by studies determining the characteristics of intravascular leukocyte flow, clearance of apoptotic neutrophils (polymorphonuclear cells [PMNs]), production of specialized proresolving lipid mediators (SPMs), generation of specific growth factors contributing to the resolution of inflammation, and liver repair. Hepatic I/R was associated with a significant reduction of netrin-1 transcript and protein in murine liver tissue. Subsequent studies in netrin-1-deficient mice revealed lower efficacies in reducing PMN infiltration, proinflammatory cytokine levels, and hepatic-specific injury enzymes. Conversely, mice treated with exogenous netrin-1 exhibited increased liver protection and repair, reducing neutrophil influx into the injury site, decreasing proinflammatory mediators, increasing efferocytosis of apoptotic PMNs, and stimulating local endogenous biosynthesis of SPMs and the generation of specific growth factors. Finally, genetic studies implicated the A2B adenosine receptor in netrin-1-mediated protection during hepatic I/R injury. CONCLUSION: The present study indicates a previously unrecognized role for netrin-1 in liver protection and its contribution to tissue homeostasis and regeneration. PMID- 26573875 TI - The impact of CDK9 on radiosensitivity, DNA damage repair and cell cycling of HNSCC cancer cells. AB - Cyclin-dependent kinase 9 (CDK9), mainly involved in regulation of transcription, has recently been shown to impact on cell cycling and DNA repair. Despite the fact that CDK9 has been proposed as potential cancer target, it remains largely elusive whether CDK9 targeting alters tumor cell radiosensitivity. Five human head and neck squamous cell carcinoma (HNSCC) cell lines (SAS, FaDu, HSC4, Cal33, UTSCC5) as well as SAS cells stably transfected with CDK9-EGFP-N1 plasmid or empty vector controls were used. Upon either CDK9 small interfering RNA knockdown or treatment with a pan-CDK inhibitor (ZK304709), colony formation, DNA double strand breaks (DSBs), apoptosis, cell cycling, and expression and phosphorylation of major cell cycle and DNA damage repair proteins were examined. While CDK9 overexpression mediated radioprotection, CDK9 depletion clearly enhanced the radiosensitivity of HNSCC cells without an induction of apoptosis. While the cell cycle and cell cycle proteins were significantly modulated by CDK9 depletion, no further alterations in these parameters were observed after combined CDK9 knockdown with irradiation. ZK304709 showed concentration-dependent cytotoxicity but failed to radiosensitize HNSCC cells. Our findings suggest a potential role of CDK9 in the radiation response of HNSCC cells. Additional studies are warranted to clarify the usefulness to target CDK9 in the clinic. PMID- 26573874 TI - Epigenetic induction of epithelial to mesenchymal transition by LCN2 mediates metastasis and tumorigenesis, which is abrogated by NF-kappaB inhibitor BRM270 in a xenograft model of lung adenocarcinoma. AB - Tumor initiating cancer stem-like cells (TICSCs) have recently become the object of intensive study. Human-Lipocalin-2 (hLCN2) acts as a biomarker for cancers. The aim of the present study was to explore new insights regarding the potential role of LCN2 in inducing epithelial to mesenchymal transition (EMT) by transfecting LCN2 into CD133+-A549-TICSCs and its cross-talk with the NF-kappaB signaling pathway in adenocarcinoma of the lung. Furthermore, EMT was confirmed by transcriptomic analysis, immunoblotting and immunocyto/histochemical analyses. Tumorigenesis and metastasis were confirmed by molecular therapeutics tracer 2DG infrared optical probe in BALB/cSIc-nude mice. It was observed that the CD133+ expressing-LCN2-A549 TICSCs population increased in adenocarcinoma of the lung compared to the normal lung tissue. The expressions of genes involved in stemness, adhesion, motility and drug efflux was higher in these cells than in their non-LCN2 expressing counterparts. The present study revealed that elevated expression of LCN2 significantly induced metastasis via EMT. Overexpression of LCN2 significantly increased stemness and tumor metastasis by modulating NF kappaB cellular signaling. BRM270, a novel inhibitor of NF-kappaB plays a significant role in the EMT reversal. BRM270, a naturaceutical induces cell shrinkage, karyorrhexis and programmed cell death (PCD) which were observed by Hoechst 33342 staining while flow cytometry analysis showed significant (P<0.05) decrease in cell population from G0-G1 phases. Also, 2DG guided in vivo model revealed that BRRM270 significantly (P<0.0003) reduced tumor metastasis and increased percent survival in real-time with complete resection. An elaborate study on the novel concept with respect to linking of naturaceutics as selective and potential anticancer agent that eliminates the elevated LCN2 induced EMT and tumor dissemination through cooperation with the NF-kappaB signaling as the baseline data for the planning of new therapeutic strategies was conducted for the first time. Our results also illustrate a molecular mechanistic approach for 2DG-guided molecular imaging-based cancer therapy using BRM270 as a novel cancer therapeutic drug to enhance the effect of doxorubicin (Dox)-resistant LCN2 induced metastasis of solid tumors in nude mice. PMID- 26573876 TI - Analysis of genetic variability in endemic medicinal plants of genus Chlorophytum from the Indian subcontinent using amplified fragment length polymorphism marker. AB - The genus Chlorophytum consists of medicinally important species like Chlorophytum borivilianum, C. tuberosum and C. attenuatum. Uncontrolled harvest of this plant from wild habitat due to its high commercial value made the species of this genus be listed in the Red Data Book of Indian plants as an endangered species. In India, approximately nineteen species of Chlorophytum are found; out of these, only C. borivilianum is cultivated commercially. The objective of this study was to measure genetic diversity, population structure and phylogenetic relationship among the species using Amplified Fragment Length Polymorphisms (AFLP). Fifteen pairs of primer (out of 64 primer pairs screened) were used to analyse the genetic diversity in eighteen species of genus Chlorophytum. Cluster analysis, estimation of the gene flow among the species and of the phylogeographic distribution of this genus were carried out using an AFLP data matrix. A high level of genetic diversity was observed on the basis of the percentage of polymorphic bands (99.91%), Shannon's information index (0.3592) and Nei's gene diversity (0.2085) at species level. Cluster analysis of UPGMA dendrogram, principal component analysis and Bayesian method analysis resolved these species in three different clusters, which was supported by morphological information. The Mantel test (r=0.4432) revealed a significant positive correlation between genetic and geographic distances. The collected data have an important implication in the identification, authentication, and conservation of the species of the genus Chlorophytum. PMID- 26573877 TI - Dose-dependent effects of isoflavone exposure during early lifetime on development and androgen sensitivity in male Wistar rats. AB - SCOPE: The aim of our study was to investigate dose-dependent effects of isoflavone (ISO) exposure during adolescence on the androgen sensitivity of various physiological end points in male Wistar rats. METHODS AND RESULTS: During embryogenesis and adolescence, rats were exposed to an ISO-depleted diet (IDD) or one of two diets enriched with different concentrations of a soy-based ISO extract causing plasma concentrations observed averagely (ISO-rich diet [IRD]low) and maximally (IRDhigh) in Asian men. Most of the rats were orchiectomized at postnatal day (PND) 81 and were treated with testosterone propionate (TP) or vehicle from PND 89 to 99. In intact rats (PND 99) body weight, food intake, and fat mass were not influenced by ISO, but serum triglycerides and hepatic fatty acid synthase expression were decreased. Trabecular bone mineral density (BMD) was reduced in IRDlow, but not in IRDhigh rats. Orchiectomy (ORX) induced loss of BMD, which was antagonized by IRDhigh. ISO increased androgen sensitivity of seminal vesicle and levator ani. Besides, ISO plasma levels were reduced by ORX compared to intact and TP-treated rats. CONCLUSION: In summary, the results of this study indicate that exposure to ISO during adolescence affects bone homeostasis, lipid metabolism, and modulates androgen sensitivity in young adult male rats. PMID- 26573878 TI - TSLP production by dendritic cells is modulated by IL-1beta and components of the endoplasmic reticulum stress response. AB - Thymic stromal lymphopoietin (TSLP) produced by epithelial cells acts on dendritic cells (DCs) to drive differentiation of TH 2-cells, and is therefore important in allergic disease pathogenesis. However, DCs themselves make significant amounts of TSLP in response to microbial products, but little is known about the key downstream signals that induce and modulate this TSLP secretion from human DCs. We show that human monocyte derived DC (mDC) secretion of TSLP in response to Candida albicans and beta-glucans requires dectin-1, Syk, NF-kappaB, and p38 MAPK signaling. In addition, TSLP production by mDCs is greatly enhanced by IL-1beta, but not TNF-alpha, in contrast to epithelial cells. Furthermore, TSLP secretion is significantly increased by signals emanating from the endoplasmic reticulum (ER) stress response, specifically the unfolded protein response sensors, inositol-requiring transmembrane kinase/endonuclease 1 and protein kinase R-like ER kinase, which are activated by dectin-1 stimulation. Thus, TSLP production by mDCs requires the integration of signals from dectin-1, the IL-1 receptor, and ER stress signaling pathways. Autocrine TSLP production is likely to play a role in mDC-controlled immune responses at sites removed from epithelial cell production of the cytokine, such as lymphoid tissue. PMID- 26573880 TI - The fitness consequences of honesty: Under-signalers have a survival advantage in song sparrows. AB - How honest or reliable signaling can evolve and be maintained has been a major question in evolutionary biology. The question is especially puzzling for a particular class of signals used in aggressive interactions: threat signals. Here, we report a study on song sparrows (Melospiza melodia) in which we assayed males with playbacks on their territories to quantify their aggressiveness (flights and close proximity) and aggressive signaling levels (rates of soft song, a close-range signal reliably predicting attack) and asked whether these traits affect individuals' survival on territory. We found that the effect of aggressive signaling via soft song interacted with aggressive behaviors such that there was a negative correlational selection: among males with low aggression, those males that signaled at higher levels (over-signalers) had higher survival whereas among males with high aggression those that signaled at low levels (under signalers) survived longer. In other words, males that deviate from reliable signaling have a survival advantage. These results, along with previous research that suggested most of the deviation from reliable signaling in this system is in the form of under-signaling (high-aggression males signaling at low levels) pose a puzzle for future research on how this reliable signaling system is maintained. PMID- 26573879 TI - Citrus flavonoid, naringenin, increases locomotor activity and reduces diacylglycerol accumulation in skeletal muscle of obese ovariectomized mice. AB - SCOPE: Estrogen deficiency has been associated with central obesity, muscle loss and metabolic syndrome in postmenopausal women. This study assessed naringenin accumulation in tissues and investigated the hypothesis that naringenin reverses diet-induced metabolic disturbances in obese ovariectomized mice. METHODS AND RESULTS: In study 1, we measured naringenin concentrations in plasma, liver, perigonadal and subcutaneous adipose tissues, and muscle of ovariectomized C57BL/6J female mice after 11 weeks of naringenin supplementation. Naringenin accumulated 5-12 times more in mice fed a 3% naringenin diet than in mice fed a 1% naringenin diet. In study 2, ovariectomized mice were fed a high-fat diet (60 kcal% fat) for 11 weeks and half of the mice were then supplemented with 3% naringenin for another 11 weeks. Dietary naringenin suppressed weight gain, lowered hyperglycemia and decreased intra-abdominal adiposity evaluated by magnetic resonance imaging. Naringenin-fed mice exhibited elevated locomotor activity monitored by infrared beam breaks, maintained muscle mass and reduced muscle diacylglycerol content. Real-time PCR analysis in muscle revealed decreased mRNA level for genes involved in de novo lipogenesis, lipolysis and triglyceride synthesis/storage. CONCLUSION: Long-term 3% naringenin supplementation resulted in significant naringenin accumulation in plasma and tissues, associated with attenuated metabolic dysregulation and muscle loss in obese ovariectomized mice. PMID- 26573881 TI - Suspending DNA Origami Between Four Gold Nanodots. AB - Rectangular DNA origami functionalized with thiols in each of the four corners immobilizes by self-assembly between lithographically patterned gold nanodots on a silicon oxide surface. PMID- 26573882 TI - Sjogren's syndrome-associated interstitial lung disease: A multicenter study. AB - Primary Sjogren syndrome (PSS) is a chronic inflammatory autoimmune disease. Interstitial lung disease (ILD) can be an extraglandular complication. OBJECTIVE: To evaluate the clinical characteristics of patients diagnosed with PSS with ILD. METHODS: Multicentre cohort study with 25 patients diagnosed with PSS and ILD. Data of PSS, prognostic factors, pulmonary involvement variables, complementary tests that suggest a worse diagnosis and treatment given were collected. EULAR index was measured for Sjogren's syndrome. RESULTS: We identified 25 patients. In 15/25 the diagnosis of ILD was done before the diagnosis of PSS. The histopathological patterns found were: 12 NSIP, 5 UIP, 4 OP, 2 LIP. PFRs showed restrictive pattern. The majority of the patients received glucocorticoid therapy, antimalarial or immunosuppressive treatment. CONCLUSIONS: Patients affected with PSS must be screened to catch a precocious diagnosis of ILD. The majority of the patients were diagnosed of ILD before being diagnosed of PSS. Multicenter cohorts are increasingly demanded and a multidisciplinary management is needed. PMID- 26573883 TI - Discriminant validity study of Achilles enthesis ultrasound. AB - OBJECTIVE: We want to know if the ultrasound examination of the Achilles tendon in spondyloarthritis is different compared to other rheumatic diseases. MATERIAL AND METHODS: We studied 97 patients divided into five groups: rheumatoid arthritis, spondyloarthritis, gout, chondrocalcinosis and osteoarthritis, exploring six elementary lesions in 194 Achilles entheses examined. RESULTS: In our study the total index ultrasonographic Achilles is higher in spondyloarthritis with significant differences. The worst elementary spondyloarthritis lesions for discriminations against other pathologies were calcification. CONCLUSIONS: This study aims to demonstrate the discriminant validity of Achilles enthesitis observed by ultrasound in spondyloarthritis compared with other rheumatic diseases that may also have ultrasound abnormalities such enthesis level. PMID- 26573884 TI - Movement Disorders From the Use of Metoclopramide and Other Antiemetics in the Treatment of Migraine. AB - Nausea and vomiting are a frequent accompaniment of migraine and anti-nausea medications are frequently used in its management. The majority of anti-nausea medications that are used in migraine are dopamine receptor blocking agents and therefore have the potential to cause drug-induced movement disorders. This article explores the risk of such drug-induced movement disorders in migraineurs who were treated with these medications. PMID- 26573885 TI - Optical Imaging and Gene Therapy with Neuroblastoma-Targeting Polymeric Nanoparticles for Potential Theranostic Applications. AB - Recently, targeted delivery systems based on functionalized polymeric nanoparticles have attracted a great deal of attention in cancer diagnosis and therapy. Specifically, as neuroblastoma occurs in infancy and childhood, targeted delivery may be critical to reduce the side effects that can occur with conventional approaches, as well as to achieve precise diagnosis and efficient therapy. Thus, biocompatible poly(d,l-lactide-co-glycolide) (PLG) nanoparticles containing an imaging probe and therapeutic gene are prepared, followed by modification with rabies virus glycoprotein (RVG) peptide for neuroblastoma targeting delivery. RVG peptide is a well-known neuronal targeting ligand and is chemically conjugated to PLG nanoparticles without changing their size or shape. RVG-modified nanoparticles are effective in specifically targeting neuroblastoma both in vitro and in vivo. RVG-modified nanoparticles loaded with a fluorescent probe are useful to detect the tumor site in a neuroblastoma-bearing mouse model, and those encapsulating a therapeutic gene cocktail (siMyc, siBcl-2, and siVEGF) significantly suppressed tumor growth in the mouse model. This approach to designing and tailoring of polymeric nanoparticles for targeted delivery may be useful in the development of multimodality systems for theranostic approaches. PMID- 26573886 TI - Bibliometric assessment of the scientific production of literature regarding Mayaro. PMID- 26573887 TI - How Financial and Reputational Incentives Can Be Used to Improve Medical Care. AB - OBJECTIVES: Narrative review of the impact of pay-for-performance (P4P) and public reporting (PR) on health care outcomes, including spillover effects and impact on disparities. PRINCIPAL FINDINGS: The impact of P4P and PR is dependent on the underlying payment system (fee-for-service, salary, capitation) into which these schemes are introduced. Both have the potential to improve care, but they can also have substantial unintended consequences. Evidence from the behavioral economics literature suggests that individual physicians will vary in how they respond to incentives. We also discuss issues to be considered when including patient-reported outcome measures (PROMs) or patient-reported experience measures into P4P and PR schemes. CONCLUSION: We provide guidance to payers and policy makers on the design of P4P and PR programs so as to maximize their benefits and minimize their unintended consequences. These include involving clinicians in the design of the program, taking into account the payment system into which new incentives are introduced, designing the structure of reward programs to maximize the likelihood of intended outcomes and minimize the likelihood of unintended consequences, designing schemes that minimize the risk of increasing disparities, providing stability of incentives over some years, and including outcomes that are relevant to patients' priorities. In addition, because of the limitations of PR and P4P as effective interventions in their own right, it is important that they are combined with other policies and interventions intended to improve quality to maximize their likely impact. PMID- 26573888 TI - Light-Emitting Diodes with Hierarchical and Multifunctional Surface Structures for High Light Extraction and an Antifouling Effect. AB - Bioinspired hierarchical structures on the surface of vertical light-emitting diodes (VLEDs) are demonstrated by combining a self-assembled dip-coating process and nanopatterning transfer method using thermal release tape. This versatile surface structure can efficiently reduce the total internal reflection and add functions, such as superhydrophobicity and high oleophobicity, to achieve an antifouling effect for VLEDs. PMID- 26573889 TI - Disability and quality of life among elderly persons with mental illness. AB - The present study was undertaken to understand the level of disability and quality of life of elderly persons with chronic and persistent mental illnesses and to compare it with those who were elderly but well with no illness. For the purpose 200 elderly persons with mental illness (PMI), attending psychiatric services were included in the study. A comparison group of 103 well elderly persons was drawn from the same study area as control group (CG). They were assessed using WHO-DAS and WHOQOL-BREF. Results revealed that PMI experienced higher disability compared to the CG. Deficits in the domain of moving around, getting along with people, engaging in life activities and participation in society contributed most to the high level of disability in the PMI group. PMI from rural area had higher disability compared to the urban group. As for QOL, elderly PMI had a poor quality of life compared to the CG. Quality of life was found to be negatively associated with level of disability. Higher the level of disability, lower was the quality of life. The authors opine that persons with chronic mental illness continue to experience psychiatric disability in old age and this cannot be attributed to normal aging. Level of disability has a negative impact on their quality of life. PMID- 26573890 TI - Using Patient-Reported Information to Improve Clinical Practice. AB - OBJECTIVE: To assess what is known about the relationship between patient experience measures and incentives designed to improve care, and to identify how public policy and medical practices can promote patient-valued outcomes in health systems with strong financial incentives. DATA SOURCES/STUDY SETTING: Existing literature (gray and peer-reviewed) on measuring patient experience and patient reported outcomes, identified from Medline and Cochrane databases; evaluations of pay-for-performance programs in the United States, Europe, and the Commonwealth countries. STUDY DESIGN/DATA COLLECTION: We analyzed (1) studies of pay-for performance, to identify those including metrics for patient experience, and (2) studies of patient experience and of patient-reported outcomes to identify evidence of influence on clinical practice, whether through public reporting or private reporting to clinicians. PRINCIPAL FINDINGS: First, we identify four forms of "patient-reported information" (PRI), each with distinctive roles shaping clinical practice: (1) patient-reported outcomes measuring self-assessed physical and mental well-being, (2) surveys of patient experience with clinicians and staff, (3) narrative accounts describing encounters with clinicians in patients' own words, and (4) complaints/grievances signaling patients' distress when treatment or outcomes fall short of expectations. Because these forms vary in crucial ways, each must be distinctively measured, deployed, and linked with financial incentives. Second, although the literature linking incentives to patients experience is limited, implementing pay-for-performance systems appears to threaten certain patient-valued aspects of health care. But incentives can be made compatible with the outcomes patients value if: (a) a sufficient portion of incentives is tied to patient-reported outcomes and experiences, (b) incentivized forms of PRI are complemented by other forms of patient feedback, and (c) health care organizations assist clinicians to interpret and respond to PRI. Finally, we identify roles for the public and private sectors in financing PRI and orchestrating an appropriate balance among its four forms. CONCLUSIONS: Unless public policies are attentive to patients' perspectives, stronger financial incentives for clinicians can threaten aspects of care that patients most value. Certain policy parameters are already clear, but additional research is required to clarify how best to collect patient narratives in varied settings, how to report narratives to consumers in conjunction with quantified metrics, and how to promote a "culture of learning" at the practice level that incorporates patient feedback. PMID- 26573891 TI - Liquid chromatography with tandem mass spectrometry quantification of urinary proanthocyanin A2 dimer and its potential use as a biomarker of cranberry intake. AB - The lack of a biomarker for the consumption of cranberries has confounded the interpretation of several studies investigating the effect of cranberry products, especially juices, on health outcomes. The objectives of this pilot study were to develop a liquid chromatography tandem mass spectrometric method for the quantification of the proanthocyanin dimer A-2 in human urine and validate urinary proanthocyanin dimer A-2 as a biomarker of cranberry intake. Five healthy, nonsmoking, premenopausal women (20-30 years of age, body mass index: 18.5-25 kg/m(2) ) were assigned to consume a cranberry beverage containing 140 mg proanthocyanin and 35 kilocalories at 237 mL/day, according to a weekly dosing schedule for 7 weeks. Eleven 24 h and morning spot urine samples each were collected from each subject. A reliable, sensitive method for the detection of proanthocyanin dimer A-2 in urine using liquid chromatography with tandem mass spectrometry was developed with a limit of quantitation of 0.25 ng/mL and a relative standard deviation of 7.26%, precision of 5.7%, and accuracy of 91.7%. While proanthocyanin dimer A-2 was quantifiable in urine, it did not appear to be excreted in a concentration that corresponded to the dosing schedule and intake of cranberry juice. PMID- 26573892 TI - The experiences of orthopaedic and trauma nurses who have cared for adults with a learning disability. AB - BACKGROUND: There is no published empirical research about the experiences of orthopaedic and trauma nurses who have cared for people with a learning disability. However, adults with a learning disability sustain more injuries, falls and accidents than the general population. Because of their increased health needs, there has been a corresponding increase in their numbers attending general/acute hospitals. The 6 Cs is a contemporary framework and has been used to gauge how orthopaedic and trauma nurses rate the Care, Communication, Competence, Commitment, Courage and Compassion for patients with a learning disability in orthopaedic and trauma hospital settings compared to patients without a learning disability. AIM: The aim of the study was to explore the experiences of orthopaedic and trauma nurses who have cared for people with a learning disability. DESIGN: The study is based on a descriptive survey design and used a questionnaire to elicit data from participants. METHODS: A convenience sample of Registered Nurses completed a questionnaire. The study was explained to delegates attending a concurrent session on the topic of acute hospital care for people with a learning disability at a conference and the questionnaire was left on a table for participants to take if they wished. Questionnaires were returned anonymously. FINDINGS: Of the participants who had completed the questionnaire 100% (n = 13) had cared for a patient with a learning disability. Using the 6 Cs as a framework suggested that care, communication and competence of nurses were worse for people with a learning disability than for people without a learning disability. Three main themes emerged regarding areas of good practices: (1) promoting a positive partnership with patients and carers; (2) modifying care and interventions; (3) supporting the healthcare team. CONCLUSION: There was evidence of good practices within orthopaedic and trauma settings such as the active involvement of family or a paid carer who is known to thepatient and the modification of care and interventions along with specialist advice and support from the Acute Liaison Learning Disability Nurse. There were areas of concern such as the lack of use of Hospital Passports and the inconsistent implementation of reasonable and achievable adjustments. It is unknown if the care for patients with a learning disability is adequate. However, the themes that have emerged accord with the key domains in 'A competency framework for orthopaedic and trauma practitioners' (Royal College of Nursing 2012a, 2012b) and therefore could be considered for inclusion in future orthopaedic and trauma competencies to enable sharing of best practices. PMID- 26573893 TI - Plant-wide control design based on steady-state combined indexes. AB - This work proposes an alternative methodology for designing multi-loop control structures based on steady-state indexes and multi-objective combinatorial optimization problems. Indeed, the simultaneous selection of the controlled variables, manipulated variables, input-output pairing, and controller size and interaction degree is performed by using a combined index which relies on the sum of square deviations and the net load evaluation assessments in conjunction. This unified approach minimizes both the dynamic simulation burden and the heuristic knowledge requirements for deciding about the final optimal control structure. Further, this methodology allows incorporating structural modifications of the optimization problem context (degrees of freedom). The case study selected is the well-known Tennessee Eastman process and a set of simulations are given to compare this approach with early works. PMID- 26573894 TI - Policy-Oriented Research on Improved Physician Incentives for Higher Value Health Care. AB - Policy makers (both public and private) are seeking ways to improve the value delivered within our health care system, that is, using fewer resources to provide the same benefit to patients, or using equivalent resources to provide more benefit. One strategy is to alter the predominant fee-for-service (FFS) economic incentives in the current system. To inform such policy changes, this paper identifies areas in which little is known about the effects of specific incentives (FFS, salary, etc.) on the two components of value: resource use and quality. Specific suggestions are offered regarding research that would be informative for policy makers, focusing on fundamental "building block" studies rather than overall evaluations of complex interventions, such as accountable care organizations. This research would better identify critical aspects of the FFS model and salary-based payments that are particularly problematic, as well as situations in which FFS or salary may be less problematic. The research would also explore when alternatives, such as episode-based payment might be feasible, or simply be hypothetical solutions. The availability of electronic health record based data in various delivery systems would allow many of these studies to be accomplished in 3-5 years with budgets manageable by public and private funding sources. PMID- 26573895 TI - Dispersive micro-solid-phase extraction of benzoylurea insecticides in honey samples with a beta-cyclodextrin-modified attapulgite composite as sorbent. AB - A beta-cyclodextrin-modified attapulgite composite was prepared and used as a dispersive micro-solid-phase extraction sorbent for the determination of benzoylurea insecticides in honey samples. Parameters that may influence the extraction efficiency, such as the type and volume of the eluent, the amount of the sorbent, the extraction time and the ionic strength were investigated and optimized using batch and column procedures. Under optimized conditions, good linearity was obtained for all of the tested compounds, with R(2) values of at least 0.9834. The limits of detection were determined in the range of 0.2-1.0 MUg/L. The recoveries of the four benzoylurea insecticides in vitex honey and acacia honey increased from 15.2 to 81.4% and from 14.2 to 82.0%, respectively. Although the beta-cyclodextrin-modified attapulgite composite did not show a brilliant adsorption capacity for the selected benzoylurea insecticides, it exhibited a higher adsorption capacity toward relatively hydrophobic compounds, such as chlorfluazuron and hexaflumuron (recoveries in vitex honey samples ranged from 70.0 to 81.4% with a precision of 1.0-3.7%). It seemed that the logPow of the benzoylurea insecticides is related to their recoveries. The results confirmed the possibility of using cyclodextrin-modified palygorskite in the determination of relatively hydrophobic trace pharmaceutical residues. PMID- 26573896 TI - Expandable proximal femoral nail versus gamma proximal femoral nail for the treatment of AO/OTA 31A1-3 fractures. AB - INTRODUCTION: The gamma-proximal femoral nail (GPFN) and the expandable proximal femoral nail (EPFN) are two commonly used intramedullary devices for the treatment of AO 31A1-3 proximal femur fractures. The aim of this study was to compare outcomes and complication rates in patients treated by both devices. PATIENTS AND METHODS: A total of 299 patients (149 in the GPFN group and 150 in the EPFN group, average age 83.6 years) were treated for AO 31A1-3 proximal femur fractures in our institution between July 2008 and February 2013. Time from presentation to surgery, level of experience of the surgeon, operative time, amount of blood loss and number of blood transfusions were recorded. Postoperative radiological variables, including peg/screw location, tip to apex distance and orthopaedic complications, as, malunion, nonunion, surgical wound infection rates, cutouts, periprosthetic fractures and the incidence of non orthopaedic complications. Functional results were estimated using the modified Harris Hip Score, and quality of life was queried by the SF-36 questionnaire. RESULTS: The GPFN and the EPFN fixation methods were similar in terms of functional outcomes, complication rates and quality of life assessments. More patients (107 vs. 73) from the GPFN group were operated within 48 h from presentation (44.8 h vs. 49.9 h for the EPFN group, p=0.351), and their surgery duration and hospitalisation were significantly longer (18.5 days vs. 26 days, respectively, p<0.001). The GPFN patients were frequently operated by junior surgeons: 90% (135) while 50.6% (76) of the EPFN operations were performed by senior doctors. Other intraoperative measures were similar between groups. Cutout was the most common complication affecting 6.7% of the GPFN group and 3.3% of the EPFN group (p=0.182). CONCLUSIONS: Good clinical outcomes and low complication rates in the GPFN and the EPFN groups indicate essentially equivalent safety and reliability on the part of both devices for the treatment of proximal femoral fractures. PMID- 26573897 TI - Treatment of ruptured Achilles tendon: Operative or non-operative procedure? AB - PURPOSE: The aim of this study was to compare the efficiency of non-operative and surgical procedures in the treatment of ruptured Achilles tendon in athletes (professional and amateur). METHODS: Ninety professional or amateur athletes with rupture of the Achilles tendon were included in the study between 1998 and 2013. The athletes were aged between 25 and 40 years (mean 34.83+/-4.65). A total of 30 athletes underwent an open procedure, 30 were treated with a percutaneous method and 30 were treated non-operatively. All operated patients were tested one year after the surgical procedure. RESULTS: An isokinetic dynamometer was used to compare the open and percutaneous methods. The results for the patients who were treated using the percutaneous method were 15% better than those for the patients who underwent the open procedure; the results for the group treated conservatively were 20% better than those for the group treated percutaneously. DISCUSSION AND CONCLUSION: The percutaneous method was easier technically than the open method. Time spent in hospital was 14.5 times shorter with the percutaneous procedure compared with the open procedure (percutaneous procedure: range 0.5-2 days, mean 0.79+/-0.36; open procedure: range 10-24 days, mean 11.46+/-2.70; p<0.00). Return to sport activities was twice as fast with the percutaneous procedure compared with the open procedure. There were no postoperative infections or reruptured Achilles tendon in the group treated with the percutaneous procedure. One patient in the group treated with the open procedure had postoperative infection (4.2%). In the non-surgical (conservatively treated) group, there were three reruptures of the Achilles tendon within one year, and one patient developed adhesions that resulted in loss of function and had to undergo an operation. The percutaneous method is the best method of surgical treatment for Achilles tendon rupture. PMID- 26573898 TI - Chronic unreduced shoulder dislocations: Experience in a developing country trauma centre. AB - Chronic shoulder dislocations are extremely rare. The goal of this retrospective study was to describe the epidemiology of chronic shoulder dislocation in our environment and to evaluate the outcome of treatment. Bio-demographic data and injury details were retrieved from case files. Definitive method of reduction and stabilisation and duration of follow-up care were also noted. Nine cases of subcoracoid anterior chronic shoulder dislocation were seen during the 6-year period of the study. Seven (78%) of these patients were male and two (22%) were female. The mean age was 42 (+/-17.5) years. The common mechanisms of injury were road traffic crash in four patients (44%), domestic falls in four patients (44%) and dislocation while getting out of bed in one patient (12%). None of the patients had neurovascular deficit at presentation. Five patients were managed operatively and four were managed non-operatively. Mean follow-up was 8 months (range 6-12 months). Clinical evaluation by Rowe shoulder score revealed that operated cases had significantly higher mean rank scores than non-operated cases using the Mann-Whitney U test. Two operated cases were graded fair and three poor. All cases managed non-operatively had poor outcome grades. Meticulous attempt at soft tissue repair and early supervised physiotherapy can contribute to a favourable outcome. PMID- 26573899 TI - Failure to rescue in trauma: Coming to terms with the second term. AB - INTRODUCTION: The failure to rescue (FTR) rate is the probability of death after a major complication and was defined in elective surgical cohorts. In elective surgery, the precedence rate (proportion of deaths preceded by major complications) approaches 100%, but recent studies in trauma report rates of only 20-25%. We hypothesised that use of high quality data would result precedence rates in higher than those derived from national datasets, and we further sought to characterise the nature of those deaths not preceded by major complications. METHODS: Prospectively collected data from 2006 to 2010 from a single level I trauma centre were used. Patients age >16 years with AIS >=2 who survived beyond the trauma bay were included. Complications, mortality, FTR, and precedence rates were calculated. Chart abstraction was performed for registry deaths without recorded complications to verify the absence of complications and determine the cause of death, after which outcomes were re-calculated. RESULTS: A total of 8004 patients were included (median age 41 (IQR 25-75), 71% male, 82% blunt, median ISS 10 (IQR 5-18)). Using registry data the precedence rate was 55%, with 132/293 (45%) deaths occurring without antecedent major complications. On chart abstraction, 11/132 (8%) patients recorded in the registry as having no complication prior to death were found to have major complications. Complication and FTR rates after chart abstraction were statistically significantly different than those derived from registry data alone (complications 16.5% vs. 16.3, FTR 12.3 vs.13, p=0.001), but this difference was unlikely to be clinically meaningful. Patients dying without complications predominantly (87%) had neurologic causes of demise. CONCLUSIONS: Use of data with near-complete ascertainment of complications results in precedence rates much higher than those from national datasets. Patients dying without precedent complications at our centre largely succumbed to progression of neurologic injury. Attempts to use FTR to compare quality between centres should be limited to high quality data. LEVEL OF EVIDENCE: Level III. RETROSPECTIVE COHORT STUDY: Outcomes. PMID- 26573900 TI - Patient comfort: A continuum starting from prehospital setting throughout the hospital admission. PMID- 26573901 TI - Mechanotransduction in primary human osteoarthritic chondrocytes is mediated by metabolism of energy, lipids, and amino acids. AB - Chondrocytes are the sole cell type found in articular cartilage and are repeatedly subjected to mechanical loading in vivo. We hypothesized that physiological dynamic compression results in changes in energy metabolism to produce proteins for maintenance of the pericellular and extracellular matrices. The objective of this study was to develop an in-depth understanding for the short term (<30min) chondrocyte response to sub-injurious, physiological compression by analyzing metabolomic profiles for human chondrocytes harvested from femoral heads of osteoarthritic donors. Cell-seeded agarose constructs were randomly assigned to experimental groups, and dynamic compression was applied for 0, 15, or 30min. Following dynamic compression, metabolites were extracted and detected by HPLC-MS. Untargeted analyzes examined changes in global metabolomics profiles and targeted analysis examined the expression of specific metabolites related to central energy metabolism. We identified hundreds of metabolites that were regulated by applied compression, and we report the detection of 16 molecules not found in existing metabolite databases. We observed patient specific mechanotransduction with aging dependence. Targeted studies found a transient increase in the ratio of NADP+ to NADPH and an initial decrease in the ratio of GDP to GTP, suggesting a flux of energy into the TCA cycle. By characterizing metabolomics profiles of primary chondrocytes in response to applied dynamic compression, this study provides insight into how OA chondrocytes respond to mechanical load. These results are consistent with increases in glycolytic energy utilization by mechanically induced signaling, and add substantial new data to a complex picture of how chondrocytes transduce mechanical loads. PMID- 26573902 TI - A machine learning approach to estimate Minimum Toe Clearance using Inertial Measurement Units. AB - Falls are the primary cause of accidental injuries (52%) and one of the leading causes of death in individuals aged 65 and above. More than 50% of falls in healthy older adults are due to tripping while walking. Minimum toe clearance (i.e., minimum height of the toe above the ground during the mid-swing phase - MTC) has been investigated as an indicator of tripping risk. There is increasing demand for practicable gait monitoring using wearable sensors such as Inertial Measurement Units (IMU) comprising accelerometers and gyroscopes due to their wearability, compactness and low cost. A major limitation however, is intrinsic noise making acceleration integration unreliable and inaccurate for estimating MTC height from IMU data. A machine learning approach to MTC height estimation was investigated in this paper incorporating features from both raw and integrated inertial signals to train Generalized Regression Neural Networks (GRNN) models using a hill-climbing feature-selection method. The GRNN based MTC height predictions demonstrated root-mean-square-error (RMSE) of 6.6mm with 9 optimum features for young adults and 7.1mm RMSE with 5 features for the older adults during treadmill walking. The GRNN based MTC height estimation method devised in this project represents approximately 68% less RMSE than other estimation techniques. The research findings show a strong potential for gait monitoring outside the laboratory to provide real-time MTC height information during everyday locomotion. PMID- 26573903 TI - Mapping the osteocytic cell response to fluid flow using RNA-Seq. AB - Bone adaptation to mechanical loading is regulated via signal transduction by mechano-sensing osteocytes. Mineral-embedded osteocytes experience strain-induced interstitial fluid flow and fluid shear stress, and broad shifts in gene expression are key components in the signaling pathways that regulate bone turnover. RNA sequencing analysis, or RNA-Seq, enables more complete characterization of mechano-responsive transcriptome regulation than previously possible. We hypothesized that RNA-Seq of osteocytic MLO-Y4 cells reveals both expected and novel gene transcript regulation in cells previously fluid flowed and analyzed using gene microarrays. MLO-Y4 cells were flowed for 2h with 1Pa oscillating fluid shear stress and post-incubated 2h. RNA-Seq of original samples detected 55 fluid flow-regulated gene transcripts (p-corrected <0.05), the same number previously detected by microarray. However, RNA-Seq demonstrated greater dynamic range, with all 55 transcripts increased >1.5-fold or decreased <0.67 fold whereas 10 of 55 met this cut-off by microarray. Analyses were complimentary in patterns of regulation, though only 6 transcripts were significant in both RNA Seq and microarray analyses: Cxcl5, Cxcl1, Zc3h12a, Ereg, Slc2a1, and Egln1. As part of a broad inflammatory response inferred by gene ontology analyses, we again observed greatest up-regulation of inflammatory C-X-C motif chemokines, and newly implicated HIF-1alpha and AMPK signaling pathways. Importantly, we detected both expected fluid flow-sensitive transcripts (e.g. Nos2 [iNOS], Ptgs2 [COX-2], Ccl7) and transcripts not previously identified as flow-sensitive, e.g. Ccl2. We found RNA-Seq advantageous over microarrays because of its greater dynamic range and ability to analyze unbiased estimation of gene expression, informing our understanding of osteocyte signaling. PMID- 26573904 TI - Quasi-linear viscoelastic properties of the human medial patello-femoral ligament. AB - The evaluation of viscoelastic properties of human medial patello-femoral ligament is fundamental to understand its physiological function and contribution as stabilizer for the selection of the methods of repair and reconstruction and for the development of scaffolds with adequate mechanical properties. In this work, 12 human specimens were tested to evaluate the time- and history-dependent non linear viscoelastic properties of human medial patello-femoral ligament using the quasi-linear viscoelastic (QLV) theory formulated by Fung et al. (1972) and modified by Abramowitch and Woo (2004). The five constant of the QLV theory, used to describe the instantaneous elastic response and the reduced relaxation function on stress relaxation experiments, were successfully evaluated. It was found that the constant A was 1.21+/-0.96MPa and the dimensionless constant B was 26.03+/-4.16. The magnitude of viscous response, the constant C, was 0.11+/-0.02 and the initial and late relaxation time constants tau1 and tau2 were 6.32+/ 1.76s and 903.47+/-504.73s respectively. The total stress relaxation was 32.7+/ 4.7%. To validate our results, the obtained constants were used to evaluate peak stresses from a cyclic stress relaxation test on three different specimens. The theoretically predicted values fit the experimental ones demonstrating that the QLV theory could be used to evaluate the viscoelastic properties of the human medial patello-femoral ligament. PMID- 26573905 TI - Opportunity Cost Neglect Attenuates the Effect of Choices on Preferences. AB - The idea that choices alter preferences has been widely studied in psychology, yet prior research has focused primarily on choices for which all alternatives were salient at the time of choice. Opportunity costs capture the value of the best forgone alternative and should be considered as part of any decision process, yet people often neglect them. How does the salience of opportunity costs at the time of choice influence subsequent evaluations of chosen and forgone options? In three experiments, we found that there was a larger postchoice spread between evaluations of focal options and opportunity costs when opportunity costs were explicit at the time of choice than when they remained implicit. PMID- 26573906 TI - In-Group Ostracism Increases High-Fidelity Imitation in Early Childhood. AB - The Cyberball paradigm was used to examine the hypothesis that children use high fidelity imitation as a reinclusion behavior in response to being ostracized by in-group members. Children (N = 176; 5- to 6-year-olds) were either included or excluded by in- or out-group members and then shown a video of an in-group or an out-group member enacting a social convention. Participants who were excluded by their in-group engaged in higher-fidelity imitation than those who were included by their in-group. Children who were included by an out-group and those who were excluded by an out-group showed no difference in imitative fidelity. Children ostracized by in-group members also displayed increased anxiety relative to children ostracized by out-group members. The data are consistent with the proposal that high-fidelity imitation functions as reinclusion behavior in the context of in-group ostracism. PMID- 26573907 TI - Development of an urban green space indicator and the public health rationale. AB - AIMS: In this study, the aim was to develop and test an urban green space indicator for public health, as proposed by the World Health Organisation (WHO) Regional Office for Europe, in order to support health and environmental policies. METHODS: We defined the indicator of green space accessibility as a proportion of an urban population living within a certain distance from a green space boundary. We developed a Geographic Information System (GIS)-based method and tested it in three case studies in Malmo, Sweden; Kaunas, Lithuania; and Utrecht, The Netherlands. Land use data in GIS from the Urban Atlas were combined with population data. Various population data formats, maximum distances to green spaces, minimum sizes of green spaces, and different definitions of green spaces were studied or discussed. RESULTS: Our results demonstrated that with increasing size of green space and decreased distance to green space, the indicator value decreased. As compared to Malmo and Utrecht, a relatively bigger proportion of the Kaunas population had access to large green spaces, at both shorter and longer distances. Our results also showed that applying the method of spatially aggregated population data was an acceptable alternative to using individual data. CONCLUSIONS: Based on reviewing the literature and the case studies, a 300 m maximum linear distance to the boundary of urban green spaces of a minimum size of 1 hectare are recommended as the default options for the indicator. The indicator can serve as a proxy measure for assessing public accessibility to urban green spaces, to provide comparable data across Europe and stimulate policy actions that recognise the importance of green spaces for sustainable public health. PMID- 26573908 TI - Health-related quality of life in patients with sickle cell disease in Saudi Arabia. AB - BACKGROUND: There is a lack of research concerning health-related quality of life (HRQoL) in Saudi patients with sickle cell disease (SCD), particularly among adult populations. The aim of the current study was to describe the characteristics of SCD patients and their impact on their quality of life (QoL). METHODS: Six hundred twenty-nine adult SCD patients who attended King Fahad Hospital in Hofuf and King Fahad Central Hospital in Jazan were included in the analysis. Demographic/clinical data were collected and an Arabic version of the Medical Outcomes 36-Item Short-Form Health Survey (SF-36) questionnaire was used to assess QoL. RESULTS: SCD patients who hold a university degree reported positive impacts on the following domains of SF-36: physical role function, vitality, emotional well being, social function, pain reduction, and general health (P = .002, P = .001, P = .001, P = .003, P = .004, and P = .001, respectively). In general, patients with fever, skin redness, swelling, or history of blood transfusion tended to impair the health status of the SF-36. A multivariate analysis revealed that patients with a university degree tended to report high scores of physical role functions, emotional role function, and vitality. Patients with regular exercise tend to increase vitality, social function, general health, and reduce pain. Unemployment tends to lessen vitality and worsen pain. On average, pain, social function, and physical function scores tended to worsen in patients with swelling or history of blood transfusion. CONCLUSIONS: This study highlighted that poor education, fever, skin redness, and swelling were negatively associated with specific components of SF-36. SCD patients with a history of blood transfusion found their QoL poorer, whereas regular exercise tended to improve QoL. PMID- 26573909 TI - HSP70 overexpression may play a protective role in the mouse embryos stimulated by CUMS. AB - BACKGROUND: We evaluated whether heat shock protein HSP70 plays a protective role in the embryos of Kunming mice subjected to chronic unpredictable mild stress. METHODS: Female mice were stimulated for 4 weeks with nine stressors and then divided into mild, moderate and severe stress groups. Superovulation was induced with a gonadotropin preparation (PMSG/HCG) and HSP70 expression in 2-cell embryos and day 4 embryos was detected by immunofluorescence (IF) and real-time polymerase chain reaction (RT-PCR). RESULTS: In the mild stress group, ovarian response and oocyte development potential were similar to those of the control group, while the HSP70 mRNA levels of the embryos were significantly higher (P < 0.05). In the severe stress group, ovarian response and oocyte development potential decreased compared with the control group (P < 0.05), while the HSP70 mRNA levels were similar. The results of the moderate stress group were intermediate among the three groups. Furthermore, HSP70 mRNA levels of the embryos were shown to be positively associated with parameters of oocyte and embryo development potential (P < 0.05). CONCLUSIONS: HSP70 overexpression may play a protective role in the embryos of the mild or moderate stress mice stimulated by chronic unpredictable mild stress. PMID- 26573910 TI - Introducing rapid diagnostic tests for malaria into registered drug shops in Uganda: lessons learned and policy implications. AB - BACKGROUND: Malaria is a major public health problem in Uganda and the current policy recommends introduction of rapid diagnostic tests for malaria (RDTs) to facilitate effective case management. However, provision of RDTs in drug shops potentially raises a new set of issues, such as adherence to RDTs results, management of severe illnesses, referral of patients, and relationship with caretakers. The main objective of the study was to examine the impact of introducing RDTs in registered drug shops in Uganda and document lessons and policy implications for future scale-up of malaria control in the private health sector. METHODS: A cluster-randomized trial introducing RDTs into registered drug shops was implemented in central Uganda from October 2010 to July 2012. An evaluation was undertaken to assess the impact and the processes involved with the introduction of RDTs into drug shops, the lessons learned and policy implications. RESULTS: Introducing RDTs into drug shops was feasible. To scale-up this intervention however, drug shop practices need to be regulated since the registration process was not clear, supervision was inadequate and record keeping was poor. Although initially it was anticipated that introducing a new practice of record keeping would be cumbersome, but at evaluation this was not found to be a constraint. This presents an important lesson for introducing health management information system into drug shops. Involving stakeholders, especially the district health team, in the design was important for ownership and sustainability. The involvement of village health teams in community sensitization to the new malaria treatment and diagnosis policy was a success and this strategy is recommended for future interventions. CONCLUSION: Introducing RDTs into drug shops was feasible and it increased appropriate treatment of malaria with artemisinin-based combination therapy. It is anticipated that the lessons presented will help better implementation of similar interventions in the private sector. PMID- 26573911 TI - Malaria prevalence in Bata district, Equatorial Guinea: a cross-sectional study. AB - BACKGROUND: Malaria has traditionally been a leading public health problem in Equatorial Guinea. After completion, in September 2011, of the integrated set of interventions against malaria launched by the Global Fund Malaria Programme in the mainland area, the epidemiological situation of malaria remains unknown. The aim of this study was to investigate the prevalence rate of malaria and associated factors based on the rapid diagnosis test (RDT) in Bata district, in order to provide evidence that will reinforce the National Malaria Control Programme. METHODS: From June to August 2013, a representative cross sectional survey using a multistage, stratified, cluster-selected sample was carried out in urban zones and rural villages from Bata district. Data on socio-demographic, health status and malaria-related behaviours was collected. Malaria diagnosis was performed by RDT. Bivariate and multivariable statistical methods were employed to assess malaria prevalence and its association with different factors. RESULTS: Prevalence of malaria was higher in rural settings (58.9 %; CI 95 % 55.2-62.5 %) than in the sampled urban communities (33.9 %; CI 95 % 31.1-36.9 %). Presence of anaemia was also high, especially in rural sites (89.6 vs. 82.8 %, p < 0.001). The analyses show that a positive RDT result was significantly associated with age group, the most affected age range being 13 months-14 years old. Other significant covariates were ethnic group (only in urban sites), number of adults living in the house (only in rural villages) previous history of fever, anaemia (only in urban sites) and sleeping under a bed net. Moreover, those who never slept under a bed net were two times more likely to have malaria. CONCLUSION: The prevalence of malaria was high in Bata district, especially in rural villages. The National Programme to fight malaria in Equatorial Guinea should take into account the differences found between rural and urban communities and age groups to target appropriately those worst affected. The findings of this study will assist in planning and undertaking regional policy and other preventive initiatives. PMID- 26573912 TI - Spatial epidemiology and serologic cohorts increase the early detection of leprosy. AB - BACKGROUND: Leprosy remains an important public health problem in some specific high-burden pockets areas, including the Brazilian Amazon region, where it is hyperendemic among children. METHODS: We selected two elementary public schools located in areas most at risk (cluster of leprosy or hyperendemic census tract) to clinically evaluate their students. We also followed anti-PGL-I seropositive and seronegative individuals and households for 2 years to compare the incidence of leprosy in both groups. RESULTS: Leprosy was detected in 11 (8.2 %) of 134 school children in high risk areas. The difference in the prevalence was statistically significant (p < .05) compared to our previous findings in randomly selected schools (63/1592; 3.9 %). The 2-year follow-up results showed that 22.3 and 9.4 % of seropositive and seronegative individuals, respectively, developed leprosy (p = .027). The odds of developing overt disease in seropositive people were 2.7 times that of negative people (p < .01), indicating that a follow-up of 10 seropositives has a >90 % probability to detect at least one new case in 2 years. The odds of clinical leprosy were also higher in "positive houses" compared to "negative houses" (p < .05), indicating that a follow-up of ten people living in households with at least one seropositive dweller have a 85 % probability to detect at least one new case in 2 years. CONCLUSIONS: Targeted screening involving school-based surveillance planned using results obtained by spatial analysis and targeted household and individual continuous surveillance based on serologic data should be applied to increase the early detection of new leprosy cases. PMID- 26573913 TI - Root iTRAQ protein profile analysis of two Citrus species differing in aluminum tolerance in response to long-term aluminum-toxicity. AB - BACKGROUND: Limited information is available on aluminum (Al)-toxicity-responsive proteins in woody plant roots. Seedlings of 'Xuegan' (Citrus sinensis) and 'Sour pummelo' (Citrus grandis) were treated for 18 weeks with nutrient solution containing 0 (control) or 1.2 mM AlCl3 . 6H2O (+Al). Thereafter, we investigated Citrus root protein profiles using isobaric tags for relative and absolute quantification (iTRAQ). The aims of this work were to determine the molecular mechanisms of plants to deal with Al-toxicity and to identify differentially expressed proteins involved in Al-tolerance. RESULTS: C. sinensis was more tolerant to Al-toxicity than C. grandis. We isolated 347 differentially expressed proteins from + Al Citrus roots. Among these proteins, 202 (96) proteins only presented in C. sinensis (C. grandis), and 49 proteins were shared by the two species. Of the 49 overlapping proteins, 45 proteins were regulated in the same direction upon Al exposure in the both species. These proteins were classified into following categories: sulfur metabolism, stress and defense response, carbohydrate and energy metabolism, nucleic acid metabolism, protein metabolism, cell transport, biological regulation and signal transduction, cell wall and cytoskeleton metabolism, and jasmonic acid (JA) biosynthesis. The higher Al tolerance of C. sinensis may be related to several factors, including: (a) activation of sulfur metabolism; (b) greatly improving the total ability of antioxidation and detoxification; (c) up-regulation of carbohydrate and energy metabolism; (d) enhancing cell transport; (e) decreased (increased) abundances of proteins involved in protein synthesis (proteiolysis); (f) keeping a better balance between protein phosphorylation and dephosphorylation; and (g) increasing JA biosynthesis. CONCLUSIONS: Our results demonstrated that metabolic flexibility was more remarkable in C. sinenis than in C. grandis roots, thus improving the Al tolerance of C. sinensis. This provided the most integrated view of the adaptive responses occurring in Al-toxicity roots. PMID- 26573914 TI - A Comprehensive Review of Immunoreceptor Regulation of Osteoclasts. AB - Osteoclasts require coordinated co-stimulation by several signaling pathways to initiate and regulate their cellular differentiation. Receptor activator for NF kappaB ligand (RANKL or TNFSF11), a tumor necrosis factor (TNF) superfamily member, is the master cytokine required for osteoclastogenesis with essential co stimulatory signals mediated by immunoreceptor tyrosine-based activation motif (ITAM)-signaling adaptors, DNAX-associated protein 12 kDa size (DAP12) and FcepsilonRI gamma chain (FcRgamma). The ITAM-signaling adaptors do not have an extracellular ligand-binding domain and, therefore, must pair with ligand-binding immunoreceptors to interact with their extracellular environment. DAP12 pairs with a number of different immunoreceptors including triggering receptor expressed on myeloid cells 2 (TREM2), myeloid DAP12-associated lectin (MDL-1), and sialic acid-binding immunoglobulin-type lectin 15 (Siglec-15); while FcRgamma pairs with a different set of receptors including osteoclast-specific activating receptor (OSCAR), paired immunoglobulin receptor A (PIR-A), and Fc receptors. The ligands for many of these receptors in the bone microenvironment remain unknown. Here, we will review immunoreceptors known to pair with either DAP12 or FcRgamma that have been shown to regulate osteoclastogenesis. Co-stimulation and the effects of ITAM-signaling have turned out to be complex, and now include paradoxical findings that ITAM-signaling adaptor-associated receptors can inhibit osteoclastogenesis and immunoreceptor tyrosine-based inhibitory motif (ITIM) receptors can promote osteoclastogenesis. Thus, co-stimulation of osteoclastogenesis continues to reveal additional complexities that are important in the regulatory mechanisms that seek to maintain bone homeostasis. PMID- 26573916 TI - Benefits and Limitations of Block Periodized Training Approaches to Athletes' Preparation: A Review. AB - The present review introduces innovative concepts of training periodization and summarizes a large body of findings characterizing their potential benefits and possible limitations. Evidence-based analysis of the traditional periodization model led to elaboration of alternative versions of athletic preparation. These alternative versions postulated the superiority of training programs with a high concentration of selected workloads compared with traditionally designed plans directed at the concurrent development of many athletic abilities at low/medium workload concentration. The training cycles of highly concentrated specialized workloads were coined "training blocks" by experts and practitioners; correspondingly, the alternative versions were termed "block periodized (BP) preparation systems" by their presenters. Ultimately, two BP training models were proposed: a concentrated unidirectional training model (CU) and a multi-targeted BP approach to athletes' preparation. The first innovative version postulated administration of highly concentrated training means for enhancement of one leading fitness component, whereas the second version proposed the development of many targeted abilities within sequenced block mesocycles containing a minimal number of compatible training modalities. Both versions differ in their methodological background, duration and content of training blocks, possibilities of providing multi-peak performances, and applicability to various sports. In recent decades, many studies have evaluated the effects of both BP training versions in different sports. Examination of the training effects producing by the CU model in combat and team sports has found significant gains in various fitness estimates but not in sport-specific performances. Similarly, utilization of a CU program by elite swimmers did not lead to substantial enhancement of their peak performances. In contrast, studies of multi-targeted BP training programs have revealed their distinct superiority compared with traditional preparation in endurance, team, and dual sports, and strength/power training and recreational athletes (28 studies). It is suggested that the CU training strategy suits athletic disciplines demanding one fitness component like explosive strength in jumping performances. Unlike this limitation, the multi-targeted BP system prompted a beneficial increase of specific preparedness in sports and disciplines in which peak performances require the application of many targeted athletic abilities. PMID- 26573915 TI - Asymptomatic Clostridium difficile colonization: epidemiology and clinical implications. AB - BACKGROUND: The epidemiology of Clostridium difficile infection (CDI) has changed over the past decades with the emergence of highly virulent strains. The role of asymptomatic C. difficile colonization as part of the clinical spectrum of CDI is complex because many risk factors are common to both disease and asymptomatic states. In this article, we review the role of asymptomatic C. difficile colonization in the progression to symptomatic CDI, describe the epidemiology of asymptomatic C. difficile colonization, assess the effectiveness of screening and intensive infection control practices for patients at risk of asymptomatic C. difficile colonization, and discuss the implications for clinical practice. METHODS: A narrative review was performed in PubMed for articles published from January 1980 to February 2015 using search terms 'Clostridium difficile' and 'colonization' or 'colonisation' or 'carriage'. RESULTS: There is no clear definition for asymptomatic CDI and the terms carriage and colonization are often used interchangeably. The prevalence of asymptomatic C. difficile colonization varies depending on a number of host, pathogen, and environmental factors; current estimates of asymptomatic colonization may be underestimated as stool culture is not practical in a clinical setting. CONCLUSIONS: Asymptomatic C. difficile colonization presents challenging concepts in the overall picture of this disease and its management. Individuals who are colonized by the organism may acquire protection from progression to disease, however they also have the potential to contribute to transmission in healthcare settings. PMID- 26573918 TI - Sex Differences in the Formation of Intracranial Aneurysms and Incidence and Outcome of Subarachnoid Hemorrhage: Review of Experimental and Human Studies. AB - Intracranial aneurysms are defined as pathological dilatations of cerebral arteries and rupture of intracranial aneurysms leads to subarachnoid hemorrhage (SAH). The goal of this review was to outline the sex differences in the formation and progression of intracranial aneurysms as well as sex-related differences in incidence and outcome of SAH. The literature review was performed using PubMed with a combination of these search terms: "subarachnoid hemorrhage," "incidence," "outcome," "sex," "gender," "male," "female," "experimental," "mice," and "rats." Studies written in English were used. Female sex is thought to be a risk factor for aneurysm formation, especially in postmenopausal age populations, suggesting the potential protective involvement of sex steroids. Female sex is also considered a risk factor for SAH occurrence. Although incidence and mortality are confirmed to be higher in females in most studies, they elucidated no clear differences in the functional outcome among SAH survivors. The effect of gender on the pathophysiology of SAH is not very well understood; nevertheless, the majority of pre-clinical studies suggest a beneficial effect of sex steroids in experimental SAH. Moreover, conflicting results exist on the role and effect of hormone replacement therapies and oral contraceptive pills on the incidence and outcome of human SAH. Sex differences exist in the formation of aneurysms as well as the incidence and mortality of SAH. Potential therapeutic effects of sex steroids have been replicated in many animal studies, but their potential use in the treatment of acute SAH in human populations needs more future study. PMID- 26573919 TI - Ginkgo biloba Extract Prevents Female Mice from Ischemic Brain Damage and the Mechanism Is Independent of the HO1/Wnt Pathway. AB - It is well known that gender differences exist in experimental or clinical stroke with respect to brain damage and loss of functional outcome. We have previously reported neuroprotective properties of Ginkgo biloba/EGb 761(r) (EGb 761) in transient and permanent mouse models of brain ischemia using male mice, and the mechanism of action was attributed to the upregulation of the heme oxygenase 1 (HO1)/Wnt pathway. Here, we sought to investigate whether EGb 761's protective effect in ovariectomized female mice following stroke is also mediated by the HO1/Wnt pathway. Female mice were ovariectomized (OVX) to remove the protective effect of estrogen and were treated with EGb 761 for 7 days prior to inducing permanent middle cerebral artery occlusion (pMCAO) and allowed to survive for an additional 7 days. At day 8, animals were sacrificed, and the brains were harvested for infarct volume analysis, western blots, and immunohistochemistry. The OVX female mice treated with EGb 761 showed significantly lower infarct size as compared to Veh/OVX animals. EGb 761 treatment in female mice inhibited apoptosis by preventing caspase-3 cleavage and blocking the extrinsic apoptotic pathway. EGb 761 pretreatment significantly enhanced neurogenesis in OVX mice as compared to the Veh/OVX group and significantly upregulated androgen receptor expression with no changes in HO1/Wnt signaling. These results suggest that EGb 761 prevented brain damage in OVX female mice by improving grip strength and neurological deficits, and the mechanism of action is not through HO1/Wnt but via blocking the extrinsic apoptotic pathway. PMID- 26573920 TI - The Variant p.(Arg183Trp) in SPTLC2 Causes Late-Onset Hereditary Sensory Neuropathy. AB - Hereditary sensory and autonomic neuropathy 1 (HSAN1) is an autosomal dominant disorder that can be caused by variants in SPTLC1 or SPTLC2, encoding subunits of serine palmitoyl-CoA transferase. Disease variants alter the enzyme's substrate specificity and lead to accumulation of neurotoxic 1-deoxysphingolipids. We describe two families with autosomal dominant HSAN1C caused by a new variant in SPTLC2, c.547C>T, p.(Arg183Trp). The variant changed a conserved amino acid and was not found in public variant databases. All patients had a relatively mild progressive distal sensory impairment, with onset after age 50. Small fibers were affected early, leading to abnormalities on quantitative sensory testing. Sural biopsy revealed a severe chronic axonal neuropathy with subtotal loss of myelinated axons, relatively preserved number of non-myelinated fibers and no signs for regeneration. Skin biopsy with PGP9.5 labeling showed lack of intraepidermal nerve endings early in the disease. Motor manifestations developed later in the disease course, but there was no evidence of autonomic involvement. Patients had elevated serum 1-deoxysphingolipids, and the variant protein produced elevated amounts of 1-deoxysphingolipids in vitro, which proved the pathogenicity of the variant. Our results expand the genetic spectrum of HSAN1C and provide further detail about the clinical characteristics. Sequencing of SPTLC2 should be considered in all patients presenting with mild late-onset sensory-predominant small or large fiber neuropathy. PMID- 26573922 TI - Length and density of filiform tongue papillae: differences between tick susceptible and resistant cattle may affect tick loads. AB - BACKGROUND: Indicine breeds of bovines are highly resistant and taurine breeds are susceptible to the cattle tick, Rhipicephalus microplus, a species which causes great damage to livestock. Animals use their tongues for self-grooming, an important behavior for ridding themselves of ectoparasites. However, the role of tongue morphology, notably the filiform papillae, in this process is not known. FINDINGS: This study compared features of the filiform papillae of tongues in eight Nelores (indicine breed) and eight Holsteins and two Brown Swiss (taurine breeds) and verified how they associate with tick loads. Biopsies were taken from identical positions of tongues and measured by scanning electron microscopy. One way analysis of variance detected significant differences between morphological features of tongues from indicine and taurine breeds: Nelores had longer papillae (mean of 2.3 mm +/- 0.029 SD; P < 0.001), and more papillae per cm(2) (mean of 25.2 papillae +/- 1.92 SD; P < 0.05) than European bovines (means of, respectively, 1.8 mm +/- 0.027 SD and 20.9 +/- 0.74 SD papillae per cm(2)). After infestations with equal numbers of larvae, loads of adult ticks were inversely correlated with length of papillae and directly correlated with distances between the apices of papillae (P = 0.014; r = -0.566 and P = 0.018; r = 0.567, Pearson product momentum correlation, respectively). CONCLUSIONS: Spacing between papillae is smaller in Nelores, thus their tongues may be rougher and, consequently, more effective in removing tick larvae during self-grooming, explaining the greater resistance to ticks among Zebu breeds of cattle. PMID- 26573923 TI - Adherence to antiretroviral therapy and retention in care for adolescents living with HIV from 10 districts in Uganda. AB - BACKGROUND: Adolescents have gained increased attention because they are the only age group where HIV related mortality is going up. We set out to describe the level and factors associated with adherence to antiretroviral therapy (ART) as well as the 1 year retention in care among adolescents in 10 representative districts in Uganda. In addition, we explored the barriers and facilitators of adherence to ART among adolescents. METHODS: The study involved 30 health facilities from 10 representative districts in Uganda. We employed both qualitative and quantitative data collection methods in convergent design. The former involved Focus group discussions with adolescents living with HIV, Key informant interviews with various stakeholders and in depth interviews with adolescents. The quantitative involved using retrospective records review to extract the last recorded adherence level from all adolescents who were active in HIV care. Factors associated with adherence were extracted from the ART cards. For the 1 year retention in care, we searched the hospital records of all adolescents in the 30 facilities who had started ART 1 year before the study to find out how many were still in care. RESULTS: Out of 1824 adolescents who were active on ART, 90.4 % (N = 1588) had >=95 % adherence recorded on their ART cards at their last clinic visit. Only location in rural health facilities was independently associated with poor adherence to ART (P = 0.008, OR 2.64 [1.28 5.43]). Of the 156 adolescents who started ART, 90 % (N = 141) were still active in care 1 year later. Stigma, discrimination and disclosure issues were the most outstanding of all barriers to adherence. Other barriers included poverty, fatigue, side effects, pill burden, depression among others. Facilitators of adherence mainly included peer support groups, counseling, supportive health care workers, short waiting time and provision of food and transport. CONCLUSION: Adherence to ART was good among adolescents. Being in rural areas was associated with poor adherence to ART and 1 year retention in care was very good among adolescents who were newly started on ART. Stigma and disclosure issues continue to be the main barriers to adherence among adolescents. PMID- 26573921 TI - Protease-activated receptors (PARs)--biology and role in cancer invasion and metastasis. AB - Although many studies have demonstrated that components of the hemostatic system may be involved in signaling leading to cancer progression, the potential mechanisms by which they contribute to cancer dissemination are not yet precisely understood. Among known coagulant factors, tissue factor (TF) and thrombin play a pivotal role in cancer invasion. They may be generated in the tumor microenvironment independently of blood coagulation and can induce cell signaling through activation of protease-activated receptors (PARs). PARs are transmembrane G-protein-coupled receptors (GPCRs) that are activated by a unique proteolytic mechanism. They play important roles in vascular physiology, neural tube closure, hemostasis, and inflammation. All of these agents (TF, thrombin, PARs-mainly PAR 1 and PAR-2) are thought to promote cancer invasion and metastasis at least in part by facilitating tumor cell migration, angiogenesis, and interactions with host vascular cells, including platelets, fibroblasts, and endothelial cells lining blood vessels. Here, we discuss the role of PARs and their activators in cancer progression, focusing on TF- and thrombin-mediated actions. Therapeutic options tailored specifically to inhibit PAR-induced signaling in cancer patients are presented as well. PMID- 26573924 TI - Clinical and diagnostic approach to patients with hypopituitarism due to traumatic brain injury (TBI), subarachnoid hemorrhage (SAH), and ischemic stroke (IS). AB - The hypothalamic-pituitary dysfunction attributable to traumatic brain injury (TBI), aneurysmal subarachnoid hemorrhage (SAH), and ischemic stroke (IS) has been lately highlighted. The diagnosis of TBI-induced-hypopituitarism, defined as a deficient secretion of one or more pituitary hormones, is made similarly to the diagnosis of classical hypopituitarism because of hypothalamic/pituitary diseases. Hypopituitarism is believed to contribute to TBI-associated morbidity and to functional and cognitive final outcome, and quality-of-life impairment. Each pituitary hormone must be tested separately, since there is a variable pattern of hormone deficiency among patients with TBI-induced-hypopituitarism. Similarly, the SAH and IS may lead to pituitary dysfunction although the literature in this field is limited. The drive to diagnose hypopituitarism is the suspect that the secretion of one/more pituitary hormone may be subnormal. This suspicion can be based upon the knowledge that the patient has an appropriate clinical context in which hypopituitarism can be present, or a symptom known as caused by hypopituitarism. Hypopituitarism should be diagnosed as a combination of low peripheral and inappropriately normal/low pituitary hormones although their basal evaluation may be not distinctive due to pulsatile, circadian, or situational secretion of some hormones. Evaluation of the somatotroph and corticotroph axes require dynamic stimulation test (ITT for both axes, GHRH + arginine test for somatotroph axis) in order to clearly separate normal from deficient responses. PMID- 26573925 TI - Effects of liraglutide on left ventricular function in patients with non-ST segment elevation myocardial infarction. AB - The influence of glucagon-like peptide-1 has been studied in several studies in patients with acute myocardial infarction, but not in patients with non-ST segment elevation myocardial infarction (NSTEMI). We planned to evaluate the effects of liraglutide on left ventricular function in patients with NSTEMI. A total of 90 patients were randomized 1:1 to receive either liraglutide (0.6 mg for 2 days, 1.2 mg for 2 days, followed by 1.8 mg for 3 days) or placebo for 7 days. Eighty-three patients completed the trial. Transthoracic echocardiography was used to assess left ventricular function. At 3 months, the primary endpoint, the difference in the change in left ventricular ejection fraction between the two groups was +4.7 % (liraglutide vs. placebo 95 % CI +0.7 to +9.2 % P = 0.009) under intention-to-treat analysis. The difference in decrease in serum glycosylated hemoglobin levels was -0.2 % (liraglutide vs. placebo 95 % CI -0.1 to -0.3 %; P < 0.001). Inflammation and oxidative stress improved significantly in the liraglutide group compared to the placebo group. Liraglutide could improve left ventricular function in patients with NSTEMI, making it a potential adjuvant therapy for NSTEMI. PMID- 26573926 TI - [Complications of Descemet Stripping Automated Endothelial Keratoplasty (DSAEK)]. AB - BACKGROUND: Lamellar keratoplasties, e.g. Descemet's stripping automated endothelial keratoplasty (DSAEK) and Descemet membrane endothelial keratoplasty (DMEK) are considered the procedures of choice for corneal endothelial diseases. In comparison to penetrating keratoplasty (PK) they are associated with faster visual rehabilitation, a lower risk of complications and a decreased necessity for follow-up visits, which reduces the burden on quality of life in elderly patients. In order to advise patients regarding the indications for surgery and to facilitate the follow-up management, it is important to know the most important complications associated with these keratoplasty techniques. RESULTS AND DISCUSSION: The most important preoperative complication is a delayed indication for the operation. In contrast to PK, DSAEK and DMEK surgery should be provided at an earlier stage of disease as chronic edema alters the stroma and reduces the speed of visual recovery. The most important complications during or early after surgery are detached lamellae, pupillary blocks with increased pressure or air bubbles in the vitreous cavity in patients with previous vitrectomy. The main long-term complications include chronic increased intraocular pressure and immune-mediated graft rejections in DSAEK patients after reducing or stopping topical corticosteroid therapy. This article describes the potential complications of endothelial keratoplasty and provides a detailed explanation of strategies to avoid these complications. PMID- 26573927 TI - [Complications of corneal lamellar surgery]. PMID- 26573928 TI - Oncogene-Induced Senescence in Pituitary Adenomas--an Immunohistochemical Study. AB - Oncogene-induced senescence (OIS) serves as an initial barrier to cancer development, being proposed as a possible explanation for the usually benign behavior of the pituitary adenomas. We aimed to explore the immunohistochemical expression of the OIS markers, senescence-associated lysosomal beta-galactosidase (SA-beta-GAL), p16, and p21 in different types of 345 pituitary adenomas and compared it with the expression in the normal pituitary and in the specimens from the repeated surgeries. SA-beta-GAL was overexpressed in the pituitary adenomas, compared to the normal pituitaries. Growth hormone (GH) producing adenomas showed the strongest SA-beta-GAL, with densely granulated (DG)-GH adenomas more reactive than the sparsely granulated (SG). Nuclear p21 was decreased in the adenomas, except for the SG-GH adenomas that had higher p21 than the normal pituitaries and the other adenomas. p16 was significantly lower in the adenomas, without type related differences. SA-beta-GAL was slightly lower and p16 slightly higher in the recurrences. Our findings indicate alterations of the senescence program in the different types of pituitary adenomas. Activation of senescence in the pituitary adenomas presents one possible explanation for their usually benign behavior, at least in the GH adenomas that show a synchronous increase of two OIS markers. However, subdivision into GH adenoma subtypes reveals differences that reflect complex regulatory mechanisms influenced by the interplay between the granularity pattern and the hormonal factors, with possible impact on the different clinical behavior of the SG- and DG-GH adenoma subtypes. p16 seems to have a more prominent role in the pituitary tumorigenesis than in the senescence. Recurrent growth in a subset of the pituitary adenomas is not associated with consistent changes in the senescence pattern. PMID- 26573929 TI - Family Emotion Expressiveness Mediates the Relations Between Maternal Emotion Regulation and Child Emotion Regulation. AB - While there is a growing body of literature examining the influence of emotion socialization on children's emotional and social development, there is less research on what predicts emotion socialization behaviors among parents. The current study explores maternal emotion regulation difficulties as a predictor of emotion socialization practices, specifically, family emotion expressiveness. Further, the current study examines the role of family emotion expressiveness as a possible mediator of the relations between maternal and child emotion regulation in a community sample of 110 mother-child dyads with preschool-aged children. Analyses revealed that positive family expressiveness mediated the relations between maternal emotion dysregulation and child emotion regulation and thus presents important clinical implications for existing emotion socialization interventions. PMID- 26573931 TI - Technique for Determining Fluids Motion Characteristics in the Vicinity of Ferromagnetic Solids Under Magneto-Chemical Treatment. AB - We report on new technique for determining and visualization of fluids motion in the vicinity of magnetized ferromagnetic surfaces under chemical dissolution and autocatalytic formation of spatiotemporal structures. The proposed method of obtaining data on the motion of fluids does not require the use of additional inclusions and allows to avoid the distortions caused by such inclusions or other changes in the nature of the reaction. The developed technique allows to obtain both the integral dependences and time frequencies distributions of the fluids over the volume of the medium under investigation. PMID- 26573930 TI - Enhanced Bioavailability and Anticancer Effect of Curcumin-Loaded Electrospun Nanofiber: In Vitro and In Vivo Study. AB - Nanofibers have attracted increasing attention in drug delivery and other biomedical applications due to their some special properties. The present study aims to prepare a fiber-based nanosolid dispersion system to enhance the bioavailability of curcumin (CUR). CUR-loaded polyvinyl pyrrolidone (CUR@PVP) nanofibers were successfully prepared via electrospinning. Scanning electron microscopy (SEM) was employed to observe the morphology of the nanofibers, and the SEM image showed that the drug-loaded nanofibers were smooth, and no CUR clusters were found on the surface of the nanofibers. The results of X-ray diffraction (XRD) demonstrated that the CUR was evenly distributed in the nanofibers in an amorphous state. Fourier transform infrared (FTIR) spectroscopy analysis indicated that intermolecular hydrogen bonding occurred between the CUR and the polymer matrix. In vitro dissolution profiles showed that CUR@PVP nanofiber could be quickly dissolved in phosphate-buffered saline (PBS) solution, while negligible dissolution was observed in pure CUR sample. Importantly, in vitro cell viability assays and in vivo animal tests revealed that the nanosolid dispersion system dramatically enhanced the bioavailability and showed effective anticancer effect of the CUR. PMID- 26573932 TI - Growth of a Novel Nanostructured ZnO Urchin: Control of Cytotoxicity and Dissolution of the ZnO Urchin. AB - The applications of zinc oxide (ZnO) nanowires (NWs) in implantable wireless devices, such as diagnostic nanobiosensors and nanobiogenerators, have recently attracted enormous attention due to their unique properties. However, for these implantable nanodevices, the biocompatibility and the ability to control the behaviour of cells in contact with ZnO NWs are demanded for the success of these implantable devices, but to date, only a few contrasting results from their biocompatibility can be found. There is a need for more research about the biocompatibility of ZnO nanostructures and the adhesion and viability of cells on the surface of ZnO nanostructures. Here, we introduce synthesis of a new nature inspired nanostructured ZnO urchin, with the dimensions of the ZnO urchin's acicula being controllable. To examine the biocompatibility and behaviour of cells in contact with the ZnO urchin, the Madin-Darby canine kidney (MDCK) epithelial cell line was chosen as an in vitro experimental model. The results of the viability assay indicated that, compared to control, the number of viable cells attached to the surface of the ZnO urchin and its surrounding area were reduced. The measurements of the Zn contents of cell media confirmed ZnO dissolution, which suggests that the ZnO dissolution in cell culture medium could lead to cytotoxicity. A purposeful reduction of ZnO cytotoxicity was achieved by surface coating of the ZnO urchin with poly(vinylidene fluorid-co hexafluoropropylene) (PVDF-HFP), which changed the material matrix to slow the Zn ion release and consequently reduce the cytotoxicity of the ZnO urchin without reducing its functionality. PMID- 26573933 TI - Focused Role of an Organic Small-Molecule PBD on Performance of the Bistable Resistive Switching. AB - An undoped organic small-molecule 2-(4-tert-butylphenyl)-5-(4-biphenylyl)-1,3,4 oxadiazole (PBD) and a kind of nanocomposite blending poly(methyl methacrylate) (PMMA) into PBD are employed to implement bistable resistive switching. For the bistable resistive switching indium tin oxide (ITO)/PBD/Al, its ON/OFF current ratio can touch 6. What is more, the ON/OFF current ratio, approaching to 10(4), is available due to the storage layer PBD:PMMA with the chemical composition 1:1 in the bistable resistive switching ITO/PBD:PMMA/Al. The capacity, data retention of more than 1 year and endurance performance (>10(4) cycles) of ITO/PBD:PMMA(1:1)/Al, exhibits better stability and reliability of the samples, which underpins the technique and application of organic nonvolatile memory. PMID- 26573934 TI - Red-Shift Effect and Sensitive Responsivity of MoS2/ZnO Flexible Photodetectors. AB - The optoelectronic characteristics of molybdenum disulfide (MoS2)/ZnO flexible photodetectors are investigated. A red-shift effect and improved photocurrent properties of the flexible devices are demonstrated. MoS2 doping improved the photocurrent properties and conductivity. The photocurrent/dark current ratios of pure ZnO and MoS2/ZnO flexible photodetectors were 10(3) and 10(4), respectively. The responsivity of MoS2/ZnO increased, and the wavelength was red-shifted. PMID- 26573935 TI - Performing high flexion activities does not seem to be crucial in developing early femoral component loosening after high-flexion TKA. AB - BACKGROUND: It is still unclear whether high flexion (HF) activities correlated with the early loosening of the femoral component and whether HF activities are possible. We investigated what is the capability for performing various HF activities, and whether high flexion activities increase the chance of aseptic loosening after HF-TKA. METHODS: We retrospectively analysed 260 patients who underwent HF-TKA using the NexGen LPS Flex between 2001 and 2009. The mean follow up was 6.7 years (range, 5-13). We evaluated range of motion, Knee Society scores, WOMAC, and serial radiographs for aseptic loosening. Responses to questions on individual HF activities were recorded on 5-point Likert scales based on difficulty (0-4). Patients were divided two groups based on their responses to squatting and kneeling, which were important weight-bearing HF activities in Asian population (HF group vs. non-HF group) for comparisons of aseptic loosening and clinical outcomes. RESULTS: More than 80 % of patients positively responded for various HF activities. The capability of HF activities showed that cross-legged sitting, squatting, and kneeling were 97.7, 51.1 and 52.7 % at the latest follow-up, respectively. Aseptic loosening was identified in two tibial components (0.8 %) but none in femoral components in non-HF group. There was no significant difference of aseptic loosening based on HF activities (0.8% vs. 0%, p = 0.063). CONCLUSIONS: The results of this study suggest that HF activities do not seem to be associated with aseptic loosening of femoral component after HF-TKA. PMID- 26573937 TI - [Workup and treatment of autoimmune encephalitis]. AB - Autoimmune encephalitis with antibodies against neuronal surface antigens is diagnosed with increasing frequency in recent years. If treated early and aggressively, these conditions often respond favourably to immunotherapy. We describe the clinical features, diagnosis and treatment of the two most common types of autoimmune encephalitis with antibodies against the N-methyl-D-aspartate receptor or the leucine-rich glioma-inactivated 1 protein. Together, these two conditions comprise 80% of the autoimmune encephalitis cases diagnosed in Denmark. Autoimmune encephalitides with rare antibodies are also summarized. PMID- 26573936 TI - A nurse-led rheumatology clinic versus rheumatologist-led clinic in monitoring of patients with chronic inflammatory arthritis undergoing biological therapy: a cost comparison study in a randomised controlled trial. AB - BACKGROUND: Recommendations for rheumatology nursing management of chronic inflammatory arthritis (CIA) from European League Against Rheumatism (EULAR) states that nurses should take part in the monitoring patients' disease and therapy in order to achieve cost savings. The aim of the study was to compare the costs of rheumatology care between a nurse-led rheumatology clinic (NLC), based on person-centred care (PCC), versus a rheumatologist-led clinic (RLC), in monitoring of patients with CIA undergoing biological therapy. METHODS: Patients with CIA undergoing biological therapy (n = 107) and a Disease Activity Score of 28 <= 3.2 were randomised to follow-up by either NLC or RLC. All patients met the rheumatologist at inclusion and after 12 months. In the intervention one of two annual monitoring visits in an RLC was replaced by a visit to an NLC. The primary outcome was total annual cost of rheumatology care. RESULTS: A total of 97 patients completed the RCT at the 12 month follow-up. Replacing one of the two annual rheumatologist monitoring visits by a nurse-led monitoring visit, resulted in no additional contacts to the rheumatology clinic, but rather a decrease in the use of resources and a reduction of costs. The total annual rheumatology care costs including fixed monitoring, variable monitoring, rehabilitation, specialist consultations, radiography, and pharmacological therapy, generated ? 14107.7 per patient in the NLC compared with ? 16274.9 in the RCL (p = 0.004), giving a ? 2167.2 (13 %) lower annual cost for the NLC. CONCLUSIONS: Patients with CIA and low disease activity or in remission undergoing biological therapy can be monitored with a reduced resource use and at a lower annual cost by an NLC, based on PCC with no difference in clinical outcomes. This could free resources for more intensive monitoring of patients early in the disease or patients with high disease activity. TRIAL REGISTRATION: The trial is registered as a clinical trial at the ClinicalTrials.gov (NCT01071447). Registration date: October 8, 2009. PMID- 26573938 TI - [Mechanism of low-back pain with focus on Modic changes]. AB - Low-back pain (LBP) pathology and pain have previously been connected with physical strain. The coping was therefore characterized by ''be careful!'' messages. In the 1990s it was shown that these physical loads virtually did not mean anything regarding disc degeneration, although loads may create LBP episodes. Genetic aspects and the demonstration in 2006 that Modic changes (MC) generally correlated with LBP changed our perception, especially because antibiotics seemed to be effective in MC. Moreover, the role of cytokines is becoming increasingly clear. The following years will be very exciting. PMID- 26573939 TI - [Thromboelastography-guided transfusion in a patient with amniotic fluid embolism and massive coagulopathic bleeding]. AB - Amniotic fluid embolism is a serious and devastating complication in obstetrics. Despite a low incidence of 1-6:100.000, it remains one of the leading causes of maternal death in developed countries. Several risk factors have been proposed, but studies are conflicting, and to date there are no ways to predict or prevent this condition. Despite early and aggressive treatment, mortality and risk of neurological impairment remain high. We present a classic case of amniotic fluid embolism during labour and briefly discuss the current recommendations for treatment. PMID- 26573940 TI - [White pupil in an infant]. AB - A whitish pupillary reflex (leukocoria) indicates abnormal reflection from intraocular pathology. In a child, leukocoria may be a sign of serious and even life-threatening eye disease (retinoblastoma), but the most common cause is congenital cataract. Both diagnoses require immediate referral to an ophthalmologist. Leukocoria is best detected by evaluating the reflex from the pupil with a handheld ophthalmoscope. We here present a case story of an infant with leukocoria that proved to be caused by unilateral congenital cataract. PMID- 26573941 TI - [The optimal timing of suture removal depends on the anatomical location]. AB - The objective of this article was to review current recommendations about the optimal timing of suture removal for percutaneous, non-absorbable sutures in surgical incisions and traumatic wounds. A review of relevant literature showed that the recommendations for timing of suture removal varied in the interval 3-14 days. Influencing factors associated with the timing of suture removal included the location of the wound, co-morbidity and signs of early wound complications. PMID- 26573942 TI - [In Process Citation]. PMID- 26573943 TI - [In Process Citation]. PMID- 26573944 TI - [In Process Citation]. PMID- 26573945 TI - [In Process Citation]. PMID- 26573946 TI - [Avoidable loss of vision in a global perspective]. AB - WHO estimates that in 2010 there were 39 million blind people and 246 million living with moderate to severe vision impairment globally. 90% of the disease burden is found in developing countries, and most of it is due to preventable or treatable eye conditions. Many of these, such as uncorrected refractive errors, can be prevented with the integration of simple primary health measures. However, as a result of an ageing population, the prevalence of chronic diseases such as diabetic retinopathy and age-related macular degeneration is on the rise. This calls for more focus on specialized treatment. PMID- 26573947 TI - [Acute oliguric renal failure and haemolytic anaemia following infectious mononucleosis]. AB - A 19-year-old man was admitted to hospital due to fatigue, nausea, abdominal pain and faint. He was pale and icteric, awake with sufficient respiration and circulation. He had infectious mononucleosis complicated with acute oliguric renal failure and severe haemolytic anaemia with a positive Coombs test. He had a cold agglutinin syndrome. The treatment comprised intermittent haemodialysis, plasmapheresis and heating. He recovered completely after two months. PMID- 26573948 TI - [Merkel cell carcinoma is a rare, aggressive neuroendocrine skin cancer]. AB - Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer with a poor survival rate. The low incidence and lack of characteristic manifestation of MCC often cause an incorrect diagnosis. A 92-year-old male presented with an asymptomatic, smooth lesion on the right cheek, which was initially diagnosed as a basal cell carcinoma. After histological diagnosis of MCC the patient underwent radical surgery, but developed metastases later. Attention to the diagnosis of this condition, patient history and initial presentation can provide clues in order to offer the right treatment with minimal delay. PMID- 26573949 TI - [Correct treatment of acute Achilles tendon rupture - the difficult choice]. AB - Treatment of acute Achilles tendon rupture in Denmark has changed from being predominantly operative to being non-operative treatment over the past five years. However, no clear evidence is found in the literature in favour of one treatment modality over another. Non-operative treatment leads to an increased risk of re-rupture and operative treatment to an increased risk of other complications such as adhesions, infection and nerve injury. When a non-operative treatment protocol is chosen it is paramount that sufficient expertise is present to guide the treatment and rehabilitation. PMID- 26573950 TI - [An algorithm for diagnosis of the floppy infant]. AB - The term "floppy infant" is used for describing children presenting with muscle hypotonia at or shortly after birth. These floppy infants are usually a diagnostic challenge due to the many rare and genetic causes of hypotonia. It is common to start by classifying the hypotonia as peripheral or central, but even from here the path to a diagnosis can be long. This article reviews the literature, mostly retrospective studies done on floppy infants and presents a new simplified algorithm to help guide the diagnostics of the hypotonic children. PMID- 26573951 TI - Adherent perinephric fat at minimally invasive partial nephrectomy is associated with adverse peri-operative outcomes and malignant renal histology. AB - OBJECTIVES: To predict adherent perinephric fat (APF) at minimally invasive partial nephrectomy (MIPN) using the Mayo adhesive probability (MAP) score and to determine the impact of MAP score and APF on MIPN outcomes. PATIENTS AND METHODS: A total of 245 patients undergoing MIPN were included in the study. The presence of APF was determined through keywords in operating notes, and radiographic data were obtained from preoperative cross-sectional imaging. Posterior fat thickness was measured between the renal capsule and the posterior abdominal wall at the level of the renal vein. Perinephric stranding was graded on a 0-3 severity scale. RESULTS: The study included 123 men and 122 women, with a median age of 55 years, body mass index of 31.7, tumour size of 2.7 cm and nephrometry score of 6. The median posterior fat thickness was 1.79 cm and MAP score 2.63. In all, 26 patients (10.6%) had evidence of APF at the time of renal surgery. Factors predictive of APF included increasing age (P = 0.001), male gender (P = 0.045), perinephric stranding (P = 0.002), posterior fat thickness (P < 0.001) and MAP score (P < 0.001). APF was associated with adverse pathological and peri operative outcomes including malignant renal histology (P = 0.04), longer operating time (P = 0.005) and greater estimated blood loss (EBL; P = 0.025). CONCLUSIONS: Specific clinical and radiographic factors predict APF at MIPN. The presence of APF is associated with adverse peri-operative outcomes including longer operating time and greater EBL. APF was also associated with renal malignancy on final pathology, but further studies are necessary to elucidate the precise underlying mechanism. PMID- 26573952 TI - Clinical significance of preoperative C-reactive protein and squamous cell carcinoma antigen levels in patients with penile squamous cell carcinoma. AB - OBJECTIVE: To evaluate the relevance of C-reactive protein (CRP) and squamous cell carcinoma antigen (SCC-Ag) levels in relation to clinicopathological factors and prognosis in penile cancer. PATIENTS AND METHODS: A total of 124 Chinese patients with penile squamous cell carcinoma (SCC), treated between November 2007 and October 2014, were analysed retrospectively. Receiver-operating characteristic curves were used to identify the combination of markers with the best sensitivity and specificity for prognosis prediction. Statistical data analysis was performed using a non-parametric method, and survival analysis was performed using the log-rank test and Cox proportional hazard model. RESULTS: Levels of CRP >=4.5 mg/L and SCC-Ag >=1.4 ng/mL were both significantly associated with lymph node metastasis (LNM) laterality (chi-squared trend test, P = 0.041), extranodal extension (chi-squared trend test, P < 0.001), pelvic LNM (chi-squared trend test, P = 0.024), pathological tumour status (chi-squared trend test, P = 0.002), pathological nodal status (chi-squared trend test, P < 0.001), and disease-specific survival (DSS; log-rank test, P < 0.001). Moreover, the influence of CRP and SCC-Ag levels on DSS (P = 0.033, hazard ratio 3.390, 95% confidence interval 1.104-10.411) remained after adjusting for smoking history, phimosis, tumour status, tumour cell differentiation and nodal status. CONCLUSIONS: The present study shows that the combined measurement of preoperative CRP and SCC-Ag levels may serve as an independent biomarker for LNM, advanced tumour stage and DSS in patients with penile SCC. PMID- 26573953 TI - Acute embryotoxic effects but no long-term reproductive effects of in ovo methylmercury exposure in zebra finches (Taeniopygia guttata). AB - Mercury bioaccumulates in terrestrial ecosystems as methylmercury (MeHg), yet little is known about its effects on terrestrial organisms, including songbirds. The authors used a model songbird species, the zebra finch (Taeniopygia guttata), to assess short-term embryotoxic effects of in ovo MeHg exposure on hatching success and posthatching growth and nestling survival, as well as longer-term effects on mating behavior and reproduction. Egg treatment groups included a low MeHg dose of 0.2 MUg Hg g(-1) egg (n = 36), a high-MeHg dose of 3.2 MUg Hg g(-1) egg (n = 49), and a control (n = 34). Doses were dissolved in nanopure filtered water and injected into the albumen on the day eggs showed signs of viability (3 d incubation). In ovo exposure to MeHg significantly reduced hatching success (53% in the high-MeHg dose group vs 94% in vehicle controls). Among hatched chicks, however, no effects of MeHg on growth, hematological variables, or nestling survival were detected. While the in ovo injection method resulted in a dose-dependent pattern of MeHg concentrations in blood of surviving chicks at 15 d and 30 d posthatching, there was evidence of rapid excretion of MeHg with nestling age during that growth period. At reproductive maturity (90 d of age), no long-term effects of in ovo exposure to MeHg on female mating behavior, reproductive effort (egg or clutch size), or growth and survivorship of offspring were observed. Environ Toxicol Chem 2016;35:1534-1540. (c) 2015 SETAC. PMID- 26573954 TI - Comparison of oncological and health-related quality of life outcomes between open and robot-assisted radical prostatectomy for localised prostate cancer - findings from the population-based Victorian Prostate Cancer Registry. AB - OBJECTIVE: To compare the short-term oncological and health-related quality of life (HRQOL) outcomes between open (ORP) and robot-assisted (RARP) radical prostatectomy in the population-based Victorian Prostate Cancer Registry. PATIENTS AND METHODS: This is a prospective cohort of patients with prostate cancer who had RP (1117 ORP and 885 RARP) between January 2009 and June 2012. The oncological outcomes of interest were: positive surgical margin (PSM) and biochemical recurrence (BCR), defined as postoperative PSA level of >0.2 ng/mL. The HRQOL outcomes were: sexual and urinary bother, assessed using the Expanded Prostate Cancer Index Composite at 1- and 2-years after diagnosis. For univariate comparison of continuous variables the Student's t-test or Mann-Whitney U-test were used, and the Pearson's chi-squared test was used for categorical variables. Bonferroni correction was applied to account for multiple testing, with a threshold for significance of P < 0.003 for univariate analyses. The inverse probability-treatment-weighting (IPTW) approach was used to adjust for differences in baseline characteristics between ORP and RARP patients [including age, National Comprehensive Cancer Network (NCCN) risk categories, hospitals, and year of RP] in all multivariate analyses. Logistic regressions were used to analyse for PSM, Cox regressions for BCR, and ordinal logistic regressions for HRQOL outcomes. All multivariate analyses also adjusted for surgeons' average annual caseload, and employed the robust standard errors for clustering by surgeon. RESULTS: ORP and RARP patients were followed for a median of 19 and 17 months, respectively. The proportion of patients with NCCN low-risk prostate cancer was significantly higher among RARP patients (21% vs 26%; P = 0.002). Most RPs was done in private hospitals (77% ORP, and 85% RARP, P < 0.001). A higher proportion of RARP patients were operated by surgeons with higher annual caseloads (65% RARP and 53% ORP operated by surgeons with >20 case/year; P < 0.001). In the IPTW-adjusted multivariate analyses, RARP patients had a lower risk of PSM (odds ratio [OR] 0.56, 95% confidence interval [CI] 0.38-0.81), and BCR (hazard ratio [HR] 0.73, 95% CI 0.55-0.99). In the sensitivity analyses (excluding public hospital patients), the lower PSM risk with RARP remained (OR 0.63, 95% CI 0.38-0.81), but the lower BCR risk with RARP was no longer statistically significant (HR 0.79, 95% CI 0.57-1.12). At 1-year follow-up, 61% of ORP and 59% of RARP patients reported 'moderate-big' sexual bother (P = 0.2), while 14% of ORP and 11% of RARP patients reported 'moderate-big' urinary bother (P = 0.08). The sexual and urinary bothers at 2 years were similar between ORP and RARP. In multivariate analyses, there were no statistically significant differences in the HRQOL outcomes between ORP and RARP. CONCLUSIONS: We report on a large population-based comparative study of ORP and RARP with better short-term oncological outcomes favouring RARP, but no significant differences in HRQOL outcomes. The results have to be interpreted taking into account significant surgeon heterogeneity in a population-based study. PMID- 26573955 TI - Effects of ivermectin application on the diversity and function of dung and soil fauna: Regulatory and scientific background information. AB - The application of veterinary medical products to livestock can impact soil organisms in manure-amended fields or adversely affect organisms that colonize dung pats of treated animals and potentially retard the degradation of dung on pastures. For this reason, the authorization process for veterinary medicinal products in the European Union includes a requirement for higher-tier tests when adverse effects on dung organisms are observed in single-species toxicity tests. However, no guidance documents for the performance of higher-tier tests are available. Hence, an international research project was undertaken to develop and validate a proposed test method under varying field conditions of climate, soil, and endemic coprophilous fauna at Lethbridge (Canada), Montpellier (France), Zurich (Switzerland), and Wageningen (The Netherlands). The specific objectives were to determine if fecal residues of an anthelmintic with known insecticidal activity (ivermectin) showed similar effects across sites on 1) insects breeding in dung of treated animals, 2) coprophilous organisms in the soil beneath the dung, and 3) rates of dung degradation. By evaluating the effects of parasiticides on communities of dung-breeding insects and soil fauna under field conditions, the test method meets the requirements of a higher-tier test as mandated by the European Union. The present study provides contextual information on authorization requirements for veterinary medicinal products and on the structure and function of dung and soil organism communities. It also provides a summary of the main findings. Subsequent studies on this issue provide detailed information on different aspects of this overall project. Environ Toxicol Chem 2016;35:1914-1923. (c) 2015 SETAC. PMID- 26573956 TI - Salt-inducible kinases mediate nutrient-sensing to link dietary sugar and tumorigenesis in Drosophila. AB - Cancer cells demand excessive nutrients to support their proliferation but how cancer cells sense and promote growth in the nutrient favorable conditions remain incompletely understood. Epidemiological studies have indicated that obesity is a risk factor for various types of cancers. Feeding Drosophila a high dietary sugar was previously demonstrated to not only direct metabolic defects including obesity and organismal insulin resistance, but also transform Ras/Src-activated cells into aggressive tumors. Here we demonstrate that Ras/Src-activated cells are sensitive to perturbations in the Hippo signaling pathway. We provide evidence that nutritional cues activate Salt-inducible kinase, leading to Hippo pathway downregulation in Ras/Src-activated cells. The result is Yorkie-dependent increase in Wingless signaling, a key mediator that promotes diet-enhanced Ras/Src-tumorigenesis in an otherwise insulin-resistant environment. Through this mechanism, Ras/Src-activated cells are positioned to efficiently respond to nutritional signals and ensure tumor growth upon nutrient rich condition including obesity. PMID- 26573958 TI - The dipeptidyl peptidase-4 inhibitor sitagliptin suppresses mouse colon tumorigenesis in type 2 diabetic mice. AB - Patients with type 2 diabetes mellitus are known to have an increased risk of colorectal neoplasia. Dipeptidyl peptidase-4 (DPP-4) inhibitors have been used as a new therapeutic tool for type 2 diabetes. Since the substrates for DPP-4 include intestinotrophic hormones and chemokines such as GLP-2 and stromal cell derived factor-1 (SDF-1), which are associated with tumor progression, DPP-4 inhibitors may increase the risk of colorectal tumors. However, the influence of DPP-4 inhibitors on colorectal neoplasia in patients with type 2 diabetes remains unknown. In the present study, we show that long-term administration of a DPP-4 inhibitor, sitagliptin (STG), suppressed colon carcinogenesis in leptin-deficient (ob/ob) C57BL/6J mice. Colonic mucosal concentrations of glucagon-like peptide-1 (GLP-1) and GLP-2 were significantly elevated in the ob/ob mice. However, mucosal GLP concentrations and the plasma level of SDF-1 were not affected by the administration of STG. Real-time PCR analysis revealed that colonic mucosal IL-6 mRNA expression, which was significantly upregulated in the ob/ob mice, was significantly suppressed by the long-term administration of STG. These results suggest that a DPP-4 inhibitor may suppress colon carcinogenesis in mice with type 2 diabetes in a GLP-independent manner. Since DPP-4 has multiple biological functions, further studies analyzing other factors related to colon carcinogenesis are needed. PMID- 26573957 TI - Reward signal in a recurrent circuit drives appetitive long-term memory formation. AB - Dopamine signals reward in animal brains. A single presentation of a sugar reward to Drosophila activates distinct subsets of dopamine neurons that independently induce short- and long-term olfactory memories (STM and LTM, respectively). In this study, we show that a recurrent reward circuit underlies the formation and consolidation of LTM. This feedback circuit is composed of a single class of reward-signaling dopamine neurons (PAM-alpha1) projecting to a restricted region of the mushroom body (MB), and a specific MB output cell type, MBON-alpha1, whose dendrites arborize that same MB compartment. Both MBON-alpha1 and PAM-alpha1 neurons are required during the acquisition and consolidation of appetitive LTM. MBON-alpha1 additionally mediates the retrieval of LTM, which is dependent on the dopamine receptor signaling in the MB alpha/beta neurons. Our results suggest that a reward signal transforms a nascent memory trace into a stable LTM using a feedback circuit at the cost of memory specificity. PMID- 26573959 TI - Articular cartilage repair with recombinant human type II collagen/polylactide scaffold in a preliminary porcine study. AB - The purpose of this study was to investigate the potential of a novel recombinant human type II collagen/polylactide scaffold (rhCo-PLA) in the repair of full thickness cartilage lesions with autologous chondrocyte implantation technique (ACI). The forming repair tissue was compared to spontaneous healing (spontaneous) and repair with a commercial porcine type I/III collagen membrane (pCo). Domestic pigs (4-month-old, n = 20) were randomized into three study groups and a circular full-thickness chondral lesion with a diameter of 8 mm was created in the right medial femoral condyle. After 3 weeks, the chondral lesions were repaired with either rhCo-PLA or pCo together with autologous chondrocytes, or the lesion was only debrided and left untreated for spontaneous repair. The repair tissue was evaluated 4 months after the second operation. Hyaline cartilage formed most frequently in the rhCo-PLA treatment group. Biomechanically, there was a trend that both treatment groups resulted in better repair tissue than spontaneous healing. Adverse subchondral bone reactions developed less frequently in the spontaneous group (40%) and the rhCo-PLA treated group (50%) than in the pCo control group (100%). However, no statistically significant differences were found between the groups. The novel rhCo-PLA biomaterial showed promising results in this proof-of-concept study, but further studies will be needed in order to determine its effectiveness in articular cartilage repair. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:745-753, 2016. PMID- 26573960 TI - Gut-derived serotonin induced by depression promotes breast cancer bone metastasis through the RUNX2/PTHrP/RANKL pathway in mice. AB - Breast cancer metastasizes to the bone in a majority of patients with advanced disease resulting in bone destruction. The underlying mechanisms are complex, and both processes are controlled by an interaction between locally and systemically derived signals. Clinically, breast cancer patients with depression have a higher risk of bone metastasis, yet the etiology and mechanisms are yet to be elucidated. MDA-MB-231 breast cancer cells were used to establish a bone metastasis model by using intracardiac injection in nude mice. Chronic mild stress (CMS) was chosen as a model of depression in mice before and after inoculation of the cells. Knockdown of the RUNX-2 gene was performed by transfection of the cells with shRNA silencing vectors against human RUNX-2. A co culture system was used to test the effect of the MDA-MB-231 cells on osteoclasts and osteoblasts. RT-PCR and western blotting were used to test gene and protein expression, respectively. We confirmed that depression induced bone metastasis by promoting osteoclast activity while inhibiting osteoblast differentiation. Free serotonin led to an increase in the expression of RUNX2 in breast cancer cells (MDA-MB-231), which directly inhibited osteoblast differentiation and stimulated osteoclast differentiation by the PTHrP/RANKL pathway, which caused bone destruction and formed osteolytic bone lesions. Additionally, the interaction between depression and breast cancer cells was interrupted by LP533401 or RUNX2 knockdown. In conclusion, depression promotes breast cancer bone metastasis partly through increasing levels of gut-derived serotonin. Activation of RUNX2 in breast cancer cells by circulating serotonin appears to dissociate coupling between osteoblasts and osteoclasts, suggesting that the suppression of gut derived serotonin decreases the rate of breast cancer bone metastasis induced by depression. PMID- 26573961 TI - A sensitive fluorescence method for detection of E. Coli using rhodamine 6G dyeing. AB - Negatively charged bacteria combined with positively charged alkaline dye rhodamine 6G (Rh6G) in NaH2 PO4 -Na2 HPO4 buffer solution pH 7.4, by electrostatic interaction. The dyed bacteria exhibited a strong fluorescence peak at 552 nm and fluorescence intensity was directly linear to Escherichia coli (E. coli), Bacillus subtilis (B. subtilis) and Staphylococcus aureus (S. aureus) concentrations in the range of 7.06 * 10(4) to 3.53 * 10(7) , 4.95 * 10(5) to 2.475 * 10(8) and 32.5 to 16250 colony forming unit/mL (cfu/mL) respectively, with detection limits of 3.2 * 10(4) cfu/mL E. coli, 2.3 * 10(5) cfu/mL B. subtilis and 16 cfu/mL S. aureus, respectively. Samples were cultured for 12 h, after which the linear detection range for E. coli was 2 to 88 cfu/mL. This simple, rapid and sensitive method was used for the analysis of water and drinking samples. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26573962 TI - Towards the optimization of the preparation procedures of PMMA bone cement. AB - The mechanical properties and thermal history of polymethyl-methacrylate bone cement vary significantly with the preparation procedure used. Because the polymerization reaction is exothermic, many researchers have attempted to minimize thermal osteonecrosis due to heat generation by altering procedures in the preparation of the cement. In most previous studies, only one or two aspects of the preparation procedure were controlled, and there has been little research that comprehensively examines the effects of preparation on the cure kinetics and resulting properties of bone cement. In this study, cement viscosity, cement layer thickness, initial cement temperature, initial metal component temperature, and mixing method were varied to assess the effects on the cement. Maximum temperature, polymerization time, necrosis index, bending strength, and porosity were chosen to evaluate the different preparation procedures, where an optimal procedure would minimize necrosis, reduce cement cure time, and maximize bending strength. Design of Experiments (DOE) was used to examine the main effects and interactions of preparation techniques. Among the most prominent results, it was found that the cure kinetics and the related quantities are primarily controlled by the initial metal component temperature and that the bending strength is most dependent on the mixing method. For the two formulations studied, the optimum preparation procedures should keep cement and metal components at room temperature prior to mixing with a vacuum mixing system. Reducing cement mantle thickness may also be advantageous, as it reduces the maximum temperature and the risk of tissue damage. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:915-923, 2016. PMID- 26573964 TI - T1rho MRI detects cartilage damage in asymptomatic individuals with a cam deformity. AB - Hips with a cam deformity are at risk for early cartilage degeneration, mainly in the anterolateral region of the joint. T1rho MRI is a described technique for assessment of proteoglycan content in hyaline cartilage and subsequently early cartilage damage. In this study, 1.5 Tesla T1rho MRI was performed on 20 asymptomatic hips with a cam deformity and compared to 16 healthy control hips. Cam deformity was defined as an alpha angle at 1:30 o'clock position over 60 degrees and/or at 3:00 o'clock position over 50.5 degrees . Hip cartilage was segmented and divided into four regions of interest (ROIs): anterolateral, anteromedial, posterolateral, and posteromedial quadrants. Mean T1rho value of the entire weight bearing cartilage in hips with a cam deformity (34.0 +/- 4.6 ms) was significantly higher compared to control hips (31.3 +/- 3.2 ms, p = 0.050). This difference reached significance in the anterolateral (p = 0.042) and posteromedial quadrants (p = 0.041). No significant correlation between the alpha angle and T1rho values was detected. The results indicate cartilage damage occurs in hips with a cam deformity before symptoms occur. A significant difference in T1rho values was found in the anterolateral quadrant, the area of direct engagement of the deformity, and in the posteromedial quadrant. To conclude, T1rho MRI can detect early chondral damage in asymptomatic hips with a cam deformity. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1004-1009, 2016. PMID- 26573965 TI - [TBK1 gene stresses the major role of autophagy in ALS]. PMID- 26573963 TI - Myeloperoxidase negatively regulates the expression of proinflammatory cytokines and chemokines by zymosan-induced mouse neutrophils. AB - OBJECTIVE: We have previously reported that myeloperoxidase-deficient (MPO(-/-)) neutrophils produce greater amounts of macrophage inflammatory protein-2 (MIP-2) upon in vitro stimulation with zymosan than wild-type neutrophils. This study aimed to examine the effect of MPO deficiency on the expression of other cytokines and chemokines. METHODS: Wild-type and MPO(-/-) neutrophils isolated from peritoneal cavity were stimulated with zymosan in vitro. Secretion of MIP 1alpha, MIP-1beta, interleukin (IL)-1alpha, IL-1beta, and tumor necrosis factor (TNF)-alpha by neutrophils was quantified by ELISA. mRNA expression in the neutrophils was analyzed by real-time reverse transcription-PCR, and the phosphorylation of extracellular-signal regulated kinase (ERK) 1/2 and p38 mitogen activated protein kinase (MAPK) in neutrophils was analyzed by western blot. For in vivo studies, mice were inoculated with zymosan intranasally, and the levels of these cytokines and chemokines were measured in the lungs. RESULTS: The MPO(-/-) neutrophils stimulated by zymosan expressed and secreted significantly higher levels of MIP-1alpha, MIP-1beta, IL-1alpha, IL-1beta, and TNF-alpha than the stimulated wild-type cells. Expression of all of these inflammatory mediators was blocked by pre-treatment with BAY11-7082, U0126, and SB203580, which are inhibitors of nuclear factor (NF)-kappaB, ERK1/2, and p38 MAPK, respectively. Enhanced expression of these inflammatory mediators is associated with elevated activation of ERK1/2 in stimulated MPO(-/-) neutrophils. In vivo, MPO(-/-) mice had significantly higher numbers of alveolar neutrophils and increased production of MIP-1alpha, MIP-1beta, IL-1alpha, IL-1beta, and TNF alpha relative to the responses seen in wild-type mice within 24 h of zymosan administration. CONCLUSION: MPO deficiency upregulates the expression of several proinflammatory cytokines and chemokines in mouse neutrophils. PMID- 26573966 TI - From sensitivity to resistance - factors affecting the response of Conyza spp. to glyphosate. AB - BACKGROUND: Conyza bonariensis and C. canadensis are troublesome weeds, particularly in fields with minimum tillage, on roadsides and in perennial crops. The distribution of these difficult-to-control species is further increased by the spread of glyphosate-resistant populations. A preliminary investigation has demonstrated the existence of various degrees of glyphosate tolerance/resistance in these populations, underscoring the need to examine the relationship between glyphosate efficacy and plant growth conditions. RESULTS: In populations exposed to glyphosate at different temperatures, glyphosate tolerance increased linearly as the temperature was increased, whereas when grown under the same temperatures, they largely responded similarly to the herbicide. Furthermore, the sensitivity of plants to glyphosate decreased significantly with plant age and increased following temporal exposure to shading. Dose-response studies confirmed the glyphosate resistance of four C. bonariensis populations that were 8-30 times more resistant to glyphosate than the most glyphosate-sensitive population. These populations retained their characteristic glyphosate resistance even under unfavourable growth conditions. CONCLUSION: These findings indicate that the effect of glyphosate on both Conyza species is strongly linked to growing conditions. This has great importance for our understanding of glyphosate resistance and for control of these weeds in agricultural systems. (c) 2015 Society of Chemical Industry. PMID- 26573967 TI - Creation of a simple distal femur morphology classification system. AB - The purpose of this study is to propose a binary classification system based on simple measurements that summarizes individual, race, and sex-specific differences in distal femur shape. Surface models of 165 distal femurs (79 female, 86 male; 85 African-American, 80 Caucasian, 28.8 +/- 7.6 years) were created with a 3-dimensional laser scanner. Surface area, width, length, curvature, and angulation were measured. Knees were classified as either type A or B within five distinct categories: (i) aspect ratio, (ii) trochlear intercondylar width ratio, (iii) trochlear tilt, (iv) medial-lateral trochlear width ratio, and (v) trochlear sulcus shape. Correlations between these measures and surface area were calculated, and receiver-operator curves were used to select cutoff values between type A and B knees to improve differentiation of femur shapes by sex or race. The cutoff values between type A and B knees for the five categories are as follows: Category I: 0.90, Category II: 0.51, Category III: 1.02, Category IV: 0.67, and Category V: 128.7 degrees . Other than category IV (medial-lateral trochlear width ratio) (p = 0.004, R = 0.22), no categories were correlated with surface area (p > 0.25). Category I (aspect ratio, cutoff = 0.90) best differentiated femurs by sex (p < 0.001, AUC = 0.80), and Category V (sulcus shape) best differentiated femurs by race (p < 0.001, AUC = 0.73). This system uses simple measurements to summarize important individual, race, and sex specific differences in distal femur shape. It can be used in a clinical setting to provide insight into the relationship between sex or race differences in knee shape and mechanically influenced knee disorders. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:924-931, 2016. PMID- 26573969 TI - Charting the landscape of priority problems in psychiatry, part 2: pathogenesis and aetiology. AB - This is the second of two companion papers proposing priority problems for research on mental disorders. Whereas the first paper focuses on questions of nosology and diagnosis, this Personal View concerns pathogenesis and aetiology of psychiatric diseases. We hope that this (non-exhaustive and subjective) list of problems, nominated by scientists and clinicians from different fields and institutions, provides guidance and perspectives for choosing future directions in psychiatric science. PMID- 26573968 TI - Plastin 3 is upregulated in iPSC-derived motoneurons from asymptomatic SMN1 deleted individuals. AB - Spinal muscular atrophy (SMA) is a devastating motoneuron (MN) disorder caused by homozygous loss of SMN1. Rarely, SMN1-deleted individuals are fully asymptomatic despite carrying identical SMN2 copies as their SMA III-affected siblings suggesting protection by genetic modifiers other than SMN2. High plastin 3 (PLS3) expression has previously been found in lymphoblastoid cells but not in fibroblasts of asymptomatic compared to symptomatic siblings. To find out whether PLS3 is also upregulated in MNs of asymptomatic individuals and thus a convincing SMA protective modifier, we generated induced pluripotent stem cells (iPSCs) from fibroblasts of three asymptomatic and three SMA III-affected siblings from two families and compared these to iPSCs from a SMA I patient and control individuals. MNs were differentiated from iPSC-derived small molecule neural precursor cells (smNPCs). All four genotype classes showed similar capacity to differentiate into MNs at day 8. However, SMA I-derived MN survival was significantly decreased while SMA III- and asymptomatic-derived MN survival was moderately reduced compared to controls at day 27. SMN expression levels and concomitant gem numbers broadly matched SMN2 copy number distribution; SMA I presented the lowest levels, whereas SMA III and asymptomatic showed similar levels. In contrast, PLS3 was significantly upregulated in mixed MN cultures from asymptomatic individuals pinpointing a tissue-specific regulation. Evidence for strong PLS3 accumulation in shaft and rim of growth cones in MN cultures from asymptomatic individuals implies an important role in neuromuscular synapse formation and maintenance. These findings provide strong evidence that PLS3 is a genuine SMA protective modifier. PMID- 26573970 TI - Charting the landscape of priority problems in psychiatry, part 1: classification and diagnosis. AB - Contemporary psychiatry faces major challenges. Its syndrome-based disease classification is not based on mechanisms and does not guide treatment, which largely depends on trial and error. The development of therapies is hindered by ignorance of potential beneficiary patient subgroups. Neuroscientific and genetics research have yet to affect disease definitions or contribute to clinical decision making. In this challenging setting, what should psychiatric research focus on? In two companion papers, we present a list of problems nominated by clinicians and researchers from different disciplines as candidates for future scientific investigation of mental disorders. These problems are loosely grouped into challenges concerning nosology and diagnosis (this Personal View) and problems related to pathogenesis and aetiology (in the companion Personal View). Motivated by successful examples in other disciplines, particularly the list of Hilbert's problems in mathematics, this subjective and eclectic list of priority problems is intended for psychiatric researchers, helping to re-focus existing research and providing perspectives for future psychiatric science. PMID- 26573971 TI - Ceci n'est pas une cigarette. PMID- 26573972 TI - Anatomic predictors of phrenic nerve injury in the setting of pulmonary vein isolation using the 28-mm second-generation cryoballoon. AB - BACKGROUND: Phrenic nerve injury (PNI) is the most frequently observed complication during pulmonary vein (PV) isolation using the second-generation cryoballoon. OBJECTIVE: The purpose of this study was to analyze anatomic predictors based on preprocedural computed tomographic imaging data. METHODS: Forty-one patients with PNI during the procedure and 123 age-, gender-, and body mass index-matched controls were included. A total of 343 right PVs were evaluated for axial/coronal orientation, ostial diameters with cross-sectional area, ovality index, and branching pattern. External angle between the right superior pulmonary vein (RSPV) and the anterolateral wall of the left atrium (LA) was measured (RSPV-LA angle). Distance from this vertex to the superior vena cava (SVC) was considered the RSPV-SVC distance. RESULTS: For the RSPV, more anterosuperior orientation, larger dimensions, shorter RSPV-SVC distance, and more obtuse RSPV-LA angle (all P <.001) were associated with PNI on univariate analysis. Independent variables after multivariable analysis were RSPV-LA angle (odds ratio 1.03 per degree, 95% confidence interval 1.01-1.04, P <.001) and RSPV area (odds ratio 1.2 per mm2, 95% confidence interval 1.1-1.3, P <.001), with a cutoff value >=141 degrees for RSPV-LA angle (91% sensitivity, 85% specificity) and >=275 mm2 for RSPV area (88% sensitivity, 85% specificity). RIPV area was an independent predictor for PNI at RIPV. A right-sided long common trunk was seen exclusively in 3 patients in the PNI group. CONCLUSION: Preprocedural anatomic assessment of right PVs is useful in evaluating the risk of PNI. Ostial vein area and external RSPV-LA angle measurement showed excellent predictive value for PNI at the RSPV. PMID- 26573973 TI - Invasive strategies and outcomes for non-ST-segment elevation acute coronary syndromes: a twelve-year experience from SWEDEHEART. AB - AIMS: Despite recommendations in recent guidelines for a routine invasive strategy for non-ST-segment elevation acute coronary syndrome (NSTE-ACS), long term data on the implementation of treatment strategies in clinical practice are not available. Our aim was to provide long-term data on the implementation of a routine invasive strategy in NSTE-ACS in clinical practice. METHODS AND RESULTS: In the SWEDEHEART registry, data from 204,092 consecutive NSTE-ACS patients admitted between 1996 and 2007 were recorded. The use of the routine invasive strategy, retrospectively defined as coronary angiography (and subsequent revascularisation) within three days after admission, increased from 3.8% in the period 1996-1998 to 37.4% in the period 2005-2007. The largest absolute increase in the use of this strategy was observed in low-risk patients, while a similar relative increase was observed in all risk categories. The use of the selective invasive strategy, defined as coronary angiography later than three days after admission or none at all, decreased from 96.2% in the period 1996-1998 to 62.5% in the period 2005-2007. In the total population, there was a gradual decrease in three-year all-cause mortality, from 29.1% in the period 1996-1998 to 23.9% in the period 2005-2007. CONCLUSIONS: There has been an increase in the use of a routine invasive strategy in NSTE-ACS patients over the course of 12 years in Sweden. There was a decrease in three-year mortality over the same time course. PMID- 26573974 TI - Transcatheter direct mitral annuloplasty with Cardioband: feasibility and efficacy trial in an acute preclinical model. AB - AIMS: The aim of the study was to report preclinical safety and feasibility of a new transcatheter direct mitral annuloplasty intervention in an acute animal model. METHODS AND RESULTS: Twenty healthy pigs underwent Cardioband (Valtech Cardio, Or Yehuda, Israel) transcatheter implantation under intracardiac echocardiographic and fluoroscopic guidance. Through a neo inferior vena cava approach, transseptal access was arranged. The device was delivered into the left atrium using a multi-steerable catheter and fixed to the mitral annulus with multiple helix anchors. Following device cinching, reduction of annular size was evaluated. In all animals the device could be successfully implanted and displayed 100% function, with the average procedure duration and fluoroscopy times being 78+/-23 minutes and 27+/-9 minutes, respectively. In total, 246 anchors (average 12.3 per device) were delivered and optimal anchor placement was achieved in 95.1%, while inadequate anchor position (4%) and injury of the coronary sinus or atrium (0.8%) occurred in the rest. Following maximal cinching, diastolic transmitral flow velocity and coaptation lengths were markedly increased (p<0.001), whereas septolateral and intercommissural distances were significantly decreased (p<0.001), when compared to pre-contraction baseline, demonstrating efficient annular reduction by the device. CONCLUSIONS: Transcatheter direct annuloplasty with a surgical-like adjustable device is feasible in the porcine animal model. The humanised porcine model has been instrumental in demonstrating feasibility and in establishing the procedural steps. PMID- 26573975 TI - Case report: Dental management of Berardinelli-Seip congenital lipodystrophy. AB - BACKGROUND: Berardinelli-Seip congenital lipodystrophy (BSCL) is a very rare autosomal recessive condition caused by mutations of the AGPAT2 gene or the BSCL2 gene. BSCL is associated with a number of dental manifestations. There are no published case reports of dental treatment under general anaesthesia (GA) in patients with this condition. CASE REPORT: A 6-year-old girl with BSCL characterised by classical features of the condition including a growth disorder, precocious puberty, endocrine disturbances, hypertrophic cardiomyopathy and fatty infiltration of the liver was referred for treatment under GA. Dental manifestations included aberrant tooth morphology, macrodontia and generalised severe crowding. TREATMENT: Dental treatment was carried out under GA following consideration of various options. In conjunction with other medical specialists, a number of peri-operative precautions were taken. Comprehensive dental care was provided which included restorations, extractions and fissure sealants. FOLLOW UP: The patient was reviewed post-operatively and at regular intervals between 3 and 6 months for review and prevention. CONCLUSION: The patient had a number of dental manifestations associated with BSCL. Peri-operative planning is essential for some patients who may have a number of medical conditions. PMID- 26573976 TI - Clinical outcome of angiosome-oriented infrapopliteal percutaneous transluminal angioplasty for isolated infrapopliteal lesions in patients with critical limb ischemia. AB - PURPOSE: We aimed to evaluate the clinical usefulness and outcome of angiosome oriented percutaneous transluminal angioplasty (IP-PTA) and its clinical outcome for isolated infrapopliteal lesions in diabetic critical limb ischemia. METHODS: We retrospectively reviewed 70 patients (82 limbs) with diabetic critical limb ischemia who had localized disease at the level of the infrapopliteal artery. Patients underwent IP-PTA between January 2011 and December 2013 and were followed up for a mean of 13 months. The primary target arterial lesions were chosen according to the angiosome concept. We evaluated clinical findings, technical success, and patients' clinical outcome. The angiographic outcome of IP PTA was assessed using the angiosome score. We analyzed the relationship between the angiosome score and the amputation rate. RESULTS: There were 69 anterior tibial artery (ATA) lesions, 70 posterior tibial artery (PTA) lesions, and 58 peroneal artery (PA) lesions. The primary target arteries were the ATA (n=43), PTA (n=26), PA (n=2), and ATA + PTA (n=11). We divided the treated limbs into target (n=63) and nontarget (n=19) groups. The overall initial technical success rate was 91.4%. Successful wound healing rates were 87.3% (55/63) and 47.3% (9/19) in the target and nontarget groups, respectively (P < 0.05). CONCLUSION: Angiosome-oriented primary targeted IP-PTA shows a highly effective treatment outcome in diabetic critical limb ischemia. In cases with inadequate angioplastic results of the target artery, IP-PTA of the nontarget artery should be recommended to improve the limb salvage rates. PMID- 26573977 TI - Effect of imaging parameters on the accuracy of apparent diffusion coefficient and optimization strategies. AB - PURPOSE: We aimed to investigate the effect of key imaging parameters on the accuracy of apparent diffusion coefficient (ADC) maps using a phantom model combined with ADC calculation simulation and propose strategies to improve the accuracy of ADC quantification. METHODS: Diffusion-weighted imaging (DWI) sequences were acquired on a phantom model using single-shot echo-planar imaging DWI at 1.5 T scanner by varying key imaging parameters including number of averages (NEX), repetition time (TR), echo time (TE), and diffusion preparation pulses. DWI signal simulations were performed for varying TR and TE. RESULTS: Magnetic resonance diffusion signal and ADC maps were dependent on TR and TE imaging parameters as well as number of diffusion preparation pulses, but not on the NEX. However, the choice of a long TR and short TE could be used to minimize their effects on the resulting DWI sequences and ADC maps. CONCLUSION: This study shows that TR and TE imaging parameters affect the diffusion images and ADC maps, but their effect can be minimized by utilizing diffusion preparation pulses. Another key imaging parameter, NEX, is less relevant to DWI and ADC quantification as long as DWI signal-to-noise ratio is above a certain level. Based on the phantom results and data simulations, DWI acquisition protocol can be optimized to obtain accurate ADC maps in routine clinical application for whole body imaging. PMID- 26573978 TI - The endovenous ASVAL method: principles and preliminary results. AB - PURPOSE: We aimed to investigate the feasibility and safety of the endovenous ambulatory selective varicose vein ablation under local anesthesia (eASVAL) method in a selected group of pa-tients with varicose disease and present the short-term results of one-year ultrasonographic follow-up. METHODS: Three hundred and ninety-five consecutive patients with varicose veins who had been treated with endovenous laser ablation (EVLA) were retrospectively reviewed over a period of two years. From this group, 41 patients who were treated using the eASVAL technique and had the great saphenous vein (GSV) preserved were included in the study. These patients had only limited segmental GSV reflux accompanied by a competent terminal valve. The eASVAL technique can be defined as EVLA of the proximal straight segments of the major tributaries connecting the symptomatic varicose veins with the GSV, followed by ultrasound-guided foam sclerotherapy of the superficial varicose veins themselves. The patients were assessed before and after the treatment by duplex scan findings and clinical assessment scores. RESULTS: The GSVs were successfully preserved in all 41 cases, and all patients showed significant clinical improvement using the eASVAL approach (P < 0.001). Segmental reflux was no longer present in 75.3% of patients. The mean diameters of the GSVs were significantly reduced at one-year follow-up (8.5 mm vs. 7.5 mm, P < 0.001). CONCLUSION: eASVAL is a feasible and safe procedure in selected patients, with promising results at one-year ultrasonographic follow-up. However, prospective studies are required, comparing this approach with the standard techniques. PMID- 26573979 TI - Institutionalising ELSA in the moment of breakdown? AB - This article discusses outcomes of a dialogue conference on 'The road ahead for ELSA in Norway: Issues of quality, influence and network cooperation' held in Oslo in December 2012. Norwegian researchers in the field of ethical, legal and social aspects of technologies (ELSA) were invited to discuss conceptual and strategic issues, as well as the setup of a researcher network. In the article I take an institutionalist approach and discuss challenges in institutionalising an ELSA network at a time when a designated ELSA funding programme is coming to an end. The research question is how the Norwegian ELSA network can succeed as a persistent network in times of greater uncertainties. The article claims that the network needs to gain legitimacy, outlines different dimensions of legitimacy and interprets the conference discussions in light of these dimensions. Central challenges and success factors facing the ELSA network are discussed and the article concludes with reflections on the potential future of ELSA in Norway. Although the article has a Norwegian context, the discussions in the article are likely to be relevant for researchers all across Europe, as similar developments are taking place also elsewhere in the European research funding context. PMID- 26573980 TI - Open Genetic Code: on open source in the life sciences. AB - The introduction of open source in the life sciences is increasingly being suggested as an alternative to patenting. This is an alternative, however, that takes its shape at the intersection of the life sciences and informatics. Numerous examples can be identified wherein open source in the life sciences refers to access, sharing and collaboration as informatic practices. This includes open source as an experimental model and as a more sophisticated approach of genetic engineering. The first section discusses the greater flexibly in regard of patenting and the relationship to the introduction of open source in the life sciences. The main argument is that the ownership of knowledge in the life sciences should be reconsidered in the context of the centrality of DNA in informatic formats. This is illustrated by discussing a range of examples of open source models. The second part focuses on open source in synthetic biology as exemplary for the re-materialization of information into food, energy, medicine and so forth. The paper ends by raising the question whether another kind of alternative might be possible: one that looks at open source as a model for an alternative to the commodification of life that is understood as an attempt to comprehensively remove the restrictions from the usage of DNA in any of its formats. PMID- 26573981 TI - The evolution of withdrawal: negotiating research relationships in biobanking. AB - The right to withdraw from research, along with the necessity of adequately informed consent, is at the heart of the post-Nuremburg code of ethical safeguards in biomedical research on human participants. As biomedical research moves away from direct interventional studies towards research using networks of linked human tissue samples and data, however, questions arise about what withdrawal can and should mean in these new contexts. Some of the more expansive traditional understandings, such as the right to withdraw from a study 'at any time' are limited in practice by the nature of biobank- supported research, particularly where it makes possible widespread dissemination and ongoing reuse of data. It is time for a more nuanced, granular arrangement for withdrawal, appropriate to the ongoing relationships between participants and long-term biobanking enterprises. PMID- 26573982 TI - The past and future of RRI. AB - Within the space of a few years, the idea of Responsible Research and Innovation, and its acronym RRI, catapulted from an obscure phrase to the topic of conferences and attempts to specify and realize it. How did this come about, and against which backdrop? What are the dynamics at present, and what do these imply for the future of RRI as a discourse, and as a patchwork of practices? It is a social innovation which creates opening in existing (and evolving) divisions of moral labour, a notion that is explained with the help of the history of responsibility language. It is filled in for the present situation and ongoing developments. Some elements may stabilize and this creates a path into the future. There will be reductions of the originally open-ended innovation, some productive, others less so. This is a reason to regularly inquire into the value of the reductions and the directions the path is taking. PMID- 26573983 TI - Precaution, governance and the failure of medical implants: the ASR((TM)) hip in the UK. AB - Hip implants have provided life-changing treatment, reducing pain and improving the mobility and independence of patients. Success has encouraged manufacturers to innovate and amend designs, engendering patient hopes in these devices. However, failures of medical implants do occur. The failure rate of the Articular Surface Replacement metal-on-metal hip system, implanted almost 100,000 times world-wide, has re-opened debate about appropriate and timely implant governance. As commercial interests, patient hopes, and devices' governance converge in a socio-technical crisis, we analyse the responses of relevant governance stakeholders in the United Kingdom between 2007 and 2014. We argue that there has been a systemic failure of the governance system entrusted with the safety of patients fitted with medical implants. Commercial considerations of medical implants and the status quo of medical implant governance have been given priority over patient safety despite the availability of significant failure data in an example of uncertainty about what constitutes appropriate precautionary action. PMID- 26573985 TI - Improving the electrochemical properties of LiNi(0.5)Co(0.2)Mn(0.3)O2 at 4.6 V cutoff potential by surface coating with Li2TiO3 for lithium-ion batteries. AB - The Li2TiO3-coated LiNi0.5Co0.2Mn0.3O2 (LTO@NCM) cathode materials are synthesized via an in situ co-precipitation method followed by the lithiation process and thermal annealing. The Li2TiO3 coating layer is designed to strongly adhere to the core-material with 3D diffusion pathways for Li(+) ions. Electrochemical tests suggest that compared with pristine NCM, Li2TiO3 serves as both a Li ion conductive layer and a protective coating layer against the attack of HF in the electrolyte, and remarkably improves the cycling performance at higher charged state and rate capability of the LTO@NCM composite material. What is more, phase transformation of NCM and dissolution of metal ions at high temperatures at 4.6 V cutoff potential are effectively suppressed after LTO coating. Our study demonstrates that LTO-coating on the surface of NCM is a viable method to improve the electrochemical performance of NCM, especially at high rates and under high-voltage charged conditions. PMID- 26573984 TI - Mobile Phone and Web 2.0 Technologies for Weight Management: A Systematic Scoping Review. AB - BACKGROUND: Widespread diffusion of mobile phone and Web 2.0 technologies make them potentially useful tools for promoting health and tackling public health issues, such as the increasing prevalence of overweight and obesity. Research in this domain is growing rapidly but, to date, no review has comprehensively and systematically documented how mobile and Web 2.0 technologies are being deployed and evaluated in relation to weight management. OBJECTIVE: To provide an up-to date, comprehensive map of the literature discussing the use of mobile phone and Web 2.0 apps for influencing behaviors related to weight management (ie, diet, physical activity [PA], weight control, etc). METHODS: A systematic scoping review of the literature was conducted based on a published protocol (registered at PROSPERO: CRD42014010323). Using a comprehensive search strategy, we searched 16 multidisciplinary electronic databases for original research documents published in English between 2004 and 2014. We used duplicate study selection and data extraction. Using an inductively developed charting tool, selected articles were thematically categorized. RESULTS: We identified 457 articles, mostly published between 2013 and 2014 in 157 different journals and 89 conference proceedings. Articles were categorized around two overarching themes, which described the use of technologies for either (1) promoting behavior change (309/457, 67.6%) or (2) measuring behavior (103/457, 22.5%). The remaining articles were overviews of apps and social media content (33/457, 7.2%) or covered a combination of these three themes (12/457, 2.6%). Within the two main overarching themes, we categorized articles as representing three phases of research development: (1) design and development, (2) feasibility studies, and (3) evaluations. Overall, articles mostly reported on evaluations of technologies for behavior change (211/457, 46.2%). CONCLUSIONS: There is an extensive body of research on mobile phone and Web 2.0 technologies for weight management. Research has reported on (1) the development, feasibility, and efficacy of persuasive mobile technologies used in interventions for behavior change (PA and diet) and (2) the design, feasibility, and accuracy of mobile phone apps for behavioral assessment. Further research has focused exclusively on analyses of the content and quality of available apps. Limited evidence exists on the use of social media for behavior change, but a segment of studies deal with content analyses of social media. Future research should analyze mobile phone and Web 2.0 technologies together by combining the evaluation of content and design aspects with usability, feasibility, and efficacy/effectiveness for behavior change, or accuracy/validity for behavior assessment, in order to understand which technological components and features are likely to result in effective interventions. PMID- 26573986 TI - Resting metabolic rate, pulmonary functions, and body composition parameters in children with attention deficit hyperactivity disorder. AB - PURPOSE: Several studies of school-aged children with attention deficit hyperactivity disorder (ADHD) have found a higher prevalence of overweight/obesity compared with the general population. However, the scientific literature contains insufficient evidence to establish clear conclusions on pulmonary functions, resting metabolic rate (RMR), and body composition in children with ADHD. This study therefore investigates the pulmonary functions tests (PFTs), RMR, and body composition parameters in children with ADHD and evaluates their quality of life. METHODS: Forty children with ADHD and 40 healthy controls participated in the study. The children's parents completed Conners' parent rating scale (CPRS) and the pediatric quality of life (PedsQL), and their teachers completed Conners' Teacher rating scale (CTRS). The child participants also completed the PedsQL. RMR, PFTs, and body composition parameters were investigated. RESULTS: No significant differences in age, gender, and socioeconomic level were found. All CPRS subscales, except anxiety and psychosomatic conditions, were significantly different (p < 0.05). According to the CTRS, inattentiveness, hyperactivity, and conduct problems were significantly higher in the ADHD group. The results showed that the ADHD group's quality of life is worse than the control group. Body mass index, body composition parameters, RMR, and PFTs were not statistically different between the children with ADHD and the healthy controls. CONCLUSIONS: Further studies with complex designs are needed to confirm the results. PMID- 26573987 TI - Eating pathology in medical students in Eastern Germany: comparison with general population and a sample at the time of the German reunification. AB - PURPOSE: Medical students have been found to be vulnerable to mental health problems due to the high pressures of medical school. Countries developing into industrial nations tend to adopt Western beauty ideals which might increase eating disorder risk. METHODS: This cross-sectional study compared eating (Eating Disorder Inventory 2 EDI-2) and general psychopathology (General Health Questionnaire-28) in medical students from the newly formed German states with a historical sample of East German medical students examined at the time of the German reunification. Current medical students were also compared to population based samples assessed before the German Reunification as well as recently to consider time trends in EDI scores. RESULTS: The current sample comprised 316 medical students (232 female) from the newly formed German states (mean age = 21.7 years, SD = 2.6). Significantly higher levels of drive for thinness as well as body dissatisfaction and higher levels of general psychopathology were displayed in female medical students 20 years after the German reunification. In male medical students, no significant changes of eating pathology were observable. However, male medical students expressed significantly more anxiety and insomnia and a higher GHQ-28 total score than their counterparts examined in 1989. CONCLUSIONS: Twenty years after the Reunification, an acculturation to Western beauty ideals seems to be more pronounced in female than in male medical students. Still, as a group, medical students from the newly formed German states did not appear to display a particular risk to develop eating disorders. However, due to the low response rate, results of this study should be interpreted cautiously. PMID- 26573988 TI - Nurses' perspectives on workplace mistreatment: A qualitative study. AB - An accurate understanding of workplace mistreatment and its impacts on nurses is crucial to hospital managers. A qualitative approach using conventional content analysis was adopted in this study to describe the perspectives of a sample of Iranian nurses concerning workplace mistreatment. After analyzing the transcribed interviews, three main themes emerged: (i) Demand for a more humanistic and appreciative environment; this theme consisted of three categories: "incompetent management practice", "invisibility of nurses", and "unethical behaviors"; (ii) Unprofessional interpersonal encounters which included three categories: "poorly defined job characteristics", "nurses' poor performance", and "inefficient supportive means and structures"; and (iii) Inaction despite injury, consisting of two categories: "passive and ineffective ways of coping with mistreatment", and "personal and professional negative impacts". Findings from this study can guide further investigation within diverse populations of Iranian nurses, as well as worldwide, in order for firm conclusions to be drawn. Future research could compare the perspectives of other stakeholders - patients and relatives, physicians, and managers concerning workplace mistreatment. PMID- 26573989 TI - Supported Lipid Bilayers for the Generation of Dynamic Cell-Material Interfaces. AB - Supported lipid bilayers (SLB) offer unique possibilities for studying cellular membranes and have been used as a synthetic architecture to interact with cells. Here, the state-of-the-art in SLB-based technology is presented. The fabrication, analysis, characteristics and modification of SLBs are described in great detail. Numerous strategies to form SLBs on different substrates, and the means to patteren them, are described. The use of SLBs as model membranes for the study of membrane organization and membrane processes in vitro is highlighted. In addition, the use of SLBs as a substratum for cell analysis is presented, with discrimination between cell-cell and cell-extracellular matrix (ECM) mimicry. The study is concluded with a discussion of the potential for in vivo applications of SLBs. PMID- 26573990 TI - Photoacids as a new fluorescence tool for tracking structural transitions of proteins: following the concentration-induced transition of bovine serum albumin. AB - Spectroscopy-based techniques for assessing structural transitions of proteins follow either an intramolecular chromophore, as in absorption-based circular dichroism (CD) or fluorescence-based tryptophan emission, or an intermolecular chromophore such as fluorescent probes. Here a new fluorescent probe method to probe the structural transition of proteins by photoacids is presented, which has a fundamentally different photo-physical origin to that of common fluorescent probes. Photoacids are molecules that release a proton upon photo-excitation. By following the steady-state and time-resolved emission of the protonated and de protonated species of the photoacid we probe the environment of its binding site in bovine serum albumin (BSA) in a wide range of weight concentrations (0.001 8%). We found a unique concentration-induced structural transition of BSA at pH2 and at concentrations of >0.75%, which involves the exposure of its hydrophobic core to the solution. We confirm our results with the common tryptophan emission method, and show that the use of photoacids can result in a much more sensitive tool. We also show that common fluorescent probes and the CD methodologies have fundamental restrictions that limit their use in a concentration-dependent study. The use of photoacids is facile and requires only a fluorospectrometer (and preferably, but not mandatorily, a time-resolution emission system). The photoacid can be either non-covalently (as in this study) or covalently attached to the molecule, and can be readily employed to follow the local environment of numerous (bio-)systems. PMID- 26573991 TI - Nutritional Risk in Major Abdominal Surgery: Protocol of a Prospective Observational Trial to Evaluate the Prognostic Value of Different Nutritional Scores in Pancreatic Surgery. AB - BACKGROUND: The influence of patients' preoperative nutritional status on their clinical outcome has already been proven. Therefore, patients with malnutrition are in need of additional therapeutic efforts. However, for pancreatic surgery, evidence suggesting the adequacy of existing nutritional assessment scores to estimate malnutrition associated with postoperative outcome is limited. OBJECTIVE: The aim of the observational trial "Nutritional Risk in Major Abdominal Surgery (NURIMAS) Pancreas" is to prospectively assess and analyze different nutritional assessment scores for their prognostic value on postoperative complications in patients undergoing pancreatic surgery. METHODS: All patients scheduled to receive elective pancreatic surgery at the University Hospital of Heidelberg will be screened for eligibility. Preoperatively, 12 nutritional assessment scores will be collected and patients will be assigned either at risk or not at risk for malnutrition. The postoperative course will be followed prospectively and complications according to the Clavien-Dindo classification will be recorded. The prognostic value for complications will be evaluated for every score in a univariable and multivariable analysis corrected for known risk factors in pancreatic surgery. RESULTS: Final data analysis is expected to be available during Spring 2016. CONCLUSIONS: The NURIMAS Pancreas trial is a monocentric, prospective, observational trial aiming to find the most predictive clinical nutritional assessment score for postoperative complications. Using the results of this protocol as a knowledge base, it is possible to conduct nutritional risk-guided intervention trials to prevent postoperative complications in the pancreatic surgical population. TRIAL REGISTRATION: germanctr.de: DRKS00006340; https://drks-neu.uniklinik freiburg.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00006340 (Archived by WebCite at http://www.webcitation.org/6bzXWSRYZ). PMID- 26573992 TI - Genetic testing of aetiology of intellectual disability in a dedicated physical healthcare outpatient clinic for adults with intellectual disability. AB - BACKGROUND: No guidelines exist for assessment of aetiology of intellectual disability in adults with intellectual disability by adult physicians, although robust guidelines exist for paediatric populations. It was speculated that the paediatric guidelines would also be suitable for adults. AIMS: In rural/regional setting with limited clinical genetics, to perform a quality assurance evaluation on genetics assessment of aetiology of developmental disability in adults attending a dedicated healthcare clinic for adults with intellectual disability, compared results with paediatric standards, speculates if these seem appropriate for adults and speculates on a role for clinical genetics services. METHODS: Retrospective chart audit of eligible patients looking at genetic clinical assessment, tests selected (molecular karyotype, G banding, metabolics), and yields of positive results. The results were compared with the recommended paediatric guidelines. RESULTS: Of 117 eligible adult patients, ideal genetic history was incomplete for 40% of patients without Down syndrome because of physician cause and lack of information. The number of abnormal genetic results increased from 46% to 66%, mainly from the molecular karyotype, though not all may have been clinically relevant. The improved yield from this test was similar to that in paediatric studies. Use of G banding and metabolic testing could be refined. CONCLUSION: Improvement can be made in clinical genetic assessment, but results generally support use of molecular karyotyping as first tier testing of cause of unknown intellectual disability in adults, as in the case for paediatric populations. The study highlights a necessary complementary role for clinical geneticists to interpret abnormal results. PMID- 26573993 TI - Gas-phase chemistry of ruthenium and rhodium carbonyl complexes. AB - Short-lived ruthenium and rhodium isotopes were produced from a (252)Cf spontaneous fission (SF) source. Their volatile carbonyl complexes were formed in gas-phase reactions in situ with the carbon-monoxide containing gas. A gas-jet system was employed to transport the volatile carbonyls from the recoil chamber to the chemical separation apparatus. The gas-phase chemical behaviors of these carbonyl complexes were studied using an online low temperature isothermal chromatography (IC) technique. Long IC columns made up of FEP Teflon were used to obtain the chemical information of the high-volatile Ru and Rh carbonyls. By excluding the influence of precursor effects, short-lived isotopes of (109-110)Ru and (111-112)Rh were used to represent the chemical behaviours of Ru and Rh carbonyls. Relative chemical yields of about 75% and 20% were measured for Ru(CO)5 and Rh(CO)4, respectively, relative to the yields of KCl aerosols transported in Ar gas. The adsorption enthalpies of ruthenium and rhodium carbonyl complexes on a Teflon surface were determined to be around DeltaHads = 33(+1)(-2) kJ mol(-1) and -36(+2)(-1) kJ mol(-1), respectively, by fitting the breakthrough curves of the corresponding carbonyl complexes with a Monte Carlo simulation program. Different from Mo and Tc carbonyls, a small amount of oxygen gas was found to be not effective for the chemical yields of ruthenium and rhodium carbonyl complexes. The general chemical behaviors of short-lived carbonyl complexes of group VI-IX elements were discussed, which can be used in the future study on the gas-phase chemistry of superheavy elements - Bh, Hs, and Mt carbonyls. PMID- 26573994 TI - Fashion misadventure: small bowel perforation caused by magnetic tongue studs usage. PMID- 26573995 TI - Stability of two-dimensional PN monolayer sheets and their electronic properties. AB - Three two-dimensional phosphorus nitride (PN) monolayer sheets (named as alpha-, beta-, and gamma-PN, respectively) with fantastic structures and properties are predicted based on first-principles calculations. The alpha-PN and gamma-PN have a buckled structure, whereas beta-PN shows puckered characteristics. Their unique structures endow these atomic PN sheets with high dynamic stabilities and anisotropic mechanical properties. They are all indirect semiconductors and their band gap sensitively depends on the in-plane strain. Moreover, the nanoribbons patterned from these three PN monolayers demonstrate a remarkable quantum size effect. In particular, the zigzag alpha-PN nanoribbon shows size-dependent ferromagnetism. Their significant properties show potential in nano-electronics. The synthesis of the three phases of the PN monolayer sheet is proposed theoretically, which is deserving of further study in experiments. PMID- 26573996 TI - Metastatic lobular carcinoma of the breast: an unusual case. PMID- 26573997 TI - Hyperbilirubinaemia: its utility in non-perforated appendicitis. AB - BACKGROUND: The diagnosis of acute appendicitis is made using clinical findings and investigations. Recent studies have suggested that serum bilirubin, a cheap and simple biochemical test, is a positive predictor in the diagnosis of appendiceal perforation and may be more specific than C-reactive protein (CRP) and white cell count (WCC). The aim of this study was to investigate the utility of the serum bilirubin level in patients with suspected acute but non-perforative appendicitis. METHODS: A retrospective chart review of 213 patients who presented with suspected appendicitis in a 6-month period to Nambour General Hospital was performed. Serum bilirubin, WCC and CRP were recorded and analysed as to their utility in relation to the final diagnosis. RESULTS: A total of 196 patients underwent an appendicectomy and 41 of these were negative. The specificity of hyperbilirubinaemia for appendicitis overall was 0.83 with a positive predictive value (PPV) of 0.86, compared with CRP (specificity 0.40, PPV 0.75) and WCC (specificity 0.67, PPV 0.85). The area under the receiver operating characteristic curve for bilirubin was 0.6289 compared to 0.6171 for CRP and 0.7219 for WCC. A subgroup analysis of those with complicated appendicitis demonstrated a PPV for bilirubin of 0.66 compared to 0.58 for WCC and 0.34 for CRP in agreement with the literature. Subgroup analysis of hyperbilirubinaemia in simple appendicitis demonstrated a PPV of 0.81 compared to CRP (0.71) and WCC (0.82). CONCLUSION: Bilirubin had a higher specificity than CRP and WCC overall in patients with appendicitis. Hyperbilirubinaemia had a high PPV in patients with simple appendicitis. PMID- 26573998 TI - A dual-emitting core-shell carbon dot-silica-phosphor composite for white light emission. AB - A unique dual-emitting core-shell carbon dot-silica-phosphor (CDSP) was constructed from carbon dots (CDs), tetraethoxysilane (TEOS) and Sr2Si5N8:Eu(2+) phosphor through a one-pot sol-gel method. Blue emitting CDs uniformly disperse in the silica layer covering the orange emitting phosphor via a polymerization process, which makes CDSP achieve even white light emission. Tunable photoluminescence of CDSP is observed and the preferable white light emission is achieved through changing the excitation wavelength or controlling the mass ratio of the phosphor. When CDSP powders with a phosphor rate of 3.9% and 5.1% are excited at a wavelength of 400 nm, preferable white light emission is observed, with Commission Internationale de l'Eclairage (CIE) coordinates of (0.32, 0.32) and (0.34, 0.32), respectively. Furthermore, CDSP can mix well with epoxy resin to emit strong and even white light, and based on this, a CDSP-based white LED with a high colour rendering index (CRI) of 94 was fabricated. PMID- 26573999 TI - Radiotherapy in well-differentiated thyroid cancer: is it underutilized? AB - BACKGROUND: The usual management of thyroid cancer is surgery and radioactive iodine. The role of external beam radiotherapy (EBRT) in well-differentiated thyroid carcinoma remains controversial. Indications for the use of EBRT, contained within both the American and British Thyroid Association published guidelines, include unresectable or non-iodine avid disease, extra-thyroidal extension or distant metastatic disease. METHODS: A retrospective review of prospectively collected data from a single Australian institution was conducted, analysing patients referred and treated with EBRT for well-differentiated thyroid carcinoma between November 1992 and July 2013. RESULTS: Of 36 patients referred, 32 were treated with EBRT. Sixteen patients in total received locoregional treatment (six radical, 10 palliative), of whom 81% (13/16) had gross disease and 88% (14/16) had recurrent disease (eight with multiple recurrences). Additionally, 63% (10/16) had multiple surgical resections and 50% (8/16) had previously received multiple courses of radioactive iodine. Overall, 67% (4/6) of patients treated with radical intent had no locoregional recurrence or progression. Thirteen of the 16 patients who received locoregional EBRT remained asymptomatic from their locoregional disease at the time of last follow-up or death. The most commonly treated distant metastatic disease site was bone, with a total of 45 sites irradiated. Of these patients, 93% and 78% were symptom-free at two and four years, respectively. CONCLUSION: Our study suggests that in a select group of patients with well-differentiated thyroid carcinoma, EBRT treatment appears to provide durable tumour and symptom control. PMID- 26574001 TI - Intimate partner violence. PMID- 26574002 TI - Frailty, thy name is Palliative! PMID- 26574003 TI - Female sexual dysfunction. PMID- 26574004 TI - Junior doctors may strike in the UK. PMID- 26574005 TI - An Amphipathic Undecapeptide with All d-Amino Acids Shows Promising Activity against Colistin-Resistant Strains of Acinetobacter baumannii and a Dual Mode of Action. AB - Multiple strains of Acinetobacter baumannii have developed multidrug resistance (MDR), leaving colistin as the only effective treatment. The cecropin-alpha melittin hybrid BP100 (KKLFKKILKYL-NH2) and its analogs have previously shown activity against a wide array of plant and human pathogens. In this study, we investigated the in vitro antibacterial activities of 18 BP100 analogs (four known and 14 new) against the MDR A. baumannii strain ATCC BAA-1605, as well as against a number of other clinically relevant human pathogens. Selected peptides were further evaluated against strains of A. baumannii that acquired resistance to colistin due to mutations of the lpxC, lpxD, pmrA, and pmrB genes. The novel analogue BP214 showed antimicrobial activity at 1 to 2 MUM and a hemolytic 50% effective concentration (EC50) of >150 MUM. The lower activity of its enantiomer suggests a dual, specific and nonspecific mode of action. Interestingly, colistin behaved antagonistically to BP214 when pmrAB and lpxC mutants were challenged. PMID- 26574006 TI - Characterization of the Antimicrobial Peptide Penisin, a Class Ia Novel Lantibiotic from Paenibacillus sp. Strain A3. AB - Attempts to isolate novel antimicrobial peptides from microbial sources have been on the rise recently, despite their low efficacy in therapeutic applications. Here, we report identification and characterization of a new efficient antimicrobial peptide from a bacterial strain designated A3 that exhibited highest identity with Paenibacillus ehimensis. Upon purification and subsequent molecular characterization of the antimicrobial peptide, referred to as penisin, we found the peptide to be a bacteriocin-like peptide. Consistent with these results, RAST analysis of the entire genome sequence revealed the presence of a lantibiotic gene cluster containing genes necessary for synthesis and maturation of a lantibiotic. While circular dichroism and one-dimension nuclear magnetic resonance experiments confirmed a random coil structure of the peptide, similar to other known lantibiotics, additional biochemical evidence suggests posttranslational modifications of the core peptide yield six thioether cross links. The deduced amino acid sequence of the putative biosynthetic gene penA showed approximately 74% similarity with elgicin A and 50% similarity with the lantibiotic paenicidin A. Penisin effectively killed methicillin-resistant Staphylococcus aureus (MRSA) and did not exhibit hemolysis activity. Unlike other lantibiotics, it effectively inhibited the growth of Gram-negative bacteria. Furthermore, 80 mg/kg of body weight of penisin significantly reduced bacterial burden in a mouse thigh infection model and protected BALB/c mice in a bacteremia model entailing infection with Staphylococcus aureus MTCC 96, suggesting that it could be a promising new antimicrobial peptide. PMID- 26574007 TI - Antipseudomonal Bacteriophage Reduces Infective Burden and Inflammatory Response in Murine Lung. AB - As antibiotic resistance increases, there is a need for new therapies to treat infection, particularly in cystic fibrosis (CF), where Pseudomonas aeruginosa is a ubiquitous pathogen associated with increased morbidity and mortality. Bacteriophages are an attractive alternative treatment, as they are specific to the target bacteria and have no documented side effects. The efficacy of phage cocktails was established in vitro. Two P. aeruginosa strains were taken forward into an acute murine infection model with bacteriophage administered either prophylactically, simultaneously, or postinfection. The infective burden and inflammation in bronchoalveolar lavage fluid (BALF) were assessed at various times. With low infective doses, both control mice and those undergoing simultaneous phage treatment cleared P. aeruginosa infection at 48 h, but there were fewer neutrophils in BALF of phage-treated mice (median, 73.2 * 10(4)/ml [range, 35.2 to 102.1 * 10(4)/ml] versus 174 * 10(4)/ml [112.1 to 266.8 * 10(4)/ml], P < 0.01 for the clinical strain; median, 122.1 * 10(4)/ml [105.4 to 187.4 * 10(4)/ml] versus 206 * 10(4)/ml [160.1 to 331.6 * 10(4)/ml], P < 0.01 for PAO1). With higher infective doses of PAO1, all phage-treated mice cleared P. aeruginosa infection at 24 h, whereas infection persisted in all control mice (median, 1,305 CFU/ml [range, 190 to 4,700 CFU/ml], P < 0.01). Bacteriophage also reduced CFU/ml in BALF when administered postinfection (24 h) and both CFU/ml and inflammatory cells in BALF when administered prophylactically. A reduction in soluble inflammatory cytokine levels in BALF was also demonstrated under different conditions. Bacteriophages are efficacious in reducing both the bacterial load and inflammation in a murine model of P. aeruginosa lung infection. This study provides proof of concept for future clinical trials in patients with CF. PMID- 26574008 TI - Distinctive Binding of Avibactam to Penicillin-Binding Proteins of Gram-Negative and Gram-Positive Bacteria. AB - Avibactam is a novel non-beta-lactam beta-lactamase inhibitor that covalently acylates a variety of beta-lactamases, causing inhibition. Although avibactam presents limited antibacterial activity, its acylation ability toward bacterial penicillin-binding proteins (PBPs) was investigated. Staphylococcus aureus was of particular interest due to the reported beta-lactamase activity of PBP4. The binding of avibactam to PBPs was measured by adding increasing concentrations to membrane preparations of a variety of Gram-positive and Gram-negative bacteria prior to addition of the fluorescent reagent Bocillin FL. Relative binding (measured here as the 50% inhibitory concentration [IC50]) to PBPs was estimated by quantification of fluorescence after gel electrophoresis. Avibactam was found to selectively bind to some PBPs. In Escherichia coli, Pseudomonas aeruginosa, Haemophilus influenzae, and S. aureus, avibactam primarily bound to PBP2, with IC50s of 0.92, 1.1, 3.0, and 51 MUg/ml, respectively, whereas binding to PBP3 was observed in Streptococcus pneumoniae (IC50, 8.1 MUg/ml). Interestingly, avibactam was able to significantly enhance labeling of S. aureus PBP4 by Bocillin FL. In PBP competition assays with S. aureus, where avibactam was used at a fixed concentration in combination with varied amounts of ceftazidime, the apparent IC50 of ceftazidime was found to be very similar to that determined for ceftazidime when used alone. In conclusion, avibactam is able to covalently bind to some bacterial PBPs. Identification of those PBP targets may allow the development of new diazabicyclooctane derivatives with improved affinity for PBPs or new combination therapies that act on multiple PBP targets. PMID- 26574009 TI - Genome Analysis of Kingella kingae Strain KWG1 Reveals How a beta-Lactamase Gene Inserted in the Chromosome of This Species. AB - We describe the genome of a penicillinase-producing Kingella kingae strain (KWG1), the first to be isolated in continental Europe, whose bla(TEM-1) gene was, for the first time in this species, found to be chromosomally inserted. The bla(TEM) gene is located in an integrative and conjugative element (ICE) inserted in Met-tRNA and comprising genes that encode resistance to sulfonamides, streptomycin, and tetracycline. This ICE is homologous to resistance-conferring plasmids of K. kingae and other Gram-negative bacteria. PMID- 26574010 TI - Emergence of Carbapenem-Resistant Serotype K1 Hypervirulent Klebsiella pneumoniae Strains in China. AB - We report the emergence of five carbapenem-resistant K1 hypervirulent Klebsiella pneumoniae (hvKP) strains which caused fatal infections in hospital patients in Zhejiang Province, China, upon entry through surgical wounds. Genotyping results revealed the existence of three genetically related strains which exhibited a new sequence type, ST1797, and revealed that all strains harbored the magA and wcaG virulence genes and a plasmid-borne bla(KPC-2) gene. These findings indicate that K1 hvKP is simultaneously hypervirulent, multidrug resistant, and transmissible. PMID- 26574011 TI - Identification of a Pyridoxine-Derived Small-Molecule Inhibitor Targeting Dengue Virus RNA-Dependent RNA Polymerase. AB - The viral RNA-dependent RNA polymerase (RdRp) activity of the dengue virus (DENV) NS5 protein is an attractive target for drug design. Here, we report the identification of a novel class of inhibitor (i.e., an active-site metal ion chelator) that acts against DENV RdRp activity. DENV RdRp utilizes a two-metal ion mechanism of catalysis; therefore, we constructed a small library of compounds, through mechanism-based drug design, aimed at chelating divalent metal ions in the catalytic site of DENV RdRp. We now describe a pyridoxine-derived small-molecule inhibitor that targets DENV RdRp and show that 5 benzenesulfonylmethyl-3-hydroxy-4-hydroxymethyl-pyridine-2-carboxylic acid hydroxyamide (termed DMB220) inhibited the RdRp activity of DENV serotypes 1 to 4 at low micromolar 50% inhibitory concentrations (IC50s of 5 to 6.7 MUM) in an enzymatic assay. The antiviral activity of DMB220 against DENV infection was also verified in a cell-based assay and showed a 50% effective concentration (EC50) of <3 MUM. Enzyme assays proved that DMB220 was competitive with nucleotide incorporation. DMB220 did not inhibit the enzymatic activity of recombinant HIV-1 reverse transcriptase and showed only weak inhibition of HIV-1 integrase strand transfer activity, indicating high specificity for DENV RdRp. S600T substitution in the DENV RdRp, which was previously shown to confer resistance to nucleoside analogue inhibitors (NI), conferred 3-fold hypersusceptibility to DMB220, and enzymatic analyses showed that this hypersusceptibility may arise from the decreased binding/incorporation efficiency of the natural NTP substrate without significantly impacting inhibitor binding. Thus, metal ion chelation at the active site of DENV RdRp represents a viable anti-DENV strategy, and DMB220 is the first of a new class of DENV inhibitor. PMID- 26574012 TI - Inhibition of Pseudomonas aeruginosa ExsA DNA-Binding Activity by N Hydroxybenzimidazoles. AB - The Pseudomonas aeruginosa type III secretion system (T3SS) is a primary virulence determinant and a potential target for antivirulence drugs. One candidate target is ExsA, a member of the AraC family of DNA-binding proteins required for expression of the T3SS. A previous study identified small molecules based on an N-hydroxybenzimidazole scaffold that inhibit the DNA-binding activity of several AraC proteins, including ExsA. In this study, we further characterized a panel of N-hydroxybenzimidazoles. The half-maximal inhibitory concentrations (IC50s) for the tested N-hydroxybenzimidazoles ranged from 8 to 45 MUM in DNA binding assays. Each of the N-hydroxybenzimidazoles protected mammalian cells from T3SS-dependent cytotoxicity, and protection correlated with reduced T3SS gene expression in a coculture infection model. Binding studies with the purified ExsA DNA-binding domain (i.e., lacking the amino-terminal self-association domain) confirmed that the activity of N-hydroxybenzimidazoles results from interactions with the DNA-binding domain. The interaction is specific, as an unrelated DNA-binding protein (Vfr) was unaffected by N-hydroxybenzimidazoles. ExsA homologs that control T3SS gene expression in Yersinia pestis, Aeromonas hydrophila, and Vibrio parahaemolyticus were also sensitive to N hydroxybenzimidazoles. Although ExsA and Y. pestis LcrF share 79% sequence identity in the DNA-binding domain, differential sensitivities to several of the N-hydroxybenzimidazoles were observed. Site-directed mutagenesis based on in silico docking of inhibitors to the DNA-binding domain, and on amino acid differences between ExsA and LcrF, resulted in the identification of several substitutions that altered the sensitivity of ExsA to N-hydroxybenzimidazoles. Development of second-generation compounds targeted to the same binding pocket could lead to drugs with improved pharmacological properties. PMID- 26574013 TI - In Vitro Antimicrobial Activity of a Siderophore Cephalosporin, S-649266, against Enterobacteriaceae Clinical Isolates, Including Carbapenem-Resistant Strains. AB - S-649266 is a novel siderophore cephalosporin antibiotic with a catechol moiety on the 3-position side chain. Two sets of clinical isolate collections were used to evaluate the antimicrobial activity of S-649266 against Enterobacteriaceae. These sets included 617 global isolates collected between 2009 and 2011 and 233 beta-lactamase-identified isolates, including 47 KPC-, 49 NDM-, 12 VIM-, and 8 IMP-producers. The MIC90 values of S-649266 against the first set of Escherichia coli, Klebsiella pneumoniae, Serratia marcescens, Citrobacter freundii, Enterobacter aerogenes, and Enterobacter cloacae isolates were all <=1 MUg/ml, and there were only 8 isolates (1.3%) among these 617 clinical isolates with MIC values of >=8 MUg/ml. In the second set, the MIC values of S-649266 were <=4 MUg/ml against 109 strains among 116 KPC-producing and class B (metallo) carbapenemase-producing strains. In addition, S-649266 showed MIC values of <=2 MUg/ml against each of the 13 strains that produced other types of carbapenemases such as SME, NMC, and OXA-48. The mechanisms of the decreased susceptibility of 7 class B carbapenemase-producing strains with MIC values of >=16 MUg/ml are uncertain. This is the first report to demonstrate that S-649266, a novel siderophore cephalosporin, has significant antimicrobial activity against Enterobacteriaceae, including strains that produce carbapenemases such as KPC and NDM-1. PMID- 26574014 TI - Molecular Characterization of a Voriconazole-Resistant, Posaconazole-Susceptible Aspergillus fumigatus Isolate in a Lung Transplant Recipient in the United States. AB - Molecular characterization of cyp51A from the azole-resistant Aspergillus fumigatus isolate 50593 from a lung transplant patient showed Y121F/T289A changes coupled with a 46-bp tandem repeat (TR46) on the promoter, whereas cyp51A from the pretherapy isolate, A. fumigatus 47381, showed no changes. This is the first reported case of A. fumigatus azole resistance due to Y121F/T289A/TR46 in the United States, suggesting that multiple mutational alterations of cyp51A resulting in high-level azole resistance could occur during prolonged antifungal therapy. PMID- 26574015 TI - Drug Susceptibility and Viral Fitness of HIV-1 with Integrase Strand Transfer Inhibitor Resistance Substitution Q148R or N155H in Combination with Nucleoside/Nucleotide Reverse Transcriptase Inhibitor Resistance Substitutions. AB - In clinical trials of coformulated elvitegravir (EVG), cobicistat (COBI), emtricitabine (FTC), and tenofovir disoproxil fumarate (TDF), emergent drug resistance predominantly involved the FTC resistance substitution M184V/I in reverse transcriptase (RT), with or without the tenofovir (TFV) resistance substitution K65R, accompanied by a primary EVG resistance substitution (E92Q, N155H, or Q148R) in integrase (IN). We previously reported that the RT-K65R, RT M184V, and IN-E92Q substitutions lacked cross-class phenotypic resistance and replicative fitness compensation. As a follow-up, the in vitro characteristics of mutant HIV-1 containing RT-K65R and/or RT-M184V with IN-Q148R or IN-N155H were also evaluated, alone and in combination, for potential interactions. Single mutants displayed reduced susceptibility to their corresponding inhibitor classes, with no cross-class resistance. Viruses with IN-Q148R or IN-N155H exhibited reduced susceptibility to EVG (137- and 40-fold, respectively) that was not affected by the addition of RT-M184V or RT-K65R/M184V. All viruses containing RT-M184V were resistant to FTC (>1,000-fold). Mutants with RT-K65R had reduced susceptibility to TFV (3.3- to 3.6-fold). Without drugs present, the viral fitness of RT and/or IN mutants was diminished relative to that of the wild type in the following genotypic order: wild type > RT-M184V >= IN-N155H ~ IN-Q148R >= RT-M184V + IN-N155H >= RT-M184V + IN-Q148R >= RT-K65R/M184V + IN-Q148R ~ RT K65R/M184V + IN-N155H. In the presence of drug concentrations approaching physiologic levels, drug resistance counteracted replication defects, allowing single mutants to outcompete the wild type with one drug present and double mutants to outcompete single mutants with two drugs present. These results suggest that during antiretroviral treatment with multiple drugs, the development of viruses with combinations of resistance substitutions may be favored despite diminished viral fitness. PMID- 26574016 TI - Selective Inactivity of Pyrazinamide against Tuberculosis in C3HeB/FeJ Mice Is Best Explained by Neutral pH of Caseum. AB - Pyrazinamide (PZA) is one of only two sterilizing drugs in the first-line antituberculosis regimen. Its activity is strongly pH dependent; the MIC changes by several orders of magnitude over a range of pH values that may be encountered in various in vivo compartments. We recently reported selective inactivity of PZA in a subset of C3HeB/FeJ mice with large caseous lung lesions. In the present study, we evaluated whether such inactivity was explained by poor penetration of PZA into such lesions or selection of drug-resistant mutants. Despite demonstrating similar dose-proportional PZA exposures in plasma, epithelial lining fluid, and lung lesions, no dose response was observed in a subset of C3HeB/FeJ mice with the highest CFU burden. Although PZA-resistant mutants eventually replaced the susceptible bacilli in BALB/c mice and in C3HeB/FeJ mice with low total CFU burdens, they never exceeded 1% of the total population in nonresponding C3HeB/FeJ mice. The selective inactivity of PZA in large caseous lesions of C3HeB/FeJ mice is best explained by the neutral pH of liquefying caseum. PMID- 26574017 TI - Efficacy and safety of intermittent preventive treatment for malaria in schoolchildren: a systematic review. AB - BACKGROUND: Intermittent preventive treatment (IPT) is a proven malaria control strategy in infants and pregnancy. School-aged children represent 26 % of the African population, and an increasing percentage of them are scholarized. Malaria is causing 50 % of deaths in this age group and malaria control efforts may shift the malaria burden to older age groups. Schools have been suggested as a platform for health interventions delivery (deworming, iron-folic acid, nutrients supplementation, (boost-)immunization) and as a possible delivery system for IPT in schoolchildren (IPTsc). However, the current evidence on the efficacy and safety of IPTsc is limited and the optimal therapeutic regimen remains controversial. METHODS: A systematic search for studies reporting efficacy and safety of IPT in schoolchildren was conducted using PubMed, Web of Science, Clinicaltrials and WHO/ICTRP database, and abstracts from congresses with the following key words: intermittent, preventive treatment AND malaria OR Plasmodium falciparum AND schoolchildren NOT infant NOT pregnancy. RESULTS: Five studies were identified. Most IPTsc regimes demonstrated substantial protection against malaria parasitaemia, with dihydroartemisinin-piperaquine (DP) given monthly having the highest protective effect (PE) (94 %; 95 % CI 93-96). Contrarily, SP did not provide any PE against parasitaemia. However, no IPT regimen provided a PE above 50 % in regard to anaemia, and highest protection was provided by SP+ amodiaquine (AQ) given four-monthly (50 %; 95 % CI 41-53). The best protection against clinical malaria was observed in children monthly treated with DP (97 %; 95 % CI 87-98). However, there was no protection when the drug was given three monthly. No severe adverse events were associated with the drugs used for IPTsc. CONCLUSION: IPTsc may reduce the malaria-related burden in schoolchildren. However, more studies assessing efficacy of IPT in particular against malaria related anaemia and clinical malaria in schoolchildren must be conducted. PMID- 26574018 TI - Deep sequencing of small RNA facilitates tissue and sex associated microRNA discovery in zebrafish. AB - BACKGROUND: The role of microRNAs in gene regulation has been well established. The extent of miRNA regulation also increases with increasing genome complexity. Though the number of genes appear to be equal between human and zebrafish, substantially less microRNAs have been discovered in zebrafish compared to human (miRBase Release 19). It appears that most of the miRNAs in zebrafish are yet to be discovered. RESULTS: We sequenced small RNAs from brain, gut, liver, ovary, testis, eye, heart and embryo of zebrafish. In brain, gut and liver sequencing was done sex specifically. Majority of the sequenced reads (16-62 %) mapped to known miRNAs, with the exception of ovary (5.7 %) and testis (7.8 %). Using the miRNA discovery tool (miRDeep2), we discovered novel miRNAs from the unannotated reads that ranged from 7.6 to 23.0 %, with exceptions of ovary (51.4 %) and testis (55.2 %). The prediction tool identified a total of 459 novel pre-miRNAs. We compared expression of miRNAs between different tissues and between males and females to identify tissue associated and sex associated miRNAs respectively. These miRNAs could serve as putative biomarkers for these tissues. The brain and liver had highest number of tissue associated (22) and sex associated (34) miRNAs, respectively. CONCLUSIONS: This study comprehensively identifies tissue and sex associated miRNAs in zebrafish. Further, we have discovered 459 novel pre miRNAs (~30 % seed homology to human miRNA) as a genomic resource which can facilitate further investigations to understand miRNA-mRNA gene regulatory networks in zebrafish which will have implications in understanding the function of human homologs. PMID- 26574019 TI - Safety and efficacy of an olive oil-based triple-chamber bag for parenteral nutrition: a prospective, randomized, multi-center clinical trial in China. AB - BACKGROUND: Small studies suggest differences in efficacy and safety exist between olive oil-based (OLIVE) and soybean oil-based (SOYBEAN) parenteral nutrition regimens in hospitalized adult patients. This large, prospective, randomized (1:1), open-label, multi-center, noninferiority study compared the delivery, efficacy, and safety of OLIVE (N = 226) with SOYBEAN (N = 232) in Chinese adults (>=18 years) admitted to a surgical service for whom parenteral nutrition was required. METHODS: Treatments were administered for a minimum of 5 days up to 14 days (to achieve approximately 25 kcal/kg/day, 0.9 g/kg/day amino acids, 0.8 g/kg/day lipid). Impact of treatment on anabolic/catabolic and serum inflammatory, chemistry, and hematological markers, safety, and ease of use were assessed. The primary efficacy variable was serum prealbumin level at Day 5. RESULTS: OLIVE (n = 219) was not inferior to SOYBEAN (n = 224) based on the prealbumin least square geometric mean [LSGM] ratio [95% CI] 1.12 [1.06, 1.19]; P = 0.002), improved the anabolic/catabolic status of patients enrolled in the study, and was well tolerated compared with SOYBEAN. Improved anabolic status was supported by significantly higher levels of prealbumin at Day 5, albumin at Day 5 and IGF-1 at Day 14 in the OLIVE group, while catabolism was similar between groups. C-reactive protein, intercellular adhesion molecule-1, procalcitonin, and oxidation were similar in each group, but infections were significantly lower with OLIVE (3.6% versus 10.4%; P < 0.01). CONCLUSIONS: OLIVE provided effective nutrition, was well tolerated, was associated with fewer infections, and conferred greater ease-of-use than SOYBEAN. TRIAL REGISTRATION: NTC 01579097. PMID- 26574020 TI - The New Kid on the Block--Incorporating Buprenorphine into a Medical Toxicology Practice. AB - Buprenorphine represents a safe and effective therapy for treating opioid dependence, alleviating craving and withdrawal symptoms in opioid-dependent patients. Buprenorphine has a "blocking" effect against the action of other opioids at the mu-receptor, preventing not only opioid-induced euphoria, but CNS and respiratory depressant effects as well. Buprenorphine was approved for the treatment of opioid dependence in 2002 after the passage of Drug Abuse Treatment Act 2000 (DATA 2000) which allowed clinicians to treat opioid-dependent patients with specifically named opioid agonist therapies in an office setting. Buprenorphine programs reduce the prevalence of HIV and hepatitis C and reduce criminal behaviors associated with illicit drug use. Patients stabilized on buprenorphine have increased employment, enhanced engagement with social services, and better overall health and well-being. PMID- 26574021 TI - Ethical Standards Help to Define the Medical Toxicologist. PMID- 26574022 TI - In Response to: "Comparison of Prothrombin Time and Aspartate Aminotransferase in Predicting Hepatotoxicity After Acetaminophen Overdose.". PMID- 26574024 TI - Effects of abhydrolase domain containing 5 gene (ABHD5) expression and variations on chicken fat metabolism. AB - Abhydrolase domain containing 5 gene (ABHD5), also known as comparative gene identification 58 (CGI-58), is a member of the alpha/beta-hydrolase family as a protein cofactor of ATGL stimulating its triacylglycerol hydrolase activity. In this study, we aim to characterize the expression and variations of ABHD5 and to study their functions in chicken fat metabolism. We compared the ABHD5 expression level in various tissues and under different nutrition conditions, identified the variations of ABHD5, and associated them with production traits in an F2 resource population of chickens. Overexpression analysis with two different genotypes and siRNA interfering analysis of ABHD5 were performed in chicken preadipocytes. Chicken ABDH5 was expressed widely and most predominantly in adipose tissue. Five SNPs of the ABHD5 gene were identified and genotyped in the F2 resource population. The c.490C > T SNP was associated with subcutaneous fat thickness (P < 0.01), carcass weight (P < 0.05), body weight (P < 0.05), shank diameter (P < 0.05), and shank length (P < 0.05). The c.423T > C SNP was also associated with chicken body weight (P < 0.05) and shank diameter (P < 0.05). In chicken preadipocytes, overexpression of wild type ABDH5 did not affect the mRNA level of ATGL (adipose triglyceride lipase) but markedly decreased (P < 0.05) the TG (triglyceride) content of the cell, whereas overexpression of mutation type ABHD5 did not affect either ATGL expression or TG content of the cell. The expression of ATGL and TG content of the cell were decreased (P < 0.05) after ABHD5 knockdown in preadipocytes. The mRNA level of ABHD5 was regulated by both feeding and fasting, and by consumption of a high fat diet. It was increased greatly by fasting (P < 0.05) and was returned to control levels after re-feeding in the adipose tissues, and down-regulated in abdominal fat (P < 0.05) and the liver (P < 0.01) of chickens with a high fat diet. These results suggest that expression and variations of ABHD5 may affect fat metabolism through regulating the activity of ATGL in chickens. PMID- 26574025 TI - Survey of egg farmers regarding the ban on conventional cages in the EU and their opinion of alternative layer housing systems in Flanders, Belgium. AB - On 1 January 2012, conventional cages for laying hens were banned in the European Union (EU); all egg farmers must now use alternative hen housing systems. In total, 218 Flemish egg farmers were surveyed in 2013 to 2014 regarding which housing systems they currently use, their degree of satisfaction with the system, and how they experienced the transition from conventional cages to an alternative system. The response rate was 58.3% (127 respondents). Of these, 43 (33.9%) were no longer active as an egg farmer, mainly due to the ban on conventional cages. The respondents who were active as egg farmers both before and after the transition (84, 66.1%) mainly judged the ban as negative for their own finances and for the competitive position of the Belgian egg industry, but were neutral or positive regarding the general consequences for their own business. Most respondents' hens were housed in either aviary systems (47.7%) or in alternative cage systems (38.2%). When choosing a new system, the fit into the farm and consumer demand were the most important factors. Consumer demand was the main reason for choosing a system with free-range access. In general, egg farmers were satisfied with the system they chose, although this differs between systems. When asked to compare the alternative systems to conventional cages, alternatives were judged to be better for hen welfare and consumer demand, but similar or worse for all other aspects, especially labor. Egg farmers previously using conventional cages judged alternative systems more negatively than those who had no prior experience with conventional cages. Farmers who had experience with free-range systems judged these more positively than those without this experience, e.g., for egg consumer demand, profitability, and hen welfare. These results can possibly be extrapolated to other EU countries in which conventional cages were the most common housing system until 2012, and lessons can be drawn from the farmers' experiences when implementing other animal welfare legislation that may require similar far-reaching adaptations for primary production. PMID- 26574023 TI - Ion efflux and influenza infection trigger NLRP3 inflammasome signaling in human dendritic cells. AB - The nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome, a multiprotein complex, is an essential intracellular mediator of antiviral immunity. In murine dendritic cells, this complex responds to a wide array of signals, including ion efflux and influenza A virus infection, to activate caspase-1-mediated proteolysis of IL-1beta and IL-18 into biologically active cytokines. However, the presence and function of the nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome in human dendritic cells, in response to various triggers, including viral infection, has not been defined clearly. Here, we delineate the contribution of the nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome to the secretion of IL-1beta, IL-18, and IL-1alpha by human dendritic cells (monocyte-derived and primary conventional dendritic cells). Activation of the nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome in human dendritic cells by various synthetic activators resulted in the secretion of bioactive IL 1beta, IL-18, and IL-1alpha and induction of pyroptotic cell death. Cellular IL 1beta release depended on potassium efflux and the activity of proteins nucleotide-binding oligomerization domain-like receptor protein 3 and caspase-1. Likewise, influenza A virus infection of dendritic cells resulted in priming and activation of the nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome and secretion of IL-1beta and IL-18 in an M2- and nucleotide binding oligomerization domain-like receptor protein 3-dependent manner. The magnitude of priming by influenza A virus varied among different strains and inversely corresponded to type I IFN production. To our knowledge, this is the first report describing the existence and function of the nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome in human dendritic cells and the ability of influenza A virus to prime and activate this pathway in human dendritic cells, with important implications for antiviral immunity and pathogenesis. PMID- 26574026 TI - Effect of insoluble fiber supplementation applied at different ages on digestive organ weight and digestive enzymes of layer-strain poultry. AB - Two experiments were conducted to study effects of dietary insoluble fiber (IF) on digestive enzyme function in layer poultry. In Experiment 1, 8 wk old pullets were fed a control diet (Group C) or a diet (Group IF) supplemented with 1% IF (Arbocel RC). After 5 wk, 6 pullets per group were killed and organ samples collected. The remaining pullets in Group C were divided into two groups: half were fed the control diet (Group C) and half were given the IF diet (Group C-IF). Similarly, half the pullets in Group IF continued on the IF diet (Group IF) and half on the control diet (Group IF-C). At 10 wk, organ samples were collected. BW at wk 5 (IF, 1364.8 g; C, 1342.9 g) and 10 wk (IF, 1678.1 g; IF-C, 1630.5 g; C IF, 1617.1 g; C, 1580.4 g) were not different. At wk 5, the relative proventricular weight (0.41 g/100 g BW) and activities of pepsin (75.3 pepsin units/g proventriculus/min) and pancreatic general proteolytic activity (GP) (122.9 MUmol tyrosine produced/g tissue) were greater (P < 0.05) than those of Group C (proventricular relative weight, 0.36; pepsin activity, 70.6; GP activity, 94.3). At wk 10, relative weights of liver and gizzard of Group IF were heavier (P < 0.05) than other treatments; activities of pepsin, GP, trypsin and chymotrypsin of IF pullets were significantly greater than other treatments as was mRNA expression for pepsinogens A (25.9 vs. 22.9) and C (13.1 vs. 10.8). In Experiment 2, 19 wk old hens were fed a control diet or a diet containing 0.8% IF (Arbocel RC) for 12 wk. Final BW after 12 wk was not different (IF, 1919.4 g; C, 1902.1 g). Pancreatic GP activity was greater (P < 0.05) in Group IF hens than Group C at wk 12 (122.2 vs. 97.0 MUmol tyrosine released/min/g tissue)) as was relative gizzard weight (1.32 vs 1.10 g/100 g BW). The significantly improved digestive organ weights and enzyme activities in IF pullets may contribute to an improvement in feed utilization. PMID- 26574027 TI - Effect of light-emitting diode (LED) vs. fluorescent (FL) lighting on laying hens in aviary hen houses: Part 2 - Egg quality, shelf-life and lipid composition. AB - In this 60-wk study, egg quality, egg shelf-life, egg cholesterol content, total yolk lipids, and yolk fatty acid composition of eggs produced by Dekalb white laying hens in commercial aviary houses with either light-emitting diode (LED) or fluorescent (FL) lighting were compared. All parameters were measured at 27, 40, and 60 wk of age, except for egg shelf-life, which was compared at 50 wk of age. The results showed that, compared to the FL regimen, the LED regimen resulted in higher egg weight, albumen height, and albumen weight at 27 wk of age, thicker shells at 40 wk of age, but lower egg weight at 60 wk of age. Egg quality change was similar between the lighting regimens during the 62-d egg storage study, indicating that LED lighting did not influence egg shelf-life. Eggs from both lighting regimens had similar cholesterol content. However, cholesterol concentration of the yolk (15.9 to 21.0 mg cholesterol/g wet weight yolk) observed in this study was higher than that of United States Department of Agriculture (USDA) database (10.85 mg/g). No significant differences in total lipids or fatty acid composition of the yolks were detected between the two lighting regimens. PMID- 26574028 TI - Effect of feed grinding methods with and without expansion on prececal and total tract mineral digestibility as well as on interior and exterior egg quality in laying hens. AB - The grinding of cereals by various milling methods as well as thermal treatment of feed may influence mineral digestibility and egg quality. The present study investigated the effect of feed produced by disc mill (D) and wedge-shaped disc mill (WSD), as mash (M) or expandate (E) on apparent ileal absorption (AIA) and apparent total digestibility (ATD) of calcium, phosphorus, magnesium, zinc, manganese, copper and iron, as well as on egg quality in laying hens. A total of 192 hens (Lohmann Brown) aged 19 wk, were assigned using a randomized design with a 2 * 2 factorial arrangement. Four experimental diets were offered ad libitum. Eggs were analyzed for weight, shape index, area, shell weight per unit surface area, yolk color, air cell, blood spot, Haugh unit, albumen and yolk measures (index, weight, height, width and length), shell measures (surface area, stability, density, thickness and membrane weight), as well as percent contents of albumen, yolk, shell, and shell membrane. The ATD for phosphorus, manganese, and copper was higher in WSD compared with D treatment (P = 0.028, P = 0.028 and P = 0.016, respectively). The interaction between milling methods and thermal treatment influenced ATD of copper (P = 0.033), which was higher in WSD+M group (41.0 +/- 20.2) compared with D+E group (-3.21 +/- 25.1), whereas no differences were observed for D+M (1.90 +/- 37.8) and WSD+E (8.02 +/- 36.2) groups. Egg stability tended to be higher in E compared with M treatment (P = 0.055). Albumen weight, percentage albumen weight, and albumen: yolk were higher and percentage yolk weight was lower in D compared with WSD treatment (P = 0.043, P = 0.027, P = 0.024, and P = 0.041, respectively). Number of blood spots was higher in E than M treatment (P = 0.053). In conclusion, use of a wedge-shaped disc mill resulted in higher ATD for phosphorus, manganese, and copper than use of a disc mill; however, digestibility for majority of minerals as well as egg quality parameters was comparable. Therefore, feed produced by either disc mill or wedge-shaped disc mill as mash or expandate may be used for laying hens without negative effects on egg quality. PMID- 26574029 TI - Dietary vitamin A supplementation improved reproductive performance by regulating ovarian expression of hormone receptors, caspase-3 and Fas in broiler breeders. AB - The effects of dietary vitamin A (VA) supplementation on reproductive performance, VA deposition, and potential mechanisms of action were studied in Chinese yellow-feathered broiler breeders. A total of 528 yellow-feathered broiler breeders that were 46 wk old were fed a corn-soybean meal basal diet supplemented with 0; 5,400; 10,800; or 21,600 IU/kg VA for 9 wk. Each dietary treatment had 6 replicates with 22 birds per replicate. After 7 wk of treatment, 60 settable eggs per replicate were collected for hatching. The results showed that dietary VA improved the laying rate, egg-to-feed ratio, and hatch weight of offspring (P < 0.05). Hepatic retinyl palmitate in broiler breeders and hatchlings (within 12 h) increased with increasing VA (P < 0.05). VA supplementation increased insulin-like growth factor 1 (IGF-I) receptor transcripts in the ovarian stroma and the walls of yellow follicles, follicle stimulating hormone (FSH) receptor expression in the walls of white and yellow follicles, and luteinizing hormone (LH) receptor and growth hormone (GH) receptor transcripts in the walls of yellow follicles (P < 0.05). Caspase-3 and Fas mRNA levels in the ovarian stroma and the walls of white and yellow follicles decreased with VA supplementation (P < 0.05). The relative expression of retinol dehydrogenase 10 (RDH10) transcripts in the walls of white follicles increased with 5,400 IU/kg VA supplementation (P < 0.05). Supplemental 21,600 IU/kg VA increased cytochrome P450 26A1 (CYP26A1) transcripts in the ovarian stroma and the walls of white follicles (P < 0.05). Dietary VA elevated retinoic acid receptor alpha (RARalpha) expression in the ovarian stroma and the walls of yellow follicles and retinoid X receptor alpha (RXRalpha) expression in the walls of yellow follicles. It was concluded that VA supplementation improved reproductive performance and hepatic storage of VA, and this was associated with the regulation of ovarian hormone receptor expression and suppression of apoptosis gene transcripts through its active metabolite retinoic acid (RA). The optimal dietary VA level for Chinese yellow-feathered broiler breeders at 46 to 54 wk of age was found to be 10,800 IU/kg. PMID- 26574030 TI - Exudate Protein Composition and Meat Tenderness of Broiler Breast Fillets. AB - The relationship between meat tenderness and the protein composition of muscle exudates collected from broiler breast fillets deboned at different postmortem times was investigated. A total of 85 broilers were processed and breast fillets from each carcass were deboned at either 2 h (early-deboned, EB) or 24 h (control) postmortem. One fillet per carcass was used for 1 d postmortem meat tenderness measurements and the other fillet was stored at 4 degrees C until 6 d postmortem for the collection of exudate prior to tenderness evaluation. Protein content and composition of muscle exudates were determined by a biuret assay and SDS-PAGE. Fillet pH, color, drip loss, and cook loss were also measured. Early deboned fillets exhibited greater (P < 0.05) Warner-Bratzler shear force (WBSF) than controls at 1 d (7.4 vs. 3.1 kg) and 6 d (4.1 vs. 2.5 kg). Deboning time did not influence pH or color values (L*a*b*). Control fillets exhibited less drip loss after 6 d of storage (P = 0.005) and less cook loss at 1 and 6 d (P < 0.001). Exudate protein concentration was not influenced by deboning time. From the SDS-PAGE profiles of the exudates, the relative abundances of seventeen protein bands were quantified. Electrophoresis analysis revealed that, in general, the protein profiles of exudates from control and EB fillets were not distinct from each other. However, the band corresponding to 225 kDa was more abundant in controls (P = 0.021). Although the protein concentrations and SDS PAGE profiles of muscle exudates varied widely between breast fillets, variations in exudate protein characteristics were not strongly associated with changes in the tenderness of broiler breast meat due to the combined effects of postmortem deboning time and post-deboning aging. PMID- 26574031 TI - Wild-type and mutant AvrA- Salmonella induce broadly similar immune pathways in the chicken ceca with key differences in signaling intermediates and inflammation. AB - Salmonella enterica serovar Typhimurium (ST) is a serious infectious disease throughout the world, and a major reservoir for Salmonella is chicken. Chicken infected with Salmonella do not develop clinical disease, this may be the result of important host interactions with key virulence proteins. To study this, we inoculated chicken with mutant Salmonella Typhimurium that lacked the virulence protein AvrA (AvrA(-)). AvrA is referred to as an avirulence factor, as it moderates the host immune response. The lack of the AvrA virulence gene in ST resulted in reduced weight gain, enhanced persistence and greater extraintestinal organ invasion in chickens, as compared to wild-type (WT) ST. Kinome analysis was performed on inoculated cecal tissue. The majority of the signal transduction pathways induced by AvrA(-) and WT ST were similar; however, we observed alterations in innate immune system signaling. In addition, a leukocyte migration pathway was altered by AvrA(-) ST that may allow greater gut barrier permeability and invasion by the mutant. Cytokine expression did not appear significantly altered at 7 d post-inoculation; at 14 d post-inoculation, there was an observed increase in the expression of anti-inflammatory IL-10 in the WT inoculated ceca. This study is the first to describe mutant AvrA(-) ST infection of chicken and provides further insight into the Salmonella responses observed in chicken relative to other species such as humans and cattle. PMID- 26574032 TI - Xanthophyll supplementation regulates carotenoid and retinoid metabolism in hens and chicks. AB - This study investigated the effects of xanthophylls (containing 40% lutein and 60% zeaxanthin; Juyuan Biochemical Co., Ltd., GuangZhou, China) on gene expression associated with carotenoid cleavage enzymes (beta-carotene 15, 15' monooxygenase, BCMO1; and beta-carotene 9', 10'-dioxygenase, BCDO2) and retinoid metabolism (lecithin:retinol acyl transferase (LRAT) and STRA6) of breeding hens and chicks. In experiment 1, 432 hens were divided into 3 groups and fed diets supplemented with zero (as the control group), 20, or 40 mg/kg xanthophyll. The liver, duodenum, jejunum, and ileum were sampled at d 35 of the trial. Results showed that 40 mg/kg xanthophyll supplementation increased BCDO2 mRNA in the liver, duodenum, and jejunum; LRAT mRNA in the jejunum; and STRA6 mRNA in the liver, while it decreased LRAT mRNA in the liver. Experiment 2 was a 2 * 2 factorial design. Male chicks hatched from a zero or 40 mg/kg xanthophyll diet of hens were fed a diet containing either zero or 40 mg/kg xanthophylls. The liver, duodenum, jejunum, and ileum were sampled at zero, 7, 14, and 21 d after hatching. Results showed that in ovo xanthophyll modulated carotenoid and retinoid metabolism mainly within one wk after hatching. The maternal effects gradually vanished and dietary effects began to work one to 2 wk after hatching. Dietary xanthophyll regulated carotenoid and retinoid metabolism mainly from 2 wk onward. The xanthophyll regulation of carotenoid and retinoid metabolism also revealed strong tissue specificity. In conclusion, xanthophyll supplementation could modulate carotenoid and retinoid metabolism in different tissues of hens and chicks. PMID- 26574033 TI - Inclusion of insoluble fiber sources in mash or pellet diets for young broilers. 1. Effects on growth performance and water intake. AB - The effects of feed form and the inclusion of insoluble fiber in the diet on growth performance and water intake were studied in female broilers from 0 to 21 d of age. The experimental design was completely randomized with 14 treatments arranged as a 2 * 7 factorial with 2 feed forms (mash vs. pelleted) and 7 diets that consisted of a control diet low in fiber (1.6% crude fiber) based on broken rice, fermented soybean meal, and fish meal and 6 extra diets that resulted from the inclusion of 3 insoluble fiber sources (oat hulls; OH, rice hulls; RH, and sunflower hulls; SFH) at 2 levels (2.5 vs. 5%). Each treatment was replicated 6 times. Broilers fed pellets had 32% greater ADG and 3% better feed to gain ratio (F:G) than those fed mash (P <= 0.001). The inclusion of the fiber sources improved ADG (P <= 0.05) and F:G (P <= 0.05). Pelleting increased (P <= 0.001) water intake from 6 to 8 d, water-to-feed intake ratio from 18 to 20 d, and moisture content of the excreta at 20 d of age. The inclusion of the insoluble fiber sources increased water intake (P <= 0.05) from d 18 to 20 but not from d 6 to 8. Increasing the level of fiber inclusion from 2.5 to 5.0% tended to increase (P = 0.086) moisture content in the excreta at d 20. Pelleting and the inclusion of insoluble fiber sources improved ADG and F:G in broilers fed low-fiber diets, and the improvements observed were more pronounced with pellets than with mash. Growth performance of young broilers improves with the addition of moderate amounts of structural insoluble fiber in the diet, regardless of feed form. The inclusion of OH or SFH into low fiber diets was more beneficial for improving broiler performance than the inclusion of RH. PMID- 26574034 TI - Expression of small intestinal nutrient transporters in embryonic and posthatch turkeys. AB - Nutrients are absorbed in the small intestine through a variety of transporter proteins, which have not been as well characterized in turkeys as in chickens. The objective of this study was to profile the mRNA expression of amino acid and monosaccharide transporters in the small intestine of male and female turkeys. Jejunum was collected during embryonic development (embryonic d 21 and 24, and d of hatch (DOH)) and duodenum, jejunum, and ileum were collected in a separate experiment during posthatch development (DOH, d 7, 14, 21, and 28). Real-time PCR was used to determine expression of aminopeptidase N (APN), one peptide (PepT1), 6 amino acid (ASCT1, b(o,+)AT, CAT1, EAAT3, LAT1, y(+)LAT2) and 3 monosaccharide (GLUT2, GLUT5, SGLT1) transporters. Data were analyzed by ANOVA using JMP Pro 11.0. APN, b(o,+)AT, PepT1, y(+)LAT2, GLUT5, and SGLT1 showed increased expression from embryonic d 21 and 24 to DOH. During posthatch, all genes except GLUT2 and SGLT1 were expressed greater in females than males. GLUT2 was expressed the same in males as females and SGLT1 was expressed greater in males than females. All basolateral membrane transporters were expressed greater during early development then decreased with age, while the brush border membrane transporters EAAT3, GLUT5, and SGLT1 showed increased expression later in development. Because turkeys showed high-level expression of the anionic amino acid transporter EAAT3, a direct comparison of tissue-specific expression of EAAT3 between chicken and turkey was conducted. The anionic amino acid transporter EAAT3 showed 6-fold greater expression in the ileum of turkeys at d 14 compared to chickens. This new knowledge can be used not only to better formulate turkey diets to accommodate increased glutamate transport, but also to optimize nutrition for both sexes. PMID- 26574035 TI - Effects of postmortem temperature on the physicochemical characteristics of prerigor Pekin duck breast muscles. AB - The effects of postmortem (PM) temperature on prerigor Pekin duck breast muscle quality were assessed. Breast meat was obtained from 90 ducks within 15 min PM and then divided into 3 storage temperature groups at 0, 15, and 30 degrees C for 24 h PM. Results revealed that the meat stored at 0 degrees C had a higher pH value than that stored at 30 degrees C. The R-value tended to increase between 15 min, 2 h, and 24 h PM, whereas the water-holding capacity decreased significantly (P < 0.05) with increasing storage time. The drip loss of treatment in meat stored at 30 degrees C was higher than in those stored at 0 and 15 degrees C. As storage periods increased, cooking loss of meat stored at each temperature increased significantly (P < 0.05) at 2 h, but storage temperature does not affect cooking loss of duck breast muscle. The shear force of breast meat at 24 h PM had the lowest value, but meat stored at 30 degrees C increased at 2 h and decreased at 24 h PM. Meat stored at 15 degrees C showed a longer sarcomere length than meat stored at 0 and 30 degrees C. The rate of muscle shortening was high during the 2 h PM for meat at the 3 temperatures. It is concluded that the different temperatures in the range of 0 to 30 degrees C affected the muscle shortening or meat quality of the duck breast meat. PMID- 26574036 TI - Replacing soybean meal with gelatin extracted from cow skin and corn protein concentrate as a protein source in broiler diets. AB - Two experiments were conducted to investigate the effects of replacing soybean meal with gelatin extracted from cow skin and corn protein concentrate as a protein source in broiler diets. Experiments were carried out as a completely randomized design where each experiment involved 4 treatments of 6 replicates and 10 chicks in each pen. Soybean meal proteins in a corn-soy control diet were replaced with 15, 30, and 45% of cow skin gelatin (CSG) or corn protein concentrate (CPC), respectively, in experiments 1 and 2. BW and cumulative feed intake were measured at 7, 21, and 42 d of age. Blood characteristics, relative organs weight and length, ileal digesta viscosity, ileal morphology, and cecal coliform and Salmonella population were measured at 42 d of age. Apparent total tract digestibility of protein was determined during 35 to 42 d of age. Replacement of soybean meal with CSG severely inhibited BW gain, decreased feed intake, and increased FCR in broilers during the experimental period (P <= 0.01). The inclusion of CPC reduced BW and increased FCR significantly (P <= 0.05) at 21 and 42 d of age without any consequence in feed intake. Protein digestibility was reduced and ileal digesta viscosity was increased linearly by increasing the amount of CSG and CPC in the control diet (P <= 0.01). Replacement of soybean meal with CSG and CPC did not significantly alter blood cell profile and plasma phosphorus, creatinine, blood urea nitrogen, Aspartate transaminase, and HDL and LDL cholesterol concentration. The inclusion of CSG linearly (P <= 0.05) increased plasma uric acid concentration and alkaline phosphatase activity. Triglyceride and cholesterol levels were decreased significantly (P <= 0.05) when the amount of CSG replacement was 15%. The results of this experiment showed that using CSG and CPC negatively affects broiler performance and therefore is not a suitable alternative to soybean meal in commercial diets. PMID- 26574037 TI - Evaluating best practices for Campylobacter and Salmonella reduction in poultry processing plants. AB - Poultry processing plants in the United States were surveyed on their current Campylobacter and Salmonella control practices. Following surveys, data were collected to develop a baseline for prevalence rates of Salmonella and Campylobacter; then changes in practices were implemented and evaluated for improvements in pathogen control. Surveys were sent to the plant Quality Assurance managers to determine production levels, antimicrobial interventions, and current pathogen testing practices. Initial sampling was performed at 6 plants with similar production volumes, at sites that included carcass samples before any pre-evisceration intervention, after exiting the inside-outside bird washer (IOBW), after exiting the pre-chiller, after exiting the primary chiller, and after exiting any post-chill intervention, as well as a water sample from each scalder, pre-chiller, primary chiller, and post-chill dip tank or finishing chiller. Enumerations and enrichments were performed for Campylobacter and Salmonella. Following the baseline sampling, changes in practices were suggested for each plant and a second sampling was conducted to determine their effectiveness. Results demonstrated that peracetic acid (PAA) was the most effective (P < 0.05) antimicrobial currently in use. The use of a post-chill antimicrobial immersion tank and/or use of a cetylpyridinium chloride (CPC) spray cabinet also displayed a further reduction in microbial levels (P < 0.05) when the primary chiller was not sufficient (P > 0.05). Microbial buildup in the immersion tanks demonstrates the need for effective cleaning, sanitation practices, and chiller maintenance to reduce contamination of poultry with Campylobacter and Salmonella. PMID- 26574038 TI - Antioxidant status of turkey breast meat and blood after feeding a diet enriched with histidine. AB - The objective of this study was to investigate the effects of 1) spray dried blood cells rich in histidine and 2) pure histidine added to feed on the antioxidant status and concentration of carnosine related components in the blood and breast meat of female turkeys. The experiment was performed on 168 Big7 turkey females randomly assigned to 3 dietary treatments: control; control with the addition of 0.18% L-histidine (His); and control with the addition of spray dried blood cells (SDBC). Birds were raised for 103 d on a floor with sawdust litter, with drinking water and feed ad libitum. The antioxidant status of blood plasma and breast muscle was analyzed by ferric reducing ability (FRAP) and by 2,2-Azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and 1,1-Diphenyl-2 picrylhydrazyl (DPPH) radicals scavenging ability. The activity of antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) was analyzed in the blood and breast meat, with the content of carnosine and anserine quantified by HPLC. Proximate analysis as well as amino acid profiling were carried out for the feed and breast muscles. Growth performance parameters also were calculated. Histidine supplementation of the turkey diet resulted in increased DPPH radical scavenging capacity in the breast muscles and blood, but did not result in higher histidine dipeptide concentrations. The enzymatic antioxidant system of turkey blood was affected by the diet with SDBC. In the plasma, the SDBC addition increased both SOD and GPx activity, and decreased GPx activity in the erythrocytes. Feeding turkeys with an SDBC containing diet increased BW and the content of isoleucine and valine in breast muscles. PMID- 26574039 TI - Impact of combined beta-glucanase and xylanase enzymes on growth performance, nutrients utilization and gut microbiota in broiler chickens fed corn or wheat based diets. AB - The effects of a xylanase and beta-glucanase (XB) blend (2,500 U of xylanase and 250 U of beta-glucanase per kg of complete feed) on growth performance, nutrients utilization and digesta microbiota in broiler chickens were investigated. A total of 140 day-old male Ross 308 broiler chicks were randomly assigned to 7 replicate cages and fed experimental diets. Diets were based on either corn or wheat without or with supplemental XB. Performance was monitored weekly and excreta were collected from d 17 to 20 for nutrients digestibility and AMEn measurements. On d 21, jejunal contents were collected for viscosity determination whereas ileal and cecal contents were obtained for microbial analysis by Illumina sequencing. Microbial data were analyzed using QIIME and PLS-DA whilst other data were analyzed using SAS. Birds fed wheat diets had higher (P < 0.001) BWG (3.4%) than birds fed corn-based diet whilst birds fed XB had better BWG (4%) and FCR (7%) than birds fed non-XB diets. Birds fed wheat diet had higher (P < 0.001) NDF (46.5%) and less (P = 0.01) CP (-5.4%) digestibility compared to birds fed corn based diet. XB reduced (P < 0.001) jejunal digesta viscosity to a greater extent in wheat diet (-31%) than in corn-based diet (-10%). Birds fed wheat-based diet with XB had higher (3.5%) starch digestibility than birds fed this diet without XB. Janthinobacterium was associated with non-XB corn-based diet, whereas Ruminococcus, Lachnospiraceae, Lactobacillaceae, Peptostreptococcaceae, Clostridiales, Acidovorax and Blautia were associated with XB corn-based diet in the ileum. A relatively similar microbiome clustering was observed in wheat-based treatments in the cecum. There were no significant (P >= 0.05) correlations between selected ileal or cecal bacterial taxa and AMEn. Diet impacted growth performance but XB was efficacious across diet types, implying that degradation of dietary fibrous components by feed enzymes may stimulate performance in young birds. Data provided significant insight on ileal and cecal microbial profile associated with the dietary types and XB; however their functional roles require further investigations. PMID- 26574040 TI - Granulosa cell responsiveness to follicle stimulating hormone during early growth of hen ovarian follicles. AB - In the laying hen ovary, the cyclic recruitment of a follicle represents a process in which a single follicle is selected to enter the rapid growth phase and undergo final maturation prior to ovulation. Published data support the proposal that final differentiation of the granulosa cell (GC) layer commences at the time of follicle selection. This process is characterized by the enhanced capacity for FSH-induced cell signaling via the protein kinase A/cyclic adenosine monophosphate (cAMP) pathway. One consequence of such signaling within the GC layer is the initial capacity for steroidogenesis (predominantly progesterone production) mediated by increased expression of mRNA encoding steroidogenic acute regulatory protein (STAR) and the cholesterol side-chain cleavage enzyme (CYP11A). Prior to selection, the GC layer remains minimally responsive to a 3 h challenge with FSH (10 ng/mL), in vitro, compared to that from the most recently selected 9- to 12-mm follicle. By comparison, when the duration of the cell culture prior to FSH challenge is increased to 18 h, GCs collected from 1- to 2 mm, 3- to 5-mm, and 6- to 8-mm follicles respond to a 3 h FSH challenge by increasing STAR expression and progesterone production, with the greatest response from GCs collected from 6- to 8-mm follicles. Culture with Bone Morphogenetic Protein 6 (BMP6) enhances both CYP11A expression and FSH responsiveness at each stage of development, with the greatest response again occurring in GCs from 6- to 8-mm follicles. Significantly, factors that activate mitogen activated protein kinase (MAPK) or protein kinase C (PKC) signaling prevent the ability of prolonged culture or culture with BMP6 to induce FSH responsiveness and the initiation of GC differentiation at each stage of development. Collectively, these results provide further support for the hypothesis that prior to follicle selection, inhibitory cell signaling (e.g., MAPK, PKC) maintains the GC layer in an undifferentiated state in follicles of all sizes, even in the presence of a differentiation-promoting signal (BMP6). The process by which the GC layer from the single 6- to 8-mm follicle selected each ovulatory cycle ultimately escapes inhibitory signaling to initiate FSH responsiveness remains to be established. PMID- 26574041 TI - New Approaches to Continuing Medical Education: a QStream (spaced education) Program for Research Translation in Ovarian Cancer. AB - Continuing medical education (CME) is challenging and often has limited impact on clinician behavior or patient outcomes. This study examined the impact of an online Qstream education program on senior clinicians to determine its utility for increasing clinician knowledge about the latest guidelines regarding genetic assessment and consideration of genetic testing for women with particular types of ovarian, fallopian tube and primary peritoneal cancer. Participants were recruited into a pilot study that involved responding to case-based scenarios at spaced and repeated intervals. At the completion of the program, semi-structured interviews were conducted to ascertain the impact on their knowledge and referral behavior. Findings from interviews were subject to thematic analysis that involved the identification of categories and themes. Twenty-one participants commenced the program, seventeen completed and twelve participated in semi structured interviews. Thematic analysis yielded several themes including knowledge change, curriculum and format and changes in referral patterns. A majority of participants (n = 10) agreed the program had helped update their knowledge about referring women, and eight agreed they would now change their referral patterns. The use of QStream as an approach to CME has significant advantages when working with busy clinicians. QStream has a well accepted format and most participants indicated it is very appropriate for disseminating updates to clinical guidelines and protocols. It is important to supplement CME programs with other implementation techniques, such as audit and feedback as multifaceted approaches are more likely to result in behavior change. PMID- 26574042 TI - Characterization of phthiocerol and phthiodiolone dimycocerosate esters of M. tuberculosis by multiple-stage linear ion-trap MS. AB - Both phthiocerol/phthiodiolone dimycocerosate (PDIM) and phenolic glycolipids are abundant virulent lipids in the cell wall of various pathogenic mycobacteria, which can synthesize a wide range of complex high-molecular-mass lipids. In this article, we describe linear ion-trap MS(n) mass spectrometric approach for structural study of PDIMs, which were desorbed as the [M + Li](+) and [M + NH(4)](+) ions by ESI. We also applied charge-switch strategy to convert the mycocerosic acid substituents to their N-(4-aminomethylphenyl) pyridinium (AMPP) derivatives and analyzed them as M (+) ions, following alkaline hydrolysis of the PDIM to release mycocerosic acids. The structural information from MS(n) on the [M + Li](+) and [M + NH(4)](+) molecular species and on the M (+) ions of the mycocerosic acid-AMPP derivative affords realization of the complex structures of PDIMs in Mycobacterium tuberculosis biofilm, differentiation of phthiocerol and phthiodiolone lipid families and complete structure identification, including the phthiocerol and phthiodiolone backbones, and the mycocerosic acid substituents, including the locations of their multiple methyl side chains, can be achieved. PMID- 26574043 TI - Role of Mitochondrial DNA in Septic AKI via Toll-Like Receptor 9. AB - Toll-like receptor 9 (TLR9) contributes to the development of polymicrobial septic AKI. However, the mechanisms that activate the TLR9 pathway and cause kidney injury during sepsis remain unknown. To determine the role of mitochondrial DNA (mtDNA) in TLR9-associated septic AKI, we established a cecal ligation and puncture (CLP) model of sepsis in wild-type (WT) and Tlr9-knockout (Tlr9KO) mice. We evaluated systemic circulation and peritoneal cavity dynamics and immune response and tubular mitochondrial dysfunction to determine upstream and downstream effects on the TLR9 pathway, respectively. CLP increased mtDNA levels in the plasma and peritoneal cavity of WT and Tlr9KO mice in the early phase, but the increase in the peritoneal cavity was significantly higher in Tlr9KO mice than in WT mice. Concomitantly, leukocyte migration to the peritoneal cavity increased, and plasma cytokine production and splenic apoptosis decreased in Tlr9KO mice compared with WT mice. Furthermore, CLP-generated renal mitochondrial oxidative stress and mitochondrial vacuolization in the proximal tubules in the early phase were reversed in Tlr9KO mice. To elucidate the effects of mtDNA on immune response and kidney injury, we intravenously injected mice with mitochondrial debris (MTD), including substantial amounts of mtDNA. MTD caused an immune response similar to that induced by CLP, including upregulated levels of plasma IL-12, splenic apoptosis, and mitochondrial injury, but this effect was attenuated by Tlr9KO. Moreover, MTD-induced renal mitochondrial injury was abolished by DNase pretreatment. These findings suggest that mtDNA activates TLR9 and contributes to cytokine production, splenic apoptosis, and kidney injury during polymicrobial sepsis. PMID- 26574044 TI - Defective Store-Operated Calcium Entry Causes Partial Nephrogenic Diabetes Insipidus. AB - Store-operated calcium entry (SOCE) is the mechanism by which extracellular signals elicit prolonged intracellular calcium elevation to drive changes in fundamental cellular processes. Here, we investigated the role of SOCE in the regulation of renal water reabsorption, using the inbred rat strain SHR-A3 as an animal model with disrupted SOCE. We found that SHR-A3, but not SHR-B2, have a novel truncating mutation in the gene encoding stromal interaction molecule 1 (STIM1), the endoplasmic reticulum calcium (Ca(2+)) sensor that triggers SOCE. Balance studies revealed increased urine volume, hypertonic plasma, polydipsia, and impaired urinary concentrating ability accompanied by elevated circulating arginine vasopressin (AVP) levels in SHR-A3 compared with SHR-B2. Isolated, split open collecting ducts (CD) from SHR-A3 displayed decreased basal intracellular Ca(2+) levels and a major defect in SOCE. Consequently, AVP failed to induce the sustained intracellular Ca(2+) mobilization that requires SOCE in CD cells from SHR-A3. This effect decreased the abundance of aquaporin 2 and enhanced its intracellular retention, suggesting impaired sensitivity of the CD to AVP in SHR A3. Stim1 knockdown in cultured mpkCCDc14 cells reduced SOCE and basal intracellular Ca(2+) levels and prevented AVP-induced translocation of aquaporin 2, further suggesting the effects in SHR-A3 result from the expression of truncated STIM1. Overall, these results identify a novel mechanism of nephrogenic diabetes insipidus and uncover a role of SOCE in renal water handling. PMID- 26574045 TI - Inhibitor of NFkappaB Kinase Subunit 2 Blockade Hinders the Initiation but Aggravates the Progression of Crescentic GN. AB - The NFkappaB transcription factor family facilitates the activation of dendritic cells (DCs) and CD4(+) T helper (Th) cells, which are important for protective adaptive immunity. Inappropriate activation of these immune cells may cause inflammatory disease, and NFkappaB inhibitors are promising anti-inflammatory drug candidates. Here, we investigated whether inhibiting the NFkappaB-inducing kinase IKK2 can attenuate crescentic GN, a severe DC- and Th cell-dependent kidney inflammatory disease. Prophylactic pharmacologic IKK2 inhibition reduced DC and Th cell activation and ameliorated nephrotoxic serum-induced GN in mice. However, therapeutic IKK2 inhibition during ongoing disease aggravated the nephritogenic immune response and disease symptoms. This effect resulted from the renal loss of regulatory T cells, which have been shown to protect against crescentic GN and which require IKK2. In conclusion, although IKK2 inhibition can suppress the induction of nephritogenic immune responses in vivo, it may aggravate such responses in clinically relevant situations, because it also impairs regulatory T cells and thereby, unleashes preexisting nephritogenic responses. Our findings argue against using IKK2 inhibitors in chronic GN and perhaps, other immune-mediated diseases. PMID- 26574046 TI - Acetazolamide Attenuates Lithium-Induced Nephrogenic Diabetes Insipidus. AB - To reduce lithium-induced nephrogenic diabetes insipidus (lithium-NDI), patients with bipolar disorder are treated with thiazide and amiloride, which are thought to induce antidiuresis by a compensatory increase in prourine uptake in proximal tubules. However, thiazides induced antidiuresis and alkalinized the urine in lithium-NDI mice lacking the sodium-chloride cotransporter, suggesting that inhibition of carbonic anhydrases (CAs) confers the beneficial thiazide effect. Therefore, we tested the effect of the CA-specific blocker acetazolamide in lithium-NDI. In collecting duct (mpkCCD) cells, acetazolamide reduced the cellular lithium content and attenuated lithium-induced downregulation of aquaporin-2 through a mechanism different from that of amiloride. Treatment of lithium-NDI mice with acetazolamide or thiazide/amiloride induced similar antidiuresis and increased urine osmolality and aquaporin-2 abundance. Thiazide/amiloride-treated mice showed hyponatremia, hyperkalemia, hypercalcemia, metabolic acidosis, and increased serum lithium concentrations, adverse effects previously observed in patients but not in acetazolamide-treated mice in this study. Furthermore, acetazolamide treatment reduced inulin clearance and cortical expression of sodium/hydrogen exchanger 3 and attenuated the increased expression of urinary PGE2 observed in lithium-NDI mice. These results show that the antidiuresis with acetazolamide was partially caused by a tubular-glomerular feedback response and reduced GFR. The tubular-glomerular feedback response and/or direct effect on collecting duct principal or intercalated cells may underlie the reduced urinary PGE2 levels with acetazolamide, thereby contributing to the attenuation of lithium-NDI. In conclusion, CA activity contributes to lithium-NDI development, and acetazolamide attenuates lithium-NDI development in mice similar to thiazide/amiloride but with fewer adverse effects. PMID- 26574047 TI - Renal 2',3'-Cyclic Nucleotide 3'-Phosphodiesterase Is an Important Determinant of AKI Severity after Ischemia-Reperfusion. AB - A positional isomer of 3',5'-cAMP, 2',3'-cAMP, is produced by kidneys in response to energy depletion, and renal 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) metabolizes 2',3'-cAMP to 2'-AMP; 2',3'-cAMP is a potent opener of mitochondrial permeability transition pores (mPTPs), which can stimulate autophagy. Because autophagy protects against AKI, it is conceivable that inhibition of CNPase protects against ischemia-reperfusion (IR) -induced AKI. Therefore, we investigated renal outcomes, mitochondrial function, number, area, and autophagy in CNPase-knockout (CNPase(-/-)) versus wild-type (WT) mice using a unique two-kidney, hanging-weight model of renal bilateral IR (20 minutes of ischemia followed by 48 hours of reperfusion). Analysis of urinary purines showed attenuated metabolism of 2',3'-cAMP to 2'-AMP in CNPase(-/-) mice. Neither genotype nor IR affected BP, heart rate, urine volume, or albumin excretion. In WT mice, renal IR reduced (14)C-inulin clearance (index of GFR) and increased renal vascular resistance (measured by transit time nanoprobes) and urinary excretion of kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin. IR did not affect these parameters in CNPase(-/-) mice. Histologic analysis revealed that IR induced severe damage in kidneys from WT mice, whereas histologic changes were minimal after IR in CNPase(-/-) mice. Measurements of renal cardiolipin levels, citrate synthase activity, rotenone-sensitive NADH oxidase activity, and proximal tubular mitochondrial and autophagosome area and number (by transmission electron microscopy) indicted accelerated autophagy/mitophagy in injured CNPase(-/-) mice. We conclude that CNPase deletion attenuates IR-induced AKI, in part by accelerating autophagy with targeted removal of damaged mitochondria. PMID- 26574048 TI - Factors influencing the use of topical repellents: implications for the effectiveness of malaria elimination strategies. AB - In Cambodia, despite an impressive decline in prevalence over the last 10 years, malaria is still a public health problem in some parts of the country. This is partly due to vectors that bite early and outdoors reducing the effectiveness of measures such as Long-Lasting Insecticidal Nets. Repellents have been suggested as an additional control measure in such settings. As part of a cluster randomized trial on the effectiveness of topical repellents in controlling malaria infections at community level, a mixed-methods study assessed user rates and determinants of use. Repellents were made widely available and Picaridin repellent reduced 97% of mosquito bites. However, despite high acceptability, daily use was observed to be low (8%) and did not correspond to the reported use in surveys (around 70%). The levels of use aimed for by the trial were never reached as the population used it variably across place (forest, farms and villages) and time (seasons), or in alternative applications (spraying on insects, on bed nets, etc.). These findings show the key role of human behavior in the effectiveness of malaria preventive measures, questioning whether malaria in low endemic settings can be reduced substantially by introducing measures without researching and optimizing community involvement strategies. PMID- 26574049 TI - Association of specific frequency bands of functional MRI signal oscillations with motor symptoms and depression in Parkinson's disease. AB - A novel empirical mode decomposition method was adopted to investigate the dissociative or interactive neural impact of depression and motor impairments in Parkinson's disease (PD). Resting-state fMRI data of 59 PD subjects were first decomposed into characteristic frequency bands, and the main effects of motor severity and depression and their interaction on the energy of blood-oxygen-level dependent signal oscillation in specific frequency bands were then evaluated. The results show that the severity of motor symptoms is negatively correlated with the energy in the frequency band of 0.10-0.25 Hz in the bilateral thalamus, but positively correlated with 0.01-0.027 Hz band energy in the bilateral postcentral gyrus. The severity of depression, on the other hand, is positively correlated with the energy of 0.10-0.25 Hz but negatively with 0.01-0.027 Hz in the bilateral subgenual gyrus. Notably, the interaction between motor and depressive symptoms is negatively correlated with the energy of 0.10-0.25 Hz in the substantia nigra, hippocampus, inferior orbitofrontal cortex, and temporoparietal junction, but positively correlated with 0.02-0.05 Hz in the same regions. These findings indicate unique associations of fMRI band signals with motor and depressive symptoms in PD in specific brain regions, which may underscore the neural impact of the comorbidity and the differentiation between the two PD related disorders. PMID- 26574050 TI - What is the effect of regular group exercise on maternal psychological outcomes and common pregnancy complaints? An assessor blinded RCT. AB - OBJECTIVE: to examine the effects of supervised group exercise on maternal psychological outcomes and commonly reported pregnancy complaints. DESIGN: an observer-blinded randomized controlled trial. SETTING: Norwegian School of Sport Sciences, Oslo, Norway. PARTICIPANTS: 105 sedentary, nulliparous pregnant women, mean age 30.7(+/- 4.0) years, pre-pregnancy BMI 23.8 (+/- 4.3), were assigned to either exercise (n=52) or control group (n= 53) at mean gestation week 17.7 (+/- 4.2). INTERVENTION: the exercise intervention followed ACOG guidelines and included a 60 minutes general fitness class, with 40 minutes of endurance training/aerobic and 20 minutes of strength training and stretching/relaxation, performed at least twice per week for a minimum of 12 weeks. MEASUREMENTS: outcome measures were assessed through standardized interviews pre- and post intervention (gestation week 36.6, +/- 0.9), and included psychological variables related to quality of life, well-being, body image and pregnancy depression, as well as assessment of 13 commonly reported pregnancy complaints. FINDINGS: post intervention, using intention to treat (ITT) analysis, women randomized to exercise rated their health significantly better compared to women in the control group (p=0.02) and reported less fatigue related to everyday activities (p=0.04). Women with complete exercise adherence (>= 24 sessions) had significantly better scores on measurements of feelings related to sadness, hopelessness and anxiety (p<0.01), compared to the control group. Contradictory, the control group reported higher life enjoyment (p<0.01). There were no significant group differences in body-image or pregnancy depression. With respect to analysing pregnancy complaints according to ITT, no differences between the groups were found. A comparison of the women who attended >= 19 (80%, n=21) or >= 24 (100%, n=14) exercise sessions with the control-participants, showed that fewer women in the exercise group reported nausea/vomiting and numbness/poor circulation in legs. KEY CONCLUSION AND IMPLICATION FOR PRACTISE: participation in regular group exercise during pregnancy contributed to improvements in some variables related to maternal well-being and quality of life. Women with high exercise adherence had significantly better results on several health variables reaping the highest benefits. A qualitative study exploring the barriers of women in achieving recommended amount of activity may be necessary to understand this population and developing better clinical practice educational tools. PMID- 26574051 TI - Probing the gravitational Faraday rotation using quasar X-ray microlensing. AB - The effect of gravitational Faraday rotation was predicted in the 1950s, but there is currently no practical method for measuring this effect. Measuring this effect is important because it will provide new evidence for correctness of general relativity, in particular, in the strong field limit. We predict that the observed degree and angle of the X-ray polarization of a cosmologically distant quasar microlensed by the random star field in a foreground galaxy or cluster lens vary rapidly and concurrently with flux during caustic-crossing events using the first simulation of quasar X-ray microlensing polarization light curves. Therefore, it is possible to detect gravitational Faraday rotation by monitoring the X-ray polarization of gravitationally microlensed quasars. Detecting this effect will also confirm the strong gravity nature of quasar X-ray emission. PMID- 26574052 TI - Controls and constrains of the membrane disrupting action of Aurein 1.2. AB - Aurein 1.2 is a 13 residue antimicrobial peptide secreted by the Australian tree frog Litoria Aurea. It is a surface-acting membrane disrupting peptide that permeabilizes bacterial membranes via the carpet mechanism; the molecular details of this process are mostly unknown. Here the mechanism of action of Aurein 1.2 was investigated with an emphasis on the role of membrane charge and C-terminal amidation of the peptide. Using quartz crystal microbalance (QCM) fingerprinting it was found that the membrane charge correlates with membrane affinity of the peptide, however the binding and the membrane disrupting processes are not charge driven; increased membrane charge reduces the membrane disrupting activity. Coarse grain simulations revealed that phenylalanine residues act as membrane anchors. Accordingly Aurein 1.2 has the ability to bind to any membrane. Furthermore, bundling precludes membrane disruption in case of wild type peptides, while non C-terminal amidated peptides form random aggregates leading to detachment from the membrane. Hence C-terminal amidation is crucial for Aurein 1.2 action. Our results suggest that Aurein 1.2 acts via aggregation driven membrane penetration. The concomitant change in the tension of the outer leaflet imposes a spontaneous curvature on the membrane, leading to disintegration. PMID- 26574053 TI - Chimeric antigen receptor T cell therapy: 25years in the making. AB - Chimeric antigen receptor (CAR) T cell therapy of cancer is generating enormous enthusiasm. Twenty-five years after the concept was first proposed, major advances in molecular biology, virology, and good manufacturing practices (GMP) grade cell production have transformed antibody-T cell chimeras from a scientific curiosity to a fact of life for academic cellular immunotherapy researchers and, increasingly, for patients. In this review, we explain the preclinical concept, outline how it has been translated to the clinic, and draw lessons from the first years of CAR T cell therapy for the practicing clinician. PMID- 26574054 TI - Potential diagnostic markers for disseminated intravascular coagulation of sepsis. AB - Disseminated intravascular coagulation (DIC) is an acquired thrombo-haemorrhagic disorder which arises in clinical scenarios like sepsis, trauma and malignancies. The clinic-laboratory diagnosis of DIC is made in a patient who develops the combination of laboratory abnormalities in the appropriate clinical scenario. The most common laboratory parameters in this setting have been the clotting profile, platelet count, serum fibrinogen and fibrin degradation markers. These tests had the advantage that they could be performed easily and in most laboratories. However, with the better understanding of the pathophysiology of DIC, in recent years, more specific tests have been suggested to be useful in this setting. The newer tests can also prove to be useful in prognostication in DIC. In addition, they may provide assistance in the selection and monitoring of patients diagnosed with DIC. PMID- 26574056 TI - Felix Voisin and the genesis of abnormals. AB - This article traces the genealogy of the category of 'abnormals' in psychiatry. It focuses on the French alienist Felix Voisin (1794-1872) who played a decisive role in the creation of alienist knowledge and institutions for problem children, criminals, idiots and lunatics. After a presentation of the category of 'abnormals' as understood at the end of the nineteenth century, I identify in the works of Voisin a key moment in the concept's evolution. I show how, based on concepts borrowed from phrenology and applied first to idiocy, Voisin allows alienism to establish links between the medico-legal (including penitentiary) and medical-educational fields (including difficult childhood). I stress the extent to which this enterprise is related to Voisin's humanism, which claimed to remodel pedagogy and the right to punish on the anthropological particularities of individuals, in order to improve them. PMID- 26574055 TI - Cervical intraepithelial neoplasia disease progression is associated with increased vaginal microbiome diversity. AB - Persistent infection with oncogenic Human Papillomavirus (HPV) is necessary for cervical carcinogenesis. Although evidence suggests that the vaginal microbiome plays a functional role in the persistence or regression of HPV infections, this has yet to be described in women with cervical intra-epithelial neoplasia (CIN). We hypothesised that increasing microbiome diversity is associated with increasing CIN severity. llumina MiSeq sequencing of 16S rRNA gene amplicons was used to characterise the vaginal microbiota of women with low-grade squamous intra-epithelial lesions (LSIL; n = 52), high-grade (HSIL; n = 92), invasive cervical cancer (ICC; n = 5) and healthy controls (n = 20). Hierarchical clustering analysis revealed an increased prevalence of microbiomes characterised by high-diversity and low levels of Lactobacillus spp. (community state type-CST IV) with increasing disease severity, irrespective of HPV status (Normal = 2/20,10%; LSIL = 11/52,21%; HSIL = 25/92,27%; ICC = 2/5,40%). Increasing disease severity was associated with decreasing relative abundance of Lactobacillus spp. The vaginal microbiome in HSIL was characterised by higher levels of Sneathia sanguinegens (P < 0.01), Anaerococcus tetradius (P < 0.05) and Peptostreptococcus anaerobius (P < 0.05) and lower levels of Lactobacillus jensenii (P < 0.01) compared to LSIL. Our results suggest advancing CIN disease severity is associated with increasing vaginal microbiota diversity and may be involved in regulating viral persistence and disease progression. PMID- 26574057 TI - The nature of delusion: psychologically explicable? psychologically inexplicable? philosophically explicable? Part 1. AB - The debate about the nature of delusion has rumbled on for over a century without resolution. The current situation is a stand-off between psychologists, who propose various theories as to the psychological explicability of delusion, and psychiatrists, who generally regard delusion as inexplicable. Our main aim in this 2-part article is to reprise the intellectual atmosphere of German psychopathology in the inter-war and immediate post-war years, when the issues concerning delusion were formulated with more sensitivity to the actual delusions encountered in clinical practice. In Part 1 we mount a critique of psychological and psychiatric theories of delusion. PMID- 26574059 TI - 'A Berlin psychiatrist with an American passport': Lothar Kalinowsky, electroconvulsive therapy and international exchange in the mid-twentieth century. AB - The emigration of Lothar Kalinowsky (1899-1992) might, at first glance, seem to be a history of coincidence and twists of fate, but it is shown to be a truly entangled and intertwined history and story. The international introduction of electroconvulsive therapy was not only closely involved with the political, scientific and economic conditions during World War II, but the story of Kalinowsky's relevance to it emerges from competing stories, told differently in Europe and the USA - and by Kalinowsky himself. Tracing these stories up to the end of the 1960s reveals Kalinowsky as an influential inheritor and patron of Berlin Biological Psychiatry, rather than telling the history of an emigre innovator of international neuropsychiatric research. PMID- 26574058 TI - Leon Marillier and the veridical hallucination in late-nineteenth- and early twentieth-century French psychology and psychopathology. AB - Recent research on the professionalization of psychology at the end of the nineteenth century shows how objects of knowledge which appear illegitimate to us today shaped the institutionalization of disciplines. The veridical or telepathic hallucination was one of these objects, constituting a field both of division and exchange between nascent psychology and disciplines known as 'psychic sciences' in France, and 'psychical research' in the Anglo-American context. In France, Leon Marillier (1862-1901) was the main protagonist in discussions concerning the concept of the veridical hallucination, which gave rise to criticisms by mental specialists and psychopathologists. After all, not only were these hallucinations supposed to occur in healthy subjects, but they also failed to correspond to the Esquirolian definition of hallucinations through being corroborated by their representation of external, objective events. PMID- 26574060 TI - The multiaxial assessment and the DSM-III: a conceptual analysis. AB - With the release of the DSM-III, multiaxial assessment, which was a new concept, was introduced to daily clinical practice. This article will review the history and the development of the concept of multiaxial assessment and will focus on the its relationship to the DSM-III. In conclusion I will discuss different critiques of the concept. PMID- 26574061 TI - Epistemological issues in the history of Italian psychiatry: the contribution of Gaetano Perusini (1879-1915). AB - In the late nineteenth and early twentieth centuries, Italian psychiatry was characterized by its emphasis on an organic explanation of mental illness. 'Cerebral mythology' was a major influence in Italy, at least until the second half of the twentieth century, often at the expense of the development of psychology. In this context, a few psychiatrists adopted a different epistemological perspective, based on a more 'integrative' view of their discipline. In particular, Gaetano Perusini stands out. He promoted the concept of psychiatry as a science which embraced many different fields, thus emphasizing the theme of pluralism, which is still debated today in the philosophy of science and psychiatric practice. PMID- 26574062 TI - The creator of the term 'anancasm' was Hungarian: Guyla Donath (1849-1944). AB - There is considerable confusion in the field of research on the history of psychiatry as to who created the term anancasm. This article seeks to clarify that the term was coined by the Hungarian psychiatrist Gyula Donath, who was born in Baja, on the Danube, and worked mainly in Budapest. Donath's publications reveal that his predominant sphere of interest and research was neurology and psychiatry. A number of his publications deal with epilepsy and obsessive compulsive disorders. After a period of intensive research, during which he spent some time in Berlin at the clinic of neuroscientist Carl Westphal, Donath proposed the term 'anancasm' in 1895 to describe compulsive mental processes. PMID- 26574063 TI - The 'Preliminary Discourse' to Methodical Nosology, by Francois Boissier de Sauvages (1772). AB - The eighteenth century witnessed an intense drive to classify diseases as natural kinds. Together with Linne, Macbride, Cullen, Sagar and Vogel, Francois Boissier de Sauvages, Professor of Medicine at Montpellier, was an important player in this process. In his monumental Nosologie Methodique, Sauvages based his nosological system on the more botanico view proposed by Thomas Sydenham, namely, that human diseases (including mental ailments) should be classified in the same way as were plants. Classic Text No. 104 is an abridged translation of the Preliminary Discourse to the Nosologie Methodique. PMID- 26574071 TI - Henri Ey's Etudes Psychiatriques, Traite des Hallucinations and La Conscience, 2nd edn: the history of the Spanish translations. PMID- 26574074 TI - [Prevalence of Mental Symptoms, Possible Cases and Disorders in Victims Displaced by the Internal Armed Conflict in Colombia: A Systematic Review]. AB - BACKGROUND: In Colombia, the internal armed conflict is a public health problem that generates various forms of violence (forced disappearances, forced displacement, massacres, torture and sexual violence). Violence is a major psychosocial stressor that impairs the mental health of the Colombian population. However, there are no real estimates on the prevalence of mental symptoms, possible cases and disorders in victims of violence in displacement situations. OBJECTIVE: To determine the prevalence of mental symptoms, possible cases and disorders due to the forced displacement of victims of the armed conflict in Colombia during the past two decades (1994-2013). METHOD: A systematic review was carried out on all available studies published over the last twenty years. The keywords used were "armed conflict", "mental disorders", "mental health", "prevalence" and "Colombia". Authors observed the frequency of symptoms, possible cases, and mental disorders. RESULTS: Thirteen studies involving adults were included. The prevalence of symptoms was observed as between 9.9% and 63%; possible cases, between 21% and 97.3%; and mental disorders, between 1.5% and 32.9%. CONCLUSIONS: The prevalence of symptoms, possible cases and mental disorders is high in this Colombian population. This finding should be interpreted with caution due to the high heterogeneity and low quality of the studies. More research is needed. PMID- 26574075 TI - [Suicidal Behavior and Attention Decifit Hyperactivity Disorder in Adolescents of Medellin (Colombia), 2011-2012]. AB - BACKGROUND: Suicide is a public health problem. In Colombia, teenagers are considered a group at high risk for suicidal behavior. OBJECTIVE: To explore the possible association between suicidal behavior and attention deficit hyperactivity disorder in adolescents of Medellin. METHODOLOGY: Observational, cross-sectional, analytical study. The Composite International Diagnostic Interview was applied to a total of 447 adolescents and the sociodemographic, clinical, familiar, and life event variables of interest were analyzed. The descriptive analysis of qualitative variables are presented as absolute values and frequencies, and the age was described with median [interquartile range]. A logistic regression model was constructed with explanatory variables that showed statistical association. Data were analyzed with SPSS(r) software version 21.0. RESULTS: Of the total, 59.1% were female, and the median age was 16 [14-18] years. Suicidal behavior was presented in 31% of females and 23% of males. Attention deficit was present in 6.3% of adolescents. The logistic regression analysis showed that the variables that best explained the suicidal behavior of adolescents were: female sex, post-traumatic stress disorder, panic disorder, and cocaine use. CONCLUSIONS: The diagnosis and early intervention of attention deficit hyperactivity disorder in children may be a useful strategy in the prevention of suicidal behavior in adolescents. PMID- 26574072 TI - Impact of diet on cardiometabolic health in children and adolescents. AB - The manifestation of cardiovascular risk factors, such as hypertension, diabetes, and particularly obesity begins in children and adolescents, with deleterious effects for cardiometabolic health at adulthood. Although the impact of diet on cardiovascular risk factors has been studied extensively in adults, showing that their cardiometabolic health is strongly lifestyle-dependent, less is known about this impact in children and adolescents. In particular, little is known about the relationship between their dietary patterns, especially when derived a posteriori, and cardiovascular risk. An adverse association of cardiovascular health and increased intake of sodium, saturated fat, meat, fast food and soft drinks has been reported in this population. In contrast, vitamin D, fiber, mono and poly-unsaturated fatty acids, dairy, fruits and vegetables were positively linked to cardiovascular health.The aim of this review was to summarize current epidemiological and experimental evidence on the impact of nutrients, foods, and dietary pattern on cardiometabolic health in children and adolescents. A comprehensive review of the literature available in English and related to diet and cardiometabolic health in this population was undertaken via the electronic databases PubMed, Cochrane Library, and Medline. PMID- 26574076 TI - [Family, Through Mental Health and Sickness]. AB - The following article arises from the study "Representaciones sociales en el campo de la salud mental" (Social Representations in the Mental Health Field), in which the objective was to address the social representations in the family context; concerning caring, as well as the burden it implies using a qualitative method. The corpus was built based on the analysis and interpretation gathered from families with mental illness members. There were 17 individual interviews, 13 group interviews and one family group of three generations, held regarding the clinical care of the family member. These interviews were held at three different hospitals in Bogota. The representation of "a family" constitutes the structuring of the meanings of family relationships that cope with mental illness built upon the social and historical life of its members. The three comprehensive categories were: a) Family in good times and bad times; b) mental illness in family interactions, and c) Care and burden. Socially speaking, mental illness can lead to dehumanization, in that it discriminates and stigmatizes, even within the family unit. Caring for a family member with mental illness comes about by hierarchical order, self assignation, and by institutionalization. This latter occurs due to lack of caregivers or because the family does not consider their home the best place to care for such a patient. PMID- 26574077 TI - [Experiences of Life and Work of a Group of Epidemiologists in Training in Order to Address Mental Health Problems and Issues at Local and Departmental Level. Medellin, 2013]. AB - OBJECTIVE: To examine, from the point of view of a group of epidemiologists in training, their life experiences and work related to addressing mental health problems and mental health issues. METHODS: An exploratory qualitative descriptive study was conducted using ethnographic tools, non-participant observation, note-taking, and group interviews (FG). RESULTS: The participants mentioned that mental health and mental health issues are managed and poorly differentiated either by them and the community in general. They also said they were not ready to handle mental problems, or have the support of services for patient care, as mental health issues have not yet been clearly dimensioned by society. Epidemiology has its limitations, it focuses on knowledge of the physical-biological aspects and the use of quantitative approach with poor integration of the qualitative approach, thus hindering the understanding of a phenomenon that exceeds the limits of a research approach. CONCLUSIONS: This approach to issues of health and mental illness widens the view of knowledge from only a single focus. It includes an understanding of the qualitative approach as an option to advance the knowledge and recognition of a public health problem overshadowed by stigma and apathy of society. PMID- 26574078 TI - [Stigma and Mental Health in Victims of Colombia's Internal Armed Conflict in Situation of Forced Displacement]. AB - BACKGROUND: The prolonged sociopolitical phenomenon of Colombian violence generated a high number of victims, many of whom suffered a continual process of internal displacement and stigma-discrimination complex. OBJECTIVE: To postulate possible mechanisms by which victims of Colombia's internal armed conflict in a situation of forced displacement were stigmatized and discriminated. RESULTS: Stigma affects mental health, not only because it represents a major stressor for discriminated individuals and groups, but also because it accounts for inequalities and inequities in health. Initially, as the victims of the internal armed conflict in situation of forced displacement were not considered as such, but as responsible for the situation. Thus, they had to cope with the social and economic inequalities, explained partially by low categorization or status that they received, possibly due to poor construction of social capital in the country. Also, victims of the internal armed conflict suffer from intersectional stigma and discrimination due to other characteristics such as gender, sexual orientation, ethnic-racial origin, or meeting criteria for a mental disorder. CONCLUSIONS: An active process of inclusive social development is required for the displaced victims of the armed conflict,in order to reduce multiple stigma and ensure their mental health. PMID- 26574079 TI - [Role of Serotonin Transporter Gene in Eating Disorders]. AB - BACKGROUND: The serotoninergic system has been implicated in mood and appetite regulation, and the serotonin transporter gene (SLC6A4) is a commonly studied candidate gene for eating disorders. However, most studies have focused on a single polymorphism (5-HTTLPR) in SLC6A4. OBJECTIVE: We present the studies published on the association between eating disorders (ED) and 5-HTTLPR polymorphism in anorexia nervosa (AN), bulimia nervosa (BN), and eating disorders not otherwise specified (EDNOS). METHOD: Search of databases: MEDLINE, ISI, and PubMed for SLC6A4 and ED. CONCLUSIONS: From a review of 37 original articles, it was suggested that carriers of S allele is a risk factor for eating disorders, especially for AN. However, BN did not show any association. Also, BMI, impulsivity, anxiety, depression, and age of onset have been associated with S allele in ED patients. PMID- 26574080 TI - [Anticonvulsant Hypersensitivity Syndrome: A Case Report]. AB - DRESS syndrome (skin reaction with eosinophilia and systemic symptoms) is an idiosyncratic drug reaction characterized by rash, fever, lymphadenopathy, and internal organ dysfunction. This case report is on a patient with bipolar affective disorder who presented with a systemic inflammatory response associated with the use of valproic acid, and an important activation of symptoms when used with other drugs with a different pharmacological action mechanism. The diagnosis of DRESS syndrome is primarily by exclusion, and its detection may be difficult, which could potentially become fatal for the patient. PMID- 26574081 TI - Shared Decisions. PMID- 26574082 TI - Quantification of emission reduction potentials of primary air pollutants from residential solid fuel combustion by adopting cleaner fuels in China. AB - Residential low efficient fuel burning is a major source of many air pollutants produced during incomplete combustions, and household air pollution has been identified as one of the top environmental risk factors. Here we compiled literature-reported emission factors of pollutants including carbon monoxide (CO), total suspended particles (TSPs), PM2.5, organic carbon (OC), elemental carbon (EC) and polycyclic aromatic hydrocarbons (PAHs) for different household energy sources, and quantified the potential for emission reduction by clean fuel adoption. The burning of crop straws, firewood and coal chunks in residential stoves had high emissions per unit fuel mass but lower thermal efficiencies, resulting in high levels of pollution emissions per unit of useful energy, whereas pelletized biofuels and coal briquettes had lower pollutant emissions and higher thermal efficiencies. Briquetting coal may lead to 82%-88% CO, 74%-99% TSP, 73%-76% PM2.5, 64%-98% OC, 92%-99% EC and 80%-83% PAH reductions compared to raw chunk coal. Biomass pelletizing technology would achieve 88%-97% CO, 73%-87% TSP, 79%-88% PM2.5, 94%-96% OC, 91%-99% EC and 63%-96% PAH reduction compared to biomass burning. The adoption of gas fuels (i.e., liquid petroleum gas, natural gas) would achieve significant pollutant reduction, nearly 96% for targeted pollutants. The reduction is related not only to fuel change, but also to the usage of high efficiency stoves. PMID- 26574083 TI - Oxidation of Cr(III) on birnessite surfaces: The effect of goethite and kaolinite. AB - Oxidation of Cr(III) by manganese oxides may pose a potential threat to environments due to the formation of toxic Cr(VI) species. At present, it was still unclear whether the extent of Cr(III) oxidation and fate of Cr(VI) would be changed when manganese oxides co-exist with other minerals, the case commonly occurring in soils. This study investigated the influence of goethite and kaolinite on Cr(III) oxidation by birnessite under acidic pH condition (pH3.5) and background electrolyte of 0.01mol/L NaCl. Goethite was found not to affect Cr(III) oxidation, which was interpreted as the result of overwhelming adsorption of cationic Cr(III) onto the negatively-charged birnessite (point of zero charge (PZC)<3.0) rather than the positively-charged goethite (PZC=8.8). However, more Cr(VI) would be retained by the surface with the increase in addition of goethite because of its strong ability on adsorption of Cr(VI) at low pH. Moreover, either Cr(III) oxidation or distribution of the generated Cr(VI) between the solid and solution phases was not affected by kaolinite (PZC<3.0), indicating its low affinity for Cr species. Reactions occurring in the present mixed systems were suggested, which could be partly representative of those in the soils and further indicates that the mobility and risk of Cr(VI) would be decreased if goethite was present. PMID- 26574084 TI - Recent improvements in oily wastewater treatment: Progress, challenges, and future opportunities. AB - Oily wastewater poses significant threats to the soil, water, air and human beings because of the hazardous nature of its oil contents. The objective of this review paper is to highlight the current and recently developed methods for oily wastewater treatment through which contaminants such as oil, fats, grease, and inorganics can be removed for safe applications. These include electrochemical treatment, membrane filtration, biological treatment, hybrid technologies, use of biosurfactants, treatment via vacuum ultraviolet radiation, and destabilization of emulsions through the use of zeolites and other natural minerals. This review encompasses innovative and novel approaches to oily wastewater treatment and provides scientific background for future work that will be aimed at reducing the adverse impact of the discharge of oily wastewater into the environment. The current challenges affecting the optimal performance of oily wastewater treatment methods and opportunities for future research development in this field are also discussed. PMID- 26574085 TI - Reductive transformation of p-nitrotoluene by a new iron-fly ash packing. AB - A new iron-fly ash packing was studied for reductive transformation of p nitrotoluene. The packing was made of iron, fly ash and kaolin with the mass ratio of 36:7:2. A reactor was designed to investigate the long-term performance of the packing. The results showed that the reduction of p-nitrotoluene increased with decreasing pH, because the reduction potential of reaction increased with the concentration of H(+). The pH was one of the key factors impacting the reductive transformation of p-nitrotoluene. Comparing iron-activated carbon packing with the new iron-fly ash packing, the reduction efficiencies were respectively 76.61% and 75.36% after 20days. The reduction efficiency for both was around 50% at 40days. It was evident that these two kinds of packing had no significant difference in their capability for p-nitrotoluene reductive transformation. Compared with iron-activated carbon, the new iron-fly ash packing had obvious advantages in terms of manufacturing costs and environmental pollution degradation. This study showed that the new iron-fly ash packing had good performance in reductive transformation of nitrotoluene compounds. PMID- 26574086 TI - Investigation on removal pathways of Di 2-ethyl hexyl phthalate from synthetic municipal wastewater using a submerged membrane bioreactor. AB - Highly hydrophobic Di 2-ethyl hexyl phthalate (DEHP) is one of the most prevalent plasticizers in wastewaters. Since its half-life in biological treatment is around 25days, it can be used as an efficiency indicator of wastewater treatment plant for the removal of hydrophobic emerging contaminants. In this study, the performance of submerged membrane bioreactor was monitored to understand the effect of DEHP on the growth of aerobic microorganisms. The data showed that the chemical oxygen demand (COD) and ammonia concentration were detected below 10 and 1.0mg/L, respectively for operating conditions of hydraulic retention time (HRT)=4 and 6hr, sludge retention time (SRT)=140day and sludge concentration between 11.5 and 15.8g volatile solid (VS)/L. The removal efficiency of DEHP under these conditions was higher and ranged between 91% and 98%. Results also showed that the removal efficiency of DEHP in biological treatment depended on the concentration of sludge, as adsorption is the main mechanism of its removal. For the submerged membrane bioreactor, the pore size is the pivotal factor for DEHP removal, since it determines the amount of soluble microbial products coming out of the process. Highly assimilated microorganisms increase the biodegradation rate, as 74% of inlet DEHP was biodegraded; however, the concentration of DEHP inside sludge was beyond the discharge limit. Understanding the fate of DEHP in membrane bioreactor, which is one of the most promising and futuristic treatment process could provide replacement for conventional processes to satisfy the future stricter regulations on emerging contaminants. PMID- 26574087 TI - Succinate-bonded pullulan: An efficient and reusable super-sorbent for cadmium uptake from spiked high-hardness groundwater. AB - Chemically modified pullulan was evaluated for its sorption efficiency and selectivity to remove cadmium (Cd) from spiked high-hardness groundwater (GW). Pullulan esterified with succinic anhydride using dimethylaminopyridine showed a fairly high degree of substitution value as confirmed by (1)H NMR spectroscopy. Pullulan succinate (Pull-Suc) was converted into the sodium salt (Pull-Suc-Na). The effect of contact time (5-200min) and pH (2-8) on Cd-uptake by the sorbent (Pull-Suc-Na) was investigated. The sorbent showed more than 90% Cd-removal in first 15min from distilled water (DW) and GW solution, respectively. Comparison of Pull-Suc-Na with other polysaccharidal sorbents suggested its high efficiency (DW 476.2mg/g and GW 454.5mg/g) and selectivity for the removal of Cd by an ion exchange mechanism, which is further supported by the negative Gibbs free energy values calculated from Langmuir isotherms. A Langmuir isotherm kinetic model provided the best fit for the sorption of Cd using Pull-Suc-Na. The sorbent showed a negligible decrease in Cd-uptake over three regeneration cycles. The thermal stability testing of the sorbents indicated that Pull-Suc-Na (sorbent) is more stable than Pull-Suc. PMID- 26574088 TI - Surface modification of polypropylene non-woven fibers with TiO2 nanoparticles via layer-by-layer self assembly method: Preparation and photocatalytic activity. AB - Polypropylene (PP) meltblown fibers were coated with titanium dioxide (TiO2) nanoparticles using layer-by-layer (LbL) deposition technique. The fibers were first modified with 3 layers of poly(4-styrenesulfonic acid) (PSS) and poly(diallyl-dimethylammonium chloride) (PDADMAC) to improve the anchoring of the TiO2 nanoparticle clusters. PDADMAC, which is positively charged, was then used as counter polyelectrolyte in tandem with anionic TiO2 nanoparticles to construct TiO2/PDADMAC bilayer in the LbL fashion. The number of deposited TiO2/PDADMAC layers was varied from 1 to 7 bilayer, and could be used to adjust TiO2 loading. The LbL technique showed higher TiO2 loading efficiency than the impregnation approach. The modified fibers were tested for their photocatalytic activity against a model dye, Methylene Blue (MB). Results showed that the TiO2 modified fibers exhibited excellent photocatalytic activity efficiency similar to that of TiO2 powder dispersed in solution. The deposition of TiO2 3 bilayer on the PP substrate was sufficient to produce nanocomposite fibers that could bleach the MB solution in less than 4hr. TiO2-LbL constructions also preserved TiO2 adhesion on substrate surface after 1cycle of photocatalytic test. Successive photocatalytic test showed decline in MB reduction rate with loss of TiO2 particles from the substrate outer surface. However, even in the third cycle, the TiO2 modified fibers are still moderately effective as it could remove more than 95% of MB after 8hr of treatment. PMID- 26574089 TI - Pollution levels and characteristics of phthalate esters in indoor air in hospitals. AB - The concentrations of phthalate esters (PAEs) in Chinese hospitals were investigated by simultaneously determining concentrations of gas- and particle phase PAEs. PAEs were detected in two third-class first-grade hospitals, two second-class first-grade hospitals, and a community health service center. Hospital drugstores had the highest concentration (24.19MUg/m(3)), which was 1.54 times that of newly decorated houses. The second highest concentration was found in the transfusion rooms, averaging 21.89MUg/m(3); this was followed by the concentrations of PAEs in the nurse's workstations, the wards, and the doctor's offices, with mean concentrations of 20.66, 20.0, and 16.92MUg/m(3), respectively. The lowest concentrations were found in the hallways (16.30MUg/m(3)). Of the six different kinds of PAEs found, major pollutants included diethyl phthalates, dibutyl phthalates, butylbenzyl phthalates and di(2 ethylhexyl) phthalates, comprising more than 80% of all PAEs present. Meanwhile, a comparison between different wards showed that PAE concentrations in the maternity wards were 1.63 times higher than in the main wards. Based on known health hazards, our results suggest that the PAEs seriously influence the health of the pregnant women and babies; therefore, it is of great importance to take the phthalate concentrations in hospitals into consideration. In addition, hospital indoor air was more seriously contaminated than the air of newly decorated houses. PMID- 26574090 TI - Toward rational design of amines for CO2 capture: Substituent effect on kinetic process for the reaction of monoethanolamine with CO2. AB - Amines have been considered as promising candidates for post-combustion CO2 capture. A mechanistic understanding for the chemical processes involved in the capture and release of CO2 is important for the rational design of amines. In this study, the structural effects of amines on the kinetic competition among three typical products (carbamates, carbamic acids and bicarbonate) from amines+CO2 were investigated, in contrast to previous thermodynamic studies to tune the reaction of amines with CO2 based on desirable reaction enthalpy and reaction stoichiometry. We used a quantum chemical method to calculate the activation energies (Ea) for the reactions of a range of substituted monoethanolamines with CO2 covering three pathways to the three products. The results indicate that the formation of carbamates is the most favorable, among the three considered products. In addition, we found that the Ea values for all pathways linearly correlate with pKa of amines, and more importantly, the kinetic competition between carbamate and bicarbonate absorption pathways varies with pKa of the amines, i.e. stronger basicity results in less difference in Ea. These results highlight the importance of the consideration of kinetic competition among different reaction pathways in amine design. PMID- 26574091 TI - Use of additive and pretreatment to control odors in municipal kitchen waste during aerobic composting. AB - The effects of adding a bulking agent and chemically pretreating municipal kitchen waste before aerobic composting were studied using a laboratory-scale system. The system used 20-L reactors and each test lasted 28days. The objective was to decrease NH3 and H2S emissions during composting. The bulking agent, dry cornstalks, was mixed with the kitchen waste to give a mixture containing 15% (wet weight) bulking agent. A combined treatment was also conducted, in which kitchen waste mixed with the bulking agent was pretreated with ferric chloride (FeCl3). Less leachate was produced by the composted kitchen waste mixed with bulking agent than by the kitchen waste alone, when the materials had reached the required maturity. The presence of cornstalks also caused less H2S to be emitted, but had little impact on the amount of NH3 emitted. The FeCl3 was found to act as an effective chemical flocculant, and its presence significantly decreased the amounts of NH3 and H2S emitted. Kitchen waste mixed with cornstalks and treated with FeCl3 emitted 42% less NH3 and 76% less H2S during composting than did pure kitchen waste. PMID- 26574092 TI - Effects of a municipal effluent on the freshwater mussel Elliptio complanata following challenge with Vibrio anguillarum. AB - The purpose of this study was to examine the cumulative effects of exposure to a pathogenic bacteria and municipal effluent in the freshwater mussel Elliptio complanata. Mussels were exposed to increasing concentrations of an ozone-treated effluent at 15 degrees C for 7days. A sub-group of mussels was inoculated with Vibrio anguillarum and exposed to the same conditions as above. After the exposure period, mussels were collected to assess hemocyte count and viability, immunocompetence (phagocytosis and nitrite production), oxidative stress/inflammation (cyclooxygenase and lipid peroxidation) and oxygen radical/xenobiotic scavenging activity (metallothioniens, glutathione S transferase). The results showed that mussels exposed to municipal effluent had increased hemocyte counts, phagocytosis, nitrites, lipid peroxidation and metallothioneins. In the inoculated mussels, the same responses were observed, in addition to cyclooxygenase and glutathione S-transferase activities. Multivariate analyses revealed that (1) the response pattern changed with effluent concentration, where increased responses observed at low effluent concentrations (>10%, V/V) were attenuated at higher effluent concentrations, (2) the effluent produced more pronounced changes in lipid peroxidation, metallothionein and hemocyte viability, and (3) the simultaneous presence of V. anguillarum led to more important changes in hemocyte count and viability and nitrite levels. In conclusion, the presence of V. anguillarum could alter the response of mussels to municipal effluent, which could lead to increased inflammation in mussels. PMID- 26574093 TI - Cobalt and sulfur co-doped nano-size TiO2 for photodegradation of various dyes and phenol. AB - Various compositions of cobalt and sulfur co-doped titania nano-photocatalyst are synthesized via sol-gel method. A number of techniques including X-ray diffraction (XRD), ultraviolet-visible (UV-Vis), Rutherford backscattering spectrometry (RBS), thermal gravimetric analysis (TGA), Raman, N2 sorption, electron microscopy are used to examine composition, crystalline phase, morphology, distribution of dopants, surface area and optical properties of synthesized materials. The synthesized materials consisted of quasispherical nanoparticles of anatase phase exhibiting a high surface area and homogeneous distribution of dopants. Cobalt and sulfur co-doped titania demonstrated remarkable structural and optical properties leading to an efficient photocatalytic activity for degradation of dyes and phenol under visible light irradiations. Moreover, the effect of dye concentration, catalyst dose and pH on photodegradation behavior of environmental pollutants and recyclability of the catalyst is also examined to optimize the activity of nano-photocatalyst and gain a better understanding of the process. PMID- 26574094 TI - Excretion of manure-borne estrogens and androgens and their potential risk estimation in the Yangtze River Basin. AB - The Yangtze River is the longest river in China, and the river basin spans one fifth of the area of the whole country. Based on statistical data, the excretion of manure-borne steroid hormones, including steroid estrogens (SEs) and steroid androgens (SAs), in 10 provinces of China within the region has been estimated. The potential environmental and ecological risk of manure-borne steroid estrogens to the surface water in this region was also assessed. The manure-borne SE and SA excretions in the 10 provinces and municipalities vary in the order: Sichuan>Hunan>Hubei>Yunnan>Jiangsu>Anhui>Jiangxi>Chongqing>Qinghai>Shanghai. The highest increase of manure-borne SEs (1434.3kg) and SAs (408.5kg) was found in Hunan and Hubei provinces, respectively, and the total excretion in 2013 was 65% more than 15years earlier in these two provinces. However, the emissions in Anhui and Shanghai decreased in this 15year period of time. Swine urine, chicken feces, cattle urine, and laying hen feces were considered the dominant sources of manure borne E1, betaE2, alphaE2, and SAs, respectively. Although Jiangsu province did not have the largest excretion of manure-borne SEs, it had the highest level of predicted 17beta-estradiol equivalency (EEQs) value of 16.65ng/L in surface water because of the limited surface water resources. According to the lowest observable effect level of 10ng/L for 17beta-estradiol, the manure-borne SEs in Jiangsu province might potentially pose ecological risk to its wild aquatic organisms. PMID- 26574095 TI - Spatial variations of macrozoobenthos and sediment nutrients in Lake Yangcheng: Emphasis on effect of pen culture of Chinese mitten crab. AB - We determined the effect of Chinese mitten crab (CMC) pen culture on the quantified spatial distribution of the macrozoobenthic community and sediment nutrients in Lake Yangcheng. Redundancy analysis indicated that water temperature, macrophyte occurrence, sediment type, and crab culture were the main environmental factors that influence the spatiotemporal macrozoobenthic distribution. Macrozoobenthic assemblages in the lake were characterized by eutrophic indicator species. In the most polluted estuaries, the abundance and diversity indices of the whole community and abundance of chironomids and oligochaetes were significantly depressed, and sediment carbon (C) and phosphorus (P) were significantly enhanced compared with those in the western, middle (MB), and eastern basin (EB). Crab culture in this lake had significant effects on the species composition of the macrozoobenthic community in one of three CMC culture pens (CP), and generally depressed the abundance of most chironomid and oligochaete species. Significantly increased diversity, evenness, sediment carbon and nitrogen content, and sediment C:P ratio in the CP were found compared with those in the three basins. However, no conspicuous difference in sediment P content between the CP and the two basins of MB and EB was detected. Our results showed that the enhanced diversity and evenness of macrozoobenthos might be associated with the joint effect of macrophyte planting and crab predation, and macrophyte planting may modify the effects of CMC culture by leading to disproportional accumulation of C and N in the sediment relative to P in the CP of the lake. PMID- 26574096 TI - Continuous desulfurization and bacterial community structure of an integrated bioreactor developed to treat SO2 from a gas stream. AB - Sulfide dioxide (SO2) is often released during the combustion processes of fossil fuels. An integrated bioreactor with two sections, namely, a suspended zone (SZ) and immobilized zone (IZ), was applied to treat SO2 for 6months. Sampling ports were set in both sections to investigate the performance and microbial characteristics of the integrated bioreactor. SO2 was effectively removed by the synergistic effect of the SZ and IZ, and more than 85% removal efficiency was achieved at steady state. The average elimination capacity of SO2 in the bioreactor was 2.80g/(m(3).hr) for the SZ and 1.50g/(m(3).hr) for the IZ. Most SO2 was eliminated in the SZ. The liquid level of the SZ and the water content ratio of the packing material in the IZ affected SO2 removal efficiency. The SZ served a key function not only in SO2 elimination, but also in moisture maintenance for the IZ. The desired water content in IZ could be feasibly maintained without any additional pre-humidification facilities. Clone libraries of 16S rDNA directly amplified from the DNA of each sample were constructed and sequenced to analyze the community composition and diversity in the individual zones. The desulfurization bacteria dominated both zones. Paenibacillus sp. was present in both zones, whereas Ralstonia sp. existed only in the SZ. The transfer of SO2 to the SZ involved dissolution in the nutrient solution and biodegradation by the sulfur-oxidizing bacteria. This work presents a potential biological treatment method for waste gases containing hydrophilic compounds. PMID- 26574097 TI - An executive review of sludge pretreatment by sonication. AB - Ultrasonication (US), which creates hydro-mechanical shear forces in cavitation, is an advanced technology in sludge pretreatment. However, there are many factors affecting the efficacy of cavitation and ultrasonication disintegration of sludge as a consequence. The objective of this work is to present an extensive review of evaluation approaches of sludge US pretreatment efficiency. Besides, optimization methodologies of related parameters, the differences of optimum values and the similarities of affecting trends on cavitation and sludge pretreatment efficiency were specifically pointed out, including ambient conditions, ultrasonic properties, and sludge characteristics. The research is a prerequisite for optimization of sludge US pretreatment efficiency in lab-scale and practical application. There is not-yet a comprehensive method to evaluate the efficiency of sludge US pretreatment, but some main parameters commonly used for this purpose are degree of sludge disintegration, proteins, particle size reduction, etc. Regarding US parameters, power input PUS, intensity IUS, and frequency FS seem to have significant effects. However, the magnitude of the effect of PUS and probe size in terms of IUS has not been clearly detailed. Investigating very low FS seems interesting but has not yet been taken into consideration. In addition, static pressure effect has been marginally studied only and investigation on the effect of pH prior to US process has been restricted. Their effects therefore should be varied separately and simultaneously with other related parameters, i.e. process conditions, ultrasonic properties, and sludge characteristics, to optimize sludge US pretreatment process. PMID- 26574098 TI - Investigation of drinking water bacterial community through high-throughput sequencing. PMID- 26574099 TI - Cadmium in soybeans and the relevance to human exposure. PMID- 26574100 TI - Absorption and recovery of n-hexane in aqueous solutions of fluorocarbon surfactants. AB - n-Hexane is widely used in industrial production as an organic solvent. As an industrial exhaust gas, the contribution of n-hexane to air pollution and damage to human health are attracting increasing attention. In the present study, aqueous solutions of two fluorocarbon surfactants (FSN100 and FSO100) were investigated for their properties of solubilization and dynamic absorption of n hexane, as well as their capacity for regeneration and n-hexane recovery by thermal distillation. The results show that the two fluorocarbon surfactants enhance dissolution and absorption of n-hexane, and their effectiveness is closely related to their concentrations in solution. For low concentration solutions (0.01%-0.30%), the partition coefficient decreases dramatically and the saturation capacity increases significantly with increasing concentration, but the changes for both are more modest when the concentration is over 0.30%. The FSO100 solution presents a smaller partition coefficient and a greater saturation capacity than the FSN100 solution at the same concentration, indicating a stronger solubilization for n-hexane. Thermal distillation is a feasible method to recover n-hexane from these absorption solutions, and to regenerate them. With 90sec heating at 80-85 degrees C, the recovery of n-hexane ranges between 81% and 85%, and the regenerated absorption solution maintains its original performance during reuse. This study provides basic information on two fluorocarbon surfactants for application in the treatment of industrial n-hexane waste gases. PMID- 26574101 TI - Effect of aeration rate on composting of penicillin mycelial dreg. AB - Pilot scale experiments with forced aeration were conducted to estimate effects of aeration rates on the performance of composting penicillin mycelial dreg using sewage sludge as inoculation. Three aeration rates of 0.15, 0.50 and 0.90L/(min.kg) organic matter (OM) were examined. The principal physicochemical parameters were monitored during the 32day composting period. Results showed that the higher aeration rate of 0.90L/(min.kg) did not corresponded to a longer thermophilic duration and higher rates of OM degradation; but the lower aeration rate of 0.15L/(min.kg) did induce an accumulation of NH4(+)-N contents due to the inhibition of nitrification. On the other hand, aeration rate has little effect on degradation of penicillin. The results show that the longest phase of thermophilic temperatures>=55 degrees C, the maximum NO3(-)-N content and seed germination, and the minimum C/N ratio were obtained with 0.50L/(min.kg) OM. Therefore, aeration rates of 0.50L/(min.kg) OM can be recommended for composting penicillin mycelial dreg. PMID- 26574102 TI - Emissions of fluorides from welding processes. AB - The levels of fluoride airborne particulates emitted from welding processes were investigated. They were sampled with the patented IOM Sampler, developed by J. H. Vincent and D. Mark at the Institute of Occupational Medicine (IOM), personal inhalable sampler for simultaneous collection of the inhalable and respirable size fractions. Ion chromatography with conductometric detection was used for quantitative analysis. The efficiency of fluoride extraction from the cellulose filter of the IOM sampler was examined using the standard sample of urban air particle matter SRM-1648a. The best results for extraction were obtained when water and the anionic surfactant N-Cetyl-N-N-N-trimethylammonium bromide (CTAB) were used in an ultrasonic bath. The limits of detection and quantification for the whole procedure were 8MUg/L and 24MUg/L, respectively. The linear range of calibration was 0.01-10mg/L, which corresponds to 0.0001-0.1mg of fluorides per m(3) in collection of a 20L air sample. The concentration of fluorides in the respirable fraction of collected air samples was in the range of 0.20 1.82mg/m(3), while the inhalable fraction contained 0.23-1.96mg/m(3) of fluorides during an eight-hour working day in the welding room. PMID- 26574103 TI - Piriformospora indica confers cadmium tolerance in Nicotiana tabacum. AB - Piriformospora indica, a root-colonizing endophytic fungus of Sebacinales, promotes plant growth and confers resistance against biotic and abiotic stresses. In order to confirm the influence of P. indica on growth, proline, malondialdehyde (MDA), chlorophyll, and cadmium (Cd) amounts in Nicotiana tabacum under Cd stress, hydroponics, pot and field trials were conducted. The results showed that P. indica can store Cd in plant roots and reduce leaf Cd content, reduce the concentration of MDA, and increase the proline and chlorophyll content and the activities of catalase, peroxidase, and superoxide dismutase under hydroponic Cd stress. RT-PCR analysis showed that the relative expression level of genes Gsh2, TaPCS1, oas1, GPX, and Hsp70 in colonized plants was 4.3, 1.4, 2.9, 1.7, and 6.9 fold higher than in un-colonized plants respectively. Cd exposure significantly reduced un-colonized plants' agronomic traits compared to P. indica-colonized ones. Our results suggested that P. indica can sequester Cd in roots, so that much less cadmium was transported to leaves, and the increased concentrations of antioxidant enzymes, pigments and proline contents, as well as the higher expression of stress-related phytochelatin biosynthesis genes in P. indica-inoculated plants, may also serve to protect N. tabacum plants against oxidative damage, enhancing Cd tolerance. PMID- 26574104 TI - Impacts of produced water origin on bacterial community structures of activated sludge. AB - The purpose of this study was to reveal how activated sludge communities respond to influent quality and indigenous communities by treating two produced waters from different origins in a batch reactor in succession. The community shift and compositions were investigated using Polymerase Chain Reaction-denaturing gradient gel electrophoresis (PCR-DGGE) and further 16S ribosomal DNA (rDNA) clone library analysis. The abundance of targeted genes for polycyclic aromatic hydrocarbon (PAH) degradation, nahAc/phnAc and C12O/C23O, was tracked to define the metabolic ability of the in situ microbial community by Most Probable Number (MPN) PCR. The biosystem performed almost the same for treatment of both produced waters in terms of removals of chemical oxygen demand (COD) and PAHs. Sludge communities were closely associated with the respective influent bacterial communities (similarity>60%), while one sludge clone library was dominated by the Betaproteobacteria (38%) and Bacteriodetes (30%) and the other was dominated by Gammaproteobacteria (52%). This suggested that different influent and water quality have an effect on sludge community compositions. In addition, the existence of catabolic genes in sludge was consistent with the potential for degradation of PAHs in the treatment of both produced waters. PMID- 26574105 TI - Impact of disinfection on drinking water biofilm bacterial community. AB - Disinfectants are commonly applied to control the growth of microorganisms in drinking water distribution systems. However, the effect of disinfection on drinking water microbial community remains poorly understood. The present study investigated the impacts of different disinfectants (chlorine and chloramine) and dosages on biofilm bacterial community in bench-scale pipe section reactors. Illumina MiSeq sequencing illustrated that disinfection strategy could affect both bacterial diversity and community structure of drinking water biofilm. Proteobacteria tended to predominate in chloraminated drinking water biofilms, while Firmicutes in chlorinated and unchlorinated biofilms. The major proteobacterial groups were influenced by both disinfectant type and dosage. In addition, chloramination had a more profound impact on bacterial community than chlorination. PMID- 26574106 TI - A review on current status of municipal solid waste management in India. AB - Municipal solid waste management is a major environmental issue in India. Due to rapid increase in urbanization, industrialization and population, the generation rate of municipal solid waste in Indian cities and towns is also increased. Mismanagement of municipal solid waste can cause adverse environmental impacts, public health risk and other socio-economic problem. This paper presents an overview of current status of solid waste management in India which can help the competent authorities responsible for municipal solid waste management and researchers to prepare more efficient plans. PMID- 26574107 TI - [Suicide Attempt and Suicide]. PMID- 26574108 TI - [Suicide Risk Assessment in the Clinical Practice Guidelines for the Diagnosis and Management of Depression in Colombia]. AB - INTRODUCTION: Suicide is the most serious complications of depression. It has high associated health costs and causes millions of deaths worldwide per year. Given its implications, it is important to know the factors that increase the risk of its occurrence and the most useful tools for addressing it. OBJECTIVES: To identify the signs and symptoms that indicate an increased risk of suicide, and factors that increase the risk in patients diagnosed with depression. To establish the tools best fitted to identify suicide risk in people with depression. METHOD: Clinical practice guidelines were developed, following those of the methodmethodological guidelines of the Ministry of Social Protection, to collect evidence and to adjust recommendations. Recommendations from the NICE90 and CANMAT guidelines were adopted and updated for questions found in these guidelines, while new recommendations were developed for questions not found in them. RESULTS: Basic points and recommendations are presented from a chapter of the clinical practice guidelines on depressive episodes and recurrent depressive disorder related to suicide risk assessment. Their corresponding recommendation levels are included. PMID- 26574109 TI - [Characterization of News on Suicide in the Printed Press in Colombia]. AB - INTRODUCTION: Suicide is a major public health problem. It is believed that the media plays an important role in the onset of suicidal behavior. Certain sub groups of the population (for instance, young people or those suffering from depression) can be especially vulnerable to engage in imitative suicidal behaviors. OBJECTIVES: To characterize news reports on suicide published in the printed press in Bogota. To identify strategies, models or structures used in the print media (newspapers) to report suicide cases. To establish whether the way of reporting suicide cases is appropriate according to the recommendations of the World Health Organization (WHO). MATERIALS AND METHODS: A detailed search was performed to find news on suicide or suicide attempts published in three Colombian newspapers -2 of them with national circulation (El Espectador and El Tiempo), and one with local circulation (El Espacio)-, during the period between August 2009 and August 2011. Compliance with WHO recommendations by the 3 newspapers was compared using Fisher tests; the frequency of news release was assessed using statistical control charts, and headlines were evaluated by lexicometric analysis. RESULTS: During the study period, a total of 135 items of news relating to cases occurring in Colombia were found. Although there were differences between the newspapers, none of them fully met the WHO recommendations. There was no clear trend in the way of presenting the news. Three styles were found in the presentation of news (suggestive, sensationalist, and revealing impact on survivors), which could be associated with each of the 3 newspapers evaluated. PMID- 26574110 TI - [Factors Associated With Suicide Attempts and Nonsuicidal Self-Injurious Behaviors in Patients With Eating Disorders]. AB - Suicide attempt (SA) and non-suicidal self-injurious behaviors (NSSI) have been described in patients with eating disorders (ED), and they have been associated with increased morbidity and poor prognosis. OBJECTIVES: To explore the presence of SA and NSSI in patients attending an outpatient ED program, as well as to evaluate the associated variables and the correlation between both types of behaviors. MATERIALS AND METHODS: A total of 908 patients of both sexes attending the Equilibrio outpatient program in Bogota were studied. The histories of SA and NSSI were systematically examined in the development of medical history by direct and structured questions to the patient, and then validated during interviews with the family. Sociodemographic and clinical variables, as well as history of traumatic experiences, were also studied. Simple frequencies were calculated, and a bivariate analysis was performed between SA, NSSI, and the other variables of the study. Finally, two models of association were designed for the multivariate analysis, using variables of clinical importance and statistical significance. RESULTS: SA sometime in their lives was reported by 13% of the patients, and 26% of them reported NSSI. The variables associated with SA were bipolar disorder (OR: 3.86, 95% CI; 2.4-6.1), borderline personality, purgative subtype of ED, and self-injury. Sexual abuse was associated with NSSI (OR: 3.48, 95%CI; 2.2-5.4), as well as bipolar disorder, trichotillomania, and suicide attempt. CONCLUSION: SA and NSSI are frequent in patients with eating disorders with multiple comorbidities, increased impulsivity and emotional dysregulation, and they should be explored and treated. PMID- 26574111 TI - [Risk Factors for Suicidal Ideation in Patients with Depressive Disorders in Colombia]. AB - INTRODUCTION: Suicidal ideation is a poor prognostic factor in patients with depression, due to the risk of suicide attempt or completed suicide. However, it is a relatively unexplored aspect in the Colombian population. It is important to identify the associated factors in order to develop appropriate treatment strategies. OBJECTIVE: To identify risk factors for suicidal ideation in patients with major depressive disorder between 18 and 65 years in 5 Colombian cities. METHODS: Data from 295 patients diagnosed with major depressive disorder were used from the Study of the Economic Burden of Depression in Colombia. The association between the clinical and psychosocial variables with the presence of suicidal ideation was assessed using two-level hierarchical models. RESULTS: Female sex was a factor associated with a lower risk of suicidal ideation. Factors associated with the presence of suicidal ideation include unemployment, smoking and alcohol use in the past 30 days, mental health perceived as fair or poor, diagnosis of double depression, inpatient treatment, low income, unemployment, and a major financial crisis in the last 2 years. CONCLUSIONS: Suicidal ideation is highly prevalent in patients with major depressive disorder. Risk factors associated with both the clinical and psychosocial domain must be carefully evaluated during risk assessment of patients with this diagnosis. PMID- 26574112 TI - [When a Suicide Attempt is Kid's Stuff]. AB - INTRODUCTION: Attempted suicide in children and adolescents is a disturbing and painful issue for patients, their families and physicians. Current medical literature provides little information about minors who attempt suicide, possibly because there is under-reporting of this condition as a diagnosis, or maybe because it is sometimes considered as a way for the child to draw attention. OBJECTIVE: To present the experience of the Department of Psychiatry (Universidad Nacional de Colombia) at the Hospital Infantil de La Misericordia, from 2003 to 2013. METHODS: An observational retrospective study was conducted by reviewing 213 cases of children and adolescents treated for attempted suicide at the Hospital Infantil de La Misericordia from January 1, 2003 to October 31, 2013, and who received hospital or outpatient care in Child Psychiatry. RESULTS: A review was performed of the diagnosis, the number of suicide attempts, the peak months of consultation for this reason, and the methods selected, as well as a detailed description of the group of patients under 12 years old, and those managed with outpatient follow-up. CONCLUSION: The average patient is a female teenager who becomes intoxicated with drugs. Most often, patients do not return to outpatient follow-up. Those with follow-up have multiple psychopathologies and a high level of suffering. The most common methods, other than poisoning by drugs, are hanging and jumping from heights. Patients under 12 years old generally have their first attempt by drug poisoning. There is a predominance of anxiety disorder and depression, with a strong association with cognitive dysfunction, as a vulnerability factor. PMID- 26574113 TI - [Suicide Ideation Among Medical Students: Prevalence and Associated Factors]. AB - INTRODUCTION: It is well documented that physicians have higher rates of suicide than the general population. This risk tends to increase even from the beginning of undergraduate training in medicine. There are few studies evaluating the frequency of suicidal behaviors in undergraduate medical students, particularly in Latin America. OBJECTIVE: To determine the lifetime prevalence and the variables associated with suicidal ideation and suicide attempts in a sample of medical students from the city of Bucaramanga, Colombia. MATERIALS AND METHODS: An analytical cross-sectional observational study was conducted to determine the lifetime prevalence of suicidal ideation and suicide attempts in a non-random sample of medical students enrolled in three medical schools in Bucaramanga. A self-administered questionnaire was voluntarily and anonymously answered by the participants. Validated versions of the CES-D and CAGE scales were used to assess the presence of depressive symptoms and problematic alcohol use, respectively. A multivariate logistic regression model was generated in order to adjust the estimates of variables associated with the outcome "suicidal ideation in life". RESULTS: The study sample consisted of 963 medical students, of which 57% (n=549) of the participants were women. The average age was 20.3 years (SD=2.3 years). Having had at least one episode of serious suicidal ideation in their lifetime was reported by 15.7% (n=149) of the students, with 5% (n=47) of the students reported having made at least one suicide attempt. Having taken antidepressants during their medical training was reported by 13.9% (n=131) of the students. The variables associated with the presence of suicidal ideation in the logistic regression model were: clinically significant depressive symptoms (OR: 6.9, 95% CI; 4.54-10.4), history of illicit psychoactive substance use (OR 2.8, 95% CI; 1.6-4.8), and perception of poor academic performance over the past year (OR: 2.2, 95% CI; 1.4-3.6). The logistic regression model correctly classified 85% of the subjects with a history of suicidal ideation. CONCLUSION: Suicidal ideation is a frequently occurring phenomenon in medical students. Medical schools need to establish screening procedures for early detection and intervention of students with emotional distress and suicide risk. PMID- 26574114 TI - [Sociodemographic Characterization of Suicidal Adults Over 60 Years Old: Bogota 2003-2007]. AB - OBJECTIVE: To identify the major epidemiological and sociodemographic characteristics of suicidal adults over 60 years old in Bogota between the years 2003 and 2007. METHODOLOGY: A descriptive-retrospective study was performed, mainly using information obtained from necropsy reports (n=98), taking into account selected epidemiological variables. The data were systematized using Epi Info 6.04 software, and were analyzed using contingency tables. RESULTS: Suicide victims of this population group are primarily male, having one of the highest suicide rates with respect to the whole population. The presence of chronic and disabling diseases was reported among the main motivations for suicide in males, while for women it was the presence of a mental disorder and/or loss of a loved one. Having family support did not affect suicide rates. The locality that had the highest suicide rates was the district of Los Martires, and there was no direct relationship between poverty rates or health insurance and the presence of the phenomenon. CONCLUSIONS: Although there has been a decrease in suicide rates for the population over 60 years old since 2003, suicide in elderly people remains a predominantly male phenomenon and an important public health problem. Due to its complexity in terms of multiple causes and multidimensionality, the protective and risk factors are just aspects to consider in terms of understanding the phenomenon and its prevention. PMID- 26574115 TI - [Depression and Life Satisfaction in People Over 60 Years Old in the City of Bogota: Survey of Health, Wellbeing and Aging (SABE)]. AB - BACKGROUND: There are multiple factors associated with suicide in elderly people and include, among others, depression, loss of independence, medical comorbidities, not being satisfied with life, or loss of hope. OBJECTIVE: To describe the prevalence of depression in a representative sample of the population over 60 years old and its associated factors. METHODS: A cross sectional study (Survey of Health, Wellbeing and Aging) was conducted in 2012. A structured questionnaire and the Yesavage depression scale were used in order to complete a descriptive analysis, as well as a chi-squared test of independence. RESULTS: The prevalence of depression was 26.3%. The associated factors are being female, low education, not receiving a pension, hypertension, a diagnosed mental illness, having had hunger in the first 15 years of life, and in the last week, no leisure activities, and worse self-perception of health. People, who are not satisfied with their lives, who do not feel that it is wonderful to live, and those who feel hopeless, are at increased risk of depression. CONCLUSIONS: There is a high prevalence of depression, and various factors associated with it, as previously reported in the literature. Poor life satisfaction was shown to be a factor related to depression. PMID- 26574116 TI - [Family, Suicide and Mourning]. AB - INTRODUCTION: Death is an event that always breaks into family life in a surprising way. Of all the deaths, suicide is the one which more strongly questions the functionality of a family and increases the risk of difficulties in the mourning process. Families in which a suicide has occurred are exposed to a greater possibility of disintegration, disorganization and pathological expressions in their members. OBJECTIVE: To present a reduced and circumscribed narrative revision, restricted to examine the relationship between suicide and the mourning process in the family. RESULTS: The suicide of a loved one is an event that may contribute to pathological grief and mental dysfunctions in surviving relatives. CONCLUSIONS: Death in the family is a natural phenomenon. However, death by suicide is one of the phenomena that can generate more alterations in the structure and organization of the family, due to the difficulty related to the mourning process. PMID- 26574117 TI - [Suicide in the Elderly]. AB - INTRODUCTION: Suicide is a public health problem worldwide, with multiple features and risk factors. It has some common and unique trends in each phase across the lifespan. OBJECTIVE: To review the medical literature related to suicide in the elderly, in order to determine the current status of this problem in the world, and especially in Colombia. METHOD: Literature review. RESULTS: There is a high volume of articles about suicide in general, even in Colombia, with many papers describing the problem in a comprehensive manner, but there is a need for more studies and publications on the scope of this problem in the elderly. PMID- 26574118 TI - Suicide Attempt and Suicide. PMID- 26574119 TI - Are two halves better than one whole? A comparison of the amount and quality of sleep obtained by healthy adult males living on split and consolidated sleep-wake schedules. AB - The aim of this study was to compare the quantity/quality of sleep obtained by people living on split and consolidated sleep-wake schedules. The study had a between-groups design, with 13 participants in a consolidated condition (all males, mean age of 22.5yr) and 16 participants in a split condition (all males, mean age of 22.6yr). Both conditions employed forced desynchrony protocols with the activity:rest ratio set at 2:1, but the consolidated condition had one sleep wake cycle every 28h (9.33+18.67), while the split condition had one sleep-wake cycle every 14h (4.67+9.33). Sleep was assessed using polysomnography. Participants in the split and consolidated conditions obtained 4.0h of sleep per 14h and 7.6h of sleep per 28h, respectively. Some differences between the groups indicated that sleep quality was lower in the split condition than the consolidated condition: the split sleeps had longer sleep onset latency (9.7 vs. 4.3min), more arousals (7.4 vs. 5.7 per hour in bed), and a greater percentage of stage 1 sleep (4.1% vs. 3.1%), than the consolidated sleeps. Other differences between the groups indicated that sleep quality was higher in the split condition than the consolidated condition: the split sleeps had a lower percentage of wake after sleep onset sleep (11.7% vs. 17.6%), and a greater percentage of slow wave sleep (30.2% vs. 23.8%), than the consolidated sleeps. These results indicate that the split schedule was not particularly harmful, and may have actually been beneficial, to sleep. Split work-rest schedules can be socially disruptive, but their use may be warranted in work settings where shiftworkers are separated from their normal family/social lives (e.g., fly-in fly-out mining) or where the need for family/social time is secondary to the task (e.g., emergency response to natural disasters). PMID- 26574120 TI - Sharing the wealth: Neuroimaging data repositories. PMID- 26574121 TI - e-Dermatology: social networks and other web based tools. AB - The use by patients of social networking sites and the Internet to look for health related information has already become an everyday phenomenon. If, as dermatologists, we want to be part of this new conversation and provide quality content, we will have to adapt to digital media and find new ways of communicating with both our patients and our colleagues. Dozens of Spanish dermatologists have already ventured into the online space and have begun to provide important content through blogs, which they also disseminate via the social media. However, the use of these new technologies can also pose certain risks from the standpoint of ethics and our codes of practice and even place an individual's digital reputation in jeopardy. Another aspect of this new situation is that the Internet produces information saturation, and the appropriate use of certain tools can help to improve our productivity and prevent such information overload or infoxication. PMID- 26574122 TI - Usefulness of the Paramedian Forehead Flap in Nasal Reconstructive Surgery: A Retrospective Series of 41 Patients. AB - INTRODUCTION: Surgical reconstruction of the external nose, a common site for nonmelanoma skin cancer, is difficult. Oncologic surgery often leaves large skin defects, occasionally involving the underlying cartilage and nasal mucosa. We describe our experience with the paramedian forehead flap for reconstruction of nasal defects. METHODOLOGY: We performed a retrospective study of consecutive patients in whom a paramedian forehead flap was used to repair surgical defects of the nose between July 2004 and March 2011. We describe the clinical and epidemiologic characteristics, the surgical technique, complications, secondary procedures, and cosmetic results. RESULTS: The series comprised 41 patients with a mean (SD) age of 67 (10.36) years. The majority were men (male to female ratio, 2.4:1). Associated risk factors included diabetes in 27% of patients, cardiovascular risk factors in 49%, and smoking or drinking in 19.5%. The tissue defects were distal in 80% of cases and nonpenetrating in 78%. The mean (SD) diameter was 21.6 (6.78) mm. Early postoperative complications occurred in 14.6% of patients and late complications in 31.7% (trap door effect in 22% and hair transposition in 19%), with a need for Readjustment in a second operation was needed in 19.5% of patients. The cosmetic results were considered acceptable or excellent in 90.2% of cases. DISCUSSION: The paramedian forehead flap is versatile and provides skin of a similar color and texture to that of the external nose. It has a reliable vascular pedicle that guarantees the viability not only of the flap but also of other tissues that may be used in combination, such as chondromucosal or chondrocutaneous grafts. Revision of the technique in a second operation may sometimes be required to achieve an optimal result. PMID- 26574123 TI - [Rethinking the organization for preventing abuse]. PMID- 26574124 TI - [A rich experience]. PMID- 26574125 TI - [The locations of mobile geriatric teams in France]. AB - Mobile geriatric teams fulfil several missions in healthcare facilities. They work within and outside hospitals. A nationwide study was carried out in 2011 and a task force was created within the French geriatric and gerontology society (SFGG) to standardise the practices of these teams in France and emphasise their place at the heart of the health care pathway of the elderly. PMID- 26574126 TI - [The role of external mobile geriatric teams in nursing homes]. AB - Since 2000, the mobile team of Bretonneau Hospital in Paris has helped to improve the assessment and care management of the elderly at home by strengthening the link between community health professionals and hospital geriatric services. In January 2008, an external mobile geriatric team working with nursing homes was created for the whole of the Paris area in order to strengthen the link between care homes accommodating often highly dependent elderly people and the hospital. PMID- 26574127 TI - [The mobile geriatric team of Bretonneau Hospital and nursing home professionals]. AB - In the wake of an experimental project, external mobile geriatric teams have been working in nursing homes in order to train the nursing teams in caring for geriatric pathologies. The mobile teams also give diagnostic and therapeutic recommendations in order to direct where necessary these dependent elderly people, often with multiple pathologies, towards geriatric care. PMID- 26574128 TI - [Benefit of a geriatric mobile team in the emergency departments: a ten-year review]. AB - A geriatric mobile team was created in the emergency department of Cochin Hospital in Paris, in 2005. This key player in the multi-disciplinary management of elderly patients in the emergency department and in the geriatric care pathway, showed, during its 10-year of existence, its utility. PMID- 26574129 TI - [Inter-disciplinary approach of a mobile team specialised in geriatric oncology]. AB - Ageing is an individual process. Chronological age does not reflect life expectancy or functional capacity. That is why, in geriatric oncology, the estimation of this capacity is a determining factor. An inter-disciplinary approach is necessary in order to coordinate the different players in the care and optimise the hospitalisation of elderly patients with multiple pathologies, all the more so when they are suffering from cancer. PMID- 26574130 TI - [The consultative missions of a mobile psychogeriatric unit]. AB - Helping elderly people over the age of 70 suffering from mental health problems to remain at home is one of the missions of the mobile psychogeriatric unit of Simone-Veil Hospital in Eaubonne. In a nursing home, then at home, the aim is to avoid certain hospitalisations. Institutions accept more readily residents with a history of psychiatric problems and the prescriptions. Furthermore, requests for intervention are better targeted by general practitioners for the benefit of the elderly patients. PMID- 26574131 TI - [Caregivers faced with anxiety-depressive disorders in elderly people with severe dementia]. AB - A survey of 104 caregivers in nursing homes assesses their knowledge of anxiety depressive disorders in patients with severe dementia with aphasia and their proposed treatment. Despite a lack of training, information and tools to assess these disorders and offer adapted care, this survey highlights in particular caregivers' concern for these issues. PMID- 26574132 TI - [Prescription for proton pump inhibitors in geriatrics]. AB - Proton pump inhibitors are widely prescribed, notably for the over 65s, despite there being significant side effects in the geriatric population. It is therefore important that doctors, caregivers and patients are fully aware of the recognised indications of PPIs and on the less well-known problems inherent to their prescription. PMID- 26574133 TI - [18/18 The cry during somnolence, morphine as a link]. PMID- 26574134 TI - [8/20 Water electrolyte disorders]. PMID- 26574135 TI - [Thromboaspiration in the treatment of ST segment elevation myocardial infarction]. AB - Routine manual thrombectomy during primary percutaneous coronary intervention might be intuitively justified. While older registers reported contradictory results, interventional cardiologists remained interested in using such devices during the mechanical treatment of acute myocardial infarction. The first studies were congruent to demonstrate a significant relationship between thromboaspiration and significant improvement of ST-segment elevation, lower distal embolization, despite TAPAS was the only to significantly reduce the mortality. Later studies were unable to confirm these promising data, avoiding routine manual thrombectomy prior to primary angioplasty to decrease cardiovascular mortality, recurrent myocardial infarction, cardiogenic shock or severe heart failure. Moreover, thrombectomy was associated with an increased rate of stroke. Should thrombectomy therefore be conclusively overlooked? It is presumably required to define which patient is eligible for thrombectomy, to define how to perfectly perform manual thrombectomy, to specify how to gently move towards the thrombus, the optimal pharmacological environment, the number of aspirations and the criterion to stop or to repeat aspiration. Indeed, while thrombectomy is nowadays scientifically downgraded, it remains of potential interest in numerous interventional cardiologists. PMID- 26574136 TI - [Ultrasound in emergency medicine]. AB - Ultrasound has revolutionized the practice of emergency medicine, particularly in prehospital setting. About a patient with dyspnea, we present the role of ultrasound in the diagnosis and emergency treatment. Echocardiography, but also hemodynamic ultrasound (vena cava) and lung exam are valuable tools. Achieving lung ultrasound and diagnostic value of B lines B are detailed. PMID- 26574137 TI - Neonatal emergency transport has played a key role in the regionalisation of perinatal care in the Liguria Region of Italy. PMID- 26574138 TI - Stephen Elledge and the DNA damage response. PMID- 26574139 TI - Editorial. PMID- 26574140 TI - Ethanol consumption produces a small increase in circulating miR-122 in healthy individuals. AB - INTRODUCTION: MicroRNA 122 (miR-122) is a new circulating biomarker for liver injury, which increases earlier than conventional markers in patients with acetaminophen hepatotoxicity. However, as co-ingestion of ethanol is common with drug overdose, a confounding effect of acute ethanol consumption on serum miR-122 must be examined. METHODS: Blood was collected from healthy volunteers before and after recreational consumption of ethanol. Routine biochemistry and haematology measurements were performed, and serum miR-122 was measured by qPCR. The primary outcome was the difference in serum miR-122 with ethanol consumption. RESULTS: We recruited 18 participants (72% male). Their mean serum ethanol concentration was 113 mg/dl (95% confidence interval [CI] 91-135 mg/dl) after consuming ethanol. Serum miR-122 increased from a mean of 71.3 million (95% CI 29.3-113.2 million) to 139.1 million (95% CI 62.6-215.7 million) copies/ml (2.2-fold increase). There was no significant difference in serum alanine aminotransferase activity before and after ethanol consumption. CONCLUSION: miR-122 increased with moderate ethanol consumption, but the fold change was modest. As increases with acetaminophen toxicity are 100- to 10 000-fold, moderate ethanol intoxication is unlikely to confound the use of this biomarker of hepatotoxicity. PMID- 26574141 TI - Reconstruction method as an independent risk factor for the postoperative decrease in hemoglobin in stage I gastric cancer. AB - BACKGROUND AND AIM: No study has compared the incidence of postoperative anemia between two reconstruction methods, Billroth-I (B-I) and Roux-en-Y (R-Y) reconstructions, after distal gastrectomy for gastric cancer (GC). In this study, we wished to examine the postoperative decrease in hemoglobin (Hb) as an indicator of iron-deficiency anemia. METHODS: We investigated a total of 119 consecutive patients who underwent distal gastrectomy with B-I or R-Y reconstruction for Stage I GC between 2006 and 2012. We retrospectively assessed the clinical data, including Hb results, of the first 2 years after surgery. RESULTS: Compared with B-I reconstruction, R-Y reconstruction was performed more frequently in older patients (P = 0.017), and it was associated with a longer surgical duration (P < 0.001), a larger amount of blood loss (P = 0.031), a higher incidence of stasis (P = 0.044), and a greater decrease in Hb for the first 2 years after surgery. Univariate and multivariate analyses identified that R-Y reconstruction was the only risk factor (P = 0.0487; odds ratio = 2.755; 95% confidence interval = 1.01-7.91) for a decrease in Hb, independent of age, tumor location, postoperative complications, and other factors. In addition, an age >= 75 was identified as an independent risk factor for a decrease in Hb, particularly for patients underwent R-Y reconstruction (P = 0.033; odds ratio = 6.99; 95% confidence interval = 1.15-68.3) according to the multivariate analysis. CONCLUSIONS: Billroth-I reconstruction might be preferable for the purpose of preventing a decrease in Hb in stage I GC patients, particularly in older patients. PMID- 26574142 TI - Letter in response to: "Stimulant-induced hyperthermia and ice-water submersion: practical considerations". PMID- 26574143 TI - Elevated H2 O2 levels in trinitrobenzene sulfate-induced colitis rats contributes to visceral hyperalgesia through interaction with the transient receptor potential ankyrin 1 cation channel. AB - BACKGROUND AND AIM: Inflammatory bowel disease is associated with chronic abdominal pain. Transient receptor potential ankyrin 1 (TRPA1) is a well-known pain sensor expressed in primary sensory neurons. Recent studies indicate that reactive oxygen species such as hydrogen peroxide (H2 O2 ) may activate TRPA1. METHODS: Colonic inflammation was induced by intra-colonic administration of trinitrobenzene sulfate (TNBS) in adult male Sprague-Dawley rats. Visceromotor response (VMR) to colorectal distention (CRD) was recorded to evaluate the visceral hyperalgesia. Rats were sacrificed 1 day after treatment with saline or TNBS; colonic tissues from the inflamed region were removed and then processed to assess the H2 O2 content. H2 O2 scavenger N-acetyl-l-cysteine or a TRPA1 antagonist, HC-030031, was intravenously administrated to the TNBS-treated rats or saline-treated rats. In a parallel experiment, intra-colonic H2 O2 -induced visceral hyperalgesia in naive rats and the effect of intravenous HC-030031 were measured based on the VMR to CRD. RESULTS: Trinitrobenzene sulfate treatment resulted in significant increase in VMR to CRD at day 1. The H2 O2 content in the inflamed region of the colon in TNBS-treated rats was significantly higher than that of saline-treated rats. N-acetyl-l-cysteine or HC-030031 significantly suppressed the enhanced VMR in TNBS-treated rats while saline-treated rats remained unaffected. Moreover, blockade of TRPA1 activation by HC-030031 significantly reversed the exogenous H2 O2 -induced visceral hyperalgesia. CONCLUSION: These results suggest that H2 O2 content of the colonic tissue is increased in the early stage of TNBS-induced colitis. The increased H2 O2 content may contribute to the visceral hyperalgesia by activating TRPA1. PMID- 26574144 TI - Novel self-assembled mesalamine-sucralfate complexes: preparation, characterization, and formulation aspects. AB - Two well-known active agents, mesalamine (MES) and sucralfate (SUC), were investigated for possible utilization as fixed-dose combination product. The anti inflammatory action of MES in association with bioadhesiveness and mucosal healing properties of SUC were considered promising for the development of a new compound containing both molecules, aimed as an improved treatment of ulcerative colitis. The present study investigates the capacity of the two active agents to interact and generate a new and stable entity via self-assembling. Spray-drying was used to co-process the two active principles from an aqueous mixture where the ratio MES:SUC was in the range 25:75, 50:50, and 75:25. The structural data (X-Ray, FTIR, SEM, DSC, and (1)H NMR) have shown that MES and SUC are interacting leading to complexes with properties differing from those of each separate active agent and from their physical blends. (1)H NMR results indicated that complexation occurred when the aqueous suspensions of drugs were mixed, prior to spray-drying. Drug-drug self-assembling was the driving mechanism in the formation of the new entity. Based on the structural data, a hypothetical structure of the complex was proposed. Co-processing of MES and SUC represents a simple and useful procedure to prepare new self-assembled compounds by valorizing the ionic interactions between the two entities. Preliminary studies with oral solid dosage forms based on MES-SUC complexes tested in vitro have shown a controlled MES release, opening the perspective of a new colon-targeted delivery system and a novel class of compounds with therapeutic application in inflammatory bowel diseases. PMID- 26574145 TI - EDUCATION AND IMAGING. Gastrointestinal: Positron emission tomography/computed tomography imaging of peritoneal carcinomatosis secondary to prostate adenocarcinoma. PMID- 26574146 TI - Impact of physiological, pathological and environmental factors on the expression and activity of human cytochrome P450 2D6 and implications in precision medicine. AB - With only 1.3-4.3% in total hepatic CYP content, human CYP2D6 can metabolize more than 160 drugs. It is a highly polymorphic enzyme and subject to marked inhibition by a number of drugs, causing a large interindividual variability in drug clearance and drug response and drug-drug interactions. The expression and activity of CYP2D6 are regulated by a number of physiological, pathological and environmental factors at transcriptional, post-transcriptional, translational and epigenetic levels. DNA hypermethylation and histone modifications can repress the expression of CYP2D6. Hepatocyte nuclear factor-4alpha binds to a directly repeated element in the promoter of CYP2D6 and thus regulates the expression of CYP2D6. Small heterodimer partner represses hepatocyte nuclear factor-4alpha mediated transactivation of CYP2D6. GW4064, a farnesoid X receptor agonist, decreases hepatic CYP2D6 expression and activity while increasing small heterodimer partner expression and its recruitment to the CYP2D6 promoter. The genotypes are key determinants of interindividual variability in CYP2D6 expression and activity. Recent genome-wide association studies have identified a large number of genes that can regulate CYP2D6. Pregnancy induces CYP2D6 via unknown mechanisms. Renal or liver diseases, smoking and alcohol use have minor to moderate effects only on CYP2D6 activity. Unlike CYP1 and 3 and other CYP2 members, CYP2D6 is resistant to typical inducers such as rifampin, phenobarbital and dexamethasone. Post-translational modifications such as phosphorylation of CYP2D6 Ser135 have been observed, but the functional impact is unknown. Further functional and validation studies are needed to clarify the role of nuclear receptors, epigenetic factors and other factors in the regulation of CYP2D6. PMID- 26574147 TI - Hepatobiliary and Pancreatic: Acute liver injury induced by Vigna angularis (adzuki bean) pastry. PMID- 26574148 TI - Nivolumab for treating non-small cell lung cancer. AB - INTRODUCTION: Diversion of the immune checkpoint PD-1/PD-L1 by a tumor in order to escape antitumor immunity is a hallmark of NSCLC, but offers promising new strategies. Nivolumab, a fully human monoclonal antibody, is the first PD-1 inhibitor to be approved to treat metastatic NSCLC after exciting results obtained from clinical trials. AREAS COVERED: This review aims to:) clarify the mechanism of action and toxicities of PD-1 inhibitors; recapitulate the results from various clinical trials that have evaluated nivolumab as a monotherapy for metastatic NSCLC; discuss the clinical and translational research axes to better use this molecule; and summarize the therapeutic combinations currently under evaluation. EXPERT OPINION: The contribution of this molecule to treat NSCLC is undeniable, making it a new standard of care after prior chemotherapy. Its toxicity profile is favorable but a good knowledge of new and potentially severe immune-related adverse effects such as endocrinopathy or interstitial pneumonitis is essential for its early detection and management. Better selection of patients is needed, particularly based on the discovery of predictive biomarkers, such as PD-L1 expression. Multiple associations with other checkpoint inhibitors, chemotherapy and targeted therapies are currently being studied and should pave the way toward new uses for this drug. PMID- 26574149 TI - The suppressive effect of nucleos(t)ide analogue treatment on the incidence of hepatocellular carcinoma in chronic hepatitis B patients. AB - The development of nucleos(t)ide analogues (NA) has influenced hepatitis B virus management. However, the annual incidence rate during NA treatment has been reported to be 0.3-1.2% in non-cirrhosis cases and 1.8-6.0% in cirrhosis cases, indicating that the suppressive effect of NA treatment on hepatocellular carcinoma (HCC) would be insufficient. Past studies, including one randomized control trial that compared lamivudine treatment with placebo, have revealed that NA treatment could suppress the incidence of HCC in patients with advanced fibrosis. However, it remains unknown whether NA treatment can suppress the incidence of HCC in chronic hepatitis patients without advanced fibrosis. The HCC incidence in patients treated with entecavir was similar to that of those treated with lamivudine, although entecavir exhibits a stronger viral suppression than lamivudine. The following risk factors related to the incidence of HCC during NA treatment have been identified: older age, male gender, pre-existing cirrhosis, a family clustering of hepatitis B virus, lower platelet counts, and higher hepatitis B core-related antigens as baseline factors and higher alpha fetoprotein levels as an on-treatment factor. Conversely, the loss of the hepatitis B surface antigen (HBsAg) by interferon or NA was correlated with a lower HCC incidence rate. Because interferon treatment has much more effects on reducing HBsAg levels compared with NA treatment, a combination treatment with NA and pegylated interferon can bring additional reduction of HBsAg levels compared with NA monotherapy. Further study is needed to clarify this. PMID- 26574150 TI - Statin pretreatment inhibits the lipopolysaccharide-induced epithelial mesenchymal transition via the downregulation of toll-like receptor 4 and nuclear factor-kappaB in human biliary epithelial cells. AB - BACKGROUND AND AIM: Epithelial-mesenchymal transition (EMT) of biliary epithelial cells (BECs) plays an important role in biliary fibrosis. This study investigated the effects of simvastatin on the lipopolysaccharide (LPS)-induced EMT and related signal pathways in BECs. METHODS: Biliary epithelial cells were exposed to LPS (2 ug/mL) or transforming growth factor beta1 (TGF-beta1) (5 ng/mL) for 5 days. The EMT was assessed by a gain of mesenchymal cell markers (vimentin, N cadherin, slug, and Twist-1) and a loss of epithelial cell markers (E-cadherin). The effects of simvastatin on the EMT induced by LPS or TGF-beta1 were determined by the changes in the levels of EMT markers and TLR4 and in the c-Jun N-terminal kinase (JNK), p38, and nuclear factor-kappaB (NF-kappaB) signaling pathways. RESULTS: Compared with the BECs treated with LPS alone, co-treatment with simvastatin and LPS induced an increase in the expression of E-cadherin and decreases in the expression levels of mesenchymal cell markers. The LPS-induced TLR4 expression level was slightly decreased by co-treatment with simvastatin. LPS-induced BEC growth was markedly inhibited by co-treatment with simvastatin. Furthermore, pretreatment with simvastatin inhibited the LPS-induced EMT in BECs by downregulating NF-kappaB and JNK phosphorylation. The suppressive effects of simvastatin pretreatment on the induction of the EMT by TGF-beta1 were also demonstrated in H69 cells. CONCLUSIONS: Our results demonstrate that LPS or TGF beta1 promote the EMT in BECs that that pretreatment with simvastatin inhibited the induced EMT by downregulating toll-like receptor 4 and NF-kappaB phosphorylation. This finding suggests that simvastatin can be considered a new agent for preventing biliary fibrosis associated with the EMT of BECs. PMID- 26574151 TI - Psychological treatments for adults with posttraumatic stress disorder: A systematic review and meta-analysis. AB - Numerous guidelines have been developed over the past decade regarding treatments for Posttraumatic stress disorder (PTSD). However, given differences in guideline recommendations, some uncertainty exists regarding the selection of effective PTSD therapies. The current manuscript assessed the efficacy, comparative effectiveness, and adverse effects of psychological treatments for adults with PTSD. We searched MEDLINE, Cochrane Library, PILOTS, Embase, CINAHL, PsycINFO, and the Web of Science. Two reviewers independently selected trials. Two reviewers assessed risk of bias and graded strength of evidence (SOE). We included 64 trials; patients generally had severe PTSD. Evidence supports efficacy of exposure therapy (high SOE) including the manualized version Prolonged Exposure (PE); cognitive therapy (CT), cognitive processing therapy (CPT), cognitive behavioral therapy (CBT)-mixed therapies (moderate SOE); eye movement desensitization and reprocessing (EMDR) and narrative exposure therapy (low-moderate SOE). Effect sizes for reducing PTSD symptoms were large (e.g., Cohen's d ~-1.0 or more compared with controls). Numbers needed to treat (NNTs) were <4 to achieve loss of PTSD diagnosis for exposure therapy, CPT, CT, CBT mixed, and EMDR. Several psychological treatments are effective for adults with PTSD. Head-to-head evidence was insufficient to determine these treatments' comparative effectiveness, and data regarding adverse events was absent from most studies. PMID- 26574152 TI - Double-Stranded Ligation Assay for the Rapid Multiplex Quantification of MicroRNAs. AB - MicroRNAs are auspicious candidates for a new generation of biomarkers. The detection of microRNA panels in body fluids promises early diagnosis of many diseases, including cancer or acute coronary syndrome. For a fast, sensitive, and specific detection of microRNA panels on the bedside, medical point-of-care systems that measure those biomarkers are required. As microchips are promising technical tools for a robust signal measurement at biochemical interfaces, we developed an assay for the electrochemical multiplex quantification of microRNAs on a CMOS chip with interdigitated gold electrode sensor positions. The method is based on the formation of a tripartite hybridization complex and subsequent both sided ligation of the target nucleic acid to a reporter and capture strand. With a time to results of 30 min, the reported assay achieves a limit of detection below 1 pM, at a specificity down to single mismatch discrimination. It also offers very good signal dynamics between 1 pM and 1 nM, thus, allowing reliable quantification of the detected microRNAs and easy implementation into automated devices due to a simple workflow. PMID- 26574154 TI - Attribution of human characteristics and bullying involvement in childhood: Distinguishing between targets. AB - This investigation researched the association between the attribution of human characteristics and bullying involvement in children by distinguishing between targets. Study 1 focused on the attribution of human characteristics by bullies, victims, bully/victims, and non-involved children toward friends and non-friends. The data from 405 children (M = 10.7 years old) showed that they attributed fewer prosocial and more antisocial human characteristics to non-friends than to friends. Moreover, boy victims attributed fewer prosocial human characteristics to non-friends than boy bullies and non-involved boys did. In addition, victims attributed more antisocial human characteristics to non-friends than non-involved children did. Study 2 addressed bullies', victims', bully/victims', and non involved children's attribution of human characteristics to each other. The data of 264 children (M = 10.0 years old) showed that bullies, victims, and bully/victims attributed fewer prosocial and more antisocial human characteristics to each other than to non-involved children. Non-involved children attributed fewer prosocial human characteristics to bully/victims than to bullies and victims, and more antisocial human characteristics to bully/victims than to victims. In addition, girls attributed more prosocial and fewer antisocial human characteristics to girls than to boys, whereas boys did not distinguish between girls and boys. Based on these findings, suggestions for future research are provided and implications for bullying prevention and intervention are discussed. Aggr. Behav. 42:394-403, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26574153 TI - Intravoxel Incoherent Motion Diffusion-weighted Magnetic Resonance Imaging for Monitoring the Early Response to ZD6474 from Nasopharyngeal Carcinoma in Nude Mouse. AB - Early therapeutic effects of anti-angiogenic agent ZD6474 upon nasopharyngeal carcinoma (NPC) in nude mouse were monitored by using intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI). Mice bearing NPC underwent IVIM DWI at baseline and after 1, 3, and 7 days of treatment with ZD6474 or vehicle (n = 12 per group). Parameters of apparent diffusion coefficient (ADC), true diffusion coefficient (D), perfusion fraction (f), and blood pseudodiffusion coefficient (D*) at different time points were compared between the two groups or within the treated group. In the treated group, the perfusion-related parameters f and D* of the tumors decreased significantly on day 1 while the diffusion related parameters ADC and D were significantly higher beginning on day 3 compared with the control group. The decreases in f on day 1 and D* on day 3 were moderately correlated with the smaller tumor size change on day 7. Moderate correlations were established between MVD and f and D* as well as between increased TUNEL or decreased Ki-67 index and ADC and D. This study supports that IVIM DWI is sensitive to detect the ZD6474-induced changes in NPC in nude mouse and the f parameter could predict early response to anti-angiogenic treatment. PMID- 26574155 TI - Interaction of cationic dodecyl-trimethyl-ammonium bromide with oxy-HbGp by isothermal titration and differential scanning calorimetric studies: Effect of proximity of isoelectric point. AB - In this work, isothermal titration and differential scanning calorimetric methods, in combination with pyrene fluorescence emission and dynamic light scattering have been used to investigate the interaction of dodecyltrimethylammonium bromide (DTAB) with the giant extracellular Glossoscolex paulistus hemoglobin (HbGp) in the oxy-form, at pH values around the isoelectric point (pI ~ 5.5). Our ITC results have shown that the interaction of DTAB with the hemoglobin is more intense at pH 7.0, with a smaller cac (critical aggregation concentration) value. The increase of protein concentration does not influence the cac value of the interaction, at both pH values. Therefore, the beginning of the DTAB-oxy-HbGp premicellar aggregates formation, in the cac region, is not affected by the increase of protein concentration. HSDSC studies show higher Tm values at pH 5.0, in the absence and presence of DTAB, when compared with pH 7.0. Furthermore, at pH 7.0, an aggregation process is observed with DTAB in the range from 0.75 to 1.5 mmol/L, noticed by the exothermic peak, and similar to that observed for pure oxy-HbGp, at pH 5.0, and in the presence of DTAB. DLS melting curves show a decrease on the hemoglobin thermal stability for the oxy-HbGp-DTAB mixtures and formation of larger aggregates, at pH 7.0. Our present data, together with previous results, support the observation that the protein structural changes, at pH 7.0, occur at smaller DTAB concentrations, as compared with pH 5.0, due to the acidic pI of protein that favors the oxy-HbGp cationic surfactant interaction at neutral pH. PMID- 26574157 TI - Prediction of morbidly adherent placenta using a scoring system. AB - OBJECTIVE: To evaluate the accuracy of an ultrasound-based scoring system for diagnosing morbidly adherent placenta (MAP). METHODS: This study included pregnant women referred to our ultrasound unit during 2013-2015 because of suspected MAP on a previous ultrasound examination or because they had at least one previous Cesarean delivery. All women were assessed using a scoring system based on the following: number and size of placental lacunae; obliteration of the demarcation between the uterus and placenta; placental location; color Doppler signals within placental lacunae; hypervascularity of the placenta-bladder and/or uteroplacental interface zone; and number of previous Cesarean deliveries. Each criterion was assigned 0, 1 or 2 points and the sum of points yielded the final score. Patients were classified into low, moderate or high probability for MAP based on the final score. The presence of MAP was determined by the surgeon at delivery and clinical descriptions were documented in the electronic patient file. Pathological diagnoses were available only in cases that underwent hysterectomy. RESULTS: In total, 258 pregnant women were included in the study, of whom 23 (8.9%) were diagnosed with MAP. There was a statistically significant difference in the prevalence of MAP when women were grouped according to the scoring system, with 0.9%, 29.4% and 84.2% in the low, moderate and high probability groups, respectively (P < 0.0001). All sonographic criteria of the scoring system were significantly associated with MAP (P < 0.0001). Receiver operating characteristics (ROC) curves for prediction of MAP using the number of placental lacunae and obliteration of the uteroplacental demarcation yielded an area under the ROC curve of 0.94 (95% CI, 0.86-1.00). CONCLUSIONS: Our proposed scoring system is highly predictive of MAP in patients at risk. This allows an adequate multidisciplinary team approach for the planning and timing of delivery in such cases. Copyright (c) 2015 ISUOG. Published by John Wiley & Sons Ltd. PMID- 26574156 TI - Trypanosoma cruzi P21: a potential novel target for chagasic cardiomyopathy therapy. AB - Chagas disease, which is caused by the parasite Trypanosoma cruzi, is an important cause of cardiomyopathy in Latin America. It is estimated that 10%-30% of all infected individuals will acquire chronic chagasic cardiomyopathy (CCC). The etiology of CCC is multifactorial and involves parasite genotype, host genetic polymorphisms, immune response, signaling pathways and autoimmune progression. Herein we verified the impact of the recombinant form of P21 (rP21), a secreted T. cruzi protein involved in host cell invasion, on progression of inflammatory process in a polyester sponge-induced inflammation model. Results indicated that rP21 can recruit immune cells induce myeloperoxidase and IL-4 production and decrease blood vessels formation compared to controls in vitro and in vivo. In conclusion, T. cruzi P21 may be a potential target for the development of P21 antagonist compounds to treat chagasic cardiomyopathy. PMID- 26574158 TI - An unusual foreign body. PMID- 26574159 TI - Pneumothorax following bronchoalveolar lavage for the diagnosis of non tuberculous mycobacterial infection. An "atypical" complication of bronchoscopy? PMID- 26574160 TI - A comparison of the intrasubject variation in drug exposure between generic and brand-name drugs: a retrospective analysis of replicate design trials. AB - AIMS: The aim of the present study was to investigate whether differences in total and peak drug exposure upon generic substitution are due to differences between formulations or to intrasubject pharmacokinetic variability of the active substance. METHODS: The study was designed as a retrospective reanalysis of existing studies. Nine replicate design bioequivalence studies representing six drug classes - i.e. for alendronate, atorvastatin, cyclosporin, ebastine, exemestane, mycophenolate mofetil, and ropinirole - were retrieved from the Dutch Medicines Regulatory Authority. RESULTS: In most studies, the intrasubject variability in total and peak drug exposure was comparable for the brand-name [in the range 0.01-0.24 for area under the concentration-time curve (AUCt ) and 0.02 0.29 for peak plasma concentration (Cmax ) on a log scale] and generic (0.01-0.23 for AUCt and 0.08-0.33 for Cmax ) drugs, and was comparable with the intrasubject variability upon switching between those drugs (0.01-0.23 for AUCt and 0.06-0.33 for Cmax ). The variance related to subject-by-formulation interaction could be considered negligible (-0.069 to 0.047 for AUCt and -0.091 to 0.02 for Cmax ). CONCLUSION: In the investigated studies, the variation in total and peak exposure seen when a patient is switched from a brand-name to a generic drug is comparable with that seen following repeated administration of the brand-name drug in the patient. Only the intrasubject variability seems to play a crucial and decisive role in the variation in drug exposure seen; no additional formulation-dependent variation in exposure is observed upon switching. Thus, our data support that, for the medicines that were included in the present investigation, from a clinical pharmacological perspective, the benefit-risk balance of a generic drug is comparable with that of the brand-name drug. PMID- 26574161 TI - Dogs cast NETs too: Canine neutrophil extracellular traps in health and immune mediated hemolytic anemia. AB - Neutrophil extracellular traps (NETs) are webs of DNA and protein with both anti microbial and pro-thrombotic properties which have not been previously reported in dogs. To confirm dog neutrophils can form NETs, neutrophils were isolated from healthy dogs, and stimulated in vitro with 2MUM, 8MUM, 31MUM, and 125MUM platelet activating factor (PAF) or 0.03MUM, 0.1MUM, 0.4MUM, 1.6MUM and 6.4MUM phorbol-12 myristate-13-acetate (PMA). Extracellular DNA was measured using the cell impermeable dye Sytox Green every hour for 4h. At 4h, extracellular DNA was significantly greater than non-stimulated cells at concentrations >=31MUM and >=0.1MUM for PAF and PMA, respectively. Cells stimulated with 31.25MUM PAF reached maximal fluorescence by 1h, whereas maximal fluorescence was not achieved until 2h for cells stimulated with 0.1MUM PMA. Immunofluorescent imaging using DAPI and anti-elastase antibody confirmed that extracellular DNA is released as NETs. As NETs have been implicated in thrombosis, nucleosomes, a marker correlated with NET formation, were measured in the serum of dogs with the thrombotic disorder primary immune-mediated hemolytic anemia (IMHA) (n=7) and healthy controls (n=20) using a commercially available ELISA. NETs were significantly higher in IMHA cases than controls (median 0.12 and 0.90, respectively, p=0.01), but there were large positive interferences associated with hemolysis and icterus. In summary, the study is the first to describe NET generation by canine neutrophils and provides preliminary evidence that a marker associated with NETs is elevated in IMHA. However, this apparent elevation must be interpreted with caution due to the effect of interference, emphasizing the need for a more specific and robust assay for NETs in clinical samples. PMID- 26574163 TI - Is ORIF actually better than the indirect fixation for treating intra-articular fractures of the base of the thumb metacarpal? PMID- 26574162 TI - Human placental renin-angiotensin system in normotensive and pre-eclamptic pregnancies at high altitude and after acute hypoxia-reoxygenation insult. AB - A functioning placental renin-angiotensin system (RAS) appears necessary for uncomplicated pregnancy and is present during placentation, which occurs under low oxygen tensions. Placental RAS is increased in pre-eclampsia (PE), characterised by placental dysfunction and elevated oxidative stress. We investigated the effect of high altitude hypoxia on the RAS and hypoxia-inducible factors (HIFs) by measuring mRNA and protein expression in term placentae from normotensive (NT) and PE women who delivered at sea level or above 3100 m, using an explant model of hypoxia-reoxygenation to assess the impact of acute oxidative stress on the RAS and HIFs. Protein levels of prorenin (P = 0.049), prorenin receptor (PRR; P = 0.0004), and angiotensin type 1 receptor (AT1R, P = 0.006) and type 2 receptor (AT2R, P = 0.002) were all significantly higher in placentae from NT women at altitude, despite mRNA expression being unaffected. However, mRNA expression of all RAS components was significantly lower in PE at altitude than at sea level, yet PRR, angiotensinogen (AGT) and AT1R proteins were all increased. The increase in transcript and protein expression of all the HIFs and NADPH oxidase 4 seen in PE compared to NT at sea level was blunted at high altitude. Experimentally induced oxidative stress stimulated AGT mRNA (P = 0.04) and protein (P = 0.025). AT1R (r = 0.77, P < 0.001) and AT2R (r = 0.81, P < 0.001) mRNA both significantly correlated with HIF-1beta, whilst AT2R also correlated with HIF-1alpha (r = 0.512, P < 0.013). Our observations suggest that the placental RAS is responsive to changes in tissue oxygenation: this could be important in the interplay between reactive oxygen species as cell-signalling molecules for angiogenesis and hence placental development and function. PMID- 26574164 TI - Piezoresistive AFM cantilevers surpassing standard optical beam deflection in low noise topography imaging. AB - Optical beam deflection (OBD) is the most prevalent method for measuring cantilever deflections in atomic force microscopy (AFM), mainly due to its excellent noise performance. In contrast, piezoresistive strain-sensing techniques provide benefits over OBD in readout size and the ability to image in light-sensitive or opaque environments, but traditionally have worse noise performance. Miniaturisation of cantilevers, however, brings much greater benefit to the noise performance of piezoresistive sensing than to OBD. In this paper, we show both theoretically and experimentally that by using small-sized piezoresistive cantilevers, the AFM imaging noise equal or lower than the OBD readout noise is feasible, at standard scanning speeds and power dissipation. We demonstrate that with both readouts we achieve a system noise of ~0.3 A at 20 kHz measurement bandwidth. Finally, we show that small-sized piezoresistive cantilevers are well suited for piezoresistive nanoscale imaging of biological and solid state samples in air. PMID- 26574165 TI - History and origin of the HIV-1 subtype C epidemic in South Africa and the greater southern African region. AB - HIV has spread at an alarming rate in South Africa, making it the country with the highest number of HIV infections. Several studies have investigated the histories of HIV-1 subtype C epidemics but none have done so in the context of social and political transformation in southern Africa. There is a need to understand how these processes affects epidemics, as socio-political transformation is a common and on-going process in Africa. Here, we genotyped strains from the start of the epidemic and applied phylodynamic techniques to determine the history of the southern Africa and South African epidemic from longitudinal sampled data. The southern African epidemic's estimated dates of origin was placed around 1960 (95% HPD 1956-64), while dynamic reconstruction revealed strong growth during the 1970s and 80s. The South African epidemic has a similar origin, caused by multiple introductions from neighbouring countries, and grew exponentially during the 1980s and 90s, coinciding with socio-political changes in South Africa. These findings provide an indication as to when the epidemic started and how it has grown, while the inclusion of sequence data from the start of the epidemic provided better estimates. The epidemic have stabilized in recent years with the expansion of antiretroviral therapy. PMID- 26574166 TI - Decoupling production from growth by magnesium sulfate limitation boosts de novo limonene production. AB - The microbial production of isoprenoids has recently developed into a prime example for successful bottom-up synthetic biology or top-down systems biology strategies. Respective fermentation processes typically rely on growing recombinant microorganisms. However, the fermentative production of isoprenoids has to compete with cellular maintenance and growth for carbon and energy. Non growing but metabolically active E. coli cells were evaluated in this study as alternative biocatalyst configurations to reduce energy and carbon loss towards biomass formation. The use of non-growing cells in an optimized fermentation medium resulted in more than fivefold increased specific limonene yields on cell dry weight and glucose, as compared to the traditional growing-cell-approach. Initially, the stability of the resting-cell activity was limited. This instability was overcome via the optimization of the minimal fermentation medium enabling high and stable limonene production rates for up to 8 h and a high specific yield of >=50 mg limonene per gram cell dry weight. Omitting MgSO4 from the fermentation medium was very promising to prohibit growth and allow high productivities. Applying a MgSO4 -limitation also improved limonene formation by growing cells during non-exponential growth involving a reduced biomass yield on glucose and a fourfold increase in specific limonene yields on biomass as compared to non-limited cultures. The control of microbial growth via the medium composition was identified as a key but yet underrated strategy for efficient isoprenoid production. Biotechnol. Bioeng. 2016;113: 1305-1314. (c) 2015 Wiley Periodicals, Inc. PMID- 26574167 TI - In defence of reviews of small trials: underpinning the generation of evidence to inform practice. PMID- 26574168 TI - Impact of natural killer cells on chronic hepatitis C and hepatocellular carcinoma. AB - Natural killer (NK) cells are involved in the pathogenesis of hepatitis C viral (HCV) infection and hepatocellular carcinoma (HCC). Recent immunological progresses have revealed the molecular mechanisms of activation or inhibition of NK cells. In patients infected with HCV, the percentages of NK cells are decreased and the NK receptor expression and function of NK cells including cytotoxicity and cytokine production are altered. These alterations in NK cells are associated with persistent infection with HCV, liver injury, liver fibrosis and liver carcinogenesis. In HCV treatment, NK cells play a role in the eradication of HCV in both interferon (IFN)-based therapy and IFN-free therapy using direct-acting antivirals (DAA). In HCC patients, the exhaustion of NK cells that represents lower cytotoxicity and impaired cytokine production may contribute to the progression of HCC. Several immunotherapies targeting NK cells have been reported. NK cell transfer and NK-activating gene therapy have been demonstrated to be effective in mouse liver cancer models and several clinical trials are ongoing. Recently, the role of major histocompatibility complex class I-related chain A (MICA), a human ligand of NKG2D, has attracted attention in the development of HCC. The expression of MICA could be controlled by anti-HCC drugs including sorafenib. A new chemo-immunotherapy may be expected in the treatment of HCC. In this review, we summarize the impact of NK cells on chronic hepatitis C and HCC. PMID- 26574169 TI - Heterogeneity and Turnover of Intermediates during Amyloid-beta (Abeta) Peptide Aggregation Studied by Fluorescence Correlation Spectroscopy. AB - Self-assembly of amyloid beta (Abeta) peptide molecules into large aggregates is a naturally occurring process driven in aqueous solution by a dynamic interplay between hydrophobic interactions among Abeta molecules, which promote aggregation, and steric and overall electrostatic hindrance, which stifles it. Abeta self-association is entropically unfavorable, as it implies order increase in the system, but under favorable kinetic conditions, the process proceeds at appreciable rates, yielding Abeta aggregates of different sizes and structures. Despite the great relevance and extensive research efforts, detailed kinetic mechanisms underlying Abeta aggregation remain only partially understood. In this study, fluorescence correlation spectroscopy (FCS) and Thioflavin T (ThT) were used to monitor the time dependent growth of structured aggregates and characterize multiple components during the aggregation of Abeta peptides in a heterogeneous aqueous solution. To this aim, we collected data during a relatively large number of observation periods, 30 consecutive measurements lasting 10 s each, at what we consider to be a constant time point in the slow aggregation process. This approach enabled monitoring the formation of nanomolar concentrations of structured amyloid aggregates and demonstrated the changing distribution of amyloid aggregate sizes throughout the aggregation process. We identified aggregates of different sizes with molecular weight from 260 to more than 1 * 10(6) kDa and revealed the hitherto unobserved kinetic turnover of intermediates during Abeta aggregation. The effect of different Abeta concentrations, Abeta:ThT ratios, differences between the 40 (Abeta40) and 42 (Abeta42) residue long variants of Abeta, and the effect of stirring were also examined. PMID- 26574170 TI - Adsorption of annealed branched polymers on curved surfaces. AB - The behavior of annealed branched polymers near adsorbing surfaces plays a fundamental role in many biological and industrial processes. Most importantly single stranded RNA in solution tends to fold up and self-bind to form a highly branched structure. Using a mean field theory, we both perturbatively and numerically examine the adsorption of branched polymers on surfaces of several different geometries in a good solvent. Independent of the geometry of the wall, we observe that as branching density increases, surface tension decreases. However, we find a coupling between the branching density and curvature in that a further lowering of surface tension occurs when the wall curves towards the polymer, but the amount of lowering of surface tension decreases when the wall curves away from the polymer. We find that for branched polymers confined into spherical cavities, most of branch-points are located in the vicinity of the interior wall and the surface tension is minimized for a critical cavity radius. For branch polymers next to sinusoidal surfaces, we find that branch-points accumulate at the valleys while end-points on the peaks. PMID- 26574171 TI - Objective endoscopic findings in patients with recurrent croup: 10-year retrospective analysis. AB - OBJECTIVE: (1) To determine the incidence and severity of subglottic stenosis on endoscopic evaluation in a pediatric population of patients with recurrent croup. (2) To determine the incidence of abnormal findings on bronchoalveolar lavage and esophageal biopsy in a pediatric population with recurrent croup. METHODS: Case series with historical chart review of clinical data for pediatric patients (age <=18 years) at a tertiary care children's hospital who underwent endoscopic evaluation of the upper aerodigestive tract with a diagnosis of recurrent croup over a ten-year period (2002-2012). Subglottic stenosis was graded on Myer-Cotton scale. Lipid-laden macrophages on bronchoalveolar lavage were noted as none/small/moderate/large with evidence of reflux noted as moderate or large. Esophageal biopsy specimens were evaluated for evidence of esophagitis. Data is expressed as mean+/-SEM. RESULTS: 1825 charts were reviewed of which 197 met inclusion criteria. Mean age at endoscopy was 53+/-3 months. Subglottic stenosis was noted in 41 patients (20.8%) with 95.1% being mild or Grade I. Abnormal findings on bronchoalveolar lavage were noted on 9.5% of bronchoalveolar lavage specimens. Abnormal esophageal biopsies were noted on 19.9% of specimens. Esophagitis was noted on 8.8% of biopsy specimens. CONCLUSIONS: Subglottic stenosis is a risk factor for recurrent croup. Evidence suggestive of reflux may be noted on bronchoalveolar lavage or esophageal biopsy, but these findings may not correlate with subglottic stenosis in recurrent croup patients. PMID- 26574172 TI - Establishment of a model of cochlear lesions in rats to study potential gene therapy for sensorineural hearing loss. AB - INTRODUCTION: Sensorineural hearing loss seriously influences a patient's daily life, and no effective treatments exist to date. Gene therapy is a potential treatment for regenerating hair cells to restore hearing. METHODS: In this study, we established a cochlear lesions model to study hair cell regeneration by co administration of kanamycin and furosemide. After the injections, we assessed the survival of outer hair cells (OHC), inner hair cells (IHC), supporting cells (SC), spiral ganglion neurons (SGN) and peripheral axons. Moreover, we used two viral vectors to detect the transgene distribution. RESULTS: Our results showed at 12h post-treatment, numerous OHC were missing in the basal turn. At 24h post treatment, all OHCs in basal half of the cochlea were lost, and by 48h, OHC loss had spread to the apical coil. Four days after the injections, all OHCs were absent. At 1mo post-treatment, the organ of Corti had collapsed. In contrast, most of the SC remained 4d after the injections. The loss of SGN and peripheral axons was consistent with this time course post-treatment. The results of transgene distribution suggested the correlative gene can be transferred into the organ of Corti using adenoviruses (AdV) vectors and lentiviruses (LV) vectors in our cochlear lesion model. COMPARISON WITH EXISTING METHOD(S): We assessed the details of HC death at more time point and chosen the time point for gene transfer in this model. CONCLUSIONS: We conclude that this cochlear lesion model would be suitable for the study of hair cell regeneration. PMID- 26574173 TI - The use of computer-aided design/manufacturing (CAD/CAM) technology to aid in the reconstruction of congenitally deficient pediatric mandibles: A case series. AB - BACKGROUND: Microvascular reconstruction of the pediatric mandible, particularly when necessitated by severe, congenital hypoplasia, presents a formidable challenge. Complex cases, however, may be simplified by computer-aided design/computer-aided manufacturing (CAD/CAM) assisted surgical planning. This series represents the senior authors' preliminary experiences with CAD/CAM assisted, microvascular reconstruction of the pediatric mandible. METHODS: Presented are two patients with hemifacial/bifacial microsomia, both with profound mandibular hypoplasia, who underwent CAD/CAM assisted reconstruction of their mandibles with vascularized fibula flaps. Surgical techniques, CAD/CAM routines employed, complications, and long-term outcomes are reported. RESULTS: Successful mandibular reconstructions were achieved in both patients with centralization of their native mandibles and augmentation of deficient mandibular subunits. No long-term complications were observed. CONCLUSIONS: CAD/CAM technology can be utilized in pediatric mandibular reconstruction, and is particularly beneficial in cases of profound, congenital hypoplasia requiring extensive, multi-planar, bony reconstructions. PMID- 26574174 TI - Letter to the Editor regarding "Predictive value of the neutrophil-to-lymphocyte ratio in patients with deep neck space infection secondary to acute bacterial tonsillitis". PMID- 26574175 TI - Antidepressants and antipsychotics classified with torsades de pointes arrhythmia risk and mortality in older adults - a Swedish nationwide study. AB - AIM: The aim of the study was to examine mortality risk associated with use of antidepressants and antipsychotics classified with torsades de pointes (TdP) risk in elderly. METHODS: A matched case-control register study was conducted in people 65 years and older dying outside hospital from 2008-2013 (n = 286,092) and matched controls (n = 1,430,460). The association between prescription of antidepressants and antipsychotics with various TdP risk according to CredibleMeds (www.crediblemeds.org) and all-cause mortality was studied by multivariate conditional logistic regression adjusted for comorbidity and several other confounders. RESULTS: Use of antidepressants classified with known or possible TdP risk, was associated with higher adjusted risk for mortality (OR 1.53, 95% CI 1.51, 1.56 and OR 1.63, 95% CI 1.61, 1.67, respectively) compared with antidepressants classified with conditional TdP risk (OR 1.25, 95% CI 1.22, 1.28) or without TdP classification (OR 0.99, 95% CI 0.94, 1.05). Antipsychotics classified with known TdP risk were associated with higher risk (OR 4.57, 95% CI 4.37, 4.78) than antipsychotics with possible risk (OR 2.58, 95% CI 2.52, 2.64) or without TdP classification (OR 2.14, 95% CI 2.03, 2.65). The following risk ranking was observed for commonly used antidepressants: mirtazapine > citalopram > sertraline > amitriptyline and for antipsychotics: haloperidol > risperidone >olanzapine > quetiapine. CONCLUSION: The CredibleMeds system predicted drug associated risk for mortality in the elderly at the risk class level. Among antipsychotics, haloperidol, and among antidepressants, mirtazapine and citalopram, were associated with the highest risks. The results suggest that the TdP risk with antidepressants and antipsychotics should be taken into consideration when prescribing to the elderly. PMID- 26574177 TI - Characterization of Homozygous Hb Setif (HBA2: c.283G>T) in the Iranian Population. AB - Hemoglobin (Hb) variants are abnormalities resulting from point mutations in either of the two alpha-globin genes (HBA2 or HBA1) or the beta-globin gene (HBB). Various reports of Hb variants have been described in Iran and other countries around the world. Hb Setif (or HBA2: c.283G>T) is one of these variants with a mutation at codon 94 of of the alpha2-globin gene that is characterized in clinically normal heterozygous individuals. We here report clinical and hematological findings in two homozygous cases of Iranian origin for this unstable Hb variant. PMID- 26574176 TI - Noradrenaline goes nuclear: epigenetic modifications during long-lasting synaptic potentiation triggered by activation of beta-adrenergic receptors. AB - KEY POINTS: Transcription is recruited by noradrenaline in the hippocampus. Epigenetic mechanisms are recruited by hippocampal noradrenergic receptor activation. Epigenetic regulation by noradrenaline offers a novel mechanism for long-term potentiation ABSTRACT: Noradrenaline (NA) is a neuromodulator that can effect long-lasting changes in synaptic strength such as long-term potentiation (LTP), a putative cellular mechanism for memory formation in the mammalian brain. Persistent LTP requires alterations in gene expression that may involve epigenetic mechanisms such as DNA methylation, histone acetylation and histone phosphorylation. It is known that beta-adrenergic receptors and NA can boost LTP maintenance by regulating translation. However, it is unclear whether NA can additionally engage epigenetic mechanisms to regulate transcription and boost LTP endurance. To address this issue, we probed NA-treated mouse hippocampal slices with pharmacological inhibitors targeting epigenetic regulatory pathways and discovered that NA activates beta-adrenergic receptors to boost LTP maintenance in area CA1 through DNA methylation and post-translational histone modifications. Specifically, NA paired with 100 Hz stimulation enhanced histone H3 acetylation and phosphorylation, both of which were required for NA-induced boosting of LTP maintenance. Together, our findings identify NA as a neuromodulatory transmitter capable of triggering epigenetic, transcriptional control of genes required for establishing persistent LTP in the mouse hippocampus. These modifications may contribute to the stabilization of memory. PMID- 26574178 TI - Sustainable production of valuable compound 3-succinoyl-pyridine by genetically engineering Pseudomonas putida using the tobacco waste. AB - Treatment of solid and liquid tobacco wastes with high nicotine content remains a longstanding challenge. Here, we explored an environmentally friendly approach to replace tobacco waste disposal with resource recovery by genetically engineering Pseudomonas putida. The biosynthesis of 3-succinoyl-pyridine (SP), a precursor in the production of hypotensive agents, from the tobacco waste was developed using whole cells of the engineered Pseudomonas strain, S16dspm. Under optimal conditions in fed-batch biotransformation, the final concentrations of product SP reached 9.8 g/L and 8.9 g/L from aqueous nicotine solution and crude suspension of the tobacco waste, respectively. In addition, the crystal compound SP produced from aqueous nicotine of the tobacco waste in batch biotransformation was of high purity and its isolation yield on nicotine was 54.2%. This study shows a promising route for processing environmental wastes as raw materials in order to produce valuable compounds. PMID- 26574179 TI - Targeting soluble proteins to exosomes using a ubiquitin tag. AB - As "natural" antigen carriers in the body, exosomes are potential vaccine vectors. A number of animal studies indicate that antigen-containing exosomes can induce a specific immune response which can protect against tumor progression or various infections. Exosomes that carry the protective antigens can be purified from cells that release them including tumor cells, dendritic cells, and macrophages. However, this strategy is restricted to proteins that are naturally targeted to exosomes and is therefore limited in the number of antigens present within exosomes. Therefore, with the goal of developing an exosome-based vaccine that is more flexible in its antigen composition and has the potential to be scalable, we have developed a new approach where recombinant soluble proteins can be packaged into exosomes and released from a transformed cell line. In this study, we determined that a C-terminal fusion of ubiquitin to EGFP, tumor antigenic protein nHer2 and Mycobacterium tuberculosis proteins Ag85B and ESAT6 served as an efficient delivery sequence into exosomes when expressed in a human embryonic kidney (HEK 293) cell line, a cell line widely used in industrial recombinant protein production. Two stably transgenic HEK293 cell lines were generated using a retroviral vector to express the Ag85B-ESAT6 fusion protein either alone or tagged at the C-terminus with ubiquitin. Both transformants released exosomes containing the fusion proteins. However, the concentration of Ag85B and ESAT6 in exosomes was increased approximately 10-fold when they were coupled to ubiquitin. Moreover, when the exosomes were used for immunization, there was a direct correlation between the amount of fusion protein within the exosomes and the number of Ag85B and ESAT6 specific INFgamma-secreting T lymphocytes in the lung and spleen. This suggests that exosomes containing recombinant antigen can be used to elicit a T cell response. In summary our data indicates that a ubiquitin-based exosomal protein delivery strategy could represent a unique approach to generate antigen-specific exosomes with the potential to be used as novel vaccines. Biotechnol. Bioeng. 2016;113: 1315-1324. (c) 2015 Wiley Periodicals, Inc. PMID- 26574180 TI - Daclatasvir and asunaprevir treatment improves liver function parameters and reduces liver fibrosis markers in chronic hepatitis C patients. AB - AIM: Although interferon (IFN)-free antiviral therapy is expected to improve the treatment response for chronic hepatitis C, the effect on liver function and liver fibrosis is unknown. In this study, we analyzed the long-term follow up of liver function parameters and liver fibrosis markers in genotype 1b hepatitis C virus (HCV)-infected patients treated with daclatasvir and asunaprevir. METHODS: Thirty patients were treated with daclatasvir and asunaprevir for 24 weeks, and 26 patients achieved sustained virological response (SVR). We measured liver function parameters, serum alanine aminotransferase (ALT) and albumin levels and liver fibrosis markers, hyaluronic acid, type IV collagen and Mac-2-binding protein (M2BPGi) before and after (median, 27 months; range, 17-47) completion of the treatment in SVR and non-SVR patients. We also measured serum alpha fetoprotein (AFP) levels during the therapy and follow-up period. RESULTS: Pretreatment serum ALT and albumin levels and liver fibrosis markers were similar between SVR and non-SVR patients. Twenty-seven months after treatment, serum ALT and albumin levels significantly improved only in SVR patients. Although there was no change in non-SVR patients, platelet count and serum liver fibrosis markers significantly improved in SVR patients. Serum AFP levels rapidly decreased during the treatment in both SVR and non-SVR patients, but the change was significant only in SVR patients. CONCLUSION: Successful viral eradication by IFN-free daclatasvir and asunaprevir therapy could lead to improved liver function parameters and reduced liver fibrosis markers and AFP levels. This treatment has the potential to improve liver fibrosis and decrease the incidence of hepatocarcinogenesis. PMID- 26574181 TI - Novel roles for phytosulfokine signalling in plant-pathogen interactions. AB - This article comments on: Evolutionarily distant pathogens require the Arabidopsis phytosulfokine signalling pathway to establish disease. PMID- 26574182 TI - Top-Down Mass Spectrometry Analysis of Membrane-Bound Light-Harvesting Complex 2 from Rhodobacter sphaeroides. AB - We report a top-down proteomic analysis of the membrane-bound peripheral light harvesting complex LH2 isolated from the purple photosynthetic bacterium Rhodobacter sphaeroides. The LH2 complex is coded for by the puc operon. The Rb. sphaeroides genome contains two puc operons, designated puc1BAC and puc2BA. Although previous work has shown consistently that the LH2 beta polypeptide coded by the puc2B gene was assembled into LH2 complexes, there are contradictory reports as to whether the Puc2A polypeptides are incorporated into LH2 complexes. Furthermore, post-translational modifications of this protein offer the prospect that it could coordinate bacteriochlorophyll a (Bchl a) by a modified N-terminal residue. Here, we describe the components of the LH2 complex on the basis of electron-capture dissociation fragmentation to confirm the identity and sequence of the protein's subunits. We found that both gene products of the beta polypeptides are expressed and assembled in the mature LH2 complex, but only the Puc1A-encoded polypeptide alpha is observed here. The methionine of the Puc2B encoded polypeptide is missing, and a carboxyl group is attached to the threonine at the N-terminus. Surprisingly, one amino acid encoded as an isoleucine in both the puc2B gene and the mRNA is found as valine in the mature LH2 complex, suggesting an unexpected and unusual post-translational modification or a specific tRNA recoding of this one amino acid. PMID- 26574183 TI - Vaccines for Antibiotic-Resistant Bacteria: Possibility or Pipe Dream? AB - The increasing incidence of infections caused by antibiotic-resistant bacteria from multiple species, together with the paucity of new antibiotics in the development pipeline, indicates that vaccines could play a role in combating these infections. The development of vaccines for these infections presents unique challenges related to target population selection, vaccine administration, and antigen identification. Advances in genomic, transcriptomic, and proteomic technologies offer great potential for identifying promising antigens that are highly conserved and expressed during human infections. Although important challenges remain, the potential health and economic benefits associated with the clinical implementation of vaccination strategies for the prevention of antibiotic-resistant infections warrant their continued development. PMID- 26574184 TI - High bicarbonate levels in narcoleptic children. AB - The objective of this study was to evaluate the levels of plasma bicarbonate levels in narcoleptic children. Clinical, electrophysiological data and bicarbonate levels were evaluated retrospectively in children seen in our paediatric national reference centre for hypersomnia. The cohort included 23 control subjects (11.5 +/- 4 years, 43% boys) and 51 patients presenting de-novo narcolepsy (N) (12.7 +/- 3.7 years, 47% boys). In narcoleptic children, cataplexy was present in 78% and DQB1*0602 was positive in 96%. The control children were less obese (2 versus 47%, P = 0.001). Compared with control subjects, narcoleptic children had higher bicarbonate levels (P = 0.02) as well as higher PCO2 (P < 0.01) and lower venous pH gas (P < 0.01). Bicarbonate levels higher than 27 mmol L(-1) were found in 41.2% of the narcoleptic children and 4.2% of the controls (P = 0.001). Bicarbonate levels were correlated with the Adapted Epworth Sleepiness Scale (P = 0.01). Narcoleptic patients without obesity often had bicarbonate levels higher than 27 mmol L (-1) (55 versus 25%, P = 0.025). No differences were found between children with and without cataplexy. In conclusion, narcoleptic patients had higher bicarbonate plasma levels compared to control children. This result could be a marker of hypoventilation in this pathology, provoking an increase in PCO2 and therefore a respiratory acidosis, compensated by an increase in plasma bicarbonates. This simple screening tool could be useful for prioritizing children for sleep laboratory evaluation in practice. PMID- 26574185 TI - A Fetus with Hb Bart's Disease Due to Maternal Uniparental Disomy for Chromosome 16. AB - We here report an unusual case of Hb Bart's (gamma4) disease. Thalassemia screening of a couple showed that the wife was an alpha(0)-thalassemia (alpha(0) thal) carrier and her husband's mean corpuscular volume (MCV) was normal. Chorionic villus sampling (CVS) was performed at 13 weeks' gestation for positive Down syndrome screening and chromosomal study of the cultured CVS showed a normal karyotype. Ultrasound examination at 22 weeks' gestation showed fetal cardiomegaly and raised middle cerebral artery peak systolic velocity. Cordocentesis confirmed fetal anemia and showed Hb Bart's disease. Multiplex gap polymerase chain reaction (gap-PCR) for alpha-thal deletions on DNA extracted from the CVS showed the presence of a homozygous alpha(0)-thal - -(SEA) (Southeast Asian) deletion. The husband was found to be a carrier of the alpha(+) thal -alpha(3.7) (rightward) deletion. Non paternity was excluded by fluorescent PCR using short tandem repeat (STR) markers on chromosomes 13, 18 and 21. A de novo terminal deletion of chromosome 16 was excluded by array comparative genomic hybridization (aCGH). Detection of uniparental disomy (UPD), using STR markers on chromosome 16 showed maternal uniparental isodisomy from 16pter to 16p13.2, and uniparental heterodisomy from 16p13.13 to 16qter. PMID- 26574186 TI - Simultaneous measurement of electroencephalography and near-infrared spectroscopy during voluntary motor preparation. AB - We investigated the relationship between electrophysiological activity and haemodynamic response during motor preparation by simultaneous recording of electroencephalography (EEG) and near-infrared spectroscopy (NIRS). It is still unknown how exactly EEG signals correlate with the haemodynamic response, although the activation in the premotor area during motor preparation has been captured by EEG and haemodynamic approaches separately. We conducted EEG-NIRS simultaneous recordings over the sensorimotor area with a self-paced button press task. Participants were instructed to press a button at their own pace after a cue was shown. The result showed that the readiness potential (RP), a negative slow potential shift occurring during motor preparation, on C3 in the extended 10 20 system occurred about 1000 ms before the movement onset. An increase in concentration of oxyhaemoglobin (oxyHb) in the premotor cortex during motor preparation was also confirmed by NIRS, which resulted in a significant correlation between the amplitude of the RP and the change in oxyHb concentration (Pearson's correlation r(2) = 0.235, p = 0.03). We show that EEG-NIRS simultaneous recording can demonstrate the correlation between the RP and haemodynamic response in the premotor cortex contralateral to the performing hand. PMID- 26574189 TI - Bespoke video vignettes - an approach to enhancing reflective learning developed by dental undergraduates and their clinical teachers. AB - This study explores the selective use of video as a medium to support reflective processes as related to dental undergraduate learning. With the objective of developing and enhancing high-quality adult dental care, the use of compiled video materials created in an undergraduate clinical setting was investigated. Video cameras were used to capture elements of reflection-in-action and reflection-on-action typically found during everyday clinical practice. 'Gold standard' or 'textbook outcomes' are rarely, if ever, fully achieved in dental practice. Real-life clinical experiences offer challenges and opportunities for both teachers and students to engage with reflective learning processes. The materials generated allowed for an experience of individual reflective learning and the creation of a data bank or archive with potential use for the benefit of a wider student cohort. Various aspects of the students' views and comments on the process of reflection were reported and explored by means of a semi structured focus group moderated by a linked educational advisor. PMID- 26574187 TI - Hypercapnia modulates cAMP signalling and cystic fibrosis transmembrane conductance regulator-dependent anion and fluid secretion in airway epithelia. AB - Hypercapnia is clinically defined as an arterial blood partial pressure of CO2 of above 40 mmHg and is a feature of chronic lung disease. In previous studies we have demonstrated that hypercapnia modulates agonist-stimulated cAMP levels through effects on transmembrane adenylyl cyclase activity. In the airways, cAMP is known to regulate cystic fibrosis transmembrane conductance regulator (CFTR) mediated anion and fluid secretion, which contributes to airway surface liquid homeostasis. The aim of the current work was to investigate if hypercapnia could modulate cAMP-regulated ion and fluid transport in human airway epithelial cells. We found that acute exposure to hypercapnia significantly reduced forskolin stimulated elevations in intracellular cAMP as well as both adenosine- and forskolin-stimulated increases in CFTR-dependent transepithelial short-circuit current, in polarised cultures of Calu-3 human airway cells. This CO2 -induced reduction in anion secretion was not due to a decrease in HCO3 (-) transport given that neither a change in CFTR-dependent HCO3 (-) efflux nor Na(+) /HCO3 (-) cotransporter-dependent HCO3 (-) influx were CO2 -sensitive. Hypercapnia also reduced the volume of forskolin-stimulated fluid secretion over 24 h, yet had no effect on the HCO3 (-) content of the secreted fluid. Our data reveal that hypercapnia reduces CFTR-dependent, electrogenic Cl(-) and fluid secretion, but not CFTR-dependent HCO3 (-) secretion, which highlights a differential sensitivity of Cl(-) and HCO3 (-) transporters to raised CO2 in Calu-3 cells. Hypercapnia also reduced forskolin-stimulated CFTR-dependent anion secretion in primary human airway epithelia. Based on current models of airways biology, a reduction in fluid secretion, associated with hypercapnia, would be predicted to have important consequences for airways hydration and the innate defence mechanisms of the lungs. PMID- 26574188 TI - External evaluation of published population pharmacokinetic models of tacrolimus in adult renal transplant recipients. AB - AIM: Several tacrolimus population pharmacokinetic models in adult renal transplant recipients have been established to facilitate dose individualization. However, their applicability when extrapolated to other clinical centres is not clear. This study aimed to (1) evaluate model external predictability and (2) analyze potential influencing factors. METHODS: Published models were screened from the literature and were evaluated using an external dataset with 52 patients (609 trough samples) collected by postoperative day 90 via methods that included (1) prediction-based prediction error (PE%), (2) simulation-based prediction- and variability-corrected visual predictive check (pvcVPC) and normalized prediction distribution error (NPDE) tests and (3) Bayesian forecasting to assess the influence of prior observations on model predictability. The factors influencing model predictability, particularly the impact of structural models, were evaluated. RESULTS: Sixteen published models were evaluated. In prediction-based diagnostics, the PE% within +/-30% was less than 50% in all models, indicating unsatisfactory predictability. In simulation-based diagnostics, both the pvcVPC and the NPDE indicated model misspecification. Bayesian forecasting improved model predictability significantly with prior 2-3 observations. The various factors influencing model extrapolation included bioassays, the covariates involved (CYP3A5*3 polymorphism, postoperative time and haematocrit) and whether non-linear kinetics were used. CONCLUSIONS: The published models were unsatisfactory in prediction- and simulation-based diagnostics, thus inappropriate for direct extrapolation correspondingly. However Bayesian forecasting could improve the predictability considerably with priors. The incorporation of non-linear pharmacokinetics in modelling might be a promising approach to improving model predictability. PMID- 26574191 TI - A simplified process design for P450 driven hydroxylation based on surface displayed enzymes. AB - New production routes for fine and bulk chemicals are important to establish further sustainable processes in industry. Besides the identification of new biocatalysts and new production routes the optimization of existing processes in regard to an improved utilization of the catalysts are needed. In this paper we describe the successful expression of P450BM3 on the surface of E. coli cells with the Autodisplay system. The successful hydroxylation of palmitic acid by using surface-displayed P450BM3 was shown. Besides optimization of surface protein expression, several cofactor regeneration systems were compared and evaluated. Afterwards, the development of a suitable process for the biocatalytic hydroxylation of fatty acids based on the re-use of the catalysts after a simple centrifugation was investigated. It was shown that the catalyst can be used for several times without any loss in activity. By using surface-displayed P450s in combination with an enzymatic cofactor regeneration system a total turnover number of up to 54,700 could be reached, to the knowledge of the authors the highest value reported for a P450 monooxygenase to date. Further optimizations of the described reaction system can have an enormous impact on the process design for more sustainable bioprocesses. Biotechnol. Bioeng. 2016;113: 1225-1233. (c) 2015 Wiley Periodicals, Inc. PMID- 26574192 TI - Doped graphene supercapacitors. AB - Heteroatom-doped graphitic frameworks have received great attention in energy research, since doping endows graphitic structures with a wide spectrum of properties, especially critical for electrochemical supercapacitors, which tend to complement or compete with the current lithium-ion battery technology/devices. This article reviews the latest developments in the chemical modification/doping strategies of graphene and highlights the versatility of such heteroatom-doped graphitic structures. Their role as supercapacitor electrodes is discussed in detail. This review is specifically focused on the concept of material synthesis, techniques for electrode fabrication and metrics of performance, predominantly covering the last four years. Challenges and insights into the future research and perspectives on the development of novel electrode architectures for electrochemical supercapacitors based on doped graphene are also discussed. PMID- 26574193 TI - Are needles of Pinus pinaster more vulnerable to xylem embolism than branches? New insights from X-ray computed tomography. AB - Plants can be highly segmented organisms with an independently redundant design of organs. In the context of plant hydraulics, leaves may be less embolism resistant than stems, allowing hydraulic failure to be restricted to distal organs that can be readily replaced. We quantified drought-induced embolism in needles and stems of Pinus pinaster using high-resolution computed tomography (HRCT). HRCT observations of needles were compared with the rehydration kinetics method to estimate the contribution of extra-xylary pathways to declining hydraulic conductance. High-resolution computed tomography images indicated that the pressure inducing 50% of embolized tracheids was similar between needle and stem xylem (P50 needle xylem = -3.62 MPa, P50 stem xylem = -3.88 MPa). Tracheids in both organs showed no difference in torus overlap of bordered pits. However, estimations of the pressure inducing 50% loss of hydraulic conductance at the whole needle level by the rehydration kinetics method were significantly higher (P50 needle = -1.71 MPa) than P50 needle xylem derived from HRCT. The vulnerability segmentation hypothesis appears to be valid only when considering hydraulic failure at the entire needle level, including extra-xylary pathways. Our findings suggest that native embolism in needles is limited and highlight the importance of imaging techniques for vulnerability curves. PMID- 26574194 TI - Editorial overview: Energy: Prospects for fuels and chemicals from a biomass based biorefinery using post-genomic chemical biology tools. PMID- 26574196 TI - A reflection on Paul von Rague Schleyer. PMID- 26574195 TI - Cost-effectiveness of motivational intervention with significant others for patients with alcohol misuse. AB - AIMS: To estimate the incremental cost, cost-effectiveness and benefit-cost ratio of incorporating a significant other (SO) into motivational intervention for alcohol misuse. DESIGN: We obtained economic data from the one year with the intervention in full operation for patients in a recent randomized trial. SETTING: The underlying trial took place at a major urban hospital in the United States. PARTICIPANTS: The trial randomized 406 (68.7% male) eligible hazardous drinkers (196 during the economic study) admitted to the emergency department or trauma unit. INTERVENTION: The motivational interview condition consisted of one in-person session featuring personalized normative feedback. The significant other motivational interview condition comprised one joint session with the participant and SO in which the SO's perspective and support were elicited. MEASUREMENTS: We ascertained activities across 445 representative time segments through work sampling (including staff idle time), calculated the incremental cost in per patient of incorporating an SO, expressed the results in 2014 US$, incorporated quality and mortality effects from a closely related trial and derived the cost per quality-adjusted life-year (QALY) gained. FINDINGS: From a health system perspective, the incremental cost per patient of adding an SO was $341.09 [95% confidence interval (CI) = $244.44-437.74]. The incremental cost per year per hazardous drinker averted was $3623 (CI = $1777-22,709), the cost per QALY gained $32,200 (CI = $15,800-201,700), and the benefit-cost ratio was 4.73 (95% CI = 0.7-9.66). If adding an SO into the intervention strategy were concentrated during the hours with highest risk or in a trauma unit, it would become even more cost-beneficial. CONCLUSIONS: Using criteria established by the World Health Organization (cost-effectiveness below the country's gross domestic product per capita), incorporating a significant other into a patient's motivational intervention for alcohol misuse is highly cost-effective. PMID- 26574197 TI - Accuracy of current all-atom force-fields in modeling protein disordered states. AB - Molecular Dynamics (MD) plays a fundamental role in characterizing protein disordered states that are emerging as crucial actors in many biological processes. Here we assess the accuracy of three current force-fields in modeling disordered peptides by combining enhanced-sampling MD simulations with NMR data. These force-fields generate significantly different conformational ensembles, and AMBER03w [ Best and Mittal J. Phys. Chem. B 2010 , 114 , 14916 - 14923 ] provides the best agreement with experiments, which is further improved by adding the ILDN corrections [ Lindorff-Larsen et al. Proteins 2010 , 78 , 1950 - 1958 ]. PMID- 26574198 TI - Basis set generation for quantum dynamics simulations using simple trajectory based methods. AB - Methods for solving the time-dependent Schrodinger equation generally employ either a global static basis set, which is fixed at the outset, or a dynamic basis set, which evolves according to classical-like or variational equations of motion; the former approach results in the well-known exponential scaling with system size, while the latter can suffer from challenging numerical problems, such as singular matrices, as well as violation of energy conservation. Here, we suggest a middle road: building a basis set using trajectories to place time independent basis functions in the regions of phase space relevant to wave function propagation. This simple approach, which potentially circumvents many of the problems traditionally associated with global or dynamic basis sets, is successfully demonstrated for two challenging benchmark problems in quantum dynamics, namely, relaxation dynamics following photoexcitation in pyrazine, and the spin Boson model. PMID- 26574199 TI - Automatic state partitioning for multibody systems (APM): an efficient algorithm for constructing Markov state models to elucidate conformational dynamics of multibody systems. AB - The conformational dynamics of multibody systems plays crucial roles in many important problems. Markov state models (MSMs) are powerful kinetic network models that can predict long-time-scale dynamics using many short molecular dynamics simulations. Although MSMs have been successfully applied to conformational changes of individual proteins, the analysis of multibody systems is still a challenge because of the complexity of the dynamics that occur on a mixture of drastically different time scales. In this work, we have developed a new algorithm, automatic state partitioning for multibody systems (APM), for constructing MSMs to elucidate the conformational dynamics of multibody systems. The APM algorithm effectively addresses different time scales in the multibody systems by directly incorporating dynamics into geometric clustering when identifying the metastable conformational states. We have applied the APM algorithm to a 2D potential that can mimic a protein-ligand binding system and the aggregation of two hydrophobic particles in water and have shown that it can yield tremendous enhancements in the computational efficiency of MSM construction and the accuracy of the models. PMID- 26574200 TI - Understanding electronically non-adiabatic relaxation dynamics in singlet fission. AB - Nonadiabatic relaxation of one singlet state into two triplet states is the key step in singlet fission dynamics, the understandings of which may help design next generation solar cells. In this work we perform the symmetrical quasi classical (SQC) nonadiabatic molecular dynamics (MD) simulation [Cotton and Miller, J. Phys. Chem. A, 2013, 117, 7190; Meyer and Miller, J. Chem. Phys. 1979, 70, 3214] for a model system to study the real-time fission dynamics. The dependence of the nonadiabatic relaxation dynamics on energy levels, electronic couplings, and electronic-phonon couplings has been examined, in comparison with other analytical approximations, such as Forster theory and Marcus theory. Unlike many other methods, the SQC nondiabatic MD simulation approach is able to describe fission dynamics efficiently and accurately enough to provide microscopic insights into singlet fission. PMID- 26574201 TI - Spin component-scaled second-order Moller-Plesset perturbation theory for calculating NMR shieldings. AB - Spin component-scaled and scaled opposite-spin second-order Moller-Plesset perturbation approaches (SCS-MP2 and SOS-MP2) are introduced for calculating NMR chemical shifts in analogy to the well-established scaled approaches for MP2 energies. Gauge-including atomic orbitals (GIAO) are employed throughout this work. The GIAO-SCS-MP2 and GIAO-SOS-MP2 methods typically show superior performance to nonscaled MP2 and are closer to the coupled-cluster singles doubles perturbative triples (CCSD(T))/cc-pVQZ reference values. In addition, the pragmatic use of mixed basis sets for the Hartree-Fock and the correlated part of NMR chemical shift calculations is shown to be beneficial. PMID- 26574202 TI - Analytical double-hybrid density functional based on the polynomial series expansion of adiabatic connection: a quadratic approximation. AB - We present a systematic derivation of double-hybrid density functional (DHDF) based on the polynomial series expansion of adiabatic connection formula in the closed interval lambda = [0,1] without a loss of generality. Because of the tendency of Wlambda having a small (but not negligible) curvature at equilibrium, we first evaluate the chemical validity of quadratic approximation for Wlambda using the large GMTKN30 benchmark database. The resulting functional, obtained analytically and denoted by quadratic adiabatic connection functional-PT2 (QACF 2), is found to be robust and accurate (2.35 kcal/mol of weighted total mean absolute deviation error, WTMAD), comparable or slightly improved compared to other flavors of existing parameter-free DHDFs (2.45 or 3.29 kcal/mol for PBE0-2 or PBE0-DH, respectively). The nonlocal expansion coefficients obtained for the current QACF-2 (aHF = 2/3, aPT2 = 1/3) also offer some interesting observation, in that the latter analytical coefficients are very similar to the empirically optimized coefficients in some of the best DHDFs today with high accuracy (1.5 kcal/mol). Effects of quadratic truncation in QACF-2 have been further assessed and justified by estimating the higher-order corrections to be as much as 0.54 kcal/mol. The present derivation and numerical experiments suggest that the quadratic lambda dependence, despite its simplicity, is a surprisingly good approximation to the adiabatic connection that can serve as a good starting point for further development of accurate parameter-free density functionals. PMID- 26574203 TI - Applications of polarizable continuum models to determine accurate solution-phase thermochemical values across a broad range of cation charge - the case of U(III VI). AB - Contributing factors to the solution-phase correction to the free energy of the molecular clusters U(H2O)n(3+/4+) and UO2(H2O)m(1+/2+) (n = 8, 9, 30, 41, 77; m = 4, 5, 30, 41, 77) have been examined as a function of cavity type in the integrated-equation-formalism-protocol (IEF) and SMD polarizable continuum models (PCMs). It is observed that the free energy correction, Gcorr, does not smoothly converge to zero as the number of explicitly solvating water molecules approaches the bulk limit, and the convergence behavior varies significantly with cavity and model. The rates of convergence of the gas-phase hydration energy, DeltaGhyd, wherein the bare metal ion is inserted into a molecular water cluster and DeltaGcorr for the reaction exhibit wide variations as a function of ion charge, cavity, and model. This is the likely source of previously reported discrepancies in predicted free energies of solvation for metal ions when using different PCM cavities and/or models. The cancellation of errors in DeltaGhyd and DeltaGcorr is optimal for clusters consisting of only a second solvation shell of explicit water molecules (n = m = 30). The UFF cavity within IEF, in particular, exhibits the most consistent cancellation of errors when using a molecular cluster consisting of a second shell of solvating water for all oxidation states of uranium, leading to accurate free energies of solvation DeltaGsolv for these species. PMID- 26574204 TI - Putting DFT to the test: a first-principles study of electronic, magnetic, and optical properties of Co3O4. AB - First-principles density functional theory (DFT) and a many-body Green's function method have been employed to elucidate the electronic, magnetic, and photonic properties of a spinel compound, Co3O4. Co3O4 is an antiferromagnetic semiconductor composed of cobalt ions in the Co(2+) and Co(3+) oxidation states. Co3O4 is believed to be a strongly correlated material, where the on-site Coulomb interaction (U) on Co d orbitals is presumably important, although this view has recently been contested. The suggested optical band gap for this material ranges from 0.8 to 2.0 eV, depending on the type of experiments and theoretical treatment. Thus, the correlated nature of the Co d orbitals in Co3O4 and the extent of the band gap are still under debate, raising questions regarding the ability of DFT to correctly treat the electronic structure in this material. To resolve the above controversies, we have employed a range of theoretical methods, including pure DFT, DFT+U, and a range-separated exchange-correlation functional (HSE06) as well as many-body Green's function theory (i.e., the GW method). We compare the electronic structure and band gap of Co3O4 with available photoemission spectroscopy and optical band gap data and confirm a direct band gap of ca. 0.8 eV. Furthermore, we have also studied the optical properties of Co3O4 by calculating the imaginary part of the dielectric function (Im(epsilon)), facilitating direct comparison with the measured optical absorption spectra. Finally, we have calculated the nearest-neighbor interaction (J1) between Co(2+) ions to understand the complex magnetic structure of Co3O4. PMID- 26574205 TI - Scalar relativistic calculations of hyperfine coupling constants using ab initio density matrix renormalization group method in combination with third-order Douglas-Kroll-Hess transformation: case studies on 4d transition metals. AB - We have developed a new computational scheme for high-accuracy prediction of the isotropic hyperfine coupling constant (HFCC) of heavy molecules, accounting for the high-level electron correlation effects, as well as the scalar-relativistic effects. For electron correlation, we employed the ab initio density matrix renormalization group (DMRG) method in conjunction with a complete active space model. The orbital-optimization procedure was employed to obtain the optimized orbitals required for accurately determining the isotropic HFCC. For the scalar relativistic effects, we initially derived and implemented the Douglas-Kroll-Hess (DKH) hyperfine coupling operators up to the third order (DKH3) by using the direct transformation scheme. A set of 4d transition-metal radicals consisting of Ag atom, PdH, and RhH2 were chosen as test cases. Good agreement between the isotropic HFCC values obtained from DMRG/DKH3 and experiment was archived. Because there are no available gas-phase values for PdH and RhH2 radicals in the literature, the results from the present high-level theory may serve as benchmark data. PMID- 26574206 TI - Multiconfiguration pair-density functional theory: barrier heights and main group and transition metal energetics. AB - Kohn-Sham density functional theory, resting on the representation of the electronic density and kinetic energy by a single Slater determinant, has revolutionized chemistry, but for open-shell systems, the Kohn-Sham Slater determinant has the wrong symmetry properties as compared to an accurate wave function. We have recently proposed a theory, called multiconfiguration pair density functional theory (MC-PDFT), in which the electronic kinetic energy and classical Coulomb energy are calculated from a multiconfiguration wave function with the correct symmetry properties, and the rest of the energy is calculated from a density functional, called the on-top density functional, that depends on the density and the on-top pair density calculated from this wave function. We also proposed a simple way to approximate the on-top density functional by translation of Kohn-Sham exchange-correlation functionals. The method is much less expensive than other post-SCF methods for calculating the dynamical correlation energy starting with a multiconfiguration self-consistent-field wave function as the reference wave function, and initial tests of the theory were quite encouraging. Here, we provide a broader test of the theory by applying it to bond energies of main-group molecules and transition metal complexes, barrier heights and reaction energies for diverse chemical reactions, proton affinities, and the water dimerization energy. Averaged over 56 data points, the mean unsigned error is 3.2 kcal/mol for MC-PDFT, as compared to 6.9 kcal/mol for Kohn Sham theory with a comparable density functional. MC-PDFT is more accurate on average than complete active space second-order perturbation theory (CASPT2) for main-group small-molecule bond energies, alkyl bond dissociation energies, transition-metal-ligand bond energies, proton affinities, and the water dimerization energy. PMID- 26574207 TI - Accurate prediction of lattice energies and structures of molecular crystals with molecular quantum chemistry methods. AB - We extend the generalized energy-based fragmentation (GEBF) approach to molecular crystals under periodic boundary conditions (PBC), and we demonstrate the performance of the method for a variety of molecular crystals. With this approach, the lattice energy of a molecular crystal can be obtained from the energies of a series of embedded subsystems, which can be computed with existing advanced molecular quantum chemistry methods. The use of the field compensation method allows the method to take long-range electrostatic interaction of the infinite crystal environment into account and make the method almost translationally invariant. The computational cost of the present method scales linearly with the number of molecules in the unit cell. Illustrative applications demonstrate that the PBC-GEBF method with explicitly correlated quantum chemistry methods is capable of providing accurate descriptions on the lattice energies and structures for various types of molecular crystals. In addition, this approach can be employed to quantify the contributions of various intermolecular interactions to the theoretical lattice energy. Such qualitative understanding is very useful for rational design of molecular crystals. PMID- 26574208 TI - Quantum chemical interpretation of ultrafast luminescence decay and intersystem crossings in rhenium(I) carbonyl bipyridine complexes. AB - Ultrafast luminescence decay and intersystem crossing processes through the seven low-lying singlet and triplet excited states of [Re (X)(CO)3(bpy)] (X = Cl, Br, I; bpy = 2,2'-bipyridine) are interpreted on the basis of time-dependent density functional theory (TD-DFT) electronic structure calculations performed in acetonitrile and including spin-orbit coupling (SOC) effects within the zeroth order approximation. It is shown that the red shift of the lowest part of the spectra by SOC increases from X = Cl (0.06 eV) to X = Br (0.09 eV) and X = I (0.18 eV) due to the participation of the triplet sublevels to the absorption. The six lowest "spin-orbit" states remain largely triplet in character and the maximum of absorption is not drastically affected by SOC. While the energy of the excited states is affected by SOC, the character of these states is not significantly modified: SOC mixes states of the same nature, namely metal-to ligand-charge-transfer/halide-to-ligand-charge-transfer (MLCT/XLCT). This mixing can be large, however, as illustrated by the S1/T2 (a(1)A"/a(3)A') mixing that amounts to about 50:50 within the series Cl > Br > I. On the basis of the optimized structures of the six lowest excited states an interpretation of the emission signals detected by ultrafast luminescence spectroscopy is proposed. It is shown that whereas the experimental Stokes shift of 6000 cm(-1) observed for the three complexes is well reproduced without SOC correction for the Cl and Br complexes, SOC effects have to be taken into account for the iodide complex. The early signal of ultrafast luminescence detected immediately after absorption at 400 nm to the S2 state, covering the 500-550 nm energy domain and characterized by a decay tau1 = 85 fs (X = Cl) and 128 fs (X = Br), is attributed to S2 calculated at 505 and 522 nm, respectively, and to some extend to T3 by SOC. The intermediate band observed at longer time-scale between 550 and 600 nm with emissive decay time tau2 = 340 fs (X = Cl) and 470 fs (X = Br) can be assigned to T2 calculated at 558 and 571 nm, respectively. The S1 state could also participate to this band by SOC. In both complexes the long-lived emission at 600 610 nm is attributed to the lowest T1 state calculated at 596 and 592 nm for the chloride and bromide complexes, respectively, and shifted to ~610 nm by SOC. Important SOC effects characterize the luminescence decay of [Re (I)(CO)3(bpy)], the mechanism of which differs significantly of the one proposed for the two other complexes. The A' spin-orbit sublevel of T3 state calculated at 512 nm with an oscillator strength of 0.17 * 10(-1) participates to the first signal characterized by a rapid decay (tau1 = 152 fs) with a maximum at 525 nm. The intermediate band covering the 550-600 nm region with a decay time tau2 = 1180 fs is assigned to the "spin-orbit" S1 state calculated at 595 nm. The S2 absorbing state calculated at 577 nm could contribute to these two signals. According to the spin-orbit sublevels calculated for T1 and T2, both states contribute to the long-lived emission detected at 600-610 nm, T1 with two sublevels A' of significant oscillator strengths of ~10(-1) being the main contributor. In order to follow the evolution of the excited states energy and SOC as a function of the Re-X stretching normal mode their potentials have been calculated without and with SOC as a function of the mass and frequency weighted Re-X stretching mode displacement from the Franck-Condon geometries. Exploratory wavepacket propagations show that SOC alone cannot account for the whole ISC process. Vibronic effects should play an important role in the ultrafast luminescence decay observed experimentally. PMID- 26574209 TI - Validation of the direct-COSMO-RS solvent model for Diels-Alder reactions in aqueous solution. AB - The modeling of chemical reactions in protic solvents tends to be far more computationally demanding than in most aprotic solvents, where bulk solvent effects are well described by dielectric continuum solvent models. In the presence of hydrogen bonds from a protic solvent to reactants, transition states or intermediates, a faithful modeling of the solvent effects usually requires some kind of molecular dynamics treatment. In contrast, the COSMO-RS (conductor like screening model for real solvents) approach has been known for about a decade to describe protic solvent effects much better than continuum solvents, in spite of being an implicit solvent model without explicit molecular dynamics. More recently, the self-consistent use of its potential in electronic-structure methods has led to the Direct-COSMO-RS approach. It allows, for example, structure optimization in the presence of a protic solvent, of solvent mixtures, as well as self-consistent property calculations. In view of recent successful tests for electron transfer in organic mixed-valence systems, in this work the wider applicability of D-COSMO-RS for organic reactivity is evaluated by computation of activation and reaction free energies, as well as transition-state structures of two prototypical Diels-Alder reactions, with an emphasis on aqueous solution. D-COSMO-RS indeed provides substantial improvements over the COSMO continuum model and in judicious testing compares well with embedded supermolecular model cluster treatments, without prior knowledge about the average numbers of hydrogen-bonding interactions present. PMID- 26574210 TI - Global hybrids from the semiclassical atom theory satisfying the local density linear response. AB - We propose global hybrid approximations of the exchange-correlation (XC) energy functional which reproduce well the modified fourth-order gradient expansion of the exchange energy in the semiclassical limit of many-electron neutral atoms and recover the full local density approximation (LDA) linear response. These XC functionals represent the hybrid versions of the APBE functional [Phys. Rev. Lett. 2011, 106, 186406] yet employing an additional correlation functional which uses the localization concept of the correlation energy density to improve the compatibility with the Hartree-Fock exchange as well as the coupling-constant resolved XC potential energy. Broad energetic and structural testing, including thermochemistry and geometry, transition metal complexes, noncovalent interactions, gold clusters and small gold-molecule interfaces, as well as an analysis of the hybrid parameters, show that our construction is quite robust. In particular, our testing shows that the resulting hybrid, including 20% of Hartree Fock exchange and named hAPBE, performs remarkably well for a broad palette of systems and properties, being generally better than popular hybrids (PBE0 and B3LYP). Semiempirical dispersion corrections are also provided. PMID- 26574211 TI - Segmented contracted basis sets optimized for nuclear magnetic shielding. AB - A family of segmented contracted basis sets is proposed, denoted pcSseg-n, which are optimized for calculating nuclear magnetic shielding constants. For the elements H-Ar, these are computationally more efficient than the previously proposed general contracted pcS-n basis sets, and the new basis sets are extended to also include the elements K-Kr. The pcSseg-n basis sets are optimized at the density functional level of theory, but it has been shown previously that these property-optimized basis sets are also suitable for calculating shielding constants with correlated wave function methods. The pcSseg-n basis sets are available in qualities ranging from (unpolarized) double-zeta to pentuple-zeta quality and should be suitable for both routine and benchmark calculations of nuclear magnetic shielding constants. The ability to rigorously separate basis set and method errors should aid in developing more accurate methods. PMID- 26574212 TI - Accurate multiple time step in biased molecular simulations. AB - Many recently introduced enhanced sampling techniques are based on biasing coarse descriptors (collective variables) of a molecular system on the fly. Sometimes the calculation of such collective variables is expensive and becomes a bottleneck in molecular dynamics simulations. An algorithm to treat smooth biasing forces within a multiple time step framework is here discussed. The implementation is simple and allows a speed up when expensive collective variables are employed. The gain can be substantial when using massively parallel or GPU-based molecular dynamics software. Moreover, a theoretical framework to assess the sampling accuracy is introduced, which can be used to assess the choice of the integration time step in both single and multiple time step biased simulations. PMID- 26574213 TI - Low-lying electronic excited states of pentacene oligomers: a comparative electronic structure study in the context of singlet fission. AB - The lowest-lying electronic excited states of pentacene and its oligomers are investigated using accurate multireference wave function methods (CASPT2/CASSCF) and the many-body Greens's function approach (GW/BSE). The results obtained for dimers and trimers of different geometry reveal a complex electronic structure, which includes locally excited, charge transfer, and multiexciton states. For singlets of single-excitation character, both approaches yield excitation energies that are in good overall quantitative agreement. While the multiexciton states are located relatively high in energy in all systems investigated, charge transfer states exist in close proximity to the lowest-lying absorbing states. The implications of the results for the mechanisms of singlet fission in pentacene are discussed. PMID- 26574214 TI - Efficient calculation of electronic absorption spectra by means of intensity selected time-dependent density functional tight binding. AB - During the last two decades density functional based linear response approaches have become the de facto standard for the calculation of optical properties of small- and medium-sized molecules. At the heart of these methods is the solution of an eigenvalue equation in the space of single-orbital transitions, whose quickly increasing number makes such calculations costly if not infeasible for larger molecules. This is especially true for time-dependent density functional tight binding (TD-DFTB), where the evaluation of the matrix elements is inexpensive. For the relatively large systems that can be studied the solution of the eigenvalue equation therefore determines the cost of the calculation. We propose to do an oscillator strength based truncation of the single-orbital transition space to reduce the computational effort of TD-DFTB based absorption spectra calculations. We show that even a sizable truncation does not destroy the principal features of the absorption spectrum, while naturally avoiding the unnecessary calculation of excitations with small oscillator strengths. We argue that the reduced computational cost of intensity-selected TD-DFTB together with its ease of use compared to other methods lowers the barrier of performing optical property calculations of large molecules and can serve to make such calculations possible in a wider array of applications. PMID- 26574215 TI - Theoretical rationalization of the singlet-triplet gap in OLEDs materials: impact of charge-transfer character. AB - New materials for OLED applications with low singlet-triplet energy splitting have been recently synthesized in order to allow for the conversion of triplet into singlet excitons (emitting light) via a Thermally Activated Delayed Fluorescence (TADF) process, which involves excited-states with a non-negligible amount of Charge-Transfer (CT). The accurate modeling of these states with Time Dependent Density Functional Theory (TD-DFT), the most used method so far because of the favorable trade-off between accuracy and computational cost, is however particularly challenging. We carefully address this issue here by considering materials with small (high) singlet-triplet gap acting as emitter (host) in OLEDs and by comparing the accuracy of TD-DFT and the corresponding Tamm-Dancoff Approximation (TDA), which is found to greatly reduce error bars with respect to experiments thanks to better estimates for the lowest singlet-triplet transition. Finally, we quantitatively correlate the singlet-triplet splitting values with the extent of CT, using for it a simple metric extracted from calculations with double-hybrid functionals, that might be applied in further molecular engineering studies. PMID- 26574216 TI - Computing excess functions of ionic solutions: the smaller-ion shell model versus the primitive model. 1. Activity coefficients. AB - The present study compares the Monte Carlo (MC) simulation of the primitive model (PM) ( Abbas, Z. et al. J. Phys. Chem. B 2009 , 113 , 5905 ), by which activity coefficients of many binary ionic solutions have been computed through adjusting ion-size parameters (ISPs) for achieving best fit with experiment, with a parallel fit and ISP adjustment, employing the Smaller-ion Shell (SiS) treatment ( Fraenkel, D. Mol. Phys. 2010 , 108 , 1435 ), a Debye-Huckel type theory ("DH SiS") considering counterions of unequal size. DH-SiS is analogous to the unrestricted PM (UPM), so the comparison is with the MC simulation of the UPM, "MC-UPM". Among the representative electrolytes NaCl, KCl, NaClO4, CaCl2, Ca(ClO4)2, and LaCl3, in water at 25 degrees C, the 1-1 electrolytes exhibit a far better fit quality for DH-SiS than for MC-UPM, and the fit extends to higher concentration. Moreover, theoretical single-ion activity coefficients derived from DH-SiS agree with experimental estimation for solutions of NaCl, CaCl2, and other electrolytes ( Fraenkel, D. J. Phys. Chem. B 2012 , 116 , 3603 ), whereas parallel MC-UPM predictions are at odds with experiment. Additional advantages of DH-SiS over MC-UPM are in (a) employing co-ion ISPs that are usually equal to the crystallographic ion diameters and (b) easily applying ISP nonadditivity in adjusting counterion ISPs. PMID- 26574217 TI - Computing excess functions of ionic solutions: the smaller-ion shell model versus the primitive model. 2. Ion-size parameters. AB - A recent Monte Carlo (MC) simulation study of the primitive model (PM) of ionic solutions ( Abbas, Z. et al. J. Phys. Chem. B 2009 , 113 , 5905 ) has resulted in an extensive "mapping" of real aqueous solutions of 1-1, 2-1, and 3-1 binary electrolytes and a list of "recommended ionic radii" for many ions. For the smaller cations, the model-experiment fitting process gave much larger radii than the respective crystallographic radii, and those cations were therefore claimed to be hydrated. In Part 1 (DOI 10.1021/ct5006938 ) of the present work, the above study for the unrestricted PM - dubbed MC-UPM - has been confronted with the Smaller-ion Shell (SiS) treatment ( Fraenkel, D. Mol. Phys. 2010 , 108 , 1435 ), or "DH-SiS", by comparing the range and quality of model-experiment fits of the mean ionic activity coefficient as a function of ionic concentration. Here I compare the ion-size parameters (ISPs) of "best fit" of the two models and argue that since ISPs derived from DH-SiS are identical with (or close to) crystallographic or thermochemical ionic diameters for both cations and anions, and they do not depend on the counterion - they are more reliable, as physicochemical entities, than the PM-derived "recommended ionic radii". PMID- 26574218 TI - Influence of the density functional and basis set on the relative stabilities of oxygenated isomers of diiron models for the active site of [FeFe]-hydrogenase. AB - A series of different density functional theory (DFT) methodologies (24 functionals) in conjunction with a variety of six different basis sets (BSs) was employed to investigate the relative stabilities in the oxygenated isomers of diiron complexes that mimic the active site of [FeFe]-hydrogenase: (MU pdt)[Fe(CO)2L][Fe(CO)2L'] (pdt = propane-1,3-dithiolate; L = L' = CO (1); L = PPh3, L' = CO (2); L = PMe3, L' = CO (3); L = L' = PMe3 (4). Although the enzyme may have a variety of possible sites for oxygenation, the model complexes would necessarily be oxygenated at either the diiron bridging site (MU-O) or at a sulfur (SO). Previous DFT studies with both B3LYP and TPSS functionals predicted a more stable MU-O isomer, whereas only the SO isomer was observed experimentally (J. Am. Chem. Soc. 2009, 131, 8296-8307). Here, further calculations reveal that the relative stabilities of the SO and MU-O isomers are extremely sensitive to the choice of the functional, moderately sensitive to the S basis set, but not to the Fe basis set. The relative free energies [Gsolv(MU-O) - Gsolv(SO)] range from +10 to -60 kcal/mol, a range much larger than what would have been expected on the basis of the previous DFT results. Benchmarking of these results against coupled cluster with single and double excitation calculations, which predict that the SO isomer is favored, shows that the best performing functionals are BP86 and PBE0, while B97-D, M05, and SVWN overestimate and B2PLYP, BH&HLYP, BMK, M06-HF, and M06-2X underestimate the energy differences. Most of the variation occurs with the MU-O isomer and appears to be associated with a functional's ability to predict the strength of the Fe-Fe bond in the reactant. With respect to the S basis set, it appears that the S?O bond is sensitive to the nature of the d polarization functions available on the S atom. The S seems to need a d function more diffuse than the d orbital optimized to provide polarization for the S atom alone; that is, S seems to need a d orbital that has strong overlap with the O atom's valence 2p. Other basis functions and the relative position of the PR3 (R = Ph and Me) substituent groups have smaller influences on the free energy differences. PMID- 26574219 TI - Finite-size effect on the charging free energy of protein in explicit solvent. AB - The finite-size effect in periodic system is examined for the charging free energy of protein in explicit solvent over a variety of charged states. The key to the finite-size correction is the self-energy, which is defined as the interaction energy of the solute with its own periodic images and the neutralizing background. By employing the thermodynamic-integration method with systematically varied sizes of the unit cell of molecular dynamics (MD) simulations, we show for ubiquitin that the self-energy corrects the finite-size effect on the charging free energy within 1 kcal/mol at total charges of -5e, 1e, neutral, and +1e and within 5 kcal/mol even for a highly charged state with +8e. We then sought the additional correction from the solvation effect using the numerical solution to the Poisson equation of the protein with implicit solvent. This correction reduces the cell-size dependence of the charging free energy at +8e to 3 kcal/mol and is well expressed as the self-energy divided by the dielectric constant of solvent water. PMID- 26574220 TI - Second-order many-body perturbation study on thermal expansion of solid carbon dioxide. AB - An embedded-fragment ab initio second-order many-body perturbation (MP2) method is applied to an infinite three-dimensional crystal of carbon dioxide phase I (CO2-I), using the aug-cc-pVDZ and aug-cc-pVTZ basis sets, the latter in conjunction with a counterpoise correction for the basis-set superposition error. The equation of state, phonon frequencies, bulk modulus, heat capacity, Gruneisen parameter (including mode Gruneisen parameters for acoustic modes), thermal expansion coefficient (alpha), and thermal pressure coefficient (beta) are computed. Of the factors that enter the expression of alpha, MP2 reproduces the experimental values of the heat capacity, Gruneisen parameter, and molar volume accurately. However, it proves to be exceedingly difficult to determine the remaining factor, the bulk modulus (B0), the computed value of which deviates from the observed value by 50-100%. As a result, alpha calculated by MP2 is systematically too low, while having the correct temperature dependence. The thermal pressure coefficient, beta = alphaB0, which is independent of B0, is more accurately reproduced by theory up to 100 K. PMID- 26574221 TI - Accurate ab initio description of adsorption on coordinatively unsaturated Cu(2+) and Fe(3+) sites in MOFs. AB - The performance of different exchange-correlation functionals was evaluated for the description of the interaction of small molecules with (i) cluster models containing Cu(2+) and Fe(3+) coordinatively unsaturated metal sites and (ii) HKUST-1 metal organic framework (MOF). Adsorbates forming dispersion-bound complexes (CH4), complexes with important dispersion and electrostatic contributions (H2, N2, CO2), and complexes stabilized also by a partial dative bond (CO, H2O, and NH3) were considered. The interaction with coordinatively unsaturated sites was evaluated with respect to the coupled-cluster calculations for Cu(2+) and Fe(3+) centers represented by cluster models. The adsorption on dispersion-stabilized sites was examined for the cage-window and the cage-center sites in HKUST-1 with respect to the experimental and DFT/CC results. None of the functionals considered can accurately describe the interaction of all seven adsorbates with Cu(2+) and Fe(3+) sites and with dispersion-dominated adsorption sites. The interaction with coordinatively unsaturated sites was frequently underestimated, for adsorbates forming a partial dative bond in particular, while the adsorption at dispersion-stabilized sites was overestimated. Consequently, interaction energies calculated for different adsorption sites were often in qualitatively incorrect order. The optimal exchange-correlation functional for a particular adsorbate/MOF can thus be found by comparing the performance of various functionals with respect to highly accurate calculations on smaller cluster models as a good representative of MOF structural building blocks. PMID- 26574222 TI - Quasiparticle interfacial level alignment of highly hybridized frontier levels: H2O on TiO2(110). AB - Knowledge of the frontier levels' alignment prior to photoirradiation is necessary to achieve a complete quantitative description of H2O photocatalysis on TiO2(110). Although H2O on rutile TiO2(110) has been thoroughly studied both experimentally and theoretically, a quantitative value for the energy of the highest H2O occupied levels is still lacking. For experiment, this is due to the H2O levels being obscured by hybridization with TiO2(110) levels in the difference spectra obtained via ultraviolet photoemission spectroscopy (UPS). For theory, this is due to inherent difficulties in properly describing many-body effects at the H2O-TiO2(110) interface. Using the projected density of states (DOS) from state-of-the-art quasiparticle (QP) G0W0, we disentangle the adsorbate and surface contributions to the complex UPS spectra of H2O on TiO2(110). We perform this separation as a function of H2O coverage and dissociation on stoichiometric and reduced surfaces. Due to hybridization with the TiO2(110) surface, the H2O 3a1 and 1b1 levels are broadened into several peaks between 5 and 1 eV below the TiO2(110) valence band maximum (VBM). These peaks have both intermolecular and interfacial bonding and antibonding character. We find the highest occupied levels of H2O adsorbed intact and dissociated on stoichiometric TiO2(110) are 1.1 and 0.9 eV below the VBM. We also find a similar energy of 1.1 eV for the highest occupied levels of H2O when adsorbed dissociatively on a bridging O vacancy of the reduced surface. In both cases, these energies are significantly higher (by 0.6 to 2.6 eV) than those estimated from UPS difference spectra, which are inconclusive in this energy region. Finally, we apply self consistent QPGW (scQPGW1) to obtain the ionization potential of the H2O-TiO2(110) interface. PMID- 26574223 TI - Electron correlation at the MgF2(110) surface: a comparison of incremental and local correlation methods. AB - We have applied the Method of Increments and the periodic Local-MP2 approach to the study of the (110) surface of magnesium fluoride, a system of significant interest in heterogeneous catalysis. After careful assessment of the approximations inherent in both methods, the two schemes, though conceptually different, are shown to yield nearly identical results. This remains true even when analyzed in fine detail through partition of the individual contribution to the total energy. This kind of partitioning also provides thorough insight into the electron correlation effects underlying the surface formation process, which are discussed in detail. PMID- 26574224 TI - Dry Martini, a coarse-grained force field for lipid membrane simulations with implicit solvent. AB - Coarse-grained (CG) models allow simulation of larger systems for longer times by decreasing the number of degrees of freedom compared with all-atom models. Here we introduce an implicit-solvent version of the popular CG Martini model, nicknamed "Dry" Martini. To account for the omitted solvent degrees of freedom, the nonbonded interaction matrix underlying the Martini force field was reparametrized. The Dry Martini force field reproduces relatively well a variety of lipid membrane properties such as area per lipid, bilayer thickness, bending modulus, and coexistence of liquid-ordered and disordered domains. Furthermore, we show that the new model can be applied to study membrane fusion and tether formation, with results similar to those of the standard Martini model. Membrane proteins can also be included, but less quantitative results are obtained. The absence of water in Dry Martini leads to a significant speedup for large systems, opening the way to the study of complex multicomponent membranes containing millions of lipids. PMID- 26574225 TI - Free energies from dynamic weighted histogram analysis using unbiased Markov state model. AB - The weighted histogram analysis method (WHAM) is widely used to obtain accurate free energies from biased molecular simulations. However, WHAM free energies can exhibit significant errors if some of the biasing windows are not fully equilibrated. To account for the lack of full equilibration, we develop the dynamic histogram analysis method (DHAM). DHAM uses a global Markov state model to obtain the free energy along the reaction coordinate. A maximum likelihood estimate of the Markov transition matrix is constructed by joint unbiasing of the transition counts from multiple umbrella-sampling simulations along discretized reaction coordinates. The free energy profile is the stationary distribution of the resulting Markov matrix. For this matrix, we derive an explicit approximation that does not require the usual iterative solution of WHAM. We apply DHAM to model systems, a chemical reaction in water treated using quantum mechanics/molecular-mechanics (QM/MM) simulations, and the Na(+) ion passage through the membrane-embedded ion channel GLIC. We find that DHAM gives accurate free energies even in cases where WHAM fails. In addition, DHAM provides kinetic information, which we here use to assess the extent of convergence in each of the simulation windows. DHAM may also prove useful in the construction of Markov state models from biased simulations in phase-space regions with otherwise low population. PMID- 26574226 TI - Modeling of enhanced catalysis in multienzyme nanostructures: effect of molecular scaffolds, spatial organization, and concentration. AB - Colocalized multistep enzymatic reaction pathways within biological catabolic and metabolic processes occur with high yield and specificity. Spatial organization on membranes or surfaces may be associated with increased efficiency of intermediate substrate transfer. Using a new Brownian dynamics package, GeomBD, we explored the geometric features of a surface-anchored enzyme system by parallel coarse-grained Brownian dynamics simulations of substrate diffusion over microsecond (MUs) to millisecond (ms) time scales. We focused on a recently developed glucose oxidase (GOx), horseradish peroxidase (HRP), and DNA origami scaffold enzyme system, where the H2O2 substrate of HRP is produced by GOx. The results revealed and explained a significant advantage in catalytic enhancement by optimizing interenzyme distance and orientation in the presence of the scaffold model. The planar scaffold colocalized the enzymes and provided a diffusive barrier that enhanced substrate transfer probability, becoming more relevant with increasing interenzyme distance. The results highlight the importance of protein geometry in the proper assessment of distance and orientation dependence on the probability of substrate transfer. They shed light on strategies for engineering multienzyme complexes and further investigation of enhanced catalytic efficiency for substrate diffusion between membrane-anchoring proteins. PMID- 26574227 TI - Challenges within the linear response approximation when studying enzyme catalysis and effects of mutations. AB - Various aspects of the linear response approximation (LRA) approach were examined when calculating reaction barriers within an enzyme and its different mutants. Scaling the electrostatic interactions is shown to slightly affect the absolute values of the barriers but not the overall trend when comparing wild-type and mutants. Convergence of the overall energetics was shown to depend on the sampling. Finally, the contribution of particular residues was shown to be significant, despite its small value. PMID- 26574228 TI - Modeling sequence-specific polymers using anisotropic coarse-grained sites allows quantitative comparison with experiment. AB - Certain sequences of peptoid polymers (synthetic analogs of peptides) assemble into bilayer nanosheets via a nonequilibrium assembly pathway of adsorption, compression, and collapse at an air-water interface. As with other large-scale dynamic processes in biology and materials science, understanding the details of this supramolecular assembly process requires a modeling approach that captures behavior on a wide range of length and time scales, from those on which individual side chains fluctuate to those on which assemblies of polymers evolve. Here, we demonstrate that a new coarse-grained modeling approach is accurate and computationally efficient enough to do so. Our approach uses only a minimal number of coarse-grained sites but retains independently fluctuating orientational degrees of freedom for each site. These orientational degrees of freedom allow us to accurately parametrize both bonded and nonbonded interactions and to generate all-atom configurations with sufficient accuracy to perform atomic scattering calculations and to interface with all-atom simulations. We have used this approach to reproduce all available experimental X-ray scattering data (for stacked nanosheets and for peptoids adsorbed at air-water interfaces and in solution), in order to resolve the microscopic, real-space structures responsible for these Fourier-space features. By interfacing with all-atom simulations, we have also laid the foundation for future multiscale simulations of sequence-specific polymers that communicate in both directions across scales. PMID- 26574229 TI - Computing the role of near attack conformations in an enzyme-catalyzed nucleophilic bimolecular reaction. AB - Near attack conformations (NACs) are conformations extending from the ground state (GS) that lie on the transition path of a chemical reaction. Here, we develop a method for computing the thermodynamic contribution to catalysis due to NAC formation in bimolecular reactions, within the limit of a classical molecular dynamics force field. We make use of the Burgi-Dunitz theory applied to large scale unbiased all-atom ensemble molecular dynamics simulations. We apply this to HIV-1 protease peptide hydrolysis, known to achieve a rate enhancement of ~1011 (DeltaGcat? ~ 15 kcal/mol) over the uncatalyzed bimolecular reaction (DeltaGnon? ~ 30 kcal/mol). The ground state consists of a nucleophilic water molecule bound to an octapeptide substrate in the active site. We first observe multiple and reversible binding of a nucleophilic water molecule into the active site giving a free energy of binding of DeltaG = -1 kcal/mol to form the GS. The free energy barriers for catalyzed and uncatalyzed NAC formation are both equivalent: DeltaGNAC? = 4.6 kcal/mol, constituting ~30% and ~15% of the overall barriers, respectively. Therefore, not only does adoption of NACs only account for minor progress along the transition path in both catalyzed and uncatalyzed reactions, but there is no preferential formation of them in the catalyzed reaction. Analysis of the catalytic hydrogen bond network reveals interactions that stabilize the GS; however, subsequent NAC formation does not preferentially favor any of the possible hydrogen bond configurations. This supports the view that the catalytic power of HIV-1 protease is not due to NAC formation. PMID- 26574230 TI - Vibrational entropy of a protein: large differences between distinct conformations. AB - In this article, it is investigated whether vibrational entropy (VE) is an important contribution to the free energy of globular proteins at ambient conditions. VE represents the major configurational-entropy contribution of these proteins. By definition, it is an average of the configurational entropies of the protein within single minima of the energy landscape, weighted by their occupation probabilities. Its large part originates from thermal motion of flexible torsion angles giving rise to the finite peak widths observed in torsion angle distributions. While VE may affect the equilibrium properties of proteins, it is usually neglected in numerical calculations as its consideration is difficult. Moreover, it is sometimes believed that all well-packed conformations of a globular protein have similar VE anyway. Here, we measure explicitly the VE for six different conformations from simulation data of a test protein. Estimates are obtained using the quasi-harmonic approximation for three coordinate sets, Cartesian, bond-angle-torsion (BAT), and a new set termed rotamer-degeneracy lifted BAT coordinates by us. The new set gives improved estimates as it overcomes a known shortcoming of the quasi-harmonic approximation caused by multiply populated rotamer states, and it may serve for VE estimation of macromolecules in a very general context. The obtained VE values depend considerably on the type of coordinates used. However, for all coordinate sets we find large entropy differences between the conformations, of the order of the overall stability of the protein. This result may have important implications on the choice of free energy expressions used in software for protein structure prediction, protein design, and NMR refinement. PMID- 26574231 TI - Accurate, precise, and efficient theoretical methods to calculate anion-pi interaction energies in model structures. AB - A correct description of the anion-pi interaction is essential for the design of selective anion receptors and channels and important for advances in the field of supramolecular chemistry. However, it is challenging to do accurate, precise, and efficient calculations of this interaction, which are lacking in the literature. In this article, by testing sets of 20 binary anion-pi complexes of fluoride, chloride, bromide, nitrate, or carbonate ions with hexafluorobenzene, 1,3,5 trifluorobenzene, 2,4,6-trifluoro-1,3,5-triazine, or 1,3,5-triazine and 30 ternary pi-anion-pi' sandwich complexes composed from the same monomers, we suggest domain-based local-pair natural orbital coupled cluster energies extrapolated to the complete basis-set limit as reference values. We give a detailed explanation of the origin of anion-pi interactions, using the permanent quadrupole moments, static dipole polarizabilities, and electrostatic potential maps. We use symmetry-adapted perturbation theory (SAPT) to calculate the components of the anion-pi interaction energies. We examine the performance of the direct random phase approximation (dRPA), the second-order screened exchange (SOSEX), local-pair natural-orbital (LPNO) coupled electron pair approximation (CEPA), and several dispersion-corrected density functionals (including generalized gradient approximation (GGA), meta-GGA, and double hybrid density functional). The LPNO-CEPA/1 results show the best agreement with the reference results. The dRPA method is only slightly less accurate and precise than the LPNO CEPA/1, but it is considerably more efficient (6-17 times faster) for the binary complexes studied in this paper. For 30 ternary pi-anion-pi' sandwich complexes, we give dRPA interaction energies as reference values. The double hybrid functionals are much more efficient but less accurate and precise than dRPA. The dispersion-corrected double hybrid PWPB95-D3(BJ) and B2PLYP-D3(BJ) functionals perform better than the GGA and meta-GGA functionals for the present test set. PMID- 26574232 TI - Prospective Epstein-Barr virus-related post-transplant lymphoproliferative disorder prevention program in pediatric allogeneic hematopoietic stem cell transplant: virological monitoring and first-line treatment. AB - BACKGROUND: In 28 pediatric allogeneic hematopoietic stem cell transplant (allo HSCT) recipients, we aimed to evaluate: (i) the impact of routine Epstein-Barr virus (EBV) DNA monitoring on the development of EBV-related post-transplant lymphoproliferative disorder (EBV-PTLD); (ii) the incidence of EBV infection and the potential risk factors; and (iii) the suitability of whole blood (WB) as clinical specimen to monitor the risk of patients to develop EBV-PTLD. METHODS: Quantitative real-time polymerase chain reaction assay was performed on WB samples for all patients. EBV DNA quantification also in peripheral blood mononuclear cells (PBMCs) samples was adopted for the patients at higher risk of developing EBV-PTLD (>= 10,000 copies/mL WB). RESULTS: High EBV DNAemia levels were observed in 37.5% of the actively infected recipients (57.1%). Severe aplastic anemia, matched-unrelated donor transplant, the reduced-intensity conditioning regimen and, to a lesser extent, the in vivo T-cell depletion with anti-thymocyte immunoglobulin were associated with high viral load. A significant correlation between EBV DNA levels in WB and PBMC samples was obtained (r = 0.755, P < 0.001). A similar kinetics of EBV DNA in the 2 blood compartments was observed. Clinically, both specimen types appeared to be equally informative to assess the risk of patients to develop PTLD. On the basis of EBV DNAemia levels, in 3 patients (10.7%) immunosuppressive therapy was reduced and 1 patient (3.5%) received early treatment for probable EBV disease. No patients developed EBV PTLD. CONCLUSION: WB proved to be a suitable clinical specimen to monitor EBV DNA load after allo-HSCT for the management of EBV infection and PTLD prevention. PMID- 26574233 TI - Increased oxidative metabolism following hypoxia in the type 2 diabetic heart, despite normal hypoxia signalling and metabolic adaptation. AB - KEY POINTS: Adaptation to hypoxia makes the heart more oxygen efficient, by metabolising more glucose. In contrast, type 2 diabetes makes the heart metabolise more fatty acids. Diabetes increases the chances of the heart being exposed to hypoxia, but whether the diabetic heart can adapt and respond is unknown. In this study we show that diabetic hearts retain the ability to adapt their metabolism in response to hypoxia, with functional hypoxia signalling pathways. However, the hypoxia-induced changes in metabolism are additive to abnormal baseline metabolism, resulting in hypoxic diabetic hearts metabolising more fat and less glucose than controls. This stops the diabetic heart being able to recover its function when stressed. These results demonstrate that the diabetic heart retains metabolic flexibility to adapt to hypoxia, but is hindered by the baseline effects of the disease. This increases our understanding of how the diabetic heart is affected by hypoxia-associated complications of the disease. ABSTRACT: Hypoxia activates the hypoxia-inducible factor (HIF), promoting glycolysis and suppressing mitochondrial respiration. In the type 2 diabetic heart, glycolysis is suppressed whereas fatty acid metabolism is promoted. The diabetic heart experiences chronic hypoxia as a consequence of increased obstructive sleep apnoea and cardiovascular disease. Given the opposing metabolic effects of hypoxia and diabetes, we questioned whether diabetes affects cardiac metabolic adaptation to hypoxia. Control and type 2 diabetic rats were housed for 3 weeks in normoxia or 11% oxygen. Metabolism and function were measured in the isolated perfused heart using radiolabelled substrates. Following chronic hypoxia, both control and diabetic hearts upregulated glycolysis, lactate efflux and glycogen content and decreased fatty acid oxidation rates, with similar activation of HIF signalling pathways. However, hypoxia-induced changes were superimposed on diabetic hearts that were metabolically abnormal in normoxia, resulting in glycolytic rates 30% lower, and fatty acid oxidation 36% higher, in hypoxic diabetic hearts than hypoxic controls. Peroxisome proliferator activated receptor alpha target proteins were suppressed by hypoxia, but activated by diabetes. Mitochondrial respiration in diabetic hearts was divergently activated following hypoxia compared with controls. These differences in metabolism were associated with decreased contractile recovery of the hypoxic diabetic heart following an acute hypoxic insult. In conclusion, type 2 diabetic hearts retain metabolic flexibility to adapt to hypoxia, with normal HIF signalling pathways. However, they are more dependent on oxidative metabolism following hypoxia due to abnormal normoxic metabolism, which was associated with a functional deficit in response to stress. PMID- 26574236 TI - Long-term benefit of liposuction in patients with lipoedema: a follow-up study after an average of 4 and 8 years. AB - BACKGROUND: Long-term results following liposuction in patients with lipoedema are available only for an average period of 4 years. OBJECTIVE: To find out whether the improvement of complaints persists for a further 4 years. METHODS: In a single-centre study, 85 patients with lipoedema had already been examined after 4 years. A mail questionnaire - often in combination with clinical controls - was repeated after another 4 years (8 years after liposuction). RESULTS: Compared with the results after 4 years, the improvement in spontaneous pain, sensitivity to pressure, oedema, bruising and restriction of movement persisted. The same held true for patient self-assessment of cosmetic appearance, quality of life and overall impairment. Eight years after surgery, the reduction in the amount of conservative treatment (combined decongestive therapy, compression garments) was similar to that observed 4 years earlier. CONCLUSION: These results demonstrate for the first time the long-lasting positive effects of liposuction in patients with lipoedema. PMID- 26574235 TI - 4beta-hydroxycholesterol correlates with dose but not steady-state concentration of carbamazepine: indication of intestinal CYP3A in biomarker formation? AB - AIM: 4beta-hydroxycholesterol (4betaOHC) is an endogenous CYP3A(4) biomarker, which is elevated by use of the CYP3A4 inducer carbamazepine. Our aim was to compare to what extent serum concentration of 4betaOHC correlates with dose (presystemic exposure) and steady-state concentration (systemic exposure) of carbamazepine. METHODS: The study was based on a therapeutic drug monitoring material, including information about daily doses and steady-state concentrations (Css ) of carbamazepine. 4betaOHC concentrations were determined in residual serum samples of 55 randomly selected carbamazepine-treated patients and 54 levetiracetam-treated patients (negative controls) by UPLC-APCI-MS/MS after liquid-liquid extraction. Correlation analyses between 4betaOHC concentration and daily dose and Css of carbamazepine, respectively, were performed by Spearman's tests. In addition, 4betaOHC concentrations in females vs. males were compared in induced and non-induced patients. RESULTS: Median 4betaOHC concentration was ~10 fold higher in carbamazepine- vs. levetiracetam-treated patients (650 vs. 54 nmol l(-1) , P < 0.0001). There was a significant, positive correlation between carbamazepine dose and 4betaOHC concentration (Spearman r = 0.53, 95% confidence interval [CI] 0.27, 0.72, P < 0.001). No significant correlation between carbamazepine Css and 4betaOHC concentration was found (Spearman r = 0.14; 95% CI -0.14, 0.40, P = 0.3). Enzyme-induced females had significantly higher 4betaOHC concentrations than males (P < 0.001), while no significant gender difference was found in non-induced patients (P = 0.52). CONCLUSION: Serum concentrations of 4betaOHC correlate with presystemic, but not systemic exposure of the CYP3A4 inducer carbamazepine. This suggests a stronger inductive effect of carbamazepine on presystemic than systemic CYP3A4 phenotype and might indicate a role of the intestine in 4betaOHC formation. Moreover, CYP3A4 inducibility seems to be higher in females than males. PMID- 26574237 TI - Solid state perovskite solar modules by vacuum-vapor assisted sequential deposition on Nd:YVO4 laser patterned rutile TiO2 nanorods. AB - The past few years have witnessed remarkable progress in solution-processed methylammonium lead halide (CH3NH3PbX3, X = halide) perovskite solar cells (PSCs) with reported photoconversion efficiency (eta) exceeding 20% in laboratory-scale devices and reaching up to 13% in their large area perovskite solar modules (PSMs). These devices mostly employ mesoporous TiO2 nanoparticles (NPs) as an electron transport layer (ETL) which provides a scaffold on which the perovskite semiconductor can grow. However, limitations exist which are due to trap-limited electron transport and non-complete pore filling. Herein, we have employed TiO2 nanorods (NRs), a material offering a two-fold higher electronic mobility and higher pore-filing compared to their particle analogues, as an ETL. A crucial issue in NRs' patterning over substrates is resolved by using precise Nd:YVO4 laser ablation, and a champion device with eta ~ 8.1% is reported via a simple and low cost vacuum-vapor assisted sequential processing (V-VASP) of a CH3NH3PbI3 film. Our experiments showed a successful demonstration of NRs-based PSMs via the V-VASP technique which can be applied to fabricate large area modules with a pin hole free, smooth and dense perovskite layer which is required to build high efficiency devices. PMID- 26574238 TI - Epistemic asymmetries in psychotherapy interaction: therapists' practices for displaying access to clients' inner experiences. AB - The relationship between a psychotherapist and a client involves a specific kind of epistemic asymmetry: in therapy sessions the talk mainly concerns the client's experience, which is unavailable, as such, to the therapist. This epistemic asymmetry is understood in different ways within different psychotherapeutic traditions. Drawing on a corpus of 70 audio-recorded sessions of cognitive psychotherapy and psychoanalysis and using the method of conversation analysis, the interactional practices of therapists for dealing with this epistemic asymmetry are investigated. Two types of epistemic practices were found to be employed by therapists while formulating and interpreting the client's inner experience. In the formulations, the therapists and clients co-described the client's experience, demonstrating that the client's inner experience was somewhat similarly available to both participants. In the interpretations, the therapists constructed an evidential foundation for the interpretation by summarising the client's talk and using the same descriptive terms as the client. Clients held therapists accountable for this epistemic work: if they failed to engage in such work, their right to know the client's inner experience was called into question. PMID- 26574239 TI - Importance of using proper post hoc test with ANOVA. PMID- 26574240 TI - Echocardiography and cardiac catheterism as complementary tools for the assessment of pulmonary circulation during exercise. PMID- 26574241 TI - Pattern mining of user interaction logs for a post-deployment usability evaluation of a radiology PACS client. AB - OBJECTIVES: To perform a post-deployment usability evaluation of a radiology Picture Archiving and Communication System (PACS) client based on pattern mining of user interaction log data, and to assess the usefulness of this approach compared to a field study. METHODS: All user actions performed on the PACS client were logged for four months. A data mining technique called closed sequential pattern mining was used to automatically extract frequently occurring interaction patterns from the log data. These patterns were used to identify usability issues with the PACS. The results of this evaluation were compared to the results of a field study based usability evaluation of the same PACS client. RESULTS: The interaction patterns revealed four usability issues: (1) the display protocols do not function properly, (2) the line measurement tool stays active until another tool is selected, rather than being deactivated after one use, (3) the PACS's built-in 3D functionality does not allow users to effectively perform certain 3D related tasks, (4) users underuse the PACS's customization possibilities. All usability issues identified based on the log data were also found in the field study, which identified 48 issues in total. CONCLUSIONS: Post-deployment usability evaluation based on pattern mining of user interaction log data provides useful insights into the way users interact with the radiology PACS client. However, it reveals few usability issues compared to a field study and should therefore not be used as the sole method of usability evaluation. PMID- 26574242 TI - Post-deployment usability evaluation of a radiology workstation. AB - OBJECTIVES: To determine the number, nature and severity of usability issues radiologists encounter while using a commercially available radiology workstation in clinical practice, and to assess how well the results of a pre-deployment usability evaluation of this workstation generalize to clinical practice. METHODS: The usability evaluation consisted of semi-structured interviews and observations of twelve users using the workstation during their daily work. Usability issues and positive usability findings were documented. Each issue was given a severity rating and its root cause was determined. Results were compared to the results of a pre-deployment usability evaluation of the same workstation. RESULTS: Ninety-two usability issues were identified, ranging from issues that cause minor frustration or delay, to issues that cause significant delays, prevent users from completing tasks, or even pose a potential threat to patient safety. The results of the pre-deployment usability evaluation had limited generalizability to clinical practice. CONCLUSIONS: This study showed that radiologists encountered a large number and a wide variety of usability issues when using a commercially available radiology workstation in clinical practice. This underlines the need for effective usability engineering in radiology. Given the limitations of pre-deployment usability evaluation in radiology, which were confirmed by our finding that the results of a pre-deployment usability evaluation of this workstation had limited generalizability to clinical practice, it is vital that radiology workstation vendors devote significant resources to usability engineering efforts before deployment of their workstation, and to continue these efforts after the workstation is deployed in a hospital. PMID- 26574243 TI - Fabrication of Electrospun Polymer Fibers with Nonspherical Cross-Sections Using a Nanopressing Technique. AB - The fabrication of electrospun polymer fibers is demonstrated with anisotropic cross-sections by applying a simple pressing method. Electrospun polystyrene or poly(methyl methacrylate) fibers are pressed by flat or patterned substrates while the samples are annealed at elevated temperatures. The shapes and morphologies of the pressed polymer fibers are controlled by the experimental conditions such as the pressing force, the pressing temperature, the pressing time, and the surface pattern of the substrate. At the same pressing force, the shape changes of the polymer fibers can be controlled by the pressing time. For shorter pressing times, the deformation process is dominated by the effect of pressing and fibers with barrel-shaped cross-sections can be generated. For longer pressing times, the effect of wetting becomes more important and fibers with dumbbell-shaped cross-sections can be obtained. Hierarchical polymer fibers with nanorods are fabricated by pressing the fibers with porous anodic aluminum oxide templates. PMID- 26574244 TI - Do drugs have access to the P-glycoprotein drug-binding pocket through gates? AB - The P-glycoprotein efflux mechanism is being studied since its identification as a leading protagonist in multidrug resistance. Recently, it was suggested that drugs enter the drug-binding pocket (DBP) through gates located between the transmembrane domains. For both a substrate and a modulator, the potential of mean force curves along the reaction coordinate obtained with the WHAM approach were similar, with no activation energy required for crossing the gate. Moreover, drug transit from bulk water into the DBP was characterized as an overall free energy downhill process. PMID- 26574245 TI - Using force-matched potentials to improve the accuracy of density functional tight binding for reactive conditions. AB - We show that force matching can be used to determine accurate empirical repulsive energies for the density functional tight binding method (DFTB) for chemical reactivity in condensed phases. Our approach yields improved results over previous parametrizations for molten liquid carbon and a phenolic polymer under combustion conditions. The method we present here allows for predictions of chemical properties over longer time periods than accessible via Kohn-Sham density functional theory while retaining its accuracy. PMID- 26574246 TI - Ab initio interactive molecular dynamics on graphical processing units (GPUs). AB - A virtual molecular modeling kit is developed based on GPU-enabled interactive ab initio molecular dynamics (MD). The code uses the TeraChem and VMD programs with a modified IMD interface. Optimization of the GPU accelerated TeraChem program specifically for small molecular systems is discussed, and a robust multiple time step integrator is employed to accurately integrate strong user-supplied pulling forces. Smooth and responsive visualization techniques are developed to allow interactive manipulation at minimum simulation rates below five MD steps per second. Representative calculations at the Hartree-Fock level of theory are demonstrated for molecular systems containing up to a few dozen atoms. PMID- 26574248 TI - Improved estimation of density of states for Monte Carlo sampling via MBAR. AB - We present a new method to calculate the density of states using the multistate Bennett acceptance ratio (MBAR) estimator. We use a combination of parallel tempering (PT) and multicanonical simulation to demonstrate the efficiency of our method in a statistical model of sampling from a two-dimensional normal mixture and also in a physical model of aggregation of lattice polymers. While MBAR has been commonly used for final estimation of thermodynamic properties, our numerical results show that the efficiency of estimation with our new approach, which uses MBAR as an intermediate step, often improves upon conventional use of MBAR. We also demonstrate that it can be beneficial in our method to use full PT samples for MBAR calculations in cases where simulation data exhibit long correlation. PMID- 26574247 TI - Binding enthalpy calculations for a neutral host-guest pair yield widely divergent salt effects across water models. AB - Dissolved salts are a part of the physiological milieu and can significantly influence the kinetics and thermodynamics of various biomolecular processes, such as binding and catalysis; thus, it is important for molecular simulations to reliably describe their effects. The present study uses a simple, nonionized host guest model system to study the sensitivity of computed binding enthalpies to the choice of water and salt models. Molecular dynamics simulations of a cucurbit[7]uril host with a neutral guest molecule show striking differences in the salt dependency of the binding enthalpy across four water models, TIP3P, SPC/E, TIP4P-Ew, and OPC, with additional sensitivity to the choice of parameters for sodium and chloride. In particular, although all of the models predict that binding will be less exothermic with increasing NaCl concentration, the strength of this effect varies by 7 kcal/mol across models. The differences appear to result primarily from differences in the number of sodium ions displaced from the host upon binding the guest rather than from differences in the enthalpy associated with this displacement, and it is the electrostatic energy that contributes most to the changes in enthalpy with increasing salt concentration. That a high sensitivity of salt affecting the choice of water model, as observed for the present host-guest system despite it being nonionized, raises issues regarding the selection and adjustment of water models for use with biological macromolecules, especially as these typically possess multiple ionized groups that can interact relatively strongly with ions in solution. PMID- 26574249 TI - Controlling the long-range corrections in atomistic Monte Carlo simulations of two-phase systems. AB - The long-range correction to the surface tension can amount to up to 55% of the calculated value of the surface tension for cutoffs in the range of 2.1-6.4 sigma. The calculation of the long-range corrections to the surface tension and to the configurational energy in two-phase systems remains an active area of research. In this work, we compare the long-range corrections methods proposed by Guo and Lu ( J. Chem. Phys. 1997 , 106 , 3688 - 3695 ) and Janecek ( J. Phys. Chem. B 2006 , 110 , 6264 - 6269 ) for the calculation of the surface tension and of the coexisting densities in Monte Carlo simulations of the truncated Lennard Jones potential and the truncated and shifted Lennard-Jones potential models. These methods require an estimate of the long-range correction at each step in the Monte Carlo simulation. We apply the full version of the Guo and Lu method, which involves the calculation of a double integral that contains a series of density differences, and we compare these results with the simplified version of the method which is routinely used in two-phase simulations. We conclude that the cutoff dependencies of the surface tension and coexisting densities are identical for the full versions of Guo and Lu and Janecek methods. We show that it is possible to avoid applying the long-range correction at every step by using the truncated Lennard-Jones potential with a cutoff rc >= 5 sigma. The long-range correction can then be applied at the end of the simulation. The limiting factor in the accurate calculation of this final correction is an accurate estimate of the coexisting densities. Link-cell simulations performed using a cutoff rc = 5.5 sigma require twice as much computing time as those with a more typical cutoff of rc = 3.0 sigma. The application of the Janecek correction increases the running time of the simulation by less than 10%, and it can be profitably applied with the shorter cutoff. PMID- 26574251 TI - Assessment of DFT methods for computing activation energies of Mo/W-mediated reactions. AB - Using high level ab initio coupled cluster calculations as reference, the performances of 15 commonly used density functionals (DFs) on activation energy calculations for typical Mo/W-mediated reactions have been systematically assessed for the first time in this work. The selected representative Mo/W mediated reactions cover a wide range from enzymatic reactions to organometallic reactions, which include Mo-catalyzed aldehyde oxidation (aldehyde oxidoreductase), Mo-catalyzed dimethyl sulfoxide (DMSO) reduction (DMSO reductase), W-catalyzed acetylene hydration (acetylene hydratase), Mo/W-mediated olefin metathesis, Mo/W-mediated olefin epoxidation, W-mediated alkyne metathesis, and W-mediated C-H bond activation. Covering both Mo- and W-mediated reactions, four DFs of B2GP-PLYP, M06, B2-PLYP, and B3LYP are uniformly recommended with and without DFT empirical dispersion correction. Among these four DFs, B3LYP is notably improved in performance by DFT empirical dispersion correction. In addition to the absolute value of calculation error, if the trend of DFT results is also a consideration, B2GP-PLYP, B2-PLYP, and M06 keep better performance than other functionals tested and constitute our final recommendation of DFs for both Mo- and W-mediated reactions. PMID- 26574250 TI - Examining the assumptions underlying continuum-solvent models. AB - Continuum-solvent models (CSMs) have successfully predicted many quantities, including the solvation-free energies (DeltaG) of small molecules, but they have not consistently succeeded at reproducing experimental binding free energies (DeltaDeltaG), especially for protein-protein complexes. Several CSMs break DeltaG into the free energy (DeltaGvdw) of inserting an uncharged molecule into solution and the free energy (DeltaGel) gained from charging. Some further divide DeltaGvdw into the free energy (DeltaGrep) of inserting a nearly hard cavity into solution and the free energy (DeltaGatt) gained from turning on dispersive interactions between the solute and solvent. We show that for 9 protein-protein complexes neither DeltaGrep nor DeltaGvdw was linear in the solvent-accessible area A, as assumed in many CSMs, and the corresponding components of DeltaDeltaG were not linear in changes in A. We show that linear response theory (LRT) yielded good estimates of DeltaGatt and DeltaDeltaGatt, but estimates of DeltaDeltaGatt obtained from either the initial or final configurations of the solvent were not consistent with those from LRT. The LRT estimates of DeltaGel differed by more than 100 kcal/mol from the explicit solvent model's (ESM's) predictions, and its estimates of the corresponding component (DeltaDeltaGel) of DeltaDeltaG differed by more than 10 kcal/mol. Finally, the Poisson-Boltzmann equation produced estimates of DeltaGel that were correlated with those from the ESM, but its estimates of DeltaDeltaGel were much less so. These findings may help explain why many CSMs have not been consistently successful at predicting DeltaDeltaG for many complexes, including protein-protein complexes. PMID- 26574252 TI - Construction and application of a new dual-hybrid random phase approximation. AB - The direct random phase approximation (dRPA) combined with Kohn-Sham reference orbitals is among the most promising tools in computational chemistry and applicable in many areas of chemistry and physics. The reason for this is that it scales as N(4) with the system size, which is a considerable advantage over the accurate ab initio wave function methods like standard coupled-cluster. dRPA also yields a considerably more accurate description of thermodynamic and electronic properties than standard density-functional theory methods. It is also able to describe strong static electron correlation effects even in large systems with a small or vanishing band gap missed by common single-reference methods. However, dRPA has several flaws due to its self-correlation error. In order to obtain accurate and precise reaction energies, barriers and noncovalent intra- and intermolecular interactions, we construct a new dual-hybrid dRPA (hybridization of exact and semilocal exchange in both the energy and the orbitals) and test the performance of this new functional on isogyric, isodesmic, hypohomodesmotic, homodesmotic, and hyperhomodesmotic reaction classes. We also use a test set of 14 Diels-Alder reactions, six atomization energies (AE6), 38 hydrocarbon atomization energies, and 100 reaction barrier heights (DBH24, HT-BH38, and NHT BH38). For noncovalent complexes, we use the NCCE31 and S22 test sets. To test the intramolecular interactions, we use a set of alkane, cysteine, phenylalanine glycine-glycine tripeptide, and monosaccharide conformers. We also discuss the delocalization and static correlation errors. We show that a universally accurate description of chemical properties can be provided by a large, 75% exact exchange mixing both in the calculation of the reference orbitals and the final energy. PMID- 26574253 TI - Complex absorbing potentials with Voronoi isosurfaces wrapping perfectly around molecules. AB - Complex absorbing potentials (CAPs) are imaginary potentials that are added to a Hamiltonian to change the boundary conditions of the problem from scattering to square-integrable. In other words, with a CAP, standard bound-state methods can be used in problems involving unbound states such as identifying resonance states and predicting their energies and lifetimes. Although in wave packet dynamics, many CAP forms are used, in electronic structure theory, the so-called box-CAP is used almost exclusively, because of the ease of evaluating its integrals in a Gaussian basis set. However, the box-CAP does has certain disadvantages. First, it will, e.g., break the symmetry of Cnv molecules if n is odd and the main axis is placed along the z-axis by the "standard orientation" of the electronic structure code. Second, it provides a CAP starting at the smallest box around the entire molecular system. For larger molecules or clusters, which do not fill the space efficiently, that implies that much "dead space" within the molecule will be left, where there is neither a CAP nor a sufficient description with basis functions. Here, two new CAP forms are introduced and systematically explored: first, a Voronoi-CAP (that is, a CAP defined in each atom's Voronoi cell), and second, a smooth Voronoi-CAP (which is similar to the Voronoi-CAP; however, the noncontinuously differentiable behavior at the surfaces between the Voronoi cells is smoothed out). Both have isosurfaces that are similar to the cavities used in solvation modeling. An obvious disadvantage of these two CAPs is that the integrals cannot be obtained analytically, but must be computed numerically. However, Voronoi-CAPs share the advantage of having the same symmetry as the molecular system, and, more importantly, considerably facilitate the treatment of larger molecules with asymmetric side chains and of molecular clusters. PMID- 26574254 TI - Multireference second order perturbation theory with a simplified treatment of dynamical correlation. AB - A multireference second order perturbation theory based on a complete active space configuration interaction (CASCI) function or density matrix renormalized group (DMRG) function has been proposed. This method may be considered as an approximation to the CAS/A approach with the same reference, in which the dynamical correlation is simplified with blocked correlated second order perturbation theory based on the generalized valence bond (GVB) reference (GVB BCPT2). This method, denoted as CASCI-BCPT2/GVB or DMRG-BCPT2/GVB, is size consistent and has a similar computational cost as the conventional second order perturbation theory (MP2). We have applied it to investigate a number of problems of chemical interest. These problems include bond-breaking potential energy surfaces in four molecules, the spectroscopic constants of six diatomic molecules, the reaction barrier for the automerization of cyclobutadiene, and the energy difference between the monocyclic and bicyclic forms of 2,6-pyridyne. Our test applications demonstrate that CASCI-BCPT2/GVB can provide comparable results with CASPT2 (second order perturbation theory based on the complete active space self-consistent-field wave function) for systems under study. Furthermore, the DMRG-BCPT2/GVB method is applicable to treat strongly correlated systems with large active spaces, which are beyond the capability of CASPT2. PMID- 26574255 TI - Efficient parallel linear scaling construction of the density matrix for Born Oppenheimer molecular dynamics. AB - We present an algorithm for the calculation of the density matrix that for insulators scales linearly with system size and parallelizes efficiently on multicore, shared memory platforms with small and controllable numerical errors. The algorithm is based on an implementation of the second-order spectral projection (SP2) algorithm [ Niklasson, A. M. N. Phys. Rev. B 2002 , 66 , 155115 ] in sparse matrix algebra with the ELLPACK-R data format. We illustrate the performance of the algorithm within self-consistent tight binding theory by total energy calculations of gas phase poly(ethylene) molecules and periodic liquid water systems containing up to 15,000 atoms on up to 16 CPU cores. We consider algorithm-specific performance aspects, such as local vs nonlocal memory access and the degree of matrix sparsity. Comparisons to sparse matrix algebra implementations using off-the-shelf libraries on multicore CPUs, graphics processing units (GPUs), and the Intel many integrated core (MIC) architecture are also presented. The accuracy and stability of the algorithm are illustrated with long duration Born-Oppenheimer molecular dynamics simulations of 1000 water molecules and a 303 atom Trp cage protein solvated by 2682 water molecules. PMID- 26574256 TI - Performance and accuracy of recursive subspace bisection for hybrid DFT calculations in inhomogeneous systems. AB - The high cost of computing the Hartree-Fock exchange energy has resulted in a limited use of hybrid density functionals in solid-state and condensed phase calculations. Approximate methods based on the use of localized orbitals have been proposed as a way to reduce this computational cost. In particular, Boys orbitals (or maximally localized Wannier functions in solids) were recently used in plane wave, first-principles molecular dynamics simulations of water. Recently, the recursive subspace bisection (RSB) method was used to compute orbitals localized in regular rectangular domains of varying shape and size, leading to efficient calculations of the Hartree-Fock exchange energy in the plane-wave, pseudopotential framework. In this paper, we use the RSB decomposition to analyze orbital localization properties in inhomogeneous systems (e.g., solid/liquid interfaces) in which localized orbitals have widely varying extent. This analysis reveals that some orbitals cannot be significantly localized and thus cannot be truncated without incurring a substantial error in computed physical properties, while other orbitals can be well localized to small domains. We take advantage of the ability to systematically reduce the error in RSB calculations through a single parameter to study the effect of orbital truncation. We present the errors in PBE0 ground state energies, ionic forces, band gaps, and relative energy differences between configurations for a variety of systems, including a tungsten oxide/water interface, a silicon/water interface, liquid water, and bulk molybdenum. We show that the RSB approach can adapt to such diverse configurations by localizing orbitals in different domains while preserving a 2-norm upper bound on the truncation error. The resulting approach allows for efficient hybrid DFT simulations of inhomogeneous systems in which the localization properties of orbitals vary during the course of the simulation. PMID- 26574257 TI - Accuracy of DLPNO-CCSD(T) method for noncovalent bond dissociation enthalpies from coinage metal cation complexes. AB - The performance of the domain based local pair-natural orbital coupled-cluster (DLPNO-CCSD(T)) method has been tested to reproduce the experimental gas phase ligand dissociation enthalpy in a series of Cu(+), Ag(+), and Au(+) complexes. For 33 Cu(+)-noncovalent ligand dissociation enthalpies, all-electron calculations with the same method result in MUE below 2.2 kcal/mol, although a MSE of 1.4 kcal/mol indicates systematic underestimation of the experimental values. Inclusion of scalar relativistic effects for Cu either via effective core potential (ECP) or Douglass-Kroll-Hess Hamiltonian, reduces the MUE below 1.7 kcal/mol and the MSE to -1.0 kcal/mol. For 24 Ag(+)-noncovalent ligand dissociation enthalpies, the DLPNO-CCSD(T) method results in a mean unsigned error (MUE) below 2.1 kcal/mol and vanishing mean signed error (MSE). For 15 Au(+)-noncovalent ligand dissociation enthalpies, the DLPNO-CCSD(T) methods provides larger MUE and MSE, equal to 3.2 and 1.7 kcal/mol, which might be related to poor precision of the experimental measurements. Overall, for the combined data set of 72 coinage metal ion complexes, DLPNO-CCSD(T) results in a MUE below 2.2 kcal/mol and an almost vanishing MSE. As for a comparison with computationally cheaper density functional theory (DFT) methods, the routinely used M06 functional results in MUE and MSE equal to 3.6 and -1.7 kcal/mol. Results converge already at CC-PVTZ quality basis set, making highly accurate DLPNO-CCSD(T) estimates affordable for routine calculations (single-point) on large transition metal complexes of >100 atoms. PMID- 26574258 TI - Integration approach at the second-order perturbation theory: applications to ionization potential and electron affinity calculations. AB - An integration approach is developed to calculate ionization potentials (IPs), and electron affinities (EAs), which is an extension of the D-DeltaMBPT(2) method [A. Beste et al., J. Chem. Phys. 2013, 138, 074101]. The latter is an extension of the single-point method of Cohen et al. [A. J. Cohen et al., J. Chem. Theory Comput. 2009, 5, 786] from the perspective of fractional charges. While relaxation effects were included only at the Hartree-Fock (HF) level in the previous methods, such effects are fully taken into account in the present method up to the second-order Moller-Plesset (MP2) level. This is made possible by deriving the full MP2 energy gradient, with respect to the orbital occupation numbers, which is solved through the coupled-perturbed HF (CP-HF) equations. PMID- 26574259 TI - Semiexperimental equilibrium structures for building blocks of organic and biological molecules: the B2PLYP route. AB - The B2PLYP double hybrid functional, coupled with the correlation-consistent triple-zeta cc-pVTZ (VTZ) basis set, has been validated in the framework of the semiexperimental (SE) approach for deriving accurate equilibrium structures of molecules containing up to 15 atoms. A systematic comparison between new B2PLYP/VTZ results and several equilibrium SE structures previously determined at other levels, in particular B3LYP/SNSD and CCSD(T) with various basis sets, has put in evidence the accuracy and the remarkable stability of such model chemistry for both equilibrium structures and vibrational corrections. New SE equilibrium structures for phenylacetylene, pyruvic acid, peroxyformic acid, and phenyl radical are discussed and compared with literature data. Particular attention has been devoted to the discussion of systems for which lack of sufficient experimental data prevents a complete SE determination. In order to obtain an accurate equilibrium SE structure for these situations, the so-called templating molecule approach is discussed and generalized with respect to our previous work. Important applications are those involving biological building blocks, like uracil and thiouracil. In addition, for more general situations the linear regression approach has been proposed and validated. PMID- 26574260 TI - Nanoscale multireference quantum chemistry: full configuration interaction on graphical processing units. AB - Methods based on a full configuration interaction (FCI) expansion in an active space of orbitals are widely used for modeling chemical phenomena such as bond breaking, multiply excited states, and conical intersections in small-to-medium sized molecules, but these phenomena occur in systems of all sizes. To scale such calculations up to the nanoscale, we have developed an implementation of FCI in which electron repulsion integral transformation and several of the more expensive steps in sigma vector formation are performed on graphical processing unit (GPU) hardware. When applied to a 1.7 * 1.4 * 1.4 nm silicon nanoparticle (Si72H64) described with the polarized, all-electron 6-31G** basis set, our implementation can solve for the ground state of the 16-active-electron/16-active orbital CASCI Hamiltonian (more than 100,000,000 configurations) in 39 min on a single NVidia K40 GPU. PMID- 26574261 TI - Polar flattening and the strength of halogen bonding. AB - The effect of polar flattening on the stability of 32 halogen-bonded complexes was investigated by utilizing CCSD(T)/CBS, DFT, and DFT-SAPT/CBS methods. It is shown that the value of polar flattening increases with the decreasing value of studied isodensity. For the complexes investigated, the polar flattening based on the isodensity of 0.001 au reaches 0.2-0.3 A and 10-15% in absolute and relative values, respectively. These geometrical changes induce differences in the stabilization energy up to 20%. PMID- 26574262 TI - Relativistic internally contracted multireference electron correlation methods. AB - We report internally contracted relativistic multireference configuration interaction (ic-MRCI), complete active space second-order perturbation (CASPT2), and strongly contracted n-electron valence state perturbation theory (NEVPT2) on the basis of the four-component Dirac Hamiltonian, enabling accurate simulations of relativistic, quasi-degenerate electronic structure of molecules containing transition-metal and heavy elements. Our derivation and implementation of ic-MRCI and CASPT2 are based on an automatic code generator that translates second quantized ansatze to tensor-based equations, and to efficient computer code. NEVPT2 is derived and implemented manually. The rovibrational transition energies and absorption spectra of HI and TlH are presented to demonstrate the accuracy of these methods. PMID- 26574263 TI - Mechanism of O((3)P) formation from a hydroxyl radical pair in aqueous solution. AB - The reaction mechanism for the rapid formation of a triplet oxygen atom, O((3)P), from a pair of triplet-state hydroxyl radicals in liquid water is explored utilizing extensive Car-Parrinello MD simulations and advanced visualization techniques. The local solvation structures, the evolution of atomic charges, atomic separations, spin densities, electron localization functions, and frontier molecular orbitals, as well as free energy profiles, evidence that the reaction proceeds through a hybrid (hydrogen atom transfer and electron-proton transfer) and hemibond-assisted reaction mechanism. A benchmarking study utilizing high level ab initio calculations to examine the interactions of a hydroxyl radical pair in the gas phase and the influence of a hemibonded water is also provided. The results presented here should serve as a foundation for further experimental and theoretical studies aimed at better understanding the role and potential applications of the triplet oxygen atom as a potent reactive oxygen species. PMID- 26574264 TI - A simple and transferable all-atom/coarse-grained hybrid model to study membrane processes. AB - We present an efficient all-atom/coarse-grained hybrid model and apply it to membrane processes. This model is an extension of the all-atom/ELBA model applied previously to processes in water. Here, we improve the efficiency of the model by implementing a multiple-time step integrator that allows the atoms and the coarse grained beads to be propagated at different timesteps. Furthermore, we fine-tune the interaction between the atoms and the coarse-grained beads by computing the potential of mean force of amino acid side chain analogs along the membrane normal and comparing to atomistic simulations. The model was independently validated on the calculation of small-molecule partition coefficients. Finally, we apply the model to membrane peptides. We studied the tilt angle of the Walp23 and Kalp23 helices in two different model membranes and the stability of the glycophorin A dimer. The model is efficient, accurate, and straightforward to use, as it does not require any extra interaction particles, layers of atomistic solvent molecules or tabulated potentials, thus offering a novel, simple approach to study membrane processes. PMID- 26574265 TI - Transferability and nonbond functional form of coarse grained force field - tested on linear alkanes. AB - Whether or not a coarse grained force field (CGFF) can be made to be transferrable is an important question to be addressed. By comparing potential energy with potential of mean force (PMF) of a molecular dimer, we proposed to use a free energy function (FE-12-6) with the parameters in entropic and energetic terms explicitly to represent the nonbond interactions in CGFF. Although the FE-12-6 function cannot accurately describe the PMF curves, a cancelation of short radii and strong repulsion makes the function a good approximation. For nonpolar molecules represented by linear alkanes, FE-12-6 is demonstrated to be highly effective in representing the nonbond interactions in CGFF. The force field parameters are well transferrable among different alkane molecules, in different thermodynamic states and for predicting various thermodynamic properties including heats of vaporization, vapor-liquid equilibrium coexistence curves, surface tensions, and liquid densities. PMID- 26574267 TI - Solvation station: microsolvation for modeling vibrational sum-frequency spectra of acids at aqueous interfaces. AB - Vibrational sum-frequency spectra of a pair of poly(methacrylic acid) isomers at an oil/water interface and glutaric acid at an air/water interface were calculated in the carbonyl stretching region. Orientational, conformational, and solvation information was determined using classical molecular dynamics (MD), while second-order susceptibility vibrational response tensors were determined for a set of density functional theory (DFT) structures. The DFT structures were microsolvated with water molecules corresponding to the major solvation states present in the MD calculations. The inclusion of the microsolvating waters incorporates solvation effects important to the carboxylic acid stretching modes in the studied spectral region. The calculated spectra strongly agree with experimental spectra when a cutoff of 1.975 A is used to define a hydrogen bond in the MD trajectories. With the chosen cutoff, the most common solvation state of the carboxylic acid moieties involves a single hydrogen bond to the carbonyl oxygen and a single hydrogen bond to the carboxylic acid hydrogen. The sensitivity of the spectra to the hydrogen bond cutoff definition and the included DFT structures was investigated. Moderate changes in the relative intensities of the contributing peaks were found in both cases. Shortening the hydrogen bond cutoff definition predictably leads to a decrease in the relative intensity of peaks corresponding to well-solvated structures, while altering the set of DFT solvation structures results in more complex behavior that is dependent on the specific structures included. PMID- 26574266 TI - Grid-based backbone correction to the ff12SB protein force field for implicit solvent simulations. AB - Force fields, such as Amber's ff12SB, can be fairly accurate models of the physical forces in proteins and other biomolecules. When coupled with accurate solvation models, force fields are able to bring insight into the conformational preferences, transitions, pathways, and free energies for these biomolecules. When computational speed/cost matters, implicit solvent is often used but at the cost of accuracy. We present an empirical grid-like correction term, in the spirit of cMAPs, to the combination of the ff12SB protein force field and the GBneck2 implicit-solvent model. Ff12SB-cMAP is parametrized on experimental helicity data. We provide validation on a set of peptides and proteins. Ff12SB cMAP successfully improves the secondary structure biases observed in ff12SB + Gbneck2. Ff12SB-cMAP can be downloaded ( https://github.com/laufercenter/Amap.git ) and used within the Amber package. It can improve the agreement of force fields + implicit solvent with experiments. PMID- 26574268 TI - Peak-shifting in real-time time-dependent density functional theory. AB - In recent years, the development and application of real-time time-dependent density functional theory (RT-TDDFT) has gained momentum as a computationally efficient method for modeling electron dynamics and properties that require going beyond a linear response of the electron density. However, the RT-TDDFT method within the adiabatic approximation can unphysically shift absorption peaks throughout the electron dynamics. Here, we investigate the origin of these time dependent resonances observed in RT-TDDFT spectra. Using both exact exchange and hybrid exchange-correlation approximate functionals, adiabatic RT-TDDFT gives time-dependent absorption spectra in which the peaks shift in energy as populations of the excited states fluctuate, while exact wave function methods yield peaks that are constant in energy but vary in intensity. The magnitude of the RT-TDDFT peak shift depends on the frequency and intensity of the applied field, in line with previous studies, but it oscillates as a function of time dependent molecular orbital populations, consistent with a time-dependent superposition electron density. For the first time, we provide a rationale for the direction and magnitude of the time-dependent peak shifts based on the molecular electronic structure. For three small molecules, H2, HeH(+), and LiH, we give contrasting examples of peak-shifting to both higher and lower energies. The shifting is explained as coupled one-electron transitions to a higher and a lower lying state. Whether the peak shifts to higher or lower energies depends on the relative energetics of these one-electron transitions. PMID- 26574269 TI - A "twist" on the interpretation of the multifluorescence patterns of DASPMI. AB - In this computational study, we describe the decay mechanism of DASPMI, providing robust and documented answers to some crucial questions of still open debates on the photophysical behavior of this cationic dye. After the initial excitation, the system evolves along a torsional motion, characterized by a quite flat potential energy surface, which crosses an intramolecular charge transfer (ICT) excited state with higher energy. A nonemissive twisted-ICT (TICT) minimum is populated, and this enhances the radiationless deactivation to the ground state. Additionally, during the twisting motion path toward the TICT minima, the system can emit in a quite wide range of angles, which should lead to a red shift of the locally excited (LE) emission and asymmetric broadening of fluorescence. This picture is fully supported by experimental evidence of the multifluorescence of DASPMI. Three twisted minima are found with different energies (namely, T1, T2, and T3). The extension of the work to charge properties shows that, in the GS, the positive charge of the molecule is mainly localized on the acceptor moiety (i.e., methyl-pyridinium), and after the excitation, the charge delocalizes over the whole molecule with a slight preference for the acceptor moiety. Because of the subsequent deactivation via twisting motions, the positive charge moves from the acceptor to the donor moiety (dimethylaminophenyl moiety) so that in TICT minima the positive charge is localized in the donor part. These large differences between charge localization in LE and TICT minima are responsible for a larger population of twisted forms in solvents of increasing polarity and the enhancement of radiationless deactivation. PMID- 26574270 TI - Open-ended recursive calculation of single residues of response functions for perturbation-dependent basis sets. AB - We present theory, implementation, and applications of a recursive scheme for the calculation of single residues of response functions that can treat perturbations that affect the basis set. This scheme enables the calculation of nonlinear light absorption properties to arbitrary order for other perturbations than an electric field. We apply this scheme for the first treatment of two-photon circular dichroism (TPCD) using London orbitals at the Hartree-Fock level of theory. In general, TPCD calculations suffer from the problem of origin dependence, which has so far been solved by using the velocity gauge for the electric dipole operator. This work now enables comparison of results from London orbital and velocity gauge based TPCD calculations. We find that the results from the two approaches both exhibit strong basis set dependence but that they are very similar with respect to their basis set convergence. PMID- 26574271 TI - Chromophore-protein coupling beyond nonpolarizable models: understanding absorption in green fluorescent protein. AB - The nature of the coupling of the photoexcited chromophore with the environment in a prototypical system like green fluorescent protein (GFP) is to date not understood, and its description still defies state-of-the-art multiscale approaches. To identify which theoretical framework of the chromophore-protein complex can realistically capture its essence, we employ here a variety of electronic-structure methods, namely, time-dependent density functional theory (TD-DFT), multireference perturbation theory (NEVPT2 and CASPT2), and quantum Monte Carlo (QMC) in combination with static point charges (QM/MM), DFT embedding (QM/DFT), and classical polarizable embedding through induced dipoles (QM/MMpol). Since structural modifications can significantly affect the photophysics of GFP, we also account for thermal fluctuations through extensive molecular dynamics simulations. We find that a treatment of the protein through static point charges leads to significantly blue-shifted excitation energies and that including thermal fluctuations does not cure the coarseness of the MM description. While TDDFT calculations on large cluster models indicate the need of a responsive protein, this response is not simply electrostatic: An improved description of the protein in the ground state or in response to the excitation of the chromophore via ground-state or state-specific DFT and MMpol embedding does not significantly modify the results obtained with static point charges. Through the use of QM/MMpol in a linear response formulation, a different picture in fact emerges in which the main environment response to the chromophore excitation is the one coupling the transition density and the corresponding induced dipoles. Such interaction leads to significant red-shifts and a satisfactory agreement with full QM cluster calculations at the same level of theory. Our findings demonstrate that, ultimately, faithfully capturing the effects of the environment in GFP requires a quantum treatment of large photoexcited regions but that a QM/classical model can be a useful approximation when extended beyond the electrostatic-only formulation. PMID- 26574272 TI - Magnetic couplings in the chemical shift of paramagnetic NMR. AB - We apply the Kurland-McGarvey (J. Magn. Reson. 1970, 2, 286) theory for the NMR shielding of paramagnetic molecules, particularly its special case limited to the ground-state multiplet characterized by zero-field splitting (ZFS) interaction of the form S.D.S. The correct formulation for this problem was recently presented by Soncini and Van den Heuvel (J. Chem. Phys. 2013, 138, 054113). With the effective electron spin quantum number S, the theory involves 2S+1 states, of which all but one are low-lying excited states, between which magnetic couplings take place by Zeeman and hyperfine interactions. We investigate these couplings as a function of temperature, focusing on both the high- and low-temperature behaviors. As has been seen in work by others, the full treatment of magnetic couplings is crucial for a realistic description of the temperature behavior of NMR shielding up to normal measurement temperatures. At high temperatures, depending on the magnitude of ZFS, the effect of magnetic couplings diminishes, and the Zeeman and hyperfine interactions become effectively averaged in the thermally occupied states of the multiplet. At still higher temperatures, the ZFS may be omitted altogether, and the shielding properties may be evaluated using a doublet-like formula, with all the 2S+1 states becoming effectively degenerate at the limit of vanishing magnetic field. We demonstrate these features using first principles calculations of Ni(II), Co(II), Cr(II), and Cr(III) complexes, which have ZFS of different sizes and signs. A non-monotonic inverse temperature dependence of the hyperfine shift is predicted for axially symmetric integer-spin systems with a positive D parameter of ZFS. This is due to the magnetic coupling terms that are proportional to kT at low temperatures, canceling the Curie-type 1/kT prefactor of the hyperfine shielding in this case. PMID- 26574273 TI - Temporal coarse graining of CO2 and N2 diffusion in zeolite NaKA: from the quantum scale to the macroscopic. AB - The kinetic CO2-over-N2 sieving capabilities in narrow pore zeolites are dependent on the free-energy barriers of diffusion between the zeolite pores, which can be fine-tuned by altering the framework composition. An ab initio level of theory is necessary to accurately compute the energy barriers, whereas it is desirable to predict the macroscopic scale diffusion for industrial applications. Using ab initio molecular dynamics on the picosecond time scale, the free-energy barriers of diffusion can be predicted for different local pore properties in order to identify those that are rate-determining for the pore-to-pore diffusion. Specifically, we investigate the effects of the Na(+)-to-K(+) exchange at the different cation sites and the CO2 loading in Zeolite NaKA. These computed energy barriers are then used as input for the Kinetic Monte Carlo method, coarse graining the dynamic simulation steps to the pore-to-pore diffusion. With this approach, we simulate how the identified rate-determining properties as well as the application of skin-layer surface defects affect the diffusion driven uptake in a realistic Zeolite NaKA powder particle model on a macroscopic time scale. Lastly, we suggest a model by combining these effects, which provides an excellent agreement with the experimental CO2 and N2 uptake behaviors presented by Liu et al. (Chem. Commun. 2010, 46, 4502-4504). PMID- 26574274 TI - Molecule-lead coupling at molecular junctions: relation between the real- and state-space perspectives. AB - We present insights into the lead-molecule coupling scheme in molecular electronics junctions. Using a "site-to-state" transformation that provides direct access to the coupling matrix elements between the molecular states and the eigenstate manifold of each lead, we find coupling bands whose character depends on the geometry and dimensionality of the lead. We use a standard tight binding model to elucidate the origin of the coupling bands and explain their nature via simple "particle-in-a-box" type considerations. We further show that these coupling bands can shed light on the charge transport behavior of the junction. The picture presented in this study is not limited to the case of molecular electronics junctions and is relevant to any scenario where a finite molecular entity is coupled to a (semi)infinite system. PMID- 26574275 TI - Molecular dynamics simulations and neutron reflectivity as an effective approach to characterize biological membranes and related macromolecular assemblies. AB - In combination with other spectroscopy, microscopy, and scattering techniques, neutron reflectivity is a powerful tool to characterize biological systems. Specular reflection of neutrons provides structural information at the nanometer and subnanometer length scales, probing the composition and organization of layered materials. Currently, analysis of neutron reflectivity data involves several simplifying assumptions about the structure of the sample under study, affecting the extraction and interpretation of information from the experimental data. Computer simulations can be used as a source of structural and dynamic data with atomic resolution. We present a novel tool to compare the structural properties determined by neutron reflectivity experiments with those obtained from molecular simulations. This tool allows benchmarking the ability of molecular dynamics simulations to reproduce experimental data, but it also promotes unbiased interpretation of experimentally determined quantities. Two application examples are presented to illustrate the capabilities of the new tool. The first example is the generation of reflectivity profiles for a 1,2 dimyristoyl-sn-glycero-3-phosphocholine (DMPC) lipid bilayer from molecular dynamics simulations using data from both atomistic and coarse-grained models, and comparison with experimentally measured data. The second example is the calculation of lipid volume changes with temperature and composition from all atoms simulations of single and mixed 1,2-di-palmitoyl-sn-glycero-3 phosphocholine (DOPC) and 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine (DPPC) bilayers. PMID- 26574276 TI - Variable-cell double-ended surface walking method for fast transition state location of solid phase transitions. AB - To identify the low energy pathway for solid-to-solid phase transition has been a great challenge in physics and material science. This work develops a new theoretical method, namely, variable-cell double-ended surface walking (VC-DESW) to locate the transition state (TS) and deduce the pathway in solid phase transition. Inherited from the DESW method ( J. Chem. Theory Comput. 2013 , 9 , 5745 ) for molecular systems, the VC-DESW method implements an efficient mechanism to couple the lattice and atom degrees of freedom. The method features with fast pseudopathway building and accurate TS location for solid phase transition systems without requiring expensive Hessian computation and iterative pathway optimization. A generalized coordinate, consisting of the lattice vectors and the scaled atomic coordinates, is designed for describing the crystal potential energy surface (PES), which is able to capture the anisotropic behavior in phase transition. By comparing with the existing method for solid phase transition in different systems, we show that the VC-DESW method can be much more efficient for finding the TS in crystal phase transition. With the combination of the recently developed unbiased stochastic surface walking pathway sampling method, the VC-DESW is further utilized to resolve the lowest energy pathway of SiO2 alpha-quartz to quartz-II phase transition from many likely reaction pathways. These new methods provide a powerful platform for understanding and predicting the solid phase transition mechanism and kinetics. PMID- 26574277 TI - Spectrum for nonmagnetic mott insulators from power functional within reduced density matrix functional theory. AB - We demonstrate that reduced density matrix functional theory (RDMFT), in conjunction with the power functional, can successfully treat the nonmagnetic insulating state of the transition metal oxides NiO and MnO, finding for both a gapped single particle spectrum. While long-range spin order is thus not necessary for qualitative agreement with experiment, we find that it is required for good agreement with the X-ray photoemission spectroscopy and Bremsstrahlung isochromat spectroscopy data. We further examine the nature of the natural orbitals in the materials, finding that they display significant Hubbard localization and are, as a consequence, very far from the corresponding Kohn-Sham orbitals. This contrasts with the case of the band insulator Si, in which the Kohn-Sham orbitals are found to be very close to the RDMFT natural orbitals. PMID- 26574278 TI - Tuning electron transport through functionalized C20H10 molecular junctions. AB - First-principles methodology based on density functional theory (DFT) is used to investigate charge transport phenomena in molecular junctions, with the central active molecular element based on corannulene, C20H10, assembled between two carbon nanotubes (CNT). A number of key factors associated with the design of the molecular nanojunction are shown to have an impact on electron transport to varying degrees, including (I) the composition of the spacer linking the leads to the active element, (II) the composition of the active molecule element, (III) the sensor capabilities of the active element, and (IV) the response of the junction to an external electric field. This study demonstrates the ability to integrate molecular electronic functionality into electronic nanocircuits and provides novel insight into the design of new types of molecular-based devices by revealing the relationship between charge transport mechanisms and the electronic structure of molecular junction components. PMID- 26574279 TI - Molecular view of ligands specificity for CAG repeats in anti-Huntington therapy. AB - Huntington's disease is a fatal and devastating neurodegenerative genetic disorder for which there is currently no cure. It is characterized by Huntingtin protein's mRNA transcripts with 36 or more CAG repeats. Inhibiting the formation of pathological complexes between these expanded transcripts and target proteins may be a valuable strategy against the disease. Yet, the rational design of molecules specifically targeting the expanded CAG repeats is limited by the lack of structural information. Here, we use well-tempered metadynamics-based free energy calculations to investigate pose and affinity of two ligands targeting CAG repeats for which affinities have been previously measured. The first consists of two 4-guanidinophenyl rings linked by an ester group. It is the most potent ligand identified so far, with Kd = 60(30) nM. The second consists of a 4-phenyl dihydroimidazole and 4-1H-indole dihydroimidazole connected by a C-C bond (Kd = 700(80) nM). Our calculations reproduce the experimental affinities and uncover the recognition pattern between ligands' and their RNA target. They also provide a molecular basis for the markedly different affinity of the two ligands for CAG repeats as observed experimentally. These findings may pave the way for a structure-based hit-to-lead optimization to further improve ligand selectivity toward CAG repeat-containing mRNAs. PMID- 26574280 TI - Molecular models of nanodiscs. AB - Nanodiscs are discoloidal protein-lipid particles that self-assemble from a mixture of lipids and membrane scaffold proteins. They form a highly soluble membrane mimetic that closely resembles a native-like lipid environment, unlike micelles. Nanodiscs are widely used for experimental studies of membrane proteins. In this work, we present a new method for building arbitrary nanodiscs using a combination of the Martini coarse-grained and all-atom force fields. We model the basic membrane scaffold protein MSP1 and its extended versions, such as MSP1E1 and MSP1E2, using a crystal structure of human apolipoprotein Apo-I. We test our method by generating nanodiscs of different sizes and compositions, including nanodiscs with embedded membrane proteins, such as bacteriorhodopsin, outer membrane protein X, and the glucose transporter. We show that properties of our nanodiscs are in general agreement with experimental data and previous computational studies. PMID- 26574281 TI - Computational prediction of molecular hydration entropy with hybrid scaled particle theory and free-energy perturbation method. AB - Despite the importance of the knowledge of molecular hydration entropy (DeltaShyd) in chemical and biological processes, the exact calculation of DeltaShyd is very difficult, because of the complexity in solute-water interactions. Although free-energy perturbation (FEP) methods have been employed quite widely in the literature, the poor convergent behavior of the van der Waals interaction term in the potential function limited the accuracy and robustness. In this study, we propose a new method for estimating DeltaShyd by means of combining the FEP approach and the scaled particle theory (or information theory) to separately calculate the electrostatic solute-water interaction term (DeltaSelec) and the hydrophobic contribution approximated by the cavity formation entropy (DeltaScav), respectively. Decomposition of DeltaShyd into DeltaScav and DeltaSelec terms is found to be very effective with a substantial accuracy enhancement in DeltaShyd estimation, when compared to the conventional full FEP calculations. DeltaScav appears to dominate over DeltaSelec in magnitude, even in the case of polar solutes, implying that the major contribution to the entropic cost for hydration comes from the formation of a solvent-excluded volume. Our hybrid scaled particle theory and FEP method is thus found to enhance the accuracy of DeltaShyd prediction by effectively complementing the conventional full FEP method. PMID- 26574282 TI - Self-assembly of triton X-100 in water solutions: a multiscale simulation study linking mesoscale to atomistic models. AB - A multiscale scheme is proposed and validated for Triton X-100 (TX-100), which is a detergent widely employed in biology. The hybrid particle field formulation of the model allows simulations of large-scale systems. The coarse-grained (CG) model, accurately validated in a wide range of concentrations, shows a critical micelle concentration, shape transition in isotropic micellar phase, and appearance of hexagonal ordered phase in the experimental ranges reported in the literature. The fine resolution of the proposed CG model allows one to obtain, by a suitable reverse mapping procedure, atomistic models of micellar assemblies and of the hexagonal phase. In particular, atomistic models of the micelles give structures in good agreement with experimental pair distance distribution functions and hydrodynamic measurements. The picture emerging by detailed analysis of simulated systems is quite complex. Polydisperse mixtures of spherical-, oblate-, and prolate-shaped aggregates have been found. The shape and the micelle behavior are mainly dictated by the aggregation number (Nagg). Micelles with low Nagg values (~40) are spherical, while those with high Nagg values (~140 or larger) are characterized by prolate ellipsoidal shapes. For intermediate Nagg values (~70), fluxional micelles alternating between oblate and prolate shapes are found. The proposed model opens the way to investigations of several mechanisms involving TX-100 assembly in protein and membrane biophysics. PMID- 26574283 TI - Quantum chemical benchmark study on 46 RNA backbone families using a dinucleotide unit. AB - We have created a benchmark set of quantum chemical structure-energy data denoted as UpU46, which consists of 46 uracil dinucleotides (UpU), representing all known 46 RNA backbone conformational families. Penalty-function-based restrained optimizations with COSMO TPSS-D3/def2-TZVP ensure a balance between keeping the target conformation and geometry relaxation. The backbone geometries are close to the clustering-means of their respective RNA bioinformatics family classification. High-level wave function methods (DLPNO-CCSD(T) as reference) and a wide-range of dispersion-corrected or inclusive DFT methods (DFT-D3, VV10, LC BOP-LRD, M06-2X, M11, and more) are used to evaluate the conformational energies. The results are compared to the Amber RNA bsc0chiOL3 force field. Most dispersion corrected DFT methods surpass the Amber force field significantly in accuracy and yield mean absolute deviations (MADs) for relative conformational energies of ~0.4-0.6 kcal/mol. Double-hybrid density functionals represent the most accurate class of density functionals. Low-cost quantum chemical methods such as PM6-D3H+, HF-3c, DFTB3-D3, as well as small basis set calculations corrected for basis set superposition errors (BSSEs) by the gCP procedure are also tested. Unfortunately, the presently available low-cost methods are struggling to describe the UpU conformational energies with satisfactory accuracy. The UpU46 benchmark is an ideal test for benchmarking and development of fast methods to describe nucleic acids, including force fields. PMID- 26574285 TI - Kinetic distance and kinetic maps from molecular dynamics simulation. AB - Characterizing macromolecular kinetics from molecular dynamics (MD) simulations requires a distance metric that can distinguish slowly interconverting states. Here, we build upon diffusion map theory and define a kinetic distance metric for irreducible Markov processes that quantifies how slowly molecular conformations interconvert. The kinetic distance can be computed given a model that approximates the eigenvalues and eigenvectors (reaction coordinates) of the MD Markov operator. Here, we employ the time-lagged independent component analysis (TICA). The TICA components can be scaled to provide a kinetic map in which the Euclidean distance corresponds to the kinetic distance. As a result, the question of how many TICA dimensions should be kept in a dimensionality reduction approach becomes obsolete, and one parameter less needs to be specified in the kinetic model construction. We demonstrate the approach using TICA and Markov state model (MSM) analyses for illustrative models, protein conformation dynamics in bovine pancreatic trypsin inhibitor and protein-inhibitor association in trypsin and benzamidine. We find that the total kinetic variance (TKV) is an excellent indicator of model quality and can be used to rank different input feature sets. PMID- 26574286 TI - Exploring LacI-DNA dynamics by multiscale simulations using the SIRAH force field. AB - The lac repressor protein (LacI) together with its target regulatory sequence are a common model for studying DNA looping and its implications on transcriptional control in bacteria. Owing to the molecular size of this system, standard all atom (AA) simulations are prohibitive for achieving relevant biological time scales. As an alternative, multiscale models, which combine AA descriptions at particular regions with coarse-grained (CG) representations of the remaining components, were used to address this computational challenge while preserving the relevant details of the system. In this work, we implement a new multiscale approach based on the SIRAH force field to gain deeper insights into the dynamics of the LacI-DNA system. Our methodology allows for a dual resolution treatment of the solute and solvent, explicitly representing the protein, DNA, and solvent environment without compromising the AA region. Starting from the P1 loop configuration in an undertwisted conformation, we were able to observe the transition to the more stable overtwisted state. Additionally, a detailed characterization of the conformational space sampled by the DNA loop was done. In agreement with experimental and theoretical evidence, we observed the transient formation of kinks at the loop, which were stabilized by the presence of counterions at the minor groove. We also show that the loop's intrinsic flexibility can account for reported FRET measurements and bent conformations required to bind the CAP transcription factor. PMID- 26574284 TI - Quantum effects in cation interactions with first and second coordination shell ligands in metalloproteins. AB - Despite decades of investigations, the principal mechanisms responsible for the high affinity and specificity of proteins for key physiological cations K(+), Na(+), and Ca(2+) remain a hotly debated topic. At the core of the debate is an apparent need (or lack thereof) for an accurate description of the electrostatic response of the charge distribution in a protein to the binding of an ion. These effects range from partial electronic polarization of the directly ligating atoms to long-range effects related to partial charge transfer and electronic delocalization effects. While accurate modeling of cation recognition by metalloproteins warrants the use of quantum-mechanics (QM) calculations, the most popular approximations used in major biomolecular simulation packages rely on the implicit modeling of electronic polarization effects. That is, high-level QM computations for ion binding to proteins are desirable, but they are often unfeasible, because of the large size of the reactive-site models and the need to sample conformational space exhaustively at finite temperature. Several solutions to this challenge have been proposed in the field, ranging from the recently developed Drude polarizable force-field for simulations of metalloproteins to approximate tight-binding density functional theory (DFTB). To delineate the usefulness of different approximations, we examined the accuracy of three recent and commonly used theoretical models and numerical algorithms, namely, CHARMM C36, the latest developed Drude polarizable force fields, and DFTB3 with the latest 3OB parameters. We performed MD simulations for 30 cation-selective proteins with high-resolution X-ray structures to create ensembles of structures for analysis with different levels of theory, e.g., additive and polarizable force fields, DFTB3, and DFT. The results from DFT computations were used to benchmark CHARMM C36, Drude, and DFTB3 performance. The explicit modeling of quantum effects unveils the key electrostatic properties of the protein sites and the importance of specific ion-protein interactions. One of the most interesting findings is that secondary coordination shells of proteins are noticeably perturbed in a cation-dependent manner, showing significant delocalization and long-range effects of charge transfer and polarization upon binding Ca(2+). PMID- 26574287 TI - Free energy and hidden barriers of the beta-sheet structure of prion protein. AB - On-the-fly free-energy parametrization is a new collective variable biasing approach akin to metadynamics with one important distinction: rather than acquiring an accelerated distribution via a history-dependent bias potential, sampling on this distribution is achieved from the beginning of the simulation using temperature-accelerated molecular dynamics. In the present work, we compare the performance of both approaches to compute the free-energy profile along a scalar collective variable measuring the H-bond registry of the beta-sheet structure of the mouse Prion protein. Both methods agree on the location of the free-energy minimum, but free-energy profiles from well-tempered metadynamics are subject to a much higher degree of statistical noise due to hidden barriers. The sensitivity of metadynamics to hidden barriers is shown to be a consequence of the history dependence of the bias potential, and we detail the nature of these barriers for the prion beta-sheet. In contrast, on-the-fly parametrization is much less sensitive to these barriers and thus displays improved convergence behavior relative to that of metadynamics. While hidden barriers are a frequent and central issue in free-energy methods, on-the-fly free-energy parametrization appears to be a robust and preferable method to confront this issue. PMID- 26574288 TI - Adaptive resolution simulation of a DNA molecule in salt solution. AB - We present a multiscale simulation of a DNA molecule in 1 M NaCl salt solution environment, employing the adaptive resolution simulation approach that allows the solvent molecules, i.e., water and ions, to change their resolution from atomistic to coarse-grained and vice versa adaptively on-the-fly. The region of high resolution moves together with the DNA center-of-mass so that the DNA itself is always modeled at high resolution. We show that our multiscale simulations yield a stable DNA-solution system, with statistical properties similar to those produced by the conventional all-atom molecular dynamics simulation. Special attention is given to the collective properties, such as the dielectric constant, as they provide a sensitive quality measure of our multiscale approach. PMID- 26574289 TI - Exploiting homology information in nontemplate based prediction of protein structures. AB - In this paper we describe a novel strategy for exploring the conformational space of proteins and show that this leads to better models for proteins the structure of which is not amenable to template based methods. Our strategy is based on the assumption that the energy global minimum of homologous proteins must correspond to similar conformations, while the precise profiles of their energy landscape, and consequently the positions of the local minima, are likely to be different. In line with this hypothesis, we apply a replica exchange Monte Carlo simulation protocol that, rather than using different parameters for each parallel simulation, uses the sequences of homologous proteins. We show that our results are competitive with respect to alternative methods, including those producing the best model for each of the analyzed targets in the CASP10 (10th Critical Assessment of techniques for protein Structure Prediction) experiment free modeling category. PMID- 26574290 TI - Correction to variational, self-consistent implementation of the Perdew-Zunger self-interaction correction with complex optimal orbitals. PMID- 26574291 TI - Correction to construction of the B88 exchange-energy functional in two dimensions. PMID- 26574293 TI - Mental and social health in disasters: the Sphere standards and post-tsunami psychosocial interventions in Asia. AB - The primary objective of this paper is to examine and inform the mental health and psychosocial support standards of the 2011 edition of the Sphere Project's Humanitarian Charter and Minimum Standards in Humanitarian Response. This is done through a qualitative analysis of internal evaluation documents, reflecting four long-term humanitarian psychosocial programmes in different countries in post tsunami Asia. The analysis yielded three overall conclusions. First, the Sphere standards on mental health and psychosocial support generally are highly relevant to long-term psychosocial interventions after disasters such as the Indian Ocean tsunami of 26 December 2004, and their application in such settings may improve the quality of the response. Second, some of the standards in the current Sphere handbook may lack sufficient guidance to ensure the quality of humanitarian response required. Third, the long-term intervention approach poses specific challenges to programming, a problem that could be addressed by including additional guidance in the publication. PMID- 26574292 TI - Ca(2+) leakage out of the sarcoplasmic reticulum is increased in type I skeletal muscle fibres in aged humans. AB - KEY POINTS: The amount of Ca(2+) stored in the sarcoplasmic reticulum (SR) of muscle fibres is decreased in aged individuals, and an important question is whether this results from increased Ca(2+) leakage out through the Ca(2+) release channels (ryanodine receptors; RyRs). The present study examined the effects of blocking the RyRs with Mg(2+), or applying a strong reducing treatment, on net Ca(2+) accumulation by the SR in skinned muscle fibres from Old (~70 years) and Young (~24 years) adults. Raising cytoplasmic [Mg(2+)] and reducing treatment increased net SR Ca(2+) accumulation in type I fibres of Old subjects relative to that in Young. The densities of RyRs and dihydropyridine receptors were not significantly changed in the muscle of Old subjects. These findings indicate that oxidative modification of the RyRs causes increased Ca(2+) leakage from the SR in muscle fibres in Old subjects, which probably deleteriously affects normal muscle function both directly and indirectly. ABSTRACT: The present study examined whether the lower Ca(2+) storage levels in the sarcoplasmic reticulum (SR) in vastus lateralis muscle fibres in Old (70 +/- 4 years) relative to Young (24 +/- 4 years) human subjects is the result of increased leakage of Ca(2+) out of the SR through the Ca(2+) release channels/ryanodine receptors (RyRs) and due to oxidative modification of the RyRs. SR Ca(2+) accumulation in mechanically skinned muscle fibres was examined in the presence of 1, 3 or 10 mm cytoplasmic Mg(2+) because raising [Mg(2+)] strongly inhibits Ca(2+) efflux through the RyRs. In type I fibres of Old subjects, SR Ca(2+) accumulation in the presence of 1 mm Mg(2+) approached saturation at shorter loading times than in Young subjects, consistent with Ca(2+) leakage limiting net uptake, and raising [Mg(2+)] to 10 mm in such fibres increased maximal SR Ca(2+) accumulation. No significant differences were seen in type II fibres. Treatment with dithiothreitol (10 mm for 5 min), a strong reducing agent, also increased maximal SR Ca(2+) accumulation at 1 mm Mg(2+) in type I fibres of Old subjects but not in other fibres. The densities of dihydropyridine receptors and RyRs were not significantly different in muscles of Old relative to Young subjects. These findings indicate that Ca(2+) leakage from the SR is increased in type I fibres in Old subjects by reversible oxidative modification of the RyRs; this increased SR Ca(2+) leak is expected to have both direct and indirect deleterious effects on Ca(2+) movements and muscle function. PMID- 26574295 TI - Solid lipid nanoparticles as a vehicle for brain-targeted drug delivery: two new strategies of functionalization with apolipoprotein E. AB - Nanotechnology can be an important tool to improve the permeability of some drugs for the blood-brain barrier. In this work we created a new system to enter the brain by functionalizing solid lipid nanoparticles with apolipoprotein E, aiming to enhance their binding to low-density lipoprotein receptors on the blood-brain barrier endothelial cells. Solid lipid nanoparticles were successfully functionalized with apolipoprotein E using two distinct strategies that took advantage of the strong interaction between biotin and avidin. Transmission electron microscopy images revealed spherical nanoparticles, and dynamic light scattering gave a Z-average under 200 nm, a polydispersity index below 0.2, and a zeta potential between -10 mV and -15 mV. The functionalization of solid lipid nanoparticles with apolipoprotein E was demonstrated by infrared spectroscopy and fluorimetric assays. In vitro cytotoxic effects were evaluated by MTT and LDH assays in the human cerebral microvascular endothelial cells (hCMEC/D3) cell line, a human blood-brain barrier model, and revealed no toxicity up to 1.5 mg ml(-1) over 4 h of incubation. The brain permeability was evaluated in transwell devices with hCMEC/D3 monolayers, and a 1.5-fold increment in barrier transit was verified for functionalized nanoparticles when compared with non-functionalized ones. The results suggested that these novel apolipoprotein E-functionalized nanoparticles resulted in dynamic stable systems capable of being used for an improved and specialized brain delivery of drugs through the blood-brain barrier. PMID- 26574296 TI - In vivo single human sweat gland activity monitoring using coherent anti-Stokes Raman scattering and two-photon excited autofluorescence microscopy. AB - BACKGROUND: Eccrine sweat secretion is of central importance for control of body temperature. Although the incidence of sweat gland dysfunction might appear of minor importance, it can be a real concern for people with either hypohidrosis or hyperhidrosis. However, sweat gland function remains relatively poorly explored. OBJECTIVES: To investigate the function of single human sweat glands. METHODS: We describe a new approach for noninvasive imaging of single sweat gland activity in human palms in vivo up to a depth of 100 MUm, based on nonlinear two-photon excited autofluorescence (TPEF) and coherent anti-Stokes Raman scattering (CARS). RESULTS: These techniques appear to be useful compared with approaches already described for imaging single sweat gland activity, as they allow better three dimensional spatial resolution of sweat pore inner morphology and real-time monitoring of individual sweat events. By filling the sweat pore with oil and tuning the CARS contrast at 2845 cm(-1) , we imaged the ejection of sweat droplets from a single sweat gland when oil is pushed out by sweat flow. On average, sweat events lasted for about 30 s every 3 min under the conditions studied. On the other hand, about 20% of sweat glands were found inactive. TPEF and CARS were also used to study, at the single pore level, the antiperspirant action of aluminium chlorohydrate (ACH) and to reveal, for the first time in vivo, the formation of a plug at the pore entrance, in agreement with reported ACH antiperspirant mechanisms. CONCLUSIONS: Although data were acquired on human palms, these techniques show great promise for a better understanding of sweat secretion physiology and should be helpful to improve the efficacy of antiperspirant formulations. PMID- 26574297 TI - Image processing based automatic diagnosis of glaucoma using wavelet features of segmented optic disc from fundus image. AB - Glaucoma is a disease of the retina which is one of the most common causes of permanent blindness worldwide. This paper presents an automatic image processing based method for glaucoma diagnosis from the digital fundus image. In this paper wavelet feature extraction has been followed by optimized genetic feature selection combined with several learning algorithms and various parameter settings. Unlike the existing research works where the features are considered from the complete fundus or a sub image of the fundus, this work is based on feature extraction from the segmented and blood vessel removed optic disc to improve the accuracy of identification. The experimental results presented in this paper indicate that the wavelet features of the segmented optic disc image are clinically more significant in comparison to features of the whole or sub fundus image in the detection of glaucoma from fundus image. Accuracy of glaucoma identification achieved in this work is 94.7% and a comparison with existing methods of glaucoma detection from fundus image indicates that the proposed approach has improved accuracy of classification. PMID- 26574298 TI - Bayesian segmentation of human facial tissue using 3D MR-CT information fusion, resolution enhancement and partial volume modelling. AB - BACKGROUND: Accurate segmentation of human head on medical images is an important process in a wide array of applications such as diagnosis, facial surgery planning, prosthesis design, and forensic identification. OBJECTIVES: In this study, a Bayesian method for segmentation of facial tissues is presented. Segmentation classes include muscle, bone, fat, air and skin. METHODS: The method presented incorporates information fusion from multiple modalities, modelling of image resolution (measurement blurring), image noise, two priors helping to reduce noise and partial volume. Image resolution modelling employed facilitates resolution enhancement and superresolution capabilities during image segmentation. Regularization based on isotropic and directional Markov Random Field priors is integrated. The Bayesian model is solved iteratively yielding tissue class labels at every voxel of the image. Sub-methods as variations of the main method are generated by using a combination of the models. RESULTS: Testing of the sub-methods is performed on two patients using single modality three dimensional (3D) image (magnetic resonance, MR or computerized tomography, CT) as well as registered MR-CT images with information fusion. Numerical, visual and statistical analyses of the methods are conducted. High segmentation accuracy values are obtained by the use of image resolution and partial volume models as well as information fusion from MR and CT images. The methods are also compared with our Bayesian segmentation method proposed in a previous study. The performance is found to be similar to our previous Bayesian approach, but the presented methods here eliminates ad hoc parameter tuning needed by the previous approach which is system and data acquisition setting dependent. CONCLUSIONS: The Bayesian approach presented provides resolution enhanced segmentation of very thin structures of the human head. Meanwhile, free parameters of the algorithm can be adjusted for different imaging systems and data acquisition settings in a more systematic way as compared with our previous study. PMID- 26574299 TI - Oxidative stress--a key emerging impact factor in health, ageing, lifestyle and aesthetics. AB - Oxidative stress is the resultant damage that arises due to redox imbalances, more specifically an increase in destructive free radicals and reduction in protection from antioxidants and the antioxidant defence pathways. Oxidation of lipids by reactive oxygen species (ROS) can damage cellular structures and result in premature cell death. At low levels, ROS-induced oxidative stress can be prevented through the action of antioxidants, however, when ROS are present in excess, inflammation and cytotoxicity eventually results leading to cellular oxidative stress damage. Increasing evidence for the role of oxidative stress in various diseases including neurological, dermatological, and cardiovascular diseases is now emerging. Mitochondria are the principal source (90%) of ROS in the cell, with superoxide radicals being generated when molecular oxygen is combined with free electrons. Given the key role of mitochondria in the generation of cellular oxidative stress it is worth considering this organelle and the process in more detail and to provide methods of intervention. PMID- 26574300 TI - The role of oxidative damage in poor scalp health: ramifications to causality and associated hair growth. AB - The oxidative stress element of unhealthy scalp leads to compromised pre-emergent hair formation and poorly formed hair as it grows. Only cosmetic solutions can minimize the impact of unhealthy hair and to achieve healthy looking and feeling hair, the scalp health must be normalized first. The objectives of this research were to both investigate whether oxidative stress was a relevant aetiological element in scalp dandruff and seborrhoeic dermatitis and whether scalp condition affects the quality of hair that grows from it. Further, this research was designed to determine whether an effective anti-dandruff shampoo would repair and protect the scalp and pre-emergent hair from oxidative stress. This study demonstrated that oxidative stress is an aetiological element relevant to the dandruff condition and that a potentiated ZPT shampoo effectively improves scalp condition, including a reduction in oxidative stress. The compromised hair condition associated with dandruff is concomitantly improved when the scalp condition is improved. It appears that there is a direct link between hair quality and scalp health. PMID- 26574301 TI - Preserving fibre health: reducing oxidative stress throughout the life of the hair fibre. AB - Hair health is an important attribute to women globally--specifically attributes such as shine, healthy tips, frizz-free and strength. However, many women will claim to have at least moderate hair damage caused by habits and practices such as washing, combing and brushing, use of heated implements and regular use of chemical treatments. The objective of this work was to investigate two mechanisms of damage--hair colouring and UV exposure--where oxidative processes are involved. The role of copper in these oxidative processes was then investigated: its presence in hair and its consequent impact on hair damage via free radical formation. Finally, the role of chelants N,N'-ethylene diamine disuccinic acid (EDDS) and histidine in preventing free radical formation was investigated and shown to improve hair health. PMID- 26574302 TI - The impact of oxidative stress on hair. AB - Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to detoxify the reactive intermediates or to repair the resulting damage. Reactive oxygen species or free radicals are highly reactive molecules that can directly damage lipids, proteins, and DNA. They are generated by a multitude of endogenous and environmental challenges, while the body possesses endogenous defense mechanisms. With age, production of free radicals increases, while the endogenous defense mechanisms decrease. This imbalance leads to progressive damage of cellular structures, presumably resulting in the aging phenotype. While the role of oxidative stress has been widely discussed in skin aging, little focus has been placed on its impact on hair condition. Moreover, most literature on age-related hair changes focuses on alopecia, but it is equally important that the hair fibers that emerge from the scalp exhibit significant age-related changes that have equal impact on the overall cosmetic properties of hair. Sources of oxidative stress with impact on the pre-emerging fiber include: oxidative metabolism, smoking, UVR, and inflammation from microbial, pollutant, or irritant origins. Sources of oxidative stress with impact on the post-emerging fiber include: UVR (enhanced by copper), chemical insults, and oxidized scalp lipids. The role of the dermatologist is recognition and treatment of pre- and post emerging factors for lifetime scalp and hair health. PMID- 26574303 TI - Energy-Efficient Computational Chemistry: Comparison of x86 and ARM Systems. AB - The computational efficiency and energy-to-solution of several applications using the GAMESS quantum chemistry suite of codes is evaluated for 32-bit and 64-bit ARM-based computers, and compared to an x86 machine. The x86 system completes all benchmark computations more quickly than either ARM system and is the best choice to minimize time to solution. The ARM64 and ARM32 computational performances are similar to each other for Hartree-Fock and density functional theory energy calculations. However, for memory-intensive second-order perturbation theory energy and gradient computations the lower ARM32 read/write memory bandwidth results in computation times as much as 86% longer than on the ARM64 system. The ARM32 system is more energy efficient than the x86 and ARM64 CPUs for all benchmarked methods, while the ARM64 CPU is more energy efficient than the x86 CPU for some core counts and molecular sizes. PMID- 26574304 TI - Efficient Sampling of High-Dimensional Free-Energy Landscapes with Parallel Bias Metadynamics. AB - Metadynamics accelerates sampling of molecular dynamics while reconstructing thermodynamic properties of selected descriptors of the system. Its main practical difficulty originates from the compromise between keeping the number of descriptors small for efficiently exploring their multidimensional free-energy landscape and biasing all of the slow motions of a process. Here we illustrate on a model system and on the tryptophan-cage miniprotein parallel bias metadynamics, a method that overcomes this issue by simultaneously applying multiple low dimensional bias potentials. PMID- 26574305 TI - Multi-Scale Approach to Non-Adiabatic Charge Transport in High-Mobility Organic Semiconductors. AB - A linear scaling QM/MM model for studying charge transport in high-mobility molecular semiconductors is presented and applied to an anthracene single crystal and a hexabenzocoronene derivative in its liquid crystalline phase. The model includes both intra- and intermolecular electron-phonon couplings, long-range interactions with the environment, and corrections to the self-interaction error of density functional theory. By performing Ehrenfest simulations of the cationic system, hole mobilities are derived and compared to the experiment. A detailed picture of the charge carrier dynamics is given, and the performance of our method is discussed. PMID- 26574306 TI - Enhancing NMR Prediction for Organic Compounds Using Molecular Dynamics. AB - NMR spectroscopy is a crucial tool in organic chemistry for the routine characterization of small molecules, structural elucidation of natural products, and study of reaction mechanisms. Although there is evidence that thermal motions strongly affect observed resonances, conventional predictions are performed only on stationary structures. Here we show that quasiclassical molecular dynamics provides a highly accurate and broadly applicable method for improving shielding predictions. Gas-phase values of the absolute shieldings of protons and carbons are predicted to nearly within experimental uncertainty, while the chemical shifts of large systems such as natural products are closely reproduced. Importantly, these results are obtained without the use of any empirical corrections. Our analysis suggests that the linear scaling factors currently employed are primarily a correction for vibrational effects. As a result, our method extends the reach of prediction methods to the study of molecules with unusual dynamics such as the iconic and controversial [18]annulene. Our predictions agree closely with experiment at both low and high temperatures and provide strong evidence that the equilibrium structure of [18]annulene is planar and aromatic. PMID- 26574307 TI - Estimation of Solvation Entropy and Enthalpy via Analysis of Water Oxygen Hydrogen Correlations. AB - A statistical-mechanical framework for estimation of solvation entropies and enthalpies is proposed, which is based on the analysis of water as a mixture of correlated water oxygens and water hydrogens. Entropic contributions of increasing order are cast in terms of a Mutual Information Expansion that is evaluated to pairwise interactions. In turn, the enthalpy is computed directly from a distance-based hydrogen bonding energy algorithm. The resulting expressions are employed for grid-based analyses of Molecular Dynamics simulations. In this first assessment of the methodology, we obtained global estimates of the excess entropy and enthalpy of water that are in good agreement with experiment and examined the method's ability to enable detailed elucidation of solvation thermodynamic structures, which can provide valuable knowledge toward molecular design. PMID- 26574308 TI - Generalized Born and Explicit Solvent Models for Free Energy Calculations in Organic Solvents: Cyclodextrin Dimerization. AB - Evaluation of solvation (binding) free energies with implicit solvent models in different dielectric environments for biological simulations as well as high throughput ligand screening remain challenging endeavors. In order to address how well implicit solvent models approximate explicit ones we examined four generalized Born models (GB(Still), GB(HCT), GB(OBC)I, and GB(OBC)II) for determining the dimerization free energy (DeltaG(0)) of beta-cyclodextrin monomers in 17 implicit solvents with dielectric constants (D) ranging from 5 to 80 and compared the results to previous free energy calculations with explicit solvents ( Zhang et al. J. Phys. Chem. B 2012 , 116 , 12684 - 12693 ). The comparison indicates that neglecting the environmental dependence of Born radii appears acceptable for such calculations involving cyclodextrin and that the GB(Still) and GB(OBC)I models yield a reasonable estimation of DeltaG(0), although the details of binding are quite different from explicit solvents. Large discrepancies between implicit and explicit solvent models occur in high dielectric media with strong hydrogen bond (HB) interruption properties. DeltaG(0) with the GB models is shown to correlate strongly to 2(D-1)/(2D+1) (R(2) ~ 0.90) in line with the Onsager reaction field ( Onsager J. Am. Chem. Soc. 1936 , 58 , 1486 - 1493 ) but to be very sensitive to D (D < 10) as well. Both high-dielectric environments where hydrogen bonds are of interest and low dielectric media such as protein binding pockets and membrane interiors therefore need to be considered with caution in GB-based calculations. Finally, a literature analysis of Gibbs energy of solvation of small molecules in organic liquids shows that the Onsager relation does not hold for real molecules since the correlation between DeltaG(0) and 2(D-1)/(2D+1) is low for most solutes. Interestingly, explicit solvent calculations of the solvation free energy ( Zhang et al. J. Chem. Inf. Model . 2015 , 55 , 1192 - 1201 ) reproduce the weak experimental correlations with 2(D-1)/(2D+1) very well. PMID- 26574309 TI - de Broglie Swapping Metadynamics for Quantum and Classical Sampling. AB - This paper builds on our previous work on Path Integral Metadynamics [ Ruge et al. J. Chem. Theory Comput. 2015 , 11 , 1383 ] in which we have accelerated sampling in quantum systems described by Feynman's Path Integrals using Metadynamics. We extend the scope of Path Integral Metadynamics by combining it with a replica exchange scheme in which artificially enhanced quantum effects play the same role as temperature does in parallel tempering. Our scheme can be adapted so as to be used in an ancillary way to sample systems described by classical statistical mechanics. Contrary to Metadynamics and many other sampling methods no collective variables need to be defined. The method in its two variants, quantum and classical, is tested in a number of examples. PMID- 26574310 TI - Fully Internally Contracted Multireference Configuration Interaction Theory Using Density Matrix Renormalization Group: A Reduced-Scaling Implementation Derived by Computer-Aided Tensor Factorization. AB - We present an extended implementation of the multireference configuration interaction (MRCI) method combined with the quantum-chemical density matrix renormalization group (DMRG). In the previous study, we introduced the combined theory, referred to as DMRGMRCI, as a method to calculate high-level dynamic electron correlation on top of the DMRG wave function that accounts for active space (or strong) correlation using a large number of active orbitals. The DMRG MRCI method is built on the full internal-contraction scheme for the compact reference treatment and on the cumulant approximation for the treatment of the four-particle rank reduced density matrix (4-RDM). The previous implementation achieved the MRCI calculations with the active space (24e,24o), which are deemed the record largest, whereas the inherent Nact 8 * N complexity of computation was found a hindrance to using further large active space. In this study, an extended optimization of the tensor contractions is developed by explicitly incorporating the rank reduction of the decomposed form of the cumulant-approximated 4-RDM into the factorization. It reduces the computational scaling (to Nact7 * N) as well as the cache-miss penalty associated with direct evaluation of complex cumulant reconstruction. The present scheme, however, faces the increased complexity of factorization patterns for optimally implementing the tensor contraction terms involving the decomposed 4-RDM objects. We address this complexity using the enhanced symbolic manipulation computer program for deriving and coding programmable equations. The new DMRG-MRCI implementation is applied to the determination of the stability of the iron(IV)-oxo porphyrin relative to the iron(V) electronic isomer (electromer) using the active space (29e,29o) (including four second d-shell orbitals of iron) with triple-zeta-quality atomic orbital basis sets. The DMRG-cu(4)-MRCI+Q model is shown to favor the triradicaloid iron(IV)-oxo state as the lowest energy state and characterize the iron(V) electromer as thermally inaccessible, supporting the earlier experimental and density functional studies. This conflicts with the previous MR calculations using the restricted activespace second-order perturbation theory (RASPT2) with the similar-size active space (29e,28o) reported by Pierloot et al. (Radon, M.; Broclawik, E.; Pierloot, K. J. Chem. Theory Comput. 2011, 7, 898), showing that the hypothetical iron(V) state indicated by recent laser flash photolysis (LFP) studies is likely thermally accessible because of its underestimated relative energy. PMID- 26574311 TI - Many-Body Basis Set Superposition Effect. AB - The basis set superposition effect (BSSE) arises in electronic structure calculations of molecular clusters when questions relating to interactions between monomers within the larger cluster are asked. The binding energy, or total energy, of the cluster may be broken down into many smaller subcluster calculations and the energies of these subsystems linearly combined to, hopefully, produce the desired quantity of interest. Unfortunately, BSSE can plague these smaller fragment calculations. In this work, we carefully examine the major sources of error associated with reproducing the binding energy and total energy of a molecular cluster. In order to do so, we decompose these energies in terms of a many-body expansion (MBE), where a "body" here refers to the monomers that make up the cluster. In our analysis, we found it necessary to introduce something we designate here as a many-ghost many-body expansion (MGMBE). The work presented here produces some surprising results, but perhaps the most significant of all is that BSSE effects up to the order of truncation in a MBE of the total energy cancel exactly. In the case of the binding energy, the only BSSE correction terms remaining arise from the removal of the one-body monomer total energies. Nevertheless, our earlier work indicated that BSSE effects continued to remain in the total energy of the cluster up to very high truncation order in the MBE. We show in this work that the vast majority of these high-order many-body effects arise from BSSE associated with the one-body monomer total energies. Also, we found that, remarkably, the complete basis set limit values for the three-body and four-body interactions differed very little from that at the MP2/aug-cc-pVDZ level for the respective subclusters embedded within a larger cluster. PMID- 26574312 TI - Off-Diagonal Self-Energy Terms and Partially Self-Consistency in GW Calculations for Single Molecules: Efficient Implementation and Quantitative Effects on Ionization Potentials. AB - The GW method in its most widespread variant takes, as an input, Kohn-Sham (KS) single particle energies and single particle states and yields results for the single-particle excitation energies that are significantly improved over the bare KS estimates. Fundamental shortcomings of density functional theory (DFT) when applied to excitation energies as well as artifacts introduced by approximate exchange-correlation (XC) functionals are thus reduced. At its heart lies the quasi-particle (qp) equation, whose solution yields the corrected excitation energies and qp-wave functions. We propose an efficient approximation scheme to treat this equation based on second-order perturbation theory and self-consistent iteration schemes. We thus avoid solving (large) eigenvalue problems at the expense of a residual error that is comparable to the intrinsic uncertainty of the GW truncation scheme and is, in this sense, insignificant. PMID- 26574313 TI - Local Current Density Calculations for Molecular Films from Ab Initio. AB - We present a formalism relying on density functional theory for the calculation of the spatially continuous electron current density j(r) and induced magnetic fields B(r) in molecular films in dc transport. The proposed method treats electron transport in graphene ribbons containing on the of order 10(3) atoms. The employed computational techniques scale efficiently when using several thousand CPUs. An application to transport through hydrogenated graphene will be presented. As we will show, the adatoms have an impact on the transmission function not only because they introduce additional states but also because their presence modifies the geometry of the carbon host lattice (lattice relaxation). PMID- 26574314 TI - Approximating CCSD(T) Nuclear Magnetic Shielding Calculations Using Composite Methods. AB - A series of composite method approximations for the computationally efficient calculation of NMR shieldings has been developed. These approximations utilize basis sets from the pcS-n series, which is shown to converge rapidly toward experimental gas-phase shieldings at CCSD(T). The possibility of using HF, B3LYP, KT3, or MP2 shieldings to approximate results at CCSD(T) was then examined. It was determined that using HF in conjunction with MP2 significantly reduces the CPU time of calculations while having a minimal impact on the accuracy of the predicted shieldings. PMID- 26574315 TI - Accuracy of Quantum Mechanically Derived Force-Fields Parameterized from Dispersion-Corrected DFT Data: The Benzene Dimer as a Prototype for Aromatic Interactions. AB - A multilevel approach is presented to assess the ability of several popular dispersion corrected density functionals (M06-2X, CAM-B3LYP-D3, BLYP-D3, and B3LYP-D3) to reliably describe two-body interaction potential energy surfaces (IPESs). To this end, the automated Picky procedure ( Cacelli et al. J. Comput. Chem. 2012 , 33 , 1055 ) was exploited, which consists in parametrizing specific intermolecular force fields through an iterative approach, based on the comparison with quantum mechanical data. For each of the tested functionals, the resulting force field was employed in classical Monte Carlo and Molecular Dynamics simulations, performed on systems of up to 1000 molecules in ambient conditions, to calculate a number of condensed phase properties. The comparison of the resulting structural and dynamic properties with experimental data allows us to assess the quality of each IPES and, consequently, even the quality of the DFT functionals. The methodology is tested on the benzene dimer, commonly used as a benchmark molecule, a prototype of aromatic interactions. The best results were obtained with the CAM-B3LYP-D3 functional. Besides assessing the reliability of DFT functionals in describing aromatic IPESs, this work provides a further step toward a robust protocol for the derivation of sound force field parameters from quantum mechanical data. This method can be relevant in all those cases where standard force fields fail in giving accurate predictions. PMID- 26574316 TI - DFTB Parameters for the Periodic Table, Part 2: Energies and Energy Gradients from Hydrogen to Calcium. AB - In the first part of this series, we presented a parametrization strategy to obtain high-quality electronic band structures on the basis of density-functional based tight-binding (DFTB) calculations and published a parameter set called QUASINANO2013.1. Here, we extend our parametrization effort to include the remaining terms that are needed to compute the total energy and its gradient, commonly referred to as repulsive potential. Instead of parametrizing these terms as a two-body potential, we calculate them explicitly from the DFTB analogues of the Kohn-Sham total energy expression. This strategy requires only two further numerical parameters per element. Thus, the atomic configuration and four real numbers per element are sufficient to define the DFTB model at this level of parametrization. The QUASINANO2015 parameter set allows the calculation of energy, structure, and electronic structure of all systems composed of elements ranging from H to Ca. Extensive benchmarks show that the overall accuracy of QUASINANO2015 is comparable to that of well-established methods, including PM7 and hand-tuned DFTB parameter sets, while coverage of a much larger range of chemical systems is available. PMID- 26574317 TI - Electronic Couplings for Resonance Energy Transfer from CCSD Calculations: From Isolated to Solvated Systems. AB - Quantum mechanical (QM) calculations of electronic couplings provide great insights for the study of resonance energy transfer (RET). However, most of these calculations rely on approximate QM methods due to the computational limitations imposed by the size of typical donor-acceptor systems. In this work, we present a novel implementation that allows computing electronic couplings at the coupled cluster singles and doubles (CCSD) level of theory. Solvent effects are also taken into account through the polarizable continuum model (PCM). As a test case, we use a dimer of indole, a common model system for tryptophan, which is routinely used as an intrinsic fluorophore in Forster resonance energy transfer studies. We consider two bright pi -> pi* states, one of which has charge transfer character. Lastly, the results are compared with those obtained by applying TD-DFT in combination with one of the most popular density functionals, B3LYP. PMID- 26574318 TI - Density Fitting and Cholesky Decomposition of the Two-Electron Integrals in Local Multireference Configuration Interaction Theory. AB - To treat large molecules with accurate ab initio quantum chemistry, reduced scaling correlated wave function methods are now commonly employed. Optimization of these wave functions in practice requires some approximation of the two electron integrals. Both Cholesky decomposition (CD) and density fitting (DF) are widely used approaches to approximate these integrals. Here, we compare CD and DF for use in local multireference singles and doubles configuration interaction (LMRSDCI). DF-LMRSDCI provides less accurate total energies than CD-LMRSDCI, but both methods are accurate for energy differences. However, DF-LMRSDCI is significantly less computationally expensive than CD-LMRSDCI on the molecules tested, suggesting that DF-LMRSDCI is an efficient, often sufficiently accurate alternative to our previously reported CD-LMRSDCI method. PMID- 26574319 TI - Linearized Coupled Cluster Correction on the Antisymmetric Product of 1-Reference Orbital Geminals. AB - We present a linearized coupled cluster (LCC) correction based on a reference state of the antisymmetric product of 1-reference orbital geminals (AP1roG). In our LCC ansatz, the cluster operator is restricted to double or to single and double excitations, as in standard single-reference CC theory. The performance of the AP1roG-LCC models is tested for the dissociation of diatomic molecules in their lowest-lying singlet state (C2, F2, and BN), the symmetric dissociation of the H50 hydrogen chain, and spectroscopic constants of the uranyl cation (UO2 2+). Our study indicates that an LCC correction based on an AP1roG reference function is more robust and reliable than corrections based on perturbation theory, yielding spectroscopic constants that are in very good agreement with theoretical reference data. PMID- 26574320 TI - Fractional Electron Loss in Approximate DFT and Hartree-Fock Theory. AB - Plots of electronic energy vs electron number, determined using approximate density functional theory (DFT) and Hartree-Fock theory, are typically piecewise convex and piecewise concave, respectively. The curves also commonly exhibit a minimum and maximum, respectively, in the neutral -> anion segment, which lead to positive DFT anion HOMO energies and positive Hartree-Fock neutral LUMO energies. These minima/maxima are a consequence of using basis sets that are local to the system, preventing fractional electron loss. Ground-state curves are presented that illustrate the idealized behavior that would occur if the basis set were to be modified to enable fractional electron loss without changing the description in the vicinity of the system. The key feature is that the energy cannot increase when the electron number increases, so the slope cannot be anywhere positive, meaning frontier orbital energies cannot be positive. For the convex (DFT) case, the idealized curve is flat beyond a critical electron number such that any additional fraction of an electron added to the system is unbound. The anion HOMO energy is zero. For the concave (Hartree-Fock) case, the idealized curve is flat up to some critical electron number, beyond which it curves down to the anion energy. A minimum fraction of an electron is required before any binding occurs, but beyond that, the full fraction abruptly binds. The neutral LUMO energy is zero. Approximate DFT and Hartree-Fock results are presented for the F -> F(-) segment, and results approaching the idealized behavior are recovered for highly diffuse basis sets. It is noted that if a DFT calculation using a highly diffuse basis set yields a negative LUMO energy then a fraction of an electron must bind and the electron affinity must be positive, irrespective of whether an electron binds experimentally. This is illustrated by calculations on Ne -> Ne(-). PMID- 26574321 TI - Auxiliary Basis Sets for Density Fitting in Explicitly Correlated Calculations: The Atoms H-Ar. AB - Auxiliary basis sets specifically matched to the correlation consistent cc-pVnZ F12 and cc-pCVnZ-F12 orbital basis sets for the elements H-Ar have been optimized at the density-fitted second-order Moller-Plesset perturbation theory level of theory for use in explicitly correlated (F12) methods, which utilize density fitting for the evaluation of two-electron integrals. Calculations of the correlation energy for a test set of small to medium sized molecules indicate that the density fitting error when using these auxiliary sets is 2 to 3 orders of magnitude smaller than the F12 orbital basis set incompleteness error. The error introduced by the use of these fitting sets within the resolution-of-the identity approximation of the many-electron integrals arising in F12 theory has also been assessed and is demonstrated to be negligible and well-controlled. General guidelines are proposed for the optimization of density fitting auxiliary basis sets for use with F12 methods for other elements. PMID- 26574322 TI - A Local Variant of the Conductor-Like Screening Model for Fragment-Based Electronic-Structure Methods. AB - Due to steadily rising computational power and sophisticated modeling approaches, increasingly larger molecular systems can be modeled with ab initio methods. An especially promising approach is subsystem methods, where the total system is broken down into smaller subunits that can be treated individually. If an implicit solvent environment such as the conductor-like screening model (COSMO) is included in the description, then additional environmental effects can be incorporated at relatively low cost. For very large systems described with subsystem methods, however, the solution of the COSMO equations can actually become the bottleneck of the calculation. A prominent example in this area is biomolecular systems such as proteins, which can, for instance, be described with frozen density embedding (FDE), especially the related 3-FDE approach. In this article, we present an alternative COSMO variant, which exploits the subsystem nature of the underlying electronic description and has been implemented in a development version of the Amsterdam Density Functional program suite (Adf). We show that the computational cost for the solvent model can be reduced dramatically while retaining the accuracy of the regular description. We compare several schemes for density and surface charge updates and assess the effect of the single tuning parameter. PMID- 26574323 TI - Scalable Electron Correlation Methods. 2. Parallel PNO-LMP2-F12 with Near Linear Scaling in the Molecular Size. AB - We present an efficient explicitly correlated pair natural orbital local second order Moller-Plesset perturbation theory (PNO-LMP2-F12) method. The method is an extension of our previously reported PNO-LMP2 approach [ Werner et al. J. Chem. Theory Comput. 2015 , 11 , 484 ]. Near linear scaling with the size of molecule is achieved by using domain approximations on both virtual and occupied orbitals, local density fitting (DF), and local resolution of the identity (RI), and by exploiting the sparsity of the local molecular orbitals (LMOs) as well as of projected atomic orbitals (PAOs). All large data structures used in the method are stored in distributed memory using Global Arrays (GAs) to achieve near inverse-linear scaling with the number of processing cores, provided that the GAs can be efficiently and independently accessed from all cores. The effect of the various domain approximations is tested for a wide range of chemical reactions. The PNO-LMP2-F12 reaction energies deviate from the canonical DF-MP2-F12 results by <=1 kJ mol(-1) using triple-zeta (VTZ-F12) basis sets and are close to the complete basis set limits. PNO-LMP2-F12 calculations on molecules of chemical interest involving a few thousand basis functions can be performed within an hour or less using a few nodes on a small computer cluster. PMID- 26574324 TI - Frozen-Density Embedding Potentials and Chiroptical Properties. AB - The efficacy of the frozen density embedding (FDE) approach to the simulation of solvent effects is examined for two key chiroptical properties-specific rotation and circular dichroism spectra. In particular, we have investigated the performance of a wave function-theory-in-density-functional-theory (WFT-in-DFT) FDE approach for computing such properties for the small, rigid chiral compound (P)-dimethylallene interacting with up to three water molecules. Although the solvent potential is obtained through DFT, the optical response is computed using coupled cluster linear response theory for mixed electric and magnetic field perturbations. We find that the FDE potential generally yields too small a shift from the isolated molecule as compared to that introduced by the explicit solvent. In one case, the FDE potential fails to reproduce a change in sign of the ORD in which the solute interacts with two solvent molecules. The source of these errors is due primarily to the lack of solvent response to the external field and is analyzed in terms of solvent-solute charge transfer excitations. PMID- 26574325 TI - Polarizable Multipole-Based Force Field for Dimethyl and Trimethyl Phosphate. AB - Phosphate groups are commonly observed in biomolecules such as nucleic acids and lipids. Due to their highly charged and polarizable nature, modeling these compounds with classical force fields is challenging. Using quantum mechanical studies and liquid-phase simulations, the AMOEBA force field for dimethyl phosphate (DMP) ion and trimethyl phosphate (TMP) has been developed. On the basis of ab initio calculations, it was found that ion binding and the solution environment significantly impact both the molecular geometry and the energy differences between conformations. Atomic multipole moments are derived from MP2/cc-pVQZ calculations of methyl phosphates at several conformations with their chemical environments taken into account. Many-body polarization is handled via a Thole-style induction model using distributed atomic polarizabilities. van der Waals parameters of phosphate and oxygen atoms are determined by fitting to the quantum mechanical interaction energy curves for water with DMP or TMP. Additional stretch-torsion and angle-torsion coupling terms were introduced in order to capture asymmetry in P-O bond lengths and angles due to the generalized anomeric effect. The resulting force field for DMP and TMP is able to accurately describe both the molecular structure and conformational energy surface, including bond and angle variations with conformation, as well as interaction of both species with water and metal ions. The force field was further validated for TMP in the condensed phase by computing hydration free energy, liquid density, and heat of vaporization. The polarization behavior between liquid TMP and TMP in water is drastically different. PMID- 26574327 TI - Benchmarking TD-DFT against Vibrationally Resolved Absorption Spectra at Room Temperature: 7-Aminocoumarins as Test Cases. AB - Time-dependent density functional theory (TD-DFT) is usually benchmarked by evaluating how the vertical excitation energies computed by using different exchange-correlation (XC) functionals compare with the maximum of the absorption spectra. However, the latter does not necessarily coincide with the vertical energies because it is affected by the vibronic band structure that has to be properly taken into account. In this work, we have evaluated the performance of several functionals belonging to different families in reproducing the vibronic structure (band shape) of four 7-aminocoumarin molecules of technological interest, whose spectra have been recorded in methylcyclohexane and acetonitrile solvents. In order to compare the computed vibronic spectra with the experimental ones in the most consistent way, the effect of temperature, often neglected, was also taken into account. We have found that no single functional provides simultaneously accurate band positions and shapes, but the combination of omegaB97X vibronic couplings with PBE0 vertical energies can lead to very satisfactory results. In addition to the assessment of XC functionals, several adiabatic and vertical models proposed in the literature to compute vibrationally resolved electronic spectra have been tested and validated with respect to experiments. On these grounds, the adiabatic Hessian model has been used to perform a complete analysis of the omegaB97X/PBE0 vibronic transitions contributing to the final band shapes of the investigated aminocoumarin molecules. PMID- 26574328 TI - Significant Contributions of the Albrecht's A Term to Nonresonant Raman Scattering Processes. AB - The Raman intensity can be well described by the famous Albrecht's Raman theory that consists of A and B terms. It is well-known that the contribution from Albrecht's A term can be neglected without any loss of accuracy for far-off resonant Raman scattering processes. However, as demonstrated in this study, we have found that this widely accepted long-standing assumption fails drastically for totally symmetric vibration modes of molecules in general off-resonant Raman scattering. Perturbed first-principles calculations for water molecule show that strong constructive interference between the A and B terms occurs for the Raman intensity of the symmetric O-H stretching mode, which can account for ~40% of the total intensity. Meanwhile, a minor destructive interference is found for the angle bending mode. The state-to-state mapping between Albrecht's theory and perturbation theory allows us to verify the accuracy of the widely employed perturbation method for the dynamic/resonant Raman intensities. The model calculations rationalized from water molecule with the bending mode show that the perturbation method is a good approximation only when the absolute energy difference between the first excited state and the incident light is more than five times greater than the vibrational energy in the ground state. PMID- 26574326 TI - 0-0 Energies Using Hybrid Schemes: Benchmarks of TD-DFT, CIS(D), ADC(2), CC2, and BSE/GW formalisms for 80 Real-Life Compounds. AB - The 0-0 energies of 80 medium and large molecules have been computed with a large panel of theoretical formalisms. We have used an approach computationally tractable for large molecules, that is, the structural and vibrational parameters are obtained with TD-DFT, the solvent effects are accounted for with the PCM model, whereas the total and transition energies have been determined with TD-DFT and with five wave function approaches accounting for contributions from double excitations, namely, CIS(D), ADC(2), CC2, SCS-CC2, and SOS-CC2, as well as Green's function based BSE/GW approach. Atomic basis sets including diffuse functions have been systematically applied, and several variations of the PCM have been evaluated. Using solvent corrections obtained with corrected linear response approach, we found that three schemes, namely, ADC(2), CC2, and BSE/GW allow one to reach a mean absolute deviation smaller than 0.15 eV compared to the measurements, the two former yielding slightly better correlation with experiments than the latter. CIS(D), SCS-CC2, and SOS-CC2 provide significantly larger deviations, though the latter approach delivers highly consistent transition energies. In addition, we show that (i) ADC(2) and CC2 values are extremely close to each other but for systems absorbing at low energies; (ii) the linear-response PCM scheme tends to overestimate solvation effects; and that (iii) the average impact of nonequilibrium correction on 0-0 energies is negligible. PMID- 26574329 TI - Many-Body Effects on the Thermodynamics of Fluids, Mixtures, and Nanoconfined Fluids. AB - Using expanded Wang-Landau simulations, we show that taking into account the many body interactions results in sharp changes in the grand-canonical partition functions of single-component systems, binary mixtures, and nanoconfined fluids. The many-body contribution, modeled with a 3-body Axilrod-Teller-Muto term, results in shifts toward higher chemical potentials of the phase transitions from low-density phases to high-density phases and accounts for deviations of more than, e.g., 20% of the value of the partition function for a single-component liquid. Using the statistical mechanics formalism, we analyze how this contribution has a strong impact on some properties (e.g., pressure, coexisting densities, and enthalpy) and a moderate impact on others (e.g., Gibbs or Helmholtz free energies). We also characterize the effect of the 3-body terms on adsorption isotherms and adsorption thermodynamic properties, thereby providing a full picture of the effect of the 3-body contribution on the thermodynamics of nanoconfined fluids. PMID- 26574330 TI - Molecular Modeling of Cetylpyridinium Bromide, a Cationic Surfactant, in Solutions and Micelle. AB - Cationic surfactants are widely used in biological and industrial processes. Notably, surfactants with pyridinium salts, such as cetylpyridinium bromide (CPB), have diverse applications. The cetylpyridium cation has a quaternary nitrogen in the aromatic heterocyclic ring of the headgroup and 16 carbons in the hydrocarbon tail. At present and in the past, it has been widely used in germicides. Recently, several interesting applications of CPB have been explored, including its use in protein folding, polymerization, enzyme studies, and gene delivery as well as in pharmaceuticals as a drug delivery tool. A molecular-level understanding of CPB and its micelle in solution can enhance its development in such applications. Herein, we have proposed the first united-atom force field for CPB that yields stable micellar aggregates in molecular dynamics (MD) simulations. The force field is validated through classical MD simulations of the CPB monomer in pure water and 1-octanol as well as in an aqueous CPB micelle. We have performed principal component analysis (PCA) and calculated the translational and rotational diffusion coefficients, spatial distribution of solvent, counterion distribution, and rotational correlation time of CPB molecule in solutions and in micelle, comparing these data to previous experimental and theoretical results for a strong validation of the force field. PCA confirms that the pyridinium ring remains planar, whereas the movement of the hydrophobic tail region leads to conformational changes during the simulations. The collective modes of the pyridinum ring were identical for CPB molecule in solution and micelle, but conformational dynamics of the CPB tail were restricted in the micelle relative to motions in water and 1-octanol. Using this force field, a spherical CPB micelle was shown to be stable throughout the course of simulation, and its solvation and structural properties are characterized. PMID- 26574331 TI - Breaking Badly: DFT-D2 Gives Sizeable Errors for Tensile Strengths in Palladium Hydride Solids. AB - Dispersion interactions play a crucial role in noncovalently bound molecular systems, and recent studies have shown that dispersion effects are also critical for accurately describing covalently bound solids. While most studies on bulk solids have solely focused on equilibrium properties (lattice constants, bulk moduli, and cohesive energies), there has been little work on assessing the importance of dispersion effects for solid-state properties far from equilibrium. In this work, we present a detailed analysis of both equilibrium and highly nonequilibrium properties (tensile strengths leading to fracture) of various palladium-hydride systems using representative DFT methods within the LDA, GGA, DFT-D2, DFT-D3, and nonlocal vdw-DFT families. Among the various DFT methods, we surprisingly find that the empirically constructed DFT-D2 functional gives extremely anomalous and qualitatively incorrect results for tensile strengths in palladium-hydride bulk solids. We present a detailed analysis of these effects and discuss the ramifications of using these methods for predicting solid-state properties far from equilibrium. Most importantly, we suggest caution in using DFT-D2 (or other coarse-grained parametrizations obtained from DFT-D2) for computing material properties under large stress/strain loads or for evaluating solid-state properties under extreme structural conditions. PMID- 26574332 TI - Coarse-Grained Ions for Nucleic Acid Modeling. AB - We present a general coarse-grained model of sodium, magnesium, spermidine, and chlorine in implicit solvent. The effective potentials between ions are systematically parametrized using a relative entropy coarse-graining approach [Carmichael, S. P. and M. S. Shell, J. Phys. Chem. B, 116, 8383-93 (2012)] that maximizes the information retained in a coarse-grained model. We describe the local distribution of ions in the vicinity of a recently published coarse-grained DNA model and demonstrate a dependence of persistence length on ionic strength that differs from that predicted by Odijk-Skolnick-Fixman theory. Consistent with experimental observations, we show that spermidine induces DNA condensation whereas magnesium and sodium do not. This model can be used alongside any coarse grained DNA model that has explicit charges and an accurate reproduction of the excluded volume of dsDNA. PMID- 26574333 TI - Flexible Boundaries for Multiresolution Solvation: An Algorithm for Spatial Multiscaling in Molecular Dynamics Simulations. AB - An algorithm is proposed for performing molecular dynamics (MD) simulations of a biomolecular solute represented at atomistic resolution surrounded by a surface layer of atomistic fine-grained (FG) solvent molecules within a bulk represented by coarse-grained (CG) solvent beads. The method, called flexible boundaries for multiresolution solvation (FBMS), is based on: (i) a three-region layering of the solvent around the solute, involving an FG layer surrounded by a mixed FG-CG buffer layer, itself surrounded by a bulk CG region; (ii) a definition of the layer boundary that relies on an effective distance to the solute surface and is thus adapted to the shape of the solute as well as adjusts to its conformational changes. The effective surface distance is defined by inverse-nth power averaging over the distances to all non-hydrogen solute atoms, and the layering is enforced by means of half-harmonic distance restraints, attractive for the FG molecules and repulsive for the CG beads. A restraint-free region at intermediate distances enables the formation of the buffer layer, where the FG and CG solvents can mix freely. The algorithm is tested and validated using the GROMOS force field and the associated FG (SPC) and CG (polarizable CGW) water models. The test systems include pure-water systems, where one FG molecule plays the role of a solute, and a deca-alanine peptide with two widely different solute shapes considered, alpha helical and fully extended. In particular, as the peptide unfolds, the number of FG molecules required to fill its close-range solvation layer increases, with the additional molecules being provided by the buffer layer. Further validation involves simulations of four proteins in multiresolution FG/CG mixtures. The resulting structural, energetic, and solvation properties are found to be similar to those observed in corresponding pure FG simulations. PMID- 26574334 TI - Inferring Transition Rates of Networks from Populations in Continuous-Time Markov Processes. AB - We are interested inferring rate processes on networks. In particular, given a network's topology, the stationary populations on its nodes, and a few global dynamical observables, can we infer all the transition rates between nodes? We draw inferences using the principle of maximum caliber (maximum path entropy). We have previously derived results for discrete-time Markov processes. Here, we treat continuous-time processes, such as dynamics among metastable states of proteins. The present work leads to a particularly important analytical result: namely, that when the network is constrained only by a mean jump rate, the rate matrix is given by a square-root dependence of the rate, kab ? (pib/pia)(1/2), on pia and pib, the stationary-state populations at nodes a and b. This leads to a fast way to estimate all of the microscopic rates in the system. As an illustration, we show that the method accurately predicts the nonequilibrium transition rates in an in silico gene expression network and transition probabilities among the metastable states of a small peptide at equilibrium. We note also that the method makes sensible predictions for so-called extra thermodynamic relationships, such as those of Bronsted, Hammond, and others. PMID- 26574335 TI - Folding Thermodynamics and Mechanism of Five Trp-Cage Variants from Replica Exchange MD Simulations with RSFF2 Force Field. AB - To test whether our recently developed residue-specific force field RSFF2 can reproduce the mutational effect on the thermal stability of Trp-cage mini-protein and decipher its detailed folding mechanism, we carried out long-time replica exchange molecular dynamics (REMD) simulations on five Trp-cage variants, including TC5b and TC10b. Initiated from their unfolded structures, the simulations not only well-reproduce their experimental structures but also their melting temperatures and folding enthalpies reasonably well. For each Trp-cage variant, the overall folding free energy landscape is apparently two-state, but some intermediate states can be observed when projected on more detailed coordinates. We also found different variants have the same major folding pathway, including the well formed PII-helix in the unfolded state, the formation of W6-P12/P18/P19 contacts and the alpha-helix before the transition state, the following formation of most native contacts, and the final native loop formation. The folding mechanism derived here is consistent with many previous simulations and experiments. PMID- 26574336 TI - Weighted Distance Functions Improve Analysis of High-Dimensional Data: Application to Molecular Dynamics Simulations. AB - Data mining techniques depend strongly on how the data are represented and how distance between samples is measured. High-dimensional data often contain a large number of irrelevant dimensions (features) for a given query. These features act as noise and obfuscate relevant information. Unsupervised approaches to mine such data require distance measures that can account for feature relevance. Molecular dynamics simulations produce high-dimensional data sets describing molecules observed in time. Here, we propose to globally or locally weight simulation features based on effective rates. This emphasizes, in a data-driven manner, slow degrees of freedom that often report on the metastable states sampled by the molecular system. We couple this idea to several unsupervised learning protocols. Our approach unmasks slow side chain dynamics within the native state of a miniprotein and reveals additional metastable conformations of a protein. The approach can be combined with most algorithms for clustering or dimensionality reduction. PMID- 26574337 TI - Nontargeted Parallel Cascade Selection Molecular Dynamics for Enhancing the Conformational Sampling of Proteins. AB - Nontargeted parallel cascade selection molecular dynamics (nt-PaCS-MD) is proposed as an efficient conformational sampling method to enhance the conformational transitions of proteins, which is an extension of the original targeted PaCS-MD (t-PaCS-MD). The original PaCS-MD comprises cycles of (i) selection of initial structures for multiple independent MD simulations toward a predetermined target and (ii) conformational sampling by the independent MDs. In nt-PaCS-MD, structures that significantly deviate from an average are regarded as candidates that have high potential to address other metastable states and are chosen as the initial structures in the selection. To select significantly deviated structures, we examine the root-mean-square deviation (RMSD) of snapshots generated from the average structure based on Gram-Schmidt orthogonalization. nt-PaCS-MD was applied to the folding of the mini-protein chignolin in implicit solvent and to the open-closed conformational transitions of T4 lysozyme (T4L) and glutamine binding protein (QBP) in explicit solvent. We show that nt-PaCS-MD can reach chignolin's native state and can also cause the open-closed transition of T4L and QBP on a nanosecond time scale, which are very efficient in terms of conformational sampling and comparable to that with t-PaCS MD. PMID- 26574338 TI - Internal Normal Mode Analysis (iNMA) Applied to Protein Conformational Flexibility. AB - We analyze the capacity of normal modes to predict observed protein conformational changes, and, notably, those induced by the formation of protein protein complexes. We show that normal modes calculated in internal coordinate space (ICS) provide better predictions. For a large test set, using the ICS approach describes the conformational changes more completely, and with fewer low frequency modes than the equivalent Cartesian coordinate modes, despite the fact that the internal coordinate calculations were restricted to torsional angles. This can be attributed to the fact that the use of ICS extends the range over which movements along the corresponding eigenvectors remain close to the true conformational energy hypersurface. We also show that the PaLaCe coarse-grain protein model performs better than a simple elastic network model. We apply ICS normal-mode analysis to protein complexes and, by extending the approach of Sunada and Go, [Sunada, S.; Go, N. J. Comput. Chem. 1995, 16, 328-336], we show that we can couple an accurate view of the Cartesian coordinate movements induced by ICS modes with the detection of the key residues responsible for the movements. PMID- 26574339 TI - Structural Ensembles of Intrinsically Disordered Proteins Depend Strongly on Force Field: A Comparison to Experiment. AB - Intrinsically disordered proteins (IDPs) are notoriously challenging to study both experimentally and computationally. The structure of IDPs cannot be described by a single conformation but must instead be described as an ensemble of interconverting conformations. Atomistic simulations are increasingly used to obtain such IDP conformational ensembles. Here, we have compared the IDP ensembles generated by eight all-atom empirical force fields against primary small-angle X-ray scattering (SAXS) and NMR data. Ensembles obtained with different force fields exhibit marked differences in chain dimensions, hydrogen bonding, and secondary structure content. These differences are unexpectedly large: changing the force field is found to have a stronger effect on secondary structure content than changing the entire peptide sequence. The CHARMM 22* ensemble performs best in this force field comparison: it has the lowest error in chemical shifts and J-couplings and agrees well with the SAXS data. A high population of left-handed alpha-helix is present in the CHARMM 36 ensemble, which is inconsistent with measured scalar couplings. To eliminate inadequate sampling as a reason for differences between force fields, extensive simulations were carried out (0.964 ms in total); the remaining small sampling uncertainty is shown to be much smaller than the observed differences. Our findings highlight how IDPs, with their rugged energy landscapes, are highly sensitive test systems that are capable of revealing force field deficiencies and, therefore, contributing to force field development. PMID- 26574340 TI - PyEMMA 2: A Software Package for Estimation, Validation, and Analysis of Markov Models. AB - Markov (state) models (MSMs) and related models of molecular kinetics have recently received a surge of interest as they can systematically reconcile simulation data from either a few long or many short simulations and allow us to analyze the essential metastable structures, thermodynamics, and kinetics of the molecular system under investigation. However, the estimation, validation, and analysis of such models is far from trivial and involves sophisticated and often numerically sensitive methods. In this work we present the open-source Python package PyEMMA ( http://pyemma.org ) that provides accurate and efficient algorithms for kinetic model construction. PyEMMA can read all common molecular dynamics data formats, helps in the selection of input features, provides easy access to dimension reduction algorithms such as principal component analysis (PCA) and time-lagged independent component analysis (TICA) and clustering algorithms such as k-means, and contains estimators for MSMs, hidden Markov models, and several other models. Systematic model validation and error calculation methods are provided. PyEMMA offers a wealth of analysis functions such that the user can conveniently compute molecular observables of interest. We have derived a systematic and accurate way to coarse-grain MSMs to few states and to illustrate the structures of the metastable states of the system. Plotting functions to produce a manuscript-ready presentation of the results are available. In this work, we demonstrate the features of the software and show new methodological concepts and results produced by PyEMMA. PMID- 26574342 TI - Correction to Enhanced Conformational Sampling Using Replica Exchange with Collective-Variable Tempering. PMID- 26574343 TI - Chronic interstitial granulomatous dermatitis in coccidioidomycosis. AB - Coccidioides species are soil-dwelling fungi endemic to the Southwest U.S.A., especially Arizona and California and Northern Mexico. The cutaneous findings of coccidioidomycosis have a wide range of pathology, which includes organism specific and reactive processes. Interstitial granulomatous dermatitis (IGD), a granuloma annulare-like reaction, has been described, in a limited form, in association with acute pulmonary coccidioidomycosis. We present a case of chronic, widespread IGD spanning over 9 years in association with an active coccidioidomycosis infection. Similar clinical and histopathological features have been described in association with drug reactions, connective tissue diseases, systemic vasculitis, lymphomas, other infectious diseases and inflammatory bowel disease. Our patient's dramatic presentation and chronic course expands upon the clinical spectrum of IGD occurring in association with pulmonary coccidioidomycosis. While IGD in association with coccidioidomycosis is rare, both dermatologists and general practitioners see IGD reactions, and our case highlights the importance of identifying the underlying driver. PMID- 26574341 TI - Empirical Optimization of Interactions between Proteins and Chemical Denaturants in Molecular Simulations. AB - Chemical denaturants are the most commonly used perturbation applied to study protein stability and folding kinetics as well as the properties of unfolded polypeptides. We build on recent work balancing the interactions of proteins and water, and accurate models for the solution properties of urea and guanidinium chloride, to develop a combined force field that is able to capture the strength of interactions between proteins and denaturants. We use solubility data for a model tetraglycine peptide in each denaturant to tune the protein-denaturant interaction by a novel simulation methodology. We validate the results against data for more complex sequences: single-molecule Forster resonance energy transfer data for a 34-residue fragment of the globular protein CspTm and photoinduced electron transfer quenching data for the disordered peptides C(AGQ)nW in denaturant solution as well as the chemical denaturation of the mini protein Trp cage. The combined force field model should aid our understanding of denaturation mechanisms and the interpretation of experiment. PMID- 26574344 TI - High thermoelectric performance in graphene nanoribbons by graphene/BN interface engineering. AB - The thermoelectric properties of in-plane heterostructures made of Graphene and hexagonal boron nitride (BN) have been investigated by means of atomistic simulation. The heterostructures consist in armchair graphene nanoribbons to the sides of which BN flakes are periodically attached. This arrangement generates a strong mismatch of phonon modes between the different sections of the ribbons, which leads to a very small phonon conductance, while the electron transmission is weakly affected. In combination with the large Seebeck coefficient resulting from the BN-induced bandgap opening or broadening, it is shown that large thermoelectric figure of merit ZT > 0.8 can be reached in perfect structures at relatively low Fermi energy, depending on the graphene nanoribbon width. The high value ZT = 1.48 may even be achieved by introducing appropriately vacancies in the channel, as a consequence of further degradation of the phonon conductance. PMID- 26574345 TI - DNA double-strand breaks caused by new and contemporary endodontic sealers. AB - AIM: To investigate the cytotoxicity and genotoxicity of a new silicate-based BioRoot RCS(r) sealer in comparison with contemporary sealers. METHODOLOGY: A periodontal ligament cell line using lentiviral gene transfer of human telomerase reverse transcriptase (hTERT) was used and exposed to subtoxic concentrations of 24-h eluates from two epoxy resin-based (AH Plus Jet(r) and Acroseal(r) ), four various methacrylate-based endodontic sealers (EndoREZ(r) , RealSeal(r) , RealSeal SE(r) and Hybrid Root SEAL(r) ) and three silicate-based sealers (BioRoot RCS(r) , iRootSP(r) and MTA Fillapex(r) ). The XTT-based cell viability assay was used for cytotoxicity screening of materials. The gamma-H2AX assay was used for genotoxicity screening. In the gamma-H2AX immunofluorescence assay, PDL hTERT cells were exposed to eluates of the substances for 6 h and DNA double strand breaks (DSB) were detected microscopically. Induced foci represented DSBs, which can induce ATM-dependent phosphorylation of the histone H2AX. The statistical significance of the differences between the experimental groups was compared using the Student's t-test (P < 0.05). RESULTS: The cytotoxicity of the 24-h eluates could be ranked in the following order: Hybrid Root SEAL(r) >RealSeal(r) >Acroseal(r) >RealSeal SE(r) >= AH Plus Jet(r) > EndoREZ(r) >MTA Fillapex(r) > iRoot SP(r) >BioRoot RCS(r) . In negative controls (cells which received medium only) 4.08 +/- 0.53 DSB foci (mean +/- SEM) whilst in positive controls 10.76 +/- 4.05 DSB foci/cell were found. BioRoot RCS(r) and RealSeal SE(r) exhibited significant differences in foci formation at 1/3 EC50 compared with their 1/10 EC50 concentration (P < 0.05). Both concentrations (1/10 and 1/3 of EC50) of AH Plus Jet(r) , Acroseal(r) , RealSeal(r) and MTA Fillapex(r) sealers were not significantly different when compared with the medium control (P < 0.05). CONCLUSIONS: New BioRoot RCS(r) was not toxic whilst Hybrid Root SEAL(r) demonstrated more toxicity and DNA double-strand breaks when compared with other resin- and silicate-based root canal sealers. PMID- 26574347 TI - New Insights into the Molecular Mechanism of E-Cadherin-Mediated Cell Adhesion by Free Energy Calculations. AB - Three-dimensional domain swapping is an important mode of protein association leading to the formation of stable dimers. Monomers associating via this mechanism mutually exchange a domain to form a homodimer. Classical cadherins, an increasingly important target for anticancer therapy, use domain swapping to mediate cell adhesion. However, despite its importance, the molecular mechanism of domain swapping is still debated. Here, we study the conformational changes that lead to activation and dimerization via domain swapping of E-cadherin. Using state-of-the-art enhanced sampling atomistic simulations, we reconstruct its conformational free energy landscape, obtaining the free energy profile connecting the inactive and active form. Our simulations predict that the E cadherin monomer populates the open and closed forms almost equally, which is in agreement with the proposed "selected fit" mechanism in which monomers in an active conformational state bind to form a homodimer, analogous to the conformational selection mechanism often observed in ligand-target binding. Moreover, we find that the open state population is increased in the presence of calcium ions at the extracellular boundary, suggesting their possible role as allosteric activators of the conformational change. PMID- 26574348 TI - An On-the-Fly Surface-Hopping Program JADE for Nonadiabatic Molecular Dynamics of Polyatomic Systems: Implementation and Applications. AB - Nonadiabatic dynamics simulations have rapidly become an indispensable tool for understanding ultrafast photochemical processes in complex systems. Here, we present our recently developed on-the-fly nonadiabatic dynamics package, JADE, which allows researchers to perform nonadiabatic excited-state dynamics simulations of polyatomic systems at an all-atomic level. The nonadiabatic dynamics is based on Tully's surface-hopping approach. Currently, several electronic structure methods (CIS, TDHF, TDDFT(RPA/TDA), and ADC(2)) are supported, especially TDDFT, aiming at performing nonadiabatic dynamics on medium to large-sized molecules. The JADE package has been interfaced with several quantum chemistry codes, including Turbomole, Gaussian, and Gamess (US). To consider environmental effects, the Langevin dynamics was introduced as an easy to-use scheme into the standard surface-hopping dynamics. The JADE package is mainly written in Fortran for greater numerical performance and Python for flexible interface construction, with the intent of providing open-source, easy to-use, well-modularized, and intuitive software in the field of simulations of photochemical and photophysical processes. To illustrate the possible applications of the JADE package, we present a few applications of excited-state dynamics for various polyatomic systems, such as the methaniminium cation, fullerene (C20), p-dimethylaminobenzonitrile (DMABN) and its primary amino derivative aminobenzonitrile (ABN), and 10-hydroxybenzo[h]quinoline (10-HBQ). PMID- 26574349 TI - Why Do Mixed Quantum-Classical Methods Describe Short-Time Dynamics through Conical Intersections So Well? Analysis of Geometric Phase Effects. AB - Adequate simulation of nonadiabatic dynamics through conical intersection requires accounting for a nontrivial geometric phase (GP) emerging in electronic and nuclear wave functions in the adiabatic representation. Popular mixed quantum classical (MQC) methods, surface hopping and Ehrenfest, do not carry a nuclear wave function to be able to incorporate the GP into nuclear dynamics. Surprisingly, the MQC methods reproduce ultrafast interstate crossing dynamics generated with the exact quantum propagation so well as if they contained information about the GP. Using two-dimensional linear vibronic coupling models we unravel how the MQC methods can effectively mimic the most significant dynamical GP effects: (1) compensation for repulsive diagonal second-order nonadiabatic couplings and (2) transfer enhancement for a fully cylindrically symmetric component of a nuclear distribution. PMID- 26574350 TI - Path Integral Metadynamics. AB - We develop a new efficient approach for the simulation of static properties of quantum systems using path integral molecular dynamics in combination with metadynamics. We use the isomorphism between a quantum system and a classical one in which a quantum particle is mapped into a ring polymer. A history dependent biasing potential is built as a function of the elastic energy of the isomorphic polymer. This enhances fluctuations in the shape and size of the necklace in a controllable manner and allows escaping deep energy minima in a limited computer time. In this way, we are able to sample high free energy regions and cross barriers, which would otherwise be insurmountable with unbiased methods. This substantially improves the ability of finding the global free energy minimum as well as exploring other metastable states. The performance of the new technique is demonstrated by illustrative applications on model potentials of varying complexity. PMID- 26574351 TI - Benchmark of Schemes for Multiscale Molecular Dynamics Simulations. AB - In multiscale molecular dynamics simulations the accuracy of detailed models is combined with the efficiency of a reduced representation. For several applications - namely those of sampling enhancement - it is desirable to combine fine-grained (FG) and coarse-grained (CG) approaches into a single hybrid approach with an adjustable mixing parameter. We present a benchmark of three algorithms that use a mixing of the two representation layers using a Lagrangian formalism. The three algorithms use three different approaches for keeping the particles at the FG level of representation together: 1) addition of forces, 2) mass scaling, and 3) temperature scaling. The benchmark is applied to liquid hexadecane and includes an evaluation of the average configurational entropy of the FG and CG subsystems. The temperature-scaling scheme achieved a 3-fold sampling speedup with little deviation of FG properties. The addition-of-forces scheme kept FG properties the best but provided little sampling speedup. The mass scaling scheme yielded a 5-fold speedup but deviated the most from FG properties. PMID- 26574352 TI - Enthalpy-Entropy Compensation upon Molecular Conformational Changes. AB - The change in free energy is the dominant factor in all chemical processes; it usually encompasses enthalpy-entropy compensation (EEC). Here, we use the free energy perturbation formalism to show that EEC is influenced by the molecular conformational changes (CCs) of the entire system comprising the solute and by the already known solvent reorganization. The internal changes of enthalpy and the entropy due to CCs upon modifying the interactions (perturbation) cancel each other exactly. The CCs influence the dissipation of the modified interactions and their contributions to the free energy. Using molecular simulations, we show that, for solvation of six different HIV-1 protease inhibitors, CCs in the solute cause EEC as large as 10-30 kcal/mol. Moreover, the EEC due to CCs in HIV-1 protease is shown to vary significantly upon modifying its bound ligand. These findings have important implications for understanding of EEC phenomena and for interpretation of thermodynamic measurements. PMID- 26574353 TI - Convexity and Stiffness in Energy Functions for Electrostatic Simulations. AB - We study the properties of convex functionals which have been proposed for the simulation of charged molecular systems within the Poisson-Boltzmann approximation. We consider the extent to which the functionals reproduce the true fluctuations of electrolytes and thus the one-loop correction to mean field theory-including the Debye-Huckel correction to the free energy of ionic solutions. We also compare the functionals for use in numerical optimization of a mean field model of a charged polymer and show that different functionals have very different stiffnesses leading to substantial differences in accuracy and speed. PMID- 26574354 TI - Comparative Assessment of DFT Performances in Ru- and Rh-Promoted sigma-Bond Activations. AB - In this work, the performances of 19 density functional theory (DFT) methods are calibrated comparatively on Ru- and Rh-promoted sigma-bond (C-H, O-H, and H-H) activations. DFT calibration reference is generated from explicitly correlated coupled cluster CCSD(T)-F12 calculations, and the 4s4p core-valence correlation effect of the two 4d platinum group transition metals is also included. Generally, the errors of DFT methods for calculating energetics of Ru-/Rh mediated reactions appear to correlate more with the magnitude of energetics itself than other factors such as metal identity. For activation energy calculations, the best performing functionals for both Ru and Rh systems are MN12SX < CAM-B3LYP < M06-L < MN12L < M06 < omegaB97X < B3LYP < LC-omegaPBE (in the order of increasing mean unsigned deviations, MUDs, of less than 2 kcal/mol). For reaction energy calculations, best functionals with MUDs less than 2 kcal/mol are PBE0 < CAM-B3LYP ~ N12SX. The effect of the DFT empirical dispersion correction on the performance of the DFT methods is beneficial for most density functionals tested in this work, reducing their MUDs to different extents. After including empirical dispersion correction, omegaB97XD, B3LYP-D3, and CAM-B3LYP-D3 (PBE0-D3, B3LYP-D3, and omegaB97XD) are the three best performing DFs for activation energy (reaction energy) calculations, from which B3LYP-D3 and omegaB97XD can notably be recommended uniformly for both the reaction energy and reaction barrier calculations. The good performance of B3LYP-D3 in quantitative description of the energetic trends further adds value to B3LYP-D3 and singles this functional out as a reasonable choice in the Ru/Rh-promoted sigma-bond activation processes. PMID- 26574355 TI - Importance and Reliability of Small Basis Set CCSD(T) Corrections to MP2 Binding and Relative Energies of Water Clusters. AB - MP2 describes hydrogen-bonded systems well, yet a higher-order electron correlation correction in the form of a CCSD(T) calculation is usually necessary to achieve benchmark quality energies. We evaluated the importance and reliability of small basis set CCSD(T) corrections to MP2 (delta(MP2)(CCSD(T))) both on the binding (DeltaE) and relative (DeltaDeltaE) energies for a large number of systems including four water dimer stationary points and 57 other clusters up to undecamers, (H2O)11. By comparing the MP2 energies with CCSD(T) and the explicitly correlated MP2-F12 energies with variants of CCSD(T)-F12 using different basis sets, we were able to establish that the correction to the binding energy (DeltaE) is sensitive to basis set size, especially for small double-zeta basis sets. On the other hand, the basis set sensitivity of the correction to the relative energy (DeltaDeltaE) within each cluster size is very small. While the delta(MP2)(CCSD(T)) correction to the binding energy might vary in magnitude with basis set size, its effect on relative energy (and hence the stability of isomers) is remarkably consistent. Therefore, we recommend the inclusion of this correction to obtain the relative stability of closely spaced isomers using a double-zeta basis set with polarization and diffuse functions such as aug-cc-pVDZ. PMID- 26574356 TI - Acceleration of High Angular Momentum Electron Repulsion Integrals and Integral Derivatives on Graphics Processing Units. AB - We present an efficient implementation of ab initio self-consistent field (SCF) energy and gradient calculations that run on Compute Unified Device Architecture (CUDA) enabled graphical processing units (GPUs) using recurrence relations. We first discuss the machine-generated code that calculates the electron-repulsion integrals (ERIs) for different ERI types. Next we describe the porting of the SCF gradient calculation to GPUs, which results in an acceleration of the computation of the first-order derivative of the ERIs. However, only s, p, and d ERIs and s and p derivatives could be executed simultaneously on GPUs using the current version of CUDA and generation of NVidia GPUs using a previously described algorithm [Miao and Merz J. Chem. Theory Comput. 2013, 9, 965-976.]. Hence, we developed an algorithm to compute f type ERIs and d type ERI derivatives on GPUs. Our benchmarks shows the performance GPU enable ERI and ERI derivative computation yielded speedups of 10-18 times relative to traditional CPU execution. An accuracy analysis using double-precision calculations demonstrates that the overall accuracy is satisfactory for most applications. PMID- 26574357 TI - Compressed Representation of Kohn-Sham Orbitals via Selected Columns of the Density Matrix. AB - Given a set of Kohn-Sham orbitals from an insulating system, we present a simple, robust, efficient, and highly parallelizable method to construct a set of optionally orthogonal, localized basis functions for the associated subspace. Our method explicitly uses the fact that density matrices associated with insulating systems decay exponentially along the off-diagonal direction in the real space representation. We avoid the usage of an optimization procedure, and the localized basis functions are constructed directly from a set of selected columns of the density matrix (SCDM). Consequently, the core portion of our localization procedure is not dependent on any adjustable parameters. The only adjustable parameters present pertain to the use of the SCDM after their computation (for example, at what value should the SCDM be truncated). Our method can be used in any electronic structure software package with an arbitrary basis set. We demonstrate the numerical accuracy and parallel scalability of the SCDM procedure using orbitals generated by the Quantum ESPRESSO software package. We also demonstrate a procedure for combining the orthogonalized SCDM with Hockney's algorithm to efficiently perform Hartree-Fock exchange energy calculations with near-linear scaling. PMID- 26574358 TI - Joint Use of Bonding Evolution Theory and QM/MM Hybrid Method for Understanding the Hydrogen Abstraction Mechanism via Cytochrome P450 Aromatase. AB - Bonding evolution theory (BET), as a combination of the electron localization function (ELF) and Thom's catastrophe theory (CT), has been coupled with quantum mechanics/molecular mechanics (QM/MM) method in order to study biochemical reaction paths. The evolution of the bond breaking/forming processes and electron pair rearrangements in an inhomogeneous dynamic environment provided by the enzyme has been elucidated. The proposed methodology is applied in an enzymatic system in order to clarify the reaction mechanism for the hydrogen abstraction of the androstenedione (ASD) substrate catalyzed by the cytochrome P450 aromatase enzyme. The use of a QM/MM Hamiltonian allows inclusion of the polarization of the charges derived from the amino acid residues in the wave function, providing a more accurate and realistic description of the chemical process. The hydrogen abstraction step is found to have five different ELF structural stability domains, whereas the C-H breaking and O-H forming bond process rearrangements are taking place in an asynchronous way. PMID- 26574359 TI - Beyond Energies: Geometries of Nonbonded Molecular Complexes as Metrics for Assessing Electronic Structure Approaches. AB - Electronic structure approaches for calculating intermolecular interactions have traditionally been benchmarked almost exclusively on the basis of energy-centric metrics. Herein, we explore the idea of utilizing a metric related to geometry. On a diverse series of noncovalently interacting systems of different sizes, from the water dimer to the coronene dimer, we evaluate a variety of electronic structure approximations with respect to their abilities to reproduce coupled cluster-level geometries. Specifically, we examine Hartree-Fock, second-order Moller-Plesset perturbation theory (MP2), attenuated MP2, scaled MP2, and a number of density functionals, many of which include empirical or nonempirical van der Waals dispersion corrections. We find a number of trends that transcend system size and interaction type. For instance, functionals incorporating VV10 nonlocal correlation tend to yield highly accurate geometries; omegaB97X-V and B97M-V, in particular, stand out. We establish that intermolecular distance, as measured by, e.g., the center-of-mass separation of two molecules, is the geometric parameter that deviates most profoundly among the various methods. This property of the equilibrium intermolecular separation, coupled with its accessibility via a small series of well-defined single-point calculations, makes it an ideal metric for the development and evaluation of electronic structure methods. PMID- 26574360 TI - Robust and Efficient Auxiliary Density Perturbation Theory Calculations. AB - A new iterative solver for the recently developed time-dependent auxiliary density perturbation theory is presented. It is based on the Eirola-Nevanlinna algorithm for large nonsymmetric linear equation systems. The new methodology is validated by static and dynamic polarizability calculations of small molecules. Comparison between the analytic and iterative solutions of the response equation system shows excellent agreement for the calculated static and dynamic polarizabilities. The new iterative solver reduces the formal scaling from [Symbol: see text](N(4)) to [Symbol: see text](N(3)). Furthermore, the observed computational scaling for linear alkane chains is N(1.6). This subquadratic behavior is possible in systems with a few hundred atoms because of the very small prefactors of the [Symbol: see text](N(3)) and [Symbol: see text](N(2)) steps remaining in the iterative solver. To demonstrate the potential of this new methodology, static polarizabilities of giant fullerenes up to C960, with more than 14,000 basis functions, are calculated. PMID- 26574361 TI - Oxidation States from Wave Function Analysis. AB - We introduce a simple and general scheme to derive from wavefuntion analysis the most appropriate atomic/fragment electron configurations in a molecular system, from which oxidation states can be inferred. The method can be applied for any level of theory for which the first-order density matrix is available, and unlike others, it is not restricted to transition metal complexes. The method relies on the so-called spin-resolved effective atomic orbitals which for the present purpose is extended here to deal with molecular fragments/ligands. We describe in detail the most important points of the new scheme, in particular the hierarchical fragment approach devised for practical applications. A number of transition metal complexes with different formal oxidation states and spin states and a set of organic and inorganic compounds are provided as illustrative examples of the new scheme. Challenging systems such as transition state structures are also tackled on equal footing. PMID- 26574362 TI - Understanding the Electronic Factors Responsible for Ligand Spin-Orbit NMR Shielding in Transition-Metal Complexes. AB - The significant role of relativistic effects in altering the NMR chemical shifts of light nuclei in heavy-element compounds has been recognized for a long time; however, full understanding of this phenomenon in relation to the electronic structure has not been achieved. In this study, the recently observed qualitative differences between the platinum and gold compounds in the magnitude and the sign of spin-orbit-induced (SO) nuclear magnetic shielding at the vicinal light atom ((13)C, (15)N), sigma(SO)(LA), are explained by the contractions of 6s and 6p atomic orbitals in Au complexes, originating in the larger Au nuclear charge and stronger scalar relativistic effects in gold complexes. This leads to the chemical activation of metal 6s and 6p atomic orbitals in Au complexes and their larger participation in bonding with the ligand, which modulates the propagation of metal-induced SO effects on the NMR signal of the LA via the Spin-Orbit/Fermi Contact (SO/FC) mechanism. The magnitude of the sigma(SO)(LA) in these square planar complexes can be understood on the basis of a balance between various metal-based 5d -> 5d* and 6p -> 6p* orbital magnetic couplings. The large and positive sigma(SO)(LA) in platinum complexes is dominated by the shielding platinum-based 5d -> 5d* magnetic couplings, whereas small or negative sigma(SO)(LA) in gold complexes is related to the deshielding contribution of the gold-based 6p -> 6p* magnetic couplings. Further, it is demonstrated that sigma(SO)(LA) correlates quantitatively with the extent of M-LA electron sharing that is the covalence of the M-LA bond (characterized by the QTAIM delocalization index, DI). The present findings will contribute to further understanding of the origin and propagation of the relativistic effects influencing the experimental NMR parameters in heavy-element systems. PMID- 26574363 TI - Discarding Information from Previous Iterations in an Optimal Way To Solve the Coupled Cluster Amplitude Equations. AB - The direct inversion of the iterative subspace (DIIS) convergence acceleration algorithm is used in most electronic structure programs to solve the nonlinear coupled cluster amplitude equations. When the DIIS algorithm is used, the storage of previous trial vectors may become a bottleneck and the discarding of trial vectors may lead to a degradation of the convergence or even divergence. We discuss an alternative way of storing information from trial vectors where only the last three trial vectors are needed to maintain the convergence of the full set of previous trial vectors, and which requires only minor modifications of an existing DIIS code. PMID- 26574364 TI - Efficient Self-Consistent Implementation of Local Hybrid Functionals. AB - Local hybrid density functionals, with position-dependent exact-exchange admixture, are an important extension to the popular global hybrid functionals, promising improved accuracy for many properties. An efficient implementation is crucial to make local hybrids available for widespread application. The resolution-of-the-identity approach used in previous implementations to compute nonstandard two-electron integrals has been found to require large uncontracted basis sets, rendering the cost of local hybrid calculations impractical for large scale systems. On the basis of recently promoted seminumerical implementations of exact exchange in global hybrid functionals, we present an efficient, self consistent implementation of local hybrid functionals within the generalized Kohn Sham scheme. The final cost of a local hybrid calculation is equal to that of a meta-GGA global hybrid using the seminumerical algorithm. Since seminumerical schemes exhibit superior scaling with respect to system and basis set size over analytical exact exchange, and this advantage is not affected by a position dependent admixture of exact exchange, local hybrid calculations for large systems are now possible. PMID- 26574365 TI - Ground and Excited States of the [Fe(H2O)6]2+ and [Fe(H2O)6]3+ Clusters: Insight into the Electronic Structure of the [Fe(H2O)6]2+-[Fe(H2O)6]3+ Complex. AB - We report the ground and low-lying electronically excited states of the [Fe(H2O)6](2+) and [Fe(H2O)6](3+) clusters using multiconfiguration electronic structure theory. In particular, we have constructed the potential energy curves (PECs) with respect to the iron-oxygen distance when removing all water ligands at the same time from the cluster minima and established their correlation to the long-range dissociation channels. Due to the fact that both the second and third ionization potentials of iron are larger than the one for water, the ground-state products asymptotically correlate with dissociation channels that are repulsive in nature at large separations, as they contain at least one H2O(+) fragment and a singly positively charged metal center (Fe(+)). The most stable equilibrium structures emanate, via intersections and/or avoided crossings, from the channels consisting of the lowest electronic states of Fe(2+)((5)D, 3d(6)) or Fe(3+)((6)S, 3d(5)) and six neutral water molecules. Upon hydration, the ground state of Fe(2+)(H2O)6 is a triply ((5)Tg) degenerate one, with the doubly ((5)Eg) degenerate state lying ~20 kcal/mol higher in energy. Similarly, the Fe(3+)(H2O)6 cluster has a ground state of (6)Ag symmetry under Th symmetry, which is well separated from the first excited state. We also examine a multitude of electronically excited states of many possible spin multiplicities and report the optimized geometries for several selected states. The PECs of those states exhibit a high density of states. Focusing on the ground and the first few excited states of the [Fe(H2O)6](2+) and [Fe(H2O)6](3+) clusters, we studied their mutual interaction in the gas phase. We obtained the optimal geometries of the Fe(2+)(H2O)6-Fe(3+)(H2O)6 gas-phase complex for different Fe-Fe distances. For distances shorter than 6.0 A, the water molecules in the respective first solvation shells located between the two metal centers were found to interact via weak hydrogen bonds. We examined a total of 10 electronic states for this complex, including those corresponding to the electron transfer (ET) from the ferrous to the ferric ion. The ET process is discussed and a possible path via a quasi-symmetric transition state is suggested. PMID- 26574366 TI - Assessment of Orbital-Optimized MP2.5 for Thermochemistry and Kinetics: Dramatic Failures of Standard Perturbation Theory Approaches for Aromatic Bond Dissociation Energies and Barrier Heights of Radical Reactions. AB - An assessment of orbital-optimized MP2.5 (OMP2.5) [ Bozkaya, U.; Sherrill, C. D. J. Chem. Phys. 2014, 141, 204105 ] for thermochemistry and kinetics is presented. The OMP2.5 method is applied to closed- and open-shell reaction energies, barrier heights, and aromatic bond dissociation energies. The performance of OMP2.5 is compared with that of the MP2, OMP2, MP2.5, MP3, OMP3, CCSD, and CCSD(T) methods. For most of the test sets, the OMP2.5 method performs better than MP2.5 and CCSD, and provides accurate results. For barrier heights of radical reactions and aromatic bond dissociation energies OMP2.5-MP2.5, OMP2-MP2, and OMP3-MP3 differences become obvious. Especially, for aromatic bond dissociation energies, standard perturbation theory (MP) approaches dramatically fail, providing mean absolute errors (MAEs) of 22.5 (MP2), 17.7 (MP2.5), and 12.8 (MP3) kcal mol(-1), while the MAE values of the orbital-optimized counterparts are 2.7, 2.4, and 2.4 kcal mol(-1), respectively. Hence, there are 5-8-folds reductions in errors when optimized orbitals are employed. Our results demonstrate that standard MP approaches dramatically fail when the reference wave function suffers from the spin-contamination problem. On the other hand, the OMP2.5 method can reduce spin contamination in the unrestricted Hartree-Fock (UHF) initial guess orbitals. For overall evaluation, we conclude that the OMP2.5 method is very helpful not only for challenging open-shell systems and transition-states but also for closed shell molecules. Hence, one may prefer OMP2.5 over MP2.5 and CCSD as an O(N(6)) method, where N is the number of basis functions, for thermochemistry and kinetics. The cost of the OMP2.5 method is comparable with that of CCSD for energy computations. However, for analytic gradient computations, the OMP2.5 method is only half as expensive as CCSD. PMID- 26574367 TI - Non-covalent Interactions of CO2 with Functional Groups of Metal-Organic Frameworks from a CCSD(T) Scheme Applicable to Large Systems. AB - The strength of interactions between CO2 and 23 building blocks of metal-organic frameworks are reported in this paper. This theoretical study is based on an incremental, explicitly correlated coupled-cluster scheme with interference effects. This scheme allows the accurate calculation of molecular complexes such as zinc acetate (32 non-hydrogen atoms) at the CCSD(T) level, close to the basis set limit. Higher CO2 affinity for complexes with nitrogen-containing heterocycles is predicted from the calculated interaction energies. The good agreement between the interaction energies obtained from the CCSD(T) scheme and DFT-D3 is discussed. PMID- 26574368 TI - Conical Intersection Optimization Using Composed Steps Inside the ONIOM(QM:MM) Scheme: CASSCF:UFF Implementation with Microiterations. AB - Three algorithms for optimization of minimum energy conical intersections (MECI) are implemented inside an ONIOM(QM:MM) scheme combined with microiterations. The algorithms follow the composed gradient (CG), composed gradient-composed steps (CG-CS), and double Newton-Raphson-composed step (DNR-CS) schemes developed previously for purely QM optimizations. The CASSCF and UFF methods are employed for the QM and MM calculations, respectively. Conical intersections are essential to describe excited state processes in chemistry, including biological systems or functional molecules, and our approach is suitable for large molecules or systems where the excitation is well localized on a fragment that can be treated at the CASSCF level. The algorithms are tested on a set of 14 large hydrocarbons composed of a medium-sized chromophore (fulvene, benzene, butadiene, and hexatriene) derivatized with alkyl substituents. Thanks to the microiteration technique, the number of steps required to optimize the MECI of the large molecules is similar to the one needed to optimize the unsubstituted chromophores at the QM level. The three tested algorithms have a similar performance, although the CG-CS implementation is the most efficient one on average. The implementation can be straightforwardly applied to ONIOM(QM:QM) schemes, and its potential is further demonstrated locating the MECI of diphenyl dibenzofulvene (DPDBF) in its crystal, which is relevant for the aggregation induced emission (AIE) of this molecule. A cluster of 12 molecules (528 atoms) is relaxed during the MECI optimization, with one molecule treated at the QM level. Our results confirm the mechanistic picture that AIE in DPDBF is due to the packing of the molecules in the crystal. Even when the molecules surrounding the excited molecule are allowed to relax, the rotation of the bulky substituents is hindered, and the conical intersection responsible for radiationless decay in solution is not accessible energetically. PMID- 26574369 TI - General-Order Many-Body Green's Function Method. AB - Electron binding energies are evaluated as differences in total energy between the N- and (N +/- 1)-electron systems calculated by the nth-order Moller-Plesset perturbation (MPn) theory using the same set of orbitals. The MPn energies up to n = 30 are, in turn, obtained by the determinant-based method of Knowles et al. (Chem. Phys. Lett. 1985, 113, 8-12). The zeroth- through third-order electron binding energies thus determined agree with those obtained by solving the Dyson equation in the diagonal and frequency-independent approximations of the self energy. However, as n -> infinity, they converge at the exact basis-set solutions from the Dyson equation with the exact self-energy, which is nondiagonal and frequency-dependent. This suggests that the MPn energy differences define an alternative diagrammatic expansion of Koopmans-like electron binding energies, which takes into account the perturbation corrections from the off-diagonal elements and frequency dependence of the irreducible self-energy. Our analysis shows that these corrections are included as semireducible and linked disconnected diagrams, respectively, which are also found in a perturbation expansion of the electron binding energies of the equation-of-motion coupled cluster methods. The rate of convergence of the electron binding energies with respect to n and its acceleration by Pade approximants are also discussed. PMID- 26574370 TI - Molecular Excitation Energies from Time-Dependent Density Functional Theory Employing Random-Phase Approximation Hessians with Exact Exchange. AB - Molecular excitation energies have been calculated with time-dependent density functional theory (TDDFT) using random-phase approximation Hessians augmented with exact exchange contributions in various orders. It has been observed that this approach yields fairly accurate local valence excitations if combined with accurate asymptotically corrected exchange-correlation potentials used in the ground-state Kohn-Sham calculations. The inclusion of long-range particle particle with hole-hole interactions in the kernel leads to errors of 0.14 eV only for the lowest excitations of a selection of three alkene, three carbonyl, and five azabenzene molecules, thus surpassing the accuracy of a number of common TDDFT and even some wave function correlation methods. In the case of long-range charge-transfer excitations, the method typically underestimates accurate reference excitation energies by 8% on average, which is better than with standard hybrid-GGA functionals but worse compared to range-separated functional approximations. PMID- 26574371 TI - The Self-Association of Graphane Is Driven by London Dispersion and Enhanced Orbital Interactions. AB - We investigated the nature of the cohesive energy between graphane sheets via multiple CH...HC interactions, using density functional theory (DFT) including dispersion correction (Grimme's D3 approach) computations of [n]graphane sigma dimers (n = 6-73). For comparison, we also evaluated the binding between graphene sheets that display prototypical pi/pi interactions. The results were analyzed using the block-localized wave function (BLW) method, which is a variant of ab initio valence bond (VB) theory. BLW interprets the intermolecular interactions in terms of frozen interaction energy (DeltaE(F)) composed of electrostatic and Pauli repulsion interactions, polarization (DeltaE(pol)), charge-transfer interaction (DeltaE(CT)), and dispersion effects (DeltaE(disp)). The BLW analysis reveals that the cohesive energy between graphane sheets is dominated by two stabilizing effects, namely intermolecular London dispersion and two-way charge transfer energy due to the sigma(CH) -> sigma*(HC) interactions. The shift of the electron density around the nonpolar covalent C-H bonds involved in the intermolecular interaction decreases the C-H bond lengths uniformly by 0.001 A. The DeltaE(CT) term, which accounts for ~15% of the total binding energy, results in the accumulation of electron density in the interface area between two layers. This accumulated electron density thus acts as an electronic "glue" for the graphane layers and constitutes an important driving force in the self association and stability of graphane under ambient conditions. Similarly, the "double faced adhesive tape" style of charge transfer interactions was also observed among graphene sheets in which it accounts for ~18% of the total binding energy. The binding energy between graphane sheets is additive and can be expressed as a sum of CH...HC interactions, or as a function of the number of C-H bonds. PMID- 26574372 TI - Permutationally Invariant Fitting of Many-Body, Non-covalent Interactions with Application to Three-Body Methane-Water-Water. AB - A modified, computationally efficient method to provide permutationally invariant polynomial bases for molecular energy surface fitting via monomial symmetrization (Xie Z.; Bowman J. M. J. Chem. Theory Comput. 2010, 6, 26-34) is reported for applications to complex systems, characterized by many-body, non-covalent interactions. Two approaches, each able to ensure the asymptotic zero-interaction limit of intrinsic potentials, are presented. They are both based on the tailored selection of a subset of the polynomials of the original basis. A computationally efficient approach exploits reduced permutational invariance and provides a compact fitting basis dependent only on intermolecular distances. We apply the original and new techniques to obtain a number of full-dimensional potentials for the intrinsic three-body methane-water-water interaction by fitting a database made of 22,592 ab initio energies calculated at the MP2-F12 level of theory with haTZ (aug-cc-pVTZ for C and O, cc-pVTZ for H) basis set. An investigation of the effects of permutational symmetry on fitting accuracy and computational costs is reported. Several of the fitted potentials are then employed to evaluate with high accuracy the three-body contribution to the CH4-H2O-H2O binding energy and the three-body energy of three conformers of the CH4@(H2O)20 cluster. PMID- 26574373 TI - MP2[V]--A Simple Approximation to Second-Order Moller-Plesset Perturbation Theory. AB - We propose a simplified variant of the dual-basis MP2[K] scheme [ J. Chem. Phys. 2011, 134, 081103] that bootstraps a small-basis MP2 result to a large-basis one. This simplified method, which we call MP2[V], assumes the occupied orbitals are adequately described by the smaller basis, and, therefore, only the relaxation of the virtual orbitals is considered when shifting to the larger basis. Numerical tests on several organic reactions and noncovalent interactions show that MP2[V] yields absolute and relative energies that are in excellent agreement with the conventional large-basis MP2 calculations but in a small fraction of the time. PMID- 26574374 TI - Systematic Parameterization of Monovalent Ions Employing the Nonbonded Model. AB - Monovalent ions play fundamental roles in many biological processes in organisms. Modeling these ions in molecular simulations continues to be a challenging problem. The 12-6 Lennard-Jones (LJ) nonbonded model is widely used to model monovalent ions in classical molecular dynamics simulations. A lot of parameterization efforts have been reported for these ions with a number of experimental end points. However, some reported parameter sets do not have a good balance between the two Lennard-Jones parameters (the van der Waals (VDW) radius and potential well depth), which affects their transferability. In the present work, via the use of a noble gas curve we fitted in former work (J. Chem. Theory Comput. 2013, 9, 2733), we reoptimized the 12-6 LJ parameters for 15 monovalent ions (11 positive and 4 negative ions) for three extensively used water models (TIP3P, SPC/E, and TIP4P(EW)). Since the 12-6 LJ nonbonded model performs poorly in some instances for these ions, we have also parameterized the 12-6-4 LJ-type nonbonded model (J. Chem. Theory Comput. 2014, 10, 289) using the same three water models. The three derived parameter sets focused on reproducing the hydration free energies (the HFE set) and the ion-oxygen distance (the IOD set) using the 12-6 LJ nonbonded model and the 12-6-4 LJ-type nonbonded model (the 12 6-4 set) overall give improved results. In particular, the final parameter sets showed better agreement with quantum mechanically calculated VDW radii and improved transferability to ion-pair solutions when compared to previous parameter sets. PMID- 26574375 TI - Charge Transfer Models of Zinc and Magnesium in Water. AB - Quantum mechanical studies point to the importance of polarization and charge transfer (CT) in zinc binding. A new CT force field is used to study these effects in ion-water dimers and in aqueous solution. Quantum mechanics calculations are carried out to determine amounts of CT. Models for zinc and magnesium are parametrized to reproduce solvation structure, hydration free energy, and CT properties. The new models are subjected to energy decomposition, in which the effects of polarization and CT are investigated. The importance of these multibody interactions in the liquid is also considered. We find that, for divalent cations, polarization and charge transfer both strongly affect binding to water. Though polarization increases the internal (self) energy of water and ions, this is more than compensated for by a stronger ion-water interaction energy. The direction of the charge transfer from the water to the cation weakens the ion-water interaction; this increase in energy is counteracted by a decrease in the system energy due to electron delocalization. PMID- 26574376 TI - First-Principles Investigation of Strong Excitonic Effects in Oxygen 1s X-ray Absorption Spectra. AB - We calculated the oxygen 1s X-ray absorption spectra (XAS) of acetone and acetic acid molecules in vacuum by utilizing the first-principles GW+Bethe-Salpeter method with an all-electron mixed basis. The calculated excitation energies show good agreement with the available experimental data without an artificial shift. The remaining error, which is less than 1% or 2-5 eV, is a significant improvement from those of time-dependent (TD) density functional methods (5% error or 27-29 eV for TD-LDA and 2.4-2.8% error or 13-15 eV for TD-B3LYP). Our method reproduces the first and second isolated peaks and broad peaks at higher photon energies, corresponding to Rydberg excitations. We observed a failure of the one-particle picture (or independent particle approximation) from our assignment of the five lowest exciton peaks and significant excitonic or state hybridization effects inherent in the core electron excitations. PMID- 26574377 TI - Polarizable QM/MM Multiconfiguration Self-Consistent Field Approach with State Specific Corrections: Environment Effects on Cytosine Absorption Spectrum. AB - We present the formulation and implementation of a polarizable quantum mechanics/molecular mechanics (QM/MM) strategy to describe environment effects in multiconfiguration self-consistent field calculations. The strategy is applied to the calculation of the vertical absorption spectrum of cytosine in water. In our approach, mutual polarization of the solute and the solvent is solved self consistently at the complete-active-space self-consistent-field (CASSCF) level, and the resulting set of charges and dipoles is used to calculate vertical excitation energies using the complete-active-space second-order perturbative (CASPT2) approach and its multistate (MS-CASPT2) variant. In order to treat multiple excited states, we converge the solvent polarization with respect to the state-averaged density of the solute. In order to obtain the final energies, however, we introduce a state-specific correction, where the solvent polarization is recomputed with the density of each state, and demonstrate that this correction brings the excitation energies closer to the values obtained with state-optimized orbitals. Comparison with PCM and nonpolarizable QM/MM calculations shows the importance of specific solute-solvent interactions and environment polarization in describing experiments. Overall, the calculated excitations for the pi -> pi* states in water show good agreement with the experimental spectrum, whereas the n -> pi* appear at energies above 6 eV, approximately 1 eV higher than in the gas phase. Beyond solvents, the new method will allow studying the impact of heterogeneous biological environments in multiple excited states, as well as the treatment of multichromophoric systems where charge transfer and exciton states play important roles. PMID- 26574378 TI - 1H Chemical Shifts in Paramagnetic Co(II) Pyrazolylborate Complexes: A First Principles Study. AB - We apply the theory of the nuclear magnetic resonance (NMR) chemical shift for paramagnetic systems to demanding cobalt(II) complexes. Paramagnetic NMR (pNMR) chemical shift results by density-functional theory (DFT) can be very far from the experimental values. Therefore, it is of interest to investigate the applicability of electron-correlated ab initio computational methods to achieve useful accuracy. Here, we use ab initio wave function based electronic structure methods to calculate the pNMR chemical shift within the theoretical framework established recently. We applied the N-electron valence-state perturbation theory (NEVPT2) on three Co(II) systems, where the active space of the underlying complete active space self-consistent field (CASSCF) wave function consists of seven electrons in the five metal 3d orbitals. These complexes have the S = 3/2 electronic ground state consisting of two doublets separated by zero-field splitting (ZFS). To calculate the hyperfine coupling tensor A, DFT was used, while the g- and ZFS-tensors were calculated using the ab initio CASSCF and NEVPT2 methods. These results were combined to obtain the total chemical shifts. The shifts obtained from these calculations are in generally good agreement with the experimental results, in some cases suggesting a reassignment of the signals. The accuracy of this mixed ab initio/DFT approach is very promising for further applications to demanding pNMR problems involving transition metals. PMID- 26574379 TI - Probing the Locality of Excited States with Linear Algebra. AB - This article reports a novel theoretical approach related to the analysis of molecular excited states. The strategy introduced here involves gathering two pieces of physical information, coming from Hilbert and direct space operations, into a general, unique quantum mechanical descriptor of electronic transitions' locality. Moreover, the projection of Hilbert and direct space-derived indices in an Argand plane delivers a straightforward way to visually probe the ability of a dye to undergo a long- or short-range charge-transfer. This information can be applied, for instance, to the analysis of the electronic response of families of dyes to light absorption by unveiling the trend of a given push-pull chromophore to increase the electronic cloud polarization magnitude of its main transition with respect to the size extension of its conjugated spacer. We finally demonstrate that all the quantities reported in this article can be reliably approximated by a linear algebraic derivation, based on the contraction of detachment/attachment density matrices from canonical to atomic space. This alternative derivation has the remarkable advantage of a very low computational cost with respect to the previously used numerical integrations, making fast and accurate characterization of large molecular systems' excited states easily affordable. PMID- 26574380 TI - Tuning Range-Separated Density Functional Theory for Photocatalytic Water Splitting Systems. AB - We discuss the system-specific optimization of long-range-separated density functional theory (DFT) for the prediction of electronic properties relevant for a photocatalytic cycle based on an Ir(III) photosensitizer (IrPS). Special attention is paid to the charge-transfer properties, which are of key importance for the photoexcitation dynamics but cannot be correctly described by means of conventional DFT. The optimization of the range-separation parameter using the DeltaSCF method is discussed for IrPS including its derivatives and complexes with electron donors and acceptors used in photocatalytic hydrogen production. Particular attention is paid to the problems arising for a description of medium effects by means of a polarizable continuum model. PMID- 26574381 TI - Excitons in Organics Using Time-Dependent Density Functional Theory: PPV, Pentacene, and Picene. AB - We apply the bootstrap kernel within time-dependent density functional theory to study the one-dimensional chain of polymer polyphenylenevinylene and molecular crystals of picene and pentacene. The absorption spectra of poly(p phenylenevinylene) has a bound excitonic peak that is well-reproduced. Pentacene and picene, electronically similar materials, have remarkably different excitonic physics, and this difference is also well captured. We show that the inclusion of local-field effects dramatically changes the spectra of both picene and pentacene but not for poly(p-phenylenevinylene). PMID- 26574382 TI - Proton Dynamics on Goethite Nanoparticles and Coupling to Electron Transport. AB - The surface chemistry of metal oxide particles is governed by the charge that develops at the interface with aqueous solution. Mineral transformation, biogeochemical reactions, remediation, and sorption dynamics are profoundly affected in response. Here we report implementation of replica-exchange constant pH molecular dynamics simulations that use classical molecular dynamics for exploring configurational space and Metropolis Monte Carlo walking through protonation space with a simulated annealing escape route from metastable configurations. By examining the archetypal metal oxide, goethite (alpha-FeOOH), we find that electrostatic potential gradients spontaneously arise between intersecting low-index crystal faces and across explicitly treated oxide nanoparticles at a magnitude exceeding the Johnson-Nyquist voltage fluctuation. Fluctuations in adsorbed proton density continuously repolarize the surface potential bias between edge-sharing crystal faces, at a rate slower than the reported electron-polaron hopping rate in goethite interiors. This suggests that these spontaneous surface potential fluctuations will control the net movement of charge carriers in the lattice. PMID- 26574383 TI - Time Recovery for a Complex Process Using Accelerated Dynamics. AB - The hyperdynamics method (HD) developed by Voter (J. Chem. Phys. 1996, 106, 4665) sets the theoretical basis to construct an accelerated simulation scheme that holds the time scale information. Since HD is based on transition state theory, pseudoequilibrium conditions (PEC) must be satisfied before any system in a trapped state may be accelerated. As the system evolves, many trapped states may appear, and the PEC must be assumed in each one to accelerate the escape. However, since the system evolution is a priori unknown, the PEC cannot be permanently assumed to be true. Furthermore, the different parameters of the bias function used may need drastic recalibration during this evolution. To overcome these problems, we present a general scheme to switch between HD and conventional molecular dynamics (MD) in an automatic fashion during the simulation. To decide when HD should start and finish, criteria based on the energetic properties of the system are introduced. On the other hand, a very simple bias function is proposed, leading to a straightforward on-the-fly set up of the required parameters. A way to measure the quality of the simulation is suggested. The efficiency of the present hybrid HD-MD method is tested for a two-dimensional model potential and for the coalescence process of two nanoparticles. In spite of the important complexity of the latter system (165 degrees of freedoms), some relevant mechanistic properties were recovered within the present method. PMID- 26574384 TI - Hydration of Two Cisplatin Aqua-Derivatives Studied by Quantum Mechanics and Molecular Dynamics Simulations. AB - The hydration of the cisplatin aqua-derivatives, cis-[PtCl(H2O)(NH3)2](+) (w cisplatin) and cis-[Pt(H2O)2(NH3)2](2+) (w2-cisplatin), has been studied by means of classical molecular dynamics simulations. The new platinum complex-water interaction potential, w-cisplatin-W, has been built on the basis of the already obtained cisplatin-water interaction potential (cisplatin-W) [J. Chem. Theory Comput. 2013 9, 4562]. That potential has been then transferred to the w2 cisplatin-W potential. The w-cisplatin and w2-cisplatin atomic charges were specifically derived from their solute's wave functions. Bulk solvent effects on the complex-water interactions have been included by means of a continuum model. Classical MD simulations with 1 platinum complex and 1000 SPC/E water molecules have been carried out. Angle-solved radial distribution functions and spatial distribution functions have been used to provide detailed pictures of the local hydration structure around the ligands (water, chloride, and ammine) and the axial region. A novel definition of a multisite cavity has been employed to compute the hydration number of complexes in order to provide a consistent definition of their first-hydration shell. Interestingly, the hydration number decreases with the increase of the complex net charge from 27 for cisplatin to 23 and 18 for w-cisplatin and w2-cisplatin, respectively. In parallel to this hydration number behavior, the compactness of the hydration shell increases when going from the neutral complex, i.e. cisplatin, to the doubly charged complex, w2 cisplatin. Quantum mechanics estimation of the hydration energies for the platinum complexes allows the computation of the reaction energy for the first- and second-hydrolysis of cisplatin in water. The agreement with experimental data is satisfactory. PMID- 26574385 TI - Chemical Potentials, Activity Coefficients, and Solubility in Aqueous NaCl Solutions: Prediction by Polarizable Force Fields. AB - We describe a computationally efficient molecular simulation methodology for calculating the concentration dependence of the chemical potentials of both solute and solvent in aqueous electrolyte solutions, based on simulations of the salt chemical potential alone. We use our approach to study the predictions for aqueous NaCl solutions at ambient conditions of these properties by the recently developed polarizable force fields (FFs) AH/BK3 of Kiss and Baranyai (J. Chem. Phys. 2013, 138, 204507) and AH/SWM4-DP of Lamoureux and Roux (J. Phys. Chem. B 2006, 110, 3308 - 3322) and by the nonpolarizable JC FF of Joung and Cheatham tailored to SPC/E water (J. Phys. Chem. B 2008, 112, 9020 - 9041). We also consider their predictions of the concentration dependence of the electrolyte activity coefficient, the crystalline solid chemical potential, the electrolyte solubility, and the solution specific volume. We first highlight the disagreement in the literature concerning calculations of solubility by means of molecular simulation in the case of the JC FF and provide strong evidence of the correctness of our methodology based on recent independently obtained results for this important test case. We then compare the predictions of the three FFs with each other and with experiment and draw conclusions concerning their relative merits, with particular emphasis on the salt chemical potential and activity coefficient vs concentration curves and their derivatives. The latter curves have only previously been available from Kirkwood-Buff integrals, which require approximate numerical integrations over system pair correlation functions at each concentration. Unlike the case of the other FFs, the AH/BK3 curves are nearly parallel to the corresponding experimental curves at moderate and higher concentrations. This leads to an excellent prediction of the water chemical potential via the Gibbs-Duhem equation and enables the activity coefficient curve to be brought into excellent agreement with experiment by incorporating an appropriate value of the standard state chemical potential in the Henry Law convention. PMID- 26574386 TI - Solution Properties of Hemicellulose Polysaccharides with Four Common Carbohydrate Force Fields. AB - Hemicellulose polysaccharides play an important role in the swelling behavior of the primary plant cell wall, and molecular dynamics simulations provide the means of gaining a concise understanding of the interactions of hemicellulose polysaccharides with water. Here, we compare four of the main polysaccharide force fields (CHARMM36 TIP3P, GROMOS56A6(CARBO) SPC, GLYCAM06h TIP3P, and GLYCAM06h TIP5P) for the most abundant hemicellulose backbone components. In particular, we compare aggregation, diffusion coefficients, system density, and investigate the free energy of hydration of saccharides in water. We find that the saccharides show nonphysical aggregation at low concentrations with the GLYCAM06h TIP3P force field, which can be rectified by the use of the TIP5P water model. As a result of the aggregation, GLYCAM06h TIP3P does not lead to reasonable diffusion coefficients whereas the diffusion coefficients, as well as the system density, agrees best with experimental data for the GLYCAM06h TIP5P force field. Overall, GLYCAM06h TIP5P gives good agreement with experimental free energy of hydration data for small saccharides. In addition, the free energy of hydration for short polysaccharides calculated with the GLYCAM06h TIP5P force field is consistent with the radial distribution functions between the polysaccharides and water, the hydration number of the polysaccharides, and the hydrogen bonds formed in the system. PMID- 26574387 TI - Evaluating Force Fields for the Computational Prediction of Ionized Arginine and Lysine Side-Chains Partitioning into Lipid Bilayers and Octanol. AB - Abundant peptides and proteins containing arginine (Arg) and lysine (Lys) amino acids can apparently permeate cell membranes with ease. However, the mechanisms by which these peptides and proteins succeed in traversing the free energy barrier imposed by cell membranes remain largely unestablished. Precise thermodynamic studies (both theoretical and experimental) on the interactions of Arg and Lys residues with model lipid bilayers can provide valuable clues to the efficacy of these cationic peptides and proteins. We have carried out molecular dynamics simulations to calculate the interactions of ionized Arg and Lys side chains with the zwitterionic 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) lipid bilayer for 10 widely used lipid/protein force fields: CHARMM36/CHARMM36, SLIPID/AMBER99SB-ILDN, OPLS-AA/OPLS-AA, Berger/OPLS-AA, Berger/GROMOS87, Berger/GROMOS53A6, GROMOS53A6/GROMOS53A6, nonpolarizable MARTINI, polarizable MARTINI, and BMW MARTINI. We performed umbrella sampling simulations to obtain the potential of mean force for Arg and Lys side-chains partitioning from water to the bilayer interior. We found significant differences between the force fields, both for the interactions between side-chains and bilayer surface, as well as the free energy cost for placing the side-chain at the center of the bilayer. These simulation results were compared with the Wimley-White interfacial scale. We also calculated the free energy cost for transferring ionized Arg and Lys side-chains from water to both dry and wet octanol. Our simulations reveal rapid diffusion of water molecules into octanol whereby the equilibrium mole fraction of water in the wet octanol phase was ~25%. Surprisingly, our free energy calculations found that the high water content in wet octanol lowered the water-to-octanol partitioning free energies for cationic residues by only 0.6 to 0.7 kcal/mol. PMID- 26574388 TI - Hybrid Quantum Mechanics/Molecular Mechanics/Coarse Grained Modeling: A Triple Resolution Approach for Biomolecular Systems. AB - We present a hybrid quantum mechanics/molecular mechanics/coarse-grained (QM/MM/CG) multiresolution approach for solvated biomolecular systems. The chemically important active-site region is treated at the QM level. The biomolecular environment is described by an atomistic MM force field, and the solvent is modeled with the CG Martini force field using standard or polarizable (pol-CG) water. Interactions within the QM, MM, and CG regions, and between the QM and MM regions, are treated in the usual manner, whereas the CG-MM and CG-QM interactions are evaluated using the virtual sites approach. The accuracy and efficiency of our implementation is tested for two enzymes, chorismate mutase (CM) and p-hydroxybenzoate hydroxylase (PHBH). In CM, the QM/MM/CG potential energy scans along the reaction coordinate yield reaction energies that are too large, both for the standard and polarizable Martini CG water models, which can be attributed to adverse effects of using large CG water beads. The inclusion of an atomistic MM water layer (10 A for uncharged CG water and 5 A for polarizable CG water) around the QM region improves the energy profiles compared to the reference QM/MM calculations. In analogous QM/MM/CG calculations on PHBH, the use of the pol-CG description for the outer water does not affect the stabilization of the highly charged FADHOOH-pOHB transition state compared to the fully atomistic QM/MM calculations. Detailed performance analysis in a glycine-water model system indicates that computation times for QM energy and gradient evaluations at the density functional level are typically reduced by 40-70% for QM/MM/CG relative to fully atomistic QM/MM calculations. PMID- 26574389 TI - Accuracy of Protein Embedding Potentials: An Analysis in Terms of Electrostatic Potentials. AB - Quantum-mechanical embedding methods have in recent years gained significant interest and may now be applied to predict a wide range of molecular properties calculated at different levels of theory. To reach a high level of accuracy in embedding methods, both the electronic structure model of the active region and the embedding potential need to be of sufficiently high quality. In fact, failures in quantum mechanics/molecular mechanics (QM/MM)-based embedding methods have often been associated with the QM/MM methodology itself; however, in many cases the reason for such failures is due to the use of an inaccurate embedding potential. In this paper, we investigate in detail the quality of the electronic component of embedding potentials designed for calculations on protein biostructures. We show that very accurate explicitly polarizable embedding potentials may be efficiently designed using fragmentation strategies combined with single-fragment ab initio calculations. In fact, due to the self-interaction error in Kohn-Sham density functional theory (KS-DFT), use of large full structure quantum-mechanical calculations based on conventional (hybrid) functionals leads to less accurate embedding potentials than fragment-based approaches. We also find that standard protein force fields yield poor embedding potentials, and it is therefore not advisable to use such force fields in general QM/MM-type calculations of molecular properties other than energies and structures. PMID- 26574390 TI - Protein Simulations in Fluids: Coupling the OPEP Coarse-Grained Force Field with Hydrodynamics. AB - A novel simulation framework that integrates the OPEP coarse-grained (CG) model for proteins with the Lattice Boltzmann (LB) methodology to account for the fluid solvent at mesoscale level is presented. OPEP is a very efficient, water-free and electrostatic-free force field that reproduces at quasi-atomistic detail processes like peptide folding, structural rearrangements, and aggregation dynamics. The LB method is based on the kinetic description of the solvent in order to solve the fluid mechanics under a wide range of conditions, with the further advantage of being highly scalable on parallel architectures. The capabilities of the approach are presented, and it is shown that the strategy is effective in exploring the role of hydrodynamics on protein relaxation and peptide aggregation. The end result is a strategy for modeling systems of thousands of proteins, such as in the case of dense protein suspensions. The future perspectives of the multiscale approach are also discussed. PMID- 26574391 TI - Pushing the Limits of a Molecular Mechanics Force Field To Probe Weak CH...pi Interactions in Proteins. AB - The relationship among biomolecular structure, dynamics, and function is far from being understood, and the role of subtle, weak interactions in stabilizing different conformational states is even less well-known. The cumulative effect of these interactions has broad implications for biomolecular stability and recognition and determines the equilibrium distribution of the ensemble of conformations that are critical for function. Here, we accurately capture the stabilizing effects of weak CH...pi interaction using an empirical molecular mechanics force field in excellent agreement with experiments. We show that the side chain of flanking C-terminal aromatic residues preferentially stabilize the cis isomer of the peptidyl-prolyl bond of the protein backbone through this weak interaction. Cis-trans isomerization of peptidyl-prolyl protein bond plays a pivotal role in many cellular processes, including signal transduction, substrate recognition, and many diseases. Although the cis isomer is relatively less stable than the trans isomer, aromatic side chains of neighboring residues can play a significant role in stabilizing the cis relative to the trans isomer. We carry out extensive regular and accelerated molecular dynamics simulations and establish an approach to simulate the pH profile of the cis/trans ratio in order to probe the stabilizing role of the CH...pi interaction. The results agree very well with NMR experiments, provide detailed atomistic description of this crucial biomolecular interaction, and underscore the importance of weak stabilizing interactions in protein function. PMID- 26574392 TI - Long-Time-Step Molecular Dynamics through Hydrogen Mass Repartitioning. AB - Previous studies have shown that the method of hydrogen mass repartitioning (HMR) is a potentially useful tool for accelerating molecular dynamics (MD) simulations. By repartitioning the mass of heavy atoms into the bonded hydrogen atoms, it is possible to slow the highest-frequency motions of the macromolecule under study, thus allowing the time step of the simulation to be increased by up to a factor of 2. In this communication, we investigate further how this mass repartitioning allows the simulation time step to be increased in a stable fashion without significantly increasing discretization error. To this end, we ran a set of simulations with different time steps and mass distributions on a three-residue peptide to get a comprehensive view of the effect of mass repartitioning and time step increase on a system whose accessible phase space is fully explored in a relatively short amount of time. We next studied a 129 residue protein, hen egg white lysozyme (HEWL), to verify that the observed behavior extends to a larger, more-realistic, system. Results for the protein include structural comparisons from MD trajectories, as well as comparisons of pKa calculations via constant-pH MD. We also calculated a potential of mean force (PMF) of a dihedral rotation for the MTS [(1-oxyl-2,2,5,5-tetramethyl-pyrroline-3 methyl)methanethiosulfonate] spin label via umbrella sampling with a set of regular MD trajectories, as well as a set of mass-repartitioned trajectories with a time step of 4 fs. Since no significant difference in kinetics or thermodynamics is observed by the use of fast HMR trajectories, further evidence is provided that long-time-step HMR MD simulations are a viable tool for accelerating MD simulations for molecules of biochemical interest. PMID- 26574393 TI - MTS-MD of Biomolecules Steered with 3D-RISM-KH Mean Solvation Forces Accelerated with Generalized Solvation Force Extrapolation. AB - We developed a generalized solvation force extrapolation (GSFE) approach to speed up multiple time step molecular dynamics (MTS-MD) of biomolecules steered with mean solvation forces obtained from the 3D-RISM-KH molecular theory of solvation (three-dimensional reference interaction site model with the Kovalenko-Hirata closure). GSFE is based on a set of techniques including the non-Eckart-like transformation of coordinate space separately for each solute atom, extension of the force-coordinate pair basis set followed by selection of the best subset, balancing the normal equations by modified least-squares minimization of deviations, and incremental increase of outer time step in motion integration. Mean solvation forces acting on the biomolecule atoms in conformations at successive inner time steps are extrapolated using a relatively small number of best (closest) solute atomic coordinates and corresponding mean solvation forces obtained at previous outer time steps by converging the 3D-RISM-KH integral equations. The MTS-MD evolution steered with GSFE of 3D-RISM-KH mean solvation forces is efficiently stabilized with our optimized isokinetic Nose-Hoover chain (OIN) thermostat. We validated the hybrid MTS-MD/OIN/GSFE/3D-RISM-KH integrator on solvated organic and biomolecules of different stiffness and complexity: asphaltene dimer in toluene solvent, hydrated alanine dipeptide, miniprotein 1L2Y, and protein G. The GSFE accuracy and the OIN efficiency allowed us to enlarge outer time steps up to huge values of 1-4 ps while accurately reproducing conformational properties. Quasidynamics steered with 3D-RISM-KH mean solvation forces achieves time scale compression of conformational changes coupled with solvent exchange, resulting in further significant acceleration of protein conformational sampling with respect to real time dynamics. Overall, this provided a 50- to 1000-fold effective speedup of conformational sampling for these systems, compared to conventional MD with explicit solvent. We have been able to fold the miniprotein from a fully denatured, extended state in about 60 ns of quasidynamics steered with 3D-RISM-KH mean solvation forces, compared to the average physical folding time of 4-9 MUs observed in experiment. PMID- 26574394 TI - Bias-Exchange Metadynamics Simulations: An Efficient Strategy for the Analysis of Conduction and Selectivity in Ion Channels. AB - Conduction through ion channels possesses two interesting features: (i) different ionic species are selected with high-selectivity and (ii) ions travel across the channel with rates approaching free-diffusion. Molecular dynamics simulations have the potential to reveal how these processes take place at the atomic level. However, analysis of conduction and selectivity at atomistic detail is still hampered by the short time scales accessible by computer simulations. Several algorithms have been developed to "accelerate" sampling along the slow degrees of freedom of the process under study and thus to probe longer time scales. In these algorithms, the slow degrees of freedom need to be defined in advance, which is a well-known shortcoming. In the particular case of ion conduction, preliminary assumptions about the number and type of ions participating in the permeation process need to be made. In this study, a novel approach for the analysis of conduction and selectivity based on bias-exchange metadynamics simulations was tested. This approach was compared with umbrella sampling simulations, using a model of a Na(+)-selective channel. Analogous conclusions resulted from both techniques, but the computational cost of bias-exchange simulations was lower. In addition, with bias-exchange metadynamics it was possible to calculate free energy profiles in the presence of a variable number and type of permeating ions. This approach might facilitate the definition of the set of collective variables required to analyze conduction and selectivity in ion channels. PMID- 26574396 TI - Significant Refinement of Protein Structure Models Using a Residue-Specific Force Field. AB - An important application of all-atom explicit-solvent molecular dynamics (MD) simulations is the refinement of protein structures from low-resolution experiments or template-based modeling. A critical requirement is that the native structure is stable with the force field. We have applied a recently developed residue-specific force field, RSFF1, to a set of 30 refinement targets from recent CASP experiments. Starting from their experimental structures, 1.0 MUs unrestrained simulations at 298 K retain most of the native structures quite well except for a few flexible terminals and long internal loops. Starting from each homology model, a 150 ns MD simulation at 380 K generates the best RMSD improvement of 0.85 A on average. The structural improvements roughly correlate with the RMSD of the initial homology models, indicating possible consistent structure refinement. Finally, targets TR614 and TR624 have been subjected to long-time replica-exchange MD simulations. Significant structural improvements are generated, with RMSD of 1.91 and 1.36 A with respect to their crystal structures. Thus, it is possible to achieve realistic refinement of protein structure models to near-experimental accuracy, using accurate force field with sufficient conformational sampling. PMID- 26574395 TI - Identification of Mutational Hot Spots for Substrate Diffusion: Application to Myoglobin. AB - The pathways by which small molecules (substrates or inhibitors) access active sites are a key aspect of the function of enzymes and other proteins. A key problem in designing or altering such proteins is to identify sites for mutation that will have the desired effect on the substrate transport properties. While specific access channels have been invoked in the past, molecular simulations suggest that multiple routes are possible, complicating the analysis. This complexity, however, can be captured by a Markov State Model (MSM) of the ligand diffusion process. We have developed a sensitivity analysis of the resulting rate matrix, which identifies the locations where mutations should have the largest effect on the diffusive on rate. We apply this method to myoglobin, which is the best characterized example both from experiment and simulation. We validate the approach by translating the sensitivity parameter obtained from this method into the CO binding rates in myoglobin upon mutation, resulting in a semi-quantitative correlation with experiments. The model is further validated against an explicit simulation for one of the experimental mutants. PMID- 26574397 TI - Efficient Handling of Molecular Flexibility in Ab Initio Generation of Crystal Structures. AB - A key step in many approaches to crystal structure prediction (CSP) is the initial generation of large numbers of candidate crystal structures via the exploration of the lattice energy surface. By using a relatively simple lattice energy approximation, this global search step aims to identify, in a computationally tractable manner, a limited number of likely candidate structures for further refinement using more detailed models. This paper presents an effective and efficient approach to modeling the effects of molecular flexibility during this initial global search. Local approximate models (LAMs), constructed via quantum mechanical (QM) calculations, are used to model the conformational energy, molecular geometry, and atomic charge distributions as functions of a subset of the conformational degrees of freedom (e.g., flexible torsion angles). The effectiveness of the new algorithm is demonstrated via its application to the recently studied 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile (ROY) molecule and to two molecules, beta-D-glucose and 1-(4-benzoylpiperazin-1-yl)-2 (4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione, a Bristol Myers Squibb molecule referenced as BMS-488043. All three molecules present significant challenges due to their high degree of flexibility. PMID- 26574398 TI - Probing Potential Energy Surface Exploration Strategies for Complex Systems. AB - The efficiency of minimum-energy configuration searching algorithms is closely linked to the energy landscape structure of complex systems, yet these algorithms often include a number of steps of which the effect is not always clear. Decoupling these steps and their impacts can allow us to better understand both their role and the nature of complex energy landscape. Here, we consider a family of minimum-energy algorithms based, directly or indirectly, on the well-known Bell-Evans-Polanyi (BEP) principle. Comparing trajectories generated with BEP based algorithms to kinetically correct off-lattice kinetic Monte Carlo schemes allow us to confirm that the BEP principle does not hold for complex systems since forward and reverse energy barriers are completely uncorrelated. As would be expected, following the lowest available energy barrier leads to rapid trapping. This is why BEP-based methods require also a direct handling of visited basins or barriers. Comparing the efficiency of these methods with a thermodynamical handling of low-energy barriers, we show that most of the efficiency of the BEP-like methods lie first and foremost in the basin management rather than in the BEP-like step. PMID- 26574399 TI - Correction to Balanced Protein-Water Interactions Improve Properties of Disordered Proteins and Non-Specific Protein Association. PMID- 26574400 TI - CAR T-cells merge into the fast lane of cancer care. AB - Chimeric antigen receptors (CARs) can be introduced into T-cells redirecting them to target specific tumor antigens. CAR-modified T cells targeting CD19 have shown remarkable activity against CD19+ malignancies including B cell acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), and non-Hodgkin lymphomas (NHL). Complete remission rates as high as 90% have been observed for patients with relapsed and refractory ALL and greater than 50% response rates have been seen in heavily pre-treated CLL and NHL. Excitingly, some remissions have been durable without any additional therapy, a finding which correlates with in-vivo T cell persistence and B-cell aplasia. The major treatment related toxicities include B-cell aplasia, neurologic toxicities, and a potentially severe cytokine release syndrome. This review summarizes outcomes for patients treated with CD19 CAR T-cells while exploring the field's challenges and future directions. PMID- 26574401 TI - Cold plasma welding of polyaniline nanofibers with enhanced electrical and mechanical properties. AB - Joining conducting polymer (CP) nanofibers into an interconnected porous network can result in good mechanical and electrical contacts between nanofibers that can be beneficial for the high performance of CP-based devices. Here, we demonstrate the cold welding of polyaniline (PAni) nanofiber loose ends with cold plasma. The room-temperature and atmospheric-pressure helium micro-plasma jet launches highly charged ion bullets at a PAni nanofiber target with high precision and the highly charged ion bullet selectively induces field emission at the sharp nanofiber loose ends. This technique joins nanofiber tips without altering the morphology of the film and protonation thus leading to significantly enhanced electrical and mechanical properties. In addition, this technique has high spatial resolution and is able to selectively weld and dope regions of nanofiber film with promising novel device applications. PMID- 26574402 TI - Three-Electron Bond Valence-Bond Structures for the Ditetracyanoethylene Dianion. AB - Using valence-bond structures of the types A . B and A?B or A-B to represent diatomic three-electron bonds, two types of valence-bond structures are constructed for the cyclic 6-electron 4-center bonding unit that is present in the ditetracyanoethylene dianion. These latter valence-bond structures, which are obtained by singlet spin-pairing the antibonding electrons of two three-electron bonds, are examples of increased-valence structures. It is shown that increased valence structures that use the A . B three-electron bond structure, which relate easily to their component Lewis structures, should be preferred to those that involve the A?B or A-B three-electron bond structures. STO-6G weights are reported for the two 6-electron 4-center increased-valence structures for the [C2]2(2-) component of the ditetracyanoethylene dianion. PMID- 26574403 TI - Effects of Polarizable Solvent Models upon the Relative Stability of an alpha Helical and a beta-Hairpin Structure of an Alanine Decapeptide. AB - The free enthalpy of changing a nonpolarizable solvent into a polarizable solvent is calculated for an alanine decapeptide solvated in water, methanol, chloroform, or carbon tetrachloride. Introducing polarizability into a water solvent does not change the relative stability between the alpha-helix and the beta-hairpin, while for methanol and chloroform the alpha-helix is stabilized by about 1 kJ mol(-1) per residue and for carbon tetrachloride by about 2 kJ mol(-1) per residue. These results suggest that the less polar the solvent is, the more the alpha-helical structure is stabilized with respect to the beta-hairpin structure by the use of a polarizable solvent model instead of a nonpolarizable one. This highlights that inclusion of polarizability in models for less polar and nonpolar solvents or protein environments is as important as, if not more important than, including polarizability in models for liquid water. PMID- 26574405 TI - Well-Tempered Variational Approach to Enhanced Sampling. AB - We propose a simple yet effective iterative scheme that allows us to employ the well-tempered distribution as a target distribution for the collective variables in our recently introduced variational approach to enhanced sampling and free energy calculations [ Valsson and Parrinello Phys. Rev. Lett. 2014 , 113 , 090601 ]. The performance of the scheme is evaluated for the three-dimensional free energy surface of alanine tetrapeptide where the convergence can be rather poor when employing the uniform target distribution. Using the well-tempered target distribution on the other hand results in a significant improvement in convergence. The results observed in this paper indicate that the well-tempered distribution is in most cases the preferred and recommended choice for the target distribution in the variational approach. PMID- 26574404 TI - Quantum Dynamics in an Explicit Solvent Environment: A Photochemical Bond Cleavage Treated with a Combined QD/MD Approach. AB - In quantum chemistry methods to describe environmental effects on different levels of complexity are available in the common program packages. Electrostatic effects of a solvent for example can be included in an implicit or explicit way. For chemical reactions with large structural changes additional mechanical effects come into play. Their treatment within a quantum dynamical context is a major challenge, especially when excited states are involved. Recently, we introduced a method that realizes an implicit description. Here, we present an approach combining quantum dynamics and molecular dynamics. It explicitly incorporates the solvent environment, whereby the electrostatic as well as the dynamic effects are captured. This new method is demonstrated for the ultrafast photoinduced bond cleavage of diphenylmethylphosphonium ions (Ph2CH-PPh3(+)), a common precursor to generate reactive carbocations in solution. PMID- 26574406 TI - Analysis of Different Fragmentation Strategies on a Variety of Large Peptides: Implementation of a Low Level of Theory in Fragment-Based Methods Can Be a Crucial Factor. AB - We have investigated the performance of two classes of fragmentation methods developed in our group (Molecules-in-Molecules (MIM) and Many-Overlapping-Body (MOB) expansion), to reproduce the unfragmented MP2 energies on a test set composed of 10 small to large biomolecules. They have also been assessed to recover the relative energies of different motifs of the acetyl(ala)18NH2 system. Performance of different bond-cutting environments and the use of Hartree-Fock and different density functionals (as a low level of theory) in conjunction with the fragmentation strategies have been analyzed. Our investigation shows that while a low level of theory (for recovering long-range interactions) may not be necessary for small peptides, it provides a very effective strategy to accurately reproduce the total and relative energies of larger peptides such as the different motifs of the acetyl(ala)18NH2 system. Employing M06-2X as the low level of theory, the calculated mean total energy deviation (maximum deviation) in the total MP2 energies for the 10 molecules in the test set at MIM(d=3.5A), MIM(eta=9), and MOB(d=5A) are 1.16 (2.31), 0.72 (1.87), and 0.43 (2.02) kcal/mol, respectively. The excellent performance suggests that such fragment-based methods should be of general use for the computation of accurate energies of large biomolecular systems. PMID- 26574407 TI - BALOO: A Fast and Versatile Code for Accurate Multireference Variational/Perturbative Calculations. AB - We present the new BALOO package for performing multireference variational/perturbative computations for medium- to large-size systems. To this end we have introduced a number of conceptual and technical improvements including full parallelization of the code, use and manipulation of a large panel of reference orbitals, implementation of diagrammatic perturbation treatment, and computation of properties by density matrix perturbed to the first-order. A number of test cases are analyzed with special reference to electronic transitions and magnetic properties to show the versatility, effectiveness, and accuracy of BALOO. PMID- 26574408 TI - Do Practical Standard Coupled Cluster Calculations Agree Better than Kohn-Sham Calculations with Currently Available Functionals When Compared to the Best Available Experimental Data for Dissociation Energies of Bonds to 3d Transition Metals? AB - Coupled-cluster (CC) methods have been extensively used as the high-level approach in quantum electronic structure theory to predict various properties of molecules when experimental results are unavailable. It is often assumed that CC methods, if they include at least up to connected-triple-excitation quasiperturbative corrections to a full treatment of single and double excitations (in particular, CCSD(T)), and a very large basis set, are more accurate than Kohn-Sham (KS) density functional theory (DFT). In the present work, we tested and compared the performance of standard CC and KS methods on bond energy calculations of 20 3d transition metal-containing diatomic molecules against the most reliable experimental data available, as collected in a database called 3dMLBE20. It is found that, although the CCSD(T) and higher levels CC methods have mean unsigned deviations from experiment that are smaller than most exchange-correlation functionals for metal-ligand bond energies of transition metals, the improvement is less than one standard deviation of the mean unsigned deviation. Furthermore, on average, almost half of the 42 exchange-correlation functionals that we tested are closer to experiment than CCSD(T) with the same extended basis set for the same molecule. The results show that, when both relativistic and core-valence correlation effects are considered, even the very high-level (expensive) CC method with single, double, triple, and perturbative quadruple cluster operators, namely, CCSDT(2)Q, averaged over 20 bond energies, gives a mean unsigned deviation (MUD(20) = 4.7 kcal/mol when one correlates only valence, 3p, and 3s electrons of transition metals and only valence electrons of ligands, or 4.6 kcal/mol when one correlates all core electrons except for 1s shells of transition metals, S, and Cl); and that is similar to some good xc functionals (e.g., B97-1 (MUD(20) = 4.5 kcal/mol) and PW6B95 (MUD(20) = 4.9 kcal/mol)) when the same basis set is used. We found that, for both coupled cluster calculations and KS calculations, the T1 diagnostics correlate the errors better than either the M diagnostics or the B1 DFT-based diagnostics. The potential use of practical standard CC methods as a benchmark theory is further confounded by the finding that CC and DFT methods usually have different signs of the error. We conclude that the available experimental data do not provide a justification for using conventional single-reference CC theory calculations to validate or test xc functionals for systems involving 3d transition metals. PMID- 26574409 TI - Construction of the Fock Matrix on a Grid-Based Molecular Orbital Basis Using GPGPUs. AB - We present a GPGPU implementation of the construction of the Fock matrix in the molecular orbital basis using the fully numerical, grid-based bubbles representation. For a test set of molecules containing up to 90 electrons, the total Hartree-Fock energies obtained from reference GTO-based calculations are reproduced within 10(-4) Eh to 10(-8) Eh for most of the molecules studied. Despite the very large number of arithmetic operations involved, the high performance obtained made the calculations possible on a single Nvidia Tesla K40 GPGPU card. PMID- 26574410 TI - Modeling Molecular Systems at Extreme Pressure by an Extension of the Polarizable Continuum Model (PCM) Based on the Symmetry-Adapted Cluster-Configuration Interaction (SAC-CI) Method: Confined Electronic Excited States of Furan as a Test Case. AB - Novel molecular photochemistry can be developed by combining high pressure and laser irradiation. For studying such high-pressure effects on the confined electronic ground and excited states, we extend the PCM (polarizable continuum model) SAC (symmetry-adapted cluster) and SAC-CI (SAC-configuration interaction) methods to the PCM-XP (extreme pressure) framework. By using the PCM-XP SAC/SAC CI method, molecular systems in various electronic states can be confined by polarizable media in a smooth and flexible way. The PCM-XP SAC/SAC-CI method is applied to a furan (C4H4O) molecule in cyclohexane at high pressure (1-60 GPa). The relationship between the calculated free-energy and cavity volume can be approximately represented with the Murnaghan equation of state. The excitation energies of furan in cyclohexane show blueshifts with increasing pressure, and the extents of the blueshifts significantly depend on the character of the excitations. Particularly large confinement effects are found in the Rydberg states. The energy ordering of the lowest Rydberg and valence states alters under high-pressure. The pressure effects on the electronic structure may be classified into two contributions: a confinement of the molecular orbital and a suppression of the mixing between the valence and Rydberg configurations. The valence or Rydberg character in an excited state is, therefore, enhanced under high pressure. PMID- 26574411 TI - Toward Fast and Accurate Evaluation of Charge On-Site Energies and Transfer Integrals in Supramolecular Architectures Using Linear Constrained Density Functional Theory (CDFT)-Based Methods. AB - A fast and accurate scheme has been developed to evaluate two key molecular parameters (on-site energies and transfer integrals) that govern charge transport in organic supramolecular architecture devices. The scheme is based on a constrained density functional theory (CDFT) approach implemented in the linear scaling BigDFT code that exploits a wavelet basis set. The method has been applied to model disordered structures generated by force-field simulations. The role of the environment on the transport parameters has been taken into account by building large clusters around the active molecules involved in the charge transfer. PMID- 26574412 TI - Big Data Meets Quantum Chemistry Approximations: The Delta-Machine Learning Approach. AB - Chemically accurate and comprehensive studies of the virtual space of all possible molecules are severely limited by the computational cost of quantum chemistry. We introduce a composite strategy that adds machine learning corrections to computationally inexpensive approximate legacy quantum methods. After training, highly accurate predictions of enthalpies, free energies, entropies, and electron correlation energies are possible, for significantly larger molecular sets than used for training. For thermochemical properties of up to 16k isomers of C7H10O2 we present numerical evidence that chemical accuracy can be reached. We also predict electron correlation energy in post Hartree-Fock methods, at the computational cost of Hartree-Fock, and we establish a qualitative relationship between molecular entropy and electron correlation. The transferability of our approach is demonstrated, using semiempirical quantum chemistry and machine learning models trained on 1 and 10% of 134k organic molecules, to reproduce enthalpies of all remaining molecules at density functional theory level of accuracy. PMID- 26574413 TI - Multireference Driven Similarity Renormalization Group: A Second-Order Perturbative Analysis. AB - We introduce a multireference version of the driven similarity renormalization group (DSRG) approach [ Evangelista , F. A. J. Chem. Phys. 2014 , 141 , 054109 ] based on a generalized reference wave function and operator normal ordering [ Kutzelnigg , W. ; Mukherjee , D. J. Chem. Phys. 1997 , 107 , 432 ]. We perform a perturbative analysis of the corresponding equations at second order and derive a novel multireference perturbation theory, termed DSRG-MRPT2. The DSRG-MRPT2 energy equation can be written in a simple and compact form and can be solved via a noniterative procedure that requires at most the three-body density cumulant of the reference. Importantly, even at the perturbation level, the multireference DSRG is free from the intruder-state problem. We propose an optimal range of the DSRG flow parameter that consistently yields reliable potential energy curves with minimal nonparallelism error. We find that the DSRG-MRPT2 can describe the potential energy curves of HF and N2, and the singlet-triplet gap of p-benzyne with an accuracy similar to that of other multireference perturbation theories. PMID- 26574414 TI - W2X and W3X-L: Cost-Effective Approximations to W2 and W4 with kJ mol(-1) Accuracy. AB - We have formulated the W2X and W3X-L protocols as cost-effective alternatives to W2 and W3/W4, respectively, and to supplement our previously developed set of W1X and W3X procedures. The W2X procedure provides an accurate approximation to the all-electron scalar-relativistic CCSD(T)/CBS energy, with a mean absolute deviation (MAD) of 0.6 kJ mol(-1) from benchmark energies provided by the CCSD(T) component in the W4 protocol. Such a performance is comparable to that of W2w (0.5 kJ mol(-1)) but comes at a significantly lower cost. Comparison of computational requirements shows that W2X should be applicable to systems that can be treated by the W1w method. Thus, W2X provides an accurate means for the treatment of medium-sized systems such as naphthalene. For the calculation of post-CCSD(T) effects, we propose a slight modification to the method used in our previously devised W3X procedure. Our new W3-type protocol (W3X-L) combines this new post-CCSD(T) treatment with our new W2X procedure. It has an MAD from benchmark values of 0.8 kJ mol(-1) for the W4-11 set, which is comparable to that for the computationally more demanding W3.2 method (0.6 kJ mol(-1)). However, the use of the even relatively modest post-CCSD(T) calculations in W3X-L still represents a computational bottleneck, and this currently restricts its application to systems up to the size of benzene with our current computing resources. PMID- 26574415 TI - Benchmark Structures and Harmonic Vibrational Frequencies Near the CCSD(T) Complete Basis Set Limit for Small Water Clusters: (H2O)n = 2, 3, 4, 5, 6. AB - A series of (H2O)n clusters ranging from the dimer to the hexamer have been characterized with the CCSD(T) and the 2-body:Many-body CCSD(T):MP2 methods near the complete basis set (CBS) limit to generate benchmark-quality optimized structures and harmonic vibrational frequencies for these important systems. Quadruple-zeta correlation-consistent basis sets that augment the O atoms with diffuse functions have been employed in the analytic computation of harmonic vibrational frequencies for the global minima of the dimer, trimer, tetramer, and pentamer as well as the ring, book, cage, and prism isomers of the hexamer. Prior calibration [J. Chem. Phys. 2013, 139, 184113 and J. Chem. Theory Comput. 2014, 10, 5426] suggests that harmonic frequencies computed with this approach will lie within a few cm(-1) of the canonical CCSD(T) CBS limit. These data are used as reference values to gauge the performance of harmonic frequencies obtained with other ab initio methods (e.g., LCCSD(T) and MP2) and water potentials (e.g., TTM3 F and WHBB). This comparison reveals that it is far more challenging to converge harmonic vibrational frequencies for the bound OH stretching modes in these (H2O)n clusters to the CCSD(T) CBS limit than the free OH stretches, the n intramonomer HOH bending modes and even the 6n - 6 intermonomer modes. Deviations associated with the bound OH stretching harmonic frequencies increase rapidly with the size of the cluster for all methods and potentials examined, as do the corresponding frequency shifts relative to the monomer OH stretches. PMID- 26574416 TI - Domain Based Pair Natural Orbital Coupled Cluster Studies on Linear and Folded Alkane Chains. AB - In this study the question of what is the last unbranched alkane that prefers a linear conformation over a folded one is revisited from a theoretical point of view. Geometries have been optimized carefully using the most accurate theoretical approach available to date for such systems, namely, doubly hybrid density functional theory in conjunction with larger quadruple-zeta quality basis sets. The resulting geometries deviate significantly from previously reported ones and have a significant impact on the predicted energetics. Electronic energies were calculated using the efficient and accurate domain local pair natural orbital coupled cluster method with single-, double-, and triple substitutions (DLPNO-CCSD(T)) electronic structure method. Owing to the method's efficiency, we were able to employ up to quadruple-zeta quality basis sets for all hydrocarbons up to C19H40. In conjunction with carefully designed basis set extrapolation techniques, it is estimated that the electronic energies reported in this study deviate less than 1 kJ/mol from the canonical CCSD(T) basis set limit. Thermodynamic corrections were calculated with the PW6B95-D3 functional and the def2-QZVP basis set. Our prediction is that the last linear conformer is either C16H34 or C17H36 with the latter being more probable. C18H38 can be safely ruled out as the most stable isomer at 100 K. These findings are in agreement with the elegant experimental studies of Suhm and co-workers. Deviations between the current and previous theoretical results are analyzed in detail. PMID- 26574417 TI - Computational Lipidomics with insane: A Versatile Tool for Generating Custom Membranes for Molecular Simulations. AB - For simulations of membranes and membrane proteins, the generation of the lipid bilayer is a critical step in the setup of the system. Membranes comprising multiple components pose a particular challenge, because the relative abundances need to be controlled and the equilibration of the system may take several microseconds. Here we present a comprehensive method for building membrane containing systems, characterized by simplicity and versatility. The program uses preset, coarse-grain lipid templates to build the membrane, and also allows on the-fly generation of simple lipid types by specifying the headgroup, linker, and lipid tails on the command line. The resulting models can be equilibrated, after which a relaxed atomistic model can be obtained by reverse transformation. For multicomponent membranes, this provides an efficient means for generating equilibrated atomistic models. The method is called insane, an acronym for INSert membrANE. The program has been made available, together with the complementary method for reverse transformation, at http://cgmartini.nl/ . This work highlights the key features of insane and presents a survey of properties for a large range of lipids as a start of a computational lipidomics project. PMID- 26574418 TI - Reactive Force Field Study of Li/C Systems for Electrical Energy Storage. AB - Graphitic carbon is still the most ubiquitously used anode material in Li-ion batteries. In spite of its ubiquity, there are few theoretical studies that fully capture the energetics and kinetics of Li in graphite and related nanostructures at experimentally relevant length, time-scales, and Li-ion concentrations. In this paper, we describe the development and application of a ReaxFF reactive force field to describe Li interactions in perfect and defective carbon-based materials using atomistic simulations. We develop force field parameters for Li-C systems using van der Waals-corrected density functional theory (DFT). Grand canonical Monte Carlo simulations of Li intercalation in perfect graphite with this new force field not only give a voltage profile in good agreement with known experimental and DFT results but also capture the in-plane Li ordering and interlayer separations for stage I and II compounds. In defective graphite, the ratio of Li/C (i.e., the capacitance increases and voltage shifts) both in proportion to the concentration of vacancy defects and metallic lithium is observed to explain the lithium plating seen in recent experiments. We also demonstrate the robustness of the force field by simulating model carbon nanostructures (i.e., both 0D and 1D structures) that can be potentially used as battery electrode materials. Whereas a 0D defective onion-like carbon facilitates fast charging/discharging rates by surface Li adsorption, a 1D defect-free carbon nanorod requires a critical density of Li for intercalation to occur at the edges. Our force field approach opens the opportunity for studying energetics and kinetics of perfect and defective Li/C structures containing thousands of atoms as a function of intercalation. This is a key step toward modeling of realistic carbon materials for energy applications. PMID- 26574419 TI - High-Dimensional Neural Network Potentials for Organic Reactions and an Improved Training Algorithm. AB - Artificial neural networks (NNs) represent a relatively recent approach for the prediction of molecular potential energies, suitable for simulations of large molecules and long time scales. By using NNs to fit electronic structure data, it is possible to obtain empirical potentials of high accuracy combined with the computational efficiency of conventional force fields. However, as opposed to the latter, changing bonding patterns and unusual coordination geometries can be described due to the underlying flexible functional form of the NNs. One of the most promising approaches in this field is the high-dimensional neural network (HDNN) method, which is especially adapted to the prediction of molecular properties. While HDNNs have been mostly used to model solid state systems and surface interactions, we present here the first application of the HDNN approach to an organic reaction, the Claisen rearrangement of allyl vinyl ether to 4 pentenal. To construct the corresponding HDNN potential, a new training algorithm is introduced. This algorithm is termed "element-decoupled" global extended Kalman filter (ED-GEKF) and is based on the decoupled Kalman filter. Using a metadynamics trajectory computed with density functional theory as reference data, we show that the ED-GEKF exhibits superior performance - both in terms of accuracy and training speed - compared to other variants of the Kalman filter hitherto employed in HDNN training. In addition, the effect of including forces during ED-GEKF training on the resulting potentials was studied. PMID- 26574420 TI - The Importance of Short- and Long-Range Exchange on Various Excited State Properties of DNA Monomers, Stacked Complexes, and Watson-Crick Pairs. AB - We present a detailed analysis of several time-dependent DFT (TD-DFT) methods, including conventional hybrid functionals and two types of nonempirically tuned range-separated functionals, for predicting a diverse set of electronic excitations in DNA nucleobase monomers and dimers. This large and extensive set of excitations comprises a total of 50 different transitions (for each tested DFT functional) that includes several n -> pi and pi -> pi* valence excitations, long range charge-transfer excitations, and extended Rydberg transitions (complete with benchmark calculations from high-level EOM-CCSD(T) methods). The presence of localized valence excitations as well as extreme long-range charge-transfer excitations in these systems poses a serious challenge for TD-DFT methods that allows us to assess the importance of both short- and long-range exchange contributions for simultaneously predicting all of these various transitions. In particular, we find that functionals that do not have both short- and full long range exchange components are unable to predict the different types of nucleobase excitations with the same accuracy. Most importantly, the current study highlights the importance of both short-range exchange and a nonempirically tuned contribution of long-range exchange for accurately predicting the diverse excitations in these challenging nucleobase systems. PMID- 26574421 TI - Transfer of Frequency-Dependent Polarizabilities: A Tool To Simulate Absorption and Circular Dichroism Molecular Spectra. AB - Absorption and circular dichroism spectra reveal important information about molecular geometry and electronic structure. For large molecules, however, spectral shapes cannot be computed directly. In the past, transition dipole coupling (TDC) and related theories were proposed as simplified ways of calculating the spectral responses of large systems. In the present study, an alternative approach better reflecting the chemical structure is explored. It is based on the transfer of complex frequency-dependent polarizabilities (TFDP) of molecular fragments. The electric dipole-electric dipole, electric dipole electric quadrupole, and electric dipole-magnetic dipole polarizabilities are obtained separately for individual chromophores and then transferred to a larger system composed of them. Time-dependent density functional theory and the sum over states methodology were employed to obtain the polarizability tensors of N methylacetamide, and porphyrin molecules were chosen for a numerical test. The TFDP fails for charge-transfer states and close chromophores; otherwise, the results suggest that this method is capable of reproducing the spectra of large systems of biochemical relevance. At the same time, it is sufficiently flexible to account for a wide range of transition energies and environmental factors instrumental in the modeling of chromophore properties. The TFDP approach also removes the need for diagonalization in TDC, making computations of larger molecular systems more time-efficient. PMID- 26574422 TI - Efficient Determination of Relative Entropy Using Combined Temperature and Hamiltonian Replica-Exchange Molecular Dynamics. AB - The performance and accuracy of different simulation schemes for estimating the entropy inferred from free energy calculations are tested. The results obtained from replica-exchange molecular dynamics (REMD) simulations based on a simplified toy model are compared to exact numerically derived ones to assess accuracy and convergence. It is observed that the error in entropy estimation decreases by at least an order of magnitude and the quantities of interest converge much faster when the simulations are coupled via a temperature REMD algorithm and the trajectories from different temperatures are combined. Simulations with the infinite-swapping method and its variants show some improvement over the traditional nearest-neighbor REMD algorithms, but they are more computationally expensive. To test the methodologies further, the free energy profile for the reversible association of two methane molecules in explicit water was calculated and decomposed into its entropic and enthalpic contributions. Finally, a strategy based on umbrella sampling computations carried out via simultaneous temperature and Hamiltonian REMD simulations is shown to yield the most accurate entropy estimation. The entropy profile between the two methane molecules displays the characteristic signature of a hydrophobic interaction. PMID- 26574423 TI - Accurate Calculation of Solvation Free Energies in Supercritical Fluids by Fully Atomistic Simulations: Probing the Theory of Solutions in Energy Representation. AB - Accurate calculation of solvation free energies (SFEs) is a fundamental problem of theoretical chemistry. In this work we perform a careful validation of the theory of solutions in energy representation (ER method) developed by Matubayasi et al. [J. Chem. Phys. 2000, 113, 6070-6081] for SFE calculations in supercritical solvents. This method can be seen as a bridge between the molecular simulations and the classical (not quantum) density functional theory (DFT) formulated in energy representation. We performed extensive calculations of SFEs of organic molecules of different chemical natures in pure supercritical CO2 (sc CO2) and in sc-CO2 with addition of 6 mol % of ethanol, acetone, and n-hexane as cosolvents. We show that the ER method reproduces SFE data calculated by a method free of theoretical approximations (the Bennett's acceptance ratio) with the mean absolute error of only 0.05 kcal/mol. However, the ER method requires by an order less computational resources. Also, we show that the quality of ER calculations should be carefully monitored since the lack of sampling can result into a considerable bias in predictions. The present calculations reproduce the trends in the cosolvent-induced solubility enhancement factors observed in experimental data. Thus, we think that molecular simulations coupled with the ER method can be used for quick calculations of the effect of variation of temperature, pressure, and cosolvent concentration on SFE and hence solubility of bioactive compounds in supercritical fluids. This should dramatically reduce the burden of experimental work on optimizing solvency of supercritical solvents. PMID- 26574424 TI - Aggregation-Induced Emission Mechanism of Dimethoxy-Tetraphenylethylene in Water Solution: Molecular Dynamics and QM/MM Investigations. AB - Molecular dynamics simulations and combined quantum mechanics and molecular mechanics calculations are employed to investigate dimethoxy-tetraphenylethylene (DMO-TPE) molecules in water solution for their detailed aggregation process and the mechanism of aggregation-induced emission. The molecular dynamics simulations show that the aggregates start to appear in the nanosecond time scale, and small molecular aggregates appear at low concentration; whereas the large aggregates with a chain-type structure appear at high concentration, and the intramolecular rotation is largely restricted by a molecular aggregated environment. The average radical distribution demonstrates that the waters join the aggregation process and that two types of hydrogen bonds between DMO-TPE and water molecules are built with the peaks at about 0.5 and 0.7 nm, respectively. The spectral features further reveal that the aggregates dominantly present J-type aggregation although they fluctuate between J-type and H-type at a given temperature. The statistical absorption, emission spectra, and the aggregation-induced emission enhancement with respect to the solution concentration agree well with the experimental measurements, indicating the significant effect of molecular environments on the molecular properties. PMID- 26574425 TI - Reparametrized E3B (Explicit Three-Body) Water Model Using the TIP4P/2005 Model as a Reference. AB - In this study, we present the third version of a water model that explicitly includes three-body interactions. The major difference between this version and the previous two is in the two-body water model we use as a reference potential; here we use the TIP4P/2005 model (previous versions used the TIP4P water model). We alter four parameters from our previous version of the model by fitting to the diffusion coefficient of the ambient liquid, the liquid and ice densities, and the melting point. We evaluate the performance of this version by calculating many other microscopic and thermodynamic static and dynamic properties as a function of temperature and near the critical point and comparing to experiment, the TIP4P/2005 model and the previous version of our three-body model. PMID- 26574426 TI - High-Throughput Simulations of Dimer and Trimer Assembly of Membrane Proteins. The DAFT Approach. AB - Interactions between membrane proteins are of great biological significance and are consequently an important target for pharmacological intervention. Unfortunately, it is still difficult to obtain detailed views on such interactions, both experimentally, where the environment hampers atomic resolution investigation, and computationally, where the time and length scales are problematic. Coarse grain simulations have alleviated the later issue, but the slow movement through the bilayer, coupled to the long life times of nonoptimal dimers, still stands in the way of characterizing binding distributions. In this work, we present DAFT, a Docking Assay For Transmembrane components, developed to identify preferred binding orientations. The method builds on a program developed recently for generating custom membranes, called insane (INSert membrANE). The key feature of DAFT is the setup of starting structures, for which optimal periodic boundary conditions are devised. The purpose of DAFT is to perform a large number of simulations with different components, starting from unbiased noninteracting initial states, such that the simulations evolve collectively, in a manner reflecting the underlying energy landscape of interaction. The implementation and characteristic features of DAFT are explained, and the efficacy and relaxation properties of the method are explored for oligomerization of glycophorin A dimers, polyleucine dimers and trimers, MS1 trimers, and rhodopsin dimers. The results suggest that, for simple helices, such as GpA and polyleucine, in POPC/DOPC membranes series of 500 simulations of 500 ns each allow characterization of the helix dimer orientations and allow comparing associating and nonassociating components. However, the results also demonstrate that short simulations may suffer significantly from nonconvergence of the ensemble and that using too few simulations may obscure or distort features of the interaction distribution. For trimers, simulation times exceeding several microseconds appear needed, due to the increased complexity. Similarly, characterization of larger proteins, such as rhodopsin, takes longer time scales due to the slower diffusion and the increased complexity of binding interfaces. DAFT and its auxiliary programs have been made available from http://cgmartini.nl/ , together with a working example. PMID- 26574428 TI - Molecular Modeling of Triton X Micelles: Force Field Parameters, Self-Assembly, and Partition Equilibria. AB - Nonionic surfactants of the Triton X-series find various applications in extraction processes and as solubilizing agents for the purification of membrane proteins. However, so far no optimized parameters are available to perform molecular simulations with a biomolecular force field. Therefore, we have determined the first optimized set of CHARMM parameters for the Triton X-series, enabling all-atom molecular dynamics (MD) simulations. In order to validate the new parameters, micellar sizes (aggregation numbers) of Triton X-114 and Triton X 100 have been investigated as a function of temperature and surfactant concentration. These results are comparable with experimental results. Furthermore, we have introduced a new algorithm to obtain micelle structures from self-assembly MD simulations for the COSMOmic method. This model allows efficient partition behavior predictions once a representative micelle structure is available. The predicted partition coefficients for the systems Triton X 114/water and Triton X-100/water are in excellent agreement with experimental results. Therefore, this method can be applied as a screening tool to find optimal solute-surfactant combinations or suitable surfactant systems for a specific application. PMID- 26574427 TI - Stacking Free Energies of All DNA and RNA Nucleoside Pairs and Dinucleoside Monophosphates Computed Using Recently Revised AMBER Parameters and Compared with Experiment. AB - We report the results of a series of 1-MUs-long explicit-solvent molecular dynamics (MD) simulations performed to compare the free energies of stacking (DeltaGstack) of all possible combinations of DNA and RNA nucleoside (NS) pairs and dinucleoside-monophosphates (DNMPs). For both NS pairs and DNMPs, we show that the computed stacking free energies are in reasonable qualitative agreement with experimental measurements and appear to provide the closest correspondence with experimental data yet found among computational studies; in all cases, however, the computed stacking free energies are too favorable relative to experimental data. Comparisons of NS-pair systems indicate that stacking interactions are very similar in RNA and DNA systems except when a thymine or uracil base is involved: the presence of a thymine base favors stacking by ~0.3 kcal/mol relative to a uracil base. One exception is found in the self-stacking of cytidines, which are found to be significantly more favorable for the DNA form; an analysis of the rotational orientations sampled during stacking events suggests that this is likely to be due to more favorable sugar-sugar interactions in stacked complexes of deoxycytidines. Comparisons of the DNMP systems indicate that stacking interactions are more favorable in RNA than in DNA except, again, when thymine or uracil bases are involved. Finally, additional simulations performed using a previous generation of the AMBER force field-in which the description of glycosidic bond rotations was less than optimal-produce computed stacking free energies that are in poorer agreement with experimental data. Overall, the simulations provide a comprehensive view of stacking thermodynamics in NS pairs and in DNMPs as predicted by a state-of-the-art MD force field. PMID- 26574430 TI - Assembly of Stefin B into Polymorphic Oligomers Probed by Discrete Molecular Dynamics. AB - Assembly of an amyloidogenic protein stefin B into molten globule oligomers is studied by efficient discrete molecular dynamics. Consistent with in vitro findings, tetramers form primarily through dimer association, resulting in a decreased trimer abundance. Oligomers up to heptamers display elongated rod-like morphologies akin to protofibrils, whereas larger oligomers, decamers through dodecamers, form elongated, branched, as well as annular structures, providing structural insights into pore forming ability and toxicity of amyloidogenic proteins. PMID- 26574431 TI - Constant-pH MD Simulations of an Oleic Acid Bilayer. AB - Oleic acid is a simple molecule with an aliphatic chain and a carboxylic group whose ionization and, consequently, intermolecular interactions are strongly dependent on the solution pH. The titration curve of these molecules was already obtained using different experimental methods, which have shown the lipid bilayer assemblies to be stable between pH 7.0 and 9.0. In this work, we take advantage of our recent implementations of periodic boundary conditions in Poisson Boltzmann calculations and ionic strength treatment in simulations of charged lipid bilayers, and we studied the ionization dependent behavior of an oleic acid bilayer using a new extension of the stochastic titration constant-pH MD method. With this new approach, we obtained titration curves that are in good agreement with the experimental data. Also, we were able to estimate the slope of the titration curve from charge fluctuations, which is an important test of thermodynamic consistency for the sampling in a constant-pH MD method. The simulations were performed for ionizations up to 50%, because an experimentally observed macroscopic transition to micelles occurs above this value. As previously seen for a binary mixture of a zwitterionic and an anionic lipid, we were able to reproduce experimental results with simulation boxes usually far from neutrality. This observation further supports the idea that a charged membrane strongly influences the ion distribution in its vicinity and that neutrality is achieved significantly far from the bilayer surface. The good results obtained with this extension of the stochastic titration constant-pH MD method strongly supports its usefulness to sample the coupling between configuration and protonation in these types of biophysical systems. This method stands now as a powerful tool to study more realistic lipid bilayers where pH can influence both the lipids and the solutes interacting with them. PMID- 26574429 TI - Parametrization of Backbone Flexibility in a Coarse-Grained Force Field for Proteins (COFFDROP) Derived from All-Atom Explicit-Solvent Molecular Dynamics Simulations of All Possible Two-Residue Peptides. AB - Recently, we reported the parametrization of a set of coarse-grained (CG) nonbonded potential functions, derived from all-atom explicit-solvent molecular dynamics (MD) simulations of amino acid pairs and designed for use in (implicit solvent) Brownian dynamics (BD) simulations of proteins; this force field was named COFFDROP (COarse-grained Force Field for Dynamic Representations Of Proteins). Here, we describe the extension of COFFDROP to include bonded backbone terms derived from fitting to results of explicit-solvent MD simulations of all possible two-residue peptides containing the 20 standard amino acids, with histidine modeled in both its protonated and neutral forms. The iterative Boltzmann inversion (IBI) method was used to optimize new CG potential functions for backbone-related terms by attempting to reproduce angle, dihedral, and distance probability distributions generated by the MD simulations. In a simple test of the transferability of the extended force field, the angle, dihedral, and distance probability distributions obtained from BD simulations of 56 three residue peptides were compared to results from corresponding explicit-solvent MD simulations. In a more challenging test of the COFFDROP force field, it was used to simulate eight intrinsically disordered proteins and was shown to quite accurately reproduce the experimental hydrodynamic radii (Rhydro), provided that the favorable nonbonded interactions of the force field were uniformly scaled downward in magnitude. Overall, the results indicate that the COFFDROP force field is likely to find use in modeling the conformational behavior of intrinsically disordered proteins and multidomain proteins connected by flexible linkers. PMID- 26574432 TI - Structures and Energy Landscapes of Hydrated Sulfate Clusters. AB - The sulfate ion is the most kosmotropic member of the Hofmeister series, but the chemical origins of this effect are unclear. We present a global optimization and energy landscape mapping study of microhydrated sulfate ions, SO4(2-)(H2O)n, in the size range 3 <= n <= 50. The clusters are modeled using a rigid-body empirical potential and optimized using basin-hopping Monte Carlo in conjunction with a move set including cycle inversions to explore hydrogen bond topologies. For clusters containing a few water molecules (n <= 6) we are able to reproduce ab initio global minima, either as global minima of the empirical potential, or as low-energy isomers. This result justifies applications to larger systems. Experimental studies have shown that dangling hydroxyl groups are present on the surfaces of pure water clusters, but absent in hydrated sulfate clusters up to n ~ 43. Our global optimization results agree with this observation, with dangling hydroxyl groups absent from the low-lying minima of small clusters, but competitive in larger clusters. PMID- 26574433 TI - AFFCK: Adaptive Force-Field-Assisted ab Initio Coalescence Kick Method for Global Minimum Search. AB - Global optimization techniques for molecules, solids, and clusters are numerous and can be algorithmically elegant. Yet many of them are time-consuming and prone to getting trapped in local minima. Among the available methods, Coalescence Kick (CK) is attractive: it combines a nearly insulting simplicity with thoroughness. A new version of CK is reported here, called Adaptive Force-Field-Assisted Coalescence Kick (AFFCK). The generation of stationary points on the potential energy surface is tremendously accelerated as compared to that of the earlier, pure ab initio CK, through the introduction of an intermediate step where structures are optimized using a classical force field (FF). The FF itself is system-specific, developed on-the-fly within the algorithm. The pre-computed energies resulting from the FF step are found to be surprisingly indicative of energies in subsequent Density Functional Theory optimization, which enables AFFCK to effectively screen thousands of initial CK-generated structures for favorable starting geometries. Additionally, AFFCK incorporates the use of symmetry operations in order to enhance the diversity in the search space, increase the chance for highly symmetric structures to appear, and speed up convergence of optimizations. A structure-recognition routine ensures diversity in the search space by preventing multiple copies of the same starting geometry from being generated and run. The tests show that AFFCK is much faster than traditional ab initio-only CK. We applied AFFCK to the search for global and low energy local minima of gas-phase clusters of boron and platinum. For Pt8 a new global minimum structure is found, which is significantly lower in energy than previously reported Pt8 minima. Although AFFCK confirms the global minima of B5( ), B8, and B9(-), it proves to be less efficient for systems with nontrivial bonding. PMID- 26574434 TI - The effect of anodized Ti on output performance of biomedical compatible triboelectric nanogenerators used for controlling the degradation of Mg-3wt%Zn 0.8wt%Zr. AB - Triboelectric nanogenerators (TENGs) can convert amorphous mechanical energy into electrical energy and solve the issue of source power for biological electronics implanted in the human body. Biomedical metal Ti was selected as the bottom plate, to fabricate a TENG with a poly-L-lactic-acid (PLLA) Ti structure. The Ti sheets were treated with a two-step anodization method, and the growth of titanium dioxide nanotube arrays (TNTAs) was controlled by variation in anodic oxidation time. The results showed that the output voltage and current of the PLLA-TNTAs biocompatible triboelectric nanogenerator (BCTENG), prepared by the two-step anodization method under 60 V for 6 h, can reach 220.6 V and 15.1 MUA, respectively. The output voltage and current increased by 96.3% and 91.1%, respectively, compared with TENGs prepared without using the anode oxidation method. The choice of materials and modification of the surface morphology of the TENG components was found to be critical for increasing the triboelectrically generated surface charge. The output of the BCTENG can regulate degradation of magnesium alloys freely by using cathodic protection. PMID- 26574435 TI - PXR stimulates growth factor-mediated hepatocyte proliferation by cross-talk with the FOXO transcription factor. AB - Growth factor-mediated hepatocyte proliferation is crucial in liver regeneration and the recovery of liver function after injury. The nuclear receptor, pregnane X receptor (PXR), is a key transcription factor for the xenobiotic-induced expression of genes associated with various liver functions. Recently, we reported that PXR activation stimulates xenobiotic-induced hepatocyte proliferation. In the present study, we investigated whether PXR activation also stimulates growth factor-mediated hepatocyte proliferation. In G0 phase synchronized, immortalized mouse hepatocytes, serum or epidermal growth factor treatment increased cell growth and this growth was augmented by the expression of mouse PXR and co-treatment with pregnenolone 16alpha-carbonitrile (PCN), a PXR ligand. In a liver regeneration model using carbon tetrachloride, PCN treatment enhanced the injury-induced increase in the number of Ki-67-positive nuclei as well as Ccna2 and Ccnb1 mRNA levels in wild-type (WT) but not Pxr-null mice. Chronological analysis of this model demonstrated that PCN treatment shifted the maximum cell proliferation to an earlier time point and increased the number of M phase cells at those time points. In WT but not Pxr-null mice, PCN treatment reduced hepatic mRNA levels of genes involved in the suppression of G0/G1- and G1/S-phase transition, e.g. Rbl2, Cdkn1a and Cdkn1b. Analysis of the Rbl2 promoter revealed that PXR activation inhibited its Forkhead box O3 (FOXO3) mediated transcription. Finally, the PXR-mediated enhancement of hepatocyte proliferation was inhibited by the expression of dominant active FOXO3 in vitro. The results of the present study suggest that PXR activation stimulates growth factor-mediated hepatocyte proliferation in mice, at least in part, through inhibiting FOXO3 from accelerating cell-cycle progression. PMID- 26574436 TI - Conformational dynamics of Ca2+-dependent responses in the polycystin-2 C terminal tail. AB - PC2 (polycystin-2) forms a Ca(2+)-permeable channel in the cell membrane and its function is regulated by cytosolic Ca(2+) levels. Mutations in the C-terminal tail of human PC2 (HPC2 Cterm) lead to autosomal dominant polycystic kidney disease. The HPC2 Cterm protein contains a Ca(2+)-binding site responsible for channel gating and function. To provide the foundation for understanding how Ca(2+) regulates the channel through the HPC2 Cterm, we characterized Ca(2+) binding and its conformational and dynamic responses within the HPC2 Cterm. By examining hydrogen-deuterium (H-D) exchange profiles, we show that part of the coiled-coil domain in the HPC2 Cterm forms a stable helix bundle regardless of the presence of Ca(2+). The HPC2 L1EF construct contains the Ca(2+)-binding EF hand and the N-terminal linker 1 region without the downstream coiled coil. We show that the linker stabilizes the Ca(2+)-bound conformation of the EF-hand, thus enhancing its Ca(2+)-binding affinity to the same level as the HPC2 Cterm. In comparison, the coiled coil is not required for the high-affinity binding. By comparing the conformational dynamics of the HPC2 Cterm and HPC2 L1EF with saturating Ca(2+), we show that the HPC2 Cterm and HPC2 L1EF share a similar increase in structural stability upon Ca(2+) binding. Nevertheless, they have different profiles of H-D exchange under non-saturating Ca(2+) conditions, implying their different conformational exchange between the Ca(2+)-bound and unbound states. The present study, for the first time, provides a complete map of dynamic responses to Ca(2+)-binding within the full-length HPC2 Cterm. Our results suggest mechanisms for functional regulation of the PC2 channel and PC2's roles in the pathophysiology of polycystic kidney disease. PMID- 26574437 TI - Efficient Determination of Free Energy Landscapes in Multiple Dimensions from Biased Umbrella Sampling Simulations Using Linear Regression. AB - The weighted histogram analysis method (WHAM) is a standard protocol for postprocessing the information from biased umbrella sampling simulations to construct the potential of mean force with respect to a set of order parameters. By virtue of the WHAM equations, the unbiased density of state is determined by satisfying a self-consistent condition through an iterative procedure. While the method works very effectively when the number of order parameters is small, its computational cost grows rapidly in higher dimension. Here, we present a simple and efficient alternative strategy, which avoids solving the self-consistent WHAM equations iteratively. An efficient multivariate linear regression framework is utilized to link the biased probability densities of individual umbrella windows and yield an unbiased global free energy landscape in the space of order parameters. It is demonstrated with practical examples that free energy landscapes that are comparable in accuracy to WHAM can be generated at a small fraction of the cost. PMID- 26574438 TI - Time-Dependent Electronic Populations in Fragment-Based Time-Dependent Density Functional Theory. AB - Conceiving a molecule as being composed of smaller molecular fragments, or subunits, is one of the pillars of the chemical and physical sciences and leads to productive methods in quantum chemistry. Using a fragmentation scheme, efficient algorithms can be proposed to address problems in the description of chemical bond formation and breaking. We present a formally exact time-dependent density functional theory for the electronic dynamics of molecular fragments with a variable number of electrons. This new formalism is an extension of previous work [Phys. Rev. Lett. 111, 023001 (2013)]. We also introduce a stable density inversion method that is applicable to time-dependent and ground-state density functional theories and their extensions, including those discussed in this work. PMID- 26574439 TI - Reliable Viscosity Calculation from Equilibrium Molecular Dynamics Simulations: A Time Decomposition Method. AB - Equilibrium molecular dynamics is often used in conjunction with a Green-Kubo integral of the pressure tensor autocorrelation function to compute the shear viscosity of fluids. This approach is computationally expensive and is subject to a large amount of variability because the plateau region of the Green-Kubo integral is difficult to identify unambiguously. Here, we propose a time decomposition approach for computing the shear viscosity using the Green-Kubo formalism. Instead of one long trajectory, multiple independent trajectories are run and the Green-Kubo relation is applied to each trajectory. The averaged running integral as a function of time is fit to a double-exponential function with a weighting function derived from the standard deviation of the running integrals. Such a weighting function minimizes the uncertainty of the estimated shear viscosity and provides an objective means of estimating the viscosity. While the formal Green-Kubo integral requires an integration to infinite time, we suggest an integration cutoff time tcut, which can be determined by the relative values of the running integral and the corresponding standard deviation. This approach for computing the shear viscosity can be easily automated and used in computational screening studies where human judgment and intervention in the data analysis are impractical. The method has been applied to the calculation of the shear viscosity of a relatively low-viscosity liquid, ethanol, and relatively high-viscosity ionic liquid, 1-n-butyl-3-methylimidazolium bis(trifluoromethane sulfonyl)imide ([BMIM][Tf2N]), over a range of temperatures. These test cases show that the method is robust and yields reproducible and reliable shear viscosity values. PMID- 26574440 TI - Predicting the Sensitivity of Multiscale Coarse-Grained Models to their Underlying Fine-Grained Model Parameters. AB - The sensitivity of a coarse-grained (CG) force field to changes in the underlying fine-grained (FG) model from which it was derived provides modeling insight for improving transferability across interaction parameters, transferability across temperature, and the calculation of thermodynamic derivatives. Methods in the literature, such as multi-trajectory finite differences and reweighted finite differences, are either too computationally demanding to calculate within acceptable noise tolerances or are too biased for practical accuracy. This work presents a new reweighting-free, single-simulation formula that allows for practical, high signal-to-noise calculations of CG model sensitivity with respect to FG model interaction parameters and thermodynamic state points. This formula, the self-consistent basis (SCB) single point formula, determines the many-body sensitivity in a single step by approximating the derivative of the many-body potential projected onto the same set of trial functions as the sensitivity. A related diagnostic formula also derived in this paper is the self-consistent iterative (SCI) single point formula, which is useful for identifying the importance of many-body sources of error and verifying CG representability of observables. The SCI formula determines the many-body sensitivity iteratively via a series of partially self-consistent, variational approximations to the complete many-body sensitivity. The new, computationally efficient SCB formula shows substantially less noise than previous methods when applied to single site methanol and solvent-free sodium chloride CG models, though bias can remain a problem. It represents a novel method for calculating alchemical transferability across interaction parameters at low computational cost and with high fidelity, and the results point to new understanding of the current limits of CG model transferability. PMID- 26574441 TI - Computing Free Energy Differences of Configurational Basins. AB - A simulation-based approach is proposed to estimate free energy differences between configurational states A and B, defined in terms of collective coordinates of the molecular system. The computational protocol is organized into three stages that can be carried on simultaneously. Two of them consist of independent simulations aimed at sampling, in turn, A and B states. In order to limit the evolution of the system around A and B, biased sampling simulations such as umbrella sampling can be employed. These simulations allow us to estimate local configuration integrals associated with A and B, which can be viewed as vibrational contributions to the free energy. Free energy evaluation is completed by the linking-path stage, in which the potential of mean force difference is estimated between two arbitrary points of the configurational surface, located the first around A and the second around B. The linking path in the space of the collective coordinates is arbitrary and can be computed with any method, starting from adaptive biasing potential/force approaches to nonequilibrium techniques. As an illustrative example, we present the calculation of free energy differences between conformational states of the alanine dipeptide in the space of backbone dihedral angles. The basic advantage of this method, that we term "path-linked domains" scheme, is to prevent accurate calculation of the whole free energy hypersurface in the space of the collective coordinates, thus limiting the statistical sampling to a minimum. Path-linked domains schemes can be applied to a variety of biochemical processes, such as protein-ligand complexation or folding-unfolding interconversion. PMID- 26574443 TI - Efficient Calculation of Accurate Reaction Energies-Assessment of Different Models in Electronic Structure Theory. AB - In this work we analyze the accuracy and the efficiency of different schemes to obtain the complete basis set limit for CCSD(T). It is found that composite schemes using an MP2 increment to reach the basis set limit provide high accuracy combined with high efficiency. In these composite schemes the MP2-F12/cc-pVTZ-F12 method is suitable to compute the MP2 contribution at the basis set limit. We propose to use the def2-TZVP or the TZVPP basis sets at the coupled cluster level in combination with the cc-pVTZ-F12 basis set at the MP2 level to compute reaction energies close to the basis set limit, if high accuracy methods like CCSD(T)(F12*) or 56-extrapolations are no longer feasible due to the computational effort. The standard deviation of CCSD(T)+DeltaMP2/cc-pVTZ-F12/def2 TZVP and CCSD(T)+DeltaMP2/cc-pVTZ-F12/TZVPP is found to be only 0.93 and 0.65 kJ/mol for a test set of 51 closed shell reactions. Furthermore, we provide a comprehensive list of different computational strategies to obtain CCSD(T) reaction energies with an efficiency and accuracy measure. Finally we analyze how different choices of the exponent in the correlation factor (gamma) change the results when using explicitly correlated methods. The statistical results in this study are based on a set of 51 reaction energies in the range of 0.7 to 631.5 kJ/mol. PMID- 26574442 TI - Enhanced Sampling of an Atomic Model with Hybrid Nonequilibrium Molecular Dynamics-Monte Carlo Simulations Guided by a Coarse-Grained Model. AB - Molecular dynamics (MD) trajectories based on a classical equation of motion provide a straightforward, albeit somewhat inefficient approach, to explore and sample the configurational space of a complex molecular system. While a broad range of techniques can be used to accelerate and enhance the sampling efficiency of classical simulations, only algorithms that are consistent with the Boltzmann equilibrium distribution yield a proper statistical mechanical computational framework. Here, a multiscale hybrid algorithm relying simultaneously on all-atom fine-grained (FG) and coarse-grained (CG) representations of a system is designed to improve sampling efficiency by combining the strength of nonequilibrium molecular dynamics (neMD) and Metropolis Monte Carlo (MC). This CG-guided hybrid neMD-MC algorithm comprises six steps: (1) a FG configuration of an atomic system is dynamically propagated for some period of time using equilibrium MD; (2) the resulting FG configuration is mapped onto a simplified CG model; (3) the CG model is propagated for a brief time interval to yield a new CG configuration; (4) the resulting CG configuration is used as a target to guide the evolution of the FG system; (5) the FG configuration (from step 1) is driven via a nonequilibrium MD (neMD) simulation toward the CG target; (6) the resulting FG configuration at the end of the neMD trajectory is then accepted or rejected according to a Metropolis criterion before returning to step 1. A symmetric two-ends momentum reversal prescription is used for the neMD trajectories of the FG system to guarantee that the CG-guided hybrid neMD-MC algorithm obeys microscopic detailed balance and rigorously yields the equilibrium Boltzmann distribution. The enhanced sampling achieved with the method is illustrated with a model system with hindered diffusion and explicit-solvent peptide simulations. Illustrative tests indicate that the method can yield a speedup of about 80 times for the model system and up to 21 times for polyalanine and (AAQAA)3 in water. PMID- 26574444 TI - Novel SCS-IL-MP2 and SOS-IL-MP2 Methods for Accurate Energetics of Large-Scale Ionic Liquid Clusters. AB - Accurate energetics of intermolecular interactions in condensed systems are challenging to predict using highly correlated quantum chemical methods due to their great computational expense. Semi-Coulomb systems such as ionic liquids, in which electrostatic, dispersion, and induction forces are equally important, represent a further challenge for wave function-based methods. Here, the application of our recently developed SCS-IL-MP2 and SOS-IL-MP2 methods is reported for ionic liquid clusters of two and four ion pairs. Correlation interaction energies were found to be within 1.5 kJ mol(-1), on average, per ion pair of the CCSD(T)/CBS benchmark, thus introducing a marked improvement by a factor of 4 to conventional MP2 within the complete basis set. The fragment molecular orbital (FMO) approach in combination with both SCS-IL-MP2 and SOS-IL MP2 has been shown to provide a reliable and computationally inexpensive alternative to CCSD(T)/CBS for large-scale calculations of ionic liquids, thus paving the way toward feasible ab initio molecular dynamics and development of reliable force fields for these condensed systems. PMID- 26574445 TI - Orbital Energies for Seniority-Zero Wave Functions. AB - A new single-pair operator for seniority-zero wave functions is introduced closely related to the single-particle Fock operator from conventional Hartree Fock theory. This allows one to ascribe orbital energies in the context of model Hamiltonians, for which no single-particle operators exist. Several applications demonstrate the usefulness of these orbital energies. In analogy to Koopmans' theorem, atomic double ionization potentials are successfully predicted. A computationally efficient second-order perturbation scheme for seniority-zero wave functions scaling quadratically with system size is defined and applied to the dissociation of nitrogen and to strongly correlated two-dimensional Heisenberg lattices. An extension of the method for full seniority is presented leading to an intruder-free single reference perturbation theory with improved asymptotic convergence. PMID- 26574446 TI - Orbital Optimization in the Active Space Decomposition Model. AB - We report the derivation and implementation of orbital optimization algorithms for the active space decomposition (ASD) model, which are extensions of complete active space self-consistent field (CASSCF) and its occupation-restricted variants in the conventional multiconfiguration electronic-structure theory. Orbital rotations between active subspaces are included in the optimization, which allows us to unambiguously partition the active space into subspaces, enabling application of ASD to electron and exciton dynamics in covalently linked chromophores. One- and two-particle reduced density matrices, which are required for evaluation of orbital gradient and approximate Hessian elements, are computed from the intermediate tensors in the ASD energy evaluation. Numerical results on 4-(2-naphthylmethyl)-benzaldehyde and [36]cyclophane and model Hamiltonian analyses of triplet energy transfer processes in the Closs systems are presented. Furthermore, model Hamiltonians for hole and electron transfer processes in anti [2.2](1,4)pentacenophane are studied using an occupation-restricted variant. PMID- 26574447 TI - Multiconfiguration Pair-Density Functional Theory Outperforms Kohn-Sham Density Functional Theory and Multireference Perturbation Theory for Ground-State and Excited-State Charge Transfer. AB - The correct description of charge transfer in ground and excited states is very important for molecular interactions, photochemistry, electrochemistry, and charge transport, but it is very challenging for Kohn-Sham (KS) density functional theory (DFT). KS-DFT exchange-correlation functionals without nonlocal exchange fail to describe both ground- and excited-state charge transfer properly. We have recently proposed a theory called multiconfiguration pair density functional theory (MC-PDFT), which is based on a combination of multiconfiguration wave function theory with a new type of density functional called an on-top density functional. Here we have used MC-PDFT to study challenging ground- and excited-state charge-transfer processes by using on-top density functionals obtained by translating KS exchange-correlation functionals. For ground-state charge transfer, MC-PDFT performs better than either the PBE exchange-correlation functional or CASPT2 wave function theory. For excited-state charge transfer, MC-PDFT (unlike KS-DFT) shows qualitatively correct behavior at long-range with great improvement in predicted excitation energies. PMID- 26574448 TI - Handling Magnetic Coupling in Trinuclear Cu(II) Complexes. AB - The problem of deriving three different two-body magnetic couplings in three electrons/three centers in a general geometric arrangement is investigated using the trinuclear Cu(II) HAKKEJ complex as a real case example. In these systems, one quartet and two doublet low lying electronic states exist, which define the magnetic spectra. However, the two possible linearly independent energy differences do not provide enough information to extract the three magnetic coupling constants. Here, we show how to obtain these parameters without making any assumption on the symmetry of the system from a combination of density functional- and wave function-based calculations. The density functional calculations explore various broken symmetry solutions and relate the corresponding energy to the expectation value of the Heisenberg Hamiltonian. This allows one to obtain all magnetic couplings, although their magnitude strongly depends on the exchange-correlation functional. Interestingly, a constant ratio between the magnetic coupling constants along a series of investigated functionals is found. This provides an additional equation to be used when relying on energy differences between spin states, which in turn allow solving the Heisenberg spectrum. The magnetic couplings thus obtained are compared to the experiment. Implications for the appropriate interpretation of the experiment and for the study of more complex systems are discussed. PMID- 26574449 TI - Magnetization Dynamics from Time-Dependent Noncollinear Spin Density Functional Theory Calculations. AB - A computational scheme, based on a time-dependent extension of noncollinear spin density functional theory, for the simultaneous simulation of charge and magnetization dynamics in molecular systems is presented. We employ a second order Magnus propagator combined with an efficient predictor-corrector scheme that allows us to treat large molecular systems over long simulation periods. The method is benchmarked against the low-frequency dynamics of the H-He-H molecule where the magnetization dynamics can be modeled by the simple classical magnetization precession of a Heisenberg-Dirac-van Vleck Hamiltonian. Furthermore, the magnetic exchange couplings of the bimetallic complex [Cu(bpy)(H2O)(NO3)2(MU-C2O4)] (BISDOW) are extracted from its low-frequency spin precession dynamics showing good agreement with the coupling obtained from ground state energy differences. Our approach opens the possibility to perform real-time simulation of spin-related phenomena using time-dependent density functional theory in realistic molecular systems. PMID- 26574450 TI - Polarizable Embedded RI-CC2 Method for Two-Photon Absorption Calculations. AB - We present a novel polarizable embedded resolution-of-identity coupled cluster singles and approximate doubles (PERI-CC2) method for calculation of two-photon absorption (TPA) spectra of large molecular systems. The method was benchmarked for three types of systems: a water-solvated molecule of formamide, a uracil molecule in aqueous solution, and a set of mutants of the channelrhodopsin (ChR) protein. The first test case shows that the PERI-CC2 method is in excellent agreement with the PE-CC2 method and in good agreement with the PE-CCSD method. The uracil test case indicates that the effects of hydrogen bonding on the TPA of a chromophore with the nearest environment is well-described with the PERI-CC2 method. Finally, the ChR calculation shows that the PERI-CC2 method is well suited and efficient for calculations on proteins with medium-sized chromophores. PMID- 26574451 TI - Accurate Electron Densities at Nuclei Using Small Ramp-Gaussian Basis Sets. AB - Electron densities at nuclei are difficult to calculate accurately with all Gaussian basis sets because they lack an electron-nuclear cusp. The newly developed mixed ramp-Gaussian basis sets, such as R-31G, possess electron-nuclear cusps due to the presence of ramp functions in the basis. The R-31G basis set is a general-purpose mixed ramp-Gaussian basis set modeled on the 6-31G basis set. The prediction of electron densities at nuclei using R-31G basis sets for Li-F outperforms Dunning, Pople, and Jensen general purpose all-Gaussian basis sets of triple-zeta quality or lower and the cc-pVQZ basis set. It is of similar quality to the specialized pcJ-0 basis set which was developed with partial decontraction of core functions and extra high exponent s-Gaussians to predict electron density at the nucleus. These results show significant advantages in the properties of mixed ramp-Gaussian basis sets compared to all-Gaussian basis sets. PMID- 26574452 TI - Ewald Summation for Molecular Simulations. AB - Ewald summation is an important technique for molecular simulation. In this article, expressions are provided for implementing Ewald summation for any inverse power potential in a range of different simulations. Energies, forces, stresses, and Hessian elements as well as truncation errors are considered. Focus is also given to methods for accelerating Ewald summation in Monte Carlo simulations, particularly in the grand canonical ensemble. Ewald techniques are applied to the simulation of CO2 adsorption and diffusion in the metal-organic framework, MOF-5. These simulations show that optimized Ewald summation can provide increased accuracy at similar computational cost compared to that of pair based methods. PMID- 26574453 TI - ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB. AB - Molecular mechanics is powerful for its speed in atomistic simulations, but an accurate force field is required. The Amber ff99SB force field improved protein secondary structure balance and dynamics from earlier force fields like ff99, but weaknesses in side chain rotamer and backbone secondary structure preferences have been identified. Here, we performed a complete refit of all amino acid side chain dihedral parameters, which had been carried over from ff94. The training set of conformations included multidimensional dihedral scans designed to improve transferability of the parameters. Improvement in all amino acids was obtained as compared to ff99SB. Parameters were also generated for alternate protonation states of ionizable side chains. Average errors in relative energies of pairs of conformations were under 1.0 kcal/mol as compared to QM, reduced 35% from ff99SB. We also took the opportunity to make empirical adjustments to the protein backbone dihedral parameters as compared to ff99SB. Multiple small adjustments of phi and psi parameters were tested against NMR scalar coupling data and secondary structure content for short peptides. The best results were obtained from a physically motivated adjustment to the phi rotational profile that compensates for lack of ff99SB QM training data in the beta-ppII transition region. Together, these backbone and side chain modifications (hereafter called ff14SB) not only better reproduced their benchmarks, but also improved secondary structure content in small peptides and reproduction of NMR chi1 scalar coupling measurements for proteins in solution. We also discuss the Amber ff12SB parameter set, a preliminary version of ff14SB that includes most of its improvements. PMID- 26574455 TI - Four-Component Relativistic Density-Functional Theory Calculations of Nuclear Spin-Rotation Constants: Relativistic Effects in p-Block Hydrides. AB - We present an implementation of the nuclear spin-rotation (SR) constants based on the relativistic four-component Dirac-Coulomb Hamiltonian. This formalism has been implemented in the framework of the Hartree-Fock and Kohn-Sham theory, allowing assessment of both pure and hybrid exchange-correlation functionals. In the density-functional theory (DFT) implementation of the response equations, a noncollinear generalized gradient approximation (GGA) has been used. The present approach enforces a restricted kinetic balance condition for the small-component basis at the integral level, leading to very efficient calculations of the property. We apply the methodology to study relativistic effects on the spin rotation constants by performing calculations on XHn (n = 1-4) for all elements X in the p-block of the periodic table and comparing the effects of relativity on the nuclear SR tensors to that observed for the nuclear magnetic shielding tensors. Correlation effects as described by the density-functional theory are shown to be significant for the spin-rotation constants, whereas the differences between the use of GGA and hybrid density functionals are much smaller. Our calculated relativistic spin-rotation constants at the DFT level of theory are only in fair agreement with available experimental data. It is shown that the scaling of the relativistic effects for the spin-rotation constants (varying between Z(3.8) and Z(4.5)) is as strong as for the chemical shieldings but with a much smaller prefactor. PMID- 26574454 TI - Refinement of Generalized Born Implicit Solvation Parameters for Nucleic Acids and Their Complexes with Proteins. AB - The Generalized Born (GB) implicit solvent model has undergone significant improvements in accuracy for modeling of proteins and small molecules. However, GB still remains a less widely explored option for nucleic acid simulations, in part because fast GB models are often unable to maintain stable nucleic acid structures or they introduce structural bias in proteins, leading to difficulty in application of GB models in simulations of protein-nucleic acid complexes. Recently, GB-neck2 was developed to improve the behavior of protein simulations. In an effort to create a more accurate model for nucleic acids, a similar procedure to the development of GB-neck2 is described here for nucleic acids. The resulting parameter set significantly reduces absolute and relative energy error relative to Poisson-Boltzmann for both nucleic acids and nucleic acid-protein complexes, when compared to its predecessor GB-neck model. This improvement in solvation energy calculation translates to increased structural stability for simulations of DNA and RNA duplexes, quadruplexes, and protein-nucleic acid complexes. The GB-neck2 model also enables successful folding of small DNA and RNA hairpins to near native structures as determined from comparison with experiment. The functional form and all required parameters are provided here and also implemented in the AMBER software. PMID- 26574456 TI - Mechanical Forces Alter Conical Intersections Topology. AB - Photoreactivity can be influenced by mechanical forces acting over a reacting chromophore. Nevertheless, the specific effect of the external forces in the photoreaction mechanism remains essentially unknown. Conical intersections are key structures in photochemistry, as they constitute the funnels connecting excited and ground states. These crossing points are well known to provide valuable information on molecular photoreactivity, including crucial aspects as potential photoproducts which may be predicted by just inspection of the branching plane vectors. Here, we outline a general framework for understanding the effect of mechanical forces on conical intersections and their implications on photoreactivity. Benzene S1/S0 conical intersection topology can be dramatically altered by applying less than 1 nN force, making the peaked pattern of the intersection become a sloped one, also provoking the transition state in the excited state to disappear. Both effects can be related to an increase in the photostability as the conical intersection becomes more accessible, and its topology in this case favors the recovery of the initial reactant. The results indicate that the presence of external forces acting over a chromophore have to be considered as a potential method for photochemical reactivity control. PMID- 26574457 TI - Spin Doublet Point Defects in Graphenes: Predictions for ESR and NMR Spectral Parameters. AB - An adatom on a graphene surface may carry a magnetic moment causing spin-half paramagnetism. This theoretically predicted phenomenon has recently also been experimentally verified. The measurements of defect-induced magnetism are mainly based on magnetometric techniques where artifacts such as environmental magnetic impurities are hard to rule out. Spectroscopic methods such as electron spin resonance (ESR) and paramagnetic nuclear magnetic resonance (pNMR) are conventionally used in the development of magnetic materials, e.g., to study paramagnetic centers. The present density functional theory study demonstrates with calculations of the ESR g-tensor and the hyperfine coupling tensors, as well as the pNMR shielding tensor, that these spectroscopies can be used to identify the paramagnetic centers in graphenes. The studied defects are hydrogen and fluorine adatoms on sp(2)-hybridized graphene, as well as hydrogen and fluorine vacancies in the sp(3)-hybridized graphane and fluorographene, respectively. The directly measurable ESR and pNMR parameters give insight into the electronic and atomic structures of these defects and may contribute to understanding carbon based magnetism via the characterization of the defect centers. We show that missing hydrogen and fluorine atoms in the functionalized graphane and fluorographene, respectively, constitute sp(2)-defect centers, in which the magnetic resonance parameters are greatly enhanced. Slowly decaying adatom induced magnetic resonance parameters with the distance from the sp(3)-defect, are found in pure graphene. PMID- 26574458 TI - Two-Dimensional Electronic Spectroscopy of Benzene, Phenol, and Their Dimer: An Efficient First-Principles Simulation Protocol. AB - First-principles simulations of two-dimensional electronic spectroscopy in the ultraviolet region (2DUV) require computationally demanding multiconfigurational approaches that can resolve doubly excited and charge transfer states, the spectroscopic fingerprints of coupled UV-active chromophores. Here, we propose an efficient approach to reduce the computational cost of accurate simulations of 2DUV spectra of benzene, phenol, and their dimer (i.e., the minimal models for studying electronic coupling of UV-chromophores in proteins). We first establish the multiconfigurational recipe with the highest accuracy by comparison with experimental data, providing reference gas-phase transition energies and dipole moments that can be used to construct exciton Hamiltonians involving high-lying excited states. We show that by reducing the active spaces and the number of configuration state functions within restricted active space schemes, the computational cost can be significantly decreased without loss of accuracy in predicting 2DUV spectra. The proposed recipe has been successfully tested on a realistic model proteic system in water. Accounting for line broadening due to thermal and solvent-induced fluctuations allows for direct comparison with experiments. PMID- 26574459 TI - Multiconfigurational Second-Order Perturbation Theory with Frozen Natural Orbitals Extended to the Treatment of Photochemical Problems. AB - A new flavor of the frozen natural orbital complete active space second-order perturbation theory method (FNO-CASPT2, Aquilante et al., J. Chem. Phys. 131, 034113) is proposed herein. In this new implementation, the virtual space in Cholesky decomposition-based CASPT2 computations (CD-CASPT2) is truncated by excluding those orbitals that contribute the least toward preserving a predefined value of the trace of an approximate density matrix, as that represents a measure of the amount of dynamic correlation retained in the model. In this way, the amount of correlation included is practically constant at all nuclear arrangements, thus allowing for the computation of smooth electronic states surfaces and energy gradients-essential requirements for theoretical studies in photochemistry. The method has been benchmarked for a series of relevant biochromophores for which large speed-ups have been recorded while retaining the accuracy achieved in the corresponding CD-CASPT2 calculations. Both vertical excitation energies and gradient calculations have been carried out to establish general guidelines as to how much correlation needs to be retained in the calculation for the results to be consistent with the CD-CASPT2 findings. Our results feature errors within a tenth of an eV for the most difficult cases and have been validated to be used for gradient computations where an up to 3-fold speed-up is observed depending on the size of the system and the basis set employed. PMID- 26574460 TI - Comprehensive Benchmark of Association (Free) Energies of Realistic Host-Guest Complexes. AB - The S12L test set for supramolecular Gibbs free energies of association DeltaGa (Grimme, S. Chem. Eur. J. 2012, 18, 9955-9964) is extended to 30 complexes (S30L), featuring more diverse interaction motifs, anions, and higher charges (-1 up to +4) as well as larger systems with up to 200 atoms. Various typical noncovalent interactions like hydrogen and halogen bonding, pi-pi stacking, nonpolar dispersion, and CH-pi and cation-dipolar interactions are represented by "real" complexes. The experimental Gibbs free energies of association (DeltaGa exp) cover a wide range from -0.7 to -24.7 kcal mol-1. In order to obtain a theoretical best estimate for DeltaGa, we test various dispersion corrected density functionals in combination with quadruple-zeta basis sets for calculating the association energies in the gas phase. Further, modern semiempirical methods are employed to obtain the thermostatistical corrections from energy to Gibbs free energy, and the COSMO-RS model with several parametrizations as well as the SMD model are used to include solvation contributions. We investigate the effect of including counterions for the charged systems (S30L-CI), which is found to overall improve the results. Our best method combination consists of PW6B95-D3 (for neutral and charged systems) or omegaB97X-D3 (for systems with counterions) energies, HF-3c thermostatistical corrections, and Gibbs free energies of solvation obtained with the COSMO-RS 2012 parameters for nonpolar solvents and 2013-fine for water. This combination gives a mean absolute deviation for DeltaGa of only 2.4 kcal mol-1 (S30L) and 2.1 kcal mol-1 (S30L-CI), with a mean deviation of almost zero compared to experiment. Regarding the relative Gibbs free energies of association for the 13 pairs of complexes which share the same host, the correct trend in binding affinities could be reproduced except for two cases. The MAD compared to experiment amounts to 1.2 kcal mol-1, and the MD is almost zero. The best-estimate theoretical corrections are used to back-correct the experimental DeltaGa values in order to get an empirical estimate for the "experimental", zero-point vibrational energy exclusive, gas phase binding energies. These are then utilized to benchmark the performance of various "lowcost" quantum chemical methods for noncovalent interactions in large systems. The performance of other common DFT methods as well as the use of semiempirical methods for structure optimizations is discussed. PMID- 26574461 TI - Thermodynamic and Transport Properties of H2O + NaCl from Polarizable Force Fields. AB - Molecular dynamics and Monte Carlo simulations were performed to obtain thermodynamic and transport properties of the binary H2O + NaCl system using the polarizable force fields of Kiss and Baranyai ( J. Chem. Phys. 2013 , 138 , 204507 and 2014 , 141 , 114501 ). In particular, liquid densities, electrolyte and crystal chemical potentials of NaCl, salt solubilities, mean ionic activity coefficients, vapor pressures, vapor-liquid interfacial tensions, and viscosities were obtained as functions of temperature, pressure, and salt concentration. We compared the performance of the polarizable force fields against fixed-point charge (nonpolarizable) models. Most of the properties of interest are better represented by the polarizable models, which also remain physically realistic at elevated temperatures. PMID- 26574462 TI - Monodisperse Clusters in Charged Attractive Colloids: Linear Renormalization of Repulsion. AB - Experiments done on polydisperse particles of cadmium selenide have recently shown that the particles form spherical isolated clusters with low polydispersity of cluster size. The computer simulation model of Xia et al. ( Nat. Nanotechnol. 2011 , 6 , 580 ) explaining this behavior used a short-range van der Waals attraction combined with a variable long-range screened electrostatic repulsion, depending linearly on the volume of the clusters. In this work, we term this dependence "linear renormalization" of the repulsive term, and we use advanced Monte Carlo simulations to investigate the kinetically slowed down phase separation in a similar but simpler model. We show that amorphous drops do not dissolve and crystallinity evolves very slowly under linear renormalization, and we confirm that low polydispersity of cluster size can also be achieved using this model. The results indicate that the linear renormalization generally leads to monodisperse clusters. PMID- 26574463 TI - Coarse-Graining the Liquid-Liquid Interfaces with the MARTINI Force Field: How Is the Interfacial Tension Reproduced? AB - We report two-phase coarse-grained (CG) simulations of organic-water liquid liquid interfaces with the MARTINI force field. We discuss the ability of the CG force field to predict quantitatively the interfacial tension of alkanes-water, benzene-water, chloroform-water, and alcohol-water systems. The performance of the prediction of the interfacial tension is evaluated through its dependence on temperature and alkane length. This study contributes to the challenging discussion about the robustness and the transferability of the MARTINI force field to interfacial properties. We have also used the distributions of the molecules along the direction normal to the interface to investigate the composition of the interfacial region and to compare the simulated densities of the coexisting phases with experiments. PMID- 26574464 TI - Partial Charges in Periodic Systems: Improving Electrostatic Potential (ESP) Fitting via Total Dipole Fluctuations and Multiframe Approaches. AB - Two major improvements to the state-of-the-art Repeating Electrostatic Potential Extracted Atomic (REPEAT) method, for generating accurate partial charges for molecular simulations of periodic structures, are here developed. The first, D REPEAT, consists in the simultaneous fit of the electrostatic potential (ESP), together with the total dipole fluctuations (TDF) of the framework. The second, M REPEAT, allows the fit of multiple ESP configurations at once. When both techniques are fused into one, DM-REPEAT method, the resulting charges become remarkably stable over a large set of fitting regions, giving a robust and physically sound solution to the buried atoms problem. The method capabilities are extensively studied in ZIF-8 framework, and subsequently applied to IRMOF-1 and ITQ-29 crystal structures. To our knowledge, this is the first time that this approach is proposed in the context of periodic systems. PMID- 26574465 TI - Optimized Exchange and Correlation Semilocal Functional for the Calculation of Energies of Formation. AB - We present a semiempirical exchange-correlation functional for density functional theory tailored to calculate energies of formation of solids. It has the same form of a Perdew-Burke-Ernzerhof functional, but three parameters have been fitted to reproduce experimental energies of formation of a representative set of binaries. The quality of the obtained functional has then been assessed for a control set of binary and ternary compounds. Our functional succeeds in reducing the error of the Perdew-Burke-Ernzerhof generalized gradient approximation for energies of formation by a factor of 2. Furthermore, this result is achieved preserving the quality of the optimized geometry. PMID- 26574466 TI - Reliable Prediction with Tuned Range-Separated Functionals of the Singlet-Triplet Gap in Organic Emitters for Thermally Activated Delayed Fluorescence. AB - The thermally activated delayed fluorescence (TADF) mechanism has recently attracted significant interest in the field of organic light-emitting diodes (OLEDs). TADF relies on the presence of a very small energy gap between the lowest singlet and triplet excited states. Here, we demonstrate that time dependent density functional theory in the Tamm-Dancoff approximation can be very successful in calculations of the lowest singlet and triplet excitation energies and the corresponding singlet-triplet gap when using nonempirically tuned range separated functionals. Such functionals provide very good estimates in a series of 17 molecules used in TADF-based OLED devices with mean absolute deviations of 0.15 eV for the vertical singlet excitation energies and 0.09 eV [0.07 eV] for the adiabatic [vertical] singlet-triplet energy gaps as well as low relative errors and high correlation coefficients compared to the corresponding experimental values. They significantly outperform conventional functionals, a feature which is rationalized on the basis of the amount of exact-exchange included and the delocalization error. The present work provides a reliable theoretical tool for the prediction and development of novel TADF-based materials with low singlet-triplet energetic splittings. PMID- 26574467 TI - Spins Dynamics in a Dissipative Environment: Hierarchal Equations of Motion Approach Using a Graphics Processing Unit (GPU). AB - A system with many energy states coupled to a harmonic oscillator bath is considered. To study quantum non-Markovian system-bath dynamics numerically rigorously and nonperturbatively, we developed a computer code for the reduced hierarchy equations of motion (HEOM) for a graphics processor unit (GPU) that can treat the system as large as 4096 energy states. The code employs a Pade spectrum decomposition (PSD) for a construction of HEOM and the exponential integrators. Dynamics of a quantum spin glass system are studied by calculating the free induction decay signal for the cases of 3 * 2 to 3 * 4 triangular lattices with antiferromagnetic interactions. We found that spins relax faster at lower temperature due to transitions through a quantum coherent state, as represented by the off-diagonal elements of the reduced density matrix, while it has been known that the spins relax slower due to suppression of thermal activation in a classical case. The decay of the spins are qualitatively similar regardless of the lattice sizes. The pathway of spin relaxation is analyzed under a sudden temperature drop condition. The Compute Unified Device Architecture (CUDA) based source code used in the present calculations is provided as Supporting Information . PMID- 26574468 TI - Insights into Stability and Folding of GNRA and UNCG Tetraloops Revealed by Microsecond Molecular Dynamics and Well-Tempered Metadynamics. AB - RNA hairpins capped by 5'-GNRA-3' or 5'-UNCG-3' tetraloops (TLs) are prominent RNA structural motifs. Despite their small size, a wealth of experimental data, and recent progress in theoretical simulations of their structural dynamics and folding, our understanding of the folding and unfolding processes of these small RNA elements is still limited. Theoretical description of the folding and unfolding processes requires robust sampling, which can be achieved by either an exhaustive time scale in standard molecular dynamics simulations or sophisticated enhanced sampling methods, using temperature acceleration or biasing potentials. Here, we study structural dynamics of 5'-GNRA-3' and 5'-UNCG-3' TLs by 15-MUs long standard simulations and a series of well-tempered metadynamics, attempting to accelerate sampling by bias in a few chosen collective variables (CVs). Both methods provide useful insights. The unfolding and refolding mechanisms of the GNRA TL observed by well-tempered metadynamics agree with the (reverse) folding mechanism suggested by recent replica exchange molecular dynamics simulations. The orientation of the glycosidic bond of the GL4 nucleobase is critical for the UUCG TL folding pathway, and our data strongly support the hypothesis that GL4 anti forms a kinetic trap along the folding pathway. Along with giving useful insight, our study also demonstrates that using only a few CVs apparently does not capture the full folding landscape of the RNA TLs. Despite using several sophisticated selections of the CVs, formation of the loop appears to remain a hidden variable, preventing a full convergence of the metadynamics. Finally, our data suggest that the unfolded state might be overstabilized by the force fields used. PMID- 26574469 TI - Role of the Molecular Environment in Flavoprotein Color and Redox Tuning: QM Cluster versus QM/MM Modeling. AB - We investigate the origin of the excitation energy shifts induced by the apoprotein in the active site of the bacterial photoreceptor BLUF (Blue Light sensor Using Flavin adenine dinucleotide). In order to compute the vertical excitation energies of three low-lying electronic states, including two pi-pi* states of flavin (S1 and S2) and a pi-pi* tyrosine-flavin electron-transfer state (ET), with respect to the energy of the closed-shell ground state (S0), we prepared alternative quantum mechanical (QM) cluster and quantum mechanics/molecular mechanics (QM/MM) models. We found that the excitation energies computed with both types of models correlate with the magnitude of the charge transfer character of the excitation. Accordingly, we conclude that the small charge transfer character of the light absorbing S0-S1 transition and the substantial charge transfer character of the nonabsorbing but redox active S0-ET transition explain the small color changes but substantial redox tuning in BLUF and also in other flavoproteins. Further analysis showed that redox tuning is governed by the electrostatic interaction in the QM/MM model and transfer of charge between the active site and its environment in the QM cluster. Moreover, the wave function polarization of the QM subsystem by the MM subsystem influences the magnitude of the charge transfer, resulting in the QM/MM and QM excitation energies that are not entirely consistent. PMID- 26574470 TI - Monte Carlo Sampling with Linear Inverse Kinematics for Simulation of Protein Flexible Regions. AB - A Monte Carlo linear inverse-kinematics method for the simulation of protein chains with fixed ends is introduced. It includes backbone bond-angle bending and simultaneous loop and ring closure to allow full proline ring flexibility. An obstacle to linear null-space methods is the eventual drift of the end group. Maintenance of the end group at its initial position by occasional reset is performed in a way that is consistent with the overall methodology and minimally disruptive to the current conformation. The implementation permitted multiple rigid regions within the chain, enabling the simulation of domain movements where domains are rigid bodies connected by flexible interdomain regions. The method was tested on polyalanine, polyglycine, loop 6 of triosephosphate isomerase, and glutamine binding protein. Simulations of glutamine binding protein, where only 11 of the 226 residues at the interdomain bending regions were flexible, accurately reproduced the experimentally determined domain movement. PMID- 26574471 TI - Exploring Multiple Binding Modes Using Confined Replica Exchange Molecular Dynamics. AB - Molecular docking is extensively applied to determine the position of a ligand on its receptor despite the rather poor correspondence between docking scores and experimental binding affinities found in several studies, especially for systems structurally unrelated with those used in the scoring functions' training sets. Here, we present a method for the prediction of binding modes and binding free energies, which uses replica exchange molecular dynamics in combination with a receptor-shaped piecewise potential, confining the ligand in the proximity of the receptor surface and limiting the accessible conformational space of interest. We assess our methodology with a set of protein receptor-ligand test cases. In every case studied, the method is able to locate the ligand on the experimentally known receptor binding site, and it gives as output the binding free energy. The added value of our approach with respect to other available methods is that it quickly performs a conformational space search, providing a set of bound (or unbound) configurations, which can be used to determine phenomenological structural and energetic properties of an experimental binding state as a result of contributions provided by diversified multiple binding poses. PMID- 26574472 TI - Martini Coarse-Grained Force Field: Extension to DNA. AB - We systematically parameterized a coarse-grained (CG) model for DNA that is compatible with the Martini force field. The model maps each nucleotide into six to seven CG beads and is parameterized following the Martini philosophy. The CG nonbonded interactions are based on partitioning of the nucleobases between polar and nonpolar solvents as well as base-base potential of mean force calculations. The bonded interactions are fit to single-stranded DNA (ssDNA) atomistic simulations and an elastic network is used to retain double-stranded DNA (dsDNA) and other specific DNA conformations. We present the implementation of the Martini DNA model and demonstrate the properties of individual bases, ssDNA as well as dsDNA, and DNA-protein complexes. The model opens up large-scale simulations of DNA interacting with a wide range of other (bio)molecules that are available within the Martini framework. PMID- 26574474 TI - Materials Design On-the-Fly. AB - The dream of any solid-state theorist is to be able to predict new materials with tailored properties from scratch, i.e., without any input from experiment. Over the past decades, we have steadily approached this goal. Recent developments in the field of high-throughput calculations focused on finding the best material for specific applications. However, a key input for these techniques still had to be obtained experimentally, namely, the crystal structure of the materials. Here, we give a step further and show that one can indeed optimize material properties using as a single starting point the knowledge of the periodic table and the fundamental laws of quantum mechanics. This is done by combining state-of-the-art methods of global structure prediction that allow us to obtain the ground-state crystal structure of arbitrary materials, with an evolutionary algorithm that optimizes the chemical composition for the desired property. As a first showcase demonstration of our method, we perform an unbiased search for superhard materials and for transparent conductors. We stress that our method is completely general and can be used to optimize any property (or combination of properties) that can be calculated in a computer. PMID- 26574473 TI - Quantifying the Binding Interaction between the Hypoxia-Inducible Transcription Factor and the von Hippel-Lindau Suppressor. AB - The hypoxia-inducible transcription factors (HIF) play a central role in the human oxygen sensing signaling pathway. The binding of the von Hippel-Lindau tumor suppressor protein (pVHL)-ElonginC-ElonginB complex (VCB) to HIF-1alpha is highly selective for the trans-4-hydroxylation form of when Pro564 in the C terminal oxygen-dependent degradation domain (ODDD) of HIF-1alpha. The binding of HIFalpha for VCB is increased by ~1000-fold upon addition of a single hydroxyl group to either of two conserved proline-residues. Here, we address how this addition governs selective recognition and characterizes the strength of the interaction of this "switch-like" signaling event. A new set of molecular mechanics parameters for 4-hydroxyproline has been developed following the CHARMM force field philosophy. Using the free energy perturbation (FEP) formalism, the difference in the binding free energies between HIF-1alpha in the nonhydroxylated and hydroxylated forms with the VCB complex was estimated using over 3 MUs of MD trajectories. These results can favorably be compared to an experimental value of ~4 kcal mol(-1). It is observed that the optimized hydrogen bonding network to the buried hydroxyprolyl group confers precise discrimination between hydroxylated and unmodified prolyl residues. These observations provide insight that will aid in developing therapeutic agents that block HIF-alpha recognition by pVHL. PMID- 26574475 TI - Accurate Complete Basis Set Extrapolation of Direct Random Phase Correlation Energies. AB - The direct random phase approximation (dRPA) is a promising way to obtain improvements upon the standard semilocal density functional results in many aspects of computational chemistry. In this paper, we address the slow convergence of the calculated dRPA correlation energy with the increase of the quality and size of the popular Gaussian-type Dunning's correlation consistent aug-cc-pVXZ split valence atomic basis set family. The cardinal number X controls the size of the basis set, and we use X = 3-6 in this study. It is known that even the very expensive X = 6 basis sets lead to large errors for the dRPA correlation energy, and thus complete basis set extrapolation is necessary. We study the basis set convergence of the dRPA correlation energies on a set of 65 hydrocarbon isomers from CH4 to C6H6. We calculate the iterative density fitted dRPA correlation energies using an efficient algorithm based on the CC-like form of the equations using the self-consistent HF orbitals. We test the popular inverse cubic, the optimized exponential, and inverse power formulas for complete basis set extrapolation. We have found that the optimized inverse power based extrapolation delivers the best energies. Further analysis showed that the optimal exponent depends on the molecular structure, and the most efficient two point energy extrapolations that use X = 3 and 4 can be improved considerably by considering the atomic composition and hybridization states of the atoms in the molecules. Our results also show that the optimized exponents that yield accurate X = 3 and 4 extrapolated dRPA energies for atoms or small molecules might be inaccurate for larger molecules. PMID- 26574476 TI - Correction to Embedded Mean-Field Theory. PMID- 26574477 TI - Ionic screening effect on low-frequency drain current fluctuations in liquid gated nanowire FETs. AB - The ionic screening effect plays an important role in determining the fundamental surface properties within liquid-semiconductor interfaces. In this study, we investigated the characteristics of low-frequency drain current noise in liquid gated nanowire (NW) field effect transistors (FETs) to obtain physical insight into the effect of ionic screening on low-frequency current fluctuation. When the NW FET was operated close to the gate voltage corresponding to the maximum transconductance, the magnitude of the low-frequency noise for the NW exposed to a low-ionic-strength buffer (0.001 M) was approximately 70% greater than that when exposed to a high-ionic-strength buffer (0.1 M). We propose a noise model, considering the charge coupling efficiency associated with the screening competition between the electrolyte buffer and the NW, to describe the ionic screening effect on the low-frequency drain current noise in liquid-gated NW FET systems. This report not only provides a physical understanding of the ionic screening effect behind the low-frequency current noise in liquid-gated FETs but also offers useful information for developing the technology of NW FETs with liquid-gated architectures for application in bioelectronics, nanosensors, and hybrid nanoelectronics. PMID- 26574479 TI - Heightening Energetic Stress Selectively Targets LKB1-Deficient Non-Small Cell Lung Cancers. AB - Inactivation of the LKB1 tumor suppressor is a frequent event in non-small cell lung carcinoma (NSCLC) leading to the activation of mTOR complex 1 (mTORC1) and sensitivity to the metabolic stress inducer phenformin. In this study, we explored the combinatorial use of phenformin with the mTOR catalytic kinase inhibitor MLN0128 as a treatment strategy for NSCLC bearing comutations in the LKB1 and KRAS genes. NSCLC is a genetically and pathologically heterogeneous disease, giving rise to lung tumors of varying histologies that include adenocarcinomas and squamous cell carcinomas (SCC). We demonstrate that phenformin in combination with MLN0128 induced a significant therapeutic response in KRAS/LKB1-mutant human cell lines and genetically engineered mouse models of NSCLC that develop both adenocarcinomas and SCCs. Specifically, we found that KRAS/LKB1-mutant lung adenocarcinomas responded strongly to phenformin + MLN0128 treatment, but the response of SCCs to single or combined treatment with MLN0128 was more attenuated due to acquired resistance to mTOR inhibition through modulation of the AKT-GSK signaling axis. Combinatorial use of the mTOR inhibitor and AKT inhibitor MK2206 robustly inhibited the growth and viability of squamous lung tumors, thus providing an effective strategy to overcome resistance. Taken together, our findings define new personalized therapeutic strategies that may be rapidly translated into clinical use for the treatment of KRAS/LKB1-mutant adenocarcinomas and squamous cell tumors. PMID- 26574481 TI - Two-color 3D-3D fusion of selective rotational cerebral angiograms: a novel approach to imaging in cerebrovascular neurosurgery. AB - BACKGROUND: Since its introduction, digital subtraction angiography has been considered the gold standard in diagnostic imaging for neurovascular disease. Modern post-processing techniques have made angiography even more informative to the cerebrovascular neurosurgeon or neurointerventionalist. Open neurosurgical procedures such as aneurysm clipping, extirpation of arteriovenous malformations, and extracranial-intracranial bypass remain important techniques in the armamentarium of a comprehensive cerebrovascular neurosurgeon. In-depth study of the anatomy of vascular pathology prior to and after surgery, often via selective cerebral angiography, is a critical component of surgical planning. However, when a vascular lesion or relevant anatomical region is perfused by two or more vascular territories, each selective angiographic imaging volume may provide an incomplete anatomical picture. METHODS: An institutional database was searched for cases in which the syngo Inspace 3D-3D fusion software was used and assisted in diagnosis and surgical management. RESULTS: In the six cases reviewed, the 3D 3D fusion imaging was crucial in understanding the anatomy of the vascular lesion and aided in surgical decision-making. The cases included two unique anterior communicating artery aneurysms, an arteriovenous malformation, an extracranial intracranial bypass, and an angiographically negative subarachnoid hemorrhage. CONCLUSIONS: This is a novel strategy of combining two independently acquired selective cerebral angiography volumes to create a more accurate representation of the vascular anatomy. Given the increasing availability of the relevant image acquisition and processing technologies, we propose this strategy as a valuable adjunct in cerebrovascular procedures. PMID- 26574482 TI - Encouraging Competition and Cooperation: The Affordable Care Act's Contradiction? AB - This introductory essay to JHPPL's special issue on accountable care organizations (ACOs) presents the broader themes addressed in the issue, including (1) a central tension between cooperation versus competition in health care markets with regard to how to bring about improved quality, lower costs, and better access; (2) US regulatory policy - whether it will be able to achieve the appropriate balance in health care markets under which ACOs could realize expected outcomes; and (3) ACO realities - whether ACOs will be able to overcome or further embed existing inequities in US health care markets. PMID- 26574480 TI - Involvement of the Hippo pathway in regeneration and fibrogenesis after ischaemic acute kidney injury: YAP is the key effector. AB - Renal tubule cells can recover after they undergo AKI (acute kidney injury). An incomplete repair of renal tubules can result in progressive fibrotic CKD (chronic kidney disease). Studies have revealed the relationship between tubular epithelial cells and kidney fibrogenesis. However, the underlying mechanism remains unclear. Hippo pathway components were evaluated in complete/incomplete repair of I/R (ischaemia/reperfusion) AKI rat models, HK-2 cells and AKI human renal biopsy samples. We found that the expression levels of the Hippo pathway components changed dynamically during kidney regeneration and fibrogenesis in rat models of I/R-induced AKI and human renal biopsy samples. The transcription cofactor YAP (Yes-associated protein) might be a key effector of renal regeneration and fibrogenesis. Our results showed further that YAP might elicit both beneficial and detrimental effects on I/R AKI. After I/R injury occurred, YAP could promote the repair of the injured epithelia. The constant YAP increase and activation might be related to interstitial fibrosis and abnormal renal tubule differentiation. These results indicate that the proper modulation of the Hippo pathway, specifically the transcription cofactor YAP, during repair might be a potent therapeutic target in AKI-CKD transition after I/R injury. PMID- 26574484 TI - The risk of arterial thrombosis increases with the use of combined oral contraceptives. PMID- 26574486 TI - Endovascular Therapy for Femoropopliteal Artery Disease and Association of Risk Factors With Primary Patency: The Implication of Critical Limb Ischemia and TASC II C/D Disease. AB - The treatment of femoropopliteal artery disease remains controversial, without clear guidelines specifying the indications for endovascular therapy (EVT). Accordingly, we retrospectively examined our experience of using EVT to treat femoropopliteal artery disease. A total of 91 limbs in 82 patients underwent EVT for the treatment of femoropopliteal artery disease. Percutaneous transluminal angioplasty alone was performed in 20 limbs, and additional stenting was performed in 71 limbs. The 1-year primary patency, primary-assisted patency, limb salvage, and survival rates were 76%, 88%, 96%, and 92%, respectively. Multivariate Cox analysis of primary patency showed that critical limb ischemia (CLI; hazard ratio [HR], 2.53; 95% confidence interval [CI], 1.08-5.33; P < .01) and TASC II C/D disease (HR, 2.70; 95% CI, 1.14-6.39; P < .05) were independent predictors of decreased primary patency. In conclusion, patients with CLI or extensive lesions have reduced patency after EVT for femoropopliteal artery disease. PMID- 26574485 TI - A MultiCenter Pilot Randomized Controlled Trial of Remote Ischemic Preconditioning in Major Vascular Surgery. AB - A pilot randomized controlled trial that evaluated the effect of remote ischemic preconditioning (RIPC) on clinical outcomes following major vascular surgery was performed. Eligible patients were those scheduled to undergo open abdominal aortic aneurysm repair, endovascular aortic aneurysm repair, carotid endarterectomy, and lower limb revascularization procedures. Patients were randomized to RIPC or to control groups. The primary outcome was a composite clinical end point comprising any of cardiovascular death, myocardial infarction, new-onset arrhythmia, cardiac arrest, congestive cardiac failure, cerebrovascular accident, renal failure requiring renal replacement therapy, mesenteric ischemia, and urgent cardiac revascularization. Secondary outcomes were components of the primary outcome and myocardial injury as assessed by serum troponin values. The primary outcome occurred in 19 (19.2%) of 99 controls and 14 (14.1%) of 99 RIPC group patients (P = .446). There were no significant differences in secondary outcomes. Our trial generated data that will guide future trials. Further trials are urgently needed. PMID- 26574487 TI - A Feasibility Pilot Trial of Individualized Homeopathic Treatment of Fatigue in Children Receiving Chemotherapy. AB - BACKGROUND: Fatigue is a major problem in children with cancer. The objective was to examine the feasibility of performing a clinical trial of homeopathic treatment for fatigue in children receiving chemotherapy. MATERIALS: This was a single-institution, open-label, pilot study. Children 2 to 18 years old, diagnosed with cancer, and receiving chemotherapy were eligible. Participants were given individualized homeopathic treatment for a maximum of 14 days. In-home or clinic assessments were conducted up to 3 times weekly. Feasibility was defined as the ability to recruit and administer homeopathy to 10 participants within 1 year. Fatigue was measured using the Symptom Distress Scale daily and the PedsQL Multidimensional Fatigue Module weekly. RESULTS: Between April 2012 and April 2014, 155 potential participants were identified. There were 45 eligible and contacted patients; 36 declined participation, 30 because they were not interested; 9 agreed to participate, but 1 participant withdrew prior to treatment initiation. Median length of homeopathic treatment was 10.5 (range = 6 to 14) days. All parents found homeopathic treatment to be easy or very easy to follow. CONCLUSIONS: Trials of individualized homeopathy for fatigue reduction in pediatric cancer are not feasible in this context; lack of interest was a primary reason. Alternative approaches to evaluating homeopathy efficacy are needed. PMID- 26574488 TI - Serum diamine oxidase activity in patients with histamine intolerance. AB - INTRODUCTION: Intolerance to various foods, excluding bona fide coeliac disease and lactose intolerance, represents a growing cause of patient visits to allergy clinics.Histamine intolerance is a long-known, multifaceted clinical condition triggered by histamine-rich foods and alcohol and/or by drugs that liberate histamine or block diamine oxidase (DAO), the main enzyme involved in the metabolism of ingested histamine. Histamine limitation diets impose complex, non standardized restrictions that may severely impact the quality of life of patients. METHODS: We retrospectively evaluated 14 patients who visited allergy outpatient facilities in northern Italy with a negative diagnosis for IgE mediated food hypersensitivity, coeliac disease, conditions related to gastric hypersecretion, and systemic nickel hypersensitivity, and who previously underwent a histamine limitation diet with benefits for their main symptoms. Serum diamine oxidase levels and the clinical response to diamine oxidase supplementation were investigated. RESULTS: We found that 10 out of 14 patients had serum DAO activity<10 U/mL, which was the threshold suggested as a cutoff for probable histamine intolerance. Moreover, 13 out of 14 patients subjectively reported a benefit in at least one of the disturbances related to food intolerances following diamine oxidase supplementation. The mean value (+/-SD) of diamine oxidase activity in the cohort of patients with histamine intolerance symptoms was 7.04+/-6.90 U/mL compared to 39.50+/-18.16 U/mL in 34 healthy controls (P=0.0031). CONCLUSION: In patients with symptoms triggered by histamine rich food, measuring the serum diamine oxidase activity can help identify subjects who can benefit from a histamine limitation diet and/or diamine oxidase supplementation.Properly designed, controlled studies investigating histamine intolerance that include histamine provocation are indispensable for providing insights into the area of food intolerances, which are currently primarily managed with non-scientific approaches in Italy. PMID- 26574489 TI - Successful Vedolizumab Therapy in a Sixteen-Year-Old Boy with Refractory Ulcerative Colitis. PMID- 26574490 TI - PET/MR Versus PET/CT Imaging: Impact on the Clinical Management of Small-Bowel Crohn's Disease. AB - BACKGROUND AND AIMS: The aim of this study was to compare the accuracy and clinical impact of hybrid positron emission tomography [PET]/magnetic resonance enterography [MR-E] and PET/computed tomography-enterography [CT-E] in patients with Crohn's disease [CD]. METHODS: A total of 35 patients with symptomatic small bowel CD who were scheduled to undergo operation were evaluated before operation by same-day PET/CT-E and PET/MR-E. PET/MR-E was also compared with MR-E alone. Imaging accuracy for detecting pathological sites and discriminating between fibrotic and inflammatory strictures was assessed. Treatment was adjusted according to imaging findings and change in medical/surgical strategy was also evaluated. RESULTS: PET/CT-E, PET/MR-E, and MR-E were equally accurate in detecting CD sites. PET/MR-E was more accurate in assessing extra-luminal disease [p = 0.002], which was associated with higher need for stoma [p = 0.022] and distant localisation [p = 0.002]. When the latter was observed, laparoscopy was started with hand-assisted device, reducing operative time [p = 0.022]. PET/MR-E was also more accurate in detecting a fibrotic component compared with PET/CT-E [p = 0.043] and with MR-E [p = 0.024]. Fibrosis was more frequently classified as inflammation with MR-E compared with PET/MR-E [p = 0.019]. Out of 8 patients with predominantly inflammatory CD who received medical treatment, 6 [75%] remained surgery free. Overall, 29 patients received surgery. At median follow-up of 9 [6 22] months, no recurrences occurred in either the medical or the surgical group. CONCLUSIONS: Preoperative PET/MR-E imaging is highly accurate for assessing CD lesions before operation and contributed to clinical management of patients with small-bowel CD more often than PET/CT-E. PMID- 26574492 TI - Differentiating between detrimental and beneficial interruptions: a mixed-methods study. AB - INTRODUCTION: Efforts to understand interruptions now span much of the last decade and a half. Often thought to negatively impact patient safety, some now acknowledge that interruptions may be beneficial and actually necessary for safety and high quality care. This study seeks a framework for differentiating between interruptions that are detrimental and those that are beneficial. METHODS: A mixed-methods approach at a US Level 1 trauma centre included direct observation of 13 registered nurses (RNs), survey of 47 RNs, retrospective observation of hands-free communication devices, and modelling of observed interruptions to key performance measures. RESULTS: On average, RNs were interrupted every 11 min, with 20.3% of their workload triggered by interruptions. While 85% of RNs agreed that interruptions place their patients at risk, only 21% agreed that all should be eliminated. During one 90-min period, 18 original events spawned 68 interruptions, 50 of these repeat messages. A statistical model, with patient measures of time and comfort, revealed that alarms and call lights returning RN's attention to the patient outside the patient room are beneficial, while interruptions in the patient room are generally detrimental. Triangulating the results, we present an emerging framework for differentiating between beneficial and detrimental interruptions based on the impact of interruptions on the RN's steady treatment and attention to the patient. CONCLUSIONS: A mixed-methods approach can help distinguish between detrimental and beneficial interruptions. While interruptions breaking the delivery of steady treatment and attention to the patient are detrimental, those returning the RN's focus to the patient, as well as those supporting patient-clinician and clinician-clinician communications are beneficial. This insight may be helpful to healthcare delivery teams tasked with improving interruption-laden processes. PMID- 26574491 TI - Fungal Dysbiosis in Mucosa-associated Microbiota of Crohn's Disease Patients. AB - BACKGROUND AND AIMS: Gut microbiota is involved in many physiological functions and its imbalance is associated with several diseases, particularly with inflammatory bowel diseases. Mucosa-associated microbiota could have a key role in induction of host immunity and in inflammatory process. Although the role of fungi has been suggested in inflammatory disease pathogenesis, the fungal microbiota has not yet been deeply explored. Here we analysed the bacterial and fungal composition of the mucosa-associated microbiota of Crohn's disease patients and healthy subjects. METHODS: Our prospective, observational study evaluated bacterial and fungal composition of mucosa-associated microbiota of 23 Crohn's disease patients [16 in flare, 7 in remission] and 10 healthy subjects, using 16S [MiSeq] and ITS2 [pyrosequencing] sequencing, respectively. Global fungal load was assessed by real time quantitative polymerase chain reaction. RESULTS: Bacterial microbiota in Crohn's disease patients was characterised by a restriction in biodiversity. with an increase of Proteobacteria and Fusobacteria. Global fungus load was significantly increased in Crohn's disease flare compared with healthy subjects [p < 0.05]. In both groups, the colonic mucosa-associated fungal microbiota was dominated by Basidiomycota and Ascomycota phyla. Cystofilobasidiaceae family and Candida glabrata species were overrepresented in Crohn's disease. Saccharomyces cerevisiae and Filobasidium uniguttulatum species were associated with non-inflamed mucosa, whereas Xylariales order was associated with inflamed mucosa. CONCLUSIONS: Our study confirms the alteration of the bacterial microbiota and is the first demonstration of the existence of an altered fungal microbiota in Crohn's disease patients, suggesting that fungi may play a role in pathogenesis. PMID- 26574493 TI - Detecting Proximal Secondary Caries Lesions: A Cost-effectiveness Analysis. AB - When choosing detection methods for secondary caries lesions, dentists need to weigh sensitivity, allowing early initiation of retreatments to avoid lesion progression, against specificity, aiming to reduce risks of false-positive diagnoses and invasive overtreatments. We assessed the cost-effectiveness of different detection methods for proximal secondary lesions using Monte Carlo microsimulations. A vital permanent molar with an occlusal-proximal restoration was simulated over the lifetime of an initially 20-y-old. Three methods were compared: biannual tactile detection, radiographic detection every 2 y, and biannual laser fluorescence detection. Methods were employed either on their own or in pairwise combinations at sensitive and specific thresholds estimated with systematically collected data. A mixed public-private payer perspective in the context of German health care was applied. Effectiveness was calculated as years of tooth retention. Net-benefit analyses were used to evaluate cost-effectiveness acceptability at different willingness-to-pay thresholds. Radiographic detection verified by tactile assessment (both at specific thresholds) was least costly (mean, 1,060 euros) but had limited effectiveness (mean retention time, 50 y). The most effective but also more costly combination was laser fluorescence detection verified by radiography, again at specific thresholds (1157 euros, 53 y, acceptable if willingness to pay >32 euro/y). In the majority of simulations, not combining detection methods or applying them at sensitive thresholds was less effective and more costly. Net benefits were not greatly altered by applying different discounting rates or using different baseline prevalence of secondary lesions. Current detection methods for secondary lesions should best be used in combination, not on their own, at specific thresholds to avoid false-positive diagnoses leading to costly and invasive overtreatment. The relevant characteristics, such as predictive value, of different methods should be assessed in longitudinal clinical studies. PMID- 26574494 TI - Difference in blood volume distribution between upright humans and standing quadrupeds. PMID- 26574495 TI - Reply to Zhang. PMID- 26574496 TI - Late diagnosis of isolated congenitally corrected transposition of the great arteries in a 92-year old woman. AB - We report the case of a 92-year old woman with congenitally corrected transposition of the great arteries (CCTGA). The case is remarkable as the CCTGA had remained undiagnosed until the diagnosis was made when the patient was aged 70 years, and had 10 pregnancies without heart failure. PMID- 26574497 TI - Anastomotic leak and stricture after hand-sewn versus linear-stapled intrathoracic oesophagogastric anastomosis: single-centre analysis of 415 oesophagectomies. AB - OBJECTIVES: There seems to be a decreased anastomotic leak rate and a late stricture formation after linear-stapled (LS) cervical oesophagogastric anastomosis compared with hand-sewn (HS) technique. The aim of our study was to compare the surgical outcomes of intrathoracic side-to-side LS and end-to-end HS anastomosis after transthoracic oesophagectomy. METHODS: We conducted a retrospective review of all patients undergoing Ivor Lewis oesophagectomy with LS or HS anastomosis for neoplasia at our institution from 2005 to 2012. Anastomotic leak was radiologically and clinically graded as minor or major. End-points included overall and major leak rate, morbidity, mortality, length of hospital stay and endoscopically identified late anastomotic stricture. A propensity score matched analysis was done to compensate for the differences in baseline characteristics between HS and LS groups. Multivariable analyses of the associations of anastomotic technique and other preoperative and pathological variables with anastomotic leak and stricture were performed. RESULTS: There were 415 patients, 134 with HS and 281 with LS anastomoses. Anastomotic leak occurred in 56 patients (13.5%), significantly more after HS than LS technique (20.9 vs 10.0%; P = 0.002). Major leak rate was not significantly different (9.0 vs 5.7%; P = 0.216, respectively). Overall morbidity (54.7%), in-hospital mortality (3.9%) and length of hospital stay (median 12 days) were not affected by the anastomotic technique. A follow-up endoscopic evaluation was available in 248 patients (59.8%). An anastomotic stricture was detected in 24 patients (9.7%), significantly more after HS than LS technique (20.3 vs 6.3%; P = 0.002). The propensity score-matched analysis of 105 patient pairs confirmed a significantly decreased overall leak rate (11.4 vs 22.9%; P = 0.045) and stricture formation (7.5 vs 18.2%; P = 0.041) in LS technique compared with HS technique. The multivariable analyses found obesity and HS anastomotic technique associated with an increased overall leak rate, chronic hepatopathy and diabetes associated with major leak and HS technique, female sex and the absence of arterial hypertension associated with increased stricture formation. CONCLUSIONS: Our non-randomized study showed that side-to-side LS technique is the preferred method of intrathoracic oesophagogastric anastomosis due to a decreased overall anastomotic leak rate and anastomotic stricture formation compared with HS technique. PMID- 26574498 TI - Effect of deslorelin on testicular function, serum dihydrotestosterone and oestradiol concentrations during and after suppression of sexual activity in tom cats. AB - Objectives The aim of the study was to evaluate the efficacy of a 4.7 mg deslorelin implant in tom cats. Methods Nine mature male cats were included in the deslorelin group and five cats in the control group. Before the study started, all cats were confirmed to have distinct sexually dimorphic behaviour. Blood samples were taken on the implantation day, at day 7 and at day 15, then monthly, in order to measure serum dihydrotestosterone (DHT) and 17beta(beta) oestradiol concentrations. The deslorelin group (n = 9) was divided into two subgroups: five cats (cats 1-5) were neutered in the postimplantation period during suppression of sexually dimorphic behaviour, and four cats (cats 6-9) were neutered after re-expression of sexually dimorphic behaviour. The control group cats (n = 5) were castrated without administration of the implant. Results Sexually dimorphic behaviours ceased within a mean +/- SD of 13-58 days (23.30 +/ 14.17) after implantation. DHT concentration decreased within 30 days. The mean duration of suppression was 26.5 +/- 7.42 months and reactivation coincided with increased DHT values reaching preimplantation concentrations within 1 month. 17beta-oestradiol concentrations significantly correlated with DHT concentrations ( P <0.01). For cats castrated during suppression of sexual behaviour, the length of the long axes of the nuclei of Leydig cells, the diameter of seminiferous tubules and the height of the epithelium of the seminiferous tubules did not change until 3-6 months after implantation, whereas at 12 and 32 months the measured values were even lower than in the control group. For cats castrasted after reactivation, the length of long axes of the nuclei of Leydig cells and the diameter of seminiferous tubules approached the values of the control group between 4 and 6 months after reactivation. Conclusions and relevance A deslorelin implant (4.7 mg) suppresses sexually dimorphic behaviour in tom cats without any side effects and with full reversibility; however, duration of suppression is highly individual. PMID- 26574499 TI - Budd-Chiara syndrome and chylothorax. PMID- 26574500 TI - Healthcare professionals are less confident in managing acute toxicity related to the use of new psychoactive substances (NPS) compared with classical recreational drugs. AB - BACKGROUND: The features of acute classical recreational drugs or new psychoactive substances (NPS) toxicity fall into three broad groups: (i) stimulant; (ii) hallucinogenic and (iii) depressant. Currently, there is no information available on healthcare professionals knowledge/confidence in managing the acute toxicity related to NPS use. AIM: We have compared knowledge and confidence of managing acute toxicity related to use of NPS with that seen with the use of to classical recreational drugs. DESIGN AND METHODS: Physicians/nurses completed a questionnaire survey to self-assess on a 5-point scale their knowledge (1-little knowledge; 5-very knowledgeable) and confidence (1-little confidence; 5-very confident) of managing acute toxicity related to the use of classical recreational drugs or NPS. Differences between knowledge and confidence for classical recreational drugs and NPS were assessed using paired Student's t-test; comparison between doctors, nurses and the frequency of managing acute classical recreational drug/NPS toxicity was assessed using unpaired Student's t-test. RESULTS: One hundred and eighty-eight (82 physicians, 106 nurses) completed the survey. Classical drug compared with NPS knowledge: nurses 2.9 +/- 1.0 vs. 2.1 +/- 1.0, P < 0.001; physicians 3.1 +/- 0.8 vs. 2.1 +/ 1.0, P < 0.001. There was no difference between nurses and physicians in classical drug (P = 0.11) or NPS (P = 0.89) knowledge. Confidence in managing classical drug toxicity compared with NPS confidence: nurses 3.0 +/- 1.1 vs. 2.3 +/- 1.1, P < 0.001; physicians 3.0 +/- 0.9 vs. 2.1 +/- 1.0, P < 0.001. There was no difference between nurses and physicians in classical drugs (P = 0.85) or NPS (P = 0.33) confidence. CONCLUSIONS: Physicians/nurses are less confident in managing acute NPS toxicity. Management of toxicity is not dependent on knowing the drug/NPS, but should be on the basis of these clinical signs/symptoms. Training/education should focus on the concept of managing the pattern of toxicity that an individual presents with rather than the actual drug(s). PMID- 26574501 TI - Spontaneously Emerging Patterns in Human Visual Cortex Reflect Responses to Naturalistic Sensory Stimuli. AB - In the absence of stimulus or task, the cortex spontaneously generates rich and consistent functional connectivity patterns (termed resting state networks) which are evident even within individual cortical areas. We and others have previously hypothesized that habitual cortical network activations during daily life contribute to the shaping of these connectivity patterns. Here we tested this hypothesis by comparing, using blood oxygen level-dependent-functional magnetic resonance imaging, the connectivity patterns that spontaneously emerge during rest in retinotopic visual areas to the patterns generated by naturalistic visual stimuli (repeated movie segments). These were then compared with connectivity patterns produced by more standard retinotopic mapping stimuli (polar and eccentricity mapping). Our results reveal that the movie-driven patterns were significantly more similar to the spontaneously emerging patterns, compared with the connectivity patterns of either eccentricity or polar mapping stimuli. Intentional visual imagery of naturalistic stimuli was unlikely to underlie these results, since they were duplicated when participants were engaged in an auditory task. Our results suggest that the connectivity patterns that appear during rest better reflect naturalistic activations rather than controlled, artificially designed stimuli. The results are compatible with the hypothesis that the spontaneous connectivity patterns in human retinotopic areas reflect the statistics of cortical coactivations during natural vision. PMID- 26574504 TI - Meeting report--Getting Into and Out of Mitosis. AB - The Company of Biologists Workshop 'Getting Into and Out of Mitosis' was held 10 13 May 2015 at Wiston House in West Sussex, UK. The workshop brought together researchers from wide-ranging disciplines and provided a forum to discuss their latest work on the control of cell division from mitotic entry to exit. This report highlights the main topics and summarises the discussion around the key themes and questions that emerged from the meeting. PMID- 26574502 TI - Development of Synaptic Boutons in Layer 4 of the Barrel Field of the Rat Somatosensory Cortex: A Quantitative Analysis. AB - Understanding the structural and functional mechanisms underlying the development of individual brain microcircuits is critical for elucidating their computational properties. As synapses are the key structures defining a given microcircuit, it is imperative to investigate their development and precise structural features. Here, synapses in cortical layer 4 were analyzed throughout the first postnatal month using high-end electron microscopy to generate realistic quantitative 3D models. Besides their overall geometry, the size of active zones and the pools of synaptic vesicles were analyzed. At postnatal day 2 only a few shaft synapses were found, but spine synapses steadily increased with ongoing corticogenesis. From postnatal day 2 to 30 synaptic boutons significantly decreased in size whereas that of active zones remained nearly unchanged despite a reshaping. During the first 2 weeks of postnatal development, a rearrangement of synaptic vesicles from a loose distribution toward a densely packed organization close to the presynaptic density was observed, accompanied by the formation of, first a putative readily releasable pool and later a recycling and reserve pool. The quantitative 3D reconstructions of synapses will enable the comparison of structural and functional aspects of signal transduction thus leading to a better understanding of networks in the developing neocortex. PMID- 26574505 TI - Photoreceptors at a glance. AB - Retinal photoreceptor cells contain a specialized outer segment (OS) compartment that functions in the capture of light and its conversion into electrical signals in a process known as phototransduction. In rods, photoisomerization of 11-cis to all-trans retinal within rhodopsin triggers a biochemical cascade culminating in the closure of cGMP-gated channels and hyperpolarization of the cell. Biochemical reactions return the cell to its 'dark state' and the visual cycle converts all trans retinal back to 11-cis retinal for rhodopsin regeneration. OS are continuously renewed, with aged membrane removed at the distal end by phagocytosis and new membrane added at the proximal end through OS disk morphogenesis linked to protein trafficking. The molecular basis for disk morphogenesis remains to be defined in detail although several models have been proposed, and molecular mechanisms underlying protein trafficking are under active investigation. The aim of this Cell Science at a Glance article and the accompanying poster is to highlight our current understanding of photoreceptor structure, phototransduction, the visual cycle, OS renewal, protein trafficking and retinal degenerative diseases. PMID- 26574506 TI - Emerging roles of PtdIns(4,5)P2--beyond the plasma membrane. AB - Phosphoinositides are a collection of lipid messengers that regulate most subcellular processes. Amongst the seven phosphoinositide species, the roles for phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] at the plasma membrane, such as in endocytosis, exocytosis, actin polymerization and focal adhesion assembly, have been extensively studied. Recent studies have argued for the existence of PtdIns(4,5)P2 at multiple intracellular compartments, including the nucleus, endosomes, lysosomes, autolysosomes, autophagic precursor membranes, ER, mitochondria and the Golgi complex. Although the generation, regulation and functions of PtdIns(4,5)P2 are less well-defined in most other intracellular compartments, accumulating evidence demonstrates crucial roles for PtdIns(4,5)P2 in endolysosomal trafficking, endosomal recycling, as well as autophagosomal pathways, which are the focus of this Commentary. We summarize and discuss how phosphatidylinositol phosphate kinases, PtdIns(4,5)P2 and PtdIns(4,5)P2-effectors regulate these intracellular protein and membrane trafficking events. PMID- 26574507 TI - Cardiac Myocyte KLF5 Regulates Ppara Expression and Cardiac Function. AB - RATIONALE: Fatty acid oxidation is transcriptionally regulated by peroxisome proliferator-activated receptor (PPAR)alpha and under normal conditions accounts for 70% of cardiac ATP content. Reduced Ppara expression during sepsis and heart failure leads to reduced fatty acid oxidation and myocardial energy deficiency. Many of the transcriptional regulators of Ppara are unknown. OBJECTIVE: To determine the role of Kruppel-like factor 5 (KLF5) in transcriptional regulation of Ppara. METHODS AND RESULTS: We discovered that KLF5 activates Ppara gene expression via direct promoter binding. This is blocked in hearts of septic mice by c-Jun, which binds an overlapping site on the Ppara promoter and reduces transcription. We generated cardiac myocyte-specific Klf5 knockout mice that showed reduced expression of cardiac Ppara and its downstream fatty acid metabolism-related targets. These changes were associated with reduced cardiac fatty acid oxidation, ATP levels, increased triglyceride accumulation, and cardiac dysfunction. Diabetic mice showed parallel changes in cardiac Klf5 and Ppara expression levels. CONCLUSIONS: Cardiac myocyte KLF5 is a transcriptional regulator of Ppara and cardiac energetics. PMID- 26574509 TI - Rethinking the Hierarchy of Sugar Utilization in Bacteria. AB - Bacteria are known to consume some sugars over others, although recent work reported by Koirala and colleagues in this issue of the Journal of Bacteriology (S. Koirala, X. Wang, and C. V. Rao, J Bacteriol 198:386-393, 2016, http://dx.doi.org/10.1128/JB.00709-15) revealed that individual cells do not necessarily follow this hierarchy. By studying the preferential consumption of l arabinose over d-xylose in Escherichia coli, those authors found that subpopulations consume one, the other, or both sugars through cross-repression between utilization pathways. Their findings challenge classic assertions about established hierarchies and can guide efforts to engineer the simultaneous utilization of multiple sugars. PMID- 26574508 TI - MglC, a Paralog of Myxococcus xanthus GTPase-Activating Protein MglB, Plays a Divergent Role in Motility Regulation. AB - In order to optimize interactions with their environment and one another, bacteria regulate their motility. In the case of the rod-shaped cells of Myxococcus xanthus, regulated motility is essential for social behaviors. M. xanthus moves over surfaces using type IV pilus-dependent motility and gliding motility. These two motility systems are coordinated by a protein module that controls cell polarity and consists of three polarly localized proteins, the small G protein MglA, the cognate MglA GTPase-activating protein MglB, and the response regulator RomR. Cellular reversals are induced by the Frz chemosensory system, and the output response regulator of this system, FrzZ, interfaces with the MglA/MglB/RomR module to invert cell polarity. Using a computational approach, we identify a paralog of MglB, MXAN_5770 (MglC). Genetic epistasis experiments demonstrate that MglC functions in the same pathway as MglA, MglB, RomR, and FrzZ and is important for regulating cellular reversals. Like MglB, MglC localizes to the cell poles asymmetrically and with a large cluster at the lagging pole. Correct polar localization of MglC depends on RomR and MglB. Consistently, MglC interacts directly with MglB and the C-terminal output domain of RomR, and we identified a surface of MglC that is necessary for the interaction with MglB and for MglC function. Together, our findings identify an additional member of the M. xanthus polarity module involved in regulating motility and demonstrate how gene duplication followed by functional divergence can add a layer of control to the complex cellular processes of motility and motility regulation. IMPORTANCE: Gene duplication and the subsequent divergence of the duplicated genes are important evolutionary mechanisms for increasing both biological complexity and regulation of biological processes. The bacterium Myxococcus xanthus is a soil bacterium with an unusually large genome that carries out several social processes, including predation of other bacterial species and formation of multicellular, spore-filled fruiting bodies. One feature of the large M. xanthus genome is that it contains many gene duplications. Here, we compare the products of one example of gene duplication and divergence, in which a paralog of the cognate MglA GTPase-activating protein MglB has acquired a different and opposing role in the regulation of cellular polarity and motility, processes critical to the bacterium's social behaviors. PMID- 26574510 TI - Formation of an Intramolecular Periplasmic Disulfide Bond in TcpP Protects TcpP and TcpH from Degradation in Vibrio cholerae. AB - TcpP and ToxR coordinately regulate transcription of toxT, the master regulator of numerous virulence factors in Vibrio cholerae. TcpP and ToxR are membrane localized transcription factors, each with a periplasmic domain containing two cysteines. In ToxR, these cysteines form an intramolecular disulfide bond and a cysteine-to-serine substitution affects activity. We determined that the two periplasmic cysteines of TcpP also form an intramolecular disulfide bond. Disruption of this intramolecular disulfide bond by mutation of either cysteine resulted in formation of intermolecular disulfide bonds. Furthermore, disruption of the intramolecular disulfide bond in TcpP decreased the stability of TcpP. While the decreased stability of TcpP-C207S resulted in a nearly complete loss of toxT activation and cholera toxin (CT) production, the second cysteine mutant, TcpP-C218S, was partially resistant to proteolytic degradation and maintained ~50% toxT activation capacity. TcpP-C218S was also TcpH independent, since deletion of tcpH did not affect the stability of TcpP-C218S, whereas wild-type TcpP was degraded in the absence of TcpH. Finally, TcpH was also unstable when intramolecular disulfides could not be formed in TcpP, suggesting that the single periplasmic cysteine in TcpH may assist with disulfide bond formation in TcpP by interacting with the periplasmic cysteines of TcpP. Consistent with this finding, a TcpH-C114S mutant was unable to stabilize TcpP and was itself unstable. Our findings demonstrate a periplasmic disulfide bond in TcpP is critical for TcpP stability and virulence gene expression. IMPORTANCE: The Vibrio cholerae transcription factor TcpP, in conjunction with ToxR, regulates transcription of toxT, the master regulator of numerous virulence factors in Vibrio cholerae. TcpP is a membrane-localized transcription factor with a periplasmic domain containing two cysteines. We determined that the two periplasmic cysteines of TcpP form an intramolecular disulfide bond and disruption of the intramolecular disulfide bond in TcpP decreased the stability of TcpP and reduced virulence gene expression. Normally TcpH, another membrane-localized periplasmic protein, protects TcpP from degradation. However, we found that TcpH was also unstable when intramolecular disulfides could not be formed in TcpP, indicating that the periplasmic cysteines of TcpP are required for functional interaction with TcpH and that this interaction is required for both TcpP and TcpH stability. PMID- 26574511 TI - 2-Aminoacrylate Stress Induces a Context-Dependent Glycine Requirement in ridA Strains of Salmonella enterica. AB - The reactive enamine 2-aminoacrylate (2AA) is a metabolic stressor capable of damaging cellular components. Members of the broadly conserved Rid (RidA/YER057c/UK114) protein family mitigate 2AA stress in vivo by facilitating enamine and/or imine hydrolysis. Previous work showed that 2AA accumulation in ridA strains of Salmonella enterica led to the inactivation of multiple target enzymes, including serine hydroxymethyltransferase (GlyA). However, the specific cause of a ridA strain's inability to grow during periods of 2AA stress had yet to be determined. Work presented here shows that glycine supplementation suppressed all 2AA-dependent ridA strain growth defects described to date. Depending on the metabolic context, glycine appeared to suppress ridA strain growth defects by eliciting a GcvB small RNA-dependent regulatory response or by serving as a precursor to one-carbon units produced by the glycine cleavage complex (GCV). In either case, the data suggest that GlyA is the most physiologically sensitive target of 2AA inactivation in S. enterica. The universally conserved nature of GlyA among free-living organisms highlights the importance of RidA in mitigating 2AA stress. IMPORTANCE: The RidA stress response prevents 2-aminoacrylate (2AA) damage from occurring in prokaryotes and eukaryotes alike. 2AA inactivation of serine hydroxymethyltransferase (GlyA) from Salmonella enterica restricts glycine and one-carbon production, ultimately reducing fitness of the organism. The cooccurrence of genes encoding 2AA production enzymes and serine hydroxy-methyltransferase (SHMT) in many genomes may in part underlie the evolutionary selection for Rid proteins to maintain appropriate glycine and one-carbon metabolism throughout life. PMID- 26574512 TI - The Gonococcal NlpD Protein Facilitates Cell Separation by Activating Peptidoglycan Cleavage by AmiC. AB - Key steps in bacterial cell division are the synthesis and subsequent hydrolysis of septal peptidoglycan (PG), which allow efficient separation of daughter cells. Extensive studies in the Gram-negative, rod-shaped bacterium Escherichia coli have revealed that this hydrolysis is highly regulated spatially and temporally. Neisseria gonorrhoeae is an obligate Gram-negative, diplococcal pathogen and is the only causative agent of the sexually transmitted infection gonorrhea. We investigated how cell separation proceeds in this diplococcal organism. We demonstrated that deletion of the nlpD gene in strain FA1090 leads to poor growth and to an altered colony and cell morphology. An isopropyl-beta-d galactopyranoside (IPTG)-regulated nlpD complemented construct can restore these defects only when IPTG is supplied in the growth medium. Thin-section transmission electron microscopy (TEM) revealed that the nlpD mutant strain grew in large clumps containing live and dead bacteria, which was consistent with deficient cell separation. Biochemical analyses of purified NlpD protein showed that it was able to bind purified PG. Finally, we showed that, although NlpD has no hydrolase activity itself, NlpD potentiates the hydrolytic activity of AmiC. These results indicate that N. gonorrhoeae NlpD is required for proper cell growth and division through its interactions with the amidase AmiC. IMPORTANCE: N. gonorrhoeae is the sole causative agent of the sexually transmitted infection gonorrhea. The incidence of antibiotic-resistant gonococcal infections has risen sharply in recent years, and N. gonorrhoeae has been classified as a "superbug" by the CDC. Since there is a dearth of new antibiotics to combat gonococcal infections, elucidating the essential cellular process of N. gonorrhoeae may point to new targets for antimicrobial therapies. Cell division and separation is one such essential process. We identified and characterized the gonococcal nlpD gene and showed that it is essential for cell separation. In contrast to other pathogenic bacteria, the gonococcal system is streamlined and does not appear to have any redundancies. PMID- 26574513 TI - Cyclic Di-GMP Regulates Multiple Cellular Functions in the Symbiotic Alphaproteobacterium Sinorhizobium meliloti. AB - Sinorhizobium meliloti undergoes major lifestyle changes between planktonic states, biofilm formation, and symbiosis with leguminous plant hosts. In many bacteria, the second messenger 3',5'-cyclic di-GMP (c-di-GMP, or cdG) promotes a sessile lifestyle by regulating a plethora of processes involved in biofilm formation, including motility and biosynthesis of exopolysaccharides (EPS). Here, we systematically investigated the role of cdG in S. meliloti Rm2011 encoding 22 proteins putatively associated with cdG synthesis, degradation, or binding. Single mutations in 21 of these genes did not cause evident changes in biofilm formation, motility, or EPS biosynthesis. In contrast, manipulation of cdG levels by overproducing endogenous or heterologous diguanylate cyclases (DGCs) or phosphodiesterases (PDEs) affected these processes and accumulation of N-Acyl homoserine lactones in the culture supernatant. Specifically, individual overexpression of the S. meliloti genes pleD, SMb20523, SMb20447, SMc01464, and SMc03178 encoding putative DGCs and of SMb21517 encoding a single-domain PDE protein had an impact and resulted in increased levels of cdG. Compared to the wild type, an S. meliloti strain that did not produce detectable levels of cdG (cdG(0)) was more sensitive to acid stress. However, it was symbiotically potent, unaffected in motility, and only slightly reduced in biofilm formation. The SMc01790-SMc01796 locus, homologous to the Agrobacterium tumefaciens uppABCDEF cluster governing biosynthesis of a unipolarly localized polysaccharide, was found to be required for cdG-stimulated biofilm formation, while the single domain PilZ protein McrA was identified as a cdG receptor protein involved in regulation of motility. IMPORTANCE: We present the first systematic genome-wide investigation of the role of 3',5'-cyclic di-GMP (c-di-GMP, or cdG) in regulation of motility, biosynthesis of exopolysaccharides, biofilm formation, quorum sensing, and symbiosis in a symbiotic alpha-rhizobial species. Phenotypes of an S. meliloti strain unable to produce cdG (cdG(0)) demonstrated that this second messenger is not essential for root nodule symbiosis but may contribute to acid tolerance. Our data further suggest that enhanced levels of cdG promote sessility of S. meliloti and uncovered a single-domain PilZ protein as regulator of motility. PMID- 26574514 TI - Biochemical Characterization of the Flagellar Rod Components of Rhodobacter sphaeroides: Properties and Interactions. AB - The flagellar basal body is a rotary motor that spans the cytoplasmic and outer membranes. The rod is a drive shaft that transmits torque generated by the motor through the hook to the filament that propels the bacterial cell. The assembly and structure of the rod are poorly understood. In a first attempt to characterize this structure in the alphaproteobacterium Rhodobacter sphaeroides, we overexpressed and purified FliE and the four related rod proteins (FlgB, FlgC, FlgF, and FlgG), and we analyzed their ability to form homo-oligomers. We found that highly purified preparations of these proteins formed high-molecular-mass oligomers that tended to dissociate in the presence of NaCl. As predicted by in silico modeling, the four rod proteins share architectural features. Using affinity blotting, we detected the heteromeric interactions between these proteins. In addition, we observed that deletion of the N- and C-terminal regions of FlgF and FlgG severely affected heteromeric but not homomeric interactions. On the basis of our findings, we propose a model of rod assembly in this bacterium. IMPORTANCE: Despite the considerable amount of research on the structure and assembly of other flagellar axial structures that has been conducted, the rod has been barely studied. An analysis of the biochemical characteristics of the flagellar rod components of the Fla1 system of R. sphaeroides is presented in this work. We also analyze the interactions of these proteins with each other and with their neighbors, and we propose a model for the order in which they are assembled. PMID- 26574515 TI - Creation of Apolipoprotein C-II (ApoC-II) Mutant Mice and Correction of Their Hypertriglyceridemia with an ApoC-II Mimetic Peptide. AB - Apolipoprotein C-II (apoC-II) is a cofactor for lipoprotein lipase, a plasma enzyme that hydrolyzes triglycerides (TGs). ApoC-II deficiency in humans results in hypertriglyceridemia. We used zinc finger nucleases to create Apoc2 mutant mice to investigate the use of C-II-a, a short apoC-II mimetic peptide, as a therapy for apoC-II deficiency. Mutant mice produced a form of apoC-II with an uncleaved signal peptide that preferentially binds high-density lipoproteins (HDLs) due to a 3-amino acid deletion at the signal peptide cleavage site. Homozygous Apoc2 mutant mice had increased plasma TG (757.5 +/- 281.2 mg/dl) and low HDL cholesterol (31.4 +/- 14.7 mg/dl) compared with wild-type mice (TG, 55.9 +/- 13.3 mg/dl; HDL cholesterol, 55.9 +/- 14.3 mg/dl). TGs were found in light (density < 1.063 g/ml) lipoproteins in the size range of very-low-density lipoprotein and chylomicron remnants (40-200 nm). Intravenous injection of C-II-a (0.2, 1, and 5 MUmol/kg) reduced plasma TG in a dose-dependent manner, with a maximum decrease of 90% occurring 30 minutes after the high dose. Plasma TG did not return to baseline until 48 hours later. Similar results were found with subcutaneous or intramuscular injections. Plasma half-life of C-II-a is 1.33 +/- 0.72 hours, indicating that C-II-a only acutely activates lipolysis, and the sustained TG reduction is due to the relatively slow rate of new TG-rich lipoprotein synthesis. In summary, we describe a novel mouse model of apoC-II deficiency and show that an apoC-II mimetic peptide can reverse the hypertriglyceridemia in these mice, and thus could be a potential new therapy for apoC-II deficiency. PMID- 26574516 TI - Comparison of Monoamine Oxidase Inhibitors in Decreasing Production of the Autotoxic Dopamine Metabolite 3,4-Dihydroxyphenylacetaldehyde in PC12 Cells. AB - According to the catecholaldehyde hypothesis, the toxic dopamine metabolite 3,4 dihydroxyphenylacetaldehyde (DOPAL) contributes to the loss of nigrostriatal dopaminergic neurons in Parkinson's disease. Monoamine oxidase-A (MAO-A) catalyzes the conversion of intraneuronal dopamine to DOPAL and may serve as a therapeutic target. The "cheese effect"-paroxysmal hypertension evoked by tyramine-containing foodstuffs-limits clinical use of irreversible MAO-A inhibitors. Combined MAO-A/B inhibition decreases DOPAL production in rat pheochromocytoma PC12 cells, but whether reversible MAO-A inhibitors or MAO-B inhibitors decrease endogenous DOPAL production is unknown. We compared the potencies of MAO inhibitors in attenuating DOPAL production and examined possible secondary effects on dopamine storage, constitutive release, synthesis, and auto oxidation. Catechol concentrations were measured in cells and medium after incubation with the irreversible MAO-A inhibitor clorgyline, three reversible MAO A inhibitors, or the MAO-B inhibitors selegiline or rasagiline for 180 minutes. Reversible MAO-A inhibitors were generally ineffective, whereas clorgyline (1 nM), rasagiline (500 nM), and selegiline (500 nM) decreased DOPAL levels in the cells and medium. All three drugs also increased dopamine and norepinephrine, decreased 3,4-dihydroxyphenylalanine, and increased cysteinyl-dopamine concentrations in the medium, suggesting increased vesicular uptake and constitutive release, decreased dopamine synthesis, and increased dopamine spontaneous oxidation. In conclusion, clorgyline, rasagiline, and selegiline decrease production of endogenous DOPAL. At relatively high concentrations, the latter drugs probably lose their selectivity for MAO-B. Possibly offsetting increased formation of potentially toxic oxidation products and decreased formation of DOPAL might account for the failure of large clinical trials of MAO B inhibitors to demonstrate slowing of neurodegeneration in Parkinson's disease. PMID- 26574517 TI - Sigma-2 Receptors Play a Role in Cellular Metabolism: Stimulation of Glycolytic Hallmarks by CM764 in Human SK-N-SH Neuroblastoma. AB - Sigma-2 receptors are attractive antineoplastic targets due to their ability to induce apoptosis and their upregulation in rapidly proliferating cancer cells compared with healthy tissue. However, this role is inconsistent with overexpression in cancer, which is typically associated with upregulation of prosurvival factors. Here, we report a novel metabolic regulatory function for sigma-2 receptors. CM764 [6-acetyl-3-(4-(4-(2-amino-4-fluorophenyl)piperazin-1 yl)butyl)benzo[d]oxazol-2(3H)-one] binds with Ki values of 86.6 +/- 2.8 and 3.5 +/- 0.9 nM at the sigma-1 and sigma-2 receptors, respectively. CM764 increased reduction of MTT [3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide] in human SK-N-SH neuroblastoma compared with untreated cells, an effect not due to proliferation. This effect was attenuated by five different sigma antagonists, including CM572 [3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)-6 isothiocyanatobenzo[d]oxazol-2(3H)-one], which has no significant affinity for sigma-1 receptors. This effect was also observed in MG-63 osteosarcoma and HEK293T cells, indicating that this function is not exclusive to neuroblastoma or to cancer cells. CM764 produced an immediate, robust, and transient increase in cytosolic calcium, consistent with sigma-2 receptor activation. Additionally, we observed an increase in the total NAD(+)/NADH level and the ATP level in CM764 treated SK-N-SH cells compared with untreated cells. After only 4 hours of treatment, basal levels of reactive oxygen species were reduced by 90% in cells treated with CM764 over untreated cells, and HIF1alpha and VEGF levels were increased after 3-24 hours of treatment. These data indicate that sigma-2 receptors may play a role in induction of glycolysis, representing a possible prosurvival function for the sigma-2 receptor that is consistent with its upregulation in cancer cells compared with healthy tissue. PMID- 26574519 TI - Erratum: Profiling ribonucleotide modifications at full-transcriptome level: a step toward MS-based epitranscriptomics. PMID- 26574522 TI - Carbon dioxide pressure-induced coagulation of microalgae. AB - The move to a low-carbon economy has generated renewed interest in microalgae for the production of biofuels with the potential mutual benefit of wastewater treatment. However, harvesting has been identified as a limiting factor to the economic viability of this process. This paper explores the harvesting of microalgae using high-pressure gas without the addition of coagulants. Coagulation of microalgae under high-pressure gas was found to be an efficient method to separate algae from suspension. The critical coagulation pressures (CCPs) for H(2) and CO(2) were determined to be 6.1 and 6.2 MPa, respectively. The CO(2)-induced decrease in solution pH positively influenced coagulation rates, without appearing to affect the CCP. This approach could be beneficial for the economic removal of microalgae from solution for the production of both biofuels and biomedical compounds without the addition of non-environmentally friendly chemicals. PMID- 26574518 TI - The recruitment of chromatin modifiers by long noncoding RNAs: lessons from PRC2. AB - Polycomb repressive complex-2 (PRC2) is a histone methyltransferase required for epigenetic silencing during development and cancer. Among chromatin modifying factors shown to be recruited and regulated by long noncoding RNAs (lncRNAs), PRC2 is one of the most studied. Mammalian PRC2 binds thousands of RNAs in vivo, and it is becoming a model system for the recruitment of chromatin modifying factors by RNA. Yet, well-defined PRC2-binding motifs within target RNAs have been elusive. From the protein side, PRC2 RNA-binding subunits contain no known RNA-binding domains, complicating functional studies. Here we provide a critical review of existing models for the recruitment of PRC2 to chromatin by RNAs. This discussion may also serve researchers who are studying the recruitment of other chromatin modifiers by lncRNAs. PMID- 26574524 TI - Green solvent for green materials: a supercritical hydrothermal method and shape controlled synthesis of Cr-doped CeO2 nanoparticles. AB - This paper describes a supercritical hydrothermal synthesis method as a green solvent process, along with products based on this method that can be used as green materials that contribute to solving environmental problems. The first part of this paper summarizes the basics of this method, including the mechanism of the reactions, specific features of the supercritical state for nanoparticle synthesis, the continuous flow-type reactor and applications; this provides a better understanding of the suitability of this method to synthesize green materials. The second part of the paper describes the method used to synthesize Cr-doped CeO(2) nanoparticles, which show an extremely high oxygen storage capacity, suggesting their high potential as an environmental catalyst. Transmission electron microscopy and scanning electron microscope images showed octahedral Cr-doped CeO(2) nanoparticles with sizes of 15-30 nm and cubic Cr doped CeO(2) nanoparticles with sizes of 5-8 nm. Octahedral Cr-doped CeO(2) nanoparticles exposing (111) facets and cubic Cr-doped CeO(2) nanoparticles exposing (100) facets were determined by high-resolution transmission electron microscopy and selected area electron diffraction. The X-ray diffraction peaks shifted to a high angle because the radius of the Cr ion is smaller than that of the Ce ion. PMID- 26574523 TI - Unlocking the potential of supported liquid phase catalysts with supercritical fluids: low temperature continuous flow catalysis with integrated product separation. AB - Solution-phase catalysis using molecular transition metal complexes is an extremely powerful tool for chemical synthesis and a key technology for sustainable manufacturing. However, as the reaction complexity and thermal sensitivity of the catalytic system increase, engineering challenges associated with product separation and catalyst recovery can override the value of the product. This persistent downstream issue often renders industrial exploitation of homogeneous catalysis uneconomical despite impressive batch performance of the catalyst. In this regard, continuous-flow systems that allow steady-state homogeneous turnover in a stationary liquid phase while at the same time effecting integrated product separation at mild process temperatures represent a particularly attractive scenario. While continuous-flow processing is a standard procedure for large volume manufacturing, capitalizing on its potential in the realm of the molecular complexity of organic synthesis is still an emerging area that requires innovative solutions. Here we highlight some recent developments which have succeeded in realizing such systems by the combination of near- and supercritical fluids with homogeneous catalysts in supported liquid phases. The cases discussed exemplify how all three levels of continuous-flow homogeneous catalysis (catalyst system, separation strategy, process scheme) must be matched to locate viable process conditions. PMID- 26574525 TI - Deposition of Ni nanoparticles onto porous supports using supercritical CO2: effect of the precursor and reduction methodology. AB - The deposition of Ni nanoparticles into porous supports is very important in catalysis. In this paper, we explore the use of supercritical CO(2) (scCO(2)) as a green solvent to deposit Ni nanoparticles on mesoporous SiO2 SBA-15 and a carbon xerogel. The good transport properties of scCO(2) allowed the efficient penetration of metal precursors dissolved in scCO(2) within the pores of the support without damaging its structure. Nickel hexafluoroacetylacetonate hydrate, nickel acetylacetonate, bis(cyclopentadienyl)nickel, Ni(NO(3))2?6H(2)O and NiCl(2)?6H(2)O were tried as precursors. Different methodologies were used: impregnation in scCO(2) and reduction in H(2)/N(2) at 400 degrees C and low pressure, reactive deposition using H(2) at 200-250 degrees C in scCO(2) and reactive deposition using ethanol at 150-200 degrees C in scCO(2). The effect of precursor and methodology on the nickel particle size and the material homogeneity (on the different substrates) was analysed. This technology offers many opportunities in the preparation of metal-nanostructured materials. PMID- 26574526 TI - Synthesis of higher alcohols from CO2 hydrogenation over a PtRu/Fe2O3 catalyst under supercritical condition. AB - Hydrogenation of CO(2) to alcohols is of great importance, especially when producing higher alcohols. In this work, we synthesized heterogeneous PtRu/Fe(2)O(3), in which the Pt and Ru bimetallic catalysts were supported on Fe(2)O(3). The catalyst was used to catalyse CO(2) hydrogenation to alcohols. It was demonstrated that the activity and selectivity could be tuned by the bimetallic composition, and the catalyst with a Pt to Ru molar ratio of 1:2 (Pt(1)Ru(2)/Fe(2)O(3)) had high activity and selectivity at 200 degrees C, which is very low for heterogeneous hydrogenation of CO(2) to produce higher alcohols. The conversion and the selectivity increased with increasing pressures of CO(2) and/or H(2). The catalyst could be reused at least five times without any obvious change in activity or selectivity. PMID- 26574527 TI - Electrochemistry in supercritical fluids. AB - A wide range of supercritical fluids (SCFs) have been studied as solvents for electrochemistry with carbon dioxide and hydrofluorocarbons (HFCs) being the most extensively studied. Recent advances have shown that it is possible to get well resolved voltammetry in SCFs by suitable choice of the conditions and the electrolyte. In this review, we discuss the voltammetry obtained in these systems, studies of the double-layer capacitance, work on the electrodeposition of metals into high aspect ratio nanopores and the use of metallocenes as redox probes and standards in both supercritical carbon dioxide-acetonitrile and supercritical HFCs. PMID- 26574528 TI - Supercritical carbon dioxide design strategies: from drug carriers to soft killers. AB - The integrated use of supercritical carbon dioxide (scCO(2)) and micro- and nanotechnologies has enabled new sustainable strategies for the manufacturing of new medications. 'Green' scCO(2)-based methodologies are well suited to improve either the synthesis or materials processing leading to the assembly of three dimensional multifunctional constructs. By using scCO(2) either as C1 feedstock or as solvent, simple, economic, efficient and clean routes can be designed to synthesize materials with unique properties such as polyurea dendrimers and oxazoline-based polymers/oligomers. These new biocompatible, biodegradable and water-soluble polymeric materials can be engineered into multifunctional constructs with antimicrobial activity, targeting moieties, labelling units and/or efficiently loaded with therapeutics. This mini-review highlights the particular features exhibited by these materials resulting directly from the followed supercritical routes. PMID- 26574529 TI - Green process for green materials: viable low-temperature lipase-catalysed synthesis of renewable telechelics in supercritical CO2. AB - We present a novel near-ambient-temperature approach to telechelic renewable polyesters by exploiting the unique properties of supercritical CO(2) (scCO(2)). Bio-based commercially available monomers have been polymerized and functional telechelic materials with targeted molecular weight prepared by end-capping the chains with molecules containing reactive moieties in a one-pot reaction. The use of scCO(2) as a reaction medium facilitates the effective use of Candida antarctica Lipase B (CaLB) as a catalyst at a temperature as low as 35 degrees C, hence avoiding side reactions, maintaining the end-capper functionality and preserving the enzyme activity. The functionalized polymer products have been characterized by (1)H nuclear magnetic resonance spectroscopy, matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry, gel permeation chromatography and differential scanning calorimetry in order to carefully assess their structural and thermal properties. We demonstrate that telechelic materials can be produced enzymatically at mild temperatures, in a solvent-free system and using renewably sourced monomers without pre-modification, by exploiting the unique properties of scCO(2). The macromolecules we prepare are ideal green precursors that can be further reacted to prepare useful bio-derived films and coatings. PMID- 26574530 TI - Supercritical water oxidation for the destruction of hazardous waste: better than incineration. AB - Supercritical water oxidation (SCWO) is an advanced process mainly employed for the treatment of hazardous stable wastes, otherwise treatable by incineration. It is based on the unique properties of water above its critical point (T(c)=675 K, P(c)=22.2 MPa), making it a superior reaction medium for the destruction of all organics in the presence of oxygen. This work presents preliminary laboratory scale studies on SCWO of nitrogen (N)-containing hazardous hydrocarbons, with a view to enhancing the process performance, using available reagents and non complex reactor design. This article investigates the destruction of dimethylformamide (DMF), carried out in a continuous (plug flow) reactor system. SCWO of DMF was enhanced by (i) a split-oxidant system, where stoichiometric oxidant was divided between two inlet ports at various ratios and (ii) the addition of isopropyl alcohol (IPA) as a co-fuel, premixed with the feedstock. Testing a range of temperatures, initial DMF concentrations, oxidant ratios, IPA ratios and oxidant split ratios, selected results were presented in terms of % total organic carbon and % N removal. Reaction kinetics were studied and showed a dramatic decrease in the activation energy upon adding IPA. Split-oxidant-feeding enhancement depended on the split ratio and secondary feed position. PMID- 26574531 TI - Solubility of CO2 in [1-n-butylthiolanium][Tf2N]+toluene mixtures: liquid-liquid phase split separation and modelling. AB - Carbon dioxide has been shown to be an effective antisolvent gas for separating organic compounds from ionic liquids (ILs) by inducing a liquid-vapour to liquid liquid-vapour transition. Using carbon dioxide, toluene can be separated from imidazolium, phosphonium and pyridinum cation-based ILs with the bis(trifluoromethylsulfonyl)imide anion, which is relatively hydrophobic and has a high toluene solubility. A new IL with relatively low viscosity is tested here for the same toluene separation process: 1-n-butylthiolanium bis(trifluoromethylsulfonyl)imide. Carbon dioxide solubility in binary and ternary systems containing toluene and 1-n-butylthiolanium bis(trifluoromethylsulfonyl)imide is measured at 298.15 and 313.15 K up to 7.4 MPa. Solubility behaviour in this IL is similar to imidazolium-based ILs with the same anion. However, phase split pressures are lower when 1-n-butylthiolanium bis (trifluoromethylsulfonyl)imide is used instead of 1- n-hexyl-3-methylimidazolium bis(trifluoromethylsu- lfonyl)imide at the same conditions of temperature and initial composition of toluene in the IL. Solubility data are modelled with the conductor-like screening model for real solvents combined with the Soave-Redlich Kwong equation of state, which provides good qualitative results. PMID- 26574532 TI - Supercritical fluids: green solvents for green chemistry? PMID- 26574533 TI - Continuous-flow hydrothermal synthesis for the production of inorganic nanomaterials. AB - As nanotechnology becomes increasingly important and ubiquitous, new and scalable synthetic approaches are needed to meet the growing demand for industrially viable routes to nanomaterial production. Continuous-flow hydrothermal synthesis or supercritical water hydrothermal synthesis (scWHS) is emerging as a versatile solution to this problem. The process was initially developed to take advantage of the tunable chemical and physical properties of superheated water to produce metal oxide nanoparticles by rapid nucleation and precipitation. The development of new mixing regimes and reactor designs has been facilitated by the modelling of reactor systems. These new reactor designs further exploit the properties of supercritical water to promote faster and more uniform mixing of reagent streams. The synthetic approach has been expanded beyond the metal oxide systems for which it was conceived, and now encompasses metal sulfides, metal phosphates, metal nanoparticles and metal-organic frameworks. In many of these cases, some degree of size and shape control can be achieved through careful consideration of both chemistry and reactor design. This review briefly considers the development of scWHS reactor technology, before highlighting some of our recent work in expanding the scope of this synthetic method to include a wide range of materials. PMID- 26574535 TI - Time window for recanalization in basilar artery occlusion: Speculative synthesis. AB - Basilar artery occlusion (BAO) is one of the most devastating forms of stroke and few patients have good outcomes without recanalization. Most centers apply recanalization therapies for BAO up to 12-24 hours after symptom onset, which is a substantially longer time window than the 4.5 hours used in anterior circulation stroke. In this speculative synthesis, we discuss recent advances in BAO treatment in order to understand why and under which circumstances longer symptom duration might not necrotize the brainstem and turn therapeutic attempts futile. We raise the possibility that distinct features of the posterior circulation, e.g., highly developed, persistent collateral arterial network, reverse filling of the distal basilar artery, and delicate plasma flow siding the clot, might sustain brittle patency of brainstem perforators in the face of stepwise growth of the thrombus. Meanwhile, the tissue clock characterizing the rapid necrosis of a typical anterior circulation penumbra will not start. During this perilous time period, recanalization at any point would salvage the brainstem from eventual necrosis caused by imminent reinforcement and further building up of the clot. PMID- 26574534 TI - Danger peptide receptor signaling in plants ensures basal immunity upon pathogen induced depletion of BAK1. AB - Pathogens infect a host by suppressing defense responses induced upon recognition of microbe-associated molecular patterns (MAMPs). Despite this suppression, MAMP receptors mediate basal resistance to limit host susceptibility, via a process that is poorly understood. The Arabidopsis leucine-rich repeat (LRR) receptor kinase BAK1 associates and functions with different cell surface LRR receptors for a wide range of ligands, including MAMPs. We report that BAK1 depletion is linked to defense activation through the endogenous PROPEP peptides (Pep epitopes) and their LRR receptor kinases PEPR1/PEPR2, despite critical defects in MAMP signaling. In bak1-knockout plants, PEPR elicitation results in extensive cell death and the prioritization of salicylate-based defenses over jasmonate based defenses, in addition to elevated proligand and receptor accumulation. BAK1 disruption stimulates the release of PROPEP3, produced in response to Pep application and during pathogen challenge, and renders PEPRs necessary for basal resistance. These findings are biologically relevant, since specific BAK1 depletion coincides with PEPR-dependent resistance to the fungal pathogen Colletotrichum higginsianum. Thus, the PEPR pathway ensures basal resistance when MAMP-triggered defenses are compromised by BAK1 depletion. PMID- 26574536 TI - CNS angiitis as a brain tumor mimic with a branching vascular abnormality on T2* MRI. PMID- 26574537 TI - Angiographic appearance of a cerebral aneurysm rupture. PMID- 26574538 TI - Clinical Reasoning: A 57-year-old woman who developed acute amnesia following fever and upper respiratory symptoms. PMID- 26574539 TI - Spatial cluster analysis of population amyotrophic lateral sclerosis risk in Ireland. PMID- 26574540 TI - CNS neutrophilic vasculitis in neuro-Sweet disease. AB - In the Clinical/Scientific Note "CNS neutrophilic vasculitis in neuro-Sweet disease" by R. Charlson et al. (Neurology(r) 2015;85:829-830), there is an error in the discussion and the references. The last name of the first author of reference 2 should be Hisanaga, not Hisanga as originally published. The authors regret the error. PMID- 26574541 TI - Teaching NeuroImages: Hippocampal foci of restricted diffusion in transient global amnesia. PMID- 26574542 TI - Teaching NeuroImages: Ornithine transcarbamylase deficiency revealed by a coma in a pregnant woman. PMID- 26574543 TI - The Non-structural Protein of Crimean-Congo Hemorrhagic Fever Virus Disrupts the Mitochondrial Membrane Potential and Induces Apoptosis. AB - Viruses have developed distinct strategies to overcome the host defense system. Regulation of apoptosis in response to viral infection is important for virus survival and dissemination. Like other viruses, Crimean-Congo hemorrhagic fever virus (CCHFV) is known to regulate apoptosis. This study, for the first time, suggests that the non-structural protein NSs of CCHFV, a member of the genus Nairovirus, induces apoptosis. In this report, we demonstrated the expression of CCHFV NSs, which contains 150 amino acid residues, in CCHFV-infected cells. CCHFV NSs undergoes active degradation during infection. We further demonstrated that ectopic expression of CCHFV NSs induces apoptosis, as reflected by caspase-3/7 activity and cleaved poly(ADP-ribose) polymerase, in different cell lines that support CCHFV replication. Using specific inhibitors, we showed that CCHFV NSs induces apoptosis via both intrinsic and extrinsic pathways. The minimal active region of the CCHFV NSs protein was determined to be 93-140 amino acid residues. Using alanine scanning, we demonstrated that Leu-127 and Leu-135 are the key residues for NSs-induced apoptosis. Interestingly, CCHFV NSs co-localizes in mitochondria and also disrupts the mitochondrial membrane potential. We also demonstrated that Leu-127 and Leu-135 are important residues for disruption of the mitochondrial membrane potential by NSs. Therefore, these results indicate that the C terminus of CCHFV NSs triggers mitochondrial membrane permeabilization, leading to activation of caspases, which, ultimately, leads to apoptosis. Given that multiple factors contribute to apoptosis during CCHFV infection, further studies are needed to define the involvement of CCHFV NSs in regulating apoptosis in infected cells. PMID- 26574544 TI - Proteolytic Processing of Neuregulin 1 Type III by Three Intramembrane-cleaving Proteases. AB - Numerous membrane-bound proteins undergo regulated intramembrane proteolysis. Regulated intramembrane proteolysis is initiated by shedding, and the remaining stubs are further processed by intramembrane-cleaving proteases (I-CLiPs). Neuregulin 1 type III (NRG1 type III) is a major physiological substrate of beta secretase (beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1)). BACE1 mediated cleavage is required to allow signaling of NRG1 type III. Because of the hairpin nature of NRG1 type III, two membrane-bound stubs with a type 1 and a type 2 orientation are generated by proteolytic processing. We demonstrate that these stubs are substrates for three I-CLiPs. The type 1-oriented stub is further cleaved by gamma-secretase at an epsilon-like site five amino acids N-terminal to the C-terminal membrane anchor and at a gamma-like site in the middle of the transmembrane domain. The epsilon-cleavage site is only one amino acid N-terminal to a Val/Leu substitution associated with schizophrenia. The mutation reduces generation of the NRG1 type III beta-peptide as well as reverses signaling. Moreover, it affects the cleavage precision of gamma-secretase at the gamma-site similar to certain Alzheimer disease-associated mutations within the amyloid precursor protein. The type 2-oriented membrane-retained stub of NRG1 type III is further processed by signal peptide peptidase-like proteases SPPL2a and SPPL2b. Expression of catalytically inactive aspartate mutations as well as treatment with 2,2'-(2-oxo-1,3-propanediyl)bis[(phenylmethoxy)carbonyl]-l-leucyl-l leucinamide ketone inhibits formation of N-terminal intracellular domains and the corresponding secreted C-peptide. Thus, NRG1 type III is the first protein substrate that is not only cleaved by multiple sheddases but is also processed by three different I-CLiPs. PMID- 26574545 TI - Ankyrin-G Inhibits Endocytosis of Cadherin Dimers. AB - Dynamic regulation of endothelial cell adhesion is central to vascular development and maintenance. Furthermore, altered endothelial adhesion is implicated in numerous diseases. Therefore, normal vascular patterning and maintenance require tight regulation of endothelial cell adhesion dynamics. However, the mechanisms that control junctional plasticity are not fully understood. Vascular endothelial cadherin (VE-cadherin) is an adhesive protein found in adherens junctions of endothelial cells. VE-cadherin mediates adhesion through trans interactions formed by its extracellular domain. Trans binding is followed by cis interactions that laterally cluster the cadherin in junctions. VE cadherin is linked to the actin cytoskeleton through cytoplasmic interactions with beta- and alpha-catenin, which serve to increase adhesive strength. Furthermore, p120-catenin binds to the cytoplasmic tail of cadherin and stabilizes it at the plasma membrane. Here we report that induced cis dimerization of VE-cadherin inhibits endocytosis independent of both p120 binding and trans interactions. However, we find that ankyrin-G, a protein that links membrane proteins to the spectrin-actin cytoskeleton, associates with VE-cadherin and inhibits its endocytosis. Ankyrin-G inhibits VE-cadherin endocytosis independent of p120 binding. We propose a model in which ankyrin-G associates with and inhibits the endocytosis of VE-cadherin cis dimers. Our findings support a novel mechanism for regulation of VE-cadherin endocytosis through ankyrin association with cadherin engaged in lateral interactions. PMID- 26574546 TI - Structural Plasticity of the Protein Plug That Traps Newly Packaged Genomes in Podoviridae Virions. AB - Bacterial viruses of the P22-like family encode a specialized tail needle essential for genome stabilization after DNA packaging and implicated in Gram negative cell envelope penetration. The atomic structure of P22 tail needle (gp26) crystallized at acidic pH reveals a slender fiber containing an N-terminal "trimer of hairpins" tip. Although the length and composition of tail needles vary significantly in Podoviridae, unexpectedly, the amino acid sequence of the N terminal tip is exceptionally conserved in more than 200 genomes of P22-like phages and prophages. In this paper, we used x-ray crystallography and EM to investigate the neutral pH structure of three tail needles from bacteriophage P22, HK620, and Sf6. In all cases, we found that the N-terminal tip is poorly structured, in stark contrast to the compact trimer of hairpins seen in gp26 crystallized at acidic pH. Hydrogen-deuterium exchange mass spectrometry, limited proteolysis, circular dichroism spectroscopy, and gel filtration chromatography revealed that the N-terminal tip is highly dynamic in solution and unlikely to adopt a stable trimeric conformation at physiological pH. This is supported by the cryo-EM reconstruction of P22 mature virion tail, where the density of gp26 N terminal tip is incompatible with a trimer of hairpins. We propose the tail needle N-terminal tip exists in two conformations: a pre-ejection extended conformation, which seals the portal vertex after genome packaging, and a postejection trimer of hairpins, which forms upon its release from the virion. The conformational plasticity of the tail needle N-terminal tip is built in the amino acid sequence, explaining its extraordinary conservation in nature. PMID- 26574548 TI - A systematic review of stroke recognition instruments in hospital and prehospital settings. AB - BACKGROUND: We undertook a systematic review of all published stroke identification instruments to describe their performance characteristics when used prospectively in any clinical setting. METHODS: A search strategy was applied to Medline and Embase for material published prior to 10 August 2015. Two authors independently screened titles, and abstracts as necessary. Data including clinical setting, reported sensitivity, specificity, positive predictive value, negative predictive value were extracted independently by two reviewers. RESULTS: 5622 references were screened by title and or abstract. 18 papers and 3 conference abstracts were included after full text review. 7 instruments were identified; Face Arm Speech Test (FAST), Recognition of Stroke in the Emergency Room (ROSIER), Los Angeles Prehospital Stroke Screen (LAPSS), Melbourne Ambulance Stroke Scale (MASS), Ontario Prehospital Stroke Screening tool (OPSS), Medic Prehospital Assessment for Code Stroke (MedPACS) and Cincinnati Prehospital Stroke Scale (CPSS). Cohorts varied between 50 and 1225 individuals, with 17.5% to 92% subsequently receiving a stroke diagnosis. Sensitivity and specificity for the same instrument varied across clinical settings. Studies varied in terms of quality, scoring 13-31/36 points using modified Standards for the Reporting of Diagnostic accuracy studies checklist. There was considerable variation in the detail reported about patient demographics, characteristics of false-negative patients and service context. Prevalence of instrument detectable stroke varied between cohorts and over time. CPSS and the similar FAST test generally report the highest level of sensitivity, with more complex instruments such as LAPSS reporting higher specificity at the cost of lower detection rates. CONCLUSIONS: Available data do not allow a strong recommendation to be made about the superiority of a stroke recognition instrument. Choice of instrument depends on intended purpose, and the consequences of a false-negative or false-positive result. PMID- 26574549 TI - The Scope and Standards of Holistic Nursing Practice: Guideposts for Development of Manuscripts. PMID- 26574547 TI - Zn2+-dependent Activation of the Trk Signaling Pathway Induces Phosphorylation of the Brain-enriched Tyrosine Phosphatase STEP: MOLECULAR BASIS FOR ZN2+-INDUCED ERK MAPK ACTIVATION. AB - Excessive release of Zn(2+) in the brain is implicated in the progression of acute brain injuries. Although several signaling cascades have been reported to be involved in Zn(2+)-induced neurotoxicity, a potential contribution of tyrosine phosphatases in this process has not been well explored. Here we show that exposure to high concentrations of Zn(2+) led to a progressive increase in phosphorylation of the striatal-enriched phosphatase (STEP), a component of the excitotoxic-signaling pathway that plays a role in neuroprotection. Zn(2+) mediated phosphorylation of STEP61 at multiple sites (hyperphosphorylation) was induced by the up-regulation of brain-derived neurotropic factor (BDNF), tropomyosin receptor kinase (Trk) signaling, and activation of cAMP-dependent PKA (protein kinase A). Mutational studies further show that differential phosphorylation of STEP61 at the PKA sites, Ser-160 and Ser-221 regulates the affinity of STEP61 toward its substrates. Consistent with these findings we also show that BDNF/Trk/PKA mediated signaling is required for Zn(2+)-induced phosphorylation of extracellular regulated kinase 2 (ERK2), a substrate of STEP that is involved in Zn(2+)-dependent neurotoxicity. The strong correlation between the temporal profile of STEP61 hyperphosphorylation and ERK2 phosphorylation indicates that loss of function of STEP61 through phosphorylation is necessary for maintaining sustained ERK2 phosphorylation. This interpretation is further supported by the findings that deletion of the STEP gene led to a rapid and sustained increase in ERK2 phosphorylation within minutes of exposure to Zn(2+). The study provides further insight into the mechanisms of regulation of STEP61 and also offers a molecular basis for the Zn(2+)-induced sustained activation of ERK2. PMID- 26574551 TI - Impact of Exposure to Electronic Cigarette Advertising on Susceptibility and Trial of Electronic Cigarettes and Cigarettes in US Young Adults: A Randomized Controlled Trial. AB - INTRODUCTION: This study assessed the impact of brief exposure to four electronic cigarette (e-cigarette) print advertisements (ads) on perceptions, intention, and subsequent use of e-cigarettes and cigarettes in US young adults. METHODS: A randomized controlled trial was conducted in a national sample of young adults from an online panel survey in 2013. Participants were randomized to ad exposure or control. Curiosity, intentions, and perceptions regarding e-cigarettes were assessed post-exposure and e-cigarette and cigarette use at 6-month follow-up. Analyses were conducted in 2014. RESULTS: Approximately 6% of young adults who had never used an e-cigarette at baseline tried an e-cigarette at 6-month follow up, half of whom were current cigarette smokers at baseline. Compared to the control group, ad exposure was associated with greater curiosity to try an e cigarette (18.3% exposed vs. 11.3% unexposed, AOR = 1.63, 95% CI = 1.18, 2.26) among never e-cigarette users and greater likelihood of e-cigarette trial at follow-up (3.6% exposed vs. 1.2% unexposed, AOR = 2.85; 95% CI = 1.07, 7.61) among never users of cigarettes and e-cigarettes. Exploratory analyses did not find an association between ad exposure and cigarette trial or past 30-day use among never users, nor cigarette use among smokers over time. Curiosity mediated the relationship between ad exposure and e-cigarette trial among e-cigarette never users. CONCLUSIONS: Exposure to e-cigarette ads may enhance curiosity and limited trial of e-cigarettes in never users. Future studies are needed to examine the net effect of curiosity and trial of e-cigarettes on longer-term patterns of tobacco use. IMPLICATIONS: This randomized trial provides the first evidence of the effect of e-cigarette advertising on a behavioral outcome in young adults. Compared to the control group, ad exposure was associated with greater curiosity to try an e-cigarette among never e-cigarette users and greater likelihood of e-cigarette trial at follow-up in a small number of never e cigarette users and greater likelihood of e-cigarette trial at follow-up among never users of cigarettes and e-cigarettes. PMID- 26574552 TI - Associations Between Cardiovascular Risk Factors, Inflammation, and Progression of Carotid Atherosclerosis Among Smokers. AB - INTRODUCTION: The high risk of cardiovascular events in smokers requires adequate control of other cardiovascular risk factors (CVRFs) to curtail atherosclerosis progression. However, it is unclear which CVRFs have the most influence on atherosclerosis progression in smokers. METHODS: In 260 smokers aged 40-70 included in a smoking cessation trial, we analyzed the association between traditional CVRFs, high-sensitivity C-reactive protein (hs-CRP), smoking cessation and 3-year progression of carotid intima-media thickness (CIMT, assessed by repeated ultrasound measurements) in a longitudinal multivariate model. RESULTS: Participants (mean age 52 years, 47% women) had a mean smoking duration of 32 years with a median daily consumption of 20 cigarettes. Baseline CIMT was 1185 MUm (95% confidence interval [CI]: 1082-1287) and increased by 93 MUm (95% CI: 25-161) and 108 MUm (95% CI: 33-183) after 1 and 3 years, respectively. Age, male sex, daily cigarette consumption, systolic blood pressure (SBP), but neither low-density lipoprotein cholesterol nor hs-CRP, were independently associated with baseline CIMT (all P <= .05). Baseline SBP, but neither low-density lipoprotein cholesterol nor hs-CRP, was associated with 3 year atherosclerosis progression (P = .01 at 3 years). The higher the SBP at baseline, the steeper was the CIMT increase over 3-year follow-up. We found an increase of 26 MUm per each 10-mmHg raise in SBP at 1 year and an increase of 39 MUm per each 10 mmHg raise in SBP at 3 years. Due to insufficient statistical power, we could not exclude an effect of smoking abstinence on CIMT progression. CONCLUSION: Control of blood pressure may be an important factor to limit atherosclerosis progression in smokers, besides support for smoking cessation. IMPLICATIONS: Among 260 smokers aged 40-70 years with a mean smoking duration of 32 years, baseline SBP was associated with atherosclerosis progression over 3 years, as measured by CIMT (P = .01 at 3 years), independently of smoking variables and other CVRFs. The higher the SBP at baseline, the steeper was the CIMT increase over 3-year follow-up. Our findings emphasize the importance of focusing not only on smoking cessation among smokers, but to simultaneously control other CVRFs, particularly blood pressure, in order to prevent future cardiovascular disease. PMID- 26574553 TI - Influence of Cigarette Package Brand on the Emotional Impact of Tobacco-Warning Images That Cover 30% of Cigarette Packs in Smokers and Nonsmokers. AB - INTRODUCTION: Research on the emotional impact of tobacco-warning images (TWIs) has not evaluated the role of context (ie, cigarette packs) as a modulator of the emotional response to TWIs. The objective of the present study was to identify the influence of the cigarette package brand on the emotional impact of TWIs that cover 30% of cigarette packs in smokers and nonsmokers using a specific methodology for the study of emotion. METHODS: The participants included 95 smokers and 111 nonsmokers who observed three TWIs under two conditions: TWIs that covered 30% of cigarette packs and TWIs alone, without brands. Additionally, 18 pictures from the International Affective Picture System were presented as comparison stimuli and to reduce the effect of habituation. The Self-Assessment Manikin was used to assess valence, arousal, and dominance dimensions. RESULTS: TWIs that covered 30% of cigarette packs were evaluated as least aversive, with lower ratings of arousal and higher ratings of dominance in both groups. Differences in the valence, arousal, and dominance dimensions were found between groups. Smokers rated TWIs that covered 30% of cigarette packs as less aversive and more arousing and gave them lower dominance scores compared with nonsmokers. CONCLUSION: The results suggest that cigarette packages modulate the emotional impact of TWIs, especially in smokers, and the minimum size of TWIs (ie, 30% of the front and back of the package) is not sufficiently large to generate an emotional impact associated with avoidance behavior. IMPLICATIONS: Cigarette packages modulate the emotional impact of TWIs, especially in smokers. The cigarette package itself is an appetitive context that captures the attention of the observer and decreases the aversive emotional response to the TWIs. The minimum size of TWIs (ie, 30% of the front and back of the package) is not sufficiently large to generate an emotional impact associated with avoidance behavior. PMID- 26574554 TI - Role of Keratinocyte Growth Factor in the Differentiation of Sweat Gland-Like Cells From Human Umbilical Cord-Derived Mesenchymal Stem Cells. AB - Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) have higher proliferation potency and lower immune resistance than human bone marrow MSCs and can differentiate into various functional cells. Many regulatory factors, including keratinocyte growth factor (KGF), are involved in the development of skin and cutaneous appendages. Although KGF is important in wound healing, the role of KGF in hUC-MSC differentiation remains unknown. In our previous work, we found the mixing medium (nine parts of basic sweat-gland [SG] medium plus one part of conditioned heat-shock SG medium) could induce hUC-MSC differentiation to sweat gland-like cells (SGCs). In this study, we further improved the inducing medium and determined the effects of KGF in hUC-MSC differentiation. We found KGF expression in the SGCs and that recombinant human KGF could induce hUC-MSC differentiation into SGCs, suggesting KGF plays a pivotal role in promoting hUC MSC differentiation to SGCs. Furthermore, the SGCs differentiated from hUC-MSCs were applied to severely burned skin of the paw of an in vivo severe combined immunodeficiency mouse burn model. Burned paws treated with SGCs could regenerate functional sparse SGs 21 days after treatment; the untreated control paws could not. Collectively, these results demonstrated that KGF is a critical growth factor for SGC differentiation from hUC-MSCs and the differentiated SGCs from hUC MSCs may have a potential therapeutic application for regeneration of destroyed SGs and injured skin. SIGNIFICANCE: There is growing evidence demonstrating a potential therapeutic application of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) in injured skin. In the current study, conditioned media and chemically defined media with recombinant human keratinocyte growth factor (KGF) could induce hUC-MSC differentiation into sweat gland-like cells (SGCs). Moreover, the differentiated SGCs from hUC-MSCs could regenerate functional sparse sweat glands in a mouse burn model, which provides further insight into the mechanisms of the role of KGF and a potential therapeutic application of differentiated SGCs for regeneration of destroyed sweat glands and injured skin. PMID- 26574555 TI - Propranolol Targets Hemangioma Stem Cells via cAMP and Mitogen-Activated Protein Kinase Regulation. AB - Infantile hemangiomas (IHs) are the most common vascular tumor and arise from a hemangioma stem cell (HemSC). Propranolol has proved efficacious for problematic IHs. Propranolol is a nonselective beta-adrenergic receptor (betaAR) antagonist that can lower cAMP levels and activate the mitogen-activated protein kinase (MAPK) pathway downstream of betaARs. We found that HemSCs express beta1AR and beta2AR in proliferating IHs and determined the role of these betaARs and the downstream pathways in mediating propranolol's effects. In isolated HemSCs, propranolol suppressed cAMP levels and activated extracellular signal-regulated kinase (ERK)1/2 in a dose-dependent fashion. Propranolol, used at doses of <10( 4) M, reduced cAMP levels and decreased HemSC proliferation and viability. Propranolol at >=10(-5) M reduced cAMP levels and activated ERK1/2, and this correlated with HemSC apoptosis and cytotoxicity at >=10(-4) M. Stimulation with a betaAR agonist, isoprenaline, promoted HemSC proliferation and rescued the antiproliferative effects of propranolol, suggesting that propranolol inhibits betaAR signaling in HemSCs. Treatment with a cAMP analog or a MAPK inhibitor partially rescued the HemSC cell viability suppressed by propranolol. A selective beta2AR antagonist mirrored propranolol's effects on HemSCs in a dose-dependent fashion, and a selective beta1AR antagonist had no effect, supporting a role for beta2AR signaling in IH pathobiology. In a mouse model of IH, propranolol reduced the vessel caliber and blood flow assessed by ultrasound Doppler and increased activation of ERK1/2 in IH cells. We have thus demonstrated that propranolol acts on HemSCs in IH to suppress proliferation and promote apoptosis in a dose dependent fashion via beta2AR perturbation, resulting in reduced cAMP and MAPK activation. SIGNIFICANCE: The present study investigated the action of propranolol in infantile hemangiomas (IHs). IHs are the most common vascular tumor in children and have been proposed to arise from a hemangioma stem cell (HemSC). Propranolol, a nonselective beta-adrenergic receptor (betaAR) antagonist, has proven efficacy; however, understanding of its mechanism of action on HemSCs is limited. The presented data demonstrate that propranolol, via betaAR perturbation, dose dependently suppresses cAMP levels and activated extracellular signal-regulated kinase 1/2. Furthermore, propranolol acts via perturbation of beta2AR, and not beta1AR, although both receptors are expressed in HemSCs. These results provide important insight into propranolol's action in IHs and can be used to guide the development of more targeted therapy. PMID- 26574556 TI - Injection of Human Cord Blood Cells With Hyaluronan Improves Postinfarction Cardiac Repair in Pigs. AB - Recent clinical trials using autologous bone marrow or peripheral blood cells to treat myocardial infarction (MI) show controversial results, although the treatment has a good safety profile. These discrepancies are likely caused by factors such as aging, systemic inflammation, and cell processing procedures, all of which might impair the regenerative capability of the cells used. Here, we tested whether injection of human cord blood mononuclear cells (CB-MNCs) combined with hyaluronan (HA) hydrogel improves cell therapy efficacy in a pig MI model. A total of 34 minipigs were divided into 5 groups: sham operation (Sham), surgically induced-MI plus injection with normal saline (MI+NS), HA only (MI+HA), CB-MNC only (MI+CB-MNC), or CB-MNC combined with HA (MI+CB-MNC/HA). Two months after the surgery, injection of MI+CB-MNC/HA showed the highest left ventricle ejection fraction (51.32%+/-0.81%) compared with MI+NS (42.87%+/-0.97%, p<.001), MI+HA (44.2%+/-0.63%, p<.001), and MI+CB-MNC (46.17%+/-0.39%, p<.001) groups. The hemodynamics data showed that MI+CB-MNC/HA improved the systolic function (+dp/dt) and diastolic function (-dp/dt) as opposed to the other experimental groups, of which the CB-MNC alone group only modestly improved the systolic function (+dp/dt). In addition, CB-MNC alone or combined with HA injection significantly decreased the scar area and promoted angiogenesis in the infarcted region. Together, these results indicate that combined CB-MNC and HA treatment improves heart performance and may be a promising treatment for ischemic heart diseases. SIGNIFICANCE: This study using healthy human cord blood mononuclear cells (CB-MNCs) to treat myocardial infarction provides preclinical evidence that combined injection of hyaluronan and human CB-MNCs after myocardial infarction significantly increases cell retention in the peri-infarct area, improves cardiac performance, and prevents cardiac remodeling. Moreover, using healthy cells to replace dysfunctional autologous cells may constitute a better strategy to achieve heart repair and regeneration. PMID- 26574557 TI - Renal Pathology in a Nontraditional Aging Model: The Naked Mole-Rat (Heterocephalus glaber). AB - The naked mole-rat (NMR; Heterocephalus glaber) is growing in popularity as a model for aging research due to its extreme longevity (up to 30 years), highly adapted physiology, and resistance to cancer, particularly when compared with traditional aging models such as laboratory mice and rats. Despite the NMR's seemingly lengthy health span, several age-related lesions have been documented. During a 15-year retrospective evaluation of a zoo-housed population, histologic changes in the kidneys were reported in 127 of 138 (92%) adult NMRs. Of these, renal tubular mineralization was very common (115 of 127; 90.6%) and found in NMRs without concurrent renal lesions (36 of 127; 28.3%). Many of the other described lesions were considered progressive stages of a single process, generally referred to as chronic nephritis or nephropathy, and diagnosed in 73 of 127 (57.5%), while end-stage renal disease was reported in only 12 (9.4%) NMRs. Renal lesions of these NMRs were comparable to disease entities reported in laboratory rats and certain strains of inbred and noninbred mice. Although many lesions of NMR kidneys were similar to those found in aged laboratory rodents, some common urinary diseases were not represented in the examined colonies. The goal of this study was to describe renal lesions in NMRs from a zoologic setting to familiarize investigators and pathologists with an apparently common and presumably age-related disease in this nontraditional model. PMID- 26574558 TI - Detection of Copy Number Imbalance in Canine Urothelial Carcinoma With Droplet Digital Polymerase Chain Reaction. AB - Urothelial carcinoma (UC) is the most common neoplasm of the canine urinary tract. Clinical presentation of UC is shared with several other, more common urinary tract disorders, and this often delays diagnosis of the UC. Definitive diagnosis of UC requires histopathologic examination of a biopsy specimen, but the cost and invasiveness for these diagnostic tests often result in most diagnoses being made on the basis of clinical findings, diagnostic imaging, and cytologic examination of urine sediment. Regardless of the diagnostic process used, most UCs currently are not diagnosed until they are at an advanced clinical stage and so are associated with poor prognosis. Improved methods for earlier and less invasive detection are needed. In a previous study, the authors demonstrated the presence of highly recurrent DNA copy number aberrations (CNAs) in canine UC and hypothesized that detection of these CNAs in tumor cells can be used as a molecular diagnostic for UC. In this study, a multiplexed droplet digital polymerase chain reaction (ddPCR) assay was detected to detect and quantify CNAs of specific regions of canine chromosomes 8, 13, 19, and 36. The assay was effective at differentiating 31 neoplastic and 25 nonneoplastic bladder tissues based on copy number, with 100% sensitivity and specificity in tissue samples. CNAs were also detected by ddPCR in 67% (12 of 18) of urine DNA specimens derived from UC patients. The findings show that ddPCR is a useful molecular technique to detect CNAs and may be used as a noninvasive molecular diagnostic test for canine UC. PMID- 26574559 TI - Evaluation of Human Semenogelin Membrane Strip Test for Species Cross-reactivity in Dogs. AB - Semenogelins are proteins originating in the seminal vesicle and are useful markers for the presumptive identification of human semen. Detection of semenogelin can be done with a commercially available membrane test. In this study, a commercially available membrane test for human semenogelin proteins was used to assess for cross-reactivity in dog bodily fluids to allow for the potential utilization for detection of human semen in dog bodily fluids. The authors analyzed canine semen and other bodily fluids, including urine, saliva, vaginal secretions, fecal material, and blood. They also examined the distribution of human semenogelin I transcripts in the canine testis, prostate, and several bodily fluids by reverse transcription polymerase chain reaction. No cross-reactivity was observed in the canine bodily fluids tested except for a single rectal swab, which was negative on a second test. Further testing should be done to validate the use of this kit for screening samples from dogs suspected to have been victims of sexual abuse. PMID- 26574560 TI - Effects of wildfire disaster exposure on male birth weight in an Australian population. AB - BACKGROUND AND OBJECTIVES: Maternal stress can depress birth weight and gestational age, with potential health effects. A growing number of studies examine the effect of maternal stress caused by environmental disasters on birth outcomes. These changes may indicate an adaptive response. In this study, we examine the effects of maternal exposure to wildfire on birth weight and gestational age, hypothesising that maternal stress will negatively influence these measures. METHODOLOGY: Using data from the Australian Capital Territory, we employed Analysis of Variance to examine the influence of the 2003 Canberra wildfires on the weight of babies born to mothers resident in fire-affected regions, while considering the role of other factors. RESULTS: We found that male infants born in the most severely fire-affected area had significantly higher average birth weights than their less exposed peers and were also heavier than males born in the same areas in non-fire years. Higher average weights were attributable to an increase in the number of macrosomic infants. There was no significant effect on the weight of female infants or on gestational age for either sex. CONCLUSIONS AND IMPLICATIONS: Our findings indicate heightened environmental responsivity in the male cohort. We find that elevated maternal stress acted to accelerate the growth of male fetuses, potentially through an elevation of maternal blood glucose levels. Like previous studies, our work finds effects of disaster exposure and suggests that fetal growth patterns respond to maternal signals. However, the direction of the change in birth weight is opposite to that of many earlier studies. PMID- 26574561 TI - Relationships Among Perceived Wellness Culture, Healthy Lifestyle Beliefs, and Healthy Behaviors in University Faculty and Staff: Implications for Practice and Future Research. AB - Identifying key factors influencing healthy lifestyle behaviors in university faculty and staff is critical in designing interventions to improve health outcomes and reduce health care costs. A descriptive study was conducted with 3,959 faculty and staff at a Midwestern, U.S. University. Key measures included perceived worksite culture, healthy lifestyle beliefs, and healthy lifestyle behaviors. Healthy lifestyle beliefs were strongly positively associated with healthy lifestyle behaviors. Regression analyses demonstrated positive healthy lifestyle behaviors based upon sex (female, Std. beta = .068, p < .001) and role (faculty, Std. beta = .059, p < .001) and a negative effect of race (African Americans, Std. beta = -.059, p < .001). The positive effect of perceived wellness culture on healthy lifestyle behaviors was completely mediated by healthy lifestyle beliefs. Interventions to enhance perceived wellness culture and healthy lifestyle beliefs should result in healthier behaviors and improved health outcomes. PMID- 26574562 TI - The Modified Apnea Test During Brain Death Determination: An Alternative in Patients With Hypoxia. AB - INTRODUCTION: Conventional apnea testing in patients with severe hypoxemia or hemodynamic instability with removal from the ventilator support is unsafe. We describe an alternative approach to apnea testing, which may be used in patients with hypoxia unable to undergo conventional apnea testing. METHODS: Case Report. A 42-year-old man had a severe traumatic brain injury resulting in diffuse cerebral edema and subarachnoid hemorrhage with herniation. His presentation was complicated by hypoxic respiratory failure from pulmonary contusions and hemorrhagic shock. On hospital day 2, the patient lost brain stem reflexes. Brain death testing with conventional apnea testing was attempted but aborted due to hypoxia. RESULTS: A modified apnea test was applied, which had been approved by appropriate hospital committees including critical care operations, ethics, and the brain death protocol council. Minute ventilation was gradually decreased by >=50% to attain a PaCo2 level >=20 mm Hg above baseline. The ventilation mode was then switched from volume control to continuous positive airway pressure while observing the patient for signs of respiration for a duration of 60 seconds. CONCLUSION: The modified apnea test does not require circuit disconnection and can be successfully applied to determine brain death without compromising safety in high-risk patients having severe hypoxia. PMID- 26574563 TI - Acoustic Methods to Monitor Protein Crystallization and to Detect Protein Crystals in Suspensions of Agarose and Lipidic Cubic Phase. AB - Improvements needed for automated crystallography include crystal detection and crystal harvesting. A technique that uses acoustic droplet ejection to harvest crystals was previously reported. Here a method is described for using the same acoustic instrument to detect protein crystals and to monitor crystal growth. Acoustic pulses were used to monitor the progress of crystallization trials and to detect the presence and location of protein crystals. Crystals were detected, and crystallization was monitored in aqueous solutions and in lipidic cubic phase. Using a commercially available acoustic instrument, crystals measuring ~150 um or larger were readily detected. Simple laboratory techniques were used to increase the sensitivity to 50 um by suspending the crystals away from the plastic surface of the crystallization plate. This increased the sensitivity by separating the strong signal generated by the plate bottom that can mask the signal from small protein crystals. It is possible to further boost the acoustic reflection from small crystals by reducing the wavelength of the incident sound pulse, but our current instrumentation does not allow this option. In the future, commercially available sound-emitting transducers with a characteristic frequency near 300 MHz should detect and monitor the growth of individual 3 um crystals. PMID- 26574564 TI - Primary Care Physicians' Attitudes Toward Postpartum Depression: Is It Part of Their Job? AB - OBJECTIVES: This study surveyed Israeli primary care physicians' attitudes and practice regarding postpartum depression (PPD). METHODS: Participants included 224 pediatricians and family practitioners responding to an online survey (65% response rate). RESULTS: Almost all respondents (98.0%) considered it important that they be able to recognize the signs of PPD. Most (89.8%) noted that if they suspected PPD, they would become somewhat involved: clarifying, keeping attentive, consulting with colleagues, and/or referring the woman to another professional. Six respondents--only family practitioners--stated that they would treat the case themselves (P = .01). Family practitioners were significantly more willing to screen for PPD than were pediatricians (91.2% vs 64.6%; P < .0001). There were no differences between physicians by region or between males and females when comparing all respondents, as well as when comparing within medical specialty (P < .05). CONCLUSIONS: There is a clear difference between considering the importance of recognizing signs of PPD and acting on it. Family practitioners had more favorable attitudes than did pediatricians, however screening in pediatric facilities is considered by many to be optimal. Hopefully future directions for medical education and health policy for family practitioners and pediatricians, as well as obstetrician/gynecologists, will meet the challenge of early identification and treatment of PPD for the benefit of women, infants and families. PMID- 26574565 TI - Shifting Patterns of Physician Home Visits. AB - OBJECTIVES: Home visits have been shown to improve quality of care and lower medical costs for complex elderly patients. We investigated trends in physician home visits and domiciliary care visits as well as physician characteristics associated with providing these services. DESIGN: Longitudinal analysis of Medicare Part B claims data for a national sample of direct patient care physicians in 2006 and 2011. Descriptive statistics were used to characterize the physician sample and to determine numbers of home visits and domiciliary visits in total and by physician specialty. SETTING: Patient homes, nursing homes, and domiciliary care facilities. PARTICIPANTS: Direct patient care physicians (n = 22,186). MEASUREMENTS: Physician demographics, specialty, practice characteristics (practice type, geographic location), number of home visits, and domiciliary visits in 2006 and 2011. RESULTS: We found a small increase (n = 63,501) in total number of home visits made to Medicare beneficiaries between 2006 and 2011 performed by a decreasing percentage of physicians (5.1%, n = 18,165 in 2006; 4.5%, n = 15,296 in 2011). There was substantial growth in domiciliary care visit numbers (n = 218,514) and a small increase in percentage of physicians delivering these services (2.0% in 2006, 2.3% in 2011). Physicians who performed home visits were more likely to be older, in rural locations, specialists in primary care, and more likely to provide nursing home and domiciliary care compared with physicians who did not make any home visits (P < .05). CONCLUSION: Home visits and domiciliary visits to Medicare beneficiaries are increasing. General internal medicine physicians provided the highest number of home and domiciliary care visits in 2006, and family physicians did so in 2011. Such delivery models show promise in lowering medical costs while providing high-quality patient care. PMID- 26574566 TI - Effectiveness of Self-Monitoring Blood Pressure in Primary Care: A Randomized Controlled Trial. AB - OBJECTIVE: To examine the effectiveness of self-monitoring blood pressure (SMBP) in a randomized controlled trial with 12 months of follow-up in a community hospital. METHODS: A total of 224 eligible patients with hypertension were randomly allocated to the SMBP (n = 111) and usual care groups (n = 113). Each patient in the SMBP group was provided with a blood pressure (BP) monitor for home BP measurement. Mixed model regression was used to compare changes in BP at months 6 and 12 and compare between groups. RESULTS: At month 12, compared with usual care, the SMBP group had average systolic BP decreased by 2.5 mm Hg. The benefit of the SMBP was found in those aged >=60 years, which significantly decreased by -8.9 mm Hg (95% CI = -15.1 to -2.7) compared with those in the usual care. For individuals aged 60 years and older in the SMBP group, the proportion of those with uncontrolled BP decreased from 90.9% at baseline to 38.2% at month 12 (P < .05). However, among those aged <60 years, SMBP did not perform better than the usual care group. CONCLUSION: For primary care setting in urban area, the SMBP resulted in lower BP in the older persons with hypertension at 12 months. Further study on effectiveness of SMBP in other settings may be warranted. PMID- 26574567 TI - Factors Influencing Physician Counseling on Cardiovascular Risk. AB - BACKGROUND AND IMPORTANCE: A significant reduction in cardiovascular disease (CVD) mortality is related to aggressive management of modifiable CVD risk factors. Therefore, patients at increased risk for CVD should not only benefit from standard pharmacotherapy but also from counseling regarding lifestyle behavioral changes. OBJECTIVE: To determine the patient factors that influence provision of cardiovascular risk reduction counseling from physicians, as well as the frequencies of counseling. DESIGN, SETTING, AND PARTICIPANTS: Secondary analysis of a prospective, randomized trial among an underserved inner-city and rural population (n = 388) with a 10% or greater CVD risk (Framingham 10-year risk score). Subjects were followed for 1 year and were seen for quarterly assessments, which included evaluation of weight, blood pressure, lipid, and glucose status. At each of the 4 quarterly visits, subjects were asked if their physician had discussed or made recommendations regarding lifestyle behaviors, specifically diet, weight loss, and exercise. RESULTS: The average patient age was 61.3 +/- 10.1 years, average A1c was 6.7 +/- 1.6%, average total cholesterol was 201 +/- 44 mg/dL. The average body mass index (BMI) was 31.8 +/- 6.4 kg/m2, and the average blood pressure was 146 +/- 18/82 +/-11 mm Hg. Using binary logistic regression analysis, BMI (P < .025) was the only clinical factor related to physician lifestyle counseling. All other risk factors showed no statistical relationship. CONCLUSION: The data indicate that BMI is the major factor associated with whether or not physicians provide counseling regarding nutrition and weight loss. Physicians may be missing important opportunities to influence behavior in patients at high risk for CVD by limiting their focus to obese patients. PMID- 26574568 TI - Destabilizing RET in targeted treatment of thyroid cancers. AB - Metastatic differentiated thyroid cancers (DTC) are resistant to traditional chemotherapy. Kinase inhibitors have shown promise in patients with progressive DTC, but dose-limiting toxicity is commonplace. HSP90 regulates protein degradation of several growth-mediating kinases such as RET, and we hypothesized that HSP90 inhibitor (AUY922) could inhibit RET-mediated medullary thyroid cancer (MTC) as well as papillary thyroid cancer (PTC) cell growth and also radioactive iodine uptake by PTC cells. Studies utilized MTC cell lines TT (C634W) and MZ-CRC 1 (M918T) and the PTC cell line TPC-1 (RET/PTC1). Cell viability was assessed with MTS assays and apoptosis by flow cytometry. Signaling target expression was determined by western blot and radioiodine uptake measured with a gamma counter. Prolonged treatment of both MTC cell lines with AUY922 simultaneously inhibited both MAPK and mTOR pathways and significantly induced apoptosis (58.7 and 78.7% reduction in MZ-CRC-1 and TT live cells respectively, following 1 MUM AUY922; P<0.02). Similarly in the PTC cell line, growth and signaling targets were inhibited, and also a 2.84-fold increase in radioiodine uptake was observed following AUY922 administration (P=0.015). AUY922 demonstrates in vitro activity against MTC and PTC cell lines. We observed a potent dose-dependent increase in apoptosis in MTC cell lines following drug administration confirming its anti tumorigenic effects. Western blots confirm inhibition of pro-survival proteins including AKT suggesting this as the mechanism of cell death. In a functional study, we observed an increase in radioiodine uptake in the PTC cell line following AUY922 treatment. We believe HSP90 inhibition could be a viable alternative for treatment of RET-driven chemo-resistant thyroid cancers. PMID- 26574569 TI - Using conjoint analysis to determine the impact of product and user characteristics on acceptability of rectal microbicides for HIV prevention among Peruvian men who have sex with men. AB - OBJECTIVES: Men who have sex with men (MSM) are in need of novel and acceptable HIV prevention interventions. In Peru, a Phase II clinical trial was recently completed evaluating rectally applied tenofovir gel among Peruvian MSM and transgender women. If deemed safe and acceptable, the product could move into efficacy testing, but acceptability data for similar products are needed now in order to prepare for future implementation. Peru is in need of expanded, national acceptability data among likely users. METHODS: Using conjoint analysis of an online cross-sectional survey taken by 1008 Peruvian MSM and transgender women, we tested the acceptability of eight hypothetical rectal microbicide (RM) products comprising six, dual-value attributes. We also assessed the relationship of select product attributes with sample characteristics. RESULTS: Highest acceptability was found for a RM that was 90% effective, used before and after sex, without side effects, costing approximately $0.30, had no prescription requirement and had a single-use applicator. Product effectiveness and presence of side effects were the factors most likely to drive RM acceptance and use. Education, sexual orientation, sexual role and concern for HIV infection were also related to aspects of RM acceptability. CONCLUSION: RM acceptability was high, confirming the results of earlier, smaller studies and placing confidence in the acceptability of RMs. Analysis of the relationships with product attributes and sample characteristics underscore the need to consider the impact of factors such as sexual orientation, sexual role, level of education and concern for HIV acquisition on RM acceptability. PMID- 26574570 TI - Association of perceived partner non-monogamy with prevalent and incident sexual concurrency. AB - OBJECTIVES: Concurrency is suggested as an important factor in sexually transmitted infection transmission and acquisition, though little is known regarding factors that may predict concurrency initiation. We examined the association between perception of a partner's non-monogamy (PPNM) and simultaneous or subsequent concurrency among at-risk heterosexual young adults in the Los Angeles area. METHODS: We used Poisson regression models to estimate the relationship between PPNM and incident concurrency among 536 participants participating in a cohort study, interviewed at 4-month periods during 1 year. Concurrency was defined as an overlap in reported sexual partnership dates; PPNM was defined as believing a partner was also having sex with someone else. RESULTS: Participants (51% female; 30% non-Hispanic white, 28% non-Hispanic black, 27% Hispanic/Latino) had a mean age of 23 years and lifetime median of nine sex partners. At each interview (baseline, 4-month, 8-month and 12-month), 4 month concurrency prevalence was, respectively, 38.8%, 27.4%, 23.1% and 24.5%. Four-month concurrency incidence at 4, 8 and 12 months was 8.5%, 10.6% and 17.8%, respectively. Participants with recent PPNM were more likely to initiate concurrency (crude 4-month RR=4.6; 95% CI 3.0, 7.0; adjusted 4-month RR=4.0, 95% CI 2.6 to 6.1). CONCLUSIONS: Recent PPNM was associated with incident concurrency. Among young adults, onset of concurrency may be stimulated, relatively quickly, by the PPNM. Programmes which promote relationship communication skills and explicit monogamy expectations may help reduce concurrency. PMID- 26574571 TI - Characteristics of adenovirus urethritis among heterosexual men and men who have sex with men: a review of clinical cases. AB - BACKGROUND: The aim of this study was to characterise the clinical features of adenovirus urethritis in men and to compare the frequency of these between heterosexual men and men who have sex with men (MSM). METHODS: This was a review of the clinical and laboratory information from men diagnosed with PCR-confirmed adenovirus urethritis at the Melbourne Sexual Health Centre between January 2006 and April 2014. RESULTS: 102 adenovirus urethritis cases were reported, among which 61 were heterosexual men and 41 MSM. Eighty-nine per cent (n=91) had signs of meatitis or conjunctivitis: 51% had meatitis only; 32% meatitis together with conjunctivitis and 6% with conjunctivitis only. The distribution of symptoms and signs was similar among heterosexual men and MSM (p values >0.1). Adenovirus was the sole pathogen found in 93% of cases, excluding gonorrhoea, chlamydia, Mycoplasma genitalium and herpes simplex virus. Only 37% had >=5 polymorphs per high-power field from a urethral smear. Where samples were still available for adenoviral sequencing (n=20), all were subgroup D. CONCLUSIONS: The clinical features of adenovirus urethritis in men can be distinctive and aid diagnosis, distinguishing it from other treatable causes of male urethritis. PMID- 26574573 TI - Inflammatory and Epigenetic Pathways for Perinatal Depression. AB - Depression during the perinatal period is common and can have adverse consequences for women and their children. Yet, the biobehavioral mechanisms underlying perinatal depression are not known. Adverse early life experiences increase the risk for adult depression. One potential mechanism by which this increased risk occurs is epigenetic embedding of inflammatory pathways. The purpose of this article is to propose a conceptual model that explicates the linkage between early life adversity and the risk for maternal depression. The model posits that early life adversity embeds a proinflammatory epigenetic signature (altered DNA methylation) that predisposes vulnerable women to depression during pregnancy and the postpartum period. As proposed, women with a history of early life adversity are more likely to exhibit higher levels of proinflammatory cytokines and lower levels of oxytocin in response to the demands of pregnancy and new motherhood, both of which are associated with the risk for perinatal depression. The model is designed to guide investigations into the biobehavioral basis for perinatal depression, with emphasis upon the impact of early life adversity. Testing this model will provide a better understanding of maternal depressive risk and improve identification of vulnerable women who would benefit from targeted interventions that can reduce the impact of perinatal depression on maternal-infant health. PMID- 26574574 TI - Evaluation of the Diagnostic Performance of Fibrin Monomer in Comparison to d Dimer in Patients With Overt and Nonovert Disseminated Intravascular Coagulation. AB - INTRODUCTION: Disseminated intravascular coagulation (DIC) is a thrombohemorrhagic disorder characterized by hyperactivation of coagulation and secondary fibrinolysis. AIM: The primary aim of this prospective study was to evaluate and compare the diagnostic performance of fibrin monomer (FM) and d dimer (DD) for the preemptive diagnosis of DIC in the early stages. MATERIALS AND METHODS: The patients were categorized into 3 groups: overt DIC, nonovert DIC, and non-DIC based on the International Society of Thrombosis and Hemostasis scoring for overt DIC and the modified nonovert-DIC criteria. Coagulation tests were performed on freshly obtained plasma. Quantitative determination of FM and DD was done by immunoturbidimetric assay. RESULTS: Median DD and FM levels in patients with overt DIC were significantly higher in comparison to the other 2 groups. Interestingly, unlike DD, the difference in FM levels was also found to be statistically significant between patients with nonovert DIC and non-DIC patients ( P = .0001). At receiver-operator characteristic curve-generated cutoff values, FM had higher specificity and negative predictive value than DD for predicting onset of overt DIC. Multivariate analysis showed that only FM was as an independent predictive factor useful in differentiating patients with overt DIC from non-DIC patients (odds ratio [OR]: 43.3; confidence interval [CI] 4.61 406.68; P value = .001) as well as in distinguishing nonovert DIC from non-DIC patients (OR:18.3; CI 3.45-97.19; P value = .001). CONCLUSION: Fibrin monomer is a better indicator than DD in distinguishing patients with overt and nonovert DIC from non-DIC patients, raising the possibility for its diagnostic utility as a marker for impending overt DIC, aiding in early diagnosis and prompt therapeutic intervention. PMID- 26574575 TI - Mortality among styrene-exposed workers in the reinforced plastic boatbuilding industry. AB - BACKGROUND: We updated mortality through 2011 for 5203 boat-building workers potentially exposed to styrene, and analysed mortality among 1678 employed a year or more between 1959 and 1978. The a priori hypotheses: excess leukaemia and lymphoma would be found. METHODS: Standardised mortality ratios (SMRs) and 95% CIs and standardised rate ratios (SRRs) used Washington State rates and a person years analysis programme, LTAS.NET. The SRR analysis compared outcomes among tertiles of estimated cumulative potential styrene exposure. RESULTS: Overall, 598 deaths (SMR=0.96, CI 0.89 to 1.04) included excess lung (SMR=1.23, CI 0.95 to 1.56) and ovarian cancer (SMR 3.08, CI 1.00 to 7.19), and chronic obstructive pulmonary disease (COPD) (SMR=1.15, CI 0.81 to 1.58). Among 580 workers with potential high-styrene exposure, COPD mortality increased 2-fold (SMR=2.02, CI 1.08 to 3.46). CONCLUSIONS: COPD was more pronounced among those with potential high-styrene exposure. However, no outcome was related to estimated cumulative styrene exposure, and there was no change when latency was taken into account. We found no excess leukaemia or lymphoma mortality. As in most occupational cohort studies, lack of information on lifestyle factors or other employment was a substantial limitation although we excluded from the analyses those (n=3525) who worked <1 year. Unanticipated excess ovarian cancer mortality could be a chance finding. Comparing subcohorts with potential high-styrene and low-styrene exposure, COPD mortality SRR was elevated while lung cancer SRR was not, suggesting that smoking was not the only cause for excess COPD mortality. PMID- 26574576 TI - Disposable nitrile gloves protect hairdressers from systemic exposure to paratoluenediamine. PMID- 26574572 TI - CYP19A1 fine-mapping and Mendelian randomization: estradiol is causal for endometrial cancer. AB - Candidate gene studies have reported CYP19A1 variants to be associated with endometrial cancer and with estradiol (E2) concentrations. We analyzed 2937 single nucleotide polymorphisms (SNPs) in 6608 endometrial cancer cases and 37 925 controls and report the first genome wide-significant association between endometrial cancer and a CYP19A1 SNP (rs727479 in intron 2, P=4.8*10(-11)). SNP rs727479 was also among those most strongly associated with circulating E2 concentrations in 2767 post-menopausal controls (P=7.4*10(-8)). The observed endometrial cancer odds ratio per rs727479 A-allele (1.15, CI=1.11-1.21) is compatible with that predicted by the observed effect on E2 concentrations (1.09, CI=1.03-1.21), consistent with the hypothesis that endometrial cancer risk is driven by E2. From 28 candidate-causal SNPs, 12 co-located with three putative gene-regulatory elements and their risk alleles associated with higher CYP19A1 expression in bioinformatical analyses. For both phenotypes, the associations with rs727479 were stronger among women with a higher BMI (Pinteraction=0.034 and 0.066 respectively), suggesting a biologically plausible gene-environment interaction. PMID- 26574577 TI - The effect of World Trade Center exposure on the latency of chronic rhinosinusitis diagnoses in New York City firefighters: 2001-2011. AB - OBJECTIVE: To assess how the effect of World Trade Center (WTC) exposure on physician-diagnosed chronic rhinosinusitis (CRS) in firefighters changed during the decade following the attack on 9/11 (11 September 2001 to 10 September 2011). METHODS: We examined temporal effects on the relation between WTC exposure and the incidence of physician diagnosed CRS in firefighters changed during the decade following the attack on 9/11 (11 September 2001 to 10 September 2011). Exposure was grouped by time of arrival at the WTC site as follows: (high) morning 11 September 2001 (n=1623); (moderate) afternoon 11 September 2001 or 12 September 2001 (n=7025); or (low) 13-24 September 2001 (n=1200). Piecewise exponential survival models were used to estimate incidences by exposure group, with change points in the relative incidences estimated by maximum likelihood. RESULTS: Incidences dramatically increased after 2007 due to a programmatic change that provided free medical treatment, but increases were similar in all exposure groups. For this reason, we observed no change point during the study period, meaning the relative incidence by exposure group (high vs moderate vs low) of CRS disease did not significantly change over the study period. The relative rate of developing CRS was 1.99 (95% CI=1.64 to 2.41) for high versus low exposure, and 1.52 (95% CI=1.28 to 1.80) for moderate versus low exposure during the 10-year follow-up period. CONCLUSIONS: The risk of CRS in FDNY firefighters appears increased with WTC-exposure, and has not diminished by time since exposure. PMID- 26574579 TI - Waste management--still a global challenge in the 21st century: An evidence-based call for action. PMID- 26574580 TI - Municipal solid waste development phases: Evidence from EU27. AB - Many countries in the European Union (EU) have very developed waste management systems. Some of its members have managed to reduce their landfilled waste to values close to zero during the last decade. Thus, European Union legislation is very stringent regarding waste management for their members and candidate countries, too. This raises the following questions: Is it possible for developing and developed countries to comply with the European Union waste legislation, and under what conditions? How did waste management develop in relation to the economic development in the countries of the European Union? The correlation between waste management practices and economic development was analysed for 27 of the European Union Member States for the time period between 1995 and 2007. In addition, a regression analysis was performed to estimate landfilling of waste in relation to gross domestic product for every country. The results showed a strong correlation between the waste management variables and the gross domestic product of the EU27 members. The definition of the municipal solid waste management development phases followed a closer analysis of the relation between gross domestic product and landfilled waste. The municipal solid waste management phases are characterised by high landfilling rates at low gross domestic product levels, and landfilling rates near zero at high gross domestic product levels. Hence the results emphasize the importance of wider understanding of what is required for developing countries to comply with the European Union initiatives, and highlight the importance of allowing developing countries to make their own paths of waste management development. PMID- 26574578 TI - Identification of the Elusive Pyruvate Reductase of Chlamydomonas reinhardtii Chloroplasts. AB - Under anoxic conditions the green alga Chlamydomonas reinhardtii activates various fermentation pathways leading to the creation of formate, acetate, ethanol and small amounts of other metabolites including d-lactate and hydrogen. Progress has been made in identifying the enzymes involved in these pathways and their subcellular locations; however, the identity of the enzyme involved in reducing pyruvate to d-lactate has remained unclear. Based on sequence comparisons, enzyme activity measurements, X-ray crystallography, biochemical fractionation and analysis of knock-down mutants, we conclude that pyruvate reduction in the chloroplast is catalyzed by a tetrameric NAD(+)-dependent d lactate dehydrogenase encoded by Cre07.g324550. Its expression during aerobic growth supports a possible function as a 'lactate valve' for the export of lactate to the mitochondrion for oxidation by cytochrome-dependent d-lactate dehydrogenases and by glycolate dehydrogenase. We also present a revised spatial model of fermentation based on our immunochemical detection of the likely pyruvate decarboxylase, PDC3, in the cytoplasm. PMID- 26574581 TI - Production of biofuels and biomolecules in the framework of circular economy: A regional case study. AB - Faced to the economic and energetic context of our society, it is widely recognised that an alternative to fossil fuels and oil-based products will be needed in the nearest future. In this way, development of urban biorefinery could bring many solutions to this problem. Study of the implementation of urban biorefinery highlights two sustainable configurations that provide solutions to the Walloon context by promoting niche markets, developing circular economy and reducing transport of supply feedstock. First, autonomous urban biorefineries are proposed, which use biological waste for the production of added value molecules and/or finished products and are energetically self-sufficient. Second, integrated urban biorefineries, which benefit from an energy supply from a nearby industrial activity. In the Walloon economic context, these types of urban biorefineries could provide solutions by promoting niche markets, developing a circular economy model, optimise the transport of supply feedstock and contribute to the sustainable development. PMID- 26574583 TI - Diesel exhaust augments allergen-induced lower airway inflammation in allergic individuals: a controlled human exposure study. AB - RATIONALE: Traffic-related air pollution has been shown to augment allergy and airway disease. However, the enhancement of allergenic effects by diesel exhaust in particular is unproven in vivo in the human lung, and underlying details of this apparent synergy are poorly understood. OBJECTIVE: To test the hypothesis that a 2 h inhalation of diesel exhaust augments lower airway inflammation and immune cell activation following segmental allergen challenge in atopic subjects. METHODS: 18 blinded atopic volunteers were exposed to filtered air or 300 ug PM(2.5)/m(3) of diesel exhaust in random fashion. 1 h post-exposure, diluent controlled segmental allergen challenge was performed; 2 days later, samples from the challenged segments were obtained by bronchoscopic lavage. Samples were analysed for markers and modifiers of allergic inflammation (eosinophils, Th2 cytokines) and adaptive immune cell activation. Mixed effects models with ordinal contrasts compared effects of single and combined exposures on these end points. RESULTS: Diesel exhaust augmented the allergen-induced increase in airway eosinophils, interleukin 5 (IL-5) and eosinophil cationic protein (ECP) and the GSTT1 null genotype was significantly associated with the augmented IL-5 response. Diesel exhaust alone also augmented markers of non-allergic inflammation and monocyte chemotactic protein (MCP)-1 and suppressed activity of macrophages and myeloid dendritic cells. CONCLUSION: Inhalation of diesel exhaust at environmentally relevant concentrations augments allergen-induced allergic inflammation in the lower airways of atopic individuals and the GSTT1 genotype enhances this response. Allergic individuals are a susceptible population to the deleterious airway effects of diesel exhaust. TRIAL REGISTRATION NUMBER: NCT01792232. PMID- 26574584 TI - Second pack survey on the prevalence of the use of smuggled cigarettes in Tehran, 2015. PMID- 26574585 TI - Challenges in Cystic Fibrosis Newborn Screening and Recommendations for Primary Care Physicians. PMID- 26574586 TI - A Case of Pediatric Q Fever Osteomyelitis Managed Without Antibiotics. AB - Q fever osteomyelitis, caused by infection with Coxiella burnetti, is rare but should be included in the differential diagnosis of children with culture negative osteomyelitis, particularly if there is a history of contact with farm animals, and/or granulomatous change on histologic examination of a bone biopsy specimen. We describe a case of Q fever osteomyelitis in a 6-year-old boy in which a decision was made not to treat the patient with combination antimicrobial agents, balancing possible risks of recurrence against potential side effects of prolonged antibiotic treatment. The patient had undergone surgical debridement of a single lesion and was completely asymptomatic after recovery from surgery. This case suggests that a conservative approach of watchful waiting in an asymptomatic patient with chronic Q fever osteomyelitis may be warranted in select cases when close follow-up is possible. PMID- 26574587 TI - Effect of Catheter Dwell Time on Risk of Central Line-Associated Bloodstream Infection in Infants. AB - BACKGROUND AND OBJECTIVE: Central venous catheters in the NICU are associated with significant morbidity and mortality because of the risk of central line associated bloodstream infections (CLABSIs). The purpose of this study was to determine the effect of catheter dwell time on risk of CLABSI. METHODS: Retrospective cohort study of 13,327 infants with 15,567 catheters (93% peripherally inserted central catheters [PICCs], 7% tunneled catheters) and 256,088 catheter days cared for in 141 NICUs. CLABSI was defined using National Health Surveillance Network criteria. We defined dwell time as the number of days from line insertion until either line removal or day of CLABSI. We generated survival curves for each week of dwell time and estimated hazard ratios for CLABSI at each week by using a Cox proportional hazards frailty model. We controlled for postmenstrual age and year, included facility as a random effect, and generated separate models by line type. RESULTS: Median postmenstrual age was 29 weeks (interquartile range 26-33). The overall incidence of CLABSI was 0.93 per 1000 catheter days. Increased dwell time was not associated with increased risk of CLABSI for PICCs. For tunneled catheters, infection incidence was significantly higher in weeks 7 and 9 compared with week 1. CONCLUSIONS: Clinicians should not routinely replace uninfected PICCs for fear of infection but should consider removing tunneled catheters before week 7 if no longer needed. Additional studies are needed to determine what daily maintenance practices may be associated with decreased risk of infection, especially for tunneled catheters. PMID- 26574589 TI - Human Milk Feeding as a Protective Factor for Retinopathy of Prematurity: A Meta analysis. AB - CONTEXT: Studies have suggested that human milk feeding decreases the incidence of retinopathy of prematurity (ROP); however, conflicting results have been reported. OBJECTIVE: The aim of this meta-analysis was to pool currently available data on incidence of ROP in infants fed human milk versus formula. DATA SOURCES: Medline, PubMed, and EBSCO were searched for articles published through February 2015. STUDY SELECTION: Longitudinal studies comparing the incidence of ROP in infants who were fed human milk and formula were selected. Studies involving donor milk were not included. DATA EXTRACTION: Two independent reviewers conducted the searches and extracted data. Meta-analysis used odds ratios (ORs), and subgroup analyses were performed. RESULTS: Five studies with 2208 preterm infants were included. Searches including various proportions of human milk versus formula, any-stage ROP, and severe ROP were defined to pool data for analyses. For any-stage ROP, the ORs (95% confidence intervals [CIs]) were as follows: exclusive human milk versus any formula, 0.29 (0.12 to 0.72); mainly human milk versus mainly formula, 0.51 (0.26 to 1.03); any human milk versus exclusive formula, 0.54 (0.15 to 1.96); and exclusive human milk versus exclusive formula, 0.25 (0.13 to 0.49). For severe ROP, they were 0.11 (0.04 to 0.30), 0.16 (0.06 to 0.43), 0.42 (0.08 to 2.18), and 0.10 (0.04 to 0.29), respectively. LIMITATIONS: Prospective randomized studies being impossible because of ethical issues, we chose observational studies for analysis. A few studies involving subgroup analyses presented high heterogeneity. CONCLUSIONS: Based on current limited evidence, in very preterm newborns, human milk feeding potentially plays a protective role in preventing any-stage ROP and severe ROP. PMID- 26574588 TI - Comparison of Health Care Spending and Utilization Among Children With Medicaid Insurance. AB - BACKGROUND AND OBJECTIVES: Opportunities to improve health care quality and contain spending may differ between high and low resource users. This study's objectives were to assess health care and spending among children with Medicaid insurance by their resource use. METHODS: Retrospective cross-sectional analysis of 2012 Medicaid health administrative data from 10 states of children ages 11 months to 18 years. Subjects were categorized into 4 spending groups, each representing ~25% of total spending: the least expensive 80% of children (n = 2,868,267), the next 15% expensive (n = 537,800), the next 4% expensive (n = 143,413), and the top 1% (n = 35,853). We compared per-member-per-month (PMPM) spending across the groups using the Kruskal-Wallis test. RESULTS: PMPM spending was $68 (least expensive 80%), $349 (next 15%), $1200 (next 4%), and $6738 (top 1%). Between the least and most expensive groups, percentages of total spending were higher for inpatient (<1% vs 46%) and mental health (7% vs 24%) but lower for emergency (15% vs 1%) and primary (23% vs 1%) care (all Ps < .001). From the least to most expensive groups, increases in PMPM spending were smallest for primary care (from $15 to $33) and much larger for inpatient ($0.28 to $3129), mental health ($4 to $1609), specialty care ($8 to $768), and pharmacy ($4 to $699). CONCLUSIONS: As resource use increases in children with Medicaid, spending rises unevenly across health services: Spending on primary care rises modestly compared with other health services. Future studies should assess whether more spending on primary care leads to better quality and cost containment for high resource users. PMID- 26574590 TI - Newborn Screening for Cystic Fibrosis in California. AB - OBJECTIVES: This article describes the methods used and the program performance results for the first 5 years of newborn screening for cystic fibrosis (CF) in California. METHODS: From July 16, 2007, to June 30, 2012, a total of 2,573,293 newborns were screened for CF by using a 3-step model: (1) measuring immunoreactive trypsinogen in all dried blood spot specimens; (2) testing 28 to 40 selected cystic fibrosis transmembrane conductance regulator (CFTR) mutations in specimens with immunoreactive trypsinogen values >=62 ng/mL (top 1.6%); and (3) performing DNA sequencing on specimens found to have only 1 mutation in step 2. Infants with >=2 mutations/variants were referred to CF care centers for diagnostic evaluation and follow-up. Infants with 1 mutation were considered carriers and their parents offered telephone genetic counseling. RESULTS: Overall, 345 CF cases, 533 CFTR-related metabolic syndrome cases, and 1617 carriers were detected; 28 cases of CF were missed. Of the 345 CF cases, 20 (5.8%) infants were initially assessed as having CFTR-related metabolic syndrome, and their CF diagnosis occurred after age 6 months (median follow-up: 4.5 years). Program sensitivity was 92%, and the positive predictive value was 34%. CF prevalence was 1 in 6899 births. A total of 303 CFTR mutations were identified, including 78 novel variants. The median age at referral to a CF care center was 34 days (18 and 37 days for step 2 and 3 screening test-positive infants, respectively). CONCLUSIONS: The 3-step model had high detection and low false positive levels in this diverse population. PMID- 26574591 TI - Improvements in Cystic Fibrosis Quarterly Visits, Lung Function Tests, and Respiratory Cultures. AB - BACKGROUND: The Cystic Fibrosis (CF) Foundation recommends patients attend clinic >=4 times per year with 4 respiratory cultures and 2 pulmonary function tests (PFTs). However, nationally only 57.4% of patients met these guidelines in 2012. We used a quality improvement program with a goal of 75% of our patients meeting this care guideline by 2012. METHODS: A 2-stage program was started in 2011. Stage 1: education of patients/caregivers on importance of quarterly visits. Stage 2: quarterly tracking system of patient appointments. Data on clinic visits, respiratory cultures, and PFTs were collected from the CF registry from January 2009 through December 2013. Statistical process control charts were used to track improvements. RESULTS: The average number of clinic visits increased significantly from 4.6 +/- 2.3 in 2009 to 6.3 +/- 4.6 in 2013 (P < .0001). The percentage of patients ages 6 through 18 completing a clinic visit, PFT, and respiratory culture per quarter increased significantly from 76.2% during 2009 to 86.4% in 2013. The percentage of patients completing >=4 clinic visits with 4 respiratory cultures and 2 PFTs improved significantly from 47.5% in 2009 to 71.0% in 2013 (P < .0001). CONCLUSIONS: A tracking system of patient appointments significantly improved adherence to the care guidelines better than education alone. The multiple-stage quality improvement program we implemented may be modifiable and able to be integrated in other CF centers or other multiple disciplinary chronic illness care centers. PMID- 26574592 TI - Risk of Infection Using Peripherally Inserted Central and Umbilical Catheters in Preterm Neonates. AB - OBJECTIVE: To compare the rates of catheter-associated bloodstream infection (CABSI) in preterm infants born at <30 weeks' gestation who received a peripherally inserted central catheter (PICC) versus an umbilical venous catheter (UVC) immediately after birth as their primary venous access. METHODS: This retrospective matched cohort study examined data from infants born at <30 weeks' gestation and admitted between January 2010 and December 2013 to neonatal units in the Canadian Neonatal Network. Eligible infants who received a PICC on the first day after birth (day 1) were matched with 2 additional groups of infants, those who received a UVC on day 1 and those who received a UVC on day 1 that was then changed for a PICC after 4 days or more. The primary outcome was number of infants with CABSI per 1000 catheter days, which was compared between the 3 groups using multivariable analyses. RESULTS: Data from 540 eligible infants were reviewed (180 per group). There was no significant difference in infants with CABSI/1000 catheter days between the 3 groups (9.3 vs 7.8 vs 8.2/1000 catheter days, respectively; P > .05) despite lower rates of late onset sepsis in the group of infants who received only a UVC. CONCLUSIONS: There was no significant difference in the incidence of CABSI between very preterm neonates who received a PICC, UVC, or UVC followed by PICC as the primary mode of venous access after birth. A prospective randomized controlled trial is justified to further guide practice regarding primary venous access and reduction of infection. PMID- 26574593 TI - MRI Brain Signal Intensity Changes of a Child During the Course of 35 Gadolinium Contrast Examinations. AB - We describe the observed and quantitative signal intensity changes in the brain on baseline precontrast T1-weighted MRI data of a pediatric patient who received 35 MRI examinations with gadolinium-based contrast agent (GBCA) between the ages of 8 and 20 years. The contrast agent this patient received belongs to a class of agents with linear molecular structures, which has been recently investigated in studies of gadolinium deposition in the brains of adult patients. Visual changes in signal intensity were assessed by 3 pediatric neuroradiologists, and progressive increases were the most evident in the dentate nuclei, the globus pallidus, and the thalamus. Quantitative measurements as determined from signal intensity ratios confirmed visual findings. The pattern of regional brain hyperintensity observed in this pediatric patient is consistent with findings from adult studies. PMID- 26574594 TI - Nontherapeutic Use of Antimicrobial Agents in Animal Agriculture: Implications for Pediatrics. AB - Antimicrobial resistance is one of the most serious threats to public health globally and threatens our ability to treat infectious diseases. Antimicrobial resistant infections are associated with increased morbidity, mortality, and health care costs. Infants and children are affected by transmission of susceptible and resistant food zoonotic pathogens through the food supply, direct contact with animals, and environmental pathways. The overuse and misuse of antimicrobial agents in veterinary and human medicine is, in large part, responsible for the emergence of antibiotic resistance. Approximately 80% of the overall tonnage of antimicrobial agents sold in the United States in 2012 was for animal use, and approximately 60% of those agents are considered important for human medicine. Most of the use involves the addition of low doses of antimicrobial agents to the feed of healthy animals over prolonged periods to promote growth and increase feed efficiency or at a range of doses to prevent disease. These nontherapeutic uses contribute to resistance and create new health dangers for humans. This report describes how antimicrobial agents are used in animal agriculture, reviews the mechanisms of how such use contributes to development of resistance, and discusses US and global initiatives to curb the use of antimicrobial agents in agriculture. PMID- 26574595 TI - Letter from the Editor-in-Chief. PMID- 26574596 TI - Novel Vein Patterns in Arabidopsis Induced by Small Molecules. AB - The critical role of veins in transporting water, nutrients, and signals suggests that some key regulators of vein formation may be genetically redundant and, thus, undetectable by forward genetic screens. To identify such regulators, we screened more than 5000 structurally diverse small molecules for compounds that alter Arabidopsis (Arabidopsis thaliana) leaf vein patterns. Many compound induced phenotypes were observed, including vein networks with an open reticulum; decreased or increased vein number and thickness; and misaligned, misshapen, or nonpolar vascular cells. Further characterization of several individual active compounds suggests that their targets include hormone cross talk, hormone dependent transcription, and PIN-FORMED trafficking. PMID- 26574597 TI - Profilin-Dependent Nucleation and Assembly of Actin Filaments Controls Cell Elongation in Arabidopsis. AB - Actin filaments in plant cells are incredibly dynamic; they undergo incessant remodeling and assembly or disassembly within seconds. These dynamic events are choreographed by a plethora of actin-binding proteins, but the exact mechanisms are poorly understood. Here, we dissect the contribution of Arabidopsis (Arabidopsis thaliana) PROFILIN1 (PRF1), a conserved actin monomer-binding protein, to actin organization and single filament dynamics during axial cell expansion of living epidermal cells. We found that reduced PRF1 levels enhanced cell and organ growth. Surprisingly, we observed that the overall frequency of nucleation events in prf1 mutants was dramatically decreased and that a subpopulation of actin filaments that assemble at high rates was reduced. To test whether profilin cooperates with plant formin proteins to execute actin nucleation and rapid filament elongation in cells, we used a pharmacological approach. Here, we used Small Molecule Inhibitor of Formin FH2 (SMIFH2), after validating its mode of action on a plant formin in vitro, and observed a reduced nucleation frequency of actin filaments in live cells. Treatment of wild-type epidermal cells with SMIFH2 mimicked the phenotype of prf1 mutants, and the nucleation frequency in prf1-2 mutant was completely insensitive to these treatments. Our data provide compelling evidence that PRF1 coordinates the stochastic dynamic properties of actin filaments by modulating formin-mediated actin nucleation and assembly during plant cell expansion. PMID- 26574598 TI - Genetic Variation for Thermotolerance in Lettuce Seed Germination Is Associated with Temperature-Sensitive Regulation of ETHYLENE RESPONSE FACTOR1 (ERF1). AB - Seeds of most lettuce (Lactuca sativa) cultivars are susceptible to thermoinhibition, or failure to germinate at temperatures above approximately 28 degrees C, creating problems for crop establishment in the field. Identifying genes controlling thermoinhibition would enable the development of cultivars lacking this trait and, therefore, being less sensitive to high temperatures during planting. Seeds of a primitive accession (PI251246) of lettuce exhibited high-temperature germination capacity up to 33 degrees C. Screening a recombinant inbred line population developed from PI215246 and cv Salinas identified a major quantitative trait locus (Htg9.1) from PI251246 associated with the high temperature germination phenotype. Further genetic analyses discovered a tight linkage of the Htg9.1 phenotype with a specific DNA marker (NM4182) located on a single genomic sequence scaffold. Expression analyses of the 44 genes encoded in this genomic region revealed that only a homolog of Arabidopsis (Arabidopsis thaliana) ETHYLENE RESPONSE FACTOR1 (termed LsERF1) was differentially expressed between PI251246 and cv Salinas seeds imbibed at high temperature (30 degrees C). LsERF1 belongs to a large family of transcription factors associated with the ethylene-signaling pathway. Physiological assays of ethylene synthesis, response, and action in parental and near-isogenic Htg9.1 genotypes strongly implicate LsERF1 as the gene responsible for the Htg9.1 phenotype, consistent with the established role for ethylene in germination thermotolerance of Compositae seeds. Expression analyses of genes associated with the abscisic acid and gibberellin biosynthetic pathways and results of biosynthetic inhibitor and hormone response experiments also support the hypothesis that differential regulation of LsERF1 expression in PI251246 seeds elevates their upper temperature limit for germination through interactions among pathways regulated by these hormones. Our results support a model in which LsERF1 acts through the promotion of gibberellin biosynthesis to counter the inhibitory effects of abscisic acid and, therefore, promote germination at high temperatures. PMID- 26574599 TI - Redox-Dependent Modulation of Anthocyanin Biosynthesis by the TCP Transcription Factor TCP15 during Exposure to High Light Intensity Conditions in Arabidopsis. AB - TCP proteins integrate a family of transcription factors involved in the regulation of developmental processes and hormone responses. It has been shown that most members of class I, one of the two classes in which the TCP family is divided, contain a conserved Cys that leads to inhibition of DNA binding when oxidized. In this work, we describe that the class-I TCP protein TCP15 inhibits anthocyanin accumulation during exposure of plants to high light intensity by modulating the expression of transcription factors involved in the induction of anthocyanin biosynthesis genes, as suggested by the study of plants that express TCP15 from the 35SCaMV promoter and mutants in TCP15 and the related gene TCP14. In addition, the effect of TCP15 on anthocyanin accumulation is lost after prolonged incubation under high light intensity conditions. We provide evidence that this is due to inactivation of TCP15 by oxidation of Cys-20 of the TCP domain. Thus, redox modulation of TCP15 activity in vivo by high light intensity may serve to adjust anthocyanin accumulation to the duration of exposure to high irradiation conditions. PMID- 26574600 TI - Alcohol Use Disorders in Primary Health Care: What Do We Know and Where Do We Go? AB - AIMS: To analyze the current paradigm and clinical practice for dealing with alcohol use disorders (AUD) in primary health care. METHODS: Analyses of guidelines and recommendations, reviews and meta-analyses. RESULTS: Many recommendations or guidelines for interventions for people with alcohol use problems in primary health care, from hazardous drinking to AUD, can be summarized in the SBIRT principle: screening for alcohol use and alcohol-related problems, brief interventions for hazardous and in some cases harmful drinking, referral to specialized treatment for people with AUD. However, while there is some evidence that these procedures are effective in reducing drinking levels, they are rarely applied in clinical practice in primary health care, and no interventions are initiated, even if the primary care physician had detected problems or AUD. Rather than asking primary health care physicians to conduct interventions which are not typical for medical doctors, we recommend treatment initiation for AUD at the primary health care level. AUD should be treated like hypertension, i.e. with regular checks for alcohol consumption, advice for behavioral interventions in case of consumption exceeding thresholds, and pharmaceutical assistance in case the behavioral interventions were not successful. Minimally, alcohol consumption should be screened for in all situations where there is a co-morbidity with alcohol being a potential cause (such as hypertension, insomnia, depression or anxiety disorders). CONCLUSIONS: A paradigm shift is proposed for dealing with problematic alcohol consumption in primary health care, where initiation for treatment for AUD is seen as the central element. PMID- 26574601 TI - Comparison of Knee Kinematics After Single-Bundle Anterior Cruciate Ligament Reconstruction via the Medial Portal Technique With a Central Femoral Tunnel and an Eccentric Femoral Tunnel and After Anatomic Double-Bundle Reconstruction: A Human Cadaveric Study. AB - BACKGROUND: Anatomic femoral tunnel placement in anterior cruciate ligament (ACL) reconstruction is considered to be a key to good primary stability of the knee. There is still no consensus on whether a centrally placed single bundle in the anatomical femoral footprint can compare with anatomic double-bundle (DB) reconstruction. PURPOSE/HYPOTHESIS: The purpose of this study was to determine knee kinematics after single-bundle ACL reconstruction via the medial portal technique using 2 different femoral tunnel positions and to compare results with those of the anatomic DB technique. The hypotheses were that (1) single-bundle reconstruction using the medial portal technique with a centrally placed femoral tunnel relative to the native footprint (SB-central technique) would more closely restore intact knee kinematics compared with the same reconstruction technique with an eccentric femoral tunnel drilled in the anteromedial bundle footprint (SB AM technique) and (2) DB reconstruction would result in superior kinematics compared with the SB-central technique. STUDY DESIGN: Controlled laboratory study. METHODS: Knee kinematics was examined in 10 fresh-frozen human cadaveric knees using a robotic/universal force-moment sensor system. Kinematics in simulated pivot-shift and 134-N anterior tibial loading tests were determined in different conditions within the same specimen: (1) intact ACL, (2) deficient ACL, (3) SB-AM, (4) SB-central, and (5) DB. RESULTS: All reconstruction techniques significantly reduced anterior tibial translation (ATT) compared with a deficient ACL at 0 degrees , 15 degrees , 30 degrees , 60 degrees , and 90 degrees in the anterior tibial loading test (P < .01, repeated-measures analysis of variance) and at 0 degrees , 15 degrees , and 30 degrees in the simulated pivot-shift test (P < .001). There were no significant differences in the SB-central group and the DB group compared with the intact ACL. Reconstruction in the SB-AM group resulted in significantly increased ATT compared with the intact ACL in near-to-extension angles in both tests (0 degrees , 15 degrees , and 30 degrees ; P < .01). SB central and DB reconstructions both resulted in significantly reduced ATT, in some tests at <=30 degrees , compared with SB-AM reconstruction (P < .05). No significant differences between the SB-central and DB groups were found (P > .05). CONCLUSION: The SB-central technique restored intact knee kinematics more closely than did SB-AM reconstruction at time zero. There were no differences in knee kinematics between the DB and SB-central techniques. CLINICAL RELEVANCE: Anatomic single-bundle ACL reconstruction provides similar knee kinematics as anatomic double-bundle reconstruction. PMID- 26574602 TI - Bone Marrow Concentrate Improves Early Cartilage Phase Maturation of a Scaffold Plug in the Knee: A Comparative Magnetic Resonance Imaging Analysis to Platelet Rich Plasma and Control. AB - BACKGROUND: Limited information exists on the clinical use of a synthetic osteochondral scaffold plug for cartilage restoration in the knee. PURPOSE/HYPOTHESIS: The purpose of this study was to compare the early magnetic resonance imaging (MRI) appearance, including quantitative T2 values, between cartilage defects treated with a scaffold versus a scaffold with platelet-rich plasma (PRP) or bone marrow aspirate concentrate (BMAC). The hypothesis was that the addition of PRP or BMAC would result in an improved cartilage appearance. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Forty-six patients with full-thickness cartilage defects of the femur were surgically treated with a control scaffold (n = 11), scaffold with PRP (n = 23), or scaffold with BMAC (n = 12) and were followed prospectively. Patients underwent MRI with a qualitative assessment and quantitative T2 mapping at 12 months after surgery. An image assessment was performed retrospectively by a blinded musculoskeletal radiologist. The cartilage phase was measured by cartilage fill and quantitative T2 values on MRI. A comparison between groups after cartilage repair was performed. RESULTS: The control scaffold group consisted of 8 male and 3 female patients (mean age, 38 years; mean body mass index [BMI], 25 kg/m(2)), the PRP group had 15 male and 8 female patients (mean age, 39 years; mean BMI, 26 kg/m(2)), and the BMAC group consisted of 8 male and 4 female patients (mean age, 36 years; mean BMI, 26 kg/m(2)). The PRP-treated (P = .002) and BMAC-treated (P = .03) scaffolds had superior cartilage fill compared with the control group. With quantitative methods, the PRP group demonstrated a mean T2 value (49.1 ms) that was similar to that of the control scaffold group (42.7 ms; P = .07), but the BMAC group demonstrated a mean T2 value (60.5 ms) closer to that of superficial hyaline cartilage (P = .01). The stratification of T2 values between the deep and superficial zones was not observed in any of the groups. CONCLUSION: In this comparative study, patients treated with scaffold implantation augmented with BMAC had improved cartilage maturation with greater fill and mean T2 values closer to that of superficial native hyaline cartilage at 12 months. Further work will determine if this translates into improved clinical outcomes. PMID- 26574603 TI - Influences of nitrogen, phosphorus and silicon addition on plant productivity and species richness in an alpine meadow. AB - Fertilization, especially with nitrogen (N), increases aboveground primary productivity (APP), but reduces plant species richness at some level. Silicon (Si) fertilization alone, or with addition of N or phosphorus (P), has multiple direct and indirect beneficial effects on plant growth and development, both for individuals and the whole community. This study aimed to examine the effects of Si, N, P, NSi and PSi combinations on APP and species richness of the community and of four functional groups in an alpine meadow. The results showed that plots fertilized with Si in combination with either N or P had higher APP than when fertilized with N or P alone. Addition of N or P increased APP, and the higher APP occurred when the highest level of N was added, indicating co-limitation of N and P, with N being most limiting. Silicon fertilization alone or with addition of N increased the APP of grasses and forbs. Nitrogen addition decreased the community species richness; Si with addition of N alleviated the loss of species richness of the whole community and the forbs group. For the four functional groups, N or P addition increased the species richness of grasses and decreased that of forbs. Our findings highlight the importance of Si in improving APP and alleviating N fertilization-induced biodiversity loss in grasslands, and will help improve our ability to predict community composition and biomass dynamics in alpine meadow ecosystems subject to changing nutrient availability. PMID- 26574604 TI - Intravital imaging of the cellular dynamics of LysM-positive cells in a murine corneal suture model. AB - BACKGROUND: Corneal suturing is a surgical procedure used in patients with corneal trauma or transplants. It was reported that endogenous neutrophils are brightly labelled in gene-targeted mice expressing enhanced green fluorescent protein (eGFP) under the control of the endogenous lysozyme M promoter (LysM-eGFP mice). METHODS: We applied intravital imaging methods to analyse in vivo the dynamics of LysM-positive granulocytes (neutrophils) in LysM-eGFP mice with corneal sutures and examined their role in the elicitation of neutrophil infiltration. RESULTS: We found that in the presuturing state, neutrophils strongly positive for LysM were located in the periphery of the corneal stromal layer; none were present in the centre of the cornea. After introducing a corneal suture, neutrophils accumulated in limbal vessels and then migrated to the corneal side and the conjunctival side, suggesting that they derived from limbal vessels. Thereafter they accumulated towards the central corneal area, arriving at the suture about 7 h after its placement. Although corneal sutures may elicit the continuous infiltration of neutrophils, their number was markedly decreased by day 1 after suture removal and continued to decrease thereafter. CONCLUSIONS: Our results showed that corneal sutures may elicit the continuous infiltration of neutrophils. PMID- 26574605 TI - Labelling people as 'High Risk': A tyranny of eminence? PMID- 26574606 TI - When are breast cancer patients at highest risk of venous thromboembolism? A cohort study using English health care data. AB - Patients with breast cancer are at increased risk of venous thromboembolism (VTE), particularly in the peridiagnosis period. However, no previous epidemiologic studies have investigated the relative impact of breast cancer treatments in a time-dependent manner. We aimed to determine the impact of breast cancer stage, biology, and treatment on the absolute and relative risks of VTE by using several recently linked data sources from England. Our cohort comprised 13,202 patients with breast cancer from the Clinical Practice Research Datalink (linked to Hospital Episode Statistics and Cancer Registry data) diagnosed between 1997 and 2006 with follow-up continuing to the end of 2010. Cox regression analysis was performed to determine which demographic, treatment related, and biological factors independently affected VTE risk. Women had an annual VTE incidence of 6% while receiving chemotherapy which was 10.8-fold higher (95% confidence interval [CI], 8.2-14.4; absolute rate [AR], 59.6 per 1000 person-years) than that in women who did not receive chemotherapy. After surgery, the risk was significantly increased in the first month (hazard ratio [HR], 2.2; 95% CI, 1.4-3.4; AR, 23.5; reference group, no surgery), but the risk was not increased after the first month. Risk of VTE was noticeably higher in the 3 months after initiation of tamoxifen compared with the risk before therapy (HR, 5.5; 95% CI, 2.3-12.7; AR, 24.1); however, initiating therapy with aromatase inhibitors was not associated with VTE (HR, 0.8; 95% CI, 0.5-1.4; AR, 28.3). In conclusion, women receiving chemotherapy for breast cancer have a clinically important risk of VTE, whereas an increased risk of VTE immediately after endocrine therapy is restricted to tamoxifen. PMID- 26574609 TI - Hunt announces L4m drive to reduce stillbirths and neonatal and maternal deaths in England. PMID- 26574608 TI - Germline RBBP6 mutations in familial myeloproliferative neoplasms. PMID- 26574610 TI - Presidential Address: Leadership - It's Not Just for Managers Anymore. PMID- 26574607 TI - Variegated RHOA mutations in adult T-cell leukemia/lymphoma. AB - Adult T-cell leukemia/lymphoma (ATLL) is a distinct form of peripheral T-cell lymphoma with poor prognosis, which is caused by the human T-lymphotropic virus type 1 (HTLV-1). In contrast to the unequivocal importance of HTLV-1 infection in the pathogenesis of ATLL, the role of acquired mutations in HTLV-1 infected T cells has not been fully elucidated, with a handful of genes known to be recurrently mutated. In this study, we identified unique RHOA mutations in ATLL through whole genome sequencing of an index case, followed by deep sequencing of 203 ATLL samples. RHOA mutations showed distinct distribution and function from those found in other cancers. Involving 15% (30/203) of ATLL cases, RHOA mutations were widely distributed across the entire coding sequence but almost invariably located at the guanosine triphosphate (GTP)-binding pocket, with Cys16Arg being most frequently observed. Unexpectedly, depending on mutation types and positions, these RHOA mutants showed different or even opposite functional consequences in terms of GTP/guanosine diphosphate (GDP)-binding kinetics, regulation of actin fibers, and transcriptional activation. The Gly17Val mutant did not bind GTP/GDP and act as a dominant negative molecule, whereas other mutants (Cys16Arg and Ala161Pro) showed fast GTP/GDP cycling with enhanced transcriptional activation. These findings suggest that both loss- and gain-of-RHOA functions could be involved in ATLL leukemogenesis. In summary, our study not only provides a novel insight into the molecular pathogenesis of ATLL but also highlights a unique role of variegation of heterologous RHOA mutations in human cancers. PMID- 26574611 TI - Treatment of peri-implantitis: Meta-analysis of findings in a systematic literature review and novel protocol proposal. AB - OBJECTIVE: To test the effectiveness of nonsurgical and surgical treatment methods for clinical and radiographic peri-implantitis symptoms resolution with respect to pocket probing depth (PD), bleeding on probing (BOP), and marginal bone-loss reduction (RBL); to propose guidelines for managing peri-implantitis. METHOD AND MATERIALS: An electronic literature search was conducted of the MEDLINE and EMBASE databases for articles published between 2002 and 2015. Sequential screening at the title/abstract and full-text levels was performed. Clinical human studies in the English language that had reported changes in PD and/or BOP and/or radiologic marginal bone level (RBL) changes after peri implantitis treatment at 6-month follow-up or longer were included. A meta analysis was performed using the random-effects model on the selected qualifying articles. RESULTS: The search resulted in 29 articles meeting the inclusion criteria. The meta-analysis demonstrated improved BOP values (P = .001; OR = 1.567; 95% CI, 1.405 to 1.748) after the nonsurgical treatment but did not reveal a statistically significant difference in the PD changes (P = .8093; standardized mean difference [SMD] = 0.346 mm; 95% CI, 0.181 to 0.512). There was a significant improvement in PD (P < .001; SMD = 1.647 mm; 95% CI, 1.414 to 1.880) and BOP values (P < .001; OR = 4.044; 95% CI, 3.571 to 4.381) after surgical treatment and an intrabony defect fill was found to be 1.66 mm (1.0) using a regenerative treatment modality. Our meta-analysis confirms there is a significant reduction in RBL after nonsurgical (P = 0.037; SMD = 0.157 mm; 95% CI, -0.183 to 0.496), resective (P = .0212; SMD = -0.116 mm; 95% CI, -0.433 to 0.201), and regenerative (P = .0305; SMD = 1.703 mm; 95% CI, 1.266 to 2.139) surgical treatment. A novel complex management and maintenance (CMM) six-step protocol is thus suggested for treatment of peri-implantitis. CONCLUSION: Regenerative surgical treatment of peri-implantitis was found to be most effective. A novel six-step protocol aimed at managing patients with peri implantitis can be a useful tool in peri-implantitis treatment. PMID- 26574612 TI - Recommendations on the clinical application of air polishing for the management of peri-implant mucositis and peri-implantitis. AB - Air polishing was introduced as an alternative approach for the supra- and submucosal biofilm management at dental implants. An international expert meeting involving competent clinicians and researchers took place during the EUROPERIO 8 conference in London, UK, on 4 June 2015. Prior to this meeting a comprehensive systematic review dealing with the efficacy of air polishing in the treatment of peri-implant mucositis and peri-implantitis was prepared and served as a basis for the group discussions. This paper summarizes the consensus statements and practical recommendations on the clinical application of air polishing for the management of peri-implant mucositis and peri-implantitis. PMID- 26574613 TI - Foreword: International Centers of Excellence for Malaria Research. PMID- 26574614 TI - Sensor Informatics and Quantified Self. PMID- 26574615 TI - Seek and ye shall find. PMID- 26574616 TI - Machine Learning and Data Mining in Medical Imaging. PMID- 26574617 TI - The Paediatric Cardiology Hall of Fame - Donald Nixon Ross. AB - Donald Nixon Ross, FRCS (4 October 1922 to 7 July 2014) was a South African-born British cardiothoracic surgeon, who developed the pulmonary autograft, known as the Ross procedure, for the treatment of aortic valve disease, and also performed the first heart transplant in the United Kingdom in 1968. This paper, written by Jane Somerville, Professor of Cardiology [Retired], Imperial College London, London, United Kingdom, provides the personal recollections about Donald Ross from Jane Somerville, and thus provides a unique snapshot of cardiac surgical history. PMID- 26574618 TI - [Not Available]. PMID- 26574619 TI - Actually, That Does Impact Coding.... PMID- 26574620 TI - ICD-10: Multiple Gestation. PMID- 26574621 TI - Reply: To PMID 25501444. PMID- 26574622 TI - Antitumor effects and molecular mechanisms of ponatinib on endometrial cancer cells harboring activating FGFR2 mutations. AB - Aberrant mutational activation of FGFR2 is associated with endometrial cancers (ECs). AP24534 (ponatinib) currently undergoing clinical trials has been known to be an orally available multi-targeted tyrosine kinase inhibitor. Our biochemical kinase assay showed that AP24534 is potent against wild-type FGFR1-4 and 5 mutant FGFRs (V561M-FGFR1, N549H-FGFR2, K650E-FGFR3, G697C-FGFR3, N535K-FGFR4) and possesses the strongest kinase-inhibitory activity on N549H-FGFR2 (IC50 of 0.5 nM) among all FGFRs tested. We therefore investigated the effects of AP24534 on endometrial cancer cells harboring activating FGFR2 mutations and explored the underlying molecular mechanisms. AP24534 significantly inhibited the proliferation of endometrial cancer cells bearing activating FGFR2 mutations (N549K, K310R/N549K, S252W) and mainly induced G1/S cell cycle arrest leading to apoptosis. AP24534 also diminished the kinase activity of immunoprecipitated FGFR2 derived from MFE-296 and MFE-280 cells and reduced the phosphorylation of FGFR2 and FRS2 on MFE-296 and AN3CA cells. AP24534 caused substantial reductions in ERK phosphorylation, PLCgamma signaling and STAT5 signal transduction on ECs bearing FGFR2 activating mutations. Akt signaling pathway was also deactivated by AP24534. AP24534 causes the chemotherapeutic effect through mainly the blockade of ERK, PLCgamma and STAT5 signal transduction on ECs. Moreover, AP24534 inhibited migration and invasion of endometrial cancer cells with FGFR2 mutations. In addition, AP24534 significantly blocked anchorage-independent growth of endometrial cancer cells. We, for the first time, report the molecular mechanisms by which AP24534 exerts antitumor effects on ECs with FGFR2 activating mutations, which would provide mechanistic insight into ongoing clinical investigations of AP24534 for ECs. PMID- 26574623 TI - Ciprofloxacin-Photoswitch Conjugates: A Facile Strategy for Photopharmacology. AB - Photopharmacology aims to locally treat diseases and study biological processes with photoresponsive drugs. Herein, easy access to photoswitchable drugs is crucial, which is supported by simple and robust drug modifications. We investigated the possibility of creating drugs that can undergo remote activation and deactivation with light, by conjugating molecular photoswitches to the exterior of an existing drug in a single chemical step. This facile strategy allows the convenient introduction of various photochromic systems into a drug molecule, rendering it photoresponsive. To demonstrate the feasibility of this approach, two photoswitch-modified ciprofloxacin antibiotics were synthesized. Remarkably, for one of them a 50-fold increase in activity compared to the original ciprofloxacin was observed. Their antimicrobial activity could be spatiotemporally controlled with light, which was exemplified by bacterial patterning studies. PMID- 26574624 TI - Effect of Grape Seed Proanthocyanidin-Gelatin Colloidal Complexes on Stability and in Vitro Digestion of Fish Oil Emulsions. AB - The colloidal complexes composed of grape seed proanthocyanidin (GSP) and gelatin (GLT), as natural antioxidants to improve stability and inhibit lipid oxidation in menhaden fish oil emulsions, were evaluated. The interactions between GSP and GLT, and the chemical structures of GSP/GLT self-assembled colloidal complexes, were characterized by isothermal titration calorimetry (ITC), circular dichroism (CD), and Fourier transform infrared spectroscopic (FTIR) studies. Fish oil was emulsified with GLT to obtain an oil-in-water (o/w) emulsion. After formation of the emulsion, GLT was fixed by GSP to obtain the GSP/GLT colloidal complexes stabilized fish oil emulsion. Menhaden oil emulsified by GSP/GLT(0.4 wt %) colloidal complexes yielded an emulsion with smaller particles and higher emulsion stability as compared to its GLT emulsified counterpart. The GSP/GLT colloidal complexes inhibited the lipid oxidation in fish oil emulsions more effectively than free GLT because the emulsified fish oil was surrounded by the antioxidant GSP/GLT colloidal complexes. The digestion rate of the fish oil emulsified with the GSP/GLT colloidal complexes was reduced as compared to that emulsified with free GLT. The extent of free fatty acids released from the GSP/GLT complexes stabilized fish oil emulsions was 63.3% under simulated digestion condition, indicating that the fish oil emulsion was considerably hydrolyzed with lipase. PMID- 26574626 TI - Structural Phase Transformation and Luminescent Properties of Ca(2-x)SrxSiO4:Ce3+ Orthosilicate Phosphors. AB - The orthosilicate phosphors demonstrate great potential in the field of solid state lighting, and the understanding of the structure-property relationships depending on their versatile polymorphs and chemical compositions is highly desirable. Here we report the structural phase transformation of Ca(2 x)SrxSiO4:Ce(3+) phosphor by Sr(2+) substituting for Ca(2+) within 0 <= x < 2. The crystal structures of Ca(2-x)SrxSiO4:Ce(3+) are divided into two groups, namely, beta phase (0 <= x < 0.15) and alpha' phase (0.18 <= x < 2), and the phase transition (beta -> alpha') mechanism originated from the controlled chemical compositions is revealed. Our findings verified that the phase transition Pnma (alpha'-phase) <-> P21/n (beta-phase) can be ascribed to the second-order type, and Sr(2+) ions in Ca(2-x)SrxSiO4 preferentially occupy the seven-coordinated Ca(2+) sites rather than the eight-coordinated sites with increasing Sr(2+) content, which was reflected from the Rietveld refinements and further clarified through the difference of the Ca-O bond length in the two polymorphs of Ca2SiO4. The emission peaks of Ce(3+) shift from 417 to 433 nm in the composition range of 0 <= x <= 0.8, and the difference in the decay curves can also verify the phase transformation process. Thermal quenching properties of selected Ca(2-x)SrxSiO4:Ce(3+) samples were evaluated, and the results show that the integral emission intensities at 200 degrees C maintain >90% of that at room temperature suggesting superior properties for the application as white light emitting diodes (w-LEDs) phosphors. PMID- 26574625 TI - Atorvastatin reduced soluble receptors of TNF-alpha in systemic lupus erythematosus. AB - OBJECTIVES: The aim of this study was to evaluate the efficacy of atorvastatin to reduce the plasma levels of TNF system molecules (TNF-alpha, sTNFR1 and sTNFR2) and to assess their association with risk factors for accelerate atherosclerosis and clinical disease activity scores in SLE patients. METHODS: In a previous study, 64 female SLE patients received 20 mg/day of atorvastatin and 24 SLE patients (non-treated group) were followed for 8 weeks. Plasma levels of TNF alpha, sTNFR 1 and sTNFR 2 were measured by ELISA, at baseline and at the end of the study. RESULTS: The plasma levels of sTNFR1 and sTNFR 2 showed a positive correlation with SLEDAI score. We also found a positive correlation between TNF alpha and sTNFR 1 levels and SLICC score. Patients with current nephritis and patients with anti-ds-DNA antibodies presented higher sTNFR1 and sTNFR2 levels. Patients with abdominal obesity and arterial hypertension also had higher plasma levels of soluble receptors. At the end of 8 weeks, we observed a significant decrease in sTNFR1 plasma levels in patients receiving atorvastatin [median (percentile), 876.5 (717-1284 pg/ml) vs. 748 (629.6-917.3 pg/ml), p=0.03], without difference regarding TNF-alpha and sTNFR2 plasma levels. The SLEDAI and SLICC scores were independent determinants of the plasma levels of sRTNF1. CONCLUSIONS: Atorvastatin reduced soluble receptors of TNF-alpha. The plasma levels of TNF-alpha, sTNFR1 and sTNFR2 may play a role in SLE activity and atherosclerosis, and might be evaluated as targets for new therapies. PMID- 26574627 TI - Effects of Double Transgenesis of Somatotrophic Axis (GH/GHR) on Skeletal Muscle Growth of Zebrafish (Danio rerio). AB - Transgenic fish for growth hormone (GH) has been considered as a potential technological improvement in aquaculture. In this study, a double-transgenic zebrafish was used to evaluate the effect of GH and its receptor (GHR) on muscle growth. Double transgenics reached the same length of GH transgenic, but with significantly less weight, featuring an unbalanced growth. The condition factor of GH/GHR-transgenic fish was lower than the other genotypes. Histological analysis showed a decrease in the percentage of thick muscle fibers in GH/GHR genotype of ~ 80% in comparison to GH-transgenic line. The analysis of gene expression showed a significant decrease in genes related to muscle growth in GH/GHR genotype. It seems that concomitant overexpression of GH and GHR resulted in a strong decrease of the somatotrophic axis intracellular signaling by diminishing its principal transcription factor signal transducer and activator of transcription 5.1 (STAT5.1). PMID- 26574628 TI - Time trends in breast cancer and menopause hormone therapy use in New Zealand. AB - OBJECTIVE: The publication of preliminary findings from the Women's Health Initiative (WHI) Study in 2002 suggested an increased risk of breast cancer among users of menopause hormone therapy (MHT). This resulted world-wide in a rapid and significant decline in the use of hormone therapy. It was later claimed that breast cancer incidence rates had fallen as a result of lower rates of hormone therapy use. Our aim was to investigate whether there was an association between changes in the use of hormone therapy and rates of breast cancer diagnosis in New Zealand subsequent to the publication of the WHI. METHOD: Validated prescription usage data along with breast cancer screening and cancer registration data were accessed. Time trends extending for 8 years after the publication of the WHI were assessed. RESULTS: The use of hormone therapy for managing menopausal symptoms fell by about 70% following the controversy about its safety. Breast cancer registration rates among women aged 50-59 years had started to fall in advance of this change in prescribing. Changes in other age groups appear to coincide with changes in the screening eligibility for the national breast screening program rather than use of hormone therapy. CONCLUSION: The time trend analysis does not support an association between changes in hormone therapy use and the incidence rate of breast cancer. PMID- 26574629 TI - GNAS Mutations in Fibrous Dysplasia: A Comparative Study of Standard Sequencing and Locked Nucleic Acid PCR Sequencing on Decalcified and Nondecalcified Formalin fixed Paraffin-embedded Tissues. AB - It is well known that fibrous dysplasia (FD) is characterized by the presence of activating mutations involving G-nucleotide binding protein-alpha subunit (GNAS) involving codon R201 and rarely codon 227 with a mutation frequency between 45% and 93%. Herein, we investigate the sensitivity of detection of GNAS mutations in exons 8 and 9 using a standard and a highly sensitive locked nucleic acid polymerase chain reaction (LNA-PCR) sequencing in 52 cases of FD. In view of the recent report of GNAS mutations in a small number of low-grade osteosarcomas, we also tested in addition 12 cases of low-grade osteosarcomas. GNAS exon 8 mutations p.R201H (31%), p.R201C (15%), and p.R201S (2%) were identified in 50% of FD cases. LNA-PCR sequencing identified only 1 positive case within the mutation negative cases tested by standard PCR and Sanger sequencing. No mutations were identified in any of the low-grade osteosarcomas by standard and LNA-PCR sequencing. There was no association between age, site, size, specimen type, and mutational status. No exon 9 or codon 227 mutations were identified in any of tested cases. There was a significant difference in the sensitivity of the assay between decalcified and nondecalcified FDs (31% vs. 70%, P=0.002). LNA-PCR has no added value in enhancing detection sensitivity for GNAS mutations in FD. In addition to decalcification, innate somatic mosaicism contributes to the decreased sensitivity in mutation detection. PMID- 26574630 TI - Prognostic Value of Coexisting Lobular Carcinoma In Situ With Invasive Lobular Carcinoma. AB - AIMS AND OBJECTIVES: Recent studies show that lobular carcinoma in situ (LCIS) and invasive lobular carcinoma (ILC) share similar genetic molecular biology. There are increasing concerns regarding the biological significance of LCIS. The aim of this study is to investigate whether the presence of coexisting LCIS in ILC affects tumor biology and behavior and to correlate it with other clinicopathologic parameters. MATERIALS AND METHODS: In this study, 254 cases of ILC were included. Clinicopathologic parameters and immunohistochemical stains for estrogen receptor (ER), progesterone receptor (PR), E-cadherin, human epidermal growth factor receptor (HER2), and MIB-1 of 254 ILC cases were retrieved. The patient with ILC and coexisting LCIS were compared with pure ILC cases with respect to different clinicopathologic parameters. RESULTS: Of the 254 cases, 107 cases were pure ILC and 147 cases were ILC with coexisting LCIS. Seventy-six (76/184, 41.32%) cases showed axillary lymph node metastases. Lymph node metastasis was absent in 108 cases, micrometastasis was present in 5 cases, and stage N1, N2, N3 in 51, 5, and 15 cases, respectively. Nodal involvement, locoregional and distant recurrence of ILC with LCIS were less frequent compared with ILC without LCIS with P-value of 0.034 and 0.007, respectively. The presence of coexisting LCIS in ILC predicted higher disease-free survival (DFS) compared with pure ILC (P=0.034, log-rank test). When divided into different strata, ER positive ILC cases with associated LCIS cases showed better DFS than ER-positive pure ILC cases (P=0.021, log-rank test). Similarly, ILC cases with LCIS in patient less than 50 years showed better DFS than the patient less than 50 years with pure ILC (P=0.045, log-rank test). CONCLUSIONS: In conclusion, ILC coexisting with lobular carcinoma in situ (ILC+LCIS) is characterized by less nodal involvement, lower locoregional, and distant recurrence and better DFS than pure ILC. When divided into different strata, ER-positive and less than 50-year groups with ILC+LCIS show even significant better DFS than pure ILC. These findings suggest that there is biological significance of coexisting LCIS in ILC and that this may have more effect on tumor aggressiveness in certain strata of ILC. PMID- 26574631 TI - False-positive EGFR Mutation-specific Immunohistochemistry in HER2-positive Breast Cancers: A Potential Diagnostic Pitfall. PMID- 26574632 TI - Noninvasive Papillary Basal-like Urothelial Carcinoma: A Subgroup of Urothelial Carcinomas With Immunohistochemical Features of Basal Urothelial Cells Associated With a High Rate of Recurrence and Progression. AB - BACKGROUND: We investigated the clinical and pathologic significance of a subgroup of noninvasive papillary urothelial carcinomas (UCs) expressing reactivity to urothelial basal cell markers. DESIGN: In total, 302 consecutive cases of noninvasive papillary UC were evaluated immunohistochemically with cytokeratin 5 (CK5)/CD44. Any UC that was reactive for greater than 25% thickness of the urothelium was designated as basal-like urothelial carcinoma (BUC); remaining UC cases were designated as non-BUC. The follow-up period was up to 3 years. Historical review of UC was extended for up to 3 retrospective years. RESULTS: Among 302 noninvasive UC, BUC was identified in 33 of 256 (12.9%) low grade UC and 8 of 46 (17%) high-grade UC (P=0.041). Immunoreactivity for CD44 was similar to that of CK5, but displayed weaker and more diffuse staining. CK20 was reactive in 9 cases, primarily high-grade BUC. Other basal cell markers (34bE12, p63, bcl2, and EP4) were found to be neither sensitive nor specific in detecting UC with high CK5 expression. In comparison with non-BUC, BUC was associated with increased multifocality, larger tumor size, higher recurrence rate, and more frequent upgrading and stage progression. In the follow-up period of 3 years, distant metastasis occurred in 6 cases of which 5 were in the BUC subgroup. CONCLUSIONS: Our results showed that noninvasive papillary BUC represents a small subset associated with increased risk of tumor recurrence and progression. The aggressive behavior is likely associated with basal-like features of BUC, as seen in carcinomas with basal cell features in other body sites. PMID- 26574633 TI - Overexpression of Carbonic Anhydrase IX is a Dismal Prognostic Marker in Breast Carcinoma in Egyptian Patients. AB - Carbonic anhydrase IX (CAIX) is an enzyme whose expression is very limited in normal tissues and it is highly expressed in various cancers. Therefore, inhibition of CAIX is considered as a promising therapeutic target for the treatment of solid tumors where hypoxic environment has developed. The aim of the current work is to evaluate the immunohistochemical (IHC) expression of CAIX in breast cancer (BC) of Egyptian patients and to investigate the associations of CAIX expression with the standard clinicopathologic features, IHC subtypes of BC, and overall survival. This retrospective study was conducted on 56 archival cases of Egyptian BC patients. Fifty-one of 56 cases (91.1%) showed positive expression of CAIX with cytoplasmic localization, whereas 5 cases (8.9%) showed negative expression. CAIX IHC overexpression is significantly associated with advanced stage and presence of coagulative tumor cell necrosis (P=0.03 and 0.02, respectively). Multivariate analysis revealed Ki67 labeling index and CAIX H score grouping (P=0.03 and 0.02, respectively) as independent prognostic factors affecting BC patients' overall survival. We concluded that CAIX could play a role in the progression of the studied BC cases. CAIX is a good candidate for target therapy. PMID- 26574634 TI - CMTM8 is Frequently Downregulated in Multiple Solid Tumors. AB - Previous studies have demonstrated that overexpression of CMTM8 inhibits cell growth and induces apoptosis in multiple types of cancer cells, whereas the downregulation of CMTM8 induces the epithelial-to-mesenchymal (EMT)-like phenotype in hepatocyte carcinoma cells, implying its important roles in tumorigenesis and tumor metastasis. No extensive studies on the expression of CMTM8 in either normal or tumorous human tissues have been reported to date. Here, using real-time quantitative polymerase chain reaction, we analyzed CMTM8 expression in multiple normal human tissue samples. Moreover, by applying high throughput immunohistochemical staining of tissue microarrays with homemade anti CMTM8 antibodies, we studied CMTM8 expression in carcinoma samples and adjacent normal samples of 6 types of human tissues. CMTM8 is widely expressed in many normal human tissues and is frequently downregulated or absent in multiple solid tumors (liver, lung, colon, rectum, esophagus, stomach). chi tests revealed a significant negative correlation between CMTM8 expression and tumorigenesis: liver, lung (squamous carcinoma), colon, rectum, P<0.0001; esophagus, P<0.001; stomach, P<0.01. Real-time quantitative polymerase chain reaction analysis of samples from esophageal carcinomas and the adjacent normal tissues revealed that CMTM8 mRNA levels are reduced in carcinomas compared with normal tissues, indicating that CMTM8 is potentially downregulated at the mRNA level (P<0.01). This is the first extensive study of CMTM8 expression in both normal and tumorous human tissues. Our findings strongly supported the potential role of CMTM8 as a novel tumor suppressor and may shape further functional studies on this gene. PMID- 26574635 TI - Expression of S100A11 is a Prognostic Factor for Disease-free Survival and Overall Survival in Patients With High-grade Serous Ovarian Cancer. AB - S100A11 is a calcium-binding protein implicated in a variety of biological functions and is overexpressed in many human cancers. However, S100A11 expression level in ovarian cancer has not been well characterized. High-grade serous ovarian cancer (HGSC) is the most common and lethal type of ovarian cancer. The aim of the present study was to investigate S100A11 expression and its clinical significance in HGSC. S100A11 expression was evaluated by Western blot in 45 snap frozen specimens (15 normal ovarian epithelia, 15 normal fallopian tube epithelia, and 15 HGSCs) and by immunohistochemistry in 211 paraffin-embedded specimens (40 normal fallopian tube epithelia, 54 normal ovarian epithelia, and 117 HGSCs). S100A11 expression was extremely elevated in HGSC compared with normal epithelial tissues and was positively correlated with FIGO stage (P=0.014), ascitic fluid volume (P=0.009), and residual disease (P=0.004) of HGSC patients. Higher S100A11 expression was associated with poorer disease-free (P=0.004) and overall (P=0.006) survival, whereas multivariate analysis revealed S100A11 to be an independent prognostic factor for disease-free (P=0.019) and overall (P=0.027) survival in patients with HGSC. In conclusion, S100A11 overexpression correlates with an aggressive malignant phenotype and may constitute a novel prognostic factor for HGSC. PMID- 26574636 TI - Expression of FOXO3a and Correlation With Histopathologic Features in Retinoblastoma. AB - Forkhead box (FOX) transcription factors are a class of highly conserved proteins, which serve critical cellular functions including cell cycle regulation. The downstream mechanisms of cell cycle regulation involve preservation of retinoblastoma protein function. Its deactivation by phosphorylation and translocation from nucleus to cytoplasm leads to cell proliferation. FOXO3a has been found to be dysregulated in few cancers. However, no study has been reported on role of FOXO3a in retinoblastoma. We assessed the expression of FOXO3a in sections of archived tissue blocks of enucleated/exenterated specimens of retinoblastoma by immunohistochemistry. The histopathologic features were reviewed and correlated with its expression. Effect of FOXO3a expression on survival was assessed. FOXO3a expression was assessed in 100 sections. Six samples did not contain any viable tissue. Retrospective data of 94 patients revealed that median age at presentation was 36 months with male:female ratio of 1.9:1. Fifty-one percent of patients were International Retinoblastoma Staging System stage 1. Of the 94 sections, 68 (72%) showed cytoplasmic expression. Choroidal invasion was associated with cytoplasmic FOXO3a (P=0.04). A trend was also noted in optic nerve cut end involvement (P=0.07). No other histopathologic features were found to be associated with FOXO3a expression. The overall survival and progression-free survival were not found to be affected by FOXO3a expression. Cytoplasmic expression of FOXO3a is frequently found in retinoblastoma and may be involved in pathogenesis. Activation by relocation of FOXO3a to nucleus may activate nonmutated retinoblastoma and may be a potential target of treatment in retinoblastoma. PMID- 26574637 TI - Immunohistochemistry Biomarkers in Nonmuscle Invasive Bladder Cancer. AB - Bladder cancer (BCa) is the most frequent urinary tract neoplasm. BCa results in significant mortality when the disease presents as muscle invasive. Around 75% to 80% of patients present with nonmuscle invasive bladder cancer (NMIBC), but recurrence and progression are significant issues, compelling current guidelines to recommend long-term surveillance. There is therefore an urgent and unmet need to identify and validate accurate biomarkers for the detection of disease recurrence to improve quality of life for the patients and reduce costs for health care providers, while maintaining or improving current outcomes. In this review, 38 publications on immunohistochemistry prognostic biomarkers, that were studied may be related in nonmuscle invasive bladder cancer, have been analyzed. The studies were organized according to the evaluated marker and their findings. It was demonstrated that the combination of independent complementary biomarkers could allow a more accurate prognosis than an isolated marker. Biomarkers, including p53, Ki-67, and CK20, with classic and prognostic factors with recurrence and novel markers such as EN2 may provide a more accurate prediction of outcome compared with any single marker, improving risk stratification and clinical management of patients with BCa. PMID- 26574638 TI - Hepatocyte Nuclear Factor-1beta Expression in Clear Cell Renal Cell Carcinoma and Urothelial Carcinoma With Clear Cell Features: A Potential Diagnostic Pitfall. AB - INTRODUCTION: Distinguishing primary ovarian clear cell carcinoma (CCC) from other tumors with clear cell features can be challenging. Hepatocyte nuclear factor-1beta (HNF-1beta) is a sensitive and specific marker for ovarian CCC. Immunohistochemical studies have shown HNF-1beta positivity in a substantial proportion of clear cell renal cell carcinoma (RCC), hepatocellular carcinomas, and clear cell pancreatic adenocarcinoma. This study was designed to evaluate the role of HNF-1beta in differentiating ovarian CCC from metastatic RCC and urothelial carcinoma (UC) with clear cell features. MATERIALS AND METHODS: Formalin-fixed paraffin-embedded tissue microarrays of 103 clear cell RCC, 8 UC with clear cell features, and 15 ovarian CCC were studied using an HNF-1beta antibody. Nuclear staining intensity and percentage of positively stained cells were assessed and scored from 0 to 3. Percentage of positive staining was scored based on the proportion of tumor cells stained. RESULTS: Sixty-three of 103 (61.2%) of clear cell RCC were positive for HNF-1beta. Staining intensity was weak in 32 of 103 cases (31.6%), moderate in 21 of 103 cases (20.4%), and strong in 10 to 103 cases (9.7%).Six of 8 (75%) UC with clear cell features showed positive staining predominantly in clear cell areas.All 15 cases of ovarian CCC were positive for HNF-1beta. DISCUSSION: Overall 61.2% of clear cell RCC and 75% of UC were immunopositive with HNF-1beta in our study. HNF-1beta has a limited utility in differentiating CCC of the genitourinary system from an ovarian primary. PMID- 26574639 TI - Synthesis and Characterization of Biomimetic Hydroxyapatite Nanoconstruct Using Chemical Gradient across Lipid Bilayer. AB - In this study, we synthesized biomimetic hydroxyapatite nanoconstruct (nanosized hydroxyapatite, NHAp) using a double emulsion technique combined with a chemical gradient across a lipid bilayer for surface modification of a titanium (Ti) implant. The synthesized NHAp was characterized by dynamic light scattering, X ray diffraction, transmission electron microscopy, and Fourier transform infrared (FTIR) spectroscopy, and it was further tested for its biocompatibility and in vitro proliferation efficacy using normal human osteoblasts (NHOst). The results showed that the synthesized NHAp had a hydrodynamic diameter of ~200 nm with high aqueous stability. The chemistry of the NHAp was confirmed by FTIR spectroscopic analysis. Typical FTIR vibrational bands corresponding to the phosphate group (PO4(3-)) present in hydroxyapatite (HAp) were observed at 670, 960, and 1000 cm( 1). A broad band at 3500 cm(-1) confirmed the presence of a structural -OH group in the NHAp. Powder X-ray crystallographic diffraction further confirmed the formation of NHAp with characteristic reflections in (002), (211), (130), and (213) planes at respective 2theta degrees. These reflection planes are similar to those of typical HAp crystallized toward (002) and (211) crystallographic planes. The mechanism of the formation of NHAp was studied using the fluorescence resonance energy transfer (FRET) technique. The FRET study showed the fluorescent recovery of a donor fluorophore and the mechanism of the insertion of lipids into nanodroplets obtained from the first water-in-oil (w/o) emulsion during the formation of the second oil-in-water (o/w) emulsion. With these confirmations, we further studied NHOst cell proliferation on a Ti surface. When NHOst were cultured on the Ti surface coated with the NHAp, a distinct proliferation pattern and cell-cell communication via cytoplasmic extension on the substrate surface were observed. In contrast, a bare Ti surface showed diminished cell size with minimal adherence. This result indicates that our NHAp covered with a phospholipid bilayer provides a proper environment essential for cell adhesion, which is especially important for bone implants, and the inclusion of NHAp on the Ti substrate would be an effective support for long-term sustainability of implants. PMID- 26574640 TI - Graphitic Carbon Nitride Sensitized with CdS Quantum Dots for Visible-Light Driven Photoelectrochemical Aptasensing of Tetracycline. AB - Graphitic carbon nitride (g-C3N4) is a new type of metal-free semiconducting material with promising applications in photocatalytic and photoelectrochemical (PEC) devices. In the present work, g-C3N4 coupled with CdS quantum dots (QDs) was synthesized and served as highly efficient photoactive species in a PEC sensor. The surface morphological analysis showed that CdS QDs with a size of ca. 4 nm were grafted on the surface of g-C3N4 with closely contacted interfaces. The UV-visible diffuse reflection spectra (DRS) indicated that the absorption of g C3N4 in the visible region was enhanced by CdS QDs. As a result, g-C3N4-CdS nanocomposites demonstrated higher PEC activity as compared with either pristine g-C3N4 or CdS QDs. When g-C3N4-CdS nanocomposites were utilized as transducer and tetracycline (TET)-binding aptamer was immobilized as biorecognition element, a visible light-driven PEC aptasensing platform for TET determination was readily fabricated. The sensor showed a linear PEC response to TET in the concentration range from 10 to 250 nM with a detection limit (3S/N) of 5.3 nM. Thus, g-C3N4 sensitized with CdS QDs was successfully demonstrated as useful photoactive nanomaterials for developing a highly sensitive and selective PEC aptasensor. PMID- 26574642 TI - Editorial. PMID- 26574641 TI - Practical approaches for the treatment of chronic heart failure: Frequently asked questions, overlooked points and controversial issues in current clinical practice. AB - Heart failure (HF) is a progressive disorder associated with impaired quality of life, high morbidity, mortality and frequent hospitalization and affects millions of people from all around the world. Despite further improvements in HF therapy, mortality and morbidity remains to be very high. The life-long treatment, frequent hospitalization, and sophisticated and very expensive device therapies for HF also leads a substantial economic burden on the health care system. Therefore, implementation of evidence-based guideline-recommended therapy is very important to overcome its worse clinical outcomes. However, HF therapy is a long process that has many drawbacks and sometimes HF guidelines cannot answers to every question which rises in everyday clinical practice. In this paper, commonly encountered questions, overlooked points, controversial issues, management strategies in grey zone and problems arising during follow up of a HF patient in real life clinical practice have been addressed in the form of expert opinions based on the available data in the literature. PMID- 26574643 TI - Theophylline Represses IL-8 Secretion from Airway Smooth Muscle Cells Independently of Phosphodiesterase Inhibition. Novel Role as a Protein Phosphatase 2A Activator. AB - Theophylline is an old drug experiencing a renaissance owing to its beneficial antiinflammatory effects in chronic respiratory diseases, such as asthma and chronic obstructive pulmonary disease. Multiple modes of antiinflammatory action have been reported, including inhibition of the enzymes that degrade cAMP phosphodiesterase (PDE). Using primary cultures of airway smooth muscle (ASM) cells, we recently revealed that PDE4 inhibitors can potentiate the antiinflammatory action of beta2-agonists by augmenting cAMP-dependent expression of the phosphatase that deactivates mitogen-activated protein kinase (MAPK)-MAPK phosphatase (MKP)-1. Therefore, the aim of this study was to address whether theophylline repressed cytokine production in a similar, PDE-dependent, MKP-1 mediated manner. Notably, theophylline did not potentiate cAMP release from ASM cells treated with the long-acting beta2-agonist formoterol. Moreover, theophylline (0.1-10 MUM) did not increase formoterol-induced MKP-1 messenger RNA expression nor protein up-regulation, consistent with the lack of cAMP generation. However, theophylline (at 10 MUM) was antiinflammatory and repressed secretion of the neutrophil chemoattractant cytokine IL-8, which is produced in response to TNF-alpha. Because theophylline's effects were independent of PDE4 inhibition or antiinflammatory MKP-1, we then wished to elucidate the novel mechanisms responsible. We investigated the impact of theophylline on protein phosphatase (PP) 2A, a master controller of multiple inflammatory signaling pathways, and show that theophylline increases TNF-alpha-induced PP2A activity in ASM cells. Confirmatory results were obtained in A549 lung epithelial cells. PP2A activators have beneficial effects in ex vivo and in vivo models of respiratory disease. Thus, our study is the first to link theophylline with PP2A activation as a novel mechanism to control respiratory inflammation. PMID- 26574644 TI - Tailored Synthesis of Porous TiO2 Nanocubes and Nanoparallelepipeds with Exposed {111} Facets and Mesoscopic Void Space: A Superior Candidate for Efficient Dye Sensitized Solar Cells. AB - Anatase TiO2 nanocubes and nanoparallelepipeds, with highly reactive {111} facets exposed, were developed for the first time through a modified one pot hydrothermal method, through the hydrolysis of tetrabutyltitanate in the presence of oleylamine as the morphology-controlling capping-agent and using ammonia/hydrofluoric acid for stabilizing the {111} faceted surfaces. These nanocubes/nanoparallelepipeds were characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), high resolution transmission electron microscopy (HRTEM) and high angle annular dark-field scanning TEM (HAADF-STEM). Accordingly, a possible growth mechanism for the nanostructures is elucidated. The morphology, surface area and the pore size distribution of the TiO2 nanostructures can be tuned simply by altering the HF and ammonia dosage in the precursor solution. More importantly, optimization of the reaction system leads to the assembly of highly crystalline, high surface area, {111} faceted anatase TiO2 nanocubes/nanoparallelepipeds to form uniform mesoscopic void space. We report the development of a novel double layered photoanode for dye sensitized solar cells (DSSCs) made of highly crystalline, self-assembled faceted TiO2 nanocrystals as upper layer and commercial titania nanoparticles paste as under layer. The bilayered DSSC made from TiO2 nanostructures with exposed {111} facets as upper layer shows a much higher power conversion efficiency (9.60%), than DSSCs fabricated with commercial (P25) titania powder (4.67%) or with anatase TiO2 nanostructures having exposed {101} facets (7.59%) as the upper layer. The improved performance in bilayered DSSC made from TiO2 nanostructures with exposed {111} facets as the upper layer is attributed to high dye adsorption and fast electron transport dynamics owing to the unique structural features of the {111} facets in TiO2. Electrochemical impedance spectroscopy (EIS) measurements conducted on the cells supported these conclusions, which showed that the bilayered DSSC made from TiO2 nanostructures with exposed {111} facets as the upper layer possessed lower charge transfer resistance, higher electron recombination resistance, longer electron lifetime and higher collector efficiency characteristics, compared to DSSCs fabricated with commercial (P25) titania powder or with anatase TiO2 nanostructures having exposed {101} facets as the upper layer. PMID- 26574645 TI - Craniopharyngioma and hypothalamic injury: latest insights into consequent eating disorders and obesity. AB - PURPOSE OF REVIEW: Hypothalamic alterations, pathological or treatment induced, have major impact on prognosis in craniopharyngioma patients mainly because of consequent hypothalamic obesity. Recent insight in molecular genetics, treatment strategies, risk factors and outcomes associated with hypothalamic obesity provide novel therapeutic perspectives. This review includes relevant publications since 2013. RECENT FINDINGS: Recent findings confirm that alterations in posterior hypothalamic areas because of tumour location and/or treatment-related injuries are associated with severe hypothalamic obesity, reduced overall survival and impaired quality of life in long-term survivors of childhood-onset craniopharyngioma. However, eating disorders are observed because of hypothalamic obesity without clear disease-specific patterns. Treatment options for hypothalamic obesity are very limited. Treatment with invasive, nonreversible bariatric methods such as Roux-en-Y gastric bypass is most efficient in weight reduction, but controversial in the paediatric population because of medical, ethical, and legal considerations. Accordingly, treatment in craniopharyngioma should focus on prevention of (further) hypothalamic injury. Presurgical imaging for grading of hypothalamic involvement should be the basis for hypothalamus-sparing strategies conducted by experienced multidisciplinary teams. SUMMARY: Until a nonsurgical therapeutic option for hypothalamic obesity for paediatric patients is found, prevention of hypothalamic injury should be the preferred treatment strategy, conducted exclusively by experienced multidisciplinary teams. PMID- 26574646 TI - The genetics of pubertal timing in the general population: recent advances and evidence for sex-specificity. AB - PURPOSE OF REVIEW: This article overviews advances in the genetics of puberty based on studies in the general population, describes evidence for sex-specific genetic effects on pubertal timing, and briefly reviews possible mechanisms mediating sexually dimorphic genetic effects. RECENT FINDINGS: Pubertal timing is highly polygenic, and many loci are conserved among ethnicities. A number of identified loci underlie both pubertal timing and related traits such as height and BMI. It is increasingly apparent that understanding the factors modulating the onset of puberty is important because the timing of this developmental stage is associated with a wider range of adult health outcomes than previously appreciated. Although most of the genetic effects underlying the timing of puberty are common between boys and girls, some effects show sex-specificity and many are epigenetically modulated. Several potential mechanisms, including hormone-independent ones, may be responsible for observed sex differences. SUMMARY: Studies of pubertal timing in the general population have provided new knowledge about the genetic architecture of this complex trait. Increasing attention paid to sex-specific effects may provide key insights into the sexual dimorphism in pubertal timing and even into the associations between puberty and adult health risks by identifying common underlying biological pathways. PMID- 26574647 TI - Pituitary gigantism: update on molecular biology and management. AB - PURPOSE OF REVIEW: To provide an update on the mechanisms leading to pituitary gigantism, as well as to familiarize the practitioner with the implication of these genetic findings on treatment decisions. RECENT FINDINGS: Prior studies have identified gigantism as a feature of a number of monogenic disorders, including mutations in the aryl hydrocarbon receptor interacting protein gene, multiple endocrine neoplasia types 1 and 4, McCune Albright syndrome, Carney complex, and the paraganglioma, pheochromocytoma, and pituitary adenoma association because of succinate dehydrogenase defects. We recently described a previously uncharacterized form of early-onset pediatric gigantism caused by microduplications on chromosome Xq26.3 and we termed it X-LAG (X-linked acrogigantism). The age of onset of increased growth in X-LAG is significantly younger than other pituitary gigantism cases, and control of growth hormone excess is particularly challenging. SUMMARY: Knowledge of the molecular defects that underlie pituitary tumorigenesis is crucial for patient care as they guide early intervention, screening for associated conditions, genetic counseling, surgical approach, and choice of medical management. Recently described microduplications of Xq26.3 account for more than 80% of the cases of early-onset pediatric gigantism. Early recognition of X-LAG may improve outcomes, as successful control of growth hormone excess requires extensive anterior pituitary resection and are difficult to manage with medical therapy alone. PMID- 26574649 TI - Validated spectrophotometric methods for determination of sodium valproate based on charge transfer complexation reactions. AB - This work presents the development, validation and application of four simple and direct spectrophotometric methods for determination of sodium valproate (VP) through charge transfer complexation reactions. The first method is based on the reaction of the drug with p-chloranilic acid (p-CA) in acetone to give a purple colored product with maximum absorbance at 524nm. The second method depends on the reaction of VP with dichlone (DC) in dimethylformamide forming a reddish orange product measured at 490nm. The third method is based upon the interaction of VP and picric acid (PA) in chloroform resulting in the formation of a yellow complex measured at 415nm. The fourth method involves the formation of a yellow complex peaking at 361nm upon the reaction of the drug with iodine in chloroform. Experimental conditions affecting the color development were studied and optimized. Stoichiometry of the reactions was determined. The proposed spectrophotometric procedures were effectively validated with respect to linearity, ranges, precision, accuracy, specificity, robustness, detection and quantification limits. Calibration curves of the formed color products with p-CA, DC, PA and iodine showed good linear relationships over the concentration ranges 24-144, 40-200, 2-20 and 1-8MUg/mL respectively. The proposed methods were successfully applied to the assay of sodium valproate in tablets and oral solution dosage forms with good accuracy and precision. Assay results were statistically compared to a reference pharmacopoeial HPLC method where no significant differences were observed between the proposed methods and reference method. PMID- 26574648 TI - Relationships between PROMPT and gene expression. AB - Most mammalian protein-coding gene promoters are divergent, yielding promoter upstream transcripts (PROMPTs) in the reverse direction from their conventionally produced mRNAs. PROMPTs are rapidly degraded by the RNA exosome rendering a general function of these molecules elusive. Yet, levels of certain PROMPTs are altered in stress conditions, like the DNA damage response (DDR), suggesting a possible regulatory role for at least a subset of these molecules. Here we manipulate PROMPT levels by either exosome depletion or UV treatment and analyze possible effects on their neighboring genes. For the CTSZ and DAP genes we find that TFIIB and TBP promoter binding decrease when PROMPTs accumulate. Moreover, DNA methylation increases concomitant with the recruitment of the DNA methyltransferase DNMT3B. Thus, although a correlation between increased PROMPT levels and decreased gene activity is generally absent, some promoters may have co-opted their divergent transcript production for regulatory purposes. PMID- 26574650 TI - Divergent Synthesis of Heparan Sulfate Oligosaccharides. AB - Heparan sulfates are implicated in a wide range of biological processes. A major challenge in deciphering their structure and activity relationship is the synthetic difficulties to access diverse heparan sulfate oligosaccharides with well-defined sulfation patterns. In order to expedite the synthesis, a divergent synthetic strategy was developed. By integrating chemical synthesis and two types of O-sulfo transferases, seven different hexasaccharides were obtained from a single hexasaccharide precursor. This approach combined the flexibility of chemical synthesis with the selectivity of enzyme-catalyzed sulfations, thus simplifying the overall synthetic operations. In an attempt to establish structure activity relationships of heparan sulfate binding with its receptor, the synthesized oligosaccharides were incorporated onto a glycan microarray, and their bindings with a growth factor FGF-2 were examined. The unique combination of chemical and enzymatic approaches expanded the capability of oligosaccharide synthesis. In addition, the well-defined heparan sulfate structures helped shine light on the fine substrate specificities of biosynthetic enzymes and confirm the potential sequence of enzymatic reactions in biosynthesis. PMID- 26574651 TI - Measurement of the Heterocyclic Amines 2-Amino-9H-pyrido[2,3-b]indole and 2-Amino 1-methyl-6-phenylimidazo[4,5-b]pyridine in Urine: Effects of Cigarette Smoking. AB - 2-Amino-9H-pyrido[2,3-b]indole (AalphaC) and 2-amino-1-methyl-6-phenylimidazo[4,5 b]pyridine (PhIP) are carcinogenic heterocyclic aromatic amines (HAAs) formed during the combustion of tobacco and during the high-temperature cooking of meats. Human enzymes biotransform AalphaC and PhIP into reactive metabolites, which can bind to DNA and lead to mutations. We sought to understand the relative contribution of smoking and diet to the exposure of AalphaC and PhIP, by determining levels of AalphaC, its ring-oxidized conjugate 2-amino-9H-pyrido[2,3 b]indole-3-yl sulfate (AalphaC-3-OSO3H), and PhIP in urine of smokers on a free choice diet before and after a six week tobacco smoking cessation study. AalphaC and AalphaC-3-OSO3H were detected in more than 90% of the urine samples of all subjects during the smoking phase. The geometric mean levels of urinary AalphaC during the smoking and cessation phases were 24.3 pg/mg creatinine and 3.2 pg/mg creatinine, and the geometric mean levels of AalphaC-3-OSO3H were 47.3 pg/mg creatinine and 3.7 pg/mg creatinine. These decreases in the mean levels of AalphaC and AalphaC-3-OSO3H were, respectively, 87% and 92%, after the cessation of tobacco (P < 0.0007). However, PhIP was detected in <10% of the urine samples, and the exposure to PhIP was not correlated to smoking. Epidemiological studies have reported that smoking is a risk factor for cancer of the liver and gastrointestinal tract. It is noteworthy that AalphaC is a hepatocellular carcinogen and induces aberrant crypt foci, early biomarkers of colon cancer, in rodents. Our urinary biomarker data demonstrate that tobacco smoking is a significant source of AalphaC exposure. Further studies are warranted to examine the potential role of AalphaC as a risk factor for hepatocellular and gastrointestinal cancer in smokers. PMID- 26574652 TI - Dibenzonaphthyridinones: Heterocycle-to-Heterocycle Synthetic Strategies and Photophysical Studies. AB - A heterocycle-to-heterocycle strategy is presented for the preparation of highly fluorescent and solvatochromic dibenzonaphthyridinones (DBNs) via methodology that leads to the formation of a tertiary, spiro-fused carbon center. A linear correlation between the results of photophysical experiments and time dependent density functional theory calculations was observed for the lambda(max) of excitation for DBNs with varying electronic character. PMID- 26574653 TI - Surface Thiolation of Al Microspheres to Deposite Thin and Compact Ag Shells for High Conductivity. AB - In this work, we have demonstrated a method for controllable thiolated functionalization coupled with electroless silver plating to achieve aluminum@silver (Al@Ag) core-shell composite particles with thin and compact layers. First, Al microspheres were functionalized by a well-known polymerizable silane coupling agent, i.e., 3-mercaptopropyltrimethoxysilane (MPTMS). Decreasing the ethanol-to-water volume ratio (F) in silane solution produces modification films with high content of thiol groups on Al microspheres, owing to the dehydration of silane molecules with hydroxyl groups on Al microspheres and self polymerization of silane molecules. Then, ethanol was used as one of the solvents to play a major role in the uniform dispersion of silane coupling agent in the solution, resulting in uniformly distributing and covalently attaching thiol groups on Al microspheres. In electroless silver plating, thiol groups being densely grafted on the surface of Al microspheres favor the heterogeneous nucleation of Ag, since the thiol group can firmly bind with Ag(+) and enable the in situ reduction by the reducing reagent. In this manner, dense Ag nuclei tend to produce thin and compact silver shells on the Al microspheres surfaces. The as obtained Al@Ag core-shell composite particles show a resistivity as low as (8.58 +/- 0.07) * 10(-5) Omega.cm even when the Ag content is as low as 15.46 wt %. Therefore, the as-obtained Al@Ag core-shell composite particles have advantages of low weight, low silver content and high conductivity, which could make it a promising candidate for application in conductive and electromagnetic shielding composite materials. PMID- 26574654 TI - The Impact of Polymer Dynamics on Photoinduced Carrier Formation in Films of Semiconducting Polymers. AB - A better understanding of the carrier formation process in photosemiconducting polymers is crucial to design and construct highly functionalized thin film organic photodevices. Almost all studies published focus on the effect of structure on the photoinduced carrier formation process. Here, we study the dynamics of polymer chain impacts on the carrier formation process for a series of poly(3-alkylthiophene)s (P3ATs) with different alkyl side-chain lengths. The formation of polarons (P) from polaron pairs (PP) was accelerated at a temperature at which the twisting motion of thiophene rings occurs. Among all P3ATs employed, in P3AT with hexyl groups, or poly(3-hexylthiophene) (P3HT), it was easiest to twist the thiophene rings and generate P from PP. The activation energy for P formation was proportional to that of thiophene ring motion. This makes it clear that chain dynamics, in addition to the crystalline structure, is a controlling factor for the carrier formation process in photosemiconducting polymers. PMID- 26574655 TI - Inheritance and Identification of a Major Quantitative Trait Locus (QTL) that Confers Resistance to Meloidogyne incognita and a Novel QTL for Plant Height in Sweet Sorghum. AB - Southern root-knot nematodes (Meloidogyne incognita) are a pest on many economically important row crop and vegetable species and management relies on chemicals, plant resistance, and cultural practices such as crop rotation. Little is known about the inheritance of resistance to M. incognita or the genomic regions associated with resistance in sorghum (Sorghum bicolor). In this study, an F2 population (n = 130) was developed between the resistant sweet sorghum cultivar 'Honey Drip' and the susceptible sweet cultivar 'Collier'. Each F2 plant was phenotyped for stalk weight, height, juice Brix, root weight, total eggs, and eggs per gram of root. Strong correlations were observed between eggs per gram of root and total eggs, height and stalk weight, and between two measurements of Brix. Genotyping-by-sequencing was used to generate single nucleotide polymorphism markers. The G-Model, single marker analysis, interval mapping, and composite interval mapping were used to identify a major quantitative trait locus (QTL) on chromosome 3 for total eggs and eggs per gram of root. Furthermore, a new QTL for plant height was also discovered on chromosome 3. Simple sequence repeat markers were developed in the total eggs and eggs per gram of root QTL region and the markers flanking the resistance gene are 4.7 and 2.4 cM away. These markers can be utilized to move the southern root-knot nematode resistance gene from Honey Drip to any sorghum line. PMID- 26574656 TI - Alcohol Use Severity Among Hispanic Emerging Adults in Higher Education: Understanding the Effect of Cultural Congruity. AB - BACKGROUND: Identifying and understanding determinants of alcohol use behavior among Hispanic college students is an increasingly important public health issue, particularly during emerging adulthood. Studies examining ethnocultural determinants of alcohol use behavior among Hispanic college students have focused on direct associations with cultural orientation (e.g., acculturation and enculturation); yet there is a need for research that accounts for the complex interplay of other culturally relevant sociocultural factors. OBJECTIVES: This study examined associations of behavioral acculturation, behavioral enculturation, and cultural congruity (perception of cultural fit between the values of the academic environment and the student's personal values) with alcohol use severity (AUS); and tested if gender moderated those associations. METHODS: A hierarchical linear regression and moderation analysis were conducted on a sample of 167 Hispanic emerging adults (ages 18-25) enrolled in college. RESULTS: All predictor variables entered in the regression model accounted for 20.9% of the variance in AUS. After controlling for demographic variables and depressive symptoms, behavioral acculturation and enculturation did not have a statistically significant association with AUS. Further, gender did not moderate either of these associations. Conversely, greater cultural congruity was associated with lower reports of AUS. A moderation analysis suggested that cultural congruity predicted lower reports of AUS among men, but not among women. CONCLUSIONS: This was the first known study to examine the association of cultural congruity with alcohol use. Findings highlight the value of examining contextual factors of culture and moving beyond reductive measures of cultural orientation. PMID- 26574657 TI - A Critical Assessment of Bias in Survey Studies Using Location-Based Sampling to Recruit Patrons in Bars. AB - Location-based sampling is a method to obtain samples of people within ecological contexts relevant to specific public health outcomes. Random selection increases generalizability; however, in some circumstances (such as surveying bar patrons), recruitment conditions increase risks of sample bias. We attempted to recruit representative samples of bars and patrons in six California cities, but low response rates precluded meaningful analysis. A systematic review of 24 similar studies revealed that none addressed the key shortcomings of our study. We recommend steps to improve studies that use location-based sampling: (i) purposively sample places of interest, (ii) use recruitment strategies appropriate to the environment, and (iii) provide full information on response rates at all levels of sampling. PMID- 26574658 TI - The Role of Moral Disengagement in Underage Drinking and Heavy Episodic Drinking. AB - OBJECTIVES: The current study had two aims. First, to develop a moral disengagement scale contextualized to underage drinking. Second, to investigate Bandura's (1986) self-regulatory model within the context of underage drinking. METHOD: Two different samples of students participated in the study. The first sample included 619 (362 females) adolescents (Mage = 15.3 years, SD = 1.09 years) and the second sample 636 (386 females) adolescents (Mage = 15.3 years, SD = 1.03 years). Students in the first sample completed the Underage Drinking Disengagement Scale (UDDS), and measures of engagement in underage drinking and heavy episodic drinking. Students in the second sample completed these measures as well as scales of general moral disengagement, personal standards, and anticipatory guilt associated with underage drinking. RESULTS: For the UDDS, exploratory and confirmatory factor analyses verified a single factor structure. The UDDS was more strongly associated with engagement in underage drinking and heavy episodic drinking than a general measure of moral disengagement. A moderated mediation analysis revealed that adolescents who negatively evaluated underage drinking reported more anticipatory guilt, and more anticipatory guilt was associated with less engagement in underage drinking and less heavy episodic drinking. This relationship was weaker at high compared to low levels of underage drinking disengagement. CONCLUSIONS/IMPORTANCE: Understanding how adolescents self-regulate their drinking, and ways that such self-regulation may be deactivated or disengaged, may help identify those adolescents at increased risk of drinking underage and of engaging in heavy episodic drinking. PMID- 26574659 TI - Erythema multiforme upon L. braziliensis infection. PMID- 26574660 TI - ERK signaling mediates long-term low concentration 3,3'-diindolylmethane inhibited nasopharyngeal carcinoma growth and metastasis: An in vitro and in vivo study. AB - It is well known that crucifers have antitumor effects and 3,3'-diindolylmethane (DIM) is one of the major bioactive components, and the associated molecular mechanisms in a short-term high-dose manner are widely discussed. However, the antitumor effects of DIM in a long-term low-dose manner in nasopharyngeal carcinoma (NPC) has not been reported yet, as to the potential mechanisms in the human body. In the present study, NPC cells were induced by 20 umol/l DIM for over a month, and the proliferation, apoptosis, migration and in vivo metastasis were investigated. The results showed that DIM significantly reduced the proliferation and migration; however, changes in apoptosis were not observed. In vivo study showed the metastasis was significantly reduced. Compared to the short term high-dose manner, incomplete similar qualities were observed; next we explored the possible signal pathway revolved, the ERK signaling showed similar changes, while the PI3K/Akt, NF-kappaB, P38, JNK pathways were significantly altered in the short-term high-dose manner (our previous study) showed no obvious change, indicating the ERK signaling may be the main effector of DIM. PMID- 26574661 TI - Test-retest reliability analysis of the Cambridge Neuropsychological Automated Tests for the assessment of dementia in older people living in retirement homes. AB - The validity of the Cambridge Neuropsychological Automated Tests has been widely studied, but their reliability has not. This study aimed to estimate the test retest reliability of these tests in a sample of 34 older adults, aged 69 to 90 years old, without neuropsychiatric diagnoses and living in retirement homes in the district of Lisbon, Portugal. The battery was administered twice, with a 4 week interval between sessions. The Paired Associates Learning (PAL), Spatial Working Memory (SWM), Rapid Visual Information Processing, and Reaction Time tests revealed measures with high-to-adequate test-retest correlations (.71-.89), although several PAL and SWM measures showed susceptibility to practice effects. Two estimated standardized regression-based methods were found to be more efficient at correcting for practice effects than a method of fixed correction. We also found weak test-retest correlations (.56-.68) for several measures. These results suggest that some, but not all, measures are suitable for cognitive assessment and monitoring in this population. PMID- 26574662 TI - Rational assembly of a biointerfaced core@shell nanocomplex towards selective and highly efficient synergistic photothermal/photodynamic therapy. AB - To optimize synergistic cancer therapy, we rationally assemble an inorganic organic nanocomplex using a folate-modified lipid bilayer spread on photosensitizer-entrapped mesoporous silica nanoparticle (MSN) coated gold nanorods (AuNRs). In this hybrid bioconjugate, the large specific surface area and pore size of AuNR@MSN guarantee a high loading capacity of small photosensitive molecules. The modification with selective mixed liposomes on the surface of AuNR@MSN enables faster cellular internalization and enhancement of endocytosis. Under one-time NIR two-photon illumination, AuNR-mediated hyperthermia can kill cancer cells directly. Meanwhile, the loaded photosensitizer, hypocrellin B, generates two kinds of reactive oxygen species (ROS) to induce cell apoptosis. Remarkably, hyperthermia can improve the yield of ROS. After intravenous injection of this bioconjugate into female BALB/c nude mice followed by laser irradiation (808 nm, 1.3 W cm(-2), 6 min), the tumor growth is suppressed completely. The tumors are not recurrent within the observation time (19 days), and the normal or main organs are not obviously pathological. Thus, such a simplified and selective cancer treatment, combining photothermal and photodynamic therapy in a synergistic manner, provides outstanding efficiency in vivo. This nanocomplex with well-defined core@shell nanostructures integrated with a two-photon technique holds great promise to improve cancer phototherapy with a high efficiency in the clinic. PMID- 26574663 TI - Application of Extra Virgin Olive Oil to Prevent Nipple Cracking in Lactating Women. AB - BACKGROUND: It is well established that extra virgin olive oil (EVOO), applied to the skin, has healing and anti-inflammatory properties. AIM: To evaluate the effectiveness of EVOO in the prevention of nipple cracking in lactating women. METHODS: Experimental, prospective, randomized study of 300 lactating women, admitted to the postpartum unit of the city's general hospital (Cienfuegos, Cuba). The study was carried out in 2012. Eligible patients were randomized into two groups of 150 women. In Group 1, EVOO was applied on the nipple after feeding, and in Group 2, drops of breast milk were applied to the nipple after feeding. Clinical evaluations were made during the first week of treatment and after the first month. All women who initiated breastfeeding were considered eligible to be included in this study; breastfeeding was characterized as the moment of mother-child interaction with suction on the nipple. Efficacy was evaluated quantitatively, as the absence of cracks in the nipple during the first 2 weeks of lactation using as the proportion of women with or without nipple cracks, and if present, whether they were moderate or slight. RESULTS: The quantitative efficacy was 97.3% and no adverse effects occurred in mothers and newborns during the administration of EVOO. DISCUSSION AND CONCLUSIONS: EVOO helps prevent nipple cracking in lactating women. It has been shown to have protective effects when breastfeeding presents technical difficulties. This conclusion is borne out by the frequency distribution results obtained, which reflect a significantly higher proportion of nipple cracking in the population that was not treated with EVOO. LINKING EVIDENCE TO ACTION: Use EVOO to prevent nipple cracking during breastfeeding by administering 3 drops on each nipple after each feeding. Decreased nipple cracking will reduce pain and enhance breastfeedinging by administering 3 drops on each nipple after each feeding, improving the health of mothers and infants. PMID- 26574664 TI - Modulation of hepatocarcinogenesis in N-methyl-N-nitrosourea treated Balb/c mice by mushroom extracts. AB - The hepatoprotective potential of edible mushrooms from Mauritius, namely Pleurotus sajor-caju and Agaricus bisporus was evaluated using an N-methyl-N nitrosourea (MNU)-induced hepatocarcinogenesis Balb/c mice model. Mushroom extracts restored normal weight in MNU treated mice over a 3 month supplementation period. Blood parameter analyses indicated a clear modulation of hemoglobin concentration, leukocyte, platelet, lymphocyte, neutrophil, monocyte and eosinophil counts in MNU-induced mice (p < 0.05). Mushroom extract supplementation effectively reduced oxidative damage in MNU-primed mice, which was marked by a significant decrease in the extent of lipid peroxidation (p < 0.05) and a concomitant increase in the enzymatic antioxidant levels, primarily catalase, superoxide dismutase, glutathione reductase and peroxidase, and FRAP values (p < 0.05). DNA protective effects of the extracts were confirmed by Raman spectroscopy, where, the MNU-DNA interaction, as evidenced by an intense peak at 1254 cm(-1), was normalized. The findings demonstrate hepatoprotective, immunomodulatory and anti-carcinogenic effects and suggest the use of mushrooms as potential dietary prophylactics in cancer chemoprevention. PMID- 26574666 TI - Primary Central Nervous System Histiocytic Sarcoma Arising After Precursor B-Cell Acute Lymphoblastic Leukemia. AB - Histiocytic sarcomas (HSs) are rare malignant neoplasms derived from histiocytes that may be associated with other hematolymphoid neoplasms. Histiocytic sarcomas rarely occur in the CNS and have not previously been reported in conjunction with prior B-cell lymphoblastic leukemia. We report the case of a 23-year-old man who presented with primary CNS HS 7 years after achieving remission for precursor B cell acute lymphoblastic leukemia (B-ALL). Molecular studies revealed clonal immunoglobulin heavy-chain (IGH) gene rearrangement within the HS, suggesting linkage to his previous B-ALL. Previously reported post-ALL HSs show a strong predilection for young males (male-to-female ratio, 20:1), whereas cases of primary CNS HS without previous ALL affected older adults with balanced sex predilection. The patient's survival at 60 months exceeds expectations when compared with that of other reported cases of de novo primary CNS HS (n = 18) and post-ALL HS at all sites (n = 19). In addition, we discuss the potential relationship between B-ALL and HS posed by other authors. PMID- 26574667 TI - Uncompacted Myelin Lamellae and Nodal Ion Channel Disruption in POEMS Syndrome. AB - To elucidate the significance of uncompacted myelin lamellae (UML) and ion channel disruption at the nodes of Ranvier in the polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome, we evaluated sural nerve biopsy specimens from 33 patients with POEMS syndrome and from 7 control patients. Uncompacted myelin lamellae distribution was assessed by electron microscopy and immunofluorescence microscopy. In the POEMS patient biopsies, UML were seen more frequently in small versus large myelinated fibers. Paranodes and Schmidt-Lanterman incisures, where normal physiologic UM is located, were frequently associated with UM. Widening of the nodes of Ranvier (i.e. segmental demyelination) was not associated with UML. There was axonal hollowing with neurofilament condensation at Schmidt-Lanterman incisures with abnormal UML, suggesting axonal damage at those sites in the POEMS patient biopsies. Myelin sheath irregularity was conspicuous in large myelinated fibers and was associated with abnormally widened bizarrely shaped Schmidt-Lanterman incisures. Indirect immunofluorescent studies revealed abnormalities of sodium (pan sodium) and potassium (KCNQ2) channels, even at nonwidened nodes of Ranvier. Thus, UML was not apparently associated with segmental demyelination but seemed to be associated with axonal damage. These observations suggest that nodal ion channel disruption may be associated with functional deficits in POEMS syndrome patient nerves. PMID- 26574668 TI - A New Mouse Model of Limb-Girdle Muscular Dystrophy Type 2I Homozygous for the Common L276I Mutation Mimicking the Mild Phenotype in Humans. AB - Limb-girdle muscular dystrophy type 2I (LGMD2I) is caused by mutations in the Fukutin-related protein (FKRP) gene, leading to inadequate glycosylation of alpha dystroglycan, an important protein linking the extracellular matrix to the cytoskeleton. We created a mouse model of the common FKRP L276I mutation and a hemizygous FKRP L276I knockout model. We studied histopathology and protein expression in the models at different ages and found that homozygous FKRP L276I mice developed a mild progressive myopathy with increased muscle regeneration and fibrosis starting from 1 year of age. This was likely caused by progressive loss of alpha-dystroglycan-specific glycosylation, which was decreased by 78% at 20 months. The homozygous FKRP knockout was embryonic lethal, but the hemizygous L276I model resembled the homozygous FKRP L276I model at comparable ages. These models emphasize the importance of FKRP in maintaining proper glycosylation of alpha-dystroglycan. The mild progression in the homozygous FKRP L276I model resembles that in patients with LGMD2I who are homozygous for the L276I mutation. This animal model could, therefore, be relevant for understanding the pathophysiology of and developing a treatment strategy for the human disorder. PMID- 26574669 TI - Blood-Brain Barrier Disruption Is an Early Event That May Persist for Many Years After Traumatic Brain Injury in Humans. AB - Traumatic brain injury (TBI) is a risk factor for dementia. Mixed neurodegenerative pathologies have been described in late survivors of TBI, but the mechanisms driving post-TBI neurodegeneration remain elusive. Increasingly, blood-brain barrier (BBB) disruption has been recognized in a range of neurologic disorders including dementias, but little is known of the consequences of TBI on the BBB. Autopsy cases of single moderate or severe TBI from the Glasgow TBI Archive (n = 70) were selected to include a range from acute (10 hours-13 days) to long-term (1-47 years) survival, together with age-matched uninjured controls (n = 21). Multiple brain regions were examined using immunohistochemistry for the BBB integrity markers fibrinogen and immunoglobulin G. After TBI, 40% of patients dying in the acute phase and 47% of those surviving a year or more from injury showed multifocal, abnormal, perivascular, and parenchymal fibrinogen and immunoglobulin G immunostaining localized to the gray matter, with preferential distribution toward the crests of gyri and deep neocortical layers. In contrast, when present, controls showed only limited localized immunostaining. These preliminary data demonstrate evidence of widespread BBB disruption in a proportion of TBI patients emerging in the acute phase and, intriguingly, persisting in a high proportion of late survivors. PMID- 26574671 TI - Clinical Outcome of Silent Subtype III Pituitary Adenomas Diagnosed by Immunohistochemistry. AB - Silent subtype III pituitary adenomas (SS-3) are nonfunctioning radiosensitive adenomas that may be associated with an increased risk of recurrence and invasion. The features that have been proposed to be diagnostically important are identifiable by electron microscopy (EM) and include an enlarged Golgi apparatus, along with several other ultrastructural features. The often limited availability of EM and the uncertainty about the relative importance of individual features pose practical challenges to the diagnosis. We hypothesized that it may be possible to diagnose SS-3 based solely on a markedly enlarged Golgi apparatus identified at the light microscopic level. In this prospective study, we used immunohistochemistry (IHC) for the Golgi apparatus with the MG-160/GLG-1 antibody to identify 10 cases with features suggestive of SS-3. Electron microscopy was performed for confirmation on 1 case. Compared with a control group of 20 conventional null cell adenomas, the SS-3 adenomas showed an increased MIB-1 proliferation index (p < 0.01), a higher risk of invasion (p < 0.01), and a higher incidence of recurrence (p < 0.01). Thus, in this first controlled study, we demonstrate that SS-3 is clinically aggressive and identifiable by IHC, without the need for EM. The routine diagnostic workup of nonsecreting adenomas should rule out SS-3, which can be done quickly and efficiently by IHC. PMID- 26574670 TI - Transmission of Soluble and Insoluble alpha-Synuclein to Mice. AB - The neurodegenerative synucleinopathies, which include Parkinson disease, multiple-system atrophy, and Lewy body disease, are characterized by the presence of abundant neuronal inclusions called Lewy bodies and Lewy neurites. These disorders remain incurable, and a greater understanding of the pathologic processes is needed for effective treatment strategies to be developed. Recent data suggest that pathogenic misfolding of the presynaptic protein, alpha synuclein (alpha-syn), and subsequent aggregation and accumulation are fundamental to the disease process. It is hypothesized that the misfolded isoform is able to induce misfolding of normal endogenous alpha-syn, much like what occurs in the prion diseases. Recent work highlighting the seeding effect of pathogenic alpha-syn has largely focused on the detergent-insoluble species of the protein. In this study, we performed intracerebral inoculations of the sarkosyl-insoluble or sarkosyl-soluble fractions of human Lewy body disease brain homogenate and show that both fractions induce CNS pathology in mice at 4 months after injection. Disease-associated deposits accumulated both near and distal to the site of the injection, suggesting a cell-to-cell spread via recruitment of alpha-syn. These results provide further insight into the prion-like mechanisms of alpha-syn and suggest that disease-associated alpha-syn is not homogeneous within a single patient but might exist in both soluble and insoluble isoforms. PMID- 26574673 TI - Speciation and Bioavailability Measurements of Environmental Plutonium Using Diffusion in Thin Films. AB - The biological uptake of plutonium (Pu) in aquatic ecosystems is of particular concern since it is an alpha-particle emitter with long half-life which can potentially contribute to the exposure of biota and humans. The diffusive gradients in thin films technique is introduced here for in-situ measurements of Pu bioavailability and speciation. A diffusion cell constructed for laboratory experiments with Pu and the newly developed protocol make it possible to simulate the environmental behavior of Pu in model solutions of various chemical compositions. Adjustment of the oxidation states to Pu(IV) and Pu(V) described in this protocol is essential in order to investigate the complex redox chemistry of plutonium in the environment. The calibration of this technique and the results obtained in the laboratory experiments enable to develop a specific DGT device for in-situ Pu measurements in freshwaters. Accelerator-based mass-spectrometry measurements of Pu accumulated by DGTs in a karst spring allowed determining the bioavailability of Pu in a mineral freshwater environment. Application of this protocol for Pu measurements using DGT devices has a large potential to improve our understanding of the speciation and the biological transfer of Pu in aquatic ecosystems. PMID- 26574674 TI - Inhibition of Kallikrein-Related Peptidases 7 and 5 by Grafting Serpin Reactive Center Loop Sequences onto Sunflower Trypsin Inhibitor-1 (SFTI-1). AB - Serpin proteins irreversibly inhibit serine proteases, but only a small part of the serpin reactive-center loop (RCL) is responsible for the initial protein protein interaction (PPI). To develop peptidic protease inhibitors, kallikrein related peptidases 7 (KLK7) and 5 (KLK5) were chosen. Firstly, we demonstrated that short peptides derived from RCL sequences can be cleaved by KLK7 in a substrate-like manner. Next, these substrates were grafted onto the protease binding loop of sunflower trypsin inhibitor-1 (SFTI-1). Peptides based on kallistatin, alpha1 -antichymotrypsin, and protein C inhibitor (PCI) inhibited KLK7 with Ki =0.4, 0.5, and 0.7 MUm, respectively. In contrast, the trypsin-like KLK5 was only blocked by the peptide derived from PCI (Ki =0.6 MUm). Thus, serpin function can be mimicked by introducing its PPI site into the rigid structure of the SFTI-1 scaffold. This approach might be applicable not only to KLKs but also to other serine protease members, thus opening up new therapeutic fields. PMID- 26574675 TI - LONG-TERM CONSERVATION OF PROTOCORMS OF Brassavola nodosa (L) LIND. (ORCHIDACEAE): EFFECT OF ABA AND A RANGE OF CRYOCONSERVATION TECHNIQUES. AB - BACKGROUND: Populations of Brassavola nodosa have been severely affected by habitat destruction and illegal collecting, and as with the majority of orchid species, it is critical to take action to guarantee their continued survival. OBJECTIVE: The present study aimed to establish protocols for the long-term conservation of protocorms of species. MATERIALS AND METHODS: Four different cryogenic techniques were compared: encapsulation-dehydration (ED), encapsulation vitrification (EV), encapsulation-dehydration-vitrification (EDV) and vitrification. RESULTS: Preculture of protocorms with ABA was a critical factor in obtaining high percentages of regrowth. With vitrification, 100% regrowth was achieved in five treatments, mainly when protocorms were dehydrated with PVS2 for 120 min. 100% regrowth was also obtained with EDV, where the protocorms were precultured with ABA 5 mg/l for 3 days and incubated with PVS2 for 60 min. With the ED, regrowth of 72% was achieved with the preculture of protocorms with ABA 5 mg/l for the three times of incubation used (3, 6 and 9 days). In the case of EV, 92% regrowth, was recorded when protocorms were precultured for 9 days with ABA 3 mg/l and incubated with PVS2 for 90 min. CONCLUSION: Although regrowth of protocorms was obtained with all the techniques used, the vitrification technique is preferred since it requires less labour and is less costly. PMID- 26574676 TI - ZYGOTIC EMBRYO CRYOPRESERVATION OF Calamus vattayila RENUKA, AN ENDANGERED RATTAN PALM OF INDIA, AS INFLUENCED BY SEED MATURITY. AB - BACKGROUND: Calamus vattayila Renuka is an endemic and endangered rattan palm of the Western Ghats, India where the development of a protocol for cryopreservation is important for their ex situ conservation in gene banks. OBJECTIVE: The objective of the study is to devise an efficient protocol for cryopreservation of the species, comparing the relative efficiency of seeds and zygotic embryos as storage material. MATERIALS AND METHODS: Mature seeds extracted from ripened fruits were subjected to cryopreservation through a simple dehydration method and zygotic embryos isolated from seeds of three different maturity stages were cryopreserved through an encapsulation-dehydration method. RESULTS: The mature seeds did not tolerate desiccation and freezing but the isolated zygotic embryos tolerated both desiccation and freezing. Embryos isolated from immature, partially mature and mature seeds harvested respectively after 160-170, 210-220 and 250-260 days after flowering possessed 82 - 86% moisture content (m.c.) and tolerated desiccation down to 9% m.c. with 80% viability. Embryos from immature seeds gave a maximum 63+/-26% regeneration after LN exposure, which is nearly equal to the corresponding desiccated control (73%). LN tolerance declined with maturity of seeds with a maximum of 49% of embryos from partially mature seeds and 25% from mature seeds subjected to LN exposure showing post-freeze recovery and regeneration. CONCLUSION: Although immature seeds collected during February March were recalcitrant (desiccation sensitivity), their embryos tolerated cryopreservation through encapsulation-dehydration better than embryos isolated from more mature seeds. PMID- 26574677 TI - EFFECT OF SEMEN EXTENDER SUPPLEMENTATION WITH TREHALOSE,VITAMIN C AND E ON POST THAW MIN PIG SPERM QUALITIES. AB - BACKGROUND: Cryopreservation of min pig sperm offers an effective method to protect this valuable genetic resource. OBJECTIVE: To determine whether the extender supplementation with some antioxidants is able to improve the quality of post-thawed sperm of min pig. MATERIALS AND METHODS: Ejaculated min pig sperm frozen in lactose-egg yolk (LEY) extender supplemented with trehalose, vitamin C and/or water-soluble vitamin E were thawed, and the quality of sperm samples were evaluated. RESULTS: The quality of post-thawed sperm samples was higher in the groups with supplementation than that of the control group (P < 0.05). Furthermore, the addition of 100 mM trehalose and 25 mM water-soluble vitamin E to the freezing extender strongly preserved the quality of the sperm (P < 0.05). CONCLUSION: Trehalose and water-soluble vitamin E in the freezing extender effectively improved post-thaw qualities of min pig sperm. PMID- 26574678 TI - EFFECT OF SOLID MEDIUM DURING COOLED STORAGE ON STALLION SPERM PARAMETERS. AB - BACKGROUND: Solid storage medium prevents cellular sedimentation, reduces metabolic demand via limiting movement, and avoids the modification of an extender composition in the sedimentary microenvironment. It has been proven to prolong spermatozoa viability in mammalians. OBJECTIVE: This experiment aims to evaluate the effect of cool storage in solid phase extender on stallion sperms. MATERIALS AND METHODS: Semen was collected from 10 Crioulo stallions (n=30) and submitted to treatments: control group (semen extender) and groups with gelatin addition in different concentrations (semen extender + 1%, 2% and 3%). Seminal analyses included motility, mitochondrial functionality, plasma membrane integrity, DNA and acrosome at 0; 24; 48 and 72 hours during cooled storage at 5 degree C. RESULTS: Motility, mitochondrial functionality, plasma membrane and acrosome integrity declined during storage time, with no statistical difference between treatments. DNA integrity did not significantly change during storage period. CONCLUSION: Solid medium was not harmful and did not improved stallion sperm parameters during cooled storage. PMID- 26574679 TI - ASSESSMENT OF MOLECULAR GENETIC STABILITY BETWEEN LONG-TERM CRYOPRESERVED AND TISSUE CULTURED WASABI (Wasabia japonica) PLANTS. AB - BACKGROUND: Maintaining the genetic integrity in long-term tissue cultured and cryopreserved plants is important for the conservation of plant genetic resources. OBJECTIVE: In this study, the genetic stability of cryopreserved wasabi shoot tips stored for 10 years at -150 degree C was visualized using Amplified Fragment Length Polymorphism (AFLP) and Methylation Sensitive Amplified Polymorphism (MSAP). MATERIALS AND METHODS: The study included plants derived from cryopreserved shoot tips after 10.5 years storage at -150 degree C (LN10yr), after 2 h storage at -196 degree C (LN2hr), cryopreservation controls (No LN cooling (TC)) and non-treated controls without LN cooling (LC). The donor plants for LN2hr, TC and LC were also maintained in vitro at 20 degree C for the same period. RESULTS: Neither technique detected genetic variations in either control or cryopreserved plants. Some mutations were noted in plants maintained in tissue culture for 10 years. Comparison of genome stability for TC and LN2hr plants showed only a minor change in DNA. However, when comparing the LC and Ln10yr, many differences were found. CONCLUSION: We conclude that cryopreservation is a superior conservation method compared to tissue culture in maintaining genetic stability for a long-term storage of wasabi germplasm. PMID- 26574680 TI - CRYOPRESERVATION STRATEGY FOR TISSUE ENGINEERING CONSTRUCTS CONSISTING OF HUMAN MESENHYMAL STEM CELLS AND HYDROGEL BIOMATERIALS. AB - BACKGROUND: The development of vitrification strategy for cell-biomaterial constructs, particularly biologically inspired nanoscale materials and hydrogels mimicking the in vivo environment is an active area. A cryopreservation strategy mimicking the in vivo environment for cell-hydrogel constructs may enhance cell proliferation and biological function. OBJECTIVE: To demonstrate the efficacy of vitrification as a platform technology involving tissue engineering and human mesenchymal stem cells (hMSCs). MATERIALS AND METHODS: Microcarriers made from alginate coated with chitosan and collagen are used. Conventional freezing and vitrification were compared. The vitrification strategy includes 10 min step-wise exposure to a vitrification solution (40% v/v EG, 0.6M sucrose) and immersion into liquid nitrogen. RESULTS: Confocal imaging of live/dead staining of hMSCs cultured on the surface of microcarriers demonstrated that vitrified cells had excellent appearance and prolonged spindle shape morphology. The proliferation ability of post-vitrified cells arbitrated to protein Ki-67 gene expression was not significantly different in comparison to untreated control, while that of post-freezing cells was almost lost. The ability of hMSCs cultured on the surface of microcarriers to proliferate has been not affected by vitrification and it was significantly better after vitrification than after conventional freezing during continuous culture. Collagen II related mRNA expression by 4 weeks post vitrification and post-freezing showed that ability to differentiate into cartilage was sustained during vitrification and reduced during conventional freezing. No significant difference was found between control and vitrification groups only. CONCLUSION: Vitrification strategy coupled with advances in hMSC expansion platform that completely preserves the ability of stem cells to proliferate and subsequently differentiate allows not only to reach a critical cell number, but also demonstrate prospects for effective utilization and transportation of cells with their support system, creating demand for novel biodegradable materials. PMID- 26574681 TI - EFFECTS OF SEMEN EXTENDER SUPPLEMENTED WITH L-METHIONINE AND PACKAGING METHODS (STRAWS AND PELLETS) ON POST-THAW GOLDFISH (Carassius auratus) SPERM QUALITY AND DNA DAMAGE. AB - BACKGROUND: Amino acids protect spermatozoa against cell damage during cryopreservation due to have antioxidant property and found in seminal plasma at high concentration. OBJECTIVE: The aim of the present work was to analyse the effect of extender supplementation with L-methionine on post-thawed sperm motility, duration and DNA damage and also it was tested the feasibility of using straws and pellets method for the cryopreservation of goldfish (Carassius auratus) sperm. MATERIALS AND METHODS: Extenders were supplemented with different L-methionine concentrations of 1 mM; 1.5 mM; 3 mM; 6 mM. Semen samples diluted at the ratio of 1 to 9 by the extenders were subjected to cryopreservation. After dilution the semen was aspirated into 0.25 ml straws and 0.1 ml pellets, the straws and pellets were placed on the tray, frozen in nitrogen vapor and plunged into liquid nitrogen. DNA damage was determined with comet assay after cryopreservation. RESULTS: Our results indicated that an increase in the concentration of L-methionine caused a significant increase in the motility rate and duration of sperm in goldfish (C. auratus) (p<0.05). In addition, duration and percentage of motility in pellets were higher than in straws. Comparing all concentrations of L-methionine, the best concentration of L-methionine was 1.5 mM. Highest post-thaw motility (45.00 +/- 7.07%) and duration of motility (17.00 +/- 0.71s) were obtained with the extender at concentration 1.5 mM in pellets. Addition of the extender with L-methionine was reduced DNA damage compared to control group. CONCLUSION: Consequently, pellets could be used for goldfish sperm cryopreservation and the tested amino acid affected the motility parameters, and semen extenders could be supplement with L-methionine. PMID- 26574682 TI - CRYOPRESERVATION OF SWEET POTATO SHOOT TIPS USING A DROPLET-VITRIFICATION PROCEDURE. AB - BACKGROUND: Sweet potato is a staple food worldwide, but a problematic species in terms of long term storage, as it is not suitable for germplasm conservation. OBJECTIVE: This study aimed to develop cryopreservation protocols for sweet potato shoot tips based on a droplet-vitrification procedure. METHODS: As a standard procedure, sweet potato shoot tips were precultured in a liquid MS medium supplemented with 10% sucrose (S-10%) and 17.5% sucrose (S-17.5%) for 31 and 17 h, respectively. They were then osmoprotected with C4-35% (17.5% glycerol + 17.5% sucrose) for 50 min and cryoprotected with PVS3 (50% glycerol + 50% sucrose) for 60 min. A set of experiments was designed to investigate critical factors, i.e. stepwise sucrose preculture, osmoprotection, cryoprotection with PVS2- and PVS3-based vitrification solutions, and their combinational effect, as well as temperature alteration through placement in a cooling/rewarming container. RESULTS: Sucrose preculture was determined to be necessary for the adaptation of sweet potato shoot tips to cryoprotection with PVS3, and the highest post-thaw (LN) regeneration rate was observed in a preculture with S-10% for 31 h -> S-17.5% for 17 h (19.0%). The effect of one-step or two-step osmoprotection was not significant on survival or regeneration of either the cryoprotected-control (LNC) or LN shoot tips. Responses of sweet potato shoot tips to osmoprotection and cryoprotection were linked to the level of sucrose preculture. The use of alumimium foil strips (droplet-vitrification) resulted in significantly higher LN survival (89.8%) and regeneration (19.0%), compared to those using cryovials (vitrification, 67.2% and 0%, respectively). LN regeneration increased by 67.5% when cryopreserved shoot tips were transferred to a new postculture medium. CONCLUSIONS: This study demonstrates that the combination of stepwise sucrose preculture with a higher final concentration (up to 17.5%), cryoprotection with PVS3 and cooling with foil strip is crucial to the regeneration of LN sweet potato shoot tips. PMID- 26574683 TI - Controllable Synthesis of Highly Luminescent Boron Nitride Quantum Dots. AB - Boron nitride quantum dots (BNQDs), as a new member of heavy metal-free quantum dots, have aroused great interest in fundamental research and practical application due to their unique physical/chemical properties. However, it is still a challenge to controllably synthesize high-quality BNQDs with high quantum yield (QY), uniform size and strong fluorescent. In this work, BNQDs have been successfully fabricated by the liquid exfoliation and the subsequent solvothermal process with respect to its facileness and easy large scale up. Importantly, BNQDs with high-quality can be controllably obtained by adjusting the synthetic parameters involved in the solvothermal process including filling factor, synthesis temperature, and duration time. Encouragingly, the as-prepared BNQDs possess strong blue luminescence with QY as high as 19.5%, which can be attributed to the synergetic effect of size, surface chemistry and edge defects. In addition, this strategy presented here provides a new reference for the controllable synthesis of other heavy metal-free QDs. Furthermore, the as prepared BNQDs are non-toxic to cells and exhibit nanosecond-scaled lifetimes, suggesting they have great potential biological and optoelectronic applications. PMID- 26574684 TI - Temporal Analysis of Market Competition and Density in Renal Transplantation Volume and Outcome. AB - BACKGROUND: Kidney transplant centers are distributed unevenly throughout 58 donor service areas (DSAs) in the United States. Market competition and transplant center density may affect transplantation access and outcomes. We evaluated the role of spatial organization of transplant centers in conjunction with market competition in the conduct of kidney transplantation. METHODS: The Scientific Registry of Transplant Recipients was queried for market characteristics associated with kidney transplantation between 2003 and 2012. Market competition was calculated using the Herfindahl Hirschman Index. Kidney transplant centers were geocoded to measure spatial organization by the average nearest neighbor (ANN) method. Kidney quality was assessed by kidney donor risk index. A hierarchical negative binomial mixed effects model tested the relationship between market characteristics and annual kidney transplants by DSA. RESULTS: About 152,071 kidney transplants were performed at 229 adult kidney transplant centers in 58 DSAs. Greater market competition was associated with kidney transplant center spatial clustering (P < 0.001). In multivariable analysis, more kidney transplant centers (incidence rate ratio [IRR], 1.04; P = 0.005), 100 more new listings (IRR, 1.02; P = 0.003), 100 more deceased donors (IRR, 1.23; P < 0.001), 100 more new dialysis registrants (IRR, 1.01; P < 0.001), and higher kidney donor risk index (IRR, 1.98; P < 0.001) were associated with increased kidney transplants. CONCLUSIONS: After controlling for market characteristics, larger numbers of kidney transplant centers were associated with more kidney transplants and increased utilization of deceased donor kidneys. This underlines the importance of understanding geography as well as competition in improving access to kidney transplantation. PMID- 26574685 TI - The effect of microbial colonization on the host proteome varies by gastrointestinal location. AB - Endogenous intestinal microbiota have wide-ranging and largely uncharacterized effects on host physiology. Here, we used reverse-phase liquid chromatography coupled tandem mass spectrometry to define the mouse intestinal proteome in the stomach, jejunum, ileum, cecum and proximal colon under three colonization states: germ-free (GF), monocolonized with Bacteroides thetaiotaomicron and conventionally raised (CR). Our analysis revealed distinct proteomic abundance profiles along the gastrointestinal (GI) tract. Unsupervised clustering showed that host protein abundance primarily depended on GI location rather than colonization state and specific proteins and functions that defined these locations were identified by random forest classifications. K-means clustering of protein abundance across locations revealed substantial differences in host protein production between CR mice relative to GF and monocolonized mice. Finally, comparison with fecal proteomic data sets suggested that the identities of stool proteins are not biased to any region of the GI tract, but are substantially impacted by the microbiota in the distal colon. PMID- 26574686 TI - Diversity in a honey bee pathogen: first report of a third master variant of the Deformed Wing Virus quasispecies. AB - Treatment of emerging RNA viruses is hampered by the high mutation and replication rates that enable these viruses to operate as a quasispecies. Declining honey bee populations have been attributed to the ectoparasitic mite Varroa destructor and its affiliation with Deformed Wing Virus (DWV). In the current study we use next-generation sequencing to investigate the DWV quasispecies in an apiary known to suffer from overwintering colony losses. We show that the DWV species complex is made up of three master variants. Our results indicate that a new DWV Type C variant is distinct from the previously described types A and B, but together they form a distinct clade compared with other members of the Iflaviridae. The molecular clock estimation predicts that Type C diverged from the other variants ~319 years ago. The discovery of a new master variant of DWV has important implications for the positive identification of the true pathogen within global honey bee populations. PMID- 26574688 TI - Short term treatment with lithium carbonate as adjunct to radioiodine treatment for long-lasting Graves' hyperthyroidism. AB - OBJECTIVE: Lithium carbonate is primarily used for the treatment of patients with bipolar affective disorders. Initial treatment of Graves' hyperthyroidism (GHT) with antithyroid drugs (ATD) has limitations at over 50% of treated patients because of significant side effects and relatively high relapses of the disease after drugs withdrawal. Till now, the influence of LiCO3on RIT outcome was mainly studied in patients with recent onset of GHT, and results were contradicted. Meta analysis of case-control studies showed higher rated hypothyroidism in patients with mood disorders treated with LiCO3(121/869) than in controls (10/578). Although in a small number of patients (n=28) with long-lasting GHT, preliminary results of ours showed that 131I treatment with LiCO3for 7 days significantly improved the efficacy of RIT versus the non-LiCO3treated patients (P<0.001). Lithium treated patients were cured faster (12 of 13 patients were cured after one month) than those treated only with 131I (8 patients were cured after one and 11/15 patients after 12 months). Fewer patients treated with 131I and LiCO3had persistent hyperthyroidism than those treated with 131I alone. There were no toxic effects of LiCO3during 7 days treatment. CONCLUSION: These observations indicate of that short-term treatment with LiCO3in GHT patients as adjunct to 131I-NaI improves the efficacy of RIT, prevents transient exacerbation of hyperthyroidism, early induction of hypothyroidism and does not worsen ophthalmopathy. PMID- 26574687 TI - Proteorhodopsin light-enhanced growth linked to vitamin-B1 acquisition in marine Flavobacteria. AB - Proteorhodopsins (PR) are light-driven proton pumps widely distributed in bacterioplankton. Although they have been thoroughly studied for more than a decade, it is still unclear how the proton motive force (pmf) generated by PR is used in most organisms. Notably, very few PR-containing bacteria show growth enhancement in the light. It has been suggested that the presence of specific functions within a genome may define the different PR-driven light responses. Thus, comparing closely related organisms that respond differently to light is an ideal setup to identify the mechanisms involved in PR light-enhanced growth. Here, we analyzed the transcriptomes of three PR-harboring Flavobacteria strains of the genus Dokdonia: Dokdonia donghaensis DSW-1(T), Dokdonia MED134 and Dokdonia PRO95, grown in identical seawater medium in light and darkness. Although only DSW-1(T) and MED134 showed light-enhanced growth, all strains expressed their PR genes at least 10 times more in the light compared with dark. According to their genomes, DSW-1(T) and MED134 are vitamin-B1 auxotrophs, and their vitamin-B1 TonB-dependent transporters (TBDT), accounted for 10-18% of all pmf-dependent transcripts. In contrast, the expression of vitamin-B1 TBDT was 10 times lower in the prototroph PRO95, whereas its vitamin-B1 synthesis genes were among the highest expressed. Our data suggest that light-enhanced growth in DSW 1(T) and MED134 derives from the use of PR-generated pmf to power the uptake of vitamin-B1, essential for central carbon metabolism, including the TCA cycle. Other pmf-generating mechanisms available in darkness are probably insufficient to power transport of enough vitamin-B1 to support maximum growth of these organisms. PMID- 26574689 TI - A combined simple bubbling method with high performance liquid chromatography purification strategy, higher radiochemical yield and purity and faster preparation of carbon-11-raclopride. AB - OBJECTIVE: Carbon-11-raclopride (11C-R) is a positron-emitting radiotracer successfully used for the study of cognitive control and widely applied in PET imaging. A simple automated preparation of 11C-R by using the reaction of carbon (11)-methyl triflate (11C-MeOTF) or 11C-methyl iodide (11C-MeI) with demethylraclopride is described. METHODS: Specifically we used a simple setup applied an additional "U" reaction vessel for 11C-MeOTf compared with 11C-MeI and assessed the influence of several solvents and of the amount of the percussor for 11C-methylation of demethylraclopride by the bubbling method. The reversal of retention order between product and its precursor has been achieved for 11C-R, enabling collection of the purified 11C-R by using the HPLC column after shorter retention time. RESULTS: By the improved radiosynthesis and purification strategy, 11C-R could be prepared with higher radiochemical yield than that of the previous studies. The yield for 11C-MeOTf was 76% and for 11C-CH3I >26% and with better radiochemical purity (>99% based on both 11C-MeOTf and 11C-MeI) as compared to the previously obtained purity of 11C-R using HPLC method with acetonitrile as a part of mobile phase. Furthermore, by using ethanol as the organic modifier, residual solvent analysis prior to human injection could be avoided and 11C-R could be injected directly following simple dilution and sterile filtration. CONCLUSION: Improved radiosynthesis and HPLC purification in combination with ethanol containing eluent, extremely shortened the time for preparation of 11C-R, gave a higher radiochemical yield and purity for 11C-R and can be used for multiple and faster synthesis of 11C-R and probably for other 11C labeled radiopharmaceuticals. PMID- 26574690 TI - Diagnostic value of (99m)Tc-3PRGD2 scintimammography for differentiation of malignant from benign breast lesions: Comparison of visual and semi-quantitative analysis. AB - OBJECTIVE: To compare the diagnostic value of visual and semi-quantitative analysis of technetium-99m-poly-ethylene glycol, 4-arginine-glycine-aspartic acid ((99m)Tc-3PRGD2) scintimammography (SMG) for better differentiation of benign from malignant breast masses, and also investigate the incremental role of semi quantitative index of SMG. SUBJECTS AND METHODS: A total of 72 patients with breast lesions were included in the study. Technetium-99m-3PRGD2 SMG was performed with single photon emission computed tomography (SPET) at 60 min after intravenous injection of 749 +/- 86MBq of the radiotracer. Images were evaluated by visual interpretation and semi-quantitative indices of tumor to non-tumor (T/N) ratios, which were compared with pathology results. Receiver operating characteristics (ROC) curve analyses were performed to determine the optimal visual grade, to calculate cut-off values of semi-quantitative indices, and to compare visual and semi-quantitative diagnostic values. RESULTS: Among the 72 patients, 89 lesions were confirmed by histopathology after fine needle aspiration biopsy or surgery, 48 malignant and 41 benign lesions. The mean T/N ratio of (99m)Tc-3PRGD2 SMG in malignant lesions was significantly higher than that in benign lesions (P<0.05). When grade 2 of the disease was used as cut-off value for the detection of primary breast cancer, the sensitivity, specificity and accuracy were 81.3%, 70.7%, and 76.4%, respectively. When a T/N ratio of 2.01 was used as cut-off value, the sensitivity, specificity and accuracy were 79.2%, 75.6%, and 77.5%, respectively. According to ROC analysis, the area under the curve for semi-quantitative analysis was higher than that for visual analysis, but the statistical difference was not significant (P=0.372). Compared with visual analysis or semi-quantitative analysis alone, the sensitivity, specificity and accuracy of visual analysis combined with semi-quantitative analysis in diagnosing primary breast cancer were higher, being: 87.5%, 82.9%, and 85.4%, respectively. The area under the curve was 0.891. CONCLUSION: Results of the present study suggest that the semi-quantitative and visual analysis statistically showed similar results. The semi-quantitative analysis provided incremental value additive to visual analysis of (99m)Tc-3PRGD2 SMG for the detection of breast cancer. It seems from our results that, when the tumor was located in the medial part of the breast, the semi-quantitative analysis gave better diagnostic results. PMID- 26574691 TI - Prognostic value of myocardial perfusion imaging and coronary artery calcium measurements in patients with end-stage renal disease. AB - OBJECTIVE: Coronary artery disease (CAD) is highly prevalent in patients with end stage renal disease (ESRD), owing to clustering of traditional and uremic specific risk factors. However, in this population asymptomatic course of CAD is common and it has been reported that myocardial perfusion imaging (MPI) with single-photon emission tomography (SPET) has lower sensitivity. In the current study, we assessed the value of MPI gated-SPET and its combination with coronary artery calcium (CAC) score measurements in risk stratification of ESRD patients. MATERIALS AND METHODS: MPI gated-SPET was performed with dual-headed SPET camera and CAC score measured by multi-detector computed tomography (MDCT) system.There were tested 77 ESRD individuals. During the follow-up study, cardiac events (CE) defined as cardiac death or nonfatal myocardial infarction (MI) or the necessity for coronary revascularization were recorded. Univariate and stepwise multivariable Cox proportional hazards-models were used to identify the predictors of CE. RESULTS: Eighteen CE were recorded during the follow-up. They were significantly associated with higher summed stress scores on MPI, higher percentage of ischaemic myocardium, higher occurrence of defects in multiple territories and higher CAC score (all with P<0.05). Univariate Cox proportional hazard-models showed that severe perfusion abnormalities as well as CAC score >=1000 were significantly associated with cardiac events (P<0.0001, P=0.0056). In stepwise Cox proportional hazards-models considering age, gender, history of diabetes mellitus, post-stress left ventricular stunning, the degree of perfusion abnormality and CAC score, only severe perfusion abnormalities and CAC score >=1000 were independent predictors of CE. There was no CE in patients with normal perfusion, normal function and zero CAC score. CONCLUSION: This study suggests that combined evaluation of MPI and CAC can predict the outcome in ESRD individuals, while severe perfusion abnormality on gated-SPET and high CAC score >=1000 are predictors of future cardiac events. PMID- 26574692 TI - Stimulated high serum thyroglobulin with negative whole body imaging do not warrant an aggressive diagnostic and therapeutic approach in differentiated thyroid cancer patients: A follow-up of 5 years or till recurrence. AB - OBJECTIVE: To study the clinical significance of stimulated high serum thyroglobulin (sTg) and of normal whole body imaging (WBI) in differentiated thyroid cancer (DTC) patients during their first follow-up and in a 5 years follow-up or till recurrence. SUBJECTS AND METHODS: Sixty four DTC patients were retrospectively studied and were divided into two groups. Group 1, of 35 patients with disease free status on their first follow-up and group 2, of 29 patients with high sTg (>2 MUg/mL), but with normal WBI, iodine-131 (131I) findings. Patients were categorized into low, intermediate and high risk patients based on the 131I WBS findings. Histology, stage and risk-categories of both groups were statistically correlated. Best sTg cut-off for predicting recurrence was generated by receiver operating characteristic (ROC). Odd ratio for sTg trend was also analyzed for risk of recurrence in group 2. Independent t test was used for progression free survival (PFS) comparison of the two groups. RESULTS: No statistical differences were seen in histology, stage and risk category distributions between the groups. Group 2 patients with high sTg (range 2.5-81 MUg/L, mean 20.5 MUg/L) on their first follow-up had higher risk of recurrence (odd ratio 4.304) but P value was insignificant (P:0.090). Eighty six per cent of group 2 patients showed decreasing trends and in 62% of group 2 patients, high serum sTg fell to normal. Indeed, decreasing trends of sTg reduced the risk of recurrence (odd ratio 1.3939, P:0.79). Analysis by ROC showed that sTg>11 MUg/L was the best cut-off in predicting recurrence with sensitivity 100% and specificity 56%. High sTg was not associated with low PFS, (P:0.232), however patients with increasing sTg had significantly shorter PFS (P<0.005). CONCLUSION: High sTg with negative 131I WBS did not warrant an aggressive DTC disease. These patients in their 5 years or till recurrence follow-up showed downward trends of serum sTg, no higher risk or recurrence and no shorter PFS. PMID- 26574693 TI - Toxicity assessment of (99m)technetium-labeled human beta-defensin-3 in CD1 mice. AB - OBJECTIVE: Human beta-defensin-3 (HBD-3) is an antimicrobial peptide which is up regulated during inflammation. Based on the previously demonstrated capacity of technetium-99m ((99m)Tc) labelled HBD-3 of distinguishing infection from inflammation in rats, we have decided to collect information on the potential toxicity of the tracer in view of its possible use for imaging in humans. MATERIALS AND METHODS: Recombinant HBD-3 underwent labeling with (99m)Tc. The CD1 mice were selected as standard rodent species. Ten mice, 5 male and 5 female, were subjected to physical examination and housed in a dedicated room in 5 per cage. After 9 days pre-test period, all mice were weighted for dose adjustment and received intravenously 6mcg/mouse of (99m)Tc-HBD-3. Mortality was recorded daily, while body weight was registered once a week. Clinical observation of animals was performed daily for sickness symptoms due to the drug treatment. At day 19 a second dose of 6mcg/mouse (99m)Tc-HBD-3, was administered. Twenty-four hours after the second dose (day 20) the animals were euthanized. A piece of liver, kidneys, heart and lungs was collected for histopathological analysis. RESULTS: Our results showed that the labelled-HBD-3 dose did not induce significant toxicity in mice. Of course these parameters were not sufficient to authorize use in humans. This non-toxic dose of HBD-3 when translated from animals to humans resulted in an equivalent dose of approximately 25 times higher than that needed for imaging. CONCLUSION: Our non toxicity data of using (99m)Tc beta-defensin-3 in mice offer a further indication in favour of the clinical use of this radiopharmaceutical in all cases where discrimination between infection and inflammation is needed. PMID- 26574694 TI - Technetium-99m labelled red blood cells scintigraphy and not iminodiacetic acid cholescintigraphy facilitates the discrimination of hepatic cirrhosis from fibrosis. AB - OBJECTIVE: This pilot study was designed to investigate the efficacy of technetium-99m labelled red blood cells ((99m)Tc-RBC) compared with (99m)Tc mebrofenin cholescintigraphy ((99m)Tc-MHS), in the diagnosis of hepatic dysfunction at early stages. SUBJECTS AND METHODS: Twenty four patients, 8 with hepatic fibrosis and 16 with cirrhosis, at Child-Pugh stage A to C and 20 age matched controls were examined by (99m)Tc-RBC and by (99m)Tc-MHS. Dynamic acquisition and static images were semiquantitatively analused by studying the liver-to-heart (L/H) ratio estimated by both the (99m)Tc-RBC and (99m)Tc-MHS methods. The L/H ratios were compared between fibrosis, cirrhotic stages and controls, by Student's t test. Linear regression analysis of the L/H ratios for both methods has been applied in the whole study population. RESULTS: Labelled RBC could statistically differentiate fibrotic from normal liver parenchyma (P<0.001), whereas the (99m)Tc-MHS could not (P: 0.13). The L/H ratios of cirrhotic lesions using both methods were significantly lower than those in controls: (P<0.000001 for (99m)Tc-RBC and P<0.0001 for (99m)Tc-MHS). Statistically significant difference was demonstrated by both modalities between fibrotic and cirrhotic lesions ((99m)Tc-RBC: P: 0.003 and (99m)Tc-MHS: P: 0.024). CONCLUSION: Our study although in a limited number of patients suggested that as opposed to (99m)Tc-MHS, scintigraphic evaluation by (99m)Tc-RBC could be useful in the discrimination of patients with liver fibrosis, cirrhosis and normal controls. PMID- 26574695 TI - [Risk factors and the progression of thyroid malignancies]. AB - OBJECTIVE: Thyroid cancer is the most common endocrine malignancy and the fifth most common malignant neoplasm of the female sex. During the past several decades, an increasing incidence of thyroid cancer has been reported. The mortality from thyroid cancer is comparatively low and remains almost stable showing a slight increase. It is currently unclear whether the observed increase in thyroid cancer is real or is due to overdiagnosis, as clinical and pathology findings may be sometimes doubtful in diagnosing the incidence and mortality of thyroid cancer. The cancer has different distribution depending on gender, race, age and environmental conditions. Despite considerable progress in the understanding of the biology and molecular pathways of carcinogenesis in the thyroid gland, less progress has been made in terms of defining a risk profile for thyroid cancer. The only risk factor which is systematically documented as carcinogenic for thyroid is exposure to ionizing radiation during childhood. Recently several studies are examining as risk factors diet and exercise, benign thyroid diseases as well as a genetic factors that influence the incidence and mortality of the disease. To the best of our knowledge there are only few epidemiological studies examining the effects of exposure to chemical agents on thyroid cancer's "behavior". CONCLUSION: The effect of risk factors for the onset and progression of malignant thyroid tumors constitutes a field that requires further study in order to provide answers on the pathogenesis of the disease, so as to take preventing measures and finally manage to decrease thyroid cancer incidence and mortality. PMID- 26574696 TI - 18F-FDG PET/CT and contrast enhanced CT in differential diagnosis between leiomyoma and gastrointestinal stromal tumor. AB - In a 49 years old woman a large abdominal tumor was diagnosed by abdominal ultrasound. Dynamic contrast-enhanced computed tomography (CECT) showed a large tumor with minute calcification and poor contrast enhancement in the left abdominal cavity. The fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) scan showed low 18F-FDG uptake in the tumor. The SUV max (early image) was 1.90, and that of the delayed image was 2.86. A gastrointestinal stromal tumor (GIST) was suspected. Tumor resection revealed that it was a leiomyoma originating in the major curvature of the stomach. In conclusion, the findings of low 18F-FDG uptake on 18F-FDG PET and poor contrast enhancement on CECT in a gastric submucosal tumor suggested of a gastric leiomyoma rather than GIST. PMID- 26574697 TI - Secondary neurolymphomatosis of spinal nerve roots detected by 18F-FDG PET/CT: a case report and differential diagnosis of the case. AB - OBJECTIVE: Neurolymphomatosis (NL) is a rare neurological manifestation of lymphoma. Clinical symptoms of NL differ greatly according to the sites involved and diagnosis with conventional imaging techniques may sometimes be difficult. We herein describe the case of a 58 years old man presenting as radiculopathy with a history of non-Hodgkin's lymphoma (NHL). Computed tomography (CT) was unrevealing and magnetic resonance imaging (MRI) was contraindicated. Fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) was performed and revealed multiple hypermetabolic lesions along the nerve roots, which corresponded to the patient's neurological symptoms. A differential diagnosis of patients with lymphomatous involvement of spinal nerve roots has been presented. CONCLUSION: Our case suggests that 18F-FDG PET/CT successfully detected the infiltration of spinal nerve roots of NL due to lymphoma. PMID- 26574698 TI - Placental-site trophoblastic tumor and fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography. AB - OBJECTIVE: Pre-operative imaging characteristics of placental site trophoblastic tumor (PSTT) are variable and non-specific. Although magnetic resonance imaging (MRI), ultrasonography, chest CT and X-rays findings have been studied the fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) findings of PSTT have not been previously documented. We present the findings of a first case of PSTT evaluated by pre-operative 18F-FDG PET/CT. A suspicious mass was biopsied and revealed PSTT in post-operative pathological examination. She was referred to the gynecology-oncology department. The 18F-FDG PET/CT scan revealed a 27 x 20 mm laterally expanded lesion that showed increased 18F-FDG uptake (SUVmax: 5.20) on the right isthmus of the uterus. The 18F-FDG PET/CT findings were in accordance with those from chest X-ray/s, CT and pelvic ultrasonography. A systematic, nerve sparing, paraaortic and pelvic lymph node dissection along with total hysterectomy and salpingoopherectomy was performed. The patient was discharged uneventfully. CONCLUSION: 18F-FDG PET/CT scan was able to identify the mass in the uterus which was shown by pathology to be PSTT. This finding of PET/CT was in accordance with other imaging techniques. Lymphatic mapping of 18F-FDG PET/CT in this case was also in accordance with surgery and pathology findings. PMID- 26574699 TI - Sarcomatoid carcinoma of the lung mimics aspergilloma on 18F-FDG PET/CT. AB - Primary PSC in the lung is a rare malignant cancer that represents a particularly aggressive subtype of non-small cell lung carcinomas (NSCLC) containing sarcoma or sarcoma-like components with spindle or giant cell features. The medical literature referring to imaging characteristics by fluorine-18-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) of these tumors is very limited. We present a case of PSC with air crescent and halo signs that resemble aspergilloma on the 18F-FDG PET/CT, scan. PMID- 26574700 TI - Imaging by 18F-FDG PET/CT of diffuse large B-cell lymphoma with cellulitis. AB - Non-Hodgkin's lymphomas (NHL) quite often present in the neck but are seldom accompanied with cellulitis at the first diagnosis of the disease. We report a 56 year old woman with gradually neck swelling, which was initially treated as cellulitis. After examined by ultrasonography, computed tomography and after pathologically assessments, the diagnosis of large B-cell lymphoma was made. This case highlights the usefulness of fluorine-18-fluorodeoxyglucose positron emission tomography (18F-FDG PET/CT) in staging and assessing treatment response in NHL. PMID- 26574702 TI - Financial costs and patients' perceptions of medical tourism in bariatric surgery. AB - SUMMARY: Many Canadians pursue surgical treatment for severe obesity outside of their province or country - so-called "medical tourism." We have managed many complications related to this evolving phenomenon. The costs associated with this care seem substantial but have not been previously quantified. We surveyed Alberta general surgeons and postoperative medical tourists to estimate costs of treating complications related to medical tourism in bariatric surgery and to understand patients' motivations for pursuing medical tourism. Our analysis suggests more than $560 000 was spent treating 59 bariatric medical tourists by 25 surgeons between 2012 and 2013. Responses from medical tourists suggest that they believe their surgeries were successful despite some having postoperative complications and lacking support from medical or surgical teams. We believe that the financial cost of treating complications related to medical tourism in Alberta is substantial and impacts existing limited resources. PMID- 26574701 TI - Recurrence of inguinal hernias repaired in a large hernia surgical specialty hospital and general hospitals in Ontario, Canada. AB - BACKGROUND: The effect of hospital specialization on the risk of hernia recurrence after inguinal hernia repair is not well described. METHODS: We studied Ontario residents who had primary elective inguinal hernia repair at an Ontario hospital between 1993 and 2007 using population-based, administrative health data. We compared patients from a large hernia specialty hospital (Shouldice Hospital) with those from general hospitals to determine the risk of recurrence. RESULTS: We studied 235 192 patients, 27.7% of whom had surgery at Shouldice hospital. The age-standardized proportion of patients who had a recurrence ranged from 5.21% (95% confidence interval [CI] 4.94%-5.49%) among patients who had surgery at the lowest volume general hospitals to 4.79% (95% CI 4.54%-5.04%) who had surgery at the highest volume general hospitals. In contrast, patients who had surgery at the Shouldice Hospital had an age standardized recurrence risk of 1.15% (95% CI 1.05%-1.25%). Compared with patients who had surgery at the lowest volume hospitals, hernia recurrence among those treated at the Shouldice Hospital was significantly lower after adjustment for the effects of age, sex, comorbidity and income level (adjusted hazard ratio 0.21, 95% CI 0.19-0.23, p < 0.001). CONCLUSION: Inguinal hernia repair at Shouldice Hospital was associated with a significantly lower risk of subsequent surgery for recurrence than repair at a general hospital. While specialty hospitals may have better outcomes for treatment of common surgical conditions than general hospitals, these benefits must be weighed against potential negative impacts on clinical care and the financial sustainability of general hospitals. PMID- 26574703 TI - Does ultrasongraphy predict intraoperative findings at cholecystectomy? An institutional review. AB - BACKGROUND: Ultrasonography (US) is the mainstay of biliary tract imaging, but few recent studies have tested its ability to diagnose acute cholecystitis (AC). Our objective was to determine how well a US diagnosis of AC correlates with the intraoperative diagnosis. We hypothesize that US underestimates this diagnosis, potentially leading to unexpected findings in the operating room (OR). METHODS: This retrospective review included all patients admitted to the acute care surgical service of a tertiary hospital in 2011 with suspected biliary pathology who underwent US and subsequent cholecystectomy. We determined the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of US using the intraoperative diagnosis as the gold standard. Further analysis identified which US findings were most predictive of an intraoperative diagnosis of AC. We used a recursive partitioning method with random forests to identify unique combinations of US findings that, together, are most predictive of AC. RESULTS: In total, 254 patients underwent US for biliary symptoms; 152 had AC diagnosed, and 143 (94%) of them underwent emergency surgery (median time to OR 23.03 hr). Ultrasonography predicted intraoperative findings with a sensitivity of 73.2%, specificity of 85.5% and PPV of 93.7%. The NPV (52.0%) was quite low. The US indicators most predictive of AC were a thick wall, a positive sonographic Murphy sign and cholelithiasis. Recursive partitioning demonstrated that a positive sonographic Murphy sign is highly predictive of intraoperative AC. CONCLUSION: Ultrasonography is highly sensitive and specific for diagnosing AC. The poor NPV confirms our hypothesis that US can underestimate AC. PMID- 26574704 TI - Elimination of 24-hour continuous medical resident duty in Quebec. AB - SUMMARY: In 2012 Quebec limited continuous in-hospital duty to 16 consecutive hours for all residents regardless of postgraduate (PGY) level. The new restrictions in Quebec appeared to have a profound, negative effect on the quality of life of surgical residents at McGill University and a perceived detrimental effect on the delivery of surgical education and patient care. Here we discuss the results of a nationwide survey that we created and distributed to general surgery residents across Canada to capture and compare their perceptions of the changes to duty hour restrictions. PMID- 26574705 TI - Point of care ultrasonography use and training among trauma providers across Canada. AB - SUMMARY: Point of care ultrasonography (POCUS) is revolutionizing care of critically ill patients. However, training in POCUS is extremely variable, with no accepted curriculum or certification process. We aimed to delineate the training experience and use of POCUS among trauma providers across Canada via a secure e-questionnaire sent to members of the Trauma Association of Canada. This commentary discusses our survey results and argues for the standardization of POCUS training and certification in Canada. PMID- 26574706 TI - S.T.A.R.T.T. plus: addition of prehospital personnel to a national multidisciplinary crisis resource management trauma team training course. AB - SUMMARY: The Simulated Trauma and Resuscitation Team Training (S.T.A.R.T.T.) course is a unique multidisciplinary trauma team training course deliberately designed to address the common crisis resource management (CRM) skills of trauma team members. Moreover, the curriculum has been updated to also target the specific learning needs of individual participating professionals: physicians, nurses and respiratory therapists. This commentary outlines further modifications to the course curriculum in order to address the needs of a relatively undertargeted group: prehospital personnel (i.e., emergency medical services). Maintenance of high participant satisfaction, regardless of profession, suggests that the S.T.A.R.T.T. course can be readily modified to incorporate prehospital personnel without losing its utility or popularity. PMID- 26574707 TI - CJS debate: Is mammography useful in average-risk screening for breast cancer? AB - SUMMARY: Given recent the debate over breast cancer screening that was reignited by the 25-year follow-up data from the Canadian National Breast Screening Study, the Canadian Journal of Surgery commissioned a group of Canadian experts to debate the value of screening mammography. We discuss the Canadian study and summarize the arguments in favour of and against screening mammography for average-risk patients. We also provide summary recommendations for the use of mammography. PMID- 26574708 TI - Efficient, versatile and practical palladium-catalyzed highly regioselective ortho-halogenation of azoxybenzenes. AB - A highly efficient and practical strategy for regio-selective ortho-halogenation (I, Br, Cl) of azoxybenzenes with NXS in the presence of palladium catalysts has been developed in good to excellent yields. The reaction proceeds smoothly and can tolerate a variety of functional groups. Moreover, this chemistry can be applied to substrates in at least a gram scale. PMID- 26574710 TI - A 48-YEar-Old Male with a Pituitary Tumor. PMID- 26574711 TI - Inter-Changeability of Impedance Devices for Lymphedema Assessment. AB - Impedance technology is a popular technique for the early detection of lymphedema. The preferred approach is to use bioimpedance spectroscopy (BIS), with measurements being made with the subject lying supine, although attempts have been made to use single or multiple frequency impedance measurements obtained while the subject is standing. The aim of the present study was to determine the equivalence of these different approaches. Impedance measurements of the individual limbs of 37 healthy individuals were determined using both a stand-on, multi-frequency impedance device and a supine impedance spectroscopy instrument. Significant differences were found between the instruments in both absolute impedance values and, importantly, inter-limb impedance ratios. Since impedance ratios in healthy individuals provide the reference standard for detection of lymphedema, these data indicate that the methods are not interchangeable. Consideration of the errors associated with each method indicates that the BIS remains the preferred method for lymphedema detection. PMID- 26574709 TI - ALS biomarkers for therapy development: State of the field and future directions. AB - Biomarkers have become the focus of intense research in the field of amyotrophic lateral sclerosis (ALS), with the hope that they might aid therapy development efforts. Notwithstanding the discovery of many candidate biomarkers, none have yet emerged as validated tools for drug development. In this review we present a nuanced view of biomarkers based on the perspective of the Food and Drug Administration; highlight the distinction between discovery and validation; describe existing and emerging resources; review leading biological fluid-based, electrophysiological, and neuroimaging candidates relevant to therapy development efforts; discuss lessons learned from biomarker initiatives in related neurodegenerative diseases; and outline specific steps that we, as a field, might take to hasten the development and validation of biomarkers that will prove useful in enhancing efforts to develop effective treatments for ALS patients. Most important among these is the proposal to establish a federated ALS Biomarker Consortium in which all interested and willing stakeholders may participate with equal opportunity to contribute to the broader mission of biomarker development and validation. PMID- 26574712 TI - Maternal body mass index and adverse pregnancy outcomes: A ghanaian cohort study. AB - OBJECTIVE: To examine the association between maternal weight at <17 weeks gestation and maternal and infant outcomes of pregnancy, delivery, and the postpartum period in pregnant Ghanaian women. METHODS: A prospective cohort study of 1,000 women in Accra, Ghana (2012-2014), was conducted. Women were classified as having overweight (BMI 25-30) and obesity (BMI >= 30), and their obstetric and infant outcomes were analyzed using multivariate logistic regression. RESULTS: The analysis included 824 women, average 28 years (SD 5.1); 313 (31.3%) had overweight and 169 (16.9%) obesity. Women with obesity had a two-fold increased risk for cesarean sections (RR 2.20, 95% CI 1.21-4.02) and more than a six-fold higher risk for pregnancy-induced hypertension (RR 6.17, 95% CI 2.90-13.13) and chronic hypertension (RR 6.00, 95% CI 1.40-25.76). Infants of women with overweight or obesity were more likely to be macrosomic (RR 2.37, 95% CI 1.13 4.97). CONCLUSIONS: The global obesity epidemic has reached women in low- and middle-income countries (LMIC) with important adverse consequences for maternal and infant health. Antenatal care in LMIC will need to anticipate this potential expansion of complications, including the development of guidelines for optimal maternity care for pregnant women with overweight and obesity. PMID- 26574713 TI - Ultrafast Bidirectional Charge Transport and Electron Decoherence at Molecule/Surface Interfaces: A Comparison of Gold, Graphene, and Graphene Nanoribbon Surfaces. AB - We investigate bidirectional femtosecond charge transfer dynamics using the core hole clock implementation of resonant photoemission spectroscopy from 4,4' bipyridine molecular layers on three different surfaces: Au(111), epitaxial graphene on Ni(111), and graphene nanoribbons. We show that the lowest unoccupied molecular orbital (LUMO) of the molecule drops partially below the Fermi level upon core-hole creation in all systems, opening an additional decay channel for the core-hole, involving electron donation from substrate to the molecule. Furthermore, using the core-hole clock method, we find that the bidirectional charge transfer time between the substrate and the molecule is fastest on Au(111), with a 2 fs time, then around 4 fs for epitaxial graphene and slowest with graphene nanoribbon surface, taking around 10 fs. Finally, we provide evidence for fast phase decoherence of the core-excited LUMO* electron through an interaction with the substrate providing the first observation of such a fast bidirectional charge transfer across an organic/graphene interface. PMID- 26574714 TI - Boron clusters in luminescent materials. AB - In recent times, luminescent materials with tunable emission properties have found applications in almost all aspects of modern material sciences. Any discussion on the recent developments in luminescent materials would be incomplete if one does not account for the versatile photophysical features of boron containing compounds. Apart from triarylboranes and tetra-coordinate borate dyes, luminescent materials consisting of boron clusters have also found immense interest in recent times. Recent studies have unveiled the opportunities hidden within boranes, carboranes and metalloboranes, etc. as active constituents of luminescent materials. From simple illustrations of luminescence, to advanced applications in LASERs, OLEDs and bioimaging, etc., the unique features of such compounds and their promising versatility have already been established. In this review, recent revelations about the excellent photophysical properties of such materials are discussed. PMID- 26574715 TI - Board Diving Regulations in Public Swimming Pools and Risk of Injury. AB - Public session access to diving boards is one of the stepping stones for those wishing to develop their skills in the sport of diving. The extent to which certain dive forms are considered risky (forward/backward/rotations) and therefore not permitted is a matter for local pool managers. In Study 1, 20 public pools with diving facilities responded to a U.K. survey concerning their diving regulation policy and related injury incidence in the previous year. More restrictive regulation of dive forms was not associated with a decrease in injuries (rs [42] = -0.20, p = 0.93). In Study 2, diving risk perception and attitudes towards regulation were compared between experienced club divers (N = 22) and nondivers (N = 22). Risk was perceived to be lower for those with experience, and these people favored less regulation. The findings are interpreted in terms of a risk thermostat model, where for complex physical performance activities such as diving, individuals may exercise caution in proportion to their ability and previous experience of success and failure related to the activity. Though intuitively appealing, restrictive regulation of public pool diving may be ineffective in practice because risk is not simplistically associated with dive forms, and divers are able to respond flexibly to risk by exercising caution where appropriate. PMID- 26574716 TI - Asthma control and exacerbations: two different sides of the same coin. AB - PURPOSE OF REVIEW: Optimal asthma management includes both the control of asthma symptoms and reducing the risk of future asthma exacerbations. Traditionally, treatment has been adjusted largely on the basis of symptoms and lung function and for many patients, this approach delivers both excellent symptom control and reduced risk. However, the relationship between these two key components of the disease may vary between different asthmatic phenotypes and disease severities and there is increasing recognition of the need for more individualized treatment approaches. RECENT FINDINGS: A number of factors which predict exacerbation risk have been identified including demographic and behavioural features and specific inflammatory biomarkers. Type-2 cytokine-driven eosinophilic airways inflammation predisposes to frequent exacerbations and predicts response to corticosteroids, and the usefulness of sputum eosinophilia as both a marker of exacerbation risk and biomarker for adjustment of corticosteroid treatment has been established for some time. However, attempts to develop surrogate markers, which would be more straightforward to deliver in the clinic, have been challenging. SUMMARY: Some patients with asthma have persistent symptoms in the absence of type-2 cytokine driven-eosinophilic airways inflammation due to noncorticosteroid responsive mechanisms (T2-low disease). Composite biomarker strategies using easily measured surrogate indicators of type-2 inflammation (such as fractional exhaled nitric oxide, blood eosinophil count and serum periostin levels) may predict exacerbation risk better but it is unclear if they can be used to adjust corticosteroid treatment. Biomarkers will be used to target novel biologic treatments but additionally may be used to optimize corticosteroid treatment dose and act as prognostics for exacerbation risk and potentially other important longer term asthma outcomes. PMID- 26574717 TI - Asthma phenotypes and endotypes: a personalized approach to treatment. AB - PURPOSE OF REVIEW: Asthma is quite common and is better described as a syndrome with a heterogeneous presentation than as a single disease. Although most individuals can be effectively managed using a guideline-directed approach to care, those with the most severe illness may benefit from a more targeted therapy. The review describes our current understanding of how asthma phenotypes (observable characteristics) and endotypes (specific biologic mechanisms) can be employed to gain insight into asthma pathobiology and personalized therapy. RECENT FINDINGS: Our understanding of the heterogeneity of asthma is increasing. The concept of asthma phenotype has become more complex, incorporating both clinical and biologic features. Several asthma endotypes (e.g., allergic bronchopulmonary mycosis, aspirin-exacerbated respiratory disease, severe late onset hypereosinophilic asthma, etc.) have been proposed, but further research is needed to delineate specific mechanisms underlying asthma pathogenesis. Several biologic therapies targeting certain phenotypes are in development and are expected to broaden our armamentarium for treatment of severe asthma. SUMMARY: Asthma is a heterogeneous condition with diverse characteristics and biologic mechanisms. Severe asthma is associated with significant morbidity and even mortality and represents a major unmet need. Stratification of asthma subtypes into phenotypes and endotypes should move the field forward in terms of more effective and personalized treatment. PMID- 26574718 TI - Airway inflammation in asthma: key players beyond the Th2 pathway. AB - PURPOSE OF REVIEW: The Th2 pathway starts with the binding of IL-4 to the IL-4 receptor followed by the phosphorylation of signal transducer and activator of transcription 6 and the activation of GATA3. The most important question relates to the sources of IL-4 and IL-4 related inflammation. Which cells other than Th2 cells are responsible for airway inflammation in asthma? RECENT FINDINGS: Accumulating data indicate that basophils contribute to endothelium-related IL-4 dependent inflammation. There is also a dendritic cell-related alternative for the induction of Th2 cells via Notch signalling. GATA3 deoxyribozyme improves asthma that is not clearly related to T-cells. The innate immune response in allergy is linked to mast cells, basophils, and the innate lymphoid cell type 2 (ILC2). ILC2s respond to IL-25, IL-33, thymic stromal lymphopoietin, and leukotrienes by producing IL-4, IL-5, and IL-13. In addition to all this inflammatory-cell-driven asthma, increasing evidence has emerged relating to smooth muscle cell activation, the endothelial and epithelial barrier functions, and improvements in the barrier function. The elevation of intracellular cyclic adenosine monophosphate because of the use of phosphodiesterase inhibitors adds to the prevention of epithelial-endothelial leakage, supports airway smooth muscle relaxation, and is immunosuppressive. CONCLUSION AND SUMMARY: IL-4 is the predominant Th2 cell cytokine. Many more cells, including eosinophils, basophils, mast cells, and ILC2, contribute to the production of IL-4 in the airways. Epithelial cells and endothelial cells lose barrier function in the context of allergic airway inflammation, and this could be at least partially remedied by increasing the intracellular cyclic adenosine monophosphate levels through phosphodiesterase inhibition. PMID- 26574719 TI - Asthma and obesity: is weight reduction the key to achieve asthma control? AB - PURPOSE OF REVIEW: Obesity has significant negative impact on asthma control and risk of exacerbations. The purpose of this review is to discuss recent studies evaluating the effects of weight reduction on asthma control in obese adults. RECENT FINDINGS: Clinical studies have shown that weight reduction in obese patients is associated with improvements in symptoms, use of controller medication, and asthma-related quality of life together with a reduction in the risk for severe exacerbations. Furthermore, several studies have also revealed improvements in lung function and airway responsiveness, and more recently it has been shown that weight reduction following bariatric surgery has positive impact on small airway function, systemic inflammation and bronchial inflammation in this group of patients, which may explain the observed improvements in symptom control and lung function. SUMMARY: Weight reduction in obese adults with asthma leads to an overall improvement in asthma control, including airway hyperresponsiveness and inflammation. Weight reduction should be a cornerstone in the management of obese patients with asthma. PMID- 26574720 TI - Pathogenesis and prevention strategies of severe asthma exacerbations in children. AB - PURPOSE OF REVIEW: Exacerbations of asthma in children are most frequently precipitated by respiratory infections with a seasonal pattern. However, management takes little account of the underlying infective or other precipitant abnormality. RECENT FINDINGS: Interactions between environmental triggers, the airway microbiome and innate immune responses are key determinants of exacerbations. Elevated innate cytokines interleukin (IL)-33 and IL-25, and abnormal molecular responses in the interferon pathway are associated with rhinoviral infections. Exacerbations caused by fungal allergens also induce IL 33, highlighting this as an attractive therapeutic target. An equal contribution of bacterial and viral infection during exacerbations, particularly in preschool children, has become increasingly apparent, but some organisms may be protective. Investigation of mechanisms underlying infection-related exacerbations especially in preschool children is needed.Progressive loss of lung function from exacerbations is most pronounced in children aged 6-11 years, and low FEV1 is now recognized as a key predictor for the development of chronic obstructive pulmonary disease and premature death. Although prevention of exacerbations is critical, suboptimal patient education, prescription and adherence to maintenance therapy, and a lack of predictive biomarkers, remain key unaddressed issues in children. SUMMARY: Precipitants and predictors of exacerbations, together with the child's age and clinical phenotype, need to be used to achieve individualized management in preference to the current uniform approach for all. PMID- 26574721 TI - Diabetic kidney disease and obstructive sleep apnea: a new frontier? AB - PURPOSE OF REVIEW: Obstructive sleep apnea (OSA) has been shown to be an independent risk factor for the development and progression of diabetes mellitus. Interestingly, there is also a strong correlation between OSA and the development and progression of chronic kidney disease (CKD). As diabetes mellitus is the most common cause of CKD, in this review we summarize the current literature regarding this interconnecting relationship between OSA, CKD, and diabetes mellitus. The literature increasingly supports a bidirectional relationship between CKD and OSA among diabetes mellitus patients leading to an increased rate of progression of diabetic nephropathy. RECENT FINDINGS: There is growing evidence that among patients with diabetes mellitus, OSA may be a strong risk factor for the development of diabetic nephropathy. The treatment of OSA in CKD patients may play a role in attenuating the rate of the progression of CKD. SUMMARY: Clinicians should have a low threshold for evaluating diabetic patients with CKD for OSA. Further studies examining if treatment of OSA would improve the outcomes of CKD patients in general and diabetic CKD patients in particular are needed. PMID- 26574722 TI - Editorial: The new look on asthma: linking phenotypes, endotypes and biomarkers to asthma management. PMID- 26574723 TI - Revisiting the role of the mast cell in asthma. AB - PURPOSE OF REVIEW: In humans, mast cells are ubiquitously present in tissues adjacent to external environment and consequently have an important sentential role in host defence, homeostasis and repair. Their key role in allergen-mediated conditions has been recognized for many decades already. So far, therapies targeting mast cells offered clinical efficacy in allergic conditions except for asthma. More recently, sophisticated sampling and detection techniques revealed pleiotrophic immunological and functional properties of mast cells in and beyond asthma with potential clinical and management implications. These findings bring back the mast cell as a key player in the field of asthma and warrant a review of the recent literature. RECENT FINDINGS: The heterogeneity of human mast cells has been recognized: MCTC expressing both tryptase and chymase and MCT expressing tryptase only. Apart from this subphenotyping, mast cells may comprise and produce several other mediators and cytokines. Their immunological and functional properties depend on their (co)localization within the human body and can alter under changing conditions (e.g. pathogens, allergens, etc). Recent data revealed a novel mast cell phenotype within the alveolar tissue of patients with asthma. Increasing evidence shows a key role for alveolar mast cells in the pathophysiology of viral respiratory infections and in the development of allergen sensitization and asthma. SUMMARY: Increasing evidence points toward a key role of mast cells in the pathophysiology and pathogenesis of asthma and this warrants further investigation and the development of effective targeted therapies. PMID- 26574724 TI - Role of T2 inflammation biomarkers in severe asthma. AB - PURPOSE OF REVIEW: Severe asthma is a heterogeneous syndrome. Classification of asthma into phenotypes and endotypes can improve understanding and treatment of the disease. Identification and utilization of biomarkers, particularly those linked to T2 inflammation, can help group patients into phenotypes, predict those who will respond to a specific therapy, and assess the response to treatment. RECENT FINDINGS: Biomarkers are present in sputum, exhaled breath, and blood of patients with asthma. These include sputum eosinophils and neutrophils, fractional excretion of nitric oxide, blood eosinophilia, IgE, and periostin. Many of these biomarkers are associated with eosinophilic inflammation propagated mainly by T2 cytokines such as IL-5 and IL-13, which are released from Th2 cells and Type 2 innate lymphoid cells. Biomarkers have been utilized in recent trials of novel biologic agents targeted at T2 inflammation and may contribute to the defining population who would respond to these therapies. SUMMARY: Despite advances in the identification and utilization of asthma biomarkers, further studies are needed to better clarify the role of biomarkers, individually or in combination, in the diagnosis and treatment of severe asthma. Future therapeutic trials should include the use of biomarkers in their design, which may lead to a more personalized approach to therapy and improved outcomes. PMID- 26574725 TI - Measuring refractive index distribution in the human eye lens. PMID- 26574726 TI - APOBEC3 in papillomavirus restriction, evolution and cancer progression. PMID- 26574727 TI - An empirically adjusted approach to reproductive number estimation for stochastic compartmental models: A case study of two Ebola outbreaks. AB - The various thresholding quantities grouped under the "Basic Reproductive Number" umbrella are often confused, but represent distinct approaches to estimating epidemic spread potential, and address different modeling needs. Here, we contrast several common reproduction measures applied to stochastic compartmental models, and introduce a new quantity dubbed the "empirically adjusted reproductive number" with several advantages. These include: more complete use of the underlying compartmental dynamics than common alternatives, use as a potential diagnostic tool to detect the presence and causes of intensity process underfitting, and the ability to provide timely feedback on disease spread. Conceptual connections between traditional reproduction measures and our approach are explored, and the behavior of our method is examined under simulation. Two illustrative examples are developed: First, the single location applications of our method are established using data from the 1995 Ebola outbreak in the Democratic Republic of the Congo and a traditional stochastic SEIR model. Second, a spatial formulation of this technique is explored in the context of the ongoing Ebola outbreak in West Africa with particular emphasis on potential use in model selection, diagnosis, and the resulting applications to estimation and prediction. Both analyses are placed in the context of a newly developed spatial analogue of the traditional SEIR modeling approach. PMID- 26574728 TI - Thermodynamics of the structural transition in metal-organic frameworks. AB - A thermodynamic study of the structural large-pore (LP) to narrow pore (NP) transition in various Metal Organic Frameworks (MOFs) is presented. First, the pressure induced transition at a constant temperature is investigated using a Tian-Calvet microcalorimeter set-up equipped with a high pressure cell. This device permits simultaneous measurements of the mechanical work and heat associated with the LP -> NP transition. It is shown that MIL-53(Al) and MIL 53(Cr) have similar thermodynamic and mechanical behaviour whilst the MIL-47(V) system is characterized by much higher transition energy and mechanical work. Second, the temperature induced transition at ambient pressure is studied by means of differential scanning calorimetry (DSC) combined with X-ray absorption spectroscopy. This set-up enables one to follow simultaneously the structural changes associated with the phase transition detected by DSC. The MIL-53(Cr)-Br functionalized MOF is chosen here as a case study where both energetics and structural changes are discussed. PMID- 26574729 TI - Advancing Patient-centered Outcomes in Emergency Diagnostic Imaging: A Research Agenda. AB - Diagnostic imaging is integral to the evaluation of many emergency department (ED) patients. However, relatively little effort has been devoted to patient centered outcomes research (PCOR) in emergency diagnostic imaging. This article provides background on this topic and the conclusions of the 2015 Academic Emergency Medicine consensus conference PCOR work group regarding "Diagnostic Imaging in the Emergency Department: A Research Agenda to Optimize Utilization." The goal was to determine a prioritized research agenda to establish which outcomes related to emergency diagnostic imaging are most important to patients, caregivers, and other key stakeholders and which methods will most optimally engage patients in the decision to undergo imaging. Case vignettes are used to emphasize these concepts as they relate to a patient's decision to seek care at an ED and the care received there. The authors discuss applicable research methods and approaches such as shared decision-making that could facilitate better integration of patient-centered outcomes and patient-reported outcomes into decisions regarding emergency diagnostic imaging. Finally, based on a modified Delphi process involving members of the PCOR work group, prioritized research questions are proposed to advance the science of patient-centered outcomes in ED diagnostic imaging. PMID- 26574731 TI - Evolutionary dynamics of the plastid inverted repeat: the effects of expansion, contraction, and loss on substitution rates. AB - Rates of nucleotide substitution were previously shown to be several times slower in the plastid inverted repeat (IR) compared with single-copy (SC) regions, suggesting that the IR provides enhanced copy-correction activity. To examine the generality of this synonymous rate dependence on the IR, we compared plastomes from 69 pairs of closely related species representing 52 families of angiosperms, gymnosperms, and ferns. We explored the breadth of IR boundary shifts in land plants and demonstrate that synonymous substitution rates are, on average, 3.7 times slower in IR genes than in SC genes. In addition, genes moved from the SC into the IR exhibit lower synonymous rates consistent with other IR genes, while genes moved from the IR into the SC exhibit higher rates consistent with other SC genes. Surprisingly, however, several plastid genes from Pelargonium, Plantago, and Silene have highly accelerated synonymous rates despite their IR localization. Together, these results provide strong evidence that the duplicative nature of the IR reduces the substitution rate within this region. The anomalously fast-evolving genes in Pelargonium, Plantago, and Silene indicate localized hypermutation, potentially induced by a higher level of error-prone double-strand break repair in these regions, which generates substitutional rate variation. PMID- 26574732 TI - Seasonal and flow-driven dynamics of particulate and dissolved mercury and methylmercury in a stream impacted by an industrial mercury source. AB - Sediments and floodplain soils in the East Fork Poplar Creek watershed (Oak Ridge, TN, USA) are contaminated with high levels of mercury (Hg) from an industrial source at the headwaters. Although baseflow conditions have been monitored, concentrations of Hg and methylmercury (MeHg) during high-flow storm events, when the stream is more hydrologically connected to the floodplain, have yet to be assessed. The present study evaluated baseflow and event-driven Hg and MeHg dynamics in East Fork Poplar Creek, 5 km upstream of the confluence with Poplar Creek, to determine the importance of hydrology to in-stream concentrations and downstream loads and to ascertain whether the dynamics are comparable to those of systems without an industrial Hg source. Particulate Hg and MeHg were positively correlated with discharge (r(2) = 0.64 and 0.58, respectively) and total suspended sediment (r(2) = 0.97 and 0.89, respectively), and dissolved Hg also increased with increasing flow (r(2) = 0.18) and was associated with increases in dissolved organic carbon (r(2) = 0.65), similar to the dynamics observed in uncontaminated systems. Dissolved MeHg decreased with increases in discharge (r(2) = 0.23) and was not related to dissolved organic carbon concentrations (p = 0.56), dynamics comparable to relatively uncontaminated watersheds with a small percentage of wetlands (<10%). Although stormflows exert a dominant control on particulate Hg, particulate MeHg, and dissolved Hg concentrations and loads, baseflows were associated with the highest dissolved MeHg concentration (0.38 ng/L) and represented the majority of the annual dissolved MeHg load. Environ Toxicol Chem 2016;35:1386-1400. Published 2015 Wiley Periodicals, Inc. on behalf of SETAC. This article is a US Government work, and as such, is in the public domain in the United States of America. PMID- 26574734 TI - Fusion Pore Size Limits 5-HT Release From Single Enterochromaffin Cell Vesicles. AB - Enterochromaffin cells are the major site of serotonin (5-HT) synthesis and secretion providing ~95% of the body's total 5-HT. 5-HT can act as a neurotransmitter or hormone and has several important endocrine and paracrine roles. We have previously demonstrated that EC cells release small amounts of 5 HT per exocytosis event compared to other endocrine cells. We utilized a recently developed method to purify EC cells to demonstrate the mechanisms underlying 5-HT packaging and release. Using the fluorescent probe FFN511, we demonstrate that EC cells express VMAT and that VMAT plays a functional role in 5-HT loading into vesicles. Carbon fiber amperometry studies illustrate that the amount of 5-HT released per exocytosis event from EC cells is dependent on both VMAT and the H(+)-ATPase pump, as demonstrated with reserpine or bafilomycin, respectively. We also demonstrate that increasing the amount of 5-HT loaded into EC cell vesicles does not result in an increase in quantal release. As this indicates that fusion pore size may be a limiting factor involved, we compared pore diameter in EC and chromaffin cells by assessing the vesicle capture of different-sized fluorescent probes to measure the extent of fusion pore dilation. This identified that EC cells have a reduced fusion pore expansion that does not exceed 9 nm in diameter. These results demonstrate that the small amounts of 5-HT released per fusion event in EC cells can be explained by a smaller fusion pore that limits 5-HT release capacity from individual vesicles. PMID- 26574733 TI - The role for human nasal epithelial nuclear factor kappa B activation in histamine-induced mucin 5 subtype B overproduction. AB - BACKGROUND: Mucin 5 subtype B (MUC5B) is 1 of the major mucins secreted by airway epithelial cells. We sought to determine the effect of histamine on MUC5B expression in human nasal epithelial cells. METHODS: Human nasal epithelial cells from allergic rhinitis patients were cultured, and stimulated with 4 concentrations of histamine, or pretreated with a specific nuclear factor-kappa B (NF-kappaB) inhibitor (Bay11-7082) before histamine stimulation. Immunocytochemistry and Western blotting were used to detect phosphorylated inhibitor of kappa B alpha (p-IkappaBalpha), NF-kappaBp65 and MUC5B protein. MUC5B content in supernatants was assayed by enzyme-linked immunosorbent assay (ELISA). RESULTS: Histamine promoted IkappaBalpha phosphorylation and NF kappaBp65 nuclear translocation. A concentration-dependent histamine-induced increase of MUC5B protein was observed, and its content in supernatants was upregulated in a concentration-dependent fashion, but these effects were attenuated by Bay11-7082. CONCLUSION: Histamine activated the IkappaBalpha/NF kappaB pathway by promoting IkappaBalpha phosphorylation and inducing NF kappaBp65 nuclear translocation, contributing to MUC5B overproduction and secretion. PMID- 26574735 TI - Dissection of the genetic architecture of rice resistance to the blast fungus Magnaporthe oryzae. AB - Resistance in rice cultivars to the rice blast fungus Magnaporthe oryzae is complex and is controlled by both major genes and quantitative trait loci (QTLs). We undertook a genome-wide association study (GWAS) using the rice diversity panel 1 (RDP1) that was genotyped using a high-density (700 000 single nucleotide polymorphisms) array and inoculated with five diverse M. oryzae isolates. We identified 97 loci associated with blast resistance (LABRs). Among them, 82 were new regions and 15 co-localized with known blast resistance loci. The top 72 LABRs explained up to 98% of the phenotypic variation. The candidate genes in the LABRs encode nucleotide-binding site leucine-rich repeat (NBS-LRR) resistance proteins, receptor-like protein kinases, transcription factors and defence related proteins. Among them, LABR_64 was strongly associated with resistance to all five isolates. We analysed the function of candidate genes underlying LABR_64 using RNA interference (RNAi) technology and identified two new resistance alleles at the Pi5 locus. We demonstrate an efficient strategy for rapid allele discovery using the power of GWAS, coupled with RNAi technology, for the dissection of complex blast resistance in rice. PMID- 26574736 TI - The phenolic acids of Agen prunes (dried plums) or Agen prune juice concentrates do not account for the protective action on bone in a rat model of postmenopausal osteoporosis. AB - Dietary supplementation with dried plum (DP) has been shown to protect against and reverse established osteopenia in ovariectomized rodents. Based on in vitro studies, we hypothesized that DP polyphenols may be responsible for that bone sparing effect. This study was designed to (1) analyze whether the main phenolic acids of DP control preosteoblast proliferation and activity in vitro; (2) determine if the polyphenolic content of DP or DP juice concentrate is the main component improving bone health in vivo; and (3) analyze whether DP metabolites directly modulate preosteoblast physiology ex vivo. In vitro, we found that neochlorogenic, chlorogenic, and caffeic acids induce the proliferation and repress the alkaline phosphatase activity of primary preosteoblasts in a dose dependent manner. In vivo, low-chlorogenic acid Agen prunes (AP) enriched with a high-fiber diet and low-chlorogenic acid AP juice concentrate prevented the decrease of total femoral bone mineral density induced by estrogen deficiency in 5-month-old female rats and positively restored the variations of the bone markers osteocalcin and deoxypyridinoline. Ex vivo, we demonstrated that serum from rats fed with low-chlorogenic acid AP enriched with a high-fiber diet showed repressed proliferation and stimulated alkaline phosphatase activity of primary preosteoblasts. Overall, the beneficial action of AP on bone health was not dependent on its polyphenolic content. PMID- 26574737 TI - Accurate label-free reaction kinetics determination using initial rate heat measurements. AB - Accurate label-free methods or assays to obtain the initial reaction rates have significant importance in fundamental studies of enzymes and in application oriented high throughput screening of enzyme activity. Here we introduce a label free approach for obtaining initial rates of enzyme activity from heat measurements, which we name initial rate calorimetry (IrCal). This approach is based on our new finding that the data recorded by isothermal titration calorimetry for the early stages of a reaction, which have been widely ignored, are correlated to the initial rates. Application of the IrCal approach to various enzymes led to accurate enzyme kinetics parameters as compared to spectroscopic methods and enabled enzyme kinetic studies with natural substrate, e.g. proteases with protein substrates. Because heat is a label-free property of almost all reactions, the IrCal approach holds promise in fundamental studies of various enzymes and in use of calorimetry for high throughput screening of enzyme activity. PMID- 26574738 TI - Thermodynamics and structure of macromolecules from flat-histogram Monte Carlo simulations. AB - Over the last decade flat-histogram Monte Carlo simulations, especially multi canonical and Wang-Landau simulations, have emerged as a strong tool to study the statistical mechanics of polymer chains. These investigations have focused on coarse-grained models of polymers on the lattice and in the continuum. Phase diagrams of chains in bulk as well as chains attached to surfaces were studied, for homopolymers as well as for protein-like models. Also, aggregation behavior in solution of these models has been investigated. We will present here the theoretical background for these simulations, explain the algorithms used and discuss their performance and give an overview over the systems studied with these methods in the literature, where we will limit ourselves to studies of coarse-grained model systems. Implementations of these algorithms on parallel computers will be also briefly described. In parallel to the development of these simulation methods, the power of a micro-canonical analysis of such simulations has been recognized, and we present the current state of the art in applying the micro-canonical analysis to phase transitions in nanoscopic polymer systems. PMID- 26574739 TI - Auxetic Perforated Mechanical Metamaterials with Randomly Oriented Cuts. AB - Perforated systems with quasi-disordered arrays of slits are found to exhibit auxetic characteristics almost as much as their traditional ordered "rotating squares" counterparts. This provides a highly robust methodology for constructing auxetics that may be used for various practical applications such as skin grafting, where a high degree of precision may not always be achievable. PMID- 26574740 TI - Instrumental variable method for time-to-event data using a pseudo-observation approach. AB - Observational studies are often in peril of unmeasured confounding. Instrumental variable analysis is a method for controlling for unmeasured confounding. As yet, theory on instrumental variable analysis of censored time-to-event data is scarce. We propose a pseudo-observation approach to instrumental variable analysis of the survival function, the restricted mean, and the cumulative incidence function in competing risks with right-censored data using generalized method of moments estimation. For the purpose of illustrating our proposed method, we study antidepressant exposure in pregnancy and risk of autism spectrum disorder in offspring, and the performance of the method is assessed through simulation studies. PMID- 26574741 TI - Autologous Germline Mitochondrial Energy Transfer (AUGMENT) in Human Assisted Reproduction. AB - Ovarian aging is characterized by a decline in both the total number and overall quality of oocytes, the latter of which has been experimentally tied to mitochondrial dysfunction. Clinical studies in the late 1990s demonstrated that transfer of cytoplasm aspirated from eggs of young female donors into eggs of infertile women at the time of intracytoplasmic sperm injection improved pregnancy success rates. However, donor mitochondria were identified in offspring, and the United States Food and Drug Administration raised questions about delivery of foreign genetic material into human eggs at the time of fertilization. Accordingly, heterologous cytoplasmic transfer, while promising, was in effect shut down as a clinical protocol. The recent discovery of adult oogonial (oocyte-generating) stem cells in mice, and subsequently in women, has since re-opened the prospects of delivering a rich source of pristine and patient matched germline mitochondria to boost egg health and embryonic developmental potential without the need for young donor eggs to obtain cytoplasm. Herein we overview the science behind this new protocol, which has been patented and termed autologous germline mitochondrial energy transfer, and its use to date in clinical studies for improving pregnancy success in women with a prior history of assisted reproduction failure. PMID- 26574742 TI - Care that Matters: Quality Measurement and Health Care. PMID- 26574743 TI - Timing of Histologic Progression from Chorio-Deciduitis to Chorio-Deciduo Amnionitis in the Setting of Preterm Labor and Preterm Premature Rupture of Membranes with Sterile Amniotic Fluid. AB - BACKGROUND: Histologic chorio-deciduitis and chorio-deciduo-amnionitis (amnionitis) in extra-placental membranes are known to represent the early and advanced stages of ascending intra-uterine infection. However, there are no data in humans about the time required for chorio-deciduitis to develop and for chorio deciduitis without amnionitis to progress to chorio-deciduitis with amnionitis, and the effect of prolongation of pregnancy on the development of chorio deciduitis and amnionitis in patients with preterm labor and intact membranes (PTL) and preterm premature rupture of membranes (preterm-PROM). We examined these issues in this study. METHODS: The study population consisted of 289 women who delivered preterm (133 cases with PTL, and 156 cases with preterm-PROM) and who had sterile amniotic fluid (AF) defined as a negative AF culture and the absence of inflammation as evidenced by a matrix metalloproteinase-8 (MMP-8) level <23 ng/ml. We examined the association between amniocentesis-to-delivery interval and inflammatory status in the extra-placental membranes (i.e., inflammation-free extra-placental membranes, choroi-deciduitis only, and chorio deciduitis with amnionitis) in patients with PTL and preterm-PROM. RESULTS: Amniocentesis-to-delivery interval was longer in cases of chorio-deciduitis with amnionitis than in cases of chorio-deciduitis only in both PTL (median [interquartile-range (IQR)]; 645.4 [319.5] vs. 113.9 [526.9] hours; P = 0.005) and preterm-PROM (131.3 [135.4] vs. 95.2 [140.5] hours; P<0.05). Amniocentesis-to delivery interval was an independent predictor of the development of both chorio deciduitis and amnionitis after correction for confounding variables such as gestational age at delivery in the setting of PTL, but not preterm-PROM. CONCLUSIONS: These data confirm for the first time that, in cases of both PTL and preterm-PROM with sterile AF, more time is required to develop chorio-deciduitis with amnionitis than chorio-deciduitis alone in extra-placental membranes. Moreover, prolongation of pregnancy is an independent predictor of the development of both chorio-deciduitis and amnionitis in cases of PTL with sterile AF. PMID- 26574744 TI - Dermoscopic Features of Vulvar Lichen Sclerosus in the Setting of a Prospective Cohort of Patients: New Observations. AB - OBJECTIVE: Dermoscopic features of vulvar lichen sclerosus (VLS) were investigated in order to determine both vascular and non-vascular features of this disease. MATERIALS AND METHODS: Dermoscopic images of 35 patients affected with histopathologically confirmed VLS were evaluated for the presence of predefined morphological criteria. RESULTS: On dermoscopy, VLS lesions exhibited very sparse vessels, mainly linear, without a specific arrangement. Dotted vessels were observed mostly in the early stage of the disease. Patchy, structureless areas, whitish to white-yellowish to pink-whitish in colour over a diffuse whitish background, were a distinctive and constant dermoscopic feature. Grey-blue dots, usually with a characteristic peppered arrangement, corresponding to dermal melanophages, were also frequently seen. Comedo-like openings and scales were observed, as well as peculiar structures like ice slivers, not identified by histological examination. CONCLUSION: Our findings show that VLS exhibits characteristic dermoscopic patterns that can aid in its clinical diagnosis. PMID- 26574745 TI - The Economic Crisis and Acute Myocardial Infarction: New Evidence Using Hospital Level Data. AB - OBJECTIVE: This research sought to assess whether and to what extent the ongoing economic crisis in Italy impacted hospitalizations, in-hospital mortality and expenditures associated with acute myocardial infarction (AMI). METHODS: The data were obtained from the hospital discharge database of the Italian Health Ministry and aggregated at the hospital level. Each hospital (n = 549) was observed for 4 years and was geographically located within a "Sistema Locale del Lavoro" (SLL, i.e., clusters of neighboring towns with a common economic structure). For each SLL, the intensity of the crisis was determined, defined as the 2012-2008 increase in the area-specific unemployment rate. A difference-in-differences (DiD) approach was employed to compare the increases in AMI-related outcomes across different quintiles of crisis intensity. RESULTS: Hospitals located in areas with the highest intensity of crisis (in the fifth quintile) had an increase of approximately 30 AMI cases annually (approximately 13%) compared with hospitals in area with lower crisis intensities (p<0.001). A significant increase in total hospital days was observed (13%, p<0.001) in addition to in-hospital mortality (17%, p<0.001). As a consequence, an increase of around ?350.000 was incurred in annual hospital expenditures for AMI (approximately 36%, p<0.001). CONCLUSIONS: More attention should be given to the increase in health needs associated with the financial crisis. Policies aimed to contrast unemployment in the community by keeping and reintegrating workers in jobs could also have positive impacts on adverse health outcomes, especially in areas of high crisis intensity. PMID- 26574746 TI - Miltefosine Lipid Nanocapsules for Single Dose Oral Treatment of Schistosomiasis Mansoni: A Preclinical Study. AB - Miltefosine (MFS) is an alkylphosphocholine used for the local treatment of cutaneous metastases of breast cancer and oral therapy of visceral leishmaniasis. Recently, the drug was reported in in vitro and preclinical studies to exert significant activity against different developmental stages of schistosomiasis mansoni, a widespread chronic neglected tropical disease (NTD). This justified MFS repurposing as a potential antischistosomal drug. However, five consecutive daily 20 mg/kg doses were needed for the treatment of schistosomiasis mansoni in mice. The present study aims at enhancing MFS efficacy to allow for a single 20mg/kg oral dose therapy using a nanotechnological approach based on lipid nanocapsules (LNCs) as oral nanovectors. MFS was incorporated in LNCs both as membrane-active structural alkylphospholipid component and active antischistosomal agent. MFS-LNC formulations showed high entrapment efficiency (EE%), good colloidal properties, sustained release pattern and physical stability. Further, LNCs generally decreased MFS-induced erythrocyte hemolytic activity used as surrogate indicator of membrane activity. While MFS-free LNCs exerted no antischistosomal effect, statistically significant enhancement was observed with all MFS-LNC formulations. A maximum effect was achieved with MFS LNCs incorporating CTAB as positive charge imparting agent or oleic acid as membrane permeabilizer. Reduction of worm load, ameliorated liver pathology and extensive damage of the worm tegument provided evidence for formulation-related efficacy enhancement. Non-compartmental analysis of pharmacokinetic data obtained in rats indicated independence of antischistosomal activity on systemic drug exposure, suggesting possible gut uptake of the stable LNCs and targeting of the fluke tegument which was verified by SEM. The study findings put forward MFS-LNCs as unique oral nanovectors combining the bioactivity of MFS and biopharmaceutical advantages of LNCs, allowing targeting via the oral route. From a clinical point of view, data suggest MFS-LNCs as a potential single dose oral nanomedicine for enhanced therapy of schistosomiasis mansoni and possibly other diseases. PMID- 26574747 TI - Demographic and Lifestyle Characteristics, but Not Apolipoprotein E Genotype, Are Associated with Intelligence among Young Chinese College Students. AB - BACKGROUND: Intelligence is an important human feature that strongly affects many life outcomes, including health, life-span, income, educational and occupational attainments. People at all ages differ in their intelligence but the origins of these differences are much debated. A variety of environmental and genetic factors have been reported to be associated with individual intelligence, yet their nature and contribution to intelligence differences have been controversial. OBJECTIVE: To investigate the contribution of apolipoprotein E (APOE) genotype, which is associated with the risk for Alzheimer's disease, as well as demographic and lifestyle characteristics, to the variation in intelligence. METHODS: A total of 607 Chinese college students aged 18 to 25 years old were included in this prospective observational study. The Chinese revision of Wechsler Adult Intelligence Scale (the fourth edition, short version) was used to determine the intelligence level of participants. Demographic and lifestyle characteristics data were obtained from self-administered questionnaires. RESULTS: No significant association was found between APOE polymorphic alleles and different intelligence quotient (IQ) measures. Interestingly, a portion of demographic and lifestyle characteristics, including age, smoking and sleep quality were significantly associated with different IQ measures. CONCLUSIONS: Our findings indicate that demographic features and lifestyle characteristics, but not APOE genotype, are associated with intelligence measures among young Chinese college students. Thus, although APOE epsilon4 allele is a strong genetic risk factor for Alzheimer's disease, it does not seem to impact intelligence at young ages. PMID- 26574748 TI - Association between BMP15 Gene Polymorphism and Reproduction Traits and Its Tissues Expression Characteristics in Chicken. AB - BMP15 (Bone morphogenetic protein 15) is an oocyte-secreted growth factor required for ovarian follicle development and ovulation in mammals, but its effects on reproduction in chickens are unclear. In this study, the association between BMP15 polymorphisms and reproduction traits were analyzed, and its expression characteristics in different tissues were explored in LaiWu Black chickens. Three single nucleotide polymorphisms (SNPs) were identified in four hundred LaiWu Black chickens. One SNP (NC_006091.3:g.1773T>C) located in exon 2 which was significantly associated with egg weight at first egg (EWFE) (P = 0.0389), was novel. Diplotypes based on the three SNPs were found to be significantly associated with egg weight at age of 43W (EW43) (P = 0.0058). The chickens with H3H3 diplotype had their first egg 0.57 days later than chickens with H5H5 diplotype and 1.21 days-3.96 days earlier than the other five diplotype chickens. The egg production at age of 43W (E43), egg production at age of 46W (E46) and egg production at age of 48W (E48) for chickens with H3H3 diplotype were the highest among all the chickens, and the E48 of chickens with H3H3 diplotype had 11.83 eggs higher than chickens with H1H5 diplotype. RT-qPCR results showed that the expression level of BMP15 gene in ovarian follicle was in the order of 4 mm>6 mm -8 mm> 15 mm -19 mm> 23 mm -29 mm > 33 mm -34 mm in diameter. The mRNA level in follicles of 4 mm and 6-8 mm in diameter were significantly higher than that in the other follicles (P<0.01). In the same week, the highest mRNA level was found in the ovary, and it was significantly different from that found in the liver and oviduct (P<0.01). Our results indicate that BMP15 plays a vital role in the development of ovary and follicles, especially in the development of primary follicles. H3H3 may be an potential advantageous molecular marker for improving reproduction traits in chickens. PMID- 26574749 TI - Microarray analysis of circulating micro RNAs in the serum of patients with polymyositis and dermatomyositis reveals a distinct disease expression profile and is associated with disease activity. AB - OBJECTIVES: The aim of this study was a large scale investigation of myositis associated circulating miRNA molecules and also determination of expression of these candidate molecules in relation to clinical activity of myositis. METHODS: RNA, containing also miRNAs, was isolated from sera of 28 patients suffering from idiopathic inflammatory myopathies (IIM) and 16 healthy controls. Expression of miRNAs was determined using a miRNA microarray method. Statistical analysis of miRNA expression was carried out using Arraystar software. RESULTS: Our results showed 23 significantly differentially expressed miRNAs. Six miRNAs were differentially expressed in IIM compared to healthy controls. In dermatomyositis (DM) we found 3 and in polymyositis (PM) 6 differentially expressed miRNAs compared to controls. Three miRNAs were up-regulated in patients with highly active disease compared to patients with low disease activity. Furthermore, we found 26 significantly differentially expressed miRNAs in SLE patients compared to IIM, DM and PM patients. CONCLUSIONS: This is the first study that comprehensively describes expression levels of circulating miRNAs in serum of patients suffering from IIM. It can be expected that some of these deregulated miRNA molecules are involved in aetiology of IIM and may potentially serve as molecular markers for IIM development or for monitoring of disease activity. PMID- 26574750 TI - Clinical Experience and Best Practices Using Epidermal Skin Grafts on Wounds. AB - Over the years, autologous skin grafting has been used extensively to achieve wound closure, optimize a functional scar, and improve aesthetic outcomes for the patient. Although a vast majority of the literature is on the use of full thickness and split-thickness skin grafts, epidermal skin grafts (ESGs) have emerged as a viable option in the reconstructive ladder when only the epidermal layer is needed. These grafts are distinct from other types of autologous skin grafts in that they can be harvested without anesthesia and leave minimal or no scarring at the donor site. In order to explore the use of ESGs in the continuum of primary wound closure, a multidisciplinary expert panel convened in October 2014, in Las Vegas, NV, to review the scientific basis and clinical uses of epidermal grafting. This publication provides an overview of epidermal grafting, recommendations for graft application, and potential roles for its use in wound care and closure. PMID- 26574751 TI - Effect of High-pressure, Intermittent Pneumatic Compression for the Treatment of Peripheral Arterial Disease and Critical Limb Ischemia in Patients Without a Surgical Option. AB - Thirty-four subjects with symptomatic peripheral arterial disease (PAD) or critical limb ischmeia (CLI) who were experiencing claudication pain, chronic resting pain, numbness, and ischemic lower leg/foot ulceration were randomized into 2 treatment groups. MATERIALS AND METHODS: Eighteen of these patients received treatment with high-pressure, intermittent pneumatic compression (HPIPC) 60 minutes twice daily for 16 weeks, and 16 subjects received standard care consisting of an exercise regimen of walking for 20 minutes twice daily for 16 weeks. The HPIPC device delivers bilateral pressures of 120 mm Hg. Cycle times provide sequential compression for 4 seconds (+/- 0.5 seconds) followed by a 16 second rest period (+/- 3.0 seconds), resulting in a 20-second cycle or 3 cycles per minute. The study was designed to measure patient-centered outcomes. The primary endpoint was peak walking time (PWT), defined as time to maximally tolerated claudication pain. Secondary endpoints included change in resting ankle brachial index, ulcer healing, relief of resting/wound pain, and quality of life (QoL) index. Age (73.7 years vs 72.7 years), baseline PWTs (1-6 minutes), and risk factors were similar in both treatment groups. RESULTS: At 4 weeks, the percent change from baseline in PWT did not vary significantly between treatment groups (17.8% for HPIPC and 17% for standard care). After 8 weeks, the percent change in PWT for the HPIPC group was 41% compared to 32% for the group receiving standard care (P = 0.062). At the 16-week time point the percent change from baseline in PWT was significantly different between treatment arms (35.5% for the standard care group and 54.7% for the group receiving HPIPC [P = 0.043]). The mean reduction in wound surface area was 57% and 71% at 12 weeks and 16 weeks, respectively, for the HPIPC group, compared to 45% and 56% for the control group. The HPIPC group reported significantly greater pain relief at the 12-week (P = 0.044) and 16- week (P = 0.038) time points. Compared to the control group, the HPIPC group reported improvement in patient-centered outcomes such as physical function and bodily pain. These differences were statistically significant (P less than 0.05) at the 16- week evaluation period. CONCLUSION: Therapy consisting of HPIPC for 2 hours daily for a period of 16 weeks significantly improved PWT, reduced resting pain, and improved healing rates, physical function, and bodily pain. There were no devicerelated complications, allowing for long-term use. This study further supports that HPIPC is safe and effective and should be considered for patients who are not candidates for endovascular or surgical procedures. Furthermore, HPIPC offers an excellent alternative for the palliative care of patients with PAD and CLI symptoms. PMID- 26574752 TI - Successful Surgical Treatment of Severe Calciphylaxis Using a Bilayer Dermal Replacement Matrix. AB - Cutaneous calciphylaxis is a rare and often intractable disease that involves subcutaneous vascular calcification, ischemia, and subsequent necrosis. Calciphylaxis has an associated 60%-80% mortality rate with sepsis as the leading cause of death. However, despite variable success rates, the proper treatment of calciphylaxis remains controversial. In this case report, the authors present a 42-year-old female who presented with bilateral lower extremity calciphylaxis in conjunction with long-standing liver disease and acute renal failure. Cure of the patient's calciphylaxis was achieved through a surgical approach using staged debridement, placement of a dermal regenerative template (Integra Dermal Regeneration Template, Integra Lifesciences, Plainsboro, NJ), and followed by successful skin grafting. This is the first successful treatment of calciphylaxis in the literature to date using dermal regenerative template material. PMID- 26574753 TI - Microbiological Features and Risk Factors in Patients With Diabetic Foot Ulcers. AB - INTRODUCTION: Approximately 25% of people with diabetes will experience diabetic foot ulcers (DFUs) during their lifetime. The present study was designed to evaluate the prevalence of diabetic foot infection among patients with DFUs and to identify the microorganisms isolated from the DFUs. This study also aimed to determine predisposing factors contributing to these infections at the authors' wound care clinic at the Rajaii and Velayat University Hospitals in Qazvin, Iran. METHODS: This cross-sectional descriptive study included 500 patients with diabetes mellitus between May 2011 and April 2013 at the authors' wound care clinic in Qazvin, Iran. All demographic, clinical, and laboratory data such as age, sex, duration of diabetes (years), duration of DFUs before inclusion in the study, size of ulcer (cm2), glycosylated hemoglobin (HbA1c), and results of ulcer culture were collected for each case. The collected data were analyzed using SPSS software (SPSS Inc, Chicago, IL). A P value less than 0.05 was considered significant. RESULTS: Overall, 54 (11%) patients with infected ulcers were found in the present study. Among patients with infected DFUs, the most commonly isolated microorganism was Pseudomonas aeruginosa, which infected 35% of patients, followed by Staphylococcus aureus in 19% of patients, and methicillin resistant S. aureus in 6% of patients. Additionally, in the multivariable logistic regression model, age > 65 years, ulcer size > 2 cm2, and HbA1c > 7% were associated with the occurrence of an infection in DFUs. CONCLUSION: Periodic examination of the feet of patients with diabetes is necessary. In addition, to decrease the prevalence of infected DFUs, more attention to the described risk factors is recommended. PMID- 26574754 TI - Clinical Usage of an Extracellular, Collagen-rich Matrix: A Case Series. AB - OASIS Ultra (Smith and Nephew, St. Petersburg, FL) is an extracellular, collagen rich matrix derived from submucosa of porcine intestine. It is composed of collagen type I, glycosaminoglycan, and proteoglycans. This extracellular matrix (ECM) differs from the single layer in thickness and offers ease of handling and application. It also stimulates cell migration and structural support, provides moisture environment, decreases inflammation, and induces cell proliferation and cellular attachments. In this case series, the authors present their experience with this product in various clinical scenarios. MATERIALS AND METHODS: The authors used the product in a variety of wounds with different etiologies to test the clinical outcome of the ECM. This was an observational case series with prospective review of 6 different patients with different types of wounds who received treatment with the ECM during their treatment. The product was applied on the following types of wounds: chronic venous ulcer, nonhealing Achilles tendon vasculitic wound, Marjolin's ulcer, posttraumatic wound, stage IV sacral coccygeal pressure wound, and complicated transmetatarsal amputation of gangrenous left forefoot diabetic wound. RESULTS: All of these wounds healed within the expected time periods and without complications. In general, healing was achieved in 4-16 weeks using 1-12 applications of the ECM. CONCLUSION: Wounds with different etiologies were successfully treated with an extracellular, collagen-rich matrix. By replacing the lost ECM to guide cellular growth and migration, this product did ultimately hasten the healing process. PMID- 26574755 TI - (In)Consistencies in Responses to Sodium Bicarbonate Supplementation: A Randomised, Repeated Measures, Counterbalanced and Double-Blind Study. AB - OBJECTIVES: Intervention studies do not account for high within-individual variation potentially compromising the magnitude of an effect. Repeat administration of a treatment allows quantification of individual responses and determination of the consistency of responses. We determined the consistency of metabolic and exercise responses following repeated administration of sodium bicarbonate (SB). DESIGN AND METHODS: 15 physically active males (age 25+/-4 y; body mass 76.0+/-7.3 kg; height 1.77+/-0.05 m) completed six cycling capacity tests at 110% of maximum power output (CCT110%) following ingestion of either 0.3 g?kg-1BM of SB (4 trials) or placebo (PL, 2 trials). Blood pH, bicarbonate, base excess and lactate were determined at baseline, pre-exercise, post-exercise and 5 min post-exercise. Total work done (TWD) was recorded as the exercise outcome. RESULTS: SB supplementation increased blood pH, bicarbonate and base excess prior to every trial (all p <= 0.001); absolute changes in pH, bicarbonate and base excess from baseline to pre-exercise were similar in all SB trials (all p > 0.05). Blood lactate was elevated following exercise in all trials (p <= 0.001), and was higher in some, but not all, SB trials compared to PL. TWD was not significantly improved with SB vs. PL in any trial (SB1: +3.6%; SB2 +0.3%; SB3: +2.1%; SB4: +6.7%; all p > 0.05), although magnitude-based inferences suggested a 93% likely improvement in SB4. Individual analysis showed ten participants improved in at least one SB trial above the normal variation of the test although five improved in none. CONCLUSIONS: The mechanism for improved exercise with SB was consistently in place prior to exercise, although this only resulted in a likely improvement in one trial. SB does not consistently improve high intensity cycling capacity, with results suggesting that caution should be taken when interpreting the results from single trials as to the efficacy of SB supplementation. TRIAL REGISTRATION: ClinicalTrials.gov NCT02474628. PMID- 26574756 TI - Prize. PMID- 26574758 TI - What do the "new" Pulmonary Hypertension Guidelines tell us: should we change our practice? PMID- 26574759 TI - The role of valve interstitial cells in valve disease. PMID- 26574757 TI - Diagnosis and management of acute heart failure. AB - Acute heart failure (AHF) is a life threatening clinical syndrome with a progressively increasing incidence in general population. Turkey is a country with a high cardiovascular mortality and recent national statistics show that the population structure has turned to an 'aged' population.As a consequence, AHF has become one of the main reasons of admission to cardiology clinics. This consensus report summarizes clinical and prognostic classification of AHF, its worldwide and national epidemiology, diagnostic work-up, principles of approach in emergency department,intensive care unit and ward, treatment in different clinical scenarios and approach in special conditions and how to plan hospital discharge. PMID- 26574760 TI - A little Red Bull may give you wings, but it probably will not affect your Tpe. PMID- 26574761 TI - Assessment of atrial conduction times in patients with mild diastolic dysfunction and normal atrial size. AB - OBJECTIVE: Abnormalities in atrial electromechanical delays (EMDs) are considered independent predictors of atrial fibrillation and can reflect atrial remodeling. The main purpose in this study was to compare inter-left and right intra-atrial EMDs of patients with mild left ventricular (LV) diastolic dysfunction, without left atrial (LA) structural remodeling in the absence of high filling pressure, with healthy individuals. METHODS: In this prospective study, a total of 41 consecutive outpatients who were referred to our echocardiography laboratory with mild diastolic dysfunction (age: 60.9+/-9.6 years) and 45 healthy control subjects who were referred from an outpatient clinic for check-up (age: 32.2+/ 10.3 years) with normal diastolic function were enrolled into this study. All subjects had normal LA volume and normal right atrial area and did not have high filling pressure. Diastolic dysfunction were determined per American Society of Echocardiography recommendations; so, the following indices were measured: peak early (E) and atrial (A) flow velocities (cm/s), E/A ratio, and deceleration time (DT) (ms) of mitral inflow, systolic (S) and diastolic (D) pulmonary vein wave velocities (cm/s) by pulse wave Doppler, and e' in septal and lateral mitral annulus by pulse wave tissue Doppler. Time interval from the onset of P wave on the ECG to the beginning of the late diastolic wave (Am wave) on tissue Doppler trace, which is named PA, was obtained from the lateral and septal mitral annulus and right ventricular (RV) tricuspid annulus as atrial conduction times (ACTs) and were named lateral PA, septal PA, and RV PA, respectively. The difference between lateral PA and septal, PA septal and RV PA was defined as left and right intra-atrial EMD, respectively. The difference between lateral PA and RV PA was defined as inter-atrial EMD. Data analysis was done by independent student's t test, Mann-Whitney U test, chi2 test, Spearman rank order, Pearson's correlation coefficient, and multivariate regression analysis in the appropriate site. RESULTS: A, DT, S/D ratio, and E/e' (average) were significantly lower in the control group, and E, D, E/A ratio, e' septal, and e' lateral wall were significantly lower in the patient group. Atrial conduction times were longer in the patient group, but in the multivariate analysis, there was no correlation between ACTs and diastolic dysfunction. There was no significant difference in left intra-atrial EMD (14.2+/-9.7 ms vs. 16.4+/-11.4 ms; p=0.336), right intra atrial EMD (12.8+/-12.2 ms vs. 15.4+/-12.1 ms; p=0.321), and inter-atrial EMD (26.9+/-13.7 ms vs. 31.7+/-13.7 ms; p=0.108) between the two groups. Multivariate analysis showed no correlation between inter- and intra-atrial EMDs and diastolic dysfunction. CONCLUSION: There was no significant difference in ACTs and inter atrial and left and right intra-atrial EMD in patients with mild LV diastolic dysfunction and normal LA volume in the absence high filling pressure compared with normal subjects. PMID- 26574762 TI - Thromboelastography for the monitoring of the antithrombotic effect of low molecular-weight heparin after major orthopedic surgery. AB - OBJECTIVE: Low-molecular-weight heparins (LMWHs) are commonly used to prevent and manage postoperative thromboembolism. In general, monitoring of anticoagulant activity by anti-Xa testing is not done properly. Thromboelastography (TEG) evaluates the viscoelastic properties of blood during coagulation. The clinical application of TEG variables in monitoring LMWH treatment is not yet well defined. METHODS: This prospective study was designed to systematically examine the correlation between anti-Xa and basic TEG parameters in monitoring LMWH treatment. We furthermore evaluated for the first time the usefulness of a composite TEG parameter, coagulation index (CI). Thirty patients undergoing unilateral or bilateral total knee replacement, admitted to the intensive care unit on a therapeutic dosage of subcutaneous enoxaparin (30-mg injections administered twice daily), were included into the study. TEG parameters and anti Xa levels were measures at baseline and 4, 12, and 24 hours after the injection. RESULTS: This study demonstrates a significant correlation between CI and plasma anti-Xa activity in surgical patients treated with enoxaparin. Although the correlation was significant between r time and anti-Xa level only at Hour 4, CI was significant for each time interval (p<0.05). CI increased immediately after T0, peaking at Hour 4, and remained elevated (relative to baseline) at Hour 24 but still did not return to admission levels. CONCLUSION: The current study may be an important first step in order to use CI to measure LMWH activity. Meanwhile, the value and usefulness of TEG in predicting bleeding or thrombotic complications following major orthopedic surgery merit further investigation. PMID- 26574763 TI - Obstructive sleep apnea and its effects on cardiovascular diseases: a narrative review. AB - Obstructive sleep apnea (OSA) occurs in 5%-14% of adults but is often undiagnosed. Apneas cause acute physiological changes, including alveolar hypoventilation and pulmonary artery vasoconstriction; they also promote chronic vascular disease secondary to increased platelet adhesiveness, endothelial dysfunction, and accelerated atherosclerosis. The Sleep Heart Health Study demonstrated that OSA is a risk factor for stroke and that an increase of 1 unit in the apnea-hypopnea index increases stroke risk by 6% in men. Patients with OSA frequently have atrial fibrillation (AF). Patients with OSA and AF have an increased incidence of stroke compared with patients with only OSA. The treatment of OSA with CPAP reduces the incidence of stroke and decreases the recurrence rate of AF in patients undergoing pulmonary vein ablation procedures. Undertreated OSA has the potential to complicate the postoperative course of patients undergoing cardiac surgery and increase the frequency of arrhythmias and ischemic events. However, one prospective study demonstrated that OSA did not increase complications during the first 30 days following surgery but increased complications during the long-term follow-up. OSA is associated with increased atherosclerotic coronary disease and the development of coronary events and congestive heart failure. In summary, patients with OSA have an increased frequency of stroke and AF. The treatment of these patients with CPAP reduces the frequency of stroke and AF recurrence rate in patients with AF undergoing either medical management or invasive procedures. However, well-designed clinical trials are necessary to answer critical questions regarding the management of OSA in patients with cardiovascular diseases. PMID- 26574764 TI - Papillary fibroelastoma associated with congenital heart disease: a coincidental association or a potential new syndrome? PMID- 26574765 TI - Bonsai-induced Kounis Syndrome in a young male patient. PMID- 26574766 TI - Bilateral pulmonary vein stenting for pulmonary vein obstruction after surgical correction of total abnormal pulmonary venous connection. PMID- 26574767 TI - Role of tirofiban with dual antiplatelet therapy in patients with STEMI undergoing primary PCI. PMID- 26574768 TI - Tirofiban usage and prognosis after myocardial infarction. PMID- 26574769 TI - Uniform criteria for diagnosing noncompaction by cMRI and echocardiography are warranted. PMID- 26574770 TI - Predictors of poor coronary collateral development in patients with stable coronary artery disease: Neutrophil-to-lymphocyte ratio and platelets. PMID- 26574773 TI - Improving the aetiological investigations of congenital hearing loss: our experience in an audit of 56 patients. PMID- 26574774 TI - Sorption Behavior of Compressed CO2 and CH4 on Ultrathin Hybrid Poly(POSS-imide) Layers. AB - Sorption of compressed gases into thin polymeric films is essential for applications including gas sensors and membrane based gas separation. For glassy polymers, the sorption behavior is dependent on the nonequilibrium status of the polymer. The uptake of molecules by a polymer is generally accompanied by dilation, or swelling, of the polymer material. In turn, this dilation can result in penetrant induced plasticization and physical aging that affect the nonequilibrium status of the polymer. Here, we investigate the dilation and sorption behavior of ultrathin membrane layers of a hybrid inorganic-organic network material that consists of alternating polyhedral oligomeric silsesquioxane and imide groups, upon exposure to compressed carbon dioxide and methane. The imide precursor contains fluoroalkene groups that provide affinity toward carbon dioxide, while the octa-functionalized silsesquioxane provides a high degree of cross-linking. This combination allows for extremely high sorption capacities, while structural rearrangements of the network are hindered. We study the simultaneous uptake of gases and dilation of the thin films at high pressures using spectroscopic ellipsometry measurements. Ellipsometry provides the changes in both the refractive index and the film thickness, and allows for accurate quantification of sorption and swelling. In contrast, gravimetric and volumetric measurements only provide a single parameter; this does not allow an accurate correction for, for instance, the changes in buoyancy because of the extensive geometrical changes of highly swelling films. The sorption behavior of the ultrathin hybrid layers depends on the fluoroalkene group content. At low pressure, the apparent molar volume of the gases is low compared to the liquid molar volume of carbon dioxide and methane, respectively. At high gas concentrations in the polymer film, the apparent molar volume of carbon dioxide and methane exceeds that of the liquid molar volume, and approaches that of the gas phase. The high sorption capacity and reversible dilation characteristics of the presented materials provide new directions for applications including gas sensors and gas separation membranes. PMID- 26574775 TI - Experimental and Computational Insight into the Chemical Bonding and Electronic Structure of Clathrate Compounds in the Sn-In-As-I System. AB - Inorganic clathrate materials are of great fundamental interest and potential practical use for application as thermoelectric materials in freon-free refrigerators, waste-heat converters, direct solar thermal energy converters, and many others. Experimental studies of their electronic structure and bonding have been, however, strongly restricted by (i) the crystal size and (ii) essential difficulties linked with the clean surface preparation. Overcoming these handicaps, we present for the first time a comprehensive picture of the electronic band structure and the chemical bonding for the Sn(24-x-delta)InxAs(22 y)I8 clathrates obtained by means of photoelectron spectroscopy and complementary quantum modeling. PMID- 26574776 TI - Toxicity Originating from Thiophene Containing Drugs: Exploring the Mechanism using Quantum Chemical Methods. AB - Drug metabolism of thiophene containing substrates by cytochrome P450s (CYP450) leads to toxic side effects, for example, nephrotoxicity (suprofen, ticlopidine), hepatotoxicity (tienilic acid), thrombotic thrombocytopenic purpura (clopidogrel), and aplastic anemia (ticlopidine). The origin of toxicity in these cases has been attributed to two different CYP450 mediated metabolic reactions: S oxidation and epoxidation. In this work, the molecular level details of the bioinorganic chemistry associated with the generation of these competitive reactions are reported. Density functional theory was utilized (i) to explore the molecular mechanism for S-oxidation and epoxidation using the radical cationic center Cpd I [(iron(IV)-oxo-heme porphine system with SH(-) as the axial ligand, to mimic CYP450s] as the model oxidant, (ii) to establish the 3D structures of the reactants, transition states, and products on both the metabolic pathways, and (iii) to examine the potential energy (PE) profile for both the pathways to determine the energetically preferred toxic metabolite formation. The energy barrier required for S-oxidation was observed to be 14.75 kcal/mol as compared to that of the epoxidation reaction (13.23 kcal/mol) on the doublet PE surface of Cpd I. The formation of the epoxide metabolite was found to be highly exothermic (-23.24 kcal/mol), as compared to S-oxidation (-8.08 kcal/mol). Hence, on a relative scale the epoxidation process was observed to be thermodynamically and kinetically more favorable. The energy profiles associated with the reactions of the S-oxide and epoxide toxic metabolites were also explored. This study helps in understanding the CYP450-catalyzed toxic reactions of drugs containing the thiophene ring at the atomic level. PMID- 26574777 TI - Biological Hydrogels Formed by Swollen Multilamellar Liposomes. AB - The self-assembly of lecithin-bile salt mixtures in solutions has long been an important research topic, not only because they are both biosurfactants closely relevant to physiological functions but also for the potential biomedical applications. In this paper, we report an unusual biological hydrogel formed by mixing bile salts and lecithin at low bile salt/lecithin molar ratios (B0) in water. The gel can be prepared at a total lipid concentration as low as ~15 wt %, and the solidlike property of the solutions was confirmed by dynamic rheological measurements. We used cryo-TEM and SAXS/SANS techniques to probe the self assembled structure and clearly evidence that the gel is made up of jammed swollen multilamellar vesicles (liposomes), instead of typical fibrous networks found in conventional gels. A mechanism-based on the strong repulsion between bilayers due to the incorporation of negatively charged bile salts is proposed to explain the swelling of the liposomes. In addition to gel, a series of phases, including viscoelastic, gel-like, and low-viscosity fluids, can be created by increasing B0. Such a variety of phase behaviors are caused by the transformation of bilayers into cylindrical and spheroidal micelles upon the change of the effective molecular geometry with B0. PMID- 26574778 TI - Palladium-Catalyzed Phosphorylation of Aryl Mesylates and Tosylates. AB - The first general palladium catalyst for the phosphorylation of aryl mesylates and tosylates is reported. The newly developed system exhibits excellent functional group compatibility. For instance, free amino, keto, ester, and amido groups, as well as heterocycles, remain intact during the course of reaction. The mesylated derivatives of biologically active compounds such as 17beta-estradiol and 6-hydroxyflavone are also shown to be applicable substrates. A one-pot phosphorylation-amination sequence is described for the facile synthesis of potential pharmacophores. PMID- 26574779 TI - Construction of Vicinal Tetrasubstituted Stereocenters with a C-F Bond through a Catalytic Enantioselective Detrifluoroacetylative Mannich Reaction. AB - An efficient asymmetric detrifluoroacetylative Mannich reaction of 2-fluoro-1,3 diketones/hydrates with isatin-derived ketimines catalyzed by a chiral copper(II) diamine complex has been realized. The reaction afforded a series of 3 substituted 3-amino-2-oxindoles bearing fluorine-containing vicinal tetrasubstituted stereocenters in high yields (up to 99%) with excellent diastereoselectivities (up to >20:1 dr) and enantioselectivities (up to 94% ee). PMID- 26574780 TI - Long noncoding RNA MEG3 is downregulated in cervical cancer and affects cell proliferation and apoptosis by regulating miR-21. AB - Recent research has found that long noncoding RNAs (lncRNAs) were involved in various human cancers. However, the role of these lncRNAs in cervical cancer remains unexplored. Therefore, we aimed to investigate the biological function of maternally expressed gene 3 (MEG3), a cancer-related lncRNA, and its underlying mechanism in cervical cancer. In this study, MEG3 expression of 108 patients' cervical cancer tissues and adjacent normal tissues was detected by quantitative real-time PCR analysis (qRT-PCR), and the functional effect of MEG3 was determined in vitro assays. We observed that MEG3 was downregulated in cervical cancer tissues, compared to the adjacent normal tissues, and was negatively related with FIGO stages, tumor size, lymphatic metastasis, HR-HPV infection and the expression of homo sapiens microRNA-21 (miR-21). Furthermore, we focused on the function and molecular mechanism of MEG3, finding that overexpression of MEG3 reduced the level of miR-21-5p expression, causing inhibition of proliferation and increased apoptosis in cervical cancer cells. In summary, our findings indicate that MEG3 function as a tumor suppressor by regulating miR-21-5p, resulting in the inhibition of tumor growth in cervical cancer. As a result, this study improves our understanding of the function of MEG3 in cervical cancer and will help to provide new potential target sites for cervical cancer treatment. PMID- 26574782 TI - MicroRNA machinery in Parkinson's disease: a platform for neurodegenerative diseases. AB - MicroRNAs (miRNAs) are noncoding RNAs that recognize their protein-coding target genes and whereby subjugate them after transcription. Despite the infancy of this field of science, the role of miRNAs in neurodegeneration is well-acknowledged. This review was conducted to indicate that Parkinson's disease (PD) is not excluded from this rule. To this end, we evaluated the existing literature and arranged PD-associated miRNAs according to their mechanism of action, particularly apoptosis, autophagy, inflammation, mitochondrial dysfunction and oxidative stress. According to this arrangement, a majority of PD-associated miRNAs were indicated to influence autophagic/apoptotic pathways. We also categorized PD-associated miRNAs according to that they could exert detrimental or beneficial or both into three sets, activator, inhibitor, and double-edged, correspondingly. Considering this criterion, a majority of PD-associated miRNAs were included in the activator category. In addition, evidences from genetic association studies investigating genetic variants of or related to miRNAs in PD patients are presented. Finally, possible applications of the miRNA machinery in PD, including mechanistic networks, diagnostic, prognostic and therapeutic potentials, are discussed. But there may be additional miRNAs involved in the pathogenesis of PD which have hitherto remained unknown and thus further studies are needed to explore the issue and to extend this platform. PMID- 26574781 TI - Immune Defense Protein Expression in Highly Purified Mouse Lung Epithelial Cells. AB - Lung epithelial cells play critical roles in initiating and modulating immune responses during pulmonary infection or injury. To better understand the spectrum of immune response-related proteins present in lung epithelial cells, we developed an improved method of isolating highly pure primary murine alveolar type (AT) II cells and murine tracheal epithelial cells (mTECs) using negative selection for a variety of lineage markers and positive selection for epithelial cell adhesion molecule (EpCAM), a pan-epithelial cell marker. This method yielded 2-3 * 10(6) ATII cells/mouse lung and 1-2 * 10(4) mTECs/trachea that were highly pure (>98%) and viable (>98%). Using these preparations, we found that both ATII cells and mTECs expressed the Lyn tyrosine kinase, which is best studied as an inhibitory kinase in hematopoietic cells. However, we found little or no expression of Syk in either ATII cells or mTECs, which is in contrast to earlier published reports. Both cell types expressed C-type lectin receptors, anaphylatoxin receptors, and various Toll-like receptors (TLRs). In addition, stimulation of ATII cells with TLR ligands led to secretion of various cytokines and chemokines. Interestingly, lyn(-/-) ATII cells were hyperresponsive to TLR3 stimulation, suggesting that, as in hematopoietic cells, Lyn might be playing an inhibitory role in ATII cells. In conclusion, the improved isolation method reported here, along with expression profiles of various immune defense proteins, will help refocus investigations of immune-related signaling events in pulmonary epithelium. PMID- 26574783 TI - Metabarcoding Analysis of Phytophthora Diversity Using Genus-Specific Primers and 454 Pyrosequencing. AB - A metabarcoding method based on genus-specific primers and 454 pyrosequencing was utilized to investigate the genetic diversity of Phytophthora spp. in soil and root samples of potted plants, from eight nurseries. Pyrosequencing enabled the detection of 25 Phytophthora phylotypes distributed in seven different clades and provided a much higher resolution than a corresponding cloning/Sanger sequencing approach. Eleven of these phylotypes, including P. cactorum, P. citricola s.str., P. palmivora, P. palmivora-like, P. megasperma or P. gonapodyides, P. ramorum, and five putative new Phytophthora species phylogenetically related to clades 1, 2, 4, 6, and 7 were detected only with the 454 pyrosequencing approach. We also found an additional 18 novel records of a phylotype in a particular nursery that were not detected with cloning/Sanger sequencing. Several aspects confirmed the reliability of the method: (i) many identical sequence types were identified independently in different nurseries, (ii) most sequence types identified with 454 pyrosequencing were identical to those from the cloning/Sanger sequencing approach and/or perfectly matched GenBank deposited sequences, and (iii) the divergence noted between sequence types of putative new Phytophthora species and all other detected sequences was sufficient to rule out sequencing errors. The proposed method represents a powerful tool to study Phytophthora diversity providing that particular attention is paid to the analysis of 454 pyrosequencing raw read sequences and to the identification of sequence types. PMID- 26574784 TI - Development and Deployment of Systems-Based Approaches for the Management of Soilborne Plant Pathogens. AB - Biological suppression of soilborne diseases with minimal use of outside interventive actions has been difficult to achieve in high input conventional crop production systems due to the inherent risk of pest resurgence. This review examines previous approaches to the management of soilborne disease as precursors to the evolution of a systems-based approach, in which plant disease suppression through natural biological feedback mechanisms in soil is incorporated into the design and operation of cropping systems. Two case studies are provided as examples in which a systems-based approach is being developed and deployed in the production of high value crops: lettuce/strawberry production in the coastal valleys of central California (United States) and sweet basil and other herb crop production in Israel. Considerations for developing and deploying system-based approaches are discussed and operational frameworks and metrics to guide their development are presented with the goal of offering a credible alternative to conventional approaches to soilborne disease management. PMID- 26574785 TI - Wheat Blast and Fusarium Head Blight Display Contrasting Interaction Patterns on Ears of Wheat Genotypes Differing in Resistance. AB - The interaction of wheat with two ear pathogens, Magnaporthe wheat blast (MWB) and Fusarium graminearum (Fusarium head blight, FHB), was studied on the phenotypic, histological, and gene expression level. Most of the 27 wheat cultivars inoculated with MWB and F. graminearum displayed inverse disease responses to blast and FHB infection. Two cultivars, Milan and Sumai 3, were selected expressing converse disease phenotypes to blast (Milan, R)/(Sumai 3, S) and FHB (Milan, S)/(Sumai 3, R). Confocal laser scanning microscopy revealed early (12 h postinoculation) colonization of the spikelets by MWB similarly on both cultivars, while F. graminearum infected anthers of the susceptible cultivar earlier. Both pathogens grew much faster in the rachilla of susceptible than resistant cultivars, indicating that resistance is mainly expressed in this part connecting the spikelet with the rachis. In general, O2(-) and H2O2 levels were unrelated to disease expression in the four studied interactions. The differential disease phenotypes, fungal spread in the rachis, and colonization patterns in the spikelets were confirmed by distinct gene expression patterns. Among the eight genes analyzed, seven were more strongly induced by FHB than by blast. Genes for chitinase (Chi2), beta-1,3-glucanase (PR2), a plant defensin homolog (PRPI), and peroxidase (Pox2) were strongly upregulated in Milan in response to both pathogens, while PR2 and PR5 (thaumatin-like protein) were transiently triggered by MWB on both cultivars. Upregulation of cinnamoyl-CoA reductase (CCR), cytochrome P450 (CYP709C1), and UDP-glycosyl transferase (UGT) were more prominent in ears infected with F. graminearum, while upregulation of UGT was higher in Sumai 3 when infected with either pathogen. Cultivar resistance to FHB was reflected by clearly higher expression levels of UGT and CYP709C1 in Sumai 3. The differential responses of wheat to the two ear pathogens demonstrated in this study makes it unlikely that common resistance genes exist for control of FHB and blast, suggesting the need to stack many genes associated with resistance in breeding programs for multiple resistance. PMID- 26574786 TI - Philadelphia chromosome-positive Acute Lymphoblastic Leukemia. PMID- 26574787 TI - THE LONG-TERM IMPACT OF CONTROLLED OVARIAN HYPERSTIMULATION ON THYROID FUNCTION. AB - OBJECTIVE: Evidence on the long-term impact of controlled ovarian hyperstimulation (COH) on thyroid function is scarce. To investigate this, we report on serum thyroid-stimulating hormone (TSH) modifications in euthyroid and hypothyroid women during COH and 3 months after the end of the stimulation cycle. METHODS: Women who underwent in vitro fertilization (IVF) and who did not become pregnant were eligible. Cases were women with treated hypothyroidism and basal serum TSH <2.5 mIU/L. Controls were euthyroid women matched to cases by age and basal serum TSH. Women could be included if serum TSH was available at 4 time points: prior to initiating COH (time 1); at the time of human chorionic gonadotropin (hCG) administration (time 2); 16 days after hCG administration (time 3); and 3 months after the end of the IVF cycle (time 4). RESULTS: Thirty seven case-control pairs were included. Serum TSH at times 1, 2, 3, and 4 was 1.7 +/- 0.6, 3.1 +/- 1.4, 3.1 +/- 1.3, and 2.7 +/- 1.7 mIU/L, and 1.7 +/- 0.6, 2.9 +/ 1.0, 2.7 +/- 1.0, and 1.9 +/- 0.7 mIU/L among cases and controls, respectively. A statistically significant difference emerged at time 4 (P<.001). In both groups, serum TSH was higher at time 4 compared to time 1. Serum TSH exceeded the recommended threshold of 2.5 mIU/L at time 4 in 51% of cases (95% confidence interval [CI], 35 to 68%) and in 16% of controls (95% CI, 4 to 28%) (P = .003). CONCLUSION: COH seems to have a long-term impact on TSH levels. The magnitude of this effect is particularly pronounced in hypothyroid women. PMID- 26574788 TI - TRENDS IN GROWTH HORMONE STIMULATION TESTING AND GROWTH HORMONE DOSING IN ADULT GROWTH HORMONE DEFICIENCY PATIENTS: RESULTS FROM THE ANSWER PROGRAM. AB - OBJECTIVE: Adult growth hormone deficiency (AGHD) results in physiologic impairments that may reduce quality of life and negatively impact body composition. AGHD can be treated with recombinant human growth hormone (GH). This study analyzes AGHD patients enrolled in the American Norditropin((r)) STUDIES: Web-Enabled-Research (ANSWER) Program/NovoNet, a U.S. observational noninterventional study of patients treated with Norditropin((r)) (somatropin [recombinant DNA origin] injection) at the discretion of their physicians. METHODS: Data were evaluated for GH stimulation test (GHST) usage and Norditropin((r)) doses over 4 years. RESULTS: Adults (N = 468) with isolated GHD (IGHD) or multiple pituitary hormone deficiency (MPHD) were evaluated. The most commonly used GHSTs were arginine + L-dopa (27%; mostly a single center) and glucagon (25%; most frequent test after 2009). The percent of patients meeting recommended test-specific cut points varied from 32 to 100%, depending on the GHST used. Mean baseline GH doses were higher for MPHD patients and for younger patients in both IGHD and MPHD groups. CONCLUSION: MPHD was more common than IGHD. Mean GH doses were higher in younger patients, consistent with a transition from higher pediatric to lower adult dosing. Over time, glucagon became the most popular GHST. The use, in some patients, of other GHSTs with cut points, as well as starting doses not consistent with current recommendations, highlights the need for continued education regarding treatment guidelines for AGHD. PMID- 26574789 TI - AUTONOMOUSLY FUNCTIONING THYROID NODULES IN PATIENTS <21 YEARS OF AGE: THE RHODE ISLAND HOSPITAL EXPERIENCE FROM 2003-2013. AB - OBJECTIVE: This study evaluates the clinical characteristics, workup, treatment, and outcomes of pediatric patients diagnosed with an autonomously functioning thyroid nodule (AFTN) in a large cohort of patients presenting for evaluation of a thyroid nodule. There are few prior studies on AFTN in pediatrics, with limited data on treatment and outcomes. Rates of malignancy in AFTN are perceived as low, but prior studies have varying reports. METHODS: This is a retrospective chart review of patients less than 21 years of age at Rhode Island Hospital over an 11 year period (2003-2013). We reviewed 354 charts, which yielded 242 patients with a diagnosis of thyroid nodule and 17 patients with AFTN. RESULTS: The prevalence of AFTN in patients presenting with thyroid nodules was 7%. Mean age of patients was 15.8 years at diagnosis, and mean nodule size was 3.3 cm. There was female predominance. Thyroid-stimulating hormone levels were suppressed at diagnosis in 87% of patients. Six patients were treated with surgery, 5 patients with radioactive iodine therapy (RAI), 2 patients with medication, and 1 patient was observed without treatment. Three patients treated with RAI required subsequent treatment for hypothyroidism or continued hyperthyroidism. One patient had papillary thyroid carcinoma based on final surgical pathology. CONCLUSION: Our study found a higher prevalence of AFTN compared to the reported prevalence in adults. We concur with the new guidelines on management of thyroid nodules in recommending surgery for treatment of AFTN, based on the variability of outcomes after treatment with RAI. PMID- 26574790 TI - METABOLIC EFFECTS OF HORMONE THERAPY IN TRANSGENDER PATIENTS. AB - OBJECTIVE: Transgender patients may seek hormone therapy to induce physical changes to simulate their expressed or experienced gender. However, many providers are uncomfortable prescribing transgender hormones due to fears over safety. The goal of this study was to determine if transgender hormone therapy with estrogen and spironolactone for male-to-female (MtF) patients or with testosterone for female-to-male (FtM) patients had adverse anthropomorphic or metabolic effects. METHODS: This retrospective chart review study analyzed changes over time for 33 MtF and 19 FtM endocrine clinic patients at an academic endocrine practice with follow-up for up to 18 months after hormone initiation. RESULTS: Compared to baseline labs obtained prior to the initiation of hormone therapy, significant changes for the MtF cohort included an increase in high density lipoprotein (HDL) and decrease in creatinine; however, triglycerides did not show a statistically significant change. In the FtM cohort, there were significant increases in body mass index, creatinine, hemoglobin, and hematocrit. Although statistically significant, these changes were minimal for both cohorts. CONCLUSION: In our practice, hormone therapy was found to be safe in this retrospective study. PMID- 26574791 TI - COMPARISON OF THE LONG-TERM EFFECTS OF LIRAGLUTIDE AND GLIMEPIRIDE MONOTHERAPY ON BONE MINERAL DENSITY IN PATIENTS WITH TYPE 2 DIABETES. AB - OBJECTIVE: Patients with type 2 diabetes have an increased risk of fragility fractures; the cause is unclear but is likely multifactorial. Some diabetes treatments induce bone loss, accentuating underlying skeletal fragility and increasing fracture risk. This subgroup analysis aimed to compare long-term effects of liraglutide and glimepiride on bone mineral density (BMD) in patients with type 2 diabetes. METHODS: LEAD-3, a 52-week, double-blind, active-control, phase III, multicenter trial, investigated the efficacy of liraglutide (1.2 and 1.8 mg/day) versus glimepiride monotherapy in type 2 diabetes. A 52-week, open label extension followed, in which participants remained on randomized therapy. A subgroup of participants underwent BMD measurement by dual-energy X-ray absorptiometry at baseline, 52, and 104 weeks. The main outcome measure was change from baseline in total body BMD at 52 and 104 weeks, assessed by analysis of covariance. RESULTS: A total of 746 patients with type 2 diabetes aged 19 to 79 years were randomized into the main trial. Of these, 61 patients (20 assigned to liraglutide 1.8 mg/day, 23 to liraglutide 1.2 mg/day, 18 to glimepiride 8 mg/day) had BMD measurements. Baseline age, body mass index, diabetes duration, glycated hemoglobin, and total BMD were similar across treatment groups. There was no apparent difference in mean total BMD change from baseline in patients receiving liraglutide 1.8 or 1.2 mg/day or glimepiride 8 mg/day at 52 or 104 weeks. CONCLUSION: In this small subgroup analysis, liraglutide monotherapy did not negatively affect total BMD in a 2-year prospective study, suggesting it may not exacerbate the consequences of bone fragility. PMID- 26574792 TI - Defining and recognising locally advanced basal cell carcinoma. AB - BACKGROUND: Rarely, basal cell carcinomas (BCCs) have the potential to become extensively invasive and destructive, a phenomenon that has led to the term "locally advanced BCC" (laBCC). We identified and described the diverse settings that could be considered "locally advanced". METHODS: The panel of experts included oncodermatologists, dermatological and maxillofacial surgeons, pathologists, radiotherapists and geriatricians. During a 1-day workshop session, an interactive flow/sequence of questions and inputs was debated. RESULTS: Discussion of nine cases permitted us to approach consensus concerning what constitutes laBCC. The expert panel retained three major components for the complete assessment of laBCC cases: factors of complexity related to the tumour itself, factors related to the operability and the technical procedure, and factors related to the patient. Competing risks of death should be precisely identified. To ensure homogeneous multidisciplinary team (MDT) decisions in different clinical settings, the panel aimed to develop a practical tool based on the three components. CONCLUSION: The grid presented is not a definitive tool, but rather, it is a method for analysing the complexity of laBCC. PMID- 26574793 TI - REP sequences: Mediators of the environmental stress response? AB - Repetitive Extragenic Palindromic (REP) sequences are highly conserved, structured, 35- to 40-nt elements located at ~500 positions around the Escherichia coli chromosome. They are found in intergenic regions and are transcribed together with their upstream genes. Although their stable stem-loop structures protect messages against exoribonuclease digestion, their primary function has remained unknown. Recently, we found that about half of all REP sequences have the potential to stall ribosomes immediately upstream of the termination codon, leading to endonucleolytic cleavage of the mRNA, and induction of the trans-translation process. As a consequence, the mRNA and almost completed protein are degraded, and protein production from the affected gene is down regulated. The process is critically dependent on the location of the REP element, with an effect only if it is within 15 nt of the termination codon. Using nrdAB as a model, we found that its down-regulation is affected by RNA helicases. Elimination of 6 helicases lowered NrdA production further, whereas overexpression of any RNA helicase partially reversed the downregulation. UV stress completely reversed down-regulation of NrdA production. Analysis of genes containing a REP sequence within 15 nt of the termination codon revealed that most, if not all, are up-regulated by environmental stress, as are RNA helicases. Based on these findings, we propose that REP-dependent downregulation serves as a mechanism to allow a rapid response to environmental stresses whereby RNA helicases partially open the REP elements enabling ribosomes to complete translation immediately increasing protein production from the affected genes. PMID- 26574794 TI - Purification of Mouse Brain Vessels. AB - In the brain, most of the vascular system consists of a selective barrier, the blood-brain barrier (BBB) that regulates the exchange of molecules and immune cells between the brain and the blood. Moreover, the huge neuronal metabolic demand requires a moment-to-moment regulation of blood flow. Notably, abnormalities of these regulations are etiological hallmarks of most brain pathologies; including glioblastoma, stroke, edema, epilepsy, degenerative diseases (ex: Parkinson's disease, Alzheimer's disease), brain tumors, as well as inflammatory conditions such as multiple sclerosis, meningitis and sepsis-induced brain dysfunctions. Thus, understanding the signaling events modulating the cerebrovascular physiology is a major challenge. Much insight into the cellular and molecular properties of the various cell types that compose the cerebrovascular system can be gained from primary culture or cell sorting from freshly dissociated brain tissue. However, properties such as cell polarity, morphology and intercellular relationships are not maintained in such preparations. The protocol that we describe here is designed to purify brain vessel fragments, whilst maintaining structural integrity. We show that isolated vessels consist of endothelial cells sealed by tight junctions that are surrounded by a continuous basal lamina. Pericytes, smooth muscle cells as well as the perivascular astrocyte endfeet membranes remain attached to the endothelial layer. Finally, we describe how to perform immunostaining experiments on purified brain vessels. PMID- 26574795 TI - A Comparative Treatment Study of Intravitreal Voriconazole and Liposomal Amphotericin B in an Aspergillus fumigatus Endophthalmitis Model. AB - PURPOSE: To compare the effects of voriconazole (VCZ) and liposomal amphotericin B (Amp-B) in an experimental model of Aspergillus fumigatus endophthalmitis. METHODS: Thirty guinea pigs received an intravitreal injection of A. fumigatus to induce endophthalmitis. The animals were randomly divided into three groups, including control (0.02 mL balanced salt solution intravitreal injection) and experimental (20 MUg VCZ/0.02 mL or 20 MUg liposomal Amp-B/0.02 mL intravitreal injection) groups. Corneal opacity, aqueous flare, and vitreous opacity were graded, and electroretinographic examinations were performed at multiple time points. At 28 days post treatment, histopathology was performed to examine the retinal architecture. RESULTS: The inflammation in the VCZ and liposomal Amp-B groups was milder than that in the control group. Corneal opacity, aqueous flare, and vitreous opacity scores, as well as electroretinographic recording, showed significantly less inflammation in the VCZ group compared with the liposomal Amp B group during the early and middle stages of endophthalmitis (P < 0.05). Normal histologic structure of the retina was observed in eyes treated with VCZ and liposomal Amp-B. CONCLUSIONS: Both intravitreal VCZ and liposomal Amp-B were effective treatments for A. fumigatus-induced endophthalmitis in guinea pigs. Voriconazole was superior to liposomal Amp-B at doses similar to the initial therapy for acute infections. Further experimental and clinical studies are required to confirm the efficacy of these two antifungal drugs. Chinese Abstract. PMID- 26574796 TI - Retinal Microglial Activation Following Topical Application of Intracellular Toll Like Receptor Ligands. AB - PURPOSE: We previously have reported that application of the intracellular toll like receptor (TLR)-9 ligand CpG-ODN onto the injured corneal surface induces widespread inflammation within the eye, including the retina. We tested the hypothesis that topical application of two other intracellular TLR agonists, Poly I:C and R848, would cause retinal microglial activation and migration into the subretinal space. METHODS: C57BL/6J wild-type and Cx3cr1gfp/+ mice were anesthetized and received central corneal abrasions followed by topical application of Poly I:C (TLR3 agonist), R848 (TLR7/8 agonist), or CpG-ODN (TLR9 agonist). Eyes were imaged in vivo by using spectral-domain optical coherence tomography to assess and quantify vitreous cells and retinal edema. Tissues were processed for whole-mount immunofluorescence staining or gene expression studies. Microglial activation was determined by morphologic changes, major histocompatibility complex (MHC) class II reactivity, and migration to the subretinal space. Expression of proinflammatory cytokine gene IL-6, IL-1beta, IFN gamma, and MCP-1 in retinal tissues were analyzed. RESULTS: At 24 hours, topical treatment with CpG-ODN and R848, but not Poly I:C, led to altered microglial morphology. One week after CpG-ODN and R848-treatment, eyes exhibited vitritis and mild inner retinal edema, increased number of subretinal Iba-1+ cells, and an increase in MHC II+ cells in the neural retina. Proinflammatory cytokine genes were upregulated after R848 treatment, whereas in the CpG-ODN group, only IL 1beta and MCP-1 were significantly upregulated. Retinal microglial activation was not observed in the Poly I:C-treated group. CONCLUSIONS: Topical application of CpG-ODN and R848, but not Poly I:C, to the damaged corneal surface can cause activation and migration of retinal microglia. PMID- 26574797 TI - Intracellular Toll-Like Receptors Help Retinal Microglia Sense Corneal Infections. PMID- 26574798 TI - Cerebral Involvement in Stargardt's Disease: A VBM and TBSS Study. AB - PURPOSE: To assess whether and to what extent macro- and/or microstructural modifications are present in the brain of patients with selective central visual loss due to a juvenile macular degeneration, Stargardt's disease (STGD), taking advantage of the complementary information provided by voxel-based morphometry (VBM) and diffusion tensor imaging (DTI). METHODS: Eighteen patients with clinical and molecular diagnosis of STGD related to ABCA4 mutations and 23 normally sighted volunteers of comparable age and sex were enrolled. Structural T1-weighted (T1w) volumes, for brain tissue volume assessment by segmentation, and DTI, for the investigation of diffusivity parameters via a tract-based spatial statistics (TBSS) procedure, were acquired at 3 Tesla in all subjects. All patients underwent a complete ophthalmologic examination, including best corrected visual acuity (BCVA), biomicroscopy, ophthalmoscopy, electroretinography (ERG), microperimetry, and optical coherence tomography (OCT). Correlations between imaging data and clinical measures were tested. RESULTS: Stargardt's disease patients showed a significant gray matter (GM) loss bilaterally in the occipital cortices, extending into the right precuneus, and in the fronto-orbital cortices. At TBSS, significant reductions in fractional anisotropy were detected throughout large regions in the supratentorial white matter (WM), more pronounced in the posterior areas. Gray matter volume correlated directly with mean visual sensitivity in the right middle frontal and left calcarine gyri, and inversely with retinal thickness in the left supramarginal gyrus. CONCLUSIONS: In STGD, widespread microstructural WM alterations are present, suggestive of minor fiber loss coupled with GM loss, also in cortical regions not traditionally linked to visual pathways, at least partly related to the retinal damage. PMID- 26574799 TI - MALDI Imaging Mass Spectrometry Spatially Maps Age-Related Deamidation and Truncation of Human Lens Aquaporin-0. AB - PURPOSE: To spatially map human lens Aquaporin-0 (AQP0) protein modifications, including lipidation, truncation, and deamidation, from birth through middle age using matrix-assisted laser desorption ionization (MALDI) imaging mass spectrometry (IMS). METHODS: Human lens sections were water-washed to facilitate detection of membrane protein AQP0. We acquired MALDI images from eight human lenses ranging in age from 2 months to 63 years. In situ tryptic digestion was used to generate peptides of AQP0 and peptide images were acquired on a 15T Fourier transform ion cyclotron resonance (FTICR) mass spectrometer. Peptide extracts were analyzed by liquid chromatography-tandem mass spectrometry (LC MS/MS) and database searched to identify peptides observed in MALDI imaging experiments. RESULTS: Unmodified, truncated, and fatty acid-acylated forms of AQP0 were detected in protein imaging experiments. Full-length AQP0 was fatty acid acylated in the core and cortex of young (2- and 4-month) lenses. Acylated and unmodified AQP0 were C-terminally truncated in older lens cores. Deamidated tryptic peptides (+0.9847 Da) were mass resolved from unmodified peptides by FTICR MS. Peptide images revealed differential localization of un-, singly-, and doubly-deamidated AQP0 C-terminal peptide (239-263). Deamidation was present at 4 months and increases with age. Liquid chromatography-MS/MS results indicated N246 undergoes deamidation more rapidly than N259. CONCLUSIONS: Results indicated AQP0 fatty acid acylation and deamidation occur during early development. Progressive age-related AQP0 processing, including deamidation and truncation, was mapped in human lenses as a function of age. The localization of these modified AQP0 forms suggests where AQP0 functions may change throughout lens development and aging. PMID- 26574800 TI - Lymphatic Markers in the Adult Human Choroid. AB - PURPOSE: Reports of lymphatics in the posterior human uvea are contradictory. We systematically analyzed the choroid by combining various lymphatic markers, following recently established guidelines for the immunohistochemical detection of ocular lymphatics. METHODS: Human choroids were prepared for flat mount serial cryosectioning. Sections were processed for immunohistochemistry of the lymphatic markers LYVE-1, PDPN, PROX1, FOXC2, VEGFR3, CCL21, and combined with alpha-smooth muscle-actin and 4',6-diamidino-2-phenylendole (DAPI). Single, double, and triple marker combinations were documented using confocal microscopy. Messenger RNA analysis for CCL21, FOXC2, LYVE-1, PDPN, PROX, and VEGFR3 was performed in choroid and skin. RESULTS: In the choroid, CCL21 immunoreactivity was detected in choroidal blood vessels, intrinsic choroidal neurons, and numerous small cells of the choroidal stroma. These small cells were not colocalized with PROX1 and PDPN, while a subpopulation of cells showed immunoreactivity for CCL21 and LYVE-1, and very occasionally PDPN-only+ cells were detected. Nuclei positive for PROX1 were never detected in the choroid, and vessel-like structures immunoreactive for LYVE 1, PDPN, or CCL21 (other than blood vessels) were never observed. Immunoreactivity of VEGFR3 was absent in the majority of choroidal blood vessels, but present in choriocapillaris, while other structures positive for VEGFR3 were not detected. Nonvascular smooth muscle cells were lacking VEGFR3 immunoreactivity. Messenger RNA analysis detected all lymphatic markers investigated and confirmed immunohistochemical results. CONCLUSIONS: By combining several lymphatic markers, single cells expressed these markers, but classical lymphatic vessels were not detected in the human choroid. Therefore, the healthy adult human choroid must be considered alymphatic, at least with the markers applied here. PMID- 26574801 TI - Adult Human Choroid: An Alymphatic Tissue? PMID- 26574802 TI - A Nonsense Mutation in FAM161A Is a Recurrent Founder Allele in Dutch and Belgian Individuals With Autosomal Recessive Retinitis Pigmentosa. AB - PURPOSE: To identify mutations in FAM161A underlying autosomal recessive retinitis pigmentosa (arRP) in the Dutch and Belgian populations and to investigate whether common FAM161A-associated phenotypic features could be identified. METHODS: Homozygosity mapping, amplification-refractory mutation system (ARMS) analysis, and Sanger sequencing were performed to identify mutations in FAM161A. Microsatellite and SNP markers were genotyped for haplotype analysis. Patients with biallelic mutations underwent detailed ophthalmologic examinations, including measuring best-corrected visual acuity, extensive fundus photography with reflectance and autofluorescence imaging, and optical coherence tomography. RESULTS: Homozygosity mapping in 230 Dutch individuals with suspected arRP yielded five individuals with a homozygous region harboring FAM161A. Sanger sequencing revealed a homozygous nonsense mutation (c.1309A>T; p.[Arg437*]) in one individual. Subsequent ARMS analysis and Sanger sequencing in Dutch and Belgian arRP patients resulted in the identification of seven additional individuals carrying the p.(Arg437*) mutation, either homozygously or compound heterozygously with another mutation. Haplotype analysis identified a shared haplotype block of 409 kb surrounding the p.(Arg437*) mutation in all patients, suggesting a founder effect. Although the age of onset was variable among patients, all eight developed pronounced outer retinal loss with severe visual field defects and a bull's eye-like maculopathy, followed by loss of central vision within 2 decades after the initial diagnosis in five subjects. CONCLUSIONS: A founder mutation in FAM161A p.(Arg437*) underlies approximately 2% of arRP cases in the Dutch and Belgian populations. The age of onset of the retinal dystrophy appears variable, but progression can be steep, with almost complete loss of central vision later in life. PMID- 26574803 TI - [The importance of adrenal vein sampling in primary aldosteronism. Necessary examination for many patients as computed tomography can lead to errors]. AB - Primary aldosteronism is the cause of hypertension in 5-10% of the hypertensive population. Almost half of all patients with primary aldosteronism have unilateral disease, i.e. the dominating aldosterone production derives from one of the adrenal glands, and the rest have bilateral disease. The treatment of choice for patients with unilateral disease is unilateral laparoscopic/retroperitoneoscopic adrenalectomy. One-third of patients with unilateral disease have normal adrenal glands on imaging studies or changes in both of the adrenal glands. Similarly, 30% of patients with bilateral excessive aldosterone production have radiological evidence of adenoma in only one of the adrenal glands. Adrenal vein sampling should be considered mandatory in patients with primary aldosteronism prior to surgical treatment. PMID- 26574804 TI - [Physical activity is just as good as CBT or drugs for depression]. AB - In this article on the effect of physical activity on depression, data have been drawn from several meta-analyses, in particular, the latest Cochrane review entitled "Exercise for depression" published in 2013. The results show that physical activity can help prevent the onset and relapse of depression. Depressed people should be recommended aerobic or muscular strength training. There is clear evidence that physical activity alone is beneficial for the treatment of mild and moderate depression and can reduce symptoms of mild to moderate depression to the same extent as standard treatments (psychotherapy and antidepressant medication). Combining physical activity with these treatments may yield additional benefits. Individuals with depression should be recommended physical activity in adjunct to psychotherapy and medication. PMID- 26574805 TI - [Physical activity--new paths and choices in the recommendations for adults]. AB - Recommendations for physical activity have been prepared by Professional Associations for Physical Activity and approved by the Swedish Society of Medicine in 2011. All adults are recommended regular aerobic and muscle strengthening physical activity. Lowest recommended dose (intensity x time) of aerobic physical activity is 150 minutes at moderate or 75 minutes at high intensity per week. More health benefits are achieved if the dose is higher than the lowest recommended dose. Longer periods of sedentary behavior should be avoided. Elderly are also recommended balance training. The benefits of physical activity outweigh the risks. The Swedish National Board of Health and Welfare recommends that the healthcare system offer counselling with the adjunct of exercise on prescription or a pedometer to persons with insufficient physical activity, i.e. less than the lowest recommended dose in the current recommendations for physical activity. PMID- 26574806 TI - [People with rheumatoid arthritis should be encouraged to engage in physical activity]. AB - Besides pharmacological treatment regular physical activity is one of the cornerstones of care in rheumatoid arthritis (RA). However, recent research has shown insufficient levels of physical activity in the RA population. This is of concern given the increased risk of cardiovascular disease. There is moderate quality evidence supporting that short-term land-based aerobic exercise on moderate to high intensity results in positive effects on oxygen uptake and pain, but not muscular strength; short-term water-based aerobic exercise on moderate to high intensity results in a positive effect on oxygen uptake; short-term land based aerobic and strengthening exercise on moderate to high intensity results in positive effects on oxygen uptake and muscular strength, but not pain, and long term land-based aerobic and strengthening exercise on moderate to high intensity results in positive effects on activity limitation, oxygen uptake and muscular strength. PMID- 26574807 TI - [Being in motion reduces the risk of disease and premature death]. AB - Regular physical activity affects most organs and tissues through a large number of mechanisms which in various ways contribute to improved function and health. Regular physical activity improves quality of life, cognitive functions, mood state and physical capacity, and lowers the risk of many diseases and premature death. Physical activity affects proteins and gene expression through signalling mechanisms, e.g. epigenetic changes. The biological response to physical activity can be markedly different between individuals, to a large degree due to genetic mechanisms. Regular aerobic physical activity (endurance training) improves cardiac function, partly due to an increased stroke volume, and lowers blood pressure due to e.g. improved vasodilation, lower arterial stiffness and increased capillarisation. Regular physical activity helps to maintain muscle mass and function and can improve brain health and function, e.g. executive and memory functions. PMID- 26574808 TI - [Assessing and evaluating physical activity during counseling in health care]. AB - To make individualized counseling possible, valid and reliable measures of physical activity are necessary. In health care, quality must be continuously secured and developed. Follow-up of life-style habits such as physical activity does not differ from monitoring of other treatment in the health care setting. After counseling and appropriate period of time, evaluation should be done to assess if there has been any change in the physical activity level. For assessment and evaluation of physical activity in routine clinical practice the National Board for Health and Social Welfare indicator questions regarding physical activity are recommended. For a more detailed assessment and evaluation of physical activity and sedentary behavior comprehensive validated instruments/diaries should be used. For precise and objective assessment and evaluation of both physical activity and sedentary behavior, movement sensors are recommended. PMID- 26574809 TI - [Aerobic physical activity lowers blood pressure in hypertension]. AB - Hypertension is one of the most important modifiable risk factors for cardiovascular morbidity and mortality. Physical inactivity plays a role in the development of (essential) hypertension. Increased physical activity may decrease the blood pressure in hypertensive individuals with 12/5 mm Hg (evidence grade +++ according to GRADE). A moderate/vigorous-intensity aerobic physical activity, at least 3 x 40-60 minutes/week, for 8 weeks, has the strongest evidence (evidence grade +++). Isometric (static) training may also decrease the blood pressure significantly (evidence grade ++). PMID- 26574810 TI - [Aerobic physical activity and dietary advice advocated in obesity and overweight]. AB - Physical activity is a key to health and plays an important role in achieving weight maintenance. The purpose of this literature review was to establish how much physical activity is needed for weight stability, to prevent weight regain in previously overweight individuals and for weight loss. The PubMed database was searched for studies of physical activity and overweight or obesity up to June 2015.To be weight stable, the scientific evidence indicates that walking at least 150 minutes/week or jogging 75 minutes/week is needed. To be weight stable after major weight loss the recommendation is at least 300 minutes/week, with the possibility to decrease the time with higher intensity. To lose weight, at least 300 minutes/week complemented with a change in diet is needed. Aerobic activity is recommended; many studies indicate that "more is better", while the magnitude of alteration in body fat by resistance training is less clear. PMID- 26574811 TI - [Training in chronic heart failure to improve the quality of life]. AB - Persons with chronic heart failure should be recommended aerobic and resistance exercise to be able to increase maximal oxygen uptake (VO2 max), walking distance, and health related quality of life (moderately strong scientific evidence - quality of evidence +++), and to reduce mortality and hospital admissions and increase muscle strength and endurance (low scientific evidence - quality of evidence ++). Prescription of exercise in chronic heart failure should always be preceded of assessments of aerobic and muscular fitness. The aerobic exercise could be conducted as continuous or interval exercise. In connection with ongoing exercise special attention is needed regarding heart rate, diverging blood pressure reactions, contingent occurrence of arrhythmias and the advent of symptoms such as dizziness and severe dyspnea. PMID- 26574813 TI - [Not Available]. PMID- 26574812 TI - [Physical activity is an important medicine]. PMID- 26574814 TI - [Sepsis--the unknown public disease of our time]. PMID- 26574815 TI - [Atrial fibrillation ablation in the clinic]. PMID- 26574816 TI - [Zip code can not determine the treatment for spinal cord injuries]. PMID- 26574817 TI - [Not Available]. PMID- 26574818 TI - [New ethics education proposed in all higher education]. PMID- 26574819 TI - [Not Available]. PMID- 26574820 TI - [Not Available]. PMID- 26574821 TI - Chronic widespread pain-the need for a standard definition. PMID- 26574822 TI - Role of extracellular calcitonin gene-related peptide in spinal cord mechanisms of cancer-induced bone pain. AB - Severe pain is a common and debilitating complication of metastatic bone cancer. Current analgesics provide insufficient pain relief and often lead to significant adverse effects. In models of cancer-induced bone pain, pathological sprouting of sensory fibers at the tumor-bone interface occurs concomitantly with reactive astrocytosis in the dorsal horn of the spinal cord. We observed that calcitonin gene-related peptide (CGRP)-fiber sprouting in the bone was associated with an increase in CGRP content in sensory neuron cell bodies in the dorsal root ganglia (DRG) and increased basal and activity-evoked release of CGRP from their central terminals in the dorsal horn. Intrathecal administration of a peptide antagonist (alpha-CGRP8-37) attenuated referred allodynia in the hind paw ipsilateral to bone cancer. CGRP receptor components (CLR and RAMP1) were up-regulated in dorsal horn neurons and expressed by reactive astrocytes. In primary cultures of astrocytes, CGRP incubation led to a concentration-dependent increase of forskolin-induced cAMP production, which was attenuated by pretreatment with CGRP8-37. Furthermore, CGRP induced ATP release in astrocytes, which was inhibited by CGRP8-37. We suggest that the peripheral increase in CGRP content observed in cancer-induced bone pain is mirrored by a central increase in the extracellular levels of CGRP. This increase in CGRP not only may facilitate glutamate-driven neuronal nociceptive signaling but also act on astrocytic CGRP receptors and lead to release of ATP. PMID- 26574824 TI - Cross-specialty training in the era of competency-based education. PMID- 26574823 TI - Postnatal maturation of the spinal-bulbo-spinal loop: brainstem control of spinal nociception is independent of sensory input in neonatal rats. AB - The rostroventral medial medulla (RVM) is part of a rapidly acting spino-bulbo spinal loop that is activated by ascending nociceptive inputs and drives descending feedback modulation of spinal nociception. In the adult rat, the RVM can facilitate or inhibit dorsal horn neuron inputs but in young animals descending facilitation dominates. It is not known whether this early life facilitation is part of a feedback loop. We hypothesized that the newborn RVM functions independently of sensory input, before the maturation of feedback control. We show here that noxious hind paw pinch evokes no fos activation in the RVM or the periaqueductal gray at postnatal day (P) 4 or P8, indicating a lack of nociceptive input at these ages. Significant fos activation was evident at P12, P21, and in adults. Furthermore, direct excitation of RVM neurons with microinjection of DL-homocysteic acid did not alter the net activity of dorsal horn neurons at P10, suggesting an absence of glutamatergic drive, whereas the same injections caused significant facilitation at P21. In contrast, silencing RVM neurons at P8 with microinjection of lidocaine inhibited dorsal horn neuron activity, indicating a tonic descending spinal facilitation from the RVM at this age. The results support the hypothesis that early life descending facilitation of spinal nociception is independent of sensory input. Since it is not altered by RVM glutamatergic receptor activation, it is likely generated by spontaneous brainstem activity. Only later in postnatal life can this descending activity be modulated by ascending nociceptive inputs in a functional spinal-bulbo-spinal loop. PMID- 26574826 TI - Why Canada needs networks to provide rural surgical care, including family doctors with essential surgical skills. AB - SUMMARY: Time is long overdue for action to improve rural surgical services in Canada. In this issue of CJS, a proposed curriculum for the provision of enhanced surgical skills (ESS) to rural family physicians offers an opportunity to fortify a seamless network of high-quality surgical care for rural Canada. It is supported and enhanced by the best available evidence and measured advice from specialists and generalists alike. Publication of this curriculum proposal provides for essential dialogue with general surgeons. We discuss why we must play an active role in the development, teaching and evaluation of ESS, or we will have minimal influence and limited grounds on which to criticize its outcome or celebrate the opportunity of success it promises. PMID- 26574827 TI - GPs with enhanced surgical skills: a questionable solution for remote surgical services. AB - SUMMARY: The Canadian College of Family Physicians recently decided to recognize family physicians with enhanced surgical skills (ESS) and has proposed a 1-year curriculum of surgical training. The purpose of this initiative is to bring or enhance surgical services to remote and underserviced areas. We feel that this proposed curriculum is overly ambitious and unrealistic and that it is unlikely to produce surgeons, or a system, capable of delivering high-quality surgical services. The convergence of a new training curriculum for general surgeons, coupled with the current oversupply of surgeons, provide an alternate pathway to meet the needs of these communities. A long-term solution will also require alternate funding models, a sophisticated and coordinated national locum service and a national review of the population and infrastructure requirements necessary for both sustainable resident surgical services and surgical outreach services. PMID- 26574828 TI - Randomized controlled trial to investigate the effect of metal clips on early migration during stent implantation for malignant esophageal stricture. AB - BACKGROUND: The rate of stent migration, especially in the short term after implantation, is high in the treatment process. We sought to explore an effective method for preventing early migration after stent implantation for malignant esophageal stricture and to provide the basis for clinical treatment. METHODS: We conducted a prospective, open-label, parallel-assignment randomized controlled trial with patients undergoing stent implantation for malignant esophageal stricture. The proximal segments of stents in the treatment group were fixed with 2 metal clips during the perioperative period of esophageal stent implantation, while no treatment was used in the control group. All patients underwent radiography at 3 and 7 days and 1 and 3 months after placement to assess the stent migration. RESULTS: There were 83 patients in our study. Demographic characteristics were similar between the groups. There was no stent migration observed in the treatment group within 2 weeks of the operation, while stent migration was observed in 6 of 41 (14.6%) cases in the control group, occurring at 3 and 7 days after placement. There were no perioperative complications. CONCLUSION: Perioperative fixation of the proximal segments of stents with metal clips is effective in preventing early stent migration. PMID- 26574829 TI - Effects of adding Braun jejunojejunostomy to standard Whipple procedure on reduction of afferent loop syndrome - a randomized clinical trial. AB - BACKGROUND: Whipple surgery (pancreaticodeudenectomy) has a high complication rate. We aimed to evaluate whether adding Braun jejunojejunostomy (side-to-side anastomosis of afferent and efferent loops distal to the gastrojejunostomy site) to a standard Whipple procedure would reduce postoperative complications. METHODS: We conducted a randomized clinical trial comparing patients who underwent standard Whipple surgery (standard group) and patients who underwent standard Whipple surgery with Braun jejunojejunostomy (Braun group). Patients were followed for 1 month after the procedure and postoperative complications were recorded. RESULTS: Our study included 30 patients: 15 in the Braun and 15 in the standard group. In the Braun group, 4 (26.7%) patients experienced 6 complications, whereas in the standard group, 7 (46.7%) patients experienced 11 complications (p = 0.14). Complications in the Braun group were gastrointestinal bleeding and wound infection (n = 1 each) and delayed gastric emptying and pulmonary infection (n = 2 each). Complications in the standard group were death, pancreatic anastomosis leak and biliary anastomosis leak (n = 1 each); gastrointestinal bleeding (n = 2); and afferent loop syndrome and delayed gastric emptying (n = 3 each). There was no significant difference between groups in the subtypes of complications. CONCLUSION: Our results showed that adding Braun jejunojejunostomy to standard Whipple procedure was associated with lower rates of afferent loop syndrome and delayed gastric emptying. However, more studies are needed to define the role of Braun jejunojejunostomy in this regard. TRIAL REGISTRATION: IRCT2014020316473N1 (www.irct.ir). PMID- 26574830 TI - Early clinical experience with the POEM procedure for achalasia. AB - BACKGROUND: Per oral endoscopic myotomy (POEM) is a viable alternative to standard Heller myotomy for surgical treatment of achalasia. Outcomes from the United States, Europe and Asia have been reported. We sought to report data after the initiation of POEM in a Canadian centre. METHODS: We enrolled patients with achalasia in a research ethics board-approved pilot study. Surgeons learned the POEM procedure in a systematic manner that included visiting experts in POEM, practice in an animal laboratory and mentoring from POEM experts. Preoperative evaluation included manometry, 24-hour pH, barium swallow, endoscopy and Eckhardt Symptom Score. All patients underwent gastrograffin swallow on postoperative day 1. Patients were re-evaluated using the Eckhardt score on postoperative day 14. RESULTS: Ten patients underwent POEM. Seven patients had previous endoscopic treatments: 6 had balloon dilatation and 1 had botulinum toxin injection. Mean preoperative Eckhardt score was 8.1 +/- 2.4. Mean preoperative lower esophageal sphincter resting and residual pressure was 32.3 +/- 9.2 and 20.8 +/- 5.3, respectively. Mean duration of surgery was 141.3 +/- 43.7 minutes. Mean length of hospital stay was 1 day. No major perioperative complications occurred. On postoperative day 14, the mean Eckhardt score was 1 +/- 1.2. CONCLUSION: Our approach to POEM introduction was systematic and deliberate. The procedure is safe, feasible and has good perioperative outcomes. Our early results are consistent with current literature. PMID- 26574831 TI - Early experience with robotic pancreatic surgery in a Canadian institution. AB - BACKGROUND: Pancreatic resections have traditionally been associated with substantial morbidity and mortality. The robotic platform is believed to improve technical aspects of the procedure while offering minimally invasive benefits. We sought to determine the safety and feasibility of the first robotic pancreaticoduodenectomies performed at our institution. METHODS: We retrospectively reviewed data on all patients who underwent robotic-assisted pancreaticoduodenectomy (RAPD) between July 2010 and June 2014 and compared them to outcomes of patients undergoing hybrid laparoscopic pancreaticoduodenectomies (HLAPD) during the same time period. RESULTS: Fifteen patients were scheduled for RAPD; 2 were converted to an open approach and 1 to a mini-laparotomy during the laparoscopic portion of the procedure. Patients who had RAPD (n = 12) had a median duration of surgery of 596.6 (range 509-799) minutes, estimated blood loss of 275 (range 50-1000) mL and median length of stay of 7.5 (range 5-57) days. Mean total opioid use up to postoperative day 7 was 142.599 +/- 68.2 versus 176.9 +/- 112.7 mg equivalents of intravenous morphine for RAPD and HLAPD, respectively. There was no significant difference between RAPD and HLAPD in any parameters, highlighting the safety and feasibility of a step-wise minimally invasive learning platform. Most patients in the RAPD group had malignant pathology (88.2%). Oncologic outcomes were maintained with no significant difference in ability to resect lymph nodes or achieve negative margins. There were 4 (28.5%) Clavien I-II complications and 3 (29.4%) Clavien III- IV complications, 2 of which required readmission. There were no reported deaths at 90 days. Complication, pancreatic leak and mortality rates did not differ significantly from our laparoscopic experience. CONCLUSION: Outcomes of RAPD and HLAPD were comparable at our centre, even during the early stages of our learning curve. These results also highlight the safety, feasibility and patient benefits of a step-wise transition from open to hybrid to fully robotic pancreaticoduodenectomies in a high-volume academic centre. PMID- 26574832 TI - Functional outcomes of acutely infected knee arthroplasty: a comparison of different surgical treatment options. AB - BACKGROUND: An infected total knee arthroplasty (TKA) can be treated with irrigation and debridement with polyethylene exchange (IDPE) or a 2-staged revision (2SR). Although research has examined infection eradication rates of both treatments, patient outcomes have not been reported. We examined patient reported outcomes following treatment compared with matched, noninfected controls. METHODS: We retrospectively identified patients with infected TKAs who had undergone the index procedure between May 1991 and November 2011. Patient reported outcomes included the 12-item Short Form Health Survey, Western Ontario and McMaster Universities Arthritis Index, and Knee Society Scores as well as range of motion. Patients with noninfected primary TKAs matched by age and age adjusted Charlson Comorbidity Index score were used as controls. Intention-to treat groups of 2SR and IDPE were used, with the IDPE group subdivided into successful and unsuccessful groups. RESULTS: We included 145 patients with infected TKAs with mean follow-up of 64.2 months and 145 controls with a mean follow-up of 35.4 months in our analysis. Outcomes of the controls and the successful IDPE groups were equivalent. The 2SR cohort had lower scores in all categories than controls. There was a 39% success rate in eradicating infection with IDPE. Patients in whom IDPE failed had lower scores in all categories than controls. There was no difference between the failed IDPE group and the 2SR group. CONCLUSION: Controversy regarding treatment options for acutely infected TKA has been focused on infection eradication. However, functional outcomes following treatment need to be taken into consideration. Patients whose infections were successfully treated with IDPE had equivalent outcomes to controls. PMID- 26574833 TI - Working toward benchmarks in orthopedic OR efficiency for joint replacement surgery in an academic centre. AB - BACKGROUND: The introduction of 4-joint operating rooms (ORs) to meet provincial wait time targets represented a major change in practice, providing an opportunity to optimize patient care within an OR time allotment of 8 hours. We reviewed our success rate completing 4 joint replacements within 8 hours and defined benchmarks for successful completion. METHODS: We reviewed the surgeries performed in the 4-joint ORs between May and October 2012. Using prospectively collected data from the Surgical Information Management System, each surgery time was divided into the following components: anesthesia preparation time (APT), surgical preparation time (SPT), procedure duration, anesthesia finishing time (AFT) and turnover time. We defined success as 4 joint replacements being completed within the allotted time. RESULTS: We reviewed 49 4-joint OR days for a total of 196 joint surgeries. Of the 49 days, 24 (49%) were successful. Only 2 surgeons had a success rate greater than 50%. Significant predictors of success were APT (odds ratio 1.09, 95% confidence interval [CI] 1.02-1.16), procedure duration (odds ratio 1.02, 95% CI 1.00-1.05) and AFT (odds ratio 1.19, 95% CI 1.06-1.34). We calculated probabilities for each component and derived benchmark times corresponding to the probability of 0.60. These benchmarks were APT of 9 min, SPT of 14 min, procedure duration of 68 min, AFT of 4 min and turnover of 15 min. CONCLUSION: We established benchmark times for the successful completion of 4 primary joint replacements within an 8-hour shift. Targeted interventions could maximize OR efficiency and enhance multidisciplinary care delivery. PMID- 26574834 TI - Is it safe to wait? The effect of surgical wait time on survival in patients with non-small cell lung cancer. AB - BACKGROUND: The effect of surgical wait times on survival in patients with non small cell lung cancer (NSCLC) remains largely unknown. Our objective was to determine the effect of surgical wait time on survival and incidence of upstaging in patients with stage I and II NSCLC. METHODS: All patients with clinical stage I and II NSCLC who underwent surgical resection in a single centre between January 2010 and December 2011 were reviewed. Analysis was stratified based on preoperative clinical stage. We assessed the effect of wait time on survival using a Cox proportional hazard model with wait time in months as a categorical variable. Incidence of upstaging at least 1 stage was assessed using logistic regression. RESULTS: We identified 222 patients: 180 were stage I and 42 were stage II. For stage I, wait times up to 4 months had no significant effect on survival or incidence of upstaging. For stage II, patients waiting between 2 and 3 months had significantly decreased survival (hazard ratio 3.6, p = 0.036) and increased incidence of upstaging (odds ratio 2.0, p = 0.020) than those waiting 0 to 1 month. For those waiting between 1 and 2 months, there was no significant difference in survival or upstaging. CONCLUSION: We did not identify an effect of wait time up to 4 months on survival or upstaging for patients with stage I NSCLC. For patients with stage II disease, wait times greater than 2 months adversely affected survival and upstaging. PMID- 26574835 TI - A proposal for the curriculum and evaluation for training rural family physicians in enhanced surgical skills. AB - SUMMARY: Rural western Canada relies heavily on family physicians with enhanced surgical skills (ESS) for surgical services. The recent decision by the College of Family Physicians of Canada (CFPC) to recognize ESS as a "community of practice" section offers a potential home akin to family practice anesthesia and emergency medicine. To our knowledge, however, a skill set for ESS in Canada has never been described formally. In this paper the Curriculum Committee of the National ESS Working Group proposes a generic curriculum for the training and evaluation of the ESS skill set. PMID- 26574836 TI - A comparison of outcomes between laparoscopic and open appendectomy in Canada. AB - SUMMARY: The benefit of a laparoscopic approach to appendectomy continues to be debated. We compared laparoscopic (LA) with open appendectomy (OA) for appendicitis in Canada using the Canadian Institute for Health Information database (2004-2008). The odds of female patients undergoing LA were 1.26 times higher than the odds of male patients, and the odds of patients with nonperforated pathology undergoing LA were 1.38 times higher than the odds of those with perforated pathology. Increasing comorbidities were associated with OA. While LA is becoming more frequent, the associated length of stay, postoperative complication rate and mortality are clearly lower than for OA. As a result, we support the continued increase in use of LA with regard to both safety and outcomes. PMID- 26574837 TI - Interpretation of surgical neuromonitoring data in Canada: our view. PMID- 26574838 TI - Interpretation of surgical neuromonitoring data in Canada: author response. PMID- 26574839 TI - Endoscopy training in Canada in general surgery residency programs: ways forward. PMID- 26574840 TI - Current use of live tissue training in trauma: a descriptive systematic review. PMID- 26574841 TI - Current use of live tissue training in trauma: a descriptive systematic review - author response. PMID- 26574842 TI - Patient views on financial relationships between surgeons and surgical device manufacturers. PMID- 26574843 TI - Patient views on financial relationships between surgeons and surgical device manufacturers: author response. PMID- 26574844 TI - Angioimmunoblastic T-cell Lymphomas With the RHOA p.Gly17Val Mutation Have Classic Clinical and Pathologic Features. AB - Angioimmunoblastic T-cell lymphoma (AITL) is a nodal-based mature T-cell lymphoma with distinctive clinical symptomatology and histology. Research into its pathogenesis supports a cellular derivation from follicular helper T cells and overexpression of genes related to B cells, follicular dendritic cells, and vascular growth. Recently, a novel recurring somatic mutation in RHOA, encoding p.Gly17Val, was discovered in nearly 70% of AITLs and in a smaller proportion of peripheral T-cell lymphomas, not otherwise specified (PTCL-NOS). We investigated a series of AITLs to compare RHOA mutated with wild-type case for clinicopathologic differences. Targeted exome and Sanger sequencing was performed on 27 AITLs and 10 PTCL-NOS. The RHOA G17V mutation was identified in 63% of the AITL cases and in none of the PTCL-NOS cases. The median variant allelic frequency was 14%, with a range of 0.4 to 50% in positive cases. RHOA G17V mutated cases had a significantly higher incidence of splenomegaly and B symptoms at diagnosis, but there was no difference in overall survival between mutated and wild-type subgroups. Cases with the RHOA G17V mutation had a significantly higher mean microvessel density (P<0.01) and expressed a greater number of follicular helper T-cell markers (P<0.05) than wild-type cases. RHOA G17V is present in a significant proportion of angioimmunoblastic lymphomas and is associated with classic pathologic features of AITL. Additional studies are needed to provide a biological or functional link between altered RHOA function and these pathologic features. PMID- 26574845 TI - Invasion Patterns of Metastatic Extrauterine High-grade Serous Carcinoma With BRCA Germline Mutation and Correlation With Clinical Outcomes. AB - Characteristic histopathologic features have been described in high-grade serous carcinoma associated with BRCA abnormalities (HGSC-BRCA), which are known to have relatively favorable clinical outcomes. The aim of this study was to evaluate the clinical significance of invasion patterns in metastatic HGSC-BRCA cases. Of the 37 cases of advanced-stage HGSC with known BRCA1 or BRCA2 germline mutation retrieved from our institutional files, 23 patients had a germline mutation of BRCA1 and 14 had a BRCA2 mutation. The pattern of invasion at metastatic sites was recorded and classified as a pushing pattern (either predominantly or exclusively), an exclusively micropapillary infiltrative pattern, or an infiltrative pattern composed of papillae, micropapillae, glands, and nests (mixed infiltrative pattern). Histologic evaluation of metastases was performed without knowledge of genotype or clinical outcome. Clinical data were abstracted from medical records. Median age was 56 years (range, 31 to 73 y). All patients presented at stage IIIC or IV and underwent complete surgical staging followed by chemotherapy. All 37 HGSC-BRCA cases showed either pushing pattern metastases (30; 81%) or infiltrative micropapillary metastases (7; 19%). No HGSC-BRCA case exhibited metastases composed solely of mixed infiltrative patterns. Among the 7 infiltrative micropapillary cases, 6 had a BRCA1 germline mutation versus 1 with a BRCA2 mutation. The median time of follow-up was 26 months (range, 13 to 49 mo). All 7 patients with infiltrative micropapillary metastases either experienced recurrence or died of disease (5 recurrences and 2 deaths), which was significantly worse than what was seen in patients with predominantly pushing pattern metastases, of whom 16 of 30 (53%) experienced recurrence (n=14) or died of disease (n=2) (P=0.03). In conclusion, the recognition of different invasion patterns of metastatic extrauterine HGSC-BRCA has prognostic implications. The infiltrative micropapillary pattern is associated with poor outcomes and is more frequently seen in BRCA1-associated HGSC than in BRCA2 cases. PMID- 26574846 TI - Atypical Renal Cysts: A Morphologic, Immunohistochemical, and Molecular Study. AB - There is a lack of standardized nomenclature for renal cysts lined by multiple cell layers or with short papillary projections but without nests of epithelial cells within the stroma. We retrieved 29 cases (15 nephrectomies, 14 partial nephrectomies) from the surgical pathology files of Johns Hopkins Hospital from 1993 to 2014 and performed immunohistochemistry for CK7, alpha-methylacyl-CoA racemase (AMACR), CAIX, and CD10 and fluorescence in situ hybridization for trisomy 7 and 17 and 3p deletion. The mean age at excision was 58 years (range, 29 to 80 y) with 16 men and 13 women. Mean size was 2.9 cm (range, 0.3 to 10 cm). The cysts were grouped by their morphology into (1) clear cell, (2) eosinophilic stratified, and (3) eosinophilic papillary. By immunohistochemistry, 7/9 (78%) of the clear cell cases were diffusely positive for both CK7 and CAIX resembling the pattern seen in clear cell papillary renal cell carcinoma. The majority of eosinophilic stratified (4/6; 67%) and eosinophilic papillary (12/14; 86%) cases were positive for CK7 and had variable staining for AMACR, CD10, or CAIX, suggesting a differentiation more aligned with papillary renal cell carcinoma. The most common molecular alterations detected were trisomy 17 (n=6) and trisomy 7 (n=4). One case showed deletion of chromosome 3p. Clinical follow-up information was available in 23 patients; 20 were alive with no evidence of disease after a median follow-up of 20 months (range, 3 to 120 mo), 1 patient was dead due to metastatic lung cancer, 1 of sepsis, and 1 of unknown reason. Atypical renal cysts present as complex radiologic lesions, as secondary lesions in patients with a renal mass, or in a background of chronic renal disease. These atypical cysts appear heterogenous, and some follow in their morphology and immunoprofile with well-established renal tumors. The presence of 3p deletion and trisomy 7/17 suggests that in some cases they may be precursors of renal cell carcinoma. Longer follow-up with more cases is needed, but on the basis of our data, these lesions should not be diagnosed as carcinoma. PMID- 26574847 TI - CD30 Expression by B and T Cells: A Frequent Finding in Angioimmunoblastic T-Cell Lymphoma and Peripheral T-Cell Lymphoma-Not Otherwise Specified. AB - CD30 expression in peripheral T-cell lymphoma (PTCL) and angioimmunoblastic T cell lymphoma (AITL) is currently of great interest because therapy targeting CD30 is of clinical benefit, but the clinical and therapeutic relevance of CD30 expression in these neoplasms still remains uncertain. The aim of this study was to better quantify CD30 expression in AITL and PTCL-not otherwise specified (NOS). The secondary objective was to determine whether CD30 cells exhibit a B cell or a T-cell phenotype. Gene expression profiling was studied in a series of 37 PTCL cases demonstrating a continuous spectrum of TNFRSF8 expression. This prompted us to study CD30 immunohistochemical (IHC) expression and mRNA levels by reverse transcription polymerase chain reaction (RT-PCR) in a different series of 51 cases (43 AITLs and 8 PTCL-NOSs) in routine samples. Double stainings with PAX5/CD30, CD3/CD30, and LEF1/CD30 were performed to study the phenotype of CD30 cells. Most (90%) of the cases showed some level of CD30 expression by IHC (1% to 95%); these levels were high (>50% of tumoral cells) in 14% of cases. CD30 expression was not detected in 10% of the cases. Quantitative RT-PCR results largely confirmed these findings, demonstrating a moderately strong correlation between global CD30 IHC and mRNA levels (r=0.65, P=1.75e-7). Forty-four of the positive cases (98%) contained CD30-positive B cells (PAX5), whereas atypical CD30-positive T cells were detected in 42 cases (93%). In conclusion, our data show that most AITL and PTCL-NOS cases express CD30, exhibiting very variable levels of CD30 expression that may be measured by IHC or RT-PCR techniques. PMID- 26574848 TI - Fumarate Hydratase-deficient Uterine Leiomyomas Occur in Both the Syndromic and Sporadic Settings. AB - Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome secondary to germline fumarate hydratase (FH) mutation presents with cutaneous and uterine leiomyomas, and a distinctive aggressive renal carcinoma. Identification of HLRCC patients presenting first with uterine leiomyomas may allow early intervention for renal carcinoma. We reviewed the morphology and immunohistochemical (IHC) findings in patients with uterine leiomyomas and confirmed or presumed HLRCC. IHC was also performed on a tissue microarray of unselected uterine leiomyomas and leiomyosarcomas. FH-deficient leiomyomas underwent Sanger and massively parallel sequencing on formalin-fixed paraffin-embedded tissue. All 5 patients with HLRCC had at least 1 FH-deficient leiomyoma: defined as completely negative FH staining with positive internal controls. One percent (12/1152) of unselected uterine leiomyomas but 0 of 88 leiomyosarcomas were FH deficient. FH-deficient leiomyoma patients were younger (42.7 vs. 48.8 y, P=0.024) and commonly demonstrated a distinctive hemangiopericytomatous vasculature. Other features reported to be associated with FH-deficient leiomyomas (hypercellularity, nuclear atypia, inclusion-like nucleoli, stromal edema) were inconstantly present. Somatic FH mutations were identified in 6 of 10 informative unselected FH-deficient leiomyomas. None of these mutations were found in the germline. We conclude that, while the great majority of patients with HLRCC will have FH-deficient leiomyomas, 1% of all uterine leiomyomas are FH deficient usually due to somatic inactivation. Although IHC screening for FH may have a role in confirming patients at high risk for hereditary disease before genetic testing, prospective identification of FH-deficient leiomyomas is of limited clinical benefit in screening unselected patients because of the relatively high incidence of somatic mutations. PMID- 26574849 TI - Relationship between preoperative cone beam computed tomography and intraoperative findings in sinus augmentation. AB - PURPOSE: To investigate whether the presence of bony septum, thickness of sinus membrane (schneiderian membrane), and residual alveolar bone height affects membrane perforation and the duration of sinus augmentation. MATERIALS AND METHODS: Preoperative cone beam computed tomography (CBCT) images obtained from patients undergoing lateral sinus augmentation were evaluated for the presence of bony septum, thickness of sinus membrane, and residual alveolar bone height. During the operation, membrane perforation and duration of surgery were noted. The Student t test was used to compare descriptive statistics (mean, standard error) and quantitative variables between groups. The Fisher exact chi(2) test was used to compare the qualitative data, and Pearson correlation test was used to evaluate the correlation between data. P < .05 was considered significant. RESULTS: Data from 57 patients were evaluated. Membrane perforation occurred in 14 patients included in the study and in 8 patients with sinus septum. A significant relationship was found between the presence of septum and membrane perforation during sinus augmentation (P = .014). However, the relationship among other CBCT and intraoperative findings was not significant. CONCLUSION: Presence of septum in the maxillary sinus increases the risk of membrane perforation, but does not extend the duration of the sinus augmentation. PMID- 26574850 TI - Torque loss of different abutment sizes before and after cyclic loading. AB - PURPOSE: The aim of this study was to compare 3.8- and 4.8-mm abutments submitted to simulations of masticatory cycles to examine whether abutment diameter and cemented vs screw-retained crowns affect torque loss of the abutments and crowns. MATERIALS AND METHODS: Forty implant/abutment sets were divided into the following groups (n = 10 in each group): (1) G4.8S included 4.8-mm abutment with screw-retained crown; (2) G4.8C included 4.8-mm abutment with cemented crown; (3) G3.8S included 3.8-mm abutment with screw-retained crown; and (4) G3.8C included 3.8-mm abutment with cemented crown. All abutments were tightened with torque values of 20 Ncm, and 10 Ncm for screw-retained crowns. Torque loss was measured before and after cycling loading (300,000 cycles). RESULTS: Torque loss of screw retained crowns significantly increased after cycling in abutments of groups G3.8S (P <= .05) and G4.8S (P = .001). No difference was noted between the abutments before cycling (P = .735), but G3.8S abutments presented greater torque loss than the other groups after cycling (P = .008). Significant differences were noted in the abutment torque loss before and after cycling loading only for the G3.8C group (P <= .05). CONCLUSION: The abutment diameter affects torque loss of screw-retained crowns and leads to failure during the test; mechanical cycling increases torque loss of abutment screw and screw-retained crowns. PMID- 26574851 TI - Piezoelectric surgery vs rotary instruments for lateral maxillary sinus floor elevation: a systematic review and meta-analysis of intra- and postoperative complications. AB - PURPOSE: Lateral maxillary sinus floor elevation (LMSFE) is a predictable preprosthetic surgical procedure that is used to overcome the limitations of the atrophied alveolar ridge for the placement of oral implants. Techniques using piezoelectric devices (PEDs) and conventional rotary instruments have been described for LMSFE in the literature, with little information regarding their efficiency in terms of membrane perforation, operating time, and implant outcomes. The aim of this systematic review was to examine the intra- and postoperative events associated with the use of PEDs and conventional rotary instruments for LMSFE. MATERIALS AND METHODS: This systematic review was prepared according to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The literature was searched for studies comparing the use of PEDs with conventional rotary instruments for LMSFE. The Cochrane Collaboration risk of bias tool was used to assess the studies selected, and meta-analyses were performed using statistical software. RESULTS: A total of 124 citations were identified. Of these, four studies with 178 LMSFEs in 120 participants were included. The pooled estimates for the risk of sinus membrane perforation did not show any significant difference between the two surgical techniques (risk ratio, 0.87; 95% confidence interval, 0.40-1.91; P = .73). Similarly, no significant difference in implant failure was found after 1 year of functional loading. The overall meta-analysis showed a statistically significant difference in the operating time between the two techniques with more time required for PED. CONCLUSION: The intra- and postoperative events associated with the use of PEDs and conventional rotary instruments for LMSFE are comparable. PMID- 26574852 TI - Stiffness, strength, and failure modes of implant-supported monolithic lithium disilicate crowns: influence of titanium and zirconia abutments. AB - PURPOSE: The objective of this study was to evaluate stiffness, strength, and failure modes of monolithic crowns produced using computer-aided design/computer assisted manufacture, which are connected to diverse titanium and zirconia abutments on an implant system with tapered, internal connections. MATERIALS AND METHODS: Twenty monolithic lithium disilicate (LS2) crowns were constructed and loaded on bone level-type implants in a universal testing machine under quasistatic conditions according to DIN ISO 14801. Comparative analysis included a 2 * 2 format: prefabricated titanium abutments using proprietary bonding bases (group A) vs nonproprietary bonding bases (group B), and customized zirconia abutments using proprietary Straumann CARES (group C) vs nonproprietary Astra Atlantis (group D) material. Stiffness and strength were assessed and calculated statistically with the Wilcoxon rank sum test. Cross-sections of each tested group were inspected microscopically. RESULTS: Loaded LS2 crowns, implants, and abutment screws in all tested specimens (groups A, B, C, and D) did not show any visible fractures. For an analysis of titanium abutments (groups A and B), stiffness and strength showed equally high stability. In contrast, proprietary and nonproprietary customized zirconia abutments exhibited statistically significant differences with a mean strength of 366 N (Astra) and 541 N (CARES) (P < .05); as well as a mean stiffness of 884 N/mm (Astra) and 1,751 N/mm (CARES) (P < .05), respectively. Microscopic cross-sections revealed cracks in all zirconia abutments (groups C and D) below the implant shoulder. CONCLUSION: Depending on the abutment design, prefabricated titanium abutment and proprietary customized zirconia implant-abutment connections in conjunction with monolithic LS2 crowns had the best results in this laboratory investigation. PMID- 26574853 TI - In vivo comparative investigation of three synthetic graft materials with varying compositions processed using different methods. AB - PURPOSE: The aim of this study was to compare the osteoconductive potential and bone-healing pattern of biphasic calcium phosphates (BCPs) with varying compositions produced using different processing methods. MATERIALS AND METHODS: Ten male New Zealand white rabbits were used. Four circular defects with a diameter of 8 mm were made in the rabbit calvarium. Each defect was assigned to one of the following BCP groups: control; BCP1, 70% hydroxyapatite (HA)/30% beta tricalcium phosphate (beta-TCP); BCP2, 30% HA/70% beta-TCP; and BCP3, 20% HA/80% beta-TCP. The rabbits were killed either 2 (n = 5) or 8 weeks (n = 5) before surgery. Histologic and histomorphometric analyses were conducted. RESULTS: The total amount of augmentation was significantly greater in the BCP groups than in the control group (P < .05). The amount of new bone formation did not differ significantly among the groups at either 2 or 8 weeks. The resorption of BCPs was significantly greater in the BCP3 group than in the BCP1 and BCP2 groups at 2 weeks, but the difference became insignificant compared with the BCP2 group at 8 weeks. The patterns of new bone formation and material resorption varied markedly among the BCP groups. New bone lined the residual particles in the BCP1 group, but filopodia-shaped new bone was observed in the BCP2 group, and collagen fragments were scattered inside the residual particles in the BCP3 group. Multiple cracklike lines were observed on the particles in the BCP3 group. CONCLUSION: The specific HA-beta-TCP ratios in the present study did not significantly influence new bone formation and space maintenance. The observed differences in healing patterns between the groups may be attributable to different physicochemical properties conferred upon the BCPs by the different processing methods used to produce them. PMID- 26574854 TI - Accuracy of linear measurements using cone beam computed tomography and panoramic radiography in dental implant treatment planning. AB - PURPOSE: The aim of this study was to investigate the accuracy of linear measurements from cone beam computed tomography (CBCT) images and digital panoramic radiographs at various implant sites. MATERIALS AND METHODS: Fifty implant sites from six skulls were marked with gutta-percha and subjected to CBCT with five different voxel protocols: 0.125 mm, 0.160 mm, and 0.250 mm with the 3D Accuitomo 170 CBCT machine and 0.200 mm and 0.300 mm with the CS 9500 CBCT machine. Images were also taken with the CS 9000 panoramic machine with three protocols: normal head, chin-up, and chin-down positions. Electronic linear measurement of bone height using the corresponding machine's software was recorded by two observers. Physical measurement using a digital caliper with +/- 0.02-mm accuracy was directly recorded at the corresponding regions as the gold standard. All image measurements were compared with the physical measurements. The paired sample correlations for physical measurement, mean difference, standard deviation, absolute error, absolute percentage error, and inter- and intraobserver reliability were calculated. RESULTS: Intraobserver and interobserver reliability was more than 0.99. Paired sample correlation between all image measurements and physical measurements was considered statistically significant at P < .05. All image measurements were underestimated by less than 2 mm, except for the chin-down position of the maxilla in the panoramic radiograph. The absolute error and absolute percentage error in the mandible were less than those in the maxilla, and values obtained with CBCT were less than those from panoramic radiographs. CONCLUSION: CBCT images using the 3D Accuitomo 170 and CS 9500 machines and digital panoramic radiographs via a picture archiving and communication system are sufficiently accurate for vertical linear measurements in dental implant treatment planning. PMID- 26574855 TI - Evaluation of host beta-globin gene fragment lengths in peri-implant crevicular fluid during the wound healing process: a pilot study. AB - PURPOSE: To evaluate the host beta-globin gene fragment lengths in the cell-free peri-implant crevicular fluid (PICF) during the wound healing process. MATERIALS AND METHODS: Nineteen patients (25 implants) were recruited into this study. As part of the control group, gingival crevicular fluids (GCF) from healthy teeth were collected before implant placement. PICF specimens from each implant were collected during weeks 2 to 12 after implant placement. All GCF and PICF specimens were centrifuged to collect the supernatant as cell-free DNA. Five primer pairs specific to the beta-globin gene for amplifying 110-base pair (bp), 325-bp, 408-bp, 536-bp, and 2-kilo-base pair (kb) amplicons were used to evaluate DNA fragment lengths with conventional polymerase chain reaction (PCR). The longest PCR amplicon of each specimen was recorded. RESULTS: The number of 536-bp amplicons (10 of 25 implant specimens) and 2-kb amplicons (8 of 25 implant specimens) in week 2 was higher than at the other visits. In the study, the mucositis group showed the highest number of 536-bp amplicons (22 of 34 implant specimens) and 2-kb amplicons (12 of 34 implant specimens), whereas the healthy implant group showed a low number of 536-bp amplicons (3 of 66 implant specimens), and the cell-free PICF specimens had no 2-kb amplicons. Furthermore, 325-bp and 110-bp amplicons were similar in number in the control teeth and healthy implants. CONCLUSION: There was a difference in the number of the longest amplicons of cell-free PICF specimens between the mucositis and healthy implant groups. This pilot study suggests that the PCR amplicon lengths of beta-globin gene fragments in cell-free PICF specimens might be used as a biomarker to monitor soft tissue inflammation around implants. PMID- 26574856 TI - Influence of implant-retained silicone oculo-palpebral prosthesis on stress distribution: a pilot study using a photoelastic model. AB - PURPOSE: The purpose of this pilot study was to evaluate the behavior of stresses surrounding orbital model implants subjected to a load of a silicone oculo palpebral prosthesis. MATERIALS AND METHODS: A photoelastic model was constructed mimicking the orbital cavity of an adult patient who underwent left orbital resection. Two 3.75 * 5-mm extraoral implants with 3.75 * 5.25-mm magnetic connectors were placed in the model to anchor a silicone oculo-palpebral prosthesis. The stress generated by prosthesis retention was evaluated using photoelasticity at 15, 30, and 60 minutes. The polariscope images were analyzed qualitatively at five areas surrounding the implants. These same areas were analyzed quantitatively using Matlab software based on the RGB color pattern. Data were compared with the Wilcoxon test. RESULTS: Using fringe localization, the qualitative analysis demonstrated that the area between the implants had the greatest stress. The quantitative analysis showed that the peri-implant stress increased significantly in proportion to the increase in prosthesis retention time. CONCLUSION: The oculo-palpebral prosthesis generated stress around the implants, and the stress intensity was directly proportional to the duration of use. PMID- 26574857 TI - Coating dental implant abutment screws with diamondlike carbon doped with diamond nanoparticles: the effect on maintaining torque after mechanical cycling. AB - PURPOSE: To determine the effect of maintaining torque after mechanical cycling of abutment screws that are coated with diamondlike carbon and coated with diamondlike carbon doped with diamond nanoparticles, with external and internal hex connections. MATERIALS AND METHODS: Sixty implants were divided into six groups according to the type of connection (external or internal hex) and the type of abutment screw (uncoated, coated with diamondlike carbon, and coated with diamondlike carbon doped with diamond nanoparticles). The implants were inserted into polyurethane resin and crowns of nickel chrome were cemented on the implants. The crowns had a hole for access to the screw. The initial torque and the torque after mechanical cycling were measured. The torque values maintained (in percentages) were evaluated. Statistical analysis was performed using one-way analysis of variance and the Tukey test, with a significance level of 5%. RESULTS: The largest torque value was maintained in uncoated screws with external hex connections, a finding that was statistically significant (P = .0001). No statistically significant differences were seen between the groups with and without coating in maintaining torque for screws with internal hex connections (P = .5476). CONCLUSION: After mechanical cycling, the diamondlike carbon with and without diamond doping on the abutment screws showed no improvement in maintaining torque in external and internal hex connections. PMID- 26574858 TI - Modal damping factor detected with an impulse-forced vibration method provides additional information on osseointegration during dental implant healing. AB - PURPOSE: To evaluate whether resonance frequency (RF) analysis combined with modal damping factor (MDF) analysis provides additional information on dental implant healing status. MATERIALS AND METHODS: In in vitro tests, epoxy resin was used to simulate the implant healing process. The RF and MDF values of the implants were measured during the entire polymerization process. Implant stability quotient (ISQ) and Periotest values (PTVs) from Ostell and Periotest devices were used to validate the apparatus. In in vivo experiments, vibrational analysis was performed on 17 dental implants in 12 patients. The RF and MDF values of the tested implants were recorded during the first 10 weeks after surgery. The effects of jaw types and primary stability on MDF healing curves were analyzed. RESULTS: In the in vitro model, the RF values obtained from the apparatus used in this study were similar to those obtained from the Osstell device. Unlike the Periotest healing curve, the MDF curve showed a 1.8-fold increase during the early phase. In clinical experiments, the mean RF values were unchanged during the first 2 weeks and increased continuously until 6 weeks. The corresponding mean MDF value decreased over time and reached 0.045 +/- 0.011 at 10 weeks, which is approximately 50% lower than the initial value. Although the RF values of the implants with higher initial frequency remained unchanged during the healing period, the MDF values decreased significantly. CONCLUSION: Analysis of RF combined with MDF provides additional information on dental implant healing status. MDF analysis can detect changes in the implant/bone complex during the healing period even in implants with higher RF values. PMID- 26574859 TI - A long-term retrospective analysis of survival rates of implants in the mandible. AB - PURPOSE: To retrospectively analyze the survival rate of endosseous dental implants placed in the edentulous or partially edentulous mandible over a long term follow-up period of 10 years or more. MATERIALS AND METHODS: The charts of patients who underwent mandibular implant placement at a private prosthodontics practice and received follow-up care for 10 years or more were included in this study. Implants were examined according to the following study variables: patient sex, patient age, degree of edentulism (fully vs partially edentulous), implant location, time of loading (delayed vs immediate), implant size and type, bone quality, prosthesis type, and the presence of other implants during placement. RESULTS: The study sample was composed of 2,394 implants placed in 470 patients with 10 to 27 years of follow-up. Of these 2,394 implants, 176 failed, resulting in an overall cumulative survival rate (CSR) of 92.6%. A total of 1,482 implants were placed in edentulous mandibles, and 912 implants were placed in partially edentulous mandibles, with CSRs of 92.6% and 92.7%, respectively. Comparisons of the study variables with respect to CSR were largely nonsignificant. However, there were significant differences in CSRs between anterior vs posterior locations and rough- vs smooth-surfaced implants in addition to some prosthesis types, ages, and bone qualities. The overall CSR of 92.6% in the present study is high and comparable to survival rates observed in previous long-term analyses of mandibular implants. The significant differences observed between implant locations, patient age groups, bone qualities, and prostheses were not suggestive of any remarkable trends. CONCLUSION: Patient sex, age, degree of edentulism, implant location, time of loading, implant size and type, bone quality, prosthesis type, and the presence of multiple implants did not result in any significant effect on long-term implant survival. The CSR observed after 10 to 27 years of follow-up in a single private prosthodontic center was high (92.6%) and supports the use of endosseous dental implants as a long-term treatment option for the rehabilitation of the edentulous and partially edentulous mandible. PMID- 26574860 TI - Minimizing excess cement in implant-supported fixed restorations using an extraoral replica technique: a prospective 1-year study. AB - PURPOSE: Cementation of implant-supported restorations poses two major challenges: (1) minimizing excess cement (reducing the risk of peri-implantitis), and (2) establishing sufficient retention (reducing the risk of decementation). This study presents the first data on a clinical cementation technique that might address both problems. MATERIALS AND METHODS: Between 2011 and 2013, 39 patients were provided with 52 implants supporting 52 single crowns (SCs). All restorations were cemented extraorally using replicas made of pattern resin and zinc oxide cement. All decementation events and the peri-implant soft tissue status were assessed and compared with those from a group of 29 patients with 40 conventionally cemented SCs (control). RESULTS: In the experimental group, after 12 months, decementation was recorded in three individuals (7.69%) with 3 SCs (5.77%). In the control group, after 12 months, no case of decementation was recorded. No cases of peri-implantitis were detected in either group. CONCLUSION: Within the limitations of this study, the authors conclude that the use of zinc oxide cement initially establishes sufficient retention of implant-supported fixed restorations independent of conventional or replica cementation techniques. PMID- 26574861 TI - Levels of bacterial contamination in fresh extraction sites after a saline rinse. AB - PURPOSE: To determine the level of bacterial contamination in immediate implantation or augmentation sites vs pristine bone, before and after saline rinses. MATERIALS AND METHODS: Bacterial samples were taken from fresh extraction sites (17 patients) and pristine bone (15 patients) before performing implant dentistry surgical procedures. Levels of bacterial contamination were estimated before and after saline rinses. Samples from the socket were placed on an agar plate for total bacterial account and on selective plates for Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis counts. RESULTS: The level of bacterial contamination before saline rinse was 1.2 * 10(4) units of bacterial colony (CFU)/mL in fresh extraction sites (study group) and 5 * 10(2) CFU/mL in pristine bone sites (control group). After a saline rinse, the bacterial level was lowered significantly to 5.2 * 10(3) CFU/mL in the study group and to zero in the control group (P < .05). Levels of bacterial contamination were higher in the mandibular sockets (7.5 * 10(3) CFU/ml) than in the maxillary sockets (5.6 * 10(3) CFU/mL), and the difference was statistically significant (P = .034). All implanted/augmented fresh or pristine sites survived in the follow-up period. CONCLUSION: Fresh extraction sockets with clinical signs of infection show bacterial presence. Pristine bone shows a lower bacterial level. Saline rinse in addition to a decontamination protocol may reduce the level of bacterial contamination significantly both in fresh extraction sites and pristine bone. PMID- 26574862 TI - Implant-supported mandibular overdentures can minimize mandibular bone resorption in edentulous patients: results of a long-term radiologic evaluation. AB - PURPOSE: It has been suggested that functional loading and light irritative stimuli could lead to changes in bone architecture, shape, and volume, and that by placing implants in the edentulous mandible and subsequently loading them, functional conditions could be created to limit bone resorption or even stimulate bone apposition (the latter was reported only for fixed implant-supported prosthetic reconstructions) in the distal area of the mandibular osseous crest. The aim of this study was to radiographically assess the bone height changes in the posterior area of the mandible after implant placement and loading with an overdenture on two or four implants over a mean follow-up period of 10.5 years. MATERIALS AND METHODS: Panoramic radiographs were taken of 82 totally edentulous patients before implant placement and at repeated follow-up intervals spread over a mean observation time of 10.5 years. All patients received an implant-supported overdenture as prosthetic treatment. The mandibular bone height in the distal part of the mandible was measured on each of the available radiographs and the initial, intermediate, and final values were compared. RESULTS: A mean mandibular bone height reduction of 0.5 mm was measured. CONCLUSION: No clinically relevant difference was found between the posterior mandible height before implant placement and at follow-up after functional loading with an implant-supported mandibular overdenture. PMID- 26574863 TI - Axial displacement of external and internal implant-abutment connection evaluated by linear mixed model analysis. AB - PURPOSE: To analyze the axial displacement of external and internal implant abutment connection after cyclic loading. MATERIALS AND METHODS: Three groups of external abutments (Ext group), an internal tapered one-piece-type abutment (Int 1 group), and an internal tapered two-piece-type abutment (Int-2 group) were prepared. Cyclic loading was applied to implant-abutment assemblies at 150 N with a frequency of 3 Hz. The amount of axial displacement, the Periotest values (PTVs), and the removal torque values(RTVs) were measured. Both a repeated measures analysis of variance and pattern analysis based on the linear mixed model were used for statistical analysis. Scanning electron microscopy (SEM) was used to evaluate the surface of the implant-abutment connection. RESULTS: The mean axial displacements after 1,000,000 cycles were 0.6 MUm in the Ext group, 3.7 MUm in the Int-1 group, and 9.0 MUm in the Int-2 group. Pattern analysis revealed a breakpoint at 171 cycles. The Ext group showed no declining pattern, and the Int-1 group showed no declining pattern after the breakpoint (171 cycles). However, the Int-2 group experienced continuous axial displacement. After cyclic loading, the PTV decreased in the Int-2 group, and the RTV decreased in all groups. SEM imaging revealed surface wear in all groups. CONCLUSION: Axial displacement and surface wear occurred in all groups. The PTVs remained stable, but the RTVs decreased after cyclic loading. Based on linear mixed model analysis, the Ext and Int-1 groups' axial displacements plateaued after little cyclic loading. The Int-2 group's rate of axial displacement slowed after 100,000 cycles. PMID- 26574864 TI - The reverse zygomatic implant: a new implant for maxillofacial reconstruction. AB - This case report describes the rehabilitation of a patient who had been treated with a hemimaxillectomy, reconstruction with a latissimus dorsi vascularized free flap, and radiotherapy for carcinoma of the sinus some years previously. Limited jaw opening, difficult access through the flap to the bony site, and the very small amount of bone available in which to anchor the implant inspired the development and use of a new "reverse zygomatic" implant. For this treatment, site preparation and implant insertion were accomplished using an extraoral approach. The implant was used along with two other conventional zygomatic implants to provide support for a milled titanium bar and overdenture to rehabilitate the maxilla. Two years later, the patient continues to enjoy a healthy reconstruction. The reverse zygomatic implant appears to show promise as a useful addition to the implant armamentarium for the treatment of the patient undergoing maxillectomy. PMID- 26574865 TI - A computer-guided bone block harvesting procedure: a proof-of-principle case report and technical notes. AB - During autogenous mandibular bone harvesting, there is a risk of damage to anatomical structures, as the surgeon has no three-dimensional control of the osteotomy planes. The aim of this proof-of-principle case report is to describe a procedure for harvesting a mandibular bone block that applies a computer-guided surgery concept. A partially dentate patient who presented with two vertical defects (one in the maxilla and one in the mandible) was selected for an autogenous mandibular bone block graft. The bone block was planned using a computer-aided design process, with ideal bone osteotomy planes defined beforehand to prevent damage to anatomical structures (nerves, dental roots, etc) and to generate a surgical guide, which defined the working directions in three dimensions for the bone-cutting instrument. Bone block dimensions were planned so that both defects could be repaired. The projected bone block was 37.5 mm in length, 10 mm in height, and 5.7 mm in thickness, and it was grafted in two vertical bone augmentations: an 8 * 21-mm mandibular defect and a 6.5 * 18-mm defect in the maxilla. Supraimposition of the preoperative and postoperative computed tomographic images revealed a procedure accuracy of 0.25 mm. This computer-guided bone harvesting technique enables clinicians to obtain sufficient autogenous bone to manage multiple defects safely. PMID- 26574866 TI - Adipose mesenchymal stem cells associated with xenograft in a guided bone regeneration model: a histomorphometric study in rabbit calvaria. AB - PURPOSE: In spite of their osteoconductive potential, the biomaterials used as substitutes for an autologous graft do not show osteoinductive or osteogenic potential. This study evaluated the association of adult mesenchymal stem cells derived from adipose tissue with xenogenic bone graft in bone regeneration in rabbit calvaria. MATERIALS AND METHODS: Mesenchymal stem cells were harvested from adipose tissue from 12 animals. These cells, combined with hydroxyapatite, were implanted in 12-mm bilateral bone defects created in the calvaria of six rabbits (test group [TG]), whereas only hydroxyapatite was implanted in the defects created in another group of six animals (control group [CG]). One grafted side of each animal was covered by a collagen membrane. After 8 weeks, the animals were sacrificed, and the region of the bone defects was removed and evaluated using histomorphometry and immunohistochemistry. RESULTS: The TG showed higher amounts (P < .05) of vital mineralized tissue and nonvital mineralized tissue, 28.24% +/- 6.17% and 27.79% +/- 2.72%, respectively, compared with the CG, 13.06% +/- 5.24% and 13.52% +/- 3.00%, respectively. In TG, no difference was observed (P < .05) in the amount of mineralized tissue between the side that was covered by the membrane vs the side without membrane coverage. On the other hand, a statistically significant difference (P < .05) was observed in the CG with regard to the amount of mineralized tissue between the sides with and without membrane coverage. CONCLUSION: These observations suggest that the association of mesenchymal stem cells derived from adipose tissue with a xenogenic bone graft was capable of promoting better bone regeneration compared with the use of a xenograft alone. Use of a membrane did not produce an increase in the regenerative potential for the TG, in contrast to the CG. PMID- 26574867 TI - Global challenges in acute diarrhea. AB - PURPOSE OF REVIEW: Childhood diarrhea is the most common cause of morbidity and mortality, especially in the low and middle-income countries. The burden of child mortality because of diarrhea has declined, but still a lot is desired not only to reduce diarrhea-specific mortality but reduce the overall incidence, and hence the morbidity associated with childhood diarrhea. RECENT FINDINGS: A recent Lancet series on diarrhea suggests that amplification of the current interventions can eliminate virtually all preventable diarrhea deaths. A refocused attention and strategy and collective effort from the multilateral entities to promote water sanitation and hygiene, rotavirus vaccination, nutrition, and improved case management can bridge gaps and tackle the existing undue burden of deaths because of diarrhea. SUMMARY: Investment toward preventing and controlling childhood diarrhea should be a priority, especially when the existing solution is plausible for implementation at scale and in underprivileged settings. PMID- 26574868 TI - The diminutive colon polyp: biopsy, snare, leave alone? AB - PURPOSE OF REVIEW: Diminutive polyps, measuring between 1 and 5 mm, represent the vast majority of colorectal polyps encountered during screening colonoscopy. Although the chance of harboring advanced adenoma or neoplastic cells is low, ensuring a complete polyp resection with clear margins is crucial to reduce the risk of interval colorectal cancer. The purpose of this review was to evaluate the different methods applied for polypectomy of diminutive polyps and clarify whether a diminutive polyp should be retrieved or left in place. RECENT FINDINGS: Cold biopsy polypectomy is indicated for resection of polyps measuring 1-3 mm and removal of 4-5 mm polyps should be ensured by cold snare polypectomy. Over the last decade, hot biopsy polypectomy has been gradually abandoned because of an increased risk of diathermic injury. The resect and discard strategy and the diagnose and disregard strategy should be performed only by expert endoscopists, who should use validated scales and document the polyp features by storing several endoscopic images. SUMMARY: Nowadays, complete resection of diminutive polyps, following the most appropriate technique, is recommended in clinical practice. The resect and discard strategy and the diagnose and disregard strategy should be reserved to expert endoscopists. PMID- 26574869 TI - Cancer surveillance in ulcerative colitis and Crohn's disease: new strategies. AB - PURPOSE OF REVIEW: Inflammatory bowel disease (IBD) patients have a higher incidence of colon cancer than the general population. Colon cancer surveillance has traditionally involved taking numerous random biopsies to provide sufficient yield to detect dysplasia. Recently, consensus guidelines have been published which promote the use of chromoendoscopy for IBD colon cancer surveillance. This presents a new set of opportunities and challenges in the evaluation and management of dysplasia in IBD. RECENT FINDINGS: Dysplasia, previously thought to be 'invisible' to the endoscopist, is now considered to be 'visible' in the majority of cases with the advent of the use of high-definition endoscopy and chromoendoscopy. This changes how we manage dysplastic lesions, providing the patient options for endoscopic resection rather than promoting total proctocolectomy. SUMMARY: Implemention of chromoendoscopy may require additional training for endoscopists unfamiliar with the technique. However, if this proves to be cost-effective and provides a higher sensitivity in dysplasia detection, then widespread education and implementation will be well worth the efforts. To do so, future studies will need to prove its benefits in preventing or reducing colon cancer morbidity and mortality in this high-risk patient population. PMID- 26574870 TI - Colonic and anorectal motility testing in the high-resolution era. AB - PURPOSE OF REVIEW: The past few years have seen an increase in the number of research and clinical groups around the world using high-resolution manometry (HRM) to record contractile activity in the anorectum and colon. Yet despite the uptake and growing number of publications, the clinical utility and potential advantages over traditional manometry remain undetermined. RECENT FINDINGS: Nearly all of the publications in the field of anorectal and colonic HRM have been published within the last 3 years. These studies have included some data on normal ranges in healthy adults, and abnormalities in patient groups with constipation or fecal incontinence, anal fissure, perineal descent, rectal cancer, and Hirschsprung's disease. Most of the studies have been conducted on adults, with only three published studies in pediatric populations. Very few studies have attempted to show advantages of HRM over traditional manometry SUMMARY: High-resolution anorectal and colonic manometry provide a more comprehensive characterization of motility patterns and coordinated activity; this may help to improve our understanding of the normal physiology and pathophysiology in these regions. To date, however, no published study has conclusively demonstrated a clinical, diagnostic, or interventional advantage over conventional manometry. PMID- 26574871 TI - Environmental enteropathy. AB - PURPOSE OF REVIEW: Environmental enteropathy has long been recognized as an important intermediary condition leading to chronic malnutrition in children in developing countries. Interest has lately renewed in this topic because of increased focus on improving the quality of lives as opposed to just saving them. Here, we provide an overview of recent scientific literature and our perspective about this disorder. RECENT FINDINGS: Current understanding of the disorder of environmental enteropathy is based on studies conducted decades ago. Results of some new studies on histopathologic characterization of environmental enteropathy are currently awaited. Given the challenges of diagnosing environmental enteropathy using the gold standard test of intestinal biopsy, different biomarkers have been tested as proxies of environmental enteropathy and eventually, chronic malnutrition. Available data fail to point toward a single ideal biomarker, though considerable work is still ongoing. A few interventional studies have also been conducted with improvement in environmental enteropathy as outcome. SUMMARY: The basic histopathology of environmental enteropathy has been defined previously, and more advanced analysis to study the pathophysiology of this disorder is currently being carried out. Many biomarkers, which represent the different mechanisms involved in environmental enteropathy, have been tested as proxies of environmental enteropathy. Although no single biomarker fits the description of an ideal biomarker yet, a few of the more promising biomarkers are being validated in different studies. Finally, the few interventions which have been tried to treat environmental enteropathy, thus far, are summarized. PMID- 26574872 TI - Ultrasound and Clinical Measures for Lymphedema. AB - BACKGROUND: Treatment for breast cancer has increased patient survivorship exponentially over the past few decades. With increased survivorship, more women are living with the longstanding effects of breast cancer treatment, such as lymphedema. Patients, health care providers, and payers depend on practical and efficient clinical measures to accurately diagnose and monitor disease progression or regression. However, current clinical measures do not include objective measures that assess lymphedetamous tissue accurately. This study compared current measures to a novel use of ultrasound (US) imaging to quantify tissue texture. METHODS AND RESULTS: Seventeen women diagnosed with lymphedema completed self-report questionnaires and then were tested twice by two lymphedema physical therapists who measured edema, fibrosis, and limb volume differences. One therapist measured subjects' limbs using US imaging and derived measures of entropy and average pixel intensity. Volume measures were consistent between therapists (p < 0.01) but palpation was not (0.01 < p < 0.72). Therapists' measures correlated better to subjects' self-report of edema (0.01 < p > 0.32) as compared to fibrosis (0.23 < p > 0.90). US measures were reliable (Cronbachs's alpha = 0.7 and 0.91 for entropy and API, respectively). Entropy measures demonstrated significant differences between subjects' involved versus uninvolved forearms (p = 0.03). CONCLUSIONS: Therapists were not consistent with each other when rating edema or fibrosis; however, they were consistent when measuring limb volume differences. US measures (entropy) demonstrated a significant difference between involved and uninvolved. US imaging, as a tool to quantify subcutaneous tissues, holds promise to be a safe, mobile, and effective method to measure lymphedema tissue texture. PMID- 26574873 TI - Enhanced Mechanical Properties of Graphene (Reduced Graphene Oxide)/Aluminum Composites with a Bioinspired Nanolaminated Structure. AB - Bulk graphene (reduced graphene oxide)-reinforced Al matrix composites with a bioinspired nanolaminated microstructure were fabricated via a composite powder assembly approach. Compared with the unreinforced Al matrix, these composites were shown to possess significantly improved stiffness and tensile strength, and a similar or even slightly higher total elongation. These observations were interpreted by the facilitated load transfer between graphene and the Al matrix, and the extrinsic toughening effect as a result of the nanolaminated microstructure. PMID- 26574874 TI - Association between single nucleotide polymorphisms of the G-protein gamma5 subunit and the risk of essential hypertension in the population of Poland. AB - INTRODUCTION: Polymorphisms in genes coding G-protein subunits (alpha, beta, and gamma) may affect the response of stimulated alpha2A-adrenergic receptors, which are involved in the regulation of blood pressure. OBJECTIVES The aim of the present study was to determine the association between the rs11559300 (A/G), rs199705300 (C/A), rs61754630 (C/T), rs13093 (C/A), and rs41284589 (C/T) single nucleotide polymorphisms (SNPs) of the gene coding G-protein gamma5 subunit (GNG5) and the risk of essential hypertension in the population of Poland. PATIENTS AND METHODS: A total number of 838 subjects were included in the study: 536 patients with diagnosed essential hypertension and 302 controls. Genotyping was performed using the polymerase chain reaction-restriction length polymorphism (PCR-RFLP) method. RESULTS: Of the studied GNG5 polymorphisms, only SNP rs13093 was significantly associated with an increased risk of essential hypertension (odds ratio [OR], 2.91; 95% confidence interval [CI], 1.68-5.05; P = 0.0036). In addition, the T allele of rs41284589 may protect against hypertriglyceridemia (OR, 0.32; 95% CI, 0.1-0.9). CONCLUSIONS: rs13093 in the promoter region of GNG5 may be associated with an increased risk of essential hypertension in the Polish population. Further studies are needed to explain the molecular mechanism by which rs13093 affects blood pressure. PMID- 26574875 TI - Robotic urinary diversion: the range of options. AB - PURPOSE OF REVIEW: To review current status and controversies on robotic intracorporeal urinary diversion (RICUD). We discuss the current status of urinary diversion, including complications and current types of RICUD, the available options for RICUD going forward for robotic radical cystectomy (RRC) patients, and the current critiques of RICUD. RECENT FINDINGS: Although the majority of centers conclude RRC with an extracorporeal urinary diversion (ECUD), the number of total RICUD being performed worldwide is increasing. Although limited, ICUD may provide comparable, if not superior, outcomes to ECUD, though at the moment this technique has been performed mostly by highly experienced and skilled robotic surgeons who have performed a high volume of ICUDs. Several ICUD options are available, and improvements and increased experience with this technique can lead to comparable outcomes; however, this is yet to be validated. SUMMARY: At the current moment ECUD is still the norm following RRC. However, ICUD is gaining steam and becoming more commonly used. Several urinary diversion options can be accomplished intracorporeally including continent and noncontinent orthotopic and nonorthotopic urinary diversions. Further experience with these techniques by additional centers is required. PMID- 26574876 TI - Detrusor underactivity in men with lower urinary tract symptoms/benign prostatic obstruction: characterization and potential impact on indications for surgical treatment of the prostate. AB - PURPOSE OF REVIEW: Detrusor underactivity is a highly prevalent type of voiding dysfunction in men and responsible for residual urine and decreased voiding efficiency. Patients with detrusor underactivity have an unfavorable outcome after prostatic surgery and do not have better long-term results than untreated detrusor underactivity patients. Therefore, differentiation between detrusor underactivity and bladder outlet obstruction (BOO) is crucial for the prediction of the outcome of prostatic surgery. RECENT FINDINGS: Patients with detrusor underactivity report more frequently about decreased/interrupted urinary flow, hesitancy, feeling of incomplete bladder emptying and/or decreased bladder sensation compared with men with normal pressure-flow studies. Determination of and differentiation between detrusor underactivity and BOO is only possible by pressure-flow studies. Threshold values for the diagnosis of detrusor underactivity have to be adjusted to the BOO-grade. A nomogram using BOO-index and maximum Watts factor is currently the most advanced tool to diagnose detrusor underactivity and/or BOO; values below the 25th percentile line indicate detrusor underactivity. It is desirable to establish tests to noninvasively diagnose detrusor underactivity. The combination of ultrasound detrusor wall thickness and bladder capacity can safely detect detrusor underactivity. SUMMARY: Careful assessment of voiding dysfunction to discriminate between detrusor underactivity and BOO should be done with pressure-flow studies, can avoid unsuccessful prostate surgery and helps in counselling patients. PMID- 26574877 TI - Is benign prostatic obstruction surgery indicated for improving overactive bladder symptoms in men with lower urinary tract symptoms? AB - PURPOSE OF REVIEW: Lower urinary tract symptoms (LUTS) in men are highly prevalent, and include both storage and voiding symptoms in many cases. The effect of benign prostatic obstruction (BPO) relief on storage symptoms remains unclear. RECENT FINDINGS: The present review summarizes data about the relation between overactive bladder (OAB), voiding symptoms, and urodynamic characteristics in men with LUTS. Pathomechanisms of OAB in a context of BPO are reviewed. Rates of persistent bladder dysfunction after BPO relief are described along with predictive factors of persisting OAB. SUMMARY: OAB is a common clinical feature in a population of male LUTS, often concomitant with voiding symptoms. Although detrusor overactivity is found in some patients with OAB and BPO, there is no absolute correspondence between clinical symptoms and urodynamic findings. In the context of BPO, OAB pathophysiology implicates nitric oxide pathway, bladder ischemia, ageing of the urinary tract, and calcium-activated potassium channels activity. BPO relief can be followed in the medium term by persistence of OAB symptoms, and preoperative detrusor overactivity has been identified as the main predictive factor. However, preoperative urodynamics remain only indicated in specific cases, when it could directly influence clinical decision-making. Antimuscarinics may be the treatment of choice for persistent symptoms after surgery, but there is no firm recommendation in this clinical setting. PMID- 26574878 TI - Current advances in male lower urinary tract symptoms assessment and management: more and more questions. PMID- 26574880 TI - Isolation of prolyl endopeptidase inhibitory peptides from a sodium caseinate hydrolysate. AB - Prolyl endopeptidase (PEP) has been associated with neurodegenerative disorders, and the PEP inhibitors can restore the memory loss caused by amnesic compounds. In this study, we investigated the PEP inhibitory activity of the enzymatic hydrolysates from various food protein sources, and isolated and identified the PEP inhibitory peptides. The hydrolysate obtained from sodium caseinate using bromelain (SC/BML) displayed the highest inhibitory activity of 86.8% at 5 mg mL( 1) in the present study, and its IC50 value against PEP was 0.77 mg mL(-1). The F 5 fraction by RP-HPLC (reversed-phase high performance liquid chromatography) from SC/BML showed the highest PEP inhibition rate of 88.4%, and 9 peptide sequences were identified. The synthetic peptides (1245.63-1787.94 Da) showed dose-dependent inhibition effects on PEP as competitive inhibitors with IC50 values between 29.8 and 650.5 MUM. The results suggest that the peptides derived from sodium caseinate have the potential to be PEP inhibitors. PMID- 26574881 TI - Preparation of carbon dots by non-focusing pulsed laser irradiation in toluene. AB - A simple approach for preparing carbon dots (CDs) by non-focusing pulsed laser irradiation in toluene was presented. The as-prepared CDs were graphite dots, which were formed by ablating the intermediate graphene. The size of the as prepared CDs could be easily controlled by the input of laser fluence. The mechanism of the photoluminescence was also discussed. PMID- 26574882 TI - Determination of rate constants for trifluoromethyl radical addition to various alkenes via a practical method. AB - A simple and practical method for the determination of rate constants for trifluoromethyl radical addition to various alkenes by applying competition kinetics is introduced. In the kinetic experiments the trifluoromethyl radicals are generated in situ from a commercially available hypervalent-iodine-CF3 reagent (Togni-reagent) by SET-reduction with TEMPONa in the presence of TEMPO and a pi-acceptor. From the relative ratio of TEMPOCF3 and CF3-addition product formed, which is readily determined by (19)F-NMR spectroscopy, rate constants for trifluoromethyl radical addition to the pi-acceptor can be calculated. The practical method is also applicable to measure rate constants for the addition of other perfluoroalkyl radicals to alkenes as documented for CF3CF2-radical addition reactions. PMID- 26574883 TI - Compact micro/nano electrohydrodynamic patterning: using a thin conductive film and a patterned template. AB - The influence of electrostatic heterogeneity on the electric-field-induced destabilization of thin ionic liquid (IL) films is investigated to control spatial ordering and to reduce the lateral dimension of structures forming on the films. Commonly used perfect dielectric (PD) films are replaced with ionic conductive films to reduce the lateral length scales to a sub-micron level in the EHD pattering process. The 3-D spatiotemporal evolution of a thin IL film interface under homogenous and heterogeneous electric fields is numerically simulated. Finite differences in the spatial directions using an adaptive time step ODE solver are used to solve the 2-D nonlinear thin film equation. The validity of our simulation technique is determined from close agreement between the simulation results of a PD film and the experimental results in the literature. Replacing the flat electrode with the patterned one is found to result in more compact and well-ordered structures particularly when an electrode with square block protrusions is used. This is attributed to better control of the characteristic spatial lengths by applying a heterogeneous electric field by patterned electrodes. The structure size in PD films is reduced by a factor of 4 when they are replaced with IL films, which results in nano-sized features with well-ordered patterns over the domain. PMID- 26574884 TI - How can carbon favor planar multi-coordination in boron-based clusters? Global structures of CB(x)E(y)(2-) (E = Al, Ga, x + y = 4). AB - With the high preference in forming multi-center bonding, boron has been a miracle ligand in constructing diverse planar multi-coordinate (pM) (tetra/hyper) species. Unfortunately, the boron ligand usually dislikes encompassing a pM carbon (pMC) due to the high competition with pM boron (pMB), which makes the realization of boron-based pMC very difficult and quite challenging. Herein, we propose a strategy that by means of cooperative doping and charge-compensation, we can successfully improve and tune the stability of pMC relative to pMB for CB4(2-). In the free CBxEy(2-) (E = Al/Ga) species, ptC is thermodynamically less stable than the global ptB in mono- and di-substituted systems, in agreement with the results of Boldyrev and Wang. However, the thermodynamic preference of pMC increases along with the Al/Ga-doping. The pMC species can be further stabilized by the introduction of the alkaline-earth counterion (Mg(2+)). CB2E2Mg (E = Al, Ga) designed in the present study represents the first successful design of a boron-based planar penta-coordinate carbon (ppC) structures as the global minima. The strategy proposed in this study should be useful in the manipulation of competition between exotic pMC and pMB in B-based systems. PMID- 26574885 TI - Synthesis of the first metal-free phosphanylphosphonate and its use in the "phospha-Wittig-Horner" reaction. AB - The synthesis of the first phophanylphosphonate, Mes*PH-PO(OEt)2 (2-H), in which the P(III) centre is not coordinated by a M(CO)5 (M = W, Mo, Cr) fragment is reported. The title compound reacts with LDA under the formation of 2-Li which is best described as the enolate form with a high double bond character between the two phosphorus centres. 2-Li is shown to engage in the phospha-Wittig-Horner reaction and converts aldehydes into phosphaalkenes that are metal-free and thus available for future manipulations at the phophorus lone pair. Using a selection of aldehydes with aliphatic, aromatic or vinylic substituents as substrates, phosphaalkene formation proceeds in high yields and high E-selectivity. The selectivity is however compromised during purification on standard silica which was found to promote E/Z isomerization. PMID- 26574886 TI - Soft particles at a fluid interface. AB - Particles added to a fluid interface can be used as a surface stabilizer in the food, oil and cosmetic industries. As an alternative to rigid particles, it is promising to consider highly deformable particles that can adapt their conformation at the interface. In this study we compute the shapes of soft elastic particles using molecular dynamics simulations of a cross-linked polymer gel, complemented by continuum calculations based on linear elasticity. It is shown that the particle shape is not only affected by the Young's modulus of the particle, but also strongly depends on whether the gel is partially or completely wetting the fluid interface. We find that the molecular simulations for the partially wetting case are very accurately described by the continuum theory. By contrast, when the gel is completely wetting the fluid interface the linear theory breaks down and we reveal that molecular details have a strong influence on the equilibrium shape. PMID- 26574887 TI - [Impact of Spinal Fractures in Horseback Riding]. AB - BACKGROUND: Injuries to the spinal cord are not only dreaded because of the high risks existing during the acute phase, but also because of their potential long term sequelae. Horseback riding also poses a high risk of spinal injuries. We therefore evaluated the most frequent characteristics of accidents leading to long-term sequelae, the primary long-term discomfort resulting from such injuries caused by horseback riding accidents and the way injured persons changed their behaviour after the accidents. PATIENTS: Our study included all cases of horseback riding injuries registered in the Department of Trauma, Hand, Plastic and Restorative Surgery at the University Hospital of Ulm between May 2005 and October 2012. Sequelae of the accidents were examined via follow-up interviews by phone. These included questions about protective gear worn during the accident as well as behavioural changes after the injury. In addition, a spine-specific questionnaire based on the Visual Analogue Scale (VAS) was used to assess long term complications. RESULTS: Overall, we recorded 50 cases of spinal injuries caused by horseback riding accidents over a time span of 7 years and 5 months. 41 (82 %) of the patients were female and 9 (18 %) were male. The average patient age was 32.0 +/- 15.2 years. All in all, the 50 patients sustained 84 injuries: 59 fractures and 25 other injuries such as distorsions or discoligamentous injuries. Most injuries were located in the lumbar spine (n = 43), corresponding to 51 % of all recorded injuries, followed by 32 % in the thoracic spine (n = 27) and 17 % in the cervical spine (n = 14). After sustaining a fracture to the spine, 9 out of 24 patients quit horseback riding. All patients used a helmet after the accident, but only 7 out of 15 used back protection. 11 out of 24 patients suffer from back pain while resting with a mean VAS score of 3.4 +/- 1.9. More than half (17 out of 24) have back pain while working with a VAS score of 4.8 +/- 2.2. CONCLUSION: The frequency and severity of back injuries sustained by horseback riders increases with age. This can be due to various reasons such as biomechanical factors. The low acceptance of back protection is remarkable. PMID- 26574888 TI - Predominance of large joint active synovitis in Asian patients with established rheumatoid arthritis. PMID- 26574889 TI - Co-transplantation of autologous OM-MSCs and OM-OECs: a novel approach for spinal cord injury. AB - Spinal cord injury (SCI) is a disastrous injury that leads to motor and sensory dysfunctions in patients. In recent years, co-transplantation has become an increasingly used therapeutic treatment for patients with SCI. Both mesenchymal stem cells (MSCs) and olfactory-ensheathing cells (OECs) have been adopted to ameliorate SCI, with promising outcomes. Remarkable effects on the rehabilitation of patients with SCI have been achieved using MSCs. Olfactory mucosa (OM) MSCs from human OM are one of the most ideal cell resources for auto-transplantation in clinical application owing to their a high proliferation rate and multipotent capability. In addition, OECs derived from OM have been used to improve functional recovery of SCI and resulted in promising functional recovery in years. Accordingly, co-transplantation of OM-MSCs coupled with OM-OECs has been adopted to improve the recovery of SCI. Here we reviewed the reported applications of OM-MSCs and OM-OECs for SCI treatment and proposed that a novel combined strategy using both autologous OM-MSCs and OM-OECs would achieve a better approach for the treatment of SCI. PMID- 26574890 TI - Angiotensin II-triggered kinase signaling cascade in the central nervous system. AB - Recent studies have projected the renin-angiotensin system as a central component of the physiological and pathological processes of assorted neurological disorders. Its primary effector hormone, angiotensin II (Ang II), not only mediates the physiological effects of vasoconstriction and blood pressure regulation in cardiovascular disease but is also implicated in a much wider range of neuronal activities and diseases, including Alzheimer's disease, neuronal injury, and cognitive disorders. Ang II produces different actions by acting on its two subtypes of receptors (AT1 and AT2); however, the well-known physiological actions of Ang II are mainly mediated through AT1 receptors. Moreover, recent studies also suggest the important functional role of AT2 receptor in the brain. Ang II acts on AT1 receptors and conducts its functions via MAP kinases (ERK1/2, JNK, and p38MAPK), glycogen synthase kinase, Rho/ROCK kinase, receptor tyrosine kinases (PDGF and EGFR), and nonreceptor tyrosine kinases (Src, Pyk2, and JAK/STAT). AT1R-mediated NADPH oxidase activation also leads to the generation of reactive oxygen species, widely implicated in neuroinflammation. These signaling cascades lead to glutamate excitotoxicity, apoptosis, cerebral infarction, astrocyte proliferation, nociception, neuroinflammation, and progression of other neurological disorders. The present review focuses on the Ang II-triggered signal transduction pathways in central nervous system. PMID- 26574891 TI - A fast and simple method for detecting and quantifying donor-derived cell-free DNA in sera of solid organ transplant recipients as a biomarker for graft function. AB - BACKGROUND: Timely detection of graft rejection is an important issue in the follow-up care after solid organ transplantation. Until now, biopsy has been considered the "gold standard" in the diagnosis of graft rejection. However, non invasive tests such as monitoring the levels of cell-free DNA (cfDNA) as a sensitive biomarker for graft integrity have attracted increasing interest. The rationale of this approach is that a rejected organ will lead to a significant release of donor-derived cfDNA, which can be detected in the serum of the transplant recipient. METHODS: We have developed a novel quantitative real-time PCR (qPCR) approach for detecting an increase of donor-derived cfDNA in the recipient's serum. Common insertion/deletion (InDel) genetic polymorphisms, which differ between donor and recipient, are targeted in our qPCR assay. In contrast to some other strategies, no specific donor/recipient constellations such as certain gender combinations or human leukocyte antigen (HLA) discrepancies are required for the application of our test. RESULTS: The method was first validated with serial dilutions of serum mixtures obtained from healthy blood donors and then used to determine donor-derived cfDNA levels in patients' sera within the first 3 days after their kidney transplantation had been performed. CONCLUSIONS: Our method represents a universally applicable, simple and cost-effective tool which can potentially be used to detect graft dysfunction in transplant recipients. PMID- 26574892 TI - Platelet volume is associated with the Framingham risk score for cardiovascular disease in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). AB - BACKGROUND: Platelet volume indices (PVI), an easy and inexpensive surrogate measure of platelet function, have been associated with cardiovascular diseases (CVD) and their risk factors. However, results are conflicting because of the lack of standardized procedures. The purpose of this study is to investigate the relationship of PVI with the Framingham risk score (FRS). METHODS: Baseline data (2008-2010) of 3115 participants enrolled in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) were used. PVI measurements were strictly controlled. The cohort was distributed according to risk factors and the general FRS was estimated. Multiple linear regression analysis was used to estimate the association between PVI and FRS. RESULTS: Mean platelet volume (MPV), platelet distribution width (PDW) and platelet large cell ratio (P-LCR) independently correlated (p<=0.01) with FRS after adjustment for confounding variables. One unit increase in MPV, PDW, or P-LCR increased the FRS by 0.59%, 0.40%, and 0.08%, respectively. Diabetics had higher (p<=0.004) MPV, PDW, and P-LCR, and hypertensive individuals had higher (p<=0.045) PDW and P-LCR. CONCLUSIONS: Increased PVI was independently correlated with higher CVD risk based on the FRS, diabetes, and systolic hypertension. Prospective follow up of this cohort is warranted to confirm that PVI is associated with the development of CVD. PMID- 26574893 TI - Screening immunofixation should replace protein electrophoresis as the initial investigation of monoclonal gammopathy: Point. AB - The reliable detection of paraprotein in serum and urine is the primary purpose of electrophoretic procedures in clinical laboratories. Screening immunofixation electrophoresis (sIFE) employs a single application of antisera directed against heavy and light chains that facilitates the detection of paraproteins that migrate in the non-gamma region or that are below the detection limit of protein electrophoresis. These paraproteins that are missed by routine electrophoresis occur in up to 27.3% of newly investigated and 13.6% of monitored patients. Small paraproteins missed by conventional electrophoretic techniques are clinically important in the diagnosis and monitoring of malignant plasma and B-cell disorders. The superior diagnostic performance of sIFE makes it suitable as the initial laboratory procedure to investigate paraproteins in complex serum and urine matrices. PMID- 26574894 TI - Adipokines in human reproduction. AB - Adipose tissue communicates with other central and peripheral organs by the synthesis and release of substances called adipokines. The most studied adipokine is leptin but others have been recently identified including resistin, adiponectin, chemerin, omentin and visfatin. These adipokines have a critical role in the development of obesity-related complications and inflammatory conditions. However, they are also involved in other functions in the organism including reproductive functions. Indeed, many groups have demonstrated that adipokine receptors, such as adiponectin and chemerin, but also adipokines themselves (adiponectin, chemerin, resistin, visfatin and omentin) are expressed in human peripheral reproductive tissues and that these adipokines are likely to exert direct effects on these tissues. After a brief description of these new adipokines, an overview of their actions in different human reproductive organs (hypothalamus, pituitary, ovary, testis, uterus and placenta) will be presented. Finally, comments will be made on the eventual alterations of these adipokines in reproductive disorders, with special attention to polycystic ovary syndrome, a disease characterized by dysfunction of gonadal axis and systemic nerve endocrine metabolic network with a prevalence of up to 10% in women of reproductive age. PMID- 26574895 TI - Prokineticins in central and peripheral control of human reproduction. AB - Prokineticin 1 (PROK1) and (PROK2), are two closely related proteins that were identified as the mammalian homologs of their two amphibian homologs, mamba intestinal toxin (MIT-1) and Bv8. PROKs activate two G-protein linked receptors (prokineticin receptor 1 and 2, PROKR1 and PROKR2). Both PROK1 and PROK2 have been found to regulate a stunning array of biological functions. In particular, PROKs stimulate gastrointestinal motility, thus accounting for their family name "prokineticins". PROK1 acts as a potent angiogenic mitogen, thus earning its other name, endocrine gland-derived vascular endothelial factor. In contrast, PROK2 signaling pathway has been shown to be a critical regulator of olfactory bulb morphogenesis and sexual maturation. During the last decade, strong evidences established the key roles of prokineticins in the control of human central and peripheral reproductive processes. PROKs act as main regulators of the physiological functions of the ovary, uterus, placenta, and testis, with marked dysfunctions in various pathological conditions such as recurrent pregnancy loss, and preeclampsia. PROKs have also been associated to the tumor development of some of these organs. In the central system, prokineticins control the migration of GnRH neurons, a key process that controls reproductive functions. Importantly, mutations in PROK2 and PROKR2 are associated to the development of Kallmann syndrome, with direct consequences on the reproductive system. This review describes the finely tuned actions of prokineticins in the control of the central and peripheral reproductive processes. Also, it discusses future research directions for the use of these cytokines as diagnostic markers for several reproductive diseases. PMID- 26574896 TI - Glycan-Mediated, Ligand-Controlled Click Chemistry for Drug-Target Identification. AB - Membrane-bound proteins are important pharmaceutical drug targets, yet few strategies exist for the identification of small-molecule-targeted membrane proteins in live-cell systems. By exploiting metabolic glycan engineering of cell membrane proteins, we have developed an in situ glycan-mediated ligand-controlled click ("GLiCo-Click") chemistry methodology that enables the attachment of small molecule chemical probes to their receptor protein through glycans on live cells. In addition to enabling receptor enrichment from cell lysates, this strategy can be used to demonstrate target receptor engagement and enables the molecular characterization of receptors. PMID- 26574897 TI - Congenital Methemoglobinemia Type II-Clinical Improvement with Short-Term Methylene Blue Treatment. AB - We report a case of prophylactic management with methylene blue (MB) in an almost 4-year-old male with congenital methemoglobinemia type II. He has a CYB5R3 compound heterozygote mutation, causing a cytochrome-b(5) reductase deficiency. Since the MB treatment regimen has commenced, his methemoglobin level has been significantly lower. He has shown modest behavioral improvements (as assessed on the Achenbach behavior report scales). There have been no iatrogenic side effects. These findings are encouraging for symptomatic improvement with regular prophylactic MB treatment but represent a single case report, which must be interpreted with caution. PMID- 26574898 TI - Clinical spectrum of valosin containing protein (VCP)-opathy. AB - INTRODUCTION: Valosin containing protein (VCP) mutations cause a rare disorder characterized by hereditary inclusion body myopathy, Paget disease of bone (PDB), and frontotemporal dementia (FTD) with variable penetrance. VCP mutations have also been linked to amyotrophic lateral sclerosis and Charcot-Marie-Tooth disease type 2. METHODS: Review of clinical, serological, electrophysiological, and myopathological findings of 6 VCP-opathy patients from 4 unrelated families. RESULTS: Patients manifested muscle weakness between ages 40 and 53 years and developed predominant asymmetric limb girdle weakness. One patient had distal weakness at onset and co-existing peripheral neuropathy. Another patient had PDB, 1 had mild cognitive deficits, and 1 had FTD. All patients had myopathic and neurogenic electromyographic findings with predominant neurogenic changes in 2. Rimmed vacuoles were infrequent, while neurogenic changes were prominent in muscle biopsies. CONCLUSIONS: VCP-opathy is a multifaceted disorder in which myopathy and peripheral neuropathy can coexist. The electrophysiological and pathological neurogenic changes raise the possibility of coexisting motor neuron involvement. Muscle Nerve, 2015 Muscle Nerve 54: 94-99, 2016 Muscle Nerve 54: 94 99, 2016. PMID- 26574900 TI - Column preconcentration and electrothermal atomic absorption spectrometric determination of rhodium in some food and standard samples. AB - In the present work, an electrothermal atomic absorption spectrometric method has been developed for the determination of ultra-trace amounts of rhodium after adsorption of its 2-(5-bromo-2-pyridylazo)-5-diethylaminophenol/tetraphenylborate ion associated complex at the surface of alumina. Several factors affecting the extraction efficiency such as the pH, type of eluent, sample and eluent flow rates, sorption capacity of alumina and sample volume were investigated and optimized. The relative standard deviation for eight measurements of 0.1 ng/mL of rhodium was +/-6.3%. In this method, the detection limit was 0.003 ng/mL in the original solution. The sorption capacity of alumina and the linear range for Rh(III) were evaluated as 0.8 mg/g and 0.015-0.45 ng/mL in the original solution, respectively. The proposed method was successfully applied for the extraction and determination of rhodium content in some food and standard samples with high recovery values. PMID- 26574899 TI - Microarray expression profiling of dysregulated long non-coding RNAs in Hirschsprung's disease reveals their potential role in molecular diagnosis. AB - BACKGROUND: Hirschsprung's disease (HSCR) is one of the common digestive disorders in the new born. Long non-coding RNAs (lncRNAs) play an important role in various biological processes. However, knowledge on lncRNAs in HSCR is limited. METHODS: The expression profile of lncRNAs in HSCR was obtained using microarray. A total of 2078 differentially expressed lncRNAs were detected by microarray in HSCR tissues compared with matched normal colon tissues (fold change >=2, p < 0.05). Candidate biomarkers were selected from these differentially expressed lncRNAs based on artificial criterion (raw signal intensity >=50; fold change >=8) and then validated in 80 pairs of HSCR and normal tissues using quantitative real-time polymerase chain reaction (qRT-PCR). Moreover, the computational analysis was used to evaluate the lncRNA-microRNA and lncRNA-protein relationships. KEY RESULTS: A panel of 5-lncRNAs was identified to distinguish HSCR from normal tissues with remarkable sensitivity and specificity. The area under the receiver operating characteristic curve (AUC) for HSCR identification in the validation set was 0.875. The bioinformatics analysis reveals that these dysregulated lncRNAs are mainly involved in RNA-protein relationships, including RNA splicing, binding, transport, processing, and localization. CONCLUSIONS & INFERENCES: Our results are the first to report the expression profile of dysregulated lncRNAs in HSCR and infer that lncRNAs may serve as novel diagnostic biomarkers for HSCR. PMID- 26574901 TI - A Novel Method of Urinary Sphincter Deficiency: Serial Histopathology Evaluation in a Rat Model of Urinary Incontinence. AB - In this study, a novel technique of irreversible sphincter deficiency by pudendal nerve transection (PNT) using 40 female rats for studying the pathophysiology of stress urinary incontinence associated with childbirth was developed. Of the 40 rats, 10 served as controls and the remaining underwent bilateral PNT at the anastomotic lumbosacral trunk level. Urethral morphological changes following bilateral PNT were assessed with serial hematoxylin and eosin (H&E) and immunohistochemistry (IHC) staining methods at 50, 90, and 130 days post intervention. Leak point pressure (LPP) measurement was used to determine the effect of pudendal injury on urethral outlet resistance after the transection. H&E and IHC staining showed irreversible loss of striated muscle mass of the sphincter region and increase in collagen deposition compatible with muscle atrophy. LPP measurements also significantly decreased following bilateral PNT. In conclusion, a novel method of irreversible sphincter insufficiency was developed. This model effectively decreased urethral outlet resistance and caused irreversible striated muscle atrophy. It was suggested that this technique can be used to develop a permanent sphincter deficiency model for the preclinical testing of treatment modalities exclusively triggering the pudendal nerve. PMID- 26574902 TI - A novel modified PAIR technique using a trocar catheter for percutaneous treatment of liver hydatid cysts: a six-year experience. AB - PURPOSE: We aimed to demonstrate the success and reliability of a novel puncture, aspiration, injection, and reaspiration (PAIR) technique in liver hydatid cysts. METHODS: Percutaneous treatment with ultrasonographic guidance was performed in 493 hepatic hydatid cysts in 374 patients. Patients were treated with a new PAIR technique by single puncture method using a 6F trocar catheter. The results of this novel technique were evaluated with regards to efficacy and safety of the procedure and complication rates. RESULTS: Out of 493 cysts, 317 were Gharbi type I (WHO CE 1) and 176 were Gharbi type II (WHO CE 3A). Of all cysts, 13 were referred to surgery because of cystobiliary fistulization. Recurrence was observed in 11 cysts one month later. Therefore, the success rate of the PAIR technique was 97.7% (469/480). Minor complications (fever, urticaria-like reactions, biliary fistula) were seen in 44 treated patients (12%, 44/374); the only major complication was reversible anaphylactic shock which was observed in two patients (0.5%, 2/374). CONCLUSION: This novel modified PAIR technique may be superior to catheterization by Seldinger technique due to its efficiency, easier application, lower severe complication rate, and lower cost. Further comparative studies are required to confirm our observations. PMID- 26574903 TI - Does an 'oversupply' of ovules cause pollen limitation? AB - Lifetime seed production can be constrained by shortfalls of pollen receipt ('pollen limitation'). The ovule oversupply hypothesis states that, in response to unpredictable pollen availability, plants evolve to produce more ovules than they expect to be fertilized, and that this results in pollen limitation of seed production. Here, we present a cartoon model and a model of optimal plant reproductive allocations under stochastic pollen receipt to evaluate the hypothesis that an oversupply of ovules leads to increased pollen limitation. We show that an oversupply of ovules has two opposing influences on pollen limitation of whole-plant seed production. First, ovule oversupply increases the likelihood that pollen receipt limits the number of ovules that can be fertilized ('prezygotic pollen limitation'). Second, ovule oversupply increases the proportion of pollen grains received that are used to fertilize ovules ('pollen use efficiency'). As a result of these opposing influences, ovule oversupply has only a modest effect on the degree to which lifetime seed production is constrained by pollen receipt, producing a small decrease in the incidence of pollen limitation. Ovule oversupply is not the cause of the pollen limitation problem, but rather is part of the evolutionary solution to that problem. PMID- 26574904 TI - Tolerance bands for functional data. AB - Often the object of inference in biomedical applications is a range that brackets a given fraction of individual observations in a population. A classical estimate of this range for univariate measurements is a "tolerance interval." This article develops its natural extension for functional measurements, a "tolerance band," and proposes a methodology for constructing its pointwise and simultaneous versions that incorporates both sparse and dense functional data. Assuming that the measurements are observed with noise, the methodology uses functional principal component analysis in a mixed model framework to represent the measurements and employs bootstrapping to approximate the tolerance factors needed for the bands. The proposed bands also account for uncertainty in the principal components decomposition. Simulations show that the methodology has, generally, acceptable performance unless the data are quite sparse and unbalanced, in which case the bands may be somewhat liberal. The methodology is illustrated using two real datasets, a sparse dataset involving CD4 cell counts and a dense dataset involving core body temperatures. PMID- 26574905 TI - Endothelial and Epithelial Cell Transition to a Mesenchymal Phenotype Was Delineated by Nestin Expression. AB - Endothelial and epithelial cell transition to a mesenchymal phenotype was identified as cellular paradigms implicated in the appearance of fibroblasts and development of reactive fibrosis in interstitial lung disease. The intermediate filament protein nestin was highly expressed in fibrotic tissue, detected in fibroblasts and participated in proliferation and migration. The present study tested the hypothesis that the transition of endothelial and epithelial cells to a mesenchymal phenotype was delineated by nestin expression. Three weeks following hypobaric hypoxia, adult male Sprague-Dawley rats characterized by alveolar and perivascular lung fibrosis were associated with increased nestin protein and mRNA levels and marked appearance of nestin/collagen type I((+)) fibroblasts. In the perivascular region of hypobaric hypoxic rats, displaced CD31((+))-endothelial cells were detected, exhibited a mesenchymal phenotype and co-expressed nestin. Likewise, epithelial cells in the lungs of hypobaric hypoxic rats transitioned to a mesenchymal phenotype distinguished by the co-expression of E-cadherin and collagen. Following the removal of FBS from primary passage rat alveolar epithelial cells, TGF-beta1 was detected in the media and a subpopulation acquired a mesenchymal phenotype characterized by E-cadherin downregulation and concomitant induction of collagen and nestin. Bone morphogenic protein-7 treatment of alveolar epithelial cells prevented E-cadherin downregulation, suppressed collagen induction but partially inhibited nestin expression. These data support the premise that the transition of endothelial and epithelial cells to a mesenchymal cell may have contributed in part to the appearance nestin/collagen type I((+))-fibroblasts and the reactive fibrotic response in the lungs of hypobaric hypoxic rats. PMID- 26574906 TI - Protein composition of 6K2-induced membrane structures formed during Potato virus A infection. AB - The definition of the precise molecular composition of membranous replication compartments is a key to understanding the mechanisms of virus multiplication. Here, we set out to investigate the protein composition of the potyviral replication complexes. We purified the potyviral 6K2 protein-induced membranous structures from Potato virus A (PVA)-infected Nicotiana benthamiana plants. For this purpose, the 6K2 protein, which is the main inducer of potyviral membrane rearrangements, was expressed in fusion with an N-terminal Twin-Strep-tag and Cerulean fluorescent protein (SC6K) from the infectious PVA cDNA. A non-tagged Cerulean-6K2 (C6K) virus and the SC6K protein alone in the absence of infection were used as controls. A purification scheme exploiting discontinuous sucrose gradient centrifugation followed by Strep-tag-based affinity chromatography was developed. Both (+)- and (-)-strand PVA RNA and viral protein VPg were co purified specifically with the affinity tagged PVA-SC6K. The purified samples, which contained individual vesicles and membrane clusters, were subjected to mass spectrometry analysis. Data analysis revealed that many of the detected viral and host proteins were either significantly enriched or fully specifically present in PVA-SC6K samples when compared with the controls. Eight of eleven potyviral proteins were identified with high confidence from the purified membrane structures formed during PVA infection. Ribosomal proteins were identified from the 6K2-induced membranes only in the presence of a replicating virus, reinforcing the tight coupling between replication and translation. A substantial number of proteins associating with chloroplasts and several host proteins previously linked with potyvirus replication complexes were co-purified with PVA derived SC6K, supporting the conclusion that the host proteins identified in this study may have relevance in PVA replication. PMID- 26574907 TI - Gender-specific differences in chronic rhinosinusitis patients electing endoscopic sinus surgery. AB - BACKGROUND: The objective of this study was to investigate gender-specific differences in chronic rhinosinusitis (CRS) patients electing endoscopic sinus surgery (ESS). METHODS: This study was a retrospective review of CRS patients electing ESS (2011-2013) at a tertiary-care center. RESULTS: ESS was elected by 272 patients (mean age 54.6 years; 48.5% female). Mean Lund-Mackay computed tomography (CT) score was 10.9; total 22-item Sino-Nasal Outcome Test (SNOT-22) score was 41.8. Compared to men, women electing ESS had lower CT score (10.1 vs 11.7; p = 0.01) but higher total SNOT-22 score (44.9 vs 39; p = 0.02). Women reported significantly worse postnasal drainage (p < 0.0001) and embarrassment (p = 0.0021). SNOT-22 scores declined with advancing age (women, p = 0.003; men, p = 0.0005). Reduction in CT scores with age was seen only in males (p = 0.03). Stratifying by age, females aged 61 to 80 years had higher SNOT-22 scores compared to male counterparts (p = 0.04), whereas CT scores were similar. More women underwent surgery for CRS without nasal polyps (CRSsNP) (54.9%) whereas more men underwent surgery for CRS with nasal polyps (CRSwNP) (57.4%), but this difference missed statistical significance (p = 0.052). Women with CRSwNP had higher SNOT-22 scores than men (p = 0.02) for similar CT scores. Men electing ESS for CRSsNP had higher CT scores than women (p = 0.02). Women with CRSsNP aged 18 to 40 years reported higher SNOT-22 scores than men (p = 0.003), even though CT scores were lower (p = 0.005). CONCLUSION: Equivalent numbers of men and women underwent ESS for CRS. Overall, women electing ESS had higher total SNOT-22 scores and lower Lund-Mackay CT scores than men. Women reported more problems with postnasal drainage (CRS overall, CRSsNP, and CRSwNP), embarrassment (CRS overall and CRSwNP), and facial pain (CRSwNP). Gender differences in CRS are poorly understood and merit further study. PMID- 26574908 TI - Conformation of poly(gamma-glutamic acid) in aqueous solution. AB - Local conformation and overall conformation of poly(gamma-DL-glutamic acid) (PgammaDLGA) and poly(gamma-L-glutamic acid) (PgammaLGA) in aqueous solution was studied as a function of degree of ionization epsilon by (1) H-NMR, circular dichroism, and potentiometric titration. It was clarified that their local conformation is represented by random coil over an entire epsilon range and their overall conformation is represented by expanded random-coil in a range of epsilon > epsilon(*) , where epsilon(*) is about 0.3, 0.35, 0.45, and 0.5 for added-salt concentration of 0.02M, 0.05M, 0.1M, and 0.2M, respectively. In a range of epsilon < epsilon(*) , however, epsilon dependence of their overall conformation is significantly differentiated from each other. PgammaDLGA tends to aggregate intramolecularly and/or intermolecularly with decreasing epsilon, but PgammaLGA still behaves as expanded random-coil. It is speculated that spatial arrangement of adjacent carboxyl groups along the backbone chain essentially affects the overall conformation of PgammaGA in acidic media. PMID- 26574909 TI - A 74-Year-Old Man with a Jugular Foramen Mass. PMID- 26574911 TI - Biofunctionalized Conducting Polymer/Carbon Microfiber Electrodes for Ultrasensitive Neural Recordings. AB - Carbon microfibers (MFs) coated with conducting polymers may provide a solution for long-term recording of activity from individual or small groups of neurons. Attaching cell adhesion molecules to the electro-sensitive surface might further improve electrode-neuron contact, thus enhancing signal stability and fidelity. We fabricated biofunctionalized microelectrodes consisting of 7-MUm diameter carbon MFs coated with poly(3,4-ethylenedioxythiophene) doped with poly[(4 styrenesulfonic acid)-co-(maleic acid)] ( PEDOT: PSS-co-MA), and linked N Cadherin to the polymer surface. These electrodes were tested for recording artificially generated electric potentials, as well as multiunit activity (MUA), sharp wave-ripple complexes (SWRs), and field excitatory postsynaptic potentials (fEPSPs) in rat hippocampal slices. The effects of electrode length and functionalization were compared. PEDOT: PSS-co-MA coating improved electric current detection and reduced the electrical noise but had no significant effect on the amplitude of recorded biopotentials. Surface biofunctionalization lowered the electric current flow, and further reduced the electrical noise. Additionally, it increased the amplitude of the recorded MUA, finally doubling the signal-to-noise ratio achieved with bare carbon MFs. Biofunctionalization benefits were apparent only for potentials from cells putatively adjacent to the microelectrode. Analysis of fEPSPs excluded adverse effects of functionalized electrodes in basal synaptic transmission. These results demonstrate the possibility of enhancing the amplitude and signal-to-noise ratio of neural recordings by coating the microelectrodes with conducting polymers modified with neural cell adhesion molecules, and support the use of biofunctionalized MFs in advanced neuroprosthetic devices. PMID- 26574910 TI - Cost-effectiveness analysis of antiviral treatment in the management of seasonal influenza A: point-of-care rapid test versus clinical judgment. AB - BACKGROUND: A point-of-care rapid test (POCRT) may help early and targeted use of antiviral drugs for the management of influenza A infection. OBJECTIVE: (i) To determine whether antiviral treatment based on a POCRT for influenza A is cost effective and, (ii) to determine the thresholds of key test parameters (sensitivity, specificity and cost) at which a POCRT based-strategy appears to be cost effective. METHODS: An hybrid " susceptible, infected, recovered (SIR) " compartmental transmission and Markov decision analytic model was used to simulate the cost-effectiveness of antiviral treatment based on a POCRT for influenza A in the social perspective. Data input parameters used were retrieved from peer-review published studies and government databases. The outcome considered was the incremental cost per life-year saved for one seasonal influenza season. RESULTS: In the base-case analysis, the antiviral treatment based on POCRT saves 2 lives/100,000 person-years and costs $7600 less than the empirical antiviral treatment based on clinical judgment alone, which demonstrates that the POCRT-based strategy is dominant. In one and two way sensitivity analyses, results were sensitive to the POCRT accuracy and cost, to the vaccination coverage as well as to the prevalence of influenza A. In probabilistic sensitivity analyses, the POCRT strategy is cost-effective in 66% of cases, for a commonly accepted threshold of $50,000 per life-year saved. CONCLUSION: The influenza antiviral treatment based on POCRT could be cost effective in specific conditions of performance, price and disease prevalence. PMID- 26574912 TI - Electrostatic Stabilization of Graphene in Organic Dispersions. AB - The exfoliation of graphite to give graphene dispersions in nonaqueous solvents is an important area with regards to scalable production of graphene in bulk quantities and its ultimate application in devices. Understanding the mechanisms governing the stability of these dispersions is therefore of both scientific interest and technological importance. Herein, we have used addition of an indifferent electrolyte to perturb few-layer graphene dispersions in a nonaqueous solvent (1,2-dichloroethane) as a way to probe the importance of interparticle electrostatic repulsions toward the overall dispersion stability. At a sufficient electrolyte concentration, complete sedimentation of the dispersions occurred over 24 h, and the relationship between dispersed graphene concentration and electrolyte concentration was consistent with a dispersion stabilized by electrostatic repulsions. We also found that an increased oxygen content in the graphite starting material produced dispersions of greater stability, indicating that the extent of oxidation is an important parameter in determining the extent of electrostatic stabilization in nonaqueous graphene dispersions. PMID- 26574913 TI - Long- and Short-Range Structure of Ferrimagnetic Iron-Chromium Maghemites. AB - Maghemite-like materials containing Fe(3+) and Cr(3+) in comparable amounts have been prepared by solution-combustion synthesis. The conditions of synthesis and the magnetic properties are described. These materials are ferrimagnetic and are much more stable than pure iron maghemite since their maghemite-hematite transformation takes place at about ~ 700 degrees C instead of ~ 300 degrees C, as usually reported. These materials were studied by synchrotron radiation X-ray diffraction (XRD) and by X-ray absorption fine structure (XAFS) of the K absorption edge of two elements. High-resolution XRD patterns were processed by means of the Rietveld method. Thus, maghemites were studied by XAFS in both Fe and Cr K-edges to clarify the short-range structure of the investigated systems. Pre-edge decomposition and theoretical modeling of X-ray absorption near edge structure transitions were performed. The extended X-ray absorption fine structure (EXAFS) spectra were fitted considering the facts that the central atom of Fe is able to occupy octahedral and tetrahedral sites, each with a weight adjustment, while Cr occupies only octahedral sites. Interatomic distances were determined for x = 1, by fitting simultaneously both Fe and Cr K-edges average EXAFS spectra. The results showed that the cation vacancies tend to follow a regular pattern within the structure of the iron-chromium maghemite (FeCrO3). PMID- 26574914 TI - H-NOX from Clostridium botulinum, like H-NOX from Thermoanaerobacter tengcongensis, Binds Oxygen but with a Less Stable Oxyferrous Heme Intermediate. AB - Heme nitric oxide/oxygen binding protein isolated from the obligate anaerobe Clostridium botulinum (Cb H-NOX) was previously reported to bind NO with a femtomolar K(D) (Nioche, P. et al. Science 2004, 306, 1550-1553). On the other hand, no oxyferrous Cb H-NOX was observed despite full conservation of the key residues that stabilize the oxyferrous complex in the H-NOX from Thermoanaerobacter tengcongensis (Tt H-NOX) (the same study). In this study, we re-measured the kinetics/affinities of Cb H-NOX for CO, NO, and O2. K(D)(CO) for the simple one-step equilibrium binding was 1.6 * 10(-7) M. The K(D)(NO) of Cb H NOX was 8.0 * 10(-11) M for the first six-coordinate NO complex, and the previous femtomolar K(D)(NO) was actually an apparent K(D) for its multiple-step NO binding. An oxyferrous Cb H-NOX was clearly observed with a K(D)(O2) of 5.3 * 10( 5) M, which is significantly higher than Tt H-NOX's K(D)(O2) = 4.4 * 10(-8) M. The gaseous ligand binding of Cb H-NOX provides another supportive example for the "sliding scale rule" hypothesis (Tsai, A.-L. et al. Antioxid. Redox Signal. 2012, 17, 1246-1263), and the presence of hydrogen bond donor Tyr139 in Cb H-NOX selectively enhanced its affinity for oxygen. PMID- 26574915 TI - Therapeutic plasma exchange for intractable pruritus secondary to primary sclerosing cholangitis. PMID- 26574916 TI - Testosterone regulation of cyclin E kinase: A key factor in determining gender differences in hepatocarcinogenesis. AB - BACKGROUND AND AIM: While gender differences in hepatocellular carcinoma (HCC) are profound, the mechanism is unclear. Using castration and hormone replacement strategies, we tested whether these gender differences are attributable to testosterone or estradiol/progesterone effects on cell cycle regulators and p53. METHODS: We studied dysplastic liver and HCCs in intact and castrated diethylnitrosamine-injected C57BL/6J male and female mice, with or without hormonal replacement. Effects of sex steroids on proliferation and survival of primary hepatocytes and primary HCC cells were also characterized. RESULTS: Diethylnitrosamine-injected female mice displayed fewer dysplastic foci and slower onset of HCC than male mice, with smaller/more differentiated tumors and fewer metastases. Castration of diethylnitrosamine-injected male mice reduced cyclin E kinase and augmented hepatocyte apoptosis compared with intact male mice; estradiol/progesterone enhanced these effects. In intact female mice, cyclin E kinase activity was less than in males; testosterone administered to ovariectomized female mice upregulated cyclin E, increased cyclin E kinase, and accelerated hepatocarcinogenesis. In vitro, testosterone increased expression of cell cycle regulators (cyclin D1, cyclin E, and cyclin-dependent kinase 2) and reduced p53 and p21, which enhanced hepatocyte viability. In contrast, estradiol both suppressed hepatocyte cell cycle markers, upregulated p53 and reduced viability of hepatocytes and HCC cells. CONCLUSIONS: Testosterone is the positive regulator of hepatocyte cell cycle via cyclin E, while estradiol plays a negative role by effects of p53 and p21. Together, both sex hormones determine the male predominance of gender differences in hepatocarcinogenesis. PMID- 26574918 TI - Striving for Reproducible Science. PMID- 26574917 TI - A Simple Synthesis of an N-Doped Carbon ORR Catalyst: Hierarchical Micro/Meso/Macro Porosity and Graphitic Shells. AB - Replacing platinum as an oxygen reduction catalyst is an important scientific and technological challenge. Herein we report a simple synthesis of a complex carbon with very good oxygen reduction reaction (ORR) activity at pH 13. Pyrolysis of magnesium nitrilotriacetate yields a carbon with hierarchical micro/meso/macro porosity, resulting from in situ templating by spontaneously forming MgO nanoparticles and from etching by pyrolysis gases. The mesopores are lined with highly graphitic shells. The high ORR activity is attributed to a good balance between high specific surface area and mass transport through the hierarchical porosity, and to improved electronic conductivity through the graphitic shells. This novel carbon has a high surface area (1320 m(2) g(-1) ), and high nitrogen content for a single precursor synthesis (~6 %). Importantly, its synthesis is both cheap and easily scalable. PMID- 26574919 TI - Enhanced Magnetocaloric Effect Driven by Interfacial Magnetic Coupling in Self Assembled Mn3O4-La(0.7)Sr(0.3)MnO3 Nanocomposites. AB - Magnetic refrigeration, resulting from the magnetocaloric effect of a material around the magnetic phase-transition temperature, is a topic of great interest as it is considered to be an alternate energy solution to conventional vapor compression refrigeration. The viability of a magnetic refrigeration system for magnetic cooling can be tested by exploiting materials in various forms, from bulk to nanostrucutres. In this study, magnetocaloric properties of self assembled Mn3O4-La(0.7)Sr(0.3)MnO3 nanocomposites, with varying doping concentrations of Mn3O4 in the form of nanocrystals embedded in the La(0.7)Sr(0.3)MnO3 matrix, are investigated. The temperatures corresponding to the paramagnetic-to-ferromagnetic transitions are higher, and the values of change in magnetic entropy under a magnetic field of 2 T show an enhancement (highest being ~130%) for the nanocomposites with low doping concentrations of Mn3O4, compared to that of pure La(0.7)Sr(0.3)MnO3 thin films. Relative cooling power remain close to those of La(0.7)Sr(0.3)MnO3. The enhanced magnetic phase transition temperature and magnetocaloric effect are interpreted and evidenced in the framework of interfacial coupling between Mn3O4 and La(0.7)Sr(0.3)MnO3. This work demonstrates the potentiality of self-assembled nanostructures for magnetic cooling near room temperature under low magnetic fields. PMID- 26574920 TI - Innovation Promoted by Regulatory Flexibility. PMID- 26574922 TI - Dehydration of Aldoximes Using PhSe(O)OH as the Pre-Catalyst in Air. AB - PhSe(O)OH was found to be a good pre-catalyst for aldoxime dehydrations in open air. Compared with the previously reported (PhSe)(2)-H(2)O(2) system, it is more stable and milder, affording broader application scopes due to a higher functional group tolerance. The control experiments for mechanism study disclosed that air was the key factor for the reaction to maintain enough concentration of PhSeOH, which should be the real catalytic species. PMID- 26574921 TI - Synthesis and Biological Activity of 2-Methylene Analogues of Calcitriol and Related Compounds. AB - In an attempt to prepare vitamin D analogues that are superagonists, (20R)- and (20S)-isomers of 1alpha-hydroxy-2-methylenevitamin D3 and 1alpha,25-dihydroxy-2 methylenevitamin D3 have been synthesized. To prepare the desired A-ring dienyne fragment, two different approaches were used, both starting from the (-)-quinic acid. The obtained derivative was subsequently coupled with the C,D-ring enol triflates derived from the corresponding Grundmann ketones, using the Sonogashira reaction. Moreover, (20R)- and (20S)-1alpha,25-dihydroxy-2-methylenevitamin D3 compounds with an (5E)-configuration were prepared by iodine catalyzed isomerization. All four 2-methylene analogues of the native hormone were characterized by high in vitro activity. As expected, the 25-desoxy analogues were much less potent. Among the synthesized compounds, two of them, 1alpha,25 dihydroxy-2-methylenevitamin D3 and its C-20 epimer, were found to be almost as active as 2-methylene-19-nor-(20S)-1alpha,25-dihydroxyvitamin D3 (2MD) on bone but more active in intestine. PMID- 26574923 TI - Nature of Activated Manganese Oxide for Oxygen Evolution. AB - Electrodeposited manganese oxide films (MnOx) are promising stable oxygen evolution catalysts. They are able to catalyze the oxygen evolution reaction in acidic solutions but with only modest activity when prepared by constant anodic potential deposition. We now show that the performance of these catalysts is improved when they are "activated" by potential cycling protocols, as measured by Tafel analysis (where lower slope is better): upon activation the Tafel slope decreases from ~120 to ~70 mV/decade in neutral conditions and from ~650 to ~90 mV/decade in acidic solutions. Electrochemical, spectroscopic, and structural methods were employed to study the activation process and support a mechanism where the original birnessite-like MnOx (delta-MnO2) undergoes a phase change, induced by comproportionation with cathodically generated Mn(OH)2, to a hausmannite-like intermediate (alpha-Mn3O4). Subsequent anodic conditioning from voltage cycling or water oxidation produces a disordered birnessite-like phase, which is highly active for oxygen evolution. At pH 2.5, the current density of activated MnOx (at an overpotential of 600 mV) is 2 orders of magnitude higher than that of the original MnOx and begins to approach that of Ru and Ir oxides in acid. PMID- 26574925 TI - Enrichment of DNRA bacteria in a continuous culture. PMID- 26574924 TI - High-temperature quantum anomalous Hall effect in honeycomb bilayer consisting of Au atoms and single-vacancy graphene. AB - The quantum anomalous Hall effect (QAHE) is predicted to be realized at high temperature in a honeycomb bilayer consisting of Au atoms and single-vacancy graphene (Au2-SVG) based on the first-principles calculations. We demonstrate that the ferromagnetic state in the Au2-SVG can be maintained up to 380 K. The combination of spatial inversion symmetry and the strong SOC introduced by the Au atoms causes a topologically nontrivial band gap as large as 36 meV and a QAHE state with Chern number C = -2. The analysis of the binding energy proved that the honeycomb bilayer is stable and feasible to be fabricated in experiment. The QAHEs in Ta2-SVG and other TM2-SVGs are also discussed. PMID- 26574926 TI - Wilfred Roling (9 December 1966 - 25 September 2015). PMID- 26574928 TI - Prospective evaluation of the psychosocial impact of the first 6 months of orthodontic treatment with fixed appliance among young adults. AB - OBJECTIVE: To evaluate the psychosocial impact of the first 6 months of orthodontic treatment with a fixed appliance among young adults and compare the results with those of a control group of patients awaiting treatment for malocclusion. MATERIALS AND METHODS: A study was conducted with a sample of 120 patients on a waiting list for orthodontic treatment at a university. The participants were allocated to an experimental group submitted to treatment and a control group awaiting treatment. The groups were matched for sex and age. All participants were instructed to answer the Brazilian version of the Psychosocial Impact of Dental Aesthetics Questionnaire (PIDAQ) at baseline and after 6 months. Statistical analysis involved the Wilcoxon test for the total PIDAQ score and the score of each subscale. All patients participated until the end of the study. RESULTS: Significant differences between baseline and the 6-month evaluation were found for the total PIDAQ score as well as the dental self-confidence and social impact subscales in both groups. No differences between baseline and the 6-month evaluation were found regarding the psychological impact or esthetic concern subscales in the control group. The patients in the experimental group reported greater esthetic impact 6 months after beginning treatment (P < .001). The first 6 months of orthodontic treatment seem to improve psychosocial impact. CONCLUSION: The first 6 months of orthodontic treatment seem to improve the psychosocial impact of malocclusion. The patients analyzed in the present study reported a greater esthetic impact and less psychological impact after 6 months of using an orthodontic appliance. PMID- 26574929 TI - A Further Note on the Thalassemia Screening Program in the Mugla Region of Turkey. PMID- 26574927 TI - C. elegans and mutants with chronic nicotine exposure as a novel model of cancer phenotype. AB - We previously investigated MET and its oncogenic mutants relevant to lung cancer in C. elegans. The inactive orthlogues of the receptor tyrosine kinase Eph and MET, namely vab-1 and RB2088 respectively, the temperature sensitive constitutively active form of KRAS, SD551 (let-60; GA89) and the inactive c-CBL equivalent mutants in sli-1 (PS2728, PS1258, and MT13032) when subjected to chronic exposure of nicotine resulted in a significant loss in egg-laying capacity and fertility. While the vab-1 mutant revealed increased circular motion in response to nicotine, the other mutant strains failed to show any effect. Overall locomotion speed increased with increasing nicotine concentration in all tested mutant strains except in the vab-1 mutants. Moreover, chronic nicotine exposure, in general, upregulated kinases and phosphatases. Taken together, these studies provide evidence in support of C. elegans as initial in vivo model to study nicotine and its effects on oncogenic mutations identified in humans. PMID- 26574930 TI - Synthesis and Functionalization of 3D Nano-graphene Materials: Graphene Aerogels and Graphene Macro Assemblies. AB - Efforts to assemble graphene into three-dimensional monolithic structures have been hampered by the high cost and poor processability of graphene. Additionally, most reported graphene assemblies are held together through physical interactions (e.g., van der Waals forces) rather than chemical bonds, which limit their mechanical strength and conductivity. This video method details recently developed strategies to fabricate mass-producible, graphene-based bulk materials derived from either polymer foams or single layer graphene oxide. These materials consist primarily of individual graphene sheets connected through covalently bound carbon linkers. They maintain the favorable properties of graphene such as high surface area and high electrical and thermal conductivity, combined with tunable pore morphology and exceptional mechanical strength and elasticity. This flexible synthetic method can be extended to the fabrication of polymer/carbon nanotube (CNT) and polymer/graphene oxide (GO) composite materials. Furthermore, additional post-synthetic functionalization with anthraquinone is described, which enables a dramatic increase in charge storage performance in supercapacitor applications. PMID- 26574931 TI - miR-155 targets Caspase-3 mRNA in activated macrophages. AB - To secure the functionality of activated macrophages in the innate immune response, efficient life span control is required. Recognition of bacterial lipopolysaccharides (LPS) by toll-like receptor 4 (TLR4) induces downstream signaling pathways, which merge to induce the expression of cytokine genes and anti-apoptotic genes. MicroRNAs (miRNAs) have emerged as important inflammatory response modulators, but information about their functional impact on apoptosis is scarce. To identify miRNAs differentially expressed in response to LPS, cDNA libraries from untreated and LPS-activated murine macrophages were analyzed by deep sequencing and regulated miRNA expression was verified by Northern blotting and qPCR. Employing TargetScan(TM) we identified CASPASE-3 (CASP-3) mRNA that encodes a key player in apoptosis as potential target of LPS-induced miR-155. LPS dependent primary macrophage activation revealed TLR4-mediated enhancement of miR 155 expression and CASP-3 mRNA reduction. Endogenous CASP-3 and cleaved CASP-3 protein declined in LPS-activated macrophages. Accumulation of miR-155 and CASP-3 mRNA in miRNA-induced silencing complexes (miRISC) was demonstrated by ARGONAUTE 2 (AGO2) immunoprecipitation. Importantly, specific antagomir transfection effectively reduced mature miR-155 and resulted in significantly elevated CASP-3 mRNA levels in activated macrophages. In vitro translation assays demonstrated that the target site in the CASP-3 mRNA 3'UTR mediates miR-155-dependent Luciferase reporter mRNA destabilization. Strikingly, Annexin V staining of macrophages transfected with antagomir-155 and stimulated with LPS prior to staurosporine (SSP) treatment implied that LPS-induced miR-155 prevents apoptosis through CASP-3 mRNA down-regulation. In conclusion, we report that miR-155 mediated CASP-3 mRNA destabilization in LPS-activated RAW 264.7 macrophages suppresses apoptosis, as a prerequisite to maintain their crucial function in inflammation. PMID- 26574933 TI - A rare cause of acute coronary syndrome in a handyman. PMID- 26574934 TI - Modified snare removal of a retained lead. PMID- 26574935 TI - The effects of free-living physical activity on mortality after congestive heart failure diagnosis. PMID- 26574936 TI - Celebrity Health Announcements and Online Health Information Seeking: An Analysis of Angelina Jolie's Preventative Health Decision. AB - On May 14, 2013, Angelina Jolie disclosed she carries BRCA1, which means she has an 87% risk of developing breast cancer during her lifetime. Jolie decided to undergo a preventative bilateral mastectomy (PBM), reducing her risk to 5%. The purpose of this study was to analyze the type of information individuals are exposed to when using the Internet to search health information regarding Jolie's decision. Qualitative content analysis revealed four main themes--information about genetics, information about a PBM, information about health care, and information about Jolie's gender identity. Broadly, the identified websites mention Jolie's high risk for developing cancer due to the genetic mutation BRCA1, describe a PBM occasionally noting reasons why she had this surgery and providing alternatives to the surgery, discuss issues related to health care services, costs, and insurances about Jolie's health decision, and portray Jolie as a sexual icon, a partner to Brad Pitt, a mother of six children, and an inspirational humanitarian. The websites also depict Jolie's health decision in positive, negative, and/or both ways. Discussion centers on how this actress' health decision impacts the public. PMID- 26574937 TI - Leadership. PMID- 26574938 TI - Are You a Leader? PMID- 26574932 TI - Prognostic impact of in-hospital hyperglycemia in hospitalized patients with acute heart failure: Results of the IN-HF (Italian Network on Heart Failure) Outcome registry. AB - OBJECTIVES: Although diabetes mellitus is frequently associated with heart failure (HF), the association between elevated admission glucose levels and adverse outcomes has not been well established in hospitalized patients with acute HF. METHODS: We prospectively evaluated in-hospital mortality, post discharge 1-year mortality and 1-year re-hospitalization rates in the Italian Network on Heart Failure (IN-HF) Outcome registry cohort of 1776 patients hospitalized with acute HF and stratified by their admission glucose levels (i.e., known diabetes, newly diagnosed hyperglycemia, no diabetes). RESULTS: Compared with those without diabetes (n = 586), patients with either known diabetes (n = 749) (unadjusted-odds ratio [OR] 1.64, 95%CI 0.99-2.70) or newly diagnosed hyperglycemia (n = 441) (unadjusted-OR 2.34, 95%CI 1.39-3.94) had higher in-hospital mortality, but comparable post-discharge 1-year mortality rates. After adjustment for age, sex, systolic blood pressure, estimated glomerular filtration rate, left ventricular ejection fraction, HF etiology and HF worsening/de novo presentation, the results remained unchanged in patients with known diabetes (adjusted-OR 1.86, 95%CI 1.01-3.42), while achieved borderline significance in those with newly diagnosed hyperglycemia (adjusted-OR 1.81, 95%CI 0.95-3.45). One-year re-hospitalization rates were lower in patients with newly diagnosed hyperglycemia (adjusted-hazard ratio 0.74, 95%CI 0.56-0.96) than in other groups. CONCLUSIONS: Elevated admission blood glucose levels are associated with poorer in-hospital survival outcomes in patients with acute HF, especially in those with previously known diabetes. This finding further highlights the importance of tight glycemic control during hospital stay and address the need of dedicated intervention studies to identify customized clinical protocols to improve in-hospital survival of these high-risk patients. PMID- 26574939 TI - The Evolution of the Society of Trauma Nurses' Leadership Institute. AB - The Society of Trauma Nurses (STN) understands the increasing complexity of trauma care and the vital leadership role nurses play. In 2009, the STN took the initiative to form a Leadership Committee tasked with researching the possibility of developing a mechanism to offer trauma leaders opportunities in leadership development. Investigation and collaboration among the committee members, with input from the Board of Directors and the organization's executive director, resulted in the STN Leadership Institute. The Leadership Institute design is to equip trauma nurses with the tools needed to effectively lead from the bedside to the boardroom and beyond through web-based modules. Operationalization of the plan took intense focus and dedicated leadership. Following a pilot study, the initial cohort ran the first quarter of 2015. Because of the positive feedback and identified opportunities for improvement, the program will continue to be offered with further expansion planning underway. PMID- 26574940 TI - Employee Engagement: How to Motivate Your Team? PMID- 26574941 TI - Creating a Geriatric-Focused Model of Care in Trauma With Geriatric Education. AB - The literature suggests that by 2050, about 40% of all trauma patients will be over age 65 years. We already exceeded this prediction at Lehigh Valley Health Network in 2013, with 46.6% of the Pennsylvania trauma registry qualifiers being age 65 or greater, and 17.7% age 85 and greater. Currently, only 8.8% of trauma centers incorporate Geriatric Resource Programs into trauma care. Our trauma team has incorporated geriatric education for nurses by incorporating an educational nursing program called Nurses Improving Care for Healthsystem Elders, to improve outcomes, reduce hospital complications, and reduce health care costs for this high-risk population. The older adult population is on the rise and trauma nurses must be provided the tools to care for this high-risk patient group. PMID- 26574942 TI - Leadership and Work-Life Balance. AB - Simply stated, work-life balance is something that is both difficult to define and difficult to achieve. Leaders, throughout the continuum of trauma care, need to have a sound understanding of what work-life balance means and set an example of a healthy work-life balance for those they lead. This article offers strategies for enhancing work-life balance and challenges individuals to use self reflection as a means to furthering their personal and professional growth. PMID- 26574943 TI - Service to People: A Must-Have Quality for Effective and Influential Leaders. PMID- 26574944 TI - Defining Leadership in a Changing Time. AB - The purpose of this article is to discuss the difference between leadership and management. Leadership and management have been discussed for many years. Both are important to achieve success in health care, but what does that really mean? Strong leaders possess qualities that inspire others to follow them. This fosters team engagement, goal achievement, and ultimately drives outcomes. Managers plan, organize, and coordinate. It takes dedication, motivation, and passion to be more than a manager and be a good leader. There is not a single correct leadership style, but there are important characteristics that all leaders must demonstrate to get the desired results with the team. In a time when health care is rapidly changing, leadership is important at all levels of an organization. PMID- 26574945 TI - The Genesis of a Trauma Performance Improvement Plan. AB - The purpose of this article is to assist the trauma medical and program director with developing a performance improvement and patients safety plan (PIPS), which is a required component of a successful trauma verification process by the American College of Surgeons. This article will review trauma quality standards and will describe in detail the required elements of a successful trauma center's performance improvement plan including a written comprehensive plan that outlines the mission and vision of the PIPS Program, authority of the PIPS Program, PIPS Program Committee reporting structure to the other hospital committees, list of required PIPS multidisciplinary team members, the operational components of the utilized data management system (trauma registry), list of indicators/audit filters, levels of review, peer determinations, corrective action plan with implementation, event resolution, and reevaluation. Strategies to develop a successful trauma performance improvement plan are presented. PMID- 26574946 TI - When a Crash Is Really an Accident: A Concept Analysis. AB - The debate over using the word accident has encouraged some groups to adopt the word crash, while other groups retain using accident. This article addresses the inconsistent and interchangeable use of the terms accident and crash. This conceptual analysis used a Critical Review Method, with Critical Theory as the theoretical framework. A literature search was conducted in MEDLINE and CINAHL for articles published through 2011. An extensive review of literature was followed by purposive sampling of articles published in 2011 across countries, disciplines, and contexts. Forty-seven articles were read in entirety, resulting in 2 themes for accident: intent and injury. Seven articles were critically analyzed for intent, injury, and underrepresented margins of society (5 articles using the term accident, 1 article using crash and accident interchangeably, and 1 using only crash). There was congruency on injury across all 7 articles. Results were mixed for intent and the incorporation of marginalized people. Although there is evidence that the use of the word accident should be maintained when the event could not have reasonably been prevented, the theoretical framework highlights this will likely perpetuate the conceptual confusion. The recommendation is to (1) identify the mechanism of injury, (2) identify event as intentional versus nonintentional, and (3) identify event as preventable versus nonpreventable. PMID- 26574949 TI - Adherence to oral and topical medication in 445 patients with tinea pedis as assessed by the Morisky Medication Adherence Scale-8. AB - BACKGROUND: Adherence is defined as the extent to which a person's behavior corresponds with recommendations from health care providers. Adherence to treatment is an important factor for a good therapeutic outcome. OBJECTIVES: This study aimed to examine the adherence of patients with tinea pedis and to clarify the factors related to it. MATERIALS AND METHODS: We assessed medication adherence for oral and topical drugs using a translated version of the Morisky Medication Adherence Scale-8 (MMAS-8) together with other background factors in 445 Japanese patients with tinea pedis, using a questionnaire in a web-based monitoring system. RESULTS: Overall, high, medium and low adherence rates as assessed by MMAS-8 were 8.7%, 31.7% and 59.6% for oral medication, and 8.6%, 17.4% and 74.0% for topical medication, respectively. The adherence level was significantly higher for oral medication than for topical medication. Subgroup analyses showed that the adherence level for topical medication was significantly higher when topical and oral medications were used in combination than when topical medication was used alone. A low adherence level was shown in employed patients, those for whom their oral medication had not been effective and those with topical medication who had visited their hospital less often than once every six months. CONCLUSION: Patient adherence to therapy can be effectively improved by selecting highly effective medication while considering the prescription of topical and oral antifungal medications concomitantly, by carefully selecting a therapy plan for employed patients and by encouraging patients to visit their doctor regularly. PMID- 26574950 TI - [Partial Nephrectomy in cT1 Renal Tumours: Conventional Laparoscopic Partial Nephrectomy Compared with LESS Partial Nephrectomy in SITUS Technique]. AB - BACKGROUND: Partial nephrectomy is the treatment of choice for clinical stage 1 renal tumours. Open partial nephrectomy is the standard operative technique. The use of minimally-invasive strategies such as laparoscopic, robot-assisted partial nephrectomy or laparoendoscopic single site (LESS) partial nephrectomy has increased in recent years. PATIENTS/MATERIAL AND METHODS: In this retrospective study, patients undergoing laparoscopic partial nephrectomy between December 2008 and November 2013 were evaluated. All patients presented with renal lesions suspicious for malignancy. Operations were performed as conventional laparoscopic transperitoneal partial nephrectomies (cLPN) or LESS partial nephrectomies (LESS PN) in SITUS technique (single incision transumbilical surgery). The aim of the study was to compare perioperative outcome parameters such as duration of surgery, time of ischaemia, complications, need for transfusion, conversion rates, changes in renal function and duration of hospital stay in both groups. RESULTS: A total of 85 laparoscopic partial nephrectomies were performed in this study (72 cLPN and 13 LESS-PN). The average tumour size was 2.68+/-1.47 cm (cLPN) vs. 2.46+/-1.11 cm (LESS-PN). The mean duration of surgery was 175.17+/-50.026 min (cLPN) and 185.77+/-35.991 min (LESS-PN). 45 (62.5%) operations (cLPN) vs. 10 (76.9%) (LESS-PN) were performed in zero-ischaemia technique. There were no significant differences in perioperative outcome parameters between both groups. Postoperative complication rates (Clavien-Dindo>=3) were 11.1% (cLPN) vs. 7.7% (LESS-PN). CONCLUSIONS: LESS partial nephrectomy in SITUS technique is an attractive alternative to conventional laparoscopic and open partial nephrectomy. PMID- 26574951 TI - [Chronic Constipation: A Geriatric Syndrome with Urological Implications]. AB - Chronic constipation, faecal and urinary incontinence are a geriatric syndrome. Chronic constipation is particularly important for the field of urology as it may be considered to trigger urological incontinence problems. Both chronic constipation and urinary incontinence are age-dependent symptoms, which are associated with a significant impact on quality of life. Chronic constipation must be taken into consideration during the diagnostic work-up and treatment of urinary incontinence. PMID- 26574952 TI - White Matter Microstructure and Cognitive Function in Young Women With Polycystic Ovary Syndrome. AB - CONTEXT: Polycystic ovary syndrome (PCOS) is a disorder characterized by insulin resistance and hyperandrogenism, which leads to an increased risk of type 2 diabetes in later life. Androgens and insulin signaling affect brain function but little is known about brain structure and function in younger adults with PCOS. OBJECTIVE: To establish whether young women with PCOS display altered white matter microstructure and cognitive function. PATIENTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: Eighteen individuals with PCOS (age, 31 +/- 6 y; body mass index [BMI] 30 +/- 6 kg/m(2)) and 18 control subjects (age, 31 +/- 7 y; BMI, 29 +/- 6 kg/m(2)), matched for age, IQ, and BMI, underwent anthropometric and metabolic evaluation, diffusion tensor MRI, a technique especially sensitive to brain white matter structure, and cognitive assessment. Cognitive scores and white matter diffusion metrics were compared between groups. White matter microstructure was evaluated across the whole white matter skeleton using tract based spatial statistics. Associations with metabolic indices were also evaluated. RESULTS: PCOS was associated with a widespread reduction in axial diffusivity (diffusion along the main axis of white matter fibers) and increased tissue volume fraction (the proportion of volume filled by white or grey matter rather than cerebrospinal fluid) in the corpus callosum. Cognitive performance was reduced compared with controls (first principal component, t = 2.9, P = .007), reflecting subtle decrements across a broad range of cognitive tests, despite similar education and premorbid intelligence. In PCOS, there was a reversal of the relationship seen in controls between brain microstructure and both androgens and insulin resistance. CONCLUSIONS: White matter microstructure is altered, and cognitive performance is compromised, in young adults with PCOS. These alterations in brain structure and function are independent of age, education and BMI. If reversible, these changes represent a potential target for treatment. PMID- 26574954 TI - Obesity Is Associated With Low NAD(+)/SIRT Pathway Expression in Adipose Tissue of BMI-Discordant Monozygotic Twins. AB - CONTEXT: Sirtuins (SIRTs) regulate cellular metabolism and mitochondrial function according to the energy state of the cell reflected by NAD(+) levels. OBJECTIVE: Our aim was to determine whether expressions of SIRTs and NAD(+) biosynthesis genes are affected by acquired obesity and how possible alterations are connected with metabolic dysfunction while controlling for genetic and familial factors. DESIGN AND PARTICIPANTS: We studied a cross-sectional sample of 40 healthy pairs of monozygotic twins, including 26 pairs who were discordant for body mass index (within-pair difference > 3 kg/m(2)), from the FinnTwin12 and FinnTwin16 cohorts. MAIN OUTCOME MEASURES: Subcutaneous adipose tissue (SAT) transcriptomics was analyzed by using Affymetrix U133 Plus 2.0 chips, total SAT (poly-ADP) ribose polymerase (PARP) activity by an ELISA kit, body composition by dual-energy x-ray absorptiometry and magnetic resonance imaging/spectroscopy, and insulin sensitivity by an oral glucose tolerance test. RESULTS: SIRT1, SIRT3, SIRT5, NAMPT, NMNAT2, NMNAT3, and NRK1 expressions were significantly down-regulated and the activity of main cellular NAD(+) consumers, PARPs, trended to be higher in the SAT of heavier co-twins of body mass index-discordant pairs. Controlling for twin-shared factors, SIRT1, SIRT3, NAMPT, NMNAT3, and NRK1 were significantly negatively correlated with adiposity, SIRT1, SIRT5, NMNAT2, NMNAT3, and NRK1 were negatively correlated with inflammation, and SIRT1 and SIRT5 were positively correlated with insulin sensitivity. Expressions of genes involved in mitochondrial unfolded protein response were also significantly down-regulated in the heavier co-twins. CONCLUSIONS: Our data highlight a strong relationship of reduced NAD(+)/SIRT pathway expression with acquired obesity, inflammation, insulin resistance, and impaired mitochondrial protein homeostasis in SAT. PMID- 26574953 TI - Dual-5alpha-Reductase Inhibition Promotes Hepatic Lipid Accumulation in Man. AB - CONTEXT: 5alpha-Reductase 1 and 2 (SRD5A1, SRD5A2) inactivate cortisol to 5alpha dihydrocortisol in addition to their role in the generation of DHT. Dutasteride (dual SRD5A1 and SRD5A2 inhibitor) and finasteride (selective SRD5A2 inhibitor) are commonly prescribed, but their potential metabolic effects have only recently been identified. OBJECTIVE: Our objective was to provide a detailed assessment of the metabolic effects of SRD5A inhibition and in particular the impact on hepatic lipid metabolism. DESIGN: We conducted a randomized study in 12 healthy male volunteers with detailed metabolic phenotyping performed before and after a 3 week treatment with finasteride (5 mg od) or dutasteride (0.5 mg od). Hepatic magnetic resonance spectroscopy (MRS) and two-step hyperinsulinemic euglycemic clamps incorporating stable isotopes with concomitant adipose tissue microdialysis were used to evaluate carbohydrate and lipid flux. Analysis of the serum metabolome was performed using ultra-HPLC-mass spectrometry. SETTING: The study was performed in the Wellcome Trust Clinical Research Facility, Queen Elizabeth Hospital, Birmingham, United Kingdom. MAIN OUTCOME MEASURE: Incorporation of hepatic lipid was measured with MRS. RESULTS: Dutasteride, not finasteride, increased hepatic insulin resistance. Intrahepatic lipid increased on MRS after dutasteride treatment and was associated with increased rates of de novo lipogenesis. Adipose tissue lipid mobilization was decreased by dutasteride. Analysis of the serum metabolome demonstrated that in the fasted state, dutasteride had a significant effect on lipid metabolism. CONCLUSIONS: Dual-SRD5A inhibition with dutasteride is associated with increased intrahepatic lipid accumulation. PMID- 26574955 TI - Genotype-Dependent Brown Adipose Tissue Activation in Patients With Pheochromocytoma and Paraganglioma. AB - CONTEXT: Patients with pheochromocytomas and paragangliomas (PGLs) may have brown adipose tissue (BAT) activation induced by catecholamine excess. (18)F fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET)/computed tomography (CT) can be used for the localization of both PGLs and BAT. It is unknown whether BAT is specifically affected by altered cellular energy metabolism in patients with SDHx- and VHL-related PGLs. OBJECTIVE: The objective of the study was to determine endocrine and paracrine effects of catecholamine excess on BAT activation in patients with PGLs as detected by (18)F-FDG PET/CT, taking into account genetic variation. DESIGN: Patients with PGLs who were fully genetically characterized underwent presurgical (18)F-FDG PET/CT imaging for tumor localization and to quantify BAT activation. SETTING: The study was conducted at a single Dutch tertiary referral center. PATIENTS AND INTERVENTION: Seventy-three patients, aged 52.4 +/- 15.4 years, with a body mass index of 25.2 +/- 4.1 kg/m(2), mean +/- SD, were grouped into sporadic, cluster 1 (SDHx, VHL) and cluster 2 (RET, NF1, MAX) mutations. MAIN OUTCOME MEASURES: (18)F-FDG mean standard uptake values were assessed in predefined BAT locations, including perirenal fat. RESULTS: Twenty-one of 73 patients (28.8%) exhibited BAT activation. BAT activation was absent in all six patients with nonsecreting PGLs. No difference in (18)F-FDG uptake by perirenal fat on the side of the pheochromocytoma and the contralateral side was observed (mean standard uptake value of 0.80 vs 0.78, respectively, P = .42). The prevalence of BAT activation did not differ between sporadic (28.9%), cluster 1 (40.0%), and cluster 2 patients (15.4%, P= .36). CONCLUSION: Patients with PGLs exhibit a high prevalence of BAT activation on (18)F-FDG PET/CT. This is likely due to systemic catecholamine excess. BAT activation is not associated with specific germline mutations. PMID- 26574957 TI - Female Physicians and the Future of Endocrinology. AB - CONTEXT: Given that approximately 70% of current endocrinology fellows are women, female physicians will compose the majority of the future endocrinology workforce. This gender shift partly reflects an apparent waning of interest in endocrinology among male trainees. It also coincides with a projected shortage of endocrinologists overall. Female physicians face unique challenges in the workplace. To continue to attract trainees to the specialty and support their success, it is imperative that these challenges be recognized, understood, and addressed. EVIDENCE ACQUISITION: A PubMed search using the terms "female physician" and "physician gender" covering the years 2000-2015 was performed. Additional references were identified through review of the citations of the retrieved articles. The following topics were identified as key to understanding the impact of this gender shift: professional satisfaction, work-life balance, income, parenthood, academic success, and patient satisfaction. EVIDENCE SYNTHESIS: Several changes can be predicted to occur as endocrinology becomes a female-predominant specialty. Although professional satisfaction should remain stable, increased burnout rates are likely. Work-life balance challenges will likely be magnified. The combined effects of occupational gender segregation and a gender pay gap are predicted to negatively impact salaries of endocrinologists of both genders. The underrepresentation of women in academic leadership may mean a lesser voice for endocrinology in this arena. Finally, gender biases evident in patient satisfaction measures--commonly used as proxies for quality of care--may disproportionately impact endocrinology. CONCLUSIONS: Endocrinology is predicted to become the most female-predominant subspecialty of internal medicine. The specialty of endocrinology should take a lead role in advocating for changes that support the success of female physicians. Strengthening and supporting the physician workforce can only serve to attract talented physicians of both genders to the specialty, which will be key to meeting the needs of the increasing numbers of patients with endocrine disorders. PMID- 26574956 TI - Biomarkers of Ectopic Fat Deposition: The Next Frontier in Serum Lipidomics. AB - CONTEXT: Strong evidence suggests that ectopic fat rather than fat mass per se drives risk for type 2 diabetes. Nonetheless, biomarkers of ectopic fat have gone unexplored. OBJECTIVE: To determine the utility of serum lipidomics to predict ectopic lipid deposition. DESIGN: Cross-sectional. SETTING: The Clinical Translational Research Center at the University of Colorado Anschutz Medical Campus. PARTICIPANTS: Endurance-trained athletes (n = 15, 41 +/- 0.9 y old; body mass index 24 +/- 0.6 kg/m(2)) and obese people with or without type 2 diabetes (n = 29, 42 +/- 1.4 y old; body mass index 32 +/- 2.5 kg/m(2)). INTERVENTION: Blood sampling and skeletal muscle biopsy. MAIN OUTCOME MEASURES: Multivariable models determined the ability of serum lipids to predict intramuscular (im) lipid accumulation of triacylglycerol (TAG), diacylglycerol (DAG), and ceramide (liquid chromatography tandem mass spectroscopy). RESULTS: Among people with obesity, serum ganglioside C22:0 and lactosylceramide C14:0 predicted muscle TAG (overall model R(2) = 0.48), whereas serum DAG C36:1 and free fatty acid (FFA) C18:4 were strong predictors of muscle DAG (overall model R(2) = 0.77), as were serum TAG C58:5, FFA C14:2 and C14:3, phosphotidylcholine C38:1, and cholesterol ester C24:1 to predict muscle ceramide (overall model R(2) = 0.85). Among endurance trained athletes, serum FFA C14:1 and sphingosine were significant predictors of muscle TAG (overall model R(2) = 0.81), whereas no models could predict intramuscular DAG or ceramide in this group. CONCLUSIONS: Different serum lipids predict intramuscular TAG accumulation in obese people vs athletes. The ability of serum lipidomics to predict intramuscular DAG and ceramide in insulin resistant humans may prove a new biomarker to determine risk for diabetes. PMID- 26574959 TI - [The Latin American Psychiatric Association]. PMID- 26574958 TI - Insulin Resistance Negatively Influences the Muscle-Dependent IGF-1-Bone Mass Relationship in Premenarcheal Girls. AB - CONTEXT: IGF-1 promotes bone growth directly and indirectly through its effects on skeletal muscle. Insulin and IGF-1 share a common cellular signaling process; thus, insulin resistance may influence the IGF-1-muscle-bone relationship. OBJECTIVE: We sought to determine the effect of insulin resistance on the muscle dependent relationship between IGF-1 and bone mass in premenarcheal girls. DESIGN, SETTING, AND PARTICIPANTS: This was a cross-sectional study conducted at a university research center involving 147 girls ages 9 to 11 years. MAIN OUTCOME MEASURES: Glucose, insulin, and IGF-1 were measured from fasting blood samples. Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated from glucose and insulin. Fat-free soft tissue (FFST) mass and bone mineral content (BMC) were measured by dual-energy x-ray absorptiometry. Our primary outcome was BMC/height. RESULTS: In our path model, IGF-1 predicted FFST mass (b = 0.018; P = .001), which in turn predicted BMC/height (b = 0.960; P < .001). IGF-1 predicted BMC/height (b = 0.001; P = .002), but not after accounting for the mediator of this relationship, FFST mass. The HOMA-IR by IGF-1 interaction negatively predicted FFST mass (b = -0.044; P = .034). HOMA-IR had a significant and negative effect on the muscle-dependent relationship between IGF-1 and BMC/height (b = -0.151; P = .047). CONCLUSIONS: Lean body mass is an important intermediary factor in the IGF-1-bone relationship. For this reason, bone development may be compromised indirectly via suboptimal IGF-1-dependent muscle development in insulin-resistant children. PMID- 26574960 TI - [Prevalence of Alcohol Abuse and Dependence in Adults With Social Phobia in Medellin]. AB - INTRODUCTION: Having a social phobia may lead to consuming alcohol for greater social assertiveness, running the risk of leading to an abuse disorder or alcohol dependence. The aim of the study was to estimate prevalence of pathological comorbidity between social phobia and alcohol consumption in adults of the city of Medellin, and the behavior of comorbidity by gender, age, presence of a father figure in childhood, and education. METHODS: Secondary analysis of the database of the first Mental Health Population Survey conducted in the city of Medellin in 2011 and 2012 based on the methodology of the World Mental Health Survey guidelines and coordinated by WHO-HARVARD. RESULTS: The lifetime prevalence of abuse and dependence in people with social phobia was 24.1% and 11.2%, respectively. For people with social phobia the prevalence was 13% for abuse and 4.4% for dependence (OR=2.11 for abuse, OR=2.46 for dependence). Annual prevalence of people with social phobia who abused or were dependent on alcohol was 7.8% and 5.9%, respectively, compared to those who do not suffer from this disorder, with a prevalence of 3.4% and 1.7%, respectively (OR=2.39 for abuse and OR=3.57 for dependence). DISCUSSION: There was significant correlation in the annual and lifetime prevalence between social phobia and the pathological consumption of alcohol. Statistically significant relationships were found for the variables associated with social phobia, however, more work is needed to confirm or refute these associations. PMID- 26574961 TI - [Psychiatric Disorders in Pediatric Patients With Systemic Lupus Erythematosus in a Reference Hospital]. AB - OBJECTIVE: To describe the psychiatric manifestations in pediatric patients with systemic erythematous lupus seen in the Fundacion Hospital de la Misericordia. METHODS: Observational descriptive study. Medical charts and test results of inpatients and outpatients between 2007 and2013 were reviewed; 39 patients were selected. SPSS 19 was used for statistical analysis. Statistical significance was considered with P=.05. RESULTS: Mean age was 13.7 (2.33), with 78.9% female. The most frequent psychiatric manifestation was anxiety (52.6%), followed by adjustment disorder and depression (36.8% each one), psychosis (10%), conversion disorder (7.9%), and obsessive compulsive disorder (5.3%). The mean SLICC score was 2.76 (2.8), and the mean SLEDAI score was 20.81 (20.82). Antinuclear antibodies were positive in 81.25%. Neuropsychiatric lupus was diagnosed in 65.8% of patients; seizures were observed in 23.7%, headache in 36.8%, stroke in 13.2%, vasculitis, chorea 5.3%, and meningitis 5.3% of patients. The mean time from lupus diagnosis was 20.47 (22.2) months, with the shortest period for adjustment disorder and the longest period in patients with conversion disorder (pseudo seizures) being 15 months and 31 months, respectively. The highest SLEDAI score was in patients with psychosis (35.5 [16.21] vs 19.08 [13.72]; P=.032), and also the highest disease damage (SLICC, 4.25 [4.03] vs 2.58 [2.67]; P=.27) in comparison with the other manifestations. CONCLUSIONS: The most frequent psychiatric manifestations were anxiety, depression, and adjustment disorder, with a higher frequency than other studies, and with lupus activity principally in patients with psychosis. PMID- 26574962 TI - [Prevalence of Variants in the Apolipoprotein E (APOE) Gene in a General Population of Adults from an Urban Area of Medellin (Antioquia)]. AB - OBJECTIVE: To determine the allelic and genotype frequencies of apolipoproteine E (APOE) gene in a representative sample of the adult population of Medellin in 2010. METHODS: A representative sample of the adult population of Medellin, was obtained by means of a multi-stage, stratified, conglomerate based sampling method. APOE genotyping was carried out on each of the participants. The sampling design was taken into consideration for the frequencies and association analysis. RESULTS: The frequencies of the APOE alleles E2, E3 and E4 were 3.9, 92.0 and 4.1%, respectively. The frequencies of the different APOE genotypes were as follows: 2/2, 0.2%; 2/3, 6.8%; 2/4, 0.6%; 3/3, 85.0%; 3/4, 7.2%, and 4/4, 0.3%. CONCLUSIONS: The allelic and genotype frequencies of APOE in an adult population of Medellin did not differ substantially from other series reported in South America. These data are important to determine the real impact of APOE on the population risk of several psychiatric diseases. PMID- 26574963 TI - [Emotional Profile of a Group of Colombian Military Victims of Landmines or Improvised Explosive Devices]. AB - INTRODUCTION: Antipersonnel Mines (MAP) and Improvised Explosive Devices (IEDs) are frequently used in Colombia as an armed resource without the need for direct combat. The Department of Antioquia has the highest number of events associated with the detonation of such battle techniques. There are no studies on the psychological effects that appear as a result of accidents with Antipersonnel Mines and IEDs in the military population. OBJECTIVE: To establish the psychological profile of a group of military victims of MAP and AEI, and a control group of soldiers who were not victims from the analysis of four emotional variables (depression, anxiety, anger and stress). METHODS: The research was conducted using a case-control design in a .quantitative, comparative, descriptive and cross-sectional study. PARTICIPANTS: A sample of 80 soldiers assigned to the Seventh Division of the National Army of Colombia at Medellin, Antioquia. The sample included a group of 30 military cases and 50 soldiers as controls. RESULTS: The anxiety state, trait anxiety, state anger, and trait anger variables showed statistically significant differences between groups. There were no significant differences in the variables depression and stress between groups variables. There was no depression, anxiety, or stress in either of the two groups, but there were clinically significant levels of anger in both groups. PMID- 26574964 TI - [Evaluation of the Methadone Maintenance Program of the Risaralda Mental Hospital]. AB - BACKGROUND: Psychosocial care and methadone maintenance treatment (MMT) are the preferred strategies for the management of heroin addicts, but the results are still unsatisfactory, justifying the search and intervention of the factors influencing the response to treatment. METHODOLOGY: In order to determine the contribution of demographic, clinical and genetic variables on serum concentrations and response to methadone, we investigated patients on MMT, who were receiving methadone in supervised and unchanged doses at least during the previous two weeks. The age, gender, body mass index (BMI), duration of heroin abuse, addiction to other drugs, criminal background, current daily methadone doses, time spent in the TMM, comorbidity and concomitant medication were recorded. Blood samples were taken for the determination of serum levels of racemic methadone and its R and S-enantiomers, and for typing of candidate alleles of POR, CYP2B6, ABCB1, GRIN1, OPRM1, SLC6A3, DbetaH and ARRB2 genes, all associated with the metabolism, tissue distribution and mechanism of action of methadone. Methadone quantification was by HPLC-DAD, and the detection of genetic markers by Real Time PCR and VNTR methods. RESULTS: A total of 80 subject volunteers were enrolled, with a mean age of 23.5 (5) years (86% male), all of them were addicts of multiple drugs, 60% with a criminal background, 5.1 (2.9) years taking heroin, and 5.3 (4) months on MMT, and taking a supervised dose of 41 (12) mg/day methadone. The (R), (S) and (R, S) methadone enantiomer trough plasma levels were, 84 (40), 84 (42), and 168 (77) ng/mL, respectively. All genotypes were in Hardy-Weinberg equilibrium. The two urine tests were negative for heroin in 61.3% (49/80) of the volunteers, the decline in cocaine/crack use was 83%, 30% of marijuana, and other psychoactives (inhalants, benzodiazepines, amphetamines) decreased to zero, while the consumption of snuff remained at 93.5% (75/80). Blood concentrations of racemic methadone and its enantiomers were significantly associated with the dose/day of the medication, but none of the other demographic, clinical or genetic variables impacted on serum levels of methadone. As for the results of the MMT, non-users and occasional users of heroin, as well as those who stopped taking other psychoactive drugs, and the ones who did not, were similar as regards the demographic, genetic and clinical variables. This included the blood metahdone concentrations, except for individuals who did not reduce their consumption of other psychoactives other than heroin, who had significantly (P=.03) higher blood levels of S-methadone, compared with those who did stop taking them. CONCLUSIONS: There was a significant reduction in the consumption of heroin and other psychoactives, and social rehabilitation of patients. However, the extensive overlap between effective and ineffective doses of methadone suggests the presence of personal and social variables that transcend the simple pharmacological management. These probably need to be addressed more successfully from the psychosocial features, particularly as regards to identifying and overcoming relapse-trigger experiences, as well as certain features of the patient, such as their psychological distress level or their psychiatric disorders. PMID- 26574965 TI - Clinical and Epidemiological Characteristics of Suicides Committed in Medellin, Colombia. AB - BACKGROUND: The purpose of this study was to identify the characteristics of individuals who committed suicide in Medellin between 2008 and 2010, and to identify variables related to the type of events. METHODS: A retrospective and descriptive analysis was conducted on data provided by the National Institute of Legal Medicine and Forensic Sciences. In addition, a univariate and bivariate analysis was used to identify the sociodemographic and medical-legal characteristics of the deceased. Multiple correspondence analysis was also used in order to establish typologies. The information was analyzed using STATA 11.0. RESULTS: Of the 389 cases occurring between 2008 and 2010, 84.6% (n=329) were men. The male to female ratio was 5:1; 64% of the cases occurred in people aged 18-45 years; 6.7% occurred in children under 18, with hanging being the method most chosen by the victims (48.3%). Exploratory analysis was used to identify a possible association between the use of violent methods and events occurring in the housing and social strata 1, 2 and 3. CONCLUSIONS: Some factors could be associated with suicide, providing data that could consolidate health intervention strategies in our population. PMID- 26574966 TI - [Factors Associated with Cognitive Decline in a Population Less than 65 Years Old. A Systematic Review]. AB - INTRODUCTION: Cognitive decline could begin 20 years before the diagnosis of dementia. Besides age, several factors related to medical, socioeconomic, and behavioral and genetic condition may be associated with cognitive decline. The aim of this systematic review was to summarize evidence on the risk and protective factors for cognitive decline in people under 65 years old. METHODS: A systematic review was conducted using a search strategy in MEDLINE and Embase, including longitudinal studies to analyze the effect of protective or risk factors on cognitive decline in a population under 65 years old. RESULTS: A total of 22 studies were included in this review. Factors such as diabetes, hyperinsulinemia, overweight or obesity, metabolic syndrome, education, physical activity, cognitive stimulation, marital status and diet, could be related to cognitive decline before 65 years of age. CONCLUSIONS: Cardiovascular risk factors and lifestyle conditions may be associated with cognitive decline before 65 years of age. However, the quality of the evidence was low. PMID- 26574967 TI - The Latin American Psychiatric Association. PMID- 26574973 TI - [What Solutions for the Financing of Innovation?]. PMID- 26574972 TI - Killer Cell Immunoglobulin-Like Receptor (KIR) Genotype Distribution in Familial Mediterranean Fever (FMF) Patients. AB - BACKGROUND Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disease predominantly affecting Mediterranean populations. The gene associated with FMF is the MEFV gene, which encodes for a protein called pyrin. Mutations of pyrin lead to uncontrolled attacks of inflammation, and subclinical inflammation continues during attack-free intervals. Killer cell immunoglobulin-like receptor (KIR) genes encode HLA class I receptors expressed by NK cells. The aim this study was to look for immunogenetic determinants in the pathogenesis of FMF and find out if KIR are related to susceptibility to disease or complications like renal amyloidosis. MATERIAL AND METHODS One hundred and five patients with FMF and 100 healthy individuals were involved in the study. Isolated DNA from peripheral blood was amplified by sequence specific PCR probes and analyzed by Luminex for KIR genotypes. Fisher Exact test was used to evaluate the variation of KIR gene distribution. RESULTS All patients and healthy controls expressed the framework genes. An activator KIR gene, KIR2DS2, was significantly more frequent in FMF patients (p=0.036). Renal amyloidosis and presence of arthritis were not associated with KIR genes and genotype. KIR3DL1 gene was more common in patients with high serum CRP (p=0.016). CONCLUSIONS According to our findings, we suggest that presence of KIR2DS2, which is an activator gene for NK cell functions, might be related to the autoinflammation in FMF. The potential effect of KIR genes on amyloidosis and other clinical features requires studies with larger sample sizes. PMID- 26574974 TI - Current Challenges and Future Directions in Screening for Brain Tumours. PMID- 26574975 TI - [Analysis of the Cochrane Review: Influenza Vaccines for Preventing Cardiovascular Disease. Cochrane Database Syst Rev. 2015;5:CD005050]. AB - Influenza infections are associated to increased risk of cardiovascular events. The systematic review of Cochrane Collaboration evaluated the role of influenza vaccination on primary or secondary prevention of cardiovascular events. The meta analysis of four randomized controlled trials with moderate quality, including 1 682 patients with coronary artery disease, showed a 55% risk reduction on cardiovascular mortality. Data evaluating the role of vaccination in primary cardiovascular prevention were not robust. Portuguese and international recommendations for influenza vaccination in patients with coronary artery disease are then supported by this systematic review. PMID- 26574976 TI - Musculoskeletal Injuries in Competitive Rowers. AB - INTRODUCTION: The objective of this study was the assessment of the injuries occurred over the competitive rowing lifetime of Portuguese senior rowers. MATERIAL AND METHODS: We sent a questionnaire to all Portuguese senior rowers medalled in the national championships during the 2013-2014 season. We analysed biometric variables, anatomic location, type and circumstances of injury occurrence, type of treatment provided and time of inactivity. For statistical analysis we used parametric and non-parametric statistics with 95% confidence levels (p < 0.05). RESULTS: The questionnaire was answered by 18 of the 18 female and 74 of the 77 male rowers. Females had significantly lower ages, heights and weights and rowed more often sculling boats (p < 0.05). The number of years of practice, as well as the number of injuries per rower was similar, for both females and males. The mean age at the first injury was significantly lower in females (p < 0.001), who also had more progressive lesions than acute ones, although not significantly. In both, the most frequent anatomical location and type of injury were the lumbar region and muscular pathology, with a higher occurrence in winter and spring, during land training. Femalessustained longer periods of inactivity, but not significantly. DISCUSSION: The results that were different from those reported by other authors may be related with differences in the studied populations or with other factors that need to be clarified. CONCLUSION: The injuries sustained by the Portuguese competitive rowers, probably associated with a lower competitive exposure of our athletes, were less severe than those generally reported in the literature. PMID- 26574977 TI - Mumps Outbreak among Highly Vaccinated Teenagers and Children in the Central Region of Portugal, 2012-2013. AB - INTRODUCTION: Mumps vaccine was introduced in the National Immunization Program in Portugal in 1987, rapidly reaching a national coverage > 92%, with important reduction in the annual incidence of the disease. We report a mumps outbreak in the Central Region of Portugal, occurred in the winter 2012-13. MATERIAL AND METHODS: Cases of salivary-gland swelling and other symptoms compatible with mumps were investigated. Geodemographics, clinical, laboratory and vaccination data were analyzed. RESULTS: Over six months, 148 outbreak-related cases were reported: 87.8% occurred in three of the 16 affected counties and 78.4% had a known epidemiological link. Median age was 14.5 years (2-62) and 70.3% were 11-20 years old; 61.5% were male. The mean duration of disease was seven days (2-20). The disease was generally mild; 80.4% had fever and in 55.4% there was unilateral involvement of the parotid gland. Seven cases had orchitis, one oophoritis and one had nephritis. Two cases were hospitalized. School transmission predominated and class attack rates were < 30%. Most of the cases occurred in vaccinated individuals (92%) of whom 86.8% had received 2 doses; 17.7% had received one dose of the vaccine containing the Rubini strain. Mumps virus genotype G was identified in 4 cases. DISCUSSION: This mumps outbreak among a highly vaccinated population, occurring mostly in teenagers at school, could be due to the partial effectiveness of the vaccine against the disease (particularly in the group vaccinated with Rubini strain), waning immunity overtime and genotype mismatch. CONCLUSIONS: This outbreak report shows the importance of discussion about the need of more booster dose of the actual vaccine or new vaccine including more genotypes to improve immunogenicity. PMID- 26574978 TI - The Impact of Cochlear Implant in the Oral Language of Children with Congenital Deafness. AB - INTRODUCTION: Children with severe to profound sensorineural deafness can acquire vocabulary and syntactic structures to communicate by oral language, after cochlear implant. AIM: Identify the linguistic skills of children with cochlear implant. MATERIAL AND METHODS: Eighteen children of both gender, between 9 and 10 years, with congenital bilateral deafness, using cochlear implant, were studied. The evaluation instrument used was Observation Chart of Language-School Level. The results were compared with standard of normal-hearing children with the same hearing age. RESULTS: The scores registered in the linguistics structures studied, comparing implanted children and standard, was: phonology, 29.44 +/- 8.4 vs. 29.68 +/- 5.90, p = 0.91; semantics, 18.55 +/- 8.89 vs. 19.20 +/- 4.85, p = 0.76; morpho-syntax 21.89 +/- 12.85 vs. 26.35 +/- 10.36, p = 0.159. Regarding the tests of semantics, there was no significant difference. Concerning the tests of morpho-syntactic structure, the difference was significant in the derivation of words, 2.83 +/- 2.81 vs. 4.65 +/- 1.64, p = 0.014. In the phonology, a significant difference was found comparing implanted children and standard, in the discrimination of pseudo words, 6.6 +/- 2.8 vs. 8.37 +/- 2.32, p = 0.023. However, in syllabic segmentation, implanted children had a mean score 8.56 +/- 1.6 significantly higher than standard, 5.9 +/- 1.58, p < 0.001. DISCUSSION: The similarity of the scores obtained by children with cochlear implants with the standard, in the language components studied confirms that cochlear implant promotes the development of oral verbal language in children with congenital deafness. CONCLUSIONS: Implanted children had acquired language skills similar to normal-hearing children with the same hearing age. PMID- 26574979 TI - Malignant Small Bowel Tumors: Diagnosis, Management and Prognosis. AB - PURPOSE: Despite being rare entities, the incidence of malignant small bowel tumors seems to be rising. The development of capsule endoscopy and balloon assisted enteroscopy provided an advance in the assessment of small bowel lesions. We aim to describe the clinical and pathological characteristics of patients with small bowel cancer and ascertain what roles these endoscopic techniques currently have. MATERIAL AND METHODS: A retrospective study of patients diagnosed with small bowel cancer, from January 2010 to October 2014, was performed. The data was submitted to statistical analysis. RESULTS: Of the 28 diagnosed patients, 54% were female. The mean age at diagnosis was 61 years. Adenocarcinoma was the most frequent tumor (n = 11), followed by sarcoma (n = 6), lymphoma (n = 6) and neuroendocrine tumors (n = 3). The main form of presentation was related to blood loss or intestinal obstruction. By the time of diagnosis, 46% of patients had distant metastasis/ unresectable cancer. Most of the tumors were diagnosed by endoscopic (41%) or imaging techniques (35%). In the first year after diagnosis, 29% of patients died. In multivariate analysis, adenocarcinoma remained an independent factor for worse survival. DISCUSSION: Patients with adenocarcinoma presented at late stages and with unresectable tumors, contributing to a worse outcome. A high degree of clinical suspicion for the diagnosis of small bowel cancer is necessary. CONCLUSION: The characteristics of the patients were generally consistent with those described in the literature. Capsule endoscopy and balloon assisted enteroscopy are useful in the diagnosis, management and surveillance of small bowel cancer. PMID- 26574980 TI - Effects of Acute Sleep Deprivation Resulting from Night Shift Work on Young Doctors. AB - INTRODUCTION: To evaluate sleep deprivation and its effects on young physicians in relation to concentration capacity and psychomotor performance. MATERIAL AND METHODS: Eighteen physicians aged 26 - 33 years were divided into 2 groups: non sleep deprived group (with no night work) and sleep deprived group (minimum 12 hour of night work/week). We applied Pittsburgh Sleep Quality Index to screen the presence of sleep pathology and Epworth Sleepiness Scale to evaluate subjective daytime sleepiness; we used actigraphy and sleep diary to assess sleep hygiene and standard sleep-wake cycles. To demonstrate the effects of sleep deprivation, we applied Toulouse-Pieron's test (concentration test) and a battery of three reaction time tasks after the night duty. RESULTS: Sleep deprived group had higher daytime sleepiness on Epworth Sleepiness Scale (p < 0.05) and during week sleep deprivation was higher (p < 0.010). The mean duration of sleep during the period of night duty was 184.2 minutes to sleep deprived group and 397.7 minutes to non-sleep deprived group (p < 0.001). In the Toulouse-Pieron's test, the sleep deprived group had more omissions (p < 0.05) with a poorer result in concentration (p < 0.05). Psychomotor tests that evaluated response to simple stimuli revealed longer response latency (p < 0.05) and more errors (p < 0.05) in Sleep deprived group; in reaction to instruction test the sleep deprived group showed worse perfection index (p < 0.05); in the fine movements test there was no statistically significant difference between the groups. DISCUSSION: Acute sleep deprivation resulting from nocturnal work in medical professions is associated with a reduction in attention and concentration and delayed response to stimuli. This may compromise patient care as well as the physician's health and quality of life. CONCLUSION: It is essential to study the effects of acute sleep deprivation on the cognitive abilities and performance of health professionals. PMID- 26574981 TI - Pulmonary Embolism in Ambulatory Oncologic Patients. AB - INTRODUCTION: The association between cancer and venous thromboembolism is known, and oncology patients present a risk six to seven times higher than the general population of a thrombotic event. Pulmonary embolism is an important cause of morbidity and mortality in this patients group, presenting an underestimated prevalence. MATERIAL AND METHODS: Retrospective study of all episodes of pulmonary embolism referenced in the last five years. We only selected oncologic outpatients and studied their demographics characteristics, risk factors associated with venous thromboembolism, presence of symptoms at diagnosis, risk stratification of venous thromboembolic events by the Khorana model, probability of mortality at 30 days and overall survival. The study is in accordance with the Helsinki declaration. RESULTS: From the 186 patients under evaluation, 55.9% were female, with median age of 64 years. The most prevalent cancers were colorectal (24.2%) and lung (17.7%), most of which had metastases (66.1%) or underwent chemotherapy (69.4%). Pulmonary embolism was a radiological finding in 69.4%, whereas no clinical variable was relevant for the presence or absence of symptoms. Mortality at 30 day resulting from pulmonary embolism was 7.5%, and it was found that symptomatic patients had a lower median survival relative to asymptomatic (12 vs. 20 months, p = 0.029). The retrospective application of the Khorana model to those undergoing chemotherapy identified 11% of individuals at high risk. DISCUSSION: Pulmonary thromboembolism was an imagiological finding in most patients, with no clinical variable able to predict the presence or absence of symptoms. Asymptomatic patients had a higher survival. CONCLUSION: In our study pulmonary embolism was apparently asymptomatic in most study patients. These data reinforce the need to evaluate the risk of venous thromboembolism in cancer outpatients and consider conducting antithrombotic prophylaxis. PMID- 26574982 TI - Assessment of Suicidal Behavior in a Psychiatric Emergency Room in Lisbon. AB - INTRODUCTION: Some studies alerted for the burden of suicidal attempters at emergency rooms. In this study we characterized the suicidal patients admitted to a Portuguese emergency room. MATERIAL AND METHODS: For three years, all patients assessed by the first author after suicidal behaviour were included. Suicidal intentionality was evaluated with the Pierce Suicide Intent Scale. Clinical records were searched for follow-up status and satisfaction level was assessed through telephone call. RESULTS: From 120 included patients 70.8% were female, with mean age of 42.35 years. Pierce Suicide Intent Scale suicidal intentionality was low in 30.1%, medium in 59.3%, and high in 10.6% of the sample. The most important predictors of Pierce Suicide Intent Scale intentionality were male gender (p < 0.001), family history of suicide (p < 0.01), divorced or widowed marital status (p < 0.013), and severe mental illness (p < 0.015). In 41.6% of the patients the follow-up status was unknown. Regarding satisfaction, only 19.5% gave a valid answer: 2.7% 'mildly satisfied', 4.4% 'moderately satisfied', and 12.5% 'very satisfied'. DISCUSSION: The Pierce Suicide Intent Scale is useful on suicidal behavior assessment at emergency rooms. Highly intentional suicidal behaviour is related to male sex, social problems and personal and familial psychiatric history. CONCLUSION: The quality of administrative records on this psychiatric emergency room setting are still unacceptable. The most important variables correlated with higher suicidal intentionality are the same described in other countries. Of the reachable patients, one fifth was satisfied with provided follow-up. We still need studies for better understanding of suicidal behaviour observed on this Portuguese emergency room. PMID- 26574983 TI - Bundle Approach to Reduce Bloodstream Infections in Neutropenic Hematologic Patients with a Long-Term Central Venous Catheter. AB - INTRODUCTION: The objective of the study was to reduce, by a bundle of interventions, the global bloodstream infections and catheter-related bloodstream infections rates in neutropenic hematology patients with a long-term central venous catheter. MATERIAL AND METHODS: This was a non-randomized prospective study. It was conducted in a 20-bed hematology oncology unit (Portuguese Institute of Oncology, Porto, Portugal) between 1st of August 2010 and 31st of January 2012. In this period we introduced a bundle of interventions (study group) and compared the results with the six months prior to implementation (control group). The interventions consisted in the use of a neutral pressure mechanical valve connector instead of a positive pressure mechanical valve connector, a more frequent change of this connector and a more efficient clean solution. One hundred and sixteen hematology patients with a long-term central venous catheter at time superior of 72 h, with 8 867 central venous catheter days [6 756 central venous catheter days in the study group and 2 111 central venous catheter days in the control group] were included in the study. RESULTS: A significant reduction in bloodstream infections rates and catheter-related bloodstream infections rates was achieved. Bloodstream infections rates: [32.69 (control group) vs. 9.43 (study group)], incidence reduction 71% [relative risk 0.2886, CI 95% (0.1793 - 0.4647), p < 0.001] and catheter-related bloodstream infections rates: [17.53 (control group) vs. 4.73 (study group)], incidence reduction 71% [relative risk 0.2936, CI 95% (0.1793 - 0.5615), p < 0.014]. No significant difference (p > 0.05) was found in the neutrophil count at the time of blood culture samples between groups: 69% (< 500 neutrophils/mm3) [71% (study group) vs. 68% (control group)]. CONCLUSIONS: The introduction of this bundle of interventions based on the variables of patient, product and practice, supported by the Healthcare and Technology Synergy framework, quickly resulted in a significant reduction of bloodstream infections and catheter-related bloodstream infections rates. PMID- 26574984 TI - Minimal Hepatic Encephalopathy: The Reality Beyond Our Eyes. AB - INTRODUCTION: Minimal hepatic encephalopathy refers to a mild neurocognitive impairment not detectable by clinical examination that can be present in cirrhotic patients. AIM: To determine the prevalence of minimal hepatic encephalopathy in a secondary healthcare center in Northern Portugal. MATERIAL AND METHODS: A cross-sectional study was conducted. Cirrhotic outpatients were included. EXCLUSION CRITERIA: overt hepatic encephalopathy, illiteracy, active alcohol consumption, psychotropic drug use and therapy with lactulose. The presence of minimal hepatic encephalopathy was defined as a value >= -4 on the Psychometric Hepatic Encephalopathy Score, calculated according to the Portuguese norms. Variables analyzed: etiology and severity of liver disease and venous blood ammonia concentration. p values < 0.05 were considered significant. RESULTS: From the 102 patients who were evaluated, 41 were included: 31 males, mean age 57 +/- 10 years, mean education 5 +/- 2 years, 31 in Child-Pugh class A, mean MELD score 6 +/- 3. Minimal hepatic encephalopathy was diagnosed in 14 (34%) patients. The presence of minimal hepatic encephalopathy was unrelated to severity of liver disease. Despite being more elevated, the mean venous ammonia concentration in minimal hepatic encephalopathy patients was not statistically different from the mean venous ammonia concentration in non-minimal hepatic encephalopathy patients (48.5 +/- 13.3 vs. 45.6 +/- 15.6 MUmol/L, p = 0.555). DISCUSSION: The prevalence of minimal hepatic encephalopathy reported is in accordance with the international published data. CONCLUSION: Minimal hepatic encephalopathy is a frequent condition that is present early in the course of cirrhosis, even in compensated cirrhotic patients. Therefore, this hidden entity should be actively pursued and managed properly. PMID- 26574985 TI - Looking for the Perfect Mentor. AB - INTRODUCTION: The authors established the profile of the Internal Medicine clinical teachers in Portugal aiming to define a future interventional strategy plan as adequate as possible to the target group and to the problems identified by the residents. MATERIAL AND METHODS: Observational, transversal, analytic study. An online anonymous questionnaire was defined, evaluating the demographic characteristics of the clinical teachers, their path in Internal Medicine and their involvement in the residents learning process. RESULTS: We collected 213 valid questionnaires, making for an estimated response rate of 28.4%. Median global satisfaction with the clinical teacher was 4.52 (+/- 1.33 points) and the classification of the relationship between resident and clinical teacher was 4.86 +/- 1.04 points. The perfect clinical teacher is defined by high standards of dedication and responsibility (4.9 +/- 1.37 points), practical (4.8 +/- 1.12 points) and theoretical skills (4.8 +/- 1.07 points). The multiple linear regression model allowed to determine predictors of the residentas satisfaction with their clinical teacher, justifying 82,5% of the variation of satisfaction with the clinical teacher (R2 = 0.83; R2 a = 0.82). DISCUSSION: Postgraduate medical education consists of an interaction between several areas of knowledge and intervening variables in the learning process having the clinical teacher in the central role. Overall, the pedagogical abilities were the most valued by the Internal Medicine residents regarding their clinical teacher, as determinants of a quality residentship. CONCLUSION: This study demonstrates the critical relevance of the clinical teacher in the satisfaction of residents with their residentship. The established multiple linear regression model highlights the impact of the clinical and pedagogical relantionship with the clinical teacher in a relevant increase in the satisfaction with the latter. PMID- 26574986 TI - Retained Textile Foreign Bodies: Experience of 27 Years. AB - INTRODUCTION AND AIM: Retained intracorporeal textile products (gossypiboma textiloma) are undesired and accidental surgical results for both patients and surgeons, which are underreported because of medicolegal remifications. Fourteen textiloma cases, who had been treated or whose treatment procedures had been followed-up personally by two general surgeons in a period of 27 years almost during their whole professional lives were presented to describe and define the clinical and pathological characteristics. MATERIAL AND METHODS: Patient characteristics including gender and age, areas of location within the body, time intervals until diagnosis, clinical presentations and complaints, treatment modalities, complications, causative surgical interventions, and diagnostic approaches were retrospectively evaluated. RESULTS: Nine female and five male patients with a mean age of 43.07 +/- 15.23 (median: 45) years at diagnosis were enrolled in the study. Cesarean section in three, inguinal hernioraphy in four, explorative laparotomy because of acute abdomen in one, sigmoid colon resection in one, appendectomy and right salpingoophorectomy in one, etrangulated incisional hernia after a previous surgical intervention because of an ovarian mass in one, thyroidectomy in one, epigastric hernioraphy in one, and bilateral segmental mastectomy with bilateral axillary sentinal lymph node dissection in one were the causative surgical interventions. Locations of textilomas were the abdominal cavity in seven, inguinal surgical wound in four, epigastric surgical wound in one, thyroidectomy lodge in one, and bilateral axillary cavities in one patient. The mean time interval until diagnosis was 14.48 (median: 5.5) months. DISCUSSION: Earlier recognition of foreign bodies can provide a better outcome. CONCLUSION: Gossypibomas are preventable iatrogenic faults which create severe problems. Strict adherence to the rules of the operation room is a must to keep the tip of the iceberg shut in the Pandora's box. PMID- 26574987 TI - [Measuring Instruments of the Quality of Life Pediatric Palliative Care]. AB - INTRODUCTION: Palliative care is closely linked to the concept of quality of life. In this work we will focus our interest on the need to assess quality of life in oncologic paediatric palliative care. OBJECTIVE: To describe/compare instruments for measuring quality of life in Oncologic paediatric palliative care. MATERIAL AND METHODS: A literature review of the sever a instruments for measuring quality of life of children under palliative care, in English and Portuguese, between 2000 and 2013, was carried out in the recognized databases for this purpose. RESULTS: We found fifteen measuring instruments: 10 of them were generic and 5 specific. For each instrument the country of origin, the target age group, fill manner, number of evaluated dimensions, description of dimensions, and number of questions, psychometric properties and validation for the Portuguese language were identified. DISCUSSION: There has been a growing concern in measuring quality of life in pediatric age. Most measuring instruments were designed, in the United States, after 1994, coinciding with the World Health Organization definition of quality of life. As regards to age, most of the instruments were developed for children aged eight or more years old and there is no one to be answered only by the child. We can see that the majority of measuring instruments, namely the most current, seeking to involve the child in evaluating his/her own health related quality of life through auto-population (n = 10). However, there is still a substantial dependence on parents for the measurement of health related quality of life of their children, despite studies demonstrates differences between the child and parents, on perception of health related quality of life. But, since many children are not able to provide data on health related quality of life either due to their age or because they are ill or with functional incapacity, the only possibility to get information about the health related quality of life of these children is to appeal to parents, who are asked to reflect on the lack of their child, or teenager. Thus full completion by parents of some measuring instruments may be justified. In Pediatrics measuring instruments of health related quality of life are multidimensional, often intended to measure the subjective point of view in relation to the impact of the disease and the treatment have on the physical, psychological and social well being. Thus, the wide range of dimensions, the differences in number of dimensions and the number of questions between the various instruments tend to reflect the different stages of psychomotor development of the target population. CONCLUSION: The most commonly measure dimensions were physical ability, emotional/psychological impact, social and at school impact, followed by pain and discomfort and activity level. The majority of instruments are designed for children aged over 8 years. A large number of the questionnaires are self completion questionnaires. Others can be completed by parents. Most of the instruments tested their internal coherence (n = 9) and, in a small number, the test-retest reproducibility (n = 7) and agreement among observers(n = 2). Most of the questionnaires reported their content validity (n = 10) and construct validity (n = 9), few have examined the validity of criterion (n = 2). Considering the examined instruments, six questionnaires are validated for the Portuguese population (five generic and one specific for oncologic disease). PMID- 26574988 TI - [Informed Treatment Consent and Refusal in Advanced Endonasal Surgery: The Ethical Dilemma of Olfaction Sacrifice in Surgery for Chronic Rhinosinusitis with Polyposis]. AB - INTRODUCTION: Olfaction is frequently affected in chronic rhino-sinusitis with polyposis and has been recognised to have important impact on quality of life. Surgical resolution on cases of maximal medical therapy failure is an option to relieve symptoms, with debates as to how extensive surgery should be. A more radical approach will achieve better disease control with less relapse, but can also compromise olfaction. This decision about a more radical surgical approach should be shared with the patient. Thorough informed consent regarding disease control and hyposmia should be taken. MATERIAL AND METHODS: Literature review and consultation with a board of experts. RESULTS AND DISCUSSION: We propose some elements to be included in the informed consent discussion, in order to broadly address the surgical limitations regarding anosmia as a frequent complaint, as well as the different options and their associated consequences. CONCLUSION: Radical surgery decision making should be shared with the patient and the informed consent should be as thorough as possible regarding disease control and hyposmia resolution. PMID- 26574989 TI - [The Role of Aspirin in Preeclampsia Prevention: State of the Art]. AB - INTRODUCTION: The role of acetyl salicylic acid (ASA or aspirin) in preeclampsia prevention and in other complications has been subject to studies and controversies for the last 30 years. The first research results concerning the role of placenta in preeclampsia have been published by the end of seventies and they showed an increase in the platelet activity and a prostaglandin synthesis disturbance, as a consequence of a deficient placentation. In the last twenty years of the XX century important studies were published on the aspirinprophylactic role in preeclampsia risk reduction. MATERIAL AND METHODS: To analyze published studies about Aspirin use for preeclampsia prevention and about the more adequate dosage to be administered, Medline was used for searching the most relevant prospective research papers on this subject in order to evaluate current evidence about the use of aspirin in this context. Relevant citations were extracted from Embase, PubMed and the Cochrane Central Register of Controlled Trials. We divided the studies in two groups; one with aspirine administration before 16 weeks and the other having a larger use, between the first and the third trimester. RESULTS AND DISCUSSION: The first group of studies, with a lesser number of cases but an earlier time of administration until 16 weeks, concluded that a positive role of aspirine was possible in reducing severity of preeclampsia; the second group with a larger number of cases but less restricted conditions and timing of administration, had controversial results, with reduced positive actions of the drug. Meta-analysis of these published studies concluded that favorable results were associated to stricter criteria and ideal timing for startingthe drug. CONCLUSION: As we do not have other pharmacologic alternatives, low dosage of Aspirin between 80-150 mg a day in the first trimester and until 16 weeks, at evening time, is a possible choice in cases of risk, and is still contributing for an early preeclampsia risk reduction. PMID- 26574990 TI - Metastasis to the Glans Penis: An Unusual Site of Rectal Cancer Recurrence. AB - Secondary malignancy of the penis is a rare clinical condition, often associated with disseminated genitourinary malignancies. The prognosis is poor and the treatment options include penectomy, local surgical excision, radiation therapy, chemotherapy and supportive therapy. Neither of these therapeutic options lead to superior treatment outcomes in the literature. The authors report the case of a 66 year-old man with a metastasis to the glans penis from a rectal adenocarcinoma, diagnosed two years after radical treatment for primary disease. The patient underwent palliative treatment with radiotherapy and chemotherapy, remaining asymptomatic and disease-free at one year follow-up. Close follow-up of patients with history of rectal adenocarcinoma is very important. Radiochemotherapy is a feasible and effective therapeutic option for penile metastasis, addressing both disease control and symptomatic improvement. PMID- 26574991 TI - [Spontaneous Non Ischaemic Blue Finger: A Rare and Benign Phenomenon]. AB - The spontaneous non-ischaemic blue finger is a rare and benign disorder, characterized by purple discoloration of a finger, with complete resolution. This article reports the case of a woman of 88 years, which after a few hours of stay in the emergency department developed without associated trauma, a purplish color of the 3rd finger of the right hand, with a palpable pulse and without temperature changes or pain. The etiological investigation was negative. The patient was assessed one week after the event and showed completeresolution. There are several diseases that share the same signs and symptoms, as such the diagnosis is based on the spontaneous violaceous color sparing the finger tip, and fast resolution without treatment. Though being a harmless phenomenon, it requires early assessment for timely differential diagnosis with severe pathologies. PMID- 26574992 TI - [Pulmonary Amyloidosis: A Diagnostic Challenge]. AB - Amyloidosis is characterized by amyloid extracellular deposition in organs and tissues. Pulmonary involvement is a rare manifestation of the disease and it can be focal or as part of systemic amyloidosis. We report two cases. Case 1: 71 year old female with bronchiectasis and Sjogrena syndrome, who complained of anorexia, weight loss and a productive cough. The diagnostic study included a surgical lung biopsy and histological examination demonstrated pulmonary amyloidosis. Case 2: 83 year-old male patient, ex-smoker, asymptomatic, whose routine chest x-ray showed a nodular opacity in the right lung field. A transthoracic biopsy revealed an amyloid lung tumor. These cases illustrate a rare disease which in Case 1 also coexisted with Sjogrenas syndrome and bronchiectasis. The most important differential diagnosis is cancer and so a definitive diagnosis is essential, as amyloidosis is usually benign and indolent. PMID- 26574993 TI - [Pneumatosis Coli Treated with Metronidazole and Hyperbaric Oxygen Therapy: A Successful Case]. AB - Pneumatosis intestinalis, characterized by the presence of gas within the bowel wall, is an uncommon condition with variable presentation. It may be idiopathic or secondary to other diseases. A computed tomography scan is the most sensitive method for diagnosis. In the absence of signs and symptoms of complications, such as perforation and peritonitis, pneumatosis intestinalis can be managed conservatively. We present the case of a 59-year-old woman with pneumatosis coli secondary to benign ovary teratoma. After surgery she remained symptomatic and was successfully treated with metronidazole and hyperbaric oxygen therapy. PMID- 26574994 TI - [Lingual Lesions in a HIV-Positive Patient]. PMID- 26574995 TI - Multiple Liver Abscesses due to Morganella morganii. PMID- 26574996 TI - [What Sir Luke Fildes 'The Doctor' Can Tell us Today]. PMID- 26574997 TI - A Model of Lymphangioleiomyomatosis in a Three-Dimensional Culture System. AB - BACKGROUND: Lymphangioleiomyomatosis (LAM) is a tumor consisting of benign looking neoplastic cells, but its wretched clinical outcome often resembles a malignant disease. LAM cell clusters (LCCs), unique microstructures commonly found in LAM-associated chylous effusion, are aggregates of LAM cells rimmed by lymphatic endothelium. LCCs seem to be crucial participants in the dissemination and progression of LAM. METHODS AND RESULTS: LCCs isolated from LAM-associated chylous effusion were embedded in a three-dimensional (3-D) culture gels, and then placed in a humidified CO2 incubator. During serial observations of their morphological changes, we found tube formations with lymphatic endothelial cells when LCCs settled side by side in 3-D gels. On the other hand, when LCCs were embedded separately enough to be isolated at their initial sites of settlement in the gels, each of LCCs gradually broke down, leaving a "cyst-like" hole after 7 days at the site where LCCs initially resided. Finally, we demonstrated that "cyst-like" hole formation in 3-D gels was inhibited with treatment with doxycycline or recombinant human VEGF receptor-3. CONCLUSIONS: We consider that our observation of this sequence in vitro illustrates how LCCs behave in vivo while enacting their important role in the progression of LAM. Our results indicate that the 3-D gel culture system for LCCs is a useful tool for exploring the effects of new therapeutic drugs under conditions when LCCs are constantly available. PMID- 26574998 TI - Signal transducer and activator of transcription 3: a year in review. AB - PURPOSE OF REVIEW: Signal transducer and activator of transcription 3 (STAT3) is an important transcription factor involved in a wide variety of cellular functions. Germline loss-of-function mutations are known to cause hyper-IgE immunodeficiency (autosomal dominant hyper IgE syndrome), whereas somatic gain-of function mutations have been described in large granular cell leukemia, and polymorphisms in STAT3 have been associated with inflammatory bowel disease and other solid organ tumors. The review examines recent discoveries in our understanding of the nonmalignant disease processes affected by STAT3 mutations in human disease. RECENT FINDINGS: Germline STAT3 gain-of-function mutations have recently been identified in patients with an early-onset autoimmunity/lymphoproliferative syndrome. STAT3 plays a previously unrecognized role in several facets of the pathogenesis of allergy. Loss-of-function STAT3 mutations revealed critical roles for STAT3 in the development and function of several lymphocyte populations and in their role in host defense. SUMMARY: The discovery of new gain-of-function mutations in STAT3, as well as new studies among patients with loss-of-function mutations, expand the understanding of the pathophysiology of STAT3 function and its importance in regulating the immune system. These findings contribute to elucidating STAT3 biology and clinical symptoms in patients with the different disease phenotypes. PMID- 26574999 TI - Phase II trial of irinotecan and metronomic temozolomide in patients with recurrent glioblastoma. AB - This phase II study was conducted to determine the efficacy and safety of metronomic temozolomide (TMZ) in combination with irinotecan in glioblastoma (GB) at first relapse. Patients with GB at first relapse received TMZ 50 mg/m/2day divided into three doses, except for a single 100 mg/m2 dose, administered between 3 and 6 h before every irinotecan infusion. Irinotecan was given intravenously at the previously established dose of 100 mg/m2 on days 8 and 22 of 28-day cycles. Treatment was given for a maximum of nine cycles or until progression or unacceptable toxicity occurred. Vascular endothelial growth factor and its soluble receptor 1, thrombospondin-1, microparticles, and microparticle dependent procoagulant activity were measured in blood before treatment. The primary objective was 6-month progression-free survival (PFS). Twenty-seven evaluable patients were enrolled. Six-month PFS was 20.8%. Median PFS was 11.6 weeks (95% confidence interval: 7.5-15.7). Stable disease was the best response for nine (37.5%) patients, with a median duration of 11.2 weeks (4.2-35.85 weeks). No differences in PFS or response were observed among patients who relapsed during or after completion of adjuvant TMZ. Grade 3/4 adverse events included lymphopenia (15%), fatigue, diarrhea and febrile neutropenia (3.7% each), lymphopenia, neutropenia, and nausea/vomiting (11.1% each). One patient died from pneumonia and one patient died from pulmonary thromboembolism. Pretreatment levels of angiogenesis biomarkers, microparticles, and microparticle related procoagulant activity were elevated in patients compared with healthy volunteers. This regimen is feasible, but failed to improve the results obtained with other second-line therapies in recurrent GB. PMID- 26575000 TI - Intensive cisplatin/oral etoposide for epithelial ovarian cancer: the Cambridge Gynae-Oncology Centre experience: too toxic for relapse? AB - Intensive cisplatin and oral etoposide for relapsed epithelial ovarian cancer (EOC), commonly known as the van der Burg (VDB) protocol, has been reported to improve response rates and progression-free survival. We report on all patients with relapsed EOC treated on the VDB protocol at the Cambridge Gynae-Oncology Centre. From the institutional databases, we identified all patients treated since 2001. We extracted demographic, clinical, treatment, and toxicity data and outcomes. We used Cox regression to identify predictors of survival. A total of 35 patients were treated on the VDB protocol. Toxicity was significant, with grade 3/4 fatigue, nausea and vomiting affecting 46, 46 and 29% of patients, respectively. Six patients had grade 3/4 infection and four (11%) deaths occurred on treatment. Efficacy was encouraging, with a radiological response rate of 43%, a median progression-free survival of 5.8 months and a median overall survival of 14.1 months. No significant difference in efficacy was seen between platinum resistant and sensitive patients. We report significant activity of the VDB protocol in a routine clinical setting. However, the high rates of serious toxicity and treatment-related deaths among patients treated with palliative intent proved unacceptable. The Cambridge Gynae-Oncology Centre no longer uses this regimen in women with relapsed EOC. PMID- 26575001 TI - Afatinib-refractory brain metastases from EGFR-mutant non-small-cell lung cancer successfully controlled with erlotinib: a case report. AB - Both afatinib and erlotinib are tyrosine kinase inhibitors that inhibit aberrant epidermal growth factor receptor (EGFR) signals in non-small-cell lung cancer (NSCLC). Afatinib is an irreversible inhibitor directed against EGFR, ErbB-2, and ErbB-4, whereas erlotinib is a reversible inhibitor directed against EGFR only. Although afatinib has been shown to be effective in the treatment for erlotinib refractory and/or gefitinib-refractory central nervous system metastases from NSCLC, little is known about the efficacy of erlotinib for afatinib-refractory central nervous system metastases. In the present report we describe a case of EGFR mutation-positive NSCLC in which brain metastases developed during first line afatinib treatment. Whole-brain radiation therapy and substitution of erlotinib for afatinib led to successful shrinkage of the brain metastases. Our report highlights the potential benefit of erlotinib for the management of brain metastases refractory over afatinib in patients with NSCLC. PMID- 26575002 TI - Atomically Thin Transition-Metal Dinitrides: High-Temperature Ferromagnetism and Half-Metallicity. AB - High-temperature ferromagnetic two-dimensional (2D) materials with flat surfaces have been a long-sought goal due to their potential in spintronics applications. Through comprehensive first-principles calculations, we show that the recently synthesized MoN2 monolayer is such a material; it is ferromagnetic with a Curie temperature of nearly 420 K, which is higher than that of any flat 2D magnetic materials studied to date. This novel property, made possible by the electron deficient nitrogen ions, render transition-metal dinitrides monolayers with unique electronic properties which can be switched from the ferromagnetic metals in MoN2, ZrN2, and TcN2 to half-metallic ones in YN2. Transition-metal dinitrides monolayers may, therefore, serve as good candidates for spintronics devices. PMID- 26575003 TI - Real-time modulated nanoparticle separation with an ultra-large dynamic range. AB - Nanoparticles exhibit size-dependent properties which make size-selective purification of proteins, DNA or synthetic nanoparticles essential for bio analytics, clinical medicine, nano-plasmonics and nano-material sciences. Current purification methods of centrifugation, column chromatography and continuous-flow techniques suffer from particle aggregation, multi-stage process, complex setups and necessary nanofabrication. These increase process costs and time, reduce efficiency and limit dynamic range. Here, we achieve an unprecedented real-time nanoparticle separation (51-1500 nm) using a large-pore (2 MUm) deterministic lateral displacement (DLD) device. No external force fields or nanofabrication are required. Instead, we investigated innate long-range electrostatic influences on nanoparticles within a fluid medium at different NaCl ionic concentrations. In this study we account for the electrostatic forces beyond Debye length and showed that they cannot be assumed as negligible especially for precise nanoparticle separation methods such as DLD. Our findings have enabled us to develop a model to simultaneously quantify and modulate the electrostatic force interactions between nanoparticle and micropore. By simply controlling buffer solutions, we achieve dynamic nanoparticle size separation on a single device with a rapid response time (<20 s) and an enlarged dynamic range (>1200%), outperforming standard benchtop centrifuge systems. This novel method and model combines device simplicity, isolation precision and dynamic flexibility, opening opportunities for high-throughput applications in nano-separation for industrial and biological applications. PMID- 26575005 TI - Surface induces different crystal structures in a room temperature switchable spin crossover compound. AB - We investigated the influence of surfaces in the formation of different crystal structures of a spin crossover compound, namely [Fe(L)2] (LH: (2-(pyrazol-1-yl)-6 (1H-tetrazol-5-yl)pyridine), which is a neutral compound thermally switchable around room temperature. We observed that the surface induces the formation of two different crystal structures, which exhibit opposite spin transitions, i.e. on heating them up to the transition temperature, one polymorph switches from high spin to low spin and the second polymorph switches irreversibly from low spin to high spin. We attributed this inversion to the presence of water molecules H-bonded to the complex tetrazolyl moieties in the crystals. Thin deposits were investigated by means of polarized optical microscopy, atomic force microscopy, X-ray diffraction, X-ray absorption spectroscopy and micro Raman spectroscopy; moreover the analysis of the Raman spectra and the interpretation of spin inversion were supported by DFT calculations. PMID- 26575006 TI - Intraoperative anaphylaxis to neuromuscular blocking agents: the incidence over 9 years at two tertiary hospitals in South Korea: A retrospective observational study. AB - BACKGROUND: Intraoperative anaphylaxis to neuromuscular blocking agents (NMBAs) is a rare event that is unpredictable and potentially life threatening. Most of the previous reports on such intraoperative anaphylaxis used market share surveys or self-reported data to estimate the incidence. OBJECTIVE: To determine the incidences of intraoperative anaphylaxis to NMBAs using electronic medical records. DESIGN: A retrospective observational study. SETTING: Two tertiary hospitals in South Korea. PATIENTS: This study involved patients exposed to NMBAs during anaesthesia between 1 January 2005 and 31 May 2014. Nineteen episodes were deemed to be intraoperative anaphylaxis to NMBAs. MAIN OUTCOME MEASURES: We calculated the incidences of intraoperative anaphylaxis to NMBAs. Exposure to the agents was determined from intraoperative records maintained in an electronic medical recording system. An anaphylactic reaction was determined from both clinical signs and the results of skin tests. RESULTS: Over 9 years, 729 429 patients were exposed to NMBA, the most frequently used being rocuronium [425 047 (58.3%)] and vecuronium [274 801 (37.7%)]. The overall incidence of intraoperative anaphylaxis was 2.6 per 100 000 (19 cases), and was higher with rocuronium (16 cases, 3.8 per 100 000) than with vecuronium (two cases, 0.7 cases per 100 000), P = 0.014. Comparing the first 3 years with the last 6 years, the incidence of intraoperative rocuronium anaphylaxis appeared to increase 1.4-fold (P = 0.006). CONCLUSION: Among commonly used NMBAs, rocuronium appears to have the highest incidence of anaphylaxis. Our findings suggest that future prospective investigation for NMBA-induced anaphylaxis should use internationally agreed skin test protocols. PMID- 26575007 TI - Preoxygenation by spontaneous breathing or noninvasive positive pressure ventilation with and without positive end-expiratory pressure. PMID- 26575008 TI - Reply to: Preoxygenation by spontaneous breathing or noninvasive positive pressure ventilation with and without positive end-expiratory pressure. PMID- 26575009 TI - Psychological distress, burnout and personality traits in Dutch anaesthesiologists: A survey. AB - BACKGROUND: The practice of anaesthesia comes with stress. If the demands of a stressful job exceed the resources of an individual, that person may develop burnout. Burnout poses a threat to the mental and physical health of the anaesthesiologist and therefore also to patient safety. OBJECTIVES: Individual differences in stress appraisal (perceived demands) are an important factor in the risk of developing burnout. To explore this possible relationship, we assessed the prevalence of psychological distress and burnout in the Dutch anaesthesiologist population and investigated the influence of personality traits. DESIGN: Survey study. SETTING: Data were collected in the Netherlands from July 2012 until December 2012. PARTICIPANTS: We sent electronic surveys to all 1955 practising resident and consultant members of the Dutch Anaesthesia Society. Of these, 655 (33.5%) were returned and could be used for analysis. MAIN OUTCOME MEASURES: Psychological distress, burnout and general personality traits were assessed using validated Dutch versions of the General Health Questionnaire (cut-off point >=2), the Maslach Burnout Inventory and the Big Five Inventory. Sociodemographic variables and personality traits were entered into regression models as predictors for burnout and psychological distress. RESULTS: Respectively, psychological distress and burnout were prevalent in 39.4 and 18% of all respondents. The prevalence of burnout was significantly different in resident and consultant anaesthesiologists: 11.3% vs. 19.8% (chi 5.4; P < 0.02). The most important personality trait influencing psychological distress and burnout was neuroticism: adjusted odds ratio 6.22 (95% confidence interval 4.35 to 8.90) and 6.40 (95% confidence interval 3.98 to 10.3), respectively. CONCLUSION: The results of this study show that psychological distress and burnout have a high prevalence in residents and consultant anaesthesiologists and that both are strongly related to personality traits, especially the trait of neuroticism. This suggests that strategies to address the problem of burnout would do well to focus on competence in coping skills and staying resilient. Personality traits could be taken into consideration during the selection of residents. In future longitudinal studies the question of how personal and situational factors interact in the development of burnout should be addressed. PMID- 26575010 TI - McGRATH MAC video laryngoscope for insertion of a transoesophageal echocardiography probe: A randomised controlled trial. AB - BACKGROUND: Transoesophageal echocardiography (TOE) probe insertion in anaesthetised patients can cause pharyngeal and oesophageal injuries. Kim et al. have shown that insertion assisted by a Macintosh laryngoscope can reduce such complications but it may sometimes be difficult to observe the passage of a TOE probe. The McGRATH MAC (McGRATH) has been shown to provide a better view of the glottis, piriform fossa and oesophageal inlet during tracheal intubation than the Macintosh. OBJECTIVE: We hypothesised that the McGRATH provided better visualisation of the oesophageal inlet and was useful as an aid to TOE probe placement, possibly reducing the incidence of pharyngeal injury related to insertion, compared with the Macintosh. DESIGN: A randomised controlled trial. SETTING: The study was conducted in a university hospital from February to December 2014. PATIENTS: One hundred patients undergoing elective surgery under intraoperative TOE monitoring were randomised to either a Macintosh group or a McGRATH group. INTERVENTIONS: Macintosh and McGRATH were used to visualise the passage of the TOE probe and guide its insertion. MAIN OUTCOME MEASURES: Visibility of the oesophageal inlet, the number of TOE insertion attempts and incidence of pharyngeal mucosal injury after the TOE probe had been removed were assessed. RESULTS: The percentage of patients in whom the oesophageal inlet was visible was higher in the McGRATH group (88%) than in the Macintosh group (41%) (P < 0.01). The number of TOE probe insertion attempts was significantly smaller in the McGRATH group than in the Macintosh group (P = 0.039). The incidence of pharyngeal mucosal injury was significantly smaller in the McGRATH group (4%) than in the Macintosh group (16%; P = 0.042). CONCLUSION: The McGRATH provided a better view of the oesophageal inlet and was useful as an aid to TOE probe placement, possibly reducing the incidence of pharyngeal injury related to its insertion. TRIAL REGISTRATION: University Hospital Medical Information Network in Japan (UMIN) 000012970. PMID- 26575011 TI - A flow visualization and superposition rheology study of shear-banding wormlike micelle solutions. AB - In this paper, we use rheometry and flow visualization to study the dynamics of the interface between shear bands in a wormlike micellar solution sheared between concentric cylinders, i.e., in a Taylor-Couette (TC) cell, and to evaluate the stress diffusion coefficient and the stress correlation length in the Johnson Segalman model. Two wormlike micellar solutions are studied: an aqueous solution of CTAB-NaNO3 and a solution of CPCl-NaSal in brine. These systems are highly elastic, exhibit Maxwellian behavior in linear viscoelasticity experiments, and shear banding in nonlinear experiments [S. Lerouge, et al., Soft Matter, 2008, 4, 1808-1819, M. A. Fardin, et al., Soft Matter, 2012, 8(39), 10072-10089, P. Ballesta, et al., J. Rheol., 2007, 51, 1047]. A large, custom-built, computer controlled TC cell allows us to rotate both cylinders independently and to visualize the flow in the r-z plane using a CCD camera. At low shear rates, the flow is stable and the fluid appears homogeneous throughout the gap between the cylinders. Above a critical shear rate, a shear banding transition occurs. This manifests itself in the formation of two distinct bands in the r-z plane, with an interface between the two bands. For sufficiently high ramp speeds, multiple steps of interface evolution are identified, as noted by Radulescu, Lerouge, and others [O. Redulescu, et al., Europhys. Lett., 2003, 62, 230, S. Lerouge, et al., Soft Matter, 2008, 4, 1808-1819]. We quantify the interface travel using direct visualization and use this measure, as well as superposition rheometry [P. Ballesta, et al., J. Rheol., 2007, 51, 1047], to determine the stress diffusion coefficient D and the stress correlation length zeta in the Johnson-Segalman model. These parameters are evaluated at different temperatures, shear rates, and gap sizes. We find that the stress diffusion coefficient and the stress correlation length exhibit a strong dependence on the gap of the Taylor-Couette cell for both shear-banding systems. For the CTAB-NaNO3 system, we report a linear dependence of the stress diffusion coefficient on temperature for the parameter range considered. In addition, we find that for this system, the stress diffusion coefficient is independent of shear rate. For the CPCl-NaSal system, we observe the same color changes in the sample reported by others on extended light exposure; however, we find that different histories of light exposure do not affect the measured stress diffusion coefficient. PMID- 26575012 TI - Turning the heat on conjugated polyelectrolytes: an off-on ratiometric nanothermometer. AB - We report a self-referenced ratiometric nanothermometer based on short conjugated polyelectrolytes. An amphiphilic macromolecule destabilizes the polymer pi-pi stacking and makes it possible to shift the equilibrium between the less emissive aggregated state (520 nm) and the brighter individual chain (450 nm) within 20.0 degrees C and 70.0 degrees C. PMID- 26575013 TI - Ankylosis of the wrist bones in patients with rheumatoid arthritis: a study with extremity-dedicated MRI. AB - OBJECTIVES: Ankylosis, or spontaneous bone fusion, of the small joints of the hand is a rare event in patients with rheumatoid arthritis (RA), being observed in 0.8% of them on conventional radiographs. It is associated with long-lasting and severe disease. In other settings, such as fracture healing, bone fusion is a reparative process. The aim of this paper is the study of the frequency of wrist ankylosis in patients with RA in comparison with other arthritides; to correlate ankylosis with disease activity. METHODS: A total of 94 patients affected by RA, 71 patients with different rheumatic conditions and 42 controls with no joint disease or with slight hand osteoarthritis were studied. DAS-28 CRP was calculated in patients with RA and psoriatic arthritis. MRI of the clinically most involved wrist was performed with a 0.2 T, extremity-dedicated MRI system. RESULTS: Of RA patients, 10/94 (10.6%) showed ankylosis in comparison with 2/113 (1.8%) controls (p=0.015). RA patients with ankylosis had longer disease duration (p=0.019) but similar disease activity. CONCLUSIONS: MRI-defined bone ankylosis is frequent in RA. It is not limited to seronegative spondyloarthritides and may be part of the bone damage observed in RA. PMID- 26575014 TI - Polymerized ionic liquid diblock copolymers: impact of water/ion clustering on ion conductivity. AB - Herein, we examine the synergistic impact of both ion clustering and block copolymer morphology on ion conductivity in two polymerized ionic liquid (PIL) diblock copolymers with similar chemistries but different side alkyl spacer chain lengths (ethyl versus undecyl). When saturated in liquid water, water/ion clusters were observed only in the PIL block copolymer with longer alkyl side chains (undecyl) as evidenced by both small-angle neutron scattering and intermediate-angle X-ray scattering, i.e., water/ion clusters form within the PIL microdomain under these conditions. The resulting bromide ion conductivity in the undecyl sample was higher than the ethyl sample (14.0 mS cm(-1)versus 6.1 mS cm( 1) at 50 degrees C in liquid water) even though both samples had the same block copolymer morphology (lamellar) and the undecyl sample had a lower ion exchange capacity (0.9 meq g(-1)versus 1.4 meq g(-1)). No water/ion clusters were observed in either sample under high humidity or dry conditions. The resulting ion conductivity in the undecyl sample with lamellar morphology was significantly higher in the liquid water saturated state compared to the high humidity state (14.0 mS cm(-1)versus 4.2 mS cm(-1)), whereas there was no difference in ion conductivity in the ethyl sample when comparing these two states. These results show that small chemical changes to ion-containing block copolymers can induce water/ion clusters within block copolymer microdomains and this can subsequently have a significant effect on ion transport. PMID- 26575015 TI - The Importance of Evaluating Frailty and Social-behavioral Factors for Managing Drugs and Dialysis Prescription in Elderly Patients. AB - Ageing is characterized by a progressive loss of complexity, which is an essential condition for making the organism capable of keeping homeostasis. Thus, senile loss of complexity makes old individuals frail: a syndrome characterized by the presence of shrinking (sarcopenia), weakness, poor endurance and energy, slowness, and low physical activity. Moreover, renal ageing progressively leads to a glomerular filtration rate (GFR) reduction, one of the main pharmacokinetic senile changes, which is not detectable by simply evaluating serum urea or creatinine values but measuring or calculating patient's GFR. Finally, current epidemiology has documented that detrimental social-behavioral factors such as low education level, poor financial-resource, depression, and isolation, also influence the onset and progression of chronic diseases, and even overall mortality, particularly in the elderly. Thus, we propose that these 3 variables: frailty phenotype, senile GFR, and detrimental social-behavioral factors, should be considered at time of prescribing drugs or medical procedures in the elderly. Additionally, they should also be considered for following patient's response to prescribed therapies in elderly patients suffering from chronic diseases (diabetes mellitus, chronic kidney disease, etc.), or on organ replacement treatments (dialysis and transplantation). PMID- 26575016 TI - Differential role of RIP1 in Smac mimetic-mediated chemosensitization of neuroblastoma cells. AB - We explored the potential of Smac mimetics, which antagonize Inhibitor of Apoptosis (IAP) proteins, for chemosensitization of neuroblastoma (NB). Here, we report that Smac mimetics, e.g. BV6, prime NB cells for chemotherapeutics including the topoisomerase II inhibitor doxorubicin (DOX) and vinca alkaloids such as Vincristine (VCR), Vinblastine (VBL) and Vinorelbine (VNR). Additionally, BV6 acts in concert with DOX or VCR to suppress long-term clonogenic growth. While BV6 causes rapid downregulation of cellular IAP (cIAP)1 protein and nuclear factor-kappaB (NF-kappaB) activation, DOX/BV6- or VCR/BV6-induced apoptosis occurs independently of NF-kappaB or TNFalpha signaling, since overexpression of dominant-negative IkappaBalpha superrepressor or the Tumor Necrosis Factor (TNF)alpha-blocking antibody Enbrel fail to block cell death. Mechanistic studies reveal that Receptor-interacting protein (RIP)1 is required for DOX/BV6-, but not for VCR/BV6-induced apoptosis, since transient or stable knockdown of RIP1 or the pharmacological RIP1 inhibitor necrostatin-1 significantly reduce apoptosis. By comparison, VCR/BV6-mediated apoptosis critically depends on the mitochondrial pathway. VCR/BV6 cotreatment causes phosphorylation of BCL-2 during mitotic arrest, enhanced activation of BAX and BAK and loss of mitochondrial membrane potential (MMP). Additionally, overexpression of BCL-2 profoundly suppresses VCR/BV6-induced apoptosis. Thus, BV6 sensitizes NB cells to chemotherapy-induced apoptosis via distinct initial signaling mechanisms depending on the chemotherapeutic drug. These findings provide novel mechanistic insights into Smac mimetic-mediated chemosensitization of NB. PMID- 26575017 TI - SET antagonist enhances the chemosensitivity of non-small cell lung cancer cells by reactivating protein phosphatase 2A. AB - SET is known as a potent PP2A inhibitor, however, its oncogenic role including its tumorigenic potential and involvement in the development of chemoresistance in non-small cell lung cancer (NSCLC) has not yet been fully discussed. In present study, we investigated the oncogenic role of SET by SET-knockdown and showed that SET silencing impaired cell growth rate, colony formation and tumor sphere formation in A549 cells. Notably, silencing SET enhanced the pro-apoptotic effects of paclitaxel, while ectopic expression of SET diminished the sensitivity of NSCLC cells to paclitaxel. Since the SET protein was shown to affect chemosensitivity, we next examined whether combining a novel SET antagonist, EMQA, sensitized NSCLC cells to paclitaxel. Both the in vitro and in vivo experiments suggested that EMQA and paclitaxel combination treatment was synergistic. Importantly, we found that downregulating p-Akt by inhibiting SET mediated protein phosphatase 2A (PP2A) inactivation determined the pro-apoptotic effects of EMQA and paclitaxel combination treatment. To dissect the critical site for EMQA functioning, we generated several truncated SET proteins. By analysis of the effects of EMQA on the binding affinities of different truncated SET proteins to PP2A-catalytic subunits, we revealed that the 227-277 amino-acid sequence is critical for EMQA-induced SET inhibition. Our findings demonstrate the critical role of SET in NSCLC, particularly in the development of chemoresistance. The synergistic effects of paclitaxel and the SET antagonist shown in current study encourage further validation of the clinical potential of this combination. PMID- 26575019 TI - Cell autonomous Vegf-C/Vegfr3 signaling in adult neural stem cells. PMID- 26575018 TI - Estrogen and estrogen receptor alpha promotes malignancy and osteoblastic tumorigenesis in prostate cancer. AB - The role of estrogen signaling in regulating prostate tumorigenesis is relatively underexplored. Although, an increasing body of evidence has linked estrogen receptor beta (ERbeta) to prostate cancer, the function of estrogen receptor alpha (ERalpha) in prostate cancer is not very well studied. We have discovered a novel role of ERalpha in the pathogenesis of prostate tumors. Here, we show that prostate cancer cells express ERalpha and estrogen induces oncogenic properties in prostate cancer cells through ERalpha. Importantly, ERalpha knockdown in the human prostate cancer PacMetUT1 cells as well as pharmacological inhibition of ERalpha with ICI 182,780 inhibited osteoblastic lesion formation and lung metastasis in vivo. Co-culture of pre-osteoblasts with cancer cells showed a significant induction of osteogenic markers in the pre-osteoblasts, which was attenuated by knockdown of ERalpha in cancer cells suggesting that estrogen/ERalpha signaling promotes crosstalk between cancer and osteoblastic progenitors to stimulate osteoblastic tumorigenesis. These results suggest that ERalpha expression in prostate cancer cells is essential for osteoblastic lesion formation and lung metastasis. Thus, inhibition of ERalpha signaling in prostate cancer cells may be a novel therapeutic strategy to inhibit the osteoblastic lesion development as well as lung metastasis in patients with advanced prostate cancer. PMID- 26575020 TI - Overexpression of HE4 (human epididymis protein 4) enhances proliferation, invasion and metastasis of ovarian cancer. AB - Overexpression of Human epididymis protein 4 (HE4) related with a role in ovarian cancer tumorigenesis while little is known about the molecular mechanism alteration by HE4 up regulation. Here we reported that overexpressed HE4 promoted ovarian cancer cells proliferation, invasion and metastasis. Furthermore, human whole genome gene expression profile microarrays revealed that 231 differentially expressed genes (DEGs) were altered in response to HE4, in which MAPK signaling, ECM receptor, cell cycle, steroid biosynthesis pathways were involved. The findings suggested that overexpressed HE4 played an important role in ovarian cancer progression and metastasis and that HE4 has the potential to serve as a novel therapeutic target for ovarian cancer. PMID- 26575021 TI - Expression profiling reveals transcriptional regulation by Fbxw7/mTOR pathway in radiation-induced mouse thymic lymphomas. AB - The tumor suppressor gene FBXW7 is deleted and mutated in many different types of human cancers. FBXW7 primarily exerts its tumor suppressor activity by ubiquitinating different oncoproteins including mTOR. Here we used gene transcript profiling to gain a deeper understanding of the role of FBXW7 in tumor development and to determine the influence of mTOR inhibition by rapamycin on tumor transcriptome and biological functions. In comparison to tumors from p53 single heterozygous (p53+/-) mice, we find that radiation-induced thymic lymphomas from Fbxw7/p53 double heterozygous (Fbxw7+/-p53+/-) mice show significant deregulation of cholesterol metabolic processes independent of rapamycin treatment, while cell cycle related genes were upregulated in tumors from placebo treated Fbxw7+/-p53+/- mice, but not in tumors from rapamycin treated Fbxw7+/-p53+/- mice. On the other hand, tumors from rapamycin treated Fbxw7+/-p53+/- mice were enriched for genes involved in the integrated stress response, an adaptive mechanism to survive in stressful environments. Finally, we demonstrated that the Fbxw7 gene signatures identified in mouse tumors significantly overlap with FBXW7 co-expressed genes in human cancers. Importantly these common FBXW7 gene signatures between mouse and human are predictive for disease-free survival in human colon, breast and lung adenocarcinoma cancer patients. These results provide novel insights into the role of FBXW7 in tumor development and have identified a number of potential targets for therapeutic intervention. PMID- 26575022 TI - Nuclear localization of the caspase-3-cleaved form of p73 in anoikis. AB - The transcription factor p73 is a homologue of p53 that can be expressed as pro- or anti-apoptotic isoforms. Unlike p53, p73 is rarely mutated or lost in cancers and it is found to replace defective p53 inducing apoptosis. Here, we investigated the p73 involvement in anoikis, a type of apoptosis caused by inadequate cell-matrix interactions. Breast cancer cell lines with different p53 status were treated with doxorubicin (DOX) or docetaxel (DOC) and cells detached from the extracellular matrix were analyzed. We demonstrate for the first time that DOX-induced cell detachment is associated with p73 cleavage and caspase activation, independently of the p53 status. However, we did not detect p73 cleavage or caspase activation in detached cells under DOC treatment. Overexpressing the apoptotic isoform of p73 led to cell detachment associated with p73 cleavage and caspase activation. Interestingly, p73 cleaved forms localize to the nucleus during the late phase of cell death indicating an increase in the transcriptional activity. Our study suggests that the cleavage of p73 on specific sites may release its pro-apoptotic function and contribute to cell death. PMID- 26575025 TI - Alopecic and Aseptic Nodules of the Scalp/Pseudocyst of the Scalp: Clinicopathological and Therapeutic Analyses in 11 Korean Patients. AB - BACKGROUND: Alopecic and aseptic nodule of the scalp (AANS) is a rare disease entity first reported in 1992 as pseudocyst of the scalp (PCS). Controversy exists regarding the histopathology and etiology of reported cases. OBJECTIVE: We performed this study to analyze the clinical and histopathologic features of AANS/PCS in Korean patients. METHODS: A retrospective review of medical records from 2008 to 2013 at Inje University Busan Paik Hospital was performed. RESULTS: Eleven patients were enrolled. All patients were male, and their mean age was 21.6 years. Most patients had a solitary nodule (10/11) located predominantly on the vertex. The mean nodule size was 20 mm. Inflammatory cell infiltration in the deep dermis was a histologic feature of AANS/PCS. Eight patients showed granulomatous infiltration. All patients were treated with short-term antibiotics and intralesional steroid injection. CONCLUSION: Our results suggest that dermatologists should consider AANS when diagnosing an alopecic nodule on the scalp. PMID- 26575023 TI - A comparison of isolated circulating tumor cells and tissue biopsies using whole genome sequencing in prostate cancer. AB - Previous studies have demonstrated focal but limited molecular similarities between circulating tumor cells (CTCs) and biopsies using isolated genetic assays. We hypothesized that molecular similarity between CTCs and tissue exists at the single cell level when characterized by whole genome sequencing (WGS). By combining the NanoVelcro CTC Chip with laser capture microdissection (LCM), we developed a platform for single-CTC WGS. We performed this procedure on CTCs and tissue samples from a patient with advanced prostate cancer who had serial biopsies over the course of his clinical history. We achieved 30X depth and >= 95% coverage. Twenty-nine percent of the somatic single nucleotide variations (SSNVs) identified were founder mutations that were also identified in CTCs. In addition, 86% of the clonal mutations identified in CTCs could be traced back to either the primary or metastatic tumors. In this patient, we identified structural variations (SVs) including an intrachromosomal rearrangement in chr3 and an interchromosomal rearrangement between chr13 and chr15. These rearrangements were shared between tumor tissues and CTCs. At the same time, highly heterogeneous short structural variants were discovered in PTEN, RB1, and BRCA2 in all tumor and CTC samples. Using high-quality WGS on single-CTCs, we identified the shared genomic alterations between CTCs and tumor tissues. This approach yielded insight into the heterogeneity of the mutational landscape of SSNVs and SVs. It may be possible to use this approach to study heterogeneity and characterize the biological evolution of a cancer during the course of its natural history. PMID- 26575024 TI - Single agent BMS-911543 Jak2 inhibitor has distinct inhibitory effects on STAT5 signaling in genetically engineered mice with pancreatic cancer. AB - The Jak/STAT pathway is activated in human pancreatic ductal adenocarcinoma (PDAC) and cooperates with mutant Kras to drive initiation and progression of PDAC in murine models. We hypothesized that the small-molecule Jak2 inhibitor (BMS-911543) would elicit anti-tumor activity against PDAC and decrease immune suppressive features of the disease. We used an aggressive genetically engineered PDAC model with mutant KrasG12D, tp53R270H, and Brca1 alleles (KPC-Brca1 mice). Mice with confirmed tumor burden were treated orally with vehicle or 30 mg/kg BMS 911543 daily for 14 days. Histologic analysis of pancreata from treated mice revealed fewer foci of adenocarcinoma and significantly decreased Ki67+ cells versus controls. In vivo administration of BMS-911543 significantly reduced pSTAT5 and FoxP3 positive cells within the pancreas, but did not alter STAT3 phosphorylation. Continuous dosing of KPC-Brca1 mice with BMS-911543 resulted in a median survival of 108 days, as compared to a median survival of 87 days in vehicle treated animals, a 23% increase (p = 0.055). In vitro experiments demonstrated that PDAC cell lines were poorly sensitive to BMS-911543, requiring high micromolar concentrations to achieve targeted inhibition of Jak/STAT signaling. Similarly, BMS-911543 had little in vitro effect on the viability of both murine and human PDAC-derived stellate cell lines. However, BMS-911543 potently inhibited phosphorylation of pSTAT3 and pSTAT5 at low micromolar doses in human PBMC and reduced in vitro differentiation of Foxp3+ T regulatory cells. These results indicate that single agent Jak2i deserves further study in preclinical models of PDAC and has distinct inhibitory effects on STAT5 mediated signaling. PMID- 26575026 TI - Ibopamine challenge testing becomes negative following successful trabeculectomy surgery. AB - BACKGROUND: The ibopamine challenge test correlates well with a patient's peak diurnal intraocular pressure (IOP) measurement. We aimed to investigate the effect that a functioning trabeculectomy has on the ibopamine challenge test. DESIGN: Non-randomized prospective clinical trial evaluating a diagnostic test. PARTICIPANTS: Thirteen patients were recruited through glaucoma clinics at the Flinders Medical Centre. Of these, seven required surgical management with trabeculectomy surgery, whilst the remainder were managed medically. METHODS: Patients underwent IOP measurement, and then two drops of Ibopamine 2% solution were instilled into the study eye of each patient. After 45 min, IOP was reassesed. A positive challenge test was considered to be a rise in IOP of greater than 3 mmHg. Changes from baseline were determined and compared between groups. Twelve months later, this test was then repeated in all patients. MAIN OUTCOME MEASURE: Change in IOP after ibopamine challenge. RESULTS: Following the ibopamine challenge, IOP increased by 9.2 mmHg (SD 2.8) (100% positive) for medically managed patients and 7.2 mmHg (SD 2.0) (100% positive) for surgically managed patients (P = 0.18). The surgically managed group then underwent trabeculectomy surgery. Twelve months later, the ibopamine challenge was repeated. Following the repeat ibopamine challenge, IOP increased by 7.2 mmHg (SD 2.3) for medically managed patients and 0.3 mmHg (SD 1.3) for surgically managed patients (P < 0.0001). The medically managed group remained 100% positive, whilst the surgically manage group became 0% positive (Fisher Exact P = 0.044). CONCLUSIONS: A glaucoma patient with a positive ibopamine challenge will show a negative challenge result when re-tested following trabeculectomy surgery. PMID- 26575027 TI - Markedly High Plasma Thrombopoietin (TPO) Level is a Predictor of Poor Response to Immunosuppressive Therapy in Children With Acquired Severe Aplastic Anemia. AB - BACKGROUND: Immunosuppressive therapy (IST) is commonly used for patients with acquired severe aplastic anemia (SAA). Because the clinical response rate and therapeutic outcome for individual patients to IST varies, an in vitro test that identifies potential responders would be desirable. METHODS: We evaluated the relationship between thrombopoietin (TPO) levels at the time of diagnosis and the response to IST at 6 months in 85 children (median age, 9.0 years; range, 1.0 15.5 years) with acquired SAA using enzyme-linked immunosorbent assay. Thirty-one age-matched healthy individuals were used as controls. All patients received antithymocyte globulin and cyclosporine. RESULTS: Overall, 39 patients (45.9%) responded to IST at 6 months. TPO plasma levels were significantly higher in nonresponders than in responders (1,555.8 vs. 1,284.7 pg/ml, respectively; P = 0.031). Multivariate analysis identified the TPO levels of >1,796.7 pg/ml (TPO high group, 20 patients; odds ratio (OR), 8.285; 95% confidence interval (CI), 2.114-32.904; P = 0.002) as independent poor predictors of IST response at 6 months. Moreover, the TPO-high group was associated with lower 5-year failure free survival rates (30% vs. 68%, P = 0.012) compared with the TPO-low group. CONCLUSION: The measurement of TPO levels at diagnosis is useful for predicting the response to IST in children with SAA and may help in decision making. PMID- 26575028 TI - Vaccination with Recombinant Microneme Proteins Confers Protection against Experimental Toxoplasmosis in Mice. AB - Toxoplasmosis, a zoonotic disease caused by Toxoplasma gondii, is an important public health problem and veterinary concern. Although there is no vaccine for human toxoplasmosis, many attempts have been made to develop one. Promising vaccine candidates utilize proteins, or their genes, from microneme organelle of T. gondii that are involved in the initial stages of host cell invasion by the parasite. In the present study, we used different recombinant microneme proteins (TgMIC1, TgMIC4, or TgMIC6) or combinations of these proteins (TgMIC1-4 and TgMIC1-4-6) to evaluate the immune response and protection against experimental toxoplasmosis in C57BL/6 mice. Vaccination with recombinant TgMIC1, TgMIC4, or TgMIC6 alone conferred partial protection, as demonstrated by reduced brain cyst burden and mortality rates after challenge. Immunization with TgMIC1-4 or TgMIC1 4-6 vaccines provided the most effective protection, since 70% and 80% of mice, respectively, survived to the acute phase of infection. In addition, these vaccinated mice, in comparison to non-vaccinated ones, showed reduced parasite burden by 59% and 68%, respectively. The protective effect was related to the cellular and humoral immune responses induced by vaccination and included the release of Th1 cytokines IFN-gamma and IL-12, antigen-stimulated spleen cell proliferation, and production of antigen-specific serum antibodies. Our results demonstrate that microneme proteins are potential vaccines against T. gondii, since their inoculation prevents or decreases the deleterious effects of the infection. PMID- 26575029 TI - Low WSS Induces Intimal Thickening, while Large WSS Variation and Inflammation Induce Medial Thinning, in an Animal Model of Atherosclerosis. AB - OBJECTIVE: Atherosclerotic plaque development in the arterial wall is the result of complex interaction between the wall's endothelial layer and blood hemodynamics. However, the interaction between hemodynamic parameters and inflammation in plaque evolution is not yet fully understood. The aim of the present study was to investigate the relation between wall shear stress (WSS) and vessel wall inflammation during atherosclerotic plaque development in a minipig model of carotid stenosis. METHODS: A surgical procedure was performed to create left common carotid artery stenosis by placement of a perivascular cuff in minipigs under atherogenic diet. Animals were followed up on 3T MRI, 1 week after surgery and 3, 6, and 8 months after initiation of the diet. Computational fluid dynamics simulation estimated WSS distribution for the first imaging point. Vascular geometries were co-registered for direct comparison of plaque development and features (Gadolinium- and USPIO-Contrast Enhanced MRI, for permeability and inflammation respectively) with the initial WSS. Histological analysis was performed and sections were matched to MR images, based on spatial landmarks. RESULTS: Vessel wall thickening, permeability and inflammation were observed distally from the stenosis. They were eccentric and facing regions of normal wall thickness. Histological analysis confirmed eccentric plaque formation with lipid infiltration, intimal thickening and medial degradation. High phagocytic activity in the stenosis region was co-localized with high WSS, corresponding to intense medial degradation observed on histology samples. CONCLUSION: Lower WSS promotes atherosclerotic plaque development distal to an induced stenosis. Vascular and perivascular inflammation locations were predominant in the high WSS stenosis segment, where medial thinning was the major consequence. PMID- 26575030 TI - Facing the diagnostic challenge: Nerve ultrasound in diabetic patients with neuropathic symptoms. AB - INTRODUCTION: We describe the nerve ultrasound findings in patients with type II diabetes mellitus who have neuropathic symptoms and signs. METHODS: Fifty-five healthy controls and 44 diabetic patients underwent clinical, sonographic, and electrophysiological evaluation. Patients were studied at a mean of 14.3 years after disease onset. RESULTS: Nerve ultrasound revealed increased cross-sectional area (CSA) in peripheral nerves at compression sites (although no clinical symptoms were present) and noncompression sites. No correlation was detected between sonographic and electrophysiological findings. A CSA increase of the tibial nerve in the popliteal fossa was detected in 5 patients with neuropathic symptoms, although electrophysiology was normal. CONCLUSIONS: Nerve ultrasound revealed crucial morphological alterations in diabetic patients. CSA enlargement at compression sites indicates subclinical nerve affection and may indicate susceptibility to entrapment syndromes. CSA increase at noncompression sites despite normal electrophysiology suggests early morphological abnormalities. Further longitudinal studies are required to confirm our results. Muscle Nerve, 2015 Muscle Nerve 54: 18-24, 2016 Muscle Nerve 54: 18-24, 2016. PMID- 26575031 TI - Internal and External Factors Related to Burnout among Iron and Steel Workers: A Cross-Sectional Study in Anshan, China. AB - BACKGROUND: Burnout is a syndrome of emotional exhaustion, cynicism and reduced professional efficacy, which can result from long-term work stress. Although the burnout level is high among iron and steel workers, little is known concerning burnout among iron and steel worker. This study aimed to evaluate the burnout and to explore its associated internal and external factors in iron and steel workers. METHODS: A cross-sectional survey was conducted in iron and steel workers at the Anshan iron-steel complex in Anshan, northeast China. Self administered questionnaires were distributed to 1,600 workers, and finally 1,300 questionnaires were returned. Burnout was measured using the Chinese version of the Maslach Burnout Inventory-General Survey (MBI-GS). Effort-reward imbalance (ERI), perceived organizational support (POS), and psychological capital (PsyCap) were measured anonymously. A hierarchical regression model was applied to explore the internal and external factors associated with burnout. RESULTS: Mean MBI-GS scores were 13.11+/-8.06 for emotional exhaustion, 6.64+/-6.44 for cynicism, and 28.96+/-10.39 for professional efficacy. Hierarchical linear regression analysis showed that ERI and POS were the most powerful predictors for emotional exhaustion and cynicism, and PsyCap was the most robust predictor for high professional efficacy. CONCLUSIONS: Chinese iron and steel workers have a high level of burnout. Burnout might be associated with internal and external factors, including ERI, POS, and PsyCap. Further studies are recommended to develop an integrated model including both internal and external factors, to reduce the level of ERI, and improve POS and workers' PsyCap, thereby alleviating the level of burnout among iron and steel workers. PMID- 26575032 TI - Voluntary Modulation of Hemodynamic Responses in Swallowing Related Motor Areas: A Near-Infrared Spectroscopy-Based Neurofeedback Study. AB - In the present study, we show for the first time that motor imagery of swallowing, which is defined as the mental imagination of a specific motor act without overt movements by muscular activity, can be successfully used as mental strategy in a neurofeedback training paradigm. Furthermore, we demonstrate its effects on cortical correlates of swallowing function. Therefore, N = 20 healthy young adults were trained to voluntarily increase their hemodynamic response in swallowing related brain areas as assessed with near-infrared spectroscopy (NIRS). During seven training sessions, participants received either feedback of concentration changes in oxygenated hemoglobin (oxy-Hb group, N = 10) or deoxygenated hemoglobin (deoxy-Hb group, N = 10) over the inferior frontal gyrus (IFG) during motor imagery of swallowing. Before and after the training, we assessed cortical activation patterns during motor execution and imagery of swallowing. The deoxy-Hb group was able to voluntarily increase deoxy-Hb over the IFG during imagery of swallowing. Furthermore, swallowing related cortical activation patterns were more pronounced during motor execution and imagery after the training compared to the pre-test, indicating cortical reorganization due to neurofeedback training. The oxy-Hb group could neither control oxy-Hb during neurofeedback training nor showed any cortical changes. Hence, successful modulation of deoxy-Hb over swallowing related brain areas led to cortical reorganization and might be useful for future treatments of swallowing dysfunction. PMID- 26575034 TI - Ineffective esophageal motility phenotypes following fundoplication in gastroesophageal reflux disease. AB - BACKGROUND: Ineffective esophageal motility (IEM) is associated with reflux disease, but its natural history is unclear. We evaluated patients undergoing repeat esophageal high resolution manometry (HRM) for symptomatic presentations after antireflux surgery (ARS) to understand the progression of IEM. METHODS: Patients with repeat HRM after ARS were included. Ineffective esophageal motility was diagnosed if >=5 sequences had distal contractile integral (DCI) <450 mmHg cm s. Augmentation of DCI following multiple rapid swallows (MRS) was assessed. The esophagogastric junction (EGJ) was interrogated using the EGJ contractile integral (EGJ-CI). Esophageal motor function was compared between patients with and without IEM. KEY RESULTS: Sixty-eight patients (53.9 +/- 1.8 years, 66.2% female) had pre- and post-ARS HRM studies 2.1 +/- 0.19 years apart. Esophagogastric junction-CI augmented by a mean of 26.3% following ARS. Four IEM phenotypes were identified: 14.7% had persistent IEM, 8.8% resolved IEM after ARS, 19.1% developed new IEM, and 57.4% had no IEM at any point. Patients with IEM had a lower DCI pre- and post-ARS, lower pre-ARS EGJ CI, and lower pre-ARS integrated relaxation pressure (p <= 0.02 for all comparisons); presenting symptoms and other EGJ metrics were similar (p >= 0.08 for all comparisons). The IEM phenotypes could be predicted by MRS DCI response patterns (p = 0.008 across groups); patients with persistent IEM had the least DCI augmentation (p = 0.007 compared to no IEM), while those who resolved IEM had DCI augmentation comparable to no IEM (p = 0.08). CONCLUSIONS & INFERENCES: Distinct phenotypes of IEM exist among symptomatic reflux patients following ARS. Provocative testing with MRS may help identify these phenotypes pre-ARS. PMID- 26575033 TI - The PneuCarriage Project: A Multi-Centre Comparative Study to Identify the Best Serotyping Methods for Examining Pneumococcal Carriage in Vaccine Evaluation Studies. AB - BACKGROUND: The pneumococcus is a diverse pathogen whose primary niche is the nasopharynx. Over 90 different serotypes exist, and nasopharyngeal carriage of multiple serotypes is common. Understanding pneumococcal carriage is essential for evaluating the impact of pneumococcal vaccines. Traditional serotyping methods are cumbersome and insufficient for detecting multiple serotype carriage, and there are few data comparing the new methods that have been developed over the past decade. We established the PneuCarriage project, a large, international multi-centre study dedicated to the identification of the best pneumococcal serotyping methods for carriage studies. METHODS AND FINDINGS: Reference sample sets were distributed to 15 research groups for blinded testing. Twenty pneumococcal serotyping methods were used to test 81 laboratory-prepared (spiked) samples. The five top-performing methods were used to test 260 nasopharyngeal (field) samples collected from children in six high-burden countries. Sensitivity and positive predictive value (PPV) were determined for the test methods and the reference method (traditional serotyping of >100 colonies from each sample). For the alternate serotyping methods, the overall sensitivity ranged from 1% to 99% (reference method 98%), and PPV from 8% to 100% (reference method 100%), when testing the spiked samples. Fifteen methods had >=70% sensitivity to detect the dominant (major) serotype, whilst only eight methods had >=70% sensitivity to detect minor serotypes. For the field samples, the overall sensitivity ranged from 74.2% to 95.8% (reference method 93.8%), and PPV from 82.2% to 96.4% (reference method 99.6%). The microarray had the highest sensitivity (95.8%) and high PPV (93.7%). The major limitation of this study is that not all of the available alternative serotyping methods were included. CONCLUSIONS: Most methods were able to detect the dominant serotype in a sample, but many performed poorly in detecting the minor serotype populations. Microarray with a culture amplification step was the top-performing method. Results from this comprehensive evaluation will inform future vaccine evaluation and impact studies, particularly in low-income settings, where pneumococcal disease burden remains high. PMID- 26575035 TI - Ssp1 CaMKK: A Sensor of Actin Polarization That Controls Mitotic Commitment through Srk1 in Schizosaccharomyces pombe. AB - BACKGROUND: Calcium/calmodulin-dependent protein kinase kinase (CaMKK) is required for diverse cellular functions. Mammalian CaMKK activates CaMKs and also the evolutionarily-conserved AMP-activated protein kinase (AMPK). The fission yeast Schizosaccharomyces pombe CaMKK, Ssp1, is required for tolerance to limited glucose through the AMPK, Ssp2, and for the integration of cell growth and division through the SAD kinase Cdr2. RESULTS: Here we report that Ssp1 controls the G2/M transition by regulating the activity of the CaMK Srk1. We show that inhibition of Cdc25 by Srk1 is regulated by Ssp1; and also that restoring growth polarity and actin localization of ssp1-deleted cells by removing the actin monomer-binding protein, twinfilin, is sufficient to suppress the ssp1 phenotype. CONCLUSIONS: These findings demonstrate that entry into mitosis is mediated by a network of proteins, including the Ssp1 and Srk1 kinases. Ssp1 connects the network of components that ensures proper polarity and cell size with the network of proteins that regulates Cdk1-cyclin B activity, in which Srk1 plays an inhibitory role. PMID- 26575036 TI - Epinephrine Improves the Efficacy of Nebulized Hypertonic Saline in Moderate Bronchiolitis: A Randomised Clinical Trial. AB - BACKGROUND AND AIMS: There is no evidence that the epinephrine-3% hypertonic saline combination is more effective than 3% hypertonic saline alone for treating infants hospitalized with acute bronchiolitis. We evaluated the efficacy of nebulized epinephrine in 3% hypertonic saline. PATIENTS AND METHODS: We performed a randomized, double-blind, placebo-controlled clinical trial in 208 infants hospitalized with acute moderate bronchiolitis. Infants were randomly assigned to receive nebulized 3% hypertonic saline with either 3 mL of epinephrine or 3 mL of placebo, administered every four hours. The primary outcome measure was the length of hospital stay. RESULTS: A total of 185 infants were analyzed: 94 in the epinephrine plus 3% hypertonic saline group and 91 in the placebo plus 3% hypertonic saline group. Baseline demographic and clinical characteristics were similar in both groups. Length of hospital stay was significantly reduced in the epinephrine group as compared with the placebo group (3.94 +/-1.88 days vs. 4.82 +/-2.30 days, P = 0.011). Disease severity also decreased significantly earlier in the epinephrine group (P = 0.029 and P = 0.036 on days 3 and 5, respectively). CONCLUSIONS: In our setting, nebulized epinephrine in 3% hypertonic saline significantly shortens hospital stay in hospitalized infants with acute moderate bronchiolitis compared to 3% hypertonic saline alone, and improves the clinical scores of severity from the third day of treatment, but not before. TRIAL REGISTRATION: EudraCT 2009-016042-57. PMID- 26575037 TI - A draft genome of the ghost moth, Thitarodes (Hepialus) sp., a medicinal caterpillar fungus. PMID- 26575038 TI - Independent Evolution of Suction Feeding in Neobatrachia: Feeding Mechanisms in Two Species of Telmatobius (Anura:Telmatobiidae). AB - The most common feeding mechanism among aquatic vertebrates as fishes, turtles, and salamanders is inertial suction. However, among the more than 6,400 species of anurans, suction feeding occurs only in pipids. Pipidae is a small basal lineage relative to Neobatrachia, an enormous clade that contains about 96% of extant anurans. The Andean neobatrachian frogs of the genus Telmatobius include strictly aquatic and semiaquatic species. Diet analyses indicate that some species of Telmatobius feed on strictly aquatic prey, but until now their feeding mechanisms have been unknown. Herein, the feeding mechanisms in two species of Telmatobius, that represent the two predominant modes of life in the genus, are explored. The semiaquatic T. oxycephalus and the fully aquatic T. rubigo are studied using high-speed cinematography and standard anatomical techniques to provide a qualitative approach to feeding behavior and a detailed morphological description of the mouth, tongue, hyoid and related muscles. T. oxycephalus uses similar mechanisms of aquatic prey capture as do the vast majority of anurans that are capable of forage in water, whereas the fully aquatic T. rubigo is an inertial suction feeder. This is the first report of an objective record of this unique feeding behavior in a Neobatrachian. Several morphological characters seem to be related with this function and are convergent with those of pipids. PMID- 26575039 TI - Acute pancreatitis following adult liver transplantation: A systematic review. AB - Although uncommon, acute pancreatitis is a well-recognized, but generally serious, complication following liver transplantation. In addition to being more prevalent in patients who underwent liver transplantation than in the general population, it has a more aggressive course and can be responsible for significant morbidity and mortality. The post-liver transplant population has altered anatomy, increased comorbidities, and requires a myriad of drugs. These characteristics make them different from the pre-transplant population. Despite their retrospective nature, prior studies have identified numerous etiological factors that are associated with an increased risk of acute pancreatitis following liver transplantation. These can be broadly classified into the following four categories: surgical and anatomical factors, infections, post transplant management, and post-transplant complications. The aim of this systematic review is to assimilate the available information regarding acute pancreatitis following adult liver transplantation to describe the risk factors and natural history of the disease and to highlight possible areas for further investigation. PMID- 26575040 TI - Impact of gender and age on the occurrence of gastric polyps: data analysis of 69575 southeastern Chinese patients. AB - BACKGROUND/AIMS: Current epidemiological data suggest that the incidence of gastric polyps (GP) is rare, and its etiology and pathogenesis are still not clear. This study analyzed and compared the occurrence and pathological types of GPs in southeast Chinese patients according to gender and age. MATERIALS AND METHODS: This was a retrospective study of patients diagnosed with GP (n=2125) in Wenzhou People's Hospital (China) between January 2004 and December 2013. The relationships between the detection rate, the characteristics of GP, and the patients' demographic data were analyzed. RESULTS: The detection rate of GP was 2.3% and 3.9% in males and females, respectively (p<0.01). The detection rate increased with increasing age in both genders. Polyps in the gastric antrum and gastric body were the most prevalent in both genders. Similarly, inflammatory polyps and hyperplastic polyps were the most prevalent in both genders. Hyperplastic polyps were more common in females than in males (28.6% vs. 24.2%, p<0.05), while there was no difference for inflammatory polyps, fundic GP, and adenoma (p>0.05). Age had no impact on the pathology of GP (p>0.05). CONCLUSIONS: The incidence of GPs was associated with gender and age. PMID- 26575041 TI - DR-70 as a novel diagnostic biomarker for gastric cancer. AB - BACKGROUND/AIMS: To assess the utility of the DR-70 immunoassay in the diagnosis of gastric cancer. MATERIALS AND METHODS: A total of 29 patients with histologically proven malignant gastric tumor and 29 healthy blood donors were enrolled in this study. DR-70 immunoassay was performed using an enzyme-linked immunosorbent assay kit to quantify the serum levels of fibrin degradation products. RESULTS: The DR-70 values in patients with gastric cancer significantly differed from the values in controls (p<0.0001). Receiver operating characteristic curve analysis revealed >=1.45 ug/mL as the best cut-off value to distinguish between patients with gastric cancer and healthy controls. The area under the receiver operating characteristic curve was 0.871. Using >=1.45 ug/mL as the cut-off value, the DR-70 immunoassay showed a good clinical performance with a sensitivity of 82.8% and a specificity of 79.3%. The positive predictive value was 80.0%, and the negative predictive value was 82.1%. CONCLUSION: The DR 70 immunoassay reliably differs between gastric cancer and healthy controls, promising to become a useful cancer detection tool in clinical practice. PMID- 26575042 TI - Meat intake and risk of inflammatory bowel disease: A meta-analysis. AB - BACKGROUND/AIMS: This meta-analysis is designed to determine the association between meat consumption and the risk of inflammatory bowel disease. MATERIALS AND METHODS: Search relevant literature published in PubMed, Cochrane before July 2015 without restrictions. Studies were included if relative ratios and the corresponding 95% confidence intervals of the risk of inflammatory bowel disease were reported with respect to meat consumption. RESULTS: Nine studies were included in this meta-analysis. Relative to those who did not or seldom eat meat, meat consumers had a significantly greater risk of inflammatory bowel disease (pooled relative ratio: 1.50, 95% confidence interval: 1.15-1.95). The funnel plot revealed no evidence for publication bias. CONCLUSION: Meat consumption may increase the risk of inflammatory bowel disease. Additional large prospective studies are warranted to verify this association. PMID- 26575043 TI - Incidence, causes, and outcomes of renal failure among cirrhotic patients. AB - BACKGROUND/AIMS: To evaluate the incidence, risk factors of RF among cirrhotic and its impact on patient's outcome. MATERIALS AND METHODS: A total of 573 cirrhotic patients were evaluated for renal failure (RF) and its causes, 212 patients (37%) were enrolled. RESULTS: Majority of the patients had post hepatitis C liver disease (n=190, 89.6%) with Child-Pugh score C (88.2%), HCC was in 21.2% of cases baseline characteristics. Infections were observed in 45.8% (n=97) of patients whereas, spontaneous bacterial peritonitis (SBP) was the most type of infection (19.3%) among cirrhotic patients with renal failure, followed by pneumonia (9.9%). Infection-induced represents 30.2% followed by hypovolemia (29.7%), whereas HRS was in 11.3%. Reversibility of the condition was seen in 81 patients (38.2%), whereas mortality was seen in 58 (27.4%) patients of RF. The reversibility was more common in the patients with infection, followed by hypovolemia. Mortality was higher in the patients with HRS followed by parenchymal renal disease. CONCLUSION: Infection-induced and hypovolemic-induced RF represent the most common and also the most correctable causes and must be considered in management protocols for early detection and treatment that will serve for a better prognosis. PMID- 26575044 TI - Acute Effects of Light on Alternative Splicing in Light-Grown Plants. AB - Light modulates plant growth and development to a great extent by regulating gene expression programs. Here, we evaluated the effect of light on alternative splicing (AS) in light-grown Arabidopsis thaliana plants using high-throughput RNA sequencing (RNA-seq). We found that an acute light pulse given in the middle of the night, a treatment that simulates photoperiod lengthening, affected AS events corresponding to 382 genes. Some of these AS events were associated with genes involved in primary metabolism and stress responses, which may help to adjust metabolic and physiological responses to seasonal changes. We also found that several core clock genes showed changes in AS in response to the light treatment, suggesting that light regulation of AS may play a role in clock entrainment. Finally, we found that many light-regulated AS events were associated with genes encoding RNA processing proteins and splicing factors, supporting the idea that light regulates this posttranscriptional regulatory layer through AS regulation of splicing factors. Interestingly, the effect of a red-light pulse on AS of a gene encoding a splicing factor was not impaired in a quintuple phytochrome mutant, providing unequivocal evidence that nonphotosensory photoreceptors control AS in light-grown plants. PMID- 26575047 TI - Columbarium Architecture (Museum of Disappearing Buildings): Alexander Brodsky and Ilya Utkin. PMID- 26575048 TI - Twitter Streams Fuel Big Data Approaches to Health Forecasting. PMID- 26575057 TI - A piece of my mind. Ditch the Scale. PMID- 26575058 TI - Individual Benefit vs Societal Effect of Antibiotic Prescribing for Preschool Children With Recurrent Wheeze. PMID- 26575059 TI - The Pendulum of Prostate Cancer Screening. PMID- 26575061 TI - Prostate Cancer Incidence and PSA Testing Patterns in Relation to USPSTF Screening Recommendations. AB - IMPORTANCE: Prostate cancer incidence in men 75 years and older substantially decreased following the 2008 US Preventive Services Task Force (USPSTF) recommendation against prostate-specific antigen (PSA)-based screening for this age group. It is unknown whether incidence has changed since the USPSTF recommendation against screening for all men in May 2012. OBJECTIVE: To examine recent changes in stage-specific prostate cancer incidence and PSA screening rates following the 2008 and 2012 USPSTF recommendations. DESIGN AND SETTINGS: Ecologic study of age-standardized prostate cancer incidence (newly diagnosed cases/100,000 men aged >=50 years) by stage from 2005 through 2012 using data from 18 population-based Surveillance, Epidemiology, and End Results (SEER) registries and PSA screening rate in the past year among men 50 years and older without a history of prostate cancer who responded to the 2005 (n = 4580), 2008 (n = 3476), 2010 (n = 4157), and 2013 (n = 6172) National Health Interview Survey (NHIS). EXPOSURES: The USPSTF recommendations to omit PSA-based screening for average-risk men. MAIN OUTCOMES AND MEASURES: Prostate cancer incidence and incidence ratios (IRs) comparing consecutive years from 2005 through 2012 by age (>=50, 50-74, and >=75 years) and SEER summary stage categorized as local/regional or distant and PSA screening rate and rate ratios (SRRs) comparing successive survey years by age. RESULTS: Prostate cancer incidence per 100,000 in men 50 years and older (N = 446,009 in SEER areas) was 534.9 in 2005, 540.8 in 2008, 505.0 in 2010, and 416.2 in 2012; rates began decreasing in 2008 and the largest decrease occurred between 2011 and 2012, from 498.3 (99% CI, 492.8-503.9) to 416.2 (99% CI, 411.2-421.2). The number of men 50 years and older diagnosed with prostate cancer nationwide declined by 33,519, from 213,562 men in 2011 to 180,043 men in 2012. Declines in incidence since 2008 were confined to local/regional-stage disease and were similar across age and race/ethnicity groups. The percentage of men 50 years and older reporting PSA screening in the past 12 months was 36.9% in 2005, 40.6% in 2008, 37.8% in 2010, and 30.8% in 2013. In relative terms, screening rates increased by 10% (SRR, 1.10; 99% CI, 1.01-1.21) between 2005 and 2008 and then decreased by 18% (SRR, 0.82; 99% CI, 0.75-0.89) between 2010 and 2013. Similar screening patterns were found in age subgroups 50 to 74 years and 75 years and older. CONCLUSIONS AND RELEVANCE: Both the incidence of early-stage prostate cancer and rates of PSA screening have declined and coincide with 2012 USPSTF recommendation to omit PSA screening from routine primary care for men. Longer follow-up is needed to see whether these decreases are associated with trends in mortality. PMID- 26575063 TI - Doing Less Is Sometimes Enough. PMID- 26575062 TI - Comparative Risk of Anaphylactic Reactions Associated With Intravenous Iron Products. AB - IMPORTANCE: All intravenous (IV) iron products are associated with anaphylaxis, but the comparative safety of each product has not been well established. OBJECTIVE: To compare the risk of anaphylaxis among marketed IV iron products. DESIGN, SETTING, AND PARTICIPANTS: Retrospective new user cohort study of IV iron recipients (n = 688,183) enrolled in the US fee-for-service Medicare program from January 2003 to December 2013. Analyses involving ferumoxytol were limited to the period January 2010 to December 2013. EXPOSURES: Administrations of IV iron dextran, gluconate, sucrose, or ferumoxytol as reported in outpatient Medicare claims data. MAIN OUTCOMES AND MEASURES: Anaphylaxis was identified using a prespecified and validated algorithm defined with standard diagnosis and procedure codes and applied to both inpatient and outpatient Medicare claims. The absolute and relative risks of anaphylaxis were estimated, adjusting for imbalances among treatment groups. RESULTS: A total of 274 anaphylaxis cases were identified at first exposure, with an additional 170 incident anaphylaxis cases identified during subsequent IV iron administrations. The risk for anaphylaxis at first exposure was 68 per 100,000 persons for iron dextran (95% CI, 57.8-78.7 per 100,000) and 24 per 100,000 persons for all nondextran IV iron products combined (iron sucrose, gluconate, and ferumoxytol) (95% CI, 20.0-29.5 per 100,000) , with an adjusted odds ratio (OR) of 2.6 (95% CI, 2.0-3.3; P < .001). At first exposure, when compared with iron sucrose, the adjusted OR of anaphylaxis for iron dextran was 3.6 (95% CI, 2.4-5.4); for iron gluconate, 2.0 (95% CI 1.2, 3.5); and for ferumoxytol, 2.2 (95% CI, 1.1-4.3). The estimated cumulative anaphylaxis risk following total iron repletion of 1000 mg administered within a 12-week period was highest with iron dextran (82 per 100,000 persons, 95% CI, 70.5- 93.1) and lowest with iron sucrose (21 per 100,000 persons, 95% CI, 15.3- 26.4). CONCLUSIONS AND RELEVANCE: Among patients in the US Medicare nondialysis population with first exposure to IV iron, the risk of anaphylaxis was highest for iron dextran and lowest for iron sucrose. PMID- 26575060 TI - Early Administration of Azithromycin and Prevention of Severe Lower Respiratory Tract Illnesses in Preschool Children With a History of Such Illnesses: A Randomized Clinical Trial. AB - IMPORTANCE: Many preschool children develop recurrent, severe episodes of lower respiratory tract illness (LRTI). Although viral infections are often present, bacteria may also contribute to illness pathogenesis. Strategies that effectively attenuate such episodes are needed. OBJECTIVE: To evaluate if early administration of azithromycin, started prior to the onset of severe LRTI symptoms, in preschool children with recurrent severe LRTIs can prevent the progression of these episodes. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled, parallel-group trial conducted across 9 academic US medical centers in the National Heart, Lung, and Blood Institute's AsthmaNet network, with enrollment starting in April 2011 and follow-up complete by December 2014. Participants were 607 children aged 12 through 71 months with histories of recurrent, severe LRTIs and minimal day-to-day impairment. INTERVENTION: Participants were randomly assigned to receive azithromycin (12 mg/kg/d for 5 days; n = 307) or matching placebo (n = 300), started early during each predefined RTI (child's signs or symptoms prior to development of LRTI), based on individualized action plans, over a 12- through 18-month period. MAIN OUTCOMES AND MEASURES: The primary outcome measure was the number of RTIs not progressing to a severe LRTI, measured at the level of the RTI, that would in clinical practice trigger the prescription of oral corticosteroids. Presence of azithromycin-resistant organisms in oropharyngeal samples, along with adverse events, were among the secondary outcome measures. RESULTS: A total of 937 treated RTIs (azithromycin group, 473; placebo group, 464) were experienced by 443 children (azithromycin group, 223; placebo group, 220), including 92 severe LRTIs (azithromycin group, 35; placebo group, 57). Azithromycin significantly reduced the risk of progressing to severe LRTI relative to placebo (hazard ratio, 0.64 [95% CI, 0.41-0.98], P = .04; absolute risk for first RTI: 0.05 for azithromycin, 0.08 for placebo; risk difference, 0.03 [95% CI, 0.00-0.06]). Induction of azithromycin-resistant organisms and adverse events were infrequently observed. CONCLUSIONS AND RELEVANCE: Among young children with histories of recurrent severe LRTIs, the use of azithromycin early during an apparent RTI compared with placebo reduced the likelihood of severe LRTI. More information is needed on the development of antibiotic-resistant pathogens with this strategy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01272635. PMID- 26575064 TI - Gradually Worsening Tattoo Lesion. PMID- 26575065 TI - Evaluating an Elevated Screening PSA Test. PMID- 26575066 TI - Prostate-Specific Antigen Screening After 2012 US Preventive Services Task Force Recommendations. PMID- 26575067 TI - Predicted vs Observed Clinical Event Risk for Cardiovascular Disease. PMID- 26575068 TI - Predicted vs Observed Clinical Event Risk for Cardiovascular Disease-Reply. PMID- 26575069 TI - Dietary Cholesterol and Blood Cholesterol Concentrations. PMID- 26575070 TI - Dietary Cholesterol and Blood Cholesterol Concentrations-Reply. PMID- 26575071 TI - Needle Exchange Programs for HIV Outbreaks. PMID- 26575073 TI - Incorrect Affiliation. PMID- 26575072 TI - Needle Exchange Programs for HIV Outbreaks-Reply. PMID- 26575074 TI - Incorrect Labels in Figure 2 Key. PMID- 26575076 TI - Women Physicians and the War. PMID- 26575077 TI - JAMA Patient Page. Prostate Cancer Screening. PMID- 26575078 TI - Assessment of Meaning in Adolescents Receiving Clinical Services in Mississippi Following the Deepwater Horizon Oil Spill: An Application of the Purpose in Life Test-Short Form (PIL-SF). AB - OBJECTIVES: This study's purpose was to assess perceived meaning in adolescents. Specifically, our goals were to examine the psychometric properties of the Purpose in Life test-Short Form (PIL-SF) and its ability to predict psychological outcomes in an adolescent sample. METHOD: Aspects of well-being (self-efficacy, life satisfaction, and resilience) and psychological distress (posttraumatic stress, depression, anxiety, and general stress) were assessed in a sample of adolescents (N = 91; 58.2% female; mean age = 14.89) receiving clinical services following the Deepwater Horizon Oil Spill. RESULTS: Meaning was positively associated with life satisfaction, self-efficacy, and resilience, and negatively associated with posttraumatic stress and depression. Meaning was not significantly related to anxiety or general stress. Females reported significantly more meaning than males, while no significant differences were noted by race/ethnicity. CONCLUSIONS: The PIL-SF is a useful measure with adolescents. Moreover, meaning is an important concept to consider with respect to disasters. PMID- 26575079 TI - Marginal regression models for clustered count data based on zero-inflated Conway Maxwell-Poisson distribution with applications. AB - Community water fluoridation is an important public health measure to prevent dental caries, but it continues to be somewhat controversial. The Iowa Fluoride Study (IFS) is a longitudinal study on a cohort of Iowa children that began in 1991. The main purposes of this study (http://www.dentistry.uiowa.edu/preventive fluoride-study) were to quantify fluoride exposures from both dietary and nondietary sources and to associate longitudinal fluoride exposures with dental fluorosis (spots on teeth) and dental caries (cavities). We analyze a subset of the IFS data by a marginal regression model with a zero-inflated version of the Conway-Maxwell-Poisson distribution for count data exhibiting excessive zeros and a wide range of dispersion patterns. In general, we introduce two estimation methods for fitting a ZICMP marginal regression model. Finite sample behaviors of the estimators and the resulting confidence intervals are studied using extensive simulation studies. We apply our methodologies to the dental caries data. Our novel modeling incorporating zero inflation, clustering, and overdispersion sheds some new light on the effect of community water fluoridation and other factors. We also include a second application of our methodology to a genomic (next generation sequencing) dataset that exhibits underdispersion. PMID- 26575080 TI - Comparative Proteomic Analysis of Two Varieties of Genetically Modified (GM) Embrapa 5.1 Common Bean (Phaseolus vulgaris L.) and Their Non-GM Counterparts. AB - The genetically modified (GM) common bean event Embrapa 5.1 was commercially approved in Brazil in 2011; it is resistant to golden mosaic virus infection. In the present work grain proteome profiles of two Embrapa 5.1 common bean varieties, Perola and Pontal, and their non-GM counterparts were compared by two dimensional gel electrophoresis (2-DE) followed by mass spectrometry (MS). Analyses detected 23 spots differentially accumulated between GM Perola and non GM Perola and 21 spots between GM Pontal and non-GM Pontal, although they were not the same proteins in Perola and Pontal varieties, indicating that the variability observed may not be due to the genetic transformation. Among them, eight proteins were identified in Perola varieties, and four proteins were identified in Pontal. Moreover, we applied principal component analysis (PCA) on 2-DE data, and variation between varieties was explained in the first two principal components. This work provides a first 2-DE-MS/MS-based analysis of Embrapa 5.1 common bean grains. PMID- 26575081 TI - 'Washout' period for oral tetracycline antibiotics prior to systemic isotretinoin. PMID- 26575082 TI - The Magnaporthe grisea species complex and plant pathogenesis. AB - TAXONOMY: Kingdom Fungi; Phylum Ascomycota; Class Sordariomycetes; Order Magnaporthales; Family Pyriculariaceae (anamorph)/Magnaporthaceae (teleomorph); Genus Pyricularia (anamorph)/Magnaporthe (teleomorph); Species P. grisea (anamorph)/M. grisea (teleomorph). HOST RANGE: Very broad at the species level, including rice, wheat, barley, millet and other species of the Poaceae (Gramineae). DISEASE SYMPTOMS: Can be found on all parts of the plant, including leaves, leaf collars, necks, panicles, pedicels, seeds and even the roots. Initial symptoms are white to grey-green lesions or spots with darker borders, whereas older lesions are elliptical or spindle-shaped and whitish to grey with necrotic borders. Lesions may enlarge and coalesce to eventually destroy the entire leaf. DISEASE CONTROL: Includes cultural strategies, genetic resistance and the application of chemical fungicides. GEOGRAPHICAL DISTRIBUTION: Widespread throughout the rice-growing regions of the globe and has been reported in more than 85 countries. GENOMIC STRUCTURE: Different isolates possess similar genomic sizes and overall genomic structures. For the laboratory strain 70-15: assembly size, 40.98 Mb; number of chromosomes, seven; number of predicted genes, 13 032; G + C composition, 51.6%; average gene contains 451.6 amino acids; mitochondrion genome size, 34.87 kb. USEFUL WEBSITE: http://www.broadinstitute.org/annotation/genome/magnaporthe_comparative/MultiHome html. PMID- 26575083 TI - A 2-Year-Old Girl with Dysmetria and Ataxia. PMID- 26575084 TI - Integration of High-Charge-Injection-Capacity Electrodes onto Polymer Softening Neural Interfaces. AB - Softening neural interfaces are implanted stiff to enable precise insertion, and they soften in physiological conditions to minimize modulus mismatch with tissue. In this work, a high-charge-injection-capacity iridium electrode fabrication process is detailed. For the first time, this process enables integration of iridium electrodes onto softening substrates using photolithography to define all features in the device. Importantly, no electroplated layers are utilized, leading to a highly scalable method for consistent device fabrication. The iridium electrode is metallically bonded to the gold conductor layer, which is covalently bonded to the softening substrate via sulfur-based click chemistry. The resulting shape-memory polymer neural interfaces can deliver more than 2 billion symmetric biphasic pulses (100 MUs/phase), with a charge of 200 MUC/cm(2) and geometric surface area (GSA) of 300 MUm(2). A transfer-by-polymerization method is used in combination with standard semiconductor processing techniques to fabricate functional neural probes onto a thiol-ene-based, thin film substrate. Electrical stability is tested under simulated physiological conditions in an accelerated electrical aging paradigm with periodic measurement of electrochemical impedance spectra (EIS) and charge storage capacity (CSC) at various intervals. Electrochemical characterization and both optical and scanning electron microscopy suggest significant breakdown of the 600 nm-thick parylene-C insulation, although no delamination of the conductors or of the final electrode interface was observed. Minor cracking at the edges of the thin film iridium electrodes was occasionally observed. The resulting devices will provide electrical recording and stimulation of the nervous system to better understand neural wiring and timing, to target treatments for debilitating diseases, and to give neuroscientists spatially selective and specific tools to interact with the body. This approach has uses for cochlear implants, nerve cuff electrodes, penetrating cortical probes, spinal stimulators, blanket electrodes for the gut, stomach, and visceral organs and a host of other custom nerve-interfacing devices. PMID- 26575085 TI - European Society of Cardiology Congress 2015 (ESC 2015). PMID- 26575086 TI - Pincer Ligand Modifications To Tune the Activation Barrier for H2 Elimination in Water Splitting Milstein Catalyst. AB - Modifications on the ligand environment of Milstein ruthenium(II) pincer hydride catalysts have been proposed to fine-tune the activation free energy, DeltaG(?) for the key step of H2 elimination in the water splitting reaction. This study conducted at the B3LYP level of density functional theory including the solvation effect reveals that changing the bulky t-butyl group at the P-arm of the pincer ligand by methyl or ethyl group can reduce the DeltaG(?) by a substantial margin, ~ 10 kcal/mol. The reduction in the steric effect of the pincer ligand causes exothermic association of the water molecule to the metal center and leads to significant stabilization of all the subsequent reaction intermediates and the transition state compared to those of the original Milstein catalyst that promotes endothermic association of the water molecule. Though electron donating groups on the pyridyl unit of the pincer ligand are advantageous for reducing the activation barrier in the gas phase, the effect is only 1-1.4 kcal/mol compared to that of an electron withdrawing group. The absolute minimum of the electrostatic potential at the hydride ligand and carbonyl stretching frequency of the catalyst are useful parameters to gauge the effect of ligand environment on the H2 elimination step of the water splitting reaction. PMID- 26575087 TI - Functionally Distinct Bacterial Cytochrome c Peroxidases Proceed through a Common (Electro)catalytic Intermediate. AB - The diheme cytochrome c peroxidase from Shewanella oneidensis (So CcP) requires a single electron reduction to convert the oxidized, as-isolated enzyme to an active conformation. We employ protein film voltammetry to investigate the mechanism of hydrogen peroxide turnover by So CcP. When the enzyme is poised in the active state by incubation with sodium l-ascorbate, the graphite electrode specifically captures a highly active state that turns over peroxide in a high potential regime. This is the first example of an on-pathway catalytic intermediate observed for a bacterial diheme cytochrome c peroxidase that requires reductive activation, consistent with the observed voltammetric response from the diheme cytochrome c peroxidase from Nitrosomonas europaea (Ne), which is constitutively active and does not require the same one electron activation. Mutational analysis at the active site of So CcP confirms that the rate-limiting step involves a proton-coupled single electron reduction of a high valent iron species centered on the low-potential heme, consistent with the same mutation in Ne CcP. The pH dependence of catalysis for wild-type So CcP suggests that reduction shifts the pK(a)'s of at least two amino acids. Mutation of His81 in "loop 1", a surface exposed loop thought to shift conformation during the reductive activation process, eliminated one of the pH dependent features, confirming that the loop 1 shifts, changing the environment of His81 during the rate-limiting step. The observed catalytic intermediate has the same electron stoichiometry and similar pH dependence to that previously reported for Ne CcP, which is constitutively active and therefore hypothesized to follow a different catalytic mechanism. The prominent similarities between the rate-limiting steps of differing mechanistic classes of bCcPs suggest unexpected similarities in the intermediates formed. PMID- 26575088 TI - The thrombotic microangiopathy Registry of North America: A United States multi institutional TMA network. AB - The thrombotic microangiopathy (TMA) Registry Network of North America (TRNA) is a collaborative network organized for the purpose of developing a multi institutional registry and network to conduct clinical studies in a rare patient population. The TRNA was founded in 2013 by four academic medical centers (Columbia University Medical Center, Duke University Medical Center, University of Alabama at Birmingham, and University of Pennsylvania) to develop a national and demographically diverse dataset of patients with TMA. A clinical database was developed by network members using REDCap (Research Electronic Data Capture), a web-based database developed for clinical research. To facilitate rapid Institutional Review Board (IRB) approval at multiple sites, the TRNA utilized IRBshare, a streamlined IRB process to allow patient recruitment and enrollment into the TMA registry. This article reviews the process used to establish the TRNA network and discusses the significance of the first multi-institutional clinical apheresis network developed in the United States. J. Clin. Apheresis 31:448-453, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26575089 TI - Erratum. PMID- 26575090 TI - Structure of the bacterial cell division determinant GpsB and its interaction with penicillin-binding proteins. AB - Each bacterium has to co-ordinate its growth with division to ensure genetic stability of the population. Consequently, cell division and growth are tightly regulated phenomena, albeit different bacteria utilise one of several alternative regulatory mechanisms to maintain control. Here we consider GpsB, which is linked to cell growth and division in Gram-positive bacteria. DeltagpsB mutants of the human pathogen Listeria monocytogenes show severe lysis, division and growth defects due to distortions of cell wall biosynthesis. Consistent with this premise, GpsB interacts both in vitro and in vivo with the major bi-functional penicillin-binding protein. We solved the crystal structure of GpsB and the interaction interfaces in both proteins are identified and validated. The inactivation of gpsB results in strongly attenuated virulence in animal experiments, comparable in degree to classical listerial virulence factor mutants. Therefore, GpsB is essential for in vitro and in vivo growth of a highly virulent food-borne pathogen, suggesting that GpsB could be a target for the future design of novel antibacterials. PMID- 26575091 TI - The American Journal of Hematology turns 40. PMID- 26575092 TI - Fluorescence, Phosphorescence, and Chemiluminescence. PMID- 26575093 TI - Visible Color Tunable Emission in Three-Dimensional Light Emitting Diodes by MgO Passivation of Pyramid Tip. AB - We demonstrated visible color tunable three-dimensional (3D) pyramidal light emitting diodes by depositing the MgO on and near the tip of the pyramid as an insulating layer. Here, we show that the degradation of the materials (i.e., p GaN) crystallinity and the built-in electric field due to the nanoscale geometry of the tip region is responsible for the large leakage current observed in LEDs. Confocal scanning electroluminescence microscopy images clearly showed that the intensity of the light emitted out of the side facet of the pyramid is much higher than that of the light extracted out of the tip surface, indicating that the MgO layer prohibited the carrier injection to the MQWs layer, suppressing the leakage occurring at or near the tip region of the pyramids. The color range of the LEDs can be also tuned by using the MgO layer, a blue-shift by 10.3 nm in the wavelength. This technique is simple and scalable, providing a promising solution for developing 3D pyramidal LEDs with low leakage current and controllable light emission. PMID- 26575094 TI - Discovery and SAR of Novel and Selective Inhibitors of Urokinase Plasminogen Activator (uPA) with an Imidazo[1,2-a]pyridine Scaffold. AB - Urokinase plasminogen activator (uPA) is a biomarker and therapeutic target for several cancer types. Its inhibition is regarded as a promising, noncytotoxic approach in cancer therapy by blocking growth and/or metastasis of solid tumors. Earlier, we reported the modified substrate activity screening (MSAS) approach and applied it for the identification of fragments with affinity for uPA's S1 pocket. Here, these fragments are transformed into a novel class of uPA inhibitors with an imidazo[1,2-a]pyridine scaffold. The SAR for uPA inhibition around this scaffold is explored, and the best compounds in the series have nanomolar uPA affinity and selectivity with respect to the related trypsin-like serine proteases (thrombin, tPA, FXa, plasmin, plasma kallikrein, trypsin, FVIIa). Finally, the approach followed for translating fragments into small molecules with a decorated scaffold architecture is conceptually straightforward and can be expected to be broadly applicable in fragment-based drug design. PMID- 26575095 TI - Regioselective Synthesis of alpha,alpha-Difluorocyclopentanone Derivatives: Domino Nickel-Catalyzed Difluorocyclopropanation/Ring-Expansion Sequence of Silyl Dienol Ethers. AB - Silyl dienol ethers prepared from alpha,beta-unsaturated ketones underwent nickel catalyzed difluorocyclopropanation of the electron-rich alkene moiety with trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate. The subsequent vinylcyclopropane-cyclopentene rearrangement afforded silyl 5,5-difluorocyclopent 1-en-1-yl ethers in good yields. The obtained five-membered silyl enol ethers were demonstrated to be versatile intermediates for the synthesis of di- and monofluorinated cyclopentanones and cyclopentenones. A nickel difluorocarbene complex is proposed as a key intermediate in the difluorocyclopropanation. PMID- 26575096 TI - Exploring the (H2C?PH2)(+):N-Base Potential Surfaces: Complexes Stabilized by Pnicogen, Hydrogen, and Tetrel Bonds. AB - Ab initio MP2/aug'-cc-pVTZ calculations have been carried out to determine the structures, binding energies, and bonding properties of complexes involving the cation (H2C?PH2)(+) and a set of sp-hybridized nitrogen bases including NCCH3, NP, NCCl, NCH, NCF, NCCN, and N2. On each (H2C?PH2)(+):N-base surface, four types of unique equilibrium structures exist: a complex with a P...N pnicogen bond formed through the pi system of (H2C?PH2)(+) (ZB-pi); a complex with a P...N pnicogen bond formed through the sigma system of (H2C?PH2)(+) (ZB-sigma); a hydrogen-bonded complex with a P-H...N hydrogen bond (HB); and a tetrel-bonded complex with a C...N bond (TB). Binding energies of complexes stabilized by the same type of intermolecular interaction decrease in the order NCCH3 > NP > NCCl > NCH > NCF > NCCN > N2. For a given base, binding energies decrease in the order ZB-pi > HB > ZB-sigma > TB, except for a reversal of HB and ZB-sigma with the weakest base N2. Binding energies of ZB-pi, HB, and ZB-sigma complexes increase exponentially as the corresponding P-N distance decreases, but the correlation is not as good between the binding energies of TB complexes and the intermolecular C N distance. Charge-transfer energies stabilize all complexes and also exhibit an exponential dependence on the corresponding intermolecular distances. EOM-CCSD spin-spin coupling constants (1p)J(P-N) for ZB-pi and ZB-sigma complexes, and (2h)J(P-N) for HB complexes increase quadratically as the corresponding P-N distance decreases. Values of (1t)J(C-N) for TB are small and show little dependence on the C-N distance. (1)J(P-H) values for the hydrogen-bonded P-H bond in HB complexes correlate with the corresponding P-H distance, whereas values of (1)J(P-H) for the non-hydrogen-bonded P-H correlate with the P-N distance. PMID- 26575097 TI - Spatiotemporal quantification of subcellular ATP levels in a single HeLa cell during changes in morphology. AB - The quantitative relationship between change in cell shape and ATP consumption is an unsolved problem in cell biology. In this study, a simultaneous imaging and image processing analysis allowed us to observe and quantify these relationships under physiological conditions, for the first time. We focused on two marginal regions of cells: the microtubule-rich 'lamella' and the actin-rich 'peripheral structure'. Simultaneous imaging and correlation analysis revealed that microtubule dynamics cause lamellar shape change accompanying an increase in ATP level. Also, image processing and spatiotemporal quantification enabled to visualize a chronological change of the relationships between the protrusion length and ATP levels, and it suggested they are influencing each other. Furthermore, inhibition of microtubule dynamics diminished motility in the peripheral structure and the range of fluctuation of ATP level in the lamella. This work clearly demonstrates that cellular motility and morphology are regulated by ATP-related cooperative function between microtubule and actin dynamics. PMID- 26575098 TI - Off-target Effects in CRISPR/Cas9-mediated Genome Engineering. AB - CRISPR/Cas9 is a versatile genome-editing technology that is widely used for studying the functionality of genetic elements, creating genetically modified organisms as well as preclinical research of genetic disorders. However, the high frequency of off-target activity (>=50%)-RGEN (RNA-guided endonuclease)-induced mutations at sites other than the intended on-target site-is one major concern, especially for therapeutic and clinical applications. Here, we review the basic mechanisms underlying off-target cutting in the CRISPR/Cas9 system, methods for detecting off-target mutations, and strategies for minimizing off-target cleavage. The improvement off-target specificity in the CRISPR/Cas9 system will provide solid genotype-phenotype correlations, and thus enable faithful interpretation of genome-editing data, which will certainly facilitate the basic and clinical application of this technology. PMID- 26575099 TI - Increased DUX4 expression during muscle differentiation correlates with decreased SMCHD1 protein levels at D4Z4. AB - Facioscapulohumeral muscular dystrophy is caused by incomplete epigenetic repression of the transcription factor DUX4 in skeletal muscle. A copy of DUX4 is located within each unit of the D4Z4 macrosatellite repeat array and its derepression in somatic cells is caused by either repeat array contraction (FSHD1) or by mutations in the chromatin repressor SMCHD1 (FSHD2). While DUX4 expression has thus far only been detected in FSHD muscle and muscle cell cultures, and increases with in vitro myogenic differentiation, the D4Z4 chromatin structure has only been studied in proliferating myoblasts or non myogenic cells. We here show that SMCHD1 protein levels at D4Z4 decline during muscle cell differentiation and correlate with DUX4 derepression. In FSHD2, but not FSHD1, the loss of SMCHD1 repressor activity is partially compensated by increased Polycomb Repressive Complex 2 (PRC2)-mediated H3K27 trimethylation at D4Z4, a situation that can be mimicked by SMCHD1 knockdown in control myotubes. In contrast, moderate overexpression of SMCHD1 results in DUX4 silencing in FSHD1 and FSHD2 myotubes demonstrating that DUX4 derepression in FSHD is reversible. Together, we show that in FSHD1 and FSHD2 the decline in SMCHD1 protein levels during muscle cell differentiation renders skeletal muscle sensitive to DUX4. PMID- 26575100 TI - Effect of 1-h moderate-intensity aerobic exercise on intramyocellular lipids in obese men before and after a lifestyle intervention. AB - Intramyocellular lipids (IMCL) are depleted in response to an acute bout of exercise in lean endurance-trained individuals; however, it is unclear whether changes in IMCL content are also seen in response to acute and chronic exercise in obese individuals. We used magnetic resonance spectroscopy in 18 obese men and 5 normal-weight controls to assess IMCL content before and after an hour of cycling at the intensity corresponding with each participant's maximal whole-body rate of fat oxidation (Fatmax). Fatmax was determined via indirect calorimetry during a graded exercise test on a cycle ergometer. The same outcome measures were reassessed in the obese group after a 16-week lifestyle intervention comprising dietary calorie restriction and exercise training. At baseline, IMCL content decreased in response to 1 h of cycling at Fatmax in controls (2.8 +/- 0.4 to 2.0 +/- 0.3 A.U., -39%, p = 0.02), but not in obese (5.4 +/- 2.1 vs. 5.2 +/- 2.2 A.U., p = 0.42). The lifestyle intervention lead to weight loss (-10.0 +/ 5.4 kg, p < 0.001), improvements in maximal aerobic power (+5.2 +/- 3.4 mL/(kg.min)), maximal fat oxidation rate (+0.19 +/- 0.22 g/min), and a 29% decrease in homeostasis model assessment score (all p < 0.05). However, when the 1 h of cycling at Fatmax was repeated after the lifestyle intervention, there remained no observable change in IMCL (4.6 +/- 1.8 vs. 4.6 +/- 1.9 A.U., p = 0.92). In summary, there was no IMCL depletion in response to 1 h of cycling at moderate intensity either before or after the lifestyle intervention in obese men. An effective lifestyle intervention including moderate-intensity exercise training did not impact rate of utilisation of IMCL during acute exercise in obese men. PMID- 26575101 TI - Impact of varying physical activity levels on airway sensitivity and bronchodilation in healthy humans. AB - The purpose of this study was to determine if the amount of physical activity influences airway sensitivity and bronchodilation in healthy subjects across a range of physical activity levels. Thirty healthy subjects (age, 21.9 +/- 2.6 years; 13 men/17 women) with normal pulmonary function reported to the laboratory on 2 separate occasions where they were randomized to breathe either hypertonic saline (HS) (nebulized hypertonic saline (25%) for 20 min) or HS followed by 5 deep inspirations (DIs), which has been reported to bronchodilate the airways. Pulmonary function tests (PFTs) were performed prior to both conditions and following the HS breathing or 5 DIs. Moderate to vigorous physical activity (MVPA) level was measured via accelerometer worn for 7 days. Following the HS breathing, forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) significantly decreased from baseline by -11.8% +/- 8.4% and -9.3% +/- 6.7%, respectively. A 2-segment linear model determined significant relationships between MVPA and percent change in FEV1 (r = 0.50) and FVC (r = 0.55). MVPA above ~497 and ~500 min/week for FEV1 and FVC, respectively, resulted in minor additional improvements (p > 0.05) in PFTs following the HS breathing. Following the DIs, FEV1 and FVC decreased (p < 0.05) by -7.3% +/- 8.6% and -5.7% +/- 5.7%, respectively, from baseline, but were not related (p > 0.05) to MVPA. In conclusion, these data demonstrate that higher MVPA levels attenuated airway sensitivity but not bronchodilation in healthy subjects. PMID- 26575102 TI - Importance of early cardiac rehabilitation on changes in exercise capacity: a retrospective pilot study. AB - Graded cardiopulmonary exercise tests were analyzed from 62 coronary artery disease patients (n = 48 males; age, 72 +/- 10 years; body mass index, 27 +/- 4 kg/m(2)) before and after 18 +/- 2 months of cardiac rehabilitation (CR). Early initiation of CR (<114 days) produced greater increases in peak metabolic equivalents (METs) compared with the late (>=114 days) CR group (68% +/- 51% vs. 41% +/- 39%, p < 0.05). A negative correlation was found between CR delay and peak METs (r = -0.32; p = 0.02). Early initiation of CR may be important to maximize cardiorespiratory adaptations to chronic exercise training. PMID- 26575103 TI - Spheroid Mesenchymal Stem Cells and Mesenchymal Stem Cell-Derived Microvesicles: Two Potential Therapeutic Strategies. AB - Mesenchymal stem cells (MSCs) have drawn worldwide attention of scientists and clinicians due to their ability to differentiate into other cell lineages, secrete paracrine factors, modulate inflammation and immunity, and also due to the effectiveness of MSCs in treating degenerative diseases. Recent studies have shown that, when cultured in spheroids, MSCs have greater differentiation ability, and increased anti-inflammatory and immunomodulatory capacities compared with traditional two-dimensional (2D) cultures. Furthermore, spheroid MSCs can be used on scale-up productions in clinically relevant manufacturing platforms. Microvesicles (MVs) are small membranous vesicles that can transfer proteins, genetic materials, and lipids to cells. MVs derived from MSCs (MSC-MVs) are not only emerging as potent transfer agents for molecular information, but also are effective in a series of tissue repair and anti-tumor experiments. Therefore, both spheroid MSCs and MSC-MVs have great potential in experimental and clinical applications. In this review, the characteristics, therapeutic applications and potential clinical translational opportunities of spheroid MSCs and MSC-MVs were discussed. PMID- 26575104 TI - Curative Stem Cell Transplantation for Severe Hb H Disease Manifesting From Early Infancy: Phenotypic and Genotypic Analyses. AB - Most people with Hb H disease live normal lives; however, a minority of cases requires lifelong regular transfusions. An atypical form of nondeletional Hb H disease was reported in a Thai boy, characterized by severe persistent hemolytic anemia since the age of 2 months. Molecular diagnosis revealed the apparent compound heterozygosity for the Southeast Asian (- -(SEA)) and alpha2 polyadenylation (polyA) signal (AATAAA>AATA- -) deletions. The proband was successfully treated with allogeneic hematopoietic stem cell transplantation (HSCT). Accurate phenotypic and genotypic diagnosis in atypically severe Hb H disease is helpful for the understanding of its pathophysiology, the institution of appropriate management, and provision of genetic counseling and prenatal diagnosis. Hematopoietic stem cell transplantation is a potentially curative treatment option for this severe alpha-thalassemia (alpha-thal) syndrome. PMID- 26575105 TI - Conditions Affecting Social Space in Drosophila melanogaster. AB - The social space assay described here can be used to quantify social interactions of Drosophila melanogaster - or other small insects - in a straightforward manner. As we previously demonstrated (1), in a two-dimensional chamber, we first force the flies to form a tight group, subsequently allowing them to take their preferred distance from each other. After the flies have settled, we measure the distance to the closest neighbor (or social space), processing a static picture with free online software (ImageJ). The analysis of the distance to the closest neighbor allows researchers to determine the effects of genetic and environmental factors on social interaction, while controlling for potential confounding factors. Diverse factors such as climbing ability, time of day, sex, and number of flies, can modify social spacing of flies. We thus propose a series of experimental controls to mitigate these confounding effects. This assay can be used for at least two purposes. First, researchers can determine how their favorite environmental shift (such as isolation, temperature, stress or toxins) will impact social spacing (1,2). Second, researchers can dissect the genetic and neural underpinnings of this basic form of social behavior (1,3). Specifically, we used it as a diagnostic tool to study the role of orthologous genes thought to be involved in social behavior in other organisms, such as candidate genes for autism in humans (4). PMID- 26575106 TI - Absolute phase effects on CPMG-type pulse sequences. AB - We describe and analyze the effects of transients within radio-frequency (RF) pulses on multiple-pulse NMR measurements such as the well-known Carr-Purcell Meiboom-Gill (CPMG) sequence. These transients are functions of the absolute RF phases at the beginning and end of the pulse, and are thus affected by the timing of the pulse sequence with respect to the period of the RF waveform. Changes in transients between refocusing pulses in CPMG-type sequences can result in signal decay, persistent oscillations, changes in echo shape, and other effects. We have explored such effects by performing experiments in two different low-frequency NMR systems. The first uses a conventional tuned-and-matched probe circuit, while the second uses an ultra-broadband un-tuned or non-resonant probe circuit. We show that there are distinct differences between the absolute phase effects in these two systems, and present simple models that explain these differences. PMID- 26575108 TI - When performance and risk taking are related: Working for rewards is related to risk taking when the value of rewards is presented briefly. AB - Valuable monetary rewards can boost human performance on various effortful tasks even when the value of the rewards is presented too briefly to allow for strategic decision making. However, the mechanism by which briefly-presented reward information influences performance has remained unclear. One possibility is that performance after briefly-presented reward information is primarily boosted via activation of the dopamine reward system, whereas performance after very visible reward information is driven more by strategic processes. To examine this hypothesis, we first presented participants with a task in which they could earn rewards of relatively low (1 cent) or high (10 cents) value, and the value information was presented either briefly (17 ms) or for an extended duration (300 ms). Furthermore, responsiveness of the dopamine system was indirectly estimated with a measure of risk taking, the Balloon Analogue Risk Task (BART). Results showed that performance after high- compared to low-value rewards was indeed related to the BART scores only when reward information was presented briefly. These results are suggestive of the possibility that brief presentation of reward information boosts performance directly via activating the dopamine system, whereas extended presentation of reward information leads to more strategic reward-driven behavior. PMID- 26575107 TI - Characterization of unstable pEntYN10 from enterotoxigenic Escherichia coli (ETEC) O169:H41. AB - Enterotoxigenic Escherichia coli (ETEC) serotype O169:H41 has been an extremely destructive epidemic ETEC type worldwide. The strain harbors a large unstable plasmid that is regarded as responsible for its virulence, although its etiology has remained unknown. To examine its genetic background specifically on the unstable retention and responsibility in the unique adherence to epithelial cells and enterotoxin production, the complete sequence of a plasmid, pEntYN10, purified from the serotype strain was determined. The length is 145,082 bp; its GC content is 46.15%. It contains 182 CDSs, which include 3 colonization factors (CFs), an enterotoxin, and large number of insertion sequences. The repertory of plasmid stability genes was extraordinarily scant. Uniquely, results showed that 3 CFs, CS6, CS8 (CFA/III)-like, and K88 (F4)-like were encoded redundantly in the plasmid with unique variations among previously known subtypes. These three CFs preserved their respective gene structures similarly to those of other ETEC strains reported previously with unique sequence variations respectively. It is particularly interesting that the K88-like gene cluster of pEntYN10 had 2 paralogous copies of faeG, which encodes the major component of fimbrial structure. It remains to be verified how the unique variations found in the CFs respectively affect the affinity to infected cells, host range, and virulence of the ETEC strain. PMID- 26575109 TI - [Autoimmune hemolytic anemia in children]. AB - Autoimmune hemolytic anemia is a rare condition in children which differs from the adult form. It is defined by immune-mediated destruction of red blood cells caused by autoantibodies. Characteristics of the autoantibodies are responsible for the various clinical entities. Classifications of autoimmune hemolytic anemia include warm autoimmune hemolytic anemia, cold autoimmune hemolytic anemia, and paroxysmal cold hemoglobinuria. For each classification, this review discusses the epidemiology, etiology, clinical presentation, laboratory evaluation, and treatment options. PMID- 26575110 TI - Listening to Chinese Immigrant Restaurant Workers in the Midwest: Application of the Culture-Centered Approach (CCA) to Explore Perceptions of Health and Health Care. AB - This study engages with the culture-centered approach (CCA) to explore Chinese immigrant restaurant workers' perception of the U.S. health care system and their interactions with the health care system in interpreting meanings of health. Chinese restaurant workers are marginalized because of their struggles on the job, their immigrant identity, and their negotiations with the structural contexts of occupation, migration status, and culture. In-depth interviews were conducted with 18 Chinese immigrant restaurant workers that lasted an average of 1.5 hours each, and were audiotaped. Interviews with participants highlighted critical issues in access to health care and the struggles experienced by restaurant workers in securing access to health, understood in the context of work. Critical to the workers' discourse is the acknowledgment of structural constraints such as lack of insurance coverage, immigration status, and lack of understanding of how the U.S. health care system works. PMID- 26575111 TI - Use of a levonorgestrel-containing intrauterine system with supplemental estrogen improves symptoms in perimenopausal women: a pilot study. AB - OBJECTIVE: The aim of this study was to compare perimenopausal symptomatology using a levonorgestrel-containing intrauterine system (LNG-IUS) + low-dose transdermal estradiol (TDE) with LNG-IUS alone. METHODS: The trial was a double blind, randomized, controlled pilot trial. Regularly cycling women aged 38 to 52 years, with at least one self-reported symptom (hot flashes, bloating, headache, adverse mood, or poor sleep), were randomized to either LNG-IUS + low-dose TDE gel (intervention) or LNG-IUS alone (control). TDE was administered once daily as a 0.06% gel containing 0.75 mg of TDE for 50 days. LNG-IUS was placed at least 90 days before TDE or placebo gel treatment to assure stable circulating LNG. Participants completed the Center for Epidemiologic Studies Depression scale (CESD), Hot Flash Related Daily Interference scale (HFRDIS), Pittsburgh Sleep Quality Index (PSQI), and Fatigue Severity Scale (FSS) at the time of LNG-IUS placement, at 90 days (the time of randomization to TDE/placebo), and 140 days (end of study). TDE and placebo groups were compared using repeated-measures analysis of variance. RESULTS: Thirty-eight women aged 42.9 +/- 2.7 years, with a mean BMI of 24.7 +/- 3.3 kg/m2, were enrolled; 20 were randomized to TDE. Women receiving TDE had significantly improved FSS scores between days 90 and 140 (mean difference TDE: -0.8 +/- 1.2 vs placebo: 0.1 +/- 0.7; P = 0.026) and borderline significant improvement in HFRDIS scores (mean difference TDE: -5.5 +/- 15.3 vs placebo: 4.2 +/- 13.1; P = 0.076). Women who reported hot flashes at baseline and who received TDE had a significant decrease in HFRDIS scores between days 90 and 140 (n = 9, P = 0.035). CESD and PSQI scores were not associated with TDE use. CONCLUSIONS: A brief, low-dose estrogen intervention, combined with a LNG-IUS, led to significant improvement of some common perimenopausal symptoms. Such a "minimalist" approach to management of the perimenopause holds promise for reducing common, bothersome perimenopausal symptoms while maintaining effective contraception. PMID- 26575112 TI - Myometrial artery calcification: significance for perimenopausal and postmenopausal women. PMID- 26575113 TI - Mucous membrane pemphigoid with severe stricture of the esophagus mediated by IgG and IgA autoantibodies to LAD-1. PMID- 26575114 TI - Patient-Reported Barriers to High-Quality, End-of-Life Care: A Multiethnic, Multilingual, Mixed-Methods Study. AB - OBJECTIVE: The study objective was to empirically identify barriers reported by multiethnic patients and families in receiving high-quality end-of-life care (EOLC). METHODS: This cross-sectional, mixed-methods study in Burmese, English, Hindi, Mandarin, Tagalog, Spanish, and Vietnamese was held in multiethnic community centers in five California cities. Data were collected in 2013-2014. A snowball sampling technique was used to accrue 387 participants-261 women, 126 men, 133 Caucasian, 204 Asian Americans, 44 African Americans, and 6 Hispanic Americans. Measured were multiethnic patient-reported barriers to high-quality EOLC. A development cohort (72 participants) of responses was analyzed qualitatively using grounded theory to identify the six key barriers to high quality EOLC. A new validation cohort (315 participants) of responses was transcribed, translated, and back-translated for verification. The codes were validated by analyses of responses from 50 randomly drawn subjects from the validation cohort. All the 315 validation cohort transcripts were coded for presence or absence of the six barriers. RESULTS: In the validation cohort, 60.6% reported barriers to receiving high-quality EOLC for persons in their culture/ethnicity. Primary patient-reported barriers were (1) finance/health insurance barriers, (2) doctor behaviors, (3) communication chasm between doctors and patients, (4) family beliefs/behaviors, (5) health system barriers, and (6) cultural/religious barriers. Age (chi(2) = 9.15, DF = 1, p = 0.003); gender (chi(2) = 6.605, DF = 1, p = 0.01); and marital status (chi(2) = 16.11 DF = 3, p = 0.001) were associated with reporting barriers; and women <80 years were most likely to report barriers to receiving high-quality EOLC. Individual responses of reported barriers were analyzed and only the participant's level of education (Friedman statistic = 2.16, DF = 10, p = 0.02) significantly influenced choices. CONCLUSION: Multiethnic patients report that high-quality EOLC is important to them; but unfortunately, a majority state that they have encountered barriers to receiving such care. Efforts must be made to rapidly improve access to culturally competent EOLC for diverse populations. PMID- 26575115 TI - Genetic Alterations in Differentiated Thyroid Cancer Patients with Acromegaly. AB - AIM: Acromegaly is associated with increased thyroid cancer risk. We aimed to analyze the frequency of point mutations of BRAF and RAS genes, and RET/PTC, PAX8/PPARgamma gene rearrangements in patients with acromegaly having differentiated thyroid cancers (DTC) and their relation with clinical and histological features. MATERIALS AND METHODS: 14 acromegalic patients (8 male, 6 female) with DTC were included. BRAF V600E and NRAS codon 61 point mutations, RET/PTC1, RET/PTC3, and PAX8/PPARgamma gene rearrangements were analyzed in thyroidectomy specimens. We selected 14 non-acromegalic patients with DTC as a control group. RESULTS: 2 patients (14.3%) were detected to have positive BRAF V600E and 3 patients (21.4%) were detected to have NRAS codon 61 mutation. NRAS codon 61 was the most frequent genetic alteration. Patients with positive mutation had aggressive histologic features more frequently than patients without mutations. Comparison of the acromegalic and non-acromegalic patients with DTC revealed that BRAF V600E mutation was more frequent in non-acromegalic patients with DTC (14.2% vs. 64.3%, p=0.02). RET/PTC 1/ 3, PAX8/PPARgamma gene rearrangements were not detected in any patient. None of the patients including the patients with positive point mutations had recurrence, and local and/or distant metastasis. CONCLUSION: NRAS codon 61 is the most frequent genetic alteration in this acromegaly series with DTC. Since acromegalic patients have lower prevalance of BRAF V600E mutation, BRAF V600E mutation may not be a causative factor in development of DTC in acromegaly. Despite the relation of BRAF V600E and NRAS codon 61 mutations with aggresive histopathologic features, their impact on tumor prognosis remains to be defined in acromegaly in further studies. PMID- 26575116 TI - Clinical Value of Thyrotropin Receptor Antibodies for the Differential Diagnosis of Interferon Induced Thyroiditis. AB - OBJECTIVE: The clinical value of thyrotropin receptor antibodies for the differential diagnosis of thyrotoxicosis induced by pegylated interferon-alpha remains unknown. We analyzed the diagnostic accuracy of thyrotropin receptor antibodies in the differential diagnosis of thyrotoxicosis in patients with chronic hepatitis C (CHC) receiving pegylated interferon-alpha plus ribavirin. METHODS: Retrospective analysis of 274 patients with CHC receiving pegylated interferon-alpha plus ribavirin. Interferon-induced thyrotoxicosis was classified according to clinical guidelines as Graves disease, autoimmune and non- autoimmune destructive thyroiditis. RESULTS: 48 (17.5%) patients developed hypothyroidism, 17 (6.2%) thyrotoxicosis (6 non- autoimmune destructive thyroiditis, 8 autoimmune destructive thyroiditis and 3 Graves disease) and 22 "de novo" thyrotropin receptor antibodies (all Graves disease, 2 of the 8 autoimmune destructive thyroiditis and 17 with normal thyroid function). The sensitivity and specificity of thyrotropin receptor antibodies for Graves disease diagnosis in patients with thyrotoxicosis were 100 and 85%, respectively. Patients with destructive thyroiditis developed hypothyroidism in 87.5% of autoimmune cases and in none of those with a non- autoimmune etiology (p<0.001). CONCLUSION: Thyrotropin receptor antibodies determination cannot replace thyroid scintigraphy for the differential diagnosis of thyrotoxicosis in CHC patients treated with pegylated interferon. PMID- 26575117 TI - Total Thyroidectomy for Amiodarone-induced Thyrotoxicosis in the Hyperthyroid State. AB - Amiodarone is a potent antiarrhythmic agent, indicated for the treatment of refractory arrhythmias, which may lead to thyrotoxicosis. In these patients, thyroidectomy is a valid therapeutic option. Antithyroid therapy in the immediate preoperative setting and the subsequently accepted minimal delay until thyroidectomy have not been clearly defined yet. The aim of the present study was to show, that total thyroidectomy under general anaesthesia in patients with amiodarone-induced thyrotoxicosis (AIT) is safe without necessarily obtaining an euthyroid state preoperatively.We conducted a retrospective cohort study of prospectively gathered data on 11 patients undergoing total thyroidectomy under general anaesthesia between January 2008 and December 2013 for AIT at our University Hospital.All patients were preoperatively treated with carbimazole, steroids and beta-receptor antagonists. Additionally, 3 patients received potassium perchlorate and in one patient carbimazole was changed to propylthiouracil. Plasmapheresis was performed in 3 patients. Only one patient was euthyroid at the time of operation. There were no significant intra- and postoperative complications, especially no signs of thyroid storm. One patient could postoperatively be removed from the cardiac transplant waiting list due to improved cardiac function.Improvements in the interdisciplinary surgical management for AIT between cardiologists, endocrinologists, anaesthetists and endocrine surgeons provide the basis of safe total thyroidectomy under general anaesthesia in hyperthyroid state. Early surgery without long delay for medical antithyroid treatment (with its potential negative side effects) is recommended. PMID- 26575118 TI - Retinol Binding Protein-4 and Adiponectin Levels in Thyroid Overt and Subclinical Dysfunction. AB - Thyroid dysfunction is accompanied by numerous changes in intermediary metabolism. Retinol binding protein-4 (RBP-4) and adiponectin are 2 adipocytokines that have multiple metabolic functions. The aim of our study was to examine serum RBP4 and adiponectin levels in clinical (before and after therapy) and subclinical hyperthyroid and hypothyroid subjects as compared to controls.150 patients with thyroid dysfunction were recruited (65 hyperthyroid and 85 hypothyroid) while 28 euthyroid subjects served as a control group. We measured anthropometric, biochemical and hormonal (free T4, free T3, TSH, insulin) parameters in all participants. RBP-4 and adiponectin were measured using commercial ELISA kits.Mean baseline levels of RBP-4 were higher in patients with clinical hypothyroidism (29.0+/-10.2 ng/ml, 25.1+/-12.6 ng/ml, 38.8+/-16.5 ng/ml, 31.9+/-13.2 ng/ml, 20.4+/-8.2 ng/ml in patients with hyperthyroidism, subclinical hyperthryrodism, hypothyroidism, subclinical hypothyroidism and controls respectively, F=4.86, P<0.001) and decreased significantly in patients with clinical hyperthyroidism and hypothyroidism after normalization of thyroid hormones' levels (from 29.0+/-10.2 to 24.9+/-8.4 ng/ml, p=0.003 and from 38.8+/ 16.5 to 29.0+/-10.8 ng/ml, p=0.001 respectively). We did not observe analogous changes in adiponectin levels in any of the studied groups.RBP-4 levels are higher in patients with clinical hypothyroidism and exhibit a marked decrease after normalization of thyroid function in both hyper and hypothyroid patients. We suggest that RBP-4 may play a role in the metabolic disturbances which accompany thyroid dysfunction. PMID- 26575119 TI - High Prolidase Levels may be a Marker of Irreversible Extracellular Matrix Changes in Controlled Acromegaly Patients? AB - The present study aimed to evaluate the activity of prolidase in controlled acromegaly patients and its association with oxidative stress. 25 acromegalic patients in remission who were followed in our outpatient clinic and 31 healthy controls were enrolled in the study. Serum growth hormone (GH), insulin-like growth factor 1 (IGF-1), total antioxidative status (TAS), total oxidative stress (TOS), total free sulfhydryl (-SH), paraoxonase (PON), arylesterase (ARE), lipid hydroperoxide (LOOH) and prolidase activity levels were measured. Percent ratio of TOS to TAS level was accepted as oxidative stress index (OSI). Serum prolidase activity, TOS, OSI, and LOOH levels were significantly higher in acromegaly patients compared to the healthy control group (p<0.001, p=0.001, p<0.001, and p<0.001, respectively). SH levels were significantly lower in the acromegaly patients compared to the healthy control group (p=0.002). Prolidase activity were positively correlated with TOS, OSI, LOOH and negatively correlated with -SH in patients with acromegaly (r=0.471, p<0.001; r=0.527, p<0.001; r=0.717, p<0.001; r=- 0.516, p<0.001, respectively). These associations were confirmed in the multiple regression analysis (R(2)=0.502, p<0.001). In conclusion, serum prolidase activity and oxidative stress levels were high in controlled acromegaly patients. These results suggest that extracellular matrix changes continue eventhough the disease is controlled, and elevated oxidative stress is involved in the increased prolidase activity in acromegaly patients. PMID- 26575120 TI - Elevated Serum Pentosidine and Decreased Serum IGF-I Levels are Associated with Loss of Muscle Mass in Postmenopausal Women with Type 2 Diabetes Mellitus. AB - Advanced glycation end-products (AGEs) play important roles in the progression of diabetic complications. Although sarcopenia is recently recognized as another complication associated with diabetes mellitus, its mechanism still remains unclear. In this study, we investigated the relationship between serum levels of pentosidine, which is one of AGEs, and insulin-like growth factor-I (IGF-I) vs. skeletal muscle mass by whole body dual-energy x-ray absorptiometry in 133 postmenopausal women with type 2 diabetes. Relative skeletal muscle mass index (RSMI) was calculated by following formula; appendicular skeletal muscle mass divided by height in meters squared. Simple correlation analyses showed that serum pentosidine levels were significantly and negatively correlated with muscle mass of legs (r=-0.21, p=0.017) and RSMI (r=-0.18, p=0.022), and that IGF-I was significantly and positively correlated with muscle mass of arms and legs (r=0.23, p=0.008 and r=0.30, p=0.001, respectively) as well as RSMI (r=0.20, p=0.022). Moreover, after adjusting for age, duration of diabetes, serum creatinine, HbA1c, and IGF-I, pentosidine was significantly and negatively associated with RSMI (beta=-0.27, p=0.018) and marginally with muscle mass of legs (beta=-0.18, p=0.071). The associations between IGF-I and indices of muscle mass such as arms, legs and RSMI were still significant after additional adjustment for pentosidine (p=0.016, 0.019 and 0.021, respectively). These findings indicate that increased serum pentosidine and decreased IGF-I are independent risk factors for loss of muscle mass in postmenopausal women with type 2 diabetes. PMID- 26575121 TI - Serum miR-21 may be a Potential Diagnostic Biomarker for Diabetic Nephropathy. AB - MiRNAs play important roles in initiation and progress of many pathologic processes. MiR-21 was closely associated with diabetic nephropathy (DN). However, whether serum miR-21 was as a potential diagnostic biomarker for DN and the relationship between serum miR-21 and tissue miR-21 remained unclear. In this study, real-time RT-PCR, cell transfection, luciferase reporter gene assays, western blot and confocal microscope were used, respectively. Here, we found that serum and renal tissue miR-21 was significantly elevated with the progress of DN. Moreover, luciferase reporter gene assays showed that smad7 was a validated miR 21 target, cell transfection showed that miR-21 overexpression downregulated target smad7 expression. Interestingly, serum miR-21 was significantly consistent with the alterations of tissue miR-21 with the development of DN. In addition, serum miR-21 was also positively correlated with GBM, GA, ACR and CCF, while negatively correlated with Ccr. Importantly, antagomiR-21 not only alleviated GBM, GA, ACR and CCF, but also ameliorated Ccr by increasing target smad7. In conclusion, our data demonstrated that serum miR-21 was closely associated with renal structure and function, and serum miR-21 may be regarded as a potential diagnostic biomarker of DN. PMID- 26575122 TI - The Efficacy and Safety of Yoga in Managing Hypertension. AB - Hypertension is a major public health problem and one of the most important causes of premature morbidity and mortality. Yoga is a traditional Indian practice that has been adapted for use in complementary and alternative medicine and mainly includes physical postures, breathing techniques, and meditation. The impact of yoga as a complementary intervention for hypertension has been investigated in a number of randomized controlled trials; with an overall effect of about 10 mmHg reduction in systolic and about 8 mmHg reduction in diastolic blood pressure. Yoga seems to be effective only for hypertension but not for prehypertension; and only as an adjunct to antihypertensive pharmacological treatment but not as an alternative therapy. Breathing and meditation rather than physical activity seem to be the active part of yoga interventions for hypertensive patients. These practices can increase parasympathic activity and decrease sympathetic activity, arguably mainly by increasing GABA activity; thus counteracting excess activity of the sympathetic nervous system which has been associated with hypertension. Although yoga has been associated with serious adverse events in single case reports, population-based surveys as well as clinical trials indicate that yoga is a relatively safe intervention that is not associated with more adverse events than other forms of physical activity. Yoga can thus be considered a safe and effective intervention for managing hypertension. Given the possibly better risk/benefit ratio, it may be advisable to focus on yogic meditation and/or breathing techniques. PMID- 26575123 TI - Diabetic Kidney Disease and Hypertension. AB - Achieving blood pressure (BP) goals is an essential goal for both primary and secondary prevention of diabetic kidney disease (DKD). Even though there is universal agreement about the importance of controlling BP, there are many issues about many aspects of hypertension management for DKD patients. These issues include: what is the optimal BP for the prevention or slowing of progression of DKD patients; what is the best method for diagnosing hypertension and monitoring BP, and what are the best medicines to use to treat hypertension in DKD patients. In this review, these issues as well as others will be discussed. PMID- 26575124 TI - [Crisis in Science and Technology in Colombia]. PMID- 26575125 TI - [The Meaning That Families Place on the Suicide of Pregnant Mothers in Antioquia, 2010-2011]. AB - OBJECTIVE: To identify the meaning that the families of two pregnant women from Antioquia placed on their suicide in 2010-2011. METHODOLOGY: A qualitative research using the phenomenological and hermeneutical approach, specifically a case study analysis. RESULTS: The category named "family task: weaving a history that helps them to understand" emerged in both families. Two trends were found in the family of Bella: "tragedy, tensions and scenarios" and "fluctuations: between fear-guilt and relief." The family of Consentida showed three trends: "trapped with no escape", "suicide and orphanhood: the understanding of Juanita" and "death is death." CONCLUSIONS: For both families, the fact that the women were pregnant had an important effect on the event of voluntary death. The construction of meaning that took place in both families followed two paths: differentiation and death itself; both can be resilient ways of coping with such a tragedy. PMID- 26575126 TI - [Pain prevalence in patients with and without OSAHS subjected to a polysomnogram: A cross-sectional study]. AB - BACKGROUND AND OBJECTIVES: Sleep disturbances apparently have a negative effect on pain or the appearance of pain itself. This suggests the need to determine whether there could be a relationship between obstructive sleep apnea-hypopnea syndrome (OSAHS) and this phenomenon. The objective of this study was to determine the pain prevalence in a population who underwent polysomnography. METHOD: A cross-sectional study of patients who underwent polisomnography, pain prevalence was measured with Mcgill pain questionnaire. RESULTS: Data was obtained from 259 patients, and it was found that 69% suffered pain, and there was a prevalence of 81% OSAHS. Those with OSAHS had a 70% pain prevalence, with 64% for those without OSAHS. CONCLUSIONS: A high pain prevalence was found this population, possibly related to the characteristic of the population, how the information was gathered, and not controlling for other illnesses related with pain. PMID- 26575127 TI - ["Accepting Demented Minds". Opinion Group, Information and Support on Stigma of Mental Illness on Facebook]. AB - INTRODUCTION: Mental illness is one of the diseases that generates more disability worldwide, and it is estimated that one in four people has or has had this kind of illness during their lives. Since the beginning, mental illness has been frequently linked to stigma and prejudice, which has important implications for the exercise of their human rights, including the right to health, as these preconceptions can delay their early detection and timely treatment. Eliminating stigma requires multiple interventions, in which the participation of people with these illnesses can be very helpful. Social networks portray an alternative for them and for people interested in this topic, helping them interact, clarify some concerns and doubts, and perhaps even modify their exclusion status. METHOD: Describing the experience of the opinion and support group on Facebook called "Aceptando mentes dementes" ("Accepting Demented Minds"), created for people with mental illnesses, their families and any person interested in this matter, which seeks to make the impact and consequences that result from stigma more noticable. Analysis of qualitative and quantitative data collected over two and a half years of operation of the group, formed by 764 members from different countries. RESULTS: The aims of the group, as regards the spreading of information, interaction through shared experiences, and obtaining support were reached. CONCLUSIONS: Social networks allow the creation of communities that share specific needs, such as understanding and support, and all this at low cost. Knowing and being conscious about the stigma linked to mental illness helps raise awareness and generate options for change. To maintain and link it to other resources, the group will be included in the web site www.mentalpuntoapoyo.com. PMID- 26575128 TI - [Burnout Syndrome in Prison Guards, Bucaramanga, Colombia, 2013]. AB - INTRODUCTION: Burnout syndrome is defined as a chronic stress response and sustained work environment, characterized by emotional exhaustion, depersonalization and personal accomplishment. Most studies have included teaching and health personnel. However, there are limitations in the development of studies on prison guards to observe this problem. OBJECTIVE: This study provides some characteristics of prison guards and seeks to highlight the behavior of the constructs of burnout according to demographic and occupational profile. METHODS: This was a descriptive cross-sectional study on 111 prison guards in the city of Bucaramanga. The Maslach Burnout Inventory was applied, as well as taking ethical considerations into account. A univariate and bivariate analysis was performed on the data. RESULTS: The mean age was 35.8 years, 76% had more than 10 years work experience, 24% have some additional academic activities at work. Only 3.7% had burnout syndrome as such. In emotional exhaustion, 25.2% are classified as high risk, 30% in depersonalization, and 16% personal accomplishment. Within the personal achievement, the group with more than 20 years experience were those who had a critical score (ANOVA chi(2), P=.002). Of those who had a risk score for depersonalization, 67% had worked more than 240 extra hours a month, with a crude odds ratio (OR)=4.66 (P=.033) and age-adjusted OR=4.65 (P=.035). CONCLUSIONS: Burnout in this occupational group was not as prevalent as in that found in other publications. In turn, of the three constructs, the most significant was depersonalization and no notable emotional burnout was observed. The most significant work variables were the number of hours worked and work experience. PMID- 26575129 TI - [Brain activitivation of euthymic patients with Type I bipolar disorder in resting state Default Mode Network]. AB - INTRODUCTION: As there are still doubts about brain connectivity in type I bipolar disorder (BID), resting-state functional magnetic resonance imaging (RS fMRI) studies are necessary during euthymia for a better control of confounding factors. OBJECTIVE: To evaluate the differences in brain activation between euthymic BID patients and control subjects using resting state- functional magnetic resonance imaging (RS-fMRI), and to identify the lithium effect in these activations. METHODS: A cross-sectional study was conducted on 21 BID patients (10 receiving lithium only, and 11 non-medicated) and 12 healthy control subjects, using RS fMRI and independent component analysis (ICA). RESULTS: Increased activation was found in the right hippocampus (P=.049) and posterior cingulate (P=.040) within the Default Mode Network (DMN) when BID and control group were compared. No statistically significant differences were identified between BID on lithium only therapy and non-medicated BID patients. CONCLUSIONS: The results suggest that there are changes in brain activation and connectivity in BID even during euthymic phase and mainly within the DMN network, which could be relevant in affect regulation. PMID- 26575130 TI - [Stigma: Barrier to Access to Mental Health Services]. AB - BACKGROUND: The perceived stigma represents a sociocultural barrier to access mental health services and prevents individuals who meet criteria for a mental disorder the possibility of receiving comprehensive and integred care. OBJECTIVE: To update institutional mechanisms by which stigma related to mental disorders, perceived and perpetrated, acts as a barrier to mental health access. RESULTS: Stigma as a barrier to access to mental health services is due to a reduction in service requests, the allocation of limited resources to mental health, the systematic process of impoverishment of the people who suffer a mental disorder, increased risk of crime, and implications in contact with the legal system, and the invisibility of the vulnerability of these people. CONCLUSIONS: Structured awareness and education programs are needed to promote awareness about mental disorders, promote community-based psychosocial rehabilitation, and reintegration into productive life process. In Colombia, the frequency and variables associated with the stigma of mental disorders needs to be studied. This knowledge will enable the implementation of measures to promote the social and labor inclusion of people who meet the criteria for mental disorders. PMID- 26575132 TI - Crisis in Science and Technology in Colombia. PMID- 26575131 TI - [The Philosophical Relevance of the Study of Schizophrenia. Methodological and Conceptual Issues]. AB - The study of mental illness involves profound methodological and philosophical debates. This article explores the disciplinary complementarity, particularly, between philosophy of mind, phenomenology, and empirical studies in psychiatry and psychopathology in the context of the understanding of schizophrenia. After clarifying the possible role of these disciplines, it is explored the way in which a certain symptom of schizophrenia (thought insertion) challenges the current phenomenological approach to the relationship between consciousness and self-awareness. Finally, it is concluded that philosophy of mind, phenomenology, and empirical studies in psychiatry and psychopathology should, necessarily, regulate their progress jointly in order to reach plausible conclusions about what we call 'schizophrenia'. PMID- 26575133 TI - High-resolution In Vivo Manual Segmentation Protocol for Human Hippocampal Subfields Using 3T Magnetic Resonance Imaging. AB - The human hippocampus has been broadly studied in the context of memory and normal brain function and its role in different neuropsychiatric disorders has been heavily studied. While many imaging studies treat the hippocampus as a single unitary neuroanatomical structure, it is, in fact, composed of several subfields that have a complex three-dimensional geometry. As such, it is known that these subfields perform specialized functions and are differentially affected through the course of different disease states. Magnetic resonance (MR) imaging can be used as a powerful tool to interrogate the morphology of the hippocampus and its subfields. Many groups use advanced imaging software and hardware (>3T) to image the subfields; however this type of technology may not be readily available in most research and clinical imaging centers. To address this need, this manuscript provides a detailed step-by-step protocol for segmenting the full anterior-posterior length of the hippocampus and its subfields: cornu ammonis (CA) 1, CA2/CA3, CA4/dentate gyrus (DG), strata radiatum/lacunosum/moleculare (SR/SL/SM), and subiculum. This protocol has been applied to five subjects (3F, 2M; age 29-57, avg. 37). Protocol reliability is assessed by resegmenting either the right or left hippocampus of each subject and computing the overlap using the Dice's kappa metric. Mean Dice's kappa (range) across the five subjects are: whole hippocampus, 0.91 (0.90-0.92); CA1, 0.78 (0.77-0.79); CA2/CA3, 0.64 (0.56-0.73); CA4/dentate gyrus, 0.83 (0.81-0.85); strata radiatum/lacunosum/moleculare, 0.71 (0.68-0.73); and subiculum 0.75 (0.72 0.78). The segmentation protocol presented here provides other laboratories with a reliable method to study the hippocampus and hippocampal subfields in vivo using commonly available MR tools. PMID- 26575137 TI - The Triaging and Treatment of Cold-Induced Injuries. AB - BACKGROUND: In Central Europe, cold-induced injuries are much less common than burns. In a burn center in western Germany, the mean ratio of these two types of injury over the past 10 years was 1 to 35. Because cold-induced injuries are so rare, physicians often do not know how to deal with them. METHODS: This article is based on a review of publications (up to December 2014) retrieved by a selective search in PubMed using the terms "freezing," "frostbite injury," "non freezing cold injury," and "frostbite review," as well as on the authors' clinical experience. RESULTS: Freezing and cold-induced trauma are part of the treatment spectrum in burn centers. The treatment of cold-induced injuries is not standardized and is based largely on case reports and observations of use. distinction is drawn between non-freezing injuries, in which there is a slow temperature drop in tissue without freezing, and freezing injuries in which ice crystals form in tissue. In all cases of cold-induced injury, the patient should be slowly warmed to 22 degrees -27 degrees C to prevent reperfusion injury. Freezing injuries are treated with warming of the body's core temperature and with the bathing of the affected body parts in warm water with added antiseptic agents. Any large or open vesicles that are already apparent should be debrided. To inhibit prostaglandin-mediated thrombosis, ibuprofen is given (12 mg/kg body weight b.i.d.). CONCLUSION: The treatment of cold-induced injuries is based on their type, severity, and timing. The recommendations above are grade C recommendations. The current approach to reperfusion has yielded promising initial results and should be further investigated in prospective studies. PMID- 26575139 TI - Pathogenicity Underestimated. PMID- 26575138 TI - Treatment Options for Statin-Associated Muscle Symptoms. AB - BACKGROUND: About 4.6 million persons in Germany are now taking statins, i.e., drugs that inhibit the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMGCoA) reductase. Statins lower the concentration of low-density lipoproteins (LDL) and thereby lessen the rate of cardiovascular events; the size of this effect depends on the extent of lowering of the LDL cholesterol concentration. Muscle symptoms are a clinically relevant side effect of statin treatment. METHODS: This review is based on pertinent publications retrieved by a selective literature search, and on the current recommendations of the European Atherosclerosis Society. RESULTS: At least 5% of patients taking statins have statin-associated muscle symptoms (SAMS). The etiology of SAMS is heterogeneous. SAMS may seriously impair quality of life and cause complications of variable severity, up to and including rhabdomyolysis (in about 1 in 100,000 cases). SAMS often lead to a reduction in the prescribed dose of the statin, while also negatively affecting drug adherence. More than 90% of patients with SAMS can keep on taking statins over the long term and gain the full clinical benefit of statin treatment after a switch to another type of statin or a readjustment of the dose or frequency of administration. If the LDL cholesterol concentration is not adequately lowered while the patient is taking a statin in the highest tolerable dose, combination therapy is indicated. CONCLUSION: SAMS are important adverse effects of statin treatment because they lessen drug adherence. Patients with SAMS should undergo a thorough diagnostic evaluation followed by appropriate counseling. In most cases, statins can be continued, with appropriate adjustments, even in the aftermath of SAMS. PMID- 26575140 TI - Real Exposure Significantly Lower. PMID- 26575141 TI - In Reply. PMID- 26575142 TI - Part of the Treatment Strategy in Other Countries. PMID- 26575143 TI - Inhibition of Grape Crown Gall by Agrobacterium vitis F2/5 Requires Two Nonribosomal Peptide Synthetases and One Polyketide Synthase. AB - Agrobacterium vitis nontumorigenic strain F2/5 is able to inhibit crown gall disease on grapevines. The mechanism of grape tumor inhibition (GTI) by F2/5 has not been fully determined. In this study, we demonstrate that two nonribosomal peptide synthetase (NRPS) genes (F-avi3342 and F-avi5730) and one polyketide synthase gene (F-avi4330) are required for GTI. Knockout of any one of them resulted in F/25 losing GTI capacity. We previously reported that F-avi3342 and F avi4330 but not F-avi5730 are required for induction of grape tissue necrosis and tobacco hypersensitive response. F-avi5730 is predicted to encode a single modular NRPS. It is located in a cluster that is homologous to the siderophore vicibactin biosynthesis locus in Rhizobium species. Individual disruption of F avi5730 and two immediate downstream genes, F-avi5731 and F-avi5732, all resulted in reduced siderophore production; however, only F-avi5730 was found to be required for GTI. Complemented F-avi5730 mutant (DeltaF-avi5730(+)) restored a wild-type level of GTI activity. It was determined that, over time, populations of DeltaF-avi4330, DeltaF-avi3342, and DeltaF-avi5730 at inoculated wound sites on grapevine did not differ from those of DeltaF-avi5730(+) indicating that loss of GTI was not due to reduced colonization of wound sites by mutants. PMID- 26575144 TI - Dexmedetomidine versus Propofol Sedation Reduces Delirium after Cardiac Surgery: A Randomized Controlled Trial. AB - BACKGROUND: Postoperative delirium (POD) is a serious complication after cardiac surgery. Use of dexmedetomidine to prevent delirium is controversial. The authors hypothesized that dexmedetomidine sedation after cardiac surgery would reduce the incidence of POD. METHODS: After institutional ethics review board approval, and informed consent, a single-blinded, prospective, randomized controlled trial was conducted in patients 60 yr or older undergoing cardiac surgery. Patients with a history of serious mental illness, delirium, and severe dementia were excluded. Upon admission to intensive care unit (ICU), patients received either dexmedetomidine (0.4 MUg/kg bolus followed by 0.2 to 0.7 MUg kg h infusion) or propofol (25 to 50 MUg kg min infusion) according to a computer-generated randomization code in blocks of four. Assessment of delirium was performed with confusion assessment method for ICU or confusion assessment method after discharge from ICU at 12-h intervals during the 5 postoperative days. Primary outcome was the incidence of POD. RESULTS: POD was present in 16 of 91 (17.5%) and 29 of 92 (31.5%) patients in dexmedetomidine and propofol groups, respectively (odds ratio, 0.46; 95% CI, 0.23 to 0.92; P = 0.028). Median onset of POD was on postoperative day 2 (1 to 4 days) versus 1 (1 to 4 days), P = 0.027, and duration of POD 2 days (1 to 4 days) versus 3 days (1 to 5 days), P = 0.04, in dexmedetomidine and propofol groups, respectively. CONCLUSIONS: When compared with propofol, dexmedetomidine sedation reduced incidence, delayed onset, and shortened duration of POD in elderly patients after cardiac surgery. The absolute risk reduction for POD was 14%, with a number needed to treat of 7.1. PMID- 26575145 TI - Impact of Perioperative Epidural Placement on Postdischarge Opioid Use in Patients Undergoing Abdominal Surgery. AB - BACKGROUND: Opioids play a crucial role in providing analgesia throughout the perioperative period; however, patients may become persistent users of these medications months after surgery. Epidurals have been posited to prevent the development of persistent pain, but there are little data on the effect of epidurals on persistent opioid use. METHODS: This study was conducted using a claims database of a large, nationwide commercial health insurer. Opioid-naive patients who underwent open abdominal surgery from January 2004 to December 2013 were included in the study. Propensity scores for epidural placement were calculated accounting for demographic characteristics, resource utilization, and comorbid conditions (including medical, psychiatric, and pain conditions). Time to-event analysis was used with the primary outcome defined as 30 days without filling an opioid prescription after discharge. In addition, total morphine equivalents dispensed within 90 days of discharge were also calculated for each patient. RESULTS: A total of 6,432 patients were included in the final propensity score-matched cohort. The Cox proportional hazards ratio was 0.96 (95% CI, 0.91 to 1.01; P = 0.0910) for the relation between epidural placement and time till a 30-day gap without filling an opioid prescription. There was no difference in the total morphine equivalents dispensed within 90 days of discharge between the groups (P = 0.7670). CONCLUSIONS: Epidural placement was not protective against persistent opioid use in a large cohort of opioid-naive patients undergoing abdominal surgery. This finding does not detract from the other potential benefits of epidural placement. More research is needed to understand the mechanism of persistent opioid use after surgery and its prevention. PMID- 26575146 TI - Planning for HIV preexposure prophylaxis introduction: lessons learned from contraception. AB - PURPOSE OF REVIEW: We summarize key lessons learned from contraceptive development and introduction, and implications for preexposure prophylaxis (PrEP). RECENT FINDINGS: New approaches to HIV prevention are urgently needed. PrEP is a new technology for HIV prevention. Uncertainty remains about its acceptance, use and potential to have an impact on the HIV epidemic. Despite imperfect use and implementation of programs, the use of modern contraception has led to significant reproductive health and social gains, making it one of the public health's major achievements. Guided by the WHO strategic approach to contraception introduction, we identified the following lessons for PrEP introduction from contraception: (1) the importance of a broader focus on the method mix rather than promotion of a single technology, (2) new technologies alone do not increase choice--service delivery systems and providers are equally important to success, and (3) that failure to account for user preferences and social context can undermine the potential of new methods to provide benefit. SUMMARY: Taking a strategic approach to PrEP introduction that includes a broader focus on the technology/user interface, the method mix, delivery strategies, and the context in which methods are introduced will benefit HIV prevention programs, and will ensure greater success. PMID- 26575147 TI - The preexposure prophylaxis revolution; from clinical trials to programmatic implementation. AB - PURPOSE OF REVIEW: An investment in preexposure prophylaxis (PrEP) delivery must have public health impact in reducing HIV infections. Sustainable delivery of PrEP requires policy, integration of services, and synergy with other existing HIV prevention programs. This review discusses key policy and programmatic considerations for implementation and scale up of PrEP in Africa. RECENT FINDINGS: PrEP delivery has been delayed by concerns about adherence and delivery in 'real world' settings. Demonstration projects and clinical service delivery models are providing evidence of PrEP effectiveness with an impact much higher than that found in randomized clinical trials. Data confirm that PrEP uptake, adherence, and retention has been high, more so by persons who perceive themselves at high risk for HIV infection, and PrEP is well tolerated. PrEP delivery is more than dispensation of a pill and programs should address other risk drivers, which differ by population. In Africa, barriers to PrEP uptake and adherence include stigma among MSM and low HIV risk perception among young women. Additional data have provided insight into optimal points of service delivery, provider training requirements and quality assurance needs. Of the 2 million new HIV infections in 2014, 70% were in Africa. PrEP use is not lifelong, and use limited to periods of risk may be both effective and cost-effective for the continent. SUMMARY: HIV prevention programs should determine strategies to identify those at substantial risk for HIV infection, formulate and deliver PrEP in combination with interventions that target social drivers of HIV vulnerability specific to each population. Policy guidance for optimal combination of interventions and service delivery avenues, clinical protocols, health infrastructure requirements are required. Cost-effectiveness and efficiency data are essential for policy guidance to navigate ethical questions over use of antiretroviral therapy for HIV-negative individuals when treatment coverage has not been attained in many parts of Africa. Countries need to invest in purposeful advocacy at both local and global forums. Failure to implement PrEP will be a failure to protect future generations. PMID- 26575149 TI - Mechanism of Exfoliation and Prediction of Materials Properties of Clay-Polymer Nanocomposites from Multiscale Modeling. AB - We describe the mechanism that leads to full exfoliation and dispersion of organophilic clays when mixed with molten hydrophilic polymers. This process is of fundamental importance for the production of clay-polymer nanocomposites with enhanced materials properties. The chemically specific nature of our multiscale approach allows us to probe how chemistry, in combination with processing conditions, produces such materials properties at the mesoscale and beyond. In general agreement with experimental observations, we find that a higher grafting density of charged quaternary ammonium surfactant ions promotes exfoliation, by a mechanism whereby the clay sheets slide transversally over one another. We can determine the elastic properties of these nanocomposites; exfoliated and partially exfoliated morphologies lead to substantial enhancement of the Young's modulus, as found experimentally. PMID- 26575150 TI - Toward highly efficient blue organic light-emitting diodes: fabricating a good quality emissive layer cast from suitable solvents. AB - Spin-cast from various solvents, emissive layers show different film morphologies and performances in solution-processed organic light-emitting diodes (OLEDs). Here we fabricated and demonstrated highly efficient blue OLEDs based on bis[3,5 difluoro-2-(2-pyridyl)phenyl]-(2-carboxypyridy)iridium(iii) by choosing several kinds of solvents for spin-coating. Experiments indicate that the single-layer device with an emissive film cast from chlorobenzene shows its best performance with a highest current efficiency of 18.99 cd A(-1), a maximum luminance of 20.5 * 10(3) cd m(-2) and an emission band centered at 474 nm. The efficiency achieved is the highest reported for solution-processed simple-manufactured OLEDs doped with transition metal phosphors emitting in the blue region. PMID- 26575148 TI - Residual inflammation and viral reservoirs: alliance against an HIV cure. AB - PURPOSE OF REVIEW: HIV persists in cellular and anatomical reservoirs during antiretroviral therapy (ART). Viral persistence is ensured by a variety of mechanisms including ongoing viral replication and proliferation of latently infected cells. In this review, we summarize recent findings establishing a link between the unresolved levels of inflammation observed in virally suppressed individuals on ART and the mechanisms responsible for HIV persistence. RECENT FINDINGS: Residual levels of viral replication during ART are associated with persistent low levels of immune activation, suggesting that unresolved inflammation can promote the replenishment of the HIV reservoir in tissues. In addition, the recent findings that the latent HIV reservoir is maintained by continuous proliferation of latently infected cells provide another mechanism by which residual inflammation could contribute to HIV persistence. SUMMARY: Residual inflammation during ART is likely to be a critical parameter contributing to HIV persistence. Therefore, reducing inflammation may be an efficient way to interfere with the maintenance of the HIV reservoir in virally suppressed individuals on ART. PMID- 26575151 TI - New hosts and genetic diversity of Flavobacterium columnare isolated from Brazilian native species and Nile tilapia. AB - Flavobacterium columnare is responsible for disease outbreaks in freshwater fish farms. Several Brazilian native fish have been commercially exploited or studied for aquaculture purposes, including Amazon catfish Leiarius marmoratus * Pseudoplatystoma fasciatum and pacama Lophiosilurus alexandri. This study aimed to identify the aetiology of disease outbreaks in Amazon catfish and pacama hatcheries and to address the genetic diversity of F. columnare isolates obtained from diseased fish. Two outbreaks in Amazon catfish and pacama hatcheries took place in 2010 and 2011. Four F. columnare strains were isolated from these fish and identified by PCR. The disease was successfully reproduced under experimental conditions for both fish species, fulfilling Koch's postulates. The genomovar of these 4 isolates and of an additional 11 isolates from Nile tilapia Oreochromis niloticus was determined by 16S rRNA restriction fragment length polymorphism PCR. The genetic diversity was evaluated by phylogenetic analysis of the 16S rRNA gene and repetitive extragenic palindromic PCR (REP-PCR). Most isolates (n = 13) belonged to genomovar II; the remaining 2 isolates (both from Nile tilapia) were assigned to genomovar I. Phylogenetic analysis and REP-PCR were able to demonstrate intragenomovar diversity. This is the first report of columnaris in Brazilian native Amazon catfish and pacama. The Brazilian F. columnare isolates showed moderate diversity, and REP-PCR was demonstrated to be a feasible method to evaluate genetic variability in this bacterium. PMID- 26575152 TI - Cynatratoside-C efficacy against theronts of Ichthyophthirius multifiliis, and toxicity tests on grass carp and mammal blood cells. AB - Infection by Ichthyophthirius multifiliis, a ciliated protozoan parasite, results in high fish mortality and causes severe economic losses in aquaculture. To find new, efficient anti-I. multifiliis agents, cynatratoside-C was isolated from Cynanchum atratum by bioassay-guided fractionation in a previous study. The present study investigated the anti-theront activity, determined the toxicity of cynatratoside-C to grass carp Ctenopharyngodon idellus and mammalian blood cells, and evaluated the protection of cynatratoside-C against I. multifiliis theront infection in grass carp. Results showed that all theronts were killed by 0.25 mg l-1 of cynatratoside-C in 186.7 +/- 5.8 min. Cynatratoside-C at 0.25 mg l-1 was effective in treating infected grass carp and protecting naive fish from I. multifiliis infestation. The 96 h median lethal concentration (LC50) of cynatratoside-C to grass carp and 4 h median effective concentration (EC50) of cynatratoside-C to theront were 46.8 and 0.088 mg l-1, respectively. In addition, the hemolysis assay demonstrated that cynatratoside-C had no cytotoxicity to rabbit red blood cells. Therefore, cynatratoside-C could be a safe and effective potential parasiticide for controlling I. multifiliis. PMID- 26575153 TI - Rapid immunochromatographic test strip to detect swimming crab Portunus trituberculatus reovirus. AB - Swimming crab reovirus (SCRV) is the causative agent of a serious disease with high mortality in cultured Portunus trituberculatus. A rapid immunochromatographic assay (ICA) was developed in a competitive assay format and optimized for the detection of SCRV. The gold probe-based ICA test comprised SCRV antigen and goat anti-chicken egg yolk antibody (IgY) sprayed onto a nitrocellulose membrane as the test line and control line, respectively. IgY-gold complexes were deposited onto the conjugate pad as detector reagents. The method showed high specificity with no cross-reactivity with other related aquatic pathogens. The detection limit of the ICA strip was 50 ug ml-1. To evaluate the performance of the ICA test, the strip and an enzyme-linked immunosorbent assay (ELISA) were applied to the same samples (n = 90 crabs). The strip successfully detected SCRV in all of the artificially infected samples. Furthermore, the ICA strip and ELISA tests had high consistency (98.28%). The strip assay requires no instruments and has a detection time of less than 10 min. It is portable and easy to perform in the field. These results indicated that the developed strip could be a promising on-site tool for screening pooled crabs to confirm SCRV infection or disease outbreaks. PMID- 26575154 TI - Are oysters being bored to death? Influence of Cliona celata on Crassostrea virginica condition, growth and survival. AB - The boring sponge Cliona celata is a nuisance species that can have deleterious effects on eastern oyster Crassostrea virginica growth, condition, and survival. Surprisingly, however, these effects have not been well documented and when examined, results have been equi-vocal. In this study, we provide a direct comparison of growth, condition, and survival of sponge-colonized and uncolonized oysters in southeast North Carolina in 2 separate experiments. In the first experiment, sponge-colonized oysters exhibited significantly slower growth rates, reduced condition, and lower survival relative to uncolonized oysters, although results may have been confounded by oyster source. In the second experiment, using smaller oysters from the same source population, growth rate was again significantly reduced in colonized oysters relative to uncolonized oysters, however neither condition nor survival differed. In field surveys of the same population, colonized individuals across a range of sizes demonstrated significantly reduced condition. Further, condition index was negatively correlated with sponge biomass, which was positively correlated with oyster size, suggesting that the impact of the sponge changes with ontogeny. By investigating clearance rates, tissue isotopic and nutrient content, as well as caloric value, this study provides further evidence that sponge presence causes the oysters to divert energy into costly shell maintenance and repair at the expense of shell and somatic growth. Thus, although variable, our results demonstrate negative impacts of sponge infestation on oyster demographics, particularly as oysters grow larger. PMID- 26575155 TI - New record and phylogenetic affinities of the oomycete Olpidiopsis feldmanni infecting Asparagopsis sp. (Rhodophyta). AB - A new geographic record of the oomycete Olpidiopsis feldmanni infecting the tetrasporophytic stage of the red alga Asparagopsis sp. from the Adriatic Sea, confirmed through morphological identification, allowed us to expand previous observations of this organism. Ultrastructural investigations of environmental material showed a large central vacuole and a cell wall thicker than previously reported from other basal oomycete pathogens of algae. Phylogenetic analysis closely associates O. feldmanni to O. bostrychiae concurrent with structural observations. This constitutes the first genetic characterisation of an Olpidiopsis species that was initially described before 1960, adding to the genetic data of 3 other marine Olpidiopsis species established and genetically characterised in the last 2 decades. The paper discusses concurrences of the ultrastructural observations made here and in previous studies of the marine Olpidiopsis species with those made on the freshwater species. PMID- 26575156 TI - Epidemiology of lobomycosis-like disease in bottlenose dolphins Tursiops spp. from South America and southern Africa. AB - We report on the epidemiology of lobomycosis-like disease (LLD), a cutaneous disorder evoking lobomycosis, in 658 common bottlenose dolphins Tursiops truncatus from South America and 94 Indo-Pacific bottlenose dolphins T. aduncus from southern Africa. Photographs and stranding records of 387 inshore residents, 60 inshore non-residents and 305 specimens of undetermined origin (inshore and offshore) were examined for the presence of LLD lesions from 2004 to 2015. Seventeen residents, 3 non-residents and 1 inshore dolphin of unknown residence status were positive. LLD lesions appeared as single or multiple, light grey to whitish nodules and plaques that may ulcerate and increase in size over time. Among resident dolphins, prevalence varied significantly among 4 communities, being low in Posorja (2.35%, n = 85), Ecuador, and high in Salinas, Ecuador (16.7%, n = 18), and Laguna, Brazil (14.3%, n = 42). LLD prevalence increased in 36 T. truncatus from Laguna from 5.6% in 2007-2009 to 13.9% in 2013-2014, albeit not significantly. The disease has persisted for years in dolphins from Mayotte, Laguna, Salinas, the Sanquianga National Park and Bahia Malaga (Colombia) but vanished from the Tramandai Estuary and the Mampituba River (Brazil). The geographical range of LLD has expanded in Brazil, South Africa and Ecuador, in areas that have been regularly surveyed for 10 to 35 yr. Two of the 21 LLD affected dolphins were found dead with extensive lesions in southern Brazil, and 2 others disappeared, and presumably died, in Ecuador. These observations stress the need for targeted epidemiological, histological and molecular studies of LLD in dolphins, especially in the Southern Hemisphere. PMID- 26575157 TI - Genetic variation underlying resistance to infectious hematopoietic necrosis virus in a steelhead trout (Oncorhynchus mykiss) population. AB - Understanding the mechanisms of host resistance to pathogens will allow insights into the response of wild populations to the emergence of new pathogens. Infectious hematopoietic necrosis virus (IHNV) is endemic to the Pacific Northwest and infectious to Pacific salmon and trout (Oncorhynchus spp.). Emergence of the M genogroup of IHNV in steelhead trout O. mykiss in the coastal streams of Washington State, between 2007 and 2011, was geographically heterogeneous. Differences in host resistance due to genetic change were hypothesized to be a factor influencing the IHNV emergence patterns. For example, juvenile steelhead trout losses at the Quinault National Fish Hatchery (QNFH) were much lower than those at a nearby facility that cultures a stock originally derived from the same source population. Using a classical quantitative genetic approach, we determined the potential for the QNFH steelhead trout population to respond to selection caused by the pathogen, by estimating the heritability for 2 traits indicative of IHNV resistance, mortality (h2 = 0.377 (0.226 - 0.550)) and days to death (h2 = 0.093 (0.018 - 0.203)). These results confirm that there is a genetic basis for resistance and that this population has the potential to adapt to IHNV. Additionally, genetic correlation between days to death and fish length suggests a correlated response in these traits to selection. Reduction of genetic variation, as well as the presence or absence of resistant alleles, could affect the ability of populations to adapt to the pathogen. Identification of the genetic basis for IHNV resistance could allow the assessment of the susceptibility of other steelhead populations. PMID- 26575158 TI - Symptoms of anxiety and depression are frequent in patients with acute hepatitis C and are not associated with disease severity. AB - OBJECTIVE: Neuropsychiatric symptoms of hepatitis C virus (HCV) infection and during peginterferon alpha therapy have been investigated in the chronic stage of the infection, but have not been described during the acute phase of the disease so far. We therefore evaluated anxiety and depression in patients with acute hepatitis C by the Hospital Anxiety and Depression Scale (HADS) within a clinical trial. METHODS: Data were analysed from the German Hep-Net Acute HCV-III study. Anxiety and depression were characterized by an anxiety (HADS-A) and a depression subscale (HADS-D). More than eight points in each subscale were considered clinically relevant. Data were prospectively collected at baseline, end of treatment and at the end of the study. RESULTS: At baseline, a HADS-A above eight points was observed significantly more frequently than a HADS-D above eight points [n=23/103 (22%) vs. n=12/103 (12%); P=0.041].A pathological HADS-A or HADS D score did not correlate with age, sex, IL28B genotype, the probable mode of infection, HCV genotype or severity of disease as investigated by alanine aminotransferase and bilirubin levels.Antiviral therapy did not influence anxiety as 12/50 (24%) of patients had HADS-A above 8 at the end of therapy. The proportion of patients with HADS-D above eight points increased from 12% at baseline to 24% (n=12/50) at the end of therapy (P=0.06). HADS results were not associated with lost to follow-up or sustained virological response rates. CONCLUSION: HADS data in acute HCV infection indicate that anxiety and depression do not correlate with severity of the disease, mode of acquisition, lost to follow-up and sustained virological response rates. PMID- 26575159 TI - Correction: Ylide formal [4 + 1] annulation. AB - Correction for 'Ylide formal [4 + 1] annulation' by Chunyin Zhu et al., Org. Biomol. Chem., 2015, 13, 2530-2536. PMID- 26575160 TI - Dynamics of a disc in a nematic liquid crystal. AB - We use lattice Boltzmann simulations to study the dynamics of a disc immersed in a nematic liquid crystal. In the absence of external torques, discs with homeotropic anchoring align with their surface normal parallel to the director of the nematic liquid crystal. In the presence of a weak magnetic field a ferromagnetic disc will rotate to equilibrate the elastic torque due to the distortion of the nematic director and the magnetic torque. When the magnetic field rotates the disc so that the angle theta between normal to the surface of the disc a and director of the liquid crystal n[combining circumflex] becomes greater than pi/2, the disc flips around the axis perpendicular to the rotation axis so that a sweeps through pi radians. An analysis of this behaviour was performed. In particular, we look at the impact of the disc thickness and edges on defect creation and the flipping transition. We also analyse the importance of backflow. PMID- 26575161 TI - Facile synthesis of covalent probes to capture enzymatic intermediates during E1 enzyme catalysis. AB - We report a facile synthetic strategy to prepare UBL-AMP electrophilic probes that form a covalent bond with the catalytic cysteine of cognate E1s, mimicking the tetrahedral intermediate of the E1-UBL-AMP complex. These probes enable the structural and biochemical study of both canonical- and non-canonical E1s. PMID- 26575162 TI - CTLA-4 Ig as an effective treatment in a patient with type I diabetes mellitus and seropositive rheumatoid arthritis. AB - We describe a patient suffering from seropositive rheumatoid arthritis (RA) and type I diabetes mellitus (T1DM), who achieved a good EULAR response together with an improvement of the glycemic profile under treatment with CTLA-4 Ig. A close association is known to exist between T1DM and RA, and CTLA-4 exon 1 polymorphism has been associated to RA with coexisting autoimmune endocrinopathies. The possible common genetic background and the potential role of CTLA-4 Ig in the early phases of T1DM, could be considered in the therapeutic interventions in RA patients with type 1 diabetes. PMID- 26575163 TI - It is time to consider the four D's of fluid management. PMID- 26575164 TI - Intra-abdominal hypertension complicating pancreatitis-induced acute respiratory distress syndrome in three patients on extracorporeal membrane oxygenation. AB - BACKGROUND: Severe acute pancreatitis is associated with sever multiorgan failure from 15 to 50%, depending on the series. In some of these patients, conventional methods of ventilation and respiratory support will fail, demanding the use of extracorporeal membrane oxygenation (ECMO). Abdominal compartment syndrome is potentially harmful in this cohort of patients. We describe the successful treatment of three patients with severe acute pancreatitis who underwent respiratory ECMO and where intra abdominal pressure was monitored regularly. METHODS: Retrospective review of case notes. RESULTS: Three patients with severe acute pancreatitis requiring ECMO suffered from increased intra abdominal pressure during their ICU stay. No surgical interventions were taken to relieve abdominal compartment syndrome. Survival to hospital discharge was 100%. CONCLUSIONS: Monitoring intraabdominal pressure is a valuable adjunct to decision making while caring for these high-risk critically ill patients. PMID- 26575165 TI - Transpulmonary pressure monitoring during mechanical ventilation: a bench-to bedside review. AB - Different ventilation strategies have been suggested in the past in patients with acute respiratory distress syndrome (ARDS). Airway pressure monitoring alone is inadequate to assure optimal ventilatory support in ARDS patients. The assessment of transpulmonary pressure (PTP) can help clinicians to tailor mechanical ventilation to the individual patient needs. Transpulmonary pressure monitoring, defined as airway pressure (Paw) minus intrathoracic pressure (ITP), provides essential information about chest wall mechanics and its effects on the respiratory system and lung mechanics. The positioning of an esophageal catheter is required to measure the esophageal pressure (Peso), which is clinically used as a surrogate for ITP or pleural pressure (Ppl), and calculates the transpulmonary pressure. The benefits of such a ventilation approach are avoiding excessive lung stress and individualizing the positive end-expiratory pressure (PEEP) setting. The aim is to prevent over-distention of alveoli and the cyclic recruitment/derecruitment or shear stress of lung parenchyma, mechanisms associated with ventilator-induced lung injury (VILI). Knowledge of the real lung distending pressure, i.e. the transpulmonary pressure, has shown to be useful in both controlled and assisted mechanical ventilation. In the latter ventilator modes, Peso measurement allows one to assess a patient's respiratory effort, patient-ventilator asynchrony, intrinsic PEEP and the calculation of work of breathing. Conditions that have an impact on Peso, such as abdominal hypertension, will also be discussed briefly. PMID- 26575166 TI - Connective tissue growth factor as a novel therapeutic target in high grade serous ovarian cancer. AB - Ovarian cancer is the most common cause of death among women with gynecologic cancer. We examined molecular profiles of fibroblasts from normal ovary and high grade serous ovarian tumors to identify novel therapeutic targets involved in tumor progression. We identified 2,300 genes that are significantly differentially expressed in tumor-associated fibroblasts. Fibroblast expression of one of these genes, connective tissue growth factor (CTGF), was confirmed by immunohistochemistry. CTGF protein expression in ovarian tumor fibroblasts significantly correlated with gene expression levels. CTGF is a secreted component of the tumor microenvironment and is being pursued as a therapeutic target in pancreatic cancer. We examined its effect in in vitro and ex vivo ovarian cancer models, and examined associations between CTGF expression and clinico-pathologic characteristics in patients. CTGF promotes migration and peritoneal adhesion of ovarian cancer cells. These effects are abrogated by FG 3019, a human monoclonal antibody against CTGF, currently under clinical investigation as a therapeutic agent. Immunohistochemical analyses of high-grade serous ovarian tumors reveal that the highest level of tumor stromal CTGF expression was correlated with the poorest prognosis. Our findings identify CTGF as a promoter of peritoneal adhesion, likely to mediate metastasis, and a potential therapeutic target in high-grade serous ovarian cancer. These results warrant further studies into the therapeutic efficacy of FG-3019 in high-grade serous ovarian cancer. PMID- 26575167 TI - Suppression of BRD4 inhibits human hepatocellular carcinoma by repressing MYC and enhancing BIM expression. AB - Bromodomain 4 (BRD4) is an epigenetic regulator that, when inhibited, has anti cancer effects. In this study, we investigated whether BRD4 could be a target for treatment of human hepatocellular carcinoma (HCC). We show that BRD4 is over expressed in HCC tissues. Suppression of BRD4, either by siRNA or using JQ1, a pharmaceutical BRD4 inhibitor, reduced cell growth and induced apoptosis in HCC cell lines while also slowing HCC xenograft tumor growth in mice. JQ1 treatment induced G1 cell cycle arrest by repressing MYC expression, which led to the up regulation of CDKN1B (P27). JQ1 also de-repressed expression of the pro-apoptotic BCL2L11 (BIM). Moreover, siRNA knockdown of BIM attenuated JQ1-triggered apoptosis in HCC cells, suggesting an essential role for BIM in mediating JQ1 anti-HCC activity. PMID- 26575168 TI - Reversal of the glycolytic phenotype of primary effusion lymphoma cells by combined targeting of cellular metabolism and PI3K/Akt/ mTOR signaling. AB - PEL is a B-cell non-Hodgkin lymphoma, occurring predominantly as a lymphomatous effusion in body cavities, characterized by aggressive clinical course, with no standard therapy. Based on previous reports that PEL cells display a Warburg phenotype, we hypothesized that the highly hypoxic environment in which they grow in vivo makes them more reliant on glycolysis, and more vulnerable to drugs targeting this pathway. We established here that indeed PEL cells in hypoxia are more sensitive to glycolysis inhibition. Furthermore, since PI3K/Akt/mTOR has been proposed as a drug target in PEL, we ascertained that pathway-specific inhibitors, namely the dual PI3K and mTOR inhibitor, PF-04691502, and the Akt inhibitor, Akti 1/2, display improved cytotoxicity to PEL cells in hypoxic conditions. Unexpectedly, we found that these drugs reduce lactate production/extracellular acidification rate, and, in combination with the glycolysis inhibitor 2-deoxyglucose (2-DG), they shift PEL cells metabolism from aerobic glycolysis towards oxidative respiration. Moreover, the associations possess strong synergistic cytotoxicity towards PEL cells, and thus may reduce adverse reaction in vivo, while displaying very low toxicity to normal lymphocytes. Finally, we showed that the association of 2-DG and PF-04691502 maintains its cytotoxic and proapoptotic effect also in PEL cells co-cultured with human primary mesothelial cells, a condition known to mimic the in vivo environment and to exert a protective and pro-survival action. All together, these results provide a compelling rationale for the clinical development of new therapies for the treatment of PEL, based on combined targeting of glycolytic metabolism and constitutively activated signaling pathways. PMID- 26575169 TI - Cerdulatinib, a novel dual SYK/JAK kinase inhibitor, has broad anti-tumor activity in both ABC and GCB types of diffuse large B cell lymphoma. AB - B-cell receptor (BCR) and JAK/STAT pathways play critical roles in diffuse large B-cell lymphoma (DLBCL). Herein, we investigated the anti-lymphoma activity of cerdulatinib, a novel compound that dually targets SYK and JAK/STAT pathways. On a tissue microarray of 62 primary DLBCL tumors, 58% expressed either phosphorylated SYK or STAT3 or both. SYK and STAT3 are also phosphorylated in a panel of eleven DLBCL cell lines although ABC and GCB subtypes exhibited different JAK/STAT and BCR signaling profiles. In both ABC and GCB cell lines, cerdulatinib induced apoptosis that was associated with caspase-3 and PARP cleavage. The compound also blocked G1/S transition and caused cell cycle arrest, accompanied by inhibition of RB phosphorylation and down-regulation of cyclin E. Phosphorylation of BCR components and STAT3 was sensitive to cerdulatinib in both ABC and GCB cell lines under stimulated conditions. Importantly, JAK/STAT and BCR signaling can be blocked by cerdulatinib in primary GCB and non-GCB DLBCL tumor cells that were accompanied by cell death. Our work provides mechanistic insights into the actions of cerdulatinib, suggesting that the drug has a broad anti-tumor activity in both ABC and GCB DLBCL, at least in part by inhibiting SYK and JAK pathways. PMID- 26575170 TI - Decreased TPD52 expression is associated with poor prognosis in primary hepatocellular carcinoma. AB - Tumor protein D52 (TPD52) has been indicated to be involved in tumorigenesis of various malignancies. But its role in hepatocellular carcinoma (HCC) is unknown. This study aimed to explore the expression of TPD52 in HCC samples and cell lines using real-time quantitative PCR, western blotting, and immunohistochemistry. The prognostic value of TPD52 in HCC was also analysed. Meanwhile, the mechanism of TPD52 in hepatocarcinogenesis was further investigated by western blotting, immunohistochemistry, over-express and knockdown studies. We found that TPD52 expression was significantly decreased in the HCC tissues and HCC cell lines. TPD52 expression was significantly correlated with tumor-nodes-metastasis (TNM) stage. Kaplan-Meier survival curves showed that high TPD52 expression was associated with improved overall survival (OS) and disease-free survival (DFS) in HCC patients. Multivariate analysis indicated that TPD52 expression was an independent prognostic marker for the OS and DFS of patients. In addition, TPD52 expression was positively correlated with p21 and p53 expression, and was negatively correlated with MDM2, BCL2 and P-GSK-3beta expression in HCC. In conclusions, our findings suggested that TPD52 is a potential tumor suppressor in HCC. It may be a novel prognostic biomarker and molecular therapy target for HCC. PMID- 26575172 TI - In vivo regeneration of renal vessels post whole decellularized kidneys transplantation. AB - Nearly 50 million patients in China live with end-stage renal disease (ESRD), and only about 4000 patients may receive kidney transplantation. The purpose of this study was to investigate regeneration of renal vessels post whole decellularized kidneys transplantation in vivo. We decellularized kidneys of donor rats by perfusing a detergent through the abdominal aorta, yielding feasible extracellular matrix, confirmed for acellularity before transplantation. Based on the concept of using the body as a bioreactor, we orthotopically transplanted the kidney and ureter scaffolds in recipient rats, and found the regeneration of vessels including artery and vein in the renal sinus following a spontaneous recanalization. Although the findings only represent an initial step toward the ultimate goal of the generation of fully functional kidneys in vivo, these findings suggest that the body itself, as the bioreactor, is a viable strategy for kidney regeneration. PMID- 26575171 TI - Bevacizumab and radiotherapy for the treatment of glioblastoma: brothers in arms or unholy alliance? AB - Glioblastoma (GBM) represents the most frequent primary brain tumor in adults and carries a dismal prognosis despite aggressive, multimodal treatment regimens involving maximal resection, radiochemotherapy, and maintenance chemotherapy. Histologically, GBMs are characterized by a high degree of VEGF-mediated vascular proliferation. In consequence, new targeted anti-angiogenic therapies, such as the monoclonal anti-VEGF-A antibody bevacizumab, have proven effective in attenuating tumor (neo)angiogenesis and were shown to possess therapeutic activity in several phase II trials. However, the role of bevacizumab in the context of multimodal therapy approaches appears to be rather complex. This review will give insights into current concepts, limitations, and controversies regarding the molecular mechanisms and the clinical benefits of bevacizumab treatment in combination with radio(chemo)therapy--particularly in face of the results of recent phase III trials, which failed to demonstrate convincing improvements in overall survival (OS). PMID- 26575173 TI - A new class of small molecule estrogen receptor-alpha antagonists that overcome anti-estrogen resistance. AB - Previous studies indicate that BRCA1 protein binds to estrogen receptor-alpha (ER) and inhibits its activity. Here, we found that BRCA1 over-expression not only inhibits ER activity in anti-estrogen-resistant LCC9 cells but also partially restores their sensitivity to Tamoxifen. To simulate the mechanism of BRCA1 inhibition of ER in the setting of Tamoxifen resistance, we created a three dimensional model of a BRCA1-binding cavity within the ER/Tamoxifen complex; and we screened a pharmacophore database to identify small molecules that could fit into this cavity. Among the top 40 "hits", six exhibited potent ER inhibitory activity in anti-estrogen-sensitive MCF-7 cells and four of the six exhibited similar activity (IC50 <= 1.0 MUM) in LCC9 cells. We validated the model by mutation analysis. Two representative compounds (4631-P/1 and 35466-L/1) inhibited ER-dependent cell proliferation in Tamoxifen-resistant cells (LCC9 and LCC2) and partially restored sensitivity to Tamoxifen. The compounds also disrupted the association of BRCA1 with ER. In electrophoretic mobility shift assays, the compounds caused dissociation of ER from a model estrogen response element. Finally, a modified form of compound 35446 (hydrochloride salt) inhibited growth of LCC9 tumor xenografts at non-toxic concentrations. These results identify a novel group of small molecules that can overcome Tamoxifen resistance. PMID- 26575175 TI - Multiphoton microscopy for rapid histopathological evaluation of kidney tumours. AB - OBJECTIVE: To explore the potential of multiphoton microscopy (MPM) for rapid evaluation and triaging of ex vivo kidney tissue. MATERIALS AND METHODS: Fresh neoplastic and non-neoplastic tissues from nephrectomy specimens (n = 40) were imaged with MPM and later submitted for routine histopathology. RESULTS: On MPM, normal kidney architecture was evident and clearly distinguishable from tumour. Forty malignant tumours (20 clear-cell renal cell carcinomas [RCCs], 10 papillary RCCs, five chromophobe RCCs and five papillary urothelial carcinomas [UCs], as diagnosed by haematoxylin and eosin staining) were imaged and subtyped as non papillary and papillary, based on their architecture. Non-papillary tumours were further classified based on their unique cytoplasmic signatures. Clear-cell RCCs had a predominant population of cells with fat droplets in cytoplasm. Chromophobe RCCs had cells with non-fatty/homogeneous cytoplasm and distinct intra cytoplasmic granules. Papillary RCCs had single-cell-lined papillae with often abundant histiocytes in their core, whereas PUC had multi-layered urothelium lined papillae. The diagnostic accuracy of tumour subtyping by two independent uropathologists was 95%. CONCLUSIONS: We showed that MPM can reliably differentiate neoplastic from non-neoplastic kidney tissue and subtype kidney tumours in fresh, unprocessed tissue, MPM might therefore be useful as a rapid real-time diagnostic tool for the evaluation of kidney biopsies, and surgical margins in partial nephrectomies, to improve overall patient management. PMID- 26575176 TI - Suprarenal Neuroblastoma Presenting in a Child With Infantile Scoliosis. PMID- 26575174 TI - Lymphadenectomy promotes tumor growth and cancer cell dissemination in the spontaneous RET mouse model of human uveal melanoma. AB - Resection of infiltrated tumor-draining lymph nodes (TDLNs) is a standard practice for the treatment of several cancers including breast cancer and melanoma. However, many randomized prospective trials have failed to show convincing clinical benefits associated with LN removal and the role of TDLNs in cancer dissemination is poorly understood. Here, we found in a well-characterized spontaneous mouse model of uveal melanoma that the growth of the primary tumor was accompanied by increased lymphangiogenesis and cancer cell colonization in the LNs draining the eyes. But, unexpectedly, early resection of the TDLNs increased the growth of the primary tumor and associated blood vessels as well as promoted cancer cell survival and dissemination. These effects were accompanied by increased tumor cell proliferation and expression of phosphorylated AKT. Topical application of a broad anti-inflammatory agent, Tobradex, or an oral treatment with cyclooxygenase-2 specific inhibitor, Celecoxib, reversed tumor progression observed after complete lymphadenectomy. Our study confirms the importance of tumor homeostasis in cancer progression by showing the enhancing effects of TDLN removal on tumor growth and cancer cell dissemination, and suggests that TDLN resection may only be beneficial if used in combination with anti-inflammatory drugs such as Tobradex and Celecoxib. PMID- 26575177 TI - Integrating Real Time Data to Improve Outcomes in Acute Kidney Injury. AB - Critically ill patients with acute kidney injury requiring renal replacement therapy have a poor prognosis. Despite well-known factors, which contribute to outcomes, including dose delivery, patients frequently miss the target dose and volume removal. One major barrier to effective care of these patients is the traditional dissociation of dialysis device data from other clinical information systems, notably the electronic health record (EHR). This lack of integration and the resulting manual documentation leads to errors and biases in documentation and missed opportunities to intervene in a timely fashion. This review summarizes the technological advancements facilitating direct connection of dialysis devices to EHRs. This connection facilitates automated data capture of many variables - including delivered dose, ultrafiltration rate and pressure measurements - which in turn can be leveraged for data mining, quality improvement and real-time targeted therapy adjustments. These interventions hold the promise to significantly improve outcomes for this patient population. PMID- 26575178 TI - Adhesive Mechanisms of Histone-Induced Neutrophil-Endothelium Interactions in the Muscle Microcirculation. AB - BACKGROUND: Extracellular histones released during cell damage have the capacity to cause tissue injury associated with increased leukocyte accumulation. However, the molecular mechanisms regulating histone-induced leukocyte recruitment remain elusive. The objective of this study was to examine the role of adhesion molecules in histone-dependent leukocyte accumulation by use of intravital microscopy of the mouse cremaster microcirculation. METHODS: Histone 3 and TNF alpha were intrascrotally administered, and anti-P-selectin, anti-P-selectin glycoprotein ligand-1 (PSGL-1), anti-membrane-activated complex-1 (Mac-1), anti lymphocyte function antigen-1 (LFA-1) antibody and neutrophil depletion antibody were injected intravenously or intraperitoneally. RESULTS: Intrascrotal injection of histone 3 dose-dependently increased leukocyte recruitment. Neutrophil depletion abolished intravascular and extravascular leukocytes after histone 3 challenge, suggesting that neutrophils were the dominating leukocyte subtype responding to histone stimulation. Pretreatment with an anti-P-selectin and an anti-PSGL-1 antibody abolished histone-stimulated neutrophil rolling, adhesion and emigration. When the anti-P-selectin or the anti-PSGL-1 antibody was administrated after histone 3 stimulation, neutrophil rolling was reduced, whereas the number of firmly adherent and emigrated neutrophils were unchanged, suggesting that the inhibitory effect of blocking P-selectin and PSGL-1 on neutrophil adhesion and recruitment was due to the reduction in neutrophil rolling. Moreover, pretreatment with antibodies against Mac-1 and LFA-1 had no effect of neutrophil rolling but abolished adhesion and emigration evoked by histone 3. Thus, our data demonstrate that P-selectin and PSGL-1 play an important role in histone-induced inflammatory cell recruitment by mediating neutrophil rolling as a precondition for histone-provoked firm adhesion and emigration in vivo. Moreover, we conclude that both Mac-1 and LFA-1 are critical in supporting histone-provoked firm adhesion of neutrophils to endothelial cells. CONCLUSION: These novel findings define specific selectins and integrins as potential targets for pharmacological intervention in histone-dependent inflammatory diseases. PMID- 26575179 TI - Holding Children for Clinical Procedures: Perseverance in Spite of or Persevering to be Child-Centered. AB - Children in acute care often need procedures and interventions, and they are frequently held, often against their wishes, to enable these procedures to be completed. This report is from a qualitative investigation in which we sought to explore what happens when children undergo clinical procedures within an acute hospital, with a focus on the use of holding for procedures. Qualitative data were generated through non-participant observation of clinical procedures (n = 31) and semi-structured interviews with health professionals (n = 22), parents (n = 21), and children (n = 4) to explore the event from the participants' perspective. Data were analyzed using constant comparison. Through the central theoretical concept of perseverance, we examined the actions, inactions and interactions of health professionals, parents and children during a clinical procedure. Two broad trajectories were noted: "perseverance in spite of," when the procedure was completed despite a child's upset and lack of co-operation; and "perseverance to be child-centered," which was characterized by a purposeful plan of action focused on a child who had been prepared and informed, and which was facilitated by a "window of opportunity" at the start of the procedure when the child was calm and engaged. Our findings highlight that professionals need to be clear about their boundaries when starting or continuing with a procedure when a child is distressed, and support preparation and engagement activities with children and parents before, during, and after clinical procedures. PMID- 26575180 TI - Effect of a local anesthetic lozenge in relief of symptoms in burning mouth syndrome. AB - OBJECTIVE: Patients with burning mouth syndrome (BMS) often represent a clinical challenge as available agents for symptomatic treatment are few and often ineffective. The aim was to evaluate the effect of a bupivacaine lozenge on oral mucosal pain, xerostomia, and taste alterations in patients with BMS. METHODS: Eighteen patients (4 men and 14 women) aged 39-71 years with BMS were included in this randomized, double-blinded, placebo-controlled, crossover trial. Lozenges (containing bupivacaine or placebo) were administrated three times a day for 2 weeks for two separate treatment periods. Assessment of oral mucosal pain, xerostomia, and taste alterations was performed in a patient diary on a visual analog scale (ranging from 0 to 100 mm) before and after the lozenge was dissolved. RESULTS: The bupivacaine lozenge significantly reduced the burning oral pain (P < 0.001), increased the sense of taste disturbances (P < 0.001), and had no impact on xerostomia, when adjusted for the treatment period. CONCLUSIONS: Our results indicate that the bupivacaine lozenge offers a novel therapeutic modality to patients with BMS, although without alleviating effect on the associated symptoms, taste alterations, and xerostomia. PMID- 26575181 TI - Acute Heat Stress and Reduced Nutrient Intake Alter Intestinal Proteomic Profile and Gene Expression in Pigs. AB - Heat stress and reduced feed intake negatively affect intestinal integrity and barrier function. Our objective was to compare ileum protein profiles of pigs subjected to 12 hours of HS, thermal neutral ad libitum feed intake, or pair-fed to heat stress feed intake under thermal neutral conditions (pair-fed thermal neutral). 2D-Differential In Gel Electrophoresis and gene expression were performed. Relative abundance of 281 and 138 spots differed due to heat stress, compared to thermal neutral and pair-fed thermal neutral pigs, respectively. However, only 20 proteins were different due to feed intake (thermal neutral versus pair-fed thermal neutral). Heat stress increased mRNA expression of heat shock proteins and protein abundance of heat shock proteins 27, 70, 90-alpha and beta were also increased. Heat stress reduced ileum abundance of several metabolic enzymes, many of which are involved in the glycolytic or TCA pathways, indicating a change in metabolic priorities. Stress response enzymes peroxiredoxin-1 and peptidyl-prolyl cis-trans isomerase A were decreased in pair fed thermal neutral and thermal neutral pigs compared to heat stress. Heat stress increased mRNA abundance markers of ileum hypoxia. Altogether, these data show that heat stress directly alters intestinal protein and mRNA profiles largely independent of reduced feed intake. These changes may be related to the reduced intestinal integrity associated with heat stress. PMID- 26575182 TI - Developing and Optimising the Use of Logic Models in Systematic Reviews: Exploring Practice and Good Practice in the Use of Programme Theory in Reviews. AB - BACKGROUND: Logic models are becoming an increasingly common feature of systematic reviews, as is the use of programme theory more generally in systematic reviewing. Logic models offer a framework to help reviewers to 'think' conceptually at various points during the review, and can be a useful tool in defining study inclusion and exclusion criteria, guiding the search strategy, identifying relevant outcomes, identifying mediating and moderating factors, and communicating review findings. METHODS AND FINDINGS: In this paper we critique the use of logic models in systematic reviews and protocols drawn from two databases representing reviews of health interventions and international development interventions. Programme theory featured only in a minority of the reviews and protocols included. Despite drawing from different disciplinary traditions, reviews and protocols from both sources shared several limitations in their use of logic models and theories of change, and these were used almost unanimously to solely depict pictorially the way in which the intervention worked. Logic models and theories of change were consequently rarely used to communicate the findings of the review. CONCLUSIONS: Logic models have the potential to be an aid integral throughout the systematic reviewing process. The absence of good practice around their use and development may be one reason for the apparent limited utility of logic models in many existing systematic reviews. These concerns are addressed in the second half of this paper, where we offer a set of principles in the use of logic models and an example of how we constructed a logic model for a review of school-based asthma interventions. PMID- 26575183 TI - Single Particle Tracking Reveals that EGFR Signaling Activity Is Amplified in Clathrin-Coated Pits. AB - Signaling from the epidermal growth factor receptor (EGFR) via phosphorylation on its C-terminal tyrosine residues requires self-association, which depends on the diffusional properties of the receptor and its density in the plasma membrane. Dimerization is a key event for EGFR activation, but the role of higher order clustering is unknown. We employed single particle tracking to relate the mobility and aggregation of EGFR to its signaling activity. EGFR mobility alternates between short-lived free, confined and immobile states. In the immobile state, EGFR tends to aggregate in clathrin-coated pits, which is further enhanced in a phosphorylation-dependent manner and does not require ligand binding. EGFR phosphorylation is further amplified by cross-phosphorylation in clathrin-coated pits. Because phosphorylated receptors can escape from the pits, local gradients of signaling active EGFR are formed. These results show that amplification of EGFR phosphorylation by receptor clustering in clathrin-coated pits supports signal activation at the plasma membrane. PMID- 26575184 TI - Anti-Inflammatory and Neuroprotective Effects of Triptolide via the NF-kappaB Signaling Pathway in a Rat MCAO Model. AB - Stroke is the leading cause of neurological disability in humans. Middle cerebral artery occlusion (MCAO) followed by reperfusion is widely accepted to mimic stroke in basic medical research. Triptolide is one of the major active components of the traditional Chinese herb Tripterygium wilfordii Hook F, and has been reported to have potent anti-inflammatory and immunosuppressive properties. Since its preclinical effects on stroke were still unclear, we decided to study the effects of Triptolide on focal cerebral ischemia/reperfusion injury in this study. The results showed that Triptolide treatment significantly attenuates brain infarction volume, water content, neurological deficits, and neuronal cell death rate, which were increased in the MCAO model rats. Immunohistochemistry was used to analyze the expression of glial fibrillary acidic protein (GFAP), Cyclooxygenase-2 (COX-2), inducible nitric oxide (iNOS), and NF-kappaB in the ischemic brains. The administration of Triptolide showed down-regulation of the iNOS, COX-2, GFAP, and NF-kappaB expression in MCAO rats. It also increased the expression of bcl-2, and suppressed levels of bax and caspase-3 compared with the MCAO group. Our findings revealed that Triptolide exerts its neuroprotective effects against inflammation with the involvement of inhibition of NF-kappaB activation. PMID- 26575185 TI - Somatic Mutation Allelic Ratio Test Using ddPCR (SMART-ddPCR): An Accurate Method for Assessment of Preferential Allelic Imbalance in Tumor DNA. AB - The extent to which heritable genetic variants can affect tumor development has yet to be fully elucidated. Tumor selection of single nucleotide polymorphism (SNP) risk alleles, a phenomenon called preferential allelic imbalance (PAI), has been demonstrated in some cancer types. We developed a novel application of digital PCR termed Somatic Mutation Allelic Ratio Test using Droplet Digital PCR (SMART-ddPCR) for accurate assessment of tumor PAI, and have applied this method to test the hypothesis that heritable SNPs associated with childhood acute lymphoblastic leukemia (ALL) may demonstrate tumor PAI. These SNPs are located at CDKN2A (rs3731217) and IKZF1 (rs4132601), genes frequently lost in ALL, and at CEBPE (rs2239633), ARID5B (rs7089424), PIP4K2A (rs10764338), and GATA3 (rs3824662), genes located on chromosomes gained in high-hyperdiploid ALL. We established thresholds of AI using constitutional DNA from SNP heterozygotes, and subsequently measured allelic copy number in tumor DNA from 19-142 heterozygote samples per SNP locus. We did not find significant tumor PAI at these loci, though CDKN2A and IKZF1 SNPs showed a trend towards preferential selection of the risk allele (p = 0.17 and p = 0.23, respectively). Using a genomic copy number control ddPCR assay, we investigated somatic copy number alterations (SCNA) underlying AI at CDKN2A and IKZF1, revealing a complex range of alterations including homozygous and hemizygous deletions and copy-neutral loss of heterozygosity, with varying degrees of clonality. Copy number estimates from ddPCR showed high agreement with those from multiplex ligation-dependent probe amplification (MLPA) assays. We demonstrate that SMART-ddPCR is a highly accurate method for investigation of tumor PAI and for assessment of the somatic alterations underlying AI. Furthermore, analysis of publicly available data from The Cancer Genome Atlas identified 16 recurrent SCNA loci that contain heritable cancer risk SNPs associated with a matching tumor type, and which represent candidate PAI regions warranting further investigation. PMID- 26575186 TI - Polyfunctional Specific Response to Echinococcus Granulosus Associates to the Biological Activity of the Cysts. AB - BACKGROUND: Cystic echinococcosis (CE) is a complex disease caused by Echinococcus granulosus (E.granulosus), and its immunophatogenesis is still not clearly defined. A peculiar feature of chronic CE is the coexistence of Th1 and Th2 responses. It has been suggested that Th1 cytokines are related to disease resistance, whereas Th2 cytokines are related to disease susceptibility and chronicity. The aim of this study was to evaluate, by multi-parametric flow cytometry (FACS), the presence of CE specific immune signatures. METHODOLOGY/PRINCIPAL FINDINGS: We enrolled 54 subjects with suspected CE; 42 of them had a confirmed diagnosis, whereas 12 were classified as NO-CE. Based on the ultrasonography images, CE patients were further categorized as being in "active stages" (25) and "inactive stages" (17). The ability of CD4+ T-cells to produce IFN-gamma, IL-2, TNF-alpha, Th2 cytokines or IL-10 was assessed by FACS on antigen-specific T-cells after overnight stimulation with Antigen B (AgB) of E.granulosus. Cytokine profiles were evaluated in all the enrolled subjects. The results show that none of the NO-CE subjects had a detectable AgB-specific response. Among the CE patients, the frequency and proportions of AgB-specific CD4+ T-cells producing IL-2+TNF-alpha+Th2+ or TNF-alpha+Th2+ were significantly increased in the "active stages" group compared to the "inactive stages" group. Moreover, an increased proportion of the total polyfunctional subsets, as triple and double-functional CD4 T-cells, was found in CE patients with active disease. The response to the mitogen, used as a control stimulus to evaluate the immune competence status, was characterized by the same cytokine subsets in all the subjects enrolled, independent of CE. CONCLUSIONS: We demonstrate, for the first time to our knowledge, that polyfunctional T-cell subsets as IL-2+TNF-alpha+Th2+ triple-positive and TNF-alpha+Th2+ double-positive specific T-cells associate with cyst biological activity. These results contribute to increase knowledge of CE immunophatogenesis and the disease outcome in terms of control and persistence. PMID- 26575187 TI - Comparing Handheld Meters and Electronic Dosimeters for Measuring Ultraviolet Levels under Shade and in the Sun. AB - This study aimed to compare the validity, reliability and practicality of alternative portable methods for measuring erythemal UVR levels in passive recreation areas in public parks. UVR levels were measured for point in time comparisons between Solarmeter 6.5 handheld meters and time-stamped electronic dosimeters in a large central park in Melbourne, Australia. Observations were made at 20 locations in the park by two research assistants under two conditions: (1) matched shade (2) contrasting shade-no shade. Comparisons were also made with scientific instruments on the UVR monitoring station rooftop and by remotely selecting UV records and forecasts on cloud-free dates of park observations. There was good agreement between the portable UVR instruments in the park setting as confirmed via Bland Altman plots, while the dosimeter appeared less sensitive to change in shade conditions. The rooftop measurements showed that the Solarmeter 6.5 UVR readings were comparable to those of the adjacent rooftop instruments. The practicalities of using the dosimeters and Solarmeters for behavioral studies are discussed. These findings provide a basis for use of the Solarmeter 6.5 to measure changes in UVR levels due to different environmental conditions with relative accuracy for intervention studies in outdoor settings. PMID- 26575188 TI - Table Correction: Parent Engagement With a Telehealth-Based Parent-Mediated Intervention Program for Children With Autism Spectrum Disorders: Predictors of Program Use and Parent Outcomes. PMID- 26575190 TI - Fourth-root summation of contrast over area: No end in sight when spatially inhomogeneous sensitivity is compensated by a witch's hat. AB - Measurements of area summation for luminance-modulated stimuli are typically confounded by variations in sensitivity across the retina. Recently we conducted a detailed analysis of sensitivity across the visual field (Baldwin, Meese, & Baker, 2012) and found it to be well described by a bilinear "witch's hat" function: Sensitivity declines rapidly over the first eight cycles or so, but more gently thereafter. Here we multiplied luminance-modulated stimuli (4 cycles/degree gratings and "Swiss cheeses") by the inverse of the witch's hat function to compensate for the inhomogeneity. This revealed summation functions that were straight lines (on double log axes) with a slope of -1/4 extending to >=33 cycles, demonstrating fourth-root summation of contrast over a wider area than has previously been reported for the central retina. Fourth-root summation is typically attributed to probability summation, but recent studies have rejected that interpretation in favor of a noisy energy model that performs local square-law transduction of the signal, adds noise at each location of the target, and then sums over signal area. Modeling shows our results to be consistent with a wide field application of such a contrast integrator. We reject a probability summation model, a quadratic model, and a matched template model of our results under the assumptions of signal detection theory. We also reject the high threshold theory of contrast detection under the assumption of probability summation over area. PMID- 26575189 TI - Interplay between Structure and Charge as a Key to Allosteric Modulation of Human 20S Proteasome by the Basic Fragment of HIV-1 Tat Protein. AB - The proteasome is a giant protease responsible for degradation of the majority of cytosolic proteins. Competitive inhibitors of the proteasome are used against aggressive blood cancers. However, broadening the use of proteasome-targeting drugs requires new mechanistic approaches to the enzyme's inhibition. In our previous studies we described Tat1 peptide, an allosteric inhibitor of the proteasome derived from a fragment of the basic domain of HIV-Tat1 protein. Here, we attempted to dissect the structural determinants of the proteasome inhibition by Tat1. Single- and multiple- alanine walking scans were performed. Tat1 analogs with stabilized beta-turn conformation at positions 4-5 and 8-9, pointed out by the molecular dynamics modeling and the alanine scan, were synthesized. Structure of Tat1 analogs were analyzed by circular dichroism, Fourier transform infrared and nuclear magnetic resonance spectroscopy studies, supplemented by molecular dynamics simulations. Biological activity tests and structural studies revealed that high flexibility and exposed positive charge are hallmarks of Tat1 peptide. Interestingly, stabilization of a beta-turn at the 8-9 position was necessary to significantly improve the inhibitory potency. PMID- 26575191 TI - Eye movements reveal distinct encoding patterns for number and cumulative surface area in random dot arrays. AB - Humans can quickly and intuitively represent the number of objects in a scene using visual evidence through the Approximate Number System (ANS). But the computations that support the encoding of visual number-the transformation from the retinal input into ANS representations-remain controversial. Two types of number encoding theories have been proposed: those arguing that number is encoded through a dedicated, enumeration computation, and those arguing that visual number is inferred from nonnumber specific visual features, such as surface area, density, convex hull, etc. Here, we attempt to adjudicate between these two theories by testing participants on both a number and a cumulative area task while also tracking their eye-movements. We hypothesize that if approximate number and surface area depend on distinct encoding computations, saccadic signatures should be distinct for the two tasks, even if the visual stimuli are identical. Consistent with this hypothesis, we find that discriminating number versus cumulative area modulates both where participants look (i.e., participants spend more time looking at the more numerous set in the number task and the larger set in the cumulative area task), and how participants look (i.e., cumulative area encoding shows fewer, longer saccades, while number encoding shows many short saccades and many switches between targets). We further identify several saccadic signatures that are associated with task difficulty and correct versus incorrect trials for both dimensions. These results suggest distinct encoding algorithms for number and cumulative area extraction, and thereby distinct representations of these dimensions. PMID- 26575192 TI - Contextual effects in visual working memory reveal hierarchically structured memory representations. AB - Influential slot and resource models of visual working memory make the assumption that items are stored in memory as independent units, and that there are no interactions between them. Consequently, these models predict that the number of items to be remembered (the set size) is the primary determinant of working memory performance, and therefore these models quantify memory capacity in terms of the number and quality of individual items that can be stored. Here we demonstrate that there is substantial variance in display difficulty within a single set size, suggesting that limits based on the number of individual items alone cannot explain working memory storage. We asked hundreds of participants to remember the same sets of displays, and discovered that participants were highly consistent in terms of which items and displays were hardest or easiest to remember. Although a simple grouping or chunking strategy could not explain this individual-display variability, a model with multiple, interacting levels of representation could explain some of the display-by-display differences. Specifically, a model that includes a hierarchical representation of items plus the mean and variance of sets of the colors on the display successfully accounts for some of the variability across displays. We conclude that working memory representations are composed only in part of individual, independent object representations, and that a major factor in how many items are remembered on a particular display is interitem representations such as perceptual grouping, ensemble, and texture representations. PMID- 26575194 TI - A bias-free measure of the tilt illusion. AB - The perceived orientation of a central test grating is influenced by the orientation structure of the surrounding image. Measurement of this "tilt illusion" traditionally requires subjects to report the orientation of the test relative to a cardinal reference (e.g., clockwise or anticlockwise of vertical). Given that the test is presented within a surround that is itself oriented clockwise or anticlockwise from vertical, there is obvious potential for the orientation of the surround to bias the subject's response irrespective of any perceptual effects. To avoid this bias, we ran a two temporal interval forced choice experiment. The two intervals contained opposite surround orientations (+/ 15 degrees ), and we manipulated the orientation of the center gratings. Participants were asked to judge which of the test gratings was closer to vertical. We found no significant difference between measurements of the tilt illusion using the traditional and two-interval procedures. We then examined interindividual differences in a larger sample and found a significant correlation between the magnitudes of the tilt illusion measured using the two procedures. Our experiments demonstrate a method free from response bias in measuring the tilt illusion although our results indicate that response biases were unlikely to factor significantly in prior tilt illusion experiments. PMID- 26575193 TI - Memory and learning with rapid audiovisual sequences. AB - We examined short-term memory for sequences of visual stimuli embedded in varying multisensory contexts. In two experiments, subjects judged the structure of the visual sequences while disregarding concurrent, but task-irrelevant auditory sequences. Stimuli were eight-item sequences in which varying luminances and frequencies were presented concurrently and rapidly (at 8 Hz). Subjects judged whether the final four items in a visual sequence identically replicated the first four items. Luminances and frequencies in each sequence were either perceptually correlated (Congruent) or were unrelated to one another (Incongruent). Experiment 1 showed that, despite encouragement to ignore the auditory stream, subjects' categorization of visual sequences was strongly influenced by the accompanying auditory sequences. Moreover, this influence tracked the similarity between a stimulus's separate audio and visual sequences, demonstrating that task-irrelevant auditory sequences underwent a considerable degree of processing. Using a variant of Hebb's repetition design, Experiment 2 compared musically trained subjects and subjects who had little or no musical training on the same task as used in Experiment 1. Test sequences included some that intermittently and randomly recurred, which produced better performance than sequences that were generated anew for each trial. The auditory component of a recurring audiovisual sequence influenced musically trained subjects more than it did other subjects. This result demonstrates that stimulus-selective, task irrelevant learning of sequences can occur even when such learning is an incidental by-product of the task being performed. PMID- 26575195 TI - Functional effects of unilateral open-angle glaucoma on the primary and extrastriate visual cortex. AB - The purpose of this study was to use functional magnetic resonance imaging (fMRI) to investigate the response of the visual cortex to unilateral primary open-angle glaucoma (POAG). Specifically, we assessed whether regions of V1 and V2 with lost input from the glaucomatous eye had a greater response to input from the nonaffected fellow eye. Nine participants with unilateral POAG causing paracentral visual field defects and four controls participated in the study. We found no evidence for an increased response to the fellow eye in glaucoma affected regions of the visual cortex; however, in agreement with previous studies, there was a pronounced, retinotopically localized reduction of activation in both the primary (V1) and extrastriate visual cortex (V2), when participants viewed through their glaucomatous eye. Our results suggest a remarkable level of stability within the adult primary and extrastriate visual cortex in response to unilateral neurodegeneration of the optic nerve. PMID- 26575196 TI - Attention modulates visual size adaptation. AB - The current study determined in healthy subjects (n = 16) whether size adaptation occurs at early, i.e., preattentive, levels of processing or whether higher cognitive processes such as attention can modulate the illusion. To investigate this issue, bottom-up stimulation was kept constant across conditions by using a single adaptation display containing both small and large adapter stimuli. Subjects' attention was directed to either the large or small adapter stimulus by means of a luminance detection task. When attention was directed toward the small as compared to the large adapter, the perceived size of the subsequent target was significantly increased. Data suggest that different size adaptation effects can be induced by one and the same stimulus depending on the current allocation of attention. This indicates that size adaptation is subject to attentional modulation. These findings are in line with previous research showing that transient as well as sustained attention modulates visual features, such as contrast sensitivity and spatial frequency, and influences adaptation in other contexts, such as motion adaptation (Alais & Blake, 1999; Lankheet & Verstraten, 1995). Based on a recently suggested model (Pooresmaeili, Arrighi, Biagi, & Morrone, 2013), according to which perceptual adaptation is based on local excitation and inhibition in V1, we conclude that guiding attention can boost these local processes in one or the other direction by increasing the weight of the attended adapter. In sum, perceptual adaptation, although reflected in changes of neural activity at early levels (as shown in the aforementioned study), is nevertheless subject to higher-order modulation. PMID- 26575198 TI - Detection and spatial characterization of minicolumnarity in the human cerebral cortex. AB - BACKGROUND: Spatial characterization of vertical organization of neurons in human cerebral cortex, cortical columnarity or minicolumns, and its possible association with various psychiatric and neurological diseases has been investigated for many years. NEW METHOD: In this study, we obtained 3D coordinates of disector sampled cells from layer III of Brodmann area 4 of the human cerebral cortex using light microscopy and 140-MUm-thick glycolmethacrylate sections. A new analytical tool called cylindrical K-function was applied for spatial point pattern analysis of 3D datasets to see whether there is a spatially organized columnar structure. In order to demonstrate the behaviour of the cylindrical K-function, the result from brain tissues was compared with two models: A homogeneous Poisson process exhibiting complete spatial randomness, and a Poisson line cluster point process. The latter is a point process model in 3D space, which exhibits spatial structure of points similar to minicolumns. RESULTS: The data show in three out of four samples nonrandom patterns in the 3D neuronal positions with the direction of minicolumns perpendicular to the pial surface of the brain - without a priori assuming the existence of minicolumns. COMPARISON WITH EXISTING METHODS: Studies on columnarity are difficult and have mainly been based on two-dimensional images analysis of thin sections of the cerebral cortex with the a priori assumption that minicolumns existed. CONCLUSIONS: A clear difference from complete spatial randomness in the data could be detected with the new tool, the cylindrical K-function, although classical functional summary statistics are less useful in this connection. PMID- 26575197 TI - ALDH1A3: A Marker of Mesenchymal Phenotype in Gliomas Associated with Cell Invasion. AB - Aldehyde dehydrogenases (ALDH) is a family of enzymes including 19 members. For now, ALDH activity had been wildly used as a marker of cancer stem cells (CSCs). But biological functions of relevant isoforms and their clinical applications are still controversial. Here, we investigate the clinical significance and potential function of ALDH1A3 in gliomas. By whole-genome transcriptome microarray and mRNA sequencing analysis, we compared the expression of ALDH1A3 in high- and low- grade gliomas as well as different molecular subtypes. Microarray analysis was performed to identify the correlated genes of ALDH1A3. We further used Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analysis to explore the biological function of ALDH1A3. Finally, by mRNA knockdown we revealed the relationship between ALDH1A3 and the ability of tumor invasion. ALDH1A3 overexpression was significantly associated with high grade as well as the higher mortality of gliomas in survival analysis. ALDH1A3 was characteristically highly expressed in Mesenchymal (Mes) subtype gliomas. Moreover, we found that ALDH1A3 was most relevant to extracellular matrix organization and cell adhesion biological process, and the ability of tumor invasion was suppressed after ALDH1A3 knockdown in vitro. In conclusion, ALDH1A3 can serve as a novel marker of Mes phenotype in gliomas with potential clinical prognostic value. The expression of ALDH1A3 is associated with tumor cell invasion. PMID- 26575199 TI - Optimal Bayesian adaptive trials when treatment efficacy depends on biomarkers. AB - Clinical biomarkers play an important role in precision medicine and are now extensively used in clinical trials, particularly in cancer. A response adaptive trial design enables researchers to use treatment results about earlier patients to aid in treatment decisions of later patients. Optimal adaptive trial designs have been developed without consideration of biomarkers. In this article, we describe the mathematical steps for computing optimal biomarker-integrated adaptive trial designs. These designs maximize the expected trial utility given any pre-specified utility function, though we focus here on maximizing patient responses within a given patient horizon. We describe the performance of the optimal design in different scenarios. We compare it to Bayesian Adaptive Randomization (BAR), which is emerging as a practical approach to develop adaptive trials. The difference in expected utility between BAR and optimal designs is smallest when the biomarker subgroups are highly imbalanced. We also compare BAR, a frequentist play-the-winner rule with integrated biomarkers and a marker-stratified balanced randomization design (BR). We show that, in contrasting two treatments, BR achieves a nearly optimal expected utility when the patient horizon is relatively large. Our work provides novel theoretical solution, as well as an absolute benchmark for the evaluation of trial designs in personalized medicine. PMID- 26575200 TI - Characterization of Phenolic Compounds and Antioxidant and Anti-inflammatory Activities from Mamuyo (Styrax ramirezii Greenm.) Fruit. AB - Extracts of Styrax ramirezii Greenm., a fruit traditionally valued for health and wellness in Mexico, were analyzed phytochemically and evaluated for antioxidant and anti-inflammatory activity. Six norneolignans were identified by HPLC-TOF-MS, and the two major compounds were isolated for further evaluation. The effects of the isolated norneolignans, egonol and homoegonol, on lipopolysaccharide (LPS) induced nitric oxide (NO) production, reactive oxygen species (ROS) production, and biomarkers of inflammation were evaluated. Of the tested compounds, egonol potently inhibited the production of NO and also significantly reduced the release of ROS. Consistent with these observations, the mRNA expression levels of inducible nitric oxide synthase (iNOS) (0.668 +/- 0.108), cyclooxygenase-2 (COX 2) (0.553 +/- 0.007), interleukin-1beta (IL-1beta) (0.093 +/- 0.005), and interleukin-6 (IL-6) (0.298 +/- 0.076) were reduced by egonol. The activity for both egonol and homoegonol increased in a concentration-dependent manner. These results suggest the potential of S. ramirezii Greenm. fruit to contribute to a healthy diet, rich in antioxidant and anti-inflammatory compounds. PMID- 26575201 TI - Risk factors for adverse outcomes of Indigenous infants hospitalized with bronchiolitis. AB - BACKGROUND: Hospitalized bronchiolitis imposes a significant burden among infants, particularly among Indigenous children. Traditional or known risk factors for severe disease are well described, but there are limited data on risks for prolonged hospitalization and persistent symptoms. Our aims were to determine factors (clinical and microbiological) associated with (i) prolonged length of stay (LOS); (ii) persistent respiratory symptoms at 3 weeks; (iii) bronchiectasis up to ~24 months post-hospitalisation; and (iv) risk of respiratory readmissions within 6 months. METHODS: Indigenous infants hospitalized with bronchiolitis were enrolled at Royal Darwin Hospital between 2008 and 2013. Standardized forms were used to record clinical data. A nasopharyngeal swab was collected at enrolment to identify respiratory viruses and bacteria. RESULTS: The median age of 232 infants was 5 months (interquartile range 3-9); 65% male. On multivariate regression, our 12 point severity score (including accessory muscle use) was the only factor associated with prolonged LOS but the effect was modest (+3.0 hr per point, 95%CI: 0.7, 5.1, P = 0.01). Presence of cough at 3 weeks increased the odds of bronchiectasis (OR 3.0, 95%CI: 1.1, 7.0, P = 0.03). Factors associated with respiratory readmissions were: previous respiratory hospitalization (OR 2.3, 95%CI: 1.0, 5.4, P = 0.05) and household smoke (OR 2.6, 95%CI: 1.0, 6.3, P = 0.04). CONCLUSION: Increased severity score is associated with prolonged LOS in Indigenous children hospitalized with bronchiolitis. As persistent symptoms at 3 weeks post hospitalization are associated with future diagnosis of bronchiectasis, optimising clinical care beyond hospitalization is needed to improve long-term respiratory outcomes for infants at risk of respiratory disease. Pediatr Pulmonol. 2016;51:613-623. (c) 2015 Wiley Periodicals, Inc. PMID- 26575202 TI - Botrydial and botcinins produced by Botrytis cinerea regulate the expression of Trichoderma arundinaceum genes involved in trichothecene biosynthesis. AB - Trichoderma arundinaceum IBT 40837 (Ta37) and Botrytis cinerea produce the sesquiterpenes harzianum A (HA) and botrydial (BOT), respectively, and also the polyketides aspinolides and botcinins (Botcs), respectively. We analysed the role of BOT and Botcs in the Ta37-B. cinerea interaction, including the transcriptomic changes in the genes involved in HA (tri) and ergosterol biosynthesis, as well as changes in the level of HA and squalene-ergosterol. We found that, when confronted with B. cinerea, the tri biosynthetic genes were up-regulated in all dual cultures analysed, but at higher levels when Ta37 was confronted with the BOT non-producer mutant bcbot2Delta. The production of HA was also higher in the interaction area with this mutant. In Ta37-bcbot2Delta confrontation experiments, the expression of the hmgR gene, encoding the 3-hydroxy-3-methylglutaryl coenzyme A reductase, which is the first enzyme of the terpene biosynthetic pathway, was also up-regulated, resulting in an increase in squalene production compared with the confrontation with B. cinerea B05.10. Botcs had an up-regulatory effect on the tri biosynthetic genes, with BotcA having a stronger effect than BotcB. The results indicate that the interaction between Ta37 and B. cinerea exerts a stimulatory effect on the expression of the tri biosynthetic genes, which, in the interaction zone, can be attenuated by BOT produced by B. cinerea B05.10. The present work provides evidence for a metabolic dialogue between T. arundinaceum and B. cinerea that is mediated by sesquiterpenes and polyketides, and that affects the outcome of the interaction of these fungi with each other and their environment. PMID- 26575203 TI - Big Data and Adverse Drug Reaction Detection. AB - Big Data holds the promise of fundamentally transforming the manner in which adverse drug reactions can be identified and evaluated. This commentary discusses new data sources that are envisioned to form a Big Data-enabled pharmacovigilance system and the role of these data in powering the future of adverse drug reactions detection. PMID- 26575204 TI - Effect of poly-herbal preparations on wound healing. PMID- 26575205 TI - Gate Modulation of Threshold Voltage Instability in Multilayer InSe Field Effect Transistors. AB - We report a modulation of threshold voltage instability of back-gated multilayer InSe FETs by gate bias stress. The performance stability of multilayer InSe FETs is affected by gate bias polar, gate bias stress time and gate bias sweep rate under ambient conditions. The on-current increases and threshold voltage shifts to negative gate bias stress direction with negative bias stress applied, which are opposite to that of positive bias stress. The intensity of gate bias stress effect is influenced by applied gate bias time and the sweep rate of gate bias stress. The behavior can be explained by the surface charge trapping model due to the adsorbing/desorbing oxygen and/or water molecules on the InSe surface. This study offers an opportunity to understand gate bias stress modulation of performance instability of back-gated multilayer InSe FETs and provides a clue for designing desirable InSe nanoelectronic and optoelectronic devices. PMID- 26575206 TI - The extent of whole-genome copy number alterations predicts aggressive features in primary melanomas. AB - Recent evidence indicates that melanoma comprises distinct types of tumors and suggests that specific morphological features may help predict its clinical behavior. Using a SNP-array approach, we quantified chromosomal copy number alterations (CNA) across the whole genome in 41 primary melanomas and found a high degree of heterogeneity in their genomic asset. Association analysis correlating the number and relative length of CNA with clinical, morphological, and dermoscopic attributes of melanoma revealed that features of aggressiveness were strongly linked to the overall amount of genomic damage. Furthermore, we observed that melanoma progression and survival were mainly affected by a low number of large chromosome losses and a high number of small gains. We identified the alterations most frequently associated with aggressive melanoma, and by integrating our data with publicly available gene expression profiles, we identified five genes which expression was found to be necessary for melanoma cells proliferation. In conclusion, this work provides new evidence that the phenotypic heterogeneity of melanoma reflects a parallel genetic diversity and lays the basis to define novel strategies for a more precise prognostic stratification of patients. PMID- 26575207 TI - Design and Synthesis of an MOF Thermometer with High Sensitivity in the Physiological Temperature Range. AB - An important result of research on mixed-lanthanide metal-organic frameworks (M'LnMOFs) is the realization of highly sensitive ratiometric luminescent thermometers. Here, we report the design and synthesis of the new M'LnMOF Tb0.80Eu0.20BPDA with high relative sensitivity in the physiological temperature regime (298-318 K). The emission intensity and luminescence lifetime were investigated and compared to those of existing materials. It was found that the temperature-dependent luminescence properties of Tb0.80Eu0.20BPDA are strongly associated with the distribution of the energy levels of the ligand. Such a property can be useful in the design of highly sensitive M'LnMOF thermometers. PMID- 26575208 TI - Mechanistic Investigation of cPMP Synthase in Molybdenum Cofactor Biosynthesis Using an Uncleavable Substrate Analogue. AB - Molybdenum cofactor (Moco) is essential for all kingdoms of life, plays central roles in various biological processes, and must be biosynthesized de novo. During its biosynthesis, the characteristic pyranopterin ring is constructed by a complex rearrangement of guanosine 5'-triphosphate (GTP) into cyclic pyranopterin monophosphate (cPMP) through the action of two enzymes, MoaA and MoaC. Recent studies revealed that MoaC catalyzes the majority of the transformation and produces cPMP from a unique cyclic nucleotide, 3',8-cyclo-7,8-dihydro-GTP (3',8 cH2GTP). However, the mechanism by which MoaC catalyzes this complex rearrangement is largely unexplored. Here, we report the mechanistic characterization of MoaC using an uncleavable substrate analogue, 3',8 cH2GMP[CH2]PP, as a probe to investigate the timing of cyclic phosphate formation. Using partially active MoaC variants, 3',8-cH2GMP[CH2]PP was found to be accepted by MoaC as a substrate and was converted to an analogue of the previously described MoaC reaction intermediate, suggesting that the early stage of catalysis proceeds without cyclic phosphate formation. In contrast, when it was incubated with wt-MoaC, 3',8-cH2GMP[CH2]PP caused mechanism-based inhibition. Detailed characterization of the inhibited MoaC suggested that 3',8-cH2GMP[CH2]PP is mainly converted to a molecule (compound Y) with an acid-labile triaminopyrimidinone base without an established pyranopterin structure. MS analysis of MoaC treated with 3',8-cH2GMP[CH2]PP provided strong evidence that compound Y forms a tight complex with MoaC likely through a covalent linkage. These observations are consistent with a mechanism in which cyclic phosphate ring formation proceeds in concert with the pterin ring formation. This mechanism would provide a thermodynamic driving force to complete the formation of the unique tetracyclic structure of cPMP. PMID- 26575209 TI - Successful treatment of exertional heat stroke using continuous plasma diafiltration. AB - We report a case of severe exertional heat stroke with multiple organ failure successfully treated with continuous plasma diafiltration (CPDF). PDF effectively removed proinflammatory cytokines, and simultaneously, supported liver function. Furthermore, CPDF therapy showed beneficial effects on multiple organ functions. These features suggest that it is a primary treatment option for exertional heat stroke with multiple organ failure. J. Clin. Apheresis 31:490-492, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26575210 TI - Toward the premotor diagnosis of Parkinson's disease: Suggestions from a modelling study. PMID- 26575211 TI - Protocatechuic Acid Restores Vascular Responses in Rats With Chronic Diabetes Induced by Streptozotocin. AB - Oxidative stress has been shown to play an important role in development of vascular dysfunction in diabetes. Protocatechuic acid (PCA) has been reported to exert antioxidant and anti-hyperglycemic activities. Diabetes was induced in male Sprague-Dawley rats by a single intraperitoneal injection of 50 mg/kg streptozotocin (STZ). The rats were maintained in a state of hyperglycemia for 12 weeks. Then, PCA (50 or 100 mg/kg/day) was administered orally or insulin (4 U/kg/day) was subcutaneous injected to the rats for 6 weeks. Blood pressure, vascular responses to vasoactive agents, vascular superoxide production, blood glucose, insulin, malondialdehyde, nitric oxide and antioxidant enzymes were examined. The diabetic rats showed weight loss, insulin deficiency, hyperglycemia, increased oxidative stress, decreased plasma nitric oxide, elevated blood pressure, increased vascular response to phenylephrine and decreased vascular responses to acetylcholine and sodium nitroprusside. PCA significantly decreased blood glucose and oxidative stress, and increased plasma nitric oxide in diabetic rats. Interestingly, PCA treatment restored blood pressure and vascular reactivity, and antioxidant enzyme activity diabetic rats. This study provides the first evidence of the efficacy of PCA in restoring the vascular reactivity of diabetic rats. The mechanism of action may be associated with an alleviation of oxidative stress. PMID- 26575212 TI - Activation of the motor cortex during phasic rapid eye movement sleep. AB - When dreaming during rapid eye movement (REM) sleep, we can perform complex motor behaviors while remaining motionless. How the motor cortex behaves during this state remains unknown. Here, using intracerebral electrodes sampling the human motor cortex in pharmacoresistant epileptic patients, we report a pattern of electroencephalographic activation during REM sleep similar to that observed during the performance of a voluntary movement during wakefulness. This pattern is present during phasic REM sleep but not during tonic REM sleep, the latter resembling relaxed wakefulness. This finding may help clarify certain phenomenological aspects observed in REM sleep behavior disorder. PMID- 26575213 TI - Facile in Situ Synthesis of Silver Nanoparticles on the Surface of Metal-Organic Framework for Ultrasensitive Surface-Enhanced Raman Scattering Detection of Dopamine. AB - Surface-enhanced Raman scattering (SERS) signals are intensively dominated by the Raman hot spots and distance between analyte molecules and metallic nanostructures. Herein, an efficient SERS substrate was developed by in situ synthesis of silver nanoparticles (AgNPs) on the surface of MIL-101 (Fe), a typical metal-organic framework (MOF). The as-prepared SERS substrate combines the numerous Raman hot spots between the high-density Ag NPs and the excellent adsorption performance of MOFs, making it an excellent SERS substrate for highly sensitive SERS detection by effectively concentrating analytes in close proximity to the Raman hot spots domains between the adjacent AgNPs. The resulting hybrid material was used for ultrasensitive SERS detection of dopamine based on the peroxidase-like activity of MIL-101 (Fe) by utilizing the enzyme-linked immunosorbent assay (ELISA) colorimetric substrate, 2,2'-azino-bis(3 ethylbenzthiazoline-6-sulfonic acid) diammonium salt (ABTS) as a SERS marker. This new developed method showed good linearity in the range from 1.054 pM to 210.8 nM for dopamine with the correlation coefficient of 0.992, detection limit of approximately 0.32 pM [signal-to-noise ratio (S/N) = 3], and acceptable recoveries ranging from 99.8% to 108.0% in human urine. These results predict that the proposed SERS system may open up a new opportunity for chemical and biological assay applications. PMID- 26575214 TI - Effect of Polymer Side Chains on Charge Generation and Disorder in PBDTTPD Solar Cells. AB - The effect of polymer side chains on device performance was investigated for PBDT(EtHex)-TPD(Oct):PC70BM and PBDT(EtHex)-TPD(EtHex):PC70BM BHJ solar cells. Going from a linear side chain on the polymer's acceptor moiety to a branched side chain was determined to have a negative impact on the overall device efficiency, because of significantly reduced short-circuit current (J(sc)) and fill factor (FF) values. Sub-bandgap external quantum efficiency (EQE) and transient photoluminescence (PL) measurements showed more-efficient carrier generation for the polymer with linear side chains, because of a higher degree of charge-transfer (CT) state delocalization, leading to more-efficient exciton dissociation. Furthermore, the increase in pi-pi stacking distance and disorder for the bulkier ethylhexyl side chain were shown to result in a lower hole mobility, a higher bimolecular recombination, and a higher energetic disorder. The use of linear side chains on the polymer's acceptor moiety was shown to promote photogeneration, because of more-effective CT states and favorable carrier transport resulting in improved solar cell performance. PMID- 26575215 TI - Chemical Constituents from the Fruiting Bodies of Hexagonia apiaria and Their Anti-inflammatory Activity. AB - A chemical investigation of the fruiting bodies of Hexagonia apiaria resulted in the identification of nine compounds including five new triterpenoids, hexagonins A-E (1-5), along with four known compounds. The purified constituents were examined for their anti-inflammatory activity. Among the tested compounds, hexatenuin A displayed the most significant inhibition of superoxide anion generation and elastase release. These triterpenoids may have potentials as anti inflammatory agents. PMID- 26575216 TI - Spatial and Temporal Patterns in Black Carbon Deposition to Dated Fennoscandian Arctic Lake Sediments from 1830 to 2010. AB - Black carbon (BC) is fine particulate matter produced by the incomplete combustion of biomass and fossil fuels. It has a strong climate warming effect that is amplified in the Arctic. Long-term trends of BC play an important role in assessing the climatic effects of BC and in model validation. However, few historical BC records exist from high latitudes. We present five lake-sediment soot-BC (SBC) records from the Fennoscandian Arctic and compare them with records of spheroidal carbonaceous fly-ash particles (SCPs), another BC component, for ca. the last 120 years. The records show spatial and temporal variation in SBC fluxes. Two northernmost lakes indicate declining values from 1960 to the present, which is consistent with modeled BC deposition and atmospheric measurements in the area. However, two lakes located closer to the Kola Peninsula (Russia) have recorded increasing SBC fluxes from 1970 to the present, which is likely caused by regional industrial emissions. The increasing trend is in agreement with a Svalbard ice-core-BC record. The results suggest that BC deposition in parts of the European Arctic may have increased over the last few decades, and further studies are needed to clarify the spatial extent of the increasing BC values and to ascertain the climatic implications. PMID- 26575217 TI - Automating X-ray Fluorescence Analysis for Rapid Astrobiology Surveys. AB - A new generation of planetary rover instruments, such as PIXL (Planetary Instrument for X-ray Lithochemistry) and SHERLOC (Scanning Habitable Environments with Raman Luminescence for Organics and Chemicals) selected for the Mars 2020 mission rover payload, aim to map mineralogical and elemental composition in situ at microscopic scales. These instruments will produce large spectral cubes with thousands of channels acquired over thousands of spatial locations, a large potential science yield limited mainly by the time required to acquire a measurement after placement. A secondary bottleneck also faces mission planners after downlink; analysts must interpret the complex data products quickly to inform tactical planning for the next command cycle. This study demonstrates operational approaches to overcome these bottlenecks by specialized early-stage science data processing. Onboard, simple real-time systems can perform a basic compositional assessment, recognizing specific features of interest and optimizing sensor integration time to characterize anomalies. On the ground, statistically motivated visualization can make raw uncalibrated data products more interpretable for tactical decision making. Techniques such as manifold dimensionality reduction can help operators comprehend large databases at a glance, identifying trends and anomalies in data. These onboard and ground-side analyses can complement a quantitative interpretation. We evaluate system performance for the case study of PIXL, an X-ray fluorescence spectrometer. Experiments on three representative samples demonstrate improved methods for onboard and ground-side automation and illustrate new astrobiological science capabilities unavailable in previous planetary instruments. KEY WORDS: Dimensionality reduction-Planetary science-Visualization. PMID- 26575219 TI - Formation of a Bridging Phosphinidene Thorium Complex. AB - The synthesis and structural determination of the first thorium phosphinidene complex are reported. The reaction of 2 equiv of (C5Me5)2Th(CH3)2 with H2P(2,4,6 (i)Pr3C6H2) at 95 degrees C produces [(C5Me5)2Th]2(MU2-P[(2,6-CH2CHCH3)2-4 (i)PrC6H2] as well as 4 equiv of methane, 2 equiv from deprotonation of the phosphine and 2 equiv from C-H bond activation of one methyl group of each of the isopropyl groups at the 2- and 6-positions. Transition state calculations indicate that the steps in the mechanism are P-H, C-H, C-H, and then P-H bond activation to form the phosphinidene. PMID- 26575218 TI - Biosignatures on Mars: What, Where, and How? Implications for the Search for Martian Life. AB - The search for traces of life is one of the principal objectives of Mars exploration. Central to this objective is the concept of habitability, the set of conditions that allows the appearance of life and successful establishment of microorganisms in any one location. While environmental conditions may have been conducive to the appearance of life early in martian history, habitable conditions were always heterogeneous on a spatial scale and in a geological time frame. This "punctuated" scenario of habitability would have had important consequences for the evolution of martian life, as well as for the presence and preservation of traces of life at a specific landing site. We hypothesize that, given the lack of long-term, continuous habitability, if martian life developed, it was (and may still be) chemotrophic and anaerobic. Obtaining nutrition from the same kinds of sources as early terrestrial chemotrophic life and living in the same kinds of environments, the fossilized traces of the latter serve as useful proxies for understanding the potential distribution of martian chemotrophs and their fossilized traces. Thus, comparison with analog, anaerobic, volcanic terrestrial environments (Early Archean >3.5-3.33 Ga) shows that the fossil remains of chemotrophs in such environments were common, although sparsely distributed, except in the vicinity of hydrothermal activity where nutrients were readily available. Moreover, the traces of these kinds of microorganisms can be well preserved, provided that they are rapidly mineralized and that the sediments in which they occur are rapidly cemented. We evaluate the biogenicity of these signatures by comparing them to possible abiotic features. Finally, we discuss the implications of different scenarios for life on Mars for detection by in situ exploration, ranging from its non-appearance, through preserved traces of life, to the presence of living microorganisms. KEY WORDS: Mars-Early Earth-Anaerobic chemotrophs-Biosignatures-Astrobiology missions to Mars. PMID- 26575220 TI - Deciphering H3K4me3 broad domains associated with gene-regulatory networks and conserved epigenomic landscapes in the human brain. AB - Regulators of the histone H3-trimethyl lysine-4 (H3K4me3) mark are significantly associated with the genetic risk architecture of common neurodevelopmental disease, including schizophrenia and autism. Typical H3K4me3 is primarily localized in the form of sharp peaks, extending in neuronal chromatin on average only across 500-1500 base pairs mostly in close proximity to annotated transcription start sites. Here, through integrative computational analysis of epigenomic and transcriptomic data based on next-generation sequencing, we investigated H3K4me3 landscapes of sorted neuronal and non-neuronal nuclei in human postmortem, non-human primate and mouse prefrontal cortex (PFC), and blood. To explore whether H3K4me3 peak signals could also extend across much broader domains, we examined broadest domain cell-type-specific H3K4me3 peaks in an unbiased manner with an innovative approach on 41+12 ChIP-seq and RNA-seq data sets. In PFC neurons, broadest H3K4me3 distribution ranged from 3.9 to 12 kb, with extremely broad peaks (~10 kb or broader) related to synaptic function and GABAergic signaling (DLX1, ELFN1, GAD1, IGSF9B and LINC00966). Broadest neuronal peaks showed distinct motif signatures and were centrally positioned in prefrontal gene-regulatory Bayesian networks and sensitive to defective neurodevelopment. Approximately 120 of the broadest H3K4me3 peaks in human PFC neurons, including many genes related to glutamatergic and dopaminergic signaling, were fully conserved in chimpanzee, macaque and mouse cortical neurons. Exploration of spread and breadth of lysine methylation markings could provide novel insights into epigenetic mechanism involved in neuropsychiatric disease and neuronal genome evolution. PMID- 26575221 TI - Brain-specific epigenetic markers of schizophrenia. AB - Epigenetics plays a crucial role in schizophrenia susceptibility. In a previous study, we identified over 4500 differentially methylated sites in prefrontal cortex (PFC) samples from schizophrenia patients. We believe this was the first genome-wide methylation study performed on human brain tissue using the Illumina Infinium HumanMethylation450 Bead Chip. To understand the biological significance of these results, we sought to identify a smaller number of differentially methylated regions (DMRs) of more functional relevance compared with individual differentially methylated sites. Since our schizophrenia whole genome methylation study was performed, another study analysing two separate data sets of post mortem tissue in the PFC from schizophrenia patients has been published. We analysed all three data sets using the bumphunter function found in the Bioconductor package minfi to identify regions that are consistently differentially methylated across distinct cohorts. We identified seven regions that are consistently differentially methylated in schizophrenia, despite considerable heterogeneity in the methylation profiles of patients with schizophrenia. The regions were near CERS3, DPPA5, PRDM9, DDX43, REC8, LY6G5C and a region on chromosome 10. Of particular interest is PRDM9 which encodes a histone methyltransferase that is essential for meiotic recombination and is known to tag genes for epigenetic transcriptional activation. These seven DMRs are likely to be key epigenetic factors in the aetiology of schizophrenia and normal brain neurodevelopment. PMID- 26575222 TI - Impulsive alcohol-related risk-behavior and emotional dysregulation among individuals with a serotonin 2B receptor stop codon. AB - A relatively common stop codon (Q20*) was identified in the serotonin 2B receptor gene (HTR2B) in a Finnish founder population in 2010 and it was associated with impulsivity. Here we examine the phenotype of HTR2B Q20* carriers in a setting comprising 14 heterozygous HTR2B Q20* carriers and 156 healthy controls without the HTR2B Q20*. The tridimensional personality questionnaire, Brown-Goodwin lifetime aggression scale, the Michigan alcoholism screening test and lifetime drinking history were used to measure personality traits, impulsive and aggressive behavior, both while sober and under the influence of alcohol, and alcohol consumption. Regression analyses showed that among the HTR2B Q20* carriers, temperamental traits resembled a passive-dependent personality profile, and the presence of the HTR2B Q20* predicted impulsive and aggressive behaviors particularly under the influence of alcohol. Results present examples of how one gene may contribute to personality structure and behaviors in a founder population and how personality may translate into behavior. PMID- 26575223 TI - Chronic corticosterone-mediated dysregulation of microRNA network in prefrontal cortex of rats: relevance to depression pathophysiology. AB - Stress plays a major role in inducing depression, which may arise from interplay between complex cascades of molecular and cellular events that influence gene expression leading to altered connectivity and neural plasticity. In recent years, microRNAs (miRNAs) have carved their own niche owing to their innate ability to induce disease phenotype by regulating expression of a large number of genes in a cohesive and coordinated manner. In this study, we examined whether miRNAs and associated gene networks have a role in chronic corticosterone (CORT; 50 mg kg(-1) * 21 days)-mediated depression in rats. Rats given chronic CORT showed key behavioral features that resembled depression phenotype. Expression analysis revealed differential regulation of 26 miRNAs (19 upregulated, 7 downregulated) in prefrontal cortex of CORT-treated rats. Interaction between altered miRNAs and target genes showed dense interconnected molecular network, in which multiple genes were predicated to be targeted by the same miRNA. A majority of altered miRNAs showed binding sites for glucocorticoid receptor element, suggesting that there may be a common regulatory mechanism of miRNA regulation by CORT. Functional clustering of predicated target genes yielded disorders such as developmental, inflammatory and psychological that could be relevant to depression. Prediction analysis of the two most prominently affected miRNAs miR 124 and miR-218 resulted into target genes that have been shown to be associated with depression and stress-related disorders. Altogether, our study suggests miRNA-mediated novel mechanism by which chronic CORT may be involved in depression pathophysiology. PMID- 26575225 TI - Future perfect. PMID- 26575224 TI - Subthreshold depression is associated with impaired resting-state functional connectivity of the cognitive control network. AB - Subthreshold depression (StD) is a prevalent condition associated with social morbidity and increased service utilization, as well as a high risk of developing into a major depressive disorder (MDD). The lack of well-defined diagnostic criteria for StD has limited research on this disorder, with very few brain imaging studies examining the neurobiology of StD. Yet, identifying the neural pathology of StD has the potential to elucidate risk factors and prognostic markers for major depression and is crucial for developing tailored treatments for patients at mild stages of depression. We investigated resting-state functional connectivity (rs-FC) of the cognitive control network (CCN), known to be dysregulated in MDD, using the bilateral dorsolateral prefrontal cortex (DLPFC) as a seed, focusing on two cohorts of StD subjects (young and middle aged) as well as matched controls. Irrespective of age, we found a significant rs FC decrease in the CCN of the StD subjects, compared with matched controls, particularly between the DLPFC and the brain regions associated with the representation of self and other mental states (temporo-parietal junction (TPJ) and precuneus), as well as salience detection and orienting (insula). The functional connectivity between the DLPFC and the left TPJ was also associated with depressive symptom scores measured by the Center for Epidemiologic Studies Depression Scale. This finding may shed light on the neural pathology of StD, leading to better understanding of mild stages of depression, its diagnosis and the development of new treatments. PMID- 26575226 TI - Targeting transcription is no longer a quixotic quest. PMID- 26575227 TI - XFELs open a new era in structural chemical biology. PMID- 26575228 TI - Voices of chemical biology. PMID- 26575235 TI - Virology: MicroRNA-lipid one-upmanship. PMID- 26575236 TI - RNA folding: A clear path to RNA catalysis. PMID- 26575237 TI - Discovery and characterization of smORF-encoded bioactive polypeptides. AB - Analysis of genomes, transcriptomes and proteomes reveals the existence of hundreds to thousands of translated, yet non-annotated, short open reading frames (small ORFs or smORFs). The discovery of smORFs and their protein products, smORF encoded polypeptides (SEPs), points to a fundamental gap in our knowledge of protein-coding genes. Various studies have identified central roles for smORFs in metabolism, apoptosis and development. The discovery of these bioactive SEPs emphasizes the functional potential of this unexplored class of biomolecules. Here, we provide an overview of this emerging field and highlight the opportunities for chemical biology to answer fundamental questions about these novel genes. Such studies will provide new insights into the protein-coding potential of genomes and identify functional genes with roles in biology and disease. PMID- 26575238 TI - Imaging and manipulating proteins in live cells through covalent labeling. AB - The past 20 years have witnessed the advent of numerous technologies to specifically and covalently label proteins in cellulo and in vivo with synthetic probes. These technologies range from self-labeling proteins tags to non-natural amino acids, and the question is no longer how we can specifically label a given protein but rather with what additional functionality we wish to equip it. In addition, progress in fields such as super-resolution microscopy and genome editing have either provided additional motivation to label proteins with advanced synthetic probes or removed some of the difficulties of conducting such experiments. By focusing on two particular applications, live-cell imaging and the generation of reversible protein switches, we outline the opportunities and challenges of the field and how the synergy between synthetic chemistry and protein engineering will make it possible to conduct experiments that are not feasible with conventional approaches. PMID- 26575239 TI - Chemical modulators of ribosome biogenesis as biological probes. AB - Small-molecule inhibitors of protein biosynthesis have been instrumental in the dissection of the complexities of ribosome structure and function. Ribosome biogenesis, on the other hand, is a complex and largely enigmatic process for which there is a paucity of chemical probes. Indeed, ribosome biogenesis has been studied almost exclusively using genetic and biochemical approaches without the benefit of small-molecule inhibitors of this process. Here, we provide a perspective on the promise of chemical inhibitors of ribosome assembly for future research. We explore key obstacles that complicate the interpretation of studies aimed at perturbing ribosome biogenesis in vivo using genetic methods, and we argue that chemical inhibitors are especially powerful because they can be used to induce perturbations in a manner that obviates these difficulties. Thus, in combination with leading-edge biochemical and structural methods, chemical probes offer unique advantages toward elucidating the molecular events that define the assembly of ribosomes. PMID- 26575240 TI - Progress and challenges for chemical probing of RNA structure inside living cells. AB - Proper gene expression is essential for the survival of every cell. Once thought to be a passive transporter of genetic information, RNA has recently emerged as a key player in nearly every pathway in the cell. A full description of its structure is critical to understanding RNA function. Decades of research have focused on utilizing chemical tools to interrogate the structures of RNAs, with recent focus shifting to performing experiments inside living cells. This Review will detail the design and utility of chemical reagents used in RNA structure probing. We also outline how these reagents have been used to gain a deeper understanding of RNA structure in vivo. We review the recent merger of chemical probing with deep sequencing. Finally, we outline some of the hurdles that remain in fully characterizing the structure of RNA inside living cells, and how chemical biology can uniquely tackle such challenges. PMID- 26575242 TI - Hydrogen-Bond Directed Regioselective Pd-Catalyzed Asymmetric Allylic Alkylation: The Construction of Chiral alpha-Amino Acids with Vicinal Tertiary and Quaternary Stereocenters. AB - A Pd-catalyzed asymmetric allylic alkylation of azlactones with 4-arylvinyl-1,3 dioxolan-2-ones was developed, providing "branched" chiral alpha-amino acids with vicinal tertiary and quaternary stereocenters, in high yields and with excellent selectivities. Mechanistic studies revealed that the formation of a hydrogen bond between the Pd-allylic complex and azlactone isomer is responsible for the excellent regioselectivities. This asymmetric alkylation can be carried out on a gram scale without a loss of catalytic efficiency, and the resulting product can be further transformed to a chiral azetidine in two simple steps. PMID- 26575241 TI - Functional genomics to uncover drug mechanism of action. AB - The upswing in US Food and Drug Administration and European Medicines Agency drug approvals in 2014 may have marked an end to the dry spell that has troubled the pharmaceutical industry over the past decade. Regardless, the attrition rate of drugs in late clinical phases remains high, and a lack of target validation has been highlighted as an explanation. This has led to a resurgence in appreciation of phenotypic drug screens, as these may be more likely to yield compounds with relevant modes of action. However, cell-based screening approaches do not directly reveal cellular targets, and hence target deconvolution and a detailed understanding of drug action are needed for efficient lead optimization and biomarker development. Here, recently developed functional genomics technologies that address this need are reviewed. The approaches pioneered in model organisms, particularly in yeast, and more recently adapted to mammalian systems are discussed. Finally, areas of particular interest and directions for future tool development are highlighted. PMID- 26575243 TI - Proteomic and Lipidomic Analysis of Nanoparticle Corona upon Contact with Lung Surfactant Reveals Differences in Protein, but Not Lipid Composition. AB - Pulmonary surfactant (PS) constitutes the first line of host defense in the deep lung. Because of its high content of phospholipids and surfactant specific proteins, the interaction of inhaled nanoparticles (NPs) with the pulmonary surfactant layer is likely to form a corona that is different to the one formed in plasma. Here we present a detailed lipidomic and proteomic analysis of NP corona formation using native porcine surfactant as a model. We analyzed the adsorbed biomolecules in the corona of three NP with different surface properties (PEG-, PLGA-, and Lipid-NP) after incubation with native porcine surfactant. Using label-free shotgun analysis for protein and LC-MS for lipid analysis, we quantitatively determined the corona composition. Our results show a conserved lipid composition in the coronas of all investigated NPs regardless of their surface properties, with only hydrophilic PEG-NPs adsorbing fewer lipids in total. In contrast, the analyzed NP displayed a marked difference in the protein corona, consisting of up to 417 different proteins. Among the proteins showing significant differences between the NP coronas, there was a striking prevalence of molecules with a notoriously high lipid and surface binding, such as, e.g., SP A, SP-D, DMBT1. Our data indicate that the selective adsorption of proteins mediates the relatively similar lipid pattern in the coronas of different NPs. On the basis of our lipidomic and proteomic analysis, we provide a detailed set of quantitative data on the composition of the surfactant corona formed upon NP inhalation, which is unique and markedly different to the plasma corona. PMID- 26575244 TI - Integration of Light Trapping Silver Nanostructures in Hydrogenated Microcrystalline Silicon Solar Cells by Transfer Printing. AB - One of the potential applications of metal nanostructures is light trapping in solar cells, where unique optical properties of nanosized metals, commonly known as plasmonic effects, play an important role. Research in this field has, however, been impeded owing to the difficulty of fabricating devices containing the desired functional metal nanostructures. In order to provide a viable strategy to this issue, we herein show a transfer printing-based approach that allows the quick and low-cost integration of designed metal nanostructures with a variety of device architectures, including solar cells. Nanopillar poly(dimethylsiloxane) (PDMS) stamps were fabricated from a commercially available nanohole plastic film as a master mold. On this nanopatterned PDMS stamps, Ag films were deposited, which were then transfer-printed onto block copolymer (binding layer)-coated hydrogenated microcrystalline Si (uc-Si:H) surface to afford ordered Ag nanodisk structures. It was confirmed that the resulting Ag nanodisk-incorporated uc-Si:H solar cells show higher performances compared to a cell without the transfer-printed Ag nanodisks, thanks to plasmonic light trapping effect derived from the Ag nanodisks. Because of the simplicity and versatility, further device application would also be feasible thorough this approach. PMID- 26575245 TI - Concurrent Percutaneous Transhepatic Papillary Balloon Dilatation Combined with Laparoscopic Cholecystectomy for the Treatment of Gallstones with Common Bile Duct Stones. AB - OBJECTIVE: To evaluate the clinical effectiveness and safety of percutaneous transhepatic papillary balloon dilatation (PPBD) combined with laparoscopic cholecystectomy (LC) for the treatment of gallstones with common bile duct stones. MATERIALS AND METHODS: From February 2012 to January 2013, 65 patients (31 males and 34 females) who had gallstones with common bile duct stones were divided into two groups: endoscopic papillary balloon dilatation (EPBD)+LC (n = 40 cases) and PPBD+LC (n = 25 cases). The maximum transverse diameter of common bile duct stoned was 15 mm. White blood cell count and serum amylase level were measured at 12 hours and 72 hours after the operation, and operation time, time of gastrointestinal function recovery, and hospitalization time were analyzed. RESULTS: No case in either group was converted to open surgery. The stones were successfully pushed out into the duodenum in all patients of both groups. One case of postoperative pancreatitis (2.5%) and 5 cases of hyperamylasemia (12.5%) occurred among the 40 patients in the EPBD+LC group. In contrast, no case of postoperative pancreatitis and 2 cases of hyperamylasemia (8%) occurred among the 25 patients in the PPBD+LC group. The serum amylase level at 12 hours postoperatively was statistically significantly different (307 +/- 39.94 IU/L in the EPBD+LC group and 193 +/- 30.78 IU/L in the PPBD+LC group; P < .05). There were no significant differences between the two groups in operative time, postoperative gastrointestinal function recovery time, or hospital stay time (P > .05). During follow-up of 2 years, 1 case of recurrence for common bile duct stones was discovered and was treated successfully with EPBD repeatedly. CONCLUSIONS: PPBD combined with LC simultaneously is an alternative effective and safe procedure for the treatment of gallstones and bile duct stones, especially for those patients who are unsuitable for endoscopic treatment. PMID- 26575246 TI - Minimally Invasive Endoscopic Surgery of Thyroglossal Duct Cysts. AB - PURPOSE: Thyroglossal duct cysts (TGDCs) may cause cosmetic defects or more serious impairments if left untreated. Our study was designed to examine the potential advantage of endoscopic surgery performed on TGDCs, especially the ability to completely resect the branches and to affect the cosmetic appearance. PATIENTS AND METHODS: Thirty-two patients from Beijing Tongren Hospital, Beijing, China, diagnosed with TGDCs were selected. Seventeen patients with TGDCs underwent traditional Sistrunk's surgery, and 15 patients underwent endoscopic cystectomy. RESULTS: All patients had complete resection and were followed up from 6 months to 4 years. None had a recurrence after endoscopic resection. However, patients in the traditional surgery group had a 5.9% (1/17) rate of recurrence. The incision length was approximately 2.1 cm in the endoscopic group compared with 5.2 cm in the traditional group. The mean time for the endoscopic operation was 97.7 minutes compared with 51.6 minutes in the traditional surgical procedure. The average length of hospital stay was 6.7 days in the endoscopic group compared with 9.7 days in the traditional group. CONCLUSIONS: Endoscope assisted small-incision thyroglossal duct cystectomy is an efficient method. It causes fewer cosmetic defects and also decreases operative time. It will likely become the new standard procedure for patients with TGDCs. PMID- 26575247 TI - Are There Specific Indications for Laparoscopic Appendectomy? A Review and Critical Appraisal of the Literature. AB - INTRODUCTION: Laparoscopic appendectomy (LA) has proven to be a feasible alternative to open appendectomy (OA). However, as some of the purported advantages of LA (versus OA) are marginal, evidence is accumulating that appendectomy may not be necessary for uncomplicated appendicitis and there is concern about using laparoscopy for all patients with suspected acute appendicitis. In spite of widespread popularity and use, the literature reporting the indications is sparse and sometimes misleading (i.e., containing distorted deductions or conclusions, also called "spin"). This study aimed to determine subsets of patients for whom LA may present real advantages over OA and to analyze the validity of specific indications for LA (instead of OA). MATERIALS AND METHODS: A systematic review and critical analysis of the literature were conducted. RESULTS: We analyzed 90 retrospective reviews, prospective studies, meta-analyses, and cohort and prospective randomized studies, presenting a total of approximately 390,000 patients, concerning potentially specific advantages of LA in the elderly, the obese, during pregnancy, and complicated appendicitis, including diffuse peritonitis and ectopic appendices. Overall, LA was associated with (1) lower overall complication rates (and notably less decompensated comorbidities), mortality, and costs, as well as shorter duration of hospital stay, in the elderly, (2) decreased morbidity (notably parietal) in the obese, and (3) potential (diagnostic) advantages in pregnancy (even though LA is associated with a higher rate of fetal loss than in OA). In complicated or ectopic appendicitis, LA is feasible and safe and, if performed without conversion, should lead to less short- and long-term parietal morbidity. However, published data are very heterogeneous, there are few sound controlled trials, and conclusions found in the literature are often based on misleading deductions or a very low level of evidence. CONCLUSIONS: LA is a safe and effective method to treat acute appendicitis in specific settings such as the elderly and the obese, as well as in ectopic appendices, with potentially specific parietal advantages in these subsets of patients. Further randomized studies and robust meta-analyses are necessary before recommending LA for complicated appendicitis and peritonitis, as well as in pregnancy. PMID- 26575248 TI - Effect of Retroperitoneal Lavage with Normal Saline Containing Adrenaline on Carbon Dioxide Absorption in Patients Undergoing Retroperitoneal Laparoscopic Surgery. AB - OBJECTIVE: To determine the effect of lavage with adrenaline solution on CO2 absorption during retroperitoneal laparoscopic surgery. MATERIALS AND METHODS: Sixty patients scheduled to undergo retroperitoneal laparoscopic surgery were divided into an AD group (lavage with normal saline containing adrenaline [1:500,000], n = 30) and an NS group (lavage with normal saline only, n = 30). After the establishment of artificial pneumoperitoneum and before the start of the operation, the retroperitoneal space was irrigated with 300 mL of normal saline with or without adrenaline, depending on the group. The lavage fluid was aspirated after 3 minutes. Heart rate (HR), mean arterial pressure (MAP), blood oxygen saturation (SpO2), partial pressure of O2 (PaO2), partial pressure of CO2 (PaCO2), and end-tidal CO2 partial pressure (PETCO2) were recorded before the lavage (T0) and at 10, 30, 60, 90, and 120 minutes (T1-T5, respectively) after the lavage. The CO2 output (VCO2) was calculated, and the incidence of intraoperative arrhythmia and postoperative complications (e.g., headache, palpitations, irritation) was determined. RESULTS: HR, MAP, SpO2, PaO2, PaCO2, PETCO2, and VCO2 at T0 did not significantly differ between the groups (P > .05). HR, PaCO2, PETCO2, and VCO2 at T1-T5 were lower in the AD group than in the NS group (P < .05). The incidence of intraoperative arrhythmia and postoperative complications was lower in the AD group than in the NS group (P < .05). CONCLUSIONS: Lavage with normal saline containing adrenaline (1:500,000) reduced CO2 absorption during retroperitoneal laparoscopic surgery, prevented hypercapnia, and decreased intra- and postoperative complications. PMID- 26575249 TI - The Efficacy of Intraoperative Neuromonitoring During Robotic Thyroidectomy: A Prospective, Randomized Case-Control Evaluation. AB - BACKGROUND: This study evaluates the efficacy of intraoperative neuromonitoring (IONM) on voice performance in robotic thyroidectomy. MATERIALS AND METHODS: The study was based on a prospective randomized series. Between June 2011 to September 2012, 50 patients with thyroid cancer who underwent robotic thyroidectomy were enrolled. The IONM and non-IONM groups consisted of 25 patients each. Voice Handicap Index (VHI), voice range profile (VRP), and laryngoscopy were used to assess voice function before surgery and at 2 weeks, 3 months, and 6 months after the operation. RESULTS: No palsy was diagnosed by laryngoscopy in either group. VHI values were similar in both groups. In the IONM group, there was significantly earlier recovery in VRP minimum intensity compared with the non-IONM group. However, there were no differences of mean change of VRP maximum frequency and intensity or minimum frequency between the two groups. CONCLUSIONS: We found that IONM facilitated more rapid recovery of voice function, especially in VRP minimum intensity, during robotic thyroid surgery. PMID- 26575250 TI - Effect of canagliflozin on liver function tests in patients with type 2 diabetes. AB - AIMS: To report changes in liver function tests observed with canagliflozin, a sodium glucose co-transporter 2 inhibitor, across phase 3 studies in patients with type 2 diabetes, and to examine the relationship between changes in liver function tests and the weight loss and glycaemic improvements observed with canagliflozin. METHODS: Data were pooled from four 26-week, placebo-controlled studies of canagliflozin 100 and 300mg (n=2313) and two 52-week, active controlled studies of canagliflozin 300mg versus sitagliptin 100mg (n=1488). Analysis of covariance was performed to determine the contribution of changes in body weight and HbA1c to the changes in liver function tests. RESULTS: Reductions in alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and gamma-glutamyl transferase, and increases in bilirubin were seen with canagliflozin 100 and 300mg versus placebo (nominal P<0.001 for alanine aminotransferase, aspartate aminotransferase and gamma-glutamyl transferase [both doses]; P<0.001 for alkaline phosphatase and P=0.015 for bilirubin [canagliflozin 300mg only]) at week 26 and with canagliflozin 300mg versus sitagliptin 100mg (nominal P<0.001 for alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase and bilirubin, and P<0.01 for alkaline phosphatase) at week 52. Few patients met predefined limits of change criteria for liver function tests, and none met Hy's law criteria. In both populations, alanine aminotransferase, aspartate aminotransferase and gamma-glutamyl transferase reductions were fully explained by HbA1c and body weight reductions. CONCLUSIONS: Canagliflozin provided improvements in liver function tests versus either placebo or sitagliptin treatments that were fully explained by the combined effects of HbA1c and body weight reductions with canagliflozin. PMID- 26575251 TI - Teaching Surgery Residents the Skills to Communicate Difficult News to Patient and Family Members: A Literature Review. AB - BACKGROUND: Trainees and practicing physicians alike find breaking bad, sad, or difficult news to a patient or family member as one of the most challenging communication tasks they perform. Interpersonal and communication skills are a core competency for resident training. However, in disciplines where technical skills have a major emphasis, such as surgery, the teaching of communication skills may not be a priority. OBJECTIVE: The objective of our study is to review literature in order to identify best practices and learning modalities used to teach surgery trainees the communication skills regarding delivery of difficult news to patients and family members. METHODS: The criteria for inclusion in this literature review were that the study (1) addresses surgeons' training (nontechnical skills) in breaking difficult news to patient and/or families, (2) describes a teaching modality or intervention targeted to teach surgery residents how to deliver difficult news to patient/family, and (3) is published in English. RESULTS: Articles (n = 225) were screened for final eligibility. After discarding duplicates and noneligible studies, and after abstract/full-text review, 18 articles were included in the final analysis. Most studies are single site; address general surgery residents at varying training levels; and include case specific, outpatient, and intensive care unit (ICU) settings. There is a paucity of studies in the trauma and unexpected death setting. There is a recent trend to use Objective Structured Clinical Examination (OSCE) both to teach and assess communication skills. Variable tools are used to assess this competency as described. CONCLUSION: Simulation and OSCE format have emerged as modalities of choice both to teach surgery residents how to deliver difficult news and to assess achievement of this competency. There is a gap in the literature regarding teaching and assessing surgery resident communication skills in delivering difficult news after unexpected events in the trauma and operating room settings. PMID- 26575252 TI - Functional Analysis of an (A)gamma-Globin Gene Promoter Variant (HBG1: g.-225_ 222delAGCA) Underlines Its Role in Increasing Fetal Hemoglobin Levels Under Erythropoietic Stress. AB - Hereditary persistence of fetal hemoglobin (HPFH) is a condition characterized by persistent gamma-globin gene expression and synthesis of high levels of fetal hemoglobin (Hb F; alpha2gamma2) during adult life. It is usually caused by promoter variants or large deletions affecting the human fetal globin (HBG1 and HBG2) genes. Some of these HPFH-causing variants, such as HBG2: g.-158 C > T, exert their effect only under conditions of erythropoietic stress, typical for beta-thalassemia (beta-thal) patients. Namely, the presence of HBG2: g.-158 C > T favors a higher Hb F response, while it has little effect in healthy individuals. We analyzed a previously reported deletion residing in the promoter region of the HBG1 gene (HBG1: g.-225_-222delAGCA), both in normal conditions and under conditions of erythropoietic stress. Our results indicate that this deletion is responsible for decreased HBG1 gene expression. Specifically, this deletion was shown to result in drastically reduced reporter gene expression in K562 cells, compared to the wild-type sequence but only under conditions of erythropoietic stress, mimicked by introduction of erythropoietin (EPO) into the cell culture. Also, electrophoretic mobility shift analysis showed that the HBG1: g.-225_ 222delAGCA deletion creates additional transcriptional factors' binding sites, which, we propose, bind a transcriptional repressor, thus decreasing the HBG1 gene promoter activity. These results are consistent with in silico analysis, which indicated that this deletion creates a binding site for GATA1, known to be a repressor of the gamma-globin gene expression. These data confirm the regulatory role of the HBG1: g.-225_-222 region that exerts its effect under conditions of erythropoietic stress characteristic for beta-thal patients. PMID- 26575253 TI - Interleukin-1beta plasma levels are associated with depression in temporal lobe epilepsy. AB - Inflammatory mediators such as cytokines are likely to contribute to the pathophysiology of epilepsy. Proinflammatory cytokines are also associated with mood disorders, such as major depression. As people with temporal lobe epilepsy (TLE) are at an increased risk of mood disorders, we attempted to evaluate peripheral levels of IL-1beta in people with TLE with depression and people with TLE without depression and in healthy controls. In a cross-sectional study, we compared three groups: 21 people with TLE without depression (TLE D-), 18 people with TLE with depression (TLE D+), and 31 controls without depression. A structured clinical interview (MINI-Plus) was used to diagnose current depression, and the Hamilton Depression Rating Scale (HAM-D) was used to quantify depressive symptoms. Plasma levels of IL-1beta were significantly higher in people with TLE with depression than in controls (p=0.004) or people with TLE without depression (p=0.006). Interleukin-1beta levels positively correlated with HAM-D scores (Spearman's rho=0.381, p=0.017) in people with TLE. Higher levels of IL-1beta in TLE seem to be associated with depression. PMID- 26575254 TI - The beliefs among patients with epilepsy in Saudi Arabia about the causes and treatment of epilepsy and other aspects. AB - PURPOSE: The current survey sought to identify the religious and cultural beliefs about the causes and treatment of epilepsy in people with epilepsy from Saudi Arabia and a number of other aspects relating to the possibility of cure, coping with the condition, and public awareness. METHODS: Study instruments were developed on the basis of the literature, a focus group of people with epilepsy, and feedback from people in the field with local knowledge. These were then piloted. A survey was then carried out among a total of 110 adults with epilepsy. Participants were asked to complete questionnaires inquiring into their beliefs about the causes and range of treatments used for epilepsy. Each participant was allowed to choose more than one cause and more than one treatment method. The questionnaires were administered face to face by a clinical psychologist (HAA) to improve the quality of the responses. RESULTS: We found that most adults with epilepsy in Saudi Arabia believe that epilepsy is a condition with multifactorial causation and for which more than one treatment method should be applied. A test from God was the most commonly ascribed cause (83% as well as 40% who believed that some cases of the illness were a punishment from God). The belief in the concept of God's will helped many in the cohort to accept their illness as part of their destiny. Ninety-six percent of the patients believed that there were also medical causes (such as an illness, brain insult, inflammation, heredity, contagion), and a similar proportion believed that there were also religious causes. Smaller proportions believed epilepsy could be due to cultural (78%) or psychosocial causes (64%). Thirty-four percent of people believed that there could be sometimes no cause, but only 2% thought that epilepsy never had any identifiable cause. Most patients did not believe that one treatment alone would help. Ninety-three percent of patients believed in medical treatment, 93% in religious treatment, and 64% in traditional treatments, and 7% believed in changing lifestyle (eating balanced food and positive thinking). Seventy-eight percent of the sample believed that their epilepsy was a curable illness. Ninety six percent believed that faith and practicing religious rituals helped in coping with epilepsy, and 92% believed that family support helped in coping with epilepsy. Nine percent of patients had stopped their medication for religious reasons or because of a sense of shame, and 7% had at one time been forced by their family to stop their medication. Ninety-two percent of the sample reported having enough family support. Ninety-five percent believed that Saudi society needs more awareness to understand epilepsy. CONCLUSION: In Saudi Arabia, religious and cultural beliefs about the causes and treatment of epilepsy exist alongside medical beliefs. The holding of religious beliefs, the practicing of religious rituals, and the presence of family support were found to be of great importance in coping with epilepsy, and their role needs to be fully appreciated in the medical management of the condition. PMID- 26575255 TI - NEREC, an effective brain mapping protocol for combined language and long-term memory functions. AB - Temporal lobe epilepsy can induce functional plasticity in temporoparietal networks involved in language and long-term memory processing. Previous studies in healthy subjects have revealed the relative difficulty for this network to respond effectively across different experimental designs, as compared to more reactive regions such as frontal lobes. For a protocol to be optimal for clinical use, it has to first show robust effects in a healthy cohort. In this study, we developed a novel experimental paradigm entitled NEREC, which is able to reveal the robust participation of temporoparietal networks in a uniquely combined language and memory task, validated in an fMRI study with healthy subjects. Concretely, NEREC is composed of two runs: (a) an intermixed language-memory task (confrontation naming associated with encoding in nonverbal items, NE) to map language (i.e., word retrieval and lexico-semantic processes) combined with simultaneous long-term verbal memory encoding (NE items named but also explicitly memorized) and (b) a memory retrieval task of items encoded during NE (word recognition, REC) intermixed with new items. Word recognition is based on both perceptual-semantic familiarity (feeling of 'know') and accessing stored memory representations (remembering). In order to maximize the remembering and recruitment of medial temporal lobe structures, we increased REC difficulty by changing the modality of stimulus presentation (from nonverbal during NE to verbal during REC). We report that (a) temporoparietal activation during NE was attributable to both lexico-semantic (language) and memory (episodic encoding and semantic retrieval) processes; that (b) encoding activated the left hippocampus, bilateral fusiform, and bilateral inferior temporal gyri; and that (c) task recognition (recollection) activated the right hippocampus and bilateral but predominant left fusiform gyrus. The novelty of this protocol consists of (a) combining two tasks in one (language and long-term memory encoding/recall) instead of applying isolated tasks to map temporoparietal regions, (b) analyzing NE data based on performances recorded during REC, (c) double-mapping networks involved in naming and in long-term memory encoding and retrieval, (d) focusing on remembering with hippocampal activation and familiarity judgment with lateral temporal cortices activation, and (e) short duration of examination and feasibility. These aspects are of particular interest in patients with TLE, who frequently show impairment of these cognitive functions. Here, we show that the novel protocol is suited for this clinical evaluation. PMID- 26575256 TI - Severity and burden of partial-onset seizures in a phase III trial of eslicarbazepine acetate. AB - OBJECTIVE: The objective of this study was to compare posttreatment seizure severity in a phase III clinical trial of eslicarbazepine acetate (ESL) as adjunctive treatment of refractory partial-onset seizures. METHODS: The Seizure Severity Questionnaire (SSQ) was administered at baseline and posttreatment. The SSQ total score (TS) and component scores (frequency and helpfulness of warning signs before seizures [BS]; severity and bothersomeness of ictal movement and altered consciousness during seizures [DS]; cognitive, emotional, and physical aspects of postictal recovery after seizures [AS]; and overall severity and bothersomeness [SB]) were calculated for the per-protocol population. Analysis of covariance, adjusted for baseline scores, estimated differences in posttreatment least square means between treatment arms. RESULTS: Out of 547 per-protocol patients, 441 had valid SSQ TS both at baseline and posttreatment. Mean posttreatment TS for ESL 1200 mg/day was significantly lower than that for placebo (2.68 vs 3.20, p<0.001), exceeding the minimal clinically important difference (MCID: 0.48). Mean DS, AS, and SB were also significantly lower with ESL 1200 mg/day; differences in AS and SB exceeded the MCIDs. The TS, DS, AS, and SB were lower for ESL 800 mg/day than for placebo; only SB was significant (p=0.013). For both ESL arms combined versus placebo, mean scores differed significantly for TS (p=0.006), DS (p=0.031), and SB (p=0.001). CONCLUSIONS: Therapeutic ESL doses led to clinically meaningful, dose-dependent reductions in seizure severity, as measured by SSQ scores. CLASSIFICATION OF EVIDENCE: This study presents Class I evidence that adjunctive ESL (800 and 1200 mg/day) led to clinically meaningful, dose-dependent seizure severity reductions, measured by the SSQ. PMID- 26575257 TI - Mortality in patients with refractory temporal lobe epilepsy at a tertiary center in Cuba. AB - OBJECTIVES: We aimed to investigate the prevalence and risk of mortality in patients with refractory temporal lobe epilepsy. METHODS: Eligible patients included all adults referred to the National Institute of Neurology (NIN) in Havana, Cuba. All patients were followed up for 9 years. All analyses were made with the data available at the last follow-up. The frequency of death related to refractory TLE was analyzed taking into account the total number of patients included in the study. We analyzed the causes of death for each case. Multivariate analysis was made to determine the specific variables related to the death. All values were statistically significant if p<0.05. RESULTS: Six out of 117 patients died during follow-up. Fifty percent of patients died because of suicide. Only the presence of aura, specifically experiential psychic auras, and prodromal depressive disorders were associated significantly with the deaths (p<0.05). Patients who died had a higher concern about their seizures than patients who were still alive at last follow-up (p<0.01); they also had a poor perception of the overall QOL (p<0.01); and they were more concerned about the possible medication side effects than patients who did not die (p<0.05). Logistic regression provided only one variable related to the deaths in our cohort in multivariate analysis: presence of prodromal depressive disorder. CONCLUSION: The causes of death in patients with refractory temporal lobe epilepsy were similar to those documented in the general population of patients with epilepsy. PMID- 26575260 TI - Enalapril Associated with Furosemide Induced Acute Kidney Injury in an Infant with Heart Failure. A Case Report, a Revision of the Literature and a Pharmacovigilance Database Analysis. AB - The use of angiotensin converting enzyme (ACE) inhibitors in combination with diuretics is a common strategy used for the treatment of patients affected by heart failure. An infant affected by initial congestive cardiac failure, after starting the treatment with enalapril in association with furosemide, developed acute kidney injury (AKI). No underlying renal disease or renal artery stenosis was found. He recovered from kidney injury after the therapy was suspended, thus suggesting that the drug combination is responsible for the onset of the adverse reaction. The present case report, the appraisal of the current knowledge on the onset of AKI and the analysis of available pharmacovigilance databases indicate that particular caution should be exercised when infants affected by heart failure are treated with the enalapril and furosemide combination therapy. Moreover, we strongly suggest an up-to-date revision of the ACE-inhibitor dosing guidelines in pediatric patients to define unambiguously the safe upper limits of this class of drugs. PMID- 26575259 TI - Maternal immune activation induces GAD1 and GAD2 promoter remodeling in the offspring prefrontal cortex. AB - Maternal infection during pregnancy increases the risk of neurodevelopmental disorders in the offspring. In addition to its influence on other neuronal systems, this early-life environmental adversity has been shown to negatively affect cortical gamma-aminobutyric acid (GABA) functions in adult life, including impaired prefrontal expression of enzymes required for GABA synthesis. The underlying molecular processes, however, remain largely unknown. In the present study, we explored whether epigenetic modifications represent a mechanism whereby maternal infection during pregnancy can induce such GABAergic impairments in the offspring. We used an established mouse model of prenatal immune challenge that is based on maternal treatment with the viral mimetic poly(I:C). We found that prenatal immune activation increased prefrontal levels of 5-methylated cytosines (5mC) and 5-hydroxymethylated cytosines (5hmC) in the promoter region of GAD1, which encodes the 67-kDa isoform of the GABA-synthesising enzyme glutamic acid decarboxylase (GAD67). The early-life challenge also increased 5mC levels at the promoter region of GAD2, which encodes the 65-kDa GAD isoform (GAD65). These effects were accompanied by elevated GAD1 and GAD2 promoter binding of methyl CpG binding protein 2 (MeCP2) and by reduced GAD67 and GAD65 mRNA expression. Moreover, the epigenetic modifications at the GAD1 promoter correlated with prenatal infection-induced impairments in working memory and social interaction. Our study thus highlights that hypermethylation of GAD1 and GAD2 promoters may be an important molecular mechanism linking prenatal infection to presynaptic GABAergic impairments and associated behavioral and cognitive abnormalities in the offspring. PMID- 26575261 TI - Abnormal Middle Cerebral Artery Doppler Associates with Spontaneous Preterm Birth in Normally Grown Fetuses. AB - OBJECTIVE: Our aim was to evaluate whether Doppler changes in the fetal middle cerebral (MCA) and umbilical arteries (UA) suggesting fetal hypoxemia precede the onset of spontaneous preterm birth (PTB). METHODS: We studied 2,340 appropriate for-gestational-age singleton pregnancies that had MCA and UA pulsatility indices (PI) recorded at 28-32 weeks. Values including the cerebroplacental ratio (CPR) were converted into multiples of the median and evaluated according to both gestational age at the onset of labor and the interval between ultrasound and labor. ROC analysis was used to calculate the ability in the prediction of spontaneous PTB before 32, 34 and 37 weeks' gestation. RESULTS: While no correlations were observed for the UA PI and CPR, lower MCA PI values were associated with an earlier onset of labor (p < 0.001) and a shorter ultrasound labor interval (p = 0.028). The ROC analysis at different gestational ages and intervals to labor indicated that MCA PI values were poorly predictive of spontaneous PTB (all areas under the curve <0.7). CONCLUSIONS: Low MCA PI values at 28-32 weeks are associated with subsequent spontaneous PTB, indicating that fetal hypoxemia unrelated with placental disease might be implicated in the onset of labor. This association, however, is unlikely to be useful in the prediction of PTB. PMID- 26575258 TI - Sofosbuvir and Velpatasvir for HCV Genotype 2 and 3 Infection. AB - BACKGROUND: In phase 2 trials, treatment with the combination of the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir resulted in high rates of sustained virologic response in patients chronically infected with hepatitis C virus (HCV) genotype 2 or 3. METHODS: We conducted two randomized, phase 3, open-label studies involving patients who had received previous treatment for HCV genotype 2 or 3 and those who had not received such treatment, including patients with compensated cirrhosis. In one trial, patients with HCV genotype 2 were randomly assigned in a 1:1 ratio to receive sofosbuvir velpatasvir, in a once-daily, fixed-dose combination tablet (134 patients), or sofosbuvir plus weight-based ribavirin (132 patients) for 12 weeks. In a second trial, patients with HCV genotype 3 were randomly assigned in a 1:1 ratio to receive sofosbuvir-velpatasvir for 12 weeks (277 patients) or sofosbuvir ribavirin for 24 weeks (275 patients). The primary end point for the two trials was a sustained virologic response at 12 weeks after the end of therapy. RESULTS: Among patients with HCV genotype 2, the rate of sustained virologic response in the sofosbuvir-velpatasvir group was 99% (95% confidence interval [CI], 96 to 100), which was superior to the rate of 94% (95% CI, 88 to 97) in the sofosbuvir ribavirin group (P=0.02). Among patients with HCV genotype 3, the rate of sustained virologic response in the sofosbuvir-velpatasvir group was 95% (95% CI, 92 to 98), which was superior to the rate of 80% (95% CI, 75 to 85) in the sofosbuvir-ribavirin group (P<0.001). The most common adverse events in the two studies were fatigue, headache, nausea, and insomnia. CONCLUSIONS: Among patients with HCV genotype 2 or 3 with or without previous treatment, including those with compensated cirrhosis, 12 weeks of treatment with sofosbuvir-velpatasvir resulted in rates of sustained virologic response that were superior to those with standard treatment with sofosbuvir-ribavirin. (Funded by Gilead Sciences; ASTRAL 2 ClinicalTrials.gov number, NCT02220998; and ASTRAL-3, NCT02201953.). PMID- 26575262 TI - Quantification of the Immunosuppressant Tacrolimus on Dried Blood Spots Using LC MS/MS. AB - The calcineurin inhibitor tacrolimus is the cornerstone of most immunosuppressive treatment protocols after solid organ transplantation in the United States. Tacrolimus is a narrow therapeutic index drug and as such requires therapeutic drug monitoring and dose adjustment based on its whole blood trough concentrations. To facilitate home therapeutic drug and adherence monitoring, the collection of dried blood spots is an attractive concept. After a finger stick, the patient collects a blood drop on filter paper at home. After the blood is dried, it is mailed to the analytical laboratory where tacrolimus is quantified using high-performance liquid chromatography-tandem mass spectrometry (HPLC MS/MS) in combination with a simple manual protein precipitation step and online column extraction. For tacrolimus analysis, a 6-mm disc is punched from the saturated center of the blood spot. The blood spot is homogenized using a bullet blender and then proteins are precipitated with methanol/0.2 M ZnSO4 containing the internal standard D2,(13)C-tacrolimus. After vortexing and centrifugation, 100 ul of supernatant is injected into an online extraction column and washed with 5 ml/min of 0.1 formic acid/acetonitrile (7:3, v:v) for 1 min. Hereafter, the switching valve is activated and the analytes are back-flushed onto the analytical column (and separated using a 0.1% formic acid/acetonitrile gradient). Tacrolimus is quantified in the positive multi reaction mode (MRM) using a tandem mass spectrometer. The assay is linear from 1 to 50 ng/ml. Inter-assay variability (3.6%-6.1%) and accuracy (91.7%-101.6%) as assessed over 20 days meet acceptance criteria. Average extraction recovery is 95.5%. There are no relevant carry-over, matrix interferences and matrix effects. Tacrolimus is stable in dried blood spots at RT and at +4 degrees C for 1 week. Extracted samples in the autosampler are stable at +4 degrees C for at least 72 hr. PMID- 26575263 TI - Identification of potential COPD genes based on multi-omics data at the functional level. AB - Chronic obstructive pulmonary disease (COPD) is a complex disease, which involves dysfunctions in multi-omics. The changes in biological processes, such as adhesion junction, signaling transduction, transcriptional regulation, and cell proliferation, will lead to the occurrence of COPD. A novel systematic approach MMMG (Methylation-MicroRNA-MRNA-GO) was proposed to identify potential COPD genes by integrating function information with a methylation profile, a microRNA expression profile and an mRNA expression profile. 8 co-functional classes and 102 potential COPD genes were identified. These genes displayed a high performance in classifying COPD patients and normal samples, revealed COPD related pathways, and have been confirmed to be associated with COPD by Matthews correlation coefficient (MCC)-values, literature, an independent data set, and pathways. The MMMG method that analyzed multi-omics data at the functional level could effectively identify potential COPD genes. These potential COPD genes would provide in-depth insights into understanding the complexity of COPD genome landscapes, improve the early diagnostics, and guide new efforts to develop therapeutics in the future. PMID- 26575264 TI - Resection of focal cortical dysplasia located in the upper pre-central gyrus. AB - The primary motor cortex of the oro-facial level can be removed without permanent deficits, because of the bilateral representation of the innate functions. In contrast, resective surgery of the hand motor cortex or higher levels presents more challenges. We treated two adult patients with intractable epilepsy caused by small focal cortical dysplasia in the pre-central gyrus located between the foot and hand primary motor cortices. Focal cortical resection was guided by cortical EEG and intra-operative motor evoked potential, resulting in seizure freedom without neurological deficits in both cases. These cases illustrate that resective surgery can be safely performed in the primary motor cortex even dorsal to the oro-facial level, as long as the critical regions of the hand and foot motor cortices remain intact. Accurate delineation of the anatomical lesion and functional areas using intra-operative neurophysiological monitoring is crucial for successful outcome of the surgery. PMID- 26575265 TI - Comparison of Anterior Segment Biometric Measurements between Pentacam HR and IOLMaster in Normal and High Myopic Eyes. AB - PURPOSE: To compare the anterior chamber depth (ACD), keratometry (K) and astigmatism measurements taken by IOLMaster and Pentacam HR in normal and high myopic (HM) eyes. DESIGN: A prospective observational case series. METHODS: Sixty six normal eyes and 59 HM eyes underwent ACD, keratometry and astigmatism measurements with both devices. Axial length (AL) was measured on IOLMaster. The interdevice agreement was evaluated using the Bland-Altman analysis and paired t test. The correlations between age and AL & ACD were analyzed. Vector analysis was used to compare astigmatism measurements. RESULTS: The ACD from IOLMaster and Pentacam HR was different for the normal group (P = 0.003) but not for the HM group (P = 0.280). IOLMaster demonstrated higher steep K and mean K values than Pentacam HR for both normal and HM groups (P<0.001 for all). IOLMaster also have higher flat K values for the HM groups (P<0.001) but were statistically equivalent with Pentacam HR for the normal group (P = 0.119) IOLMaster and Pentacam HR were different in astigmatism measurements for the normal group but were statistically equivalent for the HM group. For the normal group, age was negatively correlated with AL, IOLMaster ACD and Pentacam HR ACD (r = -0.395, P = 0.001; r = -0.715, P < 0.001; r = -0.643, P < 0.001). For the HM group, age was positively correlated with AL but negatively correlated with IOLMaster ACD and Pentacam HR ACD (r = 0.377, P = 0.003; r = -0.392, P = 0.002; r = -0.616, P < 0.001). CONCLUSIONS: The IOLMaster and Pentacam HR have significant difference in corneal power measurements for both normal and HM groups. The two instruments also differ in ACD and astigmatism measurement for the normal group. Therefore, a single instrument is recommended for studying longitudinal changes in anterior segment biometric measurements. Age should be considered as an influencing factor for both AL and ACD values in the normal and HM group. PMID- 26575266 TI - Primary Pulmonary Mucoepidermoid Carcinoma: Histopathological and Moleculargenetic Studies of 26 Cases. AB - INTRODUCTION: Pulmonary mucoepidermoid carcinoma (PMEC) is an uncommon neoplasm of the lung and the main salivary gland-type lung carcinoma. The aims of this study were to review the clinicopathological and immunohistochemical features of PMEC and characterize the genetic events in PMEC. METHODS: We reviewed the pathology cases in our hospital and found 34 initially diagnosed PMEC cases, 26 of which were confirmed as PMEC after excluding 8 cases of MEC-like pulmonary carcinoma. The clinicopathological characteristics of the 26 PMEC cases and the 8 cases of MEC-like pulmonary carcinoma were retrospectively reviewed. MAML2 rearrangement was detected by fluorescence In Situ Hybridization (FISH). Immunostains of ALK, calponin, collagen IV, CK7, EGFR, HER2, Ki-67, Muc5Ac, p63, p40, and TTF-1 were performed. DNA was extracted from 23 cases of PMEC. Mutation profiling of the EGFR, KRAS, BRAF, ALK, PIK3CA, PDGFRA, and DDR2 genes were carried out using next-generation sequencing (NGS), Sanger sequencing, and quantitative polymerase chain reaction (QPCR) in 9 successfully amplified cases. RESULTS: Twenty-six cases of PMEC (18 low-grade, 8 high-grade) included 13 men and 13 women aged 12-79 years. Twenty-two cases had a central/endobronchial growth pattern, and 4 cases had a peribronchial growth pattern. Immunohistochemically, CK7, Muc5Ac, p40, and p63 were positive in all cases (26/26);EGFR was positive in 11 cases (11/26); TTF-1, Calponin, HER2 and ALK were negative in all cases (0/26). MAML2 rearrangement was identified in 12 of 18 PMEC cases. No mutations were detected in any of the 7 genes in the 9 cases that qualified for mutation analysis. Twenty-three PMEC patients had follow-up information with a median interval of 32.6 months. Both the 5- and 10-year overall survival rates (OS) were 72.1%, and a high-grade tumor was an adverse prognostic factor in PMEC. There were 8 cases of MEC-like pulmonary carcinoma aged 36-78 years: 2 cases were located in the bronchus, and 6 cases were located in the lung. p63 and TTF-1 were positive in all cases (8/8), p40 was positive in 5 cases (5/8), and ALK was positive in 5 cases (5/8). No cases of MAML2 rearrangement were detected, but there were 5 cases of ALK rearrangement. CONCLUSIONS: PMEC is a primary malignant pulmonary tumor with a relatively good prognosis that is historically characterized by the presence of mucous cells and a lack of keratinization. There are distinct differences between PMEC and MEC like pulmonary carcinoma in tumor location preference, immunophenotype, and molecular genetics, and the differential diagnosis is critical due to the therapeutic and prognostic considerations. PMID- 26575268 TI - The expanding field of polyphosphazene high polymers. AB - The importance of phosphorus in polymer chemistry is illustrated by the growth of the broad field of polyphosphazene science. Several hundred high polymers are now known with a phosphorus-nitrogen backbone and combinations or more than 250 different organic side groups. The properties of these polymers depend on both the character of the inorganic backbone and the structure of the organic side groups. This summary reviews the synthesis pathways to these materials, the often unique structure-property relationships, and challenges for the future expansion of this field. PMID- 26575267 TI - Buttonhole Cannulation Is Not Associated with More AVF Infections in a Low-Care Satellite Dialysis Unit: A Long-Term Longitudinal Study. AB - BACKGROUND: Buttonhole cannulation (BHC) has been associated with a greater risk of arteriovenous fistula (AVF)-related infections and septicemia than the rope ladder cannulation (RLC) in in-center hemodialysis (HD). Such infections have never been studied in satellite HD units. STUDY DESIGN: Retrospective single center study. SETTING AND PARTICIPANT: All patients in our satellite HD unit using a native AVF from 1 January, 1990, to 31 December, 2012. STUDY PERIOD: Two different kinds of cannulation have been used during the study period: From 1 January, 1990 to 1, January, 1998 RLC was used in the unit (period 1). After 1 January, 1998 onwards, all the patients were switched within 3 months to BHC (period 2). OUTCOMES: Three different infectious events were observed during the two periods: local AVF infection, bacteremia, and combined infection. The aim of this study was to evaluate the incidence of AVF-related infections in our low care HD unit and to determine whether BHC is associated with an increased risk of infection in this population. RESULTS: 162 patients were analyzed; 68 patients participated to period 1 and 115 to period 2. Sixteen infectious events occurred. Incidences of AVF-related infectious events were 0.05 [95% CI, 0.02-0.16] and 0.13/1000 AVF-days [95% CI, 0.0.8-0.23], for period 1 and 2 (p = 0.44) respectively. Recurrence of AVF-related infection was observed only during period 2. Unadjusted incidence rate ratio (IRR) of all infections was 0.39 (95%CI 0.12 1.37). Two complicated infections occurred during the study period: one in period 1 and one in period 2. LIMITATIONS: Observational retrospective single centre study. CONCLUSIONS: BHC is not associated with an increased infectious incidence in our HD population from a satellite dialysis unit. In the rare patients with AVF-related infection it seems necessary to change cannulation sites as recurrence of infection might be an event more frequent with BHC. PMID- 26575269 TI - Scalable synthesis of cubic Cu(1.4)S nanoparticles with long-term stability by laser ablation of salt powder. AB - Cubic Cu(1.4)S nanoparticles were synthesized on a large scale by laser ablation of salt powder dispersed in an organic solvent. A metastable Cu(1.4)S phase was formed at high temperature in a reductive solvent and was maintained at room temperature due to the quenching effect of the pulsed laser. The cubic Cu(1.4)S nanoparticles show good stability after being exposed to ambient atmosphere for as long as 1 month. PMID- 26575270 TI - Pre-Dispersal Seed Predation in a Species-Rich Forest Community: Patterns and the Interplay with Determinants. AB - Pre-dispersal seed predation (PDSP) is commonly observed in woody plants, and recognized as a driver of seed production variability that is critical for successful regeneration. Earlier studies on PDSP and its determinants were mostly species specific, with community-level PDSP rarely estimated; and the interactions between the temporal variability of seed production and PDSP remain elusive. In this study, the community seed rain of woody plants in a mixed evergreen-deciduous broadleaf forest was monitored for seven years. We examined predation on collected seeds and analyzed the determinants of PDSP. PDSP was recorded in 17 out of 44 woody plant species, and three-quarters of PDSP was due to insect predators. Annual seed production varied substantially at community level, reversely linked with the temporal variation of PDSP rate. The PDSP rate was biased regarding fruit types, and being significantly correlated with seed mass when using phylogenetic independent contrasts (PICs) or without taking into account phylogenetic relations, especially for nuts. PDSP rate was also negatively correlated with seed density, showing a threshold-related predator satiation effect. The community-level PDSP rate was primarily determined by tree height, fruit type, and interannual variation of seed production and seed mass. Our analysis revealed a causal link between seed production and the dynamics of PDSP rate at the community level. The predator satiation effect was primarily contributed by the dominant species, whereas the rare species seemed to apply a distinct "hide-and-seek" strategy to control the risk of PDSP. The mechanistic difference of seed production between the common and rare species can shed new light on species coexistence and community assembly. Long-term monitoring of both seed rain and seed predation is required for understanding the ecological and evolutionary implications of species regeneration strategies in a species-rich forest community. PMID- 26575271 TI - Moving in and out of Poverty: The Within-Individual Association between Socioeconomic Status and Juvenile Delinquency. AB - A family's SES can be changeable over time. This study was the first to investigate if such within-individual changes in family SES are associated with parallel fluctuations in boys' delinquent behavior from childhood to adolescence. Participants were a community sample of boys and their caregivers (N = 503) who were assessed annually for ten consecutive years spanning ages 7-18. Fixed effects models revealed that changes in familial SES were related to changes in delinquency: Youths were more likely to offend during years in which their parents' SES was lower than during years in which their parents' SES was higher. Contrary to expectations, we found no evidence that this association was accounted for by families moving to different neighborhoods or by changes in parenting. Since within-individual models provide a stricter test of causality than between-individual models, these findings support claims that impacting familial SES may have a direct effect on youths' delinquency. PMID- 26575272 TI - Cumulative Incidence and Predictors of Progression in Corticosteroid-Naive Patients with Sarcoidosis. AB - BACKGROUND: Assessment of the clinical course of sarcoidosis requires long-term observation. However, the appropriate period of follow-up for sarcoidosis remains unclear, especially in patients without indication of corticosteroid therapy at the time of diagnosis. OBJECTIVE: This study aimed to clarify the cumulative incidence and identify risk factors for disease progression in corticosteroid naive sarcoidosis patients. METHODS: The clinical courses of 150 Japanese patients with sarcoidosis, who were followed for more than 2 years and had no indication for corticosteroid therapy at diagnosis, were retrospectively reviewed. Disease progression was defined as worsening of pulmonary sarcoidosis, development of new organ involvement, or extrapulmonary organ damage. The cumulative incidence of progression was estimated by generating a cumulative incidence curve with the Fine and Gray method. RESULTS: The median follow-up duration was 7.7 years (interquartile range, 4.7-13.6 years). Thirty-two (21%) patients experienced disease progression. New organ involvement appeared in 16 patients (11%). The 6-month, and 1-, 5-, 10-, and 15-year cumulative incidence of progression was 2%, 5%, 15%, 28%, and 31%, respectively. The number of organs involved at diagnosis was an independent predictor for progression with a multifactorial adjusted hazard ratio of 1.71 (95% confidence interval, 1.11 2.62). The optimal cut-off of the number of organs involved at diagnosis to identify future progression was three. CONCLUSIONS: In corticosteroid-naive sarcoidosis patients, the risks of disease progression are comparable from 0-5 years and 5-10 years after diagnosis. The number of organs involved at diagnosis is a useful predictor for progression of sarcoidosis. PMID- 26575273 TI - Folding catastrophes due to viscosity in multiferroic domains: implications for room-temperature multiferroic switching. AB - Unusual domains with curved walls and failure to satisfy the Landau-Lifshitz Kittel Law are modeled as folding catastrophes (saddle-node bifurcations). This description of ballistic motion in a viscous medium is based upon early work by Dawber et al 2003 Appl. Phys. Lett. 82 436. It suggests that ferroelectric films can exhibit folds or vortex patterns but not both. PMID- 26575274 TI - Plasmon-Enhanced below Bandgap Photoconductive Terahertz Generation and Detection. AB - We use plasmon enhancement to achieve terahertz (THz) photoconductive switches that combine the benefits of low-temperature grown GaAs with mature 1.5 MUm femtosecond lasers operating below the bandgap. These below bandgap plasmon enhanced photoconductive receivers and sources significantly outperform commercial devices based on InGaAs, both in terms of bandwidth and power, even though they operate well below saturation. This paves the way for high performance low-cost portable systems to enable emerging THz applications in spectroscopy, security, medical imaging, and communication. PMID- 26575275 TI - Do Not Give Up. PMID- 26575280 TI - Effect of salts on the solubility of ionic liquids in water: experimental and electrolyte Perturbed-Chain Statistical Associating Fluid Theory. AB - Due to scarce available experimental data, as well as due to the absence of predictive models, the influence of salts on the solubility of ionic liquids (ILs) in water is still poorly understood. To this end, this work addresses the solubility of the IL 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([C4C1im][NTf2]), at 298.15 K and 0.1 MPa, in aqueous salt solutions (from 0.1 to 1.5 mol kg(-1)). At salt molalities higher than 0.2 mol kg(-1), all salts caused salting-out of [C4C1im][NTf2] from aqueous solution with their strength decreasing in the following order: Al2(SO4)3 > ZnSO4 > K3C6H5O7 > KNaC4H4O6 > K3PO4 > Mg(CH3CO2)2 > K2HPO4 > MgSO4 > KH2PO4 > KCH3CO2. Some of these salts lead however to the salting-in of [C4C1im][NTf2] in aqueous medium at salt molalities lower than 0.2 mol kg(-1). To attempt the development of a model able to describe the salt effects, comprising both the salting-in and salting-out phenomena observed, the electrolyte Perturbed-Chain Statistical Associating Fluid Theory (ePC-SAFT) was applied using ion-specific parameters. The gathered experimental data was modelled using ePC-SAFT parameters complemented by fitting a single binary parameter between K(+) and the IL-ions to the IL solubility in K3PO4 aqueous solutions. Based on this approach, the description of anion-specific salting-out effects of the remaining potassium salts was found to be in good agreement with experimental data. Remarkably, ePC SAFT is even able to predict the salting-in effect induced by K2HPO4, based on the single K(+)/IL-ions binary parameter which was fitted to an exclusively salting-out effect promoted by K3PO4. Finally, ePC-SAFT was applied to predict the influence of other sodium salts on the [C4C1im][NTf2] solubility in water, with experimental data taken from literature, leading to an excellent description of the liquid-liquid phase behaviour. PMID- 26575281 TI - Cost-effective Decisions in Detecting Silent Common Bile Duct Gallstones During Laparoscopic Cholecystectomy. AB - OBJECTIVE: To evaluate the cost-effectiveness of routine intraoperative ultrasonography (IOUS), cholangiography (IOC), or expectant management without imaging (EM) for investigation of clinically silent common bile duct (CBD) stones during laparoscopic cholecystectomy. BACKGROUND: The optimal algorithm for the evaluation of clinically silent CBD stones during routine cholecystectomy is unclear. METHODS: A decision tree model of CBD exploration was developed to determine the optimal diagnostic approach based on preoperative probability of choledocholithiasis. The model was parameterized with meta-analyses of previously published studies. The primary outcome was incremental cost per quality-adjusted life year (QALY) gained from each diagnostic strategy. A secondary outcome was the percentage of missed stones. Costs were from the perspective of the third party payer and sensitivity analyses were performed on all model parameters. RESULTS: In the base case analysis with a prevalence of stones of 9%, IOUS was the optimal strategy, yielding more QALYs (0.9858 vs 0.9825) at a lower expected cost ($311 vs $574) than EM. IOC yielded more QALYs than EM in the base case (0.9854) but at a much higher cost ($1122). IOUS remained dominant as long as the preoperative probability of stones was above 3%; EM was the optimal strategy if the probability was less than 3%. The percentage of missed stones was 1.5% for IOUS, 1.8% for IOC and 9% for EM. CONCLUSIONS: In the detection and resultant management of CBD stones for the majority of patients undergoing laparoscopic cholecystectomy, IOUS is cost-effective relative to IOC and EM. PMID- 26575282 TI - From Bench to Bill: How a Transplant Nuance Became 1 of Only 57 Laws Passed in 2013. PMID- 26575283 TI - Giving support to others reduces sympathetic nervous system-related responses to stress. AB - Social support is a major contributor to the link between social ties and beneficial health outcomes. Research to date has focused on how receiving support from others might be good for us; however, we know less about the health effects of giving support to others. Based on prior work in animals showing that stimulating neural circuitry important for caregiving behavior can reduce sympathetic-related responses to stressors, it is possible that, in humans, giving to others can reduce stressor-evoked sympathetic nervous system responding, which has implications for health outcomes. To test the effect of giving support on the physiological stress response, participants either wrote a supportive note to a friend (support-giving condition) or wrote about their route to school/work (control condition) before undergoing a standard laboratory-based stress task. Physiological responses (heart rate, blood pressure, salivary alpha amylase, salivary cortisol), and self-reported stress were collected throughout the protocol. In line with hypotheses, support giving (vs. control) reduced sympathetic-related responses (systolic blood pressure and alpha-amylase) to the stressor. No effects of support giving were found on self-reported psychological stress or cortisol levels. Results add to existing knowledge of the pathways by which support giving may lead to health benefits and highlight the contribution of giving to others in the broader social support-health link. PMID- 26575284 TI - Willingness to Pay for Cataract Surgery Provided by a Senior Surgeon in Urban Southern China. AB - PURPOSE: To study willingness to pay for cataract surgery and surgical service provided by a senior cataract surgeon in urban Southern China. METHODS: This study was a cross-sectional willingness-to-pay (WTP) interview using bidding formats. Two-hundred eleven persons with presenting visual impairment in either eye due to cataract were enrolled at a tertiary eye hospital. Participants underwent a comprehensive eye examination and a WTP interview for both surgery and service provided by a senior surgeon. Demographic information, socioeconomic status and clinical data were recorded. RESULTS: Among 211 (98% response rate) persons completing the interview, 53.6% were women and 80.6% were retired. About 72.2% had a monthly income lower than 1000 renminbi (US $161). A total of 189 (89.6%) were willing to pay for cataract and the median amount of WTP was 6000 renminbi (US$968). And 102 (50.7%) were willing to pay additional fees for surgery performed by a senior surgeon, and the median amount of WTP was 500 renminbi (US$81). In regression models adjusting for age and gender, persons with preexisting eye diseases other than cataract, were more likely to pay for cataract surgery and service provided by a senior surgeon (P = 0.04 for both). CONCLUSIONS: In urban China, cataract patients, especially those with preexisting eye conditions, are willing to pay additional fees for a senior surgeon. Moving to a system where the price of cataract surgery is proportional to the consultant' skill and expertise is possible and may have a potential impact on waiting list and quality of eye care. Further studies are needed to examine the impact of such pricing system on attitudes and choices of cataract patients. PMID- 26575285 TI - Blockade of presynaptic 4-aminopyridine-sensitive potassium channels increases initial neurotransmitter release probability, reinstates synaptic transmission altered by GABAB receptor activation in rat midbrain periaqueductal gray. AB - The activation of gamma-aminobutyric acid receptor subtype B (GABAB) receptors in the midbrain ventrolateral periaqueductal gray (vlPAG) induces both postsynaptic and presynaptic inhibition. Whereas the postsynaptic inhibition is mediated by G protein-coupled inwardly rectifying K channels, the presynaptic inhibition of neurotransmitter release is primarily mediated by voltage-gated calcium channels. Using whole-cell recordings from acute rat PAG slices, we report here that the bath application of 4-aminopyridine, a voltage-gated K channel blocker, increases the initial GABA and glutamate release probability (P) and reinstates P depressed by presynaptic GABAB receptor activation at inhibitory and excitatory synapses, respectively. However, Ba, which blocks G protein-coupled inwardly rectifying K channels, does not produce similar effects. Our data suggest that the blockade of presynaptic 4-aminopyridine-sensitive K channels in vlPAG facilitates neurotransmitter release and reinstates synaptic transmission that has been altered by presynaptic GABAB receptor activation. Because vlPAG is involved in the descending pain control system, the present results may have potential therapeutic applications. PMID- 26575286 TI - The intellectual disability gene Kirrel3 regulates target-specific mossy fiber synapse development in the hippocampus. AB - Synaptic target specificity, whereby neurons make distinct types of synapses with different target cells, is critical for brain function, yet the mechanisms driving it are poorly understood. In this study, we demonstrate Kirrel3 regulates target-specific synapse formation at hippocampal mossy fiber (MF) synapses, which connect dentate granule (DG) neurons to both CA3 and GABAergic neurons. Here, we show Kirrel3 is required for formation of MF filopodia; the structures that give rise to DG-GABA synapses and that regulate feed-forward inhibition of CA3 neurons. Consequently, loss of Kirrel3 robustly increases CA3 neuron activity in developing mice. Alterations in the Kirrel3 gene are repeatedly associated with intellectual disabilities, but the role of Kirrel3 at synapses remained largely unknown. Our findings demonstrate that subtle synaptic changes during development impact circuit function and provide the first insight toward understanding the cellular basis of Kirrel3-dependent neurodevelopmental disorders. PMID- 26575287 TI - The human ARF tumor suppressor senses blastema activity and suppresses epimorphic tissue regeneration. AB - The control of proliferation and differentiation by tumor suppressor genes suggests that evolution of divergent tumor suppressor repertoires could influence species' regenerative capacity. To directly test that premise, we humanized the zebrafish p53 pathway by introducing regulatory and coding sequences of the human tumor suppressor ARF into the zebrafish genome. ARF was dormant during development, in uninjured adult fins, and during wound healing, but was highly expressed in the blastema during epimorphic fin regeneration after amputation. Regenerative, but not developmental signals resulted in binding of zebrafish E2f to the human ARF promoter and activated conserved ARF-dependent Tp53 functions. The context-dependent activation of ARF did not affect growth and development but inhibited regeneration, an unexpected distinct tumor suppressor response to regenerative versus developmental environments. The antagonistic pleiotropic characteristics of ARF as both tumor and regeneration suppressor imply that inducing epimorphic regeneration clinically would require modulation of ARF -p53 axis activation. PMID- 26575288 TI - Tachykinin acts upstream of autocrine Hedgehog signaling during nociceptive sensitization in Drosophila. AB - Pain signaling in vertebrates is modulated by neuropeptides like Substance P (SP). To determine whether such modulation is conserved and potentially uncover novel interactions between nociceptive signaling pathways we examined SP/Tachykinin signaling in a Drosophila model of tissue damage-induced nociceptive hypersensitivity. Tissue-specific knockdowns and genetic mutant analyses revealed that both Tachykinin and Tachykinin-like receptor (DTKR99D) are required for damage-induced thermal nociceptive sensitization. Electrophysiological recording showed that DTKR99D is required in nociceptive sensory neurons for temperature-dependent increases in firing frequency upon tissue damage. DTKR overexpression caused both behavioral and electrophysiological thermal nociceptive hypersensitivity. Hedgehog, another key regulator of nociceptive sensitization, was produced by nociceptive sensory neurons following tissue damage. Surprisingly, genetic epistasis analysis revealed that DTKR function was upstream of Hedgehog-dependent sensitization in nociceptive sensory neurons. Our results highlight a conserved role for Tachykinin signaling in regulating nociception and the power of Drosophila for genetic dissection of nociception. PMID- 26575289 TI - A network of autism linked genes stabilizes two pools of synaptic GABA(A) receptors. AB - Changing receptor abundance at synapses is an important mechanism for regulating synaptic strength. Synapses contain two pools of receptors, immobilized and diffusing receptors, both of which are confined to post-synaptic elements. Here we show that immobile and diffusing GABA(A) receptors are stabilized by distinct synaptic scaffolds at C. elegans neuromuscular junctions. Immobilized GABA(A) receptors are stabilized by binding to FRM-3/EPB4.1 and LIN-2A/CASK. Diffusing GABA(A) receptors are stabilized by the synaptic adhesion molecules Neurexin and Neuroligin. Inhibitory post-synaptic currents are eliminated in double mutants lacking both scaffolds. Neurexin, Neuroligin, and CASK mutations are all linked to Autism Spectrum Disorders (ASD). Our results suggest that these mutations may directly alter inhibitory transmission, which could contribute to the developmental and cognitive deficits observed in ASD. PMID- 26575290 TI - Pervasive transcription read-through promotes aberrant expression of oncogenes and RNA chimeras in renal carcinoma. AB - Aberrant expression of cancer genes and non-canonical RNA species is a hallmark of cancer. However, the mechanisms driving such atypical gene expression programs are incompletely understood. Here, our transcriptional profiling of a cohort of 50 primary clear cell renal cell carcinoma (ccRCC) samples from The Cancer Genome Atlas (TCGA) reveals that transcription read-through beyond the termination site is a source of transcriptome diversity in cancer cells. Amongst the genes most frequently mutated in ccRCC, we identified SETD2 inactivation as a potent enhancer of transcription read-through. We further show that invasion of neighbouring genes and generation of RNA chimeras are functional outcomes of transcription read-through. We identified the BCL2 oncogene as one of such invaded genes and detected a novel chimera, the CTSC-RAB38, in 20% of ccRCC samples. Collectively, our data highlight a novel link between transcription read through and aberrant expression of oncogenes and chimeric transcripts that is prevalent in cancer. PMID- 26575291 TI - Schematic memory components converge within angular gyrus during retrieval. AB - Mental schemas form associative knowledge structures that can promote the encoding and consolidation of new and related information. Schemas are facilitated by a distributed system that stores components separately, presumably in the form of inter-connected neocortical representations. During retrieval, these components need to be recombined into one representation, but where exactly such recombination takes place is unclear. Thus, we asked where different schema components are neuronally represented and converge during retrieval. Subjects acquired and retrieved two well-controlled, rule-based schema structures during fMRI on consecutive days. Schema retrieval was associated with midline, medial temporal, and parietal processing. We identified the multi-voxel representations of different schema components, which converged within the angular gyrus during retrieval. Critically, convergence only happened after 24-hour-consolidation and during a transfer test where schema material was applied to novel but related trials. Therefore, the angular gyrus appears to recombine consolidated schema components into one memory representation. PMID- 26575294 TI - Temperament and personality in eating disorders. AB - PURPOSE OF REVIEW: In the last decades, three main different personality domains have been investigated in the field of eating disorders: personality traits, temperament, and personality disorders. The use of a wide range of instruments and the presence of many different approaches in the definition of personality dimensions make it difficult to summarize the emerging results from different studies. The aim of this narrative review is to critically highlight and discuss all interesting developments in this field, as reflected in the recent literature. RECENT FINDINGS: The study of personality and temperament in eating disorders seems to be in line with the recently suggested dimensional approach, which highlights the importance of symptoms aggregation, rather than the categorical diagnoses. Recent literature seems to confirm that specific personality and temperamental profiles can be drawn for patients with eating disorders, which can discriminate different eating disorders' diagnoses/symptoms. SUMMARY: These observations have relevant clinical implications as treatment of eating disorders is largely based on psychotherapeutic interventions. However, large longitudinal studies are needed to better clarify the suggested relationships and to identify more defined therapeutic strategies. PMID- 26575295 TI - Anxiety as a risk factor in cardiovascular disease. AB - PURPOSE OF REVIEW: The narrative review covers recent studies of anxiety as a companion in cardiovascular disease. RECENT FINDINGS: Prospective population based studies and studies of cases with known cardiovascular disease have been conducted, as well as studies of intervention with coronary bypass grafting, heart transplants, and implantable cardioverter-defibrillators, and subsequent rehabilitation programs. Mental stress-induced myocardial ischemia (MSIMI) stands for this emerging research arena. SUMMARY: Anxiety has emerged as perhaps the most important risk factor for cardiovascular disease, determining other known risk factors, such as depression, substance use, overweight, and a sedentary lifestyle. Anxiety also increases the risk of major cardiac events in coronary heart disease. There is a need for elucidating the influence of anxiety in takotsubo and in white-coat hypertension. Managing anxiety is of vital importance in patients who have received heart transplants, to ascertain adherence to immunosuppressants. PMID- 26575292 TI - Cross-talk between PRMT1-mediated methylation and ubiquitylation on RBM15 controls RNA splicing. AB - RBM15, an RNA binding protein, determines cell-fate specification of many tissues including blood. We demonstrate that RBM15 is methylated by protein arginine methyltransferase 1 (PRMT1) at residue R578, leading to its degradation via ubiquitylation by an E3 ligase (CNOT4). Overexpression of PRMT1 in acute megakaryocytic leukemia cell lines blocks megakaryocyte terminal differentiation by downregulation of RBM15 protein level. Restoring RBM15 protein level rescues megakaryocyte terminal differentiation blocked by PRMT1 overexpression. At the molecular level, RBM15 binds to pre-messenger RNA intronic regions of genes important for megakaryopoiesis such as GATA1, RUNX1, TAL1 and c-MPL. Furthermore, preferential binding of RBM15 to specific intronic regions recruits the splicing factor SF3B1 to the same sites for alternative splicing. Therefore, PRMT1 regulates alternative RNA splicing via reducing RBM15 protein concentration. Targeting PRMT1 may be a curative therapy to restore megakaryocyte differentiation for acute megakaryocytic leukemia. PMID- 26575293 TI - Identification of a Munc13-sensitive step in chromaffin cell large dense-core vesicle exocytosis. AB - It is currently unknown whether the molecular steps of large dense-core vesicle (LDCV) docking and priming are identical to the corresponding reactions in synaptic vesicle (SV) exocytosis. Munc13s are essential for SV docking and priming, and we systematically analyzed their role in LDCV exocytosis using chromaffin cells lacking individual isoforms. We show that particularly Munc13-2 plays a fundamental role in LDCV exocytosis, but in contrast to synapses lacking Munc13s, the corresponding chromaffin cells do not exhibit a vesicle docking defect. We further demonstrate that ubMunc13-2 and Munc13-1 confer Ca(2+) dependent LDCV priming with similar affinities, but distinct kinetics. Using a mathematical model, we identify an early LDCV priming step that is strongly dependent upon Munc13s. Our data demonstrate that the molecular steps of SV and LDCV priming are very similar while SV and LDCV docking mechanisms are distinct. PMID- 26575296 TI - Novel developments in genetic and epigenetic mechanisms of anxiety. AB - PURPOSE OF REVIEW: The present review aims to deliver a systematic overview of current developments and trends in (epi)genetics of anxiety and to identify upcoming challenges and opportunities. RECENT FINDINGS: Genes related to peptide and hormone signaling have been suggested for anxiety-related phenotypes, e.g., the NPSR1 gene, which has been associated predominantly with panic disorder in women, and shown to interact with environmental factors and to influence psychometric, neurophysiological, and neuroimaging correlates of anxiety. Similar multi-level results have been reported for genetic and epigenetic variation in the OXTR gene, especially in social anxiety disorder (SAD), and for CRHR1 gene variation in women with panic disorder. Variants in RGS2 and ASIC1 genes were linked to panic disorder, with the latter also being implicated in SAD treatment response. Finally, monoaminergic 'risk' genes (SLC6A4, MAOA, HTR1A) were related to SAD, generalized anxiety disorder and women with panic disorder, anxiety traits and response to psychopharmacological and psychotherapeutic interventions. SUMMARY: Converging evidence for potential genetic and epigenetic risk markers has been gathered and future studies call for independent replications and multi level integration of dimensional approaches, environmental factors, and biological readouts, while considering sex-specific substratification. Particularly, epigenetic variation appears promising for disease course and treatment response predictions. PMID- 26575297 TI - Bipolar disorders, type 2 diabetes mellitus, and the brain. AB - PURPOSE OF REVIEW: Type 2 diabetes mellitus (T2DM) negatively affects brain structure and function. Meta-analytical data show that relative to age and sex matched non-psychiatric controls, patients with bipolar disorders have double the risk of T2DM. We review the evidence for association between T2DM and adverse clinical and brain imaging changes in bipolar disorders and summarize studies investigating effects of diabetes treatment on psychiatric and brain outcomes. RECENT FINDINGS: Participants with bipolar disorders and T2DM or insulin resistance demonstrate greater morbidity, chronicity and disability, and lower treatment response to Li. Bipolar disorders complicated by insulin resistance/T2DM are associated with smaller hippocampal and cortical gray matter volumes and lower prefrontal N-acetyl aspartate (neuronal marker). Treatment of T2DM yields preservation of brain gray matter and insulin sensitizers, such as pioglitazone, improve symptoms of depression in unipolar or bipolar disorders. SUMMARY: T2DM or insulin resistance frequently cooccur with bipolar disorders and are associated with negative psychiatric clinical outcomes and compromised brain health. This is clinically concerning, as patients with bipolar disorders have an increased risk of metabolic syndrome and yet often receive suboptimal medical care. At the same time treatment of T2DM and insulin resistance has positive effects on psychiatric and brain outcomes. These findings create a rich agenda for future research, which could enhance psychiatric pharmacopeia and directly impact patient care. PMID- 26575298 TI - The key role of extinction learning in anxiety disorders: behavioral strategies to enhance exposure-based treatments. AB - PURPOSE OF REVIEW: Extinction learning is a major mechanism for fear reduction by means of exposure. Current research targets innovative strategies to enhance fear extinction and thereby optimize exposure-based treatments for anxiety disorders. This selective review updates novel behavioral strategies that may provide cutting-edge clinical implications. RECENT FINDINGS: Recent studies provide further support for two types of enhancement strategies. Procedural enhancement strategies implemented during extinction training translate to how exposure exercises may be conducted to optimize fear extinction. These strategies mostly focus on a maximized violation of dysfunctional threat expectancies and on reducing context and stimulus specificity of extinction learning. Flanking enhancement strategies target periods before and after extinction training and inform optimal preparation and post-processing of exposure exercises. These flanking strategies focus on the enhancement of learning in general, memory (re )consolidation, and memory retrieval. SUMMARY: Behavioral strategies to enhance fear extinction may provide powerful clinical applications to further maximize the efficacy of exposure-based interventions. However, future replications, mechanistic examinations, and translational studies are warranted to verify long term effects and naturalistic utility. Future directions also comprise the interplay of optimized fear extinction with (avoidance) behavior and motivational antecedents of exposure. PMID- 26575299 TI - Mindfulness-based cognitive therapy for residual depressive symptoms and relapse prophylaxis. AB - PURPOSE OF REVIEW: The article reviews the recent evidence for mindfulness-based cognitive therapy (MBCT) for patients with residual depressive symptoms or in remitted patients at increased risk for relapse. RECENT FINDINGS: Randomized controlled trials have shifted focus from comparing MBCT with treatment-as-usual to comparing MBCT against interventions. These studies have provided evidence for the efficacy of MBCT on par with maintenance antidepressant pharmacotherapy and leading to a relative reduction of risk on the order of 30-40%. Perhaps fuelled by these data, recent efforts have focused on extending MBCT to novel populations, such as acutely depressed patients, those diagnosed with health anxiety, social anxiety, fibromyalgia, or multiple chemical sensitivities as well migrating MBCT to online platforms so that it is more widely available. Neuroimaging studies of patients in structured therapies which feature mindfulness meditation, have reported findings that parallel behavioral changes, such as increased activation in brain regions subsuming self-focus and emotion regulation (prefrontal cortex) and interoceptive awareness (insula). SUMMARY: The current evidence base for MBCT is strongest for its application as a prophylactic intervention or for residual depressive symptoms, with early data suggesting additional indications outside the mood disorders. Future work will need to address dose-effect relationships between mindfulness practice and clinical benefits, as well as establishing the rates of uptake for online MBCT so that its benefits can be compared to in-person groups. Additionally, validating current or novel neural markers of MBCT treatment response will allow for patient matching and optimization of treatment response. PMID- 26575300 TI - Cognition in major depressive disorder: a 'Systemically Important Functional Index' (SIFI). AB - PURPOSE OF REVIEW: Cognitive dysfunction in major depressive disorder (MDD) is common, pervasive across multiple subdomains of cognitive function, and is a principle determinant of health outcomes from patient, provider, and societal perspectives. The overarching aim herein is to provide rationale for the evaluation, measurement, and specific treatment of cognitive function in adults with MDD. RECENT FINDINGS: Evidence indicates that cognitive dysfunction in MDD is a critical mediator of workplace disability. Systematic evaluation and measurement of cognitive function is warranted. All individuals with MDD should be evaluated for both objective and subjective cognitive dysfunction. Although differences between antidepressants in overall antidepressant efficacy are not consistent, unequivocal differences in improving measures of cognitive function are noted with evidence indicating that vortioxetine has multidomain cognitive benefits, whereas duloxetine has replicated evidence of improving measures of acquisition and recall (i.e. memory). SUMMARY: The probability of functional recovery in MDD is likely to increase with interventions that specifically target and improve measures of cognitive function. Clinicians are encouraged to evaluate patients using a validated measure (e.g. the THINC-it tool); prevention of cognitive impairment in MDD is a critical therapeutic priority. Vortioxetine and duloxetine benefit measures of cognitive function in MDD. Preliminary evidence of beneficial effects on cognitive emotional processing are reported with ketamine. PMID- 26575301 TI - Non-uniform force allocation for area preservation in spring network models. AB - In modeling of elastic objects in a flow such as red blood cells, white blood cells, or tumor cells, several elastic moduli are involved. One of them is the area conservation modulus. In this paper, we focus on spring network models, and we introduce a new way of modeling the area preservation modulus. We take into account the current shape of the individual triangles and find the proportional allocation of area conservation forces, which would for individual triangles preserve their shapes. The analysis shows that this approach tends to regularize the triangulation. We demonstrate this effect on individual triangles as well as on the complete triangulations. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26575302 TI - Particle-on-Film Gap Plasmons on Antireflective ZnO Nanocone Arrays for Molecular Level Surface-Enhanced Raman Scattering Sensors. AB - When semiconducting nanostructures are combined with noble metals, the surface plasmons of the noble metals, in addition to the charge transfer interactions between the semiconductors and noble metals, can be utilized to provide strong surface plasmon effects. Here, we suggest a particle-film plasmonic system in conjunction with tapered ZnO nanowire arrays for ultrasensitive SERS chemical sensors. In this design, the gap plasmons between the metal nanoparticles and the metal films provide significantly improved surface-enhanced Raman spectroscopy (SERS) effects compared to those of interparticle surface plasmons. Furthermore, 3D tapered metal nanostructures with particle-film plasmonic systems enable efficient light trapping and waveguiding effects. To study the effects of various morphologies of ZnO nanostructures on the light trapping and thus the SERS enhancements, we compare the performance of three different ZnO morphologies: ZnO nanocones (NCs), nanonails (NNs), and nanorods (NRs). Finally, we demonstrate that our SERS chemical sensors enable a molecular level of detection capability of benzenethiol (100 zeptomole), rhodamine 6G (10 attomole), and adenine (10 attomole) molecules. This work presents a new design platform based on the 3D antireflective metal/semiconductor heterojunction nanostructures, which will play a critical role in the study of plasmonics and SERS chemical sensors. PMID- 26575303 TI - Testing and estimation in marker-set association study using semiparametric quantile regression kernel machine. AB - We consider quantile regression for partially linear models where an outcome of interest is related to covariates and a marker set (e.g., gene or pathway). The covariate effects are modeled parametrically and the marker set effect of multiple loci is modeled using kernel machine. We propose an efficient algorithm to solve the corresponding optimization problem for estimating the effects of covariates and also introduce a powerful test for detecting the overall effect of the marker set. Our test is motivated by traditional score test, and borrows the idea of permutation test. Our estimation and testing procedures are evaluated numerically and applied to assess genetic association of change in fasting homocysteine level using the Vitamin Intervention for Stroke Prevention Trial data. PMID- 26575304 TI - Subtype Diagnosis of Primary Aldosteronism: Approach to Different Clinical Scenarios. AB - Identification and management of patients with primary aldosteronism are of utmost importance because it is a frequent cause of endocrine hypertension, and affected patients display an increase of cardio- and cerebro-vascular events, compared to essential hypertensives. Distinction of primary aldosteronism subtypes is of particular relevance to allocate the patients to the appropriate treatment, represented by mineralocorticoid receptor antagonists for bilateral forms and unilateral adrenalectomy for patients with unilateral aldosterone secretion. Subtype differentiation of confirmed hyperaldosteronism comprises adrenal CT scanning and adrenal venous sampling. In this review, we will discuss different clinical scenarios where execution, interpretation of adrenal vein sampling and subsequent patient management might be challenging, providing the clinician with useful information to help the interpretation of controversial procedures. PMID- 26575305 TI - Cerebrovascular Complications of Diabetes: Alpha Glucosidase Inhibitor as Potential Therapy. AB - Increased risk of cerebrovascular accident in diabetes cannot be fully explained by traditional risk factors. Epidemiological studies show that postprandial hyperglycemia is strongly associated with cerebrovascular events and cerebrovascular-associated mortality. Postprandial hyperglycemia contributes to vascular damage by several mechanisms such as endothelial dysfunction, arthrosclerosis, oxidative stress, inflammation, and hypercoagulability. Hyperglycemia has deleterious effects on the vascular endothelium and leads to the development of cerebrovascular disease. Thus, an important strategy to reduce cerebrovascular risk in patients with diabetes is to reduce postprandial hyperglycemia. Glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, and alpha-glucosidase inhibitors predominantly reduce postprandial plasma glucose levels. Among all of these, alpha-glucosidase inhibitors reduces postprandial hyperglycemia by delaying carbohydrate absorption from the intestine and this mechanism provides glycemic control without exacerbating coexisting cerebrovascular risk factors. Good glycemic control is proven to reduce the risk of cardiovascular complications, but equivalent evidence for cerebrovascular risk reduction is lacking. This review examines the evidences that postprandial hyperglycemia plays a major role in vascular damage, along with the complex interplay between hyperglycemia and coexisting risk factors. Furthermore, the mechanism by which alpha-glucosidase inhibitors may prevent this vascular damage as well as risk of hypoglycemia with alpha-glucosidase inhibitors are examined. Thus, this review suggests that alpha-glucosidase inhibitors are useful in reducing the risk of cerebrovascular events in patients with diabetes. PMID- 26575306 TI - Cardiovascular Risk in Primary Hyperaldosteronism. AB - After the first cases of primary aldosteronism were described and characterized by Conn, a substantial body of experimental and clinical evidence about the long term effects of excess aldosterone on the cardiovascular system was gathered over the last 5 decades. The prevalence of primary aldosteronism varies considerably between different studies among hypertensive patients, depending on patient selection, the used diagnostic methods, and the severity of hypertension. Prevalence rates vary from 4.6 to 16.6% in those studies in which confirmatory tests to diagnose primary aldosteronism were used. There is also growing evidence indicating that prolonged exposure to elevated aldosterone concentrations is associated with target organ damage in the heart, kidney, and arterial wall, and high cardiovascular risk in patients with primary aldosteronism. Therefore, the aim of treatment should not be confined to BP normalization and hypokalemia correction, but rather should focus on restoring the deleterious effects of excess aldosterone on the cardiovascular system. Current evidence convincingly demonstrates that both surgical and medical treatment strategies beneficially affect cardiovascular outcomes and mortality in the long term. Further studies can be expected to provide better insight into the relationship between cardiovascular risk and complications and the genetic background of primary aldosteronism. PMID- 26575307 TI - Antecedents of Young Women's Sexual Risk Taking in Tourist Experiences. AB - The purpose of this phenomenological exploration was to shed light on the constellation of factors anteceding young women's sexual risk taking during their tourist experiences. A total of 15 in-depth interviews (1.5 to 2.5 hours each) with 13 women were conducted and analyzed through the lens of transcendental phenomenology. An analysis of antecedent factors revealed a confluence of sociopersonal characteristics (e.g., sexual definitions, attitudes, double standards, and age) and touristic attributes (e.g., the sense of temporariness/ephemerality, anonymity, and fun-oriented mentality depending on length, destination, and type of tourist experience) that underlie women's proclivity for and perceptions of sexual risk taking in certain travel scenarios. These result in myriad effects on physical, sexual health, sociocultural, mental, and emotional aspects of women's health and well-being. While the sociopersonal antecedents highlight the cross-pollination between sex-related perceptions in everyday life and touristic environments, the touristic antecedents emphasize the uniqueness of tourist experiences as the contexts for sexual risk taking. The findings address an underresearched topic in sex and tourism scholarship and offer implications for health education and intervention programs, pointing to the value of constructing the context-specific and gender-sensitive sexual health messages underpinned by the ideas of women's empowerment and sexual agency. PMID- 26575308 TI - Atrial tachycardia ablation in patients with a functional single ventricle after the Fontan surgery. AB - BACKGROUND: Atrial tachyarrhythmias are a leading source of morbidity and mortality after Fontan-type procedures and antiarrhythmic drug therapy is often ineffective in these patients. AIM: To evaluate short- and long-term outcomes of radiofrequency current ablation for atrial tachycardia (AT) in patients after the Fontan procedure, and to report clinical, electrophysiological and electroanatomical characteristics of these arrhythmias. METHODS: We retrospectively analysed data obtained in 8 patients (5 males, 3 females) after the Fontan procedure who underwent ablation for AT between 2002 and 2013. In order to compare the clinical impact of arrhythmia before and after ablation, we used the modified arrhythmia score, ranging from 0 (no arrhythmia activity) to 12 (very severe arrhythmia). In all patients, electroanatomical mapping using the CARTO system was performed, allowing semiquantification of low-voltage (< 0.5 mV) areas and scars. RESULTS: Seven patients had an atriopulmonary connection and 1 patient had an extracardiac conduit. The mean patient age was 9.4 +/- 3.1 years at the time of the Fontan procedure and 26.2 +/- 4.6 years at the time of the first ablation. A total of 18 ablations were performed with no complications, 1 to 4 (median 2.5) procedures per patient. In patients who had more than 1 ablation, the mean time from the first to the last procedure was 34.8 months (range 1-64 months). In individual patients, 1 to 4 (median 2.5) different ATs were observed, with the mean tachycardia cycle length of 334 +/- 95 ms. In 6 patients, low-voltage area (< 0.5 mV) comprised 25-50% of the right atrium, and in two others it comprised 10-25% and < 10% of the right atrium, respectively. Seven procedures were fully successful (ablation of all ATs), 7 were partially successful (ablation of only some AT, including clinical arrhythmia, but not of all ATs) and 4 were unsuccessful (failed ablation of clinical AT). The mean procedural, fluoroscopy and ablation times were 176 +/- 54.6, 13.7 +/- 5.7 and 21.7 +/- 11.9 min, respectively. Freedom from arrhythmia during the mean follow up of 58.6 +/- 46 months (range 11-127 months) since the last procedure was obtained in 4 patients. The median arrhythmia score after the last ablation was significantly reduced compared to baseline (4.5 vs. 8; p < 0.05). CONCLUSIONS: Catheter ablation of AT in patients after the Fontan procedure is safe but its acute and long-term efficacy is limited. Due to complex and extensive substrate, along with complex anatomy, recurrences are frequent and patients may require repeat ablation procedures. Suppression of arrhythmia is associated with an improved clinical status of the patients. PMID- 26575309 TI - EuroSCORE II does not show better accuracy nor predictive power in comparison to original EuroSCORE: a single-centre study. AB - BACKGROUND: EuroSCORE is used to predict postoperative mortality in patients undergoing cardiac surgery. Its updated version was published in 2011. AIM: To assess whether EuroSCORE II (ESII) predicts more accurately postoperative mortality after cardiac surgery in comparison with additive (addES) and logistic EuroSCORE (logES). METHODS: A total of 461 patients (aged 21-88 years, 63.4% of men) who underwent cardiac surgery (December 2010 - June 2011) were included into the prospective research. For each patient ESII, addES and logES were calculated. Accuracy, calibration, and clinical performance of these models were assessed with receiver operating characteristics analyses using the area under the curve and the Hosmer-Lemeshow test. Out of this population, a group of 300 coronary artery bypass grafting (CABG) patients (aged 42-85 years, 73% of men) was selected and statistically analysed using the same methods. RESULTS: The mortality rate was 5.21%. Predicted mortality rates were as follows: addES 4.68%, logES 4.57%, and ESII 1.89%; the accuracy was: 0.589, 0.728, and 0.726, respectively. Only logES presented good predictive power (Hosmer-Lemeshow test: c2 = 12.79, p = 0.12). In the CABG patients, the postoperative mortality rate was 5.33%. Predicted mortality rates were as follows: addES 4.69%, logES 4.59%, and ESII 1.88%; the accuracy was: 0.512, 0.691, and 0.687, respectively. In the Hosmer-Lemeshow test also logES presented good predictive power (c2 = 10.72, p = 0.218). CONCLUSIONS: EuroSCORE II did not estimate mortality risk better in comparison to its previous versions, in the entire studied population or in the CABG patients. On the basis of the analysed data, it seems that the closest to the actual risk of death for the Polish population is the EuroSCORE logistic model. PMID- 26575310 TI - The effect of left ventricular diastolic function on the secretion of B-type natriuretic peptide at rest and directly after exercise test in asymptomatic patients with diabetes or after myocardial infarction with preserved left ventricular systolic functi. AB - BACKGROUND: Clinical evaluation of patients with diabetes or after myocardial infarction (MI) with preserved left ventricular (LV) systolic function is not very precise in isolating patients at particularly high risk of developing manifest cardiac failure and associated cardiovascular incident. Early diagnosis of LV diastolic dysfunction is essential because implementation of the appropriate treatment can positively affect the course of the disease. AIM: To assess the impact of LV diastolic function on B-type natriuretic peptide (BNP) concentration at rest and immediately after exercise test, and to search for the relationship between LV diastolic function and BNP secretion, tolerance, and duration of exercise in the studied groups of patients. METHODS: Ninety-nine consecutive patients were qualified for the study: in Group 1 - patients with type 2 diabetes without a history of MI, and in Group 2 - patients after MI with preserved LV systolic function (ejection fraction >= 40%), without diabetes. The studied patients had echocardiography with LV systolic and diastolic function evaluation, an electrocardiographic exercise test and blood sampling for BNP determination before and immediately after exercise test. RESULTS: The study included 99 patients aged 40-75 years (60 patients after MI and 39 patients with diabetes). The study group included 62 patients who were diagnosed with diastolic dysfunction. Diastolic dysfunction occurred in 41 (68.4%) patients in the group after MI, and in 21 (53.8%) patients in the group with diabetes, severe disorders in the form of pseudonormal and restrictive mitral valve inflow occurred in 13 (21.7%) and five (12.8%), respectively. The average BNP concentration in patients with severe diastolic dysfunction at rest was 188.3 vs. 25.2 pg/mL in patients with normal diastolic function (p < 0.001). In all patients with severe diastolic dysfunction BNP after exercise was 285.2 vs. 37.5 pg/mL in patients with normal diastolic function, and the increase in BNP during exercise was 96.9 vs. 12.4 pg/mL, respectively. Duration of exercise and exercise tolerance in patients with normal diastolic function was better in comparison with the studied patients with disturbed diastolic function, but did not reach statistical significance. CONCLUSIONS: The BNP initial concentration and its value immediately after exercise were significantly higher in subjects with severe diastolic disorders than those in subjects with normal LV diastolic function and in subjects with impaired LV relaxation. PMID- 26575311 TI - Impact of anaemia on long-term outcomes in patients treated with first- and second-generation drug-eluting stents; Katowice-Zabrze Registry. AB - BACKGROUND: Coexisting anaemia is associated with an increased risk of major adverse cardiac and cerebrovascular events (MACCE) and bleeding complications after percutaneous coronary intervention (PCI), especially in patients with acute coronary syndrome. AIM: To assess the impact of anaemia in patients with coronary artery disease (CAD) treated with first- and second-generation drug-eluting stents (DES) on one-year MACCE. METHODS AND RESULTS: The registry included 1916 consecutive patients (UA: n = 1502, 78.3%; NSTEMI: n = 283, 14.7%; STEMI/LBBB: n = 131, 6.8%) treated either with first- (34%) or second-generation (66%) DES. The study population was divided into two groups: patients presenting with anaemia 217 (11%) and without anaemia 1699 (89%) prior to PCI. Anaemia was defined according to World Heart Organisation (haemoglobin [Hb] level < 13 g/dL for men and < 12 g/dL for women). Patients with anaemia were older (69, IQR: 61-75 vs. 62, IQR: 56-70, p < 0.001), had higher prevalence of co-morbidities: diabetes (44.7% vs. 36.4%, p = 0.020), chronic kidney disease (31.3% vs. 19.4%; p < 0.001), peripheral artery disease (10.1% vs. 5.4%, p = 0.005), and lower left ventricular ejection fraction values (50, IQR: 40-57% vs. 55, IQR: 45-60%; p < 0.001). No difference between gender in frequency of anaemia was found. Patients with anaemia more often had prior myocardial infarction (MI) (57.6% vs. 46.4%; p = 0.002) and coronary artery bypass grafting (31.3% vs. 19.4%; p < 0.001) in comparison to patients without anaemia. They also more often had multivessel disease in angiography (36.4% vs. 26.1%; p = 0.001) and more complexity CAD as measured by SYNTAX score (21, IQR: 12-27 points vs. 14, IQR: 8-22 points; p = 0.001). In-hospital risk of acute heart failure (2.7% vs. 0.7%; p = 0.006) and bleeding requiring transfusion (3.2% vs. 0.5%; p < 0.001) was significantly higher in patients with anaemia. One-year follow-up showed that there was higher rate of death in patients with anaemia. However, there were no differences in MI, stroke, target vessel revascularisation (TVR) and MACCE in comparison to patients with normal Hb. There were no differences according to type of DES (first vs. second generation) in the population of patients with anaemia. CONCLUSIONS: In patients with anaemia there is a significantly higher risk of death in 12-month follow-up, but anaemia has no impact on the incidence of MI, repeat revascularisation, stroke and MACCE. There is no advantage of II-DES over I-DES generation in terms of MACCE and TVR in patients with anaemia. PMID- 26575312 TI - Cardiac pacing in 21 patients with Emery-Dreifuss muscular dystrophy: a single centre study with a 39-year follow-up. AB - BACKGROUND: Emery-Dreifuss muscular dystrophy (EDMD) is a genetic condition associated with cardiac arrhythmias. The patients typically develop early, asymptomatic bradyarrhythmia, which may lead to sudden death, preventable with a cardiac implantable electronic device (CIED). EDMD may be characterised by atrial electrical silence. Intra-operative electrophysiological evaluation of the myocardium helps ultimately determine the true nature of the disorder and select an appropriate CIED. AIM: To analyse permanent electrotherapy procedures in EDMD patients: atrial pacing limitations that stem from the electrophysiological properties of the myocardium and long-term follow-up of implanted devices. METHODS: A total of 21 EDMD patients (mean age 29 +/- 9 years) with a CIED implanted (1976-2014) due to bradyarrhythmia were included in the study. The implantation procedures and factors determining the CIED type selection were analysed. RESULTS: CIEDs were implanted in five women and in 16 men with EDMD types 1 and 2 (mean follow-up: 11 +/- 8 years). Intra-operatively assessed atrial electrophysiology resulted in changing the planned CIED type during the procedure in three men with EDMD type 1. Eventually, we implanted: eight DDD, one VDD, 11 VVI, and one CD-DR device, with four of the patients' devices switched later from DDD to VVI mode in response to electrophysiological changes in the atria. CONCLUSIONS: Intra-operative assessment of atrial electrophysiological properties resulted in changing the planned DDD mode for VVI in 19% of patients with EDMD type 1. Progression of the underlying disease over a 39-year follow-up resulted in a later change of the initially selected pacing mode from DDD to VVI in 40% of cases. PMID- 26575313 TI - Prosthesis-patient mismatch and left ventricle systolic strain in patients with severe degenerative aortic stenosis, who are undergoing surgical valve replacement. AB - BACKGROUND: Prosthesis-patient mismatch (PPM) is an independent predictor of post operative mortality after aortic valve replacement (AVR), particularly when it is associated with a left ventricle (LV) dysfunction. Two-dimensional speckle tracking echocardiography (2D-STE) could be useful in assessing LV function in patients with PPM. AIM: To evaluate the impact of PPM on myocardial multidirectional LV systolic strain in patients who are undergoing AVR for severe degenerative aortic stenosis (AS). METHODS: Sixty-five patients (38 females, 27 males, age: 69.9 +/- 9.1 years) with severe degenerative AS and preserved LV ejection fraction were enrolled into the study. Pre- and three-month postoperative 2D-STE was performed to assess LV peak systolic longitudinal strain (LV PSLS), circumferential strain, and LV rotation. The indexed prosthesis effective orifice area (iEOAprosth) was used to define PPM (<= 0.65 cm2/m2), and it was used to distinguish the study groups: PPM (+) (n = 35) and PPM (-) (n = 30). RESULTS: A significant association of LV PSLS and interaction in the groups [PPM (+) vs. PPM (-)] and intervention (before vs. after AVR; p = 0.019) was observed - the lowest value of LV PSLS was in the PPM (+) group (-14.9 +/- 3.5%) after AVR. A significant difference in the mean delta (before/after AVR) values of LV PSLS (0.7 +/- 3.1% vs. -1.2 +/- 3.6%; p = 0.04) in the PPM (+) vs. the PPM (-) groups was found. LV PSLS correlated with iEOAprosth (r = -0.520, p < 0.001) that was obtained three months after AVR. CONCLUSIONS: The occurrence of PPM in patients undergoing AVR for severe degenerative AS was associated with reduced LV PSLS in a three-month observation. PMID- 26575314 TI - Correction: Parent Engagement With a Telehealth-Based Parent-Mediated Intervention Program for Children With Autism Spectrum Disorders: Predictors of Program Use and Parent Outcomes. PMID- 26575315 TI - Better Informed Distance Geometry: Using What We Know To Improve Conformation Generation. AB - Small organic molecules are often flexible, i.e., they can adopt a variety of low energy conformations in solution that exist in equilibrium with each other. Two main search strategies are used to generate representative conformational ensembles for molecules: systematic and stochastic. In the first approach, each rotatable bond is sampled systematically in discrete intervals, limiting its use to molecules with a small number of rotatable bonds. Stochastic methods, on the other hand, sample the conformational space of a molecule randomly and can thus be applied to more flexible molecules. Different methods employ different degrees of experimental data for conformer generation. So-called knowledge-based methods use predefined libraries of torsional angles and ring conformations. In the distance geometry approach, on the other hand, a smaller amount of empirical information is used, i.e., ideal bond lengths, ideal bond angles, and a few ideal torsional angles. Distance geometry is a computationally fast method to generate conformers, but it has the downside that purely distance-based constraints tend to lead to distorted aromatic rings and sp(2) centers. To correct this, the resulting conformations are often minimized with a force field, adding computational complexity and run time. Here we present an alternative strategy that combines the distance geometry approach with experimental torsion-angle preferences obtained from small-molecule crystallographic data. The torsional angles are described by a previously developed set of hierarchically structured SMARTS patterns. The new approach is implemented in the open-source cheminformatics library RDKit, and its performance is assessed by comparing the diversity of the generated ensemble and the ability to reproduce crystal conformations taken from the crystal structures of small molecules and protein ligand complexes. PMID- 26575316 TI - Oral cancer screening usefulness: between true and perceived effectiveness. AB - Screenings, introduced in the 1920s, became rapidly popular in healthcare settings. Chance is an intrinsic screening characteristic. Roughly one half of screened subjects are correctly classified merely by chance, and in high prevalence settings, even inaccurate screenings detect several diseased individuals by chance, thus appearing effective. The viewpoint is another variable affecting screening perceived effectiveness. For example, public health officers, who seek for mortality rate reductions, look for high sensitivity, which, in turn, is affected by disease prevalence. The relative mortality rate reduction attributable to screening may therefore be significant in high prevalence areas and irrelevant in low-prevalence areas. This explains why oral cancer visual screening is perceived effective in high-prevalence countries and ineffective in low-prevalence countries. Patients seek for reliable outcomes. Therefore, they require screenings with high positive (PV+) and negative (PV-) predictive values. In high-prevalence areas, PV+ is high, while PV- is low. The reverse occurs in low-prevalence areas. Thus, even for accurate screenings, the perceived effectiveness due to misclassification is low among false-negative patients in high-prevalence areas, who are misclassified as unaffected by the disease, and among false-positive patients in low-prevalence areas, who are subjected to psychophysical sufferings. This article explains the reasons for these and other paradoxes engendered by screening. PMID- 26575318 TI - A cyst nematode effector binds to diverse plant proteins, increases nematode susceptibility and affects root morphology. AB - Cyst nematodes are plant-parasitic roundworms that are of significance in many cropping systems around the world. Cyst nematode infection is facilitated by effector proteins secreted from the nematode into the plant host. The cDNAs of the 25A01-like effector family are novel sequences that were isolated from the oesophageal gland cells of the soybean cyst nematode (Heterodera glycines). To aid functional characterization, we identified an orthologous member of this protein family (Hs25A01) from the closely related sugar beet cyst nematode H. schachtii, which infects Arabidopsis. Constitutive expression of the Hs25A01 CDS in Arabidopsis plants caused a small increase in root length, accompanied by up to a 22% increase in susceptibility to H. schachtii. A plant-expressed RNA interference (RNAi) construct targeting Hs25A01 transcripts in invading nematodes significantly reduced host susceptibility to H. schachtii. These data document that Hs25A01 has physiological functions in planta and a role in cyst nematode parasitism. In vivo and in vitro binding assays confirmed the specific interactions of Hs25A01 with an Arabidopsis F-box-containing protein, a chalcone synthase and the translation initiation factor eIF-2 beta subunit (eIF-2bs), making these proteins probable candidates for involvement in the observed changes in plant growth and parasitism. A role of eIF-2bs in the mediation of Hs25A01 virulence function is further supported by the observation that two independent eIF-2bs Arabidopsis knock-out lines were significantly more susceptible to H. schachtii. PMID- 26575319 TI - Prevalence of Developmental Delay and Contributing Factors Among Children With Sickle Cell Disease. AB - BACKGROUND: Children with sickle cell disease (SCD) are at higher risk for deficits in cognition compared to the general population, even at young ages. Disease severity has been co-assessed in earlier studies, but the home environment has not. The purpose of the current study was to investigate the development of young children with SCD and secondarily, the impact of environmental and family factors. METHODS: The current study is a baseline cross sectional evaluation of a prospective, single-center cohort. Children with SCD between the ages of 1 and 42 months and their primary caregiver were included. Participants lived within 30 miles of the site and spoke English. Children underwent developmental evaluation using the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III). Home visits were completed and screened using the Home Observation for Measurement of the Environment (HOME). RESULTS: Over 3 years, 43 caregiver-child dyads consented and participated. Over 50% of children scored significantly below average on cognition and expressive language subscales. SCD severity was not associated with BSID-III scores. Socioeconomic status (SES) determined by the Diez-Roux method positively correlated (r = 0.401, P < 0.01) with the home environment. The HOME correlated (r = 0.360, P < 0.05) with the cognitive subscale on the BSID-III. CONCLUSIONS: Given the high prevalence of developmental delay in this population, identifying modifiable factors to maximize developmental progress is essential. The home environment would be a targeted method for intervention. Future research is needed to identify the benefits of home-based intervention for this population. PMID- 26575320 TI - Correction: A mild and facile synthesis of polyfunctionalized pyridines: merging three-component cyclization and aerobic oxidation by amine/metal catalysts. AB - Correction for 'A mild and facile synthesis of polyfunctionalized pyridines: merging three-component cyclization and aerobic oxidation by amine/metal catalysts' by Chunyin Zhu et al., Org. Biomol. Chem., 2015, 13, 6278-6285. PMID- 26575317 TI - Fibromyalgia prevalence and related factors in a large registry of patients with systemic lupus erythematosus. AB - OBJECTIVES: The objective of this study is to determine the prevalence of fibromyalgia (FM) in systemic lupus erythematosus (SLE) patients and to study its relationship to depression and other SLE-related factors. METHODS: A cross sectional data analysis from the RELESSER-Transversal Spanish Registry, which includes SLE patients in a national multicentre retrospective charts review, was performed. INCLUSION CRITERIA: patients who fulfilled >=4 ACR 1997 SLE criteria. Main variables were disease duration, depression, sociodemographics, comorbidities, SLE activity symptoms, serological findings, therapies and different disease status indices. Statistical analyses included a descriptive, associative and logistic regression analyses. A literature review was performed. RESULTS: 3,591 SLE patients were included, 90.1% women, 34.6 years of age at diagnosis (SD 14.6 years) and 93.1% Caucasians. FM prevalence was 6.2%. SLE patients with disease duration >5 years showed more FM than those with duration <5 years: 6.9% vs. 4.0%, respectively (p<0.05). SLE-FM patients showed higher prevalence of depression compared to non-FM-SLE patients: 53.1% vs. 14.6%, respectively (p<0.001). After adjusting by risk factors, the OR (CI) of suffering depression in FM-SLE patients was 6.779 (4.770-9.636), p<0.001. The OR of having secondary Sjogren's 2.447 (1.662-3.604), p<0.001, photosensitivity 2.184 (1.431 3.334), p<0.001, and oral ulcers 1.436 (1.005-2.051), p=0.047. CONCLUSIONS: Prevalence of FM in Caucasian SLE patients was high compared to the general population, and was significantly higher in those in later stages of disease. SLE patients with depression showed a strong risk of developing FM. Photosensitivity, oral ulcers and secondary Sjogren's were the only SLE-related factors associated with FM. PMID- 26575321 TI - Revisiting the concept of the (a)synchronicity of Diels-Alder reactions based on the dynamics of quasiclassical trajectories. AB - A number of model Diels-Alder (D-A) cycloaddition reactions (H2C=CH2 + cyclopentadiene and H2C=CHX + 1,3-butadiene, with X = H, F, CH3, OH, CN, NH2, and NO) were studied by static (transition state - TS and IRC) and dynamics (quasiclassical trajectories) approaches to establish the (a)synchronous character of the concerted mechanism. The use of static criteria, such as the asymmetry of the TS geometry, for classifying and quantifying the (a)synchronicity of the concerted D-A reaction mechanism is shown to be severely limited and to provide contradictory results and conclusions when compared to the dynamics approach. The time elapsed between the events is shown to be a more reliable and unbiased criterion and all the studied D-A reactions, except for the case of H2C=CHNO, are classified as synchronous, despite the gradual and quite distinct degrees of (a)symmetry of the TS structures. PMID- 26575322 TI - Commentary on "A Framework for Quantifying the Influence of Adherence and Dose Individualization". AB - Drugs that provide long durations of action after a last-taken dose are said to be "forgiving," as they allow the patient a degree of latitude in the timing of sequential doses. New research, by Assawasuwannakit et al.,(1) based on exemplary methods, enriches the pharmacometric analysis of forgiveness, which for several decades had been a simply descriptive reminder that the beneficial actions of some drugs can continue for hours or days after the disappearance of detectable drug. PMID- 26575323 TI - Bioassay of salmeterol in children using methacholine challenge with impulse oscillometry. AB - BACKGROUND: Bronchoprovocation with methacholine (MC) is the most sensitive method of determining bioequivalence of inhaled bronchodilators. FEV1 is used to determine the endpoint, but many children cannot perform spirometry reproducibly. The purpose of this study was to determine whether MC, using impulse oscillometry (IOS) as the endpoint, can differentiate between two doses of salmeterol (SM). METHODS: This was a single-blind, randomized study of 10 subjects with mild stable asthma, ages 4-11 years. None were taking a long-acting beta-agonist but most were on low-dose inhaled corticosteroid. On one study day, MC was performed 1 hr after one inhalation from each of two separate Advair 100/50 Diskus (100 MUg salmeterol treatment). On a second day, MC was performed after one inhalation from Advair Diskus and one inhalation from Flovent Diskus 100 (50 MUg salmeterol treatment). The provocative concentration of methacholine causing a 40% increase in total airway resistance (PC40 R5 ) was calculated. RESULTS: The reduction in R5 (bronchodilator effect) was 15.5% and 18.4% for 50 and 100 MUg, respectively (NS). After MC (bronchoprotective effect), the geometric mean (95%CI) PC40 R5 (mg/ml) was 2.4 (1.3-4.4) during screening, 22.9 (8.5-61.6) after 50 MUg SM and 47.0 (25.2-87.8) after 100 MUg SM (P = 0.051 for 50 vs. 100 using a linear mixed effects model). No adverse effects were observed. CONCLUSIONS: MC with IOS endpoint will be a useful method for determining bioequivalence of a generic inhaler in children. Seventy-two subjects will be required to achieve 80% power to assess bioequivalence of SM. Pediatr Pulmonol. 2016;51:570-575. (c) 2015 Wiley Periodicals, Inc. PMID- 26575324 TI - Water-Soluble 8-Hydroxyquinoline Conjugate of Amino-Glucose As Receptor for La(3+) in HEPES Buffer, on Whatman Cellulose Paper and in Living Cells. AB - A water-soluble glucopyranosyl conjugate, L, has been synthesized and characterized by different analytical and spectral techniques. The L has been demonstrated to have switch-on fluorescence enhancement of ~75 fold in the presence of La(3+) among the nine lanthanide ions studied in the HEPES buffer at pH 7.4. A minimum detection limit of 140 nM (16 +/- 2 ppb) was shown by L for La(3+) in the buffer at physiological pH. The utility of L has been demonstrated by showing its sensitivity toward La(3+) on Whatman filter paper strips. The reversible and reusable action of L has been demonstrated by monitoring the fluorescence changes as a function of the addition of La(3+) followed by F(-) and HPO4(2-) ions. The complexation of L by La(3+) was shown by absorption spectra wherein isosbestic behavior was observed. The Job's plot suggests a 2:1 complex between L and La(3+), and the same was supported by ESI-MS. The control molecular study revealed the necessity of hydroxy quinoline and the amine group for La(3+) ion binding and the glyco-moiety to bring water solubility and biocompatibility. The structural features of the [2L+La(3+)] complex were established by DFT computational calculations. The chemo-ensemble, [2L+La(3+)], is shown responsible for providing intracellular fluorescence imaging in HepG2 cells. PMID- 26575325 TI - Impact of a pilot pathway for the management of gastroenteritis-like symptoms in an emergency department: A case study following a Salmonella outbreak. AB - OBJECTIVE: This research aims to describe the effect of standard care (control) versus a clinical management pathway (intervention) on patient length of stay and admission rates during a public health emergency at one Australian ED. METHODS: A retrospective audit of hospital records for patients who presented in May 2013 with gastroenteritis-like symptoms was undertaken following a surge in patient presentations from a Salmonella outbreak. Patients who presented with gastroenteritis-like symptoms between 15 and 19 May 2013 received care according to a clinical management pathway (intervention). The focus of the intervention was based on symptom management, including a standardised approach to analgesia, anti-emetics and rehydration. Patient characteristics, such as age and gender are described using descriptive statistics. A Mann-Whitney test was used to compare continuous data, and a Fisher's exact test was used to compare categorical data, between the two groups. RESULTS: Over an 8 day period, 110 patients presented with gastroenteritis-like symptoms. The median length of stay was statistically different between the two groups (P < 0.001). More patients were admitted to hospital from the control group (n = 5) when compared with the intervention group (n = 0); however, given the small number of patients in these groups, inferential statistical analysis was not a reasonable consideration. CONCLUSION: The length of stay for patients between the two groups was statistically different, suggesting that the implementation of a clinical management pathway for patients with gastroenteritis-like symptoms reduced the ED length of stay. This finding is useful in future planning for similar public health emergency responses and/or for use when patients present with gastroenteritis-like symptoms on a daily basis. PMID- 26575326 TI - Patterns of care and treatment outcomes in older patients with biliary tract cancer. AB - BACKGROUND: Although biliary tract cancers (BTC) are common in older age-groups, treatment approaches and outcomes are understudied in this population. PATIENTS AND METHODS: Data from 913 patients diagnosed with BTC from January 1987 to July 2013 and treated at Princess Margaret Cancer Center, Toronto were analyzed. The differences in treatment patterns between older and younger patients were explored and the impact of age, patient and disease characteristics on survival outcomes was assessed. RESULTS: Three hundred and twenty one patients >= 70 years were identified. Older patients were more likely to receive best supportive care, 40% (n = 130), compared to younger patients 26% (n = 154); p < 0.0001. On multivariable analysis, factors associated with receipt of surgery included stage I/II disease (p < 0.0001) and ECOG PS < 2 (p < 0.0001). Older age was not associated with lack of surgical intervention. In comparison, older age was associated with non-receipt of palliative chemotherapy (p = 0.0007). Similar survival benefit from treatment was seen in older and younger patients. Of 626 patients that underwent either surgery or palliative chemotherapy (n = 188), the median survival was 21.1 months (95% CI 19.0-27.9) in patients >70 years of age, and 21.1 months in younger patients (n = 438) (95% CI 19.5-24.5). CONCLUSIONS: In this large retrospective analysis, older patients with BTC are less likely to undergo an intervention. However, active therapy when given is associated with similar survival benefits, irrespective of age. PMID- 26575327 TI - The genetic and genomic background of multiple myeloma patients achieving complete response after induction therapy with bortezomib, thalidomide and dexamethasone (VTD). AB - The prime focus of the current therapeutic strategy for Multiple Myeloma (MM) is to obtain an early and deep tumour burden reduction, up to the level of complete response (CR). To date, no description of the characteristics of the plasma cells (PC) prone to achieve CR has been reported. This study aimed at the molecular characterization of PC obtained at baseline from MM patients in CR after bortezomib-thalidomide-dexamethasone (VTD) first line therapy.One hundred and eighteen MM primary tumours obtained from homogeneously treated patients were profiled both for gene expression and for single nucleotide polymorphism genotype. Genomic results were used to obtain a predictor of sensitivity to VTD induction therapy, as well as to describe both the transcription and the genomic profile of PC derived from MM with subsequent optimal response to primary induction therapy.By analysing the gene profiles of CR patients, we identified a 5-gene signature predicting CR with an overall median accuracy of 75% (range: 72% 85%). In addition, we highlighted the differential expression of a series of genes, whose deregulation might explain patients' sensitivity to VTD therapy. We also showed that a small copy number loss, covering 606Kb on chromosome 1p22.1 was the most significantly associated with CR patients. PMID- 26575328 TI - Relationship of Oct-4 to malignant stage: a meta-analysis based on 502 positive/high Oct-4 cases and 522 negative/low case-free controls. AB - BACKGROUND: Octamer 4 (Oct-4), an important member of the POU domain transcription factor family, has been suggested to function as a master switch during differentiation of human somatic cells and more recently has come to be linked with neoplastic properties. The aim of this study was to evaluate the relationship between Oct-4 and cancer stage using a meta-analysis approach. MATERIALS AND METHODS: Relevant articles published as of May 2015 were retrieved from the following databases: PubMed, ISI Web of Knowledge, Embase, and Chinese National Knowledge Infrastructure (CNKI). The strengths of relationship for outcomes of interest were estimated based on odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: A total of 11 articles on Oct-4 and cancer staging that collectively included 502 positive/high Oct-4 cases and 522 negative/low case free controls were chosen. Positive/high Oct-4 was significantly associated with cancer stage in several kinds of cancer. Specifically, positive/high Oct-4 was associated with cancer stage III/IV (fixed effects: OR = 1.53, 95% CI = 1.12 2.10), primary tumor (T3-4) (random effects: OR = 1.93, 95% CI = 0.99-3.77), and cancer grade of differentiation (intermediate-poor) (random effects: OR = 3.45, 95% CI = 1.5-7.61). CONCLUSIONS: These findings suggest that positive/high Oct-4 is more strongly linked to stage III/IV cancer and cancer grade of differentiation, and is correlated with malignant characteristics that lead to poor prognosis in different types of cancer, especially in Asian. Given variability related to ethnicity and differences in cancer types, additional studies are warranted to establish the generalizability of our findings. PMID- 26575329 TI - KIAA0101 is associated with human renal cell carcinoma proliferation and migration induced by erythropoietin. AB - Erythropoietin (EPO) is a frequently prescribed anti-anemic drug for patients with advanced renal carcinoma. However, recent evidence from clinical studies suggested that EPO accelerated tumor progression and jeopardized the 5-year survival. Herein, we show, starting from the in silico microarray bioinformatics analysis, that activation of Erythropoietin signaling pathway enhanced renal clear carcinoma (RCC) progression. EPO accelerated the proliferative and migratory ability in 786-O and Caki-2 cells. Moreover, comparative proteomics expression profiling suggested that exogenous EPO stimulated RCC progression via up-regulation of KIAA0101 expression. Loss of KIAA0101 impeded the undesirable propensity of EPO in RCC. Finally, low expression of KIAA0101 was associated with the excellent prognosis and prognosticated a higher 5-year survival in human patients with renal carcinoma. Overall, KIAA0101 appears to be a key promoter of RCC malignancy induced by EPO, which provide mechanistic insights into KIAA0101 functions, and pave the road to develop new therapeutics for treatment of cancer related and chemotherapy-induced anemia in patients with RCC. PMID- 26575330 TI - Ion Channel Formation by Tau Protein: Implications for Alzheimer's Disease and Tauopathies. AB - Tau is a microtubule associated protein implicated in the pathogenesis of several neurodegenerative diseases. Because of the channel forming properties of other amyloid peptides, we employed planar lipid bilayers and atomic force microscopy to test tau for its ability to form ion permeable channels. Our results demonstrate that tau can form such channels, but only under acidic conditions. The channels formed are remarkably similar to amyloid peptide channels in their appearance, physical and electrical size, permanence, lack of ion selectivity, and multiple channel conductances. These channels differ from amyloid channels in their voltage dependence and resistance to blockade by zinc ion. These channels could explain tau's pathologic role in disease by lowering membrane potential, dysregulating calcium, depolarizing mitochondria, or depleting energy stores. Tau might also combine with amyloid beta peptides to form toxic channels. PMID- 26575332 TI - Synthesis, Structure, and Pressure-Induced Polymerization of Li3Fe(CN)6 Accompanied with Enhanced Conductivity. AB - Pressure-induced polymerization of charged triple-bond monomers like acetylide and cyanide could lead to formation of a conductive metal-carbon network composite, thus providing a new route to synthesize inorganic/organic conductors with tunable composition and properties. The industry application of this promising synthetic method is mainly limited by the reaction pressure needed, which is often too high to be reached for gram amounts of sample. Here we successfully synthesized highly conductive Li3Fe(CN)6 at maximum pressure around 5 GPa and used in situ diagnostic tools to follow the structural and functional transformations of the sample, including in situ X-ray and neutron diffraction and Raman and impedance spectroscopy, along with the neutron pair distribution function measurement on the recovered sample. The cyanide anions start to react around 1 GPa and bond to each other irreversibly at around 5 GPa, which are the lowest reaction pressures in all known metal cyanides and within the technologically achievable pressure range for industrial production. The conductivity of the polymer is above 10(-3) S . cm(-1), which reaches the range of conductive polymers. This investigation suggests that the pressure-induced polymerization route is practicable for synthesizing some types of functional conductive materials for industrial use, and further research like doping and heating can hence be motivated to synthesize novel materials under lower pressure and with better performances. PMID- 26575331 TI - Genetic variants in the vitamin D pathway genes VDBP and RXRA modulate cutaneous melanoma disease-specific survival. AB - Single nucleotide polymorphisms (SNPs) in the vitamin D pathway genes have been implicated in cutaneous melanoma (CM) risk, but their role in CM disease-specific survival (DSS) remains obscure. We comprehensively analyzed the prognostic roles of 2669 common SNPs in the vitamin D pathway genes using data from a published genome-wide association study (GWAS) at The University of Texas M.D. Anderson Cancer Center (MDACC) and then validated the SNPs of interest in another GWAS from the Nurses' Health Study and Health Professionals Follow-up Study. Among the 2669 SNPs, 203 were significantly associated with DSS in MDACC dataset (P < 0.05 and false-positive report probability < 0.2), of which 18 were the tag SNPs. In the replication, two of these 18 SNPs showed nominal significance: the VDBP rs12512631 T > C was associated with a better DSS [combined hazards ratio (HR) = 0.66]; and the same for RXRA rs7850212 C > A (combined HR = 0.38), which were further confirmed by the Fine and Gray competing-risks regression model. Further bioinformatics analyses indicated that these loci may modulate corresponding gene methylation status. PMID- 26575333 TI - What about the combined action of poly-herbal on wound healing? PMID- 26575334 TI - What Is the Optimal Sequence of Rescue Treatments for Attacks of Neuromyelitis Optica Spectrum Disorder? PMID- 26575335 TI - Intravenous infusion of amino acids in dogs attenuates hypothermia during anaesthesia and stimulates insulin secretion. AB - OBJECTIVE: To evaluate the effect of intravenous infusion of amino acids on the prevention of hypothermia during anaesthesia in dogs. STUDY DESIGN: Randomized experimental trial. ANIMALS: Seven healthy Beagle dogs. METHODS: Four concentrations of amino acids were prepared with a 10% amino acid solution and an acetated Ringer's solution, and dogs were infused with each of the solutions at 1 week intervals. Dogs were infused with amino acid solution at 12 mL kg(-1) hour( 1) for 60 minutes before and for 60 minutes after induction of anaesthesia. Acetated Ringer's solution was infused at the same rate for the remaining 60 minutes of anaesthesia. The infusion treatments were: 1) A0, nutrient-free acetated Ringer's solution; 2) A6, 0.6 g kg(-1) hour(-1) ; 3) A9, 0.9 g kg(-1) hour(-1) ; and 4) A12, 1.2 g kg(-1) hour(-1) . Rectal temperature (RT), heart rate (HR), mean arterial pressure (MAP), blood insulin, glucose, urea nitrogen (BUN) and creatinine concentrations, and time to extubation were measured. RESULTS: Before anaesthesia, RT was not affected by amino acid infusion. RT decreased progressively during anaesthesia and the absolute values of RT from 30 to 120 minutes were significantly higher in A12 than in A0 (p < 0.05). Reductions in HR and MAP during anaesthesia were attenuated by amino acid infusion in a dose dependent manner. Plasma insulin concentration was significantly higher in A12 than in A0 during amino acid infusion and the increase in insulin concentration was greater during than before anaesthesia. BUN increased during amino acid infusion in a dose- and time-dependent fashion. Time until extubation was shorter in A12 than in A0. CONCLUSIONS AND CLINICAL RELEVANCE: Amino acids infused at 1.2 g kg(-1) hour(-1) in dogs attenuated the decrease in RT, HR, and MAP during anaesthesia, and induced a significant increase in plasma insulin concentration. PMID- 26575336 TI - Localized Co-delivery of Doxorubicin, Cisplatin, and Methotrexate by Thermosensitive Hydrogels for Enhanced Osteosarcoma Treatment. AB - Localized cancer treatments with combination drugs have recently emerged as crucial approaches for effective inhibition of tumor growth and reoccurrence. In this study, we present a new strategy for the osteosarcoma treatment by localized co-delivery of multiple drugs, including doxorubicin (DOX), cisplatin (CDDP) and methotraxate (MTX), using thermosensitive PLGA-PEG-PLGA hydrogels. The release profiles of the drugs from the hydrogels were investigated in vitro. It was found that the multidrug coloaded hydrogels exhibited synergistic effects on cytotoxicity against osteosarcoma Saos-2 and MG-63 cells in vitro. After a single peritumoral injection of the drug-loaded hydrogels into nude mice bearing human osteosarcoma Saos-2 xenografts, the hydrogels coloaded with DOX, CDDP, and MTX displayed the highest tumor suppression efficacy in vivo for up to 16 days, as well as led to enhanced tumor apoptosis and increased regulation of the expressions of apoptosis-related genes. Moreover, the monitoring on the mice body change and the ex vivo histological analysis of the key organs indicated that the localized treatments caused less systemic toxicity and no obvious damage to the normal organs. Therefore, the approach of localized co-delivery of DOX, CDDP, and MTX by the thermosensitive hydrogels may be a promising approach for enhanced osteosarcoma treatment. PMID- 26575338 TI - Training: functional improvements of skeletal muscle oxidative metabolism can occur earlier than the enhancement of mitochondrial biogenesis. PMID- 26575337 TI - An amino acid code to define a protein's tertiary packing surface. AB - One difficult aspect of the protein-folding problem is characterizing the nonspecific interactions that define packing in protein tertiary structure. To better understand tertiary structure, this work extends the knob-socket model by classifying the interactions of a single knob residue packed into a set of contiguous sockets, or a pocket made up of 4 or more residues. The knob-socket construct allows for a symbolic two-dimensional mapping of pockets. The two dimensional mapping of pockets provides a simple method to investigate the variety of pocket shapes to understand the geometry of protein tertiary surfaces. The diversity of pocket geometries can be organized into groups of pockets that share a common core, which suggests that some interactions in pockets are ancillary to packing. Further analysis of pocket geometries displays a preferred configuration that is right-handed in alpha-helices and left-handed in beta sheets. The amino acid composition of pockets illustrates the importance of nonpolar amino acids in packing as well as position specificity. As expected, all pocket shapes prefer to pack with hydrophobic knobs; however, knobs are not selective for the pockets they pack. Investigating side-chain rotamer preferences for certain pocket shapes uncovers no strong correlations. These findings allow a simple vocabulary based on knobs and sockets to describe protein tertiary packing that supports improved analysis, design, and prediction of protein structure. PMID- 26575339 TI - Oxygen transport adaptations to exercise in native highland populations. PMID- 26575340 TI - The pulmonary vasculature--lessons from Tibetans and from rare diseases of oxygen sensing. AB - NEW FINDINGS: What is the topic of this review? This review is principally concerned with results from studies of the pulmonary vasculature in humans, particularly in relation to hypoxia and rare diseases that affect oxygen sensing. What advances does it highlight? This review highlights the degree to which the hypoxia-inducible factor (HIF) transcription system influences human pulmonary vascular responses to hypoxia. Upregulation of the HIF pathway augments hypoxic pulmonary vasoconstriction, while alterations to the pathway found in Tibetans are associated with suppression of the progressive increase in pulmonary artery pressure with sustained hypoxia. It also highlights the potential importance of iron, which modulates the HIF pathway, in modifying the pulmonary vascular response to hypoxia. The human pulmonary circulation loses its natural distensibility during sustained hypoxia, leading to pulmonary arterial hypertension and a much higher workload for the right ventricle. The hypoxia inducible factor (HIF) pathway is implicated in this pulmonary vascular response to continued hypoxia by animal studies, and additionally, by rare human diseases where the pathway is upregulated. However, there are no known human genetic diseases downregulating HIF. Tibetans, though, demonstrate blunted pulmonary vascular responses to sustained hypoxia. This seems to be accounted for by an altered HIF pathway as a consequence of natural selection over a period of many thousands of years lived at high altitude. In addition to genetic differences, iron is another important modulator of HIF pathway function. Experimental work in humans demonstrates that manipulation of iron stores can influence the behaviour of the pulmonary circulation during hypoxia, in ways analogous to that seen in Tibetans and patients with rare diseases that affect oxygen sensing. The importance of physiological differences in iron bioavailability in modulating hypoxic pulmonary vasoconstriction in health and disease is yet to be established. PMID- 26575341 TI - Short-term adaptation and chronic cardiac remodelling to high altitude in lowlander natives and Himalayan Sherpa. AB - NEW FINDINGS: What is the topic of this review? At high altitude, the cardiovascular system must adapt in order to meet the metabolic demand for oxygen. This review summarizes recent findings relating to short-term and life long cardiac adaptation to high altitude in the context of exercise capacity. What advances does it highlight? Both Sherpa and lowlanders exhibit smaller left ventricular volumes at high altitude; however, myocardial relaxation, as evidenced by diastolic untwist, is reduced only in Sherpa, indicating that short term hypoxia does not impair diastolic relaxation. Potential remodelling of systolic function, as evidenced by lower left ventricular systolic twist in Sherpa, may facilitate the requisite sea-level mechanical reserve required during exercise, although this remains to be confirmed. Both short-term and life-long high-altitude exposure challenge the cardiovascular system to meet the metabolic demand for O2 in a hypoxic environment. As the demand for O2 delivery increases during exercise, the circulatory component of oxygen transport is placed under additional stress. Acute adaptation and chronic remodelling of cardiac structure and function may occur to facilitate O2 delivery in lowlanders during sojourn to high altitude and in permanent highland residents. However, our understanding of cardiac structural and functional adaption in Sherpa remains confined to a higher maximal heart rate, lower pulmonary vascular resistance and no differences in resting cardiac output. Ventricular form and function are intrinsically linked through the left ventricular (LV) mechanics that facilitate efficient ejection, minimize myofibre stress during contraction and aid diastolic recoil. Recent examination of LV mechanics has allowed detailed insight into fundamental cardiac adaptation in high-altitude Sherpa. In this symposium report, we review recent advances in our understanding of LV function in both lowlanders and Sherpa at rest and discuss the potential consequences for exercise capacity. Collectively, data indicate chronic structural ventricular adaptation, with adult Sherpa having smaller absolute and relative LV size. Consistent with structural remodelling, cardiac mechanics also differ in Sherpa when compared with lowlanders at high altitude. These differences are characterized by a reduction in resting systolic deformation and slower diastolic untwisting, a surrogate of relaxation. These changes may reflect a functional cardiac adaptation that affords Sherpa the same mechanical reserve seen in lowlanders at sea level, which is absent when they ascend to high altitude. PMID- 26575342 TI - Observational Constraints on the Oxidation of NOx in the Upper Troposphere. AB - NOx (NOx = NO + NO2) regulates O3 and HOx (HOx = OH + HO2) concentrations in the upper troposphere. In the laboratory, it is difficult to measure rates and branching ratios of the chemical reactions affecting NOx at the low temperatures and pressures characteristic of the upper troposphere, making direct measurements in the atmosphere especially useful. We report quasi-Lagrangian observations of the chemical evolution of an air parcel following a lightning event that results in high NOx concentrations. These quasi-Lagrangian measurements obtained during the Deep Convective Clouds and Chemistry experiment are used to characterize the daytime rates for conversion of NOx to different peroxy nitrates, the sum of alkyl and multifunctional nitrates, and HNO3. We infer the following production rate constants [in (cm(3)/molecule)/s] at 225 K and 230 hPa: 7.2(+/-5.7) * 10( 12) (CH3O2NO2), 5.1(+/-3.1) * 10(-13) (HO2NO2), 1.3(+/-0.8) * 10(-11) (PAN), 7.3(+/-3.4) * 10(-12) (PPN), and 6.2(+/-2.9) * 10(-12) (HNO3). The HNO3 and HO2NO2 rates are ~ 30-50% lower than currently recommended whereas the other rates are consistent with current recommendations to within +/-30%. The analysis indicates that HNO3 production from the HO2 and NO reaction (if any) must be accompanied by a slower rate for the reaction of OH with NO2, keeping the total combined rate for the two processes at the rate reported for HNO3 production above. PMID- 26575343 TI - Arthroamide, a Cyclic Depsipeptide with Quorum Sensing Inhibitory Activity from Arthrobacter sp. AB - Nonfilamentous actinobacteria have been less studied as secondary metabolite producers than their filamentous counterparts such as Streptomyces. From our collection of nonfilamentous actinobacteria isolated from sandstone, an Arthrobacter strain was found to produce a new cyclic peptide arthroamide (1) together with the known compound turnagainolide A (2). These compounds inhibited the quorum sensing signaling of Staphylococcus aureus in the submicromolar to micromolar range. PMID- 26575344 TI - Premagnetization for Enhancing the Reactivity of Multiple Zerovalent Iron Samples toward Various Contaminants. AB - Premagnetization was applied to enhance the removal of various oxidative contaminants (including amaranth (AR27), lead ion (Pb(2+)), cupric ion (Cu(2+)), selenite (Se(4+)), silver ion (Ag(+)), and chromate (Cr(6+))) by zerovalent iron (ZVI) from different origins under well-controlled experimental conditions. The rate constants of contaminants by premagnetized ZVI (Mag-ZVI) samples were 1.2 12.2-fold greater than those by pristine ZVI (Pri-ZVI) samples. Generally, there was a linear correlation between the specific reaction rate constants (kSA) of one particular contaminant removal by various Pri-ZVI or Mag-ZVI samples and those of the other contaminant, which could be successfully employed to predict the kSA of one contaminant by one ZVI sample if kSA of the other contaminant by this ZVI sample was available. The specific rate constant of Fe(II) release at pH 4.0 was proposed in this study to stand for the intrinsic reactivity of a ZVI sample. All Mag-ZVI samples had higher intrinsic reactivity than their counterparts without premagnetization. There were strong correlations between the intrinsic reactivity of various Pri-ZVI/Mag-ZVI samples and the removal rate constants of a specific contaminant by these ZVI samples not only at pH 4.0 when the intrinsic reactivity was determined but also at other pH levels. This correlation could be employed to predict the removal rate constant of this contaminant by a ZVI sample that was not included in the original data set once the intrinsic reactivity of the ZVI sample was known. PMID- 26575345 TI - Photoinduced Bending of Self-Assembled Azobenzene-Siloxane Hybrid. AB - A novel azobenzene-siloxane hybrid material displaying photoinduced macroscopic motions has been prepared by one-step organosilane self-assembly. Two types of alkoxysilane precursors with either pendant or bridging azobenzene groups were synthesized via thiol-ene click reactions. Hybrid films with well-ordered lamellar structures were obtained by hydrolysis and polycondensation of these precursors. The film with solely pendant azobenzene groups showed reversible and rapid d-spacing variation upon UV-vis irradiation, which was induced by the trans cis isomerization of azobenzene moieties. The flexible, free-standing film obtained by co-condensation of two types of precursors showed reversible bending unbending motions upon UV-vis irradiation. The partial cross-linking between the siloxane layers by bridging azobenzene groups was crucial for photoinduced distortion of the film. This film possesses high elastic modulus, good thermal stability, and shows large amplitude of photoinduced bending-unbending over a wide temperature range. This is the first report on photoinduced macroscopic motions of azobenzene-containing siloxane-based materials. These materials possess great potential for applications in smart devices and energy conversion systems. PMID- 26575346 TI - A lack of 'glue' misplaces Rab27A to cause islet dysfunction in diabetes. AB - Glucose-stimulated insulin secretion (GSIS) involves interplay between metabolic and cationic events. Several lines of evidence suggest novel regulatory roles for small G proteins (Rac1, Cdc42, Rab27A) in cytoskeletal remodelling and docking of insulin granules on the plasma membrane for insulin secretion. Emerging evidence implicates novel roles for post-translational prenylation (farnesylation and geranylgeranylation) of G proteins for their targeting to appropriate membranous compartments. While several recent studies were focused on prenylating enzymes in the islet beta-cell, a significant knowledge gap exists on the regulatory roles and function of enzymes that mediate intracellular generation of prenyl pyrophosphate substrates (farnesyl and geranylgeranyl pyrophosphates) for prenyltransferases. Recent work published in The Journal of Pathology by Jiang and associates highlights requisite roles for geranylgeranyl pyrophosphate synthase (GGPPS) in islet beta-cell function in health and diabetes. These studies are timely and will form the basis for a series of new investigations to further validate roles for G-protein prenylation in GSIS under physiological conditions. They also pave the path towards the identification of potential defects in these signalling pathways in beta-cell models of impaired insulin secretion including metabolic stress and diabetes. PMID- 26575347 TI - On the decline of biodiversity due to area loss. AB - Predictions of how different facets of biodiversity decline with habitat loss are broadly needed, yet challenging. Here we provide theory and a global empirical evaluation to address this challenge. We show that extinction estimates based on endemics-area and backward species-area relationships are complementary, and the crucial difference comprises the geometry of area loss. Across three taxa on four continents, the relative loss of species, and of phylogenetic and functional diversity, is highest when habitable area disappears inward from the edge of a region, lower when it disappears from the centre outwards, and lowest when area is lost at random. In inward destruction, species loss is almost proportional to area loss, although the decline in phylogenetic and functional diversity is less severe. These trends are explained by the geometry of species ranges and the shape of phylogenetic and functional trees, which may allow baseline predictions of biodiversity decline for underexplored taxa. PMID- 26575348 TI - Thankful for the little things: A meta-analysis of gratitude interventions. AB - A recent qualitative review by Wood, Froh, and Geraghty (2010) cast doubt on the efficacy of gratitude interventions, suggesting the need to carefully attend to the quality of comparison groups. Accordingly, in a series of meta-analyses, we evaluate the efficacy of gratitude interventions (ks = 4-18; Ns = 395-1,755) relative to a measurement-only control or an alternative-activity condition across 3 outcomes (i.e., gratitude, anxiety, psychological well-being). Gratitude interventions outperformed a measurement-only control on measures of psychological well-being (d = .31, 95% confidence interval [CI = .04, .58]; k = 5) but not gratitude (d = .20; 95% CI [-.04, .44]; k = 4). Gratitude interventions outperformed an alternative-activity condition on measures of gratitude (d = .46, 95% CI [.27, .64]; k = 15) and psychological well-being (d = .17, 95% CI [.09, .24]; k = 20) but not anxiety (d = .11, 95% CI [-.08, .31]; k = 5). More-detailed subdivision was possible on studies with outcomes assessing psychological well-being. Among these, gratitude interventions outperformed an activity-matched comparison (d = .14; 95% CI [.01, .27]; k = 18). Gratitude interventions performed as well as, but not better than, a psychologically active comparison (d = -.03, 95% CI [-.13, .07]; k = 9). On the basis of these findings, we summarize the current state of the literature and make suggestions for future applied research on gratitude. (PsycINFO Database Record PMID- 26575349 TI - Beyond "born this way?" reconsidering sexual orientation beliefs and attitudes. AB - Previous research on heterosexuals' beliefs about sexual orientation (SO) has been limited in that it has generally examined heterosexuals' beliefs from an essentialist perspective. The recently developed Sexual Orientation Beliefs Scale (SOBS; Arseneau, Grzanka, Miles, & Fassinger, 2013) assesses multifarious "lay beliefs" about SO from essentialist, social constructionist, and constructivist perspectives. This study used the SOBS to explore latent group-based patterns in endorsement of these beliefs in 2 samples of undergraduate students: a mixed gender sample (n = 379) and an all-women sample (n = 266). While previous research has posited that essentialist beliefs about the innateness of SO predict positive attitudes toward sexual minorities, our research contributes to a growing body of scholarship that suggests that biological essentialism should be considered in the context of other beliefs. Using a person-centered analytic strategy, we found that that college students fell into distinct patterns of SO beliefs that are more different on beliefs about the homogeneity, discreteness, and informativeness of SO categories than on beliefs about the naturalness of SO. Individuals with higher levels of endorsement on all 4 SOBS subscales (a group we named multidimensional essentialism) and those who were highest in discreteness, homogeneity, and informativeness beliefs (i.e., high-DHI) reported higher levels of homonegativity when compared with those who were high only in naturalness beliefs. We discuss the implications of these findings for counseling and psychotherapy about SO, as well educational and social interventions. (PsycINFO Database Record PMID- 26575350 TI - The ups and downs of being lesbian, gay, and bisexual: A daily experience perspective on minority stress and support processes. AB - Daily diary methods were used to explore identity-related stress and support processes as they occurred from day-to-day in a sample of 61 lesbian, gay, and bisexual (LGB) young adults. At the end of each day for 7-10 consecutive days, participants reported on daily identity-salient experiences (ISEs), proximal minority stressors (internalized stigma, expectations of rejection), and affect (positive, negative). A multilevel latent covariate model was used to examine within- and between-person interrelations among these variables. Participants described a variety of positive and negative ISEs with both heterosexual and LGB people. These ISEs accounted for change in affect from 1 day to the next, even controlling for positive and negative experiences unrelated to identity. For example, relative to the previous day, participants experienced increases in positive affect on days featuring positive ISEs with both heterosexual people and LGB people. ISEs also predicted daily proximal stress variables, and findings differed at the 2 levels of analysis. For example, at the within-person level, participants experienced decreases in internalized stigma on days featuring positive ISEs with heterosexuals. At the between-person level, however, findings indicated that participants who generally had the highest levels of internalized stigma were more likely than others to report negative ISEs with LGB people and less likely to report positive ISEs with LGB people. Finally, proximal stress variables predicted affect at the within-person level: Affect improved on days when levels of internalized stigma and expected rejection were lower than usual. (PsycINFO Database Record PMID- 26575351 TI - Mesoporous Carbon Nanospheres Featured Fluorescent Aptasensor for Multiple Diagnosis of Cancer in Vitro and in Vivo. AB - Multiple diagnosis of cancer by a facile fluorescent sensor is extremely attractive. Herein, a Cy3-labeled ssDNA probe (P0-Cy3) was pi-pi stacked on the surface of oxidized mesoporous carbon nanospheres (OMCN) to construct the fluorescent "turn-on" aptasensor. Attributing to the intrinsic properties of OMCN, the OMCN-based aptasensor not only can be used to detect mucin1 protein in liquid with a wide range of 0.1-10.6 MUmol/L, a low detection limit of 6.52 nmol/L, and good selectivity, but also can quantify the cancer cells in solution with the linear range of 10(4)-2 * 10(6) cells/mL and a detection limit of 8500 cells/mL. Fascinatingly, this OMCN-based aptasensor was exploited to image cancer via solid tissues such as cells, tissue sections, and ex vivo and in vivo tumors, in which the obvious distinguishability between cancer and normal tissues was clearly demonstrated. This is a robust and simple detection technique, which can well achieve the multiple diagnosis of cancer in vitro and in vivo. PMID- 26575352 TI - A Brain Tumor/Organotypic Slice Co-culture System for Studying Tumor Microenvironment and Targeted Drug Therapies. AB - Brain tumors are a major cause of cancer-related morbidity and mortality. Developing new therapeutics for these cancers is difficult, as many of these tumors are not easily grown in standard culture conditions. Neurosphere cultures under serum-free conditions and orthotopic xenografts have expanded the range of tumors that can be maintained. However, many types of brain tumors remain difficult to propagate or study. This is particularly true for pediatric brain tumors such as pilocytic astrocytomas and medulloblastomas. This protocol describes a system that allows primary human brain tumors to be grown in culture. This quantitative assay can be used to investigate the effect of microenvironment on tumor growth, and to test new drug therapies. This protocol describes a system where fluorescently labeled brain tumor cells are grown on an organotypic brain slice from a juvenile mouse. The response of tumor cells to drug treatments can be studied in this assay, by analyzing changes in the number of cells on the slice over time. In addition, this system can address the nature of the microenvironment that normally fosters growth of brain tumors. This brain tumor organotypic slice co-culture assay provides a propitious system for testing new drugs on human tumor cells within a brain microenvironment. PMID- 26575353 TI - Beyond the E-Value: Stratified Statistics for Protein Domain Prediction. AB - E-values have been the dominant statistic for protein sequence analysis for the past two decades: from identifying statistically significant local sequence alignments to evaluating matches to hidden Markov models describing protein domain families. Here we formally show that for "stratified" multiple hypothesis testing problems-that is, those in which statistical tests can be partitioned naturally-controlling the local False Discovery Rate (lFDR) per stratum, or partition, yields the most predictions across the data at any given threshold on the FDR or E-value over all strata combined. For the important problem of protein domain prediction, a key step in characterizing protein structure, function and evolution, we show that stratifying statistical tests by domain family yields excellent results. We develop the first FDR-estimating algorithms for domain prediction, and evaluate how well thresholds based on q-values, E-values and lFDRs perform in domain prediction using five complementary approaches for estimating empirical FDRs in this context. We show that stratified q-value thresholds substantially outperform E-values. Contradicting our theoretical results, q-values also outperform lFDRs; however, our tests reveal a small but coherent subset of domain families, biased towards models for specific repetitive patterns, for which weaknesses in random sequence models yield notably inaccurate statistical significance measures. Usage of lFDR thresholds outperform q-values for the remaining families, which have as-expected noise, suggesting that further improvements in domain predictions can be achieved with improved modeling of random sequences. Overall, our theoretical and empirical findings suggest that the use of stratified q-values and lFDRs could result in improvements in a host of structured multiple hypothesis testing problems arising in bioinformatics, including genome-wide association studies, orthology prediction, and motif scanning. PMID- 26575354 TI - Symptomatic gastric diverticulum after gastric imbrication with conversion to sleeve gastrectomy. PMID- 26575355 TI - Response to the Letter to the Editor: laparoscopic sleeve gastrectomy in children and adolescents with Prader-Willi Syndrome: a matched control study. PMID- 26575356 TI - The Prevalence of alpha-Thalassemia and Its Relation to Plasmodium falciparum Infection in Patients Presenting to Clinics in Two Distinct Ecological Zones in Ghana. AB - Thalassemia and sickle cell disease constitute the most monogenic hemoglobin (Hb) disorders worldwide. Clinical symptoms of alpha(+)-thalassemia (alpha(+)-thal) are related to inadequate Hb production and accumulation of beta- and/or gamma globin subunits. The association of thalassemia with malaria remains contentious, though from its distribution it appears to have offered some protection against the disease. Data on the prevalence of thalassemia in Ghana and its link with malaria is scanty and restricted. It was an objective of this cross-sectional study to determine the prevalence of thalassemia in areas representing two of Ghana's distinct ecological zones. The relationship between thalassemia and Plasmodium falciparium (P. falciparum) infection was also ascertained. Overall, 277 patients presenting to health facilities in the study areas were recruited to participate. Tests were carried out to determine the presence of alpha(+)-thal, sickle cell and malaria parasites in the blood samples of participants. The outcome of this study showed an alpha(+)-thal frequency of 19.9% for heterozygotes (-alpha/alphaalpha) and 6.8% for homozygotes (-alpha/-alpha). Plasmodium falciparum was detected in 17.7% of the overall study population and 14.9% in those with alpha(+)-thal. No association was observed between those with alpha(+)-thal and the study sites (p > 0.05). A test of the Hardy-Weinberg law yielded no significant difference (p < 0.001). Findings from this study suggest a modest distribution of alpha(+)-thal in Ghana with no bias to the ecological zones. Although the prevalence and parasite density were relatively low in those with the disorder, no association was found between them. PMID- 26575357 TI - Sexual and Partner Violence Prevention and Popular Media. PMID- 26575358 TI - New Class 2 Integron In2-4 Among IncI1-Positive Escherichia coli Isolates Carrying ESBL and PMAbeta Genes from Food Animals in Portugal. AB - The impact of extended-spectrum beta-lactamases (ESBLs) and plasmid-mediated AmpC beta-lactamases (PMAbetas) of animal origin constitutes a public health concern. In this study, 179 Escherichia coli from food animals and products were analyzed, among which, 15 cephalosporin-resistant isolates harboring ESBL (CTX-M-1 [n = 8], CTX-M-14 [n = 1], SHV-12 [n = 2]) or PMAbeta [CMY-2, n = 5]) were identified in poultry and swine, from different farms of distinct regions of Portugal. The multiple sequence-type IncI1-driven spread of ESBLs and PMAbetas, flanked by widely disseminated mobile elements, was guaranteed by ST26/IncI1-harboring blaSHV-12, ST12/IncI1-harboring blaCMY-2, ST3 and ST38/IncI1-harboring blaCTX-M 1, and ST1/IncI1-harboring blaCTX-M-14. An IS10-disrupted In2-4, presenting a new attI2 recombination site, was also detected in a SHV-12/CTX-M-1-harboring isolate. This study highlights the fact that animals may act as persistent sources of ESBL- and PMAbeta-harboring plasmids genes that might be transferred to humans through direct contact or via the food chain. PMID- 26575359 TI - Simple, Effective, but Out of Reach? Public Health Implications of HCV Drugs. PMID- 26575360 TI - Linkage disequilibrium analysis of allelic heterogeneity in DNA methylation. AB - Heterogeneity of DNA methylation status among alleles is observed in various cell types and is involved in epigenetic gene regulation and cancer biology. However, the individual methylation profile within each allele has not yet been examined at the whole-genome level. In the present study, we applied linkage disequilibrium analysis to the DNA methylation data obtained from whole-genome bisulfite sequencing studies in mouse germline and other types of cells. We found that the methylation status of 2 consecutive CpG sites showed deviation from equilibrium frequency toward concordant linkage (both methylated or both unmethylated) in germline cells. In the imprinting loci where methylation of constituent alleles is known, our analysis detected the deviation toward the concordant linkage as expected. In addition, we applied this analysis to the transitional zone between methylated and unmethylated regions and to the cells undergoing epigenetic reprogramming. In both cases, deviation to the concordant linked alleles was conspicuous, indicating that the methylation pattern is not random but rather concordant within each allele. These results will provide the key to understanding the mechanism underlying allelic heterogeneity. PMID- 26575361 TI - Does motivation predict outcome of pelvic floor muscle retraining? AB - AIMS: Although pelvic floor muscle training (PFMT) is effective for stress urinary incontinence (SUI), patients need to be motivated to obtain cure. An instrument to assess motivation in such patients was published in 2009: the Incontinence Treatment Motivation Questionnaire (ITMQ). The ITMQ consists of five domains: (i) positive attitudes toward PFMT; (ii) reasons for not doing PFMT; (iii) difficulties living with incontinence; (iv) desire for treatment; and (v) incontinence severity influencing motivation. The aim of the present study was to examine the relationship between ITMQ scores and treatment success. METHODS: After referral for PFMT, women with SUI completed the ITMQ. Pre- and post treatment outcomes were the International Consultation on Incontinence Questionnaire (ICIQ) score and a 24-hr pad test. Correlations between ITMQ scores and baseline, as well as post-treatment change in ICIQ scores and pad test results were examined. Additionally, the demographics of non-participants, participants, and patients lost to follow-up were compared. RESULTS: Of 85 recruits, 18 did not complete the ITMQ, 14 were lost to follow-up, thus 53 completed the PFMT programme and undertook either one or both outcomes. Pre treatment, severity on ICIQ correlated with total ITMQ (rho = 0.33, P = 0.01). Post-treatment change in pad test was inversely correlated with Domain 2 (rho = 0.33, P = 0.03). CONCLUSIONS: The pre-treatment severity of incontinence was significantly associated with motivation for treatment. Unfortunately, post treatment change correlated with only one domain of the questionnaire. Further modification of the ITMQ is envisaged. Neurourol. Urodynam. 36:316-321, 2017. (c) 2015 Wiley Periodicals, Inc. PMID- 26575362 TI - Selective Area Modification of Silicon Surface Wettability by Pulsed UV Laser Irradiation in Liquid Environment. AB - The wettability of silicon (Si) is one of the important parameters in the technology of surface functionalization of this material and fabrication of biosensing devices. We report on a protocol of using KrF and ArF lasers irradiating Si (001) samples immersed in a liquid environment with low number of pulses and operating at moderately low pulse fluences to induce Si wettability modification. Wafers immersed for up to 4 hr in a 0.01% H2O2/H2O solution did not show measurable change in their initial contact angle (CA) ~75 degrees . However, the 500-pulse KrF and ArF lasers irradiation of such wafers in a microchamber filled with 0.01% H2O2/H2O solution at 250 and 65 mJ/cm(2), respectively, has decreased the CA to near 15 degrees , indicating the formation of a superhydrophilic surface. The formation of OH-terminated Si (001), with no measurable change of the wafer's surface morphology, has been confirmed by X-ray photoelectron spectroscopy and atomic force microscopy measurements. The selective area irradiated samples were then immersed in a biotin-conjugated fluorescein-stained nanospheres solution for 2 hr, resulting in a successful immobilization of the nanospheres in the non-irradiated area. This illustrates the potential of the method for selective area biofunctionalization and fabrication of advanced Si-based biosensing architectures. We also describe a similar protocol of irradiation of wafers immersed in methanol (CH3OH) using ArF laser operating at pulse fluence of 65 mJ/cm(2) and in situ formation of a strongly hydrophobic surface of Si (001) with the CA of 103 degrees . The XPS results indicate ArF laser induced formation of Si-(OCH3)x compounds responsible for the observed hydrophobicity. However, no such compounds were found by XPS on the Si surface irradiated by KrF laser in methanol, demonstrating the inability of the KrF laser to photodissociate methanol and create -OCH3 radicals. PMID- 26575363 TI - Current Status of the Management of Hereditary Breast and Ovarian Cancer in Asia: First Report by the Asian BRCA Consortium. AB - BACKGROUND: BRCA1/BRCA2 mutations are associated with an increased lifetime risk for hereditary breast and ovarian cancer (HBOC). Compared with the Western developed countries, genetic testing and risk assessment for HBOC in Asia are less available, thus prohibiting the appropriate surveillance, clinical strategies and cancer management. METHODS: The current status of HBOC management in 14 Asian countries, including genetic counselling/testing uptakes and clinical management options, was reviewed. We analysed how economic factors, healthcare and legal frameworks, and cultural issues affect the genetic service availability in Asia. RESULTS: In 2012, only an estimated 4,000 breast cancer cases from 14 Asian countries have benefited from genetic services. Genetic testing costs and the absence of their adoption into national healthcare systems are the main economic barriers for approaching genetic services. Training programmes, regional accredited laboratories and healthcare professionals are not readily available in most of the studied countries. A lack of legal frameworks against genetic discrimination and a lack of public awareness of cancer risk assessment also provide challenges to HBOC management in Asia. CONCLUSIONS: The Asian BRCA Consortium reports the current disparities in genetic services for HBOC in Asia and urges the policy makers, healthcare sectors and researchers to address the limitations in HBOC management. PMID- 26575364 TI - Computational prediction of secretion systems and secretomes of Brucella: identification of novel type IV effectors and their interaction with the host. AB - Brucella spp. are facultative intracellular pathogens that cause brucellosis in various mammals including humans. Brucella survive inside the host cells by forming vacuoles and subverting host defence systems. This study was aimed to predict the secretion systems and the secretomes of Brucella spp. from 39 complete genome sequences available in the databases. Furthermore, an attempt was made to identify the type IV secretion effectors and their interactions with host proteins. We predicted the secretion systems of Brucella by the KEGG pathway and SecReT4. Brucella secretomes and type IV effectors (T4SEs) were predicted through genome-wide screening using JVirGel and S4TE, respectively. Protein-protein interactions of Brucella T4SEs with their hosts were analyzed by HPIDB 2.0. Genes coding for Sec and Tat pathways of secretion and type I (T1SS), type IV (T4SS) and type V (T5SS) secretion systems were identified and they are conserved in all the species of Brucella. In addition to the well-known VirB operon coding for the type IV secretion system (T4SS), we have identified the presence of additional genes showing homology with T4SS of other organisms. On the whole, 10.26 to 14.94% of total proteomes were found to be either secreted (secretome) or membrane associated (membrane proteome). Approximately, 1.7 to 3.0% of total proteomes were identified as type IV secretion effectors (T4SEs). Prediction of protein-protein interactions showed 29 and 36 host-pathogen specific interactions between Bos taurus (cattle)-B. abortus and Ovis aries (sheep)-B. melitensis, respectively. Functional characterization of the predicted T4SEs and their interactions with their respective hosts may reveal the secrets of host specificity of Brucella. PMID- 26575365 TI - Information-seeking behaviour for epilepsy: an infodemiological study of searches for Wikipedia articles. AB - Millions of people worldwide use the internet daily as a source of health information. Wikipedia is a popular free online encyclopaedia used by patients and physicians to search for health-related information. Our aim was to evaluate information-seeking behaviour of English-speaking internet users searching Wikipedia for articles related to epilepsy and epileptic seizures. Using Wiki Trends, which provides quantitative information on daily viewing of articles, data on global search queries for Wikipedia articles related to epilepsy and seizures were analysed. The daily Wikipedia article views on syncope, psychogenic non-epileptic seizures, migraine, and multiple sclerosis served as comparative data. The period of analysis covered was from January 2008 to December 2014. Overall, the Wikipedia article "epilepsy and driving" was found to be more frequently visited than the articles "epilepsy and employment" or "epilepsy in children". Since January 2008, the Wikipedia article "multiple sclerosis" was more often visited compared to the articles "epilepsy", "syncope", "psychogenic non-epileptic seizures" or "migraine"; the article "epilepsy" ranked 3,779 and was less frequently visited than "multiple sclerosis", ranked at 571, in traffic on Wikipedia. The highest peak in search volume for the article "epilepsy" coincided with the news of a celebrity having seizures. Fears and worries about epileptic seizures, their impact on driving and employment, and news about celebrities with epilepsy might be major determinants in searching Wikipedia for information. PMID- 26575366 TI - Cepstral, Spectral and Time-Based Analysis of Voices of Esophageal Speakers. AB - OBJECTIVE: To evaluate esophageal speech quality in patients after total laryngectomy using cepstral, spectral and time-based measures. PATIENTS AND METHODS: The subjects were all males and included 20 total laryngectomy patients and 20 age-matched normal controls. The sustained vowel /a/ was measured using the tools of MDVP (Multi-Dimensional Voice Program) and ADSV (Analysis of Dysphonia in Speech and Voice). RESULTS: Compared to normal controls, esophageal speakers showed significantly lower values for cepstral peak prominence (CPP) and a low- to high-frequency spectral energy (L/H) ratio, but their mean CPP fundamental frequency (CPP F0) was higher. Highly negative correlations were found between CPP and jitter (percent jitter), shimmer (percent shimmer) and noise-to-harmonics ratio (NHR). Positive correlations were also found between L/H ratio and CPP. CPP F0 showed a positive correlation with F0, shimmer and NHR. In addition, CPP and L/H ratio parameters indicated an area under the curve of 0.93 or higher compared to that for time-based measures. CONCLUSION: This study showed that cepstral and spectral analyses are more effective than time-based analysis in examining the voice quality of alaryngeal speakers. The present findings are expected to contribute to establishing the baseline for voice quality characteristics in total laryngectomy patients. PMID- 26575367 TI - Tuning the redox properties of the titanocene(III)/(IV)-couple for atom economical catalysis in single electron steps. AB - Radical-based transformations are an attractive target for the development of catalytic processes due to ease of radical generation, high functional group tolerance and selectivity of bond-forming reactions. In spite of these appealing features, the potential of radicals as key intermediates in catalysis remains largely untapped. Herein we present recent work that exploits the innate ability of titanocene-based catalysts to undergo both oxidative addition and reductive elimination in single electron steps. We further demonstrate that tuning the redox properties of the titanocene-based catalyst can be used to develop efficient catalytic free radical processes including tetrahydrofuran synthesis, and radical arylation. PMID- 26575368 TI - A mesoionic bis(Py-tzNHC) palladium(II) complex catalyses "green" Sonogashira reaction through an unprecedented mechanism. AB - A novel bis(pyridyl-functionalized 1,2,3-triazol-5-ylidene)-palladium(II) complex [Pd(Py-tzNHC)2](2+) catalyses the copper-, amine-, phosphine-, and additive-free aerobic Sonogashira alkynylation of (hetero)aryl bromides in water as the only reaction solvent. The catalysis proceeds along two connected Pd-cycles with homogeneous bis-carbene Pd(0) and Pd(II) species, as demonstrated by electrospray ionization mass spectrometry. PMID- 26575369 TI - Comparison of Various Anthropometric Indices as Risk Factors for Hearing Impairment in Asian Women. AB - BACKGROUND: The objective of the present study was to examine the associations between various anthropometric measures and metabolic syndrome and hearing impairment in Asian women. METHODS: We identified 11,755 women who underwent voluntary routine health checkups at Yeungnam University Hospital between June 2008 and April 2014. Among these patients, 2,485 participants were <40 years old, and 1,072 participants lacked information regarding their laboratory findings or hearing and were therefore excluded. In total 8,198 participants were recruited into our study. RESULTS: The AUROC value for metabolic syndrome was 0.790 for the waist to hip ratio (WHR). The cutoff value was 0.939. The sensitivity and specificity for predicting metabolic syndrome were 72.7% and 71.7%, respectively. The AUROC value for hearing loss was 0.758 for WHR. The cutoff value was 0.932. The sensitivity and specificity for predicting hearing loss were 65.8% and 73.4%, respectively. The WHR had the highest AUC and was the best predictor of metabolic syndrome and hearing loss. Univariate and multivariate linear regression analyses showed that WHR levels were positively associated with four hearing thresholds including averaged hearing threshold and low, middle, and high frequency thresholds. In addition, multivariate logistic analysis revealed that those with a high WHR had a 1.347-fold increased risk of hearing loss compared with the participants with a low WHR. CONCLUSION: Our results demonstrated that WHR may be a surrogate marker for predicting the risk of hearing loss resulting from metabolic syndrome. PMID- 26575370 TI - GO-PCA: An Unsupervised Method to Explore Gene Expression Data Using Prior Knowledge. AB - METHOD: Genome-wide expression profiling is a widely used approach for characterizing heterogeneous populations of cells, tissues, biopsies, or other biological specimen. The exploratory analysis of such data typically relies on generic unsupervised methods, e.g. principal component analysis (PCA) or hierarchical clustering. However, generic methods fail to exploit prior knowledge about the molecular functions of genes. Here, I introduce GO-PCA, an unsupervised method that combines PCA with nonparametric GO enrichment analysis, in order to systematically search for sets of genes that are both strongly correlated and closely functionally related. These gene sets are then used to automatically generate expression signatures with functional labels, which collectively aim to provide a readily interpretable representation of biologically relevant similarities and differences. The robustness of the results obtained can be assessed by bootstrapping. RESULTS: I first applied GO-PCA to datasets containing diverse hematopoietic cell types from human and mouse, respectively. In both cases, GO-PCA generated a small number of signatures that represented the majority of lineages present, and whose labels reflected their respective biological characteristics. I then applied GO-PCA to human glioblastoma (GBM) data, and recovered signatures associated with four out of five previously defined GBM subtypes. My results demonstrate that GO-PCA is a powerful and versatile exploratory method that reduces an expression matrix containing thousands of genes to a much smaller set of interpretable signatures. In this way, GO-PCA aims to facilitate hypothesis generation, design of further analyses, and functional comparisons across datasets. PMID- 26575372 TI - Widely Tunable Infrared Antennas Using Free Carrier Refraction. AB - We demonstrate tuning of infrared Mie resonances by varying the carrier concentration in doped semiconductor antennas. We fabricate spherical silicon and germanium particles of varying sizes and doping concentrations. Single-particle infrared spectra reveal electric and magnetic dipole, quadrupole, and hexapole resonances. We subsequently demonstrate doping-dependent frequency shifts that follow simple Drude models, culminating in the emergence of plasmonic resonances at high doping levels and long wavelengths. These findings demonstrate the potential for actively tuning infrared Mie resonances by optically or electrically modulating charge carrier densities, thus providing an excellent platform for tunable metamaterials. PMID- 26575371 TI - Gonadotropin-Activated Androgen-Dependent and Independent Pathways Regulate Aquaporin Expression during Teleost (Sparus aurata) Spermatogenesis. AB - The mediation of fluid homeostasis by multiple classes of aquaporins has been suggested to be essential during spermatogenesis and spermiation. In the marine teleost gilthead seabream (Sparus aurata), seven distinct aquaporins, Aqp0a, 1aa, -1ab, -7, -8b, -9b and -10b, are differentially expressed in the somatic and germ cell lineages of the spermiating testis, but the endocrine regulation of these channels during germ cell development is unknown. In this study, we investigated the in vivo developmental expression of aquaporins in the seabream testis together with plasma androgen concentrations. We then examined the in vitro regulatory effects of recombinant piscine gonadotropins, follicle stimulating (rFsh) and luteinizing (rLh) hormones, and sex steroids on aquaporin mRNA levels during the spermatogenic cycle. During the resting phase, when plasma levels of androgens were low, the testis exclusively contained proliferating spermatogonia expressing Aqp1ab, whereas Aqp10b and -9b were localized in Sertoli and Leydig cells, respectively. At the onset of spermatogenesis and during spermiation, the increase of androgen plasma levels correlated with the additional appearance of Aqp0a and -7 in Sertoli cells, Aqp0a in spermatogonia and spermatocytes, Aqp1ab, -7 and -10b from spermatogonia to spermatozoa, and Aqp1aa and -8b in spermatids and spermatozoa. Short-term in vitro incubation of testis explants indicated that most aquaporins in Sertoli cells and early germ cells were upregulated by rFsh and/or rLh through androgen-dependent pathways, although Aqp1ab in proliferating spermatogonia was also activated by estrogens. However, expression of Aqp9b in Leydig cells, and of Aqp1aa and -7 in spermatocytes and spermatids, was also directly stimulated by rLh. These results reveal a complex gonadotropic control of aquaporin expression during seabream germ cell development, apparently involving both androgen-dependent and independent pathways, which may assure the fine tuning of aquaporin-mediated fluid secretion and absorption mechanisms in the seabream testis. PMID- 26575373 TI - Ordered state of magnetic charge in the pseudo-gap phase of a cuprate superconductor (HgBa2CuO(4+delta)). AB - A symmetry-based interpretation of published experimental results demonstrates that the pseudo-gap phase of underdoped HgBa2CuO(4+delta) (Hg1201) possesses an ordered state of magnetic charge epitomized by Cu magnetic monopoles. Magnetic properties of one-layer Hg1201 and two-layer YBa2Cu3O(6+x) (YBCO) cuprates have much in common, because their pseudo-gap phases possess the same magnetic space group, e.g. both underdoped cuprates allow the magneto-electric (Kerr) effect. Differences in their properties stem from different Cu site symmetries, leaving Cu magnetic monopoles forbidden in YBCO. Resonant x-ray Bragg diffraction experiments can complement the wealth of information available from neutron diffraction experiments on five Hg1201 samples on which our findings are based. In the case of Hg1201 emergence of the pseudo-gap phase, with time-reversal violation, is accompanied by a reduction of Cu site symmetry that includes loss of a centre of inversion symmetry. In consequence, parity-odd x-ray absorption events herald the onset of the enigmatic phase, and we predict dependence of corresponding Bragg spots on magneto-electric multipoles, including the monopole, and the azimuthal angle (crystal rotation about the Bragg wavevector). PMID- 26575374 TI - A Study of the Oxidation Behaviour of Pile Grade A (PGA) Nuclear Graphite Using Thermogravimetric Analysis (TGA), Scanning Electron Microscopy (SEM) and X-Ray Tomography (XRT). AB - Pile grade A (PGA) graphite was used as a material for moderating and reflecting neutrons in the UK's first generation Magnox nuclear power reactors. As all but one of these reactors are now shut down there is a need to understand the residual state of the material prior to decommissioning of the cores, in particular the location and concentration of key radio-contaminants such as 14C. The oxidation behaviour of unirradiated PGA graphite was studied, in the temperature range 600-1050 degrees C, in air and nitrogen using thermogravimetric analysis, scanning electron microscopy and X-ray tomography to investigate the possibility of using thermal degradation techniques to examine 14C distribution within irradiated material. The thermal decomposition of PGA graphite was observed to follow the three oxidation regimes historically identified by previous workers with limited, uniform oxidation at temperatures below 600 degrees C and substantial, external oxidation at higher temperatures. This work demonstrates that the different oxidation regimes of PGA graphite could be developed into a methodology to characterise the distribution and concentration of 14C in irradiated graphite by thermal treatment. PMID- 26575376 TI - Retained Blood Syndrome After Cardiac Surgery: A New Look at an Old Problem. AB - Retained blood occurs when drainage systems fail to adequately evacuate blood during recovery from cardiothoracic surgery. As a result, a spectrum of mechanical and inflammatory complications can ensue in the acute, subacute, and chronic setting. The objectives of this review were to define the clinical syndrome associated with retained blood over the spectrum of recovery and to review existing literature regarding how this may lead to complications and contributes to poor outcomes. To better understand and prevent this constellation of clinical complications, a literature review was conducted, which led us to create a new label that better defines the clinical entity we have titled retained blood syndrome. Analysis of published reports revealed that 13.8% to 22.7% of cardiac surgical patients develop one or more components of retained blood syndrome. This can present in the acute, subacute, or chronic setting, with different pathophysiologic mechanisms active at different times. The development of retained blood syndrome has been linked to other clinical outcomes, including the development of postoperative atrial fibrillation and infection and the need for hospital readmission. Grouping multiple objectively measurable and potentially preventable postoperative complications that share a common etiology of retained blood over the continuum of recovery demonstrates a high prevalence of retained blood syndrome. This suggests the need to develop, implement, and test clinical strategies to enhance surgical drainage and reduce postoperative complications in patients undergoing cardiothoracic surgery. PMID- 26575377 TI - Combined Mitral and Tricuspid Valve Surgery Performed via a Right Minithoracotomy Approach. AB - OBJECTIVE: Combined mitral and tricuspid valve surgery is associated with an increased perioperative morbidity and mortality. We evaluated the outcomes of a less invasive right minithoracotomy approach in patients undergoing primary or reoperative double-valve surgery. METHODS: We retrospectively evaluated 132 consecutive patients with mitral and tricuspid valve disease who underwent double valve surgery via a right minithoracotomy at our institution between January 2009 and April 2014. RESULTS: The cohort included 81 female (61%) and 51 male (39%) patients, with a mean +/- SD age of 67 +/- 13 years. The mean +/- SD preoperative left ventricular ejection fraction, mitral regurgitation grade, and creatinine were 53% +/- 12%, 3.8 +/- 0.6, and 1.26 +/- 1.17, respectively. The patients underwent primary (88%) or reoperative (12%) mitral and tricuspid valve surgery, which consisted of 88 mitral repairs (67%), 44 mitral replacements (33%), 131 tricuspid repairs (99%), and 1 tricuspid replacement (1%). Postoperatively, there were 6 cases of acute kidney injury (5%), 6 reoperations for bleeding (5%), 4 cerebrovascular accidents (3%), and 12 cases of atrial fibrillation (9%). The median intensive care unit length of stay and total hospital lengths of stay were 61 hours (interquartile range, 43-112 hours) and 8 days (interquartile range, 6 13 days), respectively. The in-hospital mortality was 4%. Actuarial survival at 1 and 5 years was 93% and 88%, respectively. CONCLUSIONS: In patients undergoing primary or reoperative mitral and tricuspid valve surgery, a right minithoracotomy approach is associated with a low perioperative morbidity and good midterm survival. PMID- 26575378 TI - Uniportal Videothoracoscopic Surgery: Our Indications and Limits. AB - OBJECTIVE: We present our experience with uniportal videothoracoscopic surgery (VATS-U), examining its indications, limits, and results. METHODS: Since January 2009, 66 patients underwent VATS-U for the following indications: pneumothorax (n = 25), lung nodule (n = 15; n = 10 with preoperative radiolocalization), wedge biopsy (n = 15), hyperhidrosis (n = 10), and chest wall schwannoma (n = 1). The conversion rate to conventional video-assisted thoracic surgery (VATS), postoperative pain, complications, residual paraesthesia, and hospitalization were analyzed. Operative time, postoperative pain, and paraesthesia were retrospectively compared with a cohort of 172 cases of conventional multiportal VATS, performed in the same period. RESULTS: Conversion to traditional VATS was necessary in two cases (pulmonary nodule, n = 1; pneumothorax, n = 1). The mean pain score was 0.8, the mean operation time was 42 minutes, and 10 patients had postoperative paraesthesia that lasted a mean of 7 days. No postoperative complications were reported, and the mean postoperative hospital stay was 3 days (range, 1-6 days). The comparison between the VATS-U and the standard multiportal VATS group showed in the VATS-U group a lower but not statistically significant pain score and paraesthesia as well as a lower and statistically significant operative time. CONCLUSIONS: Uniportal videothoracoscopic surgery has a wide range of indications: lung apex resections and pleurodesis for spontaneous pneumothorax treatment; pulmonary nodule assessment with or without preoperative localization; lung biopsy for interstitial diseases; unilateral or bilateral sympathectomy to treat hyperhidrosis; benign chest wall tumor evaluation. The limits of this technique are linked to pleural adhesions or lung nodules in difficult positions. In our experience, VATS-U results in minimal postoperative pain, allowing for fast functional recovery and a consequent short hospital stay; thus, we suggest that VATS-U is a valid alternative to traditional multiportal VATS for indications beyond cosmetic benefits. Prospective randomized trials are necessary to validate the advantages of uniportal VATS. PMID- 26575379 TI - Simulated Prosthesis Overlay for Patient-Specific Planning of Transcatheter Aortic Valve Implantation Procedures. AB - OBJECTIVE: We tested the hypothesis that simulated three-dimensional prosthesis overlay procedure planning may support valve selection in transcatheter aortic valve implantation (TAVI) procedures. METHODS: Preoperative multidimensional computed tomography (MDCT) data sets from 81 consecutive TAVI patients were included in the study. A planning tool was developed, which semiautomatically creates a three-dimensional model of the aortic root from these data. Three dimensional templates of the commonly used TAVI implants are spatially registered with the patient data and presented as graphic overlay. Fourteen physicians used the tool to perform retrospective planning of TAVI procedures. Results of prosthesis sizing were compared with the prosthesis size used in the actually performed procedure, and the patients were accordingly divided into three groups: those with equal size (concordance with retrospective planning), oversizing (retrospective planning of a smaller prosthesis), and undersizing (retrospective planning of a larger prosthesis). RESULTS: In the oversizing group, 85% of the patients had new pacemaker implantation. In the undersizing group, in 66%, at least mild paravalvular leakage was observed (greater than grade 1 in one third of the cases). In 46% of the patients in the equal-size group, neither of these complications was observed. CONCLUSIONS: Three-dimensional prosthesis overlay in MDCT-derived patient data for patient-specific planning of TAVI procedures is feasible. It may improve valve selection compared with two-dimensional MDCT planning and thus yield better outcomes. PMID- 26575380 TI - Minimally Invasive Mitral Valve Surgery in Truly High-Risk Patients: Are We Pushing the Boundaries?: An Observational Study. AB - OBJECTIVE: This study aimed to assess in a retrospective series of truly high risk patients who underwent minimally invasive mitral valve surgery: (1) postoperative and long-term results and (2) logistic EuroSCORE and EuroSCORE II discrimination power. METHODS: Between 2003 and 2013, we reviewed in our institution patients who underwent minimally invasive mitral valve surgery with or without tricuspid valve repair via right minithoracotomy with logistic EuroSCORE of 20 or higher. RESULTS: Among a total number of 1604, 88 patients were identified. Median logistic and EuroSCORE II was 27.29 (interquartile range, 15.3) and 12.7% (11.3%), respectively. Mean (SD) age was 71.9 (8.4) years; 42 were female (47.7%); 60 patients (68.1%) underwent previous sternotomy. Mitral valve was replaced in 59 (67%) and repaired in 29 (32.9%) patients; tricuspid valve repair was performed in 23 patients (26.1%). Median cardiopulmonary bypass and cross-clamp times were 157 minutes (interquartile range, 131-187 minutes) and 83 minutes (81-116 minutes), respectively; conversion to sternotomy and reopening for bleeding was necessary in 4 (4.5%) and 3 (3.4%) patients; permanent and transient neurological injuries were reported in 6 (6.8%) and 3 (3.4%) patients; acute kidney injury was reported in 13 patients (14.7%); 15 patients (17%) had pulmonary complications. Ten patients died while in the hospital (11.2%). Survival at 6 years was 78% (95% confidence interval, 69-88). CONCLUSIONS: In this series of truly high-risk patients, minimally invasive mitral surgery was associated with acceptable early mortality and morbidity as well as long-term outcomes; both logistic and EuroSCORE II showed suboptimal discrimination power. PMID- 26575381 TI - Biologic Valve Leaflet Perforation Causing Persistent Aortic Insufficiency After Successful Transcatheter Closure of Paravalvular Leak. AB - Persistent paravalvular leak after aortic valve replacement prompted transcatheter closure with an Amplatzer VSD device. Although technically a successful procedure, aortic insufficiency persisted, leading to surgical reexploration and valve replacement. PMID- 26575382 TI - Importance of Full-Length Scan of Arterial Grafts in Coronary Artery Bypass Grafting. AB - Cardiac ischemia after coronary artery bypass grafting is often caused by graft occlusion. Short- and long-term graft patency is related to the quality of the surgical technique during harvesting and anastomosis. Transit time flow measurement is a recognized technique for the quality control of grafts but may not rule out structural abnormalities in the conduits, which can cause graft occlusion. This article reports on two cases of suspected intra-arterial dissection of the left internal mammary artery despite satisfactory flow measurements. Routine ultrasound scanning of arterial conduits is helpful in distinguishing dissection and hematoma in the graft conduits. PMID- 26575383 TI - Endovascular Abdominal Aortic Aneurysm Repair Through a Persistent Sciatic Artery. AB - Conventional access for endovascular infrarenal aortic aneurysm repair is through the femoral artery. In rare circumstances, an anomalous persistent sciatic artery may replace the femoral arterial system as the main blood supply of the lower extremity. We report the case of a 64-year-old woman with a rapidly expanding infrarenal abdominal aortic aneurysm. Preoperative computed tomography revealed a right persistent sciatic artery with an ipsilateral atrophic femoral artery. Her aortic aneurysm was successfully repaired using an endovascular approach with access through the right persistent sciatic artery and contralateral femoral artery. A persistent sciatic artery can be used as an access for endovascular treatment of an infrarenal aortic aneurysm. This technique can be extrapolated to the treatment of distal or contralateral aneurysms, precluding the need for open operation. PMID- 26575384 TI - Extraction of Right-Sided Vegetation With Use of an Aspiration Catheter System. AB - Indications for surgical management of active right-sided endocarditis are under debate. In the presence of vegetation without valvular or surrounding tissue involvement, the mass may be removed with a suction device introduced via a transcatheter path. Herein, we report the successful removal of right-sided vegetation using the AngioVac Cannula, a percutaneous mechanical suction device, in three patients who presented with active endocarditis. The excellent midterm follow-up results highlight the effectiveness of such aspiration catheter systems. PMID- 26575385 TI - Aortic Annulus Stabilization Technique for Rapid Deployment Aortic Valve Replacement. AB - Rapid deployment aortic valve replacement (RDAVR) with the use of rapid deployment valve systems represents a smart alternative to the use of standard aortic bioprosthesis for aortic valve replacement. Nevertheless, its use is still debatable in patients with pure aortic valve regurgitation or true bicuspid aortic valve because of the risk of postoperative paravalvular leak. To address this issue, an optimal annulus-valve size match seems to be the ideal surgical strategy. This article describes a new technique developed to stabilize the aortic annulus and prevent paravalvular leak after RDAVR. To confirm the feasibility, this technique was performed in six patients with severe symptomatic aortic stenosis who were scheduled to undergo aortic valve replacement at our center. All patients survived surgery and were discharged from the hospital. There were no new intracardiac conduction system disturbances observed, and a permanent pacemaker implantation was not required in any of the patients. The intraoperative and postoperative echocardiogram confirmed successful positioning of the valve, and no paravalvular leak was observed. In this preliminary experience, RDAVR through a full sternotomy or an upper hemisternotomy approach with the use of aortic annulus stabilization technique was safe, and no leak was observed. Future studies on large series of patients are necessary to confirm the safety and effectiveness of this technique in preventing paravalvular leak in patients with true bicuspid aortic valves or pure aortic regurgitation. PMID- 26575386 TI - Thoracic Endovascular Aortic Repair in the Ascending Aorta. AB - Thoracic endovascular aortic repair has become an attractive alternative treatment option for thoracic aortic disease. New devices and advanced image guided procedures are continuously expanding the indications. This article focuses on technical aspects of transapical stent graft deployment for ascending aortic pathologies. With improving device technology, diverse available stent grafts, and imaging modalities, thoracic endovascular aortic repair has become safer and holds promising potential to expand treatment options, especially for high-risk patients requiring ascending aorta treatment. PMID- 26575388 TI - Formation of lipid/peptide tubules by IAPP and temporin B on supported lipid membranes. AB - The conversion of various and to is accelerated by , which are also postulated to represent targets mediating the cytotoxicity of protofibrils. Yet, our understanding of the molecular details governing -catalyzed fibrillogenesis of precursors remains limited. To obtain insight into the intricate interplay of and biophysics we have recently introduced supported bilayers (SLBs) with fluorescent analogs as model biomembranes, observed by time-lapse . Here we demonstrate that human islet () induces within minutes of its application on bilayers the expulsion of numerous flexible tubules from the . Intriguingly, these flexible tubules gradually evolve into a network of straight tubes locally attached to the substrate. Two-color imaging of the and the fluorescently labeled revealed to be distributed along the . Similar linear tubules were observed with the antimicrobial temporin B and the non-amyloidogenic rat , revealing that the above mesoscopic perturbations are not related to formation by the human . Micromanipulation experiments revealed that the linearity of the tubules was caused by tension, stretching the tubules between their points of attachment to the substrate. After longer incubation times, for SLBs containing the oxidatively modified 1-palmitoyl-2-azelaoyl-sn-glycero-3-phosphocholine (, bearing a terminal carboxyl at the end of the chain) and human (but not the other ) some of the straight transformed into highly regular helices. This is likely to reflect tension originating from an efficient aggregation of the into parallelly aligned bundles, associated with tubes containing the oxidized , possibly together with a concomitant flow of along the tubules to the immobile aggregates attaching the tubules to the substrate, these two processes cause, upon shortening of the linear scaffold, the attached excess tubule to adopt a helical morphology, coiling around the core. The above studies are in line with the multiphasic kinetics of fibrillation in the presence of oxidized containing liposomes, assessed by fluorescence enhancement. In addition to demonstrating the feasibility of SLBs as biomimetic model system for studying -assisted fibrillation, our results accentuate the role of chemical composition in modulation of different stages of this process and the associated transformation of architecture. Accordingly, changes in the chemical nature of cellular arising from pathophysiological processes such as oxidative stress may participate in the triggering amyloidogenesis as well as amplification of its detrimental effects in vivo. PMID- 26575387 TI - Circulating microRNA Profiles in Patients with Type-1 Autoimmune Hepatitis. AB - Recent studies have demonstrated that micro (mi)RNA molecules can be detected in the circulation and can serve as potential biomarkers of various diseases. This study used microarray analysis to identify aberrantly expressed circulating miRNAs in patients with type 1 autoimmune hepatitis (AIH) compared with healthy controls. Patients with well-documented and untreated AIH were selected from the National Hospital Organization (NHO)-AIH-liver-network database. They underwent blood sampling and liver biopsy with inflammation grading and fibrosis staging before receiving treatment. To further confirm the microarray data, circulating expression levels of miR-21 and miR-122 were quantified by real-time quantitative polymerase chain reaction in 46 AIH patients, 40 patients with chronic hepatitis C (CHC), and 13 healthy controls. Consistent with the microarray data, serum levels of miR-21 were significantly elevated in AIH patients compared with CHC patients and healthy controls. miR-21 and miR-122 serum levels correlated with alanine aminotransferase levels. Circulating levels of miR-21 and miR-122 were significantly reduced in AIH patients with liver cirrhosis, and were inversely correlated with increased stages of fibrosis. By contrast, levels of circulating miR-21 showed a significant correlation with the histological grades of inflammation in AIH. We postulate that aberrantly expressed serum miRNAs are potential biomarkers of AIH and could be implicated in AIH pathogenesis. Alternations of miR-21 and miR-122 serum levels could reflect their putative roles in the mediation of inflammatory processes in AIH. PMID- 26575389 TI - Ebola Response: Modeling the Risk of Heat Stress from Personal Protective Clothing. AB - INTRODUCTION: A significant number of healthcare workers have responded to aid in the relief and containment of the 2013 Ebola virus disease (EVD) outbreak in West Africa. Healthcare workers are required to wear personal protective clothing (PPC) to impede the transmission of the virus; however, the impermeable design and the hot humid environment lead to risk of heat stress. OBJECTIVE: Provide healthcare workers quantitative modeling and analysis to aid in the prevention of heat stress while wearing PPC in West Africa. METHODS: A sweating thermal manikin was used to measure the thermal (Rct) and evaporative resistance (Ret) of the five currently used levels of PPC for healthcare workers in the West Africa EVD response. Mathematical methods of predicting the rise in core body temperature (Tc) in response to clothing, activity, and environment was used to simulate different responses to PPC levels, individual body sizes, and two hot humid conditions: morning/evening (air temperature: 25 degrees C, relative humidity: 40%, mean radiant temperature: 35 degrees C, wind velocity: 1 m/s) and mid-day (30 degrees C, 60%, 70 degrees C, 1 m/s). RESULTS: Nearly still air (0.4 m/s) measures of Rct ranged from 0.18 to 0.26 m2 K/W and Ret ranged from 25.53 to 340.26 m2 Pa/W. CONCLUSION: Biophysical assessments and modeling in this study provide quantitative guidance for prevention of heat stress of healthcare workers wearing PPC responding to the EVD outbreak in West Africa. PMID- 26575390 TI - Computer-assisted designed "selenoxy-chinolin": a new catalytic mechanism of the GPx-like cycle and inhibition of metal-free and metal-associated Abeta aggregation. AB - Using support from rational computer-assisted design, a novel series of hybrids (selenoxy-chinolin) designed by fusing the metal-chelating agent CQ and the antioxidant ebselen were synthesized and evaluated as multitarget-directed ligands. Most of the hybrids demonstrated significant ability to mimic GPx, which is highly consistent with the prediction results of DFT studies for the selenenyl sulfide intermediates in the computational design. Using (77)Se, (1)H and (13)C NMR spectroscopy and high-resolution mass spectroscopy (HRMS), a novel catalytic mechanism, including a new selenium quinone active species, was first demonstrated. 2D NMR studies indicated that the typical hybrid has an effective interaction with Abeta. In addition, the optimal compound 12k was found to possess an excellent ability to scavenge peroxide and to inhibit self- and metal induced Abeta aggregation, and an ability to disassemble preformed self- and metal-induced Abeta aggregates effectively. Furthermore, 12k was able to penetrate the central nervous system (CNS) and did not exhibit any acute toxicity in mice at doses up to 2000 mg kg(-1). Overall, we demonstrated that hybrid 12k, through rational structure-based computational design, shows a potential for development as a therapeutic agent in AD. PMID- 26575391 TI - The 'Dispersal Rate' - a product dependent characteristic to predict the reliability of the calibrated in vitro SPF on WW5 plates. AB - OBJECTIVES: The evaluation of the SPF by the measurement of light transmission through a thin film on PMMA plates is an interesting alternative to the conventional in vivo method. However, during the last years an internationally acknowledged in vitro SPF measurement could not be established mainly due to bad reproducibility. With this work, we would like to give new suggestions for an improved reproducibility and to open new space for discussion. METHODS: A total of 22 o/w emulsions with well-established in vivo SPF were measured in vitro close to the international Standard ISO 24443 on two different substrates (PMMA plates: WW5 and HD6). For each product, the ratio 'in vitro SPFraw /in vivo SPF' was calculated. The composition of the products was analysed regarding a parameter that correlates with the aforementioned ratio. Additionally seven suitable calibration products were determined to transfer the in vitro SPFraw to the calibrated in vitro SPFcal . RESULTS: We could show that the results for the SPFcal matched very well for 19 measured o/w emulsions on WW5 plates. However, we found two products where the in vitro SPF was much lower than the in vivo SPF. The Dispersal Rate allows us to identify a product characteristic parameter to predict too low measured in vitro SPFs on WW5 plates. This parameter mainly refers to the ratio of water to lipids in an emulsion. We found that products with few emollients and few emulsifiers are measured too low in vitro. CONCLUSION: We suggest implementing an individual calibration of the in vitro SPF to improve the reproducibility of in vitro SPF measurements between different laboratories. Considering the Dispersal Rate helps to estimate the reliability of the in vitro SPF measured on WW5 plates. In order to evaluate whether those products with a high Dispersal Rate can also be calibrated with special standards, further measurements need to be done. We demonstrate that, besides the known parameter, also the composition of the products should be considered for the interpretation of the in vitro SPF. Our findings could explain some multiple reported problems in correlation between in vitro and in vivo SPF, especially for higher SPFs (Personal Care, November, 2014, 27). PMID- 26575392 TI - 18F-FDG-PET/CT therapy assessment of locally advanced pancreatic adenocarcinoma: impact on management and utilization of quantitative parameters for patient survival prediction. AB - OBJECTIVES: This study aims to evaluate the impact of therapy assessment PET/computed tomography (CT) scan on the management of locally advanced pancreatic adenocarcinoma (LAPC), and the value of qualitative versus quantitative PET/CT interpretation for patient outcome prediction. MATERIALS AND METHODS: Forty-two LAPC patients were retrospectively included. PET/CT was performed at a median of 4.6 weeks after completion of chemo +/- radiotherapy to assess the primary treatment response. PET was interpreted visually using a qualitative five-point scale (Hopkins criteria for therapy assessment). Quantitative PET parameters including maximum and peak standardized uptake value (SUV max and SUV peak), total lesion glycolysis, and metabolic tumor volume (MTV) were also measured using the gradient segmentation method. Kaplan-Meier and Cox regression analyses were performed. RESULTS: Thirty-five patients were followed up until death. Therapy assessment PET/CT led to a change in the overall management of 22 (52.4%) patients, prompting surgical resection (eight patients), adding radiation therapy (eight patients), or starting palliative chemotherapy (six patients). The median survival in patients with a negative or a positive PET scan, according to the Hopkins criteria, was 14.6 and 8.7 months, respectively (P=0.06). The median quantitative thresholds of SUV peak 2.64 [hazard ratio (HR)=2.67, P=0.03], total lesion glycolysis 44.0 g (HR=2.64, P=0.005), and MTV 24.7 ml (HR=2.57, P=0.008) were significant predictors of overall survival. Using combined quantitative scoring, patients with high SUV peak and high MTV (>median cut point) had a 5.45-fold (95% confidence interval: 1.76-16.87) increased risk for death compared with those with both low SUV peak and MTV (the reference group). CONCLUSION: PET-based volumetric parameters can predict survival outcomes of patients with LAPC. A combined quantitative PET/CT scoring system provides significantly improved prognostication. PMID- 26575393 TI - Sodium glucose cotransporter 2 inhibition in the diabetic kidney: an update. AB - PURPOSE OF REVIEW: The sodium glucose cotransporter 2 (SGLT2) reabsorbs most of the glucose filtered by the kidneys. SGLT2 inhibitors reduce glucose reabsorption, thereby lowering blood glucose levels, and have been approved as new antihyperglycemic drugs. Although the therapeutic strategy is very promising, many questions remain. RECENT FINDINGS: Using validated antibodies, SGLT2 expression was localized to the brush border of the early proximal tubule in the human kidney and was found upregulated in genetic murine models of type 1 and 2 diabetes. SGLT2 may functionally interact with the Na/H exchanger NHE3 in the proximal tubule. SGLT1-mediated reabsorption explains the fractional renal glucose reabsorption of 40-50% during SGLT2 inhibition. SGLT2 is expressed on pancreatic alfa cells where its inhibition induces glucagon secretion. SGLT2 inhibition lowers glomerular filtration rate in hyperfiltering diabetic patients consistent with the tubular hypothesis of diabetic hyperfiltration. New data indicate a potential of SGLT2 inhibition for renal medullary hypoxia and ketoacidosis, but also for blood glucose effect-dependent and independent nephroprotective actions, renal gluconeogenesis inhibition, reduction in cardiovascular mortality, and cancer therapy. SUMMARY: The findings expand and refine our understanding of SGLT2 and its inhibition, have relevance for clinical practice, and will help interpret ongoing clinical trials on the long-term safety and cardiovascular effects of SGLT2 inhibitors. PMID- 26575394 TI - Angiotensin converting enzyme 2 and the kidney. AB - PURPOSE OF REVIEW: Angiotensin-converting enzyme 2 (ACE2) is a monocarboxypeptidase that metabolizes angiotensin II (AngII). AngII levels can be modulated by ACE2 in tissues where the enzyme is highly expressed, such as the kidney. In the kidney, ACE2 has the potential to regulate the intrarenal renin angiotensin system (RAS), which can impact blood pressure and renal injury. Thus, in disease states where the RAS is often upregulated, the function of ACE2 plays a particularly important role. This review highlights the results of recent studies that demonstrate the interplay between ACE2 and the kidney under normal and pathological conditions. RECENT FINDINGS: ACE2 has been reported to play a key role in renal and cardiovascular function. Recent studies have implicated shedding of the membrane-bound ectodomain of ACE2 as one way in which the enzyme can be regulated and enzymatic activity altered. This posttranslational modification releases a fragment which retains enzymatic activity, and thus provides a novel mechanism by which the RAS can be altered in response to physiological stimuli. Decreased ACE2 activity is associated with increased blood pressure, diabetes, and oxidative stress, whereas, increased levels of ACE2 appear to be renoprotective. SUMMARY: A growing body of evidence, involving both experimental and human studies, points out the crucial role that ACE2 plays on the modulation of renal injury. Thus, therapeutic targets aiming to increase ACE2 activity and the ACE2-Ang(1-7)-MasR axis could potentially become clinically relevant, especially in disease states where the renal RAS is upregulated. PMID- 26575395 TI - Role of immune cells in salt-sensitive hypertension and renal injury. AB - PURPOSE OF REVIEW: Immune mechanisms exacerbate the severity of hypertension in humans and animal models of disease. This review summarizes recent mechanistic studies exploring the pathways whereby immunity influences salt-sensitive hypertension and renal disease. RECENT FINDINGS: Emphasis is placed on the role of T cell subtypes, the mechanisms of T-cell activation, and the identification of potential antigens or neoantigens. SUMMARY: Significant advancements have occurred in the search for pathways which activate the adaptive immune response. An enhanced understanding of the factors contributing to hypertension can lead to better therapies. PMID- 26575397 TI - Noteworthy observations in hypertension from 2015. PMID- 26575396 TI - Aldosterone in vascular and metabolic dysfunction. AB - PURPOSE OF REVIEW: This review will highlight recent developments in mineralocorticoid receptor research which impact aldosterone-associated vascular and cardiometabolic dysfunction. RECENT FINDINGS: The mineralocorticoid receptor is also expressed in vascular smooth muscle and vascular endothelium, and contributes to vascular function and remodeling. Adipocyte-derived leptin stimulates aldosterone secretion, which may explain the observed link between obesity and hyperaldosteronism. Adipocyte mineralocorticoid receptor overexpression produces systemic changes consistent with metabolic syndrome. Ongoing studies with novel nonsteroidal mineralocorticoid receptor antagonists may provide a novel treatment for diabetic nephropathy and heart failure in patients with chronic kidney disease, with reduced risk of hyperkalemia. SUMMARY: Ongoing research continues to demonstrate novel roles of the vascular and adipocyte mineralocorticoid receptor function, which may explain the beneficial metabolic and vascular benefits of mineralocorticoid receptor antagonists. PMID- 26575398 TI - Reduced sinonasal levels of 1alpha-hydroxylase are associated with worse quality of life in chronic rhinosinusitis with nasal polyps. AB - BACKGROUND: Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) have deficiencies in circulating and sinonasal levels of the inactive form of vitamin D3, 25-hydroxycholecalciferol (25VD3). Moreover, CRSwNP patients have reduced epithelial cell-specific expression of 1alpha-hydroxylase; the enzyme responsible for the conversion of 25VD3 to its metabolically active form, 1alpha,25 dihydroxyvitamin D3 (1,25VD3). The objective of this work was to determine the impact of sinonasal 1alpha-hydroxylase levels combined from all cellular sources on subjective disease severity and to identify variables influencing its expression. METHODS: Blood and sinus tissue explants were collected at the time of surgery from control, chronic rhinosinusitis without nasal polyps (CRSsNP), CRSwNP, and allergic fungal rhinosinusitis (AFRS) patients. 1alpha-Hydroxylase was measured by immunostaining with flow cytometric analysis. Subjective disease severity was measured by the 22-item Sino-Nasal Outcomes Test (SNOT-22). 1,25VD3 and 25VD3 were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Patients with CRSwNP or AFRS have reduced 1alpha-hydroxylase and 1,25VD3 compared to controls or CRSsNP. Circulating 1,25VD3 levels were the same among all groups. No differences in sinonasal 1alpha-hydroxylase or 1,25VD3 were found between CRSwNP and AFRS. Gender, age, race, atopy, and systemic 25VD3 had no impact on sinonasal 1alpha-hydroxylase levels in any group. However, CRSwNP patients with asthma had higher 1alpha-hydroxylase than those without asthma. Total 1alpha hydroxylase levels inversely correlated with SNOT-22 in CRSwNP, but not CRSsNP. CONCLUSION: Patients with CRSwNP and AFRS both have reduced sinonasal 1alpha hydroxylase and 1,25VD3 compared to controls or CRSsNP. Reductions in intracellular 1alpha-hydroxylase combined from all sinonasal cell types were associated with more severe subjective disease severity in CRSwNP. PMID- 26575400 TI - Nanostructured Silicon Photocathodes for Solar Water Splitting Patterned by the Self-Assembly of Lamellar Block Copolymers. AB - We studied a type of nanostructured silicon photocathode for solar water splitting, where one-dimensionally periodic lamellar nanopatterns derived from the self-assembly of symmetric poly(styrene-block-methyl methacrylate) block copolymers were incorporated on the surface of single-crystalline silicon in configurations with and without a buried metallurgical junction. The resulting nanostructured silicon photocathodes with the characteristic lamellar morphology provided suppressed front-surface reflection and increased surface area, which collectively contributed to the enhanced photocatalytic performance in the hydrogen evolution reaction. The augmented light absorption in the nanostructured silicon directly translated to the increase of the saturation current density, while the onset potential decreased with the etching depth because of the increased levels of surface recombination. The pp(+)-silicon photocathodes, compared to the n(+)pp(+)-silicon with a buried solid-state junction, exhibited a more pronounced shift of the current density-potential curves upon the introduction of the nanostructured surface owing to the corresponding increase in the liquid/silicon junction area. Systematic studies on the morphology, optical properties, and photoelectrochemical characteristics of nanostructured silicon photocathodes, in conjunction with optical modeling based on the finite difference time-domain method, provide quantitative description and optimal design rules of lamellar-patterned silicon photocathodes for solar water splitting. PMID- 26575399 TI - Identification and Analysis of Natural Killer Cells in Murine Nasal Passages. AB - BACKGROUND: Natural killer (NK) cells in the upper respiratory airways are not well characterized. In the current study, we sought to characterize and functionally assess murine nasal NK cells. METHODS: Using immunohistochemistry and flow cytometry, we compared the nasal NK cells of Ncr1GFP/+ knock-in mice, whose NK cells produced green fluorescent protein, with their splenic and pulmonary counterparts. In addition, we functionally analyzed the nasal NK cells of these mice in vitro. To assess the in vivo functions of nasal NK cells, C57BL/6 mice depleted of NK cells after treatment with PK136 antibody were nasally infected with influenza virus PR8. RESULTS: Immunohistochemical analysis confirmed the presence of NK cells in the lamina propria of nasal mucosa, and flow cytometry showed that these cells were of NK cell lineage. The expression patterns of Ly49 receptor, CD11b/CD27, CD62L and CD69 revealed that nasal NK cells had an immature and activated phenotype compared with that of their splenic and pulmonary counterparts. Effector functions including degranulation and IFN(interferon)-gamma production after in vitro stimulation with phorbol 12 myristate-13-acetate plus ionomycin or IL(interleukin)-12 plus IL-18 were dampened in nasal NK cells, and the depletion of NK cells led to an increased influenza virus titer in nasal passages. CONCLUSIONS: The NK cells of the murine nasal passage belong to the conventional NK cell linage and characteristically demonstrate an immature and activated phenotype. Despite their hyporesponsiveness in vitro, nasal NK cells play important roles in the host defense against nasal influenza virus infection. PMID- 26575401 TI - Dynamic Docking of Conformationally Constrained Macrocycles: Methods and Applications. AB - Many natural products consist of large and flexible macrocycles that engage their targets via multiple contact points. This combination of contained flexibility and large contact area often allows natural products to bind at target surfaces rather than deep pockets, making them attractive scaffolds for inhibiting protein protein interactions and other challenging therapeutic targets. The increasing ability to manipulate such compounds either biosynthetically or via semisynthetic modification means that these compounds can now be considered as starting points for medchem campaigns rather than solely as ends. Modern medchem benefits substantially from rational improvements made on the basis of molecular docking. As such, docking methods have been enhanced in recent years to deal with the complicated binding modalities and flexible scaffolds of macrocyclic natural products and natural product-like structures. Here, we comprehensively review methods for treating and docking these large macrocyclic scaffolds and discuss some of the resulting advances in medicinal chemistry. PMID- 26575402 TI - Nonparametric methods for analyzing recurrent gap time data with application to infections after hematopoietic cell transplant. AB - Infection is one of the most common complications after hematopoietic cell transplantation. Many patients experience infectious complications repeatedly after transplant. Existing statistical methods for recurrent gap time data typically assume that patients are enrolled due to the occurrence of an event of interest, and subsequently experience recurrent events of the same type; moreover, for one-sample estimation, the gap times between consecutive events are usually assumed to be identically distributed. Applying these methods to analyze the post-transplant infection data will inevitably lead to incorrect inferential results because the time from transplant to the first infection has a different biological meaning than the gap times between consecutive recurrent infections. Some unbiased yet inefficient methods include univariate survival analysis methods based on data from the first infection or bivariate serial event data methods based on the first and second infections. In this article, we propose a nonparametric estimator of the joint distribution of time from transplant to the first infection and the gap times between consecutive infections. The proposed estimator takes into account the potentially different distributions of the two types of gap times and better uses the recurrent infection data. Asymptotic properties of the proposed estimators are established. PMID- 26575403 TI - Jump Landing Characteristics Predict Lower Extremity Injuries in Indoor Team Sports. AB - The aim of this study is to investigate the predictive value of landing stability and technique to gain insight into risk factors for ankle and knee injuries in indoor team sport players. Seventy-five male and female basketball, volleyball or korfball players were screened by measuring landing stability after a single-leg jump landing and landing technique during a repeated counter movement jump by detailed 3-dimensional kinematics and kinetics. During the season 11 acute ankle injuries were reported along with 6 acute and 7 overuse knee injuries by the teams' physical therapist. Logistic regression analysis showed less landing stability in the forward and diagonal jump direction (OR 1.01-1.10, p<=0.05) in players who sustained an acute ankle injury. Furthermore landing technique with a greater ankle dorsiflexion moment increased the risk for acute ankle injury (OR 2.16, p<=0.05). A smaller knee flexion moment and greater vertical ground reaction force increased the risk of an overuse knee injury (OR 0.29 and 1.13 respectively, p<=0.05). Less one-legged landing stability and suboptimal landing technique were shown in players sustaining an acute ankle and overuse knee injury compared to healthy players. Determining both landing stability and technique may further guide injury prevention programs. PMID- 26575404 TI - VO2 Kinetics in All-out Arm Stroke, Leg Kick and Whole Stroke Front Crawl 100-m Swimming. AB - The VO2 response to extreme-intensity exercise and its relationship with sports performance are largely unexplored. This study investigated the pulmonary VO2 kinetics during all-out 100-m front crawl whole stroke swimming (S), arm stroke (A) and leg kick (L). 26 male and 10 female competitive swimmers performed an all out S trial followed by A and L of equal duration in random order. Breath-by breath VO2 was measured using a snorkel attached to a portable gas analyzer. Mean (+/-SD) primary component parameters and peak blood lactate (Lapeak) during S, A, and L were, respectively: time delay (s), 14.2 +/- 4.7, 14.3 +/- 4.5, 15.6 +/- 5.1; amplitude (ml.kg(-1).min(-1)), 46.8 +/- 6.1, 37.3 +/- 6.9, 41.0 +/- 4.7; time constant (tau, s): 9.2 +/- 3.2, 12.4 +/- 4.7, 10.1 +/- 3.2; Lapeak (mmol.l( 1)), 6.8 +/- 3.1, 6.3 +/- 2.5, 7.9 +/- 2.8. During A and L respectively, 80% and 87% of amplitude in S was reached, whereas A+L were 68% greater than in S. 100-m performance was associated to shorter cardiodynamic phase and greater VO2 amplitude and Lapeak (accounting up to 61% of performance variance), but not to tau. We conclude that (i) VO2 gain was proportional to exercise intensity and muscle mass involved, (ii) kicking is metabolically less efficient, and (iii) the main limiting factor of peak VO2 appears to be O2 delivery and not muscle extraction. PMID- 26575405 TI - Phenotypic variability related to C9orf72 mutation in a large Sardinian kindred. AB - We investigated intrafamilial phenotypic variability in carriers of the C9orf72 mutation, analysing clinical, neuropsychological and imaging characteristics of various members from a large Sardinian kindred with FTD or ALS. We compared these with those of C9 + patients in our ALS and FTD cohorts. Results showed that three patients carried the C9orf72 mutation: two with ALS and one with FTD and Parkinsonism. C9 + patients in our bvFTD Sardinian cohort had a higher frequency of Parkinsonism than non-mutated patients (75% vs. 36.3%, p <0.02). Parkinsonism was present in 2.7% of our ALS cohort and 3.3% of the C9 + patients. The prevalence of Parkinsonism in C9 + patients in the bvFTD and ALS cohorts showed a statistically significant difference (p <0.006). In conclusion, Parkinsonism was frequently associated with FTD but not ALS in a large Sardinian family, a finding reflected in the wider C9orf72 associated Sardinian ALS and FTD populations. PMID- 26575407 TI - SIRAH: a structurally unbiased coarse-grained force field for proteins with aqueous solvation and long-range electrostatics. AB - Modeling of macromolecular structures and interactions represents an important challenge for computational biology, involving different time and length scales. However, this task can be facilitated through the use of coarse-grained (CG) models, which reduce the number of degrees of freedom and allow efficient exploration of complex conformational spaces. This article presents a new CG protein model named SIRAH, developed to work with explicit solvent and to capture sequence, temperature, and ionic strength effects in a topologically unbiased manner. SIRAH is implemented in GROMACS, and interactions are calculated using a standard pairwise Hamiltonian for classical molecular dynamics simulations. We present a set of simulations that test the capability of SIRAH to produce a qualitatively correct solvation on different amino acids, hydrophilic/hydrophobic interactions, and long-range electrostatic recognition leading to spontaneous association of unstructured peptides and stable structures of single polypeptides and protein-protein complexes. PMID- 26575408 TI - Beyond naive cue combination: salience and social cues in early word learning. AB - Children learn their earliest words through social interaction, but it is unknown how much they rely on social information. Some theories argue that word learning is fundamentally social from its outset, with even the youngest infants understanding intentions and using them to infer a social partner's target of reference. In contrast, other theories argue that early word learning is largely a perceptual process in which young children map words onto salient objects. One way of unifying these accounts is to model word learning as weighted cue combination, in which children attend to many potential cues to reference, but only gradually learn the correct weight to assign each cue. We tested four predictions of this kind of naive cue combination account, using an eye-tracking paradigm that combines social word teaching and two-alternative forced-choice testing. None of the predictions were supported. We thus propose an alternative unifying account: children are sensitive to social information early, but their ability to gather and deploy this information is constrained by domain-general cognitive processes. Developmental changes in children's use of social cues emerge not from learning the predictive power of social cues, but from the gradual development of attention, memory, and speed of information processing. PMID- 26575409 TI - Predictive value of ultrasonographic assessment of disease activity in response to tumor necrosis factor-alpha inhibitor treatment in rheumatoid arthritis: a prospective cohort study. PMID- 26575410 TI - A curious case of resistance to a new encounter pathogen: myrtle rust in Australia. AB - Resistance genes (R genes) in plants mediate a highly specific response to microbial pathogens, often culminating in localized cell death. Such resistance is generally pathogen race specific and believed to be the result of evolutionary selection pressure. Where a host and pathogen do not share an evolutionary history, specific resistance is expected to be absent or rare. Puccinia psidii, the causal agent of myrtle rust, was recently introduced to Australia, a continent rich in myrtaceous taxa. Responses within species to this new pathogen range from full susceptibility to resistance. Using the myrtle rust case study, we examine models to account for the presence of resistance to new encounter pathogens, such as the retention of ancient R genes through prolonged 'trench warfare', pairing of resistance gene products and the guarding of host integrity. PMID- 26575412 TI - Expression of concern: A unifying mechanism for the rearrangement of vinyl allene oxide geometric isomers to cyclopentenones. AB - Expression of concern for 'A unifying mechanism for the rearrangement of vinyl allene oxide geometric isomers to cyclopentenones' by Adan B. Gonzalez-Perez et al., Org. Biomol. Chem., 2014, 12, 7694-7701. PMID- 26575411 TI - Pediatric Colorectal Carcinoma is Associated With Excellent Outcome in the Context of Cancer Predisposition Syndromes. AB - INTRODUCTION: Colorectal carcinoma (CRC) is the second most common adult cancer in Germany, however, it is extremely rare in children and adolescents. In these patients, previous literature describes aggressive behavior and diagnosis at advanced stage. METHOD: Thirty-one patients with CRC age <= 18 years and treated between 1990 and 2012 have been identified through the structures and registries of the German Society for Pediatric Oncology and Hematology. RESULTS: The age range was 9-18 years (median 13.5 years); the median follow-up time was 43.9 months (range 1-124 months). Twenty-six patients (84%) were tested for a genetic tumor syndrome (GTS); of these, 11 patients (35% of all patients) tested positive (eight cases of Lynch syndrome, one patient with familial adenomatous polyposis, two patients with constitutional mismatch repair deficiency). An unfavorable histology was reported in 55% of the records (n = 17), a poor differentiation (grade III) in 68% of carcinoma (n = 21). Overall survival (OS) and event-free survival at 5 years was 52.0% and 65.6%, respectively. Five-year survival according to stage was 100% in stage II (n = 2), 100% in stage III (n = 13), and 12.9% in stage IV (n = 15; P < 0.001). Five-year OS in patients with and without a defined GTS was 100% and 36.5% (P = 0.019), respectively. CONCLUSION: Children and adolescents with CRC are frequently diagnosed in advanced stages and have an unfavorable prognosis. In this study, a high percentage of pediatric CRC patients presented with a tumor predisposition syndrome and showed an especially favorable OS. PMID- 26575413 TI - Single-Particle Time-of-Flight Mass Spectrometry Utilizing a Femtosecond Desorption and Ionization Laser. AB - Single-particle time-of-flight mass spectrometry has now been used since the 1990s to determine particle-to-particle variability and internal mixing state. Instruments commonly use 193 nm excimer or 266 nm frequency-quadrupled Nd:YAG lasers to ablate and ionize particles in a single step. We describe the use of a femtosecond laser system (800 nm wavelength, 100 fs pulse duration) in combination with an existing single-particle time-of-flight mass spectrometer. The goal of this project was to determine the suitability of a femtosecond laser for single-particle studies via direct comparison to the excimer laser (193 nm wavelength, ~10 ns pulse duration) usually used with the instrument. Laser power, frequency, and polarization were varied to determine the effect on mass spectra. Atmospherically relevant materials that are often used in laboratory studies, ammonium nitrate and sodium chloride, were used for the aerosol. Detection of trace amounts of a heavy metal, lead, in an ammonium nitrate matrix was also investigated. The femtosecond ionization had a large air background not present with the 193 nm excimer and produced more multiply charged ions. Overall, we find that femtosecond laser ablation and ionization of aerosol particles is not radically different than that provided by a 193 nm excimer. PMID- 26575414 TI - Self-consistent field for fragmented quantum mechanical model of large molecular systems. AB - Fragment-based linear scaling quantum chemistry methods are a promising tool for the accurate simulation of chemical and biomolecular systems. Because of the coupled inter-fragment electrostatic interactions, a dual-layer iterative scheme is often employed to compute the fragment electronic structure and the total energy. In the dual-layer scheme, the self-consistent field (SCF) of the electronic structure of a fragment must be solved first, then followed by the updating of the inter-fragment electrostatic interactions. The two steps are sequentially carried out and repeated; as such a significant total number of fragment SCF iterations is required to converge the total energy and becomes the computational bottleneck in many fragment quantum chemistry methods. To reduce the number of fragment SCF iterations and speed up the convergence of the total energy, we develop here a new SCF scheme in which the inter-fragment interactions can be updated concurrently without converging the fragment electronic structure. By constructing the global, block-wise Fock matrix and density matrix, we prove that the commutation between the two global matrices guarantees the commutation of the corresponding matrices in each fragment. Therefore, many highly efficient numerical techniques such as the direct inversion of the iterative subspace method can be employed to converge simultaneously the electronic structure of all fragments, reducing significantly the computational cost. Numerical examples for water clusters of different sizes suggest that the method shall be very useful in improving the scalability of fragment quantum chemistry methods. PMID- 26575415 TI - Simvastatin increases AQP2 urinary excretion in hypercholesterolemic patients: A pleiotropic effect of interest for patients with impaired AQP2 trafficking. AB - We previously reported that statins improve the symptoms of X-linked nephrogenic diabetes insipidus (X-NDI) in animal models. The aim of this study was to verify whether the pleiotropic effect of statins on AQP2 trafficking and kidney concentrating ability, observed in rodents, was attainable in humans at therapeutic doses. We enrolled 24 naive hypercholesterolemic patients and measured urine excretion of AQP2 (uAQP2) at baseline and during 12 weeks of treatment with simvastatin 20 mg/day. Simvastatin induced a rapid and significant increase of uAQP2, reduced the 24-hour diuresis, and increased urine osmolality. These effects were also maintained in patients chronically treated with statins for at least 1 year. This study strongly suggests that statins may effectively enhance the efficacy of current pharmacological treatment of patients with urine concentrating defects caused by defective AQP2 plasma membrane trafficking, like X-NDI. PMID- 26575416 TI - Synthesis of New 'Hybrid' Compounds Based on Benzofuroxans and Aminoalkylnaphthalimides. AB - Pathogenic bacteria and fungi eventually develop resistance to existing drugs, and therefore, we need constant development of new drugs. The research is aimed at addressing fundamental scientific problems-the search for new biologically active compounds among several benzofuroxan-containing 'hybrid' products. N substituted naphthalimides were chosen as a second pharmacophore. Benzofuroxanes biological effects were studied by means of bacterial lux-biosensors. Compounds IIIa, IVa, IIIc, and IVc displayed more expressed bacteriotoxic action in comparison with the initial substances Ia-c and represent a certain interest for using as antibacterial substances. PMID- 26575418 TI - Scandium-Triflate/Metal-Organic Frameworks: Remarkable Adsorbents for Desulfurization and Denitrogenation. AB - Scandium-triflate (Sc(OTf)3) was introduced for the first time on metal-organic frameworks (MOFs), to utilize acidic Sc(OTf)3 for adsorptive desulfurization and denitrogenation of fuel containing benzothiophene (BT), dibenzothiophene (DBT), quinoline (QUI), and indole (IND). A remarkable improvement in the adsorption capacity (about 65% based on the weight of adsorbents; 90% based on the surface area of the adsorbents) was observed with the Sc(OTf)3/MOFs as compared to the virgin MOFs for the adsorption of BT from liquid fuel. The basic QUI was also adsorbed preferentially onto the acidic Sc(OTf)3/MOFs. However, nonsupported Sc(OTf)3 showed negligible adsorption capacities. The improved adsorptive performance for BT, DBT, and QUI might be derived from acid-base interactions between the acidic Sc(OTf)3 and basic adsorbates. On the other hand, the Sc(OTf)3, loaded on MOFs, reduced the adsorption capacity for neutral IND due to lack of interaction between the neutral adsorbate and acidic adsorbent and the reduced porosities of the modified adsorbents. The reusability of the adsorbents was found satisfactory up to the fourth run. On the basis of the result, it is suggested that metal-triflates, such as Sc(OTf)3, can be prospective materials for adsorptive desulfurization/denitrogenation of fuels when supported on porous materials such as MOFs. PMID- 26575417 TI - Occupational sitting time and risk of all-cause mortality among Japanese workers. AB - OBJECTIVES: Prolonged sitting is a health risk for cardiovascular diseases and all-cause mortality, independent of moderate-to-vigorous physical activity. Epidemiological evaluation of occupational sitting has received little attention, even though it may have a potential impact on workers' health. We prospectively examined the association between occupational sitting time and all-cause mortality. METHODS: Community-dwelling, Japanese workers aged 50-74 years who responded to a questionnaire in 2000-2003 were followed for all-cause mortality through 2011. Cox proportional hazard models were employed to calculate hazard ratios (HR) of all-cause mortality among middle (1- to <3 hours/day) or longer (>=3 hours/day) occupationally sedentary subjects by gender or types of engaging industry ("primary industry" and "secondary or tertiary industry"). RESULTS: During 368,120 person-years of follow-up (average follow-up period, 10.1 years) for the 36,516 subjects, 2209 deaths were identified. Among workers in primary industry, longer duration of occupational sitting was significantly or marginally associated with higher mortality [HR 1.23, 95% confidence interval (95% CI) 1.00 1.51 among men; HR 1.34, 95% CI 0.97-1.84 among women]. No associations were found among secondary or tertiary industry workers (men: HR 0.87, 95% CI 0.75 1.01; women: HR 1.03, 95% CI 0.77-1.39). CONCLUSIONS: Occupational sitting time increased all-cause mortality among primary industry workers, however similar relationships were not observed for secondary-tertiary workers. Future studies are needed to confirm detailed dose-response relationships by using objective measures. In addition, studies using cause-specific mortality data would be important to clarify the physiological underlying mechanism. PMID- 26575419 TI - Identification and clinical characterization of Hermansky-Pudlak syndrome alleles in the Pakistani population. PMID- 26575420 TI - Emergency Department Diagnostic Imaging: The Journey to Quality. AB - Priorities in health care delivery are shifting, with a greater focus on enhancing value, incentivizing quality, and advancing population health. While measurement of quality in emergency department (ED) care is still in its infancy, performance measures are increasingly being linked to reimbursement to encourage the delivery of high-value care. With such changes, there will be growing oversight of diagnostic imaging in all clinical settings, including the ED. Here, the authors examine the current state of quality measurement as it pertains to ED imaging. The authors review relevant policies and discuss both the associated challenges and the facilitators of using quality measures to help optimize ED imaging. Understanding such factors will help ensure the delivery of diagnostic imaging that is appropriate, high-quality, and patient-centered. PMID- 26575421 TI - Enhanced therapeutic effect of Adriamycin on multidrug resistant breast cancer by the ABCG2-siRNA loaded polymeric nanoparticles assisted with ultrasound. AB - The overexpression of the breast cancer resistance protein (ABCG2) confers resistance to Adriamycin (ADR) in breast cancer. The silencing of ABCG2 using small interfering RNA (siRNA) could be a promising approach to overcome multidrug resistance (MDR) in cancer cells. To deliver ABCG2-siRNA effectively into breast cancer cells, we used mPEG-PLGA-PLL (PEAL) nanoparticles (NPs) with ultrasound targeted microbubble destruction (UTMD). PEAL NPs were prepared with an emulsion solvent evaporation method. The NPs size was about 131.5 +/- 6.5 nm. The siRNA stability in serum was enhanced. The intracellular ADR concentration increased after the introduction of siRNA-loaded NPs. After intravenous injection of PEAL NPs in tumor-bearing mice, the ABCG2-siRNA-loaded NPs with UTMD efficiently silenced the ABCG2 gene and enhanced the ADR susceptibility of MCF-7/ADR (ADR resistant human breast cancer cells). The siRNA-loaded NPs with UTMD + ADR showed better tumor inhibition effect and good safety in vivo. These results indicate that ADR-chemotherapy in combination with ABCG2-siRNA is an attractive strategy to treat breast cancer. PMID- 26575422 TI - Intra-tumor AvidinOX allows efficacy of low dose systemic biotinylated Cetuximab in a model of head and neck cancer. AB - For locally advanced and metastatic head and neck squamous cell carcinoma (HNSCC), the current clinical use of Cetuximab in chemo/radiotherapy protocols is often associated to severe systemic toxicity. Here we report in vitro data in human FaDu pharynx SCC cells, showing that inactive concentrations of biotinylated Cetuximab (bCet) become active upon anchorage to AvidinOX on the surface of tumor cells. AvidinOX-anchored bCet induces apoptosis and DNA damage as well as specific inhibition of signaling, degradation and abrogation of nuclear translocation of EGFR. In the mouse model of FaDu cancer, we show that intra-tumor injection of AvidinOX allows anti-tumor activity of an otherwise inactive, intraperitoneally delivered, low dose bCet. Consistently with in vitro data, in vivo tumor inhibition is associated to induction of apoptosis, DNA damage and reduced angiogenesis. AvidinOX is under clinical investigation for delivering radioactive biotin to inoperable tumors (ClinicalTrials.gov NCT02053324) and present data support its use for the local treatment of HNSCC in combination with systemic administration of low dose bCet. PMID- 26575423 TI - Concomitant BET and MAPK blockade for effective treatment of ovarian cancer. AB - Ovarian cancer is the most lethal gynecologic malignancy, and it is imperative to develop new treatments to ameliorate patient survival. Using an anti-cancer drug library containing 180 small molecule inhibitors, we performed a high-content image-based screen and found that BET and MEK inhibitors are among the candidates which were able to effectively inhibit ovarian cancer cell growth. However, BET inhibition alone was largely cytostatic, possibly due to feedback activation of the MAPK pathway. Consequently, the combination of MEK and BET inhibitors suppressed both cell proliferation and survival, and was more efficacious than single agent. Mechanistically, BET and MEK inhibitors exerted synergistic effects on apoptosis regulators including BIM and BAD. Our findings support concomitant BET and MAPK blockade as an effective therapeutic strategy in ovarian cancer. PMID- 26575425 TI - Design, Synthesis, and Antiviral Activity of Novel Ribonucleosides of 1,2,3 Triazolylbenzyl-aminophosphonates. AB - A novel series of ribonucleosides of 1,2,3-triazolylbenzyl-aminophosphonates was synthesized through the Kabachnik-Fields reaction using I2 as catalyst followed by copper-catalyzed cycloaddition of the azide-alkyne reaction (CuAAC). All structures of the newly prepared compounds were characterized by (1) H NMR, (13) C NMR, and HRMS spectra. The structures of 2e, 2f, 3d, and 3g were further confirmed by X-ray diffraction analysis. These compounds were tested against various strains of DNA and RNA viruses; compounds 4b and 4c showed a modest inhibitory activity against respiratory syncytial virus (RSV) and compound 4h displayed modest inhibitory activity against Coxsackie virus B4. PMID- 26575424 TI - Formononetin, a novel FGFR2 inhibitor, potently inhibits angiogenesis and tumor growth in preclinical models. AB - Most anti-angiogenic therapies currently being evaluated in clinical trials target vascular endothelial growth factor (VEGF) pathway, however, the tumor vasculature can acquire resistance to VEGF-targeted therapy by shifting to other angiogenesis mechanisms. Therefore, other potential therapeutic agents that block non-VEGF angiogenic pathways need to be evaluated. Here we identified formononetin as a novel agent with potential anti-angiogenic and anti-cancer activities. Formononetin demonstrated inhibition of endothelial cell proliferation, migration, and tube formation in response to basic fibroblast growth factor 2 (FGF2). In ex vivo and in vivo angiogenesis assays, formononetin suppressed FGF2-induced microvessel sprouting of rat aortic rings and angiogenesis. To understand the underlying molecular basis, we examined the effects of formononetin on different molecular components in treated endothelial cell, and found that formononetin suppressed FGF2-triggered activation of FGFR2 and protein kinase B (Akt) signaling. Moreover, formononetin directly inhibited proliferation and blocked the oncogenic signaling pathways in breast cancer cell. In vivo, using xenograft models of breast cancer, formononetin showed growth inhibitory activity associated with inhibition of tumor angiogenesis. Moreover, formononetin enhanced the effect of VEGFR2 inhibitor sunitinib on tumor growth inhibition. Taken together, our results indicate that formononetin targets the FGFR2-mediated Akt signaling pathway, leading to the suppression of tumor growth and angiogenesis. PMID- 26575426 TI - Germline gene polymorphisms predisposing domestic mammals to carcinogenesis. AB - Cancer is a complex disease caused in part by predisposing germline gene polymorphisms. Knowledge of carcinogenesis in companion mammals (dog and cat) and some livestock species (pig and horse) is quite advanced. The prevalence of certain cancers varies by breed in these species, suggesting the presence of predisposing genetic variants in susceptible breeds. This review summarizes the present understanding of germline gene polymorphisms, including BRCA1, BRCA2, MC1R, KIT, NRAS and RAD51, associated with predisposition to melanoma, mammary cancer, osteosarcoma and histiocytic sarcoma in dogs, cats, pigs and horses. The predisposing variants in these species are discussed in the context of human germline gene polymorphisms associated with the same types of cancer. PMID- 26575427 TI - Charge Carriers in Hybrid Organic-Inorganic Lead Halide Perovskites Might Be Protected as Large Polarons. PMID- 26575428 TI - Multiscale Micro-Nano Nested Structures: Engineered Surface Morphology for Efficient Light Escaping in Organic Light-Emitting Diodes. AB - Various micro-to-nanometer scale structures are extremely attractive for light escaping in organic light-emitting diodes. To develop and optimize such structures, an innovative approach was demonstrated for the first time to fabricate multiscale micro-nano nested structures by photolithography with a well designed mask pattern followed by a controllable thermal reflow process. The experimental and theoretical characterizations verify that these unique nested structures hold the capability of light concentration, noticeable low haze, and efficient antireflection. As a proof-of-concept, the incorporation of this pattern onto the glass substrate efficiently facilitates light escaping from the device, resulting in current efficiency 1.60 times and external quantum efficiency 1.63 times that of a control flat device, respectively. Moreover, compared to a hexagonally arranged microlens array and quasi-random biomimetic moth eye nanostructures, the nested structures proposed here can magically tune the spatial emission profile to comply with the Lambertian radiation pattern. Hence, this novel structure is expected to be of great potential in related ubiquitous optoelectronic applications and provide scientific inspiration to other novel multiscale micro-nanostructure research. PMID- 26575429 TI - A reappraisal of adult thoracic and abdominal surface anatomy in Iranians in vivo using computed tomography. AB - Surface anatomy is a core component of human anatomy in clinical practice. It allows clinicians to assess patients accurately and quickly; however, recent studies have revealed variability among individuals and ethnicities. The aim of this study is to investigate possible variations in adult thoracic and abdominal surface anatomy landmarks in an Iranian population. This study used 100 thoracoabdominal CT scans (mean age: 47 +/- 17 years, age range: 20-77 years, 47% females), noted the most common locations of clinically relevant surface markings, and analyzed correlations between these variables and age or gender. While many common surface markings in Iranians were consistent with the evidence based literature, there were some differences. In relation to the corresponding segments of the vertebral column, the superior vena cava formation and the lower border of the pleura adjacent to the vertebral column and right kidney tended to be at higher levels in adult Iranians than a Caucasian population. There were also discrepancies between the Iranian population and commonly-referenced medical textbooks and recent evidence-based literature concerning the vertebral levels of the diaphragmatic openings of the esophagus, aorta, and inferior vena cava. This study emphasizes the need to consider evidence-based reappraisals of surface anatomy to guide clinical practice. Much of our current knowledge of surface anatomy is based on older studies of cadavers rather than living people, and does not take ethnic and individual variations into consideration. PMID- 26575431 TI - Morphogen Electrochemically Triggered Self-Construction of Polymeric Films Based on Mussel-Inspired Chemistry. AB - Inspired by the strong chemical adhesion mechanism of mussels, we designed a catechol-based electrochemically triggered self-assembly of films based on ethylene glycol molecules bearing catechol groups on both sides and denoted as bis-catechol molecules. These molecules play the role of morphogens and, in contrast to previously investigated systems, they are also one of the constituents, after reaction, of the film. Unable to interact together, commercially available poly(allylamine hydrochloride) (PAH) chains and bis catechol molecules are mixed in an aqueous solution and brought in contact with an electrode. By application of defined potential cycles, bis-catechol molecules undergo oxidation leading to molecules bearing "reactive" quinone groups which diffuse toward the solution. In this active state, the quinones react with amino groups of PAH through Michael addition and Schiff's base condensation reaction. The application of cyclic voltammetry (CV) between 0 and 500 mV (vs Ag/AgCl, scan rate of 50 mV/s) of a PAH/bis-catechol solution results in a fast self construction of a film that reaches a thickness of 40 nm after 60 min. The films present a spiky structure which is attributed to the use of bis-functionalized molecules as one component of the films. XPS measurements show the presence of both PAH and bis-catechol cross-linked together in a covalent way. We show that the amine/catechol ratio is an important parameter which governs the film buildup. For a given amine/catechol ratio, it does exist an optimum CV scan rate leading to a maximum of the film thickness as a function of the scan rate. PMID- 26575430 TI - Effects of different doses of nandrolone decanoate on estrous cycle and ovarian tissue of rats after treatment and recovery periods. AB - This study tested the hypothesis that different doses of nandrolone decanoate (ND) will cause changes in the estrous cycle and ovarian tissue of adult rats; and investigated the duration of the recovery period that is sufficient to restore the damage in the animals treated with different doses. Wistar rats were treated with ND at doses of 1.87, 3.75, 7.5 and 15 mg/kg body weight, or received mineral oil (control group) for 15 days, subcutaneously. All animals were divided into three groups according to the treatment periods: (i) ND treatment for 15 days; (ii) ND treatment followed by a 30-day recovery; and (iii) ND treatment followed by a 60-day recovery. Estrous cycle was monitored daily, and at the end of each period, the animals were euthanized for histopathological analysis. During ND treatment and after 30-day recovery, all animals exhibited persistent diestrus. After a 60-day recovery, persistent diestrus was only maintained in the group that had received the highest dose. Ovarian weight was decreased significantly after the 30-day recovery, regardless of ND doses, compared with the control group. There was a reduction (P < 0.05) in the number of corpora lutea and antral and growing follicles, in contrast to an increase (P < 0.05) in atretic follicles in a dose- and time-dependent manner. Remarkable histopathological changes occurred in the ovaries of all ND-treated groups. In conclusion, the different doses of ND caused changes in the estrous cycle and ovarian tissue of rats, and recovery periods (30 and 60 days) were insufficient to completely restore the damage in the animals treated with the highest dose. PMID- 26575432 TI - New Chitosan-Thiomer: An Efficient Colorimetric Sensor and Effective Sorbent for Mercury at Ultralow Concentration. AB - This paper describes an innovative procedure for the fabrication of a facile colorimetric sensor in one step with thiol functional group for Hg(2+) detection at trace level. The sensor was successfully synthesized via chitosan isothiouronium salt intermediate with innocuous low cost thiourea reagent under microwave irradiation. It is an innovative green approach to achieve thiol functionalization with a high degree of substitution. Thiomer was characterized by titrimetry, FTIR, (1)H NMR, elemental analysis (CHNS), and EDX for extent of modification with detail structure. The synthesized and well characterized thiomer was screened for sensor application. The sensing solution of thiomer resulted in an instantaneous sharp color change from colorless, yellow, to brown with increase in Hg(2+) concentration. Chitosan thiomer also exhibited high sensitivity and selectivity for Hg(2+) over other possible interfering ions in aqueous media. The sensing responses were visualized quantitatively with quick response, good selectivity, high sensitivity, and a low detection limit of ~0.465 ppb by the naked eye. The same was tested with a paper strip method for technological applications. Furthermore, the as-prepared sensors also exhibited exceptional sorption potential for Hg(2+) even from ultralow concentration aqueous solution and reduced the Hg(2+) concentration from 10 ppb to the extremely low level of ~0.04 ppb as studied by cyclic voltammetry. Thus, the proposed method is simple, promising, and rapid without any complicated modifying step and is an economical alternative to traditional Hg(2+) sensors for rapid sensor application in environmental water samples at ppb levels. PMID- 26575433 TI - Treatment-emergent sexual dysfunction in randomized trials of vortioxetine for major depressive disorder or generalized anxiety disorder: a pooled analysis. AB - OBJECTIVE: Antidepressants are frequently associated with treatment-emergent sexual dysfunction (TESD). Vortioxetine, which was approved for patients with major depressive disorder (MDD), has a receptor profile that suggests limited impact on sexual functioning. METHODS: Arizona Sexual Experiences Scale (ASEX) patient-level data were pooled from 7 short-term vortioxetine trials (6 in MDD, 1 in generalized anxiety disorder) and analyzed for incidence of TESD at any post baseline visit in patients without sexual dysfunction at baseline (defined as ASEX total score >=19; individual ASEX item score >=5; or a score >=4 on any 3 ASEX items). The primary objective was to confirm the non-inferiority of vortioxetine 5-20 mg/day to placebo on the incidence of TESD. Comparisons were based on the common risk difference (95% confidence interval). Additional analyses compared vortioxetine to duloxetine and duloxetine to placebo. A sensitivity analysis, defined as TESD at 2 consecutive post-baseline visits, was conducted. RESULTS: TESD incidence, relative to placebo, generally increased with vortioxetine dose with vortioxetine 5 mg non-inferior to placebo. Vortioxetine 10, 15, and 20 mg did not meet the non-inferiority criterion, but no dose had a significantly higher risk of developing TESD versus placebo. Changes in ASEX individual item scores supported the similarity of vortioxetine doses to placebo. Significantly higher TESD risk occurred with duloxetine 60 mg/day versus placebo and versus vortioxetine 5 or 10 mg. The sensitivity analysis was generally consistent with the primary analysis. Rates of spontaneously reported sexual adverse events were low. CONCLUSIONS: Vortioxetine was associated with rates of TESD that were not significantly different from placebo in short-term clinical trials. PMID- 26575434 TI - Structural Phase Transitions and Water Dynamics in Uranyl Fluoride Hydrates. AB - We report a novel production method for uranium oxyfluoride [(UO2)7F14(H2O)7].4H2O, referred to as structure D. Structure D is produced as a product of hydrating anhydrous uranyl fluoride, UO2F2, through the gas phase at ambient temperatures followed by desiccation by equilibration with a dry environment. We follow the structure of [(UO2)7F14(H2O)7].4H2O through an intermediate, liquid-like phase, wherein the coordination number of the uranyl ion is reduced to 5 (from 6 in the anhydrous structure), and a water molecule binds as an equatorial ligand to the uranyl ion. Quasielastic neutron scattering results compare well with previous measurements of mineral hydrates. The two groups of structurally distinct water molecules in D perform restricted motion on a length scale commensurate with the O-H bond (r = 0.92 A). The more tightly bound equatorial ligand waters rotate slower (Dr = 2.2 ps(-1)) than their hydrogen-bonded partners (Dr = 28.7 ps(-1)). PMID- 26575435 TI - Cytotoxic Illudane Sesquiterpenes from the Fungus Granulobasidium vellereum (Ellis and Cragin) Julich. AB - Eight illudane sesquiterpenes were obtained from the wood-decomposing fungus Granulobasidium vellereum (Ellis and Cragin) Julich; among them were the enantiomers of the known compounds illudin M (1) and dihydroilludin M (4) and the diastereomers of illudin M (2) and illudin S (3), as well as two previously undescribed illudanes (5, 6). The cytotoxicity of compounds 1-4 and 6 was evaluated against two tumor cell lines (Huh7 and MT4), which showed that compounds 1-3 had potent cytotoxic activity, whereas compounds 4 and 6 had no or only moderate effects at concentrations up to 400 MUM. Surprisingly, both compounds 2 and 3 were about 10 times more potent than 1. When the chemical reactivity of 1 and 2 was tested, compound 2 was shown to have a substantially higher reaction rate when reacted both with 2 M HCl and with cysteine, indicating that the difference in cytotoxicity is probably due to chemical reactivity and not to enzymatic affinity. PMID- 26575436 TI - Economic Dependence of U.S. Industrial Sectors on Animal-Mediated Pollination Service. AB - Declining animal pollinator health and diversity in the U.S. is a matter of growing concern and has particularly gained attention since the emergence of colony collapse disorder (CCD) in 2006. Failure to maintain adequate animal mediated pollination service to support increasing demand for pollination dependent crops poses risks for the U.S. economy. We integrate the Economic Input Output (EIO) model and network analysis with data on pollinator dependence of crops to understand the economic dependence of U.S. industrial sectors on animal mediated pollination service. The novelty of this work lies in its ability to identify industrial sectors and industrial communities (groups of closely linked sectors) that are most vulnerable to scarcity of pollination service provided by various animal species. While the economic dependence of agricultural sectors on pollination service is significant (US$14.2-23.8 billion), the higher-order economic dependence of the rest of the U.S. industrial sectors is substantially high as well (US$10.3-21.1 billion). The results are compelling as they highlight the critical importance of animal-induced pollination service for the U.S. economy, and the need to account for the role of ecosystem goods and services in product life cycles. PMID- 26575437 TI - Nuclear Magnetic Resonance (NMR) Spectroscopy For Metabolic Profiling of Medicinal Plants and Their Products. AB - NMR spectroscopy has multidisciplinary applications, including excellent impact in metabolomics. The analytical capacity of NMR spectroscopy provides information for easy qualitative and quantitative assessment of both endogenous and exogenous metabolites present in biological samples. The complexity of a particular metabolite and its contribution in a biological system are critically important for understanding the functional state that governs the organism's phenotypes. This review covers historical aspects of developments in the NMR field, its applications in chemical profiling, metabolomics, and quality control of plants and their derived medicines, foods, and other products. The bottlenecks of NMR in metabolic profiling are also discussed, keeping in view the future scope and further technological interventions. PMID- 26575438 TI - Length-Dependent Nanotransport and Charge Hopping Bottlenecks in Long Thiophene Containing pi-Conjugated Molecular Wires. AB - Self-assembled conjugated molecular wires containing thiophene up to 6 nm in length were grown layer-by-layer using click chemistry. Reflection-absorption infrared spectroscopy, ellipsometry and X-ray photoelectron spectroscopy were used to follow the stepwise growth. The electronic structure of the conjugated wires was studied with cyclic voltammetry and UV-vis spectroscopy as well as computationally with density functional theory (DFT). The current-voltage curves (+/-1 V) of the conjugated molecular wires were measured with conducting probe atomic force microscopy (CP-AFM) in which the molecular wire film bound to a gold substrate was contacted with a conductive AFM probe. By systematically measuring the low bias junction resistance as a function of length for molecules 1-4 nm long, we extracted the structure dependent tunneling attenuation factor (beta) of 3.4 nm(-1) and a contact resistance of 220 kOmega. The crossover from tunneling to hopping transport was observed at a molecular length of 4-5 nm with an activation energy of 0.35 eV extracted from Arrhenius plots of resistance versus temperature. DFT calculations revealed localizations of spin densities (polarons) on molecular wire radical cations. The calculations were employed to gauge transition state energies for hopping of polarons along wire segments. Individual estimated transition state energies were 0.2-0.4 eV, in good agreement with the experimental activation energy. The transition states correspond to flattening of dihedral angles about specific imine bonds. These results open up possibilities to further explore the influence of molecular architecture on hopping transport in molecular junctions, and highlight the utility of DFT to understand charge localization and associated hopping-based transport. PMID- 26575439 TI - Structural characterization of human heparanase reveals insights into substrate recognition. AB - Heparan sulfate (HS) is a glycosaminoglycan that forms a key component of the extracellular matrix (ECM). Breakdown of HS is carried out by heparanase (HPSE), an endo-beta-glucuronidase of the glycoside hydrolase 79 (GH79) family. Overexpression of HPSE results in breakdown of extracellular HS and release of stored growth factors and hence is strongly linked to cancer metastasis. Here we present crystal structures of human HPSE at 1.6-A to 1.9-A resolution that reveal how an endo-acting binding cleft is exposed by proteolytic activation of latent proHPSE. We used oligosaccharide complexes to map the substrate-binding and sulfate-recognition motifs. These data shed light on the structure and interactions of a key enzyme involved in ECM maintenance and provide a starting point for the design of HPSE inhibitors for use as biochemical tools and anticancer therapeutics. PMID- 26575440 TI - The effects of periodontal therapy on gingival crevicular fluid matrix metalloproteinase-8, interleukin-6 and prostaglandin E2 levels in patients with rheumatoid arthritis. AB - OBJECTIVE: The aim of this study was to evaluate the effects of non-surgical periodontal therapy on gingival crevicular fluid levels of matrix metalloproteinase-8 (MMP-8), interleukin-6 (IL-6) and prostaglandin E2 (PGE2 ) in patients with rheumatoid arthritis (RA) with periodontal disease. MATERIAL AND METHODS: Twenty-seven patients with gingivitis and periodontitis with RA, 26 patients with gingivitis and periodontitis that were systemically healthy and 13 periodontally and systemically healthy volunteers (control group) were included in this study. RA activity was assessed by disease activity score test. The clinical periodontal parameters, fasting venous blood and gingival crevicular fluid samples were obtained and gingival crevicular fluid MMP-8, IL-6 and PGE2 levels were evaluated at baseline and at 3 mo follow-up after non-surgical periodontal treatment. RESULTS: Gingival crevicular fluid MMP-8, PGE2 and IL-6 levels were higher in all groups than the control group. Following periodontal therapy, there were significant decreases in gingival crevicular fluid MMP-8, PGE2 and IL-6 levels from patients with RA with periodontitis (p < 0.05). Plaque index, gingival index and bleeding on probing were significantly correlated with IL-6 and PGE2 at baseline and at 3 mo follow-up after non-surgical periodontal treatment. CONCLUSION: Non-surgical periodontal therapy of patients with RA with periodontitis may provide beneficial effects on local inflammatory control via decreases in gingival crevicular fluid MMP-8, PGE2 and IL-6 levels. PMID- 26575441 TI - Identification of Nanoparticle Prototypes and Archetypes. AB - High-throughput (HT) computational characterization of nanomaterials is poised to accelerate novel material breakthroughs. The number of possible nanomaterials is increasing exponentially along with their complexity, and so statistical and information technology will play a fundamental role in rationalizing nanomaterials HT data. We demonstrate that multivariate statistical analysis of heterogeneous ensembles can identify the truly significant nanoparticles and their most relevant properties. Virtual samples of diamond nanoparticles and graphene nanoflakes are characterized using clustering and archetypal analysis, where we find that saturated particles are defined by their geometry, while nonsaturated nanoparticles are defined by their carbon chemistry. At the complex hull of the nanostructure spaces, a combination of complex archetypes can efficiency describe a large number of members of the ensembles, whereas the regular shapes that are typically assumed to be representative can only describe a small set of the most regular morphologies. This approach provides a route toward the characterization of computationally intractable virtual nanomaterial spaces, which can aid nanomaterials discovery in the foreseen big data scenario. PMID- 26575442 TI - Molecules and psychiatry. PMID- 26575443 TI - Molecular mechanisms and timing of cortical immune activation in schizophrenia. PMID- 26575444 TI - CHRNA7 and CHRFAM7A: psychosis and smoking? Blame the neighbors! PMID- 26575445 TI - Searching for the molecular basis of bipolar disorder. PMID- 26575446 TI - Circulating miRNA biomarkers for schizophrenia? PMID- 26575447 TI - Imaging the "GABA shift" in schizophrenia. PMID- 26575448 TI - To give up. PMID- 26575449 TI - The spectrum of psychiatric symptoms in Wilson's disease: treatment and prognostic considerations. PMID- 26575450 TI - Richard Dadd and the Fairy Feller's Master-Stroke. PMID- 26575451 TI - Post-TBI central hypogonadism and PTSD. PMID- 26575452 TI - A case study of clinical and neuroimaging outcomes following repetitive transcranial magnetic stimulation for hoarding disorder. PMID- 26575453 TI - Sudden-onset dystonia in a patient taking asenapine: interaction between ciprofloxacin and asenapine metabolism. PMID- 26575457 TI - Measuring Attachment and Internalization of Influenza A Virus in A549 Cells by Flow Cytometry. AB - Attachment to target cells followed by internalization are the very first steps of the life cycle of influenza A virus (IAV). We provide here a detailed protocol for measuring relative changes in the amount of viral particles that attach to A549 cells, a human lung epithelial cell line, as well as in the amount of particles that are internalized into the cell. We use biotinylated virus which can be easily detected following staining with Cy3-labeled streptavidin (STV Cy3). We describe the growth, purification and biotinylation of A/WSN/33, a widely used IAV laboratory strain. Cold-bound biotinylated IAV particles on A549 cells are stained with STV-Cy3 and measured using flow cytometry. To investigate uptake of viral particles, cold-bound virus is allowed to internalize at 37 degrees C. In order to differentiate between external and internalized viral particles, a blocking step is applied: Free binding spots on the biotin of attached virus on the cell surface are bound by unlabeled streptavidin (STV). Subsequent cell permeabilization and staining with STV-Cy3 then enables detection of internalized viral particles. We present a calculation to determine the relative amount of internalized virus. This assay is suitable to measure effects of drug-treatments or other manipulations on attachment or internalization of IAV. PMID- 26575458 TI - Potent and selective N-(4-sulfamoylphenyl)thiourea-based GPR55 agonists. AB - To date, many known G protein-coupled receptor 55 (GPR55) ligands are those identified among the cannabinoids. In order to further study the function of GPR55, new potent and selective ligands are needed. In this study, we utilized the screening results from PubChem bioassay AID 1961 which reports the results of Image-based HTS for Selective Agonists of GPR55. Three compounds, CID1792579, CID1252842 and CID1011163, were further evaluated and used as a starting point to create a series of nanomolar potency GPR55 agonists with N-(4 sulfamoylphenyl)thiourea scaffold. The GPR55 activity of the compounds were screened by using a commercial beta-arrestin PathHunter assay and the potential compounds were further evaluated by using a recombinant HEK cell line exhibiting GPR55-mediated effects on calcium signalling. The designed compounds were not active when tested against various endocannabinoid targets (CB1R, CB2R, FAAH, MGL, ABHD6 and ABHD12), indicating compounds' selectivity for the GPR55. Finally, structure-activity relationships of these compounds were explored. PMID- 26575459 TI - Validation of a liquid chromatography tandem mass spectrometry method to measure oxidized and reduced forms of glutathione in whole blood and verification in a mouse model as an indicator of oxidative stress. AB - As a possible marker of oxidative stress, many studies have measured whole blood reduced glutathione (GSH) and oxidized glutathione (GSSG). However, large differences in GSH and GSSG levels reported in different studies, calls for a reliable standardized method. In this study, we validate not only analytical performance of new measurement method for GSH and GSSG, but also the clinical utility of these markers in a mouse model with chronic oxidative stress. Twenty mice were randomized into four treatment groups according to iron burden: 0mg, 5mg, 10mg, or 15 mg of iron were injected into the peritoneum per day over 4 weeks. To prevent artifactual GSH auto-oxidation, we pretreated the sample with N ethylmaleimide (NEM) immediately after sample collection. After protein precipitation using sulfosalicylic acid, GSSG and GSH-NEM were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The mean GSH/GSSG ratios of the mouse model were 163.1, 31.0, 27.9, and 12.8 for control, 5mg, 10mg, and 15 mg injection groups, respectively, showing a decrease in the GSH/GSSG ratios according to the amount of oxidative stress induced. Inter-assay coefficients of variation were 4.1% for GSH-NEM and 7.3% for GSSG. Recoveries were 98.0-105.9% for GSH-NEM and 98.0-107.3% for GSSG. No ion suppression was observed at the retention time for GSH-NEM and GSSG. This study suggests an accurate method that can be used for glutathione measurement using LC-MS/MS, and showed that GSH/GSSG ratio could provide an assessment of the degree of oxidative stress. PMID- 26575460 TI - Letter from the Editor. PMID- 26575461 TI - Immunotherapeutic Approaches for the Control and Eradication of HIV. AB - Since the onset of the AIDS epidemic over 35 years ago, attempts at immunologic manipulation to develop preventative and therapeutic approaches to HIV infection have been the subject of intense focus by the scientific community. New tactics such as latency reveal agents and immune interventions with engineered and directed monoclonal antibodies, as well as vaccines for prevention and treatment are among the strategies addressed in this review. PMID- 26575462 TI - Immunotherapy for Infectious Diseases: Past, Present, and Future. AB - Passive immunotherapy for established infections, as opposed to active immunization to prevent disease, remains a tiny niche in the world of antimicrobial therapies. Many of the passive immunotherapies currently available are directed against bacterial toxins, such as botulism, or are intended for agents of bioterrorism such as anthrax, which fortunately has remained rare. The emergence of Ebola virus and multi-drug resistant pathogens, however, may breathe new life into the immunotherapy field as researchers seek non-antibiotic interventions for infectious diseases. PMID- 26575463 TI - Immunotherapy of Fungal Infections. AB - Fungal organisms are ubiquitous in the environment. Pathogenic fungi, although relatively few in the whole gamut of microbial pathogens, are able to cause disease with varying degrees of severity in individuals with normal or impaired immunity. The disease state is an outcome of the fungal pathogen's interactions with the host immunity, and therefore, it stands to reason that deep/invasive fungal diseases be amenable to immunotherapy. Therefore, antifungal immunotherapy continues to be attractive as an adjunct to the currently available antifungal chemotherapy options for a number of reasons, including the fact that existing antifungal drugs, albeit largely effective, are not without limitations, and that morbidity and mortality associated with invasive mycoses are still unacceptably high. For several decades, intense basic research efforts have been directed at development of fungal immunotherapies. Nevertheless, this approach suffers from a severe bench-bedside disconnect owing to several reasons: the chemical and biological peculiarities of the fungal antigens, the complexities of host pathogen interactions, an under-appreciation of the fungal disease landscape, the requirement of considerable financial investment to bring these therapies to clinical use, as well as practical problems associated with immunizations. In this general, non-exhaustive review, we summarize the features of ongoing research efforts directed towards devising safe and effective immunotherapeutic options for mycotic diseases, encompassing work on antifungal vaccines, adoptive cell transfers, cytokines, antimicrobial peptides (AMPs), monoclonal antibodies (mAbs), and other agents. PMID- 26575464 TI - Immunotherapeutic Biologic Agents in Autoimmune and Autoinflammatory Diseases. AB - In recent decades, innovative strategies to treat patients with inflammatory, immunologically based diseases have advanced in concert with our increased understanding of molecular immunology. Recognition of the spectrum and pathophysiology of autoimmune and autoinflammatory disorders has allowed for the development of cutting-edge therapies for such patients. In this review, key immunotherapeutic approaches for treating inflammatory autoimmune disorders, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), as well as genetic autoinflammatory diseases, such as cryopyrin associated periodic syndromes, are addressed. Indications, risks and additional considerations in the use of these agents are reviewed. PMID- 26575465 TI - An Overview of Organ-Specific Autoimmune Diseases Including Immunotherapy. AB - A significant number of individuals are affected by autoimmune diseases, which are caused by aberrant recognition of self by the immune system. A wide variety of cells and organ systems are targets of pathologic activation of the immune mediators. Effective and safe therapies aimed at managing the chronic inflammatory aspect of many autoimmune diseases remain elusive. This review will focus on the available interventions and discuss the future of the field to prevent organ destruction by the autoimmune process. PMID- 26575466 TI - Active Immunotherapy of Cancer. AB - Clinical progress in the field of cancer immunotherapy has been slow for many years but within the last 5 years, breakthrough successes have brought immunotherapy to the forefront in cancer therapy. Promising results have been observed in a variety of cancers including solid tumors and hematological malignancies with adoptive cell therapy using natural host tumor infiltrating lymphocytes, host cells that have been genetically engineered with antitumor T cell receptors or chimeric antigen receptors, immune checkpoint inhibitors like anti-CTLA-4, anti-PD-1 or PD-L1 monoclonal antibodies and oncolytic virus-based immunotherapy. However, most treatment modalities have shown limited efficacy with single therapy. The complex nature of cancer with intra- and inter-tumor antigen and genomic heterogeneity coupled with the immune suppressive microenvironment emphasizes the prospect of personalized targeted immunotherapy to manipulate the patient's own immune system against cancer. For successful, robust and long-lasting cure of cancer, a multi-modal approach is essential, combining anti-tumor cell therapy with manipulation of multiple pathways in the tumor microenvironment to ameliorate tumor-induced immunosuppression. PMID- 26575468 TI - E6 viral protein ratio correlates with outcomes in human papillomavirus related oropharyngeal cancer. AB - BACKGROUND: The study aimed to identify prognostic markers to improve the management of patients with HPV positive OSCC Methods: We determined the ratio of HPV E6*I and E6*II splice variants by quantitative RT-PCR in 177 HPV positive OSCC and correlated the findings with other clinicopathological data Results: There was no significant difference in locoregional recurrence (HR 1.72 p = 0.24) and death (HR 1.65, p = 0.13) among patients whose tumors had an E6*I/*II ratio >=1 compared with an E6*I/*II ratio of <1. Univariate analysis showed that patients with E6*I/*II >=1 OSCC were more likely to have an event. In the multivariable analysis, there was a trend for more events in patients with E6*I/*II ratio >=1 (HR 1.70, 95% CI 0.95-3.03, p = 0.07) CONCLUSION: Our data suggest that the use of HPV 16 spliced transcripts may help to predict for poorer outcomes in patients with HPV positive OSCC. PMID- 26575467 TI - Random Wiring, Ganglion Cell Mosaics, and the Functional Architecture of the Visual Cortex. AB - The architecture of iso-orientation domains in the primary visual cortex (V1) of placental carnivores and primates apparently follows species invariant quantitative laws. Dynamical optimization models assuming that neurons coordinate their stimulus preferences throughout cortical circuits linking millions of cells specifically predict these invariants. This might indicate that V1's intrinsic connectome and its functional architecture adhere to a single optimization principle with high precision and robustness. To validate this hypothesis, it is critical to closely examine the quantitative predictions of alternative candidate theories. Random feedforward wiring within the retino-cortical pathway represents a conceptually appealing alternative to dynamical circuit optimization because random dimension-expanding projections are believed to generically exhibit computationally favorable properties for stimulus representations. Here, we ask whether the quantitative invariants of V1 architecture can be explained as a generic emergent property of random wiring. We generalize and examine the stochastic wiring model proposed by Ringach and coworkers, in which iso orientation domains in the visual cortex arise through random feedforward connections between semi-regular mosaics of retinal ganglion cells (RGCs) and visual cortical neurons. We derive closed-form expressions for cortical receptive fields and domain layouts predicted by the model for perfectly hexagonal RGC mosaics. Including spatial disorder in the RGC positions considerably changes the domain layout properties as a function of disorder parameters such as position scatter and its correlations across the retina. However, independent of parameter choice, we find that the model predictions substantially deviate from the layout laws of iso-orientation domains observed experimentally. Considering random wiring with the currently most realistic model of RGC mosaic layouts, a pairwise interacting point process, the predicted layouts remain distinct from experimental observations and resemble Gaussian random fields. We conclude that V1 layout invariants are specific quantitative signatures of visual cortical optimization, which cannot be explained by generic random feedforward-wiring models. PMID- 26575469 TI - Occurrence and Characterization of Enteropathogenic Escherichia coli (EPEC) in Retail Ready-to-Eat Foods in China. AB - Enteropathogenic Escherichia coli (EPEC) is an important foodborne pathogen that potentially causes infant and adult diarrhea. The occurrence and characteristics of EPEC in retail ready-to-eat (RTE) foods have not been thoroughly investigated in China. This study aimed to investigate EPEC occurrence in retail RTE foods sold in the markets of China and to characterize the isolated EPEC by serotyping, virulence gene analyses, antibiotic susceptibility test, and molecular typing based on enterobacterial repetitive intergenic consensus-polymerase chain reaction (ERIC-PCR). From May 2012 to April 2013, 459 RTE food samples were collected from retail markets in 24 cities of China. E. coli in general, and EPEC specifically, were detected in 144 (31.4%) and 39 (8.5%) samples, respectively. Cold vegetable in sauce was the food type most frequently contaminated with EPEC (18.6%). Of 39 EPEC isolates, 38 were atypical EPEC (eae+) and 1 was typical EPEC (eae+bfpA+) by multiplex PCR assays. The virulence genes espA, espB, tir, and iha were detected in 12, 9, 2, and 1 of 39 isolates, respectively, while genes toxB, etpD, katP, and saa were not detected. O-antigen serotyping results showed that among 28 typeable isolates, the most common serotype was O119, followed by O26, O111, and O128. Many isolates were resistant to tetracycline (64.1%; 25/39), ampicillin (48.7%; 19/39), and trimethoprim/sulfamethoxazole (48.7%; 19/39). ERIC PCR indicated high genetic diversity in EPEC strains, which classified 42 strains (39 isolates and 3 reference strains) into 32 different profiles with a discrimination index of 0.981. The findings of this study highlight the need for close surveillance of the RTE foods at the level of production, packaging, and storage to minimize risks of foodborne disease. PMID- 26575470 TI - Transvaginal mesh in the media following the 2011 US food and drug administration public health notification update. AB - AIMS: Prompted by patients' changing perceptions of transvaginal mesh, this study examines how mesh has been reported in the news following the 2011 US Food and Drug Administration (FDA) updated notification about the use of mesh in the treatment of pelvic organ prolapse. METHODS: Two national newspaper databases were queried for articles discussing transvaginal mesh published within 3 years of the FDA announcement. Content analysis included headline subjects, mesh related complications, quoted sources, and the FDA recommendations. To determine whether more widely read sources publish higher quality reporting, a subgroup analysis was conducted based on newspaper circulation. RESULTS: Ninety-five articles met inclusion criteria. Mesh-related litigation was the most common headline subject (36 articles, 38%), and 54% of all articles referenced legal action. Fifty-seven articles (60%) cited at least one mesh-related complication. Only 18 articles (19%) quoted surgeons who use transvaginal mesh. For the FDA update, 40% of articles that first reported the announcement accurately specified that it applies to mesh for prolapse, not incontinence. This ambiguity persisted: half of all articles cited the warning, but only 23% distinguished between prolapse and incontinence. Higher newspaper circulation did not significantly improve the quality of reporting about the content or context of the FDA's recommendations. CONCLUSIONS: Despite frequent media coverage of transvaginal mesh and its complications since 2011, very few news sources that cited the FDA warning distinguished between prolapse and incontinence. Given prevalent reporting of mesh-related litigation, the findings raise concern about how patients perceive the safety and efficacy of transvaginal mesh, regardless of indication. Neurourol. Urodynam. 36:329-332, 2017. (c) 2015 Wiley Periodicals, Inc. PMID- 26575471 TI - Methods to Increase the Sensitivity of High Resolution Melting Single Nucleotide Polymorphism Genotyping in Malaria. AB - Despite decades of eradication efforts, malaria remains a global burden. Recent renewed interest in regional elimination and global eradication has been accompanied by increased genomic information about Plasmodium parasite species responsible for malaria, including characteristics of geographical populations as well as variations associated with reduced susceptibility to anti-malarial drugs. One common genetic variation, single-nucleotide polymorphisms (SNPs), offers attractive targets for parasite genotyping. These markers are useful not only for tracking drug resistance markers but also for tracking parasite populations using markers not under drug or other selective pressures. SNP genotyping methods offer the ability to track drug resistance as well as to fingerprint individual parasites for population surveillance, particularly in response to malaria control efforts in regions nearing elimination status. While informative SNPs have been identified that are agnostic to specific genotyping technologies, high resolution melting (HRM) analysis is particularly suited to field-based studies. Compared to standard fluorescent-probe based methods that require individual SNPs in a single labeled probe and offer at best 10% sensitivity to detect SNPs in samples that contain multiple genomes (polygenomic), HRM offers 2-5% sensitivity. Modifications to HRM, such as blocked probes and asymmetric primer concentrations as well as optimization of amplification annealing temperatures to bias PCR towards amplification of the minor allele, further increase the sensitivity of HRM. While the sensitivity improvement depends on the specific assay, we have increased detection sensitivities to less than 1% of the minor allele. In regions approaching malaria eradication, early detection of emerging or imported drug resistance is essential for prompt response. Similarly, the ability to detect polygenomic infections and differentiate imported parasite types from cryptic local reservoirs can inform control programs. This manuscript describes modifications to high resolution melting technology that further increase its sensitivity to identify polygenomic infections in patient samples. PMID- 26575472 TI - Occurrence and simulation of trihalomethanes in swimming pool water: A simple prediction method based on DOC and mass balance. AB - Trihalomethanes (THM) are the most typical disinfection by-products (DBPs) found in public swimming pool water. DBPs are produced when organic and inorganic matter in water reacts with chemical disinfectants. The irregular contribution of substances from pool visitors and long contact time with disinfectant make the forecast of THM in pool water a challenge. In this work occurrence of THM in a public indoor swimming pool was investigated and correlated with the dissolved organic carbon (DOC). Daily sampling of pool water for 26 days showed a positive correlation between DOC and THM with a time delay of about two days, while THM and DOC didn't directly correlate with the number of visitors. Based on the results and mass-balance in the pool water, a simple simulation model for estimating THM concentration in indoor swimming pool water was proposed. Formation of THM from DOC, volatilization into air and elimination by pool water treatment were included in the simulation. Formation ratio of THM gained from laboratory analysis using native pool water and information from field study in an indoor swimming pool reduced the uncertainty of the simulation. The simulation was validated by measurements in the swimming pool for 50 days. The simulated results were in good compliance with measured results. This work provides a useful and simple method for predicting THM concentration and its accumulation trend for long term in indoor swimming pool water. PMID- 26575473 TI - A study on the reactivity characteristics of dissolved effluent organic matter (EfOM) from municipal wastewater treatment plant during ozonation. AB - The reactivity of dissolved effluent organic matter (EfOM) in the process of ozonation was examined. Under different ozone dosages (0.42 +/- 0.09, 0.98 +/- 0.11 and 2.24 +/- 0.17 mgO3/mg DOC), the EfOM before and after ozonation could be classified into four fractions according to their hydrophobicities. By ozonation, the hydrophobic fractions, especially hydrophobic acid (HOA) and hydrophobic neutral (HON), were found to undergo a process of transformation into hydrophilic fractions (HI), of which the HOA were first transformed into HON, and then the majority of the HON fraction was later converted to HI by further ozonation. It was noticeable that after ozonation, the fluorescence intensity in the humic-like and protein-like regions decreased as indicated by the excitation and emission matrix (EEM) spectra for the hydrophobic fractions. By coupling the EEM spectra with the molecular size analysis using high performance size exclusion chromatography (HPSEC), the difference between the characteristic distributions of the humic-like and protein-like fluorophores were further revealed. It could thus be extrapolated that ozone might have preferentially reacted with the protein-like hydrophobic fraction with molecular weight (MW) less than 100 kDa. Moreover, by X-ray photoelectron spectroscopy (XPS) analysis, it was identified that with increasing ozone dosage (from 0 to 2.24 +/- 0.17 mgO3/mg DOC), the aromaticity of HON decreased dramatically, while aliphatics and ketones increased especially at the low ozone dose (0.42 +/- 0.09 mgO3/mg DOC). Of the EfOM fractions, the HON fraction would have a higher content of electron enriched aromatics which could preferentially react with ozone rather than the HOA fraction. PMID- 26575474 TI - Degradation of sucralose in groundwater and implications for age dating contaminated groundwater. AB - The artificial sweetener sucralose has been in use in Canada and the US since about 2000 and in the EU since 2003, and is now ubiquitous in sanitary wastewater in many parts of the world. It persists during sewage treatment and in surface water environments and as such, has been suggested as a powerful tracer of wastewater. In this study, longer-term persistence of sucralose was examined in groundwater by undertaking a series of three sampling snapshots of a well constrained wastewater plume in Canada (Long Point septic system) over a 6-year period from 2008 to 2014. A shrinking sucralose plume in 2014, compared to earlier sampling, during this period when sucralose use was likely increasing, provides clear evidence of degradation. However, depletion of sucralose from a mean of 40 MUg/L in the proximal plume zone, occurred at a relatively slow rate over a period of several months to several years. Furthermore, examination of septic tank effluent and impacted groundwater at six other sites in Canada, revealed that sucralose was present in all samples of septic tank effluent (6-98 MUg/L, n = 32) and in all groundwater samples (0.7-77 MUg/L, n = 64). Even though sucralose degradation is noted in the Long Point plume, its ubiquitous presence in the groundwater plumes at all seven sites implies a relatively slow rate of decay in many groundwater septic plume environments. Thus, sucralose has the potential to be used as an indicator of 'recent' wastewater contamination. The presence of sucralose identifies groundwater that was recharged after 2000 in Canada and the US and after 2003 in the EU and many Asian countries. PMID- 26575475 TI - Comparison of chlorination and chloramination in carbonaceous and nitrogenous disinfection byproduct formation potentials with prolonged contact time. AB - Due to decreasing water demands in Japan, hydraulic retention times of water in piped supply systems has been extended, resulting in a longer contact time with disinfectants. However, the effects of extended contact time on the formation of various disinfection byproducts (DBPs), including carbonaceous DBPs such as trihalomethane (THM) and haloacetic acid (HAA), and nitrogenous DBPs such as nitrosodimethylamine (NDMA) and nitrosomorpholine (NMor), have not yet been investigated in detail. Herein, we compared the formation of these DBPs by chlorination and chloramination for five water samples collected from rivers and a dam in Japan, all of which represent municipal water supply sources. Water samples were treated by either filtration or a combination of coagulation and filtration. Treated samples were subjected to a DBP formation potential test by either chlorine or chloramine for contact times of 1 day or 4 days. Four THM species, nine HAA species, NDMA, and NMor were measured by GC-ECD or UPLC-MS/MS. Lifetime cancer risk was calculated based on the Integrated Risk Information System unit risk information. The experiment and analysis focused on (i) prolonged contact time from 1 day to 4 days, (ii) reduction efficiency by conventional treatment, (iii) correlations between DBP formation potentials and water quality parameters, and (iv) the contribution of each species to total risk. With an increased contact time from 1 day to 4 days, THM formation increased to 420% by chloramination. Coagulation-filtration treatment showed that brominated species in THMs are less likely to be reduced. With the highest unit risk among THM species, dibromochloromethane (DBCM) showed a high correlation with bromine, but not with organic matter parameters. NDMA contributed to lifetime cancer risk. The THM formation pathway should be revisited in terms of chloramination and bromine incorporation. It is also recommended to investigate nitrosamine formation potential by chloramination. PMID- 26575476 TI - Simple combination of oxidants with zero-valent-iron (ZVI) achieved very rapid and highly efficient removal of heavy metals from water. AB - This study, for the first time, demonstrated a continuously accelerated Fe(0) corrosion driven by common oxidants (i.e., NaClO, KMnO4 or H2O2) and thereby the rapid and efficient removal of heavy metals (HMs) by zero-valent iron (ZVI) under the experimental conditions of jar tests and column running. ZVI simply coupled with NaClO, KMnO4 or H2O2 (0.5 mM) resulted in almost complete As(V) removal within only 10 min with 1000 MUg/L of initial As(V) at initial pH of 7.5(+/-0.1) and liquid solid ratio of 200:1. Simultaneous removal of 200 MUg/L of initial Cd(II) and Hg(II) to 2.4-4.4 MUg/L for Cd(II) and to 4.0-5.0 MUg/L for Hg(II) were achieved within 30 min. No deterioration of HM removal was observed during the ten recycles of jar tests. The ZVI columns activated by 0.1 mM of oxidants had stably treated 40,200 (NaClO), 20,295 (KMnO4) and 40,200 (H2O2) bed volumes (BV) of HM-contaminated drinking water, but with no any indication of As breakthrough (<10 MUg/L) even at short empty bed contact time (EBCT) of 8.0 min. The high efficiency of HMs removal from both the jar tests and column running implied a continuous and stable activation (overcoming of iron passivation) of Fe(0) surface by the oxidants. Via the proper increase in oxidant dosing, the ZVI/oxidant combination was applicable to treat highly As(V)-contaminated wastewater. During Fe(0) surface corrosion accelerated by oxidants, a large amount of fresh and reactive iron oxides and oxyhydroxides were continuously generated, which were responsible for the rapid and efficient removal of HMs through multiple mechanisms including adsorption and co-precipitation. A steady state of Fe(0) surface activation and HM removal enabled this simply coupled system to remove HMs with high speed, efficiency and perdurability. PMID- 26575477 TI - Time-of-flight mass spectrometry assessment of fluconazole and climbazole UV and UV/H2O2 degradability: Kinetics study and transformation products elucidation. AB - The efficiency of UV irradiation for the removal of the antimycotic drugs fluconazole (FCZ) and climbazole (CBZ) from water samples is evaluated. Degradation experiments, at laboratory scale, were carried out with spiked aliquots of ultrapure water solutions and treated wastewater samples using low pressure mercury lamps emitting at 254 nm. Time course of precursor pollutants and identification of arising transformation products (TPs) was performed by injection of different reaction time aliquots in a liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) system. Chemical structures of identified TPs were proposed from their full-product ion spectra, acquired using different collision energies. During UV irradiation experiments, the half-lives (t1/2) of FCZ and CBZ were similar in ultrapure water solutions and wastewater samples; however, the first species was more recalcitrant than the second one. Four TPs were identified in case of FCZ resulting from substitution of fluorine atoms by hydroxyl moieties and intramolecular cyclization with fluorine removal. CBZ interacted with UV radiation through reductive dechlorination, hydroxylation and cleavage of the ether bond; moreover, five additional primary TPs, with the same empirical formula as CBZ, were also noticed. Given the relatively long t1/2 of FCZ under direct photolysis (ca. 42 min), UV irradiation was combined with H2O2 addition to promote formation of reactive hydroxyl radicals. Under such conditions, the degradation rate of FCZ was enhanced significantly and no TPs were detected. These latter conditions allowed also the effective removal of CBZ TPs. PMID- 26575478 TI - The effect of nanocrystalline silicon host on magnetic properties of encapsulated iron oxide nanoparticles. AB - The purpose of this work is a detailed comparison of the fundamental magnetic properties of nanocomposite systems consisting of Fe3O4 nanoparticle-loaded porous silicon as well as silicon nanotubes. Such composite structures are of potential merit in the area of magnetically guided drug delivery. For magnetic systems to be utilized in biomedical applications, there are certain magnetic properties that must be fulfilled. Therefore magnetic properties of embedded Fe3O4-nanoparticles in these nanostructured silicon host matrices, porous silicon and silicon nanotubes, are investigated. Temperature-dependent magnetic investigations have been carried out for four types of iron oxide particle sizes (4, 5, 8 and 10 nm). The silicon host, in interplay with the iron oxide nanoparticle size, plays a sensitive role. It is shown that Fe3O4 loaded porous silicon and SiNTs differ significantly in their magnetic behavior, especially the transition between superparamagnetic behavior and blocked state, due to host morphology-dependent magnetic interactions. Importantly, it is found that all investigated samples meet the magnetic precondition of possible biomedical applications of exhibiting a negligible magnetic remanence at room temperature. PMID- 26575479 TI - Paediatric Intravenous Splint: A Cause of Pressure Injury during Neurosurgery in Prone Position. AB - Splint application avoids unwanted movement of limbs and kinking of intravenous catheters in infants, allowing free flow of intravenous fluids. However, if placed in contact with dependent surfaces during prone surgeries, they have the propensity to cause inadvertent pressure injuries. This occurs due to the weight of the limb and continuous friction and is augmented by a rise in the local temperature and perspiration. We wish to share our experience of such an unintentional injury caused by a paediatric intravenous splint. PMID- 26575480 TI - Postconflict Conciliation within One-Male Breeding Units in Sichuan Snub-Nosed Monkeys in the Qinling Mountains, China. AB - This study analyzed conflict and postconflict (PC) conciliation between males and females within one-male breeding units in Sichuan snub-nosed monkeys (Rhinopithecus roxellana) in the Qinling Mountains, China. The PC matched-control and time rule methods were used to collect and analyze data recorded from September 2013 to June 2014. The conciliatory tendency among individuals following conflict was 82.07%, and affiliation occurred within a few minutes after the conflict, which was not significantly different between mating and nonmating seasons. The PC conciliation scenarios were different from those reported from captivity. Lumbar hold and grooming were the most common expressions in reconciliation. In addition, bystander affiliation was uniquely found, which may be associated with the more terrestrial locomotion of R. roxellana, compared with other colobines. PMID- 26575482 TI - System Matrix Analysis for Computed Tomography Imaging. AB - In practical applications of computed tomography imaging (CT), it is often the case that the set of projection data is incomplete owing to the physical conditions of the data acquisition process. On the other hand, the high radiation dose imposed on patients is also undesired. These issues demand that high quality CT images can be reconstructed from limited projection data. For this reason, iterative methods of image reconstruction have become a topic of increased research interest. Several algorithms have been proposed for few-view CT. We consider that the accurate solution of the reconstruction problem also depends on the system matrix that simulates the scanning process. In this work, we analyze the application of the Siddon method to generate elements of the matrix and we present results based on real projection data. PMID- 26575481 TI - A Comparison of Microbial Water Quality and Diversity for Ballast and Tropical Harbor Waters. AB - Indicator organisms and antibiotic resistance were used as a proxy to measure microbial water quality of ballast tanks of ships, and surface waters in a tropical harbor. The survival of marine bacteria in ballast tanks appeared to diminish over longer water retention time, with a reduction of cell viability observed after a week based on heterotrophic plate counts. Pyrosequencing of 16S rRNA genes showed distinct differences in microbial composition of ballast and harbor waters. The harbor waters had a higher abundance of operational taxonomic units (OTUs) assigned to Cyanobacteria (Synechococcus spp.) and alpha proteobacteria (SAR11 members), while marine hydrocarbon degraders such as gamma proteobacteria (Ocenspirillaes spp., Thiotrchales spp.) and Bacteroidetes (Flavobacteriales spp.) dominated the ballast water samples. Screening of indicator organisms found Escherichia coli (E. coli), Enterococcus and Pseudomonas aeruginosa (P. aeruginosa) in two or more of the ballast and harbor water samples tested. Vibrio spp. and Salmonella spp. were detected exclusively in harbor water samples. Using quantitative PCR (qPCR), we screened for 13 antibiotic resistant gene (ARG) targets and found higher abundances of sul1 (4.13 3.44 x 102 copies/mL), dfrA (0.77-1.80 x10 copies/mL) and cfr (2.00-5.21 copies/mL) genes compared to the other ARG targets selected for this survey. These genes encode for resistance to sulfonamides, trimethoprim and chloramphenicol-florfenicol antibiotics, which are also known to persist in sediments of aquaculture farms and coastal environments. Among the ARGs screened, we found significant correlations (P<0.05) between ereA, ermG, cfr and tetO genes to one or more of the indicator organisms detected in this study, which may suggest that these members contribute to the environmental resistome. This study provides a baseline water quality survey, quantitatively assessing indicators of antibiotic resistance, potentially pathogenic organisms and a broad-brush description of difference in microbial composition and diversity between open oceans and tropical coastal environments through the use of next generation sequencing technology. PMID- 26575483 TI - An Effective Method to Identify Shared Pathways and Common Factors among Neurodegenerative Diseases. AB - Groups of distinct but related diseases often share common symptoms, which suggest likely overlaps in underlying pathogenic mechanisms. Identifying the shared pathways and common factors among those disorders can be expected to deepen our understanding for them and help designing new treatment strategies effected on those diseases. Neurodegeneration diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD), were taken as a case study in this research. Reported susceptibility genes for AD, PD and HD were collected and human protein-protein interaction network (hPPIN) was used to identify biological pathways related to neurodegeneration. 81 KEGG pathways were found to be correlated with neurodegenerative disorders. 36 out of the 81 are human disease pathways, and the remaining ones are involved in miscellaneous human functional pathways. Cancers and infectious diseases are two major subclasses within the disease group. Apoptosis is one of the most significant functional pathways. Most of those pathways found here are actually consistent with prior knowledge of neurodegenerative diseases except two cell communication pathways: adherens and tight junctions. Gene expression analysis showed a high probability that the two pathways were related to neurodegenerative diseases. A combination of common susceptibility genes and hPPIN is an effective method to study shared pathways involved in a group of closely related disorders. Common modules, which might play a bridging role in linking neurodegenerative disorders and the enriched pathways, were identified by clustering analysis. The identified shared pathways and common modules can be expected to yield clues for effective target discovery efforts on neurodegeneration. PMID- 26575484 TI - Children Living with HIV-Infected Adults: Estimates for 23 Countries in sub Saharan Africa. AB - BACKGROUND: In sub-Saharan Africa many children live in extreme poverty and experience a burden of illness and disease that is disproportionately high. The emergence of HIV and AIDS has only exacerbated long-standing challenges to improving children's health in the region, with recent cohorts experiencing pediatric AIDS and high levels of orphan status, situations which are monitored globally and receive much policy and research attention. Children's health, however, can be affected also by living with HIV-infected adults, through associated exposure to infectious diseases and the diversion of household resources away from them. While long recognized, far less research has focused on characterizing this distinct and vulnerable population of HIV-affected children. METHODS: Using Demographic and Health Survey data from 23 countries collected between 2003 and 2011, we estimate the percentage of children living in a household with at least one HIV-infected adult. We assess overlaps with orphan status and investigate the relationship between children and the adults who are infected in their households. RESULTS: The population of children living in a household with at least one HIV-infected adult is substantial where HIV prevalence is high; in Southern Africa, the percentage exceeded 10% in all countries and reached as high as 36%. This population is largely distinct from the orphan population. Among children living in households with tested, HIV infected adults, most live with parents, often mothers, who are infected; nonetheless, in most countries over 20% live in households with at least one infected adult who is not a parent. CONCLUSION: Until new infections contract significantly, improvements in HIV/AIDS treatment suggest that the population of children living with HIV-infected adults will remain substantial. It is vital to on-going efforts to reduce childhood morbidity and mortality to consider whether current care and outreach sufficiently address the distinct vulnerabilities of these children. PMID- 26575485 TI - Evidence of photo-induced dynamic competition of metallic and insulating phase in a layered manganite. AB - We show evidence that the competition between the antiferromagetic metallic phase and the charge- and orbital-ordered insulating phase at the reentrant phase boundary of a layered manganite, La0.99Sr2.01Mn2O7, can be manipulated using ultrafast optical excitation. The time-dependent evolution of the Jahn-Teller superlattice reflection, which indicates the formation of the charge and orbital order, was measured at different laser fluences. The laser-induced enhancement and reduction the Jahn-Teller reflection intensity shows a reversal of sign between earlier (~10 ns) and later (~150 ns) time delays during the relaxation after photo excitation. This effect is consistent with a scenario whereby the laser excitation modulates the local competition between the metallic and the insulating phases. PMID- 26575486 TI - Iron Chelation Inhibits Osteoclastic Differentiation In Vitro and in Tg2576 Mouse Model of Alzheimer's Disease. AB - Patients of Alzheimer's disease (AD) frequently have lower bone mineral density and higher rate of hip fracture. Tg2576, a well characterized AD animal model that ubiquitously express Swedish mutant amyloid precursor protein (APPswe), displays not only AD-relevant neuropathology, but also age-dependent bone deficits. However, the underlying mechanisms remain poorly understood. As APP is implicated as a regulator of iron export, and the metal chelation is considered as a potential therapeutic strategy for AD, we examined iron chelation's effect on the osteoporotic deficit in Tg2576 mice. Remarkably, in vivo treatment with iron chelator, clinoquinol (CQ), increased both trabecular and cortical bone mass, selectively in Tg2576, but not wild type (WT) mice. Further in vitro studies showed that low concentrations of CQ as well as deferoxamine (DFO), another iron chelator, selectively inhibited osteoclast (OC) differentiation, without an obvious effect on osteoblast (OB) differentiation. Intriguingly, both CQ and DFO's inhibitory effect on OC was more potent in bone marrow macrophages (BMMs) from Tg2576 mice than that of wild type controls. The reduction of intracellular iron levels in BMMs by CQ was also more dramatic in APPswe expressing BMMs. Taken together, these results demonstrate a potent inhibition on OC formation and activation in APPswe-expressing BMMs by iron chelation, and reveal a potential therapeutic value of CQ in treating AD-associated osteoporotic deficits. PMID- 26575488 TI - Cationic aza-macrocyclic complexes of germanium(II) and silicon(IV). AB - [GeCl2(dioxane)] reacts with the neutral aza-macrocyclic ligands L, L = Me3tacn (1,4,7-trimethyl-1,4,7-triazacyclononane), Me4cyclen (1,4,7,10-tetramethyl 1,4,7,10-tetraazacyclododecane) or Me4cyclam (1,4,8,11-tetramethyl-1,4,8,11 tetraazacyclotetradecane) and two mol. equiv. of Me3SiO3SCF3 in thf solution to yield the unusual and hydrolytically very sensitive [Ge(L)][O3SCF3]2 as white solids in moderate yield. Using shorter reaction times [Ge(Me3tacn)]Cl2 and [Ge(Me3tacn)]Cl[O3SCF3] were also isolated; the preparation of [Ge(Me4cyclen)][GeCl3]2 is also described. The structures of the Me3tacn complexes show kappa(3)-coordination of the macrocycle, with the anions interacting only weakly to produce very distorted five- or six-coordination at germanium. In contrast, the structure of [Ge(Me4cyclen)][O3SCF3]2 shows no anion interactions, and a distorted square planar geometry at germanium from coordination to the tetra-aza macrocycle. Crystal structures of the Si(iv) complexes, [SiCl3(Me3tacn)]Y (Y = O3SCF3, BAr(F); [B{3,5-(CF3)2C6H3}4]) and [SiHCl2(Me3tacn)][BAr(F)], obtained from reaction of SiCl4 or SiHCl3 with Me3tacn, followed by addition of either Me3SiO3SCF3 or Na[BAr(F)], contain distorted octahedral cations, with facialkappa(3)-coordinated Me3tacn. The open chain triamine, Me2NCH2CH2N(Me)CH2CH2NMe2 (pmdta), forms [SiCl3(pmdta)][BAr(F)] and [SiBr3(pmdta)][BAr(F)] under similar conditions, containing mer-octahedral cations. PMID- 26575487 TI - Influenza Virus Induces Cholesterol-Enriched Endocytic Recycling Compartments for Budozone Formation via Cell Cycle-Independent Centrosome Maturation. AB - Influenza virus particles are assembled at the plasma membrane in concert with incorporation of the virus genome, but the details of its spatio-temporal regulation are not understood. Here we showed that influenza virus infection induces the assembly of pericentrosomal endocytic recycling compartment (ERC) through the activation of Rab11a GTPase and cell cycle-independent maturation of centrosome by YB-1, a multifunctional protein that is involved in mitotic division, RNA metabolism and tumorigenesis. YB-1 is recruited to the centrosome in infected cells and is required for anchoring microtubules to the centrosome. We also found that viral infection accumulates cholesterol in ERC and is dependent on YB-1. Depletion of YB-1 shows reduced cholesterol-enriched ERC and prevented budozone formation at the plasma membrane. These results suggest that cholesterol in recycling endosomes, which are emanated from ERC, may trigger the virus assembly concomitantly with the packaging of the virus genome. We propose that the virus genome is transported to the plasma membrane by cholesterol enriched recycling endosomes through cell cycle-independent activation of the centrosome by YB-1. PMID- 26575489 TI - Arthroscopic knee debridement can delay total knee replacement in painful moderate haemophilic arthropathy of the knee in adult patients. AB - The role of arthroscopic debridement of the knee in haemophilia is controversial in the literature. The purpose of this study is to describe the results of arthroscopic knee debridement (AKD), with the aim of determining whether it is possible to delay total knee replacement (TKR) for painful moderate haemophilic arthropathy of the knee in adult patients. In a 14-year period (1998-2011), AKD was performed for moderate haemophilic arthropathy of the knee in 27 patients with haemophilia A. Their average age at operation was 28.6 years (range 26-39 years). Indications for surgery were as follows: more than 90 degrees of knee flexion, flexion deformity less than 30 degrees , good axial alignment of the knee, good patellar alignment, and pain above >60 points in a visual analogue scale [0 (no pain) to 100 points]. Secondary haematological prophylaxis and rehabilitation (physiotherapy) was given for at least 3 months after surgery. Follow-up was for an average of 7.5 years (range 2-14 years). We assessed the clinical outcome before surgery and at the time of latest follow-up using the Knee Society pain and function scores, the range of motion, and the radiological score of the World Federation of Haemophilia. Knee Society pain scores improved from 39 preoperatively to 66 postoperatively, and function scores improved from 36 to 52. Range of motion improved on an average from -15 degrees of extension and 90 degrees of flexion before surgery, to -5 degrees of extension and 110 degrees of flexion at the last follow-up. A radiological deterioration of 2.8 points on average was found. There were two (7.4%) postoperative complications (haemarthroses resolved by joint aspiration). One patient (3.7%) required a TKR 12.5 years later. AKD should be considered in painful moderate haemophilic arthropathy of the knee in adult patients to delay TKR. PMID- 26575490 TI - Iron and carbon monoxide attenuate Crotalus atrox venom-enhanced tissue-type plasminogen activator-initiated fibrinolysis. AB - In addition to degrading fibrinogen as a source of consumptive coagulopathy, rattlesnake venom has also been demonstrated to enhance fibrinolysis and degrade alpha-2-antiplasmin. The goals of this investigation was to characterize the kinetic fibrinolytic profile of Crotalus atrox venom in the absence and presence of tissue-type plasminogen activator (tPA), and to also ascertain if iron and carbon monoxide (CO, a positive modulator of alpha-2-antiplasmin) could attenuate venom-enhanced fibrinolysis. Utilizing thrombelastographic methods, the coagulation and fibrinolytic kinetic profiles of human plasma exposed to C. atrox venom (0-2 MUg/ml) were determined in the absence or presence of tPA (0-100 IU/ml). Then, either separately or in combination, plasma was exposed to iron (ferric chloride, 10 MUmol/l) or CO (carbon monoxide-releasing molecule-2, 100 MUmol/l) prior to incubation with venom; the plasma sample was subsequently subjected to thrombelastographic analysis with addition of tPA. Venom exposure in the absence of tPA did not result in detectable fibrinolysis. In the presence of tPA, venom markedly enhanced fibrinolysis. Iron and CO, markedly attenuated venom enhancement of fibrinolysis. C. atrox venom enhances tPA-mediated fibrinolysis, and interventions that enhance/protect alpha-2-antiplasmin activity significantly attenuate venom-enhanced fibrinolysis. Future preclinical investigation is required to determine if iron and CO can attenuate venom-mediated degradation of alpha-2-antiplasmin-dependent fibrinolytic resistance. PMID- 26575491 TI - Iron and carbon monoxide attenuate degradation of plasmatic coagulation by Crotalus atrox venom. AB - Hypofibrinogenemia is an important clinical consequence following envenomation by Crotalus species, usually attenuated or prevented by administration of antivenom. It has been determined that iron and carbon monoxide (CO) enhance fibrinogen as a thrombin substrate, likely secondary to conformational changes in molecular structure. We tested the hypothesis that pretreatment of plasma with iron and CO could attenuate the effects of exposure to Crotalus atrox venom. Human plasma was exposed to 0 to 10 MUmol/l ferric chloride (iron source) and 0 to 100 MUmol/l CO releasing molecule-2 (CO source) followed by exposure to 0 to 0.5 MUg/ml venom for 5 to 20 min. Changes in coagulation kinetics were determined with thrombelastography. Iron and CO significantly attenuated venom-mediated degradation of plasmatic coagulation in terms of onset time, velocity of clot growth and final clot strength. Further preclinical investigation of iron and CO administration as a 'bridge-to-antivenom' to preserve plasmatic coagulation is justified. PMID- 26575492 TI - Successful intravenous thrombolysis in a patient with antiphospholipid syndrome, acute ischemic stroke and severe thrombocytopenia. AB - Alteplase is the only approved drug for the treatment of acute ischemic stroke, but it is offered to a minority of patients, not only because of the short therapeutic window but also because of the numerous contraindications associated with thrombolysis, such as thrombocytopenia. There is some controversy on the true risk associated with thrombolysis in patients with thrombocytopenia. Here we report the case of a young patient, who developed an in-hospital acute ischemic stroke involving a large territory of the right middle cerebral artery, who was successfully treated with intravenous alteplase, despite having thrombocytopenia and prolonged prothrombin times due to systemic lupus erythematosus and antiphospholipid syndrome. This case exemplifies the need to reassess contraindications for thrombolysis, many based on expert opinion and not clinical evidence, especially in complex clinical situations. PMID- 26575493 TI - The monitoring of antiaggregation effect of acetylsalicylic acid therapy by measuring serum thromboxane B2 in patients with coronary artery bypass grafting. AB - Cardiovascular patients take acetylsalicylic acid (ASA) for preventing myocardial infarction and other thromboembolic complications. It is already known that in some patients this therapy is not effective. The aim of this study was to assess the percentage of ASA resistance on the sample of patients with coronary artery bypass grafting. Our study included 105 patients with coronary artery bypass grafting treated with ASA 150 mg/day or lesser. Platelet aggregation was measured by serum thromboxane B2 level as well as impedance aggregometry from whole blood to determine ASA antiaggregation effect. The percentage of ASA resistance was 41.9% with impedance aggregometry, and after determining the serum thromboxane B2 level this percentage was only 8.6%. The correlation between these two methods was weak (r = 0.443; P < 0.0001). Thromboembolic complications still occur in ASA treated patients because some patients are resistant to ASA therapy. It would be useful to monitor the effectiveness of ASA therapy and give another antiaggregation drug to these patients to reduce adverse events. The problem is which test is ideal because different tests show different percentages of ASA resistance. PMID- 26575494 TI - Mild factor XIII deficiency and concurrent hypofibrinogenemia: effect of pregnancy. AB - Factor XIII (FXIII) deficiency is a rare bleeding disorder. Patients with mild congenital FXIII deficiency tend to be asymptomatic, but may demonstrate significant bleeding symptoms with surgery, trauma, and pregnancy. Postpartum hemorrhage has been described in mild FXIII deficiency. We present a case of mild FXIII deficiency and concurrent hypofibrinogenemia manifested by recurrent postpartum hemorrhage, menorrhagia, and miscarriage. Mutational analysis identified a previously unreported heterozygous mutation of the FXIIIA subunit (p.Trp315Arg). No mutation was noted in the fibrinogen gene. FXIII levels decreased approximately 50% from nonpregnant levels to their nadir during labor, whereas fibrinogen levels rose approximately 1.5-fold from decreased nonpregnant levels to their peak at the time of labor. This case illustrates the course of mild FXIII and fibrinogen deficiencies during pregnancy, labor, and postpartum, and raises possible management options for prevention of antepartum and postpartum hemorrhage in women with these deficiencies. PMID- 26575495 TI - Mean platelet volume to platelet count ratio predicts in-hospital complications and long-term mortality in type A acute aortic dissection. AB - Type A acute aortic dissection is a life-threatening vascular emergency because of its high morbidity and mortality. Platelet is a pivotal ingredient involved in the development of acute aortic dissection. In this study, we aimed to investigate whether mean platelet volume (MPV)/platelet count ratio predicts in hospital complications and long-term mortality in type A acute aortic dissection. In this single-center and prospective cohort study, 106 consecutive patients with Stanford type A acute aortic dissection admitted to the hospital within 12 h after onset were recruited. The best cut-off value of MPV/platelet count ratio predicting all-cause mortality was determined by the receiver operator characteristic analysis. Patients were divided into high (H-MPV/platelet count) and low (L-MPV/platelet count) groups based on the cut-off value of 7.49 (10 fl/10/l). Patients were followed up for 3.5 years. Of the 106 acute aortic dissection patients, 71 (67.0%) died during the study period, with a median follow-up duration of 570 days. Compared to the L-MPV/platelet count group, patients with H-MPV/platelet count had a higher risk of in-hospital complications including hypotension, hypoxemia, myocardial ischemia/infarction, conscious disturbance, pericardial tamponade, paraplegia, and poor survival (all P < 0.05). In multivariable Cox regression models adjusted for potential confounders, MPV/platelet count ratio was positively associated with the hazard of all-cause mortality, irrespective of interventions either with medication only or urgent surgery, and the hazard ratios were 2.81 (95% confidence interval 1.28-4.48) for the H-MPV/platelet count group when taking L-MPV/platelet count group as the reference (P = 0.005). The MPV/platelet count ratio was a strong independent predictor for in-hospital complications and long-term mortality in patients with type A acute aortic dissection. PMID- 26575496 TI - Neutron diffraction and multinuclear solid state NMR investigation into the structures of oxide ion conducting La9.6Si6O26.4 and La8Sr2Si6O26, and their hydrated phases. AB - Apatite silicates are attracting significant interest as potential SOFC electrolyte materials. They are non-conventional oxide ion conductors in the sense that oxide ion interstitials, rather than vacancies, are the key defects. In this work we compare the structures of La9.6Si6O26.4 and La8Sr2Si6O26, both before and after hydration in order to gather information about the location of the interstitial oxide ion site. Neutron diffraction structural studies suggest that in the as-prepared La8Sr2Si6O26 and hydrated La8Sr2Si6O26, the interstitial oxide ion sites are close to the apatite channel centre. For La9.6Si6O26.4, a similar site close to the channel centre is observed, but on hydration of this particular sample, the interstitial site is shown to be significantly displaced away from the channel centre towards the SiO4 units. This can be explained by the need for additional displacement from the channel centre to accommodate the large amount of interstitial anions in this hydrated phase. The solid state (29)Si MAS NMR spectra are shown to be very sensitive to the different speciation exhibited by the La8Sr2Si6O26 and La9.6Si6O26.4 systems, with the former being dominated by regular SiO4 framework species and the latter being dominated by interruptions to this network caused by cation vacancies and interstitials. The corresponding (17)O MAS NMR study identifies a strong signal from the O atoms of the SiO4 groups, thus demonstrating that all of the O species in these systems are exchangeable O under heterogeneous gas phase conditions. In addition, interstitial O species attributed to pendant OH linkages on the Si positions are clearly identified and resolved, and these are removed on dehydration. This observation and assignment is corroborated by corresponding (1)H MAS NMR measurements. Overall the neutron diffraction work indicates that the interstitial site location in these apatite silicates depends on the anion content with progressive displacement towards the SiO4 tetrahedra on increasing anion content, while the observation of exchangeable O on the SiO4 groups is consistent with prior modelling predictions as to the importance on the silicate units in the conduction process. PMID- 26575498 TI - Synthesis and Structural Characterization of a Cyclen-Derived Molecular Cage. AB - Reaction of a tetrafunctionalized cyclen derivative containing four aldehyde groups with an appropriate diamine followed by reduction and demetalation highly efficiently affords a bis(cyclen)-derived molecular cage. Potentiometric investigations show that this compound forms dimetallic complexes with copper(II), with the two metal ions selectively coordinated to the cyclen units. X-ray crystallography indicates that these complexes could give rise to new cascade complexes after incorporation of anions between the metal centers. PMID- 26575497 TI - Comparative Proteome Analysis of hAT-MSCs Isolated from Chronic Renal Failure Patients with Differences in Their Bone Turnover Status. AB - The relationship between the stem cells and the bone turnover in uremic bone disease due to chronic renal failure (CRF) is not described. The aim of this study was to investigate the effect of bone turnover status on stem cell properties. To search for the presence of such link and shed some light on stem cell relevant mechanisms of bone turnover, we carried out a study with mesenchymal stem cells. Tissue biopsies were taken from the abdominal subcutaneous adipose tissue of a CRF patient with secondary hyperparathyroidism with the high turnover bone disease. This patient underwent parathyroidectomy operation (PTX) and another sample was taken from this patient after PTX. A CRF patient with adynamic bone disease with low turnover and a healthy control were also included. Mesenchymal stem cells isolated from the subjects were analyzed using proteomic and molecular approaches. Except ALP activity, the bone turnover status did not affect common stem cell properties. However, detailed proteome analysis revealed the presence of regulated protein spots. A total of 32 protein spots were identified following 2D gel electrophoresis and MALDI-TOF/TOF analyzes. The identified proteins were classified into seven distinct groups and their potential relationship to bone turnover were discussed. Distinct protein expression patterns emerged in relation to the bone turnover status indicate a possible link between the stem cells and bone turnover in uremic bone disease due to CRF. PMID- 26575499 TI - Screening adult patients with a tracheostomy tube for dysphagia: a mixed-methods study of practice in the UK. AB - BACKGROUND: Patients with tracheostomy tubes are at risk of aspiration and swallowing problems (dysphagia), and because of their medical acuity, complications in this patient population can be severe. It is well recognized that swallow screening in stroke significantly reduces potential complications by allowing early identification and appropriate management of patients at risk (by health professionals), thereby reducing delays in commencing oral intake and preventing unnecessary, costly interventions by speech and language therapists (SLTs). However, there is no standardized swallow screen for the tracheostomised population and there is a paucity of literature regarding either current or best practice in this area. AIMS: To investigate current UK practice for dysphagia screening in adult patients with tracheostomy tubes and to explore and describe health professionals' perceptions of their current practice or current systems used. METHODS & PROCEDURES: A mixed-methods approach was adopted comprising a semi-structured online questionnaire and recorded follow-up telephone interviews. Participants were SLTs, nurses and physiotherapists working with patients with tracheostomies. Responses were analysed to determine current practice with regard to swallow screening. Thematic analysis of interviews allowed further exploration and clarification of the questionnaire findings. OUTCOMES & RESULTS: A total of 221 questionnaires were completed. Approximately half (45%) the participants worked in trusts with formal swallow screens, whilst the remainder used a variety of other approaches to identify patients at risk, often relying on informal links with multidisciplinary teams (MDT). In line with current evidence, patients with neurological diagnoses and a tracheostomy were consistently referred directly to speech and language therapy (SLT). Only one-quarter of questionnaire participants thought their current system was effective at identifying patients at risk of swallowing problems. Eleven questionnaire participants were interviewed. They highlighted the important role of MDT team working here, emphasizing both its strengths and weaknesses when working with these patients. CONCLUSIONS & IMPLICATIONS: Current practice in the UK for screening patients with a tracheostomy for swallow problems is varied and often suboptimal. Despite the evidence for enhancing outcomes, MDT working is still perceived as problematic. A swallow screening tool for use with this population, to enhance MDT working whilst also ensuring that practice fits in line with current evidence, may improve patient safety and care. PMID- 26575500 TI - Will You Answer the Bell? PMID- 26575501 TI - Helping You Succeed! PMID- 26575502 TI - Hip Fractures: What Information Does the Evidence Show That Patients and Families Need to Decrease 30-Day Readmission? AB - The current bundled payment reimbursement from the Centers for Medicare & Medicaid Services will not cover the additional cost of hospital readmission for the same diagnosis, and patients with hip fractures have one of the highest cost saving opportunities when compared with other admission reasons. Common reasons for readmission to the hospital after hip fracture include pneumonia, dehydration, and mobility issues. The learning modalities including visual, aural, read/write, and kinesthetic were used to make recommendations on how the education can be incorporated into the instruction of patients with hip fractures and their families. These learning techniques can be used to develop education to decrease possibility of 30-day readmission after hip fracture. Nurses must focus their education to meet the needs of each individual patient, adapting to different types of adult learners to increase the health literacy of patients with hip fractures and their families. PMID- 26575504 TI - Postoperative Spica Cast Care: RN Comfort-Level Survey Score Improvement After a 30-Minute Educational Video. AB - Spica casts are utilized to immobilize young patients who have sustained femur fractures or who have undergone hip procedures/surgery. These casts typically need to stay in place for 4-6 weeks. Improper postoperative care can lead to unplanned, increased morbidity and sequelae. We show that with appropriate education using a video module teaching method, learners who are less familiar with the specific care of these patients and casts will gain an improved comfort level and increased knowledge base. This will translate to better patient care and more complete caregiver education for home. PMID- 26575506 TI - Can Educational Interventions Improve Osteoporotic Women's Adherence to Treatment? A Literature Review. AB - Poor adherence to medication and an unhealthy lifestyle increase risk of fracture, hospitalization, and medical costs in osteoporotic individuals. Therefore, a literature review was conducted using PubMed, CINAHL, Cochrane Library, and Scopus databases to identify educational interventions that improve adherence to medications and healthy lifestyles in osteoporotic women. The search was limited to the articles published between January 2002 and January 2015, and they were selected only if they were interventional studies. Twelve studies were included, in which 7 studies were focused on interventions to improve medication adherence, 4 studies on improving adherence to healthy lifestyles, and 1 study was focused on both. Educational interventions, such as tailored interventions with counseling sessions, were effective in improving adherence to medications and healthy lifestyles; however, educational materials such as leaflets did not improve adherence. Further studies are needed to investigate adherence to healthy lifestyles because this is poorly described in the literature. PMID- 26575508 TI - Acceptability of a Guided Imagery Intervention for Persons Undergoing a Total Knee Replacement. AB - BACKGROUND: Guided imagery (GI) has been recommended as a mind-body therapy for pain relief following orthopaedic surgery, but little is known about the acceptability of the intervention. PURPOSE: Describe the perceptions of patients undergoing total knee replacement (TKR) surgery regarding the acceptability of a customized GI intervention to promote TKR outcomes. METHODS: Narrative and survey data collected during a randomized controlled trial of the GI intervention were analyzed to assess the acceptability of the intervention. RESULTS: Most participants were satisfied with and actively engaged in the intervention, and they perceived it to be helpful. For the smaller group of participants who did not find the intervention to be acceptable, reasons for dissatisfaction and barriers to engagement were identified. CONCLUSIONS: Guided imagery is an acceptable intervention for many persons undergoing TKR surgery. The results of this study can provide information to further develop a targeted and customized GI intervention for this population. PMID- 26575509 TI - Utilizing Teach-Back to Reinforce Patient Education: A Step-by-Step Approach. AB - Teach-back is a health literacy tool that can be used by orthopaedic nurses to assess their patients' understanding of what has been taught and immediately clarify and review concepts that were misunderstood. Research supports the use of teach-back to engage patients in the learning process, thereby reducing hospital readmissions, and improving self-management, safety, patient satisfaction, and patient outcomes. Nursing journals, however, lack articles that take nurses through the steps of implementing teach-back in their practice. This article describes the four stages of teach-back and takes you step by step through the process of integrating this health literacy tool in your patient education practices. PMID- 26575511 TI - Level of Perception of Individualized Care and Satisfaction With Nursing in Orthopaedic Surgery Patients. AB - Lately, individualized nursing care and patient satisfaction are important and current issues being discussed. But there is not enough information for patients undergoing orthopaedic surgery. The aim of this study was to determine the individualized care perception and satisfaction in nursing care levels in orthopaedic surgery patients. This descriptive cross-sectional study was conducted with 156 patients who underwent orthopaedic surgery. Data were collected using the personal information form, the Individualized Care Scale, and the Newcastle Satisfaction With Nursing Scale. The Spearman correlation analysis and descriptive statistics were performed. The mean individualized care and satisfaction with nursing care scores were found to be close to the preset maximum value, and it was determined that an increase in the level of awareness about nursing interventions and the level of perceived individualized care caused an increase in satisfaction levels regarding nursing care. Nurses should recognize the importance of performing individualized care in order to increase the level of satisfaction with nursing care in orthopaedic surgery patients. PMID- 26575512 TI - Computer-Assisted Surgery for Knee Ligament Reconstruction. PMID- 26575515 TI - Endoscopic management of orbital tumors. AB - PURPOSE OF REVIEW: Orbital tumors have been classically approached via external incision. The introduction of endoscopic surgery has revolutionized the management of sinus and skull base disorder. Similarly, endoscopic techniques have been increasingly utilized to access intraorbital tumors located in the medial and inferior orbit with excellent outcomes. The history of the procedure, surgical anatomy of the orbit, patient selection, surgical planning, and the surgical techniques are discussed in this article. RECENT FINDINGS: Although the endoscopic management of orbital tumors is still in its infancy, it has already demonstrated enhanced access to the posterior orbit and orbital apex with decreased morbidity relative to external approaches. SUMMARY: A multidisciplinary team approach, including an oculoplastic surgeon, is an essential component for the surgical planning and management. As the cumulative surgical experience increases, the indications for this approach will likely continue to expand. PMID- 26575516 TI - Evaluation and treatment of isolated sphenoid sinus diseases. AB - PURPOSE OF REVIEW: To review cause, clinical evaluation, medical and surgical management of isolated sphenoid sinus diseases. RECENT FINDINGS: Early diagnosis of isolated sphenoid sinus diseases requires a high index of clinical suspicion and appropriate radiological imaging. Sphenoid sinus can be approached endoscopically via a few different surgical techniques. SUMMARY: Isolated sphenoid sinus diseases are uncommon, with nonspecific clinical presentation. Early diagnosis requires a high index of clinical suspicion, proper endoscopic nasal examination, and appropriate radiological imaging. Surgical intervention is the primary treatment modality for most of the isolated sphenoid sinus diseases. Endoscopic endonasal approach to sphenoid sinus is the technique of choice. The location of sphenoid sinus disease, the extent of the surgery, and anatomic configuration of the sphenoid sinus are the main factors that help to decide the most suitable surgical approach to the sphenoid sinus. PMID- 26575517 TI - Contemporary management of esthesioneuroblastoma. AB - PURPOSE OF REVIEW: This article provides a contemporary review of the management of esthesioneuroblastoma (ENB) within the context of recent surgical advancements, while highlighting the ongoing limitations and controversies surrounding this uncommon pathologic entity. RECENT FINDINGS: Surgical management of ENB is continuously evolving with contemporary endoscopic approaches complementing or in many cases replacing open approaches. SUMMARY: Complete surgical resection remains the mainstay definitive therapy for ENB. Aggressive, combined modality therapy appears to be justified in patients at greatest risk of developing recurrence based on advanced tumor stage and high pathologic grade. ENB requires prolonged surveillance following treatment given its tendency for late recurrence. PMID- 26575518 TI - The sinonasal bacterial microbiome in health and disease. AB - PURPOSE OF REVIEW: The development of culture-independent bacterial DNA sequencing techniques and integration into research practice has led to a burgeoning interest in the microbiome and its relevance to human health and disease. Introduction into the study of chronic rhinosinusitis in the past few years has shaped current thinking on the role of bacteria in the disease process. RECENT FINDINGS: Rich and diverse populations of bacteria inhabit the sinonasal cavity at all times. Decreased bacterial richness and diversity may be associated with disease state and outcomes. SUMMARY: Although there is much to be explored, the sinus microbiome appears to have potentially promising roles in many aspects of sinus health and disease. PMID- 26575519 TI - Bayes and empirical Bayes methods for reduced rank regression models in matched case-control studies. AB - Matched case-control studies are popular designs used in epidemiology for assessing the effects of exposures on binary traits. Modern studies increasingly enjoy the ability to examine a large number of exposures in a comprehensive manner. However, several risk factors often tend to be related in a nontrivial way, undermining efforts to identify the risk factors using standard analytic methods due to inflated type-I errors and possible masking of effects. Epidemiologists often use data reduction techniques by grouping the prognostic factors using a thematic approach, with themes deriving from biological considerations. We propose shrinkage-type estimators based on Bayesian penalization methods to estimate the effects of the risk factors using these themes. The properties of the estimators are examined using extensive simulations. The methodology is illustrated using data from a matched case control study of polychlorinated biphenyls in relation to the etiology of non Hodgkin's lymphoma. PMID- 26575520 TI - Bradycardia from flash stimulation. AB - This case study documents a patient who experienced bradycardia brought on by flash stimulation during a routine outpatient EEG recording. The patient had known photosensitive seizures in the past. During this routine EEG, the patient's heart rate dropped to about 12 beats per minute with the EEG displaying slow delta-frequency waves with no epileptiform spikes or sharp waves. During immediate follow-up, in our emergency department, the patient had a brief asystolic event, followed by bradycardia. Cardiology examinations were normal. We propose that this response was a photic-triggered reflex vasovagal reaction. PMID- 26575521 TI - Respiratory syncytial virus activity and climate parameters during a 12-year period. AB - The epidemic pattern of respiratory syncytial virus (RSV) infection during long periods and the factors that determine seasonality are not well studied. In order to correlate the RSV epidemic activity with climate parameters, we conducted a retrospective study of children (0-14 year) who were hospitalized because of respiratory tract infection and had an RSV test performed in the major tertiary pediatric hospital of Greece during a 12-year period (2002-2013). Daily data regarding temperature and humidity were obtained from the Hellenic National Meteorological Service. A total of 2030/7516 (27%) children were tested positive for RSV infection. Among RSV positive children 1945/2030 (95.8%) were infants <1 year. A peak of RSV activity was measured in years 2002, 2003, and 2006 (>35% positive). The RSV season in our area spanned from December to April, with higher incidence during January through March. The peak monthly RSV incidence was observed during February with mean temperature 10.34 degrees C and mean relative humidity 69.16%. Regarding climate conditions, a statistically significant positive correlation was found between monthly RSV activity and mean monthly relative humidity (rho = 0.66, P-value = 0.02), whereas a negative correlation was found with mean monthly temperature (rho = -0.81, P-value = 0.002). However, in the multivariable analysis, only the effect of mean monthly temperature remained statistically significant (IRR = 0.72, 95% CI: 0.68, 0.80). Further understanding of RSV seasonality in different geographic areas would be important in order to timely implement preventing strategies with immunoprophylaxis or future RSV vaccines. PMID- 26575522 TI - Modeling Structural Dynamics of Biomolecular Complexes by Coarse-Grained Molecular Simulations. AB - Due to hierarchic nature of biomolecular systems, their computational modeling calls for multiscale approaches, in which coarse-grained (CG) simulations are used to address long-time dynamics of large systems. Here, we review recent developments and applications of CG modeling methods, focusing on our methods primarily for proteins, DNA, and their complexes. These methods have been implemented in the CG biomolecular simulator, CafeMol. Our CG model has resolution such that ~10 non-hydrogen atoms are grouped into one CG particle on average. For proteins, each amino acid is represented by one CG particle. For DNA, one nucleotide is simplified by three CG particles, representing sugar, phosphate, and base. The protein modeling is based on the idea that proteins have a globally funnel-like energy landscape, which is encoded in the structure-based potential energy function. We first describe two representative minimal models of proteins, called the elastic network model and the classic Go model. We then present a more elaborate protein model, which extends the minimal model to incorporate sequence and context dependent local flexibility and nonlocal contacts. For DNA, we describe a model developed by de Pablo's group that was tuned to well reproduce sequence-dependent structural and thermodynamic experimental data for single- and double-stranded DNAs. Protein-DNA interactions are modeled either by the structure-based term for specific cases or by electrostatic and excluded volume terms for nonspecific cases. We also discuss the time scale mapping in CG molecular dynamics simulations. While the apparent single time step of our CGMD is about 10 times larger than that in the fully atomistic molecular dynamics for small-scale dynamics, large-scale motions can be further accelerated by two-orders of magnitude with the use of CG model and a low friction constant in Langevin dynamics. Next, we present four examples of applications. First, the classic Go model was used to emulate one ATP cycle of a molecular motor, kinesin. Second, nonspecific protein-DNA binding was studied by a combination of elaborate protein and DNA models. Third, a transcription factor, p53, that contains highly fluctuating regions was simulated on two perpendicularly arranged DNA segments, addressing intersegmental transfer of p53. Fourth, we simulated structural dynamics of dinucleosomes connected by a linker DNA finding distinct types of internucleosome docking and salt-concentration dependent compaction. Finally, we discuss many of limitations in the current approaches and future directions. Especially, more accurate electrostatic treatment and a phospholipid model that matches our CG resolutions are of immediate importance. PMID- 26575523 TI - Uterine electromyography during active phase compared with latent phase of labor at term. AB - INTRODUCTION: In a prospective study in a tertiary university hospital we wanted to determine whether uterine electromyography (EMG) can differentiate between the active and latent phase of labor. MATERIAL AND METHODS: Thirty women presenting at >=37(0/7) weeks of gestation with regular uterine contractions, intact membranes, and a Bishop score <6. EMG was recorded from the abdominal surface for 30 min. Latent phase was defined as no cervical change within at least 4 h. Student's t-test was used for statistical analysis (p <= 0.05 significant). Diagnostic accuracy of EMG was determined by receiver operator characteristics (ROC) analysis. The integral of the amplitudes of the power density spectrum (PDS) corresponding to the PDS energy within the "bursts" of uterine EMG activity was compared between the active and latent labor groups. RESULTS: Seventeen (57%) women were found to be in the active phase of labor and 13 (43%) were in the latent phase. The EMG PDS integral was significantly higher (p = 0.02) in the active (mean 3.40 +/- 0.82 MUV) compared with the latent (mean 1.17 +/- 0.33 MUV) phase of labor. The PDS integral had an area under the ROC curve (AUC) of 0.80 to distinguish between active and latent phases of labor, compared with number of contractions on tocodynamometry (AUC = 0.79), and Bishop score (AUC = 0.78). The combination (sum) of PDS integral, tocodynamometry, and Bishop score predicted active phase of labor with an AUC of 0.90. CONCLUSIONS: Adding uterine EMG measurements to the methods currently used in the clinics could improve the accuracy of diagnosing active labor. PMID- 26575524 TI - Mometasone furoate nasal spray in the treatment of nasal polyposis in Chinese patients: a double-blind, randomized, placebo-controlled trial. AB - BACKGROUND: Although mometasone furoate nasal spray (MFNS) has demonstrated efficacy in nasal polyposis (NP) in Western populations, data in Asian populations is limited. METHODS: This randomized, double-blind study evaluated MFNS 200 MUg twice per day (BID) vs placebo in Chinese adults with bilateral nasal polyps (graded as 1, 2, or 3 by the investigator). A 14-day placebo run-in period was followed by a 16-week treatment period with MFNS 200 MUg BID vs placebo (1:1 ratio). The co-primary endpoints were change from baseline in nasal congestion/obstruction averaged over the first 4 weeks of treatment and change from baseline in the total polyp size score (sum of scores from the left and right nasal fossa) at week 16. Secondary endpoints included other sinonasal symptoms scores and safety outcomes such as monitoring laboratory measurements, vital signs, and adverse events (AEs). RESULTS: There were 748 patients randomized, 375 received MFNS 200 MUg BID and 373 received placebo. The between treatment difference in least squares (LS) mean change from baseline in nasal congestion/obstruction over 4 weeks of treatment was -0.14 (95% confidence interval [CI], -0.22 to -0.06) for MFNS vs placebo (p = 0.0007). The between treatment difference in LS mean change from baseline in total polyp size score at week 16 was -0.30 (95% CI, -0.45 to -0.15) for MFNS vs placebo (p < 0.0001). Serious AEs were rare (0.5% and 0.8% in MFNS and placebo groups, respectively) and considered not drug-related. There were significantly more AEs of epistaxis with MFNS vs placebo (p = 0.009). CONCLUSION: This study demonstrated that MFNS was effective and well tolerated in this population of adult, Chinese patients with NP. PMID- 26575526 TI - Changes among Associate Editors. PMID- 26575525 TI - Leptosphaeria maculans effector AvrLm4-7 affects salicylic acid (SA) and ethylene (ET) signalling and hydrogen peroxide (H2 O2 ) accumulation in Brassica napus. AB - To achieve host colonization, successful pathogens need to overcome plant basal defences. For this, (hemi)biotrophic pathogens secrete effectors that interfere with a range of physiological processes of the host plant. AvrLm4-7 is one of the cloned effectors from the hemibiotrophic fungus Leptosphaeria maculans 'brassicaceae' infecting mainly oilseed rape (Brassica napus). Although its mode of action is still unknown, AvrLm4-7 is strongly involved in L. maculans virulence. Here, we investigated the effect of AvrLm4-7 on plant defence responses in a susceptible cultivar of B. napus. Using two isogenic L. maculans isolates differing in the presence of a functional AvrLm4-7 allele [absence ('a4a7') and presence ('A4A7') of the allele], the plant hormone concentrations, defence-related gene transcription and reactive oxygen species (ROS) accumulation were analysed in infected B. napus cotyledons. Various components of the plant immune system were affected. Infection with the 'A4A7' isolate caused suppression of salicylic acid- and ethylene-dependent signalling, the pathways regulating an effective defence against L. maculans infection. Furthermore, ROS accumulation was decreased in cotyledons infected with the 'A4A7' isolate. Treatment with an antioxidant agent, ascorbic acid, increased the aggressiveness of the 'a4a7' L. maculans isolate, but not that of the 'A4A7' isolate. Together, our results suggest that the increased aggressiveness of the 'A4A7' L. maculans isolate could be caused by defects in ROS-dependent defence and/or linked to suppressed SA and ET signalling. This is the first study to provide insights into the manipulation of B. napus defence responses by an effector of L. maculans. PMID- 26575527 TI - Fiber-Optic Chemical Sensors and Biosensors (2013-2015). PMID- 26575528 TI - Synergistic anticancer effects of cisplatin and histone deacetylase inhibitors (SAHA and TSA) on cholangiocarcinoma cell lines. AB - Clinical application of cisplatin against cholangiocarcinoma is often associated with resistance and toxicity posing urgent demand for combination therapy. In this study, we evaluated the combined anticancer effect of cisplatin and histone deacetylase inhibitors (HDACIs), suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA), on the cholangiocarcinoma KKU-100 and KKU-M214 cell lines. Antiproliferative activity was evaluated using MTT assay. Apoptosis induction and cell cycle arrest were analyzed by flow cytometry. Cell cycle and apoptosis regulating proteins were evaluated by western blot analysis. MTT assay showed that cisplatin, SAHA and TSA dose-dependently reduced the viability of KKU-100 and KKU-M214 cells. The combination of cisplatin and HDACIs exerted significantly more cytotoxicity than the single drugs. Combination indices below 1.0 reflect synergism between cisplatin and HDACIs, leading to positive dose reductions of cisplatin and HDACIs. Cisplatin and HDACIs alone induced G0/G1 phase arrest in KKU-100 cells, but the drug combinations increased sub-G1 percent more than either drug. However, cisplatin and HDACIs alone or in combination increased only the sub-G1 percent in KKU-M214 cells. Annexin V-FITC staining revealed that cisplatin and HDACIs combinations induced more apoptotic cell death of both KKU 100 and KKU-M214 cells than the single drug. In KKU-100 cells, growth inhibition was accompanied by upregulation of p53 and p21 and downregulation of CDK4 and Bcl 2 due to exposure to cisplatin, SAHA and TSA alone or in combination. Moreover, combination of agents exerted higher impacts on protein expression. Single agents or combination did not affect p53 expression, however, combination of cisplatin and HDACIs increased the expression of p21 in KKU-M214 cells. Taken together, cisplatin and HDACIs combination may improve the therapeutic outcome in cholangiocarcinoma patients. PMID- 26575529 TI - Modulation of Self-Assembly Process of Fibroin: An Insight for Regulating the Conformation of Silk Biomaterials. AB - Controlling the mechanism of self-assembly in proteins has emerged as a potent tool for various biomedical applications. Silk fibroin self-assembly consists of gradual conformational transition from random coil to beta-sheet structure. In this work we elucidated the intermediate secondary conformation in the presence of Ca(2+) ions during fibroin self-assembly. The interaction of fibroin and calcium ions resulted in a predominantly alpha-helical intermediate conformation, which was maintained to certain extent even in the final conformation as illustrated by circular dichroism and attenuated total reflectance-Fourier transform infrared spectroscopy. Further, to elucidate the mechanism behind this interaction molecular modeling of the N-terminal region of fibroin with Ca(2+) ions was performed. Negatively charged glutamate and aspartate amino acids play a key role in the electrostatic interaction with positively charged calcium ions. Therefore, insights about modulation of self-assembly mechanism of fibroin could potentially be utilized to develop silk-based biomaterials consisting of the desired secondary conformation. PMID- 26575531 TI - Correction: Unsymmetrical 1,1-diborated multisubstituted sp(3)-carbons formed via a metal-free concerted-asynchronous mechanism. AB - Correction for 'Unsymmetrical 1,1-diborated multisubstituted sp(3)-carbons formed via a metal-free concerted-asynchronous mechanism' by Ana B. Cuenca et al., Org. Biomol. Chem., 2015, 13, 9659-9664. PMID- 26575530 TI - Efficacy of intravenous cyclosporine in a case of cytophagic histiocytic panniculitis complicated by haemophagocytic syndrome after visceral leishmania infection. AB - Cytophagic histiocytic panniculitis (CHP) is a rare panniculitis characterized by systemic features, due to histiocytic infiltration along with haemophagocytosis, which may also appear in bone marrow, spleen, lymph nodes, and liver. Haemophagocytic lymphohistiocytosis (HLH) is a group of autoinflammatory disorders, which include macrophage activation syndrome, sometimes observed in the course of systemic autoimmune diseases, such as juvenile chronic polyarthritis, systemic lupus erythematosus or vasculitis, and infection associated haemophagocytic syndrome; if not promptly recognised and treated, HLH can be fatal. Visceral leishmaniasis (VL) is a systemic disease caused by different forms of Leishmania spp., an intracellular protozoa. VL is endemic in tropical countries such as in the Middle East and the Mediterranean. The typical clinical and laboratory features are fever, hepato-splenomegaly, hypergammaglobulinaemia and pancytopenia. The features of VL may mimic some haematologic diseases. We report a case of cytophagic histiocytic panniculitis and HLH, triggered by a previous visceral leishmania infection. Cyclosporine was quickly effective in this case, after failure of high-dose glucocorticoids, anakinra and etoposide. PMID- 26575532 TI - [Doctor and Patient Do Not See Anything]. PMID- 26575533 TI - [Iris Mammillation]. PMID- 26575534 TI - [Non-Arteritic Ischemic Optic Neuropathy (NAION)]. AB - Non-arteritic ischemic optic neuropathy (NAION) is virtually unknown outside ophthalmology. It is characterised by acute unilateral visual loss, no pain on eye movements and virtually always optic disc swelling. Optic disc oedema resolves within 1 to 2 months, leaving behind optic atrophy. Vision hardly improves. NAION is the product of local abnormalities of the vascular supply to the optic nerve and general vascular risk factors. Of these, diabetes, hypertension and especially sleep apnoea syndrome are the most important. Recurrences in the involved eye are rare; contralateral recurrence occurs in approximately 15 % of patients. There is no clear scientific evidence for any specific therapy. However, there is general agreement that it is reasonable to control risk factors. PMID- 26575535 TI - [An Unusual Cause of Increased Light Sensitivity]. AB - Photophobia is in many cases linked to pathologies of the anterior segment of the eye, e.g. cataract or iritis. We report an unusual case of increased light sensitivity due to a compressing lesion of the chiasm. Pituitary adenomas are among the most frequent intracranial tumours and can affect the chiasm - the site where all the visual afferences meet. A lesion of the chiasm is therefore particularly dangerous. Fortunately, in two-thirds of all cases, pituitary adenomas lead to hormonal dysfunction, so that magnetic resonance imaging of the brain is conducted. However, in the remainder of the cases, the ophthalmologist may be the first physician to see the patient because of visual problems. Usually patients report reduced vision or show typical visual field defects, such as bitemporal hemianopsia. However, the only pathological symptom may be increased light sensitivity. In rare cases of photophobia which cannot be explained by pathologies of the anterior segment, a compressing lesion of the chiasm should be considered. PMID- 26575536 TI - [Reproducibility of Scheimpflug Tomography Measurements Regarding Corneal Front and Back Surface Power]. AB - BACKGROUND AND PURPOSE: The Oculus Pentacam(r) is one of the most commonly used devices in ophthalmology for assessment of the anterior eye segment. The purpose of this study was to determine the reproducibility of the corneal power as measured by the Pentacam(r) in a normal population. METHODS: We enrolled 25 eyes of 25 subjects aged between 13 and 68 (46.7 +/- 21.7) years, within a spherical equivalent from - 4 D to + 4 D and refractive cylinder up to 5 D and without notable pathologies or history of surgery. A sequence of 5 measurements was performed using the Pentacam(r), the Zeiss IOLMaster(r) as well as an autorefractometer after (re-)positioning the patient's head and the measurement device. From the Pentacam(r) we collected power data for the corneal front and back surfaces, apical corneal thickness at apex and internal anterior chamber depth. From the IOLMaster(r), we extracted corneal power data, and from the autorefractometer we obtained refractive power data of both cardinal meridians. For statistical analysis, we used Cronbach's alpha as a measure of reproducibility and Spearman's rank correlation test for correlation of data. RESULTS: Pentacam(r) yields highly reproducible power data for both corneal surfaces, with Cronbach's alpha of greater than 0.97 for primary parameters (e.g. radii of curvature) and 0.9 for secondary parameters (e.g. vector components of astigmatism). Central corneal thickness and eccentricities of both surfaces as well as anterior chamber depth yielded highly reproducible values, with alpha of >= 0.97. Corneal power derived from IOLMaster(r) and objective refraction extracted from the autorefractometer yielded alpha values of around 0.9. Mean corneal power of Pentacam(r) and IOLMaster(r) correlated well, but there was no correlation to spherical equivalent. Astigmatism values from Pentacam(r) and IOLMaster(r) correlated well with each other and with refractive cylinder. CONCLUSION: Our results indicate that measurements of anterior segment using the Pentacam(r) yield highly reproducible results in a normal population without major pathologies of the anterior eye segment. PMID- 26575537 TI - [Special Diagnostics of the Cornea]. PMID- 26575539 TI - A comment on the reweighting method for accelerated molecular dynamics simulations. AB - Accelerated molecular dynamics (aMD) is a popular method for biomolecular simulations. The estimator to recover the true free energy profile, termed "reweighting", constitutes a critical part of aMD. Recently the second order cumulant expansion has been recommended as an improved reweighting method. Here we examine the validity of this reweighting method and provide an insight into the need for selecting appropriate boost potentials. PMID- 26575538 TI - Characterization of MHC Class I and beta-2-Microglobulin Expression in Pediatric Solid Malignancies to Guide Selection of Immune-Based Therapeutic Trials. AB - BACKGROUND: Over 10,000 US children are diagnosed with cancer yearly. Though outcomes have improved by optimizing conventional therapies, recent immunotherapeutic successes in adult cancers are emerging. Cytotoxic T lymphocytes (CTLs) are the primary executioners of adaptive antitumor immunity and require antigenic presentation in the context of major histocompatibility complex (MHC) class I and the associated beta-2-microglobulin (B2M). Loss of MHC I expression is a common immune escape mechanism in adult malignancies, but pediatric cancers have not been thoroughly characterized. The essential nature of MHC I expression in CTL-mediated cell death may dictate the success of immunotherapies, which rely on eliciting an adaptive response. PROCEDURE: We queried pediatric tumor microarray databases for MHC I and B2M gene expression. We detected MHC I in pediatric tumor cell lines by flow cytometry and characterized MHC I and B2M expression in patient samples by immunohistochemistry. To determine whether therapeutic approaches might enhance MHC I expression in selected models in vitro, we tested effects of exposure to IFN-gamma and histone deacetylase inhibitors. RESULTS: Pediatric tumors overall, as well as samples within select individual tumor subtypes, exhibit wide ranges of MHC I and B2M gene and protein expression. For most cell lines tested, MHC I was inducible in vitro. CONCLUSIONS: MHC I and B2M expression vary among pediatric tumor types and should be evaluated as potential biomarkers, which might identify patients most likely to benefit from MHC I dependent immunotherapies. Modulation of MHC I expression may be a promising mechanism for enhancing MHC I dependent immunotherapeutic efficacy. PMID- 26575540 TI - Adaptive-partitioning QM/MM for molecular dynamics simulations: 4. Proton hopping in bulk water. AB - By reclassifying atoms as QM or MM on-the-fly, adaptive QM/MM dynamics simulations can utilize small QM subsystems whose locations and contents are continuously and automatically updated. Although adaptive QM/MM has been applied in studies of a variety of ions, dynamics simulations of a hydrated proton in bulk water remain a challenge. The difficulty arises from the need to transfer structural features (the covalent and hydrogen bonding networks) via the Grotthuss mechanism instead of the given proton. One must therefore identify an appropriate reference point from which the QM subsystem can be positioned that continuously follows the structural variations as the proton hops. To solve this problem, we propose a proton indicator that serves as the needed reference point. The location of the proton indicator varies smoothly from the hydronium oxygen in the resting (Eigen) state to the shared proton in the transition (Zundel) state. The algorithm is implemented in the framework of a modified permuted adaptive partitioning QM/MM. As a proof of concept, we simulate an excess proton solvated in bulk water, where the QM subsystem is defined as a sphere of 4.0 A radius centered at the proton indicator. We find that the use of the proton indicator prevents abrupt changes in the location and contents of the QM subsystem. The new method yields reasonably good agreement in the proton solvation structure and in the proton transfer dynamics with previously reported conventional QM/MM dynamics simulations that employed a much larger QM subsystem (a sphere of 12 A radius). Also, the results do not change significantly with respect to variations in the time step size (0.1 or 0.5 fs), truncation of the many-body expansion of the potential (from fifth to second order), and absence/presence of thermostat. The proton indicator combined with the modified permuted adaptive-partitioning scheme thus appears to be a useful tool for studying proton transfer in solution. PMID- 26575541 TI - Potential-based dynamical reweighting for Markov state models of protein dynamics. AB - As simulators attempt to replicate the dynamics of large cellular components in silico, problems related to sampling slow, glassy degrees of freedom in molecular systems will be amplified manyfold. It is tempting to augment simulation techniques with external biases to overcome such barriers with ease; biased simulations, however, offer little utility unless equilibrium properties of interest (both kinetic and thermodynamic) can be recovered from the data generated. In this Article, we present a general scheme that harnesses the power of Markov state models (MSMs) to extract equilibrium kinetic properties from molecular dynamics trajectories collected on biased potential energy surfaces. We first validate our reweighting protocol on a simple two-well potential, and we proceed to test our method on potential-biased simulations of the Trp-cage miniprotein. In both cases, we find that equilibrium populations, time scales, and dynamical processes are reliably reproduced as compared to gold standard, unbiased data sets. We go on to discuss the limitations of our dynamical reweighting approach, and we suggest auspicious target systems for further application. PMID- 26575542 TI - Easy transition path sampling methods: flexible-length aimless shooting and permutation shooting. AB - We present new algorithms for conducting transition path sampling (TPS). Permutation shooting rigorously preserves the total energy and momentum of the initial trajectory and is simple to implement even for rigid water molecules. Versions of aimless shooting and permutation shooting that use flexible-length trajectories have simple acceptance criteria and are more computationally efficient than fixed-length versions. Flexible-length permutation shooting and inertial likelihood maximization are used to identify the reaction coordinate for vacancy migration in a two-dimensional trigonal crystal of Lennard-Jones particles. The optimized reaction coordinate eliminates nearly all recrossing of the transition state dividing surface. PMID- 26575543 TI - Adaptive switching of interaction potentials in the time domain: an extended Lagrangian approach tailored to transmute force field to QM/MM simulations and back. AB - An extended Lagrangian formalism that allows for a smooth transition between two different descriptions of interactions during a molecular dynamics simulation is presented. This time-adaptive method is particularly useful in the context of multiscale simulation as it provides a sound recipe to switch on demand between different hierarchical levels of theory, for instance between ab initio ("QM") and force field ("MM") descriptions of a given (sub)system in the course of a molecular dynamics simulation. The equations of motion can be integrated straightforwardly using the usual propagators, such as the Verlet algorithm. First test cases include a bath of harmonic oscillators, of which a subset is switched to a different force constant and/or equilibrium position, as well as an all-MM to QM/MM transition in a hydrogen-bonded water dimer. The method is then applied to a smectic 8AB8 liquid crystal and is shown to be able to switch dynamically a preselected 8AB8 molecule from an all-MM to a QM/MM description which involves partition boundaries through covalent bonds. These examples show that the extended Lagrangian approach is not only easy to implement into existing code but that it is also efficient and robust. The technique moreover provides easy access to a conserved energy quantity, also in cases when Nose-Hoover chain thermostatting is used throughout dynamical switching. A simple quadratic driving potential proves to be sufficient to guarantee a smooth transition whose time scale can be easily tuned by varying the fictitious mass parameter associated with the auxiliary variable used to extend the Lagrangian. The method is general and can be applied to time-adaptive switching on demand between two different levels of theory within the framework of hybrid scale-bridging simulations. PMID- 26575544 TI - Gluing potential energy surfaces with rare event simulations. AB - We develop a new method combining replica exchange transition interface sampling with two distinct potential energy surfaces. The method can be used to combine different levels of theory in a simulation of a molecular process (e.g., a chemical reaction), and it can serve as a dynamical version of QM-MM, connecting classical dynamics with Ab Initio dynamics in the time domain. This new method, which we coin QuanTIS, could be applied to use accurate but expensive density functional theory based molecular dynamics for the breaking and making of chemical bonds, while the diffusion of reactants in the solvent are treated with classical force fields. We exemplify the method by applying it to two simple model systems (an ion dissociation reaction and a classical hydrogen model), and we discuss a possible extension of the method in which classical force field parameters for chemical reactions can be optimized on the fly. PMID- 26575545 TI - Designing free energy surfaces that match experimental data with metadynamics. AB - Creating models that are consistent with experimental data is essential in molecular modeling. This is often done by iteratively tuning the molecular force field of a simulation to match experimental data. An alternative method is to bias a simulation, leading to a hybrid model composed of the original force field and biasing terms. We previously introduced such a method called experiment directed simulation (EDS). EDS minimally biases simulations to match average values. In this work, we introduce a new method called experiment directed metadynamics (EDM) that creates minimal biases for matching entire free energy surfaces such as radial distribution functions and phi/psi angle free energies. It is also possible with EDM to create a tunable mixture of the experimental data and free energy of the unbiased ensemble with explicit ratios. EDM can be proven to be convergent, and we also present proof, via a maximum entropy argument, that the final bias is minimal and unique. Examples of its use are given in the construction of ensembles that follow a desired free energy. The example systems studied include a Lennard-Jones fluid made to match a radial distribution function, an atomistic model augmented with bioinformatics data, and a three component electrolyte solution where ab initio simulation data is used to improve a classical empirical model. PMID- 26575546 TI - EOMIP-CCSD(2)*: an efficient method for the calculation of ionization potentials. AB - A new approximation within the domain of EOMIP-CC method is proposed. The proposed scheme is based on the perturbative truncation of the similarity transformed effective Hamiltonian matrix. We call it the EOMIP-CCSD(2)* method, which scales as noniterative N(6) and its storage requirement is very less, compared to the conventional EOMIP-CCSD method. The existing EOMIP-CCSD(2) method has a tendency to overestimate the ionization potential (IP) values. On the other hand, our new strategy corrects for the problem of such an overestimation, which is evident from the excellent agreement achieved with the experimental values. Furthermore, not only the ionization potential but also geometry and IR frequencies of problematic double radicals are estimated correctly, and the results are comparable to the CCSD(T) method, obviously at lesser computational cost. The EOMIP-CCSD(2)* method works even for the core ionization and satellite IP, where the earlier EOMIP-CCSD(2) approximation dramatically fails. PMID- 26575547 TI - Accurate description of intermolecular interactions involving ions using symmetry adapted perturbation theory. AB - Three new data sets for intermolecular interactions, AHB21 for anion-neutral dimers, CHB6 for cation-neutral dimers, and IL16 for ion pairs, are assembled here, with complete-basis CCSD(T) results for each. These benchmarks are then used to evaluate the accuracy of the single-exchange approximation that is used for exchange energies in symmetry-adapted perturbation theory (SAPT), and the accuracy of SAPT based on wave function and density-functional descriptions of the monomers is evaluated. High-level SAPT calculations afford poor results for these data sets, and this includes the recently proposed "gold", "silver", and "bronze standards" of SAPT, namely, SAPT2+(3)-deltaMP2/aug-cc-pVTZ, SAPT2+/aug-cc pVDZ, and sSAPT0/jun-cc-pVDZ, respectively [ Parker , T. M. , et al. , J. Chem. Phys. 2014 , 140 , 094106 ]. Especially poor results are obtained for symmetric shared-proton systems of the form X(-)...H(+)...X(-), for X = F, Cl, or OH. For the anionic data set, the SAPT2+(CCD)-deltaMP2/aug-cc-pVTZ method exhibits the best performance, with a mean absolute error (MAE) of 0.3 kcal/mol and a maximum error of 0.7 kcal/mol. For the cationic data set, the highest-level SAPT method, SAPT2+3-deltaMP2/aug-cc-pVQZ, outperforms the rest of the SAPT methods, with a MAE of 0.2 kcal/mol and a maximum error of 0.4 kcal/mol. For the ion-pair data set, the SAPT2+3-deltaMP2/aug-cc-pVTZ performs the best among all SAPT methods with a MAE of 0.3 kcal/mol and a maximum error of 0.9 kcal/mol. Overall, SAPT2+3 deltaMP2/aug-cc-pVTZ affords a small and balanced MAE (<0.5 kcal/mol) for all three data sets, with an overall MAE of 0.4 kcal/mol. Despite the breakdown of perturbation theory for ionic systems at short-range, SAPT can still be saved given two corrections: a "deltaHF" correction, which requires a supermolecular Hartree-Fock calculation to incorporate polarization effects beyond second order, and a "deltaMP2" correction, which requires a supermolecular MP2 calculation to account for higher-order induction-dispersion coupling. These corrections serve to remove artifacts introduced by the single exchange approximation in the exchange-induction and exchange-dispersion interactions, and obviate the need for ad hoc scaling of the first- and second-order exchange energies. Finally, some density-functional and MP2-based electronic structure methods are assessed as well, and we find that the best density-functional method for computing binding energies in these data sets is B97M-V/aug-cc-pVTZ, which affords a MAE of 0.4 kcal/mol, whereas complete-basis MP2 affords an MAE of 0.3 kcal/mol. PMID- 26575548 TI - Can density cumulant functional theory describe static correlation effects? AB - We evaluate the performance of density cumulant functional theory (DCT) for capturing static correlation effects. In particular, we examine systems with significant multideterminant character of the electronic wave function, such as the beryllium dimer, diatomic carbon, m-benzyne, 2,6-pyridyne, twisted ethylene, as well as the barrier for double-bond migration in cyclobutadiene. We compute molecular properties of these systems using the ODC-12 and DC-12 variants of DCT and compare these results to multireference configuration interaction and multireference coupled-cluster theories, as well as single-reference coupled cluster theory with single, double (CCSD), and perturbative triple excitations [CCSD(T)]. For all systems the DCT methods show intermediate performance between that of CCSD and CCSD(T), with significant improvement over the former method. In particular, for the beryllium dimer, m-benzyne, and 2,6-pyridyne, the ODC-12 method along with CCSD(T) correctly predict the global minimum structures, while CCSD predictions fail qualitatively, underestimating the multireference effects. Our results suggest that the DC-12 and ODC-12 methods are capable of describing emerging static correlation effects but should be used cautiously when highly accurate results are required. Conveniently, the appearance of multireference effects in DCT can be diagnosed by analyzing the DCT natural orbital occupations, which are readily available at the end of the energy computation. PMID- 26575549 TI - Generalized valence bond description of the ground states (X(1)Sigmag(+)) of homonuclear pnictogen diatomic molecules: N2, P2, and As2. AB - The ground state, X1Sigmag+, of N2 is a textbook example of a molecule with a triple bond consisting of one sigma and two pi bonds. This assignment, which is usually rationalized using molecular orbital (MO) theory, implicitly assumes that the spins of the three pairs of electrons involved in the bonds are singlet coupled (perfect pairing). However, for a six-electron singlet state, there are five distinct ways to couple the electron spins. The generalized valence bond (GVB) wave function lifts this restriction, including all of the five spin functions for the six electrons involved in the bond. For N2, we find that the perfect pairing spin function is indeed dominant at Re but that it becomes progressively less so from N2 to P2 and As2. Although the perfect pairing spin function is still the most important spin function in P2, the importance of a quasi-atomic spin function, which singlet couples the spins of the electrons in the sigma orbitals while high spin coupling those of the electrons in the pi orbitals on each center, has significantly increased relative to N2 and, in As2, the perfect pairing and quasi-atomic spin couplings are on essentially the same footing. This change in the spin coupling of the electrons in the bonding orbitals down the periodic table may contribute to the rather dramatic decrease in the strengths of the Pn2 bonds from N2 to As2 as well as in the increase in their chemical reactivity and should be taken into account in more detailed analyses of the bond energies in these species. We also compare the spin coupling in N2 with that in C2, where the quasi-atomic spin coupling dominants around Re. PMID- 26575550 TI - Establishing the catalytic mechanism of human pancreatic alpha-amylase with QM/MM methods. AB - In this work, we studied the catalytic mechanism of human pancreatic alpha amylase (HPA). Our goal was to determine the catalytic mechanism of HPA with atomic detail using computational methods. We demonstrated that the HPA catalytic mechanism consists of two steps, the first of which (glycosylation step) involves breaking the glycosidic bond to culminate in the formation of a covalent intermediate. The second (deglycosylation step) consists of the addition of a water molecule to release the enzyme/substrate covalent intermediate, completing the hydrolysis of the sugar. The active site was very open to the solvent. Our mechanism basically differs from the previously proposed mechanism by having two water molecules instead of only one near the active site that participate in the mechanism. We also demonstrate the relevant role of the three catalytic amino acids, two aspartate residues and a glutamate (D197, E233, and D300), during catalysis. It was also shown that the rate limiting step was glycosylation, and its activation energy was in agreement with experimental values obtained for HPA. The experimental activation energy was 14.4 kcal mol(-1), and the activation energy obtained computationally was 15.1 kcal mol(-1). PMID- 26575551 TI - Automated discovery of reaction pathways, rate constants, and transition states using reactive molecular dynamics simulations. AB - We provide a methodology for deducing quantitative reaction models from reactive molecular dynamics simulations by identifying, quantifying, and evaluating elementary reactions of classical trajectories. Simulations of the inception stage of methane oxidation are used to demonstrate our methodology. The agreement of pathways and rates with available literature data reveals the potential of reactive molecular dynamics studies for developing quantitative reaction models. PMID- 26575552 TI - Include dispersion in quantum chemical modeling of enzymatic reactions: the case of isoaspartyl dipeptidase. AB - The lack of dispersion in the B3LYP functional has been proposed to be the main origin of big errors in quantum chemical modeling of a few enzymes and transition metal complexes. In this work, the essential dispersion effects that affect quantum chemical modeling are investigated. With binuclear zinc isoaspartyl dipeptidase (IAD) as an example, dispersion is included in the modeling of enzymatic reactions by two different procedures, i.e., (i) geometry optimizations followed by single-point calculations of dispersion (approach I) and (ii) the inclusion of dispersion throughout geometry optimization and energy evaluation (approach II). Based on a 169-atom chemical model, the calculations show a qualitative consistency between approaches I and II in energetics and most key geometries, demonstrating that both approaches are available with the latter preferential since both geometry and energy are dispersion-corrected in approach II. When a smaller model without Arg233 (147 atoms) was used, an inconsistency was observed, indicating that the missing dispersion interactions are essentially responsible for determining equilibrium geometries. Other technical issues and mechanistic characteristics of IAD are also discussed, in particular with respect to the effects of Arg233. PMID- 26575553 TI - Linear basis function approach to efficient alchemical free energy calculations. 2. Inserting and deleting particles with coulombic interactions. AB - We extend our previous linear basis function approach for alchemical free energy calculations to the insertion and deletion of charged particles in dense fluids. We compute a near optimal statistical path to introduce Coulombic interactions into various molecules in solution and find that this near optimal path is only marginally more efficient than simple linear coupling of electrostatics in all cases where a repulsive core is already present. We also explore the order in which nonbonded forces are coupled to the environment in alchemical transformations. We test two sets of Lennard-Jones basis functions, a Weeks Chandler-Andersen (WCA) and a 12-6 decomposition of the repulsive and attractive forces turned on in sequence along with changes in charge, to determine a statistically optimized order in which forces should be coupled. The WCA decomposition has lower statistical uncertainty as coupling the attractive r(-6) basis function contributes non-negligible statistical error. In all cases, the charge should be coupled only after the repulsive core is fully coupled, and the WCA attractive portion can be coupled at any stage without significantly changing the efficiency. The statistical uncertainty of two of the basis function approaches with charged particles is nearly identical to the soft core approach for decoupling electrostatics, though the correlation times for sampling are often longer for a soft core electrostatics approach than the basis function approach. The basis function approach for introducing or removing molecules or functional groups thus represents a useful alternative to the soft core approach with a number of clear computational advantages. PMID- 26575554 TI - Targeting electrostatic interactions in accelerated molecular dynamics with application to protein partial unfolding. AB - Accelerated molecular dynamics (aMD) is a promising sampling method to generate an ensemble of conformations and to explore the free energy landscape of proteins in explicit solvent. Its success resides in its ability to reduce barriers in the dihedral and the total potential energy space. However, aMD simulations of large proteins can generate large fluctuations of the dihedral and total potential energy with little conformational changes in the protein structure. To facilitate wider conformational sampling of large proteins in explicit solvent, we developed a direct intrasolute electrostatic interactions accelerated MD (DISEI-aMD) approach. This method aims to reduce energy barriers within rapidly changing electrostatic interactions between solute atoms at short-range distances. It also results in improved reconstruction quality of the original statistical ensemble of the system. Recently, we characterized a pH-dependent partial unfolding of diphtheria toxin translocation domain (T-domain) using microsecond long MD simulations. In this work, we focus on the study of conformational changes of a low-pH T-domain model in explicit solvent using DISEI-aMD. On the basis of the simulations of the low-pH T-domain model, we show that the proposed sampling method accelerates conformational rearrangement significantly faster than multiple standard aMD simulations and microsecond long conventional MD simulations. PMID- 26575555 TI - Enhancing constant-pH simulation in explicit solvent with a two-dimensional replica exchange method. AB - We present a new method for enhanced sampling for constant-pH simulations in explicit water based on a two-dimensional (2D) replica exchange scheme. The new method is a significant extension of our previously developed constant-pH simulation method, which is based on enveloping distribution sampling (EDS) coupled with a one-dimensional (1D) Hamiltonian exchange method (HREM). EDS constructs a hybrid Hamiltonian from multiple discrete end state Hamiltonians that, in this case, represent different protonation states of the system. The ruggedness and heights of the hybrid Hamiltonian's energy barriers can be tuned by the smoothness parameter. Within the context of the 1D EDS-HREM method, exchanges are performed between replicas with different smoothness parameters, allowing frequent protonation-state transitions and sampling of conformations that are favored by the end-state Hamiltonians. In this work, the 1D method is extended to 2D with an additional dimension, external pH. Within the context of the 2D method (2D EDS-HREM), exchanges are performed on a lattice of Hamiltonians with different pH conditions and smoothness parameters. We demonstrate that both the 1D and 2D methods exactly reproduce the thermodynamic properties of the semigrand canonical (SGC) ensemble of a system at a given pH. We have tested our new 2D method on aspartic acid, glutamic acid, lysine, a four residue peptide (sequence KAAE), and snake cardiotoxin. In all cases, the 2D method converges faster and without loss of precision; the only limitation is a loss of flexibility in how CPU time is employed. The results for snake cardiotoxin demonstrate that the 2D method enhances protonation-state transitions, samples a wider conformational space with the same amount of computational resources, and converges significantly faster overall than the original 1D method. PMID- 26575556 TI - Multistate lambda-local-elevation umbrella-sampling (MS-lambda-LEUS): method and application to the complexation of cations by crown ethers. AB - An extension of the lambda-local-elevation umbrella-sampling (lambda-LEUS) scheme [ Bieler et al. J. Chem. Theory Comput. 2014 , 10 , 3006 ] is proposed to handle the multistate (MS) situation, i.e. the calculation of the relative free energies of multiple physical states based on a single simulation. The key element of the MS-lambda-LEUS approach is to use a single coupling variable Lambda controlling successive pairwise mutations between the states of interest in a cyclic fashion. The Lambda variable is propagated dynamically as an extended-system variable, using a coordinate transformation with plateaus and a memory-based biasing potential as in lambda-LEUS. Compared to other available MS schemes (one-step perturbation, enveloping distribution sampling and conventional lambda-dynamics) the proposed method presents a number of important advantages, namely: (i) the physical states are visited explicitly and over finite time periods; (ii) the extent of unphysical space required to ensure transitions is kept minimal and, in particular, one-dimensional; (iii) the setup protocol solely requires the topologies of the physical states; and (iv) the method only requires limited modifications in a simulation code capable of handling two-state mutations. As an initial application, the absolute binding free energies of five alkali cations to three crown ethers in three different solvents are calculated. The results are found to reproduce qualitatively the main experimental trends and, in particular, the experimental selectivity of 18C6 for K(+) in water and methanol, which is interpreted in terms of opposing trends along the cation series between the solvation free energy of the cation and the direct electrostatic interactions within the complex. PMID- 26575557 TI - Scalable evaluation of polarization energy and associated forces in polarizable molecular dynamics: II. Toward massively parallel computations using smooth particle mesh Ewald. AB - In this article, we present a parallel implementation of point dipole-based polarizable force fields for molecular dynamics (MD) simulations with periodic boundary conditions (PBC). The smooth particle mesh Ewald technique is combined with two optimal iterative strategies, namely, a preconditioned conjugate gradient solver and a Jacobi solver in conjunction with the direct inversion in the iterative subspace for convergence acceleration, to solve the polarization equations. We show that both solvers exhibit very good parallel performances and overall very competitive timings in an energy and force computation needed to perform a MD step. Various tests on large systems are provided in the context of the polarizable AMOEBA force field as implemented in the newly developed Tinker HP package, which is the first implementation of a polarizable model that makes large-scale experiments for massively parallel PBC point dipole models possible. We show that using a large number of cores offers a significant acceleration of the overall process involving the iterative methods within the context of SPME and a noticeable improvement of the memory management, giving access to very large systems (hundreds of thousands of atoms) as the algorithm naturally distributes the data on different cores. Coupled with advanced MD techniques, gains ranging from 2 to 3 orders of magnitude in time are now possible compared to nonoptimized, sequential implementations, giving new directions for polarizable molecular dynamics with periodic boundary conditions using massively parallel implementations. PMID- 26575558 TI - Molecular simulation workflows as parallel algorithms: the execution engine of Copernicus, a distributed high-performance computing platform. AB - Computational chemistry and other simulation fields are critically dependent on computing resources, but few problems scale efficiently to the hundreds of thousands of processors available in current supercomputers-particularly for molecular dynamics. This has turned into a bottleneck as new hardware generations primarily provide more processing units rather than making individual units much faster, which simulation applications are addressing by increasingly focusing on sampling with algorithms such as free-energy perturbation, Markov state modeling, metadynamics, or milestoning. All these rely on combining results from multiple simulations into a single observation. They are potentially powerful approaches that aim to predict experimental observables directly, but this comes at the expense of added complexity in selecting sampling strategies and keeping track of dozens to thousands of simulations and their dependencies. Here, we describe how the distributed execution framework Copernicus allows the expression of such algorithms in generic workflows: dataflow programs. Because dataflow algorithms explicitly state dependencies of each constituent part, algorithms only need to be described on conceptual level, after which the execution is maximally parallel. The fully automated execution facilitates the optimization of these algorithms with adaptive sampling, where undersampled regions are automatically detected and targeted without user intervention. We show how several such algorithms can be formulated for computational chemistry problems, and how they are executed efficiently with many loosely coupled simulations using either distributed or parallel resources with Copernicus. PMID- 26575559 TI - Why do TD-DFT excitation energies of BODIPY/Aza-BODIPY families largely deviate from experiment? Answers from electron correlated and multireference methods. AB - The vertical excitation energies of 17 boron-dipyrromethene (BODIPY) core structures with a variety of substituents and ring sizes are benchmarked using time-dependent density functional theory (TD-DFT) with nine different functionals combined with the cc-pVTZ basis set. When compared to experimental measurements, all functionals provide mean absolute errors (mean AEs) greater than 0.3 eV, larger than the 0.1-0.3 eV differences typically expected from TD-DFT. Due to the high linear correlation of TD-DFT results with experiment, most functionals can be used to predict excitation energies if corrected empirically. Using the CAM B3LYP functional, 0-0 transition energies are determined, and while the absolute difference is improved (mean AE = 0.478 eV compared to 0.579 eV), the correlation diminishes substantially (R(2) = 0.961 to 0.862). Two very recently introduced charge transfer (CT) indices, q(CT) and d(CT), and electron density difference (EDD) plots demonstrate that CT does not play a significant role for most of the BODIPYs examined and, thus, cannot be the source of error in TD-DFT. To assess TD DFT methods, vertical excitation energies are determined utilizing TD-HF, configuration interaction CIS and CIS(D), equation of motion EOM-CCSD, SAC-CI, and Laplace-transform based local coupled-cluster singles and approximate doubles LCC2* methods. Moreover, multireference CASSCF and CASPT2 vertical excitation energies were also obtained for all species (except CASPT2 was not feasible for the four largest systems). The SAC-CI/cc-pVDZ, LCC2*/cc-pVDZ, and CASPT2/cc-pVDZ approaches are shown to have the smallest mean AEs of 0.154, 0.109, and 0.100 eV, respectively; the utility of the LCC2* approach is demonstrated for eight extended BODIPYs and aza-BODIPYs. We found that the problems with TD-DFT arise from difficulties in dealing with the differential electron correlation (as assessed by comparing CCS, CC2, LR-CCSD, CCSDR(T), and CCSDR(3) vertical excitation energies for five compounds) and from contributions of multireference character and double excitations (from analysis of the CASSCF wave functions). PMID- 26575560 TI - Understanding the origin of the VCD signals on the basis of a nonredundant coordinate definition. AB - The relationships between the chiroptical activity and the vibrational normal modes of epichlorohydrin have been investigated on the basis of a nonredundant internal coordinate definition not reported until now. These coordinates were verified by comparing, for the lower energy conformers, the diagonal quadratic force constants and were found to display similar values among conformers and to be consistent with the molecular structure of epichlorohydrin and its vibrational circular dichroism (VCD) spectrum. Boltzmann population factors were used to calculate the weighted sum of the individual VCD and IR spectra of the three lower energy conformers, which accurately fitted the experimental spectra of (R) epichlorohydrin. The electric and magnetic transition dipole moments of the 24 vibrational normal modes were calculated for the most stable conformers. The combined analysis of these vectors and the normal mode description, given in terms of the potential energy distribution, allowed us to investigate the role of the functional groups (methylene, chlorine) and the type of internal coordinates (stretching, bending, etc.) in the chiroptical activity of the vibrations. PMID- 26575561 TI - Bright fission: singlet fission into a pair of emitting states. AB - This paper reintroduces and explores the generation of two bright states from a single photon via a singlet fission mechanism in organic materials. This particular photophysical process is labeled here as bright fission (BF). The central part of the study is devoted to set the theoretical foundations of BF by discussing possible electronic mechanisms, the role of different excited states with various physical nature, the presence of competing deactivation channels, and the possible requirements for the BF viability. In a second part, some of the properties related to BF are computationally explored in anthracene. The analysis of computed high-lying excited states identifies several optical transitions as good candidates to trigger BF in anthracene. The approximation of excitonic couplings of these high energy levels to other electronic states within the same energy range suggests possible paths to populate electronic configurations potentially able to split in two independent spin singlets, i.e. singlet-singlet states. The study also explores the electronic structure of the energetically lowest singlet-singlet states in anthracene dimers and discusses the presence of charge transfer configurations and their relation to the singlet-singlet manifold. The computational results suggest fast relaxation to the lowest singlet singlet state, from which the excitonic fission may occur. All in all, the present work aims at motivating to pursue further efforts in the study of the BF process in organic materials. PMID- 26575562 TI - Electronic excitation energies in dimers between radical ions presenting long, multicenter bonding. AB - The formation of long, multicenter dimers between radical ions is usually monitored through UV-vis spectroscopy given the characteristic low-energy absorption band that they exhibit, not observed for the parent monomers. In this work, the performance of CASPT2, RASPT2, and TD-DFT methods for obtaining excitation energies of the long, multicenter bonded pi-[TCNE]2(2-) and pi [TTF]2(2+) dimers has been addressed (TCNE = tetracyanoethylene; TTF = tetrathiafulvalene). The impact of the active space on the vertical electronic transitions computed at the RASPT2 and CASPT2 levels has been tested against experimentally observed absorption bands. Analogous tests have been carried out for a wide variety of density functionals within the TD-DFT formalism. Our calculations show that whereas CASPT2 predicts very accurate excitation energies for the pi-[TCNE]2(2-), the mean absolute error for pi-[TTF]2(2+) is higher for CASPT2 than for TD-DFT calculations, whenever pure density functionals or low % HF exchange hybrid functionals are used. Hybrid functionals with high % HF exchange (and thus RSH functionals) conduct to large errors on the excitation energies in both dimers. Furthermore, vertical electronic transitions are also obtained for 100 configurations extracted from a 45 ps molecular dynamics (CPMD) simulation aimed at providing an accurate description of the thermal fluctuation effects of a pi-[TCNE]2(2-) dimer in dichloromethane. These thermal effects explain the shape of the experimental UV-vis spectrum, where the lowest HOMO -> LUMO absorption presents a broad band and the following HOMO-1 -> LUMO absorption exhibits a narrower band. PMID- 26575563 TI - Simulating the reactions of CO2 in aqueous monoethanolamine solution by reaction ensemble Monte Carlo using the continuous fractional component method. AB - Molecular simulations were used to compute the equilibrium concentrations of the different species in CO2/monoethanolamine solutions for different CO2 loadings. Simulations were performed in the Reaction Ensemble using the continuous fractional component Monte Carlo method at temperatures of 293, 333, and 353 K. The resulting computed equilibrium concentrations are in excellent agreement with experimental data. The effect of different reaction pathways was investigated. For a complete understanding of the equilibrium speciation, it is essential to take all elementary reactions into account because considering only the overall reaction of CO2 with MEA is insufficient. The effects of electrostatics and intermolecular van der Waals interactions were also studied, clearly showing that solvation of reactants and products is essential for the reaction. The Reaction Ensemble Monte Carlo using the continuous fractional component method opens the possibility of investigating the effects of the solvent on CO2 chemisorption by eliminating the need to study different reaction pathways and concentrate only on the thermodynamics of the system. PMID- 26575564 TI - Large scale GW calculations. AB - We present GW calculations of molecules, ordered and disordered solids and interfaces, which employ an efficient contour deformation technique for frequency integration and do not require the explicit evaluation of virtual electronic states nor the inversion of dielectric matrices. We also present a parallel implementation of the algorithm, which takes advantage of separable expressions of both the single particle Green's function and the screened Coulomb interaction. The method can be used starting from density functional theory calculations performed with semilocal or hybrid functionals. We applied the newly developed technique to GW calculations of systems of unprecedented size, including water/semiconductor interfaces with thousands of electrons. PMID- 26575565 TI - Extended Lagrangian formulation of charge-constrained tight-binding molecular dynamics. AB - The extended Lagrangian Born-Oppenheimer molecular dynamics formalism [Niklasson, Phys. Rev. Lett., 2008, 100, 123004] has been applied to a tight-binding model under the constraint of local charge neutrality to yield microcanonical trajectories with both precise, long-term energy conservation and a reduced number of self-consistent field optimizations at each time step. The extended Lagrangian molecular dynamics formalism restores time reversal symmetry in the propagation of the electronic degrees of freedom, and it enables the efficient and accurate self-consistent optimization of the chemical potential and atomwise potential energy shifts in the on-site elements of the tight-binding Hamiltonian that are required when enforcing local charge neutrality. These capabilities are illustrated with microcanonical molecular dynamics simulations of a small metallic cluster using an sd-valent tight-binding model for titanium. The effects of weak dissipation on the propagation of the auxiliary degrees of freedom for the chemical potential and on-site Hamiltonian matrix elements that is used to counteract the accumulation of numerical noise during trajectories was also investigated. PMID- 26575566 TI - Multiscale modeling of drug-polymer nanoparticle assembly identifies parameters influencing drug encapsulation efficiency. AB - Using a multiscale (dual resolution) approach combining an atomistic (GROMOS96) and coarse-grain (MARTINI) force field, we have been able to simulate the process of drug-polymer nanoparticle assembly by nanoprecipitation from mixed solvents. Here, we present the development and application of this method to the interaction of three poly(glycerol adipate) polymer variants with the anticancer drug dexamethasone phosphate. Differences in encapsulation efficiency and drug loading between the polymers are in agreement with the experimental trend. Reference atomistic simulations at key points along the predicted aggregation pathway support the accuracy of the much more computationally efficient multiscale methodology. PMID- 26575567 TI - How the intercalation of phenanthroline affects the structure, energetics, and bond properties of DNA base pairs: theoretical study applied to adenine-thymine and guanine-cytosine tetramers. AB - The effects of phenanthroline (phen) intercalation on the structure, energetics, and bonding of adenine-thymine and guanine-cytosine tetramers (A-T/T-A and G-C/C G) were studied through density functional theory (DFT) using functionals that were recently improved to consider the effect of dispersion forces. Our results given by energy decomposition analysis show that the dispersion contribution, DeltaEdisp, is the most important contribution to the interaction energy, DeltaEint. However, it is not enough to compensate the Pauli repulsion term, DeltaEPauli, and the roles of the orbital contribution, DeltaEorb, and, in particular, the electrostatic contribution, DeltaEelstat, become crucial for the stabilization of the structures in the intercalation process. On the other hand, for G-C/C-G systems, hydrogen-bonding (HB) interactions are more important than stacking (S) interactions, whereas for A-T/T-A systems, HB and S become competitive. Moreover, intercalation produces important changes not only in the hydrogen bonds of base pairs, because S and HB are deeply connected, but also in other characteristic geometric parameters of the base pairs. PMID- 26575568 TI - Exploring free energy landscapes of large conformational changes: molecular dynamics with excited normal modes. AB - Proteins are found in solution as ensembles of conformations in dynamic equilibrium. Exploration of functional motions occurring on micro- to millisecond time scales by molecular dynamics (MD) simulations still remains computationally challenging. Alternatively, normal mode (NM) analysis is a well-suited method to characterize intrinsic slow collective motions, often associated with protein function, but the absence of anharmonic effects preclude a proper characterization of conformational distributions in a multidimensional NM space. Using both methods jointly appears to be an attractive approach that allows an extended sampling of the conformational space. In line with this view, the MDeNM (molecular dynamics with excited normal modes) method presented here consists of multiple-replica short MD simulations in which motions described by a given subset of low-frequency NMs are kinetically excited. This is achieved by adding additional atomic velocities along several randomly determined linear combinations of NM vectors, thus allowing an efficient coupling between slow and fast motions. The relatively high-energy conformations generated with MDeNM are further relaxed with standard MD simulations, enabling free energy landscapes to be determined. Two widely studied proteins were selected as examples: hen egg lysozyme and HIV-1 protease. In both cases, MDeNM provides a larger extent of sampling in a few nanoseconds, outperforming long standard MD simulations. A high degree of correlation with motions inferred from experimental sources (X-ray, EPR, and NMR) and with free energy estimations obtained by metadynamics was observed. Finally, the large sets of conformations obtained with MDeNM can be used to better characterize relevant dynamical populations, allowing for a better interpretation of experimental data such as SAXS curves and NMR spectra. PMID- 26575569 TI - Comparison of molecular contours for measuring writhe in atomistic supercoiled DNA. AB - DNA molecular center-lines designed from atomistic-resolution structures are compared for the evaluation of the writhe in supercoiled DNA using molecular dynamics simulations of two sets of minicircles with 260 and 336 base pairs. We present a new method called WrLINE that systematically filters out local (i.e., subhelical turn) irregularities using a sliding-window averaged over a single DNA turn and that provides a measure of DNA writhe that is suitable for comparing atomistic resolution data with those obtained from measurements of the global molecular shape. In contrast, the contour traced by the base-pair origins defined by the 3DNA program largely overestimates writhe due to the helical periodicity of DNA. Nonetheless, this local modulation of the molecular axis emerges as an internal mechanism for the DNA to confront superhelical stress, where the adjustment between low and high twist is coupled to a high and low local periodicity, respectively, mimicking the different base-stacking conformational space of A and B canonical DNA forms. PMID- 26575570 TI - Free energy surface of an intrinsically disordered protein: comparison between temperature replica exchange molecular dynamics and bias-exchange metadynamics. AB - Intrinsically disordered proteins (IDPs), which are expected to be largely unstructured under physiological conditions, make up a large fraction of eukaryotic proteins. Molecular dynamics simulations have been utilized to probe structural characteristics of these proteins, which are not always easily accessible to experiments. However, exploration of the conformational space by brute force molecular dynamics simulations is often limited by short time scales. Present literature provides a number of enhanced sampling methods to explore protein conformational space in molecular simulations more efficiently. In this work, we present a comparison of two enhanced sampling methods: temperature replica exchange molecular dynamics and bias exchange metadynamics. By investigating both the free energy landscape as a function of pertinent order parameters and the per-residue secondary structures of an IDP, namely, human islet amyloid polypeptide, we found that the two methods yield similar results as expected. We also highlight the practical difference between the two methods by describing the path that we followed to obtain both sets of data. PMID- 26575571 TI - Automated parametrization of the coarse-grained Martini force field for small organic molecules. AB - The systematic exploration of chemical compound space holds many promises toward structure-function relationships and material design. In the context of computer simulations, progress is hampered by both the sheer number of compounds and the efforts associated with parametrizing a force field for every new molecule. A coarse-grained (CG) representation provides not only a reduced phase space but also a smaller number of compounds, due to the redundancy of CG representations mapping to the same structure. Though many CG models require the explicit force field parametrization of a molecule with all others, others assume transferability by means of mixing rules, such as the Martini force field. To alleviate the burden associated with tedious parametrizations for each new compound, the present work aims at automating the mapping and parametrization of common small organic molecules for Martini. We test the method by analyzing the water/octanol partitioning of more than 650 neutral molecules, the hydration free energy of 354 others, and the free energies of hydration and solvation in octanol of another 69 compounds. Last, we compare with all-atom simulations the thermodynamics of insertion of four individual solute molecules in a phospholipid membrane. The protocol demonstrates the feasibility of an automated parametrization scheme for Martini and provides prospects for high-throughput simulation methodologies. PMID- 26575572 TI - A new force field of formamide and the effect of the dielectric constant on miscibility. AB - Current force fields underestimate significantly the dielectric constant of formamide at standard conditions. We present a derivation of an accurate potential for formamide, with a functional form based on the OPLS/AA force field. Our procedure follows the approach introduced by Salas et al. ( J. Chem. Theory Comput. 2015 , 11 , 683 - 693 ) that relies on ab initio calculations and molecular dynamics simulations. We consider several strategies to derive the atomic charges of formamide. We find that the inclusion of polarization effects in the quantum mechanical computations is essential to obtain reliable force fields. By varying the atomic charges and the Lennard-Jones parameters describing the dispersion interactions in the OPLS/AA force field, we derive an optimum set of parameters that provides accurate results for the dielectric constant, surface tension, and bulk density of liquid formamide in a wide range of thermodynamic states. We test the transferability of our parameters to investigate liquid/liquid mixtures. We have chosen as case study an equimolar mixture of formamide and hexan-2-one. This mixture involves two fluids with very different polar characteristics, namely, large differences in their dielectric constants and their performance as solvents. The new potential predicts a liquid/liquid phase separation, in good agreement with experimental data, and highlights the importance of the correct parametrization of the pure liquid phases to investigate liquid mixtures. Finally, we examine the microscopic origin of the observed inmiscibility between formamide and hexa-2-one. PMID- 26575573 TI - Kinetic network models of tryptophan mutations in beta-hairpins reveal the importance of non-native interactions. AB - We present an analysis of the most extensive explicit-solvent simulations of beta hairpins to date (9.4 ms in aggregate), with the aim of probing the effects of tryptophan mutations on folding. From molecular simulations of GB1 hairpin, trpzip4, trpzip5, and trpzip6 performed on Folding@home, Markov State Models (MSMs) were constructed using a unified set of metastable states, enabling objective comparison of folding mechanisms. MSM models display quantitative agreement with experimental structural observables and folding kinetics, and predict multimodal kinetics due to specific non-native kinetic traps, which be identified as on- or off-pathway from the network topology. We quantify kinetic frustration by several means, including the s-ensemble method to evaluate glasslike behavior. Free-energy profiles and transition state movement clearly show stabilization of non-native states as Trp mutations are introduced. Remarkably, we find that "beta-capped" sequences (trpzip4 and trpzip5) are able to overcome this frustration and remain cooperative two-state folders with a large time-scale gap. These results suggest that, while beta-capping motifs are robust, fold stabilization by tryptophan generally may require overcoming significant non-native kinetic traps, perhaps explaining their under representation in natural proteins. PMID- 26575574 TI - A coarse-grained simulation study of the structures, energetics, and dynamics of linear and circular DNA with its ions. AB - We have studied the structural, energetics, and dynamical properties of a variety of linear and circular DNA fragments using a solvent-mediated coarse-grained (CG) model of DNA with explicit ions recently developed by us [Naome et al., J. Chem. Theory Comput., 2014, 10, 3541-3549]. We particularly examined the treatment of electrostatics and determined that a large cutoff is necessary to properly reproduce the DNA flexibility. Moreover, it is crucial to include long-ranged electrostatic interactions: a Particle Mesh Ewald scheme at low resolution is sufficient to avoid structural artifacts. We calculated the ring closure probabilities, as j-factors, for DNA fragments of different lengths from equilibrium, as well as restrained molecular dynamics (MD) simulations. The latter force integration method provided accurate results without model fitting. We generated topology and energy maps for DNA minicircles of various lengths and helical densities, at low and high ion concentrations. A general trend for structure compaction is observed, driven by an increase in writhing as the ionic concentration increases. Finally, we applied a reconstruction procedure to generate detailed molecular structures from the various superhelical conformations generated by the CG MD of the DNA minicircles. These pre equilibrated reconstructed atomistic structures can serve as starting material for atomistic simulations. PMID- 26575575 TI - pKa values in proteins determined by electrostatics applied to molecular dynamics trajectories. AB - For a benchmark set of 194 measured pKa values in 13 proteins, electrostatic energy computations are performed in which pKa values are computed by solving the Poisson-Boltzmann equation. In contrast to the previous approach of Karlsberg(+) (KB(+)) that essentially used protein crystal structures with variations in their side chain conformations, the present approach (KB2(+)MD) uses protein conformations from four molecular dynamics (MD) simulations of 10 ns each. These MD simulations are performed with different specific but fixed protonation patterns, selected to sample the conformational space for the different protonation patterns faithfully. The root-mean-square deviation between computed and measured pKa values (pKa RMSD) is shown to be reduced from 1.17 pH units using KB(+) to 0.96 pH units using KB2(+)MD. The pKa RMSD can be further reduced to 0.79 pH units, if each conformation is energy-minimized with a dielectric constant of epsilonmin = 4 prior to calculating the electrostatic energy. The electrostatic energy expressions upon which the computations are based have been reformulated such that they do not involve terms that mix protein and solvent environment contributions and no thermodynamic cycle is needed. As a consequence, conformations of the titratable residues can be treated independently in the protein and solvent environments. In addition, the energy terms used here avoid the so-called intrinsic pKa and can therefore be interpreted without reference to arbitrary protonation states and conformations. PMID- 26575576 TI - CoMoDo: identifying dynamic protein domains based on covariances of motion. AB - Most large proteins are built of several domains, compact units which enable functional protein motions. Different domain assignment approaches exist, which mostly rely on concepts of stability, folding, and evolution. We describe the automatic assignment method CoMoDo, which identifies domains based on protein dynamics. Covariances of atomic fluctuations, here calculated by an Elastic Network Model, are used to group residues into domains of different hierarchical levels. The so-called dynamic domains facilitate the study of functional protein motions involved in biological processes like ligand binding and signal transduction. By applying CoMoDo to a large number of proteins, we demonstrate that dynamic domains exhibit features absent in the commonly assigned structural domains, which can deliver insight into the interactions between domains and between subunits of multimeric proteins. CoMoDo is distributed as free open source software at www.bisb.uni-bayreuth.de/CoMoDo.html . PMID- 26575577 TI - Accurate Diels-Alder reaction energies from efficient density functional calculations. AB - We assess the performance of the semilocal PBE functional; its global hybrid variants; the highly parametrized empirical M06-2X and M08-SO; the range separated rCAM-B3LYP and MCY3; the atom-pairwise or nonlocal dispersion corrected semilocal PBE and TPSS; the dispersion corrected range-separated omegaB97X-D; the dispersion corrected double hybrids such as PWPB95-D3; the direct random phase approximation, dRPA, with Hartree-Fock, Perdew-Burke-Ernzerhof, and Perdew-Burke Ernzerhof hybrid reference orbitals and the RPAX2 method based on a Perdew-Burke Ernzerhof exchange reference orbitals for the Diels-Alder, DARC; and self interaction error sensitive, SIE11, reaction energy test sets with large, augmented correlation consistent valence basis sets. The dRPA energies for the DARC test set are extrapolated to the complete basis set limit. CCSD(T)/CBS energies were used as a reference. The standard global hybrid functionals show general improvements over the typical endothermic energy error of semilocal functionals, but despite the increased accuracy the precision of the methods increases only slightly, and thus all reaction energies are simply shifted into the exothermic direction. Dispersion corrections give mixed results for the DARC test set. Vydrov-Van Voorhis 10 correction to the reaction energies gives superior quality results compared to the too-small D3 correction. Functionals parametrized for energies of noncovalent interactions like M08-SO give reasonable results without any dispersion correction. The dRPA method that seamlessly and theoretically correctly includes noncovalent interaction energies gives excellent results with properly chosen reference orbitals. As the results for the SIE11 test set and H2(+) dissociation show that the dRPA methods suffer from delocalization error, good reaction energies for the DARC test set from a given method do not prove that the method is free from delocalization error. The RPAX2 method shows good performance for the DARC, the SIE11 test sets, and for the H2(+) and H2 potential energy curves showing no one-electron self-interaction error and reduced static correlation errors at the same time. We also suggest simplified DARC6 and SIE9 test sets for future benchmarking. PMID- 26575578 TI - Correction to a solvent-mediated coarse-grained model of DNA derived with the systematic newton inversion method. PMID- 26575579 TI - Fungal biodiversity in the periglacial soil of Dosde Glacier (Valtellina, Northern Italy). AB - Periglacial areas are one of the least studied habitats on Earth, especially in terms of their fungal communities. In this work, both molecular and culture dependent methods have been used to analyse the microfungi in soils sampled on the front of the East Dosde Glacier (Valtellina, Northern Italy). Although this survey revealed a community that was rich in fungal species, a distinct group of psychrophilic microfungi has not been detected. Most of the isolated microfungi were mesophiles, which are well adapted to the sensitive climatic changes that occur in this alpine environment. A discrepancy in the results that were obtained by means of the two diagnostic approaches suggests that the used molecular methods cannot entirely replace traditional culture-dependent methods, and vice versa. PMID- 26575580 TI - Evaluation of Novel Chalcone Oximes as Inhibitors of Tyrosinase and Melanin Formation in B16 Cells. AB - A series of hydroxy-substituted chalcone oxime derivatives were synthesized. These compounds were then evaluated for their inhibitory activities on tyrosinase and melanogenesis in murine B16F10 melanoma cells. The structures of the synthesized compounds were confirmed by (1) H NMR, (13) C NMR, FTIR, and HRMS. Two of the compounds exhibited much higher tyrosinase inhibitory activities (IC50 values of 4.77 and 7.89 MUM, respectively) than the positive control, kojic acid (IC50 : 22.25 MUM). Kinetic studies revealed them to act as competitive tyrosinase inhibitors with their Ki values of 5.25 and 8.33 MUM, respectively. Both the compounds inhibited melanin production and tyrosinase activity in B16 cells. Docking results confirmed that the active inhibitors strongly interacted with the mushroom tyrosinase residues. PMID- 26575581 TI - Failure to Obtain Computed Tomography Imaging in Head Trauma: A Review of Relevant Case Law. AB - OBJECTIVES: The objectives were to describe lawsuits against providers for failing to order head computed tomography (CT) in cases of head trauma and to determine the potential effects of available clinical decision rules (CDRs) on each lawsuit. METHODS: The authors collected jury verdicts, settlements, and court opinions regarding alleged malpractice for failure to order head CT in the setting of head trauma from 1972 through February 2014 from an online legal research tool (WestlawNext). Data were abstracted onto a standardized data form. The performance of five CDRs was evaluated. RESULTS: Sixty relevant cases were identified (52 adult, eight children). Of 48 cases with known outcomes, providers were found negligent in 10 cases (six adult, four pediatric), settled in 11 cases (nine adult, two pediatric), and were found not liable in 27 cases. In all 10 cases in which providers were found negligent, every applicable CDR studied would have indicated the need for head CT. In all eight cases involving children, the applicable CDR would have suggested the need for head CT or observation. CONCLUSIONS: A review of legal cases reported in a major online legal research system revealed 60 lawsuits in which providers were sued for failing to order head CTs in cases of head trauma. In all cases in which providers were found negligent, CT imaging or observation would have been indicated by every applicable CDR. PMID- 26575582 TI - Development of 2-(Substituted Benzylamino)-4-Methyl-1, 3-Thiazole-5-Carboxylic Acid Derivatives as Xanthine Oxidase Inhibitors and Free Radical Scavengers. AB - A series of 2-(substituted benzylamino)-4-methylthiazole-5-carboxylic acid was designed and synthesized as structural analogue of febuxostat. A methylene amine spacer was incorporated between the phenyl ring and thiazole ring in contrast to febuxostat in which the phenyl ring was directly linked with the thiazole moiety. The purpose of incorporating methylene amine was to provide a heteroatom which is expected to favour hydrogen bonding within the active site residues of the enzyme xanthine oxidase. The structure of all the compounds was established by the combined use of FT-IR, NMR and MS spectral data. All the compounds were screened in vitro for their ability to inhibit the enzyme xanthine oxidase as per the reported procedure along with DPPH free radical scavenging assay. Compounds 5j, 5k and 5l demonstrated satisfactory potent xanthine oxidase inhibitory activities with IC50 values, 3.6, 8.1 and 9.9 MUm, respectively, whereas compounds 5k, 5n and 5p demonstrated moderate antioxidant activities having IC50 15.3, 17.6 and 19.6 MUm, respectively, along with xanthine oxidase inhibitory activity. Compound 5k showed moderate xanthine oxidase inhibitory activity as compared with febuxostat along with antioxidant activity. All the compounds were also studied for their binding affinity in active site of enzyme (PDB ID-1N5X). PMID- 26575583 TI - MITF and cell migration: opposing signals, similar outcome. PMID- 26575584 TI - Inhibition of mitochondrial glutaminase activity reverses acquired erlotinib resistance in non-small cell lung cancer. AB - The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib has been approved based on the clinical benefit in non-small cell lung cancer (NSCLC) patients over the past decade. Unfortunately, cancer cells become resistant to this agent via various mechanisms, and this limits the improvement in patient outcomes. Thus, it is urgent to develop novel agents to overcome erlotinib resistance. Here, we propose a novel strategy to overcome acquired erlotinib resistance in NSCLC by inhibiting glutaminase activity. Compound 968, an inhibitor of the glutaminase C (GAC), when combined with erlotinib potently inhibited the cell proliferation of erlotinib-resistant NSCLC cells HCC827ER and NCI-H1975. The combination of compound 968 and erlotinib not only decreased GAC and EGFR protein expression but also inhibited GAC activity in HCC827ER cells. The growth of erlotinib-resistant cells was glutamine-dependent as proved by GAC gene knocked down and rescue experiment. More importantly, compound 968 combined with erlotinib down-regulated the glutamine and glycolysis metabolism in erlotinib-resistant cells. Taken together, our study provides a valuable approach to overcome acquired erlotinib resistance by blocking glutamine metabolism and suggests that combination of EGFR-TKI and GAC inhibitor maybe a potential treatment strategy for acquired erlotinib-resistant NSCLC. PMID- 26575585 TI - Influence of Root Canal Posts on the Reattachment of Fragments to Endodontically Treated Fractured Incisors: An in vitro Experimental Comparison. AB - OBJECTIVE: The aim of this study was to establish the benefits of inserting a fiberglass post when bonding tooth fragments after complicated coronal fractures. METHODS: Thirty bovine incisors were randomly assigned to three groups: a control group of intact teeth (A), and two experimental groups (B and C). Coronal fragments were cut from the teeth in groups B and C, which then underwent root canal treatment, inserting posts in the teeth in group C. The coronal fragments were bonded to the teeth in both experimental groups using the same materials and technique, then the specimens were submitted to mechanical loading until fracture. RESULTS: The specimens in the experimental groups had a lower resistance to mechanical loading than the intact teeth. The mean failure load was: 352.77 (SD +/- 62.22) N in group A, 151.04 (SD +/- 45.76) N in group B, and 168.61 (SD +/- 33.59) N in group C. The difference between group A and the other two groups was statistically significant (analysis of variance test: p < 0.0001), whereas there was no statistically significant difference in the force needed to fracture the teeth in groups B and C (Tukey's test: p = 0.34). When the failure mode under loading was examined, the fractures in group C never involved new tooth substance beneath the adhesion interface, whereas in group B, this was only true in one in two cases. CONCLUSIONS: Inserting a post does not significantly improve the strength of restored teeth, but it may result in a more favorable fracture mode. CLINICAL SIGNIFICANCE: Within the limitations of this in vitro study, reattaching the fragment of a fractured tooth does not seem to restore the tooth to its original load resistance. The findings of this study indicate that inserting a fiberglass post for reinforcement purposes in fractured teeth undergoing root canal treatment is unable to significantly improve their load bearing capacity by comparison with teeth repaired without inserting a post. However, the results of the present study suggest that inserting a post may result in a more favorable fracture mode in the event of further trauma. PMID- 26575586 TI - Electrical Characteristics of the Junction between PEDOT:PSS and Thiophene Functionalized Silicon Microwires. AB - Thiophene moieties have been attached to Si microwires (Si MWs) by a two-step chlorination/alkylation reaction method. X-ray photoelectron spectroscopy indicated that saturation of the surface occurred after 30 min of reaction time. Electrical measurements using a standard probe station indicated that the junction between individual thiophene-functionalized Si MWs and the conducting polymer poly(3,4-ethylenedioxythiophene)/poly(styrenesulfonate) ( PEDOT: PSS) became more ohmic as more thiophene was added to the MW surface. Under a light limited current of 20 nA, representative of operation of Si MWs under 1 Sun illumination conditions, the iR loss of thiophene-n-Si MW/PEDOT-PSS contacts was 20 mV, representing an order of magnitude reduction compared with PEDOT-PSS junctions formed with methyl terminated n-Si MWs. Such iR losses are much less than typical catalytic overpotentials for fuel formation, and hence the thiophene functionalized Si MW contacts will not limit the performance of a Si MW array based solar fuels device under 1 Sun illumination. PMID- 26575587 TI - A novel deletion mutation in the ALOX12B gene in a Kurdish family with autosomal recessive congenital ichthyosis. PMID- 26575589 TI - Preparation of Anisotropic and Oriented Particles on a Flexible Substrate. AB - Elongated plasmonic nanoparticles show superior optical properties when compared to spherical ones. Facile, versatile and cost-effective bottom-up approaches for fabrication of anisotropic nanoparticles in solution have been developed. However, fabrication of 2-D plasmonic templates from elongated nanoparticles with spatial arrangement at the surface is still a challenge. We used controlled seed mediated growth in the presence of porous and functionalized surface of flexible polydimethylsiloxane (PDMS) templates to provide directional growth and formation of elongated gold nanoparticles (AuNPs). Atomic force microscopy (AFM) and spectroscopy revealed embedding of the particles within the functionalized porous surface of PDMS. Nanoparticles shapes were observed with transmission electron microscope (TEM), UV-Vis spectroscopy, and X-ray powder diffraction (XRPD) measurements, which revealed an overall orientation of particles at the surface. Anisotropic and oriented particles on a flexible substrate are of interest for sensing applications. PMID- 26575588 TI - Recollection. PMID- 26575590 TI - Density-Functional Theory Molecular Dynamics Simulations and Experimental Characterization of a-Al2O3/SiGe Interfaces. AB - Density-functional theory molecular dynamics simulations were employed to investigate direct interfaces between a-Al2O3 and Si0.50Ge0.50 with Si- and Ge terminations. The simulated stacks revealed mixed interfacial bonding. While Si-O and Ge-O bonds are unlikely to be problematic, bonding between Al and Si or Ge could result in metallic bond formation; however, the internal bonds of a-Al2O3 are sufficiently strong to allow just weak Al bonding to the SiGe surface thereby preventing formation of metallic-like states but leave dangling bonds. The oxide/SiGe band gaps were unpinned and close to the SiGe bulk band gap. The interfaces had SiGe dangling bonds, but they were sufficiently filled that they did not produce midgap states. Capacitance-voltage (C-V) spectroscopy and angle resolved X-ray photoelectron spectroscopy experimentally confirmed formation of interfaces with low interface trap density via direct bonding between a-Al2O3 and SiGe. PMID- 26575592 TI - Formal [3 + 2]-Cycloaddition of Donor-Acceptor Cyclopropanes to 1,3-Dienes: Cyclopentane Assembly. AB - We report a new simple method to access highly substituted cyclopentanes via Lewis acid-initiated formal [3 + 2]-cycloaddition of donor-acceptor cyclopropanes to 1,3-dienes. This process displays exceptional chemo- and regioselectivity as well as high diastereoselectivity, allowing for the synthesis of functionalized cyclopentanes and bicyclic cyclopentane-based structures in moderate to high yields. Moreover, one-pot synthesis of biologically relevant cyclopentafuranones, based on reaction of donor-acceptor cyclopropanes with dienes, has been developed. PMID- 26575591 TI - Lysine Acetylation Facilitates Spontaneous DNA Dynamics in the Nucleosome. AB - The nucleosome, comprising a histone protein core wrapped around by DNA, is the fundamental packing unit of DNA in cells. Lysine acetylation at the histone core elevates DNA accessibility in the nucleosome, the mechanism of which remains largely unknown. By employing our recently developed hybrid single molecule approach, here we report how the structural dynamics of DNA in the nucleosome is altered upon acetylation at histone H3 lysine 56 (H3K56) that is critical for elevated DNA accessibility. Our results indicate that H3K56 acetylation facilitates the structural dynamics of the DNA at the nucleosome termini that spontaneously and repeatedly open and close on a ms time scale. The results support a molecular mechanism of histone acetylation in catalyzing DNA unpacking whose efficiency is ultimately limited by the spontaneous DNA dynamics at the nucleosome temini. This study provides the first and unique experimental evidence revealing a role of protein chemical modification in directly regulating the kinetic stability of the DNA packing unit. PMID- 26575593 TI - Enhanced Inactivation of Escherichia coli and MS2 Coliphage by Cupric Ion in the Presence of Hydroxylamine: Dual Microbicidal Effects. AB - The inactivation of Escherichia coli and MS2 coliphage by Cu(II) is found to be significantly enhanced in the presence of hydroxylamine (HA). The addition of a small amount of HA (i.e., 5-20 MUM) increased the inactivation efficacies of E. coli and MS2 coliphage by 5- to 100-fold, depending on the conditions. Dual effects were anticipated to enhance the biocidal activity of Cu(II) by the addition of HA, viz. (i) the accelerated reduction of Cu(II) into Cu(I) (a stronger biocide) and (ii) the production of reactive oxidants from the reaction of Cu(I) with dissolved oxygen (evidenced by the oxidative transformation of methanol into formaldehyde). Deaeration enhanced the inactivation of E. coli but slightly decreased the inactivation efficacy of MS2 coliphage. The addition of 10 MUM hydrogen peroxide (H2O2) greatly enhanced the MS2 inactivation, whereas the same concentration of H2O2 did not significantly affect the inactivation efficacy of E. coli Observations collectively indicate that different biocidal actions lead to the inactivation of E. coli and MS2 coliphage. The toxicity of Cu(I) is dominantly responsible for the E. coli inactivation. However, for the MS2 coliphage inactivation, the oxidative damage induced by reactive oxidants is as important as the effect of Cu(I). PMID- 26575594 TI - Recent Applications for in Vitro Antioxidant Activity Assay. AB - This review presents some of the most recent aspects related to antioxidants and the basic kinetic models of inhibited autoxidation and analyzes the chemical principles of antioxidant capacity assays. Taking into account the reactions involved, in the antioxidant activity determinations, the assays can be classified into two main types: hydrogen atom transfer reactions and electron transfer. This review focuses on analytical methods used for antioxidant activity assay, published in the period 2009-2014. PMID- 26575595 TI - Hydride in BaTiO2.5H0.5: A Labile Ligand in Solid State Chemistry. AB - In synthesizing mixed anion oxides, direct syntheses have often been employed, usually involving high temperature and occasionally high pressure. Compared with these methods, here we show how the use of a titanium perovskite oxyhydride (BaTiO2.5H0.5) as a starting material enables new multistep low temperature topochemical routes to access mixed anion compounds. Similar to labile ligands in inorganic complexes, the lability of H(-) provides the necessary reactivity for syntheses, leading to reactions and products previously difficult to obtain. For example, BaTiO2.5N0.2 can be prepared with the otherwise inert N2 gas at 400-600 degrees C, in marked contrast with currently available oxynitride synthetic routes. F(-)/H(-) exchange can also be accomplished at 150 degrees C, yielding the oxyhydride-fluoride BaTi(O, H, F)3. For BaTiO2.4D0.3F0.3, we find evidence that further anionic exchange with OD(-) yields BaTiO2.4(D(-))0.26(OD(-))0.34, which implies stable coexistence of H(+) and H(-) at ambient conditions. Such an arrangement is thermodynamically unstable and would be difficult to realize otherwise. These results show that the labile nature of hydride imparts reactivity to oxide hosts, enabling it to participate in new multistep reactions and form new materials. PMID- 26575596 TI - Society for Pediatric Research 2015 Young Investigator Award: genetics of human hematopoiesis-what patients can teach us about blood cell production. AB - Blood cell production or hematopoiesis is one of the most well-understood paradigms of cell differentiation in the body. The majority of work on hematopoiesis comes from studies that have primarily been conducted in mice, zebrafish, or other valuable model systems. However, it is clear that such model organisms may not consistently and faithfully mimic what is observed in humans with blood disorders. Moreover, there is significant divergence between species that is increasingly being appreciated at the genomic level. As a result, there is an opportunity to use observations in humans to provide a refined view of hematopoiesis. Here, we discuss vignettes from our work that illustrate how insight from human genetics can improve our understanding of blood cell production and identify promising therapeutic approaches for blood disorders. PMID- 26575597 TI - Heterogeneous ageing of skeletal muscle microvascular function. AB - The distribution of blood flow to skeletal muscle during exercise is altered with advancing age. Changes in arteriolar function that are muscle specific underlie age-induced changes in blood flow distribution. With advancing age, functional adaptations that occur in resistance arterioles from oxidative muscles differ from those that occur in glycolytic muscles. Age-related adaptations of morphology, as well as changes in both endothelial and vascular smooth muscle signalling, differ in muscle of diverse fibre type. Age-induced endothelial dysfunction has been reported in most skeletal muscle arterioles; however, unique alterations in signalling contribute to the dysfunction in arterioles from oxidative muscles as compared with those from glycolytic muscles. In resistance arterioles from oxidative muscle, loss of nitric oxide signalling contributes significantly to endothelial dysfunction, whereas in resistance arterioles from glycolytic muscle, alterations in both nitric oxide and prostanoid signalling underlie endothelial dysfunction. Similarly, adaptations of the vascular smooth muscle that occur with advancing age are heterogeneous between arterioles from oxidative and glycolytic muscles. In both oxidative and glycolytic muscle, late life exercise training reverses age-related microvascular dysfunction, and exercise training appears to be particularly effective in reversing endothelial dysfunction. Patterns of microvascular ageing that develop among muscles of diverse fibre type and function may be attributable to changing patterns of physical activity with ageing. Importantly, aerobic exercise training, initiated even at an advanced age, restores muscle blood flow distribution patterns and vascular function in old animals to those seen in their young counterparts. PMID- 26575598 TI - Force-Induced Rupture of a DNA Duplex: From Fundamentals to Force Sensors. AB - The rupture of double-stranded DNA under stress is a key process in biophysics and nanotechnology. In this article, we consider the shear-induced rupture of short DNA duplexes, a system that has been given new importance by recently designed force sensors and nanotechnological devices. We argue that rupture must be understood as an activated process, where the duplex state is metastable and the strands will separate in a finite time that depends on the duplex length and the force applied. Thus, the critical shearing force required to rupture a duplex depends strongly on the time scale of observation. We use simple models of DNA to show that this approach naturally captures the observed dependence of the force required to rupture a duplex within a given time on duplex length. In particular, this critical force is zero for the shortest duplexes, before rising sharply and then plateauing in the long length limit. The prevailing approach, based on identifying when the presence of each additional base pair within the duplex is thermodynamically unfavorable rather than allowing for metastability, does not predict a time-scale-dependent critical force and does not naturally incorporate a critical force of zero for the shortest duplexes. We demonstrate that our findings have important consequences for the behavior of a new force-sensing nanodevice, which operates in a mixed mode that interpolates between shearing and unzipping. At a fixed time scale and duplex length, the critical force exhibits a sigmoidal dependence on the fraction of the duplex that is subject to shearing. PMID- 26575599 TI - The Early Development of Wheeze. Environmental Determinants and Genetic Susceptibility at 17q21. AB - RATIONALE: Growing up on a farm protects from childhood asthma and early wheeze. Virus-triggered wheeze in infancy predicts asthma in individuals with a genetic asthma risk associated with chromosome 17q21. OBJECTIVES: To test environmental determinants of infections and wheeze in the first year of life, potential modifications of these associations by 17q21, and the implications for different trajectories of wheeze. METHODS: We followed 983 children in rural areas of Europe from birth until age 6 years. Symptoms of wheeze, rhinitis, fever, and environmental exposures were documented with weekly diaries during year 1. Asthma at age 6 was defined as ever having a reported doctor's diagnosis. Single nucleotide polymorphisms related to ORMDL3 (rs8076131) and GSDMB (rs7216389, rs2290400) at 17q21 were genotyped. MEASUREMENTS AND MAIN RESULTS: Early wheeze was positively associated with presence of older siblings among carriers of known asthma risk alleles at 17q21 (e.g., rs8076131) (adjusted odds ratio [aOR], 1.53; 95% confidence interval [CI], 1.16-2.01). Exposure to farm animal sheds was inversely related to wheeze (aOR, 0.44; 95% CI, 0.33-0.60). Both effects were similarly observed in children with transient wheeze up to age 3 years without subsequent development of asthma (aOR, 1.71 [95% CI, 1.09-2.67]; and aOR, 0.48 [95% CI, 0.30-0.76], respectively). CONCLUSIONS: These findings suggest that the chromosome 17q21 locus relates to episodes of acute airway obstruction common to both transient wheeze and asthma. The previously identified asthma risk alleles are the ones susceptible to environmental influences. Thus, this gene-environment interaction reveals two faces of 17q21: The same genotype constitutes genetic risk and allows for environmental protection, thereby providing options for prospective prevention strategies. PMID- 26575600 TI - Limb-Threatening Acute Venous Thromboembolism in a Patient Undergoing Postarrest Therapeutic Hypothermia. AB - Postcardiac arrest patients are at high risk for developing venous thromboembolism (VTE). Current postarrest guidelines do not provide recommendations for prevention or surveillance of VTE and there is little guidance regarding the optimal prophylaxis or treatment of VTE during therapeutic hypothermia (TH). Many patients develop acute liver dysfunction resulting from severe global hypoperfusion during cardiac arrest, compounding concerns for bleeding with the initiation of TH. However, significant VTE may occur following arrest and can contribute to additional morbidity and mortality. The pharmacokinetics of anticoagulation, the routine treatment for VTE, have not been extensively researched or tested under hypothermic conditions. Standard approaches for prevention and treatment have been utilized, such as unfractionated heparin, but their efficacy remains uncertain. This case illustrates the significant imbalance of coagulation in a postcardiac arrest patient undergoing TH. PMID- 26575601 TI - New-onset type 2 diabetes, elevated HbA1c, anti-diabetic medications, and risk of pancreatic cancer. AB - BACKGROUND: Associations between type 2 diabetes, anti-diabetic medications and pancreatic cancer are controversial. This study aims to clarify such associations with new-onset type 2 diabetes and repeated measurements of glycated haemoglobin (HbA1c) levels. METHODS: A nested case-control study was initiated from the Health Improvement Network (THIN) in UK from 1996 to 2010. Information of pancreatic cancer cases was retrieved electronically from the medical records and manually validated. Control subjects were randomly selected and frequency-matched to the cases on sex, age, and calendar years. Multivariable unconditional logistic regression was performed to estimate odds ratios (OR) and 95% confidence intervals (CI), and adjusted for potential confounders. RESULTS: Among 1,574,768 person-years of follow-up, 529 pancreatic cancer cases and 5000 controls were identified. Type 2 diabetes, or changed HbA1c levels (rather than HbA1c levels at diabetes diagnosis) in diabetes patients (?4 mmol mol(-1) compared with <0 mmol mol(-1)) were followed by an increased OR of pancreatic cancer (OR, 2.16, 95% CI 1.72-2.72 and OR, 5.06, 95% CI 1.52-16.87, respectively). Among the anti-diabetic medications in diabetes patients, the OR for insulin users was 25.57 (95% CI 11.55-56.60), sulphonylureas 2.22 (95% CI 1.13, 4.40), and metformin users 1.46 (95% CI 0.85-2.52), compared with no use of any anti-diabetic medications. CONCLUSIONS: New-onset type 2 diabetes and, particularly, diabetes with rising HbA1c seem to be independent risk factors for pancreatic cancer. The relation between different anti-diabetic medications and pancreatic cancer seems to vary in strength, with the highest risk among users of insulin. PMID- 26575602 TI - Sexual healthcare professionals' views on HPV vaccination for men in the UK. AB - BACKGROUND: Human Papillomavirus (HPV) vaccination for men could prevent anal cancers amongst men who have sex with men (MSM). METHODS: An e-survey of attitudes towards vaccination for men in the UK was conducted in July-August 2014. RESULTS: Among 325 sexual health professionals, 14% were already vaccinating men against HPV, 83% recommended gender-neutral HPV vaccination and 65% recommended targeting MSM. Over 50% reported having poor knowledge about the use of HPV vaccine for MSM and the skills to identify MSM likely to benefit from HPV vaccination. CONCLUSIONS: Clear advice and guidelines on HPV vaccine use for men at sexual health clinics are required to ensure equitable opportunities for vaccination. PMID- 26575603 TI - Clinico-pathological nomogram for predicting BRAF mutational status of metastatic colorectal cancer. AB - BACKGROUND: In metastatic colorectal cancer (mCRC), BRAFV600E mutation has been variously associated to specific clinico-pathological features. METHODS: Two large retrospective series of mCRC patients from two Italian Institutions were used as training-set (TS) and validation-set (VS) for developing a nomogram predictive of BRAFV600E status. The model was internally and externally validated. RESULTS: In the TS, data from 596 mCRC patients were gathered (RAS wild-type (wt) 281 (47.1%); BRAFV600E mutated 54 (9.1%)); RAS and BRAFV600E mutations were mutually exclusive. In the RAS-wt population, right-sided primary (odds ratio (OR): 7.80, 95% confidence interval (CI) 3.05-19.92), female gender (OR: 2.90, 95% CI 1.14-7.37) and mucinous histology (OR: 4.95, 95% CI 1.90-12.90) were independent predictors of BRAFV600E mutation, with high replication at internal validation (100%, 93% and 98%, respectively). A predictive nomogram was calculated: patients with the highest score (right-sided primary, female and mucinous) had a 81% chance to bear a BRAFV600E-mutant tumour; accuracy measures: AUC=0.812, SE:0.034, sensitivity:81.2%; specificity:72.1%. In the VS (508 pts, RAS wt: 262 (51.6%), BRAFV600E mutated: 49 (9.6%)), right-sided primary, female gender and mucinous histology were confirmed as independent predictors of BRAFV600E mutation with high accuracy. CONCLUSIONS: Three simple and easy-to collect characteristics define a useful nomogram for predicting BRAF status in mCRC with high specificity and sensitivity. PMID- 26575604 TI - Social network typologies and mortality risk among older people in China, India, and Latin America: A 10/66 Dementia Research Group population-based cohort study. AB - BACKGROUND: Restricted social networks have been associated with higher mortality in several developed countries but there are no studies on this topic from developing countries. This gap exists despite potentially greater dependence on social networks for support and survival due to various barriers to health care and social protection schemes in this setting. Thus, this study aims to examine how social network type at baseline predicts all-cause mortality among older adults in six Latin American countries, China, and India. METHODS: Population based surveys were conducted of all individuals aged 65+ years in eight countries (Cuba, Dominican Republic, Peru, Venezuela, Mexico, Puerto Rico, China, and India). Data on mortality were obtained at follow-up (mean 3.8 years after cohort inception). Follow-up data for 13,891 individuals were analysed. Social network types were assessed using Wenger's Practitioner Assessment of Network Type (PANT). Cox proportional hazard models were constructed to estimate the impact of social network type on mortality risk in each country, adjusting for socio demographics, receipt of pension, disability, medical conditions, and depression. Meta-analysis was performed to obtain pooled estimates. RESULTS: The prevalence of private network type was 64.4% in urban China and 1.6% in rural China, while the prevalence of locally integrated type was 6.6% in urban China and 86.8% in rural China. The adjusted pooled estimates across (a) all countries and (b) Latin America showed that, compared to the locally integrated social network type, the locally self-contained [(b) HR = 1.24, 95% CI 1.01-1.51], family dependent [(a) HR = 1.13, 95% CI 1.01-1.26; (b) HR = 1.13, 95% CI 1.001-1.28], and private [(a) HR = 1.36, 95% CI 1.06-1.73; (b) HR = 1.45, 95% CI 1.20-1.75] social network types were significantly associated with higher mortality risk. CONCLUSION: Survival time is significantly reduced in individuals embedded in restricted social networks (i.e. locally self-contained, family dependent, and private network types). Social care interventions may be enhanced by addressing the needs of those most at risk of neglect and deteriorating health. Health policy makers in developing countries may use this information to plan efficient use of limited resources by targeting those embedded in restricted social networks. PMID- 26575605 TI - Subjective relative deprivation is associated with poorer physical and mental health. AB - Substantial epidemiological evidence has shown that income inequality and objective measures of relative deprivation are associated with poorer health outcomes. However, surprisingly little research has examined whether subjective feelings of relative deprivation are similarly linked with poorer health outcomes. The relative deprivation hypothesis suggests that inequality affects health at the individual level through negative consequences of social comparison. We directly examined the relationship between subjective feelings of personal relative deprivation and self-reported physical and mental health in a diverse community sample (n = 328). Results demonstrated that subjective feelings of personal relative deprivation are associated with significantly poorer physical and mental health. These relationships held even when accounting for covariates that have been previously associated with both relative deprivation and health. These results further support the link between relative deprivation and health outcomes and suggest that addressing root causes of relative deprivation may lead to greater individual health. PMID- 26575606 TI - Lifetime risk of developing impaired glucose metabolism and eventual progression from prediabetes to type 2 diabetes: a prospective cohort study. AB - BACKGROUND: Data are scarce for the lifetime risk of developing impaired glucose metabolism, including prediabetes, as are data for the risk of eventual progression from prediabetes to diabetes and for initiation of insulin treatment in previously untreated patients with diabetes. We aimed to calculate the lifetime risk of the full range of glucose impairments, from normoglycaemia to prediabetes, type 2 diabetes, and eventual insulin use. METHODS: In this prospective population-based cohort analysis, we used data from the population based Rotterdam Study. We identified diagnostic events by use of general practitioners' records, hospital discharge letters, pharmacy dispensing data, and serum fasting glucose measurements taken at the study centre (Rotterdam, Netherlands) visits. Normoglycaemia, prediabetes, and diabetes were defined on the basis of WHO criteria for fasting glucose (normoglycaemia: <=6.0 mmol/L; prediabetes: >6.0 mmol/L and <7.0 mmol/L; and diabetes >=7.0 mmol/L or use of glucose-lowering drug). We calculated lifetime risk using a modified version of survival analysis adjusted for the competing risk of death. We also estimated the lifetime risk of progression from prediabetes to overt diabetes and from diabetes free of insulin treatment to insulin use. Additionally, we calculated years lived with healthy glucose metabolism. FINDINGS: We used data from 10 050 participants from the Rotterdam Study. During a follow-up of up to 14.7 years (between April 1, 1997, and Jan 1, 2012), 1148 participants developed prediabetes, 828 developed diabetes, and 237 started insulin treatment. At age 45 years, the remaining lifetime risk was 48.7% (95% CI 46.2-51.3) for prediabetes, 31.3% (29.3-33.3) for diabetes, and 9.1% (7.8-10.3) for insulin use. In individuals aged 45 years, the lifetime risk to progress from prediabetes to diabetes was 74.0% (95% CI 67.6 80.5), and 49.1% (38.2-60.0) of the individuals with overt diabetes at this age started insulin treatment. The lifetime risks attenuated with advancing age, but increased with increasing BMI and waist circumference. On average, individuals with severe obesity lived 10 fewer years without glucose impairment compared with normal-weight individuals. INTERPRETATION: Impaired glucose metabolism is a substantial burden on population health, and our findings emphasise the need for more effective prevention strategies, which should be implemented as soon in a person's life as possible. The substantial lifetime risk of prediabetes and diabetes in lean individuals also supports risk factor control in non-obese individuals. FUNDING: Erasmus MC and Erasmus University Rotterdam; Netherlands Organisation for Scientific Research; Netherlands Organisation for Health Research and Development; Research Institute for Diseases in the Elderly; Netherlands Genomics Initiative; Netherlands Ministry of Education, Culture and Science; Netherlands Ministry of Health, Welfare and Sports; European Commission; and Municipality of Rotterdam. PMID- 26575607 TI - Type 2 diabetes: lifetime risk of advancing from prediabetes. PMID- 26575608 TI - Endocrine-disrupting chemicals and the diabetes epidemic in countries in the WHO South-East Asia region. PMID- 26575610 TI - Correction: Fungal Infection Induces Sex-Specific Transcriptional Changes and Alters Sexual Dimorphism in the Dioecious Plant Silene latifolia. PMID- 26575609 TI - Fat4 suppression induces Yap translocation accounting for the promoted proliferation and migration of gastric cancer cells. AB - Fat4 functions as a Hippo signaling regulator which is involved in mammalian tissue development, differentiation and tumorigenesis. Loss of Fat4 due to frequent gene mutation was detected in a variety of tumors including gastric cancer, where Fat4 was recognized as a tumor suppressor, repressing cancer cell proliferation and adhesion. However, the detailed mechanisms linking Fat4 to its diverse functions and clinicopathological characteristics in gastric cancer remain unclear. Here, we silenced Fat4 using Fat4-shRNA in gastric cancer cells and found that this suppression led to the increase in phosphorylated Yap and nuclear accumulation of Yap, which associated to the promoted proliferation, migration and cell cycle progression. Then we transfected a full-length Fat4 into the Fat4-silenced cells, and found the decrease in phosphorylated Yap and inhibition of the cell cycle progression. Intriguingly, Fat4 reduction also leads to the accumulation of cytoplasmic beta-catenin via the loss of restraining to cytoplasmic Yap instead of beta-catenin transcription promotion. The Fat4 silenced cells which were treated with 5-FU, Cisplatin, Oxaliplatin and Paclitaxel individually demonstrated less sensitivities to these chemotherapy drugs compared with the control cells. Furthermore, immunohistochemical analysis revealed that Fat4 expression was significantly reduced in gastric cancer tissues compared with adjacent noncancerous tissues, and negatively correlated with tumor infiltration, lymph node metastasis and cumulative survival rate. In conclusion, Fat4 expression is deceased in gastric cancer cells, leading to nuclear translocation of Yap and correlates with poor prognosis. PMID- 26575611 TI - Adherence and the Lie in a HIV Prevention Clinical Trial. AB - The lie has been presented as a performance that protects identities against moral judgment in the context of power imbalances. We explore this assertion from the perspective of a pre-exposure prophylaxis trial to prevent HIV for African women in South Africa, in which context biological evidence of widespread lying about product adherence was produced, resulting in a moral discourse that opposed altruistic and selfish motivations. In this article, we seek to understand the meaning of the lie from the perspective of women trial participants. Seeing the trial as representing a hopeful future, and perfect adherence as sustaining their investment in this, participants recited scripted accounts of adherence and performed the role of the perfect adherer, while identifying other participants as dishonest. Given that clinical trials create moral orders and adherence is key to this, we argue that women embraced the apparatus of the clinical trial to assert their moral subjectivities. PMID- 26575612 TI - [Disseminated intravascular coagulation: clinical and biological diagnosis]. AB - Disseminated intravascular coagulation (DIC) is a syndrome characterized by the systemic activation of blood coagulation. Its pathophysiological mechanisms are complex and dependent on the underlying pathology, making the clinical and biological expression of quite variable DIC. Among the various biological parameters disrupted, most are not specific, and none of them allows in itself to make the diagnosis. All this does not facilitate the task of the practitioner for diagnosis of overt DIC, much less that of the non-overt DIC, early stage whose treatment would improve the prognosis. These considerations have led to develop scores, combining several parameters depending on their availability in daily practice, as well as their diagnostic relevance. Of all the scores, the ISTH (International society of thrombosis and hemostasis) remains the most used. PMID- 26575613 TI - Reduction of urgency severity is the most important factor in the subjective therapeutic outcome of intravesical onabotulinumtoxinA injection for overactive bladder. AB - AIMS: This study investigated the relationship between the subjective outcome assessment and objective parameters after intravesical onabotulinumtoxinA injection in patients with overactive bladder (OAB). METHODS: A total of 77 consecutive patients with urodynamically confirmed detrusor overactivity were treated with intravesical 100 U of onabotulinumtoxinA in 20 divided injections (5 U in 0.5 ml normal saline each) at different sites sparing the trigone. The primary end-point was the change in the Global Response Assessment (GRA) 3 months after treatment. All patients were monitored monthly after treatment for up to 6 months. Patients were divided into successful and failed treatment groups according to change in their GRA (>=2 and <=1, respectively) at 3 months. The changes in voiding diary variables, Urgency Severity Score (USS), Overactive Bladder Symptom Score (OABSS), maximal bladder capacity (MBC), post-void residual (PVR) volume, and voiding efficiency (VE) were compared between groups at each time point. RESULTS: Overall, USS, OABSS, and MBC improved after treatment. Three months after BoNT-A injection, 49 (64%) patients reported an improvement in the GRA of 2 (n = 30) or 3 (n = 19). Patients with GRA >= 2 had significant improvements in OABSS at 3 months, and USS, OABSS, urgency urinary incontinence (UUI), and urgency episodes at 6 months compared with patients with GRA <= 1. No significant difference in MBC, PVR, or VE was noted between groups at 3 or 6 months. CONCLUSIONS: Subjectively successful treatment outcomes of intravesical onabotulinumtoxinA injection for OAB patients were associated with improvement in OAB symptoms but not increased bladder capacity. Neurourol. Urodynam. 36:338-343, 2017. (c) 2015 Wiley Periodicals, Inc. PMID- 26575614 TI - Drug outcome survey to evaluate anti-TNF treatment in rheumatoid arthritis: an Italian observational study (the DOSE study). AB - OBJECTIVES: The aim of this paper is to analyse the use of anti-TNF drugs in current Italian practice, evaluate clinical responses to treatment, and identify possible predictors of negative response in patients with rheumatoid arthritis (RA). METHODS: DOSE is a non-interventional, prospective study of patients with active RA treated for the first time with anti-TNF agents in 21 Italian hospitals. Demographic and clinical characteristics of patients, treatments and outcome measures were assessed. Outcome measures used were EULAR response, DAS28 remission and HAQ remission at 12 months. A stepwise logistic regression model was used to study the predictors of non-response. RESULTS: Of 299 RA patients (mean 53.8 +/- 12.8 years, 76.1% female), DAS28 was >5.1 in 60.5% of patients and HAQ was >1 in 65.9%. Etanercept was the most prescribed anti-TNF. DMARDs were used in 77.6% of patients (methotrexate in 59.2%). Significant improvements in clinical and laboratory parameters were observed at 12 months. The proportion of patients classed as non-responders remained high, and varied according to assessment criteria. The main predictors independently and significantly associated with a high risk of non-response were: age and female gender for all outcome criteria; high DAS28 value for disease remission; and HAQ >1 for disability remission. CONCLUSIONS: In Italian anti-TNF treatment for RA, age, gender, and high values of both disease activity and disability were predictors of non-response to first-line therapy with anti-TNF drugs. Future studies should consider optimal second-line therapies for RA patients who do not achieve remission to their first anti-TNF treatment. PMID- 26575615 TI - Streptococcus pneumoniae oropharyngeal colonization in school-age children and adolescents with type 1 diabetes mellitus: Impact of the heptavalent pneumococcal conjugate vaccine. AB - This study evaluated Streptococcus pneumoniae colonization in children and adolescents with type 1 diabetes mellitus (DM1) to investigate the theoretical risk of invasive pneumococcal disease (IPD) in these patients and the potential protective efficacy of pneumococcal conjugate vaccines (PCVs). An oropharyngeal swab was obtained from 299 patients aged 6-17 y with DM1 who were enrolled during routine clinical visits. DNA from swabs was analyzed for S. pneumoniae using real time polymerase chain reaction. S. pneumoniae was identified in the swabs of 148 subjects (49.8%). Colonization was strictly age-related and declined significantly in the group aged >=15 years (odds ratio [OR] 0.28; 95% confidence interval [CI], 0.14-0.57). Carriage was also significantly influenced by sex (lower in females: OR 0.56; 95% CI, 0.35-0.91), ethnicity (less common among non Caucasians: OR 0.34; 95% CI, 0.13-0.89), parental smoking habit (more frequent among children with at least one smoker between parents: OR 1.76; 95% CI, 0.90 2.07), and the administration of antibiotic therapy in the previous 3 months (less frequent among patients who received antibiotics: OR 0.21; 95% CI, 0.07 0.62). Multivariate analyses of the entire study population showed no association between carriage and PCV7 vaccination status. Serotypes 19F, 9V, and 4 were the most frequently identified serotypes. In conclusion, school-age children and adolescents with DM1 are frequently colonized by S. pneumoniae, and protection against pneumococcal carriage following infant and toddler vaccination was not effective after several years. Together with the need to increase vaccine uptake in all the children aged <2 years, these results suggest that PCV booster doses are needed in DM1 patients to maintain the protection offered by these vaccinations. PMID- 26575616 TI - Impact of different ratios of feedstock to liquid anaerobic digestion effluent on the performance and microbiome of solid-state anaerobic digesters digesting corn stover. AB - The objective of this study was to understand how the non-microbial factors of L AD effluent affected the microbiome composition and successions in the SS-AD digesters using both Illumina sequencing and qPCR quantification of major genera of methanogens. The SS-AD digesters started with a feedstock/total effluent (F/Et) ratio 2.2 (half of the effluent was autoclaved) performed stably, while the SS-AD digesters started with a 4.4 F/Et ratio (no autoclaved effluent) suffered from digester acidification, accumulation of volatile fatty acids, and ceased biogas production two weeks after startup. Some bacteria and methanogens were affected by non-microbial factors of the L-AD fluent. Alkalinity, the main difference between the two F/Et ratios, may be the crucial factor when SS-AD digesters were started using L-AD effluent. PMID- 26575617 TI - Comparison of digestate from solid anaerobic digesters and dewatered effluent from liquid anaerobic digesters as inocula for solid state anaerobic digestion of yard trimmings. AB - To select a proper inoculum for the solid state anaerobic digestion (SS-AD) of yard trimmings, digestate from solid anaerobic digesters and dewatered effluent from liquid anaerobic digesters were compared at substrate-to-inoculum (S/I) ratios from 0.2 to 2 (dry basis), and total solids (TS) contents from 20% to 35%. The highest methane yield of around 244L/kg VSfeed was obtained at an S/I ratio of 0.2 and TS content of 20% for both types of inoculum. The highest volumetric methane productivity was obtained with dewatered effluent at an S/I ratio of 0.6 and TS content of 24%. The two types of inoculum were found comparable regarding methane yields and volumetric methane productivities at each S/I ratio, while using dewatered effluent as inoculum reduced the startup time. An S/I ratio of 1 was determined to be a critical level and should be set as the upper limit for mesophilic SS-AD of yard trimmings. PMID- 26575618 TI - The dual effects of lignin content on enzymatic hydrolysis using film composed of cellulose and lignin as a structure model. AB - The degree of delignification during pretreatment is a critical question for economic conversion of biomass to sugar platform. Many models have been used to study the optimum lignin content in biomass, but few of them are able to study without disturbances, such as the complex component and structure of biomass. A novel film model composed of only cellulose and lignin was used to investigate the effect of lignin on enzymatic hydrolysis. High lignin-cellulose proportion (10.00-31.25%) hindered enzymatic hydrolysis, whereas low lignin-cellulose proportion (2.00-8.00%) showed a notable potential to promote enzymatic hydrolysis. The enzymatic hydrolysis rate of lignin-cellulose (6.00%) film was 11.5% higher than that of pure cellulose films. Further study indicated that the promotion was due to the enhancement of film porosity and roughness by residual lignin. Thus, based on the biomimetic model, excessive delignification is not recommended in view of efficient conversion and economy. PMID- 26575619 TI - Synchronized growth and neutral lipid accumulation in Chlorella sorokiniana FC6 IITG under continuous mode of operation. AB - Synchronized growth and neutral lipid accumulation with high lipid productivity under mixotrophic growth of the strain Chlorella sorokiniana FC6 IITG was achieved via manipulation of substrates feeding mode and supplementation of lipid elicitors in the growth medium. Screening and optimization of lipid elicitors resulted in lipid productivity of 110.59mgL(-1)day(-1) under the combined effect of lipid inducers sodium acetate and sodium chloride. Fed-batch cultivation of the strain in bioreactor with intermittent feeding of limiting nutrients and lipid inducer resulted in maximum biomass and lipid productivity of 2.08 and 0.97gL(-1)day(-1) respectively. Further, continuous production of biomass with concomitant lipid accumulation was demonstrated via continuous feeding of BG11 media supplemented with lipid inducers sodium acetate and sodium chloride. The improved biomass and lipid productivity in chemostat was found to be 2.81 and 1.27gL(-1)day(-1) respectively operated at a dilution rate of 0.54day(-1). PMID- 26575620 TI - A Structured Rehabilitation Protocol for Improved Multifunctional Prosthetic Control: A Case Study. AB - Advances in robotic systems have resulted in prostheses for the upper limb that can produce multifunctional movements. However, these sophisticated systems require upper limb amputees to learn complex control schemes. Humans have the ability to learn new movements through imitation and other learning strategies. This protocol describes a structured rehabilitation method, which includes imitation, repetition, and reinforcement learning, and aims to assess if this method can improve multifunctional prosthetic control. A left below elbow amputee, with 4 years of experience in prosthetic use, took part in this case study. The prosthesis used was a Michelangelo hand with wrist rotation, and the added features of wrist flexion and extension, which allowed more combinations of hand movements. The participant's Southampton Hand Assessment Procedure score improved from 58 to 71 following structured training. This suggests that a structured training protocol of imitation, repetition and reinforcement may have a role in learning to control a new prosthetic hand. A larger clinical study is however required to support these findings. PMID- 26575621 TI - Ultrasensitive gas detection of large-area boron-doped graphene. AB - Heteroatom doping is an efficient way to modify the chemical and electronic properties of graphene. In particular, boron doping is expected to induce a p type (boron)-conducting behavior to pristine (nondoped) graphene, which could lead to diverse applications. However, the experimental progress on atomic scale visualization and sensing properties of large-area boron-doped graphene (BG) sheets is still very scarce. This work describes the controlled growth of centimeter size, high-crystallinity BG sheets. Scanning tunneling microscopy and spectroscopy are used to visualize the atomic structure and the local density of states around boron dopants. It is confirmed that BG behaves as a p-type conductor and a unique croissant-like feature is frequently observed within the BG lattice, which is caused by the presence of boron-carbon trimers embedded within the hexagonal lattice. More interestingly, it is demonstrated for the first time that BG exhibits unique sensing capabilities when detecting toxic gases, such as NO2 and NH3, being able to detect extremely low concentrations (e.g., parts per trillion, parts per billion). This work envisions that other attractive applications could now be explored based on as-synthesized BG. PMID- 26575622 TI - Ryanodine receptor fragmentation and sarcoplasmic reticulum Ca2+ leak after one session of high-intensity interval exercise. AB - High-intensity interval training (HIIT) is a time-efficient way of improving physical performance in healthy subjects and in patients with common chronic diseases, but less so in elite endurance athletes. The mechanisms underlying the effectiveness of HIIT are uncertain. Here, recreationally active human subjects performed highly demanding HIIT consisting of 30-s bouts of all-out cycling with 4-min rest in between bouts (<=3 min total exercise time). Skeletal muscle biopsies taken 24 h after the HIIT exercise showed an extensive fragmentation of the sarcoplasmic reticulum (SR) Ca(2+) release channel, the ryanodine receptor type 1 (RyR1). The HIIT exercise also caused a prolonged force depression and triggered major changes in the expression of genes related to endurance exercise. Subsequent experiments on elite endurance athletes performing the same HIIT exercise showed no RyR1 fragmentation or prolonged changes in the expression of endurance-related genes. Finally, mechanistic experiments performed on isolated mouse muscles exposed to HIIT-mimicking stimulation showed reactive oxygen/nitrogen species (ROS)-dependent RyR1 fragmentation, calpain activation, increased SR Ca(2+) leak at rest, and depressed force production due to impaired SR Ca(2+) release upon stimulation. In conclusion, HIIT exercise induces a ROS dependent RyR1 fragmentation in muscles of recreationally active subjects, and the resulting changes in muscle fiber Ca(2+)-handling trigger muscular adaptations. However, the same HIIT exercise does not cause RyR1 fragmentation in muscles of elite endurance athletes, which may explain why HIIT is less effective in this group. PMID- 26575623 TI - Single-molecule motions and interactions in live cells reveal target search dynamics in mismatch repair. AB - MutS is responsible for initiating the correction of DNA replication errors. To understand how MutS searches for and identifies rare base-pair mismatches, we characterized the dynamic movement of MutS and the replisome in real time using superresolution microscopy and single-molecule tracking in living cells. We report that MutS dynamics are heterogeneous in cells, with one MutS population exploring the nucleoid rapidly, while another MutS population moves to and transiently dwells at the replisome region, even in the absence of appreciable mismatch formation. Analysis of MutS motion shows that the speed of MutS is correlated with its separation distance from the replisome and that MutS motion slows when it enters the replisome region. We also show that mismatch detection increases MutS speed, supporting the model for MutS sliding clamp formation after mismatch recognition. Using variants of MutS and the replication processivity clamp to impair mismatch repair, we find that MutS dynamically moves to and from the replisome before mismatch binding to scan for errors. Furthermore, a block to DNA synthesis shows that MutS is only capable of binding mismatches near the replisome. It is well-established that MutS engages in an ATPase cycle, which is necessary for signaling downstream events. We show that a variant of MutS with a nucleotide binding defect is no longer capable of dynamic movement to and from the replisome, showing that proper nucleotide binding is critical for MutS to localize to the replisome in vivo. Our results provide mechanistic insight into the trafficking and movement of MutS in live cells as it searches for mismatches. PMID- 26575624 TI - Virion-associated phosphatidylethanolamine promotes TIM1-mediated infection by Ebola, dengue, and West Nile viruses. AB - Phosphatidylserine (PS) receptors contribute to two crucial biological processes: apoptotic clearance and entry of many enveloped viruses. In both cases, they recognize PS exposed on the plasma membrane. Here we demonstrate that phosphatidylethanolamine (PE) is also a ligand for PS receptors and that this phospholipid mediates phagocytosis and viral entry. We show that a subset of PS receptors, including T-cell immunoglobulin (Ig) mucin domain protein 1 (TIM1), efficiently bind PE. We further show that PE is present in the virions of flaviviruses and filoviruses, and that the PE-specific cyclic peptide lantibiotic agent Duramycin efficiently inhibits the entry of West Nile, dengue, and Ebola viruses. The inhibitory effect of Duramycin is specific: it inhibits TIM1 mediated, but not L-SIGN-mediated, virus infection, and it does so by blocking virus attachment to TIM1. We further demonstrate that PE is exposed on the surface of apoptotic cells, and promotes their phagocytic uptake by TIM1 expressing cells. Together, our data show that PE plays a key role in TIM1 mediated virus entry, suggest that disrupting PE association with PS receptors is a promising broad-spectrum antiviral strategy, and deepen our understanding of the process by which apoptotic cells are cleared. PMID- 26575626 TI - The bioenergetic costs of a gene. AB - An enduring mystery of evolutionary genomics concerns the mechanisms responsible for lineage-specific expansions of genome size in eukaryotes, especially in multicellular species. One idea is that all excess DNA is mutationally hazardous, but weakly enough so that genome-size expansion passively emerges in species experiencing relatively low efficiency of selection owing to small effective population sizes. Another idea is that substantial gene additions were impossible without the energetic boost provided by the colonizing mitochondrion in the eukaryotic lineage. Contrary to this latter view, analysis of cellular energetics and genomics data from a wide variety of species indicates that, relative to the lifetime ATP requirements of a cell, the costs of a gene at the DNA, RNA, and protein levels decline with cell volume in both bacteria and eukaryotes. Moreover, these costs are usually sufficiently large to be perceived by natural selection in bacterial populations, but not in eukaryotes experiencing high levels of random genetic drift. Thus, for scaling reasons that are not yet understood, by virtue of their large size alone, eukaryotic cells are subject to a broader set of opportunities for the colonization of novel genes manifesting weakly advantageous or even transiently disadvantageous phenotypic effects. These results indicate that the origin of the mitochondrion was not a prerequisite for genome-size expansion. PMID- 26575625 TI - Development and aging of cortical thickness correspond to genetic organization patterns. AB - There is a growing realization that early life influences have lasting impact on brain function and structure. Recent research has demonstrated that genetic relationships in adults can be used to parcellate the cortex into regions of maximal shared genetic influence, and a major hypothesis is that genetically programmed neurodevelopmental events cause a lasting impact on the organization of the cerebral cortex observable decades later. Here we tested how developmental and lifespan changes in cortical thickness fit the underlying genetic organizational principles of cortical thickness in a longitudinal sample of 974 participants between 4.1 and 88.5 y of age with a total of 1,633 scans, including 773 scans from children below 12 y. Genetic clustering of cortical thickness was based on an independent dataset of 406 adult twins. Developmental and adult age related changes in cortical thickness followed closely the genetic organization of the cerebral cortex, with change rates varying as a function of genetic similarity between regions. Cortical regions with overlapping genetic architecture showed correlated developmental and adult age change trajectories and vice versa for regions with low genetic overlap. Thus, effects of genes on regional variations in cortical thickness in middle age can be traced to regional differences in neurodevelopmental change rates and extrapolated to further adult aging-related cortical thinning. This finding suggests that genetic factors contribute to cortical changes through life and calls for a lifespan perspective in research aimed at identifying the genetic and environmental determinants of cortical development and aging. PMID- 26575627 TI - Evolutionary origins of hepatitis A virus in small mammals. AB - Hepatitis A virus (HAV) is an ancient and ubiquitous human pathogen recovered previously only from primates. The sole species of the genus Hepatovirus, existing in both enveloped and nonenveloped forms, and with a capsid structure intermediate between that of insect viruses and mammalian picornaviruses, HAV is enigmatic in its origins. We conducted a targeted search for hepatoviruses in 15,987 specimens collected from 209 small mammal species globally and discovered highly diversified viruses in bats, rodents, hedgehogs, and shrews, which by pairwise sequence distance comprise 13 novel Hepatovirus species. Near-complete genomes from nine of these species show conservation of unique hepatovirus features, including predicted internal ribosome entry site structure, a truncated VP4 capsid protein lacking N-terminal myristoylation, a carboxyl-terminal pX extension of VP1, VP2 late domains involved in membrane envelopment, and a cis acting replication element within the 3D(pol) sequence. Antibodies in some bat sera immunoprecipitated and neutralized human HAV, suggesting conservation of critical antigenic determinants. Limited phylogenetic cosegregation among hepatoviruses and their hosts and recombination patterns are indicative of major hepatovirus host shifts in the past. Ancestral state reconstructions suggest a Hepatovirus origin in small insectivorous mammals and a rodent origin of human HAV. Patterns of infection in small mammals mimicked those of human HAV in hepatotropism, fecal shedding, acute nature, and extinction of the virus in a closed host population. The evolutionary conservation of hepatovirus structure and pathogenesis provide novel insight into the origins of HAV and highlight the utility of analyzing animal reservoirs for risk assessment of emerging viruses. PMID- 26575628 TI - Fourteen babies born after round spermatid injection into human oocytes. AB - During the human in vitro fertilization procedure in the assisted reproductive technology, intracytoplasmic sperm injection is routinely used to inject a spermatozoon or a less mature elongating spermatid into the oocyte. In some infertile men, round spermatids (haploid male germ cells that have completed meiosis) are the most mature cells visible during testicular biopsy. The microsurgical injection of a round spermatid into an oocyte as a substitute is commonly referred to as round spermatid injection (ROSI). Currently, human ROSI is considered a very inefficient procedure and of no clinical value. Herein, we report the birth and development of 14 children born to 12 women following ROSI of 734 oocytes previously activated by an electric current. The round spermatids came from men who had been diagnosed as not having spermatozoa or elongated spermatids by andrologists at other hospitals after a first Micro-TESE. A key to our success was our ability to identify round spermatids accurately before oocyte injection. As of today, all children born after ROSI in our clinic are without any unusual physical, mental, or epigenetic problems. Thus, for men whose germ cells are unable to develop beyond the round spermatid stage, ROSI can, as a last resort, enable them to have their own genetic offspring. PMID- 26575629 TI - Distinguishing the immunostimulatory properties of noncoding RNAs expressed in cancer cells. AB - Recent studies have demonstrated abundant transcription of a set of noncoding RNAs (ncRNAs) preferentially within tumors as opposed to normal tissue. Using an approach from statistical physics, we quantify global transcriptome-wide motif use for the first time, to our knowledge, in human and murine ncRNAs, determining that most have motif use consistent with the coding genome. However, an outlier subset of tumor-associated ncRNAs, typically of recent evolutionary origin, has motif use that is often indicative of pathogen-associated RNA. For instance, we show that the tumor-associated human repeat human satellite repeat II (HSATII) is enriched in motifs containing CpG dinucleotides in AU-rich contexts that most of the human genome and human adapted viruses have evolved to avoid. We demonstrate that a key subset of these ncRNAs functions as immunostimulatory "self-agonists" and directly activates cells of the mononuclear phagocytic system to produce proinflammatory cytokines. These ncRNAs arise from endogenous repetitive elements that are normally silenced, yet are often very highly expressed in cancers. We propose that the innate response in tumors may partially originate from direct interaction of immunogenic ncRNAs expressed in cancer cells with innate pattern recognition receptors, and thereby assign a previously unidentified danger associated function to a set of dark matter repetitive elements. These findings potentially reconcile several observations concerning the role of ncRNA expression in cancers and their relationship to the tumor microenvironment. PMID- 26575630 TI - Pericentromeric satellite repeat expansions through RNA-derived DNA intermediates in cancer. AB - Aberrant transcription of the pericentromeric human satellite II (HSATII) repeat is present in a wide variety of epithelial cancers. In deriving experimental systems to study its deregulation, we observed that HSATII expression is induced in colon cancer cells cultured as xenografts or under nonadherent conditions in vitro, but it is rapidly lost in standard 2D cultures. Unexpectedly, physiological induction of endogenous HSATII RNA, as well as introduction of synthetic HSATII transcripts, generated cDNA intermediates in the form of DNA/RNA hybrids. Single molecule sequencing of tumor xenografts showed that HSATII RNA derived DNA (rdDNA) molecules are stably incorporated within pericentromeric loci. Suppression of RT activity using small molecule inhibitors reduced HSATII copy gain. Analysis of whole-genome sequencing data revealed that HSATII copy number gain is a common feature in primary human colon tumors and is associated with a lower overall survival. Together, our observations suggest that cancer associated derepression of specific repetitive sequences can promote their RNA driven genomic expansion, with potential implications on pericentromeric architecture. PMID- 26575631 TI - Rising morbidity and mortality in midlife among white non-Hispanic Americans in the 21st century. AB - This paper documents a marked increase in the all-cause mortality of middle-aged white non-Hispanic men and women in the United States between 1999 and 2013. This change reversed decades of progress in mortality and was unique to the United States; no other rich country saw a similar turnaround. The midlife mortality reversal was confined to white non-Hispanics; black non-Hispanics and Hispanics at midlife, and those aged 65 and above in every racial and ethnic group, continued to see mortality rates fall. This increase for whites was largely accounted for by increasing death rates from drug and alcohol poisonings, suicide, and chronic liver diseases and cirrhosis. Although all education groups saw increases in mortality from suicide and poisonings, and an overall increase in external cause mortality, those with less education saw the most marked increases. Rising midlife mortality rates of white non-Hispanics were paralleled by increases in midlife morbidity. Self-reported declines in health, mental health, and ability to conduct activities of daily living, and increases in chronic pain and inability to work, as well as clinically measured deteriorations in liver function, all point to growing distress in this population. We comment on potential economic causes and consequences of this deterioration. PMID- 26575632 TI - Dissipation kinetics of pre-plant pesticides in greenhouse-devoted soils. AB - This work was conducted to study the distribution of methyl isothiocyanate (MITC) in greenhouse soils treated with the fumigant dazomet (DZ) from the formulated product "Basamid Granular((r))", but also of 1,3-dichloropropene (1,3-D) and chloropicrin (CP) from the fumigant "Agrocelhone NE((r))". In order to achieve this aim, several methods for the determination of fumigants residues in soils, but also pepper fruits were optimized and characterized. With independence of the soil depth, no residues of MITC, 1,3-D and CP above the detection limits were observed in soils covered with a polyethylene (PE) film (0.04 mm thick) after 27, 13 and 8 days of treatment, respectively. Liberation and dissipation curves of MITC in soil in presence of a PE film (0.04 mm) used to limit volatilization losses were also obtained. According to the results, the rate of decomposition of DZ into MITC have a half-life of 3.7 days in the surface horizon (5-10 cm) of the soil while in the subsurface horizon (15-20 cm), MITC formation rate is slightly slow (half-life of 3.2 days). With respect to the dissipation process, half-lives lower than 1 day were obtained for both depths (0.8 and 0.9 for the surface and the subsurface horizon, respectively). In the case of 1,3-D and CP in soil, the dissipation half-life of 1,3-D on soils was a bit higher than for CP (2 days vs. 1). In addition, the presence of residues of the fumigants on green pepper fruits grown on the treated soils was not detected as expected. PMID- 26575633 TI - Legacy and currently used pesticides in the atmospheric environment of Lake Victoria, East Africa. AB - The Lake Victoria watershed has extensive agricultural activity with a long history of pesticide use but there is limited information on historical use or on environmental levels. To address this data gap, high volume air samples were collected from two sites close to the northern shore of Lake Victoria; Kakira (KAK) and Entebbe (EBB). The samples, to be analyzed for pesticides, were collected over various periods between 1999 and 2004 inclusive (KAK 1999-2000, KAK 2003-2004, EBB 2003 and EBB 2004 sample sets) and from 2008 to 2010 inclusive (EBB 2008, EBB 2009 and EBB 2010 sample sets). The latter sample sets (which also included precipitation samples) were also analyzed for currently used pesticides (CUPs) including chlorpyrifos, chlorthalonil, metribuzin, trifluralin, malathion and dacthal. Chlorpyrifos was the predominant CUP in air samples with average concentrations of 93.5, 26.1 and 3.54 ng m(-3) for the EBB 2008, 2009, 2010 sample sets, respectively. Average concentrations of total endosulfan (SigmaEndo), total DDT related compounds (SigmaDDTs) and hexachlorocyclohexanes (SigmaHCHs) ranged from 12.3-282, 22.8-130 and 3.72-81.8 pg m(-3), respectively, for all the sample sets. Atmospheric prevalence of residues of persistent organic pollutants (POPs) increased with fresh emissions of endosulfan, DDT and lindane. Hexachlorobenzene (HCB), pentachlorobenzene (PeCB) and dieldrin were also detected in air samples. Transformation products, pentachloroanisole, 3,4,5 trichloroveratrole and 3,4,5,6-tetrachloroveratrole, were also detected. The five most prevalent compounds in the precipitation samples were in the order chlorpyrifos>chlorothalonil>SigmaEndo>SigmaDDTs>SigmaHCHs with average fluxes of 1123, 396, 130, 41.7 and 41.3 ng m(-2)sample(-1), respectively. PeCB exceeded HCB in precipitation samples. The reverse was true for air samples. Backward air trajectories suggested transboundary and local emission sources of the analytes. The results underscore the need for a concerted regional vigilance in management of chemicals. PMID- 26575634 TI - Phthalate metabolites in urine of Chinese young adults: Concentration, profile, exposure and cumulative risk assessment. AB - Phthalates are widely used in consumer products. People are frequently exposed to phthalates due to their applications in daily life. In this study, 14 phthalate metabolites were analyzed in 108 urine samples collected from Chinese young adults using high-performance liquid chromatography-tandem mass spectrometry. The total concentrations of 14 phthalate metabolites ranged from 71.3 to 2670 ng/mL, with the geometric mean concentration of 306 ng/mL. mBP and miBP were the two most abundant compounds, accounting for 48% of the total concentrations. Principal component analysis suggested two major sources of phthalates: one dominated by the DEHP metabolites and one by the group of mCPP, mBP and miBP metabolites. The estimated daily intakes of DMP, DEP, DBP, DiBP and DEHP were 1.68, 2.14, 4.12, 3.52 and 1.26-2.98 MUg/kg-bw/day, respectively. In a sensitivity analysis, urinary concentration and body weight were the most influential variables for human exposure estimation. Furthermore, cumulative risk for hazard quotient (HQ) and hazard index (HI) were evaluated. Nearly half of Chinese young adults had high HI values exceeding the safe threshold. This is the first study on the occurrence and human exposure to urinary phthalate metabolites with Chinese young adults. PMID- 26575636 TI - Developmental toxicity of metaldehyde in the embryos of Lymnaea stagnalis (Gastropoda: Pulmonata) co-exposed to the synergist piperonyl butoxide. AB - Metaldehyde is a widely used molluscicide in countries where damage to crops from slugs and snails is a major problem associated with warm and wet winters. In the UK it is estimated that over 8% of the area covered by arable crops is treated with formulated granular bait pellets containing metaldehyde as the main active ingredient. Metaldehyde is hydrophilic (log Kow=0.12), water soluble (200 mg.L( 1) at 17 degrees C) and has been detected in UK surface waters in the concentration range of typically 0.2-0.6 MUg.L(-1) (maximum 2.7 MUg.L(-1)) during 2008-2011. In the absence of chronic data on potential hazards to non-target freshwater molluscs, a laboratory study was conducted to investigate the impact of metaldehyde on embryo development in the gastropod Lymnaea stagnalis (RENILYS strain) and using zinc as a positive control. L. stagnalis embryos were exposed to metaldehyde under semi-static conditions at 20+/-1 degrees C and hatching success and growth (measured as shell height and intraocular distance) examined after 21 d. Exposure concentrations were verified using HPLC and gave 21 d (hatching)NOEC and (hatching)LOEC mean measured values of 36 and 116 mg MET.L( 1), respectively (equal to the 21 d (shell height)NOEC and (shell height)LOEC values). For basic research purposes, a second group of L. stagnalis embryos was co-exposed to metaldehyde and the pesticide synergist piperonyl butoxide (PBO). Co-exposure to the PBO (measured concentrations between 0.47-0.56 mg.L(-1)) reduced hatching success from 100% to 47% and resulted in a 30% reduction in embryo growth (shell height) in snail embryos co-exposed to metaldehyde at 34-36 mg.L(-1) over 21 d. In conclusion, these data suggest mollusc embryos may have some metabolic detoxication capacity for metaldehyde and further work is warranted to explore this aspect in order to support the recent initiative to include molluscs in the OECD test guideline programme. PMID- 26575635 TI - Couples' urinary concentrations of benzophenone-type ultraviolet filters and the secondary sex ratio. AB - The secondary sex ratio (SSR), defined as the ratio of males to females at birth, has been investigated in relation to endocrine disruptors to search for environmental toxicants perturbing human sex selection. Benzophenone (BP)-type ultraviolet (UV) filters, which are used in sunscreens and personal care products, have been reported to exert estrogenic and anti-androgenic activities. This study aimed to evaluate the association between maternal, paternal, and couple urinary concentrations of BP-type UV filters and the SSR, given the absence of previous investigation. The study cohort comprised 220 couples who were enrolled in the Longitudinal Investigation of Fertility and the Environment (LIFE) Study between 2005 and 2009 prior to conception and who had a singleton birth during the follow-up period. Couples' urinary concentrations of five BP type UV filters (ng/mL) were measured using triple-quadrupole tandem mass spectrometry: 2,4-dihydroxybenzophenone (BP-1), 2,2',4,4' tetrahydroxybenzophenone (BP-2), 2-hydroxy-4-methoxybenzophenone (BP-3), 2,2' dihydroxy-4-methoxybenzophenone (BP-8), and 4-hydroxybenzophenone (4-OH-BP). Modified Poisson regression models were used to estimate the relative risks (RRs) of a male birth for each BP-type UV filter, after adjusting for potential confounders. When maternal and paternal urinary BP-type UV filter concentrations were modeled jointly, both maternal BP-2 (2nd vs 1st tertile, RR, 0.62, 95% confidence interval [CI], 0.43-0.91) and paternal BP-2 (3rd vs 1st tertile, RR, 0.67, 95% CI, 0.45-0.99; p-trend, 0.04) were significantly associated with an excess of female births. Contrarily, maternal 4-OH-BP was significantly associated with an excess of male births (2nd vs 1st tertile, RR, 1.87, 95% CI, 1.27-2.74; 3rd vs 1st tertile, RR, 1.80, 95% CI, 1.13-2.87; p-trend, 0.02). Our findings provide the first evidence suggesting that BP-type UV filters may affect the SSR. However, future corroboration is needed, given the exploratory design of this study. PMID- 26575638 TI - The stability of the Au(1 1 0)-(1 * 3) surface reconstruction in electrochemical environments. AB - Changes in the reflection anisotropy (RAS) profile of the Au(1 1 0)-(1 * 3)/Na2SO4 interface over 25 h are attributed to the slow accumulation of impurities on the Au(1 1 0) surface which reduce the intensity of a transition involving a surface state that makes a positive contribution to the RAS profile at 1.8 eV. The growth in the intensity of a feature that makes a negative contribution to the RAS profile at 2.6 eV and the reduction in the intensity of contributions to higher energy is attributed to shifts in the energy of the surface band structure relative to the Fermi level caused by the accumulation of impurities. There is no clear explanation of the subsequent decay of the 2.6 eV feature or the long term reduction in intensity to high energy of the RAS profile. PMID- 26575637 TI - Improving DNA double-strand repair inhibitor KU55933 therapeutic index in cancer radiotherapy using nanoparticle drug delivery. AB - Radiotherapy is a key component of cancer treatment. Because of its importance, there has been high interest in developing agents and strategies to further improve the therapeutic index of radiotherapy. DNA double-strand repair inhibitors (DSBRIs) are among the most promising agents to improve radiotherapy. However, their clinical translation has been limited by their potential toxicity to normal tissue. Recent advances in nanomedicine offer an opportunity to overcome this limitation. In this study, we aim to demonstrate the proof of principle by developing and evaluating nanoparticle (NP) formulations of KU55933, a DSBRI. We engineered a NP formulation of KU55933 using nanoprecipitation method with different lipid polymer nanoparticle formulation. NP KU55933 using PLGA formulation has the best loading efficacy as well as prolonged drug release profile. We demonstrated that NP KU55933 is a potent radiosensitizer in vitro using clonogenic assay and is more effective as a radiosensitizer than free KU55933 in vivo using mouse xenograft models of non-small cell lung cancer (NSCLC). Western blots and immunofluorescence showed NP KU55933 exhibited more prolonged inhibition of DNA repair pathway. In addition, NP KU55933 leads to lower skin toxicity than KU55933. Our study supports further investigations using NP to deliver DSBRIs to improve cancer radiotherapy treatment. PMID- 26575639 TI - Comment on the Article by Ledermann et al. Entitled 'Effects of Cerebellothalamic Tractotomy on Cognitive and Emotional Functioning in Essential Tremor: A Preliminary Study in 5 Essential Tremor Patients'. PMID- 26575640 TI - Osseous Metaplasia and Subsequent Spontaneous Pregnancy Chance: A Case Report and Review of the Literature. AB - BACKGROUNDS: What is not clear as yet is not only the etiology, but also the management of osseous metaplasia. We describe an infertile patient with osseous metaplasia and subsequent pregnancy after treatment and review the literature from infertility perspective. METHOD: We presented a 30-year-old woman with 8 years of secondary infertility who conceived spontaneously after removal of osseous tissue by operative hysteroscopy (HS) following one failed in vitro fertilization cycle. The current literature regarding the osseous metaplasia and fertility potential after removal of osseous tissue was also systematically reviewed in which 21 reports (n = 64 women) were eligible. RESULTS: The available data suggest that restoration of endometrial cavity with HS or curettage provides a spontaneous pregnancy rate of 54.2% within 12 months. CONCLUSION: According to the available data, irrespective from the duration of subfertility, spontaneous pregnancy should be expected for at least 1 year following the 'complete' restoration of endometrial cavity. In that context, further infertility treatments such as assisted reproduction cycles should be postponed, unless there is another reason for infertility. PMID- 26575641 TI - Evolutionary Position and Leaf Toughness Control Chemical Transformation of Litter, and Drought Reinforces This Control: Evidence from a Common Garden Experiment across 48 Species. AB - Plant leaf litter is an important source of soil chemicals that are essential for the ecosystem and changes in leaf litter chemical traits during decomposition will determine the availability of multiple chemical elements recycling in the ecosystem. However, it is unclear whether the changes in litter chemical traits during decomposition and their similarities across species can be predicted, respectively, using other leaf traits or using the phylogenetic relatedness of the litter species. Here we examined the fragmentation levels, mass losses, and the changes of 10 litter chemical traits during 1-yr decomposition under different environmental conditions (within/above surrounding litter layer) for 48 temperate tree species and related them to an important leaf functional trait, i.e. leaf toughness. Leaf toughness could predict the changes well in terms of amounts, but poorly in terms of concentrations. Changes of 7 out of 10 litter chemical traits during decomposition showed a significant phylogenetic signal notably when litter was exposed above surrounding litter. These phylogenetic signals in element dynamics were stronger than those of initial elementary composition. Overall, relatively hard-to-measure ecosystem processes like element dynamics during decomposition could be partly predicted simply from phylogenies and leaf toughness measures. We suggest that the strong phylogenetic signals in chemical ecosystem functioning of species may reflect the concerted control by multiple moderately conserved traits, notably if interacting biota suffer microclimatic stress and spatial isolation from ambient litter. PMID- 26575643 TI - Direct NMR detection of the unstable "red product" from the reaction between nitroprusside and 2-mercaptosuccinic acid. AB - The reaction between nitroprusside (NP, [Fe(II)(CN)5NO](2-)) and organic thiolates (RS(-)) in aqueous solution has long been known to produce an unstable red intermediate thus often being referred to as the "red product" (RP) in the literature. While RP has always been formulated as [Fe(II)(CN)5N(O)SR](3-), it is rather difficult to study it in aqueous solution because it is not only unstable but also exhibits rapid ligand exchange. All previous studies of RP have relied on UV-vis, IR, kinetics measurements, and analysis of decomposed products. Herein we report the first comprehensive multinuclear ((1)H, (13)C, (15)N, and (17)O) NMR characterization of the RP produced from the reaction between NP and 2 mercaptosuccinic acid (MSA). The NMR chemical shifts obtained for the RP are compared with those from the free ligand (S-nitrosothiol, RS-N=O) prepared in situ by the reaction of MSA with NaNO2. We also showed that useful thermodynamic and kinetic properties of RP formation can be readily obtained from (1)H NMR studies. PMID- 26575642 TI - Cumulus Cells Block Oocyte Meiotic Resumption via Gap Junctions in Cumulus Oocyte Complexes Subjected to DNA Double-Strand Breaks. AB - During mammalian oocyte growth, genomic DNA may accumulate DNA double-strand breaks (DSBs) induced by factors such as reactive oxygen species. Recent evidence demonstrated that slight DSBs do not activate DNA damage checkpoint proteins in denuded oocytes. These oocytes, even with DNA DSBs, can resume meiosis and progress to metaphase of meiosis II. Meiotic resumption in oocytes is also controlled by the surrounding cumulus cells; accordingly, we analyzed whether cumulus-cell enclosed oocytes (CEOs) with DNA damage are able to resume meiosis. Compared with DNA-damaged denuded oocytes, we found that meiotic resumption rates of CEOs significantly decreased. To assess the mechanism by which cumulus cells block meiotic resumption in CEOs with DNA DSBs, we treated the cumulus oocyte complex with the gap junction inhibitor carbenoxolone and found that carbenoxolone can rescue the block in CEO meiosis induced by DNA DSBs. Since cumulus cell-synthesized cAMPs can pass through the gap junctions between oocyte and cumulus cell to block oocyte meiosis, we measured the expression levels of adenylate cyclase 1 (Adcy1) in cumulus cells, and G-protein coupled receptor 3 (Gpr3) and phosphodiesterase 3A (Pde3a) in oocytes, and found that the mRNA expression level of Adcy1 increased significantly in DNA-damaged cumulus cells. In conclusion, our results indicate that DNA DSBs promote cAMP synthesis in cumulus cells, and cumulus cAMPs can inhibit meiotic resumption of CEOs through gap junctions. PMID- 26575644 TI - Decreasing the Burden of Type 2 Diabetes in South Africa: The Impact of Taxing Sugar-Sweetened Beverages. AB - INTRODUCTION: Type 2 diabetes poses an increasing public health burden in South Africa (SA) with obesity as the main driver of the epidemic. Consumption of sugar sweetened beverages (SSBs) is linked to weight gain and reducing SSB consumption may significantly impact the prevalence of obesity and related diseases. We estimated the effect of a 20% SSB tax on the burden of diabetes in SA. METHODS AND FINDINGS: We constructed a life table-based model in Microsoft Excel (2010). Consumption data from the 2012 SA National Health and Nutrition Examination Survey, previously published own- and cross-price elasticities of SSBs and energy balance equations were used to estimate changes in daily energy intake and its projected impact on BMI arising from increased SSB prices. Diabetes relative risk and prevalent years lived with disability estimates from the Global Burden of Disease Study and modelled disease epidemiology estimates from a previous study were used to estimate the effect of the BMI changes on diabetes burden. Diabetes cost estimates were obtained from the South African Council for Medical Schemes. Over 20 years, a 20% SSB tax could reduce diabetes incident cases by 106 000 in women (95% uncertainty interval (UI) 70 000-142 000) and by 54 000 in men (95% UI: 33 000-80 000); and prevalence in all adults by 4.0% (95% UI: 2.7%-5.3%). Cumulatively over twenty years, approximately 21 000 (95% UI: 14 000-29 000) adult T2DM-related deaths, 374 000 DALYs attributed to T2DM (95% UI: 299 000-463 000) and over ZAR10 billion T2DM healthcare costs (95% UI: ZAR6.8-14.0 billion) equivalent to USD860 million (95% UI: USD570 million-USD1.2 billion) may be averted. CONCLUSION: Fiscal policy on SSBs has the potential to mitigate the diabetes epidemic in South Africa and contribute to the National Department of Health goals stated in the National NCD strategic plan. PMID- 26575646 TI - Seasonal Variation in Parental Care Drives Sex-Specific Foraging by a Monomorphic Seabird. AB - Evidence of sex-specific foraging in monomorphic seabirds is increasing though the underlying mechanisms remain poorly understood. We investigate differential parental care as a mechanism for sex-specific foraging in monomorphic Common Murres (Uria aalge), where the male parent alone provisions the chick after colony departure. Using a combination of geolocation-immersion loggers and stable isotopes, we assess two hypotheses: the reproductive role specialization hypothesis and the energetic constraint hypothesis. We compare the foraging behavior of females (n = 15) and males (n = 9) during bi-parental at the colony, post-fledging male-only parental care and winter when parental care is absent. As predicted by the reproductive role specialization hypothesis, we found evidence of sex-specific foraging during post-fledging only, the stage with the greatest divergence in parental care roles. Single-parenting males spent almost twice as much time diving per day and foraged at lower quality prey patches relative to independent females. This implies a potential energetic constraint for males during the estimated 62.8 +/- 8.9 days of offspring dependence at sea. Contrary to the predictions of the energetic constraint hypothesis, we found no evidence of sex-specific foraging during biparental care, suggesting that male parents did not forage for their own benefit before colony departure in anticipation of post fledging energy constraints. We hypothesize that unpredictable prey conditions at Newfoundland colonies in recent years may limit male parental ability to allocate additional time and energy to self-feeding during biparental care, without compromising chick survival. Our findings support differential parental care as a mechanism for sex-specific foraging in monomorphic murres, and highlight the need to consider ecological context in the interpretation of sex-specific foraging behavior. PMID- 26575647 TI - Correction: Crystal Structure of the Human Cytomegalovirus Glycoprotein B. PMID- 26575648 TI - Tuning Properties of MT and MSTd and Divisive Interactions for Eye-Movement Compensation. AB - The primate brain intelligently processes visual information from the world as the eyes move constantly. The brain must take into account visual motion induced by eye movements, so that visual information about the outside world can be recovered. Certain neurons in the dorsal part of monkey medial superior temporal area (MSTd) play an important role in integrating information about eye movements and visual motion. When a monkey tracks a moving target with its eyes, these neurons respond to visual motion as well as to smooth pursuit eye movements. Furthermore, the responses of some MSTd neurons to the motion of objects in the world are very similar during pursuit and during fixation, even though the visual information on the retina is altered by the pursuit eye movement. We call these neurons compensatory pursuit neurons. In this study we develop a computational model of MSTd compensatory pursuit neurons based on physiological data from single unit studies. Our model MSTd neurons can simulate the velocity tuning of monkey MSTd neurons. The model MSTd neurons also show the pursuit compensation property. We find that pursuit compensation can be achieved by divisive interaction between signals coding eye movements and signals coding visual motion. The model generates two implications that can be tested in future experiments: (1) compensatory pursuit neurons in MSTd should have the same direction preference for pursuit and retinal visual motion; (2) there should be non-compensatory pursuit neurons that show opposite preferred directions of pursuit and retinal visual motion. PMID- 26575645 TI - Helicobacter pylori Infection Induces Anemia, Depletes Serum Iron Storage, and Alters Local Iron-Related and Adult Brain Gene Expression in Male INS-GAS Mice. AB - Iron deficiency anemia (IDA) affects > 500 million people worldwide, and is linked to impaired cognitive development and function in children. Helicobacter pylori, a class 1 carcinogen, infects about half of the world's population, thus creating a high likelihood of overlapping risk. This study determined the effect of H. pylori infection on iron homeostasis in INS-GAS mice. Two replicates of INS GAS/FVB male mice (n = 9-12/group) were dosed with H. pylori (Hp) strain SS1 or sham dosed at 6-9 weeks of age, and were necropsied at 27-29 weeks of age. Hematologic and serum iron parameters were evaluated, as was gene expression in gastric and brain tissues. Serum ferritin was lower in Hp SS1-infected mice than uninfected mice (p < 0.0001). Infected mice had a lower red blood cell count (p<0.0001), hematocrit (p < 0.001), and hemoglobin concentration (p <0.0001) than uninfected mice. Relative expression of gastric hepcidin antimicrobial peptide (Hamp) was downregulated in mice infected with Hp SS1 compared to sham-dosed controls (p<0.001). Expression of bone morphogenic protein 4 (Bmp4), a growth factor upstream of hepcidin, was downregulated in gastric tissue of Hp SS1 infected mice (p<0.001). Hp SS1-infected mice had downregulated brain expression of tyrosine hydroxylase (Th) (p = 0.02). Expression of iron-responsive genes involved in myelination (myelin basic protein (Mbp) and proteolipid protein 2 (Plp2)) was downregulated in infected mice (p = 0.001 and p = 0.02). Expression of synaptic plasticity markers (brain derived neurotrophic factor 3 (Bdnf3), Psd95 (a membrane associated guanylate kinase), and insulin-like growth factor 1 (Igf1)) was also downregulated in Hp SS1-infected mice (p = 0.09, p = 0.04, p = 0.02 respectively). Infection of male INS-GAS mice with Hp SS1, without concurrent dietary iron deficiency, depleted serum ferritin, deregulated gastric and hepatic expression of iron regulatory genes, and altered iron-dependent neural processes. The use of Hp SS1-infected INS-GAS mice will be an appropriate animal model for further study of the effects of concurrent H. pylori infection and anemia on iron homeostasis and adult iron-dependent brain gene expression. PMID- 26575649 TI - Structural phase transition in a multi-induced mononuclear Fe(II) spin-crossover complex. AB - Herein, we report the investigation of a mononuclear spin-crossover complex [Fe(II)L2][ClO4]2 (L = 2,6-bis{4,4-dimethyl-4,5-dihydrooxazol-2-yl}pyridine). This compound undergoes a structural phase transition around 173 K, accompanying with an abrupt spin-transition process. Interestingly, it exhibits a multi induced spin-crossover behavior mediated by heat, light, pressure and solvent. PMID- 26575650 TI - Construction of Seven-Membered Carbocycles via Cyclopropanols. AB - A new method for seven-membered ring annulation has been devised by an intramolecular cross-coupling of cyclopropanols and aryl/alkenyl halides. This cyclization reaction is broad in scope and provides easy access to not only fused but also bridged bicyclic compounds. PMID- 26575651 TI - Dissociation between implicit and explicit expectancies of cannabis use in adolescence. AB - Cannabis is one of the most commonly drugs used by teenagers. Expectancies about its effects play a crucial role in cannabis consumption. Various tools have been used to assess expectancies, mainly self-report questionnaires measuring explicit expectancies, but implicit measures based on experimental tasks have also been developed, measuring implicit expectancies. The aim of this study was to simultaneously assess implicit/explicit expectancies related to cannabis among adolescent users and non-users. 130 teenagers attending school (55 girls) were enrolled (Age: M=16.40 years); 43.84% had never used cannabis ("non-users") and 56.16% had used cannabis ("users"). They completed self-report questionnaires evaluating cannabis use, cannabis-related problems, effect expectancies (explicit expectancies), alcohol use, social and trait anxiety, depression, as well as three Implicit Association Tests (IAT) assessing implicit expectancies. Adolescents manifested more implicit affective associations (relaxation, excitation, negative) than neutral ones regarding cannabis. These were not related to explicit expectancies. Cannabis users reported more implicit relaxation expectancies and less negative explicit expectancies than non-users. The frequency of use and related problems were positively associated with the explicit expectancies regarding relaxation and enhancement, and were negatively associated with negative explicit expectancies and negative implicit expectancies. Findings indicate that implicit and explicit expectancies play different roles in cannabis use by adolescents. The implications for experimentation and prevention are discussed. PMID- 26575652 TI - Sleepless in Seattle. PMID- 26575653 TI - Bedside Ultrasound Reduces Diagnostic Uncertainty and Guides Resuscitation in Patients With Undifferentiated Hypotension. AB - OBJECTIVES: Utilization of ultrasound in the evaluation of patients with undifferentiated hypotension has been proposed in several protocols. We sought to assess the impact of an ultrasound hypotension protocol on physicians' diagnostic certainty, diagnostic ability, and treatment and resource utilization. DESIGN: Prospective observational study. SETTING: Emergency department in a single, academic tertiary care hospital. SUBJECTS: A convenience sample of patients with a systolic blood pressure less than 90 mm Hg after an initial fluid resuscitation, who lacked an obvious source of hypotension. INTERVENTIONS: An ultrasound-trained physician performed an ultrasound on each patient using a standardized hypotension protocol. Differential diagnosis and management plan was solicited from the treating physician immediately before and after the ultrasound. Blinded chart review was conducted for management and diagnosis during the emergency department and inpatient hospital stay. MEASUREMENTS AND MAIN RESULTS: The primary endpoints were the identification of an accurate cause for hypotension and change in physicians' diagnostic uncertainty. The secondary endpoints were changes in treatment plan, use of resources, and changes in disposition after performing the ultrasound. One hundred eighteen patients with a mean age of 62 years were enrolled. There was a significant 27.7% decrease in the mean aggregate complexity of diagnostic uncertainty before and after the ultrasound hypotension protocol (1.85-1.34; -0.51 [95% CI, -0.41 to -0.62]) as well as a significant increase in the absolute proportion of patients with a definitive diagnosis from 0.8% to 12.7%. Overall, the leading diagnosis after the ultrasound hypotension protocol demonstrated excellent concordance with the blinded consensus final diagnosis (Cohen k = 0.80). Twenty-nine patients (24.6%) had a significant change in the use of IV fluids, vasoactive agents, or blood products. There were also significant changes in major diagnostic imaging (30.5%), consultation (13.6%), and emergency department disposition (11.9%). CONCLUSIONS: Clinical management involving the early use of ultrasound in patients with hypotension accurately guides diagnosis, significantly reduces physicians' diagnostic uncertainty, and substantially changes management and resource utilization in the emergency department. PMID- 26575654 TI - Just Say "Stop": Avoiding Prolonged Empiric Antibiotics. PMID- 26575655 TI - Time-Limited Trials in the ICU: Seeing the Forest Beyond the Bark and Trees. PMID- 26575656 TI - Critical Care Sans Frontiere. PMID- 26575657 TI - Postoperative Albumin: Predictive Bystander or a Window Into the Clockwork? PMID- 26575658 TI - Does Ultrasound Improve Clinical Outcomes? Prove It. PMID- 26575659 TI - Assessing Feasibility (and Increasing Simplicity) in Extracorporeal Rescue Therapy for Acute Respiratory Distress Syndrome: The Pulmonary and Renal Support in Acute Respiratory Distress Syndrome Study. PMID- 26575660 TI - The Big Difference Between Direct and Nonstop Flights Is the Intermediate Stop Along the Way to the Final Destination. PMID- 26575661 TI - Release of Endotoxin After an Arrest. PMID- 26575662 TI - Must Our Malnourished Patients Eat Right or Die? PMID- 26575663 TI - beta-Blockers and Lactate in Sepsis: Same Canary But Different Mine. PMID- 26575664 TI - The Body Mass Index Paradox. PMID- 26575665 TI - Genetic Polymorphisms in the Somatotropic Axis and Critical Illness: "SNiPping" Away at a "Growing" Canvas! PMID- 26575666 TI - High-Frequency Oscillation in Pediatric Respiratory Failure: Time to Shake It Off? PMID- 26575667 TI - Adverse Tracheal Intubation-Associated Events During Nights and Weekends on PICUs Be Prepared! PMID- 26575668 TI - Microparticles: Still Far From Being the Ideal Biomarker for Ventilator Associated Lung Injury. PMID- 26575669 TI - Defying Death. PMID- 26575670 TI - Corticosteroids in Delirium: Yet Another Critical Care Conundrum? PMID- 26575671 TI - "Delirium" Is No Delirium: On Type Specifying and Drug Response. PMID- 26575672 TI - The authors reply. PMID- 26575673 TI - Critical Care Delivery and ICU Structure-The Elephant in the Room. PMID- 26575674 TI - The authors reply. PMID- 26575675 TI - Nuclear Magnetic Resonance-Based Metabolic Markers Can Be a True Signature of Diagnosis in Critical Care Setting. PMID- 26575676 TI - The authors reply. PMID- 26575677 TI - Cyclophilin A/Cluster of Differentiation 147 Interactions and Blood-Brain Barrier Disruption After Subarachnoid Hemorrhage. PMID- 26575678 TI - The authors reply. PMID- 26575679 TI - Percutaneous Cannulation in Predominantly Venoarterial Extracorporeal Membrane Oxygenation by Intensivists. PMID- 26575680 TI - The authors reply. PMID- 26575681 TI - "Lactate Shift," Rather Than "Lactate Clearance," for Serial Blood Lactate Monitoring? PMID- 26575682 TI - The author replies. PMID- 26575683 TI - Long-Axis Versus Short-Axis View of Ultrasound-Guided Central Venous Cannulation. PMID- 26575684 TI - The authors reply. PMID- 26575685 TI - Nutritional Metabolic Condition and Long-Term Survival: How Much Is Enough? PMID- 26575686 TI - Estimating Treatment Effectiveness of Intracranial Pressure Monitoring in Traumatic Brain Injury. PMID- 26575687 TI - Multibiomarker Article Gives a Taste of What the Era of Regenerative Medicine/Tissue Engineering Pathology Will Be Like. PMID- 26575688 TI - "Just Ask" for the ABCDEFG Campaign. PMID- 26575689 TI - Mega-dose phenobarbital therapy for super-refractory status epilepticus. AB - AIMS: To evaluate the efficacy and safety of mega-dose phenobarbital (MDPB; enteral or parenteral phenobarbital >10 mg/kg/day) for treating super-refractory status epilepticus (SRSE; continuous or recurrent status epilepticus for >=24 hours after the onset of continuous anaesthetic treatment) in adult patients. METHODS: Adult patients with SRSE who were treated with MDPB in our institution from March 2005 to September 2014 were reviewed. We collected data on basic demographics, clinical features, functional status, anticonvulsant treatment, and possible adverse events. SRSE outcome was divided into six categories: successful therapy, initial failure, breakthrough seizures, withdrawal seizures, intolerable side effects, and death during treatment. RESULTS: Ten adult patients with SRSE received MDPB. Median age at seizure onset was 38 years (range: 18-59), and half were male. All patients had no history of seizures and had symptoms suggestive of viral encephalitis. Median duration of status epilepticus was 17.5 days (range: 6 60) and anaesthetics were used for a median of 14.0 days (range: 2-54) before MDPB. Successful control of SRSE was achieved in half of the patients, however, only one of ten patients was able to fully recover at discharge. Median duration of the MDPB was 45.5 days and the maximum serum phenobarbital level reached a median of 151.5 MUg/ml. Patients with successful MDPB therapy had normal brain imaging (80% vs. 0%; p=0.048) and better functional outcome at discharge and after three months of follow-up. Infection was the most critical complication, along with cardiorespiratory depression. CONCLUSION: MDPB is a therapeutic option for control of SRSE when other choices are exhausted. PMID- 26575690 TI - RNA splicing, cell signaling, and response to therapies. AB - PURPOSE OF REVIEW: PremRNA alternative splicing is more a rule than an exception as it affects more than 90% of multiexons genes and plays a key role in proteome diversity. Here, we discuss some recent studies published in the extensively growing field linking RNA splicing and cancer. RECENT FINDINGS: These last years, the development of high-throughput studies together with appropriate bioinformatic tools have led to the identification of new cancer-specific splicing patterns that allow to distinguish various cancer types, and provide new prognosis biomarkers. In addition, the functional consequences of hot spot mutations affecting various components of the spliceosome machinery in cancers have been described. As an example, missplicing of the enhancer of zeste homolog 2 histone methyltransferase premRNA in response to hot spot mutation of the splicing factor SRSF2 was found to participate to the pathogenesis of myelodysplastic syndrome. Moreover, proofs of principle that targeting the RNA splicing machinery can be used to correct aberrant missplicing, kill oncogene driven cancer cells, or reverse resistance of tumor cells to targeted therapies have been done. As another example, the core spliceosomal function was recently found to be critical for the survival of Myc-driven breast cancer cells, rendering them hypersensitive to spliceosome inhibitors. SUMMARY: Dysregulation of premRNA alternative splicing appears to be one of the hallmarks of cancer. The characterization of novel splicing signatures in cancer as well as the identification of original signaling networks involving RNA splicing regulators should allow to decipher novel oncogenic mechanisms and to develop new therapeutic strategies. PMID- 26575691 TI - Current management of pediatric thyroid disease and differentiated thyroid cancer. AB - PURPOSE OF REVIEW: In this article, we focus on the role of ultrasound and fine needle aspiration, management of benign nodules, extent of thyroid resection, management of regional lymph node disease, and risk stratification in staging for well differentiated thyroid cancer (DTC) in children. RECENT FINDINGS: The recent guidelines by the American Thyroid Association focused specifically on the management of thyroid nodules and DTC in children and adolescents marks a change from previous versions, which extrapolated adult guidelines to the pediatric population. DTC in children has a distinct presentation and clinical behavior compared with adult disease. The overall excellent outcomes for pediatric patients have led to a risk stratification approach in their management (low, intermediate, and high-risk disease groupings), aiming to minimize the potential morbidity of treatment. SUMMARY: In this review, we focus on pediatric thyroid disease, including recent studies and debates regarding the management of thyroid nodules and DTC. PMID- 26575692 TI - Results of radical surgery in women with stage IB2/IIA2 cervical cancer. AB - INTRODUCTION: There is ongoing discussion about the primary treatment of women with bulky early-stage cervical cancer. Because of the high number of patients who need adjuvant (chemo)radiotherapy after initial surgical treatment, some state that primary (chemo)radiotherapy should be the treatment of choice to prevent morbidity. The aim of our study is to assess the results of radical surgery for women with bulky early-stage cervical cancer in terms of recurrence patterns and survival. MATERIALS AND METHODS: We conducted a retrospective cohort study. We included 129 women who underwent a radical hysterectomy with pelvic lymphadenectomy for stage IB2/IIA2 cervical cancer between 1984 and June 2010. Disease-specific survival was measured using a Kaplan-Meier method and univariate and multivariate regression analyses were performed to determine prognostic factors associated with survival. A literature search was performed to analyze our data in the context of findings from the literature. RESULTS: Five-year disease-specific survival was 84%. Fifty percent of the women received adjuvant treatment. The pelvic recurrence rate was 8%. With our multivariate analysis we found that histology, tumor diameter, and parametrial involvement were independently associated with disease-specific survival. Our literature search showed wide diversity in rates of adjuvant treatment after initial surgery as well as for survival and recurrence rates. CONCLUSIONS: In the context of current knowledge about survival and side effects of various treatments for bulky early stage cervical cancer, radical surgery is a good treatment option in these patients. Depending on the type of surgery used, adjuvant radiotherapy can be minimized. PMID- 26575693 TI - High sensitivity detection of HIV-1 using two genomic targets compared with single target PCR. AB - The genetic diversity of Human Immunodeficiency Virus type-1(HIV-1) has been shown to affect the performance of Nucleic Acid Testing (NAT) of Human Immunodeficiency Virus type-1. Although, majority NAT assays were designed to detect the conserved regions of HIV-1 mutations at the primer or probe binding regions may lead to false negatives. In this study, we evaluated the feasibility of detecting two genomic targets for enhanced sensitivity. A total of 180 tests using HIV-1 VQA RNA quantitation standard, 240 tests using EQAPOL HIV-1 viral diversity subtype panel, and 30 clinical plasma samples from Cameroon were evaluated. The analysis was based on probit and hit rate. The genomic targets LOD estimated by PROBIT for the gag target was 118 cps/ml (95%CI 64 cps/ml lower bound), Pol or POL/LTR was at 40 cps/ml (95%CI 17, 16 cps/ml), LTR 45 cps/ml (95%CI 20 cps/ml lower bound), and Gag/LTR at 67.8 cps/ml (95%CI 32 cps/ml lower bound). For HIV-1 subtypes the overall reactivity was 55-100% when tested at 100 and 1000 cps/ml and combination of genomic targets detection increased the reactivity to 100%. The plasma samples evaluation showed LTR or pol/LTR combination yielded higher sensitivity for patients with lower viral load (<40 cps/ml). We conclude that detection of two HIV-1 genomic targets improved sensitivity for detection of genetically diverse HIV-1 strains. PMID- 26575694 TI - Exploratory investigation of communication management in residential-aged care: a comparison of staff knowledge, documentation and observed resident-staff communication. AB - BACKGROUND: There is a high prevalence of communication difficulty among older people living in residential-aged care. Such functional deficits can have a negative impact on resident quality of life, staff workplace satisfaction and the provision of quality care. Systematic research investigating the nature of communication management in residential-aged care and factors impacting optimal communication management is lacking. AIMS: To use data triangulation across multiple sources to describe resident-staff communication and communication management in residential-aged care. METHODS & PROCEDURES: Participants included a sample of 14 residents and 29 staff directly involved in communication interactions with residents. Data were obtained from: (1) resident file review (n = 14), (2) observation of resident-staff communication (n = 14), (3) resident surveys (n = 14) and (4) staff surveys (n = 29). Data from each source were examined separately then triangulated. OUTCOMES & RESULTS: All residents had limited opportunity for meaningful communication with staff. Documentation of residents' communication needs and strategies to facilitate resident-staff communication was insufficient to provide individualized recommendations. Although staff were observed to use various strategies to facilitate communication with residents, staff agreement about the applicability of these strategies to individual residents was inconsistent. Differences in resident staff communication for residents who experience nil/mild versus moderate/severe communication difficulty were also found. CONCLUSIONS & IMPLICATIONS: Resident staff communication and communication management in residential-aged care is limited in scope and challenged in meeting residents' individual communication needs. Improvements in both documentation and staff knowledge of residents' communication needs are necessary. Strategies to facilitate communication with individual residents must be tailored, evidence based, documented in care plans and delivered to staff through ongoing education. Increased involvement of specialist providers such as speech pathologists to support better communication management in residential-aged care may provide one way of facilitating such change. PMID- 26575695 TI - A rank-sum test for clustered data when the number of subjects in a group within a cluster is informative. AB - The Wilcoxon rank-sum test is a popular nonparametric test for comparing two independent populations (groups). In recent years, there have been renewed attempts in extending the Wilcoxon rank sum test for clustered data, one of which (Datta and Satten, 2005, Journal of the American Statistical Association 100, 908 915) addresses the issue of informative cluster size, i.e., when the outcomes and the cluster size are correlated. We are faced with a situation where the group specific marginal distribution in a cluster depends on the number of observations in that group (i.e., the intra-cluster group size). We develop a novel extension of the rank-sum test for handling this situation. We compare the performance of our test with the Datta-Satten test, as well as the naive Wilcoxon rank sum test. Using a naturally occurring simulation model of informative intra-cluster group size, we show that only our test maintains the correct size. We also compare our test with a classical signed rank test based on averages of the outcome values in each group paired by the cluster membership. While this test maintains the size, it has lower power than our test. Extensions to multiple group comparisons and the case of clusters not having samples from all groups are also discussed. We apply our test to determine whether there are differences in the attachment loss between the upper and lower teeth and between mesial and buccal sites of periodontal patients. PMID- 26575696 TI - The effects of house dust mite sublingual immunotherapy in patients with allergic rhinitis according to duration. AB - BACKGROUND: The safety and efficacy of sublingual immunotherapy (SLIT) have been demonstrated in the recent 2 decades. However, the data is still mixed regarding the efficacy of house dust mite (HDM) SLIT. The objective of this work was to evaluate the different clinical efficacy SLIT in patients with allergic rhinitis (AR) according to different durations of treatment. METHODS: A total of 500 subjects with HDM-induced AR were randomized to receive SLIT with Dermatophagoides farinae (Der.f) drops or pharmacotherapy with oral antihistamines. Patients in the SLIT group were further divided into SLIT1, SLIT2, and SLIT3 subgroups. After SLIT completion, a yearly follow-up visit was given to patients in the SLIT1 and SLIT2 subgroups. The total nasal symptom score (TNSS), the proportion of medication withdrawal, the visual analogue scale (VAS) score, and Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) scores were assessed at each monthly visit. RESULTS: Comparing with the baseline value, TNSS, VAS, and RQLQ were significantly improved in 3 SLIT subgroups after treatment (p < 0.05). In addition, patients in SLIT3 subgroup achieved the highest proportion of medication withdrawal compared to the SLIT1 and SLIT2 subgroups (p < 0.05). After 1-year follow-up, no significant differences were observed in TNSS, VAS scores, and the proportion of medication withdrawal of SLIT1 and SLIT2 subgroups (p > 0.05) with respect to the completion value. No severe systemic adverse events (AEs) were reported. CONCLUSION: The randomized study suggested that 3 year courses of SLIT in patients with AR was more efficacious than 1-year or 2 year courses. Furthermore, patients achieved 1-year long-term clinical benefits from HDM SLIT. PMID- 26575697 TI - Skp1, a component of E3 ubiquitin ligase, is necessary for growth, sporulation, development and pathogenicity in rice blast fungus (Magnaporthe oryzae). AB - Ubiqitination is an important process in eukaryotic cells involving E3 ubiquitin ligase, which co-ordinates with cell cycle proteins and controls various cell functions. Skp1 (S-phase kinase-associated protein 1) is a core component of the SCF (Skp1-Cullin 1-F-box) E3 ubiquitin ligase complex necessary for protein degradation by the 26S proteasomal pathway. The rice blast fungus Magnaporthe oryzae has a single MoSKP1(MGG_04978) required for viability. Skp1 has multiple functions; however, its roles in growth, sporulation and appressorial development are not understood. MoSKP1 complements Skp1 function in the fission yeast temperature-sensitive mutant skp1 A7, restoring the normal length of yeast cells at restrictive temperature. The MoSkp1 protein in M. oryzae is present in spores and germ tubes, and is abundantly expressed in appressoria. Various RNA interference (RNAi) and antisense transformants of MoSKP1 in B157 show reduced sporulation, defective spore morphology, lesser septation and diffuse nuclei. Further, they show elongated germ tubes and are unable to form appressoria. Transformants arrested in G1/S stage during initial spore germination show a similar phenotype to wild-type spores treated with hydroxyurea (HU). Reduced MoSkp1 transcript and protein levels in knockdown transformants result in atypical germ tube development. MoSkp1 interacts with the putative F-box protein (MGG_06351) revealing the ability to form protein complexes. Our investigation of the role of MoSKP1 suggests that a decrease in MoSkp1 manifests in decreased total protein ubiquitination and, consequently, defective cell cycle and appressorial development. Thus, MoSKP1 plays important roles in growth, sporulation, appressorial development and pathogenicity of M. oryzae. PMID- 26575698 TI - Childhood obesity in specialist care--searching for a healthy obese child. AB - INTRODUCTION: One in three obese adults is classified as metabolically healthy, but there is less evidence in obese children. We studied the overall clinical presentation of Finnish obese children and the prevalence of cardiometabolic risk factors with child-specific cut-offs. MATERIAL AND METHODS: This is a cross sectional register-based study of 2-18-year-old children (n = 900) evaluated for obesity in three hospitals in 2005-2012. Clinical and metabolic data were related to sex, age, puberty, and obesity grade and analyzed using chi-square and non parametric tests. RESULTS: In 80% of cases at least one cardiovascular risk factor was present. Only 3% of subjects for whom complete metabolic data were available (n = 360) had no metabolic disorder. Systolic blood pressure was hypertensive in 50.2% and diastolic in 14.5% of the children. The youngest children had highest body mass index SD score. Obesity was more severe in boys than girls (p < 0.001). Hypertensive systolic blood pressure values (p = 0.012), prediabetes (p < 0.001), fatty liver (p < 0.001), and dyslipidemia (p = 0.025) were more prevalent in 15-18-year-old boys than girls. CONCLUSION: Most obese children in specialist care have cardiovascular risk factors; this indicates that earlier intervention is needed. PMID- 26575699 TI - Prioritizing Unknown Transformation Products from Biologically-Treated Wastewater Using High-Resolution Mass Spectrometry, Multivariate Statistics, and Metabolic Logic. AB - Incomplete micropollutant elimination in wastewater treatment plants (WWTPs) results in transformation products (TPs) that are released into the environment. Improvements in analytical technologies have allowed researchers to identify several TPs from specific micropollutants but an overall picture of nontarget TPs is missing. In this study, we addressed this challenge by applying multivariate statistics to data collected with liquid chromatography coupled to high resolution mass spectrometry (LC-HRMS) and subsequent tandem HRMS (MS/MS) in order to characterize peaks detected in the influent and effluent of a WWTP. Known biotransformation reactions were used to link potential parent compounds and TPs, while the structural similarity of these pairs hypothesized by MS/MS similarity was used for further prioritization. The methodology was validated with a set of spiked compounds, which included 25 parent/TP pairs for which analytical standards were available. This procedure was then applied to nontarget data, and 20 potential parent and TP pairs were selected for identification. In summary, primarily a surfactant homologue series, with associated TPs, was detected. Some obstacles still remain, including spectral interferences from coeluting compounds and identification of TPs, whose structures are less likely to be present in compound databases. The workflow was developed using openly accessible tools and, after parameter adjustment, could be applied to any data set with before and after information about various biological or chemical processes. PMID- 26575700 TI - miR-382 inhibits migration and invasion by targeting ROR1 through regulating EMT in ovarian cancer. AB - Increasing evidence suggests that microRNAs (miRNAs) play a critical role in tumorigenesis. Decreased expression of miR-382 has been observed in various types of cancers. However, the biological function of miRNA-382 in ovarian cancer is still largely unknown. Here, we found miR-382 was downregulated in human ovarian cancer tissues and cell lines. miR-382 inhibited ovarian cancer cell proliferation, migration, invasion and the epithelial-mesenchymal transition (EMT). Furthermore, we identified receptor tyrosine kinase orphan receptor 1 (ROR1) as a target of miR-382, and miR-382 rescued the promotion effect of ROR1 on migration, invasion and EMT process in SKOV3 and COV434 cells. Collectively, these findings revealed that miR-382 inhibits migration and invision by targeting ROR1 through regulating EMT in ovarian cancer, and might serve as a tumor suppressor in ovarian cancer. PMID- 26575701 TI - Association of cystatin C with heart failure with preserved ejection fraction in elderly hypertensive patients: potential role of altered collagen metabolism. AB - OBJECTIVES: Cystatin C has been shown to be associated with heart failure with preserved ejection fraction (HFPEF). In addition, myocardial fibrosis has been involved in diastolic dysfunction in HFPEF. Therefore, we hypothesized that increased cystatin C levels may be associated with altered collagen metabolism, contributing to diastolic dysfunction in patients with HFPEF. METHODS: One hundred and forty-one elderly hypertensive patients with HFPEF were included. Cardiac morphology and function was assessed by echocardiography. Circulating levels of cystatin C, biomarkers of collagen type I synthesis (carboxy-terminal propeptide of procollagen type I) and degradation [matrix metalloproteinase-1 (MMP-1) and its inhibitor TIMP-1] and osteopontin were analyzed by ELISA. Twenty elderly sex-matched patients with no identifiable cardiac disease were used as controls. In-vitro studies were performed in human cardiac fibroblasts. RESULTS: Compared with controls, cystatin C was increased (P < 0.001) in patients with HFPEF, even in those with a normal estimated glomerular filtration rate (eGFR; P < 0.05). Cystatin C was directly correlated with the estimated pulmonary capillary wedge pressure (P < 0.01), TIMP-1 and osteopontin (P < 0.001) and inversely correlated with MMP-1:TIMP-1 (P < 0.01), but not with carboxy-terminal propeptide of procollagen type I or MMP-1 in all patients with HFPEF. These associations were independent of eGFR. In vitro, osteopontin (P < 0.01) and TIMP 1 (P < 0.001) increased in the supernatant of cardiac fibroblasts exposed to cystatin C. CONCLUSION: In patients with HFPEF of hypertensive origin, cystatin C is increased and associated with diastolic dysfunction and alterations in collagen metabolism independently of eGFR. An excess of cystatin C might contribute to diastolic dysfunction in HFPEF by facilitating myocardial fibrosis via accumulation of osteopontin and TIMP-1. PMID- 26575702 TI - Carotid extramedial thickness is associated with local arterial stiffness in children. AB - OBJECTIVES: Experimental evidence suggests that structural changes to the arterial adventitia may be a key vascular determinant of early arterial stiffening, although this has not been directly studied. Accordingly, we hypothesized that in young children, in whom this relationship would not be altered by atheroma, carotid extramedial thickness (EMT), a measure that incorporates the thickness of the arterial adventitia, perivascular tissues and the internal jugular venous wall, would be associated with localized arterial stiffness of the same arterial region. METHODS: We studied 248 healthy prepubescent children (aged 8 years). Carotid diameter and carotid EMT were measured by high-resolution ultrasound. Carotid blood pressure was derived from brachial blood pressure and carotid tonometry. Three measures of localized arterial stiffness (beta stiffness index, distensibility coefficient and incremental modulus of elasticity) were calculated for the common carotid artery. Results were adjusted for heart rate and DBP, two important hemodynamic determinants of arterial stiffness. RESULTS: Carotid EMT was associated with all three measures of arterial stiffness (beta stiffness index: standardized beta = 0.121, P = 0.03; distensibility coefficient: standardized beta = -0.121, P = 0.05; incremental modulus of elasticity: standardized beta = 0.140, P = 0.02). These associations remained significant after adjustment for potential confounders such as sex, height, waist circumference, BMI and body surface area. CONCLUSION: Carotid EMT is associated with the stiffness of the same arterial segment in children, suggesting that the arterial adventitia may be involved in early changes in arterial stiffness during childhood. PMID- 26575703 TI - Gender-related differences in elderly patients with myocardial infarction in a European Centre. AB - BACKGROUND: Weighing the benefit of revascularization procedures against the risk of adverse events is particularly challenging in elderly patients suffering acute myocardial infarction (AMI). Based on a general gender gap in coronary interventions, the restraint in invasive procedures may be particularly high in elderly women. We therefore investigated gender-related differences in the frequency of coronary interventions as well as gender- and age-specific outcomes after coronary interventions in patients with AMI. DESIGN: We included 906 AMI patients in the final analysis. Among patients >= 80 years (n = 453), the intention to intervention (lysis and/or coronary angiography) for women was significantly lower compared to men (65.7% vs. 80.8%; P < 0.001), whereas in patients < 80 years (n = 453), the rate was similar between both genders (94.8% vs. 95.1%, P = 0.89). However, the assessment of potential risk factors for adverse events did not explain the gender gap. When assessing the benefit of any coronary intervention (stenting and/or lysis and/or coronary artery bypass graft), elderly women benefited at least as much with a hazard ratio (HR) for cardiovascular mortality of 0.56 (95% confidence interval [CI] 0.37-0.84, P = 0.005) compared to a HR of 0.96 (95% CI 0.76-1.23, P = 0.766) in elderly men. CONCLUSION: We observed a lower intention to coronary intervention in elderly women compared with men. However, the distribution of risk factors in elderly women and men who did not undergo coronary intervention was similar and therefore seemed not to be causal for the gender gap although the benefit of any coronary interventions was even higher in elderly women. PMID- 26575704 TI - PTX-3 release is increased by monocytes from patients with primary fibromyalgia without major depression. PMID- 26575705 TI - Preface. PMID- 26575706 TI - Common-ion effects on the deliquescence lowering of crystalline ingredient blends. AB - Deliquescence points (RH0, RH0mix) of ionic crystalline food ingredients and blends thereof were determined using water activity and moisture sorption techniques. Measured RH0mix values of ingredient blends with and without a common ion were compared to Ross equation predictions of deliquescence lowering. In binary blends with no common ion, measured RH0mix values ranged from 5% RH lower to 6% RH higher than predicted; however, when a common ion was present, the measured RH0mix was consistently 6-8% RH higher than predicted. In tertiary blends with a common ion, RH0mix values were 15-18% RH higher than predicted. The higher RH0mix in blends with a common ion is caused by counterion dissociation competition from the common ion. At equilibrium, these solutions will have fewer solutes and a greater vapor pressure than assumed by the Ross equation. A modified Ross equation was developed to compensate for the common-ion effect and improve RH0mix predictions. PMID- 26575707 TI - Impact of electron beam irradiation on fish gelatin film properties. AB - The objective of this work was to display the effect of electron beam accelerator doses on properties of plasticized fish gelatin film. Electron spin resonance indicates free radical formation during irradiation, which might induce intermolecular cross-linking. Tensile strength for gelatin film significantly increases after irradiation (improved by 30% for 60 kGy). The vapour permeability is weakly affected by irradiation. Surface tension and its polar component increase significantly and are in accordance with the increase of wettability. So, irradiation may change the orientation of polar groups of gelatin at the film surface and crosslink the hydrophobic amino acids. No modification of the crystallinity of the film is observed. These findings suggest that if structure changes, it only occurs in the amorphous phase of the gelatin matrix. It is also observed that irradiation enhances the thermal stability of the gelatin film, by increasing the glass transition temperature and the degradation temperature. PMID- 26575708 TI - Calcium and ascorbic acid affect cellular structure and water mobility in apple tissue during osmotic dehydration in sucrose solutions. AB - The effects of the addition of calcium lactate and ascorbic acid to sucrose osmotic solutions on cell viability and microstructure of apple tissue were studied. In addition, water distribution and mobility modification of the different cellular compartments were observed. Fluorescence microscopy, light microscopy and time domain nuclear magnetic resonance (TD-NMR) were respectively used to evaluate cell viability and microstructural changes during osmotic dehydration. Tissues treated in a sucrose-calcium lactate-ascorbic acid solution did not show viability. Calcium lactate had some effects on cell walls and membranes. Sucrose solution visibly preserved the protoplast viability and slightly influenced the water distribution within the apple tissue, as highlighted by TD-NMR, which showed higher proton intensity in the vacuoles and lower intensity in cytoplasm-free spaces compared to other treatments. The presence of ascorbic acid enhanced calcium impregnation, which was associated with permeability changes of the cellular wall and membranes. PMID- 26575709 TI - Comparison of methods for determining the deliquescence points of single crystalline ingredients and blends. AB - Many crystalline food ingredients undergo dissolution at a critical relative humidity known as the deliquescence point (RH0). Blends of crystalline ingredients exhibit deliquescence lowering, resulting in a deliquescence point (RH0mix) lower than the individual ingredient RH0s. To determine the effects of method type and data collection parameters, these deliquescence measurement methods were compared: saturated solution water activity, dynamic vapor sorption profiles (DVS), and dynamic dewpoint sorption profiles (DDI). Water activity measurements were broadly applicable for measuring deliquescence points when 1-4 g sample, 50-125 MUL/g water:solid ratio, and 24-48 h equilibration were used. DVS and DDI techniques should be limited to samples containing 1-2 ingredients due to crystal contact point effects on RH0mix measurement. Recommended DVS parameters are: 1% RH step, 0.01% equilibrium criteria, and 3h maximum time. DDI profiles were consistent with 50-150 mL/min vapor flow rates. Ingredient mutarotation, solute interactions in solution, and contact point limitations affect the determination of deliquescence points. PMID- 26575710 TI - The kinetics of the swelling process and the release mechanisms of Coriandrum sativum L. essential oil from chitosan/alginate/inulin microcapsules. AB - The encapsulation by spray drying method of coriander essential oil (CEO) in various materials (chitosan, alginate, chitosan/alginate, chitosan/inulin) was studied. The viscoelastic properties of the oil-in-water (O/W) emulsions and the characteristics of CEO-loaded microcapsules like morphology, moisture, wettability, solubility, flowability properties, swelling and release mechanisms were investigated. The chitosan microcapsules had a brain-like structure while the alginate and chitosan/alginate microcapsules are spherical with a smooth surface. The Compressibility Index (CI=29.09-32.25%) and Hausner Ratio (HR=1.38 1.44) values showed that all the microcapsules prepared correspond to the "poor" flowability powders group. The chitosan microcapsules exhibited the maximum release rate at pH 2.5 while the alginate microcapsules exhibited the maximum release rate at pH 6.5. Kinetics and mechanism of CEO release were studied using various mathematical models such as, zero order, first order, Higuchi model and Peppas model. The diffusional exponent (n) values of Peppas equation explains a non Fickian transport mechanism and diffusion or diffusion-swelling controlled process. PMID- 26575711 TI - Differentiation of rye and wheat flour as well as mixtures by using the kinetics of Karl Fischer water titration. AB - The aim of this study was to find a simple way to differentiate between rye and wheat flour and their mixtures by using the kinetic parameters of Karl Fischer water titration (KFT). Consequently, the water content and type of molecules in rye and wheat mixtures used in Romanian bread making have been investigated by means of volumetric KFT. Further, the kinetics of KFT have been determined and novel kinetic parameters corresponding to "surface" and "strongly-retained" water molecules have been identified to discriminate between rye and wheat flour and their mixtures. The "surface" and "strongly-retained" water reaction rates well correlate with the rye content in the flour mixtures, especially at higher temperature analysis (r>0.95). These parameters can be used as indicators for quality evaluation of such type of mixtures, as well as to identify adulteration by improper use of the rye-wheat flour ratios in bread making. PMID- 26575712 TI - Effect of oil lamination between plasticized starch layers on film properties. AB - To reduce the hygroscopic character of biodegradable starch-based films, rapeseed oil was incorporated by lamination (starch-oil-starch 3-layers technique). The lipid lamination followed by starch solution casting step induced an emulsion type structure of dried films. Composite films are more opalescent and glossier than fatty free starch films. For all the films, structure is heterogeneous in the cross-section only. Adding fat induced a twice decrease of the tensile strength. Thermal gravimetry analysis did not show differences between films with and without oil. Lipid reduced the moisture absorption particularly at higher RH as well as the surface swelling index, when water droplet contact occurred. Addition of lipids always decreases the contact angle for all liquid tested, except for water. Surface affinity of films for liquids less polar that water increased with rapeseed oil addition. The addition of rapeseed oil significantly reduces water vapour and oxygen permeability. PMID- 26575713 TI - The use of potato fibre to improve bread physico-chemical properties during storage. AB - Bread staling reduction is a very important issue for the food industry. A fibre with high water holding capacity, extracted from potato peel, was studied for its ability to reduce bread staling even if employed at low level (0.4 g fibre/100 g flour). Physico-chemical properties (water activity, moisture content, frozen water content, amylopectin retrogradation) and (1)H Nuclear Magnetic Resonance molecular mobility were characterised in potato fibre added bread over 7 days of storage. Potato fibre addition in bread slightly affected water activity and moisture content, while increased frozen water content and resulted in a softer bread crumb, more importantly when the optimal amount of water was used in the formulation. Potato fibre also reduced (1)H NMR molecular mobility changes in bread crumb during storage. Potato fibre addition in bread contributed to reduce bread staling. PMID- 26575714 TI - Effect of freezing on microstructure and degree of syneresis in differently formulated fruit fillings. AB - This study describes the syneresis and its effect on microstructure in fruit fillings within a wide range of the total soluble solids content and with or without hydrocolloids upon freezing. Linear models showed the relevance of the addition of pectin and gellan gum to fillings to prevent syneresis, increasing the water-holding capacity especially after freezing. Microstructural experiments by means of NMR spin-spin relaxometry combined with fluorescence microscopy allowed to observe that the continuous hydrocolloid gel, containing the dispersed solution of native fruit parts with the addition of inulin and sugars, changed its structure/distribution according to the amount of each ingredient and due to the freezing process. Relaxometry results confirmed that hydrocolloids strength was correlated (R(2)>0.92) with water-holding capacity, due to a relationship between the signal given by the water chemically exchanging with biopolymers, and the changes in the degree of syneresis. PMID- 26575715 TI - Water and temperature contribution to the structuration of starch matrices in the presence of flavour. AB - The effect of modulating the gelatinisation extent by hydration (50/50 and 80/20 water to starch ratio) and temperature (65 or 85 degrees C) on various properties of wheat starch in presence of flavours has been studied. The hydrothermal treatments resulted in samples with different properties. The lowest residual flavour content was found in samples treated at the highest hydration and temperature (85 degrees C) while the other treatment conditions led to samples with similar residual flavour content. Ethyl hexanoate significantly increased the characteristic pasting viscosities compared to starch+/-2-hexanone; suggesting a greater structuration with ethyl hexanoate. Heating starch in excess water caused amylopectin melting, but promoted an incomplete granular swelling as revealed by RVA. This study suggested that lowering the hydration upon treatment could limit both crystal melting (with a residual crystalline content up to 38% in the most extreme conditions) and granular swelling but increased granule organisation like following annealing. PMID- 26575716 TI - Adsorption behaviour of bulgur. AB - The aim of this research was to determine the adsorption behaviour of bulgur. Three different particle sizes (250%. The A. fumigatus specific IgE increased in only five (38.5%) subjects during exacerbation. Thus, the total IgE is a useful test in monitoring treatment responses in ABPA while A. fumigatus specific IgE has limited utility. PMID- 26575792 TI - Facile Synthesis of n-type (AgIn)(x)Zn(2(1-x))S2/p-type Ag2S Nanocomposite for Visible Light Photocatalytic Reduction To Detoxify Hexavalent Chromium. AB - n-type (AgIn)(x)Zn(2(1-x))S2/p-type Ag2S nanocomposites with 10%, 20%, and 30% Ag2S loading were successfully synthesized via the simple solvothermal and sol gel methods. The as-prepared nanocomposites were characterized, and their visible light photocatalytic reductions were tested for detoxification of hexavalent chromium (Cr(VI)). The results showed only 20 mg of the as-prepared nanocomposites could reduce 100 mL of 20 ppm potassium dichromate by almost 100% in less than 90 min without adding any hole scavenger agents and pH adjustment (pH = 7). The good photocatalytic reduction was related to the narrower bandgap of (AgIn)(x)Zn(2(1-x))S2 solid solution because of the hybridized orbitals of Ag, In, Zn, and S and low recombination rate of photogenerated electron and hole pairs due to the effectiveness of p-type Ag2S and n-type (AgIn)(x)Zn(2(1-x))S2 nanoheterojunctions. This work not only gives a contribution to the creation of visible light photocatalysis for wide-bandgap semiconductors, but also extends our technological viewpoints in designing highly efficient metal sulfide photocatalyst. To the best of our knowledge, this work is the first finding of a high photocatalytic reduction of hexavalent chromium under visible light illumination by simultaneously using both concepts of p-n nanoheterojunction and solid solution in our photocatalyst design. In this present work, these concepts were used to replace the use of hole scavenger agents, which were commonly used by many other works to retard the recombination rate of photoinduced electron and hole pairs for photodegradation of hexavalent chromium. PMID- 26575790 TI - Protein 4.1N acts as a potential tumor suppressor linking PP1 to JNK-c-Jun pathway regulation in NSCLC. AB - Protein 4.1N is a member of protein 4.1 family and has been recognized as a potential tumor suppressor in solid tumors. Here, we aimed to investigate the role and mechanisms of 4.1N in non-small cell lung cancer (NSCLC). We confirmed that the expression level of 4.1N was inversely correlated with the metastatic properties of NSCLC cell lines and histological grade of clinical NSCLC tissues. Specific knockdown of 4.1N promoted tumor cell proliferation, migration and adhesion in vitro, and tumor growth and metastasis in mouse xenograft models. Furthermore, we identified PP1 as a novel 4.1N-interacting molecule, and the FERM domain of 4.1N mediated the interaction between 4.1N and PP1. Further, ectopic expression of 4.1N could inactivate JNK-c-Jun signaling pathway through enhancing PP1 activity and interaction between PP1 and p-JNK. Correspondingly, expression of potential downstream metastasis targets (ezrin and MMP9) and cell cycle targets (p53, p21 and p19) of JNK-c-Jun pathway were also regulated by 4.1N. Our data suggest that down-regulation of 4.1N expression is a critical step for NSCLC development and that repression of JNK-c-Jun signaling through PP1 is one of the key anti-tumor mechanisms of 4.1N. PMID- 26575793 TI - Evolution of increased adult longevity in Drosophila melanogaster populations selected for adaptation to larval crowding. AB - In holometabolous animals such as Drosophila melanogaster, larval crowding can affect a wide range of larval and adult traits. Adults emerging from high larval density cultures have smaller body size and increased mean life span compared to flies emerging from low larval density cultures. Therefore, adaptation to larval crowding could potentially affect adult longevity as a correlated response. We addressed this issue by studying a set of large, outbred populations of D. melanogaster, experimentally evolved for adaptation to larval crowding for 83 generations. We assayed longevity of adult flies from both selected (MCUs) and control populations (MBs) after growing them at different larval densities. We found that MCUs have evolved increased mean longevity compared to MBs at all larval densities. The interaction between selection regime and larval density was not significant, indicating that the density dependence of mean longevity had not evolved in the MCU populations. The increase in longevity in MCUs can be partially attributed to their lower rates of ageing. It is also noteworthy that reaction norm of dry body weight, a trait probably under direct selection in our populations, has indeed evolved in MCU populations. To the best of our knowledge, this is the first report of the evolution of adult longevity as a correlated response of adaptation to larval crowding. PMID- 26575794 TI - Hollow and Core-Shell Microgels at Oil-Water Interfaces: Spreading of Soft Particles Reduces the Compressibility of the Monolayer. AB - We investigate the influence of a solid core and of the cross-link density on the compression of microgel particles at oil-water interfaces by means of compression isotherms and computer simulations. We investigate particles with different morphology, namely core-shell particles containing a solid silica core surrounded by a cross-linked polymer shell of poly(N-isopropylacrylamide), and the corresponding hollow microgels where the core was dissolved. The polymer shell contains different amounts of cross-linker. The compression isotherms show that the removal of the core leads to an increase of the surface pressure at low compression, and the same effect can be observed when the polymer cross-link density is decreased. Low cross-link density and a missing core thus facilitate spreading of the polymer chains at the interface and, at high compression, hinder the transition to close hexagonal packing. Furthermore, the compression modulus only depends on the cross-link density at low compression, and no difference can be observed between the core-shell particles and the corresponding hollow microgels. It is especially remarkable that a low cross-link density leads to a high compression modulus at low compression, while this behavior is reversed at high compression. Thus, the core does not influence the particle behavior until the polymer shell is highly compressed and the core is directly exposed to the pressure. This is related to an enhanced spreading of polymer chains at the interface and thus high adsorption energy. These conclusions are fully supported by computer simulations which show that the cross-link density of the polymer shell defines the degree of deformation at the interface. Additionally, the core restricts the spreading of polymer chains at the interface. These results illustrate the special behavior of soft microgels at liquid interfaces. PMID- 26575795 TI - Role of Presolvation and Anharmonicity in Aqueous Phase Hydrated Proton Solvation and Transport. AB - Results from condensed phase ab initio molecular dynamics (AIMD) simulations suggest a proton transfer reaction is facilitated by "presolvation" in which the hydronium is transiently solvated by four water molecules, similar to the typical solvation structure of water, by accepting a weak hydrogen bond from the fourth water molecule. A new version 3.2 multistate empirical valence bond (MS-EVB 3.2) model for the hydrated excess proton incorporating this presolvation behavior is therefore developed. The classical MS-EVB simulations show similar structural properties as those of the previous model but with significantly improved diffusive behavior. The inclusion of nuclear quantum effects in the MS-EVB also provides an even better description of the proton diffusion rate. To quantify the influence of anharmonicity, a second model (aMS-EVB 3.2) is developed using the anharmonic aSPC/Fw water model, which provides similar structural properties but improved spectroscopic responses at high frequencies. PMID- 26575796 TI - Hybrid of MoS2 and Reduced Graphene Oxide: A Lightweight and Broadband Electromagnetic Wave Absorber. AB - Electromagnetic wave absorbing materials that can exhibit effective absorption in a broad bandwidth at a thin thickness are strongly desired due to their widespread applications in electronic devices. In this study, hybrids of MoS2 and reduced graphene oxide (RGO) were prepared and their microwave absorption performance was investigated for the first time. It was found that a thin sample consisting of 10 wt % MoS2/RGO hybrid in the wax matrix exhibited an effective microwave absorption bandwidth of 5.72 GHz at the thickness less than 2.0 mm. The highest reflection loss of -50.9 dB was observed at 11.68 GHz for a sample with a thickness of 2.3 mm. Results obtained in this study indicate that hybrids of MoS2 and RGO are promising microwave absorbing materials, which can exhibit broad effective absorption bandwidth at low filler loading and thin thickness. PMID- 26575797 TI - Effect of Bronsted Acids and Bases, and Lewis Acid (Sn(2+)) on the Regiochemistry of the Reaction of Amines with Trifluoromethyl-beta-diketones: Reaction of 3 Aminopyrrole to Selectively Produce Regioisomeric 1H-Pyrrolo[3,2-b]pyridines. AB - Reaction of 3-aminopyrrole (as its salt) with trifluoromethyl-beta-diketones gave gamma-1H-pyrrolo[3,2-b]pyridines via reaction at the less reactive carbonyl group. The trifluoromethyl group increased the electrophilicity of the adjacent carbonyl group and decreased the basicity of the hydroxyl group of the CF3 amino alcohol formed. This amino alcohol was formed faster, but its subsequent dehydration to the beta-enaminone was slow resulting in the preferential formation of the gamma-regioisomer. Reaction of 4,4,4-trifluoro-1-phenyl-1,3 butadione with 3-aminopyrrole was carried out using a series of 6 amine buffers. Yields of the alpha-1H-pyrrolo[3,2-b]pyridine increased as the pKa of the amine buffer decreased. Surprisingly the yield went down at higher pKas. There was a change in mechanism as the reaction mixture became more basic. With strong amines trifluoromethyl-beta-diketones were present mainly or completely as the enolate. Under reductive conditions (3-nitropyrrole/Sn/AcOH/trifluoromethyl-beta-diketone) the alpha-1H-pyrrolo[3,2-b]pyridine was the major product as a result of Lewis acid catalysis by Sn(2+). Similar alpha-regiochemistry was observed when the reaction of the 3-aminopyrrole salt with trifluoromethyl-beta-diketones was carried out in the presence of base and tin(II) acetate. PMID- 26575798 TI - Rapid, Reversible, Solid-Gas and Solution-Phase Insertion of CO2 into In-P Bonds. AB - The P,P-chelated heteroleptic complex bis[bis(diisopropylphosphino)amido]indium chloride [(i-Pr2P)2N]2InCl was prepared in high yield by treating InCl3 with 2 equiv of (i-Pr2P)2NLi in Et2O/tetrahydrofuran solution. Samples of [(i Pr2P)2N]2InCl in a pentane slurry, a CH2Cl2 solution, or in the solid state were exposed to CO2, resulting in the insertion of CO2 into two of the four M-P bonds to produce [O2CP(i-Pr2)NP(i-Pr2)]2InCl in each case. Compounds were characterized by multinuclear NMR and IR spectroscopy, as well as single-crystal X-ray diffraction. ReactIR solution studies show that the reaction is complete in less than 1 min at room temperature in solution and in less than 2 h in the solid-gas reaction. The CO2 complex is stable up to at least 60 degrees C under vacuum, but the starting material is regenerated with concomitant loss of carbon dioxide upon heating above 75 degrees C. The compound [(i-Pr2P)2N]2InCl also reacts with CS2 to give a complicated mixture of products, one of which was identified as the CS2 cleavage product [S?P(i-Pr2)NP(i-Pr2)]2InCl]2(MU-Cl)[MU-(i-Pr2P)2N)]. PMID- 26575799 TI - Nitrogen oxides under pressure: stability, ionization, polymerization, and superconductivity. AB - Nitrogen oxides are textbook class of molecular compounds, with extensive industrial applications. Nitrogen and oxygen are also among the most abundant elements in the universe. We explore the N-O system at 0 K and up to 500 GPa though ab initio evolutionary simulations. Results show that two phase transformations of stable molecular NO2 occur at 7 and 64 GPa, and followed by decomposition of NO2 at 91 GPa. All of the NO(+)NO3(-) structures are found to be metastable at T = 0 K, so experimentally reported ionic NO(+)NO3(-) is either metastable or stabilized by temperature. N2O5 becomes stable at 9 GPa, and transforms from P-1 to C2/c structure at 51 GPa. NO becomes thermodynamically stable at 198 GPa. This polymeric phase is superconducting (Tc = 2.0 K) and contains a -N-N- backbone. PMID- 26575800 TI - Lifetime Exposure to Ambient Pollution and Lung Function in Children. AB - RATIONALE: Few studies have examined associations between exposure to air pollution and childhood lung function after implementation of strict air quality regulations in the 1990s. OBJECTIVES: To assess traffic-related pollution exposure and childhood lung function. METHODS: We geocoded addresses for 614 mother-child pairs enrolled during pregnancy in the Boston area 1999-2002 and followed them until a mid-childhood visit (median age, 7.7). We calculated the proximity of the home to the nearest major roadway. We estimated first year of life, lifetime, and prior-year exposure to particulate matter with a diameter smaller than 2.5 MUm (PM2.5) by a hybrid model using satellite-derived aerosol optical depth, and to black carbon (BC) by a land-use regression model. MEASUREMENTS AND MAIN RESULTS: Residential proximity to roadway and prior-year and lifetime PM2.5 and BC exposure were all associated with lower FVC. Associations with FEV1 were also negative and proportionally similar. Pollution exposures were not associated with the FEV1/FVC ratio or bronchodilator response. Compared with distances greater than or equal to 400 m, living less than 100 m from a major roadway was associated with lower FVC (-98.6 ml; -176.3 to -21.0). Each 2 MUg/m(3) increment in prior-year PM2.5 was associated with lower FVC ( 21.8 ml; -43.9 to 0.2) and higher odds of FEV1 less than 80% predicted (1.41; 1.03-1.93). Each 0.2 MUg/m(3) increment in prior-year BC was associated with a 38.9 ml (-70.4 to -7.3) lower FVC. CONCLUSIONS: Estimates of long-term exposure to ambient pollution, including proximity to major roadway, PM2.5, and BC (a traffic-related PM2.5 constituent), were associated with lower lung function in this Boston-area cohort of children with relatively low pollution exposures. PMID- 26575801 TI - Ingestible Drug Adherence Monitors: Trending Toward a Surveillance Society? PMID- 26575802 TI - Young People's Experiences of Participation in Clinical Trials: Reasons for Taking Part. AB - Given the lack of knowledge about safety and efficacy of many treatments for children, pediatric clinical trials are important, but recruitment for pediatric research is difficult. Little is known about children's perspective on participating in trials. The purpose of this study was to understand the experiences and motivations of young people who took part in clinical trials. This is a qualitative interview study of 25 young people aged 10-23 who were invited to take part in clinical trials. Interviews were audio or video recorded and analyzed using framework analysis. Young peoples' motivations were both personal benefit and helping others. Both incentives appeared to be more complex than expected. We introduce the terms "network of exchange" and "intergenerational solidarity" to describe these motivations. To improve recruitment, professionals should be more open about research opportunities, provide better information, and give young people feedback after the trial has ended. PMID- 26575803 TI - Learning From Research Participants. PMID- 26575804 TI - Let's Be Clear About Children and Young People. PMID- 26575805 TI - The Use of Dogmas in Pediatric Research Ethics. PMID- 26575806 TI - Empirical Data on Benefits Children Experience in Clinical Research. PMID- 26575807 TI - Why Young People Participate in Clinical Trials and the Implications for Research Governance. PMID- 26575808 TI - Recruiting Children for Clinical Trials: Lessons From Pediatric Oncology. PMID- 26575809 TI - Different Context, Similar Motives: External Influences on Motivation. PMID- 26575810 TI - Young Persons in Research: A Call for the Engagement of Youth in Mental Health Research. PMID- 26575811 TI - Gatekeeping by Professionals in Recruitment of Pediatric Research Participants: Indeed an Undesirable Practice. PMID- 26575812 TI - Involving Youth Voices in Research Protocol Reviews. PMID- 26575813 TI - Should We Tell Children and Young People About the Positive Experience of Taking Part in Clinical Trials? PMID- 26575814 TI - Sleepwalking Into Infertility: The Need for a Public Health Approach Toward Advanced Maternal Age. AB - In Western countries today, a growing number of women delay motherhood until their late 30s and even 40s, as they invest time in pursuing education and career goals before starting a family. This social trend results from greater gender equality and expanded opportunities for women and is influenced by the availability of contraception and assisted reproductive technologies (ART). However, advanced maternal age is associated with increased health risks, including infertility. While individual medical solutions such as ART and elective egg freezing can promote reproductive autonomy, they entail significant risks and limitations. We thus argue that women should be better informed regarding the risks of advanced maternal age and ART, and that these individual solutions need to be supplemented by a public health approach, including policy measures that provide women with the opportunity to start a family earlier in life without sacrificing personal career goals. PMID- 26575815 TI - Perfectionism Versus Neutrality in Public Health: The Case of Advanced Maternal Age. PMID- 26575816 TI - The Limits of Reproductive Freedom: Advanced Maternal Age and Harm to the Unborn Child. PMID- 26575817 TI - "Sleepwalking into Infertility": The Need for a Gentle Wake-Up Call. PMID- 26575818 TI - Advanced Maternal Age in the Shadow of Confucianism. PMID- 26575819 TI - Is Advanced Maternal Age a Public Health Issue? PMID- 26575820 TI - Better Sex Education for Young People Is a Public Health Solution to the Problem of Advanced Maternal Age. PMID- 26575821 TI - Not Finding the Right Partner Is a Social Phenomenon Affecting Advanced Maternal Age. PMID- 26575822 TI - Human phosphodiesterase 4D7 (PDE4D7) expression is increased in TMPRSS2-ERG positive primary prostate cancer and independently adds to a reduced risk of post surgical disease progression. AB - BACKGROUND: There is an acute need to uncover biomarkers that reflect the molecular pathologies, underpinning prostate cancer progression and poor patient outcome. We have previously demonstrated that in prostate cancer cell lines PDE4D7 is downregulated in advanced cases of the disease. To investigate further the prognostic power of PDE4D7 expression during prostate cancer progression and assess how downregulation of this PDE isoform may affect disease outcome, we have examined PDE4D7 expression in physiologically relevant primary human samples. METHODS: About 1405 patient samples across 8 publically available qPCR, Affymetrix Exon 1.0 ST arrays and RNA sequencing data sets were screened for PDE4D7 expression. The TMPRSS2-ERG gene rearrangement status of patient samples was determined by transformation of the exon array and RNA seq expression data to robust z-scores followed by the application of a threshold>3 to define a positive TMPRSS2-ERG gene fusion event in a tumour sample. RESULTS: We demonstrate that PDE4D7 expression positively correlates with primary tumour development. We also show a positive association with the highly prostate cancer-specific gene rearrangement between TMPRSS2 and the ETS transcription factor family member ERG. In addition, we find that in primary TMPRSS2-ERG-positive tumours PDE4D7 expression is significantly positively correlated with low-grade disease and a reduced likelihood of progression after primary treatment. Conversely, PDE4D7 transcript levels become significantly decreased in castration resistant prostate cancer (CRPC). CONCLUSIONS: We further characterise and add physiological relevance to PDE4D7 as a novel marker that is associated with the development and progression of prostate tumours. We propose that the assessment of PDE4D7 levels may provide a novel, independent predictor of post-surgical disease progression. PMID- 26575823 TI - Reporting of cigar use among adolescent tobacco smokers. AB - INTRODUCTION: With the changing landscape of tobacco products, the divide between cigarettes and cigars is obscured, so understanding adolescent reporting of cigar use is needed to improve best practices for surveillance, screening, and prevention/intervention. This study examined adolescents' reported cigar use and correlates of use. METHODS: Participants (N=186) were 13-17year old tobacco users participating in a prospective study of adolescent smoking behaviors. Measurement occurred at baseline and 24-months, and included demographics, nicotine dependence, tobacco use, and quit attempts. Cigar use was assessed as, "have you smoked a cigar in the last 30days" and by brand specific use in the past 30days. FINDINGS: Cigar use was reported by 51 adolescents (27%), and increased to 76 (41%) when identifying by brand name. African Americans (32%) were more likely to smoke cigars than whites (10%, p<.01), Asian/Pacific Islanders (3%, p=.04), and multiracial participants (24%, p=.05). Cigarette-only users smoked more per day (p=.04) and had higher cotinine levels (p=.05) than cigar users. Number of prior quit attempts (p=.84) did not differ by group. Group differences in addiction were found between cigar users and cigarette only users (p<.01). At 24months, more baseline cigar users were tobacco abstinent than cigarette only users (16% versus 7%, p<0.01, respectively). CONCLUSIONS: Assessment of brand-specific cigars nearly doubled the reporting among adolescent users. Cigar users differed from cigarette-only users in consumption and likelihood of abstinence at 24 months. For more accurate surveillance and to inform treatment considerations, surveys of adolescent tobacco use should include cigars, including brand names, in the assessment strategy. PMID- 26575824 TI - Compression Limit of Two-Dimensional Water Constrained in Graphene Nanocapillaries. AB - Evaluation of the tensile/compression limit of a solid under conditions of tension or compression is often performed to provide mechanical properties that are critical for structure design and assessment. Algara-Siller et al. recently demonstrated that when water is constrained between two sheets of graphene, it becomes a two-dimensional (2D) liquid and then is turned into an intriguing monolayer solid with a square pattern under high lateral pressure [ Nature , 2015 , 519 , 443 - 445 ]. From a mechanics point of view, this liquid-to-solid transformation characterizes the compression limit (or metastability limit) of the 2D monolayer water. Here, we perform a simulation study of the compression limit of 2D monolayer, bilayer, and trilayer water constrained in graphene nanocapillaries. At 300 K, a myriad of 2D ice polymorphs (both crystalline-like and amorphous) are formed from the liquid water at different widths of the nanocapillaries, ranging from 6.0 to11.6 A. For monolayer water, the compression limit is typically a few hundred MPa, while for the bilayer and trilayer water, the compression limit is 1.5 GPa or higher, reflecting the ultrahigh van der Waals pressure within the graphene nanocapillaries. The compression-limit (phase) diagram is obtained at the nanocapillary width versus pressure (h-P) plane, based on the comprehensive molecular dynamics simulations at numerous thermodynamic states as well as on the Clapeyron equation. Interestingly, the compression-limit curves exhibit multiple local minima. PMID- 26575827 TI - Biotechnology Innovators To Convene in Cape Town, South Africa: Pharmacogenetics and Precision Medicine Conference (April 7-9, 2016). PMID- 26575826 TI - Combination with vorinostat overcomes ABT-263 (navitoclax) resistance of small cell lung cancer. AB - Small cell lung cancer (SCLC) is an aggressive tumor type with high mortality. One promising approach for SCLC treatment would be to utilize agents targeting molecular abnormalities regulating resistance to apoptosis. BH3 mimetic antagonists, such as ABT-737 and its orally available derivative ABT-263 (navitoclax) have been developed to block the function of pro-survival BCL-2 family members. The sensitivity of SCLC to these drugs varies over a broad range in vitro and in clinical trials. We have previously shown that the expression of Noxa, a BH3-only pro-apoptotic BCL-2 family protein, is a critical determinant of sensitivity to ABT-737. Thus, pharmacological up-regulation of Noxa could enhance cell death induced by the BH3 mimetics. We find that the combination of ABT-263 and a HDAC inhibitor, vorinostat, efficiently induces apoptosis in a variety of SCLC cell lines, including ABT-263 resistant cell lines. Cell death induced by combined treatment is Noxa- and/or BIM-dependent in some cell lines but in others appears to be mediated by down-regulation of BCL-XL and release of BAK from BCL XL and MCL-1. These results suggest that combination of HDAC inhibitors and BCL-2 inhibitors could be an alternative and effective regimen for SCLC treatment. PMID- 26575828 TI - Anakinra delayed skin allergy expressing as both injection site reactions and generalized exanthema. PMID- 26575829 TI - A risk prediction model for xerostomia: a retrospective cohort study. AB - OBJECTIVE: We investigated the prevalence of xerostomia in dental patients and built a xerostomia risk prediction model by incorporating a wide range of risk factors. MATERIALS AND METHODS: Socio-demographic data, past medical history, self-reported dry mouth and related symptoms were collected retrospectively from January 2010 to September 2013 for all new dental patients. A logistic regression framework was used to build a risk prediction model for xerostomia. External validation was performed using an independent data set to test the prediction power. RESULTS: A total of 12 682 patients were included in this analysis (54.3%, females). Xerostomia was reported by 12.2% of patients. The proportion of people reporting xerostomia was higher among those who were taking more medications (OR = 1.11, 95% CI = 1.08-1.13) or recreational drug users (OR = 1.4, 95% CI = 1.1 1.9). Rheumatic diseases (OR = 2.17, 95% CI = 1.88-2.51), psychiatric diseases (OR = 2.34, 95% CI = 2.05-2.68), eating disorders (OR = 2.28, 95% CI = 1.55-3.36) and radiotherapy (OR = 2.00, 95% CI = 1.43-2.80) were good predictors of xerostomia. For the test model performance, the ROC-AUC was 0.816 and in the external validation sample, the ROC-AUC was 0.799. CONCLUSION: The xerostomia risk prediction model had high accuracy and discriminated between high- and low risk individuals. Clinicians could use this model to identify the classes of medications and systemic diseases associated with xerostomia. PMID- 26575830 TI - Juvenile, adult and late-onset systemic lupus erythematosus: a long term follow up study from a geographic and ethnically homogeneous population. AB - OBJECTIVES: This paper aims to identify clinical and serological differences, damage accrual and mortality, in juvenile, adult and late-onset SLE. METHODS: We conducted our study with patients fulfilling SLE classification criteria taken from the Hospital Gregorio Maranon Autoimmune Systemic Rheumatic Diseases' Registry (1986 to 2012). Clinical characteristics, laboratory data and therapies used during the course of the disease were analysed with patients divided into 3 groups: juvenile-onset (<= 18 years), adult-onset (19-50) and late onset (>50 years). RESULTS: Four hundred and forty-five patients were included. Renal disease and cutaneous manifestations were more frequent in the juvenile-onset group at disease onset. During follow-up, juvenile-onset group presented a higher incidence of renal disease, malar rash, Raynaud's phenomenon, cutaneous vasculitis, and neuropsychiatric manifestations than the other two groups. Arthritis and lymphopoenia were more frequent in the adult-onset group. Arterial hypertension and neoplasm were more frequent in the late-onset group. Low serum complement, anti-dsDNA, anti-U1RNP and anti-Sm antibodies were more common in the juvenile-onset group. Patients with late-onset SLE had more damage accrual. Thirty-seven patients (8.3%) died during the study. All-cause mortality was significantly higher in the late-onset group. Age at disease onset >50 years was an independent risk factor for damage accrual (OR, 2.2; 95%CI, 1.1-4.6; p=0.029) and mortality (OR, 2.6; 95%CI, 1.1-6.3; p=0.03). CONCLUSIONS: We found significant differences in clinical and serological profiles between juvenile, adult and late-onset SLE. The most significant of which was a higher prevalence of neuropsychiatric and renal complications as well as different autoantibody signatures for the juvenile-onset group. PMID- 26575831 TI - KRN4 Controls Quantitative Variation in Maize Kernel Row Number. AB - Kernel row number (KRN) is an important component of yield during the domestication and improvement of maize and controlled by quantitative trait loci (QTL). Here, we fine-mapped a major KRN QTL, KRN4, which can enhance grain productivity by increasing KRN per ear. We found that a ~3-Kb intergenic region about 60 Kb downstream from the SBP-box gene Unbranched3 (UB3) was responsible for quantitative variation in KRN by regulating the level of UB3 expression. Within the 3-Kb region, the 1.2-Kb Presence-Absence variant was found to be strongly associated with quantitative variation in KRN in diverse maize inbred lines, and our results suggest that this 1.2-Kb transposon-containing insertion is likely responsible for increased KRN. A previously identified A/G SNP (S35, also known as Ser220Asn) in UB3 was also found to be significantly associated with KRN in our association-mapping panel. Although no visible genetic effect of S35 alone could be detected in our linkage mapping population, it was found to genetically interact with the 1.2-Kb PAV to modulate KRN. The KRN4 was under strong selection during maize domestication and the favorable allele for the 1.2 Kb PAV and S35 has been significantly enriched in modern maize improvement process. The favorable haplotype (Hap1) of 1.2-Kb-PAV-S35 was selected during temperate maize improvement, but is still rare in tropical and subtropical maize germplasm. The dissection of the KRN4 locus improves our understanding of the genetic basis of quantitative variation in complex traits in maize. PMID- 26575833 TI - Chronic Thromboembolic Pulmonary Hypertension and Assessment of Right Ventricular Function in the Piglet. AB - An original piglet model of Chronic Thromboembolic Pulmonary Hypertension (CTEPH) associated with chronic Right Ventricular (RV) dysfunction is described. Pulmonary Hypertension (PH) was induced in 3-week-old piglets by a progressive obstruction of the pulmonary vascular bed. A ligation of the left Pulmonary Artery (PA) was performed first through a mini-thoracotomy. Second, weekly embolizations of the right lower pulmonary lobe were done under fluoroscopic guidance with n-butyl-2-cyanoacrylate during 5 weeks. Mean Pulmonary Arterial Pressure (mPAP) measured by ritght heart catheterism, increased progressively, as well as Right Atrial pressure and Pulmonary Vascular Resistances (PVR) after 5 weeks compared to sham animals. Right Ventricular (RV) structural and functional remodeling were assessed by transthoracic echocardiography (RV diameters, RV wall thickness, RV systolic function). RV elastance and RV-pulmonary coupling were assessed by Pressure-Volume Loops (PVL) analysis with conductance method. Histologic study of the lung and the right ventricle were also performed. Molecular analyses on RV fresh tissues could be performed through repeated transcutaneous endomyocardial biopsies. Pulmonary microvascular disease in obstructed and unobstructed territories was studied from lung biopsies using molecular analyses and pathology. Furthermore, the reliability and the reproducibility was associated with a range of PH severity in animals. Most aspects of the human CTEPH disease were reproduced in this model, which allows new perspectives for the understanding of the underlying mechanisms (mitochondria, inflammation) and new therapeutic approaches (targeted, cellular or gene therapies) of the overloaded right ventricle but also pulmonary microvascular disease. PMID- 26575834 TI - Tuning plasmonic and chemical enhancement for SERS detection on graphene-based Au hybrids. AB - Various graphene-based Au nanocomposites have been developed as surface-enhanced Raman scattering (SERS) substrates recently. However, efficient use of SERS has been impeded by the difficulty of tuning SERS enhancement effects induced from chemical and plasmonic enhancement by different preparation methods of graphene. Herein, we developed graphene-based Au hybrids through physical sputtering gold NPs on monolayer graphene prepared by chemical vapor deposition (CVD) as a CVD G/Au hybrid, as well as graphene oxide-gold (GO/Au) and reduced-graphene oxide (rGO/Au) hybrids prepared using the chemical in situ crystallization growth method. Plasmonic and chemical enhancements were tuned effectively by simple methods in these as-prepared graphene-based Au systems. SERS performances of CVD G/Au, rGO/Au and GO/Au showed a gradually monotonic increasing tendency of enhancement factors (EFs) for adsorbed Rhodamine 6G (R6G) molecules, which show clear dependence on chemical bonds between graphene and Au, indicating that the chemical enhancement can be steadily controlled by chemical groups in a graphene based Au hybrid system. Most notably, we demonstrate that the optimized GO/Au was able to detect biomolecules of adenine, which displayed high sensitivity with a detection limit of 10(-7) M as well as good reproducibility and uniformity. PMID- 26575832 TI - Vitamin D, leptin and impact on immune response to seasonal influenza A/H1N1 vaccine in older persons. AB - BACKGROUND: Influenza-related complications are highest in the elderly. Vaccine efficacy is lower due to immunosenescence. Vitamin D's immunomodulatory role was studied in the context of vaccine response. METHODS: We evaluated the effect of baseline 25-(OH) D on vaccine-induced immunological response in a cohort of 159 healthy subjects ages 50-74 in Rochester, MN, who received one dose of seasonal trivalent 2010-2011 influenza vaccine, containing A/California/H1N1- like virus. We examined correlations between 25-(OH) D, leptin, and leptin-related gene SNPs to understand the role of leptin and vitamin D's effects. RESULTS: The median (IQR) baseline for total 25-(OH) D was 44.4 ng/mL (36.6-52.2 ng/mL). No correlation was observed with age. No correlation between 25-(OH) D levels and humoral immune outcomes existed at any timepoint. There was a weak positive correlation between 25-(OH) D levels and change (Day 75-Day 0) in influenza specific granzyme-B response (r=0.16, p=0.04). We found significant associations between 3 SNPs in the PPARG gene and 25-(OH) D levels (rs1151996, p=0.01; rs1175540, p= 0.02; rs1175544, p=0.03). CONCLUSION: Several SNPs in the PPARG gene were significantly associated with baseline 25-(OH) D levels. Understanding the functional and mechanistic relationships between vitamin D and influenza vaccine-induced immunity could assist in directing new influenza vaccine design. PMID- 26575836 TI - Anti-Coagulation and Deep Brain Stimulation: Never the Twain Shall Meet. AB - Deep brain stimulation (DBS) for movement disorders is usually performed in older patients who may be prone to vascular co-morbidities such as atrial fibrillation or valvular disease that may require anti-coagulation. This potentially increases the risk of peri-operative intra-cranial haemorrhage and thus anti-coagulation therapy is generally considered a contraindication for DBS implantation. Cessation of anti-coagulants has to be balanced with the risk of thrombosis or ischaemic complications and, to compound issues, there is a paucity of guidelines and consensus on the management of anti-coagulation in patients undergoing DBS. To date, we have performed DBS successfully in 4 patients on lifelong anti coagulation, having carefully managed their anti-coagulation in the peri operative period. One patient developed a moderate haematoma around the implantable pulse generator 2 days post-operatively that was treated conservatively. Otherwise no other adverse effects or haemorrhagic complications occurred. We therefore propose that DBS implantation in this group of patients is safe, provided strict observation of protocols and careful management of the anti coagulation therapy are undertaken. We describe the indications for anti coagulation and provide a guideline for therapy in such patients according to our experience. PMID- 26575837 TI - Mn(II) tags for DEER distance measurements in proteins via C-S attachment. AB - Mn(2+) chelating tags for Mn(2+)-Mn(2+) distance measurements by pulse EPR spectroscopy were developed. They feature a stable C-S conjugation to the protein, high reactivity towards cysteine thiols and short and rigid linkers that can be used in distance measurements with high resolution under reductive conditions. Double electron-electron resonance measurements at 95 GHz on ubiquitin labeled with these tags showed the expected narrow distance distribution. PMID- 26575838 TI - Growth and Cardiovascular Risk Factors in Prepubertal Children Born Large or Small for Gestational Age. AB - BACKGROUND: Both large and small birth sizes are associated with an increased risk of developing cardiovascular and metabolic problems later in life. We studied whether such associations can be observed at prepubertal age. METHODS: A cohort of 49 large (LGA), 56 appropriate (AGA), and 23 small for gestational age (SGA)-born children (age range 5-8 years) were studied. Being born SGA, AGA, or LGA was the exposure, and being overweight at prepubertal age was the main outcome. Blood pressure measurements, laboratory parameters, and whole-body dual energy X-ray absorptiometry were secondary outcomes. RESULTS: The LGA-born children were significantly taller than the AGA controls (p = 0.03), and the SGA children were lighter and shorter compared to the AGA (p = 0.002 and 0.001) and LGA children (p < 0.001). The mean plasma glucose was higher in the LGA than in the SGA group (p = 0.006). Being born LGA (OR 3.82) and the ponderal index Z score at birth (OR 4.24) were strong predictors for being overweight or obese in childhood. CONCLUSION: The children born LGA remained taller and heavier than those born AGA or SGA in mid-childhood, and they had a higher body mass index and body fat percentage than the SGA-born children. The differences in other cardiometabolic risk factors were minimal between the birth size groups. PMID- 26575839 TI - Factors Associated with In-Hospital Delay in Intravenous Thrombolysis for Acute Ischemic Stroke: Lessons from China. AB - In-hospital delay reduces the benefit of intravenous thrombolysis (IVT) in acute ischemic stroke (AIS), while factors affecting in-hospital delay are less well known in Chinese. We are aiming at determining the specific factors associated with in-hospital delay through a hospital based cohort. In-hospital delay was defined as door-to-needle time (DTN) >=60 min (standard delay criteria) or >=75% percentile of all DTNs (severe delay criteria). Demographic data, time intervals [onset-to-door time (OTD), DTN, door-to-examination time (DTE), door-to-imaging time (DTI), door-to-laboratory time (DTL) and final-test-to-needle time (FTN, the time interval between the time obtaining the result of the last screening test and the needle time)], medical history and additional variables were calculated using Mann-Whitney U or Pearson Chi-Square tests for group comparison, and multivariate linear regression analysis was performed to identify independent variables of in-hospital delay. A total of 202 IVT cases were enrolled. The median age was 61 years and 25.2% were female. The cutoff points for the upper quartile of DTN (severe delay criteria) was 135 min.When compared with the reference group without in-hospital delay, older age, shorter OTD and less referral were found in the standard delay group and male sex, presence with transient ischemic attacks or rapidly improving symptom, and with multi-model CT imaging were more frequent in the severe delay group. In the multivariate linear regression analysis, FTN (P<0.001) and DTL (P = 0.002) were significantly associated with standard delay; while DTE (P = 0.005), DTI (P = 0.033), DTL (P<0.001), and FTN (P<0.001) were positively associated with severe delay. There was not a significant change in the trend of DTNs during the study period (P = 0.054). In-hospital delay was due to multifactors in China, in which time delays of decision-making process and laboratory tests contributed the most. Efforts aiming at reducing the delay should be focused on the optimization for the items of screening tests and improvement of the pathway organization. PMID- 26575840 TI - MALDI MS analysis, disk diffusion and optical density measurements for the antimicrobial effect of zinc oxide nanorods integrated in graphene oxide nanostructures. AB - Graphene oxide-zinc oxide hybrid nanostructures were synthesized and they demonstrated significant and promising antimicrobial activity on pathogenic bacteria. The combination of graphene oxide with zinc oxide nanorods showed an impressive antibacterial effect under intense scrutiny as compared with individual graphene oxide or zinc oxide nanomaterials. The characterization and investigation of GO-ZnO nanorod hybrid nanostructures were conducted using UV, FTIR, XRD, SEM, EDX and TEM measurements. The antimicrobial activity of the above hybrid material was evaluated by various methods including MALDI-MS analysis, a disk diffusion assay and optical density measurements. PMID- 26575842 TI - A comparison of the amorphization of zeolitic imidazolate frameworks (ZIFs) and aluminosilicate zeolites by ball-milling. AB - X-ray diffraction has been used to investigate the kinetics of amorphization through ball-milling at 20 Hz, for five zeolitic imidazolate frameworks (ZIFs) - ZIF-8, ZIF-4, ZIF-zni, BIF-1-Li and CdIF-1. We find that the rates of amorphization for the zinc-containing ZIFs increase with increasing solvent accessible volume (SAV) in the sequence ZIF-8 > ZIF-4 > ZIF-zni. The Li-B analogue of the dense ZIF-zni amorphizes more slowly than the corresponding zinc phase, with the behaviour showing a correlation with their relative bulk moduli and SAVs. The cadmium analogue of ZIF-8 (CdIF-1) amorphizes more rapidly than the zinc counterpart, which we ascribe primarily to its relatively weak M-N bonds as well as the higher SAV. The results for the ZIFs are compared to three classical zeolites - Na-X, Na-Y and ZSM-5 - with these taking up to four times longer to amorphize. The presence of adsorbed solvent in the pores is found to render both ZIF and zeolite frameworks more resistant to amorphization. X-ray total scattering measurements show that amorphous ZIF-zni is structurally indistinguishable from amorphous ZIF-4 with both structures retaining the same short-range order that is present in their crystalline precursors. By contrast, both X-ray total scattering measurements and (113)Cd NMR measurements point to changes in the local environment of amorphous CdIF-1 compared with its crystalline CdIF-1 precursor. PMID- 26575841 TI - Isoflavone and Soyfood Intake and Colorectal Cancer Risk: A Case-Control Study in Korea. AB - We aimed to assess the relationship between dietary soyfood and isoflavone intake and colorectal cancer risk in a case-control study. A total of 901 colorectal cancer cases and 2669 controls were recruited at the National Cancer Center, Korea. A semi-quantitative food frequency questionnaire was used to assess the usual dietary habits, and the isoflavone intake level was estimated from five soyfood items. A high intake of total soy products, legumes, and sprouts was associated with a reduced risk for colorectal cancer in men and women, although the middle quartiles of intake of total soy products were associated with an elevated risk. In contrast, a high intake of fermented soy paste was associated with an elevated risk for colorectal cancer in men. The groups with the highest intake quartiles of isoflavones showed a decreased risk for colorectal cancer compared to their counterparts with the lowest intake quartiles in men (odds ratio (OR): 0.67, 95% confidence interval (CI): 0.51-0.89) and women (OR: 0.65, 95% CI: 0.43-0.99). The reduced risk for the highest intake groups persisted for distal colon cancer in men and rectal cancer in women. The association between soyfood intake and colorectal cancer risk was more prominent among post menopausal women than pre-menopausal women. In conclusion, a high intake of total soy products or dietary isoflavones was associated with a reduced risk for overall colorectal cancer, and the association may be more relevant to distal colon or rectal cancers. PMID- 26575843 TI - Fine-Grained Distribution of a Non-Native Resource Can Alter the Population Dynamics of a Native Consumer. AB - New interactions with non-native species can alter selection pressures on native species. Here, we examined the effect of the spatial distribution of a non-native species, a factor that determines ecological and evolutionary outcomes but that is poorly understood, particularly on a fine scale. Specifically, we explored a native butterfly population and a non-native plant on which the butterfly oviposits despite the plant's toxicity to larvae. We developed an individual based model to describe movement and oviposition behaviors of each butterfly, which were determined by plant distribution and the butterfly's host preference genotype. We estimated the parameter values of the model from rich field data. We simulated various patterns of plant distributions and compared the rates of butterfly population growth and changes in the allele frequency of oviposition preference. Neither the number nor mean area of patches of non-native species affected the butterfly population, whereas plant abundance, patch shape, and distance to the nearest native and non-native patches altered both the population dynamics and genetics. Furthermore, we found a dramatic decrease in population growth rates when we reduced the distance to the nearest native patch from 147 m to 136 m. Thus changes in the non-native resource distribution that are critical to the fate of the native herbivore could only be detected at a fine-grained scale that matched the scale of a female butterfly's movement. In addition, we found that the native butterfly population was unlikely to be rescued by the exclusion of the allele for acceptance of the non-native plant as a host. This study thus highlights the importance of including both ecological and evolutionary dynamics in analyses of the outcome of species interactions and provides insights into habitat management for non-native species. PMID- 26575845 TI - An Analytical Planning Model to Estimate the Optimal Density of Charging Stations for Electric Vehicles. AB - The charging infrastructure location problem is becoming more significant due to the extensive adoption of electric vehicles. Efficient charging station planning can solve deeply rooted problems, such as driving-range anxiety and the stagnation of new electric vehicle consumers. In the initial stage of introducing electric vehicles, the allocation of charging stations is difficult to determine due to the uncertainty of candidate sites and unidentified charging demands, which are determined by diverse variables. This paper introduces the Estimating the Required Density of EV Charging (ERDEC) stations model, which is an analytical approach to estimating the optimal density of charging stations for certain urban areas, which are subsequently aggregated to city level planning. The optimal charging station's density is derived to minimize the total cost. A numerical study is conducted to obtain the correlations among the various parameters in the proposed model, such as regional parameters, technological parameters and coefficient factors. To investigate the effect of technological advances, the corresponding changes in the optimal density and total cost are also examined by various combinations of technological parameters. Daejeon city in South Korea is selected for the case study to examine the applicability of the model to real-world problems. With real taxi trajectory data, the optimal density map of charging stations is generated. These results can provide the optimal number of chargers for driving without driving-range anxiety. In the initial planning phase of installing charging infrastructure, the proposed model can be applied to a relatively extensive area to encourage the usage of electric vehicles, especially areas that lack information, such as exact candidate sites for charging stations and other data related with electric vehicles. The methods and results of this paper can serve as a planning guideline to facilitate the extensive adoption of electric vehicles. PMID- 26575844 TI - Nonspreading Rift Valley Fever Virus Infection of Human Dendritic Cells Results in Downregulation of CD83 and Full Maturation of Bystander Cells. AB - Vaccines based on nonspreading Rift Valley fever virus (NSR) induce strong humoral and robust cellular immune responses with pronounced Th1 polarisation. The present work was aimed to gain insight into the molecular basis of NSR mediated immunity. Recent studies have demonstrated that wild-type Rift Valley fever virus efficiently targets and replicates in dendritic cells (DCs). We found that NSR infection of cultured human DCs results in maturation of DCs, characterized by surface upregulation of CD40, CD80, CD86, MHC-I and MHC-II and secretion of the proinflammatory cytokines IFN-beta, IL-6 and TNF. Interestingly, expression of the most prominent marker of DC maturation, CD83, was consistently downregulated at 24 hours post infection. Remarkably, NSR infection also completely abrogated CD83 upregulation by LPS. Downregulation of CD83 was not associated with reduced mRNA levels or impaired CD83 mRNA transport from the nucleus and could not be prevented by inhibition of the proteasome or endocytic degradation pathways, suggesting that suppression occurs at the translational level. In contrast to infected cells, bystander DCs displayed full maturation as evidenced by upregulation of CD83. Our results indicate that bystander DCs play an important role in NSR-mediated immunity. PMID- 26575846 TI - Correction: Aggressive Chemotherapy and the Selection of Drug Resistant Pathogens. PMID- 26575847 TI - Social Factors Influencing Russian Male Alcohol Use over the Life Course: A Qualitative Study Investigating Age Based Social Norms, Masculinity, and Workplace Context. AB - The massive fluctuations occurring in Russian alcohol-related mortality since the mid-1980s cannot be seen outside of the context of great social and economic change. There is a dearth of qualitative studies about Russian male drinking and especially needed are those that address social processes and individual changes in drinking. Conducted as part of a longitudinal study on men's alcohol consumption in Izhevsk, this qualitative study uses 25 semi-structured biographical interviews with men aged 33-60 years to explore life course variation in drinking. The dominant pattern was decreasing binge and frequent drinking as men reached middle age which was precipitated by family building, reductions in drinking with work colleagues, and health concerns. A minority of men described chaotic drinking histories with periods of abstinence and heavy drinking. The results highlight the importance of the blue-collar work environment for conditioning male heavy drinking in young adulthood through a variety of social, normative and structural mechanisms. Post-Soviet changes had a structural influence on the propensity for workplace drinking but the important social function of male drinking sessions remained. Bonding with workmates through heavy drinking was seen as an unavoidable and essential part of young men's social life. With age peer pressure to drink decreased and the need to perform the role of responsible breadwinner put different behavioural demands on men. For some resisting social pressure to drink became an important site of self determination and a mark of masculine maturity. Over the lifetime the place where masculine identity was asserted shifted from the workplace to the home, which commonly resulted in a reduction in drinking. We contribute to existing theories of Russian male drinking by showing that the performance of age-related social roles influences Russian men's drinking patterns, drinking contexts and their attitudes. Further research should be conducted investigating drinking trajectories in Russian men. PMID- 26575848 TI - Aromaticity-Dependent Regioselectivity in Pd(II)-Catalyzed C-H Direct Arylation of Aryl Ureas. AB - Palladium-catalyzed C-H direct arylation generally occurs on the ortho-position of directing groups. By comparing meta-arylated products of 2-naphthyl urea to ortho-arylated products of phenyl urea, the ortho- and meta-regioselectivity of aryl ureas were found to depend on the aromaticity of the corresponding aryl substituents. Thus, aromaticity is a new factor which can affect the regioselectivity in C-H direct arylation. The finding was further confirmed by regioselective direct arylation of indole and pyrrole derivatives. PMID- 26575849 TI - Lower birth weight is associated with alterations in dietary intake in adolescents independent of genetic factors: A twin study. AB - BACKGROUND & AIMS: Lower birth weight is associated with an increased risk of cardiovascular and metabolic disease. These associations may, at least in part, be explained by alterations in dietary intake in later life. The aim of this study is to examine whether lower birth weight is associated with alterations in dietary intake in later life, and whether this association is due to intrauterine environmental or genetic factors. METHODS: In this observational study birth weight and dietary intake were investigated in 78 dizygotic (DZ) and 94 monozygotic (MZ) adolescent same-sex twin subjects. Birth weight was obtained from the mothers. Dietary intake was assessed by two-day dietary records. RESULTS: In the total group of twins, lower birth weight was associated with higher intake of saturated fat after adjustment for current weight (1.2 per cent of total energy intake (E%) per kg increase in birth weight, P < 0.01). Intra pair analysis in all twin pairs demonstrated that twins with the lower birth weight had a 115 kcal higher total energy intake and a 0.7 E% higher saturated fat intake compared to their co-twins with the higher birth weight (P < 0.05). Intra-pair differences in birth weight were negatively associated with differences in energy intake and differences in intake of saturated fat after adjustment for differences in current weight (P = 0.07 and P < 0.05, respectively). Intra-pair differences in birth weight were positively associated with intra-pair differences in intake of dietary fibres (P < 0.05). These intra pair differences and associations were similar for DZ and MZ twins (P for difference > 0.6). CONCLUSIONS: Lower birth weight was related with higher intake of energy and saturated fat within twin pairs, and these associations were independent of zygosity, suggesting that the association between birth weight and alterations in dietary intake in later life is explained by intrauterine environmental rather than genetic factors. PMID- 26575850 TI - Cerebrospinal fluid findings after epileptic seizures. AB - We aimed to evaluate ictally-induced CSF parameter changes after seizures in adult patients without acute inflammatory diseases or infectious diseases associated with the central nervous system. In total, 151 patients were included in the study. All patients were admitted to our department of neurology following acute seizures and received an extensive work-up including EEG, cerebral imaging, and CSF examinations. CSF protein elevation was found in most patients (92; 60.9%) and was significantly associated with older age, male sex, and generalized seizures. Abnormal CSF-to-serum glucose ratio was found in only nine patients (5.9%) and did not show any significant associations. CSF lactate was elevated in 34 patients (22.5%) and showed a significant association with focal seizures with impaired consciousness, status epilepticus, the presence of EEG abnormalities in general and epileptiform potentials in particular, as well as epileptogenic lesions on cerebral imaging. Our results indicate that non-inflammatory CSF elevation of protein and lactate after epileptic seizures is relatively common, in contrast to changes in CSF-to-serum glucose ratio, and further suggest that these changes are caused by ictal activity and are related to seizure type and intensity. We found no indication that these changes may have further-reaching pathological implications besides their postictal character. PMID- 26575851 TI - Cost-analysis of robotic-assisted laparoscopic hysterectomy versus total abdominal hysterectomy for women with endometrial cancer and atypical complex hyperplasia. AB - INTRODUCTION: The aim of this study was to analyse the hospital cost of treatment with robotic-assisted laparoscopic hysterectomy and total abdominal hysterectomy for women with endometrial cancer or atypical complex hyperplasia and to identify differences in resource use and cost. MATERIAL AND METHODS: This cost analysis was based on two cohorts: women treated with robotic-assisted laparoscopic hysterectomy (n = 202) or with total abdominal hysterectomy (n = 158) at Copenhagen University Hospital, Herlev, Denmark. We conducted an activity-based cost analysis including consumables and healthcare professionals' salaries. As cost-drivers we included severe complications, duration of surgery, anesthesia and stay at the post-anesthetic care unit, as well as number of hospital bed days. Ordinary least-squares regression was used to explore the cost variation. The primary outcome was cost difference in Danish kroner between total abdominal hysterectomy and robotic-assisted laparoscopic hysterectomy. RESULTS: The average cost of consumables was 12,642 Danish kroner more expensive per patient for robotic-assisted laparoscopic hysterectomy than for total abdominal hysterectomy (2014 price level: 1? = 7.50 Danish kroner). When including all cost-drivers, the analysis showed that the robotic-assisted laparoscopic hysterectomy procedure was 9386 Danish kroner (17%) cheaper than the total abdominal hysterectomy (p = 0.003). When the robot investment was included, the cost difference reduced to 4053 Danish kroner (robotic-assisted laparoscopic hysterectomy was 7% cheaper than total abdominal hysterectomy) (p = 0.20). Increasing age and Type 2 diabetes appeared to influence the overall costs. CONCLUSION: For women with endometrial cancer or atypical complex hyperplasia, robotic-assisted laparoscopic hysterectomy was cheaper than total abdominal hysterectomy, mostly due to fewer complications and shorter length of hospital stay. PMID- 26575852 TI - Deciphering the clinical relevance of allo-human leukocyte antigen cross reactivity in mediating alloimmunity following transplantation. AB - PURPOSE OF REVIEW: Despite a growing awareness regarding the potential of cross reactive virus-specific memory T cells to mediate alloimmunity, there has been limited clinical evaluation on allograft immunopathology. This review will explore published models of human T-cell cross-reactivity and discuss criteria required to drive this mechanism as a contributing cause of allograft dysfunction in transplantation. RECENT FINDINGS: Published models of human allogeneic (allo) human leukocyte antigen (HLA) cross-reactivity have enabled dissection of the cross-reactive T cell receptor/peptide/major histocompatibility complex (TCR/peptide/MHC) interaction. In many of the models, the cross-reactive T cells express a unique TCR, although the relevance of a public cross-reactive TCR repertoire has yet to be determined. Equally, allopeptide identity, a vital component driving cross-recognition, remains unknown in the majority of models thereby prompting further characterization utilizing novel technologies. Although clinical studies examining the presence and impact of specific cross-reactive virus-specific T cells have been minimally explored, the existing data suggest that there may be a marginal set of requirements that need to be satisfied before the potentially damaging effects of allo-HLA cross-reactivity can be realized. SUMMARY: Our understanding of allo-HLA cross-reactivity continues to evolve as improved technology and novel strategies allow us to better question the contribution of allo-HLA cross-reactivity in clinically relevant allograft dysfunction. PMID- 26575853 TI - Direct and indirect allograft recognition: pathways dictating graft rejection mechanisms. AB - PURPOSE OF REVIEW: The T cell-dependent recognition of allogeneic tissues and organs is complicated by the fact that both donor and host antigen-presenting cells can present donor antigens to host T cells. As such, these pathways result in T cells that can be restricted to either donor ('direct') or host ('indirect') major histocompatibility complex (MHC). These pathways are well recognized, but how these distinct patterns actually dictate allograft recognition is less clear. Thus, the purpose of the review is to summarize results from preclinical animal models in an attempt to clarify the distinct forms of allograft rejection dictated by these recognition pathways. RECENT FINDINGS: CD4 and CD8 donor MHC restricted T cells are sufficient to reject allografts by a T-cell receptor mediated direct ('cognate') interaction using a defined array of effector molecules. Conversely, 'noncognate' host MHC-restricted CD4 T cells must interact with intermediate host-type antigen-presenting cells and so greatly amplify the response by triggering antibody and inflammatory responses. SUMMARY: Importantly, 'cognate' CD4 and CD8 T cells have strikingly similar requirements for rejection, suggesting that this effector mechanism is dictated by the nature of allograft recognition rather than by T-cell subset. Conversely, 'noncognate' allograft recognition drives an increasingly appreciated role for inciting innate immunity in mediating allograft injury. PMID- 26575854 TI - Mechanisms of antibody-mediated acute and chronic rejection of kidney allografts. AB - PURPOSE OF REVIEW: Antibody-mediated rejection is responsible for up to half of acute rejection episodes in kidney transplant patients and more than half of late graft failures. Antibodies cause acute graft abnormalities that are distinct from T cell-mediated rejection and at later times posttransplant, a distinct pathologic lesion is associated with capillary basement membrane multilayering and glomerulopathy. Despite the importance of donor-reactive antibodies as the leading cause of kidney graft failure, mechanisms underlying antibody-mediated acute and chronic kidney graft injury are poorly understood. Here, we review recent insights provided from clinical studies as well as from animal models that may help to identify new targets for therapy. RECENT FINDINGS: Studies of biopsies from kidney grafts in patients with donor-specific antibody versus those without have utilized analysis of pathologic lesions and gene expression to identify the distinct characteristics of antibody-mediated rejection. These analyses have indicated the presence of natural killer cells and their activation during antibody-mediated rejection. The impact of studies of antibody-mediated allograft injury in animal models have lagged behind these clinical studies, but have been useful in testing the activation of innate immune components within allografts in the presence of donor-specific antibodies. SUMMARY: Most insights into processes of antibody-mediated rejection of kidney grafts have come from carefully designed clinical studies. However, several new mouse models of antibody-mediated kidney allograft rejection may replicate the abnormalities observed in clinical kidney grafts and may be useful in directly testing mechanisms that underlie acute and chronic antibody-mediated graft injury. PMID- 26575855 TI - External validation of the In-hospital Mortality for PulmonAry embolism using Claims daTa (IMPACT) multivariable prediction rule. AB - OBJECTIVE: To validate the In-hospital Mortality for PulmonAry embolism using Claims daTa (IMPACT) multivariable prediction rule using admission claims data. STUDY DESIGN: Retrospective claims database analysis. METHODS: This analysis was performed using Humana admission claims data from January 2007 to March 2014. We included adult patients admitted for their first PE during this period (International Classification of Diseases, ninth edition, Clinical Modification code of 415.1x in in the primary position or secondary position when accompanied by a primary code for a PE complication). The IMPACT rule, consisting of age plus 11 comorbidities, was used to estimate patients' probability of in-hospital mortality and classify risk. Low risk was defined as in-hospital mortality <= 1.5%. IMPACT was evaluated by evaluating prognostic test characteristic values and 95% confidence intervals (CIs). RESULTS: A total of 23,858 patients admitted for PE were included, and 3.3% died in-hospital. The IMPACT prediction rule classified 2371 (9.9%) as low-risk; with a sensitivity of 97.6%, 95% CI: 96.1 98.5, specificity of 10.2%, 95% CI: 9.8-10.6, negative and positive predictive values of 99.2% (95% CI: 98.7-99.5) and 3.5% (95% CI: 3.3-3.8) and c-statistic of 0.70, 95% CI: 0.0.68-0.72, for in-hospital mortality. IMPACT classified 42.7% of patients < 65 years old as low-risk; with a sensitivity, specificity and c statistic of 85.0%, 95% CI: 77.4-90.5, 43.3%, 95% CI: 42.0-44.7 and 0.74, 95% CI: 0.69-0.78, respectively. CONCLUSION: The IMPACT prediction rule was valid when implemented in a database consisting largely of Medicare claims. Following further external validation and direct comparison to commonly used clinical prediction rules, IMPACT may become a valuable tool for payers and hospitals wishing to retrospectively assess whether their PE patients are being kept hospitalized for the optimal period of time. PMID- 26575856 TI - Bayesian predictive modeling for genomic based personalized treatment selection. AB - Efforts to personalize medicine in oncology have been limited by reductive characterizations of the intrinsically complex underlying biological phenomena. Future advances in personalized medicine will rely on molecular signatures that derive from synthesis of multifarious interdependent molecular quantities requiring robust quantitative methods. However, highly parameterized statistical models when applied in these settings often require a prohibitively large database and are sensitive to proper characterizations of the treatment-by covariate interactions, which in practice are difficult to specify and may be limited by generalized linear models. In this article, we present a Bayesian predictive framework that enables the integration of a high-dimensional set of genomic features with clinical responses and treatment histories of historical patients, providing a probabilistic basis for using the clinical and molecular information to personalize therapy for future patients. Our work represents one of the first attempts to define personalized treatment assignment rules based on large-scale genomic data. We use actual gene expression data acquired from The Cancer Genome Atlas in the settings of leukemia and glioma to explore the statistical properties of our proposed Bayesian approach for personalizing treatment selection. The method is shown to yield considerable improvements in predictive accuracy when compared to penalized regression approaches. PMID- 26575857 TI - Effect of Chronic Mild Stress on AT1 Receptor Messenger RNA Expression in the Brain and Kidney of Rats. AB - OBJECTIVE: The purpose of the study was to determine whether exposure to chronic mild stress (CMS) affects expression of angiotensin II Type 1a receptor (AT1aR) messenger RNA (mRNA) in the brain and kidney. METHODS: Male Sprague-Dawley rats were divided into an unchallenged control group, which remained at rest, and an experimental group, exposed to CMS produced by a series of unexpected, disturbing stimuli applied at random over a period of 4 weeks. After sacrificing the animals, samples of the septal/accumbal and hypothalamic/thalamic diencephalon, brain medulla, cerebellum, and the renal medulla were harvested for determination of AT1aR mRNA. RESULTS: Expression of AT1a receptor mRNA was significantly greater in the rats in the CMS condition than in the controls (septal/accumbal diencephalon: 1.689 [0.205] versus 0.027 [0.004], hypothalamic/thalamic diencephalon: 1.239 [0.101] versus 0.003 [0.001], brain medulla: 2.694 [0.295] versus 0.028 [0.003], cerebellum: 0.013 [0.002] versus 0.005 [0.001; p < .001 for all comparisons], and renal medulla: 409.92 [46.92] versus 208.06 [30.56; p < .01]). There was a significant positive correlation between AT1a mRNA expression in the septal/accumbal diencephalon and brain medulla (p < .025). CONCLUSIONS: The results provide evidence that CMS significantly enhances expression of the AT1aR gene in the brain and kidney and indicate that changes in expression of AT1aR mRNA in different brain regions during CMS may be causally related. It is suggested that the up-regulation of AT1a receptors by chronic stress may potentiate negative effects of angiotensin II in pathologies associated with activation of the renin-angiotensin system. PMID- 26575858 TI - Influence of Interoceptive Fear Learning on Visceral Perception. AB - OBJECTIVES: Interoceptive fear learning and generalization have been hypothesized to play a key role in unexplained abdominal and esophageal pain in patients with functional gastrointestinal disorders. However, there is no experimental evidence demonstrating that fear learning and generalization to visceral sensations can be established in humans and alter visceral perception. METHODS: In a novel fear learning-generalization paradigm, an innocuous esophageal balloon distension served as conditioned stimulus (CS), and distensions at three different pressure levels around the pain detection threshold were used as generalization stimuli. During fear learning, the CS was paired with a painful electrical stimulus (unconditioned stimulus) in the conditioning group (n = 30), whereas in the control group (n = 30), the unconditioned stimulus was delivered alone. Before and after fear learning, visceral perception thresholds for first sensation, discomfort, and pain and visceral discrimination sensitivity were assessed. RESULTS: Fear learning was established in the conditioning group only (potentiated eye-blink startle to the CS (t(464.06) = 3.17, p = .002), and fear generalization to other stimulus intensities was observed (t(469.12) = 2.97, p = .003; t(464.29) = 4.17, p < .001). The thresholds for first sensation habituated in the control group, whereas it remained constant in the conditioning group (F(1,43) = 9.77, p = .003). CONCLUSIONS: These data show that fear learning using visceral stimuli induces fear generalization and influences visceral perception. These findings support the idea that in functional gastrointestinal disorder, fear learning and generalization can foster gastrointestinal-specific anxiety and contribute to visceral hypersensitivity. PMID- 26575859 TI - Elucidating the Biological Mechanisms Linking Depressive Symptoms With Type 2 Diabetes in Men: The Longitudinal Effects of Inflammation, Microvascular Dysfunction, and Testosterone. AB - OBJECTIVE: This prospective cohort study sought to examine key biological measures linking depressive symptoms with Type 2 diabetes, specifically inflammation, microvascular dysfunction, and androgens. METHODS: A cohort of 688 men without diabetes who were 35 years or older were followed up for 5 years. Venous interleukin-6, high-sensitivity C-reactive protein, sE-selectin, endogenous total testosterone, fasting glucose, and glycated hemoglobin (HbA1c) were quantified at baseline and 5 years later. Depressive symptoms were assessed using the Beck Depression Inventory-I, and men were categorized into persistent, remitted, incident, and nondepressed groups (reference). Logistic regression was used to determine odds ratios (ORs) for diabetes adjusted for propensity score calculated from 18 established risk factors. RESULTS: Diabetes developed in 112 men (16.3% of sample). Persistent depressive symptoms were associated with diabetes (adjusted OR = 2.45, 95% confidence interval [CI] = 1.16-5.20, p = .019). Baseline testosterone (OR = 0.43, 95% CI = 0.22-0.81, p = .01) and follow up testosterone (OR = 0.51, 95% CI = 0.31-0.84, p = .008) were inversely associated with Type 2 diabetes. Annualized HbA1c was positively associated with annualized change in cognitive Beck Depression Inventory symptoms (beta = 0.14, p = .001) and inversely associated with annualized change in testosterone (beta = 0.10, p = .014). Annualized change in fasting glucose was associated with sE selectin (beta = 0.12, p < .001) and somatic depressive symptoms (beta = -0.12, p = .002). CONCLUSIONS: The findings suggest that lower endogenous total testosterone levels and persistent depressive symptoms were associated with Type 2 diabetes risk and HbA1c in men over a 5-year period. PMID- 26575860 TI - Peripheral neuropathy in glycogen storage disease type III: Fact or myth? AB - INTRODUCTION: The aim of this study was to assess whether peripheral neuropathy is a feature of glycogen storage disease type IIIa (GSD IIIa) in adult patients. METHODS: Medical records of a cohort of adult GSD IIIa patients who underwent electromyography (EMG) and nerve conduction studies (NCS) were reviewed, and the results were correlated with physical examination findings. RESULTS: Sixteen patients underwent EMG and NCS; 4 complained of exercise intolerance, 1 of foot paresthesia, and 11 of muscle weakness (3 proximal, 8 distal). None of the patients had sensory deficits on clinical examination. All motor and sensory conduction velocities and sensory amplitudes were within reference ranges. EMG showed myopathic motor unit potentials in 15 of the 16 patients. CONCLUSIONS: Based on the clinical examination and the NCS and EMG results, we did not identify any peripheral nerve involvement in our adult patients diagnosed with GSD III. PMID- 26575861 TI - Influence of Position and Power Output on Upper Limb Kinetics in Cycling. AB - Several suggestions on the upper limb involvement in cycling exist but, to date, no study has quantified upper limb kinetics in this task. The aim of this study was to determine how crank power and pedaling position (seated or standing) affect upper limb kinetics. Handlebar loadings and upper limb kinematics were collected from 17 participants performing seated or standing pedaling trials in a random order at 6 crank powers ranging from 20% (112 +/- 19 W) to 120% (675 +/- 113 W) of their spontaneous sit-to-stand transition power. An inverse dynamics approach was used to compute 3D moments, powers, and works at the wrist, elbow, and shoulder joints. Over 29 parameters investigated, increases in crank power were associated with increases in the magnitudes of 23 and 20 of the kinetic variables assessed in seated and standing positions, respectively. The standing position was associated with higher magnitudes of upper limb kinetics. These results suggest that both upper and lower limbs should be considered in future models to better understand whole body coordination in cycling. PMID- 26575862 TI - Doxycycline inhibits TGF-beta1-induced extracellular matrix production in nasal polyp-derived fibroblasts. AB - BACKGROUND: Doxycycline has been shown to have antibacterial and anti inflammatory effects and suppresses collagen biosynthesis. The purpose of this study was to evaluate the effects of doxycycline on transforming growth factor (TGF)-beta1-induced myofibroblast differentiation and extracellular matrix production in nasal polyp-derived fibroblasts (NPDFs). We also determined the molecular mechanisms of action for doxycycline. METHODS: NPDFs were isolated from nasal polyps from 8 patients. Doxycycline was used to pretreat TGF-beta1-induced NPDFs. Cytotoxicity was evaluated using a 3-(4,5-dimethylthiazol-2yl)-2,5 diphenyl-tetrazolium bromide assay. Expression levels of alpha-smooth muscle actin (SMA) and fibronectin were measured using Western blot, reverse transcription polymerase chain reaction, and immunofluorescence staining. Total collagen production was analyzed with the Sircol collagen assay, while mitogen activated protein kinase (MAPK) and NF-kappaB activation were determined using Western blot analysis. Luciferase assay was used to evaluate the transcriptional activity of NF-kappaB. RESULTS: Although doxycycline (0 to 40 MUg/mL) had no significant cytotoxic effects in TGF-beta1-induced NPDFs, it significantly reduced the expression levels of alpha-SMA, fibronectin, and collagen in TGF beta1-induced NPDFs in a dose-dependent manner. Doxycycline also inhibited the TGF-beta1-induced activation of p38, c-Jun NH2 -terminal kinase (JNK), and NF kappaB, and its inhibitory effects were similar to those of the specific inhibitors for each. CONCLUSION: Doxycycline has an inhibitory effect on TGF beta1-induced myofibroblast differentiation and extracellular matrix production via the p38 and JNK/NF-kappaB signal pathways in NPDFs. PMID- 26575863 TI - Comparison of gene activation by two TAL effectors from Xanthomonas axonopodis pv. manihotis reveals candidate host susceptibility genes in cassava. AB - Xanthomonas axonopodis pv. manihotis (Xam) employs transcription activator-like (TAL) effectors to promote bacterial growth and symptom formation during infection of cassava. TAL effectors are secreted via the bacterial type III secretion system into plant cells, where they are directed to the nucleus, bind DNA in plant promoters and activate the expression of downstream genes. The DNA binding activity of TAL effectors is carried out by a central domain which contains a series of repeat variable diresidues (RVDs) that dictate the sequence of bound nucleotides. TAL14Xam668 promotes virulence in Xam strain Xam668 and has been shown to activate multiple cassava genes. In this study, we used RNA sequencing to identify the full target repertoire of TAL14Xam668 in cassava, which includes over 50 genes. A subset of highly up-regulated genes was tested for activation by TAL14CIO151 from Xam strain CIO151. Although TAL14CIO151 and TAL14Xam668 differ by only a single RVD, they display differential activation of gene targets. TAL14CIO151 complements the TAL14Xam668 mutant defect, implying that shared target genes are important for TAL14Xam668 -mediated disease susceptibility. Complementation with closely related TAL effectors is a novel approach to the narrowing down of biologically relevant susceptibility genes of TAL effectors with multiple targets. This study provides an example of how TAL effector target activation by two strains within a single species of Xanthomonas can be dramatically affected by a small change in RVD-nucleotide affinity at a single site, and reflects the parameters of RVD-nucleotide interaction determined using designer TAL effectors in transient systems. PMID- 26575864 TI - Histidine-Based Lipopeptides Enhance Cleavage of Nucleic Acids: Interactions with DNA and Hydrolytic Properties. AB - Interaction studies and cleavage activity experiments were carried out between plasmid DNA and a series of histidine-based lipopeptides. Specific fluorescent probes (ethidium bromide, Hoechst 33342, and pyrene) were used to monitor intercalation, minor groove binding, and self-assembly of lipopeptides, respectively. Association between DNA and lipopeptides was thus evidenced, highlighting the importance of both histidine and hydrophobic tail in the interaction process. DNA cleavage in the presence of lipopeptides was then detected by gel electrophoresis and quantified, showing the importance of histidine and the involvement of its side-chain imidazole in the hydrolysis mechanism. These systems could then be developed as synthetic nucleases while raising concern of introducing histidine in the design of lipopeptide-based transfection vectors. PMID- 26575865 TI - RSPH9 methylation pattern as a prognostic indicator in patients with non-muscle invasive bladder cancer. AB - DNA methylation is a frequent and early epigenetic event with potential application as a biomarker for cancer detection and an indicator of disease evolution. The aim of the present study was to identify novel methylation markers for the prediction of patient outcomes using microarray analysis of DNA methylation in samples from long-term follow-up patients with non-muscle invasive bladder cancer (NMIBC). Candidate methylation markers were selected from our previously published genome-wide methylation profiles. The clinical relevance of candidate methylation markers was determined by quantitative pyrosequencing analysis of 136 human bladder specimens (8 normal controls and 128 NMIBCs). The reversibility of DNA methylation was examined by 5-Aza-CdR treatment in human bladder cancer cell lines. The methylation patterns of candidate markers were significantly associated with aggressive clinicopathological features. In multivariate regression analysis, hypermethylation of radial spoke head 9 homolog (RSPH9) was an independent predictor of disease recurrence (hazard ratio, 3.02; P=0.001) and progression (hazard ratio, 8.25; P=0.028). The methylation level of RSPH9 decreased with 5-Aza-CdR treatment and progressively increased in its absence in bladder cancer cell lines. RSPH9 methylation is an independent prognostic indicator in NMIBC patients, and could be of value for the assessment of disease recurrence and progression and for clinical decision-making regarding treatment. PMID- 26575866 TI - Exploring Distress Caused by Blame for a Negative Patient Outcome. AB - OBJECTIVE: The aim of this study was to explore blame-related distress (B-RD). BACKGROUND: No research exists describing the incidence and characteristics of consequences of blame. METHODS: Survey research was used to explore the incidence, characteristics, and consequences of the distress caused by blame in the workplace. RESULTS: B-RD is prevalent among intensive care and oncology staff. Participants reported an organizational impact to B-RD in terms of staff morale, turnover, and employee health. Management, physicians, and peers were the most frequently cited source of blame. CONCLUSIONS: A proposed model is described to relate blame to other similar constructs. PMID- 26575867 TI - Nurses' Research Capacity, Use of Evidence, and Research Productivity in Acute Care: Year 1 Findings From a Partnership Study. AB - OBJECTIVE: The aim of this study was to compare baseline and year 1 findings from a research-focused academic-service partnership (ASP) designed to increase research capacity, evidence-based practice (EBP) use, and research productivity. BACKGROUND: Few combined individual and organizational best practices could be found that successfully sustain EBP. An ASP model, using structural and enabling processes, was evaluated. METHODS: Using a nonexperimental pretest-posttest design, 67 acute care nurses who participated at baseline were resurveyed, and year 1 focus groups were conducted. RESULTS: Knowledge increased from baseline to year 1, and nurses who participated on a committee with an embedded scientist were more knowledgeable at year 1 than those who did not. While EBP confidence and self-reported EBP use did not improve, research productivity increased 33%. Year 1 focus groups identified facilitators and barriers. CONCLUSION: Findings support some EBP benefits related to a research-focused ASP including research productivity; however, implementation barriers and contextual factors may have limited potential outcomes. PMID- 26575868 TI - Distortion Pathways of Transition Metal Coordination Polyhedra Induced by Chelating Topology. AB - A continuous shape measures analysis of the coordination polyhedra of a host of transition metal complexes with bi- and multidentate ligands discloses the distortion pathway associated with each particular topology of the chelate rings formed. The basic parameter that controls the degree of distortion is the metal donor atom bond distance that induces nonideal bond angles due to the rigidity of the ligands. Thus, the degree of distortion within each family of complexes depends on the atomic size, on which the high- or low-spin state has a large effect. Special attention is therefore paid to several spin-crossover systems and to the enhanced distortions that go along with the transition from low- to high spin state affected by temperature, light, or pressure. Several families of complexes show deviations from the expected distortion pathways in the high-spin state that can be associated to the onset of intermolecular interactions such as secondary coordination of counterions or solvent molecules. Also, significant displacement of counterions in an extended solid may result from the changes in metal-ligand bond distances when ligands are involved in intermolecular hydrogen bonding. PMID- 26575869 TI - [Environmental risk factors for autism spectrum disorders in children]. AB - OBJECTIVE: To investigate the environmental risk factors for autism spectrum disorders (ASD) in children. METHODS: In this case-control study, 81 boys with ASD, 74 boys with global developmental delay (GDD), and 163 healthy boys were enrolled. A self-designed nurturing environment questionnaire was used to record general demographic data, family social-economic status, parents' living habits and environmental exposure, maternal health status during pregnancy, birth situations, and rearing environment after birth. Multivariate logistic regression was used to identify environmental risk factors for ASD and GDD. RESULTS: Multivariate logistic regression analysis showed that six environmental risk factors such as maternal occupational toxicant exposure, diseases during pregnancy and a history of passive smoking, children's birth places, the frequency of outdoor activities in the second year after birth, and the opportunities to communicate with other age-matched children were significantly associated with the incidence of ASD (OR=20.67, 3.559, 2.422, 2.646, 23.820, and 5.081, respectively; P<0.05). Among the above six risk factors, passive smoking during pregnancy, the opportunities to communicate with their peers, and the frequency of outdoor activities in the second year after birth were also significantly associated with the incidence of GDD (P<0.05). CONCLUSIONS: Maternal occupational toxicant exposure, diseases during pregnancy, and low level of children's birth places may be the specific risk factors associated with ASD, and passive smoking during pregnancy, fewer opportunities to communicate with their peers, and fewer outdoor activities in the second year after birth are non specific risk factors for ASD, indicating that the development of ASD may be influenced by both genes and environmental factors. PMID- 26575870 TI - [Significance of IKZF1 gene copy number abnormalities in BCR/ABL-negative B lineage acute lymphoblastic leukemia in children]. AB - OBJECTIVE: To identify IKZF1 gene copy number abnormalities in BCR/ABL-negative B lineage acute lymphoblastic leukemia (B-ALL) in children, and to investigate the association between such abnormalities and prognosis. METHODS: Multiplex ligation dependent probe amplification (MLPA) was applied to detect IKZF1 gene copy number abnormalities in 180 children diagnosed with BCR/ABL-negative B-ALL. These children were classified into IKZF1 deletion group and IKZF1 normal group according to the presence or absence of IKZF1 gene deletion. The association between IKZF1 copy number abnormalities and prognosis of children with BCR/ABL negative B-ALL was analyzed retrospectively. RESULTS: Among 180 children, 27 (15.0%) had IKZF1 deletion; among the 27 children, 4 had complete deletions of 8 exons of IKZF1 gene, 17 had deletion of exon 1, 3 had deletions of exons 4-7, and 3 children had deletions of exons 2-7. Compared with those in the IKZF1 normal group, children in the IKZF1 deletion group had higher white blood cell (WBC) count and percentage of individuals with high risk of minimal residual disease at the first visit. IKZF1 deletions often occurred in BCR/ABL-negative children with no special fusion gene abnormalities. They were frequently accompanied by abnormalities in chromosomes 11, 8, 5, 7, and 21. The analysis with Kaplan-Meier method showed that disease-free survival (DFS) in the IKZF1 deletion group was significantly lower than that in the IKZF1 normal group (0.740 +/- 0.096 vs 0.905 +/- 0.034; P=0.002). Cox analysis showed that after exclusion of sex, age, initial WBC count, cerebrospinal fluid state at the first visit, prednisone response, and chromosome karyotype, IKZF1 deletion still affected the children's DFS (P<0.05). CONCLUSIONS: Some children with BCR/ABL-negative B-ALL have IKZF1 deletion, and IKZF1 deletion is an independent risk factor for DFS in children with BCR/ABL-negative B-ALL. PMID- 26575872 TI - [Study on height-weight indices in newborns of different gestational ages]. AB - OBJECTIVE: To establish height-weight indices in newborns of different gestational ages and to provide reference data for evaluation of intrauterine fetal growth. METHODS: The weight, height, crown-rump length, head circumference, and chest circumference of 8 357 newborns were measured in Maternal and Child Health Care Hospital of Bao'an District of shenzhen between 2005 and 2006, with the method of fact-finding investigation with cross-sectional cluster sampling, to establish the height-weight indices in newborns of different gestational ages. RESULTS: Five gender-specific height-weight indices (Quetelet Index, QI; Kaup Index, KI; Rohrer Index, RI; Livi Index, LI; Polock Index, PI) in newborns of different gestational ages (28-44 weeks of gestation) in three different groups (boys+girls, boys, and girls) were established in Shenzhen, China, and were expressed as mean gestational weeks+/-SD. The five indices above all increased with increasing gestational age, and the highest values appeared at 41-43 gestational weeks, suggesting that body density and enrichment degree increased constantly with increasing gestational age. Three indices (QI, KI and PI) were higher in boys than in girls (P<0.05). CONCLUSIONS: With the increasing gestational age, the body density and enrichment degree of newborns increase, and the enrichment degree in boys is better than that in girls. PMID- 26575871 TI - [Value of amino-terminal pro-brain natriuretic peptide as a predictive marker of symptomatic patent ductus arteriosus in preterm infants]. AB - OBJECTIVE: To study the value of amino-terminal pro-brain natriuretic peptide (NT proBNP) in predicting symptomatic patent ductus arteriosus (sPDA) in preterm infants. METHODS: Preterm infants born at a gestational age (GA) of <= 32 weeks and diagnosed with patent ductus arteriosus (PDA) by echocardiography within 48 hours after birth between June 2014 and April 2015 were selected as subjects. Their clinical manifestations were observed, and serum NT-proBNP levels were measured and echocardiography was performed at 3 and 5 days after birth. The infants were divided into sPDA group and asymptomatic PDA (asPDA) group based on their clinical manifestations and the results of echocardiography. The correlations between serum NT-proBNP level and echocardiographic indices were analyzed. Serum NT-proBNP levels were compared between the two groups. The receiver operator characteristic (ROC) curve was applied to determine the sensitivity and specificity of serum NT-proBNP in the prediction of sPDA. RESULTS: A total of 69 preterm infants were enrolled in this study, with 13 infants in the sPDA group and 56 infants in the asPDA group. Serum NT-proBNP level was positively correlated with the diameter of the arterial duct (r=0.856; P<0.05)and the ratio of left atrial diameter to aortic root diameter (LA/AO) (r=0.713; P<0.05). At 3 and 5 days after birth, the serum NT-proBNP levels in the sPDA group were significantly higher than those in the asPDA group (P<0.05). The area under the ROC curve (AUC) for the prediction of sPDA by NT-proBNP levels at 3 days after birth was 0.949 (95% CI: 0.892-1.000; P<0.001), with a cut-off value of 27 035 pg/mL (sensitivity: 92.3%; specificity: 94.6%); the AUC for the prediction of sPDA by NT-proBNP levels at 5 days after birth was 0.924 (95% CI: 0.848-1.000; P<0.001), with a cut-off value of 6 411 pg/mL (sensitivity: 92.3%; specificity: 92.9%). CONCLUSIONS: NT-proBNP may be a quantitative index for shunt volume. The measurement of serum NT-proBNP levels on 3 and 5 days after birth may be useful to predict sPDA in preterm infants. PMID- 26575873 TI - [Investigation of pharmacokinetics and pharmacodynamics of different doses of aminophylline in very low birth weight infants]. AB - OBJECTIVE: To study the pharmacokinetic and pharmacodynamic features of different doses of aminophylline in very low birth weight (VLBW) infants with different postmenstrual ages, weights, and ages (in days). METHODS: A total of 40 VLBW infants with apnea were enrolled. After an intravenous loading dose of 5 mg/kg aminophylline, they were randomized into two groups with different maintenance doses of aminophylline (1 mg/kg and 2 mg/kg, once every 8 hours). Blood concentrations of aminophylline and liver and renal functions were monitored at 8 hours, 3 days, and 7 days after the loading dose. Attacks of apnea were documented. Pharmacokinetic data of aminophylline were compared between the two groups. RESULTS: The steady-state plasma concentration of aminophylline and plasma clearance in the 2 mg/kg group were significantly higher than those in the 1 mg/kg group (P<0.05). However, the elimination half life was shorter in the 2 mg/kg group (P<0.05). Days of apnea attacks within 7 days after birth in the 2 mg/kg group were significantly fewer than in the 1 mg/kg group (P<0.05). Aminophylline plasma clearance was positively correlated with age (in days) after birth and postmenstrual age in both groups. CONCLUSIONS: In VLBW infants, pharmacokinetics and pharmacodynamics are different when different maintenance doses of aminophylline are given. The maintenance dose of 2 mg/kg is associated with a better effect in the treatment of apnea. Postmenstrual age and age (in days) should be considered during the adjustment of dose, and routine blood concentration monitoring should be performed. PMID- 26575874 TI - [Diagnostic value of interleukin 6 for neonatal sepsis: a Meta analysis]. AB - OBJECTIVE: To evaluate the diagnostic value of interleukin 6 for neonatal sepsis. METHODS: The databases of CNKI, VIP, Wangfang, Pubmed, Embase, Web of Science, Cochrane Library were searched (by September 2014) to identify relevantly published studies about estimating the diagnostic value of interleukin 6 for neonatal sepsis. QUADAS tools were used for quality evaluation of the studies. A Meta analysis was performed by employing Meta Disc 1.4 and Stata11.0 software. Heterogeneity of the included articles was tested to select proper efficacy model for calculating pooled weighted sensitivity, specificity and 95%CI. Summary receiver operating characteristic (SROC) curve was made and the area under the curve and Q(*) index were calculated. RESULTS: A total of 33 studies including 3 135 neonates were enrolled. The sensitivity and specificity of interleukin 6 for the diagnosis of neonatal sepsis were 0.79 (95%CI: 0.76-0.81) and 0.83 (95%CI: 0.81-0.85) respectively. The area under SROC curve of interleukin 6 for the diagnosis of neonatal sepsis was 0.89 and Q(*) index was 0.83. The post-test probability of diagnosing neonatal sepsis indicated by negative interleukin 6 was 5%, while that of positive interleukin 6 was 60%. CONCLUSIONS: Interleukin 6 measurement is useful for the diagnosis of neonatal sepsis with a high sensitivity and specificity. PMID- 26575875 TI - [Value of pancreatic stone protein/regenerating protein in severity evaluation and prognosis prediction for children with sepsis]. AB - OBJECTIVE: To evaluate the value of pancreatic stone protein/regenerating protein (PSP/reg) in severity evaluation and prognosis prediction for children with sepsis. METHODS: In this prospective case-control study, 159 children with sepsis (106 cases in the sepsis group; 53 cases in the severe sepsis group, including 12 cases of septic shock) and 20 children without sepsis (control group) were enrolled. ELISA was applied to measure plasma PSP/reg levels on days 1, 3, and 7 of admission to the PICU. The Spearman rank correlation test was applied to assess the correlations between plasma PSP/reg level and serum procalcitonin (PCT), CRP, WBC count, and pediatric critical illness score (PCIS). The area under the receiver operating characteristic curve (AUC) was used to assess the value of each index in determining severity and predicting prognosis for children with sepsis. RESULTS: On day 1 of admission to the PICU, plasma PSP/reg levels in the sepsis and severe sepsis groups were significantly higher than in the control group (P<0.05), and the severe sepsis group had a significantly higher plasma PSP/reg level than the sepsis group (P<0.05). On day 1 of admission to the PICU, the survival group (n=132) had a significantly lower plasma PSP/reg level than the non-survival group (n=27) (P<0.05). On day 1 of admission to the PICU, plasma PSP/reg level in children with sepsis was positively correlated with WBC count and serum PCT level (rs=0.212 and 0.548, respectively; both P<0.05), and negatively correlated with PCIS score (rs=-0.373; P<0.05). The AUCs of plasma PSP/reg level and serum PCT for determination of severe sepsis, septic shock, and death were higher than 0.7 (P<0.05). CONCLUSIONS: PSP/reg is closely related to infection, and has a certain clinical value in risk stratification of sepsis and prognosis evaluation. PMID- 26575876 TI - [Early identification of refractory Mycoplasma pneumoniae pneumonia in children]. AB - OBJECTIVE: To investigate the clinical indicators for early identification of refractory Mycoplasma pneumoniae pneumonia (RMPP) in children. METHODS: The clinical data of 142 children with Mycoplasma pneumoniae pneumonia (MPP) between January 2014 and June 2015 were retrospectively studied. Among the 142 children, there were 32 cases of RMPP and 110 cases of non-refractory MPP. The clinical data were compared between the RMPP and non-refractory MPP groups. RESULTS: The percentage of school-age children in the RMPP group was higher than in the non refractory MPP group (P<0.05). The mean onset age in the RMPP group was older than the non-refractory MPP group (P<0.05). Steroid was used in 93.8% of RMPP children compared with 7.3% of non-refractory MPP children (P<0.001). Consolidation of lung on chest X-Ray was shown in 87.5% of RMPP children compared with 42.7% of non-refractory MPP children (P<0.001). The incidence of pleural effusion in the RMPP group was higher than in the non-refractory MPP group (P<0.001). The RMPP group had higher percentages of individuals with CRP>40 mg/L and ESR>30 mm/h+LDH>300 IU/L than the non-refractory MPP group (P<0.05). CONCLUSIONS: RMPP is common in school-age children. Consolidation of lung on chest X-Ray, pleural effusion and increased levels of CRP and ESR+LDH may be helpful to early identification of RMPP in children. PMID- 26575878 TI - [Expression and significance of adhesion molecules CD62P and CD44 in peripheral blood of infants with bronchiolitis]. AB - OBJECTIVE: To explore the expression and significance of the adhesion molecules CD62P and CD44 in the peripheral blood of infants with bronchiolitis. METHODS: Thirty-three infants with bronchiolitis in the acute phase and 19 infants with bronchiolitis in the recovery phase, who were hospitalized between November 2014 and May 2015, were enrolled. Thirty infants with bronchopneumonia and 26 infants without infection were enrolled as the bronchopneumonia group and the control group, respectively. The CD62P expression in the peripheral blood of each group was measured by flow cytometry, and the CD44 level in serum was determined using ELISA. RESULTS: The levels of the adhesion molecules CD62P and CD44 in the bronchiolitis group in the acute phase were significantly higher than those in the bronchiolitis group in the recovery phase, the bronchopneumonia group, and the control group (P<0.05). The levels of the adhesion molecules CD62P and CD44 in the bronchiolitis group in the recovery phase were also significantly higher than those in the control group (P<0.05). In the bronchiolitis group in the acute phase, there was a positive correlation between CD62P expression and serum CD44 level (r=0.91; P<0.05). CONCLUSIONS: The adhesion molecules CD62P and CD44 play an important role in the pathogenesis of bronchiolitis, and their levels can reflect the severity of inflammatory response in infants with bronchiolitis. PMID- 26575877 TI - [Pathogen detection of 1 613 cases of hospitalized children with community acquired pneumonia]. AB - OBJECTIVE: To investigate the distribution of pathogens of children with community acquired pneumonia (CAP) from the Chongqing area. METHODS: Nasopharyngeal specimens and blood specimens of 1 613 children with CAP were collected between January 2014 and December 2014 for bacterial culture and detection of 7 respiratory viruses and antibodies against Mycoplasma pneumoniae (MP). RESULTS: The overall positive rate of bacteria was 50.22% (810 cases). Hemophilus parainfluenzae (40.8%), Streptococcus pneumonia (29.7%) and Moraxelle catarrhalis (7.3%) were the predominant ones. Among the viruses, the top detected virus was respiratory syncytial virus (RSV, 58.3%), followed by parainfluenza virus type3 (17.4%) and adenovirus (14.3%). A total of 481 cases (29.82%) were MP positive. The co-infection rate was 32.18% (519 cases), and the mixed infections of bacteria and viruses were common (47.4%). CONCLUSIONS: RSV and Hemophilus parainfluenzae are the major pathogens of CAP in children from the Chongqing area. MP is also an important pathogen. The co-infection of bacteria and viruses is prevalent. PMID- 26575879 TI - [Pathogens and risk factors for ventilator-associated pneumonia in children with congenial heart disease after surgery]. AB - OBJECTIVE: To investigate the distribution and drug sensitivity of pathogens and risk factors for ventilator-associated pneumonia (VAP) in children with congenial heart disease (CAD) after surgery. METHODS: According to the occurrence of VAP, 312 children with CAD who received mechanical ventilation after surgery for 48 hours or longer between January 2012 and December 2014 were classified into VAP (n=53) and non-VAP groups (n=259). Sputum samples were collected and cultured for pathogens in children with VAP. The drug sensitivity of pathogens was analyzed. The risk factors for postoperative VAP were identified by multiple logistic regression analysis. RESULTS: The sputum cultures were positive in 51 out of 53 children with VAP, and a total of 63 positive strains were cultured, including 49 strains of Gram-negative bacteria (78%), 9 strains of Gram-positive bacteria (14%) and 5 strains of funqi (8%). The drug sensitivity test showed that Gram negative bacteria were resistant to amoxicillin, piperacillin, cefotaxime and ceftazidime, with a resistance rate of above 74%, and demonstrated a sensitivity to amikacin, polymyxin and meropenem (resistance rate of 19%-32%). Single factor analysis showed albumin levels, preoperative use of antibiotics, duration of mechanical ventilation, times of tracheal intubation, duration of anesthesia agent use, duration of acrdiopulmonary bypass, duration of aortic occlusion and use of histamin2-receptor blockade were significantly different between the VAP and non-VAP groups (P<0.05). The multiple logistic regression showed albumin levels (<35 g/L), duration of mechanical ventilation (>= 7 d), times of tracheal intubation (>= 3), duration of acrdiopulmonary bypass (>= 100 minutes) and duation of aortic occlusion (>= 60 minutes) were independent risk factors for VAP in children with CAD after surgery. CONCLUSIONS: Gram-nagative bacteria are main pathogens for VAP in children with CAD after surgery. The antibiotics should be used based on the distribution of pathogens and drug sensitivity test results of pathogens. The effective measures for prevention of VAP should be taken according to the related risk factors for VAP to reduce the morbidity of VAP in children with CAD after surgery. PMID- 26575880 TI - [A comparision of the effects of subcutaneous and sublingual immunotherapy on immunological responses in children with asthma]. AB - OBJECTIVE: To compare the difference in the effects of subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) on immunological responses in children with asthma. METHODS: A total of 86 children with asthma caused by dust mites were enrolled and divided into a SLIT group (n=29), a SCIT group (n=13), a group receiving complete SCIT course (complete SCIT group; n=14), and a group receiving conventional medication (control group, n=30). Peripheral blood mononuclear cells were isolated and stimulated with house dust mite extract for 48 hours in vitro, and the percentage of regulatory T cells (Treg%) in CD4+ T cells was measured by flow cytometry. Analysis of variance with repeated measures was applied to compare the changes in humoral immunological indices and therapeutic effects in the SCIT and SLIT groups before treatment and after 6 and 12 months of treatment. RESULTS: Before antigenic stimulation, Treg% in CD4(+) T cells in the SCIT group was significantly higher than that in the SLIT and control groups; after antigenic stimulation was given, Treg% in the four groups decreased significantly. After 6 and 12 months of immunotherapy, the SCIT group had significant changes in serum sIgE and sIgG4 levels, while the SLIT group only showed a significant change in serum sIgE level. CONCLUSIONS: Temporal difference exists in different immunotherapies to cause immunological responses in children with asthma, and immunological responses induced by SCIT may occur earlier. PMID- 26575881 TI - [Association of TIAM1 gene polymorphisms with Kawasaki disease and its clinical characteristics]. AB - OBJECTIVE: To investigate the association of single nucleotide polymorphisms (SNP) rs22833188 and rs2833195 in TIAM1 gene with the susceptibility to Kawasaki disease (KD) and its clinical characteristic in children. METHODS: A case-control study was performed in this study. One hundred and eighty-eight children with KD and 197 normal children served as controls were enrolled. The genotypes of two SNPs rs22833188 and rs2833195 in TIAM1 gene were detected using PCR-RFLP. RESULTS: There were no significant differences in the genotype (AA, AG and GG) and allele frequencies of SNP rs2833188 between the KD and control groups. Significant differences in the genotype (CC, GC and GG) frequency of SNP rs2833195 were noted between the KD and control groups (P=0.017). The frequency of C allele in the KD group was higher than in the control group (P=0.015). The polymorphism of SNP rs2833188 was associated with the occurrence of rash (P=0.011), and the polymorphism of SNP rs2833195 was associated with the occurrence of conjunctival hyperemia (P=0.021). CONCLUSIONS: The polymorphism of rs2833195 in TIAM1 gene is associated with the susceptibility to KD. The polymorphisms rs2833188 and rs2833195 in TIAM1 gene may be associated with some clinical characteristics in children with KD. PMID- 26575882 TI - [Mutation analysis of the PAH gene in children with phenylketonuria from the Qinghai area of China]. AB - OBJECTIVE: To study the mutation characteristics of the phenylalanine hydroxylase (PAH) gene in children with phenylketonuria (PKU) from the Qinghai area of China, in order to provide basic information for genetic counseling and prenatal diagnosis. METHODS: Mutations of the PAH gene were detected in the promoter and exons 1-13 and their flanking intronic sequences of PAH gene by PCR and DNA sequencing in 49 children with PKU and their parents from the Qinghai area of China. RESULTS: A total of 30 different mutations were detected in 80 out of 98 mutant alleles (82%), including 19 missense (63%), 5 nonsense (17%), 3 splice site (10%) and 3 deletions (10%). Most mutations were detected in exons 3, 6, 7, 11 and intron 4 of PAH gene. The most frequent mutations were p.R243Q (19%), IVS4 1G>A (9%), p.Y356X (7%) and p.EX6-96A>G(5%). Two novel mutations p.N93fsX5 (c.279 282delCATC) and p.G171E (c.512G>A) were found. p.H64fsX9(c.190delC) was documented for the second time in Chinese PAH gene. The mutation spectrum of the gene PAH in the Qinghai population was similar to that in other populations in North China while significantly different from that in the populations from some provinces in southern China, Japan and Europe. CONCLUSIONS: The mutations of PAH gene in the Qinghai area of China demonstrate a unique diversity, complexity and specificity. PMID- 26575883 TI - [Clinical characteristics and gene mutation analysis of one pedigree with infantile glycogen storage disease type II]. AB - The clinical data of 2 infants with infantile glycogen storage disease type II (GSD II) from one pedigree were collected. The method of dried blood spots (DBS) was applied to collect peripheral blood samples, and the activity of acid alpha-D glucosidase (GAA) in leukocytes was measured. The coding region of GAA gene in this pedigree was amplified by polymerase chain reaction and then direct sequencing was used to analyze mutations in GAA gene. The two infants were twins, who were admitted to the hospital due to feeding difficulties, generalized muscle weakness and hypotonia, cardiomegaly, and cardiac insufficiency when they were 10 months old. The GAA activity in leukocytes in the two infants was significantly lower than in normal controls. Gene sequencing revealed 2 compound heterozygous mutations in the two infants, i.e., G1942A and G2214A, respectively. G1942A had been proved pathogenic, and the latter one, G2214A, was a nonsense mutation, resulting in the change of tryptophan, the 738th amino acid of GAA, into a stop codon. The two infants were diagnosed with GSD II by gene detection and no enzyme replacement therapy could be provided to them. Follow-up visits showed that the two infants died at home at the age of 15 months and 17 months, respectively. GSD II is caused by deficiency of GAA activity resulting from mutation of GAA gene. The detection of GAA activity in peripheral blood by DBS and GAA gene detection are effective and feasible methods for diagnosis of GSD II. PMID- 26575884 TI - [Clinical features and prognostic factors in children with fulminant myocarditis]. AB - OBJECTIVE: To investigate the clinical features and prognostic factors in children with fulminant myocarditis. METHODS: The clinical data of 24 children with fulminant myocarditis were retrospectively analyzed. According to the prognosis, these children were classified into two groups: survival (n=12) and death (n=12). The risk factors influencing prognosis in children with fulminant myocarditis were identified by logistic regression analysis. RESULTS: Among the 24 cases of fulminant myocarditis, gastrointestinal symptoms were found as initial symptoms in 14 cases, neurological symptoms in 12 cases, respiratory symptoms in 1 case, and cardiac symptoms in 2 cases. On admission, serum levels of creatine kinase MB, troponin I, and brain natriuretic peptide (BNP) were all increased. Besides, left ventricular ejection fraction (LVEF) decreased in 22 cases (92%), cardiothoracic ratio increased in 10 cases, third-degree atrioventricular block was observed in 8 cases, ST-segment changes were found in 11 cases and ventricular tachycardia was identified in 2 cases. LVEF in the death group was lower than in the survival group (P<0.05), while the peak level of serum BNP during hospitalization in the death group was higher than in the survival group (P<0.05). The multivariate logistic regression analysis revealed that LVEF was the risk factor influencing prognosis (OR=7.418; P<0.05). CONCLUSIONS: Fulminant myocarditis has no specific clinical features in children. A decreased LVEF is a risk factor for poor prognosis in children with fulminant myocarditis. PMID- 26575885 TI - [Disease spectrum and causes of death in hospitalized children in an upper first class hospital in Hunan Province, China, from 2010 to 2014]. AB - OBJECTIVE: To study the disease spectrum and causes of death in hospitalized children in an upper first-class hospital in Hunan Province, China. METHODS: The medical records of hospitalized children between 2010 and 2014 in this hospital were collected and analyzed retrospectively. RESULTS: From 2010 to 2014, the number of hospitalized children increased from 7 303 in 2010 to 10 902 in 2014, and the case fatality rate declined from 0.33% to 0.20% (P<0.05). The case fatality rate was highest (0.41%) in infants and lowest (0.11%) in newborns. As for the disease spectrum for these hospitalized children, in 2010, the top three diseases were leukemia, congenital heart disease, and pneumonia; in 2011, the top three diseases were tumor chemotherapy, congenital heart disease, and pneumonia; since 2012, tumor chemotherapy, epilepsy, and pneumonia had remained the top three diseases. The top three causes of death in hospitalized children were congenital malformation (39%, 39/99), tumor (13%, 13/99), and infectious diseases/parasitic diseases (8%, 8/99). CONCLUSIONS: The number of hospitalized children is increasing, while the case fatality rate tends to decrease in this hospital. Tumor, epilepsy, pneumonia, and congenital heart disease are major diseases in hospitalized children, and congenital malformation is the primary cause of death. PMID- 26575886 TI - [Effects of asthma and inhaled corticosteroids in children on the final adult height: a systemic review and Meta analysis]. AB - OBJECTIVE: To evaluate the effects of asthma and inhaled corticosteroids (ICS) in children on the final adult height. METHODS: A search was performed to collect studies evaluating the relationship between asthma and ICS in children and the final adult height in PubMed, BCI, EMbase, Web of Science, CNKI and Wanfang databases, then a systemic review and Meta analysis were conducted. RESULTS: Six studies evaluating the relationship between childhood asthma and the final adult height were enrolled. Three of them indicated that the final adult height was not influenced by childhood asthma. Two of them suggested a mild effect, and the effect was correlated with severity of childhood asthma. One of them indicated that a lower final adult height related to childhhod asthma was found only in black females without a high school education. Four studies evaluating the relationship between ICS and the final adult height were included. Compared with the non-ICS treatment group, healthy control group and the target height, ICS treatment had no effects on the final adult height. CONCLUSIONS: Childhood asthma does not or only mildly decrease the final adult height. ICS treatment does not significantly affect the final adult height. PMID- 26575887 TI - [Effects of NK-1R inhibitor WIN62577 on the migration of airway smooth muscle cells in asthmatic rats with airway remodeling]. AB - OBJECTIVE: To study the changes in the migration of airway smooth muscle cells (ASMC) in asthmatic rats with airway remodeling and the effect of NK-1R inhibitor WIN62577 on the migration of ASMC. METHODS: Sprague-Dawley rats were randomly assigned into two groups: airway remodeling induced by asthma and normal control. ASMC from rats with asthma and airway remodeling induced by ovalbumin (OVA) inhalation for 8 weeks were primary cultured and purified. Immunofluorescence and real-time PCR were used to measure the expression of NK-1R. With NK-1R inhibitor WIN62577 treatment, the changes in the migration of ASMC were measured by transwell chambers. RESULTS: NK-1R in ASMC was expressed mainly in the cytoplasm and cell membrane in the airway remodeling group, and the mRNA expression of NK 1R was higher than the normal control group (P<0.01). The number of the migrated ASMC in the airway remodeling group was significantly higher than that in the normal control group (P<0.01). Various concentrations (10-11 mol/L, 10-10 mol/L, 10-9 mol/L and 10-8 mol/L) of WIN62577 treatment decreased the number of the migrated ASMC (P<0.05). CONCLUSIONS: NK-1R may affect airway remodeling possibly through promoting the migration ability of ASMC in rats with asthma. PMID- 26575888 TI - [Clinical characteristics of children with acute rhabdomyolysis]. PMID- 26575889 TI - [Clinical and pathological characteristics and prognosis of children with histiocytic necrotizing lymphadenitis]. PMID- 26575891 TI - IgA-Mediated Autoimmune Hemolytic Anemia: A Clinical Conundrum. PMID- 26575890 TI - A Redox-Active, Compact Molecule for Cross-Linking Amyloidogenic Peptides into Nontoxic, Off-Pathway Aggregates: In Vitro and In Vivo Efficacy and Molecular Mechanisms. AB - Chemical reagents targeting and controlling amyloidogenic peptides have received much attention for helping identify their roles in the pathogenesis of protein misfolding disorders. Herein, we report a novel strategy for redirecting amyloidogenic peptides into nontoxic, off-pathway aggregates, which utilizes redox properties of a small molecule (DMPD, N,N-dimethyl-p-phenylenediamine) to trigger covalent adduct formation with the peptide. In addition, for the first time, biochemical, biophysical, and molecular dynamics simulation studies have been performed to demonstrate a mechanistic understanding for such an interaction between a small molecule (DMPD) and amyloid-beta (Abeta) and its subsequent anti amyloidogenic activity, which, upon its transformation, generates ligand-peptide adducts via primary amine-dependent intramolecular cross-linking correlated with structural compaction. Furthermore, in vivo efficacy of DMPD toward amyloid pathology and cognitive impairment was evaluated employing 5xFAD mice of Alzheimer's disease (AD). Such a small molecule (DMPD) is indicated to noticeably reduce the overall cerebral amyloid load of soluble Abeta forms and amyloid deposits as well as significantly improve cognitive defects in the AD mouse model. Overall, our in vitro and in vivo studies of DMPD toward Abeta with the first molecular-level mechanistic investigations present the feasibility of developing new, innovative approaches that employ redox-active compounds without the structural complexity as next-generation chemical tools for amyloid management. PMID- 26575892 TI - Improved Force Field Parameters Lead to a Better Description of RNA Structure. AB - We compare the performance of two different RNA force fields in four water models in simulating the conformational ensembles r(GACC) and r(CCCC). With the increased sampling facilitated by multidimensional replica exchange molecular dynamics (M-REMD), populations are compared to NMR data to evaluate force field reliability. The combination of AMBER ff12 with vdW(bb) modifications and the OPC water model produces results in quantitative agreement with the NMR ensemble that have eluded us to date. PMID- 26575893 TI - Quantification of Entropy-Loss in Replica-Averaged Modeling. AB - Averaging across multiple replicas provides a straightforward and rigorous approach to employ averaged experimental data as restraints in molecular simulations. One significant practical obstacle is to optimally choose the number of replicas, N. Here, we describe a statistical method to estimate the intrinsic entropy-loss associated with modeling some data using N replicas, from an unbiased simulation. We discuss how having such a measure at hand may be used to assess N optimally. PMID- 26575894 TI - Ab Initio Molecular Dynamics Using Recursive, Spatially Separated, Overlapping Model Subsystems Mixed within an ONIOM-Based Fragmentation Energy Extrapolation Technique. AB - Here, we demonstrate the application of fragment-based electronic structure calculations in (a) ab initio molecular dynamics (AIMD) and (b) reduced dimensional potential calculations, for medium- and large-sized protonated water clusters. The specific fragmentation algorithm used here is derived from ONIOM, but includes multiple, overlapping "model" systems. The interaction between the various overlapping model systems is (a) approximated by invoking the principle of inclusion-exclusion at the chosen higher level of theory and (b) within a real calculation performed at the chosen lower level of theory. The fragmentation algorithm itself is written using bit-manipulation arithmetic, which will prove to be advantageous, since the number of fragments in such methods has the propensity to grow exponentially with system size. Benchmark calculations are performed for three different protonated water clusters: H9O4+, H13O6+ and H(H2O)21+. For potential energy surface benchmarks, we sample the normal coordinates and compare our surface energies with full MP2 and CCSD(T) calculations. The mean absolute error for the fragment-based algorithm is <0.05 kcal/mol, when compared with MP2 calculations, and <0.07 kcal/mol, when compared with CCSD(T) calculations over 693 different geometries for the H9O4+ system. For the larger H(H2O)21+ water cluster, the mean absolute error is on the order of a 0.1 kcal/mol, when compared with full MP2 calculations for 84 different geometries, at a fraction of the computational cost. Ab initio dynamics calculations were performed for H9O4+ and H13O6+, and the energy conservation was found to be of the order of 0.01 kcal/mol for short trajectories (on the order of a picosecond). The trajectories were kept short because our algorithm does not currently include dynamical fragmentation, which will be considered in future publications. Nevertheless, the velocity autocorrelation functions and their Fourier transforms computed from the fragment-based AIMD approaches were found to be in excellent agreement with those computed using the respective higher level of theory from the chosen hybrid calculation. PMID- 26575895 TI - A Basis Set for Peptides for the Variational Approach to Conformational Kinetics. AB - Although Markov state models have proven to be powerful tools in resolving the complex features of biomolecular kinetics, the discretization of the conformational space has been a bottleneck since the advent of the method. A recently introduced variational approach, which uses basis functions instead of crisp conformational states, opened up a route to construct kinetic models in which the discretization error can be controlled systematically. Here, we develop and test a basis set for peptides to be used in the variational approach. The basis set is constructed by combining local residue-centered kinetic modes that are obtained from kinetic models of terminally blocked amino acids. Using this basis set, we model the conformational kinetics of two hexapeptides with sequences VGLAPG and VGVAPG. Six basis functions are sufficient to represent the slow kinetic modes of these peptides. The basis set also allows for a direct interpretation of the slow kinetic modes without an additional clustering in the space of the dominant eigenvectors. Moreover, changes in the conformational kinetics due to the exchange of leucine in VGLAPG to valine in VGVAPG can be directly quantified by comparing histograms of the basis set expansion coefficients. PMID- 26575896 TI - State-Selective Excitation of Quantum Systems via Geometrical Optimization. AB - We lay out the foundations of a general method of quantum control via geometrical optimization. We apply the method to state-selective population transfer using ultrashort transform-limited pulses between manifolds of levels that may represent, e.g., state-selective transitions in molecules. Assuming that certain states can be prepared, we develop three implementations: (i) preoptimization, which implies engineering the initial state within the ground manifold or electronic state before the pulse is applied; (ii) postoptimization, which implies engineering the final state within the excited manifold or target electronic state, after the pulse; and (iii) double-time optimization, which uses both types of time-ordered manipulations. We apply the schemes to two important dynamical problems: To prepare arbitrary vibrational superposition states on the target electronic state and to select weakly coupled vibrational states. Whereas full population inversion between the electronic states only requires control at initial time in all of the ground vibrational levels, only very specific superposition states can be prepared with high fidelity by either pre- or postoptimization mechanisms. Full state-selective population inversion requires manipulating the vibrational coherences in the ground electronic state before the optical pulse is applied and in the excited electronic state afterward, but not during all times. PMID- 26575897 TI - Quantum Corrections to the Free Energy Difference between Peptides and Proteins Conformers. AB - The calculation of the free energy of conformation is key in understanding the function of biomolecules and has attracted significant interest in recent years. Most current computational approaches evaluate the difference in conformational free energy in the classical limit based on the common "dogma" that only the lowest-frequency modes make a significant contribution to it, i.e. they assume that quantum mechanical corrections are negligible. Here, I show for three biomolecular systems described in the rigid-rotor, harmonic-oscillator approximation that the zero-point energy contribution, although small, is not negligible even at room temperature. I find that a quantum correction arises from the intermediate-frequency vibrational modes and that its magnitude is strongly correlated with the number of atoms in the system. A straightforward, though approximate, way to account for this quantum correction in the calculation of conformational free-energy differences by classical molecular dynamics is presented. The relevance of the quantum correction analyzed in this paper is discussed in the context of conventional force fields for proteins. PMID- 26575898 TI - Improved Monte Carlo Scheme for Efficient Particle Transfer in Heterogeneous Systems in the Grand Canonical Ensemble: Application to Vapor-Liquid Nucleation. AB - Reformulation of existing Monte Carlo algorithms used in the study of grand canonical systems has yielded massive improvements in efficiency. Here we present an energy biasing scheme designed to address targeting issues encountered in particle swap moves using sophisticated algorithms such as the Aggregation-Volume Bias and Unbonding-Bonding methods. Specifically, this energy biasing scheme allows a particle to be inserted to (or removed from) a region that is more acceptable. As a result, this new method showed a several-fold increase in insertion/removal efficiency in addition to an accelerated rate of convergence for the thermodynamic properties of the system. PMID- 26575899 TI - Predicting Energetics of Supramolecular Systems Using the XDM Dispersion Model. AB - In this article, we examine the ability of the exchange-hole dipole moment (XDM) model of dispersion to treat large supramolecular systems. We benchmark several XDM-corrected functionals on the S12L set proposed by Grimme, which comprises large dispersion-bound host-guest systems, for which back-corrected experimental and Quantum Monte Carlo (QMC) reference data are available. PBE-XDM coupled with the relatively economical and efficient pc-2-spd basis set gives excellent statistics (mean absolute error (MAE) = 1.5 kcal/mol), below the deviation between experimental and QMC data. When compared only to the (more accurate) QMC results, PBE-XDM/pc-2-spd (MAE = 1.2 kcal/mol) outperforms all other dispersion corrected DFT results in the literature, including PBE-dDsC/QZ4P (6.2 kcal/mol), PBE-NL/def2-QZVP (4.7 kcal/mol), PBE-D2/def2-QZVP' (3.5 kcal/mol), PBE-D3/def2 QZVP'(2.3 kcal/mol), M06-L/def2-QZVP (1.9 kcal/mol), and PBE-MBD (1.8 kcal/mol), with no significant bias (mean error (ME) = 0.04 kcal/mol). PBE-XDM/pc-2-spd gives binding energies relatively close to the complete basis-set limit and does not necessitate the use of counterpoise corrections, which facilitates its use. The dipole-quadrupole and quadrupole-quadrupole pairwise dispersion terms (C8 and C10) are critical for the correct description of the dimers. XDM-corrected functionals different from PBE that work well for small dimers do not yield good accuracy for the large supramolecular systems in the S12L, presenting errors that scale linearly with the dispersion contribution to the binding energy. PMID- 26575900 TI - Applications of Time-Dependent and Time-Independent Density Functional Theory to Electronic Transitions in Tetrahedral d(0) Metal Oxides. AB - We present benchmark calculations on excitation energies based on time-dependent density functional theory (TDDFT) as well as orbital relaxed self-consistent and constricted variational DFT (RSCF-CV-DFT) with and without use of the Tamm Dancoff approximation. The compilation contains results for the 3d complexes MnO4 , CrO42-, and VO43-, as well as the 4d congeners RuO4, TcO4-, and MoO42-, and 5d homologues OsO4, ReO4-, and WO42-. Considerations have been given to the local density approximation (LDA) and the functionals BP86 and PBE based on the generalized gradient approximation (GGA), as well as the hybrids B3LYP, BHLYP, and PBE0 and the length corrected functional LCBP86. We find for the 3d complexes that RSCF-CV-DFT fares better than TDDFT. Thus, in the case of RSCF-CV-DFT, the average root-mean-square deviations (RMSDs) are 0.25-0.3 eV for GGAs, 0.1 eV for B3LYP, and 0.45 eV for BHLYP. TDDFT affords RMSDs that on average range from 0.3 eV for local functionals to 0.7 eV for BHLYP with the largest fraction of Hartree Fock (HF) exchange. TDDFT is seen to fare better among the heavier tetraoxo systems. For the 4d and 5d systems, the three functionals B3LYP, PBE0 with an intermediate fraction of HF exchange, and LCBP86 have the lowest RMSD of 0.2 eV, whereas the local functionals (LDA, BP86, BPE) and BHLYP with the highest HF fraction and LCBP86* have a somewhat larger RMSD of 0.3 eV. Nearly the same performance is observed for RSCF-CV-DFT with respect to the different functionals in the case of the 4d and 5d systems. Thus, for the heavier tetraoxo systems, the two DFT schemes are comparable in accuracy. PMID- 26575901 TI - Is It Possible To Obtain Coupled Cluster Quality Energies at near Density Functional Theory Cost? Domain-Based Local Pair Natural Orbital Coupled Cluster vs Modern Density Functional Theory. AB - The recently developed domain-based local pair natural orbital coupled cluster theory with single, double, and perturbative triple excitations (DLPNO-CCSD(T)) delivers results that are closely approaching those of the parent canonical coupled cluster method at a small fraction of the computational cost. A recent extended benchmark study established that, depending on the three main truncation thresholds, it is possible to approach the canonical CCSD(T) results within 1 kJ (default setting, TightPNO), 1 kcal/mol (default setting, NormalPNO), and 2-3 kcal (default setting, LoosePNO). Although thresholds for calculations with TightPNO are 2-4 times slower than those based on NormalPNO thresholds, they are still many orders of magnitude faster than canonical CCSD(T) calculations, even for small and medium sized molecules where there is little locality. The computational effort for the coupled cluster step scales nearly linearly with system size. Since, in many instances, the coupled cluster step in DLPNO-CCSD(T) is cheaper or at least not much more expensive than the preceding Hartree-Fock calculation, it is useful to compare the method against modern density functional theory (DFT), which requires an effort comparable to that of Hartree-Fock theory (at least if Hartree-Fock exchange is part of the functional definition). Double hybrid density functionals (DHDF's) even require a MP2-like step. The purpose of this article is to evaluate the cost vs accuracy ratio of DLPNO-CCSD(T) against modern DFT (including the PBE, B3LYP, M06-2X, B2PLYP, and B2GP-PLYP functionals and, where applicable, their van der Waals corrected counterparts). To eliminate any possible bias in favor of DLPNO-CCSD(T), we have chosen established benchmark sets that were specifically proposed for evaluating DFT functionals. It is demonstrated that DLPNO-CCSD(T) with any of the three default thresholds is more accurate than any of the DFT functionals. Furthermore, using the aug-cc-pVTZ basis set and the LoosePNO default settings, DLPNO-CCSD(T) is only about 1.2 times slower than B3LYP. With NormalPNO thresholds, DLPNO-CCSD(T) is about a factor of 2 slower than B3LYP and shows a mean absolute deviation of less than 1 kcal/mol to the reference values for the four different data sets used. Our conclusion is that coupled cluster energies can indeed be obtained at near DFT cost. PMID- 26575902 TI - Variational Optimization of the Second-Order Density Matrix Corresponding to a Seniority-Zero Configuration Interaction Wave Function. AB - We perform a direct variational determination of the second-order (two-particle) density matrix corresponding to a many-electron system, under a restricted set of the two-index N-representability P-, Q-, and G-conditions. In addition, we impose a set of necessary constraints that the two-particle density matrix must be derivable from a doubly occupied many-electron wave function, i.e., a singlet wave function for which the Slater determinant decomposition only contains determinants in which spatial orbitals are doubly occupied. We rederive the two index N-representability conditions first found by Weinhold and Wilson and apply them to various benchmark systems (linear hydrogen chains, He, N2, and CN(-)). This work is motivated by the fact that a doubly occupied many-electron wave function captures in many cases the bulk of the static correlation. Compared to the general case, the structure of doubly occupied two-particle density matrices causes the associate semidefinite program to have a very favorable scaling as L(3), where L is the number of spatial orbitals. Since the doubly occupied Hilbert space depends on the choice of the orbitals, variational calculation steps of the two-particle density matrix are interspersed with orbital optimization steps (based on Jacobi rotations in the space of the spatial orbitals). We also point to the importance of symmetry breaking of the orbitals when performing calculations in a doubly occupied framework. PMID- 26575903 TI - Multiconfiguration Pair-Density Functional Theory: A Fully Translated Gradient Approximation and Its Performance for Transition Metal Dimers and the Spectroscopy of Re2Cl8(2-). AB - We extend the on-top density functional of multiconfiguration pair-density functional theory (MC-PDFT) to include the gradient of the on-top density as well as the gradient of the density. We find that the theory is reasonably stable to this extension; furthermore, it provides improved accuracy for molecules containing transition metals. We illustrate the extended on-top density functionals by applying them to Cr2, Cu2, Ag2, Os2, and Re2Cl8(2-) as well as to our previous database of 56 data for bond dissociation energies, barrier heights, reaction energies, proton affinities, and the water dimer. The performance of MC PDFT is comparable to or better than that of CASPT2. PMID- 26575904 TI - Representative Amino Acid Side-Chain Interactions in Protein-DNA Complexes: A Comparison of Highly Accurate Correlated Ab Initio Quantum Mechanical Calculations and Efficient Approaches for Applications to Large Systems. AB - Representative pairs of amino acid side chains and nucleic acid bases extracted from available high-quality structures of protein-DNA complexes were analyzed using a range of computational methods. CCSD(T)/CBS interaction energies were calculated for the chosen 272 pairs. These reference interaction energies were used to test the MP2.5/CBS, MP2.X/CBS, MP2-F12, DFT-D3, PM6, and Amber force field methods. Method MP2.5 provided excellent agreement with reference data (root-mean-square error (RMSE) of 0.11 kcal/mol), which is more than 1 order of magnitude faster than the CCSD(T) method. When MP2-F12 and MP2.5 were combined, the results were within reasonable accuracy (0.20 kcal/mol), with a computational savings of almost 2 orders of magnitude. Therefore, this method is a promising tool for accurate calculations of interaction energies in protein-DNA motifs of up to ~100 atoms, for which CCSD(T)/CBS benchmark calculations are not feasible. B3-LYP-D3 calculated with def2-TZVPP and def2-QZVP basis sets yielded sufficiently good results with a reasonably small RMSE. This method provided better results for neutral systems, whereas positively charged species exhibited the worst agreement with the benchmark data. The Amber force field yielded unbalanced results-performing well for systems containing nonpolar amino acids but severely underestimating interaction energies for charged complexes. The semiempirical PM6 method with corrections for hydrogen bonding and dispersion energy (PM6-D3H4) exhibited considerably smaller error than the Amber force field, which makes it an effective tool for modeling extended protein-ligand complexes (of up to 10,000 atoms). PMID- 26575905 TI - Can Multiconfigurational Self-Consistent Field Theory and Density Functional Theory Correctly Predict the Ground State of Metal-Metal-Bonded Complexes? AB - The electronic structure of a diiron (FeFe) complex with strong metal-metal interaction and those of analogous complexes (CoCo, CoMn, CoFe, and FeMn) with much weaker metal-metal bonding are investigated with wave function-based methods and density functional theory. The delocalization and bonding between the metal centers in the diiron complex is only fully captured after inclusion of the complete set of 3d and 4d orbitals in the active space, a situation best suited for restricted active space (RAS) approaches. Truncation of the included set of 4d orbitals results in inappropriate localization of some 3d orbitals, incorrect description of the ground spin state as well as wrong spin state energetics, as compared to experiment. Using density functional theory, some local functionals are able to predict the correct ground spin states, and describe the chemical bonding and structural properties of all the metal-metal complexes considered in this work. In contrast, the introduction of some exact exchange results in increased localization of 3d orbitals and wrong spin state energetics, a situation that is particularly troublesome for the diiron complex. PMID- 26575906 TI - Seniority Number in Valence Bond Theory. AB - In this work, a hierarchy of valence bond (VB) methods based on the concept of seniority number, defined as the number of singly occupied orbitals in a determinant or an orbital configuration, is proposed and applied to the studies of the potential energy curves (PECs) of H8, N2, and C2 molecules. It is found that the seniority-based VB expansion converges more rapidly toward the full configuration interaction (FCI) or complete active space self-consistent field (CASSCF) limit and produces more accurate PECs with smaller nonparallelity errors than its molecular orbital (MO) theory-based analogue. Test results reveal that the nonorthogonal orbital-based VB theory provides a reverse but more efficient way to truncate the complete active Hilbert space by seniority numbers. PMID- 26575907 TI - Comparison of Property-Oriented Basis Sets for the Computation of Electronic and Nuclear Relaxation Hyperpolarizabilities. AB - In the present work, we perform an assessment of several property-oriented atomic basis sets in computing (hyper)polarizabilities with a focus on the vibrational contributions. Our analysis encompasses the Pol and LPol-ds basis sets of Sadlej and co-workers, the def2-SVPD and def2-TZVPD basis sets of Rappoport and Furche, and the ORP basis set of Baranowska-Laczkowska and Laczkowski. Additionally, we use the d-aug-cc-pVQZ and aug-cc-pVTZ basis sets of Dunning and co-workers to determine the reference estimates of the investigated electric properties for small- and medium-sized molecules, respectively. We combine these basis sets with ab initio post-Hartree-Fock quantum-chemistry approaches (including the coupled cluster method) to calculate electronic and nuclear relaxation (hyper)polarizabilities of carbon dioxide, formaldehyde, cis-diazene, and a medium-sized Schiff base. The primary finding of our study is that, among all studied property-oriented basis sets, only the def2-TZVPD and ORP basis sets yield nuclear relaxation (hyper)polarizabilities of small molecules with average absolute errors less than 5.5%. A similar accuracy for the nuclear relaxation (hyper)polarizabilites of the studied systems can also be reached using the aug cc-pVDZ basis set (5.3%), although for more accurate calculations of vibrational contributions, i.e., average absolute errors less than 1%, the aug-cc-pVTZ basis set is recommended. It was also demonstrated that anharmonic contributions to first and second hyperpolarizabilities of a medium-sized Schiff base are particularly difficult to accurately predict at the correlated level using property-oriented basis sets. For instance, the value of the nuclear relaxation first hyperpolarizability computed at the MP2/def2-TZVPD level of theory is roughly 3 times larger than that determined using the aug-cc-pVTZ basis set. We link the failure of the def2-TZVPD basis set with the difficulties in predicting the first-order field-induced coordinates. On the other hand, the aug-cc-pVDZ and ORP basis sets overestimate the property in question only by roughly 30%. In this study, we also propose a low-cost composite treatment of anharmonicity that relies on the combination of two basis sets, i.e., a large-sized basis set is employed to determine lowest-order derivatives with respect to the field-induced coordinates, and a medium-sized basis set is used to compute the higher-order derivatives. The results of calculations performed at the MP2 level of theory demonstrate that this approximate scheme is very successful at predicting nuclear relaxation hyperpolarizabilities. PMID- 26575908 TI - Aspects of Size-Consistency of Orbitally Noninvariant Size-Extensive Multireference Perturbation Theories: A Case Study Using UGA-SSMRPT2 as a Prototype. AB - Profiling a potential energy surface (PES), all the way to dissociate a molecular state into particular fragments and to display real or avoided crossings, requires a multireference description and the maintenance of size-consistency. The many body methods, which suit this purpose, should thus be size-extensive. Size-extensive theories, which are invariant with respect to transformation among active orbitals are, in principle, size-consistent. Relatively cheaper size extensive theories, which do not possess this invariance, can still be size consistent if the active orbitals are localized on the asymptotic fragments. Such methods, if perturbative in nature, require the use of an unperturbed Hamiltonian, which has orbital invariance with respect to the transformation within active, core, and virtual orbitals. The principal focus of this paper is to numerically realize size-consistency with localized active orbitals using our recently developed orbitally noninvariant Unitary Group Adapted State Specific Multireference second order Perturbation Theory (UGA-SSMRPT2) as a prototype method. Our findings expose certain generic potential pitfalls of size-extensive but orbitally noninvariant MRPT theories, which are mostly related to the inability of reaching proper localized active orbitals in the fragments due to the artifacts of the orbital generation procedure. Despite the invariance of the zeroth order CAS function, lack of invariance of the MRPT itself then leads to size-inconsistency. In particular, reaching symmetry broken fragment active orbitals is an issue of concern where suitable state-averaging might ameliorate the problem, but then one has to abandon full orbital optimization. Additionally, there can be situations where the orbitals of the fragment reached as an asymptote of the supermolecule are not the same as those obtained from the optimization of the fragments individually and will require additional transformation. Moreover, for a certain PES, one may either abandon the use of optimized orbitals for that state to preserve proper symmetry and degeneracy in the fragment orbitals or be satisfied with the use of optimized orbitals, which generate broken symmetric orbitals in the fragmentation limit. All these pathologies are illustrated using the PES of various electronic states of multiply bonded systems like N2, C2H2, HCN, C2, and O2. Subject to such proviso, the UGA-SSMRPT2 turns out to be an excellent theory for studying the PES leading to fragmentation of strongly correlated systems satisfying the requirements of size-consistency with localized active orbitals. An unexpected spin-off of our studies is the realization that the size-inextensive MRMP2, which bears a close structural similarity with our theory, might under certain situations display size-consistency. We analyze this feature concretely in our paper. Our studies may serve as a benchmark for monitoring numerically the size-consistency of any state specific multireference theory which is size-extensive but not invariant with respect to transformation of active orbitals. PMID- 26575909 TI - Energy-Specific Equation-of-Motion Coupled-Cluster Methods for High-Energy Excited States: Application to K-edge X-ray Absorption Spectroscopy. AB - Single-reference techniques based on coupled-cluster (CC) theory, in the forms of linear response (LR) or equation of motion (EOM), are highly accurate and widely used approaches for modeling valence absorption spectra. Unfortunately, these equations with singles and doubles (LR-CCSD and EOM-CCSD) scale as O(N6), which may be prohibitively expensive for the study of high-energy excited states using a conventional eigensolver. In this paper, we present an energy-specific non Hermitian eigensolver that is able to obtain high-energy excited states (e.g., XAS K-edge spectrum) at low computational cost. In addition, we also introduce an improved trial vector for iteratively solving the EOM-CCSD equation with a focus on high-energy eigenstates. The energy-specific EOM-CCSD approach and its low scaling alternatives are applied to calculations of carbon, nitrogen, oxygen, and sulfur K-edge excitations. The results are compared to other implementations of CCSD for excited states, energy-specific linear response time-dependent density functional theory (TDDFT), and experimental results with multiple statistical metrics are presented and evaluated. PMID- 26575910 TI - High On/Off Conductance Switching Ratio via H-Tautomerization in Quinone. AB - Through first-principles electron transport simulations using the nonequilibrium Green's function formalism together with density functional theory, we show that, upon H-tautomerization, a simple derivative of quinone can act as a molecular switch with high ON/OFF ratio, up to 70 at low bias voltage. This switching behavior is explained by the quantum interference effect, where the positional change of hydrogen atoms causes the energies of the transmission channels to overlap. Our results suggest that this molecule could have potential applications as an effective switching device. PMID- 26575911 TI - Attenuated MP2 with a Long-Range Dispersion Correction for Treating Nonbonded Interactions. AB - Attenuated second order Moller-Plesset theory (MP2) captures intermolecular binding energies at equilibrium geometries with high fidelity with respect to reference methods, yet must fail to reproduce dispersion energies at stretched geometries due to the removal of fully long-range dispersion. For this problem to be ameliorated, long-range correction using the VV10 van der Waals density functional is added to attenuated MP2, capturing short-range correlation with attenuated MP2 and long-range dispersion with VV10. Attenuated MP2 with long range VV10 dispersion in the aug-cc-pVTZ (aTZ) basis set, MP2-V(terfc, aTZ), is parametrized for noncovalent interactions using the S66 database and tested on a variety of noncovalent databases, describing potential energy surfaces and equilibrium binding energies equally well. Further, a spin-component scaled (SCS) version, SCS-MP2-V(2terfc, aTZ), is produced using the W4-11 database as a supplemental thermochemistry training set, and the resulting method reproduces the quality of MP2-V(terfc, aTZ) for noncovalent interactions and exceeds the performance of SCS-MP2/aTZ for thermochemistry. PMID- 26575912 TI - Current Density Functional Theory Using Meta-Generalized Gradient Exchange Correlation Functionals. AB - We present the self-consistent implementation of current-dependent (hybrid) meta generalized gradient approximation (mGGA) density functionals using London atomic orbitals. A previously proposed generalized kinetic energy density is utilized to implement mGGAs in the framework of Kohn-Sham current density functional theory (KS-CDFT). A unique feature of the nonperturbative implementation of these functionals is the ability to seamlessly explore a wide range of magnetic fields up to 1 au (~235 kT) in strength. CDFT functionals based on the TPSS and B98 forms are investigated, and their performance is assessed by comparison with accurate coupled-cluster singles, doubles, and perturbative triples (CCSD(T)) data. In the weak field regime, magnetic properties such as magnetizabilities and nuclear magnetic resonance shielding constants show modest but systematic improvements over generalized gradient approximations (GGA). However, in the strong field regime, the mGGA-based forms lead to a significantly improved description of the recently proposed perpendicular paramagnetic bonding mechanism, comparing well with CCSD(T) data. In contrast to functionals based on the vorticity, these forms are found to be numerically stable, and their accuracy at high field suggests that the extension of mGGAs to CDFT via the generalized kinetic energy density should provide a useful starting point for further development of CDFT approximations. PMID- 26575913 TI - Relation between Nonlinear Optical Properties of Push-Pull Molecules and Metric of Charge Transfer Excitations. AB - We establish the relationships between the metric of charge transfer excitation (Deltar) for the bright pipi* state and the two-photon absorption probability as well as the first hyperpolarizability for two families of push-pull pi-conjugated systems. As previously demonstrated by Guido et al. (J. Chem. Theory Comput. 2013, 9, 3118-3126), Deltar is a measure for the average hole-electron distance upon excitation and can be used to discriminate between short- and long-range electronic excitations. We indicate two new benefits from using this metric for the analyses of nonlinear optical properties of push-pull systems. First, the two photon absorption probability and the first hyperpolarizability are found to be interrelated through Deltar; if beta ~ (Deltar)(k), then roughly, delta(TPA) ~ (Deltar)(k+1). Second, a simple power relation between Deltar and the molecular hyperpolarizabilities of push-pull systems offers the possibility of estimating properties for longer molecular chains without performing calculations of high order response functions explicitly. We further demonstrate how to link the hyperpolarizabilities with the chain length of the push-pull pi-conjugated systems through the metric of charge transfer. PMID- 26575914 TI - Investigating Multireference Character and Correlation in Quantum Chemistry. AB - We review a range of multireference diagnostics for quantum chemistry and discuss them in terms of choices of the molecular orbitals. We show how an approach1 of P.-O. Lowdin can also be viewed as quantifying the electron correlation via the spatial entanglement relative to a single determinant. We consider three example systems from quantum chemistry that exhibit three different combinations of multireference character and correlation: not strongly multireference and not strongly correlated, strongly multireference but not strongly correlated, and strongly multireference together with strong correlation. We find that a multireference measure (MR) does not change substantially with the cutoff used for a Monte Carlo configuration interaction calculation and investigate the effect of using natural orbitals. We see that a coupled-cluster singles and doubles diagnostic and a density-functional theory diagnostic give a correct general prediction of the multireference character for these systems. We also look at the issue of multireference character for a collection of noninteracting hydrogen molecules and the effect of basis size on the multireference character of a stretched hydrogen molecule. PMID- 26575915 TI - Assessment of Empirical Models versus High-Accuracy Ab Initio Methods for Nucleobase Stacking: Evaluating the Importance of Charge Penetration. AB - Molecular mechanics (MM) force field models have been demonstrated to have difficulty reproducing certain potential energy surfaces of pi-stacked complexes. Here, we examine the performance of the AMBER and CHARMM models relative to high quality ab initio data across systematic helical parameter scans and typical B DNA geometries for pi-stacking energies of nucleobase dimers. These force fields perform best for typical B-DNA geometries (mean absolute error < 1 kcal mol(-1)), whereas errors typically approach ~2 kcal mol(-1) for broader potential scans, with maximum errors > 10 kcal mol(-1) relative to high-quality ab initio reference interaction energies. The adequate performance of MM models near minimum energy structures is accomplished through cancellation of errors in various energy terms, whereas large errors at short intermolecular distances are caused by large MM electrostatics errors due to a lack of explicit terms modeling charge penetration effects. PMID- 26575917 TI - A Comprehensive Comparison of the IEFPCM and SS(V)PE Continuum Solvation Methods with the COSMO Approach. AB - Dielectric continuum models are popular for modeling solvent effects in quantum chemical calculations. The polarizable continuum model (PCM) was originally published exploiting the exact dielectric boundary condition. This is nowadays called DPCM. The conductor-like screening model (COSMO) introduced a simplified and slightly empirical scaled conductor boundary condition, which turned out to reduce the errors resulting from outlying charge. This was implemented in PCM as CPCM. Later, the integral equation formalism (IEFPCM) and the formally identical SS(V)PE model of Chipman introduced a modified dielectric boundary condition combining the dielectric exactness of DPCM with the reduced outlying charge sensitivity of COSMO. In this paper, we demonstrate on two huge data sets of neutral and ionic solutes that no significant difference can be observed between the COSMO and IEFPCM, if the correct scaling factor is chosen for COSMO. PMID- 26575918 TI - Efficient Semi-numerical Implementation of Global and Local Hybrid Functionals for Time-Dependent Density Functional Theory. AB - Local hybrid functionals with position-dependent exact-exchange admixture offer increased flexibility compared to global hybrids. For sufficiently advanced functionals of this type, this is expected to hold also for a wide range of electronic excitations within time-dependent density functional theory (TDDFT). Following a recent semi-numerical implementation of local hybrid functionals for ground-state self-consistent-field calculations (Bahmann, H.; Kaupp, M. J. Chem. Theory Comput. 2015, 11, 1540-1548), the first linear-response TDDFT implementation of local hybrids is reported, using a semi-numerical integration technique. The timings and accuracy of the semi-numerical implementation are evaluated by comparison with analytical schemes for time-dependent Hartree-Fock (TDHF) and for the TPSSh global hybrid. In combination with the RI approximation to the Coulomb part of the kernel, the semi-numerical implementation is faster than the existing analytical TDDFT/TDHF implementation of global hybrid functionals in the TURBOMOLE code, even for small systems and moderate basis sets. Moreover, timings for global and local hybrids are practically equal for the semi-numerical scheme. The way to TDDFT calculations with local hybrid functionals for large systems is thus now open, and more sophisticated parametrizations of local hybrids may be evaluated. PMID- 26575916 TI - DFTB3 Parametrization for Copper: The Importance of Orbital Angular Momentum Dependence of Hubbard Parameters. AB - We report the parametrization of a density functional tight binding method (DFTB3) for copper in a spin-polarized formulation. The parametrization is consistent with the framework of 3OB for main group elements (ONCHPS) and can be readily used for biological applications that involve copper proteins/peptides. The key to our parametrization is to introduce orbital angular momentum dependence of the Hubbard parameter and its charge derivative, thus allowing the 3d and 4s orbitals to adopt different sizes and responses to the change of charge state. The parametrization has been tested by applying to a fairly broad set of molecules of biological relevance, and the properties of interest include optimized geometries, ligand binding energies, and ligand proton affinities. Compared to the reference QM level (B3LYP/aug-cc-pVTZ, which is shown here to be similar to the B97-1 and CCSD(T) results, in terms of many properties of interest for a set of small copper containing molecules), our parametrization generally gives reliable structural properties for both Cu(I) and Cu(II) compounds, although several exceptions are also noted. For energetics, the results are more accurate for neutral ligands than for charged ligands, likely reflecting the minimal basis limitation of DFTB3; the results generally outperform NDDO based methods such as PM6 and even PBE with the 6-31+G(d,p) basis. For all ligand types, single-point B3LYP calculations at DFTB3 geometries give results very close (~1-2 kcal/mol) to the reference B3LYP values, highlighting the consistency between DFTB3 and B3LYP structures. Possible further developments of the DFTB3 model for a better treatment of transition-metal ions are also discussed. In the current form, our first generation of DFTB3 copper model is expected to be particularly valuable as a method that drives sampling in systems that feature a dynamical copper binding site. PMID- 26575919 TI - Vibrational Circular Dichroism Spectra for Large Molecules through Molecules-in Molecules Fragment-Based Approach. AB - We present the first implementation of the vibrational circular dichroism (VCD) spectrum of large molecules through the Molecules-in-Molecules (MIM) fragment based method. An efficient projection of the relevant higher energy derivatives from smaller fragments to the parent molecule enables the extension of the MIM method for the evaluation of VCD spectra (MIM-VCD). The overlapping primary subsystems in this work are constructed from interacting fragments using a number based scheme and the dangling bonds are saturated with link hydrogen atoms. Independent fragment calculations are performed to evaluate the energies, Hessian matrix, atomic polar tensor (APT), and the atomic axial tensor (AAT). Subsequently, the link atom tensor components are projected back onto the corresponding host and supporting atoms through the Jacobian projection method, as in the ONIOM approach. In the two-layer model, the long-range interactions between fragments are accounted for using a less computationally intensive lower level of theory. The performance of the MIM model is calibrated on the d- and l enantiomers of 10 carbohydrate benchmark molecules, with strong intramolecular interactions. The vibrational frequencies and VCD intensities are accurately reproduced relative to the full, unfragmented, results for these systems. In addition, the MIM-VCD method is employed to predict the VCD spectra of perhydrotriphenylene and cryptophane-A, yielding spectra in agreement with experiment. The accuracy and performance of the benchmark systems validate the MIM-VCD model for exploring vibrational circular dichroism spectra of large molecules. PMID- 26575920 TI - Automated Discovery of Elementary Chemical Reaction Steps Using Freezing String and Berny Optimization Methods. AB - We present a simple protocol which allows fully automated discovery of elementary chemical reaction steps using in cooperation double- and single-ended transition state optimization algorithms--the freezing string and Berny optimization methods, respectively. To demonstrate the utility of the proposed approach, the reactivity of several single-molecule systems of combustion and atmospheric chemistry importance is investigated. The proposed algorithm allowed us to detect without any human intervention not only "known" reaction pathways, manually detected in the previous studies, but also new, previously "unknown", reaction pathways which involve significant atom rearrangements. We believe that applying such a systematic approach to elementary reaction path finding will greatly accelerate the discovery of new chemistry and will lead to more accurate computer simulations of various chemical processes. PMID- 26575921 TI - Toward Modular Analysis of Supramolecular Protein Assemblies. AB - Despite recent advances in molecular simulation technologies, analysis of high molecular-weight structures is still challenging. Here, we propose an automated model reduction procedure aiming to enable modular analysis of these structures. It employs a component mode synthesis for the reduction of finite element protein models. Reduced models may consist of real biological subunits or artificial partitions whose dynamics is described using the degrees of freedom at the substructural interfaces and a small set of dominant vibrational modes only. Notably, the proper number of dominant modes is automatically determined using a novel estimator for eigenvalue errors without calculating the reference eigensolutions of the full model. The performance of the proposed approach is thoroughly investigated by analyzing 50 representative structures including a crystal structure of GroEL and an electron density map of a ribosome. PMID- 26575922 TI - Evaluation of CM5 Charges for Nonaqueous Condensed-Phase Modeling. AB - Partial atomic charges for neutral molecules from quantum mechanical calculations are typically scaled for use in molecular modeling of liquid-phase systems. Optimal scale factors of 1.14 for CM1A and 1.27 for CM5 charges were previously determined for minimizing errors in free energies of hydration. The adequacy of the 1.14*CM1A and 1.27*CM5 models are evaluated here in pure liquid simulations in combination with the OPLS-AA force field. For 22 organic liquids, the 1.14*CM1A and 1.27*CM5 models yield mean unsigned errors (MUEs) of ca. 1.40 kcal/mol for heats of vaporization. Not surprisingly, this reflects overpolarization with the scale factors derived for aqueous media. Prediction of pure liquid properties using CM5 charges is optimized using a scale factor of 1.14, which reduces the MUE for heats of vaporization to 0.89 kcal/mol. However, due to the impracticality of using different scale factors in different explicit solvent condensed-phase simulations, a universal scale factor of 1.20 emerged for CM5 charges. This provides a balance between errors in computed pure liquid properties and free energies of hydration. Computation of free energies of hydration by the GB/SA method further found that 1.20 is equally suited for use in explicit or implicit treatments of aqueous solvation. With 1.20*CM5 charges, a variety of condensed-phase simulations can be pursued while maintaining average errors of 1.0 kcal/mol in key thermodynamic properties. PMID- 26575923 TI - Electronic Energy Transfer in Polarizable Heterogeneous Environments: A Systematic Investigation of Different Quantum Chemical Approaches. AB - Theoretical prediction of transport and optical properties of protein-pigment complexes is of significant importance when aiming at understanding the structure function relationship in such systems. Electronic energy transfer (EET) couplings represent a key property in this respect since such couplings provide important insight into the strength of interaction between photoactive pigments in protein pigment complexes. Recently, attention has been payed to how the environment modifies or even controls the electronic couplings. To enable such theoretical predictions, a fully polarizable embedding model has been suggested (Curutchet, C., et al. J. Chem. Theory Comput., 2009, 5, 1838-1848). In this work, we further develop this computational model by extending it with an ab initio derived polarizable force field including higher-order multipole moments. We use this extended model to systematically examine three different ways of obtaining EET couplings in a heterogeneous medium ranging from use of the exact transition density to a point-dipole approximation. Several interesting observations are made, for example, the explicit use of transition densities in the calculation of the electronic couplings, and also when including the explicit environment contribution, can be replaced by a much simpler transition point charge description without comprising the quality of the model predictions. PMID- 26575924 TI - Excited State Absorption from Real-Time Time-Dependent Density Functional Theory. AB - The optical response of excited states is a key property used to probe photophysical and photochemical dynamics. Additionally, materials with a large nonlinear absorption cross-section caused by two-photon (TPA) and excited state absorption (ESA) are desirable for optical limiting applications. The ability to predict the optical response of excited states would help in the interpretation of transient absorption experiments and aid in the search for and design of optical limiting materials. We have developed an approach to obtain excited state absorption spectra by combining real-time (RT) and linear-response (LR) time dependent density functional theory (TDDFT). Being based on RT-TDDFT, our method is aimed at tackling larger molecular complexes and materials systems where excited state absorption is predominantly seen and many time-resolved experimental efforts are focused. To demonstrate our method, we have calculated the ground and excited state spectra of H2+ and H2 due to the simplicity in the interpretation of the spectra. We have validated our new approach by comparing our results for butadiene with previously published results based on quadratic response (QR). We also present results for oligofluorenes, where we compare our results with both QR-TDDFT and experimental measurements. Because our method directly measures the response of an excited state, stimulated emission features are also captured; although, these features are underestimated in energy which could be attributed to a change of the reference from the ground to the excited state. PMID- 26575925 TI - Electroluminescence in Molecular Junctions: A Diagrammatic Approach. AB - We compute electroluminescent signal in a current carrying single molecule junction using a superoperator formalism. Liouville space loop diagrams are used to identify all density matrix pathways that emit photons via the electroluminescence process. A frequency resolved spectrum is expressed in terms of the various Fock space states of the isolated molecule that participate in the creation and subsequent recombination of exciton. Application is made to a multilevel Coulomb blockade model system and to a gold-benzene-1,4-dithiol-gold molecular junction. PMID- 26575926 TI - Quantum-Chemical Studies on Excitation Energy Transfer Processes in BODIPY-Based Donor-Acceptor Systems. AB - BODIPY-based excitation energy transfer (EET) cassettes are experimentally extensively studied and serve as excellent model systems for the investigation of photophysical processes, since they occur in any photosynthetic system and in organic photovoltaics. In the present work, the EET rates in five BODIPY-based EET cassettes in which anthracene serves as the donor have been determined, employing the monomer transition density approach (MTD) and the ideal dipole approximation (IDA). To this end, a new computer program has been devised that calculates the direct and exchange contributions to the excitonic coupling (EC) matrix element from transition density matrices generated by a combined density functional and multireference configuration interaction (DFT/MRCI) calculation for the monomers. EET rates have been calculated according to Fermi's Golden Rule from the EC and the spectral overlap, which was obtained from the calculated vibrationally resolved emission and absorption spectra of donor and acceptor, respectively. We find that the direct contribution to the EC matrix element is dominant in the studied EET cassettes. Furthermore, we show that the contribution of the molecular linker to the EET rate cannot be neglected. In our best fragment model, the molecular linker is attached to the donor moiety. For cassettes in which the transition dipole moments of donor and acceptor are oriented in parallel manner, our results confirm the experimental findings reported by Kim et al. [J. Phys. Chem. A 2006, 110, 20-27]. In cassettes with a perpendicular orientation of the donor and acceptor transition dipole moments, dynamic effects turn out to be important. PMID- 26575927 TI - Appraisal of Surface Hopping as a Tool for Modeling Condensed Phase Linear Absorption Spectra. AB - Whereas surface hopping is usually used to study populations and mean-field dynamics to study coherences, in two recent papers, we described a procedure for calculating dipole-dipole correlation functions (and therefore absorption spectra) directly from ensembles of surface hopping trajectories. We previously applied this method to a handful of one-dimensional model problems intended to mimic the gas phase. In this article, we now benchmark this new procedure on a set of multidimensional model problems intended to mimic the condensed phase and compare our results against other standard semiclassical methods. By comparison, we demonstrate that methods that include only dynamical information from one PES (the standard Kubo approaches) exhibit large discrepancies with the results of exact quantum dynamics. Furthermore, for model problems with nonadiabatic excited state dynamics but no quantized vibrational structure in the spectra, our surface hopping approach performs comparably to using Ehrenfest dynamics to calculate the electronic coherences. That being said, however, when quantized vibrational structures are present in the spectra but the electronic states are uncoupled, performing the dynamics on the mean PES still outperforms our present method. These benchmark results should influence future studies that use ensembles of independent semiclassical trajectories to model linear as well as multidimensional spectra in the condensed phase. PMID- 26575929 TI - Accurate Infrared (IR) Spectra for Molecules Containing the C=N Moiety by Anharmonic Computations with the Double Hybrid B2PLYP Density Functional. AB - Herein, we report a comprehensive benchmark of C=N stretching vibrations computed at harmonic and anharmonic levels with the aim of proposing and validating a reliable computational strategy to get accurate results for this puzzling vibrational mode without any ad hoc scaling factor. Anharmonic calculations employing second-order vibrational perturbation theory provide very good results when performed using the B2PLYP double-hybrid functional, in conjunction with an extended basis set and supplemented by semiempirical dispersion contributions. For larger systems, B2PLYP harmonic frequencies, together with B3LYP anharmonic corrections, offer a very good compromise between accuracy and computational cost without the need of any empirical scaling factor. PMID- 26575930 TI - Approaches for Controlling the Temperature and Pressure Range in Generalized NPT Ensembles. AB - Isobaric-multithermal and multibaric-isothermal methods are powerful methods for sampling in a wide energy and/or volume space. A finite temperature or pressure is required to study phase diagrams and many properties of many types of systems. However, it is difficult to control the temperature or pressure range because these systems move randomly in energy or volume space. Here, we develop a method to control the temperature range in the isobaric-multithermal ensemble and a method to control the pressure range in the multibaric-isothermal ensemble. These methods have the advantage of adequately determining the weight factor to create the multicanonical ensemble and can be applied to study thermodynamic properties. PMID- 26575928 TI - CC/DFT Route toward Accurate Structures and Spectroscopic Features for Observed and Elusive Conformers of Flexible Molecules: Pyruvic Acid as a Case Study. AB - The structures and relative stabilities as well as the rotational and vibrational spectra of the three low-energy conformers of pyruvic acid (PA) have been characterized using a state-of-the-art quantum-mechanical approach designed for flexible molecules. By making use of the available experimental rotational constants for several isotopologues of the most stable PA conformer, Tc-PA, the semiexperimental equilibrium structure has been derived. The latter provides a reference for the pure theoretical determination of the equilibrium geometries for all conformers, thus confirming for these structures an accuracy of 0.001 A and 0.1 deg for bond lengths and angles, respectively. Highly accurate relative energies of all conformers (Tc-, Tt-, and Ct-PA) and of the transition states connecting them are provided along with the thermodynamic properties at low and high temperatures, thus leading to conformational enthalpies accurate to 1 kJ mol(-1). Concerning microwave spectroscopy, rotational constants accurate to about 20 MHz are provided for the Tt- and Ct-PA conformers, together with the computed centrifugal-distortion constants and dipole moments required to simulate their rotational spectra. For Ct-PA, vibrational frequencies in the mid-infrared region accurate to 10 cm(-1) are reported along with theoretical estimates for the transitions in the near-infrared range, and the corresponding infrared spectrum including fundamental transitions, overtones, and combination bands has been simulated. In addition to the new data described above, theoretical results for the Tc- and Tt-PA conformers are compared with all available experimental data to further confirm the accuracy of the hybrid coupled-cluster/density functional theory (CC/DFT) protocol applied in the present study. Finally, we discuss in detail the accuracy of computational models fully based on double hybrid DFT functionals (mainly at the B2PLYP/aug-cc-pVTZ level) that avoid the use of very expensive CC calculations. PMID- 26575931 TI - Modeling Proton Dissociation and Transfer Using Dissipative Particle Dynamics Simulation. AB - We suggest a coarse-grained model for dissipative particle dynamics (DPD) simulations of solutions with dissociated protons. The model uses standard short range soft repulsion and smeared charge electrostatic potentials between the beads, representing solution components. The proton is introduced as a separate charged bead that forms dissociable bonds with proton receptor base beads, such as water or deprotonated acid anions. The proton-base bonds are described by Morse potentials. When the proton establishes the Morse bonds with two bases, they form an intermediate complex, and the proton is able to "hop" between the bases artificially mimicking the Grotthuss diffusion mechanism. By adjusting the Morse potential parameters, one can regulate the potential barrier associated with intermediate complex formation and breakup and control the hopping frequency. This makes the proposed model applicable to simulations of proton mobility and reaction equilibria between protonated and deprotonated acid forms in aqueous solutions. The proposed model provides quantitative agreement with experiments for the proton self-diffusion coefficient and hopping frequency, as well as for the degree of dissociation of benzenesulfonic acid. PMID- 26575932 TI - (Dis)similarity Index To Compare Correlated Motions in Molecular Simulations. AB - Molecular dynamics (MD) simulations are widely used to complement or guide experimental studies in the characterization of protein dynamics, thanks to improvements in force-field accuracy, along with in the software and hardware to sample the conformational landscape of proteins. Among the different applications of MD simulations, the study of correlated motions is largely employed for different purposes. Several metrics have been developed to describe correlated motions in the MD ensemble, such as methods based on Pearson Correlation or Mutual Information. Cross-correlation analysis of MD trajectories is indeed appealing not only to identify residues characterized by coupled fluctuations in protein structures but also since it can be used to extrapolate motions along directions in which major conformational changes should occur, for example on longer time scales than the ones that are actually simulated. Nevertheless, most of the MD studies employ average correlation maps and mostly in a qualitative way, even when different systems or different replicates of the same system are compared. The broad application of correlation metrics in the analysis of MD simulations, especially for comparative purposes, requires a step forward toward more quantitative and accurate comparisons. We thus here employed a simple but effective index, which is based on a normalized Frobenius norm of the differences between protein correlation maps, to compare correlated motions. We applied this index for a quantitative comparison of correlated motions from MD simulations of seven proteins of different size and fold. We also employed the index to assess the robustness of correlation description when multi-replicate MD simulations of a same system are used, and we compared our index to metrics for comparison of structural ensembles such as Root Mean Square Inner Product and the Bhattacharyya Coefficient. PMID- 26575933 TI - Adaptable Lipid Matrix Promotes Protein-Protein Association in Membranes. AB - The cell membrane is "stuffed" with proteins, whose transmembrane (TM) helical domains spontaneously associate to form functionally active complexes. For a number of membrane receptors, a modulation of TM domains' oligomerization has been shown to contribute to the development of severe pathological states, thus calling for detailed studies of the atomistic aspects of the process. Despite considerable progress achieved so far, several crucial questions still remain: How do the helices recognize each other in the membrane? What is the driving force of their association? Here, we assess the dimerization free energy of TM helices along with a careful consideration of the interplay between the structure and dynamics of protein and lipids using atomistic molecular dynamics simulations in the hydrated lipid bilayer for three different model systems - TM fragments of glycophorin A, polyalanine and polyleucine peptides. We observe that the membrane driven association of TM helices exhibits a prominent entropic character, which depends on the peptide sequence. Thus, a single TM peptide of a given composition induces strong and characteristic perturbations in the hydrophobic core of the bilayer, which may facilitate the initial "communication" between TM helices even at the distances of 20-30 A. Upon tight helix-helix association, the immobilized lipids accommodate near the peripheral surfaces of the dimer, thus disturbing the packing of the surrounding. The dimerization free energy of the modeled peptides corresponds to the strength of their interactions with lipids inside the membrane being the lowest for glycophorin A and similarly higher for both homopolymers. We propose that the ability to accommodate lipid tails determines the dimerization strength of TM peptides and that the lipid matrix directly governs their association. PMID- 26575934 TI - Evidence for a Transient Additional Ligand Binding Site in the TAS2R46 Bitter Taste Receptor. AB - Most human G protein coupled receptors (GPCRs) are activated by small molecules binding to their 7-transmembrane (7-TM) helix bundle. They belong to basally diverging branches: the 25 bitter taste 2 receptors and most members of the very large rhodopsin-like/class A GPCRs subfamily. Some members of the class A branch have been suggested to feature not only an orthosteric agonist-binding site but also a more extracellular or "vestibular" site, involved in the binding process. Here we use a hybrid molecular mechanics/coarse-grained (MM/CG) molecular dynamics approach on a widely studied bitter taste receptor (TAS2R46) receptor in complex with its agonist strychnine. Three ~1 MUs molecular simulation trajectories find two sites hosting the agonist, which together elucidate experimental data measured previously and in this work. This mechanism shares similarities with the one suggested for the evolutionarily distant class A GPCRs. It might be instrumental for the remarkably broad but specific spectrum of agonists of these chemosensory receptors. PMID- 26575936 TI - On Using Atomistic Solvent Layers in Hybrid All-Atom/Coarse-Grained Molecular Dynamics Simulations. AB - Hybrid all-atom/coarse-grained (AA-CG) simulations in which AA solutes are embedded in a CG environment can provide a significant computational speed-up over conventional fully atomistic simulations and thus alleviate the current length and time scale limitations of molecular dynamics (MD) simulations of large biomolecular systems. On one hand, coarse graining the solvent is particularly appealing, since it typically constitutes the largest part of the simulation system and thus dominates computational cost. On the other hand, retaining atomic level solvent layers around the solute is desirable for a realistic description of hydrogen bonds and other local solvation effects. Here, we devise and systematically validate fixed resolution AA-CG schemes, both with and without atomistic water layers. To quantify the accuracy and diagnose possible pitfalls, Gibbs free energies of solvation of amino acid side chain analogues were calculated, and the influence of the nature of the CG solvent surrounding (polarizable vs nonpolarizable CG water) and the size of the AA solvent region was investigated. We show that distance restraints to keep the AA solvent around the solute lead to too high of a density in the inner shell. Together with a long ranged effect due to orientational ordering of water molecules at the AA-CG boundary, this affects solvation free energies. Shifting the onset of the distance restraints slightly away from the central solute significantly improves solvation free energies, down to mean unsigned errors with respect to experiment of 2.3 and 2.6 kJ/mol for the polarizable and nonpolarizable CG water surrounding, respectively. The speed-up of the nonpolarizable model renders it computationally more attractive. The present work thus highlights challenges, and outlines possible solutions, involved with modeling the boundary between different levels of resolution in hybrid AA-CG simulations. PMID- 26575935 TI - Protein-Ligand Electrostatic Binding Free Energies from Explicit and Implicit Solvation. AB - Accurate yet efficient computational models of solvent environment are central for most calculations that rely on atomistic modeling, such as prediction of protein-ligand binding affinities. In this study, we evaluate the accuracy of a recently developed generalized Born implicit solvent model, GBNSR6 (Aguilar et al. J. Chem. Theory Comput. 2010, 6, 3613-3639), in estimating the electrostatic solvation free energies (DeltaG(pol)) and binding free energies (DeltaDeltaG(pol)) for small protein-ligand complexes. We also compare estimates based on three different explicit solvent models (TIP3P, TIP4PEw, and OPC). The two main findings are as follows. First, the deviation (RMSD = 7.04 kcal/mol) of GBNSR6 binding affinities from commonly used TIP3P reference values is comparable to the deviations between explicit models themselves, e.g. TIP4PEw vs TIP3P (RMSD = 5.30 kcal/mol). A simple uniform adjustment of the atomic radii by a single scaling factor reduces the RMS deviation of GBNSR6 from TIP3P to within the above "error margin" - differences between DeltaDeltaG(pol) estimated by different common explicit solvent models. The simple radii scaling virtually eliminates the systematic deviation (DeltaDeltaG(pol)) between GBNSR6 and two out of the three explicit water models and significantly reduces the deviation from the third explicit model. Second, the differences between electrostatic binding energy estimates from different explicit models is disturbingly large; for example, the deviation between TIP4PEw and TIP3P estimates of DeltaDeltaG(pol) values can be up to ~50% or ~9 kcal/mol, which is significantly larger than the "chemical accuracy" goal of ~1 kcal/mol. The absolute DeltaG(pol) calculated with different explicit models could differ by tens of kcal/mol. These discrepancies point to unacceptably high sensitivity of binding affinity estimates to the choice of common explicit water models. The absence of a clear "gold standard" among these models strengthens the case for the use of accurate implicit solvation models for binding energetics, which may be orders of magnitude faster. PMID- 26575937 TI - Differential Deformability of the DNA Minor Groove and Altered BI/BII Backbone Conformational Equilibrium by the Monovalent Ions Li(+), Na(+), K(+), and Rb(+) via Water-Mediated Hydrogen Bonding. AB - Recently, we reported the differential impact of the monovalent cations Li(+), Na(+), K(+), and Rb(+) on DNA conformational properties. These were identified from variations in the calculated solution-state X-ray DNA spectra as a function of the ion type in solvation buffer in MD simulations using our recently developed polarizable force field based on the classical Drude oscillator. Changes in the DNA structure were found to mainly involve variations in the minor groove width. Because minor groove dimensions vary significantly in protein-DNA complexes and have been shown to play a critical role in both specific and nonspecific DNA readout, understanding the origins of the observed differential DNA modulation by the first-group monovalent ions is of great biological importance. In the present study, we show that the primary microscopic mechanism for the phenomenon is the formation of water-mediated hydrogen bonds between solvated cations located inside the minor groove and simultaneously to two DNA strands, a process whose intensity and impact on DNA structure depends on both the type of ion and the DNA sequence. Additionally, it is shown that the formation of such ion-DNA hydrogen bond complexes appreciably modulates the conformation of the backbone by increasing the population of the BII substate. Notably, the differential impact of the ions on DNA conformational behavior is only predicted by the Drude polarizable model for DNA with virtually no effect observed from MD simulations utilizing the additive CHARMM36 model. Analysis of dipole moments of the water shows the Drude SWM4 model to possess high sensitivity to changes in the local environment, which indicates the important role of electronic polarization in the salt-dependent conformational properties. This also suggests that inclusion of polarization effects is required to model even relatively simple biological systems, such as DNA, in various ionic solutions. PMID- 26575938 TI - CHARMM-GUI Martini Maker for Coarse-Grained Simulations with the Martini Force Field. AB - Coarse-grained simulations are widely used to study large biological systems. Nonetheless, building such simulation systems becomes nontrivial, especially when membranes with various lipid types are involved. Taking advantage of the frameworks in all-atom CHARMM-GUI modules, we have developed CHARMM-GUI Martini Maker for building solution, micelle, bilayer, and vesicle systems as well as systems with randomly distributed lipids using the Martini force field. Martini Maker supports 82 lipid types and different flavors of the Martini force field, including polar and nonpolar Martini, Dry Martini, and ElNeDyn (an elastic network model for proteins). The qualities of the systems generated by Martini Maker are validated by simulations of various examples involving proteins and lipids. We expect Martini Maker to be a useful tool for modeling large, complicated biomolecular systems in a user-friendly way. PMID- 26575939 TI - Specific Ion Binding at Phospholipid Membrane Surfaces. AB - Metal cations are ubiquitous components in biological environments and play an important role in regulating cellular functions and membrane properties. By applying metadynamics simulations, we have performed systematic free energy calculations of Na(+), K(+), Ca(2+), and Mg(2+) bound to phospholipid membrane surfaces for the first time. The free energy landscapes unveil specific binding behaviors of metal cations on phospholipid membranes. Na(+) and K(+) are more likely to stay in the aqueous solution and can bind easily to a few lipid oxygens by overcoming low free energy barriers. Ca(2+) is most stable when it is bound to four lipid oxygens of the membrane rather than being hydrated in the aqueous solution. Mg(2+) is tightly hydrated, and it shows hardly any loss of a hydration water or binding directly to the membrane. When bound to the membrane, the cations' most favorable total coordination numbers with water and lipid oxygens are the same as their corresponding hydration numbers in aqueous solution, indicating a competition between ion binding to water and lipids. The binding specificity of metal cations on membranes is highly correlated with the hydration free energy and the size of the hydration shell. PMID- 26575941 TI - Optimized Finite Difference Method for the Full-Potential XANES Simulations: Application to Molecular Adsorption Geometries in MOFs and Metal-Ligand Intersystem Crossing Transients. AB - Accurate modeling of the X-ray absorption near-edge spectra (XANES) is required to unravel the local structure of metal sites in complex systems and their structural changes upon chemical or light stimuli. Two relevant examples are reported here concerning the following: (i) the effect of molecular adsorption on 3d metals hosted inside metal-organic frameworks and (ii) light induced dynamics of spin crossover in metal-organic complexes. In both cases, the amount of structural models for simulation can reach a hundred, depending on the number of structural parameters. Thus, the choice of an accurate but computationally demanding finite difference method for the ab initio X-ray absorption simulations severely restricts the range of molecular systems that can be analyzed by personal computers. Employing the FDMNES code [Phys. Rev. B, 2001, 63, 125120] we show that this problem can be handled if a proper diagonalization scheme is applied. Due to the use of dedicated solvers for sparse matrices, the calculation time was reduced by more than 1 order of magnitude compared to the standard Gaussian method, while the amount of required RAM was halved. Ni K-edge XANES simulations performed by the accelerated version of the code allowed analyzing the coordination geometry of CO and NO on the Ni active sites in CPO-27-Ni MOF. The Ni-CO configuration was found to be linear, while Ni-NO was bent by almost 90 degrees . Modeling of the Fe K-edge XANES of photoexcited aqueous [Fe(bpy)3](2+) with a 100 ps delay we identified the Fe-N distance elongation and bipyridine rotation upon transition from the initial low-spin to the final high-spin state. Subsequently, the X-ray absorption spectrum for the intermediate triplet state with expected 100 fs lifetime was theoretically predicted. PMID- 26575940 TI - C-Terminal Domain of Integrase Binds between the Two Active Sites. AB - HIV integrase (HIV-IN), one of three HIV enzymes, is a target for the treatment of AIDS, but the full biological assembly has been difficult to characterize, hampering inhibitor design. The recent crystallographic structures of integrase from prototype foamy virus (PFV-IN) with bound DNA were a breakthrough, revealing how viral DNA organizes two integrase dimers into a tetramer that has the two active sites appropriately spaced for insertion of the viral DNA into host DNA. The organization of domains within each PFV-IN protein chain, however, varies significantly from that found in HIV-IN structures. With the goal of identifying shared structural characteristics, the interactions among components of the PFV IN and HIV-IN assemblies were investigated with the macromolecular docking program DOT. DOT performs an exhaustive, rigid-body search between two macromolecules. Computational docking reproduced the crystallographic interactions of the PFV-IN catalytic and N-terminal domains with viral DNA and found similar viral DNA interactions for HIV-IN. Computational docking did not reproduce the crystallographic interactions of the PFV-IN C-terminal domain (CTD). Instead, two symmetry-related positions were found for the PFV-IN CTD that indicate formation of a CTD dimer between the two active sites. Our predicted CTD dimer is consistent with cross-linking studies showing interactions of the CTD with viral DNA that appear to be blocked in the PFV-IN structures. The CTD dimer can insert two arginine-rich loops between the two bound vDNA molecules and the host DNA, a region that is unoccupied in the PFV-IN crystallographic structures. The positive potential from these two loops would alleviate the large negative potential created by the close proximity of two viral vDNA ends, helping to bring together the two active sites and assisting host DNA binding. This study demonstrates the ability of computational docking to evaluate complex crystallographic assemblies, identify interactions that are influenced by the crystal environment, and provide plausible alternatives. PMID- 26575942 TI - Correction to An On-the-Fly Surface-Hopping Program JADE for Nonadiabatic Molecular Dynamics of Polyatomic Systems: Implementation and Applications. PMID- 26575944 TI - Advancing the Use of Administrative Data for Emergency Department Diagnostic Imaging Research. AB - Administrative data are critical to describing patterns of use, cost, and appropriateness of imaging in emergency care. These data encompass a range of source materials that have been collected primarily for a nonresearch use: documenting clinical care (e.g., medical records), administering care (e.g., picture archiving and communication systems), or financial transactions (e.g., insurance claims). These data have served as the foundation for large, descriptive studies that have documented the rise and expanded role of diagnostic imaging in the emergency department (ED). This article summarizes the discussions of the breakout session on the use of administrative data for emergency imaging research at the May 2015 Academic Emergency Medicine consensus conference, "Diagnostic Imaging in the Emergency Department: A Research Agenda to Optimize Utilization." The authors describe the areas where administrative data have been applied to research evaluating the use of diagnostic imaging in the ED, the common sources for these data, and the strengths and limitations of administrative data. Next, the future role of administrative data is examined for answering key research questions in an evolving health system increasingly focused on measuring appropriateness, ensuring quality, and improving value for health spending. This article specifically focuses on four thematic areas: data quality, appropriateness and value, special populations, and policy interventions. PMID- 26575943 TI - Maternal Serum 25-Hydroxyvitamin D Concentrations during Pregnancy and Infant Birthweight for Gestational Age: a Three-Cohort Study. AB - BACKGROUND: In response to inconsistent findings, we investigated associations between maternal serum 25-hydroxyvitamin D [25(OH)D] concentrations and infant birthweight for gestational age (BW/GA), including potential effect modification by maternal race/ethnicity and infant sex. METHODS: Data from 2558 pregnant women were combined in a nested case-control study (preterm and term) sampled from three cohorts: the Omega study, the Pregnancy, Infection and Nutrition study, and the Pregnancy Outcomes and Community Health study. Maternal 25(OH)D concentrations were sampled at 4 to 29 weeks gestation (80% 14-26 weeks). BW/GA was modelled as sex and gestational age-specific birthweight z-scores. General linear regression models (adjusting for age, education, parity, pre-pregnancy body mass index, season at blood draw, and smoking) assessed 25(OH)D concentrations in relation to BW/GA. RESULTS: Among non-Hispanic Black women, the positive association between 25(OH)D concentrations and BW/GA was of similar magnitude in pregnancies with female or male infants [beta (beta) = 0.015, standard error (SE) = 0.007, P = 0.025; beta = 0.018, SE = 0.006, P = 0.003, respectively]. Among non-Hispanic White women, 25(OH)D-BW/GA association was observed only with male infants, and the effect size was lower (beta = 0.008, SE = 0.003, P = 0.02). CONCLUSIONS: Maternal serum concentrations of 25(OH)D in early and mid-pregnancy were positively associated with BW/GA among non-Hispanic Black male and female infants and non-Hispanic White male infants. Effect modification by race/ethnicity may be due, in part, to overall lower concentrations of 25(OH)D in non-Hispanic Blacks. Reasons for effect modification by infant sex remain unclear. PMID- 26575945 TI - Regulation of the Expression of Heparan Sulfate 3-O-Sulfotransferase 3B (HS3ST3B) by Inflammatory Stimuli in Human Monocytes. AB - Heparan sulfate (HS) is recognized as an important player in a wide range of dynamic steps of inflammatory reactions. Thereby, structural HS remodeling is likely to play an important role in the regulation of inflammatory and immune responses; however, little is known about underlying mechanism. In this study, we analyzed the regulation of expression of HS 3-O-sulfotransferases (HS3STs) in response to inflammatory stimuli. We found that among the seven HS3ST isoenzymes, only the expression of HS3ST3B was markedly up-regulated in human primary monocytes and the related cell line THP1 after exposure to TLR agonists. TNF alpha was also efficient, to a lesser extent, to increase HS3ST3B expression, while IL-6, IL-4, and IFN-gamma were poor inducers. We then analyzed the molecular mechanisms that regulate the high expression of HS3ST3B in response to LPS. Based on the expression of HS3ST3B transcripts and on the response of a reporter gene containing the HS3ST3B1 promoter, we provide evidence that LPS induces a rapid and strong transcription of HS3ST3B1 gene, which was mainly dependent on the activation of NF-kappaB and JNK signaling pathways. Additionally, active p38 MAPK and de novo synthesized proteins are involved in post-transcriptional mechanisms to maintain a high level of HS3ST3B mRNA to a steady state. Altogether, our findings indicate that HS3ST3B1 gene behaves as a primary response gene, suggesting that it may play an important role in making 3 O-sulfated HS with specific functions in the regulation of inflammatory and immune responses. J. Cell. Biochem. 117: 1529-1542, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26575946 TI - Spin-Dependent Hybridization between Molecule and Metal at Room Temperature through Interlayer Exchange Coupling. AB - We experimentally and theoretically show that the magnetic coupling at room temperature between paramagnetic Mn within manganese phthalocyanine molecules and a Co layer persists when separated by a Cu spacer. The molecule's magnetization amplitude and direction can be tuned by varying the Cu-spacer thickness and evolves according to an interlayer exchange coupling mechanism. Ab initio calculations predict a highly spin-polarized density of states at the Fermi level of this metal-molecule interface, thereby strengthening prospective spintronics applications. PMID- 26575947 TI - Quality of life questionnaires in otorhinolaryngology: a systematic overview. AB - BACKGROUND: The importance of quality of life (QOL) as an endpoint and the use of validated QOL questionnaires have increased over time. OBJECTIVES: To evaluate health-related quality of life (HR-QOL) measurement instruments used in patients in otorhinolaryngology (ORL). We aimed to establish the use of QOL questionnaires in ORL over a period of time, establish the use of QOL questionnaires within different domains and determine the use of validated QOL questionnaires. MAIN OUT COME MEASURES: We performed a comprehensive search in PubMed up to 1 January 2014. Articles were included that measured HR-QOL questionnaires in clinical practice in children, adolescents or adults in 42 journals of ORL. Multiple unique QOL questionnaires, organised according to domain, time and survey of validation, were extracted from reported articles. RESULTS: Of 2442 articles, we utilised 1196 publications with a total of 2103 QOL questionnaires regarding ORL. We evaluated a variety of 363 unique QOL questionnaires in which 60% (n = 220) QOL questionnaires had been validated. We found a continuing increase in the amount of articles which used QOL questionnaires since the beginning of the 20th century, while the percentage of validated QOL questionnaires remained the same (76%). Most QOL questionnaires were used in the domains oncology (35%), otology (21%) and rhinology (20%). The domain otology had the largest amount of unique QOL questionnaires (n = 122). CONCLUSIONS: We identified and evaluated all unique HR-QOL questionnaires utilised in patients in ORL. Recently, the use of validated and non-validated HR-QOL questionnaires has increased within all domains of ORL. The assessment of QOL has become an important outcome measure in clinical practice, in medical research and for healthcare organisations. PMID- 26575948 TI - Exploring Contextual Factors of Youth Homelessness And Sexual Risk Behaviors: A Qualitative Study. AB - CONTEXT: HIV disproportionately affects homeless youth, and interventions to date have had minimal success in reducing sexual risk behaviors in this population. Few qualitative studies have been conducted to provide insight into the influence of homelessness-related factors on sexual risk behaviors. METHODS: A qualitative study with a quantitative component was conducted with a nonprobability sample of 64 homeless youth aged 14-24; participants were recruited from a variety of venues in Houston between October 2013 and March 2014. Thirteen focus group discussions were conducted; thematic analysis was used to identify themes related to HIV risk. RESULTS: Participants were predominantly black (75%), sheltered (67%) and aged 18 or older (77%). Youth discussed how the circumstances of their homelessness and the struggle to meet their immediate needs led to behaviors and experiences that put them at risk for HIV. Three themes emerged: Homeless youth frequently engage in risky sexual behavior, sometimes as a way to cope with stress; they often trade sex, either voluntarily or involuntarily, for such necessities as money or a place to sleep; and many experienced childhood sexual victimization or have been victimized since becoming homeless. Youth also described how stress, stigma and self-reliance contributed to their involvement in HIV risk behaviors. CONCLUSIONS: HIV prevention methods that target stress and stigma while respecting youths' self-reliance may help reduce sexual risk behaviors. Further research is needed to determine suitable behavioral change techniques to address these potentially modifiable factors. PMID- 26575949 TI - TERT promoter mutations associate with fast-growing melanoma. PMID- 26575950 TI - Atracurium Besylate and other neuromuscular blocking agents promote astroglial differentiation and deplete glioblastoma stem cells. AB - Glioblastoma multiforme (GBM) are the most common primary malignant brain tumor in adults, with a median survival of about one year. This poor prognosis is attributed primarily to therapeutic resistance and tumor recurrence after surgical removal, with the root cause suggested to be found in glioblastoma stem cells (GSCs). Using glial fibrillary acidic protein (GFAP) as a reporter of astrocytic differentiation, we isolated multiple clones from three independent GSC lines which express GFAP in a remarkably stable fashion. We next show that elevated expression of GFAP is associated with reduced clonogenicity in vitro and tumorigenicity in vivo. Utilizing this in vitro cell-based differentiation reporter system we screened chemical libraries and identified the non depolarizing neuromuscular blocker (NNMB), Atracurium Besylate, as a small molecule which effectively induces astroglial but not neuronal differentiation of GSCs. Functionally, Atracurium Besylate treatment significantly inhibited the clonogenic capacity of several independent patient-derived GSC neurosphere lines, a phenomenon which was largely irreversible. A second NNMB, Vecuronium, also induced GSC astrocytic differentiation while Dimethylphenylpiperazinium (DMPP), a nicotinic acetylcholine receptor (nAChR) agonist, significantly blocked Atracurium Besylate pro-differentiation activity. To investigate the clinical importance of nAChRs in gliomas, we examined clinical outcomes and found that glioma patients with tumors overexpressing CHRNA1 or CHRNA9 (encoding for the AChR-alpha1 or AChR-alpha9) exhibit significant shorter overall survival. Finally, we found that ex-vivo pre-treatment of GSCs, expressing CHRNA1 and CHRNA9, with Atracurium Besylate significantly increased the survival of mice xenotransplanted with these cells, therefore suggesting that tumor initiating subpopulations have been reduced. PMID- 26575951 TI - Defective autophagy gets to the brain. PMID- 26575952 TI - The TERT promoter SNP rs2853669 decreases E2F1 transcription factor binding and increases mortality and recurrence risks in liver cancer. AB - A common single-nucleotide polymorphism in the telomerase reverse transcriptase (TERT) promoter, rs2853669 influences patient survival rates and the risk of developing cancer. Recently, several lines of evidence suggest that the rs2853669 suppresses TERT promoter mutation-mediated TERT expression levels and cancer mortality as well as recurrence rates. However, no reports are available on the impact of rs2853669 on TERT expression in hepatocellular carcinoma (HCC) and its association with patient survival. Here, we found that HCC-related overall and recurrence-free survival rates were not associated with TERT promoter mutation individually, but rs2853669 and the TERT promoter mutation in combination were associated with poor survival rates. TERT mRNA expression and telomere fluorescence levels were greater in patients with HCC who had both the combination. The combination caused TERT promoter methylation through regulating the binding of DNA methyltransferase 1 and histone deacetylase 1 to the TERT promoter in HCC cell lines. The TERT expression level was significantly higher in HCC tumor with a methylated promoter than in that with an unmethylated promoter. In conclusion, we demonstrate a substantial role for the rs2853669 in HCC with TERT promoter mutation, which suggests that the combination of the rs2853669 and the mutation indicate poor prognoses in liver cancer. PMID- 26575953 TI - ASM in Alzheimer's disease. PMID- 26575954 TI - Catabolic pathways regulated by mTORC1 are pivotal for survival and growth of cancer cells expressing mutant Ras. AB - Oncogenic Ras stimulates macropinocytosis, a clathrin-independent endocytosis that increases the uptake of extracellular fluid. However, the functional significance of and regulatory mechanisms driving macropinocytosis in cancer cells remain largely unknown. Here, we show that extracellular macromolecules, such as albumin, internalized by Ras-expressing cells can support growth and survival under the nutrient-deprived conditions like those found in tumors. Moreover, we demonstrate that autophagy, a lysosome-mediated catabolic pathway, is required for the uptake and degradation of macropinocytic vesicles. Intracellular metabolites derived from macropinocytosis and autophagy directly influence the activity and localization of mTOR, which is ultimately responsible for the restoration of cell growth. Surprisingly, suppression of mTORC1, which typically triggers anabolic processes, facilitates macropinocytosis and thus supports cell growth and survival under the nutrient-deprived conditions. In a mouse xenograft model of pancreatic ductal adenocarcinoma, concomitant inhibition of macropinocytosis/autophagy and mTOR activity resulted in antitumor effects. These data suggest that novel anti-cancer strategies interrupting these metabolic processes and related signaling molecules may represent promising therapeutic avenues. PMID- 26575955 TI - Quantifying Lateral Inhomogeneity of Cholesterol-Containing Membranes. AB - Lateral inhomogeneity plays a critical role for many properties of cholesterol containing membranes, yet the thermodynamic forces involved in inhomogeneity remain poorly understood. Based on coarse-grained simulations of cholesterol in four increasingly unsaturated phospholipids, we computed lateral density fluctuations and free energies of domain formation, and we quantitatively relate those to variations in the chemical potential of cholesterol. Our simulations suggest that the lateral organization is dominated by weak repulsive cholesterol interactions, leading to a significantly more homogeneous distribution as compared to a two-dimensional ideal gas. Hence, phospholipids provide a "good" solvent for cholesterol. Unexpectedly, the degree of unsaturation of the phospholipid has only a minor effect on the lateral inhomogeneity of cholesterol in binary lipid mixtures. These results provide a link between functional properties and thermal fluctuations in lipid membranes. PMID- 26575956 TI - A role for ecology in the evolution of colour variation and sexual dimorphism in Hawaiian damselflies. AB - Variation in traits that are sexually dimorphic is usually attributed to sexual selection, in part because the influence of ecological differences between sexes can be difficult to identify. Sex-limited dimorphisms, however, provide an opportunity to test ecological selection disentangled from reproductive differences between the sexes. Here, we test the hypothesis that ecological differences play a role in the evolution of body colour variation within and between sexes in a radiation of endemic Hawaiian damselflies. We analysed 17 Megalagrion damselflies species in a phylogenetic linear regression, including three newly discovered cases of species with female-limited dimorphism. We find that rapid colour evolution during the radiation has resulted in no phylogenetic signal for most colour and habitat traits. However, a single ecological variable, exposure to solar radiation (as measured by canopy cover) significantly predicts body colour variation within sexes (female-limited dimorphism), between sexes (sexual dimorphism), and among populations and species. Surprisingly, the degree of sexual dimorphism in body colour is also positively correlated with the degree of habitat differences between sexes. Specifically, redder colouration is associated with more exposure to solar radiation, both within and between species. We discuss potential functions of the pigmentation, including antioxidant properties that would explain the association with light (specifically UV) exposure, and consider alternative mechanisms that may drive these patterns of sexual dimorphism and colour variation. PMID- 26575957 TI - Hierarchical Mesoporous Zinc-Nickel-Cobalt Ternary Oxide Nanowire Arrays on Nickel Foam as High-Performance Electrodes for Supercapacitors. AB - Nickel foam supported hierarchical mesoporous Zn-Ni-Co ternary oxide (ZNCO) nanowire arrays are synthesized by a simple two-step approach including a hydrothermal method and subsequent calcination process and directly utilized for supercapacitive investigation for the first time. The nickel foam supported hierarchical mesoporous ZNCO nanowire arrays possess an ultrahigh specific capacitance value of 2481.8 F g(-1) at 1 A g(-1) and excellent rate capability of about 91.9% capacitance retention at 5 A g(-1). More importantly, an asymmetric supercapacitor with a high energy density (35.6 Wh kg(-1)) and remarkable cycle stability performance (94% capacitance retention over 3000 cycles) is assembled successfully by employing the ZNCO electrode as positive electrode and activated carbon as negative electrode. The remarkable electrochemical behaviors demonstrate that the nickel foam supported hierarchical mesoporous ZNCO nanowire array electrodes are highly desirable for application as advanced supercapacitor electrodes. PMID- 26575958 TI - Spontaneous Formation of Multiarchitecture Vesicles of [C8mim]Br + [Na]DBS in Aqueous Medium: Synergic Interplay of Electrostatic, Hydrophobic, and pi-pi Stacking Interactions. AB - A mixture of a cationic surface active ionic liquid, [C8mim]Br and anionic surfactant, [Na]DBS has been shown to form unilamellar vesicles in water over an exceptionally wide mole fraction range of [C8mim]Br (x1 = 0.2 to 0.8). Formation of vesicles has been evidenced from transmission electron microscopy (TEM), cryo TEM and atomic force microscopy (AFM) imaging. Cryo-TEM imaging of an equimolar mixture showed multiarchitectural unilamellar vesicles (spherical, tubular, and ribbon). Such complex architectures were earlier reported for Janus dendrimers of different structures (Science, 2010, 328, 1014). The synergism between oppositely charged single chain surfactants to form bilayer structures has been explained based on the evidence of pi-pi stacking interaction from 2D NOESY measurements, Coulombic interactions from zeta potential measurements and magnitude of interaction parameter from the critical aggregation concentration. The aggregation concentrations were measured from tensiometry and fluorescence using pyrene as a polarity probe. The phase behavior at different mixture compositions has been revealed from turbidity measurements and visual inspection. Hydrodynamic radii of self-assembled structures in the bulk solution phase were measured from dynamic light scattering. Vesicles formed have been explored as delivery vehicles for proteins using bovine serum albumin (BSA) as model. PMID- 26575960 TI - Self-Assembled Monolayers Generated from Unsymmetrical Partially Fluorinated Spiroalkanedithiols. AB - Self-assembled monolayers (SAMs) were prepared on gold substrates from an unsymmetrical partially fluorinated spiroalkanedithiol adsorbate with the specific structure of [CH3(CH2)7][CF3(CF2)7(CH2)8]C[CH2SH]2 (SADT) and compared to SAMs formed from the semifluorinated monothiol F8H10SH [CF3(CF2)7(CH2)10SH] of analogous chain length and n-octadecanethiol. The adsorbate with two alkyl chains, one terminally fluorinated and the other nonfluorinated, was designed to form monolayers in which the bulky helical fluorocarbon segments assemble on top of an underlying layer of well-packed trans-extended alkyl chains. Different combinations of deposition solvents and temperatures were used to produce the bidentate SAMs. Characterization of the resulting monolayers revealed that SAMs formed in DMF at room temperature allow complete binding of the sulfur headgroups to the surface and exhibit higher conformational order than those produced using alternative solvent/temperature combinations. The reduced film thicknesses and enhanced wettability of the SADT SAMs, as compared to the SAMs generated from F8H10SH, suggest loose packing and an increase in the tilt of the terminal fluorocarbon chain segments. Nevertheless, the density of the underlying hydrocarbon chains of the SADT SAMs was higher than that of the F8H10SH SAMs, owing to the double-chained structure of the new adsorbate. The conformational orders of the SAM systems were observed to decrease as follows: C18SH > F8H10SH > SADT. However, the SAMs formed from this new double-chained bidentate adsorbate in DMF expose a fluorinated interface with a relatively low surface roughness, as determined by contact-angle hysteresis. PMID- 26575959 TI - Pilot conversion trial from mycophenolic acid to everolimus in ABO-incompatible kidney-transplant recipients with BK viruria and/or viremia. AB - Immunosuppression using everolimus (EVR) plus low-dose tacrolimus (Tac) is commonly used in organ transplantation. EVR has potential antiviral effects. Herein, the long-term outcomes and impacts of Tac-EVR on the BK virus are reported in ABO-incompatible kidney-transplant recipients. The initial immunosuppressive regimen combined steroids, Tac, and mycophenolic acid (MPA). At a median of 141 (34-529) days post-transplantation, seven stable ABO-incompatible kidney-transplant recipients were converted from MPA to EVR because of active BK replication, and compared with a reference group of fourteen ABO-incompatible patients receiving classical Tac plus MPA. At 1 month before conversion, at 1, 3 months after, and at last follow-up, clinical and biological parameters were monitored. The median time from conversion to the last follow-up was 784 (398 866) days. Conversion to EVR caused no change to rejection episodes or immunological status (isoagglutinin titers, anti-HLA antibodies). At last follow up, median eGFR was similar in the Tac-MPA versus Tac-EVR group (40 [range: 14 56] vs. 54.5 ml/min/1.73 m(2) [range: 0-128], P = 0.07). The major adverse event was dyslipidemia. Interestingly, conversion from MPA to EVR decreased BK viral load in five patients. ABO-incompatible kidney-transplant recipients with an active BK virus infection may benefit from conversion to EVR. PMID- 26575961 TI - Selective C-H Activation of Methoxy Groups in a Three-Component Photoreaction. AB - Surprisingly, the photocatalytic activation of ethers by H-abstraction and addition of the generated radicals to iminium ions formed in situ from aldehydes and anilines predominantly yielded the products of methoxy activation for dimethoxymethane and 1,2-dimethoxyethane. Various anilines and aromatic as well as aliphatic aldehydes are suitable reaction partners for this three-component photoreaction (Porta-type process) which also provides a simple access to 1,2 aminoalcohols. PMID- 26575962 TI - Alveolar Cleft Closure Managed by Primary Alveoloplasty. PMID- 26575963 TI - Masticatory Rehabilitation of a Patient With Cleft Lip and Palate Malformation Using a Maxillary Full-Arch Reconstruction With a Prefabricated Fibula Flap. AB - For full-arch reconstruction of an atrophied cleft maxilla with missing premaxilla, a prefabricated microvascular free bony flap is a relevant option. A fibula flap was prefabricated in a cleft patient who received six dental implants and an epithelial layer. Six weeks later, maxillary reconstruction was performed. The inpatient period could be confined to 2 weeks. A fixed provisional prosthesis was delivered after an additional 2 weeks. A prefabricated flap allows for the reduction of the interval without a dental prosthesis to only a few weeks, even when a complex full-arch reconstruction of the maxilla is required. PMID- 26575964 TI - Dose-Dependent Antiteratogenic Effects of Folic Acid on All-Trans Retinoic Acid Induced Cleft Palate in Fetal Mice. AB - OBJECTIVE: Although numerous studies have confirmed that consumption of folic acid (FA) during early pregnancy reduces the risk of oral facial clefts in newborn infants, the optimal dose of FA for reducing this risk remains unknown. We evaluated various doses of FA for their ability to reduce the incidence of all trans retinoic acid (ATRA)-induced cleft palate in mice. METHODS: Pregnant C57BL/6J mice were randomly assigned to eight groups dosed with corn oil (control group), ATRA (80 mg/kg), FA (40 mg/kg), or ATRA (80 mg/kg) + FA (2.5 mg, 5 mg, 10 mg, 20 mg, or 40 mg/kg body weight) on gestation day 11 (GD11), after which samples of maternal blood obtained on GD 11 were analyzed for serum folate levels. After receiving the doses, randomly selected mice in each dose group were sacrificed on GDs 13.5, 14.5, and 15.5, and the fetuses were removed for examination by light microscopy and scanning electron microscopy to detect the incidence of cleft palate. RESULTS: Among the pregnant mice dosed with ATRA+FA, those dosed with 5 mg/kg FA had fetuses with the lowest incidence of cleft palate. In addition, the eight groups of pregnant mice had significantly different serum folate concentrations (P < .001). CONCLUSION: When administered to pregnant mice at a specific dose and on the proper gestation day, FA showed an antiteratogenic effect by reducing the incidence of ATRA-induced cleft palate in fetal mice. PMID- 26575965 TI - Lateral Soft Palate Growth Deficiency: Case Report and Therapeutic Management. AB - We report the case of a girl with syndromic cleft palate, probably as part of a first branchial arch syndrome, who was unique in having almost complete unilateral aplasia of the soft palate. Rather than using soft tissue transplants or a prosthesis, we pioneered the use of a modified Furlow technique, which proved to be simple to perform, effective, and safe. PMID- 26575966 TI - Primary Premaxillary Setback and Repair of Bilateral Complete Cleft Lip: Indications, Technique, and Outcomes. AB - OBJECTIVE: To analyze indications and outcomes for primary premaxillary setback. DESIGN: Retrospective. SETTING: Academic children's hospital. PATIENTS: All children with bilateral complete cleft lip age <=2 years of age who had premaxillary setback by one surgeon (1992 to 2011). RESULTS: Twenty-five patients with bilateral complete cleft lip underwent primary premaxillary setback at an average age of 9 months; the mean follow-up was 47 months. There were three indications: failed dentofacial orthopedics (n = 9), delayed referral precluding manipulation (n = 10), and intact secondary alate (n = 6). Of 19 patients with bilateral complete cleft lip/palate, primary setback was combined with nasolabial repair (n = 11), adhesions (n = 2), or palatoplasty (n = 6). Patients who had nasolabial closure and setback were significantly younger than those who had combined palatal closure and setback (6.5 versus 16 months, P = .01). No patient exhibited postoperative premaxillary instability. Serial anthropometry showed similar growth of nasolabial features after both primary setback (n = 9) and active dentofacial orthopedics (n = 35). CONCLUSIONS: Primary premaxillary ostectomy and setback permits synchronous bilateral nasolabial-alveolar closure or alveolar-palatal repair in a child with intact secondary palate. This procedure should be considered whenever dentofacial orthopedics cannot be accomplished. Speech is paramount in an older child; setback with palatal closure is scheduled before nasolabial repair. Disturbance of midfacial growth is likely following primary premaxillary ostectomy and setback in patients with bilateral complete cleft lip/palate; however, most already need maxillary advancement. Furthermore, premaxillary setback permits proper primary nasolabial design and construction in appreciation of expected changes with growth. PMID- 26575967 TI - Minority and Public Insurance Status: Is There a Delay to Alveolar Bone Grafting Surgery? AB - OBJECTIVE: This study sought to determine the timing of alveolar bone grafting (ABG) surgery among children with cleft lip with or without cleft palate (CL+/-P) with regard to race and insurance status. DESIGN: A retrospective chart review of consecutive patients receiving ABG surgery was conducted. A multivariate regression model was constructed using predetermined clinical and demographic variables. SETTING: A large, urban cleft referral center. PATIENTS, PARTICIPANTS: Nonsyndromic patients with CL+/-P were eligible for study inclusion. INTERVENTIONS: ABG surgery using autogenous bone harvested from the anterior iliac crest. MAIN OUTCOME MEASURE: The primary outcome of interest was age at ABG surgery. RESULTS: A total of 233 patients underwent ABG surgery at 8.1 +/- 2.3 years of age. African American and Hispanic patients received delayed ABG surgery compared with Caucasian patients by approximately 1 year (P < .05). There was no difference in ABG surgery timing by insurance status (P > .05). CONCLUSIONS: The timing of ABG surgery varied by race but not by insurance status. Greater resources may be needed to ensure timely delivery of cleft care to African American and Hispanic children. PMID- 26575968 TI - Dental Anomalies in a Brazilian Cleft Population. AB - OBJECTIVE: The aim of this study was to radiographically investigate the prevalence of dental anomalies outside the cleft area in a group of Brazilian patients with nonsyndromic cleft lip and/or palate (NSCL/P). DESIGN, PARTICIPANTS, AND SETTING: A retrospective analysis of 207 panoramic radiographs of patients with NSCL/P aged 12 to 45 years without history of tooth extraction and orthodontic treatment was performed. RESULTS: Dental anomalies were found in 75.4% of the patients, and tooth agenesis (29.2%) and supernumerary tooth (2.6%) were the most common anomalies. The risk of agenesis was higher among the individuals with cleft palate (CP) compared with individuals with cleft lip (CL) and cleft lip and palate (CLP) (agenesis: CP versus CL: odds ratio 6.27, 95% confidence interval 2.21-17.8, P = .0003; CP versus CLP: odds ratio 2.94; 95% confidence interval 1.27-6.81, P = .01). The frequency of dental agenesis was higher in patients with unilateral complete CLP (agenesis: P < .0001), incomplete bilateral CLP (agenesis: P = .0013), complete CP (agenesis: P < .0001), and incomplete CP (agenesis: P < .0001). The frequency of supernumerary teeth was higher in patients with bilateral complete CLP (P < .0001). The frequency of dental agenesis (P < .0001) and ectopic tooth (P = .009) was higher than the frequency estimated for general population. CONCLUSIONS: The prevalence of dental anomalies in patients with NSCL/P was higher than that reported in overall population. This study found preferential associations between dental anomalies and specific extensions of NSCL/P, suggesting that dental agenesis and ectopic tooth may be part of oral cleft subphenotypes. PMID- 26575969 TI - Synthesis, Direct Formation under High Pressure, Structure, and Electronic Properties of LiNbO3-type Oxide PbZnO3. AB - A novel LiNbO3-type (LN-type) lead zinc oxide, PbZnO3, was successfully synthesized under high pressure and temperature. Rietveld structure refinement using synchrotron powder X-ray diffraction (XRD) data demonstrated that LN-type PbZnO3 crystallized into a trigonal structure with a polar space group (R3c). The bond valence sum estimated from the interatomic distances indicated that the sample possesses a Pb(4+)Zn(2+)O3 valence state. Polarization could evolve as a result of the repulsion between constituent cations because PbZnO3 does not contain a stereochemical 6s(2) cation or a Jahn-Teller active d(0) cation. Distortion of ZnO6 octahedra resulting from cation shift is comparable with that of d(0) TiO6 in ZnTiO3 and MnTiO3 with LN-type oxides, which leads to stabilization of the polar structure. PbZnO3 exhibited metallic behavior and temperature-independent diamagnetic character. In situ XRD measurement revealed that the formation of LN-type PbZnO3 occurred directly without the formation of a perovskite phase, which is unusual among LN-type materials obtained by high pressure synthesis. PMID- 26575971 TI - Poor Vitamin D Status in Healthy Populations in India: A Review of Current Evidence. AB - Vitamin D deficiency is associated with rickets in children, with osteoporosis in the elderly, is thought to increase the risk of certain cancers and of cardiovascular diseases, and may have an impact on many other health conditions. Asians are reported to have a poor vitamin D status despite adequate sunshine in their regions. Data on the extent of vitamin D deficiency at the population level from most Asian countries, including India, are limited. Part of the reason for paucity regarding vitamin D status is the absence of clear recommendations on optimal vitamin D intakes and status, as well as clear consensus on the cut-offs for deficiency. With a large country covering several latitudes, ethnicities, cultures, traditions, and attitudes, the current data on vitamin D status in India is inadequate and classified in different ways, making interpretation difficult, and is unrepresentative as it comes only from four states, with about half the data from Delhi. Poor vitamin D status is almost universally reported across all age groups with as many as 95.7 % neonates, 75 % adults and 67 % pregnant women having serum 25 hydroxy vitamin D levels < 50 nmol/L (deficient). Children and adults exposed to sunlight, living in rural or less polluted areas have been reported to have a better vitamin D status, especially in summer months. Lack of conclusive information emphasizes the need for state-specific data on the vitamin D status and the extent of sun exposure to issue recommendations for vitamin D intake in the country. PMID- 26575970 TI - Silver nanowires decorated with silver nanoparticles for low-haze flexible transparent conductive films. AB - Silver nanowires have attracted much attention for use in flexible transparent conductive films (TCFs) due to their low sheet resistance and flexibility. However, the haze was too high for replacing indium-tin-oxide in high-quality display devices. Herein, we report flexible TCFs, which were prepared using a scalable bar-coating method, with a low sheet resistance (24.1 Omega/sq at 96.4% transmittance) and a haze (1.04%) that is comparable to that of indium-tin-oxide TCFs. To decrease the haze and maintain a low sheet resistance, small diameter silver nanowires (~20 nm) were functionalized with low-temperature surface sintering silver nanoparticles (~5 nm) using bifunctional cysteamine. The silver nanowire-nanoparticle ink stability was excellent. The sheet resistance of the TCFs was decreased by 29.5% (from 34.2 to 24.1 Omega/sq) due to the functionalization at a low curing temperature of 85 degrees C. The TCFs were highly flexible and maintained their stability for more than 2 months and 10,000 bending cycles after coating with a protective layer. PMID- 26575972 TI - Oxidative Modifications of Protein Tyrosyl Residues Are Increased in Plasma of Human Subjects with Interstitial Lung Disease. AB - RATIONALE: Interstitial lung diseases (ILDs) are associated with oxidative stress. Plasma biomarkers that are directly linked to oxidative stress responses in this disease have not been identified. Stable oxidation products of tyrosine residues in proteins may reflect the oxidative microenvironment in the lung or a systemic inflammatory state. OBJECTIVES: To determine if levels of protein tyrosine oxidation are elevated in plasma of patients with ILD compared with an age- and sex-matched healthy control cohort. METHODS: Three tyrosine oxidation products (3-chlorotyrosine, 3-nitrotyrosine, and o,o'-dityrosine) were quantified by tandem mass spectrometry in cellular models, a mouse model of injury-induced fibrosis, and in plasma of healthy control subjects and patients with ILD (n = 42 in each group). MEASUREMENTS AND MAIN RESULTS: Plasma levels of 3-chlorotyrosine, 3-nitrotyrosine, and o,o'-dityrosine were markedly elevated in patients with ILD compared with control subjects with receiver operating characteristic curves separating these groups of 0.872, 0.893, and 0.997, respectively. In a murine model of lung fibrosis, levels of all three oxidative tyrosine modifications were increased in plasma and lung tissue. Cellular models support a critical role for a heme peroxidase and enzymatic sources of reactive oxygen species in the generation of these oxidized products. CONCLUSIONS: We demonstrate an increase in oxidized tyrosine moieties within proteins in the circulating plasma of patients with ILD. These data support the potential for development of oxidative stress related biomarkers in early diagnosis, prognostication, and/or in evaluating responsiveness to emerging therapies for ILD. PMID- 26575973 TI - Parthenogenetic haploid embryonic stem cells efficiently support mouse generation by oocyte injection. PMID- 26575974 TI - The quest for spatio-temporal control of CAR T cells. AB - Chimeric antigen receptors (CARs) are synthetic receptors capable of directing potent antigen-specific anti-tumor T cell responses. A recent report by Wu et al. extends a series of strategies aiming to curb excessive T cell activity, utilizing in this instance a chemical dimerizer to aggregate antigen-binding, T cell-activating and costimulatory domains. PMID- 26575975 TI - Robust fixed-time synchronization of delayed Cohen-Grossberg neural networks. AB - The fixed-time master-slave synchronization of Cohen-Grossberg neural networks with parameter uncertainties and time-varying delays is investigated. Compared with finite-time synchronization where the convergence time relies on the initial synchronization errors, the settling time of fixed-time synchronization can be adjusted to desired values regardless of initial conditions. Novel synchronization control strategy for the slave neural network is proposed. By utilizing the Filippov discontinuous theory and Lyapunov stability theory, some sufficient schemes are provided for selecting the control parameters to ensure synchronization with required convergence time and in the presence of parameter uncertainties. Corresponding criteria for tuning control inputs are also derived for the finite-time synchronization. Finally, two numerical examples are given to illustrate the validity of the theoretical results. PMID- 26575976 TI - All-Quantum-Dot Infrared Light-Emitting Diodes. AB - Colloidal quantum dots (CQDs) are promising candidates for infrared electroluminescent devices. To date, CQD-based light-emitting diodes (LEDs) have employed a CQD emission layer sandwiched between carrier transport layers built using organic materials and inorganic oxides. Herein, we report the infrared LEDs that use quantum-tuned materials for each of the hole-transporting, the electron transporting, and the light-emitting layers. We successfully tailor the bandgap and band position of each CQD-based component to produce electroluminescent devices that exhibit emission that we tune from 1220 to 1622 nm. Devices emitting at 1350 nm achieve peak external quantum efficiency up to 1.6% with a low turn-on voltage of 1.2 V, surpassing previously reported all-inorganic CQD LEDs. PMID- 26575977 TI - Circulating miR-21-5p and miR-148a-3p as emerging non-invasive biomarkers in thymic epithelial tumors. AB - Thymic epithelial cells give rise to both thymoma and thymic carcinoma. A crucial advance in thymic epithelial tumors (TET) management may derive from the identification of novel molecular biomarkers able to improve diagnosis, prognosis and treatment planning.In a previous study, we identified microRNAs that were differentially expressed in tumor vs normal thymic tissues. Among the microRNAs resulted up-regulated in TET tissues, we evaluated miR-21-5p, miR-148a-3p, miR 141-3p, miR-34b-5p, miR-34c-5p, miR-455-5p as blood plasma circulating non invasive biomarkers for TET management.We firstly report that the expression levels of specific onco-miRNAs, that we found upregulated in the blood plasma collected from TET patients at surgery, resulted significantly reduced in follow up samples.This pilot study suggests that circulating miR-21-5p and miR-148a-3p could represent novel non-invasive biomarkers to evaluate the efficacy of therapy and the prognosis of TET. PMID- 26575978 TI - Finding Text-Supported Gene-to-Disease Co-appearances with MOPED-Digger. AB - Gene/disease associations are a critical part of exploring disease causes and ultimately cures, yet the publications that might provide such information are too numerous to be manually reviewed. We present a software utility, MOPED Digger, that enables focused human assessment of literature by applying natural language processing (NLP) to search for customized lists of genes and diseases in titles and abstracts from biomedical publications. The results are ranked lists of gene/disease co-appearances and the publications that support them. Analysis of 18,159,237 PubMed title/abstracts yielded 1,796,799 gene/disease co appearances that can be used to focus attention on the most promising publications for a possible gene/disease association. An integrated score is provided to enable assessment of broadly presented published evidence to capture more tenuous connections. MOPED-Digger is written in Java and uses Apache Lucene 5.0 library. The utility runs as a command-line program with a variety of user options and is freely available for download from the MOPED 3.0 website (moped.proteinspire.org). PMID- 26575979 TI - Cognitive-behavioral therapy for externalizing disorders: A meta-analysis of treatment effectiveness. AB - Externalizing disorders are the most common and persistent forms of maladjustment in childhood. The aim of this study was to conduct a meta-analysis evaluating the effectiveness of Cognitive Behavioral Therapy (CBT) to reduce externalizing symptoms in two disorders: Attention Deficit Hyperactivity Disorder (ADHD) and Oppositive Defiant Disorder (ODD). The efficacy of CBT to improve social competence and positive parenting and reduce internalizing behaviors, parent stress and maternal depression was also explored. The database PsycInfo, PsycARTICLES, Medline and PubMed were searched to identify relevant studies. Twenty-one trials met the inclusion criteria. Results showed that the biggest improvement, after CBT, was in ODD symptoms (-0.879) followed by parental stress (-0.607), externalizing symptoms (-0.52), parenting skills (-0.381), social competence (-0.390) and ADHD symptoms (-0.343). CBT was also associated with improved attention (-0.378), aggressive behaviors (-0.284), internalizing symptoms (-0.272) and maternal depressive symptoms (-0.231). Overall, CBT is an effective treatment option for externalizing disorders and is also associated with reduced parental distress and maternal depressive symptoms. Multimodal treatments targeting both children and caregivers' symptoms (e.g. maternal depressive symptoms) appear important to produce sustained and generalized benefits. PMID- 26575980 TI - Updated results of 100 patients on clinical features and therapeutic options in necrobiosis lipoidica in a retrospective multicentre study. AB - BACKGROUND: Necrobiosis lipoidica (NL) is a rare granulomatous disorder of unknown aetiology which can manifest in ulcerative skin lesions and is widely recognised in association with diabetes. We evaluated in total 100 patients to improve knowledge about the epidemiology and clinical course of NL. Additionally we focused on treatment options according to evidence level and expert opinion. OBJECTIVE: To examine the clinical features of patients with necrobiosis lipoidica and to give recommendations for topical and systemic treatment. MATERIALS & METHODS: This multicentre retrospective study covers data from 100 patients with the diagnosis of NL of the lower leg, treated during the period between 01/2006 and 06/2014. Data from 5 German dermatological centres with 23 men and 77 women with a median age of 52 years were evaluated. We also asked 15 dermatological experts for their opinions about ulceration, associated diseases and their preferences for treatment modalities of NL. RESULTS: Patients' ages ranged from 15 to 95 years (median age 52 years, mean age 49.8 years). NL was significantly more common in women (77%). Ulceration of the NL was observed in 33% of cases, in particular in male patients and in patients with concomitant diabetes mellitus. Thyroidal disorders were found in 15% of all cases. CONCLUSION: Our data confirm that female sex, middle age and endocrine disorders like diabetes mellitus or thyroid dysfunction are characteristics of patients suffering from NL. Existing therapeutic options were very variable and - according to the opinion of our experts - only a few highly effective. PMID- 26575981 TI - Long noncoding RNA MALAT1 as a potential therapeutic target in osteosarcoma. AB - Recent studies have revealed that long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) plays an important role in the development of several solid tumors. However, the function of MALAT1 in the tumorigenesis of osteosarcoma remains unknown. In the present study, levels of MALAT1 in human osteosarcoma cell lines and tissues were detected by quantitative real-time polymerase chain reaction (RT-PCR). The roles of MALAT1 in osteosarcoma were investigated by using in vitro and in vivo assays. We observed that MALAT1 expression was up-regulated in human osteosarcoma cell lines and tissues. In vitro knockdown of MALAT1 by siRNA significantly inhibited cell proliferation and migration, and induced cell cycle arrest and apoptosis in osteosarcoma cells. In addition, MALAT1 knockdown markedly suppressed the formation of tubular network structures and caused breakage of stress fibers in osteosarcoma cell lines U2OS and MNNG/HOS. Furthermore, MALAT1 knockdown delayed tumor growth in an osteosarcoma xenograft model. Specifically, we found that administration of MALAT1 siRNA decreased the protein levels of RhoA and its downstream effectors Rho-associated coiled-coil containing protein kinases (ROCKs). Taken together, these findings suggest that MALAT1 plays an oncogenic role in osteosarcoma and may be a promising therapeutic target for the treatment of osteosarcoma patients. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:932-941, 2016. PMID- 26575982 TI - Efficacy and safety of tofacitinib in US and non-US rheumatoid arthritis patients: pooled analyses of phase II and III. AB - OBJECTIVES: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. This post-hoc pooled analysis assessed commonalities and differences in tofacitinib efficacy and safety for US versus rest of the world (ROW) populations. METHODS: Pooled phase (P) III data from patients receiving tofacitinib 5 or 10 mg twice daily (BID) or placebo were assessed for efficacy at Month 3 and for safety outcomes over 12 months. For adverse events of special interest, data on tofacitinib 5 or 10 mg BID or placebo were pooled from six PII and five PIII randomised studies. RESULTS: PIII data were available for 664 vs. 2447 and PII/PIII data for 943 vs. 3567 US vs. ROW patients, respectively. The US population had a higher proportion of Caucasians (81.5% vs. 54.4%), lower proportion of Asians (1.0% vs. 34.6%), and higher mean body weight (85.7 vs. 66.2 kg) and body mass index (31.5 vs. 25.6 kg/m2) compared with ROW. At Month 3, PIII efficacy was similar between US and ROW as assessed by ACR 20/50/70 response rates, remission rates (DAS 28-4[ESR]<2.6), and HAQ-DI scores. Diarrhoea, peripheral oedema, and upper respiratory tract infection occurred in >5% of PIII patients in the US population. Incidence rates for adverse events of special interest were similar between the US and ROW PII/PIII populations. CONCLUSIONS: Patients in the US achieved similar efficacy and safety with tofacitinib 5 and 10 mg BID compared with patients in ROW. PMID- 26575983 TI - Antibody persistence up to 5 years after vaccination of toddlers and children between 12 months and 10 years of age with a quadrivalent meningococcal ACWY tetanus toxoid conjugate vaccine. AB - We studied the persistence of serum bactericidal antibody using rabbit and human complement (rSBA/hSBA, cut-offs 1:8) 5 y after a single dose of meningococcal serogroups A, C, W, Y tetanus toxoid conjugate vaccine (MenACWY-TT) compared with age-appropriate control vaccines in toddlers and children (NCT00427908). Children were previously randomized (3:1) to receive either MenACWY-TT or control vaccine (MenC-CRM197 in 1-<2 y olds; MenACWY-polysaccharide vaccine [Men-PS] in 2-<11 y olds). Subjects with rSBA-MenC titers <1:8 at any time point were revaccinated with MenC conjugate vaccine and discontinued from the study. A repeated measurement statistical model assessed potential selection effects due to drop outs. At year 5 in MenACWY-TT-vaccinated-toddlers for serogroups A, C, W, and Y respectively, percentages with rSBA titers >=1:8 were 73.5%, 77.6%, 34.7%, and 42.9%, hSBA >=1:8 were 35.6%, 91.7%, 82.6% and 80.0%. For MenC-CRM197 recipients, 63.6% had persisting rSBA-MenC titers >=1:8 and 90.9% had hSBA-MenC >=1:8 (not significantly different versus MenACWY-TT for either assay: exploratory analyses). In 2-<11 y olds rSBA titers >=1:8 in MenACWY-TT-vaccinees were 90.8%, 90.8%, 78.6%, and 78.6% and 15.4%, 100%, 0.0%, 7.7% in Men-PS-vaccinees (significantly different for serogroups A, W and Y, exploratory analyses). Serogroups A, W and Y rSBA GMTs were >= 26-fold higher in MenACWY-TT-vaccinees. As expected, GMTs modeled at year 5 to assess the impact of subject drop out (mainly for revaccination), appeared lower for serogroup C. No vaccine-related SAEs were reported. Antibody persistence was observed for all serogroups up to 5 y after MenACWY-TT vaccination. PMID- 26575984 TI - A fluorescent probe for relay recognition of homocysteine and Group IIIA ions including Ga(III). AB - Challenging relay recognition of Hcy and Ga(3+), has been realized for the first time. Chemodosimeter 1 bearing a 1,1'-binaphthyl skeleton is a fluorescence turn on probe for Hcy over Cys. The system (2) generated from the recognition of Hcy exhibited further fluorescence enhancement for Ga(3+), which is the first example for specific fluorescent recognition of this metal ion. PMID- 26575985 TI - Thermal Imaging to Study Stress Non-invasively in Unrestrained Birds. AB - Stress, a central concept in biology, describes a suite of emergency responses to challenges. Among other responses, stress leads to a change in blood flow that results in a net influx of blood to key organs and an increase in core temperature. This stress-induced hyperthermia is used to assess stress. However, measuring core temperature is invasive. As blood flow is redirected to the core, the periphery of the body can cool. This paper describes a protocol where peripheral body temperature is measured non-invasively in wild blue tits (Cyanistes caeruleus) using infrared thermography. In the field we created a set up bringing the birds to an ideal position in front of the camera by using a baited box. The camera takes a short thermal video recording of the undisturbed bird before applying a mild stressor (closing the box and therefore capturing the bird), and the bird's response to being trapped is recorded. The bare skin of the eye-region is the warmest area in the image. This allows an automated extraction of the maximum eye-region temperature from each image frame, followed by further steps of manual data filtering removing the most common sources of errors (motion blur, blinking). This protocol provides a time series of eye-region temperature with a fine temporal resolution that allows us to study the dynamics of the stress response non-invasively. Further work needs to demonstrate the usefulness of the method to assess stress, for instance to investigate whether eye-region temperature response is proportional to the strength of the stressor. If this can be confirmed, it will provide a valuable alternative method of stress assessment in animals and will be useful to a wide range of researchers from ecologists, conservation biologists, physiologists to animal welfare researchers. PMID- 26575987 TI - Solution processable broadband transparent mixed metal oxide nanofilm optical coatings via substrate diffusion doping. AB - Devices composed of transparent materials, particularly those utilizing metal oxides, are of significant interest due to increased demand from industry for higher fidelity transparent thin film transistors, photovoltaics and a myriad of other optoelectronic devices and optics that require more cost-effective and simplified processing techniques for functional oxides and coatings. Here, we report a facile solution processed technique for the formation of a transparent thin film through an inter-diffusion process involving substrate dopant species at a range of low annealing temperatures compatible with processing conditions required by many state-of-the-art devices. The inter-diffusion process facilitates the movement of Si, Na and O species from the substrate into the as deposited vanadium oxide thin film forming a composite fully transparent V0.0352O0.547Si0.4078Na0.01. Thin film X-ray diffraction and Raman scattering spectroscopy show the crystalline component of the structure to be alpha-NaVO3 within a glassy matrix. This optical coating exhibits high broadband transparency, exceeding 90-97% absolute transmission across the UV-to-NIR spectral range, while having low roughness and free of surface defects and pinholes. The production of transparent films for advanced optoelectronic devices, optical coatings, and low- or high-k oxides is important for planar or complex shaped optics or surfaces. It provides opportunities for doping metal oxides to ternary, quaternary or other mixed metal oxides on glass, encapsulants or other substrates that facilitate diffusional movement of dopant species. PMID- 26575986 TI - Beyond the amygdala: Linguistic threat modulates peri-sylvian semantic access cortices. AB - In this study, healthy volunteers were scanned using functional magnetic resonance imaging (fMRI) to investigate the neural systems involved in processing the threatening content conveyed via visually presented "threat words." The neural responses elicited by these words were compared to those elicited by matched neutral control words. The results demonstrate that linguistic threat, when presented in written form, can selectively engage areas of lateral temporal and inferior frontal cortex, distinct from the core language areas implicated in aphasia. Additionally, linguistic threat modulates neural activity in visceral/emotional systems (amygdala, parahippocampal gyrus and periaqueductal gray), and at earlier stages of the visual-linguistic processing stream involved in visual word form representations (ventral occipitotemporal cortex). We propose a model whereby limbic activation modulates activity at multiple nodes along the visual-linguistic-semantic processing stream, including a perisylvian "semantic access network" involved in decoding word meaning, suggesting a dynamic interplay between feedforward and feedback processes. PMID- 26575989 TI - Differentiation of Sex Chromosomes and Karyotype Characterisation in the Dragonsnake Xenodermus javanicus (Squamata: Xenodermatidae). AB - Highly differentiated heteromorphic ZZ/ZW sex chromosomes with a heterochromatic W are a basic principle among advanced snakes of the lineage Colubroidea, while other snake lineages generally lack these characteristics. For the first time, we cytogenetically examined the dragonsnake, Xenodermus javanicus, a member of the family Xenodermatidae, which is phylogenetically nested between snake lineages with and without differentiated sex chromosomes. Although most snakes have a karyotype with a stable chromosomal number of 2n = 36, the dragonsnake has an unusual, derived karyotype with 2n = 32 chromosomes. We found that heteromorphic ZZ/ZW sex chromosomes with a heterochromatic W are present in the dragonsnake, which suggests that the emergence of a highly differentiated W sex chromosome within snakes predates the split of Xenodermatidae and the clade including families Pareatidae, Viperidae, Homalopsidae, Lamprophiidae, Elapidae, and Colubridae. Although accumulations of interstitial telomeric sequences have not been previously reported in snakes, by using FISH with a telomeric probe we discovered them in 6 pairs of autosomes as well as in the W sex chromosome of the dragonsnake. Similarly to advanced snakes, the sex chromosomes of the dragonsnake have a significant accumulation of repeats containing a (GATA)n sequence. The results facilitate the dating of the differentiation of sex chromosomes within snakes back to the split between Xenodermatidae and other advanced snakes, i.e. around 40-75 mya. PMID- 26575990 TI - Isopropylmagnesium chloride-promoted unilateral addition of Grignard reagents to beta-diketones: one-pot syntheses of beta-tertiary hydroxyl ketones or 3 substituted cyclic-2-enones. AB - The regioselective unilateral additions of Grignard reagents to acyclic or cyclic beta-diketones were effectively promoted by sub-stoichiometric amounts of i PrMgCl to afford beta-tertiary hydroxyl ketones or 3-substituted cyclic-2-enones, respectively. Also, the addition of Grignard reagents to acyclic beta-diketones followed by a reaction with cyclic beta-diketones in a one-pot process was put forward. The reaction mechanism was discussed in detail to explain the high regioselectivity via chemical experiments, hydrogen-deuterium exchange and mass spectrometry. PMID- 26575988 TI - Selection of an HLA-C*03:04-Restricted HIV-1 p24 Gag Sequence Variant Is Associated with Viral Escape from KIR2DL3+ Natural Killer Cells: Data from an Observational Cohort in South Africa. AB - BACKGROUND: Viruses can evade immune surveillance, but the underlying mechanisms are insufficiently understood. Here, we sought to understand the mechanisms by which natural killer (NK) cells recognize HIV-1-infected cells and how this virus can evade NK-cell-mediated immune pressure. METHODS AND FINDINGS: Two sequence mutations in p24 Gag associated with the presence of specific KIR/HLA combined genotypes were identified in HIV-1 clade C viruses from a large cohort of infected, untreated individuals in South Africa (n = 392), suggesting viral escape from KIR+ NK cells through sequence variations within HLA class I presented epitopes. One sequence polymorphism at position 303 of p24 Gag (TGag303V), selected for in infected individuals with both KIR2DL3 and HLA C*03:04, enabled significantly better binding of the inhibitory KIR2DL3 receptor to HLA-C*03:04-expressing cells presenting this variant epitope compared to the wild-type epitope (wild-type mean 18.01 +/- 10.45 standard deviation [SD] and variant mean 44.67 +/- 14.42 SD, p = 0.002). Furthermore, activation of primary KIR2DL3+ NK cells from healthy donors in response to HLA-C*03:04+ target cells presenting the variant epitope was significantly reduced in comparison to cells presenting the wild-type sequence (wild-type mean 0.78 +/- 0.07 standard error of the mean [SEM] and variant mean 0.63 +/- 0.07 SEM, p = 0.012). Structural modeling and surface plasmon resonance of KIR/peptide/HLA interactions in the context of the different viral sequence variants studied supported these results. Future studies will be needed to assess processing and antigen presentation of the investigated HIV-1 epitope in natural infection, and the consequences for viral control. CONCLUSIONS: These data provide novel insights into how viruses can evade NK cell immunity through the selection of mutations in HLA-presented epitopes that enhance binding to inhibitory NK cell receptors. Better understanding of the mechanisms by which HIV-1 evades NK-cell-mediated immune pressure and the functional validation of a structural modeling approach will facilitate the development of novel targeted immune interventions to harness the antiviral activities of NK cells. PMID- 26575991 TI - Quality of Preoperative Biopsy Is a Risk Factor for Positive Surgical Margins in Organ-Confined Prostate Cancer Treated with Nerve-Sparing Robot-Assisted Radical Prostatectomy. AB - PURPOSE: Positive surgical margins (PSM) during robot-assisted radical prostatectomy (RARP) negatively influence patients' prognosis. The aim of our study was to identify risk factors for PSM in patients with organ-confined prostate cancer (PCa). METHODS: A clinical database of all patients that underwent a RARP at our institution was used. Uni- and multivariable logistic regression analyses were conducted on the PSM rates for all patients with organ confined PCa. RESULTS: Altogether, 1,600 patients were identified, including 1,085 organ-confined PCa with a PSM rate of 7.8%. On multivariable analysis, bilateral nerve-sparing (OR 3.025, 95% CI 1.587-5.765), surgeon volume <200 cases (OR 1.881, 95% CI 1.120-3.159) and a preoperative PSA >10 ng/ml (OR 3.674, 95% CI 1.379-9.796) remained independent prognostic factors. In a subgroup of patients undergoing a nerve-sparing RARP, the quality of the prostate biopsy (OR 2.398, 95% CI 1.325-4.341) was the sole independent risk factor for a PSM. CONCLUSION: An elevated preoperative PSA, surgical experience and a nerve-sparing procedure are all significantly associated with a higher risk for a PSM after RARP. For those undergoing a nerve sparing RARP, an accurate preoperative biopsy with detailed information on the location of positive cores is essential to prevent PSMs. PMID- 26575992 TI - Synthesis and stabilization of a hypothetical porous framework based on a classic flexible metal carboxylate cluster. AB - By using pyridyl derivatives 4-cyanopyridine (4-pyCN) or nicotinate (na(-)) as terminal ligands (L(T)) to decorate the flexible trigonal-prismatic trinuclear metal carboxylate M3(MU3-O/MU3-OH)(RCOO)6(L(T))3 clusters, a theoretically predicted uninodal 6-connected flu-e network for [M3(MU3-O/MU3-OH)(bdc)3(L(T))3] (H2bdc = 1,4-benzenedicarboxylic acid) has been realized in three new porous coordination frameworks. The flu-e topology is isomeric to the uninodal 6 connected acs (MIL-88) and tetranodal 6-connected mtn-e (MIL-101) ones observed in the classic metal carboxylate framework materials, but comprises of unique cubic cages which require exceptional conformation for the trinuclear clusters. The weak coordinating 4-pyCN terminal ligands tend to leave the clusters during thermal activation, leading to framework distortion and reduction of the long range order of the flu-e network, which can only be restored by 4-pyCN instead of other guest molecules. On the other hand, the carboxylate ends of the adjacent na(-) ligands coordinate with additional metal ions to crosslink the coordination networks as new binodal 4,9-connected networks with remarkably enhanced thermal/chemical stability and porosity. PMID- 26575993 TI - Characterization of Silver Nanoparticles under Environmentally Relevant Conditions Using Asymmetrical Flow Field-Flow Fractionation (AF4). AB - The development of methods to monitor manufactured nanomaterials in the environment is one of the crucial areas for the assessment of their risk. More specifically, particle size analysis is a key element, because many properties of nanomaterial are size dependent. The sizing of nanomaterials in real environments is challenging due to their heterogeneity and reactivity with other environmental components. In this study, the fractionation and characterization of a mixture of polyvinylpyrrolidone-coated silver nanoparticles (PVP-AgNPs) of three different sizes were investigated using asymmetrical flow field-flow fractionation (AF4) coupled with UV-Vis spectrophotometry. In particular, the effects of electrolyte composition and natural organic matter (NOM) on the particle size and stability were evaluated. The fractogram peaks (i.e., stability) of three different AgNPs decreased in the presence of both 10 mM NaCl and 10 mM CaCl2, while increased with increasing concentration of humic acid (HA). In addition, the hydrodynamic diameters of AgNPs in both electrolytes slightly increased with an increase of HA concentration, suggesting the adsorption (coating) of HA onto the particle surface. It is also interesting to note that an increase in the particle size depended on the types of electrolyte, which could be explained by the conformational characteristics of the adsorbed HA layers. Consistent these results, AgNPs suspended in lake water containing relatively high concentration of organic carbon (TOC) showed higher particle stability and larger particle size (i.e., by approximately 4 nm) than those in river water. In conclusion, the application of AF4 coupled with highly sensitive detectors could be a powerful method to characterize nanoparticles in natural waters. PMID- 26575994 TI - Linear Growth and Fat and Lean Tissue Gain during Childhood: Associations with Cardiometabolic and Cognitive Outcomes in Adolescent Indian Children. AB - BACKGROUND: We aimed to determine how linear growth and fat and lean tissue gain during discrete age periods from birth to adolescence are related to adolescent cardiometabolic risk factors and cognitive ability. METHODS: Adolescents born to mothers with normal glucose tolerance during pregnancy from an Indian birth cohort (N = 486, age 13.5 years) had detailed anthropometry and measurements of body fat (fat%), fasting plasma glucose, insulin and lipid concentrations, blood pressure and cognitive function. Insulin resistance (HOMA-IR) was calculated. These outcomes were examined in relation to birth measurements and statistically independent measures (conditional SD scores) representing linear growth, and fat and lean tissue gain during birth-1, 1-2, 2-5, 5-9.5 and 9.5-13.5 years in 414 of the children with measurements at all these ages. RESULTS: Birth length and linear growth at all ages were positively associated with current height. Fat gain, particularly during 5-9.5 years was positively associated with fat% at 13.5 years (0.44 SD per SD [99.9% confidence interval: 0.29,0.58]). Greater fat gain during mid-late childhood was associated with higher systolic blood pressure (5 9.5 years: 0.23 SD per SD [0.07,0.40]) and HOMA-IR (5-9.5 years: 0.24 [0.08,0.40], 9.5-13.5 years: 0.22 [0.06,0.38]). Greater infant growth (up to age 2 years) in linear, fat or lean components was unrelated to cardiometabolic risk factors or cognitive function. CONCLUSION: This study suggests that factors that increase linear, fat and lean growth in infancy have no adverse cardiometabolic effects in this population. Factors that increase fat gain in mid-late childhood may increase cardiometabolic risk, without any benefit to cognitive abilities. PMID- 26575996 TI - Dual Solutions for Nonlinear Flow Using Lie Group Analysis. AB - 'The aim of this analysis is to investigate the existence of the dual solutions for magnetohydrodynamic (MHD) flow of an upper-convected Maxwell (UCM) fluid over a porous shrinking wall. We have employed the Lie group analysis for the simplification of the nonlinear differential system and computed the absolute invariants explicitly. An efficient numerical technique namely the shooting method has been employed for the constructions of solutions. Dual solutions are computed for velocity profile of an upper-convected Maxwell (UCM) fluid flow. Plots reflecting the impact of dual solutions for the variations of Deborah number, Hartman number, wall mass transfer are presented and analyzed. Streamlines are also plotted for the wall mass transfer effects when suction and blowing situations are considered. PMID- 26575995 TI - Does the Mother or Father Determine the Offspring Sex Ratio? Investigating the Relationship between Maternal Digit Ratio and Offspring Sex Ratio. AB - OBJECTIVE: In mammals, high parental testosterone levels present around the time of conception are thought to skew offspring sex ratio toward sons. The second to fourth digit ratio (digit ratio) is now widely accepted as a negative correlate of prenatal testosterone. Thus, we investigated the association between digit ratio and offspring sex ratio. METHODS: A total of 508 Korean patients (257 males and 251 females) less than 60 years old who had one or more offspring were prospectively enrolled. The lengths of the 2nd and 4th digits of the right hand were measured by a single investigator using a digital vernier calliper. Next, the patients' lifetime offspring birth sex ratios were investigated. RESULTS: Maternal (rather than paternal) digit ratio was significantly associated with the number of sons (r = -0.153, p = 0.015), number of daughters (r = 0.130, p = 0.039), and offspring sex ratio (r = -0.171, p = 0.007). And, the maternal digit ratio was a significant factor for predicting offspring sex ratio (B = -1.620, p = 0.008) on multiple linear regression analysis. The female patients with a lower digit ratio (< 0.95) were found to have a higher offspring sex ratio (0.609 versus 0.521, p = 0.046) compared to those with a higher digit ratio (>= 0.95). Furthermore, females in the low digit ratio group have a probability 1.138 greater of having sons than females in the high digit ratio group. CONCLUSIONS: Maternal digit ratio was negatively associated with offspring sex ratio. Females with a lower digit ratio were more likely to have more male offspring compared to those with a higher digit ratio. Thus, our results suggest that the sex of offspring might be more influenced by maternal rather than paternal factors. PMID- 26575997 TI - LONG-TERM PRECONDITIONING OF PLANTLETS: A PRACTICAL METHOD FOR ENHANCING SURVIVAL OF PINEAPPLE (Ananas comosus Merr.) SHOOT TIPS CRYOPRESERVED USING VITRIFICATION. AB - BACKGROUND: The purpose of this study was to develop an efficient cryopreservation protocol for pineapple (Ananas comosus Merr.) shoot tips. OBJECTIVE: The optimal state of pineapple plantlets was investigated by using sucrose preconditioning to enhance survival after cryostorage. METHODS: To achieve a suitable state of plantlets before cryopreservation, 0.2 M to 0.4 M sucrose concentrations combined with short- (0-7 days), medium- (15-30 days), and long-term (75-150 days) preconditioning periods were compared. RESULTS AND CONCLUSION: The highest survival (100 %) was achieved using the following procedure: intact plantlets underwent long-term preconditioning with 0.2 M sucrose for 135 days, dissected shoot tips were treated with a loading solution containing 2.0 M glycerol + 0.4 M sucrose for 60 min at 25 degree and the shoot tips were dehydrated in PVS2 for 2h at 0 degree C before being plunged in liquid nitrogen. Rewarming was conducted in a water-bath for 30 s at 40 degree C and PVS2 was replaced with a 1.2 M sucrose solution for 30 min at 25 degree C. The shoot tips were transferred on semisolid medium and left in the dark for 1 week, then in dim light for 3 weeks. PMID- 26575998 TI - COLD HARDINESS AND RANGE OF THE MYRIAPOD Angarozonium amurense (POLYZONIIDAE, DIPLOPODA, ARTHROPODA) IN PERMAFROST ENVIRONMENTS. AB - BACKGROUND: Angarozonium amurense (Gerstfeldt, 1859) is the only one out of more than a hundred diplopod species described in Siberia and the Far East that inhabits regions with solid permafrost. OBJECTIVE: To evaluate the cold hardiness of A. amurense that allows this species to inhabit permafrost regions. METHODS: The survival temperature thresholds and supercooling points (SCP) were measured. RESULTS: The temperature thresholds for adult animal survival are -8.5 C in summer and -27 C in winter. Average SCP decreases from -7.7 in summer to -16.9 in winter. Water content decreases from 55.7% in summer to 49.4% in winter. CONCLUSION: The cold hardiness of A. amurense sets the record in this class of animals. It allows it to overwinter in the upper 15 centimeters layer of soil in most biotopes of the coldest permafrost regions in North Asia. PMID- 26575999 TI - THE COMBINED USE OF HONEY, GARLIC (ALLIUM SATIVUM L.) AND SKIMMED MILK AS AN EXTENDER FOR CHILLING SHEEP SEMEN. AB - BACKGROUND: Sugars are the energetic source for sperm to maintain the metabolic process, and the antibiotics slow down sperm degradation. OBJECTIVE: To study the effects of rosemary honey as energy source and cryoprotectant in combination with garlic as a natural antibiotic on the quality of ram spermatozoa upon cooling. MATERIALS AND METHODS: The ejaculates from three rams were evaluated at different times during cooling to determine its post-dilution quality. RESULTS: Glycerol and dimethylformamide in conjunction with honey and garlic significantly improve the survival of spermatozoa. CONCLUSION: The addition of honey and garlic reduces sperm deterioration when stored at 4 degree C. PMID- 26576000 TI - PHYSIOLOGICAL, CYTOLOGICAL AND BIOCHEMICAL STABILITY OF Medicago sativa L. CELL CULTURE AFTER 27 YEARS OF CRYOGENIC STORAGE. AB - BACKGROUND: The efficiency of long-term cryogenic storage to prevent somaclonal variations in plant cell cultures and retain their major cytogenetic and biochemical traits remains under debate. In particular, it is not clear how stress conditions associated with cryopreservation, such as low temperature, dehydration and toxic action of some cryoprotectants (DMSO in particular), affect post-storage regrowth and genetic integrity of cell samples. OBJECTIVE: We assessed growth, cytogenetic and biochemical characteristics of the peroxidase producing strain of Medicago sativa L. cell culture recovered after 27 years of cryogenic storage as compared to the same culture before cryopreservation. MATERIALS AND METHODS: In 1984, M. sativa L. cell culture was cryopreserved using programmed freezing and 7% DMSO as a cryoprotectant. In 2011, after rewarming in a water bath at 40 degree C for 90 s, cell culture was recovered and proliferated. Viability, growth profile, mitotic index, ploidy level, peroxidase activity and cell response to hypothermia and osmotic stress were compared between the recovered and the initial cell cultures using the records available from 1984. RESULTS: Viability of alfalfa cell culture after rewarming was below 20% but it increased to 80% by the 27th subculture cycle. Recovered culture showed higher mitotic activity and increased number of haploid and diploid cells compared to the initial cell line. Both peroxidase activity and response to abiotic stress in the recovered cell culture were similar to that of the initial culture. CONCLUSION: Cryopreservation by programmed freezing was effective at retaining the main characteristics of M. sativa undifferentiated cell culture after 27 years of storage. According to available data, this is longest period of successful cryopreservation of plant cell cultures reported so far. After storage, there was no evidence that DMSO had any detrimental effect on cell viability, growth or cytogenetics. PMID- 26576001 TI - EFFECTS OF ORVUS ES PASTE ON THE MOTILITY AND VIABILITY OF YAK (BOS GRUNNIENS) EPIDIDYMAL AND EJACULATED SPERMATOZOA AFTER FREEZING AND THAWING. AB - BACKGROUND: The addition of the detergent Orvus ES Paste (OEP) to semen freezing extenders has been observed to improve the post-thaw survival and longevity of spermatozoa from various species but has never been evaluated for yak spermatozoa. OBJECTIVE: This study evaluated the effects of OEP on the post-thaw motility and viability of epididymal and ejaculated yak spermatozoa. MATERIALS AND METHODS: Semen samples were frozen and thawed in semen freezing extender supplemented with 0 %, 0.375 %, 0.75 % or 1.5 % OEP. The motility and viability of frozen-thawed spermatozoa were evaluated before and after 3 h of incubation. RESULTS: The addition of 0.75 % OEP to the freezing extender significantly improved the mean motility and viability values of both the epididymal and ejaculated spermatozoa immediately after thawing, but the beneficial effects on motility disappeared after 3h of incubation. CONCLUSION: Our findings indicate that the addition of 0.75 % OEP is effective for the preservation of yak spermatozoa. PMID- 26576002 TI - RELATIONSHIP BETWEEN SUPERCOOLING CAPABILITY AND CRYOPROTECTANT CONTENT IN EGGS OF PARARCYPTERA MICROPTERA MERIDIONALIS (ORTHOPTERA: ACRYPTERIDAE). AB - BACKGROUND: Grasshoppers are major agricultural pests throughout the world. The egg stage is important for the low temperature resistance, and almost all grasshoppers overwinter in the egg stage. OBJECTIVE: To study the relationship between cold hardiness and cryoprotectant content in Pararcyptera microptera meridionalis eggs. MATERIALS AND METHODS: The supercooling point (SCP) of the eggs was measured, along with the contents of water, fat, amino acids, low molecular sugars and polyols. RESULTS: SCP, water content and glucose concentration decreased during egg development, whereas the contents of fat, trehalose, glycerol, inositol and sorbitol increased. SCP is negatively correlated with the concentrations of fat, trehalose, glycerol, inositol and sorbitol, but positively with water content and glucose concentration. Among low molecular weight sugars and polyols tested in eggs, trehalose concentration was highest, followed by glycerol. Although total content of free amino acids did not change much, of the tested 17 free amino acids in eggs, proline and glutamine had increased by 46.3 % and 13.2 %, respectively, and both showed a negative correlation with SCP. Stepwise regression analysis showed that proline, glycerol, trehalose and inositol contribute most to the SCP depression. Cold acclimation at 0 degree C increased the contents of trehalose and glycerol, and decreased SCP. CONCLUSION: The increase of the supercooling capacity in P. microptera meridionalis eggs during development could be attributed mainly to proline, glycerol, trehalose and inositol. Cold acclimation enhances supercooling capacity via glycerol and trehalose. PMID- 26576003 TI - TEMPORARY STORAGE OF BOVINE SEMEN CRYOPRESERVED IN LIQUID NITROGEN ON DRY ICE AND REFREEZING OF FROZEN-THAWED SEMEN. AB - Two experiments were conducted. The purpose of Experiment 1 was to investigate whether viability of bovine semen stored in liquid nitrogen (-196 degrees C) will be adversely affected by temporary exposure to dry ice (-79 degrees C). It was convincingly shown that post thaw-motility was not affected, regardless whether semen was thawed immediately or after being returned to liquid nitrogen. Shipping or temporary storage on dry ice, thus, is a viable option. In Experiment 2, refreezing of frozen-thawed semen was attempted. The proportion of motile spermatozoa was reduced by a factor of ten to between 6.0 % and 7.4 %, regardless whether thawing occurred directly after removal from liquid nitrogen or after an interim period on dry ice. When semen was refrozen on dry ice before being returned to liquid nitrogen, motility rates were significantly improved (13.0 % to 17.0 %, P<0.05). In both experiments sperm cells that remained motile displayed vigorous forward movement and normal morphological appearance. PMID- 26576004 TI - DETERMINATION OF CONVECTIVE HEAT TRANSFER COEFFICIENT AT THE OUTER SURFACE OF A CRYOVIAL BEING PLUNGED INTO LIQUID NITROGEN. AB - BACKGROUND: Cell survival upon cryopreservation is affected by the cooling rate. However, it is difficult to model the heat transfer process or to predict the cooling curve of a cryoprotective agent (CPA) solution due to the uncertainty of its convective heat transfer coefficient (h). OBJECTIVE: To measure the h and to better understand the heat transfer process of cryovials filled with CPA solution being plunged in liquid nitrogen. MATERIALS AND METHODS: The temperatures at three locations of the CPA solution in a cryovial were measured. Different h values were selected after the cooling process was modeled as natural convection heat transfer, the film boiling and the nucleate boiling, respectively. And the temperatures of the selected points are simulated based on the selected h values. h was determined when the simulated temperature best fitted the experimental temperature. RESULTS: When the experimental results were best fitted, according to natural convection heat transfer model, h(1) = 120 W/(m(2).K) while due to film boiling and nucleate boiling regimes h(f) = 5 W/(m(2).K) followed by h(n) = 245 W/(m(2).K). These values were verified by the differential cooling rates at the three locations of a cryovial. CONCLUSION: The heat transfer process during cooling in liquid nitrogen is better modeled as film boiling followed by nucleate boiling. PMID- 26576006 TI - Electroclinical and cytogenetic features of epilepsy in cri-du-chat syndrome. AB - Cri-du-chat syndrome (CdCs) is caused by deletion in the short arm of chromosome 5, occurring in 1:15,000 to 1:50,000 live births. Recent genotype-phenotype correlation studies show the importance of 5p15.2 for facial dysmorphism and intellectual disability, and 5p15.3 for cat-like cry. Numerous reports have shown the relative rarity of epilepsy in this syndrome. We identified two cases with epilepsy in CdCs, and described their electroclinical and cytogenetic features. The first case was a 25-year-old female who had axial tonic seizures with flexion of the neck and shoulders. Interictal EEG was characterized by generalized spike and-slow-wave complexes. Her ictal EEG started with diffuse electrodecremental pattern, followed by alpha-range activities. High-resolution banding analysis of chromosomes revealed a terminal deletion of 5p14.1. The second case was a 30-year old female who had startle epilepsy with falling. Interictal EEG demonstrated generalized spike and slow waves. High-resolution banding analysis revealed a terminal deletion of 5p13.3 with additional chromosomal material of unknown origin. Based on the cases presented here, as well as those previously reported, the relationship between epilepsy and CdCs is discussed. The data suggests that although CdCs patients rarely suffer from epileptic seizures, the seizures may vary in type. PMID- 26576005 TI - Palladium-Catalyzed Benzylic C-H Arylation of Azaarylmethylamines. AB - A direct C-H functionalization approach to produce aryl(azaaryl)methylamines from azaarylmethylamines without directing groups is described. Under conditions where the azaarylmethylamines' C-H is reversibly deprotonated, a Pd(OAc)(2)/NIXANTPHOS based catalyst couples the resulting carbanions with various aryl halides to provide aryl(azaaryl)methylamines. This umpolung strategy directly provides tertiary amines without protecting or activating groups. PMID- 26576007 TI - The Influence of Growth Rate on 2H/1H Fractionation in Continuous Cultures of the Coccolithophorid Emiliania huxleyi and the Diatom Thalassiosira pseudonana. AB - The hydrogen isotope (2H/1H) ratio of lipids from phytoplankton is a powerful new tool for reconstructing hydroclimate variations in the geologic past from marine and lacustrine sediments. Water 2H/1H changes are reflected in lipid 2H/1H changes with R2 > 0.99, and salinity variations have been shown to cause about a 10/00 change in lipid delta2H values per unit (ppt) change in salinity. Less understood are the effects of growth rate, nutrient limitation and light on 2H/1H fractionation in phytoplankton. Here we present the first published study of growth rate effects on 2H/1H fractionation in the lipids of coccolithophorids grown in continuous cultures. Emiliania huxleyi was cultivated in steady state at four growth rates and the delta2H value of individual alkenones (C37:2, C37:3, C38:2, C38:3), fatty acids (C14:0, C16:0, C18:0), and 24-methyl cholest-5,22-dien 3beta-ol (brassicasterol) were measured. 2H/1H fractionation increased in all lipids as growth rate increased by 240/00 to 790/00 (div d-1)-1. We attribute this response to a proportional increase in the fraction of NADPH from Photosystem I (PS1) of photosynthesis relative to NADPH from the cytosolic oxidative pentose phosphate (OPP) pathway in the synthesis of lipids as growth rate increases. A 3-endmember model is presented in which lipid hydrogen comes from NADPH produced in PS1, NADPH produced by OPP, and intracellular water. With published values or best estimates of the fractionation factors for these sources (alphaPS1 = 0.4, alphaOPP = 0.75, and alphaH2O = 0) and half of the hydrogen in a lipid derived from water the model indicates alphalipid = 0.79. This value is within the range measured for alkenones (alphaalkenone = 0.77 to 0.81) and fatty acids (alphaFA = 0.75 to 0.82) in the chemostat cultures, but is greater than the range for brassicasterol (alphabrassicasterol = 0.68 to 0.72). The latter is attributed to a greater proportion of hydrogen from NADPH relative to water in isoprenoid lipids. The model successfully explains the increase in 2H/1H fractionation in the sterol 24-methyl-cholesta-5,24(28)-dien-3beta-ol from marine centric diatom T. pseudonana chemostat cultures as growth rate increases. Insensitivity of alphaFA in those same cultures may be attributable to a larger fraction of hydrogen in fatty acids sourced from intracellular water at the expense of NADPH as growth rate increases. The high sensitivity of alpha to growth rate in E. huxleyi lipids and a T. pseudonana sterol implies that any change in growth rate larger than ~0.15 div d-1 can cause a change in delta2Hlipid that is larger than the analytical error of the measurement (~50/00), and needs to be considered when interpreting delta2Hlipid variations in sediments. PMID- 26576008 TI - 454 Pyrosequencing of Olive (Olea europaea L.) Transcriptome in Response to Salinity. AB - Olive (Olea europaea L.) is one of the most important crops in the Mediterranean region. The expansion of cultivation in areas irrigated with low quality and saline water has negative effects on growth and productivity however the investigation of the molecular basis of salt tolerance in olive trees has been only recently initiated. To this end, we investigated the molecular response of cultivar Kalamon to salinity stress using next-generation sequencing technology to explore the transcriptome profile of olive leaves and roots and identify differentially expressed genes that are related to salt tolerance response. Out of 291,958 obtained trimmed reads, 28,270 unique transcripts were identified of which 35% are annotated, a percentage that is comparable to similar reports on non-model plants. Among the 1,624 clusters in roots that comprise more than one read, 24 were differentially expressed comprising 9 down- and 15 up-regulated genes. Respectively, inleaves, among the 2,642 clusters, 70 were identified as differentially expressed, with 14 down- and 56 up-regulated genes. Using next generation sequencing technology we were able to identify salt-response-related transcripts. Furthermore we provide an annotated transcriptome of olive as well as expression data, which are both significant tools for further molecular studies in olive. PMID- 26576009 TI - Judicious use of oxytocin augmentation for the management of prolonged labor. AB - INTRODUCTION: A protocol including judicious use of oxytocin augmentation was investigated to determine whether it would change how oxytocin was used and eventually influence labor and fetal outcomes. MATERIAL AND METHODS: The population of this cohort study comprised 20 227 delivering women with singleton pregnancies >=37 weeks, cephalic presentation, spontaneous or induced onset of labor, without previous cesarean section. Women delivering from 2009 to 2013 at Stavanger University Hospital, Norway, were included. Data were collected prospectively. Before implementing the protocol in 2010, oxytocin augmentation was used if progression of labor was perceived as slow. After implementation, oxytocin could only be started when the cervical dilation had crossed the 4-h action line in the partograph. RESULTS: The overall use of oxytocin augmentation was significantly reduced from 34.9% to 23.1% (p < 0.01). The overall frequency of emergency cesarean sections decreased from 6.9% to 5.3% (p < 0.05) and the frequency of emergency cesarean sections performed due to fetal distress was reduced from 3.2% to 2.0% (p = 0.01). The rate of women with duration of labor over 12 h increased from 4.4% to 8.5% (p < 0.01) and more women experienced severe estimated postpartum hemorrhage (2.6% vs. 3.7%; p = 0.01). The frequency of children with pH <7.1 in the umbilical artery was reduced from 4.7% to 3.2% (p < 0.01). CONCLUSIONS: The frequency of emergency cesarean section was reduced after implementing judicious use of oxytocin augmentation. Our findings may be of interest in the ongoing discussion of how the balanced use of oxytocin for labor augmentation can best be achieved. PMID- 26576010 TI - Genetic discoveries and treatment advances in neuroblastoma. AB - PURPOSE OF REVIEW: Major advances in our understanding of the genetic basis of neuroblastoma, and the role somatic alterations play in driving tumor growth, have led to improvements in risk-stratified therapy and have provided the rationale for targeted therapies. In this review, we highlight current risk-based treatment approaches and discuss the opportunities and challenges of translating recent genomic discoveries into the clinic. RECENT FINDINGS: Significant progress in the treatment of neuroblastoma has been realized using risk-based treatment strategies. Outcome has improved for all patients, including those classified as high-risk, although survival remains poor for this cohort. Integration of whole genome DNA copy number and comprehensive molecular profiles into neuroblastoma classification systems will allow more precise prognostication and refined treatment assignment. Promising treatments that include targeted systemic radiotherapy, pathway-targeted small molecules, and therapy targeted at cell surface molecules are being evaluated in clinical trials, and recent genomic discoveries in relapsed tumor samples have led to the identification of new actionable mutations. SUMMARY: The integration of refined treatment stratification based on whole-genome profiles with therapeutics that target the molecular drivers of malignant behavior in neuroblastoma has the potential to dramatically improve survival, with decreased toxicity. PMID- 26576012 TI - Effect of primary ovarian insufficiency and early natural menopause on mortality: a meta-analysis. AB - OBJECTIVE: The aim of this review was to systematically evaluate the associations of all-cause, cardiovascular and all-cancer mortality with primary ovarian insufficiency (POI) and early natural menopause (ENM). METHODS: Electronic databases for relevant studies were searched up to February 28, 2015. POI and ENM were usually defined as spontaneous menopause before age 40 years and at age 40 44 years, respectively. RESULTS: A total of nine articles were derived from seven prospective cohort studies. In all studies, age of menopause was self-reported. Our meta-analysis showed that POI women had a higher risk of death from all causes (pooled relative risk (RR) 1.39, 95% confidence interval (CI) 1.10-1.77) and ischemic heart disease (IHD) (pooled RR 1.48, 95% CI 1.02-2.16) when compared with women at normal age at natural menopause (ANM). No significant association was detected from stroke and all-cancer mortality between POI women and normal ANM women. Only a slightly higher risk of death from IHD (pooled RR 1.09, 95% CI 1.00-1.18) was found when ENM women were compared with normal ANM women. CONCLUSION: The results of our study demonstrated that POI was associated with a higher risk of IHD and all-cause mortality; ENM was only associated with a slightly higher risk of IHD mortality. PMID- 26576011 TI - Therapies on the horizon for childhood acute lymphoblastic leukemia. AB - PURPOSE OF REVIEW: The prognosis for children with the most common childhood malignancy, acute lymphoblastic leukemia (ALL), has improved dramatically. However, the burden of therapy can be substantial, with long-term side-effects, and certain subgroups continue to have a poor outcome. RECENT FINDINGS: The recent discovery of new genetic alterations in high-risk subsets provides targets for precision medicine-based interventions using existing Food and Drug Administration approved agents. Novel immunotherapeutic approaches are being deployed in relapsed ALL, one of the leading causes of cancer cell death in children. Moreover, genomic analysis has charted the evolution of tumor subclones, and relapse-specific alterations now provide a mechanistic explanation for drug resistance, setting the stage for targeted therapy. There is greater recognition that host factors - genetic polymorphisms - influence cancer risk, response to therapy, and toxicity. In the future, it is anticipated that they will be integrated into clinical decision making to maximize cure and minimize side-effects. Recent efforts to limit prophylactic central nervous system irradiation have been successful, thereby sparing many children late neurocognitive impairments. SUMMARY: Integration of advances in precision medicine approaches and novel agents will continue to increase the cure rate and decrease the burden of therapy for childhood ALL. PMID- 26576013 TI - Enhanced precision in the analysis of randomized trials with ordinal outcomes. AB - We present a general method for estimating the effect of a treatment on an ordinal outcome in randomized trials. The method is robust in that it does not rely on the proportional odds assumption. Our estimator leverages information in prognostic baseline variables, and has all of the following properties: (i) it is consistent; (ii) it is locally efficient; (iii) it is guaranteed to have equal or better asymptotic precision than both the inverse probability-weighted and the unadjusted estimators. To the best of our knowledge, this is the first estimator of the causal relation between a treatment and an ordinal outcome to satisfy these properties. We demonstrate the estimator in simulations based on resampling from a completed randomized clinical trial of a new treatment for stroke; we show potential gains of up to 39% in relative efficiency compared to the unadjusted estimator. The proposed estimator could be a useful tool for analyzing randomized trials with ordinal outcomes, since existing methods either rely on model assumptions that are untenable in many practical applications, or lack the efficiency properties of the proposed estimator. We provide R code implementing the estimator. PMID- 26576014 TI - Frequent laboratory abnormalities in CIDP patients. AB - INTRODUCTION: The role of screening laboratory tests in chronic inflammatory demyelinating polyneuropathy (CIDP) is currently unknown. The objectives of this study are to explore common laboratory test abnormalities in CIDP patients. METHODS: CIDP subjects attending the Neuromuscular Clinic between 01/2013 and 12/2014 were evaluated. Demographic data, clinical history, physical examination, and laboratory test results were extracted from their charts. RESULTS: Seventy nine charts were reviewed. Mean age was 61 +/- 11 years. Most (84%) CIDP patients had laboratory test abnormalities; the most frequent were paraproteinemia (29%) and elevated HbA1C (28%) and creatine kinase (27%). Additional abnormalities included anemia in 19%, and elevated anti-neutrophil cytoplasmic antibody, erythrocyte sedimentation rate, and urate in 17%, elevated antinuclear antibodies, rheumatoid factor, and thyroid-stimulating hormone in 11%, and abnormal C3 in 10%. CONCLUSIONS: Laboratory test abnormalities were found in most CIDP patients. The most common were paraproteinemia, higher than expected frequency of diabetes, and unexpected CK elevation. Additional abnormalities included anemia, high urate levels, and common biomarkers for vasculitic neuropathies. Muscle Nerve 53: 862-865, 2016. PMID- 26576015 TI - Knowledge, attitudes and beliefs regarding colorectal cancer screening among ethnic minority groups in the Netherlands - a qualitative study. AB - BACKGROUND: Research has shown that ethnic minority groups are less likely to participate in colorectal cancer (CRC) screening than the majority population and hence less likely to be diagnosed at an early stage when treatment is potentially more successful. OBJECTIVE: To explore knowledge, attitudes and beliefs regarding CRC and CRC screening among ethnic minority groups in the Netherlands. DESIGN: We conducted qualitative interviews with 30 first-generation immigrants born in Turkey, Morocco and Surinam. We based the topic guide on the health belief model. Framework analysis was used to analyse our data. RESULTS: Although knowledge of CRC and CRC screening was limited, all respondents felt susceptible to CRC. CRC screening was perceived to mainly benefit those individuals with poor health and symptoms. Although most respondents had a positive attitude towards CRC screening, knowledge about its potential harms was limited and self-efficacy to participate was low. Adult children acted as important mediators in providing access to information. The language barrier and low literacy formed serious barriers to informed participation in CRC screening. CONCLUSION: To ensure that all eligible individuals, including ethnic minority groups, have equal opportunities to informed participation in screening, targeted communication strategies should be developed, such as oral and visual channels, and face-to face communication in the mother tongue. This will help ethnic minority groups to make an informed decision about participation in CRC screening. PMID- 26576016 TI - Role of Endoscopic Skull Base and Keyhole Surgery for Pituitary and Parasellar Tumors Impacting Vision. AB - Significant advances over the last 2 decades in imaging technology, instrumentation, anatomical knowledge, and reconstructive techniques have resulted in the endonasal endoscopic approach becoming an integral part of modern skull base surgery. With growing use and greater experience, surgical outcomes continue to incrementally improve across many skull base pathologies, including those tumors that impact vision and ocular motility. The importance of the learning curve and use of a multi-disciplinary approach is critical to maximizing success, minimizing complications, and enhancing quality of life in these patients. Realizing the limits of the endonasal route and reasonable use of transcranial approaches such as the supraorbital eyebrow craniotomy, it may br appropriate to consider nonsurgical therapy including various forms of radiotherapy [corrected] and medical treatment options. PMID- 26576018 TI - Benign Essential Blepharospasm--There Is More to It Than Just Blinking. PMID- 26576017 TI - Benign Essential Blepharospasm is a Disorder of Neuroplasticity: Lessons From Animal Models. PMID- 26576019 TI - High-Resolution 3D Magnetic Resonance Imaging of the Sixth Cranial Nerve: Anatomic and Pathologic Considerations by Segment. AB - BACKGROUND: Weakness of the sixth cranial nerve is the most common cause of an ocular motor cranial nerve palsy. It is often difficult to identify a corresponding abnormality on neuroimaging to correlate with the clinical examination. EVIDENCE ACQUISITION: High-resolution 3D skull base magnetic resonance imaging (MRI) allows for visualization of the sixth nerve along much of its course and may increase sensitivity for abnormalities in regions that previously were challenging to evaluate. In this review, the authors share their experience with high-resolution imaging of the sixth nerve. RESULTS: For each segment, anatomic features visible on high-resolution imaging are described along with relevant pathologic entities. CONCLUSIONS: We present a segmental approach to high-resolution 3D MRI for evaluation of the sixth nerve from the nuclear to the orbital segment. PMID- 26576020 TI - A 29-Year-Old Nurse With Fatigue, Anxiety, and Depression. PMID- 26576021 TI - Should Magnetic Resonance Venography be Performed Routinely in all Patients Undergoing Evaluation for Idiopathic Intracranial Hypertension? PMID- 26576023 TI - Reactive Oxygen Species in Mitochondrial Optic Neuropathies: Comment. PMID- 26576024 TI - Reactive Oxygen Species in Mitochondrial Optic Neuropathies: Response. PMID- 26576025 TI - Evaluation of a Low-Cost Pneumatic Plantar Pressure Insole for Predicting Ground Contact Kinetics. AB - Instrumented insoles could benefit locomotion research on healthy and clinical populations by providing data in natural settings outside of the laboratory. We designed a low-cost, instrumented insole with 8 pneumatic bladders to measure localized plantar pressure information. We collected gait data during treadmill walking at 1.0 m/s and 1.5 m/s and for sit-to-stand and stand-to-sit tasks for 10 subjects. We estimated a common representation of ground kinetics (3-component force vector, 2-component center of pressure position vector, and a single component torque vector) from the insole data. We trained an intertask neural network for each component of the kinetic data. For the walking tasks at 1.0 m/s and 1.5 m/s, the normalized root mean square error was between 3.1% and 12.9% and for the sit-to-stand and stand-to-sit tasks, the normalized root mean square error was between 3.3% and 21.3% Our findings suggest that the proposed low-cost, instrumented insoles could provide useful data about movement kinetics during real-world activities. PMID- 26576026 TI - Selective loss of alpha motor neurons with sparing of gamma motor neurons and spinal cord cholinergic neurons in a mouse model of spinal muscular atrophy. AB - Spinal muscular atrophy (SMA) is a neuromuscular disease characterised primarily by loss of lower motor neurons from the ventral grey horn of the spinal cord and proximal muscle atrophy. Recent experiments utilising mouse models of SMA have demonstrated that not all motor neurons are equally susceptible to the disease, revealing that other populations of neurons can also be affected. Here, we have extended investigations of selective vulnerability of neuronal populations in the spinal cord of SMA mice to include comparative assessments of alpha motor neuron (alpha-MN) and gamma motor neuron (gamma-MN) pools, as well as other populations of cholinergic neurons. Immunohistochemical analyses of late-symptomatic SMA mouse spinal cord revealed that numbers of alpha-MNs were significantly reduced at all levels of the spinal cord compared with controls, whereas numbers of gamma MNs remained stable. Likewise, the average size of alpha-MN cell somata was decreased in SMA mice with no change occurring in gamma-MNs. Evaluation of other pools of spinal cord cholinergic neurons revealed that pre-ganglionic sympathetic neurons, central canal cluster interneurons, partition interneurons and preganglionic autonomic dorsal commissural nucleus neuron numbers all remained unaffected in SMA mice. Taken together, these findings indicate that alpha-MNs are uniquely vulnerable among cholinergic neuron populations in the SMA mouse spinal cord, with gamma-MNs and other cholinergic neuronal populations being largely spared. PMID- 26576027 TI - KIF1B promotes glioma migration and invasion via cell surface localization of MT1 MMP. AB - Malignant glioma is notorious for its aggressiveness and poor prognosis, and the invasiveness of glioma cells is the major obstacle. Accumulating evidence indicates that kinesin superfamily proteins (KIFs) may play key roles in tumor invasiveness, but the mechanisms remained unresolved. Our previous study demonstrated that membrane type 1-matrix metalloproteinase (MT1-MMP) was involved in Kinesin family member 1B (KIF1B)-modulated invasion of gastric cancer cells. Therefore, the role of KIF1B in glioma cell invasion and its relationship with MT1-MMP were explored in the present study. We found that aberrantly increased expression of KIF1B was associated with worse WHO pathological classification and Karnofsky performance status (KPS), which also showed a trend towards worse prognosis. In the transwell assay, knockdown of KIF1B using siRNA repressed U87MG and A172 glioma cell migration and invasion. Silencing KIF1B inhibited expression of membranal MT1-MMP; however, the amount of MT1-MMP in the whole cell lysate was not affected. In conclusion, targeting KIF1B may be an option for anti-invasive therapies targeting glioma. PMID- 26576028 TI - Prenatal Stress as a Modifier of Associations between Phthalate Exposure and Reproductive Development: results from a Multicentre Pregnancy Cohort Study. AB - BACKGROUND: Prenatal phthalate exposure is associated with altered male reproductive tract development, and in particular, shorter anogenital distance (AGD). AGD, a sexually dimorphic index of prenatal androgen exposure, may also be altered by prenatal stress. How these exposures interact to impact AGD is unknown. Here, we examine the extent to which associations between prenatal phthalate exposure and infant AGD are modified by prenatal exposure to stressful life events (SLEs). METHODS: Phthalate metabolites [including those of diethylhexyl phthalate (DEHP) and their molar sum (SigmaDEHP)] were measured in first trimester urine from 738 pregnant women participating in The Infant Development and the Environment Study (TIDES). Women completed questionnaires on SLEs, and permitted infant AGD measurements at birth. Subjects were classified as 'lower' and 'higher' stress (0 first trimester SLEs vs. 1+).We estimated relationships between phthalate concentrations and AGD (by infant sex and stress group) using adjusted multiple regression interaction models. RESULTS: In the lower stress group, first trimester SigmaDEHP was inversely associated with two measures of male AGD: anoscrotal distance (AGD-AS; beta = -1.78; 95% CI -2.97, 0.59) and anopenile distance (AGD-AP; beta = -1.61; 95% CI -3.01, -0.22). By contrast, associations in the higher stress group were mostly positive and non significant in male infants. No associations were observed in girls. CONCLUSIONS: Associations between prenatal phthalate exposure and altered genital development were only apparent in sons of mothers who reported no SLEs during pregnancy. Prenatal stress and phthalates may interact to shape fetal development in ways that have not been previously explored. PMID- 26576029 TI - The Colletotrichum graminicola striatin orthologue Str1 is necessary for anastomosis and is a virulence factor. AB - Striatin family proteins are key regulators in signalling pathways in fungi and animals. These scaffold proteins contain four conserved domains: a caveolin binding domain, a coiled-coil motif and a calmodulin-binding domain at the N terminus, and a WD-repeat domain at the C-terminus. Fungal striatin orthologues are associated with sexual development, hyphal growth and plant pathogenesis. In Fusarium verticillioides, the striatin orthologue Fsr1 promotes virulence in the maize stalk. The relationship between fungal striatins and pathogenicity remains largely unexplored. In this study, we demonstrate that the Colletotrichum graminicola striatin orthologue Str1 is required for full stalk rot and leaf blight virulence in maize. Pathogenicity assays show that the striatin mutant strain (Deltastr1) produces functional appressoria, but infection and colonization are attenuated. Additional phenotypes of the Deltastr1 mutant include reduced radial growth and compromised hyphal fusion. In comparison with the wild-type, Deltastr1 also shows a defect in sexual development and produces fewer and shorter conidia. Together with the fact that F. verticillioides fsr1 can complement Deltastr1, our results indicate that C. graminicola Str1 shares five phenotypes with striatin orthologues in other fungal species: hyphal growth, hyphal fusion, conidiation, sexual development and virulence. We propose that fungal striatins, like mammalian striatins, act as scaffolding molecules that cross-link multiple signal transduction pathways. PMID- 26576030 TI - A Simple and Sensitive LC-MS/MS Method for Determination of Four Major Active Diterpenoids from Andrographis paniculata in Human Plasma and Its Application to a Pilot Study. AB - Andrographis paniculata contains four major active diterpenoids, including andrographolide (1), 14-deoxy-11, 12-didehydroandrographolide (2), neoandrographolide (3), and 14-deoxyandrographolide (4), which exhibit differences in types and/or degrees of their pharmacological activity. Previous pharmacokinetic studies in humans reported only the parameters of compound 1 and its analytical method in human plasma. The purpose of this study was to develop a simple, sensitive, and selective liquid chromatography tandem-mass spectrometry technique for the simultaneous determination of all four major active diterpenoids in the A. paniculata product in human plasma. These four diterpenoids in plasma samples were extracted by a simple protein precipitation method with methanol and separated on a Kinetex C18 column using a gradient system with a mobile phase of acetonitrile and water. The liquid chromatography tandem-mass spectrometry was performed in the negative mode, and the multiple reaction monitoring mode was used for the quantitation. The method showed a good linearity over a wide concentration range of 2.50-500 ng/mL for 1 and over the range of 1.00-500 ng/mL for the other diterpenoids with a correlation coefficient R(2) > 0.995. The lower limit of quantification of 1 was found to be 2.50 ng/mL, while those of the other diterpenoids were 1.00 ng/mL. The intraday and interday accuracy (relative error) ranged from 0.03 % to 10.03 %, and the intraday and interday precisions (relative standard deviation) were in the range of 2.05-9.67 %. The extraction recovery (86.54-111.56 %) with a relative standard deviation of 2.78-8.61 % and the matrix effect (85.15-112.36 %) were within the acceptance criteria. Moreover, these four major active diterpenoids were stable in plasma samples at the studied storage conditions with a relative error <=-9.79 % and a relative standard deviation <= 9.26 %. Hence, this present method was successfully validated and used in the pilot study to determine the pharmacokinetic parameters of all four major active diterpenoids in human plasma after multiple oral doses of the A. paniculata product were administered to a healthy, Thai female volunteer. PMID- 26576031 TI - Pharmacokinetics, Tissue Distribution and Protein Binding Studies of Chrysocauloflavone I in Rats. AB - Chrysocauloflavone I, an unfrequent biflavonoid, was purified from Selaginella doederleinii in this study. It showed cytotoxic effects on three human cancer cells, NCI-H1975, A549, and HepG-2, in vitro. In silico assessment of the physicochemical properties was performed for predicting the permeability and intestinal absorption of the tested compound. Subsequently, a rapid, sensitive, and specific high-performance liquid chromatography method was developed for determination of the compound in different biological samples to ascertain the pharmacokinetics, tissue distribution, and protein binding profiles of this active ingredient in rats. After intravenous dosing of chrysocauloflavone I at different levels (10 and 20 mg/kg), the elimination half-life was approximately 85 min, and the AUC0-infinity increased with the dose from 148.52 mg/L * min for 10 mg/kg to 399.01 mg/L * min for 20 mg/kg. After single intravenous dosing (20 mg/kg), chrysocauloflavone I was detected in all tissues studied with higher levels in the heart, blood, and lungs. The results of equilibrium dialysis indicated a very high protein binding degree (over 97%) for chrysocauloflavone I. After intragastric administration of 100 mg/kg chrysocauloflavone I to rats, no parent drug was detected in the rat plasma. This is the first report of the favorable bioactivities, plasma pharmacokinetics, tissue distribution, and protein binding profiles of the rare biflavone chrysocauloflavone I. PMID- 26576032 TI - Subepithelial inflammatory load and basement membrane thickening in refractory chronic rhinosinusitis with nasal polyposis: a histopathological study. AB - BACKGROUND: A subgroup of chronic rhinosinusitis with nasal polyps (CRSwNP) patients is refractory to optimal surgical therapy and requires multiple revision sinus operations. Studies have shown that mucosal eosinophilia correlates with disease severity. We hypothesized that a high-grade tissue inflammatory load is associated with these refractory patients. METHODS: A single-surgeon, retrospective case-control study comparing 20 CRSwNP patients requiring a second surgery during follow-up (refractory group) vs a matched cohort of 20 CRSwNP patients without needing further revision surgery (control group). Hematoxylin and eosin (H&E)-stained tissue harvested intraoperatively (*2 for the refractory group) were recalled for histopathological examination of subepithelial inflammation and basement membrane (BM) thickness. RESULTS: The refractory group had a significantly higher average eosinophil count (49 vs 18), relative eosinophilia (55% vs 32%) as well as total inflammatory cell count (86 vs 49) than the control group (p < 0.05). However within the refractory group, the eosinophil-lymphocyte ratio was reduced from their first to their second (revision) surgeries whereas the total averaged inflammatory cell count remained unchanged. No significant difference in BM thickness was found between the groups. CONCLUSION: These findings suggest that a higher inflammatory and eosinophilic load is associated with refractory disease and thus may be useful in predicting need for future revision surgery in CRSwNP. PMID- 26576033 TI - Comparative Effectiveness Research: Alternatives to "Traditional" Computed Tomography Use in the Acute Care Setting. AB - Computed tomography (CT) scanning is an essential diagnostic tool and has revolutionized care of patients in the acute care setting. However, there is widespread agreement that overutilization of CT, where benefits do not exceed possible costs or harms, is occurring. The goal was to seek consensus in identifying and prioritizing research questions and themes that involve the comparative effectiveness of "traditional" CT use versus alternative diagnostic strategies in the acute care setting. A modified Delphi technique was used that included input from emergency physicians, emergency radiologists, medical physicists, and an industry expert to achieve this. PMID- 26576034 TI - KIAA2022 nonsense mutation in a symptomatic female. AB - Mutations in the KIAA2022 gene have been implicated in non-syndromic X-linked intellectual disability. Thus far, all carrier females reported have been unaffected and genotype-phenotype correlations have not been described. Herein, we report a de novo KIAA2022 nonsense mutation in a 17-year-old female with short stature, microcephaly, severe intellectual disability, poor speech, epilepsy, and autistic behavior. X-inactivation pattern is normal suggesting that the mutation is causing the phenotype. This report contests the current view that KIAA2022 mutations only affect males, which has implications for testing and genetic counseling. PMID- 26576035 TI - In vivo autofluorescence in the biological windows: the role of pigmentation. AB - Small animal deep-tissue fluorescence imaging in the second Biological Window (II BW, 1000-1350 nm) is limited by the presence of undesirable infrared-excited, infrared-emitted (900-1700 nm) autofluorescence whose origin, spectral properties and dependence on strains is still unknown. In this work, the infrared autofluorescence and laser-induced whole body heating of five different mouse strains with distinct coat colors (black, grey, agouti, white and nude) has been systematically investigated. While neither the spectral properties nor the magnitude of organ autofluorescence vary significantly between mouse strains, the coat color has been found to strongly determine both the autofluorescence intensity as well as the laser-induced whole body heating. Results included in this work reveal mouse strain as a critical parameter that has to be seriously considered in the design and performance of small animal imaging experiments based on infrared-emitting fluorescent markers. PMID- 26576036 TI - The increasing incidence of paranasal sinus fungus ball: a retrospective cohort study in two hundred forty-five patients for fifteen years. PMID- 26576037 TI - Relationship between pharmacokinetics and pharmacodynamics of clopidogrel in patients undergoing percutaneous coronary intervention: comparison between vasodilator-stimulated phosphoprotein phosphorylation assay and multiple electrode aggregometry. AB - ESSENTIALS: The reliability of platelet tests as markers of the variable bioavailability of clopidogrel is not yet defined. Kinetics of clopidogrel active metabolite (CAM) and platelet response were studied in ischemic heart disease. CAM plasma maximum concentration (Cmax ) predicted vasodilator-stimulated phosphoprotein (VASP-P). Timely performed VASP-P, not an aggregation-based test, may be a surrogate for clopidogrel bioavailability. BACKGROUND: The high inter individual variability in the inhibition of platelet function by clopidogrel is mostly explained by high variability in its transformation to an active metabolite (CAM). Objective We investigated the relations between pharmacokinetics and pharmacodynamics of CAM by comparing two methods of platelet function. METHODS: We enrolled 14 patients undergoing percutaneous coronary interventions for non-ST-segment elevation acute coronary syndrome or inducible myocardial ischemia. Plasma concentrations of clopidogrel and CAM, phosphorylation of vasodilator-stimulated phosphoprotein (VASP-P), expressed as a platelet reactivity index (PRI) and whole-blood platelet aggregation (multiple electrode aggregometer, MEA) were measured before and after a 600-mg clopidogrel loading dose (nine time-points) and before and after 75-mg maintenance doses on days 2, 7 and 30. RESULTS: Plasma concentrations of clopidogrel and CAM were highly variable. CAM reached maximal concentration (Cmax ) (median, 110.8 nm; range, 41.9-484.8) 0.5-2 h after the loading dose. A sigmoid dose-response curve defined the relations between CAMCmax and PRI after 3 to 24 h (IC50 , 459.6 nm; 95% confidence interval, 453.4-465.7; R(2) = 0.82). PRI was unchanged from baseline in patients with the lowest CAMCmax (< 83 nm, n = 7), indicating low sensitivity of VASP-P. PRI values were also predicted by CAMCmax at days 2, 7 and 30. Platelet aggregation measured by MEA did not show significant relations with either PRI or with CAM pharmacokinetics at any time-point. CONCLUSIONS: After 600 mg clopidogrel, VASP-P, but not whole-blood platelet aggregation measured by MEA, is almost entirely predicted by CAMCmax . VASP-P could be useful in studies aimed at investigating relations between CAM bioavailability and clinical events. PMID- 26576038 TI - Press or pulse exposures determine the environmental fate of cerium nanoparticles in stream mesocosms. AB - Risk-assessment models indicate that stream ecosystems receiving municipal wastewater effluent may have the greatest potential for exposure to manufactured nanoparticles. The authors determined the fate of cerium oxide (CeO2 ) nanoparticles in outdoor stream mesocosms using 1) 1-time pulse addition of CeO2 nanoparticles, representative of accidental release, and 2) continuous, low-level press addition of CeO2 nanoparticles, representative of exposure via wastewater effluent. The pulse addition led to rapid nanoparticle floc formation, which appeared to preferentially deposit on periphyton in low-energy areas downstream from the location of the input, likely as a result of gravitational sedimentation. Floc formation limited the concentration of suspended nanoparticles in stream water to <5% of target and subsequent downstream movement. In contrast, press addition of nanoparticles led to higher suspended nanoparticle concentrations (77% of target) in stream water, possibly as a result of stabilization of suspended nanoparticles through interaction with dissolved organic carbon. Smaller nanoparticle aggregates appeared to preferentially adsorb to stream surfaces in turbulent sections, where Ce concentrations were highest in the press, likely a result of stochastic encounter with the surface. Streams receiving wastewater effluent containing nanoparticles may lead to exposure of aquatic organisms over a greater spatial extent than a similar amount of nanoparticles from an accidental release. Exposure models must take into account these mechanisms controlling transport and depositional processes. PMID- 26576039 TI - A 30-Year-Old Female with a Suprasellar Tumor. PMID- 26576040 TI - Outcomes of kidney paired donation transplants in relation to shipping and cold ischaemia time. AB - To assess the impact of shipping distance and cold ischaemia time (CIT) of shipped organs in a kidney paired donation (KPD) programme, we evaluated the outcomes of the initial 100 kidney transplants performed in the Australian KPD programme. In a 44-month period, 12 centres were involved in fifteen 2-way, twenty 3-way, one 4-way and one 6-way exchanges. Sixteen kidneys were transplanted at the same hospital (CIT 2.6 +/- 0.6 h) and 84 required transport to the recipient hospital (CIT 6.8 +/- 2.8 h). A spontaneous fall in serum creatinine by at least 10% within 24 h was observed in 85% of recipients, with no difference between nonshipped and shipped kidneys. There were two cases of transient delayed graft function requiring dialysis and patient and graft survival at 1 year were 99% and 97%, respectively. There was no difference in recipients of nonshipped compared with shipped kidneys with regard to serum creatinine at 1 month (mean difference (MD) 7.3 MUmol/l, 95% CI -20.2 to 34.8, P = 0.59), 1-year graft survival (MD 3.9%, 95% CI -5.4 to 13.2, P = 0.41) or patient survival (MD -2.4%, 95% CI -10.0 to 5.2, P = 0.54). Despite prolonged CIT for interstate exchanges, the programme's decision to ship donor kidneys rather than the donor appears to be safe. PMID- 26576042 TI - Nail dermoscopy is a helpful tool in the diagnosis of onychomycosis: A case control study. PMID- 26576041 TI - Plasmonic Gold Nanorods Coverage Influence on Enhancement of the Photoluminescence of Two-Dimensional MoS2 Monolayer. AB - The 2-D transition metal dichalcogenide (TMD) semiconductors, has received great attention due to its excellent optical and electronic properties and potential applications in field-effect transistors, light emitting and sensing devices. Recently surface plasmon enhanced photoluminescence (PL) of the weak 2-D TMD atomic layers was developed to realize the potential optoelectronic devices. However, we noticed that the enhancement would not increase monotonically with increasing of metal plasmonic objects and the emission drop after the certain coverage. This study presents the optimized PL enhancement of a monolayer MoS2 in the presence of gold (Au) nanorods. A localized surface plasmon wave of Au nanorods that generated around the monolayer MoS2 can provide resonance wavelength overlapping with that of the MoS2 gain spectrum. These spatial and spectral overlapping between the localized surface plasmon polariton waves and that from MoS2 emission drastically enhanced the light emission from the MoS2 monolayer. We gave a simple model and physical interpretations to explain the phenomena. The plasmonic Au nanostructures approach provides a valuable avenue to enhancing the emitting efficiency of the 2-D nano-materials and their devices for the future optoelectronic devices and systems. PMID- 26576043 TI - Osmolarity affects matrix synthesis in the nucleus pulposus associated with the involvement of MAPK pathways: A study of ex vivo disc organ culture system. AB - Matrix homeostasis within the nucleus pulposus (NP) is important for disc function. Unfortunately, the effects of osmolarity on NP matrix synthesis in a disc organ culture system and the underlying mechanisms are largely unknown. The present study was to investigate the effects of different osmolarity modes (constant and cyclic) and osmolarity levels (hypo-, iso-, and hyper-) on NP matrix synthesis using a disc organ culture system and determine whether ERK1/2 or p38MAPK pathway has a role in this process. Porcine discs were cultured for 7 days in various osmotic media, including constant hypo-, iso-, hyper-osmolarity (330, 430, and 550 mOsm/kg, respectively) and cyclic-osmolarity (430 mOsm/kg for 8 h, followed by 550 mOsm/kg for 16 h). The role of ERK1/2 and p38MAPK pathways were determined by their inhibitors U0126 and SB202190 respectively. The expression of SOX9 and downstream aggrecan and collagen II, biochemical content, and histology were used to assess NP matrix synthesis. The findings revealed that NP matrix synthesis was promoted in iso- and cyclic-osmolarity cultures compared to hypo- or hyper-osmolarity culture although the level of matrix synthesis in cyclic-osmolarity culture did not reach that in iso-osmolarity culture. Further analysis suggested that inhibition of the ERK1/2 or p38MAPK pathway in iso- and cyclic-osmolarity cultures reduced NP matrix production. Therefore, we concluded that the effects of osmolarity on NP matrix synthesis depend on osmolarity level (hypo-, iso-, or hyper-) and osmolarity mode (constant or cyclic), and the ERK1/2 and p38MAPK pathways may participate in this process. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1092-1100, 2016. PMID- 26576044 TI - The First Use of the Global Oral Cholera Vaccine Emergency Stockpile: Lessons from South Sudan. PMID- 26576045 TI - Porous polymer scaffold for on-site delivery of stem cells--Protects from oxidative stress and potentiates wound tissue repair. AB - Wound healing by cell transplantation techniques often suffer setbacks due to oxidative stress encountered at injury sites. A porous polyethyleneglycol polyurethane (PEG-PU) scaffold that facilitates cell delivery and boosts tissue repair was developed through semi-interpenetrating polymer network approach. The key physico-chemical properties assessed confirms these polymeric matrices are highly thermostable, barostable, degrade at an acidic pH (5.8), biodegradable, cytocompatible and possess excellent porosity. Mechanism of cellular penetration into porous polymer networks was evident by a >=6 - fold increase in gene expression of MMP-13 and MMP-2 via activation of Akt and Erk. H2O2-induced apoptosis of mouse bone marrow stem cells (BMSCs) was abrogated in presence of polymer networks indicating a protective effect from oxidative stress. Transplantation of BMSC + PEG-PU at murine excisional splint wound site depicted significant increase in fibroblast proliferation, collagen deposition, anti oxidant enzyme activities of catalase, SOD and GPx. Furthermore it significantly decreased expression of pro-inflammatory cytokines (IL-1beta, TNF-alpha, IL-8, etc) with a concomitant increase in anti-inflammatory cytokines (IL-10, IL-13) at an early healing period of day 7. Finally, immunostaining revealed an enhanced engraftment and vascularity indicating an accelerated wound tissue closure. This pre-clinical study demonstrates the proof-of-concept and further necessitates their clinical evaluation as potential cell delivery vehicle scaffolds. PMID- 26576046 TI - Sunflower-type nanogels carrying a quantum dot nanoprobe for both superior gene delivery efficacy and tracing of human mesenchymal stem cells. AB - Sunflower-type nanogels carrying the QD 655 nanoprobe can be used for both gene transfection and bioimaging of hMSCs. The entry of sunflower-type nanogels into hMSCs can be possibly controlled by changing the formation of QDs. The physico chemical properties of sunflower-type nanogels internalized by hMSCs were confirmed by AFM, SEM, TEM, gel retardation, and zeta-potential analyses. The bioimaging capacity was confirmed by confocal laser microscopy, Kodak imaging, and Xenogen imaging. Specifically, we investigated the cytotoxicity of sunflower type nanogels via SNP analysis. Internalization of sunflower-type nanogels does not cause malfunction of hMSCs. PMID- 26576047 TI - Electrically driven intracellular and extracellular nanomanipulators evoke neurogenic/cardiomyogenic differentiation in human mesenchymal stem cells. AB - Nanomechanical intervention through electroactuation is an effective strategy to guide stem cell differentiation for tissue engineering and regenerative medicine. In the present study, we elucidate that physical forces exerted by electroactuated gold nanoparticles (GNPs) have a strong influence in regulating the lineage commitment of human mesenchymal stem cells (hMSCs). A novel platform that combines intracellular and extracellular GNPs as nano-manipulators was designed to trigger neurogenic/cardiomyogenic differentiation in hMSCs, in electric field stimulated culture condition. In order to mimic the native microenvironment of nerve and cardiac tissues, hMSCs were treated with physiologically relevant direct current electric field (DC EF) or pulsed electric field (PEF) stimuli, respectively. When exposed to regular intermittent cycles of DC EF stimuli, majority of the GNP actuated hMSCs acquired longer filopodial extensions with multiple branch-points possessing neural-like architecture. Such morphological changes were consistent with higher mRNA expression level for neural-specific markers. On the other hand, PEF elicited cardiomyogenic differentiation, which is commensurate with the tube-like morphological alterations along with the upregulation of cardiac specific markers. The observed effect was significantly promoted even by intracellular actuation and was found to be substrate independent. Further, we have substantiated the participation of oxidative signaling, G0/G1 cell cycle arrest and intracellular calcium [Ca(2+)]i elevation as the key upstream regulators dictating GNP assisted hMSC differentiation. Thus, by adopting dual stimulation protocols, we could successfully divert the DC EF exposed cells to differentiate predominantly into neural-like cells and PEF treated cells into cardiomyogenic-like cells, via nanoactuation of GNPs. Such a novel multifaceted approach can be exploited to combat tissue loss following brain injury or heart failure. PMID- 26576048 TI - Peripartum Anesthetic Management and Genomic Analysis of Rare Variants in a Patient with Familial Pulmonary Fibrosis. AB - A 29-year-old patient, 32 weeks' pregnant, with a history of familial interstitial fibrosis, was treated for acute hypoxemia after admission to the intensive care unit. Within 48 hours, this was followed by an emergent cesarean delivery, under general anesthesia, due to acute respiratory failure. Successful perinatal obstetric and anesthetic management resulted in the delivery of a baby and recovery of the mother. Subsequent genomic analysis using next-generation sequencing of the patient's entire exome revealed that she was a carrier of a deleterious mutation in the TERT gene, previously associated with the hereditary forms of interstitial fibrosis. PMID- 26576049 TI - Anesthetic Management of a Parturient with PHACE Syndrome for Cesarean Delivery. AB - PHACE syndrome is a disorder that features posterior fossa malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities. PHACE syndrome includes abnormalities in several organ systems that may influence anesthetic management. We discuss the anesthetic management of a 26-year-old woman with PHACE syndrome presenting for cesarean delivery. Management included careful airway examination, slowly dosed epidural anesthesia, close hemodynamic monitoring aided by a radial arterial line, and continuous intraoperative neurologic assessment. PMID- 26576050 TI - Avoiding Cardiovascular Collapse: Pediatric Cutaneous Mastocytosis and Anesthetic Challenges. AB - Mastocytosis includes a spectrum of diseases characterized by abnormal mast cell infiltration in various organs, which can lead to mast cell mediator release and immediate hypersensitivity. We review anesthetic challenges presented by a 6-year old girl with a history of mast cell mediator release because of the urticaria pigmentosa variant of cutaneous mastocytosis, factor VII deficiency, increasing episodes of urinary tract infections, and pyelonephritis. She underwent spine magnetic resonance imaging, subsequent lumbar laminectomy for fatty filum release, and a cystourethroscopy. Perioperative management included factor VII desensitization, avoidance of triggers, minimizing histamine-releasing medications, mast cell stabilization, and preparation for potential immediate hypersensitivity. PMID- 26576051 TI - Anesthesia Management for a Boy with Anti-N-Methyl-D-Aspartate Receptor Encephalitis. AB - Anti-N-methyl-D-aspartate receptor encephalitis is caused by autoantibodies to N methyl-D-aspartate receptors. This disorder is poorly understood and occurs very rarely in children. We describe a total IV anesthetic for a 4-year-old boy with anti-N-methyl-D-aspartate receptor encephalitis and review the potential drug interactions with this autoimmune disease. PMID- 26576052 TI - Anesthetic Management of an Extremely Premature, Extremely Low-Birth-Weight Infant Undergoing Bronchoscopy for Removal of an Aspirated Foreign Body. AB - We present a case of an ex-28-week, extremely low-birth-weight infant who was transferred to our institution for bronchoscopically assisted removal of an aspirated foreign body. This case presented several challenges because of the patient's extreme prematurity as well as the need for repeated tracheal extubations and reintubations during the procedure to accommodate surgical instruments in the patient's airway. We discuss the respiratory physiology, common comorbidities, and management of aspirated foreign bodies in the premature infant and emphasize the importance of clear communication in the operating room between the multidisciplinary team of physicians involved in this patient's care. PMID- 26576053 TI - Impact of Non-Native Birds on Native Ecosystems: A Global Analysis. AB - Introduction and naturalization of non-native species is one of the most important threats to global biodiversity. Birds have been widely introduced worldwide, but their impacts on populations, communities, and ecosystems have not received as much attention as those of other groups. This work is a global synthesis of the impact of nonnative birds on native ecosystems to determine (1) what groups, impacts, and locations have been best studied; (2) which taxonomic groups and which impacts have greatest effects on ecosystems, (3) how important are bird impacts at the community and ecosystem levels, and (4) what are the known benefits of nonnative birds to natural ecosystems. We conducted an extensive literature search that yielded 148 articles covering 39 species belonging to 18 families -18% of all known naturalized species. Studies were classified according to where they were conducted: Africa, Asia, Australasia, Europe, North America, South America, Islands of the Indian, of the Pacific, and of the Atlantic Ocean. Seven types of impact on native ecosystems were evaluated: competition, disease transmission, chemical, physical, or structural impact on ecosystem, grazing/ herbivory/ browsing, hybridization, predation, and interaction with other non-native species. Hybridization and disease transmission were the most important impacts, affecting the population and community levels. Ecosystem-level impacts, such as structural and chemical impacts were detected. Seven species were found to have positive impacts aside from negative ones. We provide suggestions for future studies focused on mechanisms of impact, regions, and understudied taxonomic groups. PMID- 26576054 TI - Viral Infection in Adults with Severe Acute Respiratory Infection in Colombia. AB - OBJECTIVES: To identify the viral aetiology in adult patients with severe acute respiratory infection (SARI) admitted to sentinel surveillance institutions in Bogota in 2012. DESIGN: A cross-sectional study was conducted in which microarray molecular techniques for viral identification were used on nasopharyngeal samples of adult patients submitted to the surveillance system, and further descriptions of clinical features and relevant clinical outcomes, such as mortality, need for critical care, use of mechanical ventilation and hospital stay, were obtained. SETTING: Respiratory infections requiring hospital admission in surveillance centres in Bogota, Colombia. PARTICIPANTS: Ninety-one adult patients with acute respiratory infection (55% were female). MEASUREMENTS: Viral identification, intensive care unit admission, hospital stay, and mortality. RESULTS: Viral identification was achieved for 63 patients (69.2%). Comorbidity was frequently identified and mainly involved chronic pulmonary disease or pregnancy. Influenza, Bocavirus and Adenovirus were identified in 30.8%, 28.6% and 18.7% of the cases, respectively. Admission to the intensive care unit occurred in 42.9% of the cases, while mechanical ventilation was required for 36.3%. The average hospital stay was 9.9 days, and mortality was 15.4%. Antibiotics were empirically used in 90.1% of patients. CONCLUSIONS: The prevalence of viral aetiology of SARI in this study was high, with adverse clinical outcomes, intensive care requirements and high mortality. PMID- 26576055 TI - Sleep Disruption and Daytime Sleepiness Correlating with Disease Severity and Insulin Resistance in Non-Alcoholic Fatty Liver Disease: A Comparison with Healthy Controls. AB - BACKGROUND & AIMS: Sleep disturbance is associated with the development of obesity, diabetes and hepatic steatosis in murine models. Hepatic triglyceride accumulation oscillates in a circadian rhythm regulated by clock genes, light dark cycle and feeding time in mice. The role of the sleep-wake cycle in the pathogenesis of human non-alcoholic fatty liver disease (NAFLD) is indeterminate. We sought to detail sleep characteristics, daytime sleepiness and meal times in relation to disease severity in patients with NAFLD. METHODS: Basic Sleep duration and latency, daytime sleepiness (Epworth sleepiness scale), Pittsburgh sleep quality index, positive and negative affect scale, Munich Chronotype Questionnaire and an eating habit questionnaire were assessed in 46 patients with biopsy-proven NAFLD and 22 healthy controls, and correlated with biochemical and histological parameters. RESULTS: In NAFLD compared to healthy controls, time to fall asleep was vastly prolonged (26.9 vs. 9.8 min., p = 0.0176) and sleep duration was shortened (6.3 vs. 7.2 hours, p = 0.0149). Sleep quality was poor (Pittsburgh sleep quality index 8.2 vs. 4.7, p = 0.0074) and correlated with changes in affect. Meal frequency was shifted towards night-times (p = 0.001). In NAFLD but not controls, daytime sleepiness significantly correlated with liver enzymes (ALAT [r = 0.44, p = 0.0029], ASAT [r = 0.46, p = 0.0017]) and insulin resistance (HOMA-IR [r = 0.5, p = 0.0009]) independent of cirrhosis. In patients with fibrosis, daytime sleepiness correlated with the degree of fibrosis (r = 0.364, p = 0.019). CONCLUSIONS: In NAFLD sleep duration was shortened, sleep onset was delayed and sleep quality poor. Food-intake was shifted towards the night. Daytime sleepiness was positively linked to biochemical and histologic surrogates of disease severity. The data may indicate a role for sleep-wake cycle regulation and timing of food-intake in the pathogenesis of human NAFLD as suggested from murine models. PMID- 26576057 TI - Osteomyocutaneous peroneal artery perforator flap for reconstruction of the skull base. PMID- 26576056 TI - NMR Structure and Dynamics of the Resuscitation Promoting Factor RpfC Catalytic Domain. AB - Mycobacterium tuberculosis latent infection is maintained for years with no clinical symptoms and no adverse effects for the host. The mechanism through which dormant M. tuberculosis resuscitates and enters the cell cycle leading to tuberculosis is attracting much interest. The RPF family of proteins has been found to be responsible for bacteria resuscitation and normal proliferation. This family of proteins in M. tuberculosis is composed by five homologues (named RpfA E) and understanding their conformational, structural and functional peculiarities is crucial to the design of therapeutic strategies.Therefore, we report the structural and dynamics characterization of the catalytic domain of RpfC from M. tubercolosis by combining Nuclear Magnetic Resonance, Circular Dichroism and Molecular Dynamics data. We also show how the formation of a disulfide bridge, highly conserved among the homologues, is likely to modulate the shape of the RpfC hydrophobic catalytic cleft. This might result in a protein function regulation via a "conformational editing" through a disulfide bond formation. PMID- 26576058 TI - Estimating Finite Rate of Population Increase for Sharks Based on Vital Parameters. AB - The vital parameter data for 62 stocks, covering 38 species, collected from the literature, including parameters of age, growth, and reproduction, were log transformed and analyzed using multivariate analyses. Three groups were identified and empirical equations were developed for each to describe the relationships between the predicted finite rates of population increase (lambda') and the vital parameters, maximum age (Tmax), age at maturity (Tm), annual fecundity (f/Rc)), size at birth (Lb), size at maturity (Lm), and asymptotic length (Linfinity). Group (1) included species with slow growth rates (0.034 yr( 1) < k < 0.103 yr(-1)) and extended longevity (26 yr < Tmax < 81 yr), e.g., shortfin mako Isurus oxyrinchus, dusky shark Carcharhinus obscurus, etc.; Group (2) included species with fast growth rates (0.103 yr(-1) < k < 0.358 yr(-1)) and short longevity (9 yr < Tmax < 26 yr), e.g., starspotted smoothhound Mustelus manazo, gray smoothhound M. californicus, etc.; Group (3) included late maturing species (Lm/Linfinity ? 0.75) with moderate longevity (Tmax < 29 yr), e.g., pelagic thresher Alopias pelagicus, sevengill shark Notorynchus cepedianus. The empirical equation for all data pooled was also developed. The lambda' values estimated by these empirical equations showed good agreement with those calculated using conventional demographic analysis. The predictability was further validated by an independent data set of three species. The empirical equations developed in this study not only reduce the uncertainties in estimation but also account for the difference in life history among groups. This method therefore provides an efficient and effective approach to the implementation of precautionary shark management measures. PMID- 26576060 TI - Relation Between Lift Force and Ball Spin for Different Baseball Pitches. AB - Although the lift force (F(L)) on a spinning baseball has been analyzed in previous studies, no study has analyzed such forces over a wide variety of spins. The purpose of this study was to describe the relationship between F(L) and spin for different types of pitches thrown by collegiate pitchers. Four high-speed video cameras were used to record flight trajectory and spin for 7 types of pitches. A total of 75 pitches were analyzed. The linear kinematics of the ball was determined at 0.008-s intervals during the flight, and the resultant fluid force acting on the ball was calculated with an inverse dynamics approach. The initial angular velocity of the ball was determined using a custom-made apparatus. Equations were derived to estimate the F(L) using the effective spin parameter (ESp), which is a spin parameter calculated using a component of angular velocity of the ball with the exception of the gyro-component. The results indicate that F(L) could be accurately explained from ESp and also that seam orientation (4-seam or 2-seam) did not produce a uniform effect on estimating F(L) from ESp. PMID- 26576059 TI - Hydroxyurea-Increased Fetal Hemoglobin Is Associated with Less Organ Damage and Longer Survival in Adults with Sickle Cell Anemia. AB - BACKGROUND: Adults with sickle cell anemia (HbSS) are inconsistently treated with hydroxyurea. OBJECTIVES: We retrospectively evaluated the effects of elevating fetal hemoglobin with hydroxyurea on organ damage and survival in patients enrolled in our screening study between 2001 and 2010. METHODS: An electronic medical record facilitated development of a database for comparison of study parameters based on hydroxyurea exposure and dose. This study is registered with ClinicalTrials.gov, number NCT00011648. RESULTS: Three hundred eighty-three adults with homozygous sickle cell disease were analyzed with 59 deaths during study follow-up. Cox regression analysis revealed deceased subjects had more hepatic dysfunction (elevated alkaline phosphatase, Hazard Ratio = 1.005, 95% CI 1.003-1.006, p<0.0.0001), kidney dysfunction (elevated creatinine, Hazard Ratio = 1.13, 95% CI 1.00-1.27, p = 0.043), and cardiopulmonary dysfunction (elevated tricuspid jet velocity on echocardiogram, Hazard Ratio = 2.22, 1.23-4.02, p = 0.0082). Sixty-six percent of subjects were treated with hydroxyurea, although only 66% of those received a dose within the recommended therapeutic range. Hydroxyurea use was associated with improved survival (Hazard Ratio = 0.58, 95% CI 0.34-0.97, p = 0.040). This effect was most pronounced in those taking the recommended dose of 15-35 mg/kg/day (Hazard Ratio 0.36, 95% CI 0.17-0.73, p = 0.0050). Hydroxyurea use was not associated with changes in organ function over time. Further, subjects with higher fetal hemoglobin responses to hydroxyurea were more likely to survive (p = 0.0004). While alkaline phosphatase was lowest in patients with the best fetal hemoglobin response (95.4 versus 123.6, p = 0.0065 and 96.1 versus 113.6U/L, p = 0.041 at first and last visits, respectively), other markers of organ damage were not consistently improved over time in patients with the highest fetal hemoglobin levels. CONCLUSIONS: Our data suggest that adults should be treated with the maximum tolerated hydroxyurea dose, ideally before organ damage occurs. Prospective studies are indicated to validate these findings. PMID- 26576061 TI - The effects of diversity and network ties on innovations: The emergence of a new scientific field. AB - This study examines the influence of different types of diversity, both observable and unobservable, on the creation of innovative ideas. Our framework draws upon theory and research on information processing, social categorization, coordination, and homophily to posit the influence of cognitive, gender, and country diversity on innovation. Our longitudinal model is based on a unique dataset of 1,354 researchers who helped create the new scientific field of Oncofertility, by collaborating on 469 publications over a four-year period. We capture the differences among researchers along cognitive, country and gender dimensions, as well as examine how the resulting diversity or homophily influences the formation of collaborative innovation networks. We find that innovation, operationalized as publishing in a new scientific discipline, benefits from both homophily and diversity. Homophily in country of residence and working with prior collaborators help reduce uncertainty in the interactions associated with innovation, while diversity in knowledge enables the recombinant knowledge required for innovation. PMID- 26576062 TI - Two-stage radio-frequency interferometer sensors. AB - We show that simple radio-frequency (RF) interferometers can have slow-wave positive group delay (PGD) or negative group delay (NGD), as well as superluminal propagation (SP) regions, due to a destructive interference process. These properties are easily tunable, which makes RF interferometers unique among systems that have NGD and SP regimes. A two-stage interferometer arrangement, which includes a first stage interferometer in the material-under-test path of a second stage, has significantly improved sensitivity in comparison with a one stage reference interferometer. With a power divider based first stage and at its maximum NGD frequency, the frequency sensitivity improvement is as high as 7 times. With a quadrature based first stage, the sensitivity is increased by as much as 20 times. Sensitivity improvements are also observed at PGD and SP frequency regions. PMID- 26576063 TI - Ferrohydrodynamic modeling of magnetic nanoparticle harmonic spectra for magnetic particle imaging. AB - Magnetic Particle Imaging (MPI) is an emerging imaging technique that uses magnetic nanoparticles as tracers. In order to analyze the quality of nanoparticles developed for MPI, a Magnetic Particle Spectrometer (MPS) is often employed. In this paper, we describe results for predictions of the nanoparticle harmonic spectra obtained in a MPS using three models: the first uses the Langevin function, which does not take into account finite magnetic relaxation; the second model uses the magnetization equation by Shliomis (Sh), which takes into account finite magnetic relaxation using a constant characteristic time scale; and the third model uses the magnetization equation derived by Martsenyuk, Raikher, and Shliomis (MRSh), which takes into account the effect of magnetic field magnitude on the magnetic relaxation time. We make comparisons between these models and with experiments in order to illustrate the effects of field dependent relaxation in the MPS. The models results suggest that finite relaxation results in a significant drop in signal intensity (magnitude of individual harmonics) and in faster spectral decay. Interestingly, when field dependence of the magnetic relaxation time was taken into account, through the MRSh model, the simulations predict a significant improvement in the performance of the nanoparticles, as compared to the performance predicted by the Sh equation. The comparison between the predictions from models and experimental measurements showed excellent qualitative as well as quantitative agreement up to the 19th harmonic using the Sh and MRSh equations, highlighting the potential of ferrohydrodynamic modeling in MPI. PMID- 26576064 TI - Erratum: "Magnetic nanoparticles with high specific absorption rate of electromagnetic energy at low field strength for hyperthermia therapy" [J. Appl. Phys. 117, 094302 (2015)]. AB - [This corrects the article , PMID: 25825545.]. PMID- 26576065 TI - Copper-mediated N-Arylation of Methyl 2-Aminothiophene-3-carboxylate with Organoboron Reagents. AB - A practical protocol for the synthesis of N-arylated methyl 2-aminothiophene-3 carboxylate has been developed via Chan-Lam cross-coupling. The desired products were synthesized by cross-coupling of methyl 2-aminothiophene-3-carboxylate with both arylboronic acids and potassium aryltrifluoroborate salts in moderate to good yields. A broad range of functional groups was well tolerated. PMID- 26576066 TI - Analysis of the Proportional Hazards Model with Sparse Longitudinal Covariates. AB - Regression analysis of censored failure observations via the proportional hazards model permits time-varying covariates which are observed at death times. In practice, such longitudinal covariates are typically sparse and only measured at infrequent and irregularly spaced follow-up times. Full likelihood analyses of joint models for longitudinal and survival data impose stringent modelling assumptions which are difficult to verify in practice and which are complicated both inferentially and computationally. In this article, a simple kernel weighted score function is proposed with minimal assumptions. Two scenarios are considered: half kernel estimation in which observation ceases at the time of the event and full kernel estimation for data where observation may continue after the event, as with recurrent events data. It is established that these estimators are consistent and asymptotically normal. However, they converge at rates which are slower than the parametric rates which may be achieved with fully observed covariates, with the full kernel method achieving an optimal convergence rate which is superior to that of the half kernel method. Simulation results demonstrate that the large sample approximations are adequate for practical use and may yield improved performance relative to last value carried forward approach and joint modelling method. The analysis of the data from a cardiac arrest study demonstrates the utility of the proposed methods. PMID- 26576067 TI - Effects of Antitumor Necrosis Factor Therapy on Osteoprotegerin, Neopterin, and sRANKL Concentrations in Patients with Rheumatoid Arthritis. AB - BACKGROUND: Rheumatoid arthritis is a systemic autoimmune disease characterized by joint erosions, progressive focal bone loss, and chronic inflammation. METHODS: 20 female patients with moderate-to-severe rheumatoid arthritis were treated with anti-TNF-antibody adalimumab in addition to concomitant antirheumatic therapies. Patients were assessed for overall disease activity using the DAS28 score, and neopterin, erythrocyte sedimentation rate (ESR), and C reactive protein (CRP) concentrations as well as osteoprotegerin (OPG) and soluble receptor activator of NF-kappaB ligand (sRANKL) concentrations were determined before therapy and at week 12. Neopterin as well as OPG and sRANKL were determined by commercial ELISAs. RESULTS: Before anti-TNF therapy patients presented with high disease activity and elevated concentrations of circulating inflammatory markers. OPG concentrations correlated with neopterin (rs = 0.494, p = 0.027), but not with DAS28. OPG concentrations and disease activity scores declined during anti-TNF-treatment (both p < 0.02). Patients who achieved remission (n = 7) or showed a good response according to EULAR criteria (n = 13) presented with initially higher baseline OPG levels, which subsequently decreased significantly during treatment (p = 0.018 for remission, p = 0.011 for good response). CONCLUSIONS: Adalimumab therapy was effective in modifying disease activity and reducing proinflammatory and bone remodelling cascades. PMID- 26576068 TI - Clinicopathologic and Prognostic Value of Serum Carbohydrate Antigen 19-9 in Gastric Cancer: A Meta-Analysis. AB - BACKGROUND: The clinical value of carbohydrate antigen (CA) 19-9 in gastric cancer is controversial. We evaluated the clinicopathologic and prognostic value of CA 19-9 in gastric cancer. METHODS: A literature search was conducted in PubMed and Embase databases. Odds ratios (ORs), risk ratios (RR), hazard ratios (HRs), and 95% confidence intervals (CIs) were used as effect measures. RESULTS: Thirty-eight studies were included. Results showed that there were significant differences in the incidence of high CA 19-9 levels between stages III/IV and I/II groups (OR = 3.36; 95% CI = 2.34-4.84), the pT3/T4 and pT1/T2 groups (OR = 2.40; 95% CI = 1.60-3.59), the lymph node-positive and node-negative groups (OR = 2.91; 95% CI = 2.21-3.84), the metastasis-positive and metastasis-negative groups (OR = 2.76; 95% CI = 1.12-6.82), and vessel invasion-positive and invasion negative groups (OR = 1.66; 95% CI = 1.11-2.48). Moreover, CA 19-9 was significantly associated with poor overall survival (HR = 1.83; 95% CI = 1.56 2.15), disease-free survival (HR = 1.85; 95% CI = 1.16-2.95), and disease specific survival (HR = 1.33; 95% CI = 1.10-1.60) in gastric cancer. CONCLUSIONS: Our meta-analysis showed that CA 19-9 indicates clinicopathologic characteristics of gastric cancer and is associated with a poor prognosis. PMID- 26576070 TI - Whakawhiti Korero, a Method for the Development of a Cultural Assessment Tool, Te Waka Kuaka, in Maori Traumatic Brain Injury. AB - The importance of tools for the measurement of outcomes and needs in traumatic brain injury is well recognised. The development of tools for these injuries in indigenous communities has been limited despite the well-documented disparity of brain injury. The wairua theory of traumatic brain injury (TBI) in Maori proposes that a culturally defined injury occurs in tandem with the physical injury. A cultural response is therefore indicated. This research investigates a Maori method used in the development of cultural needs assessment tool designed to further examine needs associated with the culturally determined injury and in preparation for formal validation. Whakawhiti korero is a method used to develop better statements in the development of the assessment tool. Four wananga (traditional fora) were held including one with whanau (extended family) with experience of traumatic brain injury. The approach was well received. A final version, Te Waka Kuaka, is now ready for validation. Whakawhiti korero is an indigenous method used in the development of cultural needs assessment tool in Maori traumatic brain injury. This method is likely to have wider applicability, such as Mental Health and Addictions Services, to ensure robust process of outcome measure and needs assessment development. PMID- 26576069 TI - The Role of Vitamin D in Diabetes and Cardiovascular Disease: An Updated Review of the Literature. AB - The dietary reference values for Vitamin D were set primarily considering its role in bone health, but with the discovery of Vitamin D receptors throughout body tissues, new links with other health conditions are now studied, such as for diabetes and cardiovascular diseases (CVD). This paper shall analyze and examine all new research studies carried out, especially in 2013-2015 regarding diabetes mellitus (DM) and cardiovascular diseases (CVD). Vast research has been carried out to establish strong relationship between Vitamin D serum levels, supplementation, diabetes, and CVD. However, the results from researches identified in this paper are disputable. Benefits of Vitamin D adequate levels were recognized from gestational period until later in disease development such as diabetes and/or CVD, but since not all studies are in agreement further investigation is suggested. Researches conducting large randomized controlled trials, exploring range of supplement doses, with variable baseline serum Vitamin D levels, and inclusion of array of associated parameters, are still required to conduct large-scale analysis and draw conclusion as a risk factor. Until then it is possible to conclude that maintenance of serum Vitamin D levels holds advantageous aspects in diabetic and cardiovascular conditions, and people should strive to attain them. PMID- 26576071 TI - Depression and Anxiety among Patients with Epilepsy and Multiple Sclerosis: UAE Comparative Study. AB - Depression and anxiety are highly prevalent in patients with epilepsy (PWE), with prevalence rates ranging from 20% to 55%. The cause of this increased rate is multifactorial. Depression and epilepsy are thought to share the same pathogenic mechanism. Anxiety, on the other hand, seems to have a prevalence rate among PWE comparable to, or even higher than, those reported for depression, and it is closely linked to epilepsy. To test this hypothesis, we screened for depression and anxiety 186 and 160 patients attending the epilepsy and MS clinics, respectively, using standardized screening tools to determine the rates of both depression and anxiety, comparing these rates to 186 age, sex matched controls. Among the three groups, only patients with epilepsy were at increased risk of having depression (OR = 1.9), whereas anxiety was not. This finding could point to the shared pathogenic mechanisms hypothesis between depression and epilepsy. PMID- 26576072 TI - Gender Differences in Childhood Lyme Neuroborreliosis. AB - BACKGROUND: Many neurological diseases show differences between genders. We studied gender differences in childhood Lyme neuroborreliosis (LNB) in an endemic area of Lyme borreliosis in Norway. METHODS: In a population based study, all children (<14 years of age) with symptoms suspicious of LNB, including all children with acute facial nerve palsy, were evaluated for LNB by medical history, clinical examination, blood tests, and lumbar puncture. LNB was diagnosed according to international criteria. RESULTS: 142 children were diagnosed with LNB during 2001-2009. Facial nerve palsy was more common in girls (86%) than in boys (62%) (p < 0.001), but headache and/or neck stiffness as the only symptom was more common in boys (30%) than in girls (10%) (p = 0.003). The girls were younger than boys and had a shorter duration of symptoms, but boys had a higher level of pleocytosis than girls. In a multivariate analysis, both gender and having headache and neck stiffness were associated with a higher level of pleocytosis. CONCLUSION: Girls and boys have different clinical presentations of LNB, and boys have a higher level of inflammation than girls independent of the clinical presentation. PMID- 26576073 TI - Botanical Drugs as an Emerging Strategy in Inflammatory Bowel Disease: A Review. AB - Crohn's disease and ulcerative colitis are the two most common categories of inflammatory bowel disease (IBD), which are characterized by chronic inflammation of the intestine that comprises the patients' life quality and requires sustained pharmacological and surgical treatments. Since their aetiology is not completely understood, nonfully efficient drugs have been developed and those that show effectiveness are not devoid of quite important adverse effects that impair their long-term use. Therefore, many patients try with some botanical drugs, which are safe and efficient after many years of use. However, it is necessary to properly evaluate these therapies to consider a new strategy for human IBD. In this report we have reviewed the main botanical drugs that have been assessed in clinical trials in human IBD and the mechanisms and the active compounds proposed for their beneficial effects. PMID- 26576074 TI - Exogenous S1P Exposure Potentiates Ischemic Stroke Damage That Is Reduced Possibly by Inhibiting S1P Receptor Signaling. AB - Initial and recurrent stroke produces central nervous system (CNS) damage, involving neuroinflammation. Receptor-mediated S1P signaling can influence neuroinflammation and has been implicated in cerebral ischemia through effects on the immune system. However, S1P-mediated events also occur within the brain itself where its roles during stroke have been less well studied. Here we investigated the involvement of S1P signaling in initial and recurrent stroke by using a transient middle cerebral artery occlusion/reperfusion (M/R) model combined with analyses of S1P signaling. Gene expression for S1P receptors and involved enzymes was altered during M/R, supporting changes in S1P signaling. Direct S1P microinjection into the normal CNS induced neuroglial activation, implicating S1P-initiated neuroinflammatory responses that resembled CNS changes seen during initial M/R challenge. Moreover, S1P microinjection combined with M/R potentiated brain damage, approximating a model for recurrent stroke dependent on S1P and suggesting that reduction in S1P signaling could ameliorate stroke damage. Delivery of FTY720 that removes S1P signaling with chronic exposure reduced damage in both initial and S1P-potentiated M/R-challenged brain, while reducing stroke markers like TNF-alpha. These results implicate direct S1P CNS signaling in the etiology of initial and recurrent stroke that can be therapeutically accessed by S1P modulators acting within the brain. PMID- 26576075 TI - ROS-Mediated NLRP3 Inflammasome Activity Is Essential for Burn-Induced Acute Lung Injury. AB - The NLRP3 inflammasome is necessary for initiating acute sterile inflammation. However, its role in the pathogenesis of burn-induced acute lung injury (ALI) is unknown. This study aimed to determine the role of the NLRP3 inflammasome and the signaling pathways involved in burn-induced ALI. We observed that the rat lungs exhibited enhanced inflammasome activity after burn, as evidenced by increased levels of NLRP3 expression and Caspase-1 activity and augmented inflammatory cytokines. Inhibition of NLRP3 inflammasome by BAY11-7082 attenuated burn-induced ALI, as demonstrated by the concomitant remission of histopathologic changes and the reduction of myeloperoxidase (MPO) activity, inflammatory cytokines in rat lung tissue, and protein concentrations in the bronchoalveolar lavage fluid (BALF). In the in vitro experiments, we used AMs (alveolar macrophages) challenged with burn serum to mimic the postburn microenvironment and noted that the serum significantly upregulated NLRP3 inflammasome signaling and reactive oxygen species (ROS) production. The use of ROS scavenger N-acetylcysteine (NAC) partially reversed NLRP3 inflammasome activity in cells exposed to burn serum. These results indicate that the NLRP3 inflammasome plays an essential role in burn-induced ALI and that burn-induced NLRP3 inflammasome activity is a partly ROS-dependent process. Targeting this axis may represent a promising therapeutic strategy for the treatment of burn-induced ALI. PMID- 26576076 TI - An Overview of Pathogen Recognition Receptors for Innate Immunity in Dental Pulp. AB - Pathogen recognition receptors (PRRs) are a class of germ line-encoded receptors that recognize pathogen-associated molecular patterns (PAMPs). The activation of PRRs is crucial for the initiation of innate immunity, which plays a key role in first-line defense until more specific adaptive immunity is developed. PRRs differ in the signaling cascades and host responses activated by their engagement and in their tissue distribution. Currently identified PRR families are the Toll like receptors (TLRs), the C-type lectin receptors (CLRs), the nucleotide-binding oligomerization domain-like receptors (NLRs), the retinoic acid-inducible gene-I like receptors (RLRs), and the AIM2-like receptor (ALR). The environment of the dental pulp is substantially different from that of other tissues of the body. Dental pulp resides in a low compliance root canal system that limits the expansion of pulpal tissues during inflammatory processes. An understanding of the PRRs in dental pulp is important for immunomodulation and hence for developing therapeutic targets in the field of endodontics. Here we comprehensively review recent finding on the PRRs and the mechanisms by which innate immunity is activated. We focus on the PRRs expressed on dental pulp and periapical tissues and their role in dental pulp inflammation. PMID- 26576077 TI - Hepatic immune tolerance induced by hepatic stellate cells. AB - The liver, which is a metabolic organ, plays a pivotal role in tolerance induction. Hepatic stellate cells (HpSCs), which are unique non-parenchymal cells, exert potent immunoregulatory activity during cotransplantation with allogeneic islets effectively protecting the islet allografts from rejection. Multiple mechanisms participate in the immune tolerance induced by HpSCs, including the marked expansion of myeloid-derived suppressor cells (MDSCs), attenuation of effector T cell functions and augmentation of regulatory T cells. HpSC conditioned MDSC-based immunotherapy has been conducted in mice with autoimmune disease and the results show that this technique may be promising. This article demonstrates how HpSCs orchestrate both innate immunity and adaptive immunity to build a negative network that leads to immune tolerance. PMID- 26576078 TI - Advances in alcoholic liver disease: An update on alcoholic hepatitis. AB - Alcoholic hepatitis is a pro-inflammatory chronic liver disease that is associated with high short-term morbidity and mortality (25%-35% in one month) in the setting of chronic alcohol use. Histopathology is notable for micro- and macrovesicular steatosis, acute inflammation with neutrophil infiltration, hepatocellular necrosis, perivenular and perisinusoidal fibrosis, and Mallory hyaline bodies found in ballooned hepatocytes. Other findings include the characteristic eosinophilic fibrillar material (Mallory's hyaline bodies) found in ballooned hepatocytes. The presence of focal intense lobular infiltration of neutrophils is what typically distinguishes alcoholic hepatitis from other forms of hepatitis, in which the inflammatory infiltrate is primarily composed of mononuclear cells. Management consists of a multidisciplinary approach including alcohol cessation, fluid and electrolyte correction, treatment of alcohol withdrawal, and pharmacological therapy based on the severity of the disease. Pharmacological treatment for severe alcoholic hepatitis, as defined by Maddrey's discriminant factor >= 32, consists of either prednisolone or pentoxifylline for a period of four weeks. The body of evidence for corticosteroids has been greater than pentoxifylline, although there are higher risks of complications. Recently head-to-head trials between corticosteroids and pentoxifylline have been performed, which again suggests that corticosteroids should strongly be considered over pentoxifylline. PMID- 26576079 TI - Immune dysfunction in acute alcoholic hepatitis. AB - Acute alcoholic hepatitis (AAH) is a serious complication of alcohol misuse and has high short term mortality. It is a clinical syndrome characterised by jaundice and coagulopathy in a patient with a history of recent heavy alcohol use and is associated with profound immune dysfunction with a primed but ineffective immune response against pathogens. Here, we review the current knowledge of the pathogenesis and immune defects of AAH and identify areas requiring further study. Alcohol activates the immune system primarily through the disruption of gut tight junction integrity allowing the escape of pathogen-associated molecular particles (PAMPs) into the portal venous system. PAMPs stimulate cells expressing toll-like receptors (mainly myeloid derived cells) and initiate a network of intercellular signalling by secretion of many soluble mediators including cytokines and chemokines. The latter coordinates the infiltration of neutrophils, monocytes and T cells and results in hepatic stellate cell activation, cellular damage and hepatocyte death by necrosis or apoptosis. On the converse of this immune activation is the growing evidence of impaired microbial defence. Neutrophils have reduced phagocytic capacity and oxidative burst and there is recent evidence that T cell exhaustion plays a role in this. PMID- 26576080 TI - Noninvasive assessment of alcoholic liver disease using unidimensional transient elastography (Fibroscan((r))). AB - Unidimensional transient elastography (TE) is a noninvasive technique, which has been increasingly used in the assessment of diffuse liver diseases. This paper focuses on reviewing the existing data on the use of TE in the diagnosis of fibrosis and in monitoring disease progression in alcoholic liver disease, on the factors that may influence the result of fibrosis prediction, and last but not least, on its potential use in assessing the steatosis degree. Therefore, this field is far from being exhausted and deserves more attention. Further studies are required, on large groups of biopsied patients, in order to find answers to all the remaining questions in this field. PMID- 26576081 TI - Hepatitis B among Asian Americans: Prevalence, progress, and prospects for control. AB - After tobacco use, chronic hepatitis B (CHB) viral infections are the most important cause of cancer globally in that 1 out of 3 individuals have been infected with the hepatitis B virus (HBV). Though infection rates are low (< 1%) in the United States, Asian Americans who comprise about 6% of the population experience about 60% of the CHB burden. This paper reviews the magnitude of hepatitis B (HBV) burden among Asian Americans and the progress being made to mitigate this burden, primarily through localized, community-based efforts to increase screening and vaccination among Asian American children, adolescents, and adults. This review brings to light that despite the numerous community-based screening efforts, a vast majority of Asian Americans have not been screened and that vaccination efforts, particularly for adults, are sub-optimal. Greater efforts to integrate screenings by providers within existing healthcare systems are urged. Evidence-based strategies are offered to implement CDC's three major recommendations to control and prevent hepatitis B through targeted screening and enhanced vaccination efforts. PMID- 26576082 TI - Role of occult hepatitis B virus infection in chronic hepatitis C. AB - The development of sensitive assays to detect small amounts of hepatitis B virus (HBV) DNA has favored the identification of occult hepatitis B infection (OBI), a virological condition characterized by a low level of HBV replication with detectable levels of HBV DNA in liver tissue but an absence of detectable surface antigen of HBV (HBsAg) in serum. The gold standard to diagnose OBI is the detection of HBV DNA in the hepatocytes by highly sensitive and specific techniques, a diagnostic procedure requiring liver tissue to be tested and the use of non-standardized non-commercially available techniques. Consequently, in everyday clinical practice, the detection of anti-hepatitis B core antibody (anti HBc) in serum of HBsAg-negative subjects is used as a surrogate marker to identify patients with OBI. In patients with chronic hepatitis C (CHC), OBI has been identified in nearly one-third of these cases. Considerable data suggest that OBI favors the increase of liver damage and the development of hepatocellular carcinoma (HCC) in patients with CHC. The data from other studies, however, indicate no influence of OBI on the natural history of CHC, particularly regarding the risk of developing HCC. PMID- 26576084 TI - Rapid and quantitative detection of hepatitis B virus. AB - Despite availability of a universal vaccine, hepatitis B virus (HBV) infection has a huge impact on public health worldwide. Accurate and timely diagnosis of HBV infection is needed. Rapid developments have been made in the diagnostic and monitoring methods for HBV infection, including serological and molecular assays. In clinical practice, qualitative hepatitis B surface antigen (HBsAg) testing has long served as a diagnostic marker for individuals infected with HBV. More recently, HBsAg level has been used to predict treatment outcome when determined early during treatment or at baseline. However, identification of HBV DNA positive cases that do not have detectable HBsAg has encouraged the application of molecular tests. Hence, combination of quantitative detection of HBV DNA and HBsAg can be used to discriminate patients during the course of HBV infection and to monitor therapy. This article reviews the most commonly used quantitative methods for HBsAg and HBV DNA. PMID- 26576083 TI - Hepatitis B virus burden in developing countries. AB - Hepatitis B virus (HBV) infection has shown an intermediate or high endemicity level in low-income countries over the last five decades. In recent years, however, the incidence of acute hepatitis B and the prevalence of hepatitis B surface antigen chronic carriers have decreased in several countries because of the HBV universal vaccination programs started in the nineties. Some countries, however, are still unable to implement these programs, particularly in their hyperendemic rural areas. The diffusion of HBV infection is still wide in several low-income countries where the prevention, management and treatment of HBV infection are a heavy burden for the governments and healthcare authorities. Of note, the information on the HBV epidemiology is scanty in numerous eastern European and Latin-American countries. The studies on molecular epidemiology performed in some countries provide an important contribution for a more comprehensive knowledge of HBV epidemiology, and phylogenetic studies provide information on the impact of recent and older migratory flows. PMID- 26576085 TI - Early warning and clinical outcome prediction of acute-on-chronic hepatitis B liver failure. AB - Hepatitis B virus (HBV) associated acute-on-chronic liver failure (ACLF) is an increasingly recognized fatal liver disease encompassing a severe acute exacerbation of liver function in patients with chronic hepatitis B (CHB). Despite the introduction of an artificial liver support system and antiviral therapy, the short-term prognosis of HBV-ACLF is still extremely poor unless emergency liver transplantation is performed. In such a situation, stopping or slowing the progression of CHB to ACLF at an early stage is the most effective way of reducing the morbidity and mortality of HBV-ACLF. It is well-known that the occurrence and progression of HBV-ACLF is associated with many factors, and the outcomes of HBV-ACLF patients can be significantly improved if timely and appropriate interventions are provided. In this review, we highlight recent developments in early warning and clinical outcome prediction in patients with HBV-ACLF and provide an outlook for future research in this field. PMID- 26576086 TI - Hepatitis C virus-associated neurocognitive and neuropsychiatric disorders: Advances in 2015. AB - Since its identification in 1989, hepatitis C virus (HCV) has emerged as a worldwide health problem with roughly 185 million chronic infections, representing individuals at high risk of developing cirrhosis and liver cancer. In addition to being a frequent cause of morbidity and mortality due to liver disease, HCV has emerged as an important trigger of lymphoproliferative disorders, owing to its lymphotropism, and of a wide spectrum of extra-hepatic manifestations (HCV-EHMs) affecting different organ systems. The most frequently observed HCV-EHMs include mixed cryoglobulinemia and cryoglobulinemic vasculitis, B-cell non-Hodgkin's lymphoma, nephropathies, thyreopathies, type 2 diabetes mellitus, cardiovascular diseases, and several neurological conditions. In addition, neuropsychiatric disorders and neurocognitive dysfunction are reported in nearly 50% of patients with chronic HCV infection, which are independent of the severity of liver disease or HCV replication rates. Fatigue, sleep disturbance, depression and reduced quality of life are commonly associated with neurocognitive alterations in patients with non-cirrhotic chronic HCV infection, regardless of the stage of liver fibrosis and the infecting genotype. These manifestations, which are the topic of this review, typically occur in the absence of structural brain damage or signal abnormalities on conventional brain magnetic resonance imaging (MRI), although metabolic and microstructural changes can be detected by in vivo proton magnetic resonance spectroscopy, perfusion weighted and diffusion tensor MRI, and neurophysiological tests of cognitive processing. Several lines of evidence, including comparative and longitudinal neuropsychological assessments in patients achieving spontaneous or treatment induced viral clearance, support a major pathogenic role for HCV in neuropsychiatric and neurocognitive disorders. PMID- 26576087 TI - Progress in the development of vaccines for hepatitis C virus infection. AB - The hepatitis C virus (HCV), first described in 1989, is now a leading cause of liver cirrhosis and hepatocellular carcinoma. With more than 170 million people infected globally, this virus is a major public health issue. The current standard therapy is based on interferon in combination with ribavirin. This costly therapy often fails to completely clear the infection and is associated with adverse side effects. Recent anti-HCV therapies are interferon-free direct acting antiviral (DAA) regimens for HCV, including simeprevir, sofosbuvir, and ledipasvir, which have effects on non-structural proteins. DAA regimens have several advantages, such as specifically targeting HCV viral replication, accompanied by very high sustained virological response rates and lower side effects like flu-like syndrome. These facts plus the fact that most HCV cases progress to chronic infection suggest the potential need for an efficient HCV vaccine. Different innovative methods, including methods based on peptide, recombinant protein, DNA, vector-based, and virus-like particles, have been introduced for the development of HCV vaccines. An extensive number of studies have been published on these vaccines, and some vaccines were even tested in clinical trials. In the current review, progress in the development of preventive and therapeutic vaccines against the HCV is reviewed in the context of peptide vaccines, recombinant protein vaccines, HCV-like particle, DNA vaccines and viral vectors expressing HCV genes. PMID- 26576089 TI - Nanoparticles for targeted delivery of therapeutics and small interfering RNAs in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the 5(th) most common malignancy which is responsible for more than half million annual mortalities; also, it is the third leading cause of cancer related death. Unfavorable systemic side-effects of chemotherapeutic agents and susceptibility to the degradation of small interfering RNAs (siRNAs), which can knock down a specific gene involved in the disease, have hampered their clinical application. So, it could be beneficial to develop an efficient carrier for the stabilization and specific delivery of drugs and siRNA to cells. Targeted nanoparticles have gained considerable attention as an efficient drug and gene delivery system, which is due to their capability in achieving the highest accumulation of cytotoxic agents in tumor tissue, modifiable drug pharmacokinetic- and bio-distribution, improved effectiveness of treatment, and limited side-effects. Recent studies have shed more light on the advantages of novel drug loaded carrier systems vs free drugs. Most of the animal studies have reported improvement in treatment efficacy and survival rate using novel carrier systems. Targeted delivery may be achieved passively or actively. In passive targeting, no ligand as homing device is used, while targeting is achieved by incorporating the therapeutic agent into a macromolecule or nanoparticle that passively reaches the target organ. However, in active targeting, the therapeutic agent or carrier system is conjugated to a tissue or cell-specific receptor which is over-expressed in a special malignancy using a ligand called a homing device. This review covers a broad spectrum of targeted nanoparticles as therapeutic and non-viral siRNA delivery systems, which are developed for enhanced cellular uptake and targeted gene silencing in vitro and in vivo and their characteristics and opportunities for the clinical applications of drugs and therapeutic siRNA are discussed in this article. Asialoglycoprotein receptors, low-density lipoprotein, ganglioside GM1 cell surface ligand, epidermal growth factor receptor receptors, monoclonal antibodies, retinoic acid receptors, integrin receptors targeted by Arg-Gly-Asp peptide, folate, and transferrin receptors are the most widely studied cell surface receptors which are used for the site specific delivery of drugs and siRNA-based therapeutics in HCC and discussed in detail in this article. PMID- 26576088 TI - Diagnostic and therapeutic management of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is an increasing health problem, representing the second cause of cancer-related mortality worldwide. The major risk factor for HCC is cirrhosis. In developing countries, viral hepatitis represent the major risk factor, whereas in developed countries, the epidemic of obesity, diabetes and nonalcoholic steatohepatitis contribute to the observed increase in HCC incidence. Cirrhotic patients are recommended to undergo HCC surveillance by abdominal ultrasounds at 6-mo intervals. The current diagnostic algorithms for HCC rely on typical radiological hallmarks in dynamic contrast-enhanced imaging, while the use of alpha-fetoprotein as an independent tool for HCC surveillance is not recommended by current guidelines due to its low sensitivity and specificity. Early diagnosis is crucial for curative treatments. Surgical resection, radiofrequency ablation and liver transplantation are considered the cornerstones of curative therapy, while for patients with more advanced HCC recommended options include sorafenib and trans-arterial chemo-embolization. A multidisciplinary team, consisting of hepatologists, surgeons, radiologists, oncologists and pathologists, is fundamental for a correct management. In this paper, we review the diagnostic and therapeutic management of HCC, with a focus on the most recent evidences and recommendations from guidelines. PMID- 26576090 TI - Zebrafish as a disease model for studying human hepatocellular carcinoma. AB - Liver cancer is one of the world's most common cancers and the second leading cause of cancer deaths. Hepatocellular carcinoma (HCC), a primary hepatic cancer, accounts for 90%-95% of liver cancer cases. The pathogenesis of HCC consists of a stepwise process of liver damage that extends over decades, due to hepatitis, fatty liver, fibrosis, and cirrhosis before developing fully into HCC. Multiple risk factors are highly correlated with HCC, including infection with the hepatitis B or C viruses, alcohol abuse, aflatoxin exposure, and metabolic diseases. Over the last decade, genetic alterations, which include the regulation of multiple oncogenes or tumor suppressor genes and the activation of tumorigenesis-related pathways, have also been identified as important factors in HCC. Recently, zebrafish have become an important living vertebrate model organism, especially for translational medical research. In studies focusing on the biology of cancer, carcinogen induced tumors in zebrafish were found to have many similarities to human tumors. Several zebrafish models have therefore been developed to provide insight into the pathogenesis of liver cancer and the related drug discovery and toxicology, and to enable the evaluation of novel small-molecule inhibitors. This review will focus on illustrative examples involving the application of zebrafish models to the study of human liver disease and HCC, through transgenesis, genome editing technology, xenografts, drug discovery, and drug-induced toxic liver injury. PMID- 26576091 TI - Sorafenib-based combined molecule targeting in treatment of hepatocellular carcinoma. AB - Sorafenib is the only and standard systematic chemotherapy drug for treatment of advanced hepatocellular carcinoma (HCC) at the current stage. Although sorafenib showed survival benefits in large randomized phase III studies, its clinical benefits remain modest and most often consist of temporary tumor stabilization, indicating that more effective first-line treatment regimens or second-line salvage therapies are required. The molecular pathogenesis of HCC is very complex, involving hyperactivated signal transduction pathways such as RAS/RAF/MEK/ERK and PI3K/AKT/mTOR and aberrant expression of molecules such as receptor tyrosine kinases and histone deacetylases. Simultaneous or sequential abrogation of these critical pathways or the functions of these key molecules involved in angiogenesis, proliferation, and apoptosis may yield major improvements in the management of HCC. In this review, we summarize the emerging sorafenib-based combined molecule targeting for HCC treatment and analyze the rationales of these combinations. PMID- 26576093 TI - Management of hepatitis B virus infection after liver transplantation. AB - Chronic hepatitis B virus (HBV) infection is responsible for up to 30% of cases of liver cirrhosis and up to 53% of cases of hepatocellular carcinoma. Liver transplantation (LT) is the best therapeutic option for patients with end-stage liver failure caused by HBV. The success of transplantation, though, depends on receiving prophylactic treatment against post-transplant viral reactivation. In the absence of prophylaxis, liver transplantation due to chronic hepatitis B (CHB) is associated with high rates of viral recurrence and poor survival. The introduction of treatment with hepatitis B immunoglobulins (HBIG) during the 1990s and later the incorporation of oral antiviral drugs have improved the prognosis of these patients. Thus, LT for CHB is now a universally accepted option, with an estimated 5 years survival of around 85% vs the 45% survival seen prior to the introduction of HBIG. The combination of lamivudine plus HBIG has for many years been the most widely used prophylactic regimen. However, with the appearance of new more potent oral antiviral agents associated with less resistance (e.g., entecavir and tenofovir) for the treatment of CHB, new prophylactic strategies are being designed, either in combination with HBIG or alone as a monotherapy. These advances have allowed for more personalized prophylaxis based on the individual risk profile of a given patient. In addition, the small pool of donors has required the use of anti-HBc-positive donors (with the resulting possibility of transmitting HBV from these organs), which has been made possible by suitable prophylactic regimens. PMID- 26576092 TI - Liver transplantation for hepatocellular carcinoma - factors influencing outcome and disease-free survival. AB - Hepatocellular carcinoma is one of the leading causes of cancer-related death worldwide. Liver transplantation can be a curative treatment in selected patients. However, there are several factors that influence disease-free survival after transplantation. This review addresses the pre-, intra- and postoperative factors that influence the risk of tumor recurrence after liver transplantation. PMID- 26576094 TI - Application of nucleoside analogues to liver transplant recipients with hepatitis B. AB - Hepatitis B is a common yet serious infectious disease of the liver, affecting millions of people worldwide. Liver transplantation is the only possible treatment for those who advance to end-stage liver disease. Donors positive for hepatitis B virus (HBV) core antibody (HBcAb) have previously been considered unsuitable for transplants. However, those who test negative for the more serious hepatitis B surface antigen can now be used as liver donors, thereby reducing organ shortages. Remarkable improvements have been made in the treatment against HBV, most notably with the development of nucleoside analogues (NAs), which markedly lessen cirrhosis and reduce post-transplantation HBV recurrence. However, HBV recurrence still occurs in many patients following liver transplantation due to the development of drug resistance and poor compliance with therapy. Optimized prophylactic treatment with appropriate NA usage is crucial prior to liver transplantation, and undetectable HBV DNA at the time of transplantation should be achieved. NA-based and hepatitis B immune globulin based treatment regimens can differ between patients depending on the patients' condition, virus status, and presence of drug resistance. This review focuses on the current progress in applying NAs during the perioperative period of liver transplantation and the prophylactic strategies using NAs to prevent de novo HBV infection in recipients of HBcAb-positive liver grafts. PMID- 26576095 TI - Hepatitis C virus infection: Are there still specific problems with genotype 3? AB - Hepatitis C virus (HCV) infection is one of the most common causes of chronic liver disease and the main indication for liver transplantation worldwide. As promising specific treatments have been introduced for genotype 1, clinicians and researchers are now focusing on patients infected by non-genotype 1 HCV, particularly genotype 3. Indeed, in the golden era of direct-acting antiviral drugs, genotype 3 infections are no longer considered as easy to treat and are associated with higher risk of developing severe liver injuries, such as cirrhosis and hepatocellular carcinoma. Moreover, HCV genotype 3 accounts for 40% of all HCV infections in Asia and is the most frequent genotype among HCV positive injecting drug users in several countries. Here, we review recent data on HCV genotype 3 infection/treatment, including clinical aspects and the underlying genotype-specific molecular mechanisms. PMID- 26576096 TI - Role of matrix metalloproteinases in cholestasis and hepatic ischemia/reperfusion injury: A review. AB - Matrix metalloproteinases (MMPs) are a family of proteases using zinc-dependent catalysis to break down extracellular matrix (ECM) components, allowing cell movement and tissue reorganization. Like many other proteases, MMPs are produced as zymogens, an inactive form, which are activated after their release from cells. Hepatic ischemia/reperfusion (I/R) is associated with MMP activation and release, with profound effects on tissue integrity: their inappropriate, prolonged or excessive expression has harmful consequences for the liver. Kupffer cells and hepatic stellate cells can secrete MMPs though sinusoidal endothelial cells are a further source of MMPs. After liver transplantation, biliary complications are mainly attributable to cholangiocytes, which, compared with hepatocytes, are particularly susceptible to injury and ultimately a major cause of increased graft dysfunction and patient morbidity. This paper focuses on liver I/R injury and cholestasis and reviews factors and mechanisms involved in MMP activation together with synthetic compounds used in their regulation. In this respect, recent data have demonstrated that the role of MMPs during I/R may go beyond the mere destruction of the ECM and may be much more complex than previously thought. We thus discuss the role of MMPs as an important factor in cholestasis associated with I/R injury. PMID- 26576098 TI - Is liver biopsy still needed in children with chronic viral hepatitis? AB - Liver biopsy is a standard method used for obtaining liver tissue for histopathological evaluation. Since reliable serological and virological tests are currently available, liver biopsy is no longer needed for the etiological diagnosis of chronic hepatitis B and C. However, liver histology remains the gold standard as a prognostic tool, providing information about the liver disease progression (grading of necroinflammatory activity and staging of fibrosis) and serving clinicians in the management and therapeutic decisions. In general, histopathological evaluation is indicated before starting the antiviral treatment. Main limitations of the liver biopsy include its invasive and painful procedure, sampling errors and the inter- and intra-observer variability. In addition, indications for the liver biopsy in pediatric patients with chronic viral hepatitis were questioned recently, and efforts have been made toward the development of non-invasive methods as an alternative to the liver biopsy. The most commonly used methods are novel imaging studies (elastography) and combinations of biomarkers. However, to date, none of these tests was validated in children with chronic viral hepatitis. In this review, we present the current status of the liver biopsy in the management of chronic viral hepatitis B and C in pediatric population, including specific indications, complications, contraindications, problems, limitations, and alternative non-invasive methods. PMID- 26576097 TI - Acute-on-chronic liver failure: Pathogenesis, prognostic factors and management. AB - Acute-on-chronic liver failure (ACLF) is increasingly recognized as a complex syndrome that is reversible in many cases. It is characterized by an acute deterioration of liver function in the background of a pre-existing chronic liver disease often associated with a high short-term mortality rate. Organ failure (OF) is always associated, and plays a key role in determining the course, and the outcome of the disease. The definition of ACLF remains controversial due to its overall ambiguity, with several disparate criteria among various associations dedicated to the study of liver diseases. Although the precise pathogenesis needs to be clarified, it appears that an altered host response to injury might be a contributing factor caused by immune dysfunction, ultimately leading to a pro inflammatory status, and eventually to OF. The PIRO concept (Predisposition, Insult, Response and Organ Failure) has been proposed to better approach the underlying mechanisms. It is accepted that ACLF is a different and specific form of liver failure, where a precipitating event is always involved, even though it cannot always be ascertained. According to several studies, infections and active alcoholism often trigger ACLF. Viral hepatitis, gastrointestinal haemorrhage, or drug induced liver injury, which can also provoke the syndrome. This review mainly focuses on the physiopathology and prognostic aspects. We believe these features are essential to further understanding and providing the rationale for improveddisease management strategies. PMID- 26576099 TI - Oncogenic role of p21 in hepatocarcinogenesis suggests a new treatment strategy. AB - A well-known tumor suppressor, p21, acts paradoxically by promoting tumor growth in some cellular conditions. These conflicting functions have been demonstrated in association with the HBx gene and in hepatocarcinogenesis. The molecular behavior of p21 depends on its subcellular localization. Nuclear p21 may inhibit cell proliferation and be proapoptotic, while cytoplasmic p21 may have oncogenic and anti-apoptotic functions. Because most typical tumor suppressive proteins also have different effects according to subcellular localization, elucidating the regulatory mechanisms underlying nucleo-cytoplasmic transport of these proteins would be significant and may lead to a new strategy for anti hepatocellular carcinoma (HCC) therapy. Chromosome region maintenance 1 (CRM1) is a major nuclear export receptor involved in transport of tumor suppressors from nucleus to cytoplasm. Expression of CRM1 is enhanced in a variety of malignancies and in vitro studies have shown the efficacy of specific inhibition of CRM1 against cancer cell lines. Interestingly, interferon may keep p21 in the nucleus; this is one of the mechanisms of its anti-hepatocarcinogenic function. Here we review the oncogenic property of p21, which depends on its subcellular localization, and discuss the rationale underlying a new strategy for HCC treatment and prevention. PMID- 26576100 TI - Transposon mouse models to elucidate the genetic mechanisms of hepatitis B viral induced hepatocellular carcinoma. AB - The major type of human liver cancer is hepatocellular carcinoma (HCC), and there are currently many risk factors that contribute to this deadly disease. The majority of HCC occurrences are associated with chronic hepatitis viral infection, and hepatitis B viral (HBV) infection is currently a major health problem in Eastern Asia. Elucidating the genetic mechanisms associated with HBV induced HCC has been difficult due to the heterogeneity and genetic complexity associated with this disease. A repertoire of animal models has been broadly used to study the pathophysiology and to develop potential treatment regimens for HBV associated HCC. The use of these animal models has provided valuable genetic information and has been an important contributor to uncovering the factors involved in liver malignant transformation, invasion and metastasis. Recently, transposon-based mouse models are becoming more widely used in liver cancer research to interrogate the genome by forward genetics and also used to validate genes rapidly in a reverse genetic manner. Importantly, these transposon-based rapid reverse genetic mouse models could become crucial in testing potential therapeutic agents before proceeding to clinical trials in human. Therefore, this review will cover the use of transposon-based mouse models to address the problems of liver cancer, especially HBV-associated HCC occurrences in Asia. PMID- 26576101 TI - Hypoxia inducible factor in hepatocellular carcinoma: A therapeutic target. AB - Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed and deadly cancers worldwide; its incidence has been rising in the United States due to the increase in hepatitis C associated cirrhosis and the growing epidemic of obesity. There have been no effective therapeutic options in the advanced disease setting beyond sorafenib, a multi-targeted tyrosine kinase inhibitor that showed significant survival benefit. Because of this, there is an urgent need to search for novel pathways in sorafenib experienced patients. This review will focus on the role of hypoxia and hypoxia-inducible factor alpha (HIF-1alpha) in cancer development, specifically in HCC. We will discuss the biology of HIF-1alpha, the pathways with which it interacts, and the function of HIF-1alpha in HCC. Furthermore, we will review studies highlighting the relevance of HIF-1alpha in the clinical setting, as well as the pre-clinical data supporting its further investigation. Finally, we will conclude with a discussion of the potential role of a HIF-1alpha mRNA antagonist for the treatment of HCC, and hypothesize the ways in which such an inhibitor may be best utilized in the management of advanced HCC. Hypoxia plays a significant role in the development of HCC. HIF 1alpha is a key transcription factor involved in the hypoxic response of cancer cells. It activates transcription of genes responsible for angiogenesis, glucose metabolism, proliferation, invasion and metastasis in HCC. Its involvement in multiple, essential tumor pathways makes it an attractive potential therapeutic target in HCC. PMID- 26576102 TI - Autoimmune gastritis: Pathologist's viewpoint. AB - Western countries are seeing a constant decline in the incidence of Helicobacter pylori-associated gastritis, coupled with a rising epidemiological and clinical impact of autoimmune gastritis. This latter gastropathy is due to autoimmune aggression targeting parietal cells through a complex interaction of auto antibodies against the parietal cell proton pump and intrinsic factor, and sensitized T cells. Given the specific target of this aggression, autoimmune gastritis is typically restricted to the gastric corpus-fundus mucosa. In advanced cases, the oxyntic epithelia are replaced by atrophic (and metaplastic) mucosa, creating the phenotypic background in which both gastric neuroendocrine tumors and (intestinal-type) adenocarcinomas may develop. Despite improvements in our understanding of the phenotypic changes or cascades occurring in this autoimmune setting, no reliable biomarkers are available for identifying patients at higher risk of developing a gastric neoplasm. The standardization of autoimmune gastritis histology reports and classifications in diagnostic practice is a prerequisite for implementing definitive secondary prevention strategies based on multidisciplinary diagnostic approaches integrating endoscopy, serology, histology and molecular profiling. PMID- 26576103 TI - Research progress and prospects of markers for liver cancer stem cells. AB - Liver cancer is a common malignancy and surgery is the main treatment strategy. However, the prognosis is still poor because of high frequencies of postoperative recurrence and metastasis. In recent years, cancer stem cell (CSC) theory has evolved with the concept of stem cells, and has been applied to oncological research. According to cancer stem cell theory, liver cancer can be radically cured only by eradication of liver cancer stem cells (LCSCs). This notion has lead to the isolation and identification of LCSCs, which has become a highly researched area. Analysis of LCSC markers is considered to be the primary method for identification of LCSCs. Here, we provide an overview of the current research progress and prospects of surface markers for LCSCs. PMID- 26576104 TI - Hepatocellular carcinoma in the elderly: Meta-analysis and systematic literature review. AB - AIM: To conduct a meta-analysis to investigate the clinical outcomes of surgical resection and locoregional treatments for hepatocellular carcinoma (HCC) in elderly patients defined as aged 70 years or more. METHODS: Literature documenting a comparison of clinical outcomes for elderly and non elderly patients with hepatocellular carcinoma was identified by searching PubMed, Ovid, Cochrane Library, and Web of Science databases, for those from inception to March 2015 with no limits. Dichotomous outcomes and standard meta-analysis techniques were used. Heterogeneity was tested by the Cochrane Q statistic. Pooled estimates were measured using the fixed or random effect model. RESULTS: Twenty three studies were included with a total of 12482 patients. Of these patients, 6341 were treated with surgical resection, 3138 were treated with radiofrequency ablation (RFA), and 3003 were treated with transarterial chemoembolization (TACE). Of the patients who underwent surgical resection, the elderly had significantly more respiratory co-morbidities than the younger group, with both groups having a similar proportion of cardiovascular co-morbidities and diabetes. After 1 year, the elderly group had significantly increased survival rates after surgical resection compared to the younger group (OR = 0.762, 95%CI: 0.583-0.994, P = 0.045). However, the 3-year and 5-year survival outcomes with surgical resection between the two groups were similar (OR = 0.947, 95%CI: 0.777-1.154, P = 0.67 for the third year; and OR = 1.131, 95%CI: 0.895-1.430, P = 0.304 for the fifth year). Postoperative treatment complications were similar between the elderly and younger group. The elderly group and younger group had similar survival outcomes for the first and third year after RFA (OR = 1.5, 95%CI: 0.788 2.885, P = 0.217 and OR = 1.352, 95%CI: 0.940-1.944, P = 0.104). For the fifth year, the elderly group had significantly worse survival rates compared to the younger group after RFA (OR = 1.379, 95%CI: 1.079-1.763, P = 0.01). For patients who underwent TACE, the elderly group had significantly increased survival compared to the younger group for the first and third year (OR = 0.664, 95%CI: 0.548-0.805, P = 0.00 and OR = 0.795, 95%CI: 0.663-0.953, P = 0.013). At the fifth year, there were no significant differences in overall survival between the elderly group and younger group (OR = 1.256, 95%CI: 0.806-1.957, P = 0.313). CONCLUSION: The optimal management strategy for elderly patients with HCC is dependent on patient and tumor characteristics. Compared to patients less than 70, elderly patients have similar three year survival after resection and ablation and an improved three year survival after TACE. At five years, elderly patients had a lower survival after ablation but similar survival with resection and TACE as compared to younger patients. Heterogeneity of patient populations and selection bias can explain some of these findings. Overall, elderly patients have similar success, if not better, with these treatments and should be considered for all treatments after assessment of their clinical status and cancer burden. PMID- 26576105 TI - BAYESIAN INFERENCE OF HIDDEN GAMMA WEAR PROCESS MODEL FOR SURVIVAL DATA WITH TIES. AB - Survival data often contain tied event times. Inference without careful treatment of the ties can lead to biased estimates. This paper develops the Bayesian analysis of a stochastic wear process model to fit survival data that might have a large number of ties. Under a general wear process model, we derive the likelihood of parameters. When the wear process is a Gamma process, the likelihood has a semi-closed form that allows posterior sampling to be carried out for the parameters, hence achieving model selection using Bayesian deviance information criterion. An innovative simulation algorithm via direct forward sampling and Gibbs sampling is developed to sample event times that may have ties in the presence of arbitrary covariates; this provides a tool to assess the precision of inference. An extensive simulation study is reported and a data set is used to further illustrate the proposed methodology. PMID- 26576106 TI - Systematic Review and Meta-Analysis of Studies Evaluating Diagnostic Test Accuracy: A Practical Review for Clinical Researchers-Part I. General Guidance and Tips. AB - In the field of diagnostic test accuracy (DTA), the use of systematic review and meta-analyses is steadily increasing. By means of objective evaluation of all available primary studies, these two processes generate an evidence-based systematic summary regarding a specific research topic. The methodology for systematic review and meta-analysis in DTA studies differs from that in therapeutic/interventional studies, and its content is still evolving. Here we review the overall process from a practical standpoint, which may serve as a reference for those who implement these methods. PMID- 26576107 TI - Systematic Review and Meta-Analysis of Studies Evaluating Diagnostic Test Accuracy: A Practical Review for Clinical Researchers-Part II. Statistical Methods of Meta-Analysis. AB - Meta-analysis of diagnostic test accuracy studies differs from the usual meta analysis of therapeutic/interventional studies in that, it is required to simultaneously analyze a pair of two outcome measures such as sensitivity and specificity, instead of a single outcome. Since sensitivity and specificity are generally inversely correlated and could be affected by a threshold effect, more sophisticated statistical methods are required for the meta-analysis of diagnostic test accuracy. Hierarchical models including the bivariate model and the hierarchical summary receiver operating characteristic model are increasingly being accepted as standard methods for meta-analysis of diagnostic test accuracy studies. We provide a conceptual review of statistical methods currently used and recommended for meta-analysis of diagnostic test accuracy studies. This article could serve as a methodological reference for those who perform systematic review and meta-analysis of diagnostic test accuracy studies. PMID- 26576108 TI - Imaging Findings of Liposuction with an Emphasis on Postsurgical Complications. AB - Liposuction is one of the most frequently performed cosmetic surgeries worldwide for reshaping the body contour. Although liposuction is minimally invasive and relatively safe, it is a surgical procedure, and it carries the risk of major and minor complications. These complications vary from postoperative nausea to life threatening events. Common complications include infection, abdominal wall injury, bowel herniation, bleeding, haematoma, seroma, and lymphoedema. Life threatening complications such as necrotizing fasciitis, deep vein thrombosis, and pulmonary embolism have also been reported. In this paper, we provide a brief introduction to liposuction with the related anatomy and present computed tomography and ultrasonography findings of a wide spectrum of postoperative complications associated with liposuction. PMID- 26576109 TI - Troubleshooting Arterial-Phase MR Images of Gadoxetate Disodium-Enhanced Liver. AB - Gadoxetate disodium is a widely used magnetic resonance (MR) contrast agent for liver MR imaging, and it provides both dynamic and hepatobiliary phase images. However, acquiring optimal arterial phase images at liver MR using gadoxetate disodium is more challenging than using conventional extracellular MR contrast agent because of the small volume administered, the gadolinium content of the agent, and the common occurrence of transient severe motion. In this article, we identify the challenges in obtaining high-quality arterial-phase images of gadoxetate disodium-enhanced liver MR imaging and present strategies for optimizing arterial-phase imaging based on the thorough review of recent research in this field. PMID- 26576110 TI - Reduced Field-of-View Diffusion-Weighted Magnetic Resonance Imaging of the Pancreas: Comparison with Conventional Single-Shot Echo-Planar Imaging. AB - OBJECTIVE: To investigate the image quality (IQ) and apparent diffusion coefficient (ADC) of reduced field-of-view (FOV) di-ffusion-weighted imaging (DWI) of pancreas in comparison with full FOV DWI. MATERIALS AND METHODS: In this retrospective study, 2 readers independently performed qualitative analysis of full FOV DWI (FOV, 38 * 38 cm; b-value, 0 and 500 s/mm(2)) and reduced FOV DWI (FOV, 28 * 8.5 cm; b-value, 0 and 400 s/mm(2)). Both procedures were conducted with a two-dimensional spatially selective radiofrequency excitation pulse, in 102 patients with benign or malignant pancreatic diseases (mean size, 27.5 +/- 14.4 mm). The study parameters included 1) anatomic structure visualization, 2) lesion conspicuity, 3) artifacts, 4) IQ score, and 5) subjective clinical utility for confirming or excluding initially considered differential diagnosis on conventional imaging. Another reader performed quantitative ADC measurements of focal pancreatic lesions and parenchyma. Wilcoxon signed-rank test was used to compare qualitative scores and ADCs between DWI sequences. Mann Whitney U-test was used to compare ADCs between the lesions and parenchyma. RESULTS: On qualitative analysis, reduced FOV DWI showed better anatomic structure visualization (2.76 +/- 0.79 at b = 0 s/mm(2) and 2.81 +/- 0.64 at b = 400 s/mm(2)), lesion conspicuity (3.11 +/- 0.99 at b = 0 s/mm(2) and 3.15 +/- 0.79 at b = 400 s/mm(2)), IQ score (8.51 +/- 2.05 at b = 0 s/mm(2) and 8.79 +/- 1.60 at b = 400 s/mm(2)), and higher clinical utility (3.41 +/- 0.64), as compared to full FOV DWI (anatomic structure, 2.18 +/- 0.59 at b = 0 s/mm(2) and 2.56 +/- 0.47 at b = 500 s/mm(2); lesion conspicuity, 2.55 +/- 1.07 at b = 0 s/mm(2) and 2.89 +/- 0.86 at b = 500 s/mm(2); IQ score, 7.13 +/- 1.83 at b = 0 s/mm(2) and 8.17 +/- 1.31 at b = 500 s/mm(2); clinical utility, 3.14 +/- 0.70) (p < 0.05). Artifacts were significantly improved on reduced FOV DWI (2.65 +/- 0.68) at b = 0 s/mm(2) (full FOV DWI, 2.41 +/- 0.63) (p < 0.001). On quantitative analysis, there were no significant differences between the 2 DWI sequences in ADCs of various pancreatic lesions and parenchyma (p > 0.05). ADCs of adenocarcinomas (1.061 * 10(-3) mm(2)/s +/- 0.133 at reduced FOV and 1.079 * 10(-3) mm(2)/s +/- 0.135 at full FOV) and neuroendocrine tumors (0.983 * 10(-3) mm(2)/s +/- 0.152 at reduced FOV and 1.004 * 10(-3) mm(2)/s +/- 0.153 at full FOV) were significantly lower than those of parenchyma (1.191 * 10(-3) mm(2)/s +/- 0.125 at reduced FOV and 1.218 * 10(-3) mm(2)/s +/- 0.103 at full FOV) (p < 0.05). CONCLUSION: Reduced FOV DWI of the pancreas provides better overall IQ including better anatomic detail, lesion conspicuity and subjective clinical utility. PMID- 26576111 TI - Ultrasound-Guided Percutaneous Radiofrequency Ablation of Liver Tumors: How We Do It Safely and Completely. AB - Ultrasound-guided percutaneous radiofrequency (RF) ablation has become one of the most promising local cancer therapies for both resectable and nonresectable hepatic tumors. Although RF ablation is a safe and effective technique for the treatment of liver tumors, the outcome of treatment can be closely related to the location and shape of the tumors. There may be difficulties with RF ablation of tumors that are adjacent to large vessels or extrahepatic heat-vulnerable organs and tumors in the caudate lobe, possibly resulting in major complications or treatment failure. Thus, a number of strategies have been developed to overcome these challenges, which include artificial ascites, needle track ablation, fusion imaging guidance, parallel targeting, bypass targeting, etc. Operators need to use the right strategy in the right situation to avoid the possibility of complications and incomplete thermal tissue destruction; with the right strategy, RF ablation can be performed successfully, even for hepatic tumors in high-risk locations. This article offers technical strategies that can be used to effectively perform RF ablation as well as to minimize possible complications related to the procedure with representative cases and schematic illustrations. PMID- 26576112 TI - MRI Findings of Intrinsic and Extrinsic Duodenal Abnormalities and Variations. AB - This pictorial review aims to illustrate the magnetic resonance imaging (MRI) findings and presentation patterns of anatomical variations and various benign and malignant pathologies of the duodenum, including sphincter contraction, major papilla variation, prominent papilla, diverticulum, annular pancreas, duplication cysts, choledochocele, duodenal wall thickening secondary to acute pancreatitis, postbulbar stenosis, celiac disease, fistula, choledochoduodenostomy, external compression, polyps, Peutz-Jeghers syndrome, ampullary carcinoma and adenocarcinoma. MRI is a useful imaging tool for demonstrating duodenal pathology and its anatomic relationships with adjacent organs, which is critical for establishing correct diagnosis and planning appropriate treatment, especially for surgery. PMID- 26576113 TI - Pancreatic Candidiasis That Mimics a Malignant Pancreatic Cystic Tumor on Magnetic Resonance Imaging: A Case Report in an Immunocompetent Patient. AB - Candida is a commensal organism that is frequently found in the human gastrointestinal tract. It is the most common organism that causes pancreatic fungal infections. However, magnetic resonance imaging findings of Candida infection in the pancreas have not been described. We report imaging findings of pancreatic candidiasis in a patient in immunocompetent condition. It presented as a multi-septated cystic mass with a peripheral solid component in the background of pancreatitis and restricted diffusion on diffusion-weighted image that mimicked a malignant pancreatic cystic tumor. PMID- 26576114 TI - F-18 Fluoride Positron Emission Tomography-Computed Tomography for Detecting Atherosclerotic Plaques. AB - A large number of major cardiovascular events occur in patients due to minimal or some lumen narrowing of the coronary artery. Recent biological studies have shown that the biological composition or vulnerability of the plaque is more critical for plaque rupture compared to the degree of stenosis. To overcome the limitations of anatomical images, molecular imaging techniques have been suggested as promising imaging tools in various fields. F-18 fluorodeoxyglucose (FDG), which is widely used in the field of oncology, is an example of molecular probes used in atherosclerotic plaque evaluation. FDG is a marker of plaque macrophage glucose utilization and inflammation, which is a prominent characteristic of vulnerable plaque. Recently, F-18 fluoride has been used to visualize vulnerable plaque in clinical studies. F-18 fluoride accumulates in regions of active microcalcification, which is normally observed during the early stages of plaque formation. More studies are warranted on the accumulation of F 18 fluoride and plaque formation/vulnerability; however, due to high specific accumulation, low background activity, and easy accessibility, F-18 fluoride is emerging as a promising non-invasive imaging probe to detect vulnerable plaque. PMID- 26576115 TI - Pulmonary Actinomycosis Imitating Lung Cancer on (18)F-FDG PET/CT: A Case Report and Literature Review. AB - Here we report a case of 41-year-old man with a soft tissue density mass at right upper lung and palpable abscesses at right upper backside and right wrist. (18)F fluorodeoxyglucose positron emission tomography/computed tomography demonstrated a 7.8 * 5.0 cm mass with soft-tissue density in the upper lobe of the right lung with high metabolic activity. The infiltrative mass extended to adjacent chest wall soft tissue. Final diagnosis of pulmonary actinomycosis with multiple abscesses was made. The patient responded well to antibiotics treatment. PMID- 26576116 TI - Are Irregular Hypoechoic Breast Masses on Ultrasound Always Malignancies?: A Pictorial Essay. AB - Irregular hypoechoic masses in the breast do not always indicate malignancies. Many benign breast diseases present with irregular hypoechoic masses that can mimic carcinoma on ultrasonography. Some of these diseases such as inflammation and trauma-related breast lesions could be suspected from a patient's symptoms and personal history. Careful ultrasonographic examination and biopsy could help to differentiate these from malignancies. PMID- 26576117 TI - Determining and Managing Fetal Radiation Dose from Diagnostic Radiology Procedures in Turkey. AB - OBJECTIVE: We intended to calculate approximate fetal doses in pregnant women who underwent diagnostic radiology procedures and to evaluate the safety of their pregnancies. MATERIALS AND METHODS: We contacted hospitals in different cities in Turkey where requests for fetal dose calculation are usually sent. Fetal radiation exposure was calculated for 304 cases in 218 pregnant women with gestational ages ranging from 5 days to 19 weeks, 2 days. FetDose software (ver. 4.0) was used in fetal dose calculations for radiographic and computed tomography (CT) procedures. The body was divided into three zones according to distance from the fetus. The first zone consisted of the head area, the lower extremities below the knee, and the upper extremities; the second consisted of the cervicothoracic region and upper thighs; and the third consisted of the abdominopelvic area. Fetal doses from radiologic procedures between zones were compared using the Kruskal-Wallis test and a Bonferroni-corrected Mann-Whitney U-test. RESULTS: The average fetal doses from radiography and CT in the first zone were 0.05 +/- 0.01 mGy and 0.81 +/- 0.04 mGy, respectively; 0.21 +/- 0.05 mGy and 1.77 +/- 0.22 mGy, respectively, in the second zone; and 6.42 +/- 0.82 mGy and 22.94 +/- 1.28 mGy, respectively, in the third zone (p < 0.001). Our results showed that fetal radiation exposures in our group of pregnant women did not reach the level (50 mGy) that is known to increase risk for congenital anomalies. CONCLUSION: Fetal radiation exposure in the diagnostic radiology procedures in our study did not reach risk levels that might have indicated abortion. PMID- 26576118 TI - The Safety and Clinical Outcomes of Chemoembolization in Child-Pugh Class C Patients with Hepatocellular Carcinomas. AB - OBJECTIVE: To evaluate the safety and clinical outcomes of chemoembolization in Child-Pugh class C patients with hepatocellular carcinomas (HCC). MATERIALS AND METHODS: The study comprised 55 patients with HCC who were classified as Child Pugh class C and who underwent initial chemoembolization between January 2003 and December 2012. Selective chemoembolization was performed in all technically feasible cases to minimize procedure-related complications. All adverse events within 30 days were recorded using the Common Terminology Criteria for Adverse Events (CTCAE). The tumor response to chemoembolization was evaluated using the modified Response Evaluation Criteria In Solid Tumors. RESULTS: Thirty (54.5%) patients were within the Milan criteria, and 25 (45.5%) were beyond. The mortality of study subjects at 30 days was 5.5%. Major complications were observed in five (9.1%) patients who were all beyond the Milan criteria: two hepatic failures, one hepatic encephalopathy, and two CTCAE grade 3 increases in aspartate aminotransferase/alanine aminotransferase abnormality. The mean length of hospitalization was 6.3 +/- 8.3 days (standard deviation), and 18 (32.7%) patients were discharged on the next day after chemoembolization. The tumor responses of the patients who met the Milan criteria were significantly higher (p = 0.014) than those of the patients who did not. The overall median survival was 7.1 months (95% confidence interval: 4.4-9.8 months). CONCLUSION: Even in patients with Child-Pugh class C, chemoembolization can be performed safely with a selective technique in selected cases with a small tumor burden. PMID- 26576119 TI - A New MRI Grading System for Cervical Foraminal Stenosis Based on Axial T2 Weighted Images. AB - OBJECTIVE: The purpose of this study was to evaluate the reliability of a new magnetic resonance imaging (MRI) grading system for cervical neural foraminal stenosis (NFS). MATERIALS AND METHODS: Cervical NFS at bilateral C4/5, C5/6, and C6/7 was classified into the following three grades based on the T2-weighted axial images: Grade 0 = absence of NFS, with the narrowest width of the neural foramen greater than the width of the extraforaminal nerve root (EFNR); Grade 1 = the narrowest width of the neural foramen the same or less than (but more than 50% of) the width of the EFNR; Grade 2 = the width of the neural foramen the same or less than 50% of the width of the EFNR. The MRIs of 96 patients who were over 60 years old (M:F = 50:46; mean age 68.4 years; range 61-86 years) were independently analyzed by seven radiologists. Interobserver and intraobserver agreements were analyzed using the percentage agreement, kappa statistics, and intraclass correlation coefficient (ICC). RESULTS: For the distinction among the three individual grades at all six neural foramina, the ICC ranged from 0.68 to 0.73, indicating fair to good reproducibility. The percentage agreement ranged from 60.2% to 70.6%, and the kappa values (kappa = 0.50-0.58) indicated fair to moderate agreement. The percentages of intraobserver agreement ranged from 85.4% to 93.8% (kappa = 0.80-0.92), indicating near perfect agreement. CONCLUSION: The new MRI grading system shows sufficient interobserver and intraobserver agreement to reliably assess cervical NFS. PMID- 26576120 TI - Accuracy of Diffusion Tensor Imaging for Diagnosing Cervical Spondylotic Myelopathy in Patients Showing Spinal Cord Compression. AB - OBJECTIVE: To assess the performance of diffusion tensor imaging (DTI) for the diagnosis of cervical spondylotic myelopathy (CSM) in patients with deformed spinal cord but otherwise unremarkable conventional magnetic resonance imaging (MRI) findings. MATERIALS AND METHODS: A total of 33 patients who underwent MRI of the cervical spine including DTI using two-dimensional single-shot interleaved multi-section inner volume diffusion-weighted echo-planar imaging and whose spinal cords were deformed but showed no signal changes on conventional MRI were the subjects of this study. Mean diffusivity (MD), longitudinal diffusivity (LD), radial diffusivity (RD), and fractional anisotropy (FA) were measured at the most stenotic level. The calculated performance of MD, FA, MD?FA (considered positive when both the MD and FA results were positive), LD?FA (considered positive when both the LD and FA results were positive), and RD?FA (considered positive when both the RD and FA results were positive) in diagnosing CSM were compared with each other based on the estimated cut-off values of MD, LD, RD, and FA from receiver operating characteristic curve analysis with the clinical diagnosis of CSM from medical records as the reference standard. RESULTS: The MD, LD, and RD cut-off values were 1.079 * 10(-3), 1.719 * 10(-3), and 0.749 * 10(-3) mm(2)/sec, respectively, and that of FA was 0.475. Sensitivity, specificity, positive predictive value and negative predictive value were: 100 (4/4), 44.8 (13/29), 20 (4/20), and 100 (13/13) for MD; 100 (4/4), 27.6 (8/29), 16 (4/25), and 100 (8/8) for FA; 100 (4/4), 58.6 (17/29), 25 (4/16), and 100 (17/17) for MD?FA; 100 (4/4), 68.9 (20/29), 30.8 (4/13), and 100 (20/20) for LD?FA; and 75 (3/4), 68.9 (20/29), 25 (3/12), and 95.2 (20/21) for RD?FA in percentage value. Diagnostic performance comparisons revealed significant differences only in specificity between FA and MD?FA (p = 0.003), FA and LD?FA (p < 0.001), FA and RD?FA (p < 0.001), MD and LD?FA (p = 0.024) and MD and RD?FA (p = 0.024). CONCLUSION: Fractional anisotropy combined with MD, RD, or LD is expected to be more useful than FA and MD for diagnosing CSM in patients who show deformed spinal cords without signal changes on MRI. PMID- 26576121 TI - Bone Tunnel Diameter Measured with CT after Anterior Cruciate Ligament Reconstruction Using Double-Bundle Auto-Hamstring Tendons: Clinical Implications. AB - OBJECTIVE: To evaluate the correlation between bone tunnel diameter after anterior cruciate ligament (ACL) reconstruction measured by computed tomography (CT) using multiplanar reconstruction (MPR) and stability or clinical scores. MATERIALS AND METHODS: Forty-seven patients (41 men and 6 women, mean age: 34 years) who had undergone ACL reconstruction with the double bundle technique using auto-hamstring graft and had subsequently received CT scans immediately after the surgery (T1: range, 1-4 days, mean, 2.5 days) and at a later time (T2: range, 297-644 days, mean, 410.4 days) were enrolled in this study. The diameter of each tunnel (two femoral and two tibial) at both T1 and T2 were independently measured using MPR technique by two radiologists. Stability and clinical scores were evaluated with a KT-2000 arthrometer, International Knee Documentation Committee objective scores, and the Lysholm score. Statistical analysis of the correlation between the diameter at T2 or the interval diameter change ratio ([T2 - T1] / T1) and clinical scores or stability was investigated. RESULTS: The tibial bone tunnels for the anteromedial bundles were significantly widened at T2 compared with T1 (observer 1, 0.578 mm to 0.698 mm, p value of < 0.001; observer 2, 0.581 mm to 0.707 mm, p value of < 0.001). There was no significant correlation between the diameter at T2 and stability or clinical scores and between the interval change ratio ([T2 - T1] / T1) and stability or clinical scores (corrected p values for all were 1.0). Intraobserver agreement for measurements was excellent (> 0.8) for both observers. Interobserver agreement for measurement was excellent (> 0.8) except for the most distal portion of the femoral bone tunnel for anterior medial bundle in immediate postoperative CT, which showed moderate agreement (concordance correlation coefficient = 0.6311). CONCLUSION: Neither the diameter nor its change ratio during interval follow-up is correlated with stability or clinical scores. PMID- 26576122 TI - Associations between Alpha Angle and Herniation Pit on MRI Revisited in 185 Asymptomatic Hip Joints. AB - OBJECTIVE: To evaluate the association between alpha angle and herniation pit on MRI in asymptomatic hip joints and their associations with demographic variables. MATERIALS AND METHODS: Hip MRI of 185 asymptomatic hip joints of 105 adults (age 18 to 80 years) from September 2011 through December 2012 were retrospectively studied. Alpha angles were measured on oblique axial MR images by 2 observers. Herniation pit was determined by 1 observer. Size measures, prevalence, and statistical analyses were conducted regarding its association with age, gender, laterality (right or left hip). Intra- and inter-observer agreements were determined by intra-class correlation coefficient. RESULTS: The prevalence of herniation pit in asymptomatic hips was 21.6%. The range of alpha angle was 27.6 65.0 degrees. Seventeen and 16 out of 185 (9.1% and 8.6%) hip joints showed alpha angle of >= 55 degrees in first and second measurement sessions, respectively. There was no association between alpha angle >= 55 and presence of herniation pit. There was no association between alpha angle >= 55 and the size of herniation pit. Inter-observer agreement of alpha angle was 0.485 between first measurements of first vs. second observer, respectively. Intra-observer agreement of alpha angle was 0.654, respectively. Forty (21.6%) of 185 hip joints (35 of 105 patients, 33.3%) had herniation pit, with no difference according to age, gender, or laterality of hip joint. CONCLUSION: There is no association between alpha angle >= 55 degrees and presence of herniation pit or demographic variables. PMID- 26576123 TI - Ultrasound-Guided Percutaneous Removal of Wooden Foreign Bodies in the Extremities with Hydro-Dissection Technique. AB - OBJECTIVE: We described the technique of ultrasound (US)-guided percutaneous removal of the foreign bodies (FB) with hydro-dissection in the radiologic department and presented video files of several cases. MATERIALS AND METHODS: Four patients referred to the radiology department for US evaluation and US guided percutaneous removal of the FBs in the upper and lower extremities between November, 2006 and November, 2013 were included in this study. The procedures started with US evaluation for the exact location and shape of the FB. A 5 mm sized skin incision was made at the site of the nearest point from the FB where no passing arteries or tendons were present. We adopted a hydrodissection technique to separate the FB from adjacent tissue using a 2% lidocaine solution. Injected anesthetics detached the FBs from surrounding tissue and thereby facilitated removal. After the tip of the mosquito forceps reached the FB, the wooden FBs were removed. RESULTS: The mean time required for the entire procedure was approximately 20 minutes. There were no significant complications during the US-guided removal or long-term complications after the procedure. All 4 FBs were successfully removed from the soft tissue under US guidance. CONCLUSION: Ultrasound-guided percutaneous removal of the FBs with hydro-dissection in the radiology department is a less invasive and safe method over surgical removal in the operating room. Additionally, the use of a guide wire and serial dilator may help minimize soft tissue injury and facilitate the introduction of forceps. PMID- 26576124 TI - Radiofrequency versus Ethanol Ablation for Treating Predominantly Cystic Thyroid Nodules: A Randomized Clinical Trial. AB - OBJECTIVE: To compare single-session radiofrequency ablation (RFA) and ethanol ablation (EA) for treating predominantly cystic thyroid nodules (PCTNs). MATERIALS AND METHODS: This single-blind, randomized trial was approved by the Institutional Review Board of two centers and informed consent was obtained from all patients before enrollment. Fifty patients with a single PCTN (cystic portion less than 90% and greater than 50%) were randomly assigned to be treated by either RFA (25 patients) or EA (25 patients) at two hospitals. The primary outcome was the tumor volume reduction ratio (%) at the six-month follow-up and the superiority margin was set at 13% (RFA minus EA). Analysis was performed primarily in an intention-to-treat manner. The secondary outcomes were the therapeutic success rate, improvement of symptomatic and cosmetic problems, and the number of major complications. RESULTS: The mean volume reduction was 87.5 +/ 11.5% for RFA (n = 22) and 82.4 +/- 28.6% for EA (n = 24) (p = 0.710; mean difference [95% confidence interval], 5.1% [-8.0 to 18.2]), indicating no significant difference. Regarding the secondary outcomes, therapeutic success (p = 0.490), mean symptom (p = 0.205) and cosmetic scores (p = 0.710) showed no difference. There were no major complications in either group (p > 0.99). CONCLUSION: The therapeutic efficacy of RFA is not superior to that of EA; therefore, EA might be preferable as the first-line treatment for PCTNs. PMID- 26576125 TI - Prediction of Response to Concurrent Chemoradiotherapy with Temozolomide in Glioblastoma: Application of Immediate Post-Operative Dynamic Susceptibility Contrast and Diffusion-Weighted MR Imaging. AB - OBJECTIVE: To determine whether histogram values of the normalized apparent diffusion coefficient (nADC) and normalized cerebral blood volume (nCBV) maps obtained in contrast-enhancing lesions detected on immediate post-operative MR imaging can be used to predict the patient response to concurrent chemoradiotherapy (CCRT) with temozolomide (TMZ). MATERIALS AND METHODS: Twenty four patients with GBM who had shown measurable contrast enhancement on immediate post-operative MR imaging and had subsequently undergone CCRT with TMZ were retrospectively analyzed. The corresponding histogram parameters of nCBV and nADC maps for measurable contrast-enhancing lesions were calculated. Patient groups with progression (n = 11) and non-progression (n = 13) at one year after the operation were identified, and the histogram parameters were compared between the two groups. Receiver operating characteristic (ROC) analysis was used to determine the best cutoff value for predicting progression. Progression-free survival (PFS) was determined with the Kaplan-Meier method and the log-rank test. RESULTS: The 99th percentile of the cumulative nCBV histogram (nCBV C99) on immediate post-operative MR imaging was a significant predictor of one-year progression (p = 0.033). ROC analysis showed that the best cutoff value for predicting progression after CCRT was 5.537 (sensitivity and specificity were 72.7% and 76.9%, respectively). The patients with an nCBV C99 of < 5.537 had a significantly longer PFS than those with an nCBV C99 of >= 5.537 (p = 0.026). CONCLUSION: The nCBV C99 from the cumulative histogram analysis of the nCBV from immediate post-operative MR imaging may be feasible for predicting glioblastoma response to CCRT with TMZ. PMID- 26576126 TI - Radiologic and Pathologic Findings of a Follicular Variant of Papillary Thyroid Cancer with Extensive Stromal Fat: A Case Report. AB - Thyroid cancer may have small adipose structures detected by microscopy. However, there are no reports of thyroid cancer with gross fat evaluated by radiological methods. We reported a case of a 58-year-old woman with a fat containing thyroid mass. The mass was hyperechoic and ovoid in shape with a smooth margin on ultrasonography. On computed tomography, the mass had markedly low attenuation suggestive of fat, and fine reticular and thick septa-like structures. The patient underwent a right lobectomy. The mass was finally diagnosed as a follicular variant of papillary thyroid cancer with massive stromal fat. PMID- 26576127 TI - Subtraction MR Venography Acquired from Time-Resolved Contrast-Enhanced MR Angiography: Comparison with Phase-Contrast MR Venography and Single-Phase Contrast-Enhanced MR Venography. AB - OBJECTIVE: To evaluate the image characteristics of subtraction magnetic resonance venography (SMRV) from time-resolved contrast-enhanced MR angiography (TRMRA) compared with phase-contrast MR venography (PCMRV) and single-phase contrast-enhanced MR venography (CEMRV). MATERIALS AND METHODS: Twenty-one patients who underwent brain MR venography (MRV) using standard protocols (PCMRV, CEMRV, and TRMRA) were included. SMRV was made by subtracting the arterial phase data from the venous phase data in TRMRA. Co-registration and subtraction of the two volume data was done using commercially available software. Image quality and the degree of arterial contamination of the three MRVs were compared. In the three MRVs, 19 pre-defined venous structures (14 dural sinuses and 5 cerebral veins) were evaluated. The signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) of the three MRVs were also compared. RESULTS: Single-phase contrast enhanced MR venography showed better image quality (median score 4 in both reviewers) than did the other two MRVs (p < 0.001), whereas SMRV (median score 3 in both reviewers) and PCMRV (median score 3 in both reviewers) had similar image quality (p >= 0.951). SMRV (median score 0 in both reviewers) suppressed arterial signal better than did the other MRVs (median score 1 in CEMRV, median score 2 in PCMRV, both reviewers) (p < 0.001). The dural sinus score of SMRV (median and interquartile range [IQR] 48, 43-50 for reviewer 1, 47, 43-49 for reviewer 2) was significantly higher than for PCMRV (median and IQR 31, 25-34 for reviewer 1, 30, 23-32 for reviewer 2) (p < 0.01) and did not differ from that of CEMRV (median and IQR 50, 47-52 for reviewer 1, 49, 45-51 for reviewer 2) (p = 0.146 in reviewer 1 and 0.123 in reviewer 2). The SNR and CNR of SMRV (median and IQR 104.5, 83.1-121.2 and 104.1, 74.9-120.5, respectively) were between those of CEMRV (median and IQR 150.3, 111-182.6 and 148.4, 108-178.2) and PCMRV (median and IQR 59.4, 49.2-74.9 and 53.6, 43.8-69.2). CONCLUSION: Subtraction magnetic resonance venography is a promising MRV method, with acceptable image quality and good arterial suppression. PMID- 26576129 TI - Erratum: Shear Wave Elastography for Detection of Prostate Cancer: A Preliminary Study. AB - [This corrects the article on p. 346 in vol. 15, PMID: 24843239.]. PMID- 26576128 TI - Ultrasonographic Diagnosis of Biliary Atresia Based on a Decision-Making Tree Model. AB - OBJECTIVE: To assess the diagnostic value of various ultrasound (US) findings and to make a decision-tree model for US diagnosis of biliary atresia (BA). MATERIALS AND METHODS: From March 2008 to January 2014, the following US findings were retrospectively evaluated in 100 infants with cholestatic jaundice (BA, n = 46; non-BA, n = 54): length and morphology of the gallbladder, triangular cord thickness, hepatic artery and portal vein diameters, and visualization of the common bile duct. Logistic regression analyses were performed to determine the features that would be useful in predicting BA. Conditional inference tree analysis was used to generate a decision-making tree for classifying patients into the BA or non-BA groups. RESULTS: Multivariate logistic regression analysis showed that abnormal gallbladder morphology and greater triangular cord thickness were significant predictors of BA (p = 0.003 and 0.001; adjusted odds ratio: 345.6 and 65.6, respectively). In the decision-making tree using conditional inference tree analysis, gallbladder morphology and triangular cord thickness (optimal cutoff value of triangular cord thickness, 3.4 mm) were also selected as significant discriminators for differential diagnosis of BA, and gallbladder morphology was the first discriminator. The diagnostic performance of the decision-making tree was excellent, with sensitivity of 100% (46/46), specificity of 94.4% (51/54), and overall accuracy of 97% (97/100). CONCLUSION: Abnormal gallbladder morphology and greater triangular cord thickness (> 3.4 mm) were the most useful predictors of BA on US. We suggest that the gallbladder morphology should be evaluated first and that triangular cord thickness should be evaluated subsequently in cases with normal gallbladder morphology. PMID- 26576130 TI - Erratum: Relationship between Myocardial Extracellular Space Expansion Estimated with Post-Contrast T1 Mapping MRI and Left Ventricular Remodeling and Neurohormonal Activation in Patients with Dilated Cardiomyopathy. AB - [This corrects the article on p. 1153 in vol. 16, PMID: 26355278.]. PMID- 26576132 TI - Asthma under/misdiagnosis in primary care setting: an observational community based study in Italy. AB - BACKGROUND: Published data suggest that asthma is significantly under/misdiagnosed. The present community-based study performed in Italy aims at investigating the level of asthma under/misdiagnosis among patients referring to the General Practitioner (GP) for respiratory symptoms and undergoing Inhaled corticosteroids. METHODS: A sub-analysis of a previously published observational cross-sectional study has been provided. It included subjects registered in the GP databases with at least three prescriptions of inhaled or nebulised corticosteroids during the 12 months preceding the start of the study. All subjects, independently of the diagnosis, were invited to visit their GP's office for a standardised interview and to fill the European Community Respiratory Health Survey (ECRHS) questionnaire. RESULTS: The studies involved 540 GPs in most of the Italian regions and 2090 subjects (mean age 54.9 years, 54.1 % females) were enrolled. Among them 991 cases of physician-diagnosed asthma were observed while 1099 subjects received a diagnosis other than asthma (chronic obstructive pulmonary disease, chronic upper respiratory tract infections etc.). Among the lasts, the ECRHS questionnaire was suggestive for asthma diagnosis in 365 subjects (33.2 %). CONCLUSIONS: The data suggest that there is still a large under/misdiagnosis of asthma in the Italian primary care setting, despite the spread of GINA guidelines nearly 20 years before this study. A validated tool like the ECRHS questionnaire has detected a considerable proportion of potentially asthmatic patients who should be addressed to lung function assessment to confirm the diagnosis. Further educational efforts directed to the GPs are needed to improve their diagnosis of asthma (SAM104964). PMID- 26576133 TI - Pneumoperitoneum After Percutaneous Endoscopic Gastrostomy: Does It Have Clinical Significance? PMID- 26576131 TI - Potential Therapeutic Targets in Uterine Sarcomas. AB - Uterine sarcomas are rare tumors accounting for 3,4% of all uterine cancers. Even after radical hysterectomy, most patients relapse or present with distant metastases. The very limited clinical benefit of adjuvant cytotoxic treatments is reflected by high mortality rates, emphasizing the need for new treatment strategies. This review summarizes rising potential targets in four distinct subtypes of uterine sarcomas: leiomyosarcoma, low-grade and high-grade endometrial stromal sarcoma, and undifferentiated uterine sarcoma. Based on clinical reports, promising approaches for uterine leiomyosarcoma patients include inhibition of VEGF and mTOR signaling, preferably in combination with other targeted or cytotoxic compounds. Currently, the only targeted therapy approved in leiomyosarcoma patients is pazopanib, a multitargeted inhibitor blocking VEGFR, PDGFR, FGFR, and c-KIT. Additionally, preclinical evidence suggests effect of the inhibition of histone deacetylases, tyrosine kinase receptors, and the mitotic checkpoint protein aurora kinase A. In low-grade endometrial stromal sarcomas, antihormonal therapies including aromatase inhibitors and progestins have proven activity. Other potential targets are PDGFR, VEGFR, and histone deacetylases. In high-grade ESS that carry the YWHAE/FAM22A/B fusion gene, the generated 14-3-3 oncoprotein is a putative target, next to c-KIT and the Wnt pathway. The observation of heterogeneity within uterine sarcoma subtypes warrants a personalized treatment approach. PMID- 26576135 TI - Pharmacologic Agents for Chronic Diarrhea. AB - Chronic diarrhea is usually associated with a number of non-infectious causes. When definitive treatment is unavailable, symptomatic drug therapy is indicated. Pharmacologic agents for chronic diarrhea include loperamide, 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists, diosmectite, cholestyramine, probiotics, antispasmodics, rifaximin, and anti-inflammatory agents. Loperamide, a synthetic opiate agonist, decreases peristaltic activity and inhibits secretion, resulting in the reduction of fluid and electrolyte loss and an increase in stool consistency. Cholestyramine is a bile acid sequestrant that is generally considered as the first-line treatment for bile acid diarrhea. 5-HT3 receptor antagonists have significant benefits in patients with irritable bowel syndrome (IBS) with diarrhea. Ramosetron improves stool consistency as well as global IBS symptoms. Probiotics may have a role in the prevention of antibiotic-associated diarrhea. However, data on the role of probiotics in the treatment of chronic diarrhea are lacking. Diosmectite, an absorbent, can be used for the treatment of chronic functional diarrhea, radiation-induced diarrhea, and chemotherapy-induced diarrhea. Antispasmodics including alverine citrate, mebeverine, otilonium bromide, and pinaverium bromide are used for relieving diarrheal symptoms and abdominal pain. Rifaximin can be effective for chronic diarrhea associated with IBS and small intestinal bacterial overgrowth. Budesonide is effective in both lymphocytic colitis and collagenous colitis. The efficacy of mesalazine in microscopic colitis is weak or remains uncertain. Considering their mechanisms of action, these agents should be prescribed properly. PMID- 26576136 TI - Reappraisal of Pneumoperitoneum After Percutaneous Endoscopic Gastrostomy. AB - BACKGROUND/AIMS: Pneumoperitoneum is recognized as a benign and self-limiting finding after the insertion of a percutaneous endoscopic gastrostomy (PEG) tube, while complicated pneumoperitoneum is rarely reported. The aim of this study was to reappraise pneumoperitoneum following PEG. METHODS: We retrospectively reviewed 193 patients who underwent PEG from May 2008 to May 2014. All patients had a follow-up upright chest or simple abdominal radiograph after PEG. Pneumoperitoneum was quantified by measuring the height of the air column under the diaphragm and graded as small (<2 cm), moderate (2-4 cm), or large (>4 cm). Clinically significant signs were defined as fever, abdominal tenderness or leukocytosis occurring after PEG insertion. RESULTS: Of the 193 study patients, 9 (4.6%) had a pneumoperitoneum visualized by radiographic imaging, graded as small in 5 patients, moderate in 2 patients and large in 2 patients. Clinically significant signs were observed in 5 (55.5%) patients with fever reported in 4 patients, abdominal tenderness in 4 patients and leukocytosis in 4 patients. The time to resolution of free air was 2-18 days. Two patients (22.2%) with moderate or large pneumoperitoneum after PEG died from either pneumonia or septic shock. CONCLUSIONS: The clinical course of pneumoperitoneum after PEG is not always benign and self-limiting. These findings suggest that clinicians should not neglect a moderate or large pneumoperitoneum, particularly in patients who have an altered mental status or received antibiotics, since peritoneal irritation cannot be observed under these circumstances. PMID- 26576134 TI - Recent Updates on the Treatment of Constipation. AB - The treatment of constipation aims to regulate the frequency and quantity of stool in order to promote successful defecation. Numerous studies on pharmacologic treatments and non-pharmacologic therapies for constipation have attempted to overcome limitations such as temporary and insufficient efficacy. Conventional laxatives have less adverse effects and are inexpensive, but often have limited efficacy. Recently developed enterokinetic agents and intestinal secretagogues have received attention owing to their high efficacies and low incidences of adverse events. Studies on biofeedback and surgical treatment have focused on improving symptoms as well as quality of life for patients with refractory constipation. PMID- 26576137 TI - Colonic Chicken Skin Mucosa is an Independent Endoscopic Predictor of Advanced Colorectal Adenoma. AB - BACKGROUND/AIMS: Chicken skin mucosa (CSM), surrounding colorectal adenoma, is an endoscopic finding with pale yellow-speckled mucosa; however, its clinical significance is unknown. This study aimed to evaluate the prevalence and clinical characteristics of CSM, and the association between colorectal carcinogenesis and CSM. METHODS: This cross-sectional study was performed in 733 consecutive patients who underwent endoscopic polypectomy for colorectal adenoma after the screening of colonoscopy at the Asan Health Promotion Center between June 2009 and December 2011. The colonoscopic and pathological findings of colorectal adenoma including number, size, location, dysplasia, morphology, and clinical parameters were reviewed. RESULTS: The prevalence of CSM was 30.7% (225 of 733 patients), and most CSM-related adenomas were located in the distal colon (93.3%). Histological analysis revealed lipid-laden macrophages in the lamina propria of the mucosa. Multivariate analyses showed that CSM was significantly associated with advanced pathology, including villous adenoma and high-grade dysplasia (odds ratio [OR], 2.078; 95% confidence interval [CI], 1.191-3.627; P=0.010), multiple adenomas (i.e., >=2 adenomas; OR, 1.692; 95% CI, 1.143-2.507; P=0.009), and a protruding morphology (OR, 1.493; 95% CI, 1.027-2.170; P=0.036). There were no significant differences in polyp size or clinical parameters between patients with and without CSM. CONCLUSIONS: CSM-related adenoma was mainly found in the distal colon, and was associated with advanced pathology and multiple adenomas. CSM could be a potential predictive marker of the carcinogenetic progression of distally located colorectal adenomas. PMID- 26576138 TI - Is Retroflexion Helpful in Detecting Adenomas in the Right Colon?: A Single Center Interim Analysis. AB - BACKGROUND/AIMS: Colonoscopy is less effective at screening for colorectal cancer in the right side of the colon. Retroflexion during colonoscopy is expected to improve the detection rate of colorectal adenomas. The aim of the present study was to evaluate the usefulness of retroflexion in the right-sided colon. METHODS: From April to November 2013, a total of 398 patients were enrolled in this study. For each patient, a cap-assisted colonoscopic examination was performed. After cecal intubation, a forward view examination from the cecum up to the hepatic flexure was performed and all identified polyps were removed. The colonoscope was reinserted to the cecum, and a careful second forward view examination of the cecum to the hepatic flexure was performed, with removal of additionally identified polyps. The colonoscope was then reinserted to the cecum and retroflexed; a third colonoscopic examination was then performed to the hepatic flexure in retroflexion with removal of additional polyps. Total polyp numbers and characteristics were compared between the two forward view examinations and the retroflexion examination. RESULTS: A successful retroflexion was performed in 90.2% of patients. A total of 213 polyps and 143 adenomas were detected in the right-sided colon using the routine method of examining the right colon twice in forward view. An additional 35 polyps and 24 adenomas were detected on retroflexion. Of these 35 polyps, 27 (77.1%) were small-sized polyps (<=5 mm) and 24 (71.4%) were adenomas. Finding additional adenomas using the retroflexion technique was associated with older age. CONCLUSIONS: Colonoscopic retroflexion is helpful in the detection of cecum and ascending colon adenomas, especially small-sized adenomas (<=5 mm). It is particularly useful in older patients. PMID- 26576139 TI - Clinical Features and Prognosis of Resectable Primary Colorectal Signet-Ring Cell Carcinoma. AB - BACKGROUND/AIMS: We attempted to investigate the prognosis of signet-ring cell carcinoma (SRC) patients who underwent curative surgery by comparing them with age-, sex-, and stage-matched non-mucinous adenocarcinoma (NMAC) patients. METHODS: Between January 2003 and December 2011, 19 patients with primary SRC of the colorectum underwent curative surgery. Four SRC patients under the age of 40 were excluded, and the clinicopathological data of 15 patients (7 men; median age, 56 years) were reviewed and compared with the data of 75 NMAC patients matched by age, sex, and pathologic stage. RESULTS: The median follow-up duration was 30.1 months for the SRC group and 43.7 months for the NMAC group (P=0.141). Involvement of the left side of the colon (73.3% vs. 26.7%, P=0.003) and infiltrative lesions such as Borrmann types 3 and 4 (85.7% vs. 24.0%, P=0.001) were more common in the SRC group than in the NMAC group. The five-year overall survival rate was significantly lower for patients with SRC than for those with NMAC (46.0% vs. 88.7%, hazard ratio, 6.99; 95% confidence interval, 2.33-20.95, P=0.001). CONCLUSIONS: Patients with even resectable primary colorectal SRC had a poorer prognosis than age-, sex-, and stage-matched colorectal NMAC patients. PMID- 26576140 TI - Colon Transit Time May Predict Inadequate Bowel Preparation in Patients With Chronic Constipation. AB - BACKGROUND/AIMS: We evaluated whether colonic transit time (CTT) can predict the degree of bowel preparation in patients with chronic constipation undergoing scheduled colonoscopy in order to assist in the development of better bowel preparation strategies for these patients. METHODS: We analyzed the records of 160 patients with chronic constipation from March 2007 to November 2012. We enrolled patients who had undergone a CTT test followed by colonoscopy. We defined patients with a CTT >=30 hours as the slow transit time (STT) group, and patients with a CTT <30 hours as the normal transit time (NTT) group. Boston Bowel Preparation Scale (BBPS) scores were compared between the STT and NTT groups. RESULTS: Of 160 patients with chronic constipation, 82 (51%) were included in the STT group and 78 (49%) were included in the NTT group. Patients with a BBPS score of <6 were more prevalent in the STT group than in the NTT group (31.7% vs. 10.3%, P=0.001). Multivariate analysis showed that slow CTT was an independent predictor of inadequate bowel preparation (odds ratio, 0.261; 95% confidence interval, 0.107-0.634; P=0.003). The best CTT cut-off value for predicting inadequate bowel preparation in patients with chronic constipation was 37 hours, as determined by receiver operator characteristic (ROC) curve analysis (area under the ROC curve: 0.676, specificity: 0.735, sensitivity: 0.643). CONCLUSIONS: Patients with chronic constipation and a CTT >30 hours were at risk for inadequate bowel preparation. CTT measured prior to colonoscopy could be useful for developing individualized strategies for bowel preparation in patients with slow CTT, as these patients are likely to have inadequate bowel preparation. PMID- 26576141 TI - A Rare Case of Hypermobile Mesentery With Segmental Small Bowel Pneumatosis Cystoides Intestinalis. AB - Pneumatosis intestinalis is a rare condition that affects 0.03% of the population. Pneumatosis cystoides intestinalis (PCI) is characterized by the presence of multiple gas-filled cysts in the intestinal wall and the submucosa and/or intestinal subserosa. It is usually a secondary finding caused by a wide variety of underlying gastrointestinal or extragastrointestinal diseases. Here, we present the case of a 47-year-old man who was referred to our gastroenterology department with a history suggestive of intermittent small bowel obstruction associated with abdominal pain. Abdominal computed tomography demonstrated PCI of the small bowel. The mesentery and branches of the superior mesenteric artery and superior mesenteric vein were twisted with minimal pneumoperitoneum. Exploratory laparotomy was performed, and demonstrated segmental small bowel PCI secondary to hypermobile mesentery. The affected segment of the ileum was resected, and jejunoileal anastomosis was performed. Here, we report a rare case of segmental PCI probably due to repeated twisting of hypermobile mesentery. The clinical and imaging features of this disorder may mimic those of visceral perforation or bowel ischemia. PCI can be a cause of severe abdominal pain that may require surgical intervention. PMID- 26576142 TI - Small Bowel Metastatic Cancer Observed With Double Balloon Enteroscopy in a Patient With a Past History of Multiple Cancers. AB - Small bowel tumors are very rare and generally malignant. As a result of the anatomical location and nonspecific manifestations of small bowel tumors, they are very difficult to diagnose. Balloon-assisted enteroscopy is a relatively noninvasive method compared to surgical resection, and allows for real-time observation, tissue confirmation with biopsy, and interventional procedures. Here, we report the case of a 69-year-old woman with a small bowel metastatic carcinoma observed with double balloon enteroscopy (DBE). She had a history of multiple cancers including ovarian cancer, bladder cancer, and breast cancer. The antegrade DBE procedure was performed before surgery for biopsy tissue confirmation. The patient underwent small bowel resection, and the final diagnosis was the same as that determined by preoperative biopsy. The final diagnosis was metastatic small bowel cancer originating from a cancer of the breast. This is the first detailed report of the preoperative diagnosis of small intestinal metastatic breast cancer by DBE. PMID- 26576143 TI - Removal of Rectal Foreign Bodies Using Tenaculum Forceps Under Endoscopic Assistance. AB - The incidence of rectal foreign bodies is increasing by the day, though not as common as that of upper gastrointestinal foreign bodies. Various methods for removal of foreign bodies have been reported. Removal during endoscopy using endoscopic devices is simple and safe, but if the foreign body is too large to be removed by this method, other methods are required. We report two cases of rectal foreign body removal by a relatively simple and inexpensive technique. A 42-year old man with a vibrator in the rectum was admitted due to inability to remove it by himself and various endoscopic methods failed. Finally, the vibrator was removed successfully by using tenaculum forceps under endoscopic assistance. Similarly, a 59-year-old man with a carrot in the rectum was admitted. The carrot was removed easily by using the same method as that in the previous case. The use of tenaculum forceps under endoscopic guidance may be a useful method for removal of rectal foreign bodies. PMID- 26576144 TI - A Patient With a Progressive Cecal Subepithelial Tumor. PMID- 26576145 TI - Letter: Patient Description of Rectal Effluents With Photographic Examples as a Predictive Indicator for the Quality of Bowel Preparation. PMID- 26576146 TI - Author's Reply. PMID- 26576147 TI - Bone morphogenetic protein dominantly suppresses epidermal growth factor-induced proliferative expansion of adult forebrain neural precursors. AB - A single asymmetric division by an adult neural stem cell (NSC) ultimately generates dozens of differentiated progeny, a feat made possible by the proliferative expansion of transit-amplifying progenitor cells (TAPs). Although NSC activation and TAP expansion is determined by pro- and anti-proliferative signals found within the niche, remarkably little is known about how these cells integrate simultaneous conflicting signals. We investigated this question focusing on the subventricular zone (SVZ) niche of the adult murine forebrain. Using primary cultures of SVZ cells, we demonstrate that Epidermal Growth Factor (EGF) and Bone Morphogenetic Protein (BMP)-2 are particularly powerful pro- and anti-proliferative factors for SVZ-derived neural precursors. Dose-response experiments showed that when simultaneously exposed to both signals, BMP dominantly suppressed EGF-induced proliferation; moreover, this dominance extended to all parameters of neural precursor behavior tested, including inhibition of proliferation, modulation of cell cycle, promotion of differentiation, and increase of cell death. BMP's anti-proliferative effect did not involve inhibition of mTORC1 or ERK signaling, key mediators of EGF-induced proliferation, and had distinct stage-specific consequences, promoting TAP differentiation but NSC quiescence. In line with these in vitro data, in vivo experiments showed that exogenous BMP limits EGF-induced proliferation of TAPs while inhibition of BMP-SMAD signaling promotes activation of quiescent NSCs. These findings clarify the stage-specific effects of BMPs on SVZ neural precursors, and support a hierarchical model in which the anti-proliferative effects of BMP dominate over EGF proliferation signaling to constitutively drive TAP differentiation and NSC quiescence. PMID- 26576148 TI - Outcomes of Direct Vision Internal Urethrotomy for Bulbar Urethral Strictures: Technique Modification with High Dose Triamcinolone Injection. AB - Objective. To evaluate the recurrence rate of bulbar urethral strictures managed with cold knife direct vision internal urethrotomy and high dose corticosteroid injection. Methods. 28 patients with bulbar urethral strictures underwent direct vision internal urethrotomy with high dose triamcinolone injection into the periurethral tissue and were followed up for recurrence. Results. Our cohort had a mean age of 60 years and average stricture length of 1.85 cm, and 71% underwent multiple previous urethral stricture procedures with an average of 5.7 procedures each. Our technique modification of high dose corticosteroid injection had a recurrence rate of 29% at a mean follow-up of 20 months with a low rate of urinary tract infections. In patients who failed treatment, mean time to stricture recurrence was 7 months. Patients who were successfully treated had significantly better International Prostate Symptom Scores at 6, 9, and 12 months. There was no significant difference in maximum flow velocity on Uroflowmetry at last follow-up but there was significant difference in length of follow-up (p = 0.02). Conclusions. High dose corticosteroid injection at the time of direct vision internal urethrotomy is a safe and effective procedure to delay anatomical and symptomatic recurrence of bulbar urethral strictures, particularly in those who are poor candidates for urethroplasty. PMID- 26576149 TI - Surgical Repair of Bulbar Urethral Strictures: Advantages of Ventral, Dorsal, and Lateral Approaches and When to Choose Them. AB - Objectives. To review the available literature describing the three most common approaches for buccal mucosal graft (BMG) augmentation during reconstruction of bulbar urethral strictures. Due to its excellent histological properties, buccal mucosa graft is now routinely used in urethral reconstruction. The best approach for the placement of such a graft remains controversial. Methods. PubMed search was conducted for available English literature describing outcomes of bulbar urethroplasty augmentation techniques using dorsal, ventral, and lateral approaches. Prospective and retrospective studies as well as meta-analyses and latest systematic reviews were included. Results. Most of the studies reviewed are of retrospective nature and majority described dorsal or ventral approaches. Medium- and long-term outcomes of all three approaches were comparable ranging between 80 and 88%. Conclusion. Various techniques of BMG augmentation urethroplasty have been described for repairs of bulbar urethral strictures. In this review, we describe and compare the three most common "competing" approaches for bulbar urethroplasty with utilization of BMG. PMID- 26576150 TI - Ureteral Dilatation with No Apparent Cause on Intravenous Urography: Normal or Abnormal? A Pilot Study. AB - A pilot study was done in 18 adults to assess the significance of ureteral dilatation having no apparent cause seen on Intravenous Urography (IVU). A clinicoradiological evaluation was undertaken to evaluate the cause of ureteral dilatation, including laboratory investigations and sonography of the genitourinary tract. This was followed, if required, by CT Urography (using a modified technique). In 9 out of 18 cases, the cause of ureteral dilatation on laboratory investigations was urinary tract infection (6) and tuberculosis (3). In the remaining 9 cases, CTU identified the cause as extrinsic compression by a vessel (3), extrinsic vascular compression of the ureter along with ureteritis (2), extrinsic vascular impression on the right ureter and ureteritis in the left ureter (1), ureteral stricture (2), and ureteral calculus (1). Extrinsic vascular compression and strictures did not appear to be clinically significant in our study. Hence, ureteral dilatation without any apparent cause on intravenous urogram was found to be clinically significant in 12 out of 18 (66.6%) cases. We conclude that ureteral dilatation with no apparent cause on IVU may indicate urinary tract tuberculosis, urinary tract infection (E. coli), or a missed calculus. Thus, cases with a dilated ureter on IVU, having no obvious cause, should undergo a detailed clinicoradiological evaluation and CTU should be used judiciously. PMID- 26576151 TI - Prevalence of Asymptomatic Brucellosis in Children 7 to 12 Years Old. AB - Background. Brucellosis is one of the most common diseases of humans and animals and its clinical manifestations differ from asymptomatic infection to chronic illness associated with recurrence of symptoms. This study aimed to evaluate the prevalence of brucellosis in asymptomatic children 7 to 12 years old in Kahak, Iran. Methods. In this study, 186 children 7 to 12 years old were evaluated. Demographic data and exposure to the brucellosis agent were recorded and blood samples for the Wright, Coombs, and 2ME tests were collected. All the study subjects were followed up for one year about the appearance of symptoms. Results. The mean age was 10 +/- 1.72 years and 51% were boys. Family history was positive for brucellosis in 15% of children. A total of 8 children were brucellosis seropositive and, in subsequent follow-up, 6 of them showed the disease symptoms. Conclusion. This study showed that approximately 4.3% of children in endemic areas can have asymptomatic brucellosis and many of these children may be symptomatic in short term. PMID- 26576152 TI - Evaluation of Possible Genotoxic Activity of Dirithromycin in Cultured Human Lymphocytes. AB - Dirithromycin antibiotic is a 14-membered lactone ring macrolide and is widely used in medicine to treat many different types of bacterial infections. In the present study, the possible genotoxicity of dirithromycin was evaluated in cultured human lymphocytes by using sister chromatid exchanges (SCEs), chromosome aberration (CA), and micronucleus (MN) tests and also cell proliferation kinetics such as mitotic index (MI), replication index (RI), and nuclear division index (NDI) were analyzed for cytotoxicity. Cell cultures were treated with four different concentrations of dirithromycin (37.75, 67.50, 125, and 250 ug/mL) for 24 and 48 h periods. Dirithromycin significantly induced SCE and MN frequency at all concentrations in both 24 and 48 h treated cells. In addition, CA level has been markedly increased in the cells treated with almost all concentrations of dirithromycin for 24 (except 37.75 ug/mL) and 48 h treatment periods as compared to control. However, MI, RI, and NDI values were not affected by the dirithromycin treatment (p > 0.05). The results of this study indicated that dirithromycin treatment caused genetic damage by increasing the level of cytogenetic endpoints, suggesting its genotoxic and mutagenic action on human lymphocytes in vitro. PMID- 26576154 TI - Challenges of Diabetes Self-Management in Adults Affected by Food Insecurity in a Large Urban Centre of Ontario, Canada. AB - Objective. To explore how food insecurity affects individuals' ability to manage their diabetes, as narrated by participants living in a large, culturally diverse urban centre. Design. Qualitative study comprising of in-depth interviews, using a semistructured interview guide. Setting. Participants were recruited from the local community, three community health centres, and a community-based diabetes education centre servicing a low-income population in Toronto, Ontario, Canada. Participants. Twenty-one English-speaking adults with a diagnosis of diabetes and having experienced food insecurity in the past year (based on three screening questions). Method. Using six phases of analysis, we used qualitative, deductive thematic analysis to transcribe, code, and analyze participant interviews. Main Findings. Three themes emerged from our analysis of participants' experiences of living with food insecurity and diabetes: (1) barriers to accessing and preparing food, (2) social isolation, and (3) enhancing agency and resilience. Conclusion. Food insecurity appears to negatively impact diabetes self-management. Healthcare professionals need to be cognizant of resources, skills, and supports appropriate for people with diabetes affected by food insecurity. Study findings suggest foci for enhancing diabetes self-management support. PMID- 26576153 TI - Lithium Carbonate in the Treatment of Graves' Disease with ATD-Induced Hepatic Injury or Leukopenia. AB - Objective. GD with ATD-induced hepatic injury or leukopenia occurs frequently in clinical practice. The purpose of the present study was to observe the clinical effect of lithium carbonate on hyperthyroidism in patients with GD with hepatic injury or leukopenia. Methods. Fifty-one patients with GD with hepatic injury or leukopenia participated in the study. All patients were treated with lithium carbonate, in addition to hepatoprotective drugs or drugs that increase white blood cell count. Thyroid function, liver function, and white blood cells were measured. Clinical outcomes were observed after a 1-year follow-up. Results. After treatment for 36 weeks, symptoms of hyperthyroidism and the level of thyroid hormones were improved and liver function, and white blood cells returned to a normal level. Twelve patients (23.5%) obtained clinical remission, 6 patients (11.8%) relapsed after withdrawal, 25 patients (49.0%) received radioiodine therapy, and 8 patients (15.7%) underwent surgical procedures after lithium carbonate treatment. Conclusion. Lithium carbonate has effects on the treatment of mild-to-moderate hyperthyroidism caused by GD, and it is particularly suitable for patients with ATD-induced hepatic injury or leukopenia. PMID- 26576155 TI - Incidence of Gastric Cancer in Marrakech and Casablanca, Morocco. AB - Gastric cancer is the fifth most common cancer globally with over 70% of new cases occurring in developing countries. In Morocco, oncologists in Marrakech suspected higher frequency of gastric cancer compared to Casablanca, a city 150 kilometers away. This study calculated age-specific, sex-specific, and total incidence rates of gastric cancer in Marrakech and was compared to the Casablanca population-based cancer registry. Using medical records from Center Hospital University Mohammad VI and reports from 4 main private pathology laboratories in Marrakech, we identified 774 patients for the period 2008-2012. Comparison of rates showed higher age-specific incidence in Marrakech in nearly all age groups for both genders. A higher total incidence in Marrakech than in Casablanca was found with rates of 5.50 and 3.23 per 100,000, respectively. Incidence was significantly higher among males in Marrakech than males in Casablanca (7.19 and 3.91 per 100,000, resp.) and females in Marrakech compared to females in Casablanca (3.87 and 2.58 per 100,000, resp.). Future studies should address possible underestimation of gastric cancer in Marrakech, estimate incidence in other regions of Morocco, and investigate possible risk factors to explain the difference in rates. PMID- 26576156 TI - Profiling beta Thalassemia Mutations in Consanguinity and Nonconsanguinity for Prenatal Screening and Awareness Programme. AB - Mutation spectrum varies significantly in different parts and different ethnic groups of India. Social factors such as preference to marry within the community and among 1st degree relatives (consanguinity) play an important role in impeding the gene pool of the disease within the community and so in society by and large. The present paper discusses the role of consanguinity in profiling of beta thalassemia mutation, and thus the approach for prenatal screening and prevention based awareness programme. Clinically diagnosed 516 cases of beta thalassemia were screened at molecular level. A detailed clinical Proforma was recorded with the information of origin of the family, ethnicity, and consanguinity. The present study reports that subjects originating from Uttar Pradesh, Uttarakhand, Bihar, and Jharkhand have c.92+5G>C and c.124_127delTTCT mutation as the commonest mutation compared to the subjects hailing from Madhya Pradesh and Chhattisgarh and Nepal where sickle mutation was found more common. In 40 consanguineous unions more common and specific beta mutations with higher rate of homozygosity have been reported. This consanguinity-based data helps not only in deciding target oriented prenatal diagnostic strategies but also in objective based awareness programmes in prevention of thalassemia major birth. PMID- 26576157 TI - A Comparison of Pattern of Pregnancy Loss in Women with Infertility Undergoing IVF and Women with Unexplained Recurrent Miscarriages Who Conceive Spontaneously. AB - Objective. Women with infertility and recurrent miscarriages may have an overlapping etiology. The aim of this study was to compare the pregnancy loss in pregnancies after IVF treatment with spontaneous pregnancies in women with recurrent miscarriages and to assess differences related to cause of infertility. Methods. The outcome from 1220 IVF pregnancies (Group I) was compared with 611 spontaneous pregnancies (Group II) in women with recurrent miscarriages. Subgroup analysis was performed in Group I based on cause of infertility: tubal factor (392 pregnancies); male factor (610 pregnancies); and unexplained infertility (218 pregnancies). Results. The clinical pregnancy loss rate in Group I (14.3%) was significantly lower than that of Group II (25.8%, p < 0.001) and this was independent of the cause of infertility. However the timing of pregnancy loss was similar between Groups I and II. The clinical pregnancy loss rate in Group I was similar in different causes of infertility. Conclusions. The clinical pregnancy loss rate following IVF treatment is lower than that of women with unexplained recurrent miscarriages who conceived spontaneously. This difference persists whether the infertility is secondary to tubal factors, male factors, or unexplained cause. PMID- 26576158 TI - A Case of Special Complication following a Large Amount of Polyacrylamide Hydrogel Injected into the Epicranial Aponeurosis: Leukocytopenia. AB - Polyacrylamide hydrogel (PAAG) has been used as an injectable filler for soft tissue augmentation of different body parts, such as the face, breasts, and penis. However, this is the first report of leukocytopenia after injection of a large amount of PAAG in the epicranial aponeurosis. After receiving PAAG injection for craniofacial contouring, the female patient described herein experienced recurrent swelling, temporal pain (particularly with changes in ambient temperature and facial expression), and ultimately leukocytopenia due to widespread migration of the injected PAAG. We removed most of the PAAG from the affected tissues and the leukocytopenia disappeared 1 year after the operation. Based on this case, we hypothesize that injection of a large amount of PAAG into tissues that have ample blood supply, such as the epicranial aponeurosis, may induce leukocytopenia. PMID- 26576159 TI - A Young Man Presenting with Pleuritic Chest Pain and Fever after Electrophysiological Study and Implantable Cardioverter-Defibrillator Placement: Diagnostic Difficulties and Value of Bedside Thoracic Sonography. AB - We describe the case of a 23-year-old man presenting with recurrent pleuritic chest pain and prolonged fever after electrophysiology testing and placement of an implantable cardioverter-defibrillator because of a suspected arrhythmogenic right ventricular dysplasia. The clinical suspicion was initially directed toward pneumonia with pleural effusion and later toward an infection of the cardiac device complicated by septic pulmonary embolism. The definitive diagnosis of pulmonary embolism and infarction was suggested by a point-of-care thoracic sonography, performed at the bedside by a clinician caring for the patient, and then confirmed by contrast enhanced computed tomography, which also showed thrombosis of the left iliofemoral vein, site of percutaneous puncture for cardiac catheterization. Prolonged fever was attributable to a concomitant Epstein-Barr virus primary infection that acted as confounding factor. The present report confirms the value of bedside thoracic sonography in the diagnostic evaluation of patients with nonspecific respiratory symptoms. PMID- 26576160 TI - Knowledge, Attitude, and Practice of Health Workers in a Tertiary Hospital in Ile Ife, Nigeria, towards Ebola Viral Disease. AB - Background. Health workers are more prone to Ebola viral disease (EVD) than the general population. This study assessed the preparedness of health workers in the control and management of EVD. Methods. A descriptive cross-sectional study. Consenting 400 health workers completed a semistructured questionnaire that assessed participants' general knowledge, emergency preparedness, and control and management of EVD. Data were analysed using descriptive and inferential statistics. Results. The mean age (SD) was 34.5 +/- 8.62 years ranging from 20 to 59 years. Most participants were medical doctors (24.6%) and nurses (52.2%). The majority had practised <10 years (73.8%) and were aware of the EVD outbreak in the West African subregion (85.5%). Colleagues (40%) and radio (37.2%) were their major sources of information. Only 42% had good knowledge while 27% knew that there was no vaccine presently to prevent EVD. About one-quarter (24.2%) had low risk perception. The majority (89%) felt the hospital infection control policy was inadequate to protect against EVD. The only predictor of good knowledge was participants' occupation. Conclusion. There is knowledge gap and poor infection control preparedness among respondents. Thus, knowledge and practices of health workers towards EVD need improvement. PMID- 26576161 TI - Danger Signs of Childhood Pneumonia: Caregiver Awareness and Care Seeking Behavior in a Developing Country. AB - Background. Efforts to reduce child mortality especially in Africa must as a necessity aim to decrease mortality due to pneumonia. To achieve this, preventive strategies such as expanding vaccination coverage are key. However once a child develops pneumonia prompt treatment which is essential to survival is dependent on mothers and caregiver recognition of the symptoms and danger signs of pneumonia. Methods. This community based cross-sectional study enrolled four hundred and sixty-six caregivers in Enugu state. It aimed to determine knowledge of caregivers about danger signs of pneumonia and the sociodemographic factors that influence knowledge and care seeking behaviour of caregivers. Results. There is poor knowledge of the aetiology and danger signs of pneumonia among caregivers. Higher maternal educational attainment and residence in semiurban area were significantly associated with knowledge of aetiology, danger signs, and vaccination of their children against pneumonia. Fast breathing and difficulty in breathing were the commonest known and experienced WHO recognized danger signs while fever was the commonest perceived danger sign among caregivers. Conclusion. Knowledge of danger signs and health seeking behaviour among caregivers is inadequate. There is need for intensified public and hospital based interventions targeted at mothers to improve their knowledge about pneumonia. PMID- 26576162 TI - Rules regarding marijuana and its use in personal residences: findings from marijuana users and nonusers recruited through social media. AB - Recent changes in policy and social norms related to marijuana use have increased its use and concern about how/where marijuana should be used. We aimed to characterize rules regarding marijuana and its use in homes. We recruited 1,567 US adults aged 18-34 years through Facebook advertisements to complete an online survey assessing marijuana use, social factors, perceptions of marijuana, and rules regarding marijuana and its use in the home, targeting tobacco and marijuana users to ensure the relevance of this topic. Overall, 648 (41.6%) were current marijuana users; 46.0% of participants reported that "marijuana of any type is not allowed in their home or on their property." Of those allowing marijuana on their property, 6.4% prohibited use of marijuana in their home. Of the remainder, 29.2% prohibited smoking marijuana, and 11.0% prohibited vaping, eating, or drinking marijuana. Correlates of more restrictive rules included younger age, being female, having 0.05). CONCLUSION: Tooth discoloration was similarly detectable with both of the two experimental materials. PMID- 26576164 TI - Conservative Treatment of an Invaginated Maxillary Lateral Incisor with a C shaped Canal Using Cone-Beam Computed Tomography. AB - This report describes the non-surgical treatment of an invaginated maxillary lateral incisor with two fused roots. The mesial root had a C-shaped canal, while the distal one had a type III dens invagination. Cone-beam computed tomography (CBCT) was used to help with the diagnosis and treatment decision making. Clinical and radiographic follow-up revealed satisfactory periapical repair and absence of symptoms after 15 months. PMID- 26576165 TI - Patience and Mental Health in Iranian Students. AB - BACKGROUND: While the role of some personality traits has been comprehensively explored, scientific study of others, such as patience has been neglected. Psychologists have paid scant attention to patience as a personality trait, character strength or virtue. OBJECTIVES: The current study examined the relationship between patience and life satisfaction, mental health, and personality. MATERIALS AND METHODS: A sample of 252 Iranian college students (129 females and 123 males) completed the 3-factor patience scale, satisfaction with life scale, general health questionnaire, anxiety and depression scales and mini international personality item pool-big five. RESULTS: The three types of patience (interpersonal, life hardship, and daily hassles) were associated with higher levels of life satisfaction and lower levels of depression, anxiety and psychological dysfunction. Patience also showed moderate relationship with the Big-Five factors of personality. After controlling the personality factors, patience managed to explain additional unique variance in life satisfaction and mental health indicators. CONCLUSIONS: Patience is a unique predictor of mental well-being. It is suggested that long-term patience is more important for depression and general health, whereas short-term patience is more beneficial for hedonic well-being. PMID- 26576166 TI - Antidepressant Effect of Combined Ketamine and Electroconvulsive Therapy on Patients With Major Depressive Disorder: A Randomized Trial. AB - BACKGROUND: One of the shortcomings of the available treatments for major depressive disorder (MDD) is the time delay between starting the treatment and achieving an antidepressant response. OBJECTIVES: We aimed to determine the effect of Ketamine as a synergistic antidepressant and anesthetic agent on MDD in electroconvulsive therapy (ECT). PATIENTS AND METHODS: Twenty-two patients with MDD received Ketamine and Propofol as anesthetic agents compared with 20 patients as the control group who received Propofol in a double-blind randomized clinical trial. The Hamilton rating scale for depression was used to determine the changes in symptoms severity during ECT and a 2-week follow-up. RESULTS: Both groups showed a reduction in depression severity, but there was no significant difference between the groups in the recovery process (P = 0.92). However, the cognitive performance recovery time in the Ketamine group was lower than that in the control group (P = 0.042). CONCLUSIONS: This study could not show the effect of Ketamine on depression recovery in a 2-week follow-up period. Nevertheless, Ketamine may provide a better cognitive performance in patients under ECT. PMID- 26576167 TI - Emotional Intelligence and Its Relationship With General Health Among the Students of University of Guilan, Iran. AB - BACKGROUND: Particularly, this concept has used for examination of its empact on health of various people groups. Given the importance of students' health, this study investigated the relationship between emotional intelligence and general health. OBJECTIVES: The concept of emotional intelligence has attracted growing interest from researchers working in various fields. This study investigated the relationship between emotional intelligence and general health. MATERIALS AND METHODS: In this cross-sectional study, 136 students were selected from the University of Guilan, north of Iran, using simple random sampling. The subjects completed the Schutte self-report emotional intelligence test and general health questionnaire. RESULTS: The results showed a significant correlation between emotional intelligence and general health. Also, results indicated that emotional perception and emotional utilization are predictors of general health. CONCLUSIONS: The findings reflect that emotional intelligence can play an important role in general health. PMID- 26576168 TI - Treatment Programs for Students With Attention Deficit Hyperactivity Disorder: A Meta-Analysis Study. AB - CONTEXT: The aim of this study was to determine the experimental evidence of treatment/intervention programs for deficits in social skills, attention, and behavioral disorder in children and adolescents with attention deficit hyperactivity disorder (ADHD). EVIDENCE ACQUISITION: Meta-analysis procedures were employed to investigate whether children and adolescents with ADHD exhibit deficits in attention and social skills. A total of 17 empirical research studies published between 2000 and 2013 met our inclusion criteria. Attention and social skills measures were categorized according to both modality and type of processing required. RESULTS: Children with ADHD exhibited deficits in multiple components of attention and social skills that were not related to language learning disorders and weaknesses in general intellectual abilities. The overall percentage effect for attention and social skills in students with ADHD was calculated (effect size = 0. 79, confidence interval = 0.57 - 1.08). This meta analysis study showed that treatment programs reduced attention deficit and social skills in ADHD children and adolescents. CONCLUSIONS: The evidence of attention and social skills deficits in children with ADHD supports recent studies in ADHD deficits. Further research is required to explain in detail the nature, severity, and specificity of the deficits in individuals with ADHD. PMID- 26576169 TI - The Family Challenge of Caring for the Chronically Mentally Ill: A Phenomenological Study. AB - BACKGROUND: Family caregiving for patients with chronic mental illness is influenced by various factors such as political, socioeconomic, and cultural contexts as well as related policies and health services. OBJECTIVES: The purpose of this study was to explore the challenges with which the family caregivers of patients with chronic mental illness have to contend. MATERIALS AND METHODS: The research design was qualitative with a phenomenological approach. The research population consisted of 16 long-term carers expressing interest in participating in the project. The carers were the family members of mentally ill relatives who collected their monthly medications at Farshchian Psychiatry Hospital in Hamadan in 2012. Purposive sampling was used to draw the sample. Data were collected by individual in-depth semi-structured interviews, which were tape-recorded and analyzed via Colaizzi's phenomenological method. Rigor was assessed regarding credibility, dependability, conformability, and transferability. RESULTS: Our findings highlighted 4 main themes, namely stress and emotional distress, need for education and information, socioeconomic effects and support, and physical strain. CONCLUSIONS: Families experience frustrations when providing support and care to their mentally ill relatives. They, therefore, need appropriate support and intervention by mental health services. PMID- 26576170 TI - Effect of Cognitive Behavior Group Therapy on Parenting Stress in Mothers of Children With Autism. AB - BACKGROUND: Due to the various problems of children with autism, their families and especially their mothers become exposed to stress. OBJECTIVES: This study aimed to evaluate the effect of cognitive behavior group therapy on parenting stress of mothers of children with autism. MATERIALS AND METHODS: The sample of this research consisted of sixteen mothers of children with autism. The measurement tools were the Abidin Parenting Stress questionnaire and a demographic questionnaire. The samples participated in seven sessions of cognitive behavior group therapy. The data were analyzed using the repeated measures test. RESULTS: The findings indicated significant differences between scores of pretest and posttest considering parenting stress (P = 0.03) and subscales of parenting distress (P = 0.01), yet there weren't significant differences in the other subscales (P > 0.05). CONCLUSIONS: Cognitive behavior group therapy could be an important part of interventions used to decrease parenting stress of mothers of children with autism. PMID- 26576171 TI - Self-Amputation in Two Non-Psychotic Patients. AB - Self-amputation, the extreme form of self-mutilation, is uncommon. The vast majority of cases are associated with psychosis, with a small number being assigned the controversial diagnosis of body identity integrity disorder. In this article, we report two cases of non-psychotic self-amputation and their similarities with a view to highlighting the risk factors and formulating an appropriate management plan. PMID- 26576172 TI - Investigating the Association of Mental-Social Climate and Social Anxiety With Students' Self-Efficiency. AB - BACKGROUND: The tendency and motivation to progress and achieve the ideal position have always encouraged people towards acquiring the required education. OBJECTIVES: The present research aimed to investigate the association of mental social climate and social anxiety with self-efficiency and also predict the academic self-efficiency of first grade high school students based on social anxiety and the mental-social climate of the classroom. MATERIALS AND METHODS: A total of 350 subjects (172 girls and 178 boys) have been chosen by a random clustering sampling form the first grade high school students of Qaemshahr, Iran. The academic self-efficiency questionnaire, the social anxiety scale for teenagers and the classroom mental climate scale were used to collect the required data. For data analysis, the statistical method of correlation analysis, independent t test, and multivariate regression have been used. RESULTS: The research findings showed that there was a significant negative relationship between mental-social climate of the classroom and students' self-efficiency. In addition, social anxiety has been a significant negative relationship with self efficiency. Furthermore, a significant positive relationship exists between mental-social climate and social anxiety. CONCLUSIONS: In order to develop students' self-efficacy, there should be appropriate psychosocial climate. Therefore, teachers and administrators of education must provide all necessary arrangements to improve psychosocial climate classes. PMID- 26576173 TI - Reliability and Validity of the Farsi Version of the Somatosensory Amplification Scale. AB - BACKGROUND: The somatosensory amplification scale (SSAS) is a 10-item self-report instrument designed to assess a tendency to experience normal somatic and visceral sensations as intense, noxious, and disturbing. OBJECTIVES: The present study investigated the reliability and validity of the SSAS, developed by Barsky et al. (1988), in the Iranian population. MATERIALS AND METHODS: The study was carried out on 240 patients with functional gastrointestinal disorders and 30 healthy persons selected by convenience sampling from 2013 to 2014. The patients completed the SSAS, the somatization subscale of the symptom checklist-90-revised (SCL-90-R som), and the modified somatic perception questionnaire (MSPQ), whereas the healthy persons completed just the SSAS. RESULTS: Exploratory factor analysis indicated that the one-factor solution, accounting for 29.42% of the variance, explained that the SSAS items were represented by one global dimension. The SSAS had acceptable internal consistency (alpha = 0.78) and good test-retest reliability (r = 0.80). The item-to-scale correlations varied from 0.17 to 0.55. Item 2 had the lowest item-total score correlation (r = 0.17), and the alpha coefficient for the SSAS exceeded when this item was deleted. The convergent validity of the SSAS with somatization was shown with a significant correlation between the SSAS, SCL-90-R som (r = 0.36), and MSPQ scores (r = 0.52). Discriminant validity analysis showed no significant difference in the SSAS between the patient and control groups (P > 0.05) and non-specificity of the SSAS for patients. CONCLUSIONS: In sum, the SSAS has acceptable reliability and validity for the Iranian population and the scale measures the same the original scale, namely somatosensory amplification. PMID- 26576174 TI - Comparison of Perfectionism and Related Positive-Negative Dimension in People With High Traits on Obsessive Compulsive and Eating Disorder Characteristics. AB - BACKGROUND: Psychopathological perfectionism is often correlated with obsessive compulsive eating disorders. OBJECTIVES: The purpose of this study was to investigate perfectionism in people with high traits of obsessive compulsive and eating disorder characteristics. MATERIALS AND METHODS: This study was an expo fact research. The statistical population of the research comprised of male and female undergraduate students at Tabriz and Sarab branches of Payam- e- Noor University, Tabriz Islamic University and Azarbaijan Shahid Madani university in the academic year 2012 - 2013. A group of 640 university students, using the stratified random sampling method were screened by the obsessive compulsive inventory and the eating attitude test, then a group of 143 participants with high obsessive compulsive traits with another 137 participants with high eating disorder characteristics were selected and assessed with the Perfectionism Inventory. Data were analyzed using one way analysis of variance. RESULTS: The results showed that perfectionism and related negative dimension are more commonly found in people with high obsessive-compulsive traits than eating disorder characteristics (P < 0.02). The results showed the highest contribution of maladaptive perfectionism in predicting obsessive-compulsive features and pathological eating attitude. Also, no difference was found between the two groups in terms of negative perfectionism. CONCLUSIONS: The greater association of perfectionism with symptoms of obsessive-compulsive is consistent with its phenomenological feature. Fear of failure may motivate the behavioral components of perfectionism that aim to focus on careful checking, reassurance seeking and excessive consideration before making a decision. PMID- 26576175 TI - Perceived Social Support, Self-Esteem, and Internet Addiction Among Students of Al-Zahra University, Tehran, Iran. AB - BACKGROUND: Internet addiction is a global phenomenon that causes serious problems in mental health and social communication. Students form a vulnerable group, since they have free, easy, and daily access to the internet. OBJECTIVES: The current study aimed to investigate perceived social support, self-esteem, and internet addiction among Al-Zahra University students. MATERIALS AND METHODS: In the current descriptive research, the statistical sample consisted of 101 female students residing at AL-Zahra University dormitory, Tehran, Iran. Participants were randomly selected and their identities were classified. Then, they completed the Multidimensional Scale of Perceived Social Support, Rosenberg's Self-esteem Scale, and Yang Internet Addiction Test. After completion of the questionnaires, the data were analyzed using the correlation test and stepwise regression. RESULTS: The Pearson correlation coefficient indicated significant relationships between self-esteem and internet addiction (P < 0.05, r = -0.345), perceived social support (r = 0.224, P < 0.05), and the subscale of family (r = 0.311, P < 0.05). The findings also demonstrated a significant relationship between internet addiction and perceived social support (r = -0.332, P < 0.05), the subscale of family (P < 0.05, r = -0.402), and the other subscales (P < 0.05, r = -0.287). Results of the stepwise regression showed that the scale of internet addiction and the family subscale were predicative variables for self-esteem (r = 0.137, P < 0.01, F2, 96 = 77.7). CONCLUSIONS: Findings of the current study showed that persons with low self-esteem were more vulnerable to internet addiction. PMID- 26576176 TI - Developing an Inpatient Group Psychotherapy Program: Challenges and Lessons Learnt. AB - In Iran, inpatient group psychotherapy has been limited to transient practices for research purposes or fulfilling personal interest of therapists. The goal of this paper is to share and explain the experience of developing an inpatient group psychotherapy program in Roozbeh Psychiatric Hospital, Tehran, Iran. After theoretical delineation and preparation of a draft of the program guideline, two pilot sessions were held. Based on this initial experience a final treatment guideline was prepared. Afterwards, the program was continued for more than 1 year in a female ward at Roozbeh Psychiatric Hospital. The output of this exercise was a guideline that covers important topics in development of inpatient group psychotherapy. It is concluded that inpatient group psychotherapy has its unique challenges. Of the most important challenges that can be mentioned in this regard are the participation of patients with significant differences in levels of psychopathology and psychiatric signs and symptoms, and high comorbidity with specific personality traits or disorders. Other challenges relevant to the structure of the group include items such as very limited time for working through and inevitable out-of-group contacts. PMID- 26576177 TI - Seasonal Pattern in Suicide in Iran. AB - BACKGROUND: Various studies have shown a seasonal pattern in suicide in the developed societies; however, this pattern is not taken into consideration in most countries including Iran. OBJECTIVES: The current paper studied the seasonal pattern of committing suicide in Northern Iran. MATERIALS AND METHODS: The present study was a longitudinal study with time series features. Subject included suicide attempts recorded by emergency wards of all hospitals in Mazandaran province, Iran. The variable time, in this study, was defined as each month of study years (2005 - 2011), which included 84 monthly time points. To analyze data, the Student's independent t-test and analysis of variance (ANOVA) test were used. RESULTS: Of the 14,437 suicide attempts reported during the seven year period, 5359 (37.1%) were related to males. Suicide attempts reached a peak in June (1418 cases) and November (1352 cases), but were at their lowest level in March (991 cases) (P = 0.877). CONCLUSIONS: The suicide seasonality range is broad in this part of Iran. Moreover, there were two noticeable suicide peaks in June and November. PMID- 26576178 TI - Efficacy of Zinc Sulfate as an Add-on Therapy to Risperidone Versus Risperidone Alone in Patients With Schizophrenia: A Double-Blind Randomized Placebo Controlled Trial. AB - BACKGROUND: Zinc can modulate fast-excitatory transmission, facilitate the release of amino butyric acid and potentiate nicotinic acetylcholine receptors. There are also emerging evidences discussing the implication of these neurotransmitters in pathophysiology of schizophrenia. OBJECTIVES: The purpose of this study was to evaluate the efficacy of Zn sulfate as an add-on therapy in the treatment of schizophrenia in a 6-week, double-blind and placebo-controlled trial. PATIENTS AND METHODS: Eligible participants were 30 inpatients with schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria. Patients were randomly allocated into two equal groups; one group of patients received risperidone 6 mg/day plus capsules of Zn sulfate (each containing 50 mg elemental Zn) three times a day and another group received risperidone 6 mg/day plus placebo. The Positive and Negative Syndrome Scale (PANSS) was applied to assess the psychotic symptoms and aggression risk at baseline, week 2, 4, and 6 of the study. RESULTS: The results of this study showed that both protocols significantly decreased the scores on all subscales of the PANSS and supplemental aggression risk subscale as well as PANSS total score over the study. However, this improvement was significantly higher in Zn sulfate receiving group compared to the placebo group. No major clinical side-effects were detected. CONCLUSIONS: It may be concluded that Zn is an effective adjuvant agent in the management of patients with schizophrenia. PMID- 26576179 TI - Nutritional aspect of pediatric inflammatory bowel disease: its clinical importance. AB - Inflammatory bowel disease (IBD) is a chronic inflammatory disease mainly affecting the gastrointestinal tract. The incidence of the disease is rapidly increasing worldwide, and a number of patients are diagnosed during their childhood or adolescence. Aside from controlling the gastrointestinal symptoms, nutritional aspects such as growth, bone mineral density, anemia, micronutrient deficiency, hair loss, and diet should also be closely monitored and managed by the pediatric IBD team especially since the patients are in the development phase. PMID- 26576180 TI - Diagnostic characteristics of supplemental laboratory criteria for incomplete Kawasaki disease in children with complete Kawasaki disease. AB - PURPOSE: In 2004, the American Heart Association (AHA) had published an algorithm for the diagnosis of incomplete Kawasaki disease (KD). The aim of the present study was to investigate characteristics of supplemental laboratory criteria in this algorithm. METHODS: We retrospectively examined the medical records of 355 patients with KD who were treated with intravenous immunoglobulin (IVIG) during the acute phase of the disease. Laboratory data were obtained before the initial IVIG administration and up to 10 days after fever onset. In 106 patients, laboratory testing was performed more than twice. RESULTS: The AHA supplemental laboratory criteria were fulfilled in 90 patients (25.4%), and the frequency of laboratory examination (odds ratio [OR], 1.981; 95% confidence interval [CI], 1.391-2.821; P<0.001) was a significant predictor of it. The fulfillment of AHA supplemental laboratory criteria was significantly associated with refractoriness to the initial IVIG administration (OR, 2.388; 95% CI, 1.182-4.826; P=0.013) and dilatation of coronary arteries (OR, 2.776; 95% CI, 1.519-5.074; P=0.001). CONCLUSION: Repeated laboratory testing increased the rate of fulfillment of the AHA supplemental laboratory criteria in children with KD. PMID- 26576181 TI - Uveitis as an important ocular sign to help early diagnosis in Kawasaki disease. AB - PURPOSE: Incomplete Kawasaki disease (KD) is frequently associated with delayed diagnosis and treatment. Delayed diagnosis leads to increasing risk of coronary artery aneurysm. Anterior uveitis is an important ocular sign of KD. The purpose of this study was to assess differences in laboratory findings, including echocardiographic measurements, clinical characteristics such as fever duration and treatment responses between KD patients with and those without uveitis. METHODS: We conducted a prospective study with 110 KD patients from January 2008 to June 2013. The study group (n=32, KD with uveitis) was compared with the control group (n=78, KD without uveitis). Laboratory data were obtained from each patient including complete blood count (CBC), erythrocyte sedimentation rate (ESR), platelet count, and level of alanine aminotransferase, aspartate aminotransferase, serum total protein, albumin, C-reactive protein (CRP), and N terminal probrain natriuretic peptide (NT-pro BNP). Echocardiographic measurements and intravenous immunoglobulin responses were compared between the two groups. RESULTS: The incidence of uveitis was 29.0%. Neutrophil counts and patient age were higher in the uveitis group than in the control group. ESR and CRP level were slightly increased in the uveitis group compared with the control group, but the difference between the two groups was not significant. No significant differences in coronary arterial complication and treatment responses were observed between the two groups. CONCLUSION: Uveitis is an important ocular sign in the diagnosis of incomplete KD. It is significantly associated with patient age and neutrophil count. PMID- 26576182 TI - Clinical characteristics of children and adolescents with croup and epiglottitis who visited 146 Emergency Departments in Korea. AB - PURPOSE: Croup is a common pediatric respiratory illness with symptoms of varying severity. Moreover, epiglottitis is a rare disease that can rapidly progress to life-threatening airway obstruction. Although the clinical course and treatments differ between croup and epiglottitis, they are difficult to differentiate on presentation. We aimed to compare the clinical characteristics of croup and epiglottitis in Emergency Department patients. METHODS: The 2012 National Emergency Department Information System database of 146 Korean Emergency Departments was used to investigate patients aged <=18 years presenting with croup or epiglottitis. RESULTS: We analyzed 19,374 croup patients and 236 epiglottitis patients. The male:female sex ratios were 1.9:1 and 2.3:1 and mean ages were 2.2+/-2.0 and 5.6+/-5.8 years, respectively. The peak incidence of croup was observed in July and that of epiglottitis was observed in May. The hospitalization rate was lower in croup than in epiglottitis patients, and the proportion of patients treated in the intensive care unit was lower among croup patients. The 3 most common chief complaints in both croup and epiglottitis patients were cough, fever, and dyspnea. Epiglottitis patients experienced dyspnea, sore throat, and vomiting more often than croup patients (P<0.05). CONCLUSION: Both groups had similar sex ratios, arrival times, 3 most common chief complaints, and 5 most common comorbidities. Epiglottitis patients had a lower incidence rate, higher mean age of onset, and higher hospitalization rate and experienced dyspnea, sore throat, and vomiting more often than croup patients. Our results may help in the differential diagnosis of croup and epiglottitis. PMID- 26576183 TI - Prognostic factors in children with extracranial germ cell tumors treated with cisplatin-based chemotherapy. AB - PURPOSE: To evaluate the outcomes and prognostic factors in children with extracranial germ cell tumors (GCTs) treated at a single institution. METHODS: Sixty-six children diagnosed with extracranial GCTs between 1996 and 2012 were included in the study. Primary treatment was surgical excision, followed by six cycles of cisplatin-based chemotherapy. The survival rates were compared according to the International Germ Cell Cancer Cooperative Group classification used for GCTs in adults to validate the classification guidelines for GCTs in children. RESULTS: The median patient age was 4.4 years. In 34 patients (51.5%), the primary tumor site was the gonad. Extragonadal GCTs were detected in 32 patients. The 5-year overall survival and event-free survival (EFS) were 92.0%+/ 3.5% and 90.4%+/-3.7%, respectively. In univariate analysis, tumor histology, metastasis, and elevated alpha-fetoprotein were not prognostic factors in children with extracranial GCTs. However, EFS was poorer in patients with mediastinal disease (n=12, 66.7%+/-13.6 %) than in those with nonmediastinal disease (n=54, 96.0%+/-2.8%) (P=0.001). The 5-year EFS was lower in patients older than 10 years, (n=21, 80.0%+/-8.9%) compared with those younger than 10 years (n=45, 95.2%+/-3.3%) (P=0.04). Multivariate analysis identified the mediastinal tumor site as the only independent prognostic factor. CONCLUSION: The prognosis of children with extracranial GCTs was favorable. However, nongerminomatous mediastinal tumors were associated with poor survival in children. Further research is needed to improve the prognosis of children with malignant mediastinal GCTs. PMID- 26576184 TI - Alagille syndrome and a JAG1 mutation: 41 cases of experience at a single center. AB - PURPOSE: Alagille syndrome is a complex hereditary disorder that is associated with cardiac, hepatic, skeletal, ocular, and facial abnormalities. Mutations in the Notch signaling pathway, such as in JAG1 and NOTCH2, play a key role in embryonic development. A cardiac or hepatic presentation is a critical factor for determining the prognosis. METHODS: We conducted a retrospective study of 41 patients with Alagille syndrome or a JAG1 mutation between 1983 and 2013. RESULTS: The first presentations were jaundice, murmur, cyanosis, and small bowel obstruction at a median age of 1.0 months (range, 0-24 months). The JAG1 mutation was found in 27 of the 28 genetically-tested patients. Cardiovascular anomalies were identified in 36 patients, chronic cholestasis was identified in 34, and liver transplantation was performed in 9. There was no significant correlation between the severity of the liver and cardiac diseases. The most common cardiovascular anomaly was peripheral pulmonary stenosis (83.3%), with 13 patients having significant hemodynamic derangement and 12 undergoing surgical repair. A total bilirubin level of >15 mg/dL with a complex surgical procedure increased the surgical mortality (P=0.022). Eight patients died after a median period of 2.67 years (range, 0.33-15 years). The groups with fetal presentation and with combined severe liver and heart disease had the poorest survival (P<0.001). CONCLUSION: The group with combined severe liver and heart disease had the poorest survival, and a multidisciplinary approach is necessary to improve the outcome. PMID- 26576185 TI - The first pediatric case of tularemia in Korea: manifested with pneumonia and possible infective endocarditis. AB - Tularemia is a potentially severe zoonotic disease caused by Francisella tularensis. A lack of awareness about tularemia can be embarrassing and could result in delayed treatment because of improper diagnosis. The diagnosis of tularemia is difficult, because the infections are rare and the clinical spectrum is broad. As only 1 adult case has been reported in Korea thus far, pediatricians in Korea may be unfamiliar with tularemia. We report our experience with a 14 year-old male adolescent with tularemia who presented with atypical pneumonia and possible infective endocarditis. Although the infectivity and mortality rates for tularemia are very high if left untreated, we did not suspect tularemia in this case until the incidental isolation of F. tularensis. The present case suggests that clinicians in Korea should be more aware of tularemia. This case also suggests that tularemia should be considered in undetermined cases of atypical pneumonia or acute febrile illness without local signs. PMID- 26576186 TI - Plasmaphresis therapy for pulmonary hemorrhage in a pediatric patient with IgA nephropathy. AB - IgA nephropathy usually presents as asymptomatic microscopic hematuria or proteinuria or episodic gross hematuria after upper respiratory infection. It is an uncommon cause of end-stage renal failure in childhood. Pulmonary hemorrhage associated with IgA nephropathy is an unusual life-threatening manifestation in pediatric patients and is usually treated with aggressive immunosuppression. Pulmonary hemorrhage and renal failure usually occur concurrently, and the pulmonary manifestation is believed to be caused by the same immune process. We present the case of a 14-year-old patient with IgA nephropathy who had already progressed to end-stage renal failure in spite of immunosuppression and presented with pulmonary hemorrhage during oral prednisone treatment. His lung disease was comparable to diffuse alveolar hemorrhage and was successfully treated with plasmapheresis followed by oral prednisone. This case suggests that pulmonary hemorrhage may develop independently of renal manifestation, and that plasmapheresis should be considered as adjunctive therapy to immunosuppressive medication for treating IgA nephropathy with pulmonary hemorrhage. PMID- 26576187 TI - Metastatic squamous cell non-small-cell lung cancer (NSCLC): disrupting the drug treatment paradigm with immunotherapies. AB - Lung cancer is the third most commonly diagnosed cancer and the leading cause of cancer-related death in the United States. Unlike non-squamous NSCLC, squamous NSCLC rarely harbor epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations for which there are directed therapies, and until the recent approval of immunotherapies for squamous NSCLC, a limited number of traditional cytotoxic chemotherapy drugs have been FDA-approved for use in the treatment of advanced and metastatic squamous NSCLC. Immunotherapies directed at the programmed cell death-1 receptor (PD-1) or its ligand (PD-L1) (nivolumab and pembrolizumab) have demonstrated efficacy in both nonsquamous and squamous cell NSCLC. Because of their similar mechanism of action against the PD-L1/PD-1 pathway, both drugs have similar toxicity profiles related to immune-mediated adverse reactions that can generally be monitored and managed with oral corticosteroids. This paper provides an overview of drug therapy options for squamous cell NSCLC with a focus on the evidence and clinical application of the anti-PD1 therapies. A comparison of the dosing, administration, indications, and differences in the measurement of PD-L1 expression in the clinical trials of nivolumab and pembrolizumab is also provided. PMID- 26576188 TI - Antidepressant efficacy and side-effect burden: a quick guide for clinicians. AB - Prescribing of antidepressant treatment (ADT) for major depressive disorder (MDD) has increased in quantity and popularity over the last two decades. This is likely due to the approval of safer medications, better education of clinicians and their patients, direct-to-consumer marketing practices, and less stigma associated with those taking ADT. This trend has also been met with some controversy, however, as the ongoing safety and effectiveness of these treatments have at times been called into question. This paper discusses the differing levels of evidence that support the use of ADT based on (A) Food and Drug Administration approvals, (B) data from randomized controlled trials or meta analyses and, where these are not available, the authors discuss and apply, (C) theoretical pharmacodynamic principles to justify antidepressant choice in the treatment of MDD patients. The final section discusses standard psychopharmacology guideline approaches to better alert the reader as to which practices are commonplace compared with those which are more outside of the standard of care. PMID- 26576189 TI - The Effect of Acupuncture on the Motor Function and White Matter Microstructure in Ischemic Stroke Patients. AB - Evidence shows that ischemic stroke can induce brain structural reorganization. Acupuncture is advised as an adjunct to mainstream rehabilitation after stroke. However, the effectiveness of acupuncture is inconsistent among previous studies. Fourteen ischemic patients were collected and divided into two groups: conventional treatment group (CG) and acupuncture treatment group (AG). The results of a Fugl-Meyer Assessment (FMA) and diffusion tensor imaging were collected before and after treatment. The AG exhibited a higher improvement in FMA than the CG. Repeated measures analysis of variance on diffusion data only found a significant main effect for scanning time point in all diffusion indices. In each group, a postpair t-test revealed that diffusion indices values were changed significantly after treatment intervention in the body of the corpus callosum and bilateral corticospinal tracts, the inferior longitudinal fasciculus, the inferior frontooccipital fasciculus, the superior longitudinal fasciculus, the forceps minor, the cingulum gyrus, and the thalamic radiation. However, there was no significant difference in the diffusion indices between the two groups. In conclusion, acupuncture had a better behavioral score than traditional medicine treatment. However, acupuncture did not significantly change WM in the AG compared to the CG as expected within one month after the intervention. PMID- 26576190 TI - An In Vitro System Comprising Immortalized Hypothalamic Neuronal Cells (GT1-7 Cells) for Evaluation of the Neuroendocrine Effects of Essential Oils. AB - Aromatherapy and plant-based essential oils are widely used as complementary and alternative therapies for symptoms including anxiety. Furthermore, it was reportedly effective for the care of several diseases such as Alzheimer's disease and depressive illness. To investigate the pharmacological effects of essential oils, we developed an in vitro assay system using immortalized hypothalamic neuronal cells (GT1-7 cells). In this study, we evaluated the effects of essential oils on neuronal death induced by hydrogen peroxide (H2O2), aluminum, zinc, or the antagonist of estrogen receptor (tamoxifen). Among tests of various essential oils, we found that H2O2-induced neuronal death was attenuated by the essential oils of damask rose, eucalyptus, fennel, geranium, ginger, kabosu, mandarin, myrrh, and neroli. Damask rose oil had protective effects against aluminum-induced neurotoxicity, while geranium and rosemary oil showed protective activity against zinc-induced neurotoxicity. In contrast, geranium oil and ginger oil enhanced the neurotoxicity of tamoxifen. Our in vitro assay system could be useful for the neuropharmacological and endocrine pharmacological studies of essential oils. PMID- 26576191 TI - Berberine Reduces Neurotoxicity Related to Nonalcoholic Steatohepatitis in Rats. AB - Berberine is a plant alkaloid that has several pharmacological effects such as antioxidant, antilipidemic, and anti-inflammatory effects. Nonalcoholic steatohepatitis (NASH) triggers different aspects of disorders such as impaired endogenous lipid metabolism, hypercholesterolemia, oxidative stress, and neurotoxicity. In this study, we examined the mechanism by which NASH induces neurotoxicity and the protective effect of berberine against both NASH and its associated neurotoxicity. NASH induced rats showed significant impairments in lipid metabolism with increased serum triglycerides, cholesterol, and low-density lipoprotein (LDL). The NASH induced group also demonstrated a significant oxidative stress which is characterized by increased TBARs level and decreased antioxidant capacity such as GSH and SOD levels. Moreover, the NASH induction was associated with inflammation which was demonstrated by increased TNFalpha and nitric oxide levels. Hyperglycemia and hyperinsulinemia were observed in the NASH induced group. Also, our results showed a significant increase in the expression of the acetylcholine esterase (AChE) and amyloid beta precursor protein (AbetaPP). These changes were significantly correlated with decreased insulin degrading enzyme (IDE) and beta-amyloid40 (Abeta 40) and increased beta-amyloid42 (Abeta 42) in the hippocampal region. Daily administration of berberine (50 mg/kg) for three weeks ameliorated oxidative stress, inflammation, hyperlipidemia, hyperglycemia, hyperinsulinemia, and the observed neurotoxicity. PMID- 26576192 TI - Effectiveness of Acupuncture for Treating Sciatica: A Systematic Review and Meta Analysis. AB - This is a systematic review and meta-analysis, which aimed to assess the current evidence on the effects and safety of acupuncture for treating sciatica. In this review, a total of 11 randomized controlled trials were included. As a result, we found that the use of acupuncture may be more effective than drugs and may enhance the effect of drugs for patients with sciatica, but because of the insufficient number of relevant and rigorous studies, the evidence is limited. Future trials using rigorous methodology, appropriate comparisons, and clinically relevant outcomes should be conducted. PMID- 26576193 TI - In Vivo Evaluation of the Antiasthmatic, Antitussive, and Expectorant Activities and Chemical Components of Three Elaeagnus Leaves. AB - The leaf of Elaeagnus lanceolata and Elaeagnus henryi as well as Elaeagnus pungens has been documented as an effective herb for the treatment of asthma and chronic bronchitis in traditional clinical medicine. This study was aimed at evaluating the antiasthmatic, antitussive, and expectorant activities of the water extracts from the three plants in vivo and analyzing their chemical components by HPLC-DAD. At the medium and high doses, the water extracts of three Elaeagnus leaves significantly prolonged the preconvulsive time (P < 0.01) in guinea pigs, lengthened the latent period of cough (P < 0.01) and decreased the cough frequency caused by aqueous ammonia in mice (P < 0.01), and enhanced tracheal phenol red output in mice (P < 0.01). There were no significant differences in the pharmacological actions between the three Elaeagnus leaves. Moreover, there was more similarity on overlap peaks in the range of retention time from 10 to 40 min by HPLC and many peaks that belonged to flavonoids compounds. It suggested that the main constituents of the three Elaeagnus leaves were flavonoid for the pharmacological activities. These effects were the important evidence for the traditional use of E. henryi leaf and E. lanceolata leaf as well as E. pungens to treat asthma and chronic bronchitis. PMID- 26576194 TI - Traditional Chinese Medicine and Vascular Disease. PMID- 26576195 TI - Synergy and Mode of Action of Ceftazidime plus Quercetin or Luteolin on Streptococcus pyogenes. AB - Streptococcus pyogenes causes streptococcal toxic shock syndrome. The recommended therapy has been often failure through the interfering of beta-lactamase producing bacteria (BLPB). The present study was to investigate antibacterial activity, synergy, and modes of action of luteolin and quercetin using alone and plus ceftazidime against S. pyogenes. The MICs of ceftazidime, luteolin, and quercetin against all S. pyogenes were 0.50, 128, and 128 ug mL(-1), respectively. A synergistic effect was exhibited on luteolin and quercetin plus ceftazidime against these strains at fractional inhibitory concentration indices 0.37 and 0.27, respectively, and was confirmed by the viable count. These combinations increased cytoplasmic membrane (CM) permeability, caused irregular cell shape, peptidoglycan, and CM damage, and decreased nucleic acid but increased proteins in bacterial cells. Enzyme assay demonstrated that these flavonoids had an inhibitory activity against beta-lactamase. In summary, this study provides evidence that the inhibitory mode of action of luteolin and quercetin may be mediated via three mechanisms: (1) inhibiting of peptidoglycan synthesis, (2) increasing CM permeability, and (3) decreasing nucleic acid but increasing the protein contents of bacterial cells. So, luteolin and quercetin propose the high potential to develop adjunct to ceftazidime for the treatment of coexistence of the BLPB and S. pyogenes infections. PMID- 26576196 TI - Antiamnesic Effect of Actinidia arguta Extract Intake in a Mouse Model of TMT Induced Learning and Memory Dysfunction. AB - The antiamnesic effects of ethyl acetate fraction from Actinidia arguta (EFAA) on trimethyltin- (TMT-) induced memory impairment were investigated to find the possibility of functional food substances. EFAA showed a potent AChE inhibitory effect (IC50 = 53 MUg/mL) and efficient neuroprotection against H2O2-induced oxidative stress. The administration of EFAA significantly decreased TMT-induced cognitive deficit in Y-maze, passive avoidance, and Morris water maze (MWM) tests. After the behavioral tests, the antioxidant activities were confirmed using mice brain tissues. EFAA not only showed the inhibition of AChE activity and the decline of malondialdehyde (MDA) level as a sign of lipid peroxidation but also presented the increase of the superoxide dismutase (SOD) level and the decrease of the oxidized glutathione (GSSG)/total glutathione (GSH + GSSG) ratio. Finally, the phenolics in EFAA were identified using liquid chromatography coupled with hybrid triple quadrupole-linear ion trap mass spectrometry, and four main phenolics, such as quinic acid, chlorogenic acid, caffeoyl hexose, and quercetin-3-glucoside, were identified. These results suggest that EFAA containing physiological phenolics might enhance drug-induced amnesia through AChE inhibition and neuroprotection. PMID- 26576198 TI - High-Resolution and Quantitative X-Ray Phase-Contrast Tomography for Mouse Brain Research. AB - Imaging techniques for visualizing cerebral vasculature and distinguishing functional areas are essential and critical to the study of various brain diseases. In this paper, with the X-ray phase-contrast imaging technique, we proposed an experiment scheme for the ex vivo mouse brain study, achieving both high spatial resolution and improved soft-tissue contrast. This scheme includes two steps: sample preparation and volume reconstruction. In the first step, we use heparinized saline to displace the blood inside cerebral vessels and then replace it with air making air-filled mouse brain. After sample preparation, X ray phase-contrast tomography is performed to collect the data for volume reconstruction. Here, we adopt a phase-retrieval combined filtered backprojection method to reconstruct its three-dimensional structure and redesigned the reconstruction kernel. To evaluate its performance, we carried out experiments at Shanghai Synchrotron Radiation Facility. The results show that the air-tissue structured cerebral vasculatures are highly visible with propagation-based phase contrast imaging and can be clearly resolved in reconstructed cross-images. Besides, functional areas, such as the corpus callosum, corpus striatum, and nuclei, are also clearly resolved. The proposed method is comparable with hematoxylin and eosin staining method but represents the studied mouse brain in three dimensions, offering a potential powerful tool for the research of brain disorders. PMID- 26576197 TI - Time-Delayed Models of Gene Regulatory Networks. AB - We discuss different mathematical models of gene regulatory networks as relevant to the onset and development of cancer. After discussion of alternative modelling approaches, we use a paradigmatic two-gene network to focus on the role played by time delays in the dynamics of gene regulatory networks. We contrast the dynamics of the reduced model arising in the limit of fast mRNA dynamics with that of the full model. The review concludes with the discussion of some open problems. PMID- 26576199 TI - Ensemble Merit Merge Feature Selection for Enhanced Multinomial Classification in Alzheimer's Dementia. AB - The objective of this study is to develop an ensemble classifier with Merit Merge feature selection that will enhance efficiency of classification in a multivariate multiclass medical data for effective disease diagnostics. The large volumes of features extracted from brain Magnetic Resonance Images and neuropsychological tests for diagnosis lead to more complexity in classification procedures. A higher level of objectivity than what readers have is needed to produce reliable dementia diagnostic techniques. Ensemble approach which is trained with features selected from multiple biomarkers facilitated accurate classification when compared with conventional classification techniques. Ensemble approach for feature selection is experimented with classifiers like Naive Bayes, Random forest, Support Vector Machine, and C4.5. Feature search is done with Particle Swarm Optimisation to retrieve the subset of features for further selection with the ensemble classifier. Features selected by the proposed C4.5 ensemble classifier with Particle Swarm Optimisation search, coupled with Merit Merge technique (CPEMM), outperformed bagging feature selection of SVM, NB, and Random forest classifiers. The proposed CPEMM feature selection found the best subset of features that efficiently discriminated normal individuals and patients affected with Mild Cognitive Impairment and Alzheimer's Dementia with 98.7% accuracy. PMID- 26576200 TI - Cross-sectional study about primary health care professionals views on the inclusion of the vaccine against human papillomavirus in the vaccine schedules. AB - BACKGROUND: Although the inclusion of the HPV vaccine has been registered in Spain since 2007, vaccination rates are lower than expected. The patients wish to be vaccinated is heavily influenced by information they have received from many source. The Knowledge of primary health care professionals affects the information provided to patients and is fundamental in the decision making. The aim of this study is to assess the opinions of primary health care professionals on the vaccine against HPV and their knowledge about HPV infection and its links to with gynecological and oropharyngeal cancer. METHODS: Cross-sectional study. A 19-item survey was drawn up. It included questions on basic aspects of HPV infection and marketed vaccines, personal opinion about the inclusion in the immunization schedules and their level of prescription and recommendation to patients in their clinical practice. From October 2013 to December 2013, 607 surveys were distributed among 20 primary health centers affiliated to the University Hospital 12 de Octubre. The results were analyzed using SPSS statistical package. RESULTS: One hundred sixty four successfully completed surveys were obtained for analysis. 89 % of the professionals knew about the relationship between HPV infection and cervical cancer, 57.3 % did not know any of the serotypes against which vaccines are targeted; 40.4 % believed that there is insufficient data to support the commercialization of the vaccines. Of these, 65.7 % argue that there is no data of its long-term effectiveness, 13.4 % that there is no data as to its side effects, 13.4 % believed that the cost effectiveness is not worthwhile. CONCLUSIONS: There is a strong controversy among health professionals regarding the marketing and inclusion of HPV vaccine in immunization schedules. However, the knowledge of the primary care health professionals on key aspects of infection and vaccine protection are insufficient. The training of professionals in vaccination, cervical pathology and HPV infection should be improved to provide objective information on the use as this vaccine for patients. PMID- 26576201 TI - Myobacterium bovis peri-prosthetic hip infection with successful prosthesis retention following intravesical BCG therapy for bladder carcinoma. AB - Systemic dissemination and peri-prosthetic infection of Mycobacterium bovis (M. bovis) following intravesical Bacillus Calmette-Guerin (BCG) therapy presents a rare but significant complication of treatment for non-muscle invasive bladder carcinoma. We present a patient with Mycobacterium bovis infection of a prosthetic hip nine months following BCG therapy for bladder cancer. The debridement and (implant) prosthesis retention approach in conjunction with anti tuberculous medication (DAIR) employed in this case, allowed the same prosthesis to be retained. This case report highlights the importance of physician awareness of the possibility BCG peri-prosthetic infections. PMID- 26576202 TI - Herb-drug interaction: The importance of communicating with primary care physicians. PMID- 26576203 TI - General practices' perspectives on Medicare Locals' performance are critical lessons for the success of Primary Health Networks. AB - BACKGROUND: Under a health reform after two decades, Primary Health Organisations (PHOs) in Australia were changed from Divisions of General Practice (DGP) to Medicare Locals (MLs). Following a review of Medicare Locals, in July 2015 Primary Health Networks (PHNs) replaced Medical Locals to potentially improve outcomes through supporting primary care and enhancing integration. AIMS: The aim of this paper was to gather front-line staff's perspectives on MLs and identify any lessons applicable to PHNs. METHODS: A national purposive sample of 22 high performing general practices representing all Australian states and territories was selected for semi-structured, face-to-face interviews, and a thematic analysis conducted. RESULTS: Fifty-three interviews were conducted: participants comprised 19 general practitioners (GPs), 18 practice managers (PMs), 15 practices nurses (PNs), and one community pharmacist. Most participants reflected on the difference between the DGP and MLs. Themes that emerged included ambiguity, community needs, professional development and education, communication and support, duplication in services and ignoring existing ones, recruitment and retention, and engagement and involvement. CONCLUSION: Those MLs that did well continued in an expanded way the work DGP were doing beforehand and made a seamless transition. PHNs will need to build on the strengths of previous PHOs, and create locality structures and processes that maximise the potential for clinical engagement. They will actively guide the dialogue between related microsystems: to achieve this they will have to be clinically led, change management organisations. PMID- 26576204 TI - Impact of focused training on communication skills of final-year medical students in a medical school in India. AB - BACKGROUND: Although communication skills are important for a good physician patient relationship, Indian medical curricula give very little emphasis on training medical students in this aspect. AIMS: To determine the change in communication skills of final-year medical students following focused training. METHODS: This was an educational interventional study done at Pondicherry Institute of Medical Sciences, a tertiary care teaching hospital in South India, to assess communication skills among final-year MBBS students. Fifty-two students (24 males and 28 females) participated in the study. A pre-test was conducted in the form of an objectively structured clinical examination (OSCE), followed by focused training for four hours. The same OSCE was administered as post-test. A comparison between the pre-test and post-test scores was done using Wilcoxon Signed Ranks Test. RESULTS: Ninety-six per cent of participants (50 out of 52) showed improvement in their performance after the focused training. The mean marks of the pre-test and post-test were 10.77+/- 3 and 18.04+/-2, respectively, out of a maximum mark of 20 (p<0.05). One out of 52 participants did not show any improvement, and one participant scored less in the post-test compared to the pre test. There was no significant difference in the performance between male and female students. CONCLUSION: Focused training can enhance the communication skills of medical students. Hence, it may be included in the curriculum of undergraduate medical teaching programmes in India. PMID- 26576205 TI - Notice of Retraction: Srirangaraj S, Kali A, Charles MVP. Antibiotic screening of urine culture as a tool for internal quality audit. AB - [This retracts the article on p. 73 in vol. 7, PMID: 24611076.]. PMID- 26576207 TI - Black silicon as a platform for bacterial detection. AB - Surface-enhanced Raman scattering (SERS) shows promise for identifying single bacteria, but the short range nature of the effect makes it most sensitive to the cell membrane, which provides limited information for species-level identification. Here, we show that a substrate based on black silicon can be used to impale bacteria on nanoscale SERS-active spikes, thereby producing spectra that convey information about the internal composition of the bacterial capsule. This approach holds great potential for the development of microfluidic devices for the removal and identification of single bacteria in important clinical diagnostics and environmental monitoring applications. PMID- 26576206 TI - Recreating blood-brain barrier physiology and structure on chip: A novel neurovascular microfluidic bioreactor. AB - The blood-brain barrier (BBB) is a critical structure that serves as the gatekeeper between the central nervous system and the rest of the body. It is the responsibility of the BBB to facilitate the entry of required nutrients into the brain and to exclude potentially harmful compounds; however, this complex structure has remained difficult to model faithfully in vitro. Accurate in vitro models are necessary for understanding how the BBB forms and functions, as well as for evaluating drug and toxin penetration across the barrier. Many previous models have failed to support all the cell types involved in the BBB formation and/or lacked the flow-created shear forces needed for mature tight junction formation. To address these issues and to help establish a more faithful in vitro model of the BBB, we have designed and fabricated a microfluidic device that is comprised of both a vascular chamber and a brain chamber separated by a porous membrane. This design allows for cell-to-cell communication between endothelial cells, astrocytes, and pericytes and independent perfusion of both compartments separated by the membrane. This NeuroVascular Unit (NVU) represents approximately one-millionth of the human brain, and hence, has sufficient cell mass to support a breadth of analytical measurements. The NVU has been validated with both fluorescein isothiocyanate (FITC)-dextran diffusion and transendothelial electrical resistance. The NVU has enabled in vitro modeling of the BBB using all human cell types and sampling effluent from both sides of the barrier. PMID- 26576208 TI - Cloud-Based Applications for Organizing and Reviewing Plastic Surgery Content. AB - Cloud-based applications including Box, Dropbox, Google Drive, Evernote, Notability, and Zotero are available for smartphones, tablets, and laptops and have revolutionized the manner in which medical students and surgeons read and utilize plastic surgery literature. Here we provide an overview of the use of Cloud computing in practice and propose an algorithm for organizing the vast amount of plastic surgery literature. Given the incredible amount of data being produced in plastic surgery and other surgical subspecialties, it is prudent for plastic surgeons to lead the process of providing solutions for the efficient organization and effective integration of the ever-increasing data into clinical practice. PMID- 26576209 TI - Neonatal Compartment Syndrome. PMID- 26576210 TI - Aggressive Digital Papillary Adenocarcinoma. PMID- 26576211 TI - A Population-Based Study of the Incidence and Case Fatality of Intracerebral Hemorrhage of Undetermined Etiology. AB - BACKGROUND: There is a paucity of reliable recent data regarding epidemiology of intracerebral hemorrhage (ICH) of undetermined etiology in population-based studies. OBJECTIVES: To determine the incidence and case fatality of ICH of undetermined etiology using a population-based design. METHODS: Medical records and neuroimaging data of all patients with ICH from Stearns and Benton Counties, Minnesota, between June 1st, 2012 and June 30th, 2014 were reviewed. Patients with a first-time diagnosis of ICH were categorized as of undetermined etiology if ICH was without features typical of hypertensive etiology with normal or no magnetic resonance imaging (MRI)/angiograms. We calculated the incidences of [1] probable and possible hypertensive ICH; [2] related to arteriovenous malformation, cavernous malformation, or aneurysmal rupture (angiographic or MRI diagnoses); [3] secondary to anticoagulation; and [4] of undetermined etiology adjusted for age and sex based on the 2010 US census. RESULTS: Of the 50 identified ICHs among 136,654 resident populations, seven were true incident cases of ICH of undetermined etiology in this population-based study. The age- and sex-adjusted incidence of ICH of undetermined etiology was 2.6 [95% confidence interval (CI) 0.7-4.9] per 100, 000 person-years, which was lower than probable and possible hypertensive ICH incidence of 12.8 [95% CI 8.4-17.2] per 100,000 person-years. The age-adjusted case fatality rate at 1 month was 8.14 and 0.4 per 100,000 persons for probable and possible hypertensive ICHs and ICHs of undetermined etiology, respectively. CONCLUSIONS: Our results should prompt further studies into identification of causes in ICH patients presently classified as ICH of undetermined etiology to reduce the incidence and case fatality of such ICHs. PMID- 26576212 TI - Acute Middle Cerebral Artery Occlusion Treated by Thrombectomy in a Patient with Myelodysplastic Syndrome and Severe Thrombocytopenia. AB - OBJECTIVE: Experience on thrombolysis and/or thrombectomy for acute major ischemic strokes in the setting of deep (less than 40,000/mm(3)) thrombocytopenia is limited. METHODS: Case report and review of the literature. RESULTS: A 63-year old female with myelodysplastic syndrome presented with left middle cerebral artery stroke within 2 hours of symptom onset. Severe thrombocytopenia (10.000/mm(3)) precluded systemic thrombolysis. However, endovascular thrombectomy provided successful recanalization and dramatic clinical recovery with NIHSS score decreasing from 20 to 2 soon after the procedure. Her modified Rankin scale was 1 at the end of the third month. CONCLUSION: This exceptional case highlights that neurothrombectomy could be feasible and of justifiable merit even in the setting of critically low thrombocytopenia if a meticulous procedure is followed in subjects with severe acute stroke. PMID- 26576213 TI - Traumatic Brain Injury Related to Motor Vehicle Accidents in Guinea: Impact of Treatment Delay, Access to Healthcare, and Patient's Financial Capacity on Length of Hospital Stay and In-hospital Mortality. AB - BACKGROUND: Traumatic brain injury related to road traffic accidents poses a major challenge in resource-poor settings within Guinea. OBJECTIVE: To analyze the impact of treatment delay, access to healthcare, and patient's financial capacity on duration of hospital stay and in-hospital mortality. METHODOLOGY: Data from patients with traumatic brain injury secondary to motor vehicle accident admitted to a reference hospital (public or private) in Guinea during 2009 were analyzed. The association between various factors (treatment delay, access to healthcare, and patient's financial capacity) and prolonged hospital stay (>21 days) and in-hospital mortality were analyzed using two multivariate logistic regression models. RESULTS: The mean (+/-standard deviation) duration of hospital stay was 8.0 (+/-8.1) days. The risk of prolonged hospital stay increased by 60% when the time interval between accident and hospital arrival was greater than 12 hours compared with those in whom the time interval was less than 6 hours (adjusted odds ratio [OR] = 1.6, 95% confidence interval [CI] = 1.0-2.6, p = 0.03). Compared with patients with low-financial capacity, patients with medium-financial capacity (adjusted OR = 0.6, 95% CI = 0.4-0.8, p = 0.001) and those with high capacity (adjusted OR = 0.6, 95% CI = 0.4-0.9, p = 0.02) were less likely to have a prolonged hospital stay. The risk of in-hospital mortality was 2.6 times higher in patients with time interval between accident and hospital arrival greater than 12 hours compared with those in whom the time interval was less than 6 hours (adjusted OR = 2.6, 95% CI = 1.1-6.2 p = 0.03). In-hospital mortality was not related to patient's financial capacity. CONCLUSION: Prolonged hospital stay and higher in-hospital mortality was associated with longer time interval between accident and hospital arrival. This delay is attributed to inadequate condition of intercity roads and lack of emergency medical services. PMID- 26576214 TI - Risk of In-Hospital Cardiac Arrest Among Medicare Beneficiaries Undergoing Video Electroencephalographic Monitoring. AB - PURPOSE: Sudden cardiac death is the dominant reason of sudden unexpected death in epilepsy (SUDEP). Anecdotal reports have documented cardiac arrest during video electroencephalographic (EEG) monitoring. We performed this study to determine the rate of cardiac arrest and need for cardiac resuscitation during video EEG monitoring. METHODS: We used inpatient data from the Centers for Medicare and Medicaid Services (CMS)'s Linkable 2008-2010 Medicare Data Entrepreneur's Synthetic Public Use File. Using the International Classification of Diseases 9th revision (ICD-9) primary diagnosis codes, we identified patients with epilepsy. We used the primary or secondary ICD-9 procedure codes to identify patients who underwent video EEG during admission. For primary endpoints, we identified patients who suffered cardiac arrest and those who underwent cardiorespiratory resuscitation (CPR). RESULTS: A total of 6,087 patients (mean age 76+/-12 years; 3,354 women) were included; 5,597 patients had a primary diagnosis of epilepsy and no video EEG, 240 patients had a primary diagnosis of epilepsy and underwent video EEG, and 250 patients underwent a video EEG without any diagnosis of epilepsy. A total of 12 patients (0.2%, 95% CI: 0.7-0.8) suffered a cardiac arrest during their admission. Three patients (0.1%) underwent CPR during their admission. There was no in-hospital mortality. None of the patients in those undergoing video EEG suffered cardiac arrest or underwent CPR. CONCLUSION: While the risk of cardiac arrest during video EEG monitoring may exist, the rate of such events was negligible in our study comprising of elderly Medicare patients. PMID- 26576215 TI - Disorders of the Autonomic Nervous System after Hemispheric Cerebrovascular Disorders: An Update. AB - Autonomic and cardiac dysfunction may occur after vascular brain injury without any evidence of primary heart disease. During acute stroke, autonomic dysfunction, for example, elevated arterial blood pressure, arrhythmia, and ischemic cardiac damage, has been reported, which may hinder the prognosis. Autonomic dysfunction after a stroke may involve the cardiovascular, respiratory, sudomotor, and sexual systems, but the exact mechanism is not fully understood. In this review paper, we will discuss the anatomy and physiology of the autonomic nervous system and discuss the mechanism(s) suggested to cause autonomic dysfunction after stroke. We will further elaborate on the different cerebral regions involved in autonomic dysfunction complications of stroke. Autonomic nervous system modulation is emerging as a new therapeutic target for stroke management. Understanding the pathogenesis and molecular mechanism(s) of parasympathetic and sympathetic dysfunction after stroke will facilitate the implementation of preventive and therapeutic strategies to antagonize the clinical manifestation of autonomic dysfunction and improve the outcome of stroke. PMID- 26576217 TI - Selective Nitric Oxide Synthase Inhibitor 7-Nitroindazole Protects against Cocaine-Induced Oxidative Stress in Rat Brain. AB - One of the mechanisms involved in the development of addiction, as well as in brain toxicity, is the oxidative stress. The aim of the current study was to investigate the effects of 7-nitroindazole (7-NI), a selective inhibitor of neuronal nitric oxide synthase (nNOS), on cocaine withdrawal and neurotoxicity in male Wistar rats. The animals were divided into four groups: control; group treated with cocaine (15 mg/kg(-1), i.p., 7 days); group treated with 7-NI (25 mg/kg(-1), i.p., 7 days); and a combination group (7-NI + cocaine). Cocaine repeated treatment resulted in development of physical dependence, judged by withdrawal symptoms (decreased locomotion, increased salivation and breathing rate), accompanied by an increased nNOS activity and oxidative stress. The latter was discerned by an increased formation of malondialdehyde (MDA), depletion of reduced glutathione (GSH) levels, and impairment of the enzymatic antioxidant defense system measured in whole brain. In synaptosomes, isolated from cocaine treated rats, mitochondrial activity and GSH levels were also decreased. 7-NI administered along with cocaine not only attenuated the withdrawal, due to its nNOS inhibition, but also reversed both the GSH levels and antioxidant enzyme activities near control levels. PMID- 26576216 TI - Tau Hyperphosphorylation and Oxidative Stress, a Critical Vicious Circle in Neurodegenerative Tauopathies? AB - Hyperphosphorylation and aggregation of the microtubule-associated protein tau in brain, are pathological hallmarks of a large family of neurodegenerative disorders, named tauopathies, which include Alzheimer's disease. It has been shown that increased phosphorylation of tau destabilizes tau-microtubule interactions, leading to microtubule instability, transport defects along microtubules, and ultimately neuronal death. However, although mutations of the MAPT gene have been detected in familial early-onset tauopathies, causative events in the more frequent sporadic late-onset forms and relationships between tau hyperphosphorylation and neurodegeneration remain largely elusive. Oxidative stress is a further pathological hallmark of tauopathies, but its precise role in the disease process is poorly understood. Another open question is the source of reactive oxygen species, which induce oxidative stress in brain neurons. Mitochondria have been classically viewed as a major source for oxidative stress, but microglial cells were recently identified as reactive oxygen species producers in tauopathies. Here we review the complex relationships between tau pathology and oxidative stress, placing emphasis on (i) tau protein function, (ii) origin and consequences of reactive oxygen species production, and (iii) links between tau phosphorylation and oxidative stress. Further, we go on to discuss the hypothesis that tau hyperphosphorylation and oxidative stress are two key components of a vicious circle, crucial in neurodegenerative tauopathies. PMID- 26576218 TI - Serum Oxidative Stress Markers and Genotoxic Profile Induced by Chemotherapy in Patients with Breast Cancer: A Pilot Study. AB - The aim of this study was to evaluate the oxidative parameters of erythrocytes and genotoxicity in leukocytes of patients with breast cancer. Oxidative parameters were detected by spectrophotometry and genotoxic damage by single cell gel electrophoresis. Twenty-eight women with breast cancer were monitored before chemotherapy and after the second and fourth cycles of therapy with cyclophosphamide and doxorubicin. After the fourth cycle, increases (P < 0.05) in the reactive substances to thiobarbituric acid levels, nitrite content, and superoxide dismutase activity and high rates of DNA damage in leukocytes were observed when compared with healthy women group and baseline levels. Similarly, after the second cycle, the same parameters were increased (P < 0.05) when compared with baseline levels. Increase in catalase activity was detected only after the fourth cycle and reduced glutathione levels and glutathione peroxidase activity were decreased in all cycles when compared with healthy women, as well as after the second and fourth chemotherapy cycles compared to baseline (P < 0.05). Patients with breast cancer presented an indicative of oxidative stress before, during, and after chemotherapy, as well as increased genotoxic damage in all stages of treatment, demonstrating the clinical applicability of this investigation. PMID- 26576219 TI - Protective Mechanisms of Flavonoids in Parkinson's Disease. AB - Parkinson's disease is a chronic, debilitating neurodegenerative movement disorder characterized by progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta region in human midbrain. To date, oxidative stress is the well accepted concept in the etiology and progression of Parkinson's disease. Hence, the therapeutic agent is targeted against suppressing and alleviating the oxidative stress-induced cellular damage. Within the past decades, an explosion of research discoveries has reported on the protective mechanisms of flavonoids, which are plant-based polyphenols, in the treatment of neurodegenerative disease using both in vitro and in vivo models. In this paper, we have reviewed the literature on the neuroprotective mechanisms of flavonoids in protecting the dopaminergic neurons hence reducing the symptoms of this movement disorder. The mechanism reviewed includes effect of flavonoids in activation of endogenous antioxidant enzymes, suppressing the lipid peroxidation, inhibition of inflammatory mediators, flavonoids as a mitochondrial target therapy, and modulation of gene expression in neuronal cells. PMID- 26576220 TI - Toll-Like Receptor 4 Promotes NO Synthesis by Upregulating GCHI Expression under Oxidative Stress Conditions in Sheep Monocytes/Macrophages. AB - Many groups of Gram-negative bacteria cause diseases that are harmful to sheep. Toll-like receptor 4 (TLR4), which is critical for detecting Gram-negative bacteria by the innate immune system, is activated by lipopolysaccharide (LPS) to initiate inflammatory responses and oxidative stress. Oxidation intermediates are essential activators of oxidative stress, as low levels of free radicals form a stressful oxidative environment that can clear invading pathogens. NO is an oxidation intermediate and its generation is regulated by nitric oxide synthase (iNOS). Guanosine triphosphate cyclohydrolase (GCHI) is the rate-limiting enzyme for tetrahydrobiopterin (BH4) synthesis, which is essential for the production of inducible iNOS. Previously, we made vectors to overexpress the sheep TLR4 gene. Herein, first generation (G1) of transgenic sheep was stimulated with LPS in vivo and in vitro, and oxidative stress and GCHI expression were investigated. Oxidative injury caused by TLR4 overexpression was tightly regulated in tissues. However, the transgenic (Tg) group still secreted nitric oxide (NO) when an iNOS inhibitor was added. Furthermore, GCHI expression remained upregulated in both serum and monocytes/macrophages. Thus, overexpression of TLR4 in transgenic sheep might accelerate the clearance of invading microbes through NO generation following LPS stimulation. Additionally, TLR4 overexpression also enhances GCHI activation. PMID- 26576221 TI - Nephroprotective Effects of Polydatin against Ischemia/Reperfusion Injury: A Role for the PI3K/Akt Signal Pathway. AB - Oxidative stress and inflammation are involved in the pathogenesis in renal ischemia/reperfusion (I/R) injury. It has been demonstrated that polydatin processed the antioxidative, anti-inflammatory, and nephroprotective properties. However, whether it has beneficial effects and the possible mechanisms on renal I/R injury remain unclear. In our present study I/R models were simulated both in vitro and in vivo. Compared with vehicle control, the administration of polydatin significantly improved the renal function, accelerated the mitogenic response and reduced cell apoptosis in renal I/R injury models, strongly suppressed the I/R induced upregulation of the expression of tumor necrosis factor-alpha, interleukin-1beta, cyclooxygenase-2, inducible nitric oxide synthase, prostaglandin E-2, and nitric oxide levels, and dramatically decreased contents of malondialdehyde, but it increased the activity of superoxide dismutase, glutathione transferase, glutathione peroxidase and catalase, and the level of glutathione. Further investigation showed that polydatin upregulated the phosphorylation of Akt in kidneys of I/R injury dose-dependently. However, all beneficial effects of polydatin mentioned above were counteracted when we inhibited PI3K/Akt pathway with its specific inhibitor, wortmannin. Taken together, the present findings provide the first evidence demonstrating that PD exhibited prominent nephroprotective effects against renal I/R injury by antioxidative stress and inflammation through PI3-K/Akt-dependent molecular mechanisms. PMID- 26576222 TI - Chronic Stress Facilitates the Development of Deep Venous Thrombosis. AB - The increasing pressure of modern social life intensifies the impact of stress on the development of cardiovascular diseases, which include deep venous thrombosis (DVT). Renal sympathetic denervation has been applied as one of the clinical approaches for the treatment of drug-resistant hypertension. In addition, the close relationship between oxidative stress and cardiovascular diseases has been well documented. The present study is designed to explore the mechanism by which the renal sympathetic nerve system and the oxidative stress affect the blood coagulation system in the development of DVT. Chronic foot shock model in rats was applied to mimic a state of physiological stress similar to humans. Our results showed that chronic foot shock procedure could promote DVT which may be through the activation of platelets aggregation. The aggravation of DVT and activation of platelets were alleviated by renal sympathetic denervation or antioxidant (Tempol) treatment. Concurrently, the denervation treatment could also reduce the levels of circulating oxidation factors in rats. These results demonstrate that both the renal sympathetic nerve system and the oxidative stress contribute to the development of DVT in response to chronic stress, which may provide novel strategy for treatment of clinic DVT patients. PMID- 26576223 TI - Pulmonary Protection Strategies in Cardiac Surgery: Are We Making Any Progress? AB - Pulmonary dysfunction is a common complication of cardiac surgery. The mechanisms involved in the development of pulmonary dysfunction are multifactorial and can be related to the activation of inflammatory and oxidative stress pathways. Clinical manifestation varies from mild atelectasis to severe respiratory failure. Managing pulmonary dysfunction postcardiac surgery is a multistep process that starts before surgery and continues during both the operative and postoperative phases. Different pulmonary protection strategies have evolved over the years; however, the wide acceptance and clinical application of such techniques remain hindered by the poor level of evidence or the sample size of the studies. A better understanding of available modalities and/or combinations can result in the development of customised strategies for the different cohorts of patients with the potential to hence maximise patients and institutes benefits. PMID- 26576224 TI - pCramoll and rCramoll as New Preventive Agents against the Oxidative Dysfunction Induced by Hydrogen Peroxide. AB - Oxidative stress plays an important role in the induction of cell death and is associated with various pathologic disorders; therefore, the search for natural products that attenuate the effects produced by oxidant agents is greatly increased. Here, the protective effects of native lectin from Cratylia mollis seeds (pCramoll) and recombinant Cramoll 1 (rCramoll) against H2O2-induced oxidative stress in Vero cells were evaluated. Both lectins significantly attenuated the H2O2-induced cytotoxicity in a concentration-dependent way. The maximum protective effects were 96.85 +/- 15.59% (rCramoll) and 59.48 +/- 23.44% (pCramoll). The Live/Dead analysis showed a reduction in the percentage of dead cells from 65.04 +/- 3.29% (H2O2) to 39.77 +/- 2.93% (pCramoll) and 13.90 +/- 9.01% (rCramoll). The deleterious effects of H2O2 on cell proliferation were reduced to 10.83% (pCramoll) and 24.17% (rCramoll). Lectins treatment attenuated the excessive superoxide production, the collapse of the mitochondrial membrane potential, and the lysosomal and DNA damage in H2O2-treated cells. In conclusion, our results suggest that pCramoll and rCramoll blocked H2O2-induced cytotoxicity through decreasing reactive oxygen species, restoring the mitochondrial potential, preventing the lysosomal damage and DNA fragmentation, and thus promoting cell survival and proliferation. PMID- 26576225 TI - Dandelion Extracts Protect Human Skin Fibroblasts from UVB Damage and Cellular Senescence. AB - Ultraviolet (UV) irradiation causes damage in skin by generating excessive reactive oxygen species (ROS) and induction of matrix metalloproteinases (MMPs), leading to skin photoageing. Dandelion extracts have long been used for traditional Chinese medicine and native American medicine to treat cancers, hepatitis, and digestive diseases; however, less is known on the effects of dandelion extracts in skin photoageing. Here we found that dandelion leaf and flower extracts significantly protect UVB irradiation-inhibited cell viability when added before UVB irradiation or promptly after irradiation. Dandelion leaf and flower extracts inhibited UVB irradiation-stimulated MMP activity and ROS generation. Dandelion root extracts showed less action on protecting HDFs from UVB irradiation-induced MMP activity, ROS generation, and cell death. Furthermore, dandelion leaf and flower but not root extracts stimulated glutathione generation and glutathione reductase mRNA expression in the presence or absence of UVB irradiation. We also found that dandelion leaf and flower extracts help absorb UVB irradiation. In addition, dandelion extracts significantly protected HDFs from H2O2-induced cellular senescence. In conclusion, dandelion extracts especially leaf and flower extracts are potent protective agents against UVB damage and H2O2-induced cellular senescence in HDFs by suppressing ROS generation and MMP activities and helping UVB absorption. PMID- 26576226 TI - Regulation of MUTYH, a DNA Repair Enzyme, in Renal Proximal Tubular Epithelial Cells. AB - MUTYH is a DNA repair enzyme that initiates a base excision repair (BER) by recognizing and removing 8-Oxoguanine (8-oxoG) and its paired adenine. We demonstrated that both TGF-beta1 and H2O2 treatment led to an increased 8-oxoG in cultured human proximal tubule epithelial (HK-2) cells, while the former induced epithelial-mesenchymal transition and the latter caused cell apoptosis. Without stimulation, HK-2 cells showed MUTYH expression in mitochondria. TGF-beta1 triggered a transient upregulation of mitochondrial MUTYH and induced the expression of nuclear isoforms, while H2O2 showed no role on MUTYH expression. Ureteral obstruction (UUO) mice exhibited high 8-oxoG reactivity with tubulointerstitial lesions. After obstruction, the MUTYH expression was increased only in tubules at day 3 and decreased with obvious tubular atrophy at day 10. Particularly, MUTYH was primarily located in normal tubular cytoplasm with a dominant mitochondrial form. A few cells with nuclear MUTYH expression were observed in the fibrotic interstitium. We confirmed that increased MUTYH expression was upregulated and positively correlated with the severity of kidney fibrosis. Thus, renal fibrosis caused a cell-type-specific and time-dependent response of oxidative DNA repairs, even within the same tissues. It suggests that intervention of MUTYH might be effective for therapies. PMID- 26576227 TI - Lico A Enhances Nrf2-Mediated Defense Mechanisms against t-BHP-Induced Oxidative Stress and Cell Death via Akt and ERK Activation in RAW 264.7 Cells. AB - Licochalcone A (Lico A) exhibits various biological properties, including anti inflammatory and antioxidant activities. In this study, we investigated the antioxidative potential and mechanisms of Lico A against tert-butyl hydroperoxide (t-BHP-) induced oxidative damage in RAW 264.7 cells. Our results indicated that Lico A significantly inhibited t-BHP-induced cytotoxicity, apoptosis, and reactive oxygen species (ROS) generation and reduced glutathione (GSH) depletion but increased the glutamate-cysteine ligase modifier (GCLM) subunit and the glutamate-cysteine ligase catalytic (GCLC) subunit genes expression. Additionally, Lico A dramatically upregulated the antioxidant enzyme heme oxygenase 1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf2), which were associated with inducing Nrf2 nuclear translocation, decreasing Keap1 protein expression and increasing antioxidant response element (ARE) promoter activity. Lico A also obviously induced the activation of serine/threonine kinase (Akt) and extracellular signal-regulated kinase (ERK), but PI3K/Akt and ERK inhibitors treatment displayed clearly decreased levels of LicoA-induced Nrf2 nuclear translocation and HO-1 expression, respectively. Furthermore, Lico A treatment markedly attenuated t-BHP-induced oxidative damage, which was reduced by treatment with PI3K/Akt, ERK, and HO-1 inhibitors. Therefore, Lico A might have a protective role against t-BHP-induced cytotoxicity by modulating HO-1 and by scavenging ROS via the activation of the PI3K/Akt and ERK/Nrf2 signaling pathways. PMID- 26576228 TI - Insulin Therapy of Nondiabetic Septic Patients Is Predicted by para Tyrosine/Phenylalanine Ratio and by Hydroxyl Radical-Derived Products of Phenylalanine. AB - Hydroxyl radical converts Phe to para-, meta-, and ortho-Tyr (p-Tyr, m-Tyr, o Tyr), while Phe is converted enzymatically to p-Tyr in the kidney and could serve as substrate for gluconeogenesis. Pathological isoforms m- and o-Tyr are supposed to be involved in development of hormone resistances. Role of Phe and the three Tyr isoforms in influencing insulin need was examined in 25 nondiabetic septic patients. Daily insulin dose (DID) and insulin-glucose product (IGP) were calculated. Serum and urinary levels of Phe and Tyr isoforms were determined using a rpHPLC-method. Urinary m-Tyr/p-Tyr ratio was higher in patients with DID and IGP over median compared to those below median (P = 0.005 and P = 0.01, resp.). Urinary m-Tyr and m-Tyr/p-Tyr ratio showed positive correlation with DID (P = 0.009 and P = 0.023, resp.) and with IGP (P = 0.004 and P = 0.008, resp.). Serum Phe was a negative predictor, while serum p-Tyr/Phe ratio was positive predictor of both DID and IGP. Urinary m-Tyr and urinary m-Tyr/p-Tyr, o-Tyr/p Tyr, and (m-Tyr+o-Tyr)/p-Tyr ratios were positive predictors of both DID and IGP. Phe and Tyr isoforms have a predictive role in carbohydrate metabolism of nondiabetic septic patients. Phe may serve as substrate for renal gluconeogenesis via enzymatically produced p-Tyr, while hydroxyl radical derived Phe products may interfere with insulin action. PMID- 26576230 TI - Orbitozygomatic Fracture Repairs: Are Antibiotics Necessary? AB - Orbitozygomatic fractures are one of the most common maxillofacial injuries encountered. This study aims to investigate and review the management and complications of orbitozygomatic fractures at the Royal Brisbane and Women's Hospital (RBWH). Specifically the postoperative infection rate will be closely examined to determine whether adjunctive antibiotics are necessary in its surgical management. A retrospective case selection study of all patients with orbitozygomatic fractures treated at the RBWH in 2011 was performed. The cases were collected from the maxillofacial database. Chart review of the admission with consecutive follow-up of up to 6 weeks including clinical and radiological assessment and consecutive data analysis was performed. A total of 160 patients with orbitozygomatic fractures were managed at the RBWH with three complications. Eighty-five (53.1%) cases were treated surgically and 155 (97.5%) cases had follow-up until 6 weeks postoperatively. Twenty-six surgical cases (16.3%) were treated via elevation without fixation. A further 26 surgical cases (16.3%) were treated with one fixation point, 19 cases (11.9%) with two fixation points, 12 cases (7.5%) with three fixation points, and 2 cases (1.3%) treated with four fixation points. The three complications (1.9%) returned for surgical correction without further consequence; two were due to inadequate cosmesis and one was due to exposure of the fixation plate. No early postoperative infections were seen. This study presents an excellent outcome with minimal early complications of orbitozygomatic fractures treated at the RBWH, a trauma center with high caseload. All operatively treated cases received perioperative antibiotic prophylaxis as per the unit's protocol. With a nil infection rate at the RBWH, future studies should focus on whether the use of prophylactic antibiotics is appropriate. PMID- 26576229 TI - Mechanisms of Neuronal Protection against Excitotoxicity, Endoplasmic Reticulum Stress, and Mitochondrial Dysfunction in Stroke and Neurodegenerative Diseases. AB - In stroke and neurodegenerative disease, neuronal excitotoxicity, caused by increased extracellular glutamate levels, is known to result in calcium overload and mitochondrial dysfunction. Mitochondrial deficits may involve a deficiency in energy supply as well as generation of high levels of oxidants which are key contributors to neuronal cell death through necrotic and apoptotic mechanisms. Excessive glutamate receptor stimulation also results in increased nitric oxide generation which can be detrimental to cells as nitric oxide interacts with superoxide to form the toxic molecule peroxynitrite. High level oxidant production elicits neuronal apoptosis through the actions of proapoptotic Bcl-2 family members resulting in mitochondrial permeability transition pore opening. In addition to apoptotic responses to severe stress, accumulation of misfolded proteins and high levels of oxidants can elicit endoplasmic reticulum (ER) stress pathways which may also contribute to induction of apoptosis. Two categories of therapeutics are discussed that impact major pro-death events that include induction of oxidants, calcium overload, and ER stress. The first category of therapeutic agent includes the amino acid taurine which prevents calcium overload and is also capable of preventing ER stress by inhibiting specific ER stress pathways. The second category involves N-methyl-D-aspartate receptor (NMDA receptor) partial antagonists illustrated by S-Methyl-N, N-diethyldithiocarbamate sulfoxide (DETC-MeSO), and memantine. DETC-MeSO is protective through preventing excitotoxicity and calcium overload and by blocking specific ER stress pathways. Another NMDA receptor partial antagonist is memantine which prevents excessive glutamate excitation but also remarkably allows maintenance of physiological neurotransmission. Targeting of these major sites of neuronal damage using pharmacological agents is discussed in terms of potential therapeutic approaches for neurological disorders. PMID- 26576231 TI - Does Extraction or Retention of the Wisdom Tooth at the Time of Surgery for Open Reduction and Internal Fixation of the Mandible Alter the Patient Outcome? AB - Whether to extract or retain wisdom teeth present in a fracture line is a controversial topic. This study reviewed the records of all patients who had mandibular wisdom teeth at the time of the injury, and had an open reduction and internal fixation procedure between January 2009 and January 2012. The cohort of patients who concomitantly had their wisdom tooth extracted at the time of fixation had a greater complication rate (24.3%) compared with patients who did not (14.9%). This suggests that if third molars in the line of a fracture have caries, are fractured, show signs of pericoronitis, are periodontally involved, or are interfering with the occlusion are extracted at the time of fixation, this will increase the incidence of complications. PMID- 26576232 TI - Trend and Characteristics of 2,636 Maxillofacial Fracture Cases over 32 Years in Suburban City of Japan. AB - Trend and characteristics of maxillofacial fractures in 2,636 patients over 32 years were analyzed retrospectively. Patients comprised 1,764 males and 872 females with ages ranging from 0 to 99 years. Patients younger than 30 years consisted of 60% maxillofacial fractures in the early period but decreased to 40% in the late period. In contrast, patients older than 60 years gradually increased to 30%. In terms of cause, traffic accidents consisted of more than 50%, predominantly motorcycle accidents, but gradually decreased to 40%. In contrast, falls markedly increased from less than 10 to 30%. Fractures occurred in the midface in 938 patients, in the mandible in 1,490, and in both in 208. In the midface, zygoma fractures consisted of 50% throughout the period. In the mandible, condyle fractures were observed in 40%, followed by fractures of the symphysis and angle. The ratio of condylar fractures slightly increased. Open reduction and internal fixation (ORIF) were performed in 782 patients, followed by observation in 716, maxillomandibular fixation (MMF) in 605, intramaxillary splinting (IMS) in 294, transcutaneous reduction (TCR) in 126, and others in 113. MMF markedly decreased from more than 30 to less than 5% and observation increased from 20 to 40%. PMID- 26576233 TI - A Protocol to Reduce Interobserver Variability in the Computed Tomography Measurement of Orbital Floor Fractures. AB - Orbital fracture detection and size determination from computed tomography (CT) scans affect the decision to operate, the type of surgical implant used, and postoperative outcomes. However, the lack of standardization of radiological signs often leads to the false-positive detection of orbital fractures, while nonstandardized landmarks lead to inaccurate defect measurements. We aim to design a novel protocol for CT measurement of orbital floor fractures and evaluate the interobserver variability on CT scan images. Qualitative aspects of this protocol include identifying direct and indirect signs of orbital fractures on CT scan images. Quantitative aspects of this protocol include measuring the surface area of pure orbital floor fractures using computer software. In this study, 15 independent observers without clinical experience in orbital fracture detection and measurement measured the orbital floor fractures of three randomly selected patients following the protocol. The time required for each measurement was recorded. The intraclass correlation coefficient of the surface area measurements is 0.999 (0.997-1.000) with p-value < 0.001. This suggests that any observer measuring the surface area will obtain a similar estimation of the fractured surface area. The maximum error limit was 0.901 cm(2) which is less than the margin of error of 1 cm(2) in mesh trimming for orbital reconstruction. The average duration required for each measurement was 3 minutes 19 seconds (ranging from 1 minute 35 seconds to 5 minutes). Measurements performed with our novel protocol resulted in minimal interobserver variability. This protocol is effective and generated reproducible results, is easy to teach and utilize, and its findings can be interpreted easily. PMID- 26576234 TI - An Evaluation of the Effect of Therapeutic Ultrasound on Healing of Mandibular Fracture. AB - The mandible is the most frequently fractured bone in maxillofacial trauma, the treatment of which consists of reduction and fixation of dislocated fragments by open or closed approach. Innovative techniques toward reducing the period of the postoperative intermaxillary fixation (IMF) are being researched. A relatively unknown treatment that may have an effect on fracture healing is ultrasound. Recent clinical trials have shown that low-intensity pulsed ultrasound (LIPUS) has a positive effect on bone healing. The aim of this study was to evaluate the effect of LIPUS on healing by its application in fresh, minimally displaced or undisplaced mandibular fracture in young and healthy individuals. A total of 28 healthy patients were selected randomly from the outpatient department needing treatment of mandibular fractures. They were then randomly allocated to either of the following two groups-experimental group and study group. After IMF, patients in experimental group received pulsed ultrasound signals with frequency of 1 MHz, with temporal and spatial intensity of 1.5 W/cm(2), pulsed wave for 5 minutes on every alternate day for 24 days, whereas patients in control group received no therapy except IMF. Radiographic density at the fracture zone was assessed from the radiograph by Emago (Emago, Amsterdam, Netherlands) Image Analysis software before IMF then at 1st to 5th weeks post-IMF. The amount of clinical mobility between fracture fragments was assessed by digital manipulation of fractured fragment with the help of periodontal pocket depth measuring probe in millimeters at pre-IMF and after 3 weeks. Pain was objectively measured using a visual analogue scale at weekly interval. The data collected were subjected to unpaired "t" test. The experimental group showed significant improvement in radiographic density compared with control group at 3- and 5-week interval; pain perception was significantly reduced in experimental group compared with study group in the subsequent weeks. No significant difference was found in clinical mobility between fracture fragments at 3-week interval. The present study provides a basis for application of therapeutic controlled ultrasound as an effective treatment modality to accelerate healing of fresh, minimally displaced mandibular fracture. PMID- 26576235 TI - Analysis of 1,545 Fractures of Facial Region-A Retrospective Study. AB - Incidence and etiology of facial fractures vary from region to region due to various constituents. This study was carried to evaluate the patterns and distribution of fractures in the facial region among different age groups of patients in both males and females caused due to various etiologies. This is a retrospective epidemiological study, which was performed on patients with fractures in the maxillofacial region during a period of 2005 to 2013 at Mamata Dental College and Hospital, Khammam, India. A total of 1,015 patients with 1,545 fractures were referred for treatment to department of oral and maxillofacial injuries surgery, of Mamata Dental College and Hospital, with a mean age of 31.19. The ratio of males (859):females (156) is 5.5:1. Injuries caused by motorbike injuries (34.9%) are highest. The highest frequency of fractures caused by various reasons is seen more in third decade (39%). Mandible (43.81%) is the most common fracture site in the face. Among soft tissue injuries most commonly seen are lacerations (43%). This study differentiates the etiological factors causing facial trauma in several age groups. Results of this study suggest outcomes indicate that more reliance on individual transport on motor vehicles has increased the frequency of facial bone fractures. Regardless of age, motor vehicle accidents were high in all age groups except the first decade of life and above 60 years of age when traffic accidents dominated. Thus effectiveness of current preventive measures is to be assessed, followed by instituting new guidelines for prevention and inflexible traffic rules shall be levied. More epidemiological surveys can, if encouraged to measure the frequency of fractures, better the world. PMID- 26576236 TI - Minimizing the Submandibular Incision in Endoscopic Subcondylar Fracture Repair. AB - Endoscope-assisted treatment of mandibular condylar fractures is an evolving surgical technique of this controversial subject. The approach is performed through an intraoral and additional submandibular incision. This study presents a technique for minimizing the length of the optional submandibular incision. Ten patients with displaced subcondylar fractures and malocclusion underwent endoscope-assisted open reduction and internal fixation (ORIF). A limited (<1 cm) submandibular incision (dissected under endoscopic guidance from within) was needed in eight patients to complement the intraoral incision and facilitate the reduction in the fractures. Satisfactory small scar could be obtained in all patients with neither wound complications nor facial nerve injuries. Our technique depends on dissection first then incision. Performing the external incision after complete intraoral dissection is safe for the facial nerve and minimizes scarring markedly. This very limited submandibular incision facilitates reduction in relatively difficult cases and enables clear visualization of posterior border of the mandible to confirm adequate fracture reduction. PMID- 26576237 TI - Maxillofacial Fractures Surgically Managed at Aalesund Hospital between 2002 and 2009. AB - This study analyses the demographics, etiology, and complications in patients operated for maxillofacial fractures by oral and maxillofacial surgeons at the Aalesund Hospital between 2002 and 2009. A total of 188 fractures in 139 patients were studied. The male-to-female ratio was 3.6:1 and the mean age was 35.7 +/- 17.2 years. Males were significantly younger than females (p < 0.05). Mandibular (52.7%) and zygomatic complex fractures (33.5%) were the most frequent. Most patients (41.7%) sustained their injuries as a result of interpersonal violence (IPV) followed by falls (25.9%) and traffic accidents (15.8%). Significantly more males were victims of IPV (p < 0.05). Almost half of the female cohort sustained their injuries from falling. More than half of those who sustained their injuries between midnight and morning were intoxicated. The majority of cases were treated by open reduction and internal fixation (56.8%). Posttraumatic and postoperative complications were seen in 25% of the patients, with infection (8.6%) occurring most frequently. Mandibular and zygomatic complex fractures were the most frequent in our study. IPV in association with alcohol and drugs was a major cause of maxillofacial fractures, especially among young adult males. Falls were the predominant cause of fractures among females. PMID- 26576238 TI - Treatment of Orbital Medial Wall Fractures with Titanium Mesh Plates Using Retrocaruncular Approach: Outcomes with Different Techniques. AB - Surgical management of medial wall orbital fractures should be considered to avoid diplopia and posttraumatic enophthalmos. Treatment of these fractures remains a challenge for the maxillofacial surgeon because of complex anatomy and limited vision. This article aims to retrospectively evaluate the outcomes in the repair of medial orbital wall fractures using a retrocaruncular approach and titanium meshes, comparing the placement of the titanium mesh with three different techniques: (1) conventional free hand under direct vision, (2) with the assistance of an endoscope, and (c) with the assistance of a navigation system. Eighteen patients who underwent surgery for orbital medial wall fracture were enrolled in the study. On the basis of the implant placement technique, three groups were identified: group 1 (CONV), conventional free hand under direct vision; group 2 (ENDO), endoscopically assisted; group 3 (NAVI), a navigational system assisted (BrainLab, Feldkirchen, Germany). The postoperative quality of orbital reconstruction was assessed as satisfactory in 12 cases, good in 4 cases, and unsatisfactory in 2 cases. Particularly in group 1 (CONV) in four patients out of eight, the posterior ledge of the fracture was not reached by the implant and in one patient the mesh hinged toward the ethmoid. In group 3 (NAVI), in one patient out of five, the posterior ledge of the fracture was not reached. In conclusion, titanium orbital mesh plates and retrocaruncular approach are a reliable method to obtain an accurate orbital medial wall reconstruction. The use of endoscopic assistance through the surgical incisions improves accuracy of treatment allowing better visualization of the surgical field. Navigation aided surgery is a feasible technique especially for complex orbital reconstruction to improve predictability and outcomes in orbital repair. PMID- 26576239 TI - Remodeling of Displaced Condylar Fractures with Functional Treatment: High Quality Radiographic Documentation in Three-Patient Series. AB - Treatment of condylar fractures is variable and controversial. Treatment options for management of condylar fractures include surgical and nonsurgical methods, and if a nonsurgical method is as effective as a surgical method, the former is preferred. Although plain film radiographs and functional outcomes attained through nonsurgical treatment are well established in literature, evidence of the remodeling process through detailed, high-quality imaging is lacking. The purpose of this case series is to describe and illustrate two adults and one pediatric patient with significantly displaced condylar fractures treated nonsurgically with excellent clinical results. It is unique for such patients to have pre- and posttreatment computed tomography scans with high-quality three-dimensional reconstruction as in the case of two adults and to have 3.5-year posttrauma radiographs and 14.5-year follow-up as in the case of the pediatric patient. As such, this report is useful in visually presenting three examples of repositioning and reformation of the temporomandibular joint structures in displaced condylar fractures in a postmenarche 14-year-old female patient, a 21 year-old male patient, and an 18-month-old male patient. PMID- 26576240 TI - Lower Face Asymmetry: Can We Distract the Mandibular Lower Border? AB - Orthognathic surgery and alloplastic grafting are the main stay in management in hemifacial microsomia. Distraction osteogenesis is used to increase the ramus and corpus length in the management, but here we have described a technique to increase the height of the body of the mandible using the principles of basal osteotomy and distraction osteogenesis. PMID- 26576241 TI - Medial Wall Fracture and Orbital Emphysema Mimicking Inferior Rectus Entrapment in a Child. AB - Orbital emphysema is commonly associated with fractures of the orbital floor or medial wall. The air often dissipates spontaneously, but rarely can cause increased intraocular pressure and even loss of vision. Entrapment of the extraocular muscles can also occur with orbital fractures and may require prompt treatment in the pediatric patient due to the risk muscle ischemia. Both conditions can cause diplopia due to restriction of eye movement and differentiation of the two etiologies is important to prevent unnecessary surgical exploration. Identification and prompt management of raised intraocular pressure is essential in patients with orbital trauma. We present a case of orbital emphysema mimicking inferior rectus entrapment following trauma in an 11 year-old boy. PMID- 26576242 TI - Le Fort I Approach for Midline Tumors of the Palate. AB - Midline tumors of the palate may represent a challenge for the maxillofacial surgeon. Their resection and immediate reconstruction could be hindered when a simply intraoral approach is selected. The Le Fort I downfracture approach represents an ideal technique for the management of this tumors, simplifying their resection, ensuring a tumor-free margin, and allowing their reconstruction with a temporal muscle flap. A review of this procedure is presented, highlighting the technical keys and its principal advantages. PMID- 26576243 TI - Application of Maxillomandibular Fixation for Management of Traumatic Macroglossia: A Case Report. AB - We present a case of a 14-year-old adolescent boy who has oral cavity after gunshot wound to the tongue presenting with hemorrhage from the tongue requiring coil embolization of the right lingual artery. The patient subsequently developed macroglossia, which was managed with maxillomandibular fixation for a period of 3 weeks with complete resolution of glossal edema. PMID- 26576244 TI - Penetrating Orbital-Cranial Injuries Management in a Limited Resource Hospital in Latin America. AB - Penetrating orbital-cranial injuries (POCIs) are difficult cases especially in hospitals in low-middle-income countries (LMIC) where resources are limited. We present a case series of POCI managed in a university hospital in such scenario. A retrospective case series was conducted including patients with POCI in 2011. Mechanism of injury, Glasgow Coma Scale score, imaging, medical and surgical management, complications, and Glasgow Outcome Scale (GOS) score were analyzed. A total of 30 patients with penetrating orbital injuries were admitted from March 2011 to December 2011. Of this group, only four patients were diagnosed with cranial penetration. Computed tomography (CT) angiography revealed orbital fractures and injury to frontal, temporal, or occipital lobes. Urgent craniotomy with isolation of ipsilateral carotid artery was performed. GOS score at discharge was 5 in three patients and 4 in one patient. POCIs are not uncommon in hospitals of LMIC. In such scenarios, a standard approach with CT angiography and early neurosurgical intervention results in good outcome. PMID- 26576245 TI - Complete Midline Cleft of Lower Lip, Mandible, Tongue, Floor of Mouth with Neck Contracture: A Case Report and Review of Literature. AB - Midline cleft of the lower lip and mandible is an extremely rare condition. Since 1819, when the first case was reported by Couronne, fewer than 80 cases have been described in the world literature so far. The cleft has also been described as facial cleft no. 30 by Paul Tessier. The condition varies in severity from a mild variety in which there is a submucous cleft and notching in the lower lip to a severe variety, involving the tongue, floor of the mouth, mandible, absent hyoid, atrophic neck muscles, and sternum. In this case report, a female child having complete midline cleft of the lower lip and mandible, with bifid tongue stuck to the floor of the mouth, absent hyoid bone and flexion contracture band extending from the confluence of the tip of the tongue, floor of the mouth, cleft mandible to the manubrium sterni is described, with special emphasis on surgical planning and management. PMID- 26576246 TI - Orbital Floor Fracture with Atypical Extraocular Muscle Entrapment Pattern and Intraoperative Asystole in an Adult. AB - Extraocular muscle entrapment in a nondisplaced orbital fracture, although a well known entity in pediatric trauma, is atypical in adults. It can present with a triad of bradycardia, nausea, and in rare cases, syncope, and result in severe fibrosis of damaged and incarcerated muscle. We present a case of muscle entrapment in a partially nondisplaced two-wall orbital fracture with accompanying preoperative bradycardia and intraoperative asystole in an adult. PMID- 26576247 TI - Erratum: Computer-Assisted Three-Dimensional Planning for Orbital Decompression. AB - [This corrects the article DOI: 10.1055/s-0034-1393731.]. PMID- 26576248 TI - Dynamic Cascades with Bidirectional Bootstrapping for Action Unit Detection in Spontaneous Facial Behavior. AB - Automatic facial action unit detection from video is a long-standing problem in facial expression analysis. Research has focused on registration, choice of features, and classifiers. A relatively neglected problem is the choice of training images. Nearly all previous work uses one or the other of two standard approaches. One approach assigns peak frames to the positive class and frames associated with other actions to the negative class. This approach maximizes differences between positive and negative classes, but results in a large imbalance between them, especially for infrequent AUs. The other approach reduces imbalance in class membership by including all target frames from onsets to offsets in the positive class. However, because frames near onsets and offsets often differ little from those that precede them, this approach can dramatically increase false positives. We propose a novel alternative, dynamic cascades with bidirectional bootstrapping (DCBB), to select training samples. Using an iterative approach, DCBB optimally selects positive and negative samples in the training data. Using Cascade Adaboost as basic classifier, DCBB exploits the advantages of feature selection, efficiency, and robustness of Cascade Adaboost. To provide a real-world test, we used the RU-FACS (a.k.a. M3) database of nonposed behavior recorded during interviews. For most tested action units, DCBB improved AU detection relative to alternative approaches. PMID- 26576249 TI - Porcelain repair - Influence of different systems and surface treatments on resin bond strength. AB - PURPOSE: The purpose of this study was to evaluate the bond strength of composite resin on the fracture surface of metal-ceramic depending on the repair systems and surface roughening methods. MATERIALS AND METHODS: A total of 30 disk specimens were fabricated, 15 of each were made from feldspathic porcelain and nickel-chromium base metal alloy. Each substrate was divided into three groups according to the repair method: a) application of repair system I (Intraoral Repair Kit) with diamond bur roughening (Group DP and DM), b) application of repair system I with airborne-particle abrasion (Group SP and SM), and c) application of repair system II (CoJet Intraoral Repair System, Group CP and CM). All specimens were thermocycled, and the shear bond strength was measured. The data were analyzed using the Kruskal-Wallis analysis and the Mann-Whitney test with a significance level of 0.05. RESULTS: For the porcelain specimens, group SP showed the highest shear bond strength (25.85 +/- 3.51 MPa) and group DP and CP were not significantly different. In metal specimens, group CM showed superior values of bond strength (13.81 +/- 3.45 MPa) compared to groups DM or SM. CONCLUSION: Airborne-particle abrasion and application of repair system I can be recommended in the case of a fracture localized to the porcelain. If the fracture extends to metal surface, the repair system II is worthy of consideration. PMID- 26576250 TI - Effects of core characters and veneering technique on biaxial flexural strength in porcelain fused to metal and porcelain veneered zirconia. AB - PURPOSE: The purpose of this study was to assess the impact of the core materials, thickness and fabrication methods of veneering porcelain on prosthesis fracture in the porcelain fused to metal and the porcelain veneered zirconia. MATERIALS AND METHODS: Forty nickel-chrome alloy cores and 40 zirconia cores were made. Half of each core group was 0.5 mm-in thickness and the other half was 1.0 mm-in thickness. Thus, there were four groups with 20 cores/group. Each group was divided into two subgroups with two different veneering methods (conventional powder/liquid layering technique and the heat-pressing technique). Tensile strength was measured using the biaxial flexural strength test based on the ISO standard 6872:2008 and Weibull analysis was conducted. Factors influencing fracture strength were analyzed through three-way ANOVA (alpha<=.05) and the influence of core thickness and veneering method in each core materials was assessed using two-way ANOVA (alpha<=.05). RESULTS: The biaxial flexural strength test showed that the fabrication method of veneering porcelain has the largest impact on the fracture strength followed by the core thickness and the core material. In the metal groups, both the core thickness and the fabrication method of the veneering porcelain significantly influenced on the fracture strength, while only the fabrication method affected the fracture strength in the zirconia groups. CONCLUSION: The fabrication method is more influential to the strength of a prosthesis compared to the core character determined by material and thickness of the core. PMID- 26576251 TI - Biaxial flexural strength of bilayered zirconia using various veneering ceramics. AB - PURPOSE: The aim of this study was to evaluate the biaxial flexural strength (BFS) of one zirconia-based ceramic used with various veneering ceramics. MATERIALS AND METHODS: Zirconia core material (Katana) and five veneering ceramics (Cerabien ZR; CZR, Lava Ceram; LV, Cercon Ceram Kiss; CC, IPS e.max Ceram; EM and VITA VM9; VT) were selected. Using the powder/liquid layering technique, bilayered disk specimens (diameter: 12.50 mm, thickness: 1.50 mm) were prepared to follow ISO standard 6872:2008 into five groups according to veneering ceramics as follows; Katana zirconia veneering with CZR (K/CZR), Katana zirconia veneering with LV (K/LV), Katana zirconia veneering with CC (K/CC), Katana zirconia veneering with EM (K/EM) and Katana zirconia veneering with VT (K/VT). After 20,000 thermocycling, load tests were conducted using a universal testing machine (Instron). The BFS were calculated and analyzed with one-way ANOVA and Tukey HSD (alpha=0.05). The Weibull analysis was performed for reliability of strength. The mode of fracture and fractured surface were observed by SEM. RESULTS: It showed that K/CC had significantly the highest BFS, followed by K/LV. BFS of K/CZR, K/EM and K/VT were not significantly different from each other, but were significantly lower than the other two groups. Weibull distribution reported the same trend of reliability as the BFS results. CONCLUSION: From the result of this study, the BFS of the bilayered zirconia/veneer composite did not only depend on the Young's modulus value of the materials. Further studies regarding interfacial strength and sintering factors are necessary to achieve the optimal strength. PMID- 26576252 TI - Effect of abutment shade, ceramic thickness, and coping type on the final shade of zirconia all-ceramic restorations: in vitro study of color masking ability. AB - PURPOSE: The aim of the study was to evaluate the effect of abutment shade, ceramic thickness, and coping type on the final shade of zirconia all-ceramic restorations. MATERIALS AND METHODS: Three different types of disk-shaped zirconia coping specimens (Lava, Cercon, Zirkonzahn: o10 mm * 0.4 mm) were fabricated and veneered with IPS e.max Press Ceram (shade A2), for total thicknesses of 1 and 1.5 mm. A total of sixty zirconia restoration specimens were divided into six groups based on their coping types and thicknesses. The abutment specimens (o10 mm * 7 mm) were prepared with gold alloy, base metal (nickel chromium) alloy, and four different shades (A1, A2, A3, A4) of composite resins. The average L*, a*, b* values of the zirconia specimens on the six abutment specimens were measured with a dental colorimeter, and the statistical significance in the effects of three variables was analyzed by using repeated measures analysis of variance (alpha=.05).The average shade difference (DeltaE) values of the zirconia specimens between the A2 composite resin abutment and other abutments were also evaluated. RESULTS: The effects of zirconia specimen thickness (P<.001), abutment shade (P<.001), and type of zirconia copings (P<.003) on the final shade of the zirconia restorations were significant. The average DeltaE value of Lava specimens (1 mm) between the A2 composite resin and gold alloy abutments was higher (close to the acceptability threshold of 5.5 DeltaE) than th ose between the A2 composite resin and other abutments. CONCLUSION: This in-vitro study demonstrated that abutment shade, ceramic thickness, and coping type affected the resulting shade of zirconia restorations. PMID- 26576253 TI - Loosening torque of Universal Abutment screws after cyclic loading: influence of tightening technique and screw coating. AB - PURPOSE: The purpose of this study was to evaluate the influence of tightening technique and the screw coating on the loosening torque of screws used for Universal Abutment fixation after cyclic loading. MATERIALS AND METHODS: Forty implants (Titamax Ti Cortical, HE, Neodent) (n=10) were submerged in acrylic resin and four tightening techniques for Universal Abutment fixation were evaluated: A - torque with 32 Ncm (control); B - torque with 32 Ncm holding the torque meter for 20 seconds; C - torque with 32 Ncm and retorque after 10 minutes; D - torque (32 Ncm) holding the torque meter for 20 seconds and retorque after 10 minutes as initially. Samples were divided into subgroups according to the screw used: conventional titanium screw or diamond like carbon-coated (DLC) screw. Metallic crowns were fabricated for each abutment. Samples were submitted to cyclic loading at 10(6) cycles and 130 N of force. Data were analyzed by two way ANOVA and Tukey's test (5%). RESULTS: The tightening technique did not show significant influence on the loosening torque of screws (P=.509). Conventional titanium screws showed significant higher loosening torque values than DLC (P=.000). CONCLUSION: The use of conventional titanium screw is more important than the tightening techniques employed in this study to provide long-term stability to Universal Abutment screws. PMID- 26576254 TI - Evaluation of dental panoramic radiographic findings in edentulous jaws: A retrospective study of 743 patients "Radiographic features in edentulous jaws". AB - PURPOSE: The aim of this study was to determine the frequency of significant panoramic radiographic findings and eventual treatment requirements before conventional or implant supported prosthetic treatment in asymptomatic edentulous patients. MATERIALS AND METHODS: A total of 743 asymptomatic edentulous patients were retrospectively evaluated using a digital panoramic system. We analyzed the radiographic findings, including impacted teeth, retained root fragments, foreign bodies, severe atrophy of the posterior maxillary alveolar bone, mucous retention cysts, soft tissue calcifications and radiopaque-radiolucent conditions. RESULTS: Four-hundred-eighty-seven (65.6%) patients had no radiographic finding. A total of 331 radiographic findings were detected in 256 (34%) patients. In 52.9% (n=175) of these conditions, surgical treatment was required before application of implant-supported fixed prosthesis. However, before application of conventional removable prosthesis surgical treatment was required for 6% (n=20) of these conditions. CONCLUSION: The edentulous patients who will have implant placement for implant-supported fixed prosthesis can frequently require additional surgical procedures to eliminate pathological conditions. PMID- 26576255 TI - The effect of 4,4'-bis(N,N-diethylamino) benzophenone on the degree of conversion in liquid photopolymer for dental 3D printing. AB - PURPOSE: The purpose of this preliminary study was to investigate the effects of adding 4,4'-bis(N,N-diethylamino) benzophenone (DEABP) as a co-initiator to a binary photoinitiating system (camphorquinone-amine) to analyze on the degree of conversion (DC) of a light-cured resin for dental 3D printing. MATERIALS AND METHODS: Cylindrical specimens (N=60, n=30 per group, o5 mm * 1 mm) were fabricated using bisphenol A glycerolate dimethacrylate (BisGMA) both with and without DEABP. The freshly mixed resins were exposed to light in a custom-made closed chamber with nine light-emitting diode lamps (wavelength: 405 nm; power: 840 mW/cm(2)) for polymerization at each incidence of light-irradiation at 10, 30, 60, 180, and 300 seconds, while five specimens at a time were evaluated at each given irradiation point. Fourier-transform infrared (FTIR) spectroscopy was used to measure the DC values of the resins. Two-way analysis of variance and the Duncan post hoc test were used to analyze statistically significant differences between the groups and given times (alpha=.05). RESULTS: In the DEABP-containing resin, the DC values were significantly higher at all points in time (P<.001), and also the initial polymerization velocity was faster than in the DEABP-free resin. CONCLUSION: The addition of DEABP significantly enhanced the DC values and, thus, could potentially become an efficient photoinitiator when combined with a camphorquinone-amine system and may be utilized as a more advanced photopolymerization system for dental 3D printing. PMID- 26576256 TI - Effect of metal primers and tarnish treatment on bonding between dental alloys and veneer resin. AB - PURPOSE: The aim of this study was to evaluate the effect of metal primers on the bonding of dental alloys and veneer resin. Polyvinylpyrrolidone solution's tarnish effect on bonding strength was also investigated. MATERIALS AND METHODS: Disk-shape metal specimens (diameter 8 mm, thickness 1.5 mm) were made from 3 kinds of alloy (Co-Cr, Ti and Au-Ag-Pd alloy) and divided into 4 groups per each alloy. Half specimens (n=12 per group) in tarnished group were immersed into polyvinylpyrrolidone solution for 24 hours. In Co-Cr and Ti-alloy, Alloy Primer (MDP + VBATDT) and MAC-Bond II (MAC-10) were applied, while Alloy Primer and V Primer (VBATDT) were applied to Au-Ag-Pd alloys. After surface treatment, veneering composite resin were applied and shear bond strength test were conducted. RESULTS: Alloy Primer showed higher shear bond strength than MAC-Bond II in Co-Cr alloys and Au-Ag-Pd alloy (P<.05). However, in Ti alloy, there was no significant difference between Alloy Primer and MAC-Bond II. Tarnished Co-Cr and Au-Ag-Pd alloy surfaces presented significantly decreased shear bond strength. CONCLUSION: Combined use of MDP and VBATDT were effective in bonding of the resin to Co-Cr and Au-Ag-Pd alloy. Tarnish using polyvinylpyrrolidone solution negatively affected on the bonding of veneer resin to Co-Cr and Au-Ag-Pd alloys. PMID- 26576257 TI - The effect of powder A2/powder A3 mixing ratio on color and translucency parameters of dental porcelain. AB - PURPOSE: The purpose of this study is to mix dental ceramic powder in varying ratios and evaluate the effect of the mixing ratio on color and translucency. MATERIALS AND METHODS: The ceramic powder of shade A3 of the same product was mixed with the shade A2 of three products: IPS e.max Ceram (Ivoclar Vivadent, Schaan, Liechtenstein), Vintage Halo (SHOFU Inc., Kyoto, Japan), and Ceramco 3 (Ceramco-Dentsply, Burlington, NJ, USA) in the following fixed ratios (0 wt%, 25 wt%, 50 wt%, 75 wt%, and 100 wt%) and then fired. A total of 150 specimen of ceramic fired were manufactured in a regular size (W: 8.5 mm, L: 10.5 mm, and H: 1.5 mm). For color and translucency, L*, a*, and b* were measured and Two-way analysis of variance (ANOVA) and One-way analysis of variance (ANOVA) were used for data analysis (alpha=0.05). RESULTS: The higher the mixing ratio was, L*, a*, and b* of IPS e.max Ceram were all increased, and L* of Vintage Halo was reduced and a* and b* were increased. L* and a* of Ceramco3 were reduced and b* of Ceramco3 was increased. Color difference (DeltaE*ab) was increased in all three products as the mixing ratio got higher. Increased mixing ratios resulted in decreased translucency parameter (TP) values for IPS e.max Ceram but increased TP values for Vintage Halo and Ceramco3. CONCLUSION: In this limited study, CIE L*, a*, and b* were influenced by the mixing ratio of the A3 powders and porcelain powder mixtures represented a various color and translucency. PMID- 26576258 TI - Prosthetic management of a growing patient with Russell-Silver syndrome: a clinical report. AB - Russell-Silver syndrome (RSS) is a congenital disease characterized by short stature due to growth hormone deficiency, physical asymmetry, inverted triangular face, micrognathia, prominent forehead, and hypodontia. This case report presents a prosthetic management of a 6-year-old patient with Russell-Silver syndrome treated with overdentures on the maxilla and the mandible using the remaining primary teeth. Subsequent and comprehensive dental management considering the growth and development of a young patient will be necessary. PMID- 26576259 TI - Competitive Market Analysis of Transplant Centers and Discrepancy of Wait-Listing of Recipients for Kidney Transplantation. AB - BACKGROUND: There are over 250 kidney transplant programs in the USA. OBJECTIVE: To determine if highly competitive regions, defined as regions with a higher number of transplant centers, will approve and wait-list more end-stage renal disease (ESRD) candidates for transplant despite consistent incidence and prevalence of ESRD nationwide. METHODS: ESRD Network and OPTN data completed in 2011 were obtained from all transplant centers including listing data, market saturation, market share, organs transplanted, and ESRD prevalence. Herfindahl Hirschman Index (HHI) was used to measure the size of firms in relation to the industry to determine the amount of competition. RESULTS: States were separated into 3 groups (HHI<1000 considered competitive; HHI 1000-1800 considered moderate competition; and HHI>1800 considered highly concentrated). The percentage of ESRD patients listed in competitive, moderate, and highly concentrated regions were 19.73%, 17.02%, and 13.75%, respectively. The ESRD listing difference between competitive versus highly concentrated was significant (p<0.05). CONCLUSION: When there is strong competition without a dominant center as defined by the HHI, the entire state tends to list more patients for transplant to drive up their own center's market share. Our analysis of the available national data suggests a discrepancy in access for ESRD patient to transplantation due to transplant center competition. PMID- 26576260 TI - Comparison of the Effect of Alemtuzumab versus Standard Immune Induction on Early Kidney Allograft Function in Shiraz Transplant Center. AB - BACKGROUND: Induction therapy regimens classified as conventional immunosuppressive agents and lower doses of conventional agents combined with antibodies against T-cell antigens have been purposed to prevent acute rejection after renal transplantation. Various induction agents with different doses and durations have been suggested based on the risk profile of patients. OBJECTIVE: To assess the acute rejection rate (total rate and based on the type of induction therapy regimen) during the first year after kidney transplantation, the type of acute rejection based on Banff classification and to determine the associations between rate of acute rejection, type of the rejection and induction therapy regimen. METHODS: 249 kidney transplant candidates were divided into two groups low-risk patients (n=208) who received conventional immunosuppressive agents, and high-risk patients (n=41) who received alemtuzumab-and followed for one year to detect acute rejection first diagnosed clinically, and confirmed by percutaneous kidney biopsy based on Banff criteria. RESULTS: The total incidence of acute rejection was 19.6% (20.7% of the low-risk and 14.4% of the high-risk patients). The most prevalent types of the acute rejection in patients treated with conventional immunosuppressive agents and patients received alemtuzumab as induction therapy were grade IB and grade IA, respectively. The incidence of acute rejection among recipients received a kidney from a deceased donor was 20.6% and grade IA was the most prevalent type (6.9%) whereas the most prevalent grade of acute rejection in patients who received living donor grafts was IB (8.3%). CONCLUSION: Despite the expected greater risk for acute rejection among high-risk patients, no significant difference was observed between low- and high risk patients, which may be justified by the greater efficacy of alemtuzumab compared with standard triple induction therapy in reducing the rate of acute rejection. PMID- 26576261 TI - Awareness of Religious Leaders' Fatwa and Willingness to Donate Organ. AB - BACKGROUND: It is believed that religious leaders' positive attitude towards organ donation can be an effective factor in Muslims' inclination to donate organs. OBJECTIVE: To assess the knowledge of freshmen students in Mashhad University of Medical Sciences about religious leaders' fatwa on organ donation and its effect on their willingness to donate organs. METHODS: This cross sectional study was conducted in 2013 on 400 freshmen of various medical disciplines, selected using a simple random sampling in Mashhad, Iran. Data were collected by a valid and reliable researcher-made questionnaire. Data were analyzed by multiple logistic regression analysis. RESULTS: 41.5% of the students were aware of religious authorities' views on organ donation and 55.6% were willing to donate organs. Participants' main reasons for lack of willingness to donate organs included the fear of organ donation before the brain death is confirmed (52%), unwillingness to disfigure their body (51%), and belief in the burial of organs (50%). The willingness to organ donation for students who were aware of religious leaders opinion was more than twice more than those who were not (OR: 2.56, 95% CI: 1.75-4.52). Also, female gender, the Shia religion and awareness of the correct definition of brain death were associated factors affecting the desire to donate organs, although their effects were not statistically significant on regression model. CONCLUSION: A considerable proportion of students were not aware of the religious leaders' fatwa on organ donation. The most important factor for the desire to donate organs was the awareness of religious leaders' fatwa. Therefore, it seems necessary that religious leaders' fatwa be known to all by appropriate methods. PMID- 26576262 TI - The Healing Effect of Adipose-Derived Mesenchymal Stem Cells in Full-thickness Femoral Articular Cartilage Defects of Rabbit. AB - BACKGROUND: Articular cartilage defect can lead to degradation of subchondral bone and osteoarthritis (OA). OBJECTIVE: To determine the healing effect of transplantation of adipose-derived mesenchymal stem cells (Ad-MSCs) in full thickness femoral articular cartilage defects in rabbit. METHODS: 12 rabbits were equally divided into cell-treated and control groups. In cell-treated group, 2*10(6) cells of third passage suspended in 1 mL of DMEM was injected into articular defect. The control group just received 1 mL of DMEM. Dulbecco's modified Eagles medium (DMEM) supplemented with 10% fetal bovine serum (FBS), 1% penicillin and streptomycin and 2 mM L-glutamine were used for cell culture. To induce cartilage defect, 4 mm articular cartilage full-thickness defect was created in the knee. For histological evaluation in each group (H&E, safranin-O and toluidine blue), 3 rabbits were sacrificed 4 weeks and 3 animals, 8 weeks after cell transplantation. RESULTS: In cell therapy group post-transplantation, no abnormal gross findings were noticed. Neo-formed tissues in cell-treated groups were translucent with a smooth and intact surface and less irregularity. In cell-treated group after 8 weeks post-transplantation, the overall healing score of experimental knees were superior when compared to other groups. CONCLUSION: We showed that Ad-MSCs, as an available and non-invasive produced source of cells, could be safely administered in knee osteochondral defects. PMID- 26576263 TI - Bone Reconstruction following Application of Bone Matrix Gelatin to Alveolar Defects: A Randomized Clinical Trial. AB - BACKGROUND: Conventional dentoalveolar osseous reconstruction often involves the use of graft materials with or without barrier membranes. OBJECTIVE: To evaluate the efficacy of bone induction by bone matrix gelatin (BMG), delivered on an absorbable collagen sponge (ACS), compared to a placebo (ACS alone) in human alveolar socket defects. METHODS: 20 alveolar sockets from 10 healthy adults were studied. In all cases, both the mandibular premolar area and the contralateral premolar area (as the control site) were involved. In each of the 10 patients, the extraction sites were filled randomly with BMG and ACS. The repair response was examined on day 90. Qualitative histological and quantitative histometric analysis, including the percentage of new-formed bone fill and density were done. RESULTS: Assessment of the alveolar bone indicated that patients treated with BMG had significantly (p<0.05) better bone quality and quantity compared to the controls. In addition, bone density and histology revealed no differences between the newly induced and native bone. CONCLUSION: The data from this single-blind clinical trial demonstrated that the novel combination of BMG had a striking effect on de novo osseous formation for the bone regeneration. PMID- 26576264 TI - Is the Left Kidney the Right One for Kidney Donation in Women Planning on Future Pregnancy? AB - The kidney transplantation surgery requires left nephrectomy because of the anatomical disadvantages. But hydroureteronephrosis is the most significant renal functional alteration of pregnancy, accounted for by both hormonal and mechanical factors. Dilatation of the ureters and renal pelvis is more prominent on the right side than the left side and is seen in up to 80% of pregnant women. A 23 year-old woman who become pregnant after 4 months from left kidney donation was admitted to our emergency department with acute right kidney injury during her 39(th) week of pregnancy. She did not response to conservative treatment and required emergency delivery because of the progressive increase in her serum creatinine levels. After delivery, progressive decrease at creatinine level had been observed and in one month, it had reached the normal level. Mother candidates should be advised they donate their kidneys after completing their childbearing if possible, or undergo right nephrectomy. PMID- 26576265 TI - Retained Foreign Body in Transplanted Liver. AB - Liver transplantation is a technically complex and long surgical procedure. A large quantity of various materials such as catheters, sutures, needles and clips are frequently used during the procedure. These materials may enter in the liver from the vascular or biliary orifices inadvertently. A 50-year-old patient who had hepatic failure due to HBV underwent a deceased-donor liver transplantation. The deceased donor was a 75-year-old HbsAg(+) man. The recipient had subfebrile fever and leukocytosis post-operatively. A control computed tomography revealed a cuneiform ischemic area, and a foreign body inside the right anterior portal vein branch proximal to this ischemic region. A 10-F Nelaton catheter, 5-cm long, was removed from the portal vein by surgery. Retrospectively, we understood that the portal vein was cut during the back-table procedure and the portal vein catheter was replaced with a larger one for better irrigation. Most probably, the original catheter was cut together with the portal vein, and the tip of the catheter was retained in the portal system and migrated into the liver. As far as we know, such a complication of liver transplantation has never been described previously. PMID- 26576266 TI - Wearing American Football helmets increases cervicocephalic kinaesthetic awareness in "elite" American Football players but not controls. AB - BACKGROUND: While there have been investigations into the reduced neck injury rate of wearing protective helmets, there is little information on its effects on normal kinaesthetic neck function. This study aims to quantify the kinaesthetic and movement effects of the American football helmet. METHODS: Fifteen British Collegiate American football players (mean age 22.2, SD 1.9; BMI kg.m(2) 26.3, SD 3.7) were age and size matched to 11 non-American football playing university students (mean age 22.5, SD 3.6; BMI 24.3, SD 3.3 kg.m(2)). Both groups had their active cervical range of motion and head repositioning accuracy measured during neck flexion/extension using a modified cervical range of motion device and a similarly modified football helmet. RESULTS: Wearing helmets significantly reduced active cervical range of motion in extension in both groups (P = 0.007 and P = 0.001 Controls and American Footballers respectively). While both groups had similar repositioning when not wearing a helmet (flexion P = 0.99; extension P = 0.52), when wearing helmets, American football players appeared to be more accurate in relation to cervical kinaesthetic repositioning (ANOVA: P = 0.077: flexion effect size =0.84; extension effect size =0.38). CONCLUSIONS: Wearing American football helmets significantly reduces the active cervical range of motion in extension, along with a change in the neutral head position. American footballers have a greater accuracy in repositioning their head from flexion (potentially enhanced proprioception) when wearing a helmet. This finding might allow development of a simple objective test to help discern presence of minor concussive or cervical musculoskeletal injury on or off the field. PMID- 26576267 TI - Microbiome in NAFLD and ALD. PMID- 26576268 TI - Poor quality in the reporting and use of statistical methods in public health - the case of unemployment and health. AB - BACKGROUND: It has previously been reported that many research articles fail to fulfill important criteria for statistical analyses, but, to date, these reports have not focused on public health problems. The aim of this study was to investigate the quality of reporting and use of statistical methods in articles analyzing the effect of unemployment on health. METHODS: Forty-one articles were identified and evaluated in terms of how they addressed 12 specified criteria. RESULTS: For most of these criteria, the majority of articles were inadequate. These criteria were conformity with a linear gradient (100 % of the articles), validation of the statistical model (100 %), collinearity of independent variables (97 %), fitting procedure (93 %), goodness of fit test (78 %), selection of variables (68 % for the candidate model; 88 % for the final model), and interactions between independent variables (66 %). Fewer, but still alarmingly many articles, failed to fulfill the criteria coefficients presented in statistical models (48 %), coding of variables (34 %) and discussion of methodological concerns (24 %). There was a lack of explicit reporting of statistical significance/confidence intervals; 34 % of the articles only presented p-values as being above or below the significance level, and 42 % did not present confidence intervals. Events per variable was the only criterion met at an undoubtedly acceptable level (2.5 %). CONCLUSIONS: There were critical methodological shortcomings in the reviewed studies. It is difficult to obtain unbiased estimates, but there clearly needs to be some improvement in the quality of documentation on the use and performance of statistical methods. A suggestion here is that journals not only demand that articles fulfill the criteria within the STROBE statement, but that they include additional criteria to decrease the risk of incorrect conclusions being drawn. PMID- 26576269 TI - Imaging characteristics of disseminated Geosmithia argillacea causing severe diskospondylitis and meningoencephalomyelitis in a dog. AB - A 4-year-old male castrated Labrador Retriever presented for severe spinal pain. Radiographs and magnetic resonance imaging showed evidence of diskospondylitis and meningoencephalomyelitis. Blood culture revealed a Geosmithia argillacea fungal infection after DNA sequencing, initially misdiagnosed as Penicillium species. Geosmithia argillacea should be considered as a differential for disseminated fungal diskospondylitis. PMID- 26576270 TI - Effect of proper oral rehabilitation on general health of mandibulectomy patients. AB - Here, we aimed to assess whether postoperative oral rehabilitation for mandibulectomy patients is necessary to improve patients' general health in terms of health-related quality of life. PMID- 26576271 TI - Ovarian ectopic pregnancy in adolescence. AB - Ovarian pregnancy is one of the rarest types of extrauterine pregnancy. Its preoperative diagnosis remains a challenge since it presents quite similarly to tubal pregnancy and complicated ovarian cysts. Although in most cases, histology is necessary to confirm the diagnosis, we present an ovarian pregnancy in a teenager, correctly diagnosed during ultrasound examination. PMID- 26576272 TI - Long-term persistent fetomaternal hemorrhage. AB - It is not clear that how long the affected fetuses can tolerate fetomaternal hemorrhage (FMH). Incidental serial measurements of the fetal peak systolic velocity of the middle cerebral artery and the retrospective analysis of stocked blood available incidentally indicated that our patient had suffered from FMH for at least 2 weeks prior to delivery. PMID- 26576273 TI - Implant assisted ortho-surgery in edentulous jaws: a clinical report. AB - The severely atrophy of jaws often complicates ideally oral reconstruction of esthetics and functionality, and necessitates different preprosthetic surgeries including bone grafting, ortho-surgery, and implant insertion. The mentioned procedures could be done within different approaches. This report describes the management of an edentulous case by implant insertion before orthognathic correction. PMID- 26576274 TI - Dual antiplatelet agents and Rivaroxaban for massive intracoronary thrombus in STEMI. AB - Management of intracoronary thrombus in patients presenting more than 12 hours after the onset of ST elevation myocardial infarction is challenging. We present such a case which had massive thrombus in left anterior descending artery. It was managed successfully with dual antiplatelet agents and factor Xa inhibitor rivaroxaban administered orally. PMID- 26576275 TI - High-flux hemodialysis after administering high-dose methotrexate in a patient with posttransplant lymphoproliferative disease and impaired renal function. AB - A young patient develops cerebral posttransplant lymphoproliferative disorder. Despite concurrent significantly impaired transplant kidney function use of add on high-flux hemodialysis for additional clearance made the administration of high-dose methotrexate feasible in this patient without occurence of acute chronic kidney failure and significant hematological toxicity. PMID- 26576276 TI - Can stapedius reflex testing objectively measure muscle function in Pompe patients? AB - We assessed the value of stapedius reflex testing as an objective measurement of striated muscle function in four patients with Pompe disease. Common tests of disease severity and efficacy of enzyme replacement therapy (ERT) yield highly variable results that depend on patient cooperation and day-to-day performance, whereas stapedius reflex thresholds improved in seven of eight ears after 2 years of ERT. PMID- 26576277 TI - Eculizumab as a bridge to immunosuppressive therapy in severe cold agglutinin disease of anti-Pr specificity. AB - Severe cold agglutinin disease with hemodynamic compromise requires rapid stabilization of the autoimmune hemolytic anemia as a bridge to the immunosuppressive effect of rituximab. Herein, we describe eculizumab treatment of severe complement-mediated hemolysis in a patient whose hemodynamic status deteriorated in spite of supportive blood transfusions and therapeutic plasma exchange. PMID- 26576278 TI - Severe scalp hair loss in a female patient with acromegaly treated with lanreotide autogel after unsuccessful surgery. AB - Scalp hair loss is an underreported adverse event of somatostatin analogs therapy that in severe cases may require treatment withdrawal. It can be related to an acute decrease in GH/IGF-1 levels, but a direct effect cannot be ruled out. PMID- 26576279 TI - Unusual U wave induced by reconstructed retrosternal esophagus. AB - The present case shows that a broad compression of the right ventricle by the reconstructed stomach tube after esophagus cancer surgery induced an abnormal U wave. When facing an abnormal ECG, we should keep in mind of the mechanical compression to the heart as a differential diagnosis. PMID- 26576280 TI - Iron overload-related heart failure in a patient with transfusion-dependent myelodysplastic syndrome reversed by intensive combined chelation therapy. AB - Patients with transfusion-dependent myelodysplastic syndromes (MDS) have an increased risk of cardiac events, due to both chronic anemia and iron overload. Here, we report the recovery of cardiac function after an intensive iron chelation therapy in a MDS patient who had developed heart failure due to iron overload. PMID- 26576281 TI - Spontaneous remission in three cases of AML M5 with NPM1 mutation. AB - Patients with NPM1-mutated AML M5 who develop spontaneous remission (SR) after antibiotic therapy at diagnosis seem to form a favorable prognosis and chemo sensitive subtype. We report three cases of AML M5 patients with the same genotype that experienced transient SR and are now leukemia free after standard treatment. PMID- 26576282 TI - When collateral vessels matter: asymptomatic Leriche syndrome. AB - While acute arterial occlusion causes life-threatening ischemia and organ damage requiring urgent revascularization, the incidental identification of arterial occlusions in asymptomatic patients represents a therapeutic dilemma in clinicians. Does chronic asymptomatic artery occlusion require specific treatment? PMID- 26576283 TI - Suicide in adolescents with depression: the need for early diagnosis. AB - Adolescent suicide is a public health problem worldwide. Parents and family play a crucial role in seeking professional help early enough to avoid catastrophic outcomes such as the death of a teenager. PMID- 26576284 TI - Appearance of a colovesical fistula at cystoscopy. AB - Colovesical fistulae typically present with pneumaturia and/or fecaluria. Diverticulitis, inflammatory bowel disease, and malignancies of the colon are the commonest causes. The fistulous tract and adjacent organs are best demonstrated by contrast-enhanced CT scan with rectal contrast or MRI. Biopsy at cystoscopy/colonoscopy is necessary for complete evaluation and treatment planning. PMID- 26576285 TI - Chronic total uterine inversion in an adolescent. AB - Uterine inversion is rarely seen in adolescents in western countries. But it might be seen in teenagers and adolescents due to poor conditions and early pregnancies in Africa. And early troubleshooting chronic uterine inversion represents an early resolution of the problem and allows planning pregnancy without complications. PMID- 26576286 TI - Phasic disappearance of left circumflex coronary artery from an early complication of mitral valve surgery. AB - LV pseudoaneurysm can be a late complication of mitral valve replacement. In our case, it was an early postoperative complication. This pseudoaneurysm was causing compression of LCX artery during systole, leading to presentation of NSTEMI two weeks after the surgery. PMID- 26576287 TI - Assessment of the frequency of sperm annulus defects in a large cohort of patients presenting asthenozoospermia. AB - BACKGROUND: The annulus is a ring-shaped structure located beneath the plasma membrane that connects the midpiece and the principal piece of mammalian sperm flagellum. It has been suggested that the annulus acts as a morphological organizer, guiding flagellum assembly during spermiogenesis, and as a diffusion barrier, confining proteins to distinct compartments of the flagellum in mature sperm. Previous studies on small cohorts of patients have attempted to correlate annulus defects with the occurrence of human asthenozoospermia. An absence of the annulus has been shown to be frequently associated with asthenozoospermia. FINDINGS: We tried to obtain a more precise estimate of the frequency of annulus defects, by screening a large cohort of 254 men presenting asthenozoospermia (mean progressive motility of 24 %) by the immunodetection of SLC26A8, a transmembrane protein that has been shown to be specifically localized to the annulus. By contrast to previous reports, our results indicate that annulus defects are associated with asthenozoospermia in only 1.2 % of cases. CONCLUSIONS: We conclude that defects or an absence of the annulus are not frequently associated with asthenozoospermia. The use of annulus defects as a diagnostic endpoint in patients is therefore not appropriate. PMID- 26576288 TI - Endocrine abnormalities in ring chromosome 11: a case report and review of the literature. AB - Ring chromosomes (RCs) are uncommon cytogenetic findings, and RC11 has only been described in 19 cases in the literature. Endocrine abnormalities associated with RC11 were reported for two of these cases. The clinical features of RC11 can result from an alteration in the structure of the genetic material, ring instability, mosaicism, and various extents of genetic material loss. We herein describe a case of RC11 with clinical features of 11q-syndrome and endocrine abnormalities that have not yet been reported. A 20-year-old female patient had facial dysmorphism, short stature, psychomotor developmental delays, a ventricular septal defect, and thrombocytopenia. Karyotyping demonstrated RC11 (46,XX,r(11)(p15q25)). This patient presented with clinical features that may be related to Jacobsen syndrome, which is caused by partial deletion of the long arm of chromosome 11. Regarding endocrine abnormalities, our patient presented with precocious puberty followed by severe hirsutism, androgenic alopecia, clitoromegaly, and amenorrhea, which were associated with overweight, type 2 diabetes mellitus (T2DM), and hyperinsulinemia; therefore, this case meets the diagnostic criteria for polycystic ovary syndrome. Endocrine abnormalities are rare in patients with RC11, and the association of RC11 with precocious puberty, severe clinical hyperandrogenism, insulin resistance, and T2DM has not been reported previously. We speculate that gene(s) located on chromosome 11 might be involved in the pathogenesis of these conditions. Despite the rarity of RCs, studies to correlate the genes located on the chromosomes with the phenotypes observed could lead to major advances in the understanding and treatment of more prevalent diseases. LEARNING POINTS: We hypothesize that the endocrine features of precocious puberty, severe clinical hyperandrogenism, insulin resistance, and T2DM might be associated with 11q-syndrome.A karyotype study should be performed in patients with short stature and facial dysmorphism.Early diagnosis and adequate management of these endocrine abnormalities are essential to improve the quality of life of the patient and to prevent other chronic diseases, such as diabetes and its complications. PMID- 26576289 TI - Non-infectious cholecystopathy secondary to high-dose IL-2 cancer immunotherapy. AB - Interleukin-2 (IL-2) associated cholecystopathy is a rare manifestation of IL-2 drug toxicity in the setting of cancer immunotherapy. While the imaging data and clinical presentation can easily mimic acute cholecystitis, the correct diagnosis can be made with the particular clinical history, thus avoiding inappropriate surgical management. As more cancer immunotherapies become standard oncologic treatments, specific immunotherapy-associated side effects are also expected to be encountered more frequently in the future and should be recognized as such. We present a case of IL-2-associated cholecystopathy in the setting of renal cell carcinoma immunotherapy. PMID- 26576291 TI - Corneal Biomechanical Properties in Myopic Eyes Measured by a Dynamic Scheimpflug Analyzer. AB - Purpose. To evaluate the corneal biomechanical parameters in myopic and emmetropic eyes using Corneal Visualization Scheimpflug Technology (CorVis ST). Methods. 103 myopic and emmetropic eyes of 103 patients were examined. Corneal biomechanical parameters, axial length, and mean keratometry were measured using CorVis ST, IOL Master, and topography, respectively. Corneal biomechanical properties were compared within four groups. Bivariate correlation analysis was used to assess the relationship between corneal biomechanical parameters and ocular characteristics. Results. Four of ten corneal biomechanical parameters, namely, deformation amplitude (DA), first- and second-applanation time (A1-time, A2-time), and radius at highest concavity (HC radius), were significantly different within the four groups (P < 0.05). In correlation analysis, DA was positively correlated with axial length (r = 0.20, P = 0.04); A2-time was positively correlated with spherical equivalent (SE) (r = 0.24, P = 0.02); HC radius was positively correlated with SE (r = 0.24, P = 0.02) and was negatively correlated with mean keratometry (r = -0.20, P = 0.046) and axial length (r = 0.21, P = 0.03). Conclusions. The corneal refraction-related biomechanical alterations were associated with ocular characteristics. Highly myopic eyes exhibited longer DA and smaller HC radius than do moderately myopic eyes; the eyes with longer axial length tend to have less corneal stiffness and are easier to deform under stress. PMID- 26576292 TI - The Success of Cataract Surgery and the Preoperative Measurement of Retinal Function by Electrophysiological Techniques. AB - Purpose. To study the effect of different electrophysiological methods to evaluate retinal function prior to cataract surgery. Methods. Cataract patients who had no significant other eye disease were chosen. VA, pattern visual evoked potential (PVEP), electroretinogram (ERG), and multifocal electroretinogram (mfERG) responses were measured from 150 cataract patients and 20 control subjects. Results. When the preoperative VA was more than 0.3 in cataract patients, the amplitude of PVEP was not significantly different between cataract and control subjects. The amplitude of central point mfERG was significantly lower in cataract patients compared with control group from HM to 0.8 of preoperative VA. The 95% confidence intervals (CIs) of the amplitudes of center point mfERG were calculated for a range of preoperative VA values. Most of the patients within 95% CI of the center point mfERG had a postoperative VA more than 0.5. Conclusions. The amplitude of central point mfERG in cataract patients was the most relevant parameter to the preoperative VA compared with PVEP and ERG. The 95% CI of the amplitude of central point mfERG for each level of VA could help to evaluate preoperative macular function which is used to predict the outcome of cataract surgery. PMID- 26576290 TI - Complex Membrane Channel Blockade: A Unifying Hypothesis for the Prodromal and Acute Neuropsychiatric Sequelae Resulting from Exposure to the Antimalarial Drug Mefloquine. AB - The alkaloid toxin quinine and its derivative compounds have been used for many centuries as effective medications for the prevention and treatment of malaria. More recently, synthetic derivatives, such as the quinoline derivative mefloquine (bis(trifluoromethyl)-(2-piperidyl)-4-quinolinemethanol), have been widely used to combat disease caused by chloroquine-resistant strains of the malaria parasite, Plasmodium falciparum. However, the parent compound quinine, as well as its more recent counterparts, suffers from an incidence of adverse neuropsychiatric side effects ranging from mild mood disturbances and anxiety to hallucinations, seizures, and psychosis. This review considers how the pharmacology, cellular neurobiology, and membrane channel kinetics of mefloquine could lead to the significant and sometimes life-threatening neurotoxicity associated with mefloquine exposure. A key role for mefloquine blockade of ATP sensitive potassium channels and connexins in the substantia nigra is considered as a unifying hypothesis for the pathogenesis of severe neuropsychiatric events after mefloquine exposure in humans. PMID- 26576293 TI - Comparison of ExPress Mini-Device Implantation Alone or Combined with Phacoemulsification for the Treatment of Open-Angle Glaucoma. AB - We propose comparative assessment of the effectiveness of two surgical methods for the treatment of open-angle glaucoma: (1) ExPress mini-device implantation combined with phacoemulsification and (2) ExPress mini-device implantation alone. In this prospective study, 81 patients (88 phakic eyes) with uncontrolled open angle glaucoma enrolled for surgery. They were assigned two groups, those with coexisting cataracts (46 eyes; P-ExPress group) and those with glaucoma alone (42 eyes; ExPress group). The follow-up period was 12.9 +/- 0.4 months in P-ExPress and 12.2 +/- 0.6 months in ExPress group. In both groups the following parameters were measured: best corrected visual acuity (BCVA), intraocular pressure (IOP), number of complications and necessary postoperative interventions, and number of glaucoma medications. The IOP at the end of follow-up was similar in both groups (18.8 +/- 5.9 versus 18.1 +/- 4.8 mmHg; P = 0.814). There were no statistical differences in the average number of glaucoma medications between ExPress and P ExPress groups (0.9 +/- 1.65 versus 1.3 +/- 1.7; P = 0.419) as well as in the number of postoperative complications (26 versus 21%; P = 0.179 in the P-ExPress and ExPress groups, resp.). Both methods are safe and effective for the surgical treatment of open-angle glaucoma. Coexistence of cataracts does not constitute a compelling contraindication for combined surgery. PMID- 26576294 TI - Bacterial Spectrum and Antibiotic Resistance Patterns of Ocular Infection: Differences between External and Intraocular Diseases. AB - This study aimed to compare the differences of microbial spectrum and antibiotic resistance patterns between external and intraocular bacterial infections in an eye hospital in South China. A total of 737 bacteria isolates from suspected ocular infections were included in this retrospective study covering the period 2010-2013. The organisms cultured from the ocular surface (cornea, conjunctiva) accounted for the majority of the isolates (82.77%, n = 610), followed by the intraocular (aqueous humor, vitreous fluid), which accounted for 17.23% (n = 127). The top three species accounting for the external ocular infections were S. epidermidis (35.25%), P. aeruginosa (8.03%), and S. simulans (4.43%). The top three species for the intraocular infections were S. epidermidis (14.96%), S. hominis (8.66%), and B. subtilis (7.87%). The bacteria from the external ocular surface were more sensitive to neomycin, while those from the intraocular specimens were more sensitive to levofloxacin (P < 0.01). Multidrug resistance was found in 89 bacteria (12.08%), including isolates from both external (13.28%) and intraocular samples (6.30%). The results of this study indicate that the bacteria spectrum of external and intraocular infections is variable in the setting. A high percentage of bacterial organisms were found to be primarily susceptible to neomycin for external infection and levofloxacin for intraocular infection. PMID- 26576296 TI - Pseudomonas aeruginosa Exopolyphosphatase Is Also a Polyphosphate: ADP Phosphotransferase. AB - Pseudomonas aeruginosa exopolyphosphatase (paPpx; EC 3.6.1.11) catalyzes the hydrolysis of polyphosphates (polyP), producing polyPn-1 plus inorganic phosphate (Pi). In a recent work we have shown that paPpx is involved in the pathogenesis of P. aeruginosa. The present study was aimed at performing the biochemical characterization of this enzyme. We found some properties that were already described for E. coli Ppx (ecPpx) but we also discovered new and original characteristics of paPpx: (i) the peptide that connects subdomains II and III is essential for enzyme activity; (ii) NH4 (+) is an activator of the enzyme and may function at concentrations lower than those of K(+); (iii) Zn(2+) is also an activator of paPpx and may substitute Mg(2+) in the catalytic site; and (iv) paPpx also has phosphotransferase activity, dependent on Mg(2+) and capable of producing ATP regardless of the presence or absence of K(+) or NH4 (+) ions. In addition, we detected that the active site responsible for the phosphatase activity is also responsible for the phosphotransferase activity. Through the combination of molecular modeling and docking techniques, we propose a model of the paPpx N-terminal domain in complex with a polyP chain of 7 residues long and a molecule of ADP to explain the phosphotransferase activity. PMID- 26576295 TI - Ocular Blood Flow Autoregulation Mechanisms and Methods. AB - The main function of ocular blood flow is to supply sufficient oxygen and nutrients to the eye. Local blood vessels resistance regulates overall blood distribution to the eye and can vary rapidly over time depending on ocular need. Under normal conditions, the relation between blood flow and perfusion pressure in the eye is autoregulated. Basically, autoregulation is a capacity to maintain a relatively constant level of blood flow in the presence of changes in ocular perfusion pressure and varied metabolic demand. In addition, ocular blood flow dysregulation has been demonstrated as an independent risk factor to many ocular diseases. For instance, ocular perfusion pressure plays key role in the progression of retinopathy such as glaucoma and diabetic retinopathy. In this review, different direct and indirect techniques to measure ocular blood flow and the effect of myogenic and neurogenic mechanisms on ocular blood flow are discussed. Moreover, ocular blood flow regulation in ocular disease will be described. PMID- 26576297 TI - Obesity Is Not Associated with Impaired Immune Response to Influenza Vaccination in HIV-Infected Persons. AB - Introduction. HIV-infected individuals demonstrate lower immunogenicity to the influenza vaccine, despite immunologic and virologic control of HIV infection. Obesity has been previously shown to be associated with diminished antibody responses to other vaccines in HIV-uninfected persons. However, no studies have examined if obesity is associated with diminished protective immune response to influenza vaccination among HIV-infected persons on antiretroviral therapy (ART). Methods. We performed a retrospective analysis of immunogenicity data from a clinical trial of inactivated, trivalent influenza vaccine. The primary endpoint was the proportion of participants with seroconversion, defined as >4-fold increase in anti-hemagglutinin antibody titers after vaccination. Secondary endpoints were the proportion of participants with seroprotection (defined as antibody titers of >=1 : 40) and geometric mean hemagglutination inhibition antibody titers. Results. Overall, 48 (27%) participants were obese (body mass index >= 30 kg/m(2)). Seroconversion rates were comparable between obese and nonobese subjects for all three vaccine strains. Further, postvaccination geometric mean titers did not differ by body mass index category. Conclusion. Obesity was not associated with diminished antibody response to influenza vaccination in a sample of healthy HIV-infected persons. PMID- 26576298 TI - Sedative and Analgesic Effects of Entonox Gas Compared with Midazolam and Fentanyl in Synchronized Cardioversion. AB - The purpose of this study was to determine if the Entonox gas could cause adequate analgesic and sedative effects in patients who need cardioversion. In this randomized not blinded clinical trial, the sedative and analgesic effects of midazolam and fentanyl were compared with Entonox. Eligible patients who need synchronized cardioversion because of dysrhythmia were randomly divided into two groups. The first group received intravenous midazolam and fentanyl; the second group received Entonox through a blower-dependent mask. Onset and end of sedation, sedation level, and pain score were recorded. There were nonsignificant differences between the two groups (22 patients in each group) regarding age, gender, weight, sedation level, and frequency and level of shock. The pain score recorded in the first group was 5.05 +/- 1.32, and 3.9 +/- 0.7 in the second group (P = 0.002). Furthermore, sedation duration and time to full recovery consciousness were shorter in the second group (P < 0.001). In the first group, seven patients needed additional doses to induce and maintain sedation. In addition, as a result of apnoea, four patients required airway support. None of them occurred in the second group. Entonox is a suitable medication in rapid cardioversion, as it has minimal side effects and adequate analgesic and sedative effects. PMID- 26576299 TI - The Application of Pediatric Ureteroscope for Seminal Vesiculoscopy. AB - To describe a novel technique of transurethral seminal vesiculoscopy using a pediatric ureteroscope in the diagnosis and management of persistent hematospermia, a retrospective study was carried out for 20 patients with recurrent hematospermia whom we evaluated and treated using a 6-7.5F (6F front end and 7.5F rear end) pediatric ureteroscope from August 2009 to September 2013. For the 20 patients, the age ranges from 25 to 48 years with a mean age of 36 years. The duration of the hematospermia ranges from 6 to 48 months with a mean duration of 18 months. Transurethral seminal vesiculoscopy was successfully performed in the 20 cases and the mean operative time was 35 min (ranges from 25 to 90 min). Among the 20 patients, 11 patients were found to have seminal vesiculitis, five were with seminal vesicle stone, one was with prostatic utricle stone, one was with prostate cyst, and one was with ejaculatory duct obstruction. The mean follow-up period was 7 months (ranged from 6 to 12 months). Hematospermia in 19 cases disappeared after the surgery and only in one patient the hematospermia recurred 6 months after the surgery. The cure rate was 95%. This study indicated that transurethral seminal vesiculoscopy could be performed easily using a semirigid pediatric ureteroscope with few complications and is an effective therapeutic approach for persistent hematospermia. PMID- 26576300 TI - Intravenous Contrast Medium Administration for Computed Tomography Scan in Emergency: A Possible Cause of Contrast-Induced Nephropathy. AB - The goal of this study was to assess risk for CIN after CT Scan during an emergency and to identify risk factors for the patient. Prospective review of all patients admitted to the emergency room (ER) of the Teaching Hospital of Lome (Togo) during a 2-year period. CIN was defined as an increase in serum creatinine by 0.5 mg/dL from admission after undergoing CT Scan with intravenous contrast. A total of 620 patients underwent a CT Scan in the emergency room using intravenous contrast and 672 patients took the CT Scan without intravenous contrast. Out of the patients who received intravenous contrast for CT Scan, three percent of them developed CIN during their admission. Moreover, upon discharge no patient had continued renal impairment. No patient required dialysis during their admission. The multivariate analysis of all patients who had serial creatinine levels (including those who did not receive any contrast load) shows no increased risk for acute kidney injury associated intravenous contrast (odds ratio = 0.619, p value = 0.886); only diabetes remains independent risk factor of acute kidney injury (odds ratio = 6.26, p value = 0.031). PMID- 26576301 TI - Assessment of Immunotoxicity of Dextran Coated Ferrite Nanoparticles in Albino Mice. AB - In this study, dextran coated ferrite nanoparticles (DFNPs) of size <25 nm were synthesized, characterized, and evaluated for cytotoxicity, immunotoxicity, and oxidative stress by in vitro and in vivo methods. Cytotoxicity was performed in vitro using splenocytes with different concentrations of DFNPs. Gene expression of selected cytokines (IL-1, IL-10, and TNF beta) secretion by splenocytes was evaluated. Also, 100 mg of DFNPs was injected intraperitoneally to 18 albino mice for immunological stimulations. Six animals each were sacrificed at the end of 7, 14, and 21 days. Spleen was subjected to immunotoxic response and liver was analyzed for antioxidant parameters (lipid peroxidation, reduced glutathione, glutathione peroxidase, superoxide dismutase, and glutathione reductase). The results indicated that DFNPs failed to induce any immunological reactions and no significant alternation in antioxidant defense mechanism. Also, mRNA expression of the cytokines revealed an increase in IL-10 expression and subsequent decreased expression of IL-1 and TNF beta. Eventually, DNA sequencing of liver actin gene revealed base alteration in nonconserved regions (10-20 bases) of all the treated groups when compared to control samples. Hence, it can be concluded that the DFNPs were nontoxic at the cellular level and nonimmunotoxic when exposed intraperitoneally to mice. PMID- 26576302 TI - Antidiabetic Activity of Ruellia tuberosa L., Role of alpha-Amylase Inhibitor: In Silico, In Vitro, and In Vivo Approaches. AB - Ruellia tuberosa L. is a folk remedy in the treatment of diabetes mellitus. However, its hypoglycemic activity has not been investigated so far. In the present study, the antidiabetic mechanism of the n-hexane fraction of methanolic extract (HFME) of this plant was investigated in silico, in vitro, and in vivo. In silico study was performed using AutoDock4.2 software. In vitro alpha-amylase inhibitory activity was investigated by starch-iodine method. A single dose of 450 mg/kg HFME for 14 days was subjected to an antidiabetic screening in vivo by a multiple low dose streptozotocin (MLD-STZ) induced rats. Molecular modeling results show that Betulin exhibited noncompetitive alpha-amylase inhibitory activities. The effect of HFME elicited significant reductions of diabetic rat blood glucose. A single dose administration of HFME inhibited alpha-amylase activity in vivo (P < 0.01) compared to a diabetic control group. Moreover, this extract strongly inhibited the alpha-amylase activity in vitro (IC50 0.14 +/- 0.005 mg/mL). It is concluded that HFME exerted an antidiabetic effect via alpha amylase inhibitor. Our findings provide a possible hypoglycemic action of R. tuberosa L. as an alternative therapy in the management of diabetes. PMID- 26576303 TI - Spontaneous Coronary Artery Dissection/Intramural Haematoma in Young Women with ST-Elevation Myocardial Infarction: "It Is Not Always a Plaque Rupture Event". AB - Spontaneous coronary artery dissection (SCAD) is an unusual, but increasingly recognized, cause of ST-elevation myocardial infarction (STEMI), especially among younger patients without conventional risk factors for coronary artery disease (CAD). Although dissection of the coronary intima or media is a hallmark finding, hematoma formation within the vessel wall is often present. It remains unclear whether dissection or hematoma is the primary event, but both may cause luminal stenosis and occlusion. The diagnosis of SCAD is made principally with invasive coronary angiography, although adjunctive intracoronary imaging modalities may increase the diagnostic yield. In STEMI patients, the decision whether to pursue primary percutaneous coronary intervention (PCI) or appropriate conservative medical therapy is based on clinical presentation, the extent of the dissection, the critical anatomy involvement, and the amount of ischaemic myocardium at risk. In this case report, we present two cases of young women with SCAD and STEMI, successfully treated with primary PCI. We briefly illustrate the characteristic aspects of the angiographic presentation and intravascular ultrasound-guided treatment. SCAD should always be considered in young STEMI patients without conventional risk factors for CAD with primary angioplasty to be required in patients with ongoing myocardial ischemia. PMID- 26576304 TI - Amyand's Hernia: Rare Presentation of a Common Ailment. AB - Inguinal hernia with vermiform appendix as content is known as Amyand's hernia. It is a rare entity but we encountered four cases within six months. A 52-year old female had high grade fever and evidence of inflammatory pathology involving the ileocaecal region. She was initially managed conservatively and subsequently underwent exploratory laparatomy. The appendix was perforated and herniating in the inguinal canal. Appendectomy was done with herniorrhaphy without mesh placement. A 74-year-old male with bilateral inguinal hernia, of which, the right side was more symptomatic, underwent open exploration. Operative findings revealed a lipoma of the sac and a normal appearing appendix as content. Contents were reduced without appendectomy and mesh hernioplasty was performed. A 63-year old male with an obstructed right sided hernia underwent emergency inguinal exploration which revealed edematous caecum and appendix as content without any inflammation. Contents were reduced without any resection. Herniorrhaphy was performed without mesh placement. A 66-year-old male with an uncomplicated right inguinal hernia underwent elective surgery. The sac revealed an appendix with adhesions at the neck. Contents were reduced after adhesiolysis and hernioplasty was performed with mesh placement. Emphasis is made to the rarity of disease, variation in presentation, and difference in treatment modalities depending upon the state of appendix. PMID- 26576305 TI - HbSC Disease and Spontaneous Epidural Hematoma with Kernohan's Notch Phenomena. AB - Spontaneous (nontraumatic) acute epidural hematoma is a rare and poorly understood complication of sickle cell disease. A 19-year-old African American male with hemoglobin SC disease (HbSC) presented with generalized body aches and was managed for acute painful crisis. During his hospital stay he developed rapid deterioration of his mental status and computed topography revealed a spontaneous massive epidural hematoma with mass effect and midline shift with Kernohan's notch phenomena for which urgent craniotomy and evacuation was done. We report the first case of HbSC disease associated with catastrophic epidural hematoma progressing to transtentorial herniation and Kernohan's notch phenomena within few hours with rapid clinical deterioration. The etiopathogenesis and the rare presentation are discussed in detail in this case report. PMID- 26576306 TI - Hepatosplenic Abscesses and Osteomyelitis of the Spine in an Immunocompetent Adult with Cat Scratch Disease. AB - We present an 18-year-old, immunocompetent Austrian military conscript with cervical lymphadenopathy, fever, back-pain, and persistent inflammation markers despite two weeks of antimicrobial therapy with ampicillin/sulbactam. All specific laboratory investigations for identification of a specific etiology, including blood cultures and autoantibodies, were inconspicuous. Abdominal computed tomography showed multiple hypodense hepatosplenic lesions and osteomyelitis of the thoracic and lumbar spine with base plate fracture. Based on the patient's history, clinical presentation, and radiological findings, serology for cat scratch disease (CSD) was performed and high B. henselae specific IgM and IgG antibodies were detected. Due to its variety of clinical presentations, diagnosis of CSD is challenging, especially in the absence of a history of specific exposure. This case report shall remind the physician that cat scratch disease is a common disease, mainly presenting with fever and lymphadenopathy in young patients. Nevertheless CSD has many different and rare forms of presentations, including hepatosplenic lesions and bone involvement as shown in this case. PMID- 26576307 TI - Uterine Rupture in Pregnancy following Fall from a Motorcycle: A Horrid Accident in Pregnancy-A Case Report and Review of the Literature. AB - Uterine rupture is one of the most catastrophic complications during pregnancy. It is a rare complication in developed countries but a frequent cause of maternal and perinatal morbidity and mortality in Africa. Uterine rupture occurs in 1.6% of patients suffering blunt abdominal trauma. Here we report a unique case of complete fundal rupture of the unscarred uterus following fall from motorcycle in 39-week-pregnant mother who was managed with total abdominal hysterectomy and left salpingo-oophorectomy and survived, though fetus died before intervention. We also reviewed similar cases reported from different parts of Africa. This is a preventable complication had the woman been properly instructed on transportation safety during her antenatal care visits. PMID- 26576309 TI - A Histologically Diagnosed Case with Infantile Osteopetrosis Complicated by Hypopituitarism. AB - Malignant infantile osteopetrosis is a rarely seen severe disorder which appears early in life with general sclerosis of the skeleton. It is caused by functionally defective osteoclasts which fail to resorb bone. Affected infants can exhibit a wide spectrum of clinical manifestations including impaired hematopoiesis, hepatosplenomegaly, visual impairment, and hypocalcemia. With the exception of secondary hyperparathyroidism, involvement of the endocrine system seems to be quite rare. Hypopituitarism is defined as underproduction of the growth hormone in combination with deficiencies of other pituitary hormones. Any lesion that damages hypothalamus, pituitary stalk, or anterior pituitary can cause secondary hypopituitarism. In this report, we presented a rare combination of malignant infantile osteopetrosis and secondary hypopituitarism in a newborn who presented predominantly with endocrinological symptoms. This is the first case report of malignant infantile osteopetrosis accompanied by hypopituitarism secondary to sclerosis of the sella turcica. On the other hand, this is a very interesting case which was diagnosed based on histological examination of bone marrow biopsy specimens despite lack of any clinical suspicion. PMID- 26576308 TI - Synchronous Ovarian and Endometrial Endometrioid Adenocarcinoma Presenting with Nonbacterial Thrombotic Endocarditis and Pulmonary Thromboembolism: Adenocarcinoma with Thrombotic Events. AB - Introduction. Nonbacterial thrombotic endocarditis (NBTE) is a rare manifestation of hypercoagulability in patients with malignant neoplasms. Case Report. A fifty six-year-old woman presented to the emergency service; the clinical workup revealed deep vein thrombosis in right leg and bilateral massive PTE. As the abdominal sections on the spiral CT revealed a giant pelvic mass of ovarian origin, she was referred to our hospital's gynecologic oncology department. She was scheduled for surgery under enoxaparin. She described numbness on one side of her face. Cranial imaging findings revealed acute ischemic cerebral lesions and transesophageal echocardiogram showed vegetation on the aortic cusp. Under anticoagulation treatment, she underwent hysterectomy with bilateral salpingo oophorectomy and infracolic omentectomy. After tumor resection, her neurological symptoms dissolved with aggressive anticoagulant treatment. Pathology result was synchronous endometrial and ovarian adenocarcinoma. Discussion. NBTE is a rare condition often associated with advanced malignancies. Peripheral embolism and venous thrombosis are complications that have been associated with NBTE due to hypercoagulable state. These disorders could be resistant to routine anticoagulant treatment. In case of a thrombotic complication due to ovarian malignancy, surgical resection of the primary tumor may increase the effect of anticoagulant treatment. PMID- 26576310 TI - Neonatal Hyperglycemia due to Transient Neonatal Diabetes Mellitus in Puerto Rico. AB - Neonatal hyperglycemia is a metabolic disorder found in the neonatal intensive care units. Neonatal diabetes mellitus (NDM) is a very uncommon cause of hyperglycemia in the newborn, occurring in 1 in every 400,000 births. There are two subtypes of neonatal diabetes mellitus: permanent neonatal diabetes mellitus (PNDM) and transient neonatal diabetes mellitus (TNDM). We describe a term, small for gestational age, female neonate with transient neonatal diabetes mellitus who presented with poor feeding tolerance and vomiting associated with hyperglycemia (385 mg/dL), glycosuria, and metabolic acidosis within the first 12 hours of life. The neonate was treated with intravenous insulin, obtaining a slight control of hyperglycemia. An adequate glycemia was achieved at 5 weeks of life. The molecular studies showed complete loss of maternal methylation at the TND differentially methylated region on chromosome 6q24. The etiology of this neonate's hyperglycemia was a hypomethylation of the maternal TND locus. A rare cause of neonatal diabetes mellitus must be considered if a neonate presents refractory hyperglycemia. To our knowledge, this is the first case reported in Puerto Rico of transient neonatal mellitus due to the uncommon mechanism of maternal hypomethylation of the TND locus. Its prevalence in Puerto Rico is unknown. PMID- 26576312 TI - Portomesenteric Vein Thrombosis, Bowel Gangrene, and Bilateral Pulmonary Artery Embolism Two Weeks after Laparoscopic Sleeve Gastrectomy. AB - Sleeve gastrectomy and gastric bypass surgery are popular and effective options for weight loss surgery. Portomesenteric vein thrombosis (PMVT) is a documented but rare complication of bariatric surgery. Proper surgical technique, careful postoperative prophylaxis, and early mobilization are essential to prevent this event. The diagnosis of PMVT in the postoperative period requires a high index of suspicion and early directed intervention to prevent a possibly fatal outcome. We present a case of PMVT complicated by small bowel ischemia resulting in gangrene that necessitated resection. PMID- 26576311 TI - Cavernostomy for Pulmonary Aspergillosis Associated with Destroyed Lung after Surgery for Lung Cancer: Report of 3 Cases. AB - Slow, progressive, and destructive changes in the residual lung after surgery for lung cancer, known as "destroyed lung," are delayed nonrecurrent complications. Destroyed lung can be a difficult condition to treat due to repeated infections and is therefore a complication that should not be ignored. We had three cases of intractable pulmonary aspergillosis difficult to treat associated with destroyed lung, after lung cancer surgery. Two of these patients followed a characteristic clinical course, which started with a cystic change just below the pleura and subsequently led to respiratory failure and death due to repeated infections. The third patient followed a similar clinical course and is currently under regular follow-up. Our cases suggest that concomitant occurrence of severe complications following surgery for lung cancer, such as destroyed lung and pulmonary aspergillosis, should be monitored because these complications can lead to respiratory failure and fatal clinical course. Radical surgery is not possible, especially when medical treatment is ineffective in controlling repeated infections and the patient's general condition is worsened due to prolonged chronic inflammation. Therefore, aggressive surgical intervention should be considered before patients worsen. PMID- 26576313 TI - Retracted: Fitz-Hugh-Curtis Syndrome in a Male Patient: A Case Report and Literature Review. AB - [This retracts the article DOI: 10.1155/2012/457272.]. PMID- 26576314 TI - Minimally Invasive Surgical Approach to Complicated Recurrent Pilonidal Sinus. AB - Pilonidal sinus is considered as a simple and frequently occurring disease localized at the sacrococcygeal area. However, at the intergluteal region, it can often turn into a chronic and complicated disease. In some cases, it can fistulize up to the gluteal region and appear at the secondary orifices. Minimally invasive surgical techniques are becoming widespread in recent years due to the increased experience and development of new instruments. Limited excision of the pilonidal sinus tract can be a better treatment option compared with large excisions in terms of recovery time and patient's comfort. This case study reports the single-phase surgical treatment of complicated and recurrent pilonidal sinus localized at the gluteal area, with minimal tissue loss and inflammation. PMID- 26576315 TI - Small Bowel Obstruction Secondary to Interstitial Hernia: Laparoscopic Approach. AB - Interstitial hernias are a rare entity. Most of them are detected incidentally on imaging studies. We present a case of abdominal bowel obstruction secondary to interstitial hernia on the fifth postoperative day of an open incisional hernia repair. Laparoscopy confirmed the diagnosis and led to an accurate treatment avoiding a new laparotomy. In this case, prompt surgical decision based on clinical and CT scan findings allowed a mini-invasive approach with satisfactory outcome. PMID- 26576316 TI - Prostatosymphyseal Fistula Treated by Robotic Assisted Radical Prostatectomy. AB - This case report documents a rare complication of prostate resection following a Greenlight laser procedure. The 75-year-old gentleman involved underwent photoselective vaporisation of the prostate (PVP) for clinically benign prostatic obstruction. Subsequent to PVP, the patient experienced recurrent macroscopic haematuria and pubic pain. Investigations confirmed the presence of a prostate symphyseal fistula, a rare complication of PVP. We believe this to be the first reported case of successful treatment with robotic assisted radical prostatectomy. PMID- 26576317 TI - Review of the Literature: Organ of Giraldes Epididymal Appendage Presenting as a Painless Scrotal Mass in a 19-Year-Old Male-A Rare Urologic Entity. AB - An incidental finding of a testicular mass in young male population is always a case of great concern for the patient and controversy for the physician. Differential diagnosis ranges from acute scrotum (notably testicular torsion), to acute inflammation and infection, all the way to testicular tumors. We present a case of an incidental finding of a painless testicular solid mass in a 19-year old male patient, with an end pathological result of paradidymis (organ of Giraldes) following orchiectomy. To the best of our knowledge, this is the first case of its kind to be reported in the literature. PMID- 26576318 TI - Primary Aneurysm of the Medial Marginal Vein of the Foot. AB - The primary superficial venous aneurysms of the foot are very rare. A 34-year-old female patient developed a dorsal foot mass during the second trimester of pregnancy with no history of previous trauma, puncture, or infection. One year later, she was referred to the surgical department for excision of "foot hygroma." Based on the clinical findings, the venous aneurysm was suspected and duplex ultrasound confirmed the diagnosis of the aneurysm of the medial marginal vein of the foot. Excision of aneurysm with bipolar ligation of marginal vein was performed under local anesthesia. The postoperative evolution was uneventful. The authors hope that the presented case report will increase the awareness of general practitioners, dermatologists, and surgeons regarding the superficial venous aneurysms of lower limbs. PMID- 26576319 TI - Effects of Night-Time Use of Rotigotine on Nocturnal Symptoms in Parkinson's Disease. AB - Objectives. This open-label study assessed the efficacy and safety of exclusive night-time administration of transdermal rotigotine in patients with nocturnal and early morning PD symptoms. Methods. Patients with PD and nocturnal and early morning symptoms received transdermal rotigotine patches (2-16 mg/24 h) applied in the evening and removed in the morning for 3 months. Sleep disturbance was assessed with modified Parkinson's Disease Sleep Scale (PDSS-2). Other outcomes included a pain visual analogue scale (VAS) and short-form Parkinson's Disease Questionnaire (PDQ-8) for quality of life. Results. 74 patients completed treatment in this study. At the end of treatment, PDSS-2 total score had improved by mean 10.9 points from baseline (p < 0.001). All three PDSS-2 domain scores (sleep disturbances, nocturnal motor symptoms, and nocturnal symptoms) were also significantly improved by 41%, 56%, and 48%, respectively (p < 0.001). VAS-pain score decreased from 3.2 to 2.3 (p < 0.001). PDQ-8 score decreased from 23.8 to 18.1 (p < 0.001). The most frequently reported adverse events included nausea (9%), anxiety (4%), and dizziness (4%). Conclusions. Night-time administration of transdermal rotigotine is an effective and well tolerated treatment for nocturnal symptoms in patients with PD. PMID- 26576320 TI - Mortality in Iranian Patients with Parkinson's Disease: Cumulative Impact of Cardiovascular Comorbidities as One Major Risk Factor. AB - Mortality rate, life expectancy, survival, and the impact of comorbidities on them in people with Parkinson's disease (PD) need to be assessed in settings with different sociodemographic backgrounds. We investigated mortality features in Iranian PD patients focusing on the role of cardiovascular multimorbidity on their survival. Data on mortality and comorbidity profile was gathered in a cohort of 190 individuals with idiopathic PD referred to a Movement Disorders Clinic. Standardized mortality ratio (SMR) compared to the Tehran general population was 3.44 and the life expectancy at birth was 67.4 (95% CI: 59.1-75.8) yr. Patients with at least one cardiovascular comorbidity had a shorter survival time after PD onset (14.0 versus 29.2 yr, p = 0.012). The hazard ratio for death increased 2.8 times (95% CI: 1.5-5.2, p = 0.002) with one additional cardiovascular comorbidity. Among all comorbid conditions, stroke showed the strongest independent effect on mortality in PD patients [HR = 13.1 (95% CI: 2.4 71.7), p = 0.003]. Conclusively, life expectancy was slightly lower in Iranian PD patients compared to the general population, while the SMR was high. Cardiometabolic multimorbidity substantially decreased survival in people with PD. Our study highlights the need for assessment, prevention, and treatment of cardiovascular morbidities in parkinsonian patients, given their effect on survival. PMID- 26576321 TI - Multivariate Calibration and Model Integrity for Wood Chemistry Using Fourier Transform Infrared Spectroscopy. AB - This research addressed a rapid method to monitor hardwood chemical composition by applying Fourier transform infrared (FT-IR) spectroscopy, with particular interest in model performance for interpretation and prediction. Partial least squares (PLS) and principal components regression (PCR) were chosen as the primary models for comparison. Standard laboratory chemistry methods were employed on a mixed genus/species hardwood sample set to collect the original data. PLS was found to provide better predictive capability while PCR exhibited a more precise estimate of loading peaks and suggests that PCR is better for model interpretation of key underlying functional groups. Specifically, when PCR was utilized, an error in peak loading of +/-15 cm(-1) from the true mean was quantified. Application of the first derivative appeared to assist in improving both PCR and PLS loading precision. Research results identified the wavenumbers important in the prediction of extractives, lignin, cellulose, and hemicellulose and further demonstrated the utility in FT-IR for rapid monitoring of wood chemistry. PMID- 26576322 TI - Potential Use of Natural Killer Cell Transfer Therapy in the Perioperative Period to Improve Oncologic Outcomes. AB - Immune suppression after oncologic surgery is a common phenomenon. Several studies have demonstrated that it is associated with poor survival owing to cancer progression. Immunotherapy, especially NK cell transfer therapy, is an attractive alternative because current methodologies to isolate, generate, and expand NK cells have shown good safety profiles in current active investigations. We believe that the use of NK cell transfer therapy in the context of postoperative minimal residual disease deserves significant investigation. PMID- 26576323 TI - Activation of Two Sequential H-transfers in the Thymidylate Synthase Catalyzed Reaction. AB - Thymidylate synthase (TSase) catalyzes the de novo biosynthesis of thymidylate, a precursor for DNA, and is thus an important target for chemotherapeutics and antibiotics. Two sequential C-H bond cleavages catalyzed by TSase are of particular interest: a reversible proton abstraction from the 2'-deoxy-uridylate substrate, followed by an irreversible hydride transfer forming the thymidylate product. QM/MM calculations of the former predicted a mechanism where the abstraction of the proton leads to formation of a novel nucleotide-folate intermediate that is not covalently bound to the enzyme (Wang, Z.; Ferrer, S.; Moliner, V.; Kohen, A. Biochemistry2013, 52, 2348-2358). Existence of such intermediate would hold promise as a target for a new class of drugs. Calculations of the subsequent hydride transfer predicted a concerted H-transfer and elimination of the enzymatic cysteine (Kanaan, N.; Ferrer, S.; Marti, S.; Garcia-Viloca, M.; Kohen, A.; Moliner, V. J. Am. Chem. Soc.2011, 133, 6692-6702). A key to both C-H activations is a highly conserved arginine (R166) that stabilizes the transition state of both H-transfers. Here we test these predictions by studying the R166 to lysine mutant of E. coli TSase (R166K) using intrinsic kinetic isotope effects (KIEs) and their temperature dependence to assess effects of the mutation on both chemical steps. The findings confirmed the predictions made by the QM/MM calculations, implicate R166 as an integral component of both reaction coordinates, and thus provide critical support to the nucleotide-folate intermediate as a new target for rational drug design. PMID- 26576324 TI - Quality improvement and practice-based research in neurology using the electronic medical record. AB - We describe quality improvement and practice-based research using the electronic medical record (EMR) in a community health system-based department of neurology. Our care transformation initiative targets 10 neurologic disorders (brain tumors, epilepsy, migraine, memory disorders, mild traumatic brain injury, multiple sclerosis, neuropathy, Parkinson disease, restless legs syndrome, and stroke) and brain health (risk assessments and interventions to prevent Alzheimer disease and related disorders in targeted populations). Our informatics methods include building and implementing structured clinical documentation support tools in the EMR; electronic data capture; enrollment, data quality, and descriptive reports; quality improvement projects; clinical decision support tools; subgroup-based adaptive assignments and pragmatic trials; and DNA biobanking. We are sharing EMR tools and deidentified data with other departments toward the creation of a Neurology Practice-Based Research Network. We discuss practical points to assist other clinical practices to make quality improvements and practice-based research in neurology using the EMR a reality. PMID- 26576325 TI - From Pharmacovigilance to Clinical Care Optimization. AB - In order to ensure the continued, safe administration of pharmaceuticals, particularly those agents that have been recently introduced into the market, there is a need for improved surveillance after product release. This is particularly so because drugs are used by a variety of patients whose particular characteristics may not have been fully captured in the original market approval studies. Even well-conducted, randomized controlled trials are likely to have excluded a large proportion of individuals because of any number of issues. The digitization of medical care, which yields rich and accessible drug data amenable to analytic techniques, provides an opportunity to capture the required information via observational studies. We propose the development of an open, accessible database containing properly de-identified data, to provide the substrate for the required improvement in pharmacovigilance. A range of stakeholders could use this to identify delayed and low-frequency adverse events. Moreover, its power as a research tool could extend to the detection of complex interactions, potential novel uses, and subtle subpopulation effects. This far reaching potential is demonstrated by our experience with the open Multi parameter Intelligent Monitoring in Intensive Care (MIMIC) intensive care unit database. The new database could also inform the development of objective, robust clinical practice guidelines. Careful systematization and deliberate standardization of a fully digitized pharmacovigilance process is likely to save both time and resources for healthcare in general. PMID- 26576326 TI - Production of mixed fruit (pawpaw, banana and watermelon) wine using Saccharomyces cerevisiae isolated from palm wine. AB - Pawpaw, banana and watermelon are tropical fruits with short shelf-lives under the prevailing temperatures and humid conditions in tropical countries like Nigeria. Production of wine from these fruits could help reduce the level of post harvest loss and increase variety of wines. Pawpaw, banana and watermelon were used to produce mixed fruit wines using Saccharomyces cerevisiae isolated from palm wine. Exactly 609 and 406 g each of the fruits in two-mixed and three-mixed fruit fermentation respectively were crushed using laboratory blender, mixed with distilled water (1:1 w/v), and heated for 30 min with subsequent addition of sugar (0.656 kg). The fruit musts were subjected to primary (aerobic) and secondary (anaerobic) fermentation for 4 and 21 days respectively. During fermentation, aliquots were removed from the fermentation tank for analysis. During primary fermentation, consistent increases in alcohol contents (ranging from 0.0 to 15.0 %) and total acidities (ranging from 0.20 to 0.80 %) were observed with gradual decrease in specific gravities (ranging from 1.060 to 0.9800) and pH (ranging from 4.80 to 2.90). Temperature ranged from 27 degrees C to 29 degrees C. The alcoholic content of the final wines were 17.50 +/- 0.02 % (pawpaw and watermelon), 16.00 +/- 0.02 % (pawpaw and banana), 18.50 +/- 0.02 % (banana and watermelon wine) and 18.00 +/- 0.02 % (pawpaw, banana and watermelon). The alcoholic content of the wines did not differ significantly (p > 0.05). The pH of all the wines were acidic and ranged from 2.5 +/- 0.01 to 3.8 +/ 0.01 (p > 0.05). The acid concentration (residual and volatile acidity) were within the acceptable limit and ranged from 0.35 +/- 0.02 to 0.88 +/- 0.01 % (p > 0.05). Sensory evaluation (P > 0.05) rated the wines acceptability as 'pawpaw and banana wine' > 'pawpaw and watermelon' > 'pawpaw, watermelon and banana' > 'banana and watermelon wine'. This study has shown that acceptable mixed fruit wines could be produced from the fruits with S. cerevisiae from palm wine. PMID- 26576327 TI - Development of a multiplex real-time PCR assay for detection of Mycoplasma pneumoniae, Chlamydia pneumoniae and mutations associated with macrolide resistance in Mycoplasma pneumoniae from respiratory clinical specimens. AB - The aim of this study was to improve detection of Mycoplasma pneumoniae and Chlamydia pneumoniae in clinical specimens by developing a multiplex real-time PCR assay that includes identification of macrolide-resistant M. pneumoniae. Novel assays targeting a M. pneumoniae conserved hypothetical protein gene, M. pneumoniae 23S rRNA gene mutations associated with macrolide resistance and human beta-globin gene (an endogenous internal control) were designed and combined with a previously published C. pneumoniae PCR targeting ompA gene. The resulting quadraplex PCR was validated with a panel of clinical specimens supplemented with external quality assessment specimens, simulated specimens and various bacterial and viral strains. The obtained results were compared to those obtained by reference PCRs or confirmed by sequencing (typing of macrolide resistance). The novel multiplex PCR assay was in 100 % agreement with reference PCRs. Four M. pneumoniae strains with macrolide resistance-associated mutations were identified among 42 strains, which comprises 9.5 % of the study material. Amplification of an internal control excluded sample-derived inhibition possibly leading to false negative reporting. In conclusion, we have developed a resources conserving multiplex real-time PCR assay for simultaneous detection of M. pneumoniae, C. pneumoniae and the most common mutations leading to macrolide resistance in M. pneumoniae. The assay is a widely useful tool for detection of these respiratory pathogens and will also shed light on the occurrence of macrolide resistance in M. pneumoniae. PMID- 26576328 TI - Mastectomy rates remain high in Singapore and are not associated with poorer survival after adjusting for age. AB - Recent reports have suggested that women undergoing mastectomy, instead of wide local excision (WLE) for Stage I and II breast cancers have poorer overall survival. This is particularly important in our setting where mastectomy rates are high. In this study, we evaluated the trends in mastectomy and WLE over a 10 year period at a single institute, identified factors more common among women who underwent mastectomy and specifically examined the effect of surgery on outcome. Retrospective review was performed of 2244 women who underwent curative surgery for non-metastatic breast cancer at our institute from 1st January 2001 to 31st December 2010. Mastectomy rates remained high over the 10 years, ranging from 43 to 59 %. Older women, those with symptoms, larger tumours and clinical nodal involvement were more likely to receive mastectomy (P < 0.05). The type of surgery (mastectomy or WLE) did not affect survival in women with ductal carcinoma-in situ, while women with invasive cancer appeared to survive longer when treated with WLE (P < 0.01). Surgery type was not an independent predictor of overall survival and the survival advantage with WLE did not remain after adjusting for age, implying that the effect on survival had been confounded by the fact that older women tended to undergo mastectomy. Mastectomy remains common among our local women, with further studies being needed to evaluate factors involved in decision-making. Older women and those with significant co morbidities were more likely to undergo mastectomy and this contributed to an apparent survival advantage following WLE. PMID- 26576329 TI - Preparation of diethylene glycol monomethyl ether monolaurate catalyzed by active carbon supported KF/CaO. AB - Diethylene glycol monomethyl ether monolaurate (DGMEML) was synthesized via the reaction of diethylene glycol monomethyl ether (DGME) with methyl laurate (ML) by a new solid base catalyst of KF/CaO/AC, which was prepared by impregnation method using active carbon as carrier. The catalysts were characterized by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), nitrogen physisorption-desorption and Hammett indicator methods; the effect of the mole ratio of KF to CaO, DGME to ML molar ratio, amount of catalyst, reaction time and temperature on the yield of DGMEML were studied; and the relationship between the structure of the catalyst and the yield of DGMEML was investigated. The formed KCaF3 and K2O were acting as the main active components in the catalytic transesterification; the highest yield of 96.3 % was obtained as KF-to-CaO molar ratio of 2.0, DGME to ML molar ratio of 4.0, catalyst amount of 5 wt%, and reaction time of 30 min at 75 degrees C; and the catalyst displayed good stability in the transesterification. PMID- 26576330 TI - On intra-supply chain system with an improved distribution plan, multiple sales locations and quality assurance. AB - Transnational companies, operating in extremely competitive global markets, always seek to lower different operating costs, such as inventory holding costs in their intra- supply chain system. This paper incorporates a cost reducing product distribution policy into an intra-supply chain system with multiple sales locations and quality assurance studied by [Chiu et al., Expert Syst Appl, 40:2669-2676, (2013)]. Under the proposed cost reducing distribution policy, an added initial delivery of end items is distributed to multiple sales locations to meet their demand during the production unit's uptime and rework time. After rework when the remaining production lot goes through quality assurance, n fixed quantity installments of finished items are then transported to sales locations at a fixed time interval. Mathematical modeling and optimization techniques are used to derive closed-form optimal operating policies for the proposed system. Furthermore, the study demonstrates significant savings in stock holding costs for both the production unit and sales locations. Alternative of outsourcing product delivery task to an external distributor is analyzed to assist managerial decision making in potential outsourcing issues in order to facilitate further reduction in operating costs. PMID- 26576331 TI - Prevalence, risk factors, and prognosis of peritoneal metastasis from breast cancer. AB - Peritoneal metastasis from breast cancer is a serious and deadly condition only limited considered in the literature. Our aim was to study prevalence, risk factors, and prognosis of breast cancer peritoneal metastasis. We retrospectively analyzed 3096 women with a diagnosis of invasive breast cancer. We took into consideration presence and localization of breast cancer distant metastasis as well as the possible risk factors and survival from the diagnosis of the breast cancer metastasis. The prevalence of breast cancer peritoneal metastases was 0.7 % (22/3096), representing the 7.6 % (22/289) of women affected by distant metastases. Moreover, independent risk factors for breast cancer peritoneal metastases resulted high grading, lobular invasive histology, and advanced T and N stage at diagnosis. Overall survival after metastasis diagnosis was shorter in women affected by peritoneal metastases or brain metastases in comparison to other metastatic women. Breast cancer peritoneal metastases were uncommon but not rare events with a poor prognosis after standard treatments. PMID- 26576333 TI - Extended inverse Lindley distribution: properties and application. AB - In this paper, we introduce an extension of the inverse Lindley distribution, which offers more flexibility in modeling upside-down bathtub lifetime data. Some statistical properties of the proposed distribution are explicitly derived. These include density and hazard rate functions with their behavior, moments, moment generating function, skewness, kurtosis measures, and quantile function. Maximum likelihood estimation of the parameters and their estimated asymptotic distribution and confidence intervals are derived. Renyi entropy as a measure of the uncertainty in the model is derived. The application of the model to a real data set i.e., the flood levels for the Susquehanna river at Harrisburg, Pennsylvania, over 20 four-year periods from 1890 to 1969 is compared to the fit attained by some other well-known existing distributions. PMID- 26576332 TI - Altered regulation of PDK4 expression promotes antiestrogen resistance in human breast cancer cells. AB - Acquired or de novo resistance to the selective estrogen receptor modulators tamoxifen and fulvestrant (ICI) is a major barrier to successful treatment of breast cancer. Gene expression patterns in tamoxifen resistant (TamR-MCF-7) cells were compared to their parental cells (MCF-7L) to identify an aberrantly regulated metabolic pathway. TamR-MCF-7 cells are cross resistant to ICI and doxorubicin, and have increased mitochondrial DNA. A small subset of genes had altered expression in TamR-MCF-7 relative to MCF-7L cells. One of the genes, pyruvate dehydrogenase kinase-4 (PDK4), phosphorylates pyruvate dehydrogenase (PDH). PDK4 expression was elevated in TamR-MCF-7 cells; this result was also observed in a second model of acquired antiestrogen resistance. PDK4 expression is controlled in part by glucocorticoid response elements in the PDK4 gene promoter. In MCF-7L cells, PDK4 mRNA expression was insensitive to glucocorticoid receptor agonists, while dexamethasone dramatically increased PDK4 expression in TamR-MCF-7 cells. Using siRNA to knock down PDK4 expression increased TamR-MCF-7 sensitivity to ICI; in contrast adapting cells to growth in glucose depleted media did not affect ICI sensitivity. Despite TamR-MCF-7 cells high levels of PDK4 mRNA relative to MCF-7L, TamR-MCF-7 cells have increased PDH activity. Wild type MCF-7 cells are reported to be heterozygous for a G to A mutation that results in a substitution of threonine for alanine near PDK4's catalytic site. We found loss of heterozygosity in TamR-MCF-7 cells; TamR-MCF-7 are homozygous for the wild type allele. These data support a role for altered regulation of PDH by PDK4 and altered substrate utilization in the development of drug resistance in human breast cancer cells. PMID- 26576334 TI - Distribution of health-related physical fitness in Slovak population. AB - Purpose of the study was to examine relationship between distribution of healthy fitness zone standards of high school students and their type of housing or area of residence. Study sample consisted of 684 students (284 boys, 400 girls) from urban and rural areas of the region Presov in the eastern part of Slovakia. Physical fitness was assessed by four tests: back-saver sit and reach, shoulder stretch, curl-ups and 90 degrees push-ups. Differences by place of residence and types of housing were examined by correspondence analysis of two-dimensional tables with computing Chi square value at significance level p < 0.05. Urban students performed higher level of flexibility, abdominal and upper strength and endurance than rural ones. Boys and girls living in a flat reached higher level of flexibility and abdominal strength/endurance however, they performed worse in upper strength and endurance than those living in a house. Slovak adolescents seem to have a healthier profile in abdominal muscular fitness and upper body flexibility than in lower body flexibility. The relationship between distribution of healthy fitness zone standards and residence area or housing type was revealed only in lower body flexibility, upper strength and endurance of urban and rural girls. PMID- 26576335 TI - Modeling social norms and social influence in obesity. AB - The worldwide increase in obesity has led to changes in what is considered "normal" or desirable weight, especially among populations at higher risk. We show that social norms are key to understanding the obesity epidemic, and that social influence mechanisms provide a necessary linkage between individual obesity-related behaviors and population-level characteristics. Because influence mechanisms cannot be directly observed, we show how three complex systems tools may be used to gain insights into observed epidemiologic patterns: social network analysis, agent-based modeling, and systems dynamics modeling. However, simulation and mathematical modeling approaches raise questions regarding acceptance of findings, especially among policy makers. Nevertheless, we point to modeling successes in obesity and other fields, including the NIH-funded National Collaborative on Childhood Obesity Research (NCCOR) Envison project. PMID- 26576336 TI - Are all biases missing data problems? AB - Estimating causal effects is a frequent goal of epidemiologic studies. Traditionally, there have been three established systematic threats to consistent estimation of causal effects. These three threats are bias due to confounders, selection, and measurement error. Confounding, selection, and measurement bias have typically been characterized as distinct types of biases. However, each of these biases can also be characterized as missing data problems that can be addressed with missing data solutions. Here we describe how the aforementioned systematic threats arise from missing data as well as review methods and their related assumptions for reducing each bias type. We also link the assumptions made by the reviewed methods to the missing completely at random (MCAR) and missing at random (MAR) assumptions made in the missing data framework that allow for valid inferences to be made based on the observed, incomplete data. PMID- 26576337 TI - Genetic Polymorphism and Expression of CXCR4 in Breast Cancer. AB - CXCR4 genetic polymorphisms, as well as their expression level, have been associated with cancer development and prognosis. The present study aimed to investigate the influence of CXCR4 rs2228014 polymorphism on its mRNA and protein expression in breast cancer samples. It was observed that patients presented higher CXCR4 mRNA relative expression (5.7-fold) than normal mammary gland, but this expression was not correlated with patients clinicopathological features (nuclear grade, nodal status, ER status, PR status, p53 staining, Ki67 index, and HER-2 status). Moreover, CXCR4 mRNA relative expression also did not differ regarding the presence or absence of T allele (p = 0.301). In the immunohistochemical assay, no difference was observed for CXCR4 cytoplasmic protein staining in relation to different genotypes (p = 0.757); however, high cytoplasmic CXCR4 staining was verified in invasive breast carcinoma (p < 0.01). All in all, the results from present study indicated that rs2228014 genetic variant does not alter CXCR4 mRNA or protein expression. However, this receptor was more expressed in tumor compared to normal tissue, in both RNA and protein levels, suggesting its promising applicability in the general context of mammary carcinogenesis. PMID- 26576338 TI - Smokers' sources of e-cigarette awareness and risk information. AB - INTRODUCTION: Few studies have explored sources of e-cigarette awareness and peoples' e-cigarette information needs, interests or behaviors. This study contributes to both domains of e-cigarette research. METHODS: Results are based on a 2014 e-cigarette focused survey of 519 current smokers from a nationally representative research panel. RESULTS: Smokers most frequently reported seeing e cigarettes in stores (86.4%) and used in person (83%). Many (73%) had also heard about e-cigarettes from known users, broadcast media ads (68%), other (print, online) advertisements (71.5%), and/or from the news (60.9%); sources of awareness varied by e-cigarette experience. Most smokers (59.9%) believed e cigarettes are less harmful than regular cigarettes, a belief attributed to "common sense" (76.4%), the news (39.2%) and advertisements (37.2%). However, 79.5% felt e-cigarette safety information was important. Over one-third said they would turn to a doctor first for e-cigarette safety information, though almost a quarter said they would turn to the Internet or product packaging first. Most (59.6%) ranked doctors as the most trustworthy risk source, and 6.8% had asked a health professional about e-cigarettes. CONCLUSIONS: Future research should explore the content of e-cigarette information sources, their potential impact, and ways they might be strengthened or changed through regulatory and/or educational efforts. PMID- 26576340 TI - Avian influenza A(H7N9) virus and mixed live poultry-animal markets in Guangdong province: a perfect storm in the making? PMID- 26576339 TI - Sphingosine kinase 2 is a chikungunya virus host factor co-localized with the viral replication complex. AB - Chikungunya virus (CHIKV) is a re-emerging alphavirus which causes severe and prolonged arthralgic febrile illness. The recent global spread of the virus and lack of approved therapeutic options makes it imperative to gain greater insight into the molecular mechanisms underlying CHIKV pathogenesis, in particular host factors recruited by the virus. In the current study, we identify sphingosine kinase 2 (SK2) as a CHIKV host factor co-localized with the viral replication complex (VRC) during infection. SK2 was demonstrated to co-localize with viral RNA and nonstructural proteins. Targeted impairment of SK2 expression or function significantly inhibited CHIKV infection. Furthermore, affinity purification-mass spectrometry studies revealed that SK2 associates with a number of proteins involved in cellular gene expression specifically during viral infection, suggesting a role in replication. Collectively these results identify SK2 as a novel CHIKV host factor. PMID- 26576341 TI - Effectiveness of the live attenuated rotavirus vaccine produced by a domestic manufacturer in China studied using a population-based case-control design. AB - A universal rotavirus (RV) immunization program is a potentially cost-effective measure for preventing RV infection in China. However, the efficacy of the only licensed RV vaccine (Lanzhou lamb rotavirus vaccine, LLR), which is made by a domestic manufacturer, has not been proven by a properly designed clinical trial. In October 2011 to March 2012, to measure the potential protection provided by LLR, a case-control study nested in a population-based active diarrhea surveillance study of children <5 years of age was conducted in rural Zhengding county. During the study period, 308 episodes of diarrhea were identified as being caused by RV infection, resulting in an incidence rate of 48.0/1000 people/year. The predominant RV serotype was G3 (61.5%), followed by G1 (15.2%), and G9 (6.5%). Overall, a protection of 35.0% (95% confidence interval (CI), 13.0%-52.0%) was identified, and higher protection was found among moderate RV gastroenteritis cases caused by the serotype G3 (52.0% 95% CI: 2.0%-76.1%). A concurrently conducted case-control study comparing non-RV viral diarrheal cases with non-diarrheal controls in the same population found that the RV vaccine offered no protection against non-RV diarrhea. Even under a less ideal immunization schedule, the oral LLR conferred a certain level of protection against RV gastroenteritis. However, further studies are needed to understand the full characteristics of the LLR, including its efficacy when administered following the optimal regimen, the potential risk of inducing intussusception, and the direct and indirect protective effects of LLR. PMID- 26576342 TI - Enterovirus D68 detected in children with severe acute respiratory illness in Brazil. PMID- 26576343 TI - Fruit and Vegetable Intake: Benefits and Progress of Nutrition Education Interventions- Narrative Review Article. AB - BACKGROUND: Sufficient intake of fruits and vegetables has been associated with a reduced risk of chronic diseases and body weight management but the exact mechanism is unknown. The World Health Organisation and Food and Agriculture of the United Nation reports recommend adults to consume at least five servings of fruits and vegetables per day excluding starchy vegetables. This review focuses on the importance of fruits and vegetables as well as the benefits and progress of nutrition education in improving intake. METHODS: For this narrative review, more than 100 relevant scientific articles were considered from various databases (e.g Science Direct, Pub Med and Google Scholar) using the keywords Fruit and vegetable, Nutrition education, Body weight, Obesity, Benefits and challenges. RESULTS: Existing data suggests that despite the protective effects of fruits and vegetables, their intakes are still inadequate in many countries, especially developing ones. Consequently enhancing strategies to promote fruit and vegetable intake are essential for health promotion among population. A number of reviews confirm that a well planned and behaviour focused nutrition education intervention can significantly improve behaviour and health indicators. CONCLUSION: Despite challenges in nutrition education intervention programs, they are considered as a good investment in terms of cost benefit ratio. Rapid improvement in trends of nutrition education can be seen in many countries and majority of interventions has been successful in increasing fruits and vegetables intake. It is recommended that health professionals use multiple interventions to deliver information in several smaller doses over time to ensure improved outcomes. PMID- 26576344 TI - Epidemiological Aspects of Neonatal Mortality Due To Intrauterine Infection in Kazakhstan. AB - BACKGROUND: In this study, we examined the epidemiological aspects of neonatal mortality due to intrauterine infections with regard to regional characteristics. METHODS: Consolidated report of the Ministry of Health and Social Development of the Republic of Kazakhstan on children deceased during their first 28 days of life due to intrauterine infections (P23 - congenital pneumonia, P35-39 - infectious diseases specific to the perinatal period) in the country and its regions for 2010 - 2014 was used in this investigation. Descriptive and analytical methods of medical statistics and epidemiology were used as the main method of this 5-year (2010-2014) retrospective study. RESULTS: Overall, 3,298 neonatal deaths from intrauterine infections were recorded in Kazakhstan during the period of 2010-2014, 1,925 of which were early and 1,373 were late neonatal deaths. The average annual rate of neonatal mortality rate from intrauterine infection in the country amounted to 1.73+/-0.230/00 (95% CI=1.27-2.190/00), whereas trends during the study period decreased (T=-15.3%). Regional characteristics of neonatal mortality were established. Different levels for cartograms of neonatal mortality from intrauterine infections were defined: low (up to 1.280/00), average (from 1.280/00 to 2.120/00) and high (by 2.120/00 and above). Neonatal mortality in the early and late periods was also analyzed. CONCLUSION: This is the first epidemiological study of neonatal mortality from intrauterine infection, which contains a detailed space-time evaluation. The results of this investigation can be used to improve the state program to combat infant mortality. PMID- 26576345 TI - Drinking and Driving among University Students in 22 Low, Middle Income and Emerging Economy Countries. AB - BACKGROUND: The aim of this study was investigate drinking, driving, and socio behavioral factors among university students in low and middle income and emerging economy countries. METHODS: Using anonymous questionnaires, data were collected from 18476 university students, of which 15151 (82.0%) were drivers of a car or motorcycle (41.3% men and 58.7% women), with a mean age of 20.7 years (SD=2.9), from 22 countries across Africa, Asia and Americas. RESULTS: Overall, 17.3% reported to have been driving a car or motorcycle after having had too much to drink in the past 12 months, ranging from below 5% in Bangladesh, Indonesia and Kyrgyzstan to above 35% in China, Singapore and Thailand. In multivariate logistic regression analysis, among both men and women, earlier year of study, living in an upper middle income or high income country (OR=3.58, CI=3.00-4.27 and OR=2.95, CI=2.52-3.46), low intrinsic religiosity (OR=0.67, CI=0.54-0.83 and OR=0.34, CI=0.28-0.42), injury from motorcycle accidents (OR=4.29, CI=2.69-6.82 and OR=3.24, CI=2.26-4.63), and weak belief in the importance of not drinking (OR=1.78, CI=1.50-2.11 and OR=1.61, CI=1.37-1.88) and driving were associated with drinking and driving. Further, among men, older age (OR=1.04, CI=1.01-1.07), binge drinking (OR=1.53, CI=1.27-1.86) and illicit drug use (OR=1.22, CI=1.01 1.47), and among women, younger age (OR=0.95, CI=0.97-0.98), and a lower country BAC limit (OR=0.01, CI=0.001-0.18) was associated with drinking and driving. CONCLUSION: This study confirms low to high levels of drinking and driving in different cultures across Africa, Asia and the Americas. Various factors identified can be used to guide interventions to reduce drinking and driving among university students. PMID- 26576346 TI - Effect of Genistein and L-Carnitine and Their Combination on Gene Expression of Hepatocyte HMG-COA Reductase and LDL Receptor in Experimental Nephrotic Syndrome. AB - BACKGROUND: Nephrotic syndrome is a disorder that leads to hyperlipidemia. L carnitine and genistein can effect on lipid metabolism and the syndrome. In the present study, we have delved into the separate and the twin-effects of L carnitine and genistein on the gene expressions of HMG-COA reductase and LDL receptor in experimental nephrotic syndrome. METHODS: In this controlled experimental study, 50 male Sprague-Dawley rats were randomly divided into five groups: NC (normal-control), PC (patient-control), LC (L-carnitine), G (genistein), LCG (L-carnitine-genistein). Adriamycin was used for inducing nephrotic syndrome and the spot urine samples and urine protein-to-creatinine ratio were measured. Hepatocytic RNA was extracted and real-time PCR was used for HMG-COA Reductase and LDL receptor gene Expression measurement. RESULTS: The final weight of the patients groups were lower than the NC group (P=0.001), and weight gain of the NC group was higher than the other groups (P<0.001). The proteinuria and urine protein-to-creatinine ratio showed significant differences between PC group and LC, G and LCG groups at week 7 (P<0.001). The expression of HMGCOA Reductase mRNA down regulated in LC, G and LCG groups in comparison with PC group (P<0.001). DeltaCT of LDLr mRNA showed significant differences between the PC group and the other patient groups (P<0.001). CONCLUSION: This study shows a significant decreasing (P<0.001) and non-significant increasing trend in HMG COA Reductase and LDLr gene expression, respectively, and synergistic effect of L carnitine and genistein on these genes in experimental nephrotic syndrome. PMID- 26576347 TI - Double Heterozygosity of BRCA2 and STK11 in Familial Breast Cancer Detected by Exome Sequencing. AB - BACKGROUND: Germ-line mutations of BRCA1 and BRCA2 genes are responsible for approximately 25-30% of dominantly inherited familial breast cancers; still a big part of genetic component is unknown. The aim of this study was to investigate genetic causes of familial breast cancer in a pedigree with recessive pattern of inheritance. METHODS: We applied exome sequencing as a useful approach in heterogeneous diseases gene identification in present study for familial breast cancer. Sanger sequencing was applied for validation and segregation analysis of mutations. RESULTS: Here, we describe a family with three affected sisters of early-onset invasive ductal carcinoma due to heterozygous frame shift mutation rs80359352 in BRCA2 gene as the first report in Iranian patients in association with a novel missense SNP of STK11 (p.S422G). These mutations are inherited from their normal father. CONCLUSION: Despite apparent recessive pattern of inheritance a dominant gene (here BRCA2) can be involved in pathogenesis of hereditary breast cancer which can be explained by incomplete penetrance of BRCA2 mutations. PMID- 26576348 TI - Analysis of Chemokine Receptor Gene Expression in Esophageal Cancer Cells Compared with Breast Cancer with Insights into Metastasis. AB - BACKGROUND: Chemokine receptors have been shown to play an important role in the development and metastatic spread of various malignancies. In this study, the gene expression profile of some key chemokine receptors involved in metastasis has been investigated in esophageal and breast cancer cell lines. METHODS: In a descriptive study, gene expression profile of CCR1, CCR6, CCR7, CCR9, CXCR1, and CXCR4 in human esophageal cancer cell line (KYSE-30) and human breast cancer cell line (MCF7) were analyzed using real-time PCR and their results were compared accordingly. RESULTS: We demonstrated for the first time the expression of CCR1, CCR6, CCR7, CCR9, CXCR1, and CXCR4 at transcriptional level in human esophageal cancer cell line. The expression of CCR1, CCR7 and CXCR4 were lower in esophageal compared with breast cancer cells, although without significant difference. CCR9 was highly expressed in esophageal cancer cells as compared to the breast cancer cells (P < 0.05). Similarly, the expression of CCR6 and CXCR1 were higher, although without significant difference. CONCLUSION: Esophageal cancer cells like breast cancer express some key chemokine receptors involved in metastasis. Targeting of proposed receptors in esophageal cancer may be a novel strategy for prevention of cancer metastasis. PMID- 26576349 TI - Leishmania tropica in Stray Dogs in Southeast Iran. AB - BACKGROUND: Cutaneous leishmaniasis (CL) caused by Leishmania tropica is endemic in Kerman, southeastern Iran. While dogs have long been implicated as the main domestic reservoirs of L. infantum, etiological agent of zoonotic visceral leishmaniasis (ZVL), they can also carry L. tropica infection. The objective of the present study was to determine molecular identity and to evaluate histopathological changes due to CL in dogs in a well-known focus of anthroponotic CL (ACL) in Kerman, southeastern Iran. METHODS: This study was carried out in three prospective series from 1994 to 2013 on dogs. Tissue samples were taken from 471 stray dogs. Pathological specimens including skin, spleen, liver and lymph nodes were prepared for paraffin blocks, sectioning and staining for further histopathological examination. PCR amplification of kDNA was performed to identify the causative agent and sequencing. Overall, two out of 471 stray dogs were infected with L. tropica. Hyperplasia of red pulp by the proliferation of histiocytes, lymphocytes, plasma cells and cytoplasm of histiocytes collection of amastigotes was noted. RESULTS: Based on the results of PCR products and sequencing analysis, the parasites isolated from the lesions of two dogs were characterized as L. tropica, corresponding to a band of 830 bp. CONCLUSION: This finding revealed infection with L. tropica in stray dogs in the city and suburbs of Kerman. This information is essential for public health concerns and planning effective future control programs. The role of dogs as potentional reservoir in the epidemiology of ACL needs further investigation. PMID- 26576350 TI - Designing Excellence and Quality Model for Training Centers of Primary Health Care: A Delphi Method Study. AB - BACKGROUND: Excellence and quality models are comprehensive methods for improving the quality of healthcare. The aim of this study was to design excellence and quality model for training centers of primary health care using Delphi method. METHODS: In this study, Delphi method was used. First, comprehensive information were collected using literature review. In extracted references, 39 models were identified from 34 countries and related sub-criteria and standards were extracted from 34 models (from primary 39 models). Then primary pattern including 8 criteria, 55 sub-criteria, and 236 standards was developed as a Delphi questionnaire and evaluated in four stages by 9 specialists of health care system in Tabriz and 50 specialists from all around the country. RESULTS: Designed primary model (8 criteria, 55 sub-criteria, and 236 standards) were concluded with 8 criteria, 45 sub-criteria, and 192 standards after 4 stages of evaluations by specialists. Major criteria of the model are leadership, strategic and operational planning, resource management, information analysis, human resources management, process management, costumer results, and functional results, where the top score was assigned as 1000 by specialists. Functional results had the maximum score of 195 whereas planning had the minimum score of 60. Furthermore the most and the least sub-criteria was for leadership with 10 sub-criteria and strategic planning with 3 sub-criteria, respectively. CONCLUSION: The model that introduced in this research has been designed following 34 reference models of the world. This model could provide a proper frame for managers of health system in improving quality. PMID- 26576351 TI - Demonstration of the Enhanced Disinfection of E. coli Water Contamination by Associated Solar Irradiation with Potassium Persulfate. AB - BACKGROUND: Tremendous amount of researches have investigated the issue of water photodisnfection. The aim of this research is to illustrate the influences of bacterial density, turbidity, exposure time and potassium persulfate (KPS) dosage on the efficacy of associated solar disinfection (SODIS) with KPS for E. coli (ATCC: 25922) eradication as an efficient and inexpensive process. METHODS: Desired bacterial density and turbidity was achieved by spiking of 0.5 Mc Farland (1.5*10(8) cell/ml) and sterile soil slurry in 1 liter of the commercially bottled water. RESULTS: The highest value of UVA solar irradiation measured at 13.30 p.m was 5510 MUW/Cm(2). Increase of bacterial density from 1000 to 1500 cell/ml led to an increase in disinfection lapse time, except in 2 mMol/l KPS. Spiking of 0.1 mMol/l of KPS was not effective; however, increase of KPS dosage from 0.1 mMol/l to 0.7, 1.5 and 2 mMol/l led to the enhancement of disinfection time from 4 h to 3 h and 1 h, respectively. For bacterial density of 1000 cell/ml, increasing KPS dosage up to 0.7 mMol/l had no improved effect; however, beyond this dosage the disinfection time decreased to 1 h. Without KPS and up to 150 NTU within 4 h exposure time, E. coli disinfection was completed. In 2 mMol/l KPS and 1000 and 1500 cell/ml, the 2 h contact time was sufficient up to 150 and 100 NTU, respectively; moreover, complete disinfection was not achieved at higher turbidity. CONCLUSION: Association of KPS with SODIS can lead to decreasing of water disinfection time. PMID- 26576352 TI - Relation of Stroke Risk Factors with Specific Stroke Subtypes and Territories. AB - BACKGROUND: Although the risk factors of ischemic strokes are well defined, there is slight information about their relations with the etiologies of ischemic strokes. This study investigated the distribution of ischemic stroke risk factors and their connections to diverse etiologies of cerebrovascular attack (CVA) and specific ischemic regions of brain. METHODS: In this cross sectional study, we analyzed the data of patients with definite diagnosis of CVA, excluding hemorrhagic strokes, registered in Imam Hossein Medical Center in Tehran, Iran. The data were collected from entire archived medical records from March 2010 until September 2012, retrospectively. RESULTS: Out of 1696 cases a total of 1011 subjects, 487 (48.2%) males and 524 (51.8%) females with mean age of 68.91+/ 13.54 yr were included in the study. Patients suffering from atrial fibrillation (AF), valvular heart disease (VHD), and dilated cardiomyopathy were more prone to develop cardioembolic stroke. Those with diabetes mellitus (DM), carotid artery stenosis and dyslipidemia (DLP) had a higher prevalence of macroangiopathic stroke. Ischemic heart disease (IHD), AF, and VHD were associated with stroke in the brain territory supplied by middle cerebral artery (MCA) while DM and carotid artery stenosis were correspondent with posterior cerebral artery (PCA) stroke. CONCLUSION: The diagnosis of the weight of each risk factor of ischemic strokes on different etiologies and territories of ischemia can assist care providers for a more efficient prevention of strokes. The results of this study can also be a basis for further investigations to corroborate the pathophysiology of such relations. PMID- 26576353 TI - The Effect of Injury-Related Characteristics on Changes in Marital Status after Spinal Cord Injury. AB - BACKGROUND: Spinal cord injury (SCI) imposes a significant burden on the social and marital life. Here, we assessed the divorce rate and changes in marital status among a sample of Iranian individuals with SCI. METHODS: Referred patients to Brain and Spinal Cord Injury Research Center were invited to participate in this cross-sectional investigation. The Main exclusion criteria were coincidental brain injury, history of chronic diseases before SCI and substance use. Demographic characteristics (including age, gender, educational level, marital status before and after injury and duration of marriage) and Injury characteristics (level of the injury, American spinal injury association (ASIA) scale and Spinal cord independence measure III (SCIM)) were collected. RESULTS: Total of 241 subjects with SCI participated in this investigation (164 (68%) male and 77 (32%) female). Among men, 16.5% [95% CI: 10.81%-22.18%] and among women 18.2% [95% CI: 9.58%-26.81%] got divorced after injury. Duration of marriage before injury was significantly related to lower divorce rate (P< 0.001 and 0.016 in men and women, respectively). Injury characteristics had no relationship with marital longevity. Age was a protective factor against marital dissolution only in men (P< 0.004). CONCLUSION: Our study revealed the divorce rate of 17% [95% CI: 13%-20.9%] after SCI in a sample of Iranian population. The protective influence of age in maintenance of marriage was only detected in men, which proposes existence of a sexual polymorphism in the role of age. Divorce rate was similar between two genders and injury characteristics were not related to divorce rate as well. PMID- 26576354 TI - Marital Quality Trajectory among Iranian Married Individuals: A Collectivist Perspective. AB - BACKGROUND: The trajectory of marital quality over the life course assumes a curvilinear pattern and declines over time. However, most studies to date have been conducted in developed societies, leaving the generalizability of their findings open to skepticism. In this study, we aimed to delineate the trajectory of marital satisfaction in Iran. METHODS: Using cluster-sampling method, representative sample of 800 Iranian married individuals from urban areas of seven provinces of Iran, between February and May 2011 was surveyed. Each cluster included 50 households. Sealed packages containing survey material were delivered to households. Self-administered surveys included a checklist collecting demographic and socioeconomic data, and the Comprehensive Marital Satisfaction Scale. Generalized additive models (GAM) were used to explicate the trajectory of marital satisfaction over marital duration. RESULTS: A total of 644 complete questionnaires were returned (response rate: 80.5%). Average age of the participants was 40yr and average duration of marriage 17yr. The fitted GAM showed that marital satisfaction is highest at the beginning but drastically declines over the first 10yr. After arriving a nadir, the downward progression is reversed in the next 10-15yr, reaching a level comparable to the beginning. At 23 25yr, a second declining wave initiates and marital satisfaction steadily declines thereafter. The overall shape remains the same after adjustment for number of children, economic status, and retirement. CONCLUSION: Marital trajectory assumes a curvilinear pattern and has three periods of decline, stagnation, and decline. The shape of trajectory bears similarities to the observed patterns in the US but is distinct, nevertheless. PMID- 26576355 TI - The Effect of Time-to-Provider, Left-without-Treatment and Length-of-Stay on Patient Satisfaction in Training Hospitals' Emergency Department, Iran. AB - BACKGROUND: It is necessary to consider into hospital emergency services' quantity and quality in different aspects such as time-to-provider, left-without treatment and length-of-stay. The aimof this research was to identify the effect of these factors on patient satisfaction in training hospitals. METHODS: In this descriptive-analytical and cross-sectional study, the sample size was calculated 768. The instrument included 54 questions and 8 sections. Three questions were in the field of following factors: 1) Time to provider was defined as the time from initial triage to initial provider evaluation. 2) Left-without-Treatment patients were defined as those who were initially triaged but were unable to be evaluated by a provider because they had left the ED. 3) Length-of-Stay was defined as time from initial triage to the time of final ED disposition, either discharge or admission. It was analyzed by descriptive statistics, simple logistic regression, multiple logistic regressions, simple linear regression and multiple linear regression. RESULTS: The time-to-provider lower than 15 minutes, LWOT and LOS lower than 6 hours were 92.8%, 3.9% and 90.3%, respectively. The mean of time-to provider and the mean of LOS were 18.1 minutes and 202 minutes. Time-to-Provider affected satisfaction of admission, guardians, nursing care and managing proceedings (P<0.001). LOS affected satisfaction of admission, guardians and diagnosis proceedings (P<0.01). LWOT did not affect satisfaction and its domains (P>0.05). CONCLUSION: Decreasing time-to-provider and LOS has the effect on patient satisfaction in some domains. Furthermore, left-without-treatment rate is not a good proxy of patient satisfaction. PMID- 26576356 TI - Lunate Dislocation Followed by Non-Traumatic Swimming: A Case Report. AB - A few numbers of patients admitted to the emergency department due to the lunate dislocation can cause a direct injury to the wrist ligament, which mainly occurs after wrist trauma, and often diagnosis is far from the mind. A 32 years old man due to severe pain and tenderness of the wrist started the previous day during swimming, referred to Emergency Department of Imam Reza Hospital of Mashhad, 2012. He did not recall any history of direct trauma to the wrist. However, he was prescribed NSAID and wrist splint, but the pain did not improve. In physical examination, the localized tenderness of the dorsal wrist without erythema and warmness was clearly evident and paresthesia of the skin was observed in the 4th and 5th fingers. Plain X-ray detected no fractures. The combination of these signs and symptoms prompted clinical suspicion of lunate dislocation confirmed by imaging. This patient was admitted to the orthopedic service with lunate dislocation diagnosis for the proper treatment. PMID- 26576357 TI - Who Will Feed the Giant? - Chinese Pollution and Grain Crisis. PMID- 26576358 TI - Patient's Perception on Services of Indian Multispecialty Hospitals - A Tqm Approach. PMID- 26576359 TI - The Incidence of Neonatal Cryptorchidism in Sfax, Tunisia. PMID- 26576360 TI - Correlation between Physical Activity and Arterial Stiffness in Korean Office Workers: A Community-Based Study. PMID- 26576361 TI - Chinese Medical Personnel: Better Sleep Hygiene Needed. PMID- 26576362 TI - A Cross-Sectional Study of Ascaris lumbricoides Infection in a Rural Community in Ebonyi State, Nigeria: Prevalence and Risk Factors. PMID- 26576363 TI - Accurate Estimation of Obstructive Sleep Apnea Severity Using Non Polysomnographic Features For Home-Based Screening. PMID- 26576364 TI - Prevalence of Disability in Iran. PMID- 26576365 TI - Basic Temperament among Patients with Functional Constipation. PMID- 26576366 TI - Cancer Biopsy in Ancient Persian Medicine: Do or Not to Do! PMID- 26576367 TI - Genetic of Alzheimer's Disease: A Narrative Review Article. AB - BACKGROUND: Alzheimer's disease (AD) is one of the most common problems for old peoples. Etiology of AD is not clear, but genetic factors play a major role in determining a person's risk to develop AD. Twin and family studies confirm that AD has a genetic basis. AD genetics has been split into two broad categories: early-onset and late-onset. EOAD cases are inherited in an autosomal dominant pattern. In this form, dominant mutations in genes like APP, PSEN-1 and PSEN-2 associated with AD. This study aimed to consider the role of genetic in AD. METHOD: At the first, most of the references in relation with genetic basis of AD searched from the following web-sites: PubMed, Science direct, Wiley & Sons (1995 2014). Then, the most common genes and their affects described briefly. RESULTS: Aging is the most obvious risk factor for developing AD. There is a genetic basis for AD, of course this relation is not complete but it is significant. CONCLUSION: More than thousand genes studied in relation with Alzheimer's disease. Against the improvements in understanding different aspects of AD, the accurate genetic foundation of AD remain unclear. PMID- 26576368 TI - Rate and Causes of Discharge against Medical Advice in Iranian Hospitals: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Discharge against Medical Advice (DAMA) is a problem for hospitals which may result in increasing readmissions, morbidities, inabilities, deaths and health care costs. This study, aimed to investigate the rate and causes of DAMA in Iranian hospitals. METHODS: A systematic review and meta-analysis study was conducted in 2014. Required data were collected through searching for key words included: "Discharge Against Medical Advice", "Leaving against medical advice", "causes*", "hospital" and their Persian equivalents, over databases including PubMed, OVID, Google Scholar, Embase, Scopus, Magiran, scientific information database (SID). The reference lists of the articles, certain relevant journals and web sites in this field were also searched. RESULTS: Out of 913 articles initially retrieved, finally 17 articles were incorporated into the study. There were 244858 individuals studied in the articles. Using a random effects model, the rate of DAMA in Iranian hospitals was estimated at 7.9% (6.3%-9.8%). While the highest rate of DAMA was associated with patients in departments of psychiatry (12%), the lowest rate was related to patients in departments of pediatrics (3.7). DAMA was in men more than women (P<0.05) Patient's perception of feeling of wellbeing, financial problems, family problems, the lack of attention from physicians and nurses, inappropriate behavior with patients by hospital team and the lack of timely care were mentioned as main causes for DAMA. CONCLUSION: The rate of DAMA in Iranian hospitals is relatively high. Thus effective initiatives in this area are required. PMID- 26576369 TI - The Health Literacy Status and Influencing Factors of Older Population in Xinjiang. AB - BACKGROUND: This study was to investigate the health literacy and influencing factors of older population in pension institution of Xinjiang, China. METHODS: Elderly people were selected from 44 pension institutions in Urumqi, Changji, Karamay and Shihezi and from September 2011 to June 2012 using random layer sampling method. The investigation was carried out by Chinese citizen health literacy questionnaire prepared by the China Health Education Center. Data were analyzed by Oneway ANOVA, multiple linear regression and Pearson correlation analysis. RESULTS: A total of 1396 elderly people met the inclusion criteria and their average age was (77.37 +/- 8.48) years. Their average health literacy score was (77.37 +/- 8.48) points, which was at a low level. There was significant difference in health literacy score among the factors of age, gender, race, education, household income, marital status and occupation (P<0.05). The independent influencing factors of health literacy were education, race, occupation, household income, age and marital status (P < 0.05). Correlation analysis was conducted between the scores of health knowledge, health belief, health behavior, health skill and total scores of health literacy. Health knowledge scores and total scores had highest correlation (r=0.95), followed by health belief scores and total scores (r=0.81). CONCLUSION: The correlation between health behavior scores and health skill scores was the lowest (r=0.33). The major factors that lead to low health literacy in elderly people are femininity, minority and low levels of education. PMID- 26576370 TI - Decomposing Wealth-Based Inequalities in Under-Five Mortality in West Africa. AB - BACKGROUND: This study aimed to analysis the inequalities of mortality of children under 5 years in West Africa by examining the determinants and contributing factors to the overall inequality concentration in these countries. METHOD: Data used came from the DHS surveys conducted in the six countries in West Africa: Burkina Faso (2010), Benin (2006), Cote d'Ivoire 2011), Ghana (2008), Mali (2006), Nigeria (2008) and Niger (2012). The concentration index (CI) and Generalized Linear Model (GLM) with logit link were used to access inequality. RESULTS: The results show that in all countries, the poorest Q1 have the highest proportions of deaths: Nigeria (31.4%), Cote d'Ivoire (30.4%) and Ghana (36.4%), over 30% of deaths of children under 5 years are among the children of the poorest (Q1) and the absolute differences of proportions Q1-Q5 are more than 20 points (25.8 in Ghana and 23.6 in Nigeria). The contributing factors of inequalities of child mortality were birth order, maternal age, parity and household size. Our findings also showed that the intensity of inequality varies from one country to another. CONCLUSION: The most important conclusion of this study is to reduce mortality in children under 5 years, it is needed to reduce economic and social inequalities and improve the country's economic and social condition. There is a need for monitoring and assessment inequalities by leading causes of death and morbidity among children in the region in order to advance in understanding the gaps and finding a way to reduce them in West Africa countries. PMID- 26576371 TI - A Causal Relationship of Occupational Stress among University Employees. AB - BACKGROUND: Occupational stress is a psychosocial dimension of occupational health concept on social determinants of health, especially, job & environmental condition. Recently, staff network of different government universities of Thailand have called higher education commission, and Ministry of Education, Thailand to resolve the issue of government education policy (e.g. wage inequity, poor welfare, law, and job & environment condition) that leads to their job insecurity, physical and mental health problems from occupational stress. The aim of this study was to investigate a causal relationship of occupational stress among the academic university employees. METHODS: This cross sectional research was conducted in 2014 among 2,000 academic university employees at Thai government universities using stratified random sampling. Independent variables were wage, family support, periods of duty, and job & environmental condition. Dependent variable was stress. RESULTS: Job & environmental condition, as social and environmental factor, and periods of duty as individual factor had direct effect to stress (P< 0.05). Family support, as family factor, and wage, as individual factor had direct effect to stress (P < 0.05). Both family support and wage were the causal endogenous variables. CONCLUSION: Job & environmental condition and periods of duty were increased so that it associated with occupational stress among academic university employees at moderate level. PMID- 26576372 TI - Like Mother, Like Daughter? Dietary and Non-Dietary Bone Fracture Risk Factors in Mothers and Their Daughters. AB - BACKGROUND: The aim of this study was to demonstrate similarities and differences between mothers and daughters regarding dietary and non-dietary risk factors for bone fractures and osteoporosis. METHODS: The study was carried out in 2007-2010 on 712 mothers (29-59 years) and daughters (12-21 years) family pairs. In the sub sample (170 family pairs) bone mineral density (BMD) was measured for the forearm by dual-energy x-ray absorptiometry (DXA). The consumption of dairy products was determined with a semi-quantitative food frequency questionnaire (ADOS-Ca) and calcium intake from the daily diet was calculated. RESULTS: The presence of risk factors for bone fractures in mothers and daughters was significantly correlated. The Spearman rank coefficient for dietary factors of fracture risk was 0.87 (P<0.05) in whole sub-sample, 0.94 (P<0.05) in bottom tercile of BMD, 0.82 (P<0.05) in middle tercile of BMD, 0.54 (P>0.05) in upper tercile of BMD and for non-dietary factors of fracture risk was 0.83 (P<0.05) in whole sub-sample, 0.86 (P<0.05) in bottom tercile of BMD, 0.93 (P<0.05) in middle tercile of BMD, 0.65 (P<0.05) in upper tercile of BMD. CONCLUSIONS: Our results confirm the role of the family environment for bone health and document the stronger effect of negative factors of the family environment as compared to other positive factors on bone fracture risk. PMID- 26576373 TI - Influence of Continuous Nursing on the Psychological State and Coping Style of Patients Undergoing Pacemaker Implantation. AB - BACKGROUND: Patients undergoing pacemaker implantation often experience anxiety and fear. As such, studies have focused on the mechanisms that relieve the negative emotions caused by the intervention. Continuous nursing is a safe and effective nursing mode. In this study, continuous nursing intervention was provided for elderly patients undergoing pacemaker implantation and an empirical investigation was performed to determine the effects of their negative emotion and disease-coping ability. METHODS: Overall, 114 (68 males and 46 females) elderly patients who were undergoing pacemaker implantation from Harbin City (China), were enrolled in the study. The patients were divided into two groups, namely, the control group and the intervention group, based on different nursing methods. Routine nursing was applied to the control group; continuous nursing support was provided for the intervention group from January 2014 to January 2015. The nursing results of the two groups were compared. These results were also evaluated using self-rating depression scale, self-rating anxiety scale, and trait coping style questionnaire. RESULT: The effects of depression and anxiety intervention were significant in the intervention group (P<0.05). Compared with the control group, the intervention group did not significantly differ. The coping style of the intervention group elicited significant effects. Compared with the control group, the intervention group was significantly different (P < 0.05). CONCLUSION: Continuous nursing can relieve the negative emotion and improve the negative coping style of patients undergoing pacemaker implantation. PMID- 26576374 TI - Molecular Cloning and Expression an 8-kDa Subunit of Antigen B from G1 strain of Echinococcus granulosus. AB - BACKGROUND: Echinococcosis or hydatidosis is a chronic, zoonotic worldwide infection caused by the larval stage of the dog taeniid tapeworm Echinococcus granulosus. Vaccination has been considered as one of the ways to prevent of hydatidosis in recent decades. The aim of this study was to construct a pcDNA3.1 eukaryotic expression vector containing the subunit 8-kDa antigen B (Hyd1) of E. granulosus (G1 strain) and investigate its capability to induce protein expression in mammalian cell line, as a basis toward developing a DNA vaccine against hydatidosis. METHODS: The coding sequence of HydI was amplified by PCR with the specific PCR primers from pQE/HydI, and then was sub-cloned into pcDNA3.1 plasmid as expression vector. The pcHyd1 plasmid was digested by restriction enzymes and amplified with the specific PCR primers to confirm cloning of this gene in pcDNA3 plasmid. In last step, the sub-cloned gene was expressed in mammalian cell line (NIH 3T3 cells). RESULT: The subunit 8-kDa antigen B (Hyd1) was successfully sub-cloned in pcDNA3.1 and Hyd1 protein was expressed in eukaryotic cell confirmed by SDS-PAGE and Western blot. CONCLUSION: Recombinant plasmid of pcDNA3.1 was successfully constructed and express of recombinant Hyd1 protein was confirmed. That is promising step for forthcoming measures on providing vaccine against human and animal hydatidosis. PMID- 26576375 TI - Two-Year Comparison of Growth Indices of Twins with Dissimilar Weight at Birth (Low Birth Weight vs. Normal Twin). AB - BACKGROUND: Twin pregnancies are commonly associated with low birth weight (LBW) infants. Most studies focus on growth of LBW compared with normal infants in singleton. However, there has not been any study on twins to compare LBW with normal birth weight (NBW) infants as a match control of the same twin. METHODS: This cohort study was conducted at Healthcare centers of Kashan, in 2013. Twins differing in birth weight (one with LBW and the other with NBW) were assessed using the care charts in Well Care program in regard to weight, height and head circumference measurements at birth and after 6, 12, 24 months of age and were compared separately between all matched pairs and in four sex-twin subgroups which was defined according to the sex of each twin in pairs; SF (Same-sex: Female), SM (Same-sex: Male), LF (LBW: Female) and LM (LBW: Male). RESULTS: Incidence of dissimilar twins in birth weight was 28.4%. The weight of LBW was significantly lower than the NBW cohort in SF and LF subgroups up to 24 months. The height of LBW was not significantly different from NBW cohort in SM and LM subgroups up to 24 month. Head circumference was significantly higher in LBW compared to NBW cohort in LM subgroup up to 24 month. However, these indices were significantly lower in LBW compared to NBW cohort in all pairs. CONCLUSION: Although LBW cohort was significantly lower than the NBW in growth indices at birth to 2 years old in all twins, however, highly variable results was observed in four subgroups of sex-twin. PMID- 26576376 TI - Sexuality Research in Iran: A Focus on Methodological and Ethical Considerations. AB - BACKGROUND: Research on sensitive topics, such as sexuality, could raise technical, methodological, ethical, political, and legal challenges. The aim of this paper was to draw the methodological challenges which the authors confronted during sexuality research with young population in the Iranian culture. METHODS: This study was an exploratory mixed method one conducted in 2013-14. We interviewed 63 young women aged 18-34 yr in qualitative phase and 265 young women in quantitative phase in (university and non-university) dormitories and in an Adolescent Friendly Center. Data were collected using focus group discussions and individual interviews in the qualitative phase. We employed conventional content analysis to analyze the data. To enhance the rigor of the data, multiple data collection methods, maximum variation sampling, and peer checks were applied. RESULTS: Five main themes emerged from the data: interaction with opposite sex, sexual risk, sexual protective, sex education, and sexual vulnerability. Challenges while conducting sex research have been discussed. These challenges included assumption of promiscuity, language of silence and privacy concerns, and sex segregation policy. CONCLUSION: We described the strategies applied in our study and the rationales for each strategy. Strategies applied in the present study can be employed in contexts with the similar methodological and moral concerns. PMID- 26576377 TI - Expression of Recombinant Human Amelogenin in Iranian Lizard Leishmania and Its Biological Function Assay. AB - BACKGROUND: Amelogenins are the major components of enamel matrix proteins. Enamel matrix derivatives (EMD) can be used in periodontal diseases to regenerate periodontal tissues. The main aim of this study was to evaluate expression of full-length functional recombinant human amelogenin (rhAm) in Iranian lizard Leishmania (I.L.L.) as an alternative eukaryotic expression system. METHODS: Human cDNA encoding a 175-amino acid amelogenin expression cassette was sub cloned into a pLEXSY vector. The construct was transferred into Leishmania cells by electroporation. The protein production was surveyed in the transcription and the translation levels. The expressed protein was purified and some of its biological properties were investigated in comparison to EMD and negative control. RESULTS: Expression of rhAm was confirmed by RT-PCR and western blot test in Leishmania cells. Purified rhAm significantly inhibited the formation of tartrate-resistant acid phosphatase positive (TRAP(+)) multinuclear cells in calcitriol stimulated mouse marrow cultures. Moreover, it significantly promoted proliferation and DNA synthesis in L929 mouse fibroblast cells. CONCLUSION: Functional rhAm was successfully expressed in I.L.L. Easy handling and post translation modification were the main advantages of this expression system. It is suggested to investigate molecular properties of this rhAm in the future. PMID- 26576378 TI - Comparison of Antimicrobial Effects of Three Different Mouthwashes. AB - BACKGROUND: This study investigated the in vitro and in vivo antibacterial effects of three mouthwashes on supragingival plaque microbiota. The three mouthwashes under study were 0.2% chlorhexidine (CHX), Listerine(r), and Persica (PM). Water was used as negative control. METHODS: Supragingival plaque samples were collected from 32 patients with gingivitis in the Dental School of Shahid Beheshti University of Medical Sciences in March 2014. Plaque samples were swabbed on agar plates and discs (previously immersed in the three mouthwashes) were placed on the agar. The zone of bacterial inhibition (ZOI) was measured after incubation for 24 hours. For the in vivo testing, the same plaque samples were inoculated on agar and the colony forming units (CFU) were counted. The patients were then instructed to use the mouthwashes (cases) and water (controls) for two weeks, after which plaque samples were again collected, inoculated and the CFUs were counted. RESULTS: For the ZOI test, 0.2% CHX inhibited the growth of bacteria to an average diameter of 18.38 mm, while Listerine(r), PM and water caused no inhibition of bacterial growth around the discs after 24 hours. The mean bacterial count after using 0.2% CHX for two weeks decreased by 23.13 CFU. This was followed by Listerine(r), with a mean reduction of 19.75 CFU. PM resulted in 13.5 CFU decrease in the mean bacterial count, while water reduced the bacterial count by only 1 CFU. CONCLUSION: 0.2% CHX inhibits bacterial growth considerably. All three mouthwashes can reduce total bacterial count after 2 weeks although with different mean bacterial count reduction. PMID- 26576379 TI - Triallelic Inheritance of TGM1 and ALOXE3 Mutations Associated with Severe Phenotype of Ichtyosis in an Iranian Family - A Case Report. AB - Lamellar ichthyosis is one form of congenital autosomal recessive ichthyosis. To date, seven causative genes for ARCI have been identified. To understand further the genetic spectrum of the disease, we analyzed a four-generation Iranian family with ARCI that had observable inheritance. Exome sequencing data for one of the affected individuals with ichthyosis from a consanguineous Iranian family was analyzed. Potential candidate mutations were analyzed in additional family members to determine if the putative mutation segregated with disease status. A novel homozygous mutation (p.D414V) in TGM1 and rs3027232 in ALOXE3 gene in heterozygous form were identified which segregated with disease status in the family. Bioinformatic studies with Polyphen-2 and SIFT showed that these variants are damaging. We identified a possible triallelic inheritance in this study. Moreover, this paper illustrates how advances in genome sequencing technologies could be utilized to rapidly elucidate the molecular basis of inherited skin diseases which can be caused by mutations in multiple disease genes. PMID- 26576380 TI - Uncommon Presentation of Gastric Trichobezoar: A Case Report. AB - Every material that gastrointestinal system cannot digest will make a bezoar. Trichobezoar is the result of hair ingestion whether self-hair or from others and is not a common disorder in humans. It is a hairball, which mostly has been seen in females at teenage, or adolescence. It usually locates in stomach but in rare conditions, it will pass through the intestine, and make the Rapunzel syndrome. Herein we present a 13-year-old girl suffering from gastric trichobezoar presenting with failure to thrive. PMID- 26576381 TI - Clinical and Biological Correlations in Toxoplasma gondii Infection in HIV Immune Suppressed Persons. PMID- 26576382 TI - Job Burnout and Psychological Empowerment among Police in Mainland China. PMID- 26576383 TI - The Knowledge Level of Medical Personnel in Turkey about Complementary Nutrition. PMID- 26576384 TI - Red-Green Color Vision Deficiency and Lack of Awareness among Rural School Students in India. PMID- 26576385 TI - Public Health Lesson from Shanghai New Year's Eve Stampede. PMID- 26576386 TI - Quality of Sleep Affects the Level of Anxiety and Performance of Football Athletes. PMID- 26576387 TI - Paying Out of Pocket for Healthcare in Bangladesh - A Burden on Poor? PMID- 26576388 TI - Prevalence of HBV, HCV and HIV in Inpatients of a Mental Health Hospital in Turkey, 2011-2013. PMID- 26576389 TI - The Necessity of Strategic Plan for Preparedness and Response in Iran's Hospital System. PMID- 26576390 TI - Pelvic Thrusting in a Case of Psychogenic Seizure. PMID- 26576391 TI - Risk of Repeat Surgery for Perianal Crohn Disease. PMID- 26576392 TI - Surveillance Colonoscopy After a Resection of Colorectal Cancer. PMID- 26576393 TI - Venous Thromboembolic Complications in Colorectal Surgery. PMID- 26576394 TI - Change in the Diagnosis of Appendicitis by Using a Computed Tomography Scan and the Necessity for a New Scoring System to Determine the Severity of the Appendicitis. PMID- 26576395 TI - The Clinical Features and Predictive Risk Factors for Reoperation in Patients With Perianal Crohn Diseases; A Multi-Center Study of a Korean Inflammatory Bowel Disease Study Group. AB - PURPOSE: Perianal lesions are common in Crohn disease, but their clinical course is unpredictable. Nevertheless, predicting the clinical course after surgery for perianal Crohn disease (PCD) is important because repeated operations may decrease patient's quality of life. The aim of this study was to predict the risk of reoperation in patients with PCD. METHODS: From September 1994 to February 2010, 377 patients with PCD were recruited in twelve major tertiary university affiliated hospitals and two specialized colorectal hospitals in Korea. Data on the patient's demographics, clinical features, and surgical outcomes were analyzed. RESULTS: Among 377 patients, 227 patients were ultimately included in the study. Among the 227 patients, 64 patients underwent at least one reoperation. The median period of reoperation following the first perianal surgery was 94 months. Overall 3-year, 5-year, and 10-year cumulative rates of reoperation-free individuals were 68.8%, 61.2%, and 50.5%, respectively. In multivariate analysis (Cox-regression hazard model), reoperation was significantly correlated with an age of onset less than 20 years (hazard ratio [HR], 1.93; 95% confidence interval [CI], 1.07-3.48; P = 0.03), history of abdominal surgery (HR, 1.99; 95% CI, 1.08-3.64; P = 0.03), and the type of surgery. Among types of surgery, fistulotomy or fistulectomy was associated with a decreased incidence of reoperation in comparison with incision and drainage (HR, 0.19; 95% CI, 0.09-0.42; P < 0.001). CONCLUSION: Young age of onset and a history of abdominal surgery were associated with a high risk of reoperation for PCD, and the risk of reoperation were relatively low in fistulotomy or fistulectomy procedures. PMID- 26576396 TI - Detection of Polyps After Resection of Colorectal Cancer. AB - PURPOSE: Because colonoscopy after colorectal cancer surgery is important for detecting synchronous or metachronous colorectal neoplasms, we designed this study to investigate, by using postoperative colonoscopy, the miss rate for and the location of polyps remaining after colorectal cancer surgery. METHODS: In a prospectively-collected patient database, 264 patients were shown to have undergone a colorectal cancer resection between May 2012 and June 2013. Of these, 116 who had received a complete colonoscopy preoperatively and postoperatively were included in this study. RESULTS: Of these 116 patients, 68 were males and 48 were females; their mean age was 63 years. The mean time after surgery at which postoperative colonoscopy was performed was 7.1 months (range, 3-15 months). On postoperative colonoscopy, a total of 125 polyps were detected. Of these, there were no cancerous lesions; 46 (36.8%) were neoplastic polyps, and 79 (63.2%) were nonneoplastic polyps. Fifty-nine polyps (47.2%) and 15 polyps (12%) were located in the proximal and the distal parts of the anastomosis, respectively. The miss rates for the total numbers of polyps and of neoplastic polyps remaining after surgery were 37.4% and 24.2%, respectively. The incidence of neoplastic polyps increased during postoperative colonoscopy as it had during preoperative colonoscopy (r = 0.164, P = 0.048). CONCLUSION: Colonoscopic surveillance after colorectal cancer resection results in the detection of pathologic polyps in one fourth of the cases. During postoperative colonoscopy, careful examination of the proximal colon is necessary. Patients in whom multiple neoplastic polyps had been detected during preoperative colonoscopy require careful and thorough follow-up. PMID- 26576397 TI - Risk Factors of a Pulmonary Thromboembolism After Colorectal Surgery. AB - PURPOSE: Previous studies have revealed that predictors and risk factors of pulmonary thromboembolism (PTE) are malignancy, immobilization, diabetes, and obesity in the postoperative patients. However, in patients undergoing colorectal cancer, studies of PTE have not been enough. Thus, we investigated the risk factors of PTE related to colorectal surgery. METHODS: From January 2009 to October 2014, 312 patients received colorectal surgery without other organ resection. The postoperative patients with PTE were 14 (4.5%), and they were classified by sex, age, and stage as a 1:3 paired match to the control group. A multiple logistic regression was performed to identify which factors were associated with PTE. RESULTS: One patient was in stage I, 3 in stage II, 9 in stage III, and 1 in stage IV. In the binary logistic regression analysis, history of diabetes mellitus (odds ratio, 6.498; P = 0.031) and being overweight (odds ratio, 10.018; P = 0.014) were independent risk factors for PTE in patients undergoing colorectal cancer. CONCLUSION: A history of diabetes mellitus and being overweight were independent risk factors of PTE after colorectal cancer. PMID- 26576398 TI - Predictive Factors to Distinguish Between Patients With Noncomplicated Appendicitis and Those With Complicated Appendicitis. AB - PURPOSE: Recently, randomized controlled trials have reported that conservative therapy can be a treatment option in patients with noncomplicated appendicitis. However, preoperative diagnosis of noncomplicated appendicitis is difficult. In this study, we determined predictive factors to distinguish patients with noncomplicated appendicitis from those with complicated appendicitis. METHODS: A total of 351 patients who underwent surgical treatment for acute appendicitis from January 2011 to December 2012 were included in this study. We classified patients into noncomplicated or complicated appendicitis groups based on the findings of abdominal computed tomography and pathology. We performed a retrospective analysis to find factors that could be used to discriminate between noncomplicated and complicated appendicitis. RESULTS: The mean age of the patients in the complicated appendicitis group (54.5 years) was higher than that of the patients in the noncomplicated appendicitis group (40.2 years) (P < 0.001), but the male-to-female ratios were similar. In the univariate analysis, the appendicocecal junction's diameter, appendiceal maximal diameter, appendiceal wall enhancement, periappendiceal fat infiltration, ascites, abscesses, neutrophil proportion, C-reactive protein (CRP), aspartate aminotransferase, and total bilirubin were statistically significant factors. However, in the multivariate analysis, the appendiceal maximal diameter (P = 0.018; odds ratio [OR], 1.129), periappendiceal fat infiltration (P = 0.025; OR, 5.778), ascites (P = 0.038; OR, 2.902), and CRP (P < 0.001; OR, 1.368) were statistically significant. CONCLUSION: Several factors can be used to distinguish between noncomplicated and complicated appendicitis. Using these factors, we could more accurately distinguish patients with noncomplicated appendicitis from those with complicated appendicitis. PMID- 26576399 TI - Colonic Metastasis Presenting as an Intraluminal Fungating Mass 8 Years After Surgery for Ovarian Cancer. AB - We report a case of colonic metastasis from ovarian cancer presented as an intraluminal fungating mass mimicking primary colon cancer 8 years after surgery for ovarian cancer. A 70-year-old woman presented with constipation. She had undergone an extended total abdominal hysterectomy with bilateral salpingo oophorectomy for an ovarian papillary serous cystadenocarcinoma 8 years earlier. Colonoscopy showed a large fungating mass 10 cm from the anal verge that was suspected to be colorectal cancer. A computed tomography scan showed a bulky intraluminal fungating mass in the rectosigmoid junction. After a lower anterior resection and a pathologic diagnosis, a diagnosis of a papillary serous adenocarcinoma due to metastasis from an ovarian tumor was made for this patient. PMID- 26576400 TI - Metastatic Spermatic Cord Tumor From Colorectal Cancer. AB - Metastatic tumors of the spermatic cord are extremely rare, and the prognosis for patients is typically poor. In the majority of cases, the primary tumor occurs in the gastrointestinal tract. We report a case of a 62-year-old man with a metastatic spermatic cord tumor. The patient complained of groin discomfort with a tender mass in the right inguinal area. An excisional biopsy was performed, and the pathologic finding was a metastatic mucinous adenocarcinoma. We performed a systemic evaluation including colonoscopy, abdominal computed tomography, and total-body positron emission tomography, and the primary tumor was confirmed to involve the total colon, including the cecum, sigmoid colon, and rectum. The pathologic finding for rectum revealed a mucinous adenocarcinoma compatible with a metastatic spermatic cord tumor. PMID- 26576401 TI - Erratum: Biofeedback Therapy Before Ileostomy Closure in Patients Undergoing Sphincter-Saving Surgery for Rectal Cancer: A Pilot Study. AB - [This corrects the article on p. 138 in vol. 31, PMID: 26361615.]. PMID- 26576402 TI - Intraoperative neuromonitoring of the external branch of the superior laryngeal nerve during robotic thyroid surgery: a preliminary prospective study. AB - PURPOSE: The aim of this study was to evaluate the feasibility of monitoring external branch of the superior laryngeal nerve (EBSLN) during robotic thyroid surgery. METHODS: A total of 10 patients undergoing bilateral axillo-breast approach (BABA) robotic thyroid surgery were enrolled. The nerve integrity monitor (NIM Response 2.0 System) was used for EBSLN monitoring. We performed voice assessments preoperatively and at 1 and 3 months postoperatively using Voice Handicap Index-10 (VHI-10), maximal phonation time (MPT), phonation efficient index (PEI), and laryngeal electromyography (EMG). RESULTS: A total of 19 EBSLNs were at risk and 14 EBSLNs (73.7%) were identified using neuromonitoring. VHI-10 showed a change of voice over time (0.1 vs. 3.6 vs. 1.3); however, this was not statistically significant. VHI-10 scores normalized at 3 months postoperatively compared to the preoperative scores. MPT (a) (16.0 vs. 15.6 vs. 15.4), and MPT (e) (20.1 vs. 15.4 vs. 18.5) showed no significant differences preoperatively compared to the values obtained 1 and 3 months postoperatively. There was a significant change of PEI over time (4.8 vs. 1.1 vs. 4.6) (P = 0.036); however, the values normalized at 3 months postoperatively. Laryngeal EMG results showed 4 cases (21.2%) of neuropathy of EBSLNs at 1 month postoperatively, and electrodiagnostic studies revealed nearly complete recovery of the function of EBSLNs in 4 patients at 3 months postoperatively. CONCLUSION: It is suggested that neuromonitoring of EBSLNs during BABA robotic thyroid surgery is feasible and might be helpful to preserve voice quality. PMID- 26576403 TI - Choledochoduodenal fistula in Mainland China: a review of epidemiology, etiology, diagnosis and management. AB - PURPOSE: Choledochoduodenal fistula (CDF) is an extremely rare condition even in the most populous nations. However, diagnostic tools are inadequate for the young surgeon to be made aware of such a rare condition before surgery. Hence, basic understanding of the epidemiology, etiology, and management for this unusual but discoverable condition are necessary and essential. METHODS: The exclusive case reports of CDF, which were published from 1983 to 2014 concerning mainland Chinese people, were performed to review the epidemiology, etiology, and management. RESULTS: A total of 728 cases were incorporated into this review among 48 papers. More than half of the CDF cases were female (416) with an average age of 57.3 years. CDF was usually caused by cholelithiasis (573 of 728). Epigastric pain (589 of 728) and cholangitis (395 of 728) were the most common symptoms of CDF. CDF was usually detected and confirmed by endoscopic retrograde cholangiopancreatography (ERCP) (475 of 728) in Mainland China. The fistulas larger than 1 cm (82 of 654) were recommended for surgical biliary reconstruction. Fistulas between 0.5 cm and 1.0 cm (467 of 654) which were followed frequently by cholangitis attacks also required surgery; the rest were recommended to have stone removal and/or the application of an effective biliary drainage. Fistulas less than 0.5 cm (105 of 654) were usually received conservative therapy. CONCLUSION: CDF should be considered in differential diagnosis of recurrent epigastric pain and cholangitis. A possible ERCP should be arranged to investigate carefully. Depending on the size of fistula and clinical presentation, different programs for CDF are indicated, ranging from drug therapy to choledochojejunostomy. PMID- 26576404 TI - Risk factors for prolonged operative time in single-incision laparoscopic cholecystectomy. AB - PURPOSE: We performed 3-channel single incision laparoscopic cholecystectomy (SILC) in earlier period of this study and modified our method to 4-channel SILC using a snake retractor for better operative field in later period. This study has been designed to evaluate the risk factors for prolonged operative time in SILC. METHODS: From April 2010 to August 2014, 323 cases of 3-channel SILC (Konyang standard method [KSM] group) and 399 cases of 4-channel SILC (modified KSM [mKSM] group) using a snake retractor were performed. RESULTS: The clinical characteristics were not significantly different between KSM and mKSM group except preoperative percutaneous transhepatic gallbladder drainage (PTGBD) treatment (9.6% vs. 16.5%, P < 0.007). The mean operation time was longer in mKSM group than KSM group (55.8 +/- 19.7 minutes vs. 51.7 +/- 20.1 minutes, P = 0.006). The estimated blood loss of KSM group was more than mKSM group (24.6 +/- 54.1 mL vs. 16.9 +/- 27.0 mL, P = 0.013). According to the histopathologic findings, acute cholecystitis or empyema were confirmed more in mKSM group as compared with KSM group (28% vs. 14.0%, P = 0.025). In multivariate analysis, the risk factors for prolonged operation time were drainage insertion, histopathologic findings (acute cholecystitis or empyema), surgeons' technical expertise, body mass index > 30 kg/m(2) as well as the 4-channel SILC. CONCLUSION: Among patients with these risk factors, conventional laparoscopic cholecystectomy could be considered as well although SILC might be safe and feasible modality for benign gallbladder disease. PMID- 26576405 TI - Effect of extramucin pools in gastric cancer patients. AB - PURPOSE: Mucinous gastric adenocarcinoma (MGC) is defined by the World Health Organization as a gastric adenocarcinoma with >50% extracellular mucin pools within the tumors. In this study, we attempted to analyze the clinicopathologic features of patients pathologically diagnosed as gastric cancer with lower than 50% tumor volume of extracellular mucin pool adenocarcinoma (LEMPC). We compared MGC versus nonmucinous gastric adenocarcinoma (NMGC). We were used in abbreviations LEMPC for NMGC including extracellular mucin pool. METHODS: Files of 995 patients with gastric cancer NMGC (n = 935), MGC (n = 20), LEMPC (n = 40) who underwent curative resection at Pusan National University Yangsan Hospital from December 2008 to December 2013 were retrospectively analyzed. All pathologic reports after curative resection and evaluated clinicopathologic features were reviewed to identify the effect of extracellular mucin pools in gastric cancer. RESULTS: Compared with the NMGC patients, the clinicopathological features of MGC patients were as follows: more frequent open surgery, larger tumor size, more advanced T stage and N stage, more positive lymph node metastasis, and perineural invasion. LEMPC patients showed similar features compared with NMGC patients. MGC and LEMPC patients showed similar clinicopathological features, except T stage and lymph node metastasis. CONCLUSION: LEMPC can be thought of as a previous step of MGC. It is reasonable to consider LEMPC patients in the diagnostic criteria of MGC, and to adequately treat. PMID- 26576406 TI - Clinical outcomes of staged bilateral carotid endarterectomy for bilateral carotid artery stenosis. AB - PURPOSE: This retrospective cohort study aimed to determine the clinical outcomes of staged bilateral carotid endarterectomy (CEA) for bilateral internal carotid artery (ICA) stenosis performed with a short interval between the primary and secondary CEA procedures. METHODS: In our institution, 574 consecutive patients underwent CEA between September 2007 and August 2014. Bilateral significant ICA stenosis was identified in 43 patients (7.5%) who underwent staged bilateral CEA within 30 days or less. Patients with unilateral CEA and staged bilateral CEA were compared in terms of CEA outcomes. The primary endpoint was the composite of any stroke, myocardial infarction, or death during the periprocedural period or ipsilateral stroke within 3 years after the CEA. RESULTS: Staged bilateral CEA was not associated with ipsilateral stroke (P = 0.178) during postoperative follow-up. The two groups did not differ in terms of estimated 3-year primary endpoint rates (2.8% vs. 4.7%, P = 0.456) or ipsilateral stroke-free (P = 0.225), any stroke-free (P = 0.326), or overall (P = 0.739) survival rates. CONCLUSION: Patients with bilateral significant ICA stenosis can undergo staged bilateral CEA within 30 days or less with outcomes that compare favorably with those of patients undergoing unilateral CEA. PMID- 26576407 TI - Occupational stress and related factors among surgical residents in Korea. AB - PURPOSE: The application rate for surgical residents in Korea has continuously decreased over the past few years. The demanding workload and the occupational stress of surgical training are likely causes of this problem. The aim of this study was to investigate occupational stress and its related factors in Korean surgical residents. METHODS: With the support of the Korean Surgical Society, we conducted an electronic survey of Korean surgical residents related to occupational stress. We used the Korean Occupational Stress Scale (KOSS) to measure occupational stress. We analyzed the data focused on the stress level and the factors associated with occupational stress. RESULTS: The mean KOSS score of the surgical residents was 55.39, which was significantly higher than that of practicing surgeons (48.16, P < 0.001) and the average score of specialized professionals (46.03, P < 0.001). Exercise was the only factor found to be significantly associated with KOSS score (P = 0.001) in univariate analysis. However, in multiple linear regression analysis, the mean number of assigned patients, resident occupation rate and exercise were all significantly associated with KOSS score. CONCLUSION: Surgical residents have high occupational stress compared to practicing surgeons and other professionals. Their mean number of assigned patients, resident recruitment rate and exercise were all significantly associated with occupational stress for surgical residents. PMID- 26576408 TI - Left paraduodenal hernia accompanying chylous ascites. AB - Paraduodenal hernia is by far the most common form of congenital internal hernia. Chylous ascites is an accumulation of lymphatic fluid in the peritoneal cavity. It develops when the lymphatic system is disrupted due to traumatic injury or obstruction. A 40-year-old, woman showed up to the Emergency Department with severe, colicky abdominal pain. Tenderness and rebound tenderness were observed at the left abdomen. Abdominal CT confirmed a cluster of dilated proximal small bowel loops with ischemic change, without ascites. The patient underwent an emergency surgery to relieve bowel ischemia. As soon as the peritoneum was exposed, 1.5 L of chylous fluid was found. A hernial sac was found along the posterior side of the mesentery of the inferior mesenteric artery. We resected the hernial sac and pulled out the herniated small bowel. On the sixth day after the surgery, she was discharged without any complication. PMID- 26576409 TI - Transumbilical pure single-port laparoscopic donor nephrectomy. AB - Transumbilical single-port laparoscopic donor nephrectomy (SPLDN) is a novel, rapidly evolving, minimally invasive treatment modality for kidney transplantation. This method causes minimal parietal injury, has cosmetic advantages, and allows rapid recovery because of low postoperative pain and short hospital stay. Like other abdominal surgeries, when conducted by experienced laparoscopic surgeons, it can meet the same graft requirements as conventional laparoscopic surgery. Here, we report the first two cases of transumbilical SPLDN at Daejeon St. Mary's Hospital, The Catholic University of Korea. We used the umbilicus as a common path for laparoscopic procedures and as a route for specimen retrieval. The operating times were 230 and 265 minutes in cases 1 and 2, respectively. No intra- or postoperative complications were noted. In case 1, the wound length was 4 cm and duration of hospitalization was 2 days. In case 2, the wound length was only 2.5 cm, and the duration of hospitalization was only 1 day. PMID- 26576410 TI - A new glove port for single incision procedure. AB - Single-incision laparoscopic surgery has gained increasing attention due to its potential to improve the benefits of laparoscopic surgery. However, inconvenience remains for inexperienced surgeons during surgery when instruments conflict with each other, and a glove port is used hesitantly for such diagnosis related groups (DRG) because of its high cost. Authors made a new glove port by an odd surgical gloves and one wound protectors. This glove port is ease to make besides being convenient to us, and inexpensive. This new glove port has the benefit of easy utilization and cost effectiveness for surgeons performing single-incision laparoscopic surgery. PMID- 26576411 TI - Do Three Different Passive Assessments of Quadriceps Spasticity Relate to the Functional Activity of Walking for Children Diagnosed with Cerebral Palsy? AB - A stiff-knee gait pattern is frequently associated with several impairments including quadriceps spasticity in children diagnosed with cerebral palsy (CP). The relationship of clinical measures of quadriceps spasticity and the stiff-knee gait pattern in children diagnosed with CP has not been well established. Therefore, the purpose of this study was to determine the ability of clinical measures of quadriceps spasticity (modified Ashworth scale [MAS], Ely tests, and pendulum test) to categorize a stiff-knee gait pattern in children with CP. Children were categorized as having a stiff-knee gait pattern based on kinematic and EMG gait data. Results of a logistic regression model revealed that the only significant measure was A1 of the pendulum test. Discriminant analysis functions were used to predict group membership (stiff-knee, not stiff-knee gait pattern) for each measure. The A1 of the pendulum test demonstrated the highest classification accuracy and the highest sensitivity compared to the other measures. Therefore, a negative pendulum test (indicated by an A1 value of 45 degrees or more) is more useful for ruling out a stiff-knee gait pattern compared to the other clinical measures. PMID- 26576412 TI - Acceptance and Avoidance Processes at Different Levels of Psychological Recovery from Enduring Mental Illness. AB - Objective. This study examined the use of psychological acceptance and experiential avoidance, two key concepts of Acceptance and Commitment Therapy (ACT), in the psychological recovery process of people with enduring mental illness. Method. Sixty-seven participants were recruited from the metropolitan, regional, and rural areas of New South Wales, Australia. They all presented some form of chronic mental illness (at least 12 months) as reflected in DSM-IV Axis I diagnostic criteria. The Acceptance and Action Questionnaire (AAQ-19) was used to measure the presence of psychological acceptance and experiential avoidance; the Recovery Assessment Scale (RAS) was used to examine the levels of psychological recovery; and the Scales of Psychological Well-Being was used to observe if there are benefits in utilizing psychological acceptance and experiential avoidance in the recovery process. Results. An analysis of objectively quantifiable measures found no clear correlation between the use of psychological acceptance and recovery in mental illness as measured by the RAS. The data, however, showed a relationship between psychological acceptance and some components of recovery, thereby demonstrating its possible value in the recovery process. Conclusion. The major contribution of this research was the emerging correlation that was observed between psychological acceptance and positive levels of psychological well-being among individuals with mental illness. PMID- 26576413 TI - Novel Computational Technologies for Next-Generation Sequencing Data Analysis and Their Applications. PMID- 26576415 TI - Phylogeny and Ontogeny of Erythropoiesis. PMID- 26576416 TI - Corrigendum to "Sensitization of Cancer Cells through Reduction of Total Akt and Downregulation of Salinomycin-Induced pAkt, pGSk3 beta , pTSC2, and p4EBP1 by Cotreatment with MK-2206". PMID- 26576414 TI - Proteomic Study to Survey the CIGB-552 Antitumor Effect. AB - CIGB-552 is a cell-penetrating peptide that exerts in vitro and in vivo antitumor effect on cancer cells. In the present work, the mechanism involved in such anticancer activity was studied using chemical proteomics and expression-based proteomics in culture cancer cell lines. CIGB-552 interacts with at least 55 proteins, as determined by chemical proteomics. A temporal differential proteomics based on iTRAQ quantification method was performed to identify CIGB 552 modulated proteins. The proteomic profile includes 72 differentially expressed proteins in response to CIGB-552 treatment. Proteins related to cell proliferation and apoptosis were identified by both approaches. In line with previous findings, proteomic data revealed that CIGB-552 triggers the inhibition of NF-kappaB signaling pathway. Furthermore, proteins related to cell invasion were differentially modulated by CIGB-552 treatment suggesting new potentialities of CIGB-552 as anticancer agent. Overall, the current study contributes to a better understanding of the antitumor action mechanism of CIGB-552. PMID- 26576417 TI - Phoniatrics. PMID- 26576418 TI - Antiphospholipase A2 Receptor Autoantibodies: A Step Forward in the Management of Primary Membranous Nephropathy. AB - Since the identification of PLA2R (M-type phospholipase A2 receptor) as the first human antigenic target in primary membranous nephropathy (MN), perpetual progress has been made in understanding the pathogenesis of this disease. Accumulating clinical data support a pathogenic role for the anti-PLA2R antibodies (PLA2R ABs), but confirmation in an animal model is still lacking. However, PLA2R ABs were related to disease activity and outcome, as well as to response therapy. Accordingly, PLA2R ABs assay seems to be promising tool not only to diagnose MN but also to predict the course of the disease and could open the way to personalize therapy. Nevertheless, validation of a universal assay with high precision and definition of cut-off levels, followed by larger studies with a prolonged follow-up period, are needed to confirm these prospects. PMID- 26576419 TI - Comparison of Conventional Methods and Laser-Assisted Rapid Prototyping for Manufacturing Fixed Dental Prostheses: An In Vitro Study. AB - This study assessed whether there are differences in marginal fit between laser fusion and conventional techniques to produce fixed dental prostheses (FDPs). A master steel die with 2 abutments was produced to receive a posterior 4-unit FDPs and single copings. These experimental models were divided into three groups (n = 20/group) manufactured: group 1, Ni-Cr alloy, with a lost-wax casting technique; group 2, Co-Cr alloy, with selective laser melting (SLM); and group 3, yttria tetragonal zirconia polycrystal (Y-TZP), with a milling system. All specimens were cut along the longitudinal axis and their adaptation was measured at the marginal and shoulder areas on the right and left sides of each abutment. Measurements were made using a stereomicroscope (*60 magnification) and a scanning electron microscope (*800 magnification). The data were analyzed using one-way analysis of variance and the Bonferroni post hoc test, with a significance cutoff of 5%. Significant differences (P < 0.05) were observed between group 3 and the other groups. The marginal opening was smallest with Co Cr alloy substructures, while the shoulder opening was smallest with Ni-Cr alloy substructures. Within the limitations of this study, the marginal fit of an FDP is better with rapid prototyping (RP) via SLM than conventional manufacturing systems. PMID- 26576420 TI - (18)F-FDG Uptake Characteristics in Differentiating Benign from Malignant Nasopharyngeal Lesions in Children. AB - The characteristics of FDG uptake in the physiologic and malignant nasopharynx were investigated in the paper which was correlated with either pathologic findings or clinical follow-up. Three patients had pathologically established nasopharyngeal malignancy. In the 3 nasopharyngeal malignancies, 2 had diffusely and expansively increased FDG uptake, and one had asymmetric uptake. Our results indicated that the difference between adenoid hypertrophy and malignancy is asymmetric or diffusely expansive (18)F-FDG uptake with or without correlating morphologic lesion on diagnostic CT in children under 10 years of age. The typical characteristics of physiologic and inflammatory (18)F-FDG uptake in nasopharynx are symmetrically trapezoid. Diffusely increased nasopharyngeal FDG uptake can be considered physiologic if SUVmax is less than 7.6 but should be carefully assessed by pharyngorhinoscopy if SUVmax is greater than 11 and there is no correlating morphologic lesion on diagnostic CT. The diffusely, expansively increased uptake, and asymmetric uptake in particular, should be considered as malignancy. Further biopsy is especially indicated in patients with retropharyngeal space and bilateral cervical lymph node abnormality but no history of malignancy. PMID- 26576421 TI - Puerarin Inhibits oxLDL-Induced Macrophage Activation and Foam Cell Formation in Human THP1 Macrophage. AB - Puerarin, an isoflavone derived from Kudzu roots, has been widely used for treatment of cardiovascular and cerebral vascular diseases in China and other Asian countries. However, the underlying mechanisms are largely unknown. The present study investigated whether puerarin inhibited atherogenic lipid oxLDL mediated macrophage activation and foam cell formation in human THP1 macrophage. Treatment with oxLDL significantly increased the mRNA expression of proinflammatory cytokines tumor necrosis factor alpha (TNFalpha, 160%) and interleukin (IL) 1beta (13 fold) accompanied by upregulation of toll-like receptor 4 (TLR4, 165%) and the ratio of phospho-IkappaBalpha/IkappaBalpha in THP1 macrophage. Puerarin dose-dependently prevented an increase in oxLDL-induced proinflammatory gene expression with downregulation of TLR4 and the ratio of phospho-IkappaBalpha/IkappaBalpha. Furthermore, puerarin prevented oxLDL-mediated lipid deposition and foam cell formation associated with downregulation of scavenger receptor CD36. Flow cytometry analysis showed that puerarin reduced the number of early apoptotic cells of macrophages induced by oxLDL. Our results show that puerarin has anti-inflammatory and antiatherogenic effects in vitro; the underlying mechanisms may involve the inhibition of TLR4/NFkappaB pathway and downregulation of CD36 expression. The results from the present study provide scientific evidence and may expand our armamentarium to use puerarin for prevention and treatment of cardiovascular and atherosclerotic diseases. PMID- 26576422 TI - Effects of Whole-Body Cryotherapy in Comparison with Other Physical Modalities Used with Kinesitherapy in Rheumatoid Arthritis. AB - Whole-body cryotherapy (WBC) has been frequently used to supplement the rehabilitation of patients with rheumatoid arthritis (RA). The aim of this study was to compare the effect of WBC and traditional rehabilitation (TR) on clinical parameters and systemic levels of IL-6, TNF-alpha in patients with RA. The study group comprised 25 patients who were subjected to WBC (-110 degrees C) and 19 patients who underwent a traditional rehabilitation program. Some clinical variables and levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF alpha) were used to assess the outcomes. After therapy both groups exhibited similar improvement in pain, disease activity, fatigue, time of walking, and the number of steps over a distance of 50 m. Only significantly better results were observed in HAQ in TR group (p < 0.05). However, similar significant reduction in IL-6 and TNF-alpha level was observed. The results showed positive effects of a 2 week rehabilitation program for patients with RA regardless of the kind of the applied physical procedure. PMID- 26576423 TI - Fracture Strength of Aged Monolithic and Bilayer Zirconia-Based Crowns. AB - The purpose of this study was to evaluate the effect of design and surface finishing on fracture strength of yttria-tetragonal zirconia polycrystal (Y-TZP) crowns in monolithic (1.5 mm thickness) and bilayer (0.8 mm zirconia coping and 0.7 mm porcelain veneer) configuration after artificial aging. Bovine incisors received crown preparation and Y-TZP crowns were manufactured using CAD/CAM technique, according to the following groups (n = 10): Polished monolithic zirconia crowns (PM); Glazed monolithic zirconia crowns (GM); Bi-layer crowns (BL). Crowns were cemented with resin cement, submitted to artificial aging in a chewing simulator (2.5 million cycles/80 N/artificial saliva/37 degrees C), and tested for fracture strength. Two remaining crowns referring to PM and GM groups were submitted to a chemical composition analysis to measure the level of yttrium after aging. One-way ANOVA and Tukey's test (P = .05) indicated that monolithic zirconia crowns presented similar fracture strength (PM = 3476.2 N +/- 791.7; GM = 3561.5 N +/- 991.6), which was higher than bilayer crowns (2060.4 N +/- 810.6). There was no difference in the yttrium content among the three surfaces evaluated in the monolithic crowns. Thus, monolithic zirconia crowns present higher fracture strength than bilayer veneered zirconia after artificial aging and surface finishing does not affect their fracture strength. PMID- 26576424 TI - Comparison of Propofol, Propofol-Remifentanil, and Propofol-Fentanyl Administrations with Each Other Used for the Sedation of Patients to Undergo ERCP. AB - INTRODUCTION: Using single anesthetic agent in endoscopic retrograde cholangiopancreatography (ERCP) may lead to inadequate analgesia and sedation. To achieve the adequate analgesia and sedation the single anesthetic agent doses must be increased which causes undesirable side effects. For avoiding high doses of single anesthetic agent nowadays combination with sedative agents is mostly a choice for analgesia and sedation for ERCP. AIM: The aim of this study is to investigate the effects of propofol alone, propofol + remifentanil, and propofol + fentanyl combinations on the total dose of propofol to be administered during ERCP and on the pain scores after the process. MATERIALS AND METHOD: This randomized study was performed with 90 patients (ASA I-II-III) ranging between 18 and 70 years of age who underwent sedation/analgesia for elective ERCP. The patients were administered only propofol (1.5 mg/kg) in Group Iota, remifentanil (0.05 MUg/kg) + propofol (1.5 mg/kg) combination in Group II, and fentanyl (1 MUg/kg) + propofol (1.5 mg/kg) combination in Group III. All the patients' sedation levels were assessed with the Ramsey Sedation Scale (RSS). Their recovery was assessed with the Aldrete and Numerical Rating Scale Score (NRS) at 10 min intervals. RESULTS: The total doses of propofol administered to the patients in the three groups in this study were as follows: 375 mg in Group I, 150 mg in Group II, and 245 mg in Group III. CONCLUSION: It was observed that, in the patients undergoing ERCP, administration of propofol in combination with an opioid provided effective and reliable sedation, reduced the total dose of propofol, increased the practitioner satisfaction, decreased the pain level, and provided hemodynamic stability compared to the administration of propofol alone. PMID- 26576425 TI - Systematic Review of the Use of Phytochemicals for Management of Pain in Cancer Therapy. AB - Pain in cancer therapy is a common condition and there is a need for new options in therapeutic management. While phytochemicals have been proposed as one pain management solution, knowledge of their utility is limited. The objective of this study was to perform a systematic review of the biomedical literature for the use of phytochemicals for management of cancer therapy pain in human subjects. Of an initial database search of 1,603 abstracts, 32 full-text articles were eligible for further assessment. Only 7 of these articles met all inclusion criteria for this systematic review. The average relative risk of phytochemical versus control was 1.03 [95% CI 0.59 to 2.06]. In other words (although not statistically significant), patients treated with phytochemicals were slightly more likely than patients treated with control to obtain successful management of pain in cancer therapy. We identified a lack of quality research literature on this subject and thus were unable to demonstrate a clear therapeutic benefit for either general or specific use of phytochemicals in the management of cancer pain. This lack of data is especially apparent for psychotropic phytochemicals, such as the Cannabis plant (marijuana). Additional implications of our findings are also explored. PMID- 26576426 TI - Value of Contrast-Enhanced Ultrasound in Guidance of Percutaneous Biopsy in Peripheral Pulmonary Lesions. AB - OBJECTIVES: To investigate the value of contrast-enhanced ultrasound (CEUS) in guidance of percutaneous biopsy in peripheral pulmonary lesions. METHODS: This study focused on 53 patients (male: 38, female: 15, and mean age: 55.7 years +/- 10.7) with 53 single peripheral pulmonary lesions. Before core needle (16-gauge) percutaneous biopsy, CEUS were performed in all lesions, with injection of 2.4 mL SonoVue (Bracco, Italy). The contrast-enhancement pattern, display rate of internal necrosis (nonenhanced) and active (obviously enhanced) areas, biopsy success rate, and pathological diagnosis rate were recorded. RESULTS: All the peripheral pulmonary lesions were proved pathologically as benign lesions (n = 7), primary malignancies (n = 41), or metastasis (n = 5). Forty (86.9%) malignant lesions and 4 (57.1%) benign lesions showed internal necrosis areas on CEUS. The detection rate and average size of internal necrosis areas had been significantly improved compared to conventional ultrasound (P < 0.05). After CEUS, core needle percutaneous biopsies were performed successfully in the active areas of all lesions. The sampling success rate and pathological diagnosis rate were 100% and 98.1%. CONCLUSIONS: CEUS before biopsy provided useful diagnostic information about peripheral pulmonary lesions. By depicting internal necrotic and active areas, it is a promising technique for guaranteeing the accuracy, success, and safety of core needle biopsy. PMID- 26576427 TI - Phosphorylation, Signaling, and Cancer: Targets and Targeting. PMID- 26576428 TI - Radiographic Determination of Hip Rotation Center and Femoral Offset in Japanese Adults: A Preliminary Investigation toward the Preoperative Implications in Total Hip Arthroplasty. AB - The values of hip rotation center (HRC) and femoral offset (FO) evaluated according to Caucasian anatomical landmarks have been regarded as a useful reference also for Japanese patients in total hip arthroplasty (THA). In a strict sense, however, since there can be racial differences among their anatomical morphologies, it is clinically important to reconsider those parameters for the Japanese. In the present study, in order to investigate correlations among hip and pelvic morphometric parameters, frontal radiographs were taken from 98 Japanese adults (60 males and 38 females) without acetabular dysplasia and arthropathy in the standing position. Their mean age was 62.0 +/- 16.7 years. The horizontal position of HRC was significantly correlated with the pelvic width in both genders (P = 0.0026 and 0.0010 for the males and the females, resp.). The vertical position of HRC was significantly correlated with the teardrop sacroiliac distance in the males (P = 0.0003) and with the pelvic cavity height in the females (P = 0.0067). However, in both genders, there were no correlations among FO and the other parameters analyzed in this study. Our present findings might contribute to theoretical implications of an appropriate HRC position for Japanese OA patients in THA. PMID- 26576429 TI - Defining the Role of Dexmedetomidine in the Prevention of Delirium in the Intensive Care Unit. AB - Dexmedetomidine is a highly selective alpha 2 agonist used as a sedative agent. It also provides anxiolysis and sympatholysis without significant respiratory compromise or delirium. We conducted a systematic review to examine whether sedation of patients in the intensive care unit (ICU) with dexmedetomidine was associated with a lower incidence of delirium as compared to other nondexmedetomidine sedation strategies. A search of PUBMED, EMBASE, and the Cochrane Database of Systematic Reviews yielded only three trials from 1966 through April 2015 that met our predefined inclusion criteria and assessed dexmedetomidine and outcomes of delirium as their primary endpoint. The studies varied in regard to population, comparator sedation regimen, delirium outcome measure, and dexmedetomidine dosing. All trials are limited by design issues that limit our ability definitively to conclude that dexmedetomidine prevents delirium. Evidence does suggest that dexmedetomidine may allow for avoidance of deep sedation and use of benzodiazepines, factors both observed to increase the risk for developing delirium. Our assessment of currently published literature highlights the need for ongoing research to better delineate the role of dexmedetomidine for delirium prevention. PMID- 26576430 TI - Photocatalytical Antibacterial Activity of Mixed-Phase TiO2 Nanocomposite Thin Films against Aggregatibacter actinomycetemcomitans. AB - Mixed-phase TiO2 nanocomposite thin films consisting of anatase and rutile prepared on commercially pure Ti sheets via the electrochemical anodization and annealing treatments were investigated in terms of their photocatalytic activity for antibacterial use around dental implants. The resulting films were characterized by scanning electron microscopy (SEM), and X-ray diffraction (XRD). The topology was assessed by White Light Optical Profiling (WLOP) in the Vertical Scanning Interferometer (VSI) mode. Representative height descriptive parameters of roughness R a and R z were calculated. The photocatalytic activity of the resulting TiO2 films was evaluated by the photodegradation of Rhodamine B (RhB) dye solution. The antibacterial ability of the photocatalyst was examined by Aggregatibacter actinomycetemcomitans suspensions in a colony-forming assay. XRD showed that anatase/rutile mixed-phase TiO2 thin films were predominantly in anatase and rutile that were 54.6 wt% and 41.9 wt%, respectively. Craters (2-5 um) and protruding hills (10-50 um) on Ti substrates were produced after electrochemical anodization with higher R a and R z surface roughness values. Anatase/rutile mixed-phase TiO2 thin films showed 26% photocatalytic decolorization toward RhB dye solution. The number of colonizing bacteria on anatase/rutile mixed-phase TiO2 thin films was decreased significantly in vitro. The photocatalyst was effective against A. actinomycetemcomitans colonization. PMID- 26576431 TI - Medications and Nutritional Supplements in Athletes during the 2000, 2004, 2008, and 2012 FIFA Futsal World Cups. AB - OBJECTIVE: To examine the use of medications and nutritional supplements among top-level male futsal players during international tournaments. MATERIALS AND METHODS: This retrospective survey of the four consecutive 2000 to 2012 FIFA (Federation Internationale de Football Association) Futsal World Cup tournaments analyzes data about the use of medications and nutritional supplements by each player prior to every match. A total of 5264 reports on 1064 futsal players were collected from the 188 matches played. RESULTS: A total of 4237 medications and 8494 nutritional supplements (0.8 and 1.6 per player per match, resp.) were prescribed, and 64% of the players used at least one type of medication over the four tournaments. The most frequently prescribed medication was nonsteroidal anti inflammatory drugs (NSAIDs) (41.1%), whereby 45.7% of all players consumed at least one NSAID during the tournament and 27.4% did so prior to every match. CONCLUSIONS: The intake of medications, particularly of NSAIDs, is frequently high among top-level futsal players and follows a similar pattern to that found in FIFA Football World Cups. Campaigns should be instituted to understand this prescription practice by team physicians involving professional football players, with the aim to decrease its use and to prevent athletes from potential short- and long-term risks. PMID- 26576432 TI - Identification of Gene Expression Pattern Related to Breast Cancer Survival Using Integrated TCGA Datasets and Genomic Tools. AB - Several large-scale human cancer genomics projects such as TCGA offered huge genomic and clinical data for researchers to obtain meaningful genomics alterations which intervene in the development and metastasis of the tumor. A web based TCGA data analysis platform called TCGA4U was developed in this study. TCGA4U provides a visualization solution for this study to illustrate the relationship of these genomics alternations with clinical data. A whole genome screening of the survival related gene expression patterns in breast cancer was studied. The gene list that impacts the breast cancer patient survival was divided into two patterns. Gene list of each of these patterns was separately analyzed on DAVID. The result showed that mitochondrial ribosomes play a more crucial role in the cancer development. We also reported that breast cancer patients with low HSPA2 expression level had shorter overall survival time. This is widely different to findings of HSPA2 expression pattern in other cancer types. TCGA4U provided a new perspective for the TCGA datasets. We believe it can inspire more biomedical researchers to study and explain the genomic alterations in cancer development and discover more targeted therapies to help more cancer patients. PMID- 26576433 TI - Evaluation of the Association Metformin: Plantago ovata Husk in Diabetic Rabbits. AB - In this experimental study we have investigated whether the inclusion of the dietary fiber Plantago ovata husk could be recommended as coadjuvant in treatments with oral hypoglycemic drugs. We evaluated the use of Plantago ovata husk-metformin association in diabetic rabbits by determining its effects on glucose and insulin concentrations. Six groups of 6 rabbits were used. Groups 1 to 3 were fed with standard chow and groups 4 to 6 with chow supplemented with Plantago ovata husk (3.5 mg/kg/day). Two groups (numbers 1 and 4) were used as controls (receiving standard or supplemented chow), two groups (numbers 2 and 5) received metformin orally, and the other two (numbers 3 and 6) were treated orally with metformin and psyllium. Plasma glucose concentrations were lower in groups fed with fiber-supplemented chow whereas insulin levels showed important interindividual variations. Glucose pharmacokinetics parameters showed significant differences in Cmax and t(max) in relation to fiber intake. Insulin pharmacokinetics parameters after treatment with oral metformin showed an important increase in Cmax, AUC, and t(max) in animals fed with fiber. We conclude that Plantago ovata husk intake can contribute to the oral antihyperglycemic treatment of type 2 diabetes. PMID- 26576434 TI - Serum Cystatin C, Markers of Chronic Kidney Disease, and Retinopathy in Persons with Diabetes. AB - PURPOSE: We examined the association of CKD defined by serum creatinine, serum cystatin C, and albuminuria with moderate diabetic retinopathy (DR). METHODS: We examined 1,119 Indian adults with diabetes, aged 40-80 years, who participated in the Singapore Indian Eye Study (2007-2009), a population-based cross-sectional study. The associations of CKD defined by each of the three markers alone and in combination with moderate DR were examined using logistic regression models adjusted for potential confounding factors including duration of diabetes, smoking, body mass index, systolic blood pressure, and HbA1c. RESULTS: The prevalence of moderate DR was significantly higher among those with CKD defined by triple markers (41.1%) compared to CKD defined separately by creatinine (26.6%), cystatin C (20.9%), and albuminuria (23.4%). People with CKD defined by triple markers had a fourteenfold higher odds of moderate DR (OR (95% CI) = 13.63 (6.08-30.54)) compared to those without CKD by any marker. Nearly half (48.7%) of participants with cystatin C >= 1.12 mg/L have moderate DR. CONCLUSIONS: CKD defined by a triple marker panel was strongly associated with moderate DR in this Asian population with diabetes. PMID- 26576435 TI - The Protective Effect of Transcription Factor 7-Like 2 Risk Allele rs7903146 against Elevated Fasting Plasma Triglyceride in Type 2 Diabetes: A Meta-Analysis. AB - BACKGROUND: The results from published studies regarding association of transcription factor 7-like 2 (TCF7L2) variant rs7903146 with dyslipidemia have been conflicting and inconclusive. METHODS: We carried out a meta-analysis that aimed to investigate the association of the rs7903146 variant with plasma lipid levels using electronic database and published studies. Data was extracted by a standard algorithm. Dominant, recessive, homozygote, and heterozygote comparison models were utilized. RESULTS: 24 studies incorporating 52,785 subjects were included in this meta-analysis. Overall, the minor allele (T) was associated with lower risk for hypertriglyceridemia in subjects with type 2 diabetes (dominant model: SMD = -0.04, 95% CI (-0.08, 0.00), P = 0.048, P heterogeneity = 0.47; recessive model: SMD = -0.10, 95% CI (-0.18, -0.02), P = 0.01, P heterogeneity = 0.56). No association was found between minor (T) allele and plasma TC, LDL-c, or HDL-c levels in subjects with type 2 diabetes or metabolic syndrome (MetS) and no association was found between minor (T) allele and plasma TG levels in nondiabetic subjects. CONCLUSIONS: Our meta-analysis indicated the association between TCF7L2 rs7903146 polymorphism and low plasma triglyceride (TG) level in subjects with type 2 diabetes. No association was found between rs7903146 variant and plasma lipids in nondiabetic subjects. PMID- 26576436 TI - Mechanistic Contributions of Biological Cofactors in Islet Amyloid Polypeptide Amyloidogenesis. AB - Type II diabetes mellitus is associated with the deposition of fibrillar aggregates in pancreatic islets. The major protein component of islet amyloids is the glucomodulatory hormone islet amyloid polypeptide (IAPP). Islet amyloid fibrils are virtually always associated with several biomolecules, including apolipoprotein E, metals, glycosaminoglycans, and various lipids. IAPP amyloidogenesis has been originally perceived as a self-assembly homogeneous process in which the inherent aggregation propensity of the peptide and its local concentration constitute the major driving forces to fibrillization. However, over the last two decades, numerous studies have shown a prominent role of amyloid cofactors in IAPP fibrillogenesis associated with the etiology of type II diabetes. It is increasingly evident that the biochemical microenvironment in which IAPP amyloid formation occurs and the interactions of the polypeptide with various biomolecules not only modulate the rate and extent of aggregation, but could also remodel the amyloidogenesis process as well as the structure, toxicity, and stability of the resulting fibrils. PMID- 26576438 TI - Charge-Based Inhibitors of Amylin Fibrillization and Toxicity. AB - To test the hypothesis that electrostatic repulsion is an important force opposing amyloid fibril assembly, we designed peptides that substitute strings of positively or negatively charged residues into the sequence of the amyloidogenic hormone amylin, which contributes to type 2 diabetes pathology. Arg-1 and Arg-2 substitute four positively charged arginines for segments that in structural models of amylin fibrils form the end of strand beta1 and the beginning of strand beta2, respectively. Mem-T substitutes negatively charged aspartates for the peptide segment with the largest avidity for membranes. All three charge-loaded peptides fibrillize poorly on their own and inhibit fibril elongation of WT amylin at physiological ionic strength. The inhibition of WT-amylin fibril elongation rates is salt-dependent indicating that the analogs act through electrostatic interactions. Arg-1 protects against WT-amylin cytotoxicity towards a MIN6 mouse model of pancreatic beta-cells, and Arg-2 protects at higher concentrations, whereas Mem-T has no effect. The most effective variant, Arg-1, inhibits WT-amylin fibril elongation rates with an IC50 of ~1 uM and cytotoxicity with an IC50 of ~50 uM, comparable to other types of fibrillization inhibitors reported in the literature. Taken together, these results suggest that electrostatic interactions can be exploited to develop new types of inhibitors of amyloid fibrillization and toxicity. PMID- 26576439 TI - Understanding Experimental LCMV Infection of Mice: The Role of Mathematical Models. AB - Virus infections represent complex biological systems governed by multiple-level regulatory processes of virus replication and host immune responses. Understanding of the infection means an ability to predict the systems behaviour under various conditions. Such predictions can only rely upon quantitative mathematical models. The model formulations should be tightly linked to a fundamental step called "coordinatization" (Hermann Weyl), that is, the definition of observables, parameters, and structures that enable the link with a biological phenotype. In this review, we analyse the mathematical modelling approaches to LCMV infection in mice that resulted in quantification of some fundamental parameters of the CTL-mediated virus control including the rates of T cell turnover, infected target cell elimination, and precursor frequencies. We show how the modelling approaches can be implemented to address diverse aspects of immune system functioning under normal conditions and in response to LCMV and, importantly, make quantitative predictions of the outcomes of immune system perturbations. This may highlight the notion that data-driven applications of meaningful mathematical models in infection biology remain a challenge. PMID- 26576440 TI - Effects of an Osteoporosis Prevention Program Based on Health Belief Model Among Females. AB - BACKGROUND: Several studies reported the efficacy of osteoporosis prevention interventions in improvement of people's preventive behaviors. However, there are reports that the interventions were not successful in altering osteoporosis health beliefs and preventive behaviors. OBJECTIVES: The current study aimed to assess the effect of a program based on health beliefs model (HBM) on females' health beliefs and performances about osteoporosis preventive behaviors. PATIENTS AND METHODS: This quasi-experimental study was conducted on 120 patients registered in two healthcare centers of Fasa, Fars Province, Iran in 2014. A questionnaire including demographic information and HBM constructs was employed to measure the females' beliefs regarding nutrition and walking performance in prevention of osteoporosis bone mineral density (BMD) measured at the lumbar spine and femur before, immediately after the intervention, and six months after the intervention. Data were analyzed using Chi-square, independent samples t-, Mann-Whitney U tests and repeated measures ANOVA. RESULTS: Immediately and six months after the intervention, a significant increase was found in the intervention group's health beliefs, nutrition, and walking performances to prevent osteoporosis. Six months after the intervention, lumbar spine BMD T-score increased to 0.127 +/- 0.061 in the intervention group but reduced to -0.043 +/- 0.059 in the control group. Also, hip BMD T-score increased to 0.125 +/- 0.088 in the intervention group, but decreased to -0.028 +/- 0.052 in control group. CONCLUSIONS: The current study showed the effectiveness of HBM in adoption of nutrition and walking behaviors as well as the increase of bone density to prevent osteoporosis. PMID- 26576441 TI - Comparing the Effect of Concept Mapping and Conventional Methods on Nursing Students' Practical Skill Score. AB - BACKGROUND: Development of practical skills in the field of nursing education has remained a serious and considerable challenge in nursing education. Moreover, newly graduated nurses may have weak practical skills, which can be a threat to patients' safety. OBJECTIVES: The present study was conducted to compare the effect of concept mapping and conventional methods on nursing students' practical skills. PATIENTS AND METHODS: This quasi-experimental study was conducted on 70 nursing students randomly assigned into two groups of 35 people. The intervention group was taught through concept mapping method, while the control group was taught using conventional method. A two-part instrument was used including a demographic information form and a checklist for direct observation of procedural skills. Descriptive statistics, chi-square, independent samples t-tests and paired t-test were used to analyze data. RESULTS: Before education, no significant differences were observed between the two groups in the three skills of cleaning (P = 0.251), injection (P = 0.185) and sterilizing (P = 0.568). The students mean scores were significantly increased after the education and the difference between pre and post intervention of students mean scores were significant in the both groups (P < 0.001). However, after education, in all three skills the mean scores of the intervention group were significantly higher than the control group (P < 0.001). CONCLUSIONS: Concept mapping was superior to conventional skill teaching methods. It is suggested to use concept mapping in teaching practical courses such as fundamentals of nursing. PMID- 26576437 TI - Mesenchymal Stem Cells: Rising Concerns over Their Application in Treatment of Type One Diabetes Mellitus. AB - Type 1 diabetes mellitus (T1DM) is an autoimmune disorder that leads to beta cell destruction and lowered insulin production. In recent years, stem cell therapies have opened up new horizons to treatment of diabetes mellitus. Among all kinds of stem cells, mesenchymal stem cells (MSCs) have been shown to be an interesting therapeutic option based on their immunomodulatory properties and differentiation potentials confirmed in various experimental and clinical trial studies. In this review, we discuss MSCs differential potentials in differentiation into insulin producing cells (IPCs) from various sources and also have an overview on currently understood mechanisms through which MSCs exhibit their immunomodulatory effects. Other important issues that are provided in this review, due to their importance in the field of cell therapy, are genetic manipulations (as a new biotechnological method), routes of transplantation, combination of MSCs with other cell types, frequency of transplantation, and special considerations regarding diabetic patients' autologous MSCs transplantation. At the end, utilization of biomaterials either as encapsulation tools or as scaffolds to prevent immune rejection, preparation of tridimensional vascularized microenvironment, and completed or ongoing clinical trials using MSCs are discussed. Despite all unresolved concerns about clinical applications of MSCs, this group of stem cells still remains a promising therapeutic modality for treatment of diabetes. PMID- 26576442 TI - Comparative Study of Job Burnout Among Critical Care Nurses With Fixed and Rotating Shift Schedules. AB - BACKGROUND: Nurses, as health care providers, are insurmountably obliged to the practice of shift work. Literature has reported shift working as one of the inducing factors of burnout. Despite numerous studies in this area, there are inconsistencies on the relationship between shift working and burnout among nurses, especially in those who work in critical care settings. OBJECTIVES: The aim of this study was to compare the occupational burnout in critical care nurses with and without fixed shift schedules. PATIENTS AND METHODS: In this comparative study, 130 nurses with rotating shift schedule and 130 nurses with fixed shift schedule from six university hospitals were selected using stratified random sampling. Maslach burnout inventory was used for data collection. Independent samples t-test, chi-square and one-way ANOVA tests were used to analyze the data. RESULTS: Most of the participants were females (62.7%), aged between 22 - 29 years (38.5%), married (59.2%), and had a bachelor degree (86.9%). The mean score of emotional exhaustion was significantly higher in nurses with fixed shift schedules (P < 0.001). However, no significant difference was found between the mean scores of the two groups in the personal accomplishment and depersonalization subscales (P > 0.05). Moreover, no significant difference was found in burnout mean scores between nurses with fixed morning and fixed night shifts (P > 0.05). The means of the emotional exhaustion subscale were significantly different in nurses with different characteristics (P < 0.05) except the gender and working unit. CONCLUSIONS: As a result of this study, it was found that critical care nurses with fixed shift schedules display more burnout in emotional exhaustion dimension, compared to those working with rotating shift schedules. PMID- 26576443 TI - Clinical Self-Efficacy in Senior Nursing Students: A Mixed- Methods Study. AB - BACKGROUND: Clinical education has a basic role in nursing education, and effective clinical training establishes a sense of clinical self-efficacy in senior nursing students. Self-efficacy is a key component for acting independently in the nursing profession. OBJECTIVES: This study was designed to outline senior nursing students' views about clinical self-efficacy and to determine its level in nursing students. PATIENTS AND METHODS: A mixed-methods approach, including a quantitative cross-sectional study and qualitative content analysis,was used in this study. Participants were senior nursing students who were in their two last semesters. During the initial quantitative stage, all students in the 7th and 8th semesters of the nursing major were invited to participate. They were asked to complete the Nursing Clinical Self-Efficacy Scale (NCSES) and, during the subsequent qualitative stage, the 14 students in the 7th and 8th semesters were asked to participate in semi-structured interviews. RESULTS: In the quantitative part, 58 students completed the self-efficacy questionnaire; the mean score was 219.28 +/- 35.8, which showed moderate self efficacy in students. Self-efficacy was different across skills. In the qualitative part, the 355 open codes that were extracted from the interviews were clustered to 12 categories and 3 themes. The main themes included the factors related to self-efficacy, outcomes of self-efficacy, and ways to improve self efficacy. CONCLUSIONS: Students had moderate self-efficacy. Several factors such as environment, nursing colleagues, and clinical educators could influence the creation of clinical self-efficacy in nursing students. PMID- 26576444 TI - Limited Depressive and Anxiety Symptoms Late in Pregnancy Are Not Related to Neonatal Outcomes. AB - BACKGROUND: Prior studies have reported inconsistent findings regarding the link between antenatal depressive and anxiety symptomatology, with neonatal outcomes. OBJECTIVES: The aim of the present study was to assess the possible association of prenatal depressive and anxiety symptoms, in the third trimester of pregnancy, with perinatal outcomes (birth weight of the newborn, Apgar score and the newborn's admission in neonatal intensive care unit) in a sample of pregnant women, in Greece. PATIENTS AND METHODS: A total of 117 women from Athens, during the 32(nd) to 35(th) week of pregnancy, participated in the study. Demographic and obstetric history data, as well as neonatal outcomes, were recorded. Three self-administered psychometric scales (Beck depression inventory (BDI), Edinburg postnatal depression scale (EPDS) and beck anxiety inventory (BAI)) were used to evaluate in detail the prenatal depressive and anxiety symptoms. Descriptive statistics, Spearman's Rho coefficients, Mann-Whitney U and Kruskal-Wallis testes were applied to analyze the data. RESULTS: On the basis of BDI, 81.1% of the sample showed minimal, 15.4% mild, 2.6% moderate and 0.9% severe depressive symptoms, respectively. Furthermore, 80.3% of the participants, scored on EPDS below the cut-off point for a likely diagnosis of depression. According to BAI scale, 43.6% showed minimal, 42.7% women mild, 10.3% moderate and 3.4% severe anxiety symptoms. No statistically significant correlations were found between depressive and anxiety symptoms and neonatal outcomes (birth weight, Apgar score and admission in neonatal intensive care unit). CONCLUSIONS: Limited levels of prenatal depressive and anxiety symptoms do not seem to be associated with neonatal outcomes. In clinical practice, pregnant women, who suffer from low levels of prenatal depressive and anxiety symptoms, may be reassured, in respect of the adverse outcomes of these mood symptoms on the neonate. PMID- 26576445 TI - Iraqi Nurses' Perspectives on Safety Issues in Maternity Services. AB - BACKGROUND: Studies introduce maternal and neonatal safety phenomena as important challenges to the public health, particularly in low-income countries. However, few researches are conducted on the identification of safety issues in maternity hospitals in Iraq. It was the first study on nurses' perspectives on safety issues in Kurdistan, Iraq. OBJECTIVES: The current study aimed to describe nurses' perspectives on what constitutes a safe maternity service in Kurdistan, Iraq. PATIENTS AND METHODS: A qualitative design, based on a content analysis approach, was used. Ten Kurdish nurses who worked in the delivery room of Kurdistan, Iraq maternity hospital were recruited through purposive sampling. Semi-structured interviews were performed to collect data. All interviews were audiotaped and transcribed verbatim. Sampling continued to the level of data saturation. Data analysis was performed based on the steps suggested by Graneheim and Lundman. RESULTS: Thematic analysis led to the identification of six main categories including stressful job, lack of schedule and job description, providing care with limited resources, professional unaccountability, regional sociopolitical factors, and inadequate training. CONCLUSIONS: Iraqi nurses identified factors such as limited health resources, lack of job description, and professional unaccountability as major safety issues in maternity services. These findings alarm the need to ensure the provision of females and neonates with appropriate care. This, however, would require coordination between Iraqi Kurdistan health authorities to provide midwifery care facilities, high-quality and relevant staff training, and an effective healthcare system in the maternity units. PMID- 26576446 TI - Prevention of Postpartum Hemorrhage: Our Options. PMID- 26576447 TI - In Reply to: Minimal Requirements in Reporting Qualitative and Quantitative Studies: Critics on Two Papers. PMID- 26576448 TI - Findings From a Nursing Care Audit Based on the Nursing Process: A Descriptive Study. AB - BACKGROUND: Although using the nursing process improves nursing care quality, few studies have evaluated nursing performance in accordance with nursing process steps either nationally or internationally. OBJECTIVES: This study aimed to audit nursing care based on a nursing process model. PATIENTS AND METHODS: This was a cross-sectional descriptive study in which a nursing audit checklist was designed and validated for assessing nurses' compliance with nursing process. A total of 300 nurses from various clinical settings of Tehran university of medical sciences were selected. Data were analyzed using descriptive and inferential statistics, including frequencies, Pearson correlation coefficient and independent samples t-tests. RESULTS: The compliance rate of nursing process indicators was 79.71 +/- 0.87. Mean compliance scores did not significantly differ by education level and gender. However, overall compliance scores were correlated with nurses' age (r = 0.26, P = 0.001) and work experience (r = 0.273, P = 0.001). CONCLUSIONS: Nursing process indicators can be used to audit nursing care. Such audits can be used as quality assurance tools. PMID- 26576449 TI - Minimal Requirements in Reporting of Qualitative and Quantitative Studies: Critics on Two Papers. PMID- 26576450 TI - West Nile Virus Central Nervous System Infection in Patients Treated With Rituximab: Implications for Diagnosis and Prognosis, With a Review of Literature. AB - The spectrum of West Nile virus (WNV) infection continues to be elucidated. Many cases of WNV are asymptomatic; however, in immunocompromised patients, symptoms are more likely to be severe. We describe fatal WNV central nervous system disease in lymphoma patients who received rituximab, blunting the inflammatory response and complicating diagnosis. PMID- 26576451 TI - A Study on Students Acquisition of IT Knowledge and Its Implication on M Learning. AB - The boom in mobile technology has seen a dramatic rise in its usage. This has led to usage of mobiles even in the academic context for further learning. Although the advantages of m-learning (mobile learning) are visible, studies are required to address the aspects that shape its virtual expectations. The acceptance of mobile technology relies mostly on how the students feel about mobile technology fitting into their requirements. Yet, in spite of the significance in the potential of m-learning, research studies have only inadequate data to identify the factors that influence their decision to adapt the mobile technology for the purpose of learning. To deal with this space, the present study was undertaken to correlate the IT skills of students with their impact on their acceptance of m learning. The research study found that the perceived usability along with the usefulness of m-learning impacts the association between IT expertise and the objective of learners' acceptance of m-learning. A survey of 892 students from Engineering, Arts, and Science Colleges found that IT skills influence student's acquisition of m-learning technology. Specialized and advanced skills in mobile technology along with basic skills play a significant role in influencing a student to accept m-learning. But no specific substantiation has been established to support the statement that highly developed IT skills have influenced the students to accept m-learning. PMID- 26576452 TI - Original and Mirror Face Images and Minimum Squared Error Classification for Visible Light Face Recognition. AB - In real-world applications, the image of faces varies with illumination, facial expression, and poses. It seems that more training samples are able to reveal possible images of the faces. Though minimum squared error classification (MSEC) is a widely used method, its applications on face recognition usually suffer from the problem of a limited number of training samples. In this paper, we improve MSEC by using the mirror faces as virtual training samples. We obtained the mirror faces generated from original training samples and put these two kinds of samples into a new set. The face recognition experiments show that our method does obtain high accuracy performance in classification. PMID- 26576453 TI - Morphological Spectrum of Orbitoocular Diseases in a Tertiary Health Centre in Keffi, North Central Nigeria. AB - Aim. The aim of this study was to carry out a retrospective clinicopathological analysis of the ocular lesions requiring biopsy seen in the Department of Histopathology, Federal Medical Centre (FMC), Keffi, in North Central Nigeria. Materials and Method. A retrospective review of the clinicopathologic profile of orbitoocular lesions diagnosed at the FMC, Keffi, was done. Clinical and pathological data were obtained from the patients' clinical records and original biopsy reports, respectively. Results. Sixty-six cases of orbitoocular lesions were reviewed for this study. Of the 54 cases investigated, 28 were HIV negative while 26 were HIV positive (37.1% of all cases). There were 30 cases of Ocular Surface Squamous Neoplasia (OSSN) with a male-to-female ratio of 0.9 : 1. Squamous cell carcinoma (SCC) was the most frequent OSSN with 17 cases. The mean age of cases of SCC is 37.1 +/- 7.6 SD (years). The mean age of carcinoma in situ is 35.8 +/- 11.4 years. Conclusion. There was no significant difference in the sex distribution of patients with OSSN. It is probable that a diagnosis of squamous cell carcinoma may be encountered in about a year after diagnosis of a carcinoma in situ especially if the in situ carcinoma is left untreated or improperly treated. PMID- 26576454 TI - Determinants of Method Switching among Social Franchise Clients Who Discontinued the Use of Intrauterine Contraceptive Device. AB - Introduction. Women who do not switch to alternate methods after contraceptive discontinuation, for reasons other than the desire to get pregnant or not needing it, are at obvious risk for unplanned pregnancies or unwanted births. This paper examines the factors that influence women to switch from Intrauterine Contraceptive Device (IUCD) to other methods instead of terminating contraceptive usage altogether. Methods. The data used for this study comes from a larger cross sectional survey conducted in nine (9) randomly selected districts of Sindh and Punjab provinces of Pakistan, during January 2011. Using Stata 11.2, we analyzed data on 333 women, who reported the removal of IUCDs due to reasons other than the desire to get pregnant. Results. We found that 39.9% of the women do not switch to another method of contraception within one month after IUCD discontinuation. Use of contraception before IUCD insertion increases the odds for method switching by 2.26 times after removal. Similarly, postremoval follow up by community health worker doubles (OR = 2.0) the chances of method switching. Compared with women who received free IUCD service (via voucher scheme), the method switching is 2.01 times higher among women who had paid for IUCD insertion. Conclusion. To increase the likelihood of method switching among IUCD discontinuers this study emphasizes the need for postremoval client counseling, follow-up by healthcare provider, improved choices to a wider range of contraceptives for poor clients, and user satisfaction. PMID- 26576455 TI - Practice variation in spontaneous breathing trial performance and documentation. PMID- 26576456 TI - Investigating bisulfite short-read mapping failure with hairpin bisulfite sequencing data. AB - BACKGROUND: DNA methylation is an important epigenetic mark relevant to normal development and disease genesis. A common approach to characterizing genome-wide DNA methylation is using Next Generation Sequencing technology to sequence bisulfite treated DNA. The short sequence reads are mapped to the reference genome to determine the methylation statuses of Cs. However, despite intense effort, a much smaller proportion of the reads derived from bisulfite treated DNA (usually about 40-80%) can be mapped than regular short reads mapping (> 90%), and it is unclear what factors lead to this low mapping efficiency. RESULTS: To address this issue, we used the hairpin bisulfite sequencing technology to determine sequences of both DNA double strands simultaneously. This enabled the recovery of the original non-bisulfite-converted sequences. We used Bismark for bisulfite read mapping and Bowtie2 for recovered read mapping. We found that recovering the reads improved unique mapping efficiency by 9-10% compared to the bisulfite reads. Such improvement in mapping efficiency is related to sequence entropy. CONCLUSIONS: The hairpin recovery technique improves mapping efficiency, and sequence entropy relates to mapping efficiency. PMID- 26576457 TI - [Clinical Practice Guidelines for Diagnosis, Treatment and Beginning of Psychosocial Rehabilitation of Adults With Schizophrenia: "Do Well the Things That do Well"]. PMID- 26576458 TI - [Clinical Practice Guidelines for Management of Schizophrenia: Evaluation Using AGREE II]. AB - INTRODUCTION: Colombia is developing multiple national practice guidelines from a range of diseases. Clinical practice guidelines represent a very useful tool to be able to take decision over a patient care that is widely available for the clinician. In psychiatry there are a good number of international clinical guidelines for the treatment of schizophrenia nevertheless there is no article that evaluate them scientifically METHODS: In the settings of developing a Colombian schizophrenia practice guideline, a systematic search was performed in multiple databases and the results were then evaluated by two trained persons. We present the results globally and by domains. RESULTS: We found 164 matches for possible guidelines. After screening 7 guidelines were evaluated with the AGREE II instrument. Globally and by the different domains, the National Institute for Health and Care Excellence (NICE) was the guideline that got the best score. From the guidelines that were reviewed, 4 were from Europe and only 2 were from Latin America. None of the guidelines used GRADE methodology for the recommendations. CONCLUSION: The diversity of the schizophrenia treatment guidelines does not allow an easy adoption of the recommendation by a psychiatrist in Colombia. PMID- 26576459 TI - [Antipsychotic Treatment of the Adult Patient in the Acute Phase of Schizophrenia]. AB - OBJECTIVES: To determine the efficacy and safety of different antipsychotic drugs in the management of patients diagnosed with schizophrenia in the acute phase. To formulate evidence-based recommendations on the antipsychotic (AP) drug management strategies for the treatment of the adult diagnosed with schizophrenia in the acute phase. METHOD: Clinical practice guidelines were prepared, using the guidelines of the Methodology Guide of the Ministry of Health and Social Protection, in order to identify, synthesise, and evaluate the evidence and formulate recommendations as regards the management and follow-up of adult patients diagnosed with schizophrenia. The evidence of the NICE 82 guideline was adopted and updated, which answered the question on the management of the acute phase of adults with a diagnosis of schizophrenia. The evidence and its level were presented to the Guideline Development Group (GDG) in order to formulate recommendations following the methodology proposed by the GRADE approach. RESULTS: Clozapine, olanzapine, risperidone, ziprasidone, amisulpride, paliperidone, haloperidol, quetiapine, and aripiprazole were more effective than placebo for the majority of psychotic symptoms and the abandonment of treatment, but asenapine was not. Paliperidone, risperidone, quetiapine, clozapine, and olanzapine showed significant increases in weight compared to placebo. Haloperidol, risperidone, ziprasidone, and paliperidone had a higher risk of extrapyramidal symptoms than placebo. There was a significant risk of sedation or drowsiness with, risperidone, haloperidol, ziprasidone, quetiapine, olanzapine, and clozapine in the comparisons with placebo. Of the results of the comparisons between AP, it was shown that clozapine and paliperidone had a clinically significant effect compared to haloperidol and quetiapine, respectively. Olanzapine and risperidone had a lower risk of abandoning the treatment in general, and due to adverse reactions in two comparisons of each one, haloperidol was the drug with more risk of abandoning due to adverse effects, followed by clozapine. Amisulpride, haloperidol and ziprasidone had favourable results as regards weight increase in several comparisons. Aripiprazole and paliperidone obtained a higher number of favourable results as regards sedation, and all the atypical drugs (except paliperidone) had a lower risk than the use of anti parkinsonian drugs. Of the evidence from observational studies, it was found that, in subjects with risk factors for diabetes, such as age, hypertension, and dyslipidaemia, the initial treatment and current treatment with olanzapine, as well as current treatment with clozapine, may promote the development of this disease. CONCLUSION: Although it is imperative to prescribe an antipsychotic for treatment of the acute phase, the selection of the drug depends on the particular clinical condition of each patient and their collateral effects profile. PMID- 26576460 TI - [Maintenance Treatment With Antipsychotics for Adult Patients Diagnosed With Schizophrenia]. AB - OBJECTIVES: To determine the effectiveness and security of the antipsychotics available for the management of adult patients with schizophrenia in the maintenance phase. To develop recommendations of treatment for the maintenance phase of the disease. METHODS: A clinical practice guideline was elaborated under the parameters of the Methodological Guide of the Ministerio de Salud y Proteccion Social to identify, synthesize and evaluate the evidence and make recommendations about the treatment and follow-up of adult patients with schizophrenia. The evidence of NICE guide 82 was adopted and updated. The evidence was presented to the Guideline Developing Group and recommendations, employing the GRADE system, were produced. RESULTS: 18 studies were included to evaluate the effectiveness and / or safety of different antipsychotic drugs first and second generation. Overall, antipsychotics (AP) showed superiority over placebo in relapse rate over 12 months (RR 0.59 95% CI 0.42, 0.82) and hospitalization rate over 24 months of follow-up (RR 0.38 95% 0.27, 0.55); its use is associated with increased risk of treatment dropout (RR 0.53 95% CI 0.46, 0.61) and adverse events such as weight gain, dystonia, extrapyramidal symptoms and sedation. There was no difference in the outcome of re hospitalizations, comparisons on quality of life, negative symptoms or weight gain between AP first and second generation. Continuous or standard dose regimens appear to be superior to intermittent or low doses in reducing the risk of abandonment of treatment regimes. CONCLUSION: Adult patients diagnosed with schizophrenia should receive maintenance treatment with antipsychotics. The medication of choice will depend on the management of the acute phase, the patient's tolerance to it and the presentation of adverse events. PMID- 26576461 TI - [Treatment of Adult Schizophrenic Patients With Depot Antipsychotics]. AB - OBJECTIVES: To determine the indications of long-acting antipsychotic injection and what its effectiveness and safety in adult patients with schizophrenia during the treatment maintenance phase. METHODS: A clinical practice guideline was elaborated under the parameters of the Methodological Guide of the Ministerio de Salud y Proteccion Social to identify, synthesize and evaluate the evidence and make recommendations about the treatment and follow-up of adult patients with schizophrenia. The evidence of NICE guide 82 was adopted and updated. The evidence was presented to the Guideline Developing Group and recommendations, employing the GRADE system, were produced. RESULTS: The literature review shows that the evidence has moderate to low quality. 8 articles were used. The risk of relapse was lower with depot risperidone and paliperidone palmitate when compared with placebo. For the risk of hospitalizations comparing depot antipsychotics (APD) versus oral AP, the result is inconclusive. Globally the second-generation APD had a lower risk of discontinuation when compared with placebo. The second generation AP had higher risk of extrapyramidal syndromes than placebo, as in the use of antiparkinsonian. The comparison of second-generation AP injections versus placebo showed an increased risk of early weight gain. CONCLUSION: The use of depot antipsychotics in the maintenance phase of adult patients diagnosed with schizophrenia is recommended if there is no adherence to oral antipsychotics as the patient's preference. It is not recommended depot antipsychotics in the acute phase of schizophrenia in adults. PMID- 26576462 TI - [Pharmacological Treatment for Adult Diagnosed With Schizophrenia With Agitation or Violent Behavior]. AB - OBJECTIVES: To determine the most effective pharmacological intervention and to bring recommendations for decision-making in the management of adults with schizophrenia with violent behavior or agitation. METHODS: A clinical practice guideline was elaborated under the parameters of the Methodological Guide of the Ministerio de Salud y Proteccion Social to identify, synthesize and evaluate the evidence and make recommendations about the treatment and follow-up of adult patients with schizophrenia. The evidence of NICE guide 82 was adopted and updated. The evidence was presented to the Guideline Developing Group and recommendations, employing the GRADE system, were produced. RESULTS: It is recommended the use of parenteral drugs in all agitated patient who does not respond to the measures of persuasion. The drugs with better evidence on effectiveness (control of violent behavior) are haloperidol and benzodiazepines, administered jointly or individually. Olanzapine is also an option considering that should only be used in institutions where a psychiatrist is available 24hours. Ziprasidone can be considered as a second-line drug. The information about the side effects associated with these drugs is insufficient and has low quality. CONCLUSION: Violent behavior in adults with schizophrenia represents a risk for themselves and for those around them, so the opportune implementation of interventions aimed to calm the patient, in order to prevent potential negative outcomes is necessary. It is recommended to initiate these interventions with measures of verbal persuasion, and if these measures are not effective, appropriate use of parenteral drugs: haloperidol and benzodiazepines as first line and olanzapine and ziprasidone as second choices. PMID- 26576463 TI - [Prevention and Treatment of Common Acute Adverse Effects With Antipsychotic Use in Adults With Schizophrenia Diagnosis]. AB - OBJECTIVE: To determine the most adequate strategies for the prevention and treatment of the acute adverse effects of the use of antipsychotics. METHODS: A clinical practice guideline was elaborated under the parameters of the Methodological Guide of the Ministerio de Salud y Proteccion Social to identify, synthesize and evaluate the evidence and make recommendations about the treatment and follow-up of adult patients with schizophrenia. A systematic literature search was carried out. The evidence was presented to the Guideline Developing Group and recommendations, employing the GRADE system, were produced. RESULTS: The non-pharmacological interventions such as nutritional counseling by a nutritionist, exercise and psychotherapy are effective in preventing weight gain with the use of antipsychotics. (Kg Weight reduction in DM of -3.05 (-4.16, 1.94)). The antipsychotic change from olanzapine to aripiprazole showed weight loss and decreased BMI (decreased weight in KG DM -3.21 (-9.03, -2.61). The use of beta blockers was ineffective in reducing akathisia induced by antipsychotic; using as outcome the 50% reduction of symptoms of akathisia comparing beta blockers with placebo RR was 1.4 (0.59, 1.83). CONCLUSION: It is recommended to make psychotherapeutic accompaniment and nutrition management of overweight for patients with weight gain. If these alternatives are ineffective is suggested to change the antipsychotic or consider starting metformin. For the management of drug-induced akathisia it is recommended to decrease the dose of the drug and the addition of lorazepam. It is recommended using 5mg biperiden IM or trihexyphenidyl 5mg orally in case of secondary acute dystonia and for the treatment of antipsychotic-induced parkinsonism to decrease the dose of antipsychotic or consider using 2 - 4mg/day of biperiden or diphenhydramine 50mg once daily. PMID- 26576464 TI - [Psychosocial Interventions in Acute and Maintenance Treatment of Adult Patients Diagnosed With Schizophrenia]. AB - OBJECTIVES: To determine the effectiveness of the psychosocial strategies designed to improve the outcomes in adults with schizophrenia in both, acute and stable phase of the disorder. This evidence is used to propose recommendation in the guidelines of integral attention for the diagnosis, treatment and psychosocial rehabilitation of adults with schizophrenia. METHODS: A guideline for clinical practice was developed using the methodological framework of the Ministerio de la Proteccion Social to collect evidence and grading recommendations. A search, evaluation and synthesis of evidence were carried out. The evidence was presented to the Guideline Developing Group and recommendations, employing the GRADE system, were produced. RESULTS: The psychoeducation and family intervention showed higher efficacy, compared with the usual treatment, to prevent relapses and hospital readmissions, to reduce family burden and to improve adherence to treatment. The social skill training was effective to improve symptoms, social functioning and quality of life. However, the quality of evidence was low. There was not enough evidence about the efficacy of occupational therapy, but considering patients preferences and its wide clinical utilization, the GDG suggested its inclusion. CONCLUSION: Psychoeducation, family intervention and social skill training are recommended to be offered for the treatment of schizophrenia. Furthermore, occupational therapy is suggested for inpatients and outpatients with the disorder. PMID- 26576465 TI - [Psychotherapeutic Interventions in Acute and Maintenance Treatment of Adult Patients Diagnosed With Schizophrenia]. AB - OBJECTIVES: To determine the effectiveness of the psychotherapeutic strategies designed to improve the outcomes in adults with schizophrenia in both, acute and stable phase of disease. This evidence is used to propose recommendation in the guidelines of integral attention for the diagnosis, treatment and psychosocial rehabilitation of adults with schizophrenia. METHODS: A guideline for clinical practice was developed using the methodological framework of the Ministerio de la Proteccion Social to collect evidence and grading recommendations. A search, evaluation and synthesis of evidence were carried out. The evidence was presented to the Guideline Developing Group and recommendations, employing the GRADE system, were produced. RESULTS: The cognitive behavioral therapy showed higher efficacy, compared with the usual treatment, to reduce positive symptoms, prevent relapses and hospital readmissions and to improve the occupational stats. However, the quality of evidence was low. There was not enough evidence about the efficacy of adherence, psychodynamic and support therapy. CONCLUSION: Psychotherapeutic management must be offered to the patients with schizophrenia according to their needs and clinical characteristics. Among the different psychotherapeutic modalities, cognitive behavioral therapy is recommended. PMID- 26576466 TI - [Types of Care for Adult Patients Diagnosed With Acute and Maintenance Phase Schizophrenia]. AB - OBJECTIVES: To assist the clinician in making decisions about the types of care available for adults with schizophrenia. To determine which are the modalities of treatment associated with better outcomes in adults with schizophrenia. METHODS: A clinical practice guideline was elaborated under the parameters of the Methodological Guide of the Ministerio de Salud y Proteccion Social to identify, synthesize and evaluate the evidence and make recommendations about the treatment and follow-up of adult patients with schizophrenia. The evidence of NICE guide 82 was adopted and updated. The evidence was presented to the Guideline Developing Group and recommendations, employing the GRADE system, were produced. RESULTS: Patients who were in Assertive community treatment had a lower risk of new hospitalizations. For the intensive case management, the results favored this intervention in the outcomes: medium term readmissions, social functioning and satisfaction with services. The crisis resolution teams was associated with better outcomes on outcomes of readmissions, social functioning and service satisfaction in comparison with standard care. CONCLUSION: The use of different modalities of care leads to the need of a comprehensive approach to patients to reduce the overall disability associated with the disease. Evidence shows overall benefit for most outcomes studied without encountering hazards for health of patients. This evaluation is recommended to use the professional ways of providing health services that are community-based and have a multidisciplinary group. It is not recommended the modality "day hospital" during the acute phase of schizophrenia in adults. PMID- 26576467 TI - Bio-inspired homogeneous multi-scale place recognition. AB - Robotic mapping and localization systems typically operate at either one fixed spatial scale, or over two, combining a local metric map and a global topological map. In contrast, recent high profile discoveries in neuroscience have indicated that animals such as rodents navigate the world using multiple parallel maps, with each map encoding the world at a specific spatial scale. While a number of theoretical-only investigations have hypothesized several possible benefits of such a multi-scale mapping system, no one has comprehensively investigated the potential mapping and place recognition performance benefits for navigating robots in large real world environments, especially using more than two homogeneous map scales. In this paper we present a biologically-inspired multi scale mapping system mimicking the rodent multi-scale map. Unlike hybrid metric topological multi-scale robot mapping systems, this new system is homogeneous, distinguishable only by scale, like rodent neural maps. We present methods for training each network to learn and recognize places at a specific spatial scale, and techniques for combining the output from each of these parallel networks. This approach differs from traditional probabilistic robotic methods, where place recognition spatial specificity is passively driven by models of sensor uncertainty. Instead we intentionally create parallel learning systems that learn associations between sensory input and the environment at different spatial scales. We also conduct a systematic series of experiments and parameter studies that determine the effect on performance of using different neural map scaling ratios and different numbers of discrete map scales. The results demonstrate that a multi-scale approach universally improves place recognition performance and is capable of producing better than state of the art performance compared to existing robotic navigation algorithms. We analyze the results and discuss the implications with respect to several recent discoveries and theories regarding how multi-scale neural maps are learnt and used in the mammalian brain. PMID- 26576468 TI - Evolving spatio-temporal data machines based on the NeuCube neuromorphic framework: Design methodology and selected applications. AB - The paper describes a new type of evolving connectionist systems (ECOS) called evolving spatio-temporal data machines based on neuromorphic, brain-like information processing principles (eSTDM). These are multi-modular computer systems designed to deal with large and fast spatio/spectro temporal data using spiking neural networks (SNN) as major processing modules. ECOS and eSTDM in particular can learn incrementally from data streams, can include 'on the fly' new input variables, new output class labels or regression outputs, can continuously adapt their structure and functionality, can be visualised and interpreted for new knowledge discovery and for a better understanding of the data and the processes that generated it. eSTDM can be used for early event prediction due to the ability of the SNN to spike early, before whole input vectors (they were trained on) are presented. A framework for building eSTDM called NeuCube along with a design methodology for building eSTDM using this is presented. The implementation of this framework in MATLAB, Java, and PyNN (Python) is presented. The latter facilitates the use of neuromorphic hardware platforms to run the eSTDM. Selected examples are given of eSTDM for pattern recognition and early event prediction on EEG data, fMRI data, multisensory seismic data, ecological data, climate data, audio-visual data. Future directions are discussed, including extension of the NeuCube framework for building neurogenetic eSTDM and also new applications of eSTDM. PMID- 26576469 TI - Direct Light-Driven Water Oxidation by a Ladder-Type Conjugated Polymer Photoanode. AB - A conjugated polymer known for high stability (poly[benzimidazobenzophenanthroline], coded as BBL) is examined as a photoanode for direct solar water oxidation. In aqueous electrolyte with a sacrificial hole acceptor (SO3(2-)), photoelectrodes show a morphology-dependent performance. Films prepared by a dispersion-spray method with a nanostructured surface (feature size of ~20 nm) gave photocurrents up to 0.23 +/- 0.02 mA cm(-2) at 1.23 VRHE under standard simulated solar illumination. Electrochemical impedance spectroscopy reveals a constant flat-band potential over a wide pH range at +0.31 VNHE. The solar water oxidation photocurrent with bare BBL electrodes is found to increase with increasing pH, and no evidence of semiconductor oxidation was observed over a 30 min testing time. Characterization of the photo-oxidation reaction suggests H2O2 or *OH production with the bare film, while functionalization of the interface with 1 nm of TiO2 followed by a nickel-cobalt catalyst gave solar photocurrents of 20-30 MUA cm(-2), corresponding with O2 evolution. Limitations to photocurrent production are discussed. PMID- 26576470 TI - Side Effects, Physical Health Consequences, and Mortality Associated with Abortion and Birth after an Unwanted Pregnancy. AB - INTRODUCTION: The safety of abortion in the United States has been documented extensively. In the context of unwanted pregnancy, however, there are few data comparing the health consequences of having an abortion versus carrying an unwanted pregnancy to term. METHODS: We examine and compare the self-reported physical health consequences after birth and abortion among participants of the Turnaway Study, which recruited women seeking abortions at 30 clinics across the United States. We also investigate and report maternal mortality among all women enrolled in the study. RESULTS: In our study sample, women who gave birth reported potentially life-threatening complications, such as eclampsia and postpartum hemorrhage, whereas those having abortions did not. Women who gave birth reported the need to limit physical activity for a period of time three times longer than that reported by women who received abortions. Among all women enrolled in the Turnaway Study, one maternal death was identified-one woman who had been denied an abortion died from a condition that confers a higher risk of death among pregnant women. CONCLUSION: These results reinforce the existing data on the safety of induced abortion when compared with childbirth, and highlight the risk of serious morbidity and mortality associated with childbirth after unwanted pregnancy. PMID- 26576471 TI - Regulatory focus and adherence to self-care behaviors among adults with type 2 diabetes. AB - The aims of this study were, first, to test the association between regulatory focus of adults with type 2 diabetes and their adherence to two types of self care behaviors - lifestyle change (e.g. physical activity and diet) and medical care regimens (blood-glucose monitoring, foot care and medication usage). Second, to explore whether a fit between the message framing and patients' regulatory focus would improve their intentions to adhere specifically when the type of behavior fits the patients' regulatory focus as well. A cross-sectional study was conducted among 130 adults with type 2 diabetes who were hospitalized in an academic medical center. The patients completed a set of questionnaires that included their diabetes self-care activities, regulatory focus, self-esteem and demographic, socioeconomic and clinical data. In addition, participants were exposed to either a gain-framed or a loss-framed message, and were then asked to indicate their intention to improve adherence to self-care behaviors. A multivariable linear regression model revealed that promoters reported higher adherence to lifestyle change behaviors than preventers did (B = .60, p = .028). However, no effect of regulatory focus on adherence to medical care regimens was found (B = .46, p = .114). In addition, preventers reported higher intentions to adhere to medical care behaviors when the message framing was congruent with prevention focus (B = 1.16, p = .023). However, promoters did not report higher intentions to adhere to lifestyle behaviors when the message framing was congruent with promotion focus (B = -.16, p = .765). These findings justify the need to develop tailor-made interventions that are adjusted to both patients' regulatory focus and type of health behavior. PMID- 26576472 TI - Analysis of Fetal Blood: Is There Still a Role for Prenatal Diagnosis of Thalassemia? AB - The aim of the present study was to report the use of analysis of fetal blood in prenatal diagnosis (PND) of beta- and alpha-thalassemia (beta- and alpha-thal), at a Chinese tertiary, maternity center. All cases undergoing invasive testing for PND of thalassemias from 1 January 2010 to 31 December 2014 were included. The main clinical characteristics of these invasive procedures were retrieved from the database software used for analysis. One thousand, nine hundred and six invasive PNDs were carried out for thalassemia, including 904 cases for beta-thal and 1002 for alpha-thal. In the 904 PNDs for beta-thal, chorionic villus sampling (CVS) was done in 321 cases and amniocentesis in 583 cases. No fetal blood analysis was used for cases at-risk for beta-thal. In the 1002 PNDs for alpha thal, CVS was done in 724 cases, amniocentesis in 137 cases and fetal blood analysis in 141 cases. All the 278 cases sampled by amniocentesis or fetal blood analysis were found to be affected by Hb Bart's (gamma4) disease. Currently, fetal blood analysis is considered only in relatively late gestation when Hb Bart's disease has already been identified by ultrasound in a fetus at-risk for alpha-thal. PMID- 26576473 TI - Gastric GIST with chondroid differentiation presented with gastric abscess - A case report and literature review. PMID- 26576474 TI - Lower uncarboxylated osteocalcin and higher sclerostin levels are significantly associated with coronary artery disease. AB - Systemic roles for bone-derived proteins have emerged from recent studies. In particular, the serum concentration of osteocalcin (OCN) or sclerostin was found to be associated with altered glucose metabolism or atherosclerosis. The aims of this study were to evaluate OCN and sclerostin levels in subjects who underwent coronary artery bypass graft (CABG) surgery compared with those in normal controls and to analyze their relationships with atherosclerosis. This was an age and sex-matched case-control study that included 61 male subjects who underwent CABG and 61 controls. Forty-six subjects (37.7%) with diabetes and 62 hypertensive subjects (50.8%) were included. Serum sclerostin, uncarboxylated OCN (ucOCN) and carboxylated OCN (cOCN) were measured. Coronary artery calcium (CAC) score was calculated according to Agatston's method, using a 64-slice multi detector computed tomography scanner. The levels of serum ucOCN were significantly lower and sclerostin concentrations were higher in the CABG group than in the controls (p<0.05 for both), and these significances were maintained after adjusting for atherosclerotic risk factors in both diabetic and nondiabetic patients (p<0.05 in both groups). However, there was no difference in cOCN levels between CABG patients and controls. The group with abnormal CAC scores (CAC scores >=100) had significantly higher levels of serum sclerostin (p<0.05). In multiple logistic regression analysis, both lower ucOCN and higher sclerostin levels were independently associated with CABG (odds ratio [OR] 0.43, 95% CI 0.22 0.84, p<0.05 for log(ucOCN); and OR 2.09, 95% CI 1.08-4.05, p<0.05 for log(sclerostin)). In subjects with CAD who underwent CABG, the serum ucOCN level was decreased and the sclerostin level was increased compared with those in the controls, regardless of diabetic status. Longitudinal studies are warranted to establish the precise roles of ucOCN and sclerostin in the pathogenesis of atherosclerosis. PMID- 26576475 TI - Association between the abdominal obesity anthropometric indicators and metabolic disorders in a Chinese population. AB - BACKGROUND: Obesity has become a major health problem in contemporary society and it is closely related to many chronic diseases, so it is an important issue for measuring adiposity accurately and predicting its future. Prevention and treatment of overweight and obesity has become one of the key prevention and treatment of metabolic disorders. OBJECTIVE: In this study, we compared the ability of the four anthropometric indicators (body mass index, waist circumstance, waist-height ratio, waist-to-hip ratio) to identify metabolic disorders (hypertension, hyperlipidaemia, hyperglycemia and hyperuricemia) by receiver operating characteristic (ROC) curve analyses and to provide evidence for clinical practice. METHODS: In this large scale cross-sectional study, 13,275 Han adults (including 7595 males and 5680 females) received physical examination between January, 2009 and January, 2010 in Xuanwu Hospital of Capital Medical University were investigated by the means of questionnaire, Meanwhile, the physical examination and serological results were recorded. A package known as Statistical Package for Social Scientist (SPSS) was employed to analyse the responses while t-test, one-way analysis of variance (ANOVA), ROC analysis and chi-square statistical methods were used to test the hypotheses. RESULTS: WC, WHtR, WHR and BMI were all significantly (P < 0.001) correlated with all metabolic risk factors regardless of gender. And the area under the curve (AUC) of WHtR was significantly greater than that of WC, BMI or WHR in the prediction of hypertension, hyperlipidaemia, hyperglycemia and hyperuricemia. CONCLUSION: Our data show that WHtR was the best predictor of various metabolic disorders. The diagnostic value in descending order was WHtR > WHR > WC > BMI. Therefore we recommend WHtR in assessment of obese patients, in order to better assess the risks of their metabolic diseases. PMID- 26576476 TI - The Effect of Silencing HIF-1alpha Gene in BxPC-3 Cell Line on Glycolysis-Related Gene Expression, Cell Growth, Invasion, and Apoptosis. AB - Hypoxia has been proved to be a typical character of solid tumors. Tumor cells prefer to use glucose through the glycolysis pathway instead of aerobic respiration. However, the precise molecular mechanism underlying this so-called Warburg effect remains elusive. In the current study, siRNA was synthesized and transfected into BxPC-3 cell line to silence the expression of HIF-1alpha gene. It was found that hypoxia induced hypoxia-inducible factor 1alpha (HIF-1alpha) overexpression in BxPC-3 cells, enhanced the expression of pyruvate dehydrogenase kinase 1 and lactate dehydrogenase A, thus facilitating glycolysis and making tumor cells more tolerant to hypoxic stress. The silencing of HIF-1alpha gene significantly attenuated glycolysis under hypoxic conditions, inhibited the growth and invasion ability of BxPC-3 cells, and enhanced hypoxia-induced cell apoptosis. PMID- 26576477 TI - Surface faceting and elemental diffusion behaviour at atomic scale for alloy nanoparticles during in situ annealing. AB - The catalytic performance of nanoparticles is primarily determined by the precise nature of the surface and near-surface atomic configurations, which can be tailored by post-synthesis annealing effectively and straightforwardly. Understanding the complete dynamic response of surface structure and chemistry to thermal treatments at the atomic scale is imperative for the rational design of catalyst nanoparticles. Here, by tracking the same individual Pt3Co nanoparticles during in situ annealing in a scanning transmission electron microscope, we directly discern five distinct stages of surface elemental rearrangements in Pt3Co nanoparticles at the atomic scale: initial random (alloy) elemental distribution; surface platinum-skin-layer formation; nucleation of structurally ordered domains; ordered framework development and, finally, initiation of amorphization. Furthermore, a comprehensive interplay among phase evolution, surface faceting and elemental inter-diffusion is revealed, and supported by atomistic simulations. This work may pave the way towards designing catalysts through post-synthesis annealing for optimized catalytic performance. PMID- 26576478 TI - Response to Robert Vetrugno's commentary. PMID- 26576479 TI - Safety of medical treatments for endometriosis. AB - INTRODUCTION: All medical treatments for endometriosis are equally effective in relieving pain. However, all of them alleviate pain symptoms for as long as they are used, but pain always relapses when medication is discontinued. Therefore, medications need to be used in the long term. AREAS COVERED: Formulations of estro-progestins that contain less than 50 ug of estrogen are associated with a low risk of venous thrombosis, myocardial infarction and stroke. When considering the neoplastic effects, data suggest that the overall risk of invasive cancer by age 60 is not increased in previous users of hormonal contraceptives. The use of progestins for contraception has never been associated with an increased risk of breast cancer, venous thromboembolism or bone fractures. Although more data on long-term therapy with progestins are needed, treatment of endometriosis with progestins may be feasible in women with metabolic or cardiovascular contraindications to estroprogestin. The other medications for the treatment of pain associated with endometriosis are less appropriate for long term administration because of side effects (danazol and GnRH analogues), costs (aromatase inhibitors and GnRH agonists) or necessity of complex regimens of associations (GnRH agonists and add back therapy or aromatase inhibitors plus progestins). EXPERT OPINION: Progestins and estroprogestins are safe drugs to use in the long term. Adherence to these medications may be high because, being a contraceptive, they are perceived less as a medication for the treatment of a disease. The annual cost of therapy compares favorably with other available medications. Progestins and estroprogestins represent the first-line medications for the treatment of endometriosis associated pain. PMID- 26576480 TI - In Reply. PMID- 26576481 TI - Evidence that hepatitis B virus replication in mouse cells is limited by the lack of a host cell dependency factor. AB - BACKGROUND & AIMS: Hepatitis B virus (HBV) is a major human pathogen restricted to hepatocytes. Expression of the specific receptor human sodium taurocholate cotransporting polypeptide (hNTCP) in mouse hepatocytes renders them susceptible to hepatitis delta virus (HDV), a satellite of HBV; however, HBV remains restricted at an early stage of replication. This study aims at clarifying whether this restriction is caused by the lack of a dependency factor or the activity of a restriction factor. METHODS: Six hNTCP-expressing mouse and human cell lines were generated and functionally characterized. By fusion with replication-supporting but non-infectable HepG2 cells, we analysed the ability of these heterokaryonic cells to fully support HBV replication by HBcAg expression and HBsAg/HBeAg secretion. RESULTS: While hNTCP expression in three mouse cell lines and the non-hepatic human HeLa cells conferred susceptibility to HDV, HBV replication was still restricted. Upon fusion of refractive cells to HepG2 cells, all heterokaryonic cells supported receptor-mediated infection with HBV. hNTCP was provided by the mouse cells and replication competence came from the HepG2 cell line. Transfection of a covalently closed circular DNA (cccDNA)-like molecule into non-susceptible cells promoted gene expression, indicating that the limiting step is upstream of cccDNA formation. CONCLUSIONS: In addition to the expression of hNTCP, establishment of HBV infection in mouse and non-hepatocytic human cell lines requires supplementation with a dependency factor and is not limited by a restriction factor. This result opens new avenues for the development of a fully permissive immunocompetent HBV mouse model. PMID- 26576482 TI - The association between sarcopenia and non-alcoholic fatty liver disease: Potential pitfalls in non-invasive prediction models. PMID- 26576483 TI - Enhanced expression of c-myc in hepatocytes promotes initiation and progression of alcoholic liver disease. AB - BACKGROUND & AIMS: Progression of alcoholic liver disease (ALD) can be influenced by genetic factors, which potentially include specific oncogenes and tumor suppressors. In the present study, we tested the hypothesis that aberrant expression of the proto-oncogene c-myc might exert a crucial role in the development of ALD. METHODS: Expression of c-myc was measured in biopsies of patients with ALD by quantitative real-time PCR and immunohistochemistry. Mice with transgenic expression of c-myc in hepatocytes (alb-myc(tg)) and wild-type (WT) controls were fed either control or ethanol (EtOH) containing Lieber-DeCarli diet for 4weeks to induce ALD. RESULTS: Hepatic c-myc was strongly upregulated in human patients with advanced ALD and in EtOH-fed WT mice. Transcriptome analysis indicated deregulation of pathways involved in ER-stress, p53 signaling, hepatic fibrosis, cell cycle regulation, ribosomal synthesis and glucose homeostasis in EtOH-fed alb-myc(tg) mice. Transgenic expression of c-myc in hepatocytes with simultaneous EtOH-uptake led to early ballooning degeneration, increased liver collagen deposition and hepatic lipotoxicity, together with excessive CYP2E1 derived reactive oxygen species (ROS) production. Moreover, EtOH-fed alb-myc(tg) mice exhibited substantial changes in mitochondrial morphology associated with energy dysfunction. Pathway analysis revealed that elevated c-myc expression and ethanol uptake synergistically lead to strong AKT activation, Mdm2 phosphorylation and as a consequence to inhibition of p53. CONCLUSIONS: Expression of c-myc and EtOH-uptake synergistically accelerate the progression of ALD most likely due to loss of p53-dependent protection. Thus, c-myc is a new potential marker for the early detection of ALD and identification of risk patients. PMID- 26576484 TI - Reply to "The association between sarcopenia and non-alcoholic fatty liver disease: Potential pitfalls in non-invasive prediction models". PMID- 26576486 TI - Leaching and persistence of ametryn and atrazine in red-yellow latosol. AB - This study evaluated the mobility and persistence of atrazine and ametryn in red yellow latosols using polyvinyl chloride columns with a diameter of 100 mm and a height of 15 cm. The assays simulated 60-mm rainfall events at 10-day intervals for 70 days. The persistence and leaching were evaluated for these two herbicides. The analytes obtained from the samples were quantified by gas chromatography using flame ionization detection. Compared with ametryn, atrazine showed a greater potential to reach depths below 15 cm over 30 days of simulated rain. Ametryn, however, showed greater persistence in soil at 70 days after application. The persistence of atrazine and ametryn in soil under sunlight was 10 and 144 days respectively. Atrazine was more susceptible to sunlight than ametryn because sunlight favored atrazine degradation in hydroxyatrazine. The results indicate that in red-yellow latosol, atrazine has a high leaching potential in short term, but that ametryn is more persistent and has a high leaching potential in long term. PMID- 26576485 TI - Neuronal expression of pathological tau accelerates oligodendrocyte progenitor cell differentiation. AB - Oligodendrocyte progenitor cell (OPC) differentiation is an important therapeutic target to promote remyelination in multiple sclerosis (MS). We previously reported hyperphosphorylated and aggregated microtubule-associated protein tau in MS lesions, suggesting its involvement in axonal degeneration. However, the influence of pathological tau-induced axonal damage on the potential for remyelination is unknown. Therefore, we investigated OPC differentiation in human P301S tau (P301S-htau) transgenic mice, both in vitro and in vivo following focal demyelination. In 2-month-old P301S-htau mice, which show hyperphosphorylated tau in neurons, we found atrophic axons in the spinal cord in the absence of prominent axonal degeneration. These signs of early axonal damage were associated with microgliosis and an upregulation of IL-1beta and TNFalpha. Following in vivo focal white matter demyelination we found that OPCs differentiated more efficiently in P301S-htau mice than wild type (Wt) mice. We also found an increased level of myelin basic protein within the lesions, which however did not translate into increased remyelination due to higher susceptibility of P301S-htau axons to demyelination-induced degeneration compared to Wt axons. In vitro experiments confirmed higher differentiation capacity of OPCs from P301S-htau mice compared with Wt mice-derived OPCs. Because the OPCs from P301S-htau mice do not ectopically express the transgene, and when isolated from newborn mice behave like Wt mice-derived OPCs, we infer that their enhanced differentiation capacity must have been acquired through microenvironmental priming. Our data suggest the intriguing concept that damaged axons may signal to OPCs and promote their differentiation in the attempt at rescue by remyelination. PMID- 26576487 TI - Severe acute maternal morbidity in multiple pregnancies: a nationwide cohort study. AB - BACKGROUND: Adverse neonatal outcomes in multiple pregnancies have been documented extensively, in particular those associated with the increased risk of preterm birth. Paradoxically, much less is known about adverse maternal events. The combined risk of severe acute maternal morbidity in multiple pregnancies has not been documented previously in any nationwide prospective study. OBJECTIVE: The objective of the study was to assess the risk of severe acute maternal morbidity in multiple pregnancies in a high-income European country and identify possible risk indicators. STUDY DESIGN: In a population-based cohort study including all 98 hospitals with a maternity unit in The Netherlands, pregnant women with severe acute maternal morbidity were included in the period Aug. 1, 2004, until Aug. 1, 2006. We calculated the incidence of severe acute maternal morbidity in multiple pregnancies in The Netherlands using The Netherlands Perinatal Registry. Relative risks (RR) of severe acute maternal morbidity in multiple pregnancies compared with singletons were calculated. To identify possible risk indicators, we also compared age, parity, method of conception, onset of labor, and mode of delivery for multiple pregnancies using The Netherlands Perinatal Registry as reference. RESULTS: A total of 2552 cases of severe acute maternal morbidity were reported during the 2 year study period. Among 202 multiple pregnancies (8.0%), there were 197 twins (7.8%) and 5 triplets (0.2%). The overall incidence of severe acute maternal morbidity was 7.0 per 1000 deliveries and 6.5 and 28.0 per 1000 for singletons and multiple pregnancies, respectively. The relative risk of severe acute maternal morbidity compared with singleton pregnancies was 4.3 (95% confidence interval [CI], 3.7-5.0) and increased to 6.2 (95% CI 2.5-15.3) in triplet pregnancies. Risk indicators for developing severe acute maternal morbidity in women with multiple pregnancies were age of >= 40 years, (RR, 2.5 95% CI, 1.4-4.3), nulliparity (RR, 1.8, 95% CI, 1.4-2.4), use of assisted reproductive techniques (RR, 1.9, 95% CI, 1.4-2.5), and nonspontaneous onset of delivery (RR, 1.6, 95% CI, 1.2-2.1). No significant difference was found between mono- and dichorionic twins (RR, 0.8, 95% CI, 0.6 1.2). CONCLUSION: Women with multiple pregnancies in The Netherlands have a more than 4 times elevated risk of sustaining severe acute maternal morbidity as compared with singletons. PMID- 26576488 TI - The relationship of circulating proteins in early pregnancy with preterm birth. AB - BACKGROUND: Preterm birth (PTB) (< 37 completed weeks' gestation) is a pathological outcome of pregnancy and a major global health problem. Babies born preterm have an elevated risk for long-term adverse medical and neurodevelopmental sequelae. Substantial evidence implicates intrauterine infection and/or inflammation in PTB. However, these are often relatively late findings in the process, when PTB is inevitable. Identification of earlier markers of PTB may make successful intervention possible. Although select proteins, notably those related to the inflammatory pathways, have been associated with PTB, there has been a lack of research into the role of other protein pathways in the development of PTB. The purpose of this study was to investigate, using a previously described biomarker discovery approach, a subset of circulating proteins and their association with PTB focusing on samples from early pregnancy. OBJECTIVES: The objectives of the study were as follows: (1) to perform a large-scale biomarker discovery, utilizing an innovative platform to identify proteins associated with preterm birth in plasma taken between 10 and 15 weeks' gestation and, (2) to determine which protein pathways are most strongly associated with preterm birth. To address these aims, we measured 1129 proteins in a plasma sample from early pregnancy using a multiplexed aptamer-based proteomic technology developed in Colorado by SomaLogic. STUDY DESIGN: Using a nested case-control approach, we measured proteins at a single time point in early pregnancy in 41 women who subsequently delivered preterm and 88 women who had term uncomplicated deliveries. We measured 1129 proteins using a multiplexed aptamer-based proteomic technology developed by SomaLogic. Logistic regressions and random forests were used to compare protein levels. RESULTS: The complement factors B and H and the coagulation factors IX and IX ab were the highest-ranking proteins distinguishing cases of preterm birth from term controls. The top 3 pathways associated with preterm birth were the complement cascade, the immune system, and the clotting cascade. CONCLUSION: Using a discovery approach, these data provide further confirmation that there is an association of immune- and coagulation-related events in early pregnancy with preterm birth. Thus, plasma protein profiles at 10-15 weeks of gestation are related to the development of preterm birth later in pregnancy. PMID- 26576489 TI - A genome-scale metabolic network reconstruction of tomato (Solanum lycopersicum L.) and its application to photorespiratory metabolism. AB - Tomato (Solanum lycopersicum L.) has been studied extensively due to its high economic value in the market, and high content in health-promoting antioxidant compounds. Tomato is also considered as an excellent model organism for studying the development and metabolism of fleshy fruits. However, the growth, yield and fruit quality of tomatoes can be affected by drought stress, a common abiotic stress for tomato. To investigate the potential metabolic response of tomato plants to drought, we reconstructed iHY3410, a genome-scale metabolic model of tomato leaf, and used this metabolic network to simulate tomato leaf metabolism. The resulting model includes 3410 genes and 2143 biochemical and transport reactions distributed across five intracellular organelles including cytosol, plastid, mitochondrion, peroxisome and vacuole. The model successfully described the known metabolic behaviour of tomato leaf under heterotrophic and phototrophic conditions. The in silico investigation of the metabolic characteristics for photorespiration and other relevant metabolic processes under drought stress suggested that: (i) the flux distributions through the mevalonate (MVA) pathway under drought were distinct from that under normal conditions; and (ii) the changes in fluxes through core metabolic pathways with varying flux ratio of RubisCO carboxylase to oxygenase may contribute to the adaptive stress response of plants. In addition, we improved on previous studies of reaction essentiality analysis for leaf metabolism by including potential alternative routes for compensating reaction knockouts. Altogether, the genome-scale model provides a sound framework for investigating tomato metabolism and gives valuable insights into the functional consequences of abiotic stresses. PMID- 26576491 TI - The transcriptional landscape of dorsal root ganglia after sciatic nerve transection. AB - Following peripheral nerve injury, transcriptional responses are orchestrated to regulate the expression of numerous genes in the lesioned nerve, thus activating the intrinsic regeneration program. To better understand the molecular regulation of peripheral nerve regeneration, we aimed at investigating the transcriptional landscape of dorsal root ganglia (DRGs) after sciatic nerve transection in rats. The cDNA microarray analysis was used to identify thousands of genes that were differentially expressed at different time points post nerve injury (PNI). The results from Euclidean distance matrix, principal component analysis, and hierarchical clustering indicated that 2 nodal transitions in temporal gene expressions could segregate 3 distinct transcriptional phases within the period of 14 d PNI. The 3 phases were designated as "a stress response phase", "a pre regeneration phase", and "a regeneration phase", respectively, by referring to morphological observation of post-nerve-injury changes. The gene ontology (GO) analysis revealed the distinct features of biological process, cellular component, and molecular function at each transcriptional phase. Moreover, Ingenuity Pathway Analysis suggested that differentially expressed genes, mainly transcription factors and genes associated with neurite/axon growth, might be integrated into regulatory networks to mediate the regulation of peripheral nerve regeneration in a highly cooperative manner. PMID- 26576492 TI - How regulation based on a common stomach leads to economic optimization of honeybee foraging. AB - Simple regulatory mechanisms based on the idea of the saturable 'common stomach' can control the regulation of protein foraging and protein allocation in honeybee colonies and colony-level responses to environmental changes. To study the economic benefits of pollen and nectar foraging strategies of honeybees to both plants and honeybees under different environmental conditions, a model was developed and analyzed. Reallocation of the foraging workforce according to the quality and availability of resources (an 'adaptive' strategy used by honeybees) is not only a successful strategy for the bees but also for plants, because intensified pollen foraging after rain periods (when nectar quality is low) compensates a major fraction of the pollination flights lost during the rain. The 'adaptive' strategy performed better than the'fixed' (steady, minimalistic, and non-adaptive foraging without feedback) or the 'proactive' (stockpiling in anticipation of rain) strategies in brood survival and or in nectar/sugar economics. The time pattern of rain periods has profound effect on the supply-and demand of proteins. A tropical rain pattern leads to a shortage of the influx of pollen and nectar, but it has a less profound impact on brood mortality than a typical continental rainfall pattern. Allocating more bees for pollen foraging has a detrimental effect on the nectar stores, therefore while saving larvae from starvation the 'proactive' strategy could fail to collect enough nectar for surviving winter. PMID- 26576490 TI - Identification of key amino acid residues responsible for internal and external pH sensitivity of Orai1/STIM1 channels. AB - Changes of intracellular and extracellular pH are involved in a variety of physiological and pathological processes, in which regulation of the Ca(2+) release activated Ca(2+) channel (I CRAC) by pH has been implicated. Ca(2+) entry mediated by I CRAC has been shown to be regulated by acidic or alkaline pH. Whereas several amino acid residues have been shown to contribute to extracellular pH (pHo) sensitivity, the molecular mechanism for intracellular pH (pHi) sensitivity of Orai1/STIM1 is not fully understood. By investigating a series of mutations, we find that the previously identified residue E106 is responsible for pHo sensitivity when Ca(2+) is the charge carrier. Unexpectedly, we identify that the residue E190 is responsible for pHo sensitivity when Na(+) is the charge carrier. Furthermore, the intracellular mutant H155F markedly diminishes the response to acidic and alkaline pHi, suggesting that H155 is responsible for pHi sensitivity of Orai1/STIM1. Our results indicate that, whereas H155 is the intracellular pH sensor of Orai1/STIM1, the molecular mechanism of external pH sensitivity varies depending on the permeant cations. As changes of pH are involved in various physiological/pathological functions, Orai/STIM channels may be an important mediator for various physiological and pathological processes associated with acidosis and alkalinization. PMID- 26576493 TI - Tools of gene transfer applied to the intracellular delivery of non-nucleic acid polyanionic drugs. AB - We report the first successful implementation of transfection agents to facilitate the delivery of non-nucleic acid based anti-inflammatory and anti viral drugs. In doing so, we illustrate a new paradigm in the intracellular delivery of polyanionic drugs and also extend the scope and utility of successful tools of gene transfer into a new area of biomedical research. PMID- 26576494 TI - Gaining power and precision by using model-based weights in the analysis of late stage cancer trials with substantial treatment switching. AB - In randomised controlled trials of treatments for late-stage cancer, it is common for control arm patients to receive the experimental treatment around the point of disease progression. This treatment switching can dilute the estimated treatment effect on overall survival and impact the assessment of a treatment's benefit on health economic evaluations. The rank-preserving structural failure time model of Robins and Tsiatis (Comm. Stat., 20:2609-2631) offers a potential solution to this problem and is typically implemented using the logrank test. However, in the presence of substantial switching, this test can have low power because the hazard ratio is not constant over time. Schoenfeld (Biometrika, 68:316-319) showed that when the hazard ratio is not constant, weighted versions of the logrank test become optimal. We present a weighted logrank test statistic for the late stage cancer trial context given the treatment switching pattern and working assumptions about the underlying hazard function in the population. Simulations suggest that the weighted approach can lead to large efficiency gains in either an intention-to-treat or a causal rank-preserving structural failure time model analysis compared with the unweighted approach. Furthermore, violation of the working assumptions used in the derivation of the weights only affects the efficiency of the estimates and does not induce bias or inflate the type I error rate. The weighted logrank test statistic should therefore be considered for use as part of a careful secondary, exploratory analysis of trial data affected by substantial treatment switching. PMID- 26576495 TI - Impact of cataracts and cataract surgery on quality of vision. PMID- 26576496 TI - Post-analysis methods for lactate threshold depend on training intensity and aerobic capacity in runners. An experimental laboratory study. AB - CONTEXT AND OBJECTIVE: This study aimed to evaluate different mathematical post analysis methods of determining lactate threshold in highly and lowly trained endurance runners. DESIGN AND SETTING: Experimental laboratory study, in a tertiary-level public university hospital. METHOD: Twenty-seven male endurance runners were divided into two training load groups: lowly trained (frequency < 4 times per week, < 6 consecutive months, training velocity >= 5.0 min/km) and highly trained (frequency >= 4 times per week, >= 6 consecutive months, training velocity < 5.0 min/km). The subjects performed an incremental treadmill protocol, with 1 km/h increases at each subsequent 4-minute stage. -Fingerprint -blood lactate analysis was performed at the end of each stage. The lactate threshold (i.e. the running velocity at which blood lactate levels began to exponentially increase) was measured using three different methods: increase in blood lactate of 1 mmol/l at stages (DT1), absolute 4 mmol/l blood lactate concentration (4 mmol), and the semi-log method (semi-log). ANOVA was used to compare different lactate threshold methods and training groups. RESULTS: Highly trained athletes showed significantly greater lactate thresholds than lowly trained runners, regardless of the calculation method used. When all the subject data were combined, DT1 and semi-log were not different, while 4 mmol was significantly lower than the other two methods. These same trends were observed when comparing lactate threshold methods in the lowly trained group. However, 4 mmol was only significantly lower than DT1 in the highly trained group. CONCLUSION: The 4 mmol protocol did not show lactate threshold measurements comparable with DT1 and semi log protocols among lowly trained athletes. PMID- 26576497 TI - Post-thoracotomy pain relief with subpleural analgesia or thoracic epidural analgesia: randomized clinical trial. AB - CONTEXT AND OBJECTIVE: Post-thoracotomy pain is a severe and intense pain caused by trauma to ribs, muscles and peripheral nerves. The current study aimed to compare subpleural analgesia (SPA) with thoracic epidural analgesia (TEA) in patients undergoing thoracotomy. DESIGN AND SETTING: Randomized study at Ankara Numune Education and Research Hospital, in Turkey. METHODS: Thirty patients presenting American Society of Anesthesiologists physical status I-III were scheduled for elective diagnostic thoracotomy. The patients were randomized to receive either patient-controlled SPA or patient-controlled TEA for post thoracotomy pain control over a 24-hour period. The two groups received a mixture of 3 ug/ml fentanyl along with 0.05% bupivacaine solution through a patient controlled analgesia pump. Rescue analgesia was administered intravenously, consisting of 100 mg tramadol in both groups. A visual analogue scale was used to assess pain at rest and during coughing over the course of 24 hours postoperatively. RESULTS: In the SPA group, all the patients required rescue analgesia, and five patients (33%) required rescue analgesia in the TEA group (P < 0.05). Patients who received subpleural analgesia exhibited higher visual analogue scores at rest and on coughing than patients who received thoracic epidural analgesia. None of the patients had any side-effects postoperatively, such as hypotension or respiratory depression. CONCLUSION: Thoracic epidural analgesia is superior to subpleural analgesia for relieving post-thoracotomy pain. We suggest that studies on effective drug dosages for providing subpleural analgesia are necessary. PMID- 26576498 TI - Detecting spatial genetic signatures of local adaptation in heterogeneous landscapes. AB - The spatial structure of the environment (e.g. the configuration of habitat patches) may play an important role in determining the strength of local adaptation. However, previous studies of habitat heterogeneity and local adaptation have largely been limited to simple landscapes, which poorly represent the multiscale habitat structure common in nature. Here, we use simulations to pursue two goals: (i) we explore how landscape heterogeneity, dispersal ability and selection affect the strength of local adaptation, and (ii) we evaluate the performance of several genotype-environment association (GEA) methods for detecting loci involved in local adaptation. We found that the strength of local adaptation increased in spatially aggregated selection regimes, but remained strong in patchy landscapes when selection was moderate to strong. Weak selection resulted in weak local adaptation that was relatively unaffected by landscape heterogeneity. In general, the power of detection methods closely reflected levels of local adaptation. False-positive rates (FPRs), however, showed distinct differences across GEA methods based on levels of population structure. The univariate GEA approach had high FPRs (up to 55%) under limited dispersal scenarios, due to strong isolation by distance. By contrast, multivariate, ordination-based methods had uniformly low FPRs (0-2%), suggesting these approaches can effectively control for population structure. Specifically, constrained ordinations had the best balance of high detection and low FPRs and will be a useful addition to the GEA toolkit. Our results provide both theoretical and practical insights into the conditions that shape local adaptation and how these conditions impact our ability to detect selection. PMID- 26576499 TI - Interventions for enhancing adherence to treatment in adults with bronchiectasis. AB - BACKGROUND: Bronchiectasis is characterised by a widening of the airways, leading to excess mucus production and recurrent infection. It is more prevalent in women and those in middle age. Many patients with bronchiectasis do not adhere to treatments (medications, exercise and airway clearance) prescribed for their condition. The best methods to change these adherence behaviours have not been identified. OBJECTIVES: To assess the effects of interventions to enhance adherence to any aspect of treatment in adults with bronchiectasis in terms of adherence and health outcomes, such as pulmonary exacerbations, health-related quality of life and healthcare costs. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register (CAGR), which contains trial reports identified through systematic searches of CENTRAL, MEDLINE, EMBASE, CINAHL, AMED and PsycINFO, from inception to October 2015. SELECTION CRITERIA: We planned to include randomised controlled trials (RCTs) of adults with bronchiectasis that compared any intervention aimed at enhancing adherence versus no intervention, usual care or another adherence intervention. We excluded studies of those who had bronchiectasis due to cystic fibrosis. DATA COLLECTION AND ANALYSIS: Two review authors (AMcC and ET) independently screened titles, abstracts and full texts of identified studies. MAIN RESULTS: Searches retrieved 36 studies reported in 37 articles; no eligible studies were identified. AUTHORS' CONCLUSIONS: We did not identify any studies that assessed the effect of interventions to enhance adherence to treatment in bronchiectasis. Adequately powered, well-designed trials of adherence interventions for bronchiectasis are needed. PMID- 26576500 TI - One-step production of multiple emulsions: microfluidic, polymer-stabilized and particle-stabilized approaches. AB - Multiple emulsions have great potential for application in food science as a means to reduce fat content or for controlled encapsulation and release of actives. However, neither production nor stability is straightforward. Typically, multiple emulsions are prepared via two emulsification steps and a variety of approaches have been deployed to give long-term stability. It is well known that multiple emulsions can be prepared in a single step by harnessing emulsion inversion, although the resulting emulsions are usually short lived. Recently, several contrasting methods have been demonstrated which give rise to stable multiple emulsions via one-step production processes. Here we review the current state of microfluidic, polymer-stabilized and particle-stabilized approaches; these rely on phase separation, the role of electrolyte and the trapping of solvent with particles respectively. PMID- 26576501 TI - Pentraxin-3 is upregulated in the central nervous system during MS and EAE, but does not modulate experimental neurological disease. AB - Pentraxin-3 (PTX3), an acute-phase protein released during inflammation, aids phagocytic clearance of pathogens and apoptotic cells, and plays diverse immunoregulatory roles in tissue injury. In neuroinflammatory diseases, like MS, resident microglia could become activated by endogenous agonists for Toll like receptors (TLRs). Previously we showed a strong TLR2-mediated induction of PTX3 in cultured human microglia and macrophages by HspB5, which accumulates in glia during MS. Given the anti-inflammatory effects of HspB5, we examined the contribution of PTX3 to these effects in MS and its animal model EAE. Our data indicate that TLR engagement effectively induces PTX3 expression in human microglia, and that such expression is readily detectable in MS lesions. Enhanced PTX3 expression is prominently expressed in microglia in preactive MS lesions, and in microglia/macrophages engaged in myelin phagocytosis in actively demyelinating lesions. Yet, we did not detect PTX3 in cerebrospinal fluid of MS patients. PTX3 expression is also elevated in spinal cords during chronic relapsing EAE in Biozzi ABH mice, but the EAE severity and time course in PTX3 deficient mice did not differ from WT mice. Moreover, systemic PTX3 administration did not alter the disease onset or severity. Our findings reveal local functions of PTX3 during neuroinflammation in facilitating myelin phagocytosis, but do not point to a role for PTX3 in controlling the development of autoimmune neuroinflammation. PMID- 26576502 TI - 1,3-beta-D-glucan concentrations in blood products predict false positive post transfusion results. AB - 1,3-beta-D-glucan (BDG) is increasingly used to diagnose invasive fungal infections (IFI), although false positive results are a concern. To evaluate the potential interaction of blood products with the BDG assay, human albumin (HA), fresh frozen plasma (FFP), undiluted platelet transfusion (UPT) and packed red blood cells (PRBC) were tested for their BDG content using two different b-D glucan tests. UPTs tested negative, FFP, PBRC and HA tested positive for BDG. In serial dilution, BDG concentration correlated with blood product concentration. To investigate the clinical impact of blood product transfusions, we measured BDG levels before and after the transfusion in three patients (2 PRBC, 1 HA). In the patients receiving PRBC transfusions, BDG values increased from 13 and 17 pg ml( 1) to 183 and 361 pg ml(-1), the HA transfusion increased the serum level from 42 to 58 pg ml(-1). BDG concentrations measured in blood products can be used to predict false positive BDG results. PMID- 26576503 TI - End-exercise DeltaHHb/DeltaVO2 and post-exercise local oxygen availability in relation to exercise intensity. AB - Increased local blood supply is thought to be one of the mechanisms underlying oxidative adaptations to interval training regimes. The relationship of exercise intensity with local blood supply and oxygen availability has not been sufficiently evaluated yet. The aim of this study was to examine the effect of six different intensities (40-90% peak oxygen uptake, VO2peak ) on relative changes in oxygenated, deoxygenated and total haemoglobin (DeltaO2 Hb, DeltaHHb, DeltaTHb) concentration after exercise as well as end-exercise DeltaHHb/DeltaVO2 as a marker for microvascular O2 distribution. Seventeen male subjects performed an experimental protocol consisting of 3 min cycling bouts at each exercise intensity in randomized order, separated by 5 min rests. DeltaO2 Hb and DeltaHHb were monitored with near-infrared spectroscopy of the vastus lateralis muscle, and VO2 was assessed. DeltaHHb/DeltaVO2 increased significantly from 40% to 60% VO2 peak and decreased from 60% to 90% VO2 peak. Post-exercise DeltaTHb and DeltaO2 Hb showed an overshoot in relation to pre-exercise values, which was equal after 40-60% VO2peak and rose significantly thereafter. A plateau was reached following exercise at >=80% VO2peak . The results suggest that there is an increasing mismatch of local O2 delivery and utilization during exercise up to 60% VO2peak . This insufficient local O2 distribution is progressively improved above that intensity. Further, exercise intensities of >=80% VO2peak induce highest local post-exercise O2 availability. These effects are likely due to improved microvascular perfusion by enhanced vasodilation, which could be mediated by higher lactate production and the accompanying acidosis. PMID- 26576505 TI - Adolescent Nonmedical Use of Prescription Pain Relievers, Stimulants, and Depressants, and Suicide Risk. AB - BACKGROUND: Although the link between drug abuse and suicide risk is established, few studies have examined the relationship between the nonmedical use of prescription drugs (NMUPD) and suicide risk, particularly among adolescents. OBJECTIVES: To explore the relationship between NMUPD and suicide risk among 4,148 adolescents in grades 9-12 enrolled in five public high schools. METHODS: Logistic regression models were constructed for the nonmedical use of prescription pain relievers, depressants, stimulants, and a composite measure for any NMUPD. Models were estimated before and after controlling for key covariates. RESULTS: About 21% of respondents reported lifetime NMUPD. After covariate adjustment, students who had reported any NMUPD were between 1.7 and 2.3 times more likely to report suicidal ideation, but not a suicide attempt (p < .0001). When stratified by sex and drug, nonmedical use of pain relievers, stimulants, and depressants were significantly associated with greater odds of suicidal ideation and behavior for both males and females (p < .05). However, NMUPD of pain relievers were not associated with greater odds of suicide attempts for males or females or among males who reported nonmedical use of stimulants. Nonmedical use of depressants was associated with greater odds of suicide attempts for both males and females (OR = 1.61 and 2.25, respectively) and among females who reported nonmedical use of stimulants (OR = 2.06, p < .01). CONCLUSIONS/IMPORTANCE: Results suggest that some adolescents may be inappropriately self-medicating psychological distress with prescription medications or NMUPD may promote suicide risk, especially for males and females who use depressants and females who use stimulants. PMID- 26576504 TI - Mechanisms of three-dimensional growth of thyroid cells during long-term simulated microgravity. AB - Three-dimensional multicellular spheroids (MCS) of human cells are important in cancer research. We investigated possible mechanisms of MCS formation of thyroid cells. Both, normal Nthy-ori 3-1 thyroid cells and the poorly differentiated follicular thyroid cancer cells FTC-133 formed MCS within 7 and 14 days of culturing on a Random Positioning Machine (RPM), while a part of the cells continued to grow adherently in each culture. The FTC-133 cancer cells formed larger and numerous MCS than the normal cells. In order to explain the different behaviour, we analyzed the gene expression of IL6, IL7, IL8, IL17, OPN, NGAL, VEGFA and enzymes associated cytoskeletal or membrane proteins (ACTB, TUBB, PFN1, CPNE1, TGM2, CD44, FLT1, FLK1, PKB, PKC, ERK1/2, Casp9, Col1A1) as well as the amount of secreted proteins (IL-6, IL-7, IL-8, IL-17, OPN, NGAL, VEGFA). Several of these components changed during RPM-exposure in each cell line. Striking differences between normal and malignant cells were observed in regards to the expression of genes of NGAL, VEGFA, OPN, IL6 and IL17 and to the secretion of VEGFA, IL-17, and IL-6. These results suggest several gravi-sensitive growth or angiogenesis factors being involved in 3D formation of thyroid cells cultured under simulated microgravity. PMID- 26576506 TI - A highly efficient hybrid method for calculating the hydration free energy of a protein. AB - We develop a new method for calculating the hydration free energy (HFE) of a protein with any net charge. The polar part of the energetic component in the HFE is expressed as a linear combination of four geometric measures (GMs) of the protein structure and the generalized Born (GB) energy plus a constant. The other constituents in the HFE are expressed as linear combinations of the four GMs. The coefficients (including the constant) in the linear combinations are determined using the three-dimensional reference interaction site model (3D-RISM) theory applied to sufficiently many protein structures. Once the coefficients are determined, the HFE and its constituents of any other protein structure are obtained simply by calculating the four GMs and GB energy. Our method and the 3D RISM theory give perfectly correlated results. Nevertheless, the computation time required in our method is over four orders of magnitude shorter. PMID- 26576507 TI - Structural insights into HetR-PatS interaction involved in cyanobacterial pattern formation. AB - The one-dimensional pattern of heterocyst in the model cyanobacterium Anabaena sp. PCC 7120 is coordinated by the transcription factor HetR and PatS peptide. Here we report the complex structures of HetR binding to DNA, and its hood domain (HetRHood) binding to a PatS-derived hexapeptide (PatS6) at 2.80 and 2.10 A, respectively. The intertwined HetR dimer possesses a couple of novel HTH motifs, each of which consists of two canonical alpha-helices in the DNA-binding domain and an auxiliary alpha-helix from the flap domain of the neighboring subunit. Two PatS6 peptides bind to the lateral clefts of HetRHood, and trigger significant conformational changes of the flap domain, resulting in dissociation of the auxiliary alpha-helix and eventually release of HetR from the DNA major grove. These findings provide the structural insights into a prokaryotic example of Turing model. PMID- 26576508 TI - Circulating microbial RNA and health. AB - Measurement of health indicators in the blood is a commonly performed diagnostic procedure. Two blood studies one involving extended observations on the health of an individual by integrative Personal Omics Profiling (iPOP), and the other tracking the impact of Left Ventricular Assist Device (LVAD) placement on nine heart failure patients were examined for the association of change in health status with change in microbial RNA species. Decrease in RNA expression ratios of human to bacteria and viruses accompanying deteriorated conditions was evident in both studies. Despite large between-subject variations in bacterial composition before LVAD implantation among all the patients, on day 180 after the implantation they manifested apparent between-subject bacterial similarity. In the iPOP study three periods, namely, pre-respiratory syncytial virus (RSV) infection with normal blood glucose level, RSV infection with normal blood glucose level, and post-RSV infection with high blood glucose level could be defined. The upsurge of Enterobacteria phage PhiX 174 sensu lato and Escherichia coli gene expression, in which membrane transporters, membrane receptors for environment signalling, carbohydrate catabolic genes and carbohydrate-active enzymes were enriched only throughout the second period, which suggests a potentially overlooked microbial response to or modulation of the host blood glucose level. PMID- 26576509 TI - Metabolic, synaptic and behavioral impact of 5-week chronic deep brain stimulation in hemiparkinsonian rats. AB - The long-term effects and action mechanisms of subthalamic nucleus (STN) high frequency stimulation (HFS) for Parkinson's disease still remain poorly characterized, mainly due to the lack of experimental models relevant to clinical application. To address this issue, we performed a multilevel study in freely moving hemiparkinsonian rats undergoing 5-week chronic STN HFS, using a portable constant-current microstimulator. In vivo metabolic neuroimaging by (1) H magnetic resonance spectroscopy (11.7 T) showed that STN HFS normalized the tissue levels of the neurotransmission-related metabolites glutamate, glutamine and GABA in both the striatum and substantia nigra reticulata (SNr), which were significantly increased in hemiparkinsonian rats, but further decreased nigral GABA levels below control values; taurine levels, which were not affected in hemiparkinsonian rats, were significantly reduced. Slice electrophysiological recordings revealed that STN HFS was, uniquely among antiparkinsonian treatments, able to restore both forms of corticostriatal synaptic plasticity, i.e. long-term depression and potentiation, which were impaired in hemiparkinsonian rats. Behavior analysis (staircase test) showed a progressive recovery of motor skill during the stimulation period. Altogether, these data show that chronic STN HFS efficiently counteracts metabolic and synaptic defects due to dopaminergic lesion in both the striatum and SNr. Comparison of chronic STN HFS with acute and subchronic treatment further suggests that the long-term benefits of this treatment rely both on the maintenance of acute effects and on delayed actions on the basal ganglia network. We studied the effects of chronic (5 weeks) continuous subthalamic nucleus (STN) high-frequency stimulation (HFS) in hemiparkinsonian rats. The levels of glutamate and GABA in the striatum () and substantia nigra reticulata (SNr) (), measured by in vivo proton magnetic resonance spectroscopy ((1) H-MRS), were increased by 6-hydroxydopamine (6-OHDA) lesion, which also disrupted corticostriatal synaptic plasticity () and impaired forepaw skill () in the staircase test. Five-week STN HFS normalized glutamate and GABA levels and restored both synaptic plasticity and motor function. A partial behavioral recovery was observed at 2-week STN HFS. PMID- 26576510 TI - MicroRNAs: exploring new horizons in osteoarthritis. AB - INTRODUCTION: Osteoarthritis (OA) is a common disease worldwide leading to significant morbidity. The underlying disease process is multifactorial however there is increasing focus on molecular mechanisms. MicroRNAs are small non-coding segments of RNA that have important regulatory functions at a cellular level. These molecules are readily detectable in human tissues and circulation. They are increasingly recognised as having a major role in many disease processes - including malignancy and inflammatory processes. OBJECTIVE: This review paper aims to provide a comprehensive update on the evidence for miRNA roles in OA. DESIGN: A comprehensive literature search was performed using key medical subject headings (MeSH) terms 'microRNA' and 'osteoarthritis'. RESULTS: Several miRNAs have been identified as having aberrant expression levels in OA. Some of these include miR-9, miR-27, miR-34a, miR-140, miR-146a, miR-558 and miR-602. Many of the dysregulated miRNAs have been shown to regulate expression of inflammatory pathways such as interleukin-mediated or matrix metalloproteinase-13 (MMP-13) mediated degradation of the articular cartilage extracellular matrix (ECM). MiRNAs may also play a role in pain pathways and hence expression of clinical symptoms. CONCLUSIONS: Recent evidence has shown that miRNAs in the circulation may reflect underlying disease states and hence serve as potential markers for disease activity. These findings may represent possible future therapeutic applications in the management of OA. PMID- 26576511 TI - Screening anaphylactic components of MaiLuoNing injection by using rat basophilic leukemia-2H3 cell membrane chromatography coupled with HPLC-ESI-TOF-MS. AB - MaiLuoNing injection is a traditional Chinese medicine that used clinically since the 1950s in China. However, anaphylactic reactions, through the potentiation of mast cell degranulation, have been reported. In the present study, a rat basophilic leukemia-2H3 cell membrane chromatography coupled with high performance liquid chromatography and electrospray ionization-ion trap-time of flight-mass spectrometry method was established for screening, analyzing, and identifying the potential anaphylactic components of MaiLuoNing injection. Harpagoside, a potential degranulator of rat basophilic leukemia-2H3 cells, was retained in rat basophilic leukemia-2H3 cell membrane chromatography. We aimed to evaluate the retained components to determine which of those were capable of inducing degranulation of basophilic leukemia cells. A beta-hexosaminidase assay revealed that harpagoside can induce rat basophilic leukemia-2H3 cell degranulation in a dose-dependent manner. BLBA/c mice also exhibit passive cutaneous anaphylaxis in response to harpagoside. These results indicate that rat basophilic leukemia-2H3 cell membrane chromatography coupled with high performance liquid chromatography and electrospray ionization ion trap time-of flight mass spectrometry is effective in screening for the anaphylactic components of MaiLuoNing injection. PMID- 26576512 TI - A study of farmers' flood perceptions based on the entropy method: an application from Jianghan Plain, China. AB - Using survey data from 280 farmers in Jianghan Plain, China, this paper establishes an evaluation index system for three dimensions of farmers' flood perceptions and then uses the entropy method to estimate their overall flood perception. Farmers' flood perceptions exhibit the following characteristics: (i) their flood-occurrence, flood-prevention, and overall flood perceptions gradually increase with age, whereas their flood-effects perception gradually decreases; (ii) their flood-occurrence and flood-effects perceptions gradually increase with a higher level of education, whereas their flood-prevention perception gradually decreases and their overall flood perception shows nonlinear change; (iii) flood occurrence, flood-effects, and overall flood perceptions are higher among farmers who serve in public offices than among those who do not do so; (iv) the flood occurrence, flood-effects, and overall flood perceptions of farmers who work off farm are higher than those of farmers who work solely on-farm, contrary to the flood-prevention perception; and (v) the flood-effects and flood-prevention perceptions of male farmers are lower than those of female farmers, but the flood occurrence and overall flood perceptions of male farmers are higher than those of female farmers. PMID- 26576513 TI - Restoring the youth of aged red blood cells and extending their lifespan in circulation by remodelling membrane sialic acid. AB - Membrane sialic acid (SA) plays an important role in the survival of red blood cells (RBCs), the age-related reduction in SA content negatively impacts both the structure and function of these cells. We have therefore suggested that remodelling the SA in the membrane of aged cells would help recover cellular functions characteristic of young RBCs. We developed an effective method for the re-sialylation of aged RBCs by which the cells were incubated with SA in the presence of cytidine triphosphate (CTP) and alpha-2,3-sialytransferase. We found that RBCs could be re-sialylated if they had available SA-binding groups and after the re-sialylation, aged RBCs could restore their membrane SA to the level in young RBCs. Once the membrane SA was restored, the aged RBCs showed recovery of their biophysical and biochemical properties to similar levels as in young RBCs. Their life span in circulation was also extended to twofold. Our findings indicate that remodelling membrane SA not only helps restore the youth of aged RBCs, but also helps recover injured RBCs. PMID- 26576515 TI - Identification of a major Quantitative Trait Locus determining resistance to the organophosphate temephos in the dengue vector mosquito Aedes aegypti. AB - Organophosphate insecticides (OP) have extensively been used to control mosquitoes, such as the vector Aedes aegypti. Unfortunately, OP resistance has hampered control programs worldwide. We used Quantitative Trait Locus (QTL) mapping to evaluate temephos resistance in two F1 intercross populations derived from crosses between a resistant Ae. aegypti strain (RecR) and two susceptible strains (MoyoD and Red). A single major effect QTL was identified on chromosome 2 of both segregating populations, named rtt1 (resistance to temephos 1). Bioinformatics analyses identified a cluster of carboxylesterase genes (CCE) within the rtt1 interval. qRT-PCR demonstrated that different CCEs were up regulated in F2 resistant individuals from both crosses. However, none exceeded the 2-fold expression. Primary mechanisms for temephos resistance may vary between Ae. aegypti populations, yet also appear to support previous findings suggesting that multiple linked esterase genes may contribute to temephos resistance in the RecR strain as well as other populations. PMID- 26576514 TI - Data-Driven Models of Foot-and-Mouth Disease Dynamics: A Review. AB - Foot-and-mouth disease virus (FMDV) threatens animal health and leads to considerable economic losses worldwide. Progress towards minimizing both veterinary and financial impact of the disease will be made with targeted disease control policies. To move towards targeted control, specific targets and detailed control strategies must be defined. One approach for identifying targets is to use mathematical and simulation models quantified with accurate and fine-scale data to design and evaluate alternative control policies. Nevertheless, published models of FMDV vary in modelling techniques and resolution of data incorporated. In order to determine which models and data sources contain enough detail to represent realistic control policy alternatives, we performed a systematic literature review of all FMDV dynamical models that use host data, disease data or both data types. For the purpose of evaluating modelling methodology, we classified models by control strategy represented, resolution of models and data, and location modelled. We found that modelling methodology has been well developed to the point where multiple methods are available to represent detailed and contact-specific transmission and targeted control. However, detailed host and disease data needed to quantify these models are only available from a few outbreaks. To address existing challenges in data collection, novel data sources should be considered and integrated into models of FMDV transmission and control. We suggest modelling multiple endemic areas to advance local control and global control and better understand FMDV transmission dynamics. With incorporation of additional data, models can assist with both the design of targeted control and identification of transmission drivers across geographic boundaries. PMID- 26576516 TI - Incidence, risk factors, and outcomes of opportunistic infections in pediatric renal transplant recipients. AB - OIs present significant risks to patients following solid organ transplantation. The purpose of this study was to identify risk factors for the development of OIs after kidney transplantation in pediatric patients and to evaluate the impact of OIs on outcomes in this patient population. A single-center retrospective longitudinal cohort analysis including pediatric patients 21 yr of age or younger transplanted from July 1999 to June 2013 at an academic medical center was conducted. Patients were excluded if they received multi-organ transplant. A total of 175 patients were included in the study. Patients who developed OIs were more likely to be female and younger at the time of transplant. A six-factor risk model for OI development was developed. Death, disease recurrence, and PTLD development were similar between groups but trended toward increased incidence in the OI group. Incidence of rejection was significantly higher in the OI group (p = 0.04). Patients who developed OIs had several important risk factors, including younger age, EBV-negative serostatus, CMV donor (+)/recipient (-), biopsy-proven acute rejection, ANC <1000, MMF dose >500 mg/m(2), and any infection. Incidence of rejection was higher in the OI group, but rate of graft loss was not statistically different. PMID- 26576517 TI - Pregnancy in a renal transplant recipient with HIV-1 infection: a case report. AB - We report the first case of a pregnancy in a renal transplant recipient with HIV infection. She underwent renal transplantation in 2005 and became pregnant in 2009. The patient underwent vaginal delivery and a healthy full-term, female baby was born. Almost 6 years after delivery, both mother and child were doing well. The management of concurrent renal transplantation, HIV infection and pregnancy was extremely challenging. Women with HIV infection who have undergone renal transplantation should be accurately informed of the potential health risks for them and their offspring. Multidisciplinary teams are mandatory in order to properly manage these patients. PMID- 26576518 TI - Generally speaking! PMID- 26576520 TI - Effect of fluidics on corneal endothelial cell density, central corneal thickness, and central macular thickness after phacoemulsification with torsional ultrasound. AB - AIM: To study the relative effects of high and low fluidic parameters on endothelial cell density (ECD), central corneal thickness (CCT), and central macular thickness (CMT) after phacoemulsification with torsional ultrasound. SETTINGS AND DESIGN: Prospective, randomized clinical trial based on a tertiary eye hospital. SUBJECTS AND METHODS: The study included 65 patients in each group. Patients were randomized to either the high or the low flow group using a computerized random number table. The study was patient and examiner masked. All patients underwent phacoemulsification with torsional ultrasound. Visual acuity, ECD, CCT, and CMT were measured for all patients preoperatively at 2 weeks and 6 weeks postoperatively. STATISTICAL ANALYSIS USED: The Shapiro-Wilks test was used to assess the normality of the data. Mann-Whitney U-test with the P value set at 0.05 was used to compare the two groups. RESULTS: Cumulative dissipated energy was significantly higher in the low flow group (16.44 +/- 9.07 vs. 11.74 +/- 6.68; P = 0.002). No statistically significant difference was noted between the two groups in the ECD, CCT, CMT, or corrected distance visual acuity at the end of 6 weeks. CONCLUSIONS: No significant difference was noted in the postoperative outcome between high and low flow groups. Parameters can be modified to suit the surgeon's preference, as both high and low flow parameters were found to have comparable postoperative outcomes. PMID- 26576521 TI - Sutureless scleral buckle in the management of rhegmatogenous retinal detachment. AB - PURPOSE: To evaluate the anatomical and functional outcomes of sutureless scleral buckling for the repair of rhegmatogenous retinal detachment (RD). DESIGN: Retrospective interventional case series. MATERIALS AND METHODS: Retrospective analysis of 50 eyes of 49 patients with rhegmatogenous RD, who underwent sutureless scleral buckling from January 2009 to March 2013. RESULTS: Primary retinal re-attachment rate of 86% was achieved with single surgery, but final anatomical success was 94% with additional interventions in the form of intravitreal gas, buckle revision, and/or pars plana vitrectomy. Best corrected logarithm of minimum angle of resolution visual acuity improved from 1.44 +/- 1.01 preoperatively to 0.50 +/- 0.40 at a mean follow-up of 6.7 months.XS Conclusion: Sutureless scleral buckling achieves excellent anatomical and functional success in majority of the patients with rhegmatogenous RD. PMID- 26576519 TI - Anterior segment imaging in glaucoma: An updated review. AB - Anterior segment imaging allows for an objective method of visualizing the anterior segment angle. Two of the most commonly used devices for anterior segment imaging include the anterior segment optical coherence tomography (AS OCT) and the ultrasound biomicroscopy (UBM). AS-OCT technology has several types, including time-domain, swept-source, and spectral-domain-based configurations. We performed a literature search on PubMed for articles containing the text "anterior segment OCT," "ultrasound biomicroscopy," and "anterior segment imaging" since 2004, with some pertinent references before 2004 included for completeness. This review compares the advantages and disadvantages of AS-OCT and UBM, and summarizes the most recent literature regarding the importance of these devices in glaucoma diagnosis and management. These devices not only aid in visualization of the angle, but also have important postsurgical applications in bleb and tube imaging. PMID- 26576522 TI - Transscleral fixation of closed loop haptic acrylic posterior chamber intraocular lens in aphakic nonvitrectomized eyes. AB - PURPOSE: To evaluate the outcome of transscleral fixation of closed loop haptic acrylic posterior chamber intraocular lens (PCIOL) in aphakia in nonvitrectomized eyes. MATERIALS AND METHODS: Patients with postcataract surgery aphakia, trauma with posterior capsule injury, subluxated crystalline lens, and per operative complications where sulcus implantation was not possible were included over a 1 year period. Scleral fixation of acrylic hydrophilic PCIOL was performed according to the described technique, and the patients were evaluated on the day 1, 3, 14, and at 3 and 12 months postoperatively for IOL centration, pseudophakodonesis, change in best-corrected visual acuity (BCVA), and any other complications. RESULTS: Out of twenty-nine eyes of 24 patients, who completed the study, 25 (86.2%) eyes had improved, 2 (6.9%) eyes showed no change, and 2 (6.9%) eyes had worsening of BCVA. Three (10.3%) eyes developed postoperative complications. A significant improvement in mean BCVA (P < 0.0001) was observed after the procedure. Mean duration of follow-up was 26.2 months (range 22-35 months). CONCLUSION: The use of closed loop haptic acrylic IOL for scleral fixation appears to be safe and effective alternative to conventional scleral fixated polymethyl methacrylate intraocular lenses. PMID- 26576523 TI - Changing pattern of utilization of human donor cornea in India. AB - PURPOSE: To review the changing pattern of donor, corneal utilization in an eye bank at a Tertiary Care Center in Northern India by analyzing the trend in the years 2003, 2008, and 2011. METHODS: A retrospective review of eye bank records for 3 years (2003, 2008, and 2011) was performed at the National Eye Bank. Details including a clinical grade of donor cornea, indication of corneal transplantation (therapeutic or optical), type of procedure (penetrating or lamellar keratoplasty [LK]), and clinical diagnosis of the graft recipients were recorded. Primary outcome measure was to observe any preference toward LK, judicious usage of donor corneal tissue, and impact of lamellar corneal transplant in the usage of donor corneas. Secondary outcomes included overall utilization rate and change in trend of indication for keratoplasty. RESULTS: A total of 673, 745, and 864 corneas were retrieved in the years 2003, 2008, and 2011, respectively. The percentage of donor corneal utilization increased significantly over time with the rate being 65.08%, 70.06%, and 68.29%, respectively, in the years 2003, 2008, and 2011 (P = 0.014); however, this change was reflected only in the usage of nonoptical grade corneas and not for the optical grade corneas. There was an overall increase in lamellar corneal procedures for any clinical grade of cornea (P = 0.0019); number of Descemet's stripping automated endothelial keratoplasty (DSAEK) procedures increased significantly (P < 0.001), particularly for pseudophakic corneal edema (PCE) (P = 0.0085) and failed graft (P = 0.002). Significant increase in the utilization of nonoptical grade corneas was observed over the years (P = 0.005), though the utilization did not increase significantly for optical purposes viz., LK (P = 0.08). CONCLUSIONS: Utilization rate of donor corneas increased over the years, primarily due to increase in usage of nonoptical grade corneas for therapeutic purposes. There was a procedural shift toward DSAEK for PCE and failed graft. However, an increase in usage of nonoptical grade corneas for LK, a single donor corneal tissue for two recipients, and retrieval or utilization of optical grade cornea was not observed. PMID- 26576524 TI - Ophthalmic manifestations of acute and chronic leukemias presenting to a tertiary care center in India. AB - CONTEXT: Screening for ocular manifestations of leukemia, although not a routine practice, is important as they may antedate systemic disease or form an isolated focus of its relapse. AIMS: This study evaluates the spectrum of ocular manifestations in acute and chronic leukemias presenting to a tertiary care center in India. SETTINGS AND DESIGN: Subjects of leukemia presenting to a tertiary care center in India. SUBJECTS AND METHODS: A prospective, cross sectional study looking at the spectrum of ocular manifestations in all inpatients of acute or chronic leukemia. STATISTICAL ANALYSIS USED: The collected data were analyzed using the Statistical Package for Social Sciences for Windows software, version 16 (SPSS Inc., Chicago, Illinois, USA). RESULTS: The study subjects (n = 96) comprised 61 males and 35 females whose age ranged from 18 months to 91 years (mean = 39.73, +/-22.1). There were 79 adults and 17 children, 53 new and 43 existing patients, 68 acute and 28 chronic, 61 myeloid and 35 lymphoid patients. Ocular lesions were found in 42 patients (43.8%). The ocular manifestations of leukemia were significantly (P = 0.01467) more frequent in acute 35/68 (51.9%) than chronic 7/28 (25%) leukemias. Primary or direct leukemic infiltration was seen in 8 (8.3%) subjects while secondary or indirect involvement due to anemia, thrombocytopenia, hyperviscosity, total body irradiation, and immunosuppression were seen in 42 (43.8%) subjects. Ocular changes were present in 37/79 (46.8%) adults and 5/17 (29.4%) children (P = 0.09460). Twenty-eight males (28/61) 45.9% and 14/35 (40%) females had ocular manifestations (P = 0.2874). The ocular manifestations were significantly (P = 0.01158) more frequent in myeloid leukemias 32/61 (52.9%) than lymphoid leukemias 10/35 (28.6%). CONCLUSIONS: Leukemic ophthalmic lesions were found in 42/96 (43.8%) patients. Ocular involvement is more often seen in adults, acute and myeloid leukemias. All the primary leukemic manifestations were seen in males. A periodic ophthalmic examination should be mandatory for all leukemic patients, as ocular changes are often picked up in asymptomatic patients. PMID- 26576525 TI - Transplantation of cultured rhesus monkey vascular endothelial cells to allogeneic cornea concomitant with stripping of Descemet's membrane. AB - CONTEXT: In cases of damaged corneal endothelium cells (CECs) of the eye, transplantation of cultured vascular endothelial cells (VECs) may be a viable method to restore transparency. AIMS: To evaluate the viability of replacing damaged primate CECs with cultured allogeneic VECs. SUBJECTS AND METHODS: Rhesus monkey VECs (RMVECs) were cultured and proliferating cells were labeled with bromodeoxyuridine (BrdU) in vitro. RMs of the experimental group (n = 6) underwent manual Descemettt membrane stripping with transplantation of RMVECs labeled with BrdU; those in the control group received manual Descemetnt membrane stripping without transplantation. Postoperative evaluations included the transparency and appearance of the corneal graft; distribution and ultrastructural changes of RMVECs on the inner surface of the cornea using scanning and transmission electron microscopy, and immunohistological identification of BrdU. RESULTS: At 90 days postsurgery, the corneal grafts of the monkeys in the experimental group retained better transparency than those of the controls, without corneal neovascularization or bullous keratopathy. A layer of cells with positive BrdU staining was found on the posterior surface of the treated corneas in the experimental group, while there was no VEC structure in corneal grafts from the monkeys of the control group. CONCLUSIONS: RMVECs can grow on the posterior surface of the cornea without Descemet's membrane. Cultured and transplanted RMVECs appeared similar in ultrastructure. VECs can provide a barrier to maintain corneal dehydration and transparency to some extent. PMID- 26576526 TI - Electron beam radiotherapy for the management of recurrent extensive ocular surface squamous neoplasia with orbital extension. AB - Recurrent extensive ocular surface squamous neoplasia (OSSN) with orbital invasion can be successfully managed with external radiotherapy using electrons resulting in eye and vision salvage. We report a case of right eye recurrent OSSN in an immunocompetent adult Indian male, with extensive orbital involvement. The patient had two previous surgical excisions with recurrent disease. At this stage, conventionally exenteration is considered the treatment modality. However, he was treated with 5040 cGy radiotherapy (15eV electrons) resulting in complete disease regression. At the end of 3 years follow-up, the patient was disease free, maintained a vision of 20/25, with mild dry eye, well-managed with topical lubricants. Extensive OSSN with orbital invasion does not always need exenteration. External beam electron radiotherapy provides a noninvasive cure with organ and vision salvage and should be considered in extensive OSSN not amenable to simple excision biopsies. Long-term studies to evaluate the effect of radiation on such eyes are suggested. PMID- 26576527 TI - Metastatic adenocarcinoma of the cervix presenting as a choroidal mass: A case report and review of literature of cervical metastases to the eye. AB - Cervical cancer is the most common cancer among females in India. Cervical cancer usually spreads by local extension and through the lymphatic drainage to the lymph nodes. Hematogenous spread, the mechanism responsible for distant metastases, is rarely seen in cervical malignancies. In this communication, we report a case of a 45-year-old woman who presented with unilateral decrease in vision of 3 months duration. She was found to have a serous retinal detachment with underlying diffuse, subretinal yellowish-cream colored infiltrates in the right eye, suspicious of choroidal metastases. Systemic evaluation showed disseminated systemic metastases arising from a primary adenocarcinoma of the cervix. In this communication, we review all the documented cases of metastases to the eye and adnexa arising from cervical cancer and their clinical characteristics. Unilateral choroidal metastasis arising from an adenocarcinoma of the cervix is extremely rare with only one previous documented case. Although uncommon, choroidal metastasis may be the presenting feature of primary cervical malignancy. Furthermore, cervical malignancy must be ruled out in women who present with orbital or choroidal metastases arising from unknown primary. PMID- 26576528 TI - Central retinal artery occlusion following orbital tumor resection: Is rapid intervention effective? AB - A 52-year-old male patient presented at our hospital with unilateral proptosis and vision loss in his left eye. Imaging evaluations showed orbital tumor, so the patient underwent surgery. About an hour later after tumor removal, patient developed sudden vision loss and became no light perception. Fundus evaluation revealed central retinal artery occlusion (CRAO). The patient was treated immediately with ocular massage and anterior chamber paracentesis as well as systemic therapy with mannitol and intravenous administration of acetazolamide. After thirty minutes, he recovered perception to light and then hand motion and 2 h later, it was improved to 1 m counting finger. CRAO following orbital tumor has not been reported before. We recommend ocular examination in all patients that undergo orbital surgery immediately to 2-3 h after surgery. PMID- 26576529 TI - Lipoid proteinosis: A rare entity. AB - Urbach-Wiethe syndrome or lipoid proteinosis is a rare autosomal recessive disorder characterized histologically by infiltration of Periodic acid Schiff positive hyaline material in the skin, upper aerodigestive tract, eyelids, and internal organs. Classical clinical features include scarring of the skin, beaded eyelid papules (moniliform blepharosis) and laryngeal infiltration leading to hoarseness of voice. Lipoid proteinosis can lead to life-threatening conditions such as acute respiratory distress and seizures. Awareness among ophthalmologists about this rare entity is crucial for appropriate management of these patients. PMID- 26576530 TI - Traumatic globe luxation: A case report. AB - Globe luxation is a rare clinical event. Most of the cases are usually traumatic, although spontaneous globe luxation has also been reported. The majority of the posttraumatic cases are usually associated with the injury or fracture of the bony orbit. We report here a case of globe luxation that occurred per se without any injury to the orbital or maxillo-facial bony structures. PMID- 26576531 TI - Primary orbital neuroblastoma with intraocular extension. AB - Neuroblastoma is an undifferentiated malignancy of primitive neuroblasts. Neuroblastoma is among the most common solid tumors of childhood. Orbital neuroblastoma is typically a metastatic tumor. In this case report, we describe a 2-year-old child with a rapidly progressing orbital tumor. Computed tomography revealed an orbital mass lesion with extraocular and intraocular components. An incisional biopsy was done, and a histopathological examination showed features suggestive of neuroblastoma. Systemic workup including ultrasonography of the abdomen, chest roentgenogram, whole body computed tomography, and bone scintigraphy showed no evidence of systemic involvement. The diagnosis of primary orbital neuroblastoma was made, and the child was subjected to chemotherapy followed by rapid melting of the tumor. Neuroblastoma should be considered in the differential diagnosis of childhood orbital tumors. PMID- 26576532 TI - Evaluation of choroidal thickness via enhanced depth-imaging optical coherence tomography in patients with systemic hypertension. PMID- 26576533 TI - The ROAM/EORTC-1308 trial: Radiation versus Observation following surgical resection of Atypical Meningioma: study protocol for a randomised controlled trial. AB - BACKGROUND: Atypical meningiomas are an intermediate grade brain tumour with a recurrence rate of 39-58 %. It is not known whether early adjuvant radiotherapy reduces the risk of tumour recurrence and whether the potential side-effects are justified. An alternative management strategy is to perform active monitoring with magnetic resonance imaging (MRI) and to treat at recurrence. There are no randomised controlled trials comparing these two approaches. METHODS/DESIGN: A total of 190 patients will be recruited from neurosurgical/neuro-oncology centres across the United Kingdom, Ireland and mainland Europe. Adult patients undergoing gross total resection of intracranial atypical meningioma are eligible. Patients with multiple meningioma, optic nerve sheath meningioma, previous intracranial tumour, previous cranial radiotherapy and neurofibromatosis will be excluded. Informed consent will be obtained from patients. This is a two-stage trial (both stages will run in parallel): Stage 1 (qualitative study) is designed to maximise patient and clinician acceptability, thereby optimising recruitment and retention. Patients wishing to continue will proceed to randomisation. Stage 2 (randomisation) patients will be randomised to receive either early adjuvant radiotherapy for 6 weeks (60 Gy in 30 fractions) or active monitoring. The primary outcome measure is time to MRI evidence of tumour recurrence (progression free survival (PFS)). Secondary outcome measures include assessing the toxicity of the radiotherapy, the quality of life, neurocognitive function, time to second line treatment, time to death (overall survival (OS)) and incremental cost per quality-adjusted life year (QALY) gained. DISCUSSION: ROAM/EORTC-1308 is the first multi-centre randomised controlled trial designed to determine whether early adjuvant radiotherapy reduces the risk of tumour recurrence following complete surgical resection of atypical meningioma. The results of this study will be used to inform current neurosurgery and neuro-oncology practice worldwide. TRIAL REGISTRATION: ISRCTN71502099 on 19 May 2014. PMID- 26576534 TI - Mining for novel candidate clock genes in the circadian regulatory network. AB - BACKGROUND: Most physiological processes in mammals are temporally regulated by means of a master circadian clock in the brain and peripheral oscillators in most other tissues. A transcriptional-translation feedback network of clock genes produces near 24 h oscillations in clock gene and protein expression. Here, we aim to identify novel additions to the clock network using a meta-analysis of public chromatin immunoprecipitation sequencing (ChIP-seq), proteomics and protein-protein interaction data starting from a published list of 1000 genes with robust transcriptional rhythms and circadian phenotypes of knockdowns. RESULTS: We identified 20 candidate genes including nine known clock genes that received significantly high scores and were also robust to the relative weights assigned to different data types. Our scoring was consistent with the original ranking of the 1000 genes, but also provided novel complementary insights. Candidate genes were enriched for genes expressed in a circadian manner in multiple tissues with regulation driven mainly by transcription factors BMAL1 and REV-ERB alpha,beta. Moreover, peak transcription of candidate genes was remarkably consistent across tissues. While peaks of the 1000 genes were distributed uniformly throughout the day, candidate gene peaks were strongly concentrated around dusk. Finally, we showed that binding of specific transcription factors to a gene promoter was predictive of peak transcription at a certain time of day and discuss combinatorial phase regulation. CONCLUSIONS: Combining complementary publicly-available data targeting different levels of regulation within the circadian network, we filtered the original list and found 11 novel robust candidate clock genes. Using the criteria of circadian proteomic expression, circadian expression in multiple tissues and independent gene knockdown data, we propose six genes (Por, Mtss1, Dgat2, Pim3, Ppp1r3b, Upp2) involved in metabolism and cancer for further experimental investigation. The availability of public high-throughput databases makes such meta-analysis a promising approach to test consistency between sources and tap their entire potential. PMID- 26576535 TI - Autophagy biomarkers in CSF correlates with infarct size, clinical severity and neurological outcome in AIS patients. AB - BACKGROUND: Autophagy is demonstrated to be involved in acute ischemic stroke(AIS), which, however, is confined to cells and/or animals levels. The aim of this study was to determine two autophagy biomarkers, Beclin1 and LC3B, in cerebrospinal fluid (CSF) and serum of patients with AIS, and to evaluate a possible correlation between levels of Beclin1 and LC3B and severity of neurological deficit and clinical outcome of stroke patients. METHODS: Levels of Beclin1 and LC3B were quantified by ELISA in CSF and serum collected from 37 AIS patients and 21 controls. The clinical severity at stroke onset was determined by the National Institute of Health Stroke Scale (NIHSS) and the neurological outcome was determined by the Modified Rankin Scale (mRs) and the improvement in NIHSS between stroke onset and 3 months later. Associations between autophagy biomarkers and infarct volume, NIHSS and mRs were assessed using Pearson analysis. RESULTS: The levels of Beclin1 and LC3B were increased both in CSF and serum of AIS patients relative to controls. In CSF, they were positively correlated with infarct volume and NIHSS scores, and negatively correlated with mRs scores, but no significant association was observed in serum. Moreover, AIS patients with higher levels of Beclin1 and LC3B in CSF had significantly higher improvement in NIHSS. CONCLUSION: CSF and serum levels of autophagy biomarkers are altered in AIS patients. CSF levels of autophagy biomarkers are associated with infarct volume, clinical severity of and neurological outcome. PMID- 26576536 TI - GenomicInteractions: An R/Bioconductor package for manipulating and investigating chromatin interaction data. AB - BACKGROUND: Precise quantitative and spatiotemporal control of gene expression is necessary to ensure proper cellular differentiation and the maintenance of homeostasis. The relationship between gene expression and the spatial organisation of chromatin is highly complex, interdependent and not completely understood. The development of experimental techniques to interrogate both the higher-order structure of chromatin and the interactions between regulatory elements has recently lead to important insights on how gene expression is controlled. The ability to gain these and future insights is critically dependent on computational tools for the analysis and visualisation of data produced by these techniques. RESULTS AND CONCLUSION: We have developed GenomicInteractions, a freely available R/Bioconductor package designed for processing, analysis and visualisation of data generated from various types of chromosome conformation capture experiments. The package allows the easy annotation and summarisation of large genome-wide datasets at both the level of individual interactions and sets of genomic features, and provides several different methods for interrogating and visualising this type of data. We demonstrate this package's utility by showing example analyses performed on interaction datasets generated using Hi-C and ChIA PET. PMID- 26576537 TI - The effect of kinin B1 receptor on chronic itching sensitization. AB - BACKGROUND: Altered kallikrein-related peptidase activity and bradykinin are associated with skin disorders in humans and mice under chronic inflammation conditions. The bradykinin B1 receptor (B1R), also known as one of the G-protein coupled receptor family and usually absent in intact tissues and upregulated during tissue injury, is responsible for vasodilation, capillary permeability, nociceptor sensitization, and pain; it is indispensable for physiopathological progress in chronic inflammation conditions, but its roles and effectors in the itching sensation of the allergic contact dermatitis model are poorly defined. RESULTS: We focused on incurable itching in a diphenylcyclopropenone (DCP) chronic inflammation experimental model. Preventive treatment with the B1R antagonist R892 significantly suppressed spontaneous scratching, while the B2R selective antagonist did not. B1R expression in the skin tissues of this model was detected using a quantitative, real-time polymerase chain reaction, Western blotting, and immunohistochemistry; B1R mRNA and protein levels were increased compared with a sham-treated control group. A higher B1R IHC staining signal was observed in the keratinocytes in DCP-treated mice compared with a vehicle-treated group, so we studied the B1R function when superimposed on a protease-activated receptor 2 (PAR2) background, establishing B1R as a pivotal mediator of PAR2 function in HaCaT cell lines. CONCLUSION: Our data provide evidence that B1R facilitates the chronic itching sensation related to keratinocytes in a DCP treated chronic inflammation experimental model. PMID- 26576538 TI - What is needed to guide testing for anorectal and pharyngeal Chlamydia trachomatis and Neisseria gonorrhoeae in women and men? Evidence and opinion. AB - BACKGROUND: Anorectal and pharyngeal infections with Chlamydia trachomatis (CT) and Neisseria gonorrheae (NG) are commonly observed in men who have sex with men (MSM). There is increasing evidence that such infections at extra-genital sites are also common in women. In both sexes, these infections are largely overlooked as they are not routinely tested for in regular care. Testing based on sexual behavior or symptoms would only detect half of these extra-genital infections. This paper elucidates the differences and similarities between women and MSM, regarding the epidemiology of extra-genital CT and NG. It discusses the clinical and public health impact of untested extra-genital infections, how this may impact management strategies, and thereby identifies key research areas. DISCUSSION: Extra-genital CT is as common in women as it is in MSM; NG in women is as common at their extra-genital sites as it is at their genital sites. The substantial numbers of extra-genital CT and NG being missed in women and MSM indicate a need to test and treat more patients and perhaps different choices in treatment and partner management strategies. Doing so will likely contribute to reduced morbidity and transmission in both sexes. However, in our opinion, it is clear that there are several knowledge gaps in understanding the clinical and public health impact of extra-genital CT and NG. Key research areas that need to be addressed concern associated morbidity (anorectal and reproductive morbidity due to extra-genital infections), 'the best' management strategies, including testing and treatment for extra-genital CT, extra-genital treatment resistance, transmission probabilities between partners and between anatomic sites in a woman, and impact on transmission of other infections. Data are also lacking on cost-effectiveness of pharyngeal testing, and of NG testing and anorectal CT testing in women. Gaps in the management of extra-genital CT and NG may also apply for other STIs, such Mycoplasma genitalium. Current management strategies, including testing, to address extra-genital CT and NG in both sexes are suboptimal. Comparative data on several identified key themes in women and MSM are lacking and urgently needed to guide better management of extra-genital infections. PMID- 26576539 TI - miR-27b-3p suppresses cell proliferation through targeting receptor tyrosine kinase like orphan receptor 1 in gastric cancer. AB - BACKGROUND: The receptor tyrosine kinase-like orphan receptors (ROR) family contains the atypical member ROR1, which plays an oncogenic role in several malignant tumors. However, the clinical potentials and underlying mechanisms of ROR1 in gastric cancer progression remain largely unknown. In this study, we validated the microRNA-mediated gene repression mechanism involved in the role of ROR1. METHODS: Bioinformatic prediction, luciferase reporter assay, quantitative real-time PCR (qRT-PCR) and western blotting were used to reveal the regulatory relationship between miR-27b-3p and ROR1. The expression patterns of miR-27b-3p and ROR1 in human gastric cancer (GC) specimens and cell lines were determined by microRNA RT-PCR and western blotting. Cell proliferation, colony formation assay in soft agar in vitro and tumorigenicity in vivo were performed to observe the effects of downregulation and upregulation miR-27b-3p expression on GC cell phenotypes. RESULTS: miR-27b-3p suppressed ROR1 expression by binding to the 3'UTR of ROR1 mRNA in GC cells. miR-27b-3p was significantly downregulated and reversely correlated with ROR1 protein levels in clinical samples. Analysis of the clinicopathological significance showed that miR-27b-3p and ROR1 were closely correlated with GC characteristics. Ectopic miR-27b-3p expression suppressed cell proliferation, colony formation in soft agar, xenograft tumors of GC cells. By contrast, miR-27b-3p knockdown enhanced these malignant behaviors. Our studies further revealed that the c-Src/STAT3 signaling pathway was involved in miR-27b 3p-ROR1-mediated cell proliferation regulation. CONCLUSIONS: These results show that miR-27b-3p suppresses ROR1 expression through the binding site in the 3'UTR inhibiting the cell proliferation. These findings indicate that miR-27b-3p exerts tumor-suppressive effects in GC through the suppression of oncogene ROR1 expression and suggest a therapeutic application of miR-27b-3p in GC. PMID- 26576540 TI - Osteoporosis in adults with cerebral palsy: feasibility of DXA screening and risk factors for low bone density. AB - This study aims to describe osteoporosis screening in adults with cerebral palsy (CP) and identify any associated factors. Bone mineral density (BMD) was often lower than expected-for-age in these adults, and present even in young adulthood, particularly at the spine. Low BMD is frequent in adults with CP. INTRODUCTION: This study aims to describe the feasibility of dual-energy X-Ray absorptiometry (DXA) screening in adults with cerebral palsy (CP) and identify factors associated with low bone mineral density (BMD), including longitudinal changes. METHODS: A retrospective chart review study of these adults seen at an urban academic rehabilitation clinic and who underwent DXA scan(s). BMD and Z-scores for the lumbar spine, hips, and femoral (neck and total) were recorded. The change in BMD and Z-scores from baseline to follow-up DEXA, Gross Motor Functional Classification System (GMFCS), CP pattern (hemiplegic, diplegic, or quadriplegic), body mass index (BMI), and transfer and ambulation status were assessed. RESULTS: Forty-two patients (83 % less than age 50 years) had at least one DXA. Seventeen had at least two studies, 15 without pharmacologic interventions between studies. Thirteen fractures in eight subjects were noted, most often lower limb. Fifty percent of spine studies in individuals under 50 had a Z-score of less than -2, while 25 and 30.8 % of these individuals had such scores at the right and left total hip sites, respectively. Need for transfer assistance was associated with lower BMD and Z-scores at all hip sites, but not the lumbar spine. Progressive abnormalities were seen at follow-up DXAs at some sites, however these were not statistically significant. CONCLUSIONS: Lower than expected-for-age BMD was very frequent in adults with CP with mobility limitations, present at both spine and hip sites. Low BMI and need for transfer assistance had a negative impact on BMD. Although not statistically significant, progression of abnormalities was seen at follow-up for DXAs Z-scores at some sites, which suggests longitudinal studies in this population are needed. PMID- 26576541 TI - Occupation-dependent loading increases bone strength in men. AB - SUMMARY: Ex vivo analyses of humeri and radii from an anthropological collection and in vivo analyses of the distal radius of retired men indicate that occupation dependent loading positively influences bone strength by an increase of bone size when young followed by a slowdown of the age-related endocortical and trabecular bone alteration. INTRODUCTION: Skeleton responds to mechanical stimuli, but it is not established whether chronic loading in the context of occupational activities (OA) influences bone properties. We assessed the impact of occupation-dependent loading on upper limb bone strength. METHODS: Individuals were classified according to the intensity of physical loading associated with their OA in two models. Ex vivo, computed tomography scans of the humeri and radii of 219 male skeletons (age of death, 20-93 years) from an anthropological collection of the 20th century (Simon collection) were used to determine estimates of bone strength and cross-sectional geometry. In vivo, distal radius were analysed in 180 men enrolled in the Geneva Retirees Cohort study using high-resolution peripheral quantitative computed tomography and finite element analysis. RESULTS: Heavy loading OA was associated with higher bone strength in both models. This benefit was associated with higher total area (Tt.Ar), medullary area (Me.Ar) and cortical area (Ct.Ar) in young adult skeletons, but the difference decreased in older age. In older men, the humerus supporting heavy loading had a lower Me.Ar. This effect resulted in greater asymmetries of the Me.Ar and the Ct.Ar/Tt.Ar ratio between the humeri of men with unilateral versus bilateral heavy-loading OA. In vivo, an additional benefit of heavy-loading OA was observed on the distal radius trabecular density and microstructure. CONCLUSION: Repeated occupation dependent loading positively influences bone strength by an increase of bone size when young followed by a slowdown of the age-related endocortical and trabecular bone alteration. These data supports the necessity to promote bone health in the context of sedentary occupation. PMID- 26576542 TI - Hyponatremia and hypernatremia are associated with increased 30-day mortality in hip fracture patients. AB - Using data from the Danish national registries on 7317 patients, this study shows that abnormal plasma sodium levels, in the form of hyponatremia and hypernatremia, are prevalent and associated with increased 30-day mortality in hip fracture patients. INTRODUCTION: The aim of this study was to examine the prevalence of hyponatremia and hypernatremia in patients admitted with a fractured hip as well as the association with 30-day in mortality in these patients. METHODS: A total of 7317 hip fracture patients (aged 60 years or above) with admission plasma sodium measurements were included. Data on comorbidity, medication, and death was retrieved from Danish national registries. The association between plasma sodium and mortality was examined using Cox proportional hazard models. RESULTS: The prevalence of hyponatremia and hypernatremia on admission was 19.0 and 1.7 %, respectively. Thirty-day mortality was increased for patients with hyponatremia (12.2 %, p = 0.005) and hypernatremia (15.5 %, p = 0.03) compared to normonatremic patients (9.6 %). After adjustment for possible confounding factors, hyponatremia (1.38 [1.16 1.64], p = 0.0003) and hypernatremia (1.71 [1.08-2.70], p = 0.02) were still associated with increased risk of death by 30 days. Looking at the association between changes in plasma sodium during admission and mortality, there was no difference between patients with normalized and persistent hyponatremia (10.4 vs 11.3 %, p = 0.6) while a lower mortality was found for normalized hypernatremia compared to persistent hypernatremia (12.4 vs 33.3 %, p = 0.03). CONCLUSIONS: This study shows that abnormal plasma sodium levels are prevalent in patients admitted with a fractured hip and that both hyponatremia and hypernatremia are associated with increased risk of death within 30 days of admission. PMID- 26576543 TI - Left-right differences in the proximal femur's strength of post-menopausal women: a multicentric finite element study. AB - The strength of both femurs was estimated in 198 post-menopausal women through subject-specific finite element models. Important random differences between contralateral femurs were found in a significant number of subjects, pointing to the usefulness of further studies to understand if strength-based classification of patients at risk of fracture can be affected by laterality issues. INTRODUCTION: Significant, although small, differences exist in mineral density and anatomy of contralateral proximal femurs. These differences, and their combined effect, may result in a side difference in femurs' strength. However, this has never been tested on a large sample of a homogenous population. METHODS: The strength of both femurs was estimated in 198 post-menopausal women through CT derived finite element models, built using a validated procedure, in sideways fall conditions. The impact of the resulting asymmetry on the classification of subjects at risk of fracture was analysed. RESULTS: The small difference observed between sides (the right femur on average 4 % stronger than the left) was statistically significant but mechanically negligible. In contrast, higher random differences (absolute difference between sides with respect to mean value) were found: on average close to 15 % (compared to 9.2 % for areal bone mineral density (aBMD) alone), with high scatter among the subjects. When using a threshold-based classification, the right and left femurs were discordant up to over 20 % of cases (K always lower than 0.60) but the left femur was concordant (mean K = 0.84) with the minimum strength between right and left. CONCLUSION: Considering both femurs may be important when trying to classify subjects at risk of failure with strength estimates. Future studies including fracture assessment would be necessary to quantify the real impact. PMID- 26576544 TI - Antiresorptive therapy and risk of mortality and refracture in osteoporosis related hip fracture: a nationwide study. AB - We analyzed the association of bisphosphonate therapy with mortality and hip refracture incidence among osteoporosis-related hip fracture patients in Austria. Mortality was lower in primarily female bisphosphonate users, while hip refracture incidence was generally elevated relative to controls, indicating beneficial effects of bisphosphonates other than on bone. INTRODUCTION: The purpose of this study was to analyze mortality and hip refracture risk in osteoporotic hip fracture patients with and without antiosteoporotic medication. METHODS: We retrospectively analyzed data on 31,668 Austrian patients >=50 years with a hip fracture between July 2008 and December 2010 for antiosteoporotic drug treatment with respect to outcome parameters all-cause mortality, hip refracture incidence, and hip refracture-free days. Outcomes when bisphosphonate (BP) treatment was begun before or after fracture were compared with an age- and sex matched hip fracture control without antiosteoporotic medication. RESULTS: 27.69 % of patients (33.01 % of women, 13.13 % of men) were prescribed antiosteoporotic medication, primarily BPs. Females having initiated BP treatment before first fracture had lower odds for mortality 1 and 3 year(s) post-fracture, whereas hip refracture incidence under pre-fracture BP initiation was generally higher. Treatment that was started after fracture, however, entailed significantly lower mortality hazards for both genders (HR 0.43, 95 %CI 0.36-0.52, p < 0.0001 after 1 year) but significantly higher hip refracture incidence except for patients aged 50-69 years and more hip refracture free days for females. Hip refractures overall amounted to 29.22/1000 patient years differing significantly between women and men (31.03 vs. 23.89, respectively, p < 0.0001), and longer hip refracture free survival was observed for women than for men (499 vs. 466 median days, respectively, p < 0.0001). CONCLUSIONS: Although BP use is associated with reduced mortality after hip fracture, notably among women, hip refracture incidences are likewise elevated, which is most likely accounted for by a high probability of BP prescription to more comorbid patients suffering from more severe osteoporosis. Concomitantly, through possible effects other than on bone, BPs might be able to curtail mortality. Male hip fracture patients' low treatment frequency in particular reflects underdiagnosis and undertreatment of osteoporosis in Austria. PMID- 26576545 TI - Galactomannan antigen detection using bronchial wash and bronchoalveolar lavage in patients with hematologic malignancies. AB - BACKGROUND: The diagnosis of invasive pulmonary aspergillosis is challenging. It is unclear whether galactomannan (GM) results from bronchial wash (BW) and bronchoalveolar lavage (BAL) samples differ in a clinically meaningful way. RESULTS: Ninety-six paired (BAL and BW) samples from 85 patients were included. The average age was 53 years, 61 % of the patients were male, and 74.1 % had an underlying diagnosis of AML/MDS (ALL 7.1 %, other hematologic malignancy 18.8 %). 57 (67.1 %) patients were neutropenic, and 56 (65.9 %) patients were receiving mold-active drugs at least 48 h prior to bronchoscopy. The overall agreement between GM detection from BW and BAL was 63.5 % (K = 0.152; 95 % CI 0.008-0.311) and 73 % (K = 0.149; 95 % CI 0.048-0.348) at cut off >=0.5 and >=1.0, respectively. Among 43 positive samples, using a GM cut-off of 0.5, 39 (90.5 %) were positive in BW samples whereas 12 (29.3 %) were positive in BAL samples. The median level of GM in BW (0.28) samples was significantly higher than in BAL (0.20) samples among 53 samples with negative results (P = 0.001). There was no statistically significant difference in the median GM values between the BW and BAL samples with positive results (P = 0.08). There was no significant difference in GM detection between samples with positive and negative results with regard to antifungal, beta lactam antibacterial treatment or neutropenia (60.5 vs 56.6 %; 53.9 vs 46 %; 65.1 vs 54.7 %, respectively). CONCLUSION: This retrospective study examining two collection techniques suggests that BW may have higher diagnostic yield compared to bronchoalveolar lavage for GM detection. PMID- 26576546 TI - COMT Val 158 Met polymorphism is associated with nonverbal cognition following mild traumatic brain injury. AB - Mild traumatic brain injury (mTBI) results in variable clinical outcomes, which may be influenced by genetic variation. A single-nucleotide polymorphism in catechol-o-methyltransferase (COMT), an enzyme which degrades catecholamine neurotransmitters, may influence cognitive deficits following moderate and/or severe head trauma. However, this has been disputed, and its role in mTBI has not been studied. Here, we utilize the Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK-TBI Pilot) study to investigate whether the COMT Val (158) Met polymorphism influences outcome on a cognitive battery 6 months following mTBI--Wechsler Adult Intelligence Test Processing Speed Index Composite Score (WAIS-PSI), Trail Making Test (TMT) Trail B minus Trail A time, and California Verbal Learning Test, Second Edition Trial 1-5 Standard Score (CVLT-II). All patients had an emergency department Glasgow Coma Scale (GCS) of 13-15, no acute intracranial pathology on head CT, and no polytrauma as defined by an Abbreviated Injury Scale (AIS) score of >=3 in any extracranial region. Results in 100 subjects aged 40.9 (SD 15.2) years (COMT Met (158) /Met (158) 29 %, Met (158) /Val (158) 47 %, Val (158) /Val (158) 24 %) show that the COMT Met (158) allele (mean 101.6 +/- SE 2.1) associates with higher nonverbal processing speed on the WAIS-PSI when compared to Val (158) /Val (158) homozygotes (93.8 +/- SE 3.0) after controlling for demographics and injury severity (mean increase 7.9 points, 95 % CI [1.4 to 14.3], p = 0.017). The COMT Val (158) Met polymorphism did not associate with mental flexibility on the TMT or with verbal learning on the CVLT-II. Hence, COMT Val (158) Met may preferentially modulate nonverbal cognition following uncomplicated mTBI.Registry: ClinicalTrials.gov Identifier NCT01565551. PMID- 26576547 TI - De novo missense variants in PPP2R5D are associated with intellectual disability, macrocephaly, hypotonia, and autism. AB - Protein phosphatase 2A (PP2A) is a heterotrimeric protein serine/threonine phosphatase and is involved in a broad range of cellular processes. PPP2R5D is a regulatory B subunit of PP2A and plays an important role in regulating key neuronal and developmental regulation processes such as PI3K/AKT and glycogen synthase kinase 3 beta (GSK3beta)-mediated cell growth, chromatin remodeling, and gene transcriptional regulation. Using whole-exome sequencing (WES), we identified four de novo variants in PPP2R5D in a total of seven unrelated individuals with intellectual disability (ID) and other shared clinical characteristics, including autism spectrum disorder, macrocephaly, hypotonia, seizures, and dysmorphic features. Among the four variants, two have been previously reported and two are novel. All four amino acids are highly conserved among the PP2A subunit family, and all change a negatively charged acidic glutamic acid (E) to a positively charged basic lysine (K) and are predicted to disrupt the PP2A subunit binding and impair the dephosphorylation capacity. Our data provides further support for PPP2R5D as a genetic cause of ID. PMID- 26576549 TI - Response to the Comments by Dr. Endrikat et al. on the article "Tissue gadolinium deposition in hepatorenally impaired rats exposed to Gd-EOB-DTPA: evaluation with inductively coupled plasma mass spectrometry (ICP-MS)" by Tomohiro Sato, Tsutomu Tamada, Shigeru Watanabe et al. DOI 10.1007/s11547-014-0492-y. PMID- 26576548 TI - Systematic review and clinical recommendations for dosage of supported home-based standing programs for adults with stroke, spinal cord injury and other neurological conditions. AB - BACKGROUND: Sitting for more than 8 h a day has been shown to negatively impact health and mortality while standing is the recommended healthier alternative. Home-based standing programs are commonly recommended for adults who cannot stand and/or walk independently. The aim of this systematic review is to review effectiveness of home-based standing programs for adults with neurological conditions including stroke and spinal cord injury; and to provide dosage guidelines to address body structure and function, activity and participation outcomes. METHODS: Eight electronic databases were searched, including Cochrane Library databases, MEDLINE, CINAHL and EMBASE. From 376 articles, 36 studies addressing impact of a standing intervention on adults with sub-acute or chronic neurological conditions and published between 1980 and September 2015 were included. Two reviewers independently screened titles, reviewed abstracts, evaluated full-text articles and rated quality and strength of evidence. Evidence level was rated using Oxford Centre for Evidence Based Medicine Levels and quality evaluated using a domain-based risk-of-bias rating. Outcomes were divided according to ICF components, diagnoses and dosage amounts from individual studies. GRADE and the Evidence-Alert Traffic-Lighting system were used to determine strength of recommendation and adjusted in accordance with risk-of-bias rating. RESULTS: Stronger evidence supports the impact of home-based supported standing programs on range of motion and activity, primarily for individuals with stroke or spinal cord injury while mixed evidence supports impact on bone mineral density. Evidence for other outcomes and populations is weak or very weak. CONCLUSIONS: Standing should occur 30 min 5 times a week for a positive impact on most outcomes while 60 min daily is suggested for mental function and bone mineral density. PMID- 26576550 TI - Comments on the article "Tissue gadolinium deposition in hepatorenally impaired rats exposed to Gd-EOB-DTPA: evaluation with inductively coupled plasma mass spectrometry (ICP-MS)" by Tomohiro Sato, Tsutomu Tamada, Shigeru Watanabe et al. DOI 10.1007/s11547-014-0492-y. PMID- 26576551 TI - Anxiety and depression during pregnancy in Central America: a cross-sectional study among pregnant women in the developing country Nicaragua. AB - BACKGROUND: Around the world, maternal psychopathology during pregnancy is associated with a range of negative consequences for mother and child. Nevertheless, in Central America the magnitude of this public health problem is still unknown. The objective of this first explorative study was to investigate the prevalence and severity of anxiety and depression during pregnancy in the Central American developing country Nicaragua, as well as the availability of mental health care and to compare with a developed country. METHODS: A population based cohort of pregnant women in Nicaragua (N = 98) was compared with a parallel cohort in the Netherlands (N = 4725) on symptoms of anxiety (Spielberger State Trait Anxiety Inventory) and depression (Edinburgh Postnatal Depression Scale). Associations with the women's knowledge how to reach professional psychological support were assessed using multivariable linear regression analyses. RESULTS: Of the Nicaraguan women, 41 % had symptoms of anxiety and 57 % symptoms of depression, versus 15 % and 6 % of the Dutch women. Symptom scores of both anxiety and depression were significantly higher in Nicaragua (p < 0.001). However, only 9.6 % of the women indicated that professional psychological help was available for the Nicaraguan pregnant women, which was associated with an increased anxiety score. CONCLUSIONS: In Nicaragua, both prevalence and severity of symptoms of antenatal anxiety and depression are substantially higher than in developed countries. However, availability of psychological help is very limited for pregnant Nicaraguan women. These findings indicate that there is need for further research and support for these women, to prevent negative consequences for both mother and child. PMID- 26576552 TI - Prevention of NSAID-Enteropathy: A Soluble Problem? PMID- 26576553 TI - Should Assessment of Quality Indicator of Colonoscopy Be Varied Depending on the Colonoscopic Technique Level? AB - BACKGROUND/AIM: The purpose of this research was to evaluate if withdrawal time is a useful index in spite of differences in gastroenterologists' ability and if there are other quality indicators of colonoscopy. METHODS: A total of 665 consecutive, asymptomatic individuals of average risk between 50 and 75 years of age who underwent screening colonoscopies performed by 12 gastroenterologists were included in this study. The endoscopists were classified to either the experienced group (group A, N = 6) or the under-experienced group (group B, N = 6). The endoscopists were unaware that they were being studied during the two month study period. RESULTS: In group A, adenoma detection rate was 0.56, while in group B it was 0.43 (P = 0.048). The mean withdrawal time ranged widely from 4.2 to 10.3 min per patient with a mean value of 6.83 for group A and 6.54 for group B. There was a significantly positive relationship between the number of adenomas detected and the withdrawal time for group B (r = 0.827, P = 0.005), but not for group A (r = -0.152, P = 0.584). In the case of group A, the ratio of cecal intubation time to withdrawal time (I/E ratio) less than 1 showed significantly correlated adenoma detection rate compared to I/E ratio greater than 1 (r = -0.308, P = 0.036). In the case of group B, mean I/E ratio was 1.7 and all endoscopists' I/E ratios were greater than 1. CONCLUSIONS: For experienced endoscopists, a useful supplementary quality indicator of colonoscopy is to keep intubation/withdrawal time ratio less than 1 and it is necessary for under-experienced endoscopists to try to keep enough withdrawal time. PMID- 26576554 TI - Low Alpha-Fetoprotein Levels Are Associated with Improved Survival in Hepatocellular Carcinoma Patients with Portal Vein Thrombosis. AB - BACKGROUND: Macroscopic portal vein thrombosis (PVT) is a common and dire prognostic feature of patients with hepatocellular carcinoma (HCC) and often precludes many treatments as a result. Little is known about its causes or mechanisms or clinical associations. AIMS: To examine patients with PVT in order to possibly identify prognostically different subsets. METHODS: A large cohort of non-curable patients with advanced and biopsy-proven HCC in which survival was documented, were retrospectively examined. RESULTS: We analyzed a large HCC cohort containing 366 (63.3%) PVT-positive patients and found that PVT is associated with patients having larger tumors and higher levels of alpha fetoprotein (AFP) and des-gamma carboxyprothrombin (DCP). We identified in patients with normal bilirubin levels (<= 2.0 mg/dl) two PVT-positive patients, having higher and lower AFP levels, respectively. They differed in the significantly better prognosis of the low AFP patients, which may be useful for patient management decisions. CONCLUSIONS: Patients with PVT are heterogeneous with respect to AFP levels. AFP-negative patients have a significantly better survival than those who have elevated AFP. PMID- 26576556 TI - [Deficits in provision of pain therapy in Austria]. PMID- 26576555 TI - Effectiveness and Safety of Tenofovir Disoproxil Fumarate in Chronic Hepatitis B: A 3-Year Prospective Field Practice Study in Germany. AB - BACKGROUND AND AIMS: Multiple clinical trials have demonstrated the efficacy and safety of tenofovir disoproxil fumarate (TDF) in chronic hepatitis B (CHB). However, long-term efficacy and safety data for TDF in real-life clinical practice are limited. METHODS: Prospective German field practice study in CHB mono-infected patients. Patients were TDF-naive but could have been treated previously with other HBV antivirals. RESULTS: Efficacy analysis included 400 patients; 301 (75 %) completed 36 months of TDF treatment. Both treatment-naive and treatment-experienced patients showed a rapid decline in HBV DNA within 3 months of TDF initiation. After 36 months, HBV DNA < 69 IU/mL was achieved by 91 % of treatment-naive patients (90 and 92 % in hepatitis B "e" antigen [HBeAg] positive and [HBeAg]-negative, respectively) and 96 % of treatment-experienced patients (93 and 97 %, respectively). Three patients experienced virologic breakthrough, all with reported non-compliance. Overall, 5.7 % HBeAg-positive and 2.2 % HBeAg-negative patients lost hepatitis B surface antigen. Safety data were consistent with the known TDF safety profile; the most commonly reported adverse events possibly related to TDF were fatigue (2.0 %) and headache (2.0 %). Few patients (1.3 %) experienced renal-related adverse reactions. Creatinine clearance remained relatively stable over time; patients responded favorably where TDF was dose adjusted per label for decreased creatinine clearance. CONCLUSIONS: TDF showed a favorable tolerability profile and induced rapid and sustained suppression of HBV DNA in patients with CHB treated for up to 3 years in routine clinical practice, irrespective of treatment history. Efficacy and safety in this heterogeneous patient population were consistent with data from clinical trials. PMID- 26576557 TI - Antiadherent and antibacterial properties of stainless steel and NiTi orthodontic wires coated with silver against Lactobacillus acidophilus--an in vitro study. AB - BACKGROUND: The purpose of the study is to assess the antiadherent and antibacterial properties of surface-modified stainless steel and NiTi orthodontic wires with silver against Lactobacillus acidophilus. METHODS: This study was done on 80 specimens of stainless steel and NiTi orthodontic wires. The specimens were divided into eight test groups. Each group consisted of 10 specimens. Groups containing uncoated wires acted as a control group for their respective experimental group containing coated wires. Surface modification of wires was carried out by the thermal vacuum evaporation method with silver. Wires were then subjected to microbiological tests for assessment of the antiadherent and antibacterial properties of silver coating against L. acidophilus. Mann-Whitney U test was used to analyze the colony-forming units (CFUs) in control and test groups; and Student's t test (two-tailed, dependent) was used to find the significance of study parameters on a continuous scale within each group. RESULTS: Orthodontic wires coated with silver showed an antiadherent effect against L. acidophilus compared with uncoated wires. Uncoated stainless steel and NiTi wires respectively showed 35.4 and 20.5 % increase in weight which was statistically significant (P < 0.001), whereas surface-modified wires showed only 4.08 and 4.4 % increase in weight (statistically insignificant P > 0.001). The groups containing surface-modified wires showed statistically significant decrease in the survival rate of L. acidophilus expressed as CFU and as log of colony count when compared to groups containing uncoated wires. It was 836.60 +/- 48.97 CFU in the case of uncoated stainless steel whereas it was 220.90 +/- 30.73 CFU for silver-modified stainless steel, 748.90 +/- 35.64 CFU for uncoated NiTi, and 203.20 +/- 41.94 CFU for surface-modified NiTi. CONCLUSIONS: Surface modification of orthodontic wires with silver can be used to prevent the accumulation of dental plaque and the development of dental caries during orthodontic treatment. PMID- 26576559 TI - Brentuximab-induced hand-foot syndrome in a Hodgkin lymphoma patient. PMID- 26576558 TI - Guidelines to the Practice of Anesthesia - Revised Edition 2016. AB - OVERVIEW: The Guidelines to the Practice of Anesthesia Revised Edition 2016 (the guidelines) were prepared by the Canadian Anesthesiologists' Society (CAS), which reserves the right to determine their publication and distribution. Because the guidelines are subject to revision, updated versions are published annually. The Guidelines to the Practice of Anesthesia Revised Edition 2016 supersedes all previously published versions of this document. Although the CAS encourages Canadian anesthesiologists to adhere to its practice guidelines to ensure high quality patient care, the society cannot guarantee any specific patient outcome. Each anesthesiologist should exercise his or her own professional judgement in determining the proper course of action for any patient's circumstances. The CAS assumes no responsibility or liability for any error or omission arising from the use of any information contained in its Guidelines to the Practice of Anesthesia. PMID- 26576560 TI - Prognostic value of interim and end-of-treatment FDG-PET in follicular lymphoma: a systematic review. AB - This study aimed to systematically review the prognostic value of interim and end of-treatment (18)F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) in follicular lymphoma during and after first-line therapy. The PubMed/MEDLINE database was searched for relevant original studies. Included studies were methodologically assessed, and their results were extracted and descriptively analyzed. Three studies on the prognostic value of interim FDG-PET and eight studies on the prognostic value of end-of-treatment FDG-PET were included. Overall, studies were of poor methodological quality. In addition, there was incomplete reporting of progression-free survival (PFS) and overall survival (OS) data by several studies, and none of the studies incorporated the Follicular Lymphoma International Prognostic Index (FLIPI) in the OS analyses. Two studies reported no significant difference in PFS between interim FDG-PET positive and negative patients, whereas one study reported a significant difference in PFS between the two groups. Two studies reported no significant difference in OS between interim FDG-PET positive and negative patients. Five studies reported end-of-treatment FDG-PET positive patients to have a significantly worse PFS than end-of-treatment FDG-PET negative patients, and one study reported a non-significant trend towards a worse PFS for end-of-treatment FDG-PET positive patients. Three studies reported end-of-treatment FDG-PET positive patients to have a significantly worse OS than end-of-treatment FDG-PET negative patients. In conclusion, the available evidence does not support the use of interim FDG-PET in follicular lymphoma. Although published studies suggest end of-treatment FDG-PET to be predictive of PFS and OS, they suffer from numerous biases and failure to correct OS prediction for the FLIPI. PMID- 26576561 TI - Age-dependent defects of alpha-synuclein oligomer uptake in microglia and monocytes. AB - Extracellular alpha-synuclein (alphasyn) oligomers, associated to exosomes or free, play an important role in the pathogenesis of Parkinson's disease (PD). Increasing evidence suggests that these extracellular moieties activate microglia leading to enhanced neuronal damage. Despite extensive efforts on studying neuroinflammation in PD, little is known about the impact of age on microglial activation and phagocytosis, especially of extracellular alphasyn oligomers. Here, we show that microglia isolated from adult mice, in contrast to microglia from young mice, display phagocytosis deficits of free and exosome-associated alphasyn oligomers combined with enhanced TNFalpha secretion. In addition, we describe a dysregulation of monocyte subpopulations with age in mice and humans. Accordingly, human monocytes from elderly donors also show reduced phagocytic activity of extracellular alphasyn. These findings suggest that these age-related alterations may contribute to an increased susceptibility to pathogens or abnormally folded proteins with age in neurodegenerative diseases. PMID- 26576562 TI - Propagation of tau pathology: hypotheses, discoveries, and yet unresolved questions from experimental and human brain studies. AB - Tau is a microtubule-associated protein and a key regulator of microtubule stabilization as well as the main component of neurofibrillary tangles-a principle neuropathological hallmark of Alzheimer's disease (AD)-as well as pleomorphic neuronal and glial inclusions in neurodegenerative tauopathies. Cross sectional studies of neurofibrillary pathology in AD reveal a stereotypic spatiotemporal pattern of neuronal vulnerability that correlates with disease severity; however, the relationship of this pattern to disease progression is less certain and exceptions to the typical pattern have been described in a subset of AD patients. The basis for the selective vulnerability of specific populations of neurons to tau pathology and cell death is largely unknown, although there have been a number of hypotheses based upon shared properties of vulnerable neurons (e.g., degree of axonal myelination or synaptic plasticity). A recent hypothesis for selective vulnerability takes into account the emerging science of functional connectivity based upon resting state functional magnetic resonance imaging, where subsets of neurons that fire synchronously define patterns of degeneration similar to specific neurodegenerative disorders, including various tauopathies. In the past 6 years, the concept of tau propagation has emerged from numerous studies in cell and animal models suggesting that tau moves from cell-to-cell and that this may trigger aggregation and region-to-region spread of tau pathology within the brain. How the spread of tau pathology relates to functional connectivity is an area of active investigation. Observations of templated folding and propagation of tau have prompted comparisons of tau to prions, the pathogenic proteins in transmissible spongiform encephalopathies. In this review, we discuss the most compelling studies in the field, discuss their shortcomings and consider their implications with respect to human tauopathies as well as the controversy that tauopathies may be prion-like disorders. PMID- 26576563 TI - Caustic soda ingestion in children under-5 years presenting for fluoroscopic examinations in an Academic Hospital in Ghana. AB - BACKGROUND: Disastrous effects and lifelong complications, ranging from respiratory and gastrointestinal burns to death can result from caustic soda ingestion. Accidental and non-accidental ingestions occur in different age groups. However, it is very troubling to find ingestion of caustic soda a very common occurrence among children below 5 years since they do not have the developmental level required to independently weigh up risks and are also under parental and societal protections. This study was therefore planned to investigate the ingestions of caustic soda by these children for purposes of proposing measures to curb the problem. METHODS: Descriptive survey was employed for this study. A 14-item, semi-structure questionnaire was purposively issued to 57 parents/guardians whose wards had ingested caustic soda. Data was analysed with SPSS V.20. RESULTS: Twenty-seven (47.4 %) children got access to the soda at storage, 1 (1.86 %) was administered accidentally by a sibling while 29 (50.9 %) ingested during soap preparation. In respect of the former, the majority got access because it was stored in soft drink and water bottles in their parents/guardians rooms or kitchen. For the later, the children got access to the left-over soda because the soap-makers failed to adhere to good storage and disposal practices. CONCLUSION: Storage of caustic soda in soft drink and water bottles in accessible places, and training of children to drink directly from bottles influence caustic soda ingestion in children under five. Non-compliance to good practices of storage and disposal of caustic soda during soap preparation increases exposure and access of children to caustic soda ingestion. PMID- 26576564 TI - Correcting false memories: Errors must be noticed and replaced. AB - Memory can be unreliable. For example, after reading The new baby stayed awake all night, people often misremember that the new baby cried all night (Brewer, 1977); similarly, after hearing bed, rest, and tired, people often falsely remember that sleep was on the list (Roediger & McDermott, 1995). In general, such false memories are difficult to correct, persisting despite warnings and additional study opportunities. We argue that errors must first be detected to be corrected; consistent with this argument, two experiments showed that false memories were nearly eliminated when conditions facilitated comparisons between participants' errors and corrective feedback (e.g., immediate trial-by-trial feedback that allowed direct comparisons between their responses and the correct information). However, knowledge that they had made an error was insufficient; unless the feedback message also contained the correct answer, the rate of false memories remained relatively constant. On the one hand, there is nothing special about correcting false memories: simply labeling an error as "wrong" is also insufficient for correcting other memory errors, including misremembered facts or mistranslations. However, unlike these other types of errors--which often benefit from the spacing afforded by delayed feedback--false memories require a special consideration: Learners may fail to notice their errors unless the correction conditions specifically highlight them. PMID- 26576566 TI - The pediatric gastrointestinal tract and ultrasonography. PMID- 26576567 TI - Echocardiography without electrocardiogram using nonlinear dimensionality reduction methods. AB - PURPOSE: The aim of this study is to evaluate the efficiency of a new automatic image processing technique, based on nonlinear dimensionality reduction (NLDR) to separate a cardiac cycle and also detect end-diastole (ED) (cardiac cycle start) and end-systole (ES) frames on an echocardiography system without using ECG. METHODS: Isometric feature mapping (Isomap) and locally linear embeddings (LLE) are the most popular NLDR algorithms. First, Isomap algorithm is applied on recorded echocardiography images. By this approach, the nonlinear embedded information in sequential images is represented in a two-dimensional manifold and each image is characterized by a symbol on the constructed manifold. Cyclicity analysis of the resultant manifold, which is derived from the cyclic nature of the heart motion, is used to perform cardiac cycle length estimation. Then, LLE algorithm is applied on extracted left ventricle (LV) echocardiography images of one cardiac cycle. Finally, the relationship between consecutive symbols of the resultant manifold by the LLE algorithm, which is based on LV volume changes, is used to estimate ED (cycle start) and ES frames. The proposed algorithms are quantitatively compared to those obtained by a highly experienced echocardiographer from ECG as a reference in 20 healthy volunteers and 12 subjects with pathology. RESULTS: Mean difference in cardiac cycle length, ED, and ES frame estimation between our method and ECG detection by the experienced echocardiographer is approximately 7, 17, and 17 ms (0.4, 1, and 1 frame), respectively. CONCLUSION: The proposed image-based method, based on NLDR, can be used as a useful tool for estimation of cardiac cycle length, ED and ES frames in echocardiography systems, with good agreement to ECG assessment by an experienced echocardiographer in routine clinical evaluation. PMID- 26576568 TI - JSUM ultrasound elastography practice guidelines: pancreas. AB - Ultrasound elastography is a relatively new diagnostic technique for measuring the elasticity (hardness) of tissue. Eleven years have passed since the debut of elastography. Various elastography devices are currently being marketed by manufacturers under different names. Pancreatic elastography can be used not only with transabdominal ultrasonography but also with endoscopic ultrasonography, but some types of elastography are difficult to perform for the pancreas. These guidelines aim to classify the various types of elastography into two major categories depending on the differences in the physical quantity (strain, shear wave), and to present the evidence for pancreatic elastography and how to use pancreatic elastography in the present day. But the number of reports on ultrasound elastography for the pancreas is still small, and there are no reports on some elastography devices for the pancreas. Therefore, these guidelines do not recommend methods of imaging and analysis by elastography device. PMID- 26576569 TI - Erratum to: JSUM ultrasound elastography practice guidelines: pancreas. PMID- 26576570 TI - Evolution of pancreas in aging: degenerative variation or early changes of disease? AB - Pancreatic changes in aging have been described for many decades. They involve not only pancreatic parenchyma but also pancreatic ductal, microscopic, and exocrine functional changes. There have been many studies of these changes based on pathology and various imaging modalities, as well as functional studies. The pancreatic volume was found to decrease with advancing age, with a higher incidence of pancreatic steatosis, as demonstrated in autopsy and imaging studies. The pancreatic ductal structure has been described with wide ranges of normal variation, but many studies have shown a tendency toward enlargement with advancing age. By endoscopic ultrasound imaging, the aging pancreas may exhibit abnormal findings similar to chronic pancreatitis. Microscopically, there has been evidence of patchy lobular fibrosis and papillary hyperplasia and demonstrable k-ras mutation in both normal and dysplastic ductal mucosa. The evidence of pancreatic exocrine insufficiency has yielded conflicting results, but most studies have shown a tendency toward decreased pancreatic exocrine function in the elderly. Differentiating pancreatic change in the elderly from early chronic pancreatitis may be difficult as there are limited studies to compare these two conditions in terms of structural and functional changes. PMID- 26576571 TI - Characterization of the biliary tract by virtual ultrasonography constructed by gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging. AB - PURPOSE: This study aimed at prospectively evaluating bile duct anatomy on ultrasonography and evaluating the safety and utility of radiofrequency ablation (RFA) assisted by virtual ultrasonography from gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI). METHODS: The institutional review board approved this study, and patients provided written informed consent prior to entry into the study. Bile duct anatomy was assessed in 201 patients who underwent Gd-EOB-DTPA-enhanced MRI for the evaluation of hepatic tumor. Eighty-one of these patients subsequently underwent RFA assisted by ultrasound imaging. In 23 patients, the tumor was located within 5 mm of the central bile duct, as demonstrated by MRI. RESULTS: Virtual ultrasonography constructed by Gd-EOB-enhanced MRI was able to visualize the common bile duct, left hepatic duct, and right hepatic duct in 96.5, 94.0, and 89.6 % of cases, respectively. The target hepatic tumor nodule and biliary duct could be detected with virtual ultrasonography in all patients, and no severe complications occurred. CONCLUSION: The running pattern of the bile ducts could be recognized on conventional ultrasound by referencing virtual ultrasonography constructed by Gd-EOB-DTPA-enhanced MRI. RFA assisted by this imaging strategy did not result in bile duct injury. PMID- 26576572 TI - How do the trends in the prenatal diagnosis of aneuploidy change after a non invasive prenatal test becomes available? A Japanese single center study. AB - PURPOSE: To clarify the trends in the use of the prenatal diagnosis of and screening for aneuploidy after a non-invasive prenatal test (NIPT) was made available at a single Japanese hospital. METHODS: The subjects included consecutive pregnant females who visited our hospital for maternal checkups and delivery between January 2012 and April 2014. After the subjects were divided into those who desired a prenatal diagnosis or screening before the availability of NIPT and those who did after the availability of NIPT, the frequencies of various prenatal diagnosis and screening procedures were compared between the two groups. RESULTS: A total of 544 patients who visited the hospital before NIPT was available and 703 who visited the hospital after NIPT became available were analyzed. While only 16.2 % of pregnant females received a prenatal diagnosis or screening before the NIPT was available, 27.5 % of them considered undergoing a prenatal diagnosis or screening after the NIPT was available before genetic counseling, and 24.0 % ultimately received a prenatal diagnosis or screening following genetic counseling. Of these patients, 7.7 % underwent NIPT. First trimester ultrasound screening for chromosomal abnormalities was unlikely to be selected (from 12.9 to 10.5 %, p = 0.212), although the rate of amniocentesis significantly increased after genetic counseling (from 1.5 to 3.7 %, p = 0.021). CONCLUSION: Since NIPT became available in 2013, pregnant females have demonstrated a deep interest in obtaining a prenatal diagnosis and screening. Whereas some patients choose to forgo a screening after receiving genetic counseling, others prefer invasive diagnostic tests in contrast to screening. PMID- 26576573 TI - Contrast-enhanced ultrasound for evaluation of renal trauma during acute hemorrhagic shock: a canine model. AB - PURPOSE: Contrast-enhanced ultrasound (CEUS) is a highly specific and sensitive method for assessing hemodynamically stable patients with blunt abdominal trauma. We evaluated the efficacy of CEUS in assessing renal trauma in different states of hemodynamic instability or shock. METHODS: Hemorrhagic renal lesions reflecting grade III-IV trauma were established in the kidneys of 25 mongrel dogs. Mild, moderate, and severe systemic hypotension was induced by controlled exsanguination. The features of renal trauma in CEUS and contrast-enhanced computed tomography (CECT) were assessed and compared before shock and during shock progression. RESULTS: Gross pathology showed that with trauma, the kidneys gradually shrank and became soft, and the active bleeding in the area of the renal trauma gradually reduced and stopped. No significant differences were observed in the trauma detection rates between CEUS and CECT at any stage of shock. During the baseline and mild shock stage, sonograms obtained after intravenous injection of contrast agent showed marked contrast medium extravasation and pooling at the site of active bleeding. With shock progression, the difference in enhancement between trauma areas and the surrounding renal tissue decreased: the trauma areas became indistinct and the abnormal enhancement associated with active bleeding diminished. Further, CEUS enabled visualization of changes in renal perfusion associated with shock progression. Changes in contrast agent arrival time and the time to peaking were observed earliest in the mild shock model. The contrast agent peak intensity reduced, while the washout time increased as shock progressed from moderate to severe. CONCLUSION: In our canine model, CEUS was found to be as accurate as CECT in assessing hemorrhagic renal lesions. Thus, CEUS seems a promising tool for monitoring hemodynamic changes and predicting early shock to enable the conservative treatment of severe renal trauma. PMID- 26576574 TI - Effects of gradual low-flow reperfusion postconditioning on ischemia-reperfusion injury involving incomplete testicular torsion in rabbits. AB - PURPOSE: The aim of this study was to investigate the impacts of gradual low-flow reperfusion postconditioning (GLFRP) on testicular ischemia-reperfusion injury (IRI). METHODS: A rabbit testicular ischemia model was established, and rabbits were divided into mild ischemia groups (the IRm, IPm1, IPm2, IPm3, and IPm4 groups) and moderate ischemia groups (the IRM, IPM1, IPM2, IPM3, and IPM4 groups). The IRm and IRM groups underwent direct reperfusion. The IPm1 and IPM1 groups, and the IPm3 and IPM3 groups, received 45 and 30 s maintained low-flow reperfusion. The IPm2 and IPM2 groups, and the IPm4 and IPM4 groups, were subjected to 45 and 30 s gradual low-flow reperfusion. The SOD and Johnsen's score of testicular tissue on the surgical side 3 days after reperfusion were determined. RESULTS: The SOD activities in the IP3 and IP4 groups were higher than those in the IR, IP1, and IP2 groups (P < 0.05), and those in the IP4 group were higher than those in the IP3 group (P < 0.05). The Johnsen's score in the IPm4 group was higher than that in the other groups (P < 0.05), those in the IPM groups were higher than those in the IRM group (P < 0.05), and those in the IPM3 and IPM4 groups were higher than those in the IPM1 and IPM2 groups (P < 0.05). CONCLUSIONS: GLFRP could effectively reduce testicular IRI. PMID- 26576575 TI - The reliability of color doppler "twinkling" artifact for diagnosing millimetrical nephrolithiasis: comparison with B-Mode US and CT scanning results. AB - PURPOSE: To compare the effectiveness of B-Mode and color-Doppler ultrasound imaging features, including "twinkling-artifact" with unenhanced CT for detecting millimetrical nephrolithiasis. METHODS: 397 patients were examined for suspected urolithiasis with US and CT were included. US findings such as echogenic focuses, posterior acoustic shadowing and twinkling artifact were examined for their ability to detect millimetricalcalculies (greatest diameter <=5 mm) using CT findings as the gold-standard. The accuracy of US for measuring stone size was also investigated. RESULTS: 219 millimetriccalculies in 164 cases were detected by CT. The sensitivity and positive-predictive-values for the detection of microcalculies were 76.7 and 94.9 %, 85.8 and 88.3 %, 40.6 and 97.8 %, 68.9 and 94.4 %, and 38.4 and 97.7 % for the presence of B-Mode echogenity, twinkling artifact, B-Mode echogenity with acoustic shadowing, B-Mode echogenity with twinkling-artifact, B-Mode echogenity with acoustic shadowing and twinkling artifact, respectively. No significant difference between US and CT was observed in quantification of nephrolithiasis sizes (p = 913). CONCLUSION: Twinkling artifact based color-Doppler US is preferable for the sensitive detection of millimetrical nephrolithiasis; however, the high false-positive value of this technique, which can lead to an overestimation of the stone number, has to be considered. PMID- 26576576 TI - Clinical implications of ultrasound artifacts in the cervicofacial area following injection of permanent facial fillers. AB - PURPOSE: To evaluate ultrasound (US) findings in the cervicofacial area following injection of permanent facial fillers during a long-term follow-up period. METHODS: Fifty-seven consecutive patients with a history of previous facial filler injection were enrolled at a single institution between 2010 and 2014. All patients were female, and the mean age of the patients was 60.8 years. The mean follow-up period following injection of facial fillers was 16.6 years (range 2-30 years). We analyzed US findings in the face (injection site) and neck (noninjection site). RESULTS: In all patients, face US revealed a snowstorm appearance with strong posterior acoustic shadows and multifocal small anechoic lesions with posterior stepladder artifacts in the subcutaneous fat. Neck US demonstrated the same artifacts as those on the face through local spread of fillers in 14 patients (26.4 %) and abnormal cervical lymph nodes through lymphatic spread in 34 patients (59.6 %). In abnormal cervical lymph nodes, hyperechogenicity and multiple hyperechoic foci were observed in 26 (45.6 %) and 19 (33.3 %) patients, respectively. CONCLUSION: Various artifacts may be demonstrated on US in patients with injection of permanent facial fillers. When hyperechogenicity or multiple hyperehoic foci are seen in cervical lymph nodes, the possibility of migration of facial fillers to the cervical area should be considered. PMID- 26576578 TI - Paradoxical increase in E/e' ratio after treatment of heart failure in two patients with preserved ejection fraction. AB - We report an increase in E/e' ratio after treatment of heart failure (HF) in two patients. In case 1, the E/e' ratio increased from 15 to 18 after treatment of HF. In case 2, the E/e' ratio also increased from 24 to 35. Although a high E/e' ratio suggests high pulmonary artery wedge pressure and worsening HF, the ratio may increase after improvement of HF.In the present cases of diastolic dysfunction, the high E wave did not change, but the e' wave decreased relatively. This report may suggest difficulty in evaluating hemodynamic status based on the E/e' ratio in patients with diastolic dysfunction. PMID- 26576577 TI - Relationship of intraoperative ultrasound characteristics with pathological grades and Ki-67 proliferation index in intracranial gliomas. AB - OBJECTIVE: The purpose of the present study was to investigate the relationship between the intraoperative ultrasonographic appearances and the histopathological characteristics of glial tumors using the pathological grading system and the Ki 67 proliferation index. MATERIALS AND METHODS: Patients with glial tumors who underwent surgery with the aid of intraoperative ultrasonography (IOUS) between September 2013 and August 2014 were included in the study. The lesions' IOUS characteristics were analyzed and compared with the results of surgical histopathological characteristics. Lesions were classified as low-grade gliomas (grade I-II, LGG) and high-grade gliomas (grade III-IV, HGG). The glioblastoma multiforme (grade IV, GBM) group was classified according to the Ki-67 values for further evaluation. The Chi square test (Fisher's exact test) was used for comparing the ultrasonographic characteristics of the low-grade and high-grade gliomas; HGG with different Ki-proliferation indexes. A value of P < 0.05 was considered statistically significant. RESULTS: A total of 41 patients were included. The histopathological findings revealed 15 LGG and 26 HGG. Twenty of the 26 HGG were GBM. Differences were found between the intraoperative ultrasonographic characteristics of the low-grade and high-grade glial tumors. The majority of LGGs were mildly hyperechoic and homogeneous, with distinct margins and a regular contour. HGGs were mostly highly hyperechoic, with indistinct margins, irregular contours, and a heterogeneous internal texture. Surrounding edema was seen more often in HGGs. The differences in the echogenicity of the solid parts, the internal echo patterns, margins, contours, and peripheral edema (P < 0.05) were statistically significant, but the difference in the presence of cysts (P > 0.05) was not significant. In the GBM group, all of the lesions with distinct margins and regular contours had Ki-67 values <=15 %. We compared the intraoperative ultrasonographic characteristics of the Ki-67 > 15 % group with those of the Ki-67 <= 15 % group for statistical significance. The difference between the echogenicity of the solid parts, margins, and contours was statistically significant between the groups (P < 0.05). The difference in the internal echo pattern, presence of cyst, and peripheral edema was insignificant (P > 0.05). CONCLUSIONS: IOUS is a very useful imaging technique not only in defining the borders but also in characterizing the tumoral tissue. The IOUS characteristics of the glial tumors were a valuable tool in differentiating the grades of the glial tumors and might have a relationship with the Ki-67 proliferation index. We think this theory requires further investigation in more detailed comparative studies with larger numbers of patients. PMID- 26576579 TI - A rare case of fungal endocarditis caused by Candida glabrata after completion of antibiotic therapy for Streptococcus endocarditis. AB - We present the rare case of a 76-year-old female with infective endocarditis (IE) caused by Candida glabrata. Immediately before developing the present infection, she developed IE with vegetation on the mitral annular calcification, which was caused by Streptococcus mitis and successfully treated with penicillin-G and gentamicin. However, her fever recurred, and she developed disseminated intravascular coagulation. Blood culture revealed C. glabrata, and echocardiography revealed new vegetation on the mitral valve. After 4 weeks of treatment with micafungin, prosthetic valve replacement was performed, followed by additional administration of micafungin for 4 weeks (total of 8 weeks). No relapse at 9 months after surgery has been observed. C. glabrata endocarditis is extremely rare and difficult to manage. Our case and review of past reported cases suggest that early diagnosis and initiation of treatment contribute to good prognosis of C. glabrata endocarditis. PMID- 26576580 TI - Hypopharyngeal perforation caused by intraoperative transesophageal echocardiography. AB - Intraoperative transesophageal echocardiography (TEE) is an invaluable tool for cardiac surgical decision-making. TEE is considered reasonably noninvasive and safe, but insertion and manipulation of the TEE probe can lead to complications. Here, we report a patient with aortic stenosis who experienced TEE-associated hypopharyngeal perforation at the pyriform sinus complicated by esophageal trauma, pneumomediastinum and pneumoretroperitoneum. Based on this case, we suggest that rare complications be kept in mind when using TEE intraoperatively. PMID- 26576581 TI - Primary lymphoma of the spleen mimicking simple benign cysts: contrast-enhanced ultrasonography and other imaging findings. AB - We report on a case of incidentally detected primary splenic lymphoma mimicking simple benign cysts on abdominal ultrasonography. On contrast-enhanced ultrasonography (CEUS), the lesions showed isoenhancement in the arterial phase with progressive washout and marked hypoenhancement in the parenchymal phase. This pattern enabled us to suspect the malignant nature of the disease, thus preventing a dangerous misdiagnosis. Accordingly, further characterization with other imaging studies (computed tomography, magnetic resonance imaging, and positron emission tomography) was pursued based on CEUS and taking into account the patient's clinical picture and medical history. Collectively, imaging data led us to a diagnosis of suspected primary splenic malignancy, most probably lymphoma, which was histologically confirmed on the surgical specimen after splenectomy. PMID- 26576582 TI - A case of mucinous cystic neoplasm of the pancreas misdiagnosed as a pancreatic pseudocyst at the initial exam and resected after a 2-year follow-up. AB - A 44-year-old woman was referred to our hospital because of a cystic lesion in the pancreatic body that was found by computed tomography (CT) as a result of a screening for impaired liver function after the patient presented with a high fever in 2011. Trans-abdominal ultrasonography (US) revealed a 33-mm unilocular cyst within the pancreatic body and a 5-mm hypoechoic mass in the pancreatic neck. Contrast-enhanced CT showed a slight enhancement around the cyst and a mild dilation of the main pancreatic duct, but neither septum nor nodule was detected inside. Contrast-enhanced endoscopic ultrasonography (CE-EUS) revealed a hyperechoic elevated lesion inside the cystic lesion without enhancement in the pancreatic body; CE-EUS also revealed a 5-mm homogeneous hypoechoic mass with a remarkable enhancement in the pancreatic neck with the use of Sonazoid((r)) as a contrast medium. These lesions were diagnosed as a pancreatic pseudocyst and a neuroendocrine tumor (NET), respectively, and were followed up with periodic examinations. The cystic lesion showed contraction 6 months after the initial exam. However, US revealed an enlargement of the cystic lesion to 40 mm in diameter 2 years after the initial exam, and EUS showed irregular thickening of the wall with a cyst-in-cyst appearance. The diagnoses of a mucinous cystic neoplasm (MCN) and a concomitant small NET were made after a distal pancreatectomy. We herein report a rare case of MCN that showed various morphological changes over 2 years of observation. PMID- 26576583 TI - Contrast-enhanced ultrasound findings in a case of primary chest chondrosarcoma mimicking a porta hepatis mass. AB - We report a case of a 32-year-old woman who presented with upper abdominal pain. The physical examination revealed a palpable hard mass with a well-demarcated lower margin. Laboratory tests indicated hepatitis B viral infection. Computed tomography scan with intravenous contrast depicted a huge well-demarcated heterogeneous mass at the porta hepatis with irregular peripheral rim enhancement. Contrast-enhanced ultrasound showed peripheral irregular hyper enhancement in the artery phase and hypo-enhancement in the portal and late phases. The postoperative histopathologic examination confirmed the diagnosis of low-grade chondrosarcoma. This is the first report of contrast-enhanced ultrasound findings of chondrosarcoma. There is some differential diagnosis to be discussed. PMID- 26576584 TI - Neuroendocrine tumor of gallbladder with liver and retroperitoneal metastases and a good response to the chemotherapeutical treatment. AB - Neuroendocrine carcinoma of the gallbladder is an uncommon disease. We present the case of a 45-year-old woman with a mass located in the gallbladder, whose diagnosis was based on contrast-enhanced ultrasound and magnetic resonance imaging. The tumor involved the liver and retroperitoneum, and was histopathologically confirmed by liver biopsy as a neuroendocrine tumor grade 3. The patient received chemotherapy with good response, followed by surgery with cholecystectomy and partial hepatectomy. PMID- 26576585 TI - Endoscopic ultrasonography of duodenal aberrant pancreas: comparison with histology after endoscopic resection. AB - We present the case of a 45-year-old man with an aberrant pancreas in the duodenum. He was referred to our hospital for gastric cancer screening. On upper gastrointestinal endoscopy, a submucosal tumor was noted in the second portion of the duodenum; it was 10 mm in diameter, with a smooth surface and bridging fold. Endoscopic ultrasonography (EUS) showed a hypoechoic lesion with small anechoic areas located in the third sonographic layer of the duodenum wall. To confirm the exact diagnosis, endoscopic resection was performed. The histological diagnosis was aberrant pancreas, Heinrich type II. The hypoechoic lesion and anechoic areas on EUS findings clearly corresponded with pancreatic acinus cells and duct dilation on histological findings, respectively. EUS findings are useful to diagnosis a duodenal aberrant pancreas that has ductal structures. PMID- 26576586 TI - Three-dimensional and four-dimensional HDlive-rendered images of thanatophoric dysplasia. AB - We present herein our first experience with a case of thanatophoric dysplasia (type I) that was diagnosed during the second trimester using three- and four dimensional HDlive ultrasonography. The HDlive rendering mode clearly showed the anatomical features of thanatophoric dysplasia: external malformations and skeletal abnormalities, including extremely short limbs, flattened vertebral bodies, and short horizontal ribs, among others. HDlive can provide valuable, highly realistic images for the differential diagnosis of skeletal dysplasia. It may also play an important complementary role when conventional two- and three dimensional ultrasonography does not provide sufficient definition. PMID- 26576588 TI - A kinked aortic tube graft after aortic root replacement causes heart failure: usefulness of the right parasternal approach on echocardiography. PMID- 26576587 TI - Successful ultrasound imaging of pulmonary sub-pleural hamartoma. AB - Pulmonary hamartoma, a common benign tumor of the lung, often presents as a solitary nodule on the peripheral lung, and is mainly composed of bronchial mucosa epithelial cells, chondrocytes, and adipose cells. Here, we report the case of a 42-year-old female who had a lung nodule that appeared as a homogeneous high-density shadow of a peripheral localization on chest computed tomography scan. For further evaluation, transthoracic ultrasonography examination was performed, which revealed a round, heterogenous, hypoechoic mass attached to the visceral pleura and showing obvious respiratory motions on the real-time ultrasonic images. Video-assisted thoracoscopic operation with ultrasound marking was performed, and a tumor 1.5 * 1.0 cm in size was successfully removed from this patient. The pathohistological diagnosis was pulmonary hamartoma, and the patient was successfully cured. PMID- 26576589 TI - Importance of ultrasound in work-up of a cystic neck mass. PMID- 26576590 TI - Descendent migration in vasa previa. PMID- 26576591 TI - Assessing the Deployment of Home Visiting: Learning from a State-Wide Survey of Home Visiting Programs. AB - OBJECTIVES: Large-scale planning for health and human services programming is required to inform effective public policy as well as deliver services to meet community needs. The present study demonstrates the value of collecting data directly from deliverers of home visiting programs across a state. This study was conducted in response to the Patient Protection and Affordable Care Act, which requires states to conduct a needs assessment of home visiting programs for pregnant women and young children to receive federal funding. In this paper, we provide a descriptive analysis of a needs assessment of home visiting programs in Ohio. METHODS: All programs in the state that met the federal definition of home visiting were included in this study. Program staff completed a web-based survey with open- and close-ended questions covering program management, content, goals, and characteristics of the families served. RESULTS: Consistent with the research literature, program representatives reported great diversity with regard to program management, reach, eligibility, goals, content, and services delivered, yet consistently conveyed great need for home visiting services across the state. CONCLUSIONS: Results demonstrate quantitative and qualitative assessments of need have direct implications for public policy. Given the lack of consistency highlighted in Ohio, other states are encouraged to conduct a similar needs assessment to facilitate cross-program and cross-state comparisons. Data could be used to outline a capacity-building and technical assistance agenda to ensure states can effectively meet the need for home visiting in their state. PMID- 26576592 TI - Relationship Between Dietary Sugar Intake and Dental Caries Among Japanese Preschool Children with Relatively Low Sugar Intake (Japan Nursery School SHOKUIKU Study): A Nationwide Cross-Sectional Study. AB - OBJECTIVES: The WHO has recently proposed to halve the recommendation for free sugar intake from 10 to 5 % of energy intake to reduce the incidence of diseases such as obesity and dental caries. The Japanese population is suitable to confirm the appropriateness of this proposal, because dietary sugar intake in Japan is exceptionally low among developed countries. We sought to establish a method to estimate dietary sugar intake in Japan and to examine the relationship between sugar and the number of dental caries using data obtained from the Japan Nursery School SHOKUIKU study. METHODS: Dietary intake during the preceding month and the number of caries was examined in children aged 5-6 years using a brief-type self administered diet history questionnaire for Japanese preschool children completed by their guardians and another questionnaire on lifestyle. Multivariate Poisson regression models were used for the analysis. RESULTS: When subjects were ranked into quintiles by the proportion of energy from free sugar, those in higher quintiles had more caries than those in the lowest quintile. On close analysis, the number of caries among children with a relatively small proportion of energy intake from free sugar (3.18-3.77 %) was not significantly different from that in the lowest group (0.95-3.17 %). CONCLUSIONS: The recent proposition of WHO might be valid, because the adverse effect of relatively small proportion (approximately less than 5 %) of energy intake from free sugar on caries was not detected among the subjects in this study. However, more study will be necessary to reach a conclusion. PMID- 26576594 TI - [The disease and the humanities]. PMID- 26576593 TI - S0502: A SWOG Phase III Randomized Study of Imatinib, With or Without Bevacizumab, in Patients With Untreated Metastatic or Unresectable Gastrointestinal Stromal Tumors. AB - LESSONS LEARNED: Despite having significant rationale, S0502 failed to accrue for a number of reasons.Vetting a trial first, with scientific experts and funding agencies, does not guarantee success, especially when dealing with a rare tumor and/or one with an existing highly effective therapy.In the present case, adding an intravenous drug to an oral medication as part of a regimen expected to be continued for many years likely decreased patient (and physician) convenience and, thus, interest in the study. BACKGROUND: Imatinib mesylate, a potent inhibitor of the KIT and PDGFR tyrosine kinases, is highly effective in the treatment of advanced gastrointestinal stromal tumors (GISTs). However, most imatinib-treated tumors eventually become resistant, accounting for a median progression-free survival of 19-23 months. Expression of vascular endothelial growth factor (VEGF) correlates with poor prognosis in GIST; bevacizumab, a monoclonal antibody against VEGF, is effective in a variety of solid tumors. We postulated combination therapy with imatinib plus bevacizumab would benefit patients with advanced GIST, particularly those reliant on VEGFA-dependent angiogenesis. METHODS: Patients with metastatic or surgically unresectable GIST were eligible for this phase III open-label clinical trial, S0502. At registration, patients were randomly assigned to either imatinib 400 mg (standard) or 800 mg (patients with exon 9 KIT mutations), or imatinib plus bevacizumab, 7.5 mg/kg i.v. every 3 weeks. Patients were treated to progression, symptomatic deterioration, unacceptable toxicity, treatment delay greater than 4 weeks, or patient choice to withdraw from the study. The primary objective was to determine whether the addition of bevacizumab to imatinib would improve progression-free survival (PFS) in first-line treatment of incurable GIST. RESULTS: S0502 opened on April 15, 2008. As of fall 2009, only 12 patients from at least 178 eligible SWOG centers plus those participating through Cancer Trials Support Unit had been entered in the study. Despite an aggressive promotion scheme involving the other cooperative groups and a major GIST patient advocacy group, accrual remained slow. The trial was closed on October 1, 2009, having accrued only 2% of the 572 patients planned. No scientific conclusions were forthcoming because of the small number of patients entered in the study. Two patients of the 6 in the combination arm reported grade 3 toxicities, 1 with proteinuria and 1 with fatigue, upper gastrointestinal hemorrhage, and anemia. CONCLUSION: No conclusions may be drawn from this trial and, thus, the combination of imatinib plus bevacizumab cannot be recommended for use. PMID- 26576595 TI - [The emerging concept of lung mycobiome]. PMID- 26576596 TI - [Lung resistome]. PMID- 26576598 TI - [Cerebral lymphatic drainage: implication in the brain immune privilege]. PMID- 26576597 TI - [HNF4alpha: a prince charming for terminal hepatic failure?]. PMID- 26576599 TI - [An implication of serotonergic fibers which goes beyond Levodopa-induced dyskinesia]. PMID- 26576600 TI - [Enhancing our single molecule experience using Crispr]. PMID- 26576601 TI - [Global changes and snail-borne disease: an hybrid schistosome reaches Europe]. PMID- 26576602 TI - [SphingomabTM, an anti-sphingosine 1-phosphate antibody to inhibit hypoxia]. PMID- 26576603 TI - [Postnatal subventricular zone regionalization by morphogens]. PMID- 26576604 TI - [The lung microbiome in 2015: a window on chronic lung diseases]. AB - Recent development of high-throughput sequencing methods has shown that the human respiratory tract (including lower airways) is not sterile as formerly thought, but composed of a previously unappreciated complex microbial community referred as the lung microbiome and composed of bacteria, viruses and fungi. However, many questions remain unresolved, especially in terms of lung microbiome role, its interactions with host but also with environmental pathogens. Although data are still limited, links have already been demonstrated between lung microbiome and chronic respiratory diseases (such as asthma, chronic obstructive pulmonary disease or cystic fibrosis). This lung microbiome appears to play an important role both in disease genesis and evolution, and consequently offers an emerging research field. PMID- 26576605 TI - [Neuroinflammation: Dr Jekyll or Mr Hyde?]. AB - Sheltered in a bony cage, populated by cells with little regenerative potential, the central nervous system (CNS) could likely not withstand classic inflammation without risking major sequelae. As a consequence, it had to develop an original way to provide surveillance, defence and reparation, which relies on both the complex architecture of the periphery-nervous parenchyma exchange zones, and the tightly regulated collaboration between all the cell populations that reside in or pass through the CNS. Despite its tight regulation, neuroinflammation is sometimes the cause of irreversible loss but it is also where the solution stands. The specific immune crosstalk that takes place in the CNS needs to be decoded in order to identify the best therapeutic strategies aimed at helping the CNS to restore homeostasis in problematic situations, such as in the case of neurodegenerative disorders. This review deals with this double-edged sword nature of neuroinflammation. PMID- 26576606 TI - [Tumor angiogenesis: when the Tree of Life turns bad]. AB - Angiogenesis is a highly controlled multistep process that allows the formation of a harmonious vascular network during embryonic development and in adults. In addition, tumor progression also involves a dedicated blood vessel supply to fuel the tumor mass, pirating physiological molecular and cellular mechanisms. However, tumor angiogenesis is a quite inefficient process, as perfusion is not optimal, vessel integrity is not guaranteed, and vessel network is irrationally organized. While fundamental molecular and cellular mechanisms have been the field of intense investigation, anticancer therapies have evolved with the possibility to target tumor angiogenesis. This review presents the different steps involved in the formation of normal and tumor angiogenesis, and how tumor vasculature abnormalities could contribute to tumorigenesis and conventional therapy failure. PMID- 26576607 TI - [Phosphoinositides: the lipids coordinating cell dynamics]. AB - Within the glycerophospholipid family, phosphoinositides, which are minor components of eukaryotic cell membranes, play a critical role as spatiotemporal organizers of cell dynamics. By specifically interacting with proteins, they coordinate the formation and the organization of multiprotein complexes involved in cell signaling, intracellular trafficking and cytoskeleton rearrangement. The highly precise spatiotemporal dynamics of phosphoinositides-regulated mechanisms is ensured by kinases and phosphatases that specifically produce, hydrolyze and control the interconversion of these lipids. The direct implication of these enzymes in human pathologies such as genetic diseases, cancer or infectious pathologies, and the recent arrival of inhibitors targeting some phosphoinositide kinases in clinic, illustrate the mandatory functions of these fascinating lipids. PMID- 26576608 TI - [Ageing: a matter of heart?]. AB - Ageing is considered as a major risk factor for the development of chronic diseases. Among these, heart failure seems to be particularly important for both triggering and accelerating pathological ageing. In the present review, we give a general overview of the most relevant results concerning the mechanism of normal and premature senescence of cardiomyocytes and cardiac stromal cells. In particular, we will address the role of telomere dysfunction, DNA damage response, impairment of mitochondrial function, miRNAs and secretome of senescent cells in cardiac ageing and failure. PMID- 26576609 TI - [The CRISPR system can correct or modify the expression of genes responsible for hereditary diseases]. AB - A new technology, called CRISPR, derived from the immune system of bacteria, uses a Cas9 nuclease and a guided RNA complementary to a 20 nucleotides sequence of a gene to induce double strand DNA breaks. This permits to modify specifically the targeted gene in plant, animal and human cells. Variants of the technique also permit to reduce or increase the expression of a selected gene. This technology may thus be used not only to understand the role of a gene but also to develop therapies for hereditary and acquired diseases. PMID- 26576610 TI - [Molecular pathogenesis of peripheral T cell lymphoma (2): extranodal NK/T cell lymphoma, nasal type, adult T cell leukemia/lymphoma and enteropathy associated T cell lymphoma]. AB - Peripheral T-cell lymphomas (PTCL) belong to the group of non-Hodgkin lymphoma and particularly that of mature T /NK cells lymphoproliferative neoplasms. The 2008 WHO classification describes different PTCL entities with varying prevalence. With the exception of histologic subtype "ALK positive anaplastic large cell lymphoma", PTCL are characterized by a poor prognosis. The mechanisms underlying the pathogenesis of these lymphomas are not yet fully understood, but development of genomic high-throughput analysis techniques now allows to extensively identify the molecular abnormalities present in tumor cells. This review aims to summarize the current knowledge and recent advances about the molecular events occurring at the origin or during the natural history of main entities of PTCL. The first part published in the October issue was focused on the three more frequent entities, i.e. angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma, not otherwise specified, and anaplastic large cell lymphoma. The second part presented herein will describe other subtypes less frequent and of poor prognosis : extranodal NK/T-cell lymphoma, nasal type, adult T-cell leukemia/lymphoma, and enteropathy-associated T-cell lymphoma. PMID- 26576611 TI - [CRISPR-Cas9, a new chance for somatic gene therapy]. AB - Targeted modification of genes ("gene editing") is made much easier by the recently developed CRISPR-Cas9 system. This has raised alarm about possible uses of this technology for germline modification of the human genome; however this technology has less controversial applications, notably for somatic gene therapy with already some striking demonstrations in animal systems. Because of its precision and relative ease of use, CRISPR can be expected to drive a revolution in gene therapy and to turn it into a more mainstream approach. PMID- 26576612 TI - [Involvement of researchers with patient associations: what is the role of their opinions, their clinical activity and their nature?]. AB - Although the involvement of patient associations in biomedical research is well known, conversely, researchers' views and perceptions of these associations have remained unknown. For this reason, Inserm's Patients' Association Liaison Group (GRAM) launched the CAIRNET survey in 2012, based on questionnaires and interviews conducted with researchers working at Inserm. The variety of their opinions made it possible to distinguish four profiles, the committed, the pragmatic, the reticent and the distant. Thus 41 % of respondents reported ongoing relationships with at least one association, 72 % for the committed and 16 % for the distant. Although these relationships are formed more easily among researchers involved in clinical activity, they also encourage collaborations between clinicians and basic researchers. The apparently lower degree of involvement of female researchers proved to be associated with a lower level of clinical activity, limited permanent recruitment, and a lower hierarchical status. PMID- 26576613 TI - Evaluation of data discretization methods to derive platform independent isoform expression signatures for multi-class tumor subtyping. AB - BACKGROUND: Many supervised learning algorithms have been applied in deriving gene signatures for patient stratification from gene expression data. However, transferring the multi-gene signatures from one analytical platform to another without loss of classification accuracy is a major challenge. Here, we compared three unsupervised data discretization methods--Equal-width binning, Equal frequency binning, and k-means clustering--in accurately classifying the four known subtypes of glioblastoma multiforme (GBM) when the classification algorithms were trained on the isoform-level gene expression profiles from exon array platform and tested on the corresponding profiles from RNA-seq data. RESULTS: We applied an integrated machine learning framework that involves three sequential steps; feature selection, data discretization, and classification. For models trained and tested on exon-array data, the addition of data discretization step led to robust and accurate predictive models with fewer number of variables in the final models. For models trained on exon-array data and tested on RNA-seq data, the addition of data discretization step dramatically improved the classification accuracies with Equal-frequency binning showing the highest improvement with more than 90% accuracies for all the models with features chosen by Random Forest based feature selection. Overall, SVM classifier coupled with Equal-frequency binning achieved the best accuracy (> 95%). Without data discretization, however, only 73.6% accuracy was achieved at most. CONCLUSIONS: The classification algorithms, trained and tested on data from the same platform, yielded similar accuracies in predicting the four GBM subgroups. However, when dealing with cross-platform data, from exon-array to RNA-seq, the classifiers yielded stable models with highest classification accuracies on data transformed by Equal frequency binning. The approach presented here is generally applicable to other cancer types for classification and identification of molecular subgroups by integrating data across different gene expression platforms. PMID- 26576615 TI - EHMT2 directs DNA methylation for efficient gene silencing in mouse embryos. AB - The extent to which histone modifying enzymes contribute to DNA methylation in mammals remains unclear. Previous studies suggested a link between the lysine methyltransferase EHMT2 (also known as G9A and KMT1C) and DNA methylation in the mouse. Here, we used a model of knockout mice to explore the role of EHMT2 in DNA methylation during mouse embryogenesis. The Ehmt2 gene is expressed in epiblast cells but is dispensable for global DNA methylation in embryogenesis. In contrast, EHMT2 regulates DNA methylation at specific sequences that include CpG rich promoters of germline-specific genes. These loci are bound by EHMT2 in embryonic cells, are marked by H3K9 dimethylation, and have strongly reduced DNA methylation in Ehmt2(-/-) embryos. EHMT2 also plays a role in the maintenance of germline-derived DNA methylation at one imprinted locus, the Slc38a4 gene. Finally, we show that DNA methylation is instrumental for EHMT2-mediated gene silencing in embryogenesis. Our findings identify EHMT2 as a critical factor that facilitates repressive DNA methylation at specific genomic loci during mammalian development. PMID- 26576616 TI - Experiences of Intimate Partner and Neighborhood Violence and Their Association With Mental Health in Pregnant Women. AB - Both intimate partner violence and neighborhood crime have been associated with worse mental health outcomes, but less is known about cumulative effects. This association was studied in a sample of pregnant women who were enrolled in a study of disaster exposure, prenatal care, and mental and physical health outcomes between 2010 and 2012. Women were interviewed about their exposure to intimate partner violence and perceptions of neighborhood safety, crime, and disorder. Main study outcomes included symptoms of poor mental health; including depression, pregnancy-specific anxiety (PA), and posttraumatic stress disorder (PTSD). Logistic regression was used to examine predictors of mental health with adjustment for confounders. Women who experienced high levels of intimate partner violence and perceived neighborhood violence had increased odds of probable depression in individual models. Weighted high cumulative (intimate partner and neighborhood) experiences of violence were also associated with increased odds of having probable depression when compared with those with low violence. Weighed high cumulative violence was also associated with increased odds of PTSD. This study provides additional evidence that cumulative exposure to violence is associated with poorer mental health in pregnant women. PMID- 26576614 TI - Massively parallel cis-regulatory analysis in the mammalian central nervous system. AB - Cis-regulatory elements (CREs, e.g., promoters and enhancers) regulate gene expression, and variants within CREs can modulate disease risk. Next-generation sequencing has enabled the rapid generation of genomic data that predict the locations of CREs, but a bottleneck lies in functionally interpreting these data. To address this issue, massively parallel reporter assays (MPRAs) have emerged, in which barcoded reporter libraries are introduced into cells, and the resulting barcoded transcripts are quantified by next-generation sequencing. Thus far, MPRAs have been largely restricted to assaying short CREs in a limited repertoire of cultured cell types. Here, we present two advances that extend the biological relevance and applicability of MPRAs. First, we adapt exome capture technology to instead capture candidate CREs, thereby tiling across the targeted regions and markedly increasing the length of CREs that can be readily assayed. Second, we package the library into adeno-associated virus (AAV), thereby allowing delivery to target organs in vivo. As a proof of concept, we introduce a capture library of about 46,000 constructs, corresponding to roughly 3500 DNase I hypersensitive (DHS) sites, into the mouse retina by ex vivo plasmid electroporation and into the mouse cerebral cortex by in vivo AAV injection. We demonstrate tissue specific cis-regulatory activity of DHSs and provide examples of high-resolution truncation mutation analysis for multiplex parsing of CREs. Our approach should enable massively parallel functional analysis of a wide range of CREs in any organ or species that can be infected by AAV, such as nonhuman primates and human stem cell-derived organoids. PMID- 26576617 TI - Domestic Property Violence: A Distinct and Damaging Form of Parent Abuse. AB - This article reports on the qualitative phase of mixed method research conducted in a medium-size city in New Zealand, which examined 14 parents' experiences of child- and youth-perpetrated domestic property violence (DPV). The research used semi-structured interviews and interpretative phenomenological analysis, enabling parents' perceptions of the causes and impacts of this form of family violence to be explored in depth. Three superordinate themes were identified in the analysis: damage done, the various impacts of DPV; staying safe and sane; and making sense of DPV, parents' perspectives. An ecological meaning-making theory emerged from the data and provided an overarching interpretative framework for considering the themes both separately and together. The findings showed that DPV is a distinct form of parent abuse and one that can have serious impacts of a financial, emotional, and relational nature. The theoretical and practical implications of the findings are discussed along with ideas for further research into this problem. PMID- 26576618 TI - Follow-Up Renal Assessment of Injury Long-Term After Acute Kidney Injury (FRAIL AKI). AB - BACKGROUND AND OBJECTIVES: Novel urinary kidney damage biomarkers detect AKI after cardiac surgery using cardiopulmonary bypass (CPB-AKI). Although there is growing focus on whether AKI leads to CKD, no studies have assessed whether novel urinary biomarkers remain elevated long term after CPB-AKI. We assessed whether there was clinical or biomarker evidence of long-term kidney injury in patients with CPB-AKI. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed a cross sectional evaluation for signs of chronic kidney injury using both traditional measures and novel urinary biomarkers in a population of 372 potentially eligible children (119 AKI positive and 253 AKI negative) who underwent surgery using cardiopulmonary bypass for congenital heart disease at Cincinnati Children's Hospital Medical Center between 2004 and 2007. A total of 51 patients (33 AKI positive and 18 AKI negative) agreed to long-term assessment. We also compared the urinary biomarker levels in these 51 patients with those in healthy controls of similar age. RESULTS: At long-term follow-up (mean duration+/-SD, 7+/-0.98 years), AKI-positive and AKI-negative patients had similarly normal assessments of kidney function by eGFR, proteinuria, and BP measurement. However, AKI positive patients had higher urine concentrations of IL-18 (48.5 pg/ml versus 20.3 pg/ml [P=0.01] and 20.5 pg/ml [P<0.001]) and liver-type fatty acid-binding protein (L-FABP) (5.9 ng/ml versus 3.9 ng/ml [P=0.001] and 3.2 ng/ml [P<0.001]) than did AKI-negative patients and healthy controls. CONCLUSIONS: Novel urinary biomarkers remain elevated 7 years after an episode of CPB-AKI in children. However, there is no conventional evidence of CKD in these children. These biomarkers may be a more sensitive marker of chronic kidney injury after CPB-AKI. Future studies are needed to understand the clinical relevance of persistent elevations in IL-18, kidney injury molecule-1, and L-FABP in assessments for potential long-term kidney consequences of CPB-AKI. PMID- 26576620 TI - Psychological Stress and Skin Symptoms in College Students: Results of a Cross sectional Web-based Questionnaire Study. PMID- 26576619 TI - Randomized Clinical Trial of Sodium Polystyrene Sulfonate for the Treatment of Mild Hyperkalemia in CKD. AB - BACKGROUND AND OBJECTIVES: Hyperkalemia affects up to 10% of patients with CKD. Sodium polystyrene sulfonate has long been prescribed for this condition, although evidence is lacking on its efficacy for the treatment of mild hyperkalemia over several days. This study aimed to evaluate the efficacy of sodium polystyrene sulfonate in the treatment of mild hyperkalemia. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In total, 33 outpatients with CKD and mild hyperkalemia (5.0-5.9 mEq/L) in a single teaching hospital were included in this double-blind randomized clinical trial. We randomly assigned these patients to receive either placebo or sodium polystyrene sulfonate of 30 g orally one time per day for 7 days. The primary outcome was the comparison between study groups of the mean difference of serum potassium levels between the day after the last dose of treatment and baseline. RESULTS: The mean duration of treatment was 6.9 days. Sodium polystyrene sulfonate was superior to placebo in the reduction of serum potassium levels (mean difference between groups, -1.04 mEq/L; 95% confidence interval, -1.37 to -0.71). A higher proportion of patients in the sodium polystyrene sulfonate group attained normokalemia at the end of their treatment compared with those in the placebo group, but the difference did not reach statistical significance (73% versus 38%; P=0.07). There was a trend toward higher rates of electrolytic disturbances and an increase in gastrointestinal side effects in the group receiving sodium polystyrene sulfonate. CONCLUSIONS: Sodium polystyrene sulfonate was superior to placebo in reducing serum potassium over 7 days in patients with mild hyperkalemia and CKD. PMID- 26576621 TI - Comprehensive Analysis of Low-Molecular-Weight Human Plasma Proteome Using Top Down Mass Spectrometry. AB - While human plasma serves as a great source for disease diagnosis, low-molecular weight (LMW) proteome (<30 kDa) has been shown to contain a rich source of diagnostic biomarkers. Here we employ top-down mass spectrometry to analyze the LMW proteoforms present in four types of human plasma samples pooled from three healthy controls (HCs) without immunoaffinity depletion and with depletion of the top two, six, and seven high-abundance proteins. The LMW proteoforms were first fractionated based on molecular weight using gel-eluted liquid fraction entrapment electrophoresis (GELFrEE). Then, the GELFrEE fractions containing up to 30 kDa were subjected to nanocapillary-LC-MS/MS, and the high-resolution MS and MS/MS data were processed using ProSightPC 3.0. As a result, a total of 442 LMW proteins and cleaved products, including those with post-translational modifications and single amino acid variations, were identified. From additional comparative analysis of plasma samples without immunoaffinity depletion between HCs and colorectal cancer (CRC) patients via top-down approach, tens of LMW proteoforms, including platelet factor 4, were found to show >1.5-fold changes between the plasma samples of HCs and CRC patients, and six of the LMW proteins were verified by Western blot analysis. PMID- 26576622 TI - Prediction of Stable Ruthenium Silicides from First-Principles Calculations: Stoichiometries, Crystal Structures, and Physical Properties. AB - We present results of an unbiased structure search for stable ruthenium silicide compounds with various stoichiometries, using a recently developed technique that combines particle swarm optimization algorithms with first-principles calculations. Two experimentally observed structures of ruthenium silicides, RuSi (space group P2(1)3) and Ru2Si3 (space group Pbcn), are successfully reproduced under ambient pressure conditions. In addition, a stable RuSi2 compound with beta FeSi2 structure type (space group Cmca) was found. The calculations of the formation enthalpy, elastic constants, and phonon dispersions demonstrate the Cmca-RuSi2 compound is energetically, mechanically, and dynamically stable. The analysis of electronic band structures and densities of state reveals that the Cmca-RuSi2 phase is a semiconductor with a direct band gap of 0.480 eV and is stabilized by strong covalent bonding between Ru and neighboring Si atoms. On the basis of the Mulliken overlap population analysis, the Vickers hardness of the Cmca structure RuSi2 is estimated to be 28.0 GPa, indicating its ultra incompressible nature. PMID- 26576625 TI - Fabrication and characterization of cefazolin-loaded nanofibrous mats for the recovery of post-surgical wound. AB - The aim of the present study was to evaluate the wound healing performance of cefazolin-loaded gelatin nanofiber mats in post-operative wound. The obtained nanofibers were smooth, non-beaded and having diameter ranging from 620-680 nm. Nanofiber mats that are prepared exhibit high drug entrapment, excellent oxygen permeability and sustained drug release behavior. Further, medicated nanofiber mats showed an accelerated wound healing as compared to plain cefazolin. Macroscopical and histological evaluations demonstrated that cefazolin-loaded gelatin nanofiber showed increased epithelialization rate and collagen deposition. The results indicated that therapeutic strategies offer new prospects in the management of post-operative wound repair. PMID- 26576624 TI - Anatomical variations of mandibular canal detected by panoramic radiography and CT: a systematic review and meta-analysis. AB - OBJECTIVES: To investigate the anatomical variations of the mandibular canal through assessment in situ, panoramic radiography, CT or CBCT and assess their frequency. METHODS: Articles were selected from databases (Cochrane Library, LILACS, ProQuest, PubMed, Scopus, Web of Science and Google Scholar), articles without limitations of language, in which the main objective was to evaluate the frequency of bifurcation of the mandibular canal through assessment in situ, panoramic radiography, CT or CBCT were selected. A meta-analysis of prevalence using random effects was performed. RESULTS: Using a selection process in two phases, 15 articles were identified, and a meta-analysis was conducted. The results from these meta-analyses showed that the overall prevalence of anatomical variations for in situ studies was 6.46%, and through assessment of panoramic radiography and CT or CBCT the overall prevalence shown was 4.20% and 16.25%, respectively. CONCLUSIONS: There are two types of variations of the mandibular canal: the retromolar canal and bifid mandibular canal. The frequency variations through assessing in situ, panoramic radiography and CT or CBCT were 6.46%, 4.20% and 16.25%, respectively. PMID- 26576626 TI - Sound localization measured by eye-tracking. AB - OBJECTIVE: To introduce a new method of measuring sound localization ability based on eye-tracking and to test this method by analysing the influence of mild induced conductive hearing loss on sound localization. DESIGN: Sound signals were presented from different angles, and the participant's responses were measured using an eye-tracking device. For validation, a comparison of responses to visual stimuli was performed. To test the clinical application of this method, a mild conductive hearing loss was simulated, and the impact of this change on sound localization was measured. STUDY SAMPLE: Fifteen participants. RESULTS: The system provided repeatable measurements, and there was a good correlation of sound and visual signals. A large number of trials could be completed fairly rapidly. Following the induced conductive hearing loss, a decline of 5.5 degrees in the accuracy of sound localization in the horizontal plane was found towards the side of the non-impaired ear for frontal presentations. CONCLUSIONS: Quantifying sound localization by eye-tracking was found to be feasible, fast and accurate. A mild conductive hearing loss caused a slight degradation of sound localization accuracy within the 30 degrees frontal sector, which is in good agreement with results found using methods requiring more extensive instrumentation. PMID- 26576627 TI - 2015 American Thyroid Association Guidelines for Thyroid Nodules and Differentiated Thyroid Cancer and Their Implementation in Various Care Settings. PMID- 26576628 TI - Diagnostic Accuracy of Serum CA19-9 in Patients with Cholangiocarcinoma: A Systematic Review and Meta-Analysis. AB - BACKGROUND Cholangiocarcinoma (CCA) is a relatively rare cancer worldwide; however, its incidence is extremely high in Asia. Numerous studies reported that serum carbohydrate antigen 19-9 (CA19-9) plays a role in the diagnosis of CCA patients. However, published data are inconclusive. The aim of this meta-analysis was to provide a systematic review of the diagnostic performance of CA19-9 for CCA. MATERIAL AND METHODS We searched the public databases including PubMed, Web of Science, Embase, Chinese National Knowledge Infrastructure (CNKI), and WANFANG databases for articles evaluating the diagnostic accuracy of serum CA19-9 to predict CCA. The diagnostic sensitivity (SEN), specificity (SPE), positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and summary receiver operating characteristic curve (SROC) were pooled by Meta-DiSc 1.4 software. RESULTS A total of 31 articles met the inclusion criteria, including 1,264 patients and 2,039 controls. The pooled SEN, SPE, PLR, NLR, and DOR were 0.72 (95% CI: 0.70-0.75), 0.84 (95% CI: 0.82-0.85), 4.93 (95% CI, 3.67-6.64), 0.35 (95%CI, 0.30-0.41), and 15.10 (95% CI, 10.70-21.32), respectively. The area under SROC curve was 0.8300. The subgroup analyses based on different control type, geographical location, and sample size revealed that the diagnostic accuracy of CA19-9 tends to be same in different control type, but showed low sensitivity in European patients and small size group. CONCLUSIONS Serum CA19-9 is a useful non-invasive biomarker for CCA detection and may become a clinically useful tool to identify high-risk patients. PMID- 26576629 TI - Effect of the pesticide lindane on the biomass of the microalgae Nannochloris oculata. AB - This study assesses the growth of the microalgae Nannochloris oculata in the presence of lindane and the ability of N. oculata to remove lindane from media. Algal biomass increased with 0.1 and 0.5 mg L-1 of lindane, and lindane concentrations in the media decreased. N. oculata removed 73% and 68.2% of lindane in the 0.1 and 0.5 mg L-1 media concentrations, respectively. Algal biomass decreased to the level of the control at lindane concentrations greater than 2.5 mg L-1, probably due to toxicity. N. oculata removed lindane from the media at concentrations lower than 1.0 mg L-1. Thus, N. oculata may be useful for lindane bioremediation in contaminated aquatic systems. PMID- 26576630 TI - Patterns of, and Factors Associated With, Illicit Pharmaceutical Opioid Analgesic Use in a Prospective Cohort of People Who Inject Drugs in Melbourne, Australia. AB - BACKGROUND: People who inject drugs (PWID) are a key population engaging in pharmaceutical opioid analgesic (PO) use, yet little is known about patterns of illicit PO use among this group. OBJECTIVES: The aims of this research were to measure the prevalence and frequency of lifetime and past-month illicit PO use and injection in a sample of regular PWID, to examine patterns of past-month illicit PO use within individuals over time, and to identify factors independently associated with past-month illicit PO use. METHODS: Data were drawn from a prospective cohort study of regular PWID (N = 666) in Melbourne, Australia. Data from five waves of annual data collection (including baseline) were analyzed descriptively and using generalized estimating equations (GEE). RESULTS: At baseline, 59% of participants reported lifetime illicit PO use and 20% reported past-month use, predominantly through injecting. Most illicit PO users at baseline transitioned to nonuse of illicit POs across the study period. In multivariable GEE analysis, factors associated with past-month illicit PO use included past-year arrest [adjusted odds ratio (AOR): 1.39], opioids other than heroin as drug of choice (AOR: 5.14), experiencing poorer physical health (AOR: 0.98) and a range of other drug use variables. CONCLUSIONS: We found little evidence of ongoing illicit PO use among those followed up, with illicit PO use linked to polydrug use more broadly. Nonetheless, trends in illicit PO use among PWID should continue to be monitored and harm reduction interventions implemented to reduce the associated public health risks. PMID- 26576631 TI - Synthetic investigational new drugs for the treatment of tuberculosis. AB - INTRODUCTION: Tuberculosis (TB) is a major global health concern. And while there are treatments already on the market, there is a demand for new drugs that are effective and safe against Mycobacterium tuberculosis, which reduce the number of drugs and the duration of treatment in both drug-susceptible TB and multidrug resistant TB (MDR-TB). AREA COVERED: This review covers promising novel investigational TB drugs that are currently under development. Specifically, the authors review the efficacy of novel agents for the treatment of TB in preclinical, phase I and phase II clinical trials. The authors also review the safety and tolerability profiles of these drugs. EXPERT OPINION: Bedaquiline and delamanid are the most promising novel drugs for the treatment of MDR-TB, each having high efficacy and tolerability. However, the best regimen for achieving better outcomes and reducing adverse drug reactions remains to be determined, with safety concerns regarding cardiac events due to QT prolongation still to be addressed. Pretomanid is a novel drug that potentially shortens the duration of treatment in both drug-susceptible and drug-resistant TB in combination with moxifloxacin and pyrazinamide. Linezolid shows marked efficacy in the treatment of MDR-TB and extensively drug-resistant TB (XDR-TB), but the drug is known to cause significant adverse drug reactions, including peripheral neuropathy, optic neuropathy and myelosuppression. These adverse reactions must be considered prior to prescribing long-term usage of this drug. PMID- 26576632 TI - Integrating transcriptional and protein interaction networks to prioritize condition-specific master regulators. AB - BACKGROUND: Genome-wide libraries of yeast deletion strains have been used to screen for genes that drive phenotypes such as stress response. A surprising observation emerging from these studies is that the genes with the largest changes in mRNA expression during a state transition are not those that drive that transition. Here, we show that integrating gene expression data with context independent protein interaction networks can help prioritize master regulators that drive biological phenotypes. RESULTS: Genes essential for survival had previously been shown to exhibit high centrality in protein interaction networks. However, the set of genes that drive growth in any specific condition is highly context-dependent. We inferred regulatory networks from gene expression data and transcription factor binding motifs in Saccharomyces cerevisiae, and found that high-degree nodes in regulatory networks are enriched for transcription factors that drive the corresponding phenotypes. We then found that using a metric combining protein interaction and transcriptional networks improved the enrichment for drivers in many of the contexts we examined. We applied this principle to a dataset of gene expression in normal human fibroblasts expressing a panel of viral oncogenes. We integrated regulatory interactions inferred from this data with a database of yeast two-hybrid protein interactions and ranked 571 human transcription factors by their combined network score. The ranked list was significantly enriched in known cancer genes that could not be found by standard differential expression or enrichment analyses. CONCLUSIONS: There has been increasing recognition that network-based approaches can provide insight into critical cellular elements that help define phenotypic state. Our analysis suggests that no one network, based on a single data type, captures the full spectrum of interactions. Greater insight can instead be gained by exploring multiple independent networks and by choosing an appropriate metric on each network. Moreover we can improve our ability to rank phenotypic drivers by combining the information from individual networks. We propose that such integrative network analysis could be used to combine clinical gene expression data with interaction databases to prioritize patient- and disease-specific therapeutic targets. PMID- 26576633 TI - Cognitive behavioural treatment for mild Alzheimer's patients and their caregivers (CBTAC): study protocol for a randomized controlled trial. AB - BACKGROUND: About 90 % of all persons with mild Alzheimer's disease experience neuropsychiatric symptoms, most frequently apathy, depression, anxiety and irritability. These symptoms are associated with greater morbidity, a reduced quality of life for the patient, an increased burden and depression for the caregiver, and higher costs of care and nursing home placement. Psychosocial interventions based on behaviour therapy represent the most efficacious treatment of neuropsychiatric symptoms. However, there is no study, to our knowledge, that has evaluated a multicomponent treatment programme based on comprehensive, cognitive behavioural therapy (CBT). This randomized controlled trial aims to evaluate a CBT-based treatment programme consisting of 8 modules and 25 sessions. METHODS/DESIGN: Fifty patients with mild Alzheimer's disease alone or with mild mixed dementia (Alzheimer's disease and vascular dementia) who have any neuropsychiatric symptom will be included. A caregiver must be available. The patients and their caregivers will be randomized to either the CBT-based intervention group or to the control condition group, which receives treatment as usual. The primary outcome measure is depression in the patient with Alzheimer's disease. The secondary outcome measures for a person with Alzheimer's disease are other neuropsychiatric symptoms, quality of life and coping strategies. The secondary outcome measures for a caregiver are caregiver's burden, depression, anxiety, anger, quality of life and coping strategies. Neuropsychological testing includes tests of cognitive function and activities of daily living and a global clinical assessment of severity. Participants in both groups will be assessed before and after the treatment phase (lasting approximately 9 months). Follow-up assessments will take place 6 and 12 months after treatment. All assessments will be conducted by blinded assessors. DISCUSSION: This trial has the potential to establish an empirically based psychological treatment for non-cognitive symptoms that reduce the quality of life of a person with dementia and a caregiver. This treatment approach focuses not only on the person with dementia, but also on the caregiver and on the dyad. The treatment manual will be published and training workshops will be offered, so that the information can be widely spread among healthcare professionals. TRIAL REGISTRATION: ClinicalTrials.gov NCT01273272. PMID- 26576634 TI - RNA-seq reveals differentially expressed genes of rice (Oryza sativa) spikelet in response to temperature interacting with nitrogen at meiosis stage. AB - BACKGROUND: Rice (Oryza sativa) is one of the most important cereal crops, providing food for more than half of the world's population. However, grain yields are challenged by various abiotic stresses such as drought, fertilizer, heat, and their interaction. Rice at reproductive stage is much more sensitive to environmental temperatures, and little is known about molecular mechanisms of rice spikelet in response to high temperature interacting with nitrogen (N). RESULTS: Here we reported the transcriptional profiling analysis of rice spikelet at meiosis stage using RNA sequencing (RNA-seq) as an attempt to gain insights into molecular events associated with temperature and nitrogen. This study received four treatments: 1) NN: normal nitrogen level (165 kg ha(-1)) with natural temperature (30 degrees C); 2) HH: high nitrogen level (330 kg ha(-1)) with high temperature (37 degrees C); 3) NH: normal nitrogen level and high temperature; and 4) HN: high nitrogen level and natural temperature, respectively. The de novo assembly generated 52,553,536 clean reads aligned with 72,667 unigenes. About 10 M reads were identified from each treatment. In these differentially expressed genes (DEGs), we found 151 and 323 temperature responsive DEGs in NN-vs-NH and HN-vs-HH, and 114 DEGs were co-expressed. Meanwhile, 203 and 144 nitrogen-responsive DEGs were focused in NN-vs-HN and NH vs-HH, and 111 DEGs were co-expressed. The temperature-responsive genes were principally associated with calcium-dependent protein, cytochrome, flavonoid, heat shock protein, peroxidase, ubiquitin, and transcription factor while the nitrogen-responsive genes were mainly involved in glutamine synthetase, transcription factor, anthocyanin, amino acid transporter, leucine zipper protein, and hormone. It is noted that, rice spikelet fertility was significantly decreased under high temperature, but it was more reduced under higher nitrogen. Accordingly, numerous spikelet genes involved in pollen development, pollen tube growth, pollen germination, especially sporopollenin biosynthetic process, and pollen exine formation were mainly down-regulated under high temperature. Moreover, the expression levels of co-expressed DEGs including 5 sporopollenin biosynthetic process and 7 pollen exine formation genes of NN-vs-NH were lower than that of HN-vs-HH. Therefore, these spikelet genes may play important roles in response to high temperature with high nitrogen and may be good candidates for crop improvement. CONCLUSIONS: This RNA-seq study will help elucidate the molecular mechanisms of rice spikelet defense response to high temperature interacting with high nitrogen level. PMID- 26576635 TI - Osseous vitality in single photon emission computed tomography/computed tomography (SPECT/CT) after balloon tibioplasty of the tibial plateau: a case series. AB - BACKGROUND: The minimally invasive, balloon-assisted reduction and cement augmented internal fixation of the tibial plateau is an innovative surgical procedure for tibial plateau fractures. The close proximity of balloons and cement to the knee joint poses a potential risk for osteonecrosis; especially in the case of thin bone lamellae. However, there are no studies about the vitality of the cement-surrounding tissue after these tibioplasties. Therefore, our goal was to assess the osseous vitality after cement-augmented balloon tibioplasty using single photon emission computed tomography/computed tomography (SPECT/CT) in a series of patients. METHODS: This case series evaluated available consecutive patients, whose tibial plateau fractures were treated with balloon assisted, cement-augmented tibioplasty and received a SPECT/CT. Primary outcome variables were osseous vitality on SPECT/CTs according to the semiquantitative tracer activity analysis. The mean uptake of eight tibial regions of interest was referenced to the mean uptake count on the same region of the contralateral leg to obtain a count ratio. Osteonecrosis was defined as a photopenic area or cold defect. Secondary variables included clinical and radiological follow-up data. Statistics were carried out in a descriptive pattern. RESULTS: Ten patients with a mean age of 59 years and a mean follow up of 18 months were included. Calcium phosphate (CaP) substitute bone cement was used in 60% and polymethyl methacrylate mixed with hydroxyapatite (PMMA/HA) bone cement in 40%. Normal to high SPECT/CT activity without photopenic areas were observed in all patients and the mean tracer activity ratio was four, indicating vital bone in all patients. There were no postoperative infections and only one 57 year old patient with hemineglect and CaP cement showed failed osseous consolidation. The mean Tegner and Lysholm as well as the Lysholm scores were three and 80, respectively. CONCLUSIONS: This novel study about cement-augmented balloon tibioplasties showed that osseous vitality remains intact according to SPECT/CT analysis; irrespective of the type of cement and even in the presence of thin bone lamellae. This procedure was safe and well-suited for lateral tibial plateau fractures in particular. Surgeons may consider using PMMA/HA bone cement for void filling in elderly fracture patients without concern about bone viability. PMID- 26576636 TI - Brain natriuretic peptide constitutively downregulates P2X3 receptors by controlling their phosphorylation state and membrane localization. AB - BACKGROUND: ATP-gated P2X3 receptors are important transducers of nociceptive stimuli and are almost exclusively expressed by sensory ganglion neurons. In mouse trigeminal ganglion (TG), P2X3 receptor function is unexpectedly enhanced by pharmacological block of natriuretic peptide receptor-A (NPR-A), outlining a potential inhibitory role of endogenous natriuretic peptides in nociception mediated by P2X3 receptors. Lack of change in P2X3 protein expression indicates a complex modulation whose mechanisms for downregulating P2X3 receptor function remain unclear. RESULTS: To clarify this process in mouse TG cultures, we suppressed NPR-A signaling with either siRNA of the endogenous agonist BNP, or the NPR-A blocker anantin. Thus, we investigated changes in P2X3 receptor distribution in the lipid raft membrane compartment, their phosphorylation state, as well as their function with patch clamping. Delayed onset of P2X3 desensitization was one mechanism for the anantin-induced enhancement of P2X3 activity. Anantin application caused preferential P2X3 receptor redistribution to the lipid raft compartment and decreased P2X3 serine phosphorylation, two phenomena that were not interdependent. An inhibitor of cGMP-dependent protein kinase and siRNA-mediated knockdown of BNP mimicked the effect of anantin. CONCLUSIONS: We demonstrated that in mouse trigeminal neurons endogenous BNP acts on NPR-A receptors to determine constitutive depression of P2X3 receptor function. Tonic inhibition of P2X3 receptor activity by BNP/NPR-A/PKG pathways occurs via two distinct mechanisms: P2X3 serine phosphorylation and receptor redistribution to non-raft membrane compartments. This novel mechanism of receptor control might be a target for future studies aiming at decreasing dysregulated P2X3 receptor activity in chronic pain. PMID- 26576637 TI - Benign prostatic hyperplasia complicated with T1DM can be alleviated by treadmill exercise-evidences revealed by the rat model. AB - BACKGROUND: Both benign prostatic hyperplasia (BPH) and Type-1 diabetes mellitus (T1DM) share similar epidemiologic features and are all associated with the insulin-like growth factor (IGF)-mediated hormonal imbalance. The purpose of this study is to understand whether exercise (EX) could alleviate DM and DM + BPH. METHODS: Sprague-Dawley rats were divided into eight groups: normal control, EX, BPH, BPH + EX, DM, DM + EX, BPH + DM, and BPH + DM + EX. T1DM was induced by intraperitoneal (ip) injection of streptozotocin (65 mg/kg) in Week 2, and BPH was induced by successive ip injections of Sustanon(r) (testosterone, 3.5 mg/head) plus estradiol (0.1 mg/head) from Week 3 to Week 9. Treadmill exercise training (20 m/min, 60 min per time) was performed three times per week for 6 weeks. RESULTS: In BPH + EX, EX maintained at a constant body weight (BW); and suppressed stromal layer thickening, collagen deposition, blood glucose (BG), levels of testosterone (Ts), 5alpha-reductase(5alphaRd), dihydrotestosterone (DHT), androgen receptor (AR), serum hydrogen peroxide, TBARs, and interleukin-6 (IL-6). EX recovered testes size and substantially increased nitric oxide (NO) levels. In DM + EX group, EX decreased BW, PW, nuclear proliferation, inflammatory cell aggregation, collagen deposition, and BG. As contrast, EX upregulated insulin, IGF, Ts, NO, 5alphaRd, AR, and DHT, and substantially reduced PSA. In BPH + DM + EX, EX maintained BW at a subnormal level, slightly suppressed prostate stromal inflammation, collagen deposition, and BG, moderately restored sIn and IGF. Although failed to suppress Ts, EX highly upregulated 5alphaRd and suppressed DHT and AR, together with highly upregulated NO resulting in substantially reduced PSA. CONCLUSION: EX, by remodeling androgen and NO expressions, can effectively alleviate BPH, DM, and BPH + DM. PMID- 26576638 TI - Cardiovascular magnetic resonance techniques and findings in children with myocarditis: a multicenter retrospective study. AB - BACKGROUND: Cardiovascular magnetic resonance (CMR) is increasingly used to diagnose myocarditis in adults but its use in children is not well-established. We sought to describe the presentation, CMR protocol and findings, and outcomes in a multicenter cohort of children with myocarditis. METHODS: Thirteen hospitals retrospectively identified patients meeting the following inclusion criteria: 1) diagnosis of myocarditis by the managing physicians, 2) age <21 years, 3) CMR examination within 30 days of presentation, and 4) no congenital heart disease. Clinical data and test results, including CMR findings, were abstracted from the medical record. RESULTS: For the 143 patients meeting inclusion criteria, the median age was 16.0 years (range, 0.1-20.3) and 139 (97 %) were hospitalized at the time of CMR. The median time from presentation to CMR was 2 days (0-28). The median left ventricular ejection fraction at CMR was 56 % (10-74), with 29 (20 %) below 45 %. The median right ventricular ejection fraction was 54 % (15-72), with 11 (8 %) below 40 %. There was significant variability among centers in the types of tissue characterization techniques employed (p < 0.001). Overall, late gadolinium enhancement (LGE) was used in 100 % of studies, followed by T2 weighted imaging (T2W) in 69 %, first-pass contrast perfusion (FPP) in 48 %, and early gadolinium enhancement (EGE) in 28 %. Abnormalities were most common with LGE (81 %), followed by T2W (74 %), EGE (55 %), and FPP (8 %). The CMR study was interpreted as positive for myocarditis in 117 patients (82 %), negative in 18 (13 %), and equivocal in 7 (5 %), yielding a sensitivity of 82 %. At a median follow-up of 7.1 months (0-87), all patients were alive and 5 had undergone cardiac transplantation. CMR parameters at presentation associated with persistent left ventricular dysfunction were larger left ventricular end diastolic volume and lower left and right ventricular ejection fraction but not abnormal LGE. CONCLUSIONS: Despite significant practice variation in imaging protocol among centers, CMR had a high sensitivity for the diagnosis of myocarditis in pediatric patients. Abnormalities were most often seen with LGE followed by T2W, EGE, and FPP. These findings should be useful in designing future prospective studies. PMID- 26576640 TI - Mental health service responses to human trafficking: a qualitative study of professionals' experiences of providing care. AB - BACKGROUND: Human trafficking is a global crime and human rights violation. Although research has demonstrated a high prevalence of mental disorder among trafficked people and that trafficked people are in contact with mental health services, little is known about mental health professionals' experiences of identifying and providing care for trafficked people. This study aimed to understand how people are identified as trafficked within mental health services and the challenges professionals experience in responding to trafficked people's mental health needs. METHOD: Qualitative study of electronic health records of trafficked people in contact with secondary mental health services in South East London, England. Comprehensive clinical electronic health records for over 200,000 patients in contact with secondary mental health services in South London were searched and retrieved to identify trafficked patients. Content analysis was used to establish how people were identified as trafficked, and thematic analysis was used to explore the challenges experienced in responding to mental health needs. RESULTS: The sample included 130 trafficked patients, 95 adults and 35 children. In 43 % (41/95) of adult cases and 63 % (22/35) child cases, mental health professionals were informed that their patient was a potential victim of trafficking by another service involved in their patient's care. Cases were also identified through patients disclosing their experiences of exploitation and abuse. Key challenges faced by staff included social and legal instability, difficulties ascertaining history, patients' lack of engagement, availability of services, and inter-agency working. CONCLUSIONS: Training to increase awareness, encourage helpful responses, and inform staff about the available support options would help to ensure the mental health needs of trafficked people are met. Further research is needed to establish if these challenges are similar in other health settings. PMID- 26576639 TI - PKM2 regulates neural invasion of and predicts poor prognosis for human hilar cholangiocarcinoma. AB - BACKGROUND: The therapeutic and prognostic value of the glycolytic enzymes hexokinase, phosphofructokinase, and pyruvate kinase (PK) has been implicated in a variety of cancers, while their roles in treatment of and prognosis for hilar cholangiocarcinoma (HC) remain unclear. In this study, we determined the expression of PKM2 in and its impact on biology and clinical outcome of human HC. METHODS: The regulation and function of PKM2 in HC pathogenesis was evaluated using human tissues, molecular and cell biology, and animal models, and its prognostic significance was determined according to its impact on patient survival. RESULTS: We found that expression of hexokinase 1 and the M2 splice isoform of PK (PKM2) was upregulated in HC tissues and that this expression correlated with tumor recurrence and outcome. PKM2 expression was increased in HC cases with chronic cholangitis as demonstrated by isobaric tags for relative and absolute quantification. High PKM2 expression was highly correlated with high syndecan 2 (SDC2) expression and neural invasion. PKM2 downregulation led to a decrease in SDC2 expression. Treatment with metformin markedly suppressed PKM2 and SDC2 expression at both the transcriptional and posttranscriptional levels and inhibited HC cell proliferation and tumor growth. CONCLUSIONS: PKM2 regulates neural invasion of HC cells at least in part via regulation of SDC2. Inhibition of PKM2 and SDC2 expression contributes to the therapeutic effect of metformin on HC. Therefore, PKM2 is an independent prognostic factor and potential therapeutic target for human HC. PMID- 26576641 TI - Oxidative and endoplasmic reticulum stress in beta-cell dysfunction in diabetes. AB - The inability of pancreatic beta-cells to make sufficient insulin to control blood sugar is a central feature of the aetiology of most forms of diabetes. In this review we focus on the deleterious effects of oxidative stress and endoplasmic reticulum (ER) stress on beta-cell insulin biosynthesis and secretion and on inflammatory signalling and apoptosis with a particular emphasis on type 2 diabetes (T2D). We argue that oxidative stress and ER stress are closely entwined phenomena fundamentally involved in beta-cell dysfunction by direct effects on insulin biosynthesis and due to consequences of the ER stress-induced unfolded protein response. We summarise evidence that, although these phenomenon can be driven by intrinsic beta-cell defects in rare forms of diabetes, in T2D beta-cell stress is driven by a range of local environmental factors including increased drivers of insulin biosynthesis, glucolipotoxicity and inflammatory cytokines. We describe our recent findings that a range of inflammatory cytokines contribute to beta-cell stress in diabetes and our discovery that interleukin 22 protects beta cells from oxidative stress regardless of the environmental triggers and can correct much of diabetes pathophysiology in animal models. Finally we summarise evidence that beta-cell dysfunction is reversible in T2D and discuss therapeutic opportunities for relieving oxidative and ER stress and restoring glycaemic control. PMID- 26576642 TI - H295R expression of melanocortin 2 receptor accessory protein results in ACTH responsiveness. AB - The H295R adrenocortical cell line is widely used for molecular analysis of adrenal functions but is known to have only modest ACTH responsiveness. The lack of ACTH response was linked to a low expression of its receptor, melanocortin 2 receptor (MC2R). We hypothesized that increasing the MC2R accessory protein (MRAP), which is required to traffic MC2R from the endoplasmic reticulum to the cell surface, would increase ACTH responsiveness. Lentiviral particles containing human MRAP-open reading frame were generated and transduced in H295R cells. Using antibiotic resistance, 18 clones were isolated for characterization. The most ACTH-responsive steroidogenic clone, H295RA, was used for further experiments. Successful induction of MRAP and increased expression of MC2R in H295RA cells was confirmed by quantitative real-time RT-PCR and protein analysis. Treatment with ACTH significantly increased aldosterone, cortisol, and dehydroepiandrosterone production in H295RA cells. ACTH also significantly increased transcript levels for all of the steroidogenic enzymes required to produce aldosterone, cortisol, and dehydroepiandrosterone, as well as MC2R mRNA. Using liquid chromatography/tandem mass spectrometry, we further revealed that the main unconjugated steroids produced in H295RA cells were 11-deoxycortisol, cortisol, and androstenedione. Treatment of H295RA cells with ACTH also acutely increased cAMP production and cellular protein levels for total and phosphorylated steroidogenic acute regulatory protein. In summary, through genetic manipulation, we have developed an ACTH-responsive human adrenocortical cell line. The cell line will provide a powerful in vitro tool for molecular analysis of physiologic and pathologic conditions involving the hypothalamic-pituitary-adrenal axis. PMID- 26576644 TI - Transcription factor C/EBPbeta promotes the transcription of the porcine GPR120 gene. AB - G protein-coupled receptor 120 (GPR120), an adipogenic receptor critical for the differentiation and maturation of adipocytes, plays an important role in controlling obesity in both humans and rodents and, thus, is an attractive target of obesity treatment studies. However, the mechanisms that regulate the expression of porcine GPR120 remain unclear. In this study, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) techniques were used to analyze and identify the binding of C/EBPbeta (transcription factor CCAAT/enhancer binding protein beta) to the GPR120 promoter. C/EBPbeta overexpression and RNA interference studies showed that C/EBPbeta regulated GPR120 promoter activity and endogenous GPR120 expression. The binding site of C/EBPbeta in the GPR120 promoter region from -101 to -87 was identified by promoter deletion analysis and site-directed mutagenesis. Overexpression of C/EBPbeta increased endogenous GPR120 expression in pig kidney cells (PK). Furthermore, when endogenous C/EBPbeta was knocked down, GPR120 mRNA and protein levels were decreased. The stimulatory effect of C/EBPbeta on GPR120 transcription and its ability to bind the transcription factor-binding site were confirmed by luciferase, ChIP, and EMSA. Moreover, the mRNA and protein expression levels of C/EBPbeta were induced by high fat diet feeding. Taken together, it can be concluded that C/EBPbeta plays a vital role in regulating GPR120 transcription and suggests HFD-feeding induces GPR120 transcription by influencing C/EBPbeta expression. PMID- 26576643 TI - Expression and functional studies of the GDNF family receptor alpha 3 in the pancreas. AB - The generation of therapeutic beta-cells from human pluripotent stem cells relies on the identification of growth factors that faithfully mimic pancreatic beta cell development in vitro. In this context, the aim of the study was to determine the expression and function of the glial cell line derived neurotrophic factor receptor alpha 3 (GFRalpha3) and its ligand artemin (Artn) in islet cell development and function. GFRalpha3 and Artn expression were characterized by in situ hybridization, immunochemistry, and qRT-PCR. We used GFRalpha3-deficient mice to study GFRalpha3 function and generated transgenic mice overexpressing Artn in the embryonic pancreas to study Artn function. We found that GFRalpha3 is expressed at the surface of a subset of Ngn3-positive endocrine progenitors as well as of embryonic alpha- and beta-cells, while Artn is found in the pancreatic mesenchyme. Adult beta-cells lack GFRalpha3 but alpha-cells express the receptor. GFRalpha3 was also found in parasympathetic and sympathetic intra-islet neurons as well as in glial cells in the embryonic and adult pancreas. The loss of GFRalpha3 or overexpression of Artn has no impact on Ngn3 and islet cell formation and maintenance in the embryo. Islet organization and innervation as well as glucose homeostasis is normal in GFRalpha3-deficient mice suggesting functional redundancy. PMID- 26576647 TI - Directional imbibition on a chemically patterned silicon micropillar array. AB - Directional imbibition of oils (hexadecane, tetradecane, and dodecane) and water is demonstrated on a chemically patterned silicon micropillar array. Four different directional imbibition types are shown: unidirectional, two types of bidirectional and tridirectional imbibition. The surfaces consist of a silicon micropillar array with an overlaid surface chemistry pattern. This configuration leads to anisotropic wetting behaviour into various directions of the advancing meniscus. Due to the free energy landscape obtained, the advancing meniscus gets pinned in some directions (determined by the surface chemistry pattern) while it is free to move to the remaining directions. The conditions for directional imbibition and design criteria for the surfaces are derived and discussed. PMID- 26576645 TI - Hepatitis C virus core protein modulates pRb2/p130 expression in human hepatocellular carcinoma cell lines through promoter methylation. AB - BACKGROUND: Hepatitis C Virus (HCV) infection is associated with chronically evolving disease and development of hepatocellular carcinoma (HCC), albeit the mechanism of HCC induction by HCV is still controversial. The nucleocapsid (core) protein of HCV has been shown to be directly implicated in cellular transformation and immortalization, enhancing the effect of oncogenes and decreasing the one of tumor suppressor genes, as RB1 and its protein product pRB. With the aim of identifying novel molecular mechanisms of hepatocyte transformation by HCV, we examined the effect of HCV core protein on the expression of the whole Retinoblastoma (RB) family of tumor and growth suppressor factors, i.e. pRb, p107 and pRb2/p130. METHODS: We used a model system consisting of the HuH-7, HCV-free, human hepatocellular carcinoma cell line and of the HuH-7 CORE cells derived from the former and constitutively expressing the HCV core protein. We determined pRb, p107 and pRb2/p130 protein and mRNA amount of the respective genes RB1, RBL1 and RBL2, RBL2 promoter activity and methylation as well as DNA methyltransferase 1 (DNMT1) and 3b (DNMT3b) expression level. The effect of pRb2/p130 over-expression on the HCV core-expressing HuH-7-CORE cells was also evaluated. RESULTS: We found that the HCV core protein expression down regulated pRb2/p130 protein and mRNA levels in HuH-7-CORE cells by inducing promoter hyper-methylation with the concomitant up-regulation of DNMT1 and DNMT3b expression. When pRb2/p130 expression was artificially re-established in HuH-7 CORE cells, cell cycle analysis outlined an accumulation in the G0/G1 phase, as expected. CONCLUSIONS: HCV core appears indeed able to significantly down regulate the expression and the function of two out of three RB family tumor and growth suppressor factors, i.e. pRb and pRb2/p130. The functional consequences at the level of cell cycle regulation, and possibly of more complex cell homeostatic processes, may represent a plausible molecular mechanism involved in liver transformation by HCV. PMID- 26576646 TI - Unexpected isocyanide-based three-component bicyclization for the stereoselective synthesis of densely functionalized pyrano[3,4-c]pyrroles. AB - A novel three-component bicyclization strategy for the efficient synthesis of densely functionalized pyrano[3,4-c]pyrroles has been established from readily accessible 3-aroylacrylic acids, dialkyl acetylenedicarboxylates and isocyanides. The reaction pathway involves Huisgen 1,3-dipole formation, Passerini-type reaction, Mumm rearrangement and an oxo-Diels-Alder reaction sequence, resulting in continuous multiple bond-forming events including C-N, C-O and C-H bonds to rapidly build up molecular complexity. PMID- 26576648 TI - A method for developing regulatory gene set networks to characterize complex biological systems. AB - BACKGROUND: Traditional approaches to studying molecular networks are based on linking genes or proteins. Higher-level networks linking gene sets or pathways have been proposed recently. Several types of gene set networks have been used to study complex molecular networks such as co-membership gene set networks (M-GSNs) and co-enrichment gene set networks (E-GSNs). Gene set networks are useful for studying biological mechanism of diseases and drug perturbations. RESULTS: In this study, we proposed a new approach for constructing directed, regulatory gene set networks (R-GSNs) to reveal novel relationships among gene sets or pathways. We collected several gene set collections and high-quality gene regulation data in order to construct R-GSNs in a comparative study with co-membership gene set networks (M-GSNs). We described a method for constructing both global and disease specific R-GSNs and determining their significance. To demonstrate the potential applications to disease biology studies, we constructed and analysed an R-GSN specifically built for Alzheimer's disease. CONCLUSIONS: R-GSNs can provide new biological insights complementary to those derived at the protein regulatory network level or M-GSNs. When integrated properly to functional genomics data, R GSNs can help enable future research on systems biology and translational bioinformatics. PMID- 26576649 TI - Genetic evaluation with major genes and polygenic inheritance when some animals are not genotyped using gene content multiple-trait BLUP. AB - BACKGROUND: In pedigreed populations with a major gene segregating for a quantitative trait, it is not clear how to use pedigree, genotype and phenotype information when some individuals are not genotyped. We propose to consider gene content at the major gene as a second trait correlated to the quantitative trait, in a gene content multiple-trait best linear unbiased prediction (GCMTBLUP) method. RESULTS: The genetic covariance between the trait and gene content at the major gene is a function of the substitution effect of the gene. This genetic covariance can be written in a multiple-trait form that accommodates any pattern of missing values for either genotype or phenotype data. Effects of major gene alleles and the genetic covariance between genotype at the major gene and the phenotype can be estimated using standard EM-REML or Gibbs sampling. Prediction of breeding values with genotypes at the major gene can use multiple-trait BLUP software. Major genes with more than two alleles can be considered by including negative covariances between gene contents at each different allele. We simulated two scenarios: a selected and an unselected trait with heritabilities of 0.05 and 0.5, respectively. In both cases, the major gene explained half the genetic variation. Competing methods used imputed gene contents derived by the method of Gengler et al. or by iterative peeling. Imputed gene contents, in contrast to GCMTBLUP, do not consider information on the quantitative trait for genotype prediction. GCMTBLUP gave unbiased estimates of the gene effect, in contrast to the other methods, with less bias and better or equal accuracy of prediction. GCMTBLUP improved estimation of genotypes in non-genotyped individuals, in particular if these individuals had own phenotype records and the trait had a high heritability. Ignoring the major gene in genetic evaluation led to serious biases and decreased prediction accuracy. CONCLUSIONS: CGMTBLUP is the best linear predictor of additive genetic merit including pedigree, phenotype, and genotype information at major genes, since it considers missing genotypes. Simulations confirm that it is a simple, efficient and theoretically sound method for genetic evaluation of traits influenced by polygenic inheritance and one or several major genes. PMID- 26576651 TI - The intrinsic combinatorial organization and information theoretic content of a sequence are correlated to the DNA encoded nucleosome organization of eukaryotic genomes. AB - MOTIVATION: Thanks to research spanning nearly 30 years, two major models have emerged that account for nucleosome organization in chromatin: statistical and sequence specific. The first is based on elegant, easy to compute, closed-form mathematical formulas that make no assumptions of the physical and chemical properties of the underlying DNA sequence. Moreover, they need no training on the data for their computation. The latter is based on some sequence regularities but, as opposed to the statistical model, it lacks the same type of closed-form formulas that, in this case, should be based on the DNA sequence only. RESULTS: We contribute to close this important methodological gap between the two models by providing three very simple formulas for the sequence specific one. They are all based on well-known formulas in Computer Science and Bioinformatics, and they give different quantifications of how complex a sequence is. In view of how remarkably well they perform, it is very surprising that measures of sequence complexity have not even been considered as candidates to close the mentioned gap. We provide experimental evidence that the intrinsic level of combinatorial organization and information-theoretic content of subsequences within a genome are strongly correlated to the level of DNA encoded nucleosome organization discovered by Kaplan et al Our results establish an important connection between the intrinsic complexity of subsequences in a genome and the intrinsic, i.e. DNA encoded, nucleosome organization of eukaryotic genomes. It is a first step towards a mathematical characterization of this latter 'encoding'. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. CONTACT: futro@us.ibm.com. PMID- 26576650 TI - FOXM1 and polo-like kinase 1 are co-ordinately overexpressed in patients with gastric adenocarcinomas. AB - BACKGROUND: Gastric cancers present late in life with advanced disease and carry a poor prognosis. Polo-like Kinase 1 (PLK1) is a mitotic kinase with regulatory functions during G2/M and mitosis in the cell cycle. In mammalian cells, there is an intricate co-regulatory relationship between PLK1 and the forkhead transcription factor FOXM1. It has been demonstrated that individually either PLK1 or FOXM1 expression predicts poorer survival. However, the co-expression of both of these markers in gastric adenocarcinomas has not been reported previously. METHODS: We aimed to assess the expression of PLK1 and FOXM1 in Gastric adenocarcinomas in a Western Population, to examine whether there is a relationship of PLK1 to FOXM1 in cancer samples. We assess both the protein and mRNA expression in this patient population by Tissue Microarray immunohistochemistry and RT-PCR. RESULTS: Immunohistochemistry was performed on biopsy samples from 79 patients with gastric cancer. Paired normal controls were available in 47 patients. FOXM1 expression was significantly associated with gastric adenocarcinoma (p = 0.001). PLK1 and FOXM1 co-expression was demonstrated in 6/8 (75 %) tumours when analysed by RT-PCR. FOXM1 is overexpressed in a large proportion of gastric carcinomas at the protein level and FOXM1 and PLK1 are concomitantly overexpressed at the mRNA level in this cancer type. CONCLUSIONS: This study has demonstrated that FOXM1 and its target gene PLK1 are coordinately overexpressed in a proportion of gastric adenocarcinomas. This suggests that chemotherapeutic treatments that target this pathway may be of clinical utility. PMID- 26576652 TI - Global copy number profiling of cancer genomes. AB - In this article, we introduce a robust and efficient strategy for deriving global and allele-specific copy number alternations (CNA) from cancer whole exome sequencing data based on Log R ratios and B-allele frequencies. Applying the approach to the analysis of over 200 skin cancer samples, we demonstrate its utility for discovering distinct CNA events and for deriving ancillary information such as tumor purity. AVAILABILITY AND IMPLEMENTATION: https://github.com/xfwang/CLOSE CONTACT: xuefeng.wang@stonybrook.edu or michael.krauthammer@yale.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26576653 TI - JSpeciesWS: a web server for prokaryotic species circumscription based on pairwise genome comparison. AB - JSpecies Web Server (JSpeciesWS) is a user-friendly online service for in silico calculating the extent of identity between two genomes, a parameter routinely used in the process of polyphasic microbial species circumscription. The service measures the average nucleotide identity (ANI) based on BLAST+ (ANIb) and MUMmer (ANIm), as well as correlation indexes of tetra-nucleotide signatures (Tetra). In addition, it provides a Tetra Correlation Search function, which allows to rapidly compare selected genomes against a continuously updated reference database with currently about 32 000 published whole and draft genome sequences. For comparison, own genomes can be uploaded and references can be selected from the JSpeciesWS reference database. The service indicates whether two genomes share genomic identities above or below the species embracing thresholds, and serves as a fast way to allocate unknown genomes in the frame of the hitherto sequenced species. AVAILABILITY AND IMPLEMENTATION: JSpeciesWS is available at http://jspecies.ribohost.com/jspeciesws SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. CONTACT: mrichter@ribocon.com. PMID- 26576654 TI - Prioritizing hypothesis tests for high throughput data. AB - MOTIVATION: The advent of high throughput data has led to a massive increase in the number of hypothesis tests conducted in many types of biological studies and a concomitant increase in stringency of significance thresholds. Filtering methods, which use independent information to eliminate less promising tests and thus reduce multiple testing, have been widely and successfully applied. However, key questions remain about how to best apply them: When is filtering beneficial and when is it detrimental? How good does the independent information need to be in order for filtering to be effective? How should one choose the filter cutoff that separates tests that pass the filter from those that don't? RESULT: We quantify the effect of the quality of the filter information, the filter cutoff and other factors on the effectiveness of the filter and show a number of results: If the filter has a high probability (e.g. 70%) of ranking true positive features highly (e.g. top 10%), then filtering can lead to dramatic increase (e.g. 10-fold) in discovery probability when there is high redundancy in information between hypothesis tests. Filtering is less effective when there is low redundancy between hypothesis tests and its benefit decreases rapidly as the quality of the filter information decreases. Furthermore, the outcome is highly dependent on the choice of filter cutoff. Choosing the cutoff without reference to the data will often lead to a large loss in discovery probability. However, naive optimization of the cutoff using the data will lead to inflated type I error. We introduce a data-based method for choosing the cutoff that maintains control of the family-wise error rate via a correction factor to the significance threshold. Application of this approach offers as much as a several-fold advantage in discovery probability relative to no filtering, while maintaining type I error control. We also introduce a closely related method of P-value weighting that further improves performance. AVAILABILITY AND IMPLEMENTATION: R code for calculating the correction factor is available at http://www.stat.uga.edu/people/faculty/paul-schliekelman CONTACT: pdschlie@stat.uga.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26576655 TI - Non-infectious Panniculitis during Hydroxyurea Therapy in a Patient with Myeloproliferative Disease. PMID- 26576656 TI - Understanding the experiences and needs of female commercial sex workers in Kathmandu, Nepal. AB - Through this exploratory study, we sought to better understand Nepali female commercial sex workers' (FCSWs') experiences in order to inform HIV prevention and health promotion interventions for this vulnerable and hard-to-reach population. Data were collected through phenomenological interviews with eight FCSWs. Through analysis we reveal promising intervention points to enhance FCSW health, empowerment, and overall well-being. Researchers suggest a combination of structural and individual programs is essential to improving the circumstances of Nepali FCSWs and preventing the spread of HIV. Given Nepal's limited resources and complex environment, it is imperative future prevention programs are focused and guided by FCSWs' lived experiences. PMID- 26576657 TI - Effect of different preservation processes on chemical composition and fatty acid profile of anchovy (Engraulis anchoita). AB - The effects of salting-ripening, canning and marinating processes on chemical composition and fatty acid profile of anchovy (Engraulis anchoita) were evaluated (p = 0.01), with emphasis on long-chain polyunsaturated fatty acids. Fresh anchovy showed a high proportion of PUFAs (~45 g/100 g total lipid) with an eicosapentaenoic (EPA) + docosahexaenoic (DHA) content of 27.08 g/100 g total lipid. The salting-ripening process led to the largest changes in the chemical composition and the fatty acid profile, which resulted in a reduction of ~70% on the total EPA and DHA contents (g/100 g edible portion). Contrary, canned and marinated anchovy presented a fatty acid profile similar to that of fresh anchovy. The use of vegetable oil as covering liquid led to final products with increased omega-6 PUFAs content. Despite the modifications observed, the total amount of essential EPA and DHA fatty acids provided by these products remained high compared with values reported in literature for other foods. PMID- 26576658 TI - Electric field induced reversible 180 degrees magnetization switching through tuning of interfacial exchange bias along magnetic easy-axis in multiferroic laminates. AB - E-field control of interfacial exchange coupling and deterministic switching of magnetization have been demonstrated in two sets of ferromagnetic(FM)/antiferromagnetic(AFM)/ferroelectric(FE) multiferroic heterostructures, including NiFe/NiCoO/glass/PZN-PT (011) and NiFe/FeMn/glass/PZN PT (011). We designed this experiment to achieve exchange bias tuning along the magnetic easy axis, which is critical for realizing reversible 180 degrees magnetization deterministic switching at zero or small magnetic bias. Strong exchange coupling were established across AFM-FM interfaces, which plays an important role in voltage control of magnetization switching. Through the competition between the E-field induced uniaxial anisotropy in ferromagnetic layer and unidirectional anisotropy in antiferromagnetic layer, the exchange bias was significantly shifted by up to |?Hex|/Hex = 8% in NiFe/FeMn/glass/PZN-PT (011) and 13% in NiFe/NiCoO/glass/PZN-PT (011). In addition, the square shape of the hysteresis loop, as well as a strong shape tunability of |?Hex|/Hc = 67.5 ~ 125% in NiFe/FeMn/glass/PZN-PT and 30 ~ 38% in NiFe/NiCoO/glass/PZN-PT were achieved, which lead to a near 180 degrees magnetization switching. Electrical tuning of interfacial exchange coupling in FM/AFM/FE systems paves a new way for realizing magnetoelectric random access memories and other memory technologies. PMID- 26576659 TI - Comparison between invasive and non-invasive blood pressure in young, middle and old age. AB - We aimed to compare simultaneous invasive and non-invasive blood pressure (IBP and NIBP) measurements in young, middle and old age using the data from the Multiparameter Intelligent Monitoring in Intensive Care II (MIMIC II) database. In total, 23,679 blood pressure measurements were extracted from 742 patients, divided into three groups of young, middle and old age. IBP-NIBP differences in systolic/diastolic blood pressure (SBP/DBP) were 0.1 +/- 16.5 mmHg/11.0 +/- 12.2 mmHg in young age, -2.9 +/- 19.8 mmHg/6.9 +/- 17.5 mmHg in middle age and -3.2 +/ 29.3 mmHg/8.5 +/- 19.8 mmHg in old age. The mean and standard deviation (SD) of invasive systolic blood pressure (ISBP)-non-invasive systolic blood pressure (NISBP) differences increased from young to middle then to old age, and the SD of invasive diastolic blood pressure (IDBP)-non-invasive diastolic blood pressure (NIDBP) differences also increased with age. In young, middle and old age, the correlation coefficients were 0.86, 0.79 and 0.53, respectively, between ISBP and NISBP, and 0.78, 0.78 and 0.41 between IDBP and NIDBP. In conclusion, IBP showed good correlation with NIBP in each age category. The agreement between IBP and NIBP measurements was influenced by age category. PMID- 26576660 TI - Soft and broadband infrared metamaterial absorber based on gold nanorod/liquid crystal hybrid with tunable total absorption. AB - We design a soft infrared metamaterial absorber based on gold nanorods dispersed in liquid crystal (LC) placed on a gold film and theoretically investigate its total absorption character. Because the nanorods align with the LC molecule, the gold nanorods/LC hybrid exhibits different permittivity as a function of tilt angle of LC. At a certain tilt angle, the absorber shows an omnidirectional total absorption effect. By changing the tilt angle of LC by an external electric field, the total absorption character can be adjusted. The total absorption character also depends on the concentration, geometric dimension of nanorods, and defect of nanorod arrangement in LC. When the LC contains different size of gold nanorods, a broadband absorption can be easily realized. The characteristics including flexibility, omnidirectional, broadband and tunability make the infrared metamaterial absorber possess potential use in smart metamaterial devices. PMID- 26576661 TI - Role of the clock gene Bmal1 and the gastric ghrelin-secreting cell in the circadian regulation of the ghrelin-GOAT system. AB - As adequate food intake is crucial to survival, organisms have evolved endogenous circadian clocks to generate optimal temporal patterns of food-related behavior and physiology. The gastric ghrelin-secreting cell is thought to be part of this network of peripheral food-entrainable oscillators (FEOs), regulating the circadian release of this orexigenic peptide. This study aimed to determine the role of the core clock gene Bmal1 and the gastric ghrelin-secreting cell as an FEO in the circadian rhythmicity of ghrelin expression and secretion in vivo and in vitro. Bmal1-deficient mice not only lacked circadian rhythmicity in plasma ghrelin levels and food intake, but also showed decreased gastric mRNA expression of ghrelin and ghrelin O-acyltransferase (GOAT), the ghrelin activating enzyme. Furthermore, in the absence of the hypothalamic master clock, food-related stimuli entrained the molecular clock of gastric ghrelinoma cells to regulate the rhythmic release of ghrelin. Divergent responses in octanoyl and total ghrelin release towards different food cues were observed, suggesting that the FEO also regulates the circadian rhythmicity of GOAT. Collectively, these findings indicate that circadian rhythmicity of ghrelin signaling requires Bmal1 and is driven by a food-responsive clock in the gastric ghrelin-secreting cell that not only regulates ghrelin, but also GOAT activity. PMID- 26576662 TI - Antibacterial titanium nano-patterned arrays inspired by dragonfly wings. AB - Titanium and its alloys remain the most popular choice as a medical implant material because of its desirable properties. The successful osseointegration of titanium implants is, however, adversely affected by the presence of bacterial biofilms that can form on the surface, and hence methods for preventing the formation of surface biofilms have been the subject of intensive research over the past few years. In this study, we report the response of bacteria and primary human fibroblasts to the antibacterial nanoarrays fabricated on titanium surfaces using a simple hydrothermal etching process. These fabricated titanium surfaces were shown to possess selective bactericidal activity, eliminating almost 50% of Pseudomonas aeruginosa cells and about 20% of the Staphylococcus aureus cells coming into contact with the surface. These nano-patterned surfaces were also shown to enhance the aligned attachment behavior and proliferation of primary human fibroblasts over 10 days of growth. These antibacterial surfaces, which are capable of exhibiting differential responses to bacterial and eukaryotic cells, represent surfaces that have excellent prospects for biomedical applications. PMID- 26576663 TI - Clinical acceptability study of once-daily versus twice-daily micronized purified flavonoid fraction in patients with symptomatic chronic venous disease: a randomized controlled trial. AB - BACKGROUND: The aim of this study was to compare the clinical acceptability of two dose regimens of micronized purified flavonoid fraction (MPFF): a single 1000 mg tablet once daily versus 500 mg twice daily in patients suffering from chronic venous disease (CVD). METHODS: In an international, randomized, double-blind, parallel-group study, 174 patients (Clinical Etiological Anatomic Pathophysiologic [CEAP] class C0s to C4) were randomized to MPFF 1000 mg once daily or MPFF 500 mg twice daily for 8 weeks. Adverse events (AEs) were recorded in patient-kept diaries (weeks 0, 2, 4, 8) and leg pain was assessed using a Visual Analog Scale (VAS). RESULTS: No serious AEs occurred. A total of 30 treatment-emergent adverse events (EAE) were reported (15 in each group). Three treatment-EAE in the MPFF 1000 mg group (constipation, dyspepsia, allergic dermatitis) were considered by the investigator to be related to treatment. All were of mild intensity and resolved when treatment finished. Both MPFF regimens were associated with a significant reduction in leg pain score with a reduction of 4.21 cm for MPFF 1000 mg once daily (P<0.001) and 4.01 cm for MPFF 500 mg twice daily (P<0.001). The reduction in pain was noted after 2 weeks of treatment and continuously throughout the treatment. CONCLUSIONS: Both treatment regimens were well tolerated and associated with similar reductions in leg pain after 8 weeks of treatment. The new MPFF 1000 mg dose regimen has a similar safety profile to two MPFF 500 mg tablets with the advantage of one tablet per day and potential improved patient adherence. PMID- 26576664 TI - Catheter-directed thrombolysis combined with manual aspiration thrombectomy for acute inferior vena cava filter thrombosis. AB - BACKGROUND: The occurrence of inferior vena cava (IVC) filter thrombosis has been reported, however, the optimal treatment of IVC thrombosis has not been established yet. The aim of this study was to assess the results of catheter directed thrombolysis (CDT) combined with aspiration thrombectomy (AT) in the treatment for IVC filter thrombosis. METHODS: A total of 35 consecutive patients received endovascular treatment with CDT alone or CDT with AT for IVC filter thrombosis at Second Affiliated Hospital of Suzhou University from May 2009 to May 2014 were included in this study. The procedure, complications and clinical outcome between these two groups were retrospectively reviewed. RESULTS: The mean age of patients was 44.7+/-15.8 years (range: 17-74 years). The patients were consisted of 21 males and 14 females. CDT alone and CDT with AT were performed in 16 and 19 patients, respectively. The mean procedural time in the group receiving CDT alone group was longer than in the group receiving CDT with AT (99.5+/-51.4 vs. 64.9+/-35.9 hours, P<0.05) and the dose of urokinase used during the procedure was significantly lower in the CDT + AT group (2.1+/-1.1 vs. 1.5+/-0.6 million IU, P<0.05). Besides, total number of complications in the CDT + AT group was smaller than in the group treated with CDT alone (9 vs. 4 cases, P<0.05). CONCLUSIONS: Our results confirmed that CDT with AT was a safe and effective method in the treatment of acute IVC filter thrombosis. Compared with CDT alone, it was better performing thanks to a shorter thrombolysis time and a lower urokinase dose required. In addition, it may decrease the occurrence of complications. PMID- 26576665 TI - Rapid detection of D-Dimers with mLabs(r) whole blood method for venous thromboembolism exclusion. Comparison with Vidas(r) D-Dimers assay. AB - BACKGROUND: Easy to use point of care assays for D-Dimers measurement in whole blood from patients with clinical suspicion of venous thromboembolism (VTE) will facilitate the diagnostic strategy in the Emergency Department (ED) setting. We prospectively evaluated the diagnostic performance of the point-of-care mLabs(r) Whole Blood D-Dimers test and we compared it with the Vidas(r) D-Dimers assay. METHODS: As part of the diagnostic algorithm applied in patients with clinical suspicion of VTE, the VIDAS(r) D-Dimers Test was prescribed by the emergency physician in charge. The mLabs(r) Whole Blood D-Dimers Test was used on the same samples. All patients had undergone exploration with the recommended imaging techniques for VTE diagnosis. RESULTS: Both assays were performed, on 99 emergency patients (mean age was 65 years) with clinical suspicion of VTE. In 3% of patients, VTE was documented with a reference imaging technique. The Bland and Altman test showed significant agreement between the two methods. Both assays showed equal sensitivity and negative predictive value for VTE. CONCLUSIONS: The mLabs whole blood assay is a promising point of care method for measurement of D Dimers and exclusion of VTE diagnosis in the emergency setting which should be validated in a larger prospective study. PMID- 26576666 TI - High-resolution in-depth imaging of optically cleared thick samples using an adaptive SPIM. AB - Today, Light Sheet Fluorescence Microscopy (LSFM) makes it possible to image fluorescent samples through depths of several hundreds of microns. However, LSFM also suffers from scattering, absorption and optical aberrations. Spatial variations in the refractive index inside the samples cause major changes to the light path resulting in loss of signal and contrast in the deepest regions, thus impairing in-depth imaging capability. These effects are particularly marked when inhomogeneous, complex biological samples are under study. Recently, chemical treatments have been developed to render a sample transparent by homogenizing its refractive index (RI), consequently enabling a reduction of scattering phenomena and a simplification of optical aberration patterns. One drawback of these methods is that the resulting RI of cleared samples does not match the working RI medium generally used for LSFM lenses. This RI mismatch leads to the presence of low-order aberrations and therefore to a significant degradation of image quality. In this paper, we introduce an original optical-chemical combined method based on an adaptive SPIM and a water-based clearing protocol enabling compensation for aberrations arising from RI mismatches induced by optical clearing methods and acquisition of high-resolution in-depth images of optically cleared complex thick samples such as Multi-Cellular Tumour Spheroids. PMID- 26576667 TI - Low-temperature-processed efficient semi-transparent planar perovskite solar cells for bifacial and tandem applications. AB - Semi-transparent perovskite solar cells are highly attractive for a wide range of applications, such as bifacial and tandem solar cells; however, the power conversion efficiency of semi-transparent devices still lags behind due to missing suitable transparent rear electrode or deposition process. Here we report a low-temperature process for efficient semi-transparent planar perovskite solar cells. A hybrid thermal evaporation-spin coating technique is developed to allow the introduction of PCBM in regular device configuration, which facilitates the growth of high-quality absorber, resulting in hysteresis-free devices. We employ high-mobility hydrogenated indium oxide as transparent rear electrode by room temperature radio-frequency magnetron sputtering, yielding a semi-transparent solar cell with steady-state efficiency of 14.2% along with 72% average transmittance in the near-infrared region. With such semi-transparent devices, we show a substantial power enhancement when operating as bifacial solar cell, and in combination with low-bandgap copper indium gallium diselenide we further demonstrate 20.5% efficiency in four-terminal tandem configuration. PMID- 26576668 TI - Influence of physical factors on polycyclic aromatic hydrocarbons (PAHs) content in vegetable oils. AB - The aim of this study was to test the hypothesis about physical factors causing a significant decrease of polycyclic aromatic hydrocarbon (PAH) compounds in foodstuffs. For this purpose, extraction of 16 PAHs (prioritised by EPA) from selected foodstuffs (rapeseed oil and sunflower oil) was carried out. The changes in PAH content in oils exposed to selected physical factors (UV radiation, temperature and time) were observed. Oils under study were exposed to two types of UV radiation: direct and indirect (through a glass plate). In both experiments, a reduction of 16 PAHs in oils was recorded but in the latter a PAH reduction was not as high. In another experiment, the temperature of oils was raised to 40, 100 and 200 degrees C. As a result, the content of PAHs has decreased significantly. In both cases, exposure to UV radiation and high temperature resulted in the reduction of PAHs, it was strongly correlated with the duration of experiments. The results showed relatively low contamination of oil with PAHs. Only for rapeseed oil, the level of said contamination was substantially higher than laid down limits. PMID- 26576669 TI - Potential serotonergic agents for the treatment of schizophrenia. AB - INTRODUCTION: For the last 30 years, drugs targeting serotonin receptors (5-HTR) have been intensively investigated in schizophrenia. New drugs targeting 5-HTRs are under development in patients with schizophrenia. AREAS COVERED: In this review, the authors describe the recent clinical trials for schizophrenia with selective serotonergic agents and provide an opinion on how the investigated drugs can help to fulfil current treatment needs. Clinical trials were found in US and EU clinical trial registries and in the medical literature. Relevant 5-HTR antagonists active in animal models of schizophrenia were also analysed. EXPERT OPINION: Antipsychotics reduce positive symptoms of schizophrenia (delusions, hallucinations and disordered thought), but have undesirable side effects. Moreover, satisfactory treatment of negative symptoms (apathy, poverty of speech, lack of interest in social interactions) and cognitive dysfunction is currently not available. The selective 5-HT2CR full agonist vabicaserin showed antipsychotic efficacy with fewer side effects than olanzapine. Adjunctive pimavanserin (a selective 5-HT2AR inverse agonist) facilitated antipsychotic dose and side-effect reductions. Selective 5-HT3R antagonists (ondansetron, tropisetron and granisetron) showed positive results on negative symptoms and/or cognitive impairments in phase II trials. Adjunctive ondansetron has now entered a phase III trial for such indications. Finally, 5-HTA5R and 5-HT7R antagonists have shown procognitive actions in animal models of schizophrenia. These novel serotonergic drugs seem promising for improving the current treatment of schizophrenia. PMID- 26576670 TI - An Exploration of the Four-Factor Structure of the Drinking Motives Questionnaire Revised Among Undergraduate Students in China. AB - BACKGROUND: College drinking has become a significant health issue in China; the current study addressed the gap that no prior research has investigated drinking motives among Chinese undergraduate students. OBJECTIVES: This study aimed to replicate the four-factor structure of the Drinking Motives Questionnaire-Revised (DMQ-R) reported for Western populations. Additionally, the relationships between drinking motives and alcohol use were investigated. METHODS: In 2012, 436 participants (mean age = 20.49 and SD = 1.49; 50% male) recruited from a college in China completed a self-administered survey in their classroom setting. Drinking motives were measured by the Chinese version of the DMQ-R; three indicators of alcohol use were assessed. Factor analysis was conducted to examine the factor structure of the DMQ-R, followed by regression analysis to investigate the associations between drinking motives and alcohol-related outcomes. RESULTS: Confirmatory factor analysis failed to replicate the measurement model tested, but exploratory factor analysis identified a similar four-dimensional factor structure. Reliability and convergent and discriminant validity of the four factors were acceptable. The results also showed that social motives were related to alcohol use and heavy drinking; conformity motives were related to alcohol use and alcohol-related problems. Enhancement motives were the strongest correlates of alcohol use; coping motives were the strongest correlates of heavy drinking and alcohol-related problems. CONCLUSIONS/IMPORTANCE: The DMQ-R was a reliable and valid scale measuring four types of drinking motives among Chinese college students. Findings suggested that the motivational model of alcohol use may apply to studying college drinking in China. PMID- 26576671 TI - Prediction of the gene expression in normal lung tissue by the gene expression in blood. AB - BACKGROUND: Comparative analysis of gene expression in human tissues is important for understanding the molecular mechanisms underlying tissue-specific control of gene expression. It can also open an avenue for using gene expression in blood (which is the most easily accessible human tissue) to predict gene expression in other (less accessible) tissues, which would facilitate the development of novel gene expression based models for assessing disease risk and progression. Until recently, direct comparative analysis across different tissues was not possible due to the scarcity of paired tissue samples from the same individuals. METHODS: In this study we used paired whole blood/lung gene expression data from the Genotype-Tissue Expression (GTEx) project. We built a generalized linear regression model for each gene using gene expression in lung as the outcome and gene expression in blood, age and gender as predictors. RESULTS: For ~18 % of the genes, gene expression in blood was a significant predictor of gene expression in lung. We found that the number of single nucleotide polymorphisms (SNPs) influencing expression of a given gene in either blood or lung, also known as the number of quantitative trait loci (eQTLs), was positively associated with efficacy of blood-based prediction of that gene's expression in lung. This association was strongest for shared eQTLs: those influencing gene expression in both blood and lung. CONCLUSIONS: In conclusion, for a considerable number of human genes, their expression levels in lung can be predicted using observable gene expression in blood. An abundance of shared eQTLs may explain the strong blood/lung correlations in the gene expression. PMID- 26576672 TI - Kilovoltage radiosurgery with gold nanoparticles for neovascular age-related macular degeneration (AMD): a Monte Carlo evaluation. AB - This work uses Monte Carlo radiation transport simulation to assess the potential benefits of gold nanoparticles (AuNP) in the treatment of neovascular age-related macular degeneration with stereotactic radiosurgery. Clinically, a 100 kVp x-ray beam of 4 mm diameter is aimed at the macula to deliver an ablative dose in a single fraction. In the transport model, AuNP accumulated at the bottom of the macula are targeted with a source representative of the clinical beam in order to provide enhanced dose to the diseased macular endothelial cells. It is observed that, because of the AuNP, the dose to the endothelial cells can be significantly enhanced, allowing for greater sparing of optic nerve, retina and other neighboring healthy tissue. For 20 nm diameter AuNP concentration of 32 mg g(-1), which has been shown to be achievable in vivo, a dose enhancement ratio (DER) of 1.97 was found to be possible, which could potentially be increased through appropriate optimization of beam quality and/or AuNP targeting. A significant enhancement in dose is seen in the vicinity of the AuNP layer within 30 MUm, peaked at the AuNP-tissue interface. Different angular tilting of the 4 mm beam results in a similar enhancement. The DER inside and in the penumbra of the 4 mm irradiation-field are almost the same while the actual delivered dose is more than one order of magnitude lower outside the field leading to normal tissue sparing. The prescribed dose to macular endothelial cells can be delivered using almost half of the radiation allowing reduction of dose to the neighboring organs such as retina/optic nerve by 49% when compared to a treatment without AuNP. PMID- 26576673 TI - Comparative effectiveness of electro-acupuncture plus lifestyle modification treatment for patients with simple obesity and overweight: study protocol for a randomized controlled trial. AB - BACKGROUND: Acupuncture is considered to be an effective and safe treatment for obese and overweight patients, although high-quality evidence regarding the effects of acupuncture on obesity are not conclusive. The aim of the current study is to investigate the effectiveness of electro-acupuncture plus lifestyle modification for treating obese and overweight patients, in comparison with lifestyle modification alone in China. METHODS/DESIGN: To compare the effectiveness of acupuncture plus lifestyle modification, a 2-armed, controlled trial with randomization using minimization will be conducted on 150 simple obesity and overweight patients, aged 18-50 years, for a 36-week study duration. All patients will be randomly assigned to one of two groups and will receive either acupuncture plus lifestyle modification or lifestyle modification alone. Outcomes will be evaluated at baseline and at 4 weeks, 8 weeks, and 12 weeks during treatment as well as at 6-week, 12-week, and 24-week follow-up. The primary endpoint is change of body mass index (BMI) during the 12th week. Secondary endpoints are body weight; waist-to-hip ratio; biochemical tests including serum cholesterol (TC), triglyceride (TG) and high-density lipoprotein (HDL) levels; and answers to the Short Form 36 (SF-36) and the Impact of Weight on Quality of Life Questionnaire-Lite Version (IWQOL-Lite). Statistical analyses will be based on the intention-to-treat (ITT) principle. The main endpoint will be analyzed by analysis of covariance (ANCOVA), and the objective outcome results will be analyzed by logistic regression analysis. To avoid potential confounding factors, additional sensitivity analyses will be conducted following these statistical analyses. DISCUSSION: This trial is the first to compare the effectiveness of acupuncture plus lifestyle modification for treating obesity relative to lifestyle modification treatment alone by using a pragmatic study design. We hope that the results of this study will contribute to advancing the current methodology of acupuncture trials for obesity and will facilitate the application of useful acupuncture strategies in real-world clinical settings. TRIAL REGISTRATION: ChiCTR-TRC- 12002762 . The date of registration is 31 October 2012. PMID- 26576674 TI - miR-449a targets Flot2 and inhibits gastric cancer invasion by inhibiting TGF beta-mediated EMT. AB - BACKGROUND: Flot2, a highly conserved protein of the SPFH domain containing proteins family, has recently been identified as oncogene to be involved in the tumorigenesis and metastasis of several cancers including gastric cancer. However, the underlying molecular mechanism of Flot2 in gastric cancer (GC) is largely unknown. METHODS: qRT-PCR and western blot was performed to detect miR 449a and Flot2 expression in GC cell lines and Normal human gastric epithelial cells. Then, luciferase reporter assay was used to elucidate whether Flot2 is a target gene of miR-449a. Finally, the roles and mechanism of miR-449a in regulation of tumor invasion were further investigated. RESULTS: In this study, miR-449a expression was downregulated and Flot2 was upregulated in all GC cell lines as compared with that in GES-1. luciferase reporter assay identified Flot2 as a novel direct target of miR-449a. miR-449a regulated GC cell invasion by suppressing Flot2 expression. Expression analysis of a set of epithelial mesenchymal transition (EMT) markers showed that miR-449a reduced the expression of mesenchymal markers (vimentin and N-cadherin) and induced the expression of epithelial marker (E-cadherin), which was consistent with silenced Flot2. Moreover, Flot2 is necessary for TGF-beta-induced EMT in GC cells. CONCLUSIONS: Our results demonstrated that miR-449a suppressed Flot2 expression results in decreased cell invasion through repressing TGF-beta-mediated-EMT, and provides a new theoretical basis to further investigate miR-449a-regulated Flot2 as a potential biomarker and a promising approach for GC treatment. PMID- 26576675 TI - Development of a high yield expression and purification system for Domain I of Beta-2-glycoprotein I for the treatment of APS. AB - BACKGROUND: In this paper we describe a novel method to achieve high yield bacterial expression of a small protein domain with considerable therapeutic potential; Domain I of Beta-2-glycoprotein I (beta2GPI). beta2GPI is intrinsic to the pathological progression of the Antiphospholipid Syndrome (APS). Patients develop autoantibodies targeting an epitope located on the N-terminal Domain I of beta2GPI rendering this domain of interest as a possible therapeutic. RESULTS: This new method of production of Domain I of beta2GPI has increased the production yield by ~20 fold compared to previous methods in E.coli. This largely scalable, partially automated method produces 50-75 mg of pure, folded, active Domain I of beta2GPI per litre of expression media. CONCLUSION: The application of this method may enable production of Domain I on sufficient scale to allow its use as a therapeutic. PMID- 26576676 TI - A pilot study using low-dose Spectral CT and ASIR (Adaptive Statistical Iterative Reconstruction) algorithm to diagnose solitary pulmonary nodules. AB - BACKGROUND: Lung cancer is the most common cancer which has the highest mortality rate. With the development of computed tomography (CT) techniques, the case detection rates of solitary pulmonary nodules (SPN) has constantly increased and the diagnosis accuracy of SPN has remained a hot topic in clinical and imaging diagnosis. The aim of this study was to evaluate the combination of low-dose spectral CT and ASIR (Adaptive Statistical Iterative Reconstruction) algorithm in the diagnosis of solitary pulmonary nodules (SPN). METHODS: 62 patients with SPN (42 cases of benign SPN and 20 cases of malignant SPN, pathology confirmed) were scanned by spectral CT with a dual-phase contrast-enhanced method. The iodine and water concentration (IC and WC) of the lesion and the artery in the image that had the same density were measured by the GSI (Gemstone Spectral Imaging) software. The normalized iodine and water concentration (NIC and NWC) of the lesion and the normalized iodine and water concentration difference (ICD and WCD) between the arterial and venous phases (AP and VP) were also calculated. The spectral HU (Hounsfield Unit ) curve was divided into 3 sections based on the energy (40-70, 70-100 and 100-140 keV) and the slopes (lambdaHU) in both phases were calculated. The ICAP, ICVP, WCAP and WCVP, NIC and NWC, and the lambdaHU in benign and malignant SPN were compared by independent sample t-test. RESULTS: The iodine related parameters (ICAP, ICVP, NICAP, NICVP, and the ICD) of malignant SPN were significantly higher than that of benign SPN (t = 3.310, 1.330, 2.388, 1.669 and 3.251, respectively, P <0.05). The 3 lambdaHU values of venous phase in malignant SPN were higher than that of benign SPN (t = 3.803, 2.846 and 3.205, P <0.05). The difference of water related parameters (WCAP, WCVP, NWCAP, NWCVP and WCD) between malignant and benign SPN were not significant (t = 0.666, 0.257, 0.104, 0.550 and 0.585, P > 0.05). CONCLUSIONS: The iodine related parameters and the slope of spectral curve are useful markers to distinguish the benign from the malignant lung diseases, and its application is extremely feasible in clinical applications. PMID- 26576677 TI - Genomic prediction and genome-wide association study for dagginess and host internal parasite resistance in New Zealand sheep. AB - BACKGROUND: Dagginess (faecal soiling of the perineum region) and host nematode parasite resistance are important animal welfare traits in New Zealand sheep. Genomic prediction (GP) estimates the genetic merit, as a molecular breeding value (mBV), for each trait based on many SNPs. The additional information the mBV provides (as determined by its accuracy) has led to its incorporation into breeding schemes. Some GP methods give SNP effects, which provide additional information to identify genome-wide associations (GWAS) for a trait of interest. Here we report results from a GP and GWAS study for dagginess and host nematode parasite resistance in a New Zealand sheep industry resource. RESULTS: Genomic prediction analysis was performed using 50K SNP chip data and parent average removed, de-regressed BVs for five traits, from a resource of 8705 pedigree recorded animals. The five traits were dag score at three and eight months (DAG3, DAG8) and nematode faecal egg count in summer (FEC1), autumn (FEC2) and as an adult (AFEC). The resource consisted of Romney, Coopworth, Perendale, Texel and various breed crosses (designated: CompRCP, CompRCPT and CompCRP). The pure breeds, apart from Texel, plus CompRCP were used to develop the GP. The resulting SNP effects were used to identify genetic regions associated with dagginess and parasite resistance. Accuracies of the weighted correlation between mBV and true BV ranged between -0.07 (Texel) and 0.56 (Coopworth) for DAG3 and DAG8. For FEC1, FEC2 and AFEC accuracies ranged between -0.22 (CompRCPT) and 0.69 (Coopworth). The weighted average individual accuracy (calculated from theory) ranges were 0.13 (Texel) to 0.52 (Coopworth) and 0.11 (Texel) to 0.55 (Coopworth) respectively, for dagginess and parasite traits. There was one SNP for DAG8 that reached Bonferroni significance threshold (P < 1 * 10(-6)) on OAR15, the same two SNPs for each of the parasite traits (OAR26) and none for DAG3. A notable peak was also observed on OAR7 for all the parasite traits, however, it did not reach the Bonferroni significance threshold. CONCLUSIONS: This study presents the first results of a GWAS on dagginess and faecal egg count traits in New Zealand sheep. The results suggest that there are quantitative trait loci on OAR 15 for dagginess and on OAR26 and seven for faecal egg count. PMID- 26576678 TI - Minocycline counter-regulates pro-inflammatory microglia responses in the retina and protects from degeneration. AB - BACKGROUND: Microglia reactivity is a hallmark of retinal degenerations and overwhelming microglial responses contribute to photoreceptor death. Minocycline, a semi-synthetic tetracycline analog, has potent anti-inflammatory and neuroprotective effects. Here, we investigated how minocycline affects microglia in vitro and studied its immuno-modulatory properties in a mouse model of acute retinal degeneration using bright white light exposure. METHODS: LPS-treated BV-2 microglia were stimulated with 50 MUg/ml minocycline for 6 or 24 h, respectively. Pro-inflammatory gene transcription was determined by real-time RT-PCR and nitric oxide (NO) secretion was assessed using the Griess reagent. Caspase 3/7 levels were determined in 661W photoreceptors cultured with microglia-conditioned medium in the absence or presence of minocycline supplementation. BALB/cJ mice received daily intraperitoneal injections of 45 mg/kg minocycline, starting 1 day before exposure to 15.000 lux white light for 1 hour. The effect of minocycline treatment on microglial reactivity was analyzed by immunohistochemical stainings of retinal sections and flat-mounts, and messenger RNA (mRNA) expression of microglia markers was determined using real-time RT-PCR and RNA-sequencing. Optical coherence tomography (OCT) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) stainings were used to measure the extent of retinal degeneration and photoreceptor apoptosis. RESULTS: Stimulation of LPS-activated BV-2 microglia with minocycline significantly diminished the transcription of the pro-inflammatory markers CCL2, IL6, and inducible nitric oxide synthase (iNOS). Minocycline also reduced the production of NO and dampened microglial neurotoxicity on 661W photoreceptors. Furthermore, minocycline had direct protective effects on 661W photoreceptors by decreasing caspase 3/7 activity. In mice challenged with white light, injections of minocycline strongly decreased the number of amoeboid alerted microglia in the outer retina and down-regulated the expression of the microglial activation marker translocator protein (18 kDa) (TSPO), CD68, and activated microglia/macrophage whey acidic protein (AMWAP) already 1 day after light exposure. Furthermore, RNA-seq analyses revealed the potential of minocycline to globally counter-regulate pro-inflammatory gene transcription in the light-damaged retina. The severe thinning of the outer retina and the strong induction of photoreceptor apoptosis induced by light challenge were nearly completely prevented by minocycline treatment as indicated by a preserved retinal structure and a low number of apoptotic cells. CONCLUSIONS: Minocycline potently counter-regulates microgliosis and light induced retinal damage, indicating a promising concept for the treatment of retinal pathologies. PMID- 26576679 TI - miR-634 restores drug sensitivity in resistant ovarian cancer cells by targeting the Ras-MAPK pathway. AB - BACKGROUND: Drug resistance hampers the efficient treatment of malignancies, including advanced stage ovarian cancer, which has a 5-year survival rate of only 30 %. The molecular processes underlying resistance have been extensively studied, however, not much is known about the involvement of microRNAs. METHODS: Differentially expressed microRNAs between cisplatin sensitive and resistant cancer cell line pairs were determined using microarrays. Mimics were used to study the role of microRNAs in drug sensitivity of ovarian cancer cell lines and patient derived tumor cells. Luciferase reporter constructs were used to establish regulation of target genes by microRNAs. RESULTS: MiR-634 downregulation was associated with cisplatin resistance. Overexpression of miR 634 affected cell cycle progression and enhanced apoptosis in ovarian cancer cells. miR-634 resensitized resistant ovarian cancer cell lines and patient derived drug resistant tumor cells to cisplatin. Similarly, miR-634 enhanced the response to carboplatin and doxorubicin, but not to paclitaxel. The cell cycle regulator CCND1, and Ras-MAPK pathway components GRB2, ERK2 and RSK2 were directly repressed by miR-634 overexpression. Repression of the Ras-MAPK pathway using a MEK inhibitor phenocopied the miR-634 effects on viability and chemosensitivity. CONCLUSION: miR-634 levels determine chemosensitivity in ovarian cancer cells. We identify miR-634 as a therapeutic candidate to resensitize chemotherapy resistant ovarian tumors. PMID- 26576681 TI - Histone acetyltransferase GCN5 is essential for heat stress-responsive gene activation and thermotolerance in Arabidopsis. AB - Exposure to temperatures exceeding the normal optimum levels, or heat stress (HS), constitutes an environmental disruption for plants, resulting in severe growth and development retardation. Here we show that loss of function of the Arabidopsis histone acetyltransferase GCN5 results in serious defects in terms of thermotolerance, and considerably impairs the transcriptional activation of HS responsive genes. Notably, expression of several key regulators such as the HS transcription factors HSFA2 and HSFA3, Multiprotein Bridging Factor 1c (MBF1c) and UV-HYPERSENSITIVE 6 (UVH6) is down-regulated in the gcn5 mutant under HS compared with the wild-type. Chromatin immunoprecipitation (ChIP) assays indicated that GCN5 protein is enriched at the promoter regions of HSFA3 and UVH6 genes, but not in HSFA2 and MBF1c, and that GCN5 facilitates H3K9 and H3K14 acetylation, which are associated with HSFA3 and UVH6 activation under HS. Moreover, constitutive expression of UVH6 in the gcn5 mutant partially restores heat tolerance. Taken together, our data indicate that GCN5 plays a key role in the preservation of thermotolerance via versatile regulation in Arabidopsis. In addition, expression of the wheat TaGCN5 gene re-establishes heat tolerance in Arabidopsis gcn5 mutant plants, suggesting that GCN5-mediated thermotolerance may be conserved between Arabidopsis and wheat. PMID- 26576682 TI - Naphthalimide-based fluorescent probe for selectively and specifically detecting glutathione in the lysosomes of living cells. AB - A novel naphthalimide-based fluorescent probe employing a sulfonamide unit as a thiol-responsive group is reported. It is capable of efficiently distinguishing GSH from cysteine and homocysteine. Bioimaging shows that it has high selectivity in living cells and can visualize the level of GSH in lysosomes. It is worth mentioning that different groups on the imide unit can affect the selectivity and reaction dynamics of the probe towards thiols. PMID- 26576680 TI - Mental health literacy measures evaluating knowledge, attitudes and help-seeking: a scoping review. AB - BACKGROUND: Mental health literacy has received increasing attention as a useful strategy to promote early identification of mental disorders, reduce stigma and enhance help-seeking behaviors. However, despite the abundance of research on mental health literacy interventions, there is the absence of evaluations of current available mental health literacy measures and related psychometrics. We conducted a scoping review to bridge the gap. METHODS: We searched PubMed, PsycINFO, Embase, CINAHL, Cochrane Library, and ERIC for relevant studies. We only focused on quantitative studies and English publications, however, we didn't limit study participants, locations, or publication dates. We excluded non English studies, and did not check the grey literature (non peer-reviewed publications or documents of any type) and therefore may have missed some eligible measures. RESULTS: We located 401 studies that include 69 knowledge measures (14 validated), 111 stigma measures (65 validated), and 35 help-seeking related measures (10 validated). Knowledge measures mainly investigated the ability of illness identification, and factual knowledge of mental disorders such as terminology, etiology, diagnosis, prognosis, and consequences. Stigma measures include those focused on stigma against mental illness or the mentally ill; self stigma ; experienced stigma; and stigma against mental health treatment and help seeking. Help-seeking measures included those of help-seeking attitudes, intentions to seek help, and actual help-seeking behaviors. CONCLUSIONS: Our review provides a compendium of available mental health literacy measures to facilitate applying existing measures or developing new measures. It also provides a solid database for future research on systematically assessing the quality of the included measures. PMID- 26576683 TI - Inferring speciation history in the Andes with reduced-representation sequence data: an example in the bay-backed antpittas (Aves; Grallariidae; Grallaria hypoleuca s. l.). AB - In the Andes, humid-forest organisms frequently exhibit pronounced genetic structure and geographic variation in phenotype, often coincident with physical barriers to dispersal. However, phylogenetic relationships of clades have often been difficult to resolve due to short internodes. Consequently, even in taxa with well-defined genetic structure, the temporal and geographic sequences of dispersal and vicariance events that led to this differentiation have remained opaque, hindering efforts to test the association between diversification and earth history and to understand the assembly of species-rich communities on Andean slopes. Here, we use mitochondrial DNA and thousands of short-read sequences generated with genotyping by sequencing (GBS) to examine the geographic history of speciation in a lineage of passerine birds found in the humid forest of the Andes, the 'bay-backed' antpitta complex (Grallaria hypoleuca s. l). Mitochondrial DNA genealogies documented genetic structure among clade but were poorly resolved at nodes relevant for biogeographic inference. By contrast, relationships inferred from GBS loci were highly resolved and suggested a biogeographic history in which the ancestor originated in the northern Andes and dispersed south. Our results are consistent with a scenario of vicariant speciation wherein the range of a widespread ancestor was fragmented as a result of geologic or climatic change, rather than a stepping-stone series of dispersal events across pre-existing barriers. However, our study also highlights challenges of distinguishing dispersal-mediated speciation from static vicariance. Our results further demonstrate the substantial evolutionary timescale over which the diverse biota of the Andes was assembled. PMID- 26576684 TI - Where do we start? The first survey of surgical residency education in Japan. AB - BACKGROUND: Currently, Japan does not have a national standardized program for surgical residency. Therefore, surgical education information and strategies are not shared among teaching hospitals. This was the first study aiming to clarify the current situation of surgical residency in Japan. METHODS: A questionnaire survey investigating the present situation of surgical residency was sent to the 76 teaching hospitals in Hokkaido Prefecture, Japan. RESULTS: The response rate was 64.5%. Data from the 36 hospitals with active residency programs were analyzed. Most of the program directors (79.4%) were in charge of educational work for less than 5 hours per week. Although half of the hospitals had skills laboratories or simulation centers, only 2 used them routinely for their residency program. Half of the hospitals evaluated the residents' competency and the quality of their educational programs. CONCLUSIONS: Structured programs and evaluation systems have not been integrated well into surgical residency in Japan. PMID- 26576685 TI - Passivation Using Molecular Halides Increases Quantum Dot Solar Cell Performance. AB - A solution-based passivation scheme is developed featuring the use of molecular iodine and PbS colloidal quantum dots (CQDs). The improved passivation translates into a longer carrier diffusion length in the solid film. This allows thicker solar-cell devices to be built while preserving efficient charge collection, leading to a certified power conversion efficiency of 9.9%, which is a new record in CQD solar cells. PMID- 26576686 TI - Unreliable Bodies: A Follow-up Twenty Years Later by a Mother and Daughter about the Impact of Illness and Disability on their Lives. AB - We are a mother and daughter, both health care professionals, who offer a follow up to an article we published twenty years ago about the impact of each other's ongoing, serious medical problems on our relationship. In this article, we contribute a long-term perspective on the differences between having an illness that is well or poorly understood by medical professionals and the lay community. We also discuss health in the context of identity formation and life stage, as during this interval the daughter left home, graduated college, married, and had two children. Also in this period, the mother survived a third breast cancer and other life-threatening illnesses. We discuss the impact of these experiences on each other and in other important relationships in our lives. Current discourses on daughters of breast cancer survivors do not fit our experience and we speculate about why our story differs. We find that although we continue to contend with serious medical issues that impact our own, each other's, and our families' lives, nonetheless, our lives are rich, rewarding, and "appropriate" for our life stage. That is the news. PMID- 26576688 TI - Nitrogen monoxide and carbon monoxide transfer interpretation: state of the art. AB - Just a few clinicians routinely measure the subcomponents of the lung diffusing capacity for Carbone monoxide (DLCO ). This is because the measurement of membrane and blood conductances for CO (DmCO and DbCO = thetaCO * Vc , respectively) by the classic Roughton and Forster method is complicated and time consuming. In addition, it mistakenly assumes a close relationship between alveolar oxygen partial pressure (PAO2 ) and mean intracapillary oxygen partial pressure (PcapO2 ) which is the true determinant of specific conductance of haemoglobin for CO (thetaCO ). Besides that, the critical multistep oxygenation method along with different linear equations relating 1/thetaCO to PcapO2 gave highly scattered DmCO and Vc values. The Dm and Vc can also be derived from a simultaneous measurement of DLNO and DLCO with the blood resistance for NO assumed to be negligible. However, recent in vitro and in vivo experiments point towards a finite value of thetaNO (about 4.5 mlNO * mlblood-1 * min-1 * mmHg-1 ). Putting together the arguments and our clinical data allows us to report here the state of the art in partitioning the CO diffusing capacity into its constitutive components, with the goal to encourage further studies examining the sensitivity of DmCO and Vc to alterations observed in parenchymal diseases. PMID- 26576689 TI - Shift-and-invert parallel spectral transformation eigensolver: Massively parallel performance for density-functional based tight-binding. AB - The Shift-and-invert parallel spectral transformations (SIPs), a computational approach to solve sparse eigenvalue problems, is developed for massively parallel architectures with exceptional parallel scalability and robustness. The capabilities of SIPs are demonstrated by diagonalization of density-functional based tight-binding (DFTB) Hamiltonian and overlap matrices for single-wall metallic carbon nanotubes, diamond nanowires, and bulk diamond crystals. The largest (smallest) example studied is a 128,000 (2000) atom nanotube for which ~330,000 (~5600) eigenvalues and eigenfunctions are obtained in ~190 (~5) seconds when parallelized over 266,144 (16,384) Blue Gene/Q cores. Weak scaling and strong scaling of SIPs are analyzed and the performance of SIPs is compared with other novel methods. Different matrix ordering methods are investigated to reduce the cost of the factorization step, which dominates the time-to-solution at the strong scaling limit. A parallel implementation of assembling the density matrix from the distributed eigenvectors is demonstrated. PMID- 26576690 TI - Heuristic pairwise alignment of de Bruijn graphs to facilitate simultaneous transcript discovery in related organisms from RNA-Seq data. AB - BACKGROUND: The advance of high-throughput sequencing has made it possible to obtain new transcriptomes and study splicing mechanisms in non-model organisms. In these studies, there is often a need to investigate the transcriptomes of two related organisms at the same time in order to find the similarities and differences between them. The traditional approach to address this problem is to perform de novo transcriptome assemblies to obtain predicted transcripts for these organisms independently and then employ similarity comparison algorithms to study them. RESULTS: Instead of obtaining predicted transcripts for these organisms separately from the intermediate de Bruijn graph structures employed by de novo transcriptome assembly algorithms, we develop an algorithm to allow direct comparisons between paths in two de Bruijn graphs by first enumerating short paths in both graphs, and iteratively extending paths in one graph that have high similarity to paths in the other graph to obtain longer corresponding paths between the two graphs. These paths represent predicted transcripts that are present in both organisms. CONCLUSIONS: Our approach generalizes the pairwise sequence alignment problem to allow the input to be non-linear structures, and provides a heuristic to reliably recover similar paths from the two structures. Our algorithm allows detailed investigation of the similarities and differences in alternative splicing between the two organisms at both the sequence and structure levels, even in the absence of reference transcriptomes or a closely related model organism. PMID- 26576687 TI - Comparison of different platelet count thresholds to guide administration of prophylactic platelet transfusion for preventing bleeding in people with haematological disorders after myelosuppressive chemotherapy or stem cell transplantation. AB - BACKGROUND: Platelet transfusions are used in modern clinical practice to prevent and treat bleeding in people who are thrombocytopenic due to bone marrow failure. Although considerable advances have been made in platelet transfusion therapy in the last 40 years, some areas continue to provoke debate, especially concerning the use of prophylactic platelet transfusions for the prevention of thrombocytopenic bleeding.This is an update of a Cochrane review first published in 2004, and previously updated in 2012 that addressed four separate questions: prophylactic versus therapeutic-only platelet transfusion policy; prophylactic platelet transfusion threshold; prophylactic platelet transfusion dose; and platelet transfusions compared to alternative treatments. This review has now been split into four smaller reviews looking at these questions individually; this review compares prophylactic platelet transfusion thresholds. OBJECTIVES: To determine whether different platelet transfusion thresholds for administration of prophylactic platelet transfusions (platelet transfusions given to prevent bleeding) affect the efficacy and safety of prophylactic platelet transfusions in preventing bleeding in people with haematological disorders undergoing myelosuppressive chemotherapy or haematopoietic stem cell transplantation (HSCT). SEARCH METHODS: We searched for randomised controlled trials (RCTs) in the Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library 2015, Issue 6, 23 July 2015), MEDLINE (from 1946), Embase (from 1974), CINAHL (from 1937), the Transfusion Evidence Library (from 1950), and ongoing trial databases to 23 July 2015. SELECTION CRITERIA: We included RCTs involving transfusions of platelet concentrates, prepared either from individual units of whole blood or by apheresis, and given to prevent bleeding in people with haematological disorders (receiving myelosuppressive chemotherapy or undergoing HSCT) that compared different thresholds for administration of prophylactic platelet transfusions (low trigger (5 x 10(9)/L); standard trigger (10 x 10(9)/L); higher trigger (20 x 10(9)/L, 30 x 10(9)/L, 50 x 10(9)/L); or alternative platelet trigger (for example platelet mass)). DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. MAIN RESULTS: Three trials met our predefined inclusion criteria and were included for analysis in the review (499 participants). All three trials compared a standard trigger (10 x 10(9)/L) versus a higher trigger (20 x 10(9)/L or 30 x 10(9)/L). None of the trials compared a low trigger versus a standard trigger or an alternative platelet trigger. The trials were conducted between 1991 and 2001 and enrolled participants from fairly comparable patient populations.The original review contained four trials (658 participants); in the previous update of this review we excluded one trial (159 participants) because fewer than 80% of participants had a haematological disorder. We identified no new trials in this update of the review.Overall, the methodological quality of the studies was low across different outcomes according to GRADE methodology. None of the included studies were at low risk of bias in every domain, and all the included studies had some threats to validity.Three studies reported the number of participants with at least one clinically significant bleeding episode within 30 days from the start of the study. There was no evidence of a difference in the number of participants with a clinically significant bleeding episode between the standard and higher trigger groups (three studies; 499 participants; risk ratio (RR) 1.35, 95% confidence interval (CI) 0.95 to 1.90; low-quality evidence).One study reported the number of days with a clinically significant bleeding event (adjusted for repeated measures). There was no evidence of a difference in the number of days of bleeding per participant between the standard and higher trigger groups (one study; 255 participants; relative proportion of days with World Health Organization Grade 2 or worse bleeding (RR 1.71, 95% CI 0.84 to 3.48, P = 0.162; authors' own results; low-quality evidence).Two studies reported the number of participants with severe or life-threatening bleeding. There was no evidence of any difference in the number of participants with severe or life-threatening bleeding between a standard trigger level and a higher trigger level (two studies; 421 participants; RR 0.99, 95% CI 0.52 to 1.88; low-quality evidence).Only one study reported the time to first bleeding episode. There was no evidence of any difference in the time to the first bleeding episode between a standard trigger level and a higher trigger level (one study; 255 participants; hazard ratio 1.11, 95% CI 0.64 to 1.91; low-quality evidence).Only one study reported on all-cause mortality within 30 days from the start of the study. There was no evidence of any difference in all-cause mortality between standard and higher trigger groups (one study; 255 participants; RR 1.78, 95% CI 0.83 to 3.81; low-quality evidence).Three studies reported on the number of platelet transfusions per participant. Two studies reported on the mean number of platelet transfusions per participant. There was a significant reduction in the number of platelet transfusions per participant in the standard trigger group (two studies, mean difference -2.09, 95% CI -3.20 to -0.99; low-quality evidence).One study reported on the number of transfusion reactions. There was no evidence to demonstrate any difference in transfusion reactions between the standard and higher trigger groups (one study; 79 participants; RR 0.07, 95% CI 0.00 to 1.09).None of the studies reported on quality of life. AUTHORS' CONCLUSIONS: In people with haematological disorders who are thrombocytopenic due to myelosuppressive chemotherapy or HSCT, we found low-quality evidence that a standard trigger level (10 x 10(9)/L) is associated with no increase in the risk of bleeding when compared to a higher trigger level (20 x 10(9)/L or 30 x 10(9)/L). There was low-quality evidence that a standard trigger level is associated with a decreased number of transfusion episodes when compared to a higher trigger level (20 x 10(9)/L or 30 x 10(9)/L).Findings from this review were based on three studies and 499 participants. Without further evidence, it is reasonable to continue with the current practice of administering prophylactic platelet transfusions using the standard trigger level (10 x 10(9)/L) in the absence of other risk factors for bleeding. PMID- 26576691 TI - Endo180 at the cutting edge of bone cancer treatment and beyond. AB - Skeletal bone is an attractive site for secondary tumour growth and is also home to spontaneous primary cancer. Treatment of bone metastasis is focused on limiting the vicious cycle of bone destruction with bisphosphonates or inhibition of receptor activator of nuclear factor-kappaB ligand (RANKL) with the fully human monoclonal antibody denosumab. The estimated 1 million deaths/year where bone metastasis is present, and the high healthcare costs required for its management, have ignited intensive research into the cellular and molecular pathology of osteolysis, involving interplay between tumour cells, bone-forming osteoblasts and bone-degrading osteoclasts. Compared to bone metastasis, knowledge about the pathology of primary bone cancers is limited. In recent work published in this journal, Engelholm et al provide a unique insight into how this poorly understood disease manifests and destroys bone. For the first time they have demonstrated that a mouse monoclonal antibody targeting the collagen receptor Endo180 (CD280, MRC2 uPARAP) can prevent osteolysis and bone destruction in a syngeneic model of advanced osteosarcoma. Their convincing findings make an important contribution towards Endo180-based therapy being developed as an option for the treatment of bone cancer amongst other malignancies. (c) 2015 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. PMID- 26576692 TI - Letter to the editor: First dorsal interosseous muscle contraction results in radiographic reduction of healthy thumb carpometacarpal joint. PMID- 26576693 TI - Early-onset and very-early-onset bipolar disorder: distinct or similar clinical conditions? AB - OBJECTIVE: This study aimed to examine differences in the clinical presentation of very-early-onset (VEO) and early-onset (EO) bipolar disorder (BD) not fully explored previously. METHODS: We selected two groups of subjects with BD from the Maritime Bipolar Registry based on age at onset of first major mood episode (VEO with onset prior to age 15 years; EO ranging from 15 to 18 years) and compared them with a reference group (onset after 18 years of age). There were 363 subjects (240 with bipolar I disorder and 123 with bipolar II disorder; mean age 44.2 +/- 12.8 (SD) years), with 41 subjects in the VEO and 95 in the EO groups. RESULTS: In comparison with the EO and reference groups, more subjects in the VEO group developed major depression as an index episode (88% for the VEO group versus 61% for the EO group and 54% for the reference group), and had an unremitting clinical course (65% versus 42% and 42%, respectively), rapid cycling (54% versus 34% and 28%, respectively), and comorbid attention-deficit hyperactivity disorder (17% versus 1% and 3%, respectively); a higher proportion of the VEO group had first-degree relatives with affective disorders compared with the EO and reference groups (0.41 versus 0.32 and 0.29, respectively), and they had lower scores on the Global Assessment of Functioning scale (mean scores of 64 versus 70 and 70). Overall, the EO group was similar to the reference group on most measures, except for increased suicidal behavior VEO 53%, EO 44% and reference group 25%). The results of polychotomous logistic regression also support the view that VEO BD represents a rather specific subtype of BD. CONCLUSIONS: Our results suggest the recognized correlates of early-onset BD may be driven by subjects at the lowest end of the age at onset spectrum. PMID- 26576694 TI - Leg ulcers due to foreign body reaction following silicone injections. PMID- 26576695 TI - Anatomy and physiology by Leonardo: The hidden revolution? PMID- 26576696 TI - High volume improves outcomes: The argument for centralization of rectal cancer surgery. AB - BACKGROUND: Centralization of care to "centers of excellence" in Europe has led to improved oncologic outcomes; however, little is known regarding the impact of nonmandated regionalization of rectal cancer care in the United States. METHODS: The Statewide Planning and Research Cooperative System (SPARCS) was queried for elective abdominoperineal and low anterior resections for rectal cancer from 2000 to 2011 in New York with the use of International Classification of Diseases, Ninth Revision codes. Surgeon volume and hospital volume were grouped into quartiles, and high-volume surgeons (>= 10 resections/year) and hospitals (>= 25 resections/year) were defined as the top quartile of annual caseload of rectal cancer resection and compared with the bottom 3 quartiles during analyses. Bivariate and multilevel regression analyses were performed to assess factors associated with restorative procedures, 30-day mortality, and temporal trends in these endpoints. RESULTS: Among 7,798 rectal cancer resections, the overall rate of no-restorative proctectomy and 30-day mortality decreased by 7.7% and 1.2%, respectively, from 2000 to 2011. In addition, there was a linear increase in the proportion of cases performed by both high-volume surgeons and high-volume hospitals and a decrease in the number of surgeons and hospitals performing rectal cancer surgery. High-volume surgeons at high-volume hospitals were associated independently with both less nonrestorative proctectomies (odds ratio 0.65, 95% confidence interval 0.48-0.89) and mortality (odds ratio 0.43, 95% confidence interval 0.21-0.87) rates. No patterns of significant improvement within the volume strata of the surgeon and hospitals were observed over time. CONCLUSION: This study suggests that the current trend toward regionalization of rectal cancer care to high-volume surgeons and high-volume centers has led to improved outcomes. These findings have implications regarding the policy of health care delivery in the United States, supporting referral to high-volume centers of excellence. PMID- 26576697 TI - The Interplay between Stroke Severity, Antiplatelet Use, and Aspirin Resistance in Ischemic Stroke. AB - BACKGROUND: The issue of whether prior antiplatelet use favorably affects stroke severity is currently unresolved. In this study, we evaluated the effect of antiplatelet use on clinical stroke severity and ischemic lesion volume, and assessed the confounding effect of laboratory-defined aspirin resistance on this relationship. METHODS: Admission National Institutes of Health Stroke Scale (NIHSS) score, ischemic lesion volumes on diffusion-weighted imaging (DWI), and in vitro aspirin resistance, in addition to other pertinent stroke features, were determined in a series of ischemic stroke patients. Univariate and multivariate analyses were performed to compare clinical and imaging markers of stroke severity among patients with and without prior antiplatelet use, taking into consideration the presence or absence of aspirin resistance. RESULTS: Antiplatelet users experienced more severe strokes, per NIHSS score, in comparison to antiplatelet-naive patients (P = .007). No significant difference was observed with respect to admission DWI lesion volume. When analyses were repeated after adjustment for stroke subtype and other confounders, no association was observed between antiplatelet use and stroke severity. On the other hand, NIHSS scores were significantly higher in aspirin-unresponsive patients than in both aspirin responders (P = .049) and aspirin nonusers (P = .005). CONCLUSION: We were unable to demonstrate a substantial positive influence of prestroke antiplatelet usage on stroke severity. Although the presence of more severe strokes among patients with laboratory resistance suggests a protective influence of aspirin sensitivity on stroke severity, the hypothesis could not be validated as no difference was observed among aspirin-naive and aspirin-sensitive patients with respect to admission NIHSS score or DWI lesion volume. PMID- 26576698 TI - Relationships among Communication Self-Efficacy, Communication Burden, and the Mental Health of the Families of Persons with Aphasia. AB - BACKGROUND: The purpose of this study was to elucidate the relationships among communication self-efficacy (SE), communication burden, and the mental health of the families of persons with aphasia using structural equation modeling (SEM). METHODS: This study examined 110 pairs of persons with aphasia receiving home care and 1 family caregiver per person with aphasia. The survey items for this study consisted of the Communication Self-efficacy Scale, the Communication Burden Scale, the Geriatric Depression Scale-Short Form-Japanese, and the Health Related Quality of Life: SF-8 Health Survey. The relationships between the constructive concept of "communication self-efficacy" and "communication burden," and "mental-health status" were analyzed using SEM. RESULTS: The results of the SEM analysis revealed that a high communication SE of the families was associated with low burden of communication and good mental-health status. CONCLUSIONS: Psychoeducational programs that address the communication SE of family caregivers may have the potential to reduce the burden of communication and to improve the mental health of caregivers. These programs could lead to an enhanced quality of life for both persons with aphasia and their families. PMID- 26576699 TI - Is Mean Platelet Volume a Reliable Marker to Predict Ischemic Stroke in the Follow-Up of Patients with Carotid Stenosis? AB - BACKGROUND: The objective of the study is to evaluate the reliability of mean platelet volume (MPV) for predicting ischemic stroke (cerebrovascular event [CVE]) among patients with different degrees of carotid stenosis. METHODS: Fifty two patients with CVEs, 136 patients with carotid artery disease (CAD), and 40 healthy volunteers were enrolled in this study. All participants were divided into the following groups according to CAD: absence of stenosis, less than 50% stenosis, 50%-69% stenosis, and 70% or more to total occlusion of the internal carotid artery. For each participant, the parameters of CAD were assessed using ultrasonography. To obtain the values of CRP and MPV and the leukocyte and platelet counts, all samples were processed within 30 minutes after blood collection. Univariate and multivariate analyses were used to evaluate the association between the values of serum C-reactive protein (CRP) and MPV and carotid stenosis. RESULTS: In terms of age and gender, there was no statistically significant difference between the groups (P = .094 and P = .428, respectively). However, CRP values in patients with CAD and CVEs were significantly higher than those in the controls (P < .001). There was no statistically significant difference between the CRP values in patients with CAD and CVEs (P = .249). Moreover, the MPV values did not show any significant difference between the groups (P = .053) and among the patients with CAD (P = .64). There was no positive correlation between serum CRP and MPV values in patients with CAD regarding the degree of carotid stenosis (r = .061, P = .477). CONCLUSION: The findings of this study claim that MPV has no predictive value during follow-up of the patients with CAD for CVEs. PMID- 26576700 TI - A point about stilettos. PMID- 26576701 TI - Patient age and breast resection weight affect immediate postmastectomy breast reconstruction in ductal carcinoma in situ. AB - PURPOSE: Mastectomy is necessary for 40% of the ductal carcinoma in situ. If immediate breast reconstruction (IBR) is systematically proposed, 81% of the patients would choose immediate versus delayed breast reconstruction, but the actual IBR rate is only approximately 50% of them. Therefore, the aim of this study was to identify objective characteristics that distinguish the patients who actually underwent IBR from those who did not. METHODS: Several criteria of 248 patients who have undergone mastectomy for ductal carcinoma were analyzed. Factors studied were age, body mass index, diabetes, tobacco use, and weight of the specimen of resection. RESULTS: The rate of IBR was 43%. An increase in age and weight of the resection specimen, irrespective of the body mass index, was associated with a lower rate of IBR. Thus, an increase of 100 g in the weight of the breast induces a significant reduction of the IBR (33%). CONCLUSIONS: In our series, older patients or patients with larger breasts (irrespective of the body mass index) were less likely to undergo IBR. In order to be in line with the patient's desire, the surgeons of our unit should broaden their indications of IBR. The lack of reconstruction of large breasts should certainly be compensated in part with the recent development of free tissue transfers in our unit. LEVEL OF EVIDENCE: 3. PMID- 26576702 TI - A simplified approach to reconstruction of hemipelvectomy defects with lower extremity free fillet flaps to minimize ischemia time. AB - External hemipelvectomy associated with trauma or during the operative management of musculoskeletal sarcomas may yield a soft tissue defect that can only be sufficiently covered by free tissue transfers. The application of "spare-parts surgery," such as a fillet of leg or thigh flap, uses distal uninvolved parts that are otherwise viable tissues as donor tissues to cover defects. This concept has great utility to achieve soft tissue coverage in challenging cases, such as hemipelvectomy. However, during such complicated and time-consuming cases, prolonged ischemia time of the proposed donor tissues can be problematic. We describe a technique developed by the senior author (SJK) that minimizes the ischemia time of donor free tissues during external hemipelvectomy. This technique is applicable to other surgeries where filleted spare parts are the donor-site source for free tissue transfer. PMID- 26576703 TI - Induced stabilization of columnar phases in binary mixtures of discotic liquid crystals. AB - Three discotic liquid-crystalline binary mixtures, characterized by their extent of bidispersity in molecular thickness, were investigated with molecular dynamics simulations. Each equimolar mixture contained A-type (thin) and B-type (thick) discogens. The temperature-dependence of the orientational order parameter reveals that A-type liquid samples produce ordered phases more readily, with the (hexagonal) columnar phase being the most structured variant. Moderately and strongly bidisperse mixtures produce globally-segregated samples for temperatures corresponding to ordered phases; the weakly bidisperse mixture displays microheterogeneities. Ordered phases in the B-type liquid are induced partially by the presence of the A-type fluid. In the moderately bidisperse mixture, order is induced through orientational frustration: a mixed prenematic-like phase precedes global segregation to yield nematic and columnar mesophases upon further cooling. In the strongly bidisperse mixture, order is induced less efficiently through a paranematic-like mechanism: a highly-ordered A-type fluid imparts order to B-type discogens found at the interface of a fully-segregated sample. This ordering effect permeates into the disordered B-type domain until nematic and columnar phases emerge upon further cooling. At sufficiently low temperatures, all samples investigated exhibit the (hexagonal) columnar mesophase. PMID- 26576704 TI - Extraction of quinolones from milk samples using bentonite/magnetite nanoparticles before determination by high-performance liquid chromatography with fluorimetric detection. AB - In this work, bentonite magnetic nanoparticles synthesized by a typical coprecipitation method were used as the adsorbent for the magnetic solid-phase extraction of six quinolones (ciprofloxacin, difloxacin, enrofloxacin, norfloxacin, sarafloxacin, and lomefloxacin) from milk samples followed by high performance liquid chromatography with fluorimetric detection. Under the optimized conditions, the linear quantitation range for the six quinolones was 0.3-200 ng/mL, and the correlation coefficients of the calibration curves ranged from 0.9994 to 0.9999. The detection limit of the method was 0.1 ng/mL. Recoveries of quinolones from pure and low-fat spiked milk samples varied from 80.4 to 92.7% and from 81.3 to 93.5%, respectively. These results demonstrated that the proposed method for the determination of six quinolones in milk samples was rapid, reliable, and efficient. PMID- 26576705 TI - Ligament and vein of Marshall: A therapeutic opportunity in atrial fibrillation. PMID- 26576706 TI - Eligibility and utilization of implantable cardioverter-defibrillators in a regional STEMI system. AB - BACKGROUND: Studies have shown mortality benefit for implantable cardioverter defibrillators (ICDs) in ST-elevation myocardial infarction (STEMI) patients with reduced left ventricular ejection fraction (LVEF), but contemporary eligibility and appropriate utilization of ICDs is unknown. OBJECTIVE: The purpose of this study was to determine the contemporary eligibility and appropriate utilization of ICDs post-STEMI. METHODS: Using the prospective Minneapolis Heart Institute regional STEMI registry, LVEF before discharge and at follow-up were stratified into 3 groups: normal (LVEF >=50%), mildly reduced (LVEF 35%-49%), and severely reduced (LVEF <35%). RESULTS: From March 2003 to June 2012, 3626 patients were treated. Patients with in-hospital death (n = 187), ICD in place (n = 21), negative cardiac biomarkers (n = 337), and undocumented in-hospital LVEF (n = 9) were excluded, leaving 3072 patients in the final analysis, including 1833 (59.7%) with LVEF >=50%, 875 (28.5%) with LVEF between 35% and 49%, and 364 (11.8%) with LVEF <35% before hospital discharge. Overall, 1029 patients (33.5%) underwent follow-up echocardiography >=40 days post-STEMI, including 140 of the 364 patients (38.5%) discharged with LVEF <35%. In total, 73 patients (7.1%) with follow-up echocardiography >=40 days post-STEMI met criteria for an ICD (68 LVEF <=30%, 5 LVEF 30%-35%, and New York Heart Association class II or greater). Only 26 of these patients (35.6%) underwent ICD placement within 1 year post-STEMI. Overall, only 10% to 15% of potentially eligible patients had an ICD implemented. CONCLUSION: Rates of ICD implantation in appropriate STEMI patients after 40 days are low. Strategies are needed to identify and expand access to these high-risk patients. PMID- 26576707 TI - Assessment of Chlamydia suis Infection in Pig Farmers. AB - Chlamydia suis infections are endemic in domestic pigs in Europe and can lead to conjunctivitis, pneumonia, enteritis and reproductive failure. Currently, the knowledge on the zoonotic potential of C. suis is limited. Moreover, the last decades, porcine tetracycline resistant C. suis strains have been isolated, which interfere with treatment of chlamydial infections. In this study, the presence of C. suis was examined on nine Belgian pig farms, using Chlamydia culture and a C. suis specific real-time PCR in both pigs and farmers. In addition to diagnosis for C. suis, the farmers' samples were examined using a Chlamydia trachomatis PCR. Additionally, the Chlamydia isolates were tested for the presence of the tet(C) resistance gene. C. DNA was demonstrated in pigs on all farms, and eight of nine farmers were positive in at least one anatomical site. None of the farmers tested positive for C. trachomatis. Chlamydia suis isolates were obtained from pigs of eight farms. Nine porcine C. suis isolates possessing a tet(C) gene were retrieved, originating from three farms. Moreover, C. suis isolates were identified in three human samples, including one pharyngeal and two rectal samples. These findings suggest further research on the zoonotic transfer of C. suis from pigs to humans is needed. PMID- 26576708 TI - Activation of the hip adductor muscles varies during a simulated weight-bearing task. AB - OBJECTIVE: To investigate the pattern of muscle activation of the individual hip adductor muscles using a standardised simulated unilateral weight-bearing task. DESIGN: A repeated measures design. SETTING: Laboratory. PARTICIPANTS: 20 healthy individuals (11 females, 9 males) participated in the study. Age ranged from 20 to 25 years. MAIN OUTCOME MEASUREMENTS: Surface electromyography recordings from adductor magnus and adductor longus muscles were taken at levels representing 10 50% of body weight during a simulated weight-bearing task. Electromyography (EMG) data were normalised to maximal voluntary isometric contraction. RESULTS: The adductor magnus was recruited at significantly higher levels than the adductor longus muscle during a simulated weight-bearing task performed across 10-50% of body weight (p < 0.01). CONCLUSIONS: Adductor magnus and adductor longus muscles are recruited to different extents during a simulated weight-bearing task. This information should be considered when selecting exercises for management and prevention of groin strains. Closed chain exercises with weight-bearing through the lower limb are more likely to recruit the adductor magnus muscle over the adductor longus muscle. PMID- 26576709 TI - Survival Outcomes of Dose-Escalated External Beam Radiotherapy versus Combined Brachytherapy for Intermediate and High Risk Prostate Cancer Using the National Cancer Data Base. AB - PURPOSE: We evaluated survival outcomes between dose-escalated EBRT (external beam radiotherapy) vs EBRT plus brachytherapy for intermediate and high risk prostate cancer using NCDB (National Cancer Data Base). MATERIALS AND METHODS: Patients with cN0M0 prostate cancer treated from 2004 to 2006 were divided into radiotherapy comparison groups, including EBRT alone (75.6 to 81 Gy) and EBRT (40 to 50.4 Gy) plus brachytherapy with EBRT delivered at 1.8 to 2.0 Gy per fraction. Brachytherapy data were limited to yes/no with no information on modality, dose or schedule. Eligible patients were known to have received androgen deprivation therapy. Overall survival was evaluated using multivariate Cox regression and propensity score matched analyses. RESULTS: Of the 20,279 study patients with prostate cancer, including 12,617 at intermediate risk and 7,662 at high risk, 71.3% received EBRT alone and 28.7% received EBRT plus brachytherapy. Median followup was 82 months (range 3 to 120) and median age was 70 years (range 36 to 90). On multivariate analysis compared to EBRT alone (75.6 to 81 Gy) EBRT plus brachytherapy was associated with improved survival (HR 0.75, p <0.001). This significance remained consistent for intermediate and high risk when analyzed separately (HR 0.73 and 0.76, respectively, each p <0.001). However on subset analysis compared to very high dose EBRT alone (79.2 to 81 Gy) in all patients combined EBRT plus brachytherapy was not associated with improved survival (HR 0.91, p = 0.083). CONCLUSION: Compared to EBRT (75.6 to 81 Gy) we observed an association of EBRT plus brachytherapy with a decreased risk of death in men with intermediate and high risk prostate cancer. However this association was no longer significant when EBRT doses of 79.2 to 81 Gy were used. PMID- 26576710 TI - Tanezumab Reduces Pain in Women with Interstitial Cystitis/Bladder Pain Syndrome and Patients with Nonurological Associated Somatic Syndromes. AB - PURPOSE: We performed pooled analyses from 3 small, clinical trials of tanezumab in patients with urological chronic pelvic pain, including chronic prostatitis/chronic pelvic pain syndrome and interstitial cystitis/bladder pain syndrome, to identify patient subpopulations more likely to benefit from tanezumab treatment. MATERIALS AND METHODS: Pooled analyses included data from 208 patients with interstitial cystitis/bladder pain syndrome or chronic prostatitis/chronic pelvic pain syndrome randomized to placebo (104, 65 [62.5%] female) or tanezumab (104, 63 [60.6%] female) who received 1 dose or more of study medication. Data on tanezumab were from study A4091010 (interstitial cystitis/bladder pain syndrome) on 200 MUg/kg intravenous, study A4091019 (chronic prostatitis/chronic pelvic pain syndrome) on 20 mg intravenous and study A4091035 (interstitial cystitis/bladder pain syndrome) on 20 mg subcutaneous. Primary study end points were evaluated using analysis of covariance with gender, study and baseline pain as covariates. RESULTS: For pooled analyses least squares mean (SE) change from baseline in 24-hour pain intensity vs placebo was -0.60 (0.24, 90% CI -0.99, -0.20) overall and -0.99 (0.32, p=0.002) and -0.17 (0.36, p=0.650) for females and males, respectively. The improvement in pain intensity was significant (p=0.011) for patients with symptoms suggesting the concomitant presence of nonurological associated somatic syndromes but not for those with pelvic pain symptoms only (p=0.507). CONCLUSIONS: Women with interstitial cystitis/bladder pain syndrome and patients with symptoms suggesting the concomitant presence of nonurological associated somatic syndromes were more likely to experience significant pain reduction with tanezumab than with placebo therapy. In contrast, no difference was reported in response between tanezumab and placebo therapy for men with chronic prostatitis/chronic pelvic pain syndrome symptoms only. PMID- 26576711 TI - Outcome According to Elective Pelvic Radiation Therapy in Patients With High-Risk Localized Prostate Cancer: A Secondary Analysis of the GETUG 12 Phase 3 Randomized Trial. AB - PURPOSE: The role of pelvic elective nodal irradiation (ENI) in the management of prostate cancer is controversial. This study analyzed the role of pelvic radiation therapy (RT) on the outcome in high-risk localized prostate cancer patients included in the Groupe d'Etude des Tumeurs Uro-Genitales (GETUG) 12 trial. METHODS AND MATERIALS: Patients with a nonpretreated high-risk localized prostate cancer and a staging lymphadenectomy were randomly assigned to receive either goserelin every 3 months for 3 years and 4 cycles of docetaxel plus estramustine or goserelin alone. Local therapy was administered 3 months after the start of systemic treatment. Performance of pelvic ENI was left to the treating physician. Only patients treated with primary RT were included in this analysis. The primary endpoint was biochemical progression-free survival (bPFS). RESULTS: A total of 413 patients treated from 2002 to 2006 were included, of whom 358 were treated using primary RT. A total of 208 patients received pelvic RT and 150 prostate-only RT. Prostate-specific antigen (PSA) concentration, Gleason score, or T stage did not differ according to performance of pelvic RT; pN+ patients more frequently received pelvic RT than pN0 patients (P<.0001). Median follow-up was 8.8 years. In multivariate analysis, bPFS was negatively impacted by pN stage (hazard ratio [HR]: 2.52 [95% confidence interval [CI]: 1.78-3.54], P<.0001), Gleason score 8 or higher (HR: 1.41 [95% CI: 1.03-1.93], P=.033) and PSA higher than 20 ng/mL (HR: 1.41 [95% CI: 1.02-1.96], P=.038), and positively impacted by the use of chemotherapy (HR: 0.66 [95% CI: 0.48-0.9], P=.009). There was no association between bPFS and use of pelvic ENI in multivariate analysis (HR: 1.10 [95% CI: 0.78-1.55], P=.60), even when analysis was restricted to pN0 patients (HR: 0.88 [95% CI: 0.59-1.31], P=.53). Pelvic ENI was not associated with increased acute or late patient reported toxicity. CONCLUSIONS: This unplanned analysis of a randomized trial failed to demonstrate a benefit of pelvic ENI on bPFS in high-risk localized prostate cancer patients. PMID- 26576712 TI - Peripheral Cryoablation for Treatment of Active Pars Planitis: Long-Term Outcomes of a Retrospective Study. AB - PURPOSE: To compare the long-term outcomes of peripheral retinal cryoablation to conventional treatment for active pars planitis. DESIGN: Retrospective, interventional, comparative case series. METHODS: Review at a single institution was conducted to compare the effect of cryotherapy to eyes with pars planitis to those receiving conventional therapy (topical, regionally injected, or oral corticosteroid therapy). Best-corrected visual acuity (VA), complications, resolution of cystoid macular edema (CME), and anterior chamber and vitreous inflammation were assessed. RESULTS: One hundred thirty-six eyes were treated conventionally, 50 eyes were treated with cryotherapy. Median follow-up was 60.8 months (range 8.1-223.1 months) in the cryotherapy group and 45.0 months (range 3.1-339.0 months) in the controls. There were no significant differences in baseline VA, anterior chamber and vitreous inflammation, presence of CME, and prior use of regional corticosteroid injections. VA improved over time in the cryotherapy group (slope of -0.0018 logMAR units per month; P = .023) but declined in the controls (slope of +0.0011 logMAR units per month; P = .023). Kaplan-Meier survival estimates demonstrated faster times to resolution of anterior chamber cell, vitreous cell, and CME in the cryotherapy-treated eyes. Hazard ratios of remission (adjusted for confounding factors) for vitreous cell and CME for those treated with cryotherapy compared to controls were 4.73 (95% confidence interval 1.63, 13.63; P = .004) and 6.85 (95% confidence interval 1.06, 44.78; P = .044), respectively. No ocular complications were identified in the cryotherapy group. CONCLUSIONS: These data suggest that peripheral retinal cryoablation therapy is an effective treatment for active pars planitis and may be better than conventional regional corticosteroid injections and oral corticosteroid therapy for induction of remission. PMID- 26576713 TI - Temporal changes in filtering-facepiece respirator fit. AB - A three-year study examined changes in N95 filtering-facepiece respirator (FFR) fit at six-month intervals and the relationship between fit and changes in weight for 229 subjects. During each visit, subjects performed a total of nine fit tests using three samples of the same FFR model. Inward leakage and filter penetration were measured for each donned respirator to determine face seal leakage (FSL). A total of 195 subjects completed the second visit and 134 subjects completed all seven visits. Acceptable fit was defined as 90th percentile FSL <= 5% and at least one fit factor >= 100. An unacceptable fit was observed for 14, 10, 7, 12, 15, and 16% of subjects on Visits 2-7, respectively. The predicted risk of an unacceptable fit increased with increasing length of time between fit tests, from 10% at Year 1 to 20% at Year 2 and to 25% at Year 3. Twenty-four percent of subjects who lost >= 20 lb had an unacceptable fit; these percentages ranged from 7-17% for subjects with lower weight losses or any degree of weight gain. Results support the current OSHA requirement for annual fit testing and suggest that respirator users who lose more than 20 lb should be re-tested for respirator fit. PMID- 26576714 TI - Variation of Quality of Life Data Collection Across INTERMACS Sites. AB - BACKGROUND: Given the importance of patients' health-related quality of life (HRQL) after mechanical circulatory support (MCS) device implantation, the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) collects the Kansas City Cardiomyopathy Questionnaire (KCCQ) before and after MCS. The success of data collection and potential implications of missing data on HRQL analyses are unknown. METHODS: We examined the frequency and reasons for not collecting baseline and 3-month KCCQ data across INTERMACS sites from May 2012 to December 2013. Hierarchical logistic regression was used to examine site variability (median odds ratios [MOR]) for not collecting KCCQ data to demonstrate the degree to which some sites can collect more complete data than others. RESULTS: Among 3960 and 3523 patients participating in INTERMACS before and 3 months after left ventricular assist device implantation, the KCCQ was not collected in 43.1% at baseline (range across sites, 0-100%) and 40.9% (range, 0 100%) at follow-up. The most common reasons for incomplete KCCQ data at baseline were that the patient was too sick (13.9%) and consent to participate in research was not obtained (12.4%). Significant variation across sites was observed for missingness because of patient (MOR, 2.8; P < .001) and administrative (MOR, 4.8; P < .001) reasons. The most variable patient reasons were that the patients were too stressed (MOR, 7.2; P < .001) and too busy (MOR, 10.6; P < .001). The most variable administrative reasons were that the coordinator was too busy/forgot (MOR, 7.1; P < .001) and miscellaneous reasons (MOR, 8.7; P < .001). At 3 months, significant variation persisted for both patient (MOR, 2.7; P < .001) and administrative (MOR, 3.5; P < .001) reasons. The most variability across sites was that the patient was too busy (MOR, 6.0, P < .001) and that the coordinator was too busy/forgot (MOR, 5.8; P < .001). CONCLUSIONS: Sites vary substantially in collecting KCCQ data, and many of these variations seem addressable. Improving the consistency of HRQL data collection can improve the value of INTERMACS in defining the patient-centered benefits of MCS treatment. PMID- 26576715 TI - Rationale and Design of the "Safety and Efficacy of the Combination of Loop with Thiazide-type Diuretics in Patients with Decompensated Heart Failure (CLOROTIC) Trial:" A Double-Blind, Randomized, Placebo-Controlled Study to Determine the Effect of Combined Diuretic Therapy (Loop Diuretics With Thiazide-Type Diuretics) Among Patients With Decompensated Heart Failure. AB - BACKGROUND: Fluid overload refractory to loop diuretic therapy can complicate acute or chronic heart failure (HF) management. The Safety and Efficacy of the Combination of Loop with Thiazide-type Diuretics in Patients with Decompensated Heart Failure (CLOROTIC) trial (Clinicaltrials.gov identifier NCT01647932) will test the hypothesis that blocking distal tubule sodium reabsorption with hydrochlorothiazide can antagonize the renal adaptation to chronic loop diuretic therapy and improve diuretic resistance. METHODS: CLOROTIC is a randomized, placebo-controlled, double-blind, multicenter study. Three hundred and four patients with decompensated HF will be randomly assigned to receive hydrochlorothiazide or placebo in addition to a furosemide regimen. The main inclusion criteria are: age >=18 years, history of chronic HF (irrespective of etiology and/or ejection fraction), admission for acute decompensation, and previous treatment with an oral loop diuretic for at least 1 month before randomization. The 2 coprimary endpoints are changes in body weight and changes in patient-reported dyspnea during hospital admission. Morbidity, mortality, and safety aspects will also be addressed. CONCLUSIONS: CLOROTIC is the first large scale trial to evaluate whether the addition of a thiazide diuretic (hydrochlorothiazide) to a loop diuretic (furosemide) is a safe and effective strategy for improving congestive symptoms resulting from HF. This trial will provide important information and will therefore have a major impact on treatment strategies and future trials in these patients. PMID- 26576716 TI - Extended Follow-Up of Patients With Heart Failure Receiving Autonomic Regulation Therapy in the ANTHEM-HF Study. AB - OBJECTIVE: Evaluate the effects of a novel autonomic regulation therapy (ART) via vagus nerve stimulation (VNS) in patients with chronic heart failure (HF) and reduced left ventricular ejection fraction during a 12-month follow-up period. METHODS: The Autonomic Regulation Therapy for the Improvement of Left Ventricular Function and Heart Failure Symptoms (ANTHEM-HF) study enrolled 60 subjects with New York Heart Association class II-III HF and low left ventricular ejection fraction (<=40%), who received open-loop ART using VNS randomized to left or right cervical vagus nerve placement and followed for 6 months after titration to a therapeutic output current (2.0 +/- 0.6 mA). Patients received chronic stimulation at a frequency of 10 Hz and pulse duration of 250 usec. Forty-nine subjects consented to participate in an extended follow-up study for an additional 6 months (12 months total posttitration) to determine whether the effects of therapy were maintained. RESULTS: During the 6-month extended follow up period, there were no device malfunctions or device-related serious adverse effects. There were 7 serious adverse effects unrelated to the device, including 3 deaths (2 sudden cardiac deaths, 1 worsening HF death). There were 5 nonserious adverse events that were adjudicated to be device-related. Safety and tolerability were similar, and there were no significant differences in efficacy between left- and right-sided ART. Overall, mean efficacy measure values at 12 months were not significantly different from mean values at 6 months. CONCLUSIONS: Chronic open-loop ART via left- or right-sided VNS continued to be feasible and well-tolerated in patients with HF with reduced EF. Improvements in cardiac function and HF symptoms seen after 6 months of ART were maintained at 12 months. PMID- 26576717 TI - Metabolic Syndrome and Kidney Stone Disease: A Systematic Review of Literature. AB - INTRODUCTION: Worldwide obesity has more than doubled since 1980 with more than 600 million obese patients in 2014. Metabolic syndrome (MetS) is the co occurrence of metabolic abnormalities, including centrally distributed obesity, hypertension, dyslipidemia, and hyperglycemia. With a concurrent rise in the incidence of kidney stone disease, we wanted to conduct a systematic review focused on the association of MetS to nephrolithiasis. MATERIALS AND METHODS: A systematic review was performed according to the Cochrane and preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines on all English language articles for the following relevant keywords: association, metabolic syndrome, metabolic syndrome traits, syndrome X, nephrolithiasis, kidney stones, and renal calculi. Our inclusion criteria were studies comparing the prevalence of kidney stone disease in patients with and without MetS. RESULTS: The initial literature search identified 355 potentially relevant studies. After screening, 22 full text articles were reviewed and 6 (219,255 patients) were included in the final review. All studies displayed increasing odds of nephrolithiasis with increasing number of MetS traits, where patients with three or more MetS traits tended to have a higher prevalence of nephrolithiasis. Studies also showed different significant components of MetS contributing to nephrolithiasis. CONCLUSIONS: Our review shows a definite association of MetS with kidney stone disease. Although multifactorial in etiology, lifestyle and dietary factors seem to be increasingly important in prevention of stone disease. PMID- 26576719 TI - Designing liposomal adjuvants for the next generation of vaccines. AB - Liposomes not only offer the ability to enhance drug delivery, but can effectively act as vaccine delivery systems and adjuvants. Their flexibility in size, charge, bilayer rigidity and composition allow for targeted antigen delivery via a range of administration routes. In the development of liposomal adjuvants, the type of immune response promoted has been linked to their physico chemical characteristics, with the size and charge of the liposomal particles impacting on liposome biodistribution, exposure in the lymph nodes and recruitment of the innate immune system. The addition of immunostimulatory agents can further potentiate their immunogenic properties. Here, we outline the attributes that should be considered in the design and manufacture of liposomal adjuvants for the delivery of sub-unit and nucleic acid based vaccines. PMID- 26576720 TI - A review of telemental health in international and post-disaster settings. AB - Telemental health (TMH) is an important component in meeting critical mental health needs of the global population. Mental health is an issue of global importance; an estimated 450 million people worldwide have mental or behavioural disorders, accounting for 12% of the World Health Organization's (WHO) global burden of disease. However, it is reported that 75% of people suffering from mental disorders in the Developing World receive no treatment or care. In this paper, the authors review global mental health needs with a focus on the use of TMH to meet mental health needs in international and post-disaster settings. Telemedicine and TMH have the capacity to bring evidence-based best practices in medicine and mental health to the under-served and difficult to reach areas of the world, including post-disaster settings. The authors will also report on the mental health impact of the Haiti 2010 earthquake and on the limited use of telemedicine in post-disaster Haiti. The paper will underscore the point that published papers on the use of TMH in post-disaster settings are lacking. Finally, the paper will review considerations before working in TMH in international and post-disaster settings. PMID- 26576721 TI - Regulation of the pore size by shifting the coordination sites of ligands in two MOFs: enhancement of CO2 uptake and selective sensing of nitrobenzene. AB - Two metal-organic frameworks (MOFs), namely {[Cd2(sdb)2(4-bpmh)2(H2O)]}n.2n(H2O) (1), {[Cd2(sdb)2(3-bpmh)2]}n.3n(H2O).n(C6H5NO) (2), [sdb = 4,4'-sulfonyl dibenzoic acid; 4-bpmh = N,N-bis-pyridin-4-ylmethylene-hydrazine, 3-bpmh = N,N bis-pyridin-3-ylmethylene-hydrazine, C6H5NO = 3-pyridinecarboxaldehyde] have been synthesized by the solvent diffusion technique at room temperature. Structure determination reveals that compound 1 has 2D interdigitated architectures, whereas 2 is a 2-fold interwoven 3D porous network but both 1 and 2 have a common secondary building unit (SBU) [Cd2(sdb)4(L)4] [L = 4-bpmh (1) and 3-bpmh (2)]. Gas adsorption studies demonstrate that compound 2 shows high selectivity for CO2 over CH4 and the uptake amounts are almost double in comparison with compound 1 and both the compounds show high sensitivity for nitrobenzene via the fluorescence quenching mechanism. PMID- 26576722 TI - Altered microglia morphology and higher resilience to stress-induced depression like behavior in CX3CR1-deficient mice. AB - Microglia are suggested to be involved in several neuropsychiatric diseases. Indeed changes in microglia morphology have been reported in different mouse models of depression. A crucial regulatory system for microglia function is the well-defined CX3C axis. Thus, we aimed to clarify the role of microglia and CX3CR1 in depressive behavior by subjecting CX3CR1-deficient mice to a particular chronic despair model (CDM) paradigm known to exhibit face validity to major depressive disorder. In wild-type mice we observed the development of chronic depressive-like behavior after 5days of repetitive swim stress. 3D reconstructions of Iba-1-labeled microglia in the dentate molecular layer revealed that behavioral effects were associated with changes in microglia morphology towards a state of hyper-ramification. Chronic treatment with the anti depressant venlafaxine ameliorated depression-like behavior and restored microglia morphology. In contrast, CX3CR1 deficient mice showed a clear resistance to either (i) stress-induced depressive-like behavior, (ii) changes in microglia morphology and (iii) antidepressant treatment. Our data point towards a role of hyper-ramified microglia in the etiology of chronic depression. The lack of effects in CX3CR1 deficient mice suggests that microglia hyper-ramification is controlled by neuron-microglia signaling via the CX3C axis. However, it remains to be elucidated how hyper-ramified microglia contribute to depressive-like behavior. PMID- 26576723 TI - Developmental changes in microglial mobilization are independent of apoptosis in the neonatal mouse hippocampus. AB - During CNS development, microglia transform from highly mobile amoeboid-like cells to primitive ramified forms and, finally, to highly branched but relatively stationary cells in maturity. The factors that control developmental changes in microglia are largely unknown. Because microglia detect and clear apoptotic cells, developmental changes in microglia may be controlled by neuronal apoptosis. Here, we assessed the extent to which microglial cell density, morphology, motility, and migration are regulated by developmental apoptosis, focusing on the first postnatal week in the mouse hippocampus when the density of apoptotic bodies peaks at postnatal day 4 and declines sharply thereafter. Analysis of microglial form and distribution in situ over the first postnatal week showed that, although there was little change in the number of primary microglial branches, microglial cell density increased significantly, and microglia were often seen near or engulfing apoptotic bodies. Time-lapse imaging in hippocampal slices harvested at different times over the first postnatal week showed differences in microglial motility and migration that correlated with the density of apoptotic bodies. The extent to which these changes in microglia are driven by developmental neuronal apoptosis was assessed in tissues from BAX null mice lacking apoptosis. We found that apoptosis can lead to local microglial accumulation near apoptotic neurons in the pyramidal cell body layer but, unexpectedly, loss of apoptosis did not alter overall microglial cell density in vivo or microglial motility and migration in ex vivo tissue slices. These results demonstrate that developmental changes in microglial form, distribution, motility, and migration occur essentially normally in the absence of developmental apoptosis, indicating that factors other than neuronal apoptosis regulate these features of microglial development. PMID- 26576725 TI - A(H1N1) vaccination recruits T lymphocytes to the choroid plexus for the promotion of hippocampal neurogenesis and working memory in pregnant mice. AB - We previously demonstrated that A(H1N1) influenza vaccine (AIV) promoted hippocampal neurogenesis and working memory in pregnant mice. However, the underlying mechanism of flu vaccination in neurogenesis and memory has remained unclear. In this study, we found that T lymphocytes were recruited from the periphery to the choroid plexus (CP) of the lateral and third (3rd) ventricles in pregnant mice vaccinated with AIV (Pre+AIV). Intracerebroventricular delivery of anti-TCR antibodies markedly decreased neurogenesis and the working memory of the Pre+AIV mice. Similarly, intravenous delivery of anti-CD4 antibodies to the periphery also down-regulated neurogenesis. Furthermore, AIV vaccination caused microglia to skew toward an M2-like phenotype (increased Arginase-1 and Ym1 mRNA levels), and elevated levels of brain-derived growth factor (BDNF) and insulin like growth factor-1 (IGF-1) were found in the hippocampus, whereas these effects were offset by anti-TCR antibody treatment. Additionally, in the CP, the expression level of adhesion molecules and chemokines, which assist leukocytes in permeating into the brain, were also elevated after AIV vaccination of pregnant mice. Collectively, the results suggested that the infiltrative T lymphocytes in the CP contribute to the increase in hippocampal neurogenesis and working memory caused by flu vaccination, involving activation of the brain's CP, M2 microglial polarization and neurotrophic factor expression. PMID- 26576724 TI - Microglial P2Y12 receptors regulate microglial activation and surveillance during neuropathic pain. AB - Microglial cells are critical in the pathogenesis of neuropathic pain and several microglial receptors have been proposed to mediate this process. Of these receptors, the P2Y12 receptor is a unique purinergic receptor that is exclusively expressed by microglia in the central nervous system (CNS). In this study, we set forth to investigate the role of P2Y12 receptors in microglial electrophysiological and morphological (static and dynamic) activation during spinal nerve transection (SNT)-induced neuropathic pain in mice. First, we found that a genetic deficiency of the P2Y12 receptor (P2Y12(-/-) mice) ameliorated pain hypersensitivities during the initiation phase of neuropathic pain. Next, we characterised both the electrophysiological and morphological properties of microglia in the superficial spinal cord dorsal horn following SNT injury. We show dramatic alterations including a peak at 3days post injury in microglial electrophysiology while high resolution two-photon imaging revealed significant changes of both static and dynamic microglial morphological properties by 7days post injury. Finally, in P2Y12(-/-) mice, these electrophysiological and morphological changes were ameliorated suggesting roles for P2Y12 receptors in SNT-induced microglial activation. Our results therefore indicate that P2Y12 receptors regulate microglial electrophysiological as well as static and dynamic microglial properties after peripheral nerve injury, suggesting that the microglial P2Y12 receptor could be a potential therapeutic target for the treatment of neuropathic pain. PMID- 26576727 TI - Symmetrical, Hypopigmented Papules and Plaques on the Palms Induced by Contact with Water: A Quiz--Aquagenic Wrinkling of the Palms. PMID- 26576726 TI - Apoptosome activation, an important molecular instigator in 6-mercaptopurine induced Leydig cell death. AB - Leydig cells are crucial to the production of testosterone in males. It is unknown if the cancer chemotherapeutic drug, 6-mercaptopurine (6 MP), produces Leydig cell failure among adult survivors of childhood acute lymphoblastic leukemia. Moreover, it is not known whether Leydig cell failure is due to either a loss of cells or an impairment in their function. Herein, we show, in a subset of childhood cancer survivors, that Leydig cell failure is related to the dose of 6 MP. This was extended, in a murine model, to demonstrate that 6 MP exposure induced caspase 3 activation, and the loss of Leydig cells was independent of Bak and Bax activation. The death of these non-proliferating cells was triggered by 6 MP metabolism, requiring formation of both cytosolic reactive oxygen species and thiopurine nucleotide triphosphates. The thiopurine nucleotide triphosphates (with physiological amounts of dATP) uniquely activated the apoptosome. An ABC transporter (Abcc4/Mrp4) reduced the amount of thiopurines, thereby providing protection for Leydig cells. The studies reported here demonstrate that the apoptosome is uniquely activated by thiopurine nucleotides and suggest that 6 MP induced Leydig cell death is likely a cause of Leydig cell failure in some survivors of childhood cancer. PMID- 26576728 TI - VSELs may obviate cryobanking of gonadal tissue in cancer patients for fertility preservation. AB - BACKGROUND: Infertility is an undesirable side effect and gonadal tissue banking is advocated in young cancer patients who are unable to preserve embryos or gametes prior to oncotherapy to achieve biological parenthood later on. Banking gonadal tissue is challenging and protocols to mature gametes in vitro are not yet clinically established. Transplanting ovarian cortical tissue at hetero-or orthotopic sites in women and bone marrow transplantation (BMT) in both men and women has resulted in spontaneous recovery of fertility, pregnancy and live births. Various studies in humans and mice suggest that genetic origin of offspring after BMT is similar to transplanted patient and not the donor. Thus the source of oocytes/sperm which result in spontaneous pregnancies still remains contentious. FINDINGS: Very small embryonic-like stem cells (VSELs) have been reported in adult human testis and ovary, in azoospermic testicular biopsies from survivors of childhood cancer and also in women with premature ovarian failure and menopause. VSELs survive chemotherapy because of their quiescent nature and can be detected in chemoablated mice gonads at protein and mRNA level and also by flow cytometry. Surviving VSELs spontaneously differentiate into oocyte-like structures and sperm when inhibitory factors are overcome in vitro. Transplantation of mesenchymal cells (isolated from different sources) has led to regeneration of chemoablated mouse gonads and also live births. Spermatogenesis is also restored from endogenous stem cells on inter-tubular transplantation of Sertoli cells in chemoablated mouse testis. CONCLUSIONS: Endogenous VSELs (which survive oncotherapy) can possibly regenerate non-functional gonads in cancer survivors when exposed to a healthy niche in vitro or in vivo (by way of transplanting mesenchymal cells which secrete trophic factors required for endogenous VSELs to differentiate into gametes). Presence of VSELs can also explain spontaneous pregnancies after BMT and cortical tissue transplantation (at heterotopic or orthotopic sites). This understanding once verified and accepted by the scientific community could obviate the need to remove whole ovary or testicular biopsy for cryopreservation prior to oncotherapy. PMID- 26576729 TI - Differences in hindlimb morphology of ducks and chickens: effects of domestication and selection. AB - BACKGROUND: Poultry account for the most numerous species farmed for meat and have been subject to intense selection over approximately 60 generations. To assess morphological changes which have occurred in the avian leg due to selection for rapid growth and high meat yields, divergent lines of chicken (Gallus gallus) and duck (Anas platyrhynchos) were studied between 3 and 7 weeks of age. For each line, femoral and tibiotarsal morphology was recorded using computed tomography scanning and tibiotarsal bone quality measures (stiffness, bending stress and porosity) were assessed. RESULTS: In chicken and duck, divergence in hindlimb morphology has occurred in the commercial meat lines compared to their lighter conspecifics. As expected, the differences were largest between species. Leg development nears completion much earlier in ducks than in chickens. Duck tibiotarsi showed a large degree of lateral curvature, which is expected to affect foot position during swimming and walking, and thus to influence gait. All lines have adapted their tibiotarsal morphology to suit the loading forces they experience; however bone quality was found to be poorer in chickens. CONCLUSIONS: We demonstrate that intensive selection for growth rate in both chickens and ducks has resulted in leg morphology changes, which are likely to influence gait. Ducks represent an interesting compromise of adaptation for efficient locomotion in two media-on land and in water. Some aspects of bone morphology in the duck, such as lateral curvature of the tibiotarsus, may result from adaptation to swimming, which potentially imposes limitations on terrestrial locomotion. PMID- 26576730 TI - "They should stay at their desk until the work's done": a qualitative study examining perceptions of sedentary behaviour in a desk-based occupational setting. AB - BACKGROUND: Workplace sedentary behaviour is a priority target for health promotion. However, little is known about how to effect change. We aimed to explore desk-based office workers' perceptions of factors that influenced sedentary behaviour at work and to explore the feasibility of using a novel mobile phone application to track their behaviours. METHODS: We invited office employees (n = 12) and managers (n = 2) in a software engineering company to participate in semi-structured interviews to explore perceived barriers and facilitators affecting workplace sedentary behaviour. We assessed participants' sedentary behaviours using an accelerometer before and after they used a mobile phone application to record their activities at self-selected time intervals daily for 2 weeks. Interviews were analysed using a thematic framework. RESULTS: Software engineers (5 employees; 2 managers) were interviewed; 13 tested the mobile phone application; 8 returned feedback. Major barriers to reducing workplace sedentary behaviour included the pressure of 'getting the job done', the nature of their work requiring sitting at a computer, personal preferences for the use of time at and after work, and a lack of facilities, such as a canteen, to encourage moving from their desks. Facilitators for reduced sedentariness included having a definite reason to leave their desks, social interaction and relief of physical and mental symptoms of prolonged sitting. The findings were similar for participants with different levels of overall physical activity. Valid accelerometer data were tracked for four participants: all reduced their sedentary behaviour. Participants stated that recording data using the phone application added to their day's work but the extent to which individuals perceived this as a burden varied and was counter-balanced by its perceived value in increasing awareness of sedentary behaviour. Individuals expressed a wish for flexibility in its configuration. CONCLUSIONS: These findings indicate that employers' and employees' perceptions of the cultural context and physical environment of their work, as well as personal factors, must be considered in attempting to effect changes that reduce workplace sedentary behaviour. Further research should investigate appropriate individually tailored approaches to this challenge, using a framework of behaviour change theory which takes account of specific work practices, preferences and settings. PMID- 26576731 TI - Inner retinal oxygen metabolism in the 50/10 oxygen-induced retinopathy model. AB - Retinopathy of prematurity (ROP) represents a major cause of childhood vision loss worldwide. The 50/10 oxygen-induced retinopathy (OIR) model mimics the findings of ROP, including peripheral vascular attenuation and neovascularization. The oxygen metabolism of the inner retina has not been previously explored in this model. Using visible-light optical coherence tomography (vis-OCT), we measured the oxygen saturation of hemoglobin and blood flow within inner retinal vessels, enabling us to compute the inner retinal oxygen delivery (irDO2) and metabolic rate of oxygen (irMRO2). We compared these measurements between age-matched room-air controls and rats with 50/10 OIR on postnatal day 18. To account for a 61% decrease in the irDO2 in the OIR group, we found an overall statistically significant decrease in retinal vascular density affecting the superficial and deep retinal vascular capillary networks in rats with OIR compared to controls. Furthermore, matching the reduced irDO2, we found a 59% decrease in irMRO2, which we correlated with a statistically significant reduction in retinal thickness in the OIR group, suggesting that the decreased irMRO2 was due to decreased neuronal oxygen utilization. By exploring these biological and metabolic changes in great detail, our study provides an improved understanding of the pathophysiology of OIR model. PMID- 26576732 TI - Fully automatic GBM segmentation in the TCGA-GBM dataset: Prognosis and correlation with VASARI features. AB - Reproducible definition and quantification of imaging biomarkers is essential. We evaluated a fully automatic MR-based segmentation method by comparing it to manually defined sub-volumes by experienced radiologists in the TCGA-GBM dataset, in terms of sub-volume prognosis and association with VASARI features. MRI sets of 109 GBM patients were downloaded from the Cancer Imaging archive. GBM sub compartments were defined manually and automatically using the Brain Tumor Image Analysis (BraTumIA). Spearman's correlation was used to evaluate the agreement with VASARI features. Prognostic significance was assessed using the C-index. Auto-segmented sub-volumes showed moderate to high agreement with manually delineated volumes (range (r): 0.4 - 0.86). Also, the auto and manual volumes showed similar correlation with VASARI features (auto r = 0.35, 0.43 and 0.36; manual r = 0.17, 0.67, 0.41, for contrast-enhancing, necrosis and edema, respectively). The auto-segmented contrast-enhancing volume and post-contrast abnormal volume showed the highest AUC (0.66, CI: 0.55-0.77 and 0.65, CI: 0.54 0.76), comparable to manually defined volumes (0.64, CI: 0.53-0.75 and 0.63, CI: 0.52-0.74, respectively). BraTumIA and manual tumor sub-compartments showed comparable performance in terms of prognosis and correlation with VASARI features. This method can enable more reproducible definition and quantification of imaging based biomarkers and has potential in high-throughput medical imaging research. PMID- 26576733 TI - Spontaneous brain activity following fear reminder of fear conditioning by using resting-state functional MRI. AB - Although disrupting reconsolidation may be a promising approach to attenuate or erase the expression of fear memory, it is not clear how the neural state following fear reminder contribute to the following fear extinction. To address this question, we used resting-state functional magnetic resonance imaging (rs fMRI) to measure spontaneous neuronal activity and functional connectivity (RSFC) following fear reminder. Some brain regions such as dorsal anterior cingulate (dACC) and ventromedial prefrontal cortex (vmPFC) showed increased amplitude of LFF (ALFF) in the fear reminder group than the no reminder group following fear reminder. More importantly, there was much stronger functional connectivity between the amygdala and vmPFC in the fear reminder group than those in the no reminder group. These findings suggest that the strong functional connectivity between vmPFC and amygdala following a fear reminder could serve as a key role in the followed-up fear extinction stages, which may contribute to the erasing of fear memory. PMID- 26576734 TI - Therapeutic schemes in 177Lu and 90Y-PRRT: radiobiological considerations. AB - BACKGROUND: The purpose of this work is to implement a radiobiological model to compare different treatment schedules for Peptide Receptor Radionuclide Therapy (PRRT) with 177Lu and 90Y. The principal radiobiological quantities were studied as a function of radionuclides, fractionation schemes, activity distribution in kidneys and tumor radiosensitivity. METHODS: Clinical data were used to derive representative absorbed doses for several treatment schemes for 177Lu-PRRT and for 90Y-PRRT and considered as input data for the radiobiological model. Both uniform and non-uniform activity distributions were considered for kidneys and cortex; for tumors a possible uptake reduction after each cycle and inter-patient radiosensitivity variability were investigated. Normal-Tissue-Complication Probability (NTCP) and Tumor-Control-Probability (TCP) were evaluated. RESULTS: Hyper-cycling has a limited advantage in terms of BED reduction on kidneys for 177Lu, while for 90Y the effect is sizable and helps in reducing the NTCP. For all 177Lu-schemes the renal toxicity risk is negligible while for some 90Y schemes the NTCP is not null. In case of tumor uptake reduction with cycles the treatment efficacy is reduced with a BED loss up to 46%. The TCP decreases when assuming normally-distributed tumor radiosensitivity values. CONCLUSIONS: This paper discusses how the combination of dosimetry and radiobiological modeling may help in exploring the link between the treatment schedule and the potential clinical outcome. The results highlight the capability of model to reproduce the available clinical data and provide useful qualitative information. Further investigation on dose distribution and dose uptake reduction with accurate clinical data is needed to progress in this field. PMID- 26576735 TI - Review of clinically accessible methods to determine lean body mass for normalization of standardized uptake values. AB - With the routine use of 2-deoxy-2-[18F]-fluoro-D-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) scans, metabolic activity of tumors can be quantitatively assessed through calculation of SUVs. One possible normalization parameter for the standardized uptake value (SUV) is lean body mass (LBM), which is generally calculated through predictive equations based on height and body weight. (Semi-)direct measurements of LBM could provide more accurate results in cancer populations than predictive equations based on healthy populations. In this context, four methods to determine LBM are reviewed: bioelectrical impedance analysis, dual-energy X-ray absorptiometry. CT, and magnetic resonance imaging. These methods were selected based on clinical accessibility and are compared in terms of methodology, precision and accuracy. By assessing each method's specific advantages and limitations, a well-considered choice of method can hopefully lead to more accurate SUVLBM values, hence more accurate quantitative assessment of 18F-FDG PET images. PMID- 26576736 TI - Motion correction using anatomical information in PET/CT and PET/MR hybrid imaging. AB - Respiratory and cardiac motion causes qualitative and quantitative inaccuracies in whole body multi-modality imaging such as positron emission tomography coupled with computed tomography (PET/CT) and positron emission tomography/magnetic resonance imaging (PET/MRI). Solutions presented to date include motion synchronized PET and corresponding anatomical acquisitions (four dimensional [4D] PET/CT, 4D PET/MR), frequently referred to as the gating approach. This method is based on the acquisition of an external surrogate using an external device (pressure belt, optical monitoring system, spirometer etc.), subsequently used to bin PET and CT or MR anatomical data into a number of gates. A first limitation of this method is the low signal to noise ratio (SNR) of the resulting motion synchronized PET frames, given that every reconstructed frame contains only part of the count statistics available throughout a motion average PET acquisition. Another limitation is that the complex motion of internal organs cannot be fully estimated, characterized and modelled using a mono-dimensional motion signal. In order to resolve such issues, many advanced techniques have been proposed which include three consecutive major steps. These are based on firstly acquiring an external or internal motion surrogate, estimating or modelling the internal motion using anatomical information extracted from 4D anatomical images (CT and/or MR) and finally correcting for motion either in the PET raw data space, the image space or incorporate it within the PET image reconstruction which is the most optimal based motion correction method in PET/CT and in PET/MR imaging. Current research efforts are concentrating on combining the last two steps within a joint motion estimation/motion correction approach, the exploitation of MRI specific motion characterization sequences and the combination of both respiratory and cardiac motion corrections. The goal of this review is to present and discuss the different steps of all these motion correction methods in PET/CT and PET/MR imaging for whole body applications. PMID- 26576738 TI - Novel sodium channel antagonists in the treatment of neuropathic pain. AB - INTRODUCTION: Effective and safe drugs for the treatment of neuropathic pain are still an unmet clinical need. Neuropathic pain, caused by a lesion or disease that affects the somatosensory system, is a debilitating and hampering condition that has a great economic cost and, above all, a tremendous impact on the quality of life. Sodium channels are one of the major players in generating and propagating action potentials. They represent an appealing target for researchers involved in the development of new and safer drugs useful in the treatment of neuropathic pain. The actual goal for researchers is to target sodium channels selectively to stop the abnormal signaling that characterizes neuropathic pain while leaving normal somatosensory functions intact. AREAS COVERED: This review covers the most recent publications regarding sodium channel blockers and their development as new treatments for neuropathic pain. The main areas discussed are the natural sources of new blockers, such as venom extracts and the recent efforts from many pharmaceutical companies in the field. EXPERT OPINION: There have been serious efforts by both the pharmaceutical industry and academia to develop new and safer therapeutic options for neuropathic pain. A number of different strategies have been undertaken; the main efforts directed towards the identification of selective blockers starting from both natural products or screening chemical libraries. At this time, researchers have identified and characterized selective compounds against NaV1.7 or NaV1.8 voltage-gated sodium channels but only time will tell if they reach the market. PMID- 26576737 TI - Morphology supporting function: attenuation correction for SPECT/CT, PET/CT, and PET/MR imaging. AB - Both SPECT, and in particular PET, are unique in medical imaging for their high sensitivity and direct link to a physical quantity, i.e. radiotracer concentration. This gives PET and SPECT imaging unique capabilities for accurately monitoring disease activity for the purposes of clinical management or therapy development. However, to achieve a direct quantitative connection between the underlying radiotracer concentration and the reconstructed image values several confounding physical effects have to be estimated, notably photon attenuation and scatter. With the advent of dual-modality SPECT/CT, PET/CT, and PET/MR scanners, the complementary CT or MR image data can enable these corrections, although there are unique challenges for each combination. This review covers the basic physics underlying photon attenuation and scatter and summarizes technical considerations for multimodal imaging with regard to PET and SPECT quantification and methods to address the challenges for each multimodal combination. PMID- 26576739 TI - Exploring a DNA Sequence for the Three-Dimensional Structure Determination of a Silver(I)-Mediated C-C Base Pair in a DNA Duplex By (1)H NMR Spectroscopy. AB - Recently, we discovered novel silver(I)-mediated cytosine-cytosine base pair (C Ag(I)-C) in DNA duplexes. To understand the properties of these base pairs, we searched for a DNA sequence that can be used in NMR structure determination. After extensive sequence optimizations, a non-symmetric 15-base-paired DNA duplex with a single C-Ag(I)-C base pair flanked by 14 A-T base pairs was selected. In spite of its challenging length for NMR measurements (30 independent residues) with small sequence variation, we could assign most non-exchangeable protons (254 out of 270) and imino protons for structure determination. PMID- 26576740 TI - I Believe I Can Fly!: Use of Drosophila as a Model Organism in Neuropsychopharmacology Research. AB - Neuropsychiatric disorders are of complex etiology, often including a large genetic component. In order to help identify and study the molecular and physiological mechanisms that such genes participate in, numerous animal models have been established in a variety of species. Over the past decade, this has increasingly included the vinegar fly, Drosophila melanogaster. Here, we outline why we study an invertebrate organism in the context of neuropsychiatric disorders, and we discuss how we can gain insight from studies in Drosophila. We focus on a few disorders and findings to make the larger point that modeling these diseases in flies can have both mechanistic and predictive validity. Highlighting some translational examples, we underline the fact that their brains works more like ours than one would have anticipated. PMID- 26576741 TI - p53/PUMA expression in human pulmonary fibroblasts mediates cell activation and migration in silicosis. AB - Phagocytosis of SiO2 into the lung causes an inflammatory cascade that results in fibroblast proliferation and migration, followed by fibrosis. Clinical evidence has indicated that the activation of alveolar macrophages by SiO2 produces rapid and sustained inflammation characterized by the generation of monocyte chemotactic protein 1, which, in turn, induces fibrosis. However, the details of events downstream of monocyte chemotactic protein 1 activity in pulmonary fibroblasts remain unclear. Here, to elucidate the role of p53 in fibrosis induced by silica, both the upstream molecular mechanisms and the functional effects on cell proliferation and migration were investigated. Experiments using primary cultured adult human pulmonary fibroblasts led to the following results: 1) SiO2 treatment resulted in a rapid and sustained increase in p53 and PUMA protein levels; 2) the MAPK and PI3K pathways were involved in the SiO2-induced alteration of p53 and PUMA expression; and 3) RNA interference targeting p53 and PUMA prevented the SiO2-induced increases in fibroblast activation and migration. Our study elucidated a link between SiO2-induced p53/PUMA expression in fibroblasts and cell migration, thereby providing novel insight into the potential use of p53/PUMA in the development of novel therapeutic strategies for silicosis treatment. PMID- 26576742 TI - Ethnic differences in COMT genetic effects on striatal grey matter alterations associated with childhood ADHD: A voxel-based morphometry study in a Japanese sample. AB - OBJECTIVES: Attention deficit/hyperactivity disorder (ADHD) is associated with deficits in the dopaminergic fronto-striatal systems mediating higher-level cognitive functions. We hypothesised that a dopamine-regulating gene, catechol-O methyltransferase (COMT), would have differential effects on the neural systems of different ethnic samples with ADHD. In Caucasian children with ADHD, the COMT Val-homozygotes have been previously shown to be associated with striatal grey matter volume (GMV) alterations. By using voxel-based morphometry, we examined whether Asian children with ADHD would exhibit a pattern opposite to that found in Caucasian samples. METHODS: Structural brain images were obtained for Japanese children with ADHD (n = 17; mean age = 10.3 years) and typically developing (TD) children (n = 15; mean age = 12.8 years). COMT Val158Met genotype data were also obtained for the ADHD group. RESULTS: Reduced GMV in the left striatum was observed in the ADHD group versus the TD group. This reduced GMV was modulated by COMT polymorphism; Met-carriers exhibited smaller striatal GMV than the Val/Val genotype. CONCLUSIONS: Contrasting with previous findings in Caucasians, the COMT Met allele was associated with striatal GMV alterations in Japanese children with ADHD. These results suggest the existence of ethnic differences in the COMT genetic effect on ADHD-related striatal abnormalities. PMID- 26576743 TI - Potential role of the glycolytic oscillator in acute hypoxia in tumors. AB - Tumor acute hypoxia has a dynamic component that is also, at least partially, coherent. Using blood oxygen level dependent magnetic resonance imaging, we observed coherent oscillations in hemoglobin saturation dynamics in cell line xenograft models of head and neck squamous cell carcinoma. We posit a well established biochemical nonlinear oscillatory mechanism called the glycolytic oscillator as a potential cause of the coherent oscillations in tumors. These data suggest that metabolic changes within individual tumor cells may affect the local tumor microenvironment including oxygen availability and therefore radiosensitivity. These individual cells can synchronize the oscillations in patches of similar intermediate glucose levels. These alterations have potentially important implications for radiation therapy and are a potential target for optimizing the cancer response to radiation. PMID- 26576745 TI - 2 * 2 Tables: a note on Campbell's recommendation. AB - For 2 * 2 tables, Egon Pearson's N - 1 chi-squared statistic is theoretically more sound than Karl Pearson's chi-squared statistic, and provides more accurate p values. Moreover, Egon Pearson's N - 1 chi-squared statistic is equal to the Mantel-Haenszel chi-squared statistic for a single 2 * 2 table, and as such, is often available in statistical software packages like SPSS, SAS, Stata, or R, which facilitates compliance with Ian Campbell's recommendations. PMID- 26576744 TI - Asthma characteristics and biomarkers from the Airways Disease Endotyping for Personalized Therapeutics (ADEPT) longitudinal profiling study. AB - BACKGROUND: Asthma is a heterogeneous disease and development of novel therapeutics requires an understanding of pathophysiologic phenotypes. The purpose of the ADEPT study was to correlate clinical features and biomarkers with molecular characteristics, by profiling asthma (NCT01274507). This report presents for the first time the study design, and characteristics of the recruited subjects. METHODS: Patients with a range of asthma severity and healthy non-atopic controls were enrolled. The asthmatic subjects were followed for 12 months. Assessments included history, patient questionnaires, spirometry, airway hyper-responsiveness to methacholine, fractional exhaled nitric oxide (FENO), and biomarkers measured in induced sputum, blood, and bronchoscopy samples. All subjects underwent sputum induction and 30 subjects/cohort had bronchoscopy. RESULTS: Mild (n = 52), moderate (n = 55), severe (n = 51) asthma cohorts and 30 healthy controls were enrolled from North America and Western Europe. Airflow obstruction, bronchodilator response and airways hyperresponsiveness increased with asthma severity, and severe asthma subjects had reduced forced vital capacity. Asthma control questionnaire-7 (ACQ7) scores worsened with asthma severity. In the asthmatics, mean values for all clinical and biomarker characteristics were stable over 12 months although individual variability was evident. FENO and blood eosinophils did not differ by asthma severity. Induced sputum eosinophils but not neutrophils were lower in mild compared to the moderate and severe asthma cohorts. CONCLUSIONS: The ADEPT study successfully enrolled asthmatics across a spectrum of severity and non-atopic controls. Clinical characteristics were related to asthma severity and in general asthma characteristics e.g. lung function, were stable over 12 months. Use of the ADEPT data should prove useful in defining biological phenotypes to facilitate personalized therapeutic approaches. PMID- 26576746 TI - MYBD employed by HY5 increases anthocyanin accumulation via repression of MYBL2 in Arabidopsis. AB - Photomorphogenesis is an essential program in plant development. This process is effected by the balanced cooperation of many factors under light and dark conditions. In a previous study, we showed that MYB hypocotyl elongation-related (MYBH) is involved in cell elongation. To expand our understanding of MYBH function, we performed a yeast two-hybrid assay and identified an MYB-like Domain transcription factor (MYBD). In this study, we investigated the function of MYBD, which is an MYBH homolog involved in anthocyanin accumulation. MYBD expression increased in response to light or cytokinin, and MYBD enhanced anthocyanin biosynthesis via repression of MYBL2, which encodes a transcription factor that has a negative effect on this process. In addition, MYBD binding in vivo to the MYBL2 promoter and the lower level of histone H3K9 acetylation at the upstream region of MYBL2 in MYBD over-expressing plants in comparison with wild-type plants imply that MYBD represses MYBL2 expression via an epigenetic mechanism. HY5 directly binds to the MYBD promoter, which indicates that MYBD acts on HY5 downstream in light- or cytokinin-triggered signaling pathways, leading to anthocyanin accumulation. Our results suggest that, although MYBD and MYBH are homologs, they act in opposite ways during plant photomorphogenesis, and these functions should be examined in further studies. PMID- 26576747 TI - Targeting CD30 expression in diverse Large B-cell lymphoma entities: Editorial comment to CD30 Expression and Its Correlation with MYC Rearrangement in De Novo Diffuse Large B-Cell Lymphoma. PMID- 26576748 TI - A theoretical study into a trans-dioxo Mn(V) porphyrin complex that does not follow the oxygen rebound mechanism in C-H bond activation reactions. AB - Previous experimental results revealed that the C-H bond activation reaction by a synthetic trans-dioxo Mn(V) porphyrin complex, [(TF4TMAP)OMn(V)O](3+), does not occur via the well-known oxygen rebound mechanism, which has been well demonstrated in Fe(IV)O porphyrin pi-cation radical reactions. In the present study, theoretical calculations offer an explanation through the energetics involved in the C-H bond activation reaction, where a multi-spin state scenario cannot be excluded. PMID- 26576749 TI - Impact of the Radial Artery as an Additional Arterial Conduit During In-Situ Bilateral Internal Mammary Artery Grafting: A Propensity Score-Matched Study. AB - BACKGROUND: Bilateral internal mammary artery (BIMA) grafting has been associated with improved long-term outcomes after CABG. We sought to evaluate the early results and long-term survival among coronary artery bypass graft patients who underwent in-situ BIMA grafting with the radial artery (RA) as an additional arterial conduit compared with those who underwent BIMA with additional saphenous vein graft (SVG). METHODS: Between 1991 and 2013, 1,750 consecutive patients with triple-vessel disease or left main plus right coronary system disease underwent primary isolated in-situ BIMA grafting with at least one internal mammary artery to the left anterior descending artery. Patients were divided into a BIMA-RA group (n = 255) and BIMA-SVG group (n = 1,495). Propensity score matching was used to create two comparable cohorts: 249 BIMA-RA patients were one-to-one matched to 249 BIMA-SVG patients. The date of death was obtained from provincial vital statistics. The median follow-up was 8 years. RESULTS: There was no difference in operative mortality between matched BIMA-RA and BIMA-SVG (0.8% versus 0.4%, respectively; p = 0.6). Five-year, 10-year, and 15-year survival rates were 98.3%, 92.0%, and 92.0%, respectively, among BIMA-RA patients, versus 96.5%, 93.0%, and 87.0% in the matched BIMA-SVG group (log rank p = 0.44). When we stratified the BIMA-RA patients into subgroups according to the severity of target artery stenosis, late survival was also similar among the BIMA-RA subgroups matched to BIMA-SVG patients (log rank p = 0.12). CONCLUSIONS: The use of the RA as an additional arterial graft in patients undergoing coronary artery bypass graft surgery with in-situ BIMA does not prolong late survival when compared with BIMA patients who received additional SVG. PMID- 26576750 TI - Effect of a Single Bolus of Erythropoietin on Renoprotection in Patients Undergoing Thoracic Aortic Surgery With Moderate Hypothermic Circulatory Arrest. AB - BACKGROUND: Acute kidney injury (AKI) is associated with high morbidity and mortality. Recombinant human erythropoietin has been shown to exert cytoprotection against ischemia. This study examined the effect of erythropoietin in preventing AKI during thoracic aortic surgery with moderate hypothermic circulatory arrest. METHODS: In this double-blind, randomized study, 66 patients undergoing thoracic aortic surgery with moderate hypothermic circulatory arrest (target temperature, 28 degrees C) randomly received either erythropoietin 500 IU.kg(-1) or the same amount of normal saline intravenously after anesthesia induction. The primary endpoint was incidence of AKI defined according to the RIFLE criteria during the first 7 postoperative days. RESULTS: AKI occurred in 60% of all patients. The two groups did not show any differences in the incidence and severity of AKI. Also, there was no difference in the level of serum neutrophil gelatinase-associated lipocalin between the groups. The cardiac index was higher in the erythropoietin group, however, immediately after weaning from cardiopulmonary bypass (p = 0.02). Furthermore, postoperative cardiac complications and prolonged vasopressor dependence were reduced in the erythropoietin group (p = 0.04 and p = 0.049, respectively). CONCLUSIONS: A single bolus administration of erythropoietin 500 IU.kg(-1) at anesthesia induction failed to provide renoprotection in patients who underwent thoracic aortic surgery with moderate hypothermic circulatory arrest. However, erythropoietin significantly reduced cardiac complications, and lowered the incidence of prolonged vasopressor dependence. PMID- 26576751 TI - Current Results of Surgical Aortic Valve Replacement: Insights From the German Aortic Valve Registry. AB - BACKGROUND: Conventional aortic valve replacement (AVR) remains the therapy of choice for many patients with severe aortic valve disease. The unique German Aortic Valve Registry (GARY) allows the comparison of contemporary outcomes of AVR with those of transcatheter AVRs. We report here real-world, all-comers outcomes of AVR, including combined AVR and coronary bypass grafting (AVR+CABG). METHODS: A total of 34,063 patients who received AVR (22,107 patients, 39% female; mean age 68.0 +/- 11.3 years, mean logistic European System for Cardiac Operative Risk Evaluation, 8.6%) or AVR+CABG (11,956 patients, 28% female; mean age 72.6 +/- 7.8 years, mean logistic European System for Cardiac Operative Risk Evaluation, 10.7%) between 2011 and 2013 were analyzed and followed up to assess the 1-year outcome. RESULTS: In-hospital mortality was 2.3% for AVR and 4.1% for AVR+CABG. Other important outcome variables include stroke (AVR, 1.2%; AVR+CABG, 1.9%) and new pacemaker implantation (AVR, 4.4%; AVR+CABG, 3.6%). Survival at 1 year was 93.2% for AVR and 89.4% for AVR+CABG. Total stroke rates at 1 year were 1.6% for AVR and 2.0% AVR+CABG. Quality of life assessment indicated that most patients were in New York Heart Association Functional Classification I or II (AVR, 86%; AVR+CABG, 84%) and that they were satisfied with the overall postoperative course (AVR, 88%; AVR+CABG, 87%). CONCLUSIONS: Contemporary surgical AVR yields excellent outcomes with low in-hospital mortality, a low overall complication rate, and good 1-year outcome for all risk groups. Accordingly, conventional AVR remains an important therapeutic option for many patients. PMID- 26576752 TI - Impact of Positive Margins on Survival in Patients Undergoing Esophagogastrectomy for Esophageal Cancer. AB - BACKGROUND: Multimodality treatment that includes esophagogastrectomy may represent the best option for curing accurately staged patients with esophageal cancer. We analyzed the impact of incomplete resection on outcomes after esophagogastrectomy for esophageal cancer. METHODS: The incidence of positive margins for patients who underwent esophagogastrectomy without induction therapy for pathologic T1-3N0-1M0 esophageal cancer of the mid and lower esophagus from 2003 to 2006 in the National Cancer Database was analyzed with multivariate logistic regression. The impact of positive margins on survival was assessed using Kaplan-Meier and Cox proportional hazards analysis. RESULTS: Positive margins occurred in 342 of 3,125 patients (10.9%) who met study criteria. Increasing clinical T status was an independent predictor of positive margins in multivariate analysis, but the chance of positive margins decreased with larger facility case volumes. The presence of clinical nodal disease was not predictive of an incomplete resection. The 5-year survival of patients with positive margins (13.8%, 95% confidence interval [CI]: 10.5% to 18.1%) was significantly worse than that for patients with negative margins (46.3%, 95% CI: 44.4% to 48.3%, p < 0.001). Both microscopic residual disease (hazard ratio 1.37, 95% CI: 1.16 to 1.60, p < 0.001) and gross residual disease (hazard ratio 1.98, 95% CI: 1.62 to 2.42, p < 0.001) predicted worse survival in multivariate analysis of the entire cohort. Receiving adjuvant chemoradiation therapy slightly improved 5-year survival of patients with positive margins (16.9%, 95% CI: 11.3% to 23.6%, versus 13.5%, 95% CI: 9% to 20.3%, p < 0.001). CONCLUSIONS: Positive margins are associated with poor survival, and adjuvant therapy only marginally improved prognosis. Future studies are needed to better evaluate whether induction therapy can lower the incidence of positive margins. PMID- 26576753 TI - Qualitative Analysis of Preoperative High-Resolution Computed Tomography: Risk Factors for Pulmonary Complications After Major Lung Resection. AB - BACKGROUND: Postoperative pulmonary complications after major lung resection are strongly associated with mortality. Qualitative findings of emphysema, bronchiectasis, and bronchial wall thickening on high-resolution computed tomography (HRCT) are indicators of chronic obstructive pulmonary disease and may serve as risk factors for pulmonary complications. METHODS: The subjects were 347 consecutive patients who underwent single lobectomy for pulmonary malignancy from May 2010 to December 2014. Correlations of pulmonary complications with preoperative clinical factors and HRCT findings were retrospectively examined using multivariate logistic regression analysis to compare the predictive ability for pulmonary complications using clinical variables that were reported to be risk factors. RESULTS: Patients who had pulmonary complications were more frequently male (p < 0.001), with a greater smoking history (p < 0.001), lower rate of steroid use (p < 0.001), more frequent emphysema on HRCT (p < 0.001), more frequent bronchiectasis on HRCT (p = 0.002), more frequent bronchial wall thickening on HRCT (p < 0.001), and higher rate of extended resection (p = 0.006). In multivariate analysis, HRCT findings (odds ratio [OR] 12.01, 95% confidence interval [CI]: 5.582 to 25.83, p < 0.001) and extended resection (OR 7.726, 95% CI: 1.678 to 35.57, p = 0.009) were independent risk factors for pulmonary complications. After matching of risk factors between patients with and without pulmonary complication, emphysema (OR 3.394, 95% CI: 1.781 to 6.469, p < 0.001) and bronchial wall thickening (OR 6.250, 95% CI: 2.414 to 16.18, p < 0.001) were independently associated with pulmonary complications in the model with better performance. CONCLUSIONS: Qualitative findings on HRCT are independent risk factors for pulmonary complications after lobectomy. Preoperative HRCT may be useful to predict pulmonary complications. PMID- 26576754 TI - Inferring the age of a fixed beneficial allele. AB - Estimating the age and strength of beneficial alleles is central to understanding how adaptation proceeds in response to changing environmental conditions. Several haplotype-based estimators exist for inferring the age of segregating beneficial mutations. Here, we develop an approximate Bayesian-based approach that rather estimates these parameters for fixed beneficial mutations in single populations. We integrate a range of existing diversity, site frequency spectrum, haplotype- and linkage disequilibrium-based summary statistics. We show that for strong selective sweeps on de novo mutations the method can estimate allele age and selection strength even in nonequilibrium demographic scenarios. We extend our approach to models of selection on standing variation, and co-infer the frequency at which selection began to act upon the mutation. Finally, we apply our method to estimate the age and selection strength of a previously identified mutation underpinning cryptic colour adaptation in a wild deer mouse population, and compare our findings with previously published estimates as well as with geological data pertaining to the presumed shift in selective pressure. PMID- 26576755 TI - PIMS (Positioning In Macular hole Surgery) trial - a multicentre interventional comparative randomised controlled clinical trial comparing face-down positioning, with an inactive face-forward position on the outcome of surgery for large macular holes: study protocol for a randomised controlled trial. AB - BACKGROUND: Idiopathic macular holes are an important cause of blindness. They have an annual incidence of 8 per 100,000 individuals, and prevalence of 0.2 to 3.3 per 1000 individuals with visual impairment. The condition occurs more frequently in adults aged 75 years or older. Macular holes can be repaired by surgery in which the causative tractional forces in the eye are released and a temporary bubble of gas is injected. To promote successful hole closure individuals may be advised to maintain a face-down position for up to 10 days following surgery. The aim of this study is to determine whether advice to position face-down improves the surgical success rate of closure of large (>400 MUm) macular holes, and thereby reduces the need for further surgery. METHODS/DESIGN: This will be a multicentre interventional, comparative randomised controlled clinical trial comparing face-down positioning with face-forward positioning. At the conclusion of standardised surgery across all sites, participants still eligible for inclusion will be allocated randomly 1:1 to 1 of the 2 treatment arms stratified by site, using random permuted blocks of size 4 or 6 in equal proportions. We will recruit 192 participants having surgery for large macular holes (>400 MUm); 96 in each of the 2 arms of the study. The primary objective is to determine the impact of face-down positioning on the likelihood of closure of large (>=400 MUm) full-thickness macular holes following surgery. DISCUSSION: This will be the first multicentre randomised control trial to investigate the value of face-down positioning following macular hole standardised surgery. TRIAL REGISTRATION: UK CRN: 17966 (date of registration 26 November 2014). PMID- 26576756 TI - Mechanism for Conducting Filament Growth in Self-Assembled Polymer Thin Films for Redox-Based Atomic Switches. AB - The switching mechanisms of atomic switches based on poly(ethylene oxide) (PEO) are systematically investigated. By using self-assembled PEO and Ag-PEO thin films, stack-structured devices exhibit stable bipolar switching behavior over 10(3) cycles. Direct observation of filament growth behavior in planar-structured devices reveals the effects of the polymer thin-film morphology, and the presence of electrochemically active electrodes, on the switching characteristics. PMID- 26576757 TI - The TL,NO /TL,CO ratio cannot be used to exclude pulmonary embolism. AB - BACKGROUND: The existing screening modalities for pulmonary embolism (PE), such as D-dimer and clinical prediction rules, have low positive predictive values. With its capability to indicate pulmonary vascular abnormalities, the ratio of the transfer factor of the lungs for nitric oxide and the transfer factor of the lungs for carbon monoxide (TL,NO /TL,CO ) might be an additional discriminating parameter. METHODS: Carbon monoxide/Nitric oxide diffusion measurements were performed on unselected patients seen on the emergency department for which due to suspected PE a computed tomography pulmonary angiogram (CTPA) was ordered. RESULTS: A total of 28 patients were included, PE was found in 12 on CTPA. Median TL,NO /TL,CO ratio was 4.09 (interquartile range (IQR) 3.83-4.40) in the no PE group versus 4.00 (IQR 3.78-4.32) in the PE group (P = 0.959). Median alveolar volume was 77.1% of predicted in the no PE group versus 71.0% of predicted in the PE group (P = 0.353). Median TL,CO was 75.8% of predicted in the no PE group versus 68.8% of predicted in the PE group (P = 0.120). Median TL,NO was 69.3% of predicted in the no PE group versus 60.5% of predicted in the PE group (P = 0.078). CONCLUSION: The presented data indicate that the TL,NO /TL,CO ratio cannot be used to exclude PE. PMID- 26576758 TI - Non-surgical adjunctive interventions for accelerating tooth movement in patients undergoing fixed orthodontic treatment. AB - BACKGROUND: Accelerating the rate of tooth movement may help to reduce the duration of orthodontic treatment and associated unwanted effects including root resorption and enamel demineralisation. Several methods, including surgical and non-surgical adjuncts, have been advocated to accelerate the rate of tooth movement. Non-surgical techniques include low-intensity laser irradiation, resonance vibration, pulsed electromagnetic fields, electrical currents and pharmacological approaches. OBJECTIVES: To assess the effect of non-surgical adjunctive interventions on the rate of orthodontic tooth movement and the overall duration of treatment. SEARCH METHODS: We searched the following databases on 25 November 2014: the Cochrane Oral Health Group's Trials Register (November 2014), the Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library 2014, Issue 10), MEDLINE via OVID (1946 to November 2014), EMBASE via OVID (1980 to November 2014), LILACS via BIREME (1980 to November 2014), metaRegister of Controlled Trials (November 2014), the US National Institutes of Health Trials Register (ClinicalTrials.gov; November 2014) and the WHO International Clinical Trials Registry Platform (November 2014). We checked the reference lists of all trials identified for further studies. There were no restrictions regarding language or date of publication in the searches of the electronic databases. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of people receiving orthodontic treatment using fixed appliances along with non-surgical adjunctive interventions to accelerate tooth movement. We excluded non-parallel design studies (for example, split-mouth) as we regarded them as inappropriate for assessment of the effects of this type of intervention. DATA COLLECTION AND ANALYSIS: Two review authors were responsible for study selection, risk of bias assessment and data extraction; they carried out these tasks independently. Any disagreements were resolved by discussion amongst the review team to reach consensus. The review authors contacted the corresponding authors of trials to obtain missing information and data to allow calculation of mean differences (MD), 95% confidence intervals (CI) or risk ratios (RR) when these were not reported. MAIN RESULTS: We included two studies in this review, which were both assessed as being at high risk of bias. The two studies, involving a total of 111 participants, compared the use of Tooth Masseuse and OrthoAccel with conventional treatment mechanics during orthodontic alignment and canine retraction phases, respectively. Both studies included objective assessment of the amount or rate of tooth movement, but we were not able to meta analyse this data as they used different outcome measurements at different stages of the orthodontic treatment process. One study measured subjective evaluation of pain and discomfort and the other evaluated adverse effects. The studies did not directly report either the duration of orthodontic treatment or the number of visits during active treatment.Using the Tooth Masseuse with 111 Hz at 0.06 Newtons (N) for 20 minutes daily resulted in greater reduction in irregularity in the lower incisor region over 10 weeks, assessed using Little's Irregularity Index (LII) with a mean difference (MD) of 0.6 mm (95% confidence interval (CI) 0.94 to 2.34) when compared to the control group. Pain and discomfort increased at six to eight hours after arch wire placement and after seven days, with minimal difference between the intervention and control groups. No statistical tests were provided for either variable and the differences between the two groups were not clinically important.Using OrthoAccel with 30 Hz at 0.25 N for 20 minutes daily produced a higher rate of maxillary canine distalisation in comparison to the control group (MD 0.37 mm/month; 95% CI -0.07 to 0.81; P = 0.05). Whilst this difference suggested 50% faster tooth movement using the vibrational appliance, the absolute differences were marginal and deemed clinically unimportant. Similar levels of non-serious adverse effects were reported in the intervention and control groups with a risk ratio of 0.96 (95% CI 0.32 to 2.85).Overall, the quality of the evidence was very low and therefore we cannot rely on the findings. AUTHORS' CONCLUSIONS: There is very little clinical research concerning the effectiveness of non-surgical interventions to accelerate orthodontic treatment. The available evidence is of very low quality and so it is not possible to determine if there is a positive effect of non-surgical adjunctive interventions to accelerate tooth movement. Although there have been claims that there may be a positive effect of light vibrational forces, results of the current studies do not reach either statistical or clinical significance. Further well-designed and rigorous RCTs with longer follow-up periods are required to determine whether non-surgical interventions may result in a clinically important reduction in the duration of orthodontic treatment, without any adverse effects. PMID- 26576759 TI - The non-metabolizable sucrose analog sucralose is a potent inhibitor of hormogonium differentiation in the filamentous cyanobacterium Nostoc punctiforme. AB - Nostoc punctiforme is a filamentous cyanobacterium which forms nitrogen-fixing symbioses with several different plants and fungi. Establishment of these symbioses requires the formation of motile hormogonium filaments. Once infected, the plant partner is thought to supply a hormogonium-repressing factor (HRF) to maintain the cyanobacteria in a vegetative, nitrogen-fixing state. Evidence implies that sucrose may serve as a HRF. Here, we tested the effects of sucralose, a non-metabolizable sucrose analog, on hormogonium differentiation. Sucralose inhibited hormogonium differentiation at a concentration approximately one-tenth that of sucrose. This result implies that: (1) sucrose, not a sucrose catabolite, is perceived by the cell and (2) inhibition is not due to a more general osmolarity-dependent effect. Additionally, both sucrose and sucralose induced the accrual of a polysaccharide sheath which bound specifically to the lectin ConA, indicating the presence of alpha-D-mannose and/or alpha-D-glucose. A ConA-specific polysaccharide was also found to be expressed in N. punctiforme colonies from tissue sections of the symbiotically grown hornwort Anthoceros punctatus. These findings imply that plant-derived sucrose or sucrose analogs may have multiple effects on N. punctiforme, including both repression of hormogonia and the induction of a polysaccharide sheath that may be essential to establish and maintain the symbiotic state. PMID- 26576760 TI - Assessing human-bat interactions around a protected area in northeastern Brazil. AB - BACKGROUND: Bats are key components to the Neotropical forests. Unfortunately, their bad reputation is a major obstacle in their conservation as it creates fear and hostility towards them. Understanding this reputation acquired by bats and studying interactions between bats and humans has shown fundamental promise when creating strategies to forge a non-antagonistic coexistence between both parts and in the promotion of bat conservation in areas with ever-rising human occupation. METHODS: Ninety people were surveyed from three villages that were situated around a Biological Reserve in the state of Paraiba; located in Northern Brazil. The survey was completed using semi-structured interviews addressing villager's knowledge of the biology and ecology of bats, their interactions with bats, potential medicinal uses, and their socioeconomic situation. Additionally, we sampled the bats that reside in or visit these villages. RESULTS: Bats were often considered harmful, dangerous and carriers of disease. Bats were often connected to hematophagia, as well. The respondents believe that impacts such as the deforestation are forcing bats into urban environments. With this research, we were able to register one of the few records of bats in popular medicine in Brazil. CONCLUSION: The folklore and superstition surrounding bats can form an obstacle that affects their conservation. Environmental education is an important step in order to create a harmonious coexistence between humans and bats and to mitigate the impending conflicts between humanity and nature. PMID- 26576761 TI - Re: Proposed HPV vaccination syndrome is unsubstantiated. PMID- 26576762 TI - Diagnostic imaging capabilities of the Ocelot -Optical Coherence Tomography System, ex-vivo evaluation and clinical relevance. AB - BACKGROUND: Optical coherence tomography (OCT) is a high-resolution sub-surface imaging modality using near-infrared light to provide accurate and high contrast intra-vascular images. This enables accurate assessment of diseased arteries before and after intravascular intervention. This study was designed to corroborate diagnostic imaging equivalence between the Ocelot and the Dragonfly OCT systems with regards to the intravascular features that are most important in clinical management of patients with atherosclerotic vascular disease. These intravascular features were then corroborated in vivo during treatment of peripheral arterial disease (PAD) pathology using the Ocelot catheter. METHODS: In order to compare the diagnostic information obtained by Ocelot (Avinger Inc., Redwood City, CA) and Dragonfly (St. Jude Medical, Minneapolis, MN) OCT systems, we utilized ex-vivo preparations of arterial segments. Ocelot and Dragonfly catheters were inserted into identical cadaveric femoral peripheral arteries for image acquisition and interpretation. Three independent physician interpreters assessed the images to establish accuracy and sensitivity of the diagnostic information. Histologic evaluation of the corresponding arterial segments provided the gold standard for image interpretation. In vivo clinical images were obtained during therapeutic interventions that included crossing of peripheral chronic total occlusions (CTOs) using the Ocelot catheter. RESULTS: Strong concordance was demonstrated when matching image characteristics between both OCT systems and histology. The Dragonfly and Ocelot system's vessel features were interpreted with high sensitivity (91.1-100%) and specificity (86.7-100%). Inter observer concordance was documented with excellent correlation across all vessel features. The clinical benefit that the Ocelot OCT system provided was demonstrated by comparable procedural images acquired at the point of therapy. CONCLUSIONS: The study demonstrates equivalence of image acquisition and consistent physician interpretation of images acquired by the Ocelot and the Dragonfly OCT systems in-spite of distinct image processing algorithms and catheter configurations. This represents a dramatic shift away from both fluoroscopic imaging and diagnostic-only OCT imaging during peripheral arterial intervention towards therapeutic devices that incorporate real time diagnostic OCT imaging. In the clinical practice, these diagnostic capabilities have translated to best-in-class safety and efficacy for CTO crossing using the Ocelot catheter. PMID- 26576763 TI - In vivo release and retinal toxicity of cyclosporine-loaded intravitreal device. AB - PURPOSE: To determine the in vivo release profile and retinal safety of cyclosporine A (CsA) delivered from a biodegradable poly-lactide-co-glycolide (PLGA) device in the vitreous cavity of rabbits' eyes. METHODS: A total of 60 animals (60 eyes) divided into two groups were used. For the in vivo release study, 32 eyes received PLGA implants containing 350 ug of CsA, and 16 eyes received the implants without drug (control). Four animals of CsA group and two of the control group were killed weekly until 8 weeks; the vitreous was removed, and CsA concentration was evaluated. Ophthalmological examination was performed in the animals prior to implant placement and weekly during the study period. Electroretinography (ERG) was performed in other six animals for each group, treated and control, at the beginning and at the end of the study (8 weeks) when they were killed and had their eyes processed for histology. RESULTS: No sign of inflammation was noticed on slit lamp examinations and the IOP maintained stable during the study period in CsA and control groups. CsA concentration in the vitreous (ng/ml) was 257.07 +/- 117.23, 271.15 +/- 98.96, 296.66 +/- 86.25, 256.27 +/- 99.22, 304.50 +/- 88.18, 326.35 +/- 105.24, 491.25 +/- 119.90 and 589.93 +/- 132.55 after 1, 2, 3, 4, 5, 6, 7 and 8 weeks of implantation, respectively. At the end of the study, 21.67 % of mass loss was found. The retina did not show any histological alteration in either group, but a significant reduction in dark-adapted b-wave amplitude was observed in the CsA group, with no changes in a-wave amplitude. CONCLUSIONS: These data show that the PLGA system is safe, but the selective reduction in ERG b-wave amplitude indicates that the PLGA with 350 ug CsA causes retinal function impairment, specifically on the rod postreceptor pathway, 8 weeks after implantation. These ERG changes were not associated with any histological damage as seen at the light microscopy level. PMID- 26576764 TI - The comprehensive immunomodulation of NeurimmiRs in haemocytes of oyster Crassostrea gigas after acetylcholine and norepinephrine stimulation. AB - BACKGROUND: Neural-endocrine-immune (NEI) system is a major modulation network among the nervous, endocrine and immune system and weights greatly in maintaining homeostasis of organisms during stress and infection. Some microRNAs are found interacting with NEI system (designated NeurimmiRs), addressing swift modulations on immune system. The oyster Crassostrea gigas, as an intertidal bivalve, has evolved a primary NEI system. However, the knowledge about NeurimmiRs in oysters remains largely unknown. RESULTS: Six small RNA libraries from haemocytes of oysters stimulated with acetylcholine (ACh) and norepinephrine (NE) were sequenced to identify neurotransmitter-responsive miRNAs and survey their immunomodulation roles. A total of 331 miRNAs (132 identified in the present study plus 199 identified previously) were subjected to expression analysis, and twenty-one and sixteen of them were found ACh- or NE-responsive, respectively (FDR < 0.05). Meanwhile, 21 miRNAs exhibited different expression pattern after ACh or NE stimulation. Consequently, 355 genes were predicted as putative targets of these neurotransmitter-responsive miRNAs in oyster. Through gene onthology analysis, multiple genes involved in death, immune system process and response to stimulus were annotated to be modulated by NeurimmiRs. Besides, a significant decrease in haemocyte phagocytosis and late-apoptosis or necrosis rate was observed after ACh and NE stimulation (p < 0.05) while early-apoptosis rate remained unchanged. CONCLUSIONS: A comprehensive immune-related network involving PRRs, intracellular receptors, signaling transducers and immune effectors was proposed to be modulated by ACh- and NE-responsive NeurimmiRs, which would be indispensable for oyster haemocytes to respond against stress and infection. Characterization of the NeurimmiRs would be an essential step to understand the NEI system of invertebrate and the adaptation mechanism of oyster. PMID- 26576765 TI - Adherence to gluten-free diet and barriers to adherence in patients with celiac disease. AB - BACKGROUND: While adherence to gluten-free diet (GFD) is essential for effective control of celiac disease, the level of adherence to GFD may vary. We assessed the level of adherence to GFD and identified barriers to adherence in patients with celiac disease. METHODS: Both treatment-naive and follow up patients with celiac disease were recruited from a celiac disease clinic. All the patients were assessed for symptom improvement using celiac symptom index (CSI), weight, and hemoglobin; adherence to GFD using detailed dietary history and food-labeled quiz questionnaire; identification of barriers to GFD using a self-administered 36 point questionnaire; and quality of life using a standard 36-item short form (SF36) questionnaire. RESULTS: Among the patients who were already on GFD, only 53.3% maintained an excellent or good level of adherence, which increased to 92.4% at 6 months with repeated counseling. Among the treatment-naive patients, 64.8% maintained either excellent or good compliance at 1 month after first counseling, which increased to 96.3% at 6 months with repeated counseling. The most common barrier to adherence was non-availability of GFD. Certain barriers could be modified with repeated counseling and education. Response to GFD, as measured by CSI, gain in weight, and improvement in hemoglobin, was better in those having either excellent or good compliance to GFD compared to those who remained poorly adherent. CONCLUSIONS: Repeated counseling increased the level of adherence to GFD. PMID- 26576766 TI - Are selected IL-1 polymorphisms and selected subgingival microorganisms significantly associated to periodontitis in type 2 diabetes patients? a clinical study. AB - BACKGROUND: We evaluated the periodontal conditions in patients with type 2 diabetes mellitus compared to metabolically healthy controls, and determined whether periodontal interleukin genotypes and microorganisms differed between participants with and without type 2 diabetes mellitus. METHODS: From April 2011 to July 2012, we prospectively enrolled healthy controls and patients with type 2 diabetes mellitus. Evaluation included assessment of medical and periodontal findings. We also recorded the presence of several interleukin gene variants and specific microorganisms, both available through commercially available diagnostic kits. Statistical significance was tested by the chi-square test and student's t test. RESULTS: We enrolled 52 patients with type 2 diabetes mellitus and 52 healthy controls. Compared with controls, periodontal disease was significantly more severe in patients with type 2 diabetes mellitus for the following: plaque index, bleeding on probing, pocket probing depth, clinical attachment loss, severe periodontal destruction (i.e., clinical attachment loss >= 5 mm), and number of teeth. However, statistical analysis failed to detect significant differences with respect to the periodontal-related interleukin genotypes (p >= 0.58) or the selected oral microbiota (p >= 0.15). CONCLUSION: Based on these results, it may be assumed that chronic periodontitis in patients with type 2 diabetes mellitus is most strongly associated with inadequate oral hygiene. Periodontal interleukin genotypes and differences in oral microbiota seem to play a subordinate role. PMID- 26576767 TI - Association between periodontitis, periodontopathogens and preterm birth: is it real? AB - PURPOSE: To identify the association between periodontitis and periodontal pathogens with preterm birth despite the strict control of some important confounders, such as infectious processes and criteria for diagnosis of periodontitis during pregnancy. MATERIALS AND METHODS: In this cross-sectional study were included 70 healthy puerperal women between 20 and 35 years without a history of genitourinary infections during pregnancy. Based on the gestational age they were divided into two groups: 45 with term birth (>37 weeks) and 25 with preterm birth (<37 weeks). Previous informed consent, a gynecologic and dental history that included gynecologic and obstetric background, periodontal status applying different authors' criteria of periodontitis diagnosis, presence of periodontopathogens, dental caries and oral hygiene were recorded. RESULTS: There was no association between periodontitis, periodontopathogens and preterm birth. There were no statistical differences applying different authors' criteria diagnosis of periodontitis. Gingivitis status was similar, but probing depth was greater in preterm birth subjects, perhaps they are young women, and this finding could be an early sign of periodontitis. In like manner, the main periodontal bacterial species are not associated with preterm birth, general hygiene and care habits are poorer than term birth subjects. CONCLUSION: We could suggest that preterm birth is a multifactorial condition and the role of periodontitis and the periodontopathogens itself is not sufficient to trigger the preterm birth. There are factors such as infectious processes and diagnostic criteria for periodontitis that could be responsible for controversial results. PMID- 26576768 TI - An overview of the development and application of the sonographic scoring system: differentiation of malignant from benign ovarian tumors. AB - PURPOSE: Ultrasonography is routinely used for the examination of ovarian tumors regarding preoperative diagnosis and postoperative therapeutic evaluation. However, its sensitivity and specificity in determining benign from malignant tumors should be further improved. In this study, we review the methods of sonographic scoring system for differentiating benign from malignant ovarian tumors, and its development and application. METHODS: We searched the Medline, EBSCO and China National Knowledge Infrastructure from inception to April 2015, we also used the Google Scholar search engine to obtain studies. RESULTS: The ultrasonic scoring system has important clinical value in the preoperative diagnosis of ovarian neoplasm, the sensitivity, specificity and accuracy are significantly higher than using conventional ultrasonography by various of ultrasonic techniques, including two-dimensional sonographic imaging, color Doppler imaging, power Doppler ultrasound, real-time three-dimensional ultrasound and contrast-enhanced ultrasonography. CONCLUSIONS: The sonographic scoring system can significantly improve the sensitivity, specificity and accuracy of ultrasonic diagnosis in ovarian tumors, and provides a semi-quantitative method for determining the nature of ovarian masses, guidance of the surgical treatment and evaluation of prognosis. PMID- 26576769 TI - Comment to the letter by Dr. S. Matsubara. PMID- 26576770 TI - Microbial "social networks". AB - BACKGROUND: It is well understood that distinct communities of bacteria are present at different sites of the body, and that changes in the structure of these communities have strong implications for human health. Yet, challenges remain in understanding the complex interconnections between the bacterial taxa within these microbial communities and how they change during the progression of diseases. Many recent studies attempt to analyze the human microbiome using traditional ecological measures and cataloging differences in bacterial community membership. In this paper, we show how to push metagenomic analyses beyond mundane questions related to the bacterial taxonomic profiles that differentiate one sample from another. METHODS: We develop tools and techniques that help us to investigate the nature of social interactions in microbial communities, and demonstrate ways of compactly capturing extensive information about these networks and visually conveying them in an effective manner. We define the concept of bacterial "social clubs", which are groups of taxa that tend to appear together in many samples. More importantly, we define the concept of "rival clubs", entire groups that tend to avoid occurring together in many samples. We show how to efficiently compute social clubs and rival clubs and demonstrate their utility with the help of examples including a smokers' dataset and a dataset from the Human Microbiome Project (HMP). RESULTS: The tools developed provide a framework for analyzing relationships between bacterial taxa modeled as bacterial co-occurrence networks. The computational techniques also provide a framework for identifying clubs and rival clubs and for studying differences in the microbiomes (and their interactions) of two or more collections of samples. CONCLUSIONS: Microbial relationships are similar to those found in social networks. In this work, we assume that strong (positive or negative) tendencies to co-occur or co-infect is likely to have biological, physiological, or ecological significance, possibly as a result of cooperation or competition. As a consequence of the analysis, a variety of biological interpretations are conjectured. In the human microbiome context, the pattern of strength of interactions between bacterial taxa is unique to body site. PMID- 26576771 TI - Combined Genome-Wide CSF Abeta-42's Associations and Simple Network Properties Highlight New Risk Factors for Alzheimer's Disease. AB - The abnormal deposition of amyloid-beta protein in the brain plays an important role in Alzheimer's disease (AD), being considered a potential clinical biomarker. To investigate genetic associations with amyloid-beta we used biomarker data and genome-wide variants from individuals with AD and mild cognitive impairment in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. We used a standard linear model and retested the associations with a mixed linear model to correct the residual sample structure. Both methods' results showed two identical significant SNPs associated with the A beta-42 levels in CSF (rs2075650 at intron region TOMM40 with p-value >= 1 * 10-16 and rs439401 in the intergenic region of LOC100129500 and APOC1 with p-value >= 1 * 10-9) and highlighted APOC1 and TOMM40, which are well-known genes previously associated with AD. Extending our analysis, we considered possible candidate genes mapped to SNPs with p-value >= 1 * 10-6 to explore gene-set enrichment e gene-gene network analysis, which reveals genes related to synaptic transmission, transmission of nerve impulses, cell-cell signaling and neurological processes. These genes require fine mapping and replication studies to allow more detailed understanding of how they may contribute to the genetic architecture of AD. PMID- 26576772 TI - Targeted Molecular Therapies for SBMA. AB - Spinal and bulbar muscular atrophy (SBMA) is a late-onset neuromuscular disease caused by a polyglutamine expansion in the androgen receptor gene which results in progressive spinal and bulbar motor neuron degeneration, and muscle atrophy. Although the causative genetic defect is known, until recently, the molecular pathogenesis of the disease was unclear, resulting in few, if any, targets for therapy development. However, over the past decade, our understanding of the pathomechanisms that play a role in SBMA has increased dramatically, and several of these pathways and mechanisms have now been investigated as possible therapeutic targets. In this review, we discuss some of the key pathomechanisms implicated in SBMA and describe some of the therapeutic strategies that have been tested in SBMA to date, which fall into four main categories: (i) gene silencing; (ii) protein quality control and/or increased protein degradation; (iii) androgen deprivation; and (iv) modulation of AR function. Finally, it is also now clear that in addition to a greater understanding of the molecular mechanisms that underlie disease, the development of an effective disease modifying therapy for SBMA will require the coordinated, collaborative effort of research teams with diverse areas of expertise, clinicians, pharmaceutical companies as well as patient groups. PMID- 26576773 TI - The Tau-Induced Reduction of mRNA Levels of Kv Channels in Human Neuroblastoma SK N-SH Cells. AB - Previous findings indicated that microtubule-binding protein tau and voltage gated K(+) (Kv) channels exhibit a regulatory role in cell proliferation. However, the possible interaction of tau with Kv channels remained obscure. In this report, transfection of tau plasmids into human neuroblastoma SK-N-SH cells caused a significant reduction in the messenger RNA (mRNA) levels of several Kv channels, including Kv2.1, Kv3.1, Kv5.1, Kv9.2, and KCNH4. Correspondingly, the Kv currents recorded using patch-clamp techniques were substantially declined in the tau-transfected SK-N-SH cells. Moreover, tau induction and treatment with the Kv channel blocker TEA (tetraethylammonium) were able to improve proliferation rates of SK-N-SH cells by 43.1 and 66.2%, respectively. These data suggested that the tau-mediated alteration of Kv channels could be involved in its action on neural proliferation. PMID- 26576774 TI - Chemoradiotherapy for patients with recurrent lymph-node metastasis or local recurrence of gastric cancer after curative gastrectomy. AB - OBJECTIVES: Whether chemoradiotherapy (CRT) is clinically beneficial for the management of postoperative recurrence of advanced gastric cancer remains unclear. We retrospectively studied treatment outcomes in patients who had unresectable localized recurrence after surgery for advanced gastric cancer and evaluated the safety and efficacy of CRT. METHODS: The study group comprised 21 patients who received concurrent CRT for unresectable localized recurrence after undergoing R0 resection for stage II/III advanced gastric cancer. Localized recurrence was defined as a few or limited recurrent lesions. RESULTS: The recurrence pattern was anastomotic recurrence in 7 patients, abdominal lymph-node recurrence in 12, and anastomotic recurrence plus abdominal lymph-node recurrence in 2. The median total dose of radiotherapy was 48.6 Gy (range 39.6-56.0), and the CRT completion rate was 100 % (21 of 21 patients). CRT-related grade 3 or higher toxicity comprised neutropenia in 33.3 % of patients and anorexia in 9.5 %. The response rate was 61.9 % (complete response 38.1 %, partial response 23.8 %). The median overall survival was 35.0 months. CONCLUSIONS: We conclude that CRT may become one treatment strategy for the management of unresectable localized recurrence after curative resection of advanced gastric cancer. PMID- 26576775 TI - Auxiliary subunits highlight a role for the LBD-TMD linkers in glutamate receptor desensitization. PMID- 26576776 TI - Enantioselective Multicomponent Condensation Reactions of Phenols, Aldehydes, and Boronates Catalyzed by Chiral Biphenols. AB - Chiral diols and biphenols catalyze the multicomponent condensation reaction of phenols, aldehydes, and alkenyl or aryl boronates. The condensation products are formed in good yields and enantioselectivities. The reaction proceeds via an initial Friedel-Crafts alkylation of the aldehyde and phenol to yield an ortho quinone methide that undergoes an enantioselective boronate addition. A cyclization pathway was discovered while exploring the scope of the reaction that provides access to chiral 2,4-diaryl chroman products, the core of which is a structural motif found in natural products. PMID- 26576777 TI - A new method for the extraction of fetal ECG from the dependent abdominal signals using blind source separation and adaptive noise cancellation techniques. AB - BACKGROUND: The electrocardiogram (ECG) is a diagnostic tool that records the electrical activity of the heart, and depicts it as a series of graph-like tracings, or waves. Being able to interpret these details allows diagnosis of a wide range of heart problems. Fetal electrocardiogram (FECG) extraction has an important impact in medical diagnostics during the mother pregnancy period. Since the observed FECG signals are often mixed with the maternal ECG (MECG) and the noise induced by the movement of electrodes or by mother motion, the separation process of the ECG signal sources from the observed data becomes quite complicated. One of its complexity is when the ECG sources are dependent, thus, in this paper we introduce a new approach of blind source separation (BSS) in the noisy context for both independent and dependent ECG signal source. This approach consist in denoising the observed ECG signals using a bilateral total variation (BTV) filter; then minimizing the Kullbak-Leibler divergence between copula densities to separate the FECG signal from the MECG one. RESULTS: We present simulation results illustrating the performance of our proposed method. We will consider many examples of independent/dependent source component signals. The results will be compared with those of the classical method called independent component analysis (ICA) under the same conditions. The accuracy of source estimation is evaluated through a criterion, called again the signal-to-noise ratio (SNR). The first experiment shows that our proposed method gives accurate estimation of sources in the standard case of independent components, with performance around 27 dB in term of SNR. In the second experiment, we show the capability of the proposed algorithm to successfully separate two noisy mixtures of dependent source components - with classical criterion devoted to the independent case - fails, and that our method is able to deal with the dependent case with good performance. CONCLUSIONS: In this work, we focus specifically on the separation of the ECG signal sources taken from skin two electrodes located on a pregnant woman's body. The ECG separation is interpreted as a noisy linear BSS problem with instantaneous mixtures. Firstly, a denoising step is required to reduce the noise due to motion artifacts using a BTV filter as a very effective one-pass filter for denoising. Then, we use the Kullbak-Leibler divergence between copula densities to separate the fetal heart rate from the mother one, for both independent and dependent cases. PMID- 26576778 TI - MicroRNA molecular profiling from matched tumor and bio-fluids in bladder cancer. AB - BACKGROUND: MicroRNAs have been identified as potential cancer biomarkers due to their presence and stability in many body fluids including urine and plasma, but the relationship of the pattern of expression of these messengers across various biological media has not been addressed and could provide important information in order to translate these biomarkers for epidemiologic or clinical use. METHODS: We analyzed microRNA of matched FFPE-tumor tissue, plasma, urine exosomes (n = 16) and WBCs (n = 11) from patients with bladder cancer, using Nanostring miRNA assays and droplet digital PCR for validation. Pearson correlations were used to compare expression between media. RESULTS: Numerous microRNAs were detected and overlapping from specific bio-specimen sources. MiR 4454 and miR-21 overexpression was found in three sources: tumor, WBCs and urine. Additionally, miR-15b-5p, miR-126-3p, miR-93-5p, and miR-150-5p were common to tumor/WBCs, while miR-720/3007a, miR-205, miR-200c-3p and miR-29b-3p common to tumor/urine. Significant associations were noted between the log-adjusted average miRNA counts in tumor vs. WBCs (r = 0.418 p < 0.001), and tumor vs. urine (r = 0.38 p < 0.001). No association was seen tumor vs. plasma exosome miRs (r = 0.07 p = 0.06). CONCLUSIONS: MicroRNA profiling from matched samples in patients shows a significant number of microRNAs up regulated in bladder tumors are identifiable in urine exosomes and WBCs of the same patient, but not in blood plasma. This study demonstrated varying relationships between miRNA detected in biological media from the same patient, and serves to inform the potential of urine-based microRNAs as biomarkers for bladder cancer and potentially other malignancies. PMID- 26576780 TI - Advances in ultrasound systems for hepatic lesions in Japan. PMID- 26576779 TI - First-in-human multicenter phase I study of BMS-936561 (MDX-1203), an antibody drug conjugate targeting CD70. AB - PURPOSE: The study evaluated the safety, tolerability, and pharmacokinetics of BMS-936561, a fully human monoclonal antibody-drug conjugate targeting CD70 cell surface protein. METHODS: Eligible patients had ECOG performance status 0-2 and received <=3 prior chemotherapy regimens. An initial accelerated titration design enrolling one patient per dose level was followed by 3 + 3 dose escalation with the first observation of a grade >=2 adverse event (AE). We tested escalating doses of BMS-936561 (0.5, 1, 2, 4, 8, 15 mg/kg) administered every 21 days in a 42 day cycle for a maximum of 17 cycles. Pharmacokinetic samples were collected in cycle 1. RESULTS: A total of 26 patients enrolled; 16 and 10 for the escalation and expansion cohorts, respectively. Median age was 63 years (48-74); 18 males and 25 Caucasians. There was no defined MTD per protocol, but a DLT of grade 3 hypersensitivity was recorded in 2 of 16 (13%) subjects at the highest dose of 15 mg/kg. The most frequent AEs were: fatigue (85%), nausea (54%), and decreased appetite (39%). Delayed toxicities (facial edema and pleural/pericardial effusions) occurred in 6 of 16 (38%) subjects at the 15 mg/kg dose. PK analysis showed a dose-proportional increase in active drug levels with increasing doses. There was disease stabilization in 18 of 26 patients (69%) without correlation with received dose. CONCLUSIONS: BMS-936561 is well tolerated over a wide range of doses in patients with advanced ccRCC and B-NHL. The 8 mg/kg dose was the highest best tolerated dose and the recommended dose for future studies. PMID- 26576781 TI - Elastic modulus of the femoral trochanteric region measured by scanning acoustic microscopy in elderly women. AB - PURPOSE: We have devised a method that can obtain continuous detailed distributions of the elastic modulus along the measurement line in a non decalcified specimen of human bone tissue. The aim of this study was to determine whether local variations exist in the distribution of mechanical properties within the trochanteric region of the femur of elderly females using a newly developed form of scanning acoustic microscopy (SAM) technology. METHODS: Human proximal femurs were harvested from seven female cadavers aged between 67 and 88 years at death. Using data collected with SAM, the elastic modulus of cortical and trabecular bone tissue of the lateral and medial trochanter was calculated and statistically analyzed. RESULTS: The longitudinal and transverse elastic moduli in cortical bone tissue of the lateral trochanter were found to be significantly lower than those of the medial trochanter in all specimens from individuals over age 70 (p < 0.05). Compared to that of the distal region, the longitudinal and transverse elastic moduli of trabecular bone tissue of the proximal region of the lateral trochanter were significantly lower in all specimens from individuals over age 80 (p < 0.05). CONCLUSION: Our new method allows obtaining detailed distributions of the elastic modulus of bone tissue. PMID- 26576782 TI - Estimation of in vivo cortical bone thickness using ultrasonic waves. AB - PURPOSE: To verify the measurement of cortical bone thickness at the distal radius in vivo using an ultrasonic method. METHODS: The method for estimating cortical bone thickness was derived from experiments with in vitro bovine specimens. Propagation time of echo waves and propagation time of slow waves were used for the estimation. The outside diameter of cortical bone and the cortical bone thickness at the distal 5.5 % site of radius were measured with the new ultrasonic bone measurement system, and the results were compared with X-ray pQCT clinical measurements. RESULTS: There was a high positive correlation (r: 0.76) between the cortical bone thickness measured by the new ultrasonic system and the X-ray pQCT results. CONCLUSION: We will be able to measure not only cancellous bone density but also cortical bone thickness in vivo using ultrasonic waves (without X-ray) safely and repeatedly. PMID- 26576783 TI - Temporal averaging of two-dimensional correlation functions for velocity vector imaging of cardiac blood flow. AB - PURPOSE: Ultrasonic imaging of blood flow in the cardiac lumen is a very useful tool to evaluate the pumping function of the human heart. The speckle tracking technique makes it possible to estimate the blood velocity vector. However, a stable estimation of the velocity vector of blood flow is difficult because signal-to-noise ratios of echoes from tiny blood particles are low. In this study, the speckle tracking technique with averaging of multiple two-dimensional correlation functions was employed for stable estimation of the blood velocity vector. METHODS: Multiple two-dimensional correlation functions can be averaged during a very short period by using the echo data acquired by high-frame-rate echocardiography with diverging beam transmission. A steady flow experiment using blood-mimicking fluid (mean fluid velocity 0.2 m/s, flow angle 56 degrees from the transducer surface) was implemented to investigate the effect of the averaging of two-dimensional correlation functions at a frame rate of 6024 Hz. RESULTS: First, to examine the averaging duration required for stable estimation of the flow velocity vector, the accuracies of vector estimates were evaluated at different durations for averaging of two-dimensional correlation functions in the steady flow measurement. It was found that the proposed averaging process with an averaging duration of over 8 frames could reduce the directional error in vector estimation to almost half that of the conventional speckle tracking technique. In subsequent experiments, the averaging duration was set at 12 frames corresponding to 2 ms. Measurements of steady flow at higher velocities were further implemented. The steady flow measurements with higher flow velocities of 0.4 and 0.6 m/s were simulated by changing the frame interval of the echo data at a flow velocity of 0.2 m/s. Although the averaging duration was a mere 2 ms, directional errors at mean flow velocities of 0.2, 0.4, and 0.6 m/s were reduced significantly. In an in vivo experiment of the healthy human heart, to produce a fine B-mode image, the diverging wave transmissions with different steered angles for compounding were interleaved in the transmission sequence. From the in vivo experimental result, the blood velocity vector of the left ventricular cavity showed the flow getting into/out of the cavity in ejection and early diastolic phases. Furthermore, estimated flow directions revealed rotating flow in the cavity in mid-diastole. CONCLUSION: Our proposed method has the feasibility to visualize the vortex flow by velocity vector mapping without a contrast agent. PMID- 26576784 TI - The lobar approach to breast ultrasound imaging and surgery. AB - Breast cancer is a lobar disease in the sense that, at the earliest stages, the cancer is structurally confined to a single sick lobe. The subgross morphology of breast carcinoma is often complex, as multiple invasive foci are frequently present and the ductal system often contains an extensive in situ component. Adequate preoperative visualization of all of the malignant structures within the affected breast and preoperative mapping of the lesions in relation to the surrounding normal structures are essential for successful image-guided breast surgery and therefore are key factors in assuring adequate local control of the disease. We advocate use of the lobar approach in ultrasound imaging (ducto radial echography) and breast-conserving surgery based on the lobar anatomy of the breast, the sick lobe theory, our extensive clinical experience with the approach, and favorable long-term patient outcomes. Despite abundant evidence demonstrating the advantages of the lobar approach, the number of breast centers using it in practice is still limited. In this review, we aim to call attention to the advantages of the lobar approach from the theoretical, imaging, and surgical points of view. PMID- 26576785 TI - The close linkage between the elasticity modulus measured by real-time mapping shear wave elastography and the presence of hepatocellular carcinoma in patients with a sustained virological response to interferon for chronic hepatitis C. AB - PURPOSE: Some patients develop hepatocellular carcinoma (HCC) after sustained virological response (SVR) to interferon therapy for chronic hepatitis C (CH-C). The aim of this study was to examine the linkage between liver elasticity and the presence/absence of HCC in patients after SVR. METHODS: We enrolled 42 patients who underwent real-time mapping shear wave elastography (SWE) after SVR to interferon therapy for CH-C. Of the 42 patients, six had HCC and 36 did not. We retrospectively compared the elasticity modulus and other clinical parameters between patients with and without HCC. RESULTS: Elasticity modulus measured by SWE, age, and serum albumin was significantly different between patients with and without HCC. Age, Fibrosis-4 index, serum gamma-globulin, total protein, and albumin levels were significantly correlated with the elasticity modulus. Areas under receiver operating characteristic curves of elasticity modulus, gamma globulin, and age for the presence of HCC were 0.963, 0.888, and 0.778, respectively. In patients with an elasticity modulus >=6.5 kPa, both sensitivity and specificity for the presence of HCC were 83.3 %. CONCLUSION: The study demonstrated the close linkage between the elasticity modulus measured by SWE and the presence of HCC in patients after SVR. PMID- 26576786 TI - Value of shear wave elastography for predicting hepatocellular carcinoma and esophagogastric varices in patients with chronic liver disease. AB - PURPOSE: To assess the value of shear wave elastography (SWE) for predicting the presence of hepatocellular carcinoma (HCC) and esophagogastric varices (EGV) in patients with chronic liver disease. METHODS: Liver tissue stiffness, as well as various other parameters potentially associated with HCC and portal hypertension, was measured by SWE in 273 patients with chronic liver disease. Among these patients, HCC was present in 89 and absent in 184, and EGV were present in 16 and absent in 257. The diagnostic performance of liver tissue stiffness and other clinical parameters in predicting the presence of HCC and EGV was evaluated using receiver operating characteristic (ROC) curves and the area under the ROC curve (AUROC). RESULTS: With regard to HCC, liver tissue stiffness was significantly higher in patients with HCC (18.65 +/- 10.78 kPa) than in those without HCC (10.64 +/- 8.04 kPa; P < 0.0001). Significant differences in patient age (P < 0.0001), albumin (P < 0.0001), platelet count (P < 0.0001), AFP (P < 0.0001), and DCP (P < 0.0001) were also observed between patients with and without HCC. Liver tissue stiffness showed the largest AUROC (0.791). With regard to EGV, liver tissue stiffness was significantly higher in patients with EGV (22.65 +/- 10.19 kPa) than in those without EGV (12.67 +/- 9.45 kPa; P < 0.0001). Significant differences in albumin (P < 0.0001) and platelet count (P < 0.0001) were also observed between patients with and without EGV. CONCLUSIONS: Liver tissue stiffness measured by SWE is an independent factor for predicting the presence of HCC and EGV in patients with chronic liver disease. PMID- 26576787 TI - Usefulness of ultrasonographic estimation of preperitoneal and subcutaneous fat thickness in the diagnosis of nonalcoholic fatty liver disease in diabetic patients. AB - PURPOSE: Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) have been regarded as the hepatic manifestation of metabolic syndrome. Abdominal wall fat index (AFI), defined as the ratio of preperitoneal and subcutaneous fat thickness in the abdomen estimated by ultrasonography (US), has been shown to be useful in screening for disorders related to metabolic syndrome. We investigated the relation between AFI and NAFLD/NASH in diabetic patients. METHODS: The degree of fat accumulation in the liver and the thickness of preperitoneal and subcutaneous fat were determined by US in 340 diabetic patients. An NAFLD fibrosis score (NAFLD-FS) was used to assess the advancement of hepatic fibrosis in NAFLD patients. RESULTS: Of all 340 subjects, 209 (61 %) were diagnosed with NAFLD by US. AFI of NAFLD subjects was significantly higher than that of non-NAFLD subjects. Of the 209 subjects with NAFLD, 31 (15 %) were shown to have advanced NASH fibrosis according to NAFLD-FS. Multivariate analysis identified AFI as a significant predictor of advanced fibrosis. CONCLUSION: AFI easily obtained by US was significantly related to the presence of NAFLD and/or advanced hepatic fibrosis in diabetic patients. PMID- 26576788 TI - Stereoscopic images of breast tumors using 3D real-time tissue elastography. AB - PURPOSE: This study aimed at evaluating the usefulness of 3D real-time tissue elastography (RTE) images for diagnosing breast tumors. METHODS: A total of 166 breast tumor patients who underwent conventional ultrasound and 2D and 3D RTE examinations were retrospectively analyzed. The 3D RTE images were divided into three types according to the occupancy of blue contrast images. Elastic scores (ES) were obtained by 2D RTE examination. The diagnostic accuracy of 3D and 2D RTE images in differentiating malignant from benign breast tumors was evaluated. RESULTS: Of all cases, 89.4 % of the malignant cases were Type 3 and 86.6 % of the benign cases were Type 1 or 2 according to 3D RTE images. 3D RTE Type 3 and ES >= 4 on 2D RTE examination diagnosed malignant tumors with an accuracy of 87.4 and 88.6 %, respectively. In addition, among 34 patients with an ES of 3, the presence of 3D RTE Type 3 diagnosed malignant tumors with an accuracy of 82.4 %. CONCLUSION: In this study, the utility of 3D RTE images was comparable to that of ES on 2D RTE examination in differentiating malignant from benign breast tumors. In addition, utilizing 3D RTE images in cases with an ES of 3 on 2D RTE may increase the diagnostic accuracy for breast tumors. PMID- 26576789 TI - Translabial three-dimensional ultrasound investigation of the levator hiatus in postpartum women. AB - PURPOSE: This study utilized translabial three-dimensional ultrasound to investigate the morphological characteristics of the levator hiatus and provide sonographic evidence for assessing pelvic floor dysfunction in postpartum women. METHODS: Two-hundred and one singleton primiparae without any complications underwent translabial three-dimensional ultrasound at 6 and 18 weeks after delivery, with 12 participants lost to follow-up at 18 weeks. Fifty nulliparae were enrolled as the control group. Levator hiatal morphology at rest and on Valsalva maneuver was assessed by experienced sonographers, specifically evaluating the anteroposterior diameter, left-to-right diameter, and area. RESULTS: In postpartum women at 6 weeks after delivery, all the levator hiatal parameters were significantly higher compared with those of the control group. At 18 weeks, the hiatal parameters were better than at 6 weeks but still higher than in the nulliparous controls. In all three groups, the hiatal parameters were significantly higher during the Valsalva maneuver than at rest. CONCLUSIONS: Postpartum women are prone to develop pelvic floor dysfunction as shown by an enlarged levator hiatus. Translabial three-dimensional ultrasound can be used to effectively assess the morphology and structural alterations of the levator hiatus in postpartum women, providing reliable pelvic floor imaging for early screening, diagnosis, and prevention of pelvic floor dysfunction. PMID- 26576790 TI - Real-time tissue sonoelastography for early response monitoring in cervical cancer patients treated with definitive chemoradiotherapy: preliminary results. AB - PURPOSE: To investigate the utility of real-time sonoelastography (RTE) for predicting treatment response during the course of definitive radiotherapy in patients with cervical cancer. METHODS: Cervical cancer patients were prospectively evaluated with RTE by a single operator during the course of definitive radiotherapy to analyze the associations between the change in their tumor's strain ratio (SR) and the treatment response. RESULTS: The SR of the cervical tumors was significantly higher than that of the normal cervical tissue (mean 3.8 vs 1.2; median 3.4 vs 1.1, p < 0.01). Treating the cervical tumors with definitive radiotherapy significantly reduced their SR to the same level as the normal cervix among patients who achieved a complete response to definitive radiotherapy. In contrast, among patients who developed residual disease after radiotherapy, the SR of the tumor did not decrease significantly after definitive radiotherapy. Moreover, the reduction in the tumor SR detected by RTE preceded the reduction in tumor volume as assessed by transvaginal ultrasonography. CONCLUSION: RTE is a rapid and effective method for predicting treatment response during the course of definitive radiotherapy, potentially facilitating early and personalized treatment adaptation in patients with cervical cancer. PMID- 26576791 TI - Quantitative cervical elastography during pregnancy: influence of setting features on strain calculation. AB - AIM: To evaluate the influence on feasibility and reliability of quantitative tissue Doppler imaging (TDI)-based cervical elastography of the cycle phase and of the derivative pitch (DP) selected during tissue strain (TS) calculation across all three trimesters of pregnancy. MATERIALS AND METHODS: The pilot study included 17 patients collected between the 12th and the 42nd week of gestation. The TS was measured by a single operator by quantitative elastography. The influence of DP values (5, 10, 15, and 20 mm) and phase (compression versus relaxation) was tested after a cycle of freehand compression and relaxation of the cervix through the vaginal probe. Feasibility and intra-operator intraclass correlation coefficient (ICC) agreement for strain measurement were also evaluated for every setting used. RESULTS: TS values were inversely correlated with DP and were slightly higher if measured during a compression phase. TDI based cervical elastography was feasible in all cases. Reliability for the process of strain calculation of different raw datasets was very good (ICC agreement ranging between 0.79 and 0.87), while excellent considering the same raw dataset (ICC agreement ranging between 0.93 and 0.95). CONCLUSIONS: The DP and cycle phase influenced the strain values calculated. Nonetheless, TDI-based cervical elastography was feasible and reliable for all the settings considered. PMID- 26576792 TI - Evaluation of the thickness of the medial ulnar collateral ligament in junior high and high school baseball players. AB - BACKGROUND: Thickening of the medial ulnar collateral ligament in the throwing arm of adult baseball players is a well-known phenomenon. However, onset of the thickening is unclear among young baseball players. The purpose of this study was to evaluate the thickness of the medial ulnar collateral ligament in junior high and high school baseball players. SUBJECTS AND METHODS: Seventy-one uninjured and asymptomatic junior high and high school baseball players were included in the study. Participants underwent physical examination after completing a questionnaire, followed by ultrasonographic evaluation. The thickness of the medial ulnar collateral ligament was measured bilaterally. The thickness of the throwing and non-throwing sides in high school and junior high school baseball players, and within each group, was compared and statistically analyzed. RESULTS: The medial ulnar collateral ligament in the throwing arm of high school baseball players was thicker than that in the non-throwing arm (5.5 vs. 4.4 mm), although no significant difference was seen in junior high school baseball players. High school baseball players showed a significantly thicker medial ulnar collateral ligament in the throwing arm than junior high school baseball players. CONCLUSION: Thickening of the medial ulnar collateral ligament in the throwing arm of asymptomatic and uninjured baseball players may begin by the time the players reach high school. PMID- 26576793 TI - Bioprosthetic tricuspid valve replacement in carcinoid heart disease from primary ovarian carcinoid tumor. AB - Carcinoid heart disease (CHD) commonly occurs in association with primary gastrointestinal tract carcinoid tumors with hepatic metastases. Unlike primary gastrointestinal tract carcinoid tumors, primary ovarian carcinoid tumors may cause CHD without hepatic metastases, accounting for only 0.3 % of all carcinoid tumors. Only 37 cases of CHD from primary ovarian carcinoid tumors have been reported. We present a case of CHD in which tricuspid valve thickening and shortening led to reduced valve mobility with the resulting severe tricuspid regurgitation. Considering these characteristics of an abnormal tricuspid valve, we suspected CHD, but prosthetic valve replacement was performed without sufficient systemic examination before surgery. Two years after valve replacement, the patient underwent excision of a mass in the lower abdomen, which was diagnosed as an ovarian carcinoid tumor by histopathological examination. The patient has been observed for more than 3 years after tricuspid valve replacement. She has not experienced bioprosthetic valve leaflet degeneration or dysfunction, although it has been reported that bioprosthetic valves may degenerate in patients with carcinoid tumors. Sufficient systemic examinations should be performed to explore the cause of disease. PMID- 26576794 TI - A case of a pancreatic tumor that was diagnosed as metastasis from lung cancer by endoscopic ultrasound-guided fine needle aspiration. AB - Metastatic tumors are rare in the pancreas, and some cases are difficult to distinguish from pancreatic cancer. However, distinguishing between them is very important to formulate a treatment plan. A case of a rare disease, called overlap cancer, involving metastatic tumors to the pancreas and right kidney from lung cancer, and duodenal papilla cancer, is described. Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is useful for diagnosing metastatic pancreatic tumors, particularly in patients with multiple cancers. PMID- 26576795 TI - Multiple cystic lymphangiomas of the spleen: radiologic and histopathologic findings. AB - Splenic cyst(s) may be noted as an incidental finding on conventional imaging techniques, or as a result of evaluation of a patient with left upper quadrant pain, left shoulder pain, abdominal enlargement, or splenomegaly. Lymphangioma of the spleen is an extremely rare and benign neoplasm in adults, which is characterized by cystic dilatation of the lymphatic vessels in splenic parenchyma. This report describes a case of multiple splenic lymphangiomas in a 41-year-old female. She underwent abdominal ultrasonography for a health check up. She had no symptoms, and physical examination did not reveal any abnormalities apart from splenomegaly. Ultrasonography and computed tomography showed multiple variable-sized cysts replacing the normal parenchyma of the spleen. There were wall calcifications in several cysts. The patient underwent laparoscopic splenectomy, and the final diagnosis was multiple lymphangiomas of the spleen. PMID- 26576796 TI - Wandering spleen with volvulus of pancreas. AB - Abnormal location of the spleen, which is called wandering spleen, results from laxity or absence of the splenic pedicle. In the presence of an elongated splenic pedicle, torsion of the spleen or neighboring organs may occur, which results in acute or chronic abdominal pain. In this case report, we present imaging findings of a wandering spleen that manifested with volvulus of the pancreas. PMID- 26576797 TI - Ultrasonographic and non-enhanced CT features of acute transient thyroid swelling following fine-needle aspiration biopsy: report of four cases. AB - We report four cases of acute transient thyroid swelling following fine-needle aspiration biopsy, a rare complication of still unknown origin. The ultrasonographic pattern was fairly similar to that in previous reports: swelling of the thyroid with a patchy and heterogeneous appearance and diffusely scattered hypoechoic "cracks" that showed no blood flow signals with color Doppler ultrasound. There were also some features that differed from those in previous reports. Though thyroid swelling is typically diffuse and bilateral, it was unilateral or asymmetrical in some of our cases. While thyroid swelling is said to resolve spontaneously within 1-20 h, abnormal ultrasonographic findings persisted for more than 48 h in one case. Unlike previous reports, we have experienced cases with ultrasonographic findings of concomitant minor subcapsular hematomas. In one case, CT demonstrated not only thyroid swelling but also abnormal attenuation in perithyroid tissue extending to the retro-hypopharyngeal space and to the paraesophageal mediastinum. Although vasodilatation and diffuse vascular leakage are speculated to be the underlying mechanisms, our ultrasonograms at the time of the complication failed to demonstrate enlarged intrathyroidal vessels or hypervascularity with color Doppler ultrasound. More awareness and a description of the cases may help to clarify the pathogenesis of this self-limited complication. PMID- 26576798 TI - Spontaneous regression of breast angiosarcoma after conservative treatment with radiotherapy: a case report and review of the literature. AB - Angiosarcoma of the breast is a rare disease, and approximately 1 % of all affected patients are treated with breast-conserving therapy (BCT) and radiotherapy (RT) for primary breast cancer. The prognosis for this tumor is quite dismal, with high rates of recurrence and poor overall survival. This report presents the case of a 73-year-old female who underwent BCT followed by RT for left breast carcinoma 18 years previously. The patient visited the hospital with a complaint of a new mass in the left breast. The lesion initially decreased in size; however, it subsequently began to rapidly enlarge. A core needle biopsy of the mass was performed under ultrasonography, with a diagnosis of a spindle cell sarcoma, most conceivably an angiosarcoma, originating from the left breast, suspected to be induced by RT. The tumor was resected with the surrounding skin, and immunohistochemically diagnosed as angiosarcoma of the left breast, without evidence of breast cancer in any lesion, suggesting that RT induced the tumor formation. We herein report this rare case and the ultrasound imaging findings. PMID- 26576799 TI - High-flow vascular malformation treatment using ultrasound-guided laser combined with polidocanol sclerotherapy. AB - The current treatment for vascular malformations includes surgery, sclerotherapy, and embolization. However, each method has its limitations, such as recurrence, complications, scarring, and radiation exposure. Therefore, identifying an effective, minimally invasive treatment that reduces lesion recurrence is particularly important. We describe in detail a patient who received treatment with ultrasound-guided laser interruption of feeding vessels combined with polidocanol sclerotherapy after the recurrence of forearm high-flow vascular malformation. PMID- 26576800 TI - Recurrent juvenile ischemic stroke caused by bow hunter's stroke revealed by carotid duplex ultrasonography. AB - Bow hunter's stroke (BHS) is a rare cause of vertebrobasilar insufficiency due to rotational vertebral artery (VA) occlusion associated with head turning. We report a juvenile patient presenting with recurrent ischemic stroke caused by BHS, which was revealed by carotid duplex ultrasonography. Carotid duplex ultrasonography performed in the neutral position showed normal findings. However, disappearance of end-diastolic blood flow of contralateral VAs was observed with head rotation. Digital subtraction angiography confirmed occlusion at C1/2 levels in the VA contralateral to the head rotation, bilaterally. Importantly, our patient did not recognize the association of head rotation and previous episodes of stroke. We suggest that BHS should be considered in patients with cryptogenic stroke occurring in the vertebrobasilar artery territory. PMID- 26576801 TI - Two- and three-dimensional sonographic diagnosis of multiple pregnancies (sextuplets). PMID- 26576802 TI - Intracranial sonographic features demonstrating in utero development of hemorrhagic brain damage leading to schizencephaly-associated COL4A1 mutation. PMID- 26576803 TI - Time to see the bigger picture: Individual differences in the attentional blink. AB - If two to-be-identified targets are presented in close temporal succession, identification for the second target is typically impaired. This attentional blink (AB) phenomenon has long been considered as a robust, universal cognitive limitation. However, more recent studies have demonstrated that AB task performance greatly differs between individuals, with some individuals even showing no AB in certain paradigms. Several studies have focused on these individual differences in an attempt to reveal the mechanism underlying the AB, but an overview of this approach is currently missing. Here, by reviewing studies regarding individual differences in AB task performance, we investigate how individual differences have contributed to our understanding of the AB. We show that the individual differences AB literature provides reliable indications that the AB is a multifaceted phenomenon that presumably arises from a combination of factors; individuals with higher levels of executive working memory (WM) functioning and broad attentional focus perform better in the AB paradigm than individuals with lower executive functioning of WM and narrow attentional focus. As it turns out, seeing the bigger picture certainly seems helpful for AB task performance. PMID- 26576804 TI - Is sleep deprivation a contributor to obesity in children? AB - Chronic lack of sleep (called "sleep deprivation") is common in modern societies with 24/7 availability of commodities. Accumulating evidence supports the role of reduced sleep as contributing to the current obesity epidemic in children and youth. Longitudinal studies have consistently shown that short sleep duration is associated with weight gain and the development of obesity. Recent experimental studies have reported that sleep restriction leads to weight gain in humans. Increased food intake appears to be the main mechanism by which insufficient sleep results in weight gain. Voluntary sleep restriction has been shown to increase snacking, the number of meals eaten per day, and the preference for energy-dense foods. Although the causes of sleep loss in the pediatric population are numerous, more research looking at screen exposure before bedtime and its effects on sleep is needed given the pervasiveness of electronic media devices in today's environment. Health professionals should routinely ask questions about sleep and promote a good night's sleep because insufficient sleep impacts activity and eating behaviors. Future research should examine the clinical benefits of increasing sleep duration on eating behaviors and body weight control and determine the importance of adequate sleep to improve the treatment of obesity. PMID- 26576805 TI - Sleep and obesity: an introduction. PMID- 26576806 TI - Observational, longitudinal study of delirium in consecutive unselected acute medical admissions: age-specific rates and associated factors, mortality and re admission. AB - OBJECTIVES: We aimed to determine age-specific rates of delirium and associated factors in acute medicine, and the impact of delirium on mortality and re admission on long-term follow-up. DESIGN: Observational study. Consecutive patients over two 8-week periods (2010, 2012) were screened for delirium on admission, using the confusion assessment method (CAM), and reviewed daily thereafter. Delirium diagnosis was made using the Diagnostic and Statistical Manual Fourth Edition (DSM IV) criteria. For patients aged >=65 years, potentially important covariables identified in previous studies were collected with follow-up for death and re-admission until January 2014. PARTICIPANTS: 503 consecutive patients (age median=72, range 16-99 years, 236 (48%) male). SETTING: Acute general medicine. RESULTS: Delirium occurred in 101/503 (20%) (71 on admission, 30 during admission, 17 both), with risk increasing from 3% (6/195) at <65 years to 14% (10/74) for 65-74 years and 36% (85/234) at >=75 years (p<0.0001). Among 308 patients aged >65 years, after adjustment for age, delirium was associated with previous falls (OR=2.47, 95% CI 1.45 to 4.22, p=0.001), prior dementia (2.08, 1.10 to 3.93, p=0.024), dependency (2.58, 1.48 to 4.48, p=0.001), low cognitive score (5.00, 2.50 to 9.99, p<0.0001), dehydration (3.53, 1.91 to 6.53, p<0.0001), severe illness (1.98, 1.17 to 3.38, p=0.011), pressure sore risk (5.56, 2.60 to 11.88, p<0.0001) and infection (4.88, 2.85 to 8.36, p<0.0001). Patients with delirium were more likely to fall (OR=4.55, 1.47 to 14.05, p=0.008), be incontinent of urine (3.76, 2.15 to 6.58, p<0.0001) or faeces (3.49, 1.81-6.73, p=0.0002) and be catheterised (5.08, 2.44 to 10.54, p<0.0001); and delirium was associated with stay >7 days (2.82, 1.68 to 4.75, p<0.0001), death (4.56, 1.71 to 12.17, p=0.003) and an increase in dependency among survivors (2.56, 1.37 to 4.76, p=0.003) with excess mortality still evident at 2-year follow-up. Patients with delirium had fewer re-admissions within 30-days (OR=0.32, 95% CI 0.09 to 1.1, p=0.07) and in total (median, IQR total re admissions=0, 0-1 vs 1, 0-2, p=0.01). CONCLUSIONS: Delirium affected a fifth of acute medical admissions and a third of those aged >=75 years, and was associated with increased mortality, institutionalisation and dependency, but not with increased risk of re-admission on follow-up. PMID- 26576807 TI - Open three-stage transthoracic oesophagectomy versus minimally invasive thoraco laparoscopic oesophagectomy for oesophageal cancer: protocol for a multicentre prospective, open and parallel, randomised controlled trial. AB - INTRODUCTION: Oesophageal cancer is the eighth most common cause of cancer worldwide. In 2009 in China, the incidence and death rate of oesophageal cancer was 22.14 per 100 000 person-years and 16.77 per 100 000 person-years, respectively, the highest in the world. Minimally invasive oesophagectomy (MIO) was introduced into clinical practice with the aim of reducing the morbidity rate. The mechanisms of MIO may lie in minimising the reaction to surgical injury and inflammation. There are some randomised trials regarding minimally invasive versus open oesophagectomy, with 100-850 subjects enrolled. To date, no large randomised controlled trial comparing minimally invasive versus open oesophagectomy has been reported in China, where squamous cell carcinoma predominated over adenocarcinoma of the oesophagus. METHODS AND ANALYSIS: This is a 3 year multicentre, prospective, randomised, open and parallel controlled trial, which aims to compare the effectiveness of minimally invasive thoraco laparoscopic oesophagectomy to open three-stage transthoracic oesophagectomy for resectable oesophageal cancer. Group A patients receive MIO which involves thoracoscopic oesophagectomy and laparoscopic gastric mobilisation with cervical anastomosis. Group B patients receive the open three-stage transthoracic oesophagectomy which involves a right thoracotomy and laparotomy with cervical anastomosis. Primary endpoints include respiratory complications within 30 days after operation. The secondary endpoints include other postoperative complications, influences on pulmonary function, intraoperative data including blood loss, operative time, the number and location of lymph nodes dissected, and mortality in hospital, the length of hospital stay, total expenses in hospital, mortality within 30 days, survival rate after 2 years, postoperative pain, and health-related quality of life (HRQoL). Three hundred and twenty-four patients in each group will be needed and a total of 648 patients will finally be enrolled into the study. ETHICS AND DISSEMINATION: The study protocol has been approved by the Institutional Ethics Committees of all participating institutions. The findings of this trial will be disseminated to patients and through peer-reviewed publications and international presentations. TRIAL REGISTRATION NUMBER: NCT02355249. PMID- 26576808 TI - The BMEA study: the impact of meridian balanced method electroacupuncture on women with chronic pelvic pain-a three-arm randomised controlled pilot study using a mixed-methods approach. AB - INTRODUCTION: Chronic pelvic pain (CPP) affects 3-4% of women worldwide. Proven treatments for CPP are limited and unsatisfactory. The meridian balance method (BM) electroacupuncture (EA) treatment (BMEA + Traditional Chinese Medicine Health Consultation (TCM HC) may be effective for CPP. Previous EA studies have demonstrated an analgesic effect. Large-scale studies on acupuncture for other chronic pain conditions suggest that patient-healthcare provider interaction might play a role in pain reduction. We propose a pilot study to explore the effectiveness of the meridian BMEA treatment in managing women with CPP to inform a future large randomised controlled trial. METHODS AND ANALYSIS: A 3-armed randomised controlled pilot study is proposed with an aim to recruit 30 women with CPP in National Health Service (NHS) Lothian. Randomisation will be to BMEA treatment, TCM HC or standard care (SC). Validated pain, physical and emotional functioning questionnaires will be administered to all participants at weeks 0, 4, 8 and 12. Focus group discussions will be conducted when week 12 questionnaires are completed. The primary objective is to determine, recruitment and retention rates. The secondary objectives are to assess the effectiveness and acceptability of the proposed methods of recruitment, randomisation, interventions and assessment tools. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Scotland Research Ethics Committee (REC 14/SS/1022). Data will be published in peer-reviewed journals and presented at international conferences. TRIAL REGISTRATION NUMBER: NCT02295111. PMID- 26576809 TI - Barriers and enablers to healthcare access and use among Arabic-speaking and Caucasian English-speaking patients with type 2 diabetes mellitus: a qualitative comparative study. AB - OBJECTIVE: The objective of this study was to explore the decision-making processes and associated barriers and enablers that determine access and use of healthcare services in Arabic-speaking and English-speaking Caucasian patients with diabetes in Australia. STUDY SETTING AND DESIGN: Face-to-face semistructured individual interviews and group interviews were conducted at various healthcare settings-diabetes outpatient clinics in 2 tertiary referral hospitals, 6 primary care practices and 10 community centres in Melbourne, Australia. PARTICIPANTS: A total of 100 participants with type 2 diabetes mellitus were recruited into 2 groups: 60 Arabic-speaking and 40 English-speaking Caucasian. DATA COLLECTION: Interviews were audio-taped, translated into English when necessary, transcribed and coded thematically. Sociodemographic and clinical information was gathered using a self-completed questionnaire and medical records. PRINCIPAL FINDINGS: Only Arabic-speaking migrants intentionally delayed access to healthcare services when obvious signs of diabetes were experienced, missing opportunities to detect diabetes at an early stage. Four major barriers and enablers to healthcare access and use were identified: influence of significant other(s), unique sociocultural and religious beliefs, experiences with healthcare providers and lack of knowledge about healthcare services. Compared with Arabic-speaking migrants, English-speaking participants had no reluctance to access and use medical services when signs of ill-health appeared; their treatment-seeking behaviours were straightforward. CONCLUSIONS: Arabic-speaking migrants appear to intentionally delay access to medical services even when symptomatic. Four barriers to health services access have been identified. Tailored interventions must be developed for Arabic-speaking migrants to improve access to available health services, facilitate timely diagnosis of diabetes and ultimately to improve glycaemic control. PMID- 26576810 TI - Preoperative factors affecting cost and length of stay for isolated off-pump coronary artery bypass grafting: hierarchical linear model analysis. AB - OBJECTIVE: To determine the effect of preoperative patient and hospital factors on resource use, cost and length of stay (LOS) among patients undergoing off-pump coronary artery bypass grafting (OPCAB). DESIGN: Observational retrospective study. SETTINGS: Data from the Japanese Administrative Database. PARTICIPANTS: Patients who underwent isolated, elective OPCAB between April 2011 and March 2012. PRIMARY OUTCOME MEASURES: The primary outcomes of this study were inpatient cost and LOS associated with OPCAB. A two-level hierarchical linear model was used to examine the effects of patient and hospital characteristics on inpatient costs and LOS. The independent variables were patient and hospital factors. RESULTS: We identified 2491 patients who underwent OPCAB at 268 hospitals. The mean cost of OPCAB was $40 665 +/-7774, and the mean LOS was 23.4+/-8.2 days. The study found that select patient factors and certain comorbidities were associated with a high cost and long LOS. A high hospital OPCAB volume was associated with a low cost (-6.6%; p=0.024) as well as a short LOS (-17.6%, p<0.001). CONCLUSIONS: The hospital OPCAB volume is associated with efficient resource use. The findings of the present study indicate the need to focus on hospital elective OPCAB volume in Japan in order to improve cost and LOS. PMID- 26576811 TI - What's in a name? The challenge of describing interventions in systematic reviews: analysis of a random sample of reviews of non-pharmacological stroke interventions. AB - OBJECTIVE: To assess, in a sample of systematic reviews of non-pharmacological interventions, the completeness of intervention reporting, identify the most frequently missing elements, and assess review authors' use of and beliefs about providing intervention information. DESIGN: Analysis of a random sample of systematic reviews of non-pharmacological stroke interventions; online survey of review authors. DATA SOURCES AND STUDY SELECTION: The Cochrane Library and PubMed were searched for potentially eligible systematic reviews and a random sample of these assessed for eligibility until 60 (30 Cochrane, 30 non-Cochrane) eligible reviews were identified. DATA COLLECTION: In each review, the completeness of the intervention description in each eligible trial (n=568) was assessed by 2 independent raters using the Template for Intervention Description and Replication (TIDieR) checklist. All review authors (n=46) were invited to complete a survey. RESULTS: Most reviews were missing intervention information for the majority of items. The most incompletely described items were: modifications, fidelity, materials, procedure and tailoring (missing from all interventions in 97%, 90%, 88%, 83% and 83% of reviews, respectively). Items that scored better, but were still incomplete for the majority of reviews, were: 'when and how much' (in 31% of reviews, adequate for all trials; in 57% of reviews, adequate for some trials); intervention mode (in 22% of reviews, adequate for all trials; in 38%, adequate for some trials); and location (in 19% of reviews, adequate for all trials). Of the 33 (71%) authors who responded, 58% reported having further intervention information but not including it, and 70% tried to obtain information. CONCLUSIONS: Most focus on intervention reporting has been directed at trials. Poor intervention reporting in stroke systematic reviews is prevalent, compounded by poor trial reporting. Without adequate intervention descriptions, the conduct, usability and interpretation of reviews are restricted and therefore, require action by trialists, systematic reviewers, peer reviewers and editors. PMID- 26576812 TI - Trends in clinical development timeframes for antiviral drugs launched in the UK, 1981-2014: a retrospective observational study. AB - OBJECTIVES: Recent decades have witnessed the development of highly innovative new antiviral drug therapies. However, there are concerns that rising costs and lengthening development times could have implications for future patient access to innovative new drugs. We sought to establish whether the time taken for the clinical development of new antiviral drugs launched in the UK had increased since the 1980s. DESIGN AND SETTING: Retrospective observational study of all new antiviral drugs licensed for use in the UK. PRIMARY AND SECONDARY OUTCOME MEASURES: Duration of clinical development (from initiation of studies in humans to receipt of Marketing Authorisation), subdivided into clinical trial and regulatory approval periods by the date of Marketing Authorisation Application. RESULTS: 48 new antiviral drugs were licensed for use in the UK between 1981 and 2014 (inclusive), over half (54%) initially for HIV infection. The overall mean duration of clinical development was 77.2 months, of which 64.6 months was spent in clinical trials before regulatory submission. The total time in clinical development increased from 41.7 months for drugs licensed 1981-1992 to 91.7 months for drugs licensed 2004-2014. This increase was accounted for by an increase in the clinical trials period and not the regulatory approval period, for which there was no observable trend. Drugs initially licensed to treat hepatitis C had a longer duration of clinical development than those indicated for other viral infections. However, the, initially shorter clinical development durations of drugs indicated for HIV infection increased more rapidly across the study period than those indicated for other viral infections. CONCLUSIONS: The time spent by antiviral drugs in clinical development has increased markedly in recent decades despite many initiatives to speed access to innovative new drugs. However, this represents only one part of the translational research pathway, and a complete picture of development timeframes is lacking. PMID- 26576813 TI - Potential for the use of mHealth in the management of cardiovascular disease in Kerala: a qualitative study. AB - OBJECTIVES: To assess the potential for using mHealth in cardiovascular disease (CVD) management in Kerala by exploring: (1) experiences and challenges of current CVD management; (2) current mobile phone use; (3) expectations of and barriers to mobile phone use in CVD management. DESIGN: Qualitative, semistructured, individual interviews. SETTING: 5 primary health centres in Ernakulam district, Kerala, India. PARTICIPANTS: 15 participants in total from 3 stakeholder groups: 5 patients with CVD and/or its risk factors, 5 physicians treating CVD and 5 Accredited Social Health Activists (ASHAs). Patients were sampled for maximum variation on the basis of age, sex, CVD diagnoses and risk factors. All participants had access to a mobile phone. RESULTS: The main themes identified relating to the current challenges of CVD were poor patient disease knowledge, difficulties in implementing primary prevention and poor patient lifestyles. Participants noted phone calls as the main function of current mobile phone use. The expectations of mHealth use are to: improve accessibility to healthcare knowledge; provide reminders of appointments, medication and lifestyle changes; save time, money and travel; and improve ASHA job efficacy. All perceived barriers to mHealth were noted within physician interviews. These included fears of mobile phones negatively affecting physicians' roles, the usability of mobile phones, radiation and the need for physical consultations. CONCLUSIONS: There are three main potential uses of mHealth in this population: (1) as an educational tool, to improve health education and lifestyle behaviours; (2) to optimise the use of limited resources, by overcoming geographical barriers and financial constraints; (3) to improve use of healthcare, by providing appointment and treatment reminders in order to improve disease prevention and management. Successful mHealth design, which takes barriers into account, may complement current practice and optimise use of limited resources. PMID- 26576814 TI - Reasons and remedies for under-representation of women in medical leadership roles: a qualitative study from Australia. AB - OBJECTIVE: To elicit medical leaders' views on reasons and remedies for the under representation of women in medical leadership roles. DESIGN: Qualitative study using semistructured interviews with medical practitioners who work in medical leadership roles. Interviews were transcribed verbatim and transcripts were analysed using thematic analysis. SETTING: Public hospitals, private healthcare providers, professional colleges and associations and government organisations in Australia. PARTICIPANTS: 30 medical practitioners who hold formal medical leadership roles. RESULTS: Despite dramatic increases in the entry of women into medicine in Australia, there remains a gross under-representation of women in formal, high-level medical leadership positions. The male-dominated nature of medical leadership in Australia was widely recognised by interviewees. A small number of interviewees viewed gender disparities in leadership roles as a 'natural' result of women's childrearing responsibilities. However, most interviewees believed that preventable gender-related barriers were impeding women's ability to achieve and thrive in medical leadership roles. Interviewees identified a range of potential barriers across three broad domains-perceptions of capability, capacity and credibility. As a counter to these, interviewees pointed to a range of benefits of women adopting these roles, and proposed a range of interventions that would support more women entering formal medical leadership roles. CONCLUSIONS: While women make up more than half of medical graduates in Australia today, significant barriers restrict their entry into formal medical leadership roles. These constraints have internalised, interpersonal and structural elements that can be addressed through a range of strategies for advancing the role of women in medical leadership. These findings have implications for individual medical practitioners and health services, as well as professional colleges and associations. PMID- 26576815 TI - 'Klar bleiben': a school-based alcohol prevention programme for German adolescents-study protocol for a cluster randomised controlled trial. AB - INTRODUCTION: There is a noticeable increase in hazardous alcohol use during adolescence, which is significantly associated with adverse consequences. In Germany, up to 30% of adolescents report regular heavy episodic drinking. However, only a few German prevention programmes target adolescents of legal drinking age (16 years and above); thus, this trial aims to develop, implement and evaluate 'Klar bleiben' ('Stay clearheaded'), a school-based prevention programme for grade 10 students. METHODS AND ANALYSIS: 'Klar bleiben' consists of a class commitment to drink responsibly and refrain from hazardous consumption patterns for 9 weeks. The commitment is accompanied by educational lessons on alcohol-related cognitions and consequences. It will be evaluated in a sample of approximately 3000 students (150 classes) from two German federal states (Schleswig-Holstein and Lower Saxony) via a two-armed cluster randomised controlled trial with baseline and postassessment 6 months apart. The intervention group (75 classes) will participate in 'Klar bleiben', whereas the control group (75 classes) will receive education as usual. 'Klar bleiben' addresses classes, individuals, teachers and parents. It is based on a social norms approach and aims to reduce hazardous drinking and drinking-related consequences in adolescents. Secondary outcomes include general drinking behaviour, use of other substances, alcohol-related cognitions and social factors. Covariates include sociodemographic characteristics, environmental and individual (vulnerability) factors. ETHICS AND DISSEMINATION: 'Klar bleiben' provides a multicomponent school-based programme that bridges a gap in alcohol prevention. Similar class-level and social norms-based prevention programmes have already been proven to be successful for other substances among adolescents. Thus, dissemination to other federal states as well as longer term follow-up testing of the robustness of effects is to be anticipated. The study was approved by the Ethics Committee of the German Psychological Society (RH_0620152), and study findings will be disseminated through peer-reviewed publications and conference contributions. TRIAL REGISTRATION NUMBER: German Clinical Trials Register: DRKS00009424. PMID- 26576816 TI - Prepared for what? addressing the disaster readiness gap beyond preparedness for survival. AB - BACKGROUND: Conventional disaster preparedness messaging focuses largely on promoting survival actions and communications planning for the immediate post disaster period. While such preparedness is vital, we have long-observed a gap in preventive medicine and disaster planning for building personal resilience- preventatively--to persevere through prolonged recovery timeframes. There are many helpful attitudes and behaviors that people can develop to increase their readiness and capacity for drastic life changes, encompassing not only health protective preparedness actions but health-promoting attitudes for "minding the risk" and "practicing resilience" as well. For instance, quality of life assessments and well-being interventions are widely-known for the clinically significant improvements they can produce in patient-reported outcomes. Similarly, health promotion interventions are implemented preventatively when a risk is identified yet a disease is not present, and can provide health benefits throughout people's lives, regardless of the type of adversities they eventually encounter (medical, environmental, or other). DISCUSSION: We argue there is an overlooked opportunity to leverage well-being theories and methods from clinical settings and public health practice for the purpose of preventatively boosting disaster readiness and bolstering capacity for long-term resilience. We also highlight our previously-published research indicating a role for integrating personal meaning into preparedness messages. This is an opportune time for applying well-being concepts and practices as tools for developing disaster readiness, as risk awareness grows through real-time tracking of hazardous events via social media. For example, two sudden-onset disasters occurred within ten days of each other in 2014 and caught worldwide attention for their extreme hazards, despite dramatic differences in scale. The 22 March 2014 landslide tragedy in Washington State, USA, and the 1 April 2014 Chilean earthquake and Pacific-wide tsunami alerts brought home how persistently vulnerable we all are, and how developing intrinsic personal readiness for scientifically-known risks before disaster unfolds is essential policy. Gap programming that addresses personal readiness challenges in prevention timeframes could save lives and costs. We contend that bridging this readiness gap will prevent situations where people, communities, and systems survive the initial impact, but their resilience trajectories are vulnerable to the challenges of long-haul recovery. PMID- 26576817 TI - Melanocytic nevi, genetic engineering, and journalistic disinformation. PMID- 26576818 TI - Highly Efficient Far Red/Near-Infrared Solid Fluorophores: Aggregation-Induced Emission, Intramolecular Charge Transfer, Twisted Molecular Conformation, and Bioimaging Applications. AB - The development of organic fluorophores with efficient solid-state emissions or aggregated-state emissions in the red to near-infrared region is still challenging. Reported herein are fluorophores having aggregation-induced emission ranging from the orange to far red/near-infrared (FR/NIR) region. The bioimaging performance of the designed fluorophore is shown to have potential as FR/NIR fluorescent probes for biological applications. PMID- 26576819 TI - A Randomized Controlled Trial Examining the Effect of Mindfulness Meditation on Working Memory Capacity in Adolescents. AB - PURPOSE: To investigate the effectiveness of a mindfulness meditation intervention on working memory capacity (WMC) in adolescents via a randomized controlled trial comparing mindfulness meditation to hatha yoga and a waitlist control group. METHODS: Participants (N = 198 adolescents) were recruited from a large public middle school in southwest United States and randomly assigned to mindfulness meditation, hatha yoga, or a waitlist control condition. Participants completed a computerized measure of WMC (Automated Operational Span Task) and self-report measures of perceived stress (Perceived Stress Scale) and anxiety (Screen for Childhood Anxiety Related Emotional Disorders) at preintervention and postintervention/waitlist. A series of mixed-design analyses of variance were used to examine changes in WMC, stress, and anxiety at preintervention and postintervention. RESULTS: Participants in the mindfulness meditation condition showed significant improvements in WMC, whereas those in the hatha yoga and waitlist control groups did not. No statistically significant between-group differences were found for stress or anxiety. CONCLUSIONS: This is the first study to provide support for the benefits of short-term mindfulness practice, specifically mindfulness meditation, in improving WMC in adolescents. Results highlight the importance of investigating the components of mindfulness-based interventions among adolescents given that such interventions may improve cognitive function. More broadly, mindfulness interventions may be delivered in an abridged format, thus increasing their potential for integration into school settings and into existing treatment protocols. PMID- 26576820 TI - Trajectories of Functioning Into Emerging Adulthood Following Treatment for Adolescent Depression. AB - PURPOSE: It is well established that empirically supported treatments reduce depressive symptoms for most adolescents; however, it is not yet known whether these interventions lead to sustained improvements in global functioning. The goal of this study is to assess the clinical characteristics and trajectories of long-term psychosocial functioning among emerging adults who have experienced adolescent-onset major depressive disorder. METHODS: Global functioning was assessed using the Clinical Global Assessment Scale for children (participants <=18 years), the Global Assessment of Functioning (participants >= 19 years) and the Health of the Nation Outcome Scales for Adolescents among 196 adolescents who elected to complete 3.5 years of naturalistic follow-up subsequent to their participation in the Treatment for Adolescents with Depression Study. The Treatment for Adolescents with Depression Study examined the efficacy of cognitive behavior therapy, fluoxetine, and the combination of cognitive behavior therapy and fluoxetine (combination treatment) over the course of 36 weeks. Mixed effects regression models were used to identify trajectories and clinical predictors of functioning over the naturalistic follow-up. RESULTS: Global functioning and achievement of developmental milestones (college, employment) improved over the course of follow-up for most adolescents. Depressive relapse, initial randomization to the placebo group, and the presence of multiple psychiatric comorbidities conferred risk for relatively poorer functioning. CONCLUSIONS: Functioning generally improves among most adolescents who have received empirically supported treatments. However, the presence of recurrent major depressive disorder and multiple psychiatric comorbidities is associated with poorer functioning trajectories, offering targets for maintenance treatment or secondary prevention. PMID- 26576821 TI - Cyberbullying Prevalence Among US Middle and High School-Aged Adolescents: A Systematic Review and Quality Assessment. AB - PURPOSE: Cyberbullying (CB) has established links to physical and mental health problems including depression, suicidality, substance use, and somatic symptoms. Quality reporting of CB prevalence is essential to guide evidence-based policy and prevention priorities. The purpose of this systematic review was to investigate study quality and reported prevalence among CB research studies conducted in populations of US adolescents of middle and high school age. METHODS: Searches of peer-reviewed literature published through June 2015 for "CB" and related terms were conducted using PubMed, PsycINFO, CINAHL Plus, and Web of Science. Included manuscripts reported CB prevalence in general populations of US adolescents between the ages of 10 and 19 years. Using a review tool based on the Strengthening the Reporting of Observational Studies in Epidemiology statement, reviewers independently scored study quality on study methods, results reporting, and reported prevalence. RESULTS: Search results yielded 1,447 manuscripts; 81 manuscripts representing 58 unique studies were identified as meeting inclusion criteria. Quality scores ranged between 12 and 37 total points of a possible 42 points (mean = 26.7, standard deviation = 4.6). Prevalence rates of CB ranged as follows: Perpetration, 1%-41%; victimization, 3% 72%; and overlapping perpetration and victimization, 2.3%-16.7%. CONCLUSIONS: Literature on CB in US middle and high school-aged students is robust in quantity but inconsistent in quality and reported prevalence. Consistent definitions and evidence-based measurement tools are needed. PMID- 26576822 TI - Effects of a Large-Scale Unconditional Cash Transfer Program on Mental Health Outcomes of Young People in Kenya. AB - PURPOSE: This study investigates the causal effect of Kenya's unconditional cash transfer program on mental health outcomes of young people. METHODS: Selected locations in Kenya were randomly assigned to receive unconditional cash transfers in the first phase of Kenya's Cash Transfer Program for orphans and Vulnerable Children. In intervention locations, low-income households and those with orphans and vulnerable childrens began receiving monthly cash transfers of $20 in 2007. In 2011, 4 years after program onset, data were collected on the psychosocial status for youth aged 15-24 years from households in intervention and control locations (N = 1960). The primary outcome variable was an indicator of depressive symptoms using the 10-question Center for Epidemiologic Studies Depression Scale. Secondary outcomes include an indicator for hopefulness and physical health measures. Logistic regression models that adjusted for individual and household characteristics were used to determine the effect of the cash transfer program. RESULTS: The cash transfer reduced the odds of depressive symptoms by 24 percent among young persons living in households that received cash transfers. Further analysis by gender and age revealed that the effects were only significant for young men and were larger among men aged 20-24 years and orphans. CONCLUSIONS: This study provides evidence that poverty-targeted unconditional cash transfer programs, can improve the mental health of young people in low-income countries. PMID- 26576823 TI - Quantitative resistance against Bemisia tabaci in Solanum pennellii: Genetics and metabolomics. AB - The whitefly Bemisia tabaci is a serious threat in tomato cultivation worldwide as all varieties grown today are highly susceptible to this devastating herbivorous insect. Many accessions of the tomato wild relative Solanum pennellii show a high resistance towards B. tabaci. A mapping approach was used to elucidate the genetic background of whitefly-resistance related traits and associated biochemical traits in this species. Minor quantitative trait loci (QTLs) for whitefly adult survival (AS) and oviposition rate (OR) were identified and some were confirmed in an F2 BC1 population, where they showed increased percentages of explained variance (more than 30%). Bulked segregant analyses on pools of whitefly-resistant and -susceptible F2 plants enabled the identification of metabolites that correlate either with resistance or susceptibility. Genetic mapping of these metabolites showed that a large number of them co-localize with whitefly-resistance QTLs. Some of these whitefly-resistance QTLs are hotspots for metabolite QTLs. Although a large number of metabolite QTLs correlated to whitefly resistance or susceptibility, most of them are yet unknown compounds and further studies are needed to identify the metabolic pathways and genes involved. The results indicate a direct genetic correlation between biochemical-based resistance characteristics and reduced whitefly incidence in S. pennellii. PMID- 26576824 TI - Cytoskeletal motor-driven active self-assembly in in vitro systems. AB - Molecular motor-driven self-assembly has been an active area of soft matter research for the past decade. Because molecular motors transform chemical energy into mechanical work, systems which employ molecular motors to drive self assembly processes are able to overcome kinetic and thermodynamic limits on assembly time, size, complexity, and structure. Here, we review the progress in elucidating and demonstrating the rules and capabilities of motor-driven active self-assembly. We focus on the types of structures created and the degree of control realized over these structures, and discuss the next steps necessary to achieve the full potential of this assembly mode which complements robotic manipulation and passive self-assembly. PMID- 26576825 TI - Clinical needs and outcomes of adults with intellectual disabilities accessing an inpatient assessment and treatment service and the implication for development of community services. AB - The role and future of assessment and treatment units for people with intellectual disabilities is once again the focus of debate and government policy. Reviewing the admissions to inpatient services can provide useful information about the characteristics, needs and clinical outcomes of clients. Data were collected retrospectively for all 36 referrals accepted to an inpatient assessment and treatment unit for people with intellectual disability, between January 2013 and April 2014. Clinical and demographic characteristics of service users were identified through descriptive analysis. Male service users, mild intellectual disability and diagnosis of autistic spectrum disorder were frequent, and a high proportion of admissions had complex and multiple needs. The Health of the Nation Outcome Scale-Intellectual Disabilities was used as a clinical outcome measure. We conclude with recommendations for service development following closure of our inpatient service. PMID- 26576826 TI - C5a inhibitor protects against ischemia/reperfusion injury in rat small intestine. AB - Acute mesenteric ischemia (AMI) is caused by considerable intestinal injury, which is associated with intestinal ischemia followed by reperfusion. To elucidate the mechanisms of ischemia/reperfusion injuries, a C5a inhibitory peptide termed AcPepA was used to examine the role of C5a anaphylatoxin, induction of inflammatory cells, and cell proliferation of the intestinal epithelial cells in an experimental AMI model. In this rat model, the superior mesenteric artery was occluded and subsequently reperfused (Induce-I/R). Other groups were treated with AcPepA before ischemia or reperfusion. Induce-I/R induced injuries in the intestine and AcPepA significantly decreased the proportion of severely injured villi. Induce-I/R induced secondary receptor for C5a-positive polymorphonuclear leukocytes in the vessels and CD204-positive macrophages near the injured site; this was correlated with hypoxia-induced factor 1-alpha-positive cells. Induction of these inflammatory cells was attenuated by AcPepA. In addition, AcPepA increased proliferation of epithelial cells in the villi, possibly preventing further damage. Therefore, Induce-I/R activates C5a followed by the accumulation of polymorphonuclear leukocyte and hypoxia-induced factor 1-alpha-producing macrophages, leading to villus injury. AcPepA, a C5a inhibitory peptide, blocks the deleterious effects of C5a, indicating it has a therapeutic effect on the inflammatory consequences of experimental AMI. PMID- 26576828 TI - Understanding the role of an educational model in developing knowledge of caring for older persons with dementia. AB - BACKGROUND: Statistics show that the number of older people in need of care is increasing worldwide, especially those with dementia. This implies demands on knowledge and competence among health care staff to care for them. In Sweden, Silviahemmet offers dementia care units the opportunity to become certified according to a special certification educational model. Silviahemmet provides educational programs for staff in dementia care and day care for person with dementia. All staff undergoes a systematic training course in dementia care. The aim of the study was to gain an understanding of how an educational model developed the perceived knowledge of staff caring for older persons with dementia in a nursing home. METHOD: A phenomenographical approach was used and qualitative interviews were carried out with 13 staff members in a nursing home. FINDINGS: The main results show that staff perceives the importance of knowledge, working together and creating a sense of fellowship. The care of persons with dementia requires a special approach and adherence. Participating in the educational program made the staff realize and acknowledge their tacit knowledge and the importance of reflection-in-action together in the team. CONCLUSION: The results indicate the need for a common theoretical knowledge base and value system to achieve coherence in daily work. PMID- 26576827 TI - Th17 cytokines differentiate obesity from obesity-associated type 2 diabetes and promote TNFalpha production. AB - OBJECTIVE: T cell inflammation plays pivotal roles in obesity-associated type 2 diabetes (T2DM). The identification of dominant sources of T cell inflammation in humans remains a significant gap in understanding disease pathogenesis. It was hypothesized that cytokine profiles from circulating T cells identify T cell subsets and T cell cytokines that define T2DM-associated inflammation. METHODS: Multiplex analyses were used to quantify T cell-associated cytokines in alphaCD3/alphaCD28-stimulated PBMCs, or B cell-depleted PBMCs, from subjects with T2DM or BMI-matched controls. Cytokine measurements were subjected to multivariate (principal component and partial least squares) analyses. Flow cytometry detected intracellular TNFalpha in multiple immune cell subsets in the presence/absence of antibodies that neutralize T cell cytokines. RESULTS: T cell cytokines were generally higher in T2DM samples, but Th17 cytokines are specifically important for classifying individuals correctly as T2DM. Multivariate analyses indicated that B cells support Th17 inflammation in T2DM but not control samples, while monocytes supported Th17 inflammation regardless of T2DM status. Partial least squares regression analysis indicated that both Th17 and Th1 cytokines impact %HbA1c. CONCLUSIONS: Among various T cell subsets, Th17 cells are major contributors to inflammation and hyperglycemia and are uniquely supported by B cells in obesity-associated T2DM. PMID- 26576829 TI - Systematic review of clinical applications of monitoring muscle tissue oxygenation with near-infrared spectroscopy in vascular disease. AB - BACKGROUND: The use of wavelengths of the near-infrared region by near-infrared spectroscopy (NIRS) has been studied for several applications in vascular disease. This systematic review aims to explore the clinical relevance of monitoring muscle tissue oxygenation in vascular disease with NIRS. METHODS: A systematic search in PubMed, EMBASE, CINAHL and Cochrane databases was performed to identify clinical NIRS studies, published until April 2015, involving muscle tissue oxygenation in vascular disease. RESULTS: After screening 183 manuscripts, 38 studies (n=2010) were included. Studies concerned peripheral arterial disease (PAD) (twelve studies, n=848), compartment syndrome of lower extremities (seven studies, n=205), deep vein thrombosis (DVT) (six studies, n=429), buttock and lower extremity ischaemia in abdominal aortic aneurysm repair (six studies, n=139), free flap failure (five studies, n=354), and spinal cord ischaemia in thoracoabdominal aortic aneurysm repair (two studies, n=35). Nine studies compared NIRS with gold standards and provided cut-off values. Four studies regarding chronic compartment syndrome and DVT determined higher sensitivity (78% 97%) than specificity (56%-76%). Two studies regarding PAD and buttock claudication determined higher specificity (87%-95%) than sensitivity (33%-88%). Three studies regarding free flap failure determined sensitivity and specificity of 100%. CONCLUSION: We found sufficient evidence to use NIRS in clinical setting for assessment of chronic compartment syndrome of lower extremities, and as surveillance tool for detection of free flap failure. So far, clinical relevance of routine use of NIRS in other vascular applications is less clear. Cut-off values to discriminate are not yet unanimous and better validation has to be awaited for. PMID- 26576830 TI - Feedback Activation of STAT3 as a Cancer Drug-Resistance Mechanism. AB - Signal transducer and activator of transcription 3 (STAT3) plays crucial roles in several cellular processes such as cell proliferation and survival, and has been found to be aberrantly activated in many cancers. Much research has explored the leading mechanisms for regulating the STAT3 pathway and its role in promoting tumorigenesis. We focus here on recent evidence suggesting that feedback activation of STAT3 plays a prominent role in mediating drug resistance to a broad spectrum of targeted cancer therapies and chemotherapies. We highlight the potential of co-targeting STAT3 and its primary target to overcome drug resistance, and provide perspective on repurposing clinically approved drugs as STAT3 pathway inhibitors, in combination with the FDA-approved receptor tyrosine kinase (RTK) inhibitors, to improve clinical outcome of cancer treatment. PMID- 26576831 TI - Quality Measurement: A Primer for Hand Surgeons. AB - As the government and payers place increasing emphasis on measuring and reporting quality and meeting-specific benchmarks, physicians and health care systems will continue to adapt to meet regulatory requirements. Hand surgeons' involvement in quality measure development will help ensure that our services are appropriately assessed. Moreover, by embracing a culture of quality assessment and improvement, we will improve patient care while demonstrating the importance of our services in a health care system that is transitioning from a fee-for-service model to a fee-for-value model. Understanding quality and the tools for its measurement, and the application of quality assessment and improvement methods can help hand surgeons continue to deliver high-quality care that aligns with national priorities. PMID- 26576832 TI - HPLC determination of alpha-ketoglutaramate [5-amino-2,5-dioxopentanoate] in biological samples. AB - alpha-Ketoglutaramate is an important glutamine metabolite in mammals, plants, and many bacteria. It is also a nicotine metabolite in certain bacteria. Previously published methods for the determination of alpha-ketoglutaramate in biological samples have considerable drawbacks. Here, we describe a relatively simple high-performance liquid chromatography (HPLC)-based method for measurement of alpha-ketoglutaramate in plasma and deproteinized tissues that overcomes these drawbacks. Concentrations of alpha-ketoglutaramate in normal rat liver, kidney, brain, and plasma were found to be approximately 216, 13, 6, and 19 MUM, respectively. The HPLC method should be useful for studying the role of alpha ketoglutaramate in eukaryotic glutamine metabolism and in bacterial nicotine metabolism. PMID- 26576833 TI - Definitive localization of intracellular proteins: Novel approach using CRISPR Cas9 genome editing, with glucose 6-phosphate dehydrogenase as a model. AB - Studies to determine subcellular localization and translocation of proteins are important because subcellular localization of proteins affects every aspect of cellular function. Such studies frequently utilize mutagenesis to alter amino acid sequences hypothesized to constitute subcellular localization signals. These studies often utilize fluorescent protein tags to facilitate live cell imaging. These methods are excellent for studies of monomeric proteins, but for multimeric proteins, they are unable to rule out artifacts from native protein subunits already present in the cells. That is, native monomers might direct the localization of fluorescent proteins with their localization signals obliterated. We have developed a method for ruling out such artifacts, and we use glucose 6 phosphate dehydrogenase (G6PD) as a model to demonstrate the method's utility. Because G6PD is capable of homodimerization, we employed a novel approach to remove interference from native G6PD. We produced a G6PD knockout somatic (hepatic) cell line using CRISPR-Cas9 mediated genome engineering. Transfection of G6PD knockout cells with G6PD fluorescent mutant proteins demonstrated that the major subcellular localization sequences of G6PD are within the N-terminal portion of the protein. This approach sets a new gold standard for similar studies of subcellular localization signals in all homodimerization-capable proteins. PMID- 26576834 TI - Insights from two industrial hygiene pilot e-cigarette passive vaping studies. AB - While several reports have been published using research methods of estimating exposure risk to e-cigarette vapors in nonusers, only two have directly measured indoor air concentrations from vaping using validated industrial hygiene sampling methodology. Our first study was designed to measure indoor air concentrations of nicotine, menthol, propylene glycol, glycerol, and total particulates during the use of multiple e-cigarettes in a well-characterized room over a period of time. Our second study was a repeat of the first study, and it also evaluated levels of formaldehyde. Measurements were collected using active sampling, near real-time and direct measurement techniques. Air sampling incorporated industrial hygiene sampling methodology using analytical methods established by the National Institute of Occupational Safety and Health and the Occupational Safety and Health Administration. Active samples were collected over a 12-hr period, for 4 days. Background measurements were taken in the same room the day before and the day after vaping. Panelists (n = 185 Study 1; n = 145 Study 2) used menthol and non-menthol MarkTen prototype e-cigarettes. Vaping sessions (six, 1-hr) included 3 prototypes, with total number of puffs ranging from 36-216 per session. Results of the active samples were below the limit of quantitation of the analytical methods. Near real-time data were below the lowest concentration on the established calibration curves. Data from this study indicate that the majority of chemical constituents sampled were below quantifiable levels. Formaldehyde was detected at consistent levels during all sampling periods. These two studies found that indoor vaping of MarkTen prototype e-cigarette does not produce chemical constituents at quantifiable levels or background levels using standard industrial hygiene collection techniques and analytical methods. PMID- 26576835 TI - Hypomethylating Agents as Bridging Therapy before Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Chronic Myelomonocytic Leukemia? PMID- 26576836 TI - Validation of the RobotiX Mentor Robotic Surgery Simulator. AB - OBJECTIVES: To assess face, content, and construct validity of the RobotiX Mentor virtual reality simulator, to assess its acceptability as a robotic surgery training tool and feasibility of its use, and to develop a supplementary training curriculum. SUBJECTS AND METHODS: This prospective, observational, and comparative study recruited novice (n = 20), intermediate (n = 15), and expert (n = 11) robotic surgeons as participants from institutions across the United Kingdom and at the 30th European Association of Urology Annual Meeting. Each participant completed nine surgical tasks across two modules on the simulator, followed by a questionnaire to evaluate subjective realism (face validity), task importance (content validity), feasibility, and acceptability. Outcome measures of novice, intermediate, and expert groups were compared using Mann-Whitney U tests to assess construct validity. RESULTS: Construct validity was demonstrated in a total of 17/25 performance evaluation metrics (p < 0.001). Experts performed better than intermediates with regard to time taken to complete the first (p = 0.002) and second (p = 0.043) module, number of instrument collisions (p = 0.040), path length (p = .049), number of cuts >2 mm deep (p = 0.033), average distance from suture target (p = 0.015), and number of suture breakages (p = 0.038). Participants determined both the simulator console and psychomotor tasks as highly realistic (mean: 3.7/5) and important for surgical training (4.5/5), with system pedals (4.2/5) and knot tying task (4.6/5) scoring highest, respectively. The simulator was also rated as an acceptable (4.3/5) tool for training and its use highly feasible (4.3/5). CONCLUSION: Construct, face, and content validity was established for the RobotiX Mentor, and feasibility and acceptability of incorporation into surgical training were ascertained. The RobotiX Mentor shows potential as a valuable tool for training and assessment of trainees in robotic skills. Investigation of concurrent and predictive validity is necessary to complete validation, and evaluation of learning curves would provide insight into its value for training. PMID- 26576837 TI - Dietary interventions designed to protect the perinatal brain from hypoxic ischemic encephalopathy--Creatine prophylaxis and the need for multi-organ protection. AB - Birth asphyxia or hypoxia arises from impaired placental gas exchange during labor and remains one of the leading causes of neonatal morbidity and mortality worldwide. It is a condition that can strike in pregnancies that have been uneventful until these final moments, and leads to fundamental loss of cellular energy reserves in the newborn. The cascade of metabolic changes that occurs in the brain at birth as a result of hypoxia can lead to significant damage that evolves over several hours and days, the severity of which can be ameliorated with therapeutic cerebral hypothermia. However, this treatment is only applied to a subset of newborns that meet strict inclusion criteria and is usually administered only in facilities with a high level of medical surveillance. Hence, a number of neuropharmacological interventions have been suggested as adjunct therapies to improve the efficacy of hypothermia, which alone improves survival of the post-hypoxic infant but does not altogether prevent adverse neurological outcomes. In this review we discuss the prospect of using creatine as a dietary supplement during pregnancy and nutritional intervention that can significantly decrease the risk of brain damage in the event of severe oxygen deprivation at birth. Because brain damage can also arise secondarily to compromise of other fetal organs (e.g., heart, diaphragm, kidney), and that compromise of mitochondrial function under hypoxic conditions may be a common mechanism leading to damage of these tissues, we present data suggesting that dietary creatine supplementation during pregnancy may be an effective prophylaxis that can protect the fetus from the multi-organ consequences of severe hypoxia at birth. PMID- 26576839 TI - Findings from a mixed-methods study of an interprofessional faculty development program. AB - Forty faculty members from eight schools participated in a year-long National Faculty Development Program (NFDP) conducted in 2012-2013, aimed at developing faculty knowledge and skills for interprofessional education (IPE). The NFDP included two live conferences. Between conferences, faculty teams implemented self-selected IPE projects at their home institutions and participated in coaching and peer-support conference calls. This paper describes program outcomes. A mixed methods approach was adopted. Data were gathered through online surveys and semi-structured interviews. The study explored whether faculty were satisfied with the program, believed the program was effective in developing knowledge and skills in designing, implementing, and evaluating IPE, and planned to continue newly-implemented IPE and faculty development (FD). Peer support and networking were two of the greatest perceived benefits. Further, this multi institutional program appears to have facilitated early organizational change by bringing greater contextual understanding to assumptions made at the local level that in turn could influence hidden curricula and networking. These findings may guide program planning for future FD to support IPE. PMID- 26576838 TI - Normal fasting plasma glucose predicts type 2 diabetes and cardiovascular disease in elderly population in Taiwan. AB - BACKGROUND: Hyperglycemia increases prevalence of metabolic syndrome (MetS), type 2 diabetes (T2D) and cardiovascular disease (CVD). But the role of normoglycemia on the development of T2D and CVD in elderly population remains unclear. AIM: To determine an optimal cut-off for fasting plasma glucose (FPG) to predict MetS and subsequent risk of T2D and CVD in an elderly Taiwanese population with normal FPG levels. DESIGN: Two stages included cross-sectional (Stage 1) and prospective (Stage 2) cohort study. METHODS: In Stage 1 18 287 subjects aged >=60 years were enrolled; of these, 5039 without T2D and CVD advanced to Stage 2 and a mean follow-up of 3.8 years. MetS components were analysed, and in Stage 1, FPG cut offs for MetS risk were calculated using receiver operating characteristic (ROC) curve analyses. In Stage 2, subjects without T2D and CVD in Stage 1 were classified into high-FPG and low-FPG groups based on cut-offs, and sex specific differences in incidence for T2D and CVD were calculated. RESULTS: ROC curve analysis gave an optimal FPG cut-off for MetS of 93 mg/dl and 92 mg/dl for males and females, respectively. The high-FPG group had a 1.599- and 1.353-fold higher chance of developing T2D compared with the low-FPG group for males and females, respectively (95% CI: 1.606-2.721 and 1.000-1.831, P = 0.015 and 0.05). The high-FPG group had a 1.24-fold higher chance of developing CVD for females (95% CI: 1.015-1.515, P = 0.035); however, there was no difference for males. CONCLUSIONS: Our results suggest that FPG within the normal range was associated with MetS, and elderly subjects with high normal levels have a higher incidence of developing T2D for both sexes, and CVD for females, over the short-term. PMID- 26576840 TI - Interviews with smokers about smokeless tobacco products, risk messages and news articles. AB - BACKGROUND: Smokeless tobacco (SLT) products and their communication have been topics of discussion in harm reduction debates, but little is known about smokers' perceptions of existing SLT risk messages. This study aimed to explore smokers' perceptions of SLT and snus products and news stories with different risk messages about them. METHODS: We conducted interviews with 30 smokers assigned to read 1 of 3 constructed news stories about SLT and snus with different messages about their risks relative to cigarettes: (1) a 'favourable' version (describing SLT/snus as a 'safer' smoking alternative); (2) a 'cautious' version (describing SLT/snus as having various risks); and (3) a 'mixed' version (both stating SLT risks and potential reduced-risk benefits). RESULTS: Smokers felt somewhat more informed about snus after article reading and largely found quoted sources to be credible. Though some exposed to favourable SLT/snus messages appeared to modify their beliefs about the products' acceptability and risks, many were left unchanged given pre-existing SLT risk perceptions influenced by prior SLT warnings, observed effects in known users, and concerns about SLT's mode of use. Willingness to use/not use snus in the future was also influenced by non-risk-related factors (eg, preference for smoking rituals). Many referenced e-cigarettes as being safer and more attractive smoking alternatives. CONCLUSIONS: Exposure to reduced-risk SLT information may have some impact on smokers' SLT perceptions and interest, but this might be limited by a variety of negative SLT beliefs and growth of other smoking alternatives. Future research should explore SLT risk message effects with larger samples and different study designs. PMID- 26576841 TI - Vitamin K Antagonists and Cognitive Function in Older Adults: The Three-City Cohort Study. AB - BACKGROUND: A growing body of evidence supports a beneficial role for vitamin K in brain and cognition, notably in studies where animals are rendered vitamin K deficient by warfarin, a potent vitamin K antagonist (VKA). Given VKAs are commonly used oral anticoagulants in older persons, we investigated the relationship between VKA therapy and cognitive performances over 10 years in participants of the Three-City study. METHODS: The Three-City cohort included 7,133 nondemented community dwellers, aged 65 years or older at baseline. Exposures to VKAs and platelet aggregation inhibitors, another antithrombotic agent, were determined at baseline. Participants underwent cognitive assessment at baseline and every 2 years over 10 years. Associations were analyzed with mixed linear models adjusting for many covariates including VKA and platelet aggregation inhibitor indications. RESULTS: About 239 (3.4%) and 1,192 (16.7%) of the participants were treated with VKAs and platelet aggregation inhibitors at baseline, respectively. VKA treatment was significantly associated with worse performances on Benton Visual Retention Test assessing visual memory (adjusted mean difference -0.29; p = .02 in multivariate models) and Isaacs Set Test assessing verbal fluency (adjusted mean difference -1.37; p = .0009) at baseline. Treatment with VKAs was not associated with global cognitive functioning on the Mini Mental State Examination, neither with rate of subsequent decline in scores on all three cognitive tests. No associations were found between platelet aggregation inhibitors and cognitive performances or rate of decline. CONCLUSION: These findings do not indicate a long-term detrimental effect of VKAs on cognition, but the risk-benefit balance of VKA treatment still deserves further research. PMID- 26576842 TI - Vitamin K Status and Lower Extremity Function in Older Adults: The Health Aging and Body Composition Study. AB - BACKGROUND: While low vitamin K status has been associated with several chronic diseases that can lead to lower extremity disability, it is not known if low vitamin K status is associated with worse lower extremity function. METHODS: Vitamin K status was measured according to plasma phylloquinone (vitamin K1) and dephosphorylated-uncarboxylated MGP (dp-ucMGP) in 1,089 community-dwelling older adults (mean +/- SD age =74+/-3 years; 67% female). Lower extremity function was assessed using the short physical performance battery (SPPB), gait speed, and isokinetic leg strength. Linear regression and mixed models were used to determine the cross-sectional and longitudinal associations between vitamin K status and functional outcome measures. RESULTS: Cross-sectionally, higher plasma phylloquinone was associated with better SPPB scores and 20-m gait speed (p <= .05). After 4-5 years, those with >=1.0nM plasma phylloquinone (the concentration achieved when recommended intakes are met) had better SPPB scores (p = .03) and 20-m gait speed (p < .05). Lower plasma dp-ucMGP (reflective of better vitamin K status) was associated with better SPPB scores and leg strength cross-sectionally (p <= .04), but not longitudinally. Neither measure of vitamin K status was associated with walking endurance or with the rate of decline in function. CONCLUSION: Older adults with higher vitamin K status had better physical performance scores at baseline, but data are less consistent longitudinally. Since lower extremity disability is a common consequence of multiple chronic diseases for which a role of vitamin K has been suggested, future studies are needed to determine if vitamin K supplementation could improve function in those with vitamin K insufficiency and clarify underlying mechanism(s). PMID- 26576843 TI - Perceptions of Integrated Vascular Surgery Fellowship Graduates among Community Vascular Surgeons. AB - BACKGROUND: Vascular training includes both integrated residency ("0+5") and postresidency fellowship ("5+2") programs. The impact of training models on attitudes toward graduates as prospective hires is incompletely understood, and existing studies have primarily surveyed surgeons from academic centers. We surveyed surgeons who were in active clinical practice but not affiliated with a medical school or training program to compare perceptions of integrated versus postgraduate programs. METHODS: Vascular surgeons not affiliated with a university-based practice were identified from membership rosters of one regional and one national specialty society and e-mailed an anonymous survey. The survey evaluated respondents' training, practice distribution, general surgery responsibilities, hiring practices, and perception of the integrated and postgraduate trained vascular surgeons. Agreement among specific responses was evaluated using McNemar's test. RESULTS: The survey was sent to 406 surgeons with 71 (17.5%) responding. A total of 42% of respondents indicated that half or more of their cases consisted of open procedures and 10% reported general surgery coverage as part of their practice. More respondents indicated that they consider postgraduate trained surgeons very mature (41% vs. 7%, P < 0.0001) and better prepared for open cases (89% vs. 28%, P < 0.0001), as well as endovascular cases (96% vs. 87%, P = 0.0339). Overall 84% stated that they would interview an integrated program graduate, although only 72% indicated that they would hire one. Overall 16.9% identified ability to cover general surgery as either very important or somewhat important characteristic for a potential hire. CONCLUSIONS: Perceptions of 5+2 graduates as more mature and better prepared for opens surgical cases may influence hiring practices. This suggests that attitudes toward integrated versus 5+2 trained surgeons may differ between academic and community vascular surgeons. Further research is needed to assess whether these differences are related to actual differences in graduate skills, familiarity with integrated graduates, or other factors. PMID- 26576845 TI - Proposal of a Twin Aarginine Translocator System-Mediated Constraint against Loss of ATP Synthase Genes from Nonphotosynthetic Plastid Genomes. PMID- 26576844 TI - Dynamic changes in host gene expression associated with H5N8 avian influenza virus infection in mice. AB - Emerging outbreaks of newly found, highly pathogenic avian influenza (HPAI) A(H5N8) viruses have been reported globally. Previous studies have indicated that H5N8 pathogenicity in mice is relatively moderate compared with H5N1 pathogenicity. However, detailed mechanisms underlying avian influenza pathogenicity are still undetermined. We used a high-throughput RNA-seq method to analyse host and pathogen transcriptomes in the lungs of mice infected with A/MD/Korea/W452/2014 (H5N8) and A/EM/Korea/W149/2006 (H5N1) viruses. Sequenced numbers of viral transcripts and expression levels of host immune-related genes at 1 day post infection (dpi) were higher in H5N8-infected than H5N1-infected mice. Dual sequencing of viral transcripts revealed that in contrast to the observations at 1 dpi, higher number of H5N1 genes than H5N8 genes was sequenced at 3 and 7 dpi, which is consistent with higher viral titres and virulence observed in infected lungs in vivo. Ingenuity pathway analysis revealed a more significant upregulation of death receptor signalling, driven by H5N1 than with H5N8 infection at 3 and 7 dpi. Early induction of immune response-related genes may elicit protection in H5N8-infected mice, which correlates with moderate pathogenicity in vivo. Collectively, our data provide new insight into the underlying mechanisms of the differential pathogenicity of avian influenza viruses. PMID- 26576846 TI - Regal Setting Showcases Crown Jewels of SMBE 2015 Science. PMID- 26576848 TI - Unraveling the Genetic Basis of Seahorse Male Pregnancy. PMID- 26576850 TI - Genomic Characterization of a South American Phytophthora Hybrid Mandates Reassessment of the Geographic Origins of Phytophthora infestans. AB - As the oomycete pathogen causing potato late blight disease, Phytophthora infestans triggered the famous 19th-century Irish potato famine and remains the leading cause of global commercial potato crop destruction. But the geographic origin of the genotype that caused this devastating initial outbreak remains disputed, as does the New World center of origin of the species itself. Both Mexico and South America have been proposed, generating considerable controversy. Here, we readdress the pathogen's origins using a genomic data set encompassing 71 globally sourced modern and historical samples of P. infestans and the hybrid species P. andina, a close relative known only from the Andean highlands. Previous studies have suggested that the nuclear DNA lineage behind the initial outbreaks in Europe in 1845 is now extinct. Analysis of P. andina's phased haplotypes recovered eight haploid genome sequences, four of which represent a previously unknown basal lineage of P. infestans closely related to the famine era lineage. Our analyses further reveal that clonal lineages of both P. andina and historical P. infestans diverged earlier than modern Mexican lineages, casting doubt on recent claims of a Mexican center of origin. Finally, we use haplotype phasing to demonstrate that basal branches of the clade comprising Mexican samples are occupied by clonal isolates collected from wild Solanum hosts, suggesting that modern Mexican P. infestans diversified on Solanum tuberosum after a host jump from a wild species and that the origins of P. infestans are more complex than was previously thought. PMID- 26576851 TI - Phylogenomics Controlling for Base Compositional Bias Reveals a Single Origin of Eusociality in Corbiculate Bees. AB - As increasingly large molecular data sets are collected for phylogenomics, the conflicting phylogenetic signal among gene trees poses challenges to resolve some difficult nodes of the Tree of Life. Among these nodes, the phylogenetic position of the honey bees (Apini) within the corbiculate bee group remains controversial, despite its considerable importance for understanding the emergence and maintenance of eusociality. Here, we show that this controversy stems in part from pervasive phylogenetic conflicts among GC-rich gene trees. GC-rich genes typically have a high nucleotidic heterogeneity among species, which can induce topological conflicts among gene trees. When retaining only the most GC homogeneous genes or using a nonhomogeneous model of sequence evolution, our analyses reveal a monophyletic group of the three lineages with a eusocial lifestyle (honey bees, bumble bees, and stingless bees). These phylogenetic relationships strongly suggest a single origin of eusociality in the corbiculate bees, with no reversal to solitary living in this group. To accurately reconstruct other important evolutionary steps across the Tree of Life, we suggest removing GC-rich and GC-heterogeneous genes from large phylogenomic data sets. Interpreted as a consequence of genome-wide variations in recombination rates, this GC effect can affect all taxa featuring GC-biased gene conversion, which is common in eukaryotes. PMID- 26576853 TI - Protective Effect of Rutin Against H2O2-Induced Oxidative Stress and Apoptosis in Human Lens Epithelial Cells. AB - PURPOSE: The aim of this study was to evaluate the effect of rutin on oxidative stress and apoptosis induced by H2O2 in human lens epithelial (HLE) cells and the associated mechanisms involved. METHODS: Cell viability was assessed by 4,5 dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide assay and cell apoptosis was determined by flow cytometry, TUNEL assay and DNA fragmentation assay after 24 h treatment of 100 MUM H2O2 with or without rutin pretreatment at various concentrations. The level of reactive oxygen species (ROS) was examined using 2',7'-dichlorodihydrofluorescein diacetate by flow cytometry. The activity of superoxide dismutase (SOD) was measured by xanthinoxidase method and the contents of glutathione (GSH) and malondialdehyde (MDA) were quantified by enzyme-linked immunosorbent assay. The expression change of Bcl-2, Bax and caspase-3 at mRNA and protein levels were detected by real-time polymerized chain reaction (RT-PCR) and Western-blot analysis, respectively. Activation and translocation of nuclear factor-kappaB (NF-kB/p65) were examined by Western blot and immunocytochemistry. RESULTS: Rutin pretreatment protected HLE cells from H2O2-induced cell viability decrease and apoptosis. In addition, in the presence of rutin, H2O2-induced intracellular excessive ROS and MDA were attenuated, whereas intracellular SOD and GSH depletion were prevented. Moreover, rutin also inhibited the up regulation of caspase-3 and Bax expression and rescued down-regulation of Bcl-2 expression. Lastly, rutin blocked the activation and translocation of NF-kB/p65 induced by H2O2. CONCLUSIONS: Our results demonstrated that rutin effectively protects HLE cells from H2O2-induced oxidative stress and apoptosis in a dose dependent manner. The involved mechanisms may be related to the regulation of ROS production, the inhabitation of lipid peroxidation, the protection of intracellular antioxidant system and its modulation of Bcl-2/Bax family and NF kB/p65 signaling pathway. PMID- 26576852 TI - Shared Genetic Signals of Hypoxia Adaptation in Drosophila and in High-Altitude Human Populations. AB - The ability to withstand low oxygen (hypoxia tolerance) is a polygenic and mechanistically conserved trait that has important implications for both human health and evolution. However, little is known about the diversity of genetic mechanisms involved in hypoxia adaptation in evolving populations. We used experimental evolution and whole-genome sequencing in Drosophila melanogaster to investigate the role of natural variation in adaptation to hypoxia. Using a generalized linear mixed model we identified significant allele frequency differences between three independently evolved hypoxia-tolerant populations and normoxic control populations for approximately 3,800 single nucleotide polymorphisms. Around 50% of these variants are clustered in 66 distinct genomic regions. These regions contain genes that are differentially expressed between hypoxia-tolerant and normoxic populations and several of the differentially expressed genes are associated with metabolic processes. Additional genes associated with respiratory and open tracheal system development also show evidence of directional selection. RNAi-mediated knockdown of several candidate genes' expression significantly enhanced survival in severe hypoxia. Using genomewide single nucleotide polymorphism data from four high-altitude human populations-Sherpas, Tibetans, Ethiopians, and Andeans, we found that several human orthologs of the genes under selection in flies are also likely under positive selection in all four high-altitude human populations. Thus, our results indicate that selection for hypoxia tolerance can act on standing genetic variation in similar genes and pathways present in organisms diverged by hundreds of millions of years. PMID- 26576854 TI - Risk of Acute Myocardial Infarction or Stroke in Patients with Mycosis Fungoides and Parapsoriasis. AB - Mycosis fungoides (MF) and parapsoriasis display increased inflammation, which may be associated with increased risk of arterial cardiovascular events. The aim of this Danish nationwide population-based cohort study was to assess the relative risk (RR) of acute myocardial infarction (AMI) or stroke in patients with MF and parapsoriasis. In patients with MF, the RR of AMI or stroke was 1.0 (95% confidence interval (95% CI) 0.7-1.3). In the second half of the study period, the RR was 1.8 (95% CI 1.1-2.9) during the first 5 years of follow-up. In men with parapsoriasis, the RR of AMI or stroke was 1.7 (95% CI 1.1-2.7) within the first 5 years of follow-up, whereas the RR of AMI during the first 5 years of follow-up was 2.0 (95% CI 1.2-3.4). In conclusion, patients with MF and parapsoriasis have an increased RR of AMI or stroke within the first 5 years of follow-up. PMID- 26576855 TI - New Sesquiterpene Lactone Dimer, Uvedafolin, Extracted from Eight Yacon Leaf Varieties (Smallanthus sonchifolius): Cytotoxicity in HeLa, HL-60, and Murine B16 F10 Melanoma Cell Lines. AB - Uvedafolin, 1, a new sesquiterpene lactone dimer, was isolated from the leaves of Smallanthus sonchifolius with five related compounds, 2-6, and their cytotoxicity was assessed against three tumor cell lines (HeLa, HL-60, B16-F10 melanoma). The stereostructure of 1 was newly elucidated by ESI-TOF-MS, 1D/2D NMR, and single crystal X-ray diffraction. Dimers 1 and 2 had the most effective IC50 values, 0.2 1.9 MUM, against the three tumor cell lines when compared with monomers 3-6 (IC50 values 0.7-9.9 MUM) and etoposide (IC50 values 0.8-114 MUM). The ester linkages of two sets of monomers, uvedalin, 5, and sonchifolin, 6, for 1, and enhydrin, 4, and sonchifolin, 6, for 2, as well as the acetyl group at the C-9 position, were essential for the high cytotoxicity. Dimers 1 and 2 would have potential as anticancer agents. PMID- 26576857 TI - Electrostatic-Force-Assisted Dispensing Printing to Construct High-Aspect-Ratio of 0.79 Electrodes on a Textured Surface with Improved Adhesion and Contact Resistivity. AB - As a novel route to construct fine and abnormally high-aspect-ratio electrodes with excellent adhesion and reduced contact resistivity on a textured surface, an electrostatic-force-assisted dispensing printing technique is reported and compared with conventional dispensing and electrohydrodynamic jet printing techniques. The electrostatic force applied between a silver paste and the textured surface of a crystalline silicon solar cell wafer significantly improves the physical adhesion of the electrodes, whereas those fabricated using a conventional dispensing printing technique peel off with a silver paste containing 2 wt% of a fluorosurfactant. Moreover, the contact resistivity and dimensionless deviation of total resistance are significantly reduced from 2.19 +/- 1.53 mOmega . cm(2) to 0.98 +/- 0.92 mOmega . cm(2) and from 0.10 to 0.03, respectively. By utilizing electrodes with an abnormally high-aspect-ratio of 0.79 (the measured thickness and width are 30.4 MUm and 38.3 MUm, respectively), the cell efficiency is 17.2% on a polycrystalline silicon solar cell with an emitter sheet resistance of 60 Omega/sq. This cell efficiency is considerably higher than previously reported values obtained using a conventional electrohydrodynamic jet printing technique, by +0.48-3.5%p. PMID- 26576856 TI - Differential immunogenicity between HAdV-5 and chimpanzee adenovirus vector ChAdOx1 is independent of fiber and penton RGD loop sequences in mice. AB - Replication defective adenoviruses are promising vectors for the delivery of vaccine antigens. However, the potential of a vector to elicit transgene-specific adaptive immune responses is largely dependent on the viral serotype used. HAdV-5 (Human adenovirus C) vectors are more immunogenic than chimpanzee adenovirus vectors from species Human adenovirus E (ChAdOx1 and AdC68) in mice, though the mechanisms responsible for these differences in immunogenicity remain poorly understood. In this study, superior immunogenicity was associated with markedly higher levels of transgene expression in vivo, particularly within draining lymph nodes. To investigate the viral factors contributing to these phenotypes, we generated recombinant ChAdOx1 vectors by exchanging components of the viral capsid reported to be principally involved in cell entry with the corresponding sequences from HAdV-5. Remarkably, pseudotyping with the HAdV-5 fiber and/or penton RGD loop had little to no effect on in vivo transgene expression or transgene-specific adaptive immune responses despite considerable species specific sequence heterogeneity in these components. Our results suggest that mechanisms governing vector transduction after intramuscular administration in mice may be different from those described in vitro. PMID- 26576858 TI - Betahistine reduces postoperative nausea and vomiting after laparoscopic gynecological surgery. AB - BACKGROUND: Patients undergoing laparoscopic gynecological surgery are at high risk of postoperative nausea and vomiting (PONV). We compared the antiemetic efficacy of ondansetron plus betahistine with that of ondansetron alone in this patient population. METHODS: In this randomized, double-blinded study, 168 patients were randomly allocated to receive placebo (O group) or betahistine 18 mg (OB group) orally 3 hours before surgery and 24 hours thereafter. In both groups, ondansetron 4 mg was administered at the end of surgery and 8 mg were added to an intravenous patient-controlled analgesia (IV-PCA) fentanyl solution. The primary outcome was complete response (no PONV and no rescue antiemetics) during the first 48 hours after surgery. The severity of nausea, pain score, and adverse events were assessed. RESULTS: The incidence of complete response was significantly higher in OB group than in O group (69% vs. 46%, P=0.004). The severity of nausea was lower in OB group than in O group during 30 minutes to 6 hours and 6 to 24 hours after surgery (P=0.001 and P<0.001). Pain score was similar between the groups. The incidence of dizziness was lower in OB group than in O group (13% vs. 40%, P < 0.001). Six patients (7%) in OB group and 15 patients (18%) in O group required early IV-PCA discontinuation, primarily because of PONV and/or dizziness (P=0.038). CONCLUSIONS: Compared to ondansetron alone, ondansetron plus betahistine was more effective to prevent PONV and dizziness in high-risk patients undergoing laparoscopic gynecological surgery. PMID- 26576859 TI - Progress testing in intensive care medicine training: useful and feasible?! AB - So far the in-training assessment of knowledge is perhaps underrepresented in postgraduate assessment frameworks in intensive care medicine (ICM). In most contemporary training programs a predominant emphasis is placed on workplace based learning and workplace based assessment. This article provides a concise general background on the nature and use of progress testing, and touches upon potential strengths, and constraints regarding its potential implementation and use in the postgraduate ICM training programs. PMID- 26576860 TI - Mechanical LUCAS resuscitation is effective, reduces physical workload and improves mental performance of helicopter teams. AB - BACKGROUND: Physical and mental workload during cardiopulmonary resuscitation (CPR) is challenging under extreme working conditions. We hypothesized that the mechanical chest-compression device Lund University Cardiac Assist System (LUCAS) increases the effectiveness of CPR, decreases the physical workload and improves the mental performance of the emergency medical service (EMS) staff during simulated emergency helicopter flights. METHODS: During simulated helicopter flights, 12 EMS teams performed manual or LUCAS-CPR on a manikin at random order. Compression depth, rate, overall time of compressions, application of drugs and defibrillation were recorded to test the quality of CPR. Heart rate monitoring of EMS members was used as a surrogate of physical workload. Cognitive performance was evaluated shortly after each flight by a questionnaire and a memory test about medical and extraneous items presented to the teams during the flights. RESULTS: Overall times of chest-compressions were similar, compression rate (101.7+/-9.6/min) was lower and compressions were deeper (3.9+/-0.2cm) with LUCAS as compared to manual CPR (113.3+/-19.3/min and 3.7+/-0.4cm) (P<0.01, respectively). Heart rates of the EMS staff were increased after manual as compared to mechanical CPR (100.1+/-21.0 vs. 80.4+/-11.3, P<0.01). Results of the questionnaire (93.6+/-6.9% vs. 87.0+/-7.3% correct answers, P<0.01) and memory test (22.4+/-15.4% vs. 11.3+/-7.5%, P<0.02) were significantly better after LUCAS resuscitation. Dosing of drugs, application intervals and rate of correct handling of drugs and defibrillation were not different between LUCAS or manual CPR. CONCLUSIONS: During simulated helicopter flights LUCAS-CPR improved the efficacy of chest-compressions, was physically less demanding and provided enhanced cognitive performance of the EMS team as compared to manual CPR. PMID- 26576861 TI - Investigational drugs for T-cell lymphoma. AB - INTRODUCTION: Peripheral T-cell lymphomas (PTCL) represent a heterogeneous group of malignancies frequently associated with a poor outcome. The frontline treatment strategy for PTCL relies mostly on CHOP or CHOP-like regimens, which are associated with a high failure rate and frequent relapses. AREAS COVERED: In this review, the authors present recently registered drugs and their positioning in the therapeutic armamentarium against PTCL and new drugs currently in development. The successful results in CD30-positive anaplastic large cell lymphomas suggest that a better characterization of these lymphomas could open new areas of efficient drug development. EXPERT OPINION: Advances in the field of molecular biology have started to unravel the anomalies associated with T-cell malignancies. Recent knowledge on potential epigenetic modifiers like IDH2, which is frequently mutated in angioimmunoblastic T-cell lymphoma, opens new areas of research and confirms that epigenetic drugs could represent an attractive area of clinical research. The recently developed immune checkpoints regulators might represent another area of potential interest. PMID- 26576863 TI - How I treat relapsed classical Hodgkin lymphoma after autologous stem cell transplant. AB - Despite the success of standard front-line chemotherapy for classical Hodgkin lymphoma (cHL), a subset of these patients, particularly those with poor prognostic factors at diagnosis (including the presence of B symptoms, bulky disease, advanced stage, or extranodal disease), relapse. For those patients who relapse following autologous stem cell transplant (SCT), multiple treatment options are available, including single-agent chemotherapy, combination chemotherapy strategies, radiotherapy, the immunoconjugate brentuximab, checkpoint inhibitors nivolumab and pembrolizumab, lenalidomide, everolimus, or observation in selected patients. In patients with an available donor, allogeneic SCT may also be considered. With numerous treatment options available, we advocate for a tailored therapeutic approach for patients with relapsed cHL guided by patient-specific characteristics including age, comorbidities, sites of disease (nodal or organ), previous chemosensitivity, and goals of treatment (long term disease control vs allogeneic SCT). PMID- 26576862 TI - Effectiveness and safety of Glucosamine, chondroitin, the two in combination, or celecoxib in the treatment of osteoarthritis of the knee. AB - This study aimed to investigate the effectiveness and safety of glucosamine, chondroitin, the two in combination, or celecoxib in the treatment of knee osteoarthritis (OA). PubMed, Embase and Cochrane Library were searched through from inception to February 2015. A total of 54 studies covering 16427 patients were included. Glucosamine plus chondroitin, glucosamine alone, and celecoxib were all more effective than placebo in pain relief and function improvement. Specifically, celecoxib is most likely to be the best treatment option, followed by the combination group. All treatment options showed clinically significant improvement from baseline pain, but only glucosamine plus chondroitin showed clinically significant improvement from baseline function. In terms of the structure-modifying effect, both glucosamine alone and chondroitin alone achieved a statistically significant reduction in joint space narrowing. Although no significant difference was observed among the five options with respect to the three major adverse effects (withdrawal due to adverse events, serious adverse events and the number of patients with adverse events), the additional classical meta-analysis showed that celecoxib exhibited a higher rate of gastrointestinal adverse effect comparing with the placebo group. The present study provided evidence for the symptomatic efficacy of glucosamine plus chondroitin in the treatment of knee OA. PMID- 26576864 TI - Anti-CD45 radioimmunotherapy without TBI before transplantation facilitates persistent haploidentical donor engraftment. AB - Many patients with hematologic malignancies cannot tolerate hematopoietic cell transplantation (HCT), whereas others may not have a compatible human leukocyte antigen-matched donor. To overcome these limitations, we optimized a conditioning regimen employing anti-CD45 radioimmunotherapy (RIT) replacing total body irradiation (TBI) before haploidentical HCT in a murine model. Mice received 200 to 400 MUCi (90)Y-anti-CD45 antibody (30F11), with or without fludarabine (5 days starting day -8), with cyclophosphamide (CY; days -2 and +2) for graft-versus host disease prophylaxis, and 1.5 * 10(7) haploidentical donor bone marrow cells (day 0). Haploidentical bone marrow transplantation (BMT) with 300 MUCi (90)Y anti-CD45 RIT and CY, without TBI or fludarabine, led to mixed chimeras with 81.3 +/- 10.6% mean donor origin CD8(+) cells detected 1 month after BMT, and remained stable (85.5 +/- 11% mean donor origin CD8(+) cells) 6 months after haploidentical BMT. High chimerism levels were induced across multiple hematopoietic lineages 28 days after haploidentical BMT with 69.3 +/- 14.1%, 75.6 +/- 20.2%, and 88.5 +/- 11.8% CD3(+) T cells, B220(+) B cells, and CD11b(+) myeloid cells, respectively. Fifty percent of SJL leukemia-bearing mice treated with 400 MUCi (90)Y-DOTA-30F11, CY, and haploidentical BMT were cured and lived >200 days. Mice treated with 200 MUCi (90)Y-DOTA-30F11 had a median overall survival of 73 days, while untreated leukemic mice had a median overall survival of 34 days (P < .001, Mantel-Cox test). RIT-mediated haploidentical BMT without TBI may increase treatment options for aggressive hematologic malignancies. PMID- 26576865 TI - Eliminating minimal residual disease as a therapeutic end point: working toward cure for patients with CLL. AB - Deep remission and prolonged disease-free survival can be achieved with first line chemoimmunotherapy (CIT), such as combined fludarabine, cyclophosphamide, and rituximab, in the majority of patients with chronic lymphocytic leukemia (CLL). More modest results are reported with less intense regimens like obinutuzumab plus chlorambucil. Clinical assessment has limited sensitivity in detecting residual disease responsible for subsequent relapse, even including morphologic bone marrow (BM) evaluation. Multicolor flow cytometry and polymerase chain reaction (PCR)-based methods can detect minimal residual disease (MRD) to a sensitivity of >=1:10,000 (10(-4)). Achieving BM MRD-negative complete remission (CR) is associated with superior progression-free survival (PFS) and overall survival; MRD status is the single best posttreatment predictor of long-term outcomes after CIT. Newer oral B-cell receptor signaling pathway inhibitors are highly effective at controlling disease, but best monotherapy responses are typically partial remission, and patients must remain on treatment to maintain disease control. Therapeutic progress is still needed for CLL. We propose that targeting MRD provides opportunity to realize this progress. Achieving BM MRD negative CR is a prerequisite for long-term unmaintained disease-free survival and potential for cure. We review available methodologies for detecting MRD and correlations with posttreatment outcomes. We discuss the potential utility of MRD to direct individualized therapy. Finally, we discuss the importance of MRD negative status as a surrogate marker for longer PFS in clinical studies to allow more rapid determination of clinical benefit. PMID- 26576866 TI - Multi-breed genome-wide association study reveals novel loci associated with the weight of internal organs. AB - BACKGROUND: Recently, many genome-wide association studies (GWAS) have been conducted to understand the genetic architecture of economic important traits in farm animals. Pig is widely used as a biomedical animal model for its similarity with humans in terms of organ formation and disease mechanisms. Moreover, understanding the mechanisms that underlie the development of internal organs will impact the productive potential of pigs. Our aim was to uncover new single nucleotide polymorphisms (SNPs) associated with the weight of internal organs and carcass and also potential candidate genes. METHODS: We performed GWAS for the weight of heart, liver, spleen, kidney and carcass on five pig populations (White Duroc * Erhualian F2 intercross, Sutai population, Laiwu population, Erhualian population and commercial population, for a total of 2650 individuals). Genotype data was produced using the PorcineSNP60 Beadchip array. After quality control, the data was used for association tests under a general linear mixed model. Population stratification was adjusted by including a random polygenic effect based on a matrix of genotypic relationships. A meta-analysis of our GWAS datasets was conducted by summing up the Chi square values across breeds, with the degrees of freedom of the Chi square distribution equal to the effective number of breeds. RESULTS: Thirty-nine quantitative trait loci (QTL) located on 15 chromosomes were identified by the single-population GWAS at the suggestive level. Among these, nine QTL surpassed the 5 % genome-wide significance threshold, including four for heart weight on SSC (Sus scrofa chromosome) 2, 4, 7 and 10, two for liver weight on SSC7, two for spleen weight on SSC5 and SSC7 and one for carcass weight on SSC11. The QTL on SSC7 showed pleiotropic effects for heart, liver and spleen weights in the F2 population. In addition, two QTL were detected in several populations, including one on SSC2 for heart weight in the F2 and Sutai populations and one on SSC7 for liver weight in the F2 and Laiwu populations. The meta-analysis detected four novel QTL on SSC1, 3, 8 and 16 for carcass weight. PMID- 26576867 TI - Ovarian mucinous adenocarcinoma with functioning stroma in postmenopausal women: aromatase and SF-1 expressions. AB - BACKGROUND: A high serum estradiol (E2) level is occasionally detected in postmenopausal women with common epithelial ovarian tumors with functioning stroma. It has been proven that functioning stroma has the capacity to convert androgens to estrogens. However, the mechanism of the initiation and development of functioning stroma remains unclear. CASE PRESENTATION: We present two cases of elevated E2 levels in elderly women with ovarian mucinous adenocarcinomas that contained functioning stroma. Immunohistochemical evaluation revealed high expression levels of aromatase and steroidogenic factor-1 (SF-1), which is considered to be a master regulator of steroidogenesis, in their ovarian stroma. CONCLUSIONS: These cases suggest that overexpression of SF-1 may promote estrogen biosynthesis through regulation of P450 aromatase expression in ovarian tumors with functioning stroma; this in turn induces high serum E2 levels in postmenopausal women with common epithelial ovarian tumors. PMID- 26576868 TI - We have to understand why it's tough at the top. PMID- 26576869 TI - Nurses and NHS to feel the pinch from shake-up in state pensions. PMID- 26576870 TI - Challenging staff attitudes to restraint. PMID- 26576871 TI - Public backs a pay rise for nurses, survey shows. PMID- 26576872 TI - Agency staff may lose money under new tax rules. PMID- 26576873 TI - NMC pledges to improve data-handling processes following security breaches. PMID- 26576874 TI - Nurse directors struggle to balance cuts with ensuring service quality. PMID- 26576876 TI - Healthcare assistants offer one-to-one dementia care. PMID- 26576875 TI - Paris hospitals deny emergency failings. PMID- 26576877 TI - Community nurses 'need career path'. PMID- 26576879 TI - Rio to Cape Town in aid of cancer care. PMID- 26576880 TI - Advocating self-care courses for diabetes patients 'could cut costs'. PMID- 26576881 TI - Nurses face the fallout as junior doctors vote on unsocial hours pay. PMID- 26576887 TI - Menopause. PMID- 26576888 TI - Progress in pain management. PMID- 26576889 TI - It's time to end the attack on nurses' pay. PMID- 26576890 TI - A powerful new voice for nursing. PMID- 26576902 TI - Change4Life drinks tracker. PMID- 26576903 TI - We should not return to the days of a nursing 'underclass'. PMID- 26576905 TI - 'Hello' campaign, out of the news but will never go out of style. PMID- 26576904 TI - 'Homecoming' for children's public health is no cause for celebration yet. PMID- 26576906 TI - Is advocating natural remedies harmful or merely eccentric? PMID- 26576907 TI - A united force can improve stroke care and recovery. PMID- 26576910 TI - Separate trusts are the weak link in the hospital chains proposal. PMID- 26576912 TI - How to perform chest compressions. PMID- 26576913 TI - Effect of erectile dysfunction following prostate cancer treatment. AB - Prostate cancer is the most prevalent non-cutaneous cancer in men worldwide. As a result of increased survival rates, men and their partners are living longer with the sexual sequelae of active treatments for prostate cancer, including surgery, radiotherapy and hormone therapy. The effect of erectile dysfunction on the patient and his partner is complex; many men experience psychosocial effects influenced by their hegemonic masculine beliefs. Some men experience difficulties in addressing their needs and require support while they attempt to reframe their beliefs about masculinity. The PLISSIT model can be used to guide healthcare practitioners in assessing and addressing the needs of this group of patients. The man's partner should be included in assessment and interventions where appropriate. PMID- 26576914 TI - Developing a social media platform for nurses. AB - Social media tools provide opportunities for nurses to connect with colleagues and patients and to advance personally and professionally. This article describes the process of developing an innovative social media platform at a large, multi centre teaching hospital, The Ottawa Hospital, Canada, and its benefits for nurses. The platform, TOH Nurses, was developed using a nursing process approach, involving assessment, planning, implementation and evaluation. The aim of this initiative was to address the barriers to communication inherent in the large number of nurses employed by the organisation, the physical size of the multi centre hospital and the shift-work nature of nursing. The platform was used to provide educational materials for clinical nurses, and to share information about professional practice. The implications of using a social media platform in a healthcare setting were considered carefully during its development and implementation, including concerns regarding privacy and confidentiality. PMID- 26576915 TI - Recognising and managing community-acquired pneumonia. AB - Pneumonia remains a significant cause of morbidity and mortality in the UK and yet the seriousness of the disease is underestimated. Pneumonia can be life threatening because the delicate tissues of the alveoli and pulmonary capillaries are susceptible to damage from the inflammatory response. This damage leads to consolidation that prevents the diffusion of oxygen and carbon dioxide, and this in turn can lead to respiratory failure. This article summarises guidance on the diagnosis and management of community-acquired pneumonia, and also includes information on the prevention of pneumonia. This information should be valuable to nurses working in a variety of clinical areas since patients with community acquired pneumonia are encountered in primary, intermediate, secondary and critical care. PMID- 26576916 TI - Agitation and care. PMID- 26576917 TI - Record as you learn. PMID- 26576919 TI - Doing the rounds in the US. PMID- 26576921 TI - Putting theory into practice every day. PMID- 26576923 TI - Interaction of green tea catechins with renal organic cation transporter 2. AB - 1. Green tea extract (GTE) and EGCG have previously shown to increase the uptake of MPP+ into Caco-2 cells. However, whether GTE and its derivatives interact with renal basolateral organic cation transporter 2 (Oct2) which plays a crucial role for cationic clearance remains unknown. Thus, this study assessed the potential of drug-green tea (GT) catechins and its derivatives interactions with rat Oct2 using renal cortical slices and S2 stably expressing rat Oct2 (S2rOct2). 2. Both GTE and ECG inhibited MPP+ uptake in renal slices in a concentration-dependent manner (IC50 = 2.71 +/- 0.360 mg/ml and 0.87 +/- 0.151 mM), and this inhibitory effect was reversible. Inhibition of [3H]MPP+ transport in S2rOct2 by either GTE or ECG (IC50 = 1.90 +/- 0.087 mg/ml and 1.67 +/- 0.088 mM) was also observed. 3. The weak and reversible interactions of GTE and ECG with rOct2 indicate that consumption of GT beverages could not interfere with cationic drugs secreted via renal OCT2 in humans. However, the rise of therapeutic use of GTE and ECG might have to take into account the significant possibility of adverse drug-green tea catechins interactions which could alter renal organic cation drug clearance. PMID- 26576922 TI - Systemic and coronary levels of CRP, MPO, sCD40L and PlGF in patients with coronary artery disease. AB - BACKGROUND: Biomarkers play a pivotal role in the diagnosis and management of patients with acute coronary syndrome. This study aimed to investigate the differences in level of several biomarkers, i.e. C-reactive protein, myeloperoxidase, soluble CD40 ligand and placental growth factor, between acute coronary syndrome and chronic stable angina patients. The relationship between these biomarkers in the coronary circulation and systemic circulation was also investigated. METHODS: A total of 79 patients were recruited in this study. The coronary blood was sampled from occluded coronary artery, while the peripheral venous blood was withdrawn from antecubital fossa. The serum concentrations of C reactive protein, soluble CD40 ligand and placental growth factor and plasma concentration of myeloperoxidase were measured using ELISA method. RESULTS: The systemic level of the markers measured in the peripheral venous blood was significantly increased in acute coronary syndrome compared to chronic stable angina patients. The concentrations of the C-reactive protein, myeloperoxidase and soluble CD40 ligand taken from peripheral vein were closely similar to the concentration found in coronary blood of ACS patients. The level of placental growth factor was significantly higher in coronary circulation than its systemic level. CONCLUSION: The concentration of these C-reactive protein, myeloperoxidase, soluble CD40 ligand and placental growth factor were significantly increased in acute coronary syndrome patients. The concentration of the markers measured in the systemic circulation directly reflected those in the local coronary circulation. Thus, these markers have potential to become a useful tool in predicting plaque vulnerability in the future. PMID- 26576924 TI - Childhood abuse and deprivation are associated with distinct sex-dependent differences in brain morphology. AB - Childhood adversity (CA) has been associated with long-term structural brain alterations and an increased risk for psychiatric disorders. Evidence is emerging that subtypes of CA, varying in the dimensions of threat and deprivation, lead to distinct neural and behavioral outcomes. However, these specific associations have yet to be established without potential confounders such as psychopathology. Moreover, differences in neural development and psychopathology necessitate the exploration of sexual dimorphism. Young healthy adult subjects were selected based on history of CA from a large database to assess gray matter (GM) differences associated with specific subtypes of adversity. We compared voxel based morphometry data of subjects reporting specific childhood exposure to abuse (n=127) or deprivation (n=126) and a similar sized group of controls (n=129) without reported CA. Subjects were matched on age, gender, and educational level. Differences between CA subtypes were found in the fusiform gyrus and middle occipital gyrus, where subjects with a history of deprivation showed reduced GM compared with subjects with a history of abuse. An interaction between sex and CA subtype was found. Women showed less GM in the visual posterior precuneal region after both subtypes of CA than controls. Men had less GM in the postcentral gyrus after childhood deprivation compared with abuse. Our results suggest that even in a healthy population, CA subtypes are related to specific alterations in brain structure, which are modulated by sex. These findings may help understand neurodevelopmental consequences related to CA. PMID- 26576926 TI - Feasibility of a semi-automated contrast-oriented algorithm for tumor segmentation in retrospectively gated PET images: phantom and clinical validation. AB - PET/CT plays an important role in radiotherapy planning for lung tumors. Several segmentation algorithms have been proposed for PET tumor segmentation. However, most of them do not take into account respiratory motion and are not well validated. The aim of this work was to evaluate a semi-automated contrast oriented algorithm (COA) for PET tumor segmentation adapted to retrospectively gated (4D) images. The evaluation involved a wide set of 4D-PET/CT acquisitions of dynamic experimental phantoms and lung cancer patients. In addition, segmentation accuracy of 4D-COA was compared with four other state-of-the-art algorithms. In phantom evaluation, the physical properties of the objects defined the gold standard. In clinical evaluation, the ground truth was estimated by the STAPLE (Simultaneous Truth and Performance Level Estimation) consensus of three manual PET contours by experts. Algorithm evaluation with phantoms resulted in: (i) no statistically significant diameter differences for different targets and movements (Deltaphi = 0.3 +/- 1.6 mm); (ii) reproducibility for heterogeneous and irregular targets independent of user initial interaction and (iii) good segmentation agreement for irregular targets compared to manual CT delineation in terms of Dice Similarity Coefficient (DSC = 0.66 +/- 0.04), Positive Predictive Value (PPV = 0.81 +/- 0.06) and Sensitivity (Sen. = 0.49 +/- 0.05). In clinical evaluation, the segmented volume was in reasonable agreement with the consensus volume (difference in volume (%Vol) = 40 +/- 30, DSC = 0.71 +/- 0.07 and PPV = 0.90 +/- 0.13). High accuracy in target tracking position (DeltaME) was obtained for experimental and clinical data (DeltaME(exp) = 0 +/- 3 mm; DeltaME(clin) 0.3 +/- 1.4 mm). In the comparison with other lung segmentation methods, 4D-COA has shown the highest volume accuracy in both experimental and clinical data. In conclusion, the accuracy in volume delineation, position tracking and its robustness on highly irregular target movements, make this algorithm a useful tool for 4D-PET based volume definition for radiotherapy planning of lung cancer and may help to improve the reproducibility in PET quantification for therapy response assessment and prognosis. PMID- 26576925 TI - Sialylation of the prion protein glycans controls prion replication rate and glycoform ratio. AB - Prion or PrP(Sc) is a proteinaceous infectious agent that consists of a misfolded and aggregated form of a sialoglycoprotein called prion protein or PrP(C). PrP(C) has two sialylated N-linked carbohydrates. In PrP(Sc), the glycans are directed outward, with the terminal sialic acid residues creating a negative charge on the surface of prion particles. The current study proposes a new hypothesis that electrostatic repulsion between sialic residues creates structural constraints that control prion replication and PrP(Sc) glycoform ratio. In support of this hypothesis, here we show that diglycosylated PrP(C) molecules that have more sialic groups per molecule than monoglycosylated PrP(C) were preferentially excluded from conversion. However, when partially desialylated PrP(C) was used as a substrate, recruitment of three glycoforms into PrP(Sc) was found to be proportional to their respective populations in the substrate. In addition, hypersialylated molecules were also excluded from conversion in the strains with the strongest structural constraints, a strategy that helped reduce electrostatic repulsion. Moreover, as predicted by the hypothesis, partial desialylation of PrP(C) significantly increased the replication rate. This study illustrates that sialylation of N-linked glycans creates a prion replication barrier that controls replication rate and glycoform ratios and has broad implications. PMID- 26576927 TI - Highly efficient heritable plant genome engineering using Cas9 orthologues from Streptococcus thermophilus and Staphylococcus aureus. AB - The application of the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas system of Streptococcus pyogenes (SpCas9) is currently revolutionizing genome engineering in plants. However, synthetic plant biology will require more complex manipulations of genomes and transcriptomes. The simultaneous addressing of different specific genomic sites with independent enzyme activities within the same cell is a key to this issue. Such approaches can be achieved by the adaptation of additional bacterial orthologues of the CRISPR/Cas system for use in plant cells. Here, we show that codon-optimised Cas9 orthologues from Streptococcus thermophilus (St1Cas9) and Staphylococcus aureus (SaCas9) can both be used to induce error-prone non-homologous end-joining mediated targeted mutagenesis in the model plant Arabidopsis thaliana at frequencies at least comparable to those that have previously been reported for the S. pyogenes CRISPR/Cas system. Stable inheritance of the induced targeted mutations of the ADH1 gene was demonstrated for both St1Cas9- and SaCas9-based systems at high frequencies. We were also able to demonstrate that the SaCas9 and SpCas9 proteins enhance homologous recombination via the induction of double strand breaks only in the presence of their species-specific single guide (sg) RNAs. These proteins are not prone to inter-species interference with heterologous sgRNA expression constructs. Thus, the CRISPR/Cas systems of S. pyogenes and S. aureus should be appropriate for simultaneously addressing different sequence motifs with different enzyme activities in the same plant cell. PMID- 26576928 TI - Human immunodeficiency virus and risk of porphyria cutanea tarda: a possible association examined in a large hospital. AB - BACKGROUND: Human immunodeficiency virus (HIV) infection has been reported to be a risk factor for porphyria cutanea tarda (PCT). PURPOSE: To assess the strength of the association between HIV infection and PCT in a large hospital setting. METHODS: All patients (N = 210) diagnosed of PCT between 1990 and 2014 were retrospectively investigated for HIV infection and co-precipitating factors. High performance liquid chromatography was used to assess the appearance of pre-PCT urinary porphyrin abnormalities among a group (N = 22) of HIV-infected patients without PCT using the urine of patients co-infected with hepatitis C virus (HCV) without PCT for comparison. RESULTS: Twenty-six HIV-infected patients (19 males and seven females) were diagnosed of PCT. During the same interval of time, ~8000 different patients infected with HIV were attended in the hospital of infectious diseases department. Examination of risk factors showed that 25 out of 26 of the PCT patients with HIV were co-infected with HCV. No chromatographic abnormalities were found in the urine of non-PCT-HIV-infected patients, whereas 39% co-infected patients showed urinary porphyrin abnormalities. CONCLUSIONS: In our large hospital series, the appearance of PCT among HIV-infected patients is low (<1%) and most present co-infection with HCV. Therefore, in most HIV-infected patients with PCT, hepatitis C and not HIV may induce uroporphyrinogen decarboxylase deficiency. PMID- 26576930 TI - A hierarchically porous anatase TiO2 coated-WO3 2D IO bilayer film and its photochromic properties. AB - A hierarchically porous anatase TiO2 coated-WO3 2D inverse opal (IO) bilayer film was fabricated on ITO glass using a layer by layer route with a hierarchically porous TiO2 top layer and an ordered super-macroporous WO3 2D IO bottom layer. This novel TiO2 coated-WO3 2D IO bilayer film was evaluated for photochromic applications. PMID- 26576929 TI - Early impairment of coronary microvascular perfusion capacity in rats on a high fat diet. AB - BACKGROUND: It remains to be established if, and to what extent, the coronary microcirculation becomes compromised during the development of obesity and insulin resistance. Recent studies suggest that changes in endothelial glycocalyx properties contribute to microvascular dysfunction under (pre-)diabetic conditions. Accordingly, early effects of diet-induced obesity on myocardial perfusion and function were studied in rats under baseline and hyperaemic conditions. METHODS: Rats were fed a high fat diet (HFD) for 6 weeks and myocardial microvascular perfusion was determined using first-pass perfusion MRI before and after adenosine infusion. The effect of HFD on microcirculatory properties was also assessed by sidestream darkfield (SDF) imaging of the gastrocnemius muscle. RESULTS: HFD-fed rats developed central obesity and insulin sensitivity was reduced as evidenced by the marked reduction in insulin-induced phosphorylation of Akt in both cardiac and gastrocnemius muscle. Early diet induced obesity did not lead to hypertension or cardiac hypertrophic remodeling. In chow-fed, control rats a robust increase in cardiac microvascular perfusion was observed upon adenosine infusion (+40%; p < 0.05). In contrast, the adenosine response was abrogated in rats on a HFD (+8%; N.S.). HFD neither resulted in rarefaction or loss of glycocalyx integrity in skeletal muscle, nor reduced staining intensity of the glycocalyx of cardiac capillaries. CONCLUSIONS: Alterations in coronary microcirculatory function as assessed by first-pass perfusion MRI represent one of the earliest obesity-related cardiac adaptations that can be assessed non-invasively. In this early stage of insulin resistance, disturbances in glycocalyx barrier properties appeared not to contribute to the observed changes in coronary microvascular function. PMID- 26576931 TI - Evaluating nursing hours per patient day as a nurse staffing measure. AB - AIMS: To identify the techniques used to measure nurse staffing and to evaluate the reliability, validity and limitations of nursing hours per patient day (NHPPD). BACKGROUND: Numerous studies have attempted to identify appropriate nurse staffing levels; however, variations in nurse staffing measures may have caused inconsistent findings regarding the relationships between nurse staffing and quality of care. EVALUATION: Seventeen studies using nurse staffing measures were reviewed. KEY ISSUES: Six common nurse staffing measures were identified: nurse-to-patient ratios, full-time equivalents, NHPPD, skill mix, nurse-perceived staffing adequacy and nurse-reported number of assigned patients. CONCLUSIONS: Among nurse staffing measures, NHPPD is the most frequently used and is considered to be highly beneficial. This measure shows some evidence of high inter-rater reliability. The predictive validity of NHPPD for patient falls is high, whereas that for pressure ulcers is low. IMPLICATIONS FOR NURSING MANAGEMENT: For NHPPD to be applied more effectively as a nurse staffing measure, there is a need for additional reliability testing in various types of units with large sample sizes; further validity research for additional patient outcomes; appropriate adjustments in its application to capture variations in the characteristics of nurses, patients and hospital units; and a consistent data collection procedure. PMID- 26576932 TI - Comparison of Diverse Differential Plating Methods to Enrich Bovine Spermatogonial Cells. AB - Spermatogonial stem cells (SSC) have important applications in domestic animal reproduction and advanced biotechnologies. Because differential plating is one of the most common methods used for SSC enrichment, the goal of this study was to compare three differential plating methods for the enrichment of bovine SSC. To achieve this goal, testicular parenchyma from pre-pubertal calves was minced and single cells were obtained after two enzymatic digestions. We compared three coating methods for differential plating: laminin (20 ng/ml), BSA (0.05 mg/ml) and PBS. Cells were incubated at 37 degrees C, 5% CO2 in air for 15 min onto laminin-coated dishes or 2 h onto BSA- or PBS-coated dishes. Cell viability was assessed by trypan blue exclusion method. Recovered cells were analysed for the expression of SSC molecular markers by quantitative RT-PCR (GFRA1, CXCR4, ITGA6, THY1) and flow cytometry (GFRA1, CXCR4 and ITGA6). Cells at time 0, adherent cells on laminin and non-adherent cells from BSA and PBS groups had the same cell viability (p = 0.0655). GFRA1, CXCR4 and THY1 relative gene expression was higher (p = 0.0402, p = 0.0007, p = 0.0117, respectively) for non-adherent cells selected in PBS group. Flow cytometry analysis revealed that the presence of GFRA positive (GFRA+) cells was higher in non-adherent cells from BSA and PBS groups (p < 0.001). However, laminin-adherent cells had higher number of ITGA6+ cells (p < 0.001) and lower presence of CXCR4+ cells (p = 0.0012). In conclusion, differential plating is an effective method for the enrichment of bovine undifferentiated spermatogonia and higher expression of SSC markers is obtained without laminin or BSA coating. PMID- 26576933 TI - Molecular Survey of Bartonella Species and Yersinia pestis in Rodent Fleas (Siphonaptera) From Chihuahua, Mexico. AB - Rodent fleas from northwestern Chihuahua, Mexico, were analyzed for the presence of Bartonella and Yersinia pestis. In total, 760 fleas belonging to 10 species were tested with multiplex polymerase chain reaction analysis targeting the gltA (338-bp) and pla genes (478-bp) of Bartonella and Y. pestis, respectively. Although none was positive for Y. pestis, 307 fleas were infected with Bartonella spp., resulting in an overall prevalence of 40.4%. A logistic regression analysis indicated that the presence of Bartonella is more likely to occur in some flea species. From a subset of Bartonella-positive fleas, phylogenetic analyses of gltA gene sequences revealed 13 genetic variants clustering in five phylogroups (I-V), two of which were matched with known pathogenic Bartonella species (Bartonella vinsonii subsp. arupensis and Bartonella washoensis) and two that were not related with any previously described species or subspecies of Bartonella. Variants in phylogroup V, which were mainly obtained from Meringis spp. fleas, were identical to those reported recently in their specific rodent hosts (Dipodomys spp.) in the same region, suggesting that kangaroo rats and their fleas harbor other Bartonella species not reported previously. Considering the Bartonella prevalence and the flea genotypes associated with known pathogenic Bartonella species, we suggest that analysis of rodent and flea communities in the region should continue for their potential implications for human health. Given that nearby locations in the United States have reported Y. pestis in wild animals and their fleas, we suggest conducting larger-scale studies to increase our knowledge of this bacterium. PMID- 26576934 TI - Spatial and Temporal Variation in Aedes aegypti and Aedes albopictus (Diptera: Culicidae) Numbers in the Yogyakarta Area of Java, Indonesia, With Implications for Wolbachia Releases. AB - of mosquito vector populations, particularly through Wolbachia endosymbionts. The success of these strategies depends on understanding the dynamics of vector populations. In preparation for Wolbachia releases around Yogyakarta, we have studied Aedes populations in five hamlets. Adult monitoring with BioGent- Sentinel (BG-S) traps indicated that hamlet populations had different dynamics across the year; while there was an increase in Aedes aegypti (L.) and Aedes albopictus (Skuse) numbers in the wet season, species abundance remained relatively stable in some hamlets but changed markedly (>2 fold) in others. Local rainfall a month prior to monitoring partly predicted numbers of Ae. aegypti but not Ae. albopictus. Site differences in population size indicated by BG-S traps were also evident in ovitrap data. Egg or larval collections with ovitraps repeated at the same location suggested spatial autocorrelation (<250 m) in the areas of the hamlets where Ae. aegypti numbers were high. Overall, there was a weak negative association (r<0.43) between Ae. aegypti and Ae. albopictus numbers in ovitraps when averaged across collections. Ae. albopictus numbers in ovitraps and BG-S traps were positively correlated with vegetation around areas where traps were placed, while Ae. aegypti were negatively correlated with this feature. These data inform intervention strategies by defining periods when mosquito densities are high, highlighting the importance of local site characteristics on populations, and suggesting relatively weak interactions between Ae. aegypti and Ae. albopictus. They also indicate local areas within hamlets where consistently high mosquito densities may influence Wolbachia invasions and other interventions. PMID- 26576935 TI - Monitoring Dry Season Persistence of Anopheles gambiae s.l. Populations in a Contained Semi-Field System in Southwestern Burkina Faso, West Africa. AB - To gain insight into the dry season survival strategies of Anopheles gambiae s.l., a new contained semi-field system was developed and used for the first time in Burkina Faso, West Africa. The system consisted of a screened greenhouse within which the local environment was reproduced, including all ecological requirements for mosquito development cycle completion. The system was seeded with the progenies of female Anopheles gambiae, Anopheles coluzzii, and Anopheles arabiensis collected in the vicinity of the greenhouse during the rainy season. After successful establishment in the semi-field system, mosquito populations were monitored over a 1-yr period by regular surveys of larval and adult specimens. We provided evidence for the persistence of adult mosquitoes throughout the dry season, in the absence of any suitable larval development site. During the hot and dry periods, adult insects were observed in artificial shelters (clay pots, building blocks, and dark corners). The mosquito population rapidly built up with the return of the rainy season in the area, when artificial breeding sites were refilled in the enclosure. However, only An. coluzzii and, later, An. arabiensis were detected in the subsequent rainy season, whereas no An. gambiae specimen was found. Our findings suggest that An. coluzzii and An. arabiensis may be able to aestivate throughout the dry season in Southwestern Burkina Faso, whereas An. gambiae might adopt a different dry-season survival strategy, such as long-distance re-colonization from distant locations. These results may have important implications for malaria control through targeted vector control interventions. PMID- 26576936 TI - Evaluation of Human Attachment by Larval Amblyomma maculatum (Acari: Ixodidae). AB - The tick, Amblyomma maculatum Koch (Gulf Coast tick), has recently been shown to be an important disease vector of both medical and veterinary concern. Although much is known about the behavior and ecology of adults, little is known of the immatures. Larval feeding on humans has never been demonstrated (and thus, there are no collection records from humans). In this experiment, 10 larval A. maculatum, Amblyomma americanum (L.) (a positive control), and Dermacentor variabilis (Say) (a negative control), were applied to both forearms of 10 human volunteers (five male, five female). Ticks were placed in plastic caps and secured to skin with medical-grade adhesive tape, and volunteers remained sedentary during the experiment. After 15 min, caps were removed, and attachment was determined using fine-tipped forceps. Any A. maculatum that were attached were then removed and subsequently examined microscopically to verify identification. In total, 34 ticks attached to the subjects, including 11 A. maculatum (5.5%), 23 A. americanum (11.5%), and no D. variabilis. Amblyomma maculatum attached to six volunteers, and no apparent association between gender and attachment rate was noted. No skin lesions developed in the human volunteers bit by A. maculatum. This is the first report of larval A. maculatum attaching to humans, and is significant in that Rickettsia parkeri, a human pathogen vectored by this species, has recently been reported to be transmitted transovarially. If A. maculatum are infected as larvae, they could potentially transmit R. parkeri to people. PMID- 26576937 TI - Inter- and intramuscular differences in training-induced hypertrophy of the quadriceps femoris: association with muscle activation during the first training session. AB - The purpose of this study was to examine whether inter- and intramuscular differences in hypertrophy induced by resistance training correspond to differences in muscle activation during the first training session. Eleven young men completed 12 weeks of training intervention for knee extension. Before and after the intervention, T1-weighted magnetic resonance (MR) images were recorded to determine the volume and anatomical cross-sectional area (CSA) along the length of the individual muscles of the quadriceps femoris. The T2-weighted MR images were also acquired before and immediately after the first training session. The T2 was calculated for each pixel within the quadriceps femoris, from which the muscle activation was evaluated as %activated volume and area. The results showed that the %activated volume after the first training session was significantly higher in the vastus intermedius than the vastus medialis. However, the relative change in muscle volume after the training intervention was significantly greater in the rectus femoris than the vasti muscles (vastus lateralis, intermedius and medialis). Within the rectus femoris, both the %activated area and relative increase in CSA were significantly greater in the distal region than the proximal region. In contrast, the %activated area and relative increase in CSA of the vasti were nearly uniform along each muscle. These results suggest that the muscle activation during the first training session is associated with the intramuscular difference in hypertrophy induced by training intervention, but not with the intermuscular difference. PMID- 26576938 TI - EpCAM expression in breast cancer cells is associated with enhanced bone metastasis formation. AB - Epithelial cell adhesion molecule (EpCAM) has been implicated in multiple cellular functions including cell adhesion. EpCAM has also recently been identified as a marker for cancer stem cells (CSCs). Here, we examined the roles of EpCAM in the development of bone metastasis of breast cancer by using well characterized animal models. Morphological and real-time reverse transcriptase polymerase chain reaction data showed that the EpCAM-negative and -positive (EpCAM(neg) and EpCAM(pos) ) cell populations isolated from breast cancer cell lines exhibited mesenchymal and epithelial phenotypes, respectively. Flow cytometric analysis revealed that EpCAM(pos) , but not EpCAM(neg) , cells possessed self-renewal and differentiation potentials. Tumorsphere formation in suspension cultures and tumorigenicity in the orthotopic mammary fat pad of mice were significantly greater in EpCAM(pos) cells than in EpCAM(neg) cells. The development of bone metastases induced by an intracardiac injection was markedly increased in mice inoculated with EpCAM(pos) cells. Furthermore, intracardiac inoculations of parental cells demonstrated that the EpCAM(pos) population in cancer cells that colonized in bone was significantly higher than that in parental cells. However, stable transduction of EpCAM into EpCAM(neg) cells failed to reproduce the phenotypes of EpCAM(pos) cells. These results suggest that the expression of EpCAM in breast cancer cells is associated with CSC-like phenotypes, which contribute to the promotion of bone metastases by enhancing tumorigenicity. Our results also support the possibility that the epithelial phenotypes of EpCAM-expressing cells confer advantageous properties for the development of bone metastases, at least after entering the circulation, while EpCAM is likely not solely responsible for the phenotypes of EpCAM(pos) cells. PMID- 26576940 TI - Insights into the development of Ixodes scapularis: a resource for research on a medically important tick species. AB - Ticks (Acari: Ixodida) are arthropod ectoparasites dependent on a bloodmeal from a vertebrate host at each developmental stage for completion of their life cycle. This tick feeding cycle impacts animal health by causing damage to hides, secondary infections, immune reactions and diseases caused by transmission of pathogens. The genus Ixodes includes several medically important species that vector diseases, including granulocytic anaplasmosis and Lyme disease. I. scapularis, commonly called the black-legged or deer tick, is a medically important tick species in North America and therefore was the first tick genome to be sequenced, thus serving as an important resource for tick research. This Primer focuses on the normal developmental cycle and laboratory rearing of I. scapularis. Definition of normal morphology, along with a consistent source of laboratory-reared I. scapularis, are fundamental for all aspects of future research, especially the effects of genetic manipulation and the evaluation of tick vaccine efficacy. Recent research important for the advancement of tick research, namely the development of tick cell culture systems for study of ticks and tick-borne pathogens, RNA interference for genetic manipulation of ticks and discovery of candidate antigens for development of tick vaccines, are briefly presented along with areas to target for future research. PMID- 26576941 TI - Social stress-escalated intermittent alcohol drinking: modulation by CRF-R1 in the ventral tegmental area and accumbal dopamine in mice. AB - RATIONALE: Excessive alcohol (EtOH) drinking is difficult to model in animals despite the extensive human literature demonstrating that stress increases EtOH consumption. OBJECTIVE: The current experiments show escalations in voluntary EtOH drinking caused by a history of social defeat stress and intermittent access to EtOH in C57BL/6J mice compared to non-stressed mice given intermittent EtOH or continuous EtOH. To explore a mechanistic link between stress and drinking, we studied the role of corticotropin-releasing factor type-1 receptors (CRF-R1) in the dopamine-rich ventral tegmental area (VTA). RESULTS: Intra-VTA infusions of a CRF-R1 antagonist, CP376395, infused into the VTA dose-dependently and selectively reduced intermittent EtOH intake in stressed and non-stressed mice, but not in mice given continuous EtOH. In contrast, intra-VTA infusions of the CRF-R2 antagonist astressin2B non-specifically suppressed both EtOH and H2O drinking in the stressed group without effects in the non-stressed mice. Using in vivo microdialysis in the nucleus accumbens (NAc) shell, we observed that stressed mice drinking EtOH intermittently had elevated levels of tonic dopamine concentrations compared to non-stressed drinking mice. Also, VTA CP376395 potentiated dopamine output to the NAc only in the stressed group causing further elevations of dopamine post-infusion. CONCLUSIONS: These findings illustrate a role for extrahypothalamic CRF-R1 as especially important for stress-escalated EtOH drinking beyond schedule-escalated EtOH drinking. CRF-R1 may be a mechanism for balancing the dysregulation of stress and reward in alcohol use disorders. PMID- 26576943 TI - Characterization and application of a novel bioemulsifier in crude oil degradation by Acinetobacter beijerinckii ZRS. AB - Bioemulsifiers can be applicated in a variety of areas such as bioremediation and microbial-enhanced oil recovery. The present study was aimed at bioemulsifier production, optimization, stability studies, and applications of the bioemulsifier produced by one of these strains, Acinetobacter beijerinckii ZRS. When Acinetobacter beijerinckii ZRS is cultured with hexadecane as a carbon source, it produces a novel extracellular emulsifying agent that does not cause remarkable reductions in surface tension. In order to enhance bioemulsifier production, response surface methodology was applied to optimize the culture medium. The bioemulsifier was subjected to thin-layer chromatography, Fourier transform infrared spectroscopy (FTIR), gel filtration chromatography, matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI TOF), and nuclear magnetic resonance (NMR), which allowed for the identification of a novel polymeric bioemulsifier. The bioemulsifier retained its properties at a wide range of pH values, high temperatures and high salinities (up to 5% [w/v] Na(+) and 24% Ca(2+)). To deduce the role of this bioemulsifier in a coastal zone oil spill, the propagation of oil-degrading bacteria on oil-coated grains of gravel immersed in seawater was investigated in beach-simulating tanks. The bioemulsifier played a positive role in the degradation of these hydrocarbons and increasing the light crude oil degradation rate of the bacterial strain from 37.5 to 58.3% within 56 days. Therefore, this bioemulsifier shows strong potential to be used for bioremediation of oil pollution in marine environments. PMID- 26576942 TI - Glucose improves object-location binding in visual-spatial working memory. AB - RATIONALE: There is evidence that glucose temporarily enhances cognition and that processes dependent on the hippocampus may be particularly sensitive. As the hippocampus plays a key role in binding processes, we examined the influence of glucose on memory for object-location bindings. OBJECTIVE: This study aims to study how glucose modifies performance on an object-location memory task, a task that draws heavily on hippocampal function. METHODS: Thirty-one participants received 30 g glucose or placebo in a single 1-h session. After seeing between 3 and 10 objects (words or shapes) at different locations in a 9 * 9 matrix, participants attempted to immediately reproduce the display on a blank 9 * 9 matrix. Blood glucose was measured before drink ingestion, mid-way through the session, and at the end of the session. RESULTS: Glucose significantly improves object-location binding (d = 1.08) and location memory (d = 0.83), but not object memory (d = 0.51). Increasing working memory load impairs object memory and object-location binding, and word-location binding is more successful than shape location binding, but the glucose improvement is robust across all difficulty manipulations. Within the glucose group, higher levels of circulating glucose are correlated with better binding memory and remembering the locations of successfully recalled objects. CONCLUSIONS: The glucose improvements identified are consistent with a facilitative impact on hippocampal function. The findings are discussed in the context of the relationship between cognitive processes, hippocampal function, and the implications for glucose's mode of action. PMID- 26576944 TI - Prospective, randomized comparison of gadopentetate and gadobutrol to assess chronic myocardial infarction applying cardiovascular magnetic resonance. AB - BACKGROUND: We hypothesized that the contrast medium gadobutrol is not inferior compared to Gd-DTPA in identifying and quantifying ischemic late gadolinium enhancement (LGE), even by using a lower dose. METHODS: We prospectively enrolled 30 patients with chronic myocardial infarction as visualized by LGE during clinical routine scan at 1.5 T with 0.20 mmol/kg Gd-DTPA. Participants were randomized to either 0.15 mmol/kg gadobutrol (group A) or 0.10 mmol/kg gadobutrol (group B). CMR protocol was identical in both exams. LGE was quantified using a semiautomatic approach. Signal intensities of scar, remote myocardium, blood and air were measured. Signal to noise (SNR) and contrast to noise ratios (CNR) were calculated. RESULTS: Signal intensities were not different between Gd-DTPA and gadobutrol in group A, whereas significant differences were detected in group B. SNR of injured myocardium (53.5+/-21.4 vs. 30.1+/-10.4, p = 0.0001) and CNR between injured and remote myocardium (50.3+/-20.3 vs. 27.3+/-9.3, p < 0.0001) were lower in gadobutrol. Infarct size was lower in both gadobutrol groups compared to Gd-DTPA (group A: 16.8+/-10.2 g vs. 12.8+/-6.8 g, p = 0.03; group B: 18.6+/-12.0 g vs. 14.0+/-9.9 g, p = 0.0016). CONCLUSIONS: Taking application of 0.2 mmol/kg Gd-DTPA as the reference, the delineation of infarct scar was similar with 0.15 mmol/kg gadobutrol, whereas the use 0.10 mmol/kg gadobutrol led to reduced tissue contrast. TRIAL REGISTRATION: The study had been registered under EudraCT Number: 2010-020775-22. Registration date: 2010.08.10. PMID- 26576946 TI - The efficacy of a blended motivational interviewing and problem solving therapy intervention to reduce substance use among patients presenting for emergency services in South Africa: A randomized controlled trial. AB - BACKGROUND: The treatment of substance use disorders is a public health priority, particularly in South Africa where the prevalence of these disorders is high. We tested two peer-counsellor delivered brief interventions (BIs) for risky substance use among adults presenting to emergency departments (EDs) in South Africa. METHODS: In this randomised controlled trial, we enrolled patients presenting to one of three 24-hour EDs who screened at risk for substance use according to the Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST). Eligible patients were randomly allocated to one of three conditions: Motivational Interviewing (MI), blended MI and Problem Solving Therapy (MI-PST) or a Psycho-educational Control Group (CG). The primary outcome was reduction in ASSIST scores at three months follow-up. RESULTS: Of the 2736 patients screened, 335 met inclusion criteria, were willing to participate in the intervention and were randomised to one of three conditions: 113 to MI, 112 to MI-PST and 110 to CG. ASSIST scores at three months were lower in the MI-PST group than they were in the MI and CG groups (adjusted mean difference of -1.72, 95 % CI -3.36 - 0.08). We recorded no significant difference in ASSIST scores between the CG and MI group (adjusted mean difference of -0.02, 95 % CI -2.01 - 1.96). CONCLUSION: With the addition of minimal resources, BIs are feasible to conduct in EDs in a low resourced country. These preliminary findings report that MI-PST appears to be an effective BI for reducing substance use among at risk participants. Further research is required to replicate these findings with effort to limit attrition, to determine whether reductions in substance use are persistent at 6 and 12 month follow-up and whether parallel changes occur in other indications of treatment outcomes, such as injury rates and ED presentations. TRIAL REGISTRATION: This trial registered with the Pan African Clinical Trial Registry (PACTR201308000591418). PMID- 26576947 TI - Reference-free inference of tumor phylogenies from single-cell sequencing data. AB - BACKGROUND: Effective management and treatment of cancer continues to be complicated by the rapid evolution and resulting heterogeneity of tumors. Phylogenetic study of cell populations in single tumors provides a way to delineate intra-tumoral heterogeneity and identify robust features of evolutionary processes. The introduction of single-cell sequencing has shown great promise for advancing single-tumor phylogenetics; however, the volume and high noise in these data present challenges for inference, especially with regard to chromosome abnormalities that typically dominate tumor evolution. Here, we investigate a strategy to use such data to track differences in tumor cell genomic content during progression. RESULTS: We propose a reference-free approach to mining single-cell genome sequence reads to allow predictive classification of tumors into heterogeneous cell types and reconstruct models of their evolution. The approach extracts k-mer counts from single-cell tumor genomic DNA sequences, and uses differences in normalized k-mer frequencies as a proxy for overall evolutionary distance between distinct cells. The approach computationally simplifies deriving phylogenetic markers, which normally relies on first aligning sequence reads to a reference genome and then processing the data to extract meaningful progression markers for constructing phylogenetic trees. The approach also provides a way to bypass some of the challenges that massive genome rearrangement typical of tumor genomes presents for reference-based methods. We illustrate the method on a publicly available breast tumor single-cell sequencing dataset. CONCLUSIONS: We have demonstrated a computational approach for learning tumor progression from single cell sequencing data using k-mer counts. k-mer features classify tumor cells by stage of progression with high accuracy. Phylogenies built from these k-mer spectrum distance matrices yield splits that are statistically significant when tested for their ability to partition cells at different stages of cancer. PMID- 26576948 TI - Kinesin Kip2 enhances microtubule growth in vitro through length-dependent feedback on polymerization and catastrophe. AB - The size and position of mitotic spindles is determined by the lengths of their constituent microtubules. Regulation of microtubule length requires feedback to set the balance between growth and shrinkage. Whereas negative feedback mechanisms for microtubule length control, based on depolymerizing kinesins and severing proteins, have been studied extensively, positive feedback mechanisms are not known. Here, we report that the budding yeast kinesin Kip2 is a microtubule polymerase and catastrophe inhibitor in vitro that uses its processive motor activity as part of a feedback loop to further promote microtubule growth. Positive feedback arises because longer microtubules bind more motors, which walk to the ends where they reinforce growth and inhibit catastrophe. We propose that positive feedback, common in biochemical pathways to switch between signaling states, can also be used in a mechanical signaling pathway to switch between structural states, in this case between short and long polymers. PMID- 26576949 TI - An aspartyl protease defines a novel pathway for export of Toxoplasma proteins into the host cell. AB - Infection by Toxoplasma gondii leads to massive changes to the host cell. Here, we identify a novel host cell effector export pathway that requires the Golgi resident aspartyl protease 5 (ASP5). We demonstrate that ASP5 cleaves a highly constrained amino acid motif that has similarity to the PEXEL-motif of Plasmodium parasites. We show that ASP5 matures substrates at both the N- and C-terminal ends of proteins and also controls trafficking of effectors without this motif. Furthermore, ASP5 controls establishment of the nanotubular network and is required for the efficient recruitment of host mitochondria to the vacuole. Assessment of host gene expression reveals that the ASP5-dependent pathway influences thousands of the transcriptional changes that Toxoplasma imparts on its host cell. All these changes result in attenuation of virulence of Deltaasp5 tachyzoites in vivo. This work characterizes the first identified machinery required for export of Toxoplasma effectors into the infected host cell. PMID- 26576950 TI - Inhibition by small-molecule ligands of formation of amyloid fibrils of an immunoglobulin light chain variable domain. AB - Overproduction of immunoglobulin light chains leads to systemic amyloidosis, a lethal disease characterized by the formation of amyloid fibrils in patients' tissues. Excess light chains are in equilibrium between dimers and less stable monomers which can undergo irreversible aggregation to the amyloid state. The dimers therefore must disassociate into monomers prior to forming amyloid fibrils. Here we identify ligands that inhibit amyloid formation by stabilizing the Mcg light chain variable domain dimer and shifting the equilibrium away from the amyloid-prone monomer. PMID- 26576952 TI - Synthesis of alpha,beta-Unsaturated Acylsilanes via Perrhenate-Catalyzed Meyer Schuster Rearrangement of 1-Silylalkyn-3-ols. AB - We report the synthesis of alpha,beta-unsaturated acylsilanes via the perrhenate catalyzed Meyer-Schuster rearrangement of 1-silylalkyn-3-ols. Propargylic alcohols derived from TES-acetylene and substituted benzaldehydes can be converted to acylsilanes using a combination of p-TSA.H(2)O and n-Bu(4)N.ReO(4), or Ph(3)SiOReO(3) in good yields. Some propargylic alcohols derived from ketones, as well as aliphatic and unsaturated aldehydes, can also be converted to acylsilanes; however, they were often prone to side reactions. PMID- 26576951 TI - Co-occurrence of resistance genes to antibiotics, biocides and metals reveals novel insights into their co-selection potential. AB - BACKGROUND: Antibacterial biocides and metals can co-select for antibiotic resistance when bacteria harbour resistance or tolerance genes towards both types of compounds. Despite numerous case studies, systematic and quantitative data on co-occurrence of such genes on plasmids and chromosomes is lacking, as is knowledge on environments and bacterial taxa that tend to carry resistance genes to such compounds. This effectively prevents identification of risk scenarios. Therefore, we aimed to identify general patterns for which biocide/metal resistance genes (BMRGs) and antibiotic resistance genes (ARGs) that tend to occur together. We also aimed to quantify co-occurrence of resistance genes in different environments and taxa, and investigate to what extent plasmids carrying both types of genes are conjugative and/or are carrying toxin-antitoxin systems. RESULTS: Co-occurrence patterns of resistance genes were derived from publicly available, fully sequenced bacterial genomes (n = 2522) and plasmids (n = 4582). The only BMRGs commonly co-occurring with ARGs on plasmids were mercury resistance genes and the qacE?1 gene that provides low-level resistance to quaternary ammonium compounds. Novel connections between cadmium/zinc and macrolide/aminoglycoside resistance genes were also uncovered. Several clinically important bacterial taxa were particularly prone to carry both BMRGs and ARGs. Bacteria carrying BMRGs more often carried ARGs compared to bacteria without (p < 0.0001). BMRGs were found in 86 % of bacterial genomes, and co-occurred with ARGs in 17 % of the cases. In contrast, co-occurrences of BMRGs and ARGs were rare on plasmids from all external environments (<0.7 %) but more common on those of human and domestic animal origin (5 % and 7 %, respectively). Finally, plasmids with both BMRGs and ARGs were more likely to be conjugative (p < 0.0001) and carry toxin-antitoxin systems (p < 0.0001) than plasmids without resistance genes. CONCLUSIONS: This is the first large-scale identification of compounds, taxa and environments of particular concern for co-selection of resistance against antibiotics, biocides and metals. Genetic co-occurrences suggest that plasmids provide limited opportunities for biocides and metals to promote horizontal transfer of antibiotic resistance through co-selection, whereas ample possibilities exist for indirect selection via chromosomal BMRGs. Taken together, the derived patterns improve our understanding of co-selection potential between biocides, metals and antibiotics, and thereby provide guidance for risk-reducing actions. PMID- 26576953 TI - Laryngopharyngeal symptoms in patients with chronic obstructive pulmonary disease. AB - The aim of the study was to report on the prevalence and severity of laryngopharyngeal symptoms in patients with COPD compared to controls. A total of 27 patients with COPD and 13 controls matched according to age and gender were included. Demographic data included age, gender, history of smoking and history of allergic rhinitis. The Reflux symptom Index described by Belafsky et al. was used. The frequency and average score of each of the laryngopharyngeal symptoms were computed. The mean age of patients was 61.67 +/- 11.09 years. Ninety-two percent were smokers and 11.1 % had allergy rhinitis. The mean of Total Reflux Symptom index in patients was significantly higher compared to controls (12.70 +/ 7.06 vs. 3.00 +/- 2.94). In the COPD group, 18 subjects had a positive Reflux symptom index (>11) compared to one in the control group (p value <0.05). There was also a significant difference between the means of six laryngopharyngeal symptoms in patients vs. CONTROLS: COPD patients had higher degree of hoarseness, throat clearing, excessive throat mucus, cough and sticking sensation in the throat. Laryngopharyngeal reflux is more prevalent in patients vs. CONTROLS: The frequency and severity of laryngopharyngeal symptoms is significantly higher in COPD patients. PMID- 26576954 TI - Zenker's diverticulum: Rotterdam experience. AB - Different surgical techniques exist for the treatment of Zenker's diverticulum (ZD), of which minimally invasive techniques have become the standard. We reviewed our experience with management and treatment of ZD and sought to determine what type of treatment is most effective and efficient. We selected patients who underwent treatment for ZD between January 2004 and January 2014 at our tertiary referral center. All procedures were performed by ENT surgeons. The medical records were reviewed for pre- and intraoperative characteristics and follow-up. Of our 94 patients (58 male, 36 female), 75 underwent endoscopic cricopharyngeal myotomy (42 stapler, 33 laser) and 6 received treatment via transcervical approach. 13 interventions were aborted. Mean operating time was 49.0 min for stapler, 68.3 for laser and 124.0 for the transcervical approach. Its respective median post-operative admission durations were 2.0, 3.0 and 3.0 days. After the first treatment, of the 75 endoscopic procedures, 45 patients (23 stapler, 22 laser) had complete symptom resolution. In the transcervical group 4 (67 %) patients were symptom free and one patient died of complications. In the endoscopically treated patients, ten complications occurred, of which 8 G1 and 2 G2 (Clavien Dindo classification). In the transcervical group 2 complications occurred, 1 G3b and 1 G5. Both endoscopic techniques provide efficient management of Zenker's diverticulum with the stapler-assisted modality providing a shorter surgery duration and hospital admission. Although there is no significant difference in terms of complications or recurrence rates for both endoscopic techniques, it seems that stapler patients are at higher risk of having a re intervention and of having more severe complications. PMID- 26576955 TI - Genotypic diversity and cariogenicity of Candida albicans from children with early childhood caries and caries-free children. AB - BACKGROUND: The genotypic diversity and cariogenicity of C. albicans from the dental plaque of children are poorly understood. This study aimed to explore the genotypic diversity and cariogenicity of C. albicans from children with early childhood caries and caries-free children. METHODS: Dental plaque samples from 238 children with early childhood caries and from 125 caries-free children were collected for C. albicans isolation. A PCR method based on 25S rDNA was used to analyze C. albicans genotypes, and the strains with different genotypes were tested with regard to acidogenicity and aciduricity. RESULTS: Among 129 C. albicans isolates, 79 (61.2 %) belonged to genotype A. The distribution frequency of genotypes A and C or genotypes B and C showed no significant difference between children with early childhood caries and caries-free children (p = 0.178 and 0.148), whereas genotypes A and B exhibited significantly different distributions (p = 0.010). No significant differences in aciduricity were found among the three genotypes, but the acidogenicity of genotypes B and C differed significantly from that of genotype A at pH 4.0. CONCLUSIONS: The genotypic distribution of C. albicans is associated with the caries experience of children, and the genotype may be related to its acidogenicity at pH 4.0. PMID- 26576956 TI - The Integration of Medical Toxicology and Addiction Medicine: a New Era in Patient Care. AB - Medical toxicologists are frequently called upon to treat patients who are addicted to alcohol, tobacco, or other substances across many care settings. Medical toxicologists provide service to their patients through the identification, treatment, and prevention of addiction and its co-morbidities, and practice opportunities are quite varied. Training in addiction medicine can be obtained during or after medical toxicology fellowship through resources offered by the American Society of Addiction Medicine. Additionally, the American Board of Addiction Medicine offers certification in the specialty of addiction medicine to candidates across a wide range of medical specialties. PMID- 26576957 TI - MicroRNA124 Regulated Neurite Elongation by Targeting OSBP. AB - MicroRNA-124 (miR-124), a brain-specific miRNA molecule, has been implicated in stimulating neurite outgrowth and elongation during neuronal differentiation. However, the direct target genes and the mechanisms of miR-124-induced neurite outgrowth are poorly understood. In this study, we demonstrated that miR-124 directly targeted and downregulated the endogenous expression of oxysterol binding protein (OSBP). A previous study found that the expression of miR-124 increased during brain development. In the present study, we demonstrated that the expression of OSBP decreased during the development of the C57BL/6 mouse cortex, which was negatively correlated with miR-124 expression. OSBP knockdown using specific shRNAs promoted neurite outgrowth and elongation in both Neuro-2a cells and primary cultured mouse cortical neurons. Conversely, OSBP overexpression strongly repressed the neurite elongation-enhancing effect of miR 124 in Neuro-2a cells. Our results suggested that OSBP may be a target and downstream effector of miR-124 for regulating neurite outgrowth and elongation. PMID- 26576958 TI - Meal frequency in relation to prevalence of functional dyspepsia among Iranian adults. AB - OBJECTIVE: Limited data are available linking diet-related practices to functional dyspepsia (FD). The aim of this study was to investigate the association between meal frequency and prevalence of FD among a large sample of Iranian adults. METHODS: In this cross-sectional study, 4763 individuals from the general adult population in Isfahan were asked to report on how many main meals and snacks they consumed each day. Frequency of total meals was defined by summing up the frequency of main meals and snacks. Participants were grouped into four categories: less than three, three to five, six to seven, and eight or more meals daily. FD symptoms were assessed using a validated Persian version of the Rome III questionnaire, and FD was defined as bothersome postprandial fullness, early satiation, and/or epigastric pain or epigastric burning. RESULTS: Compared with individuals who had one main meal per day, those who consumed three main meals daily had a lower chance for early satiation (odds ratio [OR], 0.44; 95% confidence interval [CI], 0.21-0.90). Findings from the analysis on snack frequency revealed that, compared with those who never consumed snacks, individuals who consumed three to five snacks daily were 39% less likely to have FD (OR, 0.61; 95% CI, 0.40-0.92), had 42% lower odds of postprandial fullness (OR, 0.58; 95% CI, 0.34-0.98), and were at 43% lower risk for epigastric pain (OR, 0.57; 95% CI, 0.34-0.97). After adjustment for potential confounders, including diet-related behaviors, individuals who consumed six to seven total meals and snacks per day had lower odds of FD (OR, 0.51; 95% CI, 0.31-0.82) compared with those with who ate fewer than three meals and snacks daily. A similar inverse association was seen between meal and snack frequency and early satiation (OR, 0.32; 95% CI, 0.16-0.63) and postprandial fullness (OR, 0.54; 95% CI, 0.29-0.98). CONCLUSION: Results from the present study demonstrated an inverse association between meal and snack frequency and prevalence of FD and its components. Prospective studies are required to confirm these findings. PMID- 26576959 TI - Vitamin B12 concentration and its association with sociodemographic factors in Colombian children: Findings from the 2010 National Nutrition Survey. AB - OBJECTIVE: Rapid changes in dietary patterns, economic development, and urbanization in low- to middle-income countries are fueling complex malnutrition states that need better characterization using population-level data. The aim of this study was to describe the key findings related to vitamin B12 status to identify the prevalence and associated sociodemographic factors in a representative sample of children in Colombia, based on the 2010 National Nutrition Survey. METHODS: We analyzed cross-sectional data from 6910 Colombian children between the ages of 5 and 12. Serum vitamin B12 concentrations were determined by chemiluminescence. Sociodemographic data was assessed by computer assisted personal interview technology. RESULTS: Of the children assessed, 2.8% had vitamin B12 deficiency, defined as levels <200 pg/mL, and 18.1% had marginal vitamin B12 deficiency, defined as levels between 200 and 300 pg/mL. A multivariate logistic regression analysis revealed increased risks for vitamin B12 deficiency among children ages >=9 y and for those living in the eastern, western, and southern regions of the country. No significant associations were found for ethnic groups, socioeconomic status, or urbanity levels. Being 11 y of age (odds ratio [OR], 2.16; 95% confidence interval [CI], 1.56-3.00; P = 0.0001), living in the west (Pacific) region of the country (OR, 3.92; 95% CI, 3.14-4.90; P = 0.0001), and being male (OR, 1.41; 95% CI, 1.20-1.65; P = 0.0001) were the factors most strongly associated with an increased risk for vitamin B12 deficiency. CONCLUSIONS: Compared with data from other Latin American countries, Colombian children have a lower prevalence of vitamin B12 deficiency; however the prevalence of marginal deficiency is substantial. Continued surveillance and implementation of interventions to improve dietary patterns among the high-risk groups identified should be considered. PMID- 26576960 TI - The associations between proprotein convertase subtilisin/kexin type 9 E670G polymorphism and the risk of coronary artery disease and serum lipid levels: a meta-analysis. AB - BACKGROUND: Studies had investigated the associations between proprotein convertase subtilisin/kexin type 9 (PCSK9) E670G polymorphism and coronary artery disease (CAD) and lipid levels, but the results were controversial. Thus, we performed this meta-analysis to investigate the association between PCSK9 E670G polymorphism and lipid levels and the susceptibility to CAD. METHODS: All relevant articles according to the inclusion criteria were retrieved and included in the present meta-analysis. Odds ratios (ORs) with 95 % confidence interval (CI) were used to analyze the strength of the association between PCSK9 E670G polymorphism and the susceptibility to CAD. At the same time, the pooled standardized mean difference (SMD) with 95 % CI was used for the meta-analysis of PCSK9 E670G polymorphism and lipid levels. The publication bias was examined by using Begg's funnel plots and Egger's test. RESULTS: A total of seventeen studies met the inclusion criteria. For CAD association, the pooled effects indicated that the G allele carriers had higher risk of CAD than non-carriers in dominant genetic model (OR:1.601, 95 % CI: 1.314-1.951, P < 0.001), as well as in allelic genetic model (OR: 1.546, 95 % CI: 1.301-1.838, P < 0.001). When the subgroup analysis stratified by ethnicity and HWE was performed, the positive result existed in most of the subgroups. For lipid levels association, the pooled effects indicated that the G allele carriers had higher TC and LDL-C levels than the non-carriers (for TC, SMD: 0.126, 95 % CI: 0.023-0.229, P = 0.016; for LDL-C, SMD: 0.170, 95 % CI: 0.053-0.287, P = 0.004, respectively). There was no difference in the levels of TG and HDL-C between the G carriers and the non carriers in the whole population (SMD: 0.031, 95 % CI: -0.048-0.110, P = 0.440; SMD: -0.123, 95 % CI: -0.251-0.006, P = 0.061, respectively). When the studies were stratified by ethnicity and type of study, the G carriers had higher TC levels than the non-carriers (SMD: 0.126, 95 % CI: 0.014-0.238, P = 0.027) in the non-Asian subgroup. The similar results existed in cohort subgroup. The association between PCSK9 E670G polymorphism and LDL-C levels was significant in all subgroups. Meanwhile, the G carriers had higher TG levels than the non carriers (SMD: 0.113, 95 % CI: 0.012-0.214, P = 0.028) in the case-control subgroup. AG + GG genotypes had lower HDL-C levels than AA genotype in Asian subgroup (SMD: -0.224, 95 % CI: -0.423- -0.025, P = 0.027) and in case-control subgroup (SMD: -0.257, 95 % CI: -0.467--0.048, P = 0.016). CONCLUSIONS: The present meta-analysis concluded that PCSK9 E670G polymorphism was associated with CAD risk and lipid levels. PMID- 26576962 TI - Erythematous induration of the chest. PMID- 26576961 TI - An expanded search for simian foamy viruses (SFV) in Brazilian New World primates identifies novel SFV lineages and host age-related infections. AB - BACKGROUND: While simian foamy viruses have co-evolved with their primate hosts for millennia, most scientific studies have focused on understanding infection in Old World primates with little knowledge available on the epidemiology and natural history of SFV infection in New World primates (NWPs). To better understand the geographic and species distribution and evolutionary history of SFV in NWPs we extend our previous studies in Brazil by screening 15 genera consisting of 29 NWP species (140 monkeys total), including five genera (Brachyteles, Cacajao, Callimico, Mico, and Pithecia) not previously analyzed. Monkey blood specimens were tested using a combination of both serology and PCR to more accurately estimate prevalence and investigate transmission patterns. Sequences were phylogenetically analyzed to infer SFV and host evolutionary histories. RESULTS: The overall serologic and molecular prevalences were 42.8 and 33.6 %, respectively, with a combined assay prevalence of 55.8 %. Discordant serology and PCR results were observed for 28.5 % of the samples, indicating that both methods are currently necessary for estimating NWP SFV prevalence. SFV prevalence in sexually mature NWPs with a positive result in any of the WB or PCR assays was 51/107 (47.7 %) compared to 20/33 (61 %) for immature animals. Epidemiological analyses revealed an increase in SFV prevalence with age in captive Cebus monkeys. Phylogenetic analysis identified novel SFVs in Cacajao, Leontopithecus, and Chiropotes species that had 6-37 % nucleotide divergence to other NWP SFV. Comparison of host and SFV phylogenies showed an overall cospeciation evolutionary history with rare ancient and contemporaneous host switching for Saimiri and Leontopithecus and Cebus xanthosternos, respectively. CONCLUSIONS: We identified novel SFV in four neotropical monkey genera in Brazil and demonstrate that SFV prevalence increases with age in Cebus monkeys. Importantly, our test results suggest that both molecular and serological screening are currently required to accurately determine infection with NWP SFV. Our study significantly expands knowledge of the epidemiology and natural history of NWP SFVs. The tools and information provided in our study will facilitate further investigation of SFV in NWPs and the potential for zoonotic infection with these viruses. PMID- 26576963 TI - Casuistry as common law morality. AB - This article elaborates on the relation between ethical casuistry and common law reasoning. Despite the frequent talk of casuistry as common law morality, remarks on this issue largely remain at the purely metaphorical level. The article outlines and scrutinizes Albert Jonsen and Stephen Toulmin's version of casuistry and its basic elements. Drawing lessons for casuistry from common law reasoning, it is argued that one generally has to be faithful to ethical paradigms. There are, however, limitations for the binding force of paradigms. The most important limitations--the possibilities of overruling and distinguishing paradigm norms- are similar in common law and in casuistry, or so it is argued. These limitations explain why casuistry is not necessarily overly conservative and conventional, which is one line of criticism to which casuists can now better respond. Another line of criticism has it that the very reasoning from case to case is extremely unclear in casuistry. I suggest a certain model of analogical reasoning to address this critique. All my suggestions to understand and to enhance casuistry make use of common law reasoning whilst remaining faithful to Jonsen and Toulmin's main ideas and commitments. Further developed along these lines, casuistry can appropriately be called "common law morality." PMID- 26576964 TI - Putting phenomenology in its place: some limits of a phenomenology of medicine. AB - Several philosophers have recently argued that phenomenology is well-suited to help understand the concepts of health, disease, and illness. The general claim is that by better analysing how illness appears to or is experienced by ill individuals--incorporating the first-person perspective--some limitations of what is seen as the currently dominant third-person or 'naturalistic' approaches to understand health and disease can be overcome. In this article, after discussing some of the main insights and benefits of the phenomenological approach, I develop three general critiques of it. First, I show that what is often referred to as naturalism tends to be misunderstood and/or misrepresented, resulting in straw-man arguments. Second, the concept of normality is often problematically employed such that some aspects of naturalism are actually presupposed by many phenomenologists of medicine. Third, several of the key phenomenological insights and concepts, e.g. having vs. being a body, the alienation of illness, the epistemic role of the first-person perspective, and the idea of health within illness, each bring with them new problems that limit their utility. While acknowledging the possible contributions of phenomenology, these criticisms point to some severe limitations of bringing phenomenological insights to bear on the problems facing philosophy of medicine that should be addressed if phenomenology is to add anything substantially new to its debates. PMID- 26576965 TI - Barriers to psychological care among primary caregivers of children undergoing hematopoietic stem cell transplantation. AB - PURPOSE: This substudy of an intervention trial aimed to describe barriers to participation in psychological care among primary caregivers of children who were about to undergo a hematopoietic stem cell transplantation (HSCT), including demographic and medical correlates. METHOD: Three hundred and twelve primary caregivers of children undergoing HSCT who were approached to participate in a psychological intervention trial (n = 218 enrollees and 94 decliners) completed a measure of barriers to psychological care. RESULTS: The most frequently endorsed barriers to care were focusing on the child as priority, not wanting to leave the child's bedside, and already having adequate psychosocial support. The least frequently endorsed barriers were location, wait times, and stigma around seeking psychological care. CONCLUSIONS: Results suggest that explaining how psychological care for a primary caregiver can positively affect their ill child may reduce barriers to seeking needed support services. Certain practical barriers to care may be irrelevant in inpatient settings where psychological support is offered. PMID- 26576966 TI - "I didn't actually know there was such a thing as rehab": survivor, family, and clinician perceptions of rehabilitation following treatment for head and neck cancer. AB - PURPOSE: The purpose of this study was to obtain first-hand contributions from survivors, family members, and front-line health care professionals regarding the rehabilitation needs for head and neck cancer (HNC) patients, to inform development of a rehabilitation intervention. METHODS: The researchers conducted a series of focus groups with the three key stakeholder groups. RESULTS: A total of seven focus groups with 40 participants were conducted, two with survivors, one with family members, and four with health care professionals. All three participant groups reported that motivation based on a strong desire to return to meaningful roles and activities, and rehabilitation resources embedded within the cancer system were important facilitators of functional recovery. Lack of access to rehabilitation services was a concern expressed repeatedly. CONCLUSION: While generalization is limited by the small sample size, findings include a comprehensive list of rehabilitation needs following treatment for HNC, factors that facilitate and hinder recovery of functional health, and specific suggestions for the development of rehabilitation consult intervention for survivors of HNC. PMID- 26576967 TI - Symptom burden in long-term germ cell tumor survivors. AB - PURPOSE: Testicular germ cell tumor (GCT) and its treatment may cause distressing long-term symptoms. We aimed to examine self-reported symptom frequency and distress as well as the impact of demographic and medical characteristics in GCT survivors. METHODS: A total of 164 GCT survivors receiving follow-up care at the University Cancer Center Hamburg and a specialized private practice facility were interviewed at a median time of 11.6 years after first diagnosis. Metastatic disease was present in 48 % of the patients and relapse had occurred in 17 %. The patients completed the short form of the Memorial Symptom Assessment Scale (MSAS SF) assessing 28 physical and 4 psychological symptoms. RESULTS: The mean number of physical symptoms was 4.5 (SD = 4.3) (psychological symptoms M = 1.4, SD = 1.4; total M = 5.9, SD = 5.2). The most frequent physical symptoms were lack of energy (49 %), feeling drowsy (42 %), sleeping problems (36 %), and difficulty in concentration (32 %). Lack of energy was experienced as highly distressing by 21 % of the patients. The most frequent psychological symptoms were irritability (47 %) and being worried (42 %). The number of physical symptoms was associated with higher age, lower socioeconomic status, and shorter time since diagnosis in multivariate regression analyses controlling for metastatic vs. localized disease, relapse, extent of surgery, number of chemotherapy cycles, and radiotherapy. CONCLUSIONS: GCT survivors suffered from a significant number of long-term symptoms. Fatigue-related symptoms were most frequent and perceived as highly distressing. Continuous attention toward fatigue is necessary throughout follow-up care to offer support in time, particularly in more vulnerable patients of higher age and lower socioeconomic status. PMID- 26576968 TI - Educational activities in the community and live demonstrations of ultrasonography. PMID- 26576969 TI - Enhanced mechanical damage to in vitro cancer cells by high-intensity-focused ultrasound in the presence of microbubbles and titanium dioxide. AB - PURPOSE: To evaluate in vitro the feasibility of therapeutic high-intensity focused ultrasound (HIFU) combined with microbubbles and titanium dioxide (TiO2). METHODS: Oral squamous cell carcinoma cells (HSC-2) were sonicated using a HIFU transducer with a resonant frequency of 3.5 MHz, 30 mm in diameter, and focal length of 50 mm. The ultrasound intensity was 210 W/cm(2), and two pulses (0.5 s each) were sonicated for each cell sample (9 * 10(4) cells per well). Immediately after HIFU, the viable cells were measured by an automated cell counter. The survival rate was measured in the presence of microbubbles (Sonazoid) and peroxo titania-silica (R-P-TS) or anatase titania-silica (R-A-TS) TiO2. RESULTS: Cell viability immediately following sonication in the presence of TiO2 (R-A-TS) and TiO2 (R-P-TS) was 65.5 +/- 0.7 and 59.4 +/- 3.3 %, respectively. A marked decrease in cell viability was seen when microbubbles were added to the above cell conditions. Specifically, cell viability decreased to 14.0 +/- 0.1 and 4.4 +/- 0.9 % when microbubbles were added to samples containing TiO2 (R-A-TS) and TiO2 (R-P-TS), respectively. CONCLUSION: Immediate in vitro cell killing was observed with short pulsed duration HIFU sonication with a combination of microbubbles and TiO2. This finding suggests that TiO2 could have caused enhanced mechanical cell destruction by microbubbles. PMID- 26576970 TI - New approach for local cancer treatment using pulsed high-intensity focused ultrasound and phase-change nanodroplets. AB - PURPOSE: The aim of this study was to investigate the combination effects of pulsed HIFU (pHIFU) and phase-change nanodroplets (PCND) as a sensitizer on efficient induction of mechanical effects of pHIFU and chemically enhanced tumor growth inhibition for local anti-tumor therapy. METHOD: Changes in growth of colon 26 tumor tissue inoculated onto CDF1 mice were evaluated by the following treatments. (1) pHIFU exposure (1.1 MHz, 3.2 kW/cm(2), 300 cycles, and 50 ms interval) for 60 s, (2) PCND (1 %) injection, (3) adriamycin (4 mg/kg) injection, (4) pHIFU exposure after PCND injection, and (5) pHIFU exposure after PCND + adriamycin injection simultaneously. RESULTS: Significant changes in tumor growth were observed in the group with combination of pHIFU and PCND, although single therapy did not show any significant difference. PCND enhanced mechanical tissue fractionation by pHIFU, which was detectable by Real-time tissue elastography. Moreover, the combination of pHIFU and PCND + Adriamycin suppressed the tumor growth for 2 weeks, and 3 of 4 mice did not show any sign of regrowth during the 30-day observation. CONCLUSION: The combination of pHIFU and PCND exerted a significant anti-tumor effect and may be a new candidate for treatment of locally advanced cancer. PMID- 26576971 TI - Ultrasound up-regulates expression of heme oxygenase-1 gene in endothelial cells. AB - PURPOSE: We found heme oxygenase-1 (HO-1) gene up-regulation in response to ultrasound stimulation in endothelial cells. This project was started to explore the mechanism since it could be applied clinically. METHODS: Quantitative real time PCR experiments were conducted to determine the appropriate condition to up regulate HO-1 gene expression. A promoter assay experiment and a microarray analysis were done to analyze signal transduction pathways to be activated in endothelial cells by ultrasound stimulation. RESULTS: Approximately, 33-fold up regulation of HO-1 mRNA was observed when endothelial cells were exposed to 1-MHz ultrasound at 0.3 W/cm(2) and DF 10 % for 20 s. Data obtained from promoter analysis and microarray analysis suggested that the Nrf2/StRE signal pathway was involved in the up-regulation. In addition, ultrasound stimulation to endothelial cells changed its gene expression profile so that it could modify the anti inflammatory, antioxidant, and vasodilatory activities in addition to pro angiogenic and vascular reconstitution activities of endothelial cells. CONCLUSION: It was suggested that ultrasound stimulation of endothelial cells up regulated HO-1 expression through intracellular oxidative stress, which subsequently changed the gene expression pattern so that it could modify vascular functions. PMID- 26576972 TI - Weighted Capon beamformer combined with coded excitation in ultrasound imaging. AB - BACKGROUND: Capon-based beamformers are well-known methods to improve the SNR and quality of medical ultrasound images. Furthermore, they can improve the resolution of the images unexpectedly more than conventional DAS beamformers. Another method used in radar, sonar, and ultrasound imaging to increase the SNR is coded excitation with linear frequency-modulated signal (chirp). METHOD: In this paper, we illustrate that the combination of coded excitation with a Capon beamformer provides better resolution and higher SNR. However, this combination suffers from high sidelobe levels. We propose a weighted Capon beamformer (WCB) with chirp excitation to suppress the sidelobes and obtain a higher contrast with approximately the same resolution as the standard Capon beamformer (SCB). The weights of the WCB are obtained using element-wise multiplication of the weights of the SCB and a desired window (Hanning) with the same dimension. RESULTS: The results show a 20 dB reduction in the sidelobe levels in simulated point targets and a 6 dB increase in background contrast in simulated cyst phantoms. PMID- 26576973 TI - Modeling the thermo-acoustic effects of thermal-dependent speed of sound and acoustic absorption of biological tissues during focused ultrasound hyperthermia. AB - PURPOSE: To evaluate the effects of thermal dependence of speed of sound (SOS) and acoustic absorption of biological tissues during noninvasive focused ultrasound (US) hyperthermia therapy. METHODS: A finite element (FE) model was used to simulate hyperthermia therapy in the liver by noninvasive focused US. The model consisted of an ultrasonic focused transducer radiating a four-layer biological medium composed of skin, fat, muscle, and liver. The acoustic field and temperature distribution along the layers were obtained after 15 s of hyperthermia therapy using the bio-heat equation. The model solution was found with and without the thermal dependence of SOS and acoustic absorption of biological tissues. RESULTS: The inclusion of the thermal dependence of the SOS generated an increment of 0.4 mm in the longitudinal focus axis of the acoustic field. Moreover, results indicate an increment of the hyperthermia area (zone with temperature above 43 degrees C), and a maximum temperature difference of almost 3.5 degrees C when the thermal dependence of absorption was taken into account. CONCLUSION: The increment of the achieved temperatures at the treatment zone indicated that the effects produced by the thermal dependence of SOS and absorption must be accounted for when planning hyperthermia treatment in order to avoid overheating undesired regions. PMID- 26576974 TI - Effects of horizontal console position on operator muscular stress during cardiac ultrasonic diagnosis. AB - Ultrasound examinations tend to put sonographers in unnatural postures, which may lead to musculoskeletal disorders. In order to address this issue, in this study, we focused on the horizontal position of the console of a diagnostic ultrasound system to quantitatively assess the influence of the work plane position on musculoskeletal stress cardiac ultrasonic diagnosis in the bed-sitting position. Five subjects were asked to simulate a scanning task that involved touching five points on the console, setting the work plane at different positions in the space. Electromyogram of each part of the body indicated that the least stressful position of the left hand was about 350 mm from the center of the trunk in the longitudinal (front-rear) direction and 100 mm left from the center of the trunk in the lateral (left-right) direction. It is necessary to rotate the console in front of the operator for this purpose. PMID- 26576975 TI - Quantitative sonographic image analysis for hepatic nodules: a pilot study. AB - PURPOSE: The aim of this study was to investigate the feasibility of quantitative image analysis to differentiate hepatic nodules on gray-scale sonographic images. METHODS: We retrospectively evaluated 35 nodules from 31 patients with hepatocellular carcinoma (HCC), 60 nodules from 58 patients with liver hemangioma, and 22 nodules from 22 patients with liver metastasis. Gray-scale sonographic images were evaluated with subjective judgment and image analysis using ImageJ software. Reviewers classified the shape of nodules as irregular or round, and the surface of nodules as rough or smooth. RESULTS: Circularity values were lower in the irregular group than in the round group (median 0.823, 0.892; range 0.641-0.915, 0.784-0.932, respectively; P = 3.21 * 10(-10)). Solidity values were lower in the rough group than in the smooth group (median 0.957, 0.968; range 0.894-0.986, 0.933-0.988, respectively; P = 1.53 * 10(-4)). The HCC group had higher circularity and solidity values than the hemangioma group. The HCC and liver metastasis groups had lower median, mean, modal, and minimum gray values than the hemangioma group. Multivariate analysis showed circularity [standardized odds ratio (OR), 2.077; 95 % confidential interval (CI) = 1.295 3.331; P = 0.002] and minimum gray value (OR 0.482; 95 % CI = 0.956-0.990; P = 0.001) as factors predictive of malignancy. The combination of subjective judgment and image analysis provided 58.3 % sensitivity and 89.5 % specificity with AUC = 0.739, representing an improvement over subjective judgment alone (68.4 % sensitivity, 75.0 % specificity, AUC = 0.701) (P = 0.008). CONCLUSION: Quantitative image analysis for ultrasonic images of hepatic nodules may correlate with subjective judgment in predicting malignancy. PMID- 26576976 TI - Effect of obstructive jaundice on hepatic hemodynamics: use of Sonazoid-enhanced ultrasonography in a prospective study of the blood flow balance between the hepatic portal vein and hepatic artery. AB - PURPOSE: To prospectively clarify the effects of obstructive jaundice (OJ) on hepatic hemodynamics using contrast-enhanced ultrasonography (US). METHODS: Subjects comprised 14 patients admitted to our hospital for OJ between April 2013 and March 2014. Contrast-enhanced US was performed using the LOGIQ E9 ultrasound device during the jaundice phase, before biliary drainage, and again after improvement of jaundice. After injecting the Sonazoid contrast agent, contrast dynamics were recorded in the right kidney and liver segments 5 or 6. Prototype software was used to calculate mean arrival time (AT) of the contrast agent in the liver parenchyma. Statistical analysis was performed to compare the mean AT in the jaundice and improved jaundice phases. RESULTS: We were unable to follow up three of the 14 patients after biliary drainage; thus, we included 11 patients for further analysis. The mean AT of the contrast agent was 2.0 +/- 1.8 and 6.1 +/- 2.3 s in the jaundice and improved jaundice phases, respectively, showing significantly shorter AT in the jaundice phase (p = 0.0033). CONCLUSION: Our findings indicate that OJ may influence the blood flow balance between the hepatic portal vein and hepatic artery. PMID- 26576977 TI - A preliminary prospective study to compare the diagnostic performance of assist strain ratio versus manual strain ratio. AB - OBJECTIVES: The objectives of this study were to demonstrate the non-inferiority of assist strain ratio (ASR)-a newly developed application tool-to manual strain ratio (MSR)-a currently available standard diagnostic tool-and to calculate the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of MSR and ASR. METHODS: Ninety-eight mass lesions in the mammary gland (30 malignant and 68 benign) were included in the study. Skilled physicians performed the elastography scanning by applying minimal vibration. MSRs were obtained and compared with ASRs calculated from the same elastography image to test the correlation between the two groups of data. RESULTS: Diagnostic performance of MSR at a cut-off of 5.0 showed a sensitivity of 84.4 %, a specificity of 80.4 %, an accuracy of 81.6 %, a PPV of 65.5 %, and an NPV of 92.1 %. Diagnostic performance of ASR at a cut-off of 5.0 showed a sensitivity of 74.4 %, a specificity of 84.3 %, an accuracy of 81.3 %, a PPV of 67.7 %, and an NPV of 88.2 %. The areas under the curve (AUCs) for MSR and ASR were found to be 0.885 and 0.875, respectively. CONCLUSION: ASR demonstrated excellent diagnostic potential and was highly correlated with MSR performed by skilled physicians (r = 0.69, p < 0.05). PMID- 26576978 TI - The role of transvaginal power Doppler ultrasound in the differential diagnosis of benign intrauterine focal lesions. AB - PURPOSE: The purpose of this prospective study was to assess the role of power Doppler imaging in the differential diagnosis of benign intrauterine focal lesions such as endometrial polyps and submucous myomas using the characteristics of power Doppler flow mapping. METHODS: A total of 480 premenopausal patients with abnormal uterine bleeding were evaluated by transvaginal ultrasonography (TVS) searching for intrauterine pathology. Sixty-four patients with a suspicious focal endometrial lesion received saline infusion sonography (SIS) after TVS. Fifty-eight patients with focal endometrial lesions underwent power Doppler ultrasound (PDUS). Three different vascular flow patterns were defined: Single vessel pattern, multiple vessel pattern, and circular flow pattern. Finally, hysteroscopic resection was performed in all cases, and Doppler flow characteristics were then compared with the final histopathological findings. RESULTS: Histopathological results were as follows: endometrial polyp: 40 (69 %), submucous myoma: 18 (31 %). Of the cases with endometrial polyps, 80 % demonstrated a single vessel pattern, 7.5 % a multiple vessel pattern, and 0 % a circular pattern. Vascularization was not observed in 12.5 % of patients with polyps. Of the cases with submucousal myomas, 72.2 % demonstrated a circular flow pattern, 27.8 % a multiple vessel pattern, and none of them showed a single vessel pattern. The sensitivity, specificity, and positive and negative predictive values of the single vessel pattern in diagnosing endometrial polyps were 80, 100, 100, and 69.2 %, respectively; and for the circular pattern in diagnosing submucous myoma, these were 72.2, 100, 100, and 88.9 %, respectively. CONCLUSION: Power Doppler blood flow mapping is a useful, practical, and noninvasive diagnostic method for the differential diagnosis of benign intrauterine focal lesions. Especially in cases of recurrent abnormal uterine bleeding, recurrent abortion, and infertility, PDUS can be preferred as a first line diagnostic method. PMID- 26576979 TI - Incomplete excision or postoperative hematoma: primary right ventricular intramyocardial lipoma involving the right ventricular outflow tract. AB - Primary benign cardiac tumors are relatively rare, and lipomas are even less frequent. We presented a case of primary intramyocardial lipoma involving the right ventricular outflow tract diagnosed through transthoracic echocardiography and surgical pathology. The tumor was completely resected. Surprisingly, an echogenic mass similar to the one seen before the operation in terms of the echogenicity and morphological characteristics was found at the same location 1 week after the complete resection. Was it an incomplete excision or a postoperative hematoma? After regular echocardiographic follow-up, the echogenic mass disappeared. It was inferred that the echogenic mass may have been a postoperative intramyocardial hematoma. PMID- 26576980 TI - Hepatic inflammatory pseudotumor: educational value of an incorrect diagnosis at contrast-enhanced ultrasound. AB - Hepatic inflammatory pseudotumor (IPT) is a rare lesion that is frequently confused with malignant tumors. According to the latest guidelines on contrast enhanced ultrasound, hypoenhancement of solid lesions in the portal and late phases corresponds to the wash-out phenomenon that characterizes malignancies. IPT may show rapid arterial enhancement and portal or late phase hypoenhancement, falsely suggesting malignancy. We report a case of a diagnostic error in which a multifocal IPT was misdiagnosed as hepatic metastases. The IPT developed after an endoscopic retrograde cholangiography was investigated by close follow-up with CEUS and contrast-enhanced CT. PMID- 26576981 TI - Ultrasonographic findings of pharyngoesophageal diverticulum: two case reports and review of literature. AB - Pharyngoesophageal diverticulum is a rare disease characterized by an alimentary tract pouch or a circular dilated cavity arising from the esophagus. Barium swallow and endoscopy are the gold standard for the diagnosis of pharyngoesophageal diverticulum. However, routine ultrasonography can be employed as a noninvasive alternative. We report two patients with cervical esophageal diverticulum diagnosed by ultrasonography. It has been reported in the literature that pharyngoesophageal diverticulum resembles a thyroid or parathyroid nodule on ultrasonogram. We summarize the ultrasonic findings of pharyngoesophageal diverticulum to avoid unnecessary fine-needle aspirate biopsy or surgical treatment. PMID- 26576982 TI - Fetal diastematomyelia associated with vertebral malformation: ultrasound, MRI, and pathomorphological findings. AB - Using a specific clinical example, we demonstrate the ability of prenatal magnetic resonance imaging (MRI) to diagnose associated spine and spinal cord malformations in the group of spinal dysraphisms. Thus, the original ultrasound (US) and MRI results for the affected fetus at week 21 are illustrated and described in detail. The paucity of reports of prenatal MR-semiotic findings of split cord malformation comparing US and pathomorphological findings at a relatively early gestational age makes the present case unique and instructive. The outstanding capability of MRI to diagnose spinal pathologies indicates the necessity of including prenatal MRI in the diagnostic algorithm to determine the severity of the lesions and the appropriate management during pregnancy, childbirth, and the early postnatal period. PMID- 26576983 TI - A case of fetal osteogenesis imperfecta type 2A: longitudinal observation of natural course in utero and pitfalls for prenatal ultrasound diagnosis. AB - We present a case of osteogenesis imperfecta (OI) type 2A in which a natural course in utero was observed from 23 weeks' gestation to term. At 23 weeks' gestation, a sonographic examination showed a cloverleaf skull-like head, a narrow thorax, and marked shortening of the long bones with bowing of the femurs and humeri. Follow-up examinations showed that the cloverleaf skull-like head was not evident at 28 weeks' gestation. Discontinuity of the ribs and femurs was observed at 26 and 30 weeks' gestation, respectively. This finding suggested bone fractures, which were confirmed by three-dimensional computed tomography at 32 weeks' gestation. Ultrasonographic findings of bones, including the long bones and calvarium, changed with advancing gestation during the second trimester. Characteristic features of OI type 2A were evident during the late second to early third trimesters. Repeated ultrasonographic examinations together with three-dimensional computed tomography are necessary for the definitive diagnosis of OI type 2A in the second trimester. PMID- 26576984 TI - Prenatal diagnosis and postnatal outcome of persistent right ductus arteriosus: a report of three cases. AB - The ductus arteriosus is a fetal vascular connection between the main pulmonary artery and aorta that diverts blood away from the pulmonary bed. Left and right ductus arteriosi emerge from embryological aortic arches. In normal embryologic cardiac development, both right aortic and ductal arches regress and the left ones persist. Persistent right ductus arteriosus (rDA) is one of the congenital anomalies of the ductal arch. In this paper, we report three cases of persistent right ductus arteriosus with right aortic arch. PMID- 26576985 TI - Ultrasound in diagnosis of intrascrotal metastasis of Wilms' tumor: first case report of a Chinese boy and review of the literature. AB - A 31-month-old boy with Wilms' tumor (WT), which primarily had originated from the left kidney, was treated with nephrectomy and adjuvant chemotherapy. 2 months after nephrectomy, a left scrotal mass was found at routine follow-up. High frequency sonography examination revealed an enlarged left testis with a heterogeneous texture and a hypoechoic solid mass in the left scrotum. Moreover, hypervascular signals presented in both the left testis and the mass on color Doppler flow imaging. Left orchiectomy was performed for suspected intrascrotal metastasis of WT, which was confirmed by histopathology examination. This was the first case of intrascrotal metastasis of WT reported in China with a detailed ultrasound description. Meanwhile, this study also reviewed the comparable diagnostic methods of intrascrotal metastasis of WT found in the English literature. PMID- 26576986 TI - Five neonatal cases of pyriform sinus fistula with cervical cystic lesion: a comparison between sonography and other modalities. AB - Pyriform sinus fistulas are an unusual cause of neck cystic lesions in neonates. A definitive diagnosis requires detection of the fistula, which originates from the pyriform sinus and extends to the cystic lesion. Sonography has been reported to be useful for detecting fistulas. However, there have been no reports of neonatal cases in which sonography could detect fistulas not detected by other modalities, such as barium esophagography, computed tomography (CT), or magnetic resonance imaging (MRI). We describe five neonatal patients with pyriform sinus fistula-appearing cervical cystic lesions. All patients were examined by sonography; of these, three patients were also examined by barium esophagography, two by CT, and one by MRI. The fistula was detected by sonography but not CT in one patient and by barium esophagography but not MRI in one. Two patients whose fistulas were detected by sonography had an oval-shaped and relatively small cystic lesion. One patient whose fistula could be detected only by barium esophagography had a relatively large cystic lesion. In two patients, whose fistulas were not detected by sonography or barium esophagography, sonography revealed air bubbles within the cystic lesions, and a pyriform sinus fistula was suspected. Without requiring ionizing radiation, sonography was thus useful in diagnosing pyriform sinus fistula-appearing cervical cystic lesions in neonatal cases. On the other hand, in two patients whose fistulas were not detected by sonography, the shape of the cystic lesion was polygonal or multicystic. In two of three patients with infectious signs, a fistula could not be detected. The shape and size of the cystic lesion and the presence of infectious signs may be important factors for detecting fistulas. PMID- 26576987 TI - Sonographic and sonoelastographic findings of a rarely seen soft tissue tumor: eccrine spiradenoma. AB - Eccrine spiradenoma is a rare benign tumor originating from sweat glands. Its sonographic characteristics have been described in only a few reports, and there is no such report available that describes sonoelastographic findings of this tumor. In this case report, we aimed to define the sonographic and sonoelastographic findings of a benign eccrine spiradenoma. PMID- 26576988 TI - Chest ultrasound findings in pulmonary alveolar microlithiasis. AB - Pulmonary alveolar microlithiasis (PAM) is a rare disorder of unknown etiology affecting people at any age. It is characterized by multiple and microscopic calcium deposits diffusely localized within the alveoli. Thorax high-resolution computed tomography is considered the gold standard for PAM imaging. Herein we report for the first time the use of trans-thoracic ultrasound (TUS) examination in a young severely obese PAM female patient, diagnosed at the age of 10, and referred to our clinic for re-staging purposes at the age of 36. Unlike expected, no reverberation or additional artifacts were appreciated on TUS examination despite the severity of the interstitial/alveolar involvement seen on conventional CT imaging. To date, no ring-down or comet-tail artifacts were detected. The only TUS finding was an increased thickness and irregular profile, more evident in the dorsal lower lung regions, of the hyper-echoic pleural line. TUS has recently aroused increasing interest among clinicians and radiologists as a useful noninvasive diagnostic tool for studying pleuro-pulmonary diseases, including interstitial lung diseases (ILDs). The peculiarity of our case is represented by the discrepancy between TUS and CT findings. Further efforts to address the usefulness and US patterns in diffuse ILDs, with the inclusion of rare disorders, are needed. PMID- 26576989 TI - Lateral cervical sinus: specific sonographic findings in two pediatric cases. AB - A lateral cervical sinus, also known as a second pharyngeal or branchial cleft fistula/sinus, occurs when the second pharyngeal arch fails to grow caudally over the third and fourth arches, leaving remnants of the second branchial clefts in contact with the surface of the neck via a narrow canal. This type of sinus is detected on the lateral aspect of the neck directly anterior to the sternocleidomastoid muscle. We report two pediatric cases with lateral cervical sinus, and pathognomonic sonographic findings to confirm the diagnosis. The first case involved a 3-month-old boy with a sinus on the lateral neck and occasional drainage from a cervical sinus opening. Sonography revealed that the sinus tract extended between the external and internal carotid arteries. In case two, a 1 month-old girl presented with a sinus on the lateral neck and signs of acute infection at the site of a pinpoint opening. Sonography revealed an oval-shaped cystic lesion and sinus tract extending between the external and internal carotid arteries. Sonography does not require radiation or sedation for children. The best choice for the first examination for lateral cervical sinus is sonography, rather than CT, MRI, or contrast fistulograms. PMID- 26576990 TI - Visualization of the spiral artery jet in fetal growth-restricted pregnancy by utilizing spatiotemporal image correlation with high-definition flow. PMID- 26576991 TI - In memory: Floyd Dunn. PMID- 26576992 TI - Editor's note. PMID- 26576994 TI - Association between smoking intensity and duration and tooth loss among Finnish middle-aged adults: The Northern Finland Birth Cohort 1966 Project. AB - BACKGROUND: Smoking is a risk factor for oral diseases and tooth loss. Our aim was to analyze the association between smoking intensity and duration and tooth loss among middle-aged Finnish adults who have enjoyed access to subsidized dental care since childhood. METHODS: This study was based on the Northern Finland Birth Cohort 1966 (NFBC1966) Project, a representative sample of Finnish 46-year-olds. Altogether 1946 46-year-olds participated in a survey and comprehensive clinical oral examinations. We measured smoking exposure in pack years (intensity) and years of smoking (duration) combined with recent smoking status (current, former, occasional or never). We used negative binomial regression models to estimate the unadjusted and adjusted relative risks (RR) with corresponding 95 % confidence intervals (CI) for tooth loss as an outcome. Gender, education, tooth brushing frequency, dental plaque, diabetes and alcohol use served as explanatory variables for the adjusted models. RESULTS: Smoking intensity associated with tooth loss in an exposure-dependent manner: those with a high number of pack-years had a significantly greater probability of tooth loss than never smokers: 11-20 pack-years (RR = 1.55, 95 % CI = 1.15-2.08) and 21 or more pack-years (RR = 1.78, 95 % CI = 1.36-2.33). Smoking duration also associated with tooth loss: those who had smoked for several years had a significantly higher probability of tooth loss than never smokers: 21-30 years of smoking (RR = 1.66, 95 % CI = 1.29-2.12) and 31 or more years of smoking (RR = 1.72, 95 % CI = 1.20-2.45). CONCLUSIONS: We found a clear intensity- and duration dependent relation between smoking and tooth loss among adults with access to subsidized dental care and in good oral health. PMID- 26576995 TI - A method for accurate spatial registration of PET images and histopathology slices. AB - BACKGROUND: Accurate alignment between histopathology slices and positron emission tomography (PET) images is important for radiopharmaceutical validation studies. Limited data is available on the registration accuracy that can be achieved between PET and histopathology slices acquired under routine pathology conditions where slices may be non-parallel, non-contiguously cut and of standard block size. The purpose of this study was to demonstrate a method for aligning PET images and histopathology slices acquired from patients with laryngeal cancer and to assess the registration accuracy obtained under these conditions. METHODS: Six subjects with laryngeal cancer underwent a (64)Cu-copper-II-diacetyl-bis(N4 methylthiosemicarbazone) ((64)Cu-ATSM) PET computed tomography (CT) scan prior to total laryngectomy. Sea urchin spines were inserted into the pathology specimen to act as fiducial markers. The specimen was fixed in formalin, as per standard histopathology operating procedures, and was then CT scanned and cut into millimetre-thick tissue slices. A subset of the tissue slices that included both tumour and fiducial markers was taken and embedded in paraffin blocks. Subsequently, microtome sectioning and haematoxylin and eosin staining were performed to produce 5-MUm-thick tissue sections for microscopic digitisation. A series of rigid registration procedures was performed between the different imaging modalities (PET; in vivo CT-i.e. the CT component of the PET-CT; ex vivo CT; histology slices) with the ex vivo CT serving as the reference image. In vivo and ex vivo CTs were registered using landmark-based registration. Histopathology and ex vivo CT images were aligned using the sea urchin spines with additional anatomical landmarks where available. Registration errors were estimated using a leave-one-out strategy for in vivo to ex vivo CT and were estimated from the RMS landmark accuracy for histopathology to ex vivo CT. RESULTS: The mean +/- SD accuracy for registration of the in vivo to ex vivo CT images was 2.66 +/- 0.66 mm, and the accuracy for registration of histopathology to ex vivo CT was 0.86 +/ 0.41 mm. Estimating the PET to in vivo CT registration accuracy to equal the PET CT alignment accuracy of 1 mm resulted in an overall average registration error between PET and histopathology slices of 3.0 +/- 0.7 mm. CONCLUSIONS: We have developed a registration method to align PET images and histopathology slices with an accuracy comparable to the spatial resolution of the PET images. PMID- 26576996 TI - Alterations in androgen deprivation enhanced prostate-specific membrane antigen (PSMA) expression in prostate cancer cells as a target for diagnostics and therapy. AB - BACKGROUND: Prostate-specific membrane antigen (PSMA) is a promising target for diagnostics and therapy of prostate carcinoma (PCa). Based on the hypothesis that PSMA expression can be modulated by variations in androgen deprivation therapy (ADT), we investigated the binding of a PSMA-directed radiopharmaceutical in vitro in order to get an insight of the interactions between altered premedication and PSMA expression before repetitive PSMA-directed PET/CT for therapy response and targeted therapy implementation. METHODS: The human castration-resistant PCa cell line VCaP (CRPC) was treated with either 1 nmol/L testosterone (T) over 20 passages yielding the androgen-sensitive cell line (revCRPC) or with 5 MUmol/L abiraterone acetate (AA) generating the abiraterone tolerant subtype CRPCAA. In these cell lines, T and AA were varied by either supply or withdrawal of T and AA. PSMA expression of the three cell culture models was detected by Western blot and immunohistochemical staining. For quantitative measurement of tracer uptake, 0.3 nmol/L (68)Ga-labelled PSMA-HBED CC peptide (100-300 kBq/ml) was added to different treated parallel cultures (n = 9 each). Time-dependent uptake per 10(6) cells of each culture was calculated and evaluated. PSMA mRNA expression was investigated by qPCR. RESULTS: PSMA expression increased dependently on intensified ADT in all three basic cell lines. (68)Ga-PSMA-HBED-CC uptake almost doubled during 3 h in all cell lines (p < 0.01). Compared to the basic cells, pre-incubation with abiraterone for 48 h resulted in a significant increased uptake in CRPC (p < 0.001). In revCRPC, 48-h AA pre-incubation resulted in an eightfold higher uptake after 3 h (p < 0.001). Additional withdrawal of external testosterone increased the uptake up to tenfold (p < 0.01). The increase of PSMA expression upon ADT and AA treatments was confirmed by qPCR and Western blot data. Furthermore, in CRPCAA, 48-h AA withdrawal increased the uptake up to fivefold (p < 0.01). CONCLUSIONS: The investigated three PCa cell culture subtypes represent a serial preclinical model of androgen deprivation therapy as a proxy for clinical situations with differing basal PSMA expression. The uptake of PSMA-binding tracers could be stimulated by therapeutic effective short-term variation in premedication in all stages of ADT response. These complex interactions have to be considered in the interpretation of diagnostic imaging using PSMA ligands as well as in the optimal timing of PSMA based therapies. PMID- 26576997 TI - An Exploratory Analysis of Work Engagement, Satisfaction, and Depression in Psychiatry Residents. AB - OBJECTIVES: This exploratory study aims to measure work engagement levels in psychiatry residents at three psychiatry residency programs using the Utrecht Work Engagement Scale (UWES). In addition, the study investigates the relationship between total engagement and its subscales, resident satisfaction, and a depression screen. METHODS: Recruitment of 53/79 residents from three psychiatry residency programs in Illinois was completed. The residents were administered a questionnaire consisting of the UWES, the Primary Care Evaluation of Mental Disorders (Prime-MD) depression screen, and a residency satisfaction scale. Statistical analysis using independent samples t test and a one-way analysis of variance was used to assess differences on engagement total score and subscales and satisfaction scale. A logistic regression was used with the engagement subscales and the satisfaction scale as predictors of belonging to the depressed or non-depressed group. RESULTS: Psychiatry residents scored in the high range for total engagement and all its subscales except for vigor which was in the moderate range. Residents who screened positive for depression reported lower total engagement than those who were negative on the depression screen. Vigor was the only significant predictor (p = .004) of being in the depressed group after logistic regression. Total engagement and the subscale of dedication significantly predicted overall residency satisfaction (beta = .473, p = .016). CONCLUSIONS: Higher total UWES-15 and its subscales of vigor and dedication are correlated with a lower rate of screening positive for depression and higher residency satisfaction. This exploratory study lends support for further study of this psychological construct in medical training programs, but replication is needed. PMID- 26576998 TI - Development of an Evidence-Based Psychotherapy Seminar for Psychiatry Residency Training. PMID- 26576999 TI - Including International Medical Graduates in Global Mental Health Training. PMID- 26577000 TI - Psychotherapy and Cognitive Behavioral Therapy Supervision in Danish Psychiatry: Training the Next Generation of Psychiatrists. AB - OBJECTIVE: Psychotherapy training is mandatory for physicians to qualify as psychiatrists in Denmark. Evidence for the effectiveness of psychotherapy has increased, and psychotherapy is increasingly included in international treatment guidelines. The authors investigated how psychiatrists in training in Denmark evaluate the opportunities to practice psychotherapy in their training and the quality of the supervision they receive in psychotherapy training, particularly for cognitive behavioral therapy (CBT). METHOD: The authors conducted a survey regarding psychotherapy training and CBT supervision among psychiatrists in training at Danish psychiatric specialist training courses. They investigated respondents' interest and experience in psychotherapy and respondents' views on the relevance and feasibility of performing psychotherapy and receiving supervision in their psychiatry training. RESULTS: Eighty-eight percent of the psychiatrists in training found psychotherapy to be a relevant part of their training; however, 77 % found it difficult to find time to practice psychotherapy and 44 % felt that practicing psychotherapy was a strain on their employer. Thirty-six percent and 53 %, respectively, had difficulties securing psychodynamic and CBT supervision. In CBT supervision, more than 60 % reported supervision that appeared to be below the expected CBT supervision standard and often so much below it might not qualify as CBT supervision. CONCLUSIONS: There is a need to focus on how to better integrate psychotherapy and supervision in the Danish psychiatric training program. Good CBT supervision may be lacking, and a way to ensure high-quality supervision is required. PMID- 26577001 TI - The Access Initiative: Improving Appropriateness of Patient Fit for Resident Case Assignment. PMID- 26577002 TI - Medical Student Education in State Psychiatric Hospitals: A Survey of US State Hospitals. AB - OBJECTIVE: State hospitals may be underutilized in medical education. US state psychiatric hospitals were surveyed on current and potential psychiatry medical student education. METHODS: A 10-item questionnaire, with multiple response formats, was sent to identified hospitals in late 2012. RESULTS: Ninety-seven of 221 hospitals contacted responded. Fifty-three (55%) reported current medical student education programs, including 27 clinical clerkship rotations. Education and training in other disciplines was prevalent in hospitals both with and without medical students. The large majority of responders expressed enthusiasm about medical education. The most frequent reported barrier to new programs was geographic distance from the school. Limited resources were limiting factors for hospitals with and without current programs. CONCLUSIONS: Only a minority of US state hospitals may be involved in medical student education. While barriers such as geographic distance may be difficult to overcome, responses suggest opportunities for expanding medical education in the state psychiatric hospitals. PMID- 26577003 TI - Linear accelerator-based flattening-filter-free stereotactic radiosurgery for trigeminal neuralgia: Feasibility and patient-reported outcomes. AB - PURPOSE: The purpose of this study was to assess the safety and outcomes of the clinical use of LINAC (linear accelerator)-based flattening-filter-free beams for delivering ablative stereotactic radiosurgery (SRS) for trigeminal neuralgia (TN). METHODS AND MATERIALS: Thirty-six consecutive patients (34 unique patients) followed up by a single neurosurgeon and diagnosed with medically refractory unilateral TN were treated with SRS. There were 14 left-sided cases (41%) and 20 right-sided cases (59%). Twenty-eight of the patients (82%) had type 1 TN, and 6 (18%) had type 2 TN. Previous treatments were as follows: 10 patients (29%) had SRS to the ipsilateral TN (8 with Gamma Knife, 2 with LINAC), 4 (12%) had percutaneous rhizotomy, and 3 (9%) had microvascular decompression. A median prescription dose of 75 Gy (range, 70-80 Gy), prescribed to the 100% isodose line, was delivered in a single fraction. Before treatment delivery, image guidance verified stereotactic frame placement, head position, and final isocenter. The volume of brainstem receiving >=10 Gy was <0.5 cm(3). At each visit, patients prospectively reported outcomes using the Barrow Neurological Institute (BNI) pain scale. RESULTS: With a median follow-up of 3.1 months (range, 0.6-24.3; mean, 5.5 months), no patient experienced grade 1+ toxicities. There were no new episodes of dysesthesia, hypoesthesia, or long-term complications related to SRS. Median baseline (pre-SRS) BNI score was 5.0 (mean, 4.7). Clinical assessment at first follow-up (median, 1 month) demonstrated a median BNI score of 3.0 (mean, 3.1). When stratified by TN subtype, both type 1 and type 2 TN patients had a median BNI score of 3.0 at first follow-up. Thirty patients (88.2%) achieved a reduction in their BNI at their first follow-up, and 5 patients (15%) achieved a score <3, which represents medication-free pain relief. The median BNI at second follow-up (average, 6.3 months) was 2.5. CONCLUSIONS: We report our experience with modern LINAC-based SRS using flattening-filter-free beams for TN. This treatment appears to be a safe and effective technique, although longer follow-up is needed to confirm durability. This modality may prove to be a viable treatment alternative for TN. PMID- 26577004 TI - Comparison of bolus electron conformal therapy plans to traditional electron and proton therapy to treat melanoma in the medial canthus. PMID- 26577005 TI - A report of metachronous orbital involvement by IgG4 disease treated successfully with low-dose radiation therapy. PMID- 26577006 TI - Fatal complications after stereotactic body radiation therapy for central lung tumors abutting the proximal bronchial tree. AB - PURPOSE: Stereotactic body radiation therapy (SBRT) is associated with excess toxicity following treatment of central lung tumors. Risk-adapted fractionation appears to have mitigated this risk, but it remains unclear whether SBRT is safe for all tumors within the central lung zone, especially those abutting the proximal bronchial tree (PBT). We investigated the dependence of toxicity on tumor proximity to PBT and whether tumors abutting the PBT had greater toxicity than other central lung tumors after SBRT. MATERIALS AND METHODS: A total of 108 patients receiving SBRT for central lung tumors were reviewed. Patients were classified based on closest distance from tumor to PBT. Primary endpoint was SBRT related death. Secondary endpoints were overall survival, local control, and grade 3+ pulmonary adverse events. We compared tumors abutting the PBT to nonabutting and those <=1 cm and >1 cm from PBT. RESULTS: Median follow-up was 22.7 months. Median distance from tumor to PBT was 1.78 cm. Eighty-eight tumors were primary lung and 20 were recurrent or metastatic; 23% of tumors were adenocarcinoma and 71% squamous cell. Median age was 77.5 years. Median dose was 4500 cGy in 5 fractions prescribed to the 100% isodose line. Eighteen patients had tumors abutting the PBT, 4 of whom experienced SBRT-related death. No other patients experienced death attributed to SBRT. Risk of SBRT-related death was significantly higher for tumors abutting the PBT compared with nonabutting tumors (P < .001). Two patients with SBRT-related death received anti-vascular endothelial growth factor therapy and experienced pulmonary hemorrhage. Patients with tumors <=1 cm from PBT had significantly more grade 3+ events than those with tumors >1cm from PBT (P = .014). CONCLUSIONS: Even with risk-adapted fractionation, tumors abutting PBT are associated with a significant and differential risk of SBRT-related toxicity and death. SBRT should be used with particular caution in central-abutting tumors, especially in the context of anti vascular endothelial growth factor therapy. PMID- 26577007 TI - The use of image guided laser interstitial thermotherapy to supplement spine stereotactic radiosurgery to manage metastatic epidural spinal cord compression: Proof of concept and dosimetric analysis. PMID- 26577008 TI - Practical implementation of quality improvement for high-dose-rate brachytherapy. AB - PURPOSE: High-dose-rate (HDR) brachytherapy is a high-risk procedure with serious errors reported in the medical literature. Our goal was to develop a quality improvement framework for HDR brachytherapy using a multidisciplinary approach. This work describes the time, personnel, and materials involved in implementation as well as staff-reported safety benefits of quality improvement checklists. METHODS AND MATERIALS: Quality improvement was achieved using a department-wide multidisciplinary approach. Process mapping of the entire HDR program, from initial scheduling through follow-up, was performed. The scope of the project was narrowed to the point of treatment delivery. Two types of multidisciplinary checklists were created: a safety-timeout checklist to ensure safety-critical actions were performed before treatment initiation; and detailed procedure checklists that served as written procedures for physicians, physicists, dosimetrists, and nurses. Implementation was carried out through initial training led by various staff members, creation of visual training guides, piloting and use of checklists for all treatments, and auditing of checklist compliance. RESULTS: Process maps of the entire HDR program were generated and used to guide subsequent changes in the treatment delivery process. A single safety-timeout checklist and the individual procedure checklists were created and used at the time of treatment delivery. The 3-month audit showed that the safety-timeout checklist was used for 100% of treatment fractions. Individual procedure checklists were used for 85% of fractions. All cross-covering physicians and physicists continued to use these checklists 100% of the time. Staff survey results indicated improvements in safety and increased benefits for cross covering staff. CONCLUSIONS: In using a multidisciplinary approach to quality improvement, process mapping and comprehensive checklists for HDR treatment delivery have been implemented. This has resulted in improved practices that are optimal in our department. This experience can provide others with practical strategies toward implementing such changes in their own facilities. PMID- 26577009 TI - Patient autonomy and shared decision making in the management of urethral cancer. PMID- 26577010 TI - Intensity modulated radiation therapy reduces gastrointestinal toxicity in locally advanced pancreas cancer. AB - PURPOSE: We compared gastrointestinal (GI) and hematologic toxicity in patients with locally advanced pancreas cancer (LAPC) undergoing definitive chemoradiation using intensity modulated radiation therapy (IMRT) or 3-dimensional conformal radiation therapy (3D-CRT) planning. METHODS AND MATERIALS: We retrospectively studied 205 patients with LAPC undergoing IMRT (n = 134) and 3D-CRT (n = 71) between May 2003 and March 2012. Patient, tumor, and treatment characteristics and acute GI/hematology toxicity according to the Common Terminology Criteria for Adverse Events, version 3.0, were recorded. Multivariable logistic regression models were used to test association between acute grade 2+ GI and hematologic toxicity outcomes and predictors. Propensity score analysis for grade 2+ GI toxicity was performed to reduce bias for confounding variables: age, gender, radiation dose, field size, and chemotherapy type. RESULTS: Median follow-up time for survivors was 22 months and was similar between groups. Median RT dose was significantly higher for IMRT versus 3D-CRT (5600 cGy vs 5040 cGy, P < .001); concurrent chemotherapy was mainly gemcitabine (56%) or 5-fluorouracil (38%). Grade 2+ GI toxicity occurred in 34% (n = 24) of 3D-CRT compared with 16% (n = 21) of IMRT patients. Using propensity score analysis, 3D-CRT had significantly higher grade 2+ GI toxicity (odds ratio, 1.26; 95% confidence interval, 1.08 1.45; P = .001). Grade 2+ hematologic toxicity was similar between IMRT and 3D CRT groups, but was significantly greater in recipients of concurrent gemcitabine than in 5-fluorouracil (62% vs 29%, P < .0001). CONCLUSIONS: IMRT is associated with significant lower grade 2+ GI toxicity versus 3D-CRT for patients undergoing definitive chemoradiation therapy for LAPC. Because IMRT is better tolerated at higher doses and may allow further dose escalation, potentially improving local control for this aggressive disease. Further prospective studies of dose escalated chemoradiation using IMRT are warranted. PMID- 26577011 TI - Evaluating the quality, clinical relevance, and resident perception of the radiation oncology in-training examination: A national survey. AB - PURPOSE: The yearly radiation oncology in-training examination (ITE) by the American College of Radiology is a widely used, norm-referenced educational assessment, with high test reliability and psychometric performance. We distributed a national survey to evaluate the academic radiation oncology community's perception of the ITE. METHODS AND MATERIALS: In June 2014, a 7 question online survey was distributed via e-mail to current radiation oncology residents, program directors, and attending physicians who had completed residency in the past 5 years or junior attendings. Survey questions were designed on a 5-point Likert scale. Sign test was performed with P <= .05 considered statistically different from neutral. RESULTS: Thirty-one program directors (33.3%), 114 junior attendings (35.4%), and 225 residents (41.2%) responded. Junior attendings and program directors reported that the ITE directly contributed to their preparation for the American Board of Radiology written certification (P = .050 and .004, respectively). Residents did not perceive the examination as an accurate assessment of relevant clinical and scientific knowledge (P < .0001) and feel the quality assurance is insufficient in its current form (P < .0001). Residents and junior attendings agree that there are factual errors, and unclear questions/answers (P < .0001 and .04, respectively). Free response suggestions included: less questions on rare disease sites (16.4%), more relevance to clinical practice (15.4%), avoiding questions that discriminate between a few percentage points (11.8%), and designing the test similar to the written certification examination (9.2%). CONCLUSIONS: Despite high examination reliability and psychometric performance, resident and attending physicians report a need for improved quality assurance and clinical relevance in the ITE. Although the current examination allows limited feedback, establishing a venue for individualized feedback may allow continual and timely improvement of the ITE. Adopting a criterion-referenced examination may further increase resident investment in and utilization of this valuable learning tool. PMID- 26577012 TI - High-Nuclearity Silver Thiolate Clusters Constructed with Phosphonates. AB - The n-butylphosphonate ligand has been employed to construct three new silver(I) thiolate compounds. Single-crystal X-ray analysis revealed that complexes 1 and 2 are Ag48 and Ag51 coordination chain polymers, while 3 contains a discrete Ag48 cluster, in which three different kinds of silver(I) thiolate cluster shells enclose three different phosphonate-functionalized silver(I) cluster cores, respectively. The structures of clusters in 1-3 feature three three-shell arrangements, S@Ag12 @(nBuPO3 )9 @Ag36 S23 , S@Ag11 @(nBuPO3 )7 (MoO4 )2 @Ag40 S27 and MoO4 @Ag12 @(nBuPO3 )8 S6 @Ag36 S24 , respectively. PMID- 26577014 TI - Zero-order release of polyphenolic drugs from dynamic, hydrogen-bonded LBL films. AB - Drug carriers capable of releasing drugs at a constant rate, or following zero order kinetics, can lead to the best control of plasma drug concentration. Here we demonstrated that zero-order release of polyphenolic drugs, including tannic acid, epigallocatechin gallate, proanthocyanidins, and theaflavin-3'-gallate, could be achieved using hydrogen-bonded layer-by-layer films as the drug carrier. The films were fabricated using the polyphenolic drugs as hydrogen donors and polyethylene glycol (PEG) as the hydrogen acceptor. Because the drugs and PEG are bonded with reversible, dynamic hydrogen bonds, the films disintegrate gradually in aqueous solutions, and thus release the drugs into the media. Furthermore, because the PEG polymers have a narrow molecular weight distribution, the films disintegrate and release the polyphenolic drugs at a constant rate. Besides allowing for zero-order release, the drug carrier developed here also provides various ways to tune the drug release rate. The drug release rate increases with decreasing molecular weight of PEG. More importantly, the release rate could be tuned using external stimuli. Increasing the pH or temperature results in accelerated drug release, while the addition of salt retards the drug release. PMID- 26577013 TI - The diagnostic potential of MPT63-derived HLA-A*0201-restricted CD8+ T-cell epitopes for active pulmonary tuberculosis. AB - MPT63 protein is found only in Mycobacterium tuberculosis complex, including M. tuberculosis and M. bovis. Detection of MPT63-specific IFN-gamma-secreting T cells could be useful for the diagnosis of tuberculosis (TB) diseases. In the present study, the HLA-A*0201 restriction of ten predicted MPT63-derived CD8(+) T cell epitopes was assessed on the basis of T2 cell line and HLA-A*0201 transgenic mice. The diagnostic potential of immunogenic peptides in active pulmonary TB patients was evaluated using an IFN-gamma enzyme-linked immunospot assay. It was found that five peptides bound to HLA-A*0201 with high affinity, whereas the remaining peptides exhibited low affinity for HLA-A*0201. Five immunogenic peptides (MPT6318-26 , MPT6329-37 , MPT6320-28 , MPT635-14 and MPT6310-19 ) elicited large numbers of cytotoxic IFN-gamma-secreting T cells in HLA-A*0201 transgenic mice. Each of the five immunogenic peptides was recognized by peripheral blood mononuclear cells from 45% to 73% of 40 HLA-A*0201 positive TB patients. The total diagnostic sensitivity of the five immunogenic peptides was higher than that of a T-SPOT.TB assay (based on ESAT-6 and CFP-10) (93% versus 90%). It is noticeable that the diagnostic sensitivity of the combination of five immunogenic peptides and T-SPOT.TB assay reached 100%. These MPT63-derived HLA A*0201-restricted CD8(+) T-cell epitopes would likely contribute to the immunological diagnosis of M. tuberculosis infection and may provide the components for designing an effective TB vaccine. PMID- 26577015 TI - 33 Years of Peritoneal Dialysis-Associated Peritonitis: A Single-Center Study in Japan. AB - Peritoneal dialysis-associated peritonitis (PD-associated peritonitis) could influence the outcome of PD patients, including technique survival. Although the use of the twin-bag system has decreased the incidence of peritonitis, the effects of biocompatible PD solutions are controversial. Additionally, since both infection-causing microorganisms and antimicrobial therapies have changed over time, the duration of treatment of peritonitis (the duration of peritonitis) seems to have changed. The study included 527 patients who received PD between January 1980 and December 2012 at a single center. We divided patients undergoing PD into three groups according to the type of PD system used, namely single-bag and conventional PD solutions (S+C group, N = 145), twin-bag and conventional PD solutions (T+C group, N = 171) and twin-bag and biocompatible PD solutions (T+B group, N = 211), and analyzed PD-associated peritonitis incidences. Incidences of PD-associated peritonitis (times per patient-months) and peritonitis-free time were 1/59.4, 1/70.6 and 1/103.1, and 52, 97, and 100 months for the S+C, T+C and T+B groups, respectively. The duration of peritonitis, has thus, become dramatically shorter in recent years. Streptococcus sp. were associated with shortest and fungi with longest durations of peritonitis. Staphylococcus sp. and Pseudomonas aeruginosa were predominant in the S+C group. The twin-bag system has made a greater contribution to reductions in PD-associated peritonitis than biocompatible PD solutions. Furthermore, changes in microorganisms, antimicrobial therapies, patient education and improved PD system devices have presumably affected the reduction in the duration of peritonitis. PMID- 26577016 TI - Disruption of S2-M4 linker coupling reveals novel subunit-specific contributions to N-methyl-d-aspartate receptor function and ethanol sensitivity. AB - The N-methyl-d-aspartate (NMDA) receptor is a glutamatergic ion channel and is a known site of ethanol action. Evidence suggests that ethanol inhibits NMDA receptor activity by reducing channel open probability and mean open time potentially via interaction with specific residues within the transmembrane (M) domains 3 and 4 of GluN subunits. Recent models of NMDAR function demonstrate that extracellular residues near the M domains are key regulators of gating, suggesting that they may contribute to ethanol sensitivity. To test this, we substituted cysteines at key positions in GluN1 and GluN2 M3-S2 and S2-M4 regions previously shown to affect channel open probability and mean open time similar to ethanol treatment. Although crosslinking of these domains was predicted to restrict linker domain movement and occlude ethanol inhibition, only intra-GluN1 M1:M4 linker-crosslinked receptors showed a decrease in ethanol sensitivity. For the converse experiment, we expressed NMDARs with glycine substitutions in the S2 M4 domain of GluN subunits to enhance M4 flexibility and recorded currents in response to ethanol. Glycine substitution in the GluN1 S2-M4 region significantly decreased glutamate potency of GluN1(A804G)/GluN2A receptors, while GluN1(A804G)/GluN2B receptors exhibited no change in glutamate sensitivity. In contrast, GluN1/GluN2B(S811G) receptors showed a 10-fold increase in glutamate potency while GluN1/GluN2A(S810G) receptors showed no change. Surprisingly, while S2-M4 glycine substitutions modulated ethanol sensitivity, this was observed only in receptors that did not display a change in agonist potency. Overall, these results suggest that S2-M4 linkers strongly influence receptor function and modestly impact ethanol efficacy in a subunit- and receptor subtype-dependent manner. PMID- 26577017 TI - Purine nucleosides in neuroregeneration and neuroprotection. AB - In the present review, we stress the importance of the purine nucleosides, adenosine and guanosine, in protecting the nervous system, both centrally and peripherally, via activation of their receptors and intracellular signalling mechanisms. A most novel part of the review focus on the mechanisms of neuronal regeneration that are targeted by nucleosides, including a recently identified action of adenosine on axonal growth and microtubule dynamics. Discussion on the role of the purine nucleosides transversally with the most established neurotrophic factors, e.g. brain derived neurotrophic factor (BDNF), glial derived neurotrophic factor (GDNF), is also focused considering the intimate relationship between some adenosine receptors, as is the case of the A2A receptors, and receptors for neurotrophins. This article is part of the Special Issue entitled 'Purines in Neurodegeneration and Neuroregeneration'. PMID- 26577018 TI - Sodium butyrate attenuates social behavior deficits and modifies the transcription of inhibitory/excitatory genes in the frontal cortex of an autism model. AB - The core behavioral symptoms of Autism Spectrum Disorders (ASD) include dysregulation of social communication and the presence of repetitive behaviors. However, there is no pharmacological agent that is currently used to target these core symptoms. Epigenetic dysregulation has been implicated in the etiology of ASD, and may present a pharmacological target. The effect of sodium butyrate, a histone deacetylase inhibitor, on social behavior and repetitive behavior, and the frontal cortex transcriptome, was examined in the BTBR autism mouse model. A 100 mg/kg dose, but not a 1200 mg/kg dose, of sodium butyrate attenuated social deficits in the BTBR mouse model. In addition, both doses decreased marble burying, an indication of repetitive behavior, but had no significant effect on self-grooming. Using RNA-seq, we determined that the 100 mg/kg dose of sodium butyrate induced changes in many behavior-related genes in the prefrontal cortex, and particularly affected genes involved in neuronal excitation or inhibition. The decrease in several excitatory neurotransmitter and neuronal activation marker genes, including cFos Grin2b, and Adra1, together with the increase in inhibitory neurotransmitter genes Drd2 and Gabrg1, suggests that sodium butyrate promotes the transcription of inhibitory pathway transcripts. Finally, DMCM, a GABA reverse agonist, decreased social behaviors in sodium-butyrate treated BTBR mice, suggesting that sodium butyrate increases social behaviors through modulation of the excitatory/inhibitory balance. Therefore, transcriptional modulation by sodium butyrate may have beneficial effects on autism related behaviors. PMID- 26577019 TI - Long-term efficacy of lipoprotein apheresis in the management of familial hypercholesterolaemia: Application of two different apheresis techniques in childhood. AB - Lipoprotein apheresis is used to treat patients with familial hypercholesterolemia (FH). The aim of the present study is to clarify the lipoprotein apheresis procedure performed by cascade filtration (CF) or double filtration plasmapheresis (DFPP) on pediatric patients in terms of side effects, laboratory results and cardiovascular follow-up. Data of ten pediatric patients were analyzed retrospectively. The average age of the patients was 12.1 +/- 3.4 years. Percentage of long term reduction of low density lipoprotein cholesterol was 62.35 +/- 7.19% (n = 3) for CF and 63.66 +/- 6.63% (n = 3) for CF plus DFPP, 64.79 +/- 8.29% (n = 7) for DFPP. Cardiovascular disease was not detected in thirty percent of the patients. Lesions remained stable in fifty percent of patients with heart valve lesions. Valvular lesions worsened in twenty percent of patients. Lipoprotein apheresis can be used effectively and successfully in pediatric patients as well as adults for homozygous FH. PMID- 26577020 TI - Web-Based Immersive Virtual Patient Simulators: Positive Effect on Clinical Reasoning in Medical Education. AB - BACKGROUND: Clinical reasoning is based on the declarative and procedural knowledge of workflows in clinical medicine. Educational approaches such as problem-based learning or mannequin simulators support learning of procedural knowledge. Immersive patient simulators (IPSs) go one step further as they allow an illusionary immersion into a synthetic world. Students can freely navigate an avatar through a three-dimensional environment, interact with the virtual surroundings, and treat virtual patients. By playful learning with IPS, medical workflows can be repetitively trained and internalized. As there are only a few university-driven IPS with a profound amount of medical knowledge available, we developed a university-based IPS framework. Our simulator is free to use and combines a high degree of immersion with in-depth medical content. By adding disease-specific content modules, the simulator framework can be expanded depending on the curricular demands. However, these new educational tools compete with the traditional teaching OBJECTIVE: It was our aim to develop an educational content module that teaches clinical and therapeutic workflows in surgical oncology. Furthermore, we wanted to examine how the use of this module affects student performance. METHODS: The new module was based on the declarative and procedural learning targets of the official German medical examination regulations. The module was added to our custom-made IPS named ALICE (Artificial Learning Interface for Clinical Education). ALICE was evaluated on 62 third-year students. RESULTS: Students showed a high degree of motivation when using the simulator as most of them had fun using it. ALICE showed positive impact on clinical reasoning as there was a significant improvement in determining the correct therapy after using the simulator. ALICE positively impacted the rise in declarative knowledge as there was improvement in answering multiple-choice questions before and after simulator use. CONCLUSIONS: ALICE has a positive effect on knowledge gain and raises students' motivation. It is a suitable tool for supporting clinical education in the blended learning context. PMID- 26577021 TI - Eicosapentaenoic acid inhibits intestinal beta-carotene absorption by downregulation of lipid transporter expression via PPAR-alpha dependent mechanism. AB - The involvement of lipid transporters, the scavenger receptor class B, type I (SR BI) and Niemann-Pick type C1 Like 1 protein (NPC1L1) in carotenoid absorption is demonstrated in intestinal cells and animal models. Dietary omega-3 fatty acids are known to possess antilipidemic properties, which could be mediated by activation of PPAR family transcription factors. The present study was conducted to determine the effect of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), on intestinal beta-carotene absorption. beta-carotene uptake in Caco-2/TC7 cells was inhibited by EPA (p < 0.01) and PPARalpha agonist (P < 0.01), but not by DHA, PPARgamma or PPARdelta agonists. Despite unaltered beta-carotene uptake, both DHA and PPARdelta agonists inhibited the NPC1L1 expression. Further, EPA also induced the expression of carnitine palmitoyl transferase 1A (CPT1A) expression, a PPARalpha target gene. Interestingly, EPA induced inhibition of beta-carotene uptake and SR B1 expression were abrogated by specific PPARalpha antagonist, but not by PPARdelta antagonist. EPA and PPARalpha agonist also inhibited the basolateral secretion of beta-carotene from Caco-2 cells grown on permeable supports. These results suggest that EPA inhibits intestinal beta carotene absorption by down regulation of SR B1 expression via PPARalpha dependent mechanism and provide an evidence for dietary modulation of intestinal beta-carotene absorption. PMID- 26577022 TI - Bioconversion of (13)C-labeled microalgal phytosterols to cholesterol by the Northern Bay scallop, Argopecten irradians irradians. AB - Bivalve mollusks lack de novo cholesterol biosynthesis capabilities and therefore rely upon dietary sources of sterols for rapid growth. Microalgae that constitute the main source of nutrition for suspension-feeding bivalves contain a diverse array of phytosterols, in most cases lacking cholesterol. Rapid growth of bivalves on microalgal diets with no cholesterol implies that some phytosterols can satisfy the dietary requirement for cholesterol through metabolic conversion to cholesterol, but such metabolic pathways have not been rigorously demonstrated. In the present study, stable isotope-labeled phytosterols were used to supplement a unialgal diet of Rhodomonas sp. and their biological transformation to cholesterol within scallop tissues was determined using (13)C NMR spectroscopy. Scallops efficiently dealkylated ?(5) C29 (24-ethyl) sterols to cholesterol, and the only C28 sterol that was dealkylated efficiently possessed the 24(28)-double bond. Non-metabolized dietary phytosterols accumulated in the soft tissues. Observed formation of ?(5,7) sterols (provitamin D) from ?(5) sterols may represent initiation of steroid hormone (possibly ecdysone) biosynthesis. These findings provide a key component necessary for formulation of nutritionally complete microalgal diets for hatchery production of seed for molluscan aquaculture. PMID- 26577023 TI - Pulmonary artery wedge pressure and exercise oscillatory ventilation in pre capillary pulmonary hypertension. PMID- 26577024 TI - Linguistic ostracism causes prejudice: Support for a serial mediation effect. AB - This research investigated the effects of linguistic ostracism, defined as any communication setting in which a target individual (or group) is ostracized by another individual (or group) in a language that the target has extremely limited ability to understand. Participants were included or ostracized by their group members during a computer-mediated group discussion. Half of the ostracized participants were linguistically ostracized via their group members conversing with one another in a language the participant did not know well (Spanish Ostracism: SO), or in a language the participant did know well (English Ostracism: EO). SO participants reported feeling less similar than both included and EO participants. SO participants also reported being angrier and expressed more prejudice than included participants (and EO participants using effect size estimates). Results also provided support for the hypothesized serial mediation model. Findings are discussed in terms of implications for intergroup relations. PMID- 26577025 TI - Steroid hormones, prostanoids, and angiogenic systems during rescue of the corpus luteum in pigs. AB - In order to characterize the transition of the corpora lutea (CL) from acquisition of luteolytic sensitivity to rescue of luteal function: i) the expression of 38 factors associated with steroids, prostanoids, and angiogenic systems and ii) concentrations of the main hormones responsible for maintenance of CL function in cyclic and pregnant pigs were examined. Additionally, the effect of prostaglandin (PG) E2 and F2 alpha on luteal function during the estrous cycle and pregnancy was evaluated in vitro. Significantly up-regulated gene expression was revealed in CL collected on day 14 of the estrous cycle (CYP19A1, ESR2, PTGS2, HIF1A, and EDN1) and on days 12-14 of pregnancy (SCARB1, PGRMC1, STAR, HSD3B1, NR5A1, PTGFR, PTGER4, and VEGFA). Elevated concentrations of estradiol-17beta and PGE2 occurred in CL on days 12 and 14 of pregnancy respectively, while an increased intraluteal PGF2 alpha content was noted on day 14 of the estrous cycle. Both PGs increased the synthesis of progesterone by cultured luteal slices obtained on day 14 of pregnancy, in contrast to the action of PGF2 alpha on the corresponding day of the estrous cycle. PGE2 stimulated cAMP production via PTGER2 and PTGER4, while PGF2 alpha elevated the content of CREB in cultured luteal slices from CL of pregnant pigs. In silico analysis showed that infiltration of lymphocytes and apoptosis of microvascular endothelium were activated in CL on day 12 of the estrous cycle vs pregnancy. Summarizing, an abundance of E2 and PGE2 during pregnancy regulates specific pathways responsible for steroidogenesis, the prostanoid signaling system and angiogenesis during rescue from luteolysis in porcine CL. PMID- 26577026 TI - Peripheral blood monocyte and T cell subsets in children with specific polysaccharide antibody deficiency (SPAD). AB - Specific polysaccharide antibody deficiency (SPAD) is a well reported immunodeficiency characterized by a failure to produce antibodies against polyvalent polysaccharide antigens, expressed by encapsulated microorganisms. The clinical presentation of these patients involves recurrent bacterial infections, being the most frequent agent Streptococcus (S.) pneumoniae. In SPAD patients few reports refer to cells other than B cells. Since the immune response to S. pneumoniae and other encapsulated bacteria was historically considered restricted to B cells, the antibody deficiency seemed enough to justify the repetitive infections in SPAD patients. Our purpose is to determine if the B cell defects reported in SPAD patients are accompanied by defects in other leukocyte subpopulations necessary for the development of a proper adaptive immune response against S. pneumoniae. We here report that age related changes observed in healthy children involving increased percentages of classical monocytes (CD14++ CD16- cells) and decreased intermediate monocytes (CD14++ CD16+ cells), are absent in SPAD patients. Alterations can also be observed in T cells, supporting that the immune deficiency in SPAD patients is more complex than what has been described up to now. PMID- 26577027 TI - The role of Jahn-Teller distortion in insulator to semiconductor phase transition in organic-inorganic hybrid compound (p-chloroanilinium)2CuCl4 at high pressure. AB - (p-Chloroanilinium)2CuCl4(C2H14Cl6CuN2) is from an important family of organic inorganic layered hybrid compounds which can be a possible candidate for multiferroicity. In situ high pressure FTIR, Raman and resistivity measurements on this compound indicate the weakening of Jahn-Teller distortion and the consequent removal of puckering of the CuCl6(4-) octahedra within the layer. These effects trigger insulator to semiconductor phase transition along with a change in the sample colour from yellow to dark red. This article explains the crucial role of the anisotropic volume reduction of the CuCl6(4-) octahedron (caused due to the quenching of Jahn-Teller distortion) in the observed insulator to semiconductor phase transition. PMID- 26577028 TI - Ring Suture Technique in Retroperitoneal Laparoscopic Partial Nephrectomy for Hilar Cancer: A New Renorrhaphy Technique. AB - BACKGROUND AND PURPOSE: To evaluate the safety and efficacy of a ring suture technique during retroperitoneal laparoscopic partial nephrectomy (RLPN) for management of renal cell carcinoma (RCC) in the renal hilum. PATIENTS AND METHODS: Data for patients with renal hilar cancer who underwent RLPN from January 2010 to March 2015 were collected. All surgeries involved the ring suture technique, following the same procedure: the renal artery was dissected and clamped, the tumor was enucleated from the kidney, defects of the vascular and collecting system were repaired, and then the edge of the renal parenchyma was sutured continuously along the border. Finally, the renal artery clamp was removed, and any injury of the vascular system was repaired if necessary. We retrospectively analyzed renal ischemic time, blood loss, and postoperative complications. RESULTS: Among the 17 patients, 11 were male (median age 61 years, range 42-71 years). Mean tumor diameter was 3.4 +/- 0.9 cm and median R.E.N.A.L. nephrometry score was 8 (range 6-10). The mean warm ischemic time was 23.0 +/- 9.2 minutes and median blood loss during surgery was 110 mL (range 70-350 mL); we had no case of uncontrollable massive bleeding. Radical nephrectomy was used in one case because of tumor embolus in a branch of the renal vein. All patients recovered well following surgery. Pathology confirmed the diagnosis of RCC in all cases, with the main subtype clear-cell carcinomas (88.2%). CONCLUSIONS: The ring suture technique is safe and effective for management of renal hilar cancer during RLPN for selected patients. PMID- 26577029 TI - Zeste tunes the timing of ecdysone actions in triggering programmed tissue degeneration in Drosophila. AB - In the pupal stage, the fly body undergoes extensive metamorphic remodeling, in which programmed cell death plays a critical role. We studied two of the constituent processes in this remodeling, salivary gland degeneration and breakdown of the eclosion muscle, which are triggered by an increase and a decrease in the circulating steroid hormone ecdysone at the start and end of metamorphosis, respectively. We found that knockdown of zeste (z), a gene encoding a sequence-specific DNA-binding protein implicated in transvection, in salivary gland cells advances the initiation of their degeneration, whereas z knockdown in neurons delays muscle breakdown. We further showed that knockdown of an ecdysone-inducible gene, E74, retards salivary gland degeneration with little effect on eclosion muscle breakdown. We propose that Z tunes the sensitivity of ecdysone targets to this hormone in order to ensure a high safety margin so that the cell death program will be activated when the ecdysone titer is at a sufficiently high level that is reached only at a defined stage during metamorphosis. PMID- 26577030 TI - Relationship Status and Long-Term Care Facility Use in Later Life. AB - OBJECTIVES: Most older adults prefer to "age in place" and avoid formal long-term care. Yet demographic shifts, including population aging and an increasing prevalence of remarried and unmarried older adults, could undermine these goals, making it important to consider carefully how and why relationship status relates to long-term care risk. METHOD: We fit hazard models to a sample of adults aged 65 and older from eight waves (1998-2012) of the Health and Retirement Study (N = 21,564). We consider risk of any long-term care facility admission, as well as risk of long-duration stays. RESULTS: Widowed, divorced, and never married adults have the highest risks of long-term care admission. Remarried and partnered adults have similar risks of long-term care admission as continuously married adults. Relationship status is more important for men than for women, especially when considering long-duration stays. Relationship status is also more significant for non-Hispanic White and Hispanic adults compared with non-Hispanic Black adults. Economic resources and, to some extent, social ties partially explain the association between relationship status and long-term care use. DISCUSSION: By addressing the prohibitive costs of long-term care services which enable aging in place (e.g., home health care), relationship status disparities in long-term care may be reduced. Future studies should consider the link between long-term care facility use and relationship status in future cohorts as well as examine how relationship status structures access to a range of long-term care options. PMID- 26577031 TI - The role of the coherence in the cross-correlation analysis of diffraction patterns from two-dimensional dense mono-disperse systems. AB - The investigation of the static and dynamic structural properties of colloidal systems relies on techniques capable of atomic resolution in real space and femtosecond resolution in time. Recently, the cross-correlation function (CCF) analysis of both X-rays and electron diffraction patterns from dilute and dense aggregates has demonstrated the ability to retrieve information on the sample's local order and symmetry. Open questions remain regarding the role of the beam coherence in the formation of the diffraction pattern and the properties of the CCF, especially in dense systems. Here, we simulate the diffraction patterns of dense two-dimensional monodisperse systems of different symmetries, varying the transverse coherence of the probing wave, and analyze their CCF. We study samples with different symmetries at different size scale, as for example, pentamers arranged into a four-fold lattice where each pentamer is surrounded by triangular lattices, both ordered and disordered. In such systems, different symmetry modulations are arising in the CCF at specific scattering vectors. We demonstrate that the amplitude of the CCF is a fingerprint of the degree of the ordering in the sample and that at partial transverse coherence, the CCF of a dense sample corresponds to that of an individual scattering object. PMID- 26577032 TI - Thioflavin T as a fluorescence probe for label-free detection of T4 polynucleotide kinase/phosphatase and its inhibitors. AB - We have developed a new methodology for label-free fluorescence turn-on detection of T4 polynucleotide kinase/phosphatase activity (T4 PNKP) using a Thioflavin T probe. This method is very sensitive with a 0.01 unit/mL limit of detection, which is better than those with labeled fluorophores. Furthermore, T4 PNKP inhibition by the inhibitor heparin is shown, demonstrating the potential to screen suitable inhibitor drugs for T4 PNKP. PMID- 26577033 TI - Development of a highly resolutive method, using a double quadruplex tetra-primer ARMS-PCR coupled with capillary electrophoresis to study CD40LG polymorphisms. AB - Polymorphisms in the CD40 ligand gene (CD40LG) are associated with various immunological disorders such as tumors, autoimmune and infectious diseases. The aim of this study was to develop a highly optimized double quadruplex tetra primer amplification refractory mutation system PCR (double quadruplex T-ARMS PCR) coupled with capillary electrophoresis to allow genotyping of eight relevant candidate CD40LG SNPs and to establish haplotypes. After conducting the double quadruplex T-ARMS-PCR, the genotypes obtained through agarose electrophoresis were compared with those obtained through capillary electrophoresis. This strategy was applied to analyze the genetic patterns of CD40LG in two distinct cohorts of blood donors (211 French and 274 Tunisian). The T-ARMS-PCR method was rapid, inexpensive, reproducible and reliable for SNP determination. Regarding the separation technique, capillary electrophoresis allows traceable and semi automated analysis while agarose electrophoresis remains a cost-effective technique that does not require specialized or costly equipment. Using these methods, we identified significantly different genetic heterogeneity between the two investigated populations (p <= 0.0001) and we also extensively characterized their haplotypes. The obtained genotype distribution and the optimized quadruplex T-ARMS-PCR technique coupled with capillary electrophoresis provides valuable information for studying pathologic inflammation leading to various diseases in which CD40LG might be a candidate gene. PMID- 26577034 TI - Preoperative supplementation with fibrinogen concentrate in cardiac surgery: A randomized controlled study. AB - BACKGROUND: Bleeding remains a severe complication in cardiac surgery. Several studies have found an association between the preoperative plasma concentration of fibrinogen and postoperative bleeding in cardiac surgery patients. This raises the question of whether preoperative supplementation with fibrinogen concentrate can reduce postoperative blood loss. METHODS: An investigator-initiated, prospective, randomized double-blind placebo-controlled study, was performed in 48 low-risk, coronary artery bypass grafting patients. Subjects were randomized to infusion of 2 g fibrinogen or placebo immediately before surgery, after induction of anaesthesia. The primary endpoint was blood loss during the first 12 h postoperatively. Secondary endpoints included the proportion of transfused subjects, the number of transfused allogeneic blood products (red blood cells, plasma and platelets), and haemoglobin concentration after surgery. Student's t test and Mann-Whitney U-test was used to compare continuous data and chi(2)-test to compare categorical data between groups. RESULTS: Median postoperative bleeding was not significantly different between the fibrinogen and placebo groups [650 (25/75th percentile 500-835) ml compared with 730 (543-980) ml, P=0.29]. The proportion of transfused subjects (33 vs 29%, P=0.76), number of perioperative transfusions of allogeneic blood products (0 (0-2 vs 0 (0-3), P=0.76) and haemoglobin concentration 24 h after surgery (107 (sd 11) vs 100 (12) g L-1, P=0.07) were not significantly different between the fibrinogen and placebo group, respectively. CONCLUSION: Preoperative supplementation with 2 g fibrinogen concentrate did not significantly influence postoperative bleeding, in coronary artery bypass grafting patients without documented hypofibrinogenaemia. CLINICAL TRIAL REGISTRATION: NCT 00968045. PMID- 26577035 TI - Comparison of positive end-expiratory pressure-induced increase in central venous pressure and passive leg raising to predict fluid responsiveness in patients with atrial fibrillation. AB - BACKGROUND: Positive end-expiratory pressure (PEEP)-induced increase in central venous pressure (CVP) has been suggested to be a robust indicator of fluid responsiveness, with heart rhythm having minimal influence. We compared the ability of PEEP-induced changes in CVP with passive leg raising (PLR)-induced changes in stroke volume index (SVI) in patients with atrial fibrillation after valvular heart surgery. METHODS: In 43 patients with atrial fibrillation after cardiac surgery, PEEP was increased from 0 to 10 cm H2O for 5 min and changes in CVP were assessed. After returning the PEEP to 0 cm H2O, PLR was performed for 5 min and changes in SVI were recorded. Finally, 300 ml of colloid was infused and haemodynamic variables were assessed 5 min after completion of a fluid challenge. Fluid responsiveness was defined as an increase in SVI >=10% measured by a pulmonary artery catheter. RESULTS: Fifteen (35%) patients were fluid responders. There was no correlation between PEEP-induced increases in CVP and changes in SVI after a fluid challenge (beta coefficient -0.052, P=0.740), whereas changes in SVI during PLR showed a significant correlation (beta coefficient 0.713, P<0.001). The area under the receiver operating characteristic curve of the PEEP induced increase in CVP and changes in SVI during PLR for fluid responsiveness was 0.556 [95% confidence interval (CI) 0.358-0.753, P=0.549) and 0.771 (95% CI 0.619-0.924, P=0.004), respectively. CONCLUSIONS: A PEEP-induced increase in CVP did not predict fluid responsiveness in patients with atrial fibrillation after cardiac surgery, but increases in SVI during PLR seem to be a valid predictor of fluid responsiveness in this subset of patients. PMID- 26577036 TI - Corrigendum. PMID- 26577037 TI - Urine measurement indicates the plasma brain natriuretic peptide concentration during optimization of heart failure treatment. AB - AIM: To assess the correlation between the amino-terminal pro-hormone brain natriuretic peptide (NT-proBNP) concentration in blood and urine during a period when actively adjusting the treatment of heart failure (HF). METHODS: Plasma and urine analyses of NT-proBNP were compared in 51 patients on admission to and discharge from a nurse-led outpatient clinic where HF treatment was optimized. The median time between the two measurements was 42 days. Correlations were analyzed using linear regression, where R(2) is the degree of variability in the plasma NT-proBNP concentration that can be accounted for by the urinary NT proBNP. RESULTS: There was a statistically significant linear relationship between the urine and plasma concentrations of NT-proBNP on both occasions, but R(2) varied greatly depending on how the data were presented. The correlation between the raw data showed an R(2) of only 30%, and it almost doubled upon logarithm transformation, which shows that the variability (error) was concentration-dependent. Correction of the urinary NT-proBNP for urinary creatinine further increased R(2) for the logarithm-transformed correlation to 68% on admission and 76% on discharge. The highest R(2) (77%) was obtained when the relative changes in urinary NT-proBNP/creatinine between admission and discharge were compared with the corresponding relative changes in the plasma concentration. The sensitivity and specificity of the urine in indicating plasma concentration changes > 10% were 82% and 86%, respectively. CONCLUSION: Relative changes in plasma NT-proBNP could be reliably estimated from urine samples during a period of optimization of HF treatment. PMID- 26577038 TI - Sodium channel-inhibiting drugs and survival of breast, colon and prostate cancer: a population-based study. AB - Metastasis is the leading cause of cancer-related deaths. Voltage-gated sodium channels (VGSCs) regulate invasion and metastasis. Several VGSC-inhibiting drugs reduce metastasis in murine cancer models. We aimed to test the hypothesis that patients taking VGSC-inhibiting drugs who developed cancer live longer than those not taking these drugs. A cohort study was performed on primary care data from the QResearch database, including patients with breast, bowel or prostate cancer. Cox proportional hazards regression was used to compare the survival from cancer diagnosis of patients taking VGSC-inhibiting drugs with those not exposed to these drugs. Median time to death was 9.7 years in the exposed group and 18.4 years in the unexposed group, and exposure to these medications significantly increased mortality. Thus, exposure to VGSC-inhibiting drugs associates with reduced survival in breast, bowel and prostate cancer patients. This finding is not consistent with the preclinical data. Despite the strengths of this study including the large sample size, the study is limited by missing information on potentially important confounders such as cancer stage, co-morbidities and cause of death. Further research, which is able to account for these confounding issues, is needed to investigate the relationship between VGSC-inhibiting drugs and cancer survival. PMID- 26577039 TI - Trends of HIV subtypes and phylogenetic dynamics among young men who have sex with men in China, 2009-2014. AB - To investigate the origins of HIV transmission and phylogenetic dynamics among men who have sex with men (MSM), a total of 1205 newly diagnosed HIV-infected 16 25 year-olds were recruited in 13 provinces across China between 2009 and 2014. Based on phylogenetic analyses of partial pol sequences, HIV-1 subtypes including CRF01_AE (45.3%), CRF07_BC (37.8%), subtype B (6.1%), and B' (3.7%), as well as some other recombinants (7.1%) were identified. In addition to two distinct CRF01_AE clusters [cluster 4 (33.7%, 406/1205) and cluster 5 (7.1%, 85/1205)], we identified a new CRF07_BC cluster (cluster 1) (36.0%, 434/1205), which entered Chinese MSMs in 2004, and had been rapidly spreading since about 2004, which indicating the third wave of the HIV epidemic among the population. Moreover, two new clusters of CRF_01B recombinants were found in this study. The complexities of HIV subtypes and recombinants strongly supports the necessity for a comprehensive study about risk behaviors and their relationship with increasing HIV epidemic subtypes among the MSM group. Implementation and evaluation of comprehensive harm reduction strategies in Chinese MSM are urgently needed. PMID- 26577040 TI - Clinical utility gene card for: Biotinidase deficiency-update 2015. PMID- 26577041 TI - Lessons from a pair of siblings with BPAN. AB - Neurodegeneration with brain iron accumulation (NBIA) encompasses a heterogeneous group of inherited progressive neurological diseases. Beta-propeller protein associated neurodegeneration (BPAN) has been estimated to account for ~7% of all cases of NBIA and has distinctive clinical and brain imaging findings. Heterozygous variants in the WDR45 gene located in Xp11.23 are responsible for BPAN. A clear female predominance supports an X-linked dominant pattern of inheritance with proposed lethality for germline variants in hemizygous males. By whole-exome sequencing, we identified an in-frame deletion in the WDR45 gene (c.161_163delTGG) in the hemizygous state in a 20-year-old man with a history of profound neurocognitive impairment and seizures. His higher functioning 14-year old sister, also with a history of intellectual disability, was found to carry the same variant in the heterozygous state. Their asymptomatic mother was mosaic for the alteration. From this pair of siblings with BPAN we conclude that: (1) inherited WDR45 variants are possible, albeit rare; (2) hemizygous germline variants in males can be viable, but likely result in a more severe phenotype; (3) for siblings with germline variants, males should be more significantly affected than females; and (4) because gonadal and germline mosaicism are possible and healthy female carriers can be found, parental testing for variants in WDR45 should be considered. PMID- 26577042 TI - Clinical utility gene card for: MAN1B1 defective congenital disorder of glycosylation. PMID- 26577045 TI - Evaluation of power of the Illumina HumanOmni5M-4v1 BeadChip to detect risk variants for human complex diseases. AB - Although emerging sequencing technologies can characterize all genetic variants, the cost is still high. Illumina released the HumanOmni5M-4v1 (Omni5) genotype array with ~4.3M assayed SNPs, a much denser array compared with other available arrays. The Omni5 balances both cost and array density. In this article, we illustrate the power of Omni5 to detect genetic associations. The Omni5 includes variants with a wide range of minor allele frequencies down to <1%. The theoretical power calculation examples indicate the increased power of the Omni5 array compared with other arrays with lower density when evaluating associations with some known loci, although there are exceptions. We further evaluate the genetic associations between known loci and several quantitative traits in the Framingham Heart Study: femoral neck bone mineral density, lumbar spine bone mineral density and hippocampal volume. Finally, we search genome wide for novel associations using the Omni5 genotypes. We compare our association results from Affymetrix 500K+MIPS 50K arrays and two imputed data sets: (1) HapMap Phase II and (2) 1000 Genomes reference panel. We observed increased evidence for genotype phenotype associations with smaller P-values for selected known loci using the Omni5 genotypes. With limited sample sizes, we identify novel variants with genome-wide significant P-values. Our observations support the notion that dense genotyping using the Omni5 can be powerful in detecting novel associated variants. Comparison with imputed data with higher density also suggests that imputation helps but cannot replace genotyping, especially when imputation quality is low. PMID- 26577044 TI - Preferences for prenatal tests for Down syndrome: an international comparison of the views of pregnant women and health professionals. AB - Non-invasive prenatal testing is increasingly available worldwide and stakeholder viewpoints are essential to guide implementation. Here we compare the preferences of women and health professionals from nine different countries towards attributes of non-invasive and invasive prenatal tests for Down syndrome. A discrete choice experiment was used to obtain participants' stated preference for prenatal tests that varied according to four attributes: accuracy, time of test, risk of miscarriage, and type of information. Pregnant women and health professionals were recruited from Canada, Denmark, Iceland, Israel, Italy, the Netherlands, Portugal, Singapore, and the United Kingdom. A total of 2666 women's and 1245 health professionals' questionnaires were included in the analysis. Differences in preferences were seen between women and health professionals within and between countries. Overall, women placed greater emphasis on test safety and comprehensive information than health professionals, who emphasised accuracy and early testing. Differences between women's and health professionals' preferences are marked between countries. Varied approaches to implementation and service delivery are therefore needed and individual countries should develop guidelines appropriate for their own social and screening contexts. PMID- 26577046 TI - Active FOXO1 Is a Key Determinant of Isoform-Specific Progesterone Receptor Transactivation and Senescence Programming. AB - Progesterone promotes differentiation coupled to proliferation and prosurvival in the breast, but inhibits estrogen-driven growth in the reproductive tract and ovaries. Herein, it is demonstrated, using progesterone receptor (PR) isoform specific ovarian cancer model systems, that PR-A and PR-B promote distinct gene expression profiles that differ from PR-driven genes in breast cancer cells. In ovarian cancer models, PR-A primarily regulates genes independently of progestin, while PR-B is the dominant ligand-dependent isoform. Notably, FOXO1 and the PR/FOXO1 target gene p21 (CDKN1A) are repressed by PR-A, but induced by PR-B. In the presence of progestin, PR-B, but not PR-A, robustly induced cellular senescence via FOXO1-dependent induction of p21 and p15 (CDKN2B). Chromatin immunoprecipitation (ChIP) assays performed on PR isoform-specific cells demonstrated that while each isoform is recruited to the same PRE-containing region of the p21 promoter in response to progestin, only PR-B elicits active chromatin marks. Overexpression of constitutively active FOXO1 in PR-A-expressing cells conferred robust ligand-dependent upregulation of the PR-B target genes GZMA, IGFBP1, and p21, and induced cellular senescence. In the presence of endogenous active FOXO1, PR-A was phosphorylated on Ser294 and transactivated PR B at PR-B target genes; these events were blocked by the FOXO1 inhibitor (AS1842856). PR isoform-specific regulation of the FOXO1/p21 axis recapitulated in human primary ovarian tumor explants treated with progestin; loss of progestin sensitivity correlated with high AKT activity. IMPLICATIONS: This study indicates FOXO1 as a critical component for progesterone signaling to promote cellular senescence and reveals a novel mechanism for transcription factor control of hormone sensitivity. PMID- 26577048 TI - Structural basis of Sorcin-mediated calcium-dependent signal transduction. AB - Sorcin is an essential penta-EF hand calcium binding protein, able to confer the multi-drug resistance phenotype to drug-sensitive cancer cells and to reduce Endoplasmic Reticulum stress and cell death. Sorcin silencing blocks cell cycle progression in mitosis and induces cell death by triggering apoptosis. Sorcin participates in the modulation of calcium homeostasis and in calcium-dependent cell signalling in normal and cancer cells. The molecular basis of Sorcin action is yet unknown. The X-ray structures of Sorcin in the apo (apoSor) and in calcium bound form (CaSor) reveal the structural basis of Sorcin action: calcium binding to the EF1-3 hands promotes a large conformational change, involving a movement of the long D-helix joining the EF1-EF2 sub-domain to EF3 and the opening of EF1. This movement promotes the exposure of a hydrophobic pocket, which can accommodate in CaSor the portion of its N-terminal domain displaying the consensus binding motif identified by phage display experiments. This domain inhibits the interaction of sorcin with PDCD6, a protein that carries the Sorcin consensus motif, co-localizes with Sorcin in the perinuclear region of the cell and in the midbody and is involved in the onset of apoptosis. PMID- 26577049 TI - Cortisol and stimulus-induced arousal level differentially impact memory for items and backgrounds. AB - Most studies examine the effects of stress on memory for visual information test memory for entire scenes. However, arousal levels may differentially influence memory for backgrounds as opposed to items. Participants encoded scenes that included a negative-high-arousal, negative-moderate-arousal, or neutral item on a neutral background. After a 30-minute (Experiment 1) or 48-hour delay (Experiment 2), participants underwent a stressor or control task while heart rate was recorded. A recognition memory task was then given with items and backgrounds presented separately. High-arousal images had a greater detriment in background memory than moderate-arousal images. Further, though there was evidence that change in cortisol level at retrieval was associated with impaired memory for items, it was not associated with detriments in background memory. Increased heart rate was associated with impaired memory for both items and backgrounds. This suggests that the level of sympathetic and cortisol reactivity differentially affects memory for items and backgrounds. PMID- 26577047 TI - Proposed therapies in primary biliary cholangitis. AB - Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is a model autoimmune disease with chronic cholestasis characterized by the hallmark of anti-mitochondrial antibodies and treated with ursodeoxycholic acid (UDCA). However, approximately 20-40% of patients incompletely respond to UDCA and have an increased risk of disease progression. Although there have been significant advances in the immunobiology of PBC, these have yet to be translated into newer therapeutic modalities. Current approaches to controlling the immune response include broad immunosuppression with corticosteroids as well as targeted therapies directed against T and B cells. In contrast, ameliorating cholestasis is the focus of other therapies in development, including obeticholic acid. In this article the authors will discuss ongoing clinical trials and, in particular, the rationale for choosing agents that may effectively target the aberrant immune response. PMID- 26577050 TI - Does metformin improve in vitro maturation and ultrastructure of oocytes retrieved from estradiol valerate polycystic ovary syndrome-induced rats. AB - BACKGROUND: Metformin decreases polycystic ovary syndrome (PCOS) symptoms, induces ovulation, and may improve developmental competence of in vitro oocyte maturation. This study was designed to define the effects of metformin on the characteristics of in vitro oocyte maturation in estradiol valerate (EV) PCOS induced rats. METHODS: Forty-five adult female Sprague-Dawley rats were randomly divided into control; sham and PCOS-induced (treated by a single dose of estradiol valerate, 4 mg/rat, IM) groups. The body weight was measured weekly for 12 weeks. At the end of week 12, the serum levels of testosterone, estrogen, progesterone, LH, and FSH and blood glucose of all the rats were measured. About 380 cumulus oocyte complexes (control, 125; sham, 122; PCOS-induced rats, 133) were incubated in Ham's F10 in the absence and/or presence of metformin (M 5( 10)) for 12, 24, 36, and 48 h. The cumulus cells expansion and nuclear and cytoplasmic maturation of the oocytes was evaluated using 1 % aceto-orcein staining, and transmission electron microscopy (TEM). RESULTS: No significant differences were observed in the body weight of the rats. The serum level of testosterone was reduced, and progesterone and LH were significantly increased in the PCOS-induced rats (p < 0.05). However, no significant differences were observed in the serum levels of estrogen and FSH among the groups. Blood glucose level was higher in the PCOS-induced rats than control, (p < 0.01). The expansion of cumulus cells was observed in the metformin-treated oocytes. The oocytes retrieved from PCOS-induced rats show a stage of meiotic division (GVBD, MI, A-T, and MII) in 57.12 % of metformin-untreated and fairly significantly increased to 64.28 % in metformin-treated oocytes, (p < 0.05), but no differences were observed in the MII stage within groups. The redistribution of some cytoplasmic organelles throughout the ooplasm, particularly the peripheral cortical granules, was defined in the metformin-treated oocytes. CONCLUSIONS: Single dose of EV can creates a reversible PCO adult rat model. Metformin enhances the COCs to initiate meiotic resumption at the first 6 h of IVM. In our study the metformin inability to show all aspects of in vitro oocyte maturation and may be resulted from deficiency of EV to induce PCOS. PMID- 26577051 TI - Prevention of Simvastatin-Induced Inhibition of Tendon Cell Proliferation and Cell Cycle Progression by Geranylgeranyl Pyrophosphate. AB - Statins have been reported to induce tendinopathy and even tendon rupture. The present study was designed to investigate the potential molecular mechanism underlying the adverse effect of simvastatin on tendon cells. An in vitro tendon healing model was performed using tendon cells isolated from rat Achilles tendons. The viability of tendon cells and cell cycle progression were examined by the MTT assay and flow cytometric analysis, respectively. Immunofluorescent staining for Ki-67 was used to assess the proliferation activity of tendon cells. Western blot analysis and coimmunoprecipitation was used to determine the protein expression of cell cycle-related proteins. To investigate the potential mechanism underlying the effect of statins on tendon cells, mevalonate, farnesyl pyrophosphate (FPP), or geranylgeranyl pyrophosphate (GGPP) was added to simvastatin-treated tendon cells. Simvastatin inhibited the in vitro tendon healing model and tendon cell proliferation in a dose-dependent manner. Immunofluorescent staining demonstrated reduced ki-67 expression in simvastatin treated tendon cells. Furthermore, simvastatin induced cell cycle arrest at the G1 phase. The expression levels of cdk1, cdk2, cyclin A, and cyclin E were downregulated by simvastatin in a dose-dependent manner. The inhibitory effect of simvastatin was proved to mediate the reduction of mevalonate, and the addition of exogenous GGPP completely prevented the inhibitory effect of simvastatin on tendon cells. The present study demonstrated, for the first time, the molecular mechanism underlying simvastatin-induced tendinopathy or tendon rupture. GGPP was shown to prevent the adverse effect of simvastatin in tendon cells without interfering with its cholesterol-reducing efficacy. PMID- 26577052 TI - DiffLogo: a comparative visualization of sequence motifs. AB - BACKGROUND: For three decades, sequence logos are the de facto standard for the visualization of sequence motifs in biology and bioinformatics. Reasons for this success story are their simplicity and clarity. The number of inferred and published motifs grows with the number of data sets and motif extraction algorithms. Hence, it becomes more and more important to perceive differences between motifs. However, motif differences are hard to detect from individual sequence logos in case of multiple motifs for one transcription factor, highly similar binding motifs of different transcription factors, or multiple motifs for one protein domain. RESULTS: Here, we present DiffLogo, a freely available, extensible, and user-friendly R package for visualizing motif differences. DiffLogo is capable of showing differences between DNA motifs as well as protein motifs in a pair-wise manner resulting in publication-ready figures. In case of more than two motifs, DiffLogo is capable of visualizing pair-wise differences in a tabular form. Here, the motifs are ordered by similarity, and the difference logos are colored for clarity. We demonstrate the benefit of DiffLogo on CTCF motifs from different human cell lines, on E-box motifs of three basic helix-loop helix transcription factors as examples for comparison of DNA motifs, and on F box domains from three different families as example for comparison of protein motifs. CONCLUSIONS: DiffLogo provides an intuitive visualization of motif differences. It enables the illustration and investigation of differences between highly similar motifs such as binding patterns of transcription factors for different cell types, treatments, and algorithmic approaches. PMID- 26577053 TI - Sulfation of 6-hydroxymelatonin, N-acetylserotonin and 4-hydroxyramelteon by the human cytosolic sulfotransferases (SULTs). AB - 1. This study aimed to investigate the involvement of sulfation in the metabolism of 6-hydroxymelatonin (6-OH-Mel), N-acetylserotonin (NAS) and 4-hydroxyramelteon (4-OH-Ram), and to identify and characterize the human cytosolic sulfotransferases (SULTs) capable of sulfating these drug compounds. 2. A systematic analysis using 13 known human SULTs revealed that SULT1A1 displayed the strongest activity in catalyzing the sulfation of 6-OH-Mel and 4-OH-Ram, whereas SULT1C4 exhibited the strongest sulfating-activity towards NAS. pH dependence and kinetic parameters of these SULT enzymes in mediating the sulfation of respective drug compounds were determined. A metabolic labeling study showed the generation and release of [35S]sulfated 6-OH-Mel, NAS and 4-OH Ram by HepG2 human hepatoma cells and Caco-2 human colon adenocarcinoma cells labeled with [35S]sulfate in the presence of these drug compounds. Cytosols of human lung, liver, kidney and small intestine were examined to verify the presence of 6-OH-Mel-, NAS- and 4-OH-Ram-sulfating activity in vivo. Of the four human organ samples tested, small intestine and liver cytosols displayed considerably higher 6-OH-Mel-, NAS- and 4-OH-Ram-sulfating activities than those of lung and kidney. 3. Collectively, these results provided a molecular basis for the metabolism of 6-OH-Mel, NAS and 4-OH-Ram through sulfation. PMID- 26577054 TI - Rectal thermometer should be used for accurate temperature reading, analysis finds. PMID- 26577056 TI - The role of dipeptide-repeat protein pathology in C9orf72 mutation cases. PMID- 26577055 TI - Laser controlled singlet oxygen generation in mitochondria to promote mitochondrial DNA replication in vitro. AB - Reports have shown that a certain level of reactive oxygen species (ROS) can promote mitochondrial DNA (mtDNA) replication. However, it is unclear whether it is the mitochondrial ROS that stimulate mtDNA replication and this requires further investigation. Here we employed a photodynamic system to achieve controlled mitochondrial singlet oxygen ((1)O2) generation. HeLa cells incubated with 5-aminolevulinic acid (ALA) were exposed to laser irradiation to induce (1)O2 generation within mitochondria. Increased mtDNA copy number was detected after low doses of 630 nm laser light in ALA-treated cells. The stimulated mtDNA replication was directly linked to mitochondrial (1)O2 generation, as verified using specific ROS scavengers. The stimulated mtDNA replication was regulated by mitochondrial transcription factor A (TFAM) and mtDNA polymerase gamma. MtDNA control region modifications were induced by (1)O2 generation in mitochondria. A marked increase in 8-Oxoguanine (8-oxoG) level was detected in ALA-treated cells after irradiation. HeLa cell growth stimulation and G1-S cell cycle transition were also observed after laser irradiation in ALA-treated cells. These cellular responses could be due to a second wave of ROS generation detected in mitochondria. In summary, we describe a controllable method of inducing mtDNA replication in vitro. PMID- 26577057 TI - Computer-aided diagnosis of pulmonary diseases using x-ray darkfield radiography. AB - In this work we develop a computer-aided diagnosis (CAD) scheme for classification of pulmonary disease for grating-based x-ray radiography. In addition to conventional transmission radiography, the grating-based technique provides a dark-field imaging modality, which utilizes the scattering properties of the x-rays. This modality has shown great potential for diagnosing early stage emphysema and fibrosis in mouse lungs in vivo. The CAD scheme is developed to assist radiologists and other medical experts to develop new diagnostic methods when evaluating grating-based images. The scheme consists of three stages: (i) automatic lung segmentation; (ii) feature extraction from lung shape and dark field image intensities; (iii) classification between healthy, emphysema and fibrosis lungs. A study of 102 mice was conducted with 34 healthy, 52 emphysema and 16 fibrosis subjects. Each image was manually annotated to build an experimental dataset. System performance was assessed by: (i) determining the quality of the segmentations; (ii) validating emphysema and fibrosis recognition by a linear support vector machine using leave-one-out cross-validation. In terms of segmentation quality, we obtained an overlap percentage (Omega) 92.63 +/- 3.65%, Dice Similarity Coefficient (DSC) 89.74 +/- 8.84% and Jaccard Similarity Coefficient 82.39 +/- 12.62%. For classification, the accuracy, sensitivity and specificity of diseased lung recognition was 100%. Classification between emphysema and fibrosis resulted in an accuracy of 93%, whilst the sensitivity was 94% and specificity 88%. In addition to the automatic classification of lungs, deviation maps created by the CAD scheme provide a visual aid for medical experts to further assess the severity of pulmonary disease in the lung, and highlights regions affected. PMID- 26577058 TI - DBEndo: a web-based endodontic case management tool. AB - BACKGROUND: The success of endodontic treatment depends-among many other factors on good documentation. Paper-based records are often difficult to read or incomplete and commercially available tools focus on billing. An electronic record captures the state of treatment at all times. Databases are a common tool in everyday life. RESULTS: Here, we present a database created for the Charite Universitatsmedizin Berlin, Germany. Through consistent digital documentation, data analytics of patients, root canal anatomies, instrumentation techniques, efficacy of chemical disinfection, root filling techniques, and corresponding recall success rates, which needed extensive research before, are now easy to perform. Tables and even graphics and data analystics are only one click away and can be exported to other programs. CONCLUSIONS: DBEndo is a database to store and visualise internally, as well as to share endodontic cases online. For academic use we provide the database including all forms and some anonymous data for free at: http://dbendo.charite.de . Through easy import and export of the data, the system is open and flexible. PMID- 26577059 TI - Hydroxyproline O-arabinosyltransferase mutants oppositely alter tip growth in Arabidopsis thaliana and Physcomitrella patens. AB - Hydroxyproline O-arabinosyltransferases (HPATs) are members of a small, deeply conserved family of plant-specific glycosyltransferases that add arabinose sugars to diverse proteins including cell wall-associated extensins and small signaling peptides. Recent genetic studies in flowering plants suggest that different HPAT homologs have been co-opted to function in diverse species-specific developmental contexts. However, nothing is known about the roles of HPATs in basal plants. We show that complete loss of HPAT function in Arabidopsis thaliana and the moss Physcomitrella patens results in a shared defect in gametophytic tip cell growth. Arabidopsis hpat1/2/3 triple knockout mutants suffer from a strong male sterility defect as a consequence of pollen tubes that fail to fully elongate following pollination. Knocking out the two HPAT genes of Physcomitrella results in larger multicellular filamentous networks due to increased elongation of protonemal tip cells. Physcomitrella hpat mutants lack cell-wall associated hydroxyproline arabinosides and can be rescued with exogenous cellulose, while global expression profiling shows that cell wall-associated genes are severely misexpressed, implicating a defect in cell wall formation during tip growth. Our findings point to a major role for HPATs in influencing cell elongation during tip growth in plants. PMID- 26577061 TI - Correction: A flow cytometer-based whole cell screening toolbox for directed hydrolase evolution through fluorescent hydrogels. AB - Correction for 'A flow cytometer-based whole cell screening toolbox for directed hydrolase evolution through fluorescent hydrogels' by Nina Lulsdorf et al., Chem. Commun., 2015, 51, 8679-8682. PMID- 26577060 TI - Conditioned medium from human bone marrow-derived mesenchymal stem cells promotes skin moisturization and effacement of wrinkles in UVB-irradiated SKH-1 hairless mice. AB - BACKGROUND: Mesenchymal stem cells (MSCs) are promising therapeutic agents for various diseases. AIMS: To investigate the effects of conditioned medium from human bone marrow-derived mesenchymal stem cells (MSC-CdM) on pro-collagen production and wrinkle formation, we performed in vitro and in vivo experiments. METHODS: We assessed the effects of MSC-CdM on proliferation and photo-aging in human dermal fibroblasts after UVB exposure using enzyme activity assays for collagen type I secretion and MMP-1. To determine the effect of topically applied MSC-CdM on wrinkle formation, MSC-CdM (1% and 10%) and vehicle (propylene glycol: ethanol, 7 : 3) were applied to the dorsal skin of UVB-irradiated hairless mice for 8 weeks. We examined the effects on wrinkle formation by assessing visual skin grading, replica, tape stripping, transepidermal water loss (TEWL), and skin hydration measurement. We also examined histology of the lesions using hematoxylin-eosin, Masson's trichrome, and immunohistochemical staining. RESULTS: MSC-CdM markedly reduced UV-induced matrix metalloproteinase-1 expression and increased pro-collagen synthesis in a dose-dependent manner. Our findings suggest that MSC-CdM induces repair of dermal damage and effacement of wrinkles on UVB irradiated hairless mice through protective effect of hydration. CONCLUSION: These results support an anti-wrinkle effect of MSC-CdM that involves increased collagen synthesis and suggest that MSC-CdM might be a potential candidate for preventing UV-induced skin damage. PMID- 26577062 TI - A single dose of mirtazapine attenuates neural responses to self-referential processing. AB - Increased self-focus is a core factor in the psychopathology of depression. Cortical midline structures (CMS) are implicated in the neurobiology of self, depression and antidepressant treatment response. Mirtazapine, an antidepressant that increases serotonin and norepinephrine release, enhances processing of positive and attenuates processing of negative emotional information in healthy volunteers after a single dose. These early changes, which are opposite to the negative information bias in depression, may be important for the therapeutic effect of mirtazapine. It nevertheless remains unresolved whether/how mirtazapine specifically influences processing of self-referential emotional information.Half of the healthy volunteers (n=15/30) received a single dose of mirtazapine, in an open-label design, two hours before functional magnetic resonance imaging (fMRI), and the other half was scanned as a control group without medication. During fMRI the participants categorized positive and negative self-referential adjectives.Mirtazapine attenuated responses to self-referential processing in the medial prefrontal cortex and the anterior cingulate cortex. Mirtazapine further decreased responses to positive self-referential processing in the posterior cingulate cortex and parietal cortex.These decreased responses of the CMS suggest that mirtazapine may rapidly improve the ability of the CMS to down-regulate self referential processing. In depressed patients, this could lead to decreased self focus and rumination, contributing to the antidepressant effect. PMID- 26577063 TI - Early antipsychotic treatment in childhood/adolescent period has long-term effects on depressive-like, anxiety-like and locomotor behaviours in adult rats. AB - Childhood/adolescent antipsychotic drug (APD) use is exponentially increasing worldwide, despite limited knowledge of the long-term effects of early APD treatment. Whilst investigations have found that early treatment has resulted in some alterations to dopamine and serotonin neurotransmission systems (essential to APD efficacy), there have only been limited studies into potential long-term behavioural changes. This study, using an animal model for childhood/adolescent APD treatment, investigated the long-term effects of aripiprazole, olanzapine and risperidone on adult behaviours of male and female rats. Open-field/holeboard, elevated plus maze (EPM), social interaction and forced swim (FS) tests were then conducted in adult rats. Our results indicated that in the male cohort, early risperidone and olanzapine treatment elicited long-term hyper-locomotor effects (open-field/holeboard and FS tests), whilst a decrease in depressive-like behaviour (in FS test) was observed in response to olanzapine treatment. Furthermore, anxiolytic-like behaviours were found following testing in the open field/holeboard and EPM in response to all three drug treatments. Effects in the female cohort, however, were to a far lesser extent, with behavioural attributes indicative of an increased depressive-like behaviour and hypo-locomotor activity exhibited in the FS test following early risperidone and olanzapine treatment. These results suggest that various APDs have different long-term effects on the behaviours of adult rats. PMID- 26577064 TI - Blood lactate levels as a biomarker of antipsychotic side effects in patients with schizophrenia. AB - BACKGROUND: Antipsychotic drugs (APs) are widely prescribed in psychiatry primarily for the treatment of psychosis in schizophrenia and bipolar disorders. An issue related to poor prognosis in patients with chronic illness relates to the accumulation of lactate levels in blood, leading to patients that become critically ill. It is suggested that haloperidol and olanzapine, as common therapy for schizophrenia, are associated with increased levels of blood lactate, which may contribute towards the extra-pyramidal side effects. AIMS AND METHOD: In this study, 88 patients attending the psychiatry outpatient clinic of Mansoura University Hospital, under treatment with typical APs (chlorpromazine or haloperidol) or the atypical APs (risperidone, olanzapine or quetiapine) were followed over a three-month period. Blood lactate levels were assessed at diagnosis, ten days and 90 days after the start of AP treatment. Extra-pyramidal symptoms (EPSs) were studied in participants during the course of this study. RESULTS: Chlorpromazine and haloperidol caused significant increases in lactate levels within the first ten days of therapy, while after 90 days, all APs showed significant increases in arterial blood lactate levels in comparison with the first baseline measurement (for all APs, p-values <0.0001). Dystonia was reported by patients on chlorpromazine, haloperidol and risperidone therapies, while Parkinsonian-like manifestations were reported with all APs tested except for quetiapine. Both dystonia and Parkinsonian-like manifestations were also observed alongside the significant increases in arterial blood lactate levels in comparison to patients on therapy not displaying EPSs. CONCLUSION: These findings suggest elevated blood lactate levels may serve as early biomarkers for occurrence of extra-pyramidal symptoms in patients on chronic APs treatment. PMID- 26577065 TI - The effect of five day dosing with THCV on THC-induced cognitive, psychological and physiological effects in healthy male human volunteers: A placebo-controlled, double-blind, crossover pilot trial. AB - RATIONALE: Cannabis is mostly grown under illegal and unregulated circumstances, which seems to favour a product increasingly high in its main cannabinoid ?-9 tetrahydrocannabinol (THC). ?-9-tetrahydrocannabivarin (THCV) is a relatively untested cannabinoid which is said to be a cannabinoid receptor neutral antagonist, and may inhibit the effects of THC. OBJECTIVES: To explore the safety and tolerability of repeated THCV administration and its effects on symptoms normally induced by THC in a sample of healthy volunteers. METHODS: Ten male cannabis users (<25 use occasions) were recruited for this within-subjects, placebo-controlled, double-blind, cross-over pilot study. 10mg oral pure THCV or placebo were administered daily for five days, followed by 1mg intravenous THC on the fifth day. RESULTS: THCV was well tolerated and subjectively indistinguishable from placebo. THC did not significantly increase psychotic symptoms, paranoia or impair short-term memory, while still producing significant intoxicating effects. Delayed verbal recall was impaired by THC and only occurred under placebo condition (Z=-2.201, p=0.028), suggesting a protective effect of THCV. THCV also inhibited THC-induced increased heart rate (Z=-2.193, p=0.028). Nine out of ten participants reported THC under THCV condition (compared to placebo) to be subjectively weaker or less intense (chi(2)=6.4, p=0.011). THCV in combination with THC significantly increased memory intrusions (Z=-2.155, p=0.031). CONCLUSION: In this first study of THC and THCV, THCV inhibited some of the well-known effects of THC, while potentiating others. These findings need to be interpreted with caution due to a small sample size and lack of THC-induced psychotomimetic and memory-impairing effect, probably owing to the choice of dose. PMID- 26577066 TI - A pilot study of cancer patients' use of traditional healers in the Radiotherapy Department, University College Hospital, Ibadan, Nigeria. AB - OBJECTIVE: This descriptive cross-sectional study assessed cancer patients' use of traditional healers, the association between delay in coming to this clinic and patients' use of traditional healers, reasons cancer patients use western medicine after trying traditional treatment and the cost of obtaining traditional treatment. METHODS: Participants were made of 400 consecutive and consenting new patients in the Department of Radiotherapy, University College Hospital (UCH), Ibadan. A validated interviewer-administered semi-structured questionnaire was used for data collection. Data was analyzed using descriptive and inferential statistics. Focus group discussions were held with some of the clients as well as the traditional healers. RESULTS: It showed that 34.5% of the patients patronized traditional healers, while 65.5% used only hospitals. The most common reason given among patients who patronized traditional healers for doing so was their desire to be healed and to be rid of pains (45.9%), while the most common reason they opt for western medicine afterwards was lack of improvement in their health condition (70.1%). The cost of traditional treatment for cancer ranged between no cost to N5,000 (that is approximately $31.25 @ $1 = N160) to be treated. The cost of orthodox care would range from a minimum of N40,000 to several millions of naira. CONCLUSIONS: Patients patronize traditional healers to be rid of pains; hence physicians should endeavor to control cancer-related symptoms, especially pains as the patients await diagnosis. Also, the low cost of obtaining traditional treatment, regular assurance of cure and other assistances given to them, could be an enticing factor in its use. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26577067 TI - Dioxygen Binding in the Active Site of Histone Demethylase JMJD2A and the Role of the Protein Environment. AB - JMJD2A catalyses the demethylation of di- and trimethylated lysine residues in histone tails and is a target for the development of new anticancer medicines. Mechanistic details of demethylation are yet to be elucidated and are important for the understanding of epigenetic processes. We have evaluated the initial step of histone demethylation by JMJD2A and demonstrate the dramatic effect of the protein environment upon oxygen binding using quantum mechanics/molecular mechanics (QM/MM) calculations. The changes in electronic structure have been studied for possible spin states and different conformations of O2 , using a combination of quantum and classical simulations. O2 binding to this histone demethylase is computed to occur preferentially as an end-on superoxo radical bound to a high-spin ferric centre, yielding an overall quintet ground state. The favourability of binding is strongly influenced by the surrounding protein: we have quantified this effect using an energy decomposition scheme into electrostatic and dispersion contributions. His182 and the methylated lysine assist while Glu184 and the oxoglutarate cofactor are deleterious for O2 binding. Charge separation in the superoxo-intermediate benefits from the electrostatic stabilization provided by the surrounding residues, stabilizing the binding process significantly. This work demonstrates the importance of the extended protein environment in oxygen binding, and the role of energy decomposition in understanding the physical origin of binding/recognition. PMID- 26577068 TI - An interactive tool for rapid biventricular analysis of congenital heart disease. AB - Cardiac malformations are the most common birth defect. Better interventions in early life have improved mortality for children with congenital heart disease, but heart failure is a significant problem in adulthood. These patients require regular imaging and analysis of biventricular (left and right ventricular) function. In this study, we describe a rapid method to analyse left and right ventricular shape and function from cardiac MRI examinations. A 4D (3D+time) finite element model template is interactively customized to the anatomy and motion of the biventricular unit. The method was validated in 17 patients and 10 ex-vivo hearts. Interactive model updates were achieved through preconditioned conjugate gradient optimization on a multithread system, and by precomputing points predicted from a coarse mesh optimization. PMID- 26577069 TI - Bony labyrinth shape variation in extant Carnivora: a case study of Musteloidea. AB - The bony labyrinth provides a proxy for the morphology of the inner ear, a primary cognitive organ involved in hearing, body perception in space, and balance in vertebrates. Bony labyrinth shape variations often are attributed to phylogenetic and ecological factors. Here we use three-dimensional (3D) geometric morphometrics to examine the phylogenetic and ecological patterns of variation in the bony labyrinth morphology of the most species-rich and ecologically diversified traditionally recognized superfamily of Carnivora, the Musteloidea (e.g. weasels, otters, badgers, red panda, skunks, raccoons, coatis). We scanned the basicrania of specimens belonging to 31 species using high-resolution X-ray computed micro-tomography (MUCT) to virtually reconstruct 3D models of the bony labyrinths. Labyrinth morphology is captured by a set of six fixed landmarks on the vestibular and cochlear systems, and 120 sliding semilandmarks, slid at the center of the semicircular canals and the cochlea. We found that the morphology of this sensory structure is not significantly influenced by bony labyrinth size, in comparisons across all musteloids or in any of the individual traditionally recognized families (Mephitidae, Procyonidae, Mustelidae). PCA (principal components analysis) of shape data revealed that bony labyrinth morphology is clearly distinguishable between musteloid families, and permutation tests of the Kmult statistic confirmed that the bony labyrinth shows a phylogenetic signal in musteloids and in most mustelids. Both the vestibular and cochlear regions display morphological differences among the musteloids sampled, associated with the size and curvature of the semicircular canals, angles between canals, presence or absence of a secondary common crus, degree of lateral compression of the vestibule, orientation of the cochlea relative to the semicircular canals, proportions of the cochlea, and degree of curvature of its turns. We detected a significant ecological signal in the bony labyrinth shape of musteloids, differentiating semi-aquatic taxa from non-aquatic ones (the taxa assigned to terrestrial, arboreal, semi-arboreal, and semi-fossorial categories), and a significant signal for mustelids, differentiating the bony labyrinths of terrestrial, semi-arboreal, arboreal, semi-fossorial and semi-aquatic species from each other. Otters and minks are distinguished from non-aquatic musteloids by an oval rather than circular anterior canal, sinuous rather than straight lateral canal, and acute rather than straight angle between the posterior and lateral semicircular canals - each of these morphological characters has been related previously to animal sensitivity for detecting head motion in space. PMID- 26577070 TI - Reducing stillbirths in low-income countries. AB - Worldwide, 98% of stillbirths occur in low-income countries (LIC), where stillbirth rates are ten-fold higher than in high-income countries (HIC). Although most HIC stillbirths occur prenatally, in LIC most stillbirths occur at term and during labor/delivery. Conditions causing stillbirths include those of maternal origin (obstructed labor, trauma, antepartum hemorrhage, preeclampsia/eclampsia, infection, diabetes, other maternal diseases), and fetal origin (fetal growth restriction, fetal distress, cord prolapse, multiples, malpresentations, congenital anomalies). In LIC, aside from infectious origins, most stillbirths are caused by fetal asphyxia. Stillbirth prevention requires recognition of maternal conditions, and care in a facility where fetal monitoring and expeditious delivery are possible, usually by cesarean section (CS). Of major causes, only syphilis and malaria can be managed prenatally. Targeting single conditions or interventions is unlikely to substantially reduce stillbirth. To reduce stillbirth rates, LIC must implement effective modern antepartum and intrapartum care, including fetal monitoring and CS. PMID- 26577072 TI - How do I get to peer review a paper? A PhD student asks.... PMID- 26577071 TI - Engineering Corynebacterium glutamicum to produce 5-aminolevulinic acid from glucose. AB - BACKGROUND: Corynebacterium glutamicum is generally regarded as a safe microorganism and is used to produce many biochemicals, including L-glutamate. 5 Aminolevulinic acid (ALA) is an L-glutamate derived non-protein amino acid, and is widely applied in fields such as medicine and agriculture. RESULTS: The products of the gltX, hemA, and hemL genes participate in the synthesis of ALA from L-glutamate. Their annotated C. glutamicum homologs were shown to be functional using heterologous complementation and overexpression techniques. Coexpression of hemA and hemL in native host led to the accumulation of ALA, suggesting the potential of C. glutamicum to produce ALA for research and commercial purposes. To improve ALA production, we constructed recombinant C. glutamicum strains expressing hemA and hemL derived from different organisms. Transcriptome analysis indicated that the dissolved oxygen level and Fe(2+) concentration had major effects on ALA synthesis. The downstream pathway of heme biosynthesis was inhibited using small molecules or introducing genetic modifications. Small-scale flask cultures of engineered C. glutamicum produced 1.79 g/L of ALA. CONCLUSION: Functional characterization of the key enzymes indicated complex regulation of the heme biosynthetic pathway in C. glutamicum. Systematic analysis and molecular genetic engineering of C. glutamicum may facilitate its development as a system for large-scale synthesis of ALA. PMID- 26577075 TI - Birth of the eukaryotes by a set of reactive innovations: New insights force us to relinquish gradual models. AB - Of two contending models for eukaryotic evolution the "archezoan" has an amitochondriate eukaryote take up an endosymbiont, while "symbiogenesis" states that an Archaeon became a eukaryote as the result of this uptake. If so, organelle formation resulting from new engulfments is simplified by the primordial symbiogenesis, and less informative regarding the bacterium-to mitochondrion conversion. Gradualist archezoan visions still permeate evolutionary thinking, but are much less likely than symbiogenesis. Genuine amitochondriate eukaryotes have never been found and rapid, explosive adaptive periods characteristic of symbiogenetic models explain this. Mitochondrial proteomes, encoded by genes of "eukaryotic origin" not easily linked to host or endosymbiont, can be understood in light of rapid adjustments to new evolutionary pressures. Symbiogenesis allows "expensive" eukaryotic inventions via efficient ATP generation by nascent mitochondria. However, efficient ATP production equals enhanced toxic internal ROS formation. The synergistic combination of these two driving forces gave rise to the rapid evolution of eukaryotes. Also watch the Video Abstract. PMID- 26577076 TI - How cooperatively breeding birds identify relatives and avoid incest: New insights into dispersal and kin recognition. AB - Cooperative breeding in birds typically occurs when offspring - usually males - delay dispersal from their natal group, remaining with the family to help rear younger kin. Sex-biased dispersal is thought to have evolved in order to reduce the risk of inbreeding, resulting in low relatedness between mates and the loss of indirect fitness benefits for the dispersing sex. In this review, we discuss several recent studies showing that dispersal patterns are more variable than previously thought, often leading to complex genetic structure within cooperative avian societies. These empirical findings accord with recent theoretical models suggesting that sex- biased dispersal is neither necessary, nor always sufficient, to prevent inbreeding. The ability to recognize relatives, primarily by learning individual or group-specific vocalizations, may play a more important role in incest avoidance than currently appreciated. PMID- 26577077 TI - Innate immunity against molecular mimicry: Examining galectin-mediated antimicrobial activity. AB - Adaptive immunity provides the unique ability to respond to a nearly infinite range of antigenic determinants. Given the inherent plasticity of the adaptive immune system, a series of tolerance mechanisms exist to reduce reactivity toward self. While this reduces the probability of autoimmunity, it also creates an important gap in adaptive immunity: the ability to recognize microbes that look like self. As a variety of microbes decorate themselves in self-like carbohydrate antigens and tolerance reduces the ability of adaptive immunity to react with self-like structures, protection against molecular mimicry likely resides within the innate arm of immunity. In this review, we will explore the potential consequences of microbial molecular mimicry, including factors within innate immunity that appear to specifically target microbes expressing self-like antigens, and therefore provide protection against molecular mimicry. PMID- 26577080 TI - Proceedings of the 1st French-Italian meeting on laminopathies and other nuclear envelope-related diseases. PMID- 26577081 TI - Slipping on salmon oil: another cause of hypercalcaemia in dogs. PMID- 26577078 TI - Abscisic acid and other plant hormones: Methods to visualize distribution and signaling. AB - The exploration of plant behavior on a cellular scale in a minimal invasive manner is key to understanding plant adaptations to their environment. Plant hormones regulate multiple aspects of growth and development and mediate environmental responses to ensure a successful life cycle. To monitor the dynamics of plant hormone actions in intact tissue, we need qualitative and quantitative tools with high temporal and spatial resolution. Here, we describe a set of biological instruments (reporters) for the analysis of the distribution and signaling of various plant hormones. Furthermore, we provide examples of their utility for gaining novel insights into plant hormone action with a deeper focus on the drought hormone abscisic acid. PMID- 26577082 TI - Reduced aggression and foraging efficiency of invasive signal crayfish (Pacifastacus leniusculus) infested with non-native branchiobdellidans (Annelida: Clitellata). AB - BACKGROUND: Biological invasions are a principal threat to global biodiversity and identifying the determinants of non-native species' success is a conservation priority. Through their ability to regulate host populations, parasites are increasingly considered as important in determining the outcome of species' invasions. Here, we present novel evidence that the common crayfish ecto symbiont, Xironogiton victoriensis (Annelida: Clitellata) can affect the behaviour of a widespread and ecologically important invader, the signal crayfish (Pacifastacus leniusculus). METHODS: To assess the signal crayfish-X. victoriensis relationship naive crayfish were infested with an intensity of worms typically observed under natural conditions. Over a 10-week period the growth rate and survivorship of these animals was monitored and compared to those of uninfested counterparts. Complementary dyadic competition and foraging experiments were run to assess the behaviour of infested compared to uninfested animals. These data were analysed using General Linear Models and Generalized Linear Mixed Models. RESULTS: Whilst X. victoriensis did not affect the growth rate or survivorship of signal crayfish under laboratory conditions, infested animals were significantly less aggressive and poorer foragers than uninfested individuals. CONCLUSIONS: Through reducing aggression and foraging efficiency, infestation with X. victoriensis may disrupt the social structure, and potentially growth rate and/or dispersal of afflicted crayfish populations, with potential effects on their invasion dynamics. This is important given the widespread invasive range of crayfish and their functional roles as ecosystem engineers and keystone species. PMID- 26577083 TI - Metabolomic profiling of urinary changes in mice with monosodium glutamate induced obesity. AB - Obesity with related complications represents a widespread health problem. The etiopathogenesis of obesity is often studied using numerous rodent models. The mouse model of monosodium glutamate (MSG)-induced obesity was exploited as a model of obesity combined with insulin resistance. The aim of this work was to characterize the metabolic status of MSG mice by NMR-based metabolomics in combination with relevant biochemical and hormonal parameters. NMR analysis of urine at 2, 6, and 9 months revealed altered metabolism of nicotinamide and polyamines, attenuated excretion of major urinary proteins, increased levels of phenylacetylglycine and allantoin, and decreased concentrations of methylamine in urine of MSG-treated mice. Altered levels of creatine, citrate, succinate, and acetate were observed at 2 months of age and approached the values of control mice with aging. The development of obesity and insulin resistance in 6-month-old MSG mice was also accompanied by decreased mRNA expressions of adiponectin, lipogenetic and lipolytic enzymes and peroxisome proliferator-activated receptor gamma in fat while mRNA expressions of lipogenetic enzymes in the liver were enhanced. At the age of 9 months, biochemical parameters of MSG mice were normalized to the values of the controls. This fact pointed to a limited predictive value of biochemical data up to age of 6 months as NMR metabolomics confirmed altered urine metabolic composition even at 9 months. PMID- 26577084 TI - DNA sequence-dependent fluorescence of doxorubicin for turn-on detection of biothiols in human serum. AB - Doxorubicin (Dox) is a DNA-targeting anthracycline antibiotic active against a wide spectrum of cancers. The interaction between Dox and double-stranded DNA (dsDNA) was used to load Dox using DNA duplexes as carriers. More importantly, the interesting DNA sequence-dependent fluorescence response of Dox could be exploited in the design of efficient Dox release systems and efficient fluorescence sensors. In this work, we demonstrated that separate introduction of G and C bases into T-rich single-stranded DNA (ssDNA) sequences afforded the best discrimination of Dox binding between dsDNA and ssDNA. For the first time, we successfully utilized this interesting DNA sequence-dependent fluorescence response of Dox as a signal transduction mechanism for the sensitive detection of biothiols in human serum. Cysteine, homocysteine, and glutathione were detected at as low as 26 nM, 37 nM, and 29 nM, respectively. The biosensors exhibited not only good selectivity, stability, and sensitivity in aqueous solutions but also a sensitive response in human serum, demonstrating their potential for diagnosis. PMID- 26577085 TI - A novel method to isolate protein N-terminal peptides from proteome samples using sulfydryl tagging and gold-nanoparticle-based depletion. AB - A novel method to isolate global N-termini using sulfydryl tagging and gold nanoparticle-based depletion (STagAu method) is presented. The N-terminal and lysine amino groups were first completely dimethylated at the protein level, after which the proteins were digested. The newly generated internal peptides were tagged with sulfydryl by Traut's reagent through digested N-terminal amines in yields of 96%. The resulting sulfydryl peptides were depleted through binding onto nano gold composite materials. The Au-S bond is stable and widely used in materials science. Nano gold composite materials showed nearly complete depletion of sulfydryl peptides. A set of the acetylated and dimethylated N-terminal peptides were analyzed by liquid chromatography-tandem mass spectrometry. This method was demonstrated to be an efficient N-terminus enrichment method because of the use of an effective derivatization reaction, in combination with robust and relative easy to implement Au-S coupling. We identified 632 N-terminal peptides from 386 proteins in a mouse liver sample. The STagAu approach presented is therefore a facile and efficient method for mass-spectrometry-based analysis of proteome N-termini or protease-generated cleavage products. PMID- 26577086 TI - A simple method for the accurate determination of the Henry's law constant for highly sorptive, semivolatile organic compounds. AB - A novel technique is developed to determine the Henry's law constants (HLCs) of seven volatile fatty acids (VFAs) with significantly high solubility using a combined application of thermal desorber/gas chromatography/mass spectrometry (TD/GC/MS). In light of the strong sorptive properties of these semi-volatile organic compounds (SVOCs), their HLCs were determined by properly evaluating the fraction lost on the surface of the materials used to induce equilibrium (vial, gas-tight syringe, and sorption tube). To this end, a total of nine repeated experiments were conducted in a closed (static) system at three different gas/liquid volume ratios. The best estimates for HLCs (M/atm) were thus 7,200 (propionic acid), 4,700 (i-butyric acid), 4,400 (n-butyric acid), 2,700 (i valeric acid), 2,400 (n-valeric acid), 1,000 (hexanoic acid), and 1,500 (heptanoic acid). The differences in the HLC values between this study and previous studies, if assessed in terms of the percent difference, ranged from 9.2% (n-valeric acid) to 55.7% (i-valeric acid). We overcame the main cause of errors encountered in previous studies by performing the proper correction of the sorptive losses of the SVOCs that inevitably took place, particularly on the walls of the equilibration systems (mainly the headspace vial and/or the glass tight syringe). PMID- 26577087 TI - SoHT 2015 - The 20th Conference of the Society of Hair Testing. PMID- 26577088 TI - Asymmetries in the production of self-directed behavior by chimpanzees and gorillas during a computerized cognitive test. AB - Self-directed behaviors (SDBs) are a commonly used behavioral indicator of arousal in nonhuman primates. Experimental manipulations, designed to increase arousal and uncertainty, have been used to elicit SDB production in primates. Beyond measuring rates of SDB production, researchers have also recorded their lateralized production by primates, thought to reflect laterality of hemispheric brain control and response to emotion. Although a handful of such studies exist, all have been conducted with chimpanzees. Expanding on this line of inquiry, we tested both chimpanzees (N = 3) and gorillas (N = 3) in a serial learning task presented on a touchscreen interface that incorporated both EASY (two-item list) and HARD (four-item list) versions of the task. Although SDB production by the apes did not differ across the two levels of task complexity, both species produced higher rates of SDB when they made an error, regardless of task difficulty. Furthermore, the apes made more SDB with the left hand-directed to the right side of their body (contralateral SDB) and left side of their body (ipsilateral SDB)-when they made an incorrect response. There was no difference in the rate of SDB produced with the right hand across correct compared to incorrect trials. The apes' responses reflect previous reports that show humans are quicker at selecting negative emotional stimuli when using their left, compared to their right, hand (the reverse is true for positive stimuli). However, previous work has shown that chimpanzees are more likely to produce (contralateral) SDB with their right hand when aroused and so we discuss our results in relation to these findings and consider how they relate to the 'right hemisphere' and 'valence' models of emotional processing in apes. PMID- 26577089 TI - Sex and species recognition by wild male southern white rhinoceros using contact pant calls. AB - Recognition of information from acoustic signals is crucial in many animals, and individuals are under selection pressure to discriminate between the signals of conspecifics and heterospecifics or males and females. Here, we first report that rhinos use information encoded in their calls to assess conspecifics and individuals of closely related species. The southern (Ceratotherium simum) and critically endangered northern (C. cottoni) white rhinos are the most social out of all the rhinoceros species and use a contact call pant. We found that southern white rhino pant calls provide reliable information about the caller's sex, age class and social situation. Playback experiments on wild territorial southern white rhinoceros males revealed that they responded more strongly to the pant calls of conspecific females compared to the calls of other territorial males. This suggests that pant calls are more important form of communication between males and females than between territorial males. Territorial southern males also discriminated between female and territorial male calls of northern species and reacted more intensively to the calls of northern than southern males. This might be caused by a novelty effect since both species naturally live in allopatry. We conclude that white rhinos can directly benefit from assessing individuals at long distances using vocal cues especially because their eyesight is poor. Pant calls thus likely play a significant role in their social relationships and spatial organization. In addition, better understanding of vocal communication in white rhinos might be helpful in conservation management particularly because of their low reproduction in captivity. PMID- 26577090 TI - Genetic association analysis of miRNA SNPs implicates MIR145 in breast cancer susceptibility. AB - BACKGROUND: MicroRNAs (miRNAs) are important small non-coding RNA molecules that regulate gene expression in cellular processes related to the pathogenesis of cancer. Genetic variation in miRNA genes could impact their synthesis and cellular effects and single nucleotide polymorphisms (SNPs) are one example of genetic variants studied in relation to breast cancer. Studies aimed at identifying miRNA SNPs (miR-SNPs) associated with breast malignancies could lead towards further understanding of the disease and to develop clinical applications for early diagnosis and treatment. METHODS: We genotyped a panel of 24 miR-SNPs using multiplex PCR and chip-based matrix assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) analysis in two Caucasian breast cancer case control populations (Primary population: 173 cases and 187 controls and secondary population: 679 cases and 301 controls). Association to breast cancer susceptibility was determined using chi-square (X (2) ) and odds ratio (OR) analysis. RESULTS: Statistical analysis showed six miR-SNPs to be non polymorphic and twelve of our selected miR-SNPs to have no association with breast cancer risk. However, we were able to show association between rs353291 (located in MIR145) and the risk of developing breast cancer in two independent case control cohorts (p = 0.041 and p = 0.023). CONCLUSIONS: Our study is the first to report an association between a miR-SNP in MIR145 and breast cancer risk in individuals of Caucasian background. This finding requires further validation through genotyping of larger cohorts or in individuals of different ethnicities to determine the potential significance of this finding as well as studies aimed to determine functional significance. PMID- 26577091 TI - Advancing heart health in North Carolina primary care: the Heart Health NOW study protocol. AB - BACKGROUND: The objective of Heart Health NOW (HHN) is to determine if primary care practice support-a comprehensive evidence-based quality improvement strategy involving practice facilitation, academic detailing, technology support, and regional learning collaboratives-accelerates widespread dissemination and implementation of evidence-based guidelines for cardiovascular disease (CVD) prevention in small- to medium-sized primary care practices and, additionally, increases practices' capacity to incorporate other evidence-based clinical guidelines in the future. METHODS/DESIGN: HHN is a stepped wedge, stratified, cluster randomized trial to evaluate the effect of primary care practice support on evidence-based CVD prevention, organizational change process measures, and patient outcomes. Each practice will start the trial as a control, receive the intervention at a randomized time point, and then enter a maintenance period 12 months after the start of the intervention. The intervention will be randomized to practices in one of four strata defined by region of the state (east or west) and degree of practice readiness for change. Seventy-five practices in each region with a high degree of readiness will be randomized 1:1:1 in blocks of 3 sometime prior to month 8 to receive the intervention at month 9, 11, or 12. An additional 75 practices within each region that have a low degree of readiness or are recruited later will be randomized 1:1 in blocks of 2 prior to month 13 to receive the intervention at month 14 or 16. The sites will be ordered within each strata based on time of enrollment with the blocking based on this ordering. Evaluation will examine the effect of primary care practice support on (1) practice-level delivery of evidence-based CVD prevention, (2) patient-level health outcomes, (3) practice-level implementation of clinical and organizational changes that support delivery of evidence-based CVD prevention, and (4) practice level capacity to implement future evidence-based clinical guidelines. DISCUSSION: Results will indicate whether primary care practice support is an effective strategy for widespread dissemination and implementation of evidence based clinical guidelines in primary care practices. Discernible reductions in cardiovascular risk in 300 practices covering over an estimated 900,000 adult patients would likely lead to prevention of thousands of cardiovascular events within 10 years. TRIAL REGISTRATION: ClinicalTrials.gov NCT02585557. PMID- 26577092 TI - Papular-purpuric gloves and socks syndrome. PMID- 26577094 TI - The role of skin biopsy in differentiating idiopathic Parkinson's disease from other types of parkinsonism. PMID- 26577093 TI - Identification of TTAGGG-binding proteins in Neurospora crassa, a fungus with vertebrate-like telomere repeats. AB - BACKGROUND: To date, telomere research in fungi has mainly focused on Saccharomyces cerevisiae and Schizosaccharomyces pombe, despite the fact that both yeasts have degenerated telomeric repeats in contrast to the canonical TTAGGG motif found in vertebrates and also several other fungi. RESULTS: Using label-free quantitative proteomics, we here investigate the telosome of Neurospora crassa, a fungus with canonical telomeric repeats. We show that at least six of the candidates detected in our screen are direct TTAGGG-repeat binding proteins. While three of the direct interactors (NCU03416 [ncTbf1], NCU01991 [ncTbf2] and NCU02182 [ncTay1]) feature the known myb/homeobox DNA interaction domain also found in the vertebrate telomeric factors, we additionally show that a zinc-finger protein (NCU07846) and two proteins without any annotated DNA-binding domain (NCU02644 and NCU05718) are also direct double strand TTAGGG binders. We further find two single-strand binders (NCU02404 [ncGbp2] and NCU07735 [ncTcg1]). CONCLUSION: By quantitative label-free interactomics we identify TTAGGG-binding proteins in Neurospora crassa, suggesting candidates for telomeric factors that are supported by phylogenomic comparison with yeast species. Intriguingly, homologs in yeast species with degenerated telomeric repeats are also TTAGGG-binding proteins, e.g. in S. cerevisiae Tbf1 recognizes the TTAGGG motif found in its subtelomeres. However, there is also a subset of proteins that is not conserved. While a rudimentary core TTAGGG-recognition machinery may be conserved across yeast species, our data suggests Neurospora as an emerging model organism with unique features. PMID- 26577095 TI - The evaluation of endodontic flare-ups and their relationship to various risk factors. AB - BACKGROUND: To evaluate the incidence of flare-ups and identify the risk factors including age, gender, tooth type, number of root canals, initial diagnosis, the type of irrigation regimen, treatment modality and the number of visits, in patients who received root canal treatment from January 2002 to January 2008. METHODS: Records of 1819 teeth belonging to 1410 patients treated by 1 endodontics specialist during 6-year period were kept. Patient, tooth, and treatment characteristics were evaluated and the relationships between these characteristics and flare-ups were studied. Statistical analysis was carried out by using Pearson Chi-square test, Fisher's Exact test, and Binary Logistic regression analyses. RESULTS: The incidence of flare-ups was 59 (3.2 %) out of 1819 teeth that received endodontic therapy. Pulpal necrosis without periapical pathosis was the most common indication for flare-up (6 %) (p < 0.01). Teeth undergoing multiple visits had a higher risk of developing flare-ups compared to those with single appointments (OR: 3.14, CI: 1.414-7.009, p < 0.01). There were also no statistically significant differences in the incidence of flare-ups regarding to age, gender, tooth type, number of root canals, treatment modality, and the irrigation solutions that used during the treatment. CONCLUSIONS: The incidence of flare-up is minimal when teeth are treated in one visit. Absence of a periapical lesion in necrotic teeth is a significant risk factor for flare-ups. PMID- 26577096 TI - Fifth Anniversary Editorial. PMID- 26577097 TI - In Vivo Wireless Monitoring System of Cardiovascular Force Data. AB - Biotelemetry provides the possibility to measure physiological data in awake, free-ranging animals without the effects of anesthesia and repeated surgery. In this project a fully implantable, telemetric system to measure biomechanical force data of the moving structures of the heart along with the ECG of experimental animals was developed. The system is based on a microcontroller with a built in bidirectional radio frequency transceiver, which allows for the implant to both receive and send data wirelessly. ECG was acquired using electrodes placed directly onto the heart, and the forces were collected using a miniature force transducer. The system was tested in a porcine model (60 kg body weight), where the system transmitted ECG and force data at a range of 5 m between the implant and the receiver. The data was displayed and saved to the hard drive of a laptop computer using a custom built software user interface. It was shown feasible to wirelessly measure forces simultaneously with physiological data from the cardiovascular system of living animals. The current system was optimized to measure forces and ECG, and more channels can be added to increase the number of parameters recorded. PMID- 26577098 TI - Implicit Partitioned Cardiovascular Fluid-Structure Interaction of the Heart Cycle Using Non-newtonian Fluid Properties and Orthotropic Material Behavior. AB - Although image-based methods like MRI are well-developed, numerical simulation can help to understand human heart function. This function results from a complex interplay of biochemistry, structural mechanics, and blood flow. The complexity of the entire system often causes one of the three parts to be neglected, which limits the truth to reality of the reduced model. This paper focuses on the interaction of myocardial stress distribution and ventricular blood flow during diastole and systole in comparison to a simulation of the same patient-specific geometry with a given wall movement (Spiegel, Stromungsmechanischer Beitrag zur Planung von Herzoperationen, 2009). The orthotropic constitutive law proposed by Holzapfel et al. (Philos. Trans. R. Soc. Lond. Ser. A, 367:3445-3475, 2009) was implemented in a finite element package to model the passive behavior of the myocardium. Then, this law was modified for contraction. Via the ALE method, the structural model was coupled to a flow model which incorporates blood rheology and the circulatory system (Oertel, Prandtl-Essentials of Fluid Mechanics, 3rd edn, Springer Science + Business Media, 2010; Oertel et al., Modelling the Human Cardiac Fluid Mechanics, 3rd edn, Universitatsverlag Karlsruhe, 2009). Comparison reveals a good quantitative and qualitative agreement with respect to fluid flow. The motion of the myocardium is consistent with physiological observations. The calculated stresses and the distribution are within the physiological range and appear to be reasonable. The coupled model presented contains many features essential to cardiac function. It is possible to calculate wall stresses as well as the characteristic ventricular fluid flow. Based on the simulations we derive two characteristics to assess the health state quantitatively including solid and fluid mechanical aspects. PMID- 26577099 TI - Improvement of Left Ventricular Asynchrony: Cases of Functional Recovery After Revascularization. AB - Assessment of regional contraction is considered important for diagnosis of coronary artery disease (CAD). We evaluated the synchronicity in regional contraction and assessed recovery from contraction insufficiency after revascularizations. Myocardial contraction parallel to the left ventricular (LV) wall was calculated using the method called quantification of segmental function by solving the Poisson equation (QSFP) from an electrocardiogram (ECG)-gated (99m)Tc-methoxyisobutylisonitrile (MIBI) single-photon emission computed tomographic (ECG-SPECT) image. Myocardial synchronous contraction was quantified using the synchronous contraction index (SCI), defined as the temporal correlation coefficient between LV volume and regional myocardial shortening. SCI was evaluated in 20 subjects, of whom 10 had CAD and 10 were normal. ECG-SPECT was performed in all the CAD patients before and after revascularization. In the 10 patients with CAD, the mean SCI before the revascularization was 62.7 +/- 19.1%, which was significantly lower than that in the normal subjects (95.0 +/- 3.0%, p = 0.002). After revascularization, a significant improvement in SCI was recorded (74.8 +/- 11.1%, p = 0.01). The territorial improvement in SCI was 12.0 +/- 15.6% (p = 0.03). Locations of abnormal cardiac contraction due to CAD were delineated by using QSFP. Therefore, SCI can be considered a valuable index for cardiac function assessment. PMID- 26577100 TI - Co-localization of Disturbed Flow Patterns and Occlusive Cardiac Allograft Vasculopathy Lesion Formation in Heart Transplant Patients. AB - Cardiac allograft vasculopathy (CAV) is one of the leading causes of morbidity and morality in orthotopic heart transplant (HTx) patients. While disturbed flow patterns have been linked to the spatial localization of atherosclerosis, the role of hemodynamics in CAV development has not been examined. HTx patients (n = 5) requiring percutaneous coronary intervention (PCI) for a focal, epicardial lesion were studied. Angiographic images were retrospectively obtained from baseline (i.e., in the presence of no observed disease) and follow-up catheterizations (i.e., at the time of PCI; 12.4 +/- 2.6 years post-HTx). Patient specific computational models were created from baseline images. Computational fluid dynamic techniques were employed to quantify the hemodynamic environment, which was expressed as normalized time-averaged WSS (TAWSSnorm; measure of temporal WSS magnitude) and normalized WSS angle deviation (WSSADnorm; measure of instantaneous WSS vector oscillation) values. Baseline hemodynamic and follow-up angiographic data were co-registered to investigate the association between WSS and subsequent occlusive CAV lesion location. Results indicate a high degree of co-localization between baseline low WSS data and follow-up occlusive CAV lesion. Local minima in TAWSSnorm were located 2.5 +/- 0.6 mm from the site of PCI. Furthermore, local maxima in WSSADnorm were located 3.9 +/- 0.7 mm from the site of PCI. In 3 patients, the occlusive lesion formed in a region that was subjected to both low and oscillatory WSS at baseline. There was discernable spatial co localization between baseline disturbed flow patterns and follow-up CAV lesions requiring PCI. These results suggest a role of fluid mechanics in the development of focal, flow-limiting CAV lesions. PMID- 26577101 TI - Suture Line Response of End-to-Side Anastomosis: A Stress Concentration Methodology. AB - End-to-side vascular anastomosis has a considerable complexity regarding the suturing of the juncture line between the artery and the graft. The present study proposes a stress-concentration methodology for the prediction of the stress distribution at the juncture line, aiming to provide generic expressions describing the response of an end-to-side anastomosis. The proposed methodology is based on general results obtained from the analysis of pipe connections, a topic that has been investigated in recent years in the field of offshore structural engineering. A key aspect for implementing the stress-concentration factor approach is the recognition that the axial load due to pressure and flow dynamics exerted along the graft axis controls the "hot spots" on the juncture line, which in turn affects the mechanical response of the sutures. Several parameters, identified to influence the suture line response, are introduced in closed-form expressions for the suture line response calculations. The obtained results compare favorably with finite element results published in the literature. The proposed model predicts analytically the suture line response of end-to-side anastomosis, while capturing the influence of and interdependence among the problem parameters. Lower values of the graft radius, the distance between sequential stitches, and the intersecting angle between the artery and the graft are some of the key parameters that reduce the suture line response. The findings of this study are broad in scope and potentially applicable to improving the end-to-side anastomosis technique through improved functionality of the sutures and optimal selection of materials and anastomosis angle. PMID- 26577102 TI - Pulse Wave Velocity Prediction and Compliance Assessment in Elastic Arterial Segments. AB - Pressure wave velocity (PWV) is commonly used as a clinical marker of vascular elasticity. Recent studies have increased clinical interest in also analyzing the impact of heart rate, blood pressure, and left ventricular ejection time on PWV. In this article we focus on the development of a theoretical one-dimensional model and validation via direct measurement of the impact of ejection time and peak pressure on PWV using an in vitro hemodynamic simulator. A simple nonlinear traveling wave model was developed for a compliant thin-walled elastic tube filled with an incompressible fluid. This model accounts for the convective fluid phenomena, elastic vessel deformation, radial motion, and inertia of the wall. An exact analytical solution for PWV is presented which incorporates peak pressure, ejection time, ejection volume, and modulus of elasticity. To assess arterial compliance, the solution is introduced in an alternative form, explicitly determining compliance of the wall as a function of the other variables. The model predicts PWV in good agreement with the measured values with a maximum difference of 3.0%. The results indicate an inverse quadratic relationship ([Formula: see text]) between ejection time and PWV, with ejection time dominating the PWV shifts (12%) over those observed with changes in peak pressure (2%). Our modeling and validation results both explain and support the emerging evidence that, both in clinical practice and clinical research, cardiac systolic function related variables should be regularly taken into account when interpreting arterial function indices, namely PWV. PMID- 26577103 TI - Variation in Cardiac Pulse Frequencies Modulates vSMC Phenotype Switching During Vascular Remodeling. AB - In vitro perfusion systems have exposed vascular constructs to mechanical conditions that emulate physiological pulse pressure and found significant improvements in graft development. However, current models maintain constant, or set pulse/shear mechanics that do not account for the natural temporal variation in frequency. With an aim to develop clinically relevant small diameter vascular grafts, these investigations detail a perfusion culture model that incorporates temporal pulse pressure variation. Our objective was to test the hypothesis that short-term variation in heart rate, such as changes in respiratory activity, plays a significant role in vascular remodeling and graft development. The pulse rate of a healthy volunteer was logged to model the effect of daily activities on heart rate. Vascular bioreactors were used to deliver perfusion conditions based on modeled frequencies of temporal pulse variability, termed Physiologically Modeled Pulse Dynamics (PMPD). Acellular scaffolds derived from the human umbilical vein were seeded with human vascular smooth muscle cells and perfused under defined pulsatile conditions. vSMC exposed to constant pulse frequencies expressed a contractile phenotype, while exposure to PMPD drove cells to a synthetic state with continued cell proliferation, increased tensile strength and stiffness as well as diminished vasoactivity. Results show the temporal variation associated with normal heart physiology to have a profound effect on vascular remodeling and vasoactive function. While these models are representative of vascular regeneration further investigation is required to understanding these and other key regulators in vSMC phenotype switching in non-pathological or wound healing states. This understanding has important clinical implications that may lead to improved treatments that enhance vessel regeneration. PMID- 26577104 TI - Comparative Study of Degradation Behavior of Bioresorbable Cardiovascular Scaffolds. AB - This comparative study investigated the biodegradation behavior and mechanism of bioresorbable cardiovascular scaffolds using bench testing under physiological conditions and in vivo experiment. The results show that the molecular weight of the scaffold decreased with respect to time after implantation in both in vivo and in vitro tests. It was found that the molecular weights of the implanted scaffolds in the in vivo and in vitro models decreased to 61.8 and 68.5% respectively 6 months after implantation, but the thermodynamic properties of the scaffold material were not significantly affected by the 6-month degradation. Moreover, the study indicated that in spite of the 6-month degradation, the scaffold maintained sufficient radial strength and mechanical integrity. Furthermore, it was noted that the changes in the trends of the mechanical properties and degradation behavior of the scaffolds in the in vitro model were coherent with the results of the in vivo study, which means the in vitro study of the degradation behavior of polylactic acid (PLA) scaffold could offer clinical relevant data and physical insights to predict the in vivo performance. PMID- 26577105 TI - Hemodynamics in Normal and Diseased Livers: Application of Image-Based Computational Models. AB - This investigation demonstrates the utility of image-based computational models in portal venous hemodynamics. The long-term objective is to develop methodologies based upon noninvasive imaging and hemodynamic computational models for blood flow in major vessels of the liver that will significantly augment and improve current practices in clinical care. Magnetic resonance imaging (MRI) and computational fluid dynamics (CFD) were used to investigate liver hemodynamics. MRI data were obtained in 7 healthy subjects and 4 patients diagnosed with cirrhosis, and computational models were developed and validated for two healthy subjects and two patients. Additional simulations of post-prandial hemodynamics and portal hypertension were completed. The MRI studies identified several new parameters (portal vein V avg/total liver volume, V var, splenic vein flow rate per total liver volume, and % splenic flow/portal vein flow) that offer statistical differentiation between healthy subjects and patients with liver disease. Computational models were used to calculate the contribution of blood supply to the right and left lobes of the liver derived from the superior mesenteric vein (greater in healthy subjects vs. patients); and simulate post prandial conditions and progressive portal hypertension. CFD offers a tool to test hypotheses without the acquisition of additional data and elucidate hemodynamic effects as disease progresses. In addition, several new MRI derived parameters have been identified as having promise to distinguish between healthy and patient groups and, potentially, to monitor disease progression. PMID- 26577106 TI - Management of infection and febrile neutropenia in patients with solid cancer. AB - An expert group from the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC, for its acronym in Spanish) and the Spanish Society of Medical Oncology (SEOM, for its acronym in Spanish) have reviewed the main aspects to be considered when evaluating patients with solid cancer and infectious complications contained in this article. Recommendations have, therefore, been put forth regarding the prophylaxis of the most prevalent infections in these patients, the use of vaccines, measures to control infection through vascular catheters, and preventing infection in light of certain surgical maneuvers. The following is a revision of the criteria for febrile neutropenia management and the use of colony-stimulating factors and closes with several guidelines for treating the cancer patient with serious infection. The document concludes with a series of measures to control hospital infection. PMID- 26577107 TI - Factors affecting the recurrence and survival of hepatocellular carcinoma after hepatectomy: a retrospective study of 601 Chinese patients. AB - OBJECTIVE: Indications for resection of hepatocellular carcinoma (HCC) remain controversial. This study aimed to identify prognostic factors that affect overall survival (OS) and disease-free survival (DFS) in patients with HCC after hepatectomy. METHODS: From 2004 to 2010, 601 patients with HCC who underwent resection were enrolled. Factors stratified into the host, biochemical, surgical treatment and tumor-related features in terms of recurrence and overall survival were analyzed. Prognostic factors were evaluated by univariate and multivariate analyses, with Kaplan-Meier survival analyses and Cox proportional hazard model. RESULTS: The overall survival rates of 1-, 3- and 5- year were 79, 62, and 54 %, and the corresponding DFS rates were 51, 38 and 31 %, respectively. In a multivariate analysis, Child-Pugh, serum AFP level, ALT level, time for hepatic resection, tumor differentiation, maximum size of tumors, local necrosis, portal vein tumor thrombus, and TNM Stage were correlated significantly with patients' OS. Gender (P = 0.046), cigarette smoking (P = 0.007), serum AFP level (P = 0.001), GGT level (P = 0.002), maximum size of tumors (P = 0.009), liver cirrhosis (P = 0.025), portal vein tumor thrombus (P = 0.022), microvascular tumor thrombus (P = 0.007) and TNM Stage (P = 0.001) were significantly affected DFS. CONCLUSION: Preoperative AFP level, maximum size of tumors, portal vein tumor thrombus and TNM Stage were revealed as important prognostic factors for OS and DFS through follow-up of a relatively large cohort of Chinese HCC patients. PMID- 26577108 TI - Paeoniflorin improves regional cerebral blood flow and suppresses inflammatory factors in the hippocampus of rats with vascular dementia. AB - OBJECTIVE: To explore the delayed neuroprotection induced by paeoniflorin (PF), the principal component of Paeoniae radix prescribed in Chinese medicine, and its underlying mechanisms in rats subjected to vascular dementia (VD). METHODS: A rat model of VD was induced by bilateral common carotid arteries occlusion (BCCAO). Low-dose or high-dose PF (20 or 40 mg/kg once per day) was administrated for 28 days after VD. The behavioral analysis of rat was measured by water morris. Regional cerebral blood volume (rCBV), regional cerebral blood flflow (rCBF) and mean transit time (MTT) were measured in the bilateral hippocampus by perfusion weighted imaging (PWI). The levels of interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-alpha) were measured by commercially available enzyme-linked immunosorbent assay kits. Protein levels were evaluated by western blot analysis. mRNA levels were evaluated by real time-polymerase chain reaction. Western blotting was used to estimate p65 translocation. RESULTS: The behavioral analysis showed that PF could decrease the escape latency time (P<0.05), and increase the residence time of the original platform quadrant and the across platform frequency in water maze in VD rats (P<0.05). Likewise, PF remarkably promoted the rCBV (P<0.05), rCBF and decreased per minute MTT (P<0.05) in hippocampus of VD rats. Furthermore, PF decreased the release of IL-1beta, IL 6 and TNF-alpha as well as inhibited the mRNA expression of IL-1beta, IL-6 and TNF-alpha in the hippocampus of VD rats (P<0.05 or P<0.01). PF also could decrease the protein expressions of inducible nitric oxide synthase and cyclooxygenase-2 in the hippocampus of VD rats (P<0.05 or P<0.01). In addition, PF signifificantly inhibited the nuclear factor kappaB (NF-kappaB) pathway in the hippocampus of VD rats. CONCLUSIONS: PF signifificantly attenuates cognitive impairment, improves hippocampus perfusion and inhibits inflflammatory response in VD rats. In addition, the anti-inflflammatory effects of PF might be due to inhibiting the NF-kappaB pathway. PF may be a potential clinical application in improving VD. PMID- 26577109 TI - Effect of traditional Chinese medicine for treating human immunodeficiency virus infections and acquired immune deficiency syndrome: Boosting immune and alleviating symptoms. AB - To respond to the human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) epidemic in China, the integration of antiretroviral therapy (ART) and traditional Chinese medicine (TCM) has important implications in health outcomes, especially in China where the use of TCM is widespread. The National Free TCM Pilot Program for HIV Infected People began in 5 provinces (Henan, Hebei, Anhui, Hubei, and Guangdong) in 2004, and quickly scaled up to 19 provinces, autonomous regions, and municipalities in China including some places with high prevalence, 26,276 adults have been treated thus far. Usually, people with HIV infection seek TCM for four main reasons: to enhance immune function, to treat symptoms, to improve quality of life, and to reduce side effects related to medications. Evidences from randomized controlled clinical trials suggested some beneficial effects of use of traditional Chinese herbal medicine for HIV infections and AIDS. More proofs from large, well-designed, rigorous trials is needed to give firm support. Challenges include interaction between herbs and antiretroviral drugs, stigma and discrimination. The Free TCM Program has made considerable progress in providing the necessary alternative care and treatment for HIV-infected people in China, and has strong government support for continued improvement and expansion, establishing and improving a work mechanism integrating Chinese and Western medicines. PMID- 26577110 TI - Anti-oxidative and anti-inflammatory effects of cinnamaldehyde on protecting high glucose-induced damage in cultured dorsal root ganglion neurons of rats. AB - OBJECTIVE: To examine the mechanism underlying the beneficial role of cinnamaldehyde on oxidative damage and apoptosis in high glucose (HG)-induced dorsal root ganglion (DRG) neurons in vitro. METHODS: HG-treated DRG neurons were developed as an in vitro model of diabetic neuropathy. The neurons were randomly divided into five groups: the control group, the HG group and the HG groups treated with 25, 50 and 100 nmol/L cinnamaldehyde, respectively. Cell viability was examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and apoptosis rate was evaluated by the in situ TdT-mediated dUTP nick end labeling (TUNEL) assay. The intracellular level of reactive oxygen species (ROS) was measured with flow cytometry. Expression of nuclear factor kappa B (NF-kappaB), inhibitor of kappaB (IkappaB), phosphorylated IkappaB (p IkappaB), tumor necrosis factor (TNF)-alpha, interleukin-6 (IL-6) and caspase-3 were determined by western blotting and real-time quantitative reverse transcription polymerase chain reaction (RT-PCR). Expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and hemeoxygenase-1 (HO-1) were also measured by western blotting. RESULTS: Cinnamaldehyde reduced HG-induced loss of viability, apoptosis and intracellular generation of ROS in the DRG neurons via inhibiting NF-kappaB activity. The western blot assay results showed that the HG induced elevated expressions of NF-kappaB, IkappaB and p-IkappaB were remarkably reduced by cinnamaldehyde treatment in a dose-dependent manner (P <0.01). The HG induced over-expression of NF-kappaB p65 mRNA was remarkably attenuated after cinnamaldehyde treatment in a dose-dependent manner (P <0.01). However, the expressions of Nrf2 and HO-1 were not upregulated. Treatment with cinnamaldehyde not only attenuated caspase-3 activation and the caspase cleavage cascade in DRG neurons, but also lowered the elevated IL-6, TNF-alpha, cyclo-oxygenase and inducible nitric oxide synthase levels, indicating a reduction in inflammatory damage. CONCLUSIONS: Cinnamaldehyde protected DRG neurons from the deleterious effects of HG through inactivation of NF-kappaB pathway but not through activation of Nrf2/HO-1. And thus cinnamaldehyde may have potential application as a treatment for DPN. PMID- 26577111 TI - Dynamics and restriction of murine leukemia virus cores in mitotic and interphase cells. AB - BACKGROUND: Murine leukemia viruses (MLVs) naturally infect unsynchronized T and B lymphocytes, thus, the incoming virus encounters both interphase and mitotic cells. While it is well accepted that MLV requires cell division to complete its replication cycle, it is not known if ab initio infection of mitotic cells can result in productive infection. This question is highly relevant since the milieu of mitotic cells is markedly different from this of interphase cells; e.g. lacking radial microtubule network and intact nuclear envelope. To follow MLV infection in mitotic and interphase cells in real-time, we employed our recently developed infectious MLV particles with labeled cores, cellular models expressing fluorescence markers of different intracellular compartments and protocols for reversible mitotic arrest of MLV-susceptible cells. RESULTS: Multi-wavelength live cell imaging was employed to simultaneously visualize GFP-labeled MLV cores, DiD-labeled viral or cellular membranes, and fluorescently-labeled microtubules or chromosomes. Cells were imaged either at interphase or upon mitotic arrest with microtubule poisons. Analysis of virus localization and trajectories revealed entry by endocytosis at interphase and mitosis, and correlation between viral mobility parameters and presence or absence of polymerized interphase microtubules. The success of infection of viruses that entered cells in mitosis was evidenced by their ability to reverse transcribe, their targeting to condensed chromosomes in the absence of radial microtubule network, and gene expression upon exit from mitosis. Comparison of infection by N, B or NB -tropic viruses in interphase and mitotic human cells revealed reduced restriction of the N-tropic virus, for infection initiated in mitosis. CONCLUSIONS: The milieu of the mitotic cells supports all necessary requirements for early stages of MLV infection. Such milieu is suboptimal for restriction of N-tropic viruses, most likely by TRIM5alpha. PMID- 26577112 TI - Near IR fluorescent conjugated poly(ethylene glycol)bisphosphonate nanoparticles for in vivo bone targeting in a young mouse model. AB - Bisphosphonate (BP) compounds are widely used in the treatment of bone disorders. This group of drugs with a high affinity to Ca(+2) ions is rapidly attracted to bone mineral, especially in areas of high resorption. We have engineered unique biodegradable BP nanoparticles (NPs) by dispersion co-polymerization of the monomers methacrylate-PEG-BP) and (3-Aminopropyl)mathacrylamide) with the crosslinker monomer tetra ethylene glycol diacrylate. These NPs possess a dual functionality: (1) covalent attachment of a dye (e.g. near IR dye) or a drug to the nanoparticles through the primary amine groups on the surface of the NPs; (2) chelation to the bone mineral hydroxyapatite through the BP on the surface of the NPs. This study describes the uptake of the unique near IR fluorescent Cy 7 conjugated BP NPs in bone of a young mouse model. Blood half-life studies revealed a relatively long half-life (approximately 5 h) due to a high concentration of PEG in the BP NPs as well as a relatively long whole body clearance (approximately 2 weeks). Body distribution studies showed a specific uptake of the BP NPs in bone. These unique engineered BP NPs are planned to be utilized in future work for diagnostic and drug delivery systems that are targeted to bone disorders. PMID- 26577113 TI - Facile microwave-assisted synthesis of benzimidazole scaffolds via Ugi-type three component condensation (3CC) reactions. AB - Two series of fused benzimidazoles were synthesized via a facile, one-pot procedure under microwave irradiation. This procedure generated the desired products in high yields and could provide a useful synthetic platform with potential applications in medicinal chemistry. PMID- 26577114 TI - A Rhodium Nanoparticle-Lewis Acidic Ionic Liquid Catalyst for the Chemoselective Reduction of Heteroarenes. AB - We describe a catalytic system composed of rhodium nanoparticles immobilized in a Lewis acidic ionic liquid. The combined system catalyzes the hydrogenation of quinolines, pyridines, benzofurans, and furan to access the corresponding heterocycles, important molecules present in fine chemicals, agrochemicals, and pharmaceuticals. The catalyst is highly selective, acting only on the heteroaromatic ring, and not interfering with other reducible functional groups. PMID- 26577115 TI - CXCR4 Expression is Associated with Poor Prognosis in Patients with Esophageal Squamous Cell Carcinoma. AB - BACKGROUND: Chemokines and their receptors are known to play important roles in the tumorigenesis of many malignancies. The chemokine CXCL12 and its receptors CXCR4 and CXCR7 were suggested to be involved in cancer invasion and metastasis. The aim of this retrospective study was to evaluate the prognostic impact of the expressions of CXCL12, CXCR4 and CXCR7 in patients with esophageal squamous cell carcinoma (ESCC). METHODS: We used immunohistochemistry (IHC) and reverse transcriptase-polymerase chain reaction (RT-PCR) to evaluate the expressions of CXCL12, CXCR4, and CXCR7 in ESCC patients' tumor biopsy specimens obtained during preoperative endoscopy or surgery. These results were compared with the patients' clinicopathological parameters and survival. RESULTS: IHC was conducted for 172 patients. High expression of CXCR4 in the cytoplasm and nuclei and that of CXCR7 were associated with poor cause-specific survival (CSS) (P= .002 and .010, respectively). The specimens from 52 of the 172 patients were examined by RT-PCR and quantitative real-time PCR. The expression levels of messenger RNA (mRNA) of CXCR4 and CXCR7 were significantly increased in the tumors compared with normal esophageal mucosae (P < .0001). The expression level of mRNA of CXCR4 was associated with poor recurrence-free survival and CSS (P = .012 and .038, respectively). CONCLUSIONS: CXCR4 expression is associated with poor prognosis in patients with ESCC. PMID- 26577116 TI - Predictive Modeling: A New Paradigm for Managing Endometrial Cancer. AB - With the abundance of new options in diagnostic and treatment modalities, a shift in the medical decision process for endometrial cancer (EC) has been observed. The emergence of individualized medicine and the increasing complexity of available medical data has lead to the development of several prediction models. In EC, those clinical models (algorithms, nomograms, and risk scoring systems) have been reported, especially for stratifying and subgrouping patients, with various unanswered questions regarding such things as the optimal surgical staging for lymph node metastasis as well as the assessment of recurrence and survival outcomes. In this review, we highlight existing prognostic and predictive models in EC, with a specific focus on their clinical applicability. We also discuss the methodologic aspects of the development of such predictive models and the steps that are required to integrate these tools into clinical decision making. In the future, the emerging field of molecular or biochemical markers research may substantially improve predictive and treatment approaches. PMID- 26577118 TI - Comparison of Survival Outcomes in Women with Unsuspected Uterine Malignancy Diagnosed After Laparotomic Versus Laparoscopic Myomectomy: A National, Population-Based Study. AB - PURPOSE: The primary objective of our study was to investigate the effect of morcellation on overall survival in women with unsuspected uterine malignancy (UUM) diagnosed after myomectomy by comparing women who underwent laparotomic myomectomy to those who underwent laparoscopic myomectomy. The secondary objective was to estimate the incidence of UUM diagnosed after myomectomy. METHODS: We analyzed the mortality and incidence of women with UUM diagnosed after myomectomy using data from the national health insurance database between 2009 and 2013. To extract women with or without UUM diagnosed after myomectomy, we used diagnosis (C54.X) and procedure codes. We used the indicator of suspicion of death to verify deaths. RESULTS: During the study period, among the study population of approximately 23 million women per year, 102144 women underwent myomectomy. Of them, 69955 and 32085 women were enrolled onto the laparotomic and laparoscopic groups, respectively. In each group, the numbers of women with UUM diagnosed after myomectomy were 76 and 50, respectively. The incidences of UUM and UUM excluding endometrial cancer, respectively, were 0.1, 0.15 % (p = 0.046) and 0.05, 0.07 % (p = 0.147) in each group, respectively. The overall 3-year survival rates for patients with UUM and UUM excluding endometrial cancer were 97.6 +/- 0.2 % (n = 23), 91.5 +/- 0.5 % (n = 12); and 93.8 +/- 0.6 % (n = 8), 93.8 +/- 0.6 % (n = 5) in each group, respectively. Additionally, there were no statistically significant differences between the groups with respect to overall survival of women with UUM with or without endometrial cancer (log-rank test; p = 0.14) (time-dependent Cox regression model; p = 0.93). CONCLUSIONS: There was no difference in the overall survival of women with UUM with or without endometrial cancer between groups. The incidence of UUM with or without endometrial cancer diagnosed after myomectomy was quite low. PMID- 26577119 TI - Transanal Endoscopic Microsurgery (TEM) Following Neoadjuvant Chemoradiation for Rectal Cancer: Outcomes of Salvage Resection for Local Recurrence. AB - BACKGROUND: Transanal endoscopic microsurgery (TEM) has been considered an alternative for selected patients with rectal cancer following neoadjuvant chemoradiation (CRT). Immediate total mesorectal completion for all patients with unfavorable pathological features would result in unnecessary protectomies in a significant proportion of patients. Instead, salvage total mesorectal excision (TME) could be restricted for patients developing local recurrence. The aim of the present study is to determine oncological outcomes of salvage resection for local recurrences following CRT and TEM. METHODS: Consecutive patients undergoing TEM following neoadjuvant CRT for rectal cancer were reviewed. Patients with "near" complete response to CRT (<=3 cm; ycT1-2N0) were offered TEM. Salvage surgery was attempted in the event of a local recurrence. RESULTS: A total of 53 patients were managed by CRT followed by TEM. Unfavorable pathological features were present in 36 patients (68 %). None of the patients underwent immediate completion TME. There were 12 patients who developed local recurrence resulting in a 2-year local recurrence-free survival of 77 % (95 % CI, 53-100 %). Of these patients, 9 developed exclusively local recurrences, and all had at least 1 unfavorable pathological feature in the specimen after TEM (100 %). Eight patients (8 of 9) underwent salvage resection (abdominoperineal resection [APR] in 87 %) with CRM+ in 7 of 8 patients (87 %). Four patients developed local re recurrence after a median 36 months of follow-up. The 2-year local re-recurrence free survival was 60 %. CONCLUSIONS: Salvage resection for local recurrence following CRT and TEM is associated with high rates of R1 resection (CRM+) and local re-recurrence. Immediate completion of TME should be considered for patients with unfavorable pathological features after TEM. PMID- 26577117 TI - Survival Benefit of Exercise Differs by Tumor IRS1 Expression Status in Colorectal Cancer. AB - BACKGROUND: High-level physical activity is associated with lower colorectal cancer (CRC) mortality, likely through insulin sensitization. Insulin receptor substrate 1 (IRS1) is a mediator of insulin and insulin-like growth factor (IGF) signaling pathways, and its down-regulation is associated with insulin resistance. Therefore, we hypothesized that tumor IRS1 expression status might modify cellular sensitivity to insulin and IGF, and the prognostic association of physical activity. METHODS: We assessed IRS1 expression level in 371 stage I-III rectal and colon cancers in the Nurses' Health Study and the Health Professionals Follow-up Study by immunohistochemistry. In survival analysis, Cox proportional hazards model was used to assess an interaction between post-diagnosis physical activity (ordinal scale of sex-specific quartiles Q1 to Q4) and IRS1 expression (ordinal scale of negative, low, and high), controlling for potential confounders, including microsatellite instability, CpG island methylator phenotype, long interspersed nucleotide element-1 (LINE-1) methylation level, and KRAS, BRAF, and PIK3CA mutation status. RESULTS: There was a statistically significant interaction between post-diagnosis physical activity and tumor IRS1 expression in CRC-specific mortality analysis (P interaction = 0.005). Multivariable hazard ratio (95% confidence interval) for higher post-diagnosis physical activity (Q3-Q4 vs. Q1-Q2) was 0.15 (0.02-1.38) in the IRS1-negative group, 0.45 (0.19-1.03) in the IRS1-low group, and 1.32 (0.50-3.53) in the IRS1 high group. CONCLUSIONS: The association of post-diagnosis physical activity with colorectal carcinoma patient survival may differ by tumor IRS1 expression level. If validated, tumor IRS1 expression status may serve as a predictive marker to identify subgroups of patients who might gain greater survival benefit from an increased level of exercise. PMID- 26577120 TI - Importance of Absent Neoplastic Epithelium in Patients Treated With Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy. AB - BACKGROUND: The importance of absent neoplastic epithelium in specimens from cytoreductive surgery (CRS) is unknown. This study aimed to investigate the prevalence and prognostic value of histopathology without neoplastic epithelium in patients treated with CRS and hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: Data were extracted from medical records and histopathology reports for patients treated with initial CRS and HIPEC at Uppsala University Hospital, Sweden, between 2004 and 2012. Patients with inoperable disease and patients undergoing palliative non-CRS surgery were excluded from the study. Patients lacking neoplastic epithelium in surgical specimens from CRS, with or without mucin, were classified as "neoplastic epithelium absent" (NEA), and patients with neoplastic epithelium were classified as "neoplastic epithelium present" (NEP). RESULTS: The study observed NEA in 78 of 353 patients (22 %). Mucin was found in 28 of the patients with NEA. For low-grade appendiceal mucinous neoplasms and adenomas, the 5-year overall survival rate was 100 % for NEA and 84 % for NEP, and the 5-year recurrence-free survival rate was 100 % for NEA and 59 % for NEP. For appendiceal/colorectal adenocarcinomas (including tumors of the small intestine), the 5-year overall survival rate was 61 % for NEA and 38 % for NEP, and the 5-year recurrence-free survival rate was 60 % for NEA and 14 % for NEP. Carcinoembryonic antigen level, peritoneal cancer index, and completeness of the cytoreduction score were lower in patients with NEA. CONCLUSIONS: A substantial proportion of patients undergoing CRS and HIPEC have NEA. These patients have a favorable prognosis and a decreased risk of recurrence. Differences in patient selection can affect the proportion of NEA and hence explain differences in survival rates between reported series. PMID- 26577121 TI - Approach to the Porta Hepatis During Cytoreductive Surgery: Technical Considerations. AB - Peritoneal carcinomatosis has until recently been considered uniformly fatal; it results in intestinal obstructions, eventually leading progression of disease and death. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy have become important options for patients with peritoneal carcinomatosis. Completeness of cytoreduction is a major determinant of survival. Frequently, the porta hepatis and the lesser sac are massively involved by tumor. Encasement of portal triad, lesser omentum, retrohepatic vena cava, duodenum, and stomach is frequently seen. The proximity to major portal structures as well as the retrohepatic vena cava makes this dissection challenging. This is the area where meticulous surgical technique and expertise are necessary to obtain complete removal of tumor. Some specific technical considerations are important to assure that all tumor is safely removed. PMID- 26577122 TI - Intraoperative Image-Guided Breast-Conservation Surgery Should be the Gold Standard. PMID- 26577123 TI - Occult Histopathology and Its Predictors in Contralateral and Bilateral Prophylactic Mastectomies. AB - BACKGROUND: The last decade has seen an increasing prevalence of prophylactic mastectomies with decreasing age of patients treated for breast cancer. Data are limited on the prevalence of histopathologic abnormalities in this population. This study aimed to measure the prevalence of histopathologic findings in contralateral prophylactic mastectomy (CPM) and bilateral prophylactic mastectomy (BPM) patients and identify predictors of findings. METHODS: Our institution's prophylactic mastectomies from 2004 to 2011 were reviewed. Breast specimens with prior malignancies were excluded. Patient factors and pathology reports were collected. Independent predictive factors were identified with univariate and multivariate logistic analysis. RESULTS: A total of 524 specimens in 454 patients were identified. Malignancy was found in 7.0% of CPM and 5.7% of BPM specimens. In CPM patients, ipsilateral lobular carcinoma-in situ [odds ratio (OR) 4.0] and mammogram risk group (OR 2.0) were predictive of malignancy. Age group (OR 1.5), ipsilateral lobular carcinoma-in situ (OR 2.3), and prior bilateral salpingo oophorectomy (OR 0.3) were predictive of moderate- to high-risk histopathology. Only increasing age group was predictive of increased moderate- to high-risk histopathology in BPM patients (OR 2.3). There were no independent predictors of malignancy in BPM. BRCA status was not predictive in either CPM or BPM. CONCLUSIONS: Patients with lobular carcinoma-in situ in the index breast or high risk mammograms have a higher prevalence of malignancies. Although BRCA patients may benefit from prophylactic mastectomy, the genetic diagnosis does not increase the prevalence of detecting occult pathology. BPM patients can be counseled about relative risk, where occult pathology increases with age. PMID- 26577124 TI - Implications of a Negative Sentinel Node on Radiation Field Design for Chest Wall Recurrences. PMID- 26577125 TI - Benign Phyllodes Tumor of the Breast Diagnosed After Ultrasound-Guided Vacuum Assisted Biopsy: Surgical Excision or Wait-and-Watch? AB - BACKGROUND: The role of tumor-free resection in the treatment of benign phyllodes tumors (PTs) is still unknown. Ultrasound-guided vacuum-assisted biopsy (UGVAB) has been used for complete removal of benign breast lesions. This retrospective study aimed to compare the risk of relapse between patients with benign PT who undergo UGVAB and those who receive surgical excision (SE). METHODS: Benign PT patients with a pathology diagnosis who had received treatment between 2005 and 2013 at the authors' hospital were identified. The patients who received UGVAB did not receive any SE. In the SE group, wide local excision or mastectomy was performed when appropriate. The Kaplan-Meier curve and Cox proportional hazards regression were used to analyze and compare the relapse-free survival (RFS) between the patients in the two groups. RESULTS: The study enrolled 225 female patients with benign PT. The patients in the UGVAB group (n = 108) had significantly smaller tumors, more fibroadenoma, a higher body mass index (BMI), and a lower Breast Imaging-Reporting and Data System classification than the patients in the SE group (n = 117). The 5-year cumulative RFS was 81.6 and 88.7 % (p = 0.11) respectively for the patients receiving UGVAB and SE during a median follow-up period of 35.5 months. After adjustment for age, tumor size, BMI, or presence of fibroadenoma, treatment (UGVAB vs. SE) was not associated with increased risk for relapse events (hazard ratio 0.34; 95 % confidence interval 0.08-1.43; p = 0.14). No distant metastasis or death events occurred. CONCLUSIONS: The patients with benign PT who received UGVAB alone did not have a significantly more compromised RFS than those who underwent SE. A prospective, randomized study is needed to confirm this observation. PMID- 26577126 TI - Olecranon bursitis. AB - BACKGROUND: Bursitis is a common medical condition, and of all the bursae in the body, the olecranon bursa is one of the most frequently affected. Bursitis at this location can be acute or chronic in timing and septic or aseptic. Distinguishing between septic and aseptic bursitis can be difficult, and the current literature is not clear on the optimum length or route of antibiotic treatment for septic cases. The current literature was reviewed to clarify these points. METHODS: The reported data for olecranon bursitis were compiled from the current literature. RESULTS: The most common physical examination findings were tenderness (88% septic, 36% aseptic), erythema/cellulitis (83% septic, 27% aseptic), warmth (84% septic, 56% aseptic), report of trauma or evidence of a skin lesion (50% septic, 25% aseptic), and fever (38% septic, 0% aseptic). General laboratory data ranges were also summarized. CONCLUSIONS: Distinguishing between septic and aseptic olecranon bursitis can be difficult because the physical and laboratory data overlap. Evidence for the optimum length and route of antibiotic treatment for septic cases also differs. In this review we have presented the current data of offending bacteria, frequency of key physical examination findings, ranges of reported laboratory data, and treatment practices so that clinicians might have a better guide for treatment. PMID- 26577127 TI - Glenoid cement mantle characterization using micro-computed tomography of three cement application techniques. AB - BACKGROUND: Numerous studies have documented the concern for progressive radiolucent lines, signifying debonding and subsequent aseptic loosening of the glenoid component. In this study, we compared 3 cementation methods to secure a central peg in 15 cadaveric glenoids. METHODS: Cement application techniques consisted of (1) compression of multiple applications of cement using manual pressure over gauze with an Adson clamp, (2) compression of multiple applications of cement using a pressurizer device, and (3) no compression of a single application of cement. Each glenoid was then imaged with high-resolution micro computed tomography and further processed by creating 3-dimensional computerized models of implant, bone, and cement geometry. Cement morphology characteristics were then analyzed in each of the models. RESULTS: There were no significant differences detected between the 2 types of compression techniques; however, there was a significant difference between compression methods and use of no compression at all. All morphologic characteristics of a larger cement mantle were significantly correlated with greater cortical contact. CONCLUSIONS: We demonstrate that compression techniques create a larger cement mantle. Increased size of the cement mantle is associated with increased contact with cortical bone at the glenoid vault. This method for characterizing the cement mantle by micro computed tomography scanning techniques and 3-dimensional analysis may also be useful in future finite element analysis studies. PMID- 26577128 TI - Empty can exercise provokes more pain and has undesirable biomechanics compared with the full can exercise. AB - BACKGROUND: The purpose of this investigation was to characterize the scapular position and scapular muscle activation during the empty can (EC) and full can (FC) exercises. The EC exercise has been shown to produce scapular kinematics associated with the mechanism leading to subacromial impingement syndrome (SAIS) but has not been investigated in patients with (SAIS). This investigation will help improve the treatment of patients with SAIS. METHODS: Participants with SAIS (n = 28) performed 5 consecutive repetitions of FC and EC exercises. Scapular and clavicular 3-dimensional positions and scapular muscle activity were measured during each exercise. Pain was measured with the numeric pain rating 11-point scale. RESULTS: Participants reported greater pain during the EC exercise vs the FC exercise (difference, 1; P = .003). During the EC exercise, participants were in greater scapular upward rotation (difference, 3 degrees ; P < .001), internal rotation (mean difference, 2 degrees ; P = .017), and clavicular elevation (difference, 3 degrees , P < .001) and in less scapular posterior tilt (difference, 2 degrees ; P < .001). There was greater activity of upper trapezius (difference, 4%, P = .002), middle trapezius (difference, 3%; P < .001), and serratus anterior (difference, 0.5%; P = .035) during ascent, and during the descent of greater upper trapezius (difference, 2%, P = .005), and middle trapezius (difference, 1%; P = .003), but less activity of the lower trapezius (difference, 1%; P = .039). CONCLUSIONS: The EC exercise was associated with more pain and scapular positions that have been reported to decrease the subacromial space. Scapular muscle activity was generally higher with the EC, which may be an attempt to control the impingement-related scapular motion. The FC exercise of elevation is preferred over the EC exercise. PMID- 26577130 TI - Enhanced effect of BCG vaccine against pulmonary Mycobacterium tuberculosis infection in mice with lung Th17 response to mycobacterial heparin-binding hemagglutinin adhesin antigen. AB - Although the BCG vaccine can prevent tuberculosis (TB) in infants, its ability to prevent adult pulmonary TB is reportedly limited. Therefore, development of a novel effective vaccine against pulmonary TB has become an international research priority. We have previously reported that intranasal vaccination of mice with a mycobacterial heparin-binding hemagglutinin adhesin (HBHA) plus mucosal adjuvant cholera toxin (CT) enhances production of IFN-gamma and anti-HBHA antibody and suppresses extrapulmonary bacterial dissemination after intranasal infection with BCG. In the present study, the effects of intranasal HBHA + CT vaccine on murine pulmonary Mycobacterium tuberculosis (Mtb) infection were examined. Intranasal HBHA + CT vaccination alone failed to reduce the bacterial burden in the infected lung. However, a combination vaccine consisting of s.c. BCG priming and an intranasal HBHA + CT booster significantly enhanced protective immunity against pulmonary Mtb infection on day 14 compared with BCG vaccine alone. Further, it was found that intranasal HBHA + CT vaccine enhanced not only IFN-gamma but also IL-17A production by HBHA-specific T cells in the lung after pulmonary Mtb infection. Therefore, this combination vaccine may be a good candidate for a new vaccine strategy against pulmonary TB. PMID- 26577129 TI - Physical Activity through Sustainable Transport Approaches (PASTA): protocol for a multi-centre, longitudinal study. AB - BACKGROUND: Physical inactivity is one of the leading risk factors for non communicable diseases, yet many are not sufficiently active. The Physical Activity through Sustainable Transport Approaches (PASTA) study aims to better understand active mobility (walking and cycling for transport solely or in combination with public transport) as an innovative approach to integrate physical activity into individuals' everyday lives. The PASTA study will collect data of multiple cities in a longitudinal cohort design to study correlates of active mobility, its effect on overall physical activity, crash risk and exposure to traffic-related air pollution. METHODS/DESIGN: A set of online questionnaires incorporating gold standard approaches from the physical activity and transport fields have been developed, piloted and are now being deployed in a longitudinal study in seven European cities (Antwerp, Barcelona, London, Oerebro, Rome, Vienna, Zurich). In total, 14000 adults are being recruited (2000 in each city). A first questionnaire collects baseline information; follow-up questionnaires sent every 13 days collect prospective data on travel behaviour, levels of physical activity and traffic safety incidents. Self-reported data will be validated with objective data in subsamples using conventional and novel methods. Accelerometers, GPS and tracking apps record routes and activity. Air pollution and physical activity are measured to study their combined effects on health biomarkers. Exposure-adjusted crash risks will be calculated for active modes, and crash location audits are performed to study the role of the built environment. Ethics committees in all seven cities have given independent approval for the study. DISCUSSION: The PASTA study collects a wealth of subjective and objective data on active mobility and physical activity. This will allow the investigation of numerous correlates of active mobility and physical activity using a data set that advances previous efforts in its richness, geographical coverage and comprehensiveness. Results will inform new health impact assessment models and support efforts to promote and facilitate active mobility in cities. PMID- 26577131 TI - Microdynamics mechanism of D2O absorption of the poly(2-hydroxyethyl methacrylate)-based contact lens hydrogel studied by two-dimensional correlation ATR-FTIR spectroscopy. AB - A good understanding of the microdynamics of the water absorption of poly(2 hydroxyethyl methacrylate) (PHEMA)-based contact lens is significant for scientific investigation and commercial applications. In this study, time dependent ATR-FTIR spectroscopy combined with the perturbation correlation moving window two-dimensional (PCMW2D) technique and 2D correlation analysis was used to study the microdynamics mechanism. PCMW2D revealed that D2O took 3.4 min to penetrate into the contact lens. PCMW2D also found the PHEMA-based contact lens underwent two processes (I and II) during D2O absorption, and the time regions of processes I and II are 3.4-12.4 min and 12.4-57.0 min. According to 2D correlation analysis, it was proved that process I has 5 steps, and process II has 3 steps. For process I, the first step is D2O hydrogen-bonding with "free" C[double bond, length as m-dash]O in the side chains. The second step is the hydrogen bond generation of the O-HO-D structure between D2O and "free" O-H groups in the side chain ends. The third step is the hydrogen bond generation of D2O and the "free" C[double bond, length as m-dash]O groups close to the crosslinking points in the contact lens. The fourth and the fifth steps are the hydration of -CH3 and -CH2- groups by D2O, respectively. For process II, the first step is the same as that of process I. The second step is the hydrogen bonds breaking of bonded O-H groups and the deuterium exchange between D2O and O H groups in the side chain ends. The third step is also related to the deuterium exchange, which is the hydrogen bonds regeneration between the dissociated C[double bond, length as m-dash]O groups and the new O-D. PMID- 26577132 TI - Automatic versus manual changeovers of norepinephrine infusion pumps in critically ill adults: a prospective controlled study. AB - BACKGROUND: Norepinephrine is a key drug for treating shock but has a short half life that requires continuous intravenous administration to maintain the constant plasma concentration needed to obtain a stable blood pressure. The small volume of the syringes used in power infusion pumps requires frequent changeovers, which can lead to norepinephrine flow interruptions responsible for hemodynamic instability. Changeovers from the nearly empty to the full syringe can be performed manually using the quick change technique (QC) or automatically using smart infusion pumps (SIP) that link two syringes. The purpose of our study was to evaluate the hypothesis that, compared to QC, SIP for norepinephrine changeovers was associated with less hemodynamic instability. METHODS: After information of the patient or next of kin, patients receiving norepinephrine for shock were allocated to QC or SIP changeovers. QC changeovers were performed by a nurse, who started a new loaded pump when the previous syringe was nearly empty. SIP changeovers were managed automatically by SIP workstations. The primary outcome was the proportion of changeovers followed by a >=20 % drop in mean arterial pressure (MAP). RESULTS: 411 changeovers were performed, 193 in the 18 patients allocated to QC and 218 in the 32 patients allocated to SIP. Baseline patient characteristics were similar in both groups. The proportion of changeovers followed by an MAP drop >=20 % was 12.4 % (24/193) with QC and 5.5 % (12/218) with SIP (P = 0.01). By multivariate analysis, two factors were independently associated with a significantly decreased risk of >=20 % MAP drops during changeovers, namely, SIP (odds ratio, 0.47; 95 % confidence interval, 0.22 0.98) and norepinephrine dosage >0.5 MUg/kg/min (odds ratio, 0.39; 95 % confidence interval, 0.19-0.81). CONCLUSIONS: The risk of MAP drops >=20 % during changeovers can be significantly diminished using SIPs instead of the QC method. TRIAL REGISTRATION: Clinicaltrial.gov NCT 01127152. PMID- 26577134 TI - In Vitro Evaluation of the Allergic Potential of Antibacterial Peptides: Camel and Citropin. AB - Peptide-based drugs are promising group of compounds which are characterized by specificity to their in vivo targets and high potency of action (antineoplastic, immunoregulatory, antibacterial). The peptides, however, involve a relatively high risk of allergic reactions that are not predictable on the basis of their sequence and chemical properties. In this study, peripheral blood was obtained from 53 patients including 38 hypersensitive patients and 15 control patients. Basophil activation stimulated by two antibacterial peptides (camel, citropin 1.1), and acetylsalicylic acid was assessed by means of BAT (basophil activation test). Basophil activation stimulated by camel occurred in 7 of 38 patients with hypersensitivity (18.42%) as well as in 2 of 15 control patients (13.33%). Basophils were activated by citropin 1.1 in 7 of 38 hypersensitive patients (18.42%) and in none of the control patients. Using the Structural Database of Allergenic Proteins, we confirmed that the examined peptides share some structural similarities with common environmental allergens. Therefore, the cross reactivity between potentially present anti-allergen IgE with examined peptides cannot be excluded. Our study proved that BAT, together with other biological tests and specific databases of allergenic compounds, may serve as an initial selection of new active peptides and proteins. PMID- 26577133 TI - Preoperative localization of an insulinoma: selective arterial calcium stimulation test performance. AB - PURPOSE: Preoperative localization of an insulinoma is recommended to improve the cure rate, but non-invasive procedures can fail to detect the tumour. The objective of the study was to assess the performance of a selective arterial calcium stimulation test in the preoperative localization of insulinomas that were not detected by conventional imaging procedures. METHODS: We conducted a monocenter retrospective case review of 13 patients who had endogenous hyperinsulinism and were treated between 1994 and 2013. Patients were selected on the basis of negative or doubtful non-invasive preoperative imaging. A selective arterial calcium stimulation test was performed by pancreatic and hepatic arteriography with selective intra-arterial calcium stimulation and hepatic venous sampling in order to obtain the plasma insulin measurement. We evaluated the efficacy of the test by comparing the results with an endoscopic ultrasound. RESULTS: Twelve of the 13 patients underwent surgery, and the presence of an insulinoma was proven in 11 patients by pathological analysis of the tumour. An endoscopic ultrasound was consistent with surgery in 71.4 % of cases, while selective arterial calcium stimulation was consistent with surgery in 90.9 % and allowed detection of an insulinoma in two additional patients with a negative endoscopic ultrasound. One false-negative and one false-positive arterial calcium test were observed. No adverse events were recorded except transient skin flush following calcium injection in one patient. CONCLUSION: The selective arterial calcium stimulation test is a sensitive diagnostic procedure for localizing insulinomas and may be considered when non-invasive radiological imaging does not allow the detection of an occult insulinoma. PMID- 26577136 TI - Reading in the dark: neural correlates and cross-modal plasticity for learning to read entire words without visual experience. AB - Cognitive neuroscience has long attempted to determine the ways in which cortical selectivity develops, and the impact of nature vs. nurture on it. Congenital blindness (CB) offers a unique opportunity to test this question as the brains of blind individuals develop without visual experience. Here we approach this question through the reading network. Several areas in the visual cortex have been implicated as part of the reading network, and one of the main ones among them is the VWFA, which is selective to the form of letters and words. But what happens in the CB brain? On the one hand, it has been shown that cross-modal plasticity leads to the recruitment of occipital areas, including the VWFA, for linguistic tasks. On the other hand, we have recently demonstrated VWFA activity for letters in contrast to other visual categories when the information is provided via other senses such as touch or audition. Which of these tasks is more dominant? By which mechanism does the CB brain process reading? Using fMRI and visual-to-auditory sensory substitution which transfers the topographical features of the letters we compare reading with semantic and scrambled conditions in a group of CB. We found activation in early auditory and visual cortices during the early processing phase (letter), while the later phase (word) showed VWFA and bilateral dorsal-intraparietal activations for words. This further supports the notion that many visual regions in general, even early visual areas, also maintain a predilection for task processing even when the modality is variable and in spite of putative lifelong linguistic cross-modal plasticity. Furthermore, we find that the VWFA is recruited preferentially for letter and word form, while it was not recruited, and even exhibited deactivation, for an immediately subsequent semantic task suggesting that despite only short sensory substitution experience orthographic task processing can dominate semantic processing in the VWFA. On a wider scope, this implies that at least in some cases cross-modal plasticity which enables the recruitment of areas for new tasks may be dominated by sensory independent task specific activation. PMID- 26577135 TI - Cardiac cytoarchitecture - why the "hardware" is important for heart function! AB - Cells that constitute fully differentiated tissues are characterised by an architecture that makes them perfectly suited for the job they have to do. This is especially obvious for cardiomyocytes, which have an extremely regular shape and display a paracrystalline arrangement of their cytoplasmic components. This article will focus on the two major cytoskeletal multiprotein complexes that are found in cardiomyocytes, the myofibrils, which are responsible for contraction and the intercalated disc, which mediates mechanical and electrochemical contact between individual cardiomyocytes. Recent studies have revealed that these two sites are also crucial in sensing excessive mechanical strain. Signalling processes will be triggered that## lead to changes in gene expression and eventually lead to an altered cardiac cytoarchitecture in the diseased heart, which results in a compromised function. Thus, understanding these changes and the signals that lead to them is crucial to design treatment strategies that can attenuate these processes. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel. PMID- 26577137 TI - Actinotignum schaalii (formerly Actinobaculum schaalii): a newly recognized pathogen-review of the literature. AB - The genus Actinotignum contains three species, Actinotignum schaalii (formerly Actinobaculum schaalii), Actinotignum urinale and Actinotignum sanguinis. A. schaalii is the species most frequently involved in human infections, with 172 cases, mostly urinary tract infections (UTIs), reported so far. Invasive infections have also been described. This facultative anaerobic Gram-positive rod is part of the urinary microbiota of healthy patients. It is responsible for UTIs, particularly in elderly men and young children. A. schaalii is an underestimated cause of UTIs because of its fastidious growth on usual media and difficulties associated with its identification using phenotypic methods. Indeed, this slow-growth bacterium requires blood-enriched media and an incubation time of 48 hours under anaerobic or 5% CO2 atmosphere. Furthermore, only matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF) or molecular-based methods allow the accurate identification of this bacteria. MALDI-TOF using Microflex LT with the Biotyper database (Bruker Daltonics, Bremen, Germany) is the most reliable technology for the routine identification of A. schaalii. The identification of this uropathogen is all the more important because it is resistant to trimethoprim/sulfamethoxazole and second-generation quinolones that are widely used in the treatment of UTIs. Antimicrobial therapy using beta-lactams prolonged for up to 2 weeks is the most efficient treatment and should be recommended. Microbiologists should assess the presence of A. schaalii in urine using appropriate culture and identification methods in the case of a direct examination that is positive for small coccoid rods, a negative nitrite urinary stick associated with leukocyturia, treatment failure with trimethoprim/sulfamethoxazole or fluoroquinolones, or undocumented, repeated UTIs. PMID- 26577138 TI - Discovering new pathogenic prokaryotes. PMID- 26577139 TI - Comparison of different methods for identification of species of the genus Raoultella: report of 11 cases of Raoultella causing bacteraemia and literature review. AB - The genus Raoultella was excised from Klebsiella in 2001, but difficulties in its identification may have led to an underestimation of its incidence and uncertainty on its pathogenic role. Recently, clinical reports involving Raoultella have increased, probably through the introduction of mass-spectrometry in clinical microbiology laboratories and the development of accurate molecular techniques. We performed a retrospective analysis using our blood culture collection (2011-14) to identify Raoultella isolates that could have been erroneously reported as Klebsiella. PCR and gene sequencing of highly specific chromosomal class A beta-lactamase genes was established as the reference method, and compared with 16S rRNA and rpobeta sequencing, as well as matrix-assisted laser desorption/ionization time-of-flight mass spectroscopy (MALDI-TOF MS), MicroScan Walkaway system and API20E biochemical identification. MALDI-TOF and rpobeta correctly identified all Raoultella isolates, whereas 16S rRNA provided inconclusive results, and MicroScan and API20E failed to detect this genus. The analysis of the clinical characteristics of all Raoultella bacteraemia cases reported in the literature supports the role of Raoultella as an opportunistic pathogen that causes biliary tract infections in elderly patients who suffer from some kind of malignancy or have undergone an invasive procedure. Two salient conclusions are that Raoultella shows tropism for the biliary tract and so its identification could help clinicians to suspect underlying biliary tract disease when bacteraemia occurs. Concomitantly, as most phenotypic identification systems are not optimized for the identification of Raoultella, the use of MALDI-TOF or additional phenotypic tests is recommended for the reliable identification of this genus. PMID- 26577140 TI - Hepatitis B virus basal core promoter/precore mutants and association with liver cirrhosis in children with chronic hepatitis B virus infection. AB - We investigated 168 children and analysed the virological characterization and association with disease progression in children with hepatitis B virus (HBV) basal core promoter/precore (BCP/PC) mutants. Among 168 patients with HBV infection (aged 0.5-18 years old, mean 10.1), 86 of them had HBV-related liver cirrhosis (LC) and 82 had HBV-related chronic hepatitis B (CHB). A direct sequencing method was employed to determine the HBV genotypes and the mutations in BCP/PC regions. In all, 133 of them were infected with genotype C viruses (79.17%); only 35 patients (20.83%) were infected with genotype B viruses. Both LC patients and CHB patients had significantly higher ratios of genotype C when compared with the ratios of genotype B (83.7%-16.3% versus 74.4%-25.6%). For patients with CHB, the prevalence of BCP/PC wild-type viruses was 52.4%; but this was only 4.7% in patients with LC. The C1653T, T1753C, A1762T/G1764A and G1896A mutations had a significantly higher prevalence in patients with LC. Among all the patients with genotype B viruses, those with LC had lower HBV DNA levels and higher G1899A mutation frequency than patients with CHB. Among all the patients with genotype C viruses, the patients with LC had higher prevalence of C1653T, A1762T/G1764A and G1896A mutation frequency, higher hepatitis B e antigen (HBeAg) -negative rates, lower viral load, lower elevated alanine aminotransferase and lower anti-HBe positive rates than CHB patients. The HBV BCP/PC variants were more common in HBeAg-negative LC patients than in the CHB group (BCP, 53.4% versus 15.6%; PC, 18.6% versus 3.7%, respectively, p < 0.001). Patients with HBV genotype C viruses, high viral load and C1653T, A1762T/G1764A, G1896A mutant viruses, were more susceptible to developing LC. PMID- 26577141 TI - A quasi-universal medium to break the aerobic/anaerobic bacterial culture dichotomy in clinical microbiology. AB - In the mid-19th century, the dichotomy between aerobic and anaerobic bacteria was introduced. Nevertheless, the aerobic growth of strictly anaerobic bacterial species such as Ruminococcus gnavus and Fusobacterium necrophorum, in a culture medium containing antioxidants, was recently demonstrated. We tested aerobically the culture of 623 bacterial strains from 276 bacterial species including 82 strictly anaerobic, 154 facultative anaerobic, 31 aerobic and nine microaerophilic bacterial species as well as ten fungi. The basic culture medium was based on Schaedler agar supplemented with 1 g/L ascorbic acid and 0.1 g/L glutathione (R-medium). We successively optimized this media, adding 0.4 g/L uric acid, using separate autoclaving of the component, or adding haemin 0.1 g/L or alpha-ketoglutarate 2 g/L. In the basic medium, 237 bacterial species and ten fungal species grew but with no growth of 36 bacterial species, including 22 strict anaerobes. Adding uric acid allowed the growth of 14 further species including eight strict anaerobes, while separate autoclaving allowed the growth of all tested bacterial strains. To extend its potential use for fastidious bacteria, we added haemin for Haemophilus influenzae, Haemophilus parainfluenzae and Eikenella corrodens and alpha-ketoglutarate for Legionella pneumophila. This medium allowed the growth of all tested strains with the exception of Mycobacterium tuberculosis and Mycobacterium bovis. Testing primoculture and more fastidious species will constitute the main work to be done, but R-medium coupled with a rapid identification method (matrix-assisted laser desorption/ionization time-of-flight mass spectrometry) will facilitate the anaerobic culture in clinical microbiology laboratories. PMID- 26577142 TI - Does bacteriology laboratory automation reduce time to results and increase quality management? AB - Due to reductions in financial and human resources, many microbiological laboratories have merged to build very large clinical microbiology laboratories, which allow the use of fully automated laboratory instruments. For clinical chemistry and haematology, automation has reduced the time to results and improved the management of laboratory quality. The aim of this review was to examine whether fully automated laboratory instruments for microbiology can reduce time to results and impact quality management. This study focused on solutions that are currently available, including the BD KiestraTM Work Cell Automation and Total Lab Automation and the Copan WASPLab((r)). PMID- 26577143 TI - Gram-negative bacteraemia; a multi-centre prospective evaluation of empiric antibiotic therapy and outcome in English acute hospitals. AB - Increasing antibiotic resistance makes choosing antibiotics for suspected Gram negative infection challenging. This study set out to identify key determinants of mortality among patients with Gram-negative bacteraemia, focusing particularly on the importance of appropriate empiric antibiotic treatment. We conducted a prospective observational study of 679 unselected adults with Gram-negative bacteraemia at ten acute english hospitals between October 2013 and March 2014. Appropriate empiric antibiotic treatment was defined as intravenous treatment on the day of blood culture collection with an antibiotic to which the cultured organism was sensitive in vitro. Mortality analyses were adjusted for patient demographics, co-morbidities and illness severity. The majority of bacteraemias were community-onset (70%); most were caused by Escherichia coli (65%), Klebsiella spp. (15%) or Pseudomonas spp. (7%). Main foci of infection were urinary tract (51%), abdomen/biliary tract (20%) and lower respiratory tract (14%). The main antibiotics used were co-amoxiclav (32%) and piperacillin tazobactam (30%) with 34% receiving combination therapy (predominantly aminoglycosides). Empiric treatment was inappropriate in 34%. All-cause mortality was 8% at 7 days and 15% at 30 days. Independent predictors of mortality (p <0.05) included older age, greater burden of co-morbid disease, severity of illness at presentation and inflammatory response. Inappropriate empiric antibiotic therapy was not associated with mortality at either time-point (adjusted OR 0.82; 95% CI 0.35-1.94 and adjusted OR 0.92; 95% CI 0.50-1.66, respectively). Although our study does not exclude an impact of empiric antibiotic choice on survival in Gram-negative bacteraemia, outcome is determined primarily by patient and disease factors. PMID- 26577144 TI - Geographically predominant genotypes of Aspergillus terreus species complex in Austria: s microsatellite typing study. AB - Aspergillus terreus species complex is recognized as a frequent agent of invasive aspergillosis in Tyrol. The reason for this specific epidemiological situation is unclear. Aspergillus terreus strains isolated from environmental and clinical sources were genotyped using a novel panel of short tandem repeats and were evaluated for virulence. Three major endemic genotypes collected from the Inn region and its side valleys were found to cause the majority of invasive A. terreus infections. All of these genotypes were of the same mating type, which suggests that a mating barrier is present between these geographically well adapted strains which is found to persist for at least 11 years. The three major genotypes were prevalent in both human infections and the environment. No major differences in virulence were observed using Galleria mellonella as model. Our data suggest a specific environmental exposure being responsible for the high incidence of A. terreus infections in Innsbruck, the Inn valley and side valleys (Tyrol, Austria). PMID- 26577145 TI - The role of multimedia in surgical skills training and assessment. AB - INTRODUCTION: Multimedia is an educational resource that can be used to supplement surgical skills training. The aim of this review was to determine the role of multimedia in surgical training and assessment by performing a systematic review of the literature. METHODS: A systematic review for published articles was conducted on the following databases: PubMed/MEDLINE (1992 to November 2014), SCOPUS (1992 to November 2014) and EMBASE (1992 to November 2014). For each study the educational content, study design, surgical skill assessed and outcomes were recorded. A standard data extraction form was created to ensure systematic retrieval of relevant information. RESULTS: 21 studies were included; 14 randomized controlled trials (RCTs) and 7 non-randomized controlled trials (Non RCTs). Technical skills were assessed in 7 RCTs and 3 non-RCTs; cognitive skills were assessed in 9 RCTs and 4 non-RCTs. In controlled studies, multimedia was associated with significant improvement in technical skills (4 studies; 4 RCTs) and cognitive skills (7 studies; 6 RCTs). In two studies multimedia was inferior in comparison to conventional teaching. Evaluation of multimedia (9 studies) demonstrated strongly favourable results. CONCLUSIONS: This review suggests that multimedia effectively facilitates both technical and cognitive skills acquisition and is well accepted as an educational resource. PMID- 26577146 TI - Utility of the Six-Spot Step Test as a Measure of Walking Performance in Ambulatory Individuals With Multiple Sclerosis. AB - OBJECTIVE: To examine the concurrent validity of the Six-Spot Step Test (SSST) with clinical measures of walking and spatiotemporal measures of gait in multiple sclerosis (MS), and to understand the utility of the SSST in individuals with both low and high levels of disability. DESIGN: Cross-sectional study. SETTING: Laboratory. PARTICIPANTS: Individuals with relapsing-remitting MS (N=29). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: In a single visit, demographic information (age, sex, Expanded Disability Status Scale [EDSS], symptom duration) and functional measures (SSST, timed Up and Go [TUG] test, timed 25-foot walk [T25FW] test, spatiotemporal measures of walking) were collected. RESULTS: The SSST demonstrates concurrent validity with the TUG test, T25FW test, and 2-minute walk test (2MWT) (P<=.0002). Both spatial and temporal measures of gait are significantly related to SSST performance (P<.004). In individuals with lower disability (EDSS score 1-3.5), the SSST remains strongly related to the TUG test and T25FW test performances, whereas it fails to relate to any other measures. However, in the higher disability group (EDSS score 4-6), the SSST is significantly related to the TUG test, T25FW test, 2MWT, walk velocity, and both temporal and spatial measures of gait. CONCLUSIONS: The SSST is an alternative test for lower-extremity function in the clinical setting that may useful in both higher and lower EDSS groups. The SSST requires minimal training to administer and may be a time-efficient measure of real-life functional performance that would be useful in large clinical trials. PMID- 26577147 TI - A comparison between two clinically applied plan library strategies in adaptive radiotherapy of bladder cancer. AB - BACKGROUND AND PURPOSE: The predominant approach to clinically applied adaptive radiotherapy (ART) for bladder cancer is daily selection of treatment plans from a plan library. In this study we have compared two clinical strategies for creating multiple planning target volumes (PTV) for ART of bladder cancer. MATERIAL AND METHODS: Online ART delivering 60 Gy in 30 fractions to the whole bladder was simulated for ten patients using two methods of creating plan libraries. In the RepeatCT method four planning CT scans were acquired at 15-min intervals, generating four CTVs with different bladder volumes. In the RepeatCBCT method one planning CT and four daily cone-beam CT images were combined using Boolean operators to form three composite CTVs. Plan selection rates and PTV volumes were evaluated, with the selected volumes averaged across 30 treatment fractions (PTV(mean)). RESULTS: The PTV(mean) volume was on average 80 cm(3) smaller (p<0.001) in the RepeatCT method than in the RepeatCBCT method. Compared to the non-adaptive treatment, the PTV(mean) was reduced by 46% (range 33-53%, RepeatCT) and 36% (range 27-44%, RepeatCBCT). CONCLUSIONS: Both methods reduced the PTV(mean) volume compared to the non-adaptive approach, but the reduction was larger using the strategy with repeat planning CT imaging. However, the strategy with combined CT and repeat CBCT imaging produced a more adequate range of PTV volumes. PMID- 26577148 TI - [Ethics in intensive care and euthanasia : With respect to inactivating defibrillators at the end of life in terminally ill patients]. AB - BACKGROUND: In critically ill patients, intensive care medical procedures allow diseases to be cured or controlled that were considered incurable many years ago. For patients with terminal heart failure or heart disease with other severe comorbidities (cancer, stroke), the questions whether the deactivation of defibrillators is appropriate or must be regarded as active euthanasia may arise. MATERIALS AND METHODS: Notable cases from the author's hospital are analyzed. The literature on the topic euthanasia and basic literature regarding defibrillator therapy are discussed. DISCUSSION AND CONCLUSION: It is undisputed that patients as part of their self-determination have the right to renounce treatment. Active euthanasia and the thereby deliberate induction of death is prohibited by law in Germany and will be prosecuted. Passive euthanasia is the omission or reduction of possibly life-prolonging treatment measures. Passive euthanasia requires the patient's consent and is legally and ethically permissible. Indirect euthanasia takes into account acceleration of death as a side effect of a medication. Unpunishable assisted suicide ("assisted suicide") is the mere assistance of self controlled and self-determined death. Assisted suicide is fundamentally not a criminal offense in Germany. Deactivation of a defibrillator is a treatment discontinuation, which is only permitted in accordance with the wishes of the patient. It is not a question of passive or active euthanasia. Involvement of a local ethics committee and/or legal consultation is certainly useful and sometimes also allows previously unrecognized questions to be answered. PMID- 26577149 TI - The Bologna criteria for poor ovarian response: a contemporary critical appraisal. AB - Postponement of child bearing and maternal age at first pregnancy are on the rise, contributing considerably to an increase in age-related infertility and the demand for assisted reproductive technologies (ART) treatment. This brings to the infertility clinics many women with low ovarian reserve and poor ovarian response (POR) to conventional stimulation. The Bologna criteria were released to standardize the definition of POR and pave the way for the formulation of evidence-based, efficient modalities of treatment for women undergoing IVF-ET. More than four years have passed since the introduction of these criteria and the debate is still ongoing whether a revision is due. Women with POR comprise several sub-groups with diverse baseline distinctiveness, a major issue that has fueled the discussion. Although antral follicle count (AFC) and anti-Mullerian hormone (AMH), are considered good predictors of ovarian reserve, their threshold values are still not universally standardized. Different definitions for sonographic AFC and diverse assays for AMH are held responsible for this delay in standardization. Adding established risk factors to the criteria will lead to more reliable and reproducible definition of a POR, especially in young women. The original criteria did not address the issue of oocyte quality, and the addition of risk factors may yield specific associations with quality vs. quantity. Patient's age is the best available criterion, although limited, to predict live-birth and presumably oocyte quality. High scale studies to validate these criteria are still missing while recent evidence raises concern regarding over diagnosis. PMID- 26577150 TI - The expression of B23 and EGR1 proteins is functionally linked in tumor cells under stress conditions. AB - BACKGROUND: The nucleolus is a multi-domain enriched with proteins involved in ribosome biogenesis, cell cycle and apoptosis control, viral replication and differentiation of stem cells. Several authors have suggested a role for the nucleolus also in malignant transformation. We have recently demonstrated that under specific circumstances the transcriptional factor EGR1 is shuttled to the nucleolus where it functions as a negative regulator of RNA polymerase I. Since this activity is hampered in ARF -/- cells, and ARF transcription is regulated by EGR1 while the turnover of ARF protein is under the control of B23, we speculated that some sort of cooperation between EGR1 and B23 might also exist. RESULTS: In this work we identified a canonical EGR1 binding site on the B23 promoter through experiments of transactivation and in vitro DNA binding assay. We then found that the levels of B23 expression are directly correlated with those of EGR1, and that this correlation applies to several cellular types and to different stress conditions. Furthermore, we showed that EGR1 stability and accumulation within the nucleolus is in turn regulated by B23 through proteasome involvement, similarly to ARF turnover. CONCLUSION: Our results highlight EGR1 as a regulator of B23 expression actively playing within the newly discovered nucleolar B23-ARF EGR1 network. PMID- 26577151 TI - Influence of selective photon shield combined with sinogram-affirmed iterative reconstruction on image quality and radiation dose during dual-energy CT angiography-mediated diagnosis of intracranial aneurysms. AB - OBJECTIVE: To investigate the influence of a selective photon shield (SPS) combined with sinogram-affirmed iterative reconstruction (SAFIRE) on image quality and radiation dose during application of dual-energy CT angiography (CTA) for diagnosis of intracranial aneurysms. METHODS: We retrospectively reviewed clinical data for 80 patients with diagnoses of spontaneous subarachnoid hemorrhage. All patients underwent three-dimensional digital subtraction angiography scans within 1 week after CTA. Data for patients in the conventional method group were subjected to filtered-back-projection reconstruction, while data for patients in the experimental method group were subjected to SAFIRE reconstruction. Image quality and scanning radiation dose were evaluated. RESULTS: Background noise was significantly lower in the experimental method group than in the conventional method group, while the mean CT value did not differ between the groups. Signal-to-noise ratios were significantly higher in the experimental method group than in the conventional method group. However, the average CT value, contrast-to-noise ratio, and image quality scores did not differ between groups. All scores indicated acceptability for clinical diagnosis. The dose index of volume and effective dose were significantly lower in the experimental method group than in the conventional method group. Surgical verification showed that the detection rates in the experimental and conventional method groups were 100% (29/29) and 96% (25/26), respectively. CONCLUSIONS: SPS combined with SAFIRE applied for analysis of dual-energy CTA data improved the quality of CT images, reduced the radiation dosage, and increased diagnostic accuracy. ADVANCES IN KNOWLEDGE: SPS combined with SAFIRE may improve the accuracy of diagnosis of intracranial aneurysms. PMID- 26577152 TI - Acute psychosis as an initial manifestation of hypothyroidism: a case report. AB - INTRODUCTION: Hypothyroidism is one of the most important causes of treatable dementia, and psychosis occasionally associated with it is known as myxedema madness. We report a case of a 90-year-old patient who developed myxedema madness acutely without overt clinical symptoms and signs suggestive of hypothyroidism. CASE PRESENTATION: A 90-year-old Japanese man, a general practitioner, was admitted to our emergency room because of acute-onset lethargy, delusions, and hallucinations. He had been actively working until 3 days before the admission. Upon admission, his general physical examination was unremarkable. However, a blood investigation showed the presence of hypothyroidism, and computed tomography revealed pleural effusion and ascites. Electroencephalography revealed diffuse slow waves with a decrease of alpha-wave activity. A single-photon emission computed tomography scan revealed a decrease of cerebral blood flow in both frontal lobes. The patient was soon treated with thyroid hormone replacement therapy. Following normalization of his thyroid function, both pleural effusion and ascites diminished and his electroencephalographic activity improved simultaneously; however, he did not recover from his psychosis. CONCLUSIONS: Myxedema madness should be kept in mind in the differential diagnosis of acute psychosis in elderly patients, particularly the oldest patients as in our case, because manifestations of hypothyroidism often may be indistinguishable from the aging process. PMID- 26577153 TI - Early transcriptional profiles in huntingtin-inducible striatal cells by microarray analyses. PMID- 26577154 TI - The effects of collective anger and fear on policy support in response to terrorist attacks. AB - Both correlational and experimental studies examined how perceived emotional responses of the majority of Americans to 9/11 affect individuals' support for government counter-terrorism policies (i.e., military intervention, anti immigration, restricting civil liberties). Study 1 found associations between perceived collective emotions (i.e., anger, fear) and individuals' own corresponding emotions and those between perceived collective anger and counter terrorism policy support. Individuals' own anger mediated the associations of collective anger with policy support. Using experimental manipulations, Study 2 showed that collective anger had a significant effect on individuals' own anger and one significant and two marginal effects on counter-terrorism policy support. Individuals' own anger mediated one of the marginal effects of collective anger on policy support. Implications of these findings are discussed in the context of terrorist threat. PMID- 26577155 TI - Computational Models & Methods in Systems Biology & Medicine. PMID- 26577156 TI - Ant colony optimisation of decision tree and contingency table models for the discovery of gene-gene interactions. AB - In this study, ant colony optimisation (ACO) algorithm is used to derive near optimal interactions between a number of single nucleotide polymorphisms (SNPs). This approach is used to discover small numbers of SNPs that are combined into a decision tree or contingency table model. The ACO algorithm is shown to be very robust as it is proven to be able to find results that are discriminatory from a statistical perspective with logical interactions, decision tree and contingency table models for various numbers of SNPs considered in the interaction. A large number of the SNPs discovered here have been already identified in large genome wide association studies to be related to type II diabetes in the literature, lending additional confidence to the results. PMID- 26577158 TI - Deploying swarm intelligence in medical imaging identifying metastasis, micro calcifications and brain image segmentation. AB - This study proposes an umbrella deployment of swarm intelligence algorithm, such as stochastic diffusion search for medical imaging applications. After summarising the results of some previous works which shows how the algorithm assists in the identification of metastasis in bone scans and microcalcifications on mammographs, for the first time, the use of the algorithm in assessing the CT images of the aorta is demonstrated along with its performance in detecting the nasogastric tube in chest X-ray. The swarm intelligence algorithm presented in this study is adapted to address these particular tasks and its functionality is investigated by running the swarms on sample CT images and X-rays whose status have been determined by senior radiologists. In addition, a hybrid swarm intelligence-learning vector quantisation (LVQ) approach is proposed in the context of magnetic resonance (MR) brain image segmentation. The particle swarm optimisation is used to train the LVQ which eliminates the iteration-dependent nature of LVQ. The proposed methodology is used to detect the tumour regions in the abnormal MR brain images. PMID- 26577157 TI - Computational approaches for understanding the diagnosis and treatment of Parkinson's disease. AB - This study describes how the application of evolutionary algorithms (EAs) can be used to study motor function in humans with Parkinson's disease (PD) and in animal models of PD. Human data is obtained using commercially available sensors via a range of non-invasive procedures that follow conventional clinical practice. EAs can then be used to classify human data for a range of uses, including diagnosis and disease monitoring. New results are presented that demonstrate how EAs can also be used to classify fruit flies with and without genetic mutations that cause Parkinson's by using measurements of the proboscis extension reflex. The case is made for a computational approach that can be applied across human and animal studies of PD and lays the way for evaluation of existing and new drug therapies in a truly objective way. PMID- 26577159 TI - Integrated dopaminergic neuronal model with reduced intracellular processes and inhibitory autoreceptors. AB - Dopamine (DA) is an important neurotransmitter for multiple brain functions, and dysfunctions of the dopaminergic system are implicated in neurological and neuropsychiatric disorders. Although the dopaminergic system has been studied at multiple levels, an integrated and efficient computational model that bridges from molecular to neuronal circuit level is still lacking. In this study, the authors aim to develop a realistic yet efficient computational model of a dopaminergic pre-synaptic terminal. They first systematically perturb the variables/substrates of an established computational model of DA synthesis, release and uptake, and based on their relative dynamical timescales and steady state changes, approximate and reduce the model into two versions: one for simulating hourly timescale, and another for millisecond timescale. They show that the original and reduced models exhibit rather similar steady and perturbed states, whereas the reduced models are more computationally efficient and illuminate the underlying key mechanisms. They then incorporate the reduced fast model into a spiking neuronal model that can realistically simulate the spiking behaviour of dopaminergic neurons. In addition, they successfully include autoreceptor-mediated inhibitory current explicitly in the neuronal model. This integrated computational model provides the first step toward an efficient computational platform for realistic multiscale simulation of dopaminergic systems in in silico neuropharmacology. PMID- 26577160 TI - Theoretical cross-comparative analysis on dynamics of small intestine and colon crypts during cancer initiation. AB - Epigenetics is emerging as a fundamentally important area of biological and medical research that has implications for our understanding of human diseases including cancer, autoimmune and neuropsychiatric disorders. In the context of recent efforts on personalised medicine, a novel research direction is concerned with identification of intra-individual epigenetic variation linked to disease predisposition and development, i.e. epigenome-wide association studies. A computational model has been developed to describe the dynamics and structure of human intestinal crypts and to perform a comparative analysis on aberrant DNA methylation level induced in these during cancer initiation. The crypt framework, AgentCrypt, is an agent-based model of crypt dynamics, which handles intra- and inter-dependencies. In addition, the AgentCrypt model is used to investigate the effect of a set of potential inhibitors with respect to methylation modification in intestinal tissue during initiation of disease. Methylation level decrease over a relatively short period of 90 days is marked for the colon compared to the small intestine, although similar alterations are induced in both tissues. In addition, inhibitor effect is notable for abnormal crypt groups, with largest average methylation differences observed ~0.75% lower in the colon and ~0.79% lower in the small intestine with inhibitor present. PMID- 26577161 TI - Investigating receptor enzyme activity using time-scale analysis. AB - At early drug discovery, purified protein-based assays are often used to characterise compound potency. In the context of dose response, it is often perceived that a time-independent inhibitor is reversible and a time-dependent inhibitor is irreversible. The legitimacy of this argument is investigated using a simple kinetics model, where it is revealed by model-based analytical analysis and numerical studies that dose response of an irreversible inhibitor may appear time-independent under certain parametric conditions. Hence, the observation of time-independence cannot be used as sole evidence for identification of inhibitor reversibility. It has also been discussed how the synthesis and degradation of a target receptor affect drug inhibition in an in vitro cell-based assay setting. These processes may also influence dose response of an irreversible inhibitor in such a way that it appears time-independent under certain conditions. Furthermore, model-based steady-state analysis reveals the complexity nature of the drug-receptor process. PMID- 26577162 TI - Modelling the role of catastrophe, crossover and katanin-mediated severing in the self-organisation of plant cortical microtubules. AB - Plant cortical microtubules can form ordered arrays through interactions among themselves. When an incident microtubule collides with a barrier microtubule it may entrain if below a certain angle. Else it undergoes collision induced catastrophe (CIC) or crosses over the barrier microtubule. It has been proposed that katanin is necessary to create order by severing these crossover sites. The authors present a three-state computational model using Arabidopsis thaliana data to show how spontaneous catastrophe, the probability of CIC versus crossover, and katanin-mediated severing at the crossover sites affect microtubule ordering. The results of the systematic simulations show that (1), the microtubule order is more sensitive to the catastrophe rate than the rescue rate; (2), at 21 degrees C, peak order is observed at 0.3 CIC and order decreases as CIC increases; and (3) at 0.2 CIC, katanin severing acting uniformly at all crossover sites is able to create order within a biologically reasonable time frame, but at lower CICs this becomes unrealistically fast. This would imply that at lower CIC levels preferential crossover site targeting and severing activity regulators would be required for katanin to bring about order. PMID- 26577163 TI - Structural and practical identifiability analysis of S-system. AB - In the field of systems biology, biological reaction networks are usually modelled by ordinary differential equations. A sub-class, the S-systems representation, is a widely used form of modelling. Existing S-systems identification techniques assume that the system itself is always structurally identifiable. However, due to practical limitations, biological reaction networks are often only partially measured. In addition, the captured data only covers a limited trajectory, therefore data can only be considered as a local snapshot of the system responses with respect to the complete set of state trajectories over the entire state space. Hence the estimated model can only reflect partial system dynamics and may not be unique. To improve the identification quality, the structural and practical identifiablility of S-system are studied. The S-system is shown to be identifiable under a set of assumptions. Then, an application on yeast fermentation pathway was conducted. Two case studies were chosen; where the first case is based on a larger state trajectories and the second case is based on a smaller one. By expanding the dataset which span a relatively larger state space, the uncertainty of the estimated system can be reduced. The results indicated that initial concentration is related to the practical identifiablity. PMID- 26577164 TI - In silico discovery of significant pathways in colorectal cancer metastasis using a two-stage optimisation approach. AB - Accurate and reliable modelling of protein-protein interaction networks for complex diseases such as colorectal cancer can help better understand mechanism of diseases and potentially discover new drugs. Different machine learning methods such as empirical mode decomposition combined with least square support vector machine, and discrete Fourier transform have been widely utilised as a classifier and for automatic discovery of biomarkers for the diagnosis of the disease. The existing methods are, however, less efficient as they tend to ignore interaction with the classifier. In this study, the authors propose a two-stage optimisation approach to effectively select biomarkers and discover interactions among them. At the first stage, particle swarm optimisation (PSO) and differential evolution (DE) are used to optimise parameters of support vector machine recursive feature elimination algorithm, and dynamic Bayesian network is then used to predict temporal relationship between biomarkers across two time points. Results show that 18 and 25 biomarkers selected by PSO and DE-based approach, respectively, yields the same accuracy of 97.3% and F1-score of 97.7 and 97.6%, respectively. The stratified analysis reveals that Alpha-2-HS glycoprotein was a dominant hub gene with multiple interactions to other genes including Fibrinogen alpha chain, which is also a potential biomarker for colorectal cancer. PMID- 26577165 TI - HeartSearcher: finds patients with similar arrhythmias based on heartbeat classification. AB - Long-term electrocardiogram data can be acquired by linking a Holter monitor to a mobile phone. However, most systems of this variety are simply designed to detect arrhythmia through heartbeat classification, and do not provide any additional support for clinical decisions. HeartSearcher identifies patients with similar arrhythmias from heartbeat classifications, by summarising each patient's typical heartbeat pattern in the form of a regular expression, and then ranking patients according to the similarities of their patterns. Results obtained using electrocardiogram data from the MIT-BIH arrhythmia database show that this abstraction reduces the volume of heartbeat classifications by 98% on average, offering great potential to support clinical decisions. PMID- 26577166 TI - Remote health monitoring system for detecting cardiac disorders. AB - Remote health monitoring system with clinical decision support system as a key component could potentially quicken the response of medical specialists to critical health emergencies experienced by their patients. A monitoring system, specifically designed for cardiac care with electrocardiogram (ECG) signal analysis as the core diagnostic technique, could play a vital role in early detection of a wide range of cardiac ailments, from a simple arrhythmia to life threatening conditions such as myocardial infarction. The system that the authors have developed consists of three major components, namely, (a) mobile gateway, deployed on patient's mobile device, that receives 12-lead ECG signals from any ECG sensor, (b) remote server component that hosts algorithms for accurate annotation and analysis of the ECG signal and (c) point of care device of the doctor to receive a diagnostic report from the server based on the analysis of ECG signals. In the present study, their focus has been toward developing a system capable of detecting critical cardiac events well in advance using an advanced remote monitoring system. A system of this kind is expected to have applications ranging from tracking wellness/fitness to detection of symptoms leading to fatal cardiac events. PMID- 26577167 TI - Lucentis offers treatment alternative for diabetic retinopathy, trial finds. PMID- 26577168 TI - New year's greetings. PMID- 26577169 TI - Bilateral ophthalmoplegia in a child with migraine. AB - BACKGROUND: In children, migraine with or without aura is a common entity, however variants like recurrent painful optic neuropathy (RPON) is rarely encountered. CASE RESULT: A 9 year old boy presented with headache for 1 week and restricted movements and drooping in both eyes for last 3 days. On examination he had bilateral ophthalmoplegia and ptosis. History of migrainous headache was present in the patient as well as his mother. His MRI brain with venogram, serum autoimmune markers, serum and urine toxicology screen and repetitive nerve stimulation test were normal. He received intravenous pulse followed by oral steroids for 6 weeks and was started on antimigraine prophylaxis. Eighteen months since the attack, he has improved completely with mild asymmetric mydriasis persisting. DISCUSSION AND CONCLUSION: This may represent first attack of RPON in a child with migraine. Rarely this may herald the onset of migraine as well, index of suspicion should be high as it is a diagnosis of exclusion and a treatable entity. PMID- 26577170 TI - Effects of vessel size, cell sedimentation and haematocrit on the adhesion of leukocytes and platelets from flowing blood. AB - BACKGROUND: Leukocytes and platelets typically fulfil their functions through adhesion to the walls of vessels with different size, haematocrit and shear rate. OBJECTIVE: We aimed to investigate differential effects of these variables on leukocyte and platelet adhesion. METHODS: Blood with varying haematocrit was perfused at a range of wall shear rates through capillaries of depth 100 or 300 um coated with P-selectin or collagen. RESULTS: Adhesion of leukocytes was much more efficient in the smaller capillaries, but was equal on the upper and lower surfaces and showed nearly identical shear rate dependence for either size of vessel. Platelets also adhered more efficiently in the smaller vessels (although the effect of size was not so great), and equally on upper and lower surfaces, but their adhesion was much less sensitive to increasing shear rate. In previous studies using vertically-orientated capillaries, leukocyte adhesion increased with increasing haematocrit (Am. J. Physiol.285 (2003), H229-H240). Here, in horizontal 100 um capillaries, leukocyte adhesion was highly efficient at haematocrit of 10% but restricted to the lower surface. Adhesion decreased initially as haematocrit was increased to 30% and then increased slightly again at 40% haematocrit. Increasing haematocrit supported a monotonic increase in platelet adhesion in the horizontal capillaries. CONCLUSIONS: Platelets adhere efficiently over a wider range of sizes and shear rates, and at high haematocrit. Leukocytes adhere better in smaller vessels and at low haematocrit in horizontal vessels. The different behaviours may represent 'rheological adaptation' to functions in inflammation vs. haemostasis. PMID- 26577171 TI - Effects of neutral polymers on the mechanics of red blood cell adhesion onto coated glass surfaces. AB - BACKGROUND: Cell-cell and cell-surface adhesion modulated by water-soluble polymers continues to be of current interest, especially since prior reports have indicated a role for depletion-mediated attractive forces. OBJECTIVE: To determine the effects of concentration and molecular mass of the neutral polymer dextran (40 kDa to 28 MDa) on the adhesion of human red blood cells (RBC) to coated glass coverslips. METHODS: Confocal-reflection interference contrast microscopy (C-IRM), in conjunction with phase contrast imaging, was utilized to measure the adhesion dynamics and contact mechanics of RBC during the initial stages of cell contact with several types of substrates. RESULTS: Adhesion is markedly increased in the presence of dextran with a molecular mass ? 70 kDa. This increased adhesiveness is attributed to reduced surface concentration of the large polymers and hence increased attractive forces due to depletion interaction. The equilibrium deformation of adhering RBC was modeled as a truncated sphere and the calculated adhesion energies were in close agreement with theoretical results. CONCLUSIONS: These results clearly demonstrate that polymer depletion can promote RBC adhesion to artificial surfaces and suggest that this phenomenon may play a role in other specific and non-specific cell-cell interactions, such as rouleau formation and RBC-endothelial cell adhesion. PMID- 26577172 TI - The effect of cations on NO2 production from the photolysis of aqueous thin water films of nitrate salts. AB - The photochemistry of nitrate ions in bulk aqueous solution is well known, yet recent evidence suggests that the photolysis of nitrate may be more efficient at the air-water interface. Whether and how this surface enhancement is altered by the presence of different cations is not known. In the present studies, thin aqueous films of nitrate salts with different cations were deposited on the walls of a Teflon chamber and irradiated with 311 nm light at 298 K. The films were generated by nebulizing aqueous 0.5 M solutions of the nitrate salts and the generation of gas-phase NO2 was monitored with time. The nitrate salts fall into three groups based on their observed rate of NO2 formation (R(NO2)): (1) RbNO3 and KNO3, which readily produce NO2 (R(NO2) > 3 ppb min(-1)), (2) Ca(NO3)2, which produces NO2 more slowly (R(NO2) < 1 ppb min(-1)), and (3) Mg(NO3)2 and NaNO3, which lie between the other two groups. Neither differences in the UV-visible spectra of the nitrate salt solutions nor the results of bulk-phase photolysis studies could explain the differences in the rates of NO2 production between these three groups. These experimental results, combined with some insights from previous molecular dynamic simulations and vibrational sum frequency generation studies, show that cations may impact the concentration of nitrate ions in the interface region, thereby directly impacting the effective quantum yields for nitrate ions. PMID- 26577175 TI - Reciprocal interaction among gasotransmitters in isolated pancreatic beta-cells. AB - We aimed to elucidate the interplay among the three well-known gas molecules, nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S), and their effects on intracellular Ca(2+) concentration ([Ca(2+)]i) and insulin secretion in rat pancreatic beta-cells. Immunofluorescence studies demonstrated the expression of constitutive enzymes that are responsible for the production of NO, CO and H2S. CO and H2S increased NO production as indicated by the increase in diaminofluorescein-2 triazole fluorescence. NO and CO induced an elevation in the sulfane sulfur pool and concomitantly H2S production. The NO- and CO-induced H2S production was partially inhibited by hypotaurine, an H2S scavenger. NO and H2S produced CO production as revealed by a myoglobin assay. A calmodulin antagonist in the absence of extracellular Ca(2+) significantly attenuated NO and H2S production. NO and CO induced a [Ca(2+)]i increase mainly via Ca(2+) release from internal stores; however, H2S induced a [Ca(2+)]i increase via the influx of extracellular Ca(2+). NO dose-dependently stimulated basal insulin release but CO dose-dependently inhibited it. H2S showed an insignificant effect on basal insulin secretion from freshly isolated pancreatic islets. Herein, we address for the first time the reciprocal and synergistic relation among gasotransmitters with diverse effects on basal insulin secretion that regulate beta-cells functions and homeostasis. PMID- 26577174 TI - Chloroquine-induced glioma cells death is associated with mitochondrial membrane potential loss, but not oxidative stress. AB - Chloroquine (CQ), a quinolone derivative widely used to treat and prevent malaria, has been shown to exert a potent adjuvant effect when combined with conventional glioblastoma therapy. Despite inducing lysosome destabilization and activating p53 in human glioma cells, the mechanisms underlying cell death induced by this drug are poorly understood. Here, we analyzed in a time- and dose dependent manner, the effects of CQ upon mitochondria integrity, autophagy regulation and redox processes in four human glioma cell lines that differ in their resistance to this drug. NAC-containing media protected cells against CQ induced loss of mitochondrial membrane potential (MMP), autophagic vacuoles (LC3II) accumulation and loss of cell viability induced by CQ. However, we noticed that part of this protection was due to media acidification in NAC preparations, alerting for problems in experimental procedures using NAC. The results indicate that although CQ induces accumulation of LC3II, mitochondria, and oxidative stress, neither of these events is clearly correlated to cell death induced by this drug. The only event elicited in all cell lines at equitoxic doses of CQ was the loss of MMP, indicating that mitochondrial stability is important for cells resistance to this drug. Finally, the data indicate that higher steady-state MMP values can predict cell resistance to CQ treatment. PMID- 26577173 TI - Therapeutic inhibition of mitochondrial reactive oxygen species with mito-TEMPO reduces diabetic cardiomyopathy. AB - AIMS: The mitochondria are important sources of reactive oxygen species (ROS) in the heart. Mitochondrial ROS production has been implicated in the pathogenesis of diabetic cardiomyopathy, suggesting that therapeutic strategies specifically targeting mitochondrial ROS may have benefit in this disease. We investigated the therapeutic effects of mitochondria-targeted antioxidant mito-TEMPO on diabetic cardiomyopathy. METHODS: The mitochondria-targeted antioxidant mito-TEMPO was administrated after diabetes onset in a mouse model of streptozotocin-induced type-1 diabetes and type-2 diabetic db/db mice. Cardiac adverse changes were analyzed and myocardial function assessed. Cultured adult cardiomyocytes were stimulated with high glucose, and mitochondrial superoxide generation and cell death were measured. RESULTS: Incubation with high glucose increased mitochondria superoxide generation in cultured cardiomyocytes, which was prevented by mito TEMPO. Co-incubation with mito-TEMPO abrogated high glucose-induced cell death. Mitochondrial ROS generation, and intracellular oxidative stress levels were induced in both type-1 and type-2 diabetic mouse hearts. Daily injection of mito TEMPO for 30 days inhibited mitochondrial ROS generation, prevented intracellular oxidative stress levels, decreased apoptosis and reduced myocardial hypertrophy in diabetic hearts, leading to improvement of myocardial function in both type-1 and type-2 diabetic mice. Incubation with mito-TEMPO or inhibition of Nox2 containing NADPH oxidase prevented oxidative stress levels and cell death in high glucose-stimulated cardiomyocytes. Mechanistic study revealed that the protective effects of mito-TEMPO were associated with down-regulation of ERK1/2 phosphorylation. CONCLUSIONS: Therapeutic inhibition of mitochondrial ROS by mito TEMPO reduced adverse cardiac changes and mitigated myocardial dysfunction in diabetic mice. Thus, mitochondria-targeted antioxidants may be an effective therapy for diabetic cardiac complications. PMID- 26577176 TI - Carboxylesterase converts Amplex red to resorufin: Implications for mitochondrial H2O2 release assays. AB - Amplex Red is a fluorescent probe that is widely used to detect hydrogen peroxide (H2O2) in a reaction where it is oxidised to resorufin by horseradish peroxidase (HRP) as a catalyst. This assay is highly rated amongst other similar probes thanks to its superior sensitivity and stability. However, we report here that Amplex Red is readily converted to resorufin by a carboxylesterase without requiring H2O2, horseradish peroxidase or oxygen: this reaction is seen in various tissue samples such as liver and kidney as well as in cultured cells, causing a serious distortion of H2O2 measurements. The reaction can be inhibited by Phenylmethyl sulfonyl fluoride (PMSF) at concentrations which do not disturb mitochondrial function nor the ability of the Amplex Red-HRP system to detect H2O2.In vitro experiments and in silico docking simulations indicate that carboxylesterases 1 and 2 recognise Amplex Red with the same kinetics as carboxylesterase-containing mitochondria. We propose two different approaches to correct for this problem and re-evaluate the commonly performed experimental procedure for the detection of H2O2 release from isolated liver mitochondria. Our results call for a serious re-examination of previous data. PMID- 26577177 TI - Assessment of electrophile damage in a human brain endothelial cell line utilizing a clickable alkyne analog of 2-chlorohexadecanal. AB - Peripheral leukocytes aggravate brain damage by releasing cytotoxic mediators that compromise blood-brain barrier function. One of the oxidants released by activated leukocytes is hypochlorous acid (HOCl) that is formed via the myeloperoxidase-H2O2-chloride system. The reaction of HOCl with the endogenous plasmalogen pool of brain endothelial cells results in the generation of 2 chlorohexadecanal (2-ClHDA), a toxic, lipid-derived electrophile that induces blood-brain barrier dysfunction in vivo. Here, we synthesized an alkynyl-analog of 2-ClHDA, 2-chlorohexadec-15-yn-1-al (2-ClHDyA) to identify potential protein targets in the human brain endothelial cell line hCMEC/D3. Similar to 2-ClHDA, 2 ClHDyA administration reduced cell viability/metabolic activity, induced processing of pro-caspase-3 and PARP, and led to endothelial barrier dysfunction at low micromolar concentrations. Protein-2-ClHDyA adducts were fluorescently labeled with tetramethylrhodamine azide (N3-TAMRA) by 1,3-dipolar cycloaddition in situ, which unveiled a preferential accumulation of 2-ClHDyA adducts in mitochondria, the Golgi, endoplasmic reticulum, and endosomes. Thirty-three proteins that are subject to 2-ClHDyA-modification in hCMEC/D3 cells were identified by mass spectrometry. Identified proteins include cytoskeletal components that are central to tight junction patterning, metabolic enzymes, induction of the oxidative stress response, and electrophile damage to the caveolar/endosomal Rab machinery. A subset of the targets was validated by a combination of N3-TAMRA click chemistry and specific antibodies by fluorescence microscopy. This novel alkyne analog is a valuable chemical tool to identify cellular organelles and protein targets of 2-ClHDA-mediated damage in settings where myeloperoxidase-derived oxidants may play a disease-propagating role. PMID- 26577178 TI - Erratum to: Surface display of an anti-DEC-205 single chain Fv fragment in Lactobacillus plantarum increases internalization and plasmid transfer to dendritic cells in vitro and in vivo. PMID- 26577179 TI - Activation of chaperone-mediated autophagy as a potential anticancer therapy. AB - Chaperone-mediated autophagy (CMA), a subtype of autophagy, delivers select proteins into the lysosome for degradation. Defects in CMA activity have previously been linked with neurodegenerative diseases due to the accumulation of misfolded proteins, but the role of CMA in cancer is currently not well defined. In a recent study, we provide a novel mechanism by which excessive activation of CMA can be exploited as a method to eliminate cancer cells by inducing metabolic catastrophe and delineate a novel strategy to promote the degradation of HK2 (hexokinase 2) in cancer cells. PMID- 26577180 TI - High yield extraction of pure spinal motor neurons, astrocytes and microglia from single embryo and adult mouse spinal cord. AB - Extraction of mouse spinal motor neurons from transgenic mouse embryos recapitulating some aspects of neurodegenerative diseases like amyotrophic lateral sclerosis has met with limited success. Furthermore, extraction and long term culture of adult mouse spinal motor neurons and glia remain also challenging. We present here a protocol designed to extract and purify high yields of motor neurons and glia from individual spinal cords collected on embryos and adult (5-month-old) normal or transgenic mice. This method is based on mild digestion of tissue followed by gradient density separation allowing to obtain two millions motor neurons over 92% pure from one E14.5 single embryo and more than 30,000 from an adult mouse. These cells can be cultured more than 14 days in vitro at a density of 100,000 cells/cm(2) to maintain optimal viability. Functional astrocytes and microglia and small gamma motor neurons can be purified at the same time. This protocol will be a powerful and reliable method to obtain motor neurons and glia to better understand mechanisms underlying spinal cord diseases. PMID- 26577181 TI - Physicochemical properties of copper important for its antibacterial activity and development of a unified model. AB - Contact killing is a novel term describing the killing of bacteria when they come in contact with metallic copper or copper-containing alloys. In recent years, the mechanism of contact killing has received much attention and many mechanistic details are available. The authors here review some of these mechanistic aspects with a focus on the critical physicochemical properties of copper which make it antibacterial. Known mechanisms of contact killing are set in context to ionic, corrosive, and physical properties of copper. The analysis reveals that the oxidation behavior of copper, paired with the solubility properties of copper oxides, are the key factors which make metallic copper antibacterial. The concept advanced here explains the unique position of copper as an antibacterial metal. Based on our model, novel design criteria for metallic antibacterial materials may be derived. PMID- 26577183 TI - Determination of arylsulfatase A pseudodeficiency allele and haplotype frequency in the Tunisian population. AB - Arylsulfatase A (ASA) is a lysosomal enzyme involved in the catabolism of cerebroside sulfate. ASA deficiency is associated with metachromatic leukodystrophy (MLD). Low ASA activities have also been reported in a more common condition with no apparent clinical consequences termed ASA pseudo-deficiency (ASA-PD) which is associated with two linked mutations in the ASA gene (c.1049A>G and c.*96A>G). This study aimed to investigate the frequency of the two ASA-PD variants and their linkage disequilibrium (LD) among Tunisians. ASA-PD variants were detected in 129 healthy Tunisians and their frequencies were compared to those described worldwide. The frequency of the PD allele was estimated at 17.4% for the overall sample, with c.1049A>G and c.*96A>G frequencies of 25.6 and 17.4%, respectively. This study also revealed a high LD between the two ASA-PD variants (r(2) = 0.61). Inter-population analysis revealed similarities in the ASA-PD genetic structure between Tunisians and populations from Middle East with c.*96A>G frequencies being the highest in the world. A significant North vs. South genetic differentiation in the ASA-PD frequency was also observed in Tunisian population who seems genetically intermediate between Africans, Middle Easterners and Europeans. This is the first report on the allele frequency of the ASA-PD in North Africa, revealing a relatively high frequency of the PD allele among Tunisians. This study gives also evidence on the importance of discriminating ASA-PD allele from pathological mutations causing MLD and supporting enzymatic activity testing with both sulfatiduria determination and genetic testing in the differential diagnosis of MLD in the Tunisian population. PMID- 26577184 TI - Increased complexin-1 and decreased miR-185 expression levels in Behcet's disease with and without neurological involvement. AB - Although complexin 1 (CPLX1) is not known as an inflammation factor, recent identification of a complexin 1 (CPLX1) polymorphism in Behcet's disease (BD) has sparked an interest in the role of this molecule in autoinflammation. DNA samples were isolated from peripheral blood mononuclear cells (PBMC) of BD and neuro Behcet's disease (NBD) patients and expression levels of CPLX1 and miR-185, a predicted target miRNA for CPLX1 and an inflammation-related miRNA, were investigated by real time PCR assays. PBMC expression levels of CPLX1 were significantly increased in BD and NBD patients. By contrast, levels of miR-185 were reduced in both patient groups. A moderate inverse correlation was found between levels of CPLX1 and miR-185. No correlation could be found between expression levels and clinical features of patients. Significant expression alterations of CPLX1 in BD and NBD patients suggest that this molecule has a proinflammatory action. The putative role of CPLX1 in BD pathogenesis remains to be further studied. PMID- 26577185 TI - Sequential splicing of a group II twintron in the marine cyanobacterium Trichodesmium. AB - The marine cyanobacterium Trichodesmium is unusual in its genomic architecture as 40% of the genome is occupied by non-coding DNA. Although the majority of it is transcribed into RNA, it is not well understood why such a large non-coding genome fraction is maintained. Mobile genetic elements can contribute to genome expansion. Many bacteria harbor introns whereas twintrons, introns-in-introns, are rare and not known to interrupt protein-coding genes in bacteria. Here we show the sequential in vivo splicing of a 5400 nt long group II twintron interrupting a highly conserved gene that is associated with RNase HI in some cyanobacteria, but free-standing in others, including Trichodesmium erythraeum. We show that twintron splicing results in a putatively functional mRNA. The full genetic arrangement was found conserved in two geospatially distinct metagenomic datasets supporting its functional relevance. We further show that splicing of the inner intron yields the free intron as a true circle. This reaction requires the spliced exon reopening (SER) reaction to provide a free 5' exon. The fact that Trichodesmium harbors a functional twintron fits in well with the high intron load of these genomes, and suggests peculiarities in its genetic machinery permitting such arrangements. PMID- 26577186 TI - Soft viscoelastic properties of nuclear actin age oocytes due to gravitational creep. AB - The actin cytoskeleton helps maintain structural organization within living cells. In large X. laevis oocytes, gravity becomes a dominant force and is countered by a nuclear actin network that prevents liquid-like nuclear bodies from immediate sedimentation and coalescence. However, nuclear actin's mechanical properties, and how they facilitate the stabilization of nuclear bodies, remain unknown. Using active microrheology, we find that nuclear actin forms a weak viscoelastic network, with a modulus of roughly 0.1 Pa. Embedded probe particles subjected to a constant force exhibit continuous displacement, due to viscoelastic creep. Gravitational forces also cause creep displacement of nuclear bodies, resulting in their asymmetric nuclear distribution. Thus, nuclear actin does not indefinitely support the emulsion of nuclear bodies, but only kinetically stabilizes them by slowing down gravitational creep to ~2 months. This is similar to the viability time of large oocytes, suggesting gravitational creep ages oocytes, with fatal consequences on long timescales. PMID- 26577187 TI - Strategy and rationale for urine collection protocols employed in the NEPTUNE study. AB - BACKGROUND: Glomerular diseases are potentially fatal, requiring aggressive interventions and close monitoring. Urine is a readily-accessible body fluid enriched in molecular signatures from the kidney and therefore particularly suited for routine clinical analysis as well as development of non-invasive biomarkers for glomerular diseases. METHODS: The Nephrotic Syndrome Study Network (NEPTUNE; ClinicalTrials.gov Identifier NCT01209000) is a North American multicenter collaborative consortium established to develop a translational research infrastructure for nephrotic syndrome. This includes standardized urine collections across all participating centers for the purpose of discovering non invasive biomarkers for patients with nephrotic syndrome due to minimal change disease, focal segmental glomerulosclerosis, and membranous nephropathy. Here we describe the organization and methods of urine procurement and banking procedures in NEPTUNE. RESULTS: We discuss the rationale for urine collection and storage conditions, and demonstrate the performance of three experimental analytes (neutrophil gelatinase-associated lipocalin [NGAL], retinol binding globulin, and alpha-1 microglobulin) under these conditions with and without urine preservatives (thymol, toluene, and boric acid). We also demonstrate the quality of RNA and protein collected from the urine cellular pellet and exosomes. CONCLUSIONS: The urine collection protocol in NEPTUNE allows robust detection of a wide range of proteins and RNAs from urine supernatant and pellets collected longitudinally from each patient over 5 years. Combined with the detailed clinical and histopathologic data, this provides a unique resource for exploration and validation of new or accepted markers of glomerular diseases. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01209000. PMID- 26577188 TI - The SloR metalloregulator is involved in the Streptococcus mutans oxidative stress response. AB - SloR, a 25-kDa metalloregulatory protein in Streptococcus mutans modulates the expression of multiple genes, including the sloABC operon that encodes essential Mn2+ transport and genes that promote cariogenesis. In this study, we report on SloC- and SloR-deficient strains of S. mutans (GMS284 and GMS584, respectively) that demonstrate compromised survivorship compared with their UA159 wild-type progenitor and their complemented strains (GMS285 and GMS585, respectively), when challenged with streptonigrin and/or in growth competition experiments. The results of streptonigrin assays revealed significantly larger zones of inhibition for GMS584 than for either UA159 or GMS585, indicating weakened S. mutans survivorship in the absence of SloR. Competition assays revealed a compromised ability for GMS284 and GMS584 to survive peroxide challenge compared with their SloC- and SloR-proficient counterparts. These findings are consistent with a role for SloC and SloR in S. mutans aerotolerance. We also predicted differential expression of oxidative stress tolerance genes in GMS584 versus UA159 and GMS585 when grown aerobically. The results of quantitative RT-PCR experiments revealed S. mutans sod, tpx, and sloC expression that was upregulated in GMS584 compared with UA159 and GMS585, indicating that the impact of oxidative stress on S. mutans is more severe in the absence of SloR than in its presence. The results of electrophoretic mobility shift assays indicate that SloR does not bind to the sod or tpx promoter regions directly, implicating intermediaries that may arbitrate the SloR response to oxidative stress. PMID- 26577189 TI - A comparative dosimetric study of left sided breast cancer after breast conserving surgery treated with VMAT and IMRT. AB - BACKGROUND AND PURPOSES: This study compared VMAT and IMRT plans for intact breast radiotherapy for left sided breast cancer and evaluated the irradiated dose of planning target volume and OARs, especially focusing on heart and coronary artery. MATERIALS AND METHODS: Eleven patients with left sided breast cancer whose breast was relatively smaller (the mean volumes is 296 cc) treated with breast-conserving surgery were prescribed radiotherapy of 50 Gy in 25 fractions using two or four-field step and shoot IMRT (2 or 4-F IMRT), and one or two-arc VMAT (1 or 2-arc VMAT). The 10 Gy electron boost to the tumor bed after delivery of 50 Gy was not included in the analysis. Multiple planning parameters for the PTV and the PRV-OARs were measured and analyzed. RESULTS: Treatment plans generated using VMAT had better PTV homogeneity than the IMRT plans. For the PRV OARs, the 1-arc VMAT had significantly higher Dmean and V5 for left lung and heart, and showed worse Dmean for liver, esophagus, spinal cord, contralateral lung and breast. In contrast, the 2-arc VMAT and the 2-F or 4-F IMRT plans showed better results for the PRV-OARs than the 1-arc VMAT. However, for the heart and coronary artery, the 1-arc VMAT showed better V20 and V40 compared with the other plans. Moreover, the 2 F-IMRT had specially advantage on V5 and V20 for heart and V5 for coronary arteries, the 2-F IMRT also showed a greater MU and treatment times. Using the table of quality score to evaluate the plans, we found that 2-F IMRT had the highest scores of 13, followed by the 2-arc VMAT plan (10 points) and 1-arc VMAT plan (8 points), and finally the 4-F IMRT plan (6 points). Moreover, when a dose comparison for heart minus coronary artery was calculated, the V20 and V40 for the rest of heart in all plans were very small and closed, indicating the dose to the coronary artery contributed dramatically to the high dose volumes for the entire heart. CONCLUSIONS: Compared to other plans, the 2-F IMRT plan with fewer monitor units and shorter delivery time is an appropriate technique for left sided breast cancer, which achieved good PTV coverage and sparing of organs at risk besides for the heart and coronary artery. PMID- 26577190 TI - Synergistic Antifungal Meroterpenes and Dioxolanone Derivatives from the Endophytic Fungus Guignardia sp. AB - Nine new meroterpenes (1-9) and one new dioxolanone derivative (10), along with seven known compounds (11-17), were isolated from solid cultures of the endophytic fungus Guignardia sp., obtained from Euphorbia sieboldiana. Their structures were elucidated by analysis of UV, IR, 1D and 2D NMR, and HRESIMS data, and their absolute configurations were determined by a combination of single-crystal X-ray studies, modified Mosher methods, and Rh2(OCOCF3)4- and Mo2(OCOCH3)4-induced electronic circular dichroism experiments. All compounds were evaluated for their inhibitory effects alone and with fluconazole on the growth and biofilms of Candida albicans. At 6.3 MUg/mL combined with 0.031 MUg/mL of fluconazole, compounds 8 and 16 were found to have prominent inhibition on the growth of C. albicans with fractional inhibitory concentration index values of 0.23 and 0.19, respectively. Combined with fluconazole, both of them (40 MUg/mL for 8 and 20 MUg/mL for 16) could also inhibit C. albicans biofilms and reverse the tolerance of C. albicans biofilms to fluconazole. PMID- 26577191 TI - Development of an improved ESAT-6 and CFP-10 peptide-based cytokine flow cytometric assay for bovine tuberculosis. AB - Control of bovine tuberculosis (bTB) continues to be a problem world-wide because of difficulties in identifying infected animals at all stages of infection. The use of the IFN-gamma release assays (IGRA) as an ancillary test with the tuberculin skin tests has improved the ability to identify infected animals. However, infected animals may still be missed. The objective of the present study was to evaluate a rapid flow-cytometric assay based on intracellular cytokine staining as an alternative to the in vitro IFN-gamma release assay (IGRA). Antigen-specific cells producing IFN-gamma were identified after a 6h stimulation with PPD-B, PPD-A and ESAT-6/CFP-10. Defined groups of animals naturally infected with Mycobacterium bovis (Mbv), animals infected with non-tuberculous mycobacteria (NTM), and uninfected control animals were analysed to evaluate the sensitivity and specificity of the optimized assay. Both antemortem and postmortem diagnostic tests were carried out to verify the status of infection. We show that IFN-gamma is induced in T cells from whole blood samples from cattle infected with Mbv 6h post stimulation with PPD-B, PPD-A and ESAT-6/CFP-10, whereas non-infected animals did not respond. Four colour flow cytometric analysis demonstrated responding cells were CD45R0(+)CD69(+)CD4(+) memory T cells. Also, the response to stimulation with ESAT-6/CFP-10 can be used to distinguish between cattle infected with Mbv and cattle exposed to NTM. Although further studies are needed, the results indicate that detection of intracellular IFN-gamma may represent an important alternative approach for improved method of detection of cattle secreting IFN-gamma below levels of detection in culture medium. PMID- 26577192 TI - Aeromonas in Arab countries: 1995-2014. AB - The aim of this review is to provide information on the prevalence, clinical syndromes, and antimicrobial resistance and therapy of Aeromonas spp. infections in Arab countries. The data were obtained by an English language literature search from 1995 to 2014 of Medline and PubMed for papers using the search terms "Aeromonas+name of Arab country (i.e. Algeria, Egypt, etc.)". Additional data were obtained from a Google search using the aforementioned terms. The organisms have been reported from diarrheal children, patients with cholera-like diarrhea, an outbreak of acute gastroenteritis and from different types of animals, foods and water source in several Arab countries in the Middle East and North Africa with predominance of A. hydrophila, A. caviae and A. sobria. Using molecular techniques few studies reported genes encoding several toxins from aeromonads isolated from different sources. Among the antimicrobials examined in the present review third generation cephalosporins, fluoroquinolones and aminoglycosides showed excellent activity and can be employed in the treatment of Aeromonas associated human infections in Arabic countries. Whenever possible, treatment should be guided by the susceptibility testing results of the isolated organism. In the future, studies employing molecular testing methods are required to provide data on circulating genospecies and their modes of transmission in the community, and on their mechanisms of resistance to antimicrobials. Microbiology laboratories and research centers are encouraged to look for these organisms in clinical, food and water sources to attain a better understanding of the public health risks from these organisms in Arab countries. PMID- 26577193 TI - Occurrence and molecular characterization of Bartonella spp. and hemoplasmas in neotropical primates from Brazilian Amazon. AB - Little is known about the prevalence and genetic diversity of Bartonella spp. and hemoplasmas in nonhuman primates (NHP). The present study aimed to investigate the occurrence of and assess the phylogenetic position of Bartonella spp. and hemoplasma species infecting neotropical NHP from Brazilian Amazon. From 2009 to 2013, a total of 98 blood samples from NHP belonging to the Family Cebidae were collected in the island of Sao Luis, state of Maranhao, of which 87 NHP were from Wild Animal Screening Center (CETAS) in the municipality of Sao Luis, and 11 (9 Sapajus sp. and 2 Saimiri sciureus) were from NHP caught in the Sitio Aguahy Private Reserve. DNA samples were screened by previously described PCR protocols for amplifying Bartonella spp. and Mycoplasma spp. based on nuoG, gltA and 16S rRNA genes, respectively. Purified amplicons were submitted to sequencing and phylogenetic analysis. Bacteremia with one or more Bartonella spp. was not detected in NHP. Conversely, 35 NHP were PCR positive to Mycoplasma spp. The Blastn analysis of seven positive randomly selected sequencing products showed percentage of identity ranging from 95% to 99% with other primates hemoplasmas. The Maximum Likelihood phylogenetic analysis based on a 1510 bp of 16S rRNA gene showed the presence of two distinct clusters, positioned within Mycoplasma haemofelis and Mycoplasma suis groups. The phylogenetic assessment suggests the presence of a novel hemoplasma species in NHP from the Brazilian Amazon. PMID- 26577194 TI - The evolutionary dynamics of highly pathogenic avian influenza H5N1 in south central Vietnam reveals multiple clades evolving from Chinese and Cambodian viruses. AB - In Vietnam, highly pathogenic avian influenza (HPAI), such as that caused by H5N1 viruses, is the most highly contagious infectious disease that has been affecting domestic poultry in recent years. Vietnam might be an evolutionary hotspot and a potential source of globally pandemic strains. However, few studies have reported viruses circulating in the south-central region of Vietnam. In the present study, 47 H5N1-positive samples were collected from both vaccinated and unvaccinated poultry farms in the South Central Coast region of Vietnam during 2013-2014, and their genetic diversity was analyzed. A common sequence motif for HPAI virus was identified at HA-cleavage sites in all samples: either RERRRKR/G (clades 2.3.2.1c and 2.3.2.1a) or REGRRKKR/G (clade 1.1.2). Phylogenetic analysis of HA genes identified three clades of HPAI H5N1: 1.1.2 (n=1), 2.3.2.1a (n=1), and 2.3.2.1c (n=45). The phylogenetic analysis indicated that these Vietnamese clades may have evolved from Chinese and Cambodian virus clades isolated in 2012-2013 but are less closely related to the clades detected from the Tyva Republic, Bulgaria, Mongolia, Japan, and Korea in 2009-2011. Detection of the coexistence of virus clades 2.3.2.1 and the very virulent 1.1.2 in the south-central regions suggests their local importance and highlights concerns regarding their spread, both northwards and southwards, as well as the potential for reassortment. The obtained data highlight the importance of regular identification of viral evolution and the development and use of region-specific vaccines. PMID- 26577195 TI - Editorial. PMID- 26577196 TI - Interpreting biomonitoring data for 2,4-dichlorophenoxyacetic acid: Update to Biomonitoring Equivalents and population biomonitoring data. AB - Urinary biomonitoring data for 2,4-dichlorophenoxyacetic acid (2,4-D) reflect aggregate population exposures to trace 2,4-D residues in diet and the environment. These data can be interpreted in the context of current risk assessments by comparison to a Biomonitoring Equivalent (BE), which is an estimate of the average biomarker concentration consistent with an exposure guidance value such as the US EPA Reference Dose (RfD). BE values are updated here from previous published BE values to reflect a change in the US EPA RfD. The US EPA RfD has been updated to reflect a revised point of departure (POD) based on new information from additional toxicological studies and updated assessment of applicable uncertainty factors. In addition, new biomonitoring data from both the US National Health and Nutrition Examination Survey (NHANES) and the Canadian Health Measures Survey (CHMS) have been published. The updated US EPA chronic RfD of 0.21 mg/kg-d results in updated BE values of 10,500 and 7000 MUg/L for adults and children, respectively. Comparison of the current population-representative data to these BE values shows that upper bound population biomarker concentrations are more than 5000-fold below BE values corresponding to the updated US EPA RfD. This biomonitoring-based risk assessment supports the conclusion that current use patterns in the US and Canada result in incidental exposures in the general population that can be considered negligible in the context of the current 2,4-D risk assessment. PMID- 26577197 TI - A global human health risk assessment for Decamethylcyclopentasiloxane (D5). AB - Decamethylcyclopentasiloxane (D5) is a low-molecular-weight cyclic siloxane used primarily as an intermediate in the production of several widely-used industrial and consumer products and intentionally added to consumer products, personal products and some dry cleaning solvents. The global use requires consideration of consumer use information and risk assessment requirements from various sources and authoritative bodies. A global "harmonized" risk assessment was conducted to meet requirements for substance-specific risk assessments conducted by regulatory agencies such as USEPA's Integrated Risk Information System (IRIS), Health Canada and various independent scientific committees of the European Commission, as well as provide guidance for chemical safety assessments under REACH in Europe, and other relevant authoritative bodies. This risk assessment incorporates global exposure information combined with a Monte Carlo analysis to determine the most significant routes of exposure, utilization of a multi-species, multi-route physiologically based pharmacokinetic (PBPK) model to estimate internal dose metrics, benchmark modeling to determine a point of departure (POD), and a margin of safety (MOS) evaluation to compare the estimates of intake with the POD. Because of the specific pharmacokinetic behaviors of D5 including high lipophilicity, high volatility with low blood-to-air partition coefficients and extensive metabolic clearance that regulate tissue dose after exposure, the use of a PBPK model was essential to provide a comparison of a dose metric that reflects these processes. The characterization of the potential for adverse effects after exposure to D5 using a MOS approach based on an internal dose metric removes the subjective application of uncertainty factors that may be applied across various regulatory agencies and allows examination of the differences between internal dose metrics associated with exposure and those associated with adverse effects. PMID- 26577198 TI - Effects of Nebulizer Position, Gas Flow, and CPAP on Aerosol Bronchodilator Delivery: An In Vitro Study. AB - BACKGROUND: The aim of this study was to investigate the effects of different delivery circuit configurations, nebulizer positions, CPAP levels, and gas flow on the amount of aerosol bronchodilator delivered during simulated spontaneous breathing in an in vitro model. METHODS: A pneumatic lung simulator was connected to 5 different circuits for aerosol delivery, 2 delivering CPAP through a high flow generator tested at 30, 60, and 90 L/min supplementary flow and 5, 10, and 15 cm H2O CPAP and 3 with no CPAP: a T-piece configuration with one extremity closed with a cap, a T-piece configuration without cap and nebulizer positioned proximally, and a T-piece configuration without cap and nebulizer positioned distally. Albuterol was collected with a filter, and the percentage amount delivered was measured by infrared spectrophotometry. RESULTS: Configurations with continuous high-flow CPAP delivered higher percentage amounts of albuterol compared with the configurations without CPAP (9.1 +/- 6.0% vs 6.2 +/- 2.8%, P = .03). Among configurations without CPAP, the best performance was obtained with a T-piece with one extremity closed with a cap. In CPAP configurations, the highest delivery (13.8 +/- 4.4%) was obtained with the nebulizer placed proximal to the lung simulator, independent of flow. CPAP at 15 cm H2O resulted in the highest albuterol delivery (P = .02). CONCLUSIONS: Based on our in vitro study, without CPAP, a T-piece with a cap at one extremity maximizes albuterol delivery. During high-flow CPAP, the nebulizer should always be placed proximal to the patient, after the T-piece, using the highest CPAP clinically indicated. PMID- 26577200 TI - Reduction of Endotracheal Tube Connector Dead Space Improves Ventilation: A Bench Test on a Model Lung Simulating an Extremely Low Birth Weight Neonate. AB - BACKGROUND: The reduction of instrumental dead space is a recognized approach to preventing ventilation-induced lung injury in premature infants. However, there are no published data regarding the effectiveness of instrumental dead-space reduction in endotracheal tube (ETT) connectors. We tested the impact of the Y piece/ETT connector pairs with reduced instrumental dead space on CO2 elimination in a model of the premature neonate lung. METHODS: The standard ETT connector was compared with a low-dead-space ETT connector and with a standard connector equipped with an insert. We compared the setups by measuring the CO2 elimination rate in an artificial lung ventilated via the connectors. The lung was connected to a ventilator via a standard circuit, a 2.5-mm ETT, and one of the connectors under investigation. The ventilator was run in volume-controlled continuous mandatory ventilation mode. RESULTS: The low-dead-space ETT connector/Y-piece and insert-equipped standard connector/Y-piece pairs had instrumental dead space reduced by 36 and 67%, respectively. With set tidal volumes (VT) of 2.5, 5, and 10 mL, in comparison with the standard ETT connector, the low-dead-space connector reduced CO2 elimination time by 4.5% (P < .05), 4.4% (P < .01), and 7.1% (not significant), respectively. The insert-equipped standard connector reduced CO2 elimination time by 13.5, 25.1, and 16.1% (all P < .01). The low-dead space connector increased inspiratory resistance by 17.8% (P < .01), 9.6% (P < .05), and 5.0% (not significant); the insert-equipped standard connector increased inspiratory resistance by 9.1, 8.4, and 5.9% (all not significant). The low-dead-space connector decreased expiratory resistance by 6.8% (P < .01) and 1.8% (not significant) and increased it by 1.4% (not significant); the insert equipped standard connector decreased expiratory resistance by 1.5 and 1% and increased it by 1% (all not significant). The low-dead-space connector increased work of breathing by 4.7% (P < .01), 3.8% (P < .01), and 2.5% (not significant); the insert-equipped standard connector increased it by 0.8% (not significant), 2.5% (P < .01), and 2.8% (P < .01). CONCLUSIONS: Both methods of instrumental dead-space reduction led to improvements in artificial lung ventilation. Negative effects on resistance and work of breathing appeared minimal. Further testing in vivo should be performed to confirm the lung model results and, if successful, translated into clinical practice. PMID- 26577199 TI - Randomized Controlled Trial of Humidified High-Flow Nasal Oxygen for Acute Respiratory Distress in the Emergency Department: The HOT-ER Study. AB - BACKGROUND: Humidified high-flow nasal cannula (HFNC) is a novel method of oxygen delivery with increasing use in emergency departments and intensive care settings despite little evidence showing benefit over standard oxygen delivery methods (standard O2). The aim of this study was to determine whether HFNC compared with standard O2 given to subjects in acute respiratory distress would reduce the need for noninvasive ventilation or invasive ventilation. METHODS: This was a pragmatic open randomized controlled trial in adult subjects with hypoxia and tachypnea presenting to a tertiary academic hospital emergency department. The primary outcome was the need for mechanical ventilation in the emergency department. RESULTS: We screened 1,287 patients, 322 met entry criteria and 19 were excluded from analysis. Of these, 165 randomized to HFNC and 138 to standard O2 were analyzed. Baseline characteristics were similar. In the HFNC group, 3.6% (95% CI 1.5-7.9%) versus 7.2% (95% CI 3.8-13%) in the standard O2 group required mechanical ventilation in the emergency department (P = .16), and 5.5% (95% CI 2.8-10.2%) in HFNC versus 11.6% (95% CI 7.2-18.1%) in the standard O2 group required mechanical ventilation within 24 h of admission (P = .053). There was no difference in mortality or stay. Adverse effects were infrequent; however, fewer subjects in the HFNC group had a fall in Glasgow coma score due to CO2 retention, 0% (95% CI 0-3%) versus 2.2% (95% CI 0.4-6%). One in 12 subjects did not tolerate HFNC. CONCLUSIONS: HFNC was not shown to reduce the need for mechanical ventilation in the emergency department for subjects with acute respiratory distress compared with standard O2, although it was safe and may reduce the need for escalation of oxygen therapy within the first 24 h of admission. PMID- 26577201 TI - Right Versus Left Prong Nasal Cannula Flow Delivery and the Effects of Nasal Cycling on Inspired F(IO2) in an Adult Anatomic Model. AB - BACKGROUND: Nasal cycling may present negative consequences for oxygen-dependent patients using a nasal cannula. This study investigates the effects of nasal cycling on the delivered F(IO2) via nasal cannula in an anatomic model following a baseline study comparing right and left prong nasal cannula oxygen flow delivery. METHODS: Flow from right and left nasal cannula prongs were measured simultaneously using thermal mass flow meters while delivering 0.5-6-L/min oxygen for 5 nasal cannulas from different manufacturers. An adult mannikin head with an anatomically correct upper airway was connected to a QuickLung Breather test lung. Nasal cannula-delivered F(IO2) was recorded using a polarographic oxygen analyzer with naris occlusion simulated by inserting a 5.0 endotracheal tube into the naris and inflating the endotracheal tube cuff. Data were recorded with both nares open, for right naris occluded and left naris patent, and for left naris occluded and right naris patent at 0.5-6 L/min. RESULTS: A paired t test demonstrated statistical differences between right and left nasal cannula prong oxygen flows (P < .01). Multivariate analysis of variance demonstrated no significant differences in nasal cannula prong flow between nasal cannula manufacturers. Repeated measures analysis of variance demonstrated significant differences for measured inspired F(IO2) (P < .01) when alternating nares were occluded and patent. The Bonferroni post hoc test showed significant differences for measured F(IO2) between patent nares and right naris patent-left naris occluded (P < .01) and between patent nares and left naris patent-right naris occluded (P < .01). Measured F(IO2) decreased by as much as 0.1 when one naris was occluded. CONCLUSIONS: Oxygen delivery by nasal cannula may be inefficient in the presence of the nasal cycle. Delivered nasal cannula oxygen concentrations decreased when bilateral nasal patency changed to unilateral nasal patency. Although statistically different, nasal cannula prong oxygen flow may not be clinically important across the full range of flows. PMID- 26577202 TI - Developing a new look. PMID- 26577203 TI - Glia in mammalian development and disease. AB - Glia account for more than half of the cells in the mammalian nervous system, and the past few decades have witnessed a flood of studies that detail novel functions for glia in nervous system development, plasticity and disease. Here, and in the accompanying poster, we review the origins of glia and discuss their diverse roles during development, in the adult nervous system and in the context of disease. PMID- 26577204 TI - Next generation limb development and evolution: old questions, new perspectives. AB - The molecular analysis of limb bud development in vertebrates continues to fuel our understanding of the gene regulatory networks that orchestrate the patterning, proliferation and differentiation of embryonic progenitor cells. In recent years, systems biology approaches have moved our understanding of the molecular control of limb organogenesis to the next level by incorporating next generation 'omics' approaches, analyses of chromatin architecture, enhancer promoter interactions and gene network simulations based on quantitative datasets into experimental analyses. This Review focuses on the insights these studies have given into the gene regulatory networks that govern limb development and into the fin-to-limb transition and digit reductions that occurred during the evolutionary diversification of tetrapod limbs. PMID- 26577205 TI - A local difference in Hedgehog signal transduction increases mechanical cell bond tension and biases cell intercalations along the Drosophila anteroposterior compartment boundary. AB - Tissue organization requires the interplay between biochemical signaling and cellular force generation. The formation of straight boundaries separating cells with different fates into compartments is important for growth and patterning during tissue development. In the developing Drosophila wing disc, maintenance of the straight anteroposterior (AP) compartment boundary involves a local increase in mechanical tension at cell bonds along the boundary. The biochemical signals that regulate mechanical tension along the AP boundary, however, remain unknown. Here, we show that a local difference in Hedgehog signal transduction activity between anterior and posterior cells is necessary and sufficient to increase mechanical tension along the AP boundary. This difference in Hedgehog signal transduction is also required to bias cell rearrangements during cell intercalations to keep the characteristic straight shape of the AP boundary. Moreover, severing cell bonds along the AP boundary does not reduce tension at neighboring bonds, implying that active mechanical tension is upregulated, cell bond by cell bond. Finally, differences in the expression of the homeodomain containing protein Engrailed also contribute to the straight shape of the AP boundary, independently of Hedgehog signal transduction and without modulating cell bond tension. Our data reveal a novel link between local differences in Hedgehog signal transduction and a local increase in active mechanical tension of cell bonds that biases junctional rearrangements. The large-scale shape of the AP boundary thus emerges from biochemical signals inducing patterns of active tension on cell bonds. PMID- 26577206 TI - Occurrence of Aelurostrongylus abstrusus and Troglostrongylus brevior in domestic cats in Greece. AB - BACKGROUND: Despite the evidence that Mediterranean Europe offers suitable conditions for the biology of felid respiratory metastrongyloids, no updated data on the presence of felid lungworms are available for Greece. Although the cat lungworm Aelurostrongylus abstrusus is considered as enzootic in domestic cats (Felis silvestris catus) living in some areas of continental Greece, conversely, Troglostrongylus brevior, has only been reported in the island of Crete. The present study aimed to evaluate the occurrence of Aelurostrongylus abstrusus and Troglostrongylus brevior in domestic cats from four different Greek locations including islands where European wildcats (Felis silvestris silvestris), believed to be the natural reservoir of T. brevior, are considered absent. METHODS: Faeces were collected from 125 stray cats in the city of Athens, and in Crete, Mykonos and Skopelos Islands, and examined by copromicroscopic techniques for the presence of lungworm larvae. When present, larvae were morphologically and molecularly identified. RESULTS: The occurrence of A. abstrusus and T. brevior was confirmed in 10 (8 %) and 7 (5.6 %) of the samples, respectively. In particular, T. brevior was detected in domestic cats in the city of Athens, and in Mykonos and Skopelos Islands, where wildcats are not present. CONCLUSIONS: This information illustrates that T. brevior may infect domestic cats regardless of the presence of the natural host. Considering the relevant clinical impact of this nematode especially in young animals, it is advisable to include troglostrongylosis in the differential diagnosis of cat respiratory diseases also where this parasite is unexpected. PMID- 26577207 TI - Erratum. PMID- 26577208 TI - The acute effects of graded physiological strain on soccer kicking performance: a randomized, controlled cross-over study. AB - PURPOSE: The aim of the present study was to examine the acute effects of graded physiological strain on soccer kicking performance. METHODS: Twenty-eight semi professional soccer players completed both experimental and control procedure. The experimental protocol incorporated repeated shooting trials combined with a progressive discontinuous maximal shuttle-run intervention. The initial running velocity was 8 km/h and increasing for 1 km/h every 3 min until exhaustion. The control protocol comprised only eight subsequent shooting trials. The soccer specific kicking accuracy (KA; average distance from the ball-entry point to the goal center), kicking velocity (KV), and kicking quality (KQ; kicking accuracy divided by the time elapsed from hitting the ball to the point of entry) were evaluated via reproducible and valid test over five individually determined exercise intensity zones. RESULTS: Compared with baseline or exercise at intensities below the second lactate threshold (LT2), physiological exertion above the LT2 (blood lactate > 4 mmol/L) resulted in meaningful decrease in KA (11-13%; p < 0.05), KV (3-4%; p < 0.05), and overall KQ (13-15%; p < 0.01). The light and moderate-intensity exercise below the LT2 had no significant effect on soccer kicking performance. CONCLUSIONS: The results suggest that high-intensity physiological exertion above the player's LT2 impairs soccer kicking performance. In contrast, light to moderate physiological stress appears to be neither harmful nor beneficial for kicking performance. PMID- 26577209 TI - High-throughput DNA sequencing to survey bacterial histidine and tyrosine decarboxylases in raw milk cheeses. AB - BACKGROUND: The aim of this study was to employ high-throughput DNA sequencing to assess the incidence of bacteria with biogenic amine (BA; histamine and tyramine) producing potential from among 10 different cheeses varieties. To facilitate this, a diagnostic approach using degenerate PCR primer pairs that were previously designed to amplify segments of the histidine (hdc) and tyrosine (tdc) decarboxylase gene clusters were employed. In contrast to previous studies in which the decarboxylase genes of specific isolates were studied, in this instance amplifications were performed using total metagenomic DNA extracts. RESULTS: Amplicons were initially cloned to facilitate Sanger sequencing of individual gene fragments to ensure that a variety of hdc and tdc genes were present. Once this was established, high throughput DNA sequencing of these amplicons was performed to provide a more in-depth analysis of the histamine- and tyramine producing bacteria present in the cheeses. High-throughput sequencing resulted in generation of a total of 1,563,764 sequencing reads and revealed that Lactobacillus curvatus, Enterococcus faecium and E. faecalis were the dominant species with tyramine producing potential, while Lb. buchneri was found to be the dominant species harbouring histaminogenic potential. Commonly used cheese starter bacteria, including Streptococcus thermophilus and Lb. delbreueckii, were also identified as having biogenic amine producing potential in the cheese studied. Molecular analysis of bacterial communities was then further complemented with HPLC quantification of histamine and tyramine in the sampled cheeses. CONCLUSIONS: In this study, high-throughput DNA sequencing successfully identified populations capable of amine production in a variety of cheeses. This approach also gave an insight into the broader hdc and tdc complement within the various cheeses. This approach can be used to detect amine producing communities not only in food matrices but also in the production environment itself. PMID- 26577210 TI - Parotid Sebaceous Carcinoma in Patient with Muir Torre Syndrome, Caused by MSH2 Mutation. AB - Sebaceous carcinoma of parotid gland are extremely rare with only 29 cases reported so far. The development of parotid sebaceous carcinoma in association with mutation in the mismatch repair gene that causes Muir Torre Syndrome (MTS), a subset of Lynch Syndrome, is still unclear. This study describes such a case and reviews the literature to see if an association between parotid sebaceous carcinoma and multiple visceral malignancies seen in Lynch Syndrome has ever been described. MTS represents a small subset of the Hereditary Non Polyposis Colorectal Carcinoma family, thought to be a subtype of Lynch Syndrome, where patients are prone to develop multiple visceral cancers involving gastrointestinal and genitourinary tract along with sebaceous and non-sebaceous tumours of the skin. MTS is a rare hereditary, autosomal dominant cancer syndrome caused by Microsatellite Instability and defect in DNA mismatch repair protein. The germline mutation involves mostly hMSH2 and hMLH1 genes. In MTS the skin of the head and neck area with the periocular region in particular, is affected but sebaceous carcinomas of the parotid associated with visceral malignancies has not yet been reported in literature. Here we report an index case of sebaceous carcinoma of parotid gland in a patient with MTS. PMID- 26577212 TI - Pharyngeal Presentation of Goltz Syndrome: A Case Report with Review of the Literature. AB - Focal dermal hypoplasia (Goltz syndrome; GS) is an X-linked dominant disorder caused by a mutation in the porcupine homolog (PORCN) gene and is typically embryonically lethal for males. The presence of disease in males is usually the result of post-zygotic mutation, but may also be due to mosaicism. The presentation of this disorder is highly variable, but generally is characterized by cutaneous, skeletal, ocular, oral, dental, and aural defects. Cutaneous manifestations include foci of hypoplastic skin, abnormal pigmentation, and papillomatous growths. We present both the first case of a patient with GS related laryngeal obstruction due to papillary lymphoid hyperplasia in an adult, and the first case in a male patient. Clinical, histologic, and genetic features of the disease are discussed. Operative technique for management of the patient with pharyngeal lesions is detailed, and intraoperative photos are showcased. The challenge in airway evaluation and management is also highlighted as manifestations of GS are rarely encountered in the airway and can cause laryngeal obstruction. PMID- 26577211 TI - Phosphaturic Mesenchymal Tumor: 2 New Oral Cases and Review of 53 Cases in the Head and Neck. AB - Phosphaturic mesenchymal tumor (PMT) is a rare neoplasm that secretes fibroblast growth factor-23 (FGF-23) and causes oncogenic osteomalacia. It occurs in adults with equal gender distribution and the most common location is the lower extremities, followed by the head and neck. Besides osteomalacia, the clinical presentation includes bone pain and multiple bone fractures. Microscopic features consist of spindle cells, multinucleated giant cells, and calcifications embedded in a chondromyxoid matrix. Laboratory findings indicate normal calcium and parathyroid levels, hypophosphatemia, and increased levels of FGF-23 that usually revert to normal after surgical removal. Due to its rarity, the purpose of the study was to report 2 new oral cases of PMT and to review the literature in the head and neck. The first case occurred in the gingiva and had been present for 6 years. The second case was a recurrence of a previously diagnosed PMT in the right mandible that metastasized to the lung and soft tissue. The literature review included 53 cases in the head and neck. There was a predilection for extra oral sites (76%) compared to intra-oral sites (24%) with paranasal sinuses considered the most common location (38%) followed by the mandible (15%). There were 9 recurrences that included 3 malignant cases indicating a potentially aggressive tumor. Due to the indeterminate biological behavior of PMT and its rarity, a comprehensive evaluation of medical, laboratory, radiographic, and histological findings are crucial for a definitive diagnosis and treatment. PMID- 26577213 TI - Processing, visualising and reconstructing network models from single-cell data. AB - New single-cell technologies readily permit gene expression profiling of thousands of cells at single-cell resolution. In this review, we will discuss methods for visualisation and interpretation of single-cell gene expression data, and the computational analysis needed to go from raw data to predictive executable models of gene regulatory network function. We will focus primarily on single-cell real-time quantitative PCR and RNA-sequencing data, but much of what we cover will also be relevant to other platforms, such as the mass cytometry technology for high-dimensional single-cell proteomics. PMID- 26577214 TI - Contamination and health risks from heavy metals in cultivated soil in Zhangjiakou City of Hebei Province, China. AB - A total of 79 topsoil samples (ranging from 0 to 20 cm in depth) were collected from a grape cultivation area of Zhangjiakou City, China. The total concentrations of As, Cd, Hg, Cr, Cu, Mn, Ni, Pb, and Zn in soil samples were determined to evaluate pollution levels and associated health risks in each sample. Pollution levels were calculated using enrichment factors (EF) and geoaccumulation index (I geo). Health risks for adults and children were quantified using hazard indexes (HI) and aggregate carcinogenic risks (ACR). The mean concentrations of measured heavy metals Cd, Hg, and Cu, only in the grape cultivation soil samples, were higher than the background values of heavy metals in Hebei Province. According to principal component analysis (PCA), the anthropogenic activities related to agronomic and fossil fuel combustion practices attributed to higher accumulations of Cd, Hg, and Cu, which have slightly polluted about 10-40% of the sampled soils. However, the HI for all of the heavy metals were lower than 1 (within safe limits), and the ACR of As was in the 10(-6)-10(-4) range (a tolerable level). This suggests the absence of both non-carcinogenic and carcinogenic health risks for adults and children through oral ingestion and dermal absorption exposure pathways in the studied area. It should be also noted that the heightened vulnerability of children to health risks was accounted for higher HI and ACR values. Consequently, heavy metal concentrations (e.g., Cd, Hg, Cu) should be periodically monitored in these soils and improved soil management practices are required to minimize possible impacts on children's health. PMID- 26577215 TI - Contamination valuation of soil and groundwater source at anaerobic municipal solid waste landfill site. AB - The present work aimed to determine the risks that formed landfill leachate from anaerobic Erbil Landfill Site (ELS) poses on groundwater source and to observe the effects of disposed municipal solid waste (MSW) on soil properties. The study further aims to fill the gap in studies on the effects of disposed MSW and produced leachate on the groundwater characteristics and soil quality at ELS, Iraq. Soil, leachate, and groundwater samples were collected from ELS for use as samples in this study. Unpolluted groundwater samples were collected from an area outside of the landfill. Field and laboratory experiments for the soil samples were conducted. Chemical analyses for the soil samples such as organic matter, total salts, and SO4 (=) were also performed. Raw leachate and groundwater samples were analyzed using physical and chemical experiments. The yields for sorptivity, steady-state infiltration rate, and hydraulic conductivity of the soil samples were 0.0006 m/?s, 0.00004 m/s, and 2.17 * 10(-5) m/s, respectively. The soil at ELS was found to be light brown clayey gravel with sand and light brown gravely lean clay layers with low permeability. Unprocessed leachate analysis identified the leachate as stabilized. Findings showed that the soil and groundwater at the anaerobic ELS were contaminated. PMID- 26577216 TI - Dynamics of ultrafine particles inside a roadway tunnel. AB - Size-segregated ultrafine particles from motor vehicles were investigated in the Craeybeckx tunnel (E19 motorway, Antwerp, Belgium) at two measurement sites, at 100 and 300 m inside the tunnel, respectively, during March 2008. It was observed that out of the three size modes, nucleation, Aitken, and accumulation, Aitken mode was the most dominant size fraction inside the tunnel. The diurnal variation in ultrafine particle (UFP) levels closely follows the vehicular traffic inside the tunnel, which was maximum during office rush hours, both in the morning and evening and minimum during night-time around 3 am. The tunnel data showed very high growth rates in comparison with free atmosphere. The average condensation sink during the growth period was 14.1-17.3 * 10(-2) s(-1). The average growth rate (GR) of geometric mean diameter was found to be 18.6 +/- 2.45 nm h(-1). It was observed that increase in Aitken mode was related to the numbers of heavy duty vehicles (HDV), as they emit mainly in the Aitken mode. The higher Aitken mode during traffic jams correlated well with HDV numbers. At the end of the tunnel, sudden dilution leading to fast coagulation was responsible for the sudden drop in the UFP number concentration. PMID- 26577217 TI - Geochemical behaviour of PM10 aerosol constituents under the influence of succeeding anticyclonic/cyclonic situations: case of Sfax City, southern Tunisia. AB - The present study investigates the geochemical behaviour of PM10 aerosol constituents (Cl, Na, Si, Al, Ca, Fe, Mg, Mn, Pb, Zn, S) at Sfax City (Tunisia) under succeeding meteorological conditions, including short-lived anticyclonic, cyclonic and prolonged anticyclonic situations. The results revealed daily total concentrations fluctuating between 4.07 and 88.51 MUg/m(3). The highest level recorded was noted to occur under the effect of the short-lived anticyclonic situation characterized by low wind speeds. It was 1.5 times higher than those recorded during cyclonic and long-lived anticyclonic situations characterized by moderate to high wind speeds. During the cyclonic situation, the marked increase of (Na and Cl) concentrations is associated with relatively high sea wind speeds (6 to 9 m/s), which are in turn responsible for a slight increase of crustal elements such as Al, Ca, Si, Fe and Mg, by the entrainment in the air of dust from roads and undeveloped areas. During the two anticyclonic situations, the simultaneous increase (due to communal transport) of crustal (Ca, Si, Al, Fe, Mg) and man-made (Mn, S, Pb, Zn) elements was noted to be associated with the dominance of terrigenious wind flows with speeds varying between 1.5 and 4 m/s. However, the significant contribution rates observed for Cl under the prevalence of such winds as compared to other crustal elements such as Fe suggested the influence of the sebkhas of Southern Tunisia. PMID- 26577218 TI - Treatment efficiency of a wet detention pond combined with filters of crushed concrete and sand: a Danish full-scale study of stormwater. AB - Traditional wet detention ponds and sand filters remove particles efficiently, whereas only a minor part of the dissolved and bioavailable load is removed. To improve the retention of dissolved substances, we tested crushed concrete as a filter material simultaneously with a traditional sand filter placed after an existing wet pond. The particulate fractions (particles, organic matter, phosphorus, and heavy metals) were removed efficiently in the pond and both filter materials, with the concrete filter often being best seen over a year. Dissolved heavy metals (lead (Pb), nickel (Ni), copper (Cu), chromium (Cr), and cadmium (Cd)) were largely retained, though a washout was observed from the pond (Ni and Cu), concrete filter (Cr), and sand filter (Ni) during the first month. The pond only retained total dissolved phosphorus (TDP) during summer. Crushed concrete and sand had a high (>70%) retention of TDP within the first months of operation, but the retention dropped in both filters due to a large oil load into the system (4 kg impermeable ha(-1) in 1 month). The poor retention might to some degree be due to mineralization processes turning particulate phosphorus (PP) into TDP. The massive oil load was retained efficiently (99.3%) in the pond and both filters, clearly illustrating that both filter materials were able to retain either oil or TDP. An additional pilot study showed that at residence times of 1 h, crushed concrete bound 90% TDP whereas sand only bound 22% TDP. Retention of TDP and PP decreased with shorter residence time in both materials, but fastest in sand. PMID- 26577219 TI - Antioxidant, antidiabetic and hypolipidemic effects of Tulbaghia violacea Harv. (wild garlic) rhizome methanolic extract in a diabetic rat model. AB - BACKGROUND: The prevalence of diabetes mellitus (DM) continues to rise alarmingly despite years of intensive research. The need to explore alternative remedies such as traditional phytotherapy has therefore become increasingly important in the management and treatment of DM. METHODS: Diabetes was induced by a single intraperitoneal (i.p) injection of streptozotocin (40 mg/kg.b.w) in male Wistar rats. The rats were divided into 5 groups as follows: non-diabetic control fed distilled water, diabetic control fed distilled water, diabetic group treated with Tulbaghia violacea (TVL) (60 mg/kg.b.w), diabetic group treated with TVL (120 mg/kg.b.w), and diabetic group treated with glibenclamide (10 mg/kg.b.w). Food and water intake, as well as urine output were measured daily, whilst body weight and fasting blood glucose were monitored weekly. On day 42, an oral glucose tolerance test was performed on all groups. After 7 weeks, the animals were sacrificed by halothane overdose, blood was removed by cardiac puncture and tissues were harvested. Assays were performed for the determination of plasma insulin, liver glycogen content, lipid peroxidation, antioxidant enzyme levels, plasma nitric oxide levels and serum lipid and liver enzyme levels. RESULTS AND DISCUSSION: TVL treatment improved body weights, significantly reduced fasting blood glucose levels, improved glucose tolerance and significantly increased plasma insulin and liver glycogen content. TVL treatment also reduced liver thiobarbituric acid reactive substances (TBARS) levels, increased liver superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx) and increased plasma nitric oxide (NO) levels. Furthermore, TVL administration reduced serum triglycerides, VLDL, total-cholesterol levels and increased HDL cholesterol levels. TVL also reduced serum levels of liver enzymes, alanine aminotransferase (ALT) and aspartate aminotransferase (AST). CONCLUSION: Data obtained in this study demonstrated the hypoglycemic, antioxidant, hepatoprotective and hypolipidemic effects of TVL in STZ-induced diabetic rats. PMID- 26577220 TI - Photosensitive form of trichothiodystrophy associated with a novel mutation in the XPD gene. PMID- 26577221 TI - Chilaiditi's sign. PMID- 26577222 TI - A man with breast discharge and headache. PMID- 26577223 TI - Cholesterol absorption and synthesis markers in Portuguese hypercholesterolemic adults: A cross-sectional study. AB - OBJECTIVE: The dynamics of cholesterol homeostasis and the development of cardiovascular disease (CVD) are complex and multifactorial, to which adds individual variability in the proportion of cholesterol from exogenous versus endogenous sources. The aim of this study was to undertake the first characterization of cholesterol absorption and synthesis profiles in Portuguese hypercholesterolemic adults through the quantification of surrogate markers, and the analysis of the predictive value of age and sex on the cholesterol homeostasis biomarkers. METHODS: Serum samples for the measurement of lipid profiles and cholesterol homeostasis markers were obtained for 100 men and 112 women, aged 30-65, with TC >= 5.2 mmol/L (~200mg/dL) and/or LDL-C >= 2.6 mmol/L (~100mg/dL), none of whom were on any lipid-lowering therapy. RESULTS: Overall, sex-specific significant differences were observed in the cholesterol homeostasis markers and lipid profiles; women had lower cholesterol synthesis marker concentrations (P<0.01 for lathosterol) and lipid parameters (except for HDL-C concentrations). Age-related significant differences were also found, including higher concentrations of cholesterol absorption markers in association with increasing age. CONCLUSION: In our study, the predictors of higher levels of cholesterol absorption markers were higher age and female gender. PMID- 26577224 TI - A 28-year-old man with syncope, hypotension, and lethargy. PMID- 26577225 TI - Ongoing challenges and controversies in ulcerative colitis surgery. AB - For patients with ulcerative colitis requiring surgery, surgical options include a total proctocolectomy with an end ileostomy and ileal pouch-anal anastomosis or a continent reservoir, or instead, a subtotal colectomy with an ileorectal anastomosis. The ileal pouch-anal anastomosis is currently considered the gold standard procedure that is employed in the majority of patients. Despite strong data supporting the feasibility, durability and the maintenance of long term functional outcomes and quality of life, certain controversies pertaining to its relative role, method of creation and effects on related pelvic structures remain a matter of debate. PMID- 26577226 TI - ATP generation in a host cell in early-phase infection is increased by upregulation of cytochrome c oxidase activity via the p2 peptide from human immunodeficiency virus type 1 Gag. AB - BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) must take advantage of its own proteins with two or more functions to successfully replicate. Although many attempts have been made to determine the function of viral proteins encoded in the HIV-1 genome, the role of the p2 peptide, a spacer between the capsid and the nucleocapsid in HIV-1 Gag in early-phase HIV infection still remains unclarified. RESULTS: In this study, we show that the p2 peptide enhances HIV-1 acute infection by increasing intracellular ATP production via the activation of mitochondrial cytochrome c oxidase (MT-CO) involved in the respiratory chain. We found that cell-permeable p2-peptide-treated cells were more effectively infected by HIV-1 than control cells. To characterize the effect of the p2 peptide on HIV 1 replication in MAGIC-5 cells, various HIV-1 cDNA products were measured by quantitative real-time PCR. The levels of the late (R/gag), 2-LTR circular (2 LTR), and integrated (Alu) forms of viral cDNAs increased in the presence of the p2 peptide. Interestingly, yeast two-hybrid analysis revealed a novel interaction between the p2 peptide and the mitochondrial intermembrane space domain (N(214) F(235)) of MT-CO subunit I (MT-CO1). Mutational analysis indicated that Gln(6) in the p2 peptide is important for the interaction with MT-CO1. The p2 peptide activated MT-CO1 in vitro in a concentration-dependent manner, and fluorescence microscopy analysis demonstrated that the p2 peptide had a significant effect on mitochondrial targeting. Furthermore, the analysis of HIV-1 lacking a functional p2 peptide demonstrated the inhibition of intracellular ATP production in MT-4 cells and monocyte-derived macrophages (MDMs) and a decrease in reverse transcription efficiency following infection of MT-4 cells and MDMs. CONCLUSIONS: These findings provide evidence that the p2 peptide is a viral positive allosteric modulator of MT-CO and the increased intracellular ATP production after HIV infection in a p2-peptide-dependent manner is essential for efficient reverse transcription in early-phase HIV-1 infection. PMID- 26577227 TI - Increased Use of Care Management Processes and Expanded Health Information Technology Functions by Practice Ownership and Medicaid Revenue. AB - Practice ownership and Medicaid revenue may affect the use of care management processes (CMPs) for chronic conditions and expansion of health information technology (HIT). Using a national cohort of medical practices, we compared the use of CMPs and HIT from 2006/2008 to 2013 by practice ownership and level of Medicaid revenue. Poisson regression models estimated changes in CMP use, and linear regression estimated changes in HIT, by practice ownership and Medicaid patient revenue, controlling for other practice characteristics. Compared with physician-owned practices, system-owned practices adopted a greater number of CMPs and HIT functions over time (p < .001). High Medicaid revenue (>=30.0%) was associated with less adoption of CMPs (p < .001) and HIT (p < .01). System-owned practices (p < .001) and community health centers (p < .001) with high Medicaid revenue were more likely than physician-owned practices with high Medicaid revenue to adopt CMPs over time. System and community health center ownership appear to help high Medicaid practices overcome CMP adoption constraints. PMID- 26577228 TI - Impact of Medicare Part D on Racial Disparities in Adherence to Cardiovascular Medications Among the Elderly. AB - Medicare Part D improved medication adherence among the elderly, but to date, its effect on disparities in adherence remains unknown. We estimated Part D impact on racial/ethnic disparities in adherence to cardiovascular medications among seniors, using pooled data from the Medical Expenditure Panel Survey (2002-2010) on 14,221 Medicare recipients (65+ years) and 3,456 near-elderly controls (60-64 years). Study sample included White, Black, or Hispanic respondents who used at least one cardiovascular medication. Twelve-month adherence was measured as having an overall proportion of days covered >=80%. Adherence disparities were defined according to the Institute of Medicine framework. Using difference-in differences logistic regression, we found Part D to be associated with a 16 percentage-point decrease in the White-Hispanic disparity in overall adherence among seniors, net of the change among controls. Black-White disparities worsened only among men, by 21 percentage points. Increasing access and improving quality of medication use among disadvantaged seniors should remain a policy priority. PMID- 26577229 TI - Crystallisation from a Water-in-Oil Emulsion as a Route to Enantiomer Separation: The Case of DL-Threonine. AB - The use of crystalliation as a means of separating enantiomers is well known. The utility of commonly applied seeding approaches is limited by the ultimate crystallisation of the antipode. Here we demonstrate how the combination of colloid science and crystal chemistry can lead to an emulsion based process yielding robust separation of a purified solid and impure liquid phases with ultimate product ee of up to 90 %. Threonine is used as a model to demonstrate the viability of the method but it is clear that extension to include, for example, simultaneous racemisation within the disperse phase is easily possible and would transform this from a separation to a preparation process. PMID- 26577230 TI - Asymptotic Model of Fluid-Tissue Interaction for Mitral Valve Dynamics. AB - The vortex formation process inside the left ventricle is intrinsically connected to the dynamics of the mitral leaflets while they interact with the flow crossing the valve during diastole. The description of the dynamics of a natural mitral valve still represents a challenging issue, especially because its material properties are not measurable in vivo. Medical imaging can provide some indications about the geometry of the valve, but not about its mechanical properties. In this work, we introduce a parametric model of the mitral valve geometry, whose motion is described in the asymptotic limit under the assumption that it moves with the flow, without any additional resistance other than that given by its shape, and without the need to specify its material properties. The mitral valve model is coupled with a simple description of the left ventricle geometry, and their dynamics is solved numerically together with the equations ruling the blood flow. The intra-ventricular flow is analyzed in its relationship with the valvular motion. It is found that the initial valve opening anticipates the peak velocity of the Early filling wave with little influence of the specific geometry; while subsequent closure and re-opening are more dependent on the intraventricular vortex dynamics and thus on the leaflets' geometry itself. The limitations and potential applications of the proposed model are discussed. PMID- 26577231 TI - Functional and Biomechanical Effects of the Edge-to-Edge Repair in the Setting of Mitral Regurgitation: Consolidated Knowledge and Novel Tools to Gain Insight into Its Percutaneous Implementation. AB - Mitral regurgitation is the most prevalent heart valve disease in the western population. When severe, it requires surgical treatment, repair being the preferred option. The edge-to-edge repair technique treats mitral regurgitation by suturing the leaflets together and creating a double-orifice valve. Due to its relative simplicity and versatility, it has become progressively more widespread. Recently, its percutaneous version has become feasible, and has raised interest thanks to the positive results of the Mitraclip((r)) device. Edge-to-edge features and evolution have stimulated debate and multidisciplinary research by both clinicians and engineers. After providing an overview of representative studies in the field, here we propose a novel computational approach to the most recent percutaneous evolution of the edge-to-edge technique. Image-based structural finite element models of three mitral valves affected by posterior prolapse were derived from cine-cardiac magnetic resonance imaging. The models accounted for the patient-specific 3D geometry of the valve, including leaflet compound curvature pattern, patient-specific motion of annulus and papillary muscles, and hyperelastic and anisotropic mechanical properties of tissues. The biomechanics of the three valves throughout the entire cardiac cycle was simulated before and after Mitraclip((r)) implantation, assessing the biomechanical impact of the procedure. For all three simulated MVs, Mitraclip((r)) implantation significantly improved systolic leaflets coaptation, without inducing major alterations in systolic peak stresses. Diastolic orifice area was decreased, by up to 58.9%, and leaflets diastolic stresses became comparable, although lower, to systolic ones. Despite established knowledge on the edge-to-edge surgical repair, latest technological advances make its percutanoues implementation a challenging field of research. The modeling approach herein proposed may be expanded to analyze clinical scenarios that are currently critical for Mitraclip((r)) implantation, helping the search for possible solutions. PMID- 26577232 TI - Open vs. Minimally Invasive Mitral Valve Surgery: Surgical Technique, Indications and Results. AB - Minimally invasive procedures are the standard approach in many centres but are still under debate in regards of inferiority compared to conventional mitral valve surgery through a median sternotomy. The aim of this review was to summarize the current literature comparing minimally invasive mitral valve surgery (MIVS) and conventional mitral valve surgery. In this review of the current literature, we summarize our findings from a recent meta-analysis and add information from papers that were published afterwards. There were no differences between patients treated minimally invasive or through a conventional sternotomy approach in regards of perioperative stroke rate and mortality. Procedural time, cardio-pulmonary-bypass time and cross-clamp time were longer in the MIVS group. In contrast, length of intensive care unit (ICU) stay and length of in hospital stay were significantly reduced in this group. Need for blood transfusion was lower in the MIVS group. Other outcomes like i.e., the rate of rethoracotomies or renal failure didn't differ between the groups. Repair rates and long-term freedom from recurrence of mitral regurgitation and reoperation are similar. Newer publications underline these findings. The current literature shows that MIVS and conventional mitral valve surgery show a similar perioperative outcome. Minimally invasive mitral valve surgery is favourable with regards to ICU stay, in hospital stay as well as need for blood transfusion. PMID- 26577233 TI - Review of Congenital Mitral Valve Stenosis: Analysis, Repair Techniques and Outcomes. AB - The spectrum of congenital mitral valve stenosis (MS) consists of a complex of defects that result in obstruction to left ventricular inflow. This spectrum includes patients with underdeveloped left heart structures (Fig. 1) to those with isolated congenital MS. The specific mitral valve defects can further be divided into categories based on the relationship to the mitral valve annulus including valvar, supravalvar and subvalvar components. Clinically, these patients present based on the degree of obstruction, associated mitral regurgitation, secondary pulmonary hypertension, associated lung disease and/or associated cardiac lesions. There are a number of factors that contribute to the successful outcomes in these patients including pre-operative imaging, aggressive surgical techniques and peri-operative management. PMID- 26577234 TI - Simultaneous in- and out-of-plane Mitral Valve Annular Force Measurements. AB - Mitral valve repair with annuloplasty is often favoured over total valve replacement. In order to develop and optimize new annuloplasty ring designs, it is important to study the complex biomechanical behaviour of the valve annulus and the subvalvular apparatus with simultaneous in- and out-of-plane restraining force measurements. A new flat D-shaped mitral valve annular force transducer was developed. The transducer was mounted with strain gauges to measure strain and calibrated to provide simultaneous restraining forces in- and out of the mitral annular plane. The force transducer was implanted and evaluated in an 80 kg porcine experimental model. Accumulation of out-of-plane restraining forces, creating strain in the anterior segment were 0.7 +/- 0.0 N (towards apex) and an average force accumulation of 1.5 +/- 0.3 N, creating strain in the commissural segments (away from apex). The accumulations of in-plane restraining forces, creating strain on the inner side of the ring were 1.7 +/- 0.2 N (away from ring center). A new mitral annular force transducer was successfully developed and evaluated in vivo. The transducer was able to measure forces simultaneously in different planes. Initial indications point towards overall agreement with previous individual force measurements in- and out-of the mitral annular plane. This can provide more detailed insight into the annular force distribution, and could potentially improve the level of evidence based mitral valve repair and support the development of future mitral annuloplasty devices. PMID- 26577235 TI - Bench Models for Assessing the Mechanics of Mitral Valve Repair and Percutaneous Surgery. AB - Rapid preclinical evaluations of mitral valve (MV) mechanics are currently best facilitated by bench models of the left ventricle (LV). This review aims to provide a comprehensive assessment of these models to aid interpretation of their resulting data, inform future experimental evaluations, and further the translation of results to procedure and device development. For this review, two types of experimental bench models were evaluated. Rigid LV models were characterized as fluid-mechanical systems capable of testing explanted MVs under static and or pulsatile left heart hemodynamics. Passive LV models were characterized as explanted hearts whose left side is placed in series with a static or pulsatile flow-loop. In both systems, MV function and mechanics can be quantitatively evaluated. Rigid and passive LV models were characterized and evaluated. The materials and methods involved in their construction, function, quantitative capabilities, and disease modeling were described. The advantages and disadvantages of each model are compared to aid the interpretation of their resulting data and inform future experimental evaluations. Repair and percutaneous studies completed in these models were additionally summarized with perspective on future advances discussed. Bench models of the LV provide excellent platforms for quantifying MV repair mechanics and function. While exceptional work has been reported, more research and development is necessary to improve techniques and devices for repair and percutaneous surgery. Continuing efforts in this field will significantly contribute to the further development of procedures and devices, predictions of long-term performance, and patient safety. PMID- 26577236 TI - Association study of MMP8 gene in osteoarthritis. AB - OBJECTIVES: Osteoarthritis (OA) is a joint disease common in the elderly. There is a prior functional evidence for different matrix metalloproteinases (MMPs), such as MMP8 and MMP9, having a role in the breakdown of cartilage extracellular matrix in OA. Thus, we analyzed whether the common genetic variants of MMP8 and MMP9 contribute to the risk of OA. MATERIALS AND METHODS: In total, 13 common tagging single-nucleotide polymorphisms (SNPs) were studied in a discovery knee OA cohort of 185 cases and 895 controls. For validation, two knee OA replication cohorts and two hand OA replication cohorts were studied (altogether 1369 OA cases, 4445 controls in the five cohorts). The chi(2) test for individual study cohorts and Cochran-Mantel-Haenszel test for combined meta-analysis were calculated using Plink. RESULTS: The rs1940475 SNP in MMP8 showed suggestive association in the discovery cohort (OR = 0.721, 95% CI 0.575-0.906; p = 0.005). Other knee and hand OA replication study cohorts showed similar trend for the predisposing allele without reaching statistical significance in independent replication cohorts nor in their meta-analysis (p > 0.05). Meta-analysis of all five hand and knee OA study cohorts yielded a p-value of 0.027 (OR = 0.904, 95% CI 0.826-0.989). CONCLUSIONS: Initial analysis of the MMP8 gene showed suggestive association between rs1940475 and knee OA, but the finding did not replicate in other study cohorts, even though the trend for predisposing allele was similar in all five cohorts. MMP-8 is a good biological candidate for OA, but our study did not find common variants with significant association in the gene. PMID- 26577237 TI - Systemic sclerosis and localized scleroderma--current concepts and novel targets for therapy. AB - Systemic sclerosis (SSc) is a chronic autoimmune disease with a high morbidity and mortality. Skin and organ fibrosis are key manifestations of SSc, for which no generally accepted therapy is available. Thus, there is a high unmet need for novel anti-fibrotic therapeutic strategies in SSc. At the same time, important progress has been made in the identification and characterization of potential molecular targets in fibrotic diseases over the recent years. In this review, we have selected four targeted therapies, which are tested in clinical trials in SSc, for in depths discussion of their preclinical characterization. Soluble guanylate cyclase (sGC) stimulators such as riociguat might target both vascular remodeling and tissue fibrosis. Blockade of interleukin-6 might be particularly promising for early inflammatory stages of SSc. Inhibition of serotonin receptor 2b signaling links platelet activation to tissue fibrosis. Targeting simultaneously multiple key molecules with the multityrosine kinase-inhibitor nintedanib might be a promising approach in complex fibrotic diseases such as SSc, in which many partially independent pathways are activated. Herein, we also give a state of the art overview of the current classification, clinical presentation, diagnostic approach, and treatment options of localized scleroderma. Finally, we discuss whether the novel targeted therapies currently tested in SSc could be used for localized scleroderma. PMID- 26577239 TI - Superficial spreading malignant melanoma in a patient on fingolimod therapy for multiple sclerosis. PMID- 26577238 TI - A bug's life in the granuloma. AB - The granuloma is the defining feature of the host response to infection with Mycobacterium tuberculosis (Mtb). Despite knowing of its existence for centuries, much remains unclear regarding the host and bacterial factors that contribute to granuloma formation, heterogeneity of presentation, and the forces at play within. Mtb is highly adapted to life within the granuloma and employs many unique strategies to both create a niche within the host as well as survive the stresses imposed upon it. Adding to the complexity of the granuloma is the vast range of pathology observed, often within the same individual. Here, we explore some of the many ways in which Mtb crafts the immune response to its liking and builds a variety of granuloma features that contribute to its survival. We also consider the multitude of ways that Mtb is adapted to life in the granuloma and how variability in the deployment of these strategies may result in different fates for both the bacterium and the host. It is through better understanding of these complex interactions that we may begin to strategize novel approaches for tuberculosis treatments. PMID- 26577241 TI - Dydrogesterone vs progesterone for luteal-phase support: systematic review and meta-analysis of randomized controlled trials. AB - OBJECTIVES: To compare the effects of dydrogesterone and progesterone for luteal phase support (LPS) in women undergoing assisted reproductive techniques (ART). METHODS: We performed a systematic review to identify relevant randomized controlled trials (RCTs) by searching the following electronic databases: Cochrane CENTRAL, PubMed, Scopus, Web of Science, ClinicalTrials.gov, ISRCTN Registry and WHO ICTRP. RESULTS: The last search was performed in October 2015. Eight RCTs were considered eligible and were included in the review and meta analyses. There was no relevant difference between oral dydrogesterone and vaginal progesterone for LPS with respect to rate of ongoing pregnancy (risk ratio (RR), 1.04 (95% CI, 0.92-1.18); I(2) , 0%; seven RCTs, 3134 women), clinical pregnancy (RR, 1.07 (95% CI, 0.93-1.23); I(2) , 34%; eight RCTs, 3809 women) or miscarriage (RR, 0.77 (95% CI, 0.53-1.10); I(2) , 0%; seven RCTs, 906 clinical pregnancies). Two of the three studies reporting on dissatisfaction of treatment identified lower levels of dissatisfaction among women using oral dydrogesterone than among women using vaginal progesterone (oral dydrogesterone vs vaginal progesterone capsules: 2/79 (2.5%) vs 90/351 (25.6%), respectively; oral dydrogesterone vs vaginal progesterone gel: 19/411 (4.6%) vs 74/411 (18.0%), respectively). The third study showed no difference in dissatisfaction rate (oral dydrogesterone vs vaginal progesterone capsules: 8/96 (8.3%) vs 8/114 (7.0%), respectively). CONCLUSIONS: Oral dydrogesterone seems to be as effective as vaginal progesterone for LPS in ART cycles, and appears to be better tolerated . Copyright (c) 2015 ISUOG. Published by John Wiley & Sons Ltd. PMID- 26577242 TI - A retrospective evaluation of polyurethane, long-stay, peripheral venous cannulae in dogs undergoing radiotherapy. AB - OBJECTIVES: The aim of this retrospective study was to review placement duration and associated complications of long-stay, peripheral venous cannulae in dogs undergoing a radiotherapy protocol. Factors affecting duration of stay of the cannulae were evaluated. METHODS: The records of patients which had a single lumen, 16-gauge, 16-cm polyurethane cannulae inserted into a peripheral vein between 2010 and 2014 were reviewed. RESULTS: Forty-one cannulae were placed in 41 patients. Median duration of cannula stay was 14 days (range 2 to 26). In 14 cases (~34%) the cannula was removed at the end of the radiotherapy course. In 13 (~32%) cases, cannula-related complications resulted in premature removal. Use of steroids and antibiotics appeared to be associated with a longer median duration of stay. CLINICAL SIGNIFICANCE: No life-threatening complications were encountered. Indwelling, polyurethane, saphenous cannulae were an effective and safe way to maintain venous access in this group of patients. Prednisolone and antibiotics were typically commenced for acute radiation side effects -midway through the protocol; therefore their association with length of stay may not be a direct result of their administration. PMID- 26577243 TI - Evaluation of a Polymeric Flap Valve-Attached Ureteral Stent for Preventing Vesicoureteral Reflux in Elevated Intravesical Pressure Conditions: A Pilot Study Using a Porcine Model. AB - OBJECTIVE: To evaluate the effectiveness of a polymeric flap valve-attached ureteral stent for preventing vesicoureteral reflux (VUR) in an animal model. MATERIALS AND METHODS: One female Yorkshire pig was included in this study. A flap valve-attached and a conventional stent was inserted in the right and left ureters, respectively. The bladder was filled with contrast medium until the intravesical pressure reached 20 cm H2O. Subsequently, simulated voiding cystourethrography (VCUG) was performed 50 times by manually compressing the suprapubic area until the intravesical pressure reached 50 cm H2O. Intravenous pyelography (IVP) was performed thereafter to evaluate the urinary drainage. In addition, an in vitro durability test of the function of the flap valve was conducted under continuous hydrostatic pressure for 24 h. RESULTS: The volume of contrast medium needed to achieve an intravesical pressure of 20 cm H2O was 1740 mL. In the repeated simulated VCUG for the right ureter, VUR grades of 0 and I were recorded in 82.0 (n = 41) and 18.0% (n = 9) tests, respectively, whereas for the left ureter, grades of I, II, and III were recorded in 14.0 (n = 7), 82.0 (n = 41), and 4.0% (n = 2), respectively. Thus, a significantly lower VUR grade was recorded for the right ureter than for the left ureter (p < 0.001). In the bilateral VUR condition, the pressure for VUR occurrence was significantly greater in the right ureter than in the left ureter (p = 0.007). No urinary obstruction was caused by the flap valve-attached ureteral stent according to the IVP findings. The in vitro durability test demonstrated slightly enhanced antireflux function and slightly decreased intraluminal drainage at 12 h, and these findings sustained thereafter. CONCLUSION: A flap valve-attached ureteral stent effectively prevented VUR under conditions of elevated intravesical pressure without urinary obstruction. PMID- 26577245 TI - Metabolomics reveals hippocampal metabolic fluctuations of postoperative fatigue syndrome and anti-fatigue effect of Carthamus tinctorius L extract in rat model. AB - Postoperative fatigue syndrome (POFS) is a common clinical complication followed by almost every major abdominal surgery. There is not a full explanation to the etiology of POFS, especially its central mechanism. Carthamus tinctorius L is a classic traditional Chinese medicine (TCM) which could exert the anti-fatigue effect on POFS. However, its mechanism is still lacking. Here, ultra-high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOFMS) based metabonomic approach was used to characterize hippocampal metabolic fluctuations of POFS in a rat model induced by partial hepatectomy (PHx), and to evaluate the anti-fatigue effect of Carthamus tinctorius L extract (CTLE). With partial least-squares discriminant analysis for classification and selection of biomarkers, fifteen hippocampal metabolites related to POFS were identified, primarily involving alanine, aspartate and glutamate metabolism, valine, leucine and isoleucine degradation, purine metabolism, phenylalanine metabolism, tryptophan metabolism, phospholipid metabolism and fatty acid metabolism. With these altered metabolic pathways as possible drug targets, we systematically analyzed the protective effect of CTLE, which showed that CTLE could provide anti-fatigue effect on POFS through partially regulating the perturbed metabolic pathways. This study indicated that UHPLC-Q-TOFMS-based metabolomics provided a powerful tool to reveal hippocampal metabolic fluctuations of POFS and study the mechanism of TCM. This article is protected by copyright. All rights reserved. PMID- 26577246 TI - Incidence of hip fracture in Kuwait: a national registry-based study. AB - The crude and age-standardized rates of hip fractures in elderly Kuwaiti subpopulation were determined for the years 2009-2012. Both rates have increased and are further expected to rise substantially in the coming decades. INTRODUCTION: It is projected that rates of hip fractures will increase in most of the Middle East countries. There are only few population-based studies investigating the incidence of hip fractures in the Arabian Gulf region. The objective of this study is to report the crude and age-standardized incidence rates of hip fracture in the Kuwaiti elderly population. METHODS: Using the Ministry of Public Health's registry data, this population-based study evaluated the incidence of hip fractures in Kuwaiti subpopulation aged 50 and above for the years 2009, 2010, 2011, and 2012. Using the world population in 2010 as a reference, these incidence rates were age-standardized and compared to data from several regions. RESULTS: Hip fracture crude incidence rates varied between 113.7 and 147.4/100,000 for males and between 135.3 and 148.1/100,000 for females, with a female/male ratio of 1.3-1.5. The combined (men and women) incidence rate of hip fractures increased by 17.1 % over the 4-year period of study (125.9/100,000 in 2009 to 147.8/100,000 in 2012). Using the world population in 2010 as a reference, the age-standardized rates were 129.5, 131.5, 154.6, and 169.8 for males and 189.6, 192.9, 197.2, and 214.4 for females, for the years 2009, 2010, 2011, and 2012, respectively. CONCLUSIONS: The hip fracture age-standardized incidence rates in the Kuwaiti subpopulation aged 50 years and above are rising and expected to increase substantially in the coming decades. PMID- 26577244 TI - Five-aza-2'-deoxycytidine-induced hypomethylation of cholesterol 25-hydroxylase gene is responsible for cell death of myelodysplasia/leukemia cells. AB - DNA methyltransferase inhibitors (DNMT inhibitors) are administered for high-risk MDS, but their action mechanisms are not fully understood. Hence, we performed a genome-wide DNA methylation assay and focused on cholesterol 25-hydroxylase (CH25H) among the genes whose expression was up-regulated and whose promoter region was hypomethylated after decitabine (DAC) treatment in vitro. CH25H catalyzes hydroxylation of cholesterol and produces 25-hydroxycholesterol (25 OHC). Although CH25H mRNA expression level was originally low in MDS/leukemia cell lines, exposure to DNMT inhibitors enhanced CH25H mRNA expression. The promoter region of CH25H was originally hypermethylated in HL-60 and MDS-L cells, but DAC treatment induced their hypomethylation together with increased CH25H mRNA expression, activation of CH25H-oxysterol pathway, 25-OHC production and apoptotic cell death. We further confirmed that normal CD34-positive cells revealed hypomethylated status of the promoter region of CH25H gene. CH25H knockdown by transfection of shRNA lentiviral vector into the cell lines partially protected the cells from DAC-induced cell death. Exogenous addition of 25-OHC suppressed leukemic cell growth. The present study raises a possibility that DNMT inhibitors activate CH25H-oxysterol pathway by their hypomethylating mechanism and induce leukemic cell death. Further investigations of the promoter analysis of CH25H gene and therapeutic effects of DNMT inhibitors on MDS/leukemia will be warranted. PMID- 26577247 TI - The effects of dexamphetamine on the resting-state electroencephalogram and functional connectivity. AB - The catecholamines-dopamine and noradrenaline-play important roles in directing and guiding behavior. Disorders of these systems, particularly within the dopamine system, are associated with several severe and chronically disabling psychiatric and neurological disorders. We used the recently published group independent components analysis (ICA) procedure outlined by Chen et al. (2013) to present the first pharmaco-EEG ICA analysis of the resting-state EEG in healthy participants administered 0.45 mg/kg dexamphetamine. Twenty-eight healthy participants between 18 and 41 were recruited. Bayesian nested-domain models that explicitly account for spatial and functional relationships were used to contrast placebo and dexamphetamine on component spectral power and several connectivity metrics. Dexamphetamine led to reductions across delta, theta, and alpha spectral power bands that were predominantly localized to Frontal and Central regions. Beta 1 and beta 2 power were reduced by dexamphetamine at Frontal ICs, while beta 2 and gamma power was enhanced by dexamphetamine in posterior regions, including the parietal, occipital-temporal, and occipital regions. Power-power coupling under dexamphetamine was similar for both states, resembling the eyes open condition under placebo. However, orthogonalized measures of power coupling and phase coupling did not show the same effect of dexamphetamine as power-power coupling. We discuss the alterations of low- and high-frequency EEG power in response to dexamphetamine within the context of disorders of dopamine regulation, in particular schizophrenia, as well as in the context of a recently hypothesized association between low-frequency power and aspects of anhedonia. Hum Brain Mapp 37:570-588, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26577248 TI - Effects of sevoflurane increments on left ventricular systolic long-axis performance during sevoflurane-remifentanil anesthesia for cardiovascular surgery. AB - BACKGROUND: The direct impact of sevoflurane on intraoperative left ventricular (LV) systolic performance during cardiac surgery has not been fully elucidated. Peak systolic tissue Doppler velocities of the lateral mitral annulus (S') have been used to evaluate LV systolic long-axis performance. We hypothesized that incremental sevoflurane concentration (1.0-3.0 inspired-vol%) would dose dependently reduce S' in patients undergoing cardiac surgery due to mitral or aortic insufficiency. METHODS: In 20 patients undergoing cardiac surgery in sevoflurane-remifentanil anesthesia, we analyzed intraoperative S' values which were determined after 10 min exposure to sevoflurane at 1.0, 2.0, and 3.0 inspired-vol% (T1, T2, and T3, respectively) with a fixed remifentanil dose (1.0 MUg/kg/min) using transesophageal echocardiography. RESULTS: Linear mixed-effect modeling demonstrated dose-dependent declines in S' according to the end-tidal sevoflurane concentration increments (C(ET)-sevoflurane, p < 0.001): the mean value of S' reduction for each 1.0 vol%-increment of C(ET)-sevoflurane was 1.7 cm/s (95 % confidence interval 1.4-2.1 cm/s). Medians of S' at T1, T2, and T3 (9.6, 8.9, and 7.5 cm/s, respectively) also exhibited significant declines (by 6.6, 15.6, and 21.2 % for T1 vs. T2, T2 vs. T3, and T1 vs. T3, p < 0.001, =0.002, and <0.001 in Friedman pairwise comparisons, respectively). CONCLUSIONS: Administering sevoflurane as a part of a sevoflurane-remifentanil anesthesia regimen appears to dose-dependently reduce S', indicating LV systolic performance, in patients undergoing cardiac surgery. Further studies may be required to evaluate the clinical implications of these findings. PMID- 26577249 TI - Deferoxamine stimulates LDLR expression and LDL uptake in HepG2 cells. AB - SCOPE: Iron overload contributes to the pathogenesis of atherosclerosis and iron chelators are beneficial through their antioxidant properties. Hepatic iron loading increases cholesterol synthesis. Whether iron depletion could affect hepatic cholesterol metabolism is unknown. METHODS AND RESULTS: We examined the effect of the iron chelator deferoxamine (DFO) on mRNA expression of genes involved in cholesterol metabolism and/or cholesterol uptake. Our results revealed that DFO increases LDL receptor (LDLR) mRNA levels in human hepatocyte derived cell lines HepG2 and Huh7 cells, and in K562 cells. In HepG2 cells, we observed that DFO increases (i) LDLR-mRNA levels in a time- and dose-dependent manner, (ii) LDLR-protein levels; (iii) cell surface LDLR; and (iv) LDL uptake. In contrast, the mRNA levels of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, sterol regulatory element-binding proteins, and the mRNA/protein levels of proprotein convertase subtilisin-kexin 9 were not modulated by DFO, suggesting that the LDLR regulation by DFO is not at the transcriptional or posttranslational levels. Since LDLR-mRNA was stabilized by DFO, a posttranscriptional mechanism is suggested for the DFO-mediated upregulation of LDLR. CONCLUSION: DFO induced an increase in LDLR expression by a posttranscriptional mechanism resulting in an enhancement of LDL uptake in HepG2 cells, suggesting increased LDLR activity as one of the underlying causes of the hypocholesterolemic effect of iron reduction. PMID- 26577250 TI - Transcatheter mitral valve implantation for inoperable severely calcified native mitral valve disease: A systematic review. AB - BACKGROUND: Transcatheter mitral valve implantation (TMVI) for severely calcified native mitral valve disease recently emerged as a treatment option in patients deemed inoperable by conventional techniques. Yet no systematic appraisal currently exists characterizing this novel treatment paradigm. METHODS: A systematic literature review summarizing the clinical, anatomical, peri- and post procedural characteristics underscoring the technical feasibility of this procedure was performed. RESULTS: Nine publications describing 11 patients [mean age 68 +/- 10 years, 82% female, 82% severe mitral stenosis (MS), 18% severe mitral regurgitation (MR)] were identified. Mean STS score, trans-mitral gradient and effective orifice area were 10.5 +/- 4.6%, 12 +/- 2.4 mm Hg and 0.93 +/- 0.06 cm(2) respectively. All patients had severe, circumferential mitral annular calcification on imaging. Dedicated balloon-expanding transcatheter aortic valves were used in 10/11 cases, with 8/11 cases involving a true percutaneous approach with peri-procedural 3D trans-esophageal echocardiographic guidance; 3/11 cases involved an open left atrial approach. Following initial balloon inflation and valve deployment, procedural success rate was 73%, without residual paravalvular leaks (PVL). Successful immediate re-deployment of a 2nd valve was needed in 2 instances following significant PVL detection. Residual trans-valvular gradients ranged from 3 to 7 mm Hg, with no patient demonstrating >grade 2 MR. All patients survived the procedure, with 2 reported deaths on days 10- and 41 post-TMVI being non-cardiac-related. Mid-term clinical follow-up, reported in 8 patients, revealed 6 patients to be alive at 3-months with much improved functional status. CONCLUSIONS: TMVI for native severely calcified mitral valve disease appears technically feasible with acceptable initial acute and mid-term hemodynamic and clinical outcomes. The outcomes of an ongoing, dedicated global Sapien TMVI registry will shed further light on this evolving treatment paradigm. PMID- 26577251 TI - Kinetic Resolution of beta-Sulfonyl Ketones through Enantioselective beta Elimination using a Cation-Binding Polyether Catalyst. AB - Reported herein is the first enantioselective beta-elimination reaction catalyzed by a chiral cation-binding polyether. By using this catalytic protocol, a wide range of beta-sulfonyl ketones could be effectively resolved with high stereoselectivity (S up to >300). Key to the success of this process is the favorable secondary interactions of the catalyst with the Lewis basic groups on the sulfone substrate. The enone product of this process can be easily converted into the racemic starting material, and allows an effective recycling and overall synthesis of chiral beta-sulfonyl ketones in high yield and excellent enantioselectivity. PMID- 26577252 TI - Rough surface Au@Ag core-shell nanoparticles to fabricating high sensitivity SERS immunochromatographic sensors. AB - Immunochromatographic sensors (ICSs) are inexpensive, simple, portable, and robust, thus making ICSs commonplace in clinical diagnoses, food testing, and environmental monitoring. However, commonly used gold nanoparticles (AuNPs) ICSs have low sensitivity. Therefore, we developed highly sensitive surface enhanced Raman scattering (SERS) ICSs. To enhance the sensitivity of SERS ICSs, rough surface core-shell Au@Ag nanoparticles (RSAu@AgNPs) were prepared by coating silver on the surface of gold nanoflowers (AuNFs). Then these nanoparticles were used as SERS substrate in the SERS ICSs, after which the SERS ICSs were implemented to detect haemoglobin and heavy metal cadmium ion (Cd(2+)). The limit of detection (LOD) of the SERS ICSs for detecting haemoglobin was 8 ng/mL, and the linear range of the SERS ICSs was from 31.3 to 2000 ng/mL. The LOD of the SERS ICSs for detecting Cd(2+) was 0.05 ng/mL and the linear analysis range was from 0.05 to 25 ng/mL. The cross reactivity of the SERS ICSs was studied and results showed that the SERS ICSs exhibited highly specific for detection of haemoglobin and Cd(2+), respectively. The SERS ICSs were then used to detect haemoglobin (spiked in serum and in stool) and Cd(2+) (spiked in tap water, river water, and soil leaching water), and the results showed high recovery. These characteristics indicated that SERS ICSs were ideal tools for clinical diagnosis and environmental pollution monitoring. PMID- 26577253 TI - Atlas-Based Automatic Generation of Subject-Specific Finite Element Tongue Meshes. AB - Generation of subject-specific 3D finite element (FE) models requires the processing of numerous medical images in order to precisely extract geometrical information about subject-specific anatomy. This processing remains extremely challenging. To overcome this difficulty, we present an automatic atlas-based method that generates subject-specific FE meshes via a 3D registration guided by Magnetic Resonance images. The method extracts a 3D transformation by registering the atlas' volume image to the subject's one, and establishes a one-to-one correspondence between the two volumes. The 3D transformation field deforms the atlas' mesh to generate the subject-specific FE mesh. To preserve the quality of the subject-specific mesh, a diffeomorphic non-rigid registration based on B spline free-form deformations is used, which guarantees a non-folding and one-to one transformation. Two evaluations of the method are provided. First, a publicly available CT-database is used to assess the capability to accurately capture the complexity of each subject-specific Lung's geometry. Second, FE tongue meshes are generated for two healthy volunteers and two patients suffering from tongue cancer using MR images. It is shown that the method generates an appropriate representation of the subject-specific geometry while preserving the quality of the FE meshes for subsequent FE analysis. To demonstrate the importance of our method in a clinical context, a subject-specific mesh is used to simulate tongue's biomechanical response to the activation of an important tongue muscle, before and after cancer surgery. PMID- 26577254 TI - Symmetric Biomechanically Guided Prone-to-Supine Breast Image Registration. AB - Prone-to-supine breast image registration has potential application in the fields of surgical and radiotherapy planning, image guided interventions, and multi modal cancer diagnosis, staging, and therapy response prediction. However, breast image registration of three dimensional images acquired in different patient positions is a challenging problem, due to large deformations induced to the soft breast tissue caused by the change in gravity loading. We present a symmetric, biomechanical simulation based registration framework which aligns the images in a central, virtually unloaded configuration. The breast tissue is modelled as a neo-Hookean material and gravity is considered as the main source of deformation in the original images. In addition to gravity, our framework successively applies image derived forces directly into the unloading simulation in place of a subsequent image registration step. This results in a biomechanically constrained deformation. Using a finite difference scheme avoids an explicit meshing step and enables simulations to be performed directly in the image space. The explicit time integration scheme allows the motion at the interface between chest and breast to be constrained along the chest wall. The feasibility and accuracy of the approach presented here was assessed by measuring the target registration error (TRE) using a numerical phantom with known ground truth deformations, nine clinical prone MRI and supine CT image pairs, one clinical prone-supine CT image pair and four prone-supine MRI image pairs. The registration reduced the mean TRE for the numerical phantom experiment from initially 19.3 to 0.9 mm and the combined mean TRE for all fourteen clinical data sets from 69.7 to 5.6 mm. PMID- 26577255 TI - Development of a High-Throughput Ultrasound Technique for the Analysis of Tissue Engineering Constructs. AB - Development of hydrogel-based tissue engineering constructs is growing at a rapid rate, yet translation to patient use has been sluggish. Years of costly preclinical tests are required to predict clinical performance and safety of these devices. The tests are invasive, destructive to the samples and, in many cases, are not representative of the ultimate in vivo scenario. Biomedical imaging has the potential to facilitate biomaterial development by enabling longitudinal noninvasive device characterization directly in situ. Among the various available imaging modalities, ultrasound stands out as an excellent candidate due to low cost, wide availability, and a favorable safety profile. The overall goal of this work was to demonstrate the utility of clinical ultrasound in longitudinal characterization of 3D hydrogel matrices supporting cell growth. Specifically, we developed a quantitative technique using clinical B-mode ultrasound to differentiate collagen content and fibroblast density within poly(ethylene glycol) (PEG) hydrogels and validated it in an in vitro phantom environment. By manipulating the hydrogel gelation, differences in ultrasound signal intensity were found between gels with collagen fibers and those with non fiber forming collagen, indicating that the technique was sensitive to the configuration of the protein. At a collagen density of 2.5 mg/mL collagen, fiber forming collagen had a significantly increased signal intensity of 14.90 +/- 2.58 * 10(-5) a.u. compared to non-fiber forming intensity at 2.74 +/- 0.36 * 10(-5) a.u. Additionally, differences in intensity were found between living and fixed fibroblasts, with an increased signal intensity detected in living cells (5.00 +/ 0.80 * 10(-5) a.u. in 1 day live cells compared to 2.26 +/- 0.39 * 10(-5) a.u.in fixed cells at a concentration of 1 * 10(6) cells/mL in gels containing collagen). Overall, there was a linear correlation >0.90 for ultrasound intensity with increasing cell density. Results demonstrate the feasibility of using clinical ultrasound for characterization of PEG-based hydrogels in a tissue mimicking phantom. The approach is clinically-relevant and could, with further validation, be utilized to nondestructively monitor in vivo performance of implanted tissue engineering scaffolds over time in preclinical and clinical settings. PMID- 26577256 TI - Effect of Dynamic Culture and Periodic Compression on Human Mesenchymal Stem Cell Proliferation and Chondrogenesis. AB - We have recently developed a bioreactor that can apply both shear and compressive forces to engineered tissues in dynamic culture. In our system, alginate hydrogel beads with encapsulated human mesenchymal stem cells (hMSCs) were cultured under different dynamic conditions while subjected to periodic, compressive force. A customized pressure sensor was developed to track the pressure fluctuations when shear forces and compressive forces were applied. Compared to static culture, dynamic culture can maintain a higher cell population throughout the study. With the application of only shear stress, qRT-PCR and immunohistochemistry revealed that hMSCs experienced less chondrogenic differentiation than the static group. The second study showed that chondrogenic differentiation was enhanced by additional mechanical compression. After 14 days, alcian blue staining showed more extracellular matrix formed in the compression group. The upregulation of the positive chondrogenic markers such as Sox 9, aggrecan, and type II collagen were demonstrated by qPCR. Our bioreactor provides a novel approach to apply mechanical forces to engineered cartilage. Results suggest that a combination of dynamic culture with proper mechanical stimulation may promote efficient progenitor cell expansion in vitro, thereby allowing the culture of clinically relevant articular chondrocytes for the treatment of articular cartilage defects. PMID- 26577257 TI - Fibrin clot structure in patients with congenital dysfibrinogenaemia. AB - The clinical phenotype of patients with congenital dysfibrinogenaemia is highly heterogeneous, from absence of symptoms to mild bleeding, or thrombosis. A few mutations are associated with a specific phenotype, but generally the clinical course is not predictable. We investigated whether fibrin clot properties are correlated with the patient's phenotype and/or genotype. Ex vivo plasma fibrin clot characteristics, including turbidity, fibrinolysis, clot permeability and fibrin fibre density assessed by laser scanner confocal microscopy were investigated in 24 genotyped patients with congenital dysfibrinogenaemia compared to normal pool plasma. Compared to normal pool plasma, the patients were characterised by slower fibrin polymerisation (lag time, 345.10 +/- 22.98 vs. 166.00s), thinner fibrin fibres (maximum absorbance, 0.15 +/- 0.01 vs. 0.31), prolonged clot lysis time (23.72 +/- 0.97 vs. 20.32 min) and larger clot pore size (21.5*10(-9) +/- 4.48*10(-9) vs. 7.96*10(-9)cm(2)). Laser scanning confocal microscopy images confirmed disorganised fibrin networks in all patients. Patients with tendency to bleed showed an increased permeability compared to asymptomatic patients (p=0.01) and to patients with a thrombotic history (p=0.02) while patients with thrombotic history had a tendency to have a prolonged clot lysis time. Fibrin clot properties were similar among hotspot mutations. Further studies including a larger number of patients are needed to evaluate whether analysis of permeability and clot lysis time may help to distinguish the clinical phenotype in these patients and to assess differences according to the genotype. PMID- 26577258 TI - Relationship between endothelial progenitor cells and vascular endothelial growth factor and its variation with exercise. AB - BACKGROUND: The aim of our study was to evaluate the effect of programmed physical activity and a single exercise test on the number of CD309+ circulating endothelial progenitor cell (EPC) and their relation to the variation in plasma levels of VEGF in chronic coronary patients. METHODS: 21 patients <75 years with chronic stable coronary artery disease were included. All patients underwent exercise myocardial perfusion SPECT. Then, participants were divided into two groups: one group (11 patients) underwent cardiac rehabilitation program and the other (10 patients) continued with the standard treatment. Blood samples were obtained at baseline, 30 min after exercise ended and at one and three months during follow-up. RESULTS: VEGF values decreased significantly after exercise SPECT test. After one month, there was a significant increase in VEGF levels compared to those measured immediately after exercise. All patients showed a decrease in the values of EPC at 1 and 3-month follow-up. There was an inverse and statistically significant relation between change of EPC and VEGF between the baseline and 1 month. CONCLUSIONS: The increase of VEGF at 1-month, with respect to baseline values correlated with decreased levels of EPC. This association was independent of the onset of ischemia in the perfusion study. PMID- 26577259 TI - Autism Characteristics in Older Adults with Depressive Disorders. AB - OBJECTIVE: To study the prevalence of autism spectrum disorder (ASD) characteristics in older adults with and without depressive disorders and the social network and past negative life events in those with a high number of ASD characteristics and those without a large number of these characteristics. METHODS: This large, multisite, naturalistic, prospective cohort study used data from the Netherlands Study of Depression in Older persons (aged 60-90 years) with (N = 259) and without (N = 114) a depressive disorder according to DSM-IV criteria. ASD characteristics were measured with the abbreviated Autism Spectrum Quotient with a cutoff score of 70. Additional measures were the Composite International Diagnostic Interview, the Inventory of Depressive Symptomatology, the Becks Anxiety Inventory, the Close Person Inventory, and the life events questionnaire. RESULTS: Of the older adults with a depressive disorder, 31% showed elevated ASD characteristics, which is much higher than the observed 6% in the comparison group. High ASD characteristics were associated with elevated depression and anxiety symptoms and more comorbid anxiety disorders. Those with a high number of ASD characteristics did not differ in the size of their social network or the number of negative life events as compared with those with less ASD characteristics. CONCLUSION: ASD might be overlooked in older adults, especially within geriatric psychiatry. When diagnosing and treating depression and anxiety in older patients, one should be attentive to ASD. PMID- 26577260 TI - Obese persons' physical activity experiences and motivations across weight changes: a qualitative exploratory study. AB - BACKGROUND: Obese individuals are encouraged to participate in physical activity. However, few qualitative studies have explored obese individuals' motivations for and experiences with physical activity. METHODS: The physical activity experiences of self-identified obese or formerly obese persons (n = 15) were explored through in-depth, semi-structured, audio-taped, repeated interviews and ethnography over one year. Participant observation occurred at multiple sites identified by participants as meaningful to them as obese persons. Data from interview transcripts and fieldnotes were analyzed via thematic content analysis. RESULTS: Underlying goals for engaging in physical activity were diverse. Emergent motivation themes included: protection, pressure, and pleasure. Participants were protective of maintaining functional capacity, establishing fit identities, and achieving weight loss. Participants also discussed feelings of excessive pressure to continue progressing toward weight and fitness goals. Enjoyment in physical activity was often a by-product for all participants and could become a sought-after endpoint. Finding an environment in which participants felt safe, accepted, and encouraged to be active was extremely important for continual engagement. CONCLUSIONS: Obese individuals enjoyed physical activity and were concerned about maintaining functional fitness. Stigmatization and untenable goals and monitoring could disrupt physical activity. PMID- 26577261 TI - Predictors of Long-Term Healthy Arterial Aging: Coronary Artery Calcium Nondevelopment in the MESA Study. AB - OBJECTIVES: This study sought to determine the predictors of healthy arterial aging. BACKGROUND: Long-term nondevelopment of coronary artery calcification (persistent CAC = 0) is a marker of healthy arterial aging. The predictors of this phenotype are not known. METHODS: We analyzed 1,850 participants from MESA (Multi-Ethnic Study of Atherosclerosis) with baseline CAC = 0 who underwent a follow-up CAC scan at visit 5 (median 9.6 years after baseline). We examined the proportion with persistent CAC = 0 and calculated multivariable relative risks and area under the receiver operating characteristic curve for prediction of this healthy arterial aging phenotype. RESULTS: We found that 55% of participants (n = 1,000) had persistent CAC = 0, and these individuals were significantly more likely to be younger, female, and have fewer traditional risk factors (RF). Participants with an ASCVD (Atherosclerotic Cardiovascular Disease Risk Score) risk score <2.5% were 53% more likely to have healthy arterial aging than were participants with an ASCVD score >=7.5%. There was no significant association between the Healthy Lifestyle variables (body mass index, physical activity, Mediterranean diet, and never smoking) and persistent CAC = 0. The area under the receiver operating characteristic curve incorporating age, sex, and ethnicity was 0.65, indicating fair to poor discrimination. No single traditional RF or combination of other risk factors increased the area under the receiver operating characteristic curve by more than 0.05. CONCLUSIONS: Whereas participants free of traditional cardiovascular disease RF were significantly more likely to have persistent CAC = 0, there was no single RF or specific low-risk RF phenotype that markedly improved the discrimination of persistent CAC = 0 over demographic variables. Therefore, we conclude that healthy arterial aging may be predominantly influenced by the long-term maintenance of a low cardiovascular disease risk profile or yet to be determined genetic factors rather than the absence of any specific RF cluster identified in late adulthood. PMID- 26577262 TI - Molecular Imaging of the Chemokine Receptor CXCR4 After Acute Myocardial Infarction. AB - OBJECTIVES: An assay for molecular imaging of myocardial CXCR4 expression was evaluated, in order to obtain mechanistic insights noninvasively based on quantitative positron emission tomography (PET). BACKGROUND: The chemokine receptor CXCR4 has emerged as a therapeutic target after acute myocardial infarction (AMI), because of its role in inflammatory and progenitor cell recruitment. METHODS: PET with the specific CXCR4 ligand, gallium-68 ((68)Ga) pentixafor, was performed in mice (n = 53) and compared with ex vivo autoradiography, immunohistochemistry, and left ventricular flow cytometry. In addition, 12 patients were imaged at 2 to 8 days after AMI. RESULTS: In mice, (68)Ga-pentixafor identified regional CXCR4 upregulation in the infarct region, peaking at 3 days (infarct/remote [I/R] ratio 1.5 +/- 0.2 at 3 days vs. 1.2 +/- 0.3 at 7 days; p = 0.03), corresponding to a flow cytometry-based peak of CD45+ leukocytes and immunohistochemical detection of CD68+ macrophages and Ly6G+ granulocytes. Blockade with the CXCR4 antagonist AMD3100 abolished the signal. No specific uptake was found in sham-operated or control animals. Long-term treatment with oral enalapril attenuated the CXCR4 signal (I/R 1.2 +/- 0.2 at 3 days and 1.0 +/- 0.0.1 at 7 days; p = 0.01 vs. untreated). Patients showed variable degrees of CXCR4 upregulation in the infarct region. No single clinical parameter allowed for prediction of CXCR4 signal strength. At multivariate analysis, a combination of infarct size and time after reperfusion predicted the CXCR4 infarct signal (rmultiple = 0.73; p = 0.03). Infarct signal in the myocardium was paralleled by elevated pentixafor uptake in bone marrow (r = 0.61; p = 0.04), which highlighted systemic interactions. CONCLUSIONS: Targeted PET imaging with (68)Ga-pentixafor identifies the global and regional CXCR4 expression pattern in myocardium and systemic organs. CXCR4 upregulation after AMI coincides with inflammatory cell infiltration, but shows interindividual variability in patients. This may have implications for the response to CXCR4- or other inflammation-targeted therapy, and for subsequent ventricular remodeling. PMID- 26577263 TI - Long-Term Clinical Impact of Coronary CT Angiography in Patients With Recent Acute-Onset Chest Pain: The Randomized Controlled CATCH Trial. AB - OBJECTIVES: The aim of the CATCH (CArdiac cT in the treatment of acute CHest pain) trial was to investigate the long-term clinical impact of a coronary computed tomographic angiography (CTA)-guided treatment strategy in patients with recent acute-onset chest pain compared to standard care. BACKGROUND: The prognostic implications of a coronary CTA-guided treatment strategy have not been compared in a randomized fashion to standard care in patients referred for acute onset chest pain. METHODS: Patients with acute chest pain but normal electrocardiograms and troponin values were randomized to treatment guided by either coronary CTA or standard care (bicycle exercise electrocardiogram or myocardial perfusion imaging). In the coronary CTA-guided group, a functional test was included in cases of nondiagnostic coronary CTA images or coronary stenoses of borderline severity. The primary endpoint was a composite of cardiac death, myocardial infarction (MI), hospitalization for unstable angina pectoris (UAP), late symptom-driven revascularizations, and readmission for chest pain. RESULTS: We randomized 299 patients to coronary CTA-guided strategy and 301 to standard care. After inclusion, 24 patients withdrew their consent. The median (interquartile range) follow-up duration was 18.7 (range 16.8 to 20.1) months. In the coronary CTA-guided group, 30 patients (11%) had a primary endpoint versus 47 patients (16%) in the standard care group (p = 0.04; hazard ratio [HR]: 0.62 [95% confidence interval: 0.40 to 0.98]). A major adverse cardiac event (cardiac death, MI, hospitalization for UAP, and late symptom-driven revascularization) was observed in 5 patients (2 MIs, 3 UAPs) in the coronary CTA-guided group versus 14 patients (1 cardiac death, 7 MIs, 5 UAPs, 1 late symptom-driven revascularization) in the standard care group (p = 0.04; HR: 0.36 [95% CI: 0.16 to 0.95]). Differences in cardiac death and MI (8 vs. 2) were insignificant (p = 0.06). CONCLUSIONS: A coronary CTA-guided treatment strategy appears to improve clinical outcome in patients with recent acute-onset chest pain and normal electrocardiograms and troponin values compared to standard care with a functional test. (Cardiac-CT in the Treatment of Acute Chest Pain [CATCH]; NCT01534000). PMID- 26577264 TI - Global Longitudinal Strain Is a Superior Predictor of All-Cause Mortality in Heart Failure With Reduced Ejection Fraction. AB - OBJECTIVES: The purpose of this study was to investigate the prognostic value of global longitudinal strain (GLS) in heart failure with reduced ejection fraction (HFrEF) patients in relation to all-cause mortality. BACKGROUND: Measurement of myocardial deformation by 2-dimensional speckle tracking echocardiography, specifically GLS, may be superior to conventional echocardiographic parameters, including left ventricular ejection fraction, in predicting all-cause mortality in HFrEF patients. METHODS: Transthoracic echocardiographic examinations were retrieved for 1,065 HFrEF patients admitted to a heart failure clinic. The echocardiographic images were analyzed, and conventional and novel echocardiographic parameters were obtained. RESULTS: Many of the conventional echocardiographic parameters proved to be predictors of mortality. However, GLS remained an independent predictor of mortality in the multivariable model after adjusting for age, sex, body mass index, total cholesterol, mean arterial pressure, heart rate, ischemic cardiomyopathy, percutaneous transluminal coronary angioplasty, coronary artery bypass graft surgery, noninsulin dependent diabetes mellitus, and conventional echocardiographic parameters (hazard ratio [HR]: 1.15; 95% confidence interval [CI]: 1.04 to 1.27; p = 0.008, per 1% decrease). No other echocardiographic parameter remained an independent predictor after adjusting for these variables. Furthermore, GLS had the highest C-statistics of all the echocardiographic parameters and added incremental prognostic value with a significant increase in the net reclassification improvement (p = 0.009). Atrial fibrillation (AF) modified the relationship between GLS and mortality (p value for interaction = 0.036); HR: 1.08 (95% CI: 0.97 to 1.19), p = 0.150 and HR: 1.22 (95% CI: 1.15 to 1.29), p < 0.001, per 1% decrease in GLS for patients with and without AF, respectively. Sex also modified the relationship between GLS and mortality (p value for interaction = 0.047); HR: 1.23 (95% CI: 1.16 to 1.30), p < 0.001 and HR: 1.09 (95% CI: 0.99 to 1.20), p = 0.083, per 1% decrease in GLS for men and women, respectively. CONCLUSIONS: GLS is an independent predictor of all cause mortality in HFrEF patients, especially in male patients without AF. Furthermore, GLS was a superior prognosticator compared with all other echocardiographic parameters. PMID- 26577265 TI - Predicting Depression among Patients with Diabetes Using Longitudinal Data. A Multilevel Regression Model. AB - INTRODUCTION: This article is part of the Focus Theme of Methods of Information in Medicine on "Big Data and Analytics in Healthcare". BACKGROUND: Depression is a common and often undiagnosed condition for patients with diabetes. It is also a condition that significantly impacts healthcare outcomes, use, and cost as well as elevating suicide risk. Therefore, a model to predict depression among diabetes patients is a promising and valuable tool for providers to proactively assess depressive symptoms and identify those with depression. OBJECTIVES: This study seeks to develop a generalized multilevel regression model, using a longitudinal data set from a recent large-scale clinical trial, to predict depression severity and presence of major depression among patients with diabetes. METHODS: Severity of depression was measured by the Patient Health Questionnaire PHQ-9 score. Predictors were selected from 29 candidate factors to develop a 2-level Poisson regression model that can make population-average predictions for all patients and subject-specific predictions for individual patients with historical records. Newly obtained patient records can be incorporated with historical records to update the prediction model. Root-mean square errors (RMSE) were used to evaluate predictive accuracy of PHQ-9 scores. The study also evaluated the classification ability of using the predicted PHQ-9 scores to classify patients as having major depression. RESULTS: Two time invariant and 10 time-varying predictors were selected for the model. Incorporating historical records and using them to update the model may improve both predictive accuracy of PHQ-9 scores and classification ability of the predicted scores. Subject-specific predictions (for individual patients with historical records) achieved RMSE about 4 and areas under the receiver operating characteristic (ROC) curve about 0.9 and are better than population-average predictions. CONCLUSIONS: The study developed a generalized multilevel regression model to predict depression and demonstrated that using generalized multilevel regression based on longitudinal patient records can achieve high predictive ability. PMID- 26577266 TI - The sunflower cataract in Wilson's disease: pathognomonic sign or rare finding? AB - The presence of Kayser-Fleischer ring in patients with Wilson's disease (WD) is well documented and included in diagnostic algorithms; however, data about the occurrence of the second postulated ophthalmological sign of WD, sunflower cataract (SC), are limited and even conflicting. The aim of our study was to verify the occurrence of SC in WD. From January 2010 to May 2015, 81 consecutive, newly diagnosed WD patients underwent detailed ophthalmological examinations, including slit lamp examination with special attention to lens transparency, to verify the presence of SC in WD-naive patients. SC was detected in only one (1.2 %) of the examined WD patients, did not impact visual acuity; moreover, completely disappeared following a year of treatment for WD. SC may be a very rare and reversible ophthalmological manifestation of WD that is observed seldom and only at the time of WD diagnosis. We postulate that a finding of SC in WD patients is an interesting finding that may occur in the course of WD, but it is not a pathognomonic sign of WD. PMID- 26577267 TI - Immunoendocrine alterations following Marine Corps Martial Arts training are associated with changes in moral cognitive processes. AB - Combined physical and psychological stress events have been associated with exacerbated endocrine responses and increased alterations in immune cell trafficking when compared to exercise stress alone. Military training programs are rigorous in nature and often purposefully delivered in environments combining high levels of both physical and mental stress. The objective of this study was to assess physiological and cognitive changes following U.S. Marine Corps Martial Arts training. Seven active-duty, male Marines were observed during a typical Marine Corps Martial Arts training session. Immune parameters, including immunomodulatory cytokines, and hormone concentrations were determined from blood samples obtained at baseline, immediately post training (IP) and at 15min intervals post-training to 1h (R15, R30, R45, R60). Assessments of cognitive moral functioning (moral judgment and intent) were recorded at intervals during recovery. There were significant fluctuations in immunoendocrine parameters. Peak endocrine measures were observed within the IP-R15 time interval. Distributions of circulating immune cells were significantly altered with neutrophils and all lymphocyte subsets elevated at IP. IFN-gamma and IL-17a exhibited small, non significant, parallel increases over the recovery period. Moral functioning was informed by different social identities during the recovery resulting in changes in moral decision-making. These data demonstrate that the Marine Corps Martial Arts Program induces significant alterations in lymphocyte and leukocyte distributions, but does not shift the balance of Th1/Th2 cytokines or induce a systemic inflammatory response. The program does, however, induce alterations in moral decision-making ability associated with the observed endocrine responses, even suggesting a potential interaction between one's social identities and endocrine responses upon moral decision-making. PMID- 26577268 TI - Treatment of IgA nephropathy. AB - The therapy of IgA nephropathy (IgAN) is cause for debate among nephrologists. Since the early 1980s, many therapeutic attempts have been proposed, but most of them did not prove efficacy. The recent KDIGO Clinical Practice Guideline for Glomerulonephritis recommend long-term ACE-I or ARB treatment when proteinuria is more than 1 g/day, with up-titration of the drug. For patients with GFR >50 ml/min and proteinuria persistently higher than 1 g/day, they suggest a 6-month course of corticosteroid therapy. Based on our experience and the results of the literature, we propose a progressive treatment, which takes into account the time the IgAN is recognized and the clinical conditions present at that time. The treatment can be summarize as follows: (1) in patients with macro-microscopic haematuria, in case with proteinuria less than 0.3 g/day, only annual controls; (2) in patients with proteinuria between 0.3 and 0.9 g/day, ACE-I and/or ARB, with titration of the drugs; (3) in patients with proteinuria higher than 1 g/day, in case with the presence of arterial hypertension and GFR up to 30 ml/min, 6 months course of corticosteroids, in addition to ACE-I and/or ARB; (4) in patients with GFR less than 30 ml/min, ACE-I/ARB, dialysis and kidney transplantation; corticosteroids should be in case considered for patients with persistently high or increasing proteinuria; (5) the immunosuppressants (cyclophosphamide and azathioprine) should be reserved for patients with progressive renal insufficiency or with vasculitic lesions on renal biopsy. PMID- 26577269 TI - Radiation hazards in pregnancy and methods of prevention. AB - The incidence of malignancy in pregnancy is low and most commonly occurs in breast, gynaecological, skin and haematological sites. The management of pregnant cancer patients is complex requiring a multidisciplinary approach to ensure the welfare of both mother and baby. Foetal radiation exposure, both diagnostic and therapeutic, must be kept to a minimum. Following the description of the deterministic and stochastic effects of foetal radiation exposure doses, radiotherapy should be avoided in the first and early second trimester. This chapter describes the possible diagnostic techniques and treatment for the common malignancies in pregnancy; some case studies indicating supradiaphragmatic radiotherapy may be safe later in pregnancy. Pelvic radiotherapy for gynaecological malignancies is not appropriate. PMID- 26577270 TI - Design, Synthesis, and Biological Evaluation of 1-Benzyl-1H-pyrazole Derivatives as Receptor Interacting Protein 1 Kinase Inhibitors. AB - Receptor interacting protein 1 (RIP1) kinase plays an important role in necroptosis, and inhibitors of the RIP1 kinase are thought to have a potential therapeutic value in the treatment of diseases related to necrosis. Herein, we report the structural optimization of a RIP1 kinase inhibitor, 1-(2,4 dichlorobenzyl)-3-nitro-1H-pyrazole (1a). A number of 1-benzyl-1H-pyrazole derivatives were synthesized and structure-activity relationship (SAR) analysis led to the discovery of a potent compound, 4b, which showed a Kd value of 0.078 MUm against the RIP1 kinase and an EC50 value of 0.160 MUm in a cell necroptosis inhibitory assay. Compound 4b also displayed considerable ability to protect the pancreas in an l-arginine-induced pancreatitis mouse model. PMID- 26577271 TI - Iron laden--A matter of life and death. PMID- 26577272 TI - Decreased Number of Mitochondria in Leukoaraiosis. AB - BACKGROUND AND AIMS: Leukoaraiosis (LA), one of the most frequent causes of an age-associated cognitive decline, can be associated with a poor quality of life, leading overall to far-reaching public health problems. Chronic hypoxia of the white matter of the brain may be a factor triggering this entity. LA may develop as a consequence of chronically insufficient cellular energy production and the accumulation of free radicals. METHODS: In this context, after hypothesizing that the number of healthy mitochondria can be crucial in this complex process, a case control LA study was carried out in which we analyzed the numbers of deleted and non-deleted mitochondria (the common D-loop deletion) per white blood cell. A total of 234 patients with LA and 123 MRI alteration-free subjects served as a control group. RESULTS: Interestingly, it emerged that the ratio of deleted relative to non-deleted mitochondria is strongly associated with the risk of LA. The calculated K ratio in the LA group was significantly lower than the K ratio in the controls (LA: K 0.37 95% CI 0.05; controls: K 0.48, 95% CI 0.076, p < 0.001). CONCLUSIONS: Our study suggests that the ratio of the dmDNA and mDNA can be of great importance in the pathogenesis of LA. PMID- 26577273 TI - Gram-positive bacterial cell envelopes: The impact on the activity of antimicrobial peptides. AB - A number of cationic antimicrobial peptides, effectors of innate immunity, are supposed to act at the cytoplasmic membrane leading to permeabilization and eventually membrane disruption. Thereby, interaction of antimicrobial peptides with anionic membrane phospholipids is considered to be a key factor in killing of bacteria. Recently, evidence was provided that killing takes place only when bacterial cell membranes are completely saturated with peptides. This adds to an ongoing debate, which role cell wall components such as peptidoglycan, lipoteichoic acid and lipopolysaccharide may play in the killing event, i.e. if they rather entrap or facilitate antimicrobial peptides access to the cytoplasmic membrane. Therefore, in this review we focused on the impact of Gram-positive cell wall components for the mode of action and activity of antimicrobial peptides as well as in innate immunity. This led us to conclude that interaction of antimicrobial peptides with peptidoglycan may not contribute to a reduction of their antimicrobial activity, whereas interaction with anionic lipoteichoic acids may reduce the local concentration of antimicrobial peptides on the cytoplasmic membrane necessary for sufficient destabilization of the membranes and bacterial killing. Further affinity studies of antimicrobial peptides toward the different cell wall as well as membrane components will be needed to address this problem on a quantitative level. This article is part of a Special Issue entitled: Antimicrobial peptides edited by Karl Lohner and Kai Hilpert. PMID- 26577274 TI - Assemblies of pore-forming toxins visualized by atomic force microscopy. AB - A number of pore-forming toxins (PFTs) can assemble on lipid membranes through their specific interactions with lipids. The oligomeric assemblies of some PFTs have been successfully revealed either by electron microscopy (EM) and/or atomic force microscopy (AFM). Unlike EM, AFM imaging can be performed under physiological conditions, enabling the real-time visualization of PFT assembly and the transition from the prepore state, in which the toxin does not span the membrane, to the pore state. In addition to characterizing PFT oligomers, AFM has also been used to examine toxin-induced alterations in membrane organization. In this review, we summarize the contributions of AFM to the understanding of both PFT assembly and PFT-induced membrane reorganization. This article is part of a Special Issue entitled: Pore-Forming Toxins edited by Mauro Dalla Serra and Franco Gambale. PMID- 26577275 TI - [Evaluation of the theatre play Have Courage! A powerful play about feelings, boundaries and trust in the frame of the national campaign for the prevention of child sexual abuse]. AB - This article reports on the evaluation of the effectiveness of a school-based preventive theatre play. The play is part of a national campaign for the prevention of child sexual abuse called Trau dich! (Have courage!). A total of 639 students in third to sixth grade from Schleswig-Holstein and Saxony participated in the study. Scenarios in the play imparted prevention messages and self-protective skills regarding situations of sexual assault or abuse, targeting children aged 8 to 12. Acquisition of knowledge about access to help systems and children's rights were measured pre- and post viewing as well as at a follow-up point two to six months later. Children estimated their competences regarding sensibility, sensing/setting boundaries, social support/to entrust oneself to somebody and knowledge. Based on cognitive empathy, children suggested self protective skills for situations of conflict. The theatre play contributed to the acquisition of knowledge and an increase of children's self-assessed knowledge and competences. They estimated their competences of distinguishing between good and bad secrets, safe and unsafe touching, and disclosing oneself to somebody; their suggestions for self-protective skills improved compared to baseline data. The effects were still present at follow-up. Girls estimated their competences and self-protective skills to have improved more than boys. Measured negative effects were only temporary. The results indicate that the interactive educative theatre play contributed effectively to the prevention of child sexual abuse through imparting knowledge, self-protective skills, and sensitization. PMID- 26577276 TI - The evaluation of risk factors for recurrent hospitalizations resulting from wheezing attacks in preschool children. AB - BACKGROUND: We aimed to evaluate the risk factors in preschool children admitted to inpatient services with a diagnosis of recurrent attacks of wheezing. METHOD: The medical files of 44 preschool children with 2 or more recurrent hospitalizations resulting from wheezing between November 2011 and January 2012 were retrospectively investigated. RESULTS: There were 28 males (64 %) and 16 females. The median age was 14 months (2.0-50). The median numbers of previous wheezing attacks and hospitalizations were 4 (2-10) and 2 (2-8), respectively. Fourteen patients (32 %) had been treated for gastroesophageal reflux (GER). The previous and recent hospital evaluations were investigated. Bronchopulmonary dysplasia and anemia were significantly more common in patients with 3 or more hospitalizations for wheezing than in those with 2 hospitalizations (p = 0.010 and p < 0.001, respectively). A review of the cases with 3 or more hospitalizations revealed that a history of GER and anemia were significant risk factors. CONCLUSION: Anemia and GER are risk factors for recurrent hospitalizations resulting from wheezing and should be treated. If the history and physical examination suggest asthma, inhaler therapy treatment should be administered, with other investigations planned for patients who do not respond to treatment as expected. PMID- 26577277 TI - Sexual minority cancer survivors' satisfaction with care. AB - Satisfaction with care is important to cancer survivors' health outcomes. Satisfaction with care is not equal for all cancer survivors, and sexual minority (i.e., lesbian, gay, and bisexual) cancer survivors may experience poor satisfaction with care. Data were drawn from the 2010 LIVESTRONG national survey. The final sample included 207 sexual minority cancer survivors and 4,899 heterosexual cancer survivors. Satisfaction with care was compared by sexual orientation, and a Poisson regression model was computed to test the associations between sexual orientation and satisfaction with care, controlling for other relevant variables. Sexual minority cancer survivors had lower satisfaction with care than did heterosexual cancer survivors (B = -0.12, SE = 0.04, Wald chi(2) = 9.25, p< .002), even controlling for demographic and clinical variables associated with care. Sexual minorities experience poorer satisfaction with care compared to heterosexual cancer survivors. Satisfaction with care is especially relevant to cancer survivorship in light of the cancer-related health disparities reported among sexual minority cancer survivors. PMID- 26577278 TI - Management of tandem internal carotid and middle cerebral arterial occlusions with endovascular multimodal reperfusion therapy. AB - The aim of this study was to evaluate the safety and efficacy of multimodal reperfusion therapy (MMRT) for tandem internal carotid artery and middle cerebral arterial (TIM) occlusions. Cases of TIM occlusion were collected and retrospectively reviewed. The analyzed objects included etiology, sites of tandem occlusion, collateral flow, location and size of infarcts. Combined with mechanical recanalization techniques and its complications, the National Institute of Health Stroke Scale (NIHSS) score and imaging data that was derived pre- and post-procedure were further contrasted. The study enrolled six patients with TIM occlusions. The mean NIHSS score on admission was 17 (range 13-20) and the median time from puncture to recanalization was 141 min (range 60-230). The substantial recanalization rate (Thrombolysis in Cerebral Infarction 2b or 3) was 83.3% and no symptomatic intracerebral hemorrhage was observed. The mean NIHSS score after three days was 14 (range 10-19) and 9 (range 3-17) following discharge. However, one patient died of pulmonary infection one month after discharge. For the five patients who survived, the modified Rankin Scale was evaluated at three months, with scores of 3, 1, 3, 5 and 3, respectively. It is concluded that endovascular therapy for acute TIM occlusions are complex, MMRT may be relatively safe and effective. PMID- 26577279 TI - MiR-21 is required for efficient kidney regeneration in fish. AB - BACKGROUND: Acute kidney injury in mammals, which is caused by cardiovascular diseases or the administration of antibiotics with nephrotoxic side-effects is a life-threatening disease, since loss of nephrons is irreversible in mammals. In contrast, fish are able to generate new nephrons even in adulthood and thus provide a good model to study renal tubular regeneration. RESULTS: Here, we investigated the early response after gentamicin-induced renal injury, using the short-lived killifish Nothobranchius furzeri. A set of microRNAs was differentially expressed after renal damage, among them miR-21, which was up regulated. A locked nucleic acid-modified antimiR-21 efficiently knocked down miR 21 activity and caused a lag in the proliferative response, enhanced apoptosis and an overall delay in regeneration. Transcriptome profiling identified apoptosis as a process that was significantly affected upon antimiR-21 administration. Together with functional data this suggests that miR-21 acts as a pro-proliferative and anti-apoptotic factor in the context of kidney regeneration in fish. Possible downstream candidate genes that mediate its effect on proliferation and apoptosis include igfbp3 and fosl1, among other genes. CONCLUSION: In summary, our findings extend the role of miR-21 in the kidney. For the first time we show its functional involvement in regeneration indicating that fast proliferation and reduced apoptosis are important for efficient renal tubular regeneration. PMID- 26577280 TI - Monostotic fibrous dysplasia of the thoracic spine: A case report. AB - BACKGROUND AND OBJECTIVE: Fibrous dysplasia (FD) is a benign bone lesion manifested by local pain, swelling and deformity change. We report a case of monostotic fibrous dysplasia of the first thoracic vertebrae that treated by radical removal and reconstruction. CASE REPORT: A 29-year-old man with monostotic fibrous dysplasia of the first thoracic vertebrae was admitted to our department because of persistent, dull back pain for 3 months. Radical removal of the first thoracic vertebrae and reconstruction were performed in a combined posterior-anterior approach. This patient experienced complete pain relief without any complication. CONCLUSION: This report presents a rare case of monostotic fibrous dysplasia of the first thoracic vertebrae, with symptoms of chronic back pain that was successfully treated with radical excision and reconstruction, providing a good option to the patient. PMID- 26577281 TI - The influence of an external breast prosthesis on the posture of women after mastectomy. AB - BACKGROUND: Previous literatures showed no evidence that wearing an external breast prosthesis may prevent changes in body posture in women who underwent mastectomy. OBJECTIVE: To determine whether the weight of an external breast prosthesis can contribute to posture changes in women post mastectomy. METHODS: Fifty-one women with unilateral mastectomy (age 58 +/- 11.39 years) were divided into 2 subgroups by their operation side. Asymmetry of body posture was evaluated by using the electromyography activity of erector spinae muscles with four different weights of breast prosthesis. RESULTS: Despite the operation side, the erector spinae muscle activities on the operation side and non-operation side were significantly different. Overall, for patients who had operation on the left side, their erector spinae muscle activity imbalance will be smaller, compared to the imbalance among patients with right operation side. The weight of the external breast prosthesis did not influence the differences of erector spinae muscle activities on the operation side and non-operation side. CONCLUSIONS: The weight of an external breast prosthesis for women after mastectomy may not be crucial when choosing a proper prosthesis. PMID- 26577282 TI - Work-related musculoskeletal disorders among physical therapists: A systematic review. AB - Physical therapists (PTs) perform demanding tasks that can lead to work-related musculoskeletal disorders (WMSD), but the rates and characteristics of WMSD among PTs are not well known. The objective of this systematic review of the literature was to integrate the information published on the prevalence, types, and risks for WMSD among PTs. Four databases were searched using combinations and synonyms for WMSD, discomfort, symptoms, and PTs. Two reviewers independently searched and screened peer-reviewed articles published in English evaluating WMSD in PTs; agreement between reviewers was evaluated. From 867 unduplicated articles, 32 were eligible and included. Up to 90% of PTs have WMSD during their careers; 50% experience WMSD within 5 years of practice. Low back was the body part most commonly affected. Female PTs and PTs working in hospitals have higher prevalence of WMSD. WMSD are associated with PTs' age, gender, specialty and job tasks. Performing manual therapy, lifting and transferring patients are tasks commonly associated with PTs' developing WMSD. The body parts affected differed by specialty and tasks. The findings presented in this review are useful to inform future research, quality improvement, and educational programs to reduce the rates of WMSD among PTs. PMID- 26577283 TI - Tropheryma whipplei bivalvular endocarditis and polyarthralgia: a case report. AB - INTRODUCTION: Tropheryma whipplei infection should be considered in patients with suspected infective endocarditis with negative blood cultures. The case (i) shows how previous symptoms can contribute to the diagnosis of this illness, and (ii) elucidates current recommended diagnostic and therapeutic approaches to Whipple's disease. CASE PRESENTATION: A 71-year-old Swiss man with a past history of 2 years of diffuse arthralgia was admitted for a possible endocarditis with severe aortic and mitral regurgitation. Serial blood cultures were negative. Our patient underwent replacement of his aortic and mitral valve by biological prostheses. T. whipplei was documented by polymerase chain reactions on both removed valves and on stools, as well as by valve histology. A combination of hydroxychloroquine and doxycycline was initiated as lifetime treatment followed by the complete disappearance of his arthralgia. CONCLUSIONS: This case report underlines the importance of considering T. whipplei as a possible causal etiology of blood culture-negative endocarditis. Lifelong antibiotic treatment should be considered for this pathogen (i) due to the significant rate of relapses, and (ii) to the risk of reinfection with another strain since these patients likely have some genetic predisposition. PMID- 26577284 TI - Antibody-Drug Conjugates. PMID- 26577287 TI - Solid Solutions of Rare Earth Cations in Mesoporous Anatase Beads and Their Performances in Dye-Sensitized Solar Cells. AB - Solid solutions of the rare earth (RE) cations Pr(3+), Nd(3+), Sm(3+), Gd(3+), Er(3+) and Yb(3+) in anatase TiO2 have been synthesized as mesoporous beads in the concentration range 0.1-0.3% of metal atoms. The solid solutions were have been characterized by XRD, SEM, diffuse reflectance UV-Vis spectroscopy, BET and BJH surface analysis. All the solid solutions possess high specific surface areas, up to more than 100 m(2)/g. The amount of adsorbed dye in each photoanode has been determined spectrophotometrically. All the samples were tested as photoanodes in dye-sensitized solar cells (DSSCs) using N719 as dye and a nonvolatile, benzonitrile based electrolyte. All the cells were have been tested by conversion efficiency (J-V), quantum efficiency (IPCE), electrochemical impedance spectroscopy (EIS) and dark current measurements. While lighter RE cations (Pr(3+), Nd(3+)) limit the performance of DSSCs compared to pure anatase mesoporous beads, cations from Sm(3+) onwards enhance the performance of the devices. A maximum conversion efficiency of 8.7% for Er(3+) at a concentration of 0.2% has been achieved. This is a remarkable efficiency value for a DSSC employing N719 dye without co-adsorbents and a nonvolatile electrolyte. For each RE cation the maximum performances are obtained for a concentration of 0.2% metal atoms. PMID- 26577285 TI - Longitudinal changes of amygdala and default mode activation in adolescents prenatally exposed to cocaine. AB - Prenatal cocaine exposure (PCE) is associated with long-term and negative effect on arousal regulation. Recent neuroimaging studies have examined brain mechanisms related to arousal dysregulation with cross-sectional experimental designs; but longitudinal changes in the brain, reflecting group differences in neurodevelopment, have never been directly examined. To directly assess the interaction of PCE and neurodevelopment, the present study used a longitudinal design to analyze functional magnetic resonance imaging (fMRI) data collected from 33 adolescents (21 with PCE and 12 non-exposed controls) while they performed the same working memory task with emotional distracters at two points in time. The mean age of participants was 14.3 years at time_1 and 16.7 years at time_2. With confounding factors statistically controlled, the fMRI data revealed significant exposure-by-time interaction in the activations of the amygdala and default mode network (DMN). For the control adolescents, brain activations associated with emotional arousal (amygdala) and cognitive effort (DMN) were both reduced at time_2 as compared to that at time_1. However, these activation reductions were not observed in the PCE group, indicating persistently high levels of emotional arousal and cognitive effort. In addition, correlations between longitudinal changes in the brain and in behavior have shown that adolescents with persistently high emotional arousal were more likely in need of high cognitive effort; and their cognitive performance was more likely to be affected by distractive challenges. The present results complement and extend previous findings from cross-sectional studies with further evidence supporting the view of PCE associated long-term teratogenic effects on arousal regulation. PMID- 26577286 TI - Interactions between N and C termini of alpha1C subunit regulate inactivation of CaV1.2 L-type Ca(2+) channel. AB - The modulation and regulation of voltage-gated Ca(2+) channels is affected by the pore-forming segments, the cytosolic parts of the channel, and interacting intracellular proteins. In this study we demonstrate a direct physical interaction between the N terminus (NT) and C terminus (CT) of the main subunit of the L-type Ca(2+) channel CaV1.2, alpha1C, and explore the importance of this interaction for the regulation of the channel. We used biochemistry to measure the strength of the interaction and to map the location of the interaction sites, and electrophysiology to investigate the functional impact of the interaction. We show that the full-length NT (amino acids 1-154) and the proximal (close to the plasma membrane) part of the CT, pCT (amino acids 1508-1669) interact with sub micromolar to low-micromolar affinity. Calmodulin (CaM) is not essential for the binding. The results further suggest that the NT-CT interaction regulates the channel's inactivation, and that Ca(2+), presumably through binding to calmodulin (CaM), reduces the strength of NT-CT interaction. We propose a molecular mechanism in which NT and CT of the channel serve as levers whose movements regulate inactivation by promoting changes in the transmembrane core of the channel via S1 (NT) or S6 (pCT) segments of domains I and IV, accordingly, and not as a kind of pore blocker. We hypothesize that Ca(2+)-CaM-induced changes in NT-CT interaction may, in part, underlie the acceleration of CaV1.2 inactivation induced by Ca(2+) entry into the cell. PMID- 26577288 TI - India meets target to reduce tuberculosis burden. PMID- 26577289 TI - MRI may be used as a prognostic indicator in patients with extra-abdominal desmoid tumours. AB - OBJECTIVE: To determine the association of MRI features of extra-abdominal desmoid tumours (DTs) with prognosis. METHODS: MRIs for 90 patients with DT were retrospectively reviewed for imaging features associated with biological behaviour. The primary end point was progression (for lesions managed with chemotherapy, radiation therapy and observation) or recurrence (following surgery). Time to event was studied using univariate and multivariable Cox proportional hazards regression models when accounting for demographic, clinicopathological and imaging variables. Kaplan-Meier plots were used to estimate event-free rate (EFR). RESULTS: Univariate analysis revealed a significant relationship between EFR and treatment, location and compartment of origin [subcutaneous (SC), superficial fascial, intramuscular (IM) and deep fascial/intermuscular]. None of the imaging features commonly associated with biological behaviour of DTs (e.g., shape, enhancement, T2 signal etc.) or surgical margins (in surgical cases) was associated with EFR. Multivariate analysis showed that treatment modality and compartment of origin were independent predictors of EFR. Superficial and deep fascial lesions had a significantly worse EFR as a group [hazard ratio: 3.9; 95% confidence interval (CI): 1.83-8.32; p = 0.0004] than did the SC and IM lesions as a group. 5-year EFR for the fascial lesions was 18% (95% CI: 6-36%), compared with 57% (95% CI: 25-79%) for the SC and IM groups. CONCLUSION: Intramuscular or SC DTs may be associated with improved prognosis. If validated on multireader and prospective studies, these results can provide for rapid risk stratification at the time of initial MRI. ADVANCES IN KNOWLEDGE: This work has shown that imaging features commonly associated with biological activity of desmoid tumours (e.g. shape, T2 signal and enhancement) do not appear to be associated with prognosis in patients undergoing a variety of treatment modalities. The compartment of origin of the lesion, which can be determined on pre-operative MRI, was shown to be associated with prognosis and can allow for risk stratification in patients with DTs. PMID- 26577290 TI - ERK2 mediates inner hair cell survival and decreases susceptibility to noise induced hearing loss. AB - Extracellular signal-regulated kinase (ERK) is a member of the family of mitogen activated protein kinases (MAPKs) and coordinately regulates a multitude of cellular processes. In response to a variety of extracellular stimuli, phosphorylation of both threonine and tyrosine residues activates ERK. Recent evidence indicates that ERK is activated in response to cellular stress such as acoustic trauma. However, the specific role of ERK isoforms in auditory function is not fully understood. Here, we show that the isoform ERK2 plays an important role in regulating hair cell (HC) survival and noise-induced hearing loss (NIHL) in mice (C57BL/6J). We found that conditional knockout mice deficient for Erk2 in the inner ear HCs had hearing comparable to control mice and exhibited no HC loss under normal conditions. However, we found that these knockout mice were more vulnerable to noise and had blunted recovery from NIHL compared to control mice. Furthermore, we observed a significantly lower survival rate of inner hair cells in these mice compared to control mice. Our results indicate that ERK2 plays important roles in the survival of HC in NIHL. PMID- 26577292 TI - Research Review: Do motor deficits during development represent an endophenotype for schizophrenia? A meta-analysis. AB - BACKGROUND: Early detection of schizophrenia risk is a critical goal in the field. Endophenotypes in children to relatives of affected individuals may contribute to this early detection. One of the lowest cost and longest theorized domains is motor development in children. METHODS: A meta-analysis was conducted comparing individuals <=21 years old with affected first-degree relatives (FDR) with (1) individuals from unaffected families (controls), or (2) individuals with FDR having other psychiatric disorders. Studies were classified by motor outcome and separate meta-analyses were performed across six correlated domains, with available N varying by domain. RESULTS: Inclusion criteria were met by k = 23 independent studies with a total N = 18,582, and N across domains varying from 167 to 8619. The youth from affected families had delays in gross and fine motor development in infancy (k = 3, n = 167, Hedges'g = 0.644, confidence intervals (CI) = [0.328, 0.960], p < .001), walking milestones (k = 3, n = 608, g = 0.444, CI = [0.108, 0.780], p = .01), coordination (k = 8, n = 8619, g = 0.625, CI = [0.453, 0.797], p < .0001), and had more abnormal movements such as involuntary movements (k = 6, n = 8365, g = 0.291, CI = [0.041, 0.542], p = .02) compared with controls. However, not all effects survived correction for publication bias. Effects for neurological soft signs were small and not reliably different from zero (k = 4, n = 548, g = 0.238, CI = [-0.106, 0.583], p = .18). When comparing the FDR group to youth from families with other psychiatric disorders, the FDR group was distinguished by poorer gross and fine motor skills (k = 2, n = 275, g = 0.847, CI = [0.393, 1.300], p < .001). CONCLUSIONS: Motor deficits during development likely represent an endophenotype for schizophrenia, although its specificity is limited in relation to other serious mental disorders. It holds promise as a low cost domain for early risk detection, although it will have to be combined with other indicators to achieve clinically usable prediction accuracy. Impaired coordination was the most robust result with a moderate effect size and lack of heterogeneity and publication bias. PMID- 26577291 TI - Histone deacetylase 3 inhibition re-establishes synaptic tagging and capture in aging through the activation of nuclear factor kappa B. AB - Aging is associated with impaired plasticity and memory. Altered epigenetic mechanisms are implicated in the impairment of memory with advanced aging. Histone deacetylase 3 (HDAC3) is an important negative regulator of memory. However, the role of HDAC3 in aged neural networks is not well established. Late long-term potentiation (late-LTP), a cellular correlate of memory and its associative mechanisms such as synaptic tagging and capture (STC) were studied in the CA1 area of hippocampal slices from 82-84 week old rats. Our findings demonstrate that aging is associated with deficits in the magnitude of LTP and impaired STC. Inhibition of HDAC3 augments the late-LTP and re-establishes STC. The augmentation of late-LTP and restoration of STC is mediated by the activation of nuclear factor kappa B (NFkappaB) pathway. We provide evidence for the promotion of associative plasticity in aged neural networks by HDAC3 inhibition and hence propose HDAC3 and NFkappaB as the possible therapeutic targets for treating age -related cognitive decline. PMID- 26577293 TI - A novel one-step expression and immobilization method for the production of biocatalytic preparations. AB - BACKGROUND: Whole cell biocatalysts and isolated enzymes are considered as state of the art in biocatalytic preparations for industrial applications. Whole cells as biocatalysts are disadvantageous if substrate or products are toxic to the cells or undesired byproducts are formed due to the cellular metabolism. The use of isolated enzymes in comparison is more expensive due to the required downstream processing. Immobilization of enzymes after purification increases preparation costs for biocatalysts significantly, but allows for the efficient reuse of the enzymes in the biocatalytic process. For a more rapid processing one step expression and immobilization is desirable. RESULTS: This study focused on the development of a new one-step expression and immobilization technique for enzymes on the example of the beta-galactosidase from Escherichia coli K12. The enzyme was expressed in E. coli with a C-terminal membrane anchor originating from cytochrome b5 from rabbit liver and was thus in situ immobilized to the inner surface of the cytosolic membrane. Then, the expression of a lytic phage protein (gene E from PhiX174) caused the formation of a pore in the cell wall of E. coli, which resulted in release of the cytosol. The cellular envelopes with immobilized enzymes were retained. Batch and fed-batch processes were developed for efficient production of these biocatalysts. It was possible to obtain cellular envelopes with up to 27,200 +/- 10,460 immobilized enzyme molecules per cellular envelope (753 +/- 190 U/gdry weight). A thorough characterization of the effects of membrane immobilization was performed. Comparison to whole cells showed that mass transfer limitation was reduced in cellular envelopes due to the pore formation. CONCLUSION: In this study the feasibility of a new one-step expression and immobilization technique for the generation of biocatalytic preparations was demonstrated. The technique could be a useful tool especially for enzyme systems, which are not suitable for whole-cell biocatalysts due to severe mass transfer limitations or undesired side reactions mediated by cytosolic enzymes. PMID- 26577294 TI - Identification of the Same Na(+)-Specific DNAzyme Motif from Two In Vitro Selections Under Different Conditions. AB - We report an investigation of the functional relationship between two independently selected RNA-cleaving DNAzymes, NaA43, and Ce13, through in vitro selection. The NaA43 DNAzyme was obtained through a combination of gel-based and column-based in vitro selection in the presence of Na(+) and reported to be highly selective for Na(+) over other metal ions. The Ce13 DNAzyme was isolated via a gel-based method in the presence of Ce(4+) and found to be active with trivalent lanthanides, Y(3+) and Pb(2+). Despite completely different activities reported for the two DNAzymes, they share a high level of sequence similarity (~60% sequence identity). In this work, we systematically analyzed the activity of both DNAzymes to elucidate their potential functional relationship. We found that Na(+) is an obligate cofactor of the Ce13 DNAzyme and lanthanides cannot initiate the cleavage reaction in the absence of Na(+). Hence, we conclude that the Ce13 DNAzyme is a variant of the NaA43 DNAzyme that catalyzes reaction in the presence Na(+) and also utilizes lanthanides in a potentially allosteric manner. These results have identified a new DNAzyme motif that is not only remarkably Na(+)-specific, but also allows for design of novel allosteric DNAzymes for different biotechnological applications. PMID- 26577296 TI - A practical approach to diseases affecting dentate nuclei. AB - A wide variety of diseases affect the dentate nuclei. When faced with the radiological demonstration of signal changes in the dentate nuclei, radiologists and clinical neurologists have to sieve through the many possibilities, which they do not encounter on a regular basis. This task can be challenging, and therefore, developing a clinical, radiological, and laboratory approach is important. Information on the topic is scattered and the subject has not yet been reviewed. In this review, a combined clinicoradiological approach is presented. The signal changes in T1, T2, fluid-attenuated inversion recovery (FLAIR), diffusion, susceptibility weighted, and gadolinium-enhanced images can give specific or highly suggestive patterns, which are illustrated. The role of computed tomography (CT) in the diagnostic process is discussed. Specific radiological patterns do not exist in a significant proportion of patients where the clinical and laboratory analysis becomes important. In this review, we group the clinical constellations to narrow down the differential diagnosis and highlight the diagnostic clinical signs, such as tendon xanthomas and Kayser Fleischer rings. As will be seen, a number of these conditions are potentially reversible, and hence, their early diagnosis is desirable. Finally, key diagnostic tests and available therapies are outlined. The practical approach thus begins with the radiologist and winds its way through the clinician, towards carefully selected diagnostic tests defining the therapy options. PMID- 26577295 TI - Incidence of lymph node metastasis in intramucosal gastric cancer measuring 30 mm or less, with ulceration; mixed, predominantly differentiated-type histology; and no lymphovascular invasion: a multicenter retrospective study. AB - BACKGROUND: Intramucosal gastric cancer, <=3 cm (<=30 mm) with ulceration, and mixed histology (predominantly differentiated), was previously considered curative after endoscopic resection, and additional surgery was thought to be unnecessary. However, as the evidence base for these criteria remains insufficient, the Japanese Gastric Cancer Treatment Guidelines, ver. 3 (2010) specify that this pathology should be considered noncurative and recommend additional surgery. We report the frequency of lymph node metastasis in patients with these conditions based on a multicenter study. METHODS: Of patients with early gastric cancer who underwent gastrectomy with lymph node dissection, those with a mixed, predominantly differentiated tumor type, ulceration, a tumor diameter <=3 cm, and no lymphovascular invasion were entered into this study. RESULTS: Four hundred and seven patients met the criteria, 21 of whom were excluded owing to a lack of available information. Thus, a total of 386 patients were included in the analysis, from 37 of the 42 member institutions. The mean study duration was 125 months. The most common combination of mixed histology was tub2 + por (67 %). None of the 386 patients had lymph node metastasis (95 % confidence interval, 0-0.8 %). CONCLUSION: The results of this retrospective study indicate that the risk of lymph node metastasis was less than 1 % among patients with the criteria defined here, considered to be criteria for noncurative resection as per the current guidelines, and suggest that observation alone without additional surgery may result in a good outcome. PMID- 26577297 TI - Treatment-refractory substance use disorder: Focus on alcohol, opioids, and cocaine. AB - Substance use disorders are common, but only a small minority of patients receive adequate treatment. Although psychosocial therapies are effective, relapse is common. This review focusses on novel pharmacological and other treatments for patients with alcohol, opioid, or cocaine use disorders who do not respond to conventional treatments. Disulfiram, acamprosate, and the opioid antagonist naltrexone have been approved for the treatment of alcoholism. A novel, "as needed" approach is the use of the mu-opioid antagonist and partial kappa agonist nalmefene to reduce alcohol consumption. Other novel pharmacological approaches include the GABA-B receptor agonist baclofen, anticonvulsants such as topiramate and gabapentin, the partial nicotine receptor agonist varenicline, and other drugs. For opioid dependence, opioid agonist therapy with methadone or buprenorphine is the first-line treatment option. Other options include oral or depot naltrexone, morphine sulfate, depot or implant formulations, and heroin (diacetylmorphine) in treatment-refractory patients. To date, no pharmacological treatment has been approved for cocaine addiction; however, 3 potential pharmacological treatments are being studied, disulfiram, methylphenidate, and modafinil. Pharmacogenetic approaches may help to optimize treatment response in otherwise treatment-refractory patients and to identify which patients are more likely to respond to treatment, and neuromodulation techniques such as repeated transcranial magnetic stimulation and deep brain stimulation also may play a role in the treatment of substance use disorders. Although no magic bullet is in sight for treatment-refractory patients, some novel medications and brain stimulation techniques have the potential to enrich treatment options at least for some patients. PMID- 26577298 TI - Magnitude and factors associated with institutional delivery service utilization among childbearing mothers in Cheha district, Gurage zone, SNNPR, Ethiopia: a community based cross sectional study. AB - BACKGROUND: Ethiopia is one of the six countries that contributes' to more than 50 % of worldwide maternal deaths. While it is revealed that delivery attended by skilled provider at health facility reduced maternal deaths, more than half of all births in Ethiopia takes place at home. According to EDHS 2011 report nine women in every ten deliver at home in Ethiopia. The situation is much worse in southern region. The aim of our study is to measure the prevalence and to identify factors associated with institutional delivery service utilization among childbearing mothers in Cheha District, SNNPR, Ethiopia. METHODS: A community based cross sectional survey was conducted in Cheha District from Dec 22, 2012 to Jan 11, 2013. Multistage sampling method was employed and 816 women who gave birth within the past 2 years and lived in Cheha district for minimum of one year prior to the survey were involved in the study. Data was entered and analyzed using Epi Info Version 7 and SPSS Version 16. Frequencies and binary logistic regression were done. Factors affecting institutional delivery were determined using multivariate logistic regression. RESULTS: A total of 31 % of women gave birth to their last child at health facility. Place of residence, ability to afford for the whole process to get delivery service at health facility, traveling time that takes to reach to health institution which provides delivery service, husband's attitude towards institutional delivery, counseling about where to deliver during ANC visit and place of birth of the 2(nd) youngest child were found to have statistically significant association with institutional delivery. CONCLUSION: Institutional delivery is low in the study area. Access to health service was found to be the most important predictor of institutional delivery among others. Accessing health facility within reasonable travel time; providing health education and BCC services to husbands and the community at large on importance of using health institution for delivery service; working to improve women's economic status; counseling women to give birth at health institution during their ANC visit and exploring the overall quality of ANC service are some of the areas where much work is needed to improve institutional delivery. PMID- 26577299 TI - Targeting Mutant AKT in Cancer. AB - The results of a phase I basket trial suggest that the AKT1 E17K mutation is a valid therapeutic target. AZD5363, an investigational pan-AKT inhibitor, may benefit patients with a range of solid tumors bearing this genetic alteration. PMID- 26577300 TI - An ADC for Triple-Negative Breast Cancer. AB - A phase II study indicates that sacituzumab govitecan (IMMU-132), a Trop-2 specific antibody linked to the irinotecan metabolite SN-38, prolongs the progression-free survival of patients with advanced triple-negative breast cancer. IMMU-132 is well tolerated, causing fewer and more manageable side effects than irinotecan. PMID- 26577301 TI - Seed migration after transperineal interstitial prostate brachytherapy by using loose seeds: Japanese prostate cancer outcome study of permanent iodine-125 seed implantation (J-POPS) multi-institutional cohort study. AB - BACKGROUND: The incidence and associated factors of loose seed migration were investigated in cohort 1 of the Japanese Prostate Cancer Outcome Study of Permanent Iodine-125 Seed Implantation (J-POPS). METHODS: The study subjects were 2160 patients, consisting of 1641 patients who underwent permanent iodine-125 seed implantation (PI) and 519 patients who underwent PI combined with external beam radiation therapy (PI + EBRT). The presence or absence of seed migration to the chest and abdominal/pelvic region was determined. RESULTS: Seed migration was observed in 22.7 % of PI group patients and 18.1 % of PI + EBRT group patients (p = 0.0276). Migration to the lungs and abdominal/pelvic region was observed in 14.6 % and 11.1 % of the patients in the PI group, and 11.2 % and 8.5 % of the patients in the PI + EBRT group, respectively. In the PI group, the number of implanted seeds was associated with the seed migration incidence. Neither the PI nor the PI + EBRT group showed any difference in the volume of the prostate receiving 100 % of the prescribed dose (V100 [%]) or the minimal dose received by 90 % of the prostate volume (D90 [Gy]) between the patients with and without seed migration. CONCLUSIONS: This prospective cohort study investigating the largest number of past cases showed no difference in D90 (Gy) or V100 (%) between seed migration or the absence thereof in both the PI group and PI + EBRT group. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00534196. PMID- 26577302 TI - Assisted reproductive technology use and outcomes among women with a history of cancer. AB - STUDY QUESTION: How do the assisted reproductive technology (ART) outcomes of women presenting for ART after cancer diagnosis compare to women without cancer? SUMMARY ANSWER: The likelihood of a live birth after ART among women with prior cancer using autologous oocytes is reduced and varies by cancer diagnosis but is similar to women without cancer when donor oocytes are used. WHAT IS KNOWN ALREADY: Premenopausal patients faced with a cancer diagnosis frequently present for fertility preservation. STUDY DESIGN, SIZE, DURATION: Population-based cohort study of women treated with ART in NY, TX and IL, USA. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with their first ART treatment between 2004 and 2009 were identified from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System database and linked to their respective State Cancer Registries based on name, date of birth and social security number. Years were rounded, i.e. year 1 = 6-18 months before treatment. This study used reports of cancer from 5 years, 6 months prior to treatment until 6 months after first ART treatment. Women who only presented for embryo banking were omitted from the analysis. The likelihood of pregnancy and of live birth with ART using autologous oocytes was modeled using logistic regression, with women without prior cancer as the reference group, adjusted for woman's age, parity, cumulative FSH dosage, infertility diagnosis, number of diagnoses, number of ART cycles, State of residency and year of ART treatment. Results of the modeling are reported as adjusted odds ratios (AORs) and (95% confidence intervals). MAIN RESULTS AND THE ROLE OF CHANCE: The study population included 53 426 women; 441 women were diagnosed with cancer within 5 years prior to ART cycle start. Mean (+/-SD) age at cancer diagnosis was 33.4 +/- 5.7 years; age at start of ART treatment was 34.9 +/- 5.8 for women with cancer compared with 35.3 +/- 5.3 years for women without cancer (P = 0.03). Live birth rates among women using autologous oocytes differed substantially by cancer status (47.7% without cancer versus 24.7% with cancer, P < 0.0001), and cancer diagnosis (ranging from 53.5% for melanoma to 14.3% for breast cancer, P < 0.0001. The live birth rates among women using donor oocytes did not vary significantly by cancer status (60.4% for women with any cancer versus 64.5% for women without cancer), or by cancer diagnosis (ranging from 57.9% for breast cancer to 63.6% for endocrine cancer). Women with breast cancer make up about one-third of all cancers in this cohort. Among women with breast cancer, 2.8% of the 106 women who underwent ART within 6 months of being diagnosed with cancer used donor oocytes compared with 34.8% of the 46 women who received ART treatment a longer time after being diagnosed with cancer (P < 0.0001). We conjecture that the former group were either unaware that they had cancer or decided to undergo ART therapy prior to cancer treatment. However, their live birth rate was only 11.7% compared with 28.8%, the overall live birth rate for all women with cancer using autologous oocytes (P < 0.0001). The live birth rate for women diagnosed with breast cancer more than 6 months before ART (23.3%) did not differ significantly from the overall live birth rate for cancer (P = 0.49). If this difference is substantiated by a larger study, it would indicate a negative effect of severe recent illness itself on ART success, rather than the poor outcome being only related to the destructive effects of chemotherapies on ovarian follicles. Alternatively, because of the short time difference between cancer diagnosis and ART treatment, these pre-existing cancers may have been detected due to the increased medical surveillance during ART therapy. In women who only used autologous oocytes, women with prior cancers were significantly less likely to become pregnant and to have a live birth than those without cancer (adjusted odds ratio (AOR): 0.34, [95% confidence interval (CI): 0.27, 0.42] and 0.36 [0.28, 0.46], respectively). This was also evident with specific cancer diagnoses: breast cancer (0.20 [0.13, 0.32] and 0.19 [0.11, 0.30], respectively), cervical cancer (0.36 [0.15, 0.87] and 0.33 [0.13, 0.84], respectively) and all female genital cancers (0.49 [0.27, 0.87] and 0.47 [0.25, 0.86], respectively). Of note, among women with cancer who became pregnant, their likelihood of having a live birth did not differ significantly from women without cancer (85.8 versus 86.7% for women using autologous oocytes, and 85.3 versus 86.9% for women using donor oocytes). LIMITATIONS, REASONS FOR CAUTION: Women may not have been residents of the individual States for the entire 5-year pre-ART period, and therefore some cancers may not have been identified through this linkage. As a result, the actual observed number of cancers may be an underestimate. In addition, the overall prevalence is low due to the age distributions. Also, because we restricted the pre-ART period to 5 years prior, we would not have identified women who were survivors of early childhood cancers (younger than age 13 years at cancer diagnosis), or who had ART more than 5 years after being diagnosed with cancer. Additional analyses are currently underway evaluating live birth outcomes after embryo banking among women with cancer prior to ART, cycles which were excluded from the analyses in this paper. Future studies are planned which will include more States, as well as linkages to vital records to obtain information on spontaneous conceptions and births, to further clarify some of the issues raised in this analysis. WIDER IMPLICATIONS OF THE FINDINGS: Since the live birth rates using donor oocytes were not reduced in women with a prior cancer, but were reduced with autologous cycles, this suggests that factors acting in the pre- or peri-conceptional periods may be responsible for the decline. STUDY FUNDING/COMPETING INTERESTS: The study was funded by grant R01 CA151973 from the National Cancer Institute, National Institutes of Health, USA. B.L. is a research consultant for the Society for Assisted Reproductive Technology. All other authors report no conflict of interest. PMID- 26577304 TI - She, he, s/he and all the others. PMID- 26577305 TI - [Re: The Norwegian Care Coordination Reform--what now?]. PMID- 26577303 TI - Postovulatory aging affects dynamics of mRNA, expression and localization of maternal effect proteins, spindle integrity and pericentromeric proteins in mouse oocytes. AB - STUDY QUESTION: Is the postovulatory aging-dependent differential decrease of mRNAs and polyadenylation of mRNAs coded by maternal effect genes associated with altered abundance and distribution of maternal effect and RNA-binding proteins (MSY2)? SUMMARY ANSWER: Postovulatory aging results in differential reduction in abundance of maternal effect proteins, loss of RNA-binding proteins from specific cytoplasmic domains and critical alterations of pericentromeric proteins without globally affecting protein abundance. WHAT IS KNOWN ALREADY: Oocyte postovulatory aging is associated with differential alteration in polyadenylation and reduction in abundance of mRNAs coded by selected maternal effect genes. RNA-binding and processing proteins are involved in storage, polyadenylation and degradation of mRNAs thus regulating stage-specific recruitment of maternal mRNAs, while chromosomal proteins that are stage-specifically expressed at pericentromeres, contribute to control of chromosome segregation and regulation of gene expression in the zygote. STUDY DESIGN, SIZE, DURATION: Germinal vesicle (GV) and metaphase II (MII) oocytes from sexually mature C57B1/6J female mice were investigated. Denuded in vivo or in vitro matured MII oocytes were postovulatory aged and analyzed by semiquantitative confocal microscopy for abundance and localization of polyadenylated RNAs, proteins of maternal effect genes (transcription activator BRG1 also known as ATP-dependent helicase SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4 (SMARCA4) and NOD-like receptor family pyrin domain containing 5 (NLRP5) also known as MATER), RNA-binding proteins (MSY2 also known as germ cell-specific Y box-binding protein, YBX2), and post-transcriptionally modified histones (trimethylated histone H3K9 and acetylated histone H4K12), as well as pericentromeric ATRX (alpha thalassemia/mental retardation syndrome X-linked, also termed ATP-dependent helicase ATRX or X-linked nuclear protein (XNP)). For proteome analysis five replicates of 30 mouse oocytes were analyzed by selected reaction monitoring (SRM). MATERIAL AND METHODS: GV and MII oocytes were obtained from large antral follicles or ampullae of sexually mature mice, respectively. Denuded MII oocytes were aged for 24 h post ovulation. For analysis of distribution and abundance of polyadenylated RNAs fixed oocytes were in situ hybridized to Cy5 labeled oligo(dT)20 nucleotides. Absolute quantification of protein concentration per oocyte of selected proteins was done by SRM proteome analysis. Relative abundance of ATRX was assessed by confocal laser scanning microscopy (CLSM) of whole mount formaldehyde fixed oocytes or after removal of zona and spreading. MSY2 protein distribution and abundance was studied in MII oocytes prior to, during and after exposure to nocodazole, or after aging for 2 h in presence of H2O2 or for 24 h in presence of a glutathione donor, glutathione ethylester (GEE). MAIN RESULTS AND ROLE OF CHANCE: The significant reduction in abundance of proteins (P < 0.001) translated from maternal mRNAs was independent of polyadenylation status, while their protein localization was not significantly changed by aging. Most of other proteins quantified by SRM analysis did not significantly change in abundance upon aging except MSY2 and GTSF1. MSY2 was enriched in the subcortical RNP domain (SCRD) and in the spindle chromosome complex (SCC) in a distinct pattern, right and left to the chromosomes. There was a significant loss of MSY2 from the SCRD (P < 0.001) and the spindle after postovulatory aging. Microtubule de- and repolymerization caused reversible loss of MSY2 spindle-association whereas H2O2 stress did not significantly decrease MSY2 abundance. Aging in presence of GEE decreased significantly (P < 0.05) the aging-related overall and cytoplasmic loss of MSY2. Postovulatory aging increased significantly spindle abnormalities, unaligned chromosomes, and abundance of acetylated histone H4K12, and decreased pericentromeric trimethylated histone H3K9 (all P < 0.001). Spreading revealed a highly significant increase in pericentromeric ATRX (P < 0.001) upon ageing. Thus, the significantly reduced abundance of MSY2 protein, especially at the SCRD and the spindle may disturb the spatial control and timely recruitment, deadenylation and degradation of developmentally important RNAs. An autonomous program of degradation appears to exist which transiently and specifically induces the loss and displacement of transcripts and specific maternal proteins independent of fertilization in aging oocytes and thereby can critically affect chromosome segregation and gene expression in the embryo after fertilization. LIMITATION, REASONS FOR CAUTION: We used the mouse oocyte to study processes associated with postovulatory aging, which may not entirely reflect processes in aging human oocytes. However, increases in spindle abnormalities, unaligned chromosomes and H4K12 acetylated histones, as well as in mRNA abundance and polyadenylation have been observed also in aged human oocytes suggesting conserved processes in aging. WIDER IMPLICATIONS OF THE FINDINGS: Postovulatory aging precociously induces alterations in expression and epigenetic modifications of chromatin by ATRX and in histone pattern in MII oocytes that normally occur after fertilization, possibly contributing to disturbances in the oocyte-to-embryo transition (OET) and the zygotic gene activation (ZGA). These observations in mouse oocytes are also relevant to explain disturbances and reduced developmental potential of aged human oocytes and caution to prevent oocyte aging in vivo and in vitro. STUDY FUNDING/COMPETING INTERESTS: The study has been supported by the German Research Foundation (DFG) (EI 199/7-1 | GR 1138/12-1 | HO 949/21-1 and FOR 1041). There is no competing interest. PMID- 26577306 TI - [Re: The emergency department needs their own specialists]. PMID- 26577307 TI - [Re: An illogical and unfortunate side effect term]. PMID- 26577308 TI - [L. Slordal and T. Christoffersen reply]. PMID- 26577309 TI - [Re: A woman in her 70s with decompensated heart failure during surgery]. PMID- 26577310 TI - [Re: A woman pregnant with twins and with polyuria and polydipsia]. PMID- 26577312 TI - [Re: People with mental disorders have shorter life expectancy]. PMID- 26577313 TI - [L. Lien and colleagues reply]. PMID- 26577314 TI - [Re: People with mental disorders have shorter life expectancy]. PMID- 26577315 TI - [Lung cancer-changes in incidence by sex, age and County of residence 1984-2013]. PMID- 26577316 TI - [Circumcision of boys]. PMID- 26577317 TI - [Are the guidelines for follow up of ADHD good enough?]. PMID- 26577318 TI - [In Process Citation]. PMID- 26577319 TI - [In Process Citation]. PMID- 26577320 TI - Living conditions in the districts of Oslo and poisonings by substances of abuse treated at casualty clinic level. AB - BACKGROUND: Use of and acute poisoning by substances of abuse represent a major health problem and are often linked to social destitution. We describe associations between place of residence, living conditions and the incidence of poisoning by substances of abuse in Oslo. MATERIAL AND METHOD: All patients who were 12 years of age or older and resident in Oslo and who were treated for acute poisoning by substances of abuse at the Oslo Accident and Emergency Outpatient Clinic (OAEOC) were included prospectively for a continuous period of one year, from October 2011 to September 2012. The 15 districts of Oslo were categorised into three groups of living conditions, from the best (I) to the poorest (III) living conditions, based on the City of Oslo's living conditions index. Homeless people were grouped separately. The incidence of poisoning by substances of abuse treated in the OAEOC was estimated. RESULTS: Of a total of 1,560 poisonings by substances of abuse, 1,094 cases (70%) affected men. The median age was 41 years. The most frequent toxic agents were ethanol, with 915 cases (59%), and heroin, with 249 cases (16%). The incidence of poisoning by substances of abuse treated in the OAEOC per year per 1,000 inhabitants amounted to 1.75 in living conditions group I, to 2.76 in living conditions group II and 3.41 in living conditions group III. Living conditions group III had a significantly higher incidence than living conditions group II (p < 0.001), and living conditions group II had a significantly higher incidence than living conditions group I (p < 0.001). INTERPRETATION: The incidence of acute poisoning by substances of abuse was higher, the poorer the living conditions in the district. PMID- 26577321 TI - Comparison of data from the Cause of Death Registry and the Norwegian Patient Register. AB - BACKGROUND: The quality of the data in the Cause of Death Registry is crucial to produce reliable statistics on causes of death. The Cancer Registry of Norway uses data from the Norwegian Patient Register to request information from hospitals regarding patients registered with cancer in the patient registry, but not in the cancer registry. We wanted to investigate whether data from the Norwegian Patient Register can also be used to advantage in the Cause of Death Registry. MATERIAL AND METHOD: Data from the Cause of Death Registry on deaths that occurred during the period 2009 - 2011 (N = 124,098) were collated with data on contact with somatic hospitals and psychiatric institutions during the last year of life, retrieved from the Norwegian Patient Register. Causes of death were grouped in the same way as in standard statistics on causes of death. RESULTS: Out of 124,098 deaths, altogether 34.9% occurred in somatic hospitals. A total of 80.9% of all deceased had been admitted to a somatic hospital and/or had attended an outpatient consultation during their last year of life. The proportion with hospital contact was highest for those whose cause of death was cancer. In cases of unknown/unspecified cause of death, more than half also had contact with hospitals, but the majority of these were registered with only outpatient consultations. Altogether 5.4% of all deceased had been admitted to and/or had an outpatient consultation in a psychiatric institution during their last year of life. For those whose cause of death was suicide, this proportion amounted to 41.8%. INTERPRETATION: In case of incomplete information on the cause of death, data from the Norwegian Patient Register can supply valuable information on where the patient has been treated, thus enabling the Cause of Death Registry to contact the hospitals in question. However, any potential benefit is restricted by the fact that deceased persons with unknown/unspecified causes of death had less frequently been admitted to hospital during their last year of life. PMID- 26577322 TI - [Obstructive sleep apnea]. PMID- 26577323 TI - [Plasma cells with inclusions]. PMID- 26577324 TI - [A woman in her 60s with acute chest pain and ST-elevations]. PMID- 26577325 TI - Investigation of obstructive respiratory disturbance during sleep. PMID- 26577326 TI - [Surrogate, surrogacy and surrogate children]. PMID- 26577328 TI - [The pursuit of education]. PMID- 26577329 TI - [A molecular biology revolution]. PMID- 26577330 TI - [Surgery for pelvic floor dysfunction]. PMID- 26577331 TI - [Differential counting of leukocytes]. PMID- 26577334 TI - Photosensitivity associated with systemic triflusal therapy. PMID- 26577333 TI - Development of loop-mediated isothermal amplification (LAMP) for simple detection of Leishmania infection. AB - BACKGROUND: Leishmaniasis is a neglected tropical disease that is caused by an obligate intracellular protozoan of the genus Leishmania. Recently, an increasing number of autochthonous leishmaniasis cases caused by L. martiniquensis and the novel species L. siamensis have been described in Thailand, rendering an accurate diagnosis of this disease critical. However, only a few laboratories are capable of diagnosing leishmaniasis in Thailand. To expand leishmaniasis diagnostic capabilities, we developed a simple colorimetric loop-mediated isothermal amplification (LAMP) technique for the direct detection of Leishmania DNA. METHODS: LAMP was performed for 75 min using four primers targeting the conserved region of the18S ribosomal RNA gene, and the DNA indicator used was malachite green (MG). To simulate crude samples, cultured promastigotes of L. siamensis were mixed with blood or saliva. Also, clinical samples (blood, saliva, and tissue biopsies) were obtained from patients with cutaneous leishmaniasis (CL) and visceral leishmaniasis (VL). All samples were boiled for 10 min and introduced directly into the LAMP reaction mixture without DNA purification. RESULTS: The use of MG resulted in an unambiguous differentiation of positive and negative controls. For L. siamensis, the detection limit was 10(3) parasites/mL or 2.5 parasites/tube. Saliva, tissue biopsies, and whole blood were indicative of active Leishmania infection, and their direct usages did not adversely affect the detection limit. In addition, this LAMP assay could detect DNA from multiple Leishmania species other than L. siamensis and L. martiniquensis, including L. aethiopica, L. braziliensis, L. donovani and L. tropica. CONCLUSIONS: The simplicity and sensitivity of LAMP in detecting active Leishmania infection could enable the rapid diagnosis of leishmaniasis, thereby facilitating the survey and control of leishmaniasis in Thailand. However, our limited number of samples warranted a further validation with a larger cohort of patients before this assay could be deployed. PMID- 26577335 TI - IgE-mediated asthma: New revelations and future insights. AB - The central role of IgE in the pathogenesis of allergic asthma has been well established; recent research has brought to light further interesting findings regarding the effects of IgE and anti-IgE therapy. This symposium explored these recent revelations and provided new insights into the importance of IgE in allergic asthma. PMID- 26577336 TI - Treatment of the acquired von Willebrand syndrome. AB - Acquired von Willebrand syndrome (aVWS) accounts for 22% of patients with abnormal von Willebrand factor. Most patients with known pathophysiological mechanisms suffer from cardiovascular, myeloproliferative and lymphoproliferative disorders. Less frequent associations are of autoimmune origin, due to hyperfibrinolysis, adsorption to tumor cells, reduced synthesis and prolonged circulation. The mechanisms leading to aVWS is hitherto not known in patients with liver and kidney diseases, drug use, glycogen storage disease, virus infections and at least 18 other disease entities. Diagnosis is complicated by the battery of tests needed, and their inherent rather low sensitivity and specificity for aVWS. Thus, even in acute bleeding situations it may take days until a firm diagnosis is settled and specific therapies can be initiated. The main aim is to shed more light onto this, compared with inherited von Willebrand disease, rare disease which affects at least 2-3% of the older population. PMID- 26577337 TI - Equation-free analysis of spike-timing-dependent plasticity. AB - Spike-timing-dependent plasticity is the process by which the strengths of connections between neurons are modified as a result of the precise timing of the action potentials fired by the neurons. We consider a model consisting of one integrate-and-fire neuron receiving excitatory inputs from a large number-here, 1000-of Poisson neurons whose synapses are plastic. When correlations are introduced between the firing times of these input neurons, the distribution of synaptic strengths shows interesting, and apparently low-dimensional, dynamical behaviour. This behaviour is analysed in two different parameter regimes using equation-free techniques, which bypass the explicit derivation of the relevant low-dimensional dynamical system. We demonstrate both coarse projective integration (which speeds up the time integration of a dynamical system) and the use of recently developed data mining techniques to identify the appropriate low dimensional description of the complex dynamical systems in our model. PMID- 26577338 TI - Asymptomatic anal sexually transmitted infections in HIV-positive men attending anal cancer screening. AB - BACKGROUND: HIV-positive men who have sex with men (HIV+MSM) have an increased risk for anal dysplasia and for sexually transmitted infections (STIs). OBJECTIVES: We determined the positivity rates of Chlamydia trachomatis (CT), Neisseria gonorrhoea (NG), Mycoplasma genitalium (MG) and syphilis in HIV+MSM participating in an anal cancer screening programme. METHODS: In total, 852 intra anal swabs were collected from 503 HIV+MSM between 2012 and 2014. Anal cytology and polymerase chain reaction assays for human papillomavirus (HPV), CT, NG and MG detection were performed. The syphilis status was determined serologically. Risk factors for STIs were explored by multiple logistic regression analysis. RESULTS: In total 20.7% (104 of 503) of the patients had an STI other than HPV within the study period. The most common was CT, found in 10.9%, followed by NG (8.9%) and MG (4.2%). Early syphilis was detected in 4.6% and past syphilis in 44.5% of the HIV+MSM. Eighteen patients (3.6%) had more than one STI episode, and 90.6% of the 127 cases of STIs were asymptomatic. Age, anal HPV infection, abnormal anal cytology and previous syphilis were risk factors for STI. CONCLUSIONS: Anal STIs are frequent and mostly asymptomatic in HIV+MSM participating in anal cancer screening. STI screening should be incorporated into anal cancer screening programmes for HIV+MSM. PMID- 26577339 TI - Pretreatment of parecoxib attenuates hepatic ischemia/reperfusion injury in rats. AB - BACKGROUND: Previous studies showed that cyclooxygenase(COX) was involved in ischemia/reperfusion (I/R) injuries. Parecoxib, a selective inhibitor for COX -2, has been shown to have protective properties in reducing I/R injury in the heart, kidney and brain. The aim of this study was to investigate the effects of parecoxib on hepatic I/R and to explore the underlying mechanisms. METHODS: Fifty two Sprague-Dawley rats were randomly divided into three groups: the sham operation (Sham) group, the hepatic ischemia/reperfusion (I/R) group, and the parecoxib pretreated I/R (I/R + Pare) group. Partial warm ischemia was produced in the left and middle hepatic lobes of Sprague-Dawley rats for 60 min, followed by 6 h of reperfusion. Rats in the I/R + Pare group received parecoxib (10 mg/kg) intraperitoneally twice a day for three consecutive days prior to ischemia. Blood and tissue samples from the groups were collected 6 h after reperfusion, and a survival study was performed. RESULTS: Pretreatment with parecoxib prior to I/R insult significantly reduced I/R-induced elevations of aminotransferases, and significantly improved the histological status of the liver. Parecoxib significantly suppressed inflammatory cascades, as demonstrated by attenuations in TNF-alpha and IL-6. Parecoxib significantly inhibited iNOS and nitrotyrosine expression after I/R and significantly attenuated I/R-induced apoptosis. The 7 day survival rate was increased by pre-administration of parecoxib. CONCLUSIONS: Administration of parecoxib prior to hepatic I/R attenuates hepatic injury through inhibition of inflammatory response and nitrosative stress. PMID- 26577340 TI - Stabilization of the Low-Spin State in a Mononuclear Iron(II) Complex and High Temperature Cooperative Spin Crossover Mediated by Hydrogen Bonding. AB - The tetrapyridyl ligand bbpya (bbpya=N,N-bis(2,2'-bipyrid-6-yl)amine) and its mononuclear coordination compound [Fe(bbpya)(NCS)2 ] (1) were prepared. According to magnetic susceptibility, differential scanning calorimetry fitted to Sorai's domain model, and powder X-ray diffraction measurements, 1 is low-spin at room temperature, and it exhibits spin crossover (SCO) at an exceptionally high transition temperature of T1/2 =418 K. Although the SCO of compound 1 spans a temperature range of more than 150 K, it is characterized by a wide (21 K) and dissymmetric hysteresis cycle, which suggests cooperativity. The crystal structure of the LS phase of compound 1 shows strong N?H???S intermolecular H bonding interactions that explain, at least in part, the cooperative SCO behavior observed for complex 1. DFT and CASPT2 calculations under vacuum demonstrate that the bbpya ligand generates a stronger ligand field around the iron(II) core than its analogue bapbpy (N,N'-di(pyrid-2-yl)-2,2'-bipyridine-6,6'-diamine); this stabilizes the LS state and destabilizes the HS state in 1 compared with [Fe(bapbpy)(NCS)2 ] (2). Periodic DFT calculations suggest that crystal-packing effects are significant for compound 2, in which they destabilize the HS state by about 1500 cm(-1) . The much lower transition temperature found for the SCO of 2 compared to 1 appears to be due to the combined effects of the different ligand field strengths and crystal packing. PMID- 26577341 TI - Sex Differences in Mobility and Spatial Cognition: A Test of the Fertility and Parental Care Hypothesis in Northwestern Namibia. AB - The fertility and parental care hypothesis interprets sex differences in some spatial-cognitive tasks as an adaptive mechanism to suppress women's travel. In particular, the hypothesis argues that estrogens constrain travel during key reproductive periods by depressing women's spatial-cognitive ability. Limiting travel reduces exposure to the dangers and caloric costs of navigating long distances into unfamiliar environments. Our study evaluates a collection of predictions drawn from the fertility and parental care hypothesis among the Twe and Himba people living in a remote region of Namibia. We find that nursing mothers travel more than women at any other stage of their reproductive career. This challenges the assumption that women limit travel during vulnerable and energetically demanding reproductive periods. In addition, we join previous studies in identifying a relationship between spatial ability and traveling among men, but not women. If spatial ability does not influence travel, hormonally induced changes in spatial ability cannot be used as a mechanism to reduce travel. Instead, it appears the fitness consequences of men's travel is a more likely target for adaptive explanations of the sex differences in spatial ability, navigation, and range size. PMID- 26577342 TI - Geographical Cues and Developmental Exposure: Navigational Style, Wayfinding Anxiety, and Childhood Experience in the Faroe Islands. AB - The current study assessed potential relationships among childhood wayfinding experience, navigational style, and adult wayfinding anxiety in the Faroe Islands. The Faroe Islands are of interest because they have an unusual geography that may promote the use of an orientational style of navigation (e.g., use of cardinal directions). Faroese adults completed questionnaires assessing (1) their permitted childhood range sizes, (2) the types of navigational strategies they use, and (3) the amount of anxiety they experience when navigating in adulthood. Males had more childhood wayfinding experience, used the orientation strategy at a higher rate, and showed lower levels of wayfinding anxiety. When compared with other cultures, both Faroese women and men appear to embrace orientation strategies at an unusually high rate. Childhood experience was not conclusively linked to later wayfinding anxiety. However, the current findings raise the possibility that children who have particularly small ranges in childhood may be especially anxious when navigating in adulthood. PMID- 26577343 TI - Antibacterial, antifungal and antioxidant activity of Olea africana against pathogenic yeast and nosocomial pathogens. AB - BACKGROUND: Olea africana leaves are used by Bapedi people to treat different ailments. The use of these leaves is not validated, therefore the aim of this study is to validate antimicrobial properties of this plant. METHODS: The ground leaves were extracted using solvents of varying polarity (hexane, chloroform, dichloromethane (DCM), ethyl acetate, acetone, ethanol, methanol, butanol and water). Thin layer chromatography (TLC) was used to analyse the chemical constituents of the extracts. The TLC plates were developed in three different solvent systems, namely, benzene/ethanol/ammonium solution (BEA), chloroform/ethyl acetate/formic acid (CEF) and ethyl acetate/methanol/water (EMW). The micro-dilution assay and bioautography method were used to evaluate the antibacterial activity of the extracts against Escherichia coli, Pseudomonas aeruginosa, Enterococcus faecalis and Staphylococcus aureus and the antifungal activity against Candida albicans and Cryptococcus neoformans. RESULTS: Methanol was the best extractant, yielding a larger amount of plant material whereas hexane yielded the least amount. In phytochemical analyses, more compounds were observed in BEA, followed by EMW and CEF. Qualitative 2, 2- diphenylpacryl-1 hydrazyl (DPPH) assay displayed that all the extracts had antioxidant activity. Antioxidant compounds could not be separated using BEA solvent system while with CEF and EMW enabled antioxidant compounds separation. The minimum inhibitory concentrations (MIC) values against test bacteria ranged between 0.16 and 2.50 mg/mL whereas against fungi, MIC ranged from 0.16 to 0.63 mg/mL. Bioautography results demonstrated that more than one compound was responsible for antimicrobial activity in the microdilution assay as the compounds were located at different Rf values. CONCLUSIONS: The results indicate that leaf extracts of Olea africana contain compounds with antioxidant, antibacterial and antifungal activities. Therefore, further studies are required to isolate the active compounds and perform other tests such as cytotoxicity. Olea africana may be a potential source of antimicrobial compounds. PMID- 26577344 TI - An overview of recent patents on musculoskeletal interface tissue engineering. AB - Interface tissue engineering involves the development of engineered grafts that promote integration between multiple tissue types. Musculoskeletal tissue interfaces are critical to the safe and efficient transmission of mechanical forces between multiple musculoskeletal tissues, e.g., between ligament and bone tissue. However, these interfaces often do not physiologically regenerate upon injury, resulting in impaired tissue function. Therefore, interface tissue engineering approaches are considered to be particularly relevant for the structural restoration of musculoskeletal tissues interfaces. In this article, we provide an overview of the various strategies used for engineering musculoskeletal tissue interfaces with a specific focus on the recent important patents that have been issued for inventions that were specifically designed for engineering musculoskeletal interfaces as well as those that show promise to be adapted for this purpose. PMID- 26577345 TI - Analyzing EEG signals to detect unexpected obstacles during walking. AB - BACKGROUND: When an unexpected perturbation in the environment occurs, the subsequent alertness state may cause a brain activation responding to that perturbation which can be detected and employed by a Brain-Computer Interface (BCI). In this work, the possibility of detecting a sudden obstacle appearance analyzing electroencephalographic (EEG) signals is assessed. For this purpose, different features of EEG signals are evaluated during the appearance of sudden obstacles while a subject is walking on a treadmill. The future goal is to use this procedure to detect any obstacle appearance during walking when the user is wearing a lower limb exoskeleton in order to generate an emergency stop command for the exoskeleton. This would enhance the user-exoskeleton interaction, improving the safety mechanisms of current exoskeletons. METHODS: In order to detect the change in the brain activity when an obstacle suddenly appears, different features of EEG signals are evaluated using the recordings of five healthy subjects. Since the change in the brain activity occurs in the time domain, the features evaluated are: common spatial patterns, average power, slope, and the coefficients of a polynomial fit. A Linear Discriminant Analysis based classifier is used to differentiate between two conditions: the appearance or not of an obstacle. The evaluation of the performance to detect the obstacles is made in terms of accuracy, true positive (TP) and false positive (FP) rates. RESULTS: From the offline analysis, the best performance is achieved when the slope or the polynomial coefficients are used as features, with average detection accuracy rates of 74.0 and 79.5 %, respectively. These results are consistent with the pseudo-online results, where a complete EEG recording is segmented into windows of 500 ms and overlapped 400 ms, and a decision about the obstacle appearance is made for each window. The results of the best subject were 11 out of 14 obstacles detected with a rate of 9.09 FPs/min, and 10 out of 14 obstacles detected with a rate of 6.34 FPs/min using slope and polynomial coefficients features, respectively. CONCLUSIONS: An EEG-based BCI can be developed to detect the appearance of unexpected obstacles. The average accuracy achieved is 79.5 % of success rate with a low number of false detections. Thus, the online performance of the BCI would be suitable for commanding in a safely way a lower limb exoskeleton during walking. PMID- 26577347 TI - Defecation: Colectomy for constipation-a time for renewed caution? PMID- 26577348 TI - Pancreatic cancer: New insights into PDAC growth promotion via a BAG3-mediated paracrine loop. PMID- 26577350 TI - Liver transplantation: Evading antigens-ABO-incompatible liver transplantation. PMID- 26577353 TI - Parent-healthcare provider interaction during peripheral vein cannulation with resistive preschool children. AB - AIM: The aim of this study was to increase understanding of parent-healthcare provider interaction in situations where newly admitted preschool children resist peripheral vein cannulation. BACKGROUND: Parent-healthcare provider interaction represents an important context for understanding children's resistance to medical procedures. Knowledge about this interaction can provide a better understanding of how restraint is used and talked about. Symbolic interactionism informed the understanding of interaction. DESIGN: An exploratory, qualitative study was chosen because little is known about these interactions. METHODS: During 2012-2013, 14 naturalistic peripheral vein cannulation -attempts with six newly hospitalized preschool children were video recorded. Eight parents/relatives, seven physicians and eight nurses participated in this study. The analytical foci of turn-taking and participant structure were used. RESULTS: The results comprised three patterns of interactions. The first pattern, 'parents supported the interaction initiated by healthcare providers', was a response to the children's expressed resistance and they performed firm restraint together. The second pattern, 'parents create distance in interaction with healthcare providers', appeared after failed attempts and had a short time span. Parents stopped following up on the healthcare providers' interaction and their restraint became less firm. In the third pattern, 'healthcare providers reorient in interaction', healthcare providers took over more of the restraint and either helped each other to continue the interaction or they stopped it. CONCLUSION: Knowledge about the identified patterns of interactions can help healthcare providers to better understand and thereby prepare both parents and themselves for situations with potential use of restraint. PMID- 26577355 TI - Understanding the Role of Sex in Heart Valve and Major Vascular Diseases. AB - Cardiovascular disease (CVD) is the major cause of mortality in the elderly population. The cost of CVD treatment and surgeries was over $300 billion in the United States alone in 2010, making this disorder a critical healthcare issue. Many studies have suggested sex as a risk factor for heart valve and major vascular diseases, such as aortic valve stenosis, mitral prolapse and regurgitation, atherosclerosis, coronary artery disease, and abdominal aortic aneurysm. Unfortunately, only a handful of studies have illustrated the role of sex in the etiology and progression of these disorders. Moreover, knowledge of biomolecular factors that affect these diseases in men and women is very limited. Numerous clinical studies have revealed obvious differences in the prevalence of these diseases between the sexes. These reports were supported by a few molecular and cellular physiology studies that associated this difference to sex and sex hormones. In particular, male sex has commonly been identified as a risk factor for majority of heart valve and vascular diseases, whereas females have been identified as higher risk for certain disorders as well. In addition, menopause is a critical issue that turns the tables against women and enhances complications in their cardiovascular structure due to hormonal change. In this review, major vascular and heart valve diseases for which sex is associated as a risk factor have been reviewed to highlight the importance of this risk factor in CVDs. PMID- 26577356 TI - Establishing the Framework for Tissue Engineered Heart Pumps. AB - Development of a natural alternative to cardiac assist devices (CADs) will pave the way to a heart failure therapy which overcomes the disadvantages of current mechanical devices. This work provides the framework for fabrication of a tissue engineered heart pump (TEHP). Artificial heart muscle (AHM) was first fabricated by culturing 4 million rat neonatal cardiac cells on the surface of a fibrin gel. To form a TEHP, AHM was wrapped around an acellular goat carotid artery (GCA) and a chitosan hollow cylinder (CHC) scaffold with either the cardiac cells directly contacting the construct periphery or separated by the fibrin gel. Histology revealed the presence of cardiac cell layer cohesion and adhesion to the fibrin gel scaffold, acellular GCA, and synthesized CHC. Expression of myocytes markers, connexin43 and alpha-actinin, was also noted. Biopotential measurements revealed the presence of ~2.5 Hz rhythmic propagation of action potential throughout the TEHP. Degradation of the fibrin gel scaffold of the AHM via endogenous proteases may be used as a means of delivering the cardiac cells to cylindrical scaffolds. Further development of the TEHP model by use of multi-stimulus bioreactors may lead to the application of bioengineered CADs. PMID- 26577357 TI - Classification of Unsteady Flow Patterns in a Rotodynamic Blood Pump: Introduction of Non-Dimensional Regime Map. AB - Rotodynamic blood pumps (also known as rotary or continuous flow blood pumps) are commonly evaluated in vitro under steady flow conditions. However, when these devices are used clinically as ventricular assist devices (VADs), the flow is pulsatile due to the contribution of the native heart. This study investigated the influence of this unsteady flow upon the internal hemodynamics of a centrifugal blood pump. The flow field within the median axial plane of the flow path was visualized with particle image velocimetry (PIV) using a transparent replica of the Levacor VAD. The replica was inserted in a dynamic cardiovascular simulator that synchronized the image acquisition to the cardiac cycle. As compared to steady flow, pulsatile conditions produced periodic, transient recirculation regions within the impeller and separation in the outlet diffuser. Dimensional analysis revealed that the flow characteristics could be uniquely described by the non-dimensional flow coefficient (Phi) and its time derivative ([Formula: see text]), thereby eliminating impeller speed from the experimental matrix. Four regimes within the Phi-[Formula: see text] plane were found to classify the flow patterns, well-attached or disturbed. These results and methods can be generalized to provide insights for both design and operation of rotodynamic blood pumps for safety and efficacy. PMID- 26577358 TI - Comparison Between Bench-Top and Computational Modelling of Cerebral Thromboembolism in Ventricular Assist Device Circulation. AB - Despite improvements in ventricular assist devices (VAD) design, VAD-induced stroke rates remain remarkably high at 14-47%. We previously employed computational fluid dynamics (CFD) to propose adjustment of VAD outflow graft (VAD-OG) implantation to reduce stoke. Herein, we present an in-vitro model of cerebral vessel embolization in VAD-assisted circulation, and compare benchtop results to CFD predictions. The benchtop flow-loop consists of a 3D printed aortic bed using Accura 60 polymer driven by a continuous-flow pump. Three hundred spherical particles simulating thrombi of 2, 3.5, and 5 mm diameters were injected at the mock VAD-OG inlet. A water and glycerin mixture (3.8 cP viscosity) synthetically mimicked blood. The flowrate was adjusted to match the CFD Reynolds number. Catch cans were used to capture and count particles reaching cerebral vessels. VAD-OG geometries were evaluated using comparison of means Z score range of -1.96 <= Z <= 1.96 to demonstrate overall agreement between computational and in-vitro techniques. Z-scores were: (i) Z = -1.05 for perpendicular (0 degrees ), (ii) Z = 0.32 for intermediate (30 degrees ), and (iii) Z = -0.52 for shallow (60 degrees ) anastomosis and confirmed agreement for all geometries. This study confirmed added benefits of using a left carotid artery bypass-graft with percent embolization reduction: 22.6% for perpendicular, 21.2% for intermediate, and 11.9% for shallow anastomoses. The shallow anastomosis demonstrated lower degrees of aortic arch flow recirculation, consistent with steady-flow computations. Quantitatively and qualitatively, contemporary steady-flow computational models for predicting VAD-induced cerebral embolization can be achieved in-vitro to validate the CFD equivalent. PMID- 26577359 TI - In Vitro Assessment of the Assisted Bidirectional Glenn Procedure for Stage One Single Ventricle Repair. AB - This in vitro study compares the hemodynamic performance of the Norwood and the Glenn circulations to assess the performance of a novel assisted bidirectional Glenn (ABG) procedure for stage one single ventricle surgery. In the ABG, the flow in a bidirectional Glenn procedure is assisted by injection of a high-energy flow stream from the systemic circulation using an aorta-caval shunt with nozzle. The aim is to explore experimentally the potential of the ABG as a surgical alternative to current surgical practice. The experiments are directly compared against previously published numerical simulations. A multiscale mock circulatory system was used to measure the hemodynamic performance of the three circulations. For each circulation, the system was tested using both low and high values of pulmonary vascular resistance. Resulting parameters measured were: pressure and flow rate at left/right pulmonary artery and superior vena cava (SVC). Systemic oxygen delivery (OD) was calculated. A parametric study of the ratio of ABG nozzle to shunt diameter was done. We report time-based comparisons with numerical simulations for the three surgical variants tested. The ABG circulation demonstrated an increase of 30-38% in pulmonary flow with a 2-3.7 mmHg increase in SVC pressure compared to the Glenn and a 4-14% higher systemic OD than either the Norwood or the Glenn. The nozzle/shunt diameter ratio affected the local hemodynamics. These experimental results agreed with those of the numerical model: mean flow values were not significantly different (p > 0.05) while mean pressures were comparable within 1.2 mmHg. The results verify the approaches providing two tools to study this complicated circulation. Using a realistic experimental model we demonstrate the performance of a novel surgical procedure with potential to improve patient hemodynamics in early palliation of the univentricular circulation. PMID- 26577360 TI - Pulmonary Hemodynamics Simulations Before Stage 2 Single Ventricle Surgery: Patient-Specific Parameter Identification and Clinical Data Assessment. AB - Single ventricle heart defects involve pathologies in which the heart has only one functional pumping chamber. In these conditions, treatment consists of three staged procedures. At stage 1 pulmonary flow is provided through an artificial shunt from the systemic circulation. Representative hemodynamics models able to explore different virtual surgical options can be built based on pre-operative imaging and patient data. In this context, the specification of boundary conditions is necessary to compute pressure and flow in the entire domain. However, these boundary conditions are rarely the measured variables. Moreover, to take into account the rest of the circulation outside of the three-dimensional modeled domain, a number of reduced order models exist. A simplified method is presented to iteratively, but automatically, tune reduced model parameters from hemodynamic data clinically measured before stage 2 surgery. Patient-specific local hemodynamics around the distal systemic-to-pulmonary shunt anastomosis and the connected pulmonary arteries are also analyzed. Multi-scale models of pre stage 2 single ventricle patients are developed, including a 3D model of shunt pulmonary connection and a number of pulmonary arteries. For each pulmonary outlet a total downstream resistance is identified, consistent with measured flow split and pressures. Target pressures such as minimum, maximum or average over one or both lungs are considered, depending on the clinical measurement. When possible, both steady and pulsatile identifications are performed. The methodology is demonstrated with six patient-specific models: the clinical target data are well-matched, except for one case where clinical data were subsequently found inconsistent. Inhomogeneous pressure, swirling blood flow patterns and very high wall shear stress 3D maps highlight similarities and differences among patients. Steady and pulsatile tuning results are similar. This work demonstrates (1) how to use routine clinical data to define boundary conditions for patient specific 3D models in pre-stage 2 single ventricle circulations and (2) how simulations can help to check the coherence of clinical data, or provide insights to clinicians that are otherwise difficult to measure, such as in the presence of kinks. Finally, the choice of steady vs. pulsatile tuning, limitations and possible extensions of this work are discussed. PMID- 26577361 TI - Quantitative Assessment of Turbulence and Flow Eccentricity in an Aortic Coarctation: Impact of Virtual Interventions. AB - Turbulence and flow eccentricity can be measured by magnetic resonance imaging (MRI) and may play an important role in the pathogenesis of numerous cardiovascular diseases. In the present study, we propose quantitative techniques to assess turbulent kinetic energy (TKE) and flow eccentricity that could assist in the evaluation and treatment of stenotic severities. These hemodynamic parameters were studied in a pre-treated aortic coarctation (CoA) and after several virtual interventions using computational fluid dynamics (CFD), to demonstrate the effect of different dilatation options on the flow field. Patient specific geometry and flow conditions were derived from MRI data. The unsteady pulsatile flow was resolved by large eddy simulation including non-Newtonian blood rheology. Results showed an inverse asymptotic relationship between the total amount of TKE and degree of dilatation of the stenosis, where turbulent flow proximal the constriction limits the possible improvement by treating the CoA alone. Spatiotemporal maps of TKE and flow eccentricity could be linked to the characteristics of the jet, where improved flow conditions were favored by an eccentric dilatation of the CoA. By including these flow markers into a combined MRI-CFD intervention framework, CoA therapy has not only the possibility to produce predictions via simulation, but can also be validated pre- and immediate post treatment, as well as during follow-up studies. PMID- 26577362 TI - A Novel Vascular Coupling System for End-to-End Anastomosis. AB - Vascular anastomosis is common during reconstructive surgeries. Traditional hand suturing techniques are time consuming, subject to human error, and require high technical expertise and complex instruments. Prior attempts to replace hand suturing technique, including staples, ring-pin devices, cuffing devices, and clips, are either more cumbersome, are unable to maintain a tight seal, or do not work for both arteries and veins. To provide a more efficient and reliable vessel anastomosis, a metal-free vascular coupling system that can be used for both arteries and veins was designed, fabricated and tested. A set of corresponding instruments were developed to facilitate the anastomosis process. Evaluation of the anastomosis by scanning electron microscopy and magnetic resonance imaging, demonstrated that the installation process does not cause damage to the vessel intima and the vascular coupling system is not exposed to the vessel lumen. Mechanical testing results showed that vessels reconnected with the vascular coupling system could withstand 12.7 +/- 2.2 N tensile force and have superior leak profiles (0.049 +/- 0.015, 0.078 +/- 0.016, 0.089 +/- 0.008 mL/s at 160, 260, 360 mmHg, respectively) compared to hand sutured vessels (0.310 +/- 0.014, 1.123 +/- 0.033, 2.092 +/- 0.072 mL/s at 160, 260, 360 mmHg, respectively). The anastomotic process was successfully demonstrated on both arteries and veins in cadaver pigs. PMID- 26577363 TI - Sequential Structural and Fluid Dynamics Analysis of Balloon-Expandable Coronary Stents: A Multivariable Statistical Analysis. AB - Several clinical studies have identified a strong correlation between neointimal hyperplasia following coronary stent deployment and both stent-induced arterial injury and altered vessel hemodynamics. As such, the sequential structural and fluid dynamics analysis of balloon-expandable stent deployment should provide a comprehensive indication of stent performance. Despite this observation, very few numerical studies of balloon-expandable coronary stents have considered both the mechanical and hemodynamic impact of stent deployment. Furthermore, in the few studies that have considered both phenomena, only a small number of stents have been considered. In this study, a sequential structural and fluid dynamics analysis methodology was employed to compare both the mechanical and hemodynamic impact of six balloon-expandable coronary stents. To investigate the relationship between stent design and performance, several common stent design properties were then identified and the dependence between these properties and both the mechanical and hemodynamic variables of interest was evaluated using statistical measures of correlation. Following the completion of the numerical analyses, stent strut thickness was identified as the only common design property that demonstrated a strong dependence with either the mean equivalent stress predicted in the artery wall or the mean relative residence time predicted on the luminal surface of the artery. These results corroborate the findings of the large-scale ISAR-STEREO clinical studies and highlight the crucial role of strut thickness in coronary stent design. The sequential structural and fluid dynamics analysis methodology and the multivariable statistical treatment of the results described in this study should prove useful in the design of future balloon-expandable coronary stents. PMID- 26577364 TI - Predictive Model Reference Adaptive Controller to Compensate Heart Motion in Minimally Invasive CABG Surgery. AB - Heart beating is a major challenge in minimally invasive coronary artery surgery. A promising solution is to develop a motion compensation robotic system that gives the surgeon an impression of operating on motionless tissue by synchronizing the surgical tool automatically with the heart tissue motion. To achieve higher control accuracy, an intelligent controller called Predictive Model Reference Adaptive Controller is presented herein, which is adapted not only by observed reference signals but, also by unknown reference signals that are not observed by a camera but could be predicted by a state space estimator. To develop such a system, first the heart surface motion is tracked by the Lucas Kanade tracking algorithm and validated by human observation. The results of implementing this control algorithm on a real human heart data set show capability of achieving a motion compensation system with high control accuracy. PMID- 26577365 TI - Particle Image Velocimetry Used to Qualitatively Validate Computational Fluid Dynamic Simulations in an Oxygenator: A Proof of Concept. AB - Computational fluid dynamics (CFD) is used to simulate blood flow inside the fiber bundles of oxygenators. The results are interpreted in terms of flow distribution, e.g., stagnation and shunt areas. However, experimental measurements that provide such information on the local flow between the fibers are missing. A transparent model of an oxygenator was built to perform particle image velocimetry (PIV), to perform the experimental validation. The similitude theory was used to adjust the size of the PIV model to the minimal resolution of the PIV system used (scale factor 3.3). A standard flow of 80 mL/min was simulated with CFD for the real oxygenator and the equivalent flow of 711 mL/min, according to the similitude theory, was investigated with PIV. CFD predicts the global size of stagnation and shunt areas well, but underestimates the streamline length and changes in velocities due to the meandering flow around the real fibers in the PIV model. Symmetrical CFD simulation cannot consider asymmetries in the flow, due to manufacturing-related asymmetries in the fiber bundle. PIV could be useful for validation of CFD simulations; measurement quality however must be improved for a quantitative validation of CFD results and the investigation of flow effects such as tortuosity and anisotropic flow behavior. PMID- 26577366 TI - Convection-Enhanced Transport into Open Cavities : Effect of Cavity Aspect Ratio. AB - Recirculating fluid regions occur in the human body both naturally and pathologically. Diffusion is commonly considered the predominant mechanism for mass transport into a recirculating flow region. While this may be true for steady flows, one must also consider the possibility of convective fluid exchange when the outer (free stream) flow is transient. In the case of an open cavity, convective exchange occurs via the formation of lobes at the downstream attachment point of the separating streamline. Previous studies revealed the effect of forcing amplitude and frequency on material transport rates into a square cavity (Horner in J Fluid Mech 452:199-229, 2002). This paper summarizes the effect of cavity aspect ratio on exchange rates. The transport process is characterized using both computational fluid dynamics modeling and dye-advection experiments. Lagrangian analysis of the computed flow field reveals the existence of turnstile lobe transport for this class of flows. Experiments show that material exchange rates do not vary linearly as a function of the cavity aspect ratio (A = W/H). Rather, optima are predicted for A ~ 2 and A ~ 2.73, with a minimum occurring at A ~ 2.5. The minimum occurs at the point where the cavity flow structure bifurcates from a single recirculating flow cell into two corner eddies. These results have significant implications for mass transport environments where the geometry of the flow domain evolves with time, such as coronary stents and growing aneurysms. Indeed, device designers may be able to take advantage of the turnstile-lobe transport mechanism to tailor deposition rates near newly implanted medical devices. PMID- 26577367 TI - A Wavelet-Based ECG Delineation Method: Adaptation to an Experimental Electrograms with Manifested Global Ischemia. AB - We present a novel wavelet-based ECG delineation method with robust classification of P wave and T wave. The work is aimed on an adaptation of the method to long-term experimental electrograms (EGs) measured on isolated rabbit heart and to evaluate the effect of global ischemia in experimental EGs on delineation performance. The algorithm was tested on a set of 263 rabbit EGs with established reference points and on human signals using standard Common Standards for Quantitative Electrocardiography Standard Database (CSEDB). On CSEDB, standard deviation (SD) of measured errors satisfies given criterions in each point and the results are comparable to other published works. In rabbit signals, our QRS detector reached sensitivity of 99.87% and positive predictivity of 99.89% despite an overlay of spectral components of QRS complex, P wave and power line noise. The algorithm shows great performance in suppressing J-point elevation and reached low overall error in both, QRS onset (SD = 2.8 ms) and QRS offset (SD = 4.3 ms) delineation. T wave offset is detected with acceptable error (SD = 12.9 ms) and sensitivity nearly 99%. Variance of the errors during global ischemia remains relatively stable, however more failures in detection of T wave and P wave occur. Due to differences in spectral and timing characteristics parameters of rabbit based algorithm have to be highly adaptable and set more precisely than in human ECG signals to reach acceptable performance. PMID- 26577368 TI - Towards a Novel Spatially-Resolved Hemolysis Detection Method Using a Fluorescent Indicator and Loaded Ghost Cells: Proof-of-Principle. AB - It is of the utmost importance to reduce flow-induced hemolysis in devices such as heart-valve prostheses and blood pumps. Thus, in vitro measurements of hemolysis are performed in order to optimize their design in this regard. However, with existing measurement methods, hemolysis can only be assessed as an integrated value over the complete test-circuit. Currently, there are no spatially-resolved in vitro hemolysis measurement techniques known to the authors that would allow for a determination of the critical regions within a device. In this study, a novel spatially-resolved measurement principle is proposed. Ghost cells (i.e. erythrocytes with a lower hemoglobin concentration) were loaded with a calcium-dicitrato complex, and a fluorescent calcium indicator was suspended in the extracellular medium. Calcium and indicator are separated until the cell membrane ruptures (i.e. hemolysis occurs). In the moment of hemolysis, the two compounds bind to each other and emit a fluorescent signal that can be recorded and spatially-resolved in a setup very similar to a standard Particle Image Velocimetry measurement. A proof-of-principle experiment was performed by intentionally inducing hemolysis in a flow-model with a surfactant. The surfactant-induced hemolysis demonstrated a clear increase of the fluorescent signal compared to that of a negative reference. Furthermore, the signal was spatially restricted to the area of hemolysis. Although further challenges need to be addressed, a successful proof-of-principle for novel spatially-resolved hemolysis detection is presented. This method can contribute to better design optimization of devices with respect to flow-induced hemolysis. PMID- 26577369 TI - Performance Evaluation of New-Generation Pulse Oximeters in the NICU: Observational Study. AB - This crossover observational study compares the data characteristics and performance of new-generation Nellcor OXIMAX and Masimo SET SmartPod pulse oximeter technologies. The study was conducted independent of either original equipment manufacturer (OEM) across eleven preterm infants in a Neonatal Intensive Care Unit (NICU). The SmartPods were integrated with Drager Infinity Delta monitors. The Delta monitor measured the heart rate (HR) using an independent electrocardiogram sensor, and the two SmartPods collected arterial oxygen saturation (SpO2) and pulse rate (PR). All patient data were non-Gaussian. Nellcor PR showed a higher correlation with the HR as compared to Masimo PR. The statistically significant difference found in their median values (1% for SpO2, 1 bpm for PR) was deemed clinically insignificant. SpO2 alarms generated by both SmartPods were observed and categorized for performance evaluation. Results for sensitivity, positive predictive value, accuracy and false alarm rates were Nellcor (80.3, 50, 44.5, 50%) and Masimo (72.2, 48.2, 40.6, 51.8%) respectively. These metrics were not statistically significantly different between the two pulse oximeters. Despite claims by OEMs, both pulse oximeters exhibited high false alarm rates, with no statistically or clinically significant difference in performance. These findings have a direct impact on alarm fatigue in the NICU. Performance evaluation studies can also impact medical device purchase decisions made by hospital administrators. PMID- 26577370 TI - Personalization Based on Grouping Strategies for Short-Term Cardiovascular Event Risk Assessment. AB - Cardiovascular diseases are the main cause of death in Europe, representing 47% of all deaths. This could be avoided, if each patient underwent the most adequate treatment. For this to happen, it is important to determine the patient's risk of having a cardiovascular event. This is known as risk assessment, and can be done using risk scores. However, there are several risk scores with similar performances, which makes it difficult to choose the most adequate one. We propose to overcome this by combining risk scores using personalization based on groups, where new patients are assigned to the most similar group and consequently to the most adequate risk score. This eliminates the need to choose a specific tool, and improves the overall performance (when compared with the performance of individual tools). This strategy was validated using the Santa Cruz Dataset. The results obtained were able to maintain the highest sensitivity while improving the specificity in 13% when compared with the highest values achieved by the selected individual risk scores (GRACE, TIMI, PURSUIT). PMID- 26577371 TI - ISUOG Practice Guidelines: role of ultrasound in twin pregnancy. PMID- 26577372 TI - Functional outcomes after different types of transoral supraglottic laryngectomy. AB - OBJECTIVES/HYPOTHESIS: To seek a correlation between the four types of transoral supraglottic laryngectomies (TSLs) according to the European Laryngological Society (ELS) and postoperative morbidity. STUDY DESIGN: Retrospective case series at an academic institution. METHODS: Chart review was done for 96 patients affected by T1-T3 supraglottic cancers (28 pT1, 46 pT2, 22 pT3) treated by TSL (29 type I, 14 type II, 35 type III, 18 type IV) with CO2 laser. Five-year overall survival (OS), disease-specific survival (DSS), local control with laser alone (LCL), and organ preservation (OP) were calculated by Kaplan-Meier curves. Thirty-six patients were submitted to swallowing evaluation by M. D. Anderson Dysphagia Inventory (MDADI), videoendoscopy of swallow (VEES), and videofluoroscopy (VFS). Hospitalization, tracheotomy, nasogastric feeding tube (NGFT), and complications were compared between type I-II versus III-IV TSLs for the entire series. MDADI and VEES/VFS scores were compared in the subgroup of 36 patients. RESULTS: Five-year OS, DSS, LCL, and OP rates were 69%, 85.9%, 89.2%, and 92.6%. Mean hospitalization was 9 days, tracheotomy was required in 7% of patients, an NGFT was required in 33%, and 11% experienced complications. Type III-IV TSLs were associated with increased hospitalization (P < .001), more NGFTs (P = .001), and 90% of complications (P = .021). Aspiration was seen in 0% and 9% of type I-II TSLs, and in 7% and 43% of type III-IV TSLs by VEES and VFS, respectively. CONCLUSIONS: Type III-IV TSLs present higher morbidity and complications, thus confirming the utility of the ELS classification in preoperative counseling and therapeutic planning. LEVEL OF EVIDENCE: 4 Laryngoscope, 126:1131-1135, 2016. PMID- 26577373 TI - Photodegradation studies of 1,4-dihydropyridine compounds by MCR analysis on UV spectral data. AB - BACKGROUND: 1,4-Dihydropyridines (DHPs) are well-known light-sensitive compounds. Photostability studies are necessary to ensure safety in therapy. MATERIALS & METHODS: Photodegradation experiments on 15 condensed DHP derivatives were made according to the International Conference on Harmonization rules. Degradation profiles were monitored by spectrophotometry and the data were processed by multivariate curve resolution analysis. RESULTS: The analysis of the spectral data showed the formation of a single photoproduct from two DHPs, due to the aromatization of the pyridine ring. Traces of a second photoproduct were revealed in 12 DHPs and a third photoproduct was verified only in one case. CONCLUSION: DHPs showed high stability when fluorine was in the position R1 of the phenyl ring or simultaneously present in R1 and R2 positions. In contrast, the presence of chlorine in R1 or R2 strongly increased the degradation. PMID- 26577375 TI - HPLC Determination of Fexofenadine in Human Plasma For Therapeutic Drug Monitoring and Pharmacokinetic Studies. AB - A simple and sensitive method was developed for fexofenadine determination in human plasma by liquid chromatography with ultraviolet detection. Satisfactory separation was achieved on a Hypersil(r) BDS C18 column (250 * 4.6 mm, 5MUm) using a mobile phase comprising 20 mm sodium dihydrogen phosphate-2 hydrate (pH adjusted to 3 with phosphoric acid)-acetonitrile at a ratio of 52:48, v/v. The elution was isocratic at ambient temperature with a flow rate of 1.0 mL/min. The UV detector was set at 215 nm for the drug and 330 nm for the internal standared (tinidazole). The total time for a chromatographic separation was ~6.5 min. Linearity was demonstrated over the concentration range 0.01-4 MUg/mL. The observed within- and between-day assay precision ranged from 0.346 to 13.6%; accuracy varied between 100.4 and 111.2%. This method was successfully applied for therapeutic drug monitoring in patients treated with clinical doses of fexofenadine and for pharmacokinetic studies. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26577374 TI - Upregulation of Ih expressed in IB4-negative Adelta nociceptive DRG neurons contributes to mechanical hypersensitivity associated with cervical radiculopathic pain. AB - Cervical radiculopathy represents aberrant mechanical hypersensitivity. Primary sensory neuron's ability to sense mechanical force forms mechanotransduction. However, whether this property undergoes activity-dependent plastic changes and underlies mechanical hypersensitivity associated with cervical radiculopathic pain (CRP) is not clear. Here we show a new CRP model producing stable mechanical compression of dorsal root ganglion (DRG), which induces dramatic behavioral mechanical hypersensitivity. Amongst nociceptive DRG neurons, a mechanically sensitive neuron, isolectin B4 negative Adelta-type (IB4(-) Adelta) DRG neuron displays spontaneous activity with hyperexcitability after chronic compression of cervical DRGs. Focal mechanical stimulation on somata of IB4(-) Adelta neuron induces abnormal hypersensitivity. Upregulated HCN1 and HCN3 channels and increased Ih current on this subset of primary nociceptors underlies the spontaneous activity together with neuronal mechanical hypersensitivity, which further contributes to the behavioral mechanical hypersensitivity associated with CRP. This study sheds new light on the functional plasticity of a specific subset of nociceptive DRG neurons to mechanical stimulation and reveals a novel mechanism that could underlie the mechanical hypersensitivity associated with cervical radiculopathy. PMID- 26577376 TI - Short- and long-term effects of clinical audits on compliance with procedures in CT scanning. AB - PURPOSE: To test the hypothesis that quality clinical audits improve compliance with the procedures in computed tomography (CT) scanning. MATERIALS AND METHODS: This retrospective study was conducted in two hospitals, based on 6950 examinations and four procedures, focusing on the acquisition length in lumbar spine CT, the default tube current applied in abdominal un-enhanced CT, the tube potential selection for portal phase abdominal CT and the use of a specific "paediatric brain CT" procedure. The first clinical audit reported compliance with these procedures. After presenting the results to the stakeholders, a second audit was conducted to measure the impact of this information on compliance and was repeated the next year. Comparisons of proportions were performed using the Chi-square Pearson test. RESULTS: Depending on the procedure, the compliance rate ranged from 27 to 88 % during the first audit. After presentation of the audit results to the stakeholders, the compliance rate ranged from 68 to 93 % and was significantly improved for all procedures (P ranging from <0.001 to 0.031) in both hospitals and remained unchanged during the third audit (P ranging from 0.114 to 0.999). CONCLUSION: Quality improvement through repeated compliance audits with CT procedures durably improves this compliance. KEY POINTS: * Compliance with CT procedures is operator-dependent and not perfect. * Compliance differs between procedures and hospitals, even within a unified department. * Compliance is improved through audits followed by communication to the stakeholders. * This improvement is sustainable over a one-year period. PMID- 26577377 TI - CLIPSeqTools--a novel bioinformatics CLIP-seq analysis suite. AB - Immunoprecipitation of RNA binding proteins (RBPs) after in vivo crosslinking, coupled with sequencing of associated RNA footprints (HITS-CLIP, CLIP-seq), is a method of choice for the identification of RNA targets and binding sites for RBPs. Compared with RNA-seq, CLIP-seq analysis is widely diverse and depending on the RBPs that are analyzed, the approaches vary significantly, necessitating the development of flexible and efficient informatics tools. In this study, we present CLIPSeqTools, a novel, highly flexible computational suite that can perform analysis from raw sequencing data with minimal user input. It contains a wide array of tools to provide an in-depth view of CLIP-seq data sets. It supports extensive customization and promotes improvization, a critical virtue, since CLIP-seq analysis is rarely well defined a priori. To highlight CLIPSeqTools capabilities, we used the suite to analyze Ago-miRNA HITS-CLIP data sets that we prepared from human brains. PMID- 26577378 TI - Systematic study of cis-antisense miRNAs in animal species reveals miR-3661 to target PPP2CA in human cells. AB - MicroRNAs (miRNAs) suppress targeting gene expression through blocking translation or triggering mRNA degradation and, in general, act in trans, through a partially complementary interaction with the 3' untranslated region (3' UTR) or coding regions of a target gene. Although it has been reported previously that some miRNAs suppress their target genes on the opposite strand with a fully complementary sequence (i.e., natural antisense miRNAs that act in cis), there is no report to systematically study such cis-antisense miRNAs in different animal species. Here we report that cis-antisense miRNAs do exist in different animal species: 48 in Caenorhabditis elegans, 17 in Drosophila, 36 in Mus musculus, and 52 in Homo sapiens using a systematical bioinformatics approach. We show that most of these cis-antisense miRNAs can efficiently reduce the expression levels of their target genes in human cells. We further investigate hsa-miR-3661, one of the predicted cis-antisense miRNAs, in detail and demonstrate that this miRNA directly targets the coding sequence of PPP2CA located on the opposite DNA strand and inhibits the PPP2CA expression. Taken together, these results indicate that cis-antisense miRNAs are conservative and functional in animal species including humans. PMID- 26577381 TI - [Lactic acidosis in the postictal state]. AB - Epilepsy is a neurological disorder with an annual incidence in the Netherlands of 30 per 100,000 people. We present two cases of a patient admitted to the emergency department upon experiencing a generalized seizure. In each case, severe metabolic lactic acidosis was identified through routine laboratory diagnostics. Based on their clinical presentation, we had no reasons to suspect another cause of this severe acidosis apart from the seizure. We repeated arterial blood sample one to two hours later and found that both pH and lactate were normalized. Severe lactic acidosis may occur in patients who experience seizures but otherwise do not require treatment. Taking an arterial blood sample from these patients in the emergency setting will be of limited value, because in most patients hyperlactatemia in the postictal state is self-limiting. In some patients, however, a persistent hyperlactatemia may indicate a serious underlying pathology. It is therefore advisable to repeat an arterial blood sample a few hours later. PMID- 26577379 TI - Suppressor of sable [Su(s)] and Wdr82 down-regulate RNA from heat-shock-inducible repetitive elements by a mechanism that involves transcription termination. AB - Although RNA polymerase II (Pol II) productively transcribes very long genes in vivo, transcription through extragenic sequences often terminates in the promoter proximal region and the nascent RNA is degraded. Mechanisms that induce early termination and RNA degradation are not well understood in multicellular organisms. Here, we present evidence that the suppressor of sable [su(s)] regulatory pathway of Drosophila melanogaster plays a role in this process. We previously showed that Su(s) promotes exosome-mediated degradation of transcripts from endogenous repeated elements at an Hsp70 locus (Hsp70-alphabeta elements). In this report, we identify Wdr82 as a component of this process and show that it works with Su(s) to inhibit Pol II elongation through Hsp70-alphabeta elements. Furthermore, we show that the unstable transcripts produced during this process are polyadenylated at heterogeneous sites that lack canonical polyadenylation signals. We define two distinct regions that mediate this regulation. These results indicate that the Su(s) pathway promotes RNA degradation and transcription termination through a novel mechanism. PMID- 26577382 TI - [The BETER survivorship care initiative for Hodgkin lymphoma; tailored survivorship care for late effects of treatment]. AB - The Dutch BETER consortium has established a national care infrastructure for Hodgkin lymphoma survivors. 'BETER' [the Dutch word for 'better'] stands for Better care after Hodgkin lymphoma (HL): Evaluation of long-term Treatment Effects and screening Recommendations. The survivorship care focuses on long-term effects of HL treatment. Over 10,000 HL survivors who were treated in the period spanning 1965-2008 have been identified. As part of the survivorship care initiative, specific BETER out-patient clinics have been set up. A dedicated website, www.beternahodgkin.nl, provides HL survivors with relevant information. The stakeholders of the BETER survivorship care programme aim to achieve an improved healthy life expectancy for patients treated for HL. PMID- 26577380 TI - Identification of Small Molecules Which Induce Skeletal Muscle Differentiation in Embryonic Stem Cells via Activation of the Wnt and Inhibition of Smad2/3 and Sonic Hedgehog Pathways. AB - The multilineage differentiation capacity of mouse and human embryonic stem (ES) cells offers a testing platform for small molecules that mediate mammalian lineage determination and cellular specialization. Here we report the identification of two small molecules which drives mouse 129 ES cell differentiation to skeletal muscle with high efficiency without any genetic modification. Mouse embryoid bodies (EBs) were used to screen a library of 1,000 small molecules to identify compounds capable of inducing high levels of Pax3 mRNA. Stimulation of EBs with SMIs (skeletal muscle inducer, SMI1 and SMI2) from the screen resulted in a high percentage of intensively twitching skeletal muscle fibers 3 weeks after induction. Gene expression profiling studies that were carried out for mode of actions analysis showed that SMIs activated genes regulated by the Wnt pathway and inhibited expression of Smad2/3 and Sonic Hedgehog (Shh) target genes. A combination of three small molecules known to modulate these three pathways acted similarly to the SMIs found here, driving ES cells from 129 as well as Balb/c and C57Bl/6 to skeletal muscle. Taken together, these data demonstrate that the SMI drives ES cells to skeletal muscle via concerted activation of the Wnt pathway, and inhibition of Smad2/3 signaling and Shh pathways. This provides important developmental biological information about skeletal muscle differentiation from embryonic stem cells and may lead to the development of new therapeutics for muscle disease. PMID- 26577383 TI - [Aseptic non-touch technique in the operating room: keep it simple]. AB - OBJECTIVE: The Dutch national patient safety platform developed a protocol for the preparation of intravenous medication; the Aseptic Non-Touch Technique (ANTT). Use of ANTT on nursing wards has shown to reduce contamination of intravenous medication. Therefore it is dictated by the Dutch Healthcare Inspectorate that this technique has to be used at all departments in the hospital, including the operating theatre. However, because of the use of air treatment and operating theatre uniforms, the operating theatre cannot be compared with a nursing ward. In this study, the bacterial contamination of syringes prepared in the operating theatre by anesthesia nurses was determined. DESIGN: Simulation study METHOD: 45 anesthesia nurses prepared 1000 syringes of 10 ml bacterial culture medium, using their routine method of drawing up iv medication from vials. Turbidity in a syringe after culturing for 14 days at 30 degrees C was used as evidence for bacterial contamination. Using questionnaires, nurses were interviewed in what degree their working method equals ANTT-protocol. We calculated how much extra time must be invested when using the strict ANTT-protocol in the operating theatre. RESULTS: Six syringes (0,6%) were contaminated. Normal dermal bacteria were identified in all syringes. The nurses who prepared the contaminated syringes worked similar manner as their colleagues. It takes an additional 54 minutes per day per operating theatre to work strictly using the ANTT technique. CONCLUSION: Contamination rates of aseptic preparations in the OR are very low, and are as low as ANTT preparations in a GMP-certified hospital pharmacy. Therefore it is legitimate to develop a modified ANTT-protocol for use in the operating theatre. PMID- 26577384 TI - [Canopy-enclosed bed for dementia patients with behavioural problems]. AB - Patients with dementia almost all have one or more symptoms of problem behaviour. This problem behaviour includes a wide range of symptoms including depression, anxiety and apathy, and behavioural problems such as aggression, general restlessness, compulsion to walk, disinhibition and calling, and psychotic disorders such as delusions and hallucinations. Due to the persistence and complexity of problem behaviour in patients with dementia, doctors often prescribe psychotropic drugs for long periods of time. In nursing homes there is a great need for non-pharmacological treatments for patients with psychological or psychiatric problems. The canopy-enclosed bed seems to meet this need and has positive effects. We observed that within a few weeks of patients getting a canopy-enclosed bed, psychotropic drugs could be reduced or even stopped. Using a canopy-enclosed bed is a measure of restraint. Therefore it remains important to carefully trade off its deployment with the intended goal. PMID- 26577385 TI - Docosahexaenoic acid inhibits inflammation via free fatty acid receptor FFA4, disruption of TAB2 interaction with TAK1/TAB1 and downregulation of ERK-dependent Egr-1 expression in EA.hy926 cells. AB - SCOPE: Inflammation is intimately associated with many cardiovascular events and docosahexaenoic acid (DHA) has been shown to protect against CVD. Egr-1 has emerged as a key regulator in the development of atherosclerosis. Free fatty acid receptor 4 (FFA4) is an n-3 FA membrane receptor. Tumor necrosis factor alpha (TNF-alpha) is an inflammatory mediator and transforming growth factor-beta activated kinase 1 (TAK1) is essential in the TNF-alpha-mediated activation of NF kappaB. We examined the mechanisms underlying DHA inhibition of inflammation in human EA.hy926 cells. METHODS AND RESULTS: TNF-alpha markedly induced the interaction between TAK1 binding protein (TAB) 2 and TAK1/TAB1, the phosphorylation of ERK, p38 MAPK and Akt, the expression of Egr-1 and ICAM-1, and HL-60 (monocyte-like) cell adhesion. Pretreatment with DHA attenuated TNF-alpha induced phosphorylation of ERK, expression of Egr-1 and ICAM-1 and HL-60 cell adhesion. Transfection with siFFA4 reversed the DHA-mediated inhibition of TNF alpha-induced Egr-1 and ICAM-1 expression, HL-60 cell adhesion and NF-kappaB and DNA-binding activity. CONCLUSION: Our results suggest that the anti-inflammatory effect of DHA on the endothelium is at least partially linked to FFA4, disruption of TAB2 interaction with TAK1/TAB1 and downregulation of ERK-dependent Egr-1 and ICAM-1 expression, which leads to less HL-60 cell adhesion to TNF-alpha stimulated EA.hy926 cells. PMID- 26577387 TI - Fundamental Difference in Reductive Lithiations with Preformed Radical Anions versus Catalytic Aromatic Electron-Transfer Agents: N,N-Dimethylaniline as an Advantageous Catalyst. AB - The reductive lithiation of phenyl thioethers, or alkyl chlorides, by either preformed aromatic radical anions or by lithium metal and an aromatic electron transfer catalyst, is commonly used to prepare organolithiums. Revealed herein is that these two methods are fundamentally different. Reductions with radical anions occur in solution, whereas the catalytic reaction occurs on the surface of lithium, which is constantly reactivated by the catalyst, an unconventional catalyst function. The order of relative reactivity is reversed in the two methods as the dominating factor switches from electronic to steric effects of the alkyl substituent. A catalytic amount of N,N-dimethylaniline (DMA) and Li ribbon can achieve reductive lithiation. DMA is significantly cheaper than alternative catalysts, and conveniently, the Li ribbon does not require the removal of the oxide coating when DMA is used as the catalyst. PMID- 26577386 TI - "Real-World" Comparison of Prasugrel With Ticagrelor in Patients With Acute Coronary Syndrome Treated With Percutaneous Coronary Intervention in the United States. AB - OBJECTIVES: The 30-day clinical outcomes with prasugrel or ticagrelor were compared using a US payer database in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). BACKGROUND: Prasugrel and ticagrelor demonstrated superior efficacy with increased non-coronary artery bypass graft major bleeding compared with clopidogrel in randomized clinical trials. No direct randomized or observational studies have compared clinical outcomes between prasugrel and ticagrelor. METHODS: Patients hospitalized for ACS PCI between August 1, 2011 and April 30, 2013 and prescribed prasugrel or ticagrelor were selected. Drug treatment cohorts were propensity matched based upon demographic and clinical characteristics. The primary objective compared 30 day net adverse clinical events (NACE) in prasugrel- and ticagrelor-treated patients using a prespecified 20% noninferiority margin. Secondary objectives included comparisons of major adverse cardiovascular events (MACE) and major bleeding. RESULTS: Data were available for 16,098 patients (prasugrel, n = 13,134; ticagrelor, n = 2,964). In unmatched cohorts, prasugrel-treated patients were younger with fewer comorbidities than ticagrelor-treated patients, and 30 day NACE rates were 5.6 and 9.3%, respectively (P < 0.001). Following propensity matching, NACE was noninferior (P < 0.001) and 22% lower in prasugrel-treated than in ticagrelor-treated patients (RR, 0.78; 95% CI, 0.64-0.94). A 30-day adjusted MACE (RR, 0.80; 95% CI, 0.64-0.98) and major bleeding (RR, 0.65; 95% CI, 0.45-0.95) were also lower in prasugrel-treated patients compared with ticagrelor treated patients. CONCLUSIONS: In this "real-world," retrospective, observational study, physicians appear to preferentially use prasugrel in younger patients with lower risk of bleeding or comorbidities compared with ticagrelor. Following adjustment, clinical outcomes associated with prasugrel use appear as good, if not better, than those associated with ticagrelor in ACS-PCI patients. (c) 2015 Wiley Periodicals, Inc. PMID- 26577388 TI - Sensitivity and Reusability of SiO2 NRs@ Au NPs SERS Substrate in Trace Monochlorobiphenyl Detection. AB - Surface-enhanced Raman scattering (SERS) effect is quite preferred to detect trace pollutants, and reusable SERS substrate is of important practical value. In this research, a kind of effective SiO2 nanorods (NRs)@ Au nanoparticles (NPs) substrate was fabricated completely with physical methods, and it was quite sensitive so that 1 * 10(-6) M monochlorobiphenyl (CB) could be detected. Furthermore, congeners of CB could be detected by reusing this kind of SERS substrate, and the cleaning treatment between every two detections was very simple. The excellent performance of the reusable SERS substrate indicated its great application potential. PMID- 26577389 TI - Investigation of Hexagonal Mesoporous Silica-Supported Composites for Trace Moisture Adsorption. AB - Moisture control is an important part of effective maintenance program for gas insulated switchgear (GIS). Herein, hexagonal mesoporous silica (HMS) materials were synthesized by adopting dodecylamine as a structure directing agent, which was then employed as a host for supporting polyethylenimine (PEI) without further calcinations or extraction treatment. The physicochemical properties of the silica support and composites were characterized, and the moisture adsorption capacity of these composites was determined. The reserved template agents resulted in a dramatic improvement in moisture adsorption amount. Among them, 50PEI/DHMS showed the highest adsorption value. The enhanced adsorption could be attributed to the generated hydrogen bonding between amino groups and H2O molecules and the improved diffusion of moisture into the bulk networks of PEI polymers due to its better spatial dispersion imposed by the long alkyl chains of template agents, which was confirmed by thermogravimetry results and hydrogen efficiency analysis. Moreover, the maintained terminal amino groups of templates could also function as active sites for moisture adsorption. The results herein imply that the PEI/DHMS composites could be appealing materials for capturing moisture in GIS. PMID- 26577390 TI - Low-Temperature Thermally Reduced Molybdenum Disulfide as a Pt-Free Counter Electrode for Dye-Sensitized Solar Cells. AB - A two-dimensional nanostructure of molybdenum disulfide (MoS2) thin film exposed layered nanosheet was prepared by a low-temperature thermally reduced (TR) method on a fluorine-doped tin oxide (FTO) glass substrate as a platinum (Pt)-free and highly electrocatalytic counter electrode (CE) for dye-sensitized solar cells (DSSCs). Thermogravimetric analysis (TGA) results show that the MoS2 sulfidization temperature was approximately 300 degrees C. X-ray photoelectron spectroscopy (XPS), high-resolution transmission electron microscopy (HRTEM), and X-ray diffraction (XRD) indicate that the stoichiometry and crystallization of MoS2 were more complete at higher temperatures; however, these temperatures reduce the number of edge-plane active sites in the short-range-order nanostructure. Accordingly, the DSSCs with 300 degrees C annealed TR-MoS2 CE exhibited an excellent photovoltaic conversion efficiency (PCE) of 6.351 %, up to 91.7 % of which is obtained using the conventional TD-Pt CE (PCE = 6.929 %). The temperature of thermal reaction and the molar ratio of reaction precursors were found to significantly influence the resulting stoichiometry and crystallization of MoS2 nanosheets, thus affecting DSSCs' performance. PMID- 26577391 TI - Substrate-Free InGaN/GaN Nanowire Light-Emitting Diodes. AB - We report on the demonstration of substrate-free nanowire/polydimethylsiloxane (PDMS) membrane light-emitting diodes (LEDs). Metal-organic vapour-phase epitaxy (MOVPE)-grown InGaN/GaN core-shell nanowires were encapsulated into PDMS layer. After metal deposition to p-GaN, a thick PDMS cap layer was spin-coated and the membrane was manually peeled from the sapphire substrate, flipped upside down onto a steel holder, and transparent indium tin oxide (ITO) contact to n-GaN was deposited. The fabricated LEDs demonstrate rectifying diode characteristics. For the electroluminescence (EL) measurements, the samples were manually bonded using silver paint. The EL spectra measured at different applied voltages demonstrate a blue shift with the current increase. This shift is explained by the current injection into the InGaN areas of the active region with different average indium content. PMID- 26577392 TI - Serum Proteins Enhance Dispersion Stability and Influence the Cytotoxicity and Dosimetry of ZnO Nanoparticles in Suspension and Adherent Cancer Cell Models. AB - Agglomeration and sedimentation of nanoparticles (NPs) within biological solutions is a major limitation in their use in many downstream applications. It has been proposed that serum proteins associate with the NP surface to form a protein corona that limits agglomeration and sedimentation. Here, we investigate the effect of fetal bovine serum (FBS) proteins on the dispersion stability, dosimetry, and NP-induced cytotoxicity of cationic zinc oxide nanoparticles (nZnO) synthesized via forced hydrolysis with a core size of 10 nm. Two different in vitro cell culture models, suspension and adherent, were evaluated by comparing a phosphate buffered saline (PBS) nZnO dispersion (nZnO/PBS) and an FBS stabilized PBS nZnO dispersion (nZnO - FBS/PBS). Surface interactions of FBS on nZnO were analyzed via spectroscopic and optical techniques. Fourier transformed infrared spectroscopy (FTIR) confirmed the adsorption of negatively charged protein components on the cationic nZnO surface through the disappearance of surfaced-adsorbed carboxyl functional groups and the subsequent detection of vibrational modes associated with the protein backbone of FBS-associated proteins. Further confirmation of these interactions was noted in the isoelectric point shift of the nZnO from the characteristic pH of 9.5 to a pH of 6.1. In nZnO - FBS/PBS dispersions, the FBS reduced agglomeration and sedimentation behaviors to impart long-term improvements (>24 h) to the nZnO dispersion stability. Furthermore, mathematical dosimetry models indicate that nZnO - FBS/PBS dispersions had consistent NP deposition patterns over time unlike unstable nZnO/PBS dispersions. In suspension cell models, the stable nZnO - FBS/PBS dispersion resulted in a ~33 % increase in the NP-induced cytotoxicity for both Jurkat leukemic and Hut-78 lymphoma cancer cells. In contrast, the nZnO - FBS/PBS dispersion resulted in 49 and 71 % reductions in the cytotoxicity observed towards the adherent breast (T-47D) and prostate (LNCaP) cancer cell lines, respectively. Presence of FBS in the NP dispersions also increased the reactive oxygen species generation. These observations indicate that the improved dispersion stability leads to increased NP bioavailability for suspension cell models and reduced NP sedimentation onto adherent cell layers resulting in more accurate in vitro toxicity assessments. PMID- 26577393 TI - Short-term effects of a dynamic neutralization system (Dynesys) for multi segmental lumbar disc herniation. AB - PURPOSE: To determine the safety and short-term curative effects of internal fixation using a dynamic neutralization system (Dynesys) for multi-segmental lumbar disc herniation (ms-LDH) with the control group treated by posterior lumbar interbody fusion (PLIF). METHODS: Forty-five patients with ms-LDH were selected as study group treated with Dynesys and 40 patients as control group with PLIF. The surgical efficacy was evaluated by comparing the visual analogue scale (VAS) scores, the Oswestry Disability Index (ODI) scores and the ROMs of the adjacent segment before and after surgery. The postoperative complications related to the implants were identified. RESULTS: All patients were followed up for an average duration of over 30 months. Dynesys stabilization resulted in significantly higher preservation of motion at the index level (p < 0.001), and significantly less (p < 0.05) hypermobility at the adjacent segments. VAS for back and leg pain and ODI improved significantly (p < 0.05) with both the methods, but there was no significant difference between the groups. CONCLUSIONS: The non-fusion fixation system Dynesys is safe and effective regarding short-term curative effects for the treatment of ms-LDH. PMID- 26577394 TI - Anatomical considerations for percutaneous trans ilio-sacroiliac S1 and S2 screw placement. AB - OBJECTIVE: To determine the presence of a consistent osseous corridor through S1 and S2 and fluoroscopic landmarks thereof, which could be used for safe trans ilio-sacroiliac screw fixation of posterior pelvic ring disorders. STUDY DESIGN: Computed tomography (CT) based anatomical investigation utilising multiplanar image and trajectory reconstruction (Agfa-IMPAX Version 5.2 software). Determination of the presence and dimension of a continuous osseous corridor in the coronal plane of the sacrum at the S1 and S2 vertebral levels. OUTCOME MEASURES: Determination of: (a) the presence of an osseous corridor in the coronal plane through S1 and S2 in males and females; (b) the dimension of the corridor with regard to diameter and length; (c) the fluoroscopic landmarks of the corridor. RESULTS: The mean cross-sectional area for S1 corridors in males and females was 2.13 and 1.47 cm(2) , respectively. The mean cross-sectional area for the S2 corridor in males and females was 1.46 and 1.13 cm(2), respectively. The limiting anatomical factor is the sagittal diameter of the sacral ala at the junction to the vertebral body. The centre of the S1 and S2 corridor is located in close proximity to the centre of the S1 and S2 vertebrae on the lateral fluoroscopic view as determined by the adjacent endplates and anterior and posterior vertebral cortices. CONCLUSION: Two-thirds of males and females have a complete osseous corridor to pass a trans-sacroiliac S1 screw of 8 mm diameter. The S2 corridor was present in all males but only in 87 % of females. Preoperative review of the axial CT slices at the midpoint of the S1 or S2 vertebral body allows the presence of a trans-sacroiliac osseous corridor to be determined by assessing the passage at the narrowest point of the corridor at the junction of the sacral ala to the vertebral body. PMID- 26577395 TI - Spinal Taenia solium cysticercosis. PMID- 26577397 TI - Polarity Thinking: Another Tool in Advancing the Knowledge of Registered Dietitian Nutritionists. PMID- 26577396 TI - Experimental Post-traumatic Stress Disorder Decreases Astrocyte Density and Changes Astrocytic Polarity in the CA1 Hippocampus of Male Rats. AB - Post-traumatic stress disorder (PTSD) is a psychiatric condition resulting from exposure to a traumatic event. It is characterized by several debilitating symptoms including re-experiencing the past trauma, avoidance behavior, increased fear, and hyperarousal. Key roles in the neuropathology of PTSD and its symptomatology have been attributed to the hippocampus and amygdala. These regions are involved in explicit memory processes and context encoding during fear conditioning. The aim of our study was to investigate whether PTSD is capable of altering the morphology, density and expression of glial fibrillary acidic protein (GFAP) in astrocytes from the CA1 region of the hippocampus and the medial amygdala and correlate the data obtained with the orientation index of the polarity of astrocytes. Thirty male rats were divided in two groups: control (n = 15) and PTSD (n = 15). The inescapable shock protocol, in which the animals are exposed to a single episode of footshock, was used to induce PTSD. Our results show that, in the hippocampus, PTSD is capable of decreasing the density of GFAP+ astrocytes as well as altering astrocytic morphology, as shown by the reductions observed in the total number of primary processes, in the number of primary processes in the lateral quadrants, and the degree of branching in the lateral quadrants. The analysis of the orientation index indicates that PTSD alters the polarity of hippocampal astrocytes. No alterations were observed in the amygdala astrocytes. Therefore, this study demonstrates notable changes in hippocampal astrocytes, supporting the concept that these cells play an important role in PTSD symptomatology. PMID- 26577398 TI - Synthesis, characterization and biocompatibility of cadmium sulfide nanoparticles capped with dextrin for in vivo and in vitro imaging application. AB - BACKGROUND: The safe use in biomedicine of semiconductor nanoparticles, also known as quantum dots (QDs), requires a detailed understanding of the biocompatibility and toxicity of QDs in human beings. The biological characteristics and physicochemical properties of QDs entail new challenges regarding the management of potential adverse health effects following exposure. At certain concentrations, the synthesis of semiconductor nanoparticles of CdS using dextrin as capping agent, at certain concentration, to reduce their toxicity and improves their biocompatibility. RESULTS: This study successfully synthesized and characterized biocompatible dextrin-coated cadmium sulfide nanoparticles (CdS-Dx/QDs). The results show that CdS-Dx/QDs are cytotoxic at high concentrations (>2 MUg/mL) in HepG2 and HEK293 cells. At low concentrations (<1 MUg/mL), CdS-Dx/QDs were not toxic to HepG2 or HeLa cells. CdS-Dx nanoparticles only induced cell death by apoptosis in HEK293 cells at 1 MUg/mL concentrations. The in vitro results showed that the cells efficiently took up the CdS-Dx/QDs and this resulted in strong fluorescence. The subcellular localization of CdS-Dx/QDs were usually small and apparently unique in the cytoplasm in HeLa cells but, in the case of HEK293 cells it were more abundant and found in cytoplasm and the nucleus. Animals treated with 100 MUg/kg of CdS Dx/QDs and sacrificed at 3, 7 and 18 h showed a differential distribution in their organs. Intense fluorescence was detected in lung and kidney, with moderate fluorescence detected in liver, spleen and brain. The biocompatibility and toxicity of CdS-Dx/QDs in animals treated daily with 100 MUg/kg for 1 week showed the highest level of fluorescence in kidney, liver and brain. Less fluorescence was detected in lung and spleen. There was also evident presence of fluorescence in testis. The histopathological and biochemical analyses showed that CdS-Dx/QDs were non-toxic for rodents. CONCLUSIONS: The in vitro and in vivo studies confirmed the effective cellular uptake and even distribution pattern of CdS Dx/QDs in tissues. CdS-Dx/QDs were biocompatible with tissues from rodents. The CdS-Dx/QDs used in this study can be potentially used in bio-imaging applications. PMID- 26577399 TI - Developmental cuprizone exposure impairs oligodendrocyte lineages differentially in cortical and white matter tissues and suppresses glutamatergic neurogenesis signals and synaptic plasticity in the hippocampal dentate gyrus of rats. AB - Developmental cuprizone (CPZ) exposure impairs rat hippocampal neurogenesis. Here, we captured the developmental neurotoxicity profile of CPZ using a region specific expression microarray analysis in the hippocampal dentate gyrus, corpus callosum, cerebral cortex and cerebellar vermis of rat offspring exposed to 0, 0.1, or 0.4% CPZ in the maternal diet from gestation day 6 to postnatal day (PND) 21. Transcripts of those genes identified as altered were subjected to immunohistochemical analysis on PNDs 21 and 77. Our results showed that transcripts for myelinogenesis-related genes, including Cnp, were selectively downregulated in the cerebral cortex by CPZ at >=0.1% or 0.4% on PND 21. CPZ at 0.4% decreased immunostaining intensity for 2',3'-cyclic-nucleotide 3' phosphodiesterase (CNPase) and CNPase(+) and OLIG2(+) oligodendrocyte densities in the cerebral cortex, whereas CNPase immunostaining intensity alone was decreased in the corpus callosum. By contrast, a striking transcript upregulation for Klotho gene and an increased density of Klotho(+) oligodendrocytes were detected in the corpus callosum at >=0.1%. In the dentate gyrus, CPZ at >=0.1% or 0.4% decreased the transcript levels for Gria1, Grin2a and Ptgs2, genes related to the synapse and synaptic transmission, and the number of GRIA1(+) and GRIN2A(+) hilar gamma-aminobutyric acid (GABA)-ergic interneurons and cyclooxygenase-2(+) granule cells. All changes were reversed at PND 77. Thus, developmental CPZ exposure reversibly decreased mature oligodendrocytes in both cortical and white matter tissues, and Klotho protected white matter oligodendrocyte growth. CPZ also reversibly targeted glutamatergic signals of GABAergic interneuron to affect dentate gyrus neurogenesis and synaptic plasticity in granule cells. PMID- 26577400 TI - Boosting in Nonlinear Regression Models with an Application to DCE-MRI Data. AB - BACKGROUND: For the statistical analysis of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) data, compartment models are a commonly used tool. By these models, the observed uptake of contrast agent in some tissue over time is linked to physiologic properties like capillary permeability and blood flow. Up to now, models of different complexity have been used, and it is still unclear which model should be used in which situation. In previous studies, it has been found that for DCE-MRI data, the number of compartments differs for different types of tissue, and that in cancerous tissue, it might actually differ over a region of voxels of one DCE-MR image. OBJECTIVES: To find the appropriate number of compartments and estimate the parameters of a regression model for each voxel in an DCE-MR image. With that, tumors in an DCE-MR image can be located, and for example therapy success can be assessed. METHODS: The observed uptake of contrast agent in a voxel of an image of some tissue is described by a concentration time curve. This curve can be modeled using a nonlinear regression model. We present a boosting approach with nonlinear regression as base procedure, which allows us to estimate the number of compartments and the related parameters for each voxel of an DCE-MR image. In addition, a spatially regularized version of this approach is proposed. RESULTS: With the proposed approach, the number of compartments - and with that the complexity of the model - per voxel is not fixed but data-driven, which allows us to fit models of adequate complexity to the concentration time curves of all voxels. The parameters of the model remain nevertheless interpretable because of the underlying compartment model. CONCLUSIONS: The proposed boosting approaches outperform all competing methods considered in this paper regarding the correct localization of tumors in DCE-MR images as well as the spatial homogeneity of the estimated number of compartments across the image, and the definition of the tumor edge. PMID- 26577403 TI - Reflections on a Career in Epilepsy. PMID- 26577401 TI - An experimentally supported model of the Bacillus subtilis global transcriptional regulatory network. AB - Organisms from all domains of life use gene regulation networks to control cell growth, identity, function, and responses to environmental challenges. Although accurate global regulatory models would provide critical evolutionary and functional insights, they remain incomplete, even for the best studied organisms. Efforts to build comprehensive networks are confounded by challenges including network scale, degree of connectivity, complexity of organism-environment interactions, and difficulty of estimating the activity of regulatory factors. Taking advantage of the large number of known regulatory interactions in Bacillus subtilis and two transcriptomics datasets (including one with 38 separate experiments collected specifically for this study), we use a new combination of network component analysis and model selection to simultaneously estimate transcription factor activities and learn a substantially expanded transcriptional regulatory network for this bacterium. In total, we predict 2,258 novel regulatory interactions and recall 74% of the previously known interactions. We obtained experimental support for 391 (out of 635 evaluated) novel regulatory edges (62% accuracy), thus significantly increasing our understanding of various cell processes, such as spore formation. PMID- 26577402 TI - Mediation Analysis of the Efficacy of the Eban HIV/STD Risk-Reduction Intervention for African American HIV Serodiscordant Couples. AB - Targeting couples is a promising behavioral HIV risk-reduction strategy, but the mechanisms underlying the effects of such interventions are unknown. We report secondary analyses testing whether Social-Cognitive-Theory variables mediated the Eban HIV-risk-reduction intervention's effects on condom-use outcomes. In a multisite randomized controlled trial conducted in four US cities, 535 African American HIV-serodiscordant couples were randomized to the Eban HIV risk reduction intervention or attention-matched control intervention. Outcomes were proportion condom-protected sex, consistent condom use, and frequency of unprotected sex measured pre-, immediately post-, and 6 and 12 months post intervention. Potential mediators included Social-Cognitive-Theory variables: outcome expectancies and self-efficacy. Mediation analyses using the product-of coefficients approach in a generalized-estimating-equations framework revealed that condom-use outcome expectancy, partner-reaction outcome expectancy, intention, self-efficacy, and safer-sex communication improved post-intervention and mediated intervention-induced improvements in condom-use outcomes. These findings underscore the importance of targeting outcome expectancies, self efficacy, and safer-sex communication in couples-level HIV risk-reduction interventions. PMID- 26577404 TI - Erratum to: Development and feasibility study of very brief interventions for physical activity in primary care. AB - Upon publication of this article [1] it has been noted that due to a technical error the publisher missed to include the Open Access Licence statement in the copyright line. The correct copyright line should have read: (c) 2015 Pears et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. PMID- 26577405 TI - [Biological basis of problematic internet use (PIN) and therapeutic implications]. AB - The repetitive excessive use of internet has led to an increasing number of reports about the negative consequences of overuse and is now viewed as an important public health issue, although the diagnosis of internet addiction remains problematic. Increasing knowledge about the neurobiological mechanism of behavioral addictions will promote future research and is essential for the development of specific and effective treatment. Growing evidence suggests that the neurobiological substrates and pathways of internet addiction resemble those of substance dependency and other forms of behavioral addictions. This paper reviews the current neuroimaging findings and genetic influencing factors for problematic internet use (PIN)/internet addiction. Recent evidence from neuro scientific studies has pointed out that certain dysfunctions in the prefrontal cortex possibly driven by impaired dopamine neurotransmission are related to symptoms of internet addiction. Finally the literature on psychological and pharmacological interventions for internet addiction will be discussed. However, due to a lack of methodological sound treatment studies in this field it is currently impossible to recommend any evidence-based treatment of internet addiction. PMID- 26577406 TI - Itinerary of high density lipoproteins in endothelial cells. AB - High density lipoprotein (HDL) and its main protein component apolipoprotein A-I (ApoA-I) have multiple anti-atherogenic functions. Some of them are exerted within the vessel wall, so that HDL needs to pass the endothelial barrier. To elucidate their itinerary through endothelial cells (ECs), we labelled ApoA-I and HDL either fluorescently or with 1.4 nm nanogold and investigated their cellular localization by using immunofluorescent microscopy (IFM) and electron microscopy (EM). HDL as well as ApoA-I is taken up by ECs into the same route of intracellular trafficking. Time kinetics and pulse chase experiments revealed that HDL is trafficked through different vesicles. HDL partially co-localized with LDL, albumin, and transferrin. HDL did not co-localize with clathrin and caveolin-1. Fluorescent HDL was recovered at small proportions in early endosomes and endosome to trans-golgi network vesicles but not at all in recycling endosomes, in late endosomes or lysosomes. EM identified HDL mainly in large filled vesicles which however upon IFM did not colocalize with markers of multivesicular bodies or autophagosomes. The uptake or cellular distribution of HDL was altered upon pharmacological interference with cytochalasine D, colchicine and dynasore. Blockage of fluid phase uptake with Amiloride or EIPA did not reduce the uptake of HDL. Neither did we observe any co-localization of HDL with dextran as the marker of fluid phase uptake. In conclusion, HDL and ApoA I are internalized and trafficked by endothelial cells through a non-classical endocytic route. PMID- 26577407 TI - Overexpression of the autophagy-related gene SiATG8a from foxtail millet (Setaria italica L.) confers tolerance to both nitrogen starvation and drought stress in Arabidopsis. AB - Autophagy is an evolutionarily conserved biological process in all eukaryotes for the degradation of intracellular components for nutrient recycling. Autophagy is known to be involved in responses to low nitrogen stress in Arabidopsis. Foxtail millet has strong abiotic stress resistance to both low nutrient and drought stress. However, to date, there have only been a few genes reported to be related with abiotic stress resistance in foxtail millet. In this study, we identified an autophagy-related gene, SiATG8a, from foxtail millet. SiATG8a is mainly expressed in stems and its expression was dramatically induced by drought stress and nitrogen starvation treatments. SiATG8a was localized in the membrane and cytoplasm of foxtail millet. Overexpression of SiATG8a in Arabidopsis conferred tolerance to both nitrogen starvation and to drought stress. Under nitrogen starvation conditions, the SiATG8a transgenic plants had larger root and leaf areas and accumulated more total nitrogen than wild-type plants. The transgenic plants had lower total protein concentrations than did the WT plants. Under drought stress, the SiATG8a transgenic plants had higher survival rates, chlorophyll content, and proline content, but had lower MDA content than wild type plants. Taken together, our results represent the first identified case where overexpression of autophagy related gene can simultaneously improve plant resistance to low nitrogen and drought stresses. These findings implicate plant autophagy in plant stress responses to low nitrogen and drought and should be helpful in efforts to improve stresses resistance to nitrogen starvation and drought of crops by genetic transformation. PMID- 26577408 TI - Significance of Ser-188 in human mitochondrial NAD kinase as determined by phosphomimetic and phosphoresistant amino-acid substitutions. AB - Human mitochondrial NAD kinase is a crucial enzyme responsible for the synthesis of mitochondrial NADP(+). Despite its significance, little is known about the regulation of this enzyme in the mitochondria. Several putative and known phosphorylation sites within the protein have been found using phosphoproteomics, and here, we examined the effect of phosphomimetic mutations at six of these sites. The enzymatic activity was downregulated by a substitution of an Asp residue at Ser-289 and Ser-376, but not a substitution of Ala, suggesting that the phosphorylation of these residues downregulates the enzyme. Moreover, the activity was completely inhibited by substituting Ser-188 with an Asp, Glu, or in particular Ala, which highlights two possibilities: first, that Ser-188 is critical for catalytic activity, and second, that phosphorylation of Ser-188 inhibits the activity. Ser-188, Ser-289, and Ser-376 were found to be highly conserved in the primary structures of mitochondrial NAD kinase homologs in higher animals. Moreover, Ser-188 has been frequently detected in human and mouse phosphorylation site studies, whereas Ser-289 and Ser-376 have not. Taken together, this indicates that Ser-188 (and perhaps the other residues) is an important phosphorylation site that can downregulate the NAD kinase activity of this critical enzyme. PMID- 26577409 TI - Directed evolution of nitrilase PpL19 from Pseudomonas psychrotolerans L19 and identification of enantiocomplementary mutants toward mandelonitrile. AB - Nitrilase PpL19 from Pseudomonas psychrotolerans L19 can hydrolyze racemic mandelonitrile to (S)-mandelic acid with an enantiomeric excess (ee) value of 52.7%. In this study, random mutagenesis combined with site-directed mutagenesis was performed to identify the key residues responsible for nitrilase enantioselectivity. Five enzyme mutants exhibiting distinct selectivity were generated and four "hot spots" (M113, R128, A136, and I168) responsible for enantioselectivity toward mandelonitrile were identified and characterized. Furthermore, through saturation mutagenesis, positions 113 and 128 were confirmed to substantially influence the enantioselectivity of PpL19, and certain replacements of the methionine at position 113, in particular, were found to reverse the enantioselectivity of PpL19 from S- to R-selectivity. Two other single mutants of the enzyme, PpL19-A136Y and -I168Y, also showed reversed selectivity and preferentially produced (R)-mandelic acid (ee values: 66.7% and 74.3%, respectively). By combining the beneficial mutations, two enantiocomplementary nitrilase mutants, PpL19-LH and PpL19-GYY, were created, which exhibited high S- and R-selectivity toward mandelonitrile, respectively: PpL19-LH showed the highest S-selectivity toward mandelonitrile ever reported (91.1% ee), and, notably, the PpL19-GYY mutant was identified to be highly R selective (90.1% ee) and thus an unexpected enantiocomplementary mutant for mandelonitrile. PMID- 26577410 TI - Sirt3 binds to and deacetylates mitochondrial pyruvate carrier 1 to enhance its activity. AB - Mitochondrial pyruvate carrier (MPC), composed of MPC1 and MPC2, can modulate pyruvate oxidation in mitochondrial and MPC1 expression correlates with poor prognosis of multiple cancers. Here, we reported that MPC1 is acetylated and its main acetylation sites are: K45 and K46. Sirt3 binds to and deacetylates MPC1. High glucose decreases MPC1 acetylation level by increasing Sirt3-MPC1 binding. Furthermore, acetylation mimic mutation of MPC1 reduces it activity and abolishes its function in inhibition of colon cancer cell growth. These results reveal a novel post-translational regulation of MPC1 by Sirt3, which is important for its activity and colon cancer cell growth. PMID- 26577411 TI - Blockade of Drp1 rescues oxidative stress-induced osteoblast dysfunction. AB - Osteoblast dysfunction, induced by oxidative stress, plays a critical role in the pathophysiology of osteoporosis. However, the underlying mechanisms remain unclarified. Imbalance of mitochondrial dynamics has been closely linked to oxidative stress. Here, we reveal an unexplored role of dynamic related protein 1(Drp1), the major regulator in mitochondrial fission, in the oxidative stress induced osteoblast injury model. We demonstrate that levels of phosphorylation and expression of Drp1 significantly increased under oxidative stress. Blockade of Drp1, through pharmaceutical inhibitor or gene knockdown, significantly protected against H2O2-induced osteoblast dysfunction, as shown by increased cell viability, improved cellular alkaline phosphatase (ALP) activity and mineralization and restored mitochondrial function. The protective effects of blocking Drp1 in H2O2-induced osteoblast dysfunction were evidenced by increased mitochondrial function and suppressed production of reactive oxygen species (ROS). These findings provide new insights into the role of the Drp1-dependent mitochondrial pathway in the pathology of osteoporosis, indicating that the Drp1 pathway may be targetable for the development of new therapeutic approaches in the prevention and the treatment of osteoporosis. PMID- 26577412 TI - Protective effect of carbenoxolone on ER stress-induced cell death in hypothalamic neurons. AB - Hypothalamic endoplasmic reticulum (ER) stress is known to be increased in obesity. Induction of ER stress on hypothalamic neurons has been reported to cause hypothalamic neuronal apoptosis and malfunction of energy balance, leading to obesity. Carbenoxolone is an 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitor that converts inactive glucocorticoid into an active form. In addition to its metabolic effect via enzyme inhibitory action, carbenoxolone has shown anti-apoptotic activity in several studies. In this study, the direct effects of carbenoxolone on ER stress and cell death in hypothalamic neurons were investigated. Carbenoxolone attenuated tunicamycin induced ER stress-mediated molecules such as spliced XBP1, ATF4, ATF6, CHOP, and ROS generation. In vivo study also revealed that carbenoxolone decreased tunicamycin-induced ER stress in the hypothalamus. In conclusion, the results of this study show that carbenoxolone has protective effects against tunicamycin induced-ER stress and apoptosis in hypothalamic neurons, suggesting its direct protective effects against obesity. Further study is warranted to clarify the effects of carbenoxolone on hypothalamic regulation of energy balance in obesity. PMID- 26577413 TI - Cellulitis-Like Rash Associated with Kawasaki Disease. AB - We present the case of a 5-year-old-boy who developed a fever and cellulitis-like groin rash 5 days before developing conjunctivitis and 6 to 7 days before other typical signs of Kawasaki disease (KD) appeared. The cellulitis failed to respond to antibiotics and no pathogens were isolated. His fever and clinical signs resolved with intravenous immunoglobulin and high-dose aspirin after discontinuation of antibiotics. Nonbacterial cellulitis is a rare presenting sign of KD, but in the appropriate clinical setting and population, a diagnosis of KD should be considered when cellulitis and fever fail to respond to an appropriate antibiotic regimen and no pathogen can be isolated. PMID- 26577414 TI - A Type 1 Diabetes Genetic Risk Score Can Aid Discrimination Between Type 1 and Type 2 Diabetes in Young Adults. AB - OBJECTIVE: With rising obesity, it is becoming increasingly difficult to distinguish between type 1 diabetes (T1D) and type 2 diabetes (T2D) in young adults. There has been substantial recent progress in identifying the contribution of common genetic variants to T1D and T2D. We aimed to determine whether a score generated from common genetic variants could be used to discriminate between T1D and T2D and also to predict severe insulin deficiency in young adults with diabetes. RESEARCH DESIGN AND METHODS: We developed genetic risk scores (GRSs) from published T1D- and T2D-associated variants. We first tested whether the scores could distinguish clinically defined T1D and T2D from the Wellcome Trust Case Control Consortium (WTCCC) (n = 3,887). We then assessed whether the T1D GRS correctly classified young adults (diagnosed at 20-40 years of age, the age-group with the most diagnostic difficulty in clinical practice; n = 223) who progressed to severe insulin deficiency <3 years from diagnosis. RESULTS: In the WTCCC, the T1D GRS, based on 30 T1D-associated risk variants, was highly discriminative of T1D and T2D (area under the curve [AUC] 0.88 [95% CI 0.87-0.89]; P < 0.0001), and the T2D GRS added little discrimination (AUC 0.89). A T1D GRS >0.280 (>50th centile in those with T1D) is indicative of T1D (50% sensitivity, 95% specificity). A low T1D GRS (<0.234, <5th centile T1D) is indicative of T2D (53% sensitivity, 95% specificity). Most discriminative ability was obtained from just nine single nucleotide polymorphisms (AUC 0.87). In young adults with diabetes, T1D GRS alone predicted progression to insulin deficiency (AUC 0.87 [95% CI 0.82-0.92]; P < 0.0001). T1D GRS, autoantibody status, and clinical features were independent and additive predictors of severe insulin deficiency (combined AUC 0.96 [95% CI 0.94-0.99]; P < 0.0001). CONCLUSIONS: A T1D GRS can accurately identify young adults with diabetes who will require insulin treatment. This will be an important addition to correctly classifying individuals with diabetes when clinical features and autoimmune markers are equivocal. PMID- 26577415 TI - Relationship Between Parental Diabetes and Presentation of Metabolic and Glycemic Function in Youth With Type 2 Diabetes: Baseline Findings From the TODAY Trial. AB - OBJECTIVE: Children whose parents have diabetes are at increased risk for developing type 2 diabetes. This report assessed relationships between parental diabetes status and baseline demographics, anthropometrics, metabolic measurements, insulin sensitivity, and beta-cell function in children recently diagnosed with type 2 diabetes. RESEARCH DESIGN AND METHODS: The sample included 632 youth (aged 10-17 years) diagnosed with type 2 diabetes for <2 years who participated in the TODAY clinical trial. Medical history data were collected at baseline by self-report from parents and family members. Youth baseline measurements included an oral glucose tolerance test and other measures collected by trained study staff. RESULTS: Youth exposed to maternal diabetes during pregnancy (whether the mother was diagnosed with diabetes prior to pregnancy or had gestational diabetes mellitus) were diagnosed at younger ages (by 0.6 years on average), had greater dysglycemia at baseline (HbA1c increased by 0.3% [3.4 mmol/mol]), and had reduced beta-cell function compared with those not exposed (C peptide index 0.063 vs. 0.092). The effect of maternal diabetes on beta-cell function was observed in non-Hispanic blacks and Hispanics but not whites. Relationships with paternal diabetes status were minimal. CONCLUSIONS: Maternal diabetes prior to or during pregnancy was associated with poorer glycemic control and beta-cell function overall but particularly in non-Hispanic black and Hispanic youth, supporting the hypothesis that fetal exposure to aberrant metabolism may have long-term effects. More targeted research is needed to understand whether the impact of maternal diabetes is modified by racial/ethnic factors or whether the pathway to youth-onset type 2 diabetes differs by race/ethnicity. PMID- 26577416 TI - Low Carbohydrate-Diet Scores and Long-term Risk of Type 2 Diabetes Among Women With a History of Gestational Diabetes Mellitus: A Prospective Cohort Study. AB - OBJECTIVE: Low-carbohydrate diets (LCDs) may improve short-term glycemic control in patients with gestational diabetes mellitus (GDM), but the long-term effect on progression from GDM to type 2 diabetes mellitus (T2DM) is unknown. We aimed to examine the long-term risk of T2DM in association with a low-carbohydrate dietary pattern among women with a history of GDM. RESEARCH DESIGN AND METHODS: Overall, 4,502 women with a history of GDM from the Nurses' Health Study II (NHSII) cohort, as part of the Diabetes & Women's Health (DWH) study, were followed up from 1991 to 2011. Overall, animal, or vegetable LCD scores, which represent adherence to different low-carbohydrate dietary patterns, were calculated using diet intake information assessed every 4 years since 1991 by validated food frequency questionnaires. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% CIs. RESULTS: We documented 722 incident cases of T2DM during 68,897 person-years of observation. The multivariable-adjusted HRs (95% CIs) of T2DM, comparing the highest with lowest quintiles, were 1.36 (1.04 1.78) for overall LCD score (P = 0.003 for trend), 1.40 (1.06-1.84) for animal LCD score (P = 0.004 for trend), and 1.19 (0.91-1.55) for vegetable LCD score (P = 0.50 for trend). CONCLUSIONS: Among women with a history of GDM, a low carbohydrate dietary pattern, particularly with high protein and fat intake mainly from animal-source foods, is associated with higher T2DM risk, whereas a low-carbohydrate dietary pattern with high protein and fat intake from plant source foods is not significantly associated with risk of T2DM. PMID- 26577419 TI - Autologous hematopoietic stem cell transplantation (AHSCT) for aggressive multiple sclerosis - whom, when and how. AB - Multiple sclerosis (MS) is an autoimmune disease of the central nervous system that leads to an inflammatory process resulting in demyelination and axonal degeneration. The most common form of MS is the relapsing-remitting MS (RRMS) characterized by the presence of numerous relapses. After few years of disease course, 90% of those patients eventually develop a secondary progressive form. About 10% of patients may suffer from a slowly progressive MS form - the primary progressive. The current treatment of RRMS includes immunomodulatory and immunosuppressive agents, which are effective, but usually in earlier and more benign forms. The immunomodulatory treatment has limited efficacy in aggressive forms of RRMS, and relapses occur despite treatment continuation. AHSCT should be considered as a therapeutic approach for patients with aggressive relapsing remitting and aggressive progressive MS who failed conventional therapy. The mechanism of action of AHSCT for MS results from resetting the aberrant patient's immune system and eliminating the autoreactive T-lymphocytes. AHSCT can serve as an effective and safe procedure only when strict neurological eligibility criteria are adhered. The procedure should be performed in highly specialized hematological centers. The aim of our paper is to summarize the current eligibility criteria for AHSCT in MS patients as well as to present data on efficacy and safety of this approach. PMID- 26577417 TI - Randomized Clinical Trial Comparing Basal Insulin Peglispro and Insulin Glargine in Patients With Type 2 Diabetes Previously Treated With Basal Insulin: IMAGINE 5. AB - OBJECTIVE: To evaluate the efficacy and safety of basal insulin peglispro (BIL) versus insulin glargine in patients with type 2 diabetes (hemoglobin A1c [HbA1c] <=9% [75 mmol/mol]) treated with basal insulin alone or with three or fewer oral antihyperglycemic medications. RESEARCH DESIGN AND METHODS: This 52-week, open label, treat-to-target study randomized patients (mean HbA1c 7.42% [57.6 mmol/mol]) to BIL (n = 307) or glargine (n = 159). The primary end point was change from baseline HbA1c to 26 weeks (0.4% [4.4 mmol/mol] noninferiority margin). RESULTS: At 26 weeks, reduction in HbA1c was superior with BIL versus glargine (-0.82% [-8.9 mmol/mol] vs. -0.29% [-3.2 mmol/mol]; least squares mean difference -0.52%, 95% CI -0.67 to -0.38 [-5.7 mmol/mol, 95% CI -7.3 to -4.2; P < 0.001); greater reduction in HbA1c with BIL was maintained at 52 weeks. More BIL patients achieved HbA1c <7% (53 mmol/mol) at weeks 26 and 52 (P < 0.001). With BIL versus glargine, nocturnal hypoglycemia rate was 60% lower, more patients achieved HbA1c <7% (53 mmol/mol) without nocturnal hypoglycemia at 26 and 52 weeks (P < 0.001), and total hypoglycemia rates were lower at 52 weeks (P = 0.03). At weeks 26 and 52, glucose variability was lower (P < 0.01), basal insulin dose was higher (P < 0.001), and triglycerides and aminotransferases were higher with BIL versus glargine (P < 0.05). Liver fat content (LFC), assessed in a subset of patients (n = 162), increased from baseline with BIL versus glargine (P < 0.001), with stable levels between 26 and 52 weeks. CONCLUSIONS: BIL provided superior glycemic control versus glargine, with reduced nocturnal and total hypoglycemia, lower glucose variability, and increased triglycerides, aminotransferases, and LFC. PMID- 26577418 TI - Consequences of Comorbidity of Elevated Stress and/or Depressive Symptoms and Incident Cardiovascular Outcomes in Diabetes: Results From the REasons for Geographic And Racial Differences in Stroke (REGARDS) Study. AB - OBJECTIVE: To evaluate the impact of comorbid depressive symptoms and/or stress on adverse cardiovascular (CV) outcomes in individuals with diabetes compared with those without diabetes. RESEARCH DESIGN AND METHODS: Investigators examined the relationship between baseline depressive symptoms and/or stress in adults with and without diabetes and physician-adjudicated incident CV outcomes including stroke, myocardial infarction/acute coronary heart disease, and CV death over a median follow-up of 5.95 years in the national REGARDS cohort study. RESULTS: Subjects included 22,003 adults (4,090 with diabetes) (mean age 64 years, 58% female, 42% black, and 56% living in the southeastern "Stroke Belt"). Elevated stress and/or depressive symptoms were more common in subjects with diabetes (36.8% vs. 29.5%; P < 0.001). In fully adjusted models, reporting either elevated stress or depressive symptoms was associated with a significantly increased incidence of stroke (HR 1.57 [95% CI 1.05, 2.33] vs. 1.01 [0.79, 1.30]) and CV death (1.53 [1.08, 2.17] vs. 1.12 [0.90, 1.38]) in subjects with diabetes but not in those without diabetes. The combination of both elevated stress and depressive symptoms in subjects with diabetes was associated with a higher incidence of CV death (2.15 [1.33, 3.47]) than either behavioral comorbidity alone (1.53 [1.08, 2.17]) and higher than in those with both elevated stress and depressive symptoms but without diabetes (1.27 [0.86, 1.88]). CONCLUSIONS: Comorbid stress and/or depressive symptoms are common in individuals with diabetes and together are associated with progressively increased risks for adverse CV outcomes. PMID- 26577420 TI - Expression of potential biomarkers associated with homologous recombination repair in patients with ovarian or triple-negative breast cancer. AB - BACKGROUND: Poly(ADP)-ribose polymerase (PARP) inhibitors such as olaparib can induce cell death in cancer cells with homologous recombination (HR) DNA repair deficiencies, such as BRCA1/2 mutations. AIM: To identify prognostic biomarkers of long-term outcomes in cancer patients. METHODS: Immunohistochemistry was used to analyse expression of key HR pathway proteins (ATM, ATR, BRCA1, MDC1, MRE11) and PARP-1 in 100 serous ovarian cancer (SOC) and 100 triple-negative breast cancer (TNBC) tumour samples from Japanese patients. RECIST assessment was used. RESULTS: Patient demographic data and BRCA1/2 mutation status were unavailable. Most proteins listed previously were detected in > 80% of tissue samples, with BRCA1 expression detected in 60-65%. A potential link between BRCA1 expression and overall survival (M stage adjusted) in SOC patients was observed, but was not statistically significant after multiple testing adjustment. Correlations between other biomarker expression and survival were not observed. In TNBC patients, MDC1 staining was associated with progressive disease, but this was not statistically significant; the analysis did not identify significant correlations between biomarker expression and disease control. Limited event numbers prevented assessment of the prognostic value of BRCA1 in TNBC. CONCLUSION: BRCA1 expression may be a candidate for a prognostic biomarker in SOC. Further studies are warranted. PMID- 26577421 TI - Losing weights: Failure to recognize and act on weight loss documented in an electronic health record. AB - BACKGROUND: Involuntary weight loss is associated with higher mortality. When this weight loss is unrecognized, opportunities for timely diagnosis of significant conditions may be missed. OBJECTIVE: To use electronic health record (EHR) data to estimate the frequency of unrecognized involuntary weight loss and its implications. METHODS: We performed a retrospective analysis of the weights recorded in an EHR of 100,000 adult patients seen in outpatient clinics over a five-year period using a novel data visualization and review tool. We reviewed charts of a random sample of 170 patients experiencing weight loss periods. Our outcomes included determinations of whether weight loss 1) was voluntary vs. involuntary; 2) was recognized and documented; and 3) possible explanations identifiable at the index visit or within the subsequent two years. RESULTS: Of 170 randomly-selected weight loss periods reviewed, 22 (13%) were involuntary, 36 (21%) were voluntary and 112 (66%) were indeterminate. Sixty-six (39%) weight loss periods were recognized by clinician at the index visits and an additional 3 (1%) at the next PCP visits. Possible explanations for weight loss emerged in the subsequent two years including medical conditions in 60 (45%), psycho-social conditions in 19 (14%), erroneous data entry in 9 (7%), voluntary weight loss in 8 (6%), and postpartum weight loss in 6 (4%). No possible explanations were found in 32 (24%). CONCLUSIONS: Periods of weight loss were common, often involuntary and frequently not recognized or documented. Many patients with involuntary weight loss had potential explanations that emerged within the subsequent two years. PMID- 26577422 TI - Using a self-service kiosk to identify behavioural health needs in a primary care clinic serving an urban, underserved population. AB - BACKGROUND: Integration of behavioural health into primary care clinics is an established model of care and important approach to eliminating mental health disparities, but demands on provider time is a barrier to mental health screening. The purpose of this study was to determine the feasibility of using a kiosk placed in a primary care clinic to screen for multiple mental health disorders. METHODS: Quality improvement initiative with Plan-Do-Study-Act implementation and time series monitoring of utilisation outcomes. RESULTS: A total of 281 screens were completed identifying positive screens for depression (30%) and bipolar disorder (17%). Post-traumatic stress disorder and concerning substance use were less common. CONCLUSIONS: Development of health information technology to facilitate behavioural health assessment in primary care is a promising approach to integrated care and provides additional benefits of population health monitoring. PMID- 26577423 TI - A Clinical Decision Support System for Chronic Pain Management in Primary Care: Usability testing and its relevance. AB - BACKGROUND: Clinical decision support systems (CDSSs) that are integrated into electronic medical records may be useful for encouraging practice change compliant with clinical practice guidelines. OBJECTIVE: To engage end users to inform early phase CDSS development through a process of usability testing. METHODS: A sequential exploratory mixed method approach was used. Interprofessional clinician participants (seven in iteration 1 and six in iteration 2) were asked to 'think aloud' while performing various tasks on the CDSS and then complete the System Usability Scale (SUS). Changes were made to the CDSS after each iteration.Results Barriers and facilitators were identified: systemic; user interface (most numerous barriers); content (most numerous facilitators) and technical. The mean SUS score was 81.1 (SD = 12.02) in iteration 1 and 70.40 (SD = 6.78) in iteration 2 (p > 0.05). CONCLUSIONS: Qualitative data from usability testing were valuable in the CDSS development process. SUS scores were of limited value at this development stage. PMID- 26577424 TI - Primary care physicians' perspectives on computer-based health risk assessment tools for chronic diseases: a mixed methods study. AB - BACKGROUND: Health risk assessment tools compute an individual's risk of developing a disease. Routine use of such tools by primary care physicians (PCPs) is potentially useful in chronic disease prevention. We sought physicians' awareness and perceptions of the usefulness, usability and feasibility of performing assessments with computer-based risk assessment tools in primary care settings. METHODS: Focus groups and usability testing with a computer-based risk assessment tool were conducted with PCPs from both university-affiliated and community-based practices. Analysis was derived from grounded theory methodology. RESULTS: PCPs (n = 30) were aware of several risk assessment tools although only select tools were used routinely. The decision to use a tool depended on how use impacted practice workflow and whether the tool had credibility. Participants felt that embedding tools in the electronic medical records (EMRs) system might allow for health information from the medical record to auto-populate into the tool. User comprehension of risk could also be improved with computer-based interfaces that present risk in different formats. CONCLUSIONS: In this study, PCPs chose to use certain tools more regularly because of usability and credibility. Despite there being differences in the particular tools a clinical practice used, there was general appreciation for the usefulness of tools for different clinical situations. Participants characterised particular features of an ideal tool, feeling strongly that embedding risk assessment tools in the EMR would maximise accessibility and use of the tool for chronic disease management. However, appropriate practice workflow integration and features that facilitate patient understanding at point-of-care are also essential. PMID- 26577425 TI - Development of the quality assessment model of EHR software in family medicine practices: research based on user satisfaction. AB - BACKGROUND: Family medicine practices (FMPs) make the basis for the Croatian health care system. Use of electronic health record (EHR) software is mandatory and it plays an important role in running these practices, but important functional features still remain uneven and largely left to the will of the software developers. OBJECTIVE: The objective of this study was to develop a novel and comprehensive model for functional evaluation of the EHR software in FMPs, based on current world standards, models and projects, as well as on actual user satisfaction and requirements. METHODS: Based on previous theoretical and experimental research in this area, we made the initial framework model consisting of six basic categories as a base for online survey questionnaire. Family doctors assessed perceived software quality by using a five-point Likert type scale. Using exploratory factor analysis and appropriate statistical methods over the collected data, the final optimal structure of the novel model was formed. Special attention was focused on the validity and quality of the novel model. RESULTS: The online survey collected a total of 384 cases. The obtained results indicate both the quality of the assessed software and the quality in use of the novel model. The intense ergonomic orientation of the novel measurement model was particularly emphasised. CONCLUSIONS: The resulting novel model is multiple validated, comprehensive and universal. It could be used to assess the user-perceived quality of almost all forms of the ambulatory EHR software and therefore useful to all stakeholders in this area of the health care informatisation. PMID- 26577426 TI - Connecting primary care clinics and community pharmacies through a nationwide electronic prescribing network: A qualitative study. AB - BACKGROUND: The use of medication is at the heart of primary care, but is also the cause for major health concerns. It is therefore important to examine the prescription of medication process. OBJECTIVE: This study identifies the barriers and facilitators perceived by community pharmacists and primary care physicians concerning the adoption of a nationwide electronic prescribing (e-prescribing) network in the province of Quebec, Canada. METHODS: We used purposive sampling to identify the most intensive users of the e-prescribing network. We conducted phone and in-person interviews. Interviews were transcribed, and we analysed their content with NVivo, using the clinical adoption framework (CAF) for the codification of the data.Results We interviewed 33 pharmacists, 2 pharmacy technicians, 11 physicians and 3 clinic managers. Adoption of the e-prescribing network was fairly low. The respondents underlined adaptation of their work environment, openness to change and perception of benefits as facilitators to the adoption of the network. However, important barriers were perceived, including system quality issues and paper prescriptions being the only legal document in the prescribing process. Even if respondents recognised that the e-prescribing network can offer substantial benefits to the prescribing process, issues still persisted and raised barriers to the full use of such a network, especially in a context where different local information systems are connected within a nationwide e-prescribing network. CONCLUSIONS: This study, based on the CAF, provides a better understanding of the factors related to the adoption of a nationwide e-prescribing network connecting primary care clinics and community pharmacies. PMID- 26577427 TI - Creating and using real-world evidence to answer questions about clinical effectiveness. AB - New forms of evidence are needed to complement evidence generated from randomised controlled trials (RCTs). Real-World Evidence (RWE) is a potential new form of evidence, but remains undefined. This paper sets to fill that gap by defining RWE as the output from a rigorous research process which: (1) includes a clear a priori statement of a hypothesis to be tested or research question to be answered; (2) defines the data sources that will be used and critically appraises their strengths and weaknesses; and (3) applies appropriate methods, including advanced analytics. These elements should be set out in advance of the study commencing, ideally in a published protocol.The strengths of RWE studies are that they are more inclusive than RCTs and can enable an evidence base to be developed around real-world effectiveness and to start to address the complications of managing other real-world problems such as multimorbidity. Computerised medical record systems and big data provide a rich source of data for RWE studies. However, guidance is needed to help assess the rigour of RWE studies so that the strength of recommendations based on their output can be determined. Additionally, RWE advanced analytics methods need better categorisation and validation.We predict that the core role of RCTs will shift towards assessing safety and achieving regulatory compliance. RWE studies, notwithstanding their limitations, may become established as the best vehicle to assess efficacy. PMID- 26577428 TI - In this issue: Time to replace doctors' judgement with computers. AB - Informaticians continue to rise to the challenge, set by the English Health Minister, of trying to replace doctors' judgement with computers. This issue describes successes and where there are barriers. However, whilst there is progress this tends to be incremental and there are grand challenges to be overcome before computers can replace clinician. These grand challenges include: (1) improving usability so it is possible to more readily incorporate technology into clinical workflow; (2) rigorous new analytic methods that make use of the mass of available data, 'Big data', to create real-world evidence; (3) faster ways of meeting regulatory and legal requirements including ensuring privacy; (4) provision of reimbursement models to fund innovative technology that can substitute for clinical time and (5) recognition that innovations that improve quality also often increase cost. Informatics more is likely to support and augment clinical decision making rather than replace clinicians. PMID- 26577429 TI - Plasma bioactive adrenomedullin as a prognostic biomarker in acute heart failure. AB - OBJECTIVE: The objective was to evaluate the prognostic performance of a new biomarker, plasma bioactive adrenomedullin (bio-ADM), for short-term clinical outcomes in acute heart failure. METHODS: A multicenter prospective cohort study of adult emergency department (ED) patients suspected of having acute heart failure was conducted to evaluate the association between plasma bio-ADM concentration and clinical outcomes. The primary outcome was a composite of the following within 30 days: death, cardiac arrest with resuscitation, respiratory failure, emergency dialysis, acute coronary syndrome, hospitalization >5 days, and repeat ED visit or hospitalization. Prognostic accuracy was evaluated with a nonparametric receiver operating characteristic curve. In addition, a multivariable logistic regression model was constructed to assess the additive prognostic performance of bio-ADM while adjusting for other biomarkers routinely used clinically, including B-type natriuretic peptide, cardiac troponin I, creatinine, and sodium concentration. RESULTS: Two hundred forty-six patients were enrolled, including 85 (34.6%) patients with the primary outcome. Plasma bio ADM concentrations were higher among patients who experienced the primary outcome (median, 80.5 pg/mL; interquartile range [IQR], 53.7-151.5 pg/mL) compared with those who did not (median, 54.4 pg/mL; IQR, 43.4-78.4 pg/mL) (P < .01). Area under the receiver operating characteristic curve was 0.70 (95% confidence interval, 0.63-0.75). After adjusting for the other biomarkers, plasma bio-ADM remained a strong predictor of the primary outcome (adjusted odds ratio per IQR change, 2.68; 95% confidence interval, 1.60-4.51). CONCLUSIONS: Bioactive adrenomedullin concentrations at the time of ED evaluation for acute heart failure were predictive of clinically important 30-day outcomes, suggesting that bio-ADM is a promising prognostic marker for further study. PMID- 26577430 TI - Looking at diabetic ketoacidosis through electrocardiogram window! AB - BACKGROUND: Initial serum potassium (K+) in diabetic ketoacidosis (DKA) often does not reflect the true amount of total body K+ storage, and it is not a good predictor of subsequent hypokalemia. In this study, we tested the hypothesis that a deficiency of the total body K+ storage can be detected initially on surface electrocardiography (ECG). METHOD: Medical records of 350 patients with a diagnosis of DKA were reviewed. Data regarding serial basic metabolic panels, arterial blood gases, serum ketones, and total K+ replacement that patient received during admission were collected. We compared biochemical findings for patients with and without QTU corrected (QTUc) prolongation by using the t test. Patients who were taking medications known to affect QTUc or cause ST-T changes were excluded. RESULTS: After exclusion criteria, 61 patients were enrolled in this study. In 38 patients (62.9%), QTUc was more than or equal to 450 milliseconds. Patients with prolonged QTc received statistically more K+ supplementation during admission (P = .014). They also had lower serum K+ level during their hospital course (P = .002) compared to patients with normal QTUc intervals. No significant difference was found between initial serum K+, calcium, glucose, anion gap, acidosis, age, or heart rate between these 2 groups. CONCLUSION: The significant relationship between K+ depletion and the ECG changes observed in this study deserves further consideration. Our findings confirm the concept that the ECG is an easy and reliable tool for early diagnosis of hypokalemia in patients with DKA. PMID- 26577431 TI - Predicting tularemia with clinical, laboratory and demographical findings in the ED. AB - INTRODUCTION: We aimed to determine clinical, laboratory and demographical characteristics of tularemia on admission to Emergency Department (ED). MATERIAL AND METHODS: Medical data of 317 patients admitted to ED and subsequently hospitalized with suspected tularemia between January 1, 2011, and May 31, 2015, were collected. Patients were divided into 2 groups according to microagglutination test results, as tularemia (+) and tularemia (-). RESULTS: Of the 317 patients involved, 49 were found to be tularemia (+) and 268 were tularemia (-). Mean age of the tularemia (+) patients was found to be higher than that of tularemia (-) patients. When compared to tularemia (-) patients, a significant portion of patients in tularemia (+) patients were elderly, living in rural areas and had contact with rodents. When clinical and laboratory findings of the 2 groups were compared, any statistical significance could not be determined. CONCLUSION: Tularemia is a disease of elderly people living in rural areas. Contact with rodents also increases risk of tularemia in suspected patients. PMID- 26577432 TI - Predictive value of C-reactive protein, ultrasound and Alvarado score in acute appendicitis: a prospective pediatric cohort. AB - PURPOSE: To evaluate whether C-reactive protein (CRP) level and ultrasound (US) results on admission could aid the diagnostic accuracy of Alvarado score. METHODS: A prospective study was performed on children <14 years admitted for suspected acute appendicitis. Patients were categorized into three groups based on the Alvarado score: group I: score 7-10, group II: score 5-6, group III: score 0-4. RESULTS: The difference between predictive values of Alvarado score alone and Alvarado score with CRP was not statically significant. The PPV increased from 74.29% (Alvarado score and CRP) to 93.75% (Alvarado score and US) in group 1 (P = .001) and the NPV increased from 64.86 and 79.69% (Alvarado score and CRP) to 82.6 and 88.2% (Alvarado score and US) in group 2 (P = .01) and group 3 (P = .001), respectively. CONCLUSIONS: Alvarado score and ultrasound taken together improve the predictive value of diagnosing acute appendicitis in children. PMID- 26577433 TI - A nomogram was developed to enhance the use of multinomial logistic regression modeling in diagnostic research. AB - OBJECTIVES: We developed a nomogram to facilitate the interpretation and presentation of results from multinomial logistic regression models. STUDY DESIGN AND SETTING: We analyzed data from 376 frail elderly with complaints of dyspnea. Potential underlying disease categories were heart failure (HF), chronic obstructive pulmonary disease (COPD), the combination of both (HF and COPD), and any other outcome (other). A nomogram for multinomial model was developed to depict the relative importance of each predictor and to calculate the probability for each disease category for a given patient. Additionally, model performance of the multinomial regression model was assessed. RESULTS: Prevalence of HF and COPD was 14% (n = 54), HF 24% (n = 90), COPD 20% (n = 75), and Other 42% (n = 157). The relative importance of the individual predictors varied across these disease categories or was even reversed. The pairwise C statistics ranged from 0.75 (between HF and Other) to 0.96 (between HF and COPD and Other). The nomogram can be used to rank the disease categories from most to least likely within each patient or to calculate the predicted probabilities. CONCLUSIONS: Our new nomogram is a useful tool to present and understand the results of a multinomial regression model and could enhance the applicability of such models in daily practice. PMID- 26577434 TI - [Antibiotic therapy of intra-abdominal infections in the era of multiresistance]. AB - Recommendations for the treatment of intra-abdominal infections (IAI) caused by drug-resistant bacteria often fail to mention the bacteria of concern (e.g. vancomycin-resistant enterococci, extended spectrum beta-lactamase-producing (ESBL) Enterobacteriaceae, multi-drug resistant Pseudomonas spp., carbapenem resistant organisms and Acinetobacter spp.) and all available drugs. The group of patients suffering from IAI due to resistant bacteria includes the entire group of postoperative and tertiary peritonitis and necrotizing pancreatitis. This article provides information for the management of a very important group of diseases with a substantial morbidity and mortality. An individual patient centered approach is mandatory to evaluate the optimal antimicrobial treatment regimen. Especially in gram-negative bacteria, which are the predominant cause only a few options remain for treatment. Clinical data with a high level of evidence are very limited. Future studies should focus on pharmacokinetic and pharmakodynamic aspects in critically ill patients, in the sense of antibiotic stewardship in order to elucidate the real life efficacy and safety of antibiotics for the treatment of life-threatening IAI. PMID- 26577435 TI - Shock wave study and theoretical modeling of the thermal decomposition of c-C4F8. AB - The thermal dissociation of octafluorocyclobutane, c-C4F8, was studied in shock waves over the range 1150-2300 K by recording UV absorption signals of CF2. It was found that the primary reaction nearly exclusively produces 2 C2F4 which afterwards decomposes to 4 CF2. A primary reaction leading to CF2 + C3F6 is not detected (an upper limit to the yield of the latter channel was found to be about 10 percent). The temperature range of earlier single pulse shock wave experiments was extended. The reaction was shown to be close to its high pressure limit. Combining high and low temperature results leads to a rate constant for the primary dissociation of k1 = 10(15.97) exp(-310.5 kJ mol(-1)/RT) s(-1) in the range 630-1330 K, over which k1 varies over nearly 14 orders of magnitude. Calculations of the energetics of the reaction pathway and the rate constants support the conclusions from the experiments. Also they shed light on the role of the 1,4-biradical CF2CF2CF2CF2 as an intermediate of the reaction. PMID- 26577436 TI - Risks and benefits of stress ulcer prophylaxis in adult neurocritical care patients: a systematic review and meta-analysis of randomized controlled trials. AB - INTRODUCTION: Neurocritical care patients are at high risk for stress-related upper gastrointestinal (UGI) bleeding. The aim of this meta-analysis was to evaluate the risks and benefits of stress ulcer prophylaxis (SUP) in this patient group. METHODS: A systematic search of major electronic literature databases was conducted. Eligible studies were randomized controlled trials (RCTs) in which researchers compared the effects of SUP (with proton pump inhibitors or histamine 2 receptor antagonists) with placebo or no prophylaxis in neurocritical care patients. The primary outcome was UGI bleeding, and secondary outcomes were all cause mortality and nosocomial pneumonia. Study heterogeneity was sought and quantified. The results were reported as risk ratios/relative risks (RRs) with 95 % confidence intervals (CIs). RESULTS: We included 8 RCTs comprising an aggregate of 829 neurocritical care patients. Among these trials, one study conducted in a non-intensive care unit setting that did not meet our inclusion criteria was ultimately included based on further evaluation. All studies were judged as having a high or unclear risk of bias. SUP was more effective than placebo or no prophylaxis at reducing UGI bleeding (random effects: RR 0.31; 95 % CI 0.20-0.47; P < 0.00001; I (2) = 45 %) and all-cause mortality (fixed effects: RR 0.70; 95 % CI 0.50-0.98; P = 0.04; I (2) = 0 %). There was no difference between SUP and placebo or no prophylaxis regarding nosocomial pneumonia (random effects: RR 1.14; 95 % CI 0.67-1.94; P = 0.62; I (2) = 42 %). The slight asymmetry of the funnel plots raised the concern of small trial bias, and apparent heterogeneity existed in participants, interventions, control treatments, and outcome measures. CONCLUSIONS: In neurocritical care patients, SUP seems to be more effective than placebo or no prophylaxis in preventing UGI bleeding and reducing all-cause mortality while not increasing the risk of nosocomial pneumonia. The robustness of this conclusion is limited by a lack of trials with a low risk of bias, sparse data, heterogeneity among trials, and a concern regarding small trial bias. TRIAL REGISTRATION: International Prospective Register of Systematic Reviews (PROSPERO) identifier: CRD42015015802 . Date of registration: 6 Jan 2015. PMID- 26577437 TI - Phosphatidylethanolamine and phosphatidylcholine biosynthesis by the Kennedy pathway occurs at different sites in Trypanosoma brucei. AB - Phosphatidylethanolamine (PE) and phosphatidylcholine (PC) are among the most abundant phospholipids in biological membranes. In many eukaryotes, the CDP ethanolamine and CDP-choline branches of the Kennedy pathway represent major and often essential routes for the production of PE and PC, with ethanolamine and choline/ethanolamine phosphotransferases (EPT and CEPT, respectively) catalysing the last reactions in the respective pathways. Although the site of PE and PC synthesis is commonly known to be the endoplasmic reticulum (ER), detailed information on the localization of the different phosphotransferases is lacking. In the unicellular parasite, Trypanosoma brucei, both branches of the Kennedy pathway are essential for cell growth in culture. We have previously reported that T. brucei EPT (TbEPT) catalyses the production of ether-type PE molecular species while T. brucei CEPT (TbCEPT) synthesizes diacyl-type PE and PC molecular species. We now show that the two enzymes localize to different sub-compartments of the ER. By expressing a series of tagged forms of the two enzymes in T. brucei parasites, in combination with sub-cellular fractionation and enzyme activity measurements, TbEPT was found exclusively in the perinuclear ER, a distinct area located close to but distinct from the nuclear membrane. In contrast, TbCEPT was detected in the bulk ER. PMID- 26577438 TI - Motion artefacts in cone beam CT: an in vitro study about the effects on the images. AB - OBJECTIVE: In cone beam CT (CBCT), imperfect patient immobility, caused by involuntary movements, is one of the most important causes of artefacts and image quality degradation. Various works in literature address this topic, but seldom is the nature of the movement correlated with the type of artefact and the image degradation in a systematic manner, and the correlation analyzed and explained. METHODS: All three types of movements that can occur during a scan-nodding, tilting and rolling-were applied to a dry skull, in various manners from abrupt to gradual through the entire scan, at different times and angles, over a wide range of displacements. 84 scans were performed, with different skull movements, and the resulting images examined by two skilled radiologists, rated in a four point scale and statistically analyzed. A commercial CBCT machine was used, featuring supine patient positioning. RESULTS: Different types of movements induce different artefacts, in different parts of the anatomy. In general, movement of short duration may lead to double contours (bilateral or monolateral depending upon the angle of the scan at which they occur), whereas gradual movements result into blurring. CONCLUSION: Not all movements cause motion artefacts that equally jeopardize the image. Rolling is the type of movement that most severely affects the image diagnostic value. ADVANCES IN KNOWLEDGE: These findings may help practitioners to identify the causes of motion artefacts and the resulting image degradation, and remediate them, and manufacturers to improve the patient-positioning devices. PMID- 26577439 TI - KATZLDA: KATZ measure for the lncRNA-disease association prediction. AB - Accumulating experimental studies have demonstrated important associations between alterations and dysregulations of lncRNAs and the development and progression of various complex human diseases. Developing effective computational models to integrate vast amount of heterogeneous biological data for the identification of potential disease-lncRNA associations has become a hot topic in the fields of human complex diseases and lncRNAs, which could benefit lncRNA biomarker detection for disease diagnosis, treatment, and prevention. Considering the limitations in previous computational methods, the model of KATZ measure for LncRNA-Disease Association prediction (KATZLDA) was developed to uncover potential lncRNA-disease associations by integrating known lncRNA-disease associations, lncRNA expression profiles, lncRNA functional similarity, disease semantic similarity, and Gaussian interaction profile kernel similarity. KATZLDA could work for diseases without known related lncRNAs and lncRNAs without known associated diseases. KATZLDA obtained reliable AUCs of 7175, 0.7886, 0.7719 in the local and global leave-one-out cross validation and 5-fold cross validation, respectively, significantly improving previous classical methods. Furthermore, case studies of colon, gastric, and renal cancer were implemented and 60% of top 10 predictions have been confirmed by recent biological experiments. It is anticipated that KATZLDA could be an important resource with potential values for biomedical researches. PMID- 26577440 TI - Primary gastric tuberculosis presenting as gastric outlet obstruction: a case report and review of the literature. AB - INTRODUCTION: Tuberculosis is a major health problem worldwide. Sudan has high burden of tuberculosis (TB) with a prevalence of 209 cases per 100,000 of the population and it is commonly presented with pulmonary disease but involvement of the gastrointestinal tract is not uncommon. Abdominal tuberculosis comprises about 1-3 % of all cases of tuberculosis and about 12% of extrapulmonary tuberculosis. It involves the ileocecal region, but involvement of stomach and duodenum are rare sites. Here we present an unusual case of gastric outlet obstruction due to gastric tuberculosis. CASE PRESENTATION: A 54-year-old Sudanese man presented with a non-bile stain persistent projectile vomiting, and epigastric pain for two years associated with marked loss of weight. There is no fever or cough. He was on antacid, physical examination showed BMI 18 and stable vital signs. He was not pale or jaundiced, there was no cervical lymphadenopathy and chest was clear. Abdominal examination was normal apart of positive succussion splash. The results of haematological tests were normal, ESR was 30 mm/hr, hepatitis B, C and HIV were negative. Upper gastrointestinal endoscopy showed that the stomach was full of fluid and food particles and ulcerated mass in the pylorus extended to the proximal part of the duodenum with severe narrowing of the pylorus. The lesion biopsied and the result revealed active inflammatory cells, cryptitis and multiple lymphoid follicles, no malignancy seen. Sonographic test showed hypodense pyloric mass, enlarged para-aortic and mesenteric lymph nodes and mild pelvic ascites. A computed tomography scan of the abdomen and pelvis showed antral hypodense lesions multiple mesenteric lymphadenopathies peritoneal thickening and ascites. Chest X-ray was normal. Intra-operative findings were dilated stomach and pylorus mass with multiple mesenteric lymph nodes, peritoneal and omental seedlings all over with small nodules on the surface of the liver, gastro-jejunostomy was done. Histopathology confirmed the diagnosis of abdominal tuberculosis. Postoperative event was uneventful. Patient received anti-tuberculous. CONCLUSIONS: Here we presented an unusual case of gastric outlet obstruction due to primary gastric tuberculosis, patient underwent surgery to relief his symptoms and received anti-tuberculous. PMID- 26577441 TI - Impact of Fish Farming on Phosphorus in Reservoir Sediments. AB - Fish farming has seriously influenced the aquatic environment in Sancha reservoir in SW China since 1985 and has been strongly restricted since 2005. Thus, phosphorus speciation in a sediment core dated between 1945 and 2010 at cm resolution and in surface sediments from Sancha reservoir may allow us track how fish farming impacts phosphorus dynamics in lake sediments. Fish farming shifts the major binding forms of phosphorus in sediments from organic to residual phosphorus, which mostly originated from fish feed. Sorption to metal oxides and association with organic matters are important mechanisms for phosphorus immobilisation with low fish farming activities, whereas calcium-bound phosphorous had an essential contribution to sediment phosphorus increases under intensive fish framing. Notwithstanding the shifting, the aforementioned phosphorus fractions are usually inert in the lake environment, therefore changing phosphorus mobility little. The use of fish feed and water-purification reagents, the most important additives for fish farming, introduce not only phosphorus but also large amounts of sand-sized minerals such as quartz into the lake, to which phosphorus weakly sorbs. The sand-sized minerals as additional sorbents increase the pool of easily mobilisable phosphorus in sediments, which will slow down the recovery of reservoir water due to its rapid re-mobilisation. PMID- 26577443 TI - Author of retracted BMJ paper is ordered to pay $C1.6m to Canadian broadcaster. PMID- 26577442 TI - Does individual variation in metabolic phenotype predict fish behaviour and performance? AB - There is increasing interest in documenting and explaining the existence of marked intraspecific variation in metabolic rate in animals, with fishes providing some of the best-studied examples. After accounting for variation due to other factors, there can typically be a two to three-fold variation among individual fishes for both standard and maximum metabolic rate (SMR and MMR). This variation is reasonably consistent over time (provided that conditions remain stable), and its underlying causes may be influenced by both genes and developmental conditions. In this paper, current knowledge of the extent and causes of individual variation in SMR, MMR and aerobic scope (AS), collectively its metabolic phenotype, is reviewed and potential links among metabolism, behaviour and performance are described. Intraspecific variation in metabolism has been found to be related to other traits: fishes with a relatively high SMR tend to be more dominant and grow faster in high food environments, but may lose their advantage and are more prone to risk-taking when conditions deteriorate. In contrast to the wide body of research examining links between SMR and behavioural traits, very little work has been directed towards understanding the ecological consequences of individual variation in MMR and AS. Although AS can differ among populations of the same species in response to performance demands, virtually nothing is known about the effects of AS on individual behaviours such as those associated with foraging or predator avoidance. Further, while factors such as food availability, temperature, hypoxia and the fish's social environment are known to alter resting and MMRs in fishes, there is a paucity of studies examining how these effects vary among individuals, and how this variation relates to behaviour. Given the observed links between metabolism and measures of performance, understanding the metabolic responses of individuals to changing environments will be a key area for future research because the environment will have a strong influence on which animals survive predation, become dominant and ultimately have the highest reproductive success. Although current evidence suggests that variation in SMR may be maintained within populations via context dependent fitness benefits, it is suggested that a more integrative approach is now required to fully understand how the environment can modulate individual performance via effects on metabolic phenotypes encompassing SMR, MMR and AS. PMID- 26577444 TI - In vivo imaging of Lactococcus lactis, Lactobacillus plantarum and Escherichia coli expressing infrared fluorescent protein in mice. AB - BACKGROUND: In vivo imaging of orally administered lactic acid bacteria (LAB) and commensal bacteria in mice is shown to provide information on the spatial and temporal distribution of bacteria in the gastrointestinal tract. The bacteria can be detected and monitored using bioluminescence or near-infrared fluorescence. RESULTS: Fluorescence imaging of bacteria was established by expressing the infrared fluorescent protein IRFP713 in Lactococcus lactis, Lactobacillus plantarum and Escherichia coli. All three bacterial species were monitored in live mice and no major differences in transit time were observed. Bacteria passed through the stomach and small intestine in 1 h and the majority were secreted from the large intestine after 6-8 h. Intestinal localization of bacteria was confirmed by imaging the isolated intestines and culturing the intestinal content. The use of fluorescence tomography for spatial localization of fluorescent bacteria has been established. The expression of an additional infrared fluorescent protein IRFP682 enabled concomitant detection of two bacterial populations in live mice. CONCLUSIONS: The present work provides a methodological basis for future studies of probiotic and theranostic actions of LAB in mouse disease models. PMID- 26577446 TI - Fraud in clinical trials: complex problem, simple solutions? PMID- 26577445 TI - Trimodality strategy for treating malignant pleural mesothelioma: results of a feasibility study of induction pemetrexed plus cisplatin followed by extrapleural pneumonectomy and postoperative hemithoracic radiation (Japan Mesothelioma Interest Group 0601 Trial). AB - PURPOSE: We conducted a prospective multi-institutional study to determine the feasibility of trimodality therapy (TMT) comprising induction chemotherapy followed by extrapleural pneumonectomy (EPP) and radiation therapy in Japanese patients with malignant pleural mesothelioma (MPM). METHODS: Major eligibility criteria were histologically confirmed diagnosis of MPM, including clinical subtypes T0-3, N0-2, M0 disease; no prior treatment for the disease; age 20-75 years; Eastern Cooperative Oncology Group performance status 0 or 1; predicted postoperative forced expiratory volume >1000 ml in 1 s; written informed consent. Treatment methods comprised induction chemotherapy using pemetrexed (500 mg/m(2)) plus cisplatin (60 mg/m(2)) for three cycles, followed by EPP and postoperative hemithoracic radiation therapy (54 Gy). Primary endpoints were macroscopic complete resection (MCR) rate for EPP and treatment-related mortality for TMT. RESULTS: Forty-two eligible patients were enrolled: median age 64.5 (range 43-74) years; M:F = 39:3, clinical stage I:II:III = 14:13:15; histological type epithelioid were sarcomatoid; biphasic; others = 28:1:9:4. Of 42 patients, 30 completed EPP with MCR and 17 completed TMT. The trial met the primary endpoints, with an MCR rate of 71 % (30/42) and treatment-related mortality of 9.5 % (4/42). Overall median survival time and 2-year survival rate for 42 registered patients were 19.9 months and 42.9 %, respectively. Two-year relapse-free survival rate of 30 patients who completed EPP with MCR was 37.0 %. CONCLUSION: This phase II study met the predefined primary endpoints, but its risk/benefit ratio was not satisfactory. PMID- 26577447 TI - Tumor hypoxia: a new PET imaging biomarker in clinical oncology. AB - Tumor hypoxia is associated with tumor progression and resistance to various treatments. Noninvasive imaging using positron emission tomography (PET) and F-18 labeled fluoromisonidazole (FMISO) was recently introduced in order to define and quantify tumor hypoxia. The FMISO uptake was closely correlated with pimonidazole immunohistochemistry and hypoxia-inducible factor 1 expression in basic studies. Tumor hypoxia in head and neck cancers and other tumors in a clinical setting may also indicate resistance to radiation and/or chemotherapy. Hypoxic imaging may thus play a new and important role for suitable radiation planning, including dose escalation and dose reduction based on the image findings. Such radiation dose painting based on the findings of hypoxia may require high-performance PET imaging to provide high target-to-background ratio images and an optimal quantitative parameter to define the hypoxic region. A multicenter prospective study using data from a large number of patients is also warranted to test the clinical value of hypoxic imaging. PMID- 26577448 TI - Persistent Organic Pollutants and Heavy Metal Concentrations in Soil from the Metropolitan Area of Monterrey, Nuevo Leon, Mexico. AB - The purpose of this study was to assess the levels of polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs), dichlorodiphenyltrichloroethane (DDT), dichlorodiphenyldichloroethane (DDE), and four heavy metals (arsenic, cadmium, and lead) in outdoor surface soils (50 samples) collected from the metropolitan area of Monterrey in Mexico. Total PBDEs levels ranged from 1.80 to 127 ug/kg, with mean total PBDEs level of 14.2 +/- 21.5 ug/kg (geometric mean +/- standard deviation). For PCBs, the mean total level in the studied soils was 23.5 +/- 20.2 ug/kg (range 4.0-65.5 ug/kg). An important finding in our study was that all soil samples (100%) had detectable levels of the metabolite p,p'-DDE. Moreover, the mean total DDT level (?p'p-DDT and p'p-DDE) was approximately 132 +/- 175 ug/kg. The mean levels for arsenic, cadmium, and lead in soil were 5.30 +/- 1.35 (range 1.55-7.85) mg/kg, 2.20 +/- 1.20 (range 0.65-6.40) mg/kg, and 455 +/- 204 (range 224-1230) mg/kg, respectively. Our study has several limitations, the most notable of which is the small sample of soils evaluated. However, this screening study provided concentration data for the occurrence of POPs and four heavy metals in soil from the metropolitan area of Monterrey, Nuevo Leon, Mexico, and taking into consideration that soil is an important pathway of exposure for people, a biomonitoring program for the surveillance of the general population in the metropolitan area of Monterrey, Nuevo Leon is deemed necessary. PMID- 26577450 TI - Use of a mobile device in mental health rehabilitation: A clinical and comprehensive analysis of 11 cases. AB - This study aimed to test the feasibility of using a mobile device (Apple technology: iPodTouch(r), iPhone(r) or iPad(r)) among people with severe mental illness (SMI) in a rehabilitation and recovery process and to document the parameters to be taken into account and the issues involved in implementing this technology in living environments and mental health care settings. A qualitative multiple case study design and multiple data sources were used to understand each case in depth. A clinical and comprehensive analysis of 11 cases was conducted with exploratory and descriptive aims (and the beginnings of explanation building). The multiple-case analysis brought out four typical profiles to illustrate the extent of integration of a personal digital assistant (PDA) as a tool to support mental health rehabilitation and recovery. Each profile highlights four categories of variables identified as determining factors in this process: (1) state of health and related difficulties (cognitive or functional); (2) relationship between comfort level with technology, motivation and personal effort deployed; (3) relationship between support required and support received; and (4) the living environment and follow-up context. This study allowed us to consider the contexts and conditions to be put in place for the successful integration of mobile technology in a mental health rehabilitation and recovery process. PMID- 26577451 TI - Corrigendum: Biosecurity Policy in the US: A Critical Assessment. AB - [This corrects the article DOI: 10.3389/fpubh.2014.00110.]. PMID- 26577449 TI - BRCA1, BRCA2 and PALB2 mutations and CHEK2 c.1100delC in different South African ethnic groups diagnosed with premenopausal and/or triple negative breast cancer. AB - BACKGROUND: Current knowledge of the aetiology of hereditary breast cancer in the four main South African population groups (black, coloured, Indian and white) is limited. Risk assessments in the black, coloured and Indian population groups are challenging because of restricted information regarding the underlying genetic contributions to inherited breast cancer in these populations. We focused this study on premenopausal patients (diagnosed with breast cancer before the age of 50; n = 78) and triple negative breast cancer (TNBC) patients (n = 30) from the four South African ethnic groups. The aim of this study was to determine the frequency and spectrum of germline mutations in BRCA1, BRCA2 and PALB2 and to evaluate the presence of the CHEK2 c.1100delC allele in these patients. METHODS: In total, 108 South African breast cancer patients underwent mutation screening using a Next-Generation Sequencing (NGS) approach in combination with Multiplex Ligation-dependent Probe Amplification (MLPA) to detect large rearrangements in BRCA1 and BRCA2. RESULTS: In 13 (12 %) patients a deleterious mutation in BRCA1/2 was detected, three of which were novel mutations in black patients. None of the study participants was found to have an unequivocal pathogenic mutation in PALB2. Two (white) patients tested positive for the CHEK2 c.1100delC mutation, however, one of these also carried a deleterious BRCA2 mutation. Additionally, six variants of unknown clinical significance were identified (4 in BRCA2, 2 in PALB2), all in black patients. Within the group of TNBC patients, a higher mutation frequency was obtained (23.3 %; 7/30) than in the group of patients diagnosed before the age of 50 (7.7 %; 6/78). CONCLUSION: This study highlights the importance of evaluating germline mutations in major breast cancer genes in all of the South African population groups. This NGS study shows that mutation analysis is warranted in South African patients with triple negative and/or in premenopausal breast cancer. PMID- 26577452 TI - Favorable outcomes in locally advanced and node positive prostate cancer patients treated with combined pelvic IMRT and androgen deprivation therapy. AB - BACKGROUND: The most appropriate treatment for men with prostate cancer and positive pelvic nodes, N+, is an area of active controversy. We report our 5 years outcomes in men with locally advanced prostate cancer (T1-T4N0-N1M0) treated with definitive radiotherapy encompassing the prostate and pelvic lymph nodes (intensity modulated radiotherapy, IMRT) and long-term androgen deprivation therapy (ADT). MATERIAL AND METHODS: Of the 138 consecutive eligible men all living patients have been followed up to almost 5 years. Survival endpoints for 5 year biochemical failure-free survival (BFFS), relapse-free survival (RFS), prostate cancer-specific survival (PCSS), and overall survival (OS) were assessed by Kaplan-Meier analysis. Univariate and multivariate Cox regression proportional hazards models were constructed for all survival endpoints. The RTOG morbidity grading system for physician rated toxicity was applied. RESULTS: Patients with locally advanced T3-T4 tumors (35 %) and N1 (51 %) have favorable outcome when long-term ADT is combined with definitive radiotherapy encompassing pelvic lymph nodes. The 5-year BFFS, RFS, PCSS and OS were 71.4, 76.2, 94.5 and 89.0 %, respectively. High Gleason sum (9-10) had a strong independent prognostic impact on BFFS, RFS and OS (p = 0.001, <0.001, and 0.005 respectively). The duration of ADT (= > 28 months) showed a significant independent association with improved PCSS (p = 0.02) and OS (p = 0.001). Lymph node involvement was not associated with survival endpoints in the multivariate analysis. The radiotherapy induced toxicity seen in our study population was moderate with rare Grade 3 GI side effects and up to 11 % for Grade 3 GU consisting mainly of urgency and frequency. CONCLUSION: Pelvic IMRT in combination with long-term ADT can achieve long lasting disease control in men with N+ disease and unfavorable prognostic factors. PMID- 26577453 TI - Natural product-derived quaternary ammonium compounds with potent antimicrobial activity. PMID- 26577455 TI - Is the thin layer of methyl aminolevulinate used during photodynamic therapy sufficient? AB - BACKGROUND: If the recommended 1.0 mm layer of methyl aminolevulinate (MAL) is used during photodynamic therapy (PDT) of large areas with multiple actinic keratoses (AK) huge amounts of cream are needed. OBJECTIVES: To report the amount of MAL used for PDT of AK and basal cell carcinomas (BCC) in daily routine. The association of protoporphyrin IX (PpIX) fluorescence and thickness of MAL was investigated in a randomized paired study in healthy volunteers. METHODS: Amount of cream used per cm(2) during conventional and daylight PDT was recorded. In 16 healthy volunteers, 0.1 mm, 0.2 mm, 0.5 mm and 1.0 mm MAL cream were applied for 3 h on tape-stripped areas on each forearm randomized to light-permeable or light impermeable occlusion. PpIX fluorescence was measured. RESULTS: Less than 0.4 mm MAL was used during PDT of BCC and 0.2 mm for AK. No difference in PpIX fluorescence was found between the different thicknesses of MAL using light impermeable occlusion. CONCLUSION: In daily routine <0.4 mm MAL was used during PDT of BCC and 0.1-0.2 mm MAL during PDT of AK. The recommended 1.0 mm MAL did not result in a higher accumulation of PpIX compared to thinner MAL layers after light-impermeable occlusion for 3 h. PMID- 26577454 TI - Targeting mTOR and p53 Signaling Inhibits Muscle Invasive Bladder Cancer In Vivo. AB - Urothelial tumors, accompanied by mutations of the tumor suppressor protein TP53 and dysregulation of mTOR signaling, are frequently associated with aggressive growth and invasiveness. We investigated whether targeting these two pathways would inhibit urothelial tumor growth and progression. Six-week-old transgenic UPII-SV40T male mice (n = 15/group) were fed control diet (AIN-76A) or experimental diets containing mTOR inhibitor (rapamycin, 8 or 16 ppm), p53 stabilizing agent [CP31398 (CP), 150 ppm], or a combination. Mice were euthanized at 40 weeks of age. Urinary bladders were collected and evaluated to determine tumor weight and histopathology. Each agent alone, and in combination, significantly inhibited tumor growth. Treatment with rapamycin alone decreased tumor weight up to 67% (P < 0.0001). Similarly, CP showed approximately 77% (P < 0.0001) suppression of tumor weight. The combination of low-dose rapamycin and CP led to approximately 83% (P < 0.0001) inhibition of tumor weight. There was no significant difference in tumor weights between rapamycin and CP treatments (P > 0.05). However, there was a significant difference between 8 ppm rapamycin and the combination treatment. Tumor invasion was also significantly inhibited in 53% (P < 0.005) and 66% (P < 0.0005) mice after 8 ppm and 16 ppm rapamycin, respectively. However, tumor invasion was suppressed in 73% (P < 0.0001) mice when CP was combined with 8 ppm rapamycin. These results suggest that targeting two or more pathways achieve better treatment efficacy than a single-agent high dose strategy that could increase the risk of side effects. A combination of CP and rapamycin may be a promising method of inhibiting muscle-invasive urothelial transitional cell carcinoma. PMID- 26577456 TI - Application of proteomics in non-small-cell lung cancer. AB - Non-small-cell lung cancer (NSCLC) is a heterogeneous disease with diverse pathological features. Clinical proteomics allows the discovery of molecular markers and new therapeutic targets for this most prevalent type of lung cancer. Some of them may be used to detect early lung cancer, while others may serve as predictive markers of resistance to different therapies. Therapeutic targets and prognostic markers in NSCLC have also been discovered. These proteomics biomarkers may help to pair the individual NSCLC patient with the best treatment option. Despite the fact that implementation of these biomarkers in the clinic appears to be scarce, the recently launched Precision Medicine Initiative may encourage their translation into clinical practice. PMID- 26577457 TI - Recommendations for a standard UK approach to incorporating umbilical cord blood into clinical transplantation practice: an update on cord blood unit selection, donor selection algorithms and conditioning protocols. AB - Allogeneic haemopoietic stem cell transplantation offers a potentially curative treatment option for a wide range of life-threatening malignant and non-malignant disorders of the bone marrow and immune system in patients of all ages. With rapidly emerging advances in the use of alternative donors, such as mismatched unrelated, cord blood and haploidentical donors, it is now possible to find a potential donor for almost all patients in whom an allograft is indicated. Therefore, for any specific patient, the transplant physician may be faced with a myriad of potential choices, including decisions concerning which donor to prioritize where there is more than one, the optimal selection of specific umbilical cord blood units and which conditioning and graft-versus-host disease prophylactic schedule to use. Donor choice may be further complicated by other important factors, such as urgency of transplant, the presence of alloantibodies, the disease status (homozygosity or heterozygosity) of sibling donors affected by inherited disorders and the cytomegalovirus serostatus of patient and donor. We report UK consensus guidelines on the selection of umbilical cord blood units, the hierarchy of donor selection and the preferred conditioning regimens for umbilical cord blood transplantation, with a summary of rationale supporting these recommendations. PMID- 26577458 TI - Risk perception and public acceptance toward a highly protested Waste-to-Energy facility. AB - The application of Waste-to-Energy treatment in Municipal Solid Waste faces strong protest by local communities, especially in cities with high population densities. This study introduces insight into the public awareness, acceptance and risk perception toward Waste-to-Energy through a structured questionnaire survey around a Waste-to-Energy facility in Shanghai, China. The Dichotomous Choice contingent valuation method was applied to study the willingness to accept of residents as an indicator of risk perception and tolerance. The factors influencing risk perception and the protest response choice were analyzed. The geographical distributions of the acceptance of Waste-to-Energy facility and protest response were explored using geographical information systems. The findings of the research indicated an encouraging vision of promoting Waste-to Energy, considering its benefits of renewable energy and the conservation of land. A high percentage of protest willingness to accept (50.94%) was highlighted with the effect of income, opinion about Waste-to-Energy, gender and perceived impact. The fuzzy classification among people with different opinions on compensation (valid 0, positive or protest willingness to accept) revealed the existing yet rejected demand of compensation among protesters. Geographical distribution in the public attitude can also be observed. Finally significant statistical relation between knowledge and risk perception indicates the need of risk communication, as well as involving public into whole management process. PMID- 26577459 TI - Targeting high value metals in lithium-ion battery recycling via shredding and size-based separation. AB - Development of lithium-ion battery recycling systems is a current focus of much research; however, significant research remains to optimize the process. One key area not studied is the utilization of mechanical pre-recycling steps to improve overall yield. This work proposes a pre-recycling process, including mechanical shredding and size-based sorting steps, with the goal of potential future scale up to the industrial level. This pre-recycling process aims to achieve material segregation with a focus on the metallic portion and provide clear targets for subsequent recycling processes. The results show that contained metallic materials can be segregated into different size fractions at different levels. For example, for lithium cobalt oxide batteries, cobalt content has been improved from 35% by weight in the metallic portion before this pre-recycling process to 82% in the ultrafine (<0.5mm) fraction and to 68% in the fine (0.5-1mm) fraction, and been excluded in the larger pieces (>6mm). However, size fractions across multiple battery chemistries showed significant variability in material concentration. This finding indicates that sorting by cathode before pre treatment could reduce the uncertainty of input materials and therefore improve the purity of output streams. Thus, battery labeling systems may be an important step towards implementation of any pre-recycling process. PMID- 26577460 TI - High-throughput sequencing of RNAs isolated by cross-linking immunoprecipitation (HITS-CLIP) reveals Argonaute-associated microRNAs and targets in Schistosoma japonicum. AB - BACKGROUND: Schistosomiasis, caused by schistosomes, is one of the most prevalent and serious parasitic diseases in tropical and subtropical countries. This pathogen has a complex life cycle and harbors a unique repertoire of genes expressed at different life-stages. Understanding the gene regulation of schistosomes will contribute to identification of novel drug targets and vaccine candidates. Some conserved and novel microRNAs (miRNAs) have been identified in schistosomes as key transcriptional and post-transcriptional regulators in the past few years; however, little is known about their specific targets. METHODS: High-throughput sequencing of RNAs isolated by cross-linking immunoprecipitation (HITS-CLIP) was used to covalently crosslink native Argonaute protein-RNA complexes in Schistosoma japonicum. An antibody against S.japonicum Argonaute proteins, was generated and used for immunoprecipitation of the crosslinked SjAgo RNA complex from soluble adult worm extract. Small RNAs, including miRNAs and their target mRNAs associated with the native SjAgo in adult parasites, were enriched and extracted for library construction. RESULTS: High-throughput sequencing produced a total of ~7.4 million high-quality reads, of which approximately 45.07 % were composed of 769 miRNAs and 35.54 % were composed of 11,854 mRNAs target sites. Further bioinformatics analysis identified 43 conserved known miRNAs and 256 novel miRNAs in the SjAgo-associated small RNA population. An average of approximately 15 target sites were predicted for each miRNA. Moreover, a positive rate of 50 % has been achieved in a small-scale verification test of the putative target sites of miRNA1. CONCLUSION: In this study, we isolated and identified small RNAs including miRNAs and their targets associated with the S. japonicum Argonaute proteins, by the HITS-CLIP method combined with bioinformatics and biologic experimental analysis. These data reveal a genome-wide miRNA-mRNA interaction map in S. japonicum in vivo, which will help us understand the complex gene regulatory network in this pathogen and thereby facilitate the development of novel drug approaches against schistosomiasis. PMID- 26577461 TI - Impact of biliary stenting on surgical outcome in patients undergoing pancreatectomy. A retrospective study in a single institution. AB - PURPOSE: There are conflicting views regarding preoperative biliary drainage in patients undergoing pancreatectomy. The aim of this study was to evaluate the effect of jaundice resolution on postoperative outcomes. METHODS: Patients who underwent pancreatectomy in a single institution since 2010 were retrospectively analyzed. They were divided into two groups, depending on the presence or not of preoperative biliary drainage. Postoperative morbidity and mortality were evaluated. RESULTS: Ninety-nine patients underwent biliary drainage by endoscopic retrograde cholangiopancreatography (ERCP) (PBD group), while 105 patients had no biliary drainage (non-PBD group). No significant difference between the two groups could be identified in terms of overall complications (p = 0.121) or mortality (p = 1). There was no significant difference regarding pancreatic fistula (p = 0.554), delayed gastric emptying (p = 0.127), hemorrhage (p = 0.426), number of reoperations (p = 1.000) or readmissions (p = 1.000). The only significant difference was found in the hospital stay, where patients who underwent preoperative biliary drainage had a prolonged length of stay of more 3 days (15.52 vs. 11.31) (p < 0.001). CONCLUSION: Preoperative biliary drainage in patients undergoing pancreatectomy does not increase the rates of postoperative morbidity or mortality, but has a negative effect on hospital stay. PMID- 26577462 TI - Tolerization against atherosclerosis using heat shock protein 60. AB - Atherosclerosis is a chronic inflammatory disease of the artery wall, and both innate and adaptive immunity play important roles in the pathogenesis of this disease. In several experimental and human experiments of early atherosclerotic lesions, it has been shown that the first pathogenic event in atherogenesis is intimal infiltration of T cells at predilection sites. These T cells react to heat shock protein 60 (HSP60), which is a ubiquitous self-antigen expressed on the surface of endothelial cells (ECs) together with adhesion molecules in response to classical risk factors for atherosclerosis. When HSP60 is expressed on the EC surface, it can act as a "danger-signal" for both cellular and humoral immune reactions. Acquired by infection or vaccination, beneficial protective immunity to microbial HSP60 and bona fide autoimmunity to biochemically altered autologous HSP60 is present in all humans. Thus, the development of atherosclerosis during aging is paid by the price for lifelong protective preexisting anti-HSP60 immunity by harmful (auto)immune cross-reactive attack on arterial ECs maltreated by atherosclerosis risk factors. This is supported by experiments, which shows that bacterial HSP60 immunization can lead and accelerate experimental atherosclerosis. This review article presents accumulating proof that supports the idea that tolerization with antigenic HSP60 protein or its peptides may arrest or even prevent atherosclerosis by increased production of regulatory T cells and/or anti-inflammatory cytokines. Recent data indicates that HSP60, or more likely some of its derivative peptides, has immunoregulatory functions. Therefore, these peptides may have important potential for being used as diagnostic agents or therapeutic targets. PMID- 26577463 TI - Salidroside protects against bleomycin-induced pulmonary fibrosis: activation of Nrf2-antioxidant signaling, and inhibition of NF-kappaB and TGF-beta1/Smad-2/-3 pathways. AB - Pulmonary fibrosis (PF) can severely disrupt lung function, leading to fatal consequences. Salidroside is a principal active ingredient of Rhodiola rosea and has recently been reported to protect against lung injures. The present study was aimed at exploring its therapeutic effects on PF. Lung fibrotic injuries were induced in SD rats by a single intratracheal instillation of 5 mg/kg bleomycin (BLM). Then, these rats were administrated with 50, 100, or 200 mg/kg salidroside for 28 days. BLM-triggered structure distortion, collagen overproduction, excessive inflammatory infiltration, and pro-inflammatory cytokine release, and oxidative stress damages in lung tissues were attenuated by salidroside in a dose dependent manner. Furthermore, salidroside was noted to inhibit IkappaBalpha phosphorylation and nuclear factor kappa B (NF-kappaB) p65 nuclear accumulation while activating Nrf2-antioxidant signaling in BLM-treated lungs. Downregulation of E-cadherin and upregulation of vimentin, fibronectin, and alpha-smooth muscle actin (alpha-SMA) indicated an epithelial-mesenchymal transition (EMT)-like shift in BLM-treated lungs. These changes were suppressed by salidroside. The expression of TGF-beta1 and the phosphorylation of its downstream targets, Smad 2/-3, were enhanced by BLM, but weakened by salidroside. Additionally, salidroside was capable of reversing the recombinant TGF-beta1-induced EMT-like changes in alveolar epithelial cells in vitro. Our study reveals that salidroside's protective effects against fibrotic lung injuries are correlated to its anti-inflammatory, antioxidative, and antifibrotic properties. PMID- 26577464 TI - Downregulation of dTps1 in Drosophila melanogaster larvae confirms involvement of trehalose in redox regulation following desiccation. AB - As a survival strategy to environmental water deficits, desiccation-tolerant organisms are commonly known for their ability to recruit stress-protective biomolecules such as trehalose. We have previously reported the pivotal role of trehalose in larval desiccation tolerance in Drosophila melanogaster. Trehalose has emerged as a versatile molecule, serving mainly as energy source in insects and also being a stress protectant. While several recent reports have revealed the unconventional role of trehalose in scavenging reactive oxygen species in yeast and plants, this aspect has not received much attention in animals. We examined the status of desiccation-induced generation of reactive oxygen species in D. melanogaster larvae and the possible involvement of trehalose in ameliorating the harmful consequences thereof. Insect trehalose synthesis is governed by the enzyme trehalose 6-phosphate synthase 1 (TPS1). Using the ubiquitous da-GAL4-driven expression of the dTps1-RNAi transgene, we generated dTps1-downregulated Drosophila larvae possessing depleted levels of dTps1 transcripts. This resulted in the inability of the larvae for trehalose synthesis, thereby allowing us to elucidate the significance of trehalose in the regulation of desiccation-responsive redox homeostasis. Furthermore, the results from molecular genetics studies, biochemical assays, electron spin resonance analyses and a simple, non-invasive method of whole larval live imaging suggested that trehalose in collaboration with superoxide dismutase (SOD) is involved in the maintenance of redox state in D. melanogaster. PMID- 26577465 TI - WTF WHO? AB - How can healthcare systems gain self-sufficiency in their procurement and distribution of blood and blood products efficiently while maintaining a degree of relatively equitable access for patients? This is a question that, at first look, the World Health Organization (WHO) has answered in detail by advocating for self-sufficiency through non-remunerated blood donation. This essay serves two purposes. First, it illustrates key differences between the WHO's policy recommendations and the realities of healthcare. For example, it can be readily demonstrated that the WHO has no empirical foundation for their claim that blood and blood products from unpaid donors is safer or more efficient than other, more commercial, avenues of procurement. Indeed, the WHO appears to take an ideological stand against compensation for blood products, which the empirical data does not support. Whether donation for blood and blood products should be compensated is a pressing ethical issue of practical import, especially if it can be shown that more market-oriented procedures leads to greater self-sufficiency, as well as safer and easier access to blood products than other alternatives. Such policy decisions should be based on the best available empirical data and ethical argumentation, rather than on political ideological grounds. Second, this essay serves as an Introduction to a special thematic issue of HEC Forum, which aims critically to explore ethical arguments in light of the best available empirical data so as to orient the blood industry towards more efficient and effective, and morally honest, procurement procedures. PMID- 26577466 TI - Socialization to professionalism in medical schools: a Canadian experience. AB - BACKGROUND: Accrediting bodies now recognize the importance of developing the professionalism competency, by setting standards that require medical schools to identify where professionalism is addressed and how it is evaluated within the formal curriculum. The objective of this study was to compare how professionalism competency is formally addressed in the curricula of Canadian medical schools, and to better understand the Canadian approach to reporting and remediation of lapses. METHODS: A literature review was performed and with the input of the AFMC(Association of Faculties of Medicine of Canada) Professionalism group, questionnaires were generated. An electronic survey was circulated to key leaders across the country at all the medical schools. In-depth telephone interviews were used to further explore themes, and a subsequent focus group was held to discuss challenges, particularly related to reporting and remediation. RESULTS: The preponderance of formal professionalism teaching remains in the form of lectures and small group sessions in the preclinical years. Formal teaching declines significantly in the clerkship/clinical years. Evaluation is usually performed by a clinical supervisor, but OSCE, portfolio, and concern notes are increasingly used. Role modeling is heavily relied upon in clinical years, suggesting faculty training can help ensure clinical teachers recognize their influence on trainees. Formal remediation strategies are in place at most schools, and often involve essay writing, reflection exercises, or completion of learning modules about professionalism. Lack of clarity on what defines a lapse and fear of reprisal (for both trainees and faculty) limits reporting. CONCLUSIONS: This study provides an overview of how professional identity formation is supported in the Canadian context, guided by the standards set out by CanMEDS. Despite a rich literature that describes the definition, program design and evaluation methods for professionalism, in some areas of the curriculum there is still an opportunity to ensure programs embrace the suggested framework. Examples of teaching and evaluation methods, deficiencies in the clinical years of study (clerkship) and challenges in addressing lapses and organizational structure are identified. The results help identify the gaps that need to be addressed and some solutions that can be modeled at other academic institutions. PMID- 26577467 TI - Functional electrical stimulation through direct 4-channel nerve stimulation to improve gait in multiple sclerosis: a feasibility study. AB - BACKGROUND: Gait dysfunction due to lower limb central paralysis, frequently involving drop foot, is a common cause of disability in multiple sclerosis and has been treated with transcutaneous functional electrical stimulation (FES). We provide here the first report of 4-channel semi-implantable FES of the peroneal nerve which has been successfully used for rehabilitation in patients following stroke. METHODS: FES was implemented via a 4-channel semi-implantable closed-loop system (ActiGait((r)), (c)Ottobock), generating dorsiflexion in drop foot. Walking distance, gait symmetry (temporospatial gait analyses, Vicon Motion Systems((r))), gait velocity (10 m walking test) and quality of life (SF-36 questionnaire) were measured to evaluate the therapeutic benefit of this system in two patients with progressive MS. RESULTS: Walking distance increased from 517 to 1884 m in Patient 1 and from 52 to 506 m in Patient 2. Gait velocity did not change significantly in Patient 1 and increased from 0.6 to 0.8 m/s in Patient 2. Maximum deviations of center of mass from the midline to each side changed significantly after 3 months of stimulation compared to baseline, decreasing from 15 to 12 mm in Patient 1 and from 47 to 37 mm in Patient 2. Both patients experienced reduced pain and fatigue and benefits to quality of life. Adverse events did not occur during the observation period. CONCLUSION: We conclude that implantable 4-channel FES systems are not only feasible but present a promising new alternative for treating central drop foot in MS patients. PMID- 26577468 TI - Oxygen-Assisted Synthesis of Mesoporous Palladium Nanoparticles as Highly Active Electrocatalysts. AB - Mesoporous Pd nanoparticles (MPNs) enclosed by high-index facets have been successfully prepared by taking advantage of successive oxygen adsorption and desorption caused by the oxidative etching effect. The as-prepared MPNs exhibit excellent performance toward formic acid electro-oxidation, which is due to the synergetic effect between the diffusion-feasible tubular mesochannels and the high index facets. PMID- 26577469 TI - Follicular dendritic cell-secreted protein may enhance osteoclastogenesis in periodontal disease. AB - PURPOSE OF THE STUDY: Follicular dendritic cell-secreted protein (FDC-SP) has been found to be expressed in periodontal ligament (PDL), a layer of soft connective tissue between tooth root and alveolar bone, and involved in immunoreaction. This study was performed to explore the potential role of FDC-SP in periodontal disease. MATERIALS AND METHODS: The human periodontal ligament cells (hPDLCs) were stimulated with Porphyromonas gingivalis (P. gingivalis) lipopolysaccharide (LPS) and FDC-SP expression was examined by real-time PCR and western blot. Then this molecule was overexpressed or silenced in hPDLCs by transfection of FDC-SP expression plasmids or its small-interfering (si) RNA, respectively, and the effects of FDC-SP on expression of osteogenesis- and osteoclastogenesis-related genes in hPDLCs were analyzed by real-time PCR and western blot. RESULTS: Our results showed that P. gingivalis LPS upregulated FDC SP expression in hPDLCs. Overexpression of FDC-SP could decrease the expression of osteogenesis-related genes, increase the expression of osteoclastogenesis related genes and RANKL/OPG ratio in hPDLCs. Meanwhile, silence of FDC-SP expression in hPDLCs remarkably inversed the above results. CONCLUSIONS: LPS induced upregulation of FDC-SP expression in hPDLCs may enhance osteoclastogenesis in periodontal disease. PMID- 26577470 TI - Contemplating a role for titanium in organisms. AB - Titanium is the ninth most abundant element in the Earth's crust and some organisms sequester it avidly, though no essential biological role has yet been recognized. This Minireview addresses how the properties of titanium, especially in an oxic aqueous environment, might make a biological role difficult to recognize. It further considers how new -omic technologies might overcome the limitations of the past and help to reveal a specific role for this metal. While studies with well established model organisms have their rightful place, organisms that are known avid binders or sequesterers of titanium should be promising places to investigate a biological role. PMID- 26577471 TI - The doctor's duty of confidentiality. PMID- 26577472 TI - Duty to care and universal access to health: In defence of a duty to care and provide universal access to health in the face of limited resources. PMID- 26577473 TI - A generalized architecture of quantum secure direct communication for N disjointed users with authentication. AB - In this paper, we generalize a secured direct communication process between N users with partial and full cooperation of quantum server. So, N - 1 disjointed users u1, u2, ..., uN-1 can transmit a secret message of classical bits to a remote user uN by utilizing the property of dense coding and Pauli unitary transformations. The authentication process between the quantum server and the users are validated by EPR entangled pair and CNOT gate. Afterwards, the remained EPR will generate shared GHZ states which are used for directly transmitting the secret message. The partial cooperation process indicates that N - 1 users can transmit a secret message directly to a remote user uN through a quantum channel. Furthermore, N - 1 users and a remote user uN can communicate without an established quantum channel among them by a full cooperation process. The security analysis of authentication and communication processes against many types of attacks proved that the attacker cannot gain any information during intercepting either authentication or communication processes. Hence, the security of transmitted message among N users is ensured as the attacker introduces an error probability irrespective of the sequence of measurement. PMID- 26577474 TI - Morphological Variations in the Canine (Canis familiaris) Right Ventricle Trabecula Septomarginalis Dextra and a Proposed Classification Scheme. AB - The trabecula septomarginalis dextra is a structure routinely mentioned in veterinary anatomy. While there are several studies on the morphology of this structure in select animal species, there are some characteristics that are not adequately described. The purpose of this study was to describe and classify this trabecula in the domestic dog using the number of branches that insert onto the ventricular free wall. In the 39 examined hearts, 17.95% were single stranded (type I) and 2.56% were y-shaped (IA). Then, 28.21% were web-like with 3 to 4 points of insertion (IB) and 51.28% were web-like with 5 or more points of insertion (IC). While the purpose of this study was to describe the morphology of this trabecula, it also showed there is variability in this structure within the same species. This undocumented variability could present a problem to researchers who use dogs as an animal model when testing catheters for invasive cardiac monitoring or cardiac stem cell therapy. Also a web-like trabecula could create problems during pacemaker lead placement for the treatment of symptomatic bradycardia because of the potential for catheter entanglement in these branches. PMID- 26577475 TI - Multiscale Interactions in a 3D Model of the Contracting Ventricle. AB - A biophysical detailed multiscale model of the myocardium is presented. The model was used to study the contribution of interrelated cellular mechanisms to global myocardial function. The multiscale model integrates cellular electrophysiology, excitation propagation dynamics and force development models into a geometrical fiber based model of the ventricle. The description of the cellular electrophysiology in this study was based on the Ten Tusscher-Noble-Noble Panfilov heterogeneous model for human ventricular myocytes. A four-state model of the sarcomeric control of contraction developed by Negroni and Lascano was employed to model the intracellular mechanism of force generation. The propagation of electrical excitation was described by a reaction-diffusion equation. The 3D geometrical model of the ventricle, based on single fiber contraction was used as a platform for the evaluation of proposed models. The model represents the myocardium as an anatomically oriented array of contracting fibers with individual fiber parameters such as size, spatial location, orientation and mechanical properties. Moreover, the contracting ventricle model interacts with intraventricular blood elements linking the contractile elements to the heart's preload and afterload, thereby producing the corresponding pressure-volume loop. The results show that the multiscale ventricle model is capable of simulating mechanical contraction, pressure generation and load interactions as well as demonstrating the individual contribution of each ion current. PMID- 26577476 TI - A Patient-Specific Computational Fluid Dynamic Model for Hemodynamic Analysis of Left Ventricle Diastolic Dysfunctions. AB - This work presents a computational fluid dynamic (CFD) model to simulate blood flows through the human heart's left ventricles (LV), providing patient-specific time-dependent hemodynamic characteristics from reconstructed MRI scans of LV. These types of blood flow visualization can be of great asset to the medical field helping medical practitioners better predict the existence of any abnormalities in the patient, hence offer an appropriate treatment. The methodology employed in this work processed geometries obtained from MRI scans of patient-specific LV throughout a cardiac cycle using computer-aided design tool. It then used unstructured mesh generation techniques to generate surface and volume meshes for flow simulations; thus provided flow visualization and characteristics in patient-specific LV. The resulting CFD model provides three dimensional velocity streamlines on the geometries at specific times in a cardiac cycle, and they are compared with existing literature findings, such as data from echocardiography particle image velocimetry. As an important flow characteristic, vortex formation of the blood flow of healthy as well as diseased subjects having a LV dysfunction condition are also obtained from simulations and further investigated for potential diagnosis. The current work established a pipeline for a non-invasive diagnostic tool for diastolic dysfunction by generating patient specific LV models and CFD models in the spatiotemporal dimensions. The proposed framework was applied for analysis of a group of normal subjects and patients with cardiac diseases. Results obtained using the numerical tool showed distinct differences in flow characteristics in the LV between patient with diastolic dysfunction and healthy subjects. In particular, vortex structures do not develop during cardiac cycles for patients while it was clearly seen in the normal subjects. The current LV CFD model has proven to be a promising technology to aid in the diagnosis of LV conditions leading to heart failures. PMID- 26577477 TI - The Effects That Cardiac Motion has on Coronary Hemodynamics and Catheter Trackability Forces for the Treatment of Coronary Artery Disease: An In Vitro Assessment. AB - The coronary arterial tree experiences large displacements due to the contraction and expansion of the cardiac muscle and may influence coronary haemodynamics and stent placement. The accurate measurement of catheter trackability forces within physiological relevant test systems is required for optimum catheter design. The effects of cardiac motion on coronary flowrates, pressure drops, and stent delivery has not been previously experimentally assessed. A cardiac simulator was designed and manufactured which replicates physiological coronary flowrates and cardiac motion within a patient-specific geometry. A motorized delivery system delivered a commercially available coronary stent system and monitored the trackability forces along three phantom patient-specific thin walled compliant coronary vessels supported by a dynamic cardiac phantom model. Pressure drop variation is more sensitive to cardiac motion than outlet flowrates. Maximum pressure drops varied from 7 to 49 mmHg for a stenosis % area reduction of 56 to 90%. There was a strong positive linear correlation of cumulative trackability force with the cumulative curvature. The maximum trackability forces and curvature ranged from 0.24 to 0.87 N and 0.06 to 0.22 mm(-1) respectively for all three vessels. There were maximum and average percentage differences in trackability forces of (23-49%) and (1.9-5.2%) respectively when comparing a static pressure case with the inclusion of pulsatile flow and cardiac motion. Cardiac motion with pulsatile flow significantly altered (p value <0.001) the trackability forces along the delivery pathways with high local percentage variations and pressure drop measurements. PMID- 26577478 TI - Experimental and Numerical Analysis of the Bulk Flow Parameters Within an Arteriovenous Fistula. AB - The creation of an arteriovenous fistula for hemodialysis has been reported to generate unstable to turbulent flow behaviour. On the other hand, the vast majority of computational fluid dynamic studies of an arteriovenous fistula use low spatial and temporal resolutions resolution in conjunction with laminar assumptions to investigate bulk flow and near wall parameters. The objective of the present study is to investigate if adequately resolved CFD can capture instabilities within an arteriovenous fistula. An experimental model of a representative fistula was created and the pressure distribution within the model was analysed for steady inlet conditions. Temporal CFD simulations with steady inflow conditions were computed for comparison. Following this verification a pulsatile simulation was employed to assess the role of pulsatility on bulk flow parameters. High frequency fluctuations beyond 100 Hz were found to occupy the venous segment of the arteriovenous fistula under pulsatile conditions and the flow within the venous segment exhibited unstable behaviour under both steady and pulsatile inlet conditions. The presence of high frequency fluctuations may be overlooked unless adequate spatial and temporal resolutions are employed. These fluctuations may impact endothelial cell function and contribute to the cascade of events leading to aggressive intimal hyperplasia and the loss of functionality of the vascular access. PMID- 26577479 TI - Dysfunction Screening in Experimental Arteriovenous Grafts for Hemodialysis Using Fractional-Order Extractor and Color Relation Analysis. AB - In physical examinations, hemodialysis access stenosis leading to dysfunction occurs at the venous anastomosis site or the outflow vein. Information from the inflow stenosis, such as blood pressure, pressure drop, and flow resistance increases, allows dysfunction screening from the stage of early clots and thrombosis to the progression of outflow stenosis. Therefore, this study proposes dysfunction screening model in experimental arteriovenous grafts (AVGs) using the fractional-order extractor (FOE) and the color relation analysis (CRA). A Sprott system was designed using an FOE to quantify the differences in transverse vibration pressures between the inflow and outflow sites of an AVG. Experimental analysis revealed that the degree of stenosis (DOS) correlated with an increase in fractional-order dynamic errors (FODEs). Exponential regression was used to fit a non-linear curve and can be used to quantify the relationship between the FODEs and DOS (R (2) = 0.8064). The specific ranges were used to evaluate the stenosis degree, such as DOS: <50, 50-80, and >80%. A CRA-based screening method was derived from the hue angle-saturation-value color model, which describes perceptual color relationships for the DOS. It has a flexibility inference manner with color visualization to represent the different stenosis degrees, which has average accuracy >90% superior to the traditional methods. This in vitro experimental study demonstrated that the proposed model can be used for dysfunction screening in stenotic AVGs. PMID- 26577480 TI - Blood Flow Versus Hematocrit in Optimization of Oxygen Transfer to Tissue During Fluid Resuscitation. AB - The effectiveness of fluid resuscitation regimens in hemorrhagic trauma is assessed based on its ability to increase oxygen concentration in tissue. Fluid resuscitation using both crystalloids and colloids fluids, creates a dilemma due to its opposing effects on oxygen transfer. It increases blood flow thereby augmenting oxygen transport but it also dilutes the blood simultaneously and reduces oxygen concentration thereby reducing oxygen transport. In this work we have studied these two opposing effects of fluid therapy on oxygen delivery to tissue. A mathematical model of oxygen diffusion from capillaries to tissue and its distribution in tissue was developed and integrated into a previously developed hemodynamic model. The capillary-tissue model was based on the Krogh structure. Compared to other models, fewer simplifying assumptions were made leading to different boundary conditions and less constraints, especially regarding capillary oxygen content at its venous end. Results showed that oxygen content in blood is the dominant factor in oxygen transport to tissue and its effect is greater than the effect of flow. The integration of the capillary/tissue model with the hemodynamic model that links administered fluids with flow and blood dilution indicated that fluid resuscitation may reduce oxygen transport to tissue. PMID- 26577481 TI - Blood Flow Simulations for the Design of Stented Valve Reducer in Enlarged Ventricular Outflow Tracts. AB - Tetralogy of Fallot is a congenital heart disease characterized over time, after the initial repair, by the absence of a functioning pulmonary valve, which causes regurgitation, and by progressive enlargement of the right ventricle outflow tract (RVOT). Due to this pathological anatomy, available transcatheter valves are usually too small to be deployed there. To avoid surgical valve replacement, an alternative consists in implanting a reducer prior to or in combination with the valve. It has been shown in animal experiments to be promising, but with some limitations. The effect of a percutaneous pulmonary valve reducer on hemodynamics in enlarged RVOT is thus studied by computational modeling. To this aim, blood flow in the RVOT is modeled with CFD coupled to a simplified valve model and 0D downstream models. Simulations are performed in an image-based geometry and boundary conditions tuned to reproduce the pathological flow without the device. Different device designs are built and compared with the initial device-free state, or with the reducer alone. Results suggest that pressure loss is higher for the reducer alone than for the full device, and that the latter successfully restores hemodynamics to a healthy state and induces a more symmetric flow in the pulmonary arteries. Moreover, pressure forces on the reducer and on the valve have the same magnitudes. Migration would occur towards the right ventricle rather than the pulmonary arteries. Results support the thesis that the reducer does not introduce clinically significant pressure gradients, as was found in animal experiments. Such study could help transfer to patients. PMID- 26577482 TI - Crack Propagation and Its Shear Mechanisms in the Bovine Descending Aorta. AB - Aortic dissection and rupture may involve circumferential shear stress in the circumferential-longitudinal plane. Inflation of bovine descending aortic ring specimens provides evidence of such shear from the non-uniform circumferential distortion of radial lines drawn on the circumferential-radial ring face. Delamination without tensile peeling induces cracks that propagate nearly circumferentially in the circumferential-longitudinal plane from the root of a radial cut representing rupture initiation in a ring. Translational shear deformation tests of small rectangular aortic wall blocks in the circumferential and longitudinal direction measure the consequences of such shear on substructures in the aortic wall, in particular the collagen fibers. The two directions of shear deformation produce no statistical difference in the shear stress response of the wall. Possibly, the interfiber connections between collagen fibers are put into tension by either translational shear deformation so that the stress measured reflects the tensile response of these connections. Wall rupture may involve failure of these connections; such failure is supported by the voids parallel to the collagen fibers observed in a histological study after translational shear. Further, interstitial fluid is redistributed by shear as evidenced by the measured weight loss of a set of specimens during the translational shear of blocks. Because the mass changes, mathematical modeling of aortic tissue in vitro as incompressible is an approximation. These observations suggest that no simple modification of classical rupture theories, whether based on energy functions, stress or strain, suffices to predict the rupture of hydrated soft biological tissue that has complex substructures. PMID- 26577483 TI - Computational Bench Testing to Evaluate the Short-Term Mechanical Performance of a Polymeric Stent. AB - Over the last decade, there has been a significant volume of research focussed on the utilization of biodegradable polymers such as poly-L-lactide-acid (PLLA) for applications associated with cardiovascular disease. More specifically, there has been an emphasis on upgrading current clinical shortfalls experienced with conventional bare metal stents and drug eluting stents. One such approach, the adaption of fully formed polymeric stents has led to a small number of products being commercialized. Unfortunately, these products are still in their market infancy, meaning there is a clear non-occurrence of long term data which can support their mechanical performance in vivo. Moreover, the load carry capacity and other mechanical properties essential to a fully optimized polymeric stent are difficult, timely and costly to establish. With the aim of compiling rapid and representative performance data for specific stent geometries, materials and designs, in addition to reducing experimental timeframes, Computational bench testing via finite element analysis (FEA) offers itself as a very powerful tool. On this basis, the research presented in this paper is concentrated on the finite element simulation of the mechanical performance of PLLA, which is a fully biodegradable polymer, in the stent application, using a non-linear viscous material model. Three physical stent geometries, typically used for fully polymeric stents, are selected, and a comparative study is performed in relation to their short-term mechanical performance, with the aid of experimental data. From the simulated output results, an informed understanding can be established in relation to radial strength, flexibility and longitudinal resistance, that can be compared with conventional permanent metal stent functionality, and the results show that it is indeed possible to generate a PLLA stent with comparable and sufficient mechanical performance. The paper also demonstrates the attractiveness of FEA as a tool for establishing fundamental mechanical characteristics of polymeric stent performance. PMID- 26577485 TI - A Novel Method for Screening Children with Isolated Bicuspid Aortic Valve. AB - This paper presents a novel processing method for heart sound signal: the statistical time growing neural network (STGNN). The STGNN performs a robust classification by merging supervised and unsupervised statistical methods to overcome non-stationary behavior of the signal. By combining available preprocessing and segmentation techniques and the STGNN classifier, we build an automatic tool for screening children with isolated BAV, the congenital heart malformation which can lead to serious cardiovascular lesions. Children with BAV (22 individuals) and healthy condition (28 individuals) are subjected to the study. The performance of the STGNN is compared to that of a time growing neural network (CTGNN) and a conventional support vector (CSVM) machine, using balanced repeated random sub sampling. The average of the accuracy/sensitivity is estimated to be 87.4/86.5 for the STGNN, 81.8/83.4 for the CTGNN, and 72.9/66.8 for the CSVM. Results show that the STGNN offers better performance and provides more immunity to the background noise as compared to the CTGNN and CSVM. The method is implementable in a computer system to be employed in primary healthcare centers to improve the screening accuracy. PMID- 26577484 TI - Development of a Cyclic Strain Bioreactor for Mechanical Enhancement and Assessment of Bioengineered Myocardial Constructs. AB - The purpose of this study was to develop enabling bioreactor technologies using a novel voice coil actuator system for investigating the effects of periodic strain on cardiac patches fabricated with rat cardiomyocytes. The bioengineered muscle constructs used in this study were formed by culturing rat neonatal primary cardiac cells on a fibrin gel. The physical design of the bioreactor was initially conceived using Solidworks to test clearances and perform structural strain analysis. Once the software design phase was completed the bioreactor was assembled using a combination of commercially available, custom machined, and 3-D printed parts. We utilized the bioreactor to evaluate the effect of a 4-h stretch protocol on the contractile properties of the tissue after which immunohistological assessment of the tissue was also performed. An increase in contractile force was observed after the strain protocol of 10% stretch at 1 Hz, with no significant increase observed in the control group. Additionally, an increase in cardiac myofibril alignment, connexin 43 expression, and collagen type I distribution were noted. In this study we demonstrated the effectiveness of a new bioreactor design to improve contractility of engineered cardiac muscle tissue. PMID- 26577486 TI - Optimal Selection of Threshold Value 'r' for Refined Multiscale Entropy. AB - Refined multiscale entropy (RMSE) technique was introduced to evaluate complexity of a time series over multiple scale factors 't'. Here threshold value 'r' is updated as 0.15 times SD of filtered scaled time series. The use of fixed threshold value 'r' in RMSE sometimes assigns very close resembling entropy values to certain time series at certain temporal scale factors and is unable to distinguish different time series optimally. The present study aims to evaluate RMSE technique by varying threshold value 'r' from 0.05 to 0.25 times SD of filtered scaled time series and finding optimal 'r' values for each scale factor at which different time series can be distinguished more effectively. The proposed RMSE was used to evaluate over HRV time series of normal sinus rhythm subjects, patients suffering from sudden cardiac death, congestive heart failure, healthy adult male, healthy adult female and mid-aged female groups as well as over synthetic simulated database for different datalengths 'N' of 3000, 3500 and 4000. The proposed RMSE results in improved discrimination among different time series. To enhance the computational capability, empirical mathematical equations have been formulated for optimal selection of threshold values 'r' as a function of SD of filtered scaled time series and datalength 'N' for each scale factor 't'. PMID- 26577487 TI - Erratum to: Quantitative Assessment of Turbulence and Flow Eccentricity in an Aortic Coarctation: Impact of Virtual Interventions. PMID- 26577488 TI - LC-MS/MS assay for the determination of lurasidone and its active metabolite, ID 14283 in human plasma and its application to a clinical pharmacokinetic study. AB - The authors proposed a sensitive, selective and rapid liquid chromatography tandem mass spectrometric (LC-MS/MS) assay procedure for the quantification of lurasidone and its active metabolite, i.e. ID-14283 in human plasma simultaneously using corresponding isotope labeled compounds as internal standards as per regulatory guidelines. After liquid-liquid extraction with tert butyl methyl ether, the analytes were chromatographed on a C18 column using an optimized mobile phase composed of 5 mm ammonium acetate (pH 5.0) and acetonitrile (15:85, v/v) and delivered at a flow rate of 1.00 mL/min. The assay exhibits excellent linearity in the concentration ranges of 0.25-100 and 0.10 14.1 ng/mL for lurasidone and ID-14283, respectively. The precision and accuracy results over five concentration levels in four different batches were well within the acceptance limits. Lurasidone and ID-14283 were found to be stable in battery of stability studies. The method was rapid with the chromatographic run time 2.5 min, which made it possible to analyze 300 samples in a single day. Additionally, this method was successfully used to estimate the in vivo plasma concentrations of lurasidone and ID-14283 obtained from a pharmacokinetic study in south Indian male subjects and the results were authenticated by conducting incurred samples reanalysis. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26577489 TI - A Framework for Training Public Health Practitioners in Crisis Decision-Making. AB - Three sets of issues tend to be overlooked in public health emergency preparedness and response, which can be addressed with new training protocols. The first issue is procedural and concerns the often intuitive (as opposed to deliberative) nature of effective crisis decision-making. The second issue is substantive and pertains to the incorporation and prioritization of ethical, political, and logistical concerns in public health emergency guidelines. The third issue is affective and concerns human feelings and human frailty, which can derail the most well designed and best practiced procedural and substantive approaches to emergency response. This article offers an outline for a decision making framework for public health emergencies that addresses and incorporates these issues within relevant guidelines and training. PMID- 26577490 TI - Molecular basis of canalization in an ascidian species complex adapted to different thermal conditions. AB - Canalization is a result of intrinsic developmental buffering that ensures phenotypic robustness under genetic variation and environmental perturbation. As a consequence, animal phenotypes are remarkably consistent within a species under a wide range of conditions, a property that seems contradictory to evolutionary change. Study of laboratory model species has uncovered several possible canalization mechanisms, however, we still do not understand how the level of buffering is controlled in natural populations. We exploit wild populations of the marine chordate Ciona intestinalis to show that levels of buffering are maternally inherited. Comparative transcriptomics show expression levels of genes encoding canonical chaperones such as Hsp70 and Hsp90 do not correlate with buffering. However the expression of genes encoding endoplasmic reticulum (ER) chaperones does correlate. We also show that ER chaperone genes are widely conserved amongst animals. Contrary to previous beliefs that expression level of Heat Shock Proteins (HSPs) can be used as a measurement of buffering levels, we propose that ER associated chaperones comprise a cellular basis for canalization. ER chaperones have been neglected by the fields of development, evolution and ecology, but their study will enhance understanding of both our evolutionary past and the impact of global environmental change. PMID- 26577491 TI - Identification of the hydroxylated derivatives of bufalin: phase I metabolites in rats. AB - Bufalin was a typical bioactive bufadienolide, existed in the traditional Chinese medicine Chan Su with the high content of 1-5%. The in vivo metabolites (1-5) of bufalin were prepared by various chromatographic techniques from the bile samples of SD rats, which were administrated with bufalin orally. Their structures were determined on the basis of the widely spectroscopic data, including HRESIMS, 1D-, and 2D NMR. And 1-3, 5 were new compounds. In the in vitro cytotoxicity assay, metabolites (1-5) showed weaker cytotoxic effects than bufalin against human cancer cell lines A549 and H1299, which indicated that the metabolism was a significant pathway for the detoxification of bufalin. Structures analyses indicated that metabolites 1-5 were hydroxylated derivatives of bufalin. This study suggested that Phase I metabolism catalyzed by CYP450 enzymes was one of the metabolic ways of bufalin, which may promote the excretion of bufalin. PMID- 26577492 TI - Monitoring EGFR T790M with plasma DNA from lung cancer patients in a prospective observational study. AB - Use of plasma DNA to detect mutations has spread widely as a form of liquid biopsy. EGFR T790M has been observed in half of lung cancer patients who have acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI). Effectiveness of monitoring T790M via plasma DNA during treatment with EGFR-TKI has not been established as an alternative to re-biopsy. This was a prospective multicenter observational study involving non-small cell lung cancer patients carrying EGFR L858R or exon 19 deletions, treated with EGFR-TKI. The primary objective was to determine whether T790M could be detected using plasma DNA in patients with progressive disease (PD). T790M was examined using the mutation-biased PCR and quenching probe (MBP-QP) method, a sensitive, fully-automated system developed in our laboratory. Eighty-nine non-small cell lung cancer patients were enrolled from seven hospitals in Japan. Sequential examinations revealed T790M in plasma DNA among 40% of patients who developed PD. Activating mutations, such as L858R and exon 19 deletions, were detected in 40% of patients using plasma DNA, and either T790M or activating mutations were observed in 62%. Dividing into four periods (before PD, at PD, at discontinuation of EGFR-TKI and subsequently), T790M was detected in 10, 19, 24 and 27% of patients, respectively. Smokers, males, patients having exon 19 deletions and patients who developed new lesions evidenced significantly frequent presence of T790M in plasma DNA. Monitoring T790M with plasma DNA using MBP-QP reflects the clinical course of lung cancer patients treated with EGFR-TKI. Detection of T790M with plasma DNA was correlated with EGFR mutation type, exon 19 deletions and tumor progression. Re-biopsy could be performed only in 14% of PD cases, suggesting difficulty in obtaining re biopsy specimens in practice. Monitoring T790M with plasma DNA reflects the clinical course, and is potentially useful in designing strategies for subsequent treatment. PMID- 26577493 TI - Effect of CDKN2A/B rs4977756 polymorphism on glioma risk: a meta-analysis of 16 studies including 24077 participants. AB - So far, epidemiological studies have been performed to investigate the association of CDKN2A/B rs4977756 polymorphism and glioma risk. However, the results from different studies remain inconsistent. To clarify these conflicts and to quantitatively evaluate the effect of rs4977756 polymorphism on glioma risk, a meta-analysis was conducted using relevant published clinical studies about rs4977756 polymorphisms and glioma risk. Relevant studies concerning the association between rs4977756 polymorphism and risk of glioma were included in this meta-analysis. Odds ratio (OR) and 95 % confidence interval (CI) were calculated under fixed or random effects models when appropriate. Subgroup analyses were performed by race. This meta-analysis included 13 studies with a total of 8129 cases and 15,858 controls. The pooled results showed that there was an obvious association of CDKN2A/B rs4977756 polymorphism with risk of glioma in all four comparison models (dominant model/AG + GG vs. AA: OR = 1.36, 95 %CI = 1.20-1.54, p < 0.01; heterozygote comparison/AG vs. AA: OR = 1.31, 95 %CI = 1.12 1.53, p < 0.01; homozygote comparison/GG versus AA: OR = 1.49, 95 %CI = 1.36 1.64, p < 0.01; additive model/G vs. A: OR = 1.23, 95 %CI = 1.18-1.28, p < 0.01, respectively). For the subgroup analyses of ethnicities, similar results were observed in Caucasians. However, the association was not found between rs4977756 polymorphism and the risk of glioma in all models for the Asian studies. The CDKN2A/B rs4977756 polymorphism is obvious increase the risk of glioma in Caucasians. Future studies are needed to confirm the results in other ethnic populations. PMID- 26577495 TI - Efficient Room-Temperature, Au(+)-Mediated Coupling of a Carbene Ligand with Methane To Generate C2Hx (x = 4, 6). AB - The thermal reactions of the closed-shell, "naked" gold-carbene complex [Au(CH2)](+) with methane have been explored by using FTICR mass spectrometry complemented by quantum chemical (QC) calculations at the CCSD(T)//BMK level of theory. Mechanistic aspects for this unprecedentedly efficient carbene insertion in the C-H bond of methane have been addressed and the origin of the counterintuitive high reactivity of [Au(CH2)](+) towards this most inert hydrocarbon is discussed. PMID- 26577494 TI - A modified method (MK method) of alcohol septal ablation for the treatment of hypertrophic obstructive cardiomyopahty. AB - Alcohol septal ablation is widely accepted as a therapeutic option for the treatment of hypertrophic obstructive cardiomyopahty. The selection of an appropriate target vessel is key for an effective and safe procedure. The target vessel sometimes bifurcates from the non-left anterior descending coronary artery, in which case these vessels are sometimes difficult to select with a wire and deliver a balloon catheter. The combined use of a microcatheter and a balloon catheter is one of the choices for treatment of patients with this type of challenging anatomy. (c) 2015 Wiley Periodicals, Inc. PMID- 26577496 TI - Hydroxytyrosol, a product from olive oil, reduces colon cancer growth by enhancing epidermal growth factor receptor degradation. AB - SCOPE: We studied the effects and mechanism of 2-(3,4-dihydroxyphenil)ethanol (or hydroxytyrosol, HT), a polyphenol from extra virgin olive oil, investigating the regulation of epidermal growth factor receptor (EGFR) expression in colon tumour cells. METHODS AND RESULTS: We demonstrate that HT significantly downregulates EGFR expression in human colorectal adenocarcinoma cells HT-29, CaCo2, and WiDr, and in HT-29 xenografts. HT accelerates EGFR degradation by reducing its half life. Specifically, HT induces EGFR ubiquitination that is mediated by phosphorylation at pY1045, the docking site for Cbl, thereby enabling receptor ubiquitination and degradation. Pretreatment with either the lysosomal inhibitor chloroquine, or the proteasomal inhibitor MG132 blocks HT-induced EGFR downregulation. In colon cancer cells, EGFR downregulation by HT is associated with reduced cell proliferation. Tumour growth and EGFR expression levels are also decreased by HT treatment in HT-29 xenograft. CONCLUSION: We conclude that HT downregulates EGFR expression via lysosomal and proteasomal degradation, activated by HT-induced EGFR phosphorylation at pY1045 and increased Cbl activity. Cbl activation induces, in turn, EGFR ubiquitination. Our results reveal a new mechanism for HT's antitumour effects that may be important for colon tumour prevention and treatment. PMID- 26577497 TI - Author Reply. PMID- 26577498 TI - Editorial Comment. PMID- 26577499 TI - Duct-to-Mucosa vs Invagination for Pancreaticojejunostomy after Pancreaticoduodenectomy: A Prospective, Randomized Controlled Trial from a Single Surgeon. AB - BACKGROUND: Pancreatic fistula (PF) is the most common significant complication after pancreaticoduodenectomy. Invagination and duct-to-mucosa anastomoses are anastomotic techniques that are commonly performed after pancreaticoduodenectomy. There are conflicting data on invagination vs duct-to-mucosa anastomoses about which is superior for minimizing the risk of PF. In addition, all previous studies involved multiple operating surgeons and failed to control for variation in surgeon expertise. STUDY DESIGN: This was a randomized controlled study comparing the outcomes of PD between patients who underwent invagination vs those who had duct-to-mucosa anastomoses. All 132 patients were operated on between October 2012 and March 2015 by a single surgeon experienced in both procedures. Pancreatic fistula was the main end point. RESULTS: Overall and clinically relevant rates of PF rate were 29.5% and 10.6%, respectively. Overall PF rates in the patients treated with invagination vs duct-to-mucosa anastomoses were 30.9% vs 28.5% (p = 0.729), respectively and the corresponding clinically relevant PF rates were 17.6% vs 3.1%, respectively (p = 0.004). Although the overall complication rates were similar in the 2 groups, severe complications were significantly more frequent in the patients treated with invagination (p = 0.013). Duct-to-mucosa anastomosis was also associated with shorter postoperative hospital stay (13 vs 15 days; p = 0.021). There was one perioperative death. Independent variables for the risk of PF were the diameter of the pancreatic duct (greater risk with smaller diameter), the underlying pathology, and male sex. CONCLUSIONS: Both methods yield similar overall rates for PF, but the rate of clinically relevant PF is lower in patients treated with duct-to-mucosa anastomosis. Additional single-surgeon studies or multi-institution randomized trials controlling for comparable expertise in both procedures should be conducted to confirm these results. PMID- 26577500 TI - Predictive value of pAKT/PTEN expression in oral squamous cell carcinoma treated with cetuximab-based chemotherapy. AB - OBJECTIVE: Molecular alterations in downstream effectors of epidermal growth factor receptor may confer resistance to epidermal growth factor receptor inhibitors. Our aim is to investigate whether PTEN/pAKT expression predicts response to cetuximab-based chemotherapy in oral squamous cell carcinoma. STUDY DESIGN: We analyzed a cohort of 50 patients with oral squamous cell carcinoma treated with cetuximab-based induction chemotherapy. PTEN expression and pAKT expression were assessed by immunohistochemistry and their correlation with treatment outcome was analyzed. RESULTS: Of the study patients, 18.4% had low PTEN expression, and 38.8% had high pAKT expression. Lower pAKT expression were associated with pathologic remission (P = .034) and better disease-free survival (P = .031). CONCLUSION: Our study demonstrates that pAKT expression is a predictive biomarker of cetuximab-based induction chemotherapy in OSCC. PMID- 26577501 TI - Effects of human Dachshund homolog 1 on the proliferation, migration, and adhesion of squamous cell carcinoma of the tongue. AB - OBJECTIVE: To investigate the expression and role of human Dachshund homolog 1 (DACH1) in the tongue squamous cell carcinoma (TSCC). STUDY DESIGN: To explore the expression, regulation, and mechanism of DACH1 in TSCC, nine samples of fresh tumor and adjacent tissues, 51 samples of paraffin-embedded TSCC and paired adjacent tissues, and TSCC cell line SCC-25 were examined. Immunohistochemistry, real-time polymerase chain reaction, Western blot, 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide, colony formation, Transwell, adhesion assays, and flow cytometry were used. RESULTS: The DACH1 expression level was significantly lower in tumors than in the adjacent tissues, and such low expression was associated with poor differentiation of tumors, late clinical stage, and lymph node metastasis. Moreover, overexpression of DACH1 might promote apoptosis and inhibit the proliferation, migration, and adhesion of SCC-25 cells. CONCLUSIONS: DACH1 may be a potential molecular target for the therapy of recurrent and metastatic TSCC. PMID- 26577502 TI - BMAA detected as neither free nor protein bound amino acid in blue mussels. AB - The results of this study imply that beta-methylamino-alanine (BMAA) obtained from extracts of blue mussels from the Swedish west coast is neither free nor protein bound. The results were obtained by separation (precipitation and ultrafiltration) of low and high molecular weight compounds from neutral extracts of blue mussels, and treatment of these extracts with low and high concentrations of acids, varying time and temperature. The main portion of BMAA was obtained from the low molecular weight fraction, released or formed at 95 degrees C in dilute acids. The measured amount of BMAA did not increase by strong acid treatment. Lysine was used as reference and was only released at significant amounts when treating the high molecular weight fraction with concentrated acid. The results also indicated that breakage of peptide bonds was not involved in the formation/release of BMAA in these extracts unless any BMAA peptide bond would be significantly more susceptible to dilute acid than e.g. the monitored lysine peptide bond. BMAA was measured using isotope dilution and detection of the underivatized compound by HILIC-UHPLC-MS/MS (Hydrophilic Interaction Liquid Chromatography, Ultra-High Performance Liquid Chromatography, tandem Mass Spectrometry). The findings might add to the understanding of conflicting data in the literature regarding the occurrence of BMAA, and have implications for studies on possible biomagnification of BMAA in the food chain and bioavailability from food. PMID- 26577504 TI - Improving Bridging from Informatics Practice to Theory. AB - BACKGROUND: In 1962, Methods of Information in Medicine ( MIM ) began to publish papers on the methodology and scientific fundamentals of organizing, representing, and analyzing data, information, and knowledge in biomedicine and health care. Considered a companion journal, Applied Clinical Informatics ( ACI ) was launched in 2009 with a mission to establish a platform that allows sharing of knowledge between clinical medicine and health IT specialists as well as to bridge gaps between visionary design and successful and pragmatic deployment of clinical information systems. Both journals are official journals of the International Medical Informatics Association. OBJECTIVES: As a follow-up to prior work, we set out to explore congruencies and interdependencies in publications of ACI and MIM. The objectives were to describe the major topics discussed in articles published in ACI in 2014 and to determine if there was evidence that theory in 2014 MIM publications was informed by practice described in ACI publications in any year. We also set out to describe lessons learned in the context of bridging informatics practice and theory and offer opinions on how ACI editorial policies could evolve to foster and improve such bridging. METHODS: We conducted a retrospective observational study and reviewed all articles published in ACI during the calendar year 2014 (Volume 5) for their main theme, conclusions, and key words. We then reviewed the citations of all MIM papers from 2014 to determine if there were references to ACI articles from any year. Lessons learned in the context of bridging informatics practice and theory and opinions on ACI editorial policies were developed by consensus among the two authors. RESULTS: A total of 70 articles were published in ACI in 2014. Clinical decision support, clinical documentation, usability, Meaningful Use, health information exchange, patient portals, and clinical research informatics emerged as major themes. Only one MIM article from 2014 cited an ACI article. There are several lessons learned including the possibility that there may not be direct links between MIM theory and ACI practice articles. ACI editorial policies will continue to evolve to reflect the breadth and depth of the practice of clinical informatics and articles received for publication. Efforts to encourage bridging of informatics practice and theory may be considered by the ACI editors. CONCLUSIONS: The lack of direct links from informatics theory-based papers published in MIM in 2014 to papers published in ACI continues as was described for papers published during 2012 to 2013 in the two companion journals. Thus, there is little evidence that theory in MIM has been informed by practice in ACI. PMID- 26577505 TI - Computed tomography morphological analysis of the scapula and its implications in shoulder arthroplasty. AB - BACKGROUND: Healthy shoulder morphology is still unclear. Since bone morphology influences prosthetic features, this is relevant for glenohumeral joint reconstruction. The objective of this study was to assess the normal values of glenoid version, maximum width, base width and vault depth on computed tomography scans. METHODS: Axial cut CT scans of 1072 healthy glenoids were retrospectively reviewed. Values of glenoid version, maximum glenoid width, glenoid base width and glenoid vault depth were measured by two different observers. Differences were determined between genders, and reproducibility and interrater reliability assessed. RESULTS: Glenoid version was 37.71 degrees +/- 10.75 degrees , range 6.20 degrees to 71.30 degrees ; maximum glenoid width was 26.06 +/- 3.27 mm, range 15.40-36.90 mm; glenoid base width was 16.59 +/- 2.61 mm, range 8.90-25.40 mm; glenoid vault depth was 9.72 +/- 1.62 mm, range 4.70-15.90 mm. All measurements except for glenoid version were significantly higher in males than in females. Reproducibility was good for every measurement, except glenoid vault depth. CONCLUSION: We found differences in maximum glenoid width, base width and vault depth by gender in a large sample. Glenoid components' maximum width was defined, as was reaming extension and orientation, the space available for implantation of the glenoid component, placement of pegs or keels in anatomic prostheses and the target for glenoid screws in inverted prostheses. LEVEL OF EVIDENCE: II. PMID- 26577506 TI - Estrogen Plus Progestin and Lung Cancer: Follow-up of the Women's Health Initiative Randomized Trial. AB - INTRODUCTION: In the Women's Health Initiative (WHI) estrogen plus progestin trial, after 5.6 years' intervention and 8 years' median follow-up, more women died from lung cancer in the hormone therapy group (hazard ratio [HR], 1.71; 95% confidence interval [CI], 1.16-2.52; P = .01). Now after 14 years' median follow up, we reexamined combined hormone therapy effects on lung cancer mortality. PATIENTS AND METHODS: In the WHI placebo-controlled trial, 16,608 postmenopausal women aged 50 to 79 years and with an intact uterus were randomly assigned to once-daily 0.625 mg conjugated equine estrogen plus 2.5 mg medroxyprogesterone acetate (n = 8506) or placebo (n = 8102). Incidence and mortality rates for lung cancer were assessed from multivariant proportional hazard models. RESULTS: After 14 years' cumulative follow-up, there were 219 lung cancers (0.19% per year) in the estrogen plus progestin group and 184 (0.17%) in the placebo group (HR, 1.12; 95% CI, 0.92-1.37; P = .24). While there were more deaths from lung cancer with combined hormone therapy (153 [0.13%] vs. 132 [0.12%], respectively), the difference was not statistically significant (HR, 1.09; 95% CI, 0.87-1.38; P = .45). The statistically significant increase in deaths from lung cancer observed during intervention in women assigned to estrogen plus progestin was attenuated after discontinuation of study pills (linear trend over time, P = .042). CONCLUSION: The increased risk of death from lung cancer observed during estrogen plus progestin use was attenuated after discontinuation of combined hormone therapy. PMID- 26577510 TI - Thalidomide for the treatment of chronic refractory pruritus. AB - Pruritus is a common and often times difficult to treat symptom in many dermatologic and systemic diseases. For pruritus with an inflammatory or autoimmune origin, therapies such as topical corticosteroids and antihistamines are often initiated. However, in the case that these and additional systemic therapies are ineffective, thalidomide, an immunomodulator and neuromodulator, may be a useful alternative treatment. Considerable relief of chronic pruritus has been demonstrated with thalidomide in case reports, case series, and controlled trials. Double-blind controlled studies demonstrated thalidomide's efficacy as an antipruritic agent in patients with uremic pruritus, primary biliary cirrhosis, and prurigo nodularis. In case reports, case series, and open label trials, thalidomide significantly reduced pruritus associated with conditions such as actinic prurigo and paraneoplastic pruritus. Because of variations in study design and evaluation of antipruritic effect, it is difficult to fully understand thalidomide's role based on the evidence described to date in the medical literature. In this review, we provide an overview of the reported findings and evaluate thalidomide's utility in managing refractory pruritus in the context of its adverse risk profile. We propose that thalidomide can be an alternative or combination antipruritic treatment for patients who do not obtain enough relief from conservative therapy. PMID- 26577511 TI - Morphological and immunohistochemical clues for the diagnosis of cutaneous leishmaniasis and the interpretation of CD1a status. AB - BACKGROUND: CD1a immunoexpression by amastigotes of Leishmania major and L tropica has been demonstrated. OBJECTIVE: We studied the CD1a and the langerin status of amastigotes in cases of L infantum. METHODS: We investigated 19 cases of cutaneous leishmaniasis. All cases were immunostained with CD1a, langerin, and CD68. We also studied 4 cases of visceral leishmaniasis. RESULTS: We found expression of CD1a by amastigotes in all of these 19 cases. CD1a(-) amastigotes are found in reticular areas of the dermis. The pattern of CD1a immunostaining of amastigotes is characteristic, with peripheral positivity, a negative nucleus in the center, and reinforcement of the kinetoplast in 1 pole. Leishmania amastigotes were langerin-negative. Visceral Leishmania amastigotes also express CD1a. LIMITATIONS: Our study was limited because it only included cases of infection by L infantum. CONCLUSIONS: (1) L infantum is CD1a(+), (2) the pattern of CD1a immunostaining of amastigotes is peculiar, (3) CD1a(-) amastigotes are found in reticular areas of the dermis, and (4) visceral Leishmania amastigotes also express CD1a. PMID- 26577509 TI - The Subthalamic Nucleus, Limbic Function, and Impulse Control. AB - It has been well documented that deep brain stimulation (DBS) of the subthalamic nucleus (STN) to address some of the disabling motor symptoms of Parkinson's disease (PD) can evoke unintended effects, especially on non-motor behavior. This observation has catalyzed more than a decade of research concentrated on establishing trends and identifying potential mechanisms for these non-motor effects. While many issues remain unresolved, the collective result of many research studies and clinical observations has been a general recognition of the role of the STN in mediating limbic function. In particular, the STN has been implicated in impulse control and the related construct of valence processing. A better understanding of STN involvement in these phenomena could have important implications for treating impulse control disorders (ICDs). ICDs affect up to 40% of PD patients on dopamine agonist therapy and approximately 15% of PD patients overall. ICDs have been reported to be associated with STN DBS. In this paper we will focus on impulse control and review pre-clinical, clinical, behavioral, imaging, and electrophysiological studies pertaining to the limbic function of the STN. PMID- 26577508 TI - Aging with HIV-1 Infection: Motor Functions, Cognition, and Attention--A Comparison with Parkinson's Disease. AB - Recent advances in highly active anti-retroviral therapy (HAART) in their various combinations have dramatically increased the life expectancies of HIV-infected persons. People diagnosed with HIV are living beyond the age of 50 but are experiencing the cumulative effects of HIV infection and aging on brain function. In HIV-infected aging individuals, the potential synergy between immunosenescence and HIV viral loads increases susceptibility to HIV-related brain injury and functional brain network degradation similar to that seen in Parkinson's disease (PD), the second most common neurodegenerative disorder in the aging population. Although there are clear diagnostic differences in the primary pathology of both diseases, i.e., death of dopamine-generating cells in the substantia nigra in PD and neuroinflammation in HIV, neurotoxicity to dopaminergic terminals in the basal ganglia (BG) has been implied in the pathogenesis of HIV and neuroinflammation in the pathogenesis of PD. Similar to PD, HIV infection affects structures of the BG, which are part of interconnected circuits including mesocorticolimbic pathways linking brainstem nuclei to BG and cortices subserving attention, cognitive control, and motor functions. The present review discusses the combined effects of aging and neuroinflammation in HIV individuals on cognition and motor function in comparison with age-related neurodegenerative processes in PD. Despite the many challenges, some HIV patients manage to age successfully, most likely by redistribution of neural network resources to enhance function, as occurs in healthy elderly; such compensation could be curtailed by emerging PD. PMID- 26577512 TI - Intralesional 5-fluorouracil (FU) as a treatment for nonmelanoma skin cancer (NMSC): A review. AB - The treatment paradigm for nonmelanoma skin cancer remains surgical. This fact combined with its remarkably high incidence positions it as the fifth most costly cancer to treat in the Medicare population. To address this, consideration of alternative medical therapeutics is warranted. Intralesional 5-fluorouracil is a potentially affordable option that may demand further investigation. This literature review examines current data on its efficacy and adverse effects. PMID- 26577513 TI - Virtual dissection and lifestyle of a 165 -million-year-old female polychelidan lobster. AB - Polychelidan lobsters are fascinating crustaceans that were known as fossils before being discovered in the deep-sea. They differ from other crustaceans by having four to five pairs of claws. Although recent palaeontological studies have clarified the systematics and phylogeny of the group, the biology of extant polychelidans and--first of all--their anatomy are poorly documented. Numerous aspects of the evolutionary history of the group remain obscure, in particular, how and when polychelidans colonized the deep-sea and became restricted to it. Surprisingly, the biology of extant polychelidans and the anatomy of all species, fossil and recent, are poorly documented. Here, X-ray microtomography (XTM), applied to an exceptionally well-preserved specimen from the La Voulte Lagerstatte, reveals for the first time vital aspects of the external and internal morphology of Voulteryon parvulus (Eryonidae), a 165-million-year-old polychelidan: 1) its mouthparts (maxillae and maxillipeds), 2) its digestive tract and 3) its reproductive organs. Comparisons with dissected specimens clearly identify this specimen as a female with mature ovaries. This set of new information offers new insights into the feeding and reproductive habits of Mesozoic polychelidans. Contrasting with other Jurassic polychelidans that lived in shallow-water environments, V. parvulus spawned in, and probably inhabited, relatively deep-water environments, as do the survivors of the group. PMID- 26577514 TI - Assessing the Impact of De Novo Social Ties within Health Intervention Settings: New Questions for Health Behavior Intervention Research. AB - Recent developments in the study of health and social networks have focused on linkages between health outcomes and naturally occurring social relations, such as friendship or kinship. Based on findings in this area, a new generation of health behavior intervention programs have been implemented that rely on the formation of new social relations among program participants. However, little is known about the qualities of these de novo social relations. We examined the social networks of 59 participants within a randomized controlled trial of an intervention designed to prevent excessive gestational weight gain. We employed exponential random graph modeling techniques to analyze supportive relationships formed between participants in the intervention arm, to detect unique effects of program participation on the likelihood of forming ties. Program participation had a positive effect on the likelihood of forming supportive social relations, however, in this particular timeframe we did not detect any additional effect of such relations on the health behaviors or outcomes of interest. Our findings raise two critical questions: do short-term group-level programs reliably lead to the formation of new social relations among participants; and do these relations have a unique effect on health outcomes relative to standard methods of health behavior intervention? PMID- 26577515 TI - Role for the PI3K/Akt/Nrf2 signaling pathway in the protective effects of carnosic acid against methylglyoxal-induced neurotoxicity in SH-SY5Y neuroblastoma cells. AB - Glycation, a process that occurs endogenously and generates advanced glycation end products (AGEs), presents an important role in cases of neurodegeneration, as for instance Alzheimer's disease (AD). Methylglyoxal (MG), a dicarbonyl compound, is the most potent inducer of AGEs, whose levels have been found increased in samples obtained from subjects suffering from AD. Moreover, MG induces protein cross-linking and redox impairment in vitro and in vivo. Carnosic acid (CA), a phenolic diterpene isolated from Rosmarinus officinalis, exerts protective effects in neuronal cells by increasing antioxidant defenses and detoxification systems. In the present work, we aimed to investigate whether there is a role for CA against MG-induced neurotoxicity. Data obtained here clearly demonstrate that CA pretreatment (1 MUM for 12 h) caused cytoprotective effects and counteracted the damage elicited by MG in SH-SY5Y cells. CA inhibited loss of mitochondrial membrane polarity (MMP) and cytochrome c release from mitochondria, consequently blocking activation of pro-apoptotic caspase enzymes. Furthermore, CA alleviated MG-induced oxidative and nitrosative damage. CA prevented MG-dependent neurotoxicity by activating the PI3K/Akt/Nrf2 signaling pathway and the antioxidant enzymes modulated by Nrf2 transcription factor. Overall, the data presented here show the protective role of CA by its ability to counteract MG negative effects. PMID- 26577516 TI - Why the FUSS (Fentanyl Urine Screen Study)? A cross-sectional survey to characterize an emerging threat to people who use drugs in British Columbia, Canada. AB - BACKGROUND: Fentanyl-detected illicit drug overdose deaths in British Columbia (BC) recently increased dramatically from 13 deaths in 2012 to 90 deaths in 2014, signaling an emerging public health concern. Illicit fentanyl is sold as pills or powders, often mixed with other substances like heroin or oxycodone; reports from coroners suggested that fentanyl was frequently taken unknowingly by people who use drugs. This study aimed to assess the prevalence and characteristics of fentanyl use among clients accessing harm reduction (HR) services in BC. METHODS: Participants attending HR services at 17 sites across BC were invited to complete an anonymous questionnaire describing drugs they have used within the last 3 days and provide a urine sample to test for fentanyl. Data from eligible participants were analyzed using descriptive, bivariate, and multivariate statistical methods. RESULTS: Surveys from 17 HR sites were received, resulting in analysis of responses from 242 eligible participants. Most participants used multiple substances (median = 3), with crystal meth (59%) and heroin (52%) use most frequently reported. Seventy participants (29%) tested positive for fentanyl, 73% of whom did not report using fentanyl. Controlling for age, gender, and health authority, reported use of fentanyl (odds ratio (OR) = 6.13, 95% confidence interval (CI) = [2.52, 15.78], p < 0.001) and crystal methamphetamine (OR = 3.82, 95% CI = [1.79, 8.63], p < 0.001) use were significantly associated with fentanyl detection. CONCLUSIONS: The proportion of those testing positive who did not report knowingly using fentanyl represents a considerable public health concern. The risk of overdose among this vulnerable population highlights the need for targeted HR strategies, such as increased accessibility to naloxone, overdose education, and urine screens. PMID- 26577517 TI - Reliability of eccentric position of the pedicle instead of central position in a thoracodorsal artery perforator flap. AB - INTRODUCTION: To obtain longer vascular pedicle in perforator flaps, surgeons often use eccentrically rather than centrally located perforators. The aim of this study was to compare the safety and reliability of thoracodorsal artery perforator (TDAP) flaps harvested with centrally or eccentrically located perforators. METHODS: Between January 2008 and March 2012, 100 TDAP flaps were used to reconstruct the lower extremity defects. Flaps longer than 10 cm, with a single musculocutaneous perforator, and one artery-one vein anastomoses were included. The cases were divided into two groups according to perforator location; Central perforators in 60 cases (group 1), and peripheral perforators in 40 cases (group 2). Total pedicle length was between the points where the perforator enters the flap to the end of the pedicle. Real pedicle length was from flap margin to the end of the pedicle. The flap dimension, total pedicle length, real pedicle length, and flap related complications were measured. RESULTS: The flaps were smaller in group 1 than in group 2 (159.6 +/- 94.08 vs.189.95 +/- 134.30 cm2 , P = 0.455). Total pedicle length was almost the same (12.12 +/- 1.57 vs.12.88 +/- 2.10 cm, P = 0.420), but the mean real pedicle length was longer in group 2 (6.13 +/- 1.33 vs.11.65 +/- 2.08 cm, P < 0.05). There were 4 cases of partial loss of flap in group 1 and 3 partial loss and one total flap loss in group 2 without significant difference (P = 0.547). CONCLUSIONS: Using eccentrically located perforators is simple method of extending real pedicle length, but there have been concerns regarding flap perfusion and distal vascularity. Our findings suggest that, in TDAP flaps, both eccentric and central perforator are safe options. (c) 2014 Wiley Periodicals, Inc. Microsurgery 37:44-48, 2017. PMID- 26577518 TI - A cost-effectiveness analysis of three components of a syndromic surveillance system for the early warning of epidemics in rural China. AB - BACKGROUND: Syndromic surveillance systems (SSSs) collect non-specific syndromes in early stages of disease outbreaks. This makes an SSS a promising tool for the early detection of epidemics. An Integrated Surveillance System in rural China (ISSC project), which added an SSS to the existing Chinese surveillance system for the early warning of epidemics, was implemented from April 2012 to March 2014 in Jiangxi and Hubei Provinces. This study aims to measure the costs and effectiveness of the three components of the SSS in the ISSC project. METHODS: The central measures of the cost-effectiveness analysis of the three components of the syndromic surveillance system were: 1) the costs per reported event, respectively, at the health facilities, the primary schools and the pharmacies; and 2) the operating costs per surveillance unit per year, respectively, at the health facilities, the primary schools and the pharmacies. Effectiveness was expressed by reporting outputs which were numbers of reported events, numbers of raw signals, and numbers of verified signals. The reported events were tracked through an internal data base. Signal verification forms and epidemiological investigation reports were collected from local country centers for disease control and prevention. We adopted project managers' perspective for the cost analysis. Total costs included set-up costs (system development and training) and operating costs (data collection, quality control and signal verification). We used self-designed questionnaires to collect cost data and received, respectively, 369 and 477 facility and staff questionnaires through a cross sectional survey with a purposive sampling following the ISSC project. All data were entered into Epidata 3.02 and exported to Stata for descriptive analysis. RESULTS: The number of daily reported events per unit was the highest at pharmacies, followed by health facilities and finally primary schools. Variances existed within the three groups and also between Jiangxi and Hubei. During a 15 month surveillance period, the number of raw signals for early warning in Jiangxi province (n = 36) was nine times of that in Hubei. Health facilities and primary schools had equal numbers of raw signals (n = 19), which was 9.5 times of that from pharmacies. Five signals were confirmed as outbreaks, of which two were influenza, two were chicken pox and one was mumps. The cost per reported event was the highest at primary schools, followed by health facilities and then pharmacies. The annual operating cost per surveillance unit was the highest at pharmacies, followed by health facilities and finally primary schools. Both the cost per reported event and the annual operating cost per surveillance unit in Jiangxi in each of the three groups were higher than their counterparts in Hubei. CONCLUSIONS: Health facilities and primary schools are better sources of syndromic surveillance data in the early warning of outbreaks. The annual operating costs of all the three components of the syndromic surveillance system in the ISSC Project were low compared to general government expenditures on health and average individual income in rural China. PMID- 26577519 TI - Nosocomial bloodstream infections caused by Escherichia coli and Klebsiella pneumoniae resistant to third-generation cephalosporins, Finland, 1999-2013: Trends, patient characteristics and mortality. AB - BACKGROUND: Few systematically collected multi-centre surveillance data on nosocomial bloodstream infections (BSI) caused by extended-spectrum beta lactamase (ESBL) producing Escherichia coli or Klebsiella pneumoniae have been published. AIM: To evaluate trends, patient characteristics and mortality of such infections, nosocomial BSI data reported by the 4-17 hospitals participating in the prospective laboratory-based surveillance during 1999-2013 were analysed. METHODS: Data were collected by local infection control nurses, patient-days were obtained from the hospital's administrative database, and dates of deaths from the population registry. Resistance to third-generation cephalosporins was further examined in the national reference laboratory. FINDINGS: A total of 16 028 nosocomial BSIs were identified; 2217 (14%) were caused by E. coli and 661 (4%) by K. pneumoniae; 207 (7%) were non-susceptible to third-generation cephalosporins, with an increasing trend from 0% in 1999 to 17% in 2013. Patient characteristics did not differ significantly between BSIs caused by third generation susceptible and resistant E. coli and K. pneumonia, but the case fatality tended to be higher. Most (88%) of the isolates reported as non susceptible to third-generation cephalosporins had ESBL phenotype, CTX-M (79%) being the most common enzyme. CONCLUSION: A sharp increase in nosocomial BSIs caused by ESBL producing bacteria was observed. Identification of patients for screening pose a challenge, emphasising the role of infection control guidelines and antibiotic policy in prevention. PMID- 26577520 TI - Aging as a Precipitating Factor in Chronic Restraint Stress-Induced Tau Aggregation Pathology, and the Protective Effects of Rosmarinic Acid. AB - Stress is an important risk factor of Alzheimer's disease (AD). It has been evidenced that stress could induce tau phosphorylation and increase tau insolubility in brain; however, little is known about the interactional effect of stress with aging on tauopathy. Therefore, we explored the effects of aging on stress-induced tauopathy and the potential mechanism in mouse model of chronic restraint stress (CRS). Here we found that in general, the level of phosphorylated tau (P-tau) was higher in brain of middle-aged mice than that in adult mice under physiological conditions. CRS-induced tau phosphorylation and its insolubility were more prominent in middle-aged mice. The increase of AT8 labeled insoluble P-tau was dramatic in middle-aged mice, which was highly ubiquitinated but did not form PHF structures. The levels of chaperones were relatively lower in middle-aged mice brain; CRS further reduced the expression, especially for HDJ2/HSP40. CRS also suppressed the expression of Pin1, the peptidylprolyl cis/trans isomerase, in middle-aged mice but not in adult mice. Downregulation of HSP40 or Pin1 caused an increase of transfected extraneous tau in 293 cells. Rosmarinic acid (RA) could effectively suppress the elevation of P tau and insoluble P-tau formation induced by CRS, and reversed the abnormal changes of chaperones and Pin1 particularly in middle-aged mice. Taken together, our findings provided evidence that aging could be a promoting factor in stress induced tauopathy, which was relevant with malregulation of chaperones and Pin1, and RA might be a promising beneficial agent for stress-induced tauopathy. PMID- 26577521 TI - Integrating Biomarkers for Underlying Alzheimer's Disease in Mild Cognitive Impairment in Daily Practice: Comparison of a Clinical Decision Support System with Individual Biomarkers. AB - BACKGROUND: Recent criteria allow biomarkers to provide evidence of Alzheimer's disease (AD) pathophysiology. How they should be implemented in daily practice remains unclear, especially in mild cognitive impairment (MCI) patients. OBJECTIVE: We evaluated how a clinical decision support system such as the PredictAD tool can aid clinicians to integrate biomarker evidence to support AD diagnosis. METHODS: With available data on demographics, cerebrospinal fluid (CSF), and MRI, we trained the PredictAD tool on a reference population of 246 controls and 491 AD patients. We then applied the identified algorithm to 211 MCI patients. For comparison, we also classified patients based on individual biomarkers (MRI; CSF) and the NIA-AA criteria. Progression to dementia was used as outcome measure. RESULTS: After a median follow up of 3 years, 72 (34%) MCI patients remained stable and 139 (66%) progressed to AD. The PredictAD tool assigned a likelihood of underlying AD to each patient (AUC 0.82). Excluding patients with missing data resulted in an AUC of 0.87. According to the NIA-AA criteria, half of the MCI patients had uninformative biomarkers, precluding an assignment of AD likelihood. A minority (41%) was assigned to high or low AD likelihood with good predictive value. The individual biomarkers showed best value for CSF total tau (AUC 0.86). CONCLUSION: The ability of the PredictAD tool to identify AD pathophysiology was comparable to individual biomarkers. The PredictAD tool has the advantage that it assigns likelihood to all patients, regardless of missing or conflicting data, allowing clinicians to integrate biomarker data in daily practice. PMID- 26577522 TI - Activities of Daily Living and Depressive Symptoms in Patients with Subjective Cognitive Decline, Mild Cognitive Impairment, and Alzheimer's Disease. AB - BACKGROUND: Subjective cognitive decline (SCD) may be an early indicator for an increased risk of dementia. The exact definition of SCD remains unclear and has recently become a major research interest. OBJECTIVES: To determine impairments in activities of daily living (ADL) and depressive symptoms in elderly individuals with SCD, mild cognitive impairment (MCI), and Alzheimer's disease (AD). METHODS: We included 752 consecutive patients suffering from SCD, non amnestic (naMCI) or amnestic MCI (aMCI), AD, and 343 healthy controls into this prospective cohort study. A neuropsychological test battery, B-ADL and BDI-II was performed. RESULTS: SCD patients showed a decreased performance in ADL compared to controls. Performance in ADL declined concurrently with cognitive abilities along the controls-SCD-naMCI-aMCI-AD continuum. Individuals with cognitive complains, no matter if SCD, MCI, or AD patients, reported more often depressive symptoms compared to healthy controls without complaints. Within all five cognitive subgroups, patients with depressive symptoms reported more difficulties in ADL in comparison to patients without depressive symptoms. Adjusting for depressive symptoms, there was no significant group difference between the control versus the SCD group (OR 1.1, CI 0.6-1.7). CONCLUSIONS: SCD is a heterogeneous clinical condition. Specific features such as slightly impaired ADL and depressive symptoms are associated with SCD. Clinical markers may serve as an indicator for preclinical AD and in combination with biomarkers guide to an early diagnosis of a progressive neurodegenerative disease. PMID- 26577523 TI - Optimization of Statistical Single Subject Analysis of Brain FDG PET for the Prognosis of Mild Cognitive Impairment-to-Alzheimer's Disease Conversion. AB - BACKGROUND: Positron emission tomography (PET) with the glucose analog F-18 fluorodeoxyglucose (FDG) is widely used in the diagnosis of neurodegenerative diseases. Guidelines recommend voxel-based statistical testing to support visual evaluation of the PET images. However, the performance of voxel-based testing strongly depends on each single preprocessing step involved. OBJECTIVE: To optimize the processing pipeline of voxel-based testing for the prognosis of dementia in subjects with amnestic mild cognitive impairment (MCI). METHODS: The study included 108 ADNI MCI subjects grouped as 'stable MCI' (n = 77) or 'MCI-to AD converter' according to their diagnostic trajectory over 3 years. Thirty-two ADNI normals served as controls. Voxel-based testing was performed with the statistical parametric mapping software (SPM8) starting with default settings. The following modifications were added step-by-step: (i) motion correction, (ii) custom-made FDG template, (iii) different reference regions for intensity scaling, and (iv) smoothing was varied between 8 and 18 mm. The t-sum score for hypometabolism within a predefined AD mask was compared between the different settings using receiver operating characteristic (ROC) analysis with respect to differentiation between 'stable MCI' and 'MCI-to-AD converter'. The area (AUC) under the ROC curve was used as performance measure. RESULTS: The default setting provided an AUC of 0.728. The modifications of the processing pipeline improved the AUC up to 0.832 (p = 0.046). Improvement of the AUC was confirmed in an independent validation sample of 241 ADNI MCI subjects (p = 0.048). CONCLUSION: The prognostic value of voxel-based single subject analysis of brain FDG PET in MCI subjects can be improved considerably by optimizing the processing pipeline. PMID- 26577524 TI - Erratum to: Bleeding Risk, Management and Outcome in Patients Receiving Non-VKA Oral Anticoagulants (NOACs). PMID- 26577525 TI - Immediate Bedding and Patient Satisfaction in a Pediatric Emergency Department. AB - BACKGROUND: Immediate bedding has been shown to increase efficiency in general emergency departments (EDs), but little has been published regarding its use in pediatric emergency medicine. OBJECTIVE: Our aims were to improve door-to provider (DTP) times and patient satisfaction and to better define the relationships between throughput times and patient satisfaction in a pediatric ED. METHODS: On November 1, 2011, we changed to a new immediate bedding triage process in our academic, urban pediatric Level I trauma center. Both outcome and balancing measures were compared for the 6 months before and after this change in process. To evaluate the relationship between throughput times and patient satisfaction, we also analyzed data collected during a 32-month period. RESULTS: The median DTP decreased from 44 min in the pre period to 25 min in the post period (Cohen's r value = 0.29; p < 0.001). The percent DTP < 30 min also significantly improved (pre: 31.8%, post: 58.2%, odds ratio = 2.99; 95% confidence interval 2.87-3.12; p < 0.001). For the benchmark satisfaction question of "likelihood to recommend," there was also an improvement in the mean responses (pre: 89.0, post: 92.7, Cohen's r value = 0.10; p = 0.03). There were no significant differences in the balancing measures of nurse practitioner productivity and compliance with two nurse-initiated protocols. There was a weak inverse correlation between throughput times and satisfaction scores (Spearman's rank correlation -0.18; p < 0.001). CONCLUSIONS: Although immediate bedding improved the front-end efficiency in our ED, it cannot yet be considered as a "best practice" in pediatric emergency medicine. PMID- 26577526 TI - The nuclear fraction of protein kinase CK2 binds to the upstream stimulatory factors (USFs) in the absence of DNA. AB - The functions of the upstream stimulatory factors USF1 and USF2 are, like those of other transcription factors, regulated by reversible phosphorylation. Besides many other kinases also protein kinase CK2 phosphorylates USF1 but not USF2. In a yeast-two-hybrid screen, however, the non-catalytic CK2beta subunit of CK2 was identified as a binding partner of USF2. This surprising observation prompted us to investigate the CK2/USF interaction in more detail in the present study. By using immunofluorescence analyses as well as co-immunoprecipitations we found that USF1 and USF2 bound to CK2alpha and CK2beta exclusively in the nucleus, though CK2beta and to a minor amount CK2alpha were also present in the cytoplasm. Furthermore, we found that unlike other substrates the phosphorylation of USF1 required the presence of the regulatory CK2beta subunit; the catalytic alpha subunit of CK2 alone was not able to phosphorylate USF1. Thus, the correct phosphorylation of USF1 is only guaranteed and strictly controlled in particular by nuclear CK2beta. Although the data indicated that a nuclear subfraction of CK2 subunits associated with USF proteins, DNA pull down experiments revealed that the CK2 subunits did not co-localize with DNA bound USF proteins indicating that the USF/CK2 interaction has a pre- or post DNA binding function. PMID- 26577527 TI - Impaired ALDH2 activity decreases the mitochondrial respiration in H9C2 cardiomyocytes. AB - Reactive oxygen species (ROS)-mediated reactive aldehydes induce cellular stress. In cardiovascular diseases such as ischemia-reperfusion injury, lipid peroxidation derived reactive aldehydes such as 4-hydroxy-2-nonenal (4HNE) are known to contribute to the pathogenesis. 4HNE is involved in ROS formation, abnormal calcium handling and more importantly defective mitochondrial respiration. Aldehyde dehydrogenase (ALDH) superfamily contains NAD(P)(+) dependent isozymes which can detoxify endogenous and exogenous aldehydes into non toxic carboxylic acids. Therefore we hypothesize that 4HNE afflicts mitochondrial respiration and leads to cell death by impairing ALDH2 activity in cultured H9C2 cardiomyocyte cell lines. H9C2 cardiomyocytes were treated with 25, 50 and 75 MUM 4HNE and its vehicle, ethanol as well as 25, 50 and 75 MUM disulfiram (DSF), an inhibitor of ALDH2 and its vehicle (DMSO) for 4 h. 4HNE significantly decreased ALDH2 activity, ALDH2 protein levels, mitochondrial respiration and mitochondrial respiratory reserve capacity, and increased 4HNE adduct formation and cell death in cultured H9C2 cardiomyocytes. ALDH2 inhibition by DSF and ALDH2 siRNA attenuated ALDH2 activity besides reducing ALDH2 levels, mitochondrial respiration and mitochondrial respiratory reserve capacity and increased cell death. Our results indicate that ALDH2 impairment can lead to poor mitochondrial respiration and increased cell death in cultured H9C2 cardiomyocytes. PMID- 26577529 TI - The Lactobacillus plantarum Eno A1 Enolase Is Involved in Immunostimulation of Caco-2 Cells and in Biofilm Development. AB - The role of probiotics in prevention and treatment of a variety of diseases is now well assessed. The presence of adhesive molecules on the cell surface of probiotics has been related to the ability to confer health benefit to the host. We have previously shown that the enolase EnoA1 of Lactobacillus plantarum, one of the most predominant species in the gut microbiota of healthy individuals, is cell surface-expressed and is involved in binding with human fibronectin and plasminogen. By means of comparative analysis between L. plantarum LM3 (wild type) and its isogenic LM3-CC1 (DeltaenoA1) mutant strain, here we show that EnoA1 affects the ability of this bacterium to modulate immune response as determined by analysis of expression of immune system molecules in Caco-2 cells. Indeed, we observed induction of TLR2 expression in cells exposed to L. plantarum LM3, while no induction was detectable in cells exposed to LM3-CC1. This difference was much less consistent when expression of TLR4 was determined in cells exposed to the two strains. Pro-inflammatory (IL-6) and anti-inflammatory cytokines (IL-10, TGF-beta), and the antimicrobial peptide HBD-2 were induced in Caco-2 cells exposed to L. plantarum LM3, while lower levels of induction were detected in cells exposed to LM3-CC1. We also analyzed the ability to develop biofilm of the two strains, and observed a decrease of about 65 % in the development of mature biofilm in LM3-CC1 compared to the wild type. PMID- 26577528 TI - PDL1 Regulation by p53 via miR-34. AB - BACKGROUND: Although clinical studies have shown promise for targeting PD1/PDL1 signaling in non-small cell lung cancer (NSCLC), the regulation of PDL1 expression is poorly understood. Here, we show that PDL1 is regulated by p53 via miR-34. METHODS: p53 wild-type and p53-deficient cell lines (p53(-/-) and p53(+/+) HCT116, p53-inducible H1299, and p53-knockdown H460) were used to determine if p53 regulates PDL1 via miR-34. PDL1 and miR-34a expression were analyzed in samples from patients with NSCLC and mutated p53 vs wild-type p53 tumors from The Cancer Genome Atlas for Lung Adenocarcinoma (TCGA LUAD). We confirmed that PDL1 is a direct target of miR-34 with western blotting and luciferase assays and used a p53(R172HDelta)g/+K-ras(LA1/+) syngeneic mouse model (n = 12) to deliver miR-34a-loaded liposomes (MRX34) plus radiotherapy (XRT) and assessed PDL1 expression and tumor-infiltrating lymphocytes (TILs). A two-sided t test was applied to compare the mean between different treatments. RESULTS: We found that p53 regulates PDL1 via miR-34, which directly binds to the PDL1 3' untranslated region in models of NSCLC (fold-change luciferase activity to control group, mean for miR-34a = 0.50, SD = 0.2, P < .001; mean for miR-34b = 0.52, SD = 0.2, P = .006; and mean for miR-34c = 0.59, SD = 0.14, and P = .006). Therapeutic delivery of MRX34, currently the subject of a phase I clinical trial, promoted TILs (mean of CD8 expression percentage of control group = 22.5%, SD = 1.9%; mean of CD8 expression percentage of MRX34 = 30.1%, SD = 3.7%, P = .016, n = 4) and reduced CD8(+)PD1(+) cells in vivo (mean of CD8/PD1 expression percentage of control group = 40.2%, SD = 6.2%; mean of CD8/PD1 expression percentage of MRX34 = 20.3%, SD = 5.1%, P = .001, n = 4). Further, MRX34 plus XRT increased CD8(+) cell numbers more than either therapy alone (mean of CD8 expression percentage of MRX34 plus XRT to control group = 44.2%, SD = 8.7%, P = .004, n = 4). Finally, miR-34a delivery reduced the numbers of radiation-induced macrophages (mean of F4-80 expression percentage of control group = 52.4%, SD = 1.7%; mean of F4-80 expression percentage of MRX34 = 40.1%, SD = 3.5%, P = .008, n = 4) and T-regulatory cells. CONCLUSIONS: We identified a novel mechanism by which tumor immune evasion is regulated by p53/miR-34/PDL1 axis. Our results suggest that delivery of miRNAs with standard therapies, such as XRT, may represent a novel therapeutic approach for lung cancer. PMID- 26577530 TI - Partial Protection Induced by 2011-2012 Influenza Vaccine Against Serologically Evidenced A(H3N2) Influenza Virus Infections in Elderly Institutionalized People. AB - Ninety-two institutionalized elderly subjects were vaccinated with trivalent influenza inactivated vaccine available for the 2011-2012 season, characterized by a prevalent circulation of A(H3N2) influenza viruses (A/Victoria/208-clade) presenting antigenic and genetic patterns different from the A(H3N2) vaccine component (A/Perth/16/2009-clade). Haemagglutination inhibiting (HI) antibody titers were determined in sera collected before, 1 and 6 months after vaccination and patients were considered positive for serological evidence of recent infection if they had a seroconversion on comparing HI titers found in sera collected 1 and 6 months after vaccination. No seroconversions were found against A(H1N1) and B vaccine components. Instead 17 volunteers seroconverted against all or at least some of the different A(H3N2) antigens examined, i.e. the 2011-2012 (A/Perth/16/2009) and the 2012-2013 (A/Victoria/361/2011) vaccine strains and four drifted viruses belonging to the A/Victoria/208-clade circulating in the area were the elderly people were living. The results obtained suggest that influenza infections in the vaccinated volunteers might be due both to a poor match between vaccine and circulating A(H3N2) viruses, since 1 month after vaccination 15 of the 17 volunteers had post-vaccination HI titers considered protective (>=40) against the A(H3N2) vaccine antigen, but not always against the epidemic strains, and to a waning of vaccine induced immune response, since 6 months after vaccination HI titers of non-infected volunteers were found to be decreased as compared with those found 1 month after vaccination. PMID- 26577531 TI - Identification of Small Molecule Inhibitors of Human As(III) S-Adenosylmethionine Methyltransferase (AS3MT). AB - Arsenic is the most ubiquitous environmental toxin and carcinogen. Long-term exposure to arsenic is associated with human diseases including cancer, cardiovascular disease, and diabetes. Human As(III) S-adenosylmethionine (SAM) methyltransferases (hAS3MT) methylates As(III) to trivalent mono- and dimethyl species that are more toxic and potentially more carcinogenic than inorganic arsenic. Modulators of hAS3MT activity may be useful for the prevention or treatment of arsenic-related diseases. Using a newly developed high-throughput assay for hAS3MT activity, we identified 10 novel noncompetitive small molecule inhibitors. In silico docking analysis with the crystal structure of an AS3MT orthologue suggests that the inhibitors bind in a cleft between domains that is distant from either the As(III) or SAM binding sites. This suggests the presence of a possible allosteric and regulatory site in the enzyme. These inhibitors may be useful tools for future research in arsenic metabolism and are the starting point for the development of drugs against hAS3MT. PMID- 26577532 TI - U.S. Immunization program adult immunization activities and resources. AB - Adults are recommended to receive vaccines based on their age, medical conditions, prior vaccinations, occupation and lifestyle. However, adult immunization coverage is low in the United States and lags substantially below Healthy People 2020 goals. To assess activities and resources designated for adult immunization programs by state and local health department immunization programs in the United States, we analyzed 2012 and 2013 data from the Centers for Disease Control and Prevention's (CDC) Program Annual Reports and Progress Assessments (PAPA) survey of CDC-funded immunization programs. Fifty-six of 64 funded US immunization programs' responses were included in the analysis. Eighty two percent of (n = 46) programs reported having a designated adult immunization coordinator in 2012 and 73% (n = 41) in 2013. Of the 46 coordinators reported in 2012, 30% (n = 14) spent more than 50% of their time on adult immunization activities, and only 24% (n = 10) of the 41 adult coordinators in 2013 spent more than 50% of their time on adult immunization activities. In 2012, 23% (n = 13) of the 56 programs had a separate immunization coalition for adults and 68% (n = 38) included adult issues in their overall immunization program coalition. In 2013, 25% (n = 14) had a separate adult immunization coalition while 57% (n = 32) incorporated adult immunizations into their overall immunization program coalition. The results indicate substantial variation across the US in public health infrastructure to support adult immunizations. Continued assessment of adult immunization resources and activities will be important in improving adult immunization coverage levels though program support. With many programs having limited resources dedicated to improving adult immunization rates in the in US, efforts by the health departments to collaborate with providers and other partners in their jurisdictions to increase awareness, increase the use of proven strategies to improve vaccination of adults, and implement the Standards for Adult Immunization Practice may lead to improved adult immunization coverage and fewer illnesses, hospitalizations and deaths from vaccine preventable diseases. PMID- 26577533 TI - Spatially uniform enhancement of single quantum dot emission using plasmonic grating decoupler. AB - We demonstrate a spatially uniform enhancement of individual quantum dot (QD) fluorescence emission using plasmonic grating decouplers on thin gold or silver films. Individual QDs are deposited within the grating in a controlled way to investigate the position dependency on both the radiation pattern and emission enhancement. We also describe the optimization of the grating decoupler. We achieve a fluorescence enhancement ~3 times higher than using flat plasmon film, for any QD position in the grating. PMID- 26577534 TI - The development of a bilayer structure of poly(propylene carbonate)/poly(3 hydroxybutyrate) blends from the demixed melt. AB - The miscibility of poly(propylene carbonate) (PPC) and poly(3-hydroxybutyrate) (PHB) blends was analyzed by differential scanning calorimetry (DSC) and polarized optical microscopy (POM). The results indicated that the blends are immiscible at most blending compositions, and a miscible blend can be obtained when the PHB content is as low as 10 wt%. The morphology of the PPC/PHB (70/30) blend film was characterized by POM, scanning electron micrography (SEM) and Fourier transform infrared spectroscopy (FTIR), and the development of a PPC-top and microporous PHB-bottom bilayer structure can be revealed. Different from the normal case, phase separation can take place on the normal direction of the film surface in the PPC/PHB (70/30) blend at 190 degrees C, attributed to the different surface energies of the two components. The continuous segregation of PPC to the top-layer can result in the crystallization of PHB at the bottom layer and conversely promote the complete development of a bilayer structure. Since the isotropic PPC layer is transparent with no birefringence, the PHB spherulite with a microporous structure at the bottom layer can be observed directly by POM. Moreover, the microporous structure of the bottom layer should be attributed to the solution cast procedure. Thus, some unique crystalline patterns may be created in the demixed crystalline/amorphous polymer blends, which differ greatly from those obtained from the miscible blend systems. PMID- 26577536 TI - Impact of doping on the carrier dynamics in graphene. AB - We present a microscopic study on the impact of doping on the carrier dynamics in graphene, in particular focusing on its influence on the technologically relevant carrier multiplication in realistic, doped graphene samples. Treating the time- and momentum-resolved carrier-light, carrier-carrier, and carrier-phonon interactions on the same microscopic footing, the appearance of Auger-induced carrier multiplication up to a Fermi level of 300 meV is revealed. Furthermore, we show that doping favors the so-called hot carrier multiplication occurring within one band. Our results are directly compared to recent time-resolved ARPES measurements and exhibit an excellent agreement on the temporal evolution of the hot carrier multiplication for n- and p-doped graphene. The gained insights shed light on the ultrafast carrier dynamics in realistic, doped graphene samples. PMID- 26577535 TI - Age-Specific Regulation of Drug-Processing Genes in Mouse Liver by Ligands of Xenobiotic-Sensing Transcription Factors. AB - The xenobiotic-sensing transcription factors (xeno-sensors) AhR, CAR, and PXR upregulate the expression of many drug-processing genes (DPGs) in liver. Previous studies have unveiled profound changes in the basal expression of DPGs during development; however, knowledge on the ontogeny of the inducibility of DPGs in response to pharmacological activation of xeno-sensors is still limited. The goal of this study was to investigate the age-specific regulation of DPGs by prototypical xeno-sensor ligands: 2,3,7,8-tetrachlorodibenzodioxin (TCDD) for AhR; 1,4-bis [2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) for CAR; and pregnane 16alpha-carbonitrile (PCN) for PXR during mouse liver development. The basal mRNAs of most DPGs were low during neonatal age, but gradually increased to adult levels, whereas some DPGs (Cyp1a2, Cyp2b10, Cyp3a11, Gstm2, Gstm3, Papss2, and Oatp1a4) exhibited an adolescent-predominant expression pattern. The inducibility of DPGs was age-specific: 1) during neonatal age, the highest fold increase in the mRNA expression was observed for Cyp1a2, Sult5a1, and Ugt1a9 by TCDD; Cyp3a11 and Mrp2 by TCPOBOP; as well as Gstm2 and Gstm3 by PCN; 2) during adolescent age, the highest fold increase in the mRNA expression was observed for Ugt1a6 and Mrp4 by TCDD, Cyp2b10, Ugt2b34, and Ugt2b35 by TCPOBOP, as well as Gsta1, Gsta4, Sult1e1, Ugt1a1, Mrp3, and Mrp4 by PCN; 3) in adults, the highest fold increase in the mRNA expression was observed for Aldh1a1, Aldh1a7, and Ugt2b36 by TCPOBOP, as well as Papss2 and Oatp1a4 by PCN. In conclusion, the inducibility of hepatic DPGs following the pharmacological activation of xeno-sensors is age specific. PMID- 26577537 TI - Exploiting HPV-Induced Carcinogenesis for a Rational Drug Development in Cervical Cancer. AB - Cervical carcinomas are almost universally associated with high-risk human papillomavirus (HPV) infections, and are a leading cause of cancer death in women worldwide. Since the late 1990s, when a spate of studies reported the benefit of cisplatin-based chemotherapy, there had been a dearth of clinical trials in cervical cancer (CC). More effective therapies in locally advanced and recurrent or metastatic CC are an urgent clinical need. In the era of molecular oncology one should look beyond conventional chemoradiation and chemotherapy for locally advanced and advanced CC. The fact that the initiating oncogenic insult, infection with a high-risk HPV and viral oncoprotein expression is common to almost all CC offers unique opportunities for disease control. Diverse biologic pathways with an implication in the development and progression of CC are being explored. For the first time, increase in overall survival has recently been obtained for advanced CC patients with a target drug, the antiangiogenic agent bevacizumab, and durable complete responses after HPV-targeted adoptive T cell therapy in metastatic CC patients were achieved. In this review, we will summarize molecular aspects of HPV infection focusing on potential targets to stop the carcinogenic process, present updated drug development data, and discuss challenges and prospects for the future. PMID- 26577538 TI - MicroRNA as Regulators of Cancer Stem Cells and Chemoresistance in Colorectal Cancer. AB - Colorectal cancer (CRC) is one of the most common cancers worldwide. The development of resistance to anti-cancer treatment is one of the major challenges in the treatment of CRC, which limits the efficacy of both conventional and targeted therapies in clinical settings. Understanding the mechanisms underpinning resistances is therefore critical in developing novel agents to reverse drug resistance and for more specific targeted treatments. Accumulating studies have reported that microRNAs (miRNAs) are key players in the regulation of cancer cells with intrinsic/acquired drug resistance through varied mechanisms that endow cells with a drug-resistant phenotype. miRNAs have been evolved in the regulation of chemoresistance to various CRC treatments and the stemness of CRC stem cells (CRSCs), sequentially modulating the sensitivity of CRC cells to anti cancer treatments. Targeting miRNAs may be a novel strategy for eradicating CRSCs, re-sensitizing drug-resistant cells to anti-cancer agents, improving drug efficiency and developing novel biological agents for CRC treatment. This paper highlights the role of miRNAs in the regulation of chemoresistance and CRSCs in CRC, with focus on the mechanisms underlying how miRNAs alter CRSCs fate, and the process of epithelial-to-mesenchymal transition, cell cycle and apoptosis in CRC cells. PMID- 26577539 TI - Can the neural-cortisol association be moderated by experience-induced changes in awareness? AB - Cortisol homeostasis is important for cognitive and affective functions that depend on cortisol-sensitive brain regions including the hippocampus and prefrontal cortex. Recent studies have shown that training induces changes in the brain. We report the findings of a longitudinal study that verified the moderation effect of experience-induced changes in awareness on the neural cortisol association in cortisol-sensitive brain regions. These findings provide the first piece of evidence that planned behavioral experience can moderate the neural-cortisol association. A range of changes in awareness was achieved in a sample of 21 Chinese participants, divided into two groups: Awareness-based compassion meditation (ABCM) (n = 10) and relaxation (n = 11). We observed that changes in awareness were significant moderators of hippocampal-cortisol changes. Furthermore, a significant negative association between changes in plasma cortisol level and the resting-state synchrony of the right hippocampal and insular-frontal-operculum regions was observed. These novel findings shed light on the inter-relationships between changes in hippocampal-cortisol levels and changes in awareness and preliminarily identify the neural underpinnings of interventions for cortisol-related abnormal functioning for further study. PMID- 26577540 TI - Impact of antibacterials on subsequent resistance and clinical outcomes in adult patients with viral pneumonia: an opportunity for stewardship. AB - INTRODUCTION: Respiratory viruses are increasingly recognized as significant etiologies of pneumonia among hospitalized patients. Advanced technologies using multiplex molecular assays and polymerase-chain reaction increase the ability to identify viral pathogens and may ultimately impact antibacterial use. METHOD: This was a single-center retrospective cohort study to evaluate the impact of antibacterials in viral pneumonia on clinical outcomes and subsequent multidrug resistant organism (MDRO) infections/colonization. Patients admitted from March 2013 to November 2014 with positive respiratory viral panels (RVP) and radiographic findings of pneumonia were included. Patients transferred from an outside hospital or not still hospitalized 72 hours after the RVP report date were excluded. Patients were categorized based on exposure to systemic antibacterials: less than 3 days representing short-course therapy and 3 to 10 days being long-course therapy. RESULTS: A total of 174 patients (long-course, n = 67; short-course, n = 28; mixed bacterial-viral infection, n = 79) were included with most being immunocompromised (56.3 %) with active malignancy the primary etiology (69.4 %). Rhinovirus/Enterovirus (23 %), Influenza (19 %), and Parainfluenza (15.5 %) were the viruses most commonly identified. A total of 13 different systemic antibacterials were used as empiric therapy in the 95 patients with pure viral infection for a total of 466 days-of-therapy. Vancomycin (50.7 %), cefepime (40.3 %), azithromycin (40.3 %), meropenem (23.9 %), and linezolid (20.9 %) were most frequently used. In-hospital mortality did not differ between patients with viral pneumonia in the short-course and long-course groups. Subsequent infection/colonization with a MDRO was more frequent in the long course group compared to the short-course group (53.2 vs 21.1 %; P = 0.027). CONCLUSION: This study found that long-course antibacterial use in the setting of viral pneumonia had no impact on clinical outcomes but increased the incidence of subsequent MDRO infection/colonization. PMID- 26577541 TI - Analysis of supratentorial cystic abnormalities using in utero MR imaging. AB - OBJECTIVE: Our anecdotal experience from foetal neuroimaging studies suggests that there are often significant disagreements between the findings of ultrasonography (USS) and in utero MR (iuMR) imaging in cases of antenatally detected supratentorial extra-axial cysts. Although this is a relatively rare clinical situation, it warrants further investigation because of the high risk of other intracranial abnormalities that are likely to cause long-term neurodevelopmental problems. METHODS: We reviewed 957 consecutive referrals for iuMR of the foetal brain over a 3.5-year period and studied all cases where the referral from USS described supratentorial extra-axial cysts in the foetus. The iuMR imaging was reviewed, and a comparison between the results of the two examinations was made. RESULTS: Supratentorial extra-axial cysts were an unusual referral for iuMR occurring in only 13/957 (1.4%) of cases. The findings on USS and iuMR imaging were conflicting in all 13 cases with intracranial pathology being excluded on iuMR imaging in 4 cases and more significant pathology being shown in 9 cases. Abnormalities of the corpus callosum were recognized in association with a cyst in eight cases, and this was recognized in only two cases on USS. Six of those cases also had abnormalities of cortical formation. CONCLUSION: iuMR imaging should be used in the assessment of pregnancies in which a supratentorial extra-axial cyst has been detected on USS. This is based on the improved primary diagnosis and a high rate of associated brain abnormalities not detected on USS. ADVANCES IN KNOWLEDGE: Our retrospective observational study examines a range of foetal intracranial abnormalities which are better defined using iuMRI. This is a previously described spectrum of neurodevelopmental anomalies which we suggest would benefit from MRI. PMID- 26577542 TI - Determination of optimal imaging settings for urolithiasis CT using filtered back projection (FBP), statistical iterative reconstruction (IR) and knowledge-based iterative model reconstruction (IMR): a physical human phantom study. AB - OBJECTIVE: The purpose of this study was to compare CT image quality for evaluating urolithiasis using filtered back projection (FBP), statistical iterative reconstruction (IR) and knowledge-based iterative model reconstruction (IMR) according to various scan parameters and radiation doses. METHODS: A 5 * 5 * 5 mm(3) uric acid stone was placed in a physical human phantom at the level of the pelvis. 3 tube voltages (120, 100 and 80 kV) and 4 current-time products (100, 70, 30 and 15 mAs) were implemented in 12 scans. Each scan was reconstructed with FBP, statistical IR (Levels 5-7) and knowledge-based IMR (soft tissue Levels 1-3). The radiation dose, objective image quality and signal-to noise ratio (SNR) were evaluated, and subjective assessments were performed. RESULTS: The effective doses ranged from 0.095 to 2.621 mSv. Knowledge-based IMR showed better objective image noise and SNR than did FBP and statistical IR. The subjective image noise of FBP was worse than that of statistical IR and knowledge based IMR. The subjective assessment scores deteriorated after a break point of 100 kV and 30 mAs. CONCLUSION: At the setting of 100 kV and 30 mAs, the radiation dose can be decreased by approximately 84% while keeping the subjective image assessment. ADVANCES IN KNOWLEDGE: Patients with urolithiasis can be evaluated with ultralow-dose non-enhanced CT using a knowledge-based IMR algorithm at a substantially reduced radiation dose with the imaging quality preserved, thereby minimizing the risks of radiation exposure while providing clinically relevant diagnostic benefits for patients. PMID- 26577543 TI - Effects of environmental fluctuations on fish metabolism: Atlantic salmon Salmo salar as a case study. AB - Using Atlantic salmon Salmo salar parr as study species, recent findings are summarized on how (1) diurnal variations in water temperature affects standard metabolic rate, (2) shelter may reduce routine metabolic rate and (3) fluctuations of water speed affect the costs of activity. The results suggest that the accuracy of bioenergetics models can be hampered if the effects of environmental fluctuations are omitted. Incorporating environmental fluctuations into estimates and models of fish metabolism will not only improve the accuracy of energy budget calculations, but also have crucial management implications for conservation and improve the capacity to predict effects of climate change. PMID- 26577544 TI - Proliferation of East Antarctic Adelie penguins in response to historical deglaciation. AB - BACKGROUND: Major, long-term environmental changes are projected in the Southern Ocean and these are likely to have impacts for marine predators such as the Adelie penguin (Pygoscelis adeliae). Decadal monitoring studies have provided insight into the short-term environmental sensitivities of Adelie penguin populations, particularly to sea ice changes. However, given the long-term nature of projected climate change, it is also prudent to consider the responses of populations to environmental change over longer time scales. We investigated the population trajectory of Adelie penguins during the last glacial-interglacial transition to determine how the species was affected by climate warming over millennia. We focussed our study on East Antarctica, which is home to 30 % of the global population of Adelie penguins. METHODS: Using mitochondrial DNA from extant colonies, we reconstructed the population trend of Adelie penguins in East Antarctica over the past 22,000 years using an extended Bayesian skyline plot method. To determine the relationship of East Antarctic Adelie penguins with populations elsewhere in Antarctica we constructed a phylogeny using mitochondrial DNA sequences. RESULTS: We found that the Adelie penguin population expanded 135-fold from approximately 14,000 years ago. The population growth was coincident with deglaciation in East Antarctica and, therefore, an increase in ice-free ground suitable for Adelie penguin nesting. Our phylogenetic analysis indicated that East Antarctic Adelie penguins share a common ancestor with Adelie penguins from the Antarctic Peninsula and Scotia Arc, with an estimated age of 29,000 years ago, in the midst of the last glacial period. This finding suggests that extant colonies in East Antarctica, the Scotia Arc and the Antarctic Peninsula were founded from a single glacial refuge. CONCLUSIONS: While changes in sea ice conditions are a critical driver of Adelie penguin population success over decadal and yearly timescales, deglaciation appears to have been the key driver of population change over millennia. This suggests that environmental drivers of population trends over thousands of years may differ to drivers over years or decades, highlighting the need to consider millennial-scale trends alongside contemporary data for the forecasting of species' abundance and distribution changes under future climate change scenarios. PMID- 26577545 TI - Do alternative methods for analysing count data produce similar estimates? Implications for meta-analyses. AB - BACKGROUND: Many randomised trials have count outcomes, such as the number of falls or the number of asthma exacerbations. These outcomes have been treated as counts, continuous outcomes or dichotomised and analysed using a variety of analytical methods. This study examines whether different methods of analysis yield estimates of intervention effect that are similar enough to be reasonably pooled in a meta-analysis. METHODS: Data were simulated for 10,000 randomised trials under three different amounts of overdispersion, four different event rates and two effect sizes. Each simulated trial was analysed using nine different methods of analysis: rate ratio, Poisson regression, negative binomial regression, risk ratio from dichotomised data, survival to the first event, two methods of adjusting for multiple survival times, ratio of means and ratio of medians. Individual patient data was gathered from eight fall prevention trials, and similar analyses were undertaken. RESULTS: All methods produced similar effect sizes when there was no difference between treatments. Results were similar when there was a moderate difference with two exceptions when the event became more common: (1) risk ratios computed from dichotomised count outcomes and hazard ratios from survival analysis of the time to the first event yielded intervention effects that differed from rate ratios estimated from the negative binomial model (reference model) and (2) the precision of the estimates differed depending on the method used, which may affect both the pooled intervention effect and the observed heterogeneity. The results of the case study of individual data from eight trials evaluating exercise programmes to prevent falls in older people supported the simulation study findings. CONCLUSIONS: Information about the differences in treatments is lost when event rates increase and the outcome is dichotomised or time to the first event is analysed otherwise similar results are obtained. Further research is needed to examine the effect of differing variances from the different methods on the confidence intervals of pooled estimates. PMID- 26577546 TI - Transitions and more. PMID- 26577547 TI - Integrating mental health specialty services via telehealth. AB - Older adults may experience a variety of mental health conditions that negatively impact quality of life and management of co-occurring medical conditions. Collaborative care models are an option to provide access to specialty mental health care; however, these programs are not widely accessible. We propose that the delivery of specialty care via telehealth is a cost effective solution to obstacles to care. PMID- 26577548 TI - Character strengths and their influencing factors among nursing students in Changsha, China: the only-child versus non-only-child. AB - The purpose of this study was to explore the differences of character strengths and their predictors between only-child and non-only-child nursing students. Using data from 742 participants, linear regression was conducted. Results indicate that there was no significant differences between the two groups concerning anxiety, depression and general self-efficacy (P>0.05). The character strengths status of only-child was better than that of non-only-child (P<0.05) and the predictors of character strengths between the two groups had some differences. This study has suggestions on how to help nursing students to improve their character strengths. PMID- 26577549 TI - What level of self-care agency in mental illness? The factors affecting self-care agency and self-care agency in patients with mental illness. AB - The purpose of this study is to evaluate self-care agency and the factors affecting self-care agency in patients with psychiatric disorders. The population of the study comprised patients diagnosed with mental disorders at the clinics of psychiatry in Erzurum Regional Training and Research Hospital and Ataturk University Research Hospital. Patient information forms and the Self-Care Agency Scale were used to collect the study data. Psychiatric nurse collected the data from the patients face to face. This study determined that the average age of the patients was determined to be 32.19+/-1.11. The findings indicated that the mean self-care agency level of the patients was 79.3+/-23.2. It was also found that the differences between sex, educational status, socio-economic status, and self care agency levels were statistically significant (p<0.05). In conclusion, the patients' self-care agency levels were determined to be mid-level. The findings suggest that people with mental disorders have difficulty identifying their need for self-care. Thus, periodic training programs are necessary to increase self care levels and further research studies of this type should be done on larger groups. PMID- 26577550 TI - Assessing engagement in people with dementia: a new approach to assessment using video analysis. AB - The study of engagement in people with dementia is important to determine the effectiveness of interventions that aim to promote meaningful activity. However, the assessment of engagement for people with dementia in relation to our current work that uses social robots is fraught with challenges. The Video Coding - Incorporating Observed Emotion (VC-IOE) protocol that focuses on six dimensions of engagement: emotional, verbal, visual, behavioral, collective and signs of agitation was therefore developed. This paper provides an overview of the concept of engagement in dementia and outlines the development of the VC-IOE to assess engagement in people with dementia when interacting with social robots. PMID- 26577551 TI - Psychiatric patients' perspective: nursing uniforms. AB - This paper studied and determined the importance of the design and color of selected uniforms of psychiatric nurses and evaluate their effects and implications for patients. In this descriptive study, a questionnaire developed by the researchers and a nursing uniforms catalog were used during the data collection stage of the research. There were 40.9% of the participants who told that the design and color of a nursing uniform is important and 31.5% of the participants selected white uniform color from the catalog for psychiatric nurses and 33.9% of the patients expressed that they find white nursing uniforms comforting. PMID- 26577552 TI - Associative stigma related to psychiatric nursing within the nursing profession. AB - This study deals with stigmas towards mental illness, individuals with mental illness, psychiatric nurses, and the role of psychiatric nursing within the nursing profession. Responses from 108 psychiatric nurses and 108 non-psychiatric nurses indicated that stigmas towards mental illness, individuals with mental illness, and the role of psychiatric nursing, are more prevalent among non psychiatric nurses; associations between these stigmas were found among both psychiatric and non-psychiatric nurses. The findings suggest that both psychiatric and non-psychiatric nurses harbor associative stigma related to the practice of psychiatric nursing. Implications are discussed. PMID- 26577553 TI - Reducing or increasing violence in forensic care: a qualitative study of inpatient experiences. AB - Semi-structured interviews with 13 forensic psychiatric inpatients that had decreased their assessed risk of violence were analyzed using interpretive description. The main contribution from this study is a detailed description of patients' own strategies to avoid violence. Participants described having an ongoing inner dialog in which they encouraged themselves, thereby increasing their self-esteem and trying to accept their current situation. An unsafe and overcrowded ward with uninterested and nonchalant staff increased the risk of aggressive behavior. In the process of decreasing violence, the patients and the forensic psychiatric nursing staff interacted to create and maintain a safe environment. PMID- 26577554 TI - From judgment to understanding: mental health nurses' perceptions of changed professional behaviors following positively changed attitudes toward self-harm. AB - Nurses experience feelings of frustration, anger and fear when caring for patients who self-harm. Training programmes were developed that aimed to positively influence nurses' knowledge, attitudes and skills. The aim of this study was to investigate professional behavior of mental health nurses with positively changed attitudes after following a training program. Using grounded theory, semi-structured interviews were conducted with 11 mental health nurses. Participants reported using less restrictive interventions, being more patient oriented, and choosing a more empathic and exploratory approach after the training. A work environment conductive to making autonomous professional decisions with supportive colleagues enabled these changes. PMID- 26577555 TI - Public and personal depression stigma in a rural American female sample. AB - We examined public and personal stigma among a community sample of 1,000 women living in primarily rural counties of Western Kentucky. Data on demographics, depression, stigma, health information sources, and availability of health services were collected via a random digit dial survey. The prevalence of depression was 15.7%. The majority of respondents (82.2%) reported congruent levels of stigma with 11.6% reporting high public and high personal stigma. However, 17.8% of respondents reported incongruent public and personal stigma. The 7.5% of women with low public and high personal stigma were older and less educated, preferred anonymous sources of health information, and reported better availability of health services. The 10.3% of women with high public and low personal stigma were younger and more educated, preferred interpersonal sources of health information, and reported poorer availability of health services. In multivariate analyses, depression and lower education were associated with any incongruent stigma, while rural residence and White race/ethnicity was associated with high personal and public stigma. Psychiatric nurses should develop community based and targeted, point-of-care interventions to reduce public and personal stigma among rural women. PMID- 26577556 TI - Transforming psychiatric mental health nursing education with team based learning. AB - The aim of this study was to evaluate the effect of the team-based learning (TBL) instructional approach on learning outcomes in an undergraduate psychiatric mental health (PMH) nursing course. An uncontrolled, before and after design was employed. Data were collected over eight consecutive semesters (N=347) before and after implementation of TBL. Two variables were selected for comparison before and after implementation: scores on PMH portion of the Evolve(r) practice exit examination and time (in hours) students reported preparing for class. After implementation, students scored higher on the PMH practice exit examination and reported increased study time. Qualitatively, students reported enjoying working in teams despite the increased study time required with the TBL method. PMID- 26577557 TI - From recovery programs to recovery-oriented practice? A qualitative study of mental health professionals' experiences when facilitating a recovery-oriented rehabilitation program. AB - INTRODUCTION: The recovery model has influenced mental health services and fostered new standards for best practice. However, knowledge about how mental health care professionals (HCPs) experience recovery-oriented programs is sparse. AIM/QUESTION: This paper explores HCPs' experiences when facilitating a recovery oriented rehabilitation program. The research question is how do HCPs experience a change in their attitude and practice when applying recovery-oriented programs? METHODS: This paper draws on semi-structured in-depth qualitative interviews conducted with 16 HCPs experienced in facilitating a recovery-oriented rehabilitation program in either the USA or Denmark. RESULTS: Three themes emerged from the HCPs' reflections on changes in attitudes and practices: "Hopeful Attitude" captures a change in the HCPs' attitude toward a more positive view on the future for clients' living with mental illness; "A New Focus in the Dialogue With Clients" thematizes how the HCPs focus more on the individual's own goal for recovery rather than disease-induced goals in the dialog with clients; "A Person-Centered Role" comprises a shift in the professional role whereby the HCPs value the client's own ideas in addition to the professional's standards. CONCLUSION: This study supports the theory of the recovery model by its empirical findings and indications that when facilitating a recovery-oriented program, HCPs experience recovery-oriented changes in their attitude toward life with mental illness, and it alters their professional practice toward a stronger focus on client's own goals during treatment. More studies are needed to further clarify how changes in HCPs' attitudes translate into changes in mental health practices. PMID- 26577558 TI - Implementing a community bullying awareness intervention in an adolescent psychiatric unit: a feasibility study. AB - PROBLEM: Adolescents with a mental health diagnosis are at risk of involvement in bullying. We tested the feasibility of a bullying awareness group intervention in an established inpatient psychiatric unit milieu. METHODS: Adolescents admitted to an urban inpatient adolescent psychiatric unit were eligible to attend two sequential 1-hour Bullying Awareness intervention group sessions. Data were collected before the first session (T1), post-both sessions (T2), and following discharge from the unit (T3). FINDINGS: A total of 65 adolescents were enrolled; most were female (66.2%), African-American (60%), and in grades 10 to 12 (57%). Intervention feasibility was achieved as >80% of participants completed all components of the intervention and 100% completed all study questionnaires at T1 and T2. Feasibility of the follow-up (T3) was not achieved. Bullying knowledge scores improved significantly from T1 to T2. CONCLUSIONS: The intervention is feasible to implement in an inpatient adolescent psychiatry unit and can improve adolescents' bullying knowledge. PMID- 26577559 TI - Trajectories of parent-adolescent relationship quality among at-risk youth: parental depression and adolescent developmental outcomes. AB - BACKGROUND: Although the parent-adolescent relationship has been studied intensely, predictors and consequences of changes in the quality of the relationship across time have not been examined. OBJECTIVES: This study examined the role of parent depression on changes in the parent-adolescent relationship, defined as support and conflict, and subsequent effects of relationship change on adolescent psychosocial outcomes including risky behavior, substance use, depressive symptoms, and hopelessness. METHOD: Using data from a large prevention study, the sample included 110 youth at risk for high school drop out from the control condition; the sample was 48.2% of female, with a mean age of 15.9years. The data, gathered from adolescents and their parents across a period of approximately 18months, were analyzed using growth mixture modeling. RESULTS: Three distinct trajectories for parent-adolescent conflict (high-decreasing, low increasing, low-stable trajectory) were identified as well as a single growth model for support, which revealed a slight decline in support across time. Parent depression was a significant predictor of perceived support, but not of membership in trajectories of conflict. Low parent-adolescent support was associated with adolescent depression and hopelessness measured 18months post baseline. Adolescents in the low but increasing conflict trajectory and those having a parent with depression reported increased depression and hopelessness 18months later. DISCUSSION: Parent-Adolescent support and conflict were associated with adolescent emotional outcomes, particularly depression and hopelessness. The findings provide evidence that will inform prevention strategies to facilitate parent-adolescent support, minimize the negative impact of relationship conflict, and thereby promote healthy psychosocial outcomes for at-risk adolescence. PMID- 26577560 TI - Social functioning and internalized stigma in individuals diagnosed with substance use disorder. AB - The aim of this descriptive study was to determine social functioning and internalized stigma in individuals with substance use disorder. The study sample consisted of 105 patients diagnosed with substance use disorder according to the DSM-IV-TR diagnostic criteria. A Descriptive Information Form, Internalized Stigma of Mental Illness Scale (ISMI) and Social Functioning Scale (SFS) were used for data collection. Average total SFS score of the patients was 103.25+/ 25.09 points, indicating an intermediate level of social functioning. Average total ISMI score of patients was 2.92+/-0.48 points, reflecting a high level of internalized stigma. A negative significant association was observed between the internalized stigma levels and social functioning of patients. These results suggest that rehabilitation of substance users should include counseling services in order to reduce internal perception of stigma and improve their social functioning. PMID- 26577561 TI - Can we have routine measurement of patient satisfaction in acute psychiatric settings? A cross sectional study. AB - Patient satisfaction is considered an important indicator of the quality of care in psychiatric services. Its importance has been widely studied, but the literature identifies methodological problems deriving from samples with low response rates and exclusion criteria which would seem to imply a kind of exclusion in the evaluations of less compliant patients. The aim of this study is to test a methodology to assess patient satisfaction with the quality of care received at an acute psychiatric ward in terms of its application in daily routine. In this cross sectional survey inpatients were given the Rome Opinion Questionnaire (ROQ). Our patients, involuntary patients included, with a 92.3% participation rate (47 patients out of 51), returned a mean general satisfaction score of 7.7/9. This response rate is higher than that reported in most previously published studies, which shows that a good level of both voluntary and involuntary patient participation may be achieved when an appropriate methodological approach is adopted. Not acknowledging patient satisfaction reduces the possibility of more effective caring actions. Measuring patient satisfaction, through use of short questionnaires, should become a routine in daily practice. PMID- 26577562 TI - Nursing interventions in managing wandering behavior in patients with dementia: a literature review. AB - Wandering behavior is common in patients with dementia. The purpose of this literature review was to define wandering, describe the factors of wandering and analyze different interventions and nursing skill of managing this behavior. Finally, barriers to and effective nursing intervention for wandering behavior will be reviewed as they appear within the literature. The search was conducted to use the PubMed, ProQuest, CINAHL, MEDLINE databases from 1990 to 2015. Search terms used included 'wandering', 'intervention', 'dementia or Alzheimer', 'nursing', and 'elopement'. The inclusion criteria were: implementing the effective nursing intervention to manage wandering behavior, scholarly and peer reviewed journals, and publication in the English language. PMID- 26577563 TI - "An ongoing struggle with the self and illness": alpha meta-synthesis of the studies of the lived experience of severe mental illness. AB - The diverse experiences of severely mentally ill persons, most of the times, have not been taken into account, or integrated to the treatment procedures. This meta synthesis aimed to examine what is like to live with severe mental illness narratives by employing a meta-ethnographic synthesis of seventeen published peer reviewed qualitative studies. Third order analysis revealed as core theme "An ongoing struggle for reconciliation with the self and the illness". Other themes included amongst others: loss of identity, pain of having had one's life stolen, being an outcast. The identification of the importance of the alterations of self identity throughout the continuum of the severe mental disorder may be the focus of targeted psychosocial interventions. PMID- 26577564 TI - Working together to combat tobacco use. PMID- 26577565 TI - Does sedentary lifestyle touch arterial health? PMID- 26577566 TI - Immunoregulatory effects on T lymphocytes by human mesenchymal stromal cells isolated from bone marrow, amniotic fluid, and placenta. AB - Mesenchymal stromal cells (MSCs) are a promising tool in cell therapies because of their multipotent, bystander, and immunomodulatory properties. Although bone marrow represents the main source of MSCs, there remains a need to identify a stem cell source that is safe and easily accessible and yields large numbers of cells without provoking debates over ethics. In this study, MSCs isolated from amniotic fluid and placenta were compared with bone marrow MSCs. Their immunomodulatory properties were studied in total activated T cells (peripheral blood mononuclear cells) stimulated with phytohemagglutinin (PHA-PBMCs). In particular, an in vitro co-culture system was established to study: (i) the effect on T-lymphocyte proliferation; (ii) the presence of T regulatory lymphocytes (Treg); (iii) the immunophenotype of various T subsets (Th1 and Th2 naive, memory, effector lymphocytes); (iv) cytokine release and master gene expression to verify Th1, Th2, and Th17 polarization; and (v) IDO production. Under all co-culture conditions with PHA-PBMCs and MSCs (independently of tissue origin), data revealed: (i) T proliferation inhibition; (ii) increase in naive T and decrease in memory T cells; (iii) increase in T regulatory lymphocytes; (iv) strong Th2 polarization associated with increased interleukin-10 and interleukin 4 levels, Th1 inhibition (significant decreases in interleukin-2, tumor necrosis factor-alpha, interferon-gamma, and interleukin-12) and Th17 induction (production of high concentrations of interleukins-6 and -17); (v) indoleamine 2,3-dioxygenase mRNA induction in MSCs co-cultured with PHA-PBMCs. AF-MSCs had a more potent immunomodulatory effect on T cells than BM-MSCs, only slightly higher than that of placenta MSCs. This study indicates that MSCs isolated from fetal tissues may be considered a good alternative to BM-MSCs for clinical applications. PMID- 26577567 TI - Activation of the NLRP3 inflammasome by cellular labile iron. AB - Cellular labile iron, which contains chelatable redox-active Fe(2+), has been implicated in iron-mediated cellular toxicity leading to multiple organ dysfunction. Iron homeostasis is controlled by monocytes/macrophages through their iron recycling and storage capacities. Furthermore, iron sequestration by monocytes/macrophages is regulated by pro-inflammatory cytokines including interleukin-1, highlighting the importance of these cells in the crosstalk between inflammation and iron homeostasis. However, a role for cellular labile iron in monocyte/macrophage-mediated inflammatory responses has not been defined. Here we describe how cellular labile iron activates the NLRP3 inflammasome in human monocytes. Stimulation of lipopolysaccharide-primed peripheral blood mononuclear cells with ferric ammonium citrate increases the level of cellular Fe(2+) levels in monocytes and induces production of interleukin-1beta in a dose dependent manner. This ferric ammonium citrate-induced interleukin-1beta production is dependent on caspase-1 and is significantly inhibited by an Fe(2+) specific chelator. Ferric ammonium citrate consistently induced interleukin-1beta secretion in THP1 cells, but not in NLRP3-deficient THP1 cells, indicating a requirement for the NLRP3 inflammasome. Additionally, activation of the inflammasome is mediated by potassium efflux, reactive oxygen species-mediated mitochondrial dysfunction, and lysosomal membrane permeabilization. Thus, these results suggest that monocytes/macrophages not only sequestrate iron during inflammation, but also mediate inflammation in response to cellular labile iron, which provides novel insights into the role of iron in chronic inflammation. PMID- 26577568 TI - Interleukin-4 and interferon-gamma orchestrate an epithelial polarization in the airways. AB - Interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) are key effector cytokines for the differentiation of T helper type 1 and 2 (Th1 and Th2) cells. Both cytokines induce fate-decisive transcription factors such as GATA3 and TBX21 that antagonize the polarized development of opposite phenotypes by direct regulation of each other's expression along with many other target genes. Although it is well established that mesenchymal cells directly respond to Th1 and Th2 cytokines, the nature of antagonistic differentiation programs in airway epithelial cells is only partially understood. In this study, primary normal human bronchial epithelial cells (NHBEs) were exposed to IL-4, IFN-gamma, or both and genome-wide transcriptome analysis was performed. The study uncovers an antagonistic regulation pattern of IL-4 and IFN-gamma in NHBEs, translating the Th1/Th2 antagonism directly in epithelial gene regulation. IL-4- and IFN-gamma induced transcription factor hubs form clusters, present in antagonistically and polarized gene regulation networks. Furthermore, the IL-4-dependent induction of IL-24 observed in rhinitis patients was downregulated by IFN-gamma, and therefore IL-24 represents a potential biomarker of allergic inflammation and a Th2 polarized condition of the epithelium. PMID- 26577569 TI - Colonic tolerance develops in the iliac lymph nodes and can be established independent of CD103(+) dendritic cells. AB - Tolerance to harmless exogenous antigens is the default immune response in the gastrointestinal tract. Although extensive studies have demonstrated the importance of the mesenteric lymph nodes (MLNs) and intestinal CD103(+) dendritic cells (DCs) in driving small intestinal tolerance to protein antigen, the structural and immunological basis of colonic tolerance remain poorly understood. We show here that the caudal and iliac lymph nodes (ILNs) are inductive sites for distal colonic immune responses and that colonic T cell-mediated tolerance induction to protein antigen is initiated in these draining lymph nodes and not in MLNs. In agreement, colonic tolerance induction was not altered by mesenteric lymphadenectomy. Despite tolerance development, CD103(+)CD11b(+) DCs, which are the major migratory DC population in the MLNs, and the tolerance-related retinoic acid-generating enzyme RALDH2 were virtually absent from the ILNs. Administration of ovalbumin (OVA) to the distal colon did increase the number of CD11c(+)MHCII(hi) migratory CD103(-)CD11b(+) and CD103(+)CD11b(-) DCs in the ILNs. Strikingly, colonic tolerance was intact in Batf3-deficient mice specifically lacking CD103(+)CD11b(-) DCs, suggesting that CD103(-) DCs in the ILNs are sufficient to drive tolerance induction after protein antigen encounter in the distal colon. Altogether, we identify different inductive sites for small intestinal and colonic T-cell responses and reveal that distinct cellular mechanisms are operative to maintain tolerance at these sites. PMID- 26577570 TI - Restoring cigarette smoke-induced impairment of efferocytosis in alveolar macrophages. AB - Cigarette smoke has been associated with susceptibility to different pulmonary and airway diseases. Impaired alveolar macrophages (AMs) that are major phagocytes in the lung have been associated with patients with airway diseases and active smokers. In the current report, we show that exposure to second-hand cigarette smoke (SHS) significantly reduced efferocytosis in vivo. More importantly, delivery of recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) to the alveolar space restored and refurbished the efferocytosis capability of AMs. Exposure to SHS significantly reduced expression of CD16/32 on AMs, and treatment with GM-CSF not only restored but also significantly increased the expression of CD16/32 on AMs. GM-CSF treatment increased uptake and digestion/removal of apoptotic cells by AMs. The latter was attributed to increased expression of Rab5 and Rab7. Increased efferocytosis of AMs was also tested in a disease condition. AMs from GM-CSF-treated, influenza-infected, SHS exposed mice showed significantly better efferocytosis activity, and mice had significantly less morbidity compared with phosphate-buffered saline-treated group. GM-CSF-treated mice had increased amphiregulin levels in the lungs, which in addition to efferocytosis of AMs may have attributed to their protection against influenza. These results will have great implications for developing therapeutic approaches by harnessing mucosal innate immunity to treat lung and airway diseases and protect against pneumonia. PMID- 26577571 TI - The effectiveness of long-lasting, insecticide-treated nets in a setting of pyrethroid resistance: a case-control study among febrile children 6 to 59 months of age in Machinga District, Malawi. AB - BACKGROUND: The escalating level of mosquito resistance to pyrethroid insecticides threatens the effectiveness of insecticide-treated nets (ITNs) for malaria control in Malawi. An evaluation of the effectiveness of ITNs for preventing malaria in children aged 6-59 months old, after 1 year of mass distribution of LLINs was conducted in Machinga District, Malawi, an area of moderate pyrethroid resistance. METHODS: A facility-based, case-control study among children 6-59 months was conducted in an area of pyrethroid resistance between March and September 2013 in Machinga District. Cases and controls were children with fever who sought care from the same hospital and tested positive and negative, respectively, for malaria parasites by microscopy. RESULTS: A high proportion of both cases (354 of 404 or 87.6 %) and controls (660 of 778 or 84.8 %) slept under an ITN the night before the survey. In univariable logistic regression, older age (24-59 months versus 6-23 months, p < 0.001), sleeping on the floor versus a mattress (p < 0.001), and open versus closed house eaves (p = 0.001) were associated with increased odds of malaria, whilst secondary education of the caretaker, having windows on multiple walls, and being in the least poor wealth quintile (p < 0.001 for each) reduced the odds of malaria; ITN use was not associated with malaria (p = 0.181). In multivariable analysis, older age (p < 0.001) and secondary education of the caregiver (p = 0.011) were the only factors significantly associated with malaria. CONCLUSION: This study did not find a significant personal protective effect of ITNs. However, high use of ITNs in the community and recent findings of lower malaria incidence in ITN users compared to bed net non-users from a cohort study in the same area suggest that ITNs provide community protection to both users and non-users alike in this area. PMID- 26577572 TI - Transverse incision transvaginal rectocele repair combined with levatorplasty and biological graft insertion: technical details and case series outcomes. AB - BACKGROUND: The purpose of this report is twofold: first, to detail our operative approach to rectocele repair, and second, to report on the outcomes. METHODS: Transverse incision transvaginal rectocele repair combined with levatorplasty and biological graft placement is detailed using hand-drawn sketches and intraoperative photographs. All patients with symptoms of functional constipation and non-emptying rectocele operated on from May 2007 to March 2013 at our institution were enrolled in this study. Data from a prospectively maintained database were retrospectively analyzed. Preoperative and postoperative functional outcomes were studied using a validated 31-point obstructed defecation (OD) scoring system. Follow-up was 1 year. RESULTS: Twenty-three patients underwent the procedure. The mean age of patients was 55 years (range 28-79 years). The OD severity score improved from the preoperative mean of 21.6 to postoperative mean of 5.5 (p = 0.001). Three out of four patients with initial symptoms of dyspareunia (75%) reported significant improvement in dyspareunia, while 2 out of 19 patients without initial symptoms of dyspareunia (11%) reported mild dyspareunia following the repair. One patient (4%) required operative drainage of a hematoma. Another patient (4%) developed symptomatic recurrence which was confirmed radiologically. CONCLUSIONS: In properly selected patients, the technique described leads to significant improvement in symptoms of OD and low recurrence without an increased rate of dyspareunia. PMID- 26577573 TI - Implant-supported single-tooth restorations. A 12-year prospective study. AB - OBJECTIVE: The aim of this study was to evaluate prospectively the 12-year outcome of implant-supported single-tooth restorations. MATERIAL AND METHODS: Originally 45 self-tapping Astra Tech TiOblast(r) ST-implants were installed by a two-stage protocol in 40 subjects requiring single-tooth prosthetic replacement for a missing tooth. Clinical and radiologic examinations were performed at completion of the prosthetic treatment 4-7 months after implant installation surgery and after 5 and 12 years in function. RESULTS: At 12 years 31 patients and 35 implants were available for evaluation. The overall failure rate after 12 years was 10.3% on the subject level and 9.1% on the implant level. The mean bone loss amounted to 0.67 mm (SD 2.20) on a subject level and 0.47 mm (1.72) on an implant level. Three subjects (10%) and three implants (8.6%) were diagnosed with peri-implantitis. Five subjects had experienced technical complications; three incidences of loosening of the abutment retention screw during the first 5 years and two minor porcelain fracture of the crown (two patients) between 5- and 12 years of follow-up. CONCLUSION: The findings reported in this 12-year prospective case series suggest that the use of the Astra Tech dental implants may be a valid treatment alternative for single-tooth replacement prostheses. PMID- 26577575 TI - NHS staff invited to comment on new policy to encourage whistleblowing. PMID- 26577574 TI - Developing therapeutic vaccines against Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common form of dementia worldwide. It is characterized by an imbalance between the production and clearance of amyloid beta (Abeta) and tau proteins. In AD these normal proteins accumulate, leading to aggregation and a conformational change forming oligomeric and fibrillary species with a high beta-sheet content. Active and passive immunotherapeutic approaches result in dramatic reduction of Abeta pathology in AD animal models. However, there is much more limited evidence in human studies of significant clinical benefits from these strategies and it is becoming apparent that they may only be effective very early in AD. Vaccination targeting only tau pathology has shown benefits in some mouse studies but human studies are limited. Greater therapeutic efficacy for the next generation of vaccine approaches will likely benefit from specifically targeting the most toxic species of Abeta and tau, ideally simultaneously. PMID- 26577576 TI - Delineating outcomes of patients with diffuse large b cell lymphoma using the national comprehensive cancer network-international prognostic index and positron emission tomography-defined remission status; a population-based analysis. AB - The recently devised National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) appears superior to the revised IPI (R-IPI) in delineating outcome in diffuse large B-cell lymphoma. We examined the outcome of a population-based cohort of 223 consecutive patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) or R-CHOP like immuno-chemotherapy between January 2005 and December 2011 by both the NCCN IPI and R-IPI, and further stratified outcome by the achievement of both computerized tomography (CT) and positron emission tomography (PET)-CT complete remission (CR), with the latter reassessed using blinded central review by an independent nuclear medicine and radiology specialist. The NCCN-IPI was superior to the R-IPI in identifying patients at very high risk of systemic and/or central nervous system relapse. Notably, both the NCCN-IPI and the R-IPI remained strongly predictive of relapse irrespective of CT or PET-defined remission status following R-CHOP. Patients with high-risk NCCN-IPI scores (>=6) have a dismal outcome following R-CHOP therapy regardless of PET-defined response to R-CHOP. Moreover, such patients appear refractory to salvage chemotherapy and thus require alternative therapeutic approaches, although age and performance status may, for many patients, preclude the safe delivery of a primary intensified regimen. By contrast, patients with NCCN-IPI 1-5 who achieve PET-CR following R CHOP have excellent outcomes and may merit reduced follow up frequency. PMID- 26577577 TI - Seasonal Changes in Bacterial Communities Cause Foaming in a Wastewater Treatment Plant. AB - Bio-foaming is a major problem in solid separation in activated sludge (AS) wastewater treatment systems. Understanding the changes in bacterial communities during sludge foaming is vital for explaining foam formation. Changes in bacterial communities in the foam, corresponding foaming AS, and non-foaming AS in a seasonal foaming wastewater treatment plant (WWTP) in Northern China were investigated by high-throughput pyrosequencing and molecular quantification-based approaches. We found that bacterial communities of the foam and the corresponding foaming AS were similar but markedly different from those of the non-foaming AS. Actinobacteria was the predominant phylum in the foam and the corresponding foaming AS, whereas Proteobacteria was predominant in the non-foaming AS. Similar to the results of most previous studies, our results showed that Candidatus "Microthrix parvicella" was the predominant filamentous bacteria in the foam and the corresponding foaming AS and was significantly enriched in the foam compared to the corresponding foaming AS. Its abundance decreased gradually with a slow disappearance of sludge foaming, indicating that its overgrowth had a direct relationship with sludge foaming. In addition to Candidatus M. parvicella, Tetrasphaera and Trichococcus might play a role in sludge foaming, because they supported the changes in AS microbial ecology for foam formation. The effluent water quality of the surveyed plant remained stable during the period of sludge foaming, but the microbial consortia responsible for nitrogen and phosphorus transformation and removal markedly changed compared to that in the non-foaming AS. This study adds to the previous understanding of bacterial communities causing foaming in WWTPs. PMID- 26577578 TI - The migration and transformation behaviors of heavy metals during the hydrothermal treatment of sewage sludge. AB - Various hydrothermal treatment methods, including hydrothermal carbonization, liquefaction and sub/super-critical water gasification, have been applied to the disposal of sewage sludge for producing bio-materials or bio-fuels. It has become a research hotspot whether the heavy metals contained in sewage sludge can be well treated/stabilized after the hydrothermal treatments. This review firstly summarized the methods of assessing heavy metals' contamination level/risk and then discussed the migration and transformation behaviors of heavy metals from the following aspects: the effect of reaction temperature, the effect of additives (catalysts and other biomass), the effect of the type of solvent and the effect of reaction time. This review can provide an important reference for the further study of the migration and transformation behaviors of heavy metals during the hydrothermal treatment of sewage sludge. PMID- 26577579 TI - Pyrosequencing reveals microbial community profile in anaerobic bio-entrapped membrane reactor for pharmaceutical wastewater treatment. AB - In this study, pharmaceutical wastewater with high salinity and total chemical oxygen demand (TCOD) was treated by an anaerobic membrane bioreactor (AnMBR) and an anaerobic bio-entrapped membrane reactor (AnBEMR). The microbial populations and communities were analyzed using the 454 pyrosequencing method. The hydraulic retention time (HRT), membrane flux and mean cell residence time (MCRT) were controlled at 30.6h, 6L/m(2)h and 100d, respectively. The results showed that the AnBEMR achieved higher TCOD removal efficiency and greater biogas production compared to the AnMBR. Through DNA pyrosequencing analysis, both the anaerobic MBRs showed similar dominant groups of bacteria and archaea. However, phylum Elusimicrobia of bacteria was only detected in the AnBEMR; the higher abundance of dominant archaeal genus Methanimicrococcus found in the AnBEMR could play an important role in degradation of the major organic pollutant (i.e., trimethylamine) present in the pharmaceutical wastewater. PMID- 26577580 TI - Prediagnostic serum glucose and lipids in relation to survival in breast cancer patients: a competing risk analysis. AB - BACKGROUND: Abnormal glucose and lipids levels may impact survival after breast cancer (BC) diagnosis, but their association to other causes of mortality such as cardiovascular (CV) disease may result in a competing risk problem. METHODS: We assessed serum glucose, triglycerides (TG) and total cholesterol (TC) measured prospectively 3 months to 3 years before diagnosis in 1798 Swedish women diagnosed with any type of BC between 1985 and 1999. In addition to using Cox regression, we employed latent class proportional hazards models to capture any heterogeneity of associations between these markers and BC death. The latter method was extended to include the primary outcome (BC death) and competing outcomes (CV death and death from other causes), allowing latent class-specific hazard estimation for cause-specific deaths. RESULTS: A lack of association between prediagnostic glucose, TG or TC with BC death was observed with Cox regression. With latent class proportional hazards model, two latent classes (Class I and II) were suggested. Class I, comprising the majority (81.5 %) of BC patients, had an increased risk of BC death following higher TG levels (HR: 1.87, 95 % CI: 1.01-3.45 for every log TG increase). Lower overall survival was observed in Class II, but no association for BC death was found. On the other hand, TC positively corresponded to CV death in Class II, and similarly, glucose to death from other causes. CONCLUSION: Addressing cohort heterogeneity in relation to BC survival is important in understanding the relationship between metabolic markers and cause-specific death in presence of competing outcomes. PMID- 26577581 TI - Effect of storage temperature and equilibration time on polymethyl methacrylate (PMMA) bone cement polymerization in joint replacement surgery. AB - BACKGROUND: In cemented joint arthroplasty, the handling characteristics (doughing, working, and setting times) of polymethyl methacrylate (PMMA) bone cement is important as it determines the amount of time surgeons have to optimally position an implant. Storage conditions (temperature and humidity) and the time given for PMMA cement to equilibrate to ambient operating theater (OT) temperatures are often unregulated and may lead to inconsistencies in its handling characteristics. This has not been previously studied. Hence, the purpose of this study was to investigate the effect of storage temperatures on the handling characteristics of PMMA cement and the duration of equilibration time needed at each storage temperature to produce consistent and reproducible doughing, setting, and working times. METHODS: SmartSet(r) HV cement was stored at three different controlled temperatures: 20 degrees C (control), 24 degrees C, and 28 degrees C for at least 24 h prior to mixing. The cement components were then brought into a room kept at 20 degrees C and 50 % humidity. Samples were allowed to equilibrate to ambient conditions for 15, 30, 45, and 60 min. The cement components were mixed and the dough time, temperature-versus-time curve (Lutron TM-947SD, Lutron Electronics, Inc., Coopersburg, PA), and setting time were recorded. Analysis was performed using the two-way ANOVA test (IBM SPSS Statistics V.22). RESULTS: At 20 degrees C (control) storage temperature, the mean setting time was 534 +/- 17 s. At 24 degrees C storage temperature, the mean setting time was 414 +/- 6 s (p < 0.001*) with 15 min of equilibration, 446 +/- 11 s (p < 0.001*) with 30 min of equilibration, 501 +/- 12 s (p < 0.001*) with 45 min of equilibration, and 528 +/- 15 (p > 0.05) with 60 min of equilibration. At 28 degrees C storage temperature, the mean setting time was 381 +/- 8 s (p < 0.001*) with 15 min of equilibration, 432 +/- 30 s (p < 0.001*) with 30 min of equilibration, 487 +/- 9 (p < 0.001*) with 45 min of equilibration, and 520 +/- 16 s (p > 0.05) with 60 min of equilibration. CONCLUSIONS: This study reflects the extent to which storage temperatures and equilibration times can potentially affect the handling characteristics of PMMA cement. We recommend institutions to have a well-regulated temperature and humidity-controlled facility for storage of bone cements and a protocol to standardize the equilibration time of cements prior to use in the OT to improve consistency and reproducibility of the handling characteristics of PMMA cement. PMID- 26577582 TI - Multi-Functionalized Carbon Nano-onions as Imaging Probes for Cancer Cells. AB - Carbon-based nanomaterials have attracted much interest during the last decade for biomedical applications. Multimodal imaging probes based on carbon nano onions (CNOs) have emerged as a platform for bioimaging because of their cell penetration properties and minimal systemic toxicity. Here, we describe the covalent functionalization of CNOs with fluorescein and folic acid moieties for both imaging and targeting cancer cells. The modified CNOs display high brightness and photostability in aqueous solutions and their selective and rapid uptake in two different cancer cell lines without significant cytotoxicity was demonstrated. The localization of the functionalized CNOs in late-endosomes cell compartments was revealed by a correlative approach with confocal and transmission electron microscopy. Understanding the biological response of functionalized CNOs with the capability to target cancer cells and localize the nanoparticles in the cellular environment, will pave the way for the development of a new generation of imaging probes for future biomedical studies. PMID- 26577583 TI - Electromyographic and laboratory findings in acute Solanum torvum poisoning. AB - CONTEXT: Solanum torvum berries, known as susumber or turkey berries, are prepared as part of traditional Jamaican dishes usually served with cod and rice. Poisoning is rare. Although toxic compounds have never been definitively isolated, previous reports suggest toxicity results from inhibition of acetylcholinesterases. We present a case of susumber berry poisoning with detailed electromyographic studies and laboratory analysis. CASE DETAILS: A 54 year-old woman presented to the Emergency Department (ED) complaining of vision, speech, and gait changes; emesis; and diffuse myalgias following consumption of susumber berries. The physical examination demonstrated an intact, lucid mental status, miosis, opsoclonus, severe dysarthria, dysmetria, mild extremity tenderness and weakness, and inability to ambulate. Her symptom constellation was interpreted as a stroke. DISCUSSION: Electromyography demonstrated a pattern of early full recruitment as well as myotonia during the period of acute toxicity. Additionally, solanaceous compounds, in particular solasonine and solanidine, were identified in leftover berries and the patient's serum. Store-bought commercial berries and subsequent serum samples were free of such toxic compounds. EMG studies, together with a laboratory analysis of berries or serum can assist in the differential diagnosis of stroke, and provide both a prognostic screening and confirmation of suspected glycoside toxicity. PMID- 26577584 TI - Behavioural response of female Culex pipiens pallens to common host plant volatiles and synthetic blends. AB - BACKGROUND: Most mosquito species need to obtain sugar from host plants. Little is known about the chemical cues that Culex pipiens pallens use during their orientation to nectar host plants. In this study, we investigated the behavioural responses of female Cx. pipiens pallens to common floral scent compounds and their blends. METHODS: Behavioural responses of female Cx. pipiens pallens to 18 individual compounds at different concentrations were determined in the olfactometer bioassays. A synthetic blend composed of behaviourally active compounds was formulated, and its attractiveness to mosquitoes was tested. Several most attractive compounds constituted a reduced blend, and its attractiveness was tested against the solvent and the full blend, respectively. Mosquito response in the olfactometer was analyzed by comparing the percentages of mosquitoes caught in the two arms by chi(2) test (observed versus expected). RESULTS: Fifteen of the 18 compounds were attractive to female Cx. pipiens pallens in the dose-dependent bioassays, with the exception of beta-pinene, acetophenone and nonanal. (68.00 +/- 2.49) % mosquitoes responded to the full blend composed of these 15 compounds on their optimal doses when tested against the solvent, with the preference index at 46.11 +/- 3.57. Six individual compounds whose preference indices were over 40 constituted the reduced blend, and it attracted (68.00 +/- 1.33) % mosquitoes when tested against the solvent while its preference index was 42.00 +/- 3.54. When tested against the full blend simultaneously in the olfactometer, the reduced blend could attract (45.00 +/- 2.69) % of released mosquitoes, which was as attractive as the full blend. CONCLUSIONS: Our results demonstrate that female Cx. pipiens pallens is differentially attracted by a variety of compounds at different concentrations. Alteration of the concentration strongly affects the attractiveness of the synthetic blend. Several floral scent volatiles might be the universal olfactory cues for various mosquito species to locate their nectar host plants, which could be potentially used in trapping devices for surveillance and control of them. PMID- 26577585 TI - Insulin augments serotonin-induced contraction via activation of the IR/PI3K/PDK1 pathway in the rat carotid artery. AB - Hyperinsulinemia associated with type 2 diabetes may contribute to the development of vascular diseases. Although we recently reported that enhanced contractile responses to serotonin (5-hydroxytryptamine, 5-HT) are observed in the arteries of type 2 diabetes models, the causative factors and detailed signaling pathways involved remain unclear. The purpose of this study was to investigate whether high insulin would be an amplifier of 5-HT-induced contraction in rat carotid arteries and whether the contraction involves phosphoinositide 3-kinase (PI3K)/3-phosphoinositide-dependent protein kinase 1 (PDK1) signaling, an insulin-mediated signaling pathway. In rat carotid arteries organ-cultured with insulin (for 24 h), (1) the contractile responses to 5-HT were significantly greater (vs. vehicle), (2) the insulin-induced enhancement of 5-HT-induced contractions was largely suppressed by inhibitors of the insulin receptor (IR) (GSK1838705A), PI3K (LY294002), and PDK1 (GSK2334470), and (3) the levels of phosphorylated forms of both PDK1 and myosin phosphatase target subunit 1 (MYPT1) were greater upon 5-HT stimulation. In addition, in rat carotid arteries organ-cultured with an activator of PDK1 (PS48), the 5-HT-induced contraction was greater, and this was suppressed by PDK1 inhibition but not PI3K inhibition. In addition, MYPT1 and PDK1 phosphorylation upon 5-HT stimulation was enhanced (vs. vehicle). These results suggest that high insulin levels amplify 5 HT-induced contraction. Moreover, the present results indicated the direct linkage between IR/PI3K/PDK1 activation and 5-HT-induced contraction in rat carotid arteries for the first time. PMID- 26577586 TI - Vesicular glutamate transporters as anion channels? AB - Since the discovery of a putative Cl(-) channel on synaptic vesicle (SV) membranes, attempts to establish its molecular identity have proven surprisingly difficult. Recent evidence has emerged to support the idea that the vesicular glutamate transporter (VGLUT), whose main function is to concentrate the excitatory neurotransmitter glutamate into SVs, can also act as the Cl(-) permeation pathway. Here, I summarize studies investigating the putative Cl(-) channel on SVs and discuss the possible roles of VGLUT-mediated Cl(-) transport on glutamate loading. PMID- 26577587 TI - Platelet Dynamics in Peritoneal Carcinomatosis Patients Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Oxaliplatin. AB - The aim of the study was to characterize the platelet count (PLT) dynamics in peritoneal carcinomatosis patients treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal oxaliplatin (HIO). Data from patients treated with CRS alone (N = 18) or CRS and HIO (N = 62) were used to estimate the baseline platelet count (PLT0), rate constants for platelet maturation (k tr ) and platelet random destruction (k s ), feedback on progenitor cell proliferation (gamma), and the drug-specific model parameters (alpha, beta). Plasma oxaliplatin concentrations, C p , reduced the proliferation rate of progenitor cells (k prol) according to a power function alpha * C p (beta) . The surgery effect on k prol and k s was explored. The typical values (between subject variability) of the PLT0, k tr , k s , gamma, alpha, and beta were estimated to be 237 * 10(9) cells/L (32.9%), 7.09 * 10(-3) h(-1) (47.1%), 8.86 * 10(-3) h(-1) (80.0%), 0.621, 0.88 L/mg (56.9%), and 2.63. Surgery induced a maximal 2.09-fold increase in k prol that was attenuated with a half-life of 8.42 days. Splenectomy decreased k s by 47.5%. Age, sex, body surface area, sex, total proteins, and HIO carrier solution did not impact the model parameters. The model developed suggests that, following CRS and HIO, thrombocytopenia and thrombocytosis were reversible and short-lasting; the severity of the thrombocytopenia and thrombocytosis was inversely correlated, with splenectomized patients having thrombocytopenia of lower severity and thrombocytosis of higher severity; and the HIO dose and treatment duration determine the severity and duration of the thrombocytopenia. Higher HIO dose or longer treatment duration could be used without substantially increasing the risk of major hematological toxicity. PMID- 26577588 TI - Safety of undiluted intracameral moxifloxacin without postoperative topical antibiotics in cataract surgery. AB - The objective of this study is to evaluate the safety of undiluted 0.5 % intracameral moxifloxacin for postoperative endophthalmitis prophylaxis in cataract surgery patients without the use of additional postoperative topical antibiotics. All phacoemulsification cataract surgeries performed by a single surgeon (B.A.) at the John A. Moran Eye Center from June 2012 to May 2015 were reviewed retrospectively. From June 2012 to April 2014, patients were given topical 0.5 % moxifloxacin postoperatively. From May 2014 to May 2015, all patients were given moxifloxacin intracamerally with no antibiotics postoperatively. The follow-up period was 1 month after surgery. Preoperative visual acuity and postoperative visual acuity, corneal edema, and anterior chamber reaction were recorded and compared between the two groups. 384 cataract surgeries were performed during the study period. None of the 384 eyes in the study developed endophthalmitis. Of those 384 eyes, 222 were included in the study for analysis based on the inclusion and exclusion criteria. 131 were part of the topical antibiotic group and 91 were part of the intracameral group. The differences in uncorrected visual acuity at 1 day postoperatively (p = 0.595) and best corrected visual acuity at 1 month postoperatively (p = 0.099) were not statistically significant. Differences in corneal edema (p = 0.370) and anterior chamber reaction (p = 0.069) at 1 day postoperatively and corneal edema (p = 0.512) and anterior chamber reaction (p = 0.512) at 1 month postoperatively were also not statistically significant. Undiluted 0.5 % moxifloxacin can be safely injected intracamerally following cataract surgery without additional postoperative antibiotic prophylaxis to prevent endophthalmitis without adverse effects on patient outcomes. PMID- 26577589 TI - Impact of acetylcholinesterase inhibitors on the occurrence of acute coronary syndrome in patients with dementia. AB - The study aimed to investigate the association of acetylcholinesterase inhibitors (AChEIs) use with the risk of acute coronary syndrome (ACS). We conducted a population-based retrospective cohort study of dementia patients during 1 January 1999 to 31 December 2008 using the National Health Insurance Database in Taiwan. New AChEI users during the study period were matched with AChEI nonusers in age matched and gender-matched cohorts. The risk of ACS associated with use of AChEIs was analyzed using modified Kaplan-Meier analysis and Cox proportional hazard models after adjustment for competing death risk. Use of AChEIs was associated with a lower incidence of ACS (212.8/10,000 person-years) compared to the matched reference cohort (268.7/10,000 person-years). The adjusted hazard ratio for ACS in patients with dementia treated with AChEIs was 0.836 (95% confidence interval, 0.750-0.933; P < 0.001). Further sensitivity analysis of different study populations demonstrated consistent results. A statistical dose-response relationship for AChEI use and ACS risk was significant for the patients with dementia. In patients with dementia, AChEI treatment was associated with decreased risk of ACS. PMID- 26577590 TI - Comparison of intravascular ultrasound guided versus angiography guided drug eluting stent implantation: a systematic review and meta-analysis. AB - BACKGROUND: Intravascular ultrasound (IVUS) can be a useful tool during drug eluting stents (DES) implantation as it allows accurate assessment of lesion severity and optimal treatment planning. However, numerous reports have shown that IVUS guided percutaneous coronary intervention is not associated with improved clinical outcomes, especially in non-complex patients and lesions. METHODS: We searched the literature in Medline, the Cochrane Library, and other internet sources to identify studies that compare clinical outcomes between IVUS guided and angiography-guided DES implantation. Random-effects model was used to assess treatment effect. RESULTS: Twenty eligible studies with a total of 29,068 patients were included in this meta-analysis. The use of IVUS was associated with significant reductions in major adverse cardiovascular events (MACE, odds ratios [OR] 0.77, 95 % confidence intervals [CI] 0.71-0.83, P < 0.001), death (OR 0.62, 95 % CI 0.54-0.71, p < 0.001), and stent thrombosis (OR 0.59, 95 % CI: 0.47-0.73, P < 0.001). The benefit was also seen in the repeated analysis of matched and randomized studies. In stratified analysis, IVUS guidance appeared to be beneficial not only in patients with complex lesions or acute coronary syndromes (ACS) but also patients with mixed lesions or presentations (MACE: OR 0.69, 95 % CI: 0.60-0.79, p < 0.001, OR 0.81, 95 % CI 0.74-0.90, p < 0.001, respectively). By employing meta-regression analysis, the benefit of IVUS is significantly pronounced in patients with complex lesions or ACS with respect to death (p = 0.048). CONCLUSIONS: IVUS guidance was associated with improved clinical outcomes, especially in patients with complex lesions admitted with ACS. Large, randomized clinical trials are warranted to identify populations and lesion characteristics where IVUS guidance would be associated with better outcomes. PMID- 26577591 TI - The acceptability of conducting data linkage research without obtaining consent: lay people's views and justifications. AB - BACKGROUND: A key ethical issue arising in data linkage research relates to consent requirements. Patients' consent preferences in the context of health research have been explored but their consent preferences regarding data linkage specifically have been under-explored. In addition, the views on data linkage are often those of patient groups. As a result, little is known about lay people's views and their preferences about consent requirements in the context of data linkage. This study explores lay people's views and justifications regarding the acceptability of conducting data linkage research without obtaining consent. METHODS: A qualitative study explored lay people's views regarding consent requirements in data linkage via four hypothetical data linkage scenarios of increasing complexity. Prior to considering the scenarios, participants were provided with information regarding best practice data linkage processes via discussion and a diagrammatic representation of the process. RESULTS: Lay people were able to understand the intricate processes involved in data linkage and the key protections afforded within a short amount of time. They were supportive of data linkage research and, on the whole, believed it should be conducted without consent provided a data linkage organization de-identifies the data used so that researchers do not handle identifiable data. Many thought that de-identified data holds a different status to identifiable data and should be used without specific consent in research that aims to benefit society. In weighing up conflicting values and interests, participants shifted consent preferences before arriving at their final consent preference for each scenario and provided justifications for their choices. They considered the protection of people's information, societal benefits, and the nature and constraints of research and recognized that these need to be balanced. CONCLUSIONS: With some exposure to the features of data linkage, lay people have the capacity to understand the processes sufficiently in order to consider ethical issues associated with consent preferences. Shifts in views reveal the complexity of such decisions. While privacy protection remained an important consideration for most participants, adequate protection measures adopted in best practice data linkage were viewed by most as protection enough for data linkage to proceed without specific individual consent. PMID- 26577592 TI - Bipolar disorder dynamics: affective instabilities, relaxation oscillations and noise. AB - Bipolar disorder is a chronic, recurrent mental illness characterized by extreme episodes of depressed and manic mood, interspersed with less severe but highly variable mood fluctuations. Here, we develop a novel mathematical approach for exploring the dynamics of bipolar disorder. We investigate how the dynamics of subjective experience of mood in bipolar disorder can be understood using a relaxation oscillator (RO) framework and test the model against mood time-series fluctuations from a set of individuals with bipolar disorder. We show that variable mood fluctuations in individuals diagnosed with bipolar disorder can be driven by the coupled effects of deterministic dynamics (captured by ROs) and noise. Using a statistical likelihood-based approach, we show that, in general, mood dynamics are described by two independent ROs with differing levels of endogenous variability among individuals. We suggest that this sort of nonlinear approach to bipolar disorder has neurobiological, cognitive and clinical implications for understanding this mental illness through a mechacognitive framework. PMID- 26577594 TI - Partially observed epidemics in wildlife hosts: modelling an outbreak of dolphin morbillivirus in the northwestern Atlantic, June 2013-2014. AB - Morbilliviruses cause major mortality in marine mammals, but the dynamics of transmission and persistence are ill understood compared to terrestrial counterparts such as measles; this is especially true for epidemics in cetaceans. However, the recent outbreak of dolphin morbillivirus in the northwestern Atlantic Ocean can provide new insights into the epidemiology and spatio-temporal spread of this pathogen. To deal with uncertainties surrounding the ecology of this system (only stranded animals were observed), we develop a statistical framework that can extract key information about the underlying transmission process given only sparse data. Our self-exciting Poisson process model suggests that individuals are infectious for at most 24 days and can transfer infection up to two latitude degrees (220 km) within this time. In addition, the effective reproduction number is generally below one, but reaches 2.6 during a period of heightened stranding numbers near Virginia Beach, Virginia, in summer 2013. Network analysis suggests local movements dominate spatial spread, with seasonal migration facilitating wider dissemination along the coast. Finally, a low virus transmission rate or high levels of pre-existing immunity can explain the lack of viral spread into the Gulf of Mexico. More generally, our approach illustrates novel methodologies for analysing very indirectly observed epidemics. PMID- 26577593 TI - A simple mechanistic explanation for original antigenic sin and its alleviation by adjuvants. AB - A large number of published studies have shown that adaptive immunity to a particular antigen, including pathogen-derived, can be boosted by another, cross reacting antigen while inducing suboptimal immunity to the latter. Although this phenomenon, called original antigenic sin (OAS), was first reported approximately 70 years ago (Francis et al. 1947 Am. J. Public Health 37, 1013-1016 (doi:10.2105/AJPH.37.8.1013)), its underlying biological mechanisms are still inadequately understood (Kim et al. Proc. Natl Acad. Sci. USA 109, 13 751-13 756 (doi:10.1073/pnas.0912458109)). Here, focusing on the humoral aspects of adaptive immunity, I propose a simple and testable mechanism: that OAS occurs when T regulatory cells induced by the first antigen decrease the dose of the second antigen that is loaded by dendritic cells and available to activate naive lymphocytes. I use both a parsimonious mathematical model and experimental data to confirm the deductive validity of this proposal. This model also explains the puzzling experimental observation that administering certain dendritic cell activating adjuvants during antigen exposure alleviates OAS. Specifically, the model predicts that such adjuvants will attenuate T regulatory suppression of naive lymphocyte activation. Together, these results suggest additional strategies for redeeming adaptive immunity from the destructive consequences of antigenic 'sin'. PMID- 26577595 TI - Adaptation options for wheat in Europe will be limited by increased adverse weather events under climate change. AB - Ways of increasing the production of wheat, the most widely grown cereal crop, will need to be found to meet the increasing demand caused by human population growth in the coming decades. This increase must occur despite the decrease in yield gains now being reported in some regions, increased price volatility and the expected increase in the frequency of adverse weather events that can reduce yields. However, if and how the frequency of adverse weather events will change over Europe, the most important wheat-growing area, has not yet been analysed. Here, we show that the accumulated probability of 11 adverse weather events with the potential to significantly reduce yield will increase markedly across all of Europe. We found that by the end of the century, the exposure of the key European wheat-growing areas, where most wheat production is currently concentrated, may increase more than twofold. However, if we consider the entire arable land area of Europe, a greater than threefold increase in risk was predicted. Therefore, shifting wheat production to new producing regions to reduce the risk might not be possible as the risk of adverse events beyond the key wheat-growing areas increases even more. Furthermore, we found a marked increase in wheat exposure to high temperatures, severe droughts and field inaccessibility compared with other types of adverse events. Our results also showed the limitations of some of the presently debated adaptation options and demonstrated the need for development of region-specific strategies. Other regions of the world could be affected by adverse weather events in the future in a way different from that considered here for Europe. This observation emphasizes the importance of conducting similar analyses for other major wheat regions. PMID- 26577597 TI - Addendum to 'A patient-specific computational model of hypoxia-modulated radiation resistance in glioblastoma using 18F-FMISO-PET'. PMID- 26577596 TI - Fold and flexibility: what can proteins' mechanical properties tell us about their folding nucleus? AB - The determination of a protein's folding nucleus, i.e. a set of native contacts playing an important role during its folding process, remains an elusive yet essential problem in biochemistry. In this work, we investigate the mechanical properties of 70 protein structures belonging to 14 protein families presenting various folds using coarse-grain Brownian dynamics simulations. The resulting rigidity profiles combined with multiple sequence alignments show that a limited set of rigid residues, which we call the consensus nucleus, occupy conserved positions along the protein sequence. These residues' side chains form a tight interaction network within the protein's core, thus making our consensus nuclei potential folding nuclei. A review of experimental and theoretical literature shows that most (above 80%) of these residues were indeed identified as folding nucleus member in earlier studies. PMID- 26577598 TI - Test-retest reliability of fMRI experiments during robot-assisted active and passive stepping. AB - BACKGROUND: Brain activity has been shown to undergo cortical and sub-cortical functional reorganisation over the course of gait rehabilitation in patients suffering from a spinal cord injury or a stroke. These changes however, have not been completely elucidated by neuroimaging to date, mainly due to the scarcity of long-term, follow-up investigations. The magnetic resonance imaging (MRI) compatible stepper MARCOS was specifically developed to enable the investigation of the supraspinal adaptations in paretic patients undergoing gait-rehabilitation in a controlled and repeatable manner. In view of future clinical research, the present study aims at examining the test-retest reliability of functional MRI (fMRI) experiments using MARCOS. METHODS: The effect of repeated active and passive stepping movements on brain activity was investigated in 16 healthy participants from fMRI data collected in two separate imaging sessions six weeks apart. Root mean square errors (RMSE) were calculated for the metrics of motor performance. Regional overlap of brain activation between sessions, as well as an intra-class correlation coefficient (ICC) was computed from the single-subject and group activation maps for five regions of interest (ROI). RESULTS: Data from eight participants had to be excluded due to excessive head motion. Reliability of motor performance was higher during passive than active movements, as seen in 4.5- to 13-fold lower RMSE for passive movements. In contrast, ICC ranged from 0.48 to 0.72 during passive movements and from 0.77 to 0.85 during active movements. Regional overlap of activations was also higher during active than during passive movements. CONCLUSION: These findings imply that an increased variability of motor performance during active movements of healthy participants may be associated with a stable neuronal activation pattern across repeated measurements. In contrast, a stable motor performance during passive movements may be accompanied by a confined reliability of brain activation across repeated measurements. PMID- 26577599 TI - Rapid genetic restoration of a keystone species exhibiting delayed demographic response. AB - Genetic founder effects are often expected when animals colonize restored habitat in fragmented landscapes, but empirical data on genetic responses to restoration are limited. We examined the genetic response of banner-tailed kangaroo rats (Dipodomys spectabilis) to landscape-scale grassland restoration in the Chihuahuan Desert of New Mexico, USA. Dipodomys spectabilis is a grassland specialist and keystone species. At sites treated with herbicide to remove shrubs, colonization by D. spectabilis is slow and populations persist at low density for >=10 years (>=6 generations). Persistence at low density and low gene flow may cause strong founder effects. We compared genetic structure of D. spectabilis populations between treated sites and remnant grasslands, and we examined how the genetic response to restoration depended on treatment age, area, and connectivity to source populations. Allelic richness and heterozygosity were similar between treated sites and remnant grasslands. Allelic richness at treated sites was greatest early in the restoration trajectory, and genetic divergence did not differ between recently colonized and established populations. These results indicated that founder effects during colonization of treated sites were weak or absent. Moreover, our results suggested founder effects were not mitigated by treatment area or connectivity. Dispersal is negatively density dependent in D. spectabilis, and we hypothesize that high gene flow may occur early in the restoration trajectory when density is low. Our study shows genetic diversity can be recovered more rapidly than demographic components of populations after habitat restoration and that founder effects are not inevitable for animals colonizing restored habitat in fragmented landscapes. PMID- 26577600 TI - Molecular cloning and expression of a GABA receptor subunit from the crayfish Procambarus clarkii. AB - Molecular cloning has introduced an unexpected, large diversity of neurotransmitter hetero- oligomeric receptors. Extensive research on the molecular structure of the gamma-aminobutyric acid receptor (GABAR) has been of great significance for understanding how the nervous system works in both vertebrates and invertebrates. However, only two examples of functional homo oligomeric GABA-activated Cl(-) channels have been reported. In the vertebrate retina, the GABArho1 subunit of various species forms homo-oligomeric receptors; in invertebrates, a cDNA encoding a functional GABA-activated Cl(-) channel has been isolated from a Drosophila melanogaster head cDNA library. When expressed in Xenopus laevis oocytes, these subunits function efficiently as a homo-oligomeric complex. To investigate the structure-function of GABA channels from the crayfish Procambarus clarkii, we cloned a subunit and expressed it in human embryonic kidney cells. Electrophysiological recordings show that this subunit forms a homo oligomeric ionotropic GABAR that gates a bicuculline-insensitive Cl(-) current. The order of potency of the agonists was GABA > trans-4-amino-crotonic acid = cis 4-aminocrotonic acid > muscimol. These data support the notion that X-organ sinus gland neurons express at least two GABA subunits responsible for the formation of hetero-oligomeric and homo-oligomeric receptors. In addition, by in situ hybridization studies we demonstrate that most X-organ neurons from crayfish eyestalk express the isolated pcGABAA beta subunit. This study increases the knowledge of the genetics of the crayfish, furthers the understanding of this important neurotransmitter receptor family, and provides insight into the evolution of these genes among vertebrates and invertebrates. PMID- 26577601 TI - Development and application of a UPLC-MS/MS method for simultaneous determination of fenofibric acid and berberine in rat plasma: application to the drug-drug pharmacokinetic interaction study of fenofibrate combined with berberine after oral administration in rats. AB - With the purpose of carrying out pharmacokinetic interaction studies ofnberberine (BBR) and fenofibrate (FBT), an UPLC-MS/MS method has been developed and validated. The analytes, BBR and fenofibric acid (FBA, metabolite of FBT) and the internal standard, tetrahydropalmatine, were extracted with dichloromethane diethyl ether (3:2, v/v) and separated on an Agilent Eclipse XDB C18 column using a mobile phase composed of acetonitrile and water. With positive ion electrospray ionization, the analytes were monitored on a triple quadrupole mass spectrometer in multiple reaction monitoring mode. Linear calibration curves were obtained over the concentration ranges of 0.1-100.0 ng/mL for BBR and 10.0-50,000.0 ng/mL for FBA. For BBR and FBA, the intra- and inter-day precisions were <11.5 and 11.9%, respectively. The accuracy was within 11.7% and 11.3%. The mean recoveries of BBR at three concentrations of 0.2, 20.0, 80.0 ng/mL were >85.6%, and those of FBA at three concentrations of 20.0, 2500.0, 40,000.0 ng/mL were >87.9%. Consequently, the proposed method was applied to the pharmacokinetic interaction study of FBT combined with BBR after oral administration in rats and was proved to be sensitive, specific and reliable to analyze BBR and FBA in biological samples simultaneously. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26577602 TI - Lipoteichoic acid of Streptococcus oralis Uo5: a novel biochemical structure comprising an unusual phosphorylcholine substitution pattern compared to Streptococcus pneumoniae. AB - Members of the Mitis group of streptococci possess teichoic acids (TAs) as integral components of their cell wall that are unique among Gram-positive bacteria. Both, lipoteichoic (LTA) and wall teichoic acid, are formed by the same biosynthetic pathway, are of high complexity and contain phosphorylcholine (P Cho) residues. These residues serve as anchors for choline-binding proteins (CBPs), some of which have been identified as virulence factors of the human pathogen Streptococcus pneumoniae. We investigated the LTA structure of its close relative Streptococcus oralis. Our analysis revealed that S. oralis Uo5 LTA has an overall architecture similar to pneumococcal LTA (pnLTA) and can be considered as a subtype of type IV LTA. Its structural complexity is even higher than that of pnLTA and its composition differs in number and type of carbohydrate moieties, inter-residue connectivities and especially the P-Cho substitution pattern. Here, we report the occurrence of a saccharide moiety substituted with two P-Cho residues, which is unique as yet in bacterial derived surface carbohydrates. Finally, we could link the observed important structural variations between S. oralis and S. pneumoniae LTA to the divergent enzymatic repertoire for their TA biosynthesis. PMID- 26577603 TI - Automated segmentation of the canine corpus callosum for the measurement of diffusion tensor imaging. AB - The goal of this study was to apply image registration-based automated segmentation methods to measure diffusion tensor imaging (DTI) metrics within the canine brain. Specifically, we hypothesized that this method could measure DTI metrics within the canine brain with greater reproducibility than with hand-drawn region of interest (ROI) methods. We performed high-resolution post-mortem DTI imaging on two canine brains on a 7 T MR scanner. We designated the two brains as brain 1 and brain 2. We measured DTI metrics within the corpus callosum of brain 1 using a hand-drawn ROI method and an automated segmentation method in which ROIs from brain 2 were transformed into the space of brain 1. We repeated both methods in order to measure their reliability. Mean differences between the two sets of hand-drawn ROIs ranged from 4% to 10%. Mean differences between the hand drawn ROIs and the automated ROIs were less than 3%. The mean differences between the first and second automated ROIs were all less than 0.25%. Our findings indicate that the image registration-based automated segmentation method was clearly the more reproducible method. These results provide the groundwork for using image registration-based automated segmentation methods to measure DTI metrics within the canine brain. Such methods will facilitate the study of white matter pathology in canine models of neurologic disease. PMID- 26577604 TI - Partial characterization of an extracellular polysaccharide produced by the moderately halophilic bacterium Halomonas xianhensis SUR308. AB - A moderately halophilic bacterium, Halomonas xianhensis SUR308 (Genbank Accession No. KJ933394) was isolated from a multi-pond solar saltern at Surala, Ganjam district, Odisha, India. The isolate produced a significant amount (7.87 g l(-1)) of extracellular polysaccharides (EPS) when grown in malt extract-yeast extract medium supplemented with 2.5% NaCl, 0.5% casein hydrolysate and 3% glucose. The EPS was isolated and purified following the conventional method of precipitation and dialysis. Chromatographic analysis (paper, GC and GC-MS) of the hydrolyzed EPS confirmed its heteropolymeric nature and showed that it is composed mainly of glucose (45.74 mol%), galactose (33.67 mol %) and mannose (17.83 mol%). Fourier transform infrared spectroscopy indicated the presence of methylene and carboxyl groups as characteristic functional groups. In addition, its proton nuclear magnetic resonance spectrum revealed functional groups specific for extracellular polysaccharides. X-ray diffraction analysis revealed the amorphous nature (CIxrd, 0.56) of the EPS. It was thermostable up to 250 degrees C and displayed pseudoplastic rheology and remarkable stability against pH and salts. These unique properties of the EPS produced by H. xianhensis indicate its potential to act as an agent for detoxification, emulsification and diverse biological activities. PMID- 26577605 TI - Mast cells: new therapeutic target in helminth immune modulation. AB - Helminth infection and their secreted antigens have a protective role in many immune-mediated inflammatory disorders such as inflammatory bowel disease, rheumatoid arthritis and multiple sclerosis. However, studies have focused primarily on identifying immune protective mechanisms of helminth infection and their secreted molecules on dendritic cells and macrophages. Given that mast cells have been shown to be implicated in the pathogenesis and progression of many inflammatory disorders, their role should also be examined and considered as cellular target for helminth-based therapies. As there is a dearth of studies examining the interaction of helminth-derived antigens and mast cells, this review will focus on the role of mast cells during helminth infection and examine our current understanding of the involvement of mast cells in TH 1/TH 17-mediated immune disorders. In this context, potential mechanisms by which helminths could target the TH 1/TH 17 promoting properties of mast cells can be identified to unveil novel therapeutic mast cell driven targets in combating these inflammatory disorders. PMID- 26577606 TI - Role for Daple in non-canonical Wnt signaling during gastric cancer invasion and metastasis. AB - In gastric cancer, the non-canonical Wnt signaling pathway is activated by Wnt5a, which has a critical role in disease outcome. Previous studies have shown that Wnt5a mediates the expression of the extracellular matrix protein laminin gamma2 through Rac and JNK activation to promote gastric cancer progression. However, the mechanism of this regulatory pathway has not been completely addressed. The scaffold protein Dvl is a major component of the Wnt signaling pathway. Here, we show that Dvl-associating protein with a high frequency of leucine residues (Daple) mediates Wnt5a-induced laminin gamma2 expression. Immunohistochemical analysis showed marked expression of Daple in advanced clinical stages of gastric cancer, where it highly correlated with Wnt5a/b and laminin gamma2 expression, the depth of wall invasion, and the frequency of lymph node metastasis. In cultured cancer cells, Daple depletion led to the suppression of Wnt5a-induced Rac and JNK activation, laminin gamma2 expression, and cell migration and invasion. Accordingly, Daple depletion also suppressed liver metastasis in a mouse xenograft model of gastric cancer. These results suggest that the non canonical Wnt signaling pathway contributes to gastric cancer progression at least in part via Daple, which provides a new therapeutic opportunity for the treatment of the disease. PMID- 26577607 TI - Pleuroparenchymal fibroelastosis: role of high-resolution computed tomography (HRCT) and CT-guided transthoracic core lung biopsy. AB - OBJECTIVES: Pleuroparenchymal fibroelastosis (PPFE) is a rare idiopathic interstitial pneumonia (IIP) with variable clinical and radiological features. Diagnosis is based on histology obtained by surgical lung biopsy, which is associated with significant mortality and morbidity. This study aims to briefly review PPFE and discuss the role of CT-guided transthoracic core lung biopsy (TTB) in its diagnosis. MATERIALS/METHODS: Four cases of PPFE diagnosed at our institution with TTB are reported and discussed. RESULTS: Clinical, radiological and histological features are in agreement with the previous literature cases. TTB provided the diagnosis in all cases. Iatrogenic pneumothorax was the main complication in all patients. Placement of a chest tube was needed in three patients. An overlap between PPFE and other interstitial lung diseases (ILD) was documented. CONCLUSION: PPFE is an underdiagnosed IIP, so radiologist awareness of it needs to be widespread in patients with fibrosis with apical-caudal distribution. Coexistence of different lung diseases strengthens the idea of a predisposing factor. TTB proved to be a good diagnostic tool and can be considered the first choice for invasive assessment of these patients. PFFE has a variable course with no established therapeutic options; therefore a multidisciplinary team is crucial in the approach to patients with ILD. MAIN MESSAGES/TEACHING POINTS: * PPFE should be considered in the differential diagnosis of fibrosis with apical-caudal distribution. * CT-guided TTB can be considered the first choice for invasive assessment of PPFE. * Site of biopsy has to be chosen carefully in order not to miss PPFE. * Coexistence of different lung diseases strengthens the idea of a predisposing factor. * A multidisciplinary team is crucial in the approach to patients with ILD. PMID- 26577609 TI - BSA-conjugated zinc oxide nanoparticles as luminescent probes for the determination of histidine. AB - Zinc oxide nanoparticles doped with bovine serum albumin were used to determine histidine in aqueous solutions using a fluorescence spectroscopic technique. The results showed that histidine effectively quenched the fluorescence of the modified ZnO nanoparticles, whereas other amino acids did not significantly affect the light emission, thereby allowing selective and sensitive histidine detection in amino acid mixtures. Under optimal conditions (pH 7.0, 25 degrees C, 10 min preincubation), the detection limit for histidine was ~ 9.87 * 10(-7) mol/L. The high value of the determined quenching rate constant Kq (3.30 * 10(13) L/mol/s) was consistent with a static quenching mechanism. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26577608 TI - Cadmium-induced and trans-generational changes in the cultivable and total seed endophytic community of Arabidopsis thaliana. AB - Trans-generational adaptation is important to respond rapidly to environmental challenges and increase overall plant fitness. Besides well-known mechanisms such as epigenetic modifications, vertically transmitted endophytic bacteria might contribute to this process. The cultivable and total endophytic communities of several generations of Arabidopsis thaliana seeds harvested from plants exposed to cadmium (Cd) or not exposed were investigated. The diversity and richness of the seed endophytic community decreased with an increasing number of generations. Aeromicrobium and Pseudonocardia were identified as indicator species in seeds from Cd-exposed plants, while Rhizobium was abundantly present in both seed types. Remarkably, Rhizobium was the only genus that was consistently detected in seeds of all generations, which suggests that the phenotypic characteristics were more important as selection criteria for which bacteria are transferred to the next plant generation than the actual genera. Production of IAA was an important trait for endophytes from both seed types, while ACC deaminase activity and Cd tolerance were mainly associated with seed endophytes from Cd-exposed plants. Understanding how different factors influence the seed endophytic community can help us to improve seed quality and plant growth through different biotechnological applications. PMID- 26577610 TI - Discovery of a sexual cycle in Talaromyces amestolkiae. AB - Talaromyces amestolkiae is a common cosmopolitan species that has been cultured from indoor house dust, sputum and lungs from cystic fibrosis patients, indoor air, wheat, soil, pineapple, sculptures and manure. It was described as an asexual Talaromyces species and was reported to produce black sclerotia. In this study we report on the induction of sexual reproductive structures in T. amestolkiae. The mating type of 18 T. amestolkiae strains was determined with MAT specific primers. Subsequently opposite mating types were inoculated on oatmeal agar and malt-extract agar and incubated 6-20 wk at 25 and 30 C in darkness. After incubation single ascospore isolations were made and evidence of recombination in the offspring was examined by amplified fragment length polymorphism and pairwise homoplasy index test, which is implemented in Splitstree4. The offspring displayed clear evidence of recombination on a genetic level as shown in the variations observed between banding patterns in the amplified fragment length polymorphism. Also a net-like and reticulated NeighborNet was observed and the pairwise homoplasy index test for recombination supported the presence of recombination (P = 0.003372). The distribution of MAT1 1 and MAT1-2 genes in the progeny showed a close to 1:1 ratio. Talaromyces amestolkiae is only the second heterothallic Talaromyces species to produce ascomata and ascospores under laboratory conditions. PMID- 26577611 TI - Two new hyaline-ascospored species of Trichoderma and their phylogenetic positions. AB - Collections of hypocrealean fungi found on decaying wood in subtropical regions of China were examined. Two new species, Trichoderma confluens and T. hubeiense, were discovered and are described. Trichoderma confluens is characterized by its widely effuse to rarely pulvinate, yellow stromata with densely disposed yellowish brown ostioles, simple acremonium- to verticillium-like conidiophores, hyaline conidia and multiform chlamydospores. Trichoderma hubeiense has pulvinate, grayish yellow stromata with brownish ostioles, trichoderma- to verticillium-like conidiophores and hyaline conidia. The phylogenetic positions of the two fungi were investigated based on sequence analyses of RNA polymerase II subunit b and translation elongation factor 1-alpha genes. The results indicate that T. confluens belongs to the Hypocreanum clade and is associated with but clearly separated from T. applanatum and T. decipiens. Trichoderma hubeiense belongs to the Polysporum clade and related to T. bavaricum but obviously differs from other members of the clade in sequence data. Morphological distinctions between the new species and their close relatives are noted and discussed. PMID- 26577612 TI - From one to six: unrecognized species diversity in the genus Acantholichen (lichenized Basidiomycota: Hygrophoraceae). AB - We present a taxonomic revision of the lichenized basidiomycete genus Acantholichen, species of which produce a characteristic blue-gray, microsquamulose thallus with spiny apical hyphal cells known as acanthohyphidia. Since its discovery, the genus was thought to be monospecific, only including the generic type, A. pannarioides. However, a detailed morphological and anatomical study of recently collected specimens from the Galapagos, Costa Rica, Brazil and Colombia, combined with a molecular phylogenetic analysis of the internal transcribed spacer (ITS1-5.8S-ITS2) region and 28S of the nuc rDNA and RPB2 sequences, revealed a much more diverse and widespread species assemblage. Based on the results of these analyses, we describe five new species in the genus: A. albomarginatus, A. campestris, A. galapagoensis, A. sorediatus and A. variabilis. We also provide an identification key to all species, anatomical and morphological descriptions, photographs and a table comparing main characters of each species. PMID- 26577613 TI - Xerotolerant fungi in house dust: taxonomy of Spiromastix, Pseudospiromastix and Sigleria gen. nov. in Spiromastigaceae (Onygenales, Eurotiomycetes). AB - During a global investigation of fungi in house dust, we isolated six novel arthroconidial fungi. Phylogenies from combined analysis of nuc rDNA 18S, 28S and internal transcribed spacers sequences demonstrated that these fungi and two species preserved in culture collections represent undescribed species of Spiromastigaceae, Onygenales. Seven of the eight species lacked sexual states and only characters of asexual states and growth rates on different media could be used to characterize them. The eighth species produced ascomata only on water agar. We introduce six new species and one new combination in Spiromastix and validate the recently proposed family Spiromastigaceae, genus Pseudospiromastix and combination Ps. tentaculata. The new genus Sigleria is proposed for two new species that differ from Spiromastix by conidiophore branching patterns, slower growth and a limited ability to utilize nitrate as a sole N source. A key to the three genera of Spiromastigaceae, Spiromastix, Pseudospiromastix and Sigleria, is provided. Phylogenetic analyses support the placement of Spiromastigaceae within Onygenales. PMID- 26577616 TI - Delayed Response to Cardiac Resynchronization: Better Late Than Never. PMID- 26577615 TI - Paradoxical Vessel Remodeling of the Proximal Segment of the Left Anterior Descending Artery Predicts Long-Term Mortality After Heart Transplantation. AB - OBJECTIVES: This study investigated the association between arterial remodeling and geographic distribution of cardiac allograft vasculopathy (CAV), and outcomes after heart transplantation. BACKGROUND: CAV is characterized by a combination of coronary intimal thickening and pathological vessel remodeling, which varies at different locations in coronary arteries. METHODS: In 100 transplant recipients, serial volumetric intravascular ultrasonography (IVUS) was performed at baseline and 1 year post-transplantation in the first 50 mm of the left anterior descending artery (LAD). IVUS indices were evaluated in the entire segment and 3 equally divided LAD segments. Paradoxical vessel remodeling was defined as [Deltavessel volume/Deltaintimal volume <0]. RESULTS: After 1 year, death or re transplantation occurred in 20 patients over a median follow-up period of 4.7 years. Paradoxical vessel remodeling was observed in 57%, 41%, 50%, and 40% for the entire vessel, proximal, middle, and distal LAD segments, respectively. Kaplan-Meier analysis revealed a significantly lower event-free rate of survival in patients with paradoxical vessel remodeling involving the proximal LAD segment, which was not present when involving the entire LAD or mid and distal LAD segments. In multivariate analysis, paradoxical vessel remodeling of the proximal LAD segment was independently associated with death or re transplantation (hazard ratio [HR]: 11.18; 95% confidence interval [CI]: 2.39 to 83.23; p = 0.0015). CONCLUSIONS: Despite the diffuse nature of CAV, paradoxical vessel remodeling of the proximal LAD segment at 1 year was the primary determinant of long-term mortality or re-transplantation. Assessment of arterial remodeling combined with coronary intimal thickening may enhance identification of high-risk patients who may benefit from closer follow-up and targeted medical therapies. PMID- 26577614 TI - Mechanisms of body weight reduction and metabolic syndrome alleviation by tea. AB - Tea, a popular beverage made from leaves of the plant Camellia sinensis, has been shown to reduce body weight, alleviate metabolic syndrome, and prevent diabetes and cardiovascular diseases in animal models and humans. Such beneficial effects have generally been observed in most human studies when the level of tea consumption was three to four cups (600-900 mg tea catechins) or more per day. Green tea is more effective than black tea. In spite of numerous studies, the fundamental mechanisms for these actions still remain unclear. From a review of the literature, we propose that the two major mechanisms are: (i) decreasing absorption of lipids and proteins by tea constituents in the intestine, thus reducing calorie intake; and (ii) activating AMP-activated protein kinase by tea polyphenols that are bioavailable in the liver, skeletal muscle, and adipose tissues. The relative importance of these two mechanisms depends on the types of tea and diet consumed by individuals. The activated AMP-activated protein kinase would decrease gluconeogenesis and fatty acid synthesis and increase catabolism, leading to body weight reduction and metabolic syndrome alleviation. Other mechanisms and the health relevance of these beneficial effects of tea consumption remain to be further investigated. PMID- 26577617 TI - Outcomes of Multiple Listing for Adult Heart Transplantation in the United States: Analysis of OPTN Data From 2000 to 2013. AB - OBJECTIVES: This study sought to assess the association of multiple listing with waitlist outcomes and post-heart transplant (HT) survival. BACKGROUND: HT candidates in the United States may register at multiple centers. Not all candidates have the resources and mobility needed for multiple listing; thus this policy may advantage wealthier and less sick patients. METHODS: We identified 33,928 adult candidates for a first single-organ HT between January 1, 2000 and December 31, 2013 in the Organ Procurement and Transplantation Network database. RESULTS: We identified 679 multiple-listed (ML) candidates (2.0%) who were younger (median age, 53 years [interquartile range (IQR): 43 to 60 years] vs. 55 years [IQR: 45 to 61 years]; p < 0.0001), more often white (76.4% vs. 70.7%; p = 0.0010) and privately insured (65.5% vs. 56.3%; p < 0.0001), and lived in zip codes with higher median incomes (US$90,153 [IQR: US$25,471 to US$253,831] vs. US$68,986 [IQR: US$19,471 to US$219,702]; p = 0.0015). Likelihood of ML increased with the primary center's median waiting time. ML candidates had lower initial priority (39.0% 1A or 1B vs. 55.1%; p < 0.0001) and predicted 90-day waitlist mortality (2.9% [IQR: 2.3% to 4.7%] vs. 3.6% [IQR: 2.3% to 6.0]%; p < 0.0001), but were frequently upgraded at secondary centers (58.2% 1A/1B; p < 0.0001 vs. ML primary listing). ML candidates had a higher HT rate (74.4% vs. 70.2%; p = 0.0196) and lower waitlist mortality (8.1% vs. 12.2%; p = 0.0011). Compared with a propensity-matched cohort, the relative ML HT rate was 3.02 (95% confidence interval: 2.59 to 3.52; p < 0.0001). There were no post-HT survival differences. CONCLUSIONS: Multiple listing is a rational response to organ shortage but may advantage patients with the means to participate rather than the most medically needy. The multiple-listing policy should be overturned. PMID- 26577618 TI - Pre-Operative Right Ventricular Dysfunction Is Associated With Gastrointestinal Bleeding in Patients Supported With Continuous-Flow Left Ventricular Assist Devices. AB - OBJECTIVES: This study sought to determine whether severe right ventricular (RV) dysfunction in the pre-operative setting is associated with an increased risk of gastrointestinal bleeding (GIB) post-left ventricular assist device (LVAD). BACKGROUND: GIB is a significant complication in patients supported with continuous-flow LVADs. The impact of RV dysfunction on the risk of GIB has not been investigated. METHODS: We retrospectively identified 212 patients who survived index hospitalization after implantation of HeartMate II (Thoratec Corp., Pleasanton, California) or Heartware HVAD (HeartWare Corp., Framingham, Massachusetts) from June 2009 to April 2013. Patients with severe RV dysfunction on pre-LVAD echocardiogram (n = 37) were compared to patients without severe RV dysfunction (n = 175). The primary outcome was freedom from GIB. RESULTS: The majority of patients were male (79%) with a median INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) profile of 2 at LVAD implantation. There were no significant differences between cohorts with respect to demographics, comorbidities, device type, international normalization ratio, or aspirin strategy. During follow-up, 81 patients had GIB events: 23 of 37 (62%) in the severe RV dysfunction group versus 58 of 175 (33%) in the control group (p = 0.001). After adjustment for age and ischemic cardiomyopathy, severe RV dysfunction was associated with increased risk of GIB (hazard ratio: 1.799, 95% confidence interval: 1.089 to 2.973, p = 0.022). CONCLUSIONS: In this single center sample of patients supported with continuous-flow LVADs, severe RV dysfunction on pre-LVAD echocardiogram was associated with an increased risk of GIB. Further studies are needed to investigate possible mechanisms by which RV dysfunction increases the risk of GIB and to identify patient populations who may benefit from alterations in antithrombotic strategies. PMID- 26577619 TI - Long-Term Echocardiographic Response to Cardiac Resynchronization Therapy in Initial Nonresponders. AB - OBJECTIVES: The aim of this study was to investigate the frequency and clinical implications of a delayed echocardiographic response to cardiac resynchronization therapy (CRT). BACKGROUND: Long-term prognosis for CRT patients is routinely based on the assessment of echocardiograms after 6 to 12 months of therapy. Some patients, however, may require a longer period of therapy before echocardiographic improvements are detectable. METHODS: This observational study included all patients with heart failure (HF) receiving a CRT device at a single center from 2003 to 2011. Eligible patients met current indications and had technically adequate echocardiograms from before implantation, approximately 1 year after implantation (mid-term), and >=3 years after implantation (long-term). A positive echocardiographic response to CRT was defined as a reduction in left ventricular end-systolic volume >=15%. All-cause mortality was compared for patients in 3 response groups: mid-term responders, long-term responders, and nonresponders. RESULTS: During this study, 294 patients met the study criteria. Of the 120 patients who were nonresponders after 1 year, 52 (43%) experienced a delayed positive response. Delayed, long-term responders had mortality and hospitalization rates similar to mid-term responders and significantly lower than nonresponders. CONCLUSIONS: Among patients surviving at least 3 years after implantation of a CRT device and with echocardiographic follow-up, a significant portion of nonresponders after 1 year of CRT experience a delayed echocardiographic response after a longer period of time. Survival and hospitalization rates were similar for all echocardiographic responders, regardless of the time at which the response occurred. PMID- 26577620 TI - The Changing Face of First-Year Intravascular Ultrasonography in Heart Transplantation. PMID- 26577621 TI - Modulation of Thrombosis Significantly Reduces Testicular Damage after Testicular Torsion in Rats: Anti-Thrombotic Treatment and Testicular Torsion. AB - OBJECTIVE: To evaluate the effects of thrombolysis and/or anticoagulation on testicular viability after testicular tortion (TT) was the aim of this study. It has been suggested that alterations of circulation during TT result in thrombus formation that might prevent sufficient perfusion after detorsion. Due to the narrow safety margin of testicular perfusion, even moderate disturbances in blood supply can cause major testicular damage. METHODS: In 112 rats, the right testicle was torsed for 3 or 6 hours. After detorsion and randomization, they received either enoxaparin, alteplase, both, or placebo, according to their subgroup. Thrombus formation was accessed via D-dimers, pDNA, oxidative testicular damage was evaluated via glutathione peroxidase and malondialdehyde, and cellular damage via inhibin B, testosterone, histological analysis (Johnsen score, Cosetino grading), and TUNEL assay. RESULTS: One hundred and twelve rats were included in the study. The treatment with alteplase or enoxaparin showed significantly less testicular damage and significantly improved Sertoli cell function. Enoxaparin significantly reduced oxidative impairment. CONCLUSION: The results of the study indicate that TT induces thrombus formation and demonstrate that modulation of thrombosis significantly ameliorates testicular damage in rats. Hence, this treatment option after TT ought to be evaluated in humans. PMID- 26577622 TI - Long-term Outcome of Ileal Ureteric Replacement With an Iliopsoas Muscle Tunnel Antirefluxing Technique for the Treatment of Long-segment Ureteric Strictures. AB - OBJECTIVE: To investigate the long-term outcome of ileal ureteric replacement using a proximal antirefluxing technique for the treatment of long-segment ureteric strictures. PATIENTS AND METHODS: Between January 1997 and December 2013, 41 patients with a long ureteral stricture or defect and 3 patients with unilateral mid-lower ureteral cancer (20 bilateral and 24 unilateral, 28 males and 16 females) were treated by ureteral substitution using a proximal antirefluxing technique. The distal part of the upper ureter (4 cm) was fixed between the psoas muscle and the ileal segment (the iliopsoas tunnel technique). The distal ileum was connected to the urinary bladder with an end-to-side anastomosis. A successful outcome was defined as the absence of major complications, worsening baseline renal function, metabolic derangements, or obstruction. RESULTS: One patient with unilateral mid-lower ureteral cancer died 3 years postoperatively because of metastasis, and the remaining 43 patients were followed for 12-180 months (mean 69 months). Intravenous urography showed that the hydronephrosis improved significantly or disappeared after 6-12 months in 34 patients, with improvement in 9 patients. Cystography showed no evidence of ileoureteral reflux. Seven patients needed long-term oral alkalization to prevent hyperchloremic acidosis. CONCLUSION: In our experience, outcomes following subtotal ureteric replacement are encouraging. The ileal ureter replacement by the proximal antirefluxing technique appears to be a reliable procedure for treating long-segment ureteral stricture and preservation of renal function. PMID- 26577624 TI - Big Data and Analytics in Healthcare. AB - This editorial is part of the Focus Theme of Methods of Information in Medicine on "Big Data and Analytics in Healthcare". The amount of data being generated in the healthcare industry is growing at a rapid rate. This has generated immense interest in leveraging the availability of healthcare data (and "big data") to improve health outcomes and reduce costs. However, the nature of healthcare data, and especially big data, presents unique challenges in processing and analyzing big data in healthcare. This Focus Theme aims to disseminate some novel approaches to address these challenges. More specifically, approaches ranging from efficient methods of processing large clinical data to predictive models that could generate better predictions from healthcare data are presented. PMID- 26577623 TI - A comparison between laparoscopic and retroperitoneoscopic approach for partial nephrectomy in children with duplex kidney: a multicentric survey. AB - PURPOSE: To compare the outcome of laparoscopic and retroperitoneoscopic approach for partial nephrectomy in infants and children with duplex kidneys. METHODS: Data of 102 patients underwent partial nephrectomy in a 5-year period using MIS procedures were analyzed. Fifty-two children underwent laparoscopic partial nephrectomy (LPN), and 50 children underwent retroperitoneoscopic partial nephrectomy (RPN). Median age at surgery was 4.2 years. Statistical analysis was performed using chi (2) test and Student's t test. RESULTS: The overall complications rate was significantly higher after RPN (15/50, 30 %) than after LPN (10/52, 19 %) [chi (2) = 0.05]. In LPN group, complications [4 urinomas, 2 symptomatic refluxing distal ureteral stumps (RDUS) and 4 urinary leakages] were conservatively managed. In RPN group, complications (6 urinomas, 8 RDUS, 1 opening of remaining calyxes) required a re-operation in 2 patients. In both groups no conversion to open surgery was reported. Operative time (LPN:166.2 min vs RPN: 255 min; p < 0.001) and hospitalization (LPN: 3.5 days vs RPN: 4.1 days; p < 0.001) were significantly shorter in LPN group. No postoperative loss of renal function was reported in both groups. CONCLUSIONS: Our results demonstrate that RPN remains a technically demanding procedure with a significantly higher complications and re-operation rate compared to LPN. In addition, length of surgery and hospitalization were significantly shorter after LPN compared to RPN. LPN seems to be a faster, safer and technically easier procedure to perform in children compared to RPN due to a larger operative space and the possibility to perform a complete ureterectomy in refluxing systems. PMID- 26577625 TI - Gait Variability Related to Muscle Quality and Muscle Power Output in Frail Nonagenarian Older Adults. AB - BACKGROUND: Frailty has become the center of attention of basic, clinical, and demographic research because of its incidence level and the gravity of adverse outcomes with age. Moreover, with advanced age, motor variability increases, particularly in gait. Muscle quality and muscle power seem to be closely associated with performance on functional tests in frail populations. Insight into the relationships among muscle power, muscle quality, and functional capacity could improve the quality of life in this population. In this study, the relationship between the quality of the muscle mass and muscle strength with gait performance in a frail population was examined. METHODS: Twenty-two institutionalized frail elderly individuals (93.1 +/- 3.6) participated in this study. Muscle quality was measured by segmenting areas of high- and low-density fibers as observed in computed tomography images. The assessed functional outcomes were leg strength and power, velocity of gait, and kinematic gait parameters obtained from a tri-axial inertial sensor. FINDINGS: Our results showed that a greater number of high-density fibers, specifically those of the quadriceps femoris muscle, were associated with better gait performance in terms of step time variability, regularity, and symmetry. Additionally, gait variability was associated with muscle power. In contrast, no significant relationship was observed between gait velocity and either muscle quality or muscle power. INTERPRETATION: Gait pattern disorders could be explained by a deterioration of the lower limb muscles. It is known that an impaired gait is an important predictor of falls in older populations; thus, the loss of muscle quality and power could underlie the impairments in motor control and balance that lead to falls and adverse outcomes. PMID- 26577626 TI - Hirayama disease. PMID- 26577627 TI - Barriers of influenza vaccination in health care personnel in France. AB - To identify barriers against influenza vaccination of health care personnel in Northern France, a cross-sectional study was conducted in health care facilities. A total of 3,213 questionnaires from 67 health care facilities were completed. In multivariate analysis using a logistic model, influenza vaccine coverage in health care personnel was significantly associated with level of knowledge about influenza disease and vaccine. PMID- 26577628 TI - Influence of biological fluids in bacterial viability on different hospital surfaces and fomites. AB - BACKGROUND: The hospital environment is susceptible to bacterial contamination along with survival in fomites and surfaces, allowing dissemination of potential pathogenic strains. The present research aimed to evaluate the influence of biological fluids in bacterial viability on fomites and surfaces commonly present in nosocomial environment. METHODS: Four different fomites and surfaces (ceramic floor, cotton fabric fragments and synthetic fibers, and eggcrate foam mattress) were contaminated with potential pathogens (Staphylococcus aureus, Escherichia coli, Enterococcus faecalis, Pseudomonas aeruginosa, and Klebsiella pneumoniae), then submitted to influence of biological fluids (blood, urine, artificial saliva). The viability of strains was evaluated at 24 hours after contamination and then in intervals of 7 days, by the colony-forming unit count technique. RESULTS: S aureus presented viability (>70 days) in all conditions tested, E faecalis and K pneumoniae had decreased viability over time, and E coli did not exhibit a growth relationship with surfaces or fluids. Persistence and adaptability capacity of potential pathogens in fomites and surfaces exposed to the patient are important for guidance, planning, and outlining of protocols for microorganism dissemination control and prevention in the health care environment. PMID- 26577629 TI - The daily risk of bacteremia during hospitalization and associated 30-day mortality evaluated in relation to the traditional classification of bacteremia. AB - BACKGROUND: We investigated the overall and daily incidence of bacteremia among hospitalized patients and evaluated the traditional classification of bacteremia (community-onset vs nosocomial based on a 48-hour time window) by means of the daily incidence and associated 30-day mortality. METHODS: In a multicenter hospital-based cohort study, we included all patients aged 15 years or older admitted to hospitals in Funen County, Denmark, during 2000-2008, and identified all first bacteremias per admission. We calculated the overall incidence of bacteremia per 1,000 admissions and 10,000 bed-days, as well as the daily incidence of bacteremia per 10,000 bed-days and associated 30-day mortality. RESULTS: We included 724,339 admissions and 10,281 bacteremias for an overall incidence of 14.2 per 1,000 admissions and 23.6 per 10,000 bed-days. The daily incidence was highest on the first 2 days of admission followed by lower incidences that were constant beyond day 12, but varied according to patient and epidemiologic characteristics. Thirty-day mortality for patients with bacteremia was 18% on day 1, 21% on day 2, and between 25% and 35% thereafter. CONCLUSIONS: Hospitalized patients were at the highest risk of bacteremia during the first 2 days followed by lower incidences that were constant beyond day 12. Thirty-day mortality was 18%-21% for patients with bacteremia on the first 2 days and 25% 35% thereafter. Our findings support the traditional classification of bacteremia. PMID- 26577630 TI - Concocting that Magic Elixir: Successful Grant Application Writing in Dissemination and Implementation Research. AB - BACKGROUND: This paper reports core competencies for dissemination and implementation (D&I) grant application writing and provides tips for writing a successful proposal. METHODS: Two related phases were used to collect the data: a card sorting process among D&I researchers and an expert review among a smaller set of researchers. Card sorting was completed by 123 respondents. In the second phase, a series of grant application writing tips were developed based on the combined 170 years of grant review experience of the writing team. RESULTS: The card sorting resulted in 12 core competencies for D&I grant application writing that covered the main sections in a grant application to the US National Institutes of Health: (a) specific aims that provide clear rationale, objectives, and an overview of the research plan; (b) significance that frames and justifies the importance of a D&I question; (c) innovation that articulates novel products and new knowledge; and (d) approach that uses a relevant D&I model, addresses measurement and the D&I context, and includes an analysis plan well-tied to the aims and measures. CONCLUSIONS: Writing a successful D&I grant application is a skill that can be learned with experience and attention to the core competencies articulated in this paper. PMID- 26577631 TI - Association between serum corin levels and risk of acute myocardial infarction. AB - BACKGROUND: Accumulating evidence has indicated that corin plays critical roles in regulating salt-water balance, blood pressure and cardiac function by activating natriuretic peptides. The present case-control study was designed to evaluate the association of serum soluble corin with acute myocardial infarction (AMI). METHODS: We enrolled 856 consecutive AMI patients and 856 control subjects and explored the possible relation between serum corin levels and AMI risk using logistic regression model. RESULTS: Patients with AMI had higher BMI, were less physically active, and were more likely to have histories of hypertension, diabetes, hyperlipidemia and smoking compared with the controls. Serum levels of corin were remarkably reduced in AMI patients (825+/-263pg/ml) compared with those in healthy controls (1246+/-425pg/ml). Odds ratios of ST elevation (STEMI) and non-ST elevation myocardial infarction (NSTEMI) were significantly decreased with the increasing levels of serum corin in both men and women (P for trend, <0.001) after adjustment for body mass index, hypertension, diabetes, hyperlipidemia, smoking, and physical activity. CONCLUSIONS: Our study demonstrates that serum levels of corin are significantly decreased in AMI patients, and it is inversely associated with the incidences of STEMI and NSTEMI in both men and women. PMID- 26577633 TI - Welcome Letter. PMID- 26577632 TI - The Importance of Ethical Peer-Review: Why Do We Ask Authors to Suggest Reviewers Anyway? PMID- 26577634 TI - Abstracts of the XXI. ISCU Congress, 20-22 November, 2015, Istanbul, TURKEY. PMID- 26577635 TI - Twiddler's syndrome in spinal cord stimulation. AB - BACKGROUND: The aims are to present a case series of Twiddler's syndrome in spinal cord stimulators with analysis of the possible mechanism of this syndrome and discuss how this phenomenon can be prevented. METHOD: Data were collected retrospectively between 2007 and 2013 for all patients presenting with failure of spinal cord stimulators. The diagnostic criterion for Twiddler's syndrome is radiological evidence of twisting of wires in the presence of failure of spinal cord stimulation. RESULTS: Our unit implants on average 110 spinal cord stimulators a year. Over the 5-year study period, all consecutive cases of spinal cord stimulation failure were studied. Three patients with Twiddler's syndrome were identified. Presentation ranged from 4 to 228 weeks after implantation. Imaging revealed repeated rotations and twisting of the wires of the spinal cord stimulators leading to hardware failure. CONCLUSIONS: To the best of our knowledge this is the first reported series of Twiddler's syndrome with implantable pulse generators (IPGs) for spinal cord stimulation. Hardware failure is not uncommon in spinal cord stimulation. Awareness and identification of Twiddler's syndrome may help prevent its occurrence and further revisions. This may be achieved by implanting the IPG in the lumbar region subcutaneously above the belt line. Psychological intervention may have a preventative role for those who are deemed at high risk of Twiddler's syndrome from initial psychological screening. PMID- 26577636 TI - Pure endoscopic transsphenoidal surgery for functional pituitary adenomas: outcomes with Cushing's disease. AB - BACKGROUND: This study was performed to examine patient outcomes following pure endoscopic transsphenoidal surgery (ETS) for Cushing's disease (CD). METHOD: We studied 64 consecutive patients who underwent 69 endoscopic transsphenoidal procedures. Radiological evaluation comprised detailed examination of preoperative magnetic resonance images (MRI), including positron emission tomography (PET) for select cases. Inferior petrosal sinus sampling (IPSS) was not performed for any patient. Remission was defined by the presence of hypocortisolemia with requirement for steroid replacement therapy or eucortisolemia with suppression to <1.8 MUg/dl after 1 mg dexamethasone on evaluation at least 3 months after surgery. RESULTS: Preoperative MRI was abnormal in 87.5 % of cases and included 11 macroadenomas (17.2 %). PET was used to localize the adenoma in four cases. For microadenomas, operative procedures executed were as follows: selective adenomectomy (n = 15), enlarged adenomectomy (n = 21) and subtotal/hemihypophysectomy (n = 17). Overall, pathological confirmation of an adenoma was possible in 58 patients (90.6 %). Forty-nine patients (76.6 %) developed hypocortisolemia (<5 MUg/dl) in the early postoperative period. Mean follow-up was 20 months (range 6-18 months). Remission was confirmed in 79.7 % of the 59 cases followed up for >3 months and was superior for microadenomas (86.4 %) versus macroadenomas (55.6 %) and equivocal MRI adenomas (66.7 %). Postoperative CSF rhinorrhea occurred in five patients, and new endocrine deficits were noted in 17.1 % patients. A nadir postoperative cortisol <2 MUg/dl in the 1st week after surgery was highly predictive of remission (p = 0.001). CONCLUSION: ETS allows for enhanced intrasellar identification of adenomatous tissue, providing remission rates that are comparable to traditional microsurgery for CD. The best predictor of remission remains induction of profound hypocortisolemia in the early postoperative period. PMID- 26577637 TI - Neurosurgical resident education in Europe--results of a multinational survey. AB - INTRODUCTION: Neurosurgical training aims at educating future generations of specialist neurosurgeons and at providing the highest-quality medical services to patients. Attaining and maintaining these highest standards constitutes a major responsibility of academic or other training medical centers. METHODS: An electronic survey was sent to European neurosurgical residents between 06/2014 and 03/2015. Multiple logistic regression analysis was used to assess the effect size of the relationship between responder-specific variables (e.g., age, gender, postgraduate year (PGY), country) and the outcomes (e.g., satisfaction). RESULTS: A total of 652 responses were collected, of which n = 532 were taken into consideration. Eighty-five percent were 26-35 years old, 76 % male, 62 % PGY 4 or higher, and 73.5 % working at a university clinic. Satisfaction rates with theoretical education such as clinical lectures (overall: 50.2 %), anatomical lectures (31.2 %), amongst others, differed largely between the EANS member countries. Likewise, satisfaction rates with practical aspects of training such as hands-on surgical experience (overall: 73.9 %), microsurgical training (52.5 %), simulator training (13.4 %), amongst others, were highly country-dependant. In general, 89.1 % of European residents carried out the first surgical procedure under supervision within the first year of training. Supervised lumbar-/cervical spine surgeries were performed by 78.2 and 17.9 % of European residents within 12 and 24 months of training, respectively, and 54.6 % of European residents operate a cranial case within the first 36 months of training. Logistic regression analysis identified countries where residents were much more or much less likely to operate as primary surgeons compared to the European average. The caseload of craniotomies per trainee (overall: 30.6 % >=10 craniotomies/month) and spinal procedures (overall: 29.7 % >=10 spinal surgeries/month) varied throughout the countries and was significantly associated with more advanced residency (craniotomy: OR 1.35, 95 % CI 1.18-1.53, p < 0.001; spinal surgery: OR 1.37, 95 % CI 1.20-1.57, p < 0.001). CONCLUSIONS: Theoretical and practical aspects of neurosurgical training are highly variable throughout European countries, despite some efforts within the last two decades to harmonize this. Some countries are rated significantly above (and others significantly below) the current European average for several analyzed parameters. It is hoped that the results of this survey should provide the incentive as well as the opportunity for a critical analysis of the local conditions for all training centers, but especially those in countries scoring significantly below the European average. PMID- 26577638 TI - Spinal myxopapillary ependymomas: a retrospective clinical and immunohistochemical study. AB - BACKGROUND: Myxopapillary ependymoma (MPE) is a rare subtype of ependymoma that develops almost exclusively within the spinal cord. Despite its benign biological nature, MPE has a propensity to recur locally or distantly. Although variables influencing the prognosis, such as age, the extent of surgery and radiotherapy, have been widely discussed, no definitive standard has been established. Compared to other spinal tumors, many fewer histological markers have been elucidated to assist the determination of the prognosis. METHODS: Twenty-seven patients who underwent resection of MPE were enrolled. We determined their demographic features, imaging characteristics, clinical presentations and outcomes, surgical procedures and histological properties by chart review, telephone contact, reviewing of surgical notes, pre-/postoperative imaging and immunohistological staining. RESULTS: GTR (gross total resection) was achieved in 18 patients (66.7 %) and STR (subtotal resection) in 9 (33.3 %). Although GTR rendered a better disease control rate, the difference was not significant. Pediatric patients suffered from a greater risk of recurrence as well as a shorter period to disease relapse. In the majority of cases, we observed the overexpression of platelet derived growth factor receptor alpha (PDGFRalpha), matrix metalloproteinase-2 (MMP2) and matrix metalloproteinase-14 (MMP14). Epidermal growth factor receptor (EGFR) was observed in the tumors of 7 of 23 nonrecurrent patients, but not in any recurrent tumors. CONCLUSIONS: The results of the present study indicate that the extent of resection and age are major factors related to tumor recurrence. Therefore, gross total resection is recommended whenever possible unless following neurological dysfunction is predictable. Moreover, pediatric patients need considerable attention after surgery, particularly in the early stages. PDGFRalpha, MMP2 and MMP14 may be new diagnostic and therapeutic targets and EGFR a potential predictor of improved prognosis for MPE. PMID- 26577639 TI - Promising clinical outcome of elderly with TBI after modern neurointensive care. AB - BACKGROUND: The increasing number of elderly patients with traumatic brain injury (TBI) leads to specific neurointensive care (NIC) challenges. Therefore, elderly subjects with TBI need to be further studied. In this study we evaluated the demographics, management and outcome of elderly TBI patients receiving modern NIC. METHODS: Patients referred to our NIC unit between 2008 and 2010 were included. Patients were divided in two age groups, elderly (E) >=65 years and younger (Y) 64-15 years. Parameters studied were the dominant finding on CT scans, neurological motor skills and consciousness, type of monitoring, neurosurgical procedures/treatments and Glasgow Outcome Scale Extended score at 6 months after injury. RESULTS: Sixty-two E (22 %) and 222 Y (78 %) patients were included. Falls were more common in E (81 %) and vehicle accidents were more common in Y patients (37 %). Acute subdural hematoma was significantly more common in E (50 % of cases) compared to Y patients (18 %). Intracranial pressure was monitored in 44 % of E and 57 % of Y patients. Evacuation of significant mass lesions was performed more common in the E group. The NIC mortality was similar in both groups (4-6 %). Favorable outcome was observed in 72 % of Y and 51 % of E patients. At the time of follow-up 25 % of E and 7 % of Y patients had died. CONCLUSIONS: The outcome of elderly patients with TBI was significantly worse than in younger patients, as expected. However, as much as 51 % of the elderly patients showed a favorable outcome after NIC. We believe that these results encourage modern NIC in elderly patients with TBI. We need to study how secondary brain injury mechanisms differ in the older patients and to identify specific outcome predictors for elderly patients with TBI. PMID- 26577640 TI - A pathogenesis related-10 protein CaARP functions as aldo/keto reductase to scavenge cytotoxic aldehydes. AB - Pathogenesis related-10 (PR-10) proteins are present as multigene family in most of the higher plants. The role of PR-10 proteins in plant is poorly understood. A sequence analysis revealed that a large number of PR-10 proteins possess conserved motifs found in aldo/keto reductases (AKRs) of yeast and fungi. We took three PR-10 proteins, CaARP from chickpea, ABR17 from pea and the major pollen allergen Bet v1 from silver birch as examples and showed that these purified recombinant proteins possessed AKR activity using various cytotoxic aldehydes including methylglyoxal and malondialdehyde as substrates and the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) as co-factor. Essential amino acids for this catalytic activity were identified by substitution with other amino acids. CaARP was able to discriminate between the reduced and oxidized forms of NADP independently of its catalytic activity and underwent structural change upon binding with NADPH. CaARP protein was preferentially localized in cytosol. When expressed in bacteria, yeast or plant, catalytically active variants of CaARP conferred tolerance to salinity, oxidative stress or cytotoxic aldehydes. CaARP-expressing plants showed lower lipid peroxidation product content in presence or absence of stress suggesting that the protein functions as a scavenger of cytotoxic aldehydes produced by metabolism and lipid peroxidation. Our result proposes a new biochemical property of a PR-10 protein. PMID- 26577641 TI - DICER1 syndrome can mimic different genetic tumor predispositions. AB - DICER1, a RNAse endonuclease involved in the processing of siRNA and microRNA, is known to play a pivotal role in the post-transcriptional regulation of gene expression. Germ line mutations in the DICER1 gene increase the risk for different types of tumors. At present, DICER1 syndrome is an established, though not well defined, member of the group of genetic tumor predisposition syndromes. Here, we report a DICER1 syndrome family with a medical history of different rare tumors mostly occurring at a young age. The tumor spectrum in this family included both DICER1 syndrome-typical forms, such as pleuropulmonary blastoma, multinodular goiter, and cystic nephroma, and not previously reported manifestations, such as pilomatrixoma, and juvenile basal cell carcinoma. The latter tumor types are usually considered to be indicators of familial adenomatous polyposis and basal cell nevus syndrome. PMID- 26577642 TI - Psychometric validation of the Weiss Functional Impairment Rating Scale-Parent Report Form in children and adolescents with attention-deficit/hyperactivity disorder. AB - BACKGROUND: Measurement properties of the Weiss Functional Impairment Rating Scale-Parent Report Form (WFIRS-P), which assesses attention deficit/hyperactivity disorder (ADHD)-related functional impairment in children/adolescents (6-17 years), were examined. METHODS: Data from seven randomized, controlled trials were pooled. Analyses were conducted in two random half-samples. WFIRS-P conceptual framework was evaluated using confirmatory factor analyses (CFA). Reliability was estimated using internal consistency (Cronbach's alpha) and test-retest reliability methods. Convergent validity was assessed using correlations between WFIRS-P domain scores and the ADHD-RS-IV and Clinical Global Impression-Severity (CGI-S) scales. Responsiveness was tested by comparing mean changes in WFIRS-P domain scores between responders and non responders based on clinical criteria. RESULTS: CFA adequately confirmed the item to-scale relationships defined in the WFIRS-P conceptual framework. Cronbach's alpha coefficient exceeded 0.7 for all domains and test-retest reliability exceeded 0.7 for all but Risky Activities. With few exceptions, WFIRS-P domains correlated significantly (p < 0.05) with ADHD-RS-IV Total, Inattention and Hyperactivity-Impulsivity scores and CGI-S at baseline and follow-up in both random half-samples. Mean changes in WFIRS-P domain scores differed significantly between responder and non-responder groups in the expected direction (p < 0.001). CONCLUSIONS: Study results support the reliability, validity and responsiveness of the WFIRS-P. Findings were replicated between two random samples, further demonstrating the robustness of results. PMID- 26577643 TI - Biomarkers in saliva for the detection of oral squamous cell carcinoma and their potential use for early diagnosis: a systematic review. AB - Objective To determine the capacity of salivary biomarkers in the early diagnosis of oral squamous cell carcinoma. Study design A systematic review of the literature was performed based on the English titles listed in the PubMed, EBSCO, Cochrane, Science Direct, ISI web Science and SciELO databases using the following search descriptors: Oral cancer, diagnosis, biomarkers, saliva and oral squamous cell carcinoma. Abstracts and full-text articles were assessed independently by two reviewers. International checklists for assessment of methodological quality were used. Levels of evidence and grades of recommendation through the Scottish Intercollegiate Guidelines Network (SIGN) template were recognized. The units of analysis were identified through a reference matrix. Results Through the research strategy and after application of different filters and considering choosing criteria, six studies were obtained for analysis. Salivary biomarkers for oral cancer most frequently found were mRNA and proteins for IL-8, CD44, MMP-1 and MMP-3. New peptide-biomarkers such as Cyfra 21-1 and ZNF510 were found. ZNF 510 was the only biomarker which increased in the population with tumour stage T1 + T2 and T3 + T4. Only one study showed a sensitivity and specificity of 96% when the biomarker ZNF 510 is employed to discriminate early and late tumour stages. Conclusions There is no sufficient scientific evidence to support the capacity of the identified salivary biomarkers for the early diagnosis of oral cancer (sub-clinical stages of the pathogenic period before cancer phenotypes are manifested). Salivary biomarkers, however, may be employed to discriminate between healthy and cancer patients. PMID- 26577644 TI - Factors influencing the priority of access to food and their effects on the carcass traits for Japanese Black (Wagyu) cattle. AB - The factors influencing the priority of access to food and the effects of the priority of access to food on their carcass traits were analyzed for Japanese Black (Wagyu) cattle in a semi-intensive fattening production system. The records of 96 clinically healthy steers and heifers were analyzed. The calves at ~3 to 4 months of age were allocated to pens with four animals per pen; all four animals in the same pen were of the same sex and of similar body size. The ranking of the animals' priority of access to food (1st, 2nd, 3rd and 4th), which was determined by the farm manager, was used as an indicator of social dominance in the present study. Four models including sire line, maternal grandsire line and the difference in the animals' birth dates as fixed effects were used to analyze factors influencing the priority of access to food. Ranking was represented by ordinal scores (highest=4, lowest=1) in Model 1, and the binary scores were assigned in Model 2 (highest=1; 2nd, 3rd and 4th=0), Model 3 (1st and 2nd=1; 3rd and 4th=0) and Model 4 (1st, 2nd and 3rd=1; lowest=0). The results showed that the difference in the animals' birth dates had a significant effect on the establishment of the priority of access to food in Model 3 (P<0.05), suggesting that animals born earlier may become more dominant in the pen. The maternal grandsire line tended to affect the social rank score in Models 2 and 3 (P<0.10). Our results indicated that the maternal grandsire line may affect the temperament of calves through their mothers' genetic performance and thereby more aggressive calves may be more dominant and have higher priority of access to food. On the other hand, there was a significant effect of the priority of access to food on beef marbling score (BMS; P<0.05), and the priority of access to food also tended to influence the carcass weight (P=0.09). The highest BMS was observed for animals with the first rank of the priority of access to food (P<0.05), and the higher-ranking animals had the tendency to be heavier carcass than the lower ranking animals. Our findings emphasized the importance of information about the priority of access to food determined by farmers' own observation on implementing best management practices in small-scaled semi-intensive beef cattle production systems. PMID- 26577645 TI - Productivity and technical efficiency of suckler beef production systems: trends for the period 1990 to 2012. AB - Over the past 23 years (1990 to 2012), French beef cattle farms have expanded in size and increased labour productivity by over 60%, chiefly, though not exclusively, through capital intensification (labour-capital substitution) and simplifying herd feeding practices (more concentrates used). The technical efficiency of beef sector production systems, as measured by the ratio of the volume value (in constant euros) of farm output excluding aids to volume of intermediate consumption, has fallen by nearly 20% while income per worker has held stable thanks to subsidies and the labour productivity gains made. This aggregate technical efficiency of beef cattle systems is positively correlated to feed self-sufficiency, which is in turn negatively correlated to farm and herd size. While volume of farm output per hectare of agricultural area has not changed, forage feed self-sufficiency decreased by 6 percentage points. The continual increase in farm size and labour productivity has come at a cost of lower production-system efficiency - a loss of technical efficiency that 20 years of genetic, technical, technological and knowledge-driven progress has barely managed to offset. PMID- 26577646 TI - A Non-randomized Comparison of Strategies for Consultation in a Community Academic Training Program to Implement an Evidence-Based Psychotherapy. AB - Despite the central role of training and consultation in the implementation of evidence-based psychological interventions (EBPIs), comprehensive reviews of research on training have highlighted serious gaps in knowledge regarding best practices. Consultation after initial didactic training appears to be of critical importance, but there has been very little research to determine optimal consultation format or interventions. This observational study compared two consultation formats that included review of session audio and feedback in the context of a program to train clinicians (n = 85) in community mental health clinics to deliver cognitive therapy (CT). A "gold standard" condition in which clinicians received individual feedback after expert consultants reviewed full sessions was compared to a group consultation format in which short segments of session audio were reviewed by a group of clinicians and an expert consultant. After adjusting for potential baseline differences between individuals in the two consultation conditions, few differences were found in terms of successful completion of the consultation phase or in terms of competence in CT at the end of consultation or after a 2 year follow-up. However, analyses did not support hypotheses regarding non-inferiority of the group consultation condition. While both groups largely maintained competence, clinicians in the group consultation condition demonstrated increases in competence over the follow-up period, while a sub-group of those in the individual condition experienced decreases. These findings, if replicated, have important implications for EBP implementation programs, as they suggest that observation and feedback is feasible in community mental health setting, and that employing this method in a group format is an effective and efficient consultation strategy that may enhance the implementation and sustainability of evidence-based psychotherapies. PMID- 26577647 TI - Longistatin in tick-saliva targets RAGE. PMID- 26577648 TI - Coping with cancer genes altered by copy number. PMID- 26577649 TI - Erratum: Stromal androgen receptor regulates the composition of the microenvironment to influence prostate cancer outcome. PMID- 26577650 TI - The epidemiology of fatal cyclist crashes over a 14-year period in Alberta, Canada. AB - BACKGROUND: Cycling is a popular recreational activity and a common transportation option; however, cycling-related injuries can be fatal. There are few studies of cycling fatalities in Canada and none in a region as sparsely populated as Alberta. METHODS: A chart review was conducted of cyclists involved in fatal crashes. Charts for deaths that occurred between 1998 and 2011 (inclusive) were identified and abstracted onto standardized forms. Personal characteristics and crash circumstances, including motor vehicle involvement, were collected; mechanisms of fatally injured cyclists across age groups were compared. Census data were used to calculate region-specific and provincial age specific cycling fatality rates. RESULTS: Charts from 101 deaths over 14 years were reviewed. Events mainly occurred during the summer. There were more fatalities in urban (64 [63 %]) than in rural settings. Collisions with motor vehicles and cyclist-only crashes accounted for 68 and 15 % of cycling fatalities, respectively. Most (87 %) deceased cyclists were male, and the median age was 47 years (inter-quartile range: 25, 58). The population-based fatality rate over the study period was highest among deceased cyclists older than 65. Helmet use was reported in 26 (26 %) cases and increased with age. Alcohol use was detected in 25 (25 %) cases. CONCLUSIONS: Fatal cycling crashes in Alberta typically involve adults riding on urban roads and collisions with motor vehicles. While helmet legislation has reduced non-fatal cycling head injuries, deaths may be further prevented by physical separation of cyclists and motor vehicles and avoidance of substance use while operating bicycles. PMID- 26577652 TI - Structural MRI Correlates of Episodic Memory Processes in Parkinson's Disease Without Mild Cognitive Impairment. AB - BACKGROUND: Changes in episodic memory are common early in Parkinson's disease (PD) and may be a risk factor for future cognitive decline. Although medial temporal lobe (MTL) memory and frontostriatal (FS) executive systems are thought to play different roles in distinct components of episodic memory impairment in PD, no study has investigated whether different aspects of memory functioning are differentially associated with MTL and FS volumes in nondemented patients without mild cognitive impairment (PD-woMCI). OBJECTIVES: The present study investigated MRI markers of different facets of memory functioning in 48 PD-woMCI patients and 42 controls. METHODS: Regional volumes were measured in structures comprising the MTL and FS systems and then correlated with key indices of memory from the California Verbal Learning Test. RESULTS: In PD-woMCI patients, memory was impaired only for verbal learning, which was not associated with executive, attention/working memory, or visuospatial functioning. Despite an absence of cortical atrophy, smaller right MTL volumes in patients were associated with poorer verbal learning, long delayed free recall, long delayed cued recall, and recognition memory hits and false positives. Smaller right pars triangularis (inferior frontal) volumes were also associated with poorer long delayed cued recall and recognition memory hits. These relationships were not found in controls. CONCLUSIONS: The findings indicate that MTL volumes are sensitive to subtle changes in almost all facets of memory in PD-woMCI, whereas FS volumes are sensitive only to memory performances in cued-testing formats. PMID- 26577655 TI - Expression of essential genes for biosynthesis of antimicrobial peptides of Bacillus is modulated by inactivated cells of target microorganisms. AB - Certain Bacillus strains are important producers of antimicrobial peptides with great potential for biological control. Antimicrobial peptide production by Bacillus amyloliquefaciens P11 was investigated in the presence of heat inactivated cells of bacteria and fungi. B. amyloliquefaciens P11 exhibited higher antimicrobial activity in the presence of inactivated cells of Staphylococcus aureus and Aspergillus parasiticus compared to other conditions tested. Expression of essential genes related to biosynthesis of the antimicrobial peptides surfactin (sfp), iturin A (lpa-14 and ituD), subtilosin A (sboA) and fengycin (fenA) was investigated by quantitative real-time PCR (qRT PCR). The genes lpa-14 and ituD were highly expressed in the presence of S. aureus (inactivated cells), indicating induction of iturin A production by B. amyloliquefaciens P11. The other inducing condition (inactivated cells of A. parasiticus) suppressed expression of lpa-14, but increased expression of ituD. A twofold increase in fenA expression was observed for both conditions, while strong suppression of sboA expression was observed in the presence of inactivated cells of S. aureus. An increase in antimicrobial activity was observed, indicating that synthesis of antimicrobial peptides may be induced by target microorganisms. PMID- 26577653 TI - Exercise Effects on Early Vocal Ultrasonic Communication Dysfunction in a PINK1 Knockout Model of Parkinson's Disease. AB - BACKGROUND: Parkinson's disease (PD) is a complex neurodegenerative disease with vocal communication deficits that manifest early, progress, and are largely resistant to medical interventions; however, they do respond to exercise-based speech and voice therapies. OBJECTIVE AND METHODS: To study how exercise-based vocal treatment can affect the progression of communication deficits related to PD, we studied ultrasonic vocalizations (USVs) in rats with homozygous knockout ( /-) of PINK1, a gene mutation known to cause PD, under the manipulation of a behavioral vocal exercise paradigm that allows us to precisely control dose and timing of exercise in the prodromal (prior to diagnosis) stages. RESULTS: We show that intensive vocal-training rescues frequency range and intensity deficits as well as leads to an increase in call complexity and duration of calls compared to sham-training; however, over time this training regime loses significant effect as the disease progresses. We also show effects of frequent handling and conspecific (male-female) interaction in the sham-training group as they demonstrated significantly higher call rate, intensity, frequency range, and call complexity compared to rats without any form of training and consequently less handling/interaction. Further, we confirm that this model exhibits progressive gross motor deficits that indicate neurodegeneration. DISCUSSION: This study suggests that the evolving nature of vocal communication deficits requires an adjustment of therapy targets and more intensive training over the course of this progressive disease and demonstrates the importance of frequent social experiences. PMID- 26577654 TI - Development and Application of a Lifestyle Score for Prevention of Lethal Prostate Cancer. AB - BACKGROUND: Several lifestyle factors have been associated with risk of lethal prostate cancer, but little is known about their combined effect. Our objective was to develop and apply a lifestyle score for prevention of lethal prostate cancer. METHODS: We developed a lifestyle score among 42 701 men in the Health Professionals Follow-up Study (HPFS) followed from 1986 to 2010 and applied it among 20 324 men in the Physicians' Health Study (PHS) followed from 1982 to 2010. One point was given for each of: not currently smoking or quit 10 or more years ago, body mass index under 30 kg/m(2), high vigorous physical activity, high intake of tomatoes and fatty fish, and low intake of processed meat. Diet only scores (range = 0-3) and total scores (range = 0-6) were calculated. We used multivariable Cox proportional hazards regression to estimate the risk of lethal prostate cancer, adjusting for potential risk factors of lethal prostate cancer. All statistical tests were two-sided. RESULTS: We observed 576 lethal prostate cancer events in HPFS and 337 in PHS. Men with 5-6 vs 0-1 points had a 68% decreased risk of lethal prostate cancer (hazard ratio [HR] = 0.32, 95% confidence interval [CI] = 0.19 to 0.52) in HPFS and a non-statistically significant 38% decreased risk (HR = 0.62, 95% CI = 0.30 to 1.26) in PHS. For dietary factors only, men with 3 vs 0 points had a 46% decreased risk (HR = 0.54, 95% CI = 0.30 to 0.96) in the HPFS and a non-statistically significant 30% decreased risk (HR = 0.70, 95% CI = 0.40 to 1.23) in PHS. CONCLUSIONS: Adhering to a healthy lifestyle, defined by not smoking, normal body weight, high physical activity, and a healthy diet, may lower risk of lethal prostate cancer. PMID- 26577656 TI - Identification and functional annotation of mycobacterial septum formation genes using cell division mutants of Escherichia coli. AB - The major virulence trait of Mycobacterium tuberculosis is its ability to enter a latent state in the face of robust host immunity. Clues to the molecular basis of latency can emerge from understanding the mechanism of cell division, beginning with identification of proteins involved in this process. Using complementation of Escherichia coli mutants, we functionally annotated M. tuberculosis and Mycobacterium smegmatis homologs of divisome proteins FtsW and AmiC. Our results demonstrate that E. coli can be used as a surrogate model to discover mycobacterial cell division genes, and should prove invaluable in delineating the mechanisms of this fundamental process in mycobacteria. PMID- 26577657 TI - A DNA tool for early detection of vaginal dysbiosis in African women. AB - A next-generation diagnostic tool for bacterial vaginosis, consisting of quantitative and/or qualitative molecular criteria, has not yet been identified. The optimal diagnostic tool should not only diagnose bacterial vaginosis in diverse populations, but should also detect early signs of transition to dysbiosis. We evaluated a tool based on log10-transformed qPCR data for Lactobacillus crispatus, Lactobacillus iners, Lactobacillus jensenii, Lactobacillus gasseri, Lactobacillus vaginalis, Lactobacillus genus, Atopobium vaginae and Gardnerella vaginalis in vaginal specimens of 426 African women to detect dysbiosis and predict transition to dysbiosis. G. vaginalis (p = 0.204) and A. vaginae (p = 0.001) were more commonly present in women who evolved to an intermediate (Nugent 4-6) or bacterial vaginosis score (Nugent 7-10) compared to women who continued to have a normal Nugent score. The combination of G. vaginalis, A. vaginae and Lactobacillus genus counts performed best for diagnostic accuracy for bacterial vaginosis--sensitivity 93.4% and specificity 83.6%; and for predictive accuracy for bacterial vaginosis--sensitivity 79% and specificity 52%. L. crispatus combinations did not perform well. We conclude that a triple-G. vaginalis-A. vaginae-Lactobacillus genus-qPCR tool holds promise for research in sub-Saharan Africa or when developed as a next-generation clinical diagnostic modality for bacterial vaginosis, ideally engineered as a rapid assay. PMID- 26577658 TI - Increased preoperative pulse pressure predicts procedural complications and mortality in patients who undergo tibial interventions for critical limb ischemia. AB - BACKGROUND: Pulse pressure is a noninvasive measure of arterial stiffness. Increased pulse pressure is associated with an increased risk of cardiovascular events and death. The effects of pulse pressure on outcomes after endovascular interventions for critical limb ischemia (CLI), however, are unknown. We thus evaluated whether increased preoperative pulse pressure was associated with adverse outcomes and mortality in patients who underwent endovascular tibial artery intervention. METHODS: All patients who underwent endovascular tibial intervention for CLI at a single institution from 2004 to 2014 were included in this study. Preoperative pulse pressure was derived from measurements obtained in the holding area before the procedure. Patients were divided into two groups on the basis of pulse pressure, <80 or >=80 mm Hg. Patient demographic characteristics and comorbidities were documented, and outcomes including procedural complications, repeat intervention, amputation, and mortality were recorded. Multivariable logistic regression was used to account for patient demographic characteristics and comorbidities. RESULTS: Of 371 patients, 186 patients had a preoperative pulse pressure <80 mm Hg and 185 had a preoperative pulse pressure >=80 mm Hg. No significant differences in patient demographic characteristics or comorbidities were identified; however, there was a trend toward older age in patients with increased pulse pressure (70 vs 72; P = .07). In univariate analysis, procedural complications (21% vs 13%; P = .02), reinterventions (26% vs 17%; P < .01), and restenosis (32% vs 23%; P = .03) were more common among patients with pulse pressure >=80. Procedural complications remained significant in multivariate analysis (odds ratio, 1.8; 95% confidence interval, 1.0-3.1; P = .04). There was no difference in 30-day mortality; however, increased mortality was seen at 5 years of follow-up (odds ratio, 1.6; 95% confidence interval, 1.0-2.5; P = .04) in multivariable analysis. CONCLUSIONS: Increased preoperative pulse pressure is associated with procedural complications and increased mortality in patients who undergo endovascular tibial intervention for CLI. It is a marker of increased risk, and might be a suitable target for interventions aimed at improving outcomes in this high-risk population. PMID- 26577659 TI - A First Principles study on Boron-doped Graphene decorated by Ni-Ti-Mg atoms for Enhanced Hydrogen Storage Performance. AB - We proposed a new solid state material for hydrogen storage, which consists of a combination of both transition and alkaline earth metal atoms decorating a boron doped graphene surface. Hydrogen adsorption and desorption on this material was investigated using density functional theory calculations. We find that the diffusion barriers for H atom migration and desorption energies are lower than for the previously designed mediums and the proposed medium can reach the gravimetric capacity of ~6.5 wt % hydrogen, which is much higher than the DOE target for the year 2015. Molecular Dynamics simulations show that metal atoms are stably adsorbed on the B doped graphene surface without clustering, which will enhance the hydrogen storage capacity. PMID- 26577660 TI - Erratum to: Generation of iPS Cells from Granulosa Cells. PMID- 26577662 TI - Predictors for mechanical ventilation and short-term prognosis in patients with Guillain-Barre syndrome. PMID- 26577661 TI - [Mechanobiology and bone metabolism: Clinical relevance for fracture treatment]. AB - Mechanical stimuli are known to significantly influence bone metabolism and fracture healing. Various studies have demonstrated the involvement of complex molecular mechanotransduction pathways, such as the Wnt/beta-catenin, bone morphogenetic protein (BMP) and estrogen receptor signaling pathways in mechanotransduction. Mechanotransduction is influenced by aging and the comorbidities of the patient. Pharmacological modulation of signal transduction influences bone formation and the mechanosensitivity of skeletal tissue. The combination of pharmacological and biomechanical therapies may be useful for the treatment of fractures with impaired healing. PMID- 26577663 TI - Using NMR to Develop New Allosteric and Allo-Network Drugs. AB - NMR is becoming an important tool for developing new allosteric and allo-network drugs that bind to allosteric sites on enzymes, partially inhibiting them and causing fewer side effects than drugs already developed that target active sites. This is based on systems thinking, in which active enzymes and other proteins are known to be flexible and interact with each other. In other words, proteins can exist in an ensemble of different conformations whose populations are tunable. NMR is being used to find the pathways through which the effects of binding of an allosteric ligand propagate. There are NMR screening assays for studying ligand binding. This includes determining the changes in the spin lattice relaxation due to changes in the mobility of atoms involved in the binding, measuring magnetization transfer from the protein to the ligand by saturation difference transfer NMR (STD-NMR) and the transfer of bulk magnetization to the ligand by water-Ligand Observed via Gradient Spectroscopy, or waterLOGSY. The chemical shifts of (1)H and (15)N of some of the atoms in amino acids change when an allosteric ligand binds to a protein. So, (1)H-(15)N heteronuclear single quantum coherence (HSQC) spectra can be used to identify key amino acids and ligand binding sites. The NMR chemical shifts of amino acids affected by ligand binding form a network that can be characterized. Allosteric networks can be identified by chemical shift covariance analysis (CHESCA). This approach has been used recently to study the binding of new molecular entities (NMEs) to potentially therapeutic drug targets. PMID- 26577664 TI - Providers' perspectives on preconception counseling and safer conception for HIV infected women. AB - INTRODUCTION: Unplanned pregnancy among HIV-infected women can have negative health consequences for women, partners, and neonates. Despite recommendations, preconception counseling (PCC) appears to be infrequently addressed in HIV care. This study explored knowledge, attitudes, and practices among health-care providers regarding PCC, safer conception and pregnancy among HIV-infected women. METHODS: Physicians, physician assistants, and nurse practitioners (n = 14) providing obstetric/gynecological and HIV care in urban south Florida public and private hospitals completed structured qualitative interviews. Dominant themes arising included provider perceptions of patient knowledge and practices, provider knowledge and attitudes regarding safer conception, and provider practices regarding reproductive health. RESULTS: Providers perceived patients to have limited reproductive knowledge. Patients' internalized HIV stigma was a barrier to patient initiation of conception-focused discussions. Provider knowledge and utilization of PCC protocols were limited. PCC barriers included competing medical priorities, failure to address fertility desires, limited knowledge, time limitations, and unclear standard of care. Providers routinely used condom-based HIV prevention as a proxy for addressing reproductive intentions. DISCUSSION: Provider, patient, and structural factors prevented implementation of PCC and provision of information on safer conception; neither were routinely discussed during consultations. Both providers and patients may benefit from interventions to enhance communication on conception. PMID- 26577665 TI - Being cosmopolitan: evolutionary history and phylogeography of a specialized raptor, the Osprey Pandion haliaetus. AB - BACKGROUND: The Osprey (Pandion haliaetus) is one of only six bird species with an almost world-wide distribution. We aimed at clarifying its phylogeographic structure and elucidating its taxonomic status (as it is currently separated into four subspecies). We tested six biogeographical scenarios to explain how the species' distribution and differentiation took place in the past and how such a specialized raptor was able to colonize most of the globe. RESULTS: Using two mitochondrial genes (cyt b and ND2), the Osprey appeared structured into four genetic groups representing quasi non-overlapping geographical regions. The group Indo-Australasia corresponds to the cristatus ssp, as well as the group Europe Africa to the haliaetus ssp. In the Americas, we found a single lineage for both carolinensis and ridgwayi ssp, whereas in north-east Asia (Siberia and Japan), we discovered a fourth new lineage. The four lineages are well differentiated, contrasting with the low genetic variability observed within each clade. Historical demographic reconstructions suggested that three of the four lineages experienced stable trends or slight demographic increases. Molecular dating estimates the initial split between lineages at about 1.16 Ma ago, in the Early Pleistocene. CONCLUSIONS: Our biogeographical inference suggests a pattern of colonization from the American continent towards the Old World. Populations of the Palearctic would represent the last outcomes of this colonization. At a global scale the Osprey complex may be composed of four different Evolutionary Significant Units, which should be treated as specific management units. Our study brought essential genetic clarifications, which have implications for conservation strategies in identifying distinct lineages across which birds should not be artificially moved through exchange/reintroduction schemes. PMID- 26577666 TI - Systematic review of the use of behaviour change techniques (BCTs) in home-based cardiac rehabilitation programmes for patients with cardiovascular disease- protocol. AB - BACKGROUND: Cardiovascular diseases (CVDs), including myocardial infarction, heart failure, peripheral arterial disease and strokes, are highly prevalent conditions and are associated with high morbidity and mortality. Cardiac rehabilitation (CR) is an effective form of secondary prevention for CVD but there is a lack of information regarding which specific behaviour change techniques (BCTs) are included in programmes that are associated with improvements in cardiovascular risk factors. This systematic review will describe the BCTs which are utilised within home-based CR programmes that are effective at reducing a spectrum of CVD risk factors. METHODS/DESIGN: The review will be reported in line with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidance. Randomised and quasi-randomised controlled trials of home-based CR initiated following a vascular event (myocardial infarction, heart failure, peripheral arterial disease and stroke patients) will be included. Articles will be identified through a comprehensive search of MEDLINE, Embase, PsycINFO, Web of Science and Cochrane Database guided by a medical librarian. Two review authors will independently screen articles retrieved from the search for eligibility and extract relevant data, identifying which specific BCTs are included in programmes that are associated with improvements in particular modifiable vascular risk factors. DISCUSSION: This review will be of value to clinicians and healthcare professionals working with cardiovascular patients by identifying specific BCTs which are used within effective home-based CR. It will also inform the future design and evaluation of complex health service interventions aimed at secondary prevention in CVD. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration CRD42015027036 . PMID- 26577667 TI - p11 regulates the surface localization of mGluR5. PMID- 26577668 TI - Decoupling gain and feedback in coherent random lasers: experiments and simulations. AB - We propose and demonstrate a coherent random laser in which the randomly distributed scattering centres are placed outside the active region. This architecture is implemented by enclosing a dye solution between two agglomerations of randomly positioned titanium dioxide nanoparticles. The same spectral signature, consisting of sharp spikes with random spectral positions, is detected emerging from both ensembles of titanium dioxide nanoparticles. We interpret this newly observed behaviour as due to the optical feedback given by back-scattered light from the scattering agglomerations, which also act as output couplers. A simple model is presented to simulate the observed behaviour, considering the amplitude and phase round trip conditions that must be satisfied to sustain lasing action. Numerical simulations reproduce the experimental reports, validating our simple model. The presented results suggest a new theoretical and experimental approach for studying the complex behavior of coherent random lasers and stimulate the realization of new devices based on the proposed architecture, with different active and scattering materials. PMID- 26577669 TI - Therapeutic efficacy of chloroquine for the treatment of Plasmodium vivax malaria among outpatients at Hossana Health Care Centre, southern Ethiopia. AB - BACKGROUND: Plasmodium vivax accounts for about 44 % of all malaria infection in Ethiopia. Chloroquine (CQ) is the first-line treatment for vivax malaria in Ethiopia. Chloroquine-resistant (CQR) P. vivax has been emerging in different parts of the world to compromise the efficacy of the drug and pose both health and economic impact in the developing world. The current study was aimed at assessing the therapeutic efficacy of CQ for the treatment of vivax malaria among outpatients at Hossana Health Care Centre, southern Ethiopia. METHODS: A one-arm, 28-day follow-up, in vivo therapeutic efficacy study was conducted from 5 April to 25 June, 2014. Sixty-three patients aged between four and 59 years were enrolled with microscopically confirmed P. vivax infection. All patients were treated with CQ 25 mg/kg for 3 days. Recurrence of parasitaemia and clinical conditions of patients were assessed on days 1, 2, 3, 7, 14, 21, and 28 during the 28-day follow-up period. Haemoglobin (Hb) level was determined on day 0, day 28 and on day of recurrence of parasitaemia by using portable spectrophotometer. RESULTS: Of the total 63 patients included in the study, 60 (95.2 %) completed their 28-day follow-up; three patients were excluded from the study: one patient due to vomiting of the second dose of drug, one patient due to Plasmodium falciparum infection and one patient lost to follow-up during the study. During enrolment, 35 (53.3 %) had a history of fever and 28 (46.7 %) had documented fever. The geometric mean of parasite density on day of enrolment was 3472 parasites/MUl. Among these, two patients had recurrent parasitaemia within the 28 day follow-up. CQ was found to be efficacious in 96.7 % of the study participants except two treatment failures detected. The failure might be due to late parasitological failure among these two patients who had recurrent parasitaemia within the 28-day follow-up. CONCLUSION: The current study revealed that CQ showed a high rate of efficacy (96.7 %) among the study participants even though some reports from previous studies elsewhere in Ethiopia showed an increase in CQR P. vivax. Thus, CQR molecular markers and regular monitoring of the pattern of resistance to CQ is needed for rapid and effective control measures of possible spread of drug resistance in the study area. PMID- 26577670 TI - Novel splice-site mutation in WDR62 revealed by whole-exome sequencing in a Sudanese family with primary microcephaly. AB - The WDR62 gene encodes a scaffold protein of the c-Jun N-terminal kinase (JNK) pathway. It plays a critical role in laying out various cellular layers in the cerebral cortex during embryogenesis, and hence the dramatic clinical features resulting from WDR62 mutations. These mutations are associated with autosomal recessive primary microcephaly 2, with or without cortical malformations (MCPH2). Using whole exome sequencing we uncovered a novel WDR62 variant; c.390G > A, from two Sudanese siblings whose parents are first cousins. The patients suffered MCPH2 with incomplete lissencephaly and developmental delay. The mutation affects the last nucleotide of exon4, and probably leads to aberrant splicing, which may result in a truncated protein lacking all functional domains. PMID- 26577671 TI - Former health secretary takes on another advisory role in private health sector. PMID- 26577672 TI - Screening and identification of immunoactive peptide mimotopes for the enhanced serodiagnosis of tuberculosis. AB - Although serological detection is a practical strategy for early detection and diagnosis of tuberculosis (TB), inconsistent and imprecise estimates of sensitivity and specificity block its development and application for clinic. New or alternative serological antigens with improved accuracy are urgently needed. A phage-displayed random peptide library was employed to screen for immunoactive peptides using specific immunoglobulin G (IgG) of TB patients as target molecules. With two screening strategies, 20 single phages displaying different sequences were obtained and no sequence homology was found among these phages. From the results of phage-ELISA, H12, TB6, TB15, and TB18 phages showed higher affinity to IgGs from TB patients(S/N >=2.1) and were identified as the positive clones. Significant differences in the detection values of sera from 47 TB patients and 37 healthy individuals were found for these four phage clones. According to the reactivity of 284 human sera to synthetic H12, TB6, TB15, and TB18 peptides as determined by ELISA, TB15 showed significantly higher areas under the curve (AUC) and sensitivity than other peptides, providing a lead molecule for the development of new serology diagnostic strategies for TB. PMID- 26577673 TI - Characterization of a recombinant 7,8-linoleate diol synthase from Glomerella cingulate. AB - A putative diol synthase from the fungus Glomerella cingulate was cloned and expressed in Escherichia coli. The putative diol synthase from G. cingulate was purified by His-Trap affinity chromatography with a specific activity of 0.87 U mg(-1), an eightfold purification, and a yield of 28%. One unit of activity was defined as the amount of enzyme required to produce 1 MUmol of 7,8-dihydroxy 9,12(Z,Z)-octadecadienoic acid (7,8-DiHODE) per min. The purified enzyme was estimated as a 127-kDa tetramer with a molecular mass of 510 kDa by gel filtration chromatography. The enzyme converted linoleic acid to a product, identified as 7S,8S-DiHODE by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) and nuclear magnetic resonance (NMR) spectroscopy. The specific activity and catalytic efficiency (k cat/K m) of 7,8-diol synthase from G. cingulate for the conversion of fatty acid to dihydroxy fatty acid followed the order linoleic acid > alpha-linolenic acid > oleic acid > palmitoleic acid, indicating that the enzyme is a 7,8-linoleate diol synthase (7,8-LDS). The activity of the enzyme for the conversion of 7,8-DiHODE from linoleic acid was maximal at pH 6.5, 40 degrees C, and 2.5% (v/v) dimethyl sulfoxide (DMSO). Under these conditions, 7,8-LDS from G. cingulate converted 1.0 mM linoleic acid to 0.62 mM 7,8-DiHODE for 30 min, with a conversion yield of 62% (mol/mol), via 8 hydroperoxy-9,12(Z,Z)-octadecadienoic acid (8-HPODE) as an intermediate. The accumulation of 8-HPODE was due to a higher 8-dioxygenase activity in the N terminal domain than hydroperoxide isomerase activity in the C-terminal domain. PMID- 26577675 TI - Oxygen uptake in Pacific salmon Oncorhynchus spp.: when ecology and physiology meet. AB - Over the past several decades, a substantial amount of research has examined how cardiorespiratory physiology supports the diverse activities performed throughout the life cycle of Pacific salmon, genus Oncorhynchus. Pioneering experiments emphasized the importance of aerobic scope in setting the functional thermal tolerance for activity in fishes. Variation in routine metabolism can have important performance and fitness consequences as it is related to dominance, aggression, boldness, territoriality, growth rate, postprandial oxygen consumption, life history, season, time of day, availability of shelter and social interactions. Wild fishes must perform many activities simultaneously (e.g. swim, obtain prey, avoid predators, compete, digest and reproduce) and oxygen delivery is allocated among competing organ systems according to the capacity of the heart to deliver blood. For example, salmonids that are simultaneously swimming and digesting trade-off maximum swimming performance in order to support the oxygen demands of digestion. As adult Pacific salmonids cease feeding in the ocean prior to their home migration, endogenous energy reserves and cardiac capacity are primarily partitioned among the demands for swimming upriver, sexual maturation and spawning behaviours. Furthermore, the upriver spawning migration is under strong selection pressure, given that Pacific salmonids are semelparous (single opportunity to spawn). Consequently, these fishes optimize energy expenditures in a number of ways: strong homing, precise migration timing, choosing forward-assist current paths and exploiting the boundary layer to avoid the strong currents in the middle of the river, using energetically efficient swimming speeds, and recovering rapidly from anaerobic swimming. Upon arrival at the spawning ground, remaining energy can be strategically allocated to the various spawning behaviours. Strong fidelity to natal streams has resulted in reproductively isolated populations that appear to be locally adapted physiologically to their specific environmental conditions. Populations with more challenging migrations have enhanced cardiorespiratory performance. Pacific salmonids are able to maintain aerobic scope across the broad range of temperatures encountered historically during their migration; however, climate change-induced river warming has created lethal conditions for many populations, raising conservation concerns. Despite considerable research examining cardiorespiratory physiology in Pacific salmonids over the last 70 years, critical knowledge gaps are identified. PMID- 26577674 TI - Identification of novel thermostable taurine-pyruvate transaminase from Geobacillus thermodenitrificans for chiral amine synthesis. AB - omega-Transaminases (omega-TAs) are one of the most popular candidate enzymes in the biosynthesis of chiral amines. Determination of yet unidentified omega-TAs is important to broaden their potential for synthetic application. Taurine-pyruvate TA (TPTA, EC 2.6.1.77) is an omega-TA belonging to class III of TAs. In this study, we cloned a novel thermostable TPTA from Geobacillus thermodenitrificans (TPTAgth) and overexpressed it in Escherichia coli. The enzyme showed the highest activity at pH 9.0 and 65 degrees C, with remarkable thermostability and tolerance toward organic solvents. Its K M and v max values for taurine were 5.3 mM and 0.28 MUmol s(-1) mg(-1), respectively. Determination of substrate tolerance indicated its broad donor and acceptor ranges for unnatural substrates. Notably, the enzyme showed relatively good activity toward ketoses, suggesting its potential for catalyzing the asymmetric synthesis of chiral amino alcohols. The active site of TPTAgth was identified by performing protein sequence alignment, three-dimensional structure simulation, and coenzyme pyridoxamine phosphate docking. The protein sequence and structure of TPTAgth were similar to those of TAs belonging to the 3N5M subfamily. Its active site was found to be its special large pocket and substrate tunnel. In addition, TPTAgth showed a unique mechanism of sulfonate/alpha-carboxylate recognition contributed by Arg163 and Gln160. We also determined the protein sequence fingerprint of TPTAs in the 3N5M subfamily, which involved Arg163 and Gln160 and seven additional residues from 413 to 419 and lacked Phe/Tyr22, Phe85, and Arg409. PMID- 26577676 TI - Renal outcome after tonsillectomy plus corticosteroid pulse therapy in patients with immunoglobulin A nephropathy: results of a multicenter cohort study. AB - BACKGROUND: In addition to renin-angiotensin system inhibition (RAS), corticosteroids are recommended for patients who have immunoglobulin A nephropathy (IgAN) with ?1 g/day proteinuria. Tonsillectomy plus corticosteroid pulse therapy (TSP) had been reported as more effective in producing clinical remission of IgAN than just oral-corticosteroid (OS) or steroid-pulse (SP) therapy-but that remained unconfirmed. Accordingly, this study compared the effects of TSP, corticosteroid therapies, and RAS on a multicenter, large-scale, long-term cohort. METHODS: 1127 biopsy-proven IgAN patients with chronic kidney disease (CKD), G1-3, treated in our hospitals March 1981-December 2013 with TSP (n = 209), SP (n = 103), OS (n = 300), or RAS, alone (n = 515), were followed until end-stage renal disease (ESRD) or death, renal survival compared by treatment and proteinuria level. Hazard ratios (HRs) of ESRD were analyzed after adjusting for sex, age, BMI, eGFR, albumin, proteinuria, hematuria, blood pressure, medications, and renal-biopsy year, with propensity-score-matched analyses performed. RESULTS: With TSP as referent, the overall HRs of SP, OS, and RAS were, respectively, 1.33 (0.44-4.04), 3.56 (1.45-8.71), and 3.64 (1.48-8.96); with proteinuria ?1.0 g/gCre, respective HRs were 2.99 (0.71-12.54), 5.04 (1.44 17.67), and 7.23 (1.98-26.40); with proteinuria <1.0 g/gCre, 0.42 (0.04-4.89), 3.24 (0.79-13.30), and 2.05 (0.52-8.05); and for patients with CKD G3, 0.37 (0.10 1.41), 2.14 (0.77-5.94), and 2.03 (0.72-5.72). Similar results were observed in models including pathological grading and/or propensity-score matching. CONCLUSION: TSP may decrease the risk of ESRD in IgAN patients better than other therapies in CKD G1-2, with proteinuria ?1.0 g/gCre, while outcome was similar to SP in CKD G3, or with proteinuria <1.0 g/gCre. PMID- 26577677 TI - Growth differentiation factor 8 suppresses cell proliferation by up-regulating CTGF expression in human granulosa cells. AB - Connective tissue growth factor (CTGF) is a matricellular protein that plays a critical role in the development of ovarian follicles. Growth differentiation factor 8 (GDF8) is mainly, but not exclusively, expressed in the mammalian musculoskeletal system and is a potent negative regulator of skeletal muscle growth. The aim of this study was to investigate the effects of GDF8 and CTGF on the regulation of cell proliferation in human granulosa cells and to examine its underlying molecular determinants. Using dual inhibition approaches (inhibitors and small interfering RNAs), we have demonstrated that GDF8 induces the up regulation of CTGF expression through the activin receptor-like kinase (ALK)4/5 mediated SMAD2/3-dependent signaling pathways. In addition, the increase in CTGF expression contributes to the GDF8-induced suppressive effect on granulosa cell proliferation. Our findings suggest that GDF8 and CTGF may play critical roles in the regulation of proliferative events in human granulosa cells. PMID- 26577679 TI - Transient cortical visual impairment after video-assisted thoracic surgery: a case report. AB - BACKGROUND: Visual loss associated with thoracic surgery has been reported mostly after coronary angiography or bypass surgery. The position of video-assisted thoracic surgery (VATS) is usually lateral, thus not compressive to the globe. Visual loss after VATS has not been reported. Herein we report a patient without any cardiovascular risk factors who experienced transient cortical blindness after an uneventful VATS. CASE PRESENTATION: A 40-year-old man noticed a visual loss at the recovery room after VATS. He showed normal pupillary reflex, normal optic disc appearance, and homonymous hemianopia respecting the vertical meridian, thus was typical for cortical visual impairment. CONCLUSIONS: Transient cortical visual impairment could be encountered after an uneventful VATS in a patient without any cardiovascular risk factors. PMID- 26577678 TI - Differential gene regulation of GHSR signaling pathway in the arcuate nucleus and NPY neurons by fasting, diet-induced obesity, and 17beta-estradiol. AB - Ghrelin's receptor, growth hormone secretagogue receptor (GHSR), is highly expressed in the arcuate nucleus (ARC) and in neuropeptide Y (NPY) neurons. Fasting, diet-induced obesity (DIO), and 17beta-estradiol (E2) influence ARC Ghsr expression. It is unknown if these effects occur in NPY neurons. Therefore, we examined the expression of Npy, Agrp, and GHSR signaling pathway genes after fasting, DIO, and E2 replacement in ARC and pools of NPY neurons. In males, fasting increased ARC Ghsr and NPY Foxo1 but decreased NPY Ucp2. In males, DIO decreased ARC and NPY Ghsr and Cpt1c. In fed females, E2 increased Agrp, Ghsr, Cpt1c, and Foxo1 in ARC. In NPY pools, E2 decreased Foxo1 in fed females but increased Foxo1 in fasted females. DIO in females suppressed Agrp and augmented Cpt1c in NPY neurons. In summary, genes involved in GHSR signaling are differentially regulated between the ARC and NPY neurons in a sex-dependent manner. PMID- 26577680 TI - The long-term outcomes following the use of inactivated autograft in the treatment of primary malignant musculoskeletal tumor. AB - BACKGROUND: Biological reconstruction surgery is a tough but alluring option for treating primary malignant musculoskeletal tumors. In this article, we evaluate the clinical outcomes of primary malignant musculoskeletal tumors treated with inactivated autograft using alcohol. METHOD: In this article, we include 58 patients who had primary malignant bone tumors treated with wide resection and recycling autograft reconstruction using alcohol between January 2003 and January 2013. The outcomes were measured by recurrence, functional status, and complications. Functional status was assessed according to the Musculoskeletal Tumor Society Score (MSTSS). The Kaplan-Meier survival curve was used to evaluate the survival rate of the patient. RESULT: The most common tumor was osteosarcoma (31 cases) followed by chondrosarcoma (10 cases). The tibia was the most frequently involved skeletal site (27 cases) followed by femur (26 cases). The median follow-up period was 54 months, ranging from 18 to 96 months. In 58 patients, 12 were with local recurrence (20.7 %), 16 with lung metastasis (27.6 %), and 13 with complications (22.4 %). The main complication was infection (8 cases). The autografts survived in 49 patients (84.5 %). The mean MSTSS score was 78.5 %, ranging from 47 to 98 %. CONCLUSION: Recycling autograft reconstruction using alcohol had favorable clinical outcomes to some degree; however, the recurrence and complication rates seem to be high. Thus, we should apply this method with caution and choose the patients with strict surgical indication. PMID- 26577681 TI - Integrating Biomaterials and Stem Cells for Neural Regeneration. AB - The central nervous system has a limited capacity to regenerate, and thus, traumatic injuries or diseases often have devastating consequences. Therefore, there is a distinct need to develop alternative treatments that can achieve functional recovery without side effects currently observed with some pharmacological treatments. Combining biomaterials with pluripotent stem cells (PSCs), either embryonic or induced, has the potential to revolutionize the treatment of neurodegenerative diseases and traumatic injuries. Biomaterials can mimic the extracellular matrix and present a myriad of relevant biochemical cues through rational design or further functionalization. Biomaterials such as nanofibers and hydrogels, including self-assembling peptide (SAP) hydrogels can provide a superior cell culture environment. When these materials are then combined with PSCs, more accurate drug screening and disease modeling could be developed, and the generation of large number of cells with the appropriate phenotype can be achieved, for subsequent use in vitro. Biomaterials have also been shown to support endogenous cell growth after implantation, and, in particular, hydrogels and SAPs have effectively acted as cell delivery vehicles, increasing cell survival after transplantation. Few studies are yet to fully exploit the combination of PSCs and innovative biomaterials; however, initial studies with neural stem cells, for example, are promising, and, hence, such a combination for use in vitro and in vivo is an exciting new direction for the field of neural regeneration. PMID- 26577682 TI - Tin Powder-Promoted One-Pot Construction of alpha-Methylene-gamma-lactams and Spirolactams from Aldehydes or Ketones, Acylhydrazines, and 2 (Bromomethyl)acrylate. AB - A concise and efficient method for the synthesis of alpha-methylene-gamma-lactams is developed from multicomponent one-pot reactions of aldehydes or ketones, hydrazides, and ethyl 2-(bromomethyl)acrylate promoted by tin powder. The reaction proceeds smoothly under mild reaction conditions without using any catalyst to give the corresponding products in high yields. alpha-Methylene-gamma spirolactams can also be prepared from cyclic ketones. PMID- 26577683 TI - Twice-daily Budesonide 2-mg Foam Induces Complete Mucosal Healing in Patients with Distal Ulcerative Colitis. AB - BACKGROUND AND AIMS: Mucosal healing is an important therapeutic goal for ulcerative colitis. Once-daily administration of budesonide 2-mg foam is widely used for inducing clinical remission. No study has assessed the usefulness of twice-daily budesonide 2mg foam on mucosal healing in ulcerative colitis patients. We explored the efficacy for mucosal healing of once- or twice-daily budesonide foam in distal ulcerative colitis patients. METHODS: This study was a multicentre, randomised, double-blind, placebo-controlled trial. In all, 165 patients with active, mild to moderate distal ulcerative colitis were randomised to three groups: once- or twice-daily budesonide 2mg/25ml foam, or placebo foam, for 6 weeks. Complete mucosal healing [endoscopic subscore = 0] and the safety profile were assessed at Week 6. Prespecified and post hoc analyses were used. RESULTS: The percentages of complete mucosal healing in the twice-daily budesonide foam group were 46.4% compared with 23.6% in the once-daily group [p = 0.0097], or 5.6% in the placebo group [p < 0.0001]. The percentages of clinical remission and the percentages of endoscopic subscore <= 1 in the twice-daily budesonide foam group were 48.2% and 76.8%, compared with 50.9% and 69.1% in the once-daily group [no difference], or 20.4% and 46.3% in the placebo group [p = 0.0029 and p = 0.0007], respectively. In the subgroup of patients with previous use of a 5-aminosalicylic acid suppository or enema, there was a greater percentage of complete mucosal healing in the twice-daily budesonide foam group [32.0%] compared with that in the once-daily [8.7%, p = 0.0774] or placebo groups [4.8%, p = 0.0763], though there was no significant difference. No serious adverse event occurred. CONCLUSIONS: A significantly greater percentage of patients receiving twice-daily administration of budesonide foam compared with once-daily administration/placebo achieved complete mucosal healing. This is the first study to evaluate the endoscopic efficacy of twice-daily administration of 6-week budesonide foam treatment for ulcerative colitis. PMID- 26577684 TI - Modulation of Macrophage Functional Polarity towards Anti-Inflammatory Phenotype with Plasmid DNA Delivery in CD44 Targeting Hyaluronic Acid Nanoparticles. AB - The purpose of this study was to modulate macrophage polarity from the pro inflammatory M1 to anti-inflammatory M2 phenotype using plasmid DNA (pDNA) expressing interleukin-4 (IL4) or interleukin-10 (IL10)-encapsulated in hyaluronic acid-poly(ethyleneimine) (HA-PEI) nanoparticles (NPs). The HA-PEI/pDNA NPs with spherical shape, average size of 186 nm were efficiently internalized by J774A.1 macrophages. Transfection of HA-PEI/pDNA-IL4 and HA-PEI/pDNA-IL10 NPs increased IL4 and IL10 gene expression in J774 macrophages which could re-program the macrophages from M1 to M2 phenotype as evidenced by a significant increase in the Arg/iNOS level, and upregulation of CD206 and CD163 compared to untreated macrophages. Following intraperitoneal (IP) injection to C57BL/6 mice, HA-PEI NPs effectively targeted peritoneal macrophages over-expressing CD44 receptor. In an in vivo model of stimulated peritoneal macrophages, IP administration of HA PEI/pDNA-IL4 and HA-PEI/pDNA-IL10 to C57BL/6 mice significantly increased the Arg/iNOS ratio and CD163 expression in the cells. Furthermore, HA-PEI/pDNA-IL10 NPs significantly increased peritoneal and serum IL10 levels which effectively suppressed LPS-induced inflammation by reducing level of TNF-alpha and IL-1beta in peritoneal macrophages and in the peritoneal fluid. The results demonstrated that pDNA-IL10-encapsulate HA-PEI NPs skewed macrophage functional polarity from M1 toward an anti-inflammatory M2 phenotype which may be a promising platform for the treatment of inflammatory diseases. PMID- 26577685 TI - Differential sialotranscriptomes of unfed and fed Rhipicephalus haemaphysaloides, with particular regard to differentially expressed genes of cysteine proteases. AB - BACKGROUND: Rhipicephalus haemaphysaloides, a hard tick, is a common ectoparasite and can be found in many countries. It is recognized as the primary vector of bovine babesiosis in the south of China. During blood feeding, the tick's salivary glands secret numerous essential multifunctional proteins. In this study, a R. haemaphysaloides salivary gland transcriptome was described following the production and analysis of the transcripts from the two cDNA libraries of unfed and fed female ticks. The study focused on the differentially expressed genes and cysteine proteases, which play essential roles in the tick life cycle, that were detected most commonly in the up-regulation libraries. METHODS: The sialotranscriptome was assembled and analyzed though bioinformatic tools and the cysteine protease which is differentially expressed form sialotranscriptome were confirmed by Real-time PCR in salivary glands and different developments of ticks. RESULTS: On the basis of sequence similarities with other species in various databases, we analyzed the unfed and fed sialotranscriptome of R. haemaphysaloides to identify the differentially expressed proteins secreted from the salivary glands during blood feeding and to investigate their biological functions. There were 25,113 transcripts (35 % of the total assembled transcripts) that showed significant similarity to known proteins with high BLAST from other species annotated. In total, 88 % and 89 % of the sequencing reads could be mapped back to assembled sequences in the unfed and fed library, respectively. Comparison of the abundance of transcripts from similar contigs of the two salivary gland cDNA libraries allowed the identification of differentially expressed genes. In total, there were 1179 up-regulated genes and 574 down-regulated genes found by comparing the two libraries. Twenty-five predicted cysteine proteases were screened from the transcript databases, whereas only six protein molecules were confirmed by gene cloning and molecular expression in E.coli which all belonged to the cysteine protease family. Bioinformatic evolutionary analysis showed the relationship of cysteine proteases in ticks with those of other species, suggesting the origin and conservation of these genes. Analysis of sequences from different tick species indicated the further relationships among the proteases, suggesting the closely related function of these genes. Thus, we confirmed their changes in unfed, fed and engorged ticks and salivary glands. The dynamic changes revealed their important roles in the tick life cycle. CONCLUSIONS: Our survey provided an insight into the R. haemaphysaloides sialotranscriptome. The dynamic changes of cysteine proteases in ticks will assist further study of these proteases, which may contribute to the development of anti-tick vaccines or drugs, as well as improving understanding of the roles of cysteine proteases in the tick life cycle. PMID- 26577686 TI - PLK-1 Expression is Associated with Histopathological Response to Neoadjuvant Therapy of Hepatic Metastasis of Colorectal Carcinoma. AB - Polo-like kinase 1 (PLK1) is a serine/threonine-protein kinase expressed during mitosis and overexpressed in multiple human cancers, including leukemia and also many solid tumors. PLK1 knockdown has been shown to block proliferation of leukemic cell lines and the clonogenic potential of tumor cells grown from patients with cancer. PLK1 inhibition is a promising strategy for the treatment of some tumors. We aim to analyze expression of PLK1 in metastatic colorectal carcinoma. Retrospective analysis of colorectal carcinomas with hepatic metastasis during follow-up receiving neoadjuvant chemotherapy (NAC), based on oxaliplatin. Immunohistochemistry for PLK-1 in paraffin-embedded tissue from the primary and also from the metastasis. 50 patients. 32% showed good histopathological response. 43% of the primaries were positive for PLK1, as opposed to 23.5% of the metastasis. Expression of PLK1 was significantly reduced in metastasis compared with the primaries (p = 0.05), what could be due to therapy or to a phenotypic change of the metastatic nodule. Analysis of the prognostic influence of PLK1 expression showed significant association between PLK1 expression in metastasis and lower overall survival (p = 0.000). We have also found a significant association between PLK1 expression and histopathological response (p = 0.02). All the tumors with high expression of PLK1 showed minor response (11/11). This study shows the association between survival and poor histopathological response to therapy and high expression of PLK1 in metastasis. Our results could open a new therapeutic approach through the inhibition of PLK1. PMID- 26577687 TI - Quantitative Evaluation of Tumour--Associated Tissue Eosinophilia and Cyclo oxegenase-2 Gene in Oral Cancer Patients with Assessment of Long Term Outcomes. AB - Various histopathological parameters have been extensively studied for prognostication of oral cancer but the focus is now getting diverted towards the role of inflammatory mediators in cancer progression. The present study was undertaken to evaluate two such components of the inflammatory milieu, tumor associated tissue eosinophilia (TATE) as well as Cyclo-oxygenase-2 (COX-2) gene expression, quantitatively in oral squamous cell carcinoma (OSCC) patients in relation to treatment outcomes and patterns of recurrence. A total of forty five patients with primary OSCC matching our inclusion criteria were selected for the study and followed up over a five year period. TATE was evaluated from the invasive front of the tumor using Haematoxylin and eosin (H & E) stained sections of histopathological specimens and graded as mild, moderate or intense. COX-2 gene expression was obtained from specimens using the reverse transcriptase- polymerase chain reaction (RT-PCR) method. A statistically significant association was observed between degree of TATE and locoregional recurrence (P < 0.001). The expression of COX-2 gene ranged from 0.4326 to 0.9998 and a higher mean COX-2 score was recorded in samples with intense degree of TATE followed by moderate and mild TATE. (P < 0.001). Using the t-test, the difference in mean COX 2 was found to be statistically significant (P < 0.001) between patients who developed locoregional recurrence and those who did not. The analysis of TATE may provide an indication of future recurrence at the time of diagnosis of OSCC. Also, the increased expression of COX-2 gene in OSCC strongly suggests its possible use as a chemopreventive/chemotherapeutic target. PMID- 26577688 TI - The Effect of Karate Techniques Training on Communication Deficit of Children with Autism Spectrum Disorders. AB - This investigation examined the long term effect of Karate techniques training on communication of children with autism spectrum disorders (ASD). Thirty school aged children with ASD were randomly assigned to an exercise (n = 15) or a control group (n = 15). Participants in the exercise group were engaged in 14 weeks of Karate techniques training. Communication deficit at baseline, post intervention (week 14), and at 1 month follow up were evaluated. Exercise group showed significant reduction in communication deficit compared to control group. Moreover, reduction in communication deficit in the exercise group at one month follow up remained unchanged compared to post-intervention time. We concluded that teaching Karate techniques to children with ASD leads to significant reduction in their communication deficit. PMID- 26577689 TI - Paradoxical role of antibodies in dengue virus infections: considerations for prophylactic vaccine development. AB - Highly effective prophylactic vaccines for flaviviruses including yellow fever virus, tick-borne encephalitis virus and Japanese encephalitis virus are currently in use. However, the development of a dengue virus (DENV) vaccine has been hampered by the requirement of simultaneous protection against four distinct serotypes and the threat that DENV-specific antibodies might either mediate neutralization or, on the contrary, exacerbate disease through the phenomenon of antibody-dependent enhancement (ADE) of infection. Therefore, understanding the cellular, biochemical and molecular basis of antibody-mediated neutralization and ADE are fundamental for the development of a safe DENV vaccine. Here we summarize current structural and mechanistic knowledge underlying these phenomena. We also review recent results demonstrating that the humoral immune response triggered during natural DENV infection is able to generate neutralizing antibodies binding complex quaternary epitopes only present on the surface of intact virions. PMID- 26577690 TI - RESTORE: an exploratory trial of a web-based intervention to enhance self management of cancer-related fatigue: findings from a qualitative process evaluation. AB - BACKGROUND: Cancer-related fatigue is a distressing symptom experienced by many after cancer treatment. An exploratory randomised controlled trial was conducted to test proof of concept of RESTORE: a web-based tool to enhance self-efficacy to manage cancer-related fatigue. This paper reports findings from a qualitative process evaluation to determine feasibility and acceptability of the intervention and trial processes. METHOD: Qualitative process evaluation carried out at the end of the trial to explore participants' experiences using semi-structured telephone interviews with a purposive sample of participants from both trial arms. Normalisation Process Theory informed data collection and analysis. Analysis involved directed content analysis within a Framework Approach. RESULTS: Nineteen participants took part. They understood the purpose and requirements of the trial and identified beneficial outcomes from taking part. For the majority, the work of the trial was easily accommodated into daily routines and did not require new skills. There were mixed views about the value of the information provided by RESTORE, depending on time since diagnosis and treatment. Personal factors, constraints of the intervention, and environmental context inhibited the integration and embedding of RESTORE into everyday life. Access to the intervention at an early stage in the treatment trajectory was important to effective utilisation, as were individual preferences for delivery of information. CONCLUSION: The theoretical foundations of the intervention were sound. Participants derived benefits from the intervention but barriers to implementation and integration suggest that RESTORE and the trial processes require some modification before testing in a full trial. TRIAL REGISTRATION: ISRCTN67521059 (10(th) October 2012). PMID- 26577693 TI - A triphenylamine-based colorimetric and fluorescent probe with donor-bridge acceptor structure for detection of G-quadruplex DNA. AB - In this Letter, three triphenylamine-based dyes (TPA-1, TPA-2a and TPA-2b) with donor-bridge-acceptor (D-p-A) structure were designed and synthesized for the purpose of G-quadruplexes recognition. In aqueous conditions, the interactions of the dyes with G-quadruplexes were studied with the aim to establish the influence of the geometry of the dyes on their binding and probing properties. Results indicate that TPA-2b displays significant selective colorimetric and fluorescent changes upon binding of G-quadruplex DNA. More importantly, its distinct color change enables visual detection and differentiation of G-quadruplexes from single and duplex DNA structures. CD titration date reveals that TPA-2b could induce and stabilize the formation of G-quadruplex structure. All these remarkable properties of TPA-2b suggest that it should have promising application in the field of G-quadruplexes research. PMID- 26577692 TI - Outcomes following the implementation of a quality control campaign to decrease sternal wound infections after coronary artery by-pass grafting. AB - BACKGROUND: Coronary artery by-pass grafting (CABG) remains the optimal strategy in achieving complete revascularization in patients with complex coronary artery disease. However, sternal wound infections (SWI), especially deep SWI are potentially severe complications to the surgery. At the department of cardiothoracic surgery in Uppsala University Hospital a gradual increase in all types of SWI occurred, which peaked in 2009. This prompted an in-depth revision of the whole surgical process. To monitor the frequency of post-operative infections all patients receive a questionnaire that enquires whether any treatment for wound infection has been carried out. METHODS: All patients operated with isolated CABG between start of 2006 and end of 2012 were included in the study. 1515 of 1642 patients answered and returned the questionnaire (92.3 %). The study period is divided into the time before the intervention program was implemented (2006-early 2010) and the time after the intervention (early 2010- end 2012). To assess whether potential differences in frequency of SWI were a consequence of change in the characteristics of the patient population rather than an effect of the intervention a retrospective assessment of medical records was performed, where multiple of the most known risk factors for developing SWI were studied. RESULTS: We noticed a clear decrease in the frequency of SWI after the intervention. This was not a consequence of a healthier population. CONCLUSIONS: Our results from implementing the intervention program are positive in that they reduce the number of SWI. As several changes in the perioperative care were introduced simultaneously we cannot deduce which is the most effective. PMID- 26577691 TI - Azacitidine with or without Entinostat for the treatment of therapy-related myeloid neoplasm: further results of the E1905 North American Leukemia Intergroup study. AB - Therapy-related myeloid neoplasms (tMN) are serious late effects of the treatment of cancer with poor response to conventional treatment. Azacitidine (AZA) has been used to treat patients with tMN but current data are retrospective. We present here 47 tMN patients prospectively enrolled as a specific cohort in the E1905 study. TheE1905 study was a randomized phase 2 study (NCT00313586) testing 10 d of AZA (50 mg/m(2) /d) +/- the histone deacetylase inhibitor entinostat (4 mg/m(2) /d PO day-3 and day-10). A total of 47 patients [29 therapy-related myelosyspastic syndrome (t-MDS) and 18 therapy-related acute myeloid leukaemia (t AML)] were recruited to the study. 24 patients were treated with AZA monotherapy and 23 with AZA+entinostat. The median number of administered cycles was 4, significantly higher in patients treated with AZA (6 cycles vs. 3 cycles, P = 0.008). Haematological normalization rates were 46% in monotherapy and 17% in the combination arm. Median overall survivals were 13 and 6 months, respectively. The novel 50 * 10 schedule of azacitidine appears effective, with response rates, when given as single agent, comparable to those for patients with de novo MDS/AML treated on the same protocol. However, the combination of AZA and entinostat was associated with increased toxicity and could not be recommended for treatment of tMN. PMID- 26577694 TI - Mechanism of action of antiepileptic ceramide from Red Sea soft coral Sarcophyton auritum. AB - Chemical investigation of the Red Sea soft coral Sarcophyton auritum led to the isolation and structure elucidation of a new ceramide N-((2S,3R,4E,6E)-1,3 dihydroxyhenicosa-4,6-dien-2-yl)tridecanamide (1). Structure elucidation was achieved using spectroscopic techniques, including 1D and 2D NMR and HRMS. The anticonvulsant activity of the isolated ceramide was measured in vivo using the pentylenetetrazole (PTZ)-induced seizure model, where it successfully antagonized the lethality of pentylenetetrazole in mice. In addition, the isolated ceramide showed good anxiolytic activity when used in the light-dark transition box and the elevated plus maze compared to diazepam. The molecular modeling studies for the antiepileptic and antianxiety mechanism of the isolated ceramide suggested a CNS depressing activity possibly through GABA and serotonin receptors modulation. The pharmacological activity of the ceramide involved agonistic activity on GABA A receptors but not 5HT3 receptors. PMID- 26577695 TI - Structural measurements and cell line studies of the copper- PEG-Amikacin complex against Mycobacterium tuberculosis. AB - The bacterium responsible for causing tuberculosis is increasing its resistance to antibiotics resulting in new multidrug-resistant Mycobacterium tuberculosis (MDR-TB) and extensively drug-resistant M. tuberculosis (XDR-TB) strains. In this study, several analytical techniques including NMR, FT-ICR, MALDI-MS, and LC-MS are used to study different aspects of the Copper-polyethylene glycol (PEG) Amikacin complex. The Cu(II) cation and the aggregate formed by PEG serve as a carrier for the antibiotic. Several Cu-PEG-Amikacin complex variations were tested against NIH-NIAID cell lines containing both resistant and nonresistant strains of M. tuberculosis. PMID- 26577696 TI - No adaptation of a herbivore to a novel host but loss of adaptation to its native host. AB - Most herbivorous arthropods are host specialists and the question is which mechanisms drive the evolution of such specialization. The theory of antagonistic pleiotropy suggests that there is a trade-off between adaptation of herbivores to a novel host and their native host. The mutation accumulation hypothesis proposes that herbivores on a novel host lose their adaptation to the native host through the accumulation of mutations with negligible effects on performance on the novel host. Experimental evidence for either of the two hypotheses is scarce. We compared the fitness of two sympatric moth strains from an introduced host and a native host. The strain from the novel host did not perform better on this host than the strain from the native host. The strain from the novel host performed less well on the native host than did the strain from the native host. Hence, selection on the novel host did not result in noticeable gain in performance, but adaptation to the native host was lost. These results are more readily explained by the mutation-accumulation hypothesis than by the trade-off hypothesis. PMID- 26577697 TI - Actinobacillus pleuropneumoniae induces SJPL cell cycle arrest in G2/M-phase and inhibits porcine reproductive and respiratory syndrome virus replication. AB - BACKGROUND: Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most important pathogens in the swine industry and causes important economic losses. No effective antiviral drugs against it are commercially available. We recently reported that the culture supernatant of Actinobacillus pleuropneumoniae, the porcine pleuropneumonia causative agent, has an antiviral activity in vitro against PRRSV in SJPL cells. Objectives of this study were (i) to identify the mechanism behind the antiviral activity displayed by A. pleuropneumoniae and (ii) to characterize the active molecules present in the bacterial culture supernatant. METHODS: Antibody microarray analysis was used in order to point out cellular pathways modulated by the A. pleuropneumoniae supernatant. Subsequent, flow cytometry analysis and cell cycle inhibitors were used to confirm antibody microarray data and to link them to the antiviral activity of the A. pleuropneumoniae supernatant. Finally, A. pleuropneumoniae supernatant characterization was partially achieved using mass spectrometry. RESULTS: Using antibody microarray, we observed modulations in G2/M-phase cell cycle regulation pathway when SJPL cells were treated with A. pleuropneumoniae culture supernatant. These modulations were confirmed by a cell cycle arrest at the G2/M-phase when cells were treated with the A. pleuropneumoniae culture supernatant. Furthermore, two G2/M-phase cell cycle inhibitors demonstrated the ability to inhibit PRRSV infection, indicating a potential key role for PRRSV infection. Finally, mass spectrometry lead to identify two molecules (m/z 515.2 and m/z 663.6) present only in the culture supernatant. CONCLUSIONS: We demonstrated for the first time that A. pleuropneumoniae is able to disrupt SJPL cell cycle resulting in inhibitory activity against PRRSV. Furthermore, two putative molecules were identified from the culture supernatant. This study highlighted the cell cycle importance for PRRSV and will allow the development of new prophylactic or therapeutic approaches against PRRSV. PMID- 26577698 TI - Polyandry and postcopulatory sexual selection in a wild population. AB - When females mate multiply, postcopulatory sexual selection can occur via sperm competition and cryptic female choice. Although postcopulatory selection has the potential to be a major force in driving evolution, few studies have estimated its strength in natural populations. Likewise, although polyandry is widespread across taxa and is the focus of a growing body of research, estimates of natural female mating rates are still limited in number. Microsatellites can be used to estimate the number of mates represented in females' sperm stores and the number of sires contributing to their offspring, enabling comparisons both of polyandry and of two components of postcopulatory selection: the proportion of males that mate but fail to sire offspring, and the degree of paternity skew among the males that do sire offspring. Here, we estimate the number of mates and sires among wild females in the Hawaiian swordtail cricket Laupala cerasina. We compare these estimates to the actual mating rates and paternity shares we observed in a semi natural population. Our results show that postcopulatory sexual selection operates strongly in this species: wild females mated with an average minimum of 3.6 males but used the sperm from only 58% of them. Furthermore, among the males that did sire offspring, paternity was significantly skewed. These patterns were similar to those observed in the field enclosure, where females mated with an average of 5.7 males and used the sperm from 62% of their mates, with paternity significantly skewed among the sires. PMID- 26577700 TI - Maximizing the Efficacy of MAPK-Targeted Treatment in PTENLOF/BRAFMUT Melanoma through PI3K and IGF1R Inhibition. AB - The introduction of MAPK pathway inhibitors paved the road for significant advancements in the treatment of BRAF-mutant (BRAF(MUT)) melanoma. However, even BRAF/MEK inhibitor combination therapy has failed to offer a curative treatment option, most likely because these pathways constitute a codependent signaling network. Concomitant PTEN loss of function (PTEN(LOF)) occurs in approximately 40% of BRAF(MUT) melanomas. In this study, we sought to identify the nodes of the PTEN/PI3K pathway that would be amenable to combined therapy with MAPK pathway inhibitors for the treatment of PTEN(LOF)/BRAF(MUT) melanoma. Large-scale compound sensitivity profiling revealed that PTEN(LOF) melanoma cell lines were sensitive to PI3Kbeta inhibitors, albeit only partially. An unbiased shRNA screen (7,500 genes and 20 shRNAs/genes) across 11 cell lines in the presence of a PI3Kbeta inhibitor identified an adaptive response involving the IGF1R-PI3Kalpha axis. Combined inhibition of the MAPK pathway, PI3Kbeta, and PI3Kalpha or insulin like growth factor receptor 1 (IGF1R) synergistically sustained pathway blockade, induced apoptosis, and inhibited tumor growth in PTEN(LOF)/BRAF(MUT) melanoma models. Notably, combined treatment with the IGF1R inhibitor, but not the PI3Kalpha inhibitor, failed to elevate glucose or insulin signaling. Taken together, our findings provide a strong rationale for testing combinations of panPI3K, PI3Kbeta + IGF1R, and MAPK pathway inhibitors in PTEN(LOF)/BRAF(MUT) melanoma patients to achieve maximal response. PMID- 26577699 TI - Fibulin-5 Blocks Microenvironmental ROS in Pancreatic Cancer. AB - Elevated oxidative stress is an aberration seen in many solid tumors, and exploiting this biochemical difference has the potential to enhance the efficacy of anticancer agents. Homeostasis of reactive oxygen species (ROS) is important for normal cell function, but excessive production of ROS can result in cellular toxicity, and therefore ROS levels must be balanced finely. Here, we highlight the relationship between the extracellular matrix and ROS production by reporting a novel function of the matricellular protein Fibulin-5 (Fbln5). We used genetically engineered mouse models of pancreatic ductal adenocarcinoma (PDAC) and found that mutation of the integrin-binding domain of Fbln5 led to decreased tumor growth, increased survival, and enhanced chemoresponse to standard PDAC therapies. Through mechanistic investigations, we found that improved survival was due to increased levels of oxidative stress in Fbln5-mutant tumors. Furthermore, loss of the Fbln5-integrin interaction augmented fibronectin signaling, driving integrin-induced ROS production in a 5-lipooxygenase-dependent manner. These data indicate that Fbln5 promotes PDAC progression by functioning as a molecular rheostat that modulates cell-ECM interactions to reduce ROS production, and thus tip the balance in favor of tumor cell survival and treatment-refractory disease. PMID- 26577701 TI - SKAP2 Promotes Podosome Formation to Facilitate Tumor-Associated Macrophage Infiltration and Metastatic Progression. AB - Tumor-associated macrophages (TAM) play complex and pivotal roles during cancer progression. A subset of metastasis-associated macrophages accumulates within metastatic sites to promote the invasion and growth of tumor cells. Src kinase associated phosphoprotein 2 (SKAP2), a substrate of Src family kinases, is highly expressed in macrophages from various tumors, but its contribution to the tumor promoting behavior of TAMs is unknown. Here, we report that SKAP2 regulates podosome formation in macrophages to promote tumor invasion and metastasis. SKAP2 physically interacted with Wiskott-Aldrich syndrome protein (WASP) and localized to podosomes, which were rarely observed in SKAP2-null macrophages. The invasion of peritoneal macrophages derived from SKAP2-null mice was significantly reduced compared with wild-type macrophages, but could be rescued by the restoration of functional SKAP2 containing an intact tyrosine phosphorylation site and the ability to interact with WASP. Furthermore, SKAP2-null mice inoculated with lung cancer cells exhibited markedly decreased lung metastases characterized by reduced macrophage infiltration compared with wild-type mice. Moreover, intravenously injected SKAP2-null macrophages failed to efficiently infiltrate established tumors and promote their growth. Taken together, these findings reveal a novel mechanism by which macrophages assemble the appropriate motile machinery to infiltrate tumors and promote disease progression, and implicate SKAP2 as an attractive candidate for therapeutically targeting TAMs. PMID- 26577702 TI - Tracing the structural evolution of eukaryotic ATP binding cassette transporter superfamily. AB - The ATP binding cassette (ABC) transporters superfamily is one of the largest classes of membrane proteins. The core of the ABC transporter protein is composed of transmembrane domains (TMDs) and nucleotide binding domains (NBD). Eukaryotes ABC transporters are classified into seven main families (ABCA to ABCG) based on sequence similarity and domain organizations. With different domain number and domain organizations, eukaryote ABC transporters show diverse structures: the single structure (NBD or TMD), the ABC2 structure (NBD-NBD), the half structure (TMD-NBD or NBD-TMD) and the full structure (TMD-NBD-TMD-NBD or NBD-TMD-NBD-TMD). However, studies on how various ABC transporter gene structures evolved is still absent. Therefore, in this study, we comprehensively investigated the structural evolution of eukaryotic ABC transporters. The seven eukaryote ABC transporter families (A to G) fell into three groups: A&G group, B,C&D group and E&F group. There were at least four times the number of NBD and TMD fusion events in the origin of the half structure transporter. Two fusion modes were found in the full and ABC2 structure origination. Based on these findings, we present a putative structural evolutionary path of eukaryote ABC transporters that will increase our understanding on their origin, divergence and function. PMID- 26577703 TI - A synergistic approach of adapalene-loaded nanostructured lipid carriers, and vitamin C co-administration for treating acne. AB - The present study documents the fabrication and characterization of a topically applicable gel loaded with nanostructured lipid carriers (NLCs) of adapalene (ADA) and vitamin C (ascorbyl-6-palmitate [AP]). The NLCs were prepared by high pressure homogenization (HPH) method followed by incorporation into AP loaded gel. The fabricated system was characterized for size, poly dispersity index, entrapment efficiency (EE) and in vitro drug release properties, and was further investigated for skin compliance, skin transport characteristics (skin permeation and bio-distribution), rheological behavior, texture profile analysis and anti acne therapeutic potential against testosterone-induced acne in male Wistar rats. The NLC-based formulation improved targeting of the skin epidermal layer and reducing systemic penetration. The co-administration of vitamin C led to an adjunct effect in acne therapy in physiological conditions. In brief, the present results suggest the potential of NLCs as a novel carrier for the dermal delivery of ADA and also the synergistic effect of vitamin C in topical therapeutics. PMID- 26577704 TI - Salient cues improve prospective remembering in Korsakoff's syndrome. AB - OBJECTIVE: Korsakoff's syndrome is characterized by deficits in episodic memory and executive functions. Both cognitive functions are needed to remember to execute delayed intentions (prospective memory, PM), an ability that is crucial for independent living in everyday life. So far, PM has only been targeted by one study in Korsakoff's syndrome. This study explored the effects of executive control demands on PM to shed further light on a possible interdependence of memory and executive functions in Korsakoff's syndrome, METHOD: Twenty-five individuals with Korsakoff's syndrome and 23 chronic alcoholics (without amnesia) performed a categorization task into which a PM task was embedded that put either high or low demands on executive control processes (using low vs. high salient cues). RESULTS: Overall, Korsakoff patients had fewer PM hits than alcoholic controls. Across groups, participants had fewer PM hits when cues were low salient as compared to high salient. Korsakoff patients performed better on PM when highly salient cues were presented than cues of low salience, while there were no differential effects for alcoholic controls. CONCLUSIONS: While overall Korsakoff patients' showed a global PM deficit, the extent of this deficit was moderated by the executive control demands of the task applied. This indicated further support for an interrelation of executive functions and memory performance in Korsakoff. PRACTITIONER POINTS: Positive clinical implications of the work Prospective memory (PM) performance in Korsakoff's syndrome is related to executive control load. Increasing cues' salience improves PM performance in Korsakoff's syndrome. Salient visual aids may be used in everyday life to improve Korsakoff individuals' planning and organization skills. Cautions or limitations of the study Results were obtained in a structured laboratory setting and need to be replicated in a more naturalistic setting to assess their transferability to everyday life. Given the relatively small sample size, individual predictors of PM performance should be determined in larger samples. PMID- 26577705 TI - Selective Coordination of Gallium(III), Zinc(II), and Copper(II) by an Asymmetric Dinucleating Ligand: A Model for Metallophosphatases. AB - Complexation studies of the dinucleating ligand H3 L (H3 L=2-{[bis(pyridin-2 ylmethyl)amino]methyl}-6-{[bis(6-pivaloylamidopyridin-2-ylmethyl)amino]methyl}-4 methylphenol), with metal-binding sites A and B, which both provide four donors to a metal ion; a tertiary amine; two pyridines (substituted with amide hydrogen bond donors in site B), and a bridging phenolate, with Zn(II) , Cu(II) , and Ga(III) are reported. The titration of H3 L with the three metal ions in solution was monitored by NMR spectroscopy or EPR and UV/Vis/near-IR spectroscopy, as well as by ESI-MS to analyze the selectivity of the two metal-ion sites A and B of this model ligand for metallophosphatases; the spectroscopic assignments are supported by X-ray crystallography results. The first Zn(II) ion coordinates to site A with unsubstituted pyridine donors and, upon addition of a second equivalent of Zn(II) , this coordinates to the sterically less accessible site B. From a similar titration with Ga(III) , it emerges that only a mononuclear complex is obtained, with the Ga(III) center coordinated to site A. When one equivalent of Ga(III) is reacted with the mononuclear Zn(II) complex, Zn(II) is forced by Ga(III) to exchange the site; this results in a dinuclear complex with Ga(III) in site A and Zn(II) in site B. With Cu(II) , two isomers are observed: one with and the other without a bridging phenolate; these differ significantly in their spectroscopic and magnetic properties. PMID- 26577706 TI - Optimized curcumin formulations for the treatment of Alzheimer's disease: A patent evaluation. PMID- 26577707 TI - LC-MS/MS method for the determination of haemanthamine in rat plasma, bile and urine and its application to a pilot pharmacokinetic study. AB - Evidence gathered in various studies points to the fact that haemanthamine, an isoquinoline alkaloid, has multiple medicinally interesting characteristics, including antitumor, antileukemic, antioxidant, antiviral, anticonvulsant and antimalarial activity. This work presents, for the first time, a universal LC MS/MS method for analysis of haemanthamine in plasma, bile and urine which has been verified in a pilot pharmacokinetic experiment on rats. Chromatographic separation was performed on a pentafluorophenyl core-shell column in gradient elution mode with a mobile phase consisting of acetonitrile-methanol-ammonium formate buffer. A sample preparation based on liquid-liquid extraction with methyl tert-butyl ether was employed with ambelline used as an internal standard. Quantification was performed using LC-MS-ESI(+) in Selected Reaction Monitoring mode. The method was validated according to the European Medicines Agency guideline in a concentration range of 0.1-10 MUmol/L in plasma, bile and urine. The concentration-time profiles of haemanthamine in plasma, bile and urine after a single i.v. bolus of 10 mg/kg have been described for the first time. The presented study addresses the lack of information on haemanthamine pharmacokinetics and also introduces a new universal method of haemanthamine analysis in complex biological matrices. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26577708 TI - Elevated CO2 promotes long-term nitrogen accumulation only in combination with nitrogen addition. AB - Biogeochemical models that incorporate nitrogen (N) limitation indicate that N availability will control the magnitude of ecosystem carbon uptake in response to rising CO2 . Some models, however, suggest that elevated CO2 may promote ecosystem N accumulation, a feedback that in the long term could circumvent N limitation of the CO2 response while mitigating N pollution. We tested this prediction using a nine-year CO2 xN experiment in a tidal marsh. Although the effects of CO2 are similar between uplands and wetlands in many respects, this experiment offers a greater likelihood of detecting CO2 effects on N retention on a decadal timescale because tidal marshes have a relatively open N cycle and can accrue soil organic matter rapidly. To determine how elevated CO2 affects N dynamics, we assessed the three primary fates of N in a tidal marsh: (1) retention in plants and soil, (2) denitrification to the atmosphere, and (3) tidal export. We assessed changes in N pools and tracked the fate of a (15) N tracer added to each plot in 2006 to quantify the fraction of added N retained in vegetation and soil, and to estimate lateral N movement. Elevated CO2 alone did not increase plant N mass, soil N mass, or (15) N label retention. Unexpectedly, CO2 and N interacted such that the combined N+CO2 treatment increased ecosystem N accumulation despite the stimulation in N losses indicated by reduced (15) N label retention. These findings suggest that in N-limited ecosystems, elevated CO2 is unlikely to increase long-term N accumulation and circumvent progressive N limitation without additional N inputs, which may relieve plant-microbe competition and allow for increased plant N uptake. PMID- 26577709 TI - Computed tomographic angiography of the superficial cerebral venous anastomosis based on volume rendering, multi-planar reconstruction, and integral imaging display. AB - As damage to the superficial cerebral venous anastomosis may create catastrophic complications even after successful surgery, it is important to visualize and determine the normal features of the venous anastomosis with computed tomographic angiography. A total of 90 patients underwent a 64-detector row helical CT scan of head. The superficial cerebral venous anastomosis was reconstructed by volume rendering, multi-planar reconstruction, and integral display algorithm. In particular, we examined the vein of Trolard, the vein of Labbe, and the vein of Sylvian, in order to analyze the venous anastomosis. The superficial cerebral venous anastomosis varied across different individuals, and in this study, six types of anastomosis were found. In 28 % of patients, no venous anastomosis was found in the unilateral cerebral hemisphere. The display rate of the vein of Trolard, the vein of Labbe, and the vein of Sylvian in contributing to venous anastomosis was 70, 80, and 91 %, respectively. The number of vein of Trolard and vein of Labbe on the left side was greater than that of those on the right side. We implemented the 64-detector row helical CT as a rapid and noninvasive method to investigate the superficial cerebral venous anastomosis in our group of patients. We performed substantial image processing for the visualization of the superficial cerebral venous anastomosis; this would not only enable the early diagnosis of cerebral venous disease, but also protect the cerebral vein during neurosurgical intervention. PMID- 26577710 TI - Physiologic outcome of varying speed rotary blood pump support algorithms: a review study. AB - Rotary blood pumps have the potential to become a viable long-term treatment option for the heart failure patients to bridge to transplantation or destination therapy. However, these devices operate at a constant speed which may lead to long term complications or they may operate in an undesired support mode such as excessive pumping in the patients' body. A possible solution to such physiological problems or using these devices as a destination therapy or maintaining the optimal support level according to changing conditions in the body is applying a varying speed rotary blood pump support. Over the years, different varying operating speed support algorithms have been proposed to alleviate the effect of the constant speed rotary blood pump support and improve the outcome of these devices. In this paper, it is aimed to compile and present proposed varying speed rotary blood pump support algorithms by classifying them according to the considered physiological problem in each study. PMID- 26577711 TI - Impact of 4D image quality on the accuracy of target definition. AB - Delineation accuracy of target shape and position depends on the image quality. This study investigates whether the image quality on standard 4D systems has an influence comparable to the overall delineation uncertainty. A moving lung target was imaged using a dynamic thorax phantom on three different 4D computed tomography (CT) systems and a 4D cone beam CT (CBCT) system using pre-defined clinical scanning protocols. Peak-to-peak motion and target volume were registered using rigid registration and automatic delineation, respectively. A spatial distribution of the imaging uncertainty was calculated as the distance deviation between the imaged target and the true target shape. The measured motions were smaller than actual motions. There were volume differences of the imaged target between respiration phases. Imaging uncertainties of >0.4 cm were measured in the motion direction which showed that there was a large distortion of the imaged target shape. Imaging uncertainties of standard 4D systems are of similar size as typical GTV-CTV expansions (0.5-1 cm) and contribute considerably to the target definition uncertainty. Optimising and validating 4D systems is recommended in order to obtain the most optimal imaged target shape. PMID- 26577712 TI - A sparse Bayesian learning based scheme for multi-movement recognition using sEMG. AB - This paper proposed a feature extraction scheme based on sparse representation considering the non-stationary property of surface electromyography (sEMG). Sparse Bayesian learning was introduced to extract the feature with optimal class separability to improve recognition accuracy of multi-movement patterns. The extracted feature, sparse representation coefficients (SRC), represented time varying characteristics of sEMG effectively because of the compressibility (or weak sparsity) of the signal in some transformed domains. We investigated the effect of the proposed feature by comparing with other fourteen individual features in offline recognition. The results demonstrated the proposed feature revealed important dynamic information in the sEMG signals. The multi-feature sets formed by the SRC and other single feature yielded more superior performance on recognition accuracy, compared with the single features. The best average recognition accuracy of 94.33% was gained by using SVM classifier with the multi feature set combining the feature SRC, Williston amplitude (WAMP), wavelength (WL) and the coefficients of the fourth order autoregressive model (ARC4) via multiple kernel learning framework. The proposed feature extraction scheme (known as SRC + WAMP + WL + ARC4) is a promising method for multi-movement recognition with high accuracy. PMID- 26577713 TI - Patient-specific geometrical modeling of orthopedic structures with high efficiency and accuracy for finite element modeling and 3D printing. AB - We improved the geometrical modeling procedure for fast and accurate reconstruction of orthopedic structures. This procedure consists of medical image segmentation, three-dimensional geometrical reconstruction, and assignment of material properties. The patient-specific orthopedic structures reconstructed by this improved procedure can be used in the virtual surgical planning, 3D printing of real orthopedic structures and finite element analysis. A conventional modeling consists of: image segmentation, geometrical reconstruction, mesh generation, and assignment of material properties. The present study modified the conventional method to enhance software operating procedures. Patient's CT images of different bones were acquired and subsequently reconstructed to give models. The reconstruction procedures were three-dimensional image segmentation, modification of the edge length and quantity of meshes, and the assignment of material properties according to the intensity of gravy value. We compared the performance of our procedures to the conventional procedures modeling in terms of software operating time, success rate and mesh quality. Our proposed framework has the following improvements in the geometrical modeling: (1) processing time: (femur: 87.16 +/- 5.90 %; pelvis: 80.16 +/- 7.67 %; thoracic vertebra: 17.81 +/- 4.36 %; P < 0.05); (2) least volume reduction (femur: 0.26 +/- 0.06 %; pelvis: 0.70 +/- 0.47, thoracic vertebra: 3.70 +/- 1.75 %; P < 0.01) and (3) mesh quality in terms of aspect ratio (femur: 8.00 +/- 7.38 %; pelvis: 17.70 +/- 9.82 %; thoracic vertebra: 13.93 +/- 9.79 %; P < 0.05) and maximum angle (femur: 4.90 +/- 5.28 %; pelvis: 17.20 +/- 19.29 %; thoracic vertebra: 3.86 +/- 3.82 %; P < 0.05). Our proposed patient-specific geometrical modeling requires less operating time and workload, but the orthopedic structures were generated at a higher rate of success as compared with the conventional method. It is expected to benefit the surgical planning of orthopedic structures with less operating time and high accuracy of modeling. PMID- 26577714 TI - Dosimetric study of different radiotherapy planning approaches for hippocampal avoidance whole-brain radiation therapy (HA-WBRT) based on fused CT and MRI imaging. AB - The purpose of this study was to compare the dosimetric characteristics for hippocampal avoidance (HA) between the treatment plans based on fused CT and MRI imaging during whole brain radiotherapy (WBRT) pertaining to: (1) 3-dimensional conformal radiotherapy (3D-CRT), (2) dynamic intensity modulated radiation therapy (dIMRT), and (3) RapidArc for patients with brain metastases. In our study, HA was defined as hippocampus beyond 5 mm, and planning target volume (PTV) was obtained subtracting HA volume from the volume of whole brain. There were 10 selected patients diagnosed with brain metastases receiving WBRT. These patients received plans for 3D-CRT (two fields), dIMRT (seven non-coplanar fields) and RapidArc (dual arc). The prescribed dose 30 Gy in 10 fractions was delivered to the whole-brain clinical target volume of patients. On the premise of meeting the clinical requirements, we compared target dose distribution, target coverage (TC), homogeneity index (HI), dose of organs at risk (OARs), monitor units (MU) and treatment time between the above three radiotherapy plans. V90 %, V95 % and TC of PTV for 3D-CRT plan were lowest of the three plans. V90 %, V95 % and HI of PTV in RapidArc plan were superior to the other two plans. TC of PTV in RapidArc plan was similar with dIMRT plan (P > 0.05). 3D-CRT was the optimal plan in the three plans for hippocampal protection. The median dose (Dmedian) and the maximum doses (Dmax) of hippocampus in 3D-CRT were 4.95, 10.87 Gy, which were lowest among the three planning approaches (P < 0.05). Dmedian and Dmax of hippocampus in dIMRT were 10.68, 14.11 Gy. Dmedian and Dmax of hippocampus in RapidArc were 10.30 gGy, 13.92 Gy. These parameters of the last two plans pertain to no significant difference (P > 0.05). When WBRT (30 Gy,10F) was equivalent to single dose 2 Gy,NTDmean of hippocampus in 3D-CRT, dIMRT and RapidArc were reduced to 3.60, 8.47, 8.20 Gy2, respectively. In addition, compared with dIMRT, MU of RapidArc was reduced and the treatment time was shortened by nearly 25 %. All three radiotherapy planning approaches in our study can meet the clinical requirements of HA. Although TC in 3D-CRT was lowest, hippocampus was protected best by this plan. So many radiation fields and the design of non-coplanar fields lead to the complication of dIMRT. TC and HI in RapidArc were superior to the other two plans with the precise of meeting the clinical requirements. The difference in protection for hippocampus between dIMRT and RapidArc was statistically significant. In addition, RapidArc can remarkably reduce MU and the treatment time. PMID- 26577715 TI - An economic analysis of private incentives to adopt DNA barcoding technology for fish species authentication in Canada. AB - The increasing spate of species substitution and mislabelling in fish markets has become a concern to the public and a challenge to both the food industry and regulators. Species substitution and mislabelling within fish supply chains occurs because of price incentives to misrepresent products for economic gain. Emerging authenticity technologies, such as the DNA barcoding technology that has been used to identify plants and animal (particularly fish) species through DNA sequencing, offer a potential technological solution to this information problem. However, the adoption of these authenticity technologies depends also on economic factors. The present study uses economic welfare analysis to examine the effects of species substitution and mislabelling in fish markets, and examines the feasibility of the technology for a typical retail store in Canada. It is assumed that increased accuracy of the technology in detecting fraud and enforcement of legal penalties and other associated costs would be likely to discourage cheating. Empirical results suggest that DNA barcoding technology would be feasible presently for a typical retail store only if authentication is done in a third party laboratory, as it may not be feasible on an individual retail store level once fixed and other associated costs of the technology are considered. PMID- 26577716 TI - 10-year trajectory of beta-cell function and insulin sensitivity in the development of type 2 diabetes: a community-based prospective cohort study. AB - BACKGROUND: The relative contributions of beta-cell function and insulin sensitivity in the pathogenesis of type 2 diabetes are not fully understood. We investigated the longitudinal change in beta-cell function and insulin sensitivity in the development of diabetes and the role of genetic variants in deterioration of glucose tolerance. METHODS: We followed up 4106 participants with normal glucose tolerance (NGT) from the Korean Genome and Epidemiology Study with oral glucose tolerance tests every 2 years for 10 years. We estimated pancreatic beta-cell function with the 60 min insulinogenic index (IGI60) and insulin sensitivity with the composite (Matsuda) insulin sensitivity index (ISI). We investigated the association of 66 known type 2 diabetes genetic variants with risk of prediabetes or diabetes and impaired beta-cell function and insulin sensitivity. FINDINGS: During 10 years of follow-up, 1093 (27%) of 4106 participants developed prediabetes and 498 (12%) participants developed diabetes. Compared with participants who remained NGT, those who progressed to diabetes had a lower IGI60 (unadjusted data 5.1 MUU/mmol [95% CI 0.5-56.1] vs 7.9 MUU/mmol [0.5-113.8]; p<0.0001) and lower ISI (unadjusted data 8.2 [2.6-26.0] vs 10.0 [3.2 31.6]; p<0.0001) at baseline. Participants who had NGT at 10 years showed a decrease in ISI (adjusted data 10.1 [9.9-10.3] vs 7.4 [7.3-7.6]; p<0.0001) but a compensatory increase in IGI60 (adjusted data 6.9 MUU/mmol [6.5-7.2] vs 11.7 MUU/mmol [11.2-12.1]; p<0.0001) compared with baseline. By contrast, participants who developed diabetes showed a decrease in ISI (adjusted data 8.4 [8.0-8.7] vs 3.0 [2.8-3.2]; p<0.0001) but no significant compensatory increase (p=0.95) in IGI60. A genetic variant near the glucokinase gene (rs4607517) was significantly associated with progression to prediabetes or diabetes (hazard ratio 1.27, 1.16 1.38; p=1.70 * 10(-7)). INTERPRETATION: Decreased beta-cell function, which might be determined partly by genetic factors, and impaired beta-cell compensation for progressive decline in insulin sensitivity are crucial factors in the deterioration of glucose tolerance. FUNDING: South Korean Ministry of Health & Welfare. PMID- 26577717 TI - Type 2 diabetes via beta-cell dysfunction in east Asian people. PMID- 26577718 TI - Obesity: A Growing Multifaceted Problem. PMID- 26577719 TI - Atrial Fibrillation and Non-cardiovascular Diseases: A Systematic Review. AB - Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with an unfavorable prognosis, increasing the risk of stroke and death. Although traditionally associated with cardiovascular diseases, there is increasing evidence of high incidence of AF in patients with highly prevalent noncardiovascular diseases, such as cancer, sepsis, chronic obstructive pulmonary disease, obstructive sleep apnea and chronic kidney disease. Therefore, considerable number of patients has been affected by these comorbidities, leading to an increased risk of adverse outcomes.The authors performed a systematic review of the literature aiming to better elucidate the interaction between these conditions.Several mechanisms seem to contribute to the concomitant presence of AF and noncardiovascular diseases. Comorbidities, advanced age, autonomic dysfunction, electrolyte disturbance and inflammation are common to these conditions and may predispose to AF.The treatment of AF in these patients represents a clinical challenge, especially in terms of antithrombotic therapy, since the scores for stratification of thromboembolic risk, such as the CHADS2 and CHA2DS2VASc scores, and the scores for hemorrhagic risk, like the HAS-BLED score have limitations when applied in these conditions.The evidence in this area is still scarce and further investigations to elucidate aspects like epidemiology, pathogenesis, prevention and treatment of AF in noncardiovascular diseases are still needed. PMID- 26577720 TI - Case 5/2015 - 88-Year-Old Female with Chronic Coronary Artery Disease, Upper Limb Thrombosis, Atrial Fibrillation and Cardiac Arrest. PMID- 26577721 TI - Coronary Fistulas in a Patient with a Novel Long QT Syndrome Mutation. PMID- 26577722 TI - Post-Hospital Syndrome: A New Challenge in Cardiovascular Practice. AB - The image of the hospital representing the modern medicine and its diagnostic and therapeutic advances becomes more evident in the face of an aging population and patients with multiple comorbidities requiring highly complex care. However, recent studies have shown a growing number of hospital readmissions within 30 days after discharge. The post-hospital syndrome is a new clinical entity associated with multiple vulnerabilities that contribute to hospital readmissions. During hospitalization, the patient is exposed to different stressors of physical, environmental, and psychosocial natures that trigger pathophysiological and multisystemic responses and increase the risk of complications after hospital discharge. Patients with a cardiac disease have high rates of readmission within 30 days. Therefore, it is important for cardiologists to recognize the post-hospital syndrome since it may impact their daily practice. This review aims at discussing the current scientific evidence regarding predictors and stressors involved in the post-hospital syndrome and the measures that are currently being taken to minimize their effects. PMID- 26577723 TI - Arteriovenous and Intercoronary Fistulae Presenting as Heart Failure in an Adult. PMID- 26577724 TI - Prevalence of entomophthoralean fungi (Entomophthoromycota) of aphids in relation to developmental stages. AB - BACKGROUND: Transmission of fungal pathogens of aphids may be affected by the host developmental stage. Brassica and Lactuca sativa L. crops were sampled in Santa Fe, Argentina, to determine the prevalence of fungal-diseased aphids and investigate the differences between developmental stages of aphids. RESULTS: The fungal pathogens identified were Zoophthora radicans (Bref.) A. Batko, Pandora neoaphidis (Remaud. & Hennebert) Humber and Entomophthora planchoniana Cornu. Their prevalence on each crop was calculated. The numbers of infected aphids were significantly different between the different developmental stages on all crops except B. oleracea var. botrytis L. CONCLUSIONS: The entomophthoralean fungi identified are important mortality factors of aphids on horticultural crops in Santa Fe. The numbers of infected nymphs and adults were significantly different, nymphs being the most affected developmental stage. (c) 2015 Society of Chemical Industry. PMID- 26577726 TI - Protein labeling in Escherichia coli with (2)H, (13)C, and (15)N. AB - A number of structural biology techniques such as nuclear magnetic resonance spectroscopy and small-angle neutron scattering can be performed with proteins with nuclei at natural isotope abundance. However, the use of proteins labeled with stable isotopes ((2)H, (13)C, and (15)N) enables greater experimental flexibility. In this chapter, several methods for uniform and fractional protein labeling with stable isotopes using Escherichia coli in a defined media are described. The methods described can be used for labeling with single or multiple isotopes. PMID- 26577725 TI - Robust high-yield methodologies for (2)H and (2)H/(15)N/(13)C labeling of proteins for structural investigations using neutron scattering and NMR. AB - We have developed a method that has proven highly reliable for the deuteration and triple labeling ((2)H/(15)N/(13)C) of a broad range of proteins by recombinant expression in Escherichia coli BL21. Typical biomass yields are 40 80g/L wet weight, yielding 50-500mg/L purified protein. This method uses a simple, relatively inexpensive defined medium, and routinely results in a high yield expression without need for optimization. The key elements are very tight control of expression, careful starter culture adaptation steps, media composition, and strict maintenance of aerobic conditions ensuring exponential growth. Temperature is reduced as required to prevent biological oxygen demand exceeding maximum aeration capacity. Glycerol is the sole carbon source. We have not encountered an upper limit for the size of proteins that can be expressed, achieving excellent expression for proteins from 11 to 154kDa and the quantity produced at 1L scale ensures that no small-angle neutron scattering, nuclear magnetic resonance, or neutron crystallography experiment is limited by the amount of deuterated material. Where difficulties remain, these tend to be cases of altered protein solubility due to high protein concentration and a D2O-based environment. PMID- 26577727 TI - Escherichia coli auxotroph host strains for amino acid-selective isotope labeling of recombinant proteins. AB - Enrichment of proteins with isotopes such as (2)H, (15)N, and (13)C is commonly carried out in magnetic resonance and vibrational spectroscopic characterization of protein structures, mechanisms, and dynamics. Although uniform isotopic labeling of proteins is straightforward, efficient labeling of proteins with only a selected set of amino acid types is often challenging. A number of approaches have been described in the literature for amino acid-selective isotope labeling of proteins, each with its own limitations. Since Escherichia coli represents the most cost-effective and widely used host for heterologous production of foreign proteins, an efficient method to express proteins selectively labeled with isotopes would be highly valuable for these studies. However, an obvious drawback is misincorporation and dilution of input isotope labels to unwanted amino acid types due to metabolic scrambling in vivo. To overcome this problem, we have generated E. coli auxotroph strains that are compatible with the widely used T7 RNA polymerase overexpression systems and that minimize metabolic scrambling. We present several examples of selective amino acid isotope labeling of simple and complex proteins with bound cofactors, as an initial guide for practical applications of these E. coli strains. PMID- 26577728 TI - (19)F-modified proteins and (19)F-containing ligands as tools in solution NMR studies of protein interactions. AB - (19)F solution NMR is a powerful and versatile tool to study protein structure and protein-ligand interactions due to the favorable NMR characteristics of the (19)F atom, its absence in naturally occurring biomolecules, and small size. Protocols to introduce (19)F atoms into both proteins and their ligands are readily available and offer the ability to conduct protein-observe (using (19)F labeled proteins) or ligand-observe (using (19)F-containing ligands) NMR experiments. This chapter provides two protocols for the (19)F-labeling of proteins, using an Escherichia coli expression system: (i) amino acid type specific incorporation of (19)F-modified amino acids and (ii) site-specific incorporation of (19)F-modified amino acids using recombinantly expressed orthogonal amber tRNA/tRNA synthetase pairs. In addition, we discuss several applications, involving (19)F-modified proteins and (19)F-containing ligands. PMID- 26577729 TI - Biopolymer deuteration for neutron scattering and other isotope-sensitive techniques. AB - The use of microbial biosynthesis to produced deuterated recombinant proteins is a well-established practice in investigations of the relationship between molecular structure and function using neutron scattering and nuclear magnetic resonance spectroscopy. However, there have been few reports of using microbial synthetic capacity to produce labeled native biopolymers. Here, we describe methods for the production of deuterated polyhydroxyalkanoate biopolyesters in bacteria, the polysaccharide chitosan in the yeast Pichia pastoris, and cellulose in the bacterium Gluconacetobacter xylinus. The resulting molecules offer not only multiple options in creating structural contrast in polymer blends and composites in structural studies but also insight into the biosynthetic pathways themselves. PMID- 26577730 TI - Production of bacterial cellulose with controlled deuterium-hydrogen substitution for neutron scattering studies. AB - Isotopic enrichment of biomacromolecules is a widely used technique that enables the investigation of the structural and dynamic properties to provide information not accessible with natural abundance isotopic composition. This study reports an approach for deuterium incorporation into bacterial cellulose. A media formulation for growth of Acetobacter xylinus subsp. sucrofermentans and Gluconacetobacter hansenii was formulated that supports cellulose production in deuterium (D) oxide. The level of D incorporation can be varied by altering the ratio of deuterated and protiated glycerol used during cell growth in the D2O based growth medium. Spectroscopic analysis and mass spectrometry show that the level of deuterium incorporation is high (>90%) for the perdeuterated form of bacterial cellulose. The small-angle neutron scattering profiles of the cellulose with different amounts of D incorporation are all similar indicating that there are no structural changes in the cellulose due to substitution of deuterium for hydrogen. In addition, by varying the amount of deuterated glycerol in the media it was possible to vary the scattering length density of the deuterated cellulose. The ability to control deuterium content of cellulose extends the range of experiments using techniques such as neutron scattering to reveal information about the structure and dynamics of cellulose, and its interactions with other biomacromolecules as well as synthetic polymers used for development of composite materials. PMID- 26577731 TI - Isotopic labeling of proteins in Halobacterium salinarum. AB - It is often necessary to obtain isotopically labeled proteins containing (15)N, (13)C, or (2)H for nuclear magnetic resonance; and (2)H for small-angle neutron scattering or neutron diffraction studies. To achieve uniform isotopic labeling, protein expression is most commonly performed in Escherichia coli or yeast using labeled media. However, proteins from extreme halophiles sometimes require a cellular environment with high ionic strength and cannot be heterologously expressed in E. coli or yeast in functional form. We present here methods for the cultivation of Halobacterium salinarum in isotopically labeled rich media, using commercially available isotopically labeled hydrolysates. The methods described here are both technically simple and relatively inexpensive. PMID- 26577732 TI - Amino acid selective unlabeling in protein NMR spectroscopy. AB - Three-dimensional structure determination of proteins by NMR requires the acquisition of multidimensional spectra followed by assignment of chemical shifts to the respective nuclei. In order to speed up this process, resonances corresponding to individual amino acid types are often selectively identified and assigned. One of the ways of achieving this is by using the method of "selective unlabeling." In this method, resonances from one or more amino acid types are suppressed selectively in the NMR spectra, which can be achieved using both cell based and cell-free methods. This helps not only in identifying them but also results in spectral simplification by reducing the number of peaks observed. Further, the assignments are not limited to amino acids that are specifically unlabeled. Using specially designed NMR experiments, assignments of amino acids in the neighborhood of those being selectively unlabeled can also be obtained. In this chapter, we discuss the theoretical and practical aspects of selective unlabeling focusing on how the sample is prepared, which amino acid or a combination of amino acids should be optimally chosen for unlabeling, and how this method can be used for sequential assignments of proteins. PMID- 26577733 TI - Isotope labeling of eukaryotic membrane proteins in yeast for solid-state NMR. AB - Solid-state NMR (ssNMR) is a rapidly developing technique for exploring structure and dynamics of membrane proteins, but its progress is hampered by its low sensitivity. Despite the latest technological advances, routine ssNMR experiments still require several milligrams of isotopically labeled protein. While production of bacterial membrane proteins on this scale is usually feasible, obtaining such quantities of eukaryotic membrane proteins is often impossible or extremely costly. We have demonstrated that, by using isotopic labeling in yeast Pichia pastoris, one can inexpensively produce milligram quantities of doubly labeled functional samples, which yield multidimensional ssNMR spectra of high resolution suitable for detailed structural investigation. This was achieved by combining protocols of economical isotope labeling of soluble proteins previously used for solution NMR with protocols of expression of eukaryotic membrane proteins successfully employed for other methods. We review two cases of such isotope labeling, of fungal rhodopsin from Leptosphaeria maculans and human aquaporin-1. PMID- 26577734 TI - Development of approaches for deuterium incorporation in plants. AB - Soon after the discovery of deuterium, efforts to utilize this stable isotope of hydrogen for labeling of plants began and have proven successful for natural abundance to 20% enrichment. However, isotopic labeling with deuterium ((2)H) in higher plants at the level of 40% and higher is complicated by both physiological responses, particularly water exchange through transpiration, and inhibitory effects of D2O on germination, rooting, and growth. The highest incorporation of 40-50% had been reported for photoheterotrophic cultivation of the duckweed Lemna. Higher substitution is desirable for certain applications using neutron scattering and nuclear magnetic resonance (NMR) techniques. (1)H(2)H NMR and mass spectroscopy are standard methods frequently used for determination of location and amount of deuterium substitution. The changes in infrared (IR) absorption observed for H to D substitution in hydroxyl and alkyl groups provide rapid initial evaluation of incorporation. Short-term experiments with cold-tolerant annual grasses can be carried out in enclosed growth containers to evaluate incorporation. Growth in individual chambers under continuous air perfusion with dried sterile-filtered air enables long-term cultivation of multiple plants at different D2O concentrations. Vegetative propagation from cuttings extends capabilities to species with low germination rates. Cultivation in 50% D2O of annual ryegrass and switchgrass following establishment of roots by growth in H2O produces samples with normal morphology and 30-40% deuterium incorporation in the biomass. Winter grain rye (Secale cereale) was found to efficiently incorporate deuterium by photosynthetic fixation from 50% D2O but did not incorporate deuterated phenylalanine-d8 from the growth medium. PMID- 26577735 TI - Isotope labeling of proteins in insect cells. AB - Protein targets of contemporary research are often membrane proteins, multiprotein complexes, secreted proteins, or other proteins of human origin. These are difficult to express in the standard expression host used for most nuclear magnetic resonance (NMR) studies, Escherichia coli. Insect cells represent an attractive alternative, since they have become a well-established expression system and simple solutions have been developed for generation of viruses to efficiently introduce the target protein DNA into cells. Insect cells enable production of a larger fraction of the human proteome in a properly folded way than bacteria, as insect cells have a very similar set of cytosolic chaperones and a closely related secretory pathway. Here, the limited and defined glycosylation pattern that insect cells produce is an advantage for structural biology studies. For these reasons, insect cells have been established as the most widely used eukaryotic expression host for crystallographic studies. In the past decade, significant advancements have enabled amino acid type-specific as well as uniform isotope labeling of proteins in insect cells, turning them into an attractive expression host for NMR studies. PMID- 26577736 TI - Effective isotope labeling of proteins in a mammalian expression system. AB - Isotope labeling of biologically interesting proteins is a prerequisite for structural and dynamics studies by NMR spectroscopy. Many of these proteins require mammalian cofactors, chaperons, or posttranslational modifications such as myristoylation, glypiation, disulfide bond formation, or N- or O-linked glycosylation; and mammalian cells have the necessary machinery to produce them in their functional forms. Here, we describe recent advances in mammalian expression, including an efficient adenoviral vector-based system, for the production of isotopically labeled proteins. This system enables expression of mammalian proteins and their complexes, including proteins that require posttranslational modifications. We describe a roadmap to produce isotopically labeled (15)N and (13)C posttranslationally modified proteins, such as the outer domain of HIV-1 gp120, which has four disulfide bonds and 15 potential sites of N linked glycosylation. These methods should allow NMR spectroscopic analysis of the structure and function of posttranslationally modified and secreted, cytoplasmic, or membrane-bound proteins. PMID- 26577737 TI - Escherichia coli cell-free protein synthesis and isotope labeling of mammalian proteins. AB - This chapter describes the cell-free protein synthesis method, using an Escherichia coli cell extract. This is a cost-effective method for milligram scale protein production and is particularly useful for the production of mammalian proteins, protein complexes, and membrane proteins that are difficult to synthesize by recombinant expression methods, using E. coli and eukaryotic cells. By adjusting the conditions of the cell-free method, zinc-binding proteins, disulfide-bonded proteins, ligand-bound proteins, etc., may also be produced. Stable isotope labeling of proteins can be accomplished by the cell free method, simply by using stable isotope-labeled amino acid(s) in the cell free reaction. Moreover, the cell-free protein synthesis method facilitates the avoidance of stable isotope scrambling and dilution over the recombinant expression methods and is therefore advantageous for amino acid-selective stable isotope labeling. Site-specific stable isotope labeling is also possible with a tRNA molecule specific to the UAG codon. By the cell-free protein synthesis method, coupled transcription-translation is performed from a plasmid vector or a PCR-amplified DNA fragment encoding the protein. A milligram quantity of protein can be produced with a milliliter-scale reaction solution in the dialysis mode. More than a thousand solution structures have been determined by NMR spectroscopy for uniformly labeled samples of human and mouse functional domain proteins, produced by the cell-free method. Here, we describe the practical aspects of mammalian protein production by the cell-free method for NMR spectroscopy. PMID- 26577738 TI - Rapid biosynthesis of stable isotope-labeled peptides from a reconstituted in vitro translation system for targeted proteomics. AB - Stable isotope-labeled peptides are routinely used as internal standards (a.k.a. reference peptides) for absolute quantitation of proteins in targeted proteomics. These peptides can either be synthesized chemically on solid supports or expressed biologically by concatenating multiple peptides together to a large protein. Neither method, however, has required versatility, convenience, and economy for making a large number of reference peptides. Here, we describe the biosynthesis of stable isotope-labeled peptides from a reconstituted Escherichia coli in vitro translation system. We provide a detailed protocol on how to express these peptides with high purity and how to determine their concentrations with easiness. Our strategy offers a general, fast, and scalable approach for the easy preparation of labeled reference peptides, which will have broad application in both basic research and translational medicine. PMID- 26577739 TI - Labeling of membrane proteins by cell-free expression. AB - The particular advantage of the cell-free reaction is that it allows a plethora of supplementation during protein expression and offers complete control over the available amino acid pool in view of concentration and composition. In combination with the fast and reliable production efficiencies of cell-free systems, the labeling and subsequent structural evaluation of very challenging targets, such as membrane proteins, comes into focus. We describe current methods for the isotopic labeling of cell-free synthesized membrane proteins and we review techniques available to the practitioner pursuing structural studies by nuclear magnetic resonance spectroscopy. Though isotopic labeling of individual amino acid types appears to be relatively straightforward, an ongoing critical issue in most labeling schemes for structural approaches is the selective substitution of deuterons for protons. While few options are available, the continuous refinement of labeling schemes in combination with improved pulse sequences and optimized instrumentation gives promising perspectives for extended applications in the structural evaluation of cell-free synthesized membrane. PMID- 26577740 TI - Selective amino acid segmental labeling of multi-domain proteins. AB - The steady technical advances of nuclear magnetic resonance (NMR) over the past decades enabled a significant increase in the molecular size of protein particles that can be subjected to a structural and functional characterization in solution. The larger molecular weight of such proteins is accompanied with an increase in NMR signals that complicate spectral interpretation due to signal overlap. The application of segmental isotope labeling to selected domains in multi-domain proteins can significantly facilitate spectral interpretation by reducing the number of observable signals. However, severe signal overlap may persist within individual domains that show low signal dispersion. To further reduce the number of signals and spectral complexity in such systems, we developed a procedure for selective amino acid-type labeling in individual domains of multi-domain proteins. This strategy combines efficient amino acid type labeling amenable by cell-free protein expression with near-seamless domain ligation achievable by expressed protein ligation. By application of simple dual labeling schemes, this approach further allows residue-specific isotope labeling to position NMR-observable probes at desired sites within segments of multi domain proteins. This chapter describes a detailed protocol for selective amino acid-type segmental labeling of multi-domain proteins and illustrates its application to a multi-domain RNA-binding protein. The applied ligation approach is further suitable for efficient ligation of unlabeled and/or uniformly labeled domains produced solely by recombinant in vivo expression. PMID- 26577741 TI - Labeling monosaccharides with stable isotopes. AB - Chemical and chemi-enzymic methods are discussed for the preparation of monosaccharide isotopomers that are singly and multiply labeled with (13)C, (2)H, (17/18)O, and (15)N isotopes. The discussion focuses primarily on chemical methods to incorporate stable isotopes into monosaccharides and not on methods to assemble labeled monosaccharides into more complex biomolecules such as oligosaccharides or oligonucleotides. Two primary isotope insertion reactions are considered: cyanohydrin reduction (CR) and molybdate-catalyzed epimerization (MCE). Both methods are described in detail, including discussions of their mechanistic features, and their advantages and limitations. The integration of CR, MCE, and other chemical synthetic processes with enzyme-mediated synthesis is also discussed to illustrate how a wide range of singly and multiply labeled monosaccharides can be prepared for subsequent use in the assembly of more complex isotopically labeled biomolecules. PMID- 26577742 TI - Stable isotope-labeled RNA phosphoramidites to facilitate dynamics by NMR. AB - Given that Ribonucleic acids (RNAs) are a central hub of various cellular processes, methods to synthesize these RNAs for biophysical studies are much needed. Here, we showcase the applicability of 6-(13)C-pyrimidine phosphoramidites to introduce isolated (13)C-(1)H spin pairs into RNAs up to 40 nucleotides long. The method allows the incorporation of 6-(13)C-uridine and cytidine residues at any desired position within a target RNA. By site-specific positioning of the (13)C-label using RNA solid phase synthesis, these stable isotope-labeling patterns are especially well suited to resolve resonance assignment ambiguities. Of even greater importance, the labeling pattern affords accurate quantification of important functional transitions of biologically relevant RNAs (e.g., riboswitch aptamer domains, viral RNAs, or ribozymes) in the MUs- to ms time regime and beyond without complications of one bond carbon scalar couplings. We outline the chemical synthesis of the 6-(13)C-pyrimidine building blocks and their use in RNA solid phase synthesis and demonstrate their utility in Carr Purcell Meiboom Gill relaxation dispersion, ZZ exchange, and chemical exchange saturation transfer NMR experiments. PMID- 26577743 TI - In vivo, large-scale preparation of uniformly (15)N- and site-specifically (13)C labeled homogeneous, recombinant RNA for NMR studies. AB - Knowledge of how ribonucleic acid (RNA) structures fold to form intricate, three dimensional structures has provided fundamental insights into understanding the biological functions of RNA. Nuclear magnetic resonance (NMR) spectroscopy is a particularly useful high-resolution technique to investigate the dynamic structure of RNA. Effective study of RNA by NMR requires enrichment with isotopes of (13)C or (15)N or both. Here, we present a method to produce milligram quantities of uniformly (15)N- and site-specifically (13)C-labeled RNAs using wild-type K12 and mutant tktA Escherichia coli in combination with a tRNA scaffold approach. The method includes a double selection protocol to obtain an E. coli clone with consistently high expression of the recombinant tRNA-scaffold. We also present protocols for the purification of the tRNA-scaffold from a total cellular RNA extract and the excision of the RNA of interest from the tRNA scaffold using DNAzymes. Finally, we showcase NMR applications to demonstrate the benefit of using in vivo site-specifically (13)C-labeled RNA. PMID- 26577744 TI - Cut and paste RNA for nuclear magnetic resonance, paramagnetic resonance enhancement, and electron paramagnetic resonance structural studies. AB - RNA is a crucial regulator involved in most molecular processes of life. Understanding its function at the molecular level requires high-resolution structural information. However, the dynamic nature of RNA complicates structure determination because crystallization is often not possible or can result in crystal-packing artifacts resulting in nonnative structures. To study RNA and its complexes in solution, we described an approach in which large multi-domain RNA or protein-RNA complex structures can be determined at high resolution from isolated domains determined by nuclear magnetic resonance (NMR) spectroscopy, and then constructing the entire macromolecular structure using electron paramagnetic resonance (EPR) long-range distance constraints. Every step in this structure determination approach requires different types of isotope or spin-labeled RNAs. Here, we present a simple modular RNA cut and paste approach including protocols to generate (1) small isotopically labeled RNAs (<10 nucleotides) for NMR structural studies, which cannot be obtained by standard protocols, (2) large segmentally isotope and/or spin-labeled RNAs for diamagnetic NMR and paramagnetic relaxation enhancement NMR, and (3) large spin-labeled RNAs for pulse EPR spectroscopy. PMID- 26577745 TI - Preface. PMID- 26577746 TI - The ontogeny of nanos homologue expression in the oligochaete annelid Tubifex tubifex. AB - We have cloned and characterized the expression of a nanos homologue (designated Ttu-nos) from the oligochaete annelid Tubifex tubifex. Ttu-nos mRNA is distributed broadly throughout the early cleavage stages. Ttu-nos is expressed in most if not all of the early blastomeres, in which Ttu-nos RNA associates with pole plasms. Ttu-nos transcripts are concentrated to 2d and 4d cells. Shortly after 2d(111) (derived from 2d cell) divides into a bilateral pair of NOPQ proteloblasts, Ttu-nos RNA vanishes from the embryo, which is soon followed by the resumption of Ttu-nos expression in nascent primary blast cells produced by teloblasts. The resumption of Ttu-nos expression occurs only in a subset of teloblast lineages (viz., M, N and Q). After Ttu-nos expression is retained in the germ band for a while, it disappears in anterior-to-posterior progression. At the end of embryogenesis, there is no trace of Ttu-nos expression. Thereafter, growing juveniles do not show any sign of Ttu-nos expression, either. The first sign of Ttu-nos expression is detected in oocytes in the ovary of young adults (ca 40 days after hatching), and its expression continues in growing oocytes that undergo yolk deposition and maturation in the ovisac. PMID- 26577748 TI - Health beliefs and their sources in Korean and Japanese nurses: A Q-methodology pilot study. AB - BACKGROUND: Many health beliefs do not have supporting scientific evidence, and are influenced by culture, gender, religion, social circumstance and popular media. Nurses may also hold non-evidenced-based beliefs that affect their own health behaviours and their practices. OBJECTIVES: Using Q-methodology, pilot Q cards representing a concourse of health beliefs for Japanese and South Korean nurses and explain the content and sources of health beliefs. DESIGN: Qualitative. SETTINGS: Two university campuses, one each in Japan and Korea. PARTICIPANTS: A convenience sample of 30 was obtained, 14 clinical nurses and 16 academic nurses. METHODS: Literature reviews and expert informants were used to develop two sets of 65 Q-cards which listed culturally appropriate health beliefs in both Japan and Korea. These beliefs were examined in four structured groups and five individual interviews in Japan, and five groups and two individual interviews in Korea. RESULTS: Our unique study revealed six categories regarding sources of health beliefs that provide rich insights about how participants accessed, processed and transmitted health information. They were more certain about knowledge from their specialty area such as that from medical or nursing resources, but derived and distributed many general health beliefs from personal experience, family and mass media. They did not always pass on accurate information to students or those in their care, and often beliefs were not based on scientific evidence. CONCLUSION: Findings highlight the dangers of clinical and academic nurses relying on health belief advice of others and passing this on to patients, students or others, without mindfully examining the basis of their beliefs through scientific evidence. PMID- 26577747 TI - Direct Observation of Early-Stage High-Dose Radiotherapy-Induced Vascular Injury via Basement Membrane-Targeting Nanoparticles. AB - Collagen IV-targeting peptide-conjugated basement membrane-targeting nanoparticles are successfully engineered to identify early-stage blood vessel injury induced by high-dose radiotherapy. PMID- 26577749 TI - Adolescent delta-9-tetrahydrocannabinol (THC) exposure fails to affect THC induced place and taste conditioning in adult male rats. AB - BACKGROUND: Adolescent initiation of drug use has been linked to problematic drug taking later in life and may represent an important variable that changes the balance of the rewarding and/or aversive effects of abused drugs which may contribute to abuse vulnerability. The current study examined the effects of adolescent THC exposure on THC-induced place preference (rewarding effects) and taste avoidance (aversive effects) conditioning in adulthood. METHODS: Forty-six male Sprague-Dawley adolescent rats received eight injections of an intermediate dose of THC (3.2mg/kg) or vehicle. After these injections, animals were allowed to mature and then trained in a combined CTA/CPP procedure in adulthood (PND ~90). Animals were given four trials of conditioning with intervening water recovery days, a final CPP test and then a one-bottle taste avoidance test. RESULTS: THC induced dose-dependent taste avoidance but did not produce place conditioning. None of these effects was impacted by adolescent THC exposure. CONCLUSIONS: Adolescent exposure to THC had no effect on THC taste and place conditioning in adulthood. The failure to see an effect of adolescent exposure was addressed in the context of other research that has assessed exposure of drugs of abuse during adolescence on drug reactivity in adulthood. PMID- 26577750 TI - Strain-dependent effects of acute caffeine on anxiety-related behavior in PVG/c, Long-Evans and Wistar rats. AB - To assess the possibility that acute caffeine's behavioral action might depend on rats' strain, effects of 50mg/kg of the drug were observed on activity, anxiety related behavior and habituation learning in male and female rats from three different strains, namely PVG/c, Long-Evans and Wistar. All subjects were tested in an open field, an elevated plus maze and a light-dark box. For the three strains combined, increased occupancy of the center of the open field and entries of the open plus-maze arms with caffeine suggested caffeine-induced anxiolysis, whereas increased grooming in the open field, decreased rearing in the plus maze and increased risk assessment in the light-dark box were consistent with anxiogenesis. Caffeine also reduced open-field rearing only for PVG/c rats, and entries into and occupation of the light side of the light-dark box only for Long Evans rats, and increased total defecation in the three types of apparatus for all three strains combined. Overall, caffeine appeared to be mainly anxiogenic. The drug also increased open-field ambulation for PVG/c rats and walking for all rats, but decreased open-field ambulation and entries into the plus maze closed arms for Wistar rats alone. In general, Wistar rats appeared to be the least and Long-Evans the most anxious of the three strains investigated. Caffeine also decreased within-session habituation of open-field ambulation for PVG/c rats alone, thereby suggesting strain-dependent interference with non-associative learning and short-term memory. Several overall sex differences were also observed that supported female rats being more active and less anxious than males. PMID- 26577751 TI - Pharmacological benefits of selective modulation of cannabinoid receptor type 2 (CB2) in experimental Alzheimer's disease. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder that pervasively affects the population across the world. Currently, there is no effective treatment available for this and existing drugs merely slow the progression of cognitive function decline. Thus, massive effort is required to find an intended therapeutic target to overcome this condition. The present study has been framed to investigate the ameliorative role of selective modulator of cannabinoid receptor type 2 (CB2), 1-phenylisatin in experimental AD condition. We have induced experimental AD in mice by using two induction models viz., intracerebroventricular (i.c.v.) administration of streptozotocin (STZ) and aluminum trichloride (AlCl3)+d-galactose. Morris water maze (MWM) and attentional set shifting test (ASST) were used to assess learning and memory. Hematoxylin eosin and Congo red staining were used to examine the structural variation in brain. Brain oxidative stress (thiobarbituric acid reactive substance and glutathione), nitric oxide levels (nitrites/nitrates), acetyl cholinesterase activity, myeloperoxidase and calcium levels were also estimated. i.c.v. STZ as well as AlCl3+d-galactose have impaired spatial and reversal learning with executive functioning, increased brain oxidative and nitrosative stress, cholinergic activity, inflammation and calcium levels. Furthermore, these agents have also enhanced the burden of Abeta plaque in the brain. Treatment with 1 phenylisatin and donepezil attenuated i.c.v. STZ as well as AlCl3+d-galactose induced impairment of learning-memory, brain biochemistry and brain damage. Hence, this study concludes that CB2 receptor modulation can be a potential therapeutic target for the management of AD. PMID- 26577752 TI - Different doses of equine chorionic gonadotropin on ovarian follicular growth and pregnancy rate of suckled Bos taurus beef cows subjected to timed artificial insemination protocol. AB - This study evaluated the effect of different doses of eCG (control, 300 or 400 IU) administered at progesterone (P4) device removal in suckled Bos taurus beef cows undergoing a timed artificial insemination (TAI) protocol. A total of 966 cows received a P4 insert and 2.0 mg intramuscular estradiol benzoate at the onset of the synchronization. After 9 days, P4 insert was removed, and 12.5 mg of dinoprost tromethamine and 1 mg of estradiol cypionate were administered, followed by TAI 48 hours later. Then, the cows received one of three treatments as follows: control (n = 323), 300 (n = 326), or 400 IU of eCG (n = 317). A subset (n = 435) of cows in anestrus had their ovaries evaluated using ultrasound at the time of P4 removal and at TAI. Data were analyzed by orthogonal contrasts (C): C1 (eCG effect) and C2 (eCG dose effect). Estrous occurrence (control = 53.7%, 300 IU = 70.6%, and 400 IU = 77.0%) and pregnancy per artificial insemination (control = 29.7%, 300 IU = 44.8%, and 400 IU = 47.6%) were improved by eCG treatment (C1; P = 0.0004 and P < 0.0001, respectively). Furthermore, the cows receiving eCG presented larger follicles at TAI (control = 13.5 +/- 0.3 mm, 300 IU = 14.0 +/- 0.2 mm, and 400 IU = 15.1 +/- 0.3 mm; P < 0.0001; C1). However, there was no effect of eCG dose on any response variables studied (C2; P > 0.15). In conclusion, the eCG treatment administered at the time of P4 removal increased the occurrence of estrus, the larger follicles at TAI, and pregnancy per artificial insemination of suckled B taurus beef cows. Despite the greater occurrence of estrus in noncyclic cows receiving 400 IU of eCG, both eCG doses (300 and 400 IU) were equally efficient to improve pregnancy to artificial insemination. PMID- 26577753 TI - Commentary to 'Trends in Treatments of Abdominal Aortic- and Iliac Aneurysm Repairs in Norway from 2001 to 2013': Mapping of Clinical Practice: A Mirror for Clinicians and Decision Makers. PMID- 26577754 TI - Relationship between etonogestrel level and BMI in women using the contraceptive implant for more than 1 year. AB - Progestin-only contraceptive methods, including the 3-year, single-rod etonogestrel (ENG) implant, may be preferred for obese women to avoid additional estrogen-related thrombosis risk; however, whether obese women receive an ENG sufficient dose to suppress ovulation is understudied. Our analysis expands on the limited information currently available by studying ENG levels related to body mass index (BMI) in a community sample of primarily Hispanic women. This cross-sectional, descriptive study of 52 long-term implant users found comparable ENG levels across a wide BMI range (p=.1). These results further support that ENG levels are independent of BMI through 3 years of implant use and are thus reassuring that ENG implants will be effective for women of all BMIs. PMID- 26577755 TI - The relationship between long-acting reversible contraception and insurance coverage: a retrospective analysis. AB - OBJECTIVE: The objective was to determine if there is a relationship between patients' financial responsibility (out-of-pocket expenses) and placement of long acting, reversible contraceptive (LARC) methods among girls and women living in Appalachia who expressed interest in LARC device placement. STUDY DESIGN: A retrospective chart analysis of patients prescribed an intrauterine device (IUD) or an etonogestrel implant between December 2011 and July 2013 in an Appalachian private practice was performed. Of the 571 identified patients aged 13 to 50, the majority were Caucasian (98.7%) and using Medicaid (53.2%). Outcomes measured the patients' decision regarding whether to use LARC after being informed of out-of pocket expenses. RESULTS: There was a dramatic increase in the proportion of patients who had LARC methods placed if expense was under $200 (p<.001). Placement rate for privately insured patients was 86.6% for those who paid less than $200 compared to 27.8% for those who paid $200 or more. Medicaid patients, for whom the device was free, had a 78.0% placement rate. For every additional $100 patients had to pay out of pocket, the odds of deciding to use the prescribed LARC method decreased. CONCLUSIONS: LARC methods are utilized significantly more often when out-of-pocket cost is low. Cost appears to be a significant barrier to device placement for the group of privately insured Appalachian patients with out-of-pocket expenses over $200. Despite the improvements in coverage for many women provided under the Affordable Care Act, cost may remain a barrier for privately insured women who are required to pay some or all of the cost of LARC methods. IMPLICATIONS: Unintended pregnancy rates in the United States remain high, especially in Appalachia. One contributing factor is reliance on user-dependent methods which have significantly high typical use failure rates. Placement of LARC methods for more patients could decrease unintended pregnancy, but device costs may be one barrier to utilization, even for those with private insurance. PMID- 26577756 TI - Phylogenetic marker development for target enrichment from transcriptome and genome skim data: the pipeline and its application in southern African Oxalis (Oxalidaceae). AB - Phylogenetics benefits from using a large number of putatively independent nuclear loci and their combination with other sources of information, such as the plastid and mitochondrial genomes. To facilitate the selection of orthologous low copy nuclear (LCN) loci for phylogenetics in nonmodel organisms, we created an automated and interactive script to select hundreds of LCN loci by a comparison between transcriptome and genome skim data. We used our script to obtain LCN genes for southern African Oxalis (Oxalidaceae), a speciose plant lineage in the Greater Cape Floristic Region. This resulted in 1164 LCN genes greater than 600 bp. Using target enrichment combined with genome skimming (Hyb-Seq), we obtained on average 1141 LCN loci, nearly the whole plastid genome and the nrDNA cistron from 23 southern African Oxalis species. Despite a wide range of gene trees, the phylogeny based on the LCN genes was very robust, as retrieved through various gene and species tree reconstruction methods as well as concatenation. Cytonuclear discordance was strong. This indicates that organellar phylogenies alone are unlikely to represent the species tree and stresses the utility of Hyb Seq in phylogenetics. PMID- 26577757 TI - A Patient with Metastatic Small-Cell Lung Cancer and Giant Right Ventricular Mass. PMID- 26577760 TI - Erratum. PMID- 26577759 TI - Rapid development of osteoarthritis following arthroscopic resection of an "os acetabuli" in a mildly dysplastic hip--a case report. PMID- 26577758 TI - Cellular and circuit models of increased resting-state network gamma activity in schizophrenia. AB - Schizophrenia (SCZ) is a disorder characterized by positive symptoms (hallucinations, delusions), negative symptoms (blunted affect, alogia, reduced sociability, and anhedonia), as well as persistent cognitive deficits (memory, concentration, and learning). While the biology underlying subjective experiences is difficult to study, abnormalities in electroencephalographic (EEG) measures offer a means to dissect potential circuit and cellular changes in brain function. EEG is indispensable for studying cerebral information processing due to the introduction of techniques for the decomposition of event-related activity into its frequency components. Specifically, brain activity in the gamma frequency range (30-80Hz) is thought to underlie cognitive function and may be used as an endophenotype to aid in diagnosis and treatment of SCZ. In this review we address evidence indicating that there is increased resting-state gamma power in SCZ. We address how modeling this aspect of the illness in animals may help treatment development as well as providing insights into the etiology of SCZ. PMID- 26577761 TI - Anterior longitudinal aortotomy in aortic valve replacement. AB - OBJECTIVES: We adopted an anterior longitudinal aortotomy in some cases of aortic valve replacement (AVR), and report them here. The potential of this method is also discussed. METHODS: We analyzed the data on 24 patients (75.5 +/- 7.8 years of age) who had undergone AVR through anterior longitudinal aortotomy. The indications for surgery were prosthetic valve complication in 5 patients, aortic stenosis (AS) with left ventricular outflow tract stenosis (LVOTS) in 16 patients, and aortic regurgitation with moderately dilated ascending aorta in 3 patients. The Konno procedure was performed in 6 cases with small aortic annuli. A longitudinal aortotomy was made at the aortic root along the left side of the right coronary ostium, and extended beyond the right coronary annulus to the interventricular septum as needed. RESULTS: Bioprostheses (21.1 +/- 1.7 mm) were used in 23 patients and a 21-mm mechanical valve for one (a 59-year-old man). One high-risk patient died of low output syndrome, leading to a mortality rate of 4.2 %. All other patients recovered well, though atrioventricular block occurred in 2 cases. CONCLUSIONS: Anterior longitudinal aortotomy provides a good field of vision at the aortic annulus and the flexibility to develop into anterior annular enlargement. Major indications for this approach are small sino-tubular junction and very small aortic annulus. This approach could be an attractive option in AVR for cases of AS with small aortic annuli and LVOTS. It could also be useful for AVR cases with moderately dilated ascending aorta requiring aortoplasty. PMID- 26577762 TI - Electronic media use and insomnia complaints in German adolescents: gender differences in use patterns and sleep problems. AB - Electronic media play an important role in the everyday lives of children and adolescents and have been shown to be associated with sleep problems. The objective of this study was to assess the associations between time spent using different electronic media and insomnia complaints (IC) in German adolescents with particular respect to gender differences in use patterns and associations with IC. Cross-sectional data of a weighted total of 7533 adolescents aged 11-17 stem from the German Health Interview and Examination Survey for Children and Adolescents (KiGGS study) that was conducted from 2003 to 2006. The assessment of IC and time spent using different electronic media (television, computer/internet, video games, total screen time, mobile phones, and music) was included in a self-report questionnaire. Binary logistic regression analyses were performed to assess associations between time spent per day with each electronic media and IC. Age, SES, emotional problems (anxiety/depression) and presence of a medical condition were considered as covariates in the adjusted model. Boys and girls were considered separately. For boys: computer/internet use of >=3 h/d (AOR = 2.56, p < 0.05) and total screen time of >=8 h/d (AOR = 2.45, p < 0.01) were associated with IC in users. Playing video games for 0.5-2 h/d reduced the odds for IC (AOR = 0.60, p < 0.05) compared to nonusers. For girls: Listening to music for >=3 h/d was associated with IC (AOR = 4.24, p < 0.05) compared to non listeners. Everyday use of electronic media devices is associated with IC in adolescents. Clinicians dealing with adolescents referred for sleep problems should be aware of gender-specific patterns of media use and sleep problems. PMID- 26577763 TI - Evaluation of pedometry as a patient-centered outcome in patients undergoing hematopoietic cell transplant (HCT): a comparison of pedometry and patient reports of symptoms, health, and quality of life. AB - AIMS: We evaluated pedometry as a novel patient-centered outcome because it enables passive continuous assessment of activity and may provide information about the consequences of symptomatic toxicity complementary to self-report. METHODS: Adult patients undergoing hematopoietic cell transplant (HCT) wore pedometers and completed PRO assessments during transplant hospitalization (4 weeks) and 4 weeks post-discharge. Patient reports of symptomatic treatment toxicities (single items from PRO-CTCAE, http://healthcaredelivery.cancer.gov/pro ctcae ) and symptoms, physical health, mental health, and quality of life (PROMIS((r)) Global-10, http://nih.promis.org ), assessed weekly with 7-day recall on Likert scales, were compared individually with pedometry data, summarized as average daily steps per week, using linear mixed models. RESULTS: Thirty-two patients [mean age 55 (SD = 14), 63 % male, 84 % white, 56 % autologous, 43 % allogeneic] completed a mean 4.6 (SD = 1.5, range 1-8) evaluable assessments. Regression model coefficients (beta) indicated within-person decrements in average daily steps were associated with increases in pain (beta = 852; 852 fewer steps per unit increase in pain score, p < 0.001), fatigue (beta = -886, p < 0.001), vomiting (beta = -518, p < 0.01), shaking/chills (beta = -587, p < 0.01), diarrhea (beta = -719, p < 0.001), shortness of breath (beta = -1018, p < 0.05), reduction in carrying out social activities (beta = 705, p < 0.01) or physical activities (beta = 618, p < 0.01), and global physical health (beta = 101, p < 0.001), but not global mental health or quality of life. CONCLUSIONS: In this small sample of HCT recipients, more severe symptoms, impaired physical health, and restrictions in the performance of usual daily activities were associated with statistically significant decrements in objectively measured daily steps. Pedometry may be a valuable outcome measure and validation anchor in clinical research. PMID- 26577764 TI - Quality of life among patients after bilateral prophylactic mastectomy: a systematic review of patient-reported outcomes. AB - PURPOSE: Bilateral prophylactic mastectomy (BPM) is effective in reducing the risk of breast cancer in women with a well-defined family history of breast cancer or in women with BRCA 1 or 2 mutations. Evaluating patient-reported outcomes following BPM are thus essential for evaluating success of BPM from patient's perspective. Our systematic review aimed to: (1) identify studies describing health-related quality of life (HRQOL) in patients following BPM with or without reconstruction; (2) assess the effect of BPM with or without reconstruction on HRQOL; and (3) identify predictors of HRQOL post-BPM. METHODS: We performed a systematic review of literature using the PRISMA guidelines. PubMed, Embase, PsycINFO, Web of Science, Scopus and Cochrane databases were searched. RESULTS: The initial search resulted in 1082 studies; 22 of these studies fulfilled our inclusion criteria. Post-BPM, patients are satisfied with the outcomes and report high psychosocial well-being and positive body image. Sexual well-being and somatosensory function are most negatively affected. Vulnerability, psychological distress and preoperative cancer distress are significant negative predictors of quality of life and body image post-BPM. CONCLUSION: There is a paucity of high-quality data on outcomes of different HRQOL domains post-BPM. Future studies should strive to use validated and breast specific PRO instruments for measuring HRQOL. This will facilitate shared decision-making by enabling surgeons to provide evidence-based answers to women contemplating BPM. PMID- 26577766 TI - Infrared spectra of primary melanomas can predict response to chemotherapy: The example of dacarbazine. AB - Metastatic melanomas are highly aggressive and median survival is 6-9months for stage IV patients in the absence of treatment with anti-tumor activity. Dacarbazine is an alkylating agent that has been widely used in the treatment of metastatic melanomas and that could be still used in combination with targeted or immune therapies. Indeed, therapeutic benefits of these treatments in monotherapy are poor and one option to improve them is to combine drugs and/or to better anticipate the individual response to a defined treatment. To our best knowledge and to date, there is no test available to predict the response of a patient to dacarbazine. We show here that examination of melanoma histological sections by infrared micro-spectroscopy reveals the sensitivity of the cancer to dacarbazine. Unsupervised analysis of the FTIR spectra evidences spontaneous and significant clustering of infrared spectra into two groups that match the clinical responsiveness of the patients to dacarbazine used as a first-line treatment. A supervised model resulted in 83% of the patient status (responder/non-responder) being correctly identified. The spectra revealed a key modification in the nature and quantity of lipids in the cells of both groups. PMID- 26577765 TI - Evaluation of RNA-binding motif protein 3 expression in urothelial carcinoma of the bladder: an immunohistochemical study. AB - BACKGROUND: RNA-binding motif protein 3 (RBM3), involved in cell survival, has paradoxically been linked to both oncogenesis as well as an increased survival in several cancers, including urothelial carcinoma (UCA). METHODS: The putative prognostic role of RBM3 was studied using cystectomy specimens with 152 invasive UCA with 35 matched metastases, 65 carcinomas in situ (CIS), 22 high-grade papillary UCAs (PAP), and 112 benign urothelium cases. RESULTS: The H-score (HS, staining intensity * % of positive cells) was used for RBM3 immunoexpression. CIS showed the highest HS (mean = 140) followed by benign urothelium (mean = 97). Metastases showed higher HS than primary invasive UCA (P <= 0.0001), and high HS was associated with a lower pT stage (P <= 0.0001) and a trend toward the absence of lymphovascular invasion (LVI, P = 0.09), but not pN stage (P = 0.35) and surgical margin status (P = 0.81). Univariate analysis (UVA) of disease recurrence only showed an association between pN stage and LVI (P = 0.005 and 0.03, respectively). On UVA of mortality, pT stage was strongly associated with death (P = 0.01) while pN stage, LVI, surgical margin status, and HS were not. Multivariate analysis confirmed the lack of HS association with recurrence (P = 0.08) and death (P = 0.32). CONCLUSIONS: Stronger RBM3 immunoexpression correlated with lower stage tumors and a diminished risk for LVI. However, RBM3 does not seem to carry a prognostic significance for clinical outcome (recurrence and mortality). The exact prognostic role of RBM3 in UCA is yet to be determined. PMID- 26577767 TI - Postoperative adjuvant treatment for gastric cancer improves long-term survival after curative resection and D2 lymphadenectomy. Results from a Latin American Center. AB - BACKGROUND: The benefits of adjuvant treatment in the context of a D2 lymph node dissection are controversial. The aim was to investigate the effects of postoperative adjuvant treatment on the survival of patients with a curative resection for gastric cancer and a D2 lymph node dissection. METHODS: We performed a retrospective cohort study. Patients operated from 1996 to 2013 were selected. We compared long term survival of patients treated with surgery alone and those with surgery plus postoperative adjuvant treatment. A multivariate analysis for survival was applied in every stage. RESULTS: The study included 580 patients. Two-hundred and four patients received postoperative adjuvant treatment (AD) and 376 patients were treated only with surgery (SU). Patients in the AD group were younger (60 versus 68, p < 0.001), had a lower rate of multiple organ resection (21% versus 39%, p < 0.001) and had less postoperative complications (14% versus 32%, p < 0.001). In the AD group, patients had more advanced disease (stage III; 77% versus 66%, p < 0.001). No difference was found in lymph nodes resected (31 versus 30, p = ns). The median survival with adjuvant treatment was 33 months (39% 5 year survival) and 22 months (31% 5 year survival) for patients without adjuvant treatment (p = 0.003). On multivariate analysis, patients with stage IIIB and IIIC had significantly better overall and disease specific long term survival with adjuvant treatment. CONCLUSIONS: These results suggest that there is a long-term survival benefit for patients treated with postoperative adjuvant treatment for stages IIIB and IIIC gastric cancer after D2 lymph node dissection. PMID- 26577768 TI - Bioinspired Breathable Architecture for Water Harvesting. AB - Thuja plicata is a coniferous tree which displays remarkable water channelling properties. In this article, an easily fabricated mesh inspired by the hierarchical macro surface structure of Thuja plicata branchlets is described which emulates this efficient water collection behaviour. The key parameters are shown to be the pore size, pore angle, mesh rotation, tilt angle (branch droop) and layering (branch overlap). Envisaged societal applications include water harvesting and low cost breathable architecture for developing countries. PMID- 26577769 TI - Human lactoferrin triggers a mitochondrial- and caspase-dependent regulated cell death in Saccharomyces cerevisiae. AB - We have previously shown that the antifungal activity of human lactoferrin (hLf) against Candida albicans relies on its ability to induce cell death associated with apoptotic markers. To gain a deeper understanding of the mechanisms underlying hLf-induced apoptosis, we characterized this cell death process in the well-established Saccharomyces cerevisiae model. Our results indicate that hLf induces cell death in S. cerevisiae in a manner that requires energy and de novo protein synthesis. Cell death is associated with nuclear chromatin condensation, preservation of plasma membrane integrity, and is Yca1p metacaspase-dependent. Lactoferrin also caused mitochondrial dysfunction associated with ROS accumulation and release of cytochrome c. Pre-incubation with oligomycin, an oxidative phosphorylation inhibitor, increased resistance to hLf and, accordingly, mutants deficient in the F1F0-ATP synthase complex were more resistant to death induced by hLf. This indicates that mitochondrial energetic metabolism plays a key role in the killing effect of hLf, though a direct role of F1F0-ATP synthase cannot be precluded. Overexpression of the anti-apoptotic protein Bcl-xL or pre-incubation with N-acetyl cysteine reduced the intracellular level of ROS and increased resistance to hLf, confirming a ROS-mediated mitochondrial cell death process. Mitochondrial involvement was further reinforced by the higher resistance of cells lacking mitochondrial DNA, or other known yeast mitochondrial apoptosis regulators, such as, Aif1p, Cyc3p and Aac1/2/3p. This study provides new insights into a detailed understanding at the molecular level of hLf-induced apoptosis, which may allow the design of new strategies to overcome the emergence of resistance of clinically relevant fungi to conventional antifungals. PMID- 26577770 TI - Assessing the risk factors of cholera epidemic in the Buea Health District of Cameroon. AB - BACKGROUND: Cholera is an acute diarrheal disease caused by the bacterium, Vibrio cholerae. A cholera epidemic occurred in Cameroon in 2010. After a cholera-free period at the end of 2010, new cases started appearing in early 2011. The disease affected 23,152 people and killed 843, with the South West Region registering 336 cases and 13 deaths. Hence, we assessed the risk factors of cholera epidemic in the Buea Health District to provide evidence-based cholera guidelines. METHODS: We conducted an unmatched case-control study. Cases were identified from health facility records and controls were neighbours of the cases in the same community. We interviewed 135 participants on socio-economic, household hygiene, food and water exposures practices using a semi-structured questionnaire. Data was analyzed using STATA. Fisher exact test and logistic regression were computed. P < 0.05 was considered to be statistically significant. RESULTS: The 135 participants included 34 (25.2 %) cholera cases and 101 (74.8 %) controls. More females [78 (57.8 %)] participated in the study. Ages ranged from 1 year 3 months to 72 years; with a mean of 29.86 (+/-14.51) years. The cholera attack rate was 0.03 % with no fatality. Most participants [129 (99.2 %)] had heard of cholera. Poor hygienic practices [77 (59.2 %)] and contaminated water sources [54 (41.5 %)] were the main reported transmission routes of cholera. Good hygienic practices [108 (83.1 %)] were the main preventive methods of cholera in both cases [23 (76.6 %)] and controls [85 (85.0 %)]. Logistic regression analysis showed age below 21 years (OR = 1.72, 95 % CI: 0.73-4.06, p = 0.251), eating outside the home (OR = 1.06, CI: 0.46-2.43, p = 1.00) and poor food preservation method (OR = 9.20, CI: 3.67-23.08, p < 0.0001) were independent risk factors of cholera. Also, irregular water supply (OR = 0.66, 95 % CI: 0.30-1.43, p = 0.320), poor kitchen facility (OR = 0.60, CI: 0.16-2.23, p = 0.560), lack of home toilet (OR = 0.69, CI: 0.25-1.86, p = 0.490), and education below tertiary (OR = 0.87, 95 % CI: 0.36-2.11, p = 0.818) were independent protective factors for the occurrence of cholera. CONCLUSION: There was a good knowledge of cholera among participants. Poor food preservation method was a significant independent risk factor of cholera. Improvement in hygiene and sanitation conditions and water infrastructural development is crucial to combating the epidemic. PMID- 26577771 TI - A Randomized, Phase I Pharmacokinetic Study Comparing SB2 and Infliximab Reference Product (Remicade((r))) in Healthy Subjects. AB - OBJECTIVE: SB2, a biosimilar to infliximab reference product (INF), has an identical amino acid sequence and similar physicochemical functional properties to its reference product. The primary objective of this study is to demonstrate pharmacokinetic (PK) bioequivalence between SB2 and EU-sourced INF (EU-INF), between SB2 and US-sourced INF (US-INF), and between EU-INF and US-INF. METHODS: This study was a randomized, single-blind, three-arm, parallel group study in 159 healthy subjects. All subjects received a single 5 mg/kg intravenous infusion of study drug and then were observed for 10 weeks to study PK, safety and immunogenicity. The primary PK parameters were area under the concentration-time curve (AUC) from time zero to infinity (AUCinf), AUC from time zero to the last quantifiable concentration (AUClast) and maximum concentration (C max). Bioequivalence for the primary PK parameters was to be concluded using an analysis of variance (ANOVA) if the 90 % confidence intervals (CIs) for the ratio of geometric least squares means (LSMeans) of the treatments compared were completely contained within the pre-defined equivalence margin, 0.8-1.25. RESULTS: All of the 90 % CIs for the geometric LSMean ratios of primary PK parameters for each comparison were within the pre-defined equivalence margin. The proportion of subjects who experienced treatment-emergent adverse events was comparable between treatments. The incidences of anti-drug antibodies between the three treatments were comparable. CONCLUSION: This study demonstrated biosimilarity of SB2 to its marketed reference products of infliximab in terms of PK equivalence in healthy subjects. SB2 was generally well tolerated and showed comparable safety and immunogenicity profiles to the reference products (ClinicalTrials.gov Identifier: NCT01922336). PMID- 26577772 TI - Causes for 30-Day Readmission following Transsphenoidal Surgery. AB - OBJECTIVE: The Affordable Care Act Readmissions Reduction Program introduced reimbursement policy changes resulting in penalties for hospitals with higher than-average readmission rates among several categories, including elective surgical cases. We examined the rate of complications resulting in 30-day readmission following endoscopic transsphenoidal surgery. STUDY DESIGN: Case series with chart review. SETTING: Academic tertiary care center. METHODS: A database of 466 consecutive patients who underwent endoscopic transsphenoidal surgery at a tertiary care center between April 2006 and July 2014 was reviewed for 30-day causes for readmission, length of stay, level of care required, and average cost. RESULTS: Twenty-nine readmissions were identified within our study period, indicating a 30-day readmission rate of 6.2%. Among all patients, rates of 30-day readmission were 2.1% for epistaxis, 1.5% for hyponatremia, 0.9% for cerebrospinal fluid leak, and 1.7% for other medical conditions. Average cost per readmission ranged from $6011 for hyponatremia to $24,613 for cerebrospinal fluid leak. CONCLUSION: Overall, the rate of 30-day readmission following endoscopic pituitary surgery is low. However, common causes of readmission do add significant cost to the overall care of this patient population. Special attention to surgical technique to prevent epistaxis and cerebrospinal fluid rhinorrhea, as well as multidisciplinary team management to avoid postoperative endocrine dysfunction, is critical to minimize these complications. PMID- 26577773 TI - Analysis of 473 US Head and Neck Cancer Trials (1996-2014): Trends, Gaps, and Opportunities. AB - OBJECTIVE: To report on types of investigations being conducted in US clinical trials, the types of therapeutic investigations that predominate, and the publication rates. STUDY DESIGN: Retrospective analysis. SETTINGS: US head and neck cancer clinical trials. SUBJECTS AND METHODS: We used the information available on ClinicalTrials.gov to identify trends in head and neck squamous cell carcinoma clinical trials to characterize the types of trials and treatments being investigated. The publication rate for these trials was also examined with PubMed.gov. RESULTS: Of the 473 trials analyzed, similar drug regimens have been used repeatedly in head and neck cancer clinical trials. Drug studies are highly represented, composing 62% of all trials. The most common drugs studied were cisplatin, cetuximab, and docetaxel. Among all head and neck cancer clinical trials, 33% included radiation therapy in their treatment, while 10% included a surgical component. Forty-nine percent of trials had their results published in a medical journal, and 70% of the publications reported positive results. CONCLUSION: Head and neck cancer trials are heavily weighted toward drug trials and demonstrate redundancy. Other therapies are underrepresented, especially surgery. There is a gap between the trials conducted and the rate of reporting, with an emphasis on positive results. Better balance in studying treatment modalities, less redundancy in clinical trials, and reporting all results have potential benefits for head and neck cancer and the public good. PMID- 26577776 TI - Suppressor Screens in Arabidopsis. AB - Genetic screens have proven to be a useful tool in the dissection of biological processes in plants. Specifically, suppressor screens have been widely used to study signal transduction pathways. Here we provide a detailed protocol for ethyl methanesulfonate (EMS) mutagenesis used in our suppressor screens in Arabidopsis and discuss the basic principles behind suppressor screen design and downstream analyses. PMID- 26577774 TI - Three-Year Outcomes of Cranial Nerve Stimulation for Obstructive Sleep Apnea: The STAR Trial. AB - OBJECTIVE: To describe the 36-month clinical and polysomnography (PSG) outcomes in an obstructive sleep apnea (OSA) cohort treated with hypoglossal cranial nerve upper airway stimulation (UAS). STUDY DESIGN: A multicenter prospective cohort study. SETTING: Industry-supported multicenter academic and clinical setting. SUBJECTS: Participants (n = 116) at 36 months from a cohort of 126 implanted participants. METHODS: Participants were enrolled in a prospective phase III trial evaluating the efficacy of UAS for moderated to severe OSA. Prospective outcomes included apnea-hypopnea index, oxygen desaturation index, other PSG measures, self-reported measures of sleepiness, sleep-related quality of life, and snoring. RESULTS: Of 126 enrolled participants, 116 (92%) completed 36-month follow-up evaluation per protocol; 98 participants additionally agreed to a voluntary 36-month PSG. Self-report daily device usage was 81%. In the PSG group, 74% met the a priori definition of success with the primary outcomes of apnea hypopnea index, reduced from the median value of 28.2 events per hour at baseline to 8.7 and 6.2 at 12 and 36 months, respectively. Similarly, self-reported outcomes improved from baseline to 12 months and were maintained at 36 months. Soft or no snoring reported by bed partner increased from 17% at baseline to 80% at 36 months. Serious device-related adverse events were rare, with 1 elective device explantation from 12 to 36 months. CONCLUSION: Long-term 3-year improvements in objective respiratory and subjective quality-of-life outcome measures are maintained. Adverse events are uncommon. UAS is a successful and appropriate long-term treatment for individuals with moderate to severe OSA. PMID- 26577777 TI - Quantitative Reverse Transcription-qPCR-Based Gene Expression Analysis in Plants. AB - The investigation of gene expression is an initial and essential step to understand the function of a gene in a physiological context. Reverse transcription-quantitative real-time PCR (RT-qPCR) assays are reproducible, quantitative, and fast. They can be adapted to study model and non-model plant species without the need to have whole genome or transcriptome sequence data available. Here, we provide a protocol for a reliable RT-qPCR assay, which can be easily adapted to any plant species of interest. We describe the design of the qPCR strategy and primer design, considerations for plant material generation, RNA preparation and cDNA synthesis, qPCR setup and run, and qPCR data analysis, interpretation, and final presentation. PMID- 26577775 TI - Lithium in the Kidney: Friend and Foe? AB - Trace amounts of lithium are essential for our physical and mental health, and administration of lithium has improved the quality of life of millions of patients with bipolar disorder for >60 years. However, in a substantial number of patients with bipolar disorder, long-term lithium therapy comes at the cost of severe renal side effects, including nephrogenic diabetes insipidus and rarely, ESRD. Although the mechanisms underlying the lithium-induced renal pathologies are becoming clearer, several recent animal studies revealed that short-term administration of lower amounts of lithium prevents different forms of experimental AKI. In this review, we discuss the knowledge of the pathologic and therapeutic effects of lithium in the kidney. Furthermore, we discuss the underlying mechanisms of these seemingly paradoxical effects of lithium, in which fine-tuned regulation of glycogen synthase kinase type 3, a prime target for lithium, seems to be key. The new discoveries regarding the protective effect of lithium against AKI in rodents call for follow-up studies in humans and suggest that long-term therapy with low lithium concentrations could be beneficial in CKD. PMID- 26577778 TI - DNA-Binding Factor Target Identification by Chromatin Immunoprecipitation (ChIP) in Plants. AB - Chromatin immunoprecipitation (ChIP) allows the precise identification of genomic loci that physically interact with a protein of interest, whether that protein is a transcription factor, a core polymerase, a histone, or other chromatin associated protein. In short, tissue is first cross-linked to freeze a population of DNA-protein interactions at a stage of interest. Chromatin is then extracted, fragmented, and incubated with a specific antibody against the protein of interest. Next, the resultant DNA-protein complexes are immunoprecipitated and captured using beads that bind to the antibody constant region. Samples are finally reverse cross-linked to separate the bound fragments and the DNA is purified. This DNA is analyzed by quantitative PCR for enrichment of genomic regions expected to be bound by the protein under study. The protocol detailed in this chapter has been successfully applied in the identification of target genes for seven transcriptional regulators of diverse classes involved in Arabidopsis thaliana floral transition. PMID- 26577779 TI - Identification of Genes Responsible for Natural Variation in Volatile Content Using Next-Generation Sequencing Technology. AB - Identification of the genes controlling the variation of key traits remains a challenge for plant researchers and represents a goal for the development of functional markers and their implementation in marker-assisted crop breeding. As an example we describe the identification of volatile organic compounds (VOCs) that segregate as single locus or mayor quantitative trait loci (QTL) in strawberry F1 segregating populations. Next, we describe a fast and efficient method for RNA extraction in strawberry that yields high-quality RNA for downstream RNA-seq analysis. Finally, two alternative methods for analysis of global transcript expression in contrasting lines will be described in order to identify the candidate gene and genes with differential expression using RNA-seq. PMID- 26577780 TI - Micro-Tom Tomato as an Alternative Plant Model System: Mutant Collection and Efficient Transformation. AB - Tomato is a model plant for fruit development, a unique feature that classical model plants such as Arabidopsis and rice do not have. The tomato genome was sequenced in 2012 and tomato is becoming very popular as an alternative system for plant research. Among many varieties of tomato, Micro-Tom has been recognized as a model cultivar for tomato research because it shares some key advantages with Arabidopsis including its small size, short life cycle, and capacity to grow under fluorescent lights at a high density. Mutants and transgenic plants are essential materials for functional genomics research, and therefore, the availability of mutant resources and methods for genetic transformation are key tools to facilitate tomato research. Here, we introduce the Micro-Tom mutant database "TOMATOMA" and an efficient transformation protocol for Micro-Tom. PMID- 26577781 TI - Culture of the Tomato Micro-Tom Cultivar in Greenhouse. AB - Micro-Tom tomato cultivar is particularly adapted to the development of genomic approaches in tomato. Here, we describe the culture of this plant in greenhouse, including climate regulation, seed sowing and watering, vegetative development, plant maintenance, including treatment of phytosanitary problems, and reproductive development. PMID- 26577782 TI - Virus-Induced Gene Silencing as a Tool to Study Tomato Fruit Biochemistry. AB - Virus-Induced Gene Silencing (VIGS) is an excellent reverse genetic tool for the study of gene function in plants, based on virus infection. In this chapter, we describe a high-throughput approach based on VIGS for the study of tomato fruit biochemistry. It comprises the selection of the sequence for silencing using bioinformatics tools, the cloning of the fragment in the Tobacco Rattle Virus (TRV), and the agroinfiltration of tomato fruits mediated by Agrobacterium tumefaciens. PMID- 26577783 TI - A Simplified and Rapid Method for the Isolation and Transfection of Arabidopsis Leaf Mesophyll Protoplasts for Large-Scale Applications. AB - Arabidopsis leaf mesophyll protoplasts constitute an important and versatile tool for conducting cell-based experiments to analyze the functions of distinct signaling pathways and cellular machineries using proteomic, biochemical, cellular, genetic, and genomic approaches. Thus, the methods for protoplast isolation and transfection have been gradually improved to achieve efficient expression of genes of interest. Although many well-established protocols have been extensively tested, their successful application is sometimes limited to researchers with a high degree of skill and experience in protoplasts handling. Here we present a detailed method for the isolation and transfection of Arabidopsis mesophyll protoplasts, in which many of the time-consuming and critical steps present in the current protocols have been simplified. The method described is fast, simple, and leads to high yields of competent protoplasts allowing large-scale applications. PMID- 26577784 TI - Preparation of Epidermal Peels and Guard Cell Protoplasts for Cellular, Electrophysiological, and -Omics Assays of Guard Cell Function. AB - Bioassays are commonly used to study stomatal phenotypes. There are multiple options in the choice of plant materials and species used for observation of stomatal and guard cell responses in vivo. Here, detailed procedures for bioassays of stomatal responses to abscisic acid (ABA) in Arabidopsis thaliana are described, including ABA promotion of stomatal closure, ABA inhibition of stomatal opening, and ABA promotion of reaction oxygen species (ROS) production in guard cells. We also include an example of a stomatal bioassay for the guard cell CO2 response using guard cell-enriched epidermal peels from Brassica napus. Highly pure preparations of guard cell protoplasts can be produced, which are also suitable for studies on guard cell signaling, as well as for studies on guard cell ion transport. Small-scale and large-scale guard cell protoplast preparations are commonly used for electrophysiological and -omics studies, respectively. We provide a procedure for small-scale guard cell protoplasting from A. thaliana. Additionally, a general protocol for large-scale preparation of guard cell protoplasts, with specifications for three different species, A. thaliana, B. napus, and Vicia faba is also provided. PMID- 26577785 TI - Application of Variable Angle Total Internal Reflection Fluorescence Microscopy to Investigate Protein Dynamics in Intact Plant Cells. AB - Variable angle total internal reflection fluorescence microscopy (VA-TIRFM) is an optical method to observe the molecular events occurring in an extremely thin region near the plasma membrane. Recently, the VA-TIRFM technique has been widely used to study fluorescently labeled target molecules in living animal and plant cells. Here, we describe the optical principle of the VA-TIRFM technique and provide a detailed experimental procedure for the study of living plant cells. PMID- 26577786 TI - Immunoprecipitation of Plasma Membrane Receptor-Like Kinases for Identification of Phosphorylation Sites and Associated Proteins. AB - Membrane proteins are difficult to study for numerous reasons. The surface of membrane proteins is relatively hydrophobic and sometimes very unstable, additionally requiring detergents for their extraction from the membrane. This leads to challenges at all levels, including expression, solubilization, purification, identification of associated proteins, and the identification of post-translational modifications. However, recent advances in immunoprecipitation technology allow to isolate membrane proteins efficiently, facilitating the study of protein-protein interactions, the identification of novel associated proteins, and to identify post-translational modifications, such as phosphorylation. Here, we describe an optimized immunoprecipitation protocol for plant plasma membrane receptor-like kinases. PMID- 26577787 TI - Yeast Three-Hybrid System for the Detection of Protein-Protein Interactions. AB - Protein-protein interaction studies provide useful insights into biological processes taking place within the living cell. A number of techniques are available to unravel large structural protein complexes, functional protein modules, and temporary protein associations occurring during signal transduction. The choice of method depends on the nature of the proteins and the interaction being studied. Here we present an optimized and simplified yeast three-hybrid method for analysis of protein interactions involving three components. PMID- 26577789 TI - Analysis of Protein-Lipid Interactions Using Purified C2 Domains. AB - C2 domains (C2s) are regulatory protein modules identified in eukaryotic proteins targeted to cell membranes. C2s were initially characterized as independently folded Ca(2+)-dependent phospholipids binding domains; however, later studies have shown that C2s have evolutionarily diverged into Ca(2+)-dependent and Ca(2+) independent forms. These forms interact and regulate their affinity to diverse lipid species using different binding mechanisms. In this protocol we describe a biochemical approach to produce, purify, and solubilize functional C2 domains bound to GST for the identification of their putative Ca(2+)-dependent and Ca(2+) independent lipid-binding partners. PMID- 26577788 TI - Cautions in Measuring In Vivo Interactions Using FRET and BiFC in Nicotiana benthamiana. AB - Bimolecular fluorescence complementation (BiFC) and Forster Resonance Energy Transfer (FRET) are two widely used techniques to investigate protein-protein interactions and subcellular compartmentalization of proteins in complexes. As of January 2015, there were 805 publications retrieved by PUBMED with the query "bimolecular fluorescence complementation" and 11,327 publications retrieved with the query "fluorescence resonance energy transfer". Only a few of these publications describe studies of plant cells. Given the importance and popularity of these techniques, applying them correctly is crucial but unfortunately many studies lack proper controls and verifications. We describe (1) BiFC and FRET problems that are frequently encountered at different stages of the protocols, (2) how to use appropriate controls, and (3) how to apply plant transformation and imaging procedures. We provide step-by-step protocols for the beginner to obtain high quality, artifact-free BiFC and FRET data. PMID- 26577790 TI - Assessing Kinase Activity in Plants with In-Gel Kinase Assays. AB - The in-gel protein kinase assay is a powerful method to measure the protein phosphorylation activity of specific protein kinases. Any protein substrate can be embedded in polyacrylamide gels where they can be phosphorylated by protein kinases that are separated in the gel under denaturing conditions and then renatured. The kinase activity can be visualized in situ in the gels by autoradiography. This method has been used to compare the activities of protein kinases in parallel samples or to identify their potential substrates. Here, we describe in detail an in-gel kinase assay to measure the activity of some protein kinases in plants. PMID- 26577791 TI - Analyses of Plant UDP-Dependent Glycosyltransferases to Identify Their Volatile Substrates Using Recombinant Proteins. AB - Glycosylation is one of major modifications for plant secondary metabolites. In the case of volatile compounds, glycosylation makes them nonvolatile and odorless. Identification of UDP-dependent glycosyltransferases responsible for volatile glycosylation is essential to understand the regulatory mechanism of volatile release from plant tissues. Here, we describe an efficient protocol to find possible combinations of volatiles/glycosyltransferases using tomato (Solanum lycopersicum) enzymes expressed in Escherichia coli. The presented method requires a basic gas chromatography system and conventional laboratory tools. PMID- 26577792 TI - Competitive Index: Mixed Infection-Based Virulence Assays for Genetic Analysis in Pseudomonas syringae-Plant Interactions. AB - When studying bacterial plant pathogens, the genetic analysis of the contribution of virulence factors to the infection process has traditionally been hindered by their high degree of functional redundancy. In recent years, it has become clear that the use of competitive index in mixed infections provides an accurate and sensitive manner of establishing virulence phenotypes for mutants for which other assays have failed. Such increases in sensitivity and accuracy are due to the direct comparison between the respective growths of the co-inoculated strains within the same infection, each strain replicating as they would in individual infections. Interferences between the co-inoculated strains must be therefore avoided using the appropriate experimental settings. In this chapter, we will present the optimal experimental conditions to achieve maximum sensitivity on virulence assays using the phytopathogenic bacterium Pseudomonas syringae, as well as some additional considerations to ensure the correct interpretations of the results. PMID- 26577793 TI - Simplified Assays for Evaluation of Resistance to Alternaria brassicicola and Turnip Mosaic Virus. AB - Studying the natural defense mechanisms developed by model plants such as Arabidopsis is an important approach towards the improvement of crop species. The availability of mutants as well as the relative easiness to silence any gene in Arabidopsis provides an invaluable source of genotypes that can be used to discover new elements involved in the defense response. Here we describe simple and reliable methods to evaluate susceptibility/resistance to the pathogenic fungus Alternaria brassicicola and the viral pathogen Turnip mosaic virus. PMID- 26577794 TI - Simultaneous Determination of Plant Hormones by GC-TOF-MS. AB - Phytohormones are key signaling molecules that coordinate plant growth and development through a range of complex interactions. Since the vast majority of plant responses to given stimuli result, amongst other factors, from a crosstalk between hormones, simultaneous analysis of multiple hormones is vital to improve our understanding of these interactions. This chapter describes a sensitive, reliable, and inexpensive method for quantification of multiple phytohormones by gas chromatography-mass spectrometry (GC-MS). PMID- 26577795 TI - Efficacy and safety of once-weekly GLP-1 receptor agonist albiglutide (HARMONY 2): 52 week primary endpoint results from a randomised, placebo-controlled trial in patients with type 2 diabetes mellitus inadequately controlled with diet and exercise. AB - AIMS/HYPOTHESIS: Additional safe and effective therapies for type 2 diabetes are needed, especially ones that do not cause weight gain and have a low risk of hypoglycaemia. The present study evaluated albiglutide as monotherapy. METHODS: In this placebo-controlled study, 309 patients (aged >= 18 years) with type 2 diabetes inadequately controlled by diet and exercise and who were not using a glucose-lowering agent (HbA1c 7.0-10.0% [53.00-85.79 mmol/mol], body mass index 20-45 kg/m(2), and fasting C-peptide >= 0.26 nmol/l) were randomised (1:1:1 on a fixed randomisation schedule using an interactive voice response system) to receive once-weekly albiglutide 30 mg (n = 102) or 50 mg (n = 102) or matching placebo (n = 105). The study treatments were blinded to both patients and study personnel. All study data were collected at individual patient clinic visits. The primary efficacy endpoint was change in HbA1c from baseline to week 52. The primary analysis was applied to the intent-to-treat population. Additional efficacy and safety endpoints were assessed. RESULTS: At week 52, both albiglutide 30 mg and 50 mg were superior to placebo in reducing HbA1c. The least squares means treatment difference from placebo was -0.84% (95% CI -1.11%, 0.58%; p < 0.0001) with albiglutide 30 mg and -1.04% (-1.31%, -0.77%; p < 0.0001) with albiglutide 50 mg. Injection-site reactions were reported more frequently with albiglutide (30 mg: 17.8%; 50 mg: 22.2%) than with placebo (9.9%). Other commonly reported adverse events included nausea, diarrhoea, vomiting and hypoglycaemia; the incidences of these were generally similar across treatment groups. CONCLUSIONS/INTERPRETATION: Albiglutide is safe and effective as monotherapy and significantly lowered HbA1c levels over 52 weeks, did not cause weight gain, and had good gastrointestinal tolerability and a low rate of hypoglycaemia compared with placebo. Trial registration ClinicalTrials.gov NCT00849017 Funding This study was sponsored by GlaxoSmithKline. PMID- 26577796 TI - Effect of atorvastatin on glycaemia progression in patients with diabetes: an analysis from the Collaborative Atorvastatin in Diabetes Trial (CARDS). AB - AIMS/HYPOTHESIS: In an individual-level analysis we examined the effect of atorvastatin on glycaemia progression in type 2 diabetes and whether glycaemia effects reduce the prevention of cardiovascular disease (CVD) with atorvastatin. METHODS: The study population comprised 2,739 people taking part in the Collaborative Atorvastatin Diabetes Study (CARDS) who were randomised to receive atorvastatin 10 mg or placebo and who had post-randomisation HbA1c data. This secondary analysis used Cox regression to estimate the effect of atorvastatin on glycaemia progression, defined as an increase in HbA1c of >= 0.5% (5.5 mmol/mol) or intensification of diabetes therapy. Mixed models were used to estimate the effect of atorvastatin on HbA1c as a continuous endpoint. RESULTS: Glycaemia progression occurred in 73.6% of participants allocated placebo and 78.1% of those allocated atorvastatin (HR 1.18 [95% CI 1.08, 1.29], p < 0.001) by the end of follow-up. The HR was 1.22 (95% CI 1.19, 1.35) in men and 1.11 (95% CI 0.95, 1.29) in women (p = 0.098 for the sex interaction). A similar effect was seen in on-treatment analyses: HR 1.20 (95% CI 1.07, 1.35), p = 0.001. The net mean treatment effect on HbA1c was 0.14% (95% CI 0.08, 0.21) (1.5 mmol/mol). The effect did not increase through time. Diabetes treatment intensification alone did not differ with statin allocation. Neither baseline nor 1-year-attained HbA1c predicted subsequent CVD, and the atorvastatin effect on CVD did not vary by HbA1c change (interaction p value 0.229). CONCLUSIONS/INTERPRETATION: The effect of atorvastatin 10 mg on glycaemia progression among those with diabetes is statistically significant but very small, is not significantly different between sexes, does not increase with duration of statin and does not have an impact on the magnitude of CVD risk reduction with atorvastatin. PMID- 26577797 TI - Brief inhalation of nitric oxide increases resuscitation success and improves 7 day-survival after cardiac arrest in rats: a randomized controlled animal study. AB - INTRODUCTION: Inhaled nitric oxide (iNO) improves outcomes when given post systemic ischemia/reperfusion injury. iNO given during cardiopulmonary resuscitation (CPR) may therefore improve return of spontaneous circulation (ROSC) rates and functional outcome after cardiac arrest (CA). METHODS: Thirty male Sprague-Dawley rats were subjected to 10 minutes of CA and at least 3 minutes of CPR. Animals were randomized to receive either 0 (n = 10, Control), 20 (n = 10, 20 ppm), or 40 (n = 10, 40 ppm) ppm iNO during CPR until 30 minutes after ROSC. A neurological deficit score was assessed daily for seven days following the experiment. On day 7, brains, hearts, and blood were sampled for histological and biochemical evaluation. RESULTS: During CPR, 20 ppm iNO significantly increased diastolic arterial pressure ( CONTROL: 57 +/- 5.04 mmHg; 20 ppm: 71.57 +/- 57.3 mmHg, p < 0.046) and decreased time to ROSC (CONTROL: 842 +/- 21 s; 20 ppm: 792 +/- 5 s, (p = 0.02)). Thirty minutes following ROSC, 20 ppm iNO resulted in an increase in mean arterial pressure ( CONTROL: 83 +/- 4 mmHg; 20 ppm: 98 +/- 4 mmHg, p = 0.035), a less pronounced rise in lactate and inflammatory cytokine levels, and attenuated cardiac damage. Inhalation of NO at 20 ppm improved neurological outcomes in rats 2 to 7 days after CA and CPR. This translated into increases in 7 day survival ( CONTROL: 4; 20 ppm: 10; 40 ppm 6, (p <= 0.05 20 ppm vs CONTROL and 40 ppm). CONCLUSIONS: Our study revealed that breathing NO during CPR markedly improved resuscitation success, 7-day neurological outcomes and survival in a rat model of VF-induced cardiac arrest and CPR. These results support the beneficial effects of NO inhalation after cardiac arrest and CPR. PMID- 26577799 TI - Novel electrochemical redox-active species: one-step synthesis of polyaniline derivative-Au/Pd and its application for multiplexed immunoassay. AB - Electrochemical redox-active species play crucial role in electrochemically multiplexed immunoassays. A one-pot method for synthesizing four kinds of new electrochemical redox-active species was reported using HAuCl4 and Na2PdCl4 as dual oxidating agents and aniline derivatives as monomers. The synthesized polyaniline derivative-Au/Pd composites, namely poly(N-methyl-o-benzenediamine) Au/Pd, poly(N-phenyl-o-phenylenediamine)-Au/Pd, poly(N-phenyl-p-phenylenediamine) Au/Pd and poly(3,3',5,5'-tetramethylbenzidine)-Au/Pd, exhibited electrochemical redox activity at -0.65 V, -0.3 V, 0.12 V, and 0.5 V, respectively. Meanwhile, these composites showed high H2O2 electrocatalytic activity because of the presence of Au/Pd. The as-prepared composites were used as electrochemical immunoprobes in simultaneous detection of four tumor biomarkers (carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA199), carbohydrate antigen 72-4 (CA724), and alpha fetoprotein (AFP)). This immunoassay shed light on potential applications in simultaneous gastric cancer (related biomarkers: CEA, CA199, CA724) and liver cancer diagnosis (related biomarkers: CEA, CA199, AFP). The present strategy to the synthesize redox species could be easily extended to other polymers such as polypyrrole derivatives and polythiophene derivatives. This would be of great significance in the electrochemical detection of more analytes. PMID- 26577800 TI - Reliable quantum certification of photonic state preparations. AB - Quantum technologies promise a variety of exciting applications. Even though impressive progress has been achieved recently, a major bottleneck currently is the lack of practical certification techniques. The challenge consists of ensuring that classically intractable quantum devices perform as expected. Here we present an experimentally friendly and reliable certification tool for photonic quantum technologies: an efficient certification test for experimental preparations of multimode pure Gaussian states, pure non-Gaussian states generated by linear-optical circuits with Fock-basis states of constant boson number as inputs, and pure states generated from the latter class by post selecting with Fock-basis measurements on ancillary modes. Only classical computing capabilities and homodyne or hetorodyne detection are required. Minimal assumptions are made on the noise or experimental capabilities of the preparation. The method constitutes a step forward in many-body quantum certification, which is ultimately about testing quantum mechanics at large scales. PMID- 26577801 TI - Persistent But Not Replicating HIV-1 Cell-Associated DNA in Semen of Long-Term ART Experienced Men. AB - BACKGROUND: The semen of HIV-1 infected men represents the main vector of HIV-1 spread following sexual transmission of cell-free or cell-associated virions. OBJECTIVE: The present study aimed to assess the impact of HAART on HIV-1 RNA/DNA and on inflammatory environment in the semen of long-term HAART-experienced men. METHODS: Forty-five paired samples of semen and blood were obtained from 37 consenting men, 10 untreated and 27 under HAART. Blood and seminal HIV RNA and DNA loads were quantified by the Abbott RealTime m2000rt assay and an inhouse real-time PCR protocol, respectively. Tat/rev/nef intra-cellular mRNA was tested by qualitative PCR. Interleukin (IL)- 1beta, IL-2, IL-6, IL-7, IL-8, IL-10, GM CSF and TNFalpha were quantified in 20 paired samples by Bio-plex(r) assay. RESULTS: No semen was found HIV RNA positive in men under HAART. Twenty-six percent of semen samples from HAART-experienced men remained positive for HIV DNA. Seminal HIV DNA was significantly associated with the duration of infection and the HIV DNA load in blood. No seminal mononuclear cells were found positive for intracellular HIV RNA in HAART experienced men. All the tested chemokines exhibited significantly higher concentration in semen than in blood in both treated and untreated men. No effect of HAART on cytokines/chimiokines loads was observed. CONCLUSION: These results demonstrate the efficacy of HAART on the reduction of seminal RNA HIV-1 loads despite the persistence of local inflammation. Moreover, in our hands the seminal cell-associated virus reservoir was not reactivated in an inflammatory environment was not productive and its reactivation seems unlikely. PMID- 26577802 TI - A new fireworm (Amphinomidae) from the Cretaceous of Lebanon identified from three-dimensionally preserved myoanatomy. AB - BACKGROUND: Rollinschaeta myoplena gen. et sp. nov is described from the Late Cretaceous (Cenomanian) Konservat-Lagerstatten of Hakel and Hjoula, Lebanon. The myoanatomy of the fossils is preserved in exceptional detail in three dimensions as calcium phosphate, allowing the musculature of the body wall, gut and parapodia to be reconstructed in detail. RESULTS: The major muscle groups of polychaetes can be identified in Rollinschaeta, including longitudinal muscle bands, circular muscles, oblique muscles, the parapodial muscle complex and the gut musculature, with a resolution sufficient to preserve individual fibres. To allow meaningful comparison with the phosphatized fossil specimens, extant polychaetes were stained with iodine and visualised using microCT. Rollinschaeta myoplena possesses two pairs of dorsal longitudinal muscles, dorsal and ventral circular muscles and a single pair of ventral longitudinal muscles. While six longitudinal muscle bands are known from other polychaete groups, their presence in combination with circular muscles is unique to Amphinomidae, allowing these fossils to be diagnosed to family level based solely on their myoanatomy. The elongate, rectilinear body and equally sized, laterally projecting parapodia of Rollinschaeta are found only within Amphinominae, demonstrating that the Cretaceous species is derived amongst Amphinomida. CONCLUSION: The uniquely preserved myoanatomy of Rollinschaeta has allowed diagnosis of a fossil annelid to subfamily level using microCT as a comparative tool for exploring myoanatomy in fossil and extant polychaetes. Our results demonstrate that fossilized muscles can provide systematically informative anatomical detail and that they should be studied when preserved. PMID- 26577803 TI - Applicability of digital analysis and imaging technology in neuropathology assessment. AB - Alzheimer's disease (AD) is a progressive neurological disorder that affects more than 30 million people worldwide. While various dementia-related losses in cognitive functioning are its hallmark clinical symptoms, ultimate diagnosis is based on manual neuropathological assessments using various schemas, including Braak staging, CERAD (Consortium to Establish a Registry for Alzheimer's Disease) and Thal phase scoring. Since these scoring systems are based on subjective assessment, there is inevitably some degree of variation between readers, which could affect ultimate neuropathology diagnosis. Here, we report a pilot study investigating the applicability of computer-driven image analysis for characterizing neuropathological features, as well as its potential to supplement or even replace manually derived ratings commonly performed in medical settings. In this work, we quantitatively measured amyloid beta (Abeta) plaque in various brain regions from 34 patients using a robust digital quantification algorithm. We next verified these digitally derived measures to the manually derived pathology ratings using correlation and ordinal logistic regression methods, while also investigating the association with other AD-related neuropathology scoring schema commonly used at autopsy, such as Braak and CERAD. In addition to successfully verifying our digital measurements of Abeta plaques with respective categorical measurements, we found significant correlations with most AD-related scoring schemas. Our results demonstrate the potential for digital analysis to be adapted to more complex staining procedures commonly used in neuropathological diagnosis. As the efficiency of scanning and digital analysis of histology images increases, we believe that the basis of our semi-automatic approach may better standardize quantification of neuropathological changes and AD diagnosis, ultimately leading to a more comprehensive understanding of neurological disorders and more efficient patient care. PMID- 26577804 TI - From autochthonous to allochthonous resources: seasonal shifts in food use by stream-dwelling YOY Arctic charr Salvelinus alpinus through the ice-free season. AB - Substantial seasonal changes in resource use associated with enhanced water column use were revealed in stream-living YOY Arctic charr Salvelinus alpinus during the ice-free season. In July, YOY individuals showed a diet dominated by aquatic invertebrates (mainly Chironomidae larvae), but despite the small size of the fish, the abundance of terrestrial insects in their diet increased markedly from July to September (from 1.9 to 62.8%). Similarly, the frequency of surface drifting foragers, i.e. individuals feeding on allochthonous resources, increased from July to September (from 20.6 to 80%); allochthonous resources thus constituting an important energy subsidy for YOY S. alpinus during the late sub Arctic summer. PMID- 26577805 TI - Standardizing Plasmodium falciparum infection prevalence measured via microscopy versus rapid diagnostic test. AB - BACKGROUND: Large-scale mapping of Plasmodium falciparum infection prevalence relies on opportunistic assemblies of infection prevalence data arising from thousands of P. falciparum parasite rate (PfPR) surveys conducted worldwide. Variance in these data is driven by both signal, the true underlying pattern of infection prevalence, and a range of factors contributing to 'noise', including sampling error, differing age ranges of subjects and differing parasite detection methods. Whilst the former two noise components have been addressed in previous studies, the effect of different diagnostic methods used to determine PfPR in different studies has not. In particular, the majority of PfPR data are based on positivity rates determined by either microscopy or rapid diagnostic test (RDT), yet these approaches are not equivalent; therefore a method is needed for standardizing RDT and microscopy-based prevalence estimates prior to use in mapping. METHODS: Twenty-five recent Demographic and Health surveys (DHS) datasets from sub-Saharan Africa provide child diagnostic test results derived using both RDT and microscopy for each individual. These prevalence estimates were aggregated across level one administrative zones and a Bayesian probit regression model fit to the microscopy- versus RDT-derived prevalence relationship. An errors-in-variables approach was employed to account for sampling error in both the dependent and independent variables. In addition to the diagnostic outcome, RDT type, fever status and recent anti-malarial treatment were extracted from the datasets in order to analyse their effect on observed malaria prevalence. RESULTS: A strong non-linear relationship between the microscopy and RDT-derived prevalence was found. The results of regressions stratified by the additional diagnostic variables (RDT type, fever status and recent anti-malarial treatment) indicate that there is a distinct and consistent difference in the relationship when the data are stratified by febrile status and RDT brand. CONCLUSIONS: The relationships defined in this research can be applied to RDT-derived PfPR data to effectively convert them to an estimate of the parasite prevalence expected using microscopy (or vice versa), thereby standardizing the dataset and improving the signal-to-noise ratio. Additionally, the results provide insight on the importance of RDT brands, febrile status and recent anti-malarial treatment for explaining inconsistencies between observed prevalence derived from different diagnostics. PMID- 26577806 TI - Chemotherapy induces stemness in osteosarcoma cells through activation of Wnt/beta-catenin signaling. AB - Development of resistance represents a major drawback in osteosarcoma treatment, despite improvements in overall survival. Treatment failure and tumor progression have been attributed to pre-existing drug-resistant clones commonly assigned to a cancer stem-like phenotype. Evidence suggests that non stem-like cells, when submitted to certain microenvironmental stimuli, can acquire a stemness phenotype thereby strengthening their capacity to handle with stressful conditions. Here, using osteosarcoma cell lines and a mouse xenograft model, we show that exposure to conventional chemotherapeutics induces a phenotypic cell transition toward a stem-like phenotype. This associates with activation of Wnt/beta-catenin signaling, up-regulation of pluripotency factors and detoxification systems (ABC transporters and Aldefluor activity) that ultimately leads to chemotherapy failure. Wnt/beta-catenin inhibition combined with doxorubicin, in the MNNG-HOS cells, prevented the up-regulation of factors linked to transition into a stem like state and can be envisaged as a way to overcome adaptive resistance. Finally, the analysis of the public R2 database, containing microarray data information from diverse osteosarcoma tissues, revealed a correlation between expression of stemness markers and a worse response to chemotherapy, which provides evidence for drug-induced phenotypic stem cell state transitions in osteosarcoma. PMID- 26577807 TI - Crosstalk between transforming growth factor-beta signaling pathway and long non coding RNAs in cancer. AB - The transforming growth factor-beta (TGF-beta) signaling pathway plays an important role in tumorigenesis by exerting either a tumor-suppressing or tumor promoting effect. Long non-coding RNAs (lncRNAs), a newly discovered class of non coding RNAs, have been widely studied in recent years and identified as crucial regulators of various biological processes, including cell cycle progression, chromatin remodeling, gene transcription, and posttranscriptional processing. Recent evidence, addressing the crosstalk between the TGF-beta signaling pathway and lncRNAs in cancer, found that several members of the TGF-beta pathway are targeted by lncRNAs, and the production of hundreds of lncRNAs is induced by TGF beta treatment. This review will summarize the latest progress on the investigation of TGF-beta pathway and lncRNA network in regulating cancer development. Further study on the network would provide a better understanding of carcinogenesis and have potentials for the prevention and treatment of malignant diseases. PMID- 26577808 TI - The influence of the pre-metastatic niche on breast cancer metastasis. AB - The emergence of metastatic disease constitutes a significant life-threatening development during cancer progression. To date, intensive efforts have been focused on understanding the intrinsic properties that confer malignant potential to cancer cells, as well as the role of the primary tumour microenvironment in promoting cancer metastasis. Beyond events occurring at the primary site, the metastatic cascade is composed of numerous barriers that must be overcome in order for disseminating cancer cells to form distal metastases. The most formidable of these is the ability of cancer cells to seed and grow in a completely foreign microenvironment. Interestingly, solid malignancies often display a particular tropism for specific tissue sites. For example, breast patients with metastatic disease will often develop bone, lung, liver or brain metastases. This mini-review will explore aspects of pre-existing and induced metastatic niches and focus on how the unique composition and function of diverse niche components, within common sites of breast cancer metastasis, enable the survival and growth of disseminated cancer cells. These common supportive functions of the niche are provided by a complex array of stromal components and molecular mechanisms that are, in part, reflective of the tissue in which the metastases arise. Finally, the metastatic niche is a dynamic structure that is continually altered and sculpted by the cancer cells during progression of the metastatic lesion. PMID- 26577809 TI - Non-canonical GLI1/2 activation by PI3K/AKT signaling in renal cell carcinoma: A novel potential therapeutic target. AB - Renal cell carcinoma (RCC) is the most lethal urologic malignancy; however, the molecular events supporting RCC carcinogenesis and progression remain poorly understood. In this study, based on the analysis of gene expression profile data from human clear cell RCC (ccRCC) and the corresponding normal tissues, we discovered that Hedgehog (HH) pathway component genes GLI1 and GLI2 were significantly elevated in ccRCC. Survival analysis of a large cohort of ccRCC samples demonstrated that the expression of GLI1 and GLI2 was negatively correlated with patient overall survival. Clinical sample-based VHL mutation and cell model-based VHL manipulation studies all indicated that the activation of GLI1 and GLI2 was not affected by VHL status. Further signaling pathway dissections demonstrated that GLI1 and GLI2 were activated by the phosphoinositide 3-kinase (PI3K)/AKT pathway, but not mediated by the canonical HH/SMO/GLI signaling. Up-regulation of GLI1 and GLI2 promoted RCC proliferation and clonogenic ability, whereas, a combination of GLIs inhibitor Gant61 and AKT inhibitor Perifosine synergistically suppressed RCC growth and induced apoptosis in vitro and in vivo. Therefore, this study identifies that GLI1 and GLI2 are critical for RCC carcinogenesis, and also provides an alternative therapeutic strategy for RCC. PMID- 26577810 TI - Long noncoding RNAs as potential biomarkers in gastric cancer: Opportunities and challenges. AB - Gastric cancer (GC) is a major threat to human health, and its prognosis is poor due to the lack of appropriate biomarkers. LncRNAs are a group of non-protein coding RNAs that regulate gene expression at the transcriptional or posttranscriptional level. LncRNAs play essential roles in GC initiation and development in the same way as oncogenes or tumour suppressor genes. Recent investigations have revealed that lncRNAs are often aberrantly expressed in GC; are involved in cell proliferation, apoptosis, migration and invasion; and correlate with the malignant phenotype of GC. LncRNAs, especially the lncRNAs present in the blood and gastric juice, show potential value as biomarkers for the diagnosis of GC or for determining disease prognosis. However, there are still many challenges to be faced before lncRNAs can be used in clinical applications. In this review, we summarise lncRNAs as the potential biomarkers for GC and the current challenges associated with the clinical application. PMID- 26577811 TI - Endothelial precursor cell-based therapy to target the pathologic angiogenesis and compensate tumor hypoxia. AB - Hypoxia-inducing pathologies as cancer develop pathologic and inefficient angiogenesis which rules tumor facilitating microenvironment, a key target for therapy. As such, the putative ability of endothelial precursor cells (EPCs) to specifically home to hypoxic sites of neovascularization prompted to design optimized, site-specific, cell-mediated, drug-/gene-targeting approach. Thus, EPC lines were established from aorta-gonad-mesonephros (AGM) of murine 10.5 dpc and 11.5 dpc embryo when endothelial repertoire is completed. Lines representing early endothelial differentiation steps were selected: MAgEC10.5 and MagEC11.5. Distinct in maturation, they differently express VEGF receptors, VE-cadherin and chemokine/receptors. MAgEC11.5, more differentiated than MAgEC 10.5, displayed faster angiogenesis in vitro, different response to hypoxia and chemokines. Both MAgEC lines cooperated to tube-like formation with mature endothelial cells and invaded tumor spheroids through a vasculogenesis-like process. In vivo, both MAgEC-formed vessels established blood flow. Intravenously injected, both MAgECs invaded Matrigel(TM)-plugs and targeted tumors. Here we show that EPCs (MAgEC11.5) target tumor angiogenesis and allow local overexpression of hypoxia driven soluble VEGF-receptor2 enabling drastic tumor growth reduction. We propose that such EPCs, able to target tumor angiogenesis, could act as therapeutic gene vehicles to inhibit tumor growth by vessel normalization resulting from tumor hypoxia alleviation. PMID- 26577812 TI - Oxygen Tension Within the Neurogenic Niche Regulates Dopaminergic Neurogenesis in the Developing Midbrain. AB - Oxygen tension is an important factor controlling stem cell proliferation and maintenance in various stem cell populations with a particular relevance in midbrain dopaminergic progenitors. Further studies have shown that the oxygen dependent transcription factor hypoxia-inducible factor 1alpha (HIF-1alpha) is involved in these processes. However, all available studies on oxygen effects in dopaminergic neuroprogenitors were performed in vitro and thus it remains unclear whether tissue oxygen tension in the embryonic midbrain is also relevant for the regulation of dopaminergic neurogenesis in vivo. We thus dissect here the effects of oxygen tension in combination with HIF-1alpha conditional knockout on dopaminergic neurogenesis by using a novel experimental design allowing for the control of oxygen tension within the microenvironment of the neurogenic niche of the murine fetal midbrain in vivo. The microenvironment of the midbrain dopaminergic neurogenic niche was detected as hypoxic with oxygen tensions below 1.1%. Maternal oxygen treatment of 10%, 21%, and 75% atmospheric oxygen tension for 48 h translates into robust changes in fetal midbrain oxygenation. Fetal midbrain hypoxia hampered the generation of dopaminergic neurons and is accompanied with restricted fetal midbrain development. In contrast, induced hyperoxia stimulated proliferation and differentiation of dopaminergic progenitors during early and late embryogenesis. Oxygen effects were not directly mediated through HIF-1alpha signaling. These data--in agreement with in vitro data-indicate that oxygen is a crucial regulator of developmental dopaminergic neurogenesis. Our study provides the initial framework for future studies on molecular mechanisms mediating oxygen regulation of dopaminergic neurogenesis within the fetal midbrain as its natural environment. PMID- 26577813 TI - Nanofabrication and coloration study of artificial Morpho butterfly wings with aligned lamellae layers. AB - The bright and iridescent blue color from Morpho butterfly wings has attracted worldwide attentions to explore its mysterious nature for long time. Although the physics of structural color by the nanophotonic structures built on the wing scales has been well established, replications of the wing structure by standard top-down lithography still remains a challenge. This paper reports a technical breakthrough to mimic the blue color of Morpho butterfly wings, by developing a novel nanofabrication process, based on electron beam lithography combined with alternate PMMA/LOR development/dissolution, for photonic structures with aligned lamellae multilayers in colorless polymers. The relationship between the coloration and geometric dimensions as well as shapes is systematically analyzed by solving Maxwell's Equations with a finite domain time difference simulator. Careful characterization of the mimicked blue by spectral measurements under both normal and oblique angles are carried out. Structural color in blue reflected by the fabricated wing scales, is demonstrated and further extended to green as an application exercise of the new technique. The effects of the regularity in the replicas on coloration are analyzed. In principle, this approach establishes a starting point for mimicking structural colors beyond the blue in Morpho butterfly wings. PMID- 26577814 TI - A rare case of cystic ganglionosis in a child with associated imaging findings. AB - Ganglia are benign soft tissue masses that are found adjacent to joints and tendons. They can be multifocal but they are rarely more numerous than a few around any given joint. "Cystic ganglionosis" has been used to describe a condition in which multifocal and extensive ganglia are present. We present a rare case of cystic ganglionosis in a Caucasian girl with clinical symptoms detected at 6 months of age. To the authors' knowledge, only a single other case report of cystic ganglionosis is documented in the English medical literature. The ganglia in this case are more extensive, manifested at an earlier age and caused erosions of multiple bones, a rarely observed complication of ganglia. Additionally, radiograph, MR and sonographic images collected over 9 years time allows for a detailed description of the imaging characteristics of this case of cystic ganglionosis, and offers unique insight into the natural history of this diagnosis. Extensive ganglia in multiple locations in a young child should alert clinicians to the possibility of cystic ganglionosis. Disease progression may lead to deleterious effects on bone warranting the use of maintenance imaging and possibly surgical resection of symptomatic lesions. PMID- 26577815 TI - Why the aspect ratio? Shape equivalence for the extinction spectra of gold nanoparticles. AB - We compare the light extinction spectra of elongated gold nanoparticles with different shapes (cylinder, spherocylinder and ellipsoid) and sizes of 10 to 100 nm. We argue that the equivalence of the various moments of mass distribution is the natural comparison criterion--rather than the length-to-diameter (aspect) ratio generally used in the literature--and that it leads to better spectral correspondence between the various shapes. PMID- 26577816 TI - Microphase separation patterns in diblock copolymers on curved surfaces using a nonlocal Cahn-Hilliard equation. AB - We investigate microphase separation patterns on curved surfaces in three dimensional space by numerically solving a nonlocal Cahn-Hilliard equation for diblock copolymers. In our model, a curved surface is implicitly represented as the zero level set of a signed distance function. We employ a discrete narrow band grid that neighbors the curved surface. Using the closest point method, we apply a pseudo-Neumann boundary at the boundary of the computational domain. The boundary treatment allows us to replace the Laplace-Beltrami operator by the standard Laplacian operator. In particular, we can apply standard finite difference schemes in order to approximate the nonlocal Cahn-Hilliard equation in the discrete narrow band domain. We employ a type of unconditionally stable scheme, which was introduced by Eyre, and use the Jacobi iterative to solve the resulting implicit discrete system of equations. In addition, we use the minimum number of grid points for the discrete narrow band domain. Therefore, the algorithm is simple and fast. Numerous computational experiments are provided to study microphase separation patterns for diblock copolymers on curved surfaces in three-dimensional space. PMID- 26577817 TI - Effect of PEO molecular weight on the miscibility and dynamics in epoxy/PEO blends. AB - In this work, the effect of poly(ethylene oxide) (PEO) molecular weight in blends of epoxy (ER) and PEO on the miscibility, inter-chain weak interactions and local dynamics were systematically investigated by multi-frequency temperature modulation DSC and solid-state NMR techniques. We found that the molecular weight (M(w)) of PEO was a crucial factor in controlling the miscibility, chain dynamics and hydrogen bonding interactions between PEO and ER. A critical PEO molecular weight (M(crit)) around 4.5k was found. PEO was well miscible with ER when the molecular weight was below M(crit), where the chain motion of PEO was restricted due to strong inter-chain hydrogen bonding interactions. However, for the blends with high molecular weight PEO (M(w) > M(crit)), the miscibility between PEO and ER was poor, and most of PEO chains were considerably mobile. Finally, polarization inversion spin exchange at magic angle (PISEMA) solid-state NMR experiment further revealed the different mobility of the PEO in ER/PEO blends with different molecular weight of PEO at molecular level. Based on the DSC and NMR results, a tentative model was proposed to illustrate the miscibility in ER/PEO blends. PMID- 26577818 TI - Liquid-body resonance while contacting a rotating superhydrophobic surface. AB - We advance a scheme in which a liquid body on a stationary tip in contact with a rotating superhydrophobic surface is able to maintain resonance primarily from stick-slip events. With tip-to-surface spacing in the range 2.73 <= h < 2.45 mm for a volume of 10 MUL, the liquid body was found to exhibit resonance independent of the speed of the drum. The mechanics were found to be due to a surface-tension-controlled vibration mode based on the natural frequency values determined. With spacing in the range 2.45 <= h < 2.15 mm imposed for a volume of 10 MUL, the contact length of the liquid body was found to vary with rotation of the SH drum. This was due to the stick-slip events being able to generate higher energy fluctuations causing the liquid-solid contact areas to vary since the almost oblate spheroid shape of the liquid body had intrinsically higher surface energies. This resulted in the natural frequency perturbations being frequency- and amplitude-modulated over a lower frequency carrier. These findings have positive implications for microfluidic sensing. PMID- 26577819 TI - German drug industry says pricing law is restricting access to some drugs. PMID- 26577820 TI - Improving transgender health by building safe clinical environments that promote existing resilience: Results from a qualitative analysis of providers. AB - BACKGROUND: Transgender (TG) individuals experience discordance between their sex at birth and their gender identity. To better understand the health care needs and characteristics of TG youth that contribute to resilience, we conducted a qualitative study with clinical and non-clinical providers. METHODS: In-depth interviews were conducted of providers (n = 11) of TG youth (ages 13-21). Convenience and purposive sampling were used to recruit participants in the Boston area. All interviews were audio-recorded and transcribed verbatim. An interview guide of 14 open-ended questions was used to guide the discussion. A grounded theory approach was utilized to code and analyze the data, including double-coding to address issues of inter-rater reliability. RESULTS: Five primary themes emerged: 1) resilience of TG youth 2) lack of access to services that influence health, 3) the critical role of social support, 4) challenges in navigating the health care system, and 5) the need for trans-affirming competency training for providers and frontline staff. CONCLUSION: The findings of this study show that providers recognize multiple barriers and challenges in the care of TG youth. However, they also identify the resilience exhibited by many youth. We propose that providers can further enhance the resilience of TG youth and help them flourish by offering them necessary resources via the creation of safe and welcoming clinical environments. PMID- 26577821 TI - Concomitant surgical ablation for atrial fibrillation (AF) in patients with significant atrial dilation >55 mm. Worth the effort? AB - BACKGROUND: Concomitant Surgical AF ablation is an established procedure, recommended in guidelines. However many surgeons are reluctant to perform AF ablation in patients with significantly enlarged left atrium. We therefore analyzed outcomes of patients with left-atrial diameter >55 mm undergoing concomitant AF ablation. METHODS: Between 05/2003 and 12/2012 124 patients with significantly enlarged left-atrium >55 mm underwent concomitant surgical AF ablation. Rhythm monitoring was accomplished by implantable loop recorder (ILR) interrogation (n = 54), or 24-h Holter-ECG (n = 70). Successful ablation was defined as AF Burden <0.5 % in ILR interrogation or absence of AF episode >30 s in 24-h Holter-ECG. Primary endpoint of the study was freedom from AF at 12 months follow-up. RESULTS: Mean patient's age was 65.7+/-9.6 years, 69.4 % were male. No major ablation or ILR related complications occurred. Mean LA diameter was 60.7+/-4.4 mm. Survival rate at one-year follow up was 94.4 %. 11 (8.8 %) patients received additional catheter-based ablation, while 23 (18.5 %) had an electrical cardioversion during follow-up period. Overall freedom from AF rate after one-year follow-up was 64.4 % and 59.4 % off antiarrhythmic drugs respectively. Logistic regression analysis identified preoperative paroxysmal AF, duration of AF and LA diameter > 70 mm as predictors for rhythm outcome at 12 months follow-up. CONCLUSION: In this patient cohort with significantly enlarged LA diameter, concomitant surgical AF ablation provided freedom from AF of 64.4 % after one-year follow-up. However in this patient population, an accurate postoperative care with interventions like medical or- electrical cardioversion and additional catheter based ablation is necessary to achieve satisfactory results. PMID- 26577822 TI - Nivolumab for the treatment of classical Hodgkin lymphoma after failure of autologous stem cell transplant and brentuximab. AB - Cancer cells are able to escape surveillance from the immune system by co-opting physiologic mechanisms such as the programmed cell death-1 (PD-1) receptor pathway. Agents able to block the interaction between the PD-1 receptor and its ligands have the potential to release T cells from tumor-induced suppression and eradicate malignant cells. Nivolumab - a PD-1 inhibitor - is approved for the treatment of patients with metastatic melanoma and lung cancer. This agent has been tested in patients with advanced Hodgkin lymphoma (HL) and showed impressive results in a phase I trial. Here we review the profile of Nivolumab including its pharmacological properties, clinical efficacy and safety in patients with advanced classical HL. PMID- 26577823 TI - Cartilage stem/progenitor cells are activated in osteoarthritis via interleukin 1beta/nerve growth factor signaling. AB - INTRODUCTION: Interleukin-1beta (IL-1beta) and nerve growth factor (NGF) are key regulators in the pathogenesis of inflammatory arthritis; specifically, IL-1beta is involved in tissue degeneration and NGF is involved in joint pain. However, the cellular and molecular interactions between IL-1beta and NGF in articular cartilage are not known. Cartilage stem/progenitor cells (CSPCs) have recently been identified in osteoarthritic (OA) cartilage on the basis of their migratory properties. Here we hypothesize that IL-1beta/NGF signaling is involved in OA cartilage degeneration by targeting CSPCs. METHOD: NGF and NGF receptor (NGFR: TrkA and p75NTR) expression in healthy and OA human articular cartilage and isolated chondrocytes was determined by immunostaining, qRT-PCR, flow cytometry and western blot. Articular cartilage derived stem/progenitor cells were collected and identified by stem/progenitor cell characteristics. 3D-cultured CSPC pellets and cartilage explants were treated with NGF and NGF neutralizing antibody, and extracellular matrix changes were examined by sulfated glycosaminoglycan (GAG) release and MMP expression and activity. RESULTS: Expression of NGF, TrkA and p75NTR was found to be elevated in human OA cartilage. Cellular changes upon IL-1beta and/or NGF treatment were then examined. NGF mRNA and NGFR proteins levels were upregulated in cultured chondrocytes exposed to IL-1beta. NGF was chemotactic for cells isolated from OA cartilage. Cells isolated on the basis of their chemotactic migration towards NGF demonstrated stem/progenitor cell characteristics, including colony-forming ability, multi-lineage differentiation potential, and stem cell surface markers. The effects of NGF perturbation in cartilage explants and 3D-cultured CSPCs were next analyzed. NGF treatment resulted in extracellular matrix catabolism indicated by increased sGAG release and MMP expression and activity; conversely, treatment with NGF neutralizing antibody inhibited increased MMP levels, and enhanced tissue inhibitor of matrix metalloprotease-1 (TIMP1) expression in OA cartilage explants. NGF blockade with neutralizing antibody also affected cartilage matrix remodeling in 3D-CSPC pellet cultures. CONCLUSION: Our results strongly suggest that NGF signaling is a contributing factor in articular cartilage degeneration in OA, which likely targets a specific subpopulation of progenitor cells, the CSPCs, affecting their migratory and matrix remodeling activities. These findings provide novel cellular/signaling therapeutic targets in osteoarthritic cartilage. PMID- 26577824 TI - Coffee provides a natural multitarget pharmacopeia against the hallmarks of cancer. AB - Coffee is the second most popular beverage in the world after water with a consumption of approximately two billion cups per day. Due to its low cost and ease of preparation, it is consumed in almost all countries and by all social classes of the population through different modes of preparation. Despites its simple appearance, a cup of coffee is in fact a complex mixture that contains hundreds of molecules, the composition and concentration of which vary widely and depend on factors including the origin of the coffee tree or its metabolism. Although an excessive consumption of coffee can be harmful, many molecules that are present in this black decoction exert anticancer properties. This review aims to describe the different primary coffee-containing substances that exert chemopreventive and bioactive activities against the different hallmarks and enabling characteristics of cancer, thus explaining the anticancer health benefit of black coffee. PMID- 26577825 TI - A randomized, double-blind, placebo-controlled, clinical trial on probiotic soy milk and soy milk: effects on epigenetics and oxidative stress in patients with type II diabetes. AB - This clinical trial aimed to discover the effects of probiotic soy milk and soy milk on MLH1 and MSH2 promoter methylation, and oxidative stress among type II diabetic patients. Forty patients with type II diabetes mellitus aged 35-68 years were assigned to two groups in this randomized, double-blind, controlled clinical trial. Patients in the intervention group consumed 200 ml/day of probiotic soy milk containing Lactobacillus plantarum A7, while those in the control group consumed 200 ml/d of conventional soy milk for 8 weeks. Fasting blood samples, anthropometric measurements, and 24-h dietary recalls were collected at the baseline and at the end of the study, respectively. Probiotic soy milk significantly decreased promoter methylation in proximal and distal MLH1 promoter region (P < 0.01 and P < 0.0001, respectively) compared with the baseline values, while plasma concentration of 8-hydroxy-2'-deoxyguanosine (8-OHdG) decreased significantly compared with soy milk (P < 0.05). In addition, a significant increase in superoxide dismutase (SOD) activity was observed in probiotic soy milk group compared with baseline value (P < 0.01). There were no significant changes from baseline in the promoter methylation of MSH2 within either group (P > 0.05). The consumption of probiotic soy milk improved antioxidant status in type II diabetic patients and may decrease promoter methylation among these patients, indicating that probiotic soy milk is a promising agent for diabetes management. PMID- 26577826 TI - Improved health perception after genetic counselling for women at high risk of breast and/or ovarian cancer: construction of new questionnaires--an Italian exploratory study. AB - BACKGROUND: Subjects referred to genetic counselling for cancer may have heightened perceptions of illness and death, even though they are healthy and this may cause anxiety and reluctance to follow through with consultation. We investigated such perceptions before and after counselling and genetic testing for cancer in a cohort of Italian women. We sought to understand the situation of the women referred by designing questionnaires administered to women at high risk of breast and/or ovarian cancer (those who had had a pathogenic mutation identified in a family member via diagnostic testing). We also assessed women after the diagnosis of breast cancers, but free of disease, to help determine risks in their families. METHODS: The first questionnaires were administered before initial counselling, and the second were completed within 20 days after the counselling. When a genetic test was proposed, the individual was asked to fill in a third questionnaire; the final questionnaire was administered after the person had received the results of the genetic test. RESULTS: We evaluated 204 subjects. Before counselling, 89 % of the subjects were worried about their risk of disease, 52 % felt "different" because of their personal and family history, and 39 % declared that their life choices were influenced by their fear of cancer. After counselling, 82 % of the subjects felt more relived about their pre existing fears and stated that this process of being seen in a clinic with genetic expertise had clarified the meaning of disease risk for them, and for 50 %, this experience had positively influenced their life choices. Thirty percentage of the subjects had a positive test; all of them felt safer in being cared for by specifically trained staff. Fifty percentage had a less informative test (e.g. "wild-type" gene found); 84 % of them were not worried by the uncertainty, and overall, 96 % considered counselling to be very useful. CONCLUSION: Candidates for genetic counselling frequently had heightened their perception of being ill, which influenced their ability to make life decisions. Genetic counselling often improves this perception, especially in subjects who have negative tests and this knowledge facilitates their life plans. After testing, most women felt satisfied and safer because of being properly followed by professionally trained and sympathetic staff. In conclusion, knowledge of the real individual risk, the presence of a professional team, and the possibility of entering a programme of controlled screening enable patients rather than living in fear and uncertainty to be less anxious about their state of health and to live with the knowledge that they are doing everything possible to care for themselves, aided by a specialized team, and that, if necessary, they would be able to take part in investigational studies. PMID- 26577827 TI - Patient preference and decision-making for initiating metastatic colorectal cancer medical treatment. AB - PURPOSE: Some medical treatment for metastatic colorectal cancer (CRC) may have marginal survival benefit, but cause toxicities. The purpose of this study is to determine metastatic CRC patients' tradeoffs in making a decision to undergo new medical treatment. METHODS: We conducted a survey of patients with a diagnosis of advanced CRC who were currently receiving or completed one chemotherapy regimen. First, patients were asked to rate the importance of 15 medical treatment-related adverse events that may arise as a consequence of chemotherapy or biological therapy in their treatment decision-making. Then, the patient identified his or her top five most important events and solicited preferences in hypothetical metastatic CRC treatment vignettes using the standard gamble technique. RESULTS: A total of 107 patients responded to the survey. From the list of medical treatment-related adverse events, patients identified clinically serious ones such as stroke, heart attack, and gastrointestinal perforation as the most important in their medical treatment decision-making, yet placed lower willingness to tolerate symptom-related events such as pain, fatigue, and depression. Generally, patients who were older, stage III versus IV and who had prior radiotherapy, lower educational attainment, and lower household income (all p <0.05) were less willing to tolerate any medical treatment-related adverse events after adjusting for other demographic and clinical characteristics. CONCLUSIONS: Variations in patients' willingness to tolerate different treatment related adverse events underscore the need for improved communications between physicians and patients about the risks and benefits of their medical treatment, which helps make a more personalized decision for metastatic CRC treatment. PMID- 26577828 TI - Prognostic implication of serum hepatocyte growth factor in stage II/III breast cancer patients who received neoadjuvant chemotherapy. AB - PURPOSE: In stage II/III breast cancer, neoadjuvant chemotherapy (NAC) is a standard treatment. Although several biomarkers are used to predict prognosis in breast cancer, there is no reliable predictive biomarker for NAC success. Recently, the hepatocyte growth factor (HGF) and cMet signaling pathway demonstrated to be involved in breast cancer tumor progression, and its potential as a biomarker is under active investigation. In this study, we assessed the potential of serum HGF as a prognostic biomarker for NAC efficacy. METHODS: Venous blood samples were drawn from patients diagnosed with stage II/III breast cancer and treated with NAC in Seoul National University Hospital from August 2004 to November 2009. Serum HGF level was determined using an ELISA system. We reviewed the medical records of the patients and investigated the association of HGF level with patients' clinicopathologic characteristics. RESULTS: A total of 121 female patients (median age = 45 years old) were included. Median level of HGF was 934 pg/ml (lower quartile: 772, upper quartile: 1145 pg/ml). Patients with higher HGF level than median value were significantly more likely to have clinically detectable regional node metastasis (p = 0.017, Fisher's exact test). Patients with complete and partial response according to the American Joint Committee on Cancer 7th Edition criteria tended to have higher HGF level (p = 0.105 by t test). Patients with an HGF level higher than the upper quartile value had longer relapse-free survival than the other patients (106 vs. 85 months, p = 0.008). CONCLUSIONS: High serum HGF levels in breast cancer patients are associated with clinically detectable regional node metastasis and, paradoxically, with longer relapse-free survival in stage II/III breast cancer. PMID- 26577830 TI - Seascape genetics along environmental gradients in the Arabian Peninsula: insights from ddRAD sequencing of anemonefishes. AB - Understanding the processes that shape patterns of genetic structure across space is a central aim of landscape genetics. However, it remains unclear how geographical features and environmental variables shape gene flow, particularly for marine species in large complex seascapes. Here, we evaluated the genomic composition of the two-band anemonefish Amphiprion bicinctus across its entire geographical range in the Red Sea and Gulf of Aden, as well as its close relative, Amphiprion omanensis endemic to the southern coast of Oman. Both the Red Sea and the Arabian Sea are complex and environmentally heterogeneous marine systems that provide an ideal scenario to address these questions. Our findings confirm the presence of two genetic clusters previously reported for A. bicinctus in the Red Sea. Genetic structure analyses suggest a complex seascape configuration, with evidence of both isolation by distance (IBD) and isolation by environment (IBE). In addition to IBD and IBE, genetic structure among sites was best explained when two barriers to gene flow were also accounted for. One of these coincides with a strong oligotrophic-eutrophic gradient at around 16-20N in the Red Sea. The other agrees with a historical bathymetric barrier at the straight of Bab al Mandab. Finally, these data support the presence of interspecific hybrids at an intermediate suture zone at Socotra and indicate complex patterns of genomic admixture in the Gulf of Aden with evidence of introgression between species. Our findings highlight the power of recent genomic approaches to resolve subtle patterns of gene flow in marine seascapes. PMID- 26577829 TI - GRPR-targeted Protein Contrast Agents for Molecular Imaging of Receptor Expression in Cancers by MRI. AB - Gastrin-releasing peptide receptor (GRPR) is differentially expressed on the surfaces of various diseased cells, including prostate and lung cancer. However, monitoring temporal and spatial expression of GRPR in vivo by clinical MRI is severely hampered by the lack of contrast agents with high relaxivity, targeting capability and tumor penetration. Here, we report the development of a GRPR targeted MRI contrast agent by grafting the GRPR targeting moiety into a scaffold protein with a designed Gd(3+) binding site (ProCA1.GRPR). In addition to its strong binding affinity for GRPR (Kd = 2.7 nM), ProCA1.GRPR has high relaxivity (r1 = 42.0 mM(-1)s(-1) at 1.5 T and 25 degrees C) and strong Gd(3+) selectivity over physiological metal ions. ProCA1.GRPR enables in vivo detection of GRPR expression and spatial distribution in both PC3 and H441 tumors in mice using MRI. ProCA1.GRPR is expected to have important preclinical and clinical implications for the early detection of cancer and for monitoring treatment effects. PMID- 26577831 TI - Improving access to medicines through centralised dispensing in the public sector: a case study of the Chronic Dispensing Unit in the Western Cape Province, South Africa. AB - BACKGROUND: The Chronic Dispensing Unit (CDU) is an out-sourced, public sector centralised dispensing service that has been operational in the Western Cape Province in South Africa since 2005. The CDU dispenses medicines for stable patients with chronic conditions. The aim is to reduce pharmacists' workload, reduce patient waiting times and decongest healthcare facilities. Our objectives are to describe the intervention's scope, illustrate its interface with the health system and describe its processes and outcomes. Secondly, to quantify the magnitude of missed appointments by enrolled patients and to describe the implications thereof in order to inform a subsequent in-depth empirical study on the underlying causes. METHODS: We adopted a case study design in order to elicit the programme theory underlying the CDU strategy. We consulted 15 senior and middle managers from the provincial Department of Health who were working closely with the intervention and the contractor using focus group discussions and key informant interviews. In addition, relevant literature, and policy and programme documents were reviewed and analysed. RESULTS: We found that the CDU scope has significantly expanded over the last 10 years owing to technological advancements. As such, in early 2015, the CDU produced nearly 300,000 parcels monthly. Medicines supply, patient enrollment processes, healthcare professionals' compliance to legislation and policies, mechanisms for medicines distribution, management of non-collected medicines (emanating from patients' missed appointments) and the array of actors involved are all central to the CDU's functioning. Missed appointments by patients are a problem, affecting an estimated 8%-12% of patients each month. However, the causes have not been investigated thoroughly. Implications of missed appointments include a cost to government for services rendered by the contractor, potential losses due to expired medicines, additional workload for the contractor and healthcare facility staff and potential negative therapeutic outcomes for patients. CONCLUSIONS: The CDU demonstrates innovation in a context of overwhelming demand for dispensing medicines for chronic conditions. However, it is not a panacea to address access to-medicines related challenges. A multi-level assessment that is currently underway will provide more insights on how existing challenges can be addressed. PMID- 26577832 TI - A qualitative study exploring the acceptability of the McNulty-Zelen design for randomised controlled trials evaluating educational interventions. AB - BACKGROUND: Traditional randomised controlled trials evaluating the effect of educational interventions in general practice may produce biased results as participants know they are being evaluated. We aimed to explore the acceptability of a McNulty-Zelen Cluster Randomised Control Trial (CRT) design which conceals from educational participants that they are in a RCT. Consent is obtained from a trusted third party considered appropriate to give consent on participants' behalf, intervention practice staff then choose whether to attend the offered education as would occur with normal continuing professional development. METHODS: We undertook semi structured telephone interviews in England with 16 general practice (GP) staff involved in a RCT evaluating an educational intervention aimed at increasing chlamydia screening tests in general practice using the McNulty-Zelen design, 4 Primary Care (PC) Research Network officers, 5 Primary Care Trust leads in Public or sexual health, and one Research Ethics committee Chair. Interviews were undertaken by members of the original intervention evaluation McNulty-Zelen design RCT study team. These experienced qualitative interviewers used an agreed semi-structured interview schedule and were careful not to lead the participants. To further mitigate against bias, the data analysis was undertaken by a researcher (CR) not involved in the original RCT. RESULTS: We reached data saturation and found five main themes; Support for the design: All found the McNulty-Zelen design acceptable because they considered that it generated more reliable evidence of the value of new educational interventions in real life GP settings. Lack of familiarity with study design: The design was novel to all. GP staff likened the evaluation using the McNulty Zelen design to audit of their activities with feedback, which were to them a daily experience and therefore acceptable. Ethical considerations: Research stakeholders considered the consent procedure should be very clear and that these trial designs should go through at least a proportionate ethical review. GP staff were happy for the PCT leads to give consent on their behalf. GP research capacity and trial participation: GP staff considered the design increased generalisability, as staff who would not normally volunteer to participate in research due to perceived time constraints and paperwork might do so. Design 'worth it': All interviewees agreed that the advantages of the "more accurate" or "truer" results and information gained about uptake of workshops within Primary Care Trusts (PCTs) outweighed any disadvantages of the consent procedure. DISCUSSION: Our RCT was evaluating the effect of an educational intervention to increase chlamydia screening tests in general practices where there was routine monitoring of testing rates; our participants may have been less enthusiastic about the design if it had been evaluating a more controversial educational area, or if data monitoring was not routine. IMPLICATIONS: The McNulty-Zelen design should be considered for the evaluation of educational interventions, but these designs should have clear consent protocols and proportionate ethical review. TRIAL REGISTRATION: The trial was registered on the UK Clinical Research Network Study Portfolio database. UKCRN9722 . PMID- 26577833 TI - Tuftsin-derived T-peptide prevents cellular immunosuppression and improves survival rate in septic mice. AB - The primary mechanisms of sepsis induced cellular immunosuppression involve immune dysfunction of T lymphocytes and negative immunoregulation of regulatory T cells (Tregs). It has been found that tuftsin is an immune modulating peptide derived from IgG in spleen. T-peptide is one of tuftsin analogs. Herein, we examined the effect of T-peptide on cell-mediated immunity in the presence of lipopolysaccharide (LPS) and the survival rate in septic mice. T-peptide regulated the proliferative ability of CD4(+)CD25(-) T cells in dual responses. Meanwhile, 10 and 100 MUg/ml T-peptides were able to enhance the apoptotic rate of CD4(+)CD25(-) T cells compared with 1 MUg/ml T-peptide, but markedly lowered interleukin (IL)-2 levels. When CD4(+)CD25(+) Tregs were treated with T-peptide for 24 hours, and co-cultured with normal CD4(+)CD25(-) T cells, the suppressive ability of CD4(+)CD25(+) Tregs on CD4(+)CD25(-) T cells was significantly lowered, along with decreased expression in forkhead/winged helix transcription factor p-3 (Foxp-3) as well as cytotoxic T lymphocyte-associated antigen (CTLA) 4, and secretion of transforming growth factor (TGF)-beta. Moreover, T-peptide has the ability to improve outcome of septic mice in a dose- and time- dependent manner, and associated with improvement in the microenvironment of cellular immunosuppression in septic mice. PMID- 26577834 TI - The Effect and Underlying Mechanism of Ethanol on Intracellular H(+) -Equivalent Membrane Transporters in Human Aorta Smooth Muscle Cells. AB - BACKGROUND: The presence of intracellular pH (pHi ) regulators, including Na(+) H(+) exchanger (NHE), Na(+) -HCO3- co-transporter (NBC), Cl(-) /OH(-) exchanger (CHE), and Cl(-) /HCO3- exchanger (AE), have been confirmed in many mammalian cells. Alcohol consumption is associated with increased risk of cardiovascular disorder. The aims of the study were to identify the possible transmembrane pHi regulators and to explore the effects of ethanol (EtOH) (10 to 300 mM) on the resting pHi and pHi regulators in human aorta smooth muscle cells (HASMCs). METHODS: HASMCs were obtained from patients undergoing heart transplant. The pHi was measured by microspectrofluorimetry with the pH-sensitive dye, BCECF-AM. RESULTS: The following results are obtained. (i) In cultured HASMCs, the resting pHi was 7.19 +/- 0.04 and 7.13 +/- 0.02 for HEPES- and CO2 /HCO3--buffered solution, respectively. (ii) Two different Na(+) -dependent acid-equivalent extruders, including NHE and Na(+) -coupled HCO3- transporter, functionally coexisted. (iii) Two different Cl(-) -dependent acid loaders (CHE and AE) were functionally identified. (iv) EtOH induced a biphasic, concentration-dependent change in resting pHi (+0.25 pH unit at 100 mM but only +0.05 pH unit at 300 mM) in bicarbonate-buffered solution, while caused a concentration-dependent decrease in resting pHi (-0.06 pH unit at 300 mM) in HEPES-buffered solution. (v) The effect of EtOH on NHE activity was also biphasic: increase of 40% at lower concentration of 10 mM, followed by decrease of 30% at higher concentration of 300 mM. (vi) The increase in Na(+) -coupled HCO3- transporter activity by EtOH was concentration dependent. (vii) The effect of EtOH on CHE and AE activities was both biphasic: increase of ~25% at 30 mM, followed by decrease of 10 to 25% at 100 mM, and finally increase of 15 to 20% at 300 mM. CONCLUSIONS: This study demonstrated that 2 acid extruders and 2 acid loaders coexisted functionally in HASMCs and that EtOH induced a biphasic, concentration-dependent change in resting pHi by altering the activity of the 2 acid extruders, NHE and Na(+) coupled HCO3- transporter, and the 2 acid loaders, CHE and AE. PMID- 26577835 TI - Reversed Crystal Growth of RHO Zeolitic Imidazolate Framework (ZIF). AB - RHO zeolitic imidazolate framework (ZIF), Zn1.33 (O.OH)0.33 (nim)1.167 (pur), crystals with a rhombic dodecahedral morphology were synthesized by a solvothermal process. The growth of the crystals was studied over time using scanning electron microscopy (SEM), transmission electron microscopy (TEM), powder X-ray diffraction (PXRD) and Brunauer-Emmett-Teller (BET) analyses, and a reversed crystal growth mechanism was revealed. Initially, precursor materials joined together to form disordered aggregates, which then underwent surface recrystallization forming a core-shell structure, in which a disordered core is encased in a layer of denser, less porous crystal. When the growth continued, the shell became less and less porous, until it was a layer of true single crystal. The crystallization then extended from the surface to the core over a six-week period until, eventually, true single crystals were formed. PMID- 26577837 TI - Barriers to the long-term recovery of individuals with disabilities following a disaster. AB - This study examines how pre-existing disabling conditions influenced the recovery process of survivors of Hurricane Katrina. It focuses specifically on the barriers that hindered the recovery process in these individuals. Focus groups were convened in four Gulf Coast states with 31 individuals with disabilities who lived in or around New Orleans, Louisiana, prior to Hurricane Katrina in August 2005. Qualitative data were analysed using grounded theory methodology. Five themes emerged as the most significant barriers to recovery: housing; transportation; employment; physical and mental health; and accessing recovery services. While these barriers to recovery were probably common to most survivors of the disaster, the research results suggest that disability status enhanced the challenges that participants experienced in negotiating the recovery process and in acquiring resources that accommodated their disabilities. The findings indicate that, when disaster recovery services and resources did not accommodate the needs of individuals with disabilities, recovery was hindered. Recovery efforts should include building accessible infrastructure and services that will allow for participation by all. PMID- 26577836 TI - Naturally occurring mutations associated with resistance to HCV NS5B polymerase and NS3 protease inhibitors in treatment-naive patients with chronic hepatitis C. AB - BACKGROUND: The detection of baseline resistance mutations to new direct-acting antivirals (DAAs) in HCV chronically infected treatment-naive patients could be important for their management and outcome prevision. In this study, we investigated the presence of mutations, which have been previously reported to be associated with resistance to DAAs in HCV polymerase (NS5B) and HCV protease (NS3) regions, in sera of treatment-naive patients. FINDINGS: HCV RNA from 152 naive patients (84 % Italian and 16 % immigrants from various countries) infected with different HCV genotypes (21,1a; 21, 1b; 2, 2a; 60, 2c; 22, 3a; 25, 4d and 1, 4k) was evaluated for sequence analysis. Amplification and sequencing of fragments in the NS5B (nt 8256-8640) and NS3 (nt 3420-3960) regions of HCV genome were carried out for 152 and 28 patients, respectively. The polymorphism C316N/H in NS5B region, associated with resistance to sofosbuvir, was detected in 9 of the 21 (43 %) analysed sequences from genotype 1b-infected patients. Naturally occurring mutations V36L, and M175L in the NS3 protease region were observed in 100 % of patients infected with subtype 2c and 4. CONCLUSION: A relevant proportion of treatment naive genotype 1b infected patients evaluated in this study harboured N316 polymorphism and might poorly respond to sofosbuvir treatment. As sofosbuvir has been approved for treatment of HCV chronic infection in USA and Europe including Italy, pre-treatment testing for N316 polymorphism on genotype 1b naive patients should be considered for this drug. PMID- 26577838 TI - Rapid and efficient method for the quantification of lychnopholide in rat plasma by liquid chromatography-tandem mass spectrometry for pharmacokinetic application. AB - Lychnopholide is a sesquiterpene lactone usually obtained from Lychnophora and Eremanthus species and has pharmacological activities that include anti inflammatory and anti-tumor. Lychnopholide isolated from Eremanthus matogrossenssis was analyzed in this study. The aims of this study were to develop and validate an analytical methodology by LC-MS/MS and to quantify lychnopholide in rat plasma. Chromatographic separation was achieved on a C18 column using isocratic elution with the mobile phase consisting of methanol and water (containing 0.1% formic acid) at a flow rate of 0.4 mL/min. The detection was performed in multiple-reaction monitoring mode using electrospray ionization in positive mode. The method validation was performed in accordance with regulatory guidelines and the results met the acceptance criteria. The linear range of detection was 10-200 ng/mL (r > 0.9961). The intra- and inter-day assay variability were <6.2 and <11.7%, respectively. The extraction recovery was approximately 63% using liquid-liquid extraction with chloroform. Lychnopholide was detected in plasma up to 60 min after intravenous administration in rats. This rapid and sensitive method for the analysis of the sesquiterpene lactone lychnopholide in rat plasma can be applied to pharmacokinetic studies of this compound. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26577840 TI - Quantifying variety-specific heat resistance and the potential for adaptation to climate change. AB - The impact of climate change on crop yields has become widely measured; however, the linkages for winter wheat are less studied due to dramatic weather changes during the long growing season that are difficult to model. Recent research suggests significant reductions under warming. A potential adaptation strategy involves the development of heat resistant varieties by breeders, combined with alternative variety selection by producers. However, the impact of heat on specific wheat varieties remains relatively unstudied due to limited data and the complex genetic basis of heat tolerance. Here, we provide a novel econometric approach that combines field-trial data with a genetic cluster mapping to group wheat varieties and estimate a separate extreme heat impact (temperatures over 34 degrees C) across 24 clusters spanning 197 varieties. We find a wide range of heterogeneous heat resistance and a trade-off between average yield and resistance. Results suggest that recently released varieties are less heat resistant than older varieties, a pattern that also holds for on-farm varieties. Currently released - but not yet adopted - varieties do not offer improved resistance relative to varieties currently grown on farm. Our findings suggest that warming impacts could be significantly reduced through advances in wheat breeding and/or adoption decisions by producers. However, current adaptation through-adoption potential is limited under a 1 degrees C warming scenario as increased heat resistance cannot be achieved without a reduction in average yields. PMID- 26577839 TI - Genetic variants in the mTOR pathway and breast cancer risk in African American women. AB - The phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin (mTOR) pathway has been implicated in breast carcinogenesis. However, there has been no large-scale investigation of genetic variants in the mTOR pathway and breast cancer risk. We examined 28847 single-nucleotide polymorphisms (SNPs) in 61 mTOR pathway genes in the African American Breast Cancer Epidemiology and Risk consortium of 3663 cases [1983 estrogen receptor-positive (ER+) and 1098 ER negative (ER-)] and 4687 controls. Gene-level analyses were conducted using the adaptive rank truncated product (ARTP) test for 10773 SNPs that were not highly correlated (r (2) < 0.8), and SNP-level analyses were conducted with logistic regression. Among genes that were prioritized (nominal P < 0.05, ARTP tests), associations were observed for intronic SNPs TSC2 rs181088346 [odds ratio (OR) of each copy of variant allele = 0.77, 95% confidence interval (CI) = 0.65-0.88 for all breast cancer] and BRAF rs114729114 (OR = 1.53, 95% CI = 1.24-1.91 for all breast cancer and OR = 2.03, 95% CI = 1.50-2.76 for ER- tumors). For ER- tumors, intronic SNPs PGF rs11542848 (OR = 1.38, 95% CI = 1.15-1.66) and rs61759375 (OR = 1.34, 95% CI = 1.14-1.57) and MAPK3 rs78564187 (OR = 1.26, 95% CI = 1.11-1.43) were associated with increased risk. These SNPs were significant at a gene-wide level (Bonferroni-corrected P < 0.05). The variant allele of RPS6KB2 rs35363135, a synonymous coding SNP, was more likely to be observed in ER- than ER+ tumors (OR = 1.18, 95% CI = 1.05-1.31, gene-wide Bonferroni-corrected P = 0.06). In conclusion, specific mTOR pathway genes are potentially important to breast cancer risk and to the ER negativity in African American women. PMID- 26577841 TI - Translating personalized genomic medicine into clinical practice: evidence, values, and health policy. PMID- 26577842 TI - Early identification and treatment of pneumonia: a call to action. PMID- 26577843 TI - Negative emotions affect postoperative scores for evaluating functional knee recovery and quality of life after total knee replacement. AB - This study aimed to determine whether psychological factors affect health-related quality of life (HRQL) and recovery of knee function in total knee replacement (TKR) patients. A total of 119 TKR patients (male: 38; female: 81) completed the Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI), State Trait Anxiety Inventory (STAI), Eysenck Personality Questionnaire-revised (EPQR-S), Knee Society Score (KSS), and HRQL (SF-36). At 1 and 6 months after surgery, anxiety, depression, and KSS scores in TKR patients were significantly better compared with those preoperatively (P<0.05). SF-36 scores at the sixth month after surgery were significantly improved compared with preoperative scores (P<0.001). Preoperative Physical Component Summary Scale (PCS) and Mental Component Summary Scale (MCS) scores were negatively associated with extraversion (E score) (B=-0.986 and -0.967, respectively, both P<0.05). Postoperative PCS and State Anxiety Inventory (SAI) scores were negatively associated with neuroticism (N score; B=-0.137 and -0.991, respectively, both P<0.05). Postoperative MCS, SAI, Trait Anxiety Inventory (TAI), and BAI scores were also negatively associated with the N score (B=-0.367, -0.107, -0.281, and -0.851, respectively, all P<0.05). The KSS function score at the sixth month after surgery was negatively associated with TAI and N scores (B=-0.315 and -0.532, respectively, both P<0.05), but positively associated with the E score (B=0.215, P<0.05). The postoperative KSS joint score was positively associated with postoperative PCS (B=0.356, P<0.05). In conclusion, for TKR patients, the scores used for evaluating recovery of knee function and HRQL after 6 months are inversely associated with the presence of negative emotions. PMID- 26577844 TI - Assessment of indicators of vitamin A status in non-cirrhotic chronic hepatitis C patients. AB - Subjects with chronic liver disease are susceptible to hypovitaminosis A due to several factors. Therefore, identifying patients with vitamin deficiency and a requirement for vitamin supplementation is important. Most studies assessing vitamin A in the context of hepatic disorders are conducted using cirrhotic patients. A cross-sectional study was conducted in 43 non-cirrhotic patients with chronic hepatitis C to evaluate markers of vitamin A status represented by serum retinol, liver retinol, and serum retinol-binding protein levels. We also performed the relative dose-response test, which provides an indirect estimate of hepatic vitamin A reserves. These vitamin A indicators were assessed according to the stage of liver fibrosis using the METAVIR score and the body mass index. The sample study was predominantly composed of male subjects (63%) with mild liver fibrosis (F1). The relative dose-response test was <20% in all subjects, indicating vitamin A sufficiency. Overweight or obese patients had higher serum retinol levels than those with a normal body mass index (2.6 and 1.9 umol/L, respectively; P<0.01). Subjects with moderate liver fibrosis (F2) showed lower levels of serum retinol (1.9 vs 2.5 umol/L, P=0.01) and retinol-binding protein levels compared with those with mild fibrosis (F1) (46.3 vs 67.7 ug/mL, P<0.01). These results suggested an effect of being overweight on serum retinol levels. Furthermore, more advanced stages of liver fibrosis were related to a decrease in serum vitamin A levels. PMID- 26577845 TI - Hormonal therapy with estradiol and drospirenone improves endothelium-dependent vasodilation in the coronary bed of ovariectomized spontaneously hypertensive rats. AB - Drospirenone (DRSP) is a progestin with anti-aldosterone properties and it reduces blood pressure in hypertensive women. However, the effects of DRSP on endothelium-dependent coronary vasodilation have not been evaluated. This study investigated the effects of combined therapy with estrogen (E2) and DRSP on endothelium-dependent vasodilation of the coronary bed of ovariectomized (OVX) spontaneously hypertensive rats. Female spontaneously hypertensive rats (n=87) at 12 weeks of age were randomly divided into sham operated (Sham), OVX, OVX treated with E2 (E2), and OVX treated with E2 and DRSP (E2+DRSP) groups. Hemodynamic parameters were directly evaluated by catheter insertion into the femoral artery. Endothelium-dependent vasodilation in response to bradykinin in the coronary arterial bed was assessed using isolated hearts according to a modified Langendorff method. Coronary protein expression of endothelial nitric oxide synthase and estrogen receptor alpha (ER-alpha) was assessed by Western blotting. Histological slices of coronary arteries were stained with hematoxylin and eosin, and morphometric parameters were analyzed. Oxidative stress was assessed in situ by dihydroethidium fluorescence. Ovariectomy increased systolic blood pressure, which was only prevented by E2+DRSP treatment. Estrogen deficiency caused endothelial dysfunction, which was prevented by both treatments. However, the vasodilator response in the E2+DRSP group was significantly higher at the three highest concentrations compared with the OVX group. Reduced ER-alpha expression in OVX rats was restored by both treatments. Morphometric parameters and oxidative stress were augmented by OVX and reduced by E2 and E2+DRSP treatments. Hormonal therapy with E2 and DRSP may be an important therapeutic option in the prevention of coronary heart disease in hypertensive post-menopausal women. PMID- 26577846 TI - Is a contrast study really necessary prior to ureteroscopy? AB - This study aimed to evaluate the effect of preoperative imaging techniques on the success and complication rates of ureteroscopy. We performed a retrospective analysis of 736 patients (455 males and 281 females), with a mean age of 45.5+/ 15.2 years (range, 1-88 years), who underwent rigid ureteroscopic procedures for removal of ureteral stones. Patients were divided into 4 groups according to the type of imaging modality used: group I, intravenous urography (n=116); group II, computed tomography (n=381); group III, computed tomography and intravenous urography (n=91), and group IV, ultrasonography and abdominal plain film (n=148). Patients' demographics, stone size and location, prior shock wave lithotripsy, lithotripsy technique, operation time, success rate, and rate of intraoperative complications were compared among the groups. There were no significant differences in success and complication rates among the groups. The stone-free rate after primary ureteroscopy was 87.1% in group I, 88.2% in group II, 96.7% in group III, and 89.9% in group IV (P=0.093). The overall incidence of intraoperative complications was 11.8%. According to the modified Satava classification system, 6.1% of patients had grade 1, 5.1% had grade 2, and 0.54% had grade 3 complications. Intraoperative complications developed in 12.1% of patients in group I, 12.6% of patients in group II, 7.7% of patients in group III, and 12.2% of patients in group IV (P=0.625). Our findings clearly demonstrate that ureteroscopic treatment of ureteral stones can be safely and effectively performed with no use of contrast study imaging, except in doubtful cases of anatomical abnormalities. PMID- 26577847 TI - Microglia and neurons in the hippocampus of migratory sandpipers. AB - The semipalmated sandpiper Calidris pusilla and the spotted sandpiper Actitis macularia are long- and short-distance migrants, respectively. C. pusilla breeds in the sub-arctic and mid-arctic tundra of Canada and Alaska and winters on the north and east coasts of South America. A. macularia breeds in a broad distribution across most of North America from the treeline to the southern United States. It winters in the southern United States, and Central and South America. The autumn migration route of C. pusilla includes a non-stop flight over the Atlantic Ocean, whereas autumn route of A. macularia is largely over land. Because of this difference in their migratory paths and the visuo-spatial recognition tasks involved, we hypothesized that hippocampal volume and neuronal and glial numbers would differ between these two species. A. macularia did not differ from C. pusilla in the total number of hippocampal neurons, but the species had a larger hippocampal formation and more hippocampal microglia. It remains to be investigated whether these differences indicate interspecies differences or neural specializations associated with different strategies of orientation and navigation. PMID- 26577848 TI - Poor sleep in middle-aged women is not associated with menopause per se. AB - Whether sleep problems of menopausal women are associated with vasomotor symptoms and/or changes in estrogen levels associated with menopause or age-related changes in sleep architecture is unclear. This study aimed to determine if poor sleep in middle-aged women is correlated with menopause. This study recruited women seeking care for the first time at the menopause outpatient department of our hospital. Inclusion criteria were an age >=40 years, not taking any medications for menopausal symptoms, and no sleeping problems or depression. Patients were assessed with the Pittsburgh Sleep Quality Index (PSQI), modified Kupperman Index (KI), and Menopause Rating Scale (MRS). A PSQI score of <7 indicated no sleep disorder and >=7 indicated a sleep disorder. Blood specimens were analyzed for follicle-stimulating hormone and estradiol levels. A total of 244 women were included in the study; 103 (42.2%) were identified as having a sleep disorder and 141 as not having one. In addition, 156 (64%) women were postmenopausal and 88 (36%) were not menopausal. Follicle-stimulating hormone and estradiol levels were similar between the groups. Patients with a sleep disorder had a significantly higher total modified KI score and total MRS score (both, P<0.001) compared with those without a sleep disorder. Correlations of the PSQI total score with the KI and MRS were similar in menopausal and non-menopausal women. These results do not support that menopause per se specifically contributes to sleep problems. PMID- 26577849 TI - Activity of the novel fungicide oxathiapiprolin against plant-pathogenic oomycetes. AB - BACKGROUND: Oxathiapiprolin was the first of the piperidinyl thiazole isoxazoline class of fungicides to be discovered and developed by DuPont in 2007. Although oxathiapiprolin has been reported to have high activity against plant-pathogenic oomycetes, such as Peronospora belbahrii, Phytophthora nicotianae and Ph. capsici, little is known about its effectiveness against other plant-pathogenic oomycetes and its protective and curative properties. RESULTS: Oxathiapiprolin exhibited substantial inhibitory activity against all of the plant-pathogenic oomycetes tested, with EC90 values ranging from 0.14 to 3.36 * 10(-3) ug mL(-1) , except the Pythium species Py. aphanidermatum and Py. deliense. Furthermore, doses as low as 10 ug mL(-1) were found to inhibit zoospore release and motility in Ph. capsici, while the mycelial development and sporangial production of Pseudoperonospora cubensis were restrained by an EC50 of 3.10 * 10(-4) and 5.17 * 10(-4) ug mL(-1) respectively. It was also found that oxathiapiprolin exhibited both protective and curative activity against the development of Ph. capsici infection in pepper plants under greenhouse conditions and in field tests. CONCLUSION: The present study demonstrated that the novel fungicide oxathiapiprolin exhibits strong inhibitory activity against a range of agriculturally important plant-pathogenic oomycetes, including Phytophthora spp., Peronophythora litchii, Plasmopara viticola, Pe. parasitica, Ps. cubensis and Py. ultimum. (c) 2015 Society of Chemical Industry. PMID- 26577850 TI - Abnormality of Wnt3a expression as novel specific biomarker for diagnosis and differentiation of hepatocellular carcinoma. AB - The member 3a of Wingless-type MMTV integration site family (Wnt3a) as an oncogene is overexpressed in many kinds of tumors with a worse outcome. However, the mechanism and alteration of Wnt3a expression in hepatocellular carcinoma (HCC) have not been clarified. In this study, the levels of Wnt3a expression were investigated in 80 HCC tissues or sera of 186 patients with chronic liver diseases. The incidence of hepatic Wnt3a expression in HCC tissues was 96.25 % and significantly higher (chi (2) = 48.818, P < 0.001) than that in their surrounding tissues (46.25 %). The higher level (>800 ng/L) of circulating Wnt3a expression was found in 92.5 % HCC patients and significantly related (P < 0.05) to alpha-fetoprotein (AFP) level, liver cirrhosis, hepatitis B virus infection, poor differentiation, tumor node metastasis, and extra-hepatic metastasis. The level of Wnt3a expression in HCC patients was obviously higher (P < 0.001) than that in any group of cases with benign liver diseases. The diagnostic specificity or the area under the receiver operating characteristic curve was 94.34 % or 0.994 in Wnt3a and 69.81 % or 0.710 in AFP for HCC, respectively. The present data suggested that Wnt3a expression associated with tumor progression should be a novel specific biomarker for diagnosis and differentiation of HCC. PMID- 26577851 TI - TNF-alpha increases the membrane expression of the chemokine receptor CCR6 in thyroid tumor cells, but not in normal thyrocytes: potential role in the metastatic spread of thyroid cancer. AB - The chemokine receptor CCR6, selectively bound by CCL20, is involved in the metastatic spread of cancer cells. Tumor necrosis factor-alpha (TNF-alpha) displays a complex pro-tumorigenic actions, but it is unknown whether this cytokine could modulate the expression of chemokine receptors in thyroid tumors. The membrane expression of CCR6 was assessed by flow cytometry and immunofluorescence, in primary cultures of normal human thyroid (NHT) cells and in thyroid cancer cell lines (TPC-1 and BCPAP), both in basal conditions and after stimulation with TNF-alpha. In basal conditions, CCR6+ cells were virtually absent in NHT cells (0.4 +/- 0.4 %), while they were detected in TPC-1 (23.6 +/- 6.6 %) and in BCPAP (12.9 +/- 9.4 %) tumor cells (ANOVA F: 10.534; p < 0.005). The incubation with TNF-alpha significantly increased the percentage of CCR6+ cells in TPC-1 (23.6 +/- 6.6 % vs. 33.1 +/- 8.7; p < 0.033) and in BCPAP (12.9 +/ 9.4 % vs. 18.1 +/- 11.5; p < 0.030), but not in NHT (0.4 +/- 0.4 % vs. 0.2 +/- 0.3; NS) cells. The magnitude of the TNF-alpha effect was similar for TPC-1 and BCPAP (~40 % vs. baseline) cells. TPC-1 cells were characterized by a greater amount of CCR6 per cell as compared with BCPAP cells, both in basal conditions (148.3 +/- 33.7 fluorescence intensity vs. 102.5 +/- 22.1 p < 0.016) and after TNF-alpha stimulation (147.8 +/- 46.3 fluorescence intensity vs. 95.3 +/- 18.5; p < 0.025). Cell migration assays showed that TNF-alpha treatment significantly increased the rate of migrated cells in those cells in which it also increased the membrane expression of CCR6 (TPC-1 and BCPAP) as compared to basal condition (p < 0.05 for both TPC-1 and BCPAP cells). No effect was observed in NHT cells in which TNF-alpha stimulation had no effect in terms of CCR6 expression. We first report that TNF-alpha enhances the expression of CCR6 in thyroid tumor cells, thus providing evidence that TNF-alpha increases the metastatic potential of thyroid tumors. PMID- 26577852 TI - A functional HOTAIR rs12826786 C>T polymorphism is associated with breast cancer susceptibility and poor clinicopathological characteristics in a Turkish population: a hospital-based case-control study. AB - Hox transcript antisense intergenic RNA (HOTAIR), a long non-coding RNA (lncRNA), is pervasively overexpressed and correlated with tumor invasion, progression, metastasis, and poor prognosis in various human cancers including breast cancer (BC) that plays a role as an oncogenic molecule. A common functional single nucleotide polymorphism (SNP) (rs12826786 C>T) at the HOTAIR promoter has been reported to influence HOTAIR expression and gastric adenocarcinoma susceptibility, but relation of HOTAIR rs12826786 C>T polymorphism with BC susceptibility and clinicopathological characteristics has yet to be reported. To explore the association of the HOTAIR rs12826786 C>T polymorphism with the risk of BC in a Turkish population, a hospital-based case-control study was carried out consisting of 123 BC patients and 122 age-matched healthy controls. HOTAIR rs12826786 C>T polymorphism was determined by real-time polymerase chain reaction (PCR) using TaqMan assay. We found that women carrying TT genotype of HOTAIR rs12826786 C>T polymorphism had an increased risk of developing BC in both codominant (odds ratio (OR) = 2.24, 95 % confidence interval (CI) 1.05-4.81, P = 0.02) and recessive (OR = 2.49, 95 % CI 1.25-4.97, P = 0.008) inheritance models. Moreover, TT genotype of HOTAIR rs12826786 C>T polymorphism was significantly related with multiple clinicopathological characteristics concerned with worse BC progression such as advanced TNM stage (III and IV), larger tumor size (T3 and T4), and distant metastasis (M1), as well as poor histological grade (III) (P < 0.05). Because of our results put forward for the first time that TT genotype of HOTAIR rs12826786 C>T polymorphism might play crucial roles in genetic susceptibility and poor prognosis for BC in Turkish population, further independent studies are needed to confirm our results in a larger series, as well as in patients of distinct populations. PMID- 26577853 TI - TIPE2 regulates tumor-associated macrophages in skin squamous cell carcinoma. AB - Tumor-associated macrophages (TAMs) play an essential role in the immunology, growth, invasion, and metastases of skin squamous cell carcinoma (SCC). However, the molecular mechanisms underlying the activation and regulation of TAMs by SCC are not completely understood. Here, in a Transwell co-culture system, we found that SCC cells induced polarization of macrophages to a M2 phenotype, evident by expression of surface markers CD163, CD206, and CD301, as well as reduction of cellular iNOS levels and augmentation of cellular arginase levels. Moreover, tumor necrosis factor (TNF)-alpha-induced protein 8-like 2 (TIPE2) was induced in macrophages by co-culturing with SCC cells. Depletion of TIPE2 in macrophages abolished the effects of co-cultured SCC cells on phenotypic modification of macrophages. Furthermore, patients with SCC were divided into two groups based on TIPE2 levels in TAMs at the time of tumor resection. We found that patients with high-TIPE2 TAMs had an overall poor 5-year survival. Together, our data suggest a previously unappreciated role of TIPE2 in the crosstalk between skin SCC and TAMs and highlight TIPE2 as a promising novel target for skin SCC treatment. PMID- 26577854 TI - BAG3 regulates cell proliferation, migration, and invasion in human colorectal cancer. AB - Bcl2-associated athanogene 3 (BAG3) has been reported to be elevated in various tumors. However, it is unclear whether BAG3 has a functional role in the initiation and progression of colorectal cancer (CRC). Here, we collected CRC samples and cell lines to validate the pathway by using gene and protein assays. RT-PCR showed that the expression of BAG3 mRNA in CRC tissues was obviously higher than that in non-tumor tissues (p < 0.001). Immunohistochemical analysis showed that immunoreactivity of BAG3 was found in most CRC tissues and strongly correlated with TNM stage (p = 0.001), differentiation (p = 0.003), and metastasis (p = 0.010). Low expression of BAG3 in HCT-8 significantly reduced cellular proliferation, migration, and invasion. The analysis of in vitro cell showed that HCT-8 cells were exposed to si-BAG3, and its growth was inhibited depending on modulation of cell cycle G1/S checkpoints and cell cycle regulators, involving cyclin D1, cyclin A2, and cyclin B1. Furthermore, suppression of the epithelial-mesenchymal transition (EMT) by si-BAG3 is linked to the decreased expression of E-cadherin and the increased expression of N-cadherin, vimentin, and MMP9. In conclusion, in the present study, we demonstrated that BAG3 overexpression plays a critical role in cell proliferation, migration, and invasion of colorectal cancer. Our data suggests targeted inhibition of BAG3 may be useful for patients with CRC. PMID- 26577855 TI - An association analysis between mitochondrial DNA content, G10398A polymorphism, HPV infection, and the prognosis of cervical cancer in the Chinese Han population. AB - The aim was to analyze quantitative (mitochondrial DNA (mtDNA) content) and qualitative (G10398A polymorphism) mtDNA alterations as well as human papillomavirus (HPV) infection in cervical cancer prognosis. One hundred and twenty-two cases of formalin-fixed paraffin-embedded cervical carcinoma specimens were collected from the Yichang Tumor Hospital and Zhongnan Hospital of Wuhan University in the recent 10 years together with medical records. A quantitative real-time PCR (RT-PCR) was used to determine the copy number of the mitochondrial DNA and HPV expression levels. G10398A polymorphism was determined by PCR-RFLP assay. The overall survival of patients with higher mtDNA content was significantly reduced compared with lower mtDNA content patients (P = 0.029). But there was no difference of prognosis between the mtDNA 10398 A allele and G allele. However, the Kaplan-Meier survival curve illustrated a significantly reduced overall survival in the patients with 10398A plus high mtDNA copy number compared with the other groups (P < 0.05). Although no association between HPV expression level and cervical cancer prognosis was observed, 10398A got increased mtDNA content compared with 10398G (P < 0.05) and 10398G displayed an increased HPV-positive rate compared with 10398A. Furthermore, HPV-18 and mtDNA content were positively related in the younger subgroup (<=45 years) (correlation coefficient = 0.456, P = 0.022). This study indicated that mtDNA content and HPV infection status are associated with cervical cancer prognosis. High mitochondrial DNA content plus 10398 A may be a marker of poor prognosis in cervical cancer. And mtDNA variation may potentially influence the predisposition to HPV infection and cervical carcinogenesis. PMID- 26577856 TI - Equating salivary lactate dehydrogenase (LDH) with LDH-5 expression in patients with oral squamous cell carcinoma: An insight into metabolic reprogramming of cancer cell as a predictor of aggressive phenotype. AB - Oral squamous cell carcinoma (OSCC) is the sixth most common human malignancy. According to World Health Organization, oral cancer has been reported to have the highest morbidity and mortality and a survival rate of approximately 50 % at 5 years from diagnosis. This is attributed to the subjectivity in TNM staging and histological grading which may result in less than optimum treatment outcomes including tumour recurrence. One of the hallmarks of cancer is aerobic glycolysis also known as the Warburg effect. This glycolytic phenotype (hypoxic state) not only confers immortality to cancer cells, but also correlates with the belligerent behaviour of various malignancies and is reflected as an increase in the expression of lactate dehydrogenase 5 (LDH-5), the main isoform of LDH catalysing the conversion of pyruvate to lactate during glycolysis. The diagnostic role of salivary LDH in assessing the metabolic phenotype of oral cancer has not been studied. Since salivary LDH is mainly sourced from oral epithelial cells, any pathological changes in the epithelium should reflect diagnostically in saliva. Thus in our current research, we made an attempt to ascertain the biological behaviour and aggressiveness of OSCC by appraising its metabolic phenotype as indirectly reflected in salivary LDH activity. We found that salivary LDH can be used to assess the aggressiveness of different histological grades of OSCC. For the first time, an evidence of differing metabolic behaviour in similar histologic tumour grade is presented. Taken together, our study examines the inclusion of salivary LDH as potential diagnostic parameter and therapeutic index in OSCC. PMID- 26577857 TI - GSTT1 and GSTM1 polymorphisms predict treatment outcome for breast cancer: a systematic review and meta-analysis. AB - Observational studies have reported controversial results on the association between GSTT1 and GSTM1 genotypes and treatment outcome of breast cancer. The purpose of this study is to evaluate the association between GSTT1 and GSTM1 and treatment outcome in breast cancer patients. Eligible studies were searched in PubMed, EMBASE, Cochrane Library, and China National Knowledge Infrastructure databases. A random-effect model or fixed-effect model was used to calculate the overall combined risk estimates. Twenty-one studies with a total of 4990 patients were included in this meta-analysis. The GSTM1 null genotype (odds ratio (OR) = 1.33, 95 % confidence interval (CI) 1.01-1.75, P = 0.046) and GSTT1/GSTM1 double null genotype (OR = 2.22, 95 % CI 1.02-4.84, P = 0.045) were significantly associated with an increased tumor response. A reduced overall survival (hazard ratio (HR) = 0.84, 95 % CI 0.72-0.98, P = 0.024) was observed in GSTM1 null genotype, especially in mixed descent (HR = 0.77, 95 % CI 0.61-0.96, P = 0.018) and large sample size (HR = 0.85, 95 % CI 0.72-0.99, P = 0.033). Evidence of publication bias was observed in GSTM1 genotype rather than in GSTT1 genotype. This meta-analysis suggests that GSTM1 null and GSTT1/GSTM1 double null polymorphisms might be significantly associated with an increased tumor response. However, the GSTM1 null genotype might be significantly associated with a reduced overall survival. Future studies are warranted to confirm these findings. PMID- 26577858 TI - Methylation-mediated repression of potential tumor suppressor miR-203a and miR 203b contributes to esophageal squamous cell carcinoma development. AB - MiRNAs regulate gene expression and play pivotal roles in biological processes. MiRNAs can be inactivated by epigenetic mechanisms, such as DNA hypermethylation of CpG sites within CpG islands. Here, we investigated the role and methylation status of miR-203a and miR-203b in esophageal cancer cell lines and primary esophageal squamous cell carcinoma (ESCC) tumors and further elucidate the role of both miRNAs in the prognosis of ESCC. The present study revealed a strong downregulation of miR-203a and miR-203b in esophageal cancer cell lines and primary ESCC samples. Treatment of esophageal cancer cells with demethylating agent 5-Aza-dC led to increased miR-203a and miR-203b expression, confirming the epigenetic regulation of both miRNAs. The inhibition of proliferation and invasiveness in esophageal cancer cells after treated with 5-Aza-dC or transfected with miR-203a or miR-203b mimics, suggesting the tumor suppressor role of both miRNAs in esophageal cancer. Furthermore, the critical CpG sites of miR-203a and miR-203b were found to be located in proximal promoter region, and the proximal promoter hypermethylation of both miRNAs was found to influence transcriptional activity. Downregulation and hypermethylation of miR-203a and miR 203b were associated with TNM stage, pathological differentiation, and lymph node metastasis. ESCC patients in stages III and IV, with reduced expression of miR 203a or hypermethylation of miR-203a or miR-203b, demonstrated poor patient survival. In summary, our results suggest that miR-203a and miR-203b may function as tumor-suppressive miRNAs that are inactivated through proximal promoter hypermethylation and miR-203a expression and methylation may be useful prognostic marker in ESCC patients. PMID- 26577860 TI - Multilocus sequence typing (MLST) of leptospiral strains isolated from two geographic locations of Tamil Nadu, India. AB - Here the rodent carrier status for the transmission of human leptospirosis in Tiruchirappalli, district, Tamil Nadu, India was assessed. The predominantly circulating leptospiral STs were recognized by multilocus sequence typing (MLST). A total of 113 rodents were trapped from different provinces of the Tiruchirappalli district. The most prevalent rodent was Bandicota bengalensis (37.2%), and of the total, 52.2% (n=59) rodents were found to be positive for leptospiral 16S rRNA. These results were validated with a leptospiral culture positivity of 45.8% (n=27). Three isolates from Chennai (2 rodents and 1 human) and 1 human isolate from Tiruchirappalli were included to understand the spatial variations and to track the source of human leptospirosis. The serogroup, serovar, and species level identification of all 31 isolates identified 28 to be Leptospira borgpetersenii serovar Javanica and three as Leptospira interrogans serovar Autumnalis. MLST analysis defined all isolates to the existing ST profiles (ST145 and ST27) with the exception of 6 L. borgpetersenii (ST DR) isolates that showed variations in the sucA and pfkB loci. The DR ST was locally confined to Chatram province of Tiruchirappalli suggesting an epidemiological link. The predominant STs, ST145 and ST-DR form a group, indicating the presence of original strain that subsequently diverged evolutionarily into two STs. The variations between L. borgpetersenii in sucA and pfkB loci may be an indication that evolutionary changes transpired in Tiruchirappalli. PMID- 26577859 TI - The oncogenetic role of stanniocalcin 1 in lung adenocarcinoma: a promising serum candidate biomarker for tracking lung adenocarcinoma progression. AB - Stanniocalcin 1 (STC1) is reported to functionally participate in the development of several cancers. However, the role of STC1 in the tumorigenesis and progression of lung adenocarcinoma remains to be fully elucidated. Here, we found that the average levels of serum STC1 were 5.47, 5.53, and 6.94 ng/mL (P = 0.0045) in the healthy subjects and patients with lung adenocarcinoma at tumor stages I-II and III-IV according to Union for International Cancer Control (UICC), respectively. Subsequently, the positive correlation between the STC1 expression level in lung adenocarcinoma tissues and tumor stages was confirmed by immunohistochemical staining assay. Additionally, studies in the STC1 overexpressing or STC1-silenced stable cell lines showed that STC1 increased cell proliferation by promoting G1/S transition in cell cycle progression via up regulating cyclin B1 and cyclin E. Moreover, studies in the STC1-overexpressing or STC1-silenced stable cell lines also showed that STC1 inhibited cell apoptosis by up-regulating the expression of anti-apoptosis proteins Bcl-2 and Bcl-xl and down-regulating the expression of pro-apoptosis proteins Bax, Bak, and Bid via the activation of the ERK and JNK signaling pathway. In addition, neutralization of STC1 with monoclonal antibody significantly increased the apoptosis of A549 cells. Taken together, our findings strongly suggest that elevated expression of STC1 protein at the III-IV stage of lung adenocarcinoma promotes tumorigenesis of lung adenocarcinoma and positively associates with the cancer progression, which may be of potential value as tumor marker in clinical tracking lung adenocarcinoma progression. PMID- 26577861 TI - Response of Termite (Blattodea: Termitoidae) Assemblages to Lower Subtropical Forest Succession: A Case Study in Dinghushan Biosphere Reserve, China. AB - Termite (Blattodea: Termitoidae) assemblages have important ecological functions and vary in structure between habitats, but have not been studied in lower subtropical forests. To examine whether differences in the richness and relative abundance of termite species and functional groups occur in lower subtropical regions, termite assemblages were sampled in Dinghushan Biosphere Reserve, China, among pine forest, pine and broad-leaved mixed forest (mixed forest), and monsoon evergreen broad-leaved forest (monsoon forest). The dominant functional group was wood-feeding termites (family Termitidae), and the mixed forest hosted the greatest richness and relative abundance. Soil-feeding termites were absent from the lower subtropical system, while humus-feeding termites were sporadically distributed in mixed forest and monsoon forest. The species richness and functional group abundance of termites in our site may be linked to the forest succession. Altitude, soil temperature, air temperature, surface air relative humidity, and litter depth were significant influences on species and functional group diversity. PMID- 26577862 TI - Evaluating the Performance and Preference of Aphytis melinus (Hymenoptera: Aphelinidae) on an Exotic Species, Acutaspis albopicta (Hemiptera: Diaspididae), and Aonidiella aurantii (Hemiptera: Diaspididae). AB - Acutaspis albopicta (Cockerell) is an exotic scale detected on imported 'Hass' avocados arriving in California from Mexico. An effort was made to understand how well this species might be biologically controlled by the parasitoid, Aphytis melinus DeBach. In no-choice trials, single life stages of A. albopicta and Aonidiella aurantii (Maskell) were exposed to one Ap. melinus female. Ap. melinus attacked and developed to adult on all A. albopicta life stages tested, which included early, middle, and late male and female second instars, and early, middle, and late female third instars. However, the proportion of scales attacked was relatively low (<=20%), as were the number of eggs laid on each scale stage. In six of seven comparisons of scale cover surface area between A. albopicta and Ao. aurantii that were similarly aged, Ao. aurantii was significantly larger. With intraspecific choice trials, females of Ap. melinus strongly preferred to parasitize the oldest and largest female scales in both single- and mixed-sex offerings. Younger, smaller scales were preferred for host feeding. Five comparisons of preference between A. albopicta and Ao. aurantii showed that Ap. melinus preferred 28- and 36-d-old Ao. aurantii females over similarly aged A. albopicta. However, Ap. melinus preferred 23-d-old males of A. albopicta. In three of five comparisons, Ao. aurantii was the preferred species to host feed on. More F1 females of Ap. melinus were recovered from both intraspecific choice trials compared with any stage in no-choice trials. Implications of incorporating Ap. melinus into biological control programs are discussed. PMID- 26577863 TI - Quantitative Analysis of Plant Consumption and Preference by Oedaleus asiaticus (Acrididae: Oedipodinae) in Changed Plant Communities Consisting of Three Grass Species. AB - We used Oedaleus asiaticus Bey-Bienko (Acrididae: Oedipodinae) as a model species to examine how plant community composition influenced grasshopper population densities and feeding habits. Our results show that in the Xinli Gol Grassland ecosystem, both plant community composition and grasshopper density vary considerably over fairly small distances, and that O. asiaticus density was directly related to the proportional abundance of specific plant species. A 60-d field-cage study showed that O. asiaticus food preference and consumption differed when the ratios of three dominant grass species (Leymus chinensis (Trin.) Tzvel, Stipa krylovii Roshev, and Cleistogenes squarrosa (Trin.) Keng) differed. The consumption of both S. krylovii and C. squarrosa increased with a corresponding increase in their respective biomass availability. Although O. asiaticus preferred S. krylovii and ate only small amounts of L. chinensis, a specific amount of L. chinensis was always consumed. Feeding of these three plant species could be divided into three levels based on diet selectivity index (SI), with O. asiaticus showing a strong preference for S. krylovii (SI > 1), over that for C. squarrosa (0.5 < SI <= 1), and a low acceptance for L. chinensis (0 < SI <= 0.5). Plant consumption and preference by O. asiaticus was in decreasing order S. krylovii>C. squarrosa>L. chinensis. This study shows that small-scale changes in plant community composition can have large affects on grasshopper diets and populations. As such, this study is useful for developing guidelines for the monitoring of O. asiaticus impacts against the background of vegetation succession and changing plant communities in response to grazing or human activities. PMID- 26577864 TI - Phonon Trapping in Pearl-Necklace-Shaped Silicon Nanowires. AB - A pearl-necklace-shaped silicon nanowire, in contrast to a smooth nanowire, presents a much lower thermal conductivity due to the phonon trapping effect. By precisely controlling the pearl size and density, this reduction can be more than 70% for the structures designed in the study, which provides a unique approach for designing high-performance nanoscale thermoelectric devices. PMID- 26577865 TI - Differences in lumbopelvic rhythm between trunk flexion and extension. AB - BACKGROUND: Trunk flexion and extension have already been found to have different characteristics, such as those in lumbopelvic rhythm. Although a more advanced method of quantifying such rhythm, lumbopelvic continuous relative phase and phase variability have not been used to explore the differences between trunk flexion and extension motions. This information is important since abnormal lumbopelvic coordination patterns increase the risk of low back pain. The current study investigated the differences in lumbopelvic rhythm between trunk flexion and extension, and how the rhythm changed within each of the two motions. METHODS: Thirteen subjects performed pace-controlled trunk flexion/extension motions in the sagittal plane while lumbar and pelvis kinematics data were recorded, such that the lumbopelvic continuous relative phase and phase variability could be calculated to quantify lumbopelvic rhythm. FINDINGS: Trunk extension motion had significantly smaller lumbopelvic continuous relative phase and phase variability than flexion motion, which indicated a more in-phase and stable rhythm. Additionally, the lumbopelvic rhythm within trunk extension motion changed from a more in-phase and stable pattern to a more out-of-phase and unstable pattern; by contrast, the opposite change (from out-of-phase and unstable to in-phase and stable) was observed in trunk flexion. INTERPRETATION: Findings of the current study provided important information about the differences in lumbopelvic rhythm between trunk flexion and extension motions. Quantifying these patterns provides the means for identifying abnormal patterns in a clinical setting, and could serve as normative benchmarks during low back pain rehabilitation plans. PMID- 26577866 TI - Inclination-dependent changes of the critical shoulder angle significantly influence superior glenohumeral joint stability. AB - BACKGROUND: The critical shoulder angle combines the acromion index and glenoid inclination and has potential to discriminate between shoulders at risk for rotator cuff tear or osteoarthritis and those that are asymptomatic. However, its biomechanics, and particularly the role of the glenoid inclination, are not yet fully understood. METHODS: A shoulder simulator was used to analyze the independent influence of glenoid inclination during abduction from 0 to 60 degrees . Spindle motors transferred tension forces by a cable-pulley on human cadaveric humeri. A six-degree-of-freedom force transducer was mounted directly behind the polyethylene glenoid to measure shear and compressive joint reaction force and calculate the instability ratio (ratio of shear and compressive joint reaction force) with the different force ratios of the deltoid and supraspinatus muscles (2:1 and 1:1). A stepwise change in the inclination by 5 degrees increments allowed simulation of a critical shoulder angle range of 20 degrees to 45 degrees . FINDINGS: Tilting the glenoid to cranial (increasing the critical shoulder angle) increases the shear joint reaction force and therefore the instability ratio. A balanced force ratio (1:1) between the deltoid and the supraspinatus allowed larger critical shoulder angles before cranial subluxation occurred than did the deltoid-dominant ratio (2:1). INTERPRETATION: Glenoid inclination-dependent changes of the critical shoulder angle have a significant impact on superior glenohumeral joint stability. The increased compensatory activity of the rotator cuff to keep the humeral head centered may lead to mechanical overload and could explain the clinically observed association between large angles and degenerative rotator cuff tears. PMID- 26577867 TI - Effectiveness of video- versus text-based computer-tailored smoking cessation interventions among smokers after one year. AB - BACKGROUND: In western countries, smoking prevalence rates are high among smokers unmotivated to quit and those with a lower socioeconomic status (LSES). Multiple computer tailoring and the use of audio-visual aids may improve such interventions and increase cessation in LSES smokers. This study assessed the 12 month effectiveness of a video- and text-based computer-tailored intervention. METHODS: A randomized controlled trial in the Netherlands was used in which smokers were allocated to the video-based condition (VC) (N=670), the text-based condition (TC) (N=708) or the control condition (CC) (brief generic text advice) (N=721). After 12months, self-reported prolonged abstinence was assessed and biochemically verified in respondents indicating to have quit smoking. Three analysis strategies were used to assess the effects: (1) multiple imputation (MI); (2) intention-to-treat (ITT); (3) complete case analysis (CC). RESULTS: VC was more effective in prolonged abstinence compared to CC (odds ratio (OR)=1.90, p=.005) and the text-based condition (OR=1.71, p=.01). VC was furthermore more effective than TC. No differences were found for SES and motivational levels. Results were similar when using ITT and CC. For our secondary outcome seven-day point prevalence abstinence; however, neither VC (OR=1.17, p=.34) or TC (OR=0.91, p=.52) outperformed the CC. CONCLUSION: The video-based computer-tailored intervention was effective in obtaining substantial long-term abstinence compared to the text-based version and a brief generic text advice. PMID- 26577868 TI - The effect of participation in an incentive-based wellness program on self reported exercise. AB - Employers are increasingly trying to promote healthy behaviors, including regular exercise, through wellness programs that offer financial incentives. However, there is limited evidence that these types of programs affect exercise habits within employee populations. In this study, we estimate the effect of participation in an incentive-based wellness program on self-reported exercise. Since 2008, the University of Minnesota's Fitness Rewards Program has offered a $20 monthly incentive to encourage fitness center utilization among its employees. Using 2006 to 2010 health risk assessments and university administrative files for 2972 employees, we conducted a retrospective cohort study utilizing propensity score methods to estimate the effect of participation in the Fitness Rewards Program on self-reported exercise days per week from 2008 to 2010. On average, participation in the program led to an increase of 0.59 vigorous exercise days per week (95% Confidence Interval: 0.42, 0.78) and 0.43 strength-building exercise days per week (95% Confidence Interval: 0.31, 0.58) in 2008 for participants relative to non-participants. Increases in exercise persisted through 2010. Employees reporting less frequent exercise prior to the program were least likely to participate in the program, but when they participated they had the largest increases in exercise compared to non participants. Offering an incentive for fitness center utilization encourages higher levels of exercise. Future policies may want to concentrate on how to motivate participation among individuals who are less frequently physically active. PMID- 26577870 TI - Effect of Antimicrobials Used in Regenerative Endodontic Procedures on 3-week-old Enterococcus faecalis Biofilm. AB - INTRODUCTION: We evaluated the effect of various antimicrobials used in endodontic regeneration on a 3-week-old Enterococcus faecalis biofilm. METHODS: E. faecalis biofilm was grown on standardized dentin samples for 3 weeks. Infected dentin samples were randomized into 8 experimental groups (n = 8) and treated with calcium hydroxide (Ca[OH]2), 500 mg/mL of double antibiotic paste (DAP, equal portions of metronidazole and ciprofloxacin), low dilutions of DAP (1 or 0.1 mg/mL loaded into a methylcellulose vehicle system), sterile saline, or placebo paste (only methylcellulose) for 7 days. The other experimental groups were treated with 1.5% sodium hypochlorite (NaOCl) or 2% chlorhexidine gluconate (CHX) solutions for 5 minutes. After the assigned treatments, the bacterial biofilms were detached from dentin, spiral plated, and quantified using an automated counting machine. Permutation tests followed by Sidak post hoc multiple comparisons were used for statistical analyses (alpha = 0.05). RESULTS: The infected dentin treated with 1.5% NaOCl or 500 mg/mL of DAP provided complete eradication of bacterial biofilm. Furthermore, the infected dentin treated with 2% CHX, Ca(OH)2, or 1 mg/mL of DAP had a comparable antibiofilm effect, but they were not able to completely eradicate bacterial biofilm. No significant difference in the antibiofilm effect was observed between 500 mg/mL of DAP, Ca(OH)2, 1.5% NaOCl, and 2% CHX. CONCLUSIONS: At least 1 mg/mL of DAP in a methylcellulose vehicle system is required to eliminate a substantial amount of E. faecalis biofilm. Furthermore, the antibiofilm effects of 1.5% NaOCl and 2% CHX irrigation solutions were comparable with that of 500 mg/mL of DAP and Ca(OH)2. PMID- 26577869 TI - Cell cycle features of C. elegans germline stem/progenitor cells vary temporally and spatially. AB - Many organisms accumulate a pool of germline stem cells during development that is maintained in later life. The dynamics of establishment, expansion and homeostatic maintenance of this pool are subject to both developmental and physiological influences including the availability of a suitable niche microenvironment, nutritional status, and age. Here, we investigated the dynamics of germline proliferation during stages of expansion and homeostasis, using the C. elegans germ line as a model. The vast majority of germ cells in the proliferative zone are in interphase stages of mitosis (G1, S, G2) rather than in the active mitotic (M) phase. We examined mitotic index and DNA content, comparing different life stages, mutants, and physiological conditions. We found that germ cells in larval stages cycle faster than in adult stages, but that this difference could not be attributed to sexual fate of the germ cells. We also found that larval germ cells exhibit a lower average DNA content compared to adult germ cells. We extended our analysis to consider the effects of distance from the niche and further found that the spatial pattern of DNA content differs between larval and adult stages in the wild type and among mutants in pathways that interfere with cell cycle progression, cell fate, or both. Finally, we characterized expansion of the proliferative pool of germ cells during adulthood, using a regeneration paradigm (ARD recovery) in which animals are starved and re fed. We compared adult stage regeneration and larval stage expansion, and found that the adult germ line is capable of rapid accumulation but does not sustain a larval-level mitotic index nor does it recapitulate the larval pattern of DNA content. The regenerated germ line does not reach the number of proliferative zone nuclei seen in the continuously fed adult. Taken together, our results suggest that cell cycle dynamics are under multiple influences including distance from the niche, age and/or maturation of the germ line, nutrition and, possibly, latitude for physical expansion. PMID- 26577871 TI - Isolation and Characterization of Human Dental Pulp Stem Cells from Cryopreserved Pulp Tissues Obtained from Teeth with Irreversible Pulpitis. AB - INTRODUCTION: Human dental pulp stem cells (DPSCs) are becoming an attractive target for therapeutic purposes because of their neural crest origin and propensity. Although DPSCs can be successfully cryopreserved, there are hardly any reports on cryopreservation of dental pulp tissues obtained from teeth diagnosed with symptomatic irreversible pulpitis during endodontic treatment and isolation and characterization of DPSCs from such cryopreserved pulp. The aim of this study was to cryopreserve the said pulp tissues to propagate and characterize isolated DPSCs. METHODS: A medium consisting of 90% fetal bovine serum and 10% dimethyl sulfoxide was used for cryopreservation of pulp tissues. DPSCs were isolated from fresh and cryopreserved pulp tissues using an enzymatic method. Cell viability and proliferation were determined using the MTT [3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. DPSC migration and interaction were analyzed with the wound healing assay. Mesenchymal characteristics of DPSCs were verified by flow cytometric analysis of cell surface CD markers. The osteogenic and adipogenic potential of DPSCs was shown by von Kossa and oil red O staining methods, respectively, and the polymerase chain reaction method. RESULT: We found no significant difference in CD marker expression and osteogenic and adipogenic differentiation potential of DPSCs obtained from fresh and cryopreserved dental pulp tissue. CONCLUSIONS: Our study shows that dental pulp can be successfully cryopreserved without losing normal characteristics and differentiation potential of their DPSCs, thus making them suitable for dental banking and future therapeutic purposes. PMID- 26577872 TI - Predictive Model of Intraoperative Pain during Endodontic Treatment: Prospective Observational Clinical Study. AB - INTRODUCTION: This observational study sought to assess the incidence of intraoperative pain (IOP) among patients receiving endodontic treatment and to construct a model for predicting the probability of IOP. METHODS: All patients attending the endodontic training clinic at Gazi University, Ankara, Turkey, during the spring term of 2014 were examined (N = 2785 patients; observation completed in 1435 patients; male: 628, female: 807; mean age: 39 years; 1655 teeth total). Demographic and clinical variables were recorded for patients requiring primary endodontic treatment. Local anesthesia was administered and routine endodontic treatment commenced. After the working length was established, each patient was asked to report any pain according to a visual analog scale. Supplementary local infiltration anesthesia was administered if necessary. If pain continued despite supplementary anesthesia, then the pain score was immediately assessed. A visual analog scale score corresponding to more than mild pain indicated IOP. A predictive model was constructed with multiple logistic regression analysis from the data of 85% of cases, with the remaining 15% of cases being used to test the external validity of the model. RESULTS: The incidence of IOP was 6.1% (101/1655 cases). One tooth from each patient was randomly selected, with 1435 teeth being retained for further analysis. A multiple logistic regression model was constructed with the variables age, tooth type, arc, pulpal diagnosis, pain present within the previous 24 hours, and anesthetic solution (P < .05). Good fits were obtained for the final model and external control, with a correct classification rate (efficiency) of 0.78, sensitivity (true positive rate) of 0.63, and specificity (true negative rate) of 0.79 for the external control. CONCLUSIONS: A successful predictive model of IOP was constructed with demographic and clinical variables. PMID- 26577873 TI - Effect of a Benzalkonium Chloride Surfactant-Sodium Hypochlorite Combination on Elimination of Enterococcus faecalis. AB - INTRODUCTION: The purpose of this investigation was to determine the effect of a sodium hypochlorite-surfactant combination on the removal of Enterococcus faecalis from infected teeth. METHODS: Sixty-four extracted human single canal anterior teeth were prepared with rotary instrumentation and sterilized. Teeth were divided into 4 groups, N = 16. Three experimental groups were inoculated with E. faecalis and cultured for 21 days before use: positive control group, no irrigation; NaOCl group, irrigated with 5 mL 6% NaOCl; and NaOCl/BAK group, irrigated with 5 mL 6% NaOCl/0.008% benzalkonium chloride (BAK). The negative control group received medium only and no inoculate. Paper point sampling of the canals was obtained before irrigation (S1) for all 4 groups and for 2 groups after irrigation (S2) to determine remaining colony-forming units. After sampling, all teeth were split in half and evaluated for bacterial viability colony-forming units and penetration of dentinal tubules by using fluorescent vital dye staining and confocal laser scanning microscopy. RESULTS: Comparison of pre-irrigation and post-irrigation paper point samples from the 2 irrigated groups showed a significant reduction in bacterial canal load (P < .001, Kruskal Wallis), with a significantly lower load in the NaOCl/BAK group than in the NaOCl group (P = .001, Mann-Whitney U test); 68.8% of the NaOCl/BAK samples gave no recoverable counts. In contrast, no significant difference between these groups was found for counts recovered from dentin. Confocal laser scanning microscopy showed no differences in tubule penetration. CONCLUSIONS: The addition of BAK to NaOCl significantly reduced the number of remaining bacteria within the canal after irrigation compared with NaOCl alone. PMID- 26577874 TI - Osteogenic and Angiogenic Response to Calcium Silicate-based Endodontic Sealers. AB - INTRODUCTION: Calcium silicate-based endodontic sealers are reported to favor the regeneration of periradicular tissues, a process requiring concerted osteogenic and angiogenic events. This study compared 4 calcium silicate-based sealers for the effects of their extracts on osteogenic and angiogenic cell behavior. METHODS: Extracts from ProRoot MTA (Dentsply Tulsa Dental, Tulsa, OK), MTA Plus (Prevest Denpro Limited, Jammu City, India), MTA Fillapex (Angelus, Londrina, PR, Brazil), and Biodentine (Septodont, Saint-Maur-des-Fosses, France) were prepared from freshly mixed sealers (0.1 g/cm(2)/mL extraction medium) and diluted (1:2 1:20). The sealers were compared for the dose- and time-dependent effects on the proliferation and differentiation of human mesenchymal stem cells (hMSCs) and human umbilical vein endothelial cells (HUVECs). An ex vivo osteogenic assay (regeneration of neonatal mice parietal bone defects) and an in vivo angiogenesis assay (chorioallantoic membrane assay) were performed. RESULTS: Diluted extracts from MTA ProRoot and MTA Plus had evident stimulatory effects on the proliferation of hMSCs, alkaline phosphatase activity, and ex vivo regeneration of bone defects. They also increased HUVEC growth; allowed normal tubularlike network organization; and, in vivo, did not affect angiogenesis. Comparatively, Biodentine also elicited a favorable response on hMSCs and HUVECs, but the overall osteogenic and angiogenic outcome was slightly lower. MTA Fillapex exhibited the highest toxicity in hMSCs and HUVECs and, unlike the other sealers, only allowed a partial regeneration of bone defects. CONCLUSIONS: The sealers caused dose- and time-dependent effects on the osteoblastic and endothelial response, eliciting similar cytocompatibility profiles. Results suggest that the induction of both osteogenic and angiogenic events may contribute to the sealers' regenerative outcome. PMID- 26577875 TI - Radiologist Point-of-Care Clinical Decision Support and Adherence to Guidelines for Incidental Lung Nodules. AB - PURPOSE: To evaluate the effect of a workstation-integrated, point-of-care, clinical decision support (CDS) tool on radiologist adherence to radiology department guidelines for follow-up of incidental pulmonary nodules detected on abdominal CT. METHODS: The CDS tool was developed to facilitate adherence to department guidelines for managing pulmonary nodules seen on abdominal CT. In October 2012, the tool was deployed within the radiology department of an academic medical center and could be used for a given abdominal CT at the discretion of the interpreting radiologist. We retrospectively identified consecutive patients who underwent abdominal CT (in the period from January 2012 to April 2013), had no comparison CT scans available, and were reported to have a solid, noncalcified, pulmonary nodule. Concordance between radiologist follow-up recommendation and department guidelines was compared among three groups: patients scanned before implementation of the CDS tool; and patients scanned after implementation, with versus without use of the tool. RESULTS: A total of 409 patients were identified, including 268 for the control group. Overall, guideline concordance was higher after CDS tool implementation (92 of 141 [65%] versus 133 of 268 [50%], P = .003). This finding was driven by the subset of post CDS implementation cases in which the CDS tool was used (57 of 141 [40%]). In these cases, guideline concordance was significantly higher (54 of 57 [95%]), compared with post-implementation cases in which CDS was not used (38 of 84 [45%], P < .001), and to a control group of patients from before implementation (133 of 268 [50%]; P < .001). CONCLUSIONS: A point-of-care CDS tool was associated with improved adherence to guidelines for follow-up of incidental pulmonary nodules. PMID- 26577876 TI - Implementation of a Novel Surveillance Template for Head and Neck Cancer: Neck Imaging Reporting and Data System (NI-RADS). PMID- 26577877 TI - What Brings Referring Providers to the Pediatric Reading Room in the Day of Remote Access to Images? PMID- 26577878 TI - Radiology Trainee Performance in Digital Breast Tomosynthesis: Relationship Between Difficulty and Error-Making Patterns. AB - PURPOSE: The aim of this study was to better understand the relationship between digital breast tomosynthesis (DBT) difficulty and radiology trainee performance. METHODS: Twenty-seven radiology residents and fellows and three expert breast imagers reviewed 60 DBT studies consisting of unilateral craniocaudal and medial lateral oblique views. Trainees had no prior DBT experience. All readers provided difficulty ratings and final BI-RADS((r)) scores. Expert breast imager consensus interpretations were used to determine the ground truth. Trainee sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were calculated for low- and high-difficulty subsets of cases as assessed by each trainee him or herself (self-assessed difficulty) and consensus expert-assessed difficulty. RESULTS: For self-assessed difficulty, the trainee AUC was 0.696 for high-difficulty and 0.704 for low-difficulty cases (P = .753). Trainee sensitivity was 0.776 for high-difficulty and 0.538 for low-difficulty cases (P < .001). Trainee specificity was 0.558 for high-difficulty and 0.810 for low difficulty cases (P < .001). For expert-assessed difficulty, the trainee AUC was 0.645 for high-difficulty and 0.816 for low-difficulty cases (P < .001). Trainee sensitivity was 0.612 for high-difficulty and .784 for low-difficulty cases (P < .001). Trainee specificity was 0.654 for high-difficulty and 0.765 for low difficulty cases (P = .021). CONCLUSIONS: Cases deemed difficult by experts were associated with decreases in trainee AUC, sensitivity, and specificity. In contrast, for self-assessed more difficult cases, the trainee AUC was unchanged because of increased sensitivity and compensatory decreased specificity. Educators should incorporate these findings when developing educational materials to teach interpretation of DBT. PMID- 26577879 TI - The Earnings and Employment Outcomes of the 2005 Cohort of Canadian Postsecondary Graduates with Disabilities. AB - Canada's fear of future skill and labor shortages has brought youth with disabilities to the forefront of public policy. Many universities are now reporting that an increased proportion of their graduating students identify as having a disability, and as a result, educational achievement-based programs designed to accommodate students' needs are growing across campuses. Despite recent attention by policymakers on improving accessibility standards and increasing employer incentives, young Canadians with disabilities continue to face barriers in their transitions to the workforce. The nature and extent of the early workforce inequalities faced by postsecondary graduates with disabilities remains unclear. This paper draws on the 2005 cohort of Statistics Canada's National Graduates Survey to examine the early workforce outcomes of postsecondary graduates with disabilities. Contrary to theories of human capital, the results reveal significant earnings gaps between graduates with and without disabilities of various fields of study and levels of schooling. Further, graduates with a disability are even more disadvantaged in terms of securing employment, as they were significantly less likely to be employed full-time, and were overrepresented among unemployed and part-time workers across various fields of study and levels of postsecondary education. PMID- 26577880 TI - Economic Benefits of Self-Employment for Canadian Immigrants. AB - This paper evaluates the economic benefits of self-employment in Canada for 12 groups of ethno-racial immigrants. It tests whether or not their self-employment earnings are higher or lower than similar groups in wage and salary employment, whether ethnic minorities earn more or less from self-employment compared to White immigrants, and whether self-employment earnings of immigrant groups vary by their industrial sectors of employment. Using the Canadian Census 2006, I show that self-employed ethno-racial immigrants earn less than White immigrants. I also show that the economic benefits of self-employment depend on the ethno racial groups and the industrial mix of their self-employment. PMID- 26577881 TI - "Let's Talk about the Institution": Same-Sex Common-Law Partners Negotiating Marriage Equality and Relationship Legitimacy. AB - The 2005 Canada-wide legalization of same-sex marriage provided same-sex couples with access to an institution they had previous been excluded from. Yet not all couples choose to marry. In this paper, we examine why this is the case, considering the role of personal, political, and historical factors. We draw on 22 interviews with people in common-law same-sex relationships in Toronto to examine how they understand their relationship within the new context of marriage equality. We find that participants feel they are held accountable to marriage as a default relationship legitimacy norm, indicating that this new institutional access is accompanied by a set of social expectations. Despite their awareness of the need to navigate a social context favoring marriage, participants individualize their relationship decisions as personal rather than political. Participants often contradict themselves as they articulate what marriage means to them, suggesting that, in this period of legal and social transition, people are negotiating multiple meanings, societal messages, and traditions when it comes to making sense of their relationship. We discuss the implications of these findings for LGBQ activism and the framing of sexuality-based inequalities in Canadian society. PMID- 26577882 TI - Squaring Up: Experiences of Transition from Off-Street Sex Work to Square Work and Duality--Concurrent Involvement in Both--in Vancouver, BC. AB - Many studies of exit from sex work are inspired by role theory, where people experience a lack of attachment to a role; are faced with individual, interactional, and structural challenges; contemplate transition and exit a role; and then struggle to establish postrole identities and new lives. This framework has been used to explicate the factors and experiences of those who leave or attempt to leave the sex industry; however, it is limited because studies present sex work as a harmful and dangerous profession that people are trapped in, escaping, or have survived. In this paper, I discuss Vancouver's history of violence against sex workers and I review research on sex work exiting and bring forward recommendations for the design of exit program based on the experiences of 22 active and former off-street sex workers from Vancouver, British Columbia. I describe study participants who include Sex-Work-No-More participants who would not return to the industry, Sex-Work-Maybe participants who consider reinvolvement, and Dual-Life participants who are employed in sex work and conventional work simultaneously. These participants uniquely challenge narrow, binary understandings of involvement and transition because they discuss their use of deception to obtain resources needed to make change; the support that clients have provided; their strategic engagement in sex work as a means to exit; their considerations of reentry; and for some, their dual employment. In light of new legislation that criminalizes activities related to sex work-the Protection of Communities and Exploited Persons Act-and the Federal government announcement of $20 million dollars for the creation of exit services nationwide, hearing from sex workers is essential to advancing agendas in this area. PMID- 26577883 TI - [In Process Citation]. AB - The aim of this study is twofold: first, to assess the statistical significance of the data used by Pierre Bourdieu in Distinction; second, to test the hypothesis that the volume of capital (i.e., the global amount of capital) allows for a finer discrimination of dispositional differences than the composition of capital (i.e., the respective weight of the different types of capital in the global amount of capital). To these ends, five data samples were submitted to bilateral between-proportion comparison tests. The findings (1) reveal that about two-thirds of the differences reported by P. Bourdieu are significant and (2) support the view that the volume of capital prevails over its composition. PMID- 26577884 TI - Exploring an Olympic "Legacy": Sport Participation in Canada before and after the 2010 Vancouver Winter Olympics. AB - Guided by the notion of a trickle-down effect, the present study examines whether sport participation in Canada increased following the 2010 Winter Olympics in Vancouver. Comparing rates of sport participation prior to and following the Games using nationally representative data, the results suggest that the Olympics had almost no impact on sport participation in Canada, although there does appear to be a modest "bounce" in sport participation in the Vancouver area immediately following the Vancouver Games. As such, if the trickle-down effect did occur, the analysis suggests that the effect was locally situated, short-lived, and small. PMID- 26577885 TI - Relationship between HbA1c and cancer in people with or without diabetes: a systematic review. AB - AIM: To identify the relationship between HbA1c and cancers in people with or without diabetes. BACKGROUND: Cancer is a major public health problem, accounting for 8.2 million deaths worldwide in 2012. HbA1c level has been associated with the risk of developing certain cancers, although the existing evidence is conflicting. METHODS: EMBASE, MEDLINE, CINAHL and the Cochrane Library were searched. Eligible articles included randomized controlled trials, cohort studies, case-control studies, systematic reviews and meta-analyses. Participants of either sex, with or without Type 1 or 2 diabetes, were included. The studies were assessed using the Scottish Intercollegiate Guidelines Network (SIGN) criteria by two independent assessors. No meta-analysis was performed because of the heterogeneity of results. RESULTS: A total of 19 studies from 1006 met the inclusion criteria, of which 14 were cohort studies and five were nested case control studies. Eight studies investigated outcomes for all cancer sites. Four of these studies reported that higher HbA1c levels were associated with higher incidence and/or mortality risk for all cancers. One study observed a U-shaped relationship between HbA1c and cancer incidence and mortality. Increasing HbA1c levels were associated with increasing risk of developing colorectal, pancreatic, respiratory and female genital tract cancers. No increased risk was observed for breast cancer, gastrointestinal or urological malignancies. CONCLUSION: HbA1c appears to be associated with cancer incidence and/or cancer mortality, but further studies are needed to fully understand the complex relationship between HbA1c and cancer. PMID- 26577886 TI - Experimental analysis of stereotypy with applications of nonparametric statistical tests for alternating treatments designs. AB - INTRODUCTION: Stereotypy is common in individuals with developmental disabilities and may become disruptive in the context of instruction. PURPOSE: The purpose of this study was to embed brief experimental analyses in the context of reading instruction to evaluate effects of antecedent and consequent variables on latencies to and durations of stereotypy. METHOD: We trained a reading instructor to implement a trial-based functional analysis and a subsequent antecedent analysis of stimulus features for an adolescent with autism in a reading clinic. We used alternating treatments designs with applications of nonparametric statistical analyses to control Type I error rates. RESULTS: Results of the experimental analyses suggested stereotypy was maintained by non-social reinforcement and informed the extent to which features of academic materials influenced levels of stereotypy. Results of nonparametric statistical analyses were consistent with conclusions based on visual analysis. CONCLUSION: Brief experimental analyses may be embedded in academic instruction to inform the stimulus conditions that influence stereotypy. PMID- 26577887 TI - Magnetic resonance spectroscopy reveals oral Lactobacillus promotion of increases in brain GABA, N-acetyl aspartate and glutamate. AB - The gut microbiome has been shown to regulate the development and functions of the enteric and central nervous systems. Its involvement in the regulation of behavior has attracted particular attention because of its potential translational importance in clinical disorders, however little is known about the pathways involved. We previously have demonstrated that administration of Lactobacillus rhamnosus (JB-1) to healthy male BALB/c mice, promotes consistent changes in GABA-A and -B receptor sub-types in specific brain regions, accompanied by reductions in anxiety and depression-related behaviors. In the present study, using magnetic resonance spectroscopy (MRS), we quantitatively assessed two clinically validated biomarkers of brain activity and function, glutamate+glutamine (Glx) and total N-acetyl aspartate+N-acetyl aspartyl glutamic acid (tNAA), as well as GABA, the chief brain inhibitory neurotransmitter. Mice received 1*10(9) cfu of JB-1 per day for 4weeks and were subjected to MRS weekly and again 4weeks after cessation of treatment to ascertain temporal changes in these neurometabolites. Baseline concentrations for Glx, tNAA and GABA were equal to 10.4+/-0.3mM, 8.7+/-0.1mM, and 1.2+/-0.1mM, respectively. Delayed increases were first seen for Glx (~10%) and NAA (~37%) at 2weeks which persisted only to the end of treatment. However, Glx was still elevated 4weeks after treatment had ceased. Significantly elevated GABA (~25%) was only seen at 4weeks. These results suggest specific metabolic pathways in our pursuit of mechanisms of action of psychoactive bacteria. They also offer through application of standard clinical neurodiagnostic techniques, translational opportunities to assess biomarkers accompanying behavioral changes induced by alterations in the gut microbiome. PMID- 26577888 TI - Commonly used Neuropsychological Tests for Spanish Speakers: Normative Data from Latin America. PMID- 26577889 TI - Methodology for the development of normative data for ten Spanish-language neuropsychological tests in eleven Latin American countries. AB - BACKGROUND: Within the field of neuropsychology, there is a significant lack of normative data for individuals in Latin America. OBJECTIVE: To describe the methodology utilized to obtain the data and create norms for 10 Spanish-language neuropsychological tests administered in 11 Latin-American countries in a sample of 3,977 healthy individuals between the ages 18 and 90. METHOD: The same data manipulation process was applied to the data collected (regardless of the scale or country) using a regression-based procedure that takes into account sex, age, and educational influences on neuropsychological test scores. CONCLUSIONS: Following this procedure, we were able to generate age, education, and sex (if relevant) based norms for each test in each of the 11 countries studied. These norms are presented in the 10 articles that comprise this special issue. PMID- 26577890 TI - [Erratum to: Treatment of congenital lacrimal duct obstruction : A prospective clinical cohort study]. PMID- 26577891 TI - Allopurinol in Vascular Disease: Is There a New Role for an Old Drug? PMID- 26577892 TI - Should Endovascular Therapy Be Considered for Patients With Connective Tissue Disorder? AB - Because of early diagnosis, strict imaging follow-up, and advances in medical and surgical management, life expectancy of Marfan patients has dramatically improved since the 1970s. Although disease of the root and ascending aorta are more frequent in patients with connective tissue disorders, a subset of patients present with diffuse disease that might involve any portion of the thoracoabdominal aorta. Thoracic endovascular aortic repair (TEVAR) has gained widespread acceptance for the treatment of different pathologies of the descending aorta. In contrast, TEVAR in patients with connective tissue disorders is associated with a high risk of early and mid-term complications and reinterventions. Currently, a consensus of experts recommend that an open approach should be reserved for use in acceptable risk candidates with connective tissue disorders. TEVAR should be considered solely in patients in a complex repeat surgical setting or in patients judged to have prohibitive open surgical risk. Finally, as a bridge to a definite open repair, TEVAR might be life-saving in patients with connective tissue disorders who present with exsanguination or severe malperfusion. Future developments in stent-graft technology might decrease stent-graft-related complications in patients with connective tissue disorders, although securing a device with radial force in a fragile aorta in the long-term will be challenging. PMID- 26577893 TI - Successful Biopsy and Removal of a Tricuspid Valve Papillary Fibroelastoma in Cardiac Catheterization Laboratory: A Case Report. AB - Papillary fibroelastomas are rare benign cardiac tumours with a predilection for cardiac valves. Because of the rarity of these tumours, management is individualized, but some recommend surgical removal of all papillary fibroelastomas due to the increased risk of embolization. We report a case of a 71-year-old man who presented with a sessile mass on the tricuspid valve. The mass, a papillary fibroelastoma, was successfully biopsied and removed in the cardiac catheterization laboratory. This report demonstrates a unique minimally invasive way of approaching a cardiac tumour wherein a major surgery was avoided. PMID- 26577894 TI - Catheter-Based Educational Experiences: A Canadian Survey of Current Residents and Recent Graduates in Cardiac Surgery. AB - The past decade has witnessed significant developments in the use of catheter based therapies in cardiovascular medicine. We sought to assess the educational opportunities for cardiac surgery trainees to determine their readiness for participation in these strategies. A web-based survey was distributed to current residents, recent graduates, and program directors in Canadian cardiac surgery residency programs from 2008-2013. The survey was distributed to 110 residents and graduates. Forty-five percent completed the survey. Thirty-five percent expressed that they experienced resistance organizing their rotations because they had to compete with non-cardiac surgery colleagues, and 6 were denied local cardiac catheterization rotations. By the end of the rotation, 56% were comfortable performing a diagnostic cardiac catheterization independently. Exposure to being the operator performing diagnostic catheterization was significantly associated with the positive perception of being able to perform a diagnostic catheterization independently (odds ratio [OR], 5.14; 95% confidence interval [CI], 1.33-19.81; P = 0.017). Eighty-eight percent of respondents expressed the need for more exposure in catheter-based rotations. Seven of 11 program directors completed the survey. All believed such rotations should be mandatory and foresaw a bigger role for hybrid catheter-based/cardiac surgery procedures in the future. Trainees and program directors perceive that increased exposure to catheter-based therapies is important to career development as a cardiac surgeon. This survey will contribute to the development of a cardiac surgery training curriculum as we foresee more hybrid and team procedures. PMID- 26577895 TI - Evidence, Guidelines, and Gut Checks: Musings on Entering the Post-Statin Era of Lipid Management. AB - This viewpoint describes the results of a survey administered to 55 physicians who are key opinion leader experts in dyslipidemia management and thoroughly knowledgeable about current guidelines and emerging therapies. The purpose was to determine the level of low density lipoprotein-cholesterol (LDL-C) achieved with maximally tolerated statin monotherapy that would trigger a preference by most for use of the soon to be available proprotein convertase subtilisin/kexin type 9 inhibitor as the next add-on agent. Because current guidelines suggest a uniform LDL-C goal when treating patients meeting guideline indications for therapy, it was expected that the size of the gap between LDL-C goal and LDL-C attained with maximally tolerated statins would uniformly dictate when proprotein convertase subtilisin/kexin type 9 inhibitors would be desired. This expectation, however, was not met. In particular, the results suggest that primary prevention patients and patients with chronic kidney disease do not appear to represent high priority circumstances for achieving even the current LDL-C goal despite existing guidelines. Implications for future guidelines in the post-statin era are discussed. PMID- 26577896 TI - Tribulations of Recent Cardiology Trials, the Audacity of Hope, and HOPE-3. PMID- 26577898 TI - Non-anatomical reconstruction of lateral ulnar collateral ligament of the elbow after tumor resection. AB - We present the case of an 80-year-old man with a tumor recurrence on his right arm 6 years after initial treatment. The lateral aspect of the elbow joint, involving overlaying skin, muscles, tendons, joint capsule, lateral collateral ligament complex, the lateral 1/3 of the capitellum, and lateral epicondyle of humerus were excised in the tumor resection. Intraoperative assessment revealed multidirectional instability of the elbow, and joint stabilization was needed. Because the lateral epicondyle was resected, graft placement in an anatomical position was impossible to carry out. Therefore, non-anatomical reconstruction of lateral ulnar collateral ligament with palmaris longus tendon graft was performed. The skin was reconstructed using an antegrade pedicled radial forearm flap. For wrist extension reconstruction, the pronator quadratus tendon was transferred to the extensor carpi radialis brevis tendon. One year after the operation, elbow range of motion was 5-130 degrees . The patient remains symptom free. The Mayo elbow performance score is good. The Musculoskeletal Tumor Society rating score is excellent. To our knowledge, this is the first report of an elbow lateral ulnar collateral ligament reconstruction after tumor resection. PMID- 26577897 TI - Cerebral Hemodynamics During Exercise and Recovery in Heart Transplant Recipients. AB - BACKGROUND: The aims of this work were (1) to compare cerebral oxygenation perfusion (COP), central hemodynamics, and peak oxygen uptake (Vo2peak) in heart transplant recipients (HTRs) vs age-matched healthy controls (AMHCs) during exercise and recovery and (2) to study the relationships between COP, central hemodynamics, and Vo2peak in HTRs and AMHCs. METHODS: Twenty-six HTRs (3 women) and 27 AMHCs (5 women) were recruited. Maximal cardiopulmonary function (gas exchange analysis), cardiac hemodynamics (impedance cardiography), and left frontal COP (near-infrared spectroscopy) were measured continuously during and after a maximal ergocycle (Ergoline 800S, Bitz, Germany) test. RESULTS: Compared with AMHCs, HTRs had lower Vo2peak, maximal cardiac index (CImax), and maximal ventilatory variables (P < 0.05). COP was lower during exercise (oxyhemoglobin [DeltaO2Hb], 50% and 75% of VO2peak, total hemoglobin [DeltatHb], 100% of VO2peak; P < 0.05), and recovery in HTRs (DeltaO2Hb, minutes 2-5; DeltatHb, minutes 1-5; P < 0.05) compared with AMHCs. End-tidal pressure of CO2 was lower during exercise compared with that in AMHCs (P < 0.0001). In HTRs, CImax was positively correlated with exercise cerebral hemodynamics (R = 0.54-0.60; P < 0.01). CONCLUSIONS: In HTRs, COP was reduced during exercise and recovery compared with that in AMHCs, potentially because of a combination of blunted cerebral vasodilation by CO2, cerebrovascular dysfunction, reduced cardiac function, and medication. The impaired VO2peak observed in HTRs was mainly caused by reduced maximal ventilation and CI. In HTRs, COP is impaired and is correlated with cardiac function, potentially impacting cognitive function. Therefore, we need to study which interventions (eg, exercise training) are most effective for improving or normalizing (or both) COP during and after exercise in HTRs. PMID- 26577899 TI - Pharyngeal arch artery defects and lethal malformations of the aortic arch and its branches in mice deficient for the Hrt1/Hey1 transcription factor. AB - The aortic arch and major branch arteries are formed from the three pairs of pharyngeal arch arteries (PAAs) during embryonic development. Their morphological defects are clinically observed as isolated diseases, as a part of complicated cardiovascular anomalies or as a manifestation of multi-organ syndromes such as 22q11.2 deletion syndrome. Although numerous genes have been implicated in PAA formation and remodeling, detailed mechanisms remain poorly understood. Here we report that the mice null for Hrt1/Hey1, a gene encoding a downstream transcription factor of Notch and ALK1 signaling pathways, show perinatal lethality on the C57BL/6N, C57BL/6N * C57BL/6J or C57BL/6N * 129X1/SvJ background. Hrt1/Hey1 null embryos display abnormal development of the fourth PAA (PAA4), which results in congenital vascular defects including right-sided aortic arch, interruption of the aortic arch and aberrant origin of the right subclavian artery. Impaired vessel formation occurs randomly in PAA4 of Hrt1/Hey1 null embryos, which likely causes the variability of congenital malformations. Endothelial cells in PAA4 of null embryos differentiate normally but are structurally disorganized at embryonic day 10.5 and 11.5. Vascular smooth muscle cells are nearly absent in the structurally-defective PAA4, despite the appropriate migration of cardiac neural crest cells into the fourth pharyngeal arches. Endothelial expression of Jag1 is down-regulated in the structurally defective PAA4 of null embryos, which may be one of the mechanisms underlying the suppression of vascular smooth muscle cell differentiation. While the direct downstream phenomena of the Hrt1/Hey1 deficiency remain to be clarified, we suggest that Hrt1/Hey1-dependent transcriptional regulation has an important role in PAA formation during embryonic development. PMID- 26577900 TI - Binocular summation of chance decisions. AB - Seeing with two eyes usually helps one respond faster. Here we show that with ambiguous stimuli, binocular viewing can paradoxically slow down reaction time. This is explained by the observers basing their decision on a noisy neuronal representation within the visual system, with the added noise breaking the symmetry between the two possible interpretations. Binocular integration improves the representation by reducing the noise, increasing ambiguity, and decision time. The neuronal Accumulator (Race) model is applied to quantify the underlying binocular integration. The model accounts for the distributions of reaction times, and predicts suboptimal integration between eyes. We conclude that under ambiguous stimulation neuronal noise within the visual system determines responses. PMID- 26577901 TI - Complete genome sequence of novel T7-like virus vB_KpnP_KpV289 with lytic activity against Klebsiella pneumoniae. AB - A novel bacteriophage, vB_KpnP_KpV289, lytic for hypermucoviscous strains of Klebsiella pneumoniae, was attributed to the family Podoviridae, subfamily Autographivirinae, genus T7likevirus based on transmission electron microscopy and genome analysis. The complete genome of the bacteriophage vB_KpnP_KpV289 consists of a linear double-stranded DNA of 41,054 bp including 179-bp direct repeat sequences at the ends and 51 open reading frames (ORFs). The G+C content is 52.56 %. The phage was shown to lyse 15 out of 140 (10.7 %) K. pneumoniae strains belonged to the capsular types K-1, K-2, and K-57 and strains without a determined capsular type, including a hypermucoviscous strain of the novel sequence type ST-1554. PMID- 26577902 TI - Clinical validation of a novel real-time human papillomavirus assay for simultaneous detection of 14 high-risk HPV type and genotyping HPV type 16 and 18 in China. AB - In the present study, we describe the laboratory workflow and the clinical validation of a novel multiplex real-time PCR-based HPV assay in China. The cross sectional validation analysis showed that this assay worked well for detection of 14 HR-HPV types and identification of HPV 16 and 18 in a single sensitive assay that is suitable for both clinical usage and high-throughput cervical screening purposes. We predict that this accurate, high-throughput and low-cost HPV assay can greatly reduce the heavy economic burden of HPV detection in China. PMID- 26577903 TI - Down-regulation of Arabidopsis DND1 orthologs in potato and tomato leads to broad spectrum resistance to late blight and powdery mildew. AB - Multiple susceptibility genes (S), identified in Arabidopsis, have been shown to be functionally conserved in crop plants. Mutations in these S genes result in resistance to different pathogens, opening a new way to achieve plant disease resistance. The aim of this study was to investigate the role of Defense No Death 1 (DND1) in susceptibility of tomato and potato to late blight (Phytophthora infestans). In Arabidopsis, the dnd1 mutant has broad-spectrum resistance against several fungal, bacterial, and viral pathogens. However this mutation is also associated with a dwarfed phenotype. Using an RNAi approach, we silenced AtDND1 orthologs in potato and tomato. Our results showed that silencing of the DND1 ortholog in both crops resulted in resistance to the pathogenic oomycete P. infestans and to two powdery mildew species, Oidium neolycopersici and Golovinomyces orontii. The resistance to P. infestans in potato was effective to four different isolates although the level of resistance (complete or partial) was dependent on the aggressiveness of the isolate. In tomato, DND1-silenced plants showed a severe dwarf phenotype and autonecrosis, whereas DND1-silenced potato plants were not dwarfed and showed a less pronounced autonecrosis. Our results indicate that S gene function of DND1 is conserved in tomato and potato. We discuss the possibilities of using RNAi silencing or loss-of-function mutations of DND1 orthologs, as well as additional S gene orthologs from Arabidopsis, to breed for resistance to pathogens in crop plants. PMID- 26577904 TI - Organelle reorganization in bovine oocytes during dominant follicle growth and regression. AB - BACKGROUND: We tested the hypothesis that organelles in bovine oocytes undergo changes in number and spatial distribution in a manner specific for phase of follicle development. METHODS: Cumulus-oocyte-complexes were collected from Hereford heifers by ultrasound-guided follicle aspiration from dominant follicles in the growing phase (n = 5; Day 0 = ovulation), static phase (n = 5), regressing phase (n = 7) of Wave 1 and from preovulatory follicles (n = 5). Oocytes were processed and transmission electron micrographs of ooplasm representing peripheral, perinuclear and central regions were evaluated using standard stereological methods. RESULTS: The number of mitochondria and volume occupied by lipid droplets was higher (P < 0.03) in oocytes from regressing follicles (193.0 +/- 10.4/1000 MUm(3) and 3.5 +/- 0.7 %) than growing and preovulatory stages (118.7 +/- 14.4/1000 MUm(3) and 1.1 +/- 0.3 %; 150.5 +/- 28.7/1000 MUm(3) and 1.6 +/- 0.2 %, respectively). Oocytes from growing, static and preovulatory follicles had >70 % mitochondria in the peripheral regions whereas oocytes from regressing follicles had an even distribution. Oocytes from growing follicles had more lipid droplets in peripheral region than in central region (86.9 vs. 13.1 %). Percent surface area of mitochondria in contact with lipid droplets increased from growing (2.3 %) to static, regressing or preovulatory follicle stage (8.9, 6.1 and 6.2 %). The amount, size and distribution of other organelles did not differ among phases (P > 0.11). CONCLUSIONS: Our hypothesis was supported in that mitochondrial number increased and translocation occurred from a peripheral to an even distribution as follicles entered the regressing phase. In addition, lipid droplets underwent spatial reorganization from a peripheral to an even distribution during the growing phase and mitochondria-lipid contact area increased with follicle maturation. PMID- 26577905 TI - Why (and When) Straight Women Trust Gay Men: Ulterior Mating Motives and Female Competition. AB - Previous findings indicate that heterosexual women experience a greater sense of comfort and trust in their friendships with gay men than in their friendships with heterosexual individuals. In the present studies, we tested a hypothesis that not only explains why women exhibit increased trust in gay men but also yields novel predictions about when (i.e., in what contexts) this phenomenon is likely to occur. Specifically, we propose that gay men's lack of motives to mate with women or to compete with them for mates enhances women's trust in gay men and openness to befriend them. Study 1 demonstrated that women placed greater trust in a gay man's mating-but not non-mating (e.g., career) advice-than in the same advice given by heterosexual individuals. Study 2 showed that women perceived a gay man to be more sincere in scenarios relevant to sexual and competitive mating deception. In Study 3, exposing women to a visualization of increased mating competition enhanced their trust in gay men; when mating competition was salient, women's trust in mating information from a gay man was amplified. Study 4 showed that women who perceived higher levels of mating competition were more open to befriending gay men. Together, these converging findings support our central hypothesis, which not only provides a distal explanation for the trust that straight women place in gay men, but also provides novel insights into previously unidentified contexts that facilitate the formation and strengthening of this unique bond. PMID- 26577906 TI - Parents and adolescents preferences for asthma control: a best-worst scaling choice experiment using an orthogonal main effects design. AB - BACKGROUND: The preferences of parents and children with asthma influence their ability to manage a child's asthma and achieve good control. Potential differences between parents and adolescents with respect to specific parameters of asthma control are not considered in clinical asthma guidelines. The objective was to measure and compare the preferences of parents and adolescents with asthma with regard to asthma control parameters using best worst scaling (BWS). METHODS: Fifty-two parents of children with asthma and 44 adolescents with asthma participated in a BWS study to quantify preferences regarding night-time symptoms, wheezing/chest tightening, changes in asthma medications, emergency visits and physical activity limitations. Conditional logit regression was used to determine each group's utility for each level of each asthma control parameter. RESULTS: Parents displayed the strongest positive preference for the absence of night-time symptoms (beta = 2.09, p < 0.00001) and the strongest negative preference for 10 emergency room visits per year (beta = -2.15, p < 0.00001). Adolescents displayed the strongest positive preference for the absence of physical activity limitations (beta = 2.17, p < 0.00001) and the strongest negative preference for ten physical activity limitations per month (beta = 1.97). Both groups were least concerned with changes to medications. CONCLUSION: Parents and adolescents placed different weights on the importance of asthma control parameters and each group displayed unique preferences. Understanding the relative importance placed on each parameter by parents and adolescents is essential for designing effective patient-focused disease management plans. PMID- 26577909 TI - A pathological scoring system in the diagnosis and judgment of prognosis of biliary atresia. AB - OBJECTIVE: The purpose of this study was to evaluate the diagnostic and prognostic value of a histological scoring system in biliary atresia (BA). METHODS: From June 2013 to July 2014, 86 wedge liver biopsy specimens were obtained from infants with neonatal cholestasis (58 patients with biliary atresia and 28 patients with non-obstructive cholestasis as control) in our center. A pathologist, single-blinded to the final diagnosis, made the histological diagnosis individually based on an 8-feature (liver fibrosis, portal ductal proliferation, bile plugs in portal ductules, cholestasis, hepatocellular changes inflammatory cells infiltration in portal region, extramedullary hematopoiesis, and ductal plate malformation), 21-point (0 to 21) scoring system. RESULTS: In this retrospective study, ductular reaction (bile ductular proliferation) and liver fibrosis in the portal area, bile plugs, and ductal plate malformation were the best indicators of BA. With the scoring system, a score of >=8 had the best diagnostic utility to differentiate BA from other intrahepatic cholestasis histologically (sensitivity 94.7%, specificity 86.2%, accuracy 91.9%). Liver fibrosis and ductal plate malformation were confirmed to be related with the prognosis. CONCLUSIONS: An 8-feature, 21-point histological scoring system has a good diagnostic accuracy in the interpretation of liver histology in neonatal cholestasis. The use of liver fibrosis and ductal plate malformation are also feasible to assess the prognosis. PMID- 26577908 TI - Roles of nitric oxide and intestinal microbiota in the pathogenesis of necrotizing enterocolitis. AB - Necrotizing enterocolitis remains one of the most vexing problems in the neonatal intensive care unit. Risk factors for NEC include prematurity, formula feeding, and inappropriate microbial colonization of the GI tract. The pathogenesis of NEC is believed to involve weakening of the intestinal barrier by perinatal insults, translocation of luminal bacteria across the weakened barrier, an exuberant inflammatory response, and exacerbation of the barrier damage by inflammatory factors, leading to a vicious cycle of inflammation-inflicted epithelial damage. Nitric oxide (NO), produced by inducible NO synthase (iNOS) and reactive NO oxidation intermediates play a prominent role in the intestinal barrier damage by inducing enterocyte apoptosis and inhibiting the epithelial restitution processes, namely enterocyte proliferation and migration. The factors that govern iNOS upregulation in the intestine are not well understood, which hampers efforts in developing NO/iNOS-targeted therapies. Similarly, efforts to identify bacteria or bacterial colonization patterns associated with NEC have met with limited success, because the same bacterial species can be found in NEC and in non-NEC subjects. However, microbiome studies have identified the three important characteristics of early bacterial populations of the GI tract: high diversity, low complexity, and fluidity. Whether NEC is caused by specific bacteria remains a matter of debate, but data from hospital outbreaks of NEC strongly argue in favor of the infectious nature of this disease. Studies in Cronobacter muytjensii have established that the ability to induce NEC is the property of specific strains rather than the species as a whole. Progress in our understanding of the roles of bacteria in NEC will require microbiological experiments and genome-wide analysis of virulence factors. PMID- 26577910 TI - Paravertebral regional blocks decrease length of stay following surgery for pectus excavatum in children. AB - PURPOSE: Management of postoperative pain following repair of pectus excavatum has traditionally included thoracic epidural analgesia, narcotics, and benzodiazepines. We hypothesized that the use of intercostal or paravertebral regional blocks could result in decreased inpatient length of stay (LOS). METHODS: We conducted a retrospective cohort study of 137 patients (118 Nuss and 19 Ravitch - Nuss and Ravitch patients were analyzed separately) who underwent surgical repair of pectus excavatum with pain management via epidural, intercostal, or paravertebral analgesia from January 2009-December 2012. Measured outcomes included LOS, pain scores, benzodiazepine/narcotic requirements, emesis, professional fees, hospital cost, and total cost. RESULTS: In the Nuss patients, LOS was significantly reduced in the paravertebral group (p<0.005) and the intercostal group (p<0.005) compared to the epidural group, but was paradoxically countered by a nonsignificant increase in total cost (p=0.09). While benzodiazepine doses/day was not increased in the paravertebral group (p=0.08), an increase was seen in narcotic use (p<0.005). Despite increased narcotic use, no differences were seen in emesis between epidural and paravertebral use. Compared to epidural, pain scores were higher for both intercostal and paravertebral on day one (p<0.005), but equivalent for paravertebral on day three (p=0.62). The Ravitch group was too small for detailed independent statistical analysis but followed the same overall trend seen in the Nuss patients. CONCLUSION: Our use of paravertebral continuous infusion pain catheters for pectus excavatum repair was an effective alternative to epidural analgesia resulting in shorter LOS but not a decrease in overall cost. PMID- 26577911 TI - Mortality after emergency department thoracotomy for pediatric blunt trauma: Analysis of the National Trauma Data Bank 2007-2012. AB - PURPOSE: The purpose of this study was to determine the proportion of children who survived after emergency department thoracotomy (EDT) for blunt trauma using a national database. METHODS: A review of the National Trauma Data Bank was performed for years 2007-2012 to identify children <18 years of age who underwent EDT for blunt trauma. RESULTS: Eighty-four children <18 years of age underwent EDT after blunt trauma. Every child died during their hospitalization. The median age was 15 (IQR 6-17) years. Mean injury severity score (ISS) was 34.2 (SD 20.8), and 56% had an ISS of 26-75. Data for "signs of life" were available for 21 children. Fifteen (71%) had signs of life upon ED arrival. Sixty percent of children died in the ED. Of those who survived to the operating room (OR), 66% died in the OR. Four children (5%) survived more than 24 hours in the intensive care unit, three of whom had a maximum head abbreviated injury score of 5. CONCLUSION: There were no survivors after EDT for blunt trauma in the pediatric population in this national dataset. Usual indicators for EDT after blunt trauma in adults may not apply in children, and use should be discouraged without compelling evidence of a reversible cause of extremis. PMID- 26577912 TI - Peritoneal VEGF-A expression is regulated by TGF-beta1 through an ID1 pathway in women with endometriosis. AB - VEGF-A, an angiogenic factor, is increased in the peritoneal fluid of women with endometriosis. The cytokine TGF-beta1 is thought to play a role in the establishment of endometriosis lesions. Inhibitor of DNA binding (ID) proteins are transcriptional targets of TGF-beta1 and ID1 has been implicated in VEGF-A regulation during tumor angiogenesis. Herein, we determined whether peritoneal expression of VEGF-A is regulated by TGF-beta1 through the ID1 pathway in women with endometriosis. VEGF-A was measured in peritoneal fluid by ELISA (n = 16). VEGF-A and ID1 expression was examined in peritoneal biopsies (n = 13), and primary peritoneal and immortalized mesothelial cells (MeT5A) by immunohistochemistry, qRT-PCR and ELISA. VEGF-A was increased in peritoneal fluid from women with endometriosis and levels correlated with TGF-beta1 concentrations (P < 0.05). VEGF-A was immunolocalized to peritoneal mesothelium and TGF-beta1 increased VEGFA mRNA (P < 0.05) and protein (P < 0.05) in mesothelial cells. ID1 was increased in peritoneum from women with endometriosis and TGF-beta1 increased concentrations of ID1 mRNA (P < 0.05) in mesothelial cells. VEGF-A regulation through ID1 was confirmed by siRNA in MeT5A cells (P < 0.05). Our data supports role for ID1 in the pathophysiology of endometriosis, as an effector of TGFbeta1 dependent upregulation of VEGF-A, and highlights a novel potential therapeutic target. PMID- 26577914 TI - Patterning two-dimensional free-standing surfaces with mesoporous conducting polymers. AB - The ability to pattern functional moieties with well-defined architectures is highly important in material science, nanotechnology and bioengineering. Although two-dimensional surfaces can serve as attractive platforms, direct patterning them in solution with regular arrays remains a major challenge. Here we develop a versatile route to pattern two-dimensional free-standing surfaces in a controlled manner assisted by monomicelle close-packing assembly of block copolymers, which is unambiguously revealed by direct visual observation. This strategy allows for bottom-up patterning of polypyrrole and polyaniline with adjustable mesopores on various functional free-standing surfaces, including two-dimensional graphene, molybdenum sulfide, titania nanosheets and even on one-dimensional carbon nanotubes. As exemplified by graphene oxide-based mesoporous polypyrrole nanosheets, the unique sandwich structure with adjustable pore sizes (5-20 nm) and thickness (35-45 nm) as well as enlarged specific surface area (85 m(2) g( 1)) provides excellent specific capacitance and rate performance for supercapacitors. Therefore, this approach will shed light on developing solution based soft patterning of given interfaces towards bespoke functions. PMID- 26577915 TI - Acoustic Communication in Rats: Effects of Social Experiences on Ultrasonic Vocalizations as Socio-affective Signals. AB - Ultrasonic vocalizations (USV) serve important communicative functions as socio affective signals in rats. In aversive situations, such as inter-male aggression and predator exposure, 22-kHz USV are emitted. They likely function as appeasement signals during fighting and/or as alarm calls to warn conspecifics. In appetitive situations, 50-kHz USV are uttered, most notably during social interactions, such as rough-and-tumble play and mating. It is believed that they fulfill an affiliative function as social contact calls. Social experiences or their lack, such as social isolation, can have profound impact on the emission of 22- and 50-kHz USV by the sender in later life, albeit direction and strength of observed effects vary, with time point of occurrence and duration being critical determinants. Little, however, is known about how social experiences affect the behavioral responses evoked by 22- and 50-kHz USV in the recipient. By means of our 50-kHz USV radial maze playback paradigm, we recently showed that the behavioral response elicited in the recipient is affected by post-weaning social isolation. Rats exposed to four weeks of isolation during the rough-and-tumble play period did not display social approach behavior toward 50-kHz USV but some signs of social avoidance. We further found that physical environmental enrichment providing minimal opportunities for social interactions has similar detrimental effects. Together, this indicates that social experiences can affect socio-affective communication in rodents, both at the level of sender and recipient. Deficits seen following post-weaning social isolation or physical environmental enrichment might be useful to model aspects of neurodevelopmental disorders characterized by social and communication deficits, such as autism and schizophrenia. PMID- 26577916 TI - eComment. Novel smartphone-dependent electrocardiographic patient monitoring after surgical atrial fibrillation ablation. PMID- 26577917 TI - International comparison of death place for suicide; a population-level eight country death certificate study. AB - PURPOSE: The places of death for people who died of suicide were compared across eight countries and socio-demographic factors associated with home suicide deaths identified. METHODS: Death certificate data were analyzed; using multivariable binary logistic regression to determine associations. RESULTS: National suicide death rates ranged from 1.4 % (Mexico) to 6.4 % (South Korea). The proportion of suicide deaths occurring at home was high, ranging from 29.9 % (South Korea) to 65.8 % (Belgium). Being older, female, widowed/separated, highly educated and living in an urban area were risk factors for home suicide. CONCLUSIONS: Home suicide deaths need specific attention in prevention programs. PMID- 26577918 TI - The prevalence of mental disorders among upper primary school children in Kenya. AB - PURPOSE: The aim of this study was to estimate the prevalence and correlates of mental disorders among upper primary school children in grades five through seven in Kenya. METHODS: The Youth Self Report (YSR) instrument was adapted for use in Kenyan schools and administered to 2267 school children in grades five through seven from 23 randomly selected schools. We estimated the prevalence of DSM-IV mental disorders, and used logistic regression analyses to examine the socio demographic factors associated with each disorder. RESULTS: The prevalence of any mental disorder among Kenyan school children was 37.7 % (95 % CI = 35.7-39.7 %). Somatic complaints were the most prevalent (29.6 %, 95 % CI = 27.8-31.5 %), followed by affective disorders (14.1 %, 95 % CI = 12.7-15.6 %) and conduct disorder (12.5 %, 95 % CI = 11.2-13.9). The presence of one or more comorbid mental disorder was seen among 18.2 % (95 % CI = 16.6-19.8 %) of children. Male sex, living in a peri-urban vs. rural area, being held back in school, having divorced or separated parents, and having an employed mother were associated with an increased likelihood of having most of the mental disorders examined, whereas increasing age was associated with a reduced likelihood. CONCLUSIONS: We observed a high prevalence of mental disorders among school children in Kenya. If not detected early, these disorders may interfere with children's psychological, social, and educational development. Our findings highlight the importance of implementing screening measures in schools that can detect single and multiple disorders in order to improve the mental health and well-being of the next generation. PMID- 26577919 TI - What is the right temperature to cool post-cardiac arrest patients? AB - CITATION: Niklas Nielsen, Wetterslev J, Cronberg T, Erlinge D, Gasche Y, Hassager C, Horn J, Hovdenes J, Kjaergaard J, Kuiper M, Pellis T, Stammet P, Wanscher M, Wise MP, Aneman A, Al-Subaie N, Boesgaard S, Bro-Jeppesen J, Brunetti I, Bugge JF, Hingston CD, Juffermans NP, Koopmans M, Kober L, Langorgen J, Lilja G, Moller JE, Rundgren M, Rylander C, Smid O, Werer C, Winkel P, Friberg H. Targeted temperature management at 33 degrees C versus 36 degrees C after cardiac arrest. N Engl J Med. 2013;369:2197-206. doi: 10.1056/NEJMoa1310519 . Epub 2013 Nov 17. Pub Med PMID: 20089970. BACKGROUND: Brain ischemia and reperfusion injury leading to tissue degeneration and loss of neurological function following return of spontaneous circulation after cardiac arrest (CA) is a well-known entity. Two landmark trials in 2002 showed improved survival and neurological outcome of comatose survivors of out-of-hospital cardiac arrest (OHCA) of presumed cardiac origin when the patients were subjected to therapeutic hypothermia of 32 to 34 degrees C for 12 to 24 hours. However, the optimal target temperature for these cohorts is yet to be established and also it is not clear whether strict fever management and maintaining near normal body temperature are alone sufficient to improve the outcome. METHODS: OBJECTIVE: The objective is to determine whether a hypothermic goal of a near-normal body temperature of 36 degrees C reduces all cause mortality compared with a moderate hypothermia of 33 degrees C for the unconscious survivors of OHCA of presumed cardiac origin when subjected randomly to these different targeted temperatures. DESIGN: A multicenter, international, open label, randomized controlled trial. SETTING: Thirty-six ICUs in Europe and Australia participated in this study. PARTICIPANTS: Unconscious adults (older than 18 years of age) who survived (Glasgow coma scale less than 8) OHCA due to presumed cardiac origin with subsequent persistent return of spontaneous circulation (more than 20 minutes without chest compressions). INTERVENTION: The above participant cohorts were randomized to targeted body temperature of either 33 degrees C or 36 degrees C for 36 hours after the CA with gradual rewarming of both groups to 37 degrees C (hourly increments of 0.5 degrees C) after the initial 28 hours. Body temperatures in both the groups were then maintained below 37.5 degrees C for 72 hours after the initial 36 hours. OUTCOMES: Primary outcome measure of all-cause mortality in both the groups at the end of the trial with the secondary outcome measure of all-cause mortality, composite neurological function as evaluated by cerebral performance category scale and modified ranking scale at the end of 180 days were studied. RESULTS: Out of the 939 participants, all-cause mortality at the end of the trial was 50 % in the 33 degrees C group (225 of 466 patients) compared with 48 % in the 36 degrees C group (235 of 473 patients); the hazard ratio with a temperature of 33 degrees C was 1.06 (95 % confidence interval (CI) 0.89 to 1.28, P = 0.51). At the end of 180 days, 54 % of patients in the 33 degrees C group versus 52 % in the 36 degrees C group had died or had poor neurological outcome according to cerebral performance category (risk ratio 1.02, 95 % CI 0.88 to 1.16, P = 0.78) but the modified ranking scale at the end of 180 days was unchanged (52 %) in both groups (risk ratio 1.01, 95 % CI 0.89 to 1.14, P = 0.87). CONCLUSIONS: Maintaining targeted lower normothermia of 36 degrees C had similar outcomes compared with induced moderate hypothermia of 33 degrees C for unconscious survivors of OHCA of presumed cardiac cause. PMID- 26577920 TI - A 36-year-old man with fourth ventricular mass. PMID- 26577921 TI - Cell type-specific abundance of 4EBP1 primes prostate cancer sensitivity or resistance to PI3K pathway inhibitors. AB - Pharmacological inhibitors against the PI3K-AKT-mTOR (phosphatidylinositol 3 kinase-AKT-mammalian target of rapamycin) pathway, a frequently deregulated signaling pathway in cancer, are clinically promising, but the development of drug resistance is a major limitation. We found that 4EBP1, the central inhibitor of cap-dependent translation, was a critical regulator of both prostate cancer initiation and maintenance downstream of mTOR signaling in a genetic mouse model. 4EBP1 abundance was distinctly different between the epithelial cell types of the normal prostate. Of tumor-prone prostate epithelial cell types, luminal epithelial cells exhibited the highest transcript and protein abundance of 4EBP1 and the lowest protein synthesis rates, which mediated resistance to both pharmacologic and genetic inhibition of the PI3K-AKT-mTOR signaling pathway. Decreasing total 4EBP1 abundance reversed resistance in drug-insensitive cells. Increased 4EBP1 abundance was a common feature in prostate cancer patients who had been treated with the PI3K pathway inhibitor BKM120; thus, 4EBP1 may be associated with drug resistance in human tumors. Our findings reveal a molecular program controlling cell type-specific 4EBP1 abundance coupled to the regulation of global protein synthesis rates that renders each epithelial cell type of the prostate uniquely sensitive or resistant to inhibitors of the PI3K-AKT-mTOR signaling pathway. PMID- 26577922 TI - The interaction of uPAR with VEGFR2 promotes VEGF-induced angiogenesis. AB - In endothelial cells, binding of vascular endothelial growth factor (VEGF) to the receptor VEGFR2 activates multiple signaling pathways that trigger processes such as proliferation, survival, and migration that are necessary for angiogenesis. VEGF-bound VEGFR2 becomes internalized, which is a key step in the proangiogenic signal. We showed that the urokinase plasminogen activator receptor (uPAR) interacted with VEGFR2 and described the mechanism by which this interaction mediated VEGF signaling and promoted angiogenesis. Knockdown of uPAR in human umbilical vein endothelial cells (HUVECs) impaired VEGFR2 signaling, and uPAR deficiency in mice prevented VEGF-induced angiogenesis. Upon exposure of HUVECs to VEGF, uPAR recruited the low-density lipoprotein receptor-related protein 1 (LRP-1) to VEGFR2, which induced VEGFR2 internalization. Thus, the uPAR-VEGFR2 interaction is crucial for VEGF signaling in endothelial cells. PMID- 26577923 TI - The hepatitis C virus protein NS3 suppresses TNF-alpha-stimulated activation of NF-kappaB by targeting LUBAC. AB - The transcription factor nuclear factor kappaB (NF-kappaB) is crucial for innate immune defense against viral infections, and its activation requires the ubiquitylation of upstream proteins, including the adaptor protein NEMO (NF kappaB essential modulator). Many infectious pathogens, including hepatitis C virus (HCV), inhibit NF-kappaB signaling in host cells, which promotes pathogen survival. Frequently, HCV-infected individuals develop a chronic infection, which suggests that HCV can subvert host antiviral responses. We found that HCV infection and replication inhibited the activation of NF-kappaB by the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha), which was mediated by the viral protein NS3 and, to a lesser extent, NS5B. NS3 directly interacted with linear ubiquitin chain assembly complex (LUBAC), competed with NEMO for binding to LUBAC, and inhibited the LUBAC-mediated linear ubiquitylation of NEMO and the subsequent activation of NF-kappaB. Together, our results highlight an immune evasion strategy adopted by HCV to modulate host antiviral responses and enhance virus survival and persistence. PMID- 26577925 TI - Apoptosis-Inducing Effects of Amaryllidaceae Alkaloids. AB - The Amaryllidaceae occupies a privileged status amongst medicinal plants in having delivered the Alzheimer's drug galanthamine to the clinical market. Following its resounding success, there have been several positive indicators for the emergence of an anticancer drug from the family due to the potent antiproliferative activities manifested by several of its alkaloid constituents. Of these, the phenanthridones such as pancratistatin hold most promise as potential chemotherapeutics having succumbed to various phases of clinical trials. Other cytotoxic targets of the Amaryllidaceae are to be found within the lycorane and crinane groups, as exemplified by crinine and lycorine. Although the molecular targets of these alkaloids still remain elusive, much effort has gone into understanding their mode of action in cancer cells. Recent findings have shown that the apoptotic pathway may be a key factor in cancer cell death instigated by Amaryllidaceae alkaloids. As such, this review seeks to: (a) examine the apoptotic effects of Amaryllidaceae alkaloids in cancer cells; (b) explore the molecular basis to these effects; and (c) provide a pharmacophoric rationale in support of these activities. PMID- 26577924 TI - Optimizing protocols for extraction of bacteriophages prior to metagenomic analyses of phage communities in the human gut. AB - BACKGROUND: The human gut is densely populated with archaea, eukaryotes, bacteria, and their viruses, such as bacteriophages. Advances in high-throughput sequencing (HTS) as well as bioinformatics have opened new opportunities for characterizing the viral communities harbored in our gut. However, limited attention has been given to the efficiency of protocols dealing with extraction of phages from fecal communities prior to HTS and their impact on the metagenomic dataset. RESULTS: We describe two optimized methods for extraction of phages from fecal samples based on tangential-flow filtration (TFF) and polyethylene glycol precipitation (PEG) approaches using an adapted method from a published protocol as control (literature-adapted protocol (LIT)). To quantify phage recovery, samples were spiked with low numbers of c2, phi29, and T4 phages (representatives of the Siphoviridae, Podoviridae, and Myoviridae families, respectively) and their concentration (plaque-forming units) followed at every step during the extraction procedure. Compared with LIT, TFF and PEG had higher recovery of all spiked phages, yielding up to 16 times more phage particles (PPs) and up to 68 times more phage DNA per volume, increasing thus the chances of extracting low abundant phages. TFF- and PEG-derived metaviromes showed 10% increase in relative abundance of Caudovirales and unclassified phages infecting gut-associated bacteria (>92% for TFF and PEG, 82.4% for LIT). Our methods obtained lower relative abundance of the Myoviridae family (<16%) as compared to the reference protocol (22%). This decline, however, was not considered a true loss of Myoviridae phages but rather a greater level of extraction of Siphoviridae phages (TFF and PEG >32.5%, LIT 22.6%), which was achieved with the enhanced conditions of our procedures (e.g., reduced filter clogging). A high degree of phage diversity in samples extracted using TFF and PEG was documented by transmission electron microscopy. CONCLUSIONS: Two procedures (TFF and PEG) for extraction of bacteriophages from fecal samples were optimized using a set of spiked bacteriophages as process control. These protocols are highly efficient tools for extraction and purification of PPs prior to HTS in phage-metavirome studies. Our methods can be easily modified, being thus applicable and adjustable for in principle any solid environmental material in dissolution. PMID- 26577926 TI - Peptidyl Arginine Deiminases and Neurodegenerative Diseases. AB - Peptidyl arginine deiminases (PADs) are a small group of isozymes that convert Arg residues on the surface of proteins into citrulline residues, typically as a part of posttranslational processing. PADs are present in most of the tissues, and the isozyme distribution is tissue-specific. In the past 15 years, it is becoming apparent that PADs are either upregulated or their catalytic activity is enhanced in certain disease conditions, including neurological diseases. In particular, hypercitrullinated proteins and elevated PAD activities are discovered in neurodegenerative conditions such as multiple sclerosis, Alzheimer's disease etc. This review article reviews the status of PAD enzymes as targets in neurodegenerative conditions, and briefly outlines the efforts in medicinal chemistry to identify PAD inhibitors for the treatment of various neurodegenerative conditions. PMID- 26577927 TI - A systematic review of reasons for gatekeeping in palliative care research. AB - BACKGROUND: When healthcare professionals or other involved parties prevent eligible patients from entering a trial as a research subject, they are gatekeeping. This phenomenon is a persistent problem in palliative care research and thought to be responsible for the failure of many studies. AIM: To identify potential gatekeepers and explore their reasons for gatekeeping in palliative care research. DESIGN: A 'Review of Reasons' based on the systematic Preferred Reporting Items for Systematic Reviews and Meta-Analyses approach and a thematic synthesis. DATA SOURCE: PubMed, Embase, Cumulative Index to Nursing and Allied Health Literature and PsycINFO from 2000 to May 20 2015 were searched. Studies in children (aged <18 years) and patients with dementia were excluded. RESULTS: Thirty papers on gatekeeping in palliative care research were included. Five groups of potential gatekeepers were identified: healthcare professionals, research ethics committees, management, relatives and researchers. The fear of burdening vulnerable patients was the most reported reason for gatekeeping. Other reasons included 'difficulty with disclosure of health status', 'fear of burdening the patient's relatives', 'doubts about the importance or quality of the study', 'reticent attitude towards research and (research) expertise' and 'logistics'. In hospice and homecare settings, the pursuit of comfort care may trigger a protective attitude. Gatekeeping is also rooted in a (perceived) lack of skills to recruit patients with advanced illness. CONCLUSION: Gatekeeping is motivated by the general assumption of vulnerability of patients, coupled with an emphasis on the duty to protect patients. Research is easily perceived as a threat to patient well-being, and the benefits appear to be overlooked. The patients' perspective concerning study participation is needed to gain a full understanding and to address gatekeeping in palliative care research. PMID- 26577928 TI - Student nurses' experience of and attitudes towards care of the dying: A cross sectional study. AB - BACKGROUND: Nurses are the professional group with the greatest contact with those at the end of life and their attitudes towards the care of the dying is important in care delivery. AIM: We investigated the relationship between student nurses' attitudes towards care of the dying and (1) demographics, (2) course factors and (3) experience of caring for people who are dying. DESIGN: A cross sectional survey using the Frommelt's Attitude Toward Care of the Dying scale to measure respondents' attitudes. SETTING/PARTICIPANTS: Nursing students studying at a university in the United Kingdom. RESULTS: A total of 567 completed questionnaires were returned, with 91.9% of respondents being classed as having a positive attitude towards care of the dying (Frommelt's Attitude Toward Care of the Dying score ?65). In adjusted analysis, higher (more positive) Frommelt's Attitude Toward Care of the Dying scores were associated with time on course and experience of caring for the dying. Third-year students had a score of 2.18 points greater than those in their first year (95% confidence interval: 0.36 4.01, p = 0.017). The adjusted differences in scores were 2.22 points greater for those who had prepared a dead body (95% confidence interval: 0.57-3.87, p = 0.008), 2.95 points greater for those who had cared for a dying patient (95% confidence interval: 1.09-4.08, p = 0.002) and 2.03 points greater for those who had cared for a dying relative or friend (95% confidence interval: 0.69-3.37, p = 0.003). CONCLUSION: The length of time in education and practical experience of caring for dying individuals are independently associated with positive attitudes towards care of the dying among student nurses. PMID- 26577929 TI - Secondary metabolites extracted from marine sponge associated Comamonas testosteroni and Citrobacter freundii as potential antimicrobials against MDR pathogens and hypothetical leads for VP40 matrix protein of Ebola virus: an in vitro and in silico investigation. AB - The current study explores therapeutic potential of metabolites extracted from marine sponge (Cliona sp.)-associated bacteria against MDR pathogens and predicts the binding prospective of probable lead molecules against VP40 target of Ebola virus. The metabolite-producing bacteria were characterized by agar overlay assay and as per the protocols in Bergey's manual of determinative bacteriology. The antibacterial activities of extracted metabolites were tested against clinical pathogens by well-diffusion assay. The selected metabolite producers were characterized by 16S rDNA sequencing. Chemical screening and Fourier Transform Infrared (FTIR) analysis for selected compounds were performed. The probable lead molecules present in the metabolites were hypothesized based on proximate analysis, FTIR data, and literature survey. The drug-like properties and binding potential of lead molecules against VP40 target of Ebola virus were hypothesized by computational virtual screening and molecular docking. The current study demonstrated that clear zones around bacterial colonies in agar overlay assay. Antibiotic sensitivity profiling demonstrated that the clinical isolates were multi-drug resistant, however; most of them showed sensitivity to secondary metabolites (MIC-15 MUl/well). The proximate and FTIR analysis suggested that probable metabolites belonged to alkaloids with O-H, C-H, C=O, and N-H groups. 16S rDNA characterization of selected metabolite producers demonstrated that 96% and 99% sequence identity to Comamonas testosteroni and Citrobacter freundii, respectively. The docking studies suggested that molecules such as Gymnastatin, Sorbicillactone, Marizomib, and Daryamide can designed as probable lead candidates against VP40 target of Ebola virus. PMID- 26577930 TI - Molecular characterization of misidentified Plasmodium ovale imported cases in Singapore. AB - BACKGROUND: Plasmodium ovale, considered the rarest of the malaria parasites of humans, consists of two morphologically identical but genetically distinct sympatric species, Plasmodium ovale curtisi and Plasmodium ovale wallikeri. These parasites resemble morphologically to Plasmodium vivax with which they also share a tertian periodicity and the ability to cause relapses, making them easily misidentified as P. vivax. Plasmodium ovale infections are rarely reported, but given the likelihood of misidentification, their prevalence might be underestimated. METHODS: Morphological and molecular analysis of confirmed malaria cases admitted in Singapore in 2012-2014 detected nine imported P. ovale cases that had been misidentified as P. vivax. Since P. ovale had not been previously officially reported in Singapore, a retrospective analysis of available, frozen, archival blood samples was performed and returned two additional misidentified P. ovale cases in 2003 and 2006. These eleven P. ovale samples were characterized with respect to seven molecular markers (ssrRNA, Potra, Porbp2, Pog3p, dhfr-ts, cytb, cox1) used in recent studies to distinguish between the two sympatric species, and to a further three genes (tufa, clpC and asl). RESULTS: The morphological features of P. ovale and the differential diagnosis with P. vivax were reviewed and illustrated by microphotographs. The genetic dimorphism between P. ovale curtisi and P. ovale wallikeri was assessed by ten molecular markers distributed across the three genomes of the parasite (Genbank KP050361-KP050470). The data obtained for seven of these markers were compared with those published and confirmed that both P. ovale species were present. This dimorphism was also confirmed for the first time on: (1) two genes from the apicoplast genome (tufA and clpC genes); and, (2) the asl gene that was used for phylogenetic analyses of other Plasmodium species, and that was found to harbour the highest number of dimorphic loci between the two P. ovale species. CONCLUSION: Misidentified P. ovale infections are reported for the first time among imported malaria cases in Singapore. Genetic dimorphism between P. ovale curtisi and P. ovale wallikeri was confirmed using markers from the parasites' three genomes. The apparent increase of imported P. ovale since 2012 (with yearly detection of cases) is puzzling. Given decrease in the overall number of malaria cases recorded in Singapore since 2010 the 'resurgence' of this neglected species raises public health concerns. PMID- 26577931 TI - TrkB activation by 7, 8-dihydroxyflavone increases synapse AMPA subunits and ameliorates spatial memory deficits in a mouse model of Alzheimer's disease. AB - We recently demonstrated that activation of tyrosine receptor kinase B (TrkB) by 7, 8-dihydroxyflavone (7, 8-DHF), the selective TrkB agonist, increased surface alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors (AMPARs) AMPA receptor subunit GluR1 (GluA1) subunit expression at the synapses of Fragile X Syndrome mutant mice. This present study investigated the effects of 7, 8-DHF on both memory function and synapse structure in relation to the synapse protein level of AMPARs in the Tg2576 Alzheimer's disease (AD) mouse model. The study found that chronic oral administration of 7, 8-DHF significantly improved spatial memory and minimized dendrite loss in the hippocampus of Tg2576 mice. A key feature of 7, 8-DHF action was the increased expression of both GluA1 and GluA2 at synapses. Interestingly, 7, 8-DHF had no effect on the attenuation of amyloid precursor protein or Abeta exhibiting in the Tg2576 AD brains, yet it activated the phosphorylation of TrkB receptors and its downstream signals including CaMKII, Akt, Erk1/2, and cAMP-response element-binding protein. Importantly, cyclotraxin B (a TrkB inhibitor), U0126 (a Ras-ERK pathway inhibitor), Wortmannin (an Akt phosphorylation inhibitor), and KN-93 (a CaMKII inhibitor) counteracted the enhanced expression and phosphorylation of AMPAR subunits induced by 7, 8-DHF. Collectively, our results demonstrated that 7, 8 DHF acted on TrkB and resolved learning and memory impairments in the absence of reduced amyloid in amyloid precursor protein transgenic mice partially through improved synaptic structure and enhanced synaptic AMPARs. The findings suggest that the application of 7, 8-DHF may be a promising new approach to improve cognitive abilities in AD. We provided extensive data demonstrating that 7, 8 dihydroflavone, the TrkB agonist, improved Tg2576 mice spatial memory. This improvement is correlated with a reversion to normal values of GluA1 and GluA2 AMPA receptor subunits and dendritic spines in CA1. This work suggests that 7, 8 DHF is a suitable drug to potentiate in vivo Tropomyosin receptor kinase B (TrkB) signaling in the Alzheimer's disease mice model. PMID- 26577933 TI - Emerging role of PLAG1 as a regulator of growth and reproduction. AB - Pleomorphic adenoma gene 1 (PLAG1) belongs to the PLAG family of zinc finger transcription factors along with PLAG-like 1 and PLAG-like 2. The PLAG1 gene is best known as an oncogene associated with certain types of cancer, most notably pleomorphic adenomas of the salivary gland. While the mechanisms of PLAG1-induced tumorigenesis are reasonably well understood, the role of PLAG1 in normal physiology is less clear. It is known that PLAG1 is involved in cell proliferation by directly regulating a wide array of target genes, including a number of growth factors such as insulin-like growth factor 2. This is likely to be a central mode of action for PLAG1 both in embryonic development and in cancer. The phenotype of Plag1 knockout mice suggests an important role for PLAG1 also in postnatal growth and reproduction, as PLAG1 deficiency causes growth retardation and reduced fertility. A role for PLAG1 in growth and reproduction is further corroborated by genome-wide association studies in humans and domestic animals in which polymorphisms in the PLAG1 genomic region are associated with body growth and reproductive traits. Here we review the current evidence for PLAG1 as a regulator of growth and fertility and discuss possible endocrine mechanisms involved. PMID- 26577934 TI - Novel adipocyte aminopeptidases are selectively upregulated by insulin in healthy and obese rats. AB - The lack of a complete assembly of the sensitivity of subcellular aminopeptidase (AP) activities to insulin in different pathophysiological conditions has hampered the complete view of the adipocyte metabolic pathways and its implications in these conditions. Here we investigated the influence of insulin on basic AP (APB), neutral puromycin-sensitive AP (PSA), and neutral puromycin insensitive AP (APM) in high and low density microsomal and plasma membrane fractions from adipocytes of healthy and obese rats. Catalytic activities of these enzymes were fluorometrically monitoring in these fractions with or without insulin stimulus. Canonical traffic such as insulin-regulated AP was not detected for these novel adipocyte APs in healthy and obese rats. However, insulin increased APM in low density microsomal and plasma membrane fractions from healthy rats, APB in high density microsomal fraction from obese rats and PSA in plasma membrane fraction from healthy rats. A new concept of intracellular compartment-dependent upregulation of AP enzyme activities by insulin emerges from these data. This relatively selective regulation has pathophysiological significance, since these enzymes are well known to act as catalysts and receptor of peptides directly related to energy metabolism. Overall, the regulation of each one of these enzyme activities reflects certain dysfunction in obese individuals. PMID- 26577935 TI - An unusual case of neurothekeoma of the arm in an adult. AB - Neurothekeomas are uncommon benign neoplasms with a peripheral nerve sheath origin. This tumor usually involves dermis and is described as a small, solitary, slow growing and reddish to flesh-colored nodule or papule. Neurothekeoma preferentially affects the central aspect of the face, the arms or shoulders of women in the second and third decades of life. This is the first case report of neurothekeoma involving the wrist developing from synovial tissue and with uncertain clinical behavior in an adult female. The tumor was completely excised under brachial plexus block. Histopathologically, the examination of the microscopic slides revealed the presence of a 20-mm diameter, well-circumscribed and multilobulated tumor composed of abundant myxoid stroma with cellular elements; with immunohistochemistry there was positivity to vimentin but S100 protein, epithelial membrane antigen, cytokeratin AE1-3, CD99 and CD34 were all negative. This pattern suggested a myxoid tumor form of neurothekeoma, mixed subtype. The patient had an atypical local recurrence and was re-operated after 3 months. After 12 months there was no evidence of clinical recurrences confirmed by magnetic resonance evaluation. Basically, our case report adds an important element in the correct clinical management of neurotecheomas: faced with a histological diagnosis with an unusual localization and mixed or hypercellular type, clinicians must consider the possibility of an early local recurrence, suggesting a close clinical and radiological follow-up. PMID- 26577932 TI - The serotonin system in autism spectrum disorder: From biomarker to animal models. AB - Elevated whole blood serotonin, or hyperserotonemia, was the first biomarker identified in autism spectrum disorder (ASD) and is present in more than 25% of affected children. The serotonin system is a logical candidate for involvement in ASD due to its pleiotropic role across multiple brain systems both dynamically and across development. Tantalizing clues connect this peripheral biomarker with changes in brain and behavior in ASD, but the contribution of the serotonin system to ASD pathophysiology remains incompletely understood. Studies of whole blood serotonin levels in ASD and in a large founder population indicate greater heritability than for the disorder itself and suggest an association with recurrence risk. Emerging data from both neuroimaging and postmortem samples also indicate changes in the brain serotonin system in ASD. Genetic linkage and association studies of both whole blood serotonin levels and of ASD risk point to the chromosomal region containing the serotonin transporter (SERT) gene in males but not in females. In ASD families with evidence of linkage to this region, multiple rare SERT amino acid variants lead to a convergent increase in serotonin uptake in cell models. A knock-in mouse model of one of these variants, SERT Gly56Ala, recapitulates the hyperserotonemia biomarker and shows increased brain serotonin clearance, increased serotonin receptor sensitivity, and altered social, communication, and repetitive behaviors. Data from other rodent models also suggest an important role for the serotonin system in social behavior, in cognitive flexibility, and in sensory development. Recent work indicates that reciprocal interactions between serotonin and other systems, such as oxytocin, may be particularly important for social behavior. Collectively, these data point to the serotonin system as a prime candidate for treatment development in a subgroup of children defined by a robust, heritable biomarker. PMID- 26577936 TI - Effectiveness of intra-articular injections of sodium hyaluronate-chondroitin sulfate in knee osteoarthritis: a multicenter prospective study. AB - BACKGROUND: Intra-articular injection of hyaluronic acid is a well-established therapy for the treatment of knee osteoarthritis. The aim of the study was to assess the effectiveness and safety of the use of Arthrum HCS((r)) (40 mg hyaluronic acid and 40 mg chondroitin sulfate in 2 mL). MATERIALS AND METHODS: This was an open, multicenter, prospective study. Men or women over 40 years of age with documented knee osteoarthritis and WOMAC subscore A (severity of pain) >=25 were enrolled. They received three weekly intra-articular injections of sodium hyaluronate 2 % and chondroitin sulfate 2 % in combination. WOMAC subscore A was assessed at 1, 3 and 6 months after the last injection. RESULTS: One hundred and twelve patients were included (women, 66 %). The mean (SD) WOMAC subscore A decreased from 52.1 (15.2) at inclusion to 20.5 (19.7) at month 6 (P < 0.0001). The mean subscore was already significantly decreased 1 month after the last injection at 25.7 (P < 0.0001). Pain relief and consumption of analgesic drugs, both assessed with visual analogic scale (VAS), consistently decreased. The investigators were satisfied/very satisfied as regards the therapeutic effectiveness of sodium hyaluronate-chondroitin sulfate in reducing pain (77 %), improving mobility (78 %) and reducing the consumption of analgesics (74 %). Only one adverse effect was reported by one patient (knee tumefaction). CONCLUSION: These results suggest that intra-articular injections of Arthrum HCS((r)) (sodium hyaluronate plus chondroitin sulfate) in patients with knee osteoarthritis are efficient and safe. These results should be confirmed in a randomized controlled study. LEVEL OF EVIDENCE: IV. PMID- 26577937 TI - Mid-term results of Miller-Galante unicompartmental knee replacement for medial compartment knee osteoarthritis. AB - BACKGROUND: The purpose of this study is to analyse and report the mid-term results of 175 unicompartmental knee replacement (UKR) procedures performed for medial compartment knee arthritis from January 2001 to January 2010. MATERIALS AND METHODS: The cohort participants were selected after stringent inclusion criteria and the average follow-up was 5.6 years (range 2-10 years). The fixed bearing UKR procedure was carried out on all patients. RESULTS: The pre-operative mean knee range of movement improved from 100 degrees +/- 11.3 degrees to 118.3 degrees +/- 12 degrees (p value <0.001). The pre-operative mean Knee Society (KS) knee and functional score improved from 47 +/- 5.5 and 55.1 +/- 4.6 to 91.8 +/- 9.2 and 92 +/- 10.1 (p value <0.001), respectively. The revision rate of the cohort was 4 % (seven knees) and implant survival rate was 96 % at the end of 10 years; 87 % of the cohort were satisfied with the procedure and had a normal gait pattern. In this study, there was no statistical difference between groups with a body mass index (BMI) <=30 kg/m(2) and those with a BMI >=30 kg/m(2), and between groups aged <=55 years and those aged >=55 years, in clinical and functional outcome following UKR. CONCLUSION: This study confirms that fixed-bearing UKR gives excellent results in patients with medial compartment knee arthritis who comply with the inclusion criteria. Age and BMI were not considered to influence the clinical and functional outcomes. Level of evidence-III. PMID- 26577938 TI - Diagnostic value of combining 11C-choline and 18F-FDG PET/CT in hepatocellular carcinoma. AB - PURPOSE: In this prospective study, our goal was to emphasize the diagnostic value of combining (11)C-choline and (18)F-FDG PET/CT for hepatocellular carcinoma (HCC) in patients with chronic liver disease. METHODS: Thirty-three consecutive patients were enrolled. All patients were suspected to have HCC based on CT and/or MRI imaging. A final diagnosis was obtained by histopathological examination or by imaging alone according to American Association for the Study of Liver Disease criteria. All patients underwent PET/CT with both tracers within a median of 5 days. All lesions showing higher tracer uptake than normal liver were considered positive for HCC. We examined how tracer uptake was related to biological (serum alpha-fetoprotein levels) and pathological (differentiation status, peritumoral capsule and vascular invasion) prognostic markers of HCC, as well as clinical observations at 6 months (recurrence and death). RESULTS: Twenty eight HCC, four cholangiocarcinomas and one adenoma were diagnosed. In the HCC patients, the sensitivity of (11)C-choline, (18)F-FDG and combined (11)C-choline and (18)F-FDG PET/CT for the detection of HCC was 75 %, 36 % and 93 %, respectively. Serum alpha-fetoprotein levels >200 ng/ml were more frequent among patients with (18)F-FDG-positive lesions than those with (18)F-FDG-negative lesions (p < 0.05). Early recurrence (n=2) or early death (n=5) occurred more frequently in patients with (18)F-FDG-positive lesions than in those with (18)F FDG-negative lesions (p < 0.05). CONCLUSION: The combined use of (11)C-choline and (18)F-FDG PET/CT detected HCC with high sensitivity. This approach appears to be of potential prognostic value and may facilitate the selection of patients for surgical resection or liver transplantation. PMID- 26577939 TI - Central serotonin transporter availability in highly obese individuals compared with non-obese controls: A [(11)C] DASB positron emission tomography study. AB - PURPOSE: The role of the central serotonin (5-hydroxytryptamine, 5-HT) system in feeding has been extensively studied in animals with the 5-HT family of transporters (5-HTT) being identified as key molecules in the regulation of satiety and body weight. Aberrant 5-HT transmission has been implicated in the pathogenesis of human obesity by in vivo positron emission tomography (PET) and single-photon emission computed tomography (SPECT) imaging techniques. However, results obtained thus far from studies of central 5-HTT availability have been inconsistent, which is thought to be brought about mainly by the low number of individuals with a high body mass index (BMI) previously used. The aim of this study was therefore to assess 5-HTT availability in the brains of highly obese otherwise healthy individuals compared with non-obese healthy controls. METHODS: We performed PET using the 5-HTT selective radiotracer [(11)C] DASB on 30 highly obese (BMI range between 35 and 55 kg/m(2)) and 15 age- and sex-matched non-obese volunteers (BMI range between 19 and 27 kg/m(2)) in a cross-sectional study design. The 5-HTT binding potential (BPND) was used as the outcome parameter. RESULTS: On a group level, there was no significant difference in 5-HTT BPND in various cortical and subcortical regions in individuals with the highest BMI compared with non-obese controls, while statistical models showed minor effects of age, sex, and the degree of depression on 5-HTT BPND. CONCLUSION: The overall finding of a lack of significantly altered 5-HTT availability together with its high variance in obese individuals justifies the investigation of individual behavioral responses to external and internal cues which may further define distinct phenotypes and subgroups in human obesity. PMID- 26577940 TI - Quantitative and qualitative analysis of [(18)F]FDG and [(18)F]FAZA positron emission tomography of head and neck cancers and associations with HPV status and treatment outcome. AB - PURPOSE: While methods for imaging tumor hypoxia with positron emission tomography (PET) have been developed, optimal methods for interpreting and utilizing these datasets in the clinic remain unclear. In this study, we analyzed hypoxia PET images of head and neck cancer patients and compared imaging metrics with human papilloma virus (HPV) status and clinical outcome. METHODS: Forty-one patients treated as part of a phase III trial of the hypoxic cytotoxin tirapazamine (TROG 02.02) were imaged with PET using fluorodeoxyglucose (FDG) and fluoroazomycin arabinoside (FAZA). FDG and FAZA PET images were interpreted qualitatively and quantitatively, and compared with tumor T stage, HPV status, and treatment outcome using multivariate statistics. RESULTS: PET signals in the tumor and lymph nodes exhibited significant intra- and inter-patient variability. The FAZA hypoxic volume demonstrated a significant correlation with tumor T stage. PET-hypoxic tumors treated with cisplatin exhibited significantly worse treatment outcomes relative to PET-oxic tumors or PET-hypoxic tumors treated with tirapazamine. CONCLUSION: Quantitative analysis of FAZA PET yielded metrics that correlated with clinical T stage and were capable of stratifying patient outcome. These results encourage further development of this technology, with particular emphasis on establishment of robust quantitative methods. PMID- 26577942 TI - Tasers. PMID- 26577941 TI - The role of patient-based treatment planning in peptide receptor radionuclide therapy. AB - BACKGROUND: Accurate treatment planning is recommended in peptide-receptor radionuclide therapy (PRRT) to minimize the toxicity to organs at risk while maximizing tumor cell sterilization. The aim of this study was to quantify the effect of different degrees of individualization on the prediction accuracy of individual therapeutic biodistributions in patients with neuroendocrine tumors (NETs). METHODS: A recently developed physiologically based pharmacokinetic (PBPK) model was fitted to the biokinetic data of 15 patients with NETs after pre therapeutic injection of (111)In-DTPAOC. Mathematical phantom patients (MPP) were defined using the assumed true (true MPP), mean (MPP 1A) and median (MPP 1B) parameter values of the patient group. Alterations of the degree of individualization were introduced to both mean and median patients by including patient-specific information as a priori knowledge: physical parameters and hematocrit (MPP 2A/2B). Successively, measurable individual biokinetic parameters were added: tumor volume V tu (MPP 3A/3B), glomerular filtration rate GFR (MPP 4A/4B), and tumor perfusion f tu (MPP 5A/5B). Furthermore, parameters of MPP 5A/5B and a simulated (68)Ga-DOTATATE PET measurement 60 min p.i. were used together with the population values used as Bayesian parameters (MPP 6A/6B). Therapeutic biodistributions were simulated assuming an infusion of (90)Y DOTATATE (3.3 GBq) over 30 min to all MPPs. Time-integrated activity coefficients were predicted for all MPPs and compared to the true MPPs for each patient in tumor, kidneys, spleen, liver, remainder, and whole body to obtain the relative differences RD. RESULTS: The large RD values of MPP 1A [RDtumor = (625 +/- 1266)%, RDkidneys = (11 +/- 38)%], and MPP 1B [RDtumor = (197 +/- 505)%, RDkidneys = (11 +/- 39)%] demonstrate that individual treatment planning is needed due to large physiological differences between patients. Although addition of individual patient parameters reduced the deviations considerably [MPP 5A: RDtumor = (-2 +/- 27)% and RDkidneys = (16 +/- 43)%; MPP 5B: RDtumor = (2 +/- 28)% and RDkidneys = (7 +/- 40)%] errors were still large. For the kidneys, prediction accuracy was considerably improved by including the PET measurement [MPP 6A/MPP 6B: RDtumor = (-2 +/- 22)% and RDkidneys = (-0.1 +/- 0.5)%]. CONCLUSION: Individualized treatment planning is needed in the investigated patient group. The use of a PBPK model and the inclusion of patient specific data, e.g., weight, tumor volume, and glomerular filtration rate, do not suffice to predict the therapeutic biodistribution. Integrating all available a priori information in the PBPK model and using additionally PET data measured at one time point for tumor, kidneys, spleen, and liver could possibly be sufficient to perform an individualized treatment planning. PMID- 26577943 TI - A randomized controlled trial of hospital versus home based therapy with oral amoxicillin for severe pneumonia in children aged 3 - 59 months: The IndiaCLEN Severe Pneumonia Oral Therapy (ISPOT) Study. AB - BACKGROUND: Pneumonia is the leading cause of child mortality under five years of age worldwide. For pneumonia with chest indrawing in children aged 3-59 months, injectable penicillin and hospitalization was the recommended treatment. This increased the health care cost and exposure to nosocomial infections. We compared the clinical and cost outcomes of a seven day treatment with oral amoxicillin with the first 48 h of treatment given in the hospital (hospital group) or at home (home group). METHODS: We conducted an open-label, multi-center, two-arm randomized clinical trial at six tertiary hospitals in India. Children aged 3 to 59 months with chest indrawing pneumonia were randomized to home or hospital group. Clinical outcomes, treatment adherence, and patient safety were monitored through home visits on day 3, 5, 8, and 14 with an additional visit for the home group at 24 h. Clinical outcomes included treatment failure rates up to 7 days (primary outcome) and between 8-14 days (secondary outcome) using the intention to treat and per protocol analyses. Cost outcomes included direct medical, direct non-medical and indirect costs for a random 17% subsample using the micro-costing technique. RESULTS: 1118 children were enrolled and randomized to home (n = 554) or hospital group (n = 564). Both groups had similar baseline characteristics. Overall treatment failure rate was 11.5% (per protocol analysis). The hospital group was significantly more likely to fail treatment than the home group in the intention to treat analysis. Predictors with increased risk of treatment failure at any time were age 3-11 months, receiving antibiotics within 48 h prior to enrolment and use of high polluting fuel. Death rates at 7 or 14 days did not differ significantly. (Difference -0.0%; 95% CI -0.5 to 0.5). The median total treatment cost was Rs. 399 for the home group versus Rs. 602 for the hospital group (p < 0.001), for the same effect of 5% failure rate at the end of 7 days of treatment in the random subsample. CONCLUSIONS: Home based oral amoxicillin treatment was equivalent to hospital treatment for first 48 h in selected children of chest indrawing pneumonia and was cheaper. Consistent with the recent WHO simplified guidelines, management with home based oral amoxicillin for select children with only fast breathing and chest-indrawing can be a cost effective intervention. TRIAL REGISTRATION: ClinicalTrials.gov NCT01386840, registered 25th June 2011 and the Indian Council of Medical Research REFCTRI/2010/000629. PMID- 26577944 TI - Reduction in deep sternal wound infection with use of a peristernal cable-tie closure system: a retrospective case series. AB - BACKGROUND: Deep sternal wound infections are a rare but serious complication after median sternotomy. We evaluated the incidence of deep sternal wound infection associated with two techniques for sternal closure. METHODS: In this retrospective case series, we recorded the method of sternal closure in consecutive patients undergoing a variety of cardiothoracic surgical procedures. Sternal closure in the historical control group was performed using trans sternal, stainless-steel wire sutures; subsequent patients were closed using wire sutures in conjunction with a novel, peristernal cable-tie closure system to reinforce the corpus sterni. Perioperative care was standardized between groups. Demographics, risk factors, and postoperative outcomes were analyzed. RESULTS: Between July 2010 and July 2014, 609 consecutive adult patients underwent sternal closure following open median sternotomy at a single hospital in Mobile, Alabama. Sternal closure was accomplished with wire sutures in the first 309 patients and with cable-tie reinforcement in the subsequent 300 patients. Baseline characteristics were comparable between groups, except that the cable-tie group exhibited greater preoperative comorbidity. Mean body mass index was comparable between groups (30.2 +/- 6.6 kg/m(2) wire suture versus 30.5 +/- 7.7 cable-tie, p = 0.568). Deep sternal wound infection occurred in 2.6 % (8/309) patients in the wire-suture group, whereas no deep sternal wound infections were observed in the cable tie group (p = 0.008). CONCLUSIONS: The peristernal cable-tie system was a simple and reliable method for sternal closure after open median sternotomy, and was associated with a reduced risk of deep sternal wound infection, even in an obese and comorbid population. PMID- 26577945 TI - Is RANKL inhibition both anti-resorptive and anabolic in rheumatoid arthritis? AB - A small peptide, OP3-4, blocks receptor activator of NF-kappaB from binding to its ligand, receptor activator of NF-kappaB ligand (RANKL), and was reported recently to inhibit bone resorption, promote bone formation and protect cartilage in a preclinical rheumatoid arthritis model. The latter effects may result from inhibition of RANKL reverse signalling in osteoblasts and chondrocytes. Whether other RANKL inhibitors, such as denosumab, share this action is not known, but OP3-4 at least has potential to provide anabolic treatment for both systemic and focal bone loss in inflammatory arthritis. PMID- 26577946 TI - Serum Amyloid P-Component Prevents Cardiac Remodeling in Hypertensive Heart Disease. AB - The potential for serum amyloid P-component (SAP) to prevent cardiac remodeling and identify worsening diastolic dysfunction (DD) was investigated. The anti fibrotic potential of SAP was tested in an animal model of hypertensive heart disease (spontaneously hypertensive rats treated with SAP [SHR - SAP] * 12 weeks). Biomarker analysis included a prospective study of 60 patients with asymptomatic progressive DD. Compared with vehicle-treated Wistar-Kyoto rats (WKY V), the vehicle-treated SHRs (SHR-V) exhibited significant increases in left ventricular mass, perivascular collagen, cardiomyocyte size, and macrophage infiltration. SAP administration was associated with significantly lower left ventricular mass (p < 0.01), perivascular collagen (p < 0.01), and cardiomyocyte size (p < 0.01). Macrophage infiltration was significantly attenuated in the SHR SAP group. Biomarker analysis showed significant decreases in SAP concentration over time in patients with progressive DD (p < 0.05). Our results indicate that SAP prevents cardiac remodeling by inhibiting recruitment of pro-fibrotic macrophages and that depleted SAP levels identify patients with advancing DD suggesting a role for SAP therapy. PMID- 26577947 TI - Large-scale developing of simple sequence repeat markers and probing its correlation with ramie (Boehmeria nivea L.) fiber quality. AB - Marker-assisted selection is an important component of the discipline of molecular breeding. Using DNA markers to assist in plant breeding, the efficiency and precision could be greatly increased. However, the scarcity number of identified DNA markers has hindered the research and the breeding process of ramie (Boehmeria nivea L.) in many aspects, especially fiber quality, one of the top-priority breeding objectives of ramie. In this study, 4230 SSR loci were identified in 3969 unigenes (6.80 % of 58,369), which were de novo assembled from the transcriptome involving different ramie fiber developmental stages. Among these SSRs, the dinucleotides (1599, 37.80 %) and trinucleotides (772, 18.25 %) were most abundant; the motifs AG/CT (1140, 26.94 %), AT/AT (407, 9.62 %) and AGA/TCT (246, 8.31 %) comprised the three most abundant repeats. A total of 2431 primer pairs were designed flanking the SSRs and 1050 of them were employed in PCR amplification for their usefulness using three ramie cultivars. The results showed that 88.10 % of these primers could generate positive PCR bands in any of the three cultivars. Further phylogenetic analysis that conducted from the PCR amplification of 52 specifically sifted SSR primers within 17 cultivars approved that the possible correlation may exist between the primers and ramie fiber quality. These developed SSR markers could be applied in downstream studies, like genetic and physical maps, quantitative trait loci mapping, genetic diversity studies and cultivar fingerprinting, and breeding processes of ramie with better fiber quality under further confirmation of the correlation with ramie fiber quality. PMID- 26577948 TI - The AP-3 adaptor complex mediates sorting of yeast and mammalian PQ-loop-family basic amino acid transporters to the vacuolar/lysosomal membrane. AB - The limiting membrane of lysosomes in animal cells and that of the vacuole in yeast include a wide variety of transporters, but little is known about how these proteins reach their destination membrane. The mammalian PQLC2 protein catalyzes efflux of basic amino acids from the lysosome, and the similar Ypq1, -2, and -3 proteins of yeast perform an equivalent function at the vacuole. We here show that the Ypq proteins are delivered to the vacuolar membrane via the alkaline phosphatase (ALP) trafficking pathway, which requires the AP-3 adaptor complex. When traffic via this pathway is deficient, the Ypq proteins pass through endosomes from where Ypq1 and Ypq2 properly reach the vacuolar membrane whereas Ypq3 is missorted to the vacuolar lumen via the multivesicular body pathway. When produced in yeast, PQLC2 also reaches the vacuolar membrane via the ALP pathway, but tends to sort to the vacuolar lumen if AP-3 is defective. Finally, in HeLa cells, inhibiting the synthesis of an AP-3 subunit also impairs sorting of PQLC2 to lysosomes. Our results suggest the existence of a conserved AP-3-dependent trafficking pathway for proper delivery of basic amino acid exporters to the yeast vacuole and to lysosomes of human cells. PMID- 26577949 TI - Is preoperative MRCP necessary for patients with gallstones? An analysis of the factors related to missed diagnosis of choledocholithiasis by preoperative ultrasound. AB - BACKGROUND: The diagnosis of associated choledocholithiasis prior to cholecystectomy for patients with gallstones is important for the surgical decision and treatment efficacy. However, whether ultrasound is sufficient for preoperative diagnosis of choledocholithiasis remains controversial, with different opinions on whether routine magnetic resonance cholangiopancreatography (MRCP) is needed to detect the possible presence of common bile duct (CBD) stones. METHODS: In this study, a total of 413 patients with gallstones who were admitted to the Department of General Surgery of the First Affiliated Hospital of Harbin Medical University in China for a period of 3 years and underwent both ultrasound and MRCP examinations were retrospectively analysed. After reviewing and screening these cases according to the literature, 11 indicators including gender, age, alanine aminotransferase, aspartate aminotransferase, total bilirubin, direct bilirubin, indirect bilirubin, alkaline phosphatase, gamma aminotransferase, CBD diameter, and concurrent acute cholecystitis were selected and comparatively analysed. RESULTS: Among the 413 patients, a total of 109 cases showed concurrent gallstones and choledocholithiasis, accounting for 26.39 % of all cases. Among them, 60 cases of choledocholithiasis were revealed by ultrasound examination, accounting for 55.05 %, while 49 cases of choledocholithiasis were not detected by ultrasound examination but were confirmed by MRCP instead (the missed diagnosis rate of ultrasound was 44.95 %). The results of statistical analysis suggested that alanine aminotransferase, acute cholecystitis, and CBD diameter were the three most relevant factors for missed diagnosis by ultrasound. CONCLUSION: The accuracy of preoperative ultrasonography for the diagnosis of associated CBD stones for patients with gallstones is not high. However, elevated alanine aminotransferase, concurrent acute cholecystitis, and CBD diameter were identified as key factors that may affect the accuracy of the diagnosis. Thus, routine preoperative MRCP examination is suggested for patients with gallstones to rule out possible concomitant CBD stones. PMID- 26577950 TI - Biological and clinical significance of loss of heterozygosity at the INPP4B gene locus in Japanese breast cancer. AB - PURPOSE: INPP4B is considered to function as a putative tumor suppressor through its inhibitory function of Akt. In various malignant tumors, loss of heterozygosity (LOH) at the chromosomal region containing INPP4B and lower expression of INPP4B has been reported. The purpose of this study was to examine the frequency of the INPP4B LOH and its association with the clinicopathological characteristics and prognosis in breast cancer of Japanese women. METHODS: The allelic alteration at the INPP4B and PTEN gene loci was analyzed in 277 invasive primary breast carcinomas. The relationships between INPP4B LOH and the clinicopathological features were investigated. RESULTS: Among the 238 informative cases for the evaluation, LOH at the INPP4B gene locus was observed in 43 tumors (18.1%). INPP4B LOH was significantly correlated with ER and PR negativity (p = 0.0009 and p = 0.0029, respectively), higher nuclear grade (p < 0.0001), higher Ki67 labeling index (p = 0.0006), triple-negative (TN) subtype (p = 0.0005) and PTEN LOH (p < 0.0001). INPP4B LOH was significantly associated with poorer prognosis, in terms of the relapse-free survival (RFS) and overall survival (OS). According to the multivariate analyses, INPP4B LOH was not independently associated with the prognosis. CONCLUSION: The incidence of INPP4B LOH was significantly higher in the TN subtype and positively correlated with PTEN LOH. INPP4B LOH was associated with more aggressive and proliferative phenotype. INPP4B LOH was also associated with poorer prognosis. PMID- 26577951 TI - When should surgeons retire? AB - BACKGROUND: Retirement policies for surgeons differ worldwide. A range of normal human functional abilities decline as part of the ageing process. As life expectancy and their population increases, the performance ability of ageing surgeons is now a growing concern in relation to patient care. The aim was to explore the effects of ageing on surgeons' performance, and to identify current practical methods for transitioning surgeons out of practice at the appropriate time and age. METHODS: A narrative review was performed in MEDLINE using the terms 'ageing' and 'surgeon'. Additional articles were hand-picked. Modified PRISMA guidelines informed the selection of articles for inclusion. Articles were included only if they explored age-related changes in brain biology and the effect of ageing on surgeons' performance. RESULTS: The literature search yielded 1811 articles; of these, 36 articles were included in the final review. Wide variation in ability was observed across ageing individuals (both surgical and lay). Considerable variation in the effects of the surgeon's age on patient mortality and postoperative complications was noted. A lack of neuroimaging research exploring the ageing of surgeons' brains specifically, and lack of real markers available for measuring surgical performance, both hinder further investigation. Standard retirement policies in accordance with age-related surgical ability are lacking in most countries around the world. CONCLUSION: Competence should be assessed at an individual level, focusing on functional ability over chronological age; this should inform retirement policies for surgeons. PMID- 26577952 TI - Role of shame and body esteem in cortisol stress responses. AB - Studies assessing the role of shame in HPA axis reactivity report mixed findings. Discrepancies may be due to methodological difficulties and inter-individual differences in the propensity to experience shame in a stressful situation. Hence, the current study combined self-report of shame and facial coding of shame expressions and assessed the role of body esteem as a moderator of the shame stress link. For this, 44 healthy students (24F, age 20.5 +/- 2.1 years) were exposed to an acute psychosocial stress paradigm (Trier Social Stress Test: TSST). Salivary cortisol levels were measured throughout the protocol. Trait shame was measured before the stress test, and state shame immediately afterwards. Video recordings of the TSST were coded to determine emotion expressions. State shame was neither associated with cortisol stress responses nor with body esteem (self-report: all ps >= .24; expression: all ps >= .31). In contrast, higher trait shame was associated with both negative body esteem (p = .049) and stronger cortisol stress responses (p = .013). Lastly, having lower body esteem predicted stronger cortisol stress responses (p = .022); however, it did not significantly moderate the association between shame indices and cortisol stress responses (all ps >= .94). These findings suggest that body esteem and trait shame independently contribute to strength of cortisol stress responses. Thus, in addition to trait shame, body esteem emerged as an important predictor of cortisol stress responses and as such, a potential contributor to stress related negative health outcomes. PMID- 26577953 TI - Results of a hypertension and diabetes treatment program in the slums of Nairobi: a retrospective cohort study. AB - BACKGROUND: Cardiovascular diseases (CVD) are the world's leading cause of death and their prevalence is rising. Diabetes and hypertension, major risk factors for CVD, are highly prevalent among the urban poor in Africa, but treatment options are often limited in such settings. This study reports on the results of an intervention for the treatment of diabetes and hypertension for adult residents of two slums in Nairobi, Kenya. METHODS: After setting up two clinics in two slums in Nairobi, hypertension and/or diabetes patients were seen by a clinician monthly. Socio-demographic characteristics and clinical data were collected over a 34-month period. Records were analyzed for 726 patients who visited the clinics at least once to determine clinic attendance and compliance patterns using survival analysis. We also examined changes in systolic blood pressure (SBP), diastolic blood pressure (DBP) and random blood glucose (RBG) during the course of the program. RESULTS: There was poor compliance with clinic attendance as only 3.4% of patients attended the clinics on a regular (monthly) basis throughout the 34-month period. 75% of hypertension patients were not compliant after four visits and 27% of patients had only one clinic visit. Significant reduction of mean SBP and DBP (150.4 mmHg to 141.5 mmHg, P = .003, and 89.3 mmHg to 83.2 mmHg, P < .001) was seen for all patients that stayed in care for at least one year. CONCLUSIONS: Establishing a preventative care and treatment system in low resource settings for CVD is challenging due to high dropout rates and non compliance. Innovative strategies are needed to ensure that benefits of treatment programs are sustained for long-term CVD risk reduction in poor urban populations. PMID- 26577954 TI - New evidence for hybrid zones of forest and savanna elephants in Central and West Africa. AB - The African elephant consists of forest and savanna subspecies. Both subspecies are highly endangered due to severe poaching and habitat loss, and knowledge of their population structure is vital to their conservation. Previous studies have demonstrated marked genetic and morphological differences between forest and savanna elephants, and despite extensive sampling, genetic evidence of hybridization between them has been restricted largely to a few hybrids in the Garamba region of northeastern Democratic Republic of Congo (DRC). Here, we present new genetic data on hybridization from previously unsampled areas of Africa. Novel statistical methods applied to these data identify 46 hybrid samples--many more than have been previously identified--only two of which are from the Garamba region. The remaining 44 are from three other geographically distinct locations: a major hybrid zone along the border of the DRC and Uganda, a second potential hybrid zone in Central African Republic and a smaller fraction of hybrids in the Pendjari-Arli complex of West Africa. Most of the hybrids show evidence of interbreeding over more than one generation, demonstrating that hybrids are fertile. Mitochondrial and Y chromosome data demonstrate that the hybridization is bidirectional, involving males and females from both subspecies. We hypothesize that the hybrid zones may have been facilitated by poaching and habitat modification. The localized geography and rarity of hybrid zones, their possible facilitation from human pressures, and the high divergence and genetic distinctness of forest and savanna elephants throughout their ranges, are consistent with calls for separate species classification. PMID- 26577955 TI - The enhanced expression of death receptor 5 (DR5) mediated by HBV X protein through NF-kappaB pathway is associated with cell apoptosis induced by (TNF-alpha related apoptosis inducing ligand) TRAIL in hepatoma cells. AB - BACKGROUND: HBV X protein (HBX) is associated with cell apoptosis mediated by TNF alpha related apoptosis inducing ligand (TRAIL), while the role of HBX on the expressions of TRAIL receptors death receptor 4 (DR4) and DR5 are unclear. In this study, we detected the cell apoptosis induced by TRAIL as well as gene and protein expressions of DR4 and DR5 in Huh-7 cells steadily transfected with HBX (Huh-7-HBX cells). In addition, we investigated the activation of different pathways associated with the expressions of TRAIL receptors in Huh-7-HBX cells. METHODS: The apoptosis of Huh-7-HBX cells induced by TRAIL was evaluated by flow cytometry analysis. The levels of DR4 and DR5 expression in cells were determined by real-time PCR and western blotting analysis. The activities of JNK pathway and NF-kappaB (NF-kappaB) pathway were demonstrated by western blotting assay. RESULTS: Compared to control cells, the percentage of cell apoptosis was increased in Huh-7-HBX cells. The increased expressions of DR4 and DR5 on gene and protein levels were observed in Huh-7-HBX cells. Further researches suggested that activation of JNK pathway was increased but not involved in the expression of TRAIL receptors in HBX positive cells. The activation of NF-kappaB pathway increased and was responsible for DR5 expression and cell apoptosis in HBX positive cells. CONCLUSIONS: These results demonstrate that increased apoptosis induced by TRAIL is associated with increased expression of DR5 that mediated by HBX through NF-kappaB pathway. This finding provides a critical insight into the mechanism of hepatocyte apoptosis mediated by HBX in HBV infection. PMID- 26577956 TI - Secukinumab for treating plaque psoriasis. AB - INTRODUCTION: Plaque psoriasis is a chronic inflammatory disease that can result in significant physical, psychological and quality of life impairments. Until recently, biologic treatment for psoriasis was limited to tumor necrosis factor alpha inhibitors and an interleukin (IL)-12/23 p40 subunit inhibitor. Newly developed biologics targeting the pro-inflammatory IL-17A cytokine have shown success in providing higher levels of clinical efficacy in patients with psoriasis. Secukinumab, a member of this novel class of IL-17 inhibitors, is the latest biologic to receive US FDA approval for the treatment of moderate-to severe plaque psoriasis. AREAS COVERED: This comprehensive review will cover the pharmacology, efficacy, safety and future role of secukinumab and other IL-17 blockers in the treatment of plaque psoriasis. EXPERT OPINION: While biologics have revolutionized patient care for chronic plaque psoriasis, they are associated with loss of response over time. When treatment failure occurs with existing biologics, physicians are left with few alternative treatment options to offer patients. The introduction of secukinumab has provided an additional therapeutic agent that offers improved skin clearance, better health related quality of life and a favorable side-effect profile. PMID- 26577957 TI - The application of HPLC-MS/MS to studies of pharmacokinetics and interconversion of isoliquiritigenin and neoisoliquiritigenin in rats. AB - A specific and sensitive HPLC-MS/MS method was developed and validated for the simultaneously quantification of isoliquiritigenin (ISL) and neoisoliquiritin (NIS) in rat plasma by oral administration. Analytes were analyzed on an Agilent 6460 LC-MS/MS system (Agilent, USA) using an Agilent Zorbax SB-C18 column (4.6 * 150 mm, 5 MUm). Gradient elution was applied for the analyte separation using a mobile phase composed of 0.1% formic acid aqueous solution and methanol at a flow rate of 1.0 mL/min with a total running time of 12 min. The calibration curves for ISL and NIS showed good linearity in the concentrations ranging from 0.001 to 4.000 MUg/mL with correlation coefficients >0.998. The precision, accuracy, recovery and stability were deemed acceptable. The method was applied to the pharmacokinetics study of ISL and NIS in rats by single and combination administration. The result showed that Cmax and AUC0->t of ISL were markedly increased from 0.53 to 1.20 MUg/mL, and from 69.63 to 200.74 min MUg/mL by combination administration. The mean t1/2 value was also prolonged from 64.55 to 203.74 min in the combination group. These results indicated that NIS may have been metabolized to ISL which increased the absorption and extended the elimination of ISL. However, little difference was found for NIS pharmacokinetics parameters between single NIS and the combination group, which suggested that there was no significant biotransformation of ISL to NIS. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26577958 TI - Comparison on thermal transport properties of graphene and phosphorene nanoribbons. AB - We investigate ballistic thermal transport at low temperatures in graphene and phosphorene nanoribbons (PNRS) modulated with a double-cavity quantum structure. A comparative analysis for thermal transport in these two kinds of nanomaterials is made. The results show that the thermal conductance in PNRS is greater than that in graphene nanoribbons (GNRS). The ratio kG/kP (kG is the thermal conductivity in GNRS and kP is the thermal conductivity in PNRS) decreases with lower temperature or for narrower nanoribbons, and increases with higher temperature or for wider nanoribbons. The greater thermal conductance and thermal conductivity in PNRS originate from the lower cutoff frequencies of the acoustic modes. PMID- 26577959 TI - Pathogen Reduction Technology in Transfusion: Where Do We Stand? PMID- 26577960 TI - Micromechanical Intervention in Sandwich Restoration. AB - OBJECTIVE: To evaluate the sealing ability of two different types of Glass Ionomer Cements (GICs) used for sandwich restorations and assess the effect of acid etching of GIC on microleakage at GIC-resin composite interface. STUDY DESIGN: Experimental study. PLACE AND DURATION OF STUDY: Department of Operative, DIEKIOHS (DUHS) and NED University, Karachi, from February to June 2011. METHODOLOGY: Eighty cavities were prepared on the proximal surfaces of 40 permanent human premolars (2 cavities per tooth), assigned to 4 groups (n=20) and restored as follows: Group CIE - Conventional GIC (CI) was applied onto the axial and cervical cavity walls, allowed setting for 5 minutes and acid etched (E) along the cavity margins with 37% phosphoric acid for 15 seconds, washed for 30 seconds and dried; the adhesive system was applied and light cured for 10 seconds, completing the restoration with composite resin light cured for 40 seconds; Group CIN - same as Group CIE, except for acid etching of the CI surface; Group RME - same as CIE, but using a resin modified GIC (RMGIC); Group RMN - same as Group RME, except for acid etching of the RMGIC surface. Specimens were soaked in 1% methylene blue dye solution at 37ºC for 24 hours, rinsed under running water for 15 minutes, bisected mesiodistally and dye penetration was measured following the ISO/TS 11405-2003 standard. Kruskal Wallis and post Hoc tests significant differences in the microleakage among all the four groups. RESULTS: There was a significant difference between the two groups of GICs (RMGIC and CI, p=0.001). There was no significant difference in between the two sub groups that is between CIN and CIE (p=0.656), and between Groups RME and RMN (p=0.995). CONCLUSION: Phosphoric acid etching of GIC, prior to the placement of composite resin, does not improve the sealing ability of sandwich restorations. RMGIC was more effective in preventing dye penetration at the GIC-resin composite dentine interfaces than CI. PMID- 26577961 TI - Diffusion-weighted MR Imaging and ADC Mapping in Differentiating Benign from Malignant Thyroid Nodules. AB - OBJECTIVE: To determine the diagnostic accuracy of Diffusion-Weighted Imaging (DWI) and Apparent Diffusion Coefficient (ADC) mapping in differentiating benign from malignant thyroid nodules by taking histopathology as the gold standard. STUDY DESIGN: Across-sectional analytical study. PLACE AND DURATION OF STUDY: Department of Radiology at Combined Military Hospital (CMH), Lahore, from August 2012 to July 2013. METHODOLOGY: Thirty-five patients, who were referred to radiology department of CMH, Lahore, for ultrasound or Fine Needle Aspiration Cytology (FNAC) of thyroid gland, fulfilling the inclusion and exclusion criteria, were included in the study. They were evaluated on 1.5 Tesla MRI machine with T1- and T2-weighted imaging as well as fat-suppressed technique. DWI was done using b-values of 0 and 1000 s/mm2and ADC values were calculated for the thyroid nodules. All of these patients were subjected to ultrasound guided core biopsy and histopathology results were correlated with ADC values. RESULTS: The benign nodules showed facilitated diffusion while malignant nodules showed restricted diffusion. T-test was used to assess the difference in mean ADC values between benign and malignant nodules. The mean ADC value of the malignant thyroid nodules (0.94 ±0.16 x 10-3mm2/s) was significantly lower than that of the benign thyroid nodules (1.93 ±0.13 x 10-3mm2/s) (p-value < 0.05). ADC value of 1.6 x 10-3mm2/s was used as a cut-off, for differentiating benign from malignant thyroid nodules. The sensitivity, specificity, PPV, NPV and diagnostic accuracy of DWI and ADC values in differentiating benign from malignant thyroid nodules were 93%, 95%, 93%, 95% and 92.3%, respectively. CONCLUSION: DWI is a non invasive diagnostic tool for characterization and differentiation between benign and malignant thyroid nodules. It not only decreases the burden of unnecessary surgeries when pre-operative FNAC and biopsy are inconclusive, but is also helpful in reaching a definite diagnosis when a nodule is not amendable to biopsy due to any reason. PMID- 26577962 TI - Comparison of Negative Pressure Wound Therapy Using Vacuum-Assisted Closure with Advanced Moist Wound Therapy in the Treatment of Diabetic Foot Ulcers. AB - OBJECTIVE: To evaluate the clinical efficacy of Negative Pressure Wound Therapy (NPWT) using Vacuum Assisted Closure (VAC) compared with Advanced Moist Wound Therapy (AMWT) to treat Diabetic Foot Ulcer (DFU). STUDY DESIGN: Randomized control trial. PLACE AND DURATION OF STUDY: Surgical Department, Combined Military Hospital (CMH) / Military Hospital (MH), Rawalpindi, from November 2010 to June 2012. METHODOLOGY: The study consisted of 278 patients, with 139 patients each in Group 'A' and 'B', who were subjected to AMWT and NPWT, respectively. Wound was assessed digitally every week for 2 weeks. Wound dimension and surface area were determined using University of Texas Health Centre at San Antonio (UTHCSA) image tool version 3.0. Efficacies of AMWT and NPWT were compared in terms of reduction in wound area over 2 weeks. RESULTS: Mean age of presentation in group A was 55.88 +/- 10.97 years while in group B, it was 56.83 +/- 11.3 (p=0.48). Mean duration of diabetes at presentation was 15.65 +/- 4.86 and 15.96 +/- 5.79 years in group A and B, respectively (p=0.74). Majority of patients had Wagner's grade 2 ulcer (82% in group A and 87.8% in group B, p= 0.18). Initial wound size in group A was 15.07 +/- 2.92 cm2 and in group B 15.09 +/- 2.81 cm2 (p = 0.95). Wound size measured after 2 weeks, treatment was in group A13.70 +/- 2.92 cm2 and in group B 11.53 +/- 2.78 cm2 (p < 0.001). Wound area reduction in both groups revealed statistically significant faster healing in group B as compared to group A (p < 0.001). CONCLUSION: NPWT using VAC was more efficacious than AMWT in the management of diabetic foot ulcers. PMID- 26577963 TI - Spectrum of Histopathological Findings in Postmenopausal Bleeding. AB - OBJECTIVE: To determine the frequencies of histopathological findings in endometrial and endocervical biopsy samples with clinical history of Postmenopausal Bleeding (PMB). STUDY DESIGN: Descriptive cross-sectional study. PLACE AND DURATION OF STUDY: Section of Histopathology, Department of Pathology and Laboratory Medicine, The Aga Khan University Hospital, Karachi, from February 2012 to January 2013. METHODOLOGY: A total of 157 consecutive endometrial and endocervical biopsy specimens with history of postmenopausal bleeding were included. After microscopic examination, frequencies of histological findings in different age groups were generated. Chi-square and independent sample t-tests were applied to see whether the difference was significant which was set at p < 0.05. RESULTS: One hundred and twenty-one (77.1%) specimens showed benign pathologies while 36 (22.9%) were malignant. Endometrial polyp was seen in 67 (42.7%) cases followed by endometrial carcinomas in 25 (15.9%), endometrial hyperplasia in 21 (13.4%), cervical carcinoma in 12 (7.6%) and cervical polyps in 9 (5.7%) cases. A highly significant increase in the percentage of malignant and pre-malignant lesions was seen with increasing age group (p < 0.001). Mean age of patients with type-2 endometrial carcinoma was higher than type-1 endometrial carcinoma but statistical significance was not observed (70.2 +/-6.5 vs. 61.8 +/ 9.1 years respectively, p=0.069). CONCLUSION: Although benign pathologies were more common in postmenopausal bleeding but the collective proportion of endometrial and cervical malignancies and pre-malignant conditions was quite high. Therefore, PMB should be urgently evaluated for cause and early commencement of treatment. PMID- 26577964 TI - Aneurysmal Subarachnoid Hemorrhage: Outcome of Aneurysm Clipping Versus Coiling in Anterior Circulation Aneurysm. AB - OBJECTIVE: To compare the neurological outcome of microsurgical clipping versus coiling in patients with anterior circulation aneurysm. STUDY DESIGN: Comparative study. PLACE AND DURATION OF STUDY: Department of Neurosurgery, Lahore General Hospital, Lahore, from January 2010 to December 2013. METHODOLOGY: Patients aged 14 - 60 years, with ruptured cerebral aneurysm of anterior circulation and World Federation of Neurosurgical Society (WFNS) grades 1, 2 and 3 were included. Patients more than 60 years, medically unfit patient and posterior circulation aneurysms and WFNS grades 4 and 5 were excluded. Aneurysm sac obliteration was done in randomized manner with microsurgical clipping or coiling. Postoperatively, the patients were assessed and followed-up upto one year for outcome parameters on the bases of WFNS grade and Modified Ranking Scale (mRS) as favourable (mRS <=2 ) and unfavourable (mRS > 2). RESULTS: Among 140 subjects selected for study, 70 were included in group A, i.e. coiling and other 70 were in group B, i.e. clipping. The median age of patients in group A was 52.5 +/- 10 years and in group B was 51.00 +/- 10 years. Overall, 56 (40%) males, 28 (60%) males in each group; and 84 (60%) females, 42 (60%) in each group were included. The male to female ratio in this study was 1:1.5. In group A, i.e. coiling, 27 (38.6%) patients had no disability (grades 1 and 2), 25 (35.7%) were slightly disabled (grade 3) and 18 (25.7%) had moderate disability (grade 4); whereas in group B, i.e. clipping group 23 (32.9%) patients had no disability (grades 1 and 2), 23 (32.9%) were slightly disabled (grade 3) and 24 (34.3%) had moderate disability (grade 4). At one year follow-up, in group A, favourable outcome was achieved in 56 (80%) of patients compared to 48 (68.6%) in group B; whilst, 14 (20%) patients in group Aand 22 (33.1%) in group B showed unfavourable outcome. Although mortality rate was higher in clipping (n=3, 4.3%) as compared to coiling (n=1, 1.4%), but was not statistically significant (p = 0.310). CONCLUSION: Endovascular coiling of anterior circulation aneurysms is safe and as effective and successful as aneurysm clipping and is less invasive also. PMID- 26577965 TI - Frequency and Severity of Acute Toxicity of Pelvic Radiotherapy for Gynecological Cancer. AB - OBJECTIVE: To determine the frequency and severity of acute toxicity of pelvic radiotherapy for gynecological cancer. STUDY DESIGN: A case series. PLACE AND DURATION OF STUDY: Department of Oncology, The Aga Khan University Hospital, Karachi, from March 2011 to June 2012. METHODOLOGY: A total of 99 patients with histologically proven uterine and cervical cancer, receiving radiation therapy, were enrolled into the study after informed consent on justification of inclusion and exclusion criteria. Patients were evaluated for the frequency and severity of pelvic radiotherapy's side effects according to toxicity criteria based on RTOG/EORTC and CTC version 2 criteria at the start, during and at the end of treatment. The data was analyzed by using SPSS version 16. RESULTS: Out of the 99 enrolled patients, 58 (58.6%) had uterine and 41 (41.4%) had cervical cancer. Mean age was 54.54 +/- 10.29 years. Thirty-five (35.4%) patients received chemotherapy with RT. Mean RT dose was 60.72 +/- 7.15 Gy. The most common gastrointestinal adverse effect was diarrhea in 64 (64.6%) followed by proctitis in 55 (55.5%), nausea in 33 (33.3%) and vomiting in 16 (16.2%) patients. Grade (G) 1 was the most frequently observed severity. The most common hematological toxicity was anemia in 37.8% (n=31/82) {(G1=18 (21.9%), G2=11 (13.4%), G3=2 (2.4%)} followed by thrombocytopenia in 22.8% (21/92) {(G1=16 (17.3%), G2=2 (2.1%), G3=3 (3.2%)} and neutropenia in 21 (21.2%) {(G1=12 (12.1%), G2=5 (5%), G3=3 (3%), G4=1 (1%)}. Urinary toxicity was observed in 49 (49.5%) patients. On stratification, chemotherapy and higher RT dose were strong predictor of increased hematological and upper gastrointestinal toxicity (p < 0.05) and age > 60 years for diarrhea (p < 0.05). CONCLUSION: The frequency and severity of acute toxicity of pelvic radiotherapy in women with gynecologic cancers was found intermediate to high. PMID- 26577966 TI - Changes in Central Corneal Thickness and Endothelial Cell Count Following Pediatric Cataract Surgery. AB - OBJECTIVE: To evaluate the mean changes in Central Corneal Thickness (CCT) and Endothelial Cell Count (ECC) in eyes after pediatric cataract surgery with foldable intraocular lens using scleral tunnel incision micro-surgical technique. STUDY DESIGN: Qausi experimental study. PLACE AND DURATION OF STUDY: Department of Pediatric Ophthalmology and Strabismus, Al-Shifa Trust Eye Hospital, Rawalpindi, from May 2011 to March 2012. METHODOLOGY: Fifty-two eyes of 37 children with pediatric cataract were included in the study. Extracapsular Cataract Extraction (ECE) with foldable Intra Ocular Lens (IOL) implantation using sclera tunnel incision was performed in all children. Endothelial Cell Count (ECC) and Central Corneal Thickness (CCT) were recorded before surgery and 1 month, 3 months and 6 months after surgery and the effect of currently practiced surgical technique on ECC and CCT was evaluated. RESULTS: The mean age at the time of surgery was 8.8 +/-2.7 years (range: 4 to 15 years). The postoperative ECC and CCT were significantly different from the pre-operative values. Mean pre-operative ECC was 3175.3 +/-218.4 cell/mm2 and in first postoperative month the mean ECC was 3113.4 +/-210.8 cell/mm2(p<0.0001). In the 3rd and 6th month postoperative means ECC were 3052 +/-202.5 cell/mm2(p<0.0001) and 3015 +/-190.6 cell/mm2(p<0.0001), respectively. The mean cell loss at first postoperative month was 1.95% and at 3rd and 6th postoperative month were 3.9% and 5.05%, respectively. Mean pre-operative CCT was 514 +/-49.9 um and first postoperative mean CCT after 1 month was 524.1 +/-25 um (p = 0.084). After the 3rd and 6th months postoperative, mean CCT were 527.3 +/-24.6 um, and 530 +/-24.5 um, respectively. Third and 6th months postoperative means were significantly higher than baseline CCT, p = 0.024 and 0.007, respectively. CONCLUSION: Endothelial cell loss with closed chamber micro-surgical technique using scleral tunnel incision is within acceptable limits and within the range of normal ECC in children. PMID- 26577967 TI - Comparison of Intercanine and Intermolar Width Between Cleft Lip Palate and Normal Class I Occlusion Group. AB - OBJECTIVE: To determine the mean difference of arch dimensions (both intercanine and intermolar width) between cleft lip palate and normal class I occlusion group. STUDY DESIGN: Cross-sectional analytic study. PLACE AND DURATION OF STUDY: Dr. Ishrat-ul-Ebad Khan Institute of Oral Health Sciences, [Dow University of Health Sciences (DUHS)], Karachi, from March 2012 to April 2013. METHODOLOGY: Group 1 consisted of 32 subjects with complete repaired, non-syndromic unilateral and bilateral cleft lip palate. Group 2 consisted of 32 subjects with normal facial morphology and class I occlusion. Exclusion criteria were cleft lip palate subjects with systemic diseases, any arch expansion procedure, incomplete repaired palate, open fistulas, developmental or acquired craniofacial muscular deformities, autoimmune conditions, syndromes, endocrine abnormalities, neurological problems, or previous history of orthodontic treatment and signs and symptoms of temporomandibular disorders, history of trauma, impacted or missing teeth, periodontally involved teeth, subdivision molar classification, skeletal base II and III with molar class I. The transverse width (intercanine and intermolar width) of dental casts was measured with the help of digital caliper. The intercanine width was measured between cusp tips of the canine while the intermolar width distance was measured between mesiobuccal cusp tips of first molars, and buccal grooves of the mandibular first molars in both cleft lip palate and normal class I occlusion group, respectively. RESULTS: There were 64 subjects with mean 14.7 ±6.8 years in the cleft palate and 14.7 ±6.3 years in the normal group. There was statistically significant differences found between intercanine and intermolar width in maxillary arch (p < 0.001). In mandibular arch, only intercanine width has showed significant difference (p < 0.001) between cleft and normal occlusion class I group. CONCLUSION: Maxillary and mandibular intercanine width was found to be significantly reduced in cleft lip palate group (both unilateral and bilateral) as compared to normal class I occlusion group. PMID- 26577968 TI - Constipation in Pediatric Patients with Lower Urinary Tract Symptoms. AB - OBJECTIVE: To determine the frequency of constipation in patients with pediatric age group presenting with Lower Urinary Tract Symptoms (LUTS). STUDY DESIGN: Descriptive study. PLACE AND DURATION OF STUDY: Outpatient Department of Urology in Pakistan Kidney Institute at Shifa International Hospital, Islamabad, from November 2012 to February 2014. METHODOLOGY: Two hundred pediatric patients presenting with Lower Urinary Tract Symptoms (LUTS) were studied in terms of age, gender, obstructive and irritative types of LUTS along with any associated symptoms. Constipation was assessed by Bristol stool chart in these patients. Patients with exstrophy of bladder were excluded from the study. Descriptive statistics were measured for both qualitative and quantitative variables. For qualitative variables like gender, presenting symptoms, constipation and stool types, percentages and frequencies were calculated. For quantitative variables like age, percentages / mean ±SD were calculated. RESULTS: Mean age was 6.87 ±3.64 years with a range of 2 - 14 years. Constipation was found in 37.5% of the pediatric patients with lower urinary tract symptoms. CONCLUSION: Constipation is frequent and overlooked problem in pediatric patients having urinary symptoms. Irritative lower urinary tract symptoms are more common. Children up to 5 years of age are the most common sufferers. Knowing the burden of constipation in such patients can help physicians in better treatment of such cases. PMID- 26577969 TI - Behavioral Benefits of Camel Milk in Subjects with Autism Spectrum Disorder. AB - OBJECTIVE: To investigate the possible therapeutic effects of camel milk on behavioral characteristics as an interventional strategy in autistic children. STUDY DESIGN: Double-blind, Randomized Clinical Trial (RCT). PLACE AND DURATION OF STUDY: Autism Research and Treatment Center, Al-Amodi Autism Research Chair, Department of Physiology, Faculty of Medicine, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia, from October 2012 to May 2013. METHODOLOGY: Changes in behavioral characteristics in 65 (boys=60, girls=5) children with autism (aged from 2 to 12 years) were assessed. The behavioral symptoms were evaluated by Childhood Autism Rating Scale (CARS), Social Responsiveness Scale (SRS), and Autism Treatment Evaluation Checklist (ATEC) before and after the 2 weeks of camel milk therapy. RESULTS: Significant differences were detected on Autism Spectrum Disorder (ASD) by CARS, SRS and ATEC scales, following 2 weeks of camel milk consumption, but not in the placebo group. CONCLUSION: The present study demonstrates that camel milk could be very promising therapeutic intervention in ASD. Further wide scale studies are strongly recommended. PMID- 26577970 TI - E. coli Resistance to Ciprofloxacin and Common Associated Factors. AB - OBJECTIVE: To determine the frequency of E. coli resistance to ciprofloxacin and common factors leading to it among patients presenting with urinary tract infection. STUDY DESIGN: Descriptive cross-sectional study. PLACE AND DURATION OF STUDY: Department of Medicine, Ayub Teaching Hospital, Abbottabad, from December 2011 to June 2012. METHODOLOGY: A total of 166 patients, > 18 years of age of both gender, who presented with features of UTI and had urine culture positive for E.coli were included in the study. The urine samples were further tested for ciprofloxacin resistance and the patients were further checked for the common factors leading to E.coli resistance to ciprofloxacin. RESULTS: Among 166 patients, 41 were male and 125 were female patients. Sixty-six (39.8%) E. coli isolates showed ciprofloxacin resistance. Male gender (p-value 0.001), previous history of recurrent UTI (p = 0.008, OR = 2.37), history of prior use of ciprofloxacin (p = 0.018, OR = 2.16) and history of catheterization (p = 0.005, OR = 4.80) were independent risk factors found in this study for the development of ciprofloxacin resistant UTIs. CONCLUSION: Ciprofloxacin resistance rates of E.coli were high at over 39.8%. The risk factors that affected the ciprofloxacin resistance rates of E.coli were prior use of ciprofloxacin, recurrent UTI, previous catheterization and male gender. Ciprofloxacin should be prescribed cautiously in patients with these risk factors and urine culture and sensitivity test should be performed for optimal treatment. PMID- 26577971 TI - Dengue-induced Acute Kidney Injury (DAKI): A Neglected and Fatal Complication of Dengue Viral Infection--A Systematic Review. AB - Dengue Viral Infection (DVI) imperils an estimated 2.5 billion people living in tropical and subtropical regions. World Health Organization (2011) guidelines also classified dengue as 'Expanded Dengue Syndrome' to incorporate wide spectrum of unusual manifestations of dengue infection affecting various organ systems - including liver, kidney, heart and brain. Renal involvements are least appreciated area of dengue infection, therefore, we systematically reviewed studies describing renal disorders in dengue infection, with emphasis on Acute Kidney Injury (AKI). The purpose of current review is to underscore clinicians’attention to this neglected intricacy of DVI. It suggests that dengue induced renal involvements vary from glomerulonephritis, nephrotic range proteinuria and AKI. We observed great disparity in incidence of AKI among dengue patients, based upon criteria used to define AKI. AKI among dengue patients was found to be associated with significant morbidity, mortality and longer hospitalization, adding financial burden to patients and healthcare system. Additionally, we identified several predictors of AKI in dengue patients including old age, obesity, severe dengue infection and concurrent bacterial or viral infection. Direct viral injury and deposition of antigen-antibody complex in glomerulus were found to be possible causes of renal disorders in dengue infection. Prior knowledge of clinico-laboratory characteristics and risk factors with early detection of AKI by using appropriate criteria would not only reduce morbidity and mortality but also decrease burden to patients and healthcare system. PMID- 26577972 TI - Modification of Cabrol Patch for Control of Aortic Root Bleeding. AB - Rate of bleeding following aortic root replacement is reported in upto 24% of cases. Bleeding significant enough to require re-operation is reported in upto 4% of cases. We performed a modification of Cabrol patch to control bleeding from complicated aortic root replacement procedure. We used a perigraft - right-atrial fistula technique to control bleeding from aortic root area using a bovine pericardial patch. Patient had an uneventful hospital course and was discharged on postoperative day 14. PMID- 26577973 TI - Postpancreatitis Abscess of Falciform Ligament: An Unusual Presentation. AB - Pathologies of the falciform ligament are extremely rare entities ranging from cyst and hematoma to abscess and gangrene. Intestinal obstruction, secondary to extensive falciform ligament abscess, has not been reported to date. On account of being rare, diseases of falciform ligament have perplexing presentations leading to unwanted delays in diagnosis and management. These may present with abdominal wall ecchymoses (Cullen's sign - pancreatitis, portal hypertension), an abdominal mass, features of abscess, intestinal obstruction or peritonitis. Abscess may be an indicator of underlying liver or biliary pathology. Appreciating these as important differentials while working up patients with similar features, would markedly reduce missed diagnoses and improve surgical management. We present the case of a 40-year Pakistani gentleman who had duodenal obstruction owing to the presence of falciform ligament abscess resulting from a rather ignored episode of pancreatitis, mimicking malignancy. PMID- 26577974 TI - Giant Acrochordon Arising from the Thigh. AB - Acrochordons commonly develop from skin on the neck and axillar region, but may be found on any region of body. Although some predisposing factors have been implicated, the definite etiology has yet to be determined. We report the case of a 46-year female patient who presented with a large mass lesion on the inner aspect of the thigh. She stated that the swelling had emerged some 20 years ago and had progressively grown since then. Magnetic resonance imaging revealed a solid lesion with no anatomic relationship with musculoskeletal structures. Taking into account the basal width of the lesion, spinal anesthesia was administered and the lesion was excised with an intact surgical border of approximately 1 cm. The resulting defect was primarily closed. Ahistopathologic examination led to the diagnosis of an acrochordon with a size of 20 x 14 cm. To the best of our knowledge, this is the largest acrochordon lesion with the widest base reported in the literature. PMID- 26577975 TI - Congenital Malaria: A Rare Entity. AB - Congenital malaria is the presence of malarial parasites in the blood of newborns. The disease is acquired from mother either during pregnancy or perinatally at the time of birth. Congenital malaria in an endemic area can present without an obvious history of fever and parasitaemia in both mother and her infant. A case of Plasmodium vivax malaria in a 6-week infant is documented. Infant presented with pallor, jaundice and massive spleen. Laboratory tests revealed anaemia, thrombocytopenia and bilirubinemia. Peripheral smear examination revealed parasitaemia. Points favoring transplacental transmission are first born child, the presence of relatively high parasite count, gametocytemia and massive spleen. Peripheral smear examination should be done in all hospitalized patients. Prevention of malaria should be considered in all pregnant patients. PMID- 26577976 TI - Laryngeal Fracture Caused by a Lacrosse Ball. AB - Neck injuries in lacrosse are rare and mostly involve the musculoskeletal system. The lacrosse ball is a solid rubber ball of approximately 20 cm in diameter and the fastest shot recorded in professional lacrosse is over 100 mph. Despite wearing full protection, the neck remains prone to blunt trauma by this ball. A 23-year man sustained a direct blow to his left neck by a lacrosse ball during play, resulting in immediate aphonia and stridor. CT scan confirmed a left thyroid lamina fracture. The patient was treated conservatively and his airway was monitored for 24 hours. He made a full recovery. It is important that lacrosse players should be aware of this potential injury and appropriate precautions should be taken to avoid this trauma. PMID- 26577977 TI - Intramuscular Haemangioma of Triceps Muscle. PMID- 26577978 TI - Carbonmonoxide Post-interval Syndrome. PMID- 26577979 TI - Conflicts and natural disaster management: a comparative study of flood control in the Republic of Korea and the United States. AB - The purpose of this research is to analyse the conflicts that arise among major stakeholders during the process of disaster management and to suggest policy recommendations for improving disaster management systems. It describes several important conflict cases that have occurred among major stakeholders, such as governments, private-sector entities, and non-governmental organisations, during natural disaster management. In addition, it probes the similarities and the differences between such conflicts in the Republic of Korea and the United States. The differences between them may originate from a range of factors, such as the disaster itself, cultural features, management practices, and government organisation. However, the conflicts also are very similar in some ways, as the motivations and the behaviour of stakeholders during a disaster are alike in both countries. Based on this comparison, the study presents some common and important implications for successful disaster management practices in Korea and the US, as well as in many other nations around the world. PMID- 26577980 TI - Progress of modern agricultural chemistry and future prospects. AB - Agriculture is facing an enormous challenge: it must ensure that enough high quality food is available to meet the needs of a continually growing population. Current and future agronomic production of food, feed, fuel and fibre requires innovative solutions for existing and future challenges, such as climate change, resistance to pests, increased regulatory demands, renewable raw materials or requirements resulting from food chain partnerships. Modern agricultural chemistry has to support farmers to manage these tasks. Today, the so-called 'side effects' of agrochemicals regarding yield and quality are gaining more importance. Agrochemical companies with a strong research and development focus will have the opportunity to shape the future of agriculture by delivering innovative integrated solutions. This review gives a comprehensive overview of the innovative products launched over the past 10 years and describes the progress of modern agricultural chemistry and its future prospects. PMID- 26577981 TI - Secretory component mediates Candida albicans binding to epithelial cells. AB - OBJECTIVES: Candida albicans attaches to oral surfaces via a number of mechanisms including adherence mediated by salivary components adsorbed to the C. albicans cell surface. Our goal was to identify the salivary molecules involved. MATERIALS AND METHODS: Biotinylated salivary polypeptides that were bound by C. albicans were detected in extracts from washed, saliva-treated yeast cells by polyacrylamide gel electrophoresis and electroblot or immunoblot transfer analysis and purified by electroelution. Purified material was tested for the ability to promote the adherence of radiolabelled C. albicans yeast cells to cultured epithelial monolayers. RESULTS: Three of the polypeptides bound by C. albicans cells were identified as components of secretory IgA, including secretory component. Using non-denaturing polyacrylamide gel electrophoresis, we demonstrated that secretory component could be detected in its free form in saliva, and was bound by yeast cells. Secretory component which was purified by electroelution from non-denaturing PAGE-separated saliva, without detectable complete IgA, promoted adherence of yeast cells to cultured epithelial monolayers in a dose-dependent fashion. CONCLUSION: These results indicate that despite the inhibitory effect on adherence of IgA specific to C. albicans, IgA components, in particular secretory component, also promote binding to cultured epithelial monolayers. PMID- 26577983 TI - Virus-like nanostructures for tuning immune response. AB - Synthetic vaccines utilize viral signatures to trigger immune responses. Although the immune responses raised against the biochemical signatures of viruses are well characterized, the mechanism of how they affect immune response in the context of physical signatures is not well studied. In this work, we investigated the ability of zero- and one-dimensional self-assembled peptide nanostructures carrying unmethylated CpG motifs (signature of viral DNA) for tuning immune response. These nanostructures represent the two most common viral shapes, spheres and rods. The nanofibrous structures were found to direct immune response towards Th1 phenotype, which is responsible for acting against intracellular pathogens such as viruses, to a greater extent than nanospheres and CpG ODN alone. In addition, nanofibers exhibited enhanced uptake into dendritic cells compared to nanospheres or the ODN itself. The chemical stability of the ODN against nuclease-mediated degradation was also observed to be enhanced when complexed with the peptide nanostructures. In vivo studies showed that nanofibers promoted antigen-specific IgG production over 10-fold better than CpG ODN alone. To the best of our knowledge, this is the first report showing the modulation of the nature of an immune response through the shape of the carrier system. PMID- 26577984 TI - Engineering serendipity: High-throughput discovery of materials that resist bacterial attachment. AB - Controlling the colonisation of materials by microorganisms is important in a wide range of industries and clinical settings. To date, the underlying mechanisms that govern the interactions of bacteria with material surfaces remain poorly understood, limiting the ab initio design and engineering of biomaterials to control bacterial attachment. Combinatorial approaches involving high throughput screening have emerged as key tools for identifying materials to control bacterial attachment. The hundreds of different materials assessed using these methods can be carried out with the aid of computational modelling. This approach can develop an understanding of the rules used to predict bacterial attachment to surfaces of non-toxic synthetic materials. Here we outline our view on the state of this field and the challenges and opportunities in this area for the coming years. STATEMENT OF SIGNIFICANCE: This opinion article on high throughput screening methods reflects one aspect of how the field of biomaterials research has developed and progressed. The piece takes the reader through key developments in biomaterials discovery, particularly focusing on need to reduce bacterial colonisation of surfaces. Such bacterial resistant surfaces are increasingly required in this age of antibiotic resistance. The influence and origin of high-throughput methods are discussed with insights into the future of biomaterials development where computational methods may drive materials development into new fertile areas of discovery. New biomaterials will exhibit responsiveness to adapt to the biological environment and promote better integration and reduced rejection or infection. PMID- 26577985 TI - 3D printed Ti6Al4V implant surface promotes bone maturation and retains a higher density of less aged osteocytes at the bone-implant interface. AB - For load-bearing orthopaedic applications, metal implants having an interconnected pore structure exhibit the potential to facilitate bone ingrowth and the possibility for reducing the stiffness mismatch between the implant and bone, thus eliminating stress-shielding effects. 3D printed solid and macro porous Ti6Al4V implants were evaluated after six-months healing in adult sheep femora. The ultrastructural composition of the bone-implant interface was investigated using Raman spectroscopy and electron microscopy, in a correlative manner. The mineral crystallinity and the mineral-to-matrix ratios of the interfacial tissue and the native bone were found to be similar. However, lower Ca/P ratios, lower carbonate content, but higher proline, phenylalanine and tyrosine levels indicated that the interfacial tissue remained less mature. Bone healing was more advanced at the porous implant surface (vs. the solid implant surface) based on the interfacial tissue nu1 CO3(2-)/nu2 PO4(3-) ratio, phenylalanine and tyrosine levels approaching those of the native bone. The mechanosensing infrastructure in bone, the osteocyte lacuno-canalicular network, retained ~40% more canaliculi per osteocyte lacuna, i.e., a 'less aged' morphology at the interface. The osteocyte density per mineralised surface area was ~36-71% higher at the interface after extended healing periods. STATEMENT OF SIGNIFICANCE: In osseointegration research, the success of an implant surface or design is commonly determined by quantifying the amount of new bone, rather than its maturation, composition and structure. This work describes a novel correlative methodology to investigate the ultrastructure and composition of bone formed around and within 3D printed Ti6Al4V implants having an interconnected open-pore structure. Raman spectroscopy demonstrates that the molecular composition of the interfacial tissue at different implant surfaces may vary, suggesting differences in the extent to which bone maturation occurs even after long-term healing. Bone maturation corresponded well with the structural parameters associated with remodelling kinetics, for example, the osteocyte density and the average number of canaliculi per osteocyte lacuna. PMID- 26577986 TI - An in vivo study on the metabolism and osteogenic activity of bioabsorbable Mg 1Sr alloy. AB - Previous studies indicated that local delivery of strontium effectively increased bone quality and formation around osseointegrating implants. Therefore, implant materials with long-lasting and controllable strontium release are avidly pursued. The central objective of the present study was to investigate the in vivo biocompatibility, metabolism and osteogenic activity of the bioabsorbable Mg 1Sr (wt.%, nominal composition) alloy for bone regeneration. The general corrosion rate of the alloy implant as a femoral fracture fixation device was 0.55+/-0.03mm.y(-1) (mean value+/-standard deviation) in New Zealand White rabbits which meet the bone implantation requirements and can be adjusted by material processing methods. All rabbits survived and the histological evaluation showed no abnormal physiology or diseases 16 weeks post-implantation. The degradation process of the alloy did not significantly alter 16 primary indexes of hematology, cardiac damage, inflammation, hepatic functions and metabolic process. Significant increases in peri-implant bone volume and direct bone-to implant contact (48.3%+/-15.3% and 15.9%+/-5.6%, respectively) as well as the expressions of four osteogenesis related genes (runt-related transcription factor 2, alkaline phosphatase, osteocalcin, and collagen, type I, alpha 1) were observed after 16 weeks implantation for the Mg-1Sr group when compared to the pure Mg group. The sound osteogenic properties of the Mg-1Sr alloy by long lasting and controllable Sr release suggesting a very attractive clinical potential. STATEMENT OF SIGNIFICANCE: Sr (strontium) has exhibited pronounced effects to reduce the bone fracture risk in osteoporotic patients. Nonetheless, long-lasting local Sr release is hardly achieved by traditional methods like surface treatment. Therefore, a more efficient Sr local delivery platform is in high clinical demand. The stable and adjustable degradation process of Mg alloy makes it an ideal Sr delivery platform. We combine the well-known osteogenic properties of strontium with magnesium to manufacture bioabsorbable Mg-1Sr alloy with stable Sr release based on our previous studies. The in vitro and in vivo results both showed the alloy's suitable degradation rate and biocompatibility, and the sound osteogenic properties and stimulation effect on bone formation suggest its very attractive clinical potential. PMID- 26577987 TI - Mechanical restoration and failure analyses of a hydrogel and scaffold composite strategy for annulus fibrosus repair. AB - Unrepaired defects in the annulus fibrosus of intervertebral disks are associated with degeneration and persistent back pain. A clinical need exists for a disk repair strategy that can seal annular defects, be easily delivered during surgical procedures, and restore biomechanics with low risk of herniation. Multiple annulus repair strategies were developed using poly(trimethylene carbonate) scaffolds optimized for cell delivery, polyurethane membranes designed to prevent herniation, and fibrin-genipin adhesive tuned to annulus fibrosus shear properties. This three-part study evaluated repair strategies for biomechanical restoration, herniation risk and failure mode in torsion, bending and compression at physiological and hyper-physiological loads using a bovine injury model. Fibrin-genipin hydrogel restored some torsional stiffness, bending ROM and disk height loss, with negligible herniation risk and failure was observed histologically at the fibrin-genipin mid-substance following rigorous loading. Scaffold-based repairs partially restored biomechanics, but had high herniation risk even when stabilized with sutured membranes and failure was observed histologically at the interface between scaffold and fibrin-genipin adhesive. Fibrin-genipin was the simplest annulus fibrosus repair solution evaluated that involved an easily deliverable adhesive that filled irregularly shaped annular defects and partially restored disk biomechanics with low herniation risk, suggesting further evaluation for disk repair may be warranted. STATEMENT OF SIGNIFICANCE: Lower back pain is the leading cause of global disability and commonly caused by defects and failure of intervertebral disk tissues resulting in herniation and compression of adjacent nerves. Annulus fibrosus repair materials and techniques have not been successful due to the challenging mechanical and chemical microenvironment and the needs to restore biomechanical behaviors and promote healing with negligible herniation risk while being delivered during surgical procedures. This work addressed this challenging biomaterial and clinical problem using novel materials including an adhesive hydrogel, a scaffold capable of cell delivery, and a membrane to prevent herniation. Composite repair strategies were evaluated and optimized in quantitative three-part study that rigorously evaluated disk repair and provided a framework for evaluating alternate repair techniques. PMID- 26577988 TI - Crosslinking of extracellular matrix scaffolds derived from pluripotent stem cell aggregates modulates neural differentiation. AB - At various developmental stages, pluripotent stem cells (PSCs) and their progeny secrete a large amount of extracellular matrices (ECMs) which could interact with regulatory growth factors to modulate stem cell lineage commitment. ECMs derived from PSC can be used as unique scaffolds that provide broad signaling capacities to mediate cellular differentiation. However, the rapid degradation of ECMs can impact their applications as the scaffolds for in vitro cell expansion and in vivo transplantation. To address this issue, this study investigated the effects of crosslinking on the ECMs derived from embryonic stem cells (ESCs) and the regulatory capacity of the crosslinked ECMs on the proliferation and differentiation of reseeded ESC-derived neural progenitor cells (NPCs). To create different biological cues, undifferentiated aggregates, spontaneous embryoid bodies, and ESC-derived NPC aggregates were decellularized. The derived ECMs were crosslinked using genipin or glutaraldehyde to enhance the scaffold stability. ESC-derived NPC aggregates were reseeded on different ECM scaffolds and differential cellular compositions of neural progenitors, neurons, and glial cells were observed. The results indicate that ESC-derived ECM scaffolds affect neural differentiation through intrinsic biological cues and biophysical properties. These scaffolds have potential for in vitro cell culture and in vivo tissue regeneration study. STATEMENT OF SIGNIFICANCE: Dynamic interactions of acellular extracellular matrices and stem cells are critical for lineage-specific commitment and tissue regeneration. Understanding the synergistic effects of biochemical, biological, and biophysical properties of acellular matrices would facilitate scaffold design and the functional regulation of stem cells. The present study assessed the influence of crosslinked embryonic stem cell-derived extracellular matrix on neural differentiation and revealed the synergistic interactions of various matrix properties. While embryonic stem cell-derived matrices have been assessed as tissue engineering scaffolds, the impact of crosslinking on the embryonic stem cell-derived matrices to modulate neural differentiation has not been studied. The results from this study provide novel knowledge on the interface of embryonic stem cell-derived extracellular matrix and neural aggregates. The findings reported in this manuscript are significant for stem cell differentiation toward the applications in stem cell-based drug screening, disease modeling, and cell therapies. PMID- 26577989 TI - Characterization of irreversible physio-mechanical processes in stretched fetal membranes. AB - We perform bulge tests on live fetal membrane (FM) tissues that simulate the mechanical conditions prior to contractions. Experimental results reveal an irreversible mechanical behavior that appears during loading and is significantly different than the mechanical behavior that appears during unloading or in subsequent loading cycles. The irreversible behavior results in a residual strain that does not recover upon unloading and remains the same for at least 1h after the FM is unloaded. Surprisingly, the irreversible behavior demonstrates a linear stress-strain relation. We introduce a new model for the mechanical response of collagen tissues, which accounts for the irreversible deformation and provides predictions in agreement with our experimental results. The basic assumption of the model is that the constitutive stress-strain relationship of individual elements that compose the collagen fibers has a plateau segment during which an irreversible transformation/deformation occurs. Fittings of calculated and measured stress-strain curves reveal a well-defined single-value property of collagenous tissues, which is related to the threshold strain epsilonth for irreversible transformation. Further discussion of several physio-mechanical processes that can induce irreversible behavior indicate that the most probable process, which is in agreement with our results for epsilonth, is a phase transformation of collagen molecules from an alpha-helix to a beta-sheet structure. A phase transformation is a manifestation of a significant change in the molecular structure of the collagen tissues that can alter connections with surrounding molecules and may lead to critical biological changes, e.g., an initiation of labor. STATEMENT OF SIGNIFICANCE: This study is driven by the hypothesis that pre-contraction mechanical stretch of the fetal membrane (FM) can lead to a change in the microstructure of the FM, which in turn induces a critical biological (hormonal) change that leads to the initiation of labor. We present mechanical characterizations of live FM tissues that reveal a significant irreversible process and a new model for the mechanical response of collagen tissues, which accounts for this process. Fittings of calculated and measured results reveal a well-defined single-value property of collagenous tissues, which is related to the threshold strain for irreversible transformation. Further discussion indicates that the irreversible deformation is induced by a phase transformation of collagen molecules that can lead to critical biological changes. PMID- 26577990 TI - Synthesis and Biological Evaluation of Lactimidomycin and Its Analogues. AB - The studies culminating in the total synthesis of the glutarimide-containing eukaryote translation elongation inhibitor lactimidomycin are described. The optimized synthetic route features a Zn(II)-mediated intramolecular Horner Wadsworth-Emmons (HWE) reaction resulting in a highly stereoselective formation of the strained 12-membered macrolactone of lactimidomycin on a 423 mg scale. The presence of the E,Z-diene functionality was found to be key for effective macrocyclizations as a complete removal of these unsaturation units resulted in exclusive formation of the dimer rather than monocyclic enoate. The synthetic route features a late-stage installation of the glutarimide functionality via an asymmetric catalytic Mukaiyama aldol reaction, which allows for a quick generation of lactimidomycin homolog 55 containing two additional carbons in the glutarimide side chain. Similar to lactimidomycin, this analog was found to possess cytotoxicity against MDA-MB-231 breast cancer cells (GI50 =1-3 MUM) using in vitro 2D and 3D assays. Although lactimidomycin was found to be the most potent compound in terms of anticancer activity, 55 as well as truncated analogues 50-52 lacking the glutarimide side-chain were found to be significantly less toxic against human mammary epithelial cells. PMID- 26577991 TI - The Dietary Flavonoid Rhamnetin Inhibits Both Inflammation and Excitotoxicity During Ethanol Withdrawal in Rat Organotypic Hippocampal Slice Cultures. AB - BACKGROUND: Ethanol (EtOH) causes neurotoxicity via several mechanisms including neuroinflammation (during EtOH exposure), and excitotoxicity (during EtOH withdrawal [EWD]). Alpha7 nicotinic acetylcholine receptor (nAChR) selective agonists have the potential to reduce both. The aim of this study was to evaluate the anti-inflammatory and neuroprotective potential of rhamnetin, a dietary flavonoid with alpha7 nAChR selective activity, in an in vitro model of EtOH induced neurotoxicity. METHODS: The anti-inflammatory and neuroprotective properties of rhamnetin were assessed in neonatal organotypic hippocampal slice cultures undergoing EWD (or not) and challenged with N-methyl-D-aspartate (NMDA) and/or lipopolysaccharide (LPS). Neurotoxicity was determined using propidium iodide uptake, and the inflammatory response was evaluated by measuring the release of tumor necrosis factor (TNF)-alpha (NO; quantified by ELISA) and nitric oxide (quantified by the Griess reaction) into culture media. RESULTS: As predicted, rhamnetin reduced LPS-induced release of TNF-alpha and NO both under control conditions and during EWD. Additionally, rhamnetin had no effect on NMDA induced neurotoxicity under control conditions, but significantly reduced NMDA toxicity during EWD. In contrast, rhamnetin had no effect on neurotoxicity induced by NMDA and LPS combined despite reducing TNF-alpha and NO levels under these conditions. CONCLUSIONS: Rhamnetin is anti-inflammatory and neuroprotective during EWD and therefore has potential value in treating neurotoxicity caused by EtOH. PMID- 26577992 TI - Hypoventilation exacerbates the cardiovascular depression caused by a high volume of lumbosacral epidural bupivacaine in two isoflurane-anesthetized dogs. PMID- 26577993 TI - Analysis of early and long-term outcomes of acute type A aortic dissection according to the new international aortic arch surgery study group recommendations. AB - To evaluate predictors of early and long-term outcomes of surgical repair of acute Type A aortic dissection. Retrospective single-centre study evaluating patients surgically treated between 1998 and 2013. Clinical follow-up was performed. Complications were classified according to the International Aortic Arch Surgery Study Group recommendations. Statistical analysis included univariate and multivariate analysis of preoperative and operative data. One hundred eighty-five patients were evaluated. The follow-up was complete for 180 patients (97 %). Mean age was 63 years, 82 % had a DeBakey type I aortic dissection, 18 % a type II. Eleven patients (6 %) died intraoperatively, 119 of the remaining (68 %) had postoperative complications. Thirty-day mortality was 21 % (38 patients). Average ICU and hospital stay were 6 and 14 days, respectively. During a mean follow-up time of 6 +/- 4 years we observed 44 deaths (31 %). Twenty patients (14 %) needed late thoracic aorta reoperation. Results from the multivariate analysis are as follows. Thirty-day mortality was associated with abdominal pain at presentation (p < 0.01). The incidence of postoperative complications was related to older age at intervention (p < 0.01) and longer cross-clamp time (p < 0.01). Mortality at follow-up was significantly increased by older age at intervention (p < 0.01), with a logarithmic growth after 60 years, female sex (p < 0.01), preoperative limb ischemia (p = 0.02) and DHCA (p < 0.01). The surgical results of type A aortic dissection are affected by age at intervention with a logarithmic increase of late mortality in patients older than 60 years. PMID- 26577995 TI - Characterization and evaluation of a folic acid receptor-targeted cyclodextrin complex as an anticancer drug delivery system. AB - To improve the water solubility and tumor targeting ability of docetaxel (DTX), and thus enhance the drug's antitumor efficacy and safety, a novel folate receptor (FR)-targeted cyclodextrin drug delivery vehicle (FA-CD) was successfully synthesized. The synthesis of the designed cyclodextrin was confirmed by Fourier transform infrared spectroscopy (FTIR), proton nuclear magnetic resonance (1H NMR), and differential scanning calorimetry (DSC). The in vitro cytotoxicity was investigated using a 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay and the results showed that no significant differences (p>0.05) appeared in cytotoxicity between the different cyclodextrins in the different cell lines. Besides, the DTX/FA-CD inclusion complex was prepared. The cellular uptake and competition assays were examined using the HepG2, HeLa, and KB cell lines, which have different levels of folate receptor expression. Interestingly, the Cy5.5/FA-CD complex had higher uptake in the HepG2, HeLa, and KB cells, compared with non-targeted Cy5.5/CD complex (p<0.001). The time-dependent drug uptake into KB cells observed by LSCM confirmed the drug delivery via endocytic routes. Data from the competition assays, especially in KB cells, showed that a significant inhibitory effect (p<0.001) was obtained when the concentration of FA was increased, and suggested that the Cy5.5/FA-CD was internalized through a FR-mediated mechanism. Moreover, the in vitro bioactivity assay also demonstrated efficient antitumor activity, and the order of the cell viabilities (% of control) was OB>HepG2>HeLa>KB for DTX/FA-CD (p<0.001). For DTX/CD, however, it displayed minimum antitumor behavior in all cell types. An apoptosis study by FCM and LSCM also revealed that the FA modified complexes were more effective in inducing apoptosis in FR-expressing cells. Finally, an in vivo biodistribution study in KB-bearing healthy mice revealed that the DTX/FA-CD complex has enhanced tumor-targeting efficacy and diminished systemic side effects. These results suggest that the novel FR targeted cyclodextrin complex is a promising alternative as an anticancer drug delivery system. PMID- 26577994 TI - Bone marrow fat and the decline of B lymphopoiesis in rabbits. AB - B lymphopoiesis is necessary to generate a diverse pool of naive B cells that are able to respond to a broad spectrum of antigens during immune responses to pathogens and to vaccination. Rabbits have been utilized for many years to generate high affinity monoclonal and polyclonal antibodies. Specific antibodies generated in rabbits have greatly advanced scientific discoveries, but the unique qualities of rabbit B cell development have been underappreciated. Unlike in humans and mice, where B lymphopoiesis declines in mid to late life, B lymphopoiesis in rabbits arrests early in life, between 2 and 4 months of age. This review focuses on the early loss of B cell development in rabbits and the contribution of the bone marrow microenvironment to this process. We also propose directions for future research in this area, and discuss how the rabbit can be used as a model to understand the decline of B lymphopoiesis that occurs in humans late in life. Such studies will be important for developing therapeutics targeted to prevent and/or reverse declining B lymphopoiesis in the elderly, as well as boosting immunity and antibody responses after infection or vaccination. PMID- 26577996 TI - Prevalence of Hypovitaminosis D Among Jordanian Healthy Infants: A Descriptive Cross Sectional Study. AB - To determine vitamin D deficiency and associated risk factors of hypovitaminosis D among Jordanian healthy infants. DESIGN AND METHODS: A total of 171 infants receiving a routine health check at a Maternal and Child Health Care Center were recruited. Plasma vitamin D 25-OHD level was assessed using a standard analysis of a blood sample. Other data collected included age, gender, birth order, season of birth, and mode of feeding. RESULTS: Prevalence of vitamin D deficiency (<=15 ng/mL) was 77% (132 out of 171 infants). Infants at risk of vitamin D deficiency were those between 1 to 6 months of age, male, third born or later, born in winter, and exclusively breastfed. The multivariate model showed birth order to be the largest contributor of vitamin D deficiency (R(2)=0.196), followed by breastfed infants (R(2)=0.071), infants born in winter (R(2)=0.037), male gender (R(2)=0.028), and infants aged between 1 and 6 months (R(2)=0.027). CONCLUSION: Hypovitaminosis D appears to be more common among healthy infants in Jordan. Hypovitaminosis D was found to be common among third or later exclusively breastfeed male infants aged 1 to 6 months who were born during winter. PRACTICE IMPLICATION: Maternal and child health nurses have a critical role to play in educating mothers about the importance of preventing hypovitaminosis D through adequate sun exposure and ensuring adequate supplementation. A higher dose of vitamin D supplementation for high-risk infants beyond the age of 1 year from developing countries should be administered. PMID- 26577997 TI - Arthroscopic suture retrievers and shuttles: a biomechanical investigation of the force required for tendon penetration and defect size. AB - BACKGROUND: To compare instruments designed for arthroscopic suture handling during arthroscopic rotator cuff repair, to assess the force needed to penetrate the tendon, and to evaluate the residual defect size. METHODS: Twenty-one instruments were each tested ten times on thawed sheep infraspinatus tendons. The force needed to pierce the tendon with each instrument was measured using a custom setup. Bone wax plates were used to make the perforation marks visible and to quantify the lesions each instrument created. RESULTS: The force to pierce a tendon had a range of 5.6-18.5 N/mm. Within the group of suture retrievers, the angled instruments required in average 85 % higher forces than straight instruments. The lesion area had a range of 2-7 mm(2). Suture retrievers produced significantly larger lesion sizes compared with suture shuttles. CONCLUSION: For the identical task of passing a suture through a tendon, differences exist regarding the ease of tendon penetration and potential damage to the tendon for different tools. The design, function, and resulting lesion size may be relevant and important for surgical handling and to avoid excess structural damage to the tendon. These results suggest that choosing the most appropriate tools for arthroscopic suture stitching influences the ease of handling and final integrity of the tissue. PMID- 26577998 TI - A randomized controlled trial of levofloxacin, terazosin, and combination therapy in patients with category III chronic prostatitis/chronic pelvic pain syndrome. AB - OBJECTIVE: To explore the efficacy of levofloxacin, terazosin, and their combination in patients with category III chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). METHODS: A total of 115 patients with category III CP/CPPS receiving 6-week therapy were randomly divided into the levofloxacin group (n = 38), terazosin group (n = 38), and combination group (n = 39). The primary endpoint was the response rate (i.e., the change from baseline) in the total and domain scores of the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI). Secondary endpoints were expressed as prostatic secretion-white blood cell (EPS-WBC) and International Index of Erectile Function-5 (IIEF-5). RESULTS: After 6 weeks, the response rate of NIH-CPSI scores was 45.1, 22.4, and 50.0 % in the levofloxacin group, terazosin group, and combination group, respectively. Furthermore, no significant difference in NIH-CPSI scores was observed between IIIA and IIIB patients in each arm. Levofloxacin alone or levofloxacin plus terazosin could significantly reduce EPS-WBC counts compared with terazosin alone. Finally, no significant difference was found between the three arms in terms of IIEF-5 scores. CONCLUSION: A 6-week short-term treatment of levofloxacin or levofloxacin plus terazosin was more effective than terazosin alone in patients with category III CP/CPPS. Furthermore, levofloxacin treatment was not different from levofloxacin plus terazosin treatment in terms of treatment effect. PMID- 26577999 TI - BDNF-hypersecreting human umbilical cord blood mesenchymal stem cells promote erectile function in a rat model of cavernous nerve electrocautery injury. AB - PURPOSE: Erectile dysfunction (ED) continues to be a significant problem for men following radical prostatectomy. We hypothesize that intracavernous injection of BDNF-hypersecreting human umbilical cord blood mesenchymal stem cells (hUCB-MSCs) can ameliorate ED in a rat model of cavernous nerve electrocautery injury (CNEI). METHODS: Forty-two male Sprague-Dawley rats were randomly divided into four groups: sham + PBS (n = 6), CNEI + PBS (n = 12), CNEI + hUCB-MSCs (n = 12) and CNEI + BDNF-hUCB-MSCs (n = 12). At day 28 post-surgery, erectile function was examined and specimens were harvested for histology. Immunofluorescence staining, Masson's trichrome staining and transmission electron microscopy were performed to determine the structural changes in corpus cavernosum. Cells that are injected into penis were labeled by BrdU and tracked by immunofluorescence staining. Three days post-surgery, the concentration of BDNF protein in penile tissues was measured by Western blotting. RESULTS: Rats intracavernosally injected with BDNF hUCB-MSCs showed the most significant improvement in the ratio of maximal ICP to MAP (ICP/MAP). Histological examinations showed moderate recovery of nNOS positive nerve fibers, ratio of smooth muscle to collagen and smooth muscle content in the CNEI + hUCB-MSCs group and remarkable recovery in the CNEI + BDNF hUCB-MSCs group compared to the CNEI + PBS group. By TEM examination, atrophy of myelinated and non-myelinated nerve fibers was noted in CNEI + PBS group and significant recovery was observed in two treated groups. There were more BrdU positive cells in the BDNF-hUCB-MSCs group than in the hUCB-MSCs group both in the penis and in the MPG. Three days post-surgery, the concentration of BDNF protein in penile tissues in BDNF-hUCB-MSCs group was much higher than in other groups. CONCLUSIONS: Intracavernous injection of BDNF-hypersecreting hUCB-MSCs can enhance the recovery of erectile function, promote the CNs regeneration and inhibit corpus cavernosum fibrosis after CNEI in a rat model. PMID- 26578000 TI - Appraisal of a redundant report on lanthanum carbonate. PMID- 26578001 TI - Bladder recovery relates with increased mid-cingulate perfusion after shunt surgery in idiopathic normal-pressure hydrocephalus: a single-photon emission tomography study. AB - AIMS OF STUDY: It is reported that severe bladder disorder in idiopathic normal pressure hydrocephalus (iNPH) is predicted by right frontal hypoperfusion. However, it is not known whether bladder recovery is predicted by brain perfusion change after shunt surgery. To address this issue, we compared bladder and brain function before and after shunt surgery in iNPH. METHODS: We enrolled 75 patients in the study. Before and 12 months after shunt surgery, we analyzed brain perfusion by SPECT and bladder disorder by a specialized grading scale. The scale consisted of grade 0, none; grade 1, urinary urgency and frequency; grade 2, urinary incontinence 1-3 times a week; grade 3, urinary incontinence >daily; and grade 4, loss of bladder control. More than one grade improvement is defined as improvement, and more than one grade decrement as worsening; otherwise no changes. RESULTS: Comparing before and after surgery, in the bladder-no-change group (32 cases) there was an increase in blood flow which is regarded as reversal of enlargement in the Sylvian fissure and lateral ventricles (served as control). In contrast, in the bladder-improved group (32 cases) there was an increase in bilateral mid-cingulate, parietal, and left frontal blood flow (p < 0.05). In the bladder-worsened group (11 cases) no significant blood flow change was observed. CONCLUSION: The present study showed that after shunt surgery, bladder recovery is related with mid-cingulate perfusion increase in patients with iNPH. The underlying mechanism might be functional restoration of the mid cingulate that normally inhibits the micturition reflex. PMID- 26578002 TI - Future requirements for and supply of ophthalmologists for an aging population in Singapore. AB - BACKGROUND: Singapore's population, as that of many other countries, is aging; this is likely to lead to an increase in eye diseases and the demand for eye care. Since ophthalmologist training is long and expensive, early planning is essential. This paper forecasts workforce and training requirements for Singapore up to the year 2040 under several plausible future scenarios. METHODS: The Singapore Eye Care Workforce Model was created as a continuous time compartment model with explicit workforce stocks using system dynamics. The model has three modules: prevalence of eye disease, demand, and workforce requirements. The model is used to simulate the prevalence of eye diseases, patient visits, and workforce requirements for the public sector under different scenarios in order to determine training requirements. RESULTS: Four scenarios were constructed. Under the baseline business-as-usual scenario, the required number of ophthalmologists is projected to increase by 117% from 2015 to 2040. Under the current policy scenario (assuming an increase of service uptake due to increased awareness, availability, and accessibility of eye care services), the increase will be 175%, while under the new model of care scenario (considering the additional effect of providing some services by non-ophthalmologists) the increase will only be 150%. The moderated workload scenario (assuming in addition a reduction of the clinical workload) projects an increase in the required number of ophthalmologists of 192% by 2040. Considering the uncertainties in the projected demand for eye care services, under the business-as-usual scenario, a residency intake of 8-22 residents per year is required, 17-21 under the current policy scenario, 14-18 under the new model of care scenario, and, under the moderated workload scenario, an intake of 18-23 residents per year is required. CONCLUSIONS: The results show that under all scenarios considered, Singapore's aging and growing population will result in an almost doubling of the number of Singaporeans with eye conditions, a significant increase in public sector eye care demand and, consequently, a greater requirement for ophthalmologists. PMID- 26578004 TI - Wheel of time. PMID- 26578003 TI - Microfluidic emulation of mechanical circulatory support device shear-mediated platelet activation. AB - Thrombosis of ventricular assist devices (VADs) compromises their performance, with associated risks of systemic embolization, stroke, pump stop and possible death. Anti-thrombotic (AT) drugs, utilized to limit thrombosis, are largely dosed empirically, with limited testing of their efficacy. Further, such testing, if performed, typically examines efficacy under static conditions, which is not reflective of actual shear-mediated flow. Here we adopted our previously developed Device Thrombogenicity Emulation methodology to design microfluidic platforms able to emulate representative shear stress profiles of mechanical circulatory support (MCS) devices. Our long-term goal is to utilize these systems for point-of-care (POC) personalized testing of AT efficacy under specific, individual shear profiles. First, we designed different types of microfluidic channels able to replicate sample shear stress patterns observed in MCS devices. Second, we explored the flexibility of microfluidic technology in generating dynamic shear stress profiles by modulating the geometrical features of the channels. Finally, we designed microfluidic channel systems able to emulate the shear stress profiles of two commercial VADs. From CFD analyses, the VAD emulating microfluidic systems were able to replicate the main characteristics of the shear stress waveforms of the macroscale VADs (i.e., shear stress peaks and duration). Our results establish the basis for development of a lab-on-chip POC system able to perform device-specific and patient-specific platelet activation state assays. PMID- 26578005 TI - The 21st Century Cures Act: can the regulatory framework survive the "cures"? PMID- 26578006 TI - [Academic review of global health approaches: an analytical framework]. AB - In order to identify perspectives on global health, this essay analyzes different trends from academia that have enriched global health and international health. A database was constructed with information from the world's leading global health centers. The search covered authors on global diplomacy and global health and was performed in PubMed, LILACS, and Google Scholar with the key words "global health" and "international health". Research and training centers in different countries have taken various academic approaches to global health; various interests and ideological orientations have emerged in relation to the global health concept. Based on the mosaic of global health centers and their positions, the review concludes that the new concept reflects the construction of a paradigm of renewal in international health and global health, the pre-paradigmatic stage of which has still not reached a final version. PMID- 26578007 TI - Validity of the Brazilian version of the Godin-Shephard Leisure-Time Physical Activity Questionnaire. AB - This study provides evidence of construct validity for the Brazilian version of the Godin-Shephard Leisure-Time Physical Activity Questionnaire (GSLTPAQ), a 1 item instrument used among 236 participants referred for cardiopulmonary exercise testing. The Baecke Habitual Physical Activity Questionnaire (Baecke-HPA) was used to evaluate convergent and divergent validity. The self-reported measure of walking (QCAF) evaluated the convergent validity. Cardiorespiratory fitness assessed convergent validity by the Veterans Specific Activity Questionnaire (VSAQ), peak measured (VO2peak) and maximum predicted (VO2pred) oxygen uptake. Partial adjusted correlation coefficients between the GSLTPAQ, Baecke-HPA, QCAF, VO2pred and VSAQ provided evidence for convergent validity; while divergent validity was supported by the absence of correlations between the GSLTPAQ and the Occupational Physical Activity domain (Baecke-HPA). The GSLTPAQ presents level 3 of evidence of construct validity and may be useful to assess leisure-time physical activity among patients with cardiovascular disease and healthy individuals. PMID- 26578008 TI - [The position of the Brazilian Federal Board of Medicine on incentives for reimbursement of childbirth care and the impact on cesarean rates]. AB - This study analyzed incentives for reimbursement of childbirth care advocated by the Brazilian Federal Board of Medicine (CFM) and their impact on cesarean rates. A consecutive sample of 600 postpartum women was surveyed. The overall cesarean rate was 59.2%, as compared to 92.3% among women that had the same physician for their prenatal care and childbirth. Cesarean rates were significantly greater in the groups of women with higher prevalence of the same physician during prenatal care and delivery, that is, higher rates were associated with older maternal age (PR = 1.65), more schooling (PR = 1.25), prenatal care in the private sector (PR = 1.39) or through private health plans (PR = 1.43), previous cesarean section (PR = 2.78), and admission earlier in labor (PR = 1.93). The results challenge the position by the CFM that financial incentives for women to have the same obstetrician during prenatal care and labor would encourage normal childbirth, when these women are precisely the ones with the highest cesarean rates. PMID- 26578009 TI - [Comment on the paper by Freitas et al]. PMID- 26578010 TI - [The authors reply]. PMID- 26578011 TI - [Demographic, socioeconomic, and health profile of working and non-working Brazilian children and adolescents: an analysis of inequalities]. AB - The objectives of this study were to describe the work done by Brazilian children and adolescents and compare the socioeconomic and health profile of those that worked (or were looking for work) versus non-working youngsters. Based on the 2008 Brazilian National Sample Household Survey (PNAD/2008), we selected children and adolescents 5 to 17 years of age, divided into two analytical categories: "workers" (working or looking for employment) and "non-workers". We calculated prevalence rates for the characteristics of their main work, as well as socioeconomic and health variables comparing the two categories. Poisson regression was used to estimate prevalence ratios, adjusted by health characteristics, with "non-workers" as the reference category. Compared to "non workers", the "workers" category was associated with a higher proportion of boys; age 14 to 17 years; black or brown skin color; lower school attendance; and worse housing conditions. Child labor was associated with worse self-rated health; chronic backache; arthritis or rheumatism; and depression. Effective policies to support families need to be strengthened to effectively fight child labor. PMID- 26578012 TI - Testing the applicability of a model of oral health-related quality of life. AB - The aim of this study was to test Wilson & Cleary's conceptual model of the direct and mediated pathways between clinical and non-clinical variables in relation to oral health-related quality of life. A random sample of 578 older people was evaluated. Wilson & Cleary's conceptual model was tested using structural equations modeling including: biological variables, symptom status, functional health, oral health perceptions, oral health-related quality of life. Oral health-related quality of life was assessed with the Oral Health Impact Profile-14 (OHIP-14). In the final model, edentulism was negatively correlated to dissatisfaction of appearance of their dental prostheses (r = -0.25). Worse functional status was correlated with poor oral health perception (r = 0.24). Being aged over 68 (r = 0.25), being a female (r = 0.39) and living in rural areas (r = 0.15) had a direct effect on the edentulism. Age had a direct effect on OHIP-14 (r = -0.15). There was an indirect effect of sex on OHIP-14 via functional status (r = 0.12). The present findings partially support Wilson & Cleary's model framework. PMID- 26578013 TI - [Factors associated with neurodevelopment in children 6-18 months of age in public daycare centers in Joao Pessoa, Paraiba State, Brazil]. AB - This study aimed to determine the prevalence of altered neurodevelopment in children in public daycare centers in Joao Pessoa, Paraiba State, Brazil, and to analyze factors associated with child development. A cross-sectional study was conducted in a sample of children 6 to 18 months of age enrolled in daycare. Child development was assessed by the Denver II Screening Test. Biological, riables were studied with a questionnaire and form. Associations were adjusted using logistic regression. Altered development was present in 52.7% of the children and was associated with age > 12 months (OR = 4.3), vaginal delivery (OR = 4.4), neonatal phototherapy (OR = 7.9), and daycare centers not supported by the Family Health Strategy (OR = 2.9). The findings suggest that child development reflects the family's conditions and the care received from educational and healthcare services. PMID- 26578014 TI - [Tobacco control policy and variation in Brazilian family spending on cigarettes: results of the Brazilian Household Budget Surveys in 2002/2003 and 2008/2009]. AB - This study aimed to describe trends in family spending on cigarettes and its share of family budget, comparing 2002 and 2009, using the Brazilian Household Budget Surveys from 2002/2003 and 2008/2009. The Expanded Consumer Price Index (IPCA) was used. The proportion of families that purchased cigarettes decreased from 23.5% to 18.2%, however their spending increased from BRL 55.36 to BRL 59.45. Spending on cigarettes was proportional to family income and head-of family's schooling. Higher-income families still accounted for most of the expenditure, although the share of family income spent on cigarettes declined. The share of income for purchasing cigarettes was 5.2% in the lowest income quintile and 1.2% in the highest. Tobacco control policy has succeeded in reducing smoking prevalence in Brazil. However, economic measures are still important in the country, since the family's share of income and spending on cigarettes have decreased. PMID- 26578015 TI - C-reactive protein, physical activity and cardiorespiratory fitness in Portuguese adolescents: a cross-sectional study. AB - The goal of this study was to investigate the association of physical activity (PA) and cardiorespiratory fitness with C-reactive protein (CRP) concentration in adolescents. The sample included 386 Portuguese adolescents (n = 207, female), age 12-18 years, assessed in the year 2012. The PA was assessed with the use of accelerometers, and the cardiorespiratory fitness was assessed by the Fitnessgram Pacer test. Blood samples were collected after a 10-hour fasting, and high sensitivity PCR concentration was further assessed. Significant associations between CRP and cardiorespiratory fitness were found for females (r = -0.313; p < 0.001) and males (r = -0.163; p < 0.05); however, when adjusted by the BMI, the associations remained significant only for females (r = -0.215; p < 0.001). Regarding the association between CRP and PA, no significant associations were found for both genders. Therefore, CRP is apparently negatively associated with cardiorespiratory fitness, with differences between males and females; for females it seems less dependent than BMI. PMID- 26578016 TI - [Alcohol use alone and in combination with other drugs among truck drivers on highways in Sao Paulo State, Brazil: a cross-sectional study]. AB - Traffic accidents cause more than a million deaths per year worldwide. Brazil is one of the leading countries in traffic accidents. Since alcohol is a known etiological factor for traffic accidents, the pattern of alcohol use alone and in combination with other drugs was assessed in a convenience sample of 684 truck drivers in Sao Paulo State, Brazil. 67.3% of participants reported alcohol use in the previous 30 days, 34.6% reported heavy drinking, 26% binge drinking, and 9.2% were at risk of developing alcohol addiction. Furthermore, 54.6% reported multiple drug use, mostly alcohol with tobacco and energy drinks. Truck drivers that reported multiple drug use showed heavier alcohol use than those who consumed only alcohol. Drinking and driving is problematic and can be aggravated by multiple drug use. The authors thus suggest monitoring the issue, which creates serious problems for users and society as a whole. PMID- 26578017 TI - [Factors associated with adequate prenatal care and delivery in Sao Tome and Principe, 2008-2009]. AB - We investigated factors associated with adequacy of prenatal and childbirth care for women in Sao Tome and Principe. Data were analyzed from the Demographic and Health Survey on a sample of 1,326 newborn infants whose mothers were 15-49 years of age. The survey took place from September 2008 to March 2009. We used multilevel and multinomial logistic regression to analyze the association between demographic and socioeconomic factors and the target outcomes. Prenatal care was adequate in 26% of the sample, and 7% of deliveries were performed by physicians and 76% by nurses or nurse assistants. Statistically significant factors for prenatal care were birth order, maternal schooling, and index of economic well being. The most important variables for adequate delivery were: birth order, maternal schooling, index of economic well-being, and place of residence. The study showed that socioeconomic factors have the greatest influence on adequate prenatal care and delivery. Future health policies should target social inequalities in Sao Tome and Principe. PMID- 26578018 TI - [The influence of structural and organizational factors on the performance of primary health care in Belo Horizonte, Minas Gerais State, Brazil, according to nurses and managers]. AB - The aim of this study was to evaluate the performance of primary health care (PHC) in Belo Horizonte, Minas Gerais State, Brazil, using the Portuguese language version of the Primary Health Care Assessment Tool among nurses and managers of family health teams. Total PHC score was 0.75 (good). The dimensions first contact (0.95), longitudinality (0.83), comprehensiveness (0.83), and coordination (0.78) performed the best. Family approach, community orientation, and access received the lowest scores (0.68, 0.56, and 0.45, respectively). Better PHC performance was associated with the following factors (p < 0.05): availability of health care equipment and other inputs (adjusted PR = 1.57), education and training for family health teams (PR = 1.44), a physician on duty for more than 30 hours per week (PR = 1.42), and presence of four or more teams per primary care unit (PR = 1.09). The results show the importance of structural and organizational factors for PHC performance and suggest that permanent evaluation can identify aspects that require quality improvement. PMID- 26578019 TI - [Hearing loss in urban transportation workers in Greater Metropolitan Belo Horizonte, Minas Gerais State, Brazil]. AB - This study analyzed the association between self-reported diagnosis of hearing loss and individual and occupational factors among urban transportation workers in Greater Metropolitan Belo Horizonte, Minas Gerais State, Brazil. The sample size was calculated by quotas and stratified by occupation (drivers and fare collectors) in the urban transportation companies in Belo Horizonte, Betim, and Contagem. Data were collected with face-to-face interviews and recorded by the interviewers on netbooks. The dependent variable was defined as an affirmative response to the question on prevailing medical diagnosis of hearing loss. The independent variables were organized in three blocks: social and demographic characteristics, lifestyle, and work aspects. Diagnosis of hearing loss was reported by 213 of the 1,527 workers and was associated with age and diagnosis of tinnitus. At the occupational level, hearing loss was associated with history of sick leave, time-on-the-job, and two environmental risks, unbearable noise and whole-body vibration. Measures to prevent hearing loss are needed for urban transportation workers. PMID- 26578020 TI - [Children with tuberculosis: situations and interactions in family health care]. AB - This qualitative study analyzed meanings associated with tuberculosis (TB) in children. Interviews were conducted with lay caregivers and health professionals in six health situations in a vulnerable territory. Data collection was followed by thematic content analysis and interpretation in consultation with the literature concerning the concepts of stigma, childhood illness, and preservation of the facade. The results showed that the discussion on the meanings of TB in children involves relativity of the core family concept and valuation of their network of relationships. The complexity of TB in children requires an expanded understanding of their health situation and interactions among the surrounding relationships. The health professional's role in identifying and managing possibilities for care and diagnostic and therapeutic difficulties is an important tool for health promotion in children. PMID- 26578021 TI - Lung cancer mortality trends in Chile and six-year projections using Bayesian dynamic linear models. AB - The objectives were to analyze lung cancer mortality trends in Chile from 1990 to 2009, and to project the rates six years forward. Lung cancer mortality data were obtained from the Chilean Ministry of Health. To obtain mortality rates, population projections were used, based on the 2002 National Census. Rates were adjusted using the world standard population as reference. Bayesian dynamic linear models were fitted to estimate trends from 1990 to 2009 and to obtain projections for 2010-2015. During the period under study, there was a 19.9% reduction in the lung cancer mortality rate in men. In women, there was increase of 28.4%. The second-order model showed a better fit for men, and the first-order model a better fit for women. Between 2010 and 2015 the downward trend continued in men, while a trend to stabilization was projected for lung cancer mortality in women in Chile. This analytical approach could be useful implement surveillance systems for chronic non-communicable disease and to evaluate preventive strategies. PMID- 26578022 TI - Social determinants of nonadherence to tuberculosis treatment in Buenos Aires, Argentina. AB - This study aimed to identify the individual and environmental determinants of nonadherence to tuberculosis (TB) treatment in selected districts in the Buenos Aires Metropolitan Area, in Argentina. We conducted a cross-sectional study using a hierarchical model. Using primary and secondary data, logistic regression was performed to analyze two types of determinants. The likelihood of nonadherence to treatment was greatest among male patients. The following factors led to a greater likelihood of nonadherence to treatment: patients living in a home without running water; head of household without medical insurance; need to use more than one means of transport to reach the health center; place of residence in an area with a high proportion of households connected to the natural gas network; place of residence in an area where a large proportion of families fall below the minimum threshold of subsistence capacity; place of residence in an area where a high proportion of households do not have flushing toilets and basic sanitation. Our results show that social and economic factors - related to both individual and environmental characteristics - influence adherence to TB treatment. PMID- 26578023 TI - [Weight/head circumference ratio at birth for assessing fetal growth]. AB - The objective of this study was to use weight/head circumference ratio at birth to assess fetal growth. A retrospective cohort study was conducted in Zona da Mata, Pernambuco State, Brazil, with 915 term infants. Infants' anthropometric measurements and data on prenatal care, smoking during pregnancy, family income, and maternal schooling and nutritional status were collected in the first 24 hours after birth. Infants were classified as proportionate (weight/head circumference ratio >= 0.90) versus disproportionate (< 0.90). Lower mean weight/head circumference ratio was associated with maternal smoking, younger age, inadequate prenatal care, and low BMI, height, and triceps skinfold thickness. Mean weight, length, head and chest circumference, arm circumference, and triceps skinfold thickness were lower among infants with disproportionate weight/head circumference ratio, independently of sex. In conclusion, weight/head circumference ratio and birth weight are important indicators of fetal growth. PMID- 26578024 TI - [AIDS in children: the influence of socioeconomic differences in Fortaleza, Ceara State, Brazil]. AB - This study aimed to analyze the relationship between pediatric AIDS cases and neighborhood socioeconomic characteristics in Fortaleza, Ceara State, Brazil. This was an ecological and descriptive study with socioeconomic data from the 2010 Population Census and AIDS data in children for 2001-2011 from the Information System on Notifiable Diseases. Pearson's correlation was performed and the Moran index was used to verify spatial autocorrelation. A multinomial model was used to identify clusters. Of the total sample, 57.8% were male. In 18.8% of the children, the diagnosis was made after two years of age. There was a positive spatial correlation between AIDS cases in children and income (I = 0.6; p = 0.001) and the proportion of poor (I = 0.5; p = 0.001). Neighborhoods with these characteristics are mainly located in the Northwest and Southwest areas of the city. Spatial correlation between pediatric AIDS cases and socioeconomic indicators highlights the need for interventions aimed at improving health and living conditions. PMID- 26578025 TI - [Evolution of overweight and obesity into adulthood, Pelotas, Rio Grande do Sul State, Brazil, 1982-2012]. AB - This study assessed the prevalence of overweight and obesity in adolescence and adulthood among subjects enrolled in the 1982 Pelotas Birth Cohort, Rio Grande do Sul State, Brazil, according to social and demographic characteristics. In 1982, hospital births in Pelotas were identified and all live born infants (n = 5,914) were examined and have been followed since. The data were collected at 15, 18, 23, and 30 years of age. In women, prevalence of overweight increased from 23.6% at 15 years to 52.4% at 30 years of age, while obesity increased from 6.6% to 23.8%. In men, overweight increased from 22.9% to 62.9%, and obesity from 7.5% to 22.1%. Overweight and obesity increased more among individuals of both sexes with lower socioeconomic status, which can lead to more inequality in the occurrence of chronic diseases. PMID- 26578026 TI - [Why are diagnosis-related groups unpopular in Colombia?]. AB - The aim of this study was to explore the determinants of non-implementation of diagnosis-related groups (DRGs) by hospitals in Colombia. A qualitative case was carried out to analyze the directors' perceptions in six hospitals with and without DRGs in Bogota. The interviews are based on the Innovation Diffusion Theory. The directors had similar perceptions of the determinates. DRGs were seen as positive, but encountered organizational and institutional obstacles. Without a targeted public policy, the likelihood of implementing DRGs in Colombia is slight. PMID- 26578027 TI - Idarucizumab: First Global Approval. AB - Idarucizumab (Praxbind((r))) is a fully humanized, monoclonal antibody fragment developed by Boehringer Ingelheim as a specific antidote to reverse the anticoagulant effect of the direct oral thrombin inhibitor dabigatran etexilate (Pradaxa((r))). Idarucizumab received its first global approval, in the USA, in October 2015 for use in adult patients treated with dabigatran etexilate when rapid reversal of its anticoagulant effects is required for emergency surgery/urgent procedures or in life-threatening or uncontrolled bleeding. Regulatory applications have been submitted in Canada and in the EU, where it has received a positive opinion from the European Medicines Agency's Committee for Medicinal Products for Human Use. This article summarizes the milestones in the development of idarucizumab leading to this first approval for reversing the anticoagulant effects of dabigatran in adults. PMID- 26578028 TI - A world of hurt: failure to achieve treatment goals in patients with gout requires a paradigm shift. AB - BACKGROUND: Gout continues to be underdiagnosed and poorly managed despite the potential for cure. US and European management guidelines recommend treating to target serum urate (sUA) levels of <6 mg/dL (or <5 mg/dL to durably improve severe symptoms), with use of regular sUA monitoring, but studies suggest relatively poor adherence to these recommendations. This study investigates the real-world state of gout management in the United States by describing the characteristics of a large patient population treated in primary care and rheumatology settings. METHODS: A retrospective chart audit, conducted among 124 primary care physicians and 125 rheumatologists, included 1245 patients with gout. Physicians completed structured case report forms capturing 12 months of sUA laboratory values, flare counts, comorbidities, types and doses of treatment, treatment duration, diagnosis date, physician specialty and socio-demographic factors. Focusing on the xanthine oxidase inhibitors (n = 858), descriptive statistics and multivariate models characterized relationships between patient characteristics, disease control, and treatment. RESULTS: Only 83 (11%) patients achieved disease control, defined as a 12-month average sUA <=6 mg/dL, no flares, and no tophi. Patients with greatest disease severity (defined as sUA >6 mg/dL, >=2 flares per year, and tophi) were more likely to have kidney disease and other comorbidities. In a multivariate model, predictors of more severe gout were rheumatologist (vs primary care) management, febuxostat (vs allopurinol) use and presence of comorbid conditions. CONCLUSION: Our findings confirm the inadequacy of gout management in the real-world setting. Regular monitoring, including sUA measurement as recommended in guidelines, is important to assess gout control. Our analyses also demonstrate that patients with more severe gout are more likely to have comorbid conditions, be treated by a specialist and use newer therapies. PMID- 26578029 TI - Maximizing anthracycline tolerability in hematologic malignancies: Treat to each heart's content. AB - Anthracyclines are the cornerstone of therapy for a wide spectrum of malignancies and have improved patient survival. Concern for anthracycline-related cardiotoxicity often leads to dose reductions or use of second-line regimens, which may adversely impact survival. Development of cardiotoxicity depends on a combination of cumulative dose modulated by individual patient characteristics, which we have termed individual cardiotoxic threshold (ICT). Patients with cancer often have characteristics such as age, gender, genetic predisposition and preexisting cardiovascular disease that can potentiate cardiotoxicity. Specialty cardiovascular assessment, more sensitive monitoring technology, and timely interventions in selected patients can decrease cardiotoxicity and improve patient outcomes. Prophylaxis with cardioprotective agents and other strategies have shown promising results in randomized trials and may improve tolerance to anthracyclines. In this review we introduce the concept of ICT and critically analyze the evidence supporting existing strategies to modulate it and increase cardiovascular tolerability of anthracyclines. PMID- 26578030 TI - Thermoplasmonic effect of silver nanoparticles modulates peptide amphiphile fiber into nanowreath-like assembly. AB - This study demonstrates the beneficial role of di-tryptophan containing short peptide amphiphiles (sPA), for the synthesis and stabilization of AgNPs in the presence of sunlight followed by garlanding of AgNPs along the fibrous network of sPA. Such hybrid structures were precisely and selectively moulded into a nanowreath-type morphology due to the thermoplasmonic effect of AgNPs, and can be used for several bio-nanotechnological applications. PMID- 26578031 TI - Bony findings detected by MRI may reflect the pathophysiology of osteoarthritis with thumb carpometacarpal joint pain. AB - BACKGROUND: Osteoarthritis (OA) is the most common skeletal disease worldwide. Although thumb carpametacarpal joint (CMJ) OA is also frequently encountered, the etiologies remain largely unknown. METHOD: We analyzed 20 patients who had thumb CMJ OA with accompanying joint pain and categorized a total of 37 thumbs according to the Eaton and Littler staging system. RESULTS: In patients with advanced OA, bone alterations as detected by magnetic resonance imaging (MRI) were observed in almost all of the painful joints. The frequency of bone alterations in the thumb CMJ increased with OA severity. In contrast, MRI revealed no bone alterations in thumbs with no pain and less pain in bilateral thumb basal pain, even in radiographically advanced OA. CONCLUSIONS: While the incidence of bone cysts in the CMJ was higher with OA staging, OA severity had no apparent correlation with pain. Thus, it is possible that the cause of thumb CMJ pain in advanced OA is bone alterations. PMID- 26578032 TI - Binary Superlattices from {Mo132} Polyoxometalates and Maghemite Nanocrystals: Long-Range Ordering and Fine-Tuning of Dipole Interactions. AB - In the present article, the successful coassembly of spherical 6.2 nm maghemite (gamma-Fe2O3) nanocrystals and giant polyoxometalates (POMs) such as 2.9 nm {Mo132} is demonstrated. To do so, colloidal solutions of oleic acid-capped gamma Fe2O3 and long-chain alkylammonium-encapsulated {Mo132 } dispersed in chloroform are mixed together and supported self-organized binary superlattices are obtained upon the solvent evaporation on immersed substrates. Both electronic microscopy and small angles X-ray scattering data reveal an AB-type structure and an enhanced structuration of the magnetic nanocrystals (MNCs) assembly with POMs in octahedral interstices. Therefore, {Mo132} acts as an efficient binder constituent for improving the nanocrystals ordering in 3D films. Interestingly, in the case of didodecyldimethylammonium (C12)-encapsulated POMs, the long-range ordered binary assemblies are obtained while preserving the nanocrystals magnetic properties due to weak POMs-MNCs interactions. On the other hand, POMs of larger effective diameter can be employed as spacer blocks for MNCs as shown by using {Mo132} capped with dioctadecyldimethylammonium (C18) displaying longer chains. In that case, it is shown that POMs can also be used for fine-tuning the dipolar interactions in gamma-Fe2O3 nanocrystal assemblies. PMID- 26578033 TI - Costs, affordability, and feasibility of an essential package of cancer control interventions in low-income and middle-income countries: key messages from Disease Control Priorities, 3rd edition. AB - Investments in cancer control--prevention, detection, diagnosis, surgery, other treatment, and palliative care--are increasingly needed in low-income and particularly in middle-income countries, where most of the world's cancer deaths occur without treatment or palliation. To help countries expand locally appropriate services, Cancer (the third volume of nine in Disease Control Priorities, 3rd edition) developed an essential package of potentially cost effective measures for countries to consider and adapt. Interventions included in the package are: prevention of tobacco-related cancer and virus-related liver and cervical cancers; diagnosis and treatment of early breast cancer, cervical cancer, and selected childhood cancers; and widespread availability of palliative care, including opioids. These interventions would cost an additional US$20 billion per year worldwide, constituting 3% of total public spending on health in low-income and middle-income countries. With implementation of an appropriately tailored package, most countries could substantially reduce suffering and premature death from cancer before 2030, with even greater improvements in later decades. PMID- 26578034 TI - Cloud condensation nucleation activities of calcium carbonate and its atmospheric ageing products. AB - Aerosol particles can serve as cloud condensation nuclei (CCN) to form cloud droplets, and its composition is a main factor governing whether an aerosol particle is an effective CCN. Pure mineral dust particles are poor CCN; however, changes in chemical composition of mineral dust aerosol particles, due to heterogeneous reactions with reactive trace gases in the troposphere, can modify their CCN properties. In this study we investigated the CCN activities of CaCO3 (as a surrogate for mineral dust) and its six atmospheric ageing products: Ca(NO3)2, CaCl2, CaSO4, Ca(CH3SO3)2, Ca(HCOO)2, and Ca(CH3COO)2. CaCO3 has a very low CCN activity with a hygroscopicity parameter (kappa) of 0.001-0.003. The CCN activities of its potential atmospheric ageing products are significantly higher. For example, we determined that Ca(NO3)2, CaCl2 and Ca(HCOO)2 have kappa values of ~0.50, similar to that of (NH4)2SO4. Ca(CH3COO)2 has slightly lower CCN activity with a kappa value of ~0.40, and the kappa value of CaSO4 is around 0.02. We further show that exposure of CaCO3 particles to N2O5 at 0% relative humidity (RH) significantly enhances their CCN activity, with kappa values increasing to around 0.02-0.04. Within the experimental uncertainties, it appears that the variation in exposure to N2O5 from ~550 to 15,000 ppbv s does not change the CCN activities of aged CaCO3 particles. This observation indicates that the CaCO3 surface may be already saturated at the shortest exposure. We also discussed the atmospheric implications of our study, and suggested that the rate of change in CCN activities of mineral dust particles in the troposphere is important to determine their roles in cloud formation. PMID- 26578036 TI - Microbial metagenomics of oil sands tailings ponds: small bugs, big data. PMID- 26578035 TI - First Experience of Ultrasound-guided Percutaneous Ablation for Recurrent Hepatoblastoma after Liver Resection in Children. AB - This study aimed to summarize the first experience with ultrasound-guided percutaneous ablation treatment (PAT) for recurrent hepatoblastoma (HB) after liver resection in children. From August 2013 to October 2014, PAT was used to treat 5 children with a total of 8 recurrent HB (mean size, 1.4 +/- 0.8 cm; size range, 0.7-3.1 cm), including 4 patients with 7 tumors in the liver and 1 patient with 1 tumor in the lung. Technical success was achieved in all patients (5/5, 100%). The complete ablation rate after the first ablation session was 80% (4/5) on a patient-by-patient basis and 87.5% (7/8) on a tumor-by-tumor basis. Only 1 patient developed a fever with temperature >39 degrees C; it lasted 4 days after radiofrequency ablation (RFA) and was resolved by conservative therapy. During the follow-up period, new intrahepatic recurrences after PAT were detected in two patients. One died due to tumor progression 4 months after ablation. The median overall survival time after PAT was 13.8 months. PAT is a safe and promising therapy for children with recurrent HB after liver resection, and further investigation in large-scale randomized clinical trials is required to determine its role in the treatment of this disease. PMID- 26578037 TI - Cerebral autoregulation and white matter lesions in Parkinson's disease and multiple system atrophy. AB - Cerebral autoregulation is a complex homeostatic process which ensures constant brain blood supply, despite continuous blood pressure fluctuations. Recent evidence suggests that in Parkinson's disease (PD) and multiple system atrophy (MSA) this process is maintained in a broadened range of blood pressure values, consistent with an adaptive mechanism to increase tolerance to orthostatic hypotension. In PD and MSA orthostatic hypotension may be accompanied by supine hypertension which has been recently linked with cerebral white matter lesions in these conditions. We hypothesize that cerebral autoregulation adaptation to chronic orthostatic hypotension may be directly related with an increase susceptibility to hypertensive peaks. Evaluation of cerebral autoregulatory behavior may thus represent a novel approach to simultaneously target orthostatic symptoms and silent end-organ damage in alpha-synucleinopathies, with a beneficial impact on cerebrovascular and cognitive outcome. PMID- 26578038 TI - Rotigotine effect on sleep in a de novo Parkinson's Disease patient affected by periodic limb movement disorder. PMID- 26578039 TI - Small fiber neuropathy in Parkinson's disease: A clinical, pathological and corneal confocal microscopy study. AB - Autonomic and somatic denervation is well established in Parkinson's disease (PD). OBJECTIVES: (1) To determine whether corneal confocal microscopy (CCM) can non-invasively demonstrate small nerve fiber damage in PD. (2) To identify relationships between corneal nerve parameters, intraepidermal nerve fiber density (IENFD) and clinical features of PD. METHODS: Twenty-six PD patients and 26 controls underwent CCM of both eyes. 24/26 PD patients and 10/26 controls underwent skin biopsies from the dorsa of both feet. PD patients underwent assessment of parasympathetic function [deep breathing heart rate variability (DB HRV)], autonomic symptoms [scale for outcomes in Parkinson's disease - autonomic symptoms (SCOPA-AUT)], motor symptoms [UPDRS-III "ON"] and cumulative Levodopa dose. RESULTS: PD patients had significantly reduced corneal nerve fiber density (CNFD) with increased corneal nerve branch density (CNBD) and corneal nerve fiber length (CNFL) compared to controls. CNBD and CNFL but not CNFD correlated inversely with UPDRS-III and SCOPA-AUT. All CCM parameters correlated strongly with DB-HRV. There was no correlation between CCM parameters and disease duration, cumulative Levodopa dose or pain. IENFD was significantly reduced in PD compared to controls and correlated with CNFD and UPDRS-III. However, unlike CCM measures, IENFD correlated with disease duration and cumulative Levodopa dose but not with autonomic dysfunction. CONCLUSION: CCM identifies corneal nerve fiber pathology, which correlates with autonomic symptoms, parasympathetic deficits and motor scores in patients with PD. IENFD is also reduced and correlates with CNFD and motor symptoms but not parasympathetic deficits, indicating it detects different aspects of peripheral nerve pathology in PD. PMID- 26578040 TI - Early-onset spastic paraparesis as presenting sign of familial Creutzfeldt-Jakob disease. PMID- 26578041 TI - Minimal clinically important difference on the Motor Examination part of MDS UPDRS. AB - BACKGROUND: Recent studies increasingly utilize the Movement Disorders Society Sponsored Unified Parkinson's Disease Rating Scale (MDS-UPDRS). However, the minimal clinically important difference (MCID) has not been fully established for MDS-UPDRS yet. OBJECTIVE: To assess the MCID thresholds for MDS-UPDRS Motor Examination (Part III). METHODS: 728 paired investigations of 260 patients were included. At each visit both MDS-UPDRS and Clinician-reported Global Impression Improvement (CGI-I) scales were assessed. MDS-UPDRS Motor Examination (ME) score changes associated with CGI-I score 4 (no change) were compared with MDS-UPDRS ME score changes associated with CGI-I score 3 (minimal improvement) and CGI-I score 5 (minimal worsening). Both anchor- and distribution-based techniques were utilized to determine the magnitude of MCID. RESULTS: The MCID estimates for MDS UPDRS ME were asymmetric: -3.25 points for detecting minimal, but clinically pertinent, improvement and 4.63 points for observing minimal, but clinically pertinent, worsening. CONCLUSIONS: MCID is the smallest change of scores that are clinically meaningful to patients. These MCID estimates may allow the judgement of a numeric change in MDS-UPDRS ME on its clinical importance. PMID- 26578043 TI - [Impact of early lymphopenia on the risk of febrile neutropenia and hematological toxicity]. AB - BACKGROUND: Hematologic toxicity is a severe complication of chemotherapy. The objective of our study is to evaluate the impact of early lymphopenia on the risk of occurrence of febrile neutropenia and hematological toxicity after aggressive chemotherapy for Hodgkin lymphoma or high grade non-Hodgkin lymphoma. METHODS: This prospective study involved 42 patients who received 193 cycles of chemotherapy in 2009. We assessed the impact of lymphopenia on day 1 and 8 on the risk of occurrence of febrile neutropenia. We also investigated the relation between the occurrence of hematologic toxicity after the first cycle and the subsequent cycles. RESULTS: Febrile neutropenia was observed in 25% of cycles. Grade 3/4 hematologic toxicity occurred in 63% of cycles. Growth factors were used in 79% of cycles. Lymphopenia <= 700/mm3 on day1 and 8 was noted in 21% and 65% of cycles. If the lymphocyte count was <=700/mm3 on day1, the risk of febrile neutropenia was significantly higher (p=0.042) and the mean duration of antibiotic therapy longer (p = 0.013). Lymphopenia <=700/mm3 on day 8 was associated with a greater risk of febrile neutropenia in univariate analysis (OR=2.4; p=0.02). Moreover analyzes showed that this factor was significantly associated with increase in hematologic toxicity (p=0.02), duration of neutropenia (p=0.001) and duration of antibiotics (p=0.05). Hematologic toxicity during the first cycle was predictive of its occurrence in subsequent cycles of chemotherapy (p=0.028). CONCLUSION: Our results confirmed the impact of early lymphopenia on the occurrence of febrile neutropenia and hematologic toxicity after aggressive chemotherapy for Hodgkin lymphoma or high grade non Hodgkin lymphoma. PMID- 26578042 TI - [Prevalence of smoking among 741 High school students from Dakar. Carbon monoxide measurement]. AB - BACKGROUND: Tobacco consumption is a net increase in our areas. In Senegal, as in other African countries, sponsorship of cultural and sporting events in schools promote tobacco use among schoolchildren. Our objective was to assess the prevalence of tobacco in the French School of Jean Mermoz of Dakar by a survey completed by a measurement of carbon monoxide (CO) in expired air. METHODS: seven hundred forty-one students (n = 402 girls and n = 339 boys), aged 11 to 18 years of French and African cultures, participated in the study. A questionnaire with several items of smoking has been distributed to them . Two weeks after the collection of questionnaires, the CO measuring for all students was conducted. RESULTS: The prevalence of smoking in High School was 23.1% and smoking was found more in boys according to the questionnaire and piCO+TM with 13.7% and 7.1% respectively. It affected over the upper age class or equal to fifteen years. The most mentioned reason for the initiation of smoking (45.4% of smokers) was curiosity with a need to be free, followed by the influence of the environment famial (44.4%) and friendly (20.5%). The measurement of carbon monoxide showed that 12.4% of our subjects had a smoking profile with 8% light smoking, 1% moderate smoking, and severe smoking was 3% of our students. A significant difference (p = 0.0021) between the two prevalences was found. CONCLUSION: The carbon monoxide intoxication by tobacco use is responsible for microcirculatory accidents such as tissue hypoxia, whereas smoking affects young students, in which the phenomenon is more precocious. Thus it is urgent to establish a policy of tobacco control in schools. PMID- 26578044 TI - [Women smoking in the Tunisian center: socio demographic characteristics and effects on functional respiratory parameters]. AB - Objectives of this study were to describe sociodemographic characteristics of Tunisian woman smoker and to study her respiratory functional profile. METHODS: all women answered for a questionnaire and benefited of a total physical plethysmography and of a carbon monoxide lung transfer measure (TLCO). RESULTS: 101 smoking women were selected. These women consumed cigarettes (74 %), the snuff "neffa "(10 %) and the water pipe (15 %). A chronic bronchitis was present at 22 women. A proximal bronchial obstruction was found at 11 women who were consumer of the "neffa" and cigarettes. A lower airway obstruction was found in all women consumer of water pipe. The TLCO was low at "neffa" group of women. CONCLUSION: woman smoking has a negative influence on pulmonary function which depends on sociocultural characteristics and on the history of smoking. PMID- 26578045 TI - [Metastatic non-small cell lung cancer: a Tunisian retrospective study about 100 cases]. AB - BACKGROUND: Non-small cell lung cancer (NSCLC) is the most common histologic form, leading causes of cancer death among masculine population. Half of CNPC was metastatic at diagnosis. AIM: To report the epidemiologic, anatomoclinic profile, therapeutic protocols and results of a retrospective study of non-small cell lung cancer (NSCLC) initially metastatic. METHODS: our retrospective study include patients with NSCLC histologically confirmed with inaugural metastasis collected from January 1999 to december 2012. We had analysed epidemiologic, anatomopathologic data (TNM 2009), therapeutic protocols and results in term of overall survival, median survival and event free survival. RESULTS: 100 case of NSCLC have been collected, mea nage was 57 years (22 to 81) and sex -ratio was 4,6. The majority of cases (74%) had a good performance statut (PS <= 2). Pathologic analysis leads to 81 cases of adenocarcinoma (ADK), 16 epidermoid carcinoma. 34% was stager T4 and 31% N2. Metastasis was located to bone in 36 cases, pleural in 26 cases, controlateral lung 26 cases, adrenal gland 17 cases and brain in 13 cases. 82% of patients underwent polychemotherapy as first line of treatment based on regimens conteined platine with mean number of 4 cycles. We have observed 4% of complete response, 61 of partial response, 20% of stabilisation, and 15% of progression. A palliatif radiotherapy of bone or brain metastasis was performed in 38 % of cases. With a median follow-up of 71 months (12 to 130 months), mean survival was 11 months; overall survival (Kaplan-Meier) at 1, 3 and 5 years was respectively 44, 13 and 0 %. CONCLUSION: Despite therapeutic progress in management of NSCLC, the prognosis of metastatic forms still reserved with a poor mean survival reported in litterature (12 years) valideted in our study. This push us to improve research mainly since advent of targeted therapy wich still a promising way in the management of these tumors. PMID- 26578046 TI - [Prevalence of alcoholism in primary care in the governorate of Sousse]. AB - BACKGROUND: The prevalence related to alcohol use disorders in adults is 1.7%. It varies around the world. In Tunisia, as in most Arab and Muslim countries, alcohol consumption is still a taboo and little studied. AIMS: To estimate the prevalence of alcohol abuse and dependence Band to assess associated socio demographic factors in primary care patients in Sousse governorate. METHOD: It's a descriptive study carried out between June and November 2006. The sample included 30 primary care units in Sousse governorate, chosen by a stratified random method. We used the Composite International Diagnostic Interview (CIDI 2.1) translated and validated in Tunisian dialect. RESULTS: Our sample included 2577 participants. The lifetime prevalence of alcohol abuse and during the last 12 months were 2.8% and 1%. Those of alcohol dependence were respectively 0.7% and 0.3%. Only one case of alcohol abuse was found among women and no cases of dependence have been noticed. For men's, the prevalence of alcohol abuse at the lifetime and during the last 12 months were 12.8 % and 4.5 %. For men's alcohol dependence, prevalence rates were 3% and 1.6 %. Associated factors with abuse or alcohol dependence were studied in men's sample (n=560). Alcohol abuse was more common after multivariate logistic regression in the age group betwen18 and 34 years and in those with a diploma. Alcohol dependence was associated with only high level of education. CONCLUSION: Our study provides further evidence that alcohol abuse and dependence in primary care remain low compared to other international studies and highlights the role of primary care physicians in the screening of these health problems especially among men. PMID- 26578047 TI - [Attention Deficit Hyperactivity disorder at schools in Sfax-Tunisia]. AB - BACKGROUND: Frequency, social impact, the negative effects of ADHD on personal development, make it a public health problem. Tunisian existing data confirm its frequency and severity in clinical population. The absence of data in student population has led us to develop this work.The objectives of our study were to study epidemiological profile of ADHD in school population. METHODS: The analysis involved a cross-sectional descriptive study conducted from April 2008 to October 2008 using a representative randomized multistage sample of schoolchildren between 6 and 12 years old. Measurement was performed in two stages first the parents and teachers of each children filled Conners questionnaire separately then students with the score in subscales inattention, hyperactivity with impulsivity higher than 70 were selected for psychiatric interview. Psychiatric interview was intended to confirm or refute the diagnosis of ADHD. The diagnoses were made according to DSM IV-TR. To study the possible associated factors with the disorder they were compared in children with ADHD and children without the disorder taken as controls. RESULTS: A total of 51 students out of 513 had ADHD. Prevalence was found to be 9,94%. For the study of factors associated with ADHD were found in males, neonatal hospitalization, psychiatric and family history of ADHD and the existence of a family dysfunctionment. CONCLUSION: Our prevalence is similar to the majority of those reported by studies conducted through the same methodology as ours. The etiology of ADHD is not unequivocal. The disorder appears to be multifactorial. PMID- 26578048 TI - [Etiologic profile of digital necrosis in an internal medicine department]. AB - BACKGROUND: Digital necrosis is a frequent event in vascular pathology. They are multiple etiologies and are the translation of a general or locoregional pathology. The aim of our study was to clarify the various causes of digital necrosis in an internal medicine department. METHODS: We conducted a retrospective study of 23 cases of digital necrosis collected in the internal medicine department of the hospital Habib Thameur over a period from January 1998 to April 2011 . RESULTS: There were 16 women and 7 men with mean age of 46 years. The cardiovascular risk factors were observed in 39.13% cases. Digital necroses were interested fingers in 73.91% and toes in 30.43% of the cases. The causes were dominated by the connective diseases. The treatment was symptomatic in all cases and etiologic in only two cases. CONCLUSION: In internal medicine, the causes are dominated by connectivites. The prognosis is especially functional. It remains unfavorable in spite of the improvement of the therapeutic and etiologic care. PMID- 26578049 TI - [Profile of non-traumatic osteoarticular diseases in elderly black Africans: about 157 cases seen in Abidjan]. AB - BACKGROUND: The aging of the world population is a phenomenon that is growing progressively. Specific knowledge of osteoarticular disorders in the elderly in black Africa seems limited. AIM: Describe the epidemiological, clinical and etiological characteristics of non-traumatic osteoarticular disorders in elderly black Africans. METHODS: Retrospective and descriptive study concerning black africans patients aged 60 years and over hospitalized in the department of Rheumatology of hospital center of Cocody (Abidjan) in a period of 7 years from January 2000 to December 2007. Were included, 157 records of black africans patients, suffering from a osteoarticular disorder non traumatic with an accurate diagnosis. A structured questionnaire was used to gather epidemiological, clinical and etiological characteristics. RESULTS: The prevalence of elders was 5% of all patients seen in the period of study. The average age was 67 years with the predominance of women (59,7%) and sex-ratio was 0,68. Housewives were predominant (40,6%). The reason for hospitalization was a pain from spine (85,8%) dominated by common low back pain (84,4%). Fever (51,9%) and impaired general health (53.4%) were dominant extraarticular signs. The main etiologies were degenerative (50.5%) with a predominance of common low back pain (38.2%), followed by bacterial osteitis and/or bacterial arthritis (20.5%) and malignancies (hematologic malignancies and metastasis of cancer) in 15.9% of cases. Degenerative pathology was significantly observed in females (p=0.004). CONCLUSION: Non-traumatic osteoarticular diseases in elderly black africans are little frequent in Abidjan and are dominated by degenerative diseases of spine. PMID- 26578050 TI - [Results of total knee arthroplasty on excessive genu varum superior to 20 degrees ]. AB - BACKGROUND: Total knee arthroplasty on excessive genu varum is a more demanding technique and gives worst results than procedures on moderate deformations. It remains a subject of controversies due to the lack of consensus. The purpose of our study is to evaluate the results of total knee arthroplasty (TKA) on excessive genu varum (superior to 20 degrees ) by analyzing pre and post operative clinical and radiological parameters. METHODS: We reviewed retrospectively 40 TKA in 33 patients (seven patients operated bilaterally) performed for genu varum superior to 20 degrees between 2004 and 2011. Pre and post operative evaluation of patients were done according to the International Knee Society score. RESULTS: The mean age of our patients was 67 years with a female predominance. Tricompartmental arthritis was the etiology in all cases. Pre operative IKS score and HKA angle were respectively 52,36 /200 points and 155,7 degrees . The mean follow up was 4 years. Our results were generally satisfactory. The post operative IKS score was 155,36 points (mean joint score of 85.85 points and mean functional score of 69.26 Points) and the post operative HKA angle was 176,17 degrees . Only 60 degrees of patients had normal HKA angle. We noted aseptic loosening of the tibial component in 3 cases. CONCLUSION: TKA on excessive genu varum is more demanding technique. Pre operative planning after analyzing different clinical and radiological parameters is necessary to obtain a good functional outcome while minimizing the rate of complications. PMID- 26578051 TI - [Isokinetic profile of knee muscles in Tunisian competitive footballers]. AB - BACKGROUND: During football several joints are greatly demanded, especially the knees.The interest of the isokinetic is to detect an imbalance between agonist and antagonist muscles of the muscle leg and between dominant and non dominant leg, in order to prevent injuries and to improve the physical fitness of young soccer players. AIM: evaluate the isokinetic profile of flexor and extensor muscles of the knee of competitive footballers Methods : Prospective study conducted in the department of Physical and Rehabilitation Medicine of the Military Tunis Hospital, including 15 competitive footballers and evaluated during the month of August 2012. All patients underwent an isokinetic assessment of agonist and antagonist muscles of the knees in concentric mode 3 speed 60 degrees / 120 degrees and 180 degrees (with analysis of figures and curves), using a Biodex dynamometer. The selected parameters were the time of maximum force (MFM) of the knee flexors and extensors, and the agonists / antagonists ratio (IJ / Q). The data were analyzed by SPSS software. RESULTS: 15 competitive footballers were included. The average age is 23.20 years +/- 3.99 years, ranging from 18 to 28 years. The average size is 167.13 cm +/- 3.6 cm with a range of 163 and 172 cm. The average weight is 60.87 kg +/- 5.97 with a range of 50 to 70 kg. The isokinetic evaluation showed a statistically significant superiority of the flexor muscles of the right knee compared with those of the left knee at the speed 60 / s (p = 0.046) and 120 / s (p = 0.031), whereas this difference has not been found for the extensors muscles. The values of the ratio of quadriceps to hamstring increases with the speed of movement performed, the maximum moment / weight moving in the opposite direction. CONCLUSION: The isokinetic evaluation allows an objective assessment of the flexor and extensor muscles of the knee footballers, in order to correct imbalance and preserve the sporting future of the young footballers. PMID- 26578052 TI - The Pollen-Food Olive-Olive Syndrome. AB - BACKGROUND: The pollen-foods syndrome is rare and of difficult diagnosis. The aim is to report a rare case, it's the four case reported in the literature. CASE REPORT: A 48-year-old woman presenting with palatal itching and generalized urticaria following ingestion of olive fruit, 5 years after being diagnosed with olive pollinosis. She did not have a history of other food allergy or urticaria. The prick-test was positive in olive pollen.The olive pollen specific IgE was positive. The oral provocation test was positive for olives and negative for olive oil. The diagnosis of "pollen-food olive-olive syndrome" was accepted. Interestingly, in this rare case the patient developed olive fruit allergy in the presence of olive pollinosis, but did not experience allergic symptoms to fruits other than olive. CONCLUSION: In spite its rarity this syndrome should be evoke particularly in our country. PMID- 26578053 TI - Salmonella enteriditis inducing cutaneous leucocytoclasic vasculitis: An unusual complication in a patient with an interleukine- 12 receptor beta-1 deficiency. PMID- 26578054 TI - Adenocarcinoma of the colon complicated by a psoas abscess: An exceptional mode of revelation. PMID- 26578055 TI - Severe haemophilia B revealed by intracranial hemorrhage in a newborn. PMID- 26578056 TI - [Rare cause of fever in pregnant women: Hemophagocytic syndrome]. PMID- 26578057 TI - Neoplasia in horseshoe kidney: A diagnostic and therapeutic dilemma. PMID- 26578058 TI - [An exceptional location of pilomatricoma with a rare complication]. PMID- 26578059 TI - [Excellent reponse to radiotherapy in Nelson's syndrome after failed surgery]. PMID- 26578060 TI - Modulation of cortical and spinal inhibition with functional recovery of upper extremity motor function among patients with chronic stroke. AB - PURPOSE: We hypothesized that recovery of upper extremity motor function is associated with reduction of intracortical inhibition and improved reciprocal inhibition. This study examines the relationships of functional recovery in chronic stroke with the intracortical inhibition and spinal reciprocal inhibition. METHODS: Participants were 61 patients with chronic hemiparetic stroke. The participants were applied hybrid assistive neuromuscular dynamic stimulation (HANDS) therapy for 3 weeks. The Fugl-Meyer test upper extremity motor score (FM) and modified Ashworth scale (MAS) were assessed before (T0), immediately after (T1) and 3 months after (T2) the end of HANDS therapy. A paired pulse TMS paradigm was applied to assess short intracortical inhibition (SICI). Reciprocal inhibition (RI) was assessed with H reflex conditioning-test paradigm. RESULTS: FM and MAS were improved until T2. The change of FM from T0 to T2 was positively correlated with the change in affected SICI from T0 toT1. The change of wrist MAS from T0 to T1 was positively correlated with the change of RI. CONCLUSIONS: In chronic stroke patients with moderate or severe hemiparesis, well recovered patients showed disinhibition of ipsilesional hemisphere and increased resiprocal inhibition of forearm. PMID- 26578061 TI - Application of artificial neural network to investigate the effects of 5 fluorouracil on ribonucleotides and deoxyribonucleotides in HepG2 cells. AB - Endogenous ribonucleotides and deoxyribonucleotides are essential metabolites that play important roles in a broad range of key cellular functions. Their intracellular levels could also reflect the action of nucleoside analogues. We investigated the effects of 5-fluorouracil (5-FU) on ribonucleotide and deoxyribonucleotide pool sizes in cells upon exposure to 5-FU for different durations. Unsupervised and supervised artificial neural networks were compared for comprehensive analysis of global responses to 5-FU. As expected, deoxyuridine monophosphate (dUMP) increased after 5-FU incubation due to the inhibition of thymine monophosphate (TMP) synthesis. Interestingly, the accumulation of dUMP could not lead to increased levels of deoxyuridine triphosphate (dUTP) and deoxyuridine diphosphate (dUDP). After the initial fall in intracellular deoxythymidine triphosphate (TTP) concentration, its level recovered and increased from 48 h exposure to 5-FU, although deoxythymidine diphosphate (TDP) and TMP continued to decrease compared with the control group. These findings suggest 5-FU treatment caused unexpected changes in intracellular purine polls, such as increases in deoxyadenosine triphosphate (dATP), adenosine-triphosphate (ATP), guanosine triphosphate (GTP) pools. Further elucidation of the mechanism of action of 5-FU in causing these changes should enhance development of strategies that will increase the anticancer activity of 5-FU while decreasing its resistance. PMID- 26578063 TI - Metabolism of the14C-labeled herbicide clodinafop-propargyl in plant cell cultures of wheat and tobacco. AB - The metabolism of 14C-clodinafop-propargyl (CfP) was examined in cell cultures of wheat (Triticum aestivum L. cv. 'Heines Koga II') and tobacco (Nicotiana tabacum L.). Besides the non-transgenic tobacco culture, cultures transformed separately with cDNA of human cytochrome P450-monooxygenases (P450s) CYP1A1, CYP1A2, CYP3A4, CYP2B6 and CYP2C19 were examined. Experiments with wheat were executed in the presence and absence of safener cloquintocet-mexyl (CqM). After 48 h of incubation, only about 10% of applied 14C was found in media (both tobacco and wheat). Non-extractable residues of 14C-CfP in wheat cells were 16.54% (without CqM) and 30.87% (with CqM). In all tobacco cultures, 82.41-92.46% of applied radioactivity was recovered in cell extracts. In contrast to wheat, non extractable residues amounted only to 1.50-2.82%. As determined by radio-thin layer chromatography (TLC) and -high-performance liquid chromatography (HPLC), the parent CfP was not found in the cell extracts of wheat; in tobacco cell extracts, only traces of CfP were detected. After a hydrolysis of assumed carbohydrate conjugates of CfP derived polar 14C-labeled compounds, TLC and HPLC analysis showed that in wheat, a more complex pattern of metabolites of CfP were observed as compared to all tobacco cultures. In hydrolysates resulting from wheat, the identity of three primary products was confirmed by means of GC-EI-MS: free acid clodinafop (Cf), hydroxy-Cf hydroxylated at the pyridinyl moiety, and 4 (5-chloro-3-fluoropyridin-2-yloxy)phenol. In hydrolysates derived from all tobacco cultures, main metabolite was Cf besides only traces of further unidentified products. Differences among the different tobacco cultures (non transgenic, transgenic) did not emerge. According to kinetics of disappearance of primary metabolite Cf as well as formation of polar soluble products and non extractable residues, metabolization of CfP proceeded at a noticeably higher rate in wheat cells treated with safener CqM than in cells without CqM treatment. Thus, these results indicated a stimulation of CfP's metabolism by CqM, although metabolic profiles observed in CqM treated and non-treated cells (after hydrolysis) were qualitatively similar. The findings obtained from all tobacco cultures suggested that with the exception of ester cleavage to Cf, CfP cannot be metabolized by tobacco itself or by the human P450s examined. PMID- 26578062 TI - Urinary organophosphate metabolite levels in Palestinian pregnant women: results of the Middle East Regional Cooperation Project. AB - The purpose of the study was to measure urinary organophosphate (OP) metabolites in Palestinian pregnant women, and to compare levels with those in pregnant women in Jerusalem and women from the general population in Israel. We measured six dialkyl phosphates in urine samples collected from 148 pregnant women from the West Bank area. Median total dimethyl phosphate (DM(total)) levels were significantly lower in Palestinian women compared to Jerusalem pregnant women and women in Israel (p = 0.041). In Palestinian women reporting that their place of residence was near an agricultural field, DM(total) levels were significantly higher (p = 0.037). Lower urinary excretion of dimethyl phosphate pesticide metabolites in Palestinian women compared to Israeli women may result from lower consumption of fruits and vegetables in the Palestinian population. Our findings highlight differences in OP pesticide exposure in populations with close geographical proximity but with differences in culture, diet, lifestyle, and regulatory oversight of pesticides. PMID- 26578064 TI - Ethanol determination in frozen fruit pulps: an application of quantitative nuclear magnetic resonance. AB - This study reports the chemical composition of five types of industrial frozen fruit pulps (acerola, cashew, grape, passion fruit and pineapple fruit pulps) and compares them with homemade pulps at two different stages of ripening. The fruit pulps were characterized by analyzing their metabolic profiles and determining their ethanol content using quantitative Nuclear Magnetic Resonance (qNMR). In addition, principal component analysis (PCA) was applied to extract more information from the NMR data. We detected ethanol in all industrial and homemade pulps; and acetic acid in cashew, grape and passion fruit industrial and homemade pulps. The ethanol content in some industrial pulps is above the level recommended by regulatory agencies and is near the levels of some post-ripened homemade pulps. This study demonstrates that qNMR can be used to rapidly detect ethanol content in frozen fruit pulps and food derivatives. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26578065 TI - A coherent transcriptional feed-forward motif model for mediating auxin-sensitive PIN3 expression during lateral root development. AB - Multiple plant developmental processes, such as lateral root development, depend on auxin distribution patterns that are in part generated by the PIN-formed family of auxin-efflux transporters. Here we propose that AUXIN RESPONSE FACTOR7 (ARF7) and the ARF7-regulated FOUR LIPS/MYB124 (FLP) transcription factors jointly form a coherent feed-forward motif that mediates the auxin-responsive PIN3 transcription in planta to steer the early steps of lateral root formation. This regulatory mechanism might endow the PIN3 circuitry with a temporal 'memory' of auxin stimuli, potentially maintaining and enhancing the robustness of the auxin flux directionality during lateral root development. The cooperative action between canonical auxin signalling and other transcription factors might constitute a general mechanism by which transcriptional auxin-sensitivity can be regulated at a tissue-specific level. PMID- 26578066 TI - Ligand-induced expansion of the S1' site in the anthrax toxin lethal factor. AB - The Bacillus anthracis lethal factor (LF) is one component of a tripartite exotoxin partly responsible for persistent anthrax cytotoxicity after initial bacterial infection. Inhibitors of the zinc metalloproteinase have been investigated as potential therapeutic agents, but LF is a challenging target because inhibitors lack sufficient selectivity or possess poor pharmaceutical properties. These structural studies reveal an alternate conformation of the enzyme, induced upon binding of specific inhibitors, that opens a previously unobserved deep pocket termed S1'(*) which might afford new opportunities to design selective inhibitors that target this subsite. PMID- 26578067 TI - The benefit of HER2-targeted therapies on overall survival of patients with metastatic HER2-positive breast cancer--a systematic review. AB - INTRODUCTION: This study aimed at evaluating the overall survival (OS) gain associated with human epidermal growth factor receptor 2 (HER2)-directed therapies in patients with metastatic breast cancer (mBC). METHODS: A bibliographic search was conducted in PubMed and Cochrane databases. Only phase III randomized controlled trials (RCTs) including HER2-positive (HER2+) mBC patients were included in this review. OS was defined as time from randomization until the occurrence of death from any cause. Studies have been grouped according to the line of treatment, i.e., first-line or second-line or beyond. RESULTS: Nineteen RCTs were eligible for inclusion, of which 12 assessed therapies targeting HER2+ mBC in the first-line setting. OS improved from 20.3 months in the first RCT (standard chemotherapy; Slamon et al. (N Engl J Med 344:783-92, 2001)) evaluating HER2-targeting therapies to 48 months in the study of Swain et al. (Lancet Oncol 14:461-71, 2013), with triple combination of pertuzumab, trastuzumab and docetaxel. Seven RCTs evaluated the OS of HER2-targeting therapies in the second-line setting and beyond. The OS in second-line setting improved from 15.3 months (capecitabine; Cameron et al. (Breast Cancer Res Treat 112:533-43, 2008)) to 30.7 months (trastuzumab emtansine; Verma et al. (N Engl J Med 367:1783-91, 2012)). In the third-line setting, the association of lapatinib and trastuzumab has demonstrated to improve OS to 4.5 months compared with lapatinib alone (14 months vs. 9.5 months; Blackwell et al. (J Clin Oncol 30:2585 92, 2012)). CONCLUSIONS: HER2-directed therapies had an undeniable beneficial impact on the OS of patients with HER2+ mBC. The triple combination of docetaxel, pertuzumab and trastuzumab is associated with a survival extent of more than 4.5 years, compared with a life expectancy of 1.5 years achieved 14 years ago. PMID- 26578070 TI - 1,8- and 1,4-cineole enhance spontaneous excitatory transmission by activating different types of transient receptor potential channels in the rat spinal substantia gelatinosa. AB - Although transient receptor potential (TRP) channels expressed in the spinal substantia gelatinosa play a role in modulating nociceptive transmission, their properties have not been fully examined yet. In order to address this issue, the effects of 1,8-cineole and its stereoisomer 1,4-cineole on excitatory transmission were examined by applying the whole-cell patch-clamp technique to substantia gelatinosa neurons in adult rat spinal cord slices. Miniature excitatory postsynaptic current frequency was increased by 1,8- and 1,4-cineole. The cineole activities were repeated and resistant to voltage-gated Na+ -channel blocker tetrodotoxin. The 1,8-cineole activity was inhibited by TRP ankyrin-1 (TRPA1) antagonists (HC-030031 and mecamylamine) but not TRP vanilloid-1 (TRPV1) antagonists (capsazepine and SB-366791), whereas the 1,4-cineole activity was depressed by the TRPV1 but not TRPA1 antagonists. Although 1,8- and 1,4-cineole reportedly activate TRP melastatin-8 (TRPM8) channels, their activities were unaffected by TRPM8 antagonist 4-(3-chloro-2-pyridinyl)-N-[4-(1,1 dimethylethyl)phenyl]-1-piperazinecarboxamide. Monosynaptically evoked C-fiber, but not Adelta-fiber excitatory postsynaptic current amplitude, was reduced by 1,8- and 1,4-cineole. These results indicate that 1,8- and 1,4-cineole increase spontaneous l-glutamate release from nerve terminals by activating TRPA1 and TRPV1 channels, respectively, while inhibiting C-fiber but not Adelta-fiber evoked l-glutamate release. This difference between 1,8- and 1,4-cineole may serve to know the properties of TRP channels located in the central terminals of primary-afferent neurons. The spinal dorsal horn lamina II (substantia gelatinosa; SG) plays a pivotal role in regulating nociceptive transmission from the periphery. We found out in the SG that 1,4- and 1,8-cineole activate TRPV1 and TRPA1 channels, respectively, located in primary-afferent, possibly C-fiber, central terminals. This difference may serve to know the properties of TRP channels expressed in the central terminals. PMID- 26578069 TI - Genomic insights into the evolution of hybrid isoprenoid biosynthetic gene clusters in the MAR4 marine streptomycete clade. AB - BACKGROUND: Considerable advances have been made in our understanding of the molecular genetics of secondary metabolite biosynthesis. Coupled with increased access to genome sequence data, new insight can be gained into the diversity and distributions of secondary metabolite biosynthetic gene clusters and the evolutionary processes that generate them. Here we examine the distribution of gene clusters predicted to encode the biosynthesis of a structurally diverse class of molecules called hybrid isoprenoids (HIs) in the genus Streptomyces. These compounds are derived from a mixed biosynthetic origin that is characterized by the incorporation of a terpene moiety onto a variety of chemical scaffolds and include many potent antibiotic and cytotoxic agents. RESULTS: One hundred and twenty Streptomyces genomes were searched for HI biosynthetic gene clusters using ABBA prenyltransferases (PTases) as queries. These enzymes are responsible for a key step in HI biosynthesis. The strains included 12 that belong to the 'MAR4' clade, a largely marine-derived lineage linked to the production of diverse HI secondary metabolites. We found ABBA PTase homologs in all of the MAR4 genomes, which averaged five copies per strain, compared with 21 % of the non-MAR4 genomes, which averaged one copy per strain. Phylogenetic analyses suggest that MAR4 PTase diversity has arisen by a combination of horizontal gene transfer and gene duplication. Furthermore, there is evidence that HI gene cluster diversity is generated by the horizontal exchange of orthologous PTases among clusters. Many putative HI gene clusters have not been linked to their secondary metabolic products, suggesting that MAR4 strains will yield additional new compounds in this structure class. Finally, we confirm that the mevalonate pathway is not always present in genomes that contain HI gene clusters and thus is not a reliable query for identifying strains with the potential to produce HI secondary metabolites. CONCLUSIONS: We found that marine derived MAR4 streptomycetes possess a relatively high genetic potential for HI biosynthesis. The combination of horizontal gene transfer, duplication, and rearrangement indicate that complex evolutionary processes account for the high level of HI gene cluster diversity in these bacteria, the products of which may provide a yet to be defined adaptation to the marine environment. PMID- 26578071 TI - The Persian methamphetamine use in methadone treatment in Iran: implication for prevention and treatment in an upper-middle income country. AB - As the most populated Persian Gulf country in West Asia, methamphetamine use in methadone maintenance treatment (MMT) is a new health concern in Iran. Methamphetamine use in MMT can originate in methadone misconceptions or the stimulant effects of methamphetamine use. Several research studies have highlighted the prevalence of methamphetamine use in Iran and conducting further studies on this issue is being developed. Opiate use is treated with MMT. But, there is no effective pharmacological treatment for methamphetamine use and cognitive-behavioral interventions have still remained the best practice. As a psychostimulant drug, methamphetamine use can lead to poor treatment outcomes or even treatment failure among patients in MMT. Therefore, the implementation of methamphetamine education and prevention programs in MMT is required. Prescribing adequate methadone dose and the treatment of comorbidities as well as, doing a series of activities outside treatment is underscored. Methamphetamine use has a chronic nature and methamphetamine treatment is a long-term procedure with a high rate of relapse. Therefore, the implementation of long-term motivational interviewing, teaching necessary skills to prevent relapse and case management is highlighted. A long-term collaboration between treatment teams, patients and their families is suggested to manage methamphetamine use in MMT. PMID- 26578072 TI - Genome-wide study on intramuscular fat in Italian Large White pig breed using the PorcineSNP60 BeadChip. AB - Genome-wide association study results are presented for intramuscular fat in Italian Large White pig breed. A total of 886 individuals were genotyped with PorcineSNP60 BeadChip. After quality control performed with plink software and in R environment, 49 208 markers remained for the association analysis. The genome wide association studies was conducted using linear mixed model implemented in GenABEL. We detected seven new SNPs of genes till now not found associated to intramuscular fat (IMF). Three markers map in a wide intergenic region rich of QTL linked to fat traits, one map 388 kb upstream the gene SDK1, one map inside PPP3CA gene, one inside SCPEP1 gene and the last is not mapped in the porcine genome yet. Associations here presented indicate a moderate effect of these genes on IMF. In particular, PPP3CA, that is involved in the oxidative metabolism of skeletal muscle, could be considerated as an interesting candidate gene for IMF content in pigs. However, further studies are needed to clarify the role of these genes on the physiological processes involved in IMF regulation. These results may be useful to control this trait that is important in terms of nutritional, technological and organoleptic characteristics of fresh meat and processed products. PMID- 26578073 TI - Three-part mould technique for fabrication of hollow thumb prosthesis: A case report. AB - BACKGROUND: The purpose of this article is to describe a technique which helps in fabrication of glove-type hollow thumb prosthesis using three-part mould technique. CASE DESCRIPTION AND METHODS: Patient reported to the Department of Private dental clinic, Delhi, India with a chief complaint of missing partial left thumb and wanted to get it replaced. A complete clinical hand examination was carried out, which revealed a residual stump of 1 cm length. After ensuring the medical conditions to be normal, fabrication of hollow thumb prosthesis was planned using three-part mould technique. FINDINGS AND OUTCOMES: The prosthesis delivered to the patient was highly retentive because of its glove-type retention and lighter weight; feedback from the patient regarding retention was excellent. The prosthesis was aesthetically pleasing because of its excellent colour matching with the skin, and each and every part of the prosthesis could be colour customized because of easy retrieval of the third part of the mould, as well. CONCLUSION: A technique of hollow thumb prosthesis has been described in this article which helps in reduction in weight, easy packing of silicone material into the mould and easy colour customization at the knuckles area of the dorsal and ventral aspect of the prosthesis. CLINICAL RELEVANCE: This three-part mould technique helps to fabricate hollow prosthesis which increases retainability and at the same time allows easy packing of silicone material and easy colour customization at the knuckles area of the prosthesis. PMID- 26578074 TI - Trimethoprim-Sulfamethoxazole Therapy Reduces Failure and Recurrence in Methicillin-Resistant Staphylococcus aureus Skin Abscesses after Surgical Drainage. AB - OBJECTIVE: To determine whether a 3-day vs 10-day course of antibiotics after surgical drainage of skin abscesses is associated with different failure and recurrence rates. STUDY DESIGN: Patients age 3 months to 17 years seeking care at a pediatric emergency department with an uncomplicated skin abscess that required surgical drainage were randomized to receive 3 or 10 days of oral trimethoprim sulfamethoxazole therapy. Patients were evaluated 10-14 days later to assess clinical outcome. Patients were followed for 6 months to determine the cumulative rate of recurrent skin infections. RESULTS: Among the 249 patients who were enrolled, 87% of wound cultures grew Staphylococcus aureus (S aureus) (55% methicillin-resistant S aureus [MRSA], 32% methicillin-sensitive S aureus), 11% other organisms, and 2% no growth. Thirteen patients experienced treatment failure. Among all patients, no significant difference in failure rates between the 3- and 10-day treatment groups was found. After we stratified patients by the infecting organism, only patients with MRSA infection were more likely to experience treatment failure in the 3-day group than the 10-day group (P = .03, rate difference 10.1%, 95% CI 2.1%-18.2%) Recurrent infection within 1 month of surgical drainage was more likely in patients infected with MRSA who received 3 days of antibiotics. (P = .046, rate difference 10.3%, 95% CI 0.8%-19.9%). CONCLUSION: Patients with MRSA skin abscesses are more likely to experience treatment failure and recurrent skin infection if given 3 rather than 10 days of trimethoprim-sulfamethoxazole after surgical drainage. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02024867. PMID- 26578075 TI - Gabapentin Use in the Neonatal Intensive Care Unit. AB - Gabapentin was used for the treatment of term and preterm infants with suspected visceral hyperalgesia caused by a variety of neurologic and gastrointestinal morbidities. Improved feeding tolerance and decreased irritability were seen, as well as decreased usage of opioids and benzodiazepines. Adverse events occurred with abrupt discontinuation of this medication. PMID- 26578076 TI - Characterization of a recent malaria outbreak in the autonomous indigenous region of Guna Yala, Panama. AB - BACKGROUND: This study aims to describe the epidemiological and entomological factors associated with a recent malaria outbreak that occurred in 2012 in a socially marginalized population from Guna Yala Comarca in Panama. METHODS: A descriptive and observational study was conducted by analysing demographic and epidemiological data from all malaria cases registered during 2012 in the Comarca Guna Yala, Panama. Malaria intensity indicators were calculated during the study period. Entomological evaluations were performed monthly, from October to December 2012, in the three communities that presented the most intense malaria transmission during the first semester of 2012. Anopheles breeding habitats were also characterized. RESULTS: During the studied period, 6754 blood smears were examined (17.8 % of the total population), and 143 were confirmed as positive for Plasmodium vivax. A significant increase of malaria transmission risk indicators (API: 3.8/1000, SPR: 2.1 %) was observed in Guna Yula, when compared with previous years, and also in comparison with estimates from the whole country. Anopheles albimanus was the most abundant and widespread (877; 72.0 %) vector species found in the three localities, followed by Anopheles punctimacula (231; 19.0 %) and Anopheles aquasalis (110; 9.0 %). Three An. albimanus pools were positive for P. vivax, showing an overall pooled prevalence estimate of 0.014. CONCLUSIONS: Data analysis confirmed that during 2012 a malaria epidemic occurred in Guna Yala. Panama. This study provides baseline data on the local epidemiology of malaria in this vulnerable region of Panama. This information will be useful for targeting control strategies by the National Malaria Control Programme. PMID- 26578077 TI - A threshold of mechanical strain intensity for the direct activation of osteoblast function exists in a murine maxilla loading model. AB - The response to the mechanical loading of bone tissue has been extensively investigated; however, precisely how much strain intensity is necessary to promote bone formation remains unclear. Combination studies utilizing histomorphometric and numerical analyses were performed using the established murine maxilla loading model to clarify the threshold of mechanical strain needed to accelerate bone formation activity. For 7 days, 191 kPa loading stimulation for 30 min/day was applied to C57BL/6J mice. Two regions of interest, the AWAY region (away from the loading site) and the NEAR region (near the loading site), were determined. The inflammatory score increased in the NEAR region, but not in the AWAY region. A strain intensity map obtained from [Formula: see text] images was superimposed onto the images of the bone formation inhibitor, sclerostin positive cell localization. The number of sclerostin-positive cells significantly decreased after mechanical loading of more than [Formula: see text] in the AWAY region, but not in the NEAR region. The mineral apposition rate, which shows the bone formation ability of osteoblasts, was accelerated at the site of surface strain intensity, namely around [Formula: see text], but not at the site of lower surface strain intensity, which was around [Formula: see text] in the AWAY region, thus suggesting the existence of a strain intensity threshold for promoting bone formation. Taken together, our data suggest that a threshold of mechanical strain intensity for the direct activation of osteoblast function and the reduction of sclerostin exists in a murine maxilla loading model in the non inflammatory region. PMID- 26578078 TI - Consideration of multiple load cases is critical in modelling orthotropic bone adaptation in the femur. AB - Functional adaptation of the femur has been investigated in several studies by embedding bone remodelling algorithms in finite element (FE) models, with simplifications often made to the representation of bone's material symmetry and mechanical environment. An orthotropic strain-driven adaptation algorithm is proposed in order to predict the femur's volumetric material property distribution and directionality of its internal structures within a continuum. The algorithm was applied to a FE model of the femur, with muscles, ligaments and joints included explicitly. Multiple load cases representing distinct frames of two activities of daily living (walking and stair climbing) were considered. It is hypothesised that low shear moduli occur in areas of bone that are simply loaded and high shear moduli in areas subjected to complex loading conditions. In addition, it is investigated whether material properties of different femoral regions are stimulated by different activities. The loading and boundary conditions were considered to provide a physiological mechanical environment. The resulting volumetric material property distribution and directionalities agreed with ex vivo imaging data for the whole femur. Regions where non-orthogonal trabecular crossing has been documented coincided with higher values of predicted shear moduli. The topological influence of the different activities modelled was analysed. The influence of stair climbing on the properties of the femoral neck region is highlighted. It is recommended that multiple load cases should be considered when modelling bone adaptation. The orthotropic model of the complete femur is released with this study. PMID- 26578079 TI - Morphologic and angular planning for cam resection in femoro-acetabular impingement: value of the omega angle. AB - PURPOSE: The alpha angle is used to quantify in a single plane the head-neck junction deformity of cam femoro-acetabular impingement (FAI). When the deformity overlaps the superior retinaculum, femoral head osteoplasty in this area can jeopardise intra-articular vascular structures. This study proposes a new angular measure of the linear radial extension of cam deformity as a planning tool for bone resection and compares the accuracy of femoral head osteoplasty using open and arthroscopic surgery. METHODS: Twenty-five symptomatic patients operated on for FAI were included in this study. Radial magnetic resonance imaging (MRI) was done before and after surgery. Bi-dimensional coordinates of the vascular foramina and radial extension of the deformity (omega angle) were measured. This extension was correlated with the vascular foramina location and alpha-angle value. Accuracy of resection and hip function were evaluated before and after surgery. RESULTS: The cam lesion frequently extended posteriorly. No relation between values of alpha and omega angles was found. Cam resection was complete in 88 % of cases; there was a significant improvement in outcome score after surgery. CONCLUSIONS: This study showed that alpha angle, measured in one plane, was not a predictor of the radial extension of cam deformity. To achieve a full resection, it was frequently necessary to extend the femoral head osteoplasty over the retinacular area. Pre-operative determination of the omega angle and location of the vascular foramina helped improve cam resection safety and accuracy. PMID- 26578080 TI - Total knee arthroplasty in advanced tuberculous arthritis of the knee. AB - BACKGROUND: Controversies regarding the treatment of advanced tuberculosis of the knee still exist. We retrospectively investigated protocols of total knee arthroplasty (TKA) and their efficacy in patients with advanced tuberculosis. METHODS: Nine TKAs associated with advanced tuberculosis were performed at our institution between 2008 and 2013, with a mean follow-up of 4.4 years (range 2-7 years). In four cases with elevated inflammatory biomarkers, patients received three months of antitubercular drug treatment followed by two-stage TKA. In the remaining five cases with normal biomarkers, patients received one-stage TKA with no pre-operative drug therapy. All patients received antitubercular therapy for one year post-operatively. Clinical and radiological data during follow-up were gathered to evaluate the effects of treatment. RESULTS: There was no tuberculosis reactivation and all cases demonstrated marked improvement in function and favorable states of prostheses. Specifically, the mean Hospital for Special Surgery (HSS) knee score increased from 44.8 (range 30-60) preoperatively to 82.7 (range 64-92) at last follow-up (P < 0.05). The average range of motion was 56 degrees (range 10 degrees to 90 degrees ) before surgery and 94 degrees (range 80-110) at final follow-up (P < 0.05). Elevated erythrocyte sedimentation rates (ESR) and C-reactive protein (CRP) levels returned to normal in a mean of 4.0 months (range 3-5 months) and 3.9 months (range 3-6 months) post-operatively, respectively. CONCLUSION: Although a consensus of views regarding surgical timing, prosthesis selection, and peri-operative antitubercular therapy has not been reached, our results suggest that TKA can be performed for advanced tuberculous arthritis. PMID- 26578081 TI - Anxiolytic-Like Effects of Increased Ghrelin Receptor Signaling in the Amygdala. AB - BACKGROUND: Besides the well-known effects of ghrelin on adiposity and food intake regulation, the ghrelin system has been shown to regulate aspects of behavior including anxiety and stress. However, the effect of virus-mediated overexpression of the ghrelin receptor in the amygdala has not previously been addressed directly. METHODS: First, we examined the acute effect of peripheral ghrelin administration on anxiety- and depression-like behavior using the open field, elevated plus maze, forced swim, and tail suspension tests. Next, we examined the effect of peripheral ghrelin administration and ghrelin receptor deficiency on stress in a familiar and social environment using the Intellicage system. Importantly, we also used a novel approach to study ghrelin receptor signaling in the brain by overexpressing the ghrelin receptor in the amygdala. We examined the effect of ghrelin receptor overexpression on anxiety-related behavior before and after acute stress and measured the modulation of serotonin receptor expression. RESULTS: We found that ghrelin caused an anxiolytic-like effect in both the open field and elevated plus maze tests. Additionally, it attenuated air-puff-induced stress in the social environment, while the opposite was shown in ghrelin receptor deficient mice. Finally, we found that overexpression of the ghrelin receptor in the basolateral division of the amygdala caused an anxiolytic-like effect and decreased the 5HT1a receptor expression. CONCLUSIONS: Ghrelin administration and overexpression of the ghrelin receptor in the amygdala induces anxiolytic-like behavior. Since the ghrelin receptor has high constitutive activity, ligand-independent signaling in vivo may be important for the observed anxiolytic-like effects. The anxiolytic effects seem to be mediated independently from the HPA axis, potentially engaging the central serotonin system. PMID- 26578082 TI - Effects of Low-Dose and Very Low-Dose Ketamine among Patients with Major Depression: a Systematic Review and Meta-Analysis. AB - BACKGROUND: Several recent trials indicate low-dose ketamine produces rapid antidepressant effects. However, uncertainty remains in several areas: dose response, consistency across patient groups, effects on suicidality, and possible biases arising from crossover trials. METHODS: A systematic search was conducted for relevant randomized trials in Medline, Embase, and PsycINFO databases up to August 2014. The primary endpoints were change in depression scale scores at days 1, 3 and 7, remission, response, suicidality, safety, and tolerability. Data were independently abstracted by 2 reviewers. Where possible, unpublished data were obtained on treatment effects in the first period of crossover trials. RESULTS: Nine trials were identified, including 201 patients (52% female, mean age 46 years). Six trials assessed low-dose ketamine (0.5 mg/kg i.v.) and 3 tested very low-dose ketamine (one trial assessed 50 mg intra-nasal spray, another assessed 0.1-0.4 mg/kg i.v., and another assessed 0.1-0.5 mg/kg i.v., intramuscular, or s.c.). At day 3, the reduction in depression severity score was less marked in the very low-dose trials (P homogeneity <.05) and among bipolar patients. In analyses excluding the second period of crossover trials, response rates at day 7 were increased with ketamine (relative risk 3.4, 95% CI 1.6-7.1, P=.001), as were remission rates (relative risk 2.6, CI 1.2-5.7, P=.02). The absolute benefits were large, with day 7 remission rates of 24% vs 6% (P=.02). Seven trials provided unpublished data on suicidality item scores, which were reduced on days 1 and 3 (both P<.01) but not day 7. CONCLUSION: Low-dose ketamine appears more effective than very low dose. There is substantial heterogeneity in clinical response, with remission among one-fifth of patients at 1 week but most others having benefits that are less durable. Larger, longer term parallel group trials are needed to determine if efficacy can be extended and to further assess safety. PMID- 26578083 TI - Motivational processes in mild cognitive impairment and Alzheimer's disease: results from the Motivational Reserve in Alzheimer's (MoReA) study. AB - BACKGROUND: Brain reserve, i.e., the ability of the brain to tolerate age- and disease-related changes in a way that cognitive function is still maintained, is assumed to be based on the lifelong training of various abilities. The Motivational Reserve in Alzheimer's (MoReA) is a longitudinal study that aims to examine motivational processes as a protective factor in mild Alzheimer's dementia (AD) and mild cognitive impairment (MCI). This paper presents the results of motivational variables, frequency of diagnoses, and prediction of global cognition as well as depression in a one-year longitudinal study. METHODS: The sample consists of 64 subjects with MCI and 47 subjects with mild AD at baseline. At baseline, the physical/neurological examinations, standard clinical assessment, neuropsychological testing, and assessment of motivational variables were performed. At follow-up (FU) one year later, neuropsychological testing including cognition, functional abilities, behavioral and affective symptoms, and global clinical assessments of severity have been repeated. RESULTS: AD cases have lower motivational capacities as measured with a midlife motivation-related occupational score and informant-reported present motivational processes, but do not differ with regard to delay of gratification (DoG) and self-reported motivational processes. DoG and delay discounting (DD) were relatively stable during the measurement interval. However, 20 % of the MCI cases converted to mild AD at FU, and 17 % of the mild AD cases converted to moderate AD. The rate of depression of Alzheimer's disease was 9 at baseline and 21 % at FU, and the rate of apathy was 7 and 14 %, respectively. Global cognition at FU was mainly predicted by baseline global cognition but also by one of the motivational variables (scenario test). Depression at FU was predicted mainly by two motivational variables (self-reported and informant-reported motivational processes). CONCLUSIONS: This research might inform motivation-related strategies for prevention and early intervention with older people or people at risk for AD. PMID- 26578085 TI - Should GPs be paid to reduce unnecessary referrals? PMID- 26578084 TI - Initial report of the osteogenesis imperfecta adult natural history initiative. AB - BACKGROUND: A better understanding of the natural history of osteogenesis imperfecta (OI) in adulthood should improve health care for patients with this rare condition. METHODS: The Osteogenesis Imperfecta Foundation established the Adult Natural History Initiative (ANHI) in 2010 to give voice to the health concerns of the adult OI community and to begin to address existing knowledge gaps for this condition. Using a web-based platform, 959 adults with self reported OI, representing a wide range of self-reported disease severity, reported symptoms and health conditions, estimated the impact of these concerns on present and future health-related quality of life (QoL) and completed a Patient-Reported Outcomes Measurement Information System (PROMIS(r)) survey of health issues. RESULTS: Adults with OI report lower general physical health status (p < .0001), exhibit a higher prevalence of auditory (58% of sample versus 2-16% of normalized population) and musculoskeletal (64% of sample versus 1-3% of normalized population) concerns than the general population, but report generally similar mental health status. Musculoskeletal, auditory, pulmonary, endocrine, and gastrointestinal issues are particular future health-related QoL concerns for these adults. Numerous other statistically significant differences exist among adults with OI as well as between adults with OI and the referent PROMIS(r) population, but the clinical significance of these differences is uncertain. CONCLUSIONS: Adults with OI report lower general health status but are otherwise more similar to the general population than might have been expected. While reassuring, further analysis of the extensive OI-ANHI databank should help identify areas of unique clinical concern and for future research. The OI-ANHI survey experience supports an internet-based strategy for successful patient centered outcomes research in rare disease populations. PMID- 26578086 TI - Radon level in a Nigerian University Campus. AB - BACKGROUND: Globally, radon is a natural contaminant that affects indoor air quality. Several epidemiological studies have implicated high radon levels in the causality of lung cancer. The study therefore determined the environmental level of radon in selective offices in the Obafemi Awolowo University, Ile-Ife. The study employed a descriptive cross-sectional design. A Pro 3-series radon detector was used to determine the radon levels in randomly selected offices. The instrument was set-up in each office and after 48 h, reading was taken and recorded on a proforma data sheet. The structural characteristics of the offices were also assessed by observation. RESULTS: The result revealed that the radon level obtained in the sampled offices ranged from 0.0 to 5.3 pCi/L (196 Bq/m(3)). The median concentration of radon obtained from sampled offices was 0.9 pCi/L. Almost all (95 %) of the offices had radon levels within the 'permissible' reference level recommended by World Health Organization. Radon levels also showed a statistically significant decline with height of office building with the mean concentration of radon in offices located on the basement, ground floor and first floor being 1.54 +/- 1.32, 0.99 +/- 0.56, 0.63 +/- 0.41 pCi/L respectively, (F statistic 5.8, p < 0.001). CONCLUSION: The radon levels obtained in most assessed offices in Obafemi Awolowo University were found to be within the permissible reference levels. Mitigation measures should be put in place in the few offices above permissible levels. PMID- 26578087 TI - How do general practitioners use 'safety netting' in acutely ill children? AB - BACKGROUND: 'Safety netting' advice allows general practitioners (GPs) to cope with diagnostic uncertainty in primary care. It informs patients on 'red flag' features and when and how to seek further help. There is, however, insufficient evidence to support useful choices regarding 'safety netting' procedures. OBJECTIVES: To explore how GPs apply 'safety netting' in acutely ill children in Flanders. METHODS: We designed a qualitative study consisting of semi-structured interviews with 37 GPs across Flanders. Two researchers performed qualitative analysis based on grounded theory components. RESULTS: Although unfamiliar with the term, GPs perform 'safety netting' in every acutely ill child, guided by their intuition without the use of specific guidelines. They communicate 'red flag' features, expected time course of illness and how and when to re-consult and try to tailor their advice to the context, patient and specific illness. Overall, GPs perceive 'safety netting' as an important element of the consultation, acknowledging personal and parental limitations, such as parents' interpretation of their advice. GPs do not feel a need for any form of support in the near future. CONCLUSION: GPs apply 'safety netting' intuitively and tailor the content. Further research should focus on the impact of 'safety netting' on morbidity and how the advice is conveyed to parents. PMID- 26578088 TI - Reproductive systems biology tackles global issues of population growth, food safety and reproductive health. PMID- 26578089 TI - National proficiency-gain curves for minimally invasive gastrointestinal cancer surgery. AB - BACKGROUND: Minimal access surgery for gastrointestinal cancer has short-term benefits but is associated with a proficiency-gain curve. The aim of this study was to define national proficiency-gain curves for minimal access colorectal and oesophagogastric surgery, and to determine the impact on clinical outcomes. METHODS: All adult patients undergoing minimal access oesophageal, colonic and rectal surgery between 2002 and 2012 were identified from the Hospital Episode Statistics database. Proficiency-gain curves were created using risk-adjusted cumulative sum analysis. Change points were identified, and bootstrapping was performed with 1000 iterations to identify a confidence level. The primary outcome was 30-day mortality; secondary outcomes were 90-day mortality, reintervention, conversion and length of hospital stay. RESULTS: Some 1696, 15 008 and 16 701 minimal access oesophageal, rectal and colonic cancer resections were performed during the study period. The change point in the proficiency-gain curve for 30-day mortality for oesophageal, rectal and colonic surgery was 19 (confidence level 98.4 per cent), 20 (99.2 per cent) and three (99.5 per cent) procedures; the mortality rate fell from 4.0 to 2.0 per cent (relative risk reduction (RRR) 0.50, P = 0.033), from 2.1 to 1.2 per cent (RRR 0.43, P < 0.001) and from 2.4 to 1.8 per cent (RRR 0.25, P = 0.058) respectively. The change point in the proficiency-gain curve for reintervention in oesophageal, rectal and colonic resection was 19 (98.1 per cent), 32 (99.5 per cent) and 26 (99.2 per cent) procedures respectively. There were also significant proficiency-gain curves for 90-day mortality, conversion and length of stay. CONCLUSION: The introduction of minimal access gastrointestinal cancer surgery has been associated with a proficiency-gain curve for mortality and major morbidity at a national level. Unnecessary patient harm should be avoided by appropriate training and monitoring of new surgical techniques. PMID- 26578090 TI - The role of parasite-driven selection in shaping landscape genomic structure in red grouse (Lagopus lagopus scotica). AB - Landscape genomics promises to provide novel insights into how neutral and adaptive processes shape genome-wide variation within and among populations. However, there has been little emphasis on examining whether individual-based phenotype-genotype relationships derived from approaches such as genome-wide association (GWAS) manifest themselves as a population-level signature of selection in a landscape context. The two may prove irreconcilable as individual level patterns become diluted by high levels of gene flow and complex phenotypic or environmental heterogeneity. We illustrate this issue with a case study that examines the role of the highly prevalent gastrointestinal nematode Trichostrongylus tenuis in shaping genomic signatures of selection in red grouse (Lagopus lagopus scotica). Individual-level GWAS involving 384 SNPs has previously identified five SNPs that explain variation in T. tenuis burden. Here, we examine whether these same SNPs display population-level relationships between T. tenuis burden and genetic structure across a small-scale landscape of 21 sites with heterogeneous parasite pressure. Moreover, we identify adaptive SNPs showing signatures of directional selection using F(ST) outlier analysis and relate population- and individual-level patterns of multilocus neutral and adaptive genetic structure to T. tenuis burden. The five candidate SNPs for parasite driven selection were neither associated with T. tenuis burden on a population level, nor under directional selection. Similarly, there was no evidence of parasite-driven selection in SNPs identified as candidates for directional selection. We discuss these results in the context of red grouse ecology and highlight the broader consequences for the utility of landscape genomics approaches for identifying signatures of selection. PMID- 26578092 TI - Sizing the optimal dimensions of a vaccine delivery system: a particulate matter. AB - Encapsulation of subunit antigens into particulate vaccine delivery systems is a promising strategy to enhance their immunogenicity. The most basic physical parameter of these particles, their size, has a profound effect on the immunogenicity of the vaccine. Interestingly, the optimal particle size varies depending on the desired type of immunological memory and the route of administration. In this editorial, we draw attention to the effect of particle size on the resulting immune response and accentuate the importance of adequate particle sizing methods, within and beyond the intended size range of the delivery vehicle, to assess vaccine quality. PMID- 26578091 TI - Molecular cloning and characterization of amh and dax1 genes and their expression during sex inversion in rice-field eel Monopterus albus. AB - The full-length cDNAs of amh and dax1 in the hermaphrodite, rice-field eel (Monopterus albus), were cloned and characterized in this study. Multiple sequence alignment revealed Dax1 was well conserved among vertebrates, whereas Amh had a low degree of similarity between different vertebrates. Their expression profiles in gonads during the course of sex inversion and tissues were investigated. The tissue distribution indicated amh was expressed mostly in gonads and was scarcely detectable in other tissues, whereas the expression of dax1 was widespread among the different tissues, especially liver and gonads. amh was scarcely detectable in ovaries whereas it was abundantly expressed in both ovotestis and testis. By contrast, dax1 was highly expressed in ovaries, especially in ?IV (ovaries in IV stage), but it was decreased significantly in ?/?I (ovotestis in I stage). Its expression was increased again in ?/?III (ovotestis in III stage), and then decreased to a low level in testis. These significant different expression patterns of amh and dax1 suggest the increase of amh expression and the decline of dax1 expression are important for the activation of testis development, and the high level of amh and a low level of dax1 expression are necessary for maintenance of testis function. PMID- 26578093 TI - On the Origin of Heterotrophy. AB - The theory of autotrophic origins of life posits that the first cells on Earth satisfied their carbon needs from CO2. At hydrothermal vents, spontaneous synthesis of methane via serpentinization links an energy metabolic reaction with a geochemical homologue. If the first cells were autotrophs, how did the first heterotrophs arise, and what was their substrate? We propose that cell mass roughly similar to the composition of Escherichia coli was the substrate for the first chemoorganoheterotrophs. Amino acid fermentations, pathways typical of anaerobic clostridia and common among anaerobic archaea, in addition to clostridial type purine fermentations, might have been the first forms of heterotrophic carbon and energy metabolism. Ribose was probably the first abundant sugar, and the archaeal type III RubisCO pathway of nucleoside monophosphate conversion to 3-phosphoglycerate might be a relic of ancient heterotrophy. Participation of chemiosmotic coupling and flavin-based electron bifurcation--a soluble energy coupling process--in clostridial amino acid and purine fermentations is consistent with an autotrophic origin of both metabolism and heterotrophy, as is the involvement of S(0) as an electron acceptor in the facilitated fermentations of anaerobic heterotrophic archaea. PMID- 26578094 TI - Ultra-performance liquid chromatography-tandem mass spectrometric assay for the simultaneous determination of brucine, strychnine and brucine N-oxide in rat plasma: application to a pharmacokinetic study. AB - A rapid, simple and sensitive UHPLC-MS/MS method was developed and validated for the simultaneous determination of brucine, strychnine and brucine N-oxide in rat plasma using huperzine A as an internal standard (IS) after protein precipitation with methanol. The analytes were separated on a Purospher(r) STAR RP18 UHPLC column (2 um, 2.1 * 100 mm) by gradient elution using a mobile phase composed of methanol and water (containing 0.1% formic acid) at a flow rate of 0.3 mL/min. Brucine, strychnine, brucine N-oxide and IS were detected in positive ion multiple reaction monitoring mode by means of an electrospray ionization interface (m/z 395.2 -> 324.1, m/z 335.2 -> 184.1, m/z 411.2 -> 394.2, m/z 243.1 > 226.1). The calibration curve was linear over the range of 1-500 ng/mL for brucine and strychnine and 0.2-50 ng/mL for brucine N-oxide. The intra- and inter day precisions of these analytes were all within 15% and the accuracy ranged from 85 to 115%. The stability experiment indicated that the plasma samples at three concentration levels were stable under different conditions. The developed method was successfully applied for the first time to pharmacokinetic studies of brucine, strychnine and brucine N-oxide following a single oral and intravenous administration of modified total alkaloid fraction in rats. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26578095 TI - An ultrastructural study of Trichophyton rubrum induced onychomycosis. AB - BACKGROUND: Trichophyton rubrum (T.rubrum) caused onychomycosis is the most common nail fungal disease. The common diagnostic methods are direct microscopic examination and fungal culture. In this study we used scanning electron microscopy (SEM) and transmission electron microscopy (TEM) to study the subungual ultrastructural changes in T. rubrum induced onychomycosis. METHODS: Six outpatients with onychomycosis were recruited and T.rubrum infection was confirmed by fungal culture. Six toenail samples were collected and prepared for SEM characterization. The cultured fugal colonies were prepared for SEM and TEM characterization. RESULTS: 1) SEM showed significant structural damages and the formation of a thin layer or a single layer of keratinocytes in all infected nail plates. Hyphae (piercing or penetrating keratinocytes layers), arthrospores and local bacterial aggregation were observed on the ventral surface of the nail plates. 2) SEM of the cultured fungal colony showed relatively straight, highly branched hyphae and microconidias; TEM showed branching hyphae that were composed of double-layer cell walls. Hyphae had nucleus, mitochondria, liposomes, lysosomes, scattered rough endoplasmic reticulum, myeloid bodies and aggregated ribosomes. There were high-density particles outside the hyphae. CONCLUSION: SEM showed a large number of hyphae penetrated the keratinocytes layer, suggesting that T. rubrum can cause severe damage to the stratum corneum. TEM showed the ultrastructural features of T. rubrum-induced infection before treatment. PMID- 26578096 TI - Transesophageal Doppler reliably tracks changes in cardiac output in comparison with intermittent pulmonary artery thermodilution in cardiac surgery patients. AB - In this study a comparison of cardiac output (CO) measurements obtained with CardioQ transesophageal Doppler (TED) and pulmonary artery catheter (PAC) thermodilution (TD) technique was done in a systematic set-up, with induced changes in preload, afterload and heart rate. Twenty-five patients completed the study. Each patient were placed in the following successive positions: (1) supine, (2) head-down tilt, (3) head-up tilt, (4) supine, (5) supine with phenylephrine administration, (6) pace heart rate 80 beats per minute (bpm), (7) pace heart rate 110 bpm. The agreement of compared data was investigated by Bland Altman plots, and to assess trending ability a four quadrants plot and a polar plot were constructed. Both methods showed an acceptable precision 6.4 % (PAC TD) and 12.8 % (TED). In comparison with PAC TD, the TED was associated with a mean bias in supine position of -0.30 l min-1 (95 % CI -0.88; 0.27), wide limits of agreement, a percentage error of 69.5 %, and a trending ability with a concordance rate of 92 %, angular bias of 1.1 degrees and a radial sector size of 40.0 degrees corresponding to an acceptable trending ability. In comparison with PAC TD, the CardioQ TED showed a low mean bias, wide limits of agreement and a larger percentage error than should be expected from the precision of the two methods. However, an acceptable trending ability was found. Thus, the CardioQ TED should not replace CO measurements done by PAC TD, but could be a valuable tool in guiding therapy. PMID- 26578097 TI - Monitoring sleep depth: analysis of bispectral index (BIS) based on polysomnographic recordings and sleep deprivation. AB - The assessment and management of sleep are increasingly recommended in the clinical practice. Polysomnography (PSG) is considered the gold standard test to monitor sleep objectively, but some practical and technical constraints exist due to environmental and patient considerations. Bispectral index (BIS) monitoring is commonly used in clinical practice for guiding anesthetic administration and provides an index based on relationships between EEG components. Due to similarities in EEG synchronization between anesthesia and sleep, several studies have assessed BIS as a sleep monitor with contradictory results. The aim of this study was to evaluate objectively both the feasibility and reliability of BIS for sleep monitoring through a robust methodology, which included full PSG recordings at a baseline situation and after 40 h of sleep deprivation. Results confirmed that the BIS index was highly correlated with the hypnogram (0.89 +/- 0.02), showing a progressive decrease as sleep deepened, and an increase during REM sleep (awake: 91.77 +/- 8.42; stage N1: 83.95 +/- 11.05; stage N2: 71.71 +/- 11.99; stage N3: 42.41 +/- 9.14; REM: 80.11 +/- 8.73). Mean and median BIS values were lower in the post-deprivation night than in the baseline night, showing statistical differences for the slow wave sleep (baseline: 42.41 +/- 9.14 vs. post-deprivation: 39.49 +/- 10.27; p = 0.02). BIS scores were able to discriminate properly between deep (N3) and light (N1, N2) sleep. BIS values during REM overlapped those of other sleep stages, although EMG activity provided by the BIS monitor could help to identify REM sleep if needed. In conclusion, BIS monitors could provide a useful measure of sleep depth in especially particular situations such as intensive care units, and they could be used as an alternative for sleep monitoring in order to reduce PSG-derived costs and to increase capacity in ambulatory care. PMID- 26578098 TI - Cross sectional study on attitudes of Serbian mothers with preschool children: should a HIV-positive female teacher be allowed to continue teaching in school? AB - BACKGROUND: HIV/AIDS continues to be a serious challenge to public health and human rights in the new millennium. The objective of this survey was to identify the correlation between socio-demographic characteristics and knowledge, attitudes and practices of mothers with preschool children, and their attitude towards whether a HIV-positive female teacher should be allowed to continue teaching in school. METHOD: This survey was additional study analysis of the Multiple Indicator Cluster Survey (MICS) in the Republic of Serbia conducted in the period November-December 2010 following the UNICEF methodology. Women deemed eligible for the survey were those who had children under five, had never lost a child, were not pregnant at the time of inquiry and who had a clear attitude ("yes" or "no") towards whether a HIV-positive female teacher should be allowed to continue teaching in school. The criteria were met by 2309 out of 2992 interviewed women. Pearson chi-square and t-test were used to analyse the differences in respondents' attitude towards whether a HIV-positive female teacher should be allowed to continue teaching in school. Variables that were significantly associated with the dependent variable (p < 0.05) were entered into a multiple logistic regression model. RESULTS: The respondents who were more likely to think that a HIV positive teacher should not be allowed to teach in school were those: who did not know that a healthy-looking person can be HIV positive (OR = 1.84; 95% CI = 1.19-2.83), who would not buy (OR = 29.90; 95% CI = 22.52-39.71) or did not know/were not sure (OR = 2.21; 95% CI = 1.46-3.33) whether they would buy vegetables from a HIV-positive vendor and women who did not know/were not sure (OR = 2.97; 95% CI = 1.64-5.39) whether they would take care of a family member sick with AIDS in their own home. CONCLUSION: Misconceptions about HIV transmission represent a major barrier to combating HIV/AIDS epidemic and HIV/AIDS-related stigma. It is, therefore, necessary to continue education and raising awareness of human rights both among the population living with HIV and the general population. PMID- 26578099 TI - Characterization of two HIV-1 infectors during initial antiretroviral treatment, and the emergence of phenotypic resistance in reverse transcriptase-associated mutation patterns. AB - BACKGROUND: Highly active antiretroviral therapy (HAART) is recommended to control the infection of HIV-1. HIV-1 drug resistance becomes an obstacle to HAART due to the accumulation of specific mutations in the RT coding region. The development of resistance mutations may be more complex than previously thought. METHODS: We followed two HIV-1 infectors from a HIV-1 drug resistance surveillance cohort in Henan province and evaluated CD4+ T-cell number and viral load thereafter at ten time-periods and characterized their reverse transcriptase associated mutation patterns at each time point. Then we constructed the recombinant virus strains with these mutation patterns to mimick the viruses and test the phenotypic resistance caused by the mutation patterns on TZM-b1 cells. RESULTS: CD4+ T-cell number initially increased and then decreased rapidly, while viral load decreased and then dropped sharply during initial antiretroviral treatment. The number of mutations and the combination patterns of mutations increased over time. According to the phenotypic resistance performed by recombinant virus strains, VirusT215Y/V179E/Y181C/H221Y exhibited high levels of resistance to EFV (5.57-fold), and T215Y/V179E-containing virus increased 20.20 fold in AZT resistance (p < 0.01). VirusT215Y/V179E/Y181C increased markedly in EFV resistance (p < 0.01). The IC50 for VirusT215Y/V179E/H221Y was similar to that for VirusT215Y/V179E/Y181C. VirusT215Y/K103N/Y181C/H221Y induced a dramatic IC50 increase of all the four agents (Efavirenz EFV, Zidovudine AZT, Lamivudine 3TC, and Stavudine d4T) (p < 0.01). As for VirusT215Y/K103N/Y181C, only the IC50 of EFV was significantly increased. T215Y/K103N resulted in a 26.36-fold increase in EFV (p < 0.01). T215Y/K103N/H221Y significantly increased the resistance to AZT and 3TC. The IC50 of EFV with T215Y/V179E was lower than with T215Y/K103N (F = 93.10, P < 0.0001). With T215Y/V179E, Y181C significantly increase in EFV resistance, while the interaction between 181 and 221 in EFV was not statistically significant (F = 1.20, P = 0.3052). With T215Y/K103N, neither H221Y nor Y181C showed a significant increase in EFV resistance, but the interaction between 181 and 221 was statistically significant (F = 38.12, P = 0.0003). CONCLUSIONS: Data in this study suggests that pathways of viral evolution toward drug resistance appear to proceed through distinct steps and at different rates. Phenotypic resistance using recombinant virus strains with different combination of mutation patterns reveals that interactions among mutations may provide information on the impact of these mutations on drug resistance. All the result provides reference to optimize clinical treatment schedule. PMID- 26578100 TI - Enhancing the methanol tolerance of platinum nanoparticles for the cathode reaction of direct methanol fuel cells through a geometric design. AB - Mastery over the structure of nanoparticles might be an effective way to enhance their performance for a given application. Herein we demonstrate the design of cage-bell nanostructures to enhance the methanol tolerance of platinum (Pt) nanoparticles while remaining their catalytic activity for oxygen reduction reaction. This strategy starts with the synthesis of core-shell-shell nanoparticles with Pt and silver (Ag) residing respectively in the core and inner shell regions, which are then agitated with saturated sodium chloride (NaCl) solution to eliminate the Ag component from the inner shell region, leading to the formation of bimetallic nanoparticles with a cage-bell structure, defined as a movable Pt core enclosed by a metal shell with nano-channels, which exhibit superior methanol-tolerant property in catalyzing oxygen reduction reaction due to the different diffusion behaviour of methanol and oxygen in the porous metal shell of cage-bell structured nanoparticles. In particular, the use of remarkably inexpensive chemical agent (NaCl) to promote the formation of cage-bell structured particles containing a wide spectrum of metal shells highlights its engineering merit to produce highly selective electrocatalysts on a large scale for the cathode reaction of direct methanol fuel cells. PMID- 26578101 TI - Our Odyssey with Functionalized Chiral Phosphines: From Optical Resolution to Asymmetric Synthesis to Catalysis. AB - Our journey in organophosphorus research over the past 26 years is compiled in this Personal Account. Advances in palladacycle design have engendered a shift in our focus from template-mediated transformations to catalysis for the direct preparation of chiral phosphines containing a wide variety of functional groups. Novel approaches to access previously inaccessible phosphines and their applications in cancer research are summarized herein. PMID- 26578102 TI - Towards a natural disaster intervention and recovery framework. AB - Contemporary responses to facilitate long-term recovery from large-scale natural disasters juxtapose between those of humanitarian agencies and governments and those of the affected community. The extent to which these mechanisms articulate is crucial to the recovery propensity of the affected communities. This research examines such action by exploring the relationship between the scale of post disaster response interventions, the extent of community participation in them, and their impact on community recovery, using a community wealth capital framework. The investigation was applied to a study of the longer-term community recovery of the island of Vilufushi, Republic of Maldives, which was almost completely destroyed by the Indian Ocean tsunami of 26 December 2004. Data were analysed through the employment of a pattern match technique and a holistic recovery network analysis. The research framework, informed by the case-study results, other long-term recovery evaluations, and existing resilience theory, is reconfigured as a testable roadmap for future post-disaster interventions. PMID- 26578104 TI - Macroscopic CNT fibres inducing non-epitaxial nucleation and orientation of semicrystalline polymers. AB - In the presence of macroscopic fibres of carbon nanotubes (CNT), various semicrystalline polymers are shown to present accelerated crystallisation through the formation of a transcrystalline (TC) layer perpendicular to the fibre axis. From differential scanning calorimetry, polarized optical microscopy and X-ray diffraction we establish this to be due to much faster nucleation rates at the fibre surface. The formation of a TC layers is demonstrated for polyvinyldene fluoride, isotactic polypropylene and poly(lactic acid) in spite of the large differences in their chemistry and structure unit cells, suggesting that epitaxy in terms of lattice type or size matching is not a prerequisite. For the three polymers as well as poly(ether ether ketone), the TC layer is identically oriented with the chain axis in the lamella parallel to the CNTs, as observed by wide and small angle X-ray scattering. These results point to polymer chain orientation at the point of adsorption and the formation of a mesomorphic layer as possible steps in the fast nucleation of oriented lamella, with wetting of the CNT fibre surface by the molten semi-crystalline polymer a key condition for heterogeneous nucleation to take place. PMID- 26578103 TI - The role of infection and sepsis in the Brazilian Network for Surveillance of Severe Maternal Morbidity. AB - OBJECTIVE: To identify the burden of severe infection within the Brazilian Network for Surveillance of Severe Maternal Morbidity and factors associated with worse maternal outcomes. METHODS: This was a multicentre cross-sectional study involving 27 referral maternity hospitals in Brazil. WHO's standardised criteria for potentially life-threatening conditions and maternal near miss were used to identify cases through prospective surveillance and the main cause of morbidity was identified as infection or other causes (hypertension, haemorrhage or clinical/surgical). Complications due to infection were compared to complications due to the remaining causes of morbidity. Factors associated with a severe maternal outcome were assessed for the cases of infection. RESULTS: A total of 502 (5.3%) cases of maternal morbidity were associated with severe infection vs. 9053 cases (94.7%) with other causes. Considering increased severity of cases, infection was responsible for one-fourth of all maternal near miss (23.6%) and nearly half (46.4%) of maternal deaths, with a maternal near miss to maternal death ratio three times (2.8:1) that of cases without infection (7.8:1) and a high mortality index (26.3%). Within cases of infection, substandard care was present in over one half of the severe maternal outcome cases. Factors independently associated with worse maternal outcomes were HIV/AIDS, hysterectomy, prolonged hospitalisation, intensive care admission and delays in medical care. CONCLUSIONS: Infection is an alarming cause of maternal morbidity and mortality and timely diagnosis and adequate management are key to improving outcomes during pregnancy. Delays should be addressed, risk factors identified, and specific protocols of surveillance and care developed for use during pregnancy. PMID- 26578105 TI - Addressing the Glycine-Rich Loop of Protein Kinases by a Multi-Facetted Interaction Network: Inhibition of PKA and a PKB Mimic. AB - Protein kinases continue to be hot targets in drug discovery research, as they are involved in many essential cellular processes and their deregulation can lead to a variety of diseases. A series of 32 enantiomerically pure inhibitors was synthesized and tested towards protein kinase A (PKA) and protein kinase B mimic PKAB3 (PKA triple mutant). The ligands bind to the hinge region, ribose pocket, and glycine-rich loop at the ATP site. Biological assays showed high potency against PKA, with Ki values in the low nanomolar range. The investigation demonstrates the significance of targeting the often neglected glycine-rich loop for gaining high binding potency. X-ray co-crystal structures revealed a multi facetted network of ligand-loop interactions for the tightest binders, involving orthogonal dipolar contacts, sulfur and other dispersive contacts, amide-pi stacking, and H-bonding to organofluorine, besides efficient water replacement. The network was analyzed in a computational approach. PMID- 26578106 TI - The New York Surgical Society. PMID- 26578107 TI - Comparing the endothelialisation of extracellular matrix bioscaffolds with coated synthetic vascular graft materials. AB - INTRODUCTION: Existing synthetic vascular grafts have unacceptably high failure rates when replacing below knee arteries. In vitro endothelialisation is a technique, which has been shown to enhance the patency rates of below knee vascular grafts. Synthetic materials are however poor cellular substrates and must be combined with coatings to promote cellular growth and attachment. The most common coating clinically is fibrin-coated ePTFE. The aim of our study was to compare the endothelialisation of fibrin-coated ePTFE with novel extracellular matrix (ECM) biomaterials that we hypothesise will provide a superior substrate for cell growth. METHODS: Human endothelial cells were cultured on ECM scaffolds and fibrin-coated ePTFE. Uncoated Dacron and ePTFE acted as controls. The cells were examined for viability, phenotype, adhesion and proliferation. Cell morphology was accessed using scanning electron microscopy. RESULTS: Cells remained viable and produced von Willebrand factor on all substrates tested. ECM scaffolds and fibrin-modified ePTFE achieved statistically higher attachment efficiency when compared to both uncoated synthetic graft materials (p <= 0.001). At 90 min 80 +/- 3.6% of cells had attached to the ECM scaffold compared to Dacron (30 +/- 4.5%, n = 3) and ePTFE (33 +/- 2.5%, n = 3). There was no difference in adhesion rates between ECM scaffolds and fibrin-coated ePTFE (p = 1.00). Endothelial cells proliferated fastest on ECM scaffolds when compared to all other materials tested (p < 0.001) and reached confluency on day seven. CONCLUSION: ECM bioscaffolds offer an improved substrate for promoting rapid endothelialisation compared to fibrin-coated ePTFE by combining firm cellular anchorage and superior cell expansion. PMID- 26578108 TI - Feasibility and safety of conservative surgery for the treatment of spermatic cord leiomyosarcoma. AB - OBJECTIVES: To assess the feasibility and the safety of conservative surgery to treat spermatic cord leiomyosarcoma. METHODS: Patients undergoing inguinoscrotal exploration in 10 different Urological Centers with diagnosis of leiomyosarcoma were enrolled. Preoperative evaluation included physical examination, Scrotal US, Abdominal CT and Scrotal MRI in selected cases. Patients underwent organ sparing surgery or orchiectomy in case of intraoperative FSE was positive for a local infiltration. Data collected were: age, presence of infiltration, length of the lesion, number of lesions, definitive histological outcome, pre and postoperative testosterone level. Follow up was performed with abdomen CT scan and scrotal US. RESULTS: From January 2007 to December 2013, 23 patients (mean age: 64.7 yrs) were diagnosed with spermatic cord leiomyosarcoma. Each patients underwent scrotal US. 10 patients underwent radical orchiectomy and 13 patients underwent conservative surgery. Mean follow up was 36.5 months. 5 patients (21.7%) developed a recurrent disease, 18 patients (78.3%) had a negative follow up (mean time: 40.8 months). Statistical analysis reveals that there is a significant correlation between number of lesions, length of the lesions and recurrent disease. CONCLUSIONS: Spermatic cord leiomyosarcoma is a rare disease. Conservative surgical treatment of spermatic cord leiomyosarcoma is a feasible therapeutic option for small, single and not infiltrating lesion. PMID- 26578109 TI - Strengthening the delivery of asthma and chronic obstructive pulmonary disease care at primary health-care facilities: study design of a cluster randomized controlled trial in Pakistan. AB - BACKGROUND: Respiratory diseases, namely asthma and chronic obstructive pulmonary disease (COPD), account for one-fourth of the patients at the primary health-care (PHC) facilities in Pakistan. Standard care practices to manage these diseases are necessary to reduce the morbidity and mortality rate associated with non communicable diseases in developing countries. OBJECTIVE: To develop and measure the effectiveness of operational guidelines and implementation materials, with sound scientific evidence, for expanding lung health care, especially asthma and COPD through PHC facilities already strengthened for tuberculosis (TB) care in Pakistan. DESIGN: A cluster randomized controlled trial with two arms (intervention and control), with qualitative and costing study components, is being conducted in 34 clusters; 17 clusters per arm (428 asthma and 306 COPD patients), in three districts in Pakistan from October 2014 to December 2016. The intervention consists of enhanced case management of asthma and COPD patients through strengthening of PHC facilities. The main outcomes to be measured are asthma and COPD control among the registered cases at 6 months. Cluster- and individual-level analyses will be done according to intention to treat. Residual confounding will be addressed by multivariable logistic and linear regression models for asthma and COPD control, respectively. The trial is registered with ISRCTN registry (ISRCTN 17409338). CONCLUSIONS: Currently, only about 20% of the estimated prevalent asthma and COPD cases are being identified and reported through the respective PHC network. Lung health care and prevention has not been effectively integrated into the core PHC package, although a very well functioning TB program exists at the PHC level. Inclusion of these diseases in the already existent TB program is expected to increase detection rates and care for asthma and COPD. PMID- 26578110 TI - Intervening in the local health system to improve diabetes care: lessons from a health service experiment in a poor urban neighborhood in India. AB - BACKGROUND: Many efficacious health service interventions to improve diabetes care are known. However, there is little evidence on whether such interventions are effective while delivered in real-world resource-constrained settings. OBJECTIVE: To evaluate an intervention aimed at improving diabetes care using the RE-AIM (reach, efficacy/effectiveness, adoption, implementation, and maintenance) framework. DESIGN: A quasi-experimental study was conducted in a poor urban neighborhood in South India. Four health facilities delivered the intervention (n=163 diabetes patients) and the four matched facilities served as control (n=154). The intervention included provision of culturally appropriate education to diabetes patients, use of generic medications, and standard treatment guidelines for diabetes management. Patients were surveyed before and after the 6 month intervention period. We did field observations and interviews with the doctors at the intervention facilities. Quantitative data were used to assess the reach of the intervention and its effectiveness on patients' knowledge, practice, healthcare expenditure, and glycemic control through a difference-in-differences analysis. Qualitative data were analyzed thematically to understand adoption, implementation, and maintenance of the intervention. RESULTS: Reach: Of those who visited intervention facilities, 52.3% were exposed to the education component and only 7.2% were prescribed generic medications. The doctors rarely used the standard treatment guidelines for diabetes management. EFFECTIVENESS: The intervention did not have a statistically and clinically significant impact on the knowledge, healthcare expenditure, or glycemic control of the patients, with marginal reduction in their practice score. Adoption: All the facilities adopted the education component, while all but one facility adopted the prescription of generic medications. IMPLEMENTATION: There was poor implementation of the intervention, particularly with regard to the use of generic medications and the standard treatment guidelines. Doctors' concerns about the efficacy, quality, availability, and acceptability by patients of generic medications explained limited prescriptions of generic medications. The patients' perception that ailments should be treated through medications limited the use of non-medical management by the doctors in early stages of diabetes. The other reason for the limited use of the standard treatment guidelines was that these doctors mainly provided follow-up care to patients who were previously put on a given treatment plan by specialists. Maintenance: The intervention facilities continued using posters and television monitors for health education after the intervention period. The use of generic medications and standard treatment guidelines for diabetes management remained very limited. CONCLUSIONS: Implementing efficacious health service intervention in a real-world resource-constrained setting is challenging and may not prove effective in improving patient outcomes. Interventions need to consider patients' and healthcare providers' experiences and perceptions and how macro-level policies translate into practice within local health systems. PMID- 26578111 TI - Systematic Review of Fetal Alcohol Spectrum Disorder Interventions Across the Life Span. AB - BACKGROUND: Individuals with fetal alcohol spectrum disorders (FASDs) can experience profound impairments and long-term adverse outcomes. This systematic review adopts a life span perspective providing an extensive analysis of the available literature. METHODS: Studies were identified from PsycInfo, PubMed, Scopus, Web of Knowledge, CINAHL, ERIC, The Cochrane Central Register of Controlled Trials, and gray literature. Two reviewers independently screened the title and abstract of each reference, and the methodological rigor of the included studies was assessed using the Effective Public Health Project assessment tool. RESULTS: Thirty-two studies met the inclusion criteria, of which the vast majority targeted early to middle childhood. Two studies focused on early intervention in the postnatal period, and 6 studies aimed to improve attention and/or self-regulation in childhood. Three of these provided promising evidence on improving self-regulatory difficulties for children with FASDs. Nine studies focused on improving specific areas of dysfunction. Six studies addressed social skills; 3 of these used an adaptation of a well-validated social skills program. Three studies provided promising initial evidence that parents and caregivers could benefit from support with child behavior and a further 4 studies provided education and advocacy for parents/caregivers, teachers, or child welfare workers. The final 2 studies were aimed at supporting parents who were themselves affected by prenatal alcohol exposure. CONCLUSIONS: There is growing evidence for interventions that improve outcomes for early to middle childhood. However, a lack of research exists outside of this developmental period. This lack of research is concerning given the potential positive impact of early intervention, for individuals and, financially, for governments. In addition, the lack of interventions for adolescents and adults further highlights the widening developmental gap and the potential influence of secondary disabilities for this at-risk population. PMID- 26578112 TI - The tomato mutant ars1 (altered response to salt stress 1) identifies an R1-type MYB transcription factor involved in stomatal closure under salt acclimation. AB - A screening under salt stress conditions of a T-DNA mutant collection of tomato (Solanum lycopersicum L.) led to the identification of the altered response to salt stress 1 (ars1) mutant, which showed a salt-sensitive phenotype. Genetic analysis of the ars1 mutation revealed that a single T-DNA insertion in the ARS1 gene was responsible of the mutant phenotype. ARS1 coded for an R1-MYB type transcription factor and its expression was induced by salinity in leaves. The mutant reduced fruit yield under salt acclimation while in the absence of stress the disruption of ARS1 did not affect this agronomic trait. The stomatal behaviour of ars1 mutant leaves induced higher Na(+) accumulation via the transpiration stream, as the decreases of stomatal conductance and transpiration rate induced by salt stress were markedly lower in the mutant plants. Moreover, the mutation affected stomatal closure in a response mediated by abscisic acid (ABA). The characterization of tomato transgenic lines silencing and overexpressing ARS1 corroborates the role of the gene in regulating the water loss via transpiration under salinity. Together, our results show that ARS1 tomato gene contributes to reduce transpirational water loss under salt stress. Finally, this gene could be interesting for tomato molecular breeding, because its manipulation could lead to improved stress tolerance without yield penalty under optimal culture conditions. PMID- 26578113 TI - Maturation status of sarcomere structure and function in human iPSC-derived cardiac myocytes. AB - Human heart failure due to myocardial infarction is a major health concern. The paucity of organs for transplantation limits curative approaches for the diseased and failing adult heart. Human induced pluripotent stem cell-derived cardiac myocytes (hiPSC-CMs) have the potential to provide a long-term, viable, regenerative-medicine alternative. Significant progress has been made with regard to efficient cardiac myocyte generation from hiPSCs. However, directing hiPSC-CMs to acquire the physiological structure, gene expression profile and function akin to mature cardiac tissue remains a major obstacle. Thus, hiPSC-CMs have several hurdles to overcome before they find their way into translational medicine. In this review, we address the progress that has been made, the void in knowledge and the challenges that remain. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel. PMID- 26578115 TI - Production of recombinant PvDBPII, receptor binding domain of Plasmodium vivax Duffy binding protein, and evaluation of immunogenicity to identify an adjuvant formulation for vaccine development. AB - Plasmodium vivax is dependent on interaction with the Duffy antigen receptor for chemokines (DARC) for invasion of human erythrocytes. The P. vivax Duffy binding protein (PvDBP) mediates interaction of P. vivax merozoites with DARC. The DARC receptor-binding domain lies in a conserved N-terminal cysteine-rich region of PvDBP referred to as region II (PvDBPII). PvDBPII is an attractive vaccine candidate since antibodies raised against PvDBPII block erythrocyte invasion by P. vivax. Here, we describe methods to produce recombinant PvDBPII in its correctly folded conformation. A synthetic gene optimized for expression of PvDBPII in Escherichia coli and fed batch fermentation process based on exponential feeding strategy was used to achieve high levels of expression of recombinant PvDBPII. Recombinant PvDBPII was isolated from inclusion bodies, refolded by rapid dilution and purified by ion exchange chromatography. Purified recombinant PvDBPII was characterized for identity, purity and functional activity using standardized release assays. Recombinant PvDBPII formulated with various human compatible adjuvants including glycosylpyranosyl lipid A-stable emulsion (GLA-SE) and alhydrogel was used for immunogenicity studies in small animals to downselect a suitable formulation for clinical development. Sera collected from immunized animals were tested for recognition of PvDBPII and inhibition of PvDBPII-DARC binding. GLA-SE formulations of PvDBPII yielded higher ELISA and binding inhibition titres compared to PvDBPII formulated with alhydrogel. These data support further development of a recombinant vaccine for P. vivax based on PvDBPII formulated with GLA-SE. PMID- 26578116 TI - Life after acute fibrinous and organizing pneumonia: a case report of a patient 30 months after diagnosis and review of the literature. AB - Acute fibrinous and organizing pneumonia (AFOP) is a rare histologic interstitial pneumonia pattern recently described in the literature with fewer than 120 cases published. AFOP is often difficult to diagnose and may be mistaken for other pulmonary disorders such as interstitial pneumonias or pneumonitides. Patients often present with vague symptoms of cough, dyspnea, hemoptysis, fatigue, and occasionally respiratory failure. Radiological findings show diffuse patchy opacities and ground glass appearance of the lungs. On histologic examination, intra-alveolar fibrin balls are observed. We discuss a case of a man who presented with hemoptysis and dyspnea and whose open lung biopsy revealed AFOP. We will describe the presentation, diagnosis, and post-discharge course, and review the current literature. There are only 4 cases which have reported the patients' course of disease after 1 year, the longest being 2 years. To our knowledge, this is the only case of AFOP in the literature that describes the course of a patient more than 2 years after the diagnosis of AFOP, and is the most comprehensive review of the current literature. PMID- 26578114 TI - BIN1 regulates dynamic t-tubule membrane. AB - Cardiac transverse tubules (t-tubules) are specific membrane organelles critical in calcium signaling and excitation-contraction coupling required for beat-to beat heart contraction. T-tubules are highly branched and form an interconnected network that penetrates the myocyte interior to form junctions with the sarcoplasmic reticulum. T-tubules are selectively enriched with specific ion channels and proteins crucial in calcium transient development necessary in excitation-contraction coupling, thus t-tubules are a key component of cardiac myocyte function. In this review, we focus primarily on two proteins concentrated within the t-tubular network, the L-type calcium channel (LTCC) and associated membrane anchor protein, bridging integrator 1 (BIN1). Here, we provide an overview of current knowledge in t-tubule morphology, composition, microdomains, as well as the dynamics of the t-tubule network. Secondly, we highlight multiple aspects of BIN1-dependent t-tubule function, which includes forward trafficking of LTCCs to t-tubules, LTCC clustering at t-tubule surface, microdomain organization and regulation at t-tubule membrane, and the formation of a slow diffusion barrier within t-tubules. Lastly, we describe progress in characterizing how acquired human heart failure can be attributed to abnormal BIN1 transcription and associated t-tubule remodeling. Understanding BIN1 regulated cardiac t-tubule biology in human heart failure management has the dual benefit of promoting progress in both biomarker development and therapeutic target identification. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel. PMID- 26578117 TI - Short-term treatment outcome of pulpotomies in primary molars using mineral trioxide aggregate and Biodentine: a randomized clinical trial. AB - INTRODUCTION: An ideal pulpotomy agent for primary molars has been sought for many years. Recently, new materials that allow regeneration of residual pulp tissue have been developed. In this study, we compared the preliminary clinical results obtained using Biodentine and mineral trioxide aggregate (MTA) as pulp dressing agents in pulpotomies of primary molars. METHODS: A randomized clinical study was performed in children aged 4-9 years with at least one primary tooth with decay or caries requiring pulp treatment. A total of 90 primary molars requiring pulpotomy were randomly allocated to the MTA or Biodentine group, and 84 pulpotomies were performed. Clinical and radiographic evaluations were undertaken 6 and 12 months after treatment. All teeth were restored with a reinforced zinc oxide-eugenol base and stainless steel crowns. Statistical analysis using Fisher's exact test was performed to determine the significant differences between the groups. RESULTS: A total of four clinical failures were observed; all involved gingival inflammation. The clinical success rate in the MTA Group after 12 months was 92 % (36/39), whereas the Biodentine Group obtained 97 % (38/39) (p = 0.346). All radiographic failures were observed at the 12-month follow-up evaluation. One molar from MTA Group showed internal resorption obtaining a radiographic success rate of 97 % (38/39). Two molars from the Biodentine Group showed radiographic failure (1 internal resorption and 1 periradicular radiolucency) obtaining a radiographic success rate of 95 % (37/39). CONCLUSIONS: Biodentine showed similar clinical results as MTA with comparable success rates when used for pulpotomies of primary molars. However, longer follow-up studies are required to confirm our findings. CLINICAL RELEVANCE: This article demonstrates the effectiveness of Biodentine as a primary teeth pulpotomy material, performing similar results as MTA at 12-months evaluation. PMID- 26578118 TI - Epulis: a study of 92 cases with special emphasis on histopathological diagnosis and associated clinical data. AB - OBJECTIVES: Aim of the present study was clinical and histopathological evaluation of a series of epulides to provide clinicians data to frequency distribution and biological behaviour of different underlying entities. MATERIALS AND METHODS: Ninety-two cases of epulides removed by CO2-laser at the Department of Oral Surgery and Radiology, Medical University of Graz from 2000 to 2014 were studied retrospectively for clinical data and histopathological diagnosis. RESULTS: In the presented study, histopathological examination revealed peripheral ossifying fibroma (32.6 %), fibroma/fibrosis (29.3 %), giant cell lesion (13.1 %) and granuloma pyogenicum (8.7 %) as the most frequent underlying entities. For the first time, hyperplastic squamous epithelium (7.6 %), granulation tissue (5.4 %) and peripheral odontogenic fibromas (3.3 %) were detected to clinically appear as epulides. Irrespective of the histological diagnosis, the mean age in our patients was 43.8 years. The majority of the lesions were found in the frontal region of both jaws. In all cases, the patients showed poor oral hygiene, local gingivitis and some of them an occlusal trauma. CONCLUSIONS: To identify different entities with different biological behaviour, to exclude malignant tumours and to identify new entities among epulides, histopathological examination is required. Poor oral hygiene and occlusal trauma seem to play an important role in the pathogenesis and could be risk factors for recurrences. CLINICAL RELEVANCE: Frequency distribution of different entities in epulides is provided to clinicians, and new histopathological entities were detected to clinically appear as epulides. PMID- 26578119 TI - Oral pregabalin for postoperative pain relief after third molar extraction: a randomized controlled clinical trial. AB - OBJECTIVES: The aim of this randomized controlled clinical trial was to evaluate the efficacy and safety of pregabalin administered pre- and postoperatively in patients with pain and swelling due to the surgical removal of impacted lower third molars. MATERIALS AND METHODS: The final study sample comprised 60 volunteers (23 males and 37 females). Group 1 (n = 30) received 75 mg oral pregabalin 1 h before surgery and 1 h after surgery. Group 2 (n = 30) served as a control group and received no pregabalin. Both groups were administered with 650 mg paracetamol every 8 h for 2 days. Postoperative pain intensity and swelling were measured using a visual analog scale (VAS); pain relief experienced was reported using a four-point verbal rating scale (VRS); the rescue medication requirement, adverse effects, and global impression of the medication were also recorded. RESULTS: No significant difference in pain intensity (VAS) was observed between the groups. However, fewer rescue medication tablets were needed by pregabalin-treated patients than by controls (p = 0.021). The frequency and intensity of adverse effects were significantly higher in pregabalin-treated patients (p < 0.001), although no serious adverse events occurred. No significant difference in the degree of swelling was observed in any measurement except that from mandibular angle to lip junction, which showed lesser inflammation in the pregabalin group at 24 h post-surgery (p = 0.011). The global opinion on the medication received was more positive in the pregabalin group (p = 0.042). CONCLUSIONS: The administration of pregabalin reduces the requirement for rescue medication after third molar surgery and results in a more constant pain level, with fewer peaks of pain intensity. CLINICAL RELEVANCE: These findings suggest that pregabalin may be useful to control acute postoperative pain. Adverse effects are known to be reduced at the low pregabalin dose used in our study. PMID- 26578122 TI - Jornal Brasileiro de Pneumologia: forty years of history. PMID- 26578120 TI - Facial asymmetry quantitative evaluation in oculoauriculovertebral spectrum. AB - OBJECTIVES: Facial asymmetries in oculoauriculovertebral spectrum (OAVS) patients might require surgical corrections that are mostly based on qualitative approach and surgeon's experience. The present study aimed to develop a quantitative 3D CT imaging-based procedure suitable for maxillo-facial surgery planning in OAVS patients. MATERIALS AND METHODS: Thirteen OAVS patients (mean age 3.5 +/- 4.0 years; range 0.2-14.2, 6 females) and 13 controls (mean age 7.1 +/- 5.3 years; range 0.6-15.7, 5 females) who underwent head CT examination were retrospectively enrolled. Eight bilateral anatomical facial landmarks were defined on 3D CT images (porion, orbitale, most anterior point of frontozygomatic suture, most superior point of temporozygomatic suture, most posterior-lateral point of the maxilla, gonion, condylion, mental foramen) and distance from orthogonal planes (in millimeters) was used to evaluate the asymmetry on each axis and to calculate a global asymmetry index of each anatomical landmark. Mean asymmetry values and relative confidence intervals were obtained from the control group. RESULTS: OAVS patients showed 2.5 +/- 1.8 landmarks above the confidence interval while considering the global asymmetry values; 12 patients (92%) showed at least one pathologically asymmetric landmark. Considering each axis, the mean number of pathologically asymmetric landmarks increased to 5.5 +/- 2.6 (p = 0.002) and all patients presented at least one significant landmark asymmetry. CONCLUSIONS: Modern CT-based 3D reconstructions allow accurate assessment of facial bone asymmetries in patients affected by OAVS. The evaluation as a global score and in different orthogonal axes provides precise quantitative data suitable for maxillo facial surgical planning. CLINICAL RELEVANCE: CT-based 3D reconstruction might allow a quantitative approach for planning and following-up maxillo-facial surgery in OAVS patients. PMID- 26578123 TI - Jornal Brasileiro de Pneumologia: 40 years of tradition. PMID- 26578124 TI - Jornal de Pneumologia 1995-1998. PMID- 26578125 TI - Gratitude for my time at the Jornal de Pneumologia. PMID- 26578126 TI - My time at the JBP. PMID- 26578127 TI - My time at the Jornal Brasileiro de Pneumologia. PMID- 26578128 TI - My time at the JBP. PMID- 26578129 TI - The next 40 years. PMID- 26578130 TI - Study of inhaler technique in asthma patients: differences between pediatric and adult patients. AB - OBJECTIVE: Inhaler technique comprises a set of procedures for drug delivery to the respiratory system. The oral inhalation of medications is the first-line treatment for lung diseases. Using the proper inhaler technique ensures sufficient drug deposition in the distal airways, optimizing therapeutic effects and reducing side effects. The purposes of this study were to assess inhaler technique in pediatric and adult patients with asthma; to determine the most common errors in each group of patients; and to compare the results between the two groups. METHODS: This was a descriptive cross-sectional study. Using a ten step protocol, we assessed inhaler technique in 135 pediatric asthma patients and 128 adult asthma patients. RESULTS: The most common error among the pediatric patients was failing to execute a 10-s breath-hold after inhalation, whereas the most common error among the adult patients was failing to exhale fully before using the inhaler. CONCLUSIONS: Pediatric asthma patients appear to perform most of the inhaler technique steps correctly. However, the same does not seem to be true for adult patients. PMID- 26578131 TI - Diagnostic value of endobronchial ultrasound-guided transbronchial needle aspiration in various lung diseases. AB - OBJECTIVE: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS TBNA) is a new method for the diagnosis and staging of lung disease, and its use is increasing worldwide. It has been used as a means of diagnosing lung cancer in its initial stages, and there are data supporting its use for the diagnosis of benign lung disease. The aim of this study was to share our experience with EBUS TBNA and discuss its diagnostic value. METHODS: We retrospectively analyzed the results related to 159 patients who underwent EBUS-TBNA at our pulmonary medicine clinic between 2010 and 2013. We recorded the location and size of lymph nodes seen during EBUS. Lymph nodes that appeared to be affected on EBUS were sampled at least twice. We recorded the diagnostic results of EBUS-TBNA and (for cases in which EBUS-TBNA yielded an inconclusive diagnosis) the final diagnoses after further investigation and follow-up. RESULTS: We evaluated 159 patients, of whom 89 (56%) were male and 70 (44%) were female. The mean age was 54.6 +/- 14.2 years among the male patients and 51.9 +/- 11.3 years among the female patients. Of the 159 patients evaluated, 115 (84%) were correctly diagnosed by EBUS. The diagnostic accuracy of EBUS-TBNA was 83% for benign granulomatous diseases and 77% for malignant diseases. CONCLUSIONS: The diagnostic value of EBUS-TBNA is also high for benign pathologies, such as sarcoidosis and tuberculosis. In patients with mediastinal disorders, the use of EBUS-TBNA should be encouraged, primarily because it markedly reduces the need for mediastinoscopy. PMID- 26578132 TI - Sarcopenia in COPD: relationship with COPD severity and prognosis. AB - OBJECTIVE: To evaluate the prevalence of sarcopenia in COPD patients, as well as to determine whether sarcopenia correlates with the severity and prognosis of COPD. METHODS: A cross-sectional study with COPD patients followed at the pulmonary outpatient clinic of our institution. The patients underwent dual energy X-ray absorptiometry. The diagnosis of sarcopenia was made on the basis of the skeletal muscle index, defined as appendicular lean mass/height2 only for low weight subjects and adjusted for fat mass in normal/overweight subjects. Disease severity (COPD stage) was evaluated with the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria. The degree of obstruction and prognosis were determined by the Body mass index, airflow Obstruction, Dyspnea, and Exercise capacity (BODE) index. RESULTS: We recruited 91 patients (50 females), with a mean age of 67.4 +/- 8.7 years and a mean BMI of 25.8 +/- 6.1 kg/m2. Sarcopenia was observed in 36 (39.6%) of the patients, with no differences related to gender, age, or smoking status. Sarcopenia was not associated with the GOLD stage or with FEV1 (used as an indicator of the degree of obstruction). The BMI, percentage of body fat, and total lean mass were lower in the patients with sarcopenia than in those without (p < 0.001). Sarcopenia was more prevalent among the patients in BODE quartile 3 or 4 than among those in BODE quartile 1 or 2 (p = 0.009). The multivariate analysis showed that the BODE quartile was significantly associated with sarcopenia, regardless of age, gender, smoking status, and GOLD stage. CONCLUSIONS: In COPD patients, sarcopenia appears to be associated with unfavorable changes in body composition and with a poor prognosis. PMID- 26578133 TI - Determining respiratory system resistance and reactance by impulse oscillometry in obese individuals. AB - OBJECTIVE: To evaluate peripheral respiratory system resistance and reactance (Rrs and Xrs, respectively) in obese individuals. METHODS: We recruited 99 individuals, dividing them into four groups by body mass index (BMI): < 30.0 kg/m2 (control, n = 31); 30.0-39.9 kg/m2 (obesity, n = 13); 40.0-49.9 kg/m2 (severe obesity, n = 28); and >= 50.0 kg/m2 (morbid obesity, n = 13). Using impulse oscillometry, we measured total Rrs, central Rrs, and Xrs. Peripheral Rrs was calculated as the difference between total Rrs and central Rrs. All subjects also underwent spirometry. RESULTS: Of the 99 individuals recruited, 14 were excluded because they failed to perform forced expiratory maneuvers correctly during spirometry. The individuals in the severe obesity and morbid obesity groups showed higher peripheral Rrs and lower Xrs in comparison with those in the two other groups. CONCLUSIONS: Having a BMI >= 40 kg/m2 was associated with a significant increase in peripheral Rrs and with a decrease in Xrs. PMID- 26578134 TI - Lung function and left ventricular hypertrophy in morbidly obese candidates for bariatric surgery. AB - OBJECTIVE: To look for correlations between lung function and cardiac dimension variables in morbidly obese patients, in order to test the hypothesis that the relative size of the small airways is independently correlated with left ventricular hypertrophy. METHODS: This was a retrospective study involving 192 medical records containing a clinical protocol employed in candidates for bariatric surgery between January of 2006 and December of 2010. RESULTS: Of the 192 patients evaluated, 39 (10 males and 29 females) met the inclusion criteria. The mean BMI of the patients was 49.2 +/- 7.6 kg/m2, and the mean age was 35.5 +/ 7.7 years. The FEF25-75/FVC, % correlated significantly with left ventricular posterior wall thickness and relative left ventricular posterior wall thickness, those correlations remaining statistically significant (r = -0.355 and r = 0.349, respectively) after adjustment for weight, gender, and history of systemic arterial hypertension. Stepwise multivariate linear regression analysis showed that FVC and FEV1 were the major determinants of left ventricular mass (in grams or indexed to body surface area). CONCLUSIONS: A reduction in the relative size of the small airways appears to be independently correlated with obesity-related cardiac hypertrophy, regardless of factors affecting respiratory mechanics (BMI and weight), gender, or history of systemic arterial hypertension. However, FEV1 and FVC might be important predictors of left ventricular mass in morbidly obese individuals. PMID- 26578135 TI - Depression, anxiety, stress, and motivation over the course of smoking cessation treatment. AB - OBJECTIVE: To evaluate changes in the levels of patient anxiety, depression, motivation, and stress over the course of smoking cessation treatment. METHODS: This cohort study involved patients enrolled in a smoking cessation program in Cuiaba, Brazil. We selected patients who completed the program in six months or less (n = 142). Patient evaluations were conducted at enrollment (evaluation 1 [E1]); after 45 days of treatment with medication and cognitive-behavioral therapy (E2); and at the end of the six-month study period (E3). Patients were evaluated with a standardized questionnaire (to collect sociodemographic data and determine smoking status), as well as with the University of Rhode Island Change Assessment scale, Beck Anxiety Inventory, Beck Depression Inventory, and Lipp Inventory of Stress Symptoms for Adults. The data were analyzed with the nonparametric Wilcoxon test for paired comparisons. To compare treatment success (smoking cessation) with treatment failure, the test for two proportions was used. RESULTS: Among the 142 patients evaluated, there were improvements, in terms of the levels of anxiety, depression, motivation, and stress, between E1 and E2, as well as between E1 and E3. In addition, treatment success correlated significantly with the levels of motivation and anxiety throughout the study period, whereas it correlated significantly with the level of depression only at E2 and E3. CONCLUSIONS: We conclude that there are in fact changes in the levels of patient anxiety, depression, motivation, and stress over the course of smoking cessation treatment. Those changes appear to be more pronounced in patients in whom the treatment succeeded. PMID- 26578136 TI - Factors predictive of obstructive sleep apnea in patients undergoing pre operative evaluation for bariatric surgery and referred to a sleep laboratory for polysomnography. AB - OBJECTIVE: To identify the main predictive factors for obtaining a diagnosis of obstructive sleep apnea (OSA) in patients awaiting bariatric surgery. METHODS: Retrospective study of consecutive patients undergoing pre-operative evaluation for bariatric surgery and referred for in-laboratory polysomnography. Eight variables were evaluated: sex, age, neck circumference (NC), BMI, Epworth Sleepiness Scale (ESS) score, snoring, observed apnea, and hypertension. We employed ROC curve analysis to determine the best cut-off value for each variable and multiple linear regression to identify independent predictors of OSA severity. RESULTS: We evaluated 1,089 patients, of whom 781 (71.7%) were female. The overall prevalence of OSA-defined as an apnea/hypopnea index (AHI) >= 5.0 events/h-was 74.8%. The best cut-off values for NC, BMI, age, and ESS score were 42 cm, 42 kg/m2, 37 years, and 10 points, respectively. All eight variables were found to be independent predictors of a diagnosis of OSA in general, and all but one were found to be independent predictors of a diagnosis of moderate/severe OSA (AHI >= 15.0 events/h), the exception being hypertension. We devised a 6-item model, designated the NO-OSAS model(NC, Obesity, Observed apnea, Snoring, Age, and Sex), with a cut-off value of >= 3 for identifying high-risk patients. For a diagnosis of moderate/severe OSA, the model showed 70.8% accuracy, 82.8% sensitivity, and 57.9% specificity. CONCLUSIONS: In our sample of patients awaiting bariatric surgery, there was a high prevalence of OSA. At a cut-off value of >= 3, the proposed 6-item model showed good accuracy for a diagnosis of moderate/severe OSA. PMID- 26578137 TI - Control measures to trace <= 15-year-old contacts of index cases of active pulmonary tuberculosis. AB - This was descriptive study carried out in a medium-sized Brazilian city. In <= 15 year-old contacts of index cases of active pulmonary tuberculosis, we assessed compliance with the Brazilian national guidelines for tuberculosis control. We interviewed 43 contacts and their legal guardians. Approximately 80% of the contacts were not assessed by the municipal public health care system, and only 21% underwent tuberculin skin testing. The results obtained with the Chi-square Automatic Interaction Detector method suggest that health care teams have a biased attitude toward assessing such contacts and underscore the need for training health professionals regarding tuberculosis control programs. PMID- 26578138 TI - Update on diagnosis and treatment of idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis is a type of chronic fibrosing interstitial pneumonia, of unknown etiology, which is associated with a progressive decrease in pulmonary function and with high mortality rates. Interest in and knowledge of this disorder have grown substantially in recent years. In this review article, we broadly discuss distinct aspects related to the diagnosis and treatment of idiopathic pulmonary fibrosis. We list the current diagnostic criteria and describe the therapeutic approaches currently available, symptomatic treatments, the action of new drugs that are effective in slowing the decline in pulmonary function, and indications for lung transplantation. PMID- 26578139 TI - Inhalation therapy in mechanical ventilation. AB - Patients with obstructive lung disease often require ventilatory support via invasive or noninvasive mechanical ventilation, depending on the severity of the exacerbation. The use of inhaled bronchodilators can significantly reduce airway resistance, contributing to the improvement of respiratory mechanics and patient ventilator synchrony. Although various studies have been published on this topic, little is known about the effectiveness of the bronchodilators routinely prescribed for patients on mechanical ventilation or about the deposition of those drugs throughout the lungs. The inhaled bronchodilators most commonly used in ICUs are beta adrenergic agonists and anticholinergics. Various factors might influence the effect of bronchodilators, including ventilation mode, position of the spacer in the circuit, tube size, formulation, drug dose, severity of the disease, and patient-ventilator synchrony. Knowledge of the pharmacological properties of bronchodilators and the appropriate techniques for their administration is fundamental to optimizing the treatment of these patients. PMID- 26578140 TI - Acute invasive pulmonary aspergillosis, shortly after occupational exposure to polluted muddy water, in a previously healthy subject. AB - Invasive pulmonary aspergillosis (IPA) predominantly occurs in severely neutropenic immunocompromised subjects. The occurrence of acute IPA after brief but massive exposure to Aspergillus conidia in previously healthy subjects has been documented, although only six such cases have been reported. The diagnosis was delayed in all six of the affected patients, five of whom died. We report the case of a 50-year-old HIV-negative male, a water pipeline maintenance worker, who presented with acute-onset dyspnea and fever one day after working for 2 h in a deep pit containing polluted, muddy water. Over a one-month period, his general condition deteriorated markedly, despite antibiotic therapy. Imaging showed bilateral diffuse nodules with cavitation, some of which were surrounded by ground-glass opacity suggestive of a halo sign (a hallmark of IPA). Cultures (of sputum/bronchial aspirate samples) and serology were positive for Aspergillus fumigatus. After being started on itraconazole, the patient improved. We conclude that massive exposure to Aspergillus conidia can lead to acute IPA in immunocompetent subjects. PMID- 26578141 TI - Idiopathic pleuroparenchymal fibroelastosis: incidental findings in a patient with suspected pneumonia. PMID- 26578142 TI - BCGitis: A rare complication after intravesical BCG therapy. PMID- 26578143 TI - Bronchiectasis caused by common variable immunodeficiency. PMID- 26578144 TI - Diffuse lung cysts. PMID- 26578145 TI - What does the p value really mean? PMID- 26578146 TI - Right lung exclusion in massive pulmonary thromboembolism. PMID- 26578147 TI - Properties of Polyhydroxyalkanoate Granules and Bioemulsifiers from Pseudomonas sp. and Burkholderia sp. Isolates Growing on Glucose. AB - A Burkholderia and Pseudomonas species designated as AB4 and AS1, respectively, were isolated from soil containing decomposing straw or sugar cane bagasse collected from Brazil. This study sought to evaluate the capacities of culture media, cell-free medium, and crude lysate preparations (containing PHB inclusion bodies) from bacterial cell cultures to stabilize emulsions with several hydrophobic compounds. Four conditions showed good production of bioemulsifiers (E24 >= 50 %), headed by substantially cell-free media from bacterial cell cultures in which bacterial isolates from Burkholderia sp. strain AB4 and Pseudomonas sp. strain AS1 were grown. Our results revealed that the both isolates (AB4 and AS1 strains) exhibited high emulsification indices (indicating usefulness in bioremediation) and good stabilities. PMID- 26578148 TI - The Induction of Growth Inhibition and Apoptosis in HeLa and MCF-7 Cells by Teucrium sandrasicum, Having Effective Antioxidant Properties. AB - The hidromethanolic (Met/W), ethyl acetate (EA(EA/W)), and water (W(EA/W)) extracts from Teucrium sandrasicum leaves (L) and flowers (F) were investigated for antioxidant properties and antiproliferative effects on HeLa, MCF-7, and L929. The highest DPPH scavenging, metal chelating capacities, and total phenolic and flavonoid contents were observed in Met/WL. The highest hydroxyl scavenging and reducing power capacities were found in EA(EA/W)L. Met/WL, EA(EA/W)L and EA(EA/W)F inhibited cancer cell growths, while they did not show significant cytotoxicity on L929. While the reactive oxygen species (ROS) levels were generally close to controls in HeLa, they were induced in MCF-7 with the treatment of Met/WL, EA(EA/W)L, and EA(EA/W)F and acted as antioxidant for L929. The highest apoptosis inductions were observed in Met/WL-treated HeLa and EA(EA/W)L-treated MCF-7, which were supported with the changes in mitochondrial membrane potentials. The highest caspase-9 activities were found in Met/WL treated HeLa and EA(EA/W)F-treated MCF-7. Caspase-3 activity was only induced in EA(EA/W)F-treated HeLa. PMID- 26578149 TI - Extracorporeal Treatment in Phenytoin Poisoning: Systematic Review and Recommendations from the EXTRIP (Extracorporeal Treatments in Poisoning) Workgroup. AB - The Extracorporeal Treatments in Poisoning (EXTRIP) Workgroup conducted a systematic literature review using a standardized process to develop evidence based recommendations on the use of extracorporeal treatment (ECTR) in patients with phenytoin poisoning. The authors reviewed all articles, extracted data, summarized findings, and proposed structured voting statements following a predetermined format. A 2-round modified Delphi method was used to reach a consensus on voting statements, and the RAND/UCLA Appropriateness Method was used to quantify disagreement. 51 articles met the inclusion criteria. Only case reports, case series, and pharmacokinetic studies were identified, yielding a very low quality of evidence. Clinical data from 31 patients and toxicokinetic grading from 46 patients were abstracted. The workgroup concluded that phenytoin is moderately dialyzable (level of evidence = C) despite its high protein binding and made the following recommendations. ECTR would be reasonable in select cases of severe phenytoin poisoning (neutral recommendation, 3D). ECTR is suggested if prolonged coma is present or expected (graded 2D) and it would be reasonable if prolonged incapacitating ataxia is present or expected (graded 3D). If ECTR is used, it should be discontinued when clinical improvement is apparent (graded 1D). The preferred ECTR modality in phenytoin poisoning is intermittent hemodialysis (graded 1D), but hemoperfusion is an acceptable alternative if hemodialysis is not available (graded 1D). In summary, phenytoin appears to be amenable to extracorporeal removal. However, because of the low incidence of irreversible tissue injury or death related to phenytoin poisoning and the relatively limited effect of ECTR on phenytoin removal, the workgroup proposed the use of ECTR only in very select patients with severe phenytoin poisoning. PMID- 26578150 TI - Psychometric evaluation of spinal assessment methods to screen for scoliosis in children and adolescents with cerebral palsy. AB - BACKGROUND: In cerebral palsy (CP) there is an increased risk of scoliosis. It is important to identify a progressive scoliosis early-on because the results of surgery depend on the magnitude of the curve. The Swedish follow-up program for cerebral palsy (CPUP) includes clinical examinations of the spine. The reliability and validity of the assessment method have not been studied. In this study we evaluate the interrater reliability of the clinical spinal examination used in CPUP and scoliometer measurement in children with CP and we evaluate their validity compared to radiographic examination. METHODS: Twenty-eight children (6-16 years) with CP in Gross Motor Function Classification System levels II-V were included. Clinical spinal examinations and scoliometer measurements in sitting position were performed by three independent examiners. The results were compared to the Cobb angle as determined by radiographic measurement. Interrater reliability was calculated using weighted kappa. Concurrent validity was analyzed using the Cobb angle as gold standard. Sensitivity, specificity, area under receiver operating characteristic curves (AUC) and likelihood ratios (LR) were calculated. Cut-off values for scoliosis were set to >= 20 degrees Cobb angle and >= 7 degrees scoliometer angle. RESULTS: There was an excellent interrater reliability for both clinical examination (weighted kappa = 0.96) and scoliometer measurement (weighted kappa = 0.86). The clinical examination showed a sensitivity of 75 % (95 % CI: 19.4-99.4 %), specificity of 95.8 % (95 % CI: 78.9-99.9 %) and an AUC of 0.85 (95 % CI: 0.61-1.00). The positive LR was 18 and the negative LR was 0.3. The scoliometer measurement showed a sensitivity of 50 % (95 % CI: 6.8-93.2 %), specificity of 91.7 % (95 % CI: 73.0-99.0 %) and AUC of 0.71 (95 % CI: 0.42-0.99). The positive LR was 6 and the negative LR was 0.5. CONCLUSION: The psychometric evaluation of the clinical examination showed an excellent interrater reliability and a high concurrent validity compared to the Cobb angle. The findings should be interpreted cautiously until research with larger samples may further quantify the psychometric properties. Clinical spinal examinations seem appropriate as a screening tool to identify scoliosis in children with CP. PMID- 26578151 TI - Lack of concordance amongst measurements of individual anaerobic threshold and maximal lactate steady state on a cycle ergometer. AB - INTRODUCTION: The calculation of exertion intensity, in which a change is produced in the metabolic processes which provide the energy to maintain physical work, has been defined as the anaerobic threshold (AT). The direct calculation of maximal lactate steady state (MLSS) would require exertion intensities over a long period of time and with sufficient rest periods which would prove significantly difficult for daily practice. Many protocols have been used for the indirect calculation of MLSS. OBJECTIVES: The aim of this study is to determine if the results of measurements with 12 different AT calculation methods and calculation software [Keul, Simon, Stegmann, Bunc, Dickhuth (TKM and WLa), Dmax, Freiburg, Geiger-Hille, Log-Log, Lactate Minimum] can be used interchangeably, including the method of the fixed threshold of Mader/OBLA's 4 mmol/l and then to compare them with the direct measurement of MLSS. METHODS: There were two parts to this research. Phase 1: results from 162 exertion tests chosen at random from the 1560 tests. Phase 2: sixteen athletes (n = 16) carried out different tests on five consecutive days. RESULTS: There was very high concordance among all the methods [intraclass correlation coefficient (ICC) > 0.90], except Log-Log in relation to the Stegamnn, Dmax, Dickhuth-WLa and Geiger-Hille. The Dickhuth-TKM showed a high tendency towards concordance, with Dmax (2.2 W) and Dickhuth-WLa (0.1 W). The Dickhuth-TKM method presented a high tendency to concordance with Dickhuth-WLa (0.5 W), Freiburg (7.4 W), MLSS (2.0 W), Bunc (8.9 W), Dmax (0.1 W). The calculation of MLSS power showed a high tendency to concordance, with Dickhuth-TKM (2 W), Dmax (2.1 W), Dickhuth-WLa (1.5 W). CONCLUSION: The fixed threshold of 4 mmol/l or OBLA produces slightly different and higher results than those obtained with all the methods analyzed, including MLSS, meaning an overestimation of power in the individual anaerobic threshold. The Dickhuth-TKM, Dmax and Dickhuth-WLa methods defined a high concordance on a cycle ergometer. Dickhuth-TKM, Dmax, Dickhuth-WLa described a high concordance with the power calculated to know the MLSS. PMID- 26578152 TI - Erratum to: First molecular detection of porcine circovirus type 2 in bovids in China. PMID- 26578153 TI - Duck hepatitis A virus serotype 1 minigenome: a model for studying the viral 3'UTR effect on viral translation. AB - To date, the genetic replication and translation mechanisms as well as the pathogenesis of duck hepatitis A virus type 1 (DHAV-1) have not been adequately characterized due to the lack of a reliable and efficient cell culture system. Although the full-length infections clone system is the best platform to manipulate the virus, it is relatively difficult to assemble this system due to the lack of a suitable cell line. It has been proven that the minigenome system an efficient reverse genetics system for the study of RNA viruses. In some cases, it can be used to displace the infectious clone of RNA viruses. Here, we generated a minigenome for DHAV-1 with two luciferase reporter genes, firefly luciferase (Fluc) and Renilla luciferase (Rluc). The Rluc gene was used as a reference gene for the normalization of the Fluc gene expression in transfected cells, which provided a platform for studying the regulatory mechanisms of DHAV 1. Furthermore, to investigate the role of DHAV-3'UTR in the regulation of viral protein translation, deletions in the 3'UTR were introduced into the DHAV-1 minigenome. Luciferase activity, an indicator of virus translation, was then determined. These results showed that a minigenome system for DHAV-1 was successfully constructed for the first time and that the complete or partial deletion of the DHAV-3'UTR did not affect the expression level of the reporter gene, indicating that DHAV-1 translation may not be modulated by the viral genomic 3'UTR sequence. PMID- 26578154 TI - Recent advances in transition-metal dichalcogenide based nanomaterials for water splitting. AB - The desire for sustainable and clean energy future continues to be the concern of the scientific community. Researchers are incessantly targeting the development of scalable and abundant electro- or photo-catalysts for water splitting. Owing to their suitable band-gap and excellent stability, an enormous amount of transition-metal dichalcogenides (TMDs) with hierarchical nanostructures have been extensively explored. Herein, we present an overview of the recent research progresses in the design, characterization and applications of the TMD-based electro- or photo-catalysts for hydrogen and oxygen evolution. Emphasis is given to the layered and pyrite-phase structured TMDs encompassing semiconducting and metallic nanomaterials. Illustrative results and the future prospects are pointed out. This review will provide the readers with insight into the state-of-the-art research progresses in TMD based nanomaterials for water splitting. PMID- 26578155 TI - Regional differences of outpatient physician supply as a theoretical economic and empirical generalized linear model. AB - BACKGROUND: Regional differences in physician supply can be found in many health care systems, regardless of their organizational and financial structure. A theoretical model is developed for the physicians' decision on office allocation, covering demand-side factors and a consumption time function. METHODS: To test the propositions following the theoretical model, generalized linear models were estimated to explain differences in 412 German districts. Various factors found in the literature were included to control for physicians' regional preferences. RESULTS: Evidence in favor of the first three propositions of the theoretical model could be found. Specialists show a stronger association to higher populated districts than GPs. Although indicators for regional preferences are significantly correlated with physician density, their coefficients are not as high as population density. CONCLUSIONS: If regional disparities should be addressed by political actions, the focus should be to counteract those parameters representing physicians' preferences in over- and undersupplied regions. PMID- 26578156 TI - Neonatal cellular and gene therapies for mucopolysaccharidoses: the earlier the better? AB - Mucopolysaccharidoses (MPSs) are a group of lysosomal storage disorders (LSDs). The increasing interest in newborn screening procedures for LSDs underlines the need for alternative cellular and gene therapy approaches to be developed during the perinatal period, supporting the treatment of MPS patients before the onset of clinical signs and symptoms. The rationale for considering these early therapies results from the clinical experience in the treatment of MPSs and other genetic disorders. The normal or gene-corrected hematopoiesis transplanted in patients can produce the missing protein at levels sufficient to improve and/or halt the disease-related abnormalities. However, these current therapies are only partially successful, probably due to the limited efficacy of the protein provided through the hematopoiesis. An alternative explanation is that the time at which the cellular or gene therapy procedures are performed could be too late to prevent pre-existing or progressive organ damage. Considering these aspects, in the last several years, novel cellular and gene therapy approaches have been tested in different animal models at birth, a highly early stage, showing that precocious treatment is critical to prevent long-term pathological consequences. This review provides insights into the state-of-art accomplishments made with neonatal cellular and gene-based therapies and the major barriers that need to be overcome before they can be implemented in the medical community. PMID- 26578157 TI - Erratum to: Safety Considerations of Inhaled Corticosteroids in the Elderly. AB - Inhaled corticosteroids (ICSs) are widely used in the treatment of patients with chronic obstructive pulmonary diseases. However, high-dose regimens and long-term use of ICSs have the potential to cause a variety of local and systemic side effects such as candidiasis, cataracts, glaucoma, and osteoporosis. The use of ICSs can also be associated with the risk of bone fractures, diabetes mellitus and pneumonia. These ICS-related side effects are of particular importance in elderly patients due to the presence of comorbidities and age-related behavioral, cognitive, and psychological problems, which can all interact with inhaled treatment. We reviewed the available literature on the clinically relevant side effects of ICSs in the elderly to provide practical measures to properly monitor and manage the risk of ICSs in the geriatric population. Inspection of the mouth, monitoring of ocular pressure, and use of bone-protective drugs may be necessary in patients on prolonged ICS therapy. Above all, the use of the lowest possible ICS dose and a careful re-assessment of the inhalation procedure should be recommended. Taken together, these observations suggest that physicians should use ICSs appropriately for those patients in whom the benefit will outweigh the risk, especially chronic obstructive pulmonary disease (COPD) patients with previous frequent exacerbations. Given the paucity of information on the topic and the need to extrapolate the results from studies with broader age ranges, we strongly encourage the design of specifically tailored clinical studies in the elderly. PMID- 26578158 TI - Unusual cause of intestinal perforation in granulomatosis with polyangiitis (Wegener's). PMID- 26578159 TI - Gestation age dependent transfer of human immunoglobulins across placenta in timed-pregnant guinea pigs. AB - INTRODUCTION: When administered during pregnancy, antibodies and other biologic drugs that contain the Fc part of the IgG molecule can traverse the placenta. Although it is generally accepted that the FcRn receptor mediates this process, gaps remain in our understanding of underlying details in humans and in common laboratory animal species. METHODS: We expanded our previous studies in timed pregnant guinea pigs to both measure the transport of human (h) IgG at earlier gestation ages in vivo and evaluate FcRn function in vitro using Surface Plasmon Resonance (SPR) and Madin-Darby canine kidney cells (MDCK) that express guinea pig (gp) FcRn. RESULTS: In timed-pregnant guinea pigs both the average concentration of hIgG in the fetus and its ratio to maternal hIgG concentration increase exponentially with gestation age. Thus, hIgG fetal:maternal concentration ratios increase from an average of 1% to 3%, 17%, and 76% on GD ~26, 35, 46, and 54, respectively. In vitro, gpFcRn immobilized on a solid surface can bind hIgG and gpIgG preparations in a similar manner. All engineered human Fc isotype-specific constructs were internalized by MDCK-gpFcRn cells at significant levels. While not significant, their recycling and hIgG transcytosis by this cell line also trend higher than background controls. DISCUSSION: Pregnant guinea pigs exhibit similarities with humans in the degree and timing of transplacental transfer as well as the ability of their FcRn to bind and internalize hIgG in vitro. Further studies are needed to guide building appropriate systems for the evaluation of FcRn mediated function of human immunoglobulin therapies. PMID- 26578160 TI - Hybrid Flexible Resistive Random Access Memory-Gated Transistor for Novel Nonvolatile Data Storage. AB - Here, a single-device demonstration of novel hybrid architecture is reported to achieve programmable transistor nodes which have analogies to flash memory by incorporating a resistive switching random access memory (RRAM) device as a resistive switch gate for field effect transistor (FET) on a flexible substrate. A high performance flexible RRAM with a three-layered structure is fabricated by utilizing solution-processed MoS2 nanosheets sandwiched between poly(methyl methacrylate) polymer layers. Gate coupling with the pentacene-based transistor can be controlled by the RRAM memory state to produce a nonprogrammed state (inactive) and a programmed state (active) with a well-defined memory window. Compared to the reference flash memory device based on the MoS2 floating gate, the hybrid device presents robust access speed and retention ability. Furthermore, the hybrid RRAM-gated FET is used to build an integrated logic circuit and a wide logic window in inverter logic is achieved. The controllable, well-defined memory window, long retention time, and fast access speed of this novel hybrid device may open up new possibilities of realizing fully functional nonvolatile memory for high-performance flexible electronics. PMID- 26578161 TI - Adapting to climate change in the agricultural sector. PMID- 26578162 TI - Biomechanical measures in participants with shoulder pain: Intra-rater reliability. AB - Biomechanical measures are used to characterize the mechanisms of treatment for shoulder pain. The objective was to characterize test-retest reliability and measurement error of shoulder surface electromyographic(sEMG) and kinematic measures. Individuals(n = 12) with subacromial pain syndrome were tested at 2 visits. Five repetitions of shoulder scapular plane elevation were performed while collecting sEMG of the upper trapezius(UT), middle trapezius(MT), lower trapezius(LT), serratus anterior(SA) middle-deltoid, and infraspinatus muscles during ascending and descending phases. Simultaneously, electromagnetic sensors measured 3-dimensional kinematics of scapular internal/external rotation, upward/downward rotation, posterior/anterior tilt, and clavicular elevation/depression and clavicular protraction/retraction. Kinematic and sEMG variables were reduced for the total phase of ascending and descending elevation (30 degrees -120 degrees , 120 degrees -30 degrees ), at 30 degrees intervals for sEMG, and at every 30 degrees discrete kinematic angle. The intraclass correlation coefficients(ICC) ranged from 0.08 to 0.99 for sEMG and 0.23-0.95 for kinematics. Correspondingly, the standard error of the measurement(SEM) and minimal detectable change(MDC) for sEMG measures varied from 2.3% to 103.8% of a reference contraction(REF-contraction). For kinematics, the SEM and MDC varied from 1.4 degrees to 5.9 degrees . Between-day reliability was good to very good, except for scapular internal/external rotation kinematics, and sEMG for the LT, UT, and SA. sEMG error values were highest (>25%REF-contraction) for most of the LT, UT, and SA variables. Kinematic error values indicate changes or differences of 2 degrees -3 degrees are meaningful, except for upward/downward rotation and internal/external rotation with MDCs of 4 degrees -6 degrees . Generally, data from the total phase of movement had better reliability and lower error than the data from sEMG interval or kinematic discrete angles. PMID- 26578163 TI - Patient-Reported Outcome (PRO) questionnaires for people with pain in any spine region. A systematic review. AB - BACKGROUND/OBJECTIVE: This systematic review investigates the measurement properties of Patient-Reported Outcome (PRO) questionnaires which evaluate disability associated with pain in any area of the spine. METHOD: PRO questionnaires for people with pain in any spinal region were identified from existing systematic reviews and recent studies. Databases were searched for studies which evaluated the measurement properties of the included questionnaires to August 2015. Data synthesis used a levels of evidence approach which considered study methodological quality. RESULTS: The Extended Aberdeen Back Pain Scale (EA), Functional Rating Index (FRI) and Spine Functional Index (SFI) were identified as eligible for this review. The FRI was evaluated in 15 studies, with positive results for internal consistency, structural validity, hypothesis testing and responsiveness, negative results for measurement error and conflicting results for reliability. The SFI was evaluated in 3 studies with positive results for internal consistency, reliability, content validity, and structural validity. Conflicting results were found for hypothesis testing. The EA was evaluated in 3 studies which found negative results for internal consistency and structural validity. CONCLUSIONS: The FRI is provisionally recommended for the assessment of disability in people with multi-area spinal pain. This conclusion is based on studies of mainly fair methodological quality. PMID- 26578164 TI - Not seeing or feeling is still believing: conscious and non-conscious pain modulation after direct and observational learning. AB - Our experience with the world is shaped not only directly through personal exposure but also indirectly through observing others and learning from their experiences. Using a conditioning paradigm, we investigated how directly and observationally learned information can affect pain perception, both consciously and non-consciously. Differences between direct and observed cues were manifest in higher pain ratings and larger skin conductance responses to directly experienced cues. However, the pain modulation effects produced by conditioning were of comparable magnitude for direct and observational learning. These results suggest that social observation can induce positive and negative pain modulation. Importantly, the fact that cues learned by observation and activated non consciously still produced a robust conditioning effect that withstood extinction highlights the role of indirect exposure in placebo and nocebo effects. PMID- 26578167 TI - Testing children's ability to correctly use the "Shadow Rule" for sun protection. AB - INTRODUCTION: The "Shadow Rule" (SR) is a useful, immediate indicator of sunburn risk following the mnemonic "Short shadow? Seek shade!" However, some question people's ability to discern when their shadows are shorter or longer than them. METHODS: N = 76 10-year-old children were taught the SR and then asked to estimate their sun-cast shadow length relative to their height and whether this meant they should seek shade. Children were then asked to estimate a doll's shadow length at 10 systematically randomised angles. RESULTS: Children experienced greatest difficulty judging their shadows' lengths when they were equal to their height. At all other angles, they demonstrated high accuracy and 92 % of the time on average could correctly interpret the SR. CONCLUSIONS: Ten year-old children appear capable, and by extension adults too, of applying the SR. Future research is now required to establish if education about the SR will translate into sun protection behaviour change. PMID- 26578166 TI - Tianma Gouteng Yin, a Traditional Chinese Medicine decoction, exerts neuroprotective effects in animal and cellular models of Parkinson's disease. AB - Tianma Gouteng Yin (TGY) is a traditional Chinese medicine (TCM) decoction widely used to treat symptoms associated with typical Parkinson's disease (PD). In this study, the neuroprotective effects of water extract of TGY were tested on rotenone-intoxicated and human alpha-synuclein transgenic Drosophila PD models. In addition, the neuroprotective effect of TGY was also evaluated in the human dopaminergic neuroblastoma SH-SY5Y cell line treated with rotenone and the rotenone intoxicated hemi-parkinsonian rats. In rotenone-induced PD models, TGY improved survival rate, alleviated impaired locomotor function of Drosophila, mitigated the loss of dopaminergic neurons in hemi-parkinsonian rats and alleviated apoptotic cell death in SH-SY5Y cells; in alpha-synuclein transgenic Drosophila, TGY reduced the level of alpha-synuclein and prevented degeneration of dopaminergic neurons. Conclusively, TGY is neuroprotective in PD models both in vivo and in vitro. PMID- 26578168 TI - Evaluation of microbially enhanced composting of sophora flavescens residues. AB - The effects of inoculants on the composting of Sophora flavescens residues were evaluated based on several physical, chemical and biological parameters, as well as the infrared spectra. Compared to the control compost without inoculants, the treatment compost with inoculants (Bacillus subtilis strain G-13 and Chaetomium thermophilum strain GF-1) had a significantly longer thermophilic duration, higher cellulase activity and a higher degradation rate of cellulose, hemicellulose and lignin (P < 0.05). Thus, a higher maturity degree of compost with apparently lower C:N ratio (15.88 vs. 17.77) and NH4-N:NO3-N ratio (0.16 vs. 0.20) was obtained with the inoculation comparing with the control (P < 0.05). Besides, the inoculants could markedly accelerate the composting process and increase the maturity degree of compost as indicated by the germination index (GI) in which the treatment reached the highest GI of 133.2% at day 15 while the control achieved the highest GI of 125.7% at day 30 of the composting. Inoculation with B. subtilis and C. thermophilum is a useful method to enhance the S. flavescens residues composting according to this study. PMID- 26578170 TI - Endoscopic management of sump syndrome resulting from endoscopic choledochogastrostomy. PMID- 26578169 TI - Transcriptional regulation of PIN genes by FOUR LIPS and MYB88 during Arabidopsis root gravitropism. AB - PIN proteins are auxin export carriers that direct intercellular auxin flow and in turn regulate many aspects of plant growth and development including responses to environmental changes. The Arabidopsis R2R3-MYB transcription factor FOUR LIPS (FLP) and its paralogue MYB88 regulate terminal divisions during stomatal development, as well as female reproductive development and stress responses. Here we show that FLP and MYB88 act redundantly but differentially in regulating the transcription of PIN3 and PIN7 in gravity-sensing cells of primary and lateral roots. On the one hand, FLP is involved in responses to gravity stimulation in primary roots, whereas on the other, FLP and MYB88 function complementarily in establishing the gravitropic set-point angles of lateral roots. Our results support a model in which FLP and MYB88 expression specifically determines the temporal-spatial patterns of PIN3 and PIN7 transcription that are closely associated with their preferential functions during root responses to gravity. PMID- 26578171 TI - Management of acute hemorrhagic pancreatitis after EUS-guided FNA of a pancreatic cyst. PMID- 26578172 TI - Can venous-to-arterial carbon dioxide differences reflect microcirculatory alterations in patients with septic shock? AB - PURPOSE: Septic shock has been associated with microvascular alterations and these in turn with the development of organ dysfunction. Despite advances in video microscopic techniques, evaluation of microcirculation at the bedside is still limited. Venous-to-arterial carbon dioxide difference (Pv-aCO2) may be increased even when venous O2 saturation (SvO2) and cardiac output look normal, which could suggests microvascular derangements. We sought to evaluate whether Pv aCO2 can reflect the adequacy of microvascular perfusion during the early stages of resuscitation of septic shock. METHODS: Prospective observational study including 75 patients with septic shock in a 60-bed mixed ICU. Arterial and mixed venous blood gases and hemodynamic variables were obtained at catheter insertion (T0) and 6 h after (T6). Using a sidestream dark-field device, we simultaneously acquired sublingual microcirculatory images for blinded semiquantitative analysis. Pv-aCO2 was defined as the difference between mixed-venous and arterial CO2 partial pressures. RESULTS: Progressively lower percentages of small perfused vessels (PPV), lower functional capillary density, and higher heterogeneity of microvascular blood flow were observed at higher Pv-aCO2 values at both T0 and T6. Pv-aCO2 was significantly correlated to PPV (T0: coefficient -5.35, 95 % CI 6.41 to -4.29, p < 0.001; T6: coefficient, -3.49, 95 % CI -4.43 to -2.55, p < 0.001) and changes in Pv-aCO2 between T0 and T6 were significantly related to changes in PPV (R (2) = 0.42, p < 0.001). Absolute values and changes in Pv-aCO2 were not related to global hemodynamic variables. Good agreement between venous to-arterial CO2 and PPV was maintained even after corrections for the Haldane effect. CONCLUSIONS: During early phases of resuscitation of septic shock, Pv aCO2 could reflect the adequacy of microvascular blood flow. PMID- 26578173 TI - Electromyography and nerve conduction studies in critical care: step by step in the right direction. PMID- 26578175 TI - Genetic association between leg conformation in young pigs and sow longevity. AB - Longevity is important in pig production with respect to both economic and ethical aspects. Direct selection for longevity might be ineffective because 'true' longevity can only be recorded when a sow has been culled or died. Thus, indirect selection for longevity using information from other traits that can be recorded early in life and are genetically correlated with longevity might be an alternative. Leg conformation has been included in many breeding schemes for a number of years. However, proving that leg conformation traits are good early indicators for longevity still remains. Our aim was to study genetic associations between leg conformation traits of young (5 months; 100 kg) Swedish Yorkshire pigs in nucleus herds and longevity traits of sows in nucleus and multiplier herds. Data included 97 533 animals with information on conformation (Movement and Overall score) recorded at performance testing and 26 962 sows with information on longevity. The longevity traits were as follows: stayability from 1st to 2nd parity, lifetime number of litters and lifetime number of born alive piglets. Genetic analyses were performed with both linear models using REML and linear-threshold models using Bayesian methods. Heritabilities estimated using the Bayesian method were higher than those estimated using REML, ranging from 0.10 to 0.24 and 0.07 to 0.20, respectively. All estimated genetic correlations between conformation and longevity traits were significant and favourable. Heritabilities and genetic correlations between conformation and longevity indicate that selection on leg conformation should improve sow longevity. PMID- 26578176 TI - The Cpf1 CRISPR-Cas protein expands genome-editing tools. AB - CRISPR-Cas systems have immense biotechnological utility. A recent study reveals the potential of the Cpf1 nuclease to complement and extend the existing CRISPR Cas9 genome-editing tools. PMID- 26578177 TI - Perineural expression of high-mobility group box-1 contributes to long-lasting mechanical hypersensitivity via matrix metalloprotease-9 up-regulation in mice with painful peripheral neuropathy. AB - High-mobility group box-1 (HMGB1) has been shown to be critical in the modulation of nociceptive transduction following a peripheral neuropathy. However, the precise role of peripherally expressed HMGB1 in neuropathic pain has yet to be fully elaborated. Following a partial sciatic nerve ligation (PSNL) in mice, a persistent ipsilateral up-regulation of HMGB1 was observed from 3 to 21 days after PSNL, in paralleled with a robust ipsilateral hind paw mechanical hypersensitivity. Increased HMGB1 was detected in both infiltrating macrophages and proliferating Schwann cells in the ipsilateral nerve 14 days following PSNL. Repeated perineural treatment with anti-HMGB1 antibody significantly ameliorated PSNL-induced mechanical hypersensitivity. Several pronociceptive molecules, including matrix metalloprotease-9 (MMP-9), tumor necrosis factor-alpha, interleukin-1beta (IL-1beta), and cyclooxygenase-2, were up-regulated in injured sciatic nerve 14 days following PSNL. Repeated perineural treatment with an anti HMGB1 antibody significantly suppressed expression of MMP-9, but not other pronociceptive molecules. Perineural treatment with a selective MMP-9 inhibitor ameliorated PSNL-induced mechanical hypersensitivity. The current findings demonstrate that the maintenance of the neuropathic state following an injured nerve is dependent on the up-regulation of HMGB1 and MMP-9. Thus, blocking HMGB1 function in sciatic nerve could be a potent therapeutic strategy for the treatment of neuropathic pain. Increased peripheral high-mobility group box-1 (HMGB1) is involved in the modulation of nociceptive transduction following a peripheral neuropathy. Following nerve injury in mice, increased HMGB1 is detected in both infiltrating macrophages and proliferating Schwann cells in the ipsilateral nerve. Repeated perineural treatment with anti-HMGB1 antibody significantly ameliorates nerve injury-induced mechanical hypersensitivity, and suppresses expression of matrix metalloprotease-9 (MMP-9). The findings demonstrate that the maintenance of the neuropathic state following an injury nerve is dependent on the up-regulation of HMGB1 and MMP-9. PMID- 26578178 TI - Cardiac tumors: To treat or not to treat (or both)? PMID- 26578179 TI - Right ventricular and epicardial tumors from benign metastasizing uterine leiomyoma. PMID- 26578180 TI - Using social media effectively in a surgical practice. PMID- 26578181 TI - Iatrogenic aortic dissection in an infant with persistent fifth aortic arch and congenital heart defects. PMID- 26578182 TI - Antithrombin levels during pediatric cardiopulmonary bypass: Key to changing a decades-old paradigm for anticoagulation? PMID- 26578183 TI - Epicardial adipose hypertrophy: The Phantom of the Opera. PMID- 26578184 TI - Allostery in BAX protein activation. AB - BAX is a member of the proapoptotic BCL-2 family of proteins, which is involved in the regulation of the intrinsic pathway of apoptosis. In the process of apoptosis, BH3-only molecules activate cytosolic BAX. Activated BAX molecules insert into the mitochondrial outer membrane with their [Formula: see text]-helix and form oligomers that lead to membrane poration, resulting in the release of apoptogenic factors including cytochrome c. Recently, a novel interaction site for the binding of the BIM SAHB ligand to BAX was reported. BIM SAHB binding was shown to invoke the exposure of the 6A7 epitope (amino acids 13-19) and of the BH3 domain of BAX, followed by mobilization of the BAX [Formula: see text]-helix. However, the intramolecular pathway for signal transmission in BAX, from BIM SAHB binding to mobilization of the [Formula: see text]-helix largely remained elusive. For a molecular understanding of the activation of BAX, and thus the first steps in apoptosis, we performed microsecond atomistic molecular dynamics simulations both of the BAX protein and of the BAX:BIM SAHB complex in aqueous solution. In agreement with experiment, the 6A7 and BH3 domains adopt a more solvent-exposed conformation within the BAX:BIM SAHB complex. BIM SAHB binding was found to stabilize the secondary structure of the [Formula: see text]9-helix. A force distribution analysis revealed a force network of residue-residue interactions responsible for signal transmission from the BIM SAHB binding site predominantly via the [Formula: see text]4- and [Formula: see text]6-helices to the [Formula: see text]9-helix on the opposite site of the protein. PMID- 26578185 TI - Anti-H1N1 virus, cytotoxic and Nrf2 activation activities of chemical constituents from Scutellaria baicalensis. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Huang-Qin, derived from the roots of Scutellaria baicalensis Georgi, is a popular Chinese herbal medicine mainly used to treat influenza and cancer. This study aims to elucidate the anti-influenza, anti cancer and anti-oxidation effective components of S. baicalensis. MATERIALS AND METHODS: Various column chromatography techniques and semi-preparative HPLC were used to isolate Scutellaria compounds, and their structures were identified by HRESIMS and NMR spectroscopic analysis. The pure compounds were evaluated for anti-influenza activities against A/WSN/33 (H1N1) virus in MDCK cells, cytotoxic activities against HepG2, SW480 and MCF7 human cancer cells by MTS assay, and antioxidant activities by Nrf2 luciferase reporter assay. In addition, the contents of 12 major compounds in 27 batches of S. baicalensis were simultaneously determined by a fully validated UPLC/UV method. RESULTS: A total of thirty compounds (1-30), including four new ones (3, 7, 11 and 23), were isolated from S. baicalensis. Baicalin (15), baicalein (26), wogonin (27), chrysin (28) and oroxylin A (30) showed potent anti-H1N1 activities, with IC50 values of 7.4, 7.5, 2.1, 7.7 and 12.8 MUM, respectively, which were remarkably more potent than the positive drug Osv-P (oseltamivir phosphate, IC50 45.6 MUM). Most free flavones (26-28 and 30) showed significant cytotoxic activities at 10 MUM (up to 61.2% inhibition rate). Furthermore, 30 could activate Nrf2 transcription by 3.8-fold of the control at 10 MUM. UPLC analysis indicated the 12 major compounds (including the bioactive ones) accounted for 195.93 +/- 43.9 mg g(-)(1) of the herbal materials. CONCLUSION: This study demonstrated that free flavones showed potent anti-influenza, anti-cancer and anti-oxidative activities. They are important effective components of S. baicalensis, and can be used as chemical markers for quality control of this herbal medicine. PMID- 26578186 TI - Anticoagulant activity of crude extract of Holotrichia diomphalia larvae. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Holotrichia diomphalia larvae are one classical folk medicinal material in East Asia which has clinically been used to promote blood circulation and dispel blood stasis for several hundred years. AIM OF THE STUDY: The anticoagulant activity of crude extract of H. diomphalia larvae (CEHDL) in vitro and in vivo was evaluated to explore its mechanism as antithrombotic medicine. MATERIALS AND METHODS: The effects of CEHDL on plasma recalcification time, platelet aggregation, bleeding time, hydrolysis of fibrinogen and fibrin were measured with normal human plasma, plasma-rich platelet, transected mouse tails and bovine fibrinogen; the anti-thrombosis activities of CEHDL in vitro and in vivo were analyzed with clots lysis assay and carrageenan-induced mouse tail thrombosis model. RESULTS: CEHDL was found to contain large numbers of proteins and could inhibit blood coagulation and platelet aggregation in a dose-dependent manner. Furthermore, CEHDL preferentially cleaved alpha- and beta-chains followed by gamma-chains of fibrinogen. Besides, CEHDL could directly degrade fibrin rather than activate plasminogen. It has been noted that fibrinogenolytic activity of CEHDL could be unaffected by metal ions such as Mg(2+), Ca(2+), Zn(2+), Fe(2+), Fe(3+), Cu(2+) and buffers with pH 3-10. Moreover, protease inhibitors like TPSI, aprotinin, leupetin, PMSF, DTT and EDTA only slightly or not inhibited fibrinogenolytic activity of CEHDL. However, CEHDL could be completely inactivated at 75 degrees C and 100 degrees C. In addition, CEHDL exhibited anti-thrombosis activities in both blood clot lysis assay and carrageenan-induced thrombosis model. CONCLUSION: CEHDL possessed potent anticoagulant activity and several fibrin(ogen)olytic agents from H. diomphalia larvae were responsible for its antithrombotic effect as medicine. PMID- 26578187 TI - Sequencing-based high throughput mutation detection in bread wheat. AB - BACKGROUND: Forward genetic approaches have limited use for agronomic traits that can't be reliably scored on a single plant basis. Thus, mutants in wheat and other crops are more useful for gene function studies by reverse genetic approach. With a long-term goal to develop a sequence-based mutation detection resource in hexaploid wheat, we conducted a feasibility study to accurately differentiate induced mutations from the homoeologs' sequence variations present among the three wheat genomes. RESULTS: A reduced representation ApeKI library consisting of 21 Ethylmethane Sulfonate (EMS) induced mutants and two wild type cv. Indian plants was developed using individual barcode adapters and sequenced. A novel bioinformatics pipeline was developed to identify sequence variants using 178,464 wheat unigenes as a reference wheat transcriptome. In total, 14,130 mutational changes [Single Nucleotide Polymorphisms (SNPs) and Insertions/Deletions (INDELs)] and 150,511 homoeologous sequence changes were detected. On an average, 662 SNPs (ranging from 46 to 1,330) and 10 small INDELs (ranging from 0 to 23) were identified for each of the mutants. A mutation frequency of one per 5 Kb was observed with 70 % being transitions and 30 % transversions. The pipeline was tested using the known sequence changes in the three wheat genes. Genes present in the distal regions of the chromosomes were found to be more prone to EMS compared to genes present in the proximal regions. Redefined parameters identified a total of 28,348 mutational changes (1,349/plant). CONCLUSIONS: We conclude that sequencing based mutation detection is a valuable method to identify induced mutations at large. PMID- 26578188 TI - Evidence-based medicine and clinical fluorodeoxyglucose PET/MRI in oncology. AB - Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI) is a hybrid of two technologies each with its own evidence for clinical effectiveness. This article amalgamates evidence for clinical effectiveness of fluorodeoxyglucose (FDG) PET/CT and MRI as separate modalities with current evidence for hybrid PET/MRI and considers whether such an approach might provide a stronger case for the clinical use of PET/MRI at an earlier stage.Because links between diagnostic accuracy and health outcomes have already been established for FDG-PET/CT in the investigation of suspected residual or recurrent malignancies, evidence showing improved diagnostic performance and therapeutic impact from the use of PET/MRI as an alternative would imply clinical effectiveness of this modality for this application. A meta-analysis of studies comparing FDG-PET/CT to MRI in patients with suspected residual disease or recurrence of tumours indicates complementary roles for these modalities. PET demonstrates greater sensitivity for recurrence within lymph nodes whereas MRI is more effective that PET/CT in the detection of skeletal and hepatic recurrence. A review of studies assessing therapeutic impact of PET/MRI suggests a greater likelihood for change in clinical management when PET/MRI is used for assessment of suspected residual or recurrent disease rather than tumour staging.Supplementing the evidence-base for FDG-PET/MRI with studies that compare the components of this hybrid technology deployed separately indicates that FDG-PET/MRI is likely to be clinical effective for the investigation of patients with a range of suspected residual or recurrent cancers. This indication should therefore be prioritised for further health technology assessment. PMID- 26578189 TI - Chronic diseases among the elderly in a rural Vietnam: prevalence, associated socio-demographic factors and healthcare expenditures. AB - BACKGROUND: Globally, the population of elderly persons is increasing as well as the prevalence of chronic diseases. This change is causing increased healthcare costs to health care systems threatening to push many households into poverty. Low and middle income countries are projected to experience the greatest impact from this change. This study aims to describe the prevalence of common chronic diseases (CCDs) among the elderly in Vietnam, the associated socio-demographic factors and healthcare expenditures. METHODS: This is a cross-sectional study in the FilaBavi demographic surveillance site in Vietnam. 2873 persons over 60 years were randomly sampled. Prevalence of CCDs was reported from study subjects who previously were informed by physicians. Healthcare expenditures were determined from recall of expenses during the last hospital visit. Binomial logistic regression was done to determine the socio demographic predictors of having a CCD or multiple CCDs. Mean healthcare expenditures for the elderly with CCDs and those without CCDs were summarised and compared. RESULTS: Forty two percent of the elderly were found to have at least one CCD. Joint problems were the most common CCD at 35 %, followed by hypertension at 15 % and chronic bronchitis at 11 %. Being female (OR = 1.51, 95 % CI = 1.03-2.21, p-value = 0.036), higher education (OR = 2.54, 95 % CI = 1.13-5.74, p-value = 0.025) and having advanced age (OR = 1.92, 95 % CI = 1.22-3.00, p-value = 0.005), were associated with common chronic diseases in the elderly. Outpatient healthcare expenditures were found to be significantly higher for the elderly with CCDs than those without CCDs. CONCLUSIONS: Higher education and being female are important key predictors of having a CCD, while wealth quintile is a predictor of multimorbidity, in the elderly. Healthcare expenditures for outpatient health services are higher for elderly persons with CCDs and these costs should be targeted when planning for financial protection. PMID- 26578190 TI - OsHKT2;2/1-mediated Na(+) influx over K(+) uptake in roots potentially increases toxic Na(+) accumulation in a salt-tolerant landrace of rice Nona Bokra upon salinity stress. AB - HKT transporters are Na(+)-permeable membrane proteins, which mediate Na(+) and K(+) homeostasis in K(+)-depleted and saline environments in plants. Class II HKT transporters, a distinct subgroup found predominantly in monocots, are known to mediate Na(+)-K(+) co-transport in principle. Here we report features of ion transport functions of No-OsHKT2;2/1, a class II transporter identified in a salt tolerant landrace of indica rice, Nona Bokra. We profiled No-OsHKT2;2/1 expression in organs of Nona Bokra plants with or without salinity stress. Dominant accumulation of the No-OsHKT2;2/1 transcript in K(+)-starved roots of Nona Bokra plants largely disappeared in response to 50 mM NaCl. We found that No OsHKT2;2/1 expressed in the high-affinity K(+) uptake deficient mutant of Saccharomyces cerevisiae and Xenopus laevis oocytes shows robust K(+) selectivity even in the presence of a large amount of NaCl as reported previously. However, No-OsHKT2;2/1-expressing yeast cells exhibited Na(+) hypersensitive growth under various concentrations of K(+) and Na(+) as the cells expressing Po-OsHKT2;2, a similar class II transporter from another salt tolerant indica rice Pokkali, when compared with the growth of cells harboring empty vector or cells expressing OsHKT2;4. The OsHKT2;4 protein expressed in Xenopus oocytes showed strong K(+) selectivity in the presence of 50 mM NaCl in comparison with No-OsHKT2;2/1 and Po OsHKT2;2. Together with apparent plasma membrane-localization of No-OsHKT2;2/1, these results point to possibilities that No-OsHKT2;2/1 could mediate destructive Na(+) influx over K(+) uptake in Nona Bokra plants upon salinity stress, and that a predominant physiological function of No-OsHKT2;2/1 might be the acquisition of Na(+) and K(+) in K(+)-limited environments. PMID- 26578191 TI - A new find of the fossil Cyclosorus from the Eocene of South China and its paleoclimatic implication. AB - The thelypteroid ferns are widely distributed across tropical regions around the world, but information about their fossil representatives is scarce. A new species, Cyclosorus scutum Naugolnykh, Wang, Han et Jin was discovered from the Eocene Changchang Formation of Hainan Island, South China, and is described on the basis of sterile and fertile leaves, sori, sporangia and spores preserved in situ. Discovery of this new species clearly shows that climatic conditions of that time in this area were humid, i.e. warm and wet. PMID- 26578192 TI - Development and validation of the short version of the diabetes obstacles questionnaire (DOQ-30) in six European countries. AB - BACKGROUND: Patients with type 2 diabetes reveal different obstacles in living with the disease. The EGPRN initiated a qualitative research EUROBSTACLE to create a broadly conceptualized diabetes-related quality of life (DR-QoL) instrument. It led to the development of the diabetes obstacle questionnaire (DOQ), a five-point Likert-scaled measure, consisting of 78 items in eight scales. OBJECTIVES: To develop and validate a short, easy-to-use version of the DOQ. METHODS: A cross-sectional study with the DOQ was carried out. Participants answered the DOQ and GPs added some clinical data from their medical records. Data of 853 patients from Belgium, France, Estonia, Serbia, Slovenia, and Turkey were included in the analysis. The selection of items for the short version of the DOQ was achieved with exploratory factor analysis (EFA). Construct validity was proved with EFA and Pearson correlations between the DOQ and the new DOQ-30. Internal reliability was established with Cronbach's alpha. RESULTS: DOQ-30 resulted in 30 items in nine subscales. It explained 49.8% of items' variance. It shows a considerable good internal reliability and construct validity. CONCLUSION: The DOQ-30 is a five-point Likert-scaled broadly conceptualized measure of DR-QoL. It addresses a variety of obstacles, such as social, psychological, cognitive and behavioural. The DOQ-30 is ready for implementation in general practice and research in Europe as a valuable instrument to assess DR QoL. PMID- 26578193 TI - Profile of Patients Undergoing Gluteoplasty. AB - BACKGROUND: Gluteal augmentation surgery has grown by 42 % per year; however, the epidemiological profile of patients who seek this treatment has never been studied. OBJECTIVE: To establish the epidemiological profile of patients who have undergone gluteoplasty surgery, evaluating their level of satisfaction and the social impact caused by the surgery. METHODS: Fifty patients, with ages ranging from 23 to 57 years replied to a specific questionnaire and the esthetic result of the surgery was evaluated. Thirty-seven patients were analyzed prospectively, using CT scans and gluteal reconstruction. The esthetic result was evaluated by eight plastic surgeon specialists from SBCP. RESULTS: About satisfaction and quality of life, 98 % of the patients demonstrated improvement in some aspect of life. Analysis of the marital status of patients showed that 24 % of them have changed it. Therefore, all cases showed positive correlations between implant size and monthly income, age and satisfaction of patients. There has also been a positive correlation between implant size and recovery time. There was no statistically significant correlation between the esthetic result and the implant volume or the anthropometric measurements. CONCLUSIONS: The epidemiological profile of patients undergoing gluteoplasty augmentation with implants is predominantly white skin, 36 years old, unrelated to the occupation or socioeconomic status. Augmentation gluteoplasty with implants is a surgery with a high level of satisfaction to patients, improving life in many aspects but, mainly, affectively. Its outcome produces a natural look and is hardly noticed by others. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. PMID- 26578194 TI - Introducing the Body-QoL(r): A New Patient-Reported Outcome Instrument for Measuring Body Satisfaction-Related Quality of Life in Aesthetic and Post bariatric Body Contouring Patients. AB - OBJECTIVE: To develop a new patient-reported outcome instrument (PRO) to measure body-related satisfaction quality of life (QoL). METHODS: Standard 3-phase PRO design was followed; in the first phase, a qualitative design was used in 45 patients to develop a conceptual framework and to create preliminary scale domains and items. In phase 2, large-scale population testing on 1340 subjects was performed to reduce items and domains. In phase 3, final testing of the developed instrument on 34 patients was performed. Statistics used include Factor, RASCH, and multivariate regression analysis. Psychometric properties measured were internal reliability, item-rest, item-test, and test-retest correlations. RESULTS: The PRO-developed instrument is composed of four domains (satisfaction with the abdomen, sex life, self-esteem and social life, and physical symptoms) and 20 items in total. The score can range from 20 (worst) to 100 (best). Responsiveness was 100 %, internal reliability 93.3 %, and test retest concordance 97.7 %. Body image-related QoL was superior in men than women (p < 0.001) and decreased with increasing age (p = 0.004) and BMI (p < 0.001). Post-bariatric body contouring patients score lower than cosmetic patients in all domains of the Body-QoL instrument (p < 0.001). After surgery, the score improves by on average 21.9 +/- 16.9 (effect size 1.8, p < 0.001). CONCLUSIONS: Body satisfaction-related QoL can be measured reliably with the Body-QoL instrument. It can be used to quantify the improvement in cosmetic and post-bariatric patients including non- or minimally invasive procedures, suction assisted lipectomy, abdominoplasty, lipoabdominoplasty, and lower body lift and to give an evidence-based approach to standard practice. LEVEL OF EVIDENCE I: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. PMID- 26578195 TI - The future of transcatheter aortic valve implantation. AB - Since the introduction of transcatheter aortic valve implantation (TAVI) into clinical practice, the treatment of aortic stenosis has changed dramatically. In the past, medical therapy with or without balloon aortic valvuloplasty was the only option for inoperable patients. More recently, TAVI has become the treatment of choice for these patients and the preferred alternative for high-risk operable patients. Surgical aortic valve replacement (SAVR) currently remains the gold standard for patients at low or intermediate operative risk. As randomized trials have demonstrated comparable results between TAVI and SAVR in the high-risk population, there is now a clear trend towards performing TAVI even in intermediate-risk patients while awaiting the results of randomized trials in that population. Nevertheless, there are still questions regarding TAVI involving paravalvular leak (PVL), stroke, pacemaker requirements, and durability that remain to be more definitively answered before TAVI can routinely be performed in a broader, lower risk population. Improvements in patient selection, imaging, and second and third generation devices have decreased the incidence of PVLs and vascular complications that followed the earliest TAVI procedures, but the rates of perioperative stroke and permanent pacemaker implantation must still be addressed. Furthermore, the long-term durability of TAVI devices and a role for post-procedure antithrombotic management remain unanswered. Until these questions are more clearly answered, it is the Heart Team's task to determine the optimal treatment for each patient based on risk scores, frailty metrics, comorbidities, patient preference, and potential for improvement in quality of life. PMID- 26578196 TI - Successful launch of a comprehensive European registry for the cardiomyopathies. PMID- 26578197 TI - Novel mechanisms in the pathogenesis of atrial fibrillation: practical applications. AB - Intensive research over the last few decades has seen significant advances in our understanding of the complex mechanisms underlying atrial fibrillation (AF). The epidemic of AF and related hospitalizations has been described as a 'rising tide' with estimates of the global AF burden showing no sign of retreat. There is urgency for effective translational programs in this field to facilitate more individualized and targeted therapy to modify the abnormal atrial substrate responsible for the perpetuation of this arrhythmia. In this review, we chose to focus on several novel aspects of AF pathogenesis whereby practical applications in clinical practice are currently available or potentially not too far away. Specifically, we explored the contribution of atrial fibrosis, epicardial adipose tissue, autonomic nervous system, hyper-coagulability, and focal drivers to adverse atrial remodelling and AF persistence. We also highlighted the potential practical means of monitoring and targeting these factors to achieve better outcomes in patients suffering from this debilitating illness. Emerging data also support a new paradigm for targeting AF substrate with aggressive risk factor management. Finally, multi-disciplinary integrated care approach has shown great promise in improving cardiovascular outcomes of patients with AF along with potential cost savings. PMID- 26578198 TI - Electrocardiographic anterior T-wave inversion in athletes of different ethnicities: differential diagnosis between athlete's heart and cardiomyopathy. AB - AIMS: Anterior T-wave inversion (TWI) is a recognized variant in athletes of African/Afro Caribbean origin and some endurance athletes; however, the presence of this specific repolarization anomaly also raises the possibility of cardiomyopathy. The differentiation between physiological adaptation and cardiomyopathy may be facilitated by examining other repolarization parameters, notably the J-point and the ST-segment. METHODS AND RESULTS: We compared the electrocardiogram pattern of anterior TWI in a series of 80 healthy athletes (median age 21 years, 75% males); 95 patients with hypertrophic cardiomyopathy (HCM) (median age 46 years, 75% males), including 26 affected athletes; and 58 patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) (median age 32 years, 71% males), including 9 affected athletes. Athletes and patients were of either white/Caucasian or black/Afro Caribbean descent and showed TWI >=1 mm in >=2 contiguous anterior leads (V1-V4). We aimed to identify repolarization patterns for differentiating physiologic from pathologic TWI. After adjustment for age, gender, and ethnicity, J-point elevation <1 mm (but no ST-segment elevation without J-point elevation) in the anterior leads showing TWI and TWI extending beyond V4 remained independent predictors for both ARVC, with OR = 569 (95% CI = 38-8545; P < 0.001) and OR = 6.0 (95% CI = 1.2-37.8; P = 0.03), respectively, and HCM with OR = 227 (95% CI = 12-1620; P < 0.001) and OR = 331 (95% CI = 20-2752; P = 0.001), respectively. In athletes with anterior TWI, the combination of J-point elevation >=1 mm and TWI not extending beyond V4 excluded a cardiomyopathy, either ARVC or HCM, with 100% sensitivity and 55% specificity. CONCLUSION: The combination of J-point elevation and TWI confined to lead V1-V4 offers the potential for an accurate differentiation between 'physiologic' and 'cardiomyopathic' anterior TWI, among athletes of both white/Caucasian or black/Afro Caribbean descent. Conversely, ST-segment elevation without J-point elevation preceding anterior TWI may reflect cardiomyopathy. PMID- 26578200 TI - Improving outcomes in heart failure: a personal perspective. PMID- 26578199 TI - NADPH oxidase 4 protects against development of endothelial dysfunction and atherosclerosis in LDL receptor deficient mice. AB - AIMS: Endothelial dysfunction is an early step in the development of atherosclerosis. Increased formation of superoxide anions by NADPH oxidase Nox1, 2, and 5 reduces nitric oxide availability and can promote endothelial dysfunction. In contrast, recent evidence supports a vasoprotective role of H2O2 produced by main endothelial isoform Nox4. Therefore, we analysed the impact of genetic deletion of Nox4 on endothelial dysfunction and atherosclerosis in the low-density lipoprotein receptor (Ldlr) knockout model. METHODS AND RESULTS: Ex vivo analysis of endothelial function by Mulvany myograph showed impaired endothelial function in thoracic aorta of Nox4(-/-)/Ldlr(-/-) mice. Further progression of endothelial dysfunction due to high-fat diet increased atherosclerotic plaque burden and galectin-3 staining in Nox4(-/-)/Ldlr(-/-) mice compared with Ldlr(-/-) mice. Under physiological conditions, loss of Nox4 does not influence aortic vascular function. In this setting, loss of Nox4-derived H2O2 production could be partially compensated for by nNOS upregulation. Using an innovative optical coherence tomography approach, we were able to analyse endothelial function by flow-mediated vasodilation in the murine saphenous artery in vivo. This new approach revealed an altered flow-mediated dilation in Nox4(-/ ) mice, indicating a role for Nox4 under physiological conditions in peripheral arteries in vivo. CONCLUSIONS: Nox4 plays an important role in maintaining endothelial function under physiological and pathological conditions. Loss of Nox4-derived H2O2 could be partially compensated for by nNOS upregulation, but severe endothelial dysfunction is not reversible. This leads to increased atherosclerosis under atherosclerotic prone conditions. PMID- 26578201 TI - Correlates of pre-hospital morphine use in ST-elevation myocardial infarction patients and its association with in-hospital outcomes and long-term mortality: the FAST-MI (French Registry of Acute ST-elevation and non-ST-elevation Myocardial Infarction) programme. AB - AIMS: The use of opioids is recommended for pain relief in patients with myocardial infarction (MI) but may delay antiplatelet agent absorption, potentially leading to decreased treatment efficacy. METHODS AND RESULTS: In hospital complications (death, non-fatal re-MI, stroke, stent thrombosis, and bleeding) and 1-year survival according to pre-hospital morphine use were assessed in 2438 ST-elevation MI (STEMI) patients from the French Registry of Acute ST-elevation and non-ST-elevation Myocardial Infarction (FAST-MI) 2010. The analyses were replicated in the 1726 STEMI patients of the FAST-MI 2005 cohort, in which polymorphisms of CYP2C19 and ABCB1 had been assessed. Specific subgroup analyses taking into account these genetic polymorphisms were performed in patients pre-treated with thienopyridines. The 453 patients (19%) receiving morphine pre-hospital were younger, more often male, with a lower GRACE score and higher chest pain levels. After adjustment for baseline differences, in-hospital complications and 1-year survival (hazard ratio = 0.69; 95% confidence interval: 0.35-1.37) were not increased according to pre-hospital morphine use. After propensity score matching, 1-year survival according to pre-hospital morphine was also similar. Consistent results were found in the replication cohort, including in those receiving pre-hospital thienopyridines and whatever the genetic polymorphisms of CYP2C19 and ABCB1. CONCLUSION: In two independent everyday-life cohorts, pre-hospital morphine use in STEMI patients was not associated with worse in-hospital complications and 1-year mortality. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT00673036 (FAST-MI 2005); NCT01237418 (FAST-MI 2010). PMID- 26578202 TI - The impact of proprotein convertase subtilisin-kexin type 9 serine protease inhibitors on lipid levels and outcomes in patients with primary hypercholesterolaemia: a network meta-analysis. AB - AIMS: We performed a network meta-analysis of randomized controlled trials (RCTs) in patients with primary hypercholesterolaemia to compare the impact of proprotein convertase subtilisin-kexin type 9 serine protease (PCSK9) inhibitors with placebo and ezetimibe on lipid levels and outcomes. METHODS AND RESULTS: MEDLINE/PubMed, Cochrane CENTRAL, and ClinicalTrials.gov were searched for RCTs assessing PCSK9 inhibitors vs. other therapies in patients with primary hypercholesterolaemia. Network meta-analysis with both a frequentist approach and a Bayesian framework was performed to directly and indirectly compare PCSK9 inhibition on lipid levels with ezetimibe and placebo. Odds ratios with 95% confidence intervals (OR [95% CIs]) were generated with random-effects models to compare outcomes. Our meta-analysis included 17 RCTs with 13 083 patients that were randomized to PCSK9 inhibitors (n = 8250), placebo (n = 3957), ezetimibe (n = 846), or PCSK9 inhibitors and ezetimibe (n = 30). The mean age was 59 +/- 10, 52% were male, 34% had coronary artery disease, 51% had hypertension, 19% had diabetes mellitus, baseline LDL of 122 +/- 36 mg/dL, total cholesterol of 199 +/- 39 mg/dL, and HDL of 51 +/- 14 mg/dL. inhibitors significantly reduced LDL cholesterol by 57% relative to placebo (P < 0.001) and 36.1% relative to ezetimibe (P < 0.001). Proprotein convertase subtilisin-kexin type 9 serine protease inhibitors reduced the incidence of all-cause mortality [OR 0.43 (95% CI 0.22-0.82), P = 0.01] but was associated with an increased incidence of neurocognitive adverse events [OR 2.34 (95% CI 1.11-4.93), I(2) = 4%, P = 0.02] when compared with placebo. CONCLUSION: Proprotein convertase subtilisin-kexin type 9 serine protease inhibition significantly improved lipid profiles and reduced the incidence of all-cause mortality compared with placebo but had a higher rate of neurocognitive adverse events. Thus, PCSK9 inhibitor therapy may serve as an alternative for patients with statin intolerance and for those who do not respond to other lipid reduction therapy. PMID- 26578203 TI - Novel mutations in the genes TGM1 and ALOXE3 underlying autosomal recessive congenital ichthyosis. AB - BACKGROUND: Ichthyoses are clinically characterized by scaling or hyperkeratosis of the skin or both. It can be an isolated condition limited to the skin or appear secondarily with involvement of other cutaneous or systemic abnormalities. METHODS: The present study investigated clinical and molecular characterization of three consanguineous families (A, B, C) segregating two different forms of autosomal recessive congenital ichthyosis (ARCI). Linkage in three consanguineous families (A, B, C) segregating two different forms of ARCI was searched by typing microsatellite and single nucleotide polymorphism marker analysis. Sequencing of the two genes TGM1 and ALOXE3 was performed by the dideoxy chain termination method. RESULTS: Genome-wide linkage analysis established linkage in family A to TGM1 gene on chromosome 14q11 and in families B and C to ALOXE3 gene on chromosome 17p13. Subsequently, sequencing of these genes using samples from affected family members led to the identification of three novel mutations: a missense variant p.Trp455Arg in TGM1 (family A); a nonsense variant p.Arg140* in ALOXE3 (family B); and a complex rearrangement in ALOXE3 (family C). CONCLUSION: The present study further extends the spectrum of mutations in the two genes involved in causing ARCI. Characterizing the clinical spectrum resulting from mutations in the TGM1 and ALOXE3 genes will improve diagnosis and may direct clinical care of the family members. PMID- 26578205 TI - Effectiveness of the first French psychoeducational program on unipolar depression: study protocol for a randomized controlled trial. AB - BACKGROUND: Major Depressive Disorder (MDD) is highly prevalent and was associated with greater morbidity, mortality (including suicide), and healthcare costs. By 2030, MDD will become the leading cause of disability in high-income countries. Notably, among patients with a previous experience of a major depressive episode, it was indeed estimated that up to 85 % of those patients will suffer from relapse. Two main factors were associated with a significantly higher risk of relapse: poor medication adherence and low self-efficacy in disease management. Interestingly, these issues could become the targets of psychoeducational programs for chronic diseases. Indded psychoeducational program for depression are recommended in international guidelines, but have not yet been proposed in France. METHODS/DESIGN: We propose to evaluate the first French psychoeducational program for depression "ENVIE" in a multicenter randomized controlled trial. The group intervention will include 9 weekly sessions. Its aim is to educate patients on the latest knowledge on depression and effective treatments through didactic and interactive sessions. Patients will experiment the latest innovating psychological skills (from acceptance and commitment therapy) to cope with depressive symptoms and maintain motivation in behavioral activation. In total, 332 unipolar non-chronic (<2 years) outpatients with moderate to severe depression, without psychotic features, will be randomly allocated to the add-on ENVIE program (N = 166) or to a waiting list (N = 166). The follow-up will last 15 months and include 5 assessment visits. The primary endpoint will be the remission rate of the index episode at 15 months post inclusion, defined by a Montgomery and Asberg Depression Rating Scale (MADRS) score <= 12 over an 8-week period, and without relapse during follow-up. We will also assess the response rate and relapse at 15 months post-inclusion, hospitalization rate and adherence to treatment during the follow-up period, quality of life and global functioning upon inclusion and at 9 and 15 months post inclusion. DISCUSSION: If the proposed trial shows the effectiveness of the intervention, but also an increased remission rate in depressed outpatients at 15 months post-inclusion, in addition to improved treatment adherence in patients, it will further promotes arguments in favor of a wide dissemination of psychoeducational programs for depression. TRIAL REGISTRATION: This trial is registered under number 2015-A00249-40 (PURE clinical trial: NCT02501226 ) (June 30th, 2015). PMID- 26578204 TI - The population genetics of drug resistance evolution in natural populations of viral, bacterial and eukaryotic pathogens. AB - Drug resistance is a costly consequence of pathogen evolution and a major concern in public health. In this review, we show how population genetics can be used to study the evolution of drug resistance and also how drug resistance evolution is informative as an evolutionary model system. We highlight five examples from diverse organisms with particular focus on: (i) identifying drug resistance loci in the malaria parasite Plasmodium falciparum using the genomic signatures of selective sweeps, (ii) determining the role of epistasis in drug resistance evolution in influenza, (iii) quantifying the role of standing genetic variation in the evolution of drug resistance in HIV, (iv) using drug resistance mutations to study clonal interference dynamics in tuberculosis and (v) analysing the population structure of the core and accessory genome of Staphylococcus aureus to understand the spread of methicillin resistance. Throughout this review, we discuss the uses of sequence data and population genetic theory in studying the evolution of drug resistance. PMID- 26578206 TI - Genetic Associations of Interleukin-related Genes with Graves' Ophthalmopathy: a Systematic Review and Meta-analysis. AB - Graves' ophthalmopathy (GO) is the commonest extra-thyroidal manifestation of Graves' disease (GD). Associations between interleukin-related (IL) gene polymorphisms and GO have been reported in different populations. We aim to confirm such associations by conducting a meta-analysis. Totally 382 publications were retrieved in MEDLINE and EMBASE up to 25/2/2015. After removing the duplicates and assessing the studies, we retrieved 16 studies that met the selection criteria for meta-analysis, involving 12 polymorphisms in 8 IL-related genes, and 1650 GO cases and 2909 GD controls. The summary odds ratio (OR) and 95% confidence intervals (CI) were estimated. We found one polymorphism in IL1A (rs1800587, c.-889C>T) showing a suggestive association with GO in the meta analysis (allelic model [T vs. C]: OR = 1.62, 95% CI: 1.00-2.62, P = 0.050, I(2) = 53.7%; recessive model [TT vs. TC + CC]: OR = 2.39, 95% CI: 1.07-5.37, P = 0.039, I(2) = 23.6%; heterozygous model [TC vs. CC]: OR = 1.52, 95% CI: 1.04 2.22, P = 0.034, I(2) = 37.0%). No association with GO was detected for the other 7 genes (IL1B, IL1RA, IL4, IL6, IL12B, IL13 and IL23R). Our results thus indicate that IL1A is likely to be a genetic biomarker for GO. Further studies with larger sample sizes are warranted to confirm the associations of IL1A and other IL related genes with GO. PMID- 26578208 TI - Improved therapeutic activity of HER2 Affibody-targeted cisplatin liposomes in HER2-expressing breast tumor models. AB - OBJECTIVES: The purpose of this study was to investigate whether the conjugation of anti-HER2-Affibody to cisplatin PEGylated liposome can efficiently enhance the therapeutic effectiveness of the targeted liposome. METHODS: First, Affibody molecules were incubated with Mal-PEG2000-DSPE micelle to afford formation of a maleimide-mediated thioether coupling to the COOH-terminal cysteine of Affibody. Cisplatin-loaded liposomes composed of hydrogenated soy phosphatidylcholine/ cholesterol/mPEG2000-DSPE (56.5:38.5:5 molar ratio) (150 mM) were prepared and characterized by their physicochemical properties. Affibody-conjugated micelles were then transferred into preformed liposomes by means of post insertion. The cytotoxicity and cellular uptake of Affibody-targeted (affisome) and nontargeted liposomes were tested in HER2(+) SK-BR-3, and the in vivo therapeutic activity was evaluated in TUBO breast cancer models. RESULTS: Anti-HER2 affisome demonstrated a higher amount of platinum intracellularly, and affected HER2(+)-SK BR-3 cell death was at lower concentrations compared with its liposome counterparts. Further, cisplatin-affisome showed greater therapeutic efficiency than nontargeted liposome in HER2(+)-TUBO models. Equally promising, the affisome treated mice did extend the survival of animals by several days and even left one tumor-free survivor. CONCLUSIONS: Affibody-targeting endowed cisplatin liposomes with significantly enhanced, albeit modest, therapeutic activity in HER2 overexpressing tumor model; however, further values are yet to be determined to advance clinical translation of these targeted nanoparticulates. PMID- 26578209 TI - Incidence of graft extrusion following minimally invasive transforaminal lumbar interbody fusion. AB - Minimally invasive transforaminal lumbar interbody fusion (MI-TLIF) has been scrutinized for having a complex learning curve. Careful assessment of MI-TLIF complications and critical analyses of prevention may aid a safe adoption of this technique. The current report focuses on the incidence of interbody cage extrusions following MI-TLIF in a series of 513 patients. The authors discuss their experience with graft extrusions and provide methods to minimize this complication. This study retrospectively reviewed 513 prospectively followed patients who underwent MI-TLIF over a 10 year period. The inclusion criteria consisted of all patients who underwent one to three level MI-TLIF, from whom the incidence of cage extrusion was analyzed. Cage extrusion was defined as an interbody graft migrating outside the cephalad and caudal vertebral body posterior margin. Cage extrusions were diagnosed by comparing the intraoperative radiographs to the postoperative radiographs. Patients with >10 degrees coronal curves, significant sagittal malalignment, infection, and preoperative instrumentation failure were excluded. Of 513 patients undergoing MI-TLIF, five patients (0.97%) were diagnosed with cage migrations. The mean follow-up duration was 13.6 +/- standard deviation of 8.8 months. Complications included asymptomatic cage migration alone (two patients) neurological decline (two patients) and epidural hematoma (one patient). On average, cage migrations cost a university hospital an additional $US17,217 for revision treatment. While the incidence of cage migrations is low (0.97%), it can lead to postoperative complications that require revision surgery and increased hospital costs. The risk for this significant complication can be minimized with proper technique and patient selection. PMID- 26578210 TI - Simultaneous analysis of mono-, di-, and tri-ethanolamine in cosmetic products using liquid chromatography coupled tandem mass spectrometry. AB - Alkanolamines such as monoethanolamine (MEA), diethanolamine (DEA), and triethanolamine (TEA) are used as wetting agents in shampoos, lotions, creams, and other cosmetics. DEA is widely used to provide lather in shampoos and maintain a favorable consistency in lotions and creams. Although DEA is not harmful, it may react with other ingredients in the cosmetic formula after extended storage periods to form an extremely potent carcinogen called nitrosodiethanolamine (NDEA), which is readily absorbed through the skin and has been linked to the development of stomach, esophagus, liver, and bladder cancers. The purpose of this study was to develop a simultaneous quantification method for measurement of MEA, DEA, and TEA in cosmetic products. Liquid chromatography coupled tandem mass spectrometry (LC-MS/MS) was performed using a hydrophilic interaction liquid chromatography (HILIC) column with isocratic elution containing acetonitrile and 5 mM ammonium formate in water (88:12, v/v). Identification and quantification of alkanolamines were performed using MS/MS monitoring to assess the transition from precursor to product ion of MEA (m/z, 61.1 -> 44.0), DEA (m/z, 106.1 -> 88.0), TEA (m/z, 150.1 -> 130.0), and the internal standard triethylamine (m/z, 102.2 -> 58.0). Alkanolamines extractions were simplified using a single extraction with acetonitrile in the cosmetic matrix. Performance of the method was evaluated with quality parameters such as specificity, carry-over, linearity and calibration, correlation of determination (R(2)), detection limit, precision, accuracy, and recovery. Calibration curves of MEA (2.9-1000 ppb), DEA (1-1000 ppb), and TEA (1-1000 ppb) were constructed by plotting concentration versus peak-area ratio (analyte/internal standard with a correlation coefficient greater than 0.99). The intra- and inter-assay accuracy ranged from 92.92 to 101.15 % for all analytes. The intra- and inter-assay precision for MEA, DEA, and TEA showed all coefficients of variance were less than 9.38 % for QC samples. Limits of detection and limits of quantification were 2.00 and 15.63 ppb for MEA, 0.49 and 1.96 ppb for DEA, and 0.49 and 1.96 ppb for TEA, respectively. This novel quantification method simplified sample preparation and allowed accurate and reproducible quantification of alkanolamines in the ng/g cosmetic weight (ppb) range for several cosmetic products. PMID- 26578207 TI - Next generation sequencing in a large cohort of patients presenting with neuromuscular disease before or at birth. AB - BACKGROUND: Fetal akinesia/hypokinesia, arthrogryposis and severe congenital myopathies are heterogeneous conditions usually presenting before or at birth. Although numerous causative genes have been identified for each of these disease groups, in many cases a specific genetic diagnosis remains elusive. Due to the emergence of next generation sequencing, virtually the entire coding region of an individual's DNA can now be analysed through "whole" exome sequencing, enabling almost all known and novel disease genes to be investigated for disorders such as these. METHODS: Genomic DNA samples from 45 patients with fetal akinesia/hypokinesia, arthrogryposis or severe congenital myopathies from 38 unrelated families were subjected to next generation sequencing. Clinical features and diagnoses for each patient were supplied by referring clinicians. Genomic DNA was used for either whole exome sequencing or a custom-designed neuromuscular sub-exomic supercapture array containing 277 genes responsible for various neuromuscular diseases. Candidate disease-causing variants were investigated and confirmed using Sanger sequencing. Some of the cases within this cohort study have been published previously as separate studies. RESULTS: A conclusive genetic diagnosis was achieved for 18 of the 38 families. Within this cohort, mutations were found in eight previously known neuromuscular disease genes (CHRND, CHNRG, ECEL1, GBE1, MTM1, MYH3, NEB and RYR1) and four novel neuromuscular disease genes were identified and have been published as separate reports (GPR126, KLHL40, KLHL41 and SPEG). In addition, novel mutations were identified in CHRND, KLHL40, NEB and RYR1. Autosomal dominant, autosomal recessive, X-linked, and de novo modes of inheritance were observed. CONCLUSIONS: By using next generation sequencing on a cohort of 38 unrelated families with fetal akinesia/hypokinesia, arthrogryposis, or severe congenital myopathy we therefore obtained a genetic diagnosis for 47% of families. This study highlights the power and capacity of next generation sequencing (i) to determine the aetiology of genetically heterogeneous neuromuscular diseases, (ii) to identify novel disease genes in small pedigrees or isolated cases and (iii) to refine the interplay between genetic diagnosis and clinical evaluation and management. PMID- 26578211 TI - Association between body composition and khat chewing in Ethiopian adults. AB - BACKGROUND: Khat (Catha edulis Forsk) is a psychostimulant herb widely cultivated and used in Ethiopia. The link between khat use and body composition is little known. OBJECTIVE: The aim was to determine the association between body composition and khat use. METHODS: We recruited 415 individuals 18-78 years of age from Jimma Town. Sociodemographic and lifestyle data were collected using structured questionnaires. Fat mass (FM, kg) and fat-free mass (FFM, kg) were estimated from whole-body bio impedance. Weight (kg), FM and FFM were indexed to height (m) as BMI (kg/m(2)), fat mass index (FMI) (kg/m) and fat-free mass index (FFMI) (kg/m), respectively. Independent predictors of BMI, FMI and FFMI were identified using regression analysis. RESULT: Participants' mean +/- SD of age was 37 +/- 13 years and 205 (53.2 %) were males. Mean +/- SD of BMI, FMI and FFMI were 21.0 kg/m(2) +/- 4.1, 6.8 kg/m +/- 5.2 and 27.9 kg/m +/- 3.8, respectively. Multivariable model showed that, compared with non-chewers, khat chewers had a lower BMI (B = -1.56, 95 % CI -0.78, -2.33) and FMI (B = 2.19, 95 % CI -1.32, 3.06). FMI was lower in cigarette smokers than non-smokers by -1.36 kg/m (95 % CI -0.23, -2.49). Concurrently, khat and cigarette users increased FMI by 2.78 (95 % CI 0.11, 5.44). FFMI decreased with age (B = -0.02, 95 % CI -0.05, -0.002). CONCLUSION: FMI and BMI were lower in khat users than non-users, but there was no difference in lean mass. The consequence of this body composition change should be investigated. PMID- 26578213 TI - [Executive function and behavior in university drinkers]. AB - OBJECTIVES: Establish the profile of executive function and behavior in fifty consumers of alcohol are located in a high-risk level according to the Alcohol Use Disorders Identification Test (AUDIT) and which belong to different universities in the city of Bogota. MATERIAL AND METHODS: Was used analytical transverse design, and were taken as study variables executive function (inhibition, monitoring, sequencing, planning, cognitive flexibility, working memory, attentional control, categorization and concept formation) and executive behavior (decision making, impulse control, emotional feedback, empathy and theory of mind). RESULTS AND CONCLUTIONS: Results showed that there is a greater number of cognitive domains of executive function involved in contrast to those of executive behavior. Such is for inhibition, sequencing, attention control (processing speed), categorization, cognitive flexibility, self monitoring and planning. PMID- 26578214 TI - [Spontaneous speech prosody and discourse analysis in schizophrenia and Fronto Temporal Dementia (FTD) patients]. AB - Patients with schizophrenia and Frontotemporal Dementia (FTD) in their linguistic variants share some language characteristics such as the lexical access difficulties, disordered speech with disruptions, many pauses, interruptions and reformulations. For the schizophrenia patients it reflects a difficulty of affect expression, while for the FTD patients it reflects a linguistic issue. METHODS: This study, through an analysis of a series of cases assessed Clinic both in memory and on the Mental Health Unit of HUSI-PUJ (Hospital Universitario San Ignacio), with additional language assessment (analysis speech and acoustic analysis), present distinctive features of the DFT in its linguistic variants and schizophrenia that will guide the specialist in finding early markers of a differential diagnosis. RESULTS: In patients with FTD language variants, in 100% of cases there is a difficulty understanding linguistic structure of complex type; and important speech fluency problems. In patients with schizophrenia, there are significant alterations in the expression of the suprasegmental elements of speech, as well as disruptions in discourse. CONCLUSIONS: We present how depth language assessment allows to reassess some of the rules for the speech and prosody analysis of patients with dementia and schizophrenia; we suggest how elements of speech are useful in guiding the diagnosis and correlate functional compromise in everyday psychiatrist's practice. PMID- 26578215 TI - [Validation of the Cognitive Impairment in Psychiatry (SCIP-S) Screen Scale in Patients with Bipolar Disorder I]. AB - BACKGROUND: The Spanish version of the cognitive impairment in psychiatry scale screening scale has been developed as a response to the needs arising in clinical practice during the evaluation of mental illness patients, but the performance is not known in the Colombian population with bipolar disorder I. This paper tries to establish construct validity and stability of the scale in patients with bipolar disorder I in the city of Manizales. METHODS: Construct validity was estimated by comparing the measurement in two divergent groups, a control group and a group with bipolar disorder I. It was also compared to a Neuropsychological battery measuring the same scale domains. The correlation between each one of the sub-tests of the scale and stability was evaluated through the reliability test retest in the group with bipolar disorder I. RESULTS: The scale showed discriminatory capacity in cognitive functioning between the control group and the group with bipolar disorder I. The correlation with the neuropsychological battery was estimated by the Spearman test showing results between 0.36 and 0.77, and the correlation between each sub-test of the scale showed correlations between 0.39 and 0.72. Test-retest was measured with the intraclass correlation coefficient (ICC) and their values were between 0.77 and 0.91. CONCLUSIONS: The Spanish version of screening scale in the cognitive disorder in psychiatry shows acceptable validity and reliability as a measurement tool in clinical psychiatric practice. PMID- 26578216 TI - [Association between inequality and suicide rate in Colombia (1994-2013)]. AB - INTRODUCTION: Income inequality is directly related to the mental health of the population. However, the relationship between income inequality and suicide rates in Colombia has still not been explored. OBJECTIVE: To estimate the relationship between inequality and suicide rates in Colombia from 1994 to 2013. METHODS: An ecological study was conducted, in which the correlation was estimated (Spearman) between inequality (Gini coefficient) and suicide rate between 1994 and 2013, according to official information available from the National Administrative Department of Statistics (DANE), and the National Institute of Forensic Science and Forensic Medicine. RESULTS: A Gini coefficient between 0.53 and 0.60 (median, 0.65 [interquartile range, 0.54-0.57]) was observed, and suicide rates were between 3.84 and 5.26 (median, 4.20 [4.08-4.86]). The correlation between inequality and suicide rates was positive and statistically significant (r=.70; p<.001). CONCLUSIONS: There is a positive association between economic inequality and suicide rate in Colombia. It is important to achieve greater equity in the distribution of income to reduce suicide rate in the country. PMID- 26578217 TI - [Electrocardiographic abnormalities in anorexia nervosa: a critical review of the literature]. AB - BACKGROUND: Anorexia nervosa is an eating disorder in which cardiac arrhythmias and sudden death are frequent causes of mortality, which makes electrocardiographic monitoring indispensable in these patients. There are many suggestive findings but results are contradictory, making a critical review of the scientific literature is necessary. METHODS: The most relevant studies on electrocardiographic (EKG) changes in patients with AN, found in PubMed from 1974 to February 2014, were reviewed using the MeSH terms: eating disorders, nervosa anorexia, sinus bradycardia, QT prolongation, QT dispersion, electrocardiography, EKG, and electrocardiogram. FINDINGS AND DISCUSSION: The two most common EKG findings reported in the literature are sinus bradycardia and changes in depolarization, as shown by prolongation and increased dispersion of the QT interval. Electrolyte disturbances seem to be the cause of these disturbances in some patients, but other reasons are also discussed in detail, such as QRS right axis deviation, disturbances of heart rate variability, low R wave voltage in V6, amplitude decrease of the QRS and T wave, and QRS prolongation. The majority of authors report that these changes are reversible after treatment of AN. CONCLUSIONS: These findings support the need for initial and follow-up EKGs in patients with AN and for early diagnosis and treatment of cardiovascular disturbances that are associated with morbidity and mortality. They also support the need for the rational use of psychopharmacology, and that does not increase the risk of arrhythmias and sudden death in these patients. PMID- 26578218 TI - [Historical trauma. Systematic review of a different approach to armed conflict]. AB - INTRODUCTION: Historical trauma (HT) is a collective trauma inflicted on a group of people who share an identity or affiliation, and is often characterized by the transgenerational legacy of traumatic experiences, and expressed through various psychological and social responses. This construct is proposed in contrast to post-traumatic stress disorder (PTSD) due to limitations identified with the latter diagnostic category when addressing collective trauma, especially in situations of political and social violence. The purpose of this article is to review the literature published so far on HT. METHODS: A search was performed using the terms "historical trauma" and "mental health" or "trauma historico" and "salud mental" in the scientific databases, EMBASE, Ebscohost, JSTOR, ProQuest, LILACS, SciELO, PsycARTICLES, ISI Web of Science and PubMed. RESULTS: The authors reviewed HT definition, paramount characteristics of its traumatic experience, and several theories of on the transgenerational succession if these experiences occur, as well as possible consequences of traumatic events at individual, family and social level. Common characteristics of different therapeutic models are highlighted, in addition to some recommendations for their application. CONCLUSIONS: PTSD has clear limitations in addressing community and cumulative traumatic experiences related to specific social and historical contexts. The authors discuss the potential utility of HT in this task. Finally, several gaps in current knowledge regarding this construct are mentioned, and some recommendations for future research are indicated. PMID- 26578219 TI - [22q11.2DS Syndrome as a Genetic Subtype of Schizophrenia]. AB - INTRODUCTION: The 22q11.2 deletion syndrome (22q11.2DS) is associated with the microdeletion of this chromosomal region, and represents the second most common genetic syndrome after Down's syndrome. In patients with schizophrenia, 22q11.2DS has a prevalence of 2%, and in selected groups can be increased to between 32 53%. OBJECTIVE: To describe the generalities of 22q11.2DS syndrome as a genetic subtype of schizophrenia, its clinical characteristics, molecular genetic aspects, and frequency in different populations. METHODS: A review was performed from 1967 to 2013 in scientific databases, compiling articles about 22q11.2DS syndrome and its association with schizophrenia. RESULTS: The 22q11.2 DS syndrome has a variable phenotype associated with other genetic syndromes, birth defects in many tissues and organs, and a high rate of psychiatric disorders, particularly schizophrenia. Likewise, it has been identified in clinical populations with schizophrenia selected by the presence of common syndromic characteristics. FISH, qPCR and MLPA techniques, and recently, aCGH and NGS technologies, are being used to diagnose this microdeletion. CONCLUSIONS: It is important in clinical practice to remember that people suffering the 22q11.2DS have a high genetic risk for developing schizophrenia, and it is considered that the simultaneous presence of this disease and 22q11.2DS represents a genetic subtype of schizophrenia. There are clear phenotypic criteria, molecular and cytogenetic methods to diagnose this group of patients, and to optimize a multidisciplinary approach in their monitoring. PMID- 26578220 TI - [Ekbom syndrome: apropos of a case]. AB - The Ekbom syndrome or delusional parasitosis is an uncommon psychiatric condition, in which the main symptom is the delusion of being infested with living organisms such as parasites, bacteria, virus, bugs or worms. The case is presented of a 34 year-old man with symptoms compatible with the syndrome. The available literature is briefly reviewed and theoretical correlation with clinical symptomatology is made. The patient had a primary and mixed Ekbom syndrome. PMID- 26578221 TI - [Are Mental Disorders Natural Kinds?]. AB - A problem for both philosophers of Psychiatry and Psychiatrists within the domain of nosology is to determine which could be the more appropriate model to classify mental illnesses. Such an endeavor also requires questioning the very nature of mental illness. While trying to cope with the philosophical challenges of such a task, Peter Zachar purports to show that the nosological work in Psychiatry should not adhere to the model of natural kinds. He even considers that it is mistaken to treat mental disorders as natural kinds. Nonetheless, Zachar's view on the existence of natural kinds-even in domains where there is little room for doubting about their existence, like Chemistry-is very unstable. In 2001 he holds that there are no natural kinds, but in 2008 he argues that his objections to the model of natural kinds are more the manifestation of his skepticism against a tradition. Although the problem of the existence of natural kinds shall not be dealt with in this article, a brief description on how deflated is Zachar's view on this matter in 2008 is presented, with the central part of the article devoted to reconstruct and examine his rationale for the thesis that mental disorders are not natural kinds. In the critical section of this paper, it is suggested that, although Zachar's thesis may be right, the arguments he gives to support it are quite flawed. PMID- 26578222 TI - Mental Health Research: A commitment from everyone. PMID- 26578223 TI - Predator-induced neophobia in juvenile cichlids. AB - Predation is an important but often fluctuating selection factor for prey animals. Accordingly, individuals plastically adopt antipredator strategies in response to current predation risk. Recently, it was proposed that predation risk also plastically induces neophobia (an antipredator response towards novel cues). Previous studies, however, do not allow a differentiation between general neophobia and sensory channel-specific neophobic responses. Therefore, we tested the neophobia hypothesis focusing on adjustment in shoaling behavior in response to a novel cue addressing a different sensory channel than the one from which predation risk was initially perceived. From hatching onwards, juveniles of the cichlid Pelvicachromis taeniatus were exposed to different chemical cues in a split-clutch design: conspecific alarm cues which signal predation risk and heterospecific alarm cues or distilled water as controls. At 2 months of age, their shoaling behavior was examined prior and subsequent to a tactical disturbance cue. We found that fish previously exposed to predation risk formed more compact shoals relative to the control groups in response to the novel disturbance cue. Moreover, the relationship between shoal density and shoal homogeneity was also affected by experienced predation risk. Our findings indicate predator-induced, increased cross-sensory sensitivity towards novel cues making neophobia an effective antipredator mechanism. PMID- 26578224 TI - An HPLC method with diode array detector for the simultaneous quantification of chloroquine and desethylchloroquine in plasma and whole blood samples from Plasmodium vivax patients in Vietnam, using quinine as an internal standard. AB - A sensitive, simple method for quantification of chloroquine (CQ) and desethylchloroquine (MCQ) in whole blood and plasma from Plasmodium vivax patients has been developed using HPLC with diode array detection (DAD). Solid phase extraction on Isolute-96-CBA was employed to process 100 MUL of plasma/whole blood samples. CQ, MCQ and quinine were separated using a mobile phase of phosphate buffer 25 mm, pH 2.60-acetonitrile (88:12, v/v) with 2 mm sodium perchlorate on a Zorbax SB-CN 150 * 4.6 mm, 5 MUm column at a flow rate of 1.2 mL/min, at ambient temperature in 10 min, with the DAD wavelength of 343 nm. The method was linear over the range of 10-5000 ng/mL for both CQ and MCQ in plasma and whole blood. The limit of detection was 4 ng/mL and limit of quantification was 10 ng/mL in both plasma and blood for CQ and MCQ. The intra-, inter- and total assay precision were <10% for CQ and MCQ in plasma and whole blood. In plasma, the accuracies varied between 101 and 103%, whereas in whole blood, the accuracies ranged from 97.0 to 102% for CQ and MCQ. The method is an ideal technique with simple facilities and instruments, bringing about good separation in comparison with previous methods. (c) 2016 The Authors Biomedical Chromatography Published by John Wiley & Sons Ltd. PMID- 26578225 TI - An unexpected headline: more US white people are dying. PMID- 26578226 TI - Risks and benefits of speech recognition for clinical documentation: a systematic review. AB - OBJECTIVE: To review literature assessing the impact of speech recognition (SR) on clinical documentation. METHODS: Studies published prior to December 2014 reporting clinical documentation using SR were identified by searching Scopus, Compendex and Inspect, PubMed, and Google Scholar. Outcome variables analyzed included dictation and editing time, document turnaround time (TAT), SR accuracy, error rates per document, and economic benefit. Twenty-three articles met inclusion criteria from a pool of 441. RESULTS: Most studies compared SR to dictation and transcription (DT) in radiology, and heterogeneity across studies was high. Document editing time increased using SR compared to DT in four of six studies (+1876.47% to -16.50%). Dictation time similarly increased in three of five studies (+91.60% to -25.00%). TAT consistently improved using SR compared to DT (16.41% to 82.34%); across all studies the improvement was 0.90% per year. SR accuracy was reported in ten studies (88.90% to 96.00%) and appears to improve 0.03% per year as the technology matured. Mean number of errors per report increased using SR (0.05 to 6.66) compared to DT (0.02 to 0.40). Economic benefits were poorly reported. CONCLUSIONS: SR is steadily maturing and offers some advantages for clinical documentation. However, evidence supporting the use of SR is weak, and further investigation is required to assess the impact of SR on documentation error types, rates, and clinical outcomes. PMID- 26578227 TI - Rising drug allergy alert overrides in electronic health records: an observational retrospective study of a decade of experience. AB - OBJECTIVE: There have been growing concerns about the impact of drug allergy alerts on patient safety and provider alert fatigue. The authors aimed to explore the common drug allergy alerts over the last 10 years and the reasons why providers tend to override these alerts. DESIGN: Retrospective observational cross-sectional study (2004-2013). MATERIALS AND METHODS: Drug allergy alert data (n = 611,192) were collected from two large academic hospitals in Boston, MA (USA). RESULTS: Overall, the authors found an increase in the rate of drug allergy alert overrides, from 83.3% in 2004 to 87.6% in 2013 (P < .001). Alarmingly, alerts for immune mediated and life threatening reactions with definite allergen and prescribed medication matches were overridden 72.8% and 74.1% of the time, respectively. However, providers were less likely to override these alerts compared to possible (cross-sensitivity) or probable (allergen group) matches (P < .001). The most common drug allergy alerts were triggered by allergies to narcotics (48%) and other analgesics (6%), antibiotics (10%), and statins (2%). Only slightly more than one-third of the reactions (34.2%) were potentially immune mediated. Finally, more than half of the overrides reasons pointed to irrelevant alerts (i.e., patient has tolerated the medication before, 50.9%) and providers were significantly more likely to override repeated alerts (89.7%) rather than first time alerts (77.4%, P < .001). DISCUSSION AND CONCLUSIONS: These findings underline the urgent need for more efforts to provide more accurate and relevant drug allergy alerts to help reduce alert override rates and improve alert fatigue. PMID- 26578228 TI - Anti-Di(b) causing hemolytic disease of the fetus and newborn and the challenges of anti-Di(b) in perinatal management in China. PMID- 26578229 TI - Erratum to: Molecular epidemiology and phylogenetic analysis of Hepatitis B virus in a group of migrants in Italy. PMID- 26578230 TI - Disaster preparedness in a complex urban system: the case of Kathmandu Valley, Nepal. AB - The city is a growing centre of humanitarian concern. Yet, aid agencies, governments and donors are only beginning to comprehend the scale and, importantly, the complexity of the humanitarian challenge in urban areas. Using the case study of the Kathmandu Valley, Nepal, this paper examines the analytical utility of recent research on complex urban systems in strengthening scholarly understanding of urban disaster risk management, and outlines its operational relevance to disaster preparedness. Drawing on a literature review and 26 interviews with actors from across the Government of Nepal, the International Red Cross and Red Crescent Movement, non-governmental organisations, United Nations agencies, and at-risk communities, the study argues that complexity can be seen as a defining feature of urban systems and the risks that confront them. To manage risk in these systems effectively, preparedness efforts must be based on adaptive and agile approaches, incorporating the use of network analysis, partnerships, and new technologies. PMID- 26578231 TI - Impact of Genetic Counseling and Testing on Altruistic Motivations to Test for BRCA1/2: a Longitudinal Study. AB - Despite the importance of altruism in an individual's participation in genetic counseling and testing, little research has explored the change in altruistic motivations to test over time. This study analyzed altruistic motivations to test and change in altruistic motivations after genetic counseling and testing among individuals (N = 120) at elevated risk for BRCA1/2 mutations. The perceived benefits of genetic testing were assessed and utilized in a mixed-methods, repeated measures design at three time points: pre-counseling, counseling and post-genetic testing, along with transcripts of genetic counseling sessions. Qualitative analysis using an immersion/crystallization method resulted in six common perceived benefits of testing: cancer prevention, awareness, family's survival, relief from anxiety, for science, and future planning. Perceived benefits were then coded into three categories according to Hamilton's kin selection theory: altruistic motivation, personal motivation, and motivation for mutual benefit. At pre-counseling, those with a personal cancer history (p = 0.003) and those with one or more children (p = 0.013), were significantly more likely to cite altruistic motivations to test. Altruistic motivations significantly increased post-counseling (p = 0.01) but declined post-testing (p < 0.001). Labov's narrative analysis further elucidated the context of altruistic and personal motivations. The possibility of a positive test result might have led those with personal history of cancer to have altruistic motivations for testing. Genetic counseling may have increased altruistic motivations to help family and may be a prime opportunity to discuss other forms of altruism. PMID- 26578232 TI - Communication of Psychiatric Risk in 22q11.2 Deletion Syndrome: A Pilot Project. AB - Individuals with 22q11.2 deletion syndrome (22q11.2DS) have an increased chance of developing a psychiatric disorder. While parents of children affected by 22q11.2DS typically receive counseling about risk for non-psychiatric health concerns, genetic counselors may be reluctant to discuss psychiatric risk. Further education of genetic counselors may be necessary to encourage discussion of psychiatric risk with these families. The goal of this project was to develop recommendations for genetic counselors to provide psychiatric risk information to families affected by 22q11.2DS. The recommendations were developed by synthesizing resources in the literature about risk communication. These recommendations were refined following an online focus group meeting with five health care professionals who were recruited for participation from 22q11.2DS clinics across the U.S.A. The focus group data revealed three themes related to discussion of psychiatric risk: 1) Stepwise approach, 2) Discussing treatment options and reducing risks, and 3) Addressing stigma. These recommendations may be used as a foundation for a future clinical protocol to encourage discussion about the risk for psychiatric illness at an earlier point in the diagnostic process for 22q11.2DS and to provide improved information, support and resources to affected families. PMID- 26578233 TI - Ultra-fast pulse propagation in nonlinear graphene/silicon ridge waveguide. AB - We report the femtosecond laser propagation in a hybrid graphene/silicon ridge waveguide with demonstration of the ultra-large Kerr coefficient of graphene. We also fabricated a slot-like graphene/silicon ridge waveguide which can enhance its effective Kerr coefficient 1.5 times compared with the graphene/silicon ridge waveguide. Both transverse-electric-like (TE-like) mode and transverse-magnetic like (TM-like) mode are experimentally measured and numerically analyzed. The results show nonlinearity dependence on mode polarization not in graphene/silicon ridge waveguide but in slot-like graphene/silicon ridge waveguide. Great spectral broadening was observed due to self-phase modulation (SPM) after propagation in the hybrid waveguide with length of 2 mm. Power dependence property of the slot like hybrid waveguide is also measured and numerically analyzed. The results also confirm the effective Kerr coefficient estimation of the hybrid structures. Spectral blue shift of the output pulse was observed in the slot-like graphene/silicon ridge waveguide. One possible explanation is that the blue shift was caused by the ultra-fast free carrier effect with the optical absorption of the doped graphene. This interesting effect can be used for soliton compression in femtosecond region. We also discussed the broadband anomalous dispersion of the Kerr coefficient of graphene. PMID- 26578234 TI - Low-intensity continuous ultrasound triggers effective bisphosphonate anticancer activity in breast cancer. AB - Ultrasound (US) is a non-ionizing pressure wave that can produce mechanical and thermal effects. Bisphosphonates have demonstrated clinical utility in bone metastases treatment. Preclinical studies suggest that bisphosphonates have anticancer activity. However, bisphosphonates exhibit a high affinity for bone mineral, which reduces their bioavailability for tumor cells. Ultrasound has been shown to be effective for drug delivery but in interaction with gas bubbles or encapsulated drugs. We examined the effects of a clinically relevant dose of bisphosphonate zoledronate (ZOL) in combination with US. In a bone metastasis model, mice treated with ZOL+US had osteolytic lesions that were 58% smaller than those of ZOL-treated animals as well as a reduced skeletal tumor burden. In a model of primary tumors, ZOL+US treatment reduced by 42% the tumor volume, compared with ZOL-treated animals. Using a fluorescent bisphosphonate, we demonstrated that US forced the release of bisphosphonate from the bone surface, enabling a continuous impregnation of the bone marrow. Additionally, US forced the penetration of ZOL within tumors, as demonstrated by the intratumoral accumulation of unprenylated Rap1A, a surrogate marker of ZOL antitumor activity. Our findings made US a promising modality to trigger bisphosphonate anticancer activity in bone metastases and in primary tumors. PMID- 26578235 TI - In silico evaluation and exploration of antibiotic tuberculosis treatment regimens. AB - BACKGROUND: Improvement in tuberculosis treatment regimens requires selection of antibiotics and dosing schedules from a large design space of possibilities. Incomplete knowledge of antibiotic and host immune dynamics in tuberculosis granulomas impacts clinical trial design and success, and variations among clinical trials hamper side-by-side comparison of regimens. Our objective is to systematically evaluate the efficacy of isoniazid and rifampin regimens, and identify modifications to these antibiotics that improve treatment outcomes. RESULTS: We pair a spatio-temporal computational model of host immunity with pharmacokinetic and pharmacodynamic data on isoniazid and rifampin. The model is calibrated to plasma pharmacokinetic and granuloma bacterial load data from non human primate models of tuberculosis and to tissue and granuloma measurements of isoniazid and rifampin in rabbit granulomas. We predict the efficacy of regimens containing different doses and frequencies of isoniazid and rifampin. We predict impacts of pharmacokinetic/pharmacodynamic modifications on antibiotic efficacy. We demonstrate that suboptimal antibiotic concentrations within granulomas lead to poor performance of intermittent regimens compared to daily regimens. Improvements from dose and frequency changes are limited by inherent antibiotic properties, and we propose that changes in intracellular accumulation ratios and antimicrobial activity would lead to the most significant improvements in treatment outcomes. Results suggest that an increased risk of drug resistance in fully intermittent as compared to daily regimens arises from higher bacterial population levels early during treatment. CONCLUSIONS: Our systems pharmacology approach complements efforts to accelerate tuberculosis therapeutic development. PMID- 26578236 TI - Interleukin-27 ameliorates coxsackievirus-B3-induced viral myocarditis by inhibiting Th17 cells. AB - BACKGROUND: Interleukin (IL)-27, which has both pro and anti- inflammatory properties, is a new discovered heterodimeric cytokine that belongs to IL-12 family. However, the expression pattern and functional role of IL-27 in viral myocarditis (VMC) has not been investigated. METHODS: BALB/c mice were intraperitoneally (i.p) infected with Coxsackie virus B3 (CVB3) for establishing VMC models. Mice were then injected i.p. with Anti-Mouse IL-27 p28Ab or recombinant IL-27 for neutralization and overexpression of IL-27. The survival rates of mice were recorded and the kinetics of IL-27 expression, the frequencies of Th17 cells and the expression of inflammatory cytokine in CVB3-infected mice were determined by ELISA, real-time PCR and flow cytometry. RESULTS: The IL-27 expression in heart tissues and serum in coxsackievirus B3 (CVB3)-induced myocarditis mice peaked on day 4 but then rapidly decreased during the late infectious stage of CVB3, high IL-27 levels were negatively correlated with bodyweight loss (r = -0.71, P = 0.021) and myocardial pathological score (r = 0.85, P = 0.0018). Additionally, neutralization of IL-27 with Anti-IL-27 Ab accelerated, whereas systemic administration of recombinant mouse IL-27 ameliorated CVB3-induced myocarditis. The protective role of IL-27 in VMC was reflected by an improved survival rate, increased bodyweights, and reduced pathological scores in Anti-IL-27 group compared with IgG control group. Mechanistic investigations showed that IL-27 inhibited Th17 cells frequencies and IL-17 production, as well as the Th17-related proinflammatory cytokines in heart tissues. CONCLUSIONS: Our results demonstrate that that IL-27 effectively protects the myocardium from the pathogenesis of CVB3 induced myocarditis, which may be attributable to reduced Th17 production. IL-27 might serve as a novel therapeutic treatment for VMC. PMID- 26578238 TI - Feeding Two Birds with One Scone: The Case of Varenicline. PMID- 26578237 TI - Correlation between endogenous polyamines in human cardiac tissues and clinical parameters in patients with heart failure. AB - Polyamines contribute to several physiological and pathological processes, including cardiac hypertrophy in experimental animals. This involves an increase in ornithine decarboxylase (ODC) activity and intracellular polyamines associated with cyclic adenosine monophosphate (cAMP) increases. The aim of the study was to establish the role of these in the human heart in living patients. For this, polyamines (by high performance liquid chromatography) and the activity of ODC and N(1)-acetylpolyamine oxidases (APAO) were determined in the right atrial appendage of 17 patients undergoing extracorporeal circulation to correlate with clinical parameters. There existed enzymatic activity associated with the homeostasis of polyamines. Left atria size was positively associated with ODC (r = 0.661, P = 0.027) and negatively with APAO-N(1) -acetylspermine (r = -0.769, P = 0.026), suggesting that increased levels of polyamines are associated with left atrial hemodynamic overload. Left ventricular ejection fraction (LVEF) and heart rate were positively associated with spermidine (r = 0.690, P = 0.003; r = 0.590, P = 0.021) and negatively with N(1)-acetylspermidine (r = -0.554, P = 0.032; r = 0.644, P = 0.018). LVEF was negatively correlated with cAMP levels (r = -0.835, P = 0.001) and with cAMP/ODC (r = -0.794, P = 0.011), cAMP/spermidine (r = -0.813, P = 0.001) and cAMP/spermine (r = -0.747, P = 0.003) ratios. Abnormal LVEF patients showed decreased ODC activity and spermidine, and increased N(1) acetylspermidine, and cAMP. Spermine decreased in congestive heart failure patients. The trace amine isoamylamine negatively correlated with septal wall thickness (r = -0.634, P = 0.008) and was increased in cardiac heart failure. The results indicated that modifications in polyamine homeostasis might be associated with cardiac function and remodelling. Increased cAMP might have a deleterious effect on function. Further studies should confirm these findings and the involvement of polyamines in different stages of heart failure. PMID- 26578239 TI - Enhancing blast disease resistance by overexpression of the calcium-dependent protein kinase OsCPK4 in rice. AB - Rice is the most important staple food for more than half of the human population, and blast disease is the most serious disease affecting global rice production. In this work, the isoform OsCPK4 of the rice calcium-dependent protein kinase family is reported as a regulator of rice immunity to blast fungal infection. It shows that overexpression of OsCPK4 gene in rice plants enhances resistance to blast disease by preventing fungal penetration. The constitutive accumulation of OsCPK4 protein prepares rice plants for a rapid and potentiated defence response, including the production of reactive oxygen species, callose deposition and defence gene expression. OsCPK4 overexpression leads also to constitutive increased content of the glycosylated salicylic acid hormone in leaves without compromising rice yield. Given that OsCPK4 overexpression was known to confer also salt and drought tolerance in rice, the results reported in this article demonstrate that OsCPK4 acts as a convergence component that positively modulates both biotic and abiotic signalling pathways. Altogether, our findings indicate that OsCPK4 is a potential molecular target to improve not only abiotic stress tolerance, but also blast disease resistance of rice crops. PMID- 26578240 TI - Neuroblastoma Amplified Sequence (NBAS) mutation in recurrent acute liver failure: Confirmatory report in a sibship with very early onset, osteoporosis and developmental delay. AB - BACKGROUND: Recently, biallelic mutations in the Neuroblastoma Amplified Sequence NBAS gene have been identified in ten patients that present recurrent acute liver failure (RALF) in early infancy. In addition to severe liver dysfunction, some of these individuals also suffered from other comorbidities including cardiomyopathy, neurologic phenotypes and gastrointestinal immune defects. Here we report on a consanguineous Lebanese family with three siblings affected by RALF. Of note, neonatal spontaneous fractures, developmental delay, prominent eyes, generalized hirsutism, gum hypertrophy, and hepato-splenomegaly were also present. METHODS: Whole-genome SNP genotyping in all the patients, followed by exome sequencing was performed in one of the affected siblings. RESULTS: A homozygous c.409C > T (p.Arg137Trp) missense mutation in NBAS was identified in all patients. CONCLUSION: Overall, our findings confirm the involvement of NBAS in the pathogenesis of this condition characterized by severe liver dysfunction and help expand its phenotypical spectrum. PMID- 26578241 TI - Associated congenital anomalies among cases with Down syndrome. AB - Down syndrome (DS) is the most common congenital anomaly widely studied for at least 150 years. However, the type and the frequency of congenital anomalies associated with DS are still controversial. Despite prenatal diagnosis and elective termination of pregnancy for fetal anomalies, in Europe, from 2008 to 2012 the live birth prevalence of DS per 10,000 was 10. 2. The objectives of this study were to examine the major congenital anomalies occurring in infants and fetuses with Down syndrome. The material for this study came from 402,532 consecutive pregnancies of known outcome registered by our registry of congenital anomalies between 1979 and 2008. Four hundred sixty seven (64%) out of the 728 cases with DS registered had at least one major associated congenital anomaly. The most common associated anomalies were cardiac anomalies, 323 cases (44%), followed by digestive system anomalies, 42 cases (6%), musculoskeletal system anomalies, 35 cases (5%), urinary system anomalies, 28 cases (4%), respiratory system anomalies, 13 cases (2%), and other system anomalies, 26 cases (3.6%). Among the cases with DS with congenital heart defects, the most common cardiac anomaly was atrioventricular septal defect (30%) followed by atrial septum defect (25%), ventricular septal defect (22%), patent ductus arteriosus (5%), coarctation of aorta (5%), and tetralogy of Fallot (3%). Among the cases with DS with a digestive system anomaly recorded, duodenal atresia (67%), Hirschsprung disease (14%), and tracheo-esophageal atresia (10%) were the most common. Fourteen (2%) of the cases with DS had an obstructive anomaly of the renal pelvis, including hydronephrosis. The other most common anomalies associated with cases with DS were syndactyly, club foot, polydactyly, limb reduction, cataract, hydrocephaly, cleft palate, hypospadias and diaphragmatic hernia. Many studies to assess the anomalies associated with DS have reported various results. There is no agreement in the literature as to which associated anomalies are most common in cases with DS with associated anomalies. In this study we observed a higher percentage of associated anomalies than in the other reported series as well as an increase in the incidence of duodenal atresia, urinary system anomalies, musculoskeletal system anomalies, and respiratory system anomalies, and a decrease in the incidence of anal atresia, annular pancreas, and limb reduction defects. In conclusion, we observed a high prevalence of total congenital anomalies and specific patterns of malformations associated with Down syndrome which emphasizes the need to evaluate carefully all cases with Down syndrome for possible associated major congenital anomalies. PMID- 26578242 TI - Construction of bacterial ghosts for transfer and expression of a chimeric hepatitis C virus gene in macrophages. AB - The bacterial ghost (BG) production is a field of biotechnology for applications in vaccine and drug delivery. We assessed the capacity of BG for delivery of a recombinant gene encoded for both cell mediated and antibody dependent epitopes of hepatitis C virus (HCV) into murine macrophages. Escherichia coli (E. coli) cells were transformed with the lysis plasmid (pHH43). To produce chimeric gene, NS3 (non-structural protein 3) and core regions of HCV genome were fused together by splicing by overlap extension (SOEing) PCR and were cloned into plasmid pEGFP C1. Bacterial ghosts were loaded with recombinant pEGFP-C1 and then were transferred to murine macrophages (RAW 264.7). To investigate plasmid transfection and chimeric mRNA transcription, fluorescent microscopy and RT-PCR were used. In vitro studies indicated that bacterial ghosts loaded with pEGFP-C1 plasmid were efficiently taken up by murine macrophages and indicated a high transfection rate (62%), as shown by fluorescent microscopy. RT-PCR from extracted intracellular mRNAs for chimeric Core-NS3 gene showed a specific 607 bp fragment of the gene. The sequence analysis of purified PCR products demonstrated the expected unique mRNA sequence. We constructed a chimeric HCV gene containing both cell mediated and antibody dependent epitopes with a significant expression in murine macrophages delivered by bacterial ghost. PMID- 26578243 TI - Distribution of cold adaptation proteins in microbial mats in Lake Joyce, Antarctica: Analysis of metagenomic data by using two bioinformatics tools. AB - In this study, we report the distribution and abundance of cold-adaptation proteins in microbial mat communities in the perennially ice-covered Lake Joyce, located in the McMurdo Dry Valleys, Antarctica. We have used MG-RAST and R code bioinformatics tools on Illumina HiSeq2000 shotgun metagenomic data and compared the filtering efficacy of these two methods on cold-adaptation proteins. Overall, the abundance of cold-shock DEAD-box protein A (CSDA), antifreeze proteins (AFPs), fatty acid desaturase (FAD), trehalose synthase (TS), and cold-shock family of proteins (CSPs) were present in all mat samples at high, moderate, or low levels, whereas the ice nucleation protein (INP) was present only in the ice and bulbous mat samples at insignificant levels. Considering the near homogeneous temperature profile of Lake Joyce (0.08-0.29 degrees C), the distribution and abundance of these proteins across various mat samples predictively correlated with known functional attributes necessary for microbial communities to thrive in this ecosystem. The comparison of the MG-RAST and the R code methods showed dissimilar occurrences of the cold-adaptation protein sequences, though with insignificant ANOSIM (R = 0.357; p-value = 0.012), ADONIS (R(2) = 0.274; p-value = 0.03) and STAMP (p-values = 0.521-0.984) statistical analyses. Furthermore, filtering targeted sequences using the R code accounted for taxonomic groups by avoiding sequence redundancies, whereas the MG-RAST provided total counts resulting in a higher sequence output. The results from this study revealed for the first time the distribution of cold-adaptation proteins in six different types of microbial mats in Lake Joyce, while suggesting a simpler and more manageable user-defined method of R code, as compared to a web-based MG-RAST pipeline. PMID- 26578244 TI - High dynamic range detection of Chlamydia trachomatis growth by direct quantitative PCR of the infected cells. AB - Chlamydiae are obligate intracellular bacteria developing in an intracytoplasmic niche, the inclusion. Chlamydia growth measurement by inclusion counting is a key task in the development of novel antichlamydial antibiotics and in vaccine studies. Most of the current counting methods rely on the immunofluorescent staining of the inclusions and either manual or automatic microscopy detection and enumeration. The manual method is highly labor intensive, while the automatic methods are either medium-throughput or require automatic microscopy. The sensitive and specific PCR technology could be an effective method for growth related chlamydial DNA detection; however the currently described PCR approaches have a major limitation, the requirement of purification of DNA or RNA from the infected cells. This limitation makes this approach unfeasible for high throughput screenings. To overcome this, we developed a quantitative PCR (qPCR) method for the detection of Chlamydia trachomatis DNA directly from the infected HeLa cells. With our method we were able to detect the bacterial growth in a 4 log scale (multiplicity of infection (MOI): 64 to 0.0039), with high correlation between the biological and technical replicates. As a further proof of the method, we applied the direct qPCR for antibiotic minimum inhibitory concentration (MIC) measurements. The measured MICs of moxifloxacin, tetracycline, clarithromycin and compound PCC00213 were 0.031 MUg/ml, 0.031 MUg/ml, 0.0039 MUg/ml and 6.2 MUg/ml respectively, identical or close to the already published MIC values. Our direct qPCR method for chlamydial growth and antibiotic MIC determination is less time-consuming, more objective and more sensitive than the currently applied manual or automatic fluorescent microscopy- based methods. PMID- 26578245 TI - Measuring microbial metabolism in atypical environments: Bentonite in used nuclear fuel storage. AB - Genomics enjoys overwhelming popularity in the study of microbial ecology. However, extreme or atypical environments often limit the use of such well established tools and consequently demand a novel approach. The bentonite clay matrix proposed for use in Deep Geological Repositories for the long-term storage of used nuclear fuel is one such challenging microbial habitat. Simple, accessible tools were developed for the study of microbial ecology and metabolic processes that occur within this habitat, since the understanding of the microbiota-niche interaction is fundamental to describing microbial impacts on engineered systems such as compacted bentonite barriers. Even when genomic tools are useful for the study of community composition, techniques to describe such microbial impacts and niche interactions should complement these. Tools optimised for assessing localised microbial activity within bentonite included: (a) the qualitative use of the resazurin-resorufin indicator system for redox localisation, (b) the use of a CaCl2 buffer for the localisation of pH, and (c) fluorometry for the localisation of precipitated sulphide. The use of the Carbon Dioxide Evolution Monitoring System was also validated for measuring microbial activity in desiccated and saturated bentonite. Finally, the buffering of highly basic bentonite at neutral pH improved the success of isolation of microbial populations, but not DNA, from the bentonite matrix. Thus, accessible techniques were optimised for exploring microbial metabolism in the atypical environments of clay matrices and desiccated conditions. These tools have application to the applied field of used nuclear fuel management, as well as for examining the fundamental biogeochemical cycles active in sedimentary and deep geological environments. PMID- 26578246 TI - Risk factors associated with Chagas disease in pregnant women in Santander, a highly endemic Colombian area. AB - OBJECTIVE: To determine the prevalence and risk factors associated with Chagas disease in pregnant women in an endemic area of Santander, Colombia. METHODS: Cross-sectional study included 23 municipalities of Santander, Colombia. Serological IFAT and ELISA tests were undertaken to detect IgG anti- Trypanosoma cruzi. A questionnaire was conducted for assessing the risk factors of each participant. Newborns were evaluated at birth and followed up to 1 year of age to determine congenital infection. RESULTS: An overall prevalence of 3.2% (95% CI 2.4-4.2) among 1518 pregnant women was detected. Prevalences by provinces were as follows: Guanentina: 6.0% (95% CI 4.1-8.5), Garcia Rovira: 2.9% (95% CI: 1.5-4.8) and Comunera: 0.4% (0.4-2.3). The main risk factors identified were age >32 years old (OR: 2.1; 95% CI: 1.1-3.9); currently having a thatched roof (OR: 11.8; CI95% 2.2-63.2) and a thatched roof during childhood (OR: 3.0; 95% CI: 1.4-6.6); having below primary school education level (OR: 4.6; 95% CI: 2.2-9.5); and a history of a close contact with the vector (triatomine bugs) at least once during their lifetime (OR: 6.9; 95% CI: 3.7-12.9). No congenital cases were detected by parasitological or serological techniques. CONCLUSIONS: Prevalence of Chagas disease in pregnant women is a potential source of infection in this Colombian endemic area. The main risk factors associated with seropositivity were related to conditions favouring the contact with the vector. The results show that it is necessary to continue an active surveillance in order to offer diagnosis and treatment to mothers and their newborns in addition to screening to pregnant women from endemic areas. PMID- 26578247 TI - TALENs-mediated gene disruption of myostatin produces a larger phenotype of medaka with an apparently compromised immune system. AB - Although myostatin, a suppressor of skeletal muscle development and growth, has been well studied in mammals, its function in fish remains unclear. In this study, we used a popular genome editing tool with high efficiency and target specificity (TALENs; transcription activator-like effector nucleases) to mutate the genome sequence of myostatin (MSTN) in medaka (Oryzias latipes). After the TALEN pair targeting OlMyostatin was injected into fertilized medaka eggs, mutant G0 fish carrying different TALENs-induced frameshifts in the OlMSTN coding sequence were mated together in order to transmit the mutant sequences to the F1 generation. Two F1 mutants with frameshifted myostatin alleles were then mated to produce the F2 generation, and these F2 OlMSTN null (MSTN(-/-)) medaka were evaluated for growth performance. The F2 fish showed significantly increased body length and weight compared to the wild type fish at the juvenile and post juvenile stages. At the post-juvenile stage, the average body weight of the MSTN( /-) medaka was ~25% greater than the wild type. However, we also found that when the F3 generation were challenged with red spotted grouper nervous necrosis virus (RGNNV), the expression levels of the interferon-stimulated genes were lower than in the wild type, and the virus copy number was maintained at a high level. We therefore conclude that although the MSTN(-/-) medaka had a larger phenotype, their immune system appeared to be at least partially suppressed or undeveloped. PMID- 26578248 TI - Transcriptome analysis of the Larimichthys crocea liver in response to Cryptocaryon irritans. AB - The large yellow croaker (Larimichthys crocea) is an economically important marine fish cultured in China and East Asian countries and is facing a serious threat from Cryptocaryon irritans, which is a protozoan ectoparasite that infects most reared marine fish species. To understand the molecular immune mechanisms underlying the response to C. irritans, we first performed a comparative gene transcription analysis using livers from C. irritans-immunized L. croceas and from a control group through RNA-Seq technology. After the removal of low-quality sequences and assembly, 51360 contigs were obtained, with an average length of 1066.93 bp. Further, a blast analysis indicates that 30747 contigs can be annotated based on homology with matches in the NT, NR, gene, and string databases. A gene ontology analysis was used to classify 21598 genes according to three major functional categories: molecular function, cellular component, and biological process. Moreover, 14470 genes were found in 303 KEGG pathways. We used RSEM and EdgeR to determine that 3841 genes were significantly differentially expressed (FDR < 0.001), including 2129 up-regulated genes and 1712 down-regulated genes. A significant enrichment analysis of these differentially expressed genes and isogenes revealed major immune-related pathways, including the toll-like receptor, complement and coagulation cascades, and chemokine signaling pathways. In addition, 28748 potential simple sequence repeats (SSRs) were detected from 12776 transcripts, and 62992 candidate single nucleotide polymorphisms (SNPs) were identified in the L. croceas liver transcriptome. This study characterized a gene expression pattern for normal and C. irritans-immunized L. croceas for the first time and not only sheds new light on the molecular mechanisms underlying the host-C. irritans interaction but also facilitates future studies on L. croceas gene expression and functional genomics. PMID- 26578249 TI - Proteomic analysis of hemolymph from poly(I:C)-stimulated Crassostrea gigas. AB - Synthetic double stranded RNA (Poly(I:C)) injection of Crassostrea gigas results in a systemic antiviral response involving many evolutionary conserved antiviral effectors (ISGs). Compared to mammals, the timing of C. gigas ISG expression to viral or poly(I:C) injection is delayed (>12 h p.i.). It could be interpreted that a cytokine is responsible for the systemic, but delayed expression of C. gigas ISGs. We therefore analysed the acellular fraction of C. gigas hemolymph by two-dimensional electrophoresis (2-DE) to identify hemolymph proteins induced by poly(I:C). Poly(I:C) injection increased the relative intensity of four protein spots. These protein spots were identified by tandem mass spectrometry (LC-MS/MS) as a small heat shock protein (sHSP), poly(I:C)-inducible protein 1 (PIP1) and two isoforms of C1q-domain containing protein (C1qDC). RT-qPCR analysis confirmed that the genes encoding these proteins are induced in hemocytes of C. gigas injected with poly(I:C) (p < 0.05). Proteomic data from this experiment corroborates previous microarray and whole transcriptome studies that have reported up-regulation of C1qDC and sHSP during mass mortality events among farmed oysters. PMID- 26578250 TI - A cystatin F homologue from large yellow croaker (Larimichthys crocea) inhibits activity of multiple cysteine proteinases and Ii chain processing in vitro. AB - Cystatin F, a member of the family II cystatins, plays important roles in immune response-related processes through inhibiting specific enzyme targets. In this study, a cystatin F homologue, LycCysF, was identified and characterized from large yellow croaker (Larimichthys crocea). The deduced LycCysF protein exhibits a typical structural feature of type II cystatins, including three evolutionally conserved motifs, Gly(35), QVVRG(79-83) and PW(130-131). Tissue expression analysis showed that LycCysF mRNA was expressed in all tissues examined, albeit at different levels. Recombinant LycCysF (rLycCysF) produced in Pichia pastoris could inhibit the activity of multiple cysteine proteases, including papain, legumain and recombinant large yellow croaker cathepsin B, L and S. Moreover, rLycCysF could inhibit the Ii chain processing by recombinant cathepsin S in vitro. These data suggest that LycCysF may participate in regulation of cathepsins and MHC-II associated Ii chain processing. In addition, mammalian cystatin F is produced as an inactive dimer, becoming activated by proteolysis in the endo/lysosome of immune cells and then exerts its function of regulating downstream proteases activity. However, the N-terminal extension and two additional cysteine residues responsible for dimer formation are absent in LycCysF and cystatin F from other fish species, reptiles and Aves, indicating that these proteins can not form dimer and may regulate the proteases activity via an alternate pathway distinct from mammalian cystatin F. To our knowledge, this is the first report on molecular characteristics of a teleost cystatin F and its role in Ii chain processing. PMID- 26578251 TI - Identification and characterization of nascent polypeptide-associated complex alpha from Chinese mitten crab (Eriocheir sinensis): A novel stress and immune response gene in crustaceans. AB - Disease in aquatic animals is tightly linked to environmental challenges and their immune responses are greatly modified by their external environment. The chaperone protein nascent polypeptide-associated complex alpha (NACA) has been suggested to play important roles in the cellular response to stress and immune challenges, while the related biological functions remain largely unknown in invertebrates. In the present study we identified a NACA gene (termed EsNACA) from Chinese mitten crab Eriocheir sinensis and analyzed its expression changes in response to ambient (salinity and pH) stresses and immune challenges. The EsNACA protein is comprised of 209 amino acid residues with a conserved DNA binding domain, a C-Jun binding domain, a NAC domain and an ubiquitin-associated domain and shows the highest sequence identity (87%) with its counterpart in shrimp Penaeus monodon. EsNACA mRNA transcripts are presented in all tested normal tissues with predominant expression in hepatopancreas and lower expression in hemocytes. In addition, EsNACA expression was significantly altered in response to the ambient salinity (150/00 and 300/00 salinities) and pH (pH 6 and 8.5) stresses in gill, hepatopancreas, muscle, hemocytes and intestine tissues. Furthermore, EsNACA gene expression was substantially induced upon LPS and Poly(I:C) immune stimulations in E. sinensis hemocytes in vitro. Finally, EsNACA expression was up-regulated in E. sinensis hemocytes, gill, hepatopancreas, intestine and muscle tissues in response to Vibrio anguillarum challenges in vivo. Taken together, our findings for the first time show that EsNACA is an inducible gene involved in stress and immune response in crustaceans. PMID- 26578252 TI - The funding landscape for HIV in Asia and the Pacific. AB - INTRODUCTION: Despite recent and robust economic growth across the Asia-Pacific region, the majority of low- and middle-income countries in the region remain dependent on some donor support for HIV programmes. We describe the availability of bilateral and multilateral official development assistance (ODA) for HIV programmes in the region. METHODS: The donor countries considered in this analysis are Australia, Canada, Denmark, France, Germany, Netherlands, Norway, Sweden, the United Kingdom and the United States. To estimate bilateral and multilateral ODA financing for HIV programmes in the Asia-Pacific region between 2004 and 2013, we obtained funding data from the Organisation for Economic Co operation and Development Creditor Reporting System database. Where possible, we checked these amounts against the funding data available from government aid agencies. Estimates of multilateral ODA financing for HIV/AIDS were based on the country allocations announcement by the Global Fund to Fight AIDS, Tuberculosis and Malaria (the Global Fund) for the period 2014 to 2016. RESULTS: Countries in the Asia-Pacific region receive the largest share of aid for HIV from the Global Fund. Bilateral funding for HIV in the region has been relatively stable over the last decade and is projected to remain below 10% of the worldwide response to the epidemic. Bilateral donors continue to prioritize ODA for HIV to other regions, particularly sub-Saharan Africa; Australia is an exception in prioritizing the Asia-Pacific region, but the United States is the bilateral donor providing the greatest amount of assistance in the region. Funding from the Global Fund has increased consistently since 2005, reaching a total of US$1.2 billion for the Asia-Pacific region from 2014 to 2016. CONCLUSIONS: Even with Global Fund allocations, countries in the Asia-Pacific region will not have enough resources to meet their epidemiological targets. Prevention funding is particularly vulnerable and requires greater domestic leadership and coordination. Bilateral donors are still crucially important in the response to HIV throughout the Asia Pacific region. PMID- 26578253 TI - The effects of whole body vibration in patients with type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Whole body vibration (WBV) has been used to increase physical activity levels in patients with type 2 diabetes mellitus (T2DM). OBJECTIVE: To carry out a systematic review of the effects of WBV on the glycemic control, cardiovascular risk factors, and physical and functional capacity of patients with T2DM. METHOD: MEDLINE, LILACS, PEDro, and Cochrane Central Register of Controlled Trials were searched up to June 1st, 2015. Randomized controlled trials investigating the effects of WBV, compared to control or other intervention, on blood glucose levels, blood and physical cardiovascular risk factors, and physical and functional capacity in adult individuals with T2DM. Two independent reviewers extracted the data regarding authors, year of publication, number of participants, gender, age, WBV parameters and description of intervention, type of comparison, and mean and standard deviation of pre and post assessments. RESULTS: Out of 585 potentially eligible articles, two studies (reported in four manuscripts) were considered eligible. WBV interventions provided a significant reduction of 25.7 ml/dl (95% CI:-45.3 to -6.1; I2: 19%) in 12 hours fasting blood glucose compared with no intervention. Improvements in glycated hemoglobin, cardiovascular risk factors, and physical and functional capacity were found only at 12 weeks after WBV intervention in comparison with no intervention. CONCLUSION: WBV combined with exercise seems to improve glycemic control slightly in patients with T2DM in an exposure-dependent way. Large and well-designed trials are still needed to establish the efficacy and understand whether the effects were attributed to vibration, exercise, or a combination of both. PMID- 26578254 TI - Effects of diaphragmatic control on the assessment of sniff nasal inspiratory pressure and maximum relaxation rate. AB - OBJECTIVE: To assess the influence of diaphragmatic activation control (diaphC) on Sniff Nasal-Inspiratory Pressure (SNIP) and Maximum Relaxation Rate of inspiratory muscles (MRR) in healthy subjects. METHOD: Twenty subjects (9 male; age: 23 (SD=2.9) years; BMI: 23.8 (SD=3) kg/m2; FEV1/FVC: 0.9 (SD=0.1)] performed 5 sniff maneuvers in two different moments: with or without instruction on diaphC. Before the first maneuver, a brief explanation was given to the subjects on how to perform the sniff test. For sniff test with diaphC, subjects were instructed to perform intense diaphragm activation. The best SNIP and MRR values were used for analysis. MRR was calculated as the ratio of first derivative of pressure over time (dP/dtmax) and were normalized by dividing it by peak pressure (SNIP) from the same maneuver. RESULTS: SNIP values were significantly different in maneuvers with and without diaphC [without diaphC: -100 (SD=27.1) cmH2O/ with diaphC: -72.8 (SD=22.3) cmH2O; p<0.0001], normalized MRR values were not statistically different [without diaphC: -9.7 (SD=2.6); with diaphC: -8.9 (SD=1.5); p=0.19]. Without diaphC, 40% of the sample did not reach the appropriate sniff criteria found in the literature. CONCLUSION: Diaphragmatic control performed during SNIP test influences obtained inspiratory pressure, being lower when diaphC is performed. However, there was no influence on normalized MRR. PMID- 26578255 TI - Heavy metals in soils along unpaved roads in south west Cameroon: Contamination levels and health risks. AB - Soils enriched with heavy metals from vehicular emission present a significant exposure route of heavy metals to individuals using unpaved roads. This study assessed the extent of Cd, Cr, Co, Cu, Ni, Pb and Zn contamination of soils along unpaved roads in Cameroon, and the health risks presented by incidental ingestion and dermal contact with the soils using metal contamination factor (CF) pollution load index, hazard quotients (HQ) and chronic hazard index (CHI). CF values obtained (0.9-12.2) indicate moderate to high contamination levels. HQ values for Cr, Cd and Pb exceeded the reference doses. Moderate health hazard exists for road users in the areas with intense anthropogenic activities and high average daily traffic (ADT) volume according to CHI values (1-4) obtained. The economy and quality of life in cities with unpaved roads could be threatened by health challenges resulting from long-term exposure to heavy metal derived from high ADT volumes. PMID- 26578256 TI - Does my brain want what my eyes like? - How food liking and choice influence spatio-temporal brain dynamics of food viewing. AB - How food valuation and decision-making influence the perception of food is of major interest to better understand food intake behavior and, by extension, body weight management. Our study investigated behavioral responses and spatio temporal brain dynamics by means of visual evoked potentials (VEPs) in twenty-two normal-weight participants when viewing pairs of food photographs. Participants rated how much they liked each food item (valuation) and subsequently chose between the two alternative food images. Unsurprisingly, strongly liked foods were also chosen most often. Foods were rated faster as strongly liked than as mildly liked or disliked irrespective of whether they were subsequently chosen over an alternative. Moreover, strongly liked foods were subsequently also chosen faster than the less liked alternatives. Response times during valuation and choice were positively correlated, but only when foods were liked; the faster participants rated foods as strongly liked, the faster they were in choosing the food item over an alternative. VEP modulations by the level of liking attributed as well as the subsequent choice were found as early as 135-180ms after food image onset. Analyses of neural source activity patterns over this time interval revealed an interaction between liking and the subsequent choice within the insula, dorsal frontal and superior parietal regions. The neural responses to food viewing were found to be modulated by the attributed level of liking only when foods were chosen, not when they were dismissed for an alternative. Therein, the responses to disliked foods were generally greater than those to foods that were liked more. Moreover, the responses to disliked but chosen foods were greater than responses to disliked foods which were subsequently dismissed for an alternative offer. Our findings show that the spatio-temporal brain dynamics to food viewing are immediately influenced both by how much foods are liked and by choices taken on them. These valuation and choice processes are subserved by brain regions involved in salience and reward attribution as well as in decision making processes, which are likely to influence prospective dietary choices in everyday life. PMID- 26578257 TI - Trying to Lose Weight and Alcohol Misuse Among High School Girls: Findings From the U.S. National 2011 Youth Risk Behavior Survey. AB - BACKGROUND: Trying to lose weight has been associated with alcohol use among college-aged females. Excessive drinking along with purging as a method for weight control has been documented in this population. However, little is known about the relationship between alcohol use and trying to lose weight among high school girls. OBJECTIVES: To examine the relationship between trying to lose weight and past 30-day (1) alcohol use and (2) binge drinking (separately). METHODS: Using data from the National 2011 YRBS, we examined these relationships among 5,106 girls aged 14-18+ who reported ever using alcohol. Survey-weighted iterative logistic regression models were conducted. RESULTS: 44.0% of girls reported current alcohol use with 27.8% reporting binge drinking. While a significant relationship was not found between trying to lose weight and current alcohol use in the final multivariable model, a significant relationship was found between trying to lose weight and binge drinking (AOR: 1.24, 95% CI: 1.02 1.52). Additional variables that were found to be associated with an increased odds of binge drinking included: being in 11th and 12th grades compared to being in 9th grade, screening positively for depression, and current cigarette use. Variables associated with a decreased odds included: talking to an adult/teacher about a problem, and identifying as Black/African American compared to White. CONCLUSIONS/IMPORTANCE: Understanding the relationship between trying to lose weight and binge drinking among high school students is important, as these behaviors may be a precursor to risk behaviors later in life and need to be more fully examined. PMID- 26578258 TI - Disruptive mood dysregulation disorder in ICD-11: a new disorder or ODD with a specifier for chronic irritability? PMID- 26578259 TI - Hierarchical 3-dimensional nickel-iron nanosheet arrays on carbon fiber paper as a novel electrode for non-enzymatic glucose sensing. AB - Three-dimensional nickel-iron (3-D/Ni-Fe) nanostructures are exciting candidates for various applications because they produce more reaction-active sites than 1-D and 2-D nanostructured materials and exhibit attractive optical, electrical and catalytic properties. In this work, freestanding 3-D/Ni-Fe interconnected hierarchical nanosheets, hierarchical nanospheres, and porous nanospheres are directly grown on a flexible carbon fiber paper (CFP) substrate by a single-step hydrothermal process. Among the nanostructures, 3-D/Ni-Fe interconnected hierarchical nanosheets show excellent electrochemical properties because of its high conductivity, large specific active surface area, and mesopores on its walls (vide infra). The 3-D/Ni-Fe hierarchical nanosheet array modified CFP substrate is further explored as a novel electrode for electrochemical non-enzymatic glucose sensor application. The 3-D/Ni-Fe hierarchical nanosheet arrays exhibit significant catalytic activity towards the electrochemical oxidation of glucose, as compared to the 3-D/Ni-Fe hierarchical nanospheres, and porous nanospheres. The 3-D/Ni-Fe hierarchical nanosheet arrays can access a large amount of glucose molecules on their surface (mesopore walls) for an efficient electrocatalytic oxidation process. Moreover, 3-D/Ni-Fe hierarchical nanosheet arrays showed higher sensitivity (7.90 MUA MUM(-1) cm(-2)) with wide linear glucose concentration ranging from 0.05 MUM to 0.2 mM, and the low detection limit (LOD) of 0.031 MUM (S/N = 3) is achieved by the amperometry method. Further, the 3-D/Ni Fe hierarchical nanosheet array modified CFP electrode can be demonstrated to have excellent selectivity towards the detection of glucose in the presence of 500-fold excess of major important interferents. All these results indicate that 3-D/Ni-Fe hierarchical nanosheet arrays are promising candidates for non enzymatic glucose sensing. PMID- 26578260 TI - Gram-negative organisms in peritoneal dialysis peritonitis: an early indication for surgery in patients with haemolytic uraemic syndrome? AB - PURPOSE: Haemolytic uraemic syndrome (HUS) is the commonest childhood cause of acute renal failure. Peritoneal dialysis peritonitis (PDP) is a well-recognised complication, with some children requiring surgical intervention (SI). The aim of this study is to determine whether the presence of enteric organisms in cases of PDP might predict the need for SI. METHODS: Retrospective, 5-year (2009-2014) case note review of all HUS cases requiring PD presenting to a single centre. Mann-Whitney U test was used for continuous non-parametric data and chi (2) for categorical data. RESULTS: 48 children required PD for HUS, 18/48 (38 %) developed PDP and of these 5/18 (28 %) required SI (subtotal colectomy n = 4, small bowel resection n = 1). Peritoneal fluid was cultured as part of the work up for PDP. The presence of enteric organisms was associated with a 10.4 fold relative risk of requiring surgery (p = 0.02, 95 % CI 1.5-71.9), with 4/5 of these patients requiring surgery (median 17 days post-culture result). Only 1/13 patients not requiring surgery grew gram-negative bacteria. CONCLUSION: The presence of enteric bacteria in patients with PDP significantly decreases the chances of successful conservative management. In these patients early involvement of the surgical team is essential with a low threshold for SI. PMID- 26578263 TI - Alliance Against Cancer, the network of Italian cancer centers bridging research and care. AB - Alliance Against Cancer (ACC) was established in Rome in 2002 as a consortium of six Italian comprehensive cancer centers (Founders). The aims of ACC were to promote a network among Italian oncologic institutions in order to develop specific, advanced projects in clinical and translational research. During the following years, many additional full and associate members joined ACC, that presently includes the National Institute of Health, 17 research-oriented hospitals, scientific and patient organizations. Furthermore, in the last three years ACC underwent a reorganization process that redesigned the structure, governance and major activities. The present goal of ACC is to achieve high standards of care across Italy, to implement and harmonize principles of modern personalized and precision medicine, by developing cost effective processes and to provide tailored information to cancer patients. We herein summarize some of the major initiatives that ACC is currently developing to reach its goal, including tumor genetic screening programs, establishment of clinical trial programs for cancer patients treated in Italian cancer centers, facilitate their access to innovative drugs under development, improve quality through an European accreditation process (European Organization of Cancer Institutes), and develop international partnerships. In conclusion, ACC is a growing organization, trying to respond to the need of networking in Italy and may contribute significantly to improve the way we face cancer in Europe. PMID- 26578261 TI - Non-Canonical (RANKL-Independent) Pathways of Osteoclast Differentiation and Their Role in Musculoskeletal Diseases. AB - Osteoclasts are multinucleated cells derived from mononuclear phagocyte precursors (monocytes, macrophages); in the canonical pathway of osteoclastogenesis, these cells fuse and differentiate to form specialised bone resorbing osteoclasts in the presence of receptor activator for nuclear factor kappa B ligand (RANKL). Non-canonical pathways of osteoclastogenesis have been described in which several cytokines and growth factors are able to substitute for RANKL. These humoral factors can generally be divided into those which, like RANKL, are tumour necrosis family (TNF) superfamily members and those which are not; the former include TNFalpha lymphotoxin exhibiting inducible expression and competing with herpes simplex virus glycoprotein D for herpesvirus entry mediator, a receptor expressed by T lymphocytes (LIGHT), a proliferation inducing ligand (APRIL) and B cell activating factor (BAFF); the latter include transforming growth factor beta (TGF-beta), interleukin-6 (IL-6), IL-8, IL-11, nerve growth factor (NGF), insulin-like growth factor-I (IGF-I) and IGF-II. This review summarises the evidence for these RANKL substitutes in inducing osteoclast differentiation from tissue-derived and circulating mononuclear phagocytes. It also assesses the role these factors are likely to play in promoting the pathological bone resorption seen in many inflammatory and neoplastic lesions of bone and joint including rheumatoid arthritis, aseptic implant loosening and primary and secondary tumours of bone. PMID- 26578262 TI - Osteoarthritis and frailty in elderly individuals across six European countries: results from the European Project on OSteoArthritis (EPOSA). AB - BACKGROUND: Osteoarthritis (OA) is the most common cause of disability in the elderly. Clinical frailty is associated with high mortality, but few studies have explored the relationship between OA and frailty. The objective of this study was to consider the association between OA and frailty/pre-frailty in an elderly population comprised of six European cohorts participating in the EPOSA project. METHODS: Longitudinal study using baseline data and first follow-up waves, from EPOSA; 2,455 individuals aged 65-85 years were recruited from pre-existing population-based cohorts in Germany, Italy, the Netherlands, Spain, Sweden and the United Kingdom. Data were collected on clinical OA at any site (hand, knee or hip), based on the clinical classification criteria developed by the American College of Rheumatology (ACR). Frailty was defined according to Fried's criteria. The covariates considered were age, gender, educational level, obesity and country. We used multinomial logistic regression to analyse the associations between OA, frailty/pre-frailty and other covariates. RESULTS: The overall prevalence of clinical OA at any site was 30.4 % (95 % CI:28.6-32.2); frailty was present in 10.2 % (95 % CI:9.0-11.4) and pre-frailty in 51.0 % (95 % CI:49.0 53.0). The odds of frailty was 2.96 (95 % CI:2.11-4.16) and pre-frailty 1.54 (95 % CI:1.24-1.91) as high among OA individuals than those without OA. The association remained when Knee OA, hip OA or hand OA were considered separately, and was stronger in those with increasing number of joints. CONCLUSIONS: Clinical OA is associated with frailty and pre-frailty in older adults in European countries. This association might be considered when designing appropriate intervention strategies for OA management. PMID- 26578264 TI - Potentiation of Acetylcholine-Mediated Facilitation of Inhibitory Synaptic Transmission by an Azaindolizione Derivative, ZSET1446 (ST101), in the Rat Hippocampus. AB - The integrity of the hippocampal network depends on the coordination of excitatory and inhibitory signaling, which are under dynamic control by various regulatory influences such as the cholinergic systems. ZSET1446 (ST101; spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one) is a newly synthesized azaindolizinone derivative that significantly improves learning deficits in various types of Alzheimer disease (AD) models in rats. We examined the effect of ZSET1446 on the nicotinic acetylcholine (ACh) receptor (nAChR)-mediated regulation of synaptic transmission in hippocampal slices of rats. ZSET1446 significantly potentiated the facilitatory effect of nicotine and ACh on the frequency of spontaneous postsynaptic currents (sPSCs) recorded in CA1 pyramidal neurons with a maximum effect at 100 pM (tested range, 10 pM-1000 pM). The basal sPSC frequency without ACh was not affected. Such potentiation by ZSET1446 was observed in both the pharmacologic isolations of inhibitory and excitatory sPSCs and markedly reduced by blockade of either alpha7 or alpha4beta2 nAChRs. ZSET1446 did not affect ACh-activated inward currents or depolarization of interneurons in the stratum radiatum and the lacunosum moleculare. These results indicate that ZSET1446 potentiates the nicotine-mediated enhancement of synaptic transmission in the hippocampal neurons without affecting nAChRs themselves, providing a novel possible mechanism of procognitive action that might improve learning deficits in clinical therapy. PMID- 26578265 TI - Tonically Active cAMP-Dependent Signaling in the Ventrolateral Medulla Regulates Sympathetic and Cardiac Vagal Outflows. AB - The ventrolateral medulla contains presympathetic and vagal preganglionic neurons that control vasomotor and cardiac vagal tone, respectively. G protein-coupled receptors influence the activity of these neurons. Galpha s activates adenylyl cyclases, which drive cyclic adenosine monophosphate (cAMP)-dependent targets: protein kinase A (PKA), the exchange protein activated by cAMP (EPAC), and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. The aim was to determine the cardiovascular effects of activating and inhibiting these targets at presympathetic and cardiac vagal preganglionic neurons. Urethane anesthetized rats were instrumented to measure splanchnic sympathetic nerve activity (sSNA), arterial pressure (AP), heart rate (HR), as well as baroreceptor and somatosympathetic reflex function, or were spinally transected and instrumented to measure HR, AP, and cardiac baroreflex function. All drugs were injected bilaterally. In the rostral ventrolateral medulla (RVLM), Sp-cAMPs and 8 Br-cAMP, which activate PKA, as well as 8-pCPT, which activates EPAC, increased sSNA, AP, and HR. Sp-cAMPs also facilitated the reflexes tested. Sp-cAMPs also increased cardiac vagal drive and facilitated cardiac baroreflex sensitivity. Blockade of PKA, using Rp-cAMPs or H-89 in the RVLM, increased sSNA, AP, and HR and increased HR when cardiac vagal preganglionic neurons were targeted. Brefeldin A, which inhibits EPAC, and ZD7288, which inhibits HCN channels, each alone had no effect. Cumulative, sequential blockade of all three inhibitors resulted in sympathoinhibition. The major findings indicate that Galpha s-linked receptors in the ventral medulla can be recruited to drive both sympathetic and parasympathetic outflows and that tonically active PKA-dependent signaling contributes to the maintenance of both sympathetic vasomotor and cardiac vagal tone. PMID- 26578266 TI - Histones Differentially Modulate the Anticoagulant and Profibrinolytic Activities of Heparin, Heparin Derivatives, and Dabigatran. AB - The antithrombin activity of unfractionated heparin (UFH) is offset by extracellular histones, which, along with DNA, represent a novel mediator of thrombosis and a structural component of thrombi. Here, we systematically evaluated the effect of histones, DNA, and histone-DNA complexes on the anticoagulant and profibrinolytic activities of UFH, its derivatives enoxaparin and fondaparinux, and the direct thrombin inhibitor dabigatran. Thrombin generation was assessed by calibrated automated thrombinography, inhibition of factor Xa and thrombin by synthetic substrates, tissue plasminogen activator mediated clot lysis by turbidimetry, and thrombin-activatable fibrinolysis inhibitor (TAFI) activation by a functional assay. Histones alone delayed coagulation and slightly stimulated fibrinolysis. The anticoagulant activity of UFH and enoxaparin was markedly inhibited by histones, whereas that of fondaparinux was enhanced. Histones neutralized both the anti-Xa and anti-IIa activities of UFH and preferentially blocked the anti-IIa activity of enoxaparin. The anti-Xa activity of fondaparinux was not influenced by histones when analyzed by chromogenic substrates, but was potentiated in a plasma prothrombinase assay. Histones inhibited the profibrinolytic activity of UFH and enoxaparin and enhanced that of fondaparinux by acting on the modulation of TAFI activation by anticoagulants. Histone H1 was mainly responsible for these effects. Histone-DNA complexes, as well as intact neutrophil extracellular traps, impaired the activities of UFH, enoxaparin, and fondaparinux. Dabigatran was not noticeably affected by histones and/or DNA, whatever the assay performed. In conclusion, histones and DNA present in the forming clot may variably influence the antithrombotic activities of anticoagulants, suggesting a potential therapeutic advantage of dabigatran and fondaparinux over heparins. PMID- 26578267 TI - A Novel Allosteric Insulin Receptor-Activating Antibody Reduces Hyperglycemia without Hypoglycemia in Diabetic Cynomolgus Monkeys. AB - XMetA is a fully human, allosteric monoclonal antibody that binds the insulin receptor with high affinity and mimics the glucoregulatory, but not the mitogenic, actions of insulin. Here we evaluated the efficacy of both single and repeat s.c. administrations of XMetA in reducing hyperglycemia in obese cynomolgus monkeys with naturally developed type 2 diabetes, a model that shares many features of human diabetes. The data show that a single s.c. administration of XMetA at dose levels ranging from 1.5 to 10 mg/kg markedly reduced fasting hyperglycemia, with a peak effect occurring 1 to 2 days after administration, and sustained for up to 1 week. XMetA's effect on hyperglycemia was observed without elevations in serum insulin and was concomitant with reduced serum C-peptide levels, even at the lowest dose. Subchronic effects were evaluated via once weekly s.c. administration of XMetA, 10 mg/kg, for 6 weeks. XMetA treatment resulted in robust weekly decreases in fasting glucose levels averaging approximately 30% throughout the study, along with a significant absolute reduction from the vehicle control baseline of 1.2% in hemoglobin A1c, a marker of long-term glycemic status. XMetA treatment was well tolerated with no injection-site reactions, no body weight gain, and no episodes of clinical hypoglycemia. Thus, XMetA shows acute and subchronic improvements in glycemic control in spontaneously diabetic cynomolgus monkeys with a broad safety margin. This profile supports the development of XMetA as a novel glucose-lowering therapeutic agent for the management of type 2 diabetes. PMID- 26578268 TI - Magnetic interactions in the Zn-Co-O system: tuning local structure, valence and carrier type from extremely Co doped ZnO to ZnCo2O4. AB - We have investigated the relation between local structure, valence and carrier type with magnetism in the Zn-Co-O system. Thin films ranging from wurtzite Zn(1 x)Co(x)O (Co:ZnO) to ZnCo2O4 spinel were grown on c-sapphire substrates. On the one hand, the unprecedented doping of x = 0.6 Co in ZnO enables to study the structural and magnetic properties well-above the coalescence limit. On the other hand, the ZnCo2O4 spinel provides a p-type environment. We find a strong correlation between local structure, valence and carrier type throughout the Zn Co-O system. In contrast to earlier publications neither 60% Co:ZnO nor ZnCo2O4 exhibit any sign of ferromagnetic order despite of the high concentration of magnetic ions and a p-type carrier background. Instead, antiferromagnetic exchange is found to be the predominant magnetic interaction in the Zn-Co-O system. PMID- 26578270 TI - Characterization of endoproteolytic processing of dynorphins by proprotein convertases using mouse spinal cord S9 fractions and mass spectrometry. AB - Dynorphins are important neuropeptides with a central role in nociception and pain alleviation. Many mechanisms regulate endogenous dynorphin concentrations, including proteolysis. Proprotein convertases (PCs) are widely expressed in the central nervous system and specifically cleave at C-terminal of either a pair of basic amino acids, or a single basic residue. The proteolysis control of endogenous big dynorphin (BDyn) and dynorphin A (Dyn A) levels has a profound impact on pain perception and the role of PCs remain unclear. The objective of this study was to decipher the role of PC1 and PC2 in the proteolysis control of BDyn and Dyn A levels using cellular fractions of spinal cords from wild-type (WT), PC1(-/+) and PC2(-/+) animals and mass spectrometry. Our results clearly demonstrate that both PC1 and PC2 are involved in the proteolysis regulation of BDyn and Dyn A with a more important role for PC1. C-terminal processing of BDyn generates specific peptide fragments dynorphin 1-19, dynorphin 1-13, dynorphin 1 11 and dynorphin 1-7, and C-terminal processing of Dyn A generates dynorphin 1 13, dynorphin 1-11 and dynorphin 1-7, all these peptide fragments are associated with PC1 or PC2 processing. Moreover, the proteolysis of BDyn leads to the formation of Dyn A and Leu-Enk, two important opioid peptides. The rate of formation of both is significantly reduced in cellular fractions of spinal cord mutant mice. As a consequence, even the partial inhibition of PC1 or PC2 may impair the endogenous opioid system. PMID- 26578271 TI - Prevalence of knee osteoarthritis, risk factors, and quality of life: The Fifth Korean National Health And Nutrition Examination Survey. AB - AIM: Although there have been regional population-based studies on the prevalence of knee osteoarthritis (KOA) and its risk factors in South Koreans, those studies in common had limited external validity. This study aims to estimate the national prevalence of KOA and its risk factors using a complex sampling design. METHODS: This was a cross-sectional study including 9512 participants aged >= 50 years of The Fifth Korean National Health and Nutrition Examination Survey, who were selected using two-step stratified clustered equal-probability systematic sampling. Radiographic KOA (RKOA) was defined as a Kellgren-Lawrence grade of >= 2. Symptoms of KOA were evaluated through a health interview. Obesity was defined as a body mass index >= 27.5 kg/m2. Quality of life was measured by the Korean version of European Quality of Life Questionnaire (EQ-5D). RESULTS: The prevalence of RKOA was 21.1% (95% CI: 19.6-22.8%) in men, and 43.8% (42.0-45.6%) in women. The prevalence of symptomatic RKOA (SRKOA) was 4.4% (3.8-5.2%) and 19.2% (17.9-20.6%) in men and women, respectively. The EQ-5D index was lower in participants with KOA. When plotted against mean age and prevalence of obesity, regions with a higher mean age and prevalence of obesity had higher prevalence of KOA, which was also observed at the individual level. The prevalence of SRKOA was 36.6% (29.7-44.1%) in women in Jeju province. CONCLUSION: The prevalence of SRKOA in women reached 36.6% in high-risk groups accompanied by low quality of life. The results suggest that the disease burden of KOA is high in South Korea. PMID- 26578272 TI - Cyber threats to health information systems: A systematic review. AB - BACKGROUND: Recent legislation empowering providers to embrace the electronic exchange of health information leaves the healthcare industry increasingly vulnerable to cybercrime. The objective of this systematic review is to identify the biggest threats to healthcare via cybercrime. OBJECTIVE: The rationale behind this systematic review is to provide a framework for future research by identifying themes and trends of cybercrime in the healthcare industry. METHODS: The authors conducted a systematic search through the CINAHL, Academic Search Complete, PubMed, and ScienceDirect databases to gather literature relative to cyber threats in healthcare. All authors reviewed the articles collected and excluded literature that did not focus on the objective. RESULTS: Researchers selected and examined 19 articles for common themes. The most prevalent cyber criminal activity in healthcare is identity theft through data breach. Other concepts identified are internal threats, external threats, cyber-squatting, and cyberterrorism. CONCLUSIONS: The industry has now come to rely heavily on digital technologies, which increase risks such as denial of service and data breaches. Current healthcare cyber-security systems do not rival the capabilities of cyber criminals. Security of information is a costly resource and therefore many HCOs may hesitate to invest what is required to protect sensitive information. PMID- 26578273 TI - Initial assessment of facial nerve paralysis based on motion analysis using an optical flow method. AB - An initial assessment method that can classify as well as categorize the severity of paralysis into one of six levels according to the House-Brackmann (HB) system based on facial landmarks motion using an Optical Flow (OF) algorithm is proposed. The desired landmarks were obtained from the video recordings of 5 normal and 3 Bell's Palsy subjects and tracked using the Kanade-Lucas-Tomasi (KLT) method. A new scoring system based on the motion analysis using area measurement is proposed. This scoring system uses the individual scores from the facial exercises and grades the paralysis based on the HB system. The proposed method has obtained promising results and may play a pivotal role towards improved rehabilitation programs for patients. PMID- 26578274 TI - Improved contact lens disinfection by exposure to violet radiation. AB - BACKGROUND: Conventional procedures for contact lens disinfection, based on solutions with aggressive chemical ingredients, not only affect microorganisms but operate likewise damaging towards the epithelial eye surface. OBJECTIVE: The aim of this study was to evaluate the applicability of an alternative or complementary disinfection procedure for contact lenses based on irradiation within the visible wavelength range. METHODS: Suspensions of S. auricularis, B. subtilis and E. coli were exposed to 405 nm irradiation, for determining the disinfection efficacy. Surviving rates were analyzed by membrane filtration as well as a semi-quantitative analysis using DipSlides. RESULTS: A significant antibacterial effect of the 405 nm irradiation is verifiable for all probed bacteria. Using S. auricularis, there has been no colony forming after an irradiation exposure of 2 hours. CONCLUSION: The hitherto existing results give reason for the assumption that violet LEDs integrated in contact lens cases will provide a subsidiary disinfection activity and maybe even offer the reduction of chemical ingredients in lens cleaning solutions to become gentler to the eye. In addition the danger of a rerise of the germ concentration after the completion of the disinfection procedure will be reduced. PMID- 26578275 TI - Time sequence image analysis of positron emission tomography using wavelet transformation. AB - This paper presents the time sequence image analysis technique of positron emission tomography (PET) using a wavelet transformation method. The abdominal cavity of a person taking [18F]Fluoro-2-deoxy-2-D-glucose (18F-FDG) was scanned by the dynamic PET. The organ selection with dynamic PET images was conducted by the wavelet transformation to implement automatic selection of the region of interest (ROI). The image segmentation was carried out by the processes of sampling, wavelet transformation, erosion, dilation, and superimposition. Wavelet constructed image (WCI) contours were created by sampling 512 images from 1960 consecutive dynamic sequence PET images. The image segmentation technology developed can help doctors automatically select ROI, accurately identify lesion locations of organs, and thus effectively reduce human operation time and errors. PMID- 26578276 TI - The development and evaluation of a nursing information system for caring clinical in-patient. AB - The research aimed to develop a nursing information system in order to simplify the admission procedure for caring clinical in-patient, enhance the efficiency of medical information documentation. Therefore, by correctly delivering patients' health records, and providing continues care, patient safety and care quality would be effectively improved. The study method was to apply Spiral Model development system to compose a nursing information team. By using strategies of data collection, working environment observation, applying use-case modeling, and conferences of Joint Application Design (JAD) to complete the system requirement analysis and design. The Admission Care Management Information System (ACMIS) mainly included: (1) Admission nursing management information system. (2) Inter shift meeting information management system. (3) The linkage of drug management system and physical examination record system. The framework contained qualitative and quantitative components that provided both formative and summative elements of the evaluation. System evaluation was to apply information success model, and developed questionnaire of consisting nurses' acceptance and satisfaction. The results of questionnaires were users' satisfaction, the perceived self-involvement, age and information quality were positively to personal and organizational effectiveness. According to the results of this study, the Admission Care Management Information System was practical to simplifying clinic working procedure and effective in communicating and documenting admission medical information. PMID- 26578277 TI - Fool-proofing design and crisis management for customized intelligent physical fitness and healthcare system. AB - In recent years, it is quite important to develop a customized system which can enhance physical fitness and health for people. And the system reliability is more important. In the paper, a fool-proofing design and crisis management for customized physical fitness and healthcare system is proposed. It is designed to prevent the failure of the various mechanisms of customized physical fitness and healthcare system, including records, surveillance, assessments, predictions, diagnosis, prescription, and scheduling. It is separated into (1) fool-proofing design module (2) crisis management module. The fool-proofing indexes are set to prevent the failure of the various mechanisms. The states of the various mechanisms are managed by the auto-checked fool-proofing indexes. If mistakes prevention was fail, we have to execute the crisis management for stopping harmful results. The crisis management will find the error level and response the solution by using fuzzy method. By the experiments, we can find the advantages of the fool-proofing design and crisis management for customized physical fitness and healthcare system. And it is effective to prevent the failure of the various mechanisms of intelligent customized physical fitness and healthcare system. PMID- 26578278 TI - A novel GNRs-PEI/GNRs-PEI-folate for efficiently delivering siRNA. AB - RNA interference (RNAi) employs double-stranded RNA or siRNA (small interfering RNA) to silence gene expression in cells. The widespread use of RNAi therapeutics requires the development of clinically suitable, safe and effective delivery vehicles. PEI (Poly(ethylene imine)) carrying the positive charges has attracted considerable attention for siRNA delivery. Gold nanorods (GNRs) exhibit specially localized surface plasmon resonance when excited by the visible and near-infrared laser, which is useful for photothermal therapy. However, the toxicity derived from a large amount of the surfactant cetyltrimethylammonium bromide (CTAB) during GNR synthesis severely limits their medical applications. Here, we report the synthesis of GNRs-PEI/GNRs-PEI-folate to improve biocompatibility, siRNA delivery and photothermal therapy of GNRs. Firstly, GNRs were synthesized according to the seed-mediated template-assisted protocol. The characterization results of GNRs showed: the size was length about 218 nm and width about 26.8 nm; the Zeta potential was +38.1 mV derived from CTAB on their surface; the dipole resonance extinction spectrum peak was 752 nm which is effective for photothermal therapy in vivo. Secondly, we synthesized PEI-MUA (Mercaptoundecanoic acid) and PEI-MUA-folate based on the chemical reaction between amino group of PEI and carboxyl group of MUA or Folate. PEI-MUA or PEI-MUA-folate to replace CTAB on GNRs obtained the GNRs-MUA-PEI system or the GNRs-MUA-PEI-folate system due to the solid conjugation between the thiol group of MUA and GNRs. The products were measured using the FTIR Spectrometer, and the spectra suggest MUA-PEI or PEI-MUA folate has successfully replaced CTAB on the surface of GNRs. Finally, GNRs-MUA PEI was incubated with siRNA-Cy3. The unbound siRNA-Cy3 was measured the intensity of fluorescence for calculating the uploaded amount of siRNA by GNRs MUA-PEI, and the results indicate that the uploaded percentage of siRNA is about 70%. We conclude that the GNRs-MUA-PEI system is an effective siRNA loading vehicle. PMID- 26578279 TI - An intelligent health monitoring system using radio-frequency identification technology. AB - Long-term care (LTC) for the elderly has become extremely important in recent years. It is necessary for the different physiological monitoring systems to be integrated on the same interface to help oversee and manage the elderly's needs. This paper presents a novel health monitoring system for LTC services using radio frequency identification (RFID) technology. Dual-band RFID protocols were included in the system, in which the high-frequency (HF) band of 13.56 MHz was used to identify individuals and the microwave band of 2.45 GHz was used to monitor physiological information. Distinct physiological data, including oxyhemoglobin saturation by pulse oximetry (SpO2), blood pressure, blood sugar, electrocardiogram (ECG) readings, body temperature, and respiration rate, were monitored by various biosensors. The intelligent RFID health monitoring system provided the features of the real-time acquisition of biomedical signals and the identification of personal information pertaining to the elderly and patients in nursing homes. PMID- 26578280 TI - Posterior dislocation of the hip with bilateral femoral fractures: An unusual combination. AB - Posterior hip dislocation with concomitant femoral fracture is very rare. Here, we report a rare case of a 43-year-old man who was injured in a car accident. The patient sustained right posterior hip dislocation with concomitant right acetabular transverse and posterior wall fracture, ipsilateral femoral shaft fracture, and contralateral proximal femoral fracture (AO type 31-A3). Closed reduction of the hip was attempted, but failed. The acetabular fracture and posterior hip dislocation were reduced and acetabular fracture was fixed using plates through the Kocher-Langenbeck approach. The ipsilateral femoral fracture was treated with closed reduction and intramedullary nailing. The contralateral femoral fracture was treated with closed reduction and Gamma 3 nailing. Postoperative X-rays revealed reduction of the fractures. The patient achieved bone union and recovered function of the hip 4 months after surgery. PMID- 26578281 TI - Malnutrition in geriatric trauma patients: Screening methods in comparison. AB - BACKGROUND: Malnutrition in geriatric patients is very common and an important outcome factor when treating injuries and fractures. There is actually no clear definition of the term malnutrition or recommendation for a screening method. OBJECTIVE: The purpose of this study was to determine the nutritional status of geriatric trauma patients using different screening procedures. We tested whether the body mass index (BMI) gives indication for malnutrition or if there is a correlation with more specific test procedures. METHODS: The BMI and the data of three specific screening procedures, Subjective Global Assessment (SGA), Nutritional Risk Screening (NRS) and Mini Nutritional Assessment (MNA) were calculated; clinical parameters were registered. RESULTS: There was proof of correlation (p< 0.001) between BMI and SGA; also between BMI and NRS was a significant correlation (p= 0.0004). There was less significant correlation between BMI and MNA (p= 0.05). All three screening methods correlated (p< 0.01). CONCLUSIONS: BMI and subjective statements provide first important information. The SGA not only correlates well with the BMI, but also complements the overall picture with individual information regarding medical history and clinical findings. Other more extensive methods, such as the NRS and the MNA, also show correlation and complement the overall picture with individual information. PMID- 26578282 TI - A mobile asset sharing policy for hospitals with real time locating systems. AB - BACKGROUND: Each year, hospitals lose a considerable amount of time and money due to misplaced mobile assets. In addition the assets which remain in departments that frequently use them depreciate early, while other assets of the same type in different departments are rarely used. A real time locating system can prevent these losses when used with appropriate asset sharing policies. OBJECTIVE: This research quantifies the amount of time a medium size hospital saves by using real time locating system and proposes an asset selection rule to eliminate the asset usage imbalance problem. METHODS: The asset selection rule proposed is based on multi objective optimization techniques. The effectiveness of this rule on asset to patient time and asset utilization rate variance performance measures were tested using discrete event simulation method. RESULTS: Results show that the proposed asset selection rule improved the usage balance significantly. Sensitivity analysis showed that the proposed rule is robust to changes in demand rates and user preferences. CONCLUSIONS: Real time locating systems enable saving considerable amount of time in hospitals, and they can still be improved by integrating decision support mechanisms. Combining tracking technology and asset selection rules helps improve healthcare services. PMID- 26578283 TI - Rehabilitation of the psychomotor consequences of falling in an elderly population: A pilot study to evaluate feasibility and tolerability of virtual reality training. AB - BACKGROUND: A fall in elderly subjects can lead to serious psychological consequences. These symptoms can develop into Fear of Falling with behavioural disorders comparable to PTSD that may severely limit autonomy. Virtual reality training (VRT) could be seen as a worthwhile therapeutic approach for this syndrome since it has been shown to be a useful tool for motor rehabilitation or combat-related PTSD. We thus developed a training scenario for VRT with psychomotor therapists. OBJECTIVE: To test the feasibility and acceptability of VRT when used by elderly adults for fall rehabilitation. METHODS: Our population of 8 patients older than 75 years, with a Mini Mental Score Examination greater than 18/30 performed sessions of VRT and answered a questionnaire on the feasibility and acceptability of it. RESULTS: This sample showed a highly favourable response to the prototype of VRT. They found it easy to use, enjoyed the experience, and thought it realistic and helpful. CONCLUSION: The conclusions of our study are limited by sample size. However, applications with VRT can offer the potential of an acceptable technique for elderly subjects. The next step will be to show the efficacy of this method in the management of post-fall PTSD. PMID- 26578284 TI - An experimental analysis of the strength of the taper joint. AB - BACKGROUND: The strength of the taper joint plays a vital role in orthopedics which takes the full load of our body. Till date various techniques has been used for the stem manufacturing and an alternative to all those has been presented in the article. OBJECTIVE: This Paper deals with the experimental analysis of the taper connection.The results of the experiment has also been validated during the experimentation process. METHODS: In case of our experimentation stems of taper joints were implemented in the hips. RESULTS: Microscopy based analysis revealed that there was almost no damage in the stems being developed during the process of experimentation. CONCLUSIONS: As a result it could be summarized that the stem developed during the experimental process were more reliable and free from any type of fretting. PMID- 26578285 TI - Internet based personalized feedback interventions for gamblers in Singapore: First results. AB - BACKGROUND: Problem or pathological gambling has been a worldwide concern in the recent years, especially so with the advances in the technology, facilitating easier access to various means of gambling. Along with the advances in web-based and smartphone technologies, these technologies have been recently applied as adjunctive clinical tools to help gamblers. Taking into careful consideration the existing evidence base for Internet based interventions for pathological gambling, it seemed that the current published literature has demonstrated largely the efficacy of a personalized feedback intervention for pathological gambling; and further studies are still under-going to try and demonstrate the clinical feasibility of online web-based cognitive behavioral interventions for pathological gamblers. OBJECTIVES: Given this, the aims of the current study are to (a) replicate an online personalized feedback intervention and determine its receptiveness in an Asian cohort of gamblers; and (b) to identify the demographics and characteristics of Asian gamblers who would utilize an online intervention. METHODOLOGY: The workgroup at the National Addiction Management Service, Singapore conceptualized the online personalized feedback intervention for gamblers. The English version was launched on the 31st of March 2014 and the Chinese version was launched on the 30th of September 2014. RESULTS: A cumulative total of 708 participants took part with rhe mean age of the participants being 32.70 (SD = 11.638), with 89.1% males and 10.9% females. The mean problem gambling severity score (PGSI) was 10.80 (SD = 8.13), with the vast majority participating in Casino gambling on board a cruise (36.0%). Of significance, approximately 59.2% of the participants who sought help with our online e intervention did have a diagnosis of problem gambling. CONCLUSIONS: This is one of the first few studies to demonstrate and replicate the potential use of an Internet based intervention for non-problem and problem gamblers. The current study has demonstrated that individuals are generally receptive towards such an intervention. PMID- 26578286 TI - The investigation of anti-inflammatory activity of volatile oil of Angelica sinensis by plasma metabolomics approach. AB - Angelica sinensis (AS) is an important medicinal plant, and volatile oil is the main pharmacologically active ingredient. This study was aimed to investigate the anti-inflammatory activity of the volatile oil of A. sinensis (VOAS) and explore its potential anti-inflammatory mechanism by plasma metabolomics approach. Rat acute inflammation was induced by subcutaneous injection of carrageenan in hind paws. Paw edema, histamine (HIS) and 5-hydroxytryptamine (5-HT) were detected. Then, we analyzed plasma metabolic profiling of acute inflammation and performed pathway analysis on the metabolite markers reversed after VOAS administration and further integration of metabolic networks. The results showed that VOAS could alleviate the paw edema and decrease plasma HIS and 5-HT levels. Fourteen metabolite markers of acute inflammation were screened, and the levels were all reversed to different degrees after VOAS administration. These metabolite markers mainly related to linoleic acid metabolism, ascorbate and aldarate metabolism, arachidonic acid metabolism, glyoxylate and dicarboxylate metabolism, and glycine, serine and threonine metabolism. In metabolic networks, glycine and arachidonic acid were node molecules. It indicated that VOAS could significantly inhibit systemic inflammatory response triggered by acute local stimulation and it exerted anti-inflammatory activity mainly through regulating the disturbed metabolic networks centered on glycine and arachidonic acid. PMID- 26578287 TI - Ultrawide electrical tuning of light matter interaction in a high electron mobility transistor structure. AB - The interaction between intersubband resonances (ISRs) and metamaterial microcavities constitutes a strongly coupled system where new resonances form that depend on the coupling strength. Here we present experimental evidence of strong coupling between the cavity resonance of a terahertz metamaterial and the ISR in a high electron mobility transistor (HEMT) structure. The device is electrically switched from an uncoupled to a strongly coupled regime by tuning the ISR with epitaxially grown transparent gate. The asymmetric potential in the HEMT structure enables ultrawide electrical tuning of ISR, which is an order of magnitude higher as compared to an equivalent square well. For a single heterojunction with a triangular confinement, we achieve an avoided splitting of 0.52 THz, which is a significant fraction of the bare intersubband resonance at 2 THz. PMID- 26578288 TI - The Emerging Neuroscience of Social Media. AB - Social media use is a global phenomenon, with almost two billion people worldwide regularly using these websites. As Internet access around the world increases, so will the number of social media users. Neuroscientists can capitalize on the ubiquity of social media use to gain novel insights about social cognitive processes and the neural systems that support them. This review outlines social motives that drive people to use social media, proposes neural systems supporting social media use, and describes approaches neuroscientists can use to conduct research with social media. We close by noting important directions and ethical considerations of future research with social media. PMID- 26578289 TI - Genomics, animal models, and emerging diseases: relevance to One Health and food security. PMID- 26578291 TI - Effects of humic acids derived from lignite and cattle manure on antioxidant enzymatic activities of barley root. AB - To investigate the effects of humic acids (HAs) on the ability of plants to defend themselves against oxidative stress, barley was hydroponically cultured in the absence and presence of HAs, and the antioxidant enzymatic activities (catalase, superoxide dismutase, ascorbate and glutathione peroxidases) of root tissue were evaluated. Auxin-like structures in HAs, which were extracted from an oxidation product of lignite (LHA) and compost derived from cattle manure (CHA), were identified by pyrolysis-gas chromatography/mass spectrometry (GC/MS) with tetramethylammonium hydroxide. The LHA, which had the lower molecular weight, was more effective in promoting the growth of barley root than CHA. However, the amounts of auxin-like structures in the CHA were much higher than those for LHA. The antioxidant enzymatic activities were initially decreased in the presence of LHA and CHA at the first day after refreshing the culture solution, but were significantly increased on the second day. The CHA sample, which contained relatively high levels of phenolic acids that contained auxin-like structures, was effective in increasing four types of enzymatic activities, while the activities of catalase and ascorbate peroxidase were increased in the presence of LHA, which contains naphthalene derivatives. These results indicate that using HAs as a supplement can be effective in enhancing antioxidation enzymatic activities, while the appearance of the effects is retarded because of the decomposition and release of auxin-like compounds from HAs by organic acids from the plant roots. PMID- 26578290 TI - Hospital-acquired Anemia in Critically Ill Dogs and Cats: A Multi-Institutional Study. AB - BACKGROUND: Hospital-acquired anemia is commonly described in people but limited information currently is available regarding its prevalence in animals. HYPOTHESIS/OBJECTIVES: Assess the prevalence of hospital-acquired anemia in hospitalized critically ill dogs and cats, and examine its relationship with phlebotomy practices, transfusion administration, and survival to discharge. ANIMALS: Eight hundred and fifty-one client-owned animals (688 dogs and 163 cats). METHODS: A multicenter, observational study was conducted in which packed cell volume (PCV) was recorded at the time of admission and on subsequent hospitalization days. Signalment, number of blood samples obtained, underlying disease, whether or not blood products were administered, duration of hospitalization, and survival to discharge were recorded. RESULTS: Admission anemia prevalence was 32%, with overall prevalence during the hospitalization period of 56%. The last recorded PCV was significantly lower than the admission PCV for both dogs (admission PCV, 42% [range, 6-67%]; last recorded PCV, 34% [range, 4-64%], P < .0001) and cats (admission PCV, 31% [range, 6-55%]; last recorded PCV, 26% [range, 10-46%], P < .0001). Patients that developed anemia had significantly more blood samples obtained (nonanemic, 5 blood samples [range, 2 54]; anemic, 7 blood samples [range, 2-49], P < .0001). Hospitalized cats were significantly more likely to develop anemia compared to dogs (P < .0001), but anemic dogs were significantly less likely to survive to discharge (P = .0001). Surgical patients were at higher risk of developing hospital-acquired anemia compared to medical patients (OR, 0.63; 95% CI, 0.4-0.9; P = .01). CONCLUSIONS AND CLINICAL RELEVANCE: Hospital-acquired anemia occurred frequently, especially in surgical patients. Additional studies focused on the direct effect of phlebotomy practices on the likelihood of anemia development in hospitalized animals are warranted. PMID- 26578292 TI - Chiral Nanostructures from Helical Copolymer-Metal Complexes: Tunable Cation-pi Interactions and Sergeants and Soldiers Effect. AB - Poly(phenylacetylene) (PPA) copolymers containing (R)- or (S)-MPA as minor chiral pendant can be forced to selectively adopt the right- o left-handed helix, in the presence of small amounts of Na(+) or Ag(+) ("Sergeants and Soldiers Effect") by addition of a donor cosolvent. The helical sense depends exclusively on the chiral monomer/donor cosolvent ratio, and this allows a perfect on/off tuning of the helicity of the copolymer. When the amount of the donor cosolvent is low, the metal ion complex is stabilized by a cation-pi interaction, which is selectively cleaved when the amount of cosolvent is higher. Macroscopically chiral nanospheres and nanotubes composed by helical copolymers with P or M helical sense are also described. Our results demonstrate that it is possible to obtain the two enantiomeric helical structures (P and M helicities) and the corresponding nanospheres and nanotubes from a single helical copolymer, by controlled activation/deactivation of the Sergeant and Soldiers Effect with a donor cosolvent. PMID- 26578294 TI - The use of a chemically defined artificial diet as a tool to study Aedes aegypti physiology. AB - Aedes aegypti mosquitoes obtain from vertebrate blood nutrients that are essential to oogenesis, such as proteins and lipids. As with all insects, mosquitoes do not synthesize cholesterol but take it from the diet. Here, we used a chemically defined artificial diet, hereafter referred to as Substitute Blood Meal (SBM), that was supplemented with cholesterol to test the nutritional role of cholesterol. SBM-fed and blood-fed mosquitoes were compared regarding several aspects of the insect physiology that are influenced by a blood meal, including egg laying, peritrophic matrix formation, gut microbiota proliferation, generation of reactive oxygen species (ROS) and expression of antioxidant genes, such as catalase and ferritin. Our results show that SBM induced a physiological response that was very similar to a regular blood meal. Depending on the nutritional life history of the mosquito since the larval stage, the presence of cholesterol in the diet increased egg development, suggesting that the teneral reserves of cholesterol in the newly hatched female are determinant of reproductive performance. We propose here the use of SBM as a tool to study other aspects of the physiology of mosquitoes, including their interaction with microbiota and pathogens. PMID- 26578293 TI - Chemical basis for the recognition of trimethyllysine by epigenetic reader proteins. AB - A large number of structurally diverse epigenetic reader proteins specifically recognize methylated lysine residues on histone proteins. Here we describe comparative thermodynamic, structural and computational studies on recognition of the positively charged natural trimethyllysine and its neutral analogues by reader proteins. This work provides experimental and theoretical evidence that reader proteins predominantly recognize trimethyllysine via a combination of favourable cation-pi interactions and the release of the high-energy water molecules that occupy the aromatic cage of reader proteins on the association with the trimethyllysine side chain. These results have implications in rational drug design by specifically targeting the aromatic cage of readers of trimethyllysine. PMID- 26578295 TI - Temporal variability of marine debris deposition at Tern Island in the Northwestern Hawaiian Islands. AB - A twenty-two year record of marine debris collected on Tern Island is used to characterize the temporal variability of debris deposition at a coral atoll in the Northwestern Hawaiian Islands. Debris deposition tends to be episodic, without a significant relationship to local forcing processes associated with winds, sea level, waves, and proximity to the Subtropical Convergence Zone. The General NOAA Operational Modeling Environment is used to estimate likely debris pathways for Tern Island. The majority of modeled arrivals come from the northeast following prevailing trade winds and surface currents, with trajectories indicating the importance of the convergence zone, or garbage patch, in the North Pacific High region. Although debris deposition does not generally exhibit a significant seasonal cycle, some debris types contain considerable 3 cycle/yr variability that is coherent with wind and surface pressure over a broad region north of Tern. PMID- 26578297 TI - Response of benthos to ocean outfall discharges: does a general pattern exist? AB - We assessed the effects of 40 ocean outfalls on adjacent macrobenthic invertebrates. Data were obtained from a review of gray and peer-review literature. Different parameters describing the outfall characteristics were compiled (length, maximum depth, treatment level, flow and organic matter mass discharged). Exposure to wave action was represented by significant wave height. The magnitude of the effect was categorized in three impact levels and classified considering different ecological indicators. A theoretical predictive model was formulated in which the lower the organic matter and the higher the energy of the system, the lower the benthic impact. The main conclusion was that the general pattern of the succession of benthic communities brought about by ocean outfalls fits the model of Pearson-Rosenberg but with some deviations i) the probability of a significant impact is much lower, ii) not all the successional stages occur and, iii) the magnitude of the changes are usually lower. PMID- 26578296 TI - Speciation and risk of heavy metals in sediments and human health implications of heavy metals in edible nekton in Beibu Gulf, China: A case study of Qinzhou Bay. AB - We investigated the total concentrations of heavy metals in surface sediments and nekton, along with sediment metal chemical partitioning in Qinzhou Bay of the Beibu Gulf. Cd was preferentially associated with the acid-soluble fraction and Pb mainly with the reducible fraction, whereas a major portion of Cr, Ni, Cu, and Zn was strongly associated with the residual fractions. A principal component analysis (PCA) in sediment metal speciation revealed three groupings (Cd; Pb; Cr, Ni, Cu, and Zn) that mainly resulted from different distributions of the metals in the various fractions. The Cr concentrations in nekton species were higher than maximum Cr concentrations permitted by the Chinese National Standard (GB 2762-2012). Taking as a whole, surface sediments of Qinzhou Bay had a 21% incidence calculation of adverse biological effects, based on the mean probable effects-levels quotient. A human health risk assessment indicated no significant adverse health effects from consumption of nekton. PMID- 26578298 TI - A novel preparation method of paclitaxcel-loaded folate-modified chitosan microparticles and in vitro evaluation. AB - A new chitosan microparticles loading paclitaxel (PTX) for application as an oral delivery system were developed using a novel double emulsion crosslinking method. To improve the targeted effect, folic acid (FA) was introduced onto the surface of microparticles using chemical method. The method was based on Schiff reaction between amino group of chitosan and carboxyl group of FA, and folate-chitosan (FA CS) conjugate was characterized using infrared spectrum analysis (FT-IR), and the microparticles were named as FA-CS-PTX/MPs. FA-CS-PTX/MPs had larger size of average diameter 223.6 nm, while PTX-loaded chitosan microparticles (CS-PTX/MPs) had 179.1 nm average diameter. The zeta potential of CS-PTX/MPs and FA-CS-PTX/MPs was 22.3 and 33.1 mV, respectively. SEM and TEM showed both the two microparticles had well-defined spherical structure. The in vitro drug release was studied under different pH conditions, and a two-phase kinetics model was found to be the most adequate kinetic model. Furthermore, the cytotoxicity activities of drug-carriers against L929 cells and the cellular uptake of PTX loaded microparticles against HepG2 cells were investigated. Results demonstrated that FA-CS-PTX/MPs might be a promising drug carrier for promoting PTX cellular uptake and could be used as a potential tumor-targeted drug vector. PMID- 26578299 TI - The protective role of isorhamnetin on human brain microvascular endothelial cells from cytotoxicity induced by methylglyoxal and oxygen-glucose deprivation. AB - As the first target of stroke, cerebral endothelial cells play a key role in brain vascular repair and maintenance, and their function is impeded in diabetes. Methylglyoxal (MGO), a reactive dicarbonyl produced during glucose metabolism, accumulates in diabetic patients. MGO and MGO-induced advanced glycation end products (AGEs) could ameliorate stroke-induced brain vascular damage, closely related with ECs dysfunction. Using MGO plus oxygen-glucose deprivation (OGD) to mimic diabetic stroke, we reported the protective effect of isorhamnetin on OGD induced cytotoxicity after MGO treatment on primary human brain microvascular endothelial cells (HBMEC) and explored the underlying mechanisms. Treatment of MGO for 24 h significantly enhanced 3-h OGD-induced HBMEC toxic effect, which was inhibited by pretreatment of isorhamnetin (100 MUmol/L). Moreover, the protective effect of isorhamnetin is multiple function dependent, which includes anti inflammation, anti-oxidative stress and anti-apoptosis effects. Besides its well known inhibition on the mitochondria-dependent or intrinsic apoptotic pathway, isorhamnetin also reduced activation of the extrinsic apoptotic pathway, as characterized by the decreased expression and activity of caspase 3 and caspase 8. Furthermore, pretreatment with isorhamnetin specifically inhibited FAS/FASL expression and suppressed nuclear factor-kappa B nuclear translocation. Taken together, our results indicated that isorhamnetin protected against OGD-induced cytotoxicity after MGO treatment in cultured HBMEC due to its multiple protective effects and could inhibit Fas-mediated extrinsic apoptosis. Therefore, isorhamnetin is a promising reagent for the treatment of hyperglycemia and ischemia-induced cerebral vascular degeneration. A proposed model of the potential protective mechanism of isorhamnetin, a metabolite of quercetin, on methylglyoxal (MGO) treatment plus oxygen-glucose deprivation (OGD) exposure induced cytotoxicity in cultured human brain microvascular endothelial cells. Isorhamnetin inhibits FasL-mediated extrinsic apoptosis and neurotrophic factor kappaB (NF-kappaB) nuclear translocation, which can induce the cell DNA damage. Therefore, the protective effect of isorhamnetin occurs through multiple functions, including anti-inflammation, anti-oxidative stress and anti-apoptosis. Therefore, isorhamnetin is a promising reagent for the treatment of hyperglycemia and ischemia-induced cerebral vascular degeneration. PMID- 26578300 TI - Facilitating tailored therapeutic strategies for glioblastoma through an orthotopic patient-derived xenograft platform. AB - Despite years of research into its pathobiology and continuing clinical trials for novel therapies, the prognosis for patients with glioblastoma (GBM) remains dismal. An important obstacle against treatment efficacy may be a high degree of intra- and inter-tumoral heterogeneity within GBMs, which may be caused by the presence of self-renewing GBM stem cells (GSCs). Recent advances in multi-omics technology introduce new possibilities for applying personalized strategies to GBM therapy. As drug discovery is accelerating with the transition from non selective, cytotoxic therapy to a precision, targeted approach, the appropriate in vivo platform for GBM is critical for validating drug targets and prioritizing candidates for clinical studies, for co-development of companion diagnostics and, ultimately, for drug approval. Here we will describe GBM orthotopic patient derived xenografts (PDXs) as more useful, clinically relevant resources for individually tailored strategies for GBM. PMID- 26578301 TI - Molecular identification of Histoplasma capsulatum using rolling circle amplification. AB - Histoplasmosis is a systemic fungal disease that occurs worldwide, causing symptomatic infection mostly in immunocompromised hosts. Etiological agent is the dimorphic fungus, Histoplasma capsulatum, which occurs in soil contaminated with bird or bat droppings. Major limitation in recognition of H. capsulatum infections is the low awareness, since other diseases may have similar symptomatology. The molecular methods have gained importance because of unambiguous diagnostic ability and efficiency. The aim of this study was to develop and evaluate a padlock probe in view of rolling circle amplification (RCA) detection method which targets ITS (Internal Transcribed Spacer) rDNA of H. capsulatum enabling rapid and specific detection of the fungus in clinical samples. Two padlock probes were designed and one of these (HcPL2) allowed specific amplification of H. capsulatum DNA while no cross-reactivity was observed with fungi used as negative controls. This method proved to be effective for H. capsulatum specific identification and demonstrated to be faster than the traditional method of microbiological identification. PMID- 26578303 TI - Real time dynamic MRI by exploiting spatial and temporal sparsity. AB - Online imaging requires that the reconstruction of current frame only depends on the previous frames, and real time imaging is the desired case. In this work, we propose a novel scheme for real time dynamic magnetic resonance imaging (dMRI) reconstruction. Different from previous methods, the reconstructions of the second frame to the last frame are independent in our scheme, which only require the first frame as the reference image. Therefore, this scheme can be naturally implemented in parallel. After the first frame is reconstructed, all the later frames can be processed as soon as the k-space data are acquired. As an extension of the conventional spatial total variation, a new online model called dynamic total variation is used to exploit the sparsity on both spatial and temporal domains in dMRI. In real time dMRI, each frame is required to be reconstructed very fast. We then design a novel reweighted least squares algorithm to solve the challenging problem. Motivated by the special structure of partial Fourier transform in sparse MRI, this algorithm is accelerated by the preconditioned conjugate gradient descent method. The proposed method is compared with 4 state of-the-art online and offline methods on two in-vivo cardiac dMRI datasets. The experimental results show that our method significantly outperforms previous online methods, and is comparable to the offline methods in terms of reconstruction accuracy. PMID- 26578304 TI - Total and intercondylar notch bone resection in posterior stabilized knee arthroplasty: analysis of five manufacturer designs. AB - PURPOSE: The study aimed to volumetrically measure and compare the bone amount removed through the intercondylar femoral notch and the total bone amount removed through five different brands of implant design in order to provide orthopaedic surgeons with opinions in respect of implant selection. METHODS: Ten implants from five different total knee arthroplasty implant manufacturers, namely Nex-Gen Legacy, Genesis 2 PS, Vanguard, Sigma PS and Scorpio NRG PS, were applied to a total of 50 sawbone models. Equal or the closest sizes of each brand on the anteroposterior plane were selected, and cuts were made following the standard technique. The removed bone pieces were measured in terms of volume and length in three planes, and were statistically analysed. RESULTS: The comparison made by excluding femoral notch cuts did not produce any statistically significant difference between the amounts of bone removed. The following data were volumetrically obtained from the intercondylar femoral notch cut: Vanguard (3.6 +/- 0.4 cm3), Nex-Gen (3.7 +/- 0.5 cm3), Sigma (5.7 +/- 0.4 cm3), Genesis 2 (6.3 +/- 0.3 cm3) and Scorpio NRG (6.7 +/- 0.7 cm3). There was no statistical difference between Genesis 2 and Scorpio NRG (n.s.), or between Nex-Gen and Vanguard (n.s.). The smallest volumetric value measured in the removed intercondylar femoral notch cut was obtained using Vanguard. CONCLUSION: There are significant differences between implant designs in terms of preserving bone stock, and a large proportion of the difference arises from the intercondylar femoral notch cut. PMID- 26578305 TI - Locking plate versus non-locking plate in open-wedge high tibial osteotomy: a meta-analysis. AB - PURPOSE: The purpose of this study was to conduct a meta-analysis to determine whether the locking plate or non-locking plate results in better opening-wedge high tibial osteotomy (OWHTO) outcomes. METHODS: The MEDLINE, EMBASE, COCHRANE, and KOREAMED register databases were searched for studies. The eligibility criteria for inclusion in the review were studies that compared the locking plate with the non-locking plate for OWHTO, and those that provided clear descriptions of surgical techniques and outcomes. The key outcomes of interest were union rate, correction loss angle, correction loss rate, and full weight-bearing starting point. The statistical software "RevMan" was used in statistical analysis. RESULTS: Five studies were included in the meta-analysis. Among their reported results, there were no differences in the incidence of union [risk ratio (RR) = 1.01, p = 0.34], non-locking plate was associated with lower incidence of correction maintenance (RR = 1.13, p = 0.0006) and greater angle of correction loss [mean difference (MD) = -2.06, p < 0.00001], and locking plate was associated with a significant improvement in Knee society score and function score (MD = 5.77, p < 0.0001; MD = 7.50, p = 0.0005). CONCLUSIONS: Locking plate provides better clinical outcomes and reduced correction loss rates and angles as compared to non-locking plate for fixation with OWHTO. LEVEL OF EVIDENCE: IV. PMID- 26578306 TI - Changes in femoral posterior condylar offset and knee flexion after PCL substituting total knee arthroplasty: comparison of anterior and posterior referencing systems. AB - PURPOSE: Anterior referencing and posterior referencing are two major techniques for positioning femoral components and balancing the sagittal plane during total knee arthroplasty (TKA). The purpose of this study was to evaluate the changes in medial and lateral posterior condylar offset (PCO) after bilateral TKA using anterior referencing (AR) or posterior referencing (PR) systems and compare the effect of the PCO changes on knee flexion. METHODS: Twenty female patients (mean age, 68.6 years) underwent bilateral TKA using the AR technique in one knee and the PR technique in the contralateral knee. Three-dimensional reconstructed computed tomographic images from the sagittal plane were used to evaluate PCO before and after arthroplasty. Knee Society scores and range of motion were evaluated postoperatively at a mean of 2.9 years. RESULTS: Postoperative medial and lateral PCOs were significantly greater (p < 0.001 and p = 0.048, respectively) in the AR group (30.9 +/- 2.2 and 29.1 +/- 1.5 mm, respectively) than those in the PR group (29.1 +/- 2.7 and 27.3 +/- 2.3 mm, respectively). In addition, the degree of change in the PCO after TKA was greater in the AR group than in the PR group. On the final follow-up, no differences in the degree of knee flexion were observed between the two groups (124.7 degrees for AR and 124.5 degrees for PR). Knee Society scores were similar in the two groups both preoperatively and postoperatively. On the final follow-up, individual changes in the medial and lateral PCO were not associated with changes in the knee flexion angle. CONCLUSIONS: Restoration of PCO after TKA was more accurate with the PR technique than with the AR technique. However, the postoperative differences in PCO showed no correlation with changes in knee flexion 2 years after PCL substituting TKA. LEVEL OF EVIDENCE: Therapeutic study, Level I. PMID- 26578307 TI - Physicians' attitudes toward home healthcare services in Turkey: A qualitative study. AB - BACKGROUND: Because of the growth of the older population and the prevalence of chronic diseases, home care services (HCS) have become an important aspect of healthcare worldwide. However, various difficulties and deficiencies are present in the provision of these recently implemented services in Turkey. Modifications to home healthcare services are in progress. OBJECTIVE: Physicians have an active role in home healthcare services. The present study was performed to examine physicians' attitudes toward this service in detail. METHODS: Twenty-six physicians who provide home healthcare services in the city of Ankara were included in the study. We conducted in-depth, semi-structured, face-to-face interviews. The interviews were audio-recorded, transcribed, and qualitatively analysed. RESULTS: Most physicians thought that home care could be provided to patients who are bedridden, are very old, have a chronic disease, have problems leaving the house, or do not have family support. They also expressed displeasure about the abuse of services and discordance of organization between hospitals and primary care centres. They noted that real circumstances in practice were not compatible with regulations and that cooperation and coordination between departments are necessary and important. CONCLUSION: The current study underlines physicians' interest in and support of the home care system, which has various drawbacks and limitations. Legislation needs to be further changed to improve the quality of service and eliminate deficiencies in home healthcare. PMID- 26578308 TI - Common beans and cowpeas as complementary foods to reduce environmental enteric dysfunction and stunting in Malawian children: study protocol for two randomized controlled trials. AB - BACKGROUND: Interventions to decrease the burden of childhood malnutrition are urgently needed, as millions of children die annually owing to undernutrition and hundreds of millions more are left cognitively and physically stunted. Environmental enteric dysfunction (EED), a pervasive chronic subclinical inflammatory condition among children that develops when complementary foods are introduced, places them at high risk of stunting, malabsorption, and poor oral vaccine efficacy. Improved interventions to reduce the burden of EED and stunting are expected to markedly improve the nutritional status and survival of children throughout resource-limited settings. METHODS/DESIGN: We will conduct, in parallel, two prospective randomized controlled clinical trials to determine whether common beans or cowpeas improve growth, ameliorate EED, and alter the intestinal microbiome during a high-risk period in the lives of rural Malawian children. Study 1 will enroll children at 6 months of age and randomize them to receive common beans, cowpeas, or a standard complementary food for 6 months. Anthropometry will be compared among the three groups; EED will be assessed using a dual-sugar absorption test and by quantifying human intestinal mRNA for inflammatory messages; and the intestinal microbiota will be characterized by deep sequencing of fecal DNA, to enumerate host microbial populations and their metabolic capacity. Study 2 will enroll children 12-23 months old and follow them for 12 months, with similar interventions and assessments as Study 1. DISCUSSION: By amalgamating the power of rigorous clinical trials and advanced biological analysis, we aim to elucidate the potential of two grain legumes to reduce stunting and EED in a high-risk population. Legumes have potential as an affordable and effective complementary food intervention, given their cultural acceptability, nutritional content, and agricultural feasibility in sub-Saharan Africa. TRIAL REGISTRATION: Clinicaltrials.gov NCT02472262 and NCT02472301 . PMID- 26578309 TI - The alignment of enzymatic steps reveals similar metabolic pathways and probable recruitment events in Gammaproteobacteria. AB - BACKGROUND: It is generally accepted that gene duplication followed by functional divergence is one of the main sources of metabolic diversity. In this regard, there is an increasing interest in the development of methods that allow the systematic identification of these evolutionary events in metabolism. Here, we used a method not based on biomolecular sequence analysis to compare and identify common and variable routes in the metabolism of 40 Gammaproteobacteria species. METHOD: The metabolic maps deposited in the KEGG database were transformed into linear Enzymatic Step Sequences (ESS) by using the breadth-first search algorithm. These ESS represent subsequent enzymes linked to each other, where their catalytic activities are encoded in the Enzyme Commission numbers. The ESS were compared in an all-against-all (pairwise comparisons) approach by using a dynamic programming algorithm, leaving only a set of significant pairs. RESULTS AND CONCLUSION: From these comparisons, we identified a set of functionally conserved enzymatic steps in different metabolic maps, in which cell wall components and fatty acid and lysine biosynthesis were included. In addition, we found that pathways associated with biosynthesis share a higher proportion of similar ESS than degradation pathways and secondary metabolism pathways. Also, maps associated with the metabolism of similar compounds contain a high proportion of similar ESS, such as those maps from nucleotide metabolism pathways, in particular the inosine monophosphate pathway. Furthermore, diverse ESS associated with the low part of the glycolysis pathway were identified as functionally similar to multiple metabolic pathways. In summary, our comparisons may help to identify similar reactions in different metabolic pathways and could reinforce the patchwork model in the evolution of metabolism in Gammaproteobacteria. PMID- 26578310 TI - The role of MCP-1-CCR2 ligand-receptor axis in chondrocyte degradation and disease progress in knee osteoarthritis. AB - BACKGROUND: Osteoarthritis (OA) is a common arthritic disease and multifactorial whole-joint disease. Interactions of chemokines and OA is inadequately documented. RESULTS: In vivo and in vitro studies were conducted to investigate monocyte chemoattractant protein 1 (MCP-1) and receptor chemokine (C-C motif) receptor 2 (CCR2) in chondrocyte degradation and cartilage degeneration. Chondrocytes from 16 OA patients and 6 normal controls were involved in this study. After stimulation of MCP-1, the expression of MCP-1 and CCR2 increased significantly (P < 0.001) and the expression of MMP-13 also increased (P < 0.05). MCP-1 stimulation also induced (or enhanced) the apoptosis of OA chondrocytes (P < 0.05). Additionally, the degradation of cartilage matrix markers (metalloproteinase 3 and 13, MMP3 and MMP13) in the culture medium of normal chondrocytes was also assessed. Furthermore, intra-articular injection of MCP-1 in mouse knees induced cartilage degradation and the CCR2 antagonist did not impede cartilage destroy in rats knees of monosodium iodoacetate (MIA) model. CONCLUSIONS: The results of this study demonstrate that the MCP-1-CCR2 ligand receptor axis plays a special role in the initiation and progression of OA pathology. Patients with ambiguous etiology can gain some insight from the MCP-1 CCR2 ligand-receptor axis. PMID- 26578311 TI - Opportunistic cutaneous fungal infections in the inpatient setting. PMID- 26578312 TI - The rate of adaptive evolution in animal mitochondria. AB - We have investigated whether there is adaptive evolution in mitochondrial DNA, using an extensive data set containing over 500 animal species from a wide range of taxonomic groups. We apply a variety of McDonald-Kreitman style methods to the data. We find that the evolution of mitochondrial DNA is dominated by slightly deleterious mutations, a finding which is supported by a number of previous studies. However, when we control for the presence of deleterious mutations using a new method, we find that mitochondria undergo a significant amount of adaptive evolution, with an estimated 26% (95% confidence intervals: 5.7-45%) of nonsynonymous substitutions fixed by adaptive evolution. We further find some weak evidence that the rate of adaptive evolution is correlated to synonymous diversity. We interpret this as evidence that at least some adaptive evolution is limited by the supply of mutations. PMID- 26578313 TI - Integrating mass spectrometry and genomics for cyanobacterial metabolite discovery. AB - Filamentous marine cyanobacteria produce bioactive natural products with both potential therapeutic value and capacity to be harmful to human health. Genome sequencing has revealed that cyanobacteria have the capacity to produce many more secondary metabolites than have been characterized. The biosynthetic pathways that encode cyanobacterial natural products are mostly uncharacterized, and lack of cyanobacterial genetic tools has largely prevented their heterologous expression. Hence, a combination of cutting edge and traditional techniques has been required to elucidate their secondary metabolite biosynthetic pathways. Here, we review the discovery and refined biochemical understanding of the olefin synthase and fatty acid ACP reductase/aldehyde deformylating oxygenase pathways to hydrocarbons, and the curacin A, jamaicamide A, lyngbyabellin, columbamide, and a trans-acyltransferase macrolactone pathway encoding phormidolide. We integrate into this discussion the use of genomics, mass spectrometric networking, biochemical characterization, and isolation and structure elucidation techniques. PMID- 26578314 TI - Analysing implementer narratives on addressing health inequity through convergent action on the social determinants of health in India. AB - BACKGROUND: Understanding health inequity in India is a challenge, given the complexity that characterise the lives of its residents. Interpreting constructive action to address health inequity in the country is rare, though much exhorted by the global research community. We critically analysed operational understandings of inequity embedded in convergent actions to address health-related inequalities by stakeholders in varying contexts within the country. METHODS: Two implementer groups were purposively chosen to reflect on their experiences addressing inequalities in health (and its determinants) in the public sector working in rural areas and in the private non-profit sector working in urban areas. A representing co-author from each group developed narratives around how they operationally defined, monitored, and addressed health inequality in their work. These narratives were content analysed by two other co-authors to draw out common and disparate themes characterising each action context, operational definitions, shifts and changes in strategies and definitions, and outcomes (both intended and unintended). Findings were reviewed by all authors to develop case studies. RESULTS: We theorised that action to address health inequality converges around a unifying theme or pivot, and developed a heuristic that describes the features of this convergence. In one case, the convergence was a single decision-making platform for deliberation around myriad village development issues, while in the other, convergence brought together communities, legal, police, and health system action around one salient health issue. One case emphasized demand generation, the other was focussed on improving quality and supply of services. In both cases, the operationalization of equity broke beyond a biomedical or clinical focus. Dearth of data meant that implementers exercised various strategies to gather it, and to develop interventions - always around a core issue or population. CONCLUSIONS: This exercise demonstrated the possibility of constructive engagement between implementers and researchers to understand and theorize action on health equity and the social determinants of health. This heuristic developed may be of use not just for further research, but also for on going appraisal and design of policy and praxis, both sensitive to and reflective of Indian concerns and understandings. PMID- 26578315 TI - The Preservation of Cued Recall in the Acute Mentally Fatigued State: A Randomised Crossover Study. AB - PURPOSE: The objective of this study is to investigate the impact of acute mental fatigue on the recall of clinical information in the non-sleep-deprived state. Acute mental fatigue in the non-sleep-deprived subject is rarely studied in the medical workforce. Patient handover has been highlighted as an area of high risk especially in fatigued subjects. This study evaluates the deterioration in recall of clinical information over 2 h with cognitively demanding work in non-sleep deprived subjects. METHOD: A randomised crossover study involving twenty medical students assessed free (presentation) and cued (MCQ) recall of clinical case histories at 0 and 2 h under low and high cognitive load using the N-Back task. Acute mental fatigue was assessed through the Visual Analogue Scale, Stanford Scale and NASA-TLX Mental Workload Rating Scale. RESULTS: Free recall is significantly impaired by increased cognitive load (p < 0.05) with subjects demonstrating perceived mental fatigue during the high cognitive load assessment. There was no significant difference in the amount of information retrieved by cued recall under high and low cognitive load conditions (p = 1). DISCUSSION: This study demonstrates the loss of clinical information over a short time period involving a mentally fatiguing, high cognitive load task. Free recall for the handover of clinical information is unreliable. Memory cues maintain recall of clinical information. This study provides evidence towards the requirement for standardisation of a structured patient handover. The use of memory cues (involving recognition memory and cued recall methodology) would be beneficial in a handover checklist to aid recall of clinical information and supports evidence for their adoption into clinical practice. PMID- 26578316 TI - Factors that Can Promote or Impede the Advancement of Women as Leaders in Surgery: Results from an International Survey. AB - BACKGROUND: Compared with male surgeons, women have less success advancing their careers and are underrepresented in leadership positions in surgery. The purpose of this study is to identify the qualifications necessary to become leaders in surgery and the career barriers faced by women surgeons in various cultural environments. METHODS: A survey was performed with women surgeons in Japan, USA, Finland, and Hong Kong, China, to assess various barriers faced by women surgeons in the respective countries. To develop appropriate survey tool, a preliminary questionnaire was distributed to leaders in surgery and also in various organizations worldwide. RESULTS: The response rate was 23 % with 225 of 964 survey returned. Japanese women surgeons identify lacked family support as impeding a successful surgical career. US women surgeons feel more latent gender discrimination. Finnish women surgeons are less likely to need to sacrifice work life balance, when holding leadership positions. Women surgeons worldwide are highly motivated to develop their career and agree the percentage of women surgeons in leadership positions should be increased. CONCLUSIONS: Women surgeons in different countries perceive different challenges. We must develop strategies and should not hesitate to negotiate to overcome these issues to reach leadership positions in surgery. This may be accomplished through networking worldwide to improve current conditions and obstacles. PMID- 26578317 TI - The Role of Magnesium in Post-thyroidectomy Hypocalcemia. AB - BACKGROUND: The purpose of this study was to determine the prevalence of hypomagnesemia in patients undergoing thyroidectomy and evaluate the relationship of hypomagnesemia with transient and severe hypocalcemia. MATERIALS AND METHODS: This was a prospective observational study of 50 patients undergoing thyroidectomy. Blood samples were collected pre- and postoperatively for calcium, albumin, magnesium, phosphorous and parathormone (PTH). Signs, symptoms of hypocalcemia and volume of intravenous fluids used perioperatively were documented. The statistical analysis was performed using STATA I/C 10.1. RESULTS: Preoperatively, twelve patients (24 %) had hypomagnesemia and one (2 %) hypocalcemia. On the first postoperative day, hypomagnesemia was seen in 70 % and hypocalcemia in 30 %. A similar trend was observed in the fall and rise of postoperative calcium and magnesium values (p = 0.41). Severe hypocalcemia was present in three patients (6 %). All three patients had a very low postoperative PTH (<2 pg/ml). Among them, two patients (66 %) had hypomagnesemia and their hypocalcemia responded to intravenous magnesium correction. Significant risk factors for postoperative hypocalcemia include a higher volume of fluid used perioperatively and low postoperative PTH (<8 pg/ml) (p = 0.01 and 0.03, respectively). CONCLUSION: Preoperative hypomagnesemia (24 %) was prevalent in this cohort of patients. Postoperative hypomagnesemia is a common event (70 %) following total thyroidectomy, and magnesium levels tend to mimic the calcium levels postoperatively. The cause of hypocalcemia post-thyroidectomy in this study is mainly a factor of parathyroid function and fluid status. Severe hypocalcemia is a rare event, and hypomagnesemia is associated in the majority of these patients. The role of magnesium correction to alleviate severe hypocalcemia needs to be further studied. PMID- 26578318 TI - Effect of Glyceryl Trinitrate Ointment on Pain Control After Hemorrhoidectomy: A Meta-analysis of Randomized Controlled Trials. AB - BACKGROUND: Hemorrhoidectomy is associated with postoperative pain and prolonged wound healing. Glyceryl trinitrate has been shown to decrease muscle spasm and increase anodermal blood flow. A meta-analysis of randomized controlled trials was conducted to evaluate the efficacy of topical glyceryl trinitrate application in pain relief after hemorrhoidectomy. METHODS: PubMed, EMBASE, Cochrane Library, Scopus, and ClinicalTrials.gov registries were searched for studies published before August 2015. Individual effect sizes were standardized, and a meta analysis was conducted to calculate a pooled effect size using random effects models. Pain was assessed using a visual analog scale on days 1, 3, 7, and 14 after operation. Secondary outcomes included time taken to resume routine activities, wound healing at 3 weeks after operation, complication, and headache incidence. RESULTS: A total of 12 trials with 1095 patients were reviewed. Significant pain reduction was observed on days 1, 3, 7, and 14 after hemorrhoidectomy in the glyceryl trinitrate groups. Glyceryl trinitrate-treated patients appeared to resume routine activities earlier than those in the control group (weight mean difference -7.52; 95% confidence interval: 16.13-1.08). The wound healing rates 3 weeks after operation were significant higher in the glyceryl trinitrate-treated groups than in the control group (risk ratio 1.79; 95% confidence interval: 1.38-2.33). However, the incidence of headache significantly increased in the glyceryl trinitrate group (risk ratio 3.68; 95% confidence interval: 1.62-8.34). CONCLUSION: Topical application of glyceryl trinitrate effectively relieves pain and promotes wound healing after hemorrhoidectomy; however, the substantial headache incidence may limit extensive application. PMID- 26578319 TI - The Sternocleidomastoid Muscle Flap: A Versatile Local Method for Repair of External Penetrating Injuries of Hypopharyngeal-Cervical Esophageal Funnel. AB - INTRODUCTION: A primary repair of external penetrating injury to hypopharyngeal cervical esophageal (HP-CE) funnel without reinforcement has more complications if compared with muscle reinforcement. The aim of the present study was to assess the outcome of using sternocleidomastoid (SCM) muscle flap for reinforcement of primary repair of HP-CE funnel injury. The study proposed an algorithm for different uses of SCM flap repair according to site and size of funnel perforation. PATIENTS AND METHODS: A prospective analysis of 12 patients, who had surgical treatment for external penetrating injuries of HP-CE funnel between January 2011 and September 2014, was recorded. The following factors were studied for each case: demographic data, Revised Trauma Score (RTS), mechanism of injury, time interval between injury and definitive surgical care, injury morphology, any associated injuries, technique of SCM flap used, length of hospital stay, and surgical outcome and complications. RESULTS: They were 10 males and 2 females and the mean age was 31.9 years. The cause of injury was stab wound in 5 (41.7 %) cases, gunshot injury in 4 (33.3 %) cases and 3 (25 %) cases after anterior cervical spine surgery. Isolated injury to HP and CE was recorded in 5 cases (41.7 %) for each site. However, 2 (16.7 %) cases had injury to both HP and CE. Cranially based SCM flap was mainly used in cases with HP injury and caudally based flap in CE cases with some limitations. The whole muscle flap was used in large (>= 1 cm) defects while and the split muscle flap in small (<1 cm) defects. Oral intake started 7 days postoperatively with only one (8.3 %) case of small leakage, which was treated conservatively. CONCLUSION: The SCM flap is a very useful and versatile tool in reinforcement of HP-CE funnel injury with the advantages of high success rates of leakage prevention. PMID- 26578320 TI - Prevalence of Inguinal Hernia in Adult Men in the Ashanti Region of Ghana. AB - BACKGROUND: Inguinal hernia is thought to be common in rural Ghana, though no recent data exist on hernia prevalence in the country. This information is needed to guide policy and increase access to safe hernia repair in Ghana and other low resource settings. METHODS: Adult men randomly selected from the Barekese sub district of Ashanti Region, Ghana were examined by surgeons for the presence of inguinal hernia. Men with hernia completed a survey on demographics, knowledge of the disease, and barriers to surgical treatment. RESULTS: A total of 803 participants were examined, while 105 participants completed the survey. The prevalence of inguinal hernia was 10.8 % (95 % CI 8.0, 13.6 %), and 2.2 % (95 % CI 0, 5.4 %) of participants had scars indicative of previous repair, making the overall prevalence of treated and untreated inguinal hernia 13.0 % (95 % CI 10.2, 15.7 %). Prevalence of inguinal hernia increased with age; 35.4 % (95 % CI 23.6, 47.2 %) of men aged 65 and older had inguinal hernia. Untreated inguinal hernia was associated with lower socio-economic status. Of those with inguinal hernia, 52.4 % did not know the cause of hernia. The most common reason cited for failing to seek medical care was cost (48.2 %). CONCLUSION: Although inguinal hernia is common among adult men living in rural Ghana, surgical repair rates are low. We propose a multi-faceted public health campaign aimed at increasing access to safe hernia repair in Ghana. This approach includes a training program of non-surgeons in inguinal hernia repair headed by the Ghana Hernia Society and could be adapted for use in other low-resource settings. PMID- 26578321 TI - Presentation and Outcomes After Surgery for Primary Hyperparathyroidism During an 18-Year Period. AB - PURPOSE: The objective of this study is to analyze whether the trend towards operating on patients with less severe primary hyperparathyroidism (pHPT) than earlier is reflected in a change of preoperative presentation and surgical outcome. METHODS: In this longitudinal cohort study, patients with pHPT subjected to first time surgery were compared in three time periods: 1989-1994, 1995-2000, and 2001-2006 in this longitudinal cohort study. RESULTS: There were 404 patients. Median levels of preoperative ionized calcium were lower in 2001-2006 compared to 1989-1994; 1.45 versus 1.50 versus 1.45 mmol/L; p < 0.001. Preoperative parathyroid hormone levels in patients with parathyroid adenoma were lower in 2001-2006 than in 1989-1994; 10.0 versus 11.6 pmol/L; p 0.04. Median preoperative bone mineral density, BMD, in the whole cohort did not differ between time periods. Median pre- and postoperative glomeruli filtration rate, GFR, and 25-hydroxy-vitamin D3 remained unchanged between period 1 and period 3. Adenoma weight was lower in 2001-2006 than 1989-1994; 0.70 versus 0.50 g; p 0.04. Cure rate did not change during observation time. There was no evidence for differences in change of BMD (femoral neck) after surgery between period 2 and 3 1995-2000 and 2001-2006, 0.798 versus 0.795 g/cm(2); p 0.67. GFR did not change significantly between 1989-1994 and 2001-2006, 74 versus 77 mL/min; p 0.43. CONCLUSIONS: A significant change towards operating patients with smaller adenomas and lower preoperative calcium levels was evident throughout the observation period, but this did not correlate with differences in preoperative renal or skeletal function. We found no evidence for a change of postoperative renal function or skeletal function during observation time. PMID- 26578322 TI - The Effectiveness of Radioactive Iodine Remnant Ablation for Papillary Thyroid Microcarcinoma: A Systematic Review and Meta-analysis. AB - BACKGROUND: This systematic review and meta-analysis aimed to evaluate the effectiveness of radioactive iodine (RAI) remnant ablation for thyroid cancer related outcomes of patients with papillary thyroid microcarcinoma (PTMC). METHODS: A systematic literature search of PubMed, EMBASE OvidSP, and EBSCO was conducted. Studies were selected that provided multivariable analysis of the effectiveness of RAI ablation or provided specific data of a 10 years history of thyroid cancer-related outcomes in patients that presented with PTMC. RESULTS: Nineteen studies met the inclusion criteria. A multivariable analysis of the effectiveness of RAI ablation for any recurrence or thyroid cancer-related mortality in patients with PTMC was performed in several studies, among which only one study reported a positive result. Furthermore, for PTMC patients treated by total or near-total thyroidectomy (TT/NT), with or without RAI ablative therapy, the meta-analysis suggested that RAI ablation did not decrease the 10 years history of any tumor recurrence (relative risk [RR] 0.96; 95% confidence interval [CI] 0.63-1.48; P = 0.87), locoregional recurrence (RR 1.15; 95% CI 0.75 1.76; P = 0.51), distant metastases (RR 0.32; 95% CI 0.08-1.32; P = 0.11) or thyroid cancer-related mortality (RR 0.76; 95% CI 0.22-2.63; P = 0.66). CONCLUSIONS: With regard to multivariable analyses, there was almost no positive treatment effect of RAI ablation noted for patients with PTMC. For PTMC patients already treated by TT/NT, incremental RAI ablation may not be beneficial at decreasing the 10 years recurrence of PTMC or incidence of thyroid cancer-related mortality. PMID- 26578324 TI - Clinical potential of electroporation for gene therapy and DNA vaccine delivery. AB - INTRODUCTION: Electroporation allows efficient delivery of DNA into cells and tissues, thereby improving the expression of therapeutic or immunogenic proteins that are encoded by plasmid DNA. This simple and versatile method holds a great potential and could address unmet medical needs such as the prevention or treatment of many cancers or infectious diseases. AREAS COVERED: This review explores the electroporation mechanism and the parameters affecting its efficacy. An analysis of past and current clinical trials focused on DNA electroporation is presented. The pathologies addressed, the protocol used, the treatment outcome and the tolerability are highlighted. In addition, several of the possible optimization strategies for improving patient compliance and therapeutic efficacy are discussed such as plasmid design, use of genetic adjuvants for DNA vaccines, choice of appropriate delivery site and electrodes as well as pulse parameters. EXPERT OPINION: The growing number of clinical trials and the results already available underline the strong potential of DNA electroporation which combines both safety and efficiency. Nevertheless, it remains critical to further increase fundamental knowledge to refine future strategies, to develop concerted and common DNA electroporation protocols and to continue exploring new electroporation-based therapeutic options. PMID- 26578323 TI - Co-ultramicronized Palmitoylethanolamide/Luteolin Promotes the Maturation of Oligodendrocyte Precursor Cells. AB - Oligodendrocytes have limited ability to repair the damage to themselves or to other nerve cells, as seen in demyelinating diseases like multiple sclerosis. An important strategy may be to replace the lost oligodendrocytes and/or promote the maturation of undifferentiated oligodendrocyte precursor cells (OPCs). Recent studies show that a composite of co-ultramicronized N-palmitoylethanolamine (PEA) and luteolin (co-ultramicronized PEA/luteolin, 10:1 by mass) is efficacious in improving outcome in experimental models of spinal cord and traumatic brain injuries. Here, we examined the ability of co-ultramicronized PEA/luteolin to promote progression of OPCs into a more differentiated phenotype. OPCs derived from newborn rat cortex were placed in culture and treated the following day with 10 MUM co-ultramicronized PEA/luteolin. Cells were collected 1, 4 and 8 days later and analyzed for expression of myelin basic protein (MBP). qPCR and Western blot analyses revealed a time-dependent increase in expression of both mRNA for MBP and MBP content, along with an increased expression of genes involved in lipid biogenesis. Ultramicronized PEA or luteolin, either singly or in simple combination, were ineffective. Further, co-ultramicronized PEA/luteolin promoted morphological development of OPCs and total protein content without affecting proliferation. Co-ultramicronized PEA/luteolin may represent a novel pharmacological strategy to promote OPC maturation. PMID- 26578325 TI - 1,2,3-Triazole pharmacophore-based benzofused nitrogen/sulfur heterocycles with potential anti-Moraxella catarrhalis activity. AB - Versatile 1,2,3-triazole pharmacophore-based benzofused heterocycles containing halogen-substituted aromatic (9-17 and 25-28), 7-substituted coumarin (18-23 and 29-30) or penciclovir-like subunit (31a,b-38a) were designed and synthesized to evaluate their antibacterial activities against selected Gram-positive and Gram negative bacteria. Hybridization approach using environmentally friendly Cu(I) catalyzed click reaction under microwave irradiation was adopted in the synthesis of regioselective 1,4-disubstituted 1,2,3-triazole tethered heterocycles (9-23 and 25-30), while post-N-alkylation of NH-1,2,3-triazoles afforded both 2,4- (31a 38a) and 1,4-disubstituted (31b-33b, 35b-37b) 1,2,3-triazole regioisomers. The compounds 18-23 and 25-30 revealed fluorescence in the violet region of the visible spectrum with a strong influence of phenyl spacer in 25-30 on both wavelength and emission intensity. Fusion of selected subunits led to new hybrid architecture, benzothiazole-1,2,3-triazole-coumarin 29 that demonstrated extremely narrow spectrum activity towards fastidious Gram-negative bacteria Moraxella catarrhalis. Selected hybrid showed the potency against Moraxella catarrhalis (MIC?0.25MUg/mL) comparable to that of reference antibiotic azithromycin, which suggested that further investigations are necessary to optimize this potential hit compound as a new anti-Moraxella catarrhalis agent. PMID- 26578327 TI - [The recertification on the way]. PMID- 26578326 TI - A qualitative process evaluation of a randomised controlled trial of a parenting intervention in community (school) settings for children at risk of attention deficit hyperactivity disorder (ADHD). AB - BACKGROUND: Interventions for parents of children experiencing emotional and/or behavioural difficulties can help to improve their children's health, educational and social outcomes. However, the desirability and acceptability of screening and offering such interventions for attention-deficit hyperactivity disorder (ADHD) type problems are currently unclear. This article is a qualitative process evaluation of a pragmatic cluster randomised controlled trial (Trial registration: ISRCTN87634685; reported elsewhere) to assess the feasibility and acceptability of a school-based parenting intervention programme for parents and teachers of children with high levels of ADHD symptoms. METHODS: Parents (n = 22) and teaching staff (n = 29) took part in semi-structured group or individual interviews, either by telephone or face-to-face, following the main trial. Interviews were digitally-recorded, transcribed verbatim and subjected to thematic analysis. RESULTS: The parenting intervention was acceptable to parents and teachers, and they were enthusiastic about the need for parenting groups in the school environment and stressed the importance of parent-school collaboration. Parents generally stated a preference for universal recruitment approaches to such programmes whilst teachers described the need to target specific parents. Most parents who took part in the parenting intervention described it favourably and many saw benefits, at least in the short-term. Parents differed in their preferred group size, with some desiring one-to-one sessions and others favouring a larger group. Non-attending parents reported barriers to attendance such as fear of attending in a group, previous use of the programme, work and other commitments. Suggestions to improve the programme included: clearer communication; offering booster sessions; and greater collaboration with teachers. CONCLUSIONS: It is feasible to deliver parenting intervention programmes within or near schools. The intervention was acceptable to the majority of parents, thus retention was high, but recruitment was difficult and reaching the parents with the most need was challenging. The findings of the process evaluation identified greater benefits to families than were apparent in the main trial. Recommendations identified by parents and teaching staff may be used to inform service delivery and future research to enhance recruitment to parenting interventions in the school environment. PMID- 26578328 TI - [Adoption by same-sex couples in Colombia]. PMID- 26578329 TI - [Differential effects of attention deficit/hyperactivity disorder subtypes in event-related potentials]. AB - BACKGROUND: To better understand the neurophysiological substrates in attention deficit/hyperactivity disorder (ADHD), a study was performed on of event-related potentials (ERPs) in Colombian patients with inattentive and combined ADHD. METHODS: A case-control, cross-sectional study was designed. The sample was composed of 180 subjects between 5 and 15 years of age (mean, 9.25+/-2.6), from local schools in Manizales. The sample was divided equally in ADHD or control groups and the subjects were paired by age and gender. The diagnosis was made using the DSM-IV-TR criteria, the Conners and WISC-III test, a psychiatric interview (MINIKID), and a medical evaluation. ERPs were recorded in a visual and auditory passive oddball paradigm. Latency and amplitude of N100, N200 and P300 components for common and rare stimuli were used for statistical comparisons. RESULTS: ADHD subjects show differences in the N200 amplitude and P300 latency in the auditory task. The N200 amplitude was reduced in response to visual stimuli. ADHD subjects with combined symptoms show a delayed P300 in response to auditory stimuli, whereas inattentive subjects exhibited differences in the amplitude of N100 and N200. Combined ADHD patients showed longer N100 latency and smaller N200 P300 amplitude compared to inattentive ADHD subjects. CONCLUSIONS: The results show differences in the event-related potentials between combined and inattentive ADHD subjects. PMID- 26578330 TI - [Validity and Reliability of the Attitudes Toward Sexuality in the Elderly Questionnaire in Cartagena, Colombia]. AB - BACKGROUND: There are many stereotypes and prejudices about the sexual lives of the elderly. However, there are no validated and reliable tools for measuring these in the Latin-American context. OBJECTIVE: To determine the internal consistency, dimensionality, differential item functioning (DIF) by gender and stability of the Attitudes towards Sexuality in the Elderly Questionnaire (ASEQ) in adults over 60 years-old in Cartagena, Colombia. METHOD: A validation study was designed that included a sample of 130 participants without cognitive impairment attending a Life Center. The ages ranged between 60 and 90 years (mean, 73.7+/-8.0), and there were 61.5% females. Internal consistency was calculated using Cronbach alpha and McDonald omega, exploratory factor analysis (EFA) (dimensionality), DIF by gender (item response theory) with Kendall correlation, and stability (reproducibility) with Pearson correlation and intraclass correlation coefficient (ICC). RESULTS: The ASEQ showed high internal consistency on the first application (alpha=.83 and omega=.87) and in the second one (alpha=.85 and omega=.89). AFE showed two salient factors (prejudices and limitations) that explained 42.6% of the total variance. The IDF presented appropriate coefficients, with the exception of item 14 that showed a high value (tau=.37). ASEQ showed high stability (r=.82 and ICC=.89; 95% confidence interval, 0.83- 0.92; P<.001). CONCLUSIONS: ASEQ is a two-dimensional and reliable scale in older adults attending a Life Center in Cartagena, Colombia. New studies are required to evaluate the performance in a representative sample. PMID- 26578331 TI - [Trends in the consumption of anxiolytic and hypnotic drugs in a Colombian population]. AB - INTRODUCTION: In Latin America, psychotropic medications are the third most marketed drug group, especially antidepressants (35%) and anxiolytics (5%). The objective of this study was to determine the trends in the consumption and the costs of anxiolytic and hypnotic drugs in a population of patients enrolled in the Health System of Colombia. MATERIAL AND METHODS: A descriptive, observational study was performed using the data recorded inprescriptions for any anxiolytic or hypnotic drug prescribed to outpatients in the period between January 2008 and December 2013 in a population of 3.5 million people. Sociodemographic, pharmacological variables, overall costs, and cost per thousand inhabitants per day (CHD), were also recorded. RESULTS: The number of patients who received the drugs studied varied from 11,097 to 19,231 between 2008 and 2013. The most used drugs were clonazepam (44.1% of formulations), alprazolam (31.2%), and lorazepam (13.2%). The invoiced value of anxiolytics increased from US$ 207,673.63 in 2008 to US$ 488,977 in 2013, an increase of 135.4%. The CHD was US$ 0.31 for benzodiazepines, and US$ 0.02 for zaleplon, zolpidem and zopiclone (Z drugs) for 2008, and US$ 0.36 and US$ 0.02 in 2013 respectively. The CHD declined after 2010 following the introduction of generic drugs. CONCLUSIONS: Patients receiving benzodiazepines in Colombia are mostly women, average age 55 years, with very low frequency in defined daily doses per thousand inhabitants when compared with other countries. PMID- 26578332 TI - [Suicidal ideation and associated factors in inmates of a prison of Antioquia, Colombia]. AB - INTRODUCTION: Suicidal behavior shows high numbers in prison population; hence, the following research was developed, which aimed to identify the sociodemographic, family, personal and imprisonment factors that are associated with suicidal ideation in inmates of a prison of Antioquia, Colombia. MATERIAL AND METHODS: A cross descriptive study was carried out. It was applied the Suicide Orientation Inventory Test ISO-30, as well as a survey, in order to investigate sociodemographic, family and imprisonment aspects of a group of 154 inmates. Univariate and bivariate analysis were applied to the collected data by using Excel and OpenEpi programs. RESULTS: 14.9% had high suicidal ideation. By analyzing the distribution of high suicidal ideation in the variables studied, it was found that the highest rates occurred in those who had previous attempts, 61.1%; a history of domestic violence, 50.0%; no schooling, 33.3%; those with a family history of suicide, 28.6%; and those without a definite sentence 22.9%. A significant association was found between the ideation and having committed previous suicide attempts (P<.01; rp=7.4), belonging to households with domestic violence (P=.03; rp=4.0), being single (P=.04; rp=2.2) and being under 30 years old (P=.04; rp=2.1). CONCLUSIONS: The high suicidal rates are much greater than those found in the general population; it is therefore recommended to the professionals of the institution to address the risk factors found here, in order to develop prevention and intervention programs. PMID- 26578333 TI - [Men caretakers of life: Training in gender-sensitive masculinities for the prevention of violence towards women in Medellin]. AB - The training strategies targeted at men so as to reflect on the cultural patterns of patriarchy are an alternative in the promotion of human rights, the prevention of violence towards women and the mainstreaming of gender equality in public policies. With a socio-critical pedagogical approach, we conducted a Training Certification Program in gender equality and gender-sensitive masculinities, for a group of 76 male civil servants and civic leaders in the Colombian city of Medellin, for the purpose of questioning their gender socialization in the patriarchal model, directed towards the development and execution of social, educational or communications projects. The projects proposed by the participants criticize the andro-centric, sexist and discriminatory discourses regarding women that circulate in a manner predominant in their academic, workplace and family ambits, with a gender political commitment and respect for diversity. PMID- 26578334 TI - [Sociodemographic characteristics and mental disorders in children and adolescents psychiatric outpatient clinic children of Medellin]. AB - INTRODUCTION: Mental disorders in the world affecting 15% to 30% in children and adolescents, altering its function and emotional, cognitive and social. Affect interpersonal relationships, school performance and increased substance use and the risk of suicide. OBJECTIVE: describe the social-demographic characteristics and mental disorders of children and adolescents of psychiatric consultation. METHOD: Retrospective descriptive study that analyzed all the histories of children and adolescents of both sexes from 5 to 16 years who attended for the first time outpatient psychiatry university clinic of Medellin, from July 2010 to July 2012. RESULTS: We studied 197 patients, the average age was 11+/-3.5 years, male sex was the most common 69%, 46.2% belonged to nuclear family. The most prevalent psychiatric disorders were 44.2% ADHD, depressive disorders 9.1% and 8.1% TOC. 61% had psychiatric comorbidity, the most frequent was oppositional defiant disorder with ADHD 35.6%. CONCLUSIONS: The frequency of mental disorders and comorbidities found in this study were similar to those reported by other researchers. PMID- 26578335 TI - [Affective syndromes in liver transplant recipients: ?mediated neurotoxicity immunosuppressive?]. AB - INTRODUCTION: The onset of affective and psychotic in liver transplant patients symptoms, raises the need to explore the possible etiologies of mental symptoms. METHODOLOGY: Case report and literature review. RESULTS: Four clinical cases of patients undergoing orthotopic liver transplantation, who in the early post transplant showed affective symptoms, delusions and psychomotor agitation for which they needed psychiatric hospitalization and treatment with psychotropic drugs are presented. Three of the patients had clinical improvement and one patient died by suicide. DISCUSSION: The development of mental symptoms in the post-transplant period opens the possibility of considering the secondary organic mental disorder a basic condition. CONCLUSIONS: The adverse drug reaction may explain affective mental disorders in these four cases were reported. PMID- 26578336 TI - Development of an intraoral device for social inclusion of a physically disabled patient. AB - The aim of this study is to describe the use of an intraoral assistive technology for a patient with idiopathic generalized muscular dystonia, presenting temporomandibular disorder and severe anterior tooth mobility and diastema. A multidisciplinary team developed an intraoral device to provide typing and painting functions, and promote relaxation of masticatory muscles without compromising the teeth and supporting tissue structures. The occlusal splint associated with the device promoted muscle relaxation and relief of the signs and symptoms of temporomandibular dysfunction, in this case with generalized muscle dystonia, allowing typing and painting with her mouth without causing tooth mobility or occlusal alteration. This intraoral device has low cost, easy adaptation and was efficient in TMD symptoms. Furthermore, the patient returned to her rehabilitation allowing performance of her duties without compromising dental structures, facilitating the social and the digital inclusion. PMID- 26578337 TI - A retrospective cohort study on fertility in the Norwegian Coldblooded trotter after artificial insemination with cooled, shipped versus fresh extended semen. AB - BACKGROUND: Pregnancy rates with cooled equine semen can be unsatisfactory and show great variation. Information about first cycle pregnancy rates and pregnancy rates per cycle are often lacking from publicly available records. This retrospective cohort study was performed to evaluate the fertility of the Norwegian Coldblooded trotter. The aim of the study was to compare the breeding results after insemination with fresh, extended with those of cooled, shipped semen among Norwegian Coldblooded trotter mares. First cycle pregnancy rate was the main parameter used to measure fertility. Stud-books were collected from four studs from the years 2006-2010. Statistical analyses were done in Stata using Chi square test and multivariable analyses where different models were compared based on Akaike's information criterion. RESULTS: First cycle pregnancy rate, seasonal pregnancy rate and foaling rate all showed significant differences (P < 0.0001) when comparing mares inseminated at stud with mares inseminated with cooled, shipped semen, favoring artificial insemination (AI) at stud. First cycle pregnancy rate was 55.1 % for mares inseminated at stud with fresh extended semen and 42.2 % for mares inseminated with cooled shipped semen. The overall pregnancy rate per cycle was 84.4 % for AI at stud and 66.9 % for cooled, shipped semen. The parameters stud, mare age, number of inseminations within an estrus cycle and individual stallion were also investigated for influence on fertility. CONCLUSIONS: Few retrospective studies include the parameter of first cycle pregnancy rates. Our study does not differ dramatically when comparing seasonal pregnancy rates and foaling rates with similar studies. Fertility parameters for the Norwegian Coldblooded trotter do not differ significantly from most other studies of Coldblooded mares and other mare breeds around the world. But the difference in fertility parameters between AI at stud to AI with cooled semen between our study and others, indicates that higher pregnancy rates in Norwegian Coldblooded trotter may be possible. PMID- 26578338 TI - Human leucocyte antigen alloimmunisation in repeatedly transfused thalassemic Egyptian children and its relation to febrile non-haemolytic transfusion reactions. AB - OBJECTIVES: To document the incidence of lymphocytotoxic antibodies (LCA) in chronically transfused children with beta thalassemia major and the relationship between alloimmunisation and febrile non-haemolytic transfusion reactions. We also compared the effect of leucoreduced-packed red blood cells (RBCs) by bed side filtration and washed RBCs in preventing FNHTRs and in inducing haemoglobin rise. BACKGROUND: Alloimmunisation to human leucocytic antigens is one of the common complications of transfusions, particularly in chronically transfused patients as those with thalassemia major, a common disease in Northern Egypt. METHODS/MATERIALS: LCA were screened for in 45 chronically transfused beta thalassemia major children (group I), 20 splenectomised ones (group II) and 20 healthy controls (group III), using qualitative lymphocytotoxic antibody (LCA) enzyme-linked immunosorbent assay (ELISA) kit. RESULTS: Nine out of 65 thalassemic children (~14%) were positive for LCA antibodies. Frequency of transfusions and LCA positivity were significantly higher in group I than group II (p = 0.036 and 0.014). There was no statistically significant difference between LCA positive and negative cases regarding age of starting transfusion, frequency of transfusions or FNHTRs. There was no statistically significant difference between washed and filtered RBCs in reducing FNHTRs (p = 1.000) and in inducing haemoglobin rise in positive LCA cases (p = 0.409). CONCLUSION: Human leukocyte antigen (HLA) alloimmunisation was only 14% in the children with beta thalassemia major we studied. Surprisingly FNHTRs were not more common in those with HLA antibodies. Splenectomy plays a role in reducing the frequency of transfusion and HLA alloimmunisation. Washed and filtered RBCs are comparable in reducing FNHTRs and in inducing haemoglobin rise. PMID- 26578339 TI - Long term follow-up of persistent choroidal folds and hyperopic shift after complete removal of a retrobulbar mass. AB - BACKGROUND: Hyperopic shift and chorioretinal folds are common findings with intraorbital masses compressing the posterior pole of the globe. These signs usually regress after complete tumour excision. To the best of our knowledge this is the first reported case, where optical coherence tomography was used to document persistent chorioretinal folds after complete excision of a retrobulbar mass. CASE PRESENTATION: A 47-year-old Caucasian woman was referred to our department with long-documented hyperopic shift and gradually decreasing vision in her left eye. Optical coherence tomography showed chorioretinal folds. Magnetic resonance imaging revealed a retrobulbar mass which caused flattening of the posterior pole of the globe. The tumour was successfully removed, and was confirmed to be a cavernous haemangioma on histological assessment. 3 years after surgery the patient still has a similar amount of hyperopia and chorioretinal folds. CONCLUSION: Choroidal folds and hyperopic shift may persist after complete tumour removal. Long term follow-up is advised to rule out recurrence of the intraorbital mass. PMID- 26578340 TI - The nuclear disaster management system in Taiwan: a case study of the third (Maanshan) nuclear power plant. AB - This paper explores the effectiveness of the nuclear disaster management system in Taiwan via a review of the third (Maanshan) nuclear power plant. In doing so, the Fukushima Daiichi nuclear disaster in Japan on 11 March 2011 is reviewed and compared with the situation in Taiwan. The latter's nuclear disaster management system is examined with respect to three key variables: information; mobilisation; and inter-organisational cooperation. In-depth interviews with 10 policy stakeholders with different backgrounds serve as the research method. The results point up the need for improvement in all dimensions. In addition, they highlight three principal problems with the nuclear disaster management system: (i) it might not be possible to provide first-hand nuclear disaster information immediately to the communities surrounding the Maanshan facility in Pingtung County, southern Taiwan; (ii) the availability of medical resources for treating radiation in Hengchun Township is limited; and (iii) the inter-organisational relationships for addressing nuclear disasters need to be strengthened. Hence, cooperation among related organisations is necessary. PMID- 26578341 TI - Visible-Light Actinometry and Intermittent Illumination as Convenient Tools to Study Ru(bpy)3Cl2 Mediated Photoredox Transformations. AB - Photoredox catalysis provides many green opportunities for radical-mediated synthetic transformations. However, the determination of the underlying mechanisms has been challenging due to lack of quantitative methods that can be easily implemented in synthetic labs, where this research tends to be centered. We report here on the development, characterization and calibration of a novel actinometer based on the photocatalyst tris(2,2'-bipyridyl)ruthenium(II) chloride (Ru(bpy)3Cl2). By using the same molecule as the photocatalyst and the actinometer, we eliminate problems associated with matching sample spectral distribution, lamp-sample spectral overlap and other problems intrinsic to doing quantitative photochemistry in a laboratory that has little expertise in this area. In order to validate our actinometer system in determining the quantum yield of a Ru(bpy)3Cl2 photosensitized reaction, we test the Ru(bpy)3Cl2 catalyzed oxidation of benzhydrol to benzophenone as a model chain reaction. We also revive the rotating sector method by updating the technique for modern LED technologies and demonstrate how intermittent illumination on the timescale of milliseconds to seconds can help probe a chain reaction, using the benzhydrol to benzophenone oxidation to validate the technique. We envision these methods to have great implications in the field of photoredox catalysis, providing researchers with valuable research tools. PMID- 26578342 TI - Structure-based Design Targeted at LOX-1, a Receptor for Oxidized Low-Density Lipoprotein. AB - Atherosclerosis related cardiovascular diseases continue to be the primary cause of mortality in developed countries. The elevated level of low density lipoprotein (LDL) is generally considered to be the driver of atherosclerosis, but recent years have seen a shift in this perception in that the vascular plaque buildup is mainly caused by oxidized LDL (ox-LDL) rather than native-LDL. The scavenger receptor LOX-1 found in endothelial cells binds and internalizes ox-LDL which leads to the initiation of plaque formation in arteries. Using virtual screening techniques, we identified a few potential small molecule inhibitors of LOX-1 and tested their inhibitory potential using differential scanning fluorimetry and various cellular assays. Two of these molecules significantly reduced the uptake of ox-LDL by human endothelial cells, LOX-1 transcription and the activation of ERK1/2 and p38 MAPKs in human endothelial cells. In addition, these molecules suppressed ox-LDL-induced VCAM-1 expression and monocyte adhesion onto human endothelial cells demonstrating their therapeutic potential. PMID- 26578343 TI - Biotechnological enhancement of capsaicin biosynthesis in cell suspension cultures of Naga King Chili (Capsicum chinense Jacq.). AB - Cell suspension cultures were initiated from hypocotyl derived callus to induce capsaicin biosynthesis in suspension cultures of Naga King Chili (Capsicum chinense Jacq.). Efficient capsaicin production with high growth index (GI) was obtained by exposing cells to salicylic acid (SA) and calcium channel modulators in suspension cultures. The time course of capsaicin formation is related to the cell growth profile in a batch culture. Cells cultivated in the standard medium (SM) initially showed low level of capsaicin yield during active growth. When the cells approached stationary phase, cell growth and cell viability decreased whereas capsaicin production increased continuously. In the fed-batch cultures, the highest capsaicin yield (567.4 +/- 8.1 MUgg(1) fresh weight) (f.wt) was obtained by feeding the cells with 1 mM SA. However, SA feeding during cultivation repressed the cell growth. Enhanced cell growth (3.1 +/- 0.1 GI/culture) and capsaicin yield (534 +/- 7.8 MUgg(-1)f.wt) were obtained when the cells were fed with calcium ionophore A23187 (0.5 mM) on day 25 as compared to the control. Addition of the calcium channel blocker verapamil hydrochloride (100 mM) inhibited cell growth and capsaicin production in Naga King Chili suspension cell cultures. PMID- 26578344 TI - Imiquimod-induced apoptosis of melanoma cells is mediated by ER stress-dependent Noxa induction and enhanced by NF-kappaB inhibition. AB - Melanoma is characterized by dysregulated intracellular signalling pathways including an impairment of the cell death machinery, ultimately resulting in melanoma resistance, survival and progression. This explains the tumour's extraordinary resistance to the standard treatment. Imiquimod is a topical immune response modifier (imidazoquinoline) with both antiviral and antitumour activities. The mechanism by which imiquimod triggers the apoptosis of melanoma cells has now been carefully elucidated. Imiquimod-induced apoptosis is associated with the activation of apoptosis signalling regulating kinase1/c-Jun-N terminal kinase/p38 pathways and the induction of endoplasmic stress characterized by the activation of the protein kinase RNA-like endoplasmic reticulum kinase signalling pathway, increase in intracellular Ca(2+) release, degradation of calpain and subsequent cleavage of caspase-4. Moreover, imiquimod triggers the activation of NF-kappaB and the expression of the inhibitor of apoptosis proteins (IAPs) such as, X-linked IAP (XIAP) together with the accumulation of reactive oxygen species (ROS). Also, imiquimod triggers mitochondrial dysregulation characterized by the loss of mitochondrial membrane potential (Deltapsim), the increase in cytochrome c release, and cleavage of caspase-9, caspase-3 and poly(ADP-ribose) polymerase (PARP). Inhibitors of specific pathways, permit the elucidation of possible mechanisms of imiquimod induced apoptosis. They demonstrate that inhibition of NF-kB by the inhibitor of nuclear factor kappa-B kinase (IKK) inhibitor Bay 11-782 or knockdown of XIAP induces melanoma apoptosis in cells exposed to imiquimod. These findings support the use of either IKK inhibitors or IAP antagonists as adjuvant therapies to improve the effectiveness topical imiquimod in the treatment of melanoma. PMID- 26578345 TI - BK Channel beta1 Subunit Contributes to Behavioral Adaptations Elicited by Chronic Intermittent Ethanol Exposure. AB - BACKGROUND: Large conductance, calcium- and voltage-activated potassium (BK) channels regulate neuronal excitability and neurotransmission. They can be directly activated by ethanol (EtOH) and they may be implicated in EtOH dependence. In this study, we sought to determine the influence of the auxiliary beta1 and beta4 subunits on EtOH metabolism, acute sensitivity to EtOH intoxication, acute functional tolerance, chronic tolerance, and handling-induced convulsions during withdrawal. METHODS: Motor coordination, righting reflex, and body temperature were evaluated in BK beta1 and beta4 knockout, heterozygous, and wild-type mice following acute EtOH administration. Chronic tolerance and physical dependence were induced by chronic intermittent inhalation of EtOH vapor. RESULTS: Constitutive deficiency in BK beta1 or beta4 subunits did not alter the clearance rate of EtOH, acute sensitivity to EtOH-induced ataxia, sedation, and hypothermia, nor acute functional tolerance to ataxia. BK beta1 deletion reduced chronic tolerance to sedation and abolished chronic tolerance to hypothermia, while BK beta4 deletion did not affect these adaptations to chronic EtOH exposure. Finally, the absence of BK beta1 accelerated the appearance, while the absence of BK beta4 delayed the resolution, of the hyperexcitable state associated with EtOH withdrawal. CONCLUSIONS: Altogether, the present findings reveal the critical role of BK beta1 in behavioral adaptations to prolonged, repeated EtOH intoxication. PMID- 26578346 TI - A comparative study of the effects of retinol and retinoic acid on histological, molecular, and clinical properties of human skin. AB - BACKGROUND: All-trans retinol, a precursor of retinoic acid, is an effective anti aging treatment widely used in skin care products. In comparison, topical retinoic acid is believed to provide even greater anti-aging effects; however, there is limited research directly comparing the effects of retinol and retinoic acid on skin. OBJECTIVES: In this study, we compare the effects of retinol and retinoic acid on skin structure and expression of skin function-related genes and proteins. We also examine the effect of retinol treatment on skin appearance. METHODS: Skin histology was examined by H&E staining and in vivo confocal microscopy. Expression levels of skin genes and proteins were analyzed using RT PCR and immunohistochemistry. The efficacy of a retinol formulation in improving skin appearance was assessed using digital image-based wrinkle analysis. RESULTS: Four weeks of retinoic acid and retinol treatments both increased epidermal thickness, and upregulated genes for collagen type 1 (COL1A1), and collagen type 3 (COL3A1) with corresponding increases in procollagen I and procollagen III protein expression. Facial image analysis showed a significant reduction in facial wrinkles following 12 weeks of retinol application. CONCLUSIONS: The results of this study demonstrate that topical application of retinol significantly affects both cellular and molecular properties of the epidermis and dermis, as shown by skin biopsy and noninvasive imaging analyses. Although the magnitude tends to be smaller, retinol induces similar changes in skin histology, and gene and protein expression as compared to retinoic acid application. These results were confirmed by the significant facial anti-aging effect observed in the retinol efficacy clinical study. PMID- 26578347 TI - Antenatal blood pressure for prediction of pre-eclampsia, preterm birth, and small for gestational age babies: development and validation in two general population cohorts. AB - STUDY QUESTION: Can routine antenatal blood pressure measurements between 20 and 36 weeks' gestation contribute to the prediction of pre-eclampsia and its associated adverse outcomes? METHODS: This study used repeated antenatal measurements of blood pressure from 12 996 women in the Avon Longitudinal Study of Parents and Children (ALSPAC) to develop prediction models and validated these in 3005 women from the Southampton Women's Survey (SWS). A model based on maternal early pregnancy characteristics only (BMI, height, age, parity, smoking, existing and previous gestational hypertension and diabetes, and ethnicity) plus initial mean arterial pressure was compared with a model additionally including current mean arterial pressure, a model including the deviation of current mean arterial pressure from a stratified normogram, and a model including both at different gestational ages from 20-36 weeks. STUDY ANSWER AND LIMITATIONS: The addition of blood pressure measurements from 28 weeks onwards improved prediction models compared with use of early pregnancy risk factors alone, but they contributed little to the prediction of preterm birth or small for gestational age. Though multiple imputation of missing data was used to increase the sample size and minimise selection bias, the validation sample might have been slightly underpowered as the number of cases of pre-eclampsia was just below the recommended 100. Several risk factors were self reported, potentially introducing measurement error, but this reflects how information would be obtained in clinical practice. WHAT THIS STUDY ADDS: The addition of routinely collected blood pressure measurements from 28 weeks onwards improves predictive models for pre-eclampsia based on blood pressure in early pregnancy and other characteristics, facilitating a reduction in scheduled antenatal care. FUNDING, COMPETING INTERESTS, DATA SHARING: UK Wellcome Trust, US National Institutes of Health, and UK Medical Research Council. Other funding sources for authors are detailed in the full online paper. With the exceptions of CM-W, HMI, and KMG there were no competing interests. PMID- 26578348 TI - Characterization of the inflammatory cell infiltrate and expression of costimulatory molecules in chronic echinococcus granulosus infection of the human liver. AB - BACKGROUND: The local immune responses to chronic echinococcal infections in various organs are largely unknown. Since the liver is the most frequently involved organ in such infections in human we aimed to characterize the inflammatory as well as immune cell infiltrate around hydatid cysts in the liver and compared to common inflammatory processes of the liver. METHOD: Surgical samples from the liver of 21 cystic echinococcosis (CE) patients were studied and the distribution of different types of inflammatory and immune cells were determined by immunohistochemistry. Furthermore, expression levels of costimulatory CTLA4, CD28, CD80 and CD86 molecules were measured at RNA level by PCR. Liver biopsy samples from patients with steatohepatitis (SH, n = 11) and chronic hepatitis (CH, n = 11) were used as non-inflammatory and chronic inflammatory controls, respectively. The composition and density of the inflammatory and immune cell infiltrates have been compared by using morphometry. RESULTS: CD3+ T cells predominated the inflammatory infiltrate in all pathological processes, while in CE samples CD20+ B cells, in CH samples CD68+ macrophages were also frequent. Both myeloperoxidase (MPO) + leukocytes and CD68+ macrophages were found to be significantly decreased in CE as compared to either SH or CH samples. Concerning T cell subtypes, only CD8+ T cells were found to be significantly decreased in SH samples. CD1a + dendritic cells were almost completely missing from CE biopsies unlike in any other sample types. There were no differences detected in the mRNA expression of costimulatory molecules except decreased expression of CD28 in CE samples. CONCLUSION: In the hydatid lesions of the liver of chronic echinococcal infections T cell-mediated immunity seems to be impaired as compared to other types of chronic inflammatory processes, suggesting an immunosuppressive role for Echinococcus granulosus, which deserve further attentions. PMID- 26578349 TI - Addressing Breast Cancer Health Disparities in the Mississippi Delta Through an Innovative Partnership for Education, Detection, and Screening. AB - Projects to reduce disparities in cancer treatment and research include collaborative partnerships and multiple strategies to promote community awareness, education, and engagement. This is especially needed in underserved areas such as the Mississippi Delta where more women are diagnosed at regional and distant stages of breast cancer. The purpose for this project was to increase the relatively low screening rate for African American women in the Mississippi Delta through a partnership between the Mississippi Network for Cancer Control and Prevention at The University of Southern Mississippi, The Fannie Lou Hamer Cancer Foundation and the Mississippi State Department of Health to decrease health disparities in breast cancer through increased awareness on self-early detection methods, leveraging resources to provide mammography screenings, and adequate follow-up with services and treatment for abnormal findings. Through this collaborative effort, over 500 women in three rural Mississippi Delta counties were identified, provided community education on early self-detection, and given appointments for mammography screenings within one fiscal year. PMID- 26578350 TI - Building Social Capital Through a Peer-Led Community Health Workshop: A Pilot with the Bhutanese Refugee Community. AB - Despite the high health and mental health care needs, resettled refugees often face cultural and linguistic challenges that hinder the access to appropriate and timely interventions and services. Additionally, such concepts as preventive health or mental health treatment are foreign to this population, which creates additional burdens to the refugee community that already have difficulty navigating a complex health care system in the U.S. To address multiple and complex gaps in health and mental health support for the refugee community, requested is an innovative approach that can convey culturally responsive and effective interventions for health promotion, such as peer-based health education. Few studies have been conducted on the effectiveness of peer-led community health interventions with refugee populations in the U.S. resettlement context. However, peer-led interventions have been shown to be effective when working with cultural minorities and interventions in an international context. Adopting a social capital framework, the current study conducted qualitative evaluation on the impact of a pilot peer-led community health workshop (CHW) in the Bhutanese refugee community. A hybrid thematic analysis of focus group discussion data revealed the improvement in health promotion outcomes and health practice, as well as perceived emotional health. The results also showed that the peer-led CHW provided a platform of community building and participation, while increasing a sense of community, sense of belonging and unity. The findings posit that a peer-led intervention model provides culturally responsive and effective tools for building social capital and promoting community health in the refugee community. PMID- 26578351 TI - Propranolol Treatment of Cavernous Malformations with Symptomatic Hemorrhage. AB - BACKGROUND: Cerebral cavernous malformations are more common than generally thought, affecting approximately 1 in every 250 adults. Most of these lesions are asymptomatic or have a relatively benign course, but a small minority behave aggressively and present with recurrent episodes of symptomatic hemorrhage. A safe and effective medical treatment option for the management of this latter group would be useful. Propranolol has recently been shown to be effective in the treatment of infantile hemangioma, a close pathologic counterpart of cavernous malformations. These results suggest a potential role for propranolol treatment in the management of patients with symptomatic cavernous malformations. METHODS: Low-dose propranolol (20 mg, three times daily) was used to treat 2 adult female patients in their mid- to late fifties, both of whom had symptomatic cavernous malformations and a history of repeated hemorrhage. Serial magnetic resonance imaging studies after the initiation of propranolol demonstrated regression of the lesions and no evidence of recurrent hemorrhage. CONCLUSIONS: Propranolol may offer a safe and effective treatment for patients who have cavernous malformations with symptomatic hemorrhage. Additional studies are needed to confirm these findings. PMID- 26578352 TI - Analyzing Th17 cell differentiation dynamics using a novel integrative modeling framework for time-course RNA sequencing data. AB - BACKGROUND: The differentiation of naive CD 4(+) helper T (Th) cells into effector Th17 cells is steered by extracellular cytokines that activate and control the lineage specific transcriptional program. While the inducing cytokine signals and core transcription factors driving the differentiation towards Th17 lineage are well known, detailed mechanistic interactions between the key components are poorly understood. RESULTS: We develop an integrative modeling framework which combines RNA sequencing data with mathematical modeling and enables us to construct a mechanistic model for the core Th17 regulatory network in a data-driven manner. CONCLUSIONS: Our results show significant evidence, for instance, for inhibitory mechanisms between the transcription factors and reveal a previously unknown dependency between the dosage of the inducing cytokine TGF beta and the expression of the master regulator of competing (induced) regulatory T cell lineage. Further, our experimental validation approves this dependency in Th17 polarizing conditions. PMID- 26578353 TI - Seasonal malaria chemoprevention in an area of extended seasonal transmission in Ashanti, Ghana: an individually randomised clinical trial. AB - OBJECTIVE: To investigate the effectiveness of seasonal malaria chemoprevention (SMC) and community case management with long-acting artemisinin-based combination therapies (ACTs) for the control of malaria in areas of extended seasonal malaria transmission. METHOD: Individually randomised, placebo controlled trial in the Ashanti Region of Ghana. A total of 2400 children aged 3 59 months received either: (i) a short-acting ACT for case management of malaria (artemether-lumefantrine, AL) plus placebo SMC, or (ii) a long-acting ACT (dihydroartemisinin-piperaquine, DP) for case management plus placebo SMC or (iii) AL for case management plus active SMC with sulphadoxine-pyrimethamine and amodiaquine. SMC or placebo was delivered on five occasions during the rainy season. Malaria cases were managed by community health workers, who used rapid diagnostic tests to confirm infection prior to treatment. RESULTS: The incidence of malaria was lower in children given SMC during the rainy season. Compared to those given placebo SMC and AL for case management, the adjusted hazard ratio (aHR) was 0.62 (95% CI: 0.41, 0.93), P = 0.020 by intention to treat and 0.53 (95% CI: 0.29, 0.95), P = 0.033 among children given five SMC courses. There were no major differences between groups given different ACTs for case management (aHR DP vs. AL 1.18 (95% CI 0.83, 1.67), P = 0.356). CONCLUSION: SMC may have an important public health impact in areas with a longer transmission season, but further optimisation of SMC schedules is needed to maximise its impact in such settings. PMID- 26578354 TI - Age-related effects on verbal and visuospatial memory are mediated by theta and alpha II rhythms. AB - Both electrical brain activity during rest and memory functions change across the lifespan. Moreover, electrical brain activity is associated with memory functions. However, the interplay between all these effects has been investigated only scarcely. The present study investigated the extent to which the power of resting-state electroencephalographic (EEG) frequencies mediates the impact of aging on verbal and visuospatial memory. Seventy healthy participants with 22 to 83years of age completed a visuospatial and verbal learning and memory test and provided eyes-open and eyes-closed resting-state EEG data. Robust age-related effects on behavioral and EEG data were observed. Mediation analyses showed that the relative power of the theta (4-8Hz) frequency band in fronto-central locations partly explained the negative age-related effect on delayed recall in the verbal memory task. The relative power of the alpha II (10-12Hz) frequency band in mainly parietal locations partly explained the negative impact of age on immediate and delayed recall in the visuospatial task. Results indicate that spontaneous brain activity carries specific information about aging processes and predicts the level of competence in verbal and visuospatial memory tasks. PMID- 26578356 TI - The History of Bracing for Scoliosis. PMID- 26578355 TI - Fabrication of three-dimensional hydrogel scaffolds for modeling shunt failure by tissue obstruction in hydrocephalus. AB - BACKGROUND: Shunt obstruction in the treatment of hydrocephalus is poorly understood, is multi-factorial, and in many cases is modeled ineffectively. Several mechanisms may be responsible, one of which involves shunt infiltration by reactive cells from the brain parenchyma. This has not been modeled in culture and cannot be consistently examined in vivo without a large sample size. METHODS: We have developed and tested a three-dimensional in vitro model of astrocyte migration and proliferation around clinical grade ventricular catheters and into catheter holes that mimics the development of cellular outgrowth from the parenchyma that may contribute to shunt obstruction. RESULTS: Cell attachment and growth was observed on shunt catheters for as long as 80 days with at least 77% viability until 51 days. The model can be used to study cellular attachment to ventricular catheters under both static and pulsatile flow conditions, which better mimic physiological cerebrospinal fluid dynamics and shunt system flow rates (0.25 mL/min, 100 pulses/min). Pulsatile flow through the ventricular catheter decreased cell attachment/growth by 63% after 18 h. Under both conditions it was possible to observe cells accumulating around and in shunt catheter holes. CONCLUSIONS: Alone or in combination with previously-published culture models of shunt obstruction, this model serves as a relevant test bed to analyze mechanisms of shunt failure and to test catheter modifications that will prevent cell attachment and growth. PMID- 26578357 TI - Needle in a Haystack: When Syncope Is Not Benign. PMID- 26578358 TI - Differences Between Radiologically Confirmed Pneumonia With and Without Pleural Fluid in Hospitalized Children Younger Than 5 Years in Southern Israel. AB - We compared demographic and clinical characteristics of pneumonia with and without pleural fluid (PF and Pn, respectively) in hospitalized children younger than 5 years in southern Israel, between 2002 and 2011. Overall, 108 PF and 5811 Pn episodes were recorded. Children with PF were older. Prematurity (6.6% vs 14.0%) and asthma (9.9% vs 23.5%) were less common in PF. Mean temperature and saturation were higher in PF while hemoglobin and sodium levels were lower in PF compared with Pn. Nasal washes were obtained in 30.6% and 39.9% of PF and Pn episodes, respectively, with respiratory syncytial virus identified more commonly in Pn (24.2% vs 42.3%). Streptococcus pneumoniae was identified in 5.2% and 0.9% of blood cultures in PF and Pn, respectively. In conclusion, PF differed from Pn in demographic and clinical characteristics, possibly due to differences in etiology. Although both diseases are considered bacterial, a high proportion of viral etiology was found in both, especially in Pn. PMID- 26578359 TI - Spatiotemporal dynamics of cortical perfusion in response to thalamic deep brain stimulation. AB - Deep brain stimulation (DBS) has revolutionized the treatment of movement disorders. The parameters of electrical stimulation are important to its therapeutic effect and remain a source of clinical controversy. DBS exerts its actions not only locally at the site of stimulation but also remotely through afferent and efferent connections, which are vital to its clinical effects. Yet, only a few studies have examined how cortical activity changes in response to various electrical parameters. Here, we investigated how the parameters of thalamic DBS alter cortical perfusion in rats using intrinsic optical imaging. We hypothesized that thalamic DBS will increase perfusion in primary motor cortex (M1), proportional to amplitude, pulse width, or frequency of the stimulation applied. We applied 45 different combinations of amplitude, pulse width and frequency in the ventro-lateral (VL) nucleus of the thalamus in anesthetized rats while measuring perfusion in M1. VL thalamic DBS reduced cortical reflectance, which corresponds to an increase in cortical perfusion. We computed the maximum change in reflectance (MCR) as well as the spatial spread of MCR in each trial. Both MCR and spatial spread increased linearly with increases in current amplitude or pulse width of stimulation; however, the effect of frequency was non linear. Stimulation at 20 Hz was significantly different from that at higher frequencies while stimulation at higher frequencies did not differ significantly from each other. Moreover, the effect of pulse width on MCR was larger than the effect of amplitude. The proportional increase in M1 perfusion due to increase in amplitude or pulse width suggests that both activate more neural elements and increase the volume of tissue activated. These results should help clinicians set parameters of DBS. The use of optical imaging to monitor effects of DBS on M1 may not only help understand DBS mechanisms, but may also provide feedback for closed loop DBS devices. PMID- 26578360 TI - Shared topics on the experience of people with haemophilia living in the UK and the USA and the influence of individual and contextual variables: Results from the HERO qualitative study. AB - The study illuminates the subjective experience of haemophilia in people who took part in the Haemophilia Experience, Results and Opportunities (HERO) initiative, a quali-quantitative research program aimed at exploring psychosocial issues concerning this illness around the world. Applying a bottom-up analytic process with the help of software for textual data, we investigated 19 interviews in order to describe the core themes and the latent factors of speech, to explore the role of different variables in shaping the participants' illness experiences. The five themes detected are feeling different from others, body pain, acquisition of knowledge and resources, family history, and integration of care practices in everyday life. We illustrate how nationality, age, family situation, the use of prophylaxis or on-demand treatment, and the presence of human immunodeficiency virus or hepatitis C virus affect the experience of our participants in different ways. Findings are used to bring insights on research, clinical practice, and psychosocial support. PMID- 26578361 TI - Effects of Different Therapeutic Ultrasound Waveforms on Endothelial Function in Healthy Volunteers: A Randomized Clinical Trial. AB - The purpose of this study was to determine the effects of different therapeutic 1 MHz ultrasound waveforms on endothelial function before and after cyclooxygenase (COX) inhibition. Forty-two healthy volunteers aged 27.2 +/- 3.8 y underwent interventions and an evaluation for endothelial function (n = 15; with COX inhibition, n = 15; duration of the vasodilator effect, n = 12) by technique flow mediated dilation. Continuous ultrasound therapy (0.4 W/cm(2 SATA)), pulsed ultrasound therapy (20% duty cycle, 0.08 W/cm(2 SATA)) or placebo (equipment power off) was randomly applied over the brachial artery for 5 min. COX inhibition (aspirin) was carried out 30 min before treatments. In relation to the placebo, flow-mediated dilation increased by 4.8% using continuous ultrasound and by 3.4% using pulsed ultrasound. After COX, flow-mediated dilation was enhanced by 2.1% by continuous ultrasound and 2.6% by pulsed ultrasound. This vasodilation persisted for 20 min. Continuous and pulsed therapeutic 1-MHz ultrasound waveforms improved endothelial function in humans, which provided them with anti inflammatory vascular effects. PMID- 26578362 TI - DBU-mediated metal-free oxidative cyanation of alpha-amino carbonyl compounds: using molecular oxygen as the oxidant. AB - A novel DBU-mediated oxidative cyanation of alpha-amino carbonyl compounds by using air as the sole oxidant was developed under mild metal-free conditions for the first time. The reaction involves a tandem oxidation/Strecker reaction/oxidation process and provides a new and efficient method for the construction of alpha-iminonitriles in good to high yields in a single step. PMID- 26578364 TI - Locally produced estrogen through aromatization might enhance tissue expression of pituitary tumor transforming gene and fibroblast growth factor 2 in growth hormone-secreting adenomas. AB - Aromatase, a key enzyme in local estrogen synthesis, is expressed in different pituitary tumors including growth hormone (GH)-secreting adenomas. We aimed to evaluate aromatase, estrogen receptor alpha (ERalpha), estrogen receptor beta (ERbeta), pituitary tumor transforming gene (PTTG), and fibroblast growth factor 2 (FGF2) expressions in GH-secreting adenomas, and investigate their correlation with clinical, pathologic, and radiologic parameters. This cross-sectional study was conducted in a tertiary center in Turkey. Protein expressions were determined via immunohistochemical staining in ex vivo tumor samples of 62 patients with acromegaly and ten normal pituitary tissues. Concordantly increased aromatase, PTTG, and FGF2 expressions were detected in the tumor samples as compared with controls (p < 0.001 for all). None of the tumors expressed ERalpha while ERbeta was detected only in mixed somatotroph adenomas. Aromatase, ERbeta, PTTG expressions were not significantly different between patients with and without remission (p > 0.05 for all). FGF2 expression was significantly higher in patients without postoperative and late remission (p = 0.002 and p = 0.012, respectively), with sphenoid bone invasion, optic chiasm compression, and somatostatin analog resistance (p = 0.005, p = 0.033, and p = 0.013, respectively). Aromatase, PTTG and FGF2 expressions were positively correlated with each other (r = 0,311, p = 0.008 for aromatase, FGF2; r = 0.380, p = 0.001 for aromatase, PTTG; r = 0.400, p = 0.001 for FGF2, PTTG). PTTG-mediated FGF2 upregulation is associated with more aggressive tumor features in patients with acromegaly. Also, locally produced estrogen through aromatization might have a role in this phenomenon. PMID- 26578365 TI - Copeptin under glucagon stimulation. AB - Stimulation of growth hormone (GH) and adrenocorticotropic hormone (ACTH) secretion by glucagon is a standard procedure to assess pituitary dysfunction but the pathomechanism of glucagon action remains unclear. As arginine vasopressin (AVP) may act on the release of both, GH and ACTH, we tested here the role of AVP in GST by measuring a stable precursor fragment, copeptin, which is stoichiometrically secreted with AVP in a 1:1 ratio. ACTH, cortisol, GH, and copeptin were measured at 0, 60, 90, 120, 150, and 180 min during GST in 79 subjects: healthy controls (Group 1, n = 32), subjects with pituitary disease, but with adequate cortisol and GH responses during GST (Group 2, n = 29), and those with overt hypopituitarism (Group 3, n = 18). Copeptin concentrations significantly increased over baseline 150 and 180 min following glucagon stimulation in controls and patients with intact pituitary function but not in hypopituitarism. Copeptin concentrations were stimulated over time and the maximal increment correlated with ACTH, while correlations between copeptin and GH were weaker. Interestingly, copeptin as well as GH secretion was significantly attenuated when comparing subjects within the highest to those in the lowest BMI quartile (p < 0.05). Copeptin is significantly released following glucagon stimulation. As this release is BMI-dependent, the time-dependent relation between copeptin and GH may be obscured, whereas the close relation to ACTH suggests that AVP/copeptin release might be linked to the activation of the adrenal axis. PMID- 26578366 TI - Calcitriol attenuates cardiac remodeling and dysfunction in a murine model of polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) is a complex reproductive and metabolic disorder affecting 10 % of reproductive-aged women, and is well associated with an increased prevalence of cardiovascular risk factors. However, there are few data concerning the direct association of PCOS with cardiac pathologies. The present study aims to investigate the changes in cardiac structure, function, and cardiomyocyte survival in a PCOS model, and explore the possible effect of calcitriol administration on these changes. PCOS was induced in C57BL/6J female mice by chronic dihydrotestosterone administration, as evidenced by irregular estrous cycles, obesity and dyslipidemia. PCOS mice progressively developed cardiac abnormalities including cardiac hypertrophy, interstitial fibrosis, myocardial apoptosis, and cardiac dysfunction. Conversely, concomitant administration of calcitriol significantly attenuated cardiac remodeling and cardiomyocyte apoptosis, and improved cardiac function. Molecular analysis revealed that the beneficial effect of calcitriol was associated with normalized autophagy function by increasing phosphorylation levels of AMP-activated protein kinase and inhibiting phosphorylation levels of mammalian target of rapamycin complex. Our findings provide the first evidence for the presence of cardiac remodeling in a PCOS model, and vitamin D supplementation may be a potential therapeutic strategy for the prevention and treatment of PCOS-related cardiac remodeling. PMID- 26578368 TI - [Not Available]. PMID- 26578367 TI - Long-term exposure to electromagnetic radiation from mobile phones and Wi-Fi devices decreases plasma prolactin, progesterone, and estrogen levels but increases uterine oxidative stress in pregnant rats and their offspring. AB - We investigated the effects of mobile phone (900 and 1800 MHz)- and Wi-Fi (2450 MHz)-induced electromagnetic radiation (EMR) exposure on uterine oxidative stress and plasma hormone levels in pregnant rats and their offspring. Thirty-two rats and their forty newborn offspring were divided into the following four groups according to the type of EMR exposure they were subjected to: the control, 900, 1800, and 2450 MHz groups. Each experimental group was exposed to EMR for 60 min/day during the pregnancy and growth periods. The pregnant rats were allowed to stand for four generations (total 52 weeks) before, plasma and uterine samples were obtained. During the 4th, 5th, and 6th weeks of the experiment, plasma and uterine samples were also obtained from the developing rats. Although uterine lipid peroxidation increased in the EMR groups, uterine glutathione peroxidase activity (4th and 5th weeks) and plasma prolactin levels (6th week) in developing rats decreased in these groups. In the maternal rats, the plasma prolactin, estrogen, and progesterone levels decreased in the EMR groups, while the plasma total oxidant status, and body temperatures increased. There were no changes in the levels of reduced glutathione, total antioxidants, or vitamins A, C, and E in the uterine and plasma samples of maternal rats. In conclusion, although EMR exposure decreased the prolactin, estrogen, and progesterone levels in the plasma of maternal rats and their offspring, EMR-induced oxidative stress in the uteri of maternal rats increased during the development of offspring. Mobile phone- and Wi-Fi-induced EMR may be one cause of increased oxidative uterine injury in growing rats and decreased hormone levels in maternal rats. GRAPHICAL ABSTRACT: TRPV1 cation channels are the possible molecular pathways responsible for changes in the hormone, oxidative stress, and body temperature levels in the uterus of maternal rats following a year-long exposure to electromagnetic radiation exposure from mobile phones and Wi-Fi devices. It is likely that TRPV1-mediated Ca(2+) entry in the uterus of pregnant rats involves accumulation of oxidative stress and opening of mitochondrial membrane pores that consequently leads to mitochondrial dysfunction, substantial swelling of the mitochondria with rupture of the outer membrane and release of oxidants such as superoxide (O2 (-)) and hydrogen peroxide (H2O2). The superoxide radical is converted to H2O2 by superoxide dismutase (SOD) enzyme. Glutathione peroxidase (GSH-Px) is an important antioxidant enzyme for removing lipid hydroperoxides and hydrogen peroxide and it catalyzes the reduction of H2O2 to water. PMID- 26578369 TI - [Innovative potential of a "discipline trialogue" between diaconical science, psychology and theology]. PMID- 26578370 TI - Effect of exercises with weight vests and a patient education programme for women with osteopenia and a healed wrist fracture: a randomized, controlled trial of the OsteoACTIVE programme. AB - BACKGROUND: Exercise programmes have shown to be important for the prevention of fractures in patients with established osteoporosis. However, few studies have evaluated the effect of such programmes for women with low bone mineral density (BMD) (osteoporosis or osteopenia) who have already suffered a fracture. Studies have indicated that exercise programmes concentrating on muscular strength and dynamic balance have a positive effect on significant risk factors for falls such as quadriceps strength and balance. The aim of the present study was to assess the effect of a 6-month exercise programme and a patient education component (OsteoACTIVE) on quadriceps strength, BMD, dynamic balance, walking capacity, physical activity level and quality of life in postmenopausal women with osteopenia and a previous wrist fracture. METHODS: Eighty postmenopausal women with low BMD and a healed wrist fracture were randomized to OsteoACTIVE (n = 42) (age 65.5, range 51.2-79.2 years) or patient education only (control group) (n = 38) (age 63.9, range 52.7-86.8 years). Follow-up was conducted after 6 months (end of intervention) and 1 year. Outcome measures included quadriceps strength, BMD, dynamic balance, walking capacity, physical activity level and quality of life. RESULTS: Thirty-five participants (83 %) completed the OsteoACTIVE programme. Mean adherence to OsteoACTIVE was 87 % (range 48-100 %). Twenty-five participants (72 %) met the a priori goal of 80 % adherence to the program. No adverse events were reported. There were no significant differences between the two groups over the 1-year follow-up for any of the outcome measures. CONCLUSION: The OsteoACTIVE rehabilitation programme revealed no significant effect on quadriceps strength, BMD, dynamic balance, walking capacity or self-reported functional outcomes over the 1-year follow-up. TRIAL REGISTRATION: NCT01357278 at ClinicalTrials.gov (date of registration 2010-04-21). PMID- 26578371 TI - Field-scale study of the influence of differing remediation strategies on trace metal geochemistry in metal mine tailings from the Irish Midlands. AB - Mine tailings represent a globally significant source of potentially harmful elements (PHEs) to the environment. The management of large volumes of mine tailings represents a major challenge to the mining industry and environmental managers. This field-scale study evaluates the impact of two highly contrasting remediation approaches to the management and stabilisation of mine tailings. The geochemistry of the tailings, overlying amendment layers and vegetation are examined in the light of the different management approaches. Pseudo-total As, Cd and Pb concentrations and solid-state partitioning (speciation), determined via sequential extraction, were established for two Tailings Management Facilities (TMFs) in Ireland subjected to the following: (1) a 'walk-away' approach (Silvermines) and (2) application of an amendment layer (Galmoy). PHE concentrations in roots and herbage of grasses growing on the TMFs were also determined. Results identify very different PHE concentration profiles with depth through the TMFs and the impact of remediation approach on concentrations and their potential bioavailability in the rooting zone of grass species. Data also highlight the importance of choice of grass species in remediation approaches and the benefits of relatively shallow-rooting Agrostis capillaris and Festuca rubra varieties. In addition, data from the Galmoy TMF indicate the importance of regional soil geochemistry for interpreting the influence of the PHE geochemistry of capping and amendment layers applied to mine tailings. PMID- 26578372 TI - Statistical investigation on the role of supporting electrolytes during NTA degradation on BDD anodes. AB - This work reported a comparative study on the electrochemical incineration of nitrilotriacetic acid (NTA) in the presence of different supporting electrolytes (Na2SO4 and NaCl). Galvanostatic electrolyses were conducted in an undivided electrochemical cell containing boron-doped diamond (BDD) anode and platinum cathode. Initial solution pH, flow rate, applied current density, and supporting electrolyte concentration were selected as variables, besides the mineralization efficiency of NTA that was selected as response. Central composite rotatable design and response surface methodology were employed here to examine the statistical significance of the selected variables, as well as to determine the optimal conditions of the degradation process. Under the same operating conditions, two regression models were thus constructed to illustrate the differing impact of supporting electrolytes in BDD anode cells. The kinetics for NTA degradation followed different reaction orders for the two scenarios (in the absence and presence of NaCl), indicating the complex interaction between hydroxyl radicals and active chlorine. Despite this, the experimental results demonstrated that effective mineralization of NTA might also be achieved in the presence of chlorides (of lower concentrations). Besides, in the case of chlorides, the average mass transfer coefficient of the system was found to be strongly dependent on the initial solution pH. Lastly, a plausible reaction sequence concerning the electrolytic oxidation of NTA in chloride media was also proposed. PMID- 26578374 TI - Enrichment of denitrifying methanotrophic bacteria from Taihu sediments by a membrane biofilm bioreactor at ambient temperature. AB - Denitrification coupled to anaerobic methane oxidation is a recently discovered process performed by bacteria affiliated to the NC10 phylum. These microorganisms could play important roles in the energy-efficient way of anaerobic wastewater treatment where residual dissolved methane might be removed at the expense of nitrate or nitrite. The difficulty to enrich these microorganisms due to a slow growth rate, especially at low temperatures, limited its application in engineering field. In this study, an NC10 bacteria community was enriched from Taihu sediments by a membrane biofilm bioreactor at ambient temperature of 10-25 degrees C. After 13 months enrichment, the maximum denitrification rate of the enriched culture reached 0.54 mM day(-1) for nitrate and 1.06 mM day(-1) for nitrite. Anaerobic methane oxidation coupled denitrification was estimated from the (13)C-labeled CO2 ((13)CO2) production during batch incubations with (13)CH4. Furthermore, analysis of 16S rRNA genes clone library confirmed the presence of NC10 phylum bacteria and fluorescence in situ hybridization showed that NC10 bacteria dominated the reactor. All of the results indicated the NC10 bacteria community was competitive in terms of treating nitrate-contaminated water or wastewater under natural conditions. PMID- 26578373 TI - Concentrations and dissipation of difenoconazole and fluxapyroxad residues in apples and soil, determined by ultrahigh-performance liquid chromatography electrospray ionization tandem mass spectrometry. AB - A new combined difenoconazole and fluxapyroxad fungicide formulation, as an 11.7 % suspension concentrate (SC), has been introduced as part of a resistance management strategy. The dissipation of difenoconazole and fluxapyroxad applied to apples and the residues remaining in the apples were determined. The 11.7 % SC was sprayed onto apple trees and soil in Beijing, Shandong, and Anhui provinces, China, at an application rate of 118 g a.i. ha(-1), then the dissipation of difenoconazole and fluxapyroxad was monitored. The residual difenoconazole and fluxapyroxad concentrations were determined by ultrahigh-performance liquid chromatography tandem mass spectrometry. The difenoconazole half-lives in apples and soil were 6.2-9.5 and 21.0-27.7 days, respectively. The fluxapyroxad half lives in apples and soil were 9.4-12.6 and 10.3-36.5 days, respectively. Difenoconazole and fluxapyroxad residues in apples and soil after the 11.7 % SC had been sprayed twice and three times, with 10 days between applications, at 78 and 118 g a.i. ha(-1) were measured. Representative apple and soil samples were collected after the last treatment, at preharvest intervals of 14, 21, and 28 days. The difenoconazole residue concentrations in apples and soil were 0.002 0.052 and 0.002-0.298 mg kg(-1), respectively. The fluxapyroxad residue concentrations in apples and soil were 0.002-0.093 and 0.008-1.219 mg kg(-1), respectively. The difenoconazole and fluxapyroxad residue concentrations in apples were lower than the maximum residue limits (0.5 and 0.8 mg kg(-1), respectively). An application rate of 78 g a.i. ha(-1) is therefore recommended to ensure that treated apples can be considered safe for humans to consume. PMID- 26578376 TI - Microbial ecotoxicology: an emerging discipline facing contemporary environmental threats. PMID- 26578375 TI - Removal of fluorescent dissolved organic matter in biologically treated textile effluents by NDMP anion exchange process: efficiency and mechanism. AB - The efficiency and mechanism of anion exchange resin Nanda Magnetic Polymer (NDMP) for removal of fluorescent dissolved organic matter in biologically treated textile effluents were studied. The bench-scale experiments showed that as well as activated carbon, anion exchange resin could efficiently remove both aniline-like and humic-like fluorescent components, which can be up to 40 % of dissolved organic matter. The humic-like fluorescent component HS-Em460-Ex3 was more hydrophilic than HS-Em430-Ex2 and contained fewer alkyl chains but more acid groups. As a result, HS-Em460-Ex3 was eliminated more preferentially by NDMP anion exchange. However, compared with adsorption resins, the polarity of fluorescent components had a relatively small effect on the performance of anion exchange resin. The long-term pilot-scale experiments showed that the NDMP anion exchange process could remove approximately 30 % of the chemical oxygen demand and about 90 % of color from the biologically treated textile effluents. Once the issue of waste brine from resin desorption is solved, the NDMP anion exchange process could be a promising alternative for the advanced treatment of textile effluents. PMID- 26578377 TI - Evolution of the anthropogenic impact in the Augusta Harbor (Eastern Sicily, Italy) in the last decades: benthic foraminifera as indicators of environmental status. AB - The study of benthic foraminifera in sediment cores provides the opportunity to recognize environmental changes, including those due to the anthropogenic impact. The integration of these data with chemical-physical parameters provides a comprehensive quality assessment. This research was applied to a sediment core collected in the Augusta bay, where a very large commercial and military harbor and one of the largest petrochemical poles in Europe are present. Inside the petrochemical area also operated, from 1958 to 2003, a chlor-alkali plant with mercury cell technology which caused anthropic contamination of surrounding land and marine areas. The sediment core was collected in front of this plant and characterized for grain size and pollutants directly associated to chlor-alkali activity, such as mercury (Hg), barium (Ba), polychlorobiphenyls (PCBs), and polycyclic aromatic hydrocarbons (PAHs). Composition of foraminiferal assemblages and faunal parameters such as specific diversity, faunal density, abundance of abnormal specimens, and foraminiferal size were investigated as potential indicators of environmental status. Statistical analysis indicated a main common origin for Hg, Ba, and PCBs and the influence of pollutants on species distribution and faunal diversity and density. Exceptionally high Hg concentrations (63-680 mg/kg d.w.) were recorded in the whole core, where the geochronological study attributed the most contaminated levels to the period of maximum activity of the chlor-alkali plant, while a decrease of contamination was recorded after the stop of the activity. Distinct foraminiferal assemblages identified different ecozones along the core, which suggested decreasing anthropogenic impact from the bottom to the top. PMID- 26578378 TI - Effects of long-term radionuclide and heavy metal contamination on the activity of microbial communities, inhabiting uranium mining impacted soils. AB - Ore mining and processing have greatly altered ecosystems, often limiting their capacity to provide ecosystem services critical to our survival. The soil environments of two abandoned uranium mines were chosen to analyze the effects of long-term uranium and heavy metal contamination on soil microbial communities using dehydrogenase and phosphatase activities as indicators of metal stress. The levels of soil contamination were low, ranging from 'precaution' to 'moderate', calculated as Nemerow index. Multivariate analyses of enzyme activities revealed the following: (i) spatial pattern of microbial endpoints where the more contaminated soils had higher dehydrogenase and phosphatase activities, (ii) biological grouping of soils depended on both the level of soil contamination and management practice, (iii) significant correlations between both dehydrogenase and alkaline phosphatase activities and soil organic matter and metals (Cd, Co, Cr, and Zn, but not U), and (iv) multiple relationships between the alkaline than the acid phosphatase and the environmental factors. The results showed an evidence of microbial tolerance and adaptation to the soil contamination established during the long-term metal exposure and the key role of soil organic matter in maintaining high microbial enzyme activities and mitigating the metal toxicity. Additionally, the results suggested that the soil microbial communities are able to reduce the metal stress by intensive phosphatase synthesis, benefiting a passive environmental remediation and provision of vital ecosystem services. PMID- 26578379 TI - Fate of ivermectin in the terrestrial and aquatic environment: mobility, degradation, and toxicity towards Daphnia similis. AB - Ivermectin (IVM) is a broad-spectrum antiparasitic drug that is regularly employed in veterinary medicine. In this work, the sorption and desorption of IVM in two Brazilian soils (N1-sand and S2-clay) as well as its leaching capacity, dissipation under aerobic conditions, and degradation in aqueous solution by photocatalysis with TiO2 in suspension were evaluated. The kinetic sorption curves of IVM were adjusted to a pseudo-second-order model. The sorption and desorption data were well fitted with the Freundlich isotherms in the log form (r > 0.96). The Freundlich sorption coefficient (K F (ads) ) and the Freundlich desorption coefficient (K F (des) ) were 77.7 and 120 MUg(1-1/n) (cm(3))(1/n) g( 1) and 74.5 and 138 MUg(1-1/n) (cm(3))(1/n) g(-1), for soils N1 and S2, respectively. A greater leaching capacity of IVM was observed for the sandy soil N1 than for the clay soil S2. Under aerobic conditions, the dissipation (DT50) at 19.3 degrees C was 15.5 days (soil N1) and 11.5 days (soil S2). Photocatalysis with UVC and TiO2 in suspension resulted in the degradation of 98 % of IVM (500 MUg L(-1)) in water in 600 s. The toxicity (Daphnia similis) of the solutions submitted to the photocatalytic process was completely eliminated after 10 min. PMID- 26578380 TI - Fluorescence quenching effects of antibiotics on the main components of dissolved organic matter. AB - Dissolved organic matter (DOM) in wastewater can be characterized using fluorescence excitation-emission matrix and parallel factor (EEM-PARAFAC) analysis. Wastewater from animal farms or pharmaceutical plants usually contains high concentration of antibiotics. In this study, the quenching effect of antibiotics on the typical components of DOM was explored using fluorescence EEM PARAFAC analysis. Four antibiotics (roxarsone, sulfaquinoxaline sodium, oxytetracycline, and erythromycin) at the concentration of 0.5~4.0 mg/L and three typical components of DOM (tyrosine, tryptophan, and humic acid) were selected. Fluorescence quenching effects were observed with the addition of antibiotics. Among these four antibiotics, roxarsone (2.9~20.2 %), sulfaquinoxaline sodium (0~32.0 %), and oxytetracycline (0~41.8 %) led to a stronger quenching effect than erythromycin (0~8.0 %). From the side of DOM, tyrosine and tryptophan (0.5~41.8 %) exhibited a similar quenching effect, but they were higher than humic acids (0~20.2 %) at the same concentration of antibiotics. For humic acid, a significant quenching effect was observed only with the addition of roxarsone. This might be the first report about the fluorescence quenching effect caused by antibiotics. The results from this study confirmed the interference of antibiotics on the fluorescence intensity of the main components of DOM and highlighted the importance of correcting fluorescence data in the wastewater containing antibiotics. PMID- 26578381 TI - Occurrence of perchloroethylene in surface water and fish in a river ecosystem affected by groundwater contamination. AB - Long-term monitoring of the content of perchloroethylene (PCE) in a river ecosystem affected by groundwater contamination was performed at a site in the Czech Republic. The quality of surface water was monitored quarterly between 1994 and 2013, and fish were collected from the affected ecosystem to analyse the content of PCE in their tissue in 1998, 2011 and 2012. Concentrations of PCE (9 140 MUg/kg) in the tissue of fish collected from the contaminated part of the river were elevated compared to the part of the river unaffected by the contamination (ND to 5 MUg/kg PCE). The quality of surface water has improved as a result of groundwater remediation during the evaluated period. Before the remedial action, PCE concentrations ranged from 30 to 95 MUg/L (1994-1997). Following commencement of remedial activities in September 1997, a decrease in the content of PCE in the surface water to 7.3 MUg/L (1998) and further to 1 MUg/L (2011) and 1.1 MUg/L (2012) led to a progressive decrease in the average concentration of PCE in the fish muscle tissue from 79 MUg/kg (1998) to 24 (2011) and 30 MUg/kg (2012), respectively. It was determined that the bioconcentration of PCE does not have a linear dependence because the decrease in contamination in the fish muscle tissue is not directly proportional to the decrease in contamination in the river water. The observed average bioconcentration factors were 24 and 28 for the lower concentrations of PCE and 11 for the higher concentrations of PCE in the river. In terms of age, length and weight of the collected fish, weight had the greatest significance for bioconcentration, followed by the length, with age being evaluated as a less significant factor. PMID- 26578382 TI - Is pulmonary artery dissection predictable? PMID- 26578384 TI - Periorbital edema as an initial sign of systemic lupus erythematosus in an adolescent girl. PMID- 26578383 TI - Novel morphology changes from 3D ordered macroporous structure to V2O5 nanofiber grassland and its application in electrochromism. AB - Because vanadium pentoxide (V2O5) is the only oxide that shows both anodic and cathodic coloration electrochromism, the reversible lithium ion insertion/extraction processes in V2O5 lead to not only reversible optical parameter changes but also multicolor changes for esthetics. Because of the outstanding electrochemical properties of V2O5 nanofibers, they show great potential to enhance V2O5 electrochromism. However, the development and practical application of V2O5 nanofibers are still lacking, because traditional preparation approaches have several drawbacks, such as multiple processing steps, unsatisfactory electrical contact with the substrate, expensive equipment, and rigorous experimental conditions. Herein, we first report a novel and convenient strategy to prepare grass-like nanofiber-stacked V2O5 films by a simple annealing treatment of an amorphous, three-dimensionally ordered macroporous vanadia film. The V2O5 nanofiber grassland exhibits promising transmittance modulation, fast switching responses, and high color contrast because of the outstanding electrochemical properties of V2O5 nanofibers as well as the high Li-ion diffusion coefficients and good electrical contact with the substrate. Moreover, the morphology transformation mechanism is investigated in detail. PMID- 26578385 TI - Effect of cognitive rehabilitation in a case of thalamic astrocytoma. AB - We describe the effectiveness of rehabilitative training for a neuropsychological deficit following the removal and treatment of a fibrillary astrocytoma (Grade II) in a young man. The rehabilitative training was based on cognitive and motivational techniques and has been carried out for a period of 3 months (2 times per week). The results, even if limited to a single case, seem to support the idea that cognitive rehabilitation should facilitate the brain's reorganization of basic cognitive functions in the neuro-oncologic field. PMID- 26578386 TI - The many levels of causal brain network discovery: Comment on "Foundational perspectives on causality in large-scale brain networks" by M. Mannino and S.L. Bressler. PMID- 26578387 TI - Critical perspectives on causality and inference in brain networks: Allusions, illusions, solutions?: Comment on: "Foundational perspectives on causality in large-scale brain networks" by M. Mannino and S.L. Bressler. PMID- 26578388 TI - Crosstalk between SDF-1/CXCR4 and SDF-1/CXCR7 in cardiac stem cell migration. AB - Stromal cell-derived factor 1 (SDF-1) is a chemokine that can be expressed in injured cardiomyocytes after myocardial infarction (MI). By combining with its receptor CXCR4, SDF-1 induced stem and progenitor cells migration. CXCR7, a novel receptor for SDF-1, has been identified recently. We aimed to explore the roles of SDF-1/CXCR4 and SDF-1/CXCR7 pathway and their crosstalk in CSCs migration. In the present study, CXCR4 and CXCR7 expression were identified in CSCs. Transwell assay showed that SDF-1 caused CSCs migration in a dose- and time-dependent manner, which could be significantly suppressed by CXCR4 or CXCR7 siRNA. Phospho ERK, phospho-Akt and Raf-1 significantly elevated in CSCs with SDF-1 stimulation. Knockdown of CXCR4 or CXCR7 significantly decreased phospho-ERK or phospho-Akt, respectively, and eventually resulted in the inhibition of CSCs migration. Moreover, western blot showed that MK2206 (Akt inhibitor) increased the expression of phospho-ERK and Raf-1, whereas PD98059 (ERK inhibitor) had no effect on phospho-Akt and Raf-1. GW5074 (Raf-1 inhibitor) upregulated the expression of phospho-ERK, but had no effect on phospho-Akt. The present study indicated that SDF-1/CXCR7/Akt and SDF-1/CXCR4/ERK pathway played important roles in CSCs migration. Akt phosphorylation inhibited Raf-1 activity, which in turn dephosphorylated ERK and negatively regulated CSCs migration. PMID- 26578389 TI - Individualised quality of life as a measure to guide treatment choices in squamous cell carcinoma of the head and neck. AB - In patients with advanced squamous cell carcinoma of the head and neck (SCCHN), aggressive treatment is effective, but can significantly impact their health related quality of life (HRQoL), particularly if there is damage to the structures involved in swallowing, breathing, speech or physical appearance. Long term psychosocial support may be required for patients whose basic functioning and social interactions are affected. In randomised clinical trials in SCCHN, HRQoL has not been routinely reported and, with a number of different HRQoL tools available, data for many of the parameters that patients consider important in their day-to-day lives are not widely available to clinicians. In addition, the assessment of HRQoL outside of the clinical trial setting is even scarcer. In an era of personalised medicine, an individualised approach to assessing QoL (iQoL) is of paramount importance when treating and monitoring patients with SCCHN; by responding to QoL concerns, appropriate treatment regimens that result in meaningful improvements in clinical outcomes and quality of survival (QoS) for patients can be adopted. In this review we describe the tools available for assessing HRQoL in cancer patients and provide an overview of the HRQoL data currently available in head and neck cancer. How this information can be used to individualise treatment to optimise clinical outcomes, maximise the patient's day to-day living and minimise healthcare spending in SCCHN is discussed. PMID- 26578390 TI - Identification of potential biomarkers to differentially diagnose solid pseudopapillary tumors and pancreatic malignancies via a gene regulatory network. AB - BACKGROUND: Solid pseudopapillary neoplasms (SPN) are pancreatic tumors with low malignant potential and good prognosis. However, differential diagnosis between SPN and pancreatic malignancies including pancreatic neuroendocrine tumor (PanNET) and ductal adenocarcinoma (PDAC) is difficult. This study tried to identify candidate biomarkers for the distinction between SPN and the two malignant pancreatic tumors by examining the gene regulatory network of SPN. METHODS: The gene regulatory network for SPN was constructed by a co-expression model. Genes that have been reported to be correlated with SPN were used as the clues to hunt more SPN-related genes in the network according to a shortest path approach. By means of the K-nearest neighbor algorithm (KNN) classifier evaluated by the jackknife test, sets of genes to distinguish SPN and malignant pancreatic tumors were determined. RESULTS: We took a new strategy to identify candidate biomarkers for differentiating SPN from the two malignant pancreatic tumors PanNET and PDAC by analyzing shortest paths among SPN-related genes in the gene regulatory network. 43 new SPN-relevant genes were discovered, among which, we found hsa-miR-194 and hsa-miR-7 along with 7 transcription factors (TFs) such as SOX11, SMAD3 and SOX4 etc. could correctly differentiate SPN from PanNET, while hsa-miR-204 and 4 TFs such as SOX9, TCF7 and PPARD etc. were demonstrated as the potential markers for SPN versus PDAC. 14 genes were demonstrated to serve as the candidate biomarkers for distinguishing SPN from PanNET and PDAC when considering them as malignant pancreatic tumors together. CONCLUSION: This study provides new candidate genes related to SPN and the potential biomarkers to differentiate SPN from PanNET and PDAC, which may help to diagnose patients with SPN in clinical setting. Furthermore, candidate biomarkers such as SOX11 and hsa-miR-204 which could cause cell proliferation but inhibit invasion or metastasis may be of importance in understanding the molecular mechanism of pancreatic oncogenesis and could be possible therapeutic targets for malignant pancreatic tumors. PMID- 26578391 TI - Magnetic Bead/Gold Nanoparticle Double-Labeled Primers for Electrochemical Detection of Isothermal Amplified Leishmania DNA. AB - A novel methodology for the isothermal amplification of Leishmania DNA using labeled primers combined with the advantages of magnetic purification/preconcentration and the use of gold nanoparticle (AuNP) tags for the sensitive electrochemical detection of such amplified DNA is developed. Primers labeled with AuNPs and magnetic beads (MBs) are used for the first time for the isothermal amplification reaction, being the amplified product ready for the electrochemical detection. The electrocatalytic activity of the AuNP tags toward the hydrogen evolution reaction allows the rapid quantification of the DNA on screen-printed carbon electrodes. Amplified products from the blood of dogs with Leishmania (positive samples) are discriminated from those of healthy dogs (blank samples). Quantitative studies demonstrate that the optimized method allows us to detect less than one parasite per microliter of blood (8 * 10(-3) parasites in the isothermal amplification reaction). This pioneering approach is much more sensitive than traditional methods based on real-time polymerase chain reaction (PCR), and is also more rapid, cheap, and user-friendly. PMID- 26578392 TI - Early inflammation-associated factors blunt sterol regulatory element-binding proteins-1-mediated lipogenesis in high-fat diet-fed APPSWE /PSEN1dE9 mouse model of Alzheimer's disease. AB - Alzheimer's disease (AD) patients have an increased incidence of Type 2 diabetes (T2D); however, the underlying mechanisms are not well understood. Since AD is considered a multifactorial disease that affects both the central nerves system and periphery and the dysregulation of hepatic lipid and glucose metabolism play critical roles in T2D, we, therefore, aim to explore the influence of AD genotype on the liver during the progress of high-fat diet (HFD)-induced T2D. Fourteen week-old female APPSWE /PSEN1dE9 (AD) mice and age-, gender-matched wild-type controls C57BL/6J (WT) mice were fed a HFD (45% kcal fat content) or a standard chow diet (chow, 12% kcal fat content) for 22 weeks. The effects of diet and genotype were analyzed. Mouse primary hepatocytes were used to decipher the underlying mechanisms. HFD induced significantly higher body weight gain, more severe hyperglycemia, glucose intolerance and hepatic insulin resistance in AD mice than in WT mice. However, AD mice showed reduced HFD-induced hepatic steatosis, and SREBP-1-mediated lipogenic signaling was activated by HFD in WT mice but not in AD mice. In addition, 14-week-old AD mice exhibited higher expression of NF-kappaB p65, p-JNK and p-p38MAPK, as well as higher hepatic and serum contents of IL-6 and TNFalpha. In mouse primary hepatocyte cultures, IL-6 and TNFalpha inhibited high-glucose plus insulin-induced activation of SREBP-1 mediated lipogenic signaling and biosynthesis of non-esterified fatty acid and triglyceride. Early inflammation-associated factors most likely diminish HFD induced hepatic lipid deposition by inhibiting SREBP-1-mediated de novo lipogenesis, thus driving substrate flux to glucose production for hyperglycemia and hepatic insulin resistance in T2D development. Alzheimer's disease (AD) is a multifactorial disease affecting both central nerves system and periphery organs. Therefore, we explored the hepatic susceptibility to high-fat diet (HFD) in AD mice. We found that AD mice were resistant to HFD-induced hepatic fat accumulation in spite of more severe obesity, hyperglycemia, glucose intolerance and hepatic insulin resistance. Mechanistically, AD mice exhibited hepatic inflammation at an early stage, which inhibited sterol regulatory element-binding proteins-1 (SREBP-1)-mediated de novo lipogenesis, and most likely drive substrate flux to glucose production for hyperglycemia and hepatic insulin resistance. Cover Image for this issue: doi: 10.1111/jnc.13306. PMID- 26578394 TI - Natural killer cell-mediated damage of clinical isolates of mucormycetes. AB - Haematopoietic stem cell transplant (HSCT) recipients are at high risk for mucormycosis, which has a mortality of up to 90%. The adoptive transfer of Natural killer (NK) cells is a promising therapeutic option in order to improve the reconstitution of host immunity after HSCT and to directly combat the fungal pathogen. As a number of fungal pathogens have developed strategies to evade the innate immune system, we investigated the interaction of human NK cells with various clinical isolates of different species of mucormycetes. Our results show that human IL-2 prestimulated NK cells damaged all mucormycetes tested. The extent of the damage depended, at least in part, on the growth curve characteristics of the individual fungal isolate. All isolates decreased the secretion of interferon-gamma by NK cells to a similar extent. Our data suggest that NK cells damage a wide spectrum of mucormycetes, but that the antifungal effect is higher if NK cells are administered at an early time point of infection. PMID- 26578395 TI - Hemodynamic monitoring: To calibrate or not to calibrate? Part 2--Non-calibrated techniques. AB - There is much evidence that fluid overload leads to adverse outcomes in perioperative and critically ill patients. Cardiac output monitoring can help us guiding initial and ongoing fluid resuscitation and can help us to assess whether a patient will be responsive to fluids when hypotensive. In recent years, many sophisticated devices that measure a variety of hemodynamic parameters have evolved on the market. We wanted to provide an overview of the different techniques available today, including their validation in different patient populations. In this second part of the review, we focus on non-calibrated techniques, both invasive and non-invasive. For each technique a short overview of the working principle, together with the advantages, disadvantages and the available validation literature is listed. Many promising minimal invasive monitoring devices can help us to further optimize our hemodynamic treatment in both the perioperative and critical care setting. However, the validation data are scarce for many of these techniques, especially in complex circumstances with changing hemodynamics (preload, afterload and contractility), as with the use of fluids and vasoactive medication. The measurements made by these devices, therefore, need to be interpreted with caution. Further improvements and more validation data are needed before these techniques can be implemented in common day practice. Moreover, in severely shocked hemodynamic unstable patients, calibrated techniques are to be preferred over those which are uncalibrated. Hence, the new techniques not only need to be accurate, but also need to be precise in order to keep track of changes. PMID- 26578396 TI - Fluid therapy in critically ill patients: perspectives from the right heart. AB - As right heart function can affect outcome in the critically ill patient, a thorough understanding of factors determining right heart performance in health and disease is pivotal for the critical care physician. This review focuses on fluid therapy, which remains controversial in the setting of impending or overt right heart failure. In this context, we will attempt to elucidate which patients are likely to benefit from fluid administration and for which patients fluid therapy would likely be harmful. Following a general discussion of right heart function and failure, we specifically focus on important causes of right heart failure in the critically ill, i.e. sepsis induced myocardial dysfunction, the acute respiratory distress syndrome, acute pulmonary embolism and the effects of positive pressure ventilation. It is argued that fluid therapy should always be cautiously administered with the right heart in mind, which calls for close multimodal monitoring. PMID- 26578397 TI - Perioperative goal directed therapy using automated closed-loop fluid management: the future? AB - Although surgery has become much safer, it has also becoming increasingly more complex and perioperative complications continue to impact millions of patients worldwide each year. Perioperative hemodynamic optimization utilizing Goal Directed Therapy (GDT) has attracted considerable interest within the last decade due to its ability to improve postoperative short and long-term outcomes in patients undergoing higher risk surgeries. The concept of GDT in this context can be loosely defined as collecting data from minimally invasive hemodynamic monitors with the intention of using such data (flow-related parameters and/or dynamic parameters of fluid responsiveness) to titrate therapeutic interventions (intravenous fluids and/or inotropic therapy administration) with the ultimate aim of optimizing end organ tissue perfusion. Recently, the increasing amount of evidence supporting the implementation of GDT strategies has been considered so robust as to allow for the creation of national recommendations in the United Kingdom (UK), France, and Europe. These recommendations from such influential scientific societies and the potential clinical and economic benefits of GDT protocols need to also be examined within the current shift from a "pay for service" to a "pay for performance" health care system. This shift is strongly encouraged within emerging systems such as the Perioperative Surgical Home (PSH) paradigm from the United States. As a result, hospitals and clinicians around the world have become increasingly incentivized to implement perioperative hemodynamic optimization using GDT strategies within their departments. Unfortunately, its adoption continues to be quite limited and a lack of standardized criteria for perioperative fluid administrations has resulted in significant clinical variability among practitioners. This current review will provide a brief up-to-date overview of GDT, discuss current clinical practice, analyze why implementation has been limited and finally, describe the newer closed-loop GDT concept along with its potential risks and benefits. PMID- 26578398 TI - Critical care ultrasound in cardiac arrest. Technological requirements for performing the SESAME-protocol--a holistic approach. AB - The use of ultrasound has gained its place in critical care as part of our day-to day monitoring tools. A better understanding of ultrasound techniques and recent publications including protocols for the lungs, the abdomen and the blood vessels has introduced ultrasound to the bedside of our ICU patients. However, we will prove in this paper that early machines, dating back more than 25 years, were perfectly able to do the job as compared to modern laptop machines with more features but few additional advantages. Ultrasound is not only a diagnostic tool, but should also be seen as an extension of the traditional physical examination. This paper will focus on the use of the SESAME-protocol in cardiac arrest. The SESAME-protocol suggests starting with a lung scan to rule out possible causes leading to cardiac arrest. Firstly, pneumothorax needs to be ruled out. Secondly, a partial diagnosis of pulmonary embolism is done following the BLUE-protocol. Thirdly, fluid therapy can be guided, following the FALLS-protocol. The SESAME protocol continues by scanning the lower femoral veins to check for signs of deep venous thrombosis, followed by (or before, in case of trauma) the abdomen to detect massive bleeding. Next comes the pericardium, to exclude pericardial tamponade. Finally, a transthoracic cardiac ultrasound is performed to check for other (cardiac) causes leading to cardiac arrest. The emphasis is on a holistic approach, where ultrasound can be seen as the modern stethoscope needed by clinicians to complete the full physiological examination of their critically ill unstable patients. PMID- 26578393 TI - Aging and the cardiac collagen matrix: Novel mediators of fibrotic remodelling. AB - Cardiovascular disease is a leading cause of death worldwide and there is a pressing need for new therapeutic strategies to treat such conditions. The risk of developing cardiovascular disease increases dramatically with age, yet the majority of experimental research is executed using young animals. The cardiac extracellular matrix (ECM), consisting predominantly of fibrillar collagen, preserves myocardial integrity, provides a means of force transmission and supports myocyte geometry. Disruptions to the finely balanced control of collagen synthesis, post-synthetic deposition, post-translational modification and degradation may have detrimental effects on myocardial functionality. It is now well established that the aged heart is characterized by fibrotic remodelling, but the mechanisms responsible for this are incompletely understood. Furthermore, studies using aged animal models suggest that interstitial remodelling with disease may be age-dependent. Thus with the identification of new therapeutic strategies targeting fibrotic remodelling, it may be necessary to consider age dependent mechanisms. In this review, we discuss remodelling of the cardiac collagen matrix as a function of age, whilst highlighting potential novel mediators of age-dependent fibrotic pathways. PMID- 26578399 TI - Hemodynamic monitoring: To calibrate or not to calibrate? Part 1--Calibrated techniques. AB - Over recent decades, hemodynamic monitoring has evolved from basic cardiac output monitoring techniques to a broad variety of sophisticated monitoring devices with extra parameters. In order to reduce morbidity and mortality and optimize therapeutic strategies, different monitoring techniques can be used to guide fluid resuscitation and other medical management. Generally, they can be divided in calibrated and non-calibrated techniques. In the first part of this review, the available calibrated techniques, ranging from invasive to non-invasive, will be discussed. We performed a review of the literature in order to give an overview of the current hemodynamic monitoring devices. For each monitoring system, a short overview of the physical principles, the advantages and disadvantages and the available literature with regard to validation is given. Currently, many promising hemodynamic monitoring devices are readily available in order to optimize therapeutic management in both perioperative and ICU settings. Although several of these calibrated techniques have been validated in the literature, not all techniques have been shown to reduce morbidity and mortality. Many new techniques, especially some non-calibrated devices, lack good validation data in different clinical settings (sepsis, trauma, burns, etc.). The cardiac output values obtained with these techniques need therefore to be interpreted with caution as will be discussed in the second part of this concise review. Transthoracic echocardiography forms a good initial choice to assess hemodynamics in critically ill patients after initial stabilisation. However in complex situations or in patients not responding to fluid resuscitation alone, advanced hemodynamic monitoring is recommended with the use of calibrated techniques like transpulmonary thermodilution. Calibrated techniques are preferred in patients with severe shock and changing conditions of preload, afterload and contractility. The use of the pulmonary artery catheter should be reserved for patients with right ventricular failure in order to assess the effect of medical treatment. PMID- 26578400 TI - Initial resuscitation from severe sepsis: one size does not fit all. AB - Over recent decades many recommendations for the management of patients with sepsis and septic shock have been published, mainly as the Surviving Sepsis Campaign (SSC) guidelines. In order to use these recommendations at the bedside one must fully understand their limitations, especially with regard to preload assessment, fluid responsiveness and cardiac output. In this review we will discuss the evidence behind the bundles presented by the Surviving Sepsis Campaign and will try to explain why some recommendations may need to be updated. Barometric preload indicators, such as central venous pressure (CVP) or pulmonary artery occlusion pressure, can be persistently low or erroneously increased, as is the case in situations of increased intrathoracic pressure, as seen with the application of high positive end-expiratory pressure, or in situations with increased intra-abdominal pressure. Chasing a CVP of 8 to 12 mm Hg may lead to under-resuscitation in these situations. On the other hand, a low CVP does not always correspond to fluid responsiveness and may lead to over-resuscitation and all the deleterious effects on end-organ function associated with fluid overload. We will suggest the introduction of new variables and more dynamic measurements. During the initial resuscitation phase, it is equally important to assess fluid responsiveness, either with a passive leg raising manoeuvre or an end-expiratory occlusion test. The use of functional hemodynamics with stroke volume variation or pulse pressure variation may further help to identify patients who will respond to fluid administration or not. Furthermore, ongoing fluid resuscitation beyond the first 24 hours guided by CVP may lead to futile fluid loading. In patients that do not transgress spontaneously from the Ebb to Flow phase of shock, one should consider (active) de-resuscitation guided by extravascular lung water index measurements. PMID- 26578401 TI - Prospective assessment of the decision-making impact of the Breast Cancer Index in recommending extended adjuvant endocrine therapy for patients with early-stage ER-positive breast cancer. AB - Extended adjuvant endocrine therapy (10 vs. 5 years) trials have demonstrated improved outcomes in early-stage estrogen receptor (ER)-positive breast cancer; however, the absolute benefit is modest, and toxicity and tolerability challenges remain. Predictive and prognostic information from genomic analysis may help inform this clinical decision. The purpose of this study was to assess the impact of the Breast Cancer Index (BCI) on physician recommendations for extended endocrine therapy and on patient anxiety and decision conflict. Patients with stage I-III, ER-positive breast cancer who completed at least 3.5 years of adjuvant endocrine therapy were offered participation. Genomic classification with BCI was performed on archived tumor tissues and the results were reported to the treating physician who discussed results with the patient. Patients and physicians completed pre- and post-test questionnaires regarding preferences for extended endocrine therapy. Patients also completed the validated traditional Decisional Conflict Scale (DCS) and State Trait Anxiety Inventory forms (STAI-Y1) pre- and post-test. 96 patients were enrolled at the Yale Cancer Center [median age 60.5 years (range 45-87), 79% postmenopausal, 60% stage I). BCI predicted a low risk of late recurrence in 59% of patients versus intermediate/high in 24 and 17%, respectively. Physician recommendations for extended endocrine therapy changed for 26% of patients after considering BCI results, with a net decrease in recommendations for extended endocrine therapy from 74 to 54%. After testing, fewer patients wanted to continue extended therapy and decision conflict and anxiety also decreased. Mean STAI and DCS scores were 31.3 versus 29.1 (p = 0.031) and 20.9 versus 10.8 (p < 0.001) pre- and post-test, respectively. Incorporation of BCI into risk/benefit discussions regarding extended endocrine therapy resulted in changes in treatment recommendations and improved patient satisfaction. PMID- 26578402 TI - Using Classification and Regression Trees (CART) to Identify Prescribing Thresholds for Cardiovascular Disease. AB - BACKGROUND AND OBJECTIVE: Many guidelines for clinical decisions are hierarchical and nonlinear. Evaluating if these guidelines are used in practice requires methods that can identify such structures and thresholds. Classification and regression trees (CART) were used to analyse prescribing patterns of Australian general practitioners (GPs) for the primary prevention of cardiovascular disease (CVD). Our aim was to identify if GPs use absolute risk (AR) guidelines in favour of individual risk factors to inform their prescribing decisions of lipid lowering medications. METHODS: We employed administrative prescribing information that is linked to patient-level data from a clinical assessment and patient survey (the AusHeart Study), and assessed prescribing of lipid-lowering medications over a 12-month period for patients (n = 1903) who were not using such medications prior to recruitment. CART models were developed to explain prescribing practice. Out-of-sample performance was evaluated using receiver operating characteristic (ROC) curves, and optimised via pruning. RESULTS: We found that individual risk factors (low-density lipoprotein, diabetes, triglycerides and a history of CVD), GP-estimated rather than Framingham AR, and sociodemographic factors (household income, education) were the predominant drivers of GP prescribing. However, sociodemographic factors and some individual risk factors (triglycerides and CVD history) only become relevant for patients with a particular profile of other risk factors. The ROC area under the curve was 0.63 (95% confidence interval [CI] 0.60-0.64). CONCLUSIONS: There is little evidence that AR guidelines recommended by the National Heart Foundation and National Vascular Disease Prevention Alliance, or conditional individual risk eligibility guidelines from the Pharmaceutical Benefits Scheme, are adopted in prescribing practice. The hierarchy of conditional relationships between risk factors and socioeconomic factors identified by CART provides new insights into prescribing decisions. Overall, CART is a useful addition to the analyst's toolkit when investigating healthcare decisions. PMID- 26578403 TI - Use of Value of Information in Healthcare Decision Making: Exploring Multiple Perspectives. AB - BACKGROUND: Value of information (VOI) is a tool that can be used to inform decisions concerning additional research in healthcare. VOI estimates the value of obtaining additional information and indicates the optimal design for additional research. Although it is recognized as good practice in handling uncertainty, it is still hardly used in decision making in the Netherlands. OBJECTIVE: This paper aims to examine the potential value of VOI, barriers and facilitators and the way forward with the use of VOI in the decision-making process for reimbursement of pharmaceuticals in the Netherlands. METHODS: Three focus group interviews were conducted with researchers, policy makers, and representatives of pharmaceutical companies. RESULTS: The results revealed that although all stakeholders recognize the relevance of VOI, it is hardly used and many barriers to the performance and use of VOI were identified. One of these barriers is that not all uncertainties are easily incorporated in VOI, and the results may be biased if structural uncertainties are ignored. Furthermore, not all research designs indicated by VOI may be feasible in practice. CONCLUSIONS: To fully embed VOI into current decision-making processes, a threshold incremental cost-effectiveness ratio and guidelines that clarify when and how VOI should be performed are needed. In addition, it should be clear to all stakeholders how the results of VOI are used in decision making. PMID- 26578404 TI - Patient-Controlled Therapy of Breathlessness in Palliative Care: A New Therapeutic Concept for Opioid Administration? AB - CONTEXT: Breathlessness is one of the most distressing symptoms experienced by patients with advanced cancer and noncancer diagnoses alike. Often, severity of breathlessness increases quickly, calling for rapid symptom control. Oral, buccal, and parenteral routes of provider-controlled drug administration have been described. It is unclear whether patient-controlled therapy (PCT) systems would be an additional treatment option. OBJECTIVES: To investigate whether intravenous opioid PCT can be an effective therapeutic method to reduce breathlessness in patients with advanced disease. Secondary aims were to study the feasibility and acceptance of opioid PCT in patients with refractory breathlessness. METHODS: This was a pilot observational study with 18 inpatients with advanced disease and refractory breathlessness receiving opioid PCT. Breathlessness was measured on a self-reported numeric rating scale. Richmond Agitation Sedation Scale scores, Palliative Performance Scale scores, vital signs, and a self-developed patient satisfaction questionnaire were used for measuring secondary outcomes. Descriptive and interference analyses (Friedman test) and post hoc analyses (Wilcoxon tests and Bonferroni corrections) were performed. RESULTS: Eighteen of 815 patients (advanced cancer; median age = 57.5 years [range 36-81]; 77.8% female) received breathlessness symptom control with opioid PCT; daily morphine equivalent dose at Day 1 was median = 20.3 mg (5.0 49.6 mg); Day 2: 13.0 mg (1.0-78.5 mg); Day 3: 16.0 mg (8.3-47.0 mg). Numeric rating scale of current breathlessness decreased (baseline: median = 5 [range 1 10]; Day 1: median = 4 [range 0-8], P < 0.01; Day 2: median = 4 [range 0-5], P < 0.01). Physiological parameters were stable over time. On Day 3, 12/12 patients confirmed that this mode of application provided relief of breathlessness. CONCLUSION: Opioid PCT is a feasible and acceptable therapeutic method to reduce refractory breathlessness in palliative care patients. PMID- 26578406 TI - An adaptive classification model for peptide identification. AB - BACKGROUND: Peptide sequence assignment is the central task in protein identification with MS/MS-based strategies. Although a number of post-database search algorithms for filtering target peptide spectrum matches (PSMs) have been developed, the discrepancy among the output PSMs is usually significant, remaining a few disputable PSMs. Current studies show that a number of target PSMs which are close to decoy PSMs can hardly be separated from those decoys by only using the discrimination function. RESULTS: In this paper, we assign each target PSM a weight showing its possibility of being correct. We employ a SVM based learning model to search the optimal weight for each target PSM and develop a new score system, CRanker, to rank all target PSMs. Due to the large PSM datasets generated in routine database searches, we use the Cholesky factorization technique for storing a kernel matrix to reduce the memory requirement. CONCLUSIONS: Compared with PeptideProphet and Percolator, CRanker has identified more PSMs under similar false discover rates over different datasets. CRanker has shown consistent performance on different test sets, validated the reasonability the proposed model. PMID- 26578407 TI - The immunoproteasome controls the availability of the cardioprotective pattern recognition molecule Pentraxin3. AB - Cardiomyocyte death as a result of viral infection is an excellent model for dissecting the inflammatory stress response that occurs in heart tissue. We reported earlier that a specific proteasome isoform, the immunoproteasome, prevents exacerbation of coxsackievirus B3 (CVB3)-induced myocardial destruction and preserves cell vitality in heart tissue inflammation. Following the aim to decipher molecular targets of immunoproteasome-dependent proteolysis, we investigated the function and regulation of the soluble PRR Pentraxin3 (PTX3). We show that the ablation of PTX3 in mice aggravated CVB3-triggered inflammatory injury of heart tissue, without having any significant effect on viral titers. Thus, there might be a role of PTX3 in preventing damage-associated molecular pattern-induced cell death. We found that the catalytic activity of the immunoproteasome subunit LMP7 regulates the timely availability of factors controlling PTX3 production. We report on immunoproteasome-dependent alteration of ERK1/2 and p38MAPKs, which were both found to be involved in PTX3 expression control. Our finding of a cardioprotective function of immunoproteasome-dependent PTX3 expression revealed a crucial mechanism of the stress-induced damage response in myocardial inflammation. In addition to antigen presentation and cytokine production, proteolysis by the immunoproteasome can also regulate the innate immune response during viral infection. PMID- 26578408 TI - Diffractive Optical Analysis for Refractive Index Sensing using Transparent Phase Gratings. AB - We report the implementation of a micro-patterned, glass-based photonic sensing element that is capable of label-free biosensing. The diffractive optical analyzer is based on the differential response of diffracted orders to bulk as well as surface refractive index changes. The differential read-out suppresses signal drifts and enables time-resolved determination of refractive index changes in the sample cell. A remarkable feature of this device is that under appropriate conditions, the measurement sensitivity of the sensor can be enhanced by more than two orders of magnitude due to interference between multiply reflected diffracted orders. A noise-equivalent limit of detection (LoD) of 6 * 10(-7) was achieved with this technique with scope for further improvement. PMID- 26578409 TI - Antihyperglycemic effect of short-term arginyl-fructose supplementation in subjects with prediabetes and newly diagnosed type 2 diabetes: randomized, double blinded, placebo-controlled trial. AB - BACKGROUND: A previous study reported that arginyl-fructose may have great value as a functional food with antioxidant and antidiabetic activities. However, there have been few clinical studies on the efficacy of arginyl-fructose supplementation for blood glucose control. METHODS: In this double-blind, placebo controlled study, 60 Korean subjects with prediabetes or type 2 diabetes mellitus were randomly assigned to placebo or test groups. The test group subjects received 1500 mg/day arginyl-fructose. Fasting serum levels of glucose, hemoglobin A1c, insulin, and free fatty acids were measured by 2-hour oral glucose tolerance tests at baseline and after the 6-week intervention. Eleven subjects dropped out or were excluded during the trial. The data for the remaining 49 were statistically analyzed using Student's t-test and paired t test. RESULTS: After the 6-week intervention, the test group showed significant reductions in serum glucose levels at 30 minutes (-19.4 +/- 5.62 mg/dL) and 60 minutes (-15.4 +/- 7.01 mg/dL) and reduced glucose area under the curve (-27.4 +/ 8.59 mg/dL) compared with those of the placebo control group. The changes (differences from baseline) in serum glucose levels at 60 minutes and glucose area under the curve in the test group differed significantly from those in the control group even after adjusting for baseline values. In contrast, glucose related biomarkers including hemoglobin A1c, insulin, and C-peptide levels were not significantly improved by the dietary intervention with arginyl-fructose. CONCLUSIONS: Arginyl-fructose supplementation (1500 mg/day) may be beneficial for reducing postprandial blood glucose levels in patients with prediabetes or type 2 diabetes mellitus. TRIAL REGISTRATION: ClinicalTrials.gov NCT02285231 . Registered 11 May 2014. PMID- 26578411 TI - [The right to die with dignity]. PMID- 26578410 TI - Time course of the response to ACTH in pig: biological and transcriptomic study. AB - BACKGROUND: HPA axis plays a major role in physiological homeostasis. It is also involved in stress and adaptive response to the environment. In farm animals in general and specifically in pigs, breeding strategies have highly favored production traits such as lean growth rate, feed efficiency and prolificacy at the cost of robustness. On the hypothesis that the HPA axis could contribute to the trade-off between robustness and production traits, we have designed this experiment to explore individual variation in the biological response to the main stress hormone, cortisol, in pigs. We used ACTH injections to trigger production of cortisol in 120 juvenile Large White (LW) pigs from 28 litters and the kinetics of the response was measured with biological variables and whole blood gene expression at 4 time points. A multilevel statistical analysis was used to take into account the longitudinal aspect of the data. RESULTS: Cortisol level reached its peak 1 h after ACTH injection. White blood cell composition was modified with a decrease of lymphocytes and monocytes and an increase of granulocytes (F D R<0.05). Basal level of cortisol was correlated with birth and weaning weights. Microarray analysis identified 65 unique genes of which expression responded to the injection of ACTH (adjusted P<0.05). These genes were classified into 4 clusters with distinctive kinetics in response to ACTH injection. The first cluster identified genes strongly correlated to cortisol and previously reported as being regulated by glucocorticoids. In particular, DDIT4, DUSP1, FKBP5, IL7R, NFKBIA, PER1, RGS2 and RHOB were shown to be connected to each other by the glucocorticoid receptor NR3C1. Most of the differentially expressed genes that encode transcription factors have not been described yet as being important in transcription networks involved in stress response. Their co expression may mean co-regulation and they could thus provide new patterns of biomarkers of the individual sensitivity to cortisol. CONCLUSIONS: We identified 65 genes as biological markers of HPA axis activation at the gene expression level. These genes might be candidates for a better understanding of the molecular mechanisms of the stress response. PMID- 26578412 TI - [Hematological Evaluation and Monitoring in Adult Patients Diagnosed With Schizophrenia]. AB - OBJECTIVES: To guide the clinician in taking decisions on the best strategies for assessing and monitoring the risk of blood disorders in adults diagnosed with schizophrenia in pharmacological treatment. METHOD: A clinical practice guideline was developed following the guidelines of the Methodological Guide of the Ministry of Social Protection to collect evidence and grade recommendations. De novoliterature researchwas performed. RESULTS: With the use of antipsychotics there isriskofreduccion in the leukocyte count and the risk of agranulocytosis,the later associated with the use of clozapine, although it is a rare event(0.8%) can be fatal; this effect occurs most frequently in the first twelve weeks of treatment and the risk is maintained aroundthe first year of it. CONCLUSION: The recommendations were considered strongin all hematologic related monitoring.A blood count should be taken at the start of pharmacological treatment. If the patient is started on clozapine one shouldbe taken weekly during the first three months, monthly until completing one year and every six months thereafter. If there is a decrease in white blood cell count the patient should be monitored regularly, stopping if is a less than 3,500 cells/mm(3) and consider referral if is less than 2,000 cells/mm(3). PMID- 26578413 TI - [Excessive Daytime Sleepiness, Poor Quality Sleep, and Low Academic Performance in Medical Students]. AB - INTRODUCTION: Quality of sleep and excessive daytime sleepiness (EDS) affect cognitive ability and performance of medical students. This study attempts to determine the prevalence of EDS, sleep quality, and assess their association with poor academic performance in this population. MATERIAL AND METHODS: A descriptive, observational study was conducted on a random sample of 217 medical students from the Universidad Tecnologica de Pereira, who completed the Pittsburgh Sleep Quality Index (PSQI) questionnaire and the Epworth sleepiness scale. Sociodemographic, clinic and academic variables were also measured. Multivariate analyses for poor academic performance were performed. RESULTS: The included students had a mean age of 21.7+/-3.3 years, of whom 59.4% were men. Almost half (49.8%) had EDS criteria, and 79.3% were poor sleepers (PSQI >= 5), while 43.3% had poor academic performance during the last semester. The bivariate analysis showed that having used tobacco or alcohol until intoxicated, fairly bad subjective sleep quality, sleep efficiency < 65%, and being a poor sleeper were associated with increased risk of low performance. Sleep efficiency < 65% was statistically associated with poor academic performance (P=.024; OR = 4.23; 95% CI, 1.12-15.42) in the multivariate analysis. CONCLUSIONS: A poor sleep quality determined by low efficiency was related to poor academic achievement at the end of semester in medical students. PMID- 26578414 TI - [Psychoeducation in schizophrenia]. AB - BACKGROUND: The treatment of schizophrenia includes the use of psychotropic drugs, psychotherapy, and psychosocial interventions that include psychoeducation. This strategy has been defined as the delivery of information about the disorder and its treatment in a systematic and structured way. OBJECTIVE: To review the literature on the efficacy of psychoeducation in schizophrenia. METHODS: A search in PubMed, SciELO, EMBASE and PsycINFO was made with the terms "psychoeducation", "schizophrenia" and "psychosocial intervention". Articles in Spanish and English language were reviewed. RESULTS: Psychoeducation can be applied to patients, family or both, and individually or in groups. The number of sessions can vary. There have been many studies that seek to determine the efficacy of psychoeducation in the clinical course, family dynamics and stigma, with results that favor its implementation, but so far it has not been possible to determine exactly how best to apply psychoeducation, mainly because of the great variability of designs. CONCLUSIONS: The studies on psychoeducation have shown efficacy. However, this might be an overestimation, as there is a high risk of bias. Consequently, there is not enough evidence. At least for now, it is reasonable to complement pharmacotherapy with psycoeducation. PMID- 26578415 TI - [Description of Clinical and Neurocognitive Profiles in Offspring of Bipolar-Type I Parents From a Multimodal Intervention Program: Prisma]. AB - INTRODUCTION: Offspring of bipolar parents are a high risk population for the develop of mental diseases, their study allow determining the genetic risk, early symptoms, prodromes and psychopathology of bipolar disorder. OBJECTIVE: To describe the psychopathological characteristics and neurocognitives profiles of the offspring of bipolar type I parents. And to identify the presence of sub syndromal symptoms in all the symptom domains. METHODS: A descriptive and cross sectional study was conducted on 110 offspring between 6 and 30 years old. Semi structured diagnostic interviews were performed. The intelectual coeficient was determined and a neuropsychological assessment was performed on 89 offspring. RESULTS: The most prevalent disorder in the offspring was ADHD (27.6%), with major depression (15.5%) and separation anxiety (14.1%) also being prevalent. Seven patients of the sample were diagnosed with bipolar disorder. There was a statistically significant difference between the age groups for ADHD prevalence. The most frequent sub-syndromal symptoms were observed in the disruptive group. Alterations in the cognitive domains: attention, verbal fluency, work memory, and speed of information processing, were observed in the group younger than 18 years. CONCLUSIONS: The offspring of bipolar parents have an elevated rate of psychopathology and cognitive alterations. They are a high risk population for the development of mental disease. These subjects also require close longitudinal observation and early and preventive therapeuthic interventions. PMID- 26578416 TI - [Sociodemographic Traits and Comorbidities in Pathological Gamblers With a Suicide Attempt in Spain]. AB - OBJECTIVE: Suicide is the first cause of non-natural death in Spain. Among addictive disorders, pathological gambling is one the most significant independent risk factors for suicidal behavior. The objective of this study is to describe and compare the sociodemographic traits, comorbidity and attempt characteristics, between suicide attempters who fulfill diagnostic criteria for pathological gambling and those who do not. METHODS: A total of 345 patients admitted to the emergency department of a University Hospital in Madrid between 1999 and 2004 were interviewed for this study. To describe and compare the demographic characteristics, comorbidity and those related to attempted suicide, using logistic regression models adjusted for sex and age were used. RESULTS: Suicide attempters who fulfilled diagnostic criteria for pathological gambling were predominantly male, with a low education level, and had more offspring. Furthermore, these patients had more comorbidities, such as: global substance dependence, nicotine, cocaine and opioid dependence. CONCLUSIONS: The present study suggests that pathological gamblers represent a distinct subgroup among suicide attempters, with particular characteristics, similar to those found in pathological gamblers in the general population. PMID- 26578417 TI - [Structure and Family Type in Patients With Substance Abuse or Dependence Psychoactive Rehabilitation Center of Addiction in the Municipality of Chia Cundinamarca]. AB - OBJECTIVE: To determine the family type, family structure in a group of patients with a diagnosis of substance abuse or dependence who were at a rehabilitation center for addiction during the period between August and October 2009. METHODS: Through a descriptive qualitative-interpretative methodology 10 patients who met inclusion criteria for substance dependence or abuse were studied. The fieldwork and transcripts were made for three months by non-participant observation, non structured interviews and examination of patients' clinical history. RESULTS: Seven of the families interviewed were single-parent families with an unconventional organization on "gender roles". Single-parent families favored loneliness, difficulty in rule-setting, de-idealization of the place of the father in the family structure and a constant search for complicity. In the analysis by categories, we found that in 10 families in the study of individuals with addictions it is common to find family structure characteristics such as inadequate communication, lack of authority rules and limits, presence of triangulations, the lack of cohesion due to the existence of a disconnected relationship pattern and changed roles compared to conventional gender. The search for the affection of the mother at her emotional overload absence of roles and lack of father, raised by the separation of the couple, was found as an essential aspect underlying the addictive behavior. A pattern of parental abandonment is configured. CONCLUSION: The findings confirmed what has been mentioned by various authors regarding the characteristics of the family typology structure and personal factors in patients with addictions, in addition to their need for affection combined with the desire for the mother's presence. The family typology does not determine for itself the abuse of psychoactive substances, but the influence of other factors such as family structure, especially deficient affective interactions, which should be considered in the development of therapeutic strategies. PMID- 26578418 TI - [Binge Eating Disorder: Prevalence, Associated Factors and Obesity in University Students]. AB - BACKGROUND: Binge eating disorder (BED) is a disorder of eating behavior that can affect people of all ages. AIM: To determine the prevalence of BED according to criteria of the Diagnostic and Statistical Manual of Mental Disorders-V, associated factors and their relationship to obesity in university students at Barquisimeto (Venezuela), between September 2013 and February 2014. PATIENTS AND METHODS: A study was conducted on a sample of 497 university students of both sexes (371 females), between 18 and 28 years old. A questionnaire was applied and anthropometric measurements were recorder: Weight, height, body mass index (BMI), waist circumference (CW) and waist-height ratio (WHR). RESULTS: The prevalence of BED was 3.20%. Factors associated with BED were body image dissatisfaction, family dysfunction, and depressive symptoms. BED was significantly associated with global obesity and central obesity. CONCLUSIONS: Changes in diagnostic criteria of BED, introduced in DSM-V, do not appear to increase the prevalence of BED. Important psychosocial factors associated with BED were identified. BED was strongly associated with global and central obesity. Further studies need to be carried out, withmore rigorous designs to elucidate the effects of the new definition by DSM-V, and to determine the causal nature of the associations found. PMID- 26578419 TI - [Rhabdomyolysis in a Bipolar Adolescent. Analysis of Associated Factors]. AB - OBJECTIVE: To describe a case of rhabdomyolysis associated with the use of quetiapine and lamotrigine in an adolescent treated for bipolar disorder. METHOD: Description of the clinical case, analysis of the associated factors and a non systematic review of the relevant literature. RESULTS: An 18 year old male, with bipolar disorder and treated pharmacologically with quetiapine and lamotrigine, after two weeks of physical activity presents with rhabdomyolysis. Quetiapine and exercise have been associated with rhabdomyolysis. The mediator mechanism of this association has not been found, although it has been established that there is neuromuscular dysfunction and an increase in sarcomere permeability. CONCLUSIONS: This clinical case allowed the complex interaction between antipsychotic agents and increased physical activity to be observed in a psychiatric adolescent patient, as well as the appearance of a potentially lethal medical complication. PMID- 26578420 TI - [Epistemic and historical elucidation of the borderline personality disorder]. AB - INTRODUCTION: The particularities of those that have been considered "hard cases" in the clinical field, and their relationship with personality disorders, are discussed together with their quintessential conceptual and diagnostic model: the borderline personalities. The aim of the study is to historically and epistemologically rebuild their origins within psychiatry and psychoanalysis. METHODS AND RESULTS: From a classical epistemological and historical study, a brief tour is made through the nineteenth century alienism and the postulate of "partial insanity". Next, a passage is spawned through the concepts that emerged from this postulate: "monomania" and "moral insanity", up to mid-century Kraepelin and the "fundamental states" of manic-depressive insanity as pathological constitutional forms or characters, and reaching the twentieth century with characterology and psychopathic personalities. Finally, psychoanalysis is analyzed as the main source of borderline personality disorders arising from the problems encountered in analytical treatments and the development of the notion of "character neurosis". CONCLUSIONS: Borderline personality disorders are the result of the conjunction of a number of factors, heirs of the notion of "partial insanity", of the fundamental states of manic depression insanity, of characterology, of the idea of constitutions and pathological personalities, together with the emerging concerns of psychoanalysis in the early twentieth century. PMID- 26578421 TI - Perceived coercion in inpatients with Anorexia nervosa: Associations with illness severity and hospital course. AB - OBJECTIVE: The use of coercion in the treatment for anorexia nervosa (AN) is controversial and the limited studies to date have focused on involuntary treatment. However, coercive pressure for treatment that does not include legal measures is common in voluntarily admitted patients with AN. Empirical data examining the effect of non-legal forms of coerced care on hospital outcomes are needed. METHOD: Participants (N = 202) with AN, Avoidant/Restrictive Food Intake Disorder (ARFID), or subthreshold AN admitted to a hospital-based behavioral specialty program completed questionnaires assessing illness severity and perceived coercion around the admissions process. Hospital course variables included inpatient length of stay, successful transition to a step-down partial hospitalization program, and achievement of target weight prior to program discharge. RESULTS: Higher perceived coercion at admission was associated with increased drive for thinness and body dissatisfaction, but not with admission BMI. Perceived coercion was not related to inpatient length of stay, rate of weight gain, or achievement of target weight although it was predictive of premature drop-out prior to transition to an integrated partial hospitalization program. DISCUSSION: These results, from an adequately powered sample, demonstrate that perceived coercion at admission to a hospital-based behavioral treatment program was not associated with rate of inpatient weight gain or achieving weight restoration, suggesting that coercive pressure to enter treatment does not necessarily undermine formation of a therapeutic alliance or clinical progress. Future studies should examine perceived coercion and long-term outcomes, patient views on coercive pressures, and the effect of different forms of leveraged treatment. PMID- 26578422 TI - Comparison of the intraocular pressure-lowering effect and safety of brimonidine/timolol fixed combination and 0.5% timolol in normal-tension glaucoma patients. AB - PURPOSE: To compare the therapeutic efficacy and safety of brimonidine/timolol fixed-combination (BTFC) and 0.5% timolol ophthalmic solution in normal-tension glaucoma (NTG) patients. METHODS: This was a multi-institution, randomized, active-controlled, open-label, parallel-group study. After a full ophthalmic and glaucoma examination, a total of 110 NTG patients--55 undergoing therapy with BTFC and 55 0.5%, with timolol--participated in this study. Among them, 1 failed to meet the inclusion/exclusion criteria, 10 revoked their consent to participate in the study, 3 had adverse reactions, and 1 had a drug adherence rate of less than 70%. Ultimately, a total of 95 patients--48 in the BTFC group and 47 in the 0.5% timolol group--completed the study. The study visits took place at baseline and at 4 and 12 weeks. Diurnal IOP was measured at 9 a.m., 11 a.m., and 5 p.m. during the baseline visit and the visit at 12 weeks after eye-drop instillation. At each follow-up visit, compliance was assessed. Throughout the study, all adverse events were recorded and monitored by the investigators. RESULTS: The average difference in IOP change measured at 11 a.m. 12 weeks after administration between the two groups was 2.10 +/- 2.59 mmHg. The BTFC group had a better IOP-lowering effect at all time points than did the 0.5% timolol group. The ratio of patients whose average IOP had decreased by >20% after 4 and 12 weeks was 50 and 56% in the BTFC group, respectively, whereas it was 29.41 and 23.53% in the 0.5% timolol group, respectively (p = 0.034, <0.001). CONCLUSIONS: BTFC has a superior IOP-lowering effect than 0.5% timolol in NTG patients. PMID- 26578423 TI - The status of occupational blood and infectious body fluids exposures in five blood centres in China: a 5-year review. AB - BACKGROUND: Little information about the occupational exposures to blood and body fluid (BBF) among blood service workers (BSWs) in blood stations in China is available currently. OBJECTIVES: To assess current status of occupational exposure to BBF and assess the knowledge about occupational blood-borne pathogen exposures and universal precaution among BSWs in blood donations in China. To understand the incidence of occupational exposure in five blood centres in China. METHODS: A cross-sectional study was conducted from January 2008 to December 2013. RESULTS: There were a total of 99 BBF exposures reported during the study period. The total incidence of BBF exposures was 4.4 per 100 person-years. Higher rates were observed for persons employed less than five years and persons less than 45 years old. Nurses have the highest percentage (49.5%) of BBF exposures. BBF exposures occurred most commonly during the afternoon (62.7%). Percutaneous injuries were the most common BBF exposures. Most incidents occurred during sharps use (73.4%). The major cause of occupational exposure was that there was no continuous training (48.4%) and improper use of equipment (23.2%). Only 56.6% of BBF exposures had appropriate first aid measures. During this research work, one staff member was reported to have seroconverted to syphilis after BBF exposure. CONCLUSIONS: To reduce BBF exposures, it is urgent to take several effective actions in China, including improved occupational health systems, adequate education, administrative support, increased use of standard precautions, better safety devices/products and work practices. PMID- 26578424 TI - A post-earthquake psychopathological investigation in Armenia: methodology, summary of findings, and follow-up. AB - The post-earthquake psychopathological investigation (PEPSI) was designed to probe the short-and long-term effects of the earthquake in northern Armenia on 7 December 1988 on survivors' mental and physical health. Four phases of this study have been conducted to date, and, overall, more than 80 per cent of a sub-sample of 1,773 drawn from an initial cohort of 32,743 was successfully followed during 2012. This paper describes the methodology employed in the evaluation, summarises previous findings, details the current objectives, and examines the general characteristics of the sample based on the most recent follow-up phase outcomes. Despite a significant decrease in psychopathology rates between 1990 and 2012, prevalence rates of post-traumatic stress disorder and depression among study participants in 2012 were greater than 15 and 26 per cent, respectively. The paper also notes the strengths and limitations of the study vis-a-vis future research and highlights the importance and potential practical implications of similar assessments and their outcomes. PMID- 26578425 TI - Synthesis of Large Area Graphene for High Performance in Flexible Optoelectronic Devices. AB - This work demonstrates an attractive low-cost route to obtain large area and high quality graphene films by using the ultra-smooth copper foils which are typically used as the negative electrodes in lithium-ion batteries. We first compared the electronic transport properties of our new graphene film with the one synthesized by using commonly used standard copper foils in chemical vapor deposition (CVD). We observed a stark improvement in the electrical performance of the transistors realized on our graphene films. To study the optical properties on large area, we transferred CVD based graphene to transparent flexible substrates using hot lamination method and performed large area optical scanning. We demonstrate the promise of our high quality graphene films for large areas with ~400 cm(2) flexible optical modulators. We obtained a profound light modulation over a broad spectrum by using the fabricated large area transparent graphene supercapacitors and we compared the performance of our devices with the one based on graphene from standard copper. We propose that the copper foils used in the lithium-ion batteries could be used to obtain high-quality graphene at much lower-cost, with the improved performance of electrical transport and optical properties in the devices made from them. PMID- 26578426 TI - Conversion of biomass-derived sorbitol to glycols over carbon-materials supported Ru-based catalysts. AB - Ruthenium (Ru) supported on activated carbon (AC) and carbon nanotubes (CNTs) was carried out in the hydrogenolysis of sorbitol to ethylene glycol (EG) and 1,2 propanediol (1,2-PD) under the promotion of tungsten (WOx) species and different bases. Their catalytic activities and glycols selectivities strongly depended on the support properties and location of Ru on CNTs, owning to the altered metal support interactions and electronic state of ruthenium. Ru located outside of the tubes showed excellent catalytic performance than those encapsulated inside the nanotubes. Additionally, the introduction of WOx into Ru/CNTs significantly improved the hydrogenolysis activities, and a complete conversion of sorbitol with up to 60.2% 1,2-PD and EG yields was obtained on RuWOx/CNTs catalyst upon addition of Ca(OH)2. Stability study showed that this catalyst was highly stable against leaching and poisoning and could be recycled several times. PMID- 26578427 TI - CYP1A1 rs1048943 and rs4646903 polymorphisms associated with laryngeal cancer susceptibility among Asian populations: a meta-analysis. AB - Many studies have investigated the association between CYP1A1 rs1048943 and rs4646903 polymorphisms and laryngeal cancer risk, but their results have been inconsistent. The PubMed and CNKI were searched for case-control studies published up to 01 July 2015. Data were extracted and pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated. In this meta-analysis, we assessed 10 published studies involving comprising 748 laryngeal cancer cases and 1558 controls of the association between CYP1A1 rs1048943 and rs4646903 polymorphisms and laryngeal cancer risk. For CYP1A1 rs1048943 of the homozygote G/G and G allele carriers (A/G + G/G) versus A/A, the pooled ORs were 1.77 (95% CI = 1.28-2.81, P = 0.007 for heterogeneity) and 1.86 (95% CI = 1.45-2.40, P = 0.000 for heterogeneity). For CYP1A1 rs4646903 of the homozygote G/G and G allele carriers (A/G + G/G) versus A/A, the pooled ORs were 1.53 (95% CI = 1.31-2.21, P = 0.012 for heterogeneity) and 1.33(95% CI = 1.04-1.71, P = 0.029 for heterogeneity). In the stratified analysis by ethnicity, the significantly risks were found among Asians for both the G allele carriers and homozygote G/G. However, no significant associations were found in Caucasian population all genetic models. These results from the meta-analysis suggest that CYP1A1 rs1048943 and rs4646903 polymorphisms contribute to risk of laryngeal cancer among Asian populations. PMID- 26578428 TI - Exposure to Chronic Mild Stress Differentially Alters Corticotropin-Releasing Hormone and Arginine Vasopressin mRNA Expression in the Stress-Responsive Neurocircuitry of Male and Female Rats Prenatally Exposed to Alcohol. AB - BACKGROUND: Prenatal alcohol exposure (PAE) results in dysregulation of the offspring hypothalamic-pituitary-adrenal (HPA) axis, increasing sensitivity to stressors and vulnerability to stress-related disorders. We have previously shown that exposure to chronic mild stress (CMS) in adulthood significantly increases anxiety-like behaviors (elevated plus maze) in PAE males and females compared to controls. To explore neurobiological mechanisms linking HPA dysregulation and altered anxiety-like behavior, we investigated neuropeptide (corticotropin releasing hormone [CRH] and arginine vasopressin [AVP]) expression in brain areas involved in the stress neurocircuitry of animals from this previous behavioral study. METHODS: Adult PAE, pair-fed (PF), and ad libitum fed control (C) male and female offspring exposed to CMS or remaining undisturbed (non-CMS) were terminated 30 minutes following behavioral testing. RESULTS: In the paraventricular nucleus, CMS increased CRH mRNA levels in PAE compared to PF and C males and increased AVP mRNA levels in PAE compared to C males, with no differential effects for CRH or AVP in females. In the central nucleus of the amygdala, there was an increase in CRH mRNA expression overall, regardless of CMS condition or sex, in PAE compared to C animals. Moreover, in PF males, CMS increased AVP mRNA levels in the paraventricular nucleus, resulting in a decreased CRH/AVP ratio compared to PAE males, and decreased amygdala CRH mRNA compared to that in the non-CMS condition. CONCLUSIONS: CMS differentially altered central HPA peptide expression in PAE and PF animals compared to their control counterparts, with a possible shift toward greater CRH mediation of HPA regulation in PAE males, and greater AVP mediation of HPA regulation in PF males. However, changes in CRH and AVP expression do not align fully with the anxiogenic profile observed in our previous behavior study, suggesting that other neuronal substrates and limbic forebrain regions also contribute to increased anxiety-like behavior following CMS. PMID- 26578429 TI - The efficacy and safety of combined microneedle fractional radiofrequency and sublative fractional radiofrequency for acne scars in Asian skin. AB - BACKGROUND: Microneedle fractional radiofrequency has been reported to be effective for improving wrinkles, enlarged pores and various scars. Sublative fractional radiofrequency has been shown to induce both fractional ablation of epidermis and upper dermal remodelling, which had rejuvenation effects in photoaged skin. Both modalities may have the potential synergy to improve acne scars. OBJECTIVE: To evaluate the efficacy and safety of combined microneedle and sublative fractional radiofrequency for acne scars in Asian skin. METHODS: Twenty subjects comprised 11 males and 9 females (mean age 23.65 +/- 2.94, skin phototype III-IV) with moderate to severe acne scars. The subjects received three consecutive combined microneedle and sublative fractional radiofrequency at 4 week intervals over 12 weeks. Both blinded dermatologists and subjects assessed the clinical improvement based on the standardized photography and questionnaires, respectively. The quartile grading scale was utilized and defined as follows: grade 1, 0-25% improvement; grade 2, 26-50% improvement; grade 3, 51 75% improvement and grade 4, 76-100% improvement. RESULTS: All 20 subjects were assessed to have grade 2 or more clinical improvement by physicians; four (20%) had grade 4, 10 (50%) had grade 3, and six (30%) had grade 2 improvement. The subjects' grading also showed a good concordance as indicated by Kappa index of 0.695. The mean duration of post-therapy crusting was 5.2 days and post-therapy erythema lasted 2.5 days. CONCLUSION: Combined microneedle and sublative fractional radiofrequency can have a positive therapeutic effect with no serious complications and may provide a new therapeutic approach on acne scars in Asians. PMID- 26578430 TI - Utility of Saxagliptin in the Treatment of Type 2 Diabetes: Review of Efficacy and Safety. AB - INTRODUCTION: Type 2 diabetes mellitus (T2DM) is a complex disease in which multiple organs and hormones contribute to the pathogenesis of disease. The intestinal hormone, glucagon-like peptide-1 (GLP-1), secreted in response to nutrient ingestion, increases insulin secretion from pancreatic beta-cells and reduces glucagon secretion from pancreatic alpha-cells. GLP-1 is inactivated by the dipeptidyl peptidase-4 (DPP-4) enzyme. Saxagliptin is a DPP-4 inhibitor that prevents the degradation of endogenous GLP-1 and prolongs its actions on insulin and glucagon secretion. This article reviews the efficacy and safety of saxagliptin in patients with T2DM. METHODS: A PubMed literature search was conducted to identify relevant, peer-reviewed saxagliptin clinical trial articles published between January 2008 and June 2015. Search terms included "saxagliptin" and "DPP-4 inhibitors". RESULTS: In clinical trials, saxagliptin significantly improved glycemic control when used as monotherapy or as add-on therapy to other antidiabetes agents and was associated with a low risk of hypoglycemia. In a large cardiovascular (CV) outcomes trial (SAVOR) in patients with T2DM and with established CV disease or multiple CV risk factors, saxagliptin neither increased nor decreased CV risk compared with placebo as assessed by the composite end point of death from CV causes, nonfatal myocardial infarction, or nonfatal stroke. Unexpectedly, more patients in the saxagliptin (3.5%) than in the placebo group (2.8%) were hospitalized for heart failure. CONCLUSION: Saxagliptin demonstrated statistically significant and clinically meaningful improvements in glycemic control and a low risk of hypoglycemia in patients with T2DM. However, this positive profile needs to be tempered by the observation of an increased risk of hospitalization for heart failure in the SAVOR trial. Results from ongoing CV outcome trials with other DPP-4 inhibitors may provide additional data on how best to manage patients with T2DM who are at risk for heart failure. FUNDING: AstraZeneca LP. PMID- 26578431 TI - Postural Stability in Osteoarthritis of the Knee and Hip: Analysis of Association With Pain Catastrophizing and Fear-Avoidance Beliefs. AB - BACKGROUND: Persons with knee osteoarthritis (OA) are at risk of having sensations of instability and sometimes experience buckling. The instability has been associated with psychosocial dysfunction, such as fear of movement, and impaired physical functioning. A high degree of fear of movement is positively correlated with avoidance in other conditions. OBJECTIVE: To evaluate the relationship between postural stability, the degree of pain catastrophizing, and fear-avoidance beliefs in subjects with knee and hip OA. DESIGN: Descriptive, cross-sectional study. SETTING: Four primary health care centers. SUBJECTS: Eighty subjects with knee or combined knee and hip OA. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASUREMENTS: Postural stability was evaluated using the Multi-Directional Functional Reach Test (MDFRT), and a battery of self-reports was used to assess the following aspects: pain catastrophizing (Pain Catastrophizing Scale), fear-avoidance beliefs (Tampa Scale for Kinesiophobia [TSK-11] and the Fear-Avoidance Beliefs Questionnaire), pain (visual analog scale), disability (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC]), and self-efficacy (Chronic Pain Self-Efficacy Scale [CPSS]). RESULTS: The correlation analysis showed that scores on the MDFRT were negatively associated with scores on the TSK-11 for activity avoidance (r = -0.54; P < .001) and positively associated with the scores on the CPSS for coping (r = 0.59; P < .001). The scores for the MDFRT to the right and the total WOMAC were negatively associated (r = -0.61, P <.001). The scores for the MDFRT to the left were positively associated with the CPSS scores for coping (r = 0.64, P < .001). The scores for the MDFRT forward were predicted by CPSS and TSK-11 scores (28.9% of variance), as well as activity avoidance, avoidance of physical activity, helplessness (34.7% of variance), and CPSS pain coping (34.3% of variance). CONCLUSIONS: These findings suggest that pain catastrophizing and fear-avoidance beliefs are related with postural stability in subjects with knee and hip OA. Postural stability is negatively correlated with pain catastrophizing and TSK activity avoidance. Thus, based on these results, psychosocial factors should be taken into consideration in the assessment and treatment of patients with hip and knee OA. PMID- 26578432 TI - Decreased hernia recurrence using autologous platelet-rich plasma (PRP) with StratticeTM mesh in a rodent ventral hernia model. AB - BACKGROUND: Recurrence after ventral hernia repair (VHR) remains a multifactorial problem still plaguing surgeons today. Some of the many contributing factors include mechanical strain, poor tissue-mesh integration, and degradation of matrices. The high recurrence rate witnessed with the use of acellular dermal matrices (ADM) for definitive hernia repair has reduced their use largely to bridging repair and breast reconstruction. Modalities that improve classic cellular metrics of successful VHR could theoretically result in improved rates of hernia recurrence; autologous platelet-rich plasma (PRP) may represent one such tool, but has been underinvestigated for this purpose. METHODS: Lewis rats (32) had chronic ventral hernias created surgically and then repaired with StratticeTM mesh alone (control) or mesh + autologous PRP. Samples were harvested at 3 and 6 months postoperatively and compared for gross, histologic, and molecular outcomes of: neovascularization, tissue incorporation, peritoneal adhesions, hernia recurrence, and residual mesh thickness. RESULTS: Compared to control at 3 months postoperatively, PRP-treated rats displayed significantly more neovascularization of implanted mesh and considerable upregulation of both angiogenic genes (vEGF 2.73-fold, vWF 2.21-fold) and myofibroblastic genes (alphaSMA 9.68-fold, FSP-1 3.61-fold, Col1a1 3.32-fold, Col31a1 3.29-fold). Histologically, they also showed enhanced tissue deposition/ingrowth and diminished chronic immune cell infiltration. Peritoneal adhesions were less severe at both 3 (1.88 vs. 2.94) and 6 months (1.63 vs. 2.75) by Modified Hopkins Adhesion Scoring. PRP-treated rats experienced decreased hernia recurrence at 6 months (0/10 vs. 7/10) and had significantly improved ADM preservation as evidenced by quantification of residual mesh thickness. CONCLUSIONS: PRP is an autologous source of pro-regenerative growth factors and chemokines uniquely suited to soft tissue wound healing. When applied to a model of chronic VHR, it incites enhanced angiogenesis, myofibroblast recruitment and tissue ingrowth, ADM preservation, less severe peritoneal adhesions, and diminished hernia recurrence. We advocate further investigation regarding PRP augmentation of human VHR. PMID- 26578433 TI - Incidence, risk factors and consequences of bile leakage following laparoscopic major hepatectomy. AB - BACKGROUND: Bile leakage (BL) remains a common cause of major morbidity after open major liver resection but has only been poorly described in patients undergoing laparoscopic major hepatectomy (LMH). The present study aimed to determine the incidence, risk factors and consequences of BL following LMH. METHODS: All 223 patients undergoing LMH between 2000 and 2013 at two tertiary referral centres were retrospectively analysed. BL was defined according to the International Study Group of Liver Surgery, and its incidence and consequences were assessed. Risk factors for BL were determined on multivariate analysis. RESULTS: BL occurred in 30 (13.5 %) patients, and its incidence remained stable over time (p = 0.200). BL was diagnosed following the presence of bile into the abdominal drain in 14 (46.7 %) patients and after drainage of symptomatic abdominal collections in 16 (53.3 %) patients without intra-operative drain placement. Grade A, B and C BL occurred in 3 (10.0 %), 23 (76.6 %) and 4 (13.4 %) cases, respectively. Interventional procedures for BL included endoscopic retrograde cholangiography, percutaneous and surgical drainage in 10 (33.3 %), 23 (76.7 %) and 4 (13.3 %) patients, respectively. BL was associated with significantly increased rates of symptomatic pleural effusion (30.0 vs. 11.4 %, p = 0.006), multiorgan failure (13.3 vs. 3.6 %, p = 0.022), postoperative death (10.0 vs. 1.6 %, p = 0.008) and prolonged hospital stay (18 vs. 8 days, p < 0.001). On multivariable analysis, BMI > 28 kg/m(2) (OR 2.439, 95 % CI 1.878 2.771, p = 0.036), history of hepatectomy (OR 1.675, 95 % CI 1.256-2.035, p = 0.044) and biliary reconstruction (OR 1.975, 95 % CI 1.452-2.371, p = 0.039) were significantly associated with increased risk of BL. CONCLUSIONS AND RELEVANCE: After LMH, BL occurred in 13.5 % of the patients and was associated with significant morbidity. Patients with one or several risk factors for BL should benefit intra-operative drain placement. PMID- 26578434 TI - Laparoscopic ventral hernia repair with primary fascial closure versus bridged repair: a risk-adjusted comparative study. AB - BACKGROUND: Laparoscopy, specifically the bridged mesh technique, is a popular means used for ventral hernia repair. While laparoscopy has decreased the incidence of surgical site infection (SSI), hernia recurrence rates remain unchanged. Some surgeons advocate laparoscopic primary fascial closure (PFC) with placement of intraperitoneal mesh to decrease recurrence rates. We hypothesize that in patients undergoing laparoscopic ventral hernia repair (LVHR), PFC compared to a bridged mesh repair decreases hernia recurrence rates. METHODS: A multicenter, retrospective database of all ventral hernia repairs performed from 2010-2012 was accessed. Patients who underwent LVHR with mesh were reviewed. Patients who had PFC were compared to bridged repair. Primary outcome was hernia recurrence determined by clinical examination or CT scan. Secondary outcomes included SSI and seroma formation. RESULTS: A total of 1594 patients were identified. Following exclusion, a total of 196 patients were left who underwent LVHR with a mean follow-up period of 17.5 months. Ninety-seven patients underwent PFC, while 99 underwent bridged repairs. Initial comparisons between both groups was negative for any significant statistical difference in terms of recurrence, seroma formation, SSI, deep/organ space SSI, reoperation, and readmission. The same initial findings held true during subgroup analysis. Propensity score analysis was then performed for recurrence, seroma, and SSI controlling for age, gender, immune status, ASA class, BMI, smoking status, and acute repair. No statistically significant differences were identified in either group. CONCLUSION: Primary fascial closure during laparoscopic hernia repairs did not result in reduced recurrence, seroma, and SSI as compared to bridge repairs in a retrospective, multi-institutional study. However, additional research is needed to further evaluate benefits to the patient in terms of pain, function, cosmesis, and overall satisfaction. Randomized, blinded, control trials should focus on these parameters in future investigations. PMID- 26578435 TI - Impact of a preoperatively estimated prostate volume using transrectal ultrasonography on surgical and oncological outcomes in a single surgeon's experience with robot-assisted radical prostatectomy. AB - BACKGROUND: To assess the impact of preoperatively estimated prostate volume (PV) using transrectal ultrasonography (TRUS) on surgical and oncological outcomes in robot-assisted radical prostatectomy (RARP). METHODS: We analyzed the experience of a single surgeon at our hospital who performed 436 RARPs without neoadjuvant hormone therapy between August 2006 and December 2013. Patients were divided into three groups according to their preoperative PV calculated using TRUS (PV <= 20 cm(3): group 1, n = 61; 20 < PV < 50 cm(3): group 2, n = 303; PV >= 50 cm(3): group 3, n = 72). RESULTS: Blood loss was significantly higher in group 3 than in group 1 and group 2. In stage pT2 patients, the rate of positive surgical margin (PSM) was significantly lower in group 3 than in group 1. In addition, perioperative complications significantly increased with increasing PV, while the extraprostatic extension (EPE) rate significantly decreased with increasing PV. The preoperative biopsy Gleason score, prostate-specific antigen (PSA) density, and clinical T2 stage were inversely correlated with increasing PV. Biochemical recurrence-free survival after RARP was significantly lower in group 1 than in groups 2 and 3. CONCLUSIONS: A large prostate size was significantly associated with increased blood loss and a higher rate of perioperative complications. A small prostate size was associated with a higher PSM rate, PSA density, Gleason score, EPE rate, and biochemical recurrence rate. These results suggest that RARP was technically challenging in patients with large prostates, whereas small prostates were associated with unfavorable oncological outcomes. PMID- 26578436 TI - The genetic diversity of Epstein-Barr virus in the setting of transplantation relative to non-transplant settings: A feasibility study. AB - This study examines EBV strains from transplant patients and patients with IM by sequencing major EBV genes. We also used NGS to detect EBV DNA within total genomic DNA, and to evaluate its genetic variation. Sanger sequencing of major EBV genes was used to compare SNVs from samples taken from transplant patients vs. patients with IM. We sequenced EBV DNA from a healthy EBV-seropositive individual on a HiSeq 2000 instrument. Data were mapped to the EBV reference genomes (AG876 and B95-8). The number of EBNA2 SNVs was higher than for EBNA1 and the other genes sequenced within comparable reference coordinates. For EBNA2, there was a median of 15 SNV among transplant samples compared with 10 among IM samples (p = 0.036). EBNA1 showed little variation between samples. For NGS, we identified 640 and 892 variants at an unadjusted p value of 5 * 10(-8) for AG876 and B95-8 genomes, respectively. We used complementary sequence strategies to examine EBV genetic diversity and its application to transplantation. The results provide the framework for further characterization of EBV strains and related outcomes after organ transplantation. PMID- 26578437 TI - Development of PEGylated peptide probes conjugated with (18)F-labeled BODIPY for PET/optical imaging of MT1-MMP activity. AB - Since the processing activity of the matrix metalloproteinase MT1-MMP regulates various cellular functions such as motility, invasion, growth, differentiation and apoptosis, precise in vivo evaluation of MT1-MMP activity in cancers can provide beneficial information for both basic and clinical studies. For this purpose, we designed a cleavable Positron Emission Tomography (PET)/optical imaging probe consisting of BODIPY650/665 and polyethylene glycol (PEG) conjugated to opposite ends of MT1-MMP substrate peptides. We used in vitro and in vivo fluorescence experiments to select suitable substrate peptide sequences and PEG sizes for the MT1-MMP probes and obtained an optimized structure referred to here as MBP-2k. Radiofluorinated MBP-2k ([(18)F]MBP-2k) was then successfully synthesized via an (18)F-(19)F isotopic exchange reaction in BODIPY650/665. After intravenous injection into mice with xenografted tumors, [(18)F]MBP-2k showed significantly higher accumulation in HT1080 tumors with high MT1-MMP activity than in A549 tumors that have low MT1-MMP activity. Moreover, PET images showed better contrast in HT1080 tumors. These results show that [(18)F]MBP-2k can be used as a hybrid PET/optical imaging agent and is a promising probe for non invasive monitoring of MT1-MMP activity in cancers. This probe may also efficiently combine targeted tumor imaging with image-guided surgery that could be beneficial for patients in the future. PMID- 26578438 TI - Porphyrin-phospholipid liposomes with tunable leakiness. AB - Drug bioavailability is a key consideration for drug delivery systems. When loaded with doxorubicin, liposomes containing 5 molar % porphyrin-phospholipid (HPPH liposomes) exhibited in vitro and in vivo serum stability that could be fine-tuned by varying the drug-to-lipid ratio. A higher drug loading ratio destabilized the liposomes, in contrast to standard liposomes which displayed an opposite and less pronounced trend. Following systemic administration of HPPH liposomes, near infrared laser irradiation induced vascular photodynamic damage, resulting in enhanced liposomal doxorubicin accumulation in tumors. In laser irradiated tumors, the use of leaky HPPH liposomes resulted in improved doxorubicin bioavailability compared to stable standard liposomes. Using this approach, a single photo-treatment with 10mg/kg doxorubicin rapidly eradicated tumors in athymic nude mice bearing KB or MIA Paca-2 xenografts. PMID- 26578440 TI - A three-drug nanoscale drug delivery system designed for preferential lymphatic uptake for the treatment of metastatic melanoma. AB - Metastatic melanoma has a high mortality rate due to lymphatic progression of the disease. Current treatment is surgery followed by radiation and intravenous chemotherapy. However, drawbacks for current chemotherapeutics lie in the fact that they develop resistance and do not achieve therapeutic concentrations in the lymphatic system. We hypothesize that a three-drug nanoscale drug delivery system, tailored for lymphatic uptake, administered subcutaneously, will have decreased drug resistance and therefore offer better therapeutic outcomes. We prepared and characterized nanoparticles (NPs) with docetaxel, everolimus, and LY294002 in polyethyleneglycol-block-poly(epsilon-caprolactone) (PEG-PCL) polymer with different charge distributions by modifying the ratio of anionic and neutral end groups on the PEG block. These NPs are similarly sized (~48 nm), with neutral, partially charged, or fully charged surface. The NPs are able to load ~2mg/mL of each drug and are stable for 24h. The NPs are assessed for safety and efficacy in two transgenic metastatic melanoma mouse models. All the NPs were safe in both models based on general appearance, weight changes, death, and blood biochemical analyses. The partially charged NPs are most effective in decreasing the number of melanocytes at both the proximal (sentinel) lymph node (LN) and the distal LN from the injection site. The neutral NPs are efficacious at the proximal LN, while the fully charged NPs have no effect on either LNs. Thus, our data indicates that the NP surface charge and lymphatic efficacy are closely tied to each other and the partially charged NPs have the highest potential in treating metastatic melanoma. PMID- 26578441 TI - Colorful patterns indicate common ancestry in diverged tiger beetle taxa: Molecular phylogeny, biogeography, and evolution of elytral coloration of the genus Cicindela subgenus Sophiodela and its allies. AB - We investigated the phylogenetic relationships among tiger beetles of the subtribe Cicindelina (=Cicindela s. lat.; Coleoptera: Cicindelidae) mainly from the Oriental and Sino-Japanese zoogeographic regions using one mitochondrial and three nuclear gene sequences to examine the position of the subgenus Sophiodela, currently classified in the genus Cicindela s. str., their biogeography, and the evolution of their brilliant coloration. The subgenus Sophiodela was not related to the other subgenera of Cicindela s. str. but was closely related to the genus Cosmodela. In addition, the Oriental genus Calochroa was polyphyletic with three lineages, one of which was closely related to Sophiodela and Cosmodela. The clade comprising Sophiodela, Cosmodela and two Calochroa species, referred to here as the Sophiodela group, was strongly supported, and most species in this clade had similar brilliant coloration. The Sophiodela group was related to the genera Calomera, Cicindela (excluding Sophiodela) and Cicindelidia, and these were related to Lophyra, Hipparidium and Calochroa, except species in the Sophiodela group. Divergence time estimation suggested that these worldwide Cicindelina groups diverged in the early Oligocene, and the Sophiodela group, which is found in the Oriental and Sino-Japanese zoogeographic regions, in the mid Miocene. Some components of the elytral pattern related to maculation and coloration in the Cicindelina taxa studied contained weak, but significant, phylogenetic signals and were partly associated with habitat types. Therefore, the brilliant coloration of the Sophiodela was related to both phylogeny and habitat adaptation, although the function of coloration needs to be studied. PMID- 26578439 TI - Elastin-like polypeptides: Therapeutic applications for an emerging class of nanomedicines. AB - Elastin-like polypeptides (ELPs) constitute a genetically engineered class of 'protein polymers' derived from human tropoelastin. They exhibit a reversible phase separation whereby samples remain soluble below a transition temperature (Tt) but form amorphous coacervates above Tt. Their phase behavior has many possible applications in purification, sensing, activation, and nanoassembly. As humanized polypeptides, they are non-immunogenic, substrates for proteolytic biodegradation, and can be decorated with pharmacologically active peptides, proteins, and small molecules. Recombinant synthesis additionally allows precise control over ELP architecture and molecular weight, resulting in protein polymers with uniform physicochemical properties suited to the design of multifunctional biologics. As such, ELPs have been employed for various uses including as anti cancer agents, ocular drug delivery vehicles, and protein trafficking modulators. This review aims to offer the reader a catalogue of ELPs, their various applications, and potential for commercialization across a broad spectrum of fields. PMID- 26578443 TI - Richer countries should help poorer ones plan for the next pandemic. PMID- 26578442 TI - Model-based approaches for ivabradine development in paediatric population, part II: PK and PK/PD assessment. AB - The objectives of this work were first to describe the pharmacokinetic (PK) of ivabradine and its active metabolite in a paediatric patient population after repeated oral administration of ivabradine using a population PK approach, and secondly to assess whether the blood/plasma ratio and the pharmacokinetic/pharmacodynamic (PK/PD) relationship are preserved in the paediatric population in comparison to adult. PK data for 70 patients were obtained after blood sampling using dried blood spot and one plasma sample in order to assess the relationship between blood and plasma concentration. In order to describe ivabradine and its metabolite blood concentrations in children, a joint population PK model was developed taking into account weight & age effects on PK parameters. Plasma PK exposure parameters were calculated in children using plasma PK profiles. In order to assess the PK/PD relationship in children, an adult PK/PD model was used. The relationship between blood and plasma concentrations was described using linear mixed effect models. Two and one compartment models best described parent and metabolite dispositions. Weight effects were fixed to the allometric values of 3/4 on clearance (CL) and 1 on volume. A maturation function was added on metabolite formation clearance (CL PM ) reflecting enzyme maturation. Plasma exposure comparison indicated that higher dose/kg were necessary to achieve a similar exposure between younger and older children. No differences between age classes were observed in terms of range of exposure at the maintenance dose. The PK/PD relationship in adult patients is conserved in children. PMID- 26578444 TI - Early Catheter Removal after Robot-assisted Radical Prostatectomy: Surgical Technique and Outcomes for the Aalst Technique (ECaRemA Study). AB - BACKGROUND: Robot-assisted radical prostatectomy (RARP) is a widespread option for the treatment of patients with clinically localised prostate cancer. Modifications in the surgical technique may help to further improve functional outcomes. OBJECTIVE: To assess the outcome of early catheter removal 48h after surgery, as opposed to standard catheter removal 6 d after surgery following RARP, using a newly developed surgical technique for posterior reconstruction and anastomosis (Aalst technique). DESIGN, SETTING, AND PARTICIPANTS: Patients scheduled for RARP were prospectively scheduled for early catheter removal at postoperative d 2 (group A, n=37) and standard catheter removal at postoperative d 6 (group B, n=37). SURGICAL PROCEDURE: RARP was performed using the Da Vinci Si system. The Aalst technique for the urethro-vesical anastomosis including posterior reconstruction was used as previously described. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was spontaneous voiding after catheter removal. Secondary endpoints were rate of anastomotic urinary leakage after catheter removal, presence and severity of urethral, perineal, and abdominal pain, as well as patient's bother after catheter removal using visual analogue scale (VAS) scores. Rate and severity of urinary incontinence after catheter removal were assessed using the International Consultation on Incontinence Questionnaire-Male Lower Urinary Tract Symptoms Module (ICIQ-MLUTS) questionnaire. RESULTS AND LIMITATIONS: There was no significant difference between the groups with regard to baseline and perioperative parameters, as well as pathological features; however, significantly more patients underwent bilateral nerve-sparing procedures in group A (34 vs 23, p=0.008). After catheter removal, patients in both groups showed spontaneous voiding, whereas only 11% and 8% of the patients in group A and group B experienced urinary retention after catheter removal (p=0.7). Patients in group B had significantly higher maximum flow rates, but lower voided volumes after catheter removal in comparison with patients in group A (21ml/s vs 10ml/s, p<=0.001 and 170ml vs 200ml, p<=0.001, respectively). ICIQ-MLUTS questionnaire and VAS scores showed no significant differences between the groups at any time point. CONCLUSIONS: The Aalst technique allows the removal of catheters 2 d after RARP and results in spontaneous voiding. Early removal showed no increased rate of urinary leakage, no negative impact on short-term continence and on perineal, urethral or penile pain, and no increase in urinary retention rates. Future studies have to confirm these results with longer follow-up including detailed parameters on return to daily activity. PATIENT SUMMARY: We provide evidence that it is possible to remove the bladder catheter as early as 2 d after robot-assisted radical prostatectomy without any negative effects on voiding and pain parameters. Thus, leaving the hospital early without a catheter in place could represent a significant and relevant benefit for the patient. PMID- 26578445 TI - Idiopathic Epiretinal Membrane and Vitreomacular Traction Preferred Practice Pattern((r)) Guidelines. AB - IDIOPATHIC EPIRETINAL MEMBRANE AND VITREOMACULAR TRACTION PREFERRED PRACTICE PATTERN(r) GUIDELINES: New evidence-based Idiopathic Epiretinal Membrane and Vitreomacular Traction Preferred Practice Pattern(r) (PPP) guidelines, describing recommendations for the diagnosis, treatment, and management of patients. PMID- 26578446 TI - First-Year Visual Acuity Outcomes of Providing Aflibercept According to the VIEW Study Protocol for Age-Related Macular Degeneration. AB - PURPOSE: Aflibercept has the potential advantage of reducing capacity problems by allowing 2 monthly visits for patients with neovascular macular degeneration (nAMD) compared with monthly pro re nata regimens that are the most commonly used in the United Kingdom. This study aimed to report the visual outcomes achieved in routine clinical practice using the VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW) protocol at 1 year and compare with trials data and other real-world reports. DESIGN: Retrospective data analysis from an electronic medical record. PARTICIPANTS: Consecutive series of treatment-naive patients initiated on aflibercept for nAMD at least 1 year before data extraction. METHODS: Data were anonymized and remotely extracted from 16 centers in the United Kingdom that use the same electronic medical record (EMR) system (Medisoft Ophthalmology; Medisoft Limited, Leeds, UK). MAIN OUTCOME MEASURES: The minimum data set defined before first data entry and mandated by the EMR included age, gender, visual acuity, injection episodes, and complications. RESULTS: The mean age was 80.0 years (median, 81.0 years) and 63.7% were women. During the first year of treatment with aflibercept, 1840 treatment-naive eyes of 1682 patients received a median of 8 (mean, 7.0) injections at a median of 8 (mean, 7.3) visits. The mean baseline visual acuity was 53.7 letters, improving to 58.8 letters (+5.1-letter gain) at 1 year. In first-treated eyes, the respective figures were 52.7 letters at baseline and 58.2 letters at 1 year, a gain of +5.5 letters. The proportion achieving 70 letters or more increased from 16.4% at baseline to 33.7% at 1 year, and 92% avoided moderate visual loss at 1 year. CONCLUSIONS: The visual acuity outcomes are comparable to randomized trials and better than many previous real-world data collections, with a mean +5.1-letter gain at 1 year compared with +8.4 letters in the integrated analysis of the VIEW 1 and VIEW 2 studies. Early visual gains were maintained through the year. Collection of outcomes beyond clinical trials can have limitations but better reflect the full pool of patients actually treated and are important to determine whether a particular treatment is performing as expected. Such data also have the potential to improve services by setting up a mechanism to compare sites. PMID- 26578447 TI - Precision Pulse Capsulotomy: Preclinical Safety and Performance of a New Capsulotomy Technology. AB - PURPOSE: To assess the preclinical safety and performance of a new precision pulse capsulotomy (PPC) method. DESIGN: Human cadaver eye studies and surgical, slit-lamp, and histopathologic evaluation in a consecutive series of 20 live rabbits. PARTICIPANTS: Human cadaver eyes and New Zealand white rabbits. METHODS: Precision pulse capsulotomy uses a highly focused, fast, multipulse, low-energy discharge to produce a perfectly round anterior capsulotomy instantaneously and simultaneously along all 360 degrees . Capsulotomies are performed using a disposable handpiece with a soft collapsible tip and circular nitinol cutting element. Miyake-Apple imaging and scanning electron microscopy (SEM) of PPC were conducted in human cadaver eyes. Surgical, postoperative slit-lamp, and histopathologic assessments of PPC were performed in 20 live rabbits and were compared with manual continuous curvilinear capsulorrhexis (CCC) in the fellow eye. Anterior chamber (AC) thermocouple temperature measurements were evaluated in a subset of rabbit eyes. MAIN OUTCOME MEASURES: Capsulotomy edge circularity, SEM morphologic features and zonular movement with PPC in human cadaver eyes. Anterior chamber temperature during PPC and grading of ocular inflammation, corneal endothelial damage, anterior capsular opacification (ACO), and posterior capsular opacification (PCO). RESULTS: Miyake-Apple imaging showed minimal zonular stress, and thermocouple measurements demonstrated negligible AC temperature changes during PPC. Precision pulse capsulotomy produced round, complete capsulotomies in all 20 rabbit eyes, leading to successful in-the-bag intraocular lens (IOL) implantation. Slit-lamp examinations at 3 days and 1, 2, and 4 weeks after surgery showed no significant differences between PPC and CCC in corneal edema, AC inflammatory reaction, capsular fibrosis, ACO, and PCO. Postmortem studies showed no difference in the corneal endothelium between PPC and CCC eyes. All IOLs were well centered in PPC eyes, and histopathologic analysis showed no greater inflammatory infiltrates. CONCLUSIONS: Precision pulse capsulotomy is a new method to automate consistent creation of a perfectly circular anterior capsulotomy with a disposable handheld instrument that can be used in the normal phacoemulsification surgical sequence. Compared with CCC in fellow rabbit eyes, PPC was equally safe and showed no greater zonular stress compared with CCC in human cadaver eyes. Human cadaver eye SEM showed a much smoother capsulotomy edge compared to those produced by femtosecond laser. PMID- 26578448 TI - Drusen Volume and Retinal Pigment Epithelium Abnormal Thinning Volume Predict 2 Year Progression of Age-Related Macular Degeneration. AB - PURPOSE: To analyze the value of novel measures of retinal pigment epithelium drusen complex (RPEDC) volume to predict 2-year disease progression of intermediate age-related macular degeneration (AMD). DESIGN: Prospective, observational study. PARTICIPANTS: Three hundred forty-five AMD and 122 non-AMD participants enrolled in the Age Related Eye Disease Study 2 Ancillary Spectral Domain (SD) Optical Coherence Tomography (OCT) study. METHODS: High-density SD OCT macular volumes were obtained at yearly study visits. The RPEDC abnormal thickening (henceforth, OCT drusen) and RPEDC abnormal thinning (RAT) volumes were generated by semiautomated segmentation of total RPEDC within a 5-mm diameter macular field. MAIN OUTCOME MEASURES: Volume change and odds ratio (OR) with 95% confidence intervals (CI) for progression to advanced AMD with choroidal neovascularization (CNV) or central geographic atrophy (GA). RESULTS: Complete volumes were obtained in 265 and 266 AMD eyes and in 115 and 97 control eyes at baseline and at year 2, respectively. In AMD eyes, mean (standard deviation) OCT drusen volume increased from 0.08 mm(3) (0.16 mm(3)) to 0.10 mm(3) (0.23 mm(3); P < 0.001), and RAT volume increased from 8.3 * 10(-4) mm(3) (20.8 * 10(-4) mm(3)) to 18.4 * 10(-4) mm(3) (46.6 * 10(-4) mm(3); P < 0.001). Greater baseline OCT drusen volume was associated with 2-year progression to CNV (P = 0.002). Odds of developing CNV increased by 31% for every 0.1-mm(3) increase in baseline OCT drusen volume (OR, 1.31; 95% CI, 1.06-1.63; P = 0.013). Greater baseline RAT volume was associated with significant 2-year increase in RAT volume (P < 0.001), noncentral GA (P < 0.001), and progression to central GA (P < 0.001). Odds of developing central GA increased by 32% for every 0.001-mm(3) increase in baseline RAT volume (OR, 1.32; 95% CI, 1.14-1.53; P < 0.001). In non-AMD eyes, all volumes were significantly lower than AMD eyes and showed no significant 2-year change. CONCLUSIONS: Macular OCT drusen and RAT volumes increased significantly in AMD eyes over 2 years. These quantitative SD OCT biomarkers predict 2-year AMD progression and may serve as useful biomarkers for future clinical trials. PMID- 26578449 TI - Liquefaction of Lignocellulose in Fluid Catalytic Cracker Feed: A Process Concept Study. AB - We report a process concept for lignocellulose liquefaction in a refinery stream that will be coprocessed with the resulting biocrude and that, therefore, does not require the recovery and recycling of the liquefaction solvent. Light cycle oil and vacuum gas oil were found to be the two most promising solvents. Both refinery streams could provide a liquid yield of 58 C % (64 % energy yield). A techno-economic assessment indicates that the biocrude could be produced at an energy-equivalent crude oil price of 51-64 $ per barrel at a wood cost of 85 $ per dry ton. PMID- 26578450 TI - Allo-reactive T cells for the treatment of hematological malignancies. AB - Several mechanisms can be responsible for control of hematological tumors by allo reactive T cells. Following allogeneic stem cell transplantation (alloSCT) donor T cells recognizing genetic disparities presented on recipient cells and not on donor cells are main effectors of tumor control, but also of the detrimental graft versus host disease (GVHD). Since after transplantation normal hematopoiesis is of donor origin, any T cell response directed against polymorphic antigens expressed on hematopoietic recipient cells but not on donor cells will result in an anti-tumor response not affecting normal hematopoiesis. After fully HLA-matched alloSCT, T cells recognizing polymorphic peptides derived from proteins encoded by genes selectively expressed in hematopoietic lineages may result in anti-tumor responses without GVHD. Due to the high susceptibility of hematopoietic cells for T cell recognition, a low amplitude of the overall T cell response may also be in favor of the anti-tumor reactivity in hematological malignancies. A mismatch between donor and patient for specific HLA-alleles can also be exploited to induce a selective T cell response against patient (malignant) hematopoietic cells. If restricting HLA class II molecules are selectively expressed on hematopoietic cells under non-inflammatory circumstances, allo HLA class-II responses may control the tumor with limited risk of GVHD. Alternatively, T cells recognizing hematopoiesis-restricted antigens presented in the context of mismatched HLA alleles may be used to treat patients with hematological cancers. This review discusses various ways to manipulate the allo-immune response aiming to exploit the powerful ability of allo-reactive T-cells to control the malignancies without causing severe damage to non-hematopoietic tissues. PMID- 26578452 TI - Tumor-infiltrating lymphocytes for the treatment of metastatic cancer. AB - Over the past few years melanoma incidence has been rising steadily, resulting in an increase in melanoma related mortality. Until recently, therapeutic options for metastatic melanoma were scarce. Chemotherapy and, in some countries, IL-2 were the only registered treatment modalities. In the last five years, treatment with immunotherapy (anti CTLA-4, anti PD-1, or the combination of these antibodies) has shown very promising results and was able to improve survival in patients with metastatic melanoma. Adoptive cell therapy using tumor-infiltrating lymphocytes is yet another, but highly promising, immunotherapeutic strategy for patients with metastatic melanoma. This review will discuss the development of TIL as a treatment option for melanoma, its mode of action and simplification over time, and the possibilities to expand this therapy to other types of cancer. Also, the future directions of TIL based therapies will be highlighted. PMID- 26578453 TI - ABCG2 in peptic ulcer: gene expression and mutation analysis. AB - The aim of this study was to evaluate the participation of polymorphism at position C421A and mRNA expression of the ABCG2 gene in the development of peptic ulcers, which is a very common and severe disease. ABCG2, encoded by the ABCG2 gene, has been found inter alia in the gastrointestinal tract, where it plays a protective role eliminating xenobiotics from cells into the extracellular environment. The materials for the study were biopsies of gastric mucosa taken during a routine endoscopy. For genotyping by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) at position C421A, DNA was isolated from 201 samples, while for the mRNA expression level by real-time PCR, RNA was isolated from 60 patients. The control group of healthy individuals consisted of 97 blood donors. The dominant genotype in the group of peptic ulcer patients and healthy individuals was homozygous CC. No statistically significant differences between healthy individuals and the whole group of peptic ulcer patients and, likewise, between the subgroups of peptic ulcer patients (infected and uninfected with Helicobacter pylori) were found. ABCG2 expression relative to GAPDH expression was found in 38 of the 60 gastric mucosa samples. The expression level of the gene varies greatly among cases. The statistically significant differences between the intensity (p = 0.0375) of H. pylori infection and ABCG2 gene expression have been shown. It was observed that the more intense the infection, the higher the level of ABCG2 expression. PMID- 26578454 TI - Theoretical study on alkali-metal doped N3H3 complexes: an in-depth understanding of the origin of electride and alkalide and their large nonlinear optical properties. AB - By doping the model complexant N3H3 with one or two lithium atoms, the geometrical and electronic structures as well as static electric properties of the resulting Li(N3H3), (N3H3)Li' and Li(N3H3)Li' complexes can be explored using the B3LYP, BHandHLYP, CAM-B3LYP and MP2 methods. All three complexes, especially Li(N3H3), were found to have large first hyperpolarizabilities (beta 0). Meanwhile, Li(N3H3) and Li(N3H3)Li' exhibited electride and alkalide characteristics, respectively. The dependance of electric properties of alkalide Li(N3H3)Li' on the alkali atoms involved and the complexant layer number were revealed by investigating the related M(N3H3)Li' and Li(N3H3)M' (M = Na and K), and Li(N3H3) n Li' (n = 2, 3) systems. Note that the beta 0 value of alkalide M(N3H3)M' increased not only with the increasing atomic number of the M'(-) anion but also with that of the M(+) cation, which differs from previously reported cases. In addition, the electric properties of the Li(N3H3)Li' alkalide were enhanced by increasing the complexant layers. However, it was found that both the complexant-complexant and the complexant-Li' interactions reduced with the addition of N3H3 layers, so no stable structures were found for larger Li(N3H3) n Li' complexes. Graphical Abstract Geometrical and electronic structures as well as static electric properties of Li(N3H3), (N3H3)Li' and Li(N3H3)Li' complexes were explored using B3LYP, BHandHLYP, CAM-B3LYP and MP2 methods. PMID- 26578456 TI - Pigmented Pheochromocytoma: an Unusual Variant of a Common Tumor. AB - Pheochromocytoma is a neuroendocrine tumor arising from the adrenal medulla. A number of variants of pheochromocytoma are known; however, pigmented pheochromocytoma is extremely rare, with only few cases reported in literature. We report the cases of two patients with pigmented pheochromocytoma. Case 1 was a 28-year-old female who presented with complaints of breathlessness, palpitations, and anxiety for 5 years, which had worsened over the last 8 months. Computed tomography (CT) abdomen showed a right suprarenal mass. Case 2 was that of an 18 year-old girl who presented with similar complaints and was diagnosed with hypertension. CT abdomen showed bilateral adrenal masses. Urinary vanillyl mandelic acid was raised in both patients. Sections examined from all three tumors showed cells arranged in Zellballen pattern, separated by thin fibrovascular septae. Tumor cells showed moderate to marked nuclear pleomorphism in case 1. Mitoses were, however, not seen. There was no evidence of capsular or vascular invasion. Many of the tumor cells showed intracytoplasmic black pigment, which was positive for Fontana-Masson and was bleach-labile, confirming it as melanin. Hemosiderin deposition was also identified. Large areas of hemorrhagic necrosis were seen in case 1. Tumor cells were immunopositive for chromogranin and synaptophysin, while they were negative for HMB-45. Electron microscopy was performed. A final diagnosis of pigmented pheochromocytoma was rendered in both cases. Pigmented pheochromocytoma is a very rare tumor, which needs to be differentiated from other pigmented tumors like malignant melanoma of adrenal gland and pigmented adrenal adenoma. Histochemistry and immunohistochemistry help in making this distinction. PMID- 26578451 TI - Negative immune checkpoints on T lymphocytes and their relevance to cancer immunotherapy. AB - The term 'inhibitory checkpoint' refers to the broad spectrum of co-receptors expressed by T cells that negatively regulate T cell activation thus playing a crucial role in maintaining peripheral self-tolerance. Co-inhibitory receptor ligands are highly expressed by a variety of malignancies allowing evasion of anti-tumour immunity. Recent studies demonstrate that manipulation of these co inhibitory pathways can remove the immunological brakes that impede endogenous immune responses against tumours. Antibodies that block the interactions between co-inhibitory receptors and their ligands have delivered very promising clinical responses, as has been shown by recent successful trials targeting the CTLA-4 and PD-1 pathways. In this review, we discuss the mechanisms of action and expression pattern of co-inhibitory receptors on different T cells subsets, emphasising differences between CD4(+) and CD8(+) T cells. We also summarise recent clinical findings utilising immune checkpoint blockade. PMID- 26578458 TI - Effects of a Pilates exercise program on muscle strength, postural control and body composition: results from a pilot study in a group of post-menopausal women. AB - Participation in exercise programs is heartily recommended for older adults since the level of physical fitness directly influences functional independence. The aim of this present study was to investigate the effects of supervised Pilates exercise training on the physical function, hypothesizing that a period of Pilates exercise training (PET) can increase overall muscle strength, body composition, and balance, during single and dual-task conditions, in a group of post-menopausal women. Twenty-five subjects, aged 59 to 66 years old, were recruited. Eligible participants were assessed prior and after 3 months of PET performed twice per week. Muscular strength was evaluated with handgrip strength (HGS) test, 30-s chair sit-to-stand test (30CST), and abdominal strength (AST) test. Postural control and dual-task performance were measured through a stabilometric platform while dynamic balance with 8 ft up and go test. Finally, body composition was assessed by means of dual-energy X-ray absorptiometry. Statistically significant improvements were detected on HGS (+8.22%), 30CST (+23.41%), 8 ft up and go test (-5.95%), AST (+30.81%), medio-lateral oscillations in open eyes and dual-task condition (-22.03% and -10.37%). Pilates was effective in increasing upper body, lower body, and abdominal muscle strength. No changes on body composition were detected. Results on this investigation indicated also that 12-week of mat Pilates is not sufficient to determine a clinical meaningful improvement on static balance in single and dual task conditions. PMID- 26578457 TI - Effects of age on the amplitude, frequency and perceived quality of voice. AB - The manner and extent to which voice amplitude and frequency control mechanisms change with age is not well understood. The related question of whether the assessment of one's own voice evolves with age, concomitant with the acoustical changes that the voice undergoes, also remains unanswered. In the present study, we characterized the aging of voice production mechanisms (amplitude, frequency), compared the aging voice in different experimental contexts (vowel utterance, connected speech) and examined the relationship between voice self-assessment and age-related voice acoustical changes. Eighty healthy adults (20 to 75 years old) participated in the study, which involved computation of several acoustical measures of voice (including measures of fundamental frequency, voice amplitude, and stability) as well as self-assessments of voice. Because depression is frequent in older adults, depression and anxiety scores were also measured. As was expected, analyses revealed age effects on most acoustical measures. However, there was no interaction between age and the ability to produce high/low voice amplitude/frequency, suggesting that voice amplitude and frequency control mechanisms are preserved in aging. Multiple mediation analyses demonstrated that the relationship between age and voice self-assessment was moderated by depression and anxiety scores. Taken together, these results reveal that while voice production undergoes important changes throughout aging, the ability to increase/decrease the amplitude and frequency of voice are preserved, at least within the age range studied, and that depression and anxiety scores have a stronger impact on perceived voice quality than acoustical changes themselves. PMID- 26578459 TI - Effect of a physical training program using the Pilates method on flexibility in elderly subjects. AB - The adaptations of the human body resulting from the aging process especially loss of flexibility can increase the risk of falls and the risk of developing other health conditions. Exercise training, in particular the Pilates exercise method, has become an important form of physical activity that minimizes the deleterious effects of aging on flexibility. Few studies have evaluated the effect of this training method on body flexibility among elderly. We aimed to evaluate the effects of physical training using the Pilates method on body flexibility of elderly individuals. Eighteen elderly women and two elderly men (aged 70 +/- 4 years) followed a 10-week Pilates training program. Individuals were recruited from the local community via open invitations. At study entry, none of them had limited mobility (walking requiring the use of walkers or canes). Furthermore, those with neurologic, muscular, or psychiatric disorders as well as those using an assistive device for ambulation were excluded secondary to limited participation. Flexibility assessment tests (flexion, extension, right and left tilt, and right and left rotation of the cervical and thoracolumbar spine; flexion, extension, abduction, and lateral and medial right and left rotation of the glenohumeral joint; flexion, extension, abduction, adduction, and lateral and medial rotation of the right and left hip; and flexion of the right and left knee) were performed by a blinded evaluator using a flexometer before and after the training period. All assessments were carried out at the same time of day. There was an observed increase in flexion (22.86%; p < 0.001), extension (10.49%; p < 0.036), and rotation to the left side (20.45%; p < 0.019) of the cervical spine; flexion (16.45%; p < 0.001), extension (23.74%; p = 0.006), lateral bending right (39.52%; p < 0.001) and left (38.02%; p < 0.001), and right rotation (24.85%; p < 0.001) and left (24.24%; p < 0.001) of the thoracolumbar spine; flexion (right--8.80%, p = 0.034; left--7.03%, p = 0.050), abduction (right--20.69%, p < 0.001; left--16.26%, p = 0.005), and external rotation (right -116.07% and left--143%; p < 0.001 for both directions) of the glenohumeral joint; flexion (right--15.83%, p = 0.050; left--9.55%, p = 0.047) of the hips; and bending (right--14.20%, p = 0.006; left--15.20%, p = 0.017) the knees. The joint with the greatest magnitude of improvement was the thoracolumbar spine. Thus, this type of training may minimize the deleterious effects of aging and may improve the functionality of elderly individuals, which would reduce the likelihood of accidents (especially falls). PMID- 26578461 TI - Simplifying and expanding the screening for peptides <2 kDa by direct urine injection, liquid chromatography, and ion mobility mass spectrometry. AB - The analysis of low-molecular-mass peptides in doping controls has become a mandatory aspect in sports drug testing and, thus, the number of samples that has to be tested for these analytes has been steadily increasing. Several peptides <2 kDa with performance-enhancing properties are covered by the list of prohibited substances of the World Anti-Doping Agency including Desmopressin, LH-RH, Buserelin, Triptorelin, Leuprolide, GHRP-1, GHRP-2, GHRP-3, GHRP-4, GHRP-5,GHRP 6, Alexamorelin, Ipamorelin, Hexarelin, ARA-290, AOD-9604, TB-500 and Anamorelin. With the presented method employing direct urine injection into a liquid chromatograph followed by ion-mobility time-of-flight mass spectrometry, a facile, specific and sensitive assay for the aforementioned peptidic compounds is provided. The accomplished sensitivity allows for limits of detection between 50 and 500 pg/mL and thus covers the minimum required performance level of 2 ng/mL accordingly. The method is precise (imprecision <20%) and linear in the estimated working range between 0 and 10 ng/mL. The stability of the peptides in urine was tested, and -20 degrees C was found to be the appropriate storage temperature for sports drug testing. Finally, proof-of-concept was shown by analysing elimination study urine samples collected from individuals having administered GHRP-6, GHRP 2, or LHRH. PMID- 26578460 TI - Effects of white matter lesions on trunk stability during dual-task walking among older adults with mild cognitive impairment. AB - The linkage between gait and cognition has been shown in cases of white matter lesion (WML) that affect gait in older adults. Dual-task walking is believed to be cognitively demanding and to alter trunk movement, and gait impairment in people with mild cognitive impairment (MCI) is highlighted under this condition. However, the association between dual-task walking and structural changes in the brain, particularly with WML, in people with MCI is still unclear. The aim of this study was to examine the association between trunk stability during dual task walking and WML in 560 older adults with MCI. We measured magnetic resonance imaging (MRI) and gait variables. Gait variables included harmonic ratio in vertical, mediolateral, and anteroposterior directions, analyzed using a tri axial accelerometer attached to the lower trunk. Walking conditions were normal walking and dual-task walking (counting backwards while walking) conditions. Demographical data and brain atrophy were measured as covariates. Subjects were classified into non-severe WML (n = 451, mean age = 73.2 years) and severe WML (n = 109, mean age = 75.9 years) groups. Linear mixed-effects model analysis controlled for covariates showed dual-task-related changes in all harmonic ratios associated with WML (p < 0.05). Even after adjustment for executive function, harmonic ratio in the mediolateral direction was significantly associated with WML (p < 0.05). Our findings revealed that WMLs were associated with trunk stability in dual-task walking. Further studies are required to investigate the neural basis for deficits in gait ability among MCI subjects. PMID- 26578462 TI - Prognostic and diagnostic value of EEG signal coupling measures in coma. AB - OBJECTIVE: Our aim was to assess the diagnostic and predictive value of several quantitative EEG (qEEG) analysis methods in comatose patients. METHODS: In 79 patients, coupling between EEG signals on the left-right (inter-hemispheric) axis and on the anterior-posterior (intra-hemispheric) axis was measured with four synchronization measures: relative delta power asymmetry, cross-correlation, symbolic mutual information and transfer entropy directionality. Results were compared with etiology of coma and clinical outcome. Using cross-validation, the predictive value of measure combinations was assessed with a Bayes classifier with mixture of Gaussians. RESULTS: Five of eight measures showed a statistically significant difference between patients grouped according to outcome; one measure revealed differences in patients grouped according to the etiology. Interestingly, a high level of synchrony between the left and right hemisphere was associated with mortality on intensive care unit, whereas higher synchrony between anterior and posterior brain regions was associated with survival. The combination with the best predictive value reached an area-under the curve of 0.875 (for patients with post anoxic encephalopathy: 0.946). CONCLUSIONS: EEG synchronization measures can contribute to clinical assessment, and provide new approaches for understanding the pathophysiology of coma. SIGNIFICANCE: Prognostication in coma remains a challenging task. qEEG could improve current multi-modal approaches. PMID- 26578463 TI - Source of care and variation in long-acting reversible contraception use. AB - OBJECTIVE: To examine variation in long acting reversible contraception (LARC) use by source of birth control services. DESIGN: Cross-sectional study. SETTING: Not applicable. PATIENT(S): Sexually active women who received contraceptive services in the past 12 months, who were neither pregnant nor trying to become pregnant and who were not sterilized and nor were their partners sterilized. INTERVENTION(S): Three multinomial logistic regression models assessed the relationship between source of services and LARC use, controlling for covariates. The odds of LARC use were compared with LARC nonuse, high-efficacy use, and low efficacy use. MAIN OUTCOME MEASURE(S): Reported LARC method use. RESULT(S): There was no statistically significant difference in LARC use between women receiving services from community or public health clinics and women receiving services from private clinics. Women receiving care at a family-planning clinics had lower odds of LARC use versus LARC nonuse (odds ratio [OR] = 0.27; 95% confidence interval [CI], 0.10-0.74), versus high-efficacy method use (OR = 0.32; 95% CI, 0.11-0.88) and versus low-efficacy method use (OR = 0.13; 95% CI, 0.02-0.87) compared with those receiving services at private clinics. CONCLUSION(S): Women receiving care from family-planning clinics had lower odds of LARC use compared with those receiving care from a private doctor's office or health maintenance organization facility. PMID- 26578464 TI - Breeding Restrictions Decrease the Prevalence of Myxomatous Mitral Valve Disease in Cavalier King Charles Spaniels over an 8- to 10-Year Period. AB - BACKGROUND: Cavalier King Charles Spaniels (CKCS) are predisposed to myxomatous mitral valve disease (MMVD). Studies have indicated a strong genetic background. OBJECTIVE: The aim of this study was to evaluate the effect of a breeding scheme involving auscultation and echocardiography. ANIMALS: In the Danish Kennel Club mandatory breeding scheme, 997 purebred CKCS were examined during the period 2002 2011. Each dog was evaluated 1-4 times with a total of 1,380 examinations. METHODS: Auscultation and echocardiography were performed to evaluate mitral regurgitation murmur severity and degree of mitral valve prolapse (MVP). The odds of having mitral regurgitation murmur or MVP > grade 1 in 2010-2011 compared to 2002-2003 were estimated using logistic regression analysis including age and sex as covariates. Odds were estimated for dogs that were products of the breeding scheme (defined as dogs with both parents approved by the breeding scheme before breeding) and non-products of the breeding scheme (defined as dogs with at least 1 parent with unknown cardiac status). RESULTS: In 2010-2011, the odds of having mitral regurgitation murmur were 0.27 if dogs were a product of the breeding scheme compared with dogs in 2002-2003, reflecting a 73% decreased risk (P < .0001). If non-products of the breeding scheme examined in 2010-2011 were compared with dogs in 2002-2003, no difference in odds was found (P = .49). CONCLUSION AND CLINICAL IMPORTANCE: A mandatory breeding scheme based on auscultation and echocardiography findings significantly decreased the prevalence of MMVD over the 8- to 10-year period. Such a breeding scheme therefore is recommended for CKCS. PMID- 26578465 TI - Vinculin: An Unfolding Tale. PMID- 26578466 TI - Suitability of the in vitro Caco-2 assay to predict the oral absorption of aromatic amine hair dyes. AB - Oral absorption is a key element for safety assessments of cosmetic ingredients, including hair dye molecules. Reliable in vitro methods are needed since the European Union has banned the use of animals for the testing of cosmetic ingredients. Caco-2 cells were used to measure the intestinal permeability characteristics (Papp) of 14 aromatic amine hair dye molecules with varying chemical structures, and the data were compared with historical in vivo oral absorption rat data. The majority of the hair dyes exhibited Papp values that indicated good in vivo absorption. The moderate to high oral absorption findings, i.e. >=60%, were confirmed in in vivo rat studies. Moreover, the compound with a very low Papp value (APB: 3-((9,10-dihydro-9,10-dioxo-4-(methylamino)-1 anthracenyl)amino)-N,N-dimethyl-N-propyl-1-propanaminium) was poorly absorbed in vivo as well (5% of the dose). This data set suggests that the Caco-2 cell model is a reliable in vitro tool for the determination of the intestinal absorption of aromatic amines with diverse chemical structures. When used in combination with other in vitro assays for metabolism and skin penetration, the Caco-2 model can contribute to the prediction and mechanistic interpretation of the absorption, metabolism and elimination properties of cosmetic ingredients without the use of animals. PMID- 26578467 TI - Effects of the water soluble fraction of gasoline on ZFL cell line: Cytotoxicity, genotoxicity and oxidative stress. AB - This work aimed to evaluate the effects of different dilutions of gasoline water soluble fraction (GSF) on Danio rerio hepatocyte cell line (ZFL). Two tests were used to assess cell viability, MTT reduction assay (MTT) and the Trypan blue (TB) exclusion test. Oxidative stress was evaluated through the quantification of reactive oxygen species (ROS) and the assessment of the total antioxidant capacity against peroxyl radicals (ACAP) and the comet assay was employed to assess DNA damage. ZFL cells were exposed to 5, 10, 25 and 50% GSF or only to saline for 1, 3 and 6h. The GSF exhibited concentration-dependent cytotoxicity, and longer exposure times resulted in lower cell viability as indicated by both MTT and TB assays. The establishment of oxidative stress in cells exposed to GSF was not observed at any exposure period and the lower ROS levels could be related to the increased antioxidant capacity after 6-hour exposure. DNA damage was significantly increased after exposure to GSF at the three experimental times. Taking together these results show that GSF has a genotoxic potential at the lower concentrations and becomes cytotoxic at higher concentrations and that ZFL can be considered a good biological model for in vitro toxicological studies. PMID- 26578469 TI - [Invitation to renew bonds]. PMID- 26578468 TI - Comparison of left ventricular manual versus automated derived longitudinal strain: implications for clinical practice and research. AB - Systolic global longitudinal strain (GLS) is emerging as a useful metric of ventricular function in heart failure and usually assessed using post-processing software. The purpose of this study was to investigate whether longitudinal strain (LS) derived using manual-tracings of ventricular lengths (manual-LS) can be reliable and time efficient when compared to LS obtained by post-processing software (software-LS). Apical 4-chamber view images were retrospectively examined in 50 healthy controls, 100 patients with dilated cardiomyopathy (DCM), and 100 with hypertrophic cardiomyopathy (HCM). We measured endocardial and mid wall manual-LS and software-LS, using peak of average regional curve [software LS(a)] and global ventricular lengths [software-LS(l)] according to definition of Lagragian strain. We compared manual-LS and software-LS by using Bland-Altman plot and coefficient of variation (COV). In addition, test-retest was also performed for further assessment of variability in measurements. While manual-LS was obtained in all subjects, software-LS could be obtained in 238 subjects (95%). The time spent for obtaining manual-LS was significantly shorter than for the software-LS (94 +/- 39 s vs. 141 +/- 79 s, P < 0.001). Overall, manual-LS had an excellent correlation with both software-LS (a) (R(2) = 0.93, P < 0.001) and software-LS(l) (R(2) = 0.84, P < 0.001). The bias (95%CI) between endocardial manual-LS and software-LS(a) was 0.4% [-2.8, 3.6%] in absolute and 3.5% [-17.0, 24.0%] in relative difference while it was 0.4% [-2.5, 3.3%] and 3.4% [-16.2, 23.1%], respectively with software-LS(l). Mid-wall manual-LS and mid-wall software-LS(a) also had good agreement [a bias (95% CI) for absolute value of 0.1% [-2.1, 2.5%] in HCM, and 0.2% [-2.2, 2.6%] in controls]. The COV for manual and software derived LS were below 6%. Test-retest showed good variability for both methods (COVs were 5.8 and 4.7 for endocardial and mid-wall manual-LS, and 4.6 and 4.9 for endocardial and mid-wall software-LS(a), respectively. Manual-LS appears to be as reproducible as software-LS; this may be of value especially when global strain is the metric of interest. PMID- 26578470 TI - [Burnout Syndrome, Family and Work Related Variables on General Practitioners in Bogota. A Strategy of Work Quality]. AB - BACKGROUND: The burnout syndrome is a set of work-related symptoms related to weariness and exhaustion, in response to the emotional stress at work and its consequences. The aim of the study was to measure the frequency of burnout in General Practitioners (GPs) from 3 private institutions in Bogota, Colombia and to determine the associated factors according to the variables taken into account. METHODS: It is a descriptive cross-sectional study which was used to analyse the Questionnaire for Burnout Syndrome (CESQT). The population was 106 GPs. RESULTS: The level of burnout was at a critical level in 6.6% of the GP population. The variables showed that having a stable partner and children are a protective factor. By contrast, work in emergency rooms is a risk factor. PMID- 26578471 TI - [Characterization of Adult Patients Diagnosed With Sleep Apnea in a Sleep Clinic in the City of Pereira (Colombia)]. AB - OBJECTIVES: To characterize adult patients with sleep apnea attending Pereira's sleep apnea clinic between July and August 2011. METHODS: Cross-sectional descriptive study. A personal semi-structured survey was performed, with full medical history, focused on perceived symptoms of mental and non-mental comorbidity. RESULTS: Fourty-three patients with diagnosis of sleep apnea were evaluated. These were compared with 21 patients without this diagnosis. The social demographic characteristics were similar to that reported in the literature. There were statistical significances for snoring, sleep apnea, corporal mass index, waist/hip index and dyslipidemia. The logistic regression analysis showed sex, Pittsburgh's quality of sleep index and body mass index as predictor variables. CONCLUSIONS: There are clinical and anthropometrics variables that can help the health professionals to suspect a sleep apnea diagnosis in a patient and provide better treatment to decrease its morbidity and mortality. PMID- 26578472 TI - [Factorial Structure of the Cardiff Anomalous Perceptions Scale (CAPS) in a Colombian Population Sample]. AB - BACKGROUND: The continuum hypothesis of psychosis assumes that hallucinations are not exclusive of psychotic disorders. A number of psychometric tests have been developed to assess psychosis using a dimensional model. OBJECTIVES: To determine the factorial structure of the Cardiff Anomalous Perceptions Scale (CAPS) for the Colombian population, and to contrast the fit of two factor models previously reported in the literature by conducting a confirmatory factor analysis (CFA). METHODS: This was a cross-sectional study in which 207 subjects from the general population were assessed using the Cardiff Anomalous Perceptions Scale. RESULTS: A two-factor structure with acceptable ordinal alpha coefficients (alpha=.88 and alpha=.87) was found. One factor gathered items related to multimodal perceptual alterations, and a second factor grouped items related with experiences linked to the temporal lobe. The analysis of the first factor indicated that it was dependent on cultural issues for the interpretation of sensations. The second factor appeared almost unchanged on diverse populations, suggesting its transcultural character. When comparing the models proposed by Bell et al. and Jaen-Moreno et al. using the data obtained from the sample, the confirmatory factor analysis conducted indicated inadequate goodness-of-fit indexes (chi(2)). However, some incremental goodness-of-fit indexes (normalized chi(2) [RMSEA]) were acceptable. The Jaen-Moreno et al. model showed the best fit to the data collected from the Colombian sample. CONCLUSIONS: The factorial structure of CAPS for the Colombian population appears to be sensitive to cultural issues, especially when describing anomalous sensorial experiences. PMID- 26578473 TI - [Metabolic Control, Evaluation and Follow-up Interventions in Patients With Schizophrenia]. AB - OBJECTIVES: To determine the laboratory tests, related to metabolic risk that should be practiced to adult patients diagnosed with schizophrenia. To assist the clinician decision-making process about complementary diagnostic evaluation strategies in adult diagnosed with schizophrenia. METHODS: A clinical practice guideline was elaborated under the parameters of the Methodological Guide of the Ministerio de Salud y Proteccion Social to identify, synthesize and evaluate the evidence and make recommendations about the treatment and follow-up of adult patients with schizophrenia. The evidence of NICE guide 82 was adopted and updated. The evidence was presented to the Guideline Developing Group and recommendations, employing the GRADE system, were produced. RESULTS: The risk of overall mortality in schizophrenia is higher than in the general population excluding suicide. Results related with mortality associated to antipsychotics showed contradictory results. Metabolic outcomes showed a higher incidence and association with schizophrenia and treatment with antipsychotics (AP). The diagnosis of dyslipidemia in men with schizophrenia appears to be lower in comparison with the general population. However, changes in weight, blood sugar levels, HDL cholesterol and triglycerides are influenced by the use of antipsychotics in general there is a higher risk of developing diabetes mellitus in adults with schizophrenia. CONCLUSION: Based on the evidence found a plan was formulated for the evaluation of physiological and paraclinical variables during and before the management with AP in adult diagnosed with schizophrenia. The overall quality of evidence is low considering that most of the reports come from observational studies that have risk of bias and some designs have methodological limitations. PMID- 26578474 TI - [Actigraphy in Bipolar Disorder and First Degree Relatives]. AB - BACKGROUND: Bipolar disorder is a disabling disease that involves a significant economic costs to the health system, making it is essential to investigate possible early predictors such as changes in sleep-wake cycle in high-risk populations. OBJECTIVE: To review the available literature on alterations in the sleep-wake cycle and circadian rhythm in patients with bipolar disorder and their first degree relatives. METHODS: A literature search was performed in the data bases, Access Medicine, ClinicalKey, EMBASE, JAMA, Lilacs, OVID, Oxford Journals, ScienceDirect, SciELO, APA y PsycNET. Articles in both English and Spanish were reviewed, without limits by study type. RESULTS: Actigraphy is a non-invasive, useful method for assessing sleep-wake cycle disturbances in the active phases of bipolar disorder, and during euthymia periods. Actigraphy showed good sensitivity to predict true sleep, but low specificity, compared with polysomnography. Although studies in bipolar offspring and relatives are scarce, they show sleep changes similar to bipolar patients. CONCLUSIONS: Actigraphy may be a good screening tool of sleep/wake cycle in patients with bipolar disorders, because it is economic, non-invasive and sensitive. Longitudinal studies are required to evaluate its potential use as a risk marker. PMID- 26578475 TI - [Conversion Disorder in Children and Adolescents]. AB - BACKGROUND: Conversion disorder is diagnosed late, by exclusion and with a high risk of complications. There is a wide experience in adults that is not extrapolated to paediatric patients. According to the literature, the prognosis is better in children, but this changes when other variables such are included, such as comorbidities, late diagnosis and a very convincing social image of the neurological disease. OBJECTIVE: To review the medical literature on the clinical features, diagnosis, comorbidities and treatment of this disorder. METHODS: A literature research was performed on Medline and Pubmed, the terms used were "conversion disorder", pseudoseizures, treatment, clinic, children ("conversion disorder" OR hysteria OR hysterical) (child OR children OR childhood OR pediatric OR paediatric). The most relevant material found is included in this review. CONCLUSIONS: Conversion disorder is often an imprecise diagnosis in high complexity paediatric services. No consensus was found in the literature search on how to treat patients after the initial diagnosis. The evidence that it becomes chronic is not strong enough, just as the evidence is not convincing enough to argue that comorbidity factors are those maintained over time. Clearly, there is no medical experience of the natural history of this disorder in children and adolescents. It is only known is that it is a complex condition, on which there is experience only in the diagnosis and treatment of the acute state, but not so in the long-term care. It is proposed that each patient is studied in detail in order to define the psychiatric diagnosis and its treatment. PMID- 26578476 TI - [The Stigma-discrimination Complex Associated With Mental Disorder as a Risk Factor for Suicide]. AB - BACKGROUND: The concept stigma-discrimination complex associated with mental disorder (SDCAMD) is proposed to encompass the terms used in the attribution theory: stigma, stereotype, prejudice and discrimination. SDCAMD is one of the most frequent disorders worldwide. Internalized and perceived SDCAMD may explain a number of suicide cases. OBJECTIVE: To update the factors that may explain the association between SDCAMD and suicide, and postulate possible underlying mechanisms. RESULTS: Articles were identified in MEDLINE using the descriptors for "stigma", "mental disorders" and "suicide" or "suicide rate". Articles published between January 2000 and June 2014 were included. Reviews and case studies were not considered. The two included studies showed that stigma increased the risk of suicidal behaviors. It was evident that people who meet criteria for mental disorder and reported high self-stigma made a greater number of suicide attempts, and countries with high stigma in the general population have a higher suicide rate. It was considered that the relationship between SDCAMD and suicide is established by a set of interrelated mechanisms. A "direct" mechanism involving perceived stigma and is configured as a barrier to access mental health services, and an "indirect" mechanism involving the self-stigma, which increases the vulnerability to depressive episodes and repeated self injurious behaviors that ultimately end in suicide. CONCLUSIONS: The SDCAMD impacts negatively on the quality of life of people who meet criteria for mental disorders, and accounts for a significant number of suicides. One way is related to the perceived stigma that is configured as a barrier to access mental health services and, the second one includes repeated self-injurious behaviors that reduce self-esteem and increases perceived stress. Further research is required to increase the knowledge of this association. PMID- 26578477 TI - [Trazodone in REM sleep behavior disorder]. AB - This case concerns an elderly man with a REM sleep behavior disorder, who was initially offered a pharmacological treatment with clonazepam, recommended by other articles, but with poor adherence due to its adverse reactions and persistence of symptoms. He was then offered a treatment with Trazodone was offered, achieving a complete remission of symptoms, with no reported side effects. It is clear that Trazodone has no known indication for this type of disorder; nevertheless, it was considered in this case because of its pharmacological profile, obtaining satisfactory results. Further research is needed in order to document thoroughly the mechanisms of action, efficacy and utility of this molecule in cases such as the one presented. PMID- 26578478 TI - [Psychosis Associated With Fahr's Syndrome: A Case Report]. AB - INTRODUCTION: Fahr syndrome (SF) is a rare neurological disorder, characterized by abnormal deposition of calcium in brain areas that control movement. OBJECTIVE: The case is presented of a 41-year-old female with a convulsive syndrome, psychotic disorder, neurocognitive disorde,r and intellectual disability associated with bilateral brain calcifications and altered calcium/phosphorus metabolism in the context of hypoparathyroidism. METHOD: Case report. RESULTS: The calcifications found in the patient could be the cause of psychotic symptoms and cognitive impairment. Diagnostic imaging, laboratory tests, psychiatric and neuropsychological assessments are presented. The clinical presentation of this case is compared with similar ones reported in the literature. Therapeutic approaches and clinical outcomes are described. CONCLUSIONS: Fahr's syndrome should be suspected in patients with neuropsychiatric disorders and seizures. Neuroimaging studies, and the determining of phosphorus and calcium metabolism and parathyroid hormone levels are important in this type of patient. PMID- 26578479 TI - British Military surgical key performance indicators: time for an update? AB - BACKGROUND: Key performance indicators (KPIs) are metrics that compare actual care against an ideal structure, process or outcome standard. KPIs designed to assess performance in deployed military surgical facilities have previously been published. This study aimed to review the overall performance of surgical trauma care for casualties treated at Role 3 Camp Bastion, Medical Treatment Facility, Afghanistan, in light of the existing Defence Medical Services (DMS) KPIs. The secondary aims were to assess the utility of the surgical KPIs and make recommendations for future surgical trauma care review. METHODS: Data on 22 surgical parameters were prospectively collected for 150 injured patients who had primary surgery at Camp Bastion between 1 May 2013 and 20 August 2013. Additional information for these patients was obtained using the Joint Theatre Trauma Register. The authors assessed data recording, applicability and compliance with the KPIs. RESULTS: Median data recording was 100% (IQR 98%-100%), median applicability was 56% (IQR 10%-99%) and median compliance was 78% (IQR 58%-93%). One KPI was not applicable to any patient in our population. Eleven KPIs achieved >80% compliance, five KPIs had 80%-60% compliance and five KPIs had <60% compliance. Recommendations are made for minor modifications to the current KPIs. CONCLUSION: 78% compliance with the DMS KPIs provides a snapshot of the performance of the surgical aspect of military trauma care in 2013. The KPIs highlight areas for improvement in service delivery. Individual KPI development should be driven by evidence and reflect advances in practice and knowledge. A method of stakeholder consultation, and sequential refinement following evidence review, may be the right process to develop the future set of DMS KPIs. PMID- 26578480 TI - Radiographic Morphologic Characteristics of Bunionette Deformity. AB - BACKGROUND: Bunionette deformity is characterized as head hypertrophy, lateral bowing, or splaying of the fifth metatarsal, or a combination of these deformities. Most previous studies have focused on the fourth and fifth metatarsals; few have analyzed the radiographic morphologic characteristics of the entire foot. The morphologic characteristics of the entire foot in cases of symptomatic bunionette deformity were analyzed with a radiographic image-mapping system. METHODS: The system was used for the morphologic analysis of 112 feet with symptomatic deformity and 123 asymptomatic control feet. The mapping system includes 2-dimensional coordinates. We compared morphologies of both groups on the basis of simple models prepared from x and y coordinates of each reference point, calculated by using the mapping system and various angle measurements. We set cutoff values and categorized cases according to Fallat's system. We evaluated the characteristics of each type and a new deformity type (type V) wherein no measurement exceeded the cutoff values. RESULTS: The heads of the third, fourth, and fifth metatarsals were more laterally displaced, and the angles between the metatarsal axes were larger in the deformity group. Comparison of deformity types showed that the morphology of the fifth metatarsal might be only one cause of deformity. The intermetatarsal angles between the second and third metatarsals and between the third and fourth metatarsals were larger in deformity type II and type V feet than in control feet. Additionally, the intermetatarsal angles between the third and fourth metatarsals and between the fourth and fifth metatarsals were larger in deformity type III and type IV feet than in control feet. CONCLUSION: We believe it is necessary to not only focus on the fourth and fifth metatarsals, but also assess the morphologic characteristics of the entire foot in patients with a bunionette, including splaying of all the metatarsals and the forefoot width, when planning surgery. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 26578481 TI - Return to Sports and Physical Activities After the Modified Lapidus Procedure for Hallux Valgus in Young Patients. AB - BACKGROUND: The modified Lapidus procedure has successfully relieved pain and corrected deformity in patients with hallux valgus, but its effect on participation in specific sports and physical activities remains unclear. Our goals were to assess sports and physical activities in young patients following the modified Lapidus procedure and to compare these with clinical outcomes. METHODS: Fifty-eight eligible patients were identified from a retrospective registry review. Of these, 48 (83%) were reached for follow-up at a mean of 2.8 (range, 1.0 to 6.1) years and had a mean age at surgery of 37.3 (range, 14.1 to 49.3) years. Physical activity participation was evaluated with a new sports specific, patient-administered questionnaire. Clinical outcomes were evaluated with the Foot and Ankle Outcome Score (FAOS) and compared to sports outcomes. RESULTS: Patients participated in 26 different physical activities, consisting of 212 total physical activities preoperatively and 209 total postoperatively. The most common were walking, running, bicycling, and swimming. Compared to preoperatively, patients rated 29% of activities as less difficult, 52% as the same, and 19% as more difficult and rated participation levels as improved in 40%, the same in 41%, and impaired in 19%. Eighty-one percent of patients were satisfied with their operative outcome in regard to return to physical activity. Changes in the FAOS Pain subscore were significantly associated with improvements in physical activity difficulty (P < .05), and changes in the Pain, Sports, and QOL subscores were significantly associated with changes in physical activity participation levels (P < .05). CONCLUSION: Four in 5 patients were able to participate in previous sports and physical activities, including high-impact activities, at their preoperative participation level or better after the modified Lapidus procedure, and were satisfied with surgery in regard to return to previous activity. However, several patients had increased difficulty and impaired participation in physical activity postoperatively. Altogether, this suggests that the procedure is a viable treatment option for hallux valgus in young, active patients. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 26578483 TI - Power and passion. PMID- 26578482 TI - Outcomes of Tibiotalocalcaneal Arthrodesis Through a Posterior Achilles Tendon Splitting Approach. AB - BACKGROUND: A number of operative approaches have been described to perform a tibiotalocalcaneal (TTC) arthrodesis. Here we present the largest reported series of a posterior Achilles tendon-splitting approach for TTC fusion. METHODS: With institutional review board approval, a retrospective review of the TTC fusions performed at a single academic institution was carried out. Orthopedic surgeons specializing in foot and ankle surgery performed all procedures. Eligible patients included all those who underwent a TTC fusion via a posterior approach and had at least a 2-year follow-up. Forty-one patients underwent TTC arthrodesis through a posterior Achilles tendon-splitting approach. Mean age at surgery was 56.9+/-15.0 years. There were 21 female and 20 male patients. Preoperative diagnoses included arthritis (n = 13 patients), failed total ankle arthroplasty (9), avascular necrosis of the talus (9), prior nonunion of the ankle and/or subtalar joint (6), Charcot neuro-arthropathy (2), and stage IV flatfoot deformity (2). In 37 patients (90.2%), a hindfoot intramedullary arthrodesis nail was used, with posterior plate or supplemental screw augmentation in 17 patients. Posterior plate stabilization alone was utilized in 4 cases (9.8%). RESULTS: The fusion rate was 80.4%. Eight patients developed a nonunion of the subtalar, tibiotalar, or both joints. Complications were observed in 17 patients (41.4%). Of these, ankle nonunion (19.5%), tibial stress fracture (17%), postoperative cellulitis and superficial wound breakdown (9.7%), subtalar nonunion (4.8%), and TTC malunion (2.4%) were the most frequently identified. One patient eventually underwent amputation (2.4%). CONCLUSION: We believe that posterior Achilles tendon-splitting approach for tibiotalocalcaneal arthrodesis was a safe and effective method, with similar union and complications rates to some previously described techniques. We believe the posterior approach is advantageous as it provides simultaneous access to both the ankle and subtalar joints and allows for dissection to occur between angiosomes, which may preserve blood supply to the skin. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 26578484 TI - Diagnosis of small partial-thickness rotator cuff tears using vibro acoustography. AB - PURPOSE: Vibro-acoustography is a new imaging technique based on the dynamic radiation force of ultrasound. The purpose of this study was to apply this new imaging technique to the diagnosis of small partial-thickness rotator cuff tears and to determine how small of tears could be detected with this imaging technique. METHODS: Seven supraspinatus tendons excised from embalmed cadavers were used. Three different sizes of partial-thickness bursal-sided tears (1, 3, and 5 mm(3)) were created in each specimen. The intersection of two co-focused ultrasound beams of slightly different frequency was swept across the intended imaging area. The acoustic emission data were collected and used to form and display a vibro-acoustography image of the tendon. Vibro-acoustography images were read by two orthopedic surgeons. RESULTS: The rotator cuff tear could be detected by vibro-acoustography in all specimens. The diagnostic concordance rate was 90.5 % and the kappa coefficient value was 0.88, which resulted in a high concordance. The diagnostic concordance rate for the 1 mm tear was 71.3 %, which was low concordance (kappa = 0.481), whereas that for the 3 and 5 mm tears was 100 %. CONCLUSIONS: We were able to detect a 3-mm tear by using vibro acoustography. There is a possibility that this new imaging technique could become a useful imaging tool for the diagnosis of small partial-thickness rotator cuff tears. PMID- 26578485 TI - Combination of ultrasound and newly synthesized magnetic nanocapsules affects the temperature profile of CT26 tumors in BALB/c mice. AB - PURPOSE: To investigate the effects of a combination of 3-MHz ultrasound waves with a new magnetic nanocapsule containing 5-fluorouracil (5-Fu) on the temperature profile of a mouse colon tumor (CT26) in BALB/c mice. METHODS: Firstly, 5-Fu-loaded magnetic nanocapsules were synthesized using a multiple emulsion solvent evaporation procedure. Magnetic resonance imaging (MRI) was performed to evaluate the efficiency of nanocapsule localization in the tumor during magnetic drug targeting (MDT). Tumors were separately exposed to 3-MHz ultrasound waves at the intensities of 0.1, 0.3, 0.5, and 1 W/cm(2) for 10 min in the absence and presence of nanocapsules. The temperature of the tumor was recorded at 1-min intervals. RESULTS: The effective diameter of the nanocapsules was approximately 70 nm, and it was demonstrated that magnetic nanoparticles were well dispersed inside the nanocapsules. MRI confirmed that the magnetic nanocapsules were successfully targeted to the tumor after accomplishing MDT. Temperature change due to sonication of the tumor was strongly intensity dependent. Moreover, temperature-time curves revealed that the magnetic nanocapsules significantly affected the temperature rise profile of a sonicated tumor. CONCLUSION: Data presented in this study would be helpful to develop an ultrasound-mediated MDT procedure so that temperature changes of the tumor and its surrounding normal tissues may be controllable. PMID- 26578486 TI - Poly(vinyl alcohol) gel ultrasound phantom with durability and visibility of internal flow. AB - PURPOSE: Among various existing flow phantoms, none is characterized by appropriate acoustic, visibility, and durability properties simultaneously. The aim of this study was to develop a durable ultrasound phantom with visibility of the internal flow. METHODS: Poly(vinyl alcohol) (PVA) gel was chosen as the basic material. The acoustic properties of various PVA gels were measured with 40-MHz ultrasound, the compositions of PVA, dimethyl sulfoxide (DMSO), and glass microbeads being changed, while visually checking the transparency. Wall-less ultrasound flow phantoms with a straight channel 2 mm in diameter were made from PVA gel, and ultrasound B-mode imaging was conducted with blood-mimicking fluid flow. RESULTS: The acoustic properties of in vivo soft tissue were reproduced by PVA gel with a PVA concentration of 15 mass% and a glass microbead concentration of 2.9 mass% in a solvent of 98 mol% DMSO, showing acoustic properties of 1567 +/ 4 m/s and 56 +/- 5 dB/cm. The PVA gel was durable with visibility of the flow in the ultrasound phantom. The ultrasound B-mode image of the ultrasound flow phantom showed features approximating those of a mouse carotid artery. CONCLUSION: A durable PVA gel ultrasound phantom with visibility of the internal flow was developed. PMID- 26578487 TI - Tumor boundary detection in ultrasound imagery using multi-scale generalized gradient vector flow. AB - PURPOSE: As a key technology in high-intensity focused ultrasound (HIFU) ablation systems, a precise ultrasound image segmentation method for tumor boundary detection is helpful for ablation of tumors and avoiding tumor recurrence. This study explores a new deformable snake model called multi-scale generalized gradient vector flow (MS-GGVF) to segment ultrasound images in HIFU ablation. METHODS: The main idea of the technique is dealing with two issues including spurious boundary attenuation and setting the standard deviation of the Gaussian filter. We assign the standard deviation as scales to build the MS-GGVF model and create a signed distance map to use its gradient direction information and magnitude information to refine the multi-scale edge map by attenuating spurious boundaries and highlighting the real boundary. In addition, a fast generalized gradient vector flow computation algorithm based on an augmented Lagrangian method is introduced to calculate the external force vector field to improve the computation efficiency of our model. RESULTS: The experimental segmentations were similar to the ground truths delineated by two medical physicians with high area overlap measure and low mean contour distance. CONCLUSION: The experimental results demonstrate that the proposed algorithm is robust, reliable, and precise for tumor boundary detection in HIFU ablation systems. PMID- 26578488 TI - Experimental system for in-situ measurement of temperature rise in animal tissue under exposure to acoustic radiation force impulse. AB - PURPOSE: Acoustic radiation force impulse (ARFI) has recently been used for tissue elasticity measurement and imaging. On the other hand, it is predicted that a rise in temperature occurs. In-situ measurement of temperature rise in animal experiments is important, yet measurement using thermocouples has some problems such as position mismatch of the temperature measuring junction of the thermocouple and the focal point of ultrasound. Therefore, an in-situ measurement system for solving the above problems was developed in this study. METHODS: The developed system is composed mainly of an ultrasound irradiation unit including a custom-made focused transducer with a through hole for inserting a thin-wire thermocouple, and a temperature measurement unit including the thermocouple. RESULTS: The feasibility of the developed system was evaluated by means of experiments using a tissue-mimicking material (TMM), a TMM containing a bone model or a chicken bone, and an extracted porcine liver. The similarity between the experimental results and the results of simulation using a finite element method (FEM) implied the reasonableness of in-situ temperature rise measured by the developed system. CONCLUSION: The developed system will become a useful tool for measuring in-situ temperature rise in animal experiments and obtaining findings with respect to the relationship between ultrasound irradiation conditions and in-situ temperature rise. PMID- 26578489 TI - The arrhythmogenic effect of ultrasonic exposure with acoustic radiation force (ARF) impulse on the rabbit heart with ultrasound contrast agent perfluorobutane. AB - PURPOSE: Acoustic radiation force (ARF) impulse can be used to estimate the elasticity of cardiac muscle. The purpose of this study was to evaluate the effect of ARF on the heart with concomitant administration of the ultrasound contrast agent (UCA) perfluorobutane for recently developed elasticity imaging such as shear wave imaging. METHODS: Ultrasound with ARF was applied to the heart of Japanese white rabbit with or without UCA administration. During the exposure, electrocardiographs were recorded. RESULTS: Following the exposure of ultrasound with a duration of 10 ms and a mechanical index (MI) of 4.0 to the heart, extra waves (QRS complex) were observed only after UCA administration. Although life threatening arrhythmia was not observed, a greater increase in the frequency of the extra waves was observed following a drip infusion compared with a single (bolus) UCA infusion. In addition, 16.3 % of extra waves were followed by arterial pressure pulse. CONCLUSIONS: Cardiac ultrasound with higher MI and longer duration should be carefully considered, particularly with the concomitant use of UCA and higher MI. PMID- 26578490 TI - Accurate ultrasound imaging based on range point migration method for the depiction of fetal surface. AB - PURPOSE: The purpose of this study is to evaluate the performance of a modified range point migration (RPM) method using a semi-broad transmit beam for fetal surface imaging. METHODS: The conventional RPM method depicts accurate images of target surfaces by estimating the reflection point on a target surface from the path length of plural transmit-and-receive element combinations. However, the conventional RPM method depicts false images when echoes from different targets are received simultaneously. For the elimination of false images in the employment of the RPM method, we propose a modified RPM method with a semi-broad transmit beam to decrease the number of targets in each measurement region. RESULTS: The modified RPM method depicted two acrylic cylinders of 2 cm in diameter with a root-mean-square error (RMSE) of 0.062 mm, where the RMSE of the migration method was 0.145 mm. The modified RPM method also succeeded in depicting a 7-month fetal phantom with a RMSE of 0.058 mm relative to a 3D image acquired using optical measurement. CONCLUSION: This study shows the potential of the modified RPM method in achieving accurate surface imaging of multiple targets using a semi-broad beam, indicating that the method is suitable for fetal surface imaging. PMID- 26578491 TI - Microscopic observation of glass bead movement in soft tissue-mimicking phantom under ultrasound PW mode scanning. AB - Previous studies have demonstrated that stones and calcification in soft tissue show special enhancement in response to color flow (CF) or pulse Doppler (PW) mode ultrasound scan. This phenomenon is known as the "twinkling sign (TS)". The authors conducted an in vitro experiment to investigate the mechanism of TS occurrence by observing a glass bead in a transparent PVA-H soft tissue-mimicking phantom. The TS in PW mode showed a low-power and slow-velocity spectrum. At the same time, analysis of images by high-speed camera showed that the glass bead in the phantom oscillated following the pulse repetition frequency (PRF) of the PW mode ultrasound scan. The harmonic oscillations were confirmed, as well. The ultrasound radiation force-driven micro-oscillation possibly affects the ultrasound propagation around the scatterer and triggers random signals in the received echo signals. The results indicate that TS is a phenomenon based on complicated acoustic-mechanical interaction of multiple mechanisms. Further investigation is required for gaining a full understanding of the mechanism of TS occurrence and its clinical application. PMID- 26578492 TI - HDlive rendering images of the fetal stomach: a preliminary report. AB - PURPOSE: This study aimed to show reconstruction of the fetal stomach using the HDlive rendering mode in ultrasound. METHODS: Seventeen healthy singleton fetuses at 18-34 weeks' gestational age were observed using the HDlive rendering mode of ultrasound in utero. RESULTS: In all of the fetuses, we identified specific spatial structures, including macroscopic anatomical features (e.g., the pyrous, cardia, fundus, and great curvature) of the fetal stomach, using the HDlive rendering mode. In particular, HDlive rendering images showed remarkably fine details that appeared as if they were being viewed under an endoscope, with visible rugal folds after 27 weeks' gestational age. CONCLUSION: Our study suggests that the HDlive rendering mode can be used as an additional method for evaluating the fetal stomach. The HDlive rendering mode shows detailed 3D structural images and anatomically realistic images of the fetal stomach. This technique may be effective in prenatal diagnosis for examining detailed information of fetal organs. PMID- 26578493 TI - Reference ranges of liver and spleen dimensions in term infants: sonographic measurements. AB - PURPOSE: To determine reference values of ultrasonographic measurements of the liver and spleen in newborns and to provide a reference chart to use easily in daily practice. METHODS: In this prospective study, spleen and liver dimensions were evaluated in 384 healthy newborns with a gestation age >=37 weeks in an obstetrics clinic and neonatal intensive care unit with sonography within the first week of life. Relationships of all dimensions with sex, gestational age, height, and weight were statistically analyzed. RESULTS: No statistically significant differences were found between the two sexes in any dimensions of the liver and spleen (p > 0.05). Longitudinal and anteroposterior dimensions of the liver and spleen showed no correlation with the gestational age. All dimensions of the liver and spleen showed a high correlation with the height and weight. Weight was the best correlated with all dimensions. CONCLUSION: The reference values of spleen and liver lengths and diagrams from this study may be useful in the sonographic evaluation of the spleen and liver in newborns. PMID- 26578494 TI - Characteristic sonographic features of cribriform papillary thyroid carcinoma for differentiation from other thyroid nodules. AB - PURPOSE: The purpose of this paper is to clarify the sonographic features and differential diagnoses of the cribriform variant of papillary thyroid carcinoma (CV-PTC). METHODS: We retrospectively reviewed 24 nodules obtained from 22 CV-PTC cases. As control groups, we chose 50 cases each of conventional papillary carcinoma (C-PTC), follicular tumor, and nodular goiter. RESULTS: All of the cases were young women aged 35 years or younger. Serum thyroglobulin levels were normal or slightly elevated. The incidences of smooth or focal jagged margin, hypoechoic nodule, lateral shadow, posterior acoustic enhancement, poor marginal and internal vascularity, and no microcalcification were 100, 100, 91.7, 95.8, 100, and 95.8 %, respectively. The sensitivity and specificity of the requirement were 87.5 and 92.5 %, respectively. Sonographic findings of CV-PTC were similar to those of follicular tumor or nodular goiter rather than C-PTC. CONCLUSION: The criteria for suspecting CV-PTC we proposed provided high sensitivity and specificity. We should be aware that the sonographic findings of CV-PTC are similar to those of follicular tumor or nodular goiter rather than C-PTC. Clinical findings including gender, age, and serum thyroglobulin level may provide us with useful information. PMID- 26578496 TI - Benign nodular hyperplasia of the liver-pedunculated form: diagnostic contributions of ultrasonography and consideration of exophytic liver tumors. AB - Focal nodular hyperplasia (FNH) is an asymptomatic benign liver tumor that may be detected accidentally during an abdominal ultrasound examination; it is associated with unspecific complaints, sometimes painful. Diagnosis can be precise using imaging techniques like ultrasonography. The diagnostic criteria are represented by the spatial display of the tumoral vessels and their hemodynamic characteristics. Sometimes differential diagnostic issues occur with other benign or malignant liver tumors. We present the case of a young female patient without a personal pathological history, who complained of intense, diffuse, intermittent, non-systematic abdominal pain and who underwent ultrasound examination, followed by contrast-enhanced ultrasound. With this technique, we evidenced a solid extrahepatic tumor, which was mobile at the patient's change of position and had the hemodynamic features of FNH. The article also tackles the problem of intra-abdominal pedunculated tumors. PMID- 26578495 TI - Inflammatory myofibroblastic tumor of the gallbladder: imaging aspects. AB - Inflammatory myofibroblastic tumors (IMT) are rare benign lesions that may often be mistaken for malignancies due to their imaging resemblance. There are a limited number of case reports in the literature on the location at the level of the gallbladder. We present a case of IMT of the gallbladder that emphasizes the importance of conventional ultrasound as the primary method of detection, as well as the role of contrast-enhanced ultrasound and strain elastography in describing the lesion, thus contributing to the differential diagnosis. PMID- 26578497 TI - Giant peripancreatic artery aneurysm with emphasis on contrast-enhanced ultrasound: report of two cases. AB - Visceral artery aneurysms have a potential possibility of rupture with life threatening hemorrhage, and prompt detection and optimal treatment are required clinically. Actually, abdominal ultrasound plays a major role in detection of visceral artery aneurysms. Besides, the administration of contrast agents can highly improve the characterization of the lesion. Herein, we present two cases of giant peripancreatic artery aneurysm with emphasis on contrast-enhanced ultrasound (CEUS). Case 1 was a 54-year-old asymptomatic man who was diagnosed with a 12.1 cm * 5.2 cm splenic artery aneurysm in the absence of a clear etiologic factor. Case 2 was a 37-year-old man with a 6.3 cm * 5.3 cm pancreaticoduodenal artery pseudoaneurysm associated with chronic pancreatitis. Both diagnoses were confirmed by contrast-enhanced computer tomography (CECT) and digital subtracted angiography (DSA). Transcatheter embolization occlusion using coiling was successfully performed for both cases. Postoperative computed tomography angiography (CTA) showed complete occlusion. It is suggested that CEUS seems to be a promising diagnostic option and contributes to preoperative treatment planning for patients with peripancreatic artery aneurysm. PMID- 26578498 TI - Prenatal diagnosis of Klippel-Trenaunay-Weber syndrome with Kasabach-Merritt syndrome in utero. AB - Klippel-Trenaunay-Weber syndrome (KTWS), a congenital disease characterized by cutaneous hemangiomas, soft tissue and bone hypertrophy, and occasionally arteriovenous malformations, is extremely rare and its natural history in utero is unknown. We present a prenatally diagnosed case of KTWS complicated with Kasabach-Merritt syndrome in utero and fetal hydrops from acute anemia. The fetus was diagnosed with KTWS at 24 weeks of gestation based on the ultrasound findings of hemangiomas and unilateral hypertrophy of the lower extremity. Acute enlargement of the hemangiomas and the appearance of new retroperitoneal hemangiomas were detected at 27 weeks, along with skin edema and cardiomegaly. Doppler examination showed elevated peak systolic velocity in the middle cerebral artery, indicating acute fetal anemia. We believe the fetus's condition was complicated with Kasabach-Merritt syndrome in utero, which caused acute hemolytic anemia leading to high-output cardiac failure and fetal hydrops. PMID- 26578499 TI - Prenatal diagnosis of enterolithiasis at 18 weeks: multiple foci of intraluminal calcified meconium within echogenic bowel. AB - Enterolithiasis is an uncommon finding of a dilated hyperechogenic bowel with multiple ball-like echogenic structures at a routine prenatal check-up using ultrasonography. We here report a case of prenatally diagnosed enterolithiasis at 18 weeks of gestation, showing multiple hyperechogenic foci rolling within the bowel fluid after peristalsis. The size of the dilated bowel gradually increased during pregnancy. Magnetic resonance image demonstrated the dilated lower bowel with blind-ending rectum. A postnatal contrast medium study with retrograde urethrography revealed a middle imperforate anus and a rectourethral fistula. A careful examination, even before 20 weeks of gestation, is extremely useful in demonstrating intraluminal coarse calcifications within an echogenic bowel. PMID- 26578500 TI - Ruptured rudimentary horn pregnancy with a history of an uneventful vaginal delivery. AB - Pregnancy in a rudimentary uterine horn is a rare event with an estimated incidence of 1 in 76,000 to 1 in 1,40,000 pregnancies. Unicornuate uterus with a rudimentary horn has a high incidence of obstetric and gynecological complications. Ruptured ectopic pregnancy in the rudimentary horn is one of the most dreaded complications, which can have grave consequences for both mother and fetus. In the majority of the cases, it is detected after rupture of the horn, usually during the first or second trimester of pregnancy. An ultrasonographic diagnosis made prior to rupture of the rudimentary horn may prevent this catastrophic outcome. We report a case of a G2 P1 L1 with a ruptured left rudimentary horn pregnancy at 16 weeks of gestation that was misdiagnosed as a pregnancy in the left uterine horn of a bicornuate uterus on prior prenatal ultrasound. The patient presented to our hospital with abdominal pain and vaginal bleeding. A diagnosis of ruptured left rudimentary horn pregnancy was made on the basis of emergency ultrasound and was later confirmed on laparotomy. The left rudimentary horn along with the ipsilateral fallopian tube was excised. PMID- 26578501 TI - Axillary arch: detailed ultrasonographic images with multiplanar CT correlation. AB - The axillary arch is a common but rarely recognized anatomical variant of the axillary musculature. We report the first detailed presentation of the ultrasonographic features of the axillary arch and a correlation of these findings with multiplanar reformation CT images incorporating a schematic anatomical diagram in a 44-year-old woman complaining of a palpable non-tender mass in the axillary region due to a unilateral axillary arch. The clinical significance of the axillary arch is discussed. PMID- 26578502 TI - Focal megalencephaly: intraoperative ultrasound imaging in epilepsy surgery. AB - Hemimegalencephaly is a rare neuronal migration disorder that can be defined as abnormal neural and glial proliferation localized to all or part of a cerebral hemisphere. Most patients demonstrate intractable epilepsy, with early onset before 1 year of age. Surgical resection is one of the treatment options. In recent years, many advanced intraoperative techniques have been used for brain surgery for various pathologies. Intraoperative ultrasonography is a time-saving and noninvasive method for intraoperative imaging. In this report, we present the use of intraoperative ultrasonography in a patient with focal megalencephaly as an anatomical navigation with the functional navigation system, electrocorticography. In this report, we present the use of intraoperative ultrasonography in a patient with focal megalencephaly as an anatomical navigation with the functional navigation system, electrocorticography. PMID- 26578503 TI - Synovitis and osteitis in the left sternoclavicular joint in a 60-year-old woman. PMID- 26578504 TI - Intraparietal suture: a normality variable rarely described. PMID- 26578506 TI - Pelvic mass in a young woman with a background of ovarian dysgerminoma: differential diagnosis. PMID- 26578505 TI - A rare comorbidity: neurosarcoidosis and cutaneous sarcoidosis. AB - We present a case of a neurosarcoidosis patient with skin lesions. A 50-year-old woman was admitted with a 1-year history of violaceous, smooth and shiny plaques on her face and right arm. These lesions were biopsied and the histological examination indicated sarcoidosis. The patient had a history of headache and syncope that lasted for about 1 h. Brain CT showed masses measuring 37*20 mm in both frontal lobes. Thoracic and abdominal CT showed many pathologically enlarged lymph nodes. The patient was diagnosed with cutaneous, lung and neuronal sarcoidosis, and treated with 20 mg/day methylprednisolone, 15 mg/week methotrexate, 10 mg/week folic acid, 400 mg/day hydroxychloroquine and 800 mg/day carbamazepine. One month later, the patient's neurological symptoms had improved and her skin lesions had decreased. At 6-month follow-up, the size of the cranial masses had markedly regressed. PMID- 26578507 TI - Successful laparoscopic transabdominal cerclage in uterus didelphys. AB - The incidence of uterus didelphys is around 3/10,000 women. It is a class III Mullerian duct anomaly resulting from a complete non-fusion of the paired Mullerian ducts between the 12th and 16th weeks of gestation. Although the prevalence of cervical insufficiency in women with uterus didelphys is unknown, the incidence of cervical insufficiency in women with Mullerian anomalies has been reported as high as 30%. We present a case of successful pregnancy outcome following a laparoscopic transabdominal cerclage in a woman with uterus didelphys and cervical insufficiency. The case demonstrates that laparoscopic transabdominal cerclage can be performed successfully in women with uterus didelphys and a satisfactory obstetric outcome can be achieved. PMID- 26578508 TI - Not walking? An uncommon spinal pathology. PMID- 26578509 TI - Neural stem cells and neuro/gliogenesis in the central nervous system: understanding the structural and functional plasticity of the developing, mature, and diseased brain. AB - Neurons and glia in the central nervous system (CNS) originate from neural stem cells (NSCs). Knowledge of the mechanisms of neuro/gliogenesis from NSCs is fundamental to our understanding of how complex brain architecture and function develop. NSCs are present not only in the developing brain but also in the mature brain in adults. Adult neurogenesis likely provides remarkable plasticity to the mature brain. In addition, recent progress in basic research in mental disorders suggests an etiological link with impaired neuro/gliogenesis in particular brain regions. Here, we review the recent progress and discuss future directions in stem cell and neuro/gliogenesis biology by introducing several topics presented at a joint meeting of the Japanese Association of Anatomists and the Physiological Society of Japan in 2015. Collectively, these topics indicated that neuro/gliogenesis from NSCs is a common event occurring in many brain regions at various ages in animals. Given that significant structural and functional changes in cells and neural networks are accompanied by neuro/gliogenesis from NSCs and the integration of newly generated cells into the network, stem cell and neuro/gliogenesis biology provides a good platform from which to develop an integrated understanding of the structural and functional plasticity that underlies the development of the CNS, its remodeling in adulthood, and the recovery from diseases that affect it. PMID- 26578510 TI - Chaplains on the Medical Team: A Qualitative Analysis of an Interprofessional Curriculum for Internal Medicine Residents and Chaplain Interns. AB - Improved collaboration between physicians and chaplains has the potential to improve patient experiences. To better understand the benefits and challenges of learning together, the authors conducted several focus groups with participants in an interprofessional curriculum that partnered internal medicine residents with chaplain interns in the clinical setting. The authors derived four major qualitative themes from the transcripts: (1) physician learners became aware of effective communication skills for addressing spirituality. (2) Chaplain interns enhanced the delivery of team-based patient-centered care. (3) Chaplains were seen as a source of emotional support to the medical team. (4) The partnership has three keys to success: adequate introductions for team members, clear expectations for participants, and opportunities for feedback. The themes presented indicate several benefits of pairing physicians and chaplains in the setting of direct patient care and suggest that this is an effective approach to incorporating spirituality in medical training. PMID- 26578511 TI - Characterization of a Cyanobacterial Chloride-pumping Rhodopsin and Its Conversion into a Proton Pump. AB - Light-driven ion-pumping rhodopsins are widely distributed in microorganisms and are now classified into the categories of outward H(+) and Na(+) pumps and an inward Cl(-) pump. These different types share a common protein architecture and utilize the photoisomerization of the same chromophore, retinal, to evoke photoreactions. Despite these similarities, successful pump-to-pump conversion had been confined to only the H(+) pump bacteriorhodopsin, which was converted to a Cl(-) pump in 1995 by a single amino acid replacement. In this study we report the first success of the reverse conversion from a Cl(-) pump to a H(+) pump. A novel microbial rhodopsin (MrHR) from the cyanobacterium Mastigocladopsis repens functions as a Cl(-) pump and belongs to a cluster that is far distant from the known Cl(-) pumps. With a single amino acid replacement, MrHR is converted to a H(+) pump in which dissociable residues function almost completely in the H(+) relay reactions. MrHR most likely evolved from a H(+) pump, but it has not yet been highly optimized into a mature Cl(-) pump. PMID- 26578512 TI - Biochemical Activities of the Wiskott-Aldrich Syndrome Homology Region 2 Domains of Sarcomere Length Short (SALS) Protein. AB - Drosophila melanogaster sarcomere length short (SALS) is a recently identified Wiskott-Aldrich syndrome protein homology 2 (WH2) domain protein involved in skeletal muscle thin filament regulation. SALS was shown to be important for the establishment of the proper length and organization of sarcomeric actin filaments. Here, we present the first detailed characterization of the biochemical activities of the tandem WH2 domains of SALS (SALS-WH2). Our results revealed that SALS-WH2 binds both monomeric and filamentous actin and shifts the monomer-filament equilibrium toward the monomeric actin. In addition, SALS-WH2 can bind to but fails to depolymerize phalloidin- or jasplakinolide-bound actin filaments. These interactions endow SALS-WH2 with the following two major activities in the regulation of actin dynamics: SALS-WH2 sequesters actin monomers into non-polymerizable complexes and enhances actin filament disassembly by severing, which is modulated by tropomyosin. We also show that profilin does not influence the activities of the WH2 domains of SALS in actin dynamics. In conclusion, the tandem WH2 domains of SALS are multifunctional regulators of actin dynamics. Our findings suggest that the activities of the WH2 domains do not reconstitute the presumed biological function of the full-length protein. Consequently, the interactions of the WH2 domains of SALS with actin must be tuned in the cellular context by other modules of the protein and/or sarcomeric components for its proper functioning. PMID- 26578513 TI - Distinct Splice Variants of Dynamin-related Protein 1 Differentially Utilize Mitochondrial Fission Factor as an Effector of Cooperative GTPase Activity. AB - Multiple isoforms of the mitochondrial fission GTPase dynamin-related protein 1 (Drp1) arise from the alternative splicing of its single gene-encoded pre-mRNA transcript. Among these, the longer Drp1 isoforms, expressed selectively in neurons, bear unique polypeptide sequences within their GTPase and variable domains, known as the A-insert and the B-insert, respectively. Their functions remain unresolved. A comparison of the various biochemical and biophysical properties of the neuronally expressed isoforms with that of the ubiquitously expressed, and shortest, Drp1 isoform (Drp1-short) has revealed the effect of these inserts on Drp1 function. Utilizing various biochemical, biophysical, and cellular approaches, we find that the A- and B-inserts distinctly alter the oligomerization propensity of Drp1 in solution as well as the preferred curvature of helical Drp1 self-assembly on membranes. Consequently, these sequences also suppress Drp1 cooperative GTPase activity. Mitochondrial fission factor (Mff), a tail-anchored membrane protein of the mitochondrial outer membrane that recruits Drp1 to sites of ensuing fission, differentially stimulates the disparate Drp1 isoforms and alleviates the autoinhibitory effect imposed by these sequences on Drp1 function. Moreover, the differential stimulatory effects of Mff on Drp1 isoforms are dependent on the mitochondrial lipid, cardiolipin (CL). Although Mff stimulation of the intrinsically cooperative Drp1-short isoform is relatively modest, CL-independent, and even counter-productive at high CL concentrations, Mff stimulation of the much less cooperative longest Drp1 isoform (Drp1-long) is robust and occurs synergistically with increasing CL content. Thus, membrane anchored Mff differentially regulates various Drp1 isoforms by functioning as an allosteric effector of cooperative GTPase activity. PMID- 26578514 TI - Dynamin-related Protein 1 Oligomerization in Solution Impairs Functional Interactions with Membrane-anchored Mitochondrial Fission Factor. AB - Mitochondrial fission is a crucial cellular process mediated by the mechanoenzymatic GTPase, dynamin-related protein 1 (Drp1). During mitochondrial division, Drp1 is recruited from the cytosol to the outer mitochondrial membrane by one, or several, integral membrane proteins. One such Drp1 partner protein, mitochondrial fission factor (Mff), is essential for mitochondrial division, but its mechanism of action remains unexplored. Previous studies have been limited by a weak interaction between Drp1 and Mff in vitro. Through refined in vitro reconstitution approaches and multiple independent assays, we show that removal of the regulatory variable domain (VD) in Drp1 enhances formation of a functional Drp1-Mff copolymer. This protein assembly exhibits greatly stimulated cooperative GTPase activity in solution. Moreover, when Mff was anchored to a lipid template, to mimic a more physiologic environment, significant stimulation of GTPase activity was observed with both WT and DeltaVD Drp1. Contrary to recent findings, we show that premature Drp1 self-assembly in solution impairs functional interactions with membrane-anchored Mff. Instead, dimeric Drp1 species are selectively recruited by Mff to initiate assembly of a functional fission complex. Correspondingly, we also found that the coiled-coil motif in Mff is not essential for Drp1 interactions, but rather serves to augment cooperative self assembly of Drp1 proximal to the membrane. Taken together, our findings provide a mechanism wherein the multimeric states of both Mff and Drp1 regulate their collaborative interaction. PMID- 26578515 TI - Cell Migration and Invadopodia Formation Require a Membrane-binding Domain of CARMIL2. AB - CARMILs regulate capping protein (CP), a critical determinant of actin assembly and actin-based cell motility. Vertebrates have three conserved CARMIL genes with distinct functions. In migrating cells, CARMIL2 is important for cell polarity, lamellipodial assembly, ruffling, and macropinocytosis. In cells, CARMIL2 localizes with a distinctive dual pattern to vimentin intermediate filaments and to membranes at leading edges and macropinosomes. The mechanism by which CARMIL2 localizes to membranes has not been defined. Here, we report that CARMIL2 has a conserved membrane-binding domain composed of basic and hydrophobic residues, which is necessary and sufficient for membrane localization, based on expression studies in cells and on direct binding of purified protein to lipids. Most important, we find that the membrane-binding domain is necessary for CARMIL2 to function in cells, based on rescue expression with a set of biochemically defined mutants. CARMIL1 and CARMIL3 contain similar membrane-binding domains, based on sequence analysis and on experiments, but other CPI motif proteins, such as CD2AP, do not. Based on these results, we propose a model in which the membrane binding domain of CARMIL2 tethers this multidomain protein to the membrane, where it links dynamic vimentin filaments with regulation of actin assembly via CP. PMID- 26578517 TI - Transcriptional and Translational Modulation of myo-Inositol Oxygenase (Miox) by Fatty Acids: IMPLICATIONS IN RENAL TUBULAR INJURY INDUCED IN OBESITY AND DIABETES. AB - The kidney is one of the target organs for various metabolic diseases, including diabetes, metabolic syndrome, and obesity. Most of the metabolic studies underscore glomerular pathobiology, although the tubulo-interstitial compartment has been underemphasized. This study highlights mechanisms concerning the pathobiology of tubular injury in the context of myo-inositol oxygenase (Miox), a tubular enzyme. The kidneys of mice fed a high fat diet (HFD) had increased Miox expression and activity, and the latter was related to phosphorylation of serine/threonine residues. Also, expression of sterol regulatory element-binding protein1 (Srebp1) and markers of cellular/nuclear damage was increased along with accentuated apoptosis and loss of tubular brush border. Similar results were observed in cells treated with palmitate/BSA. Multiple sterol-response elements and E-box motifs were found in the miox promoter, and its activity was modulated by palmitate/BSA. Electrophoretic mobility and ChIP assays confirmed binding of Srebp to consensus sequences of the miox promoter. Exposure of palmitate/BSA treated cells to rapamycin normalized Miox expression and prevented Srebp1 nuclear translocation. In addition, rapamycin treatment reduced p53 expression and apoptosis. Like rapamycin, srebp siRNA reduced Miox expression. Increased expression of Miox was associated with the generation of reactive oxygen species (ROS) in kidney tubules of mice fed an HFD and cell exposed to palmitate/BSA. Both miox and srebp1 siRNAs reduced generation of ROS. Collectively, these findings suggest that HFD or fatty acids modulate transcriptional, translational, and post-translational regulation of Miox expression/activity and underscore Miox being a novel target of the transcription factor Srebp1. Conceivably, activation of the mTORC1/Srebp1/Miox pathway leads to the generation of ROS culminating into tubulo-interstitial injury in states of obesity. PMID- 26578516 TI - Annexin A6 and Late Endosomal Cholesterol Modulate Integrin Recycling and Cell Migration. AB - Annexins are a family of proteins that bind to phospholipids in a calcium dependent manner. Earlier studies implicated annexin A6 (AnxA6) to inhibit secretion and participate in the organization of the extracellular matrix. We recently showed that elevated AnxA6 levels significantly reduced secretion of the extracellular matrix protein fibronectin (FN). Because FN is directly linked to the ability of cells to migrate, this prompted us to investigate the role of AnxA6 in cell migration. Up-regulation of AnxA6 in several cell models was associated with reduced cell migration in wound healing, individual cell tracking and three-dimensional migration/invasion assays. The reduced ability of AnxA6 expressing cells to migrate was associated with decreased cell surface expression of alphaVbeta3 and alpha5beta1 integrins, both FN receptors. Mechanistically, we found that elevated AnxA6 levels interfered with syntaxin-6 (Stx6)-dependent recycling of integrins to the cell surface. AnxA6 overexpression caused mislocalization and accumulation of Stx6 and integrins in recycling endosomes, whereas siRNA-mediated AnxA6 knockdown did not modify the trafficking of integrins. Given our recent findings that inhibition of cholesterol export from late endosomes (LEs) inhibits Stx6-dependent integrin recycling and that elevated AnxA6 levels cause LE cholesterol accumulation, we propose that AnxA6 and blockage of LE cholesterol transport are critical for endosomal function required for Stx6-mediated recycling of integrins in cell migration. PMID- 26578519 TI - Eukaryotic Initiation Factor eIFiso4G1 and eIFiso4G2 Are Isoforms Exhibiting Distinct Functional Differences in Supporting Translation in Arabidopsis. AB - The eukaryotic translation initiation factor (eIF) 4G is required during protein synthesis to promote the assembly of several factors involved in the recruitment of a 40S ribosomal subunit to an mRNA. Although many eukaryotes express two eIF4G isoforms that are highly similar, the eIF4G isoforms in plants, referred to as eIF4G and eIFiso4G, are highly divergent in size, sequence, and domain organization but both can interact with eIF4A, eIF4B, eIF4E isoforms, and the poly(A)-binding protein. Nevertheless, eIF4G and eIFiso4G from wheat exhibit preferences in the mRNAs they translate optimally. For example, mRNA containing the 5'-leader (called Omega) of tobacco mosaic virus preferentially uses eIF4G in wheat germ lysate. In this study, the eIF4G isoform specificity of Omega was used to examine functional differences of the eIF4G isoforms in Arabidopsis. As in wheat, Omega-mediated translation was reduced in an eif4g null mutant. Loss of the eIFiso4G1 isoform, which is similar in sequence to wheat eIFiso4G, did not substantially affect Omega-mediated translation. However, loss of the eIFiso4G2 isoform substantially reduced Omega-mediated translation. eIFiso4G2 is substantially divergent from eIFiso4G1 and is present only in the Brassicaceae, suggesting a recent evolution. eIFiso4G2 isoforms exhibit sequence-specific differences in regions representing partner protein and RNA binding sites. Loss of any eIF4G isoform also resulted in a substantial reduction in reporter transcript level. These results suggest that eIFiso4G2 appeared late in plant evolution and exhibits more functional similarity with eIF4G than with eIFiso4G1 during Omega-mediated translation. PMID- 26578518 TI - Antibody Response to Serpin B13 Induces Adaptive Changes in Mouse Pancreatic Islets and Slows Down the Decline in the Residual Beta Cell Function in Children with Recent Onset of Type 1 Diabetes Mellitus. AB - Type 1 diabetes mellitus (T1D) is characterized by a heightened antibody (Ab) response to pancreatic islet self-antigens, which is a biomarker of progressive islet pathology. We recently identified a novel antibody to clade B serpin that reduces islet-associated T cell accumulation and is linked to the delayed onset of T1D. As natural immunity to clade B arises early in life, we hypothesized that it may influence islet development during that time. To test this possibility healthy young Balb/c male mice were injected with serpin B13 mAb or IgG control and examined for the number and cellularity of pancreatic islets by immunofluorescence and FACS. Beta cell proliferation was assessed by measuring nucleotide analog 5-ethynyl-2'-deoxyuridine (5-EdU) incorporation into the DNA and islet Reg gene expression was measured by real time PCR. Human studies involved measuring anti-serpin B13 autoantibodies by Luminex. We found that injecting anti-serpin B13 monoclonal Ab enhanced beta cell proliferation and Reg gene expression, induced the generation of ~80 pancreatic islets per animal, and ultimately led to increase in the beta cell mass. These findings are relevant to human T1D because our analysis of subjects just diagnosed with T1D revealed an association between baseline anti-serpin activity and slower residual beta cell function decline in the first year after the onset of diabetes. Our findings reveal a new role for the anti-serpin immunological response in promoting adaptive changes in the endocrine pancreas and suggests that enhancement of this response could potentially help impede the progression of T1D in humans. PMID- 26578520 TI - Hypoxia Potentiates Palmitate-induced Pro-inflammatory Activation of Primary Human Macrophages. AB - Pro-inflammatory cytokines secreted by adipose tissue macrophages (ATMs) contribute to chronic low-grade inflammation and obesity-induced insulin resistance. Recent studies have shown that adipose tissue hypoxia promotes an inflammatory phenotype in ATMs. However, our understanding of how hypoxia modulates the response of ATMs to free fatty acids within obese adipose tissue is limited. We examined the effects of hypoxia (1% O2) on the pro-inflammatory responses of human monocyte-derived macrophages to the saturated fatty acid palmitate. Compared with normoxia, hypoxia significantly increased palmitate induced mRNA expression and protein secretion of IL-6 and IL-1beta. Although palmitate-induced endoplasmic reticulum stress and nuclear factor kappaB pathway activation were not enhanced by hypoxia, hypoxia increased the activation of JNK and p38 mitogen-activated protein kinase signaling in palmitate-treated cells. Inhibition of JNK blocked the hypoxic induction of pro-inflammatory cytokine expression, whereas knockdown of hypoxia-induced transcription factors HIF-1alpha and HIF-2alpha alone or in combination failed to reduce IL-6 and only modestly reduced IL-1beta gene expression in palmitate-treated hypoxic macrophages. Enhanced pro-inflammatory cytokine production and JNK activity under hypoxia were prevented by inhibiting reactive oxygen species generation. In addition, silencing of dual-specificity phosphatase 16 increased normoxic levels of IL-6 and IL-1beta and reduced the hypoxic potentiation in palmitate-treated macrophages. The secretome of hypoxic palmitate-treated macrophages promoted IL-6 and macrophage chemoattractant protein 1 expression in primary human adipocytes, which was sensitive to macrophage JNK inhibition. Our results reveal that the coexistence of hypoxia along with free fatty acids exacerbates macrophage mediated inflammation. PMID- 26578522 TI - Indian Medical Association calls off protest after government agrees to discuss demands. PMID- 26578521 TI - Mutations in Replicative Stress Response Pathways Are Associated with S Phase specific Defects in Nucleotide Excision Repair. AB - Nucleotide excision repair (NER) is a highly conserved pathway that removes helix distorting DNA lesions induced by a plethora of mutagens, including UV light. Our laboratory previously demonstrated that human cells deficient in either ATM and Rad3-related (ATR) kinase or translesion DNA polymerase eta (i.e. key proteins that promote the completion of DNA replication in response to UV-induced replicative stress) are characterized by profound inhibition of NER exclusively during S phase. Toward elucidating the mechanistic basis of this phenomenon, we developed a novel assay to quantify NER kinetics as a function of cell cycle in the model organism Saccharomyces cerevisiae. Using this assay, we demonstrate that in yeast, deficiency of the ATR homologue Mec1 or of any among several other proteins involved in the cellular response to replicative stress significantly abrogates NER uniquely during S phase. Moreover, initiation of DNA replication is required for manifestation of this defect, and S phase NER proficiency is correlated with the capacity of individual mutants to respond to replicative stress. Importantly, we demonstrate that partial depletion of Rfa1 recapitulates defective S phase-specific NER in wild type yeast; moreover, ectopic RPA1-3 overexpression rescues such deficiency in either ATR- or polymerase eta-deficient human cells. Our results strongly suggest that reduction of NER capacity during periods of enhanced replicative stress, ostensibly caused by inordinate sequestration of RPA at stalled DNA replication forks, represents a conserved feature of the multifaceted eukaryotic DNA damage response. PMID- 26578524 TI - Modeling and Simulation of In Vivo Drug Effects. AB - The concept of a pharmacokinetics-pharmacodynamics (PK/PD) assessment of drug development candidates is well established in pharmaceutical research and development, and PK/PD modeling is common practice in all pharmaceutical companies. A recent analysis (Morgan et al., Drug Discov Today 17(9-10):419-424, 2012) revealed however that insufficient certainty in the integrity of the causal chain of fundamental pharmacological steps from drug dosing through systemic exposure, target tissue exposure, and engagement of molecular target to pharmacological response is still the major driver of failure in phase II of clinical drug development. Despite the rise of molecular biomarkers, ethical, scientific, and practical constraints very often still prevent a direct assessment of each necessary step ultimately leading to an intended drug effect or an unintended adverse reaction. Yet, incomplete investigation of the causality of drug responses is a major risk for translational assessments and the prediction of drug responses in different species or other populations. Mechanism based modeling and simulation (M&S) offers a means to investigate complex physiological and pharmacological processes and to complement experimental data for non-accessible steps in the pharmacological causal chain. With the help of two examples, it is illustrated, what level of physiological detail, state-of-the art models can represent, how predictive these models are and how mechanism-based approaches can be combined with empirical correlation-based concepts. PMID- 26578523 TI - Neural Control of Energy Expenditure. AB - The continuous rise in obesity is a major concern for future healthcare management. Many strategies to control body weight focus on a permanent modification of food intake with limited success in the long term. Metabolism or energy expenditure is the other side of the coin for the regulation of body weight, and strategies to enhance energy expenditure are a current focus for obesity treatment, especially since the (re)-discovery of the energy depleting brown adipose tissue in adult humans. Conversely, several human illnesses like neurodegenerative diseases, cancer, or autoimmune deficiency syndrome suffer from increased energy expenditure and severe weight loss. Thus, strategies to modulate energy expenditure to target weight gain or loss would improve life expectancies and quality of life in many human patients. The aim of this book chapter is to give an overview of our current understanding and recent progress in energy expenditure control with specific emphasis on central control mechanisms. PMID- 26578526 TI - Effectiveness and risks of cricoid pressure during rapid sequence induction for endotracheal intubation. AB - BACKGROUND: Rapid sequence induction (RSI) for endotracheal intubation is a technique widely used in anaesthesia, emergency and intensive care medicine to secure an airway in patients deemed at risk of pulmonary aspiration. Cricoid pressure is conceptually used to reduce the risk of aspiration by compressing the oesophagus. OBJECTIVES: To identify and evaluate all randomized controlled trials (RCTs) involving participants undergoing elective or emergency airway management via RSI and compare participants who have cricoid pressure administered with participants who do not have cricoid pressure administered. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2015, Issue 4), MEDLINE via OvidSP (1946 to May 2015), EMBASE via OvidSP (1980 to May 2015), ISI Web of Science (from 1940 to May 2015) and CINAHL via EBSCOhost (1982 to May 2015). SELECTION CRITERIA: We included all RCTs comparing people undergoing RSI who have cricoid pressure applied, either intermittently or continuously, with people undergoing RSI who do not have cricoid pressure applied in the context of endotracheal intubation using a direct laryngoscopic technique. We included both elective and emergency cases. We included studies of blinded and unblinded participants. Participants (male or female) were involved in any type of procedure where general anaesthetic utilizing RSI or emergency airway management utilizing RSI and endotracheal intubation was undertaken. We expected the control arm to be the absence of cricoid pressure at any stage during RSI. The primary outcome of interest was the reported event rate or prevalence of aspiration determined by a) documented gastric aspiration determined by visual inspection of aspirated stomach contents on laryngoscopy; b) pepsin detection in tracheal aspirate using the Ufberg method; c) post-anaesthetic radiographic changes suggestive of aspiration pneumonitis or d) any combination of a to c. Secondary outcomes of interest included documented impaired visualization of the airway by a treating laryngoscopist, force applied during cricoid pressure, the direction of application of force of applied cricoid pressure, independent risk factors for aspiration and whether the person applying cricoid pressure had previously done so in an emergency airway context. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the titles and abstracts of all the studies obtained from the search using recognition of words such as 'cricoid pressure', 'rapid sequence intubation', 'emergency airway management' and 'aspiration'. Two authors independently determined the study inclusion by using a study eligibility form that we developed for the purpose of this review. We also reported the decisions regarding inclusion and exclusion in accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement. We assumed that studies that did not describe the use of RSI in their title, abstract or methodology used an alternative method of anaesthetic induction or emergency airway management and thus we excluded them. Data extracted from included studies comprised study characteristics, participant demographics, intervention and comparison details plus outcome measures and results. We contacted primary authors of studies with missing or unreported but potentially relevant data to obtain missing data. MAIN RESULTS: Of 493 records that we identified from databases as a result of the search (excluding duplicates), we regarded 70 abstracts/titles as potentially relevant studies. Independent scrutiny of these 70 titles and abstracts identified 29 potentially relevant studies. Of the 29 potentially relevant studies, one study met the criteria for inclusion. This study was a RCT that compared participants undergoing RSI and endotracheal intubation in the context of elective surgery requiring a general anaesthetic. Forty participants were recruited, 20 of whom had cricoid pressure applied and 20 of whom had cricoid pressure simulated. The main outcomes reported were systolic arterial pressure and heart rate after laryngoscopy and tracheal intubation. We did not consider these outcomes relevant for the purposes of this systematic review. The search also identified one study that could potentially be included in an updated systematic review in the future, but was at the time of the search a proposal for a trial only and had no reported outcomes at this time. AUTHORS' CONCLUSIONS: There is currently no information available from published RCTs on clinically relevant outcome measures with respect to the application of cricoid pressure during RSI in the context of endotracheal intubation. On the basis of the findings of non-RCT literature, however, cricoid pressure may not be necessary to undertake RSI safely, and therefore well-designed and conducted RCTs should nonetheless be encouraged to properly assess the safety and effectiveness of cricoid pressure. PMID- 26578525 TI - The multiple neural networks of familiarity: A meta-analysis of functional imaging studies. AB - Recent research has demonstrated the critical role of the feeling of familiarity in recognition memory. Various neuroimaging paradigms have been developed to identify the brain regions that sustain the processing of familiarity; however, there is still considerable controversy about the functional significance of each brain region implicated in familiarity-based retrieval. Here, we focused on the differences between paradigms that assess familiarity, with or without the encoding phase. We used the activation likelihood estimation (ALE) algorithm to conduct a whole-brain meta-analysis of neuroimaging studies that involved a familiarity task. Sixty-nine studies, performed in healthy subjects to determine the specific functions of the identified regions in familiarity processing, were finally selected. Distinct subanalyses were performed according to the experimental procedures used in the original studies. The ALE clusters that were highlighted revealed common activations for paradigms with and without encoding in the prefrontal cortex and in the parietal cortex. Additionally, supplementary activations related to specific familiarity (i.e., without the encoding phase) were observed in the limbic system (i.e., the amygdala, hippocampus, cingulate cortex, and insula) and in the associative sensory areas. The differences in the reported findings for different procedures are possibly due to differences in the concept of familiarity. To aid the exploration of the neural correlates of familiarity in future studies, the strengths and weaknesses of these experimental procedures are critically discussed. PMID- 26578527 TI - Erratum to: Modulation of CYP19 expression by cabbage juices and their active components: indole-3-carbinol and 3,3'-diindolymethane in human breast epithelial cell lines. PMID- 26578528 TI - Mediterranean diet score and total and cardiovascular mortality in Eastern Europe: the HAPIEE study. AB - PURPOSE: Mediterranean-type dietary pattern has been associated with lower risk of cardiovascular (CVD) and other chronic diseases, primarily in Southern European populations. We examined whether Mediterranean diet score (MDS) is associated with total, CVD, coronary heart disease (CHD) and stroke mortality in a prospective cohort study in three Eastern European populations. METHODS: A total of 19,333 male and female participants of the Health Alcohol and Psychosocial factors in Eastern Europe (HAPIEE) study in the Czech Republic, Poland and the Russian Federation were included in the analysis. Diet was assessed by food frequency questionnaire, and MDS was derived from consumption of nine groups of food using absolute cut-offs. Mortality was ascertained by linkage with death registers. RESULTS: Over the median follow-up time of 7 years, 1314 participants died. The proportion of participants with high adherence to Mediterranean diet was low (25 %). One standard deviation (SD) increase in the MDS (equivalent to 2.2 point increase in the score) was found to be inversely associated with death from all causes (HR, 95 % CI 0.93, 0.88-0.98) and CVD (0.90, 0.81-0.99) even after multivariable adjustment. Inverse but statistically not significant link was found for CHD (0.90, 0.78-1.03) and stroke (0.87, 0.71 1.07). The MDS effects were similar in each country cohort. CONCLUSION: Higher adherence to the Mediterranean diet was associated with reduced risk of total and CVD deaths in these large Eastern European urban populations. The application of MDS with absolute cut-offs appears suitable for non-Mediterranean populations. PMID- 26578529 TI - Fish oil diet in pregnancy and lactation reduces pup weight and modifies newborn hepatic metabolic adaptations in rats. AB - PURPOSE: To determine the effects of a diet containing fish oil (FD) during pregnancy and lactation in rats on the metabolic adaptations made by the offspring during early extrauterine life and to compare it to an olive oil diet (OD). METHODS: Rats were mated and randomly allocated to OD or FD containing 10 % of the corresponding oil. During lactation, litters were adjusted to eight pups per dam. Fetuses of 20 days and pups of 0, 1, 10, 20 and 30 days of age were studied. RESULTS: Body weight and length were lower in pups of the FD group from birth. The diet, milk, pups' plasma and liver of FD group had higher proportions of n-3 LCPUFA, but the content of arachidonic acid (ARA) was lower. Plasma glucose was higher, but unesterified fatty acids, triacylglycerols (TAG), 3 hydroxybutyrate and liver TAG in 1-day-old pups were lower in the FD group, and differences in some of these variables were also found in pups up to 30 days old. Liver lipoprotein lipase activity and mRNA expression, and the expression of carnitine palmitoyl transferase I, acyl-CoA oxidase and 3-hydroxy 3-methyl glutaryl-CoA synthase increased more at birth in pups of the FD group, but the expression of sterol regulatory element binding protein-1c and Delta6-desaturase mRNA was lower in the FD group. CONCLUSIONS: Maternal intake of high n-3 LCPUFA retards postnatal development, which could be the result of impaired ARA synthesis, and affects hepatic metabolic adaptations to extrauterine life. PMID- 26578530 TI - Hepatic DNA hydroxymethylation is site-specifically altered by chronic alcohol consumption and aging. AB - PURPOSE: Global DNA hydroxymethylation is markedly decreased in human cancers, including hepatocellular carcinoma, which is associated with chronic alcohol consumption and aging. Because gene-specific changes in hydroxymethylcytosine may affect gene transcription, giving rise to a carcinogenic environment, we determined genome-wide site-specific changes in hepatic hydroxymethylcytosine that are associated with chronic alcohol consumption and aging. METHODS: Young (4 months) and old (18 months) male C57Bl/6 mice were fed either an ethanol containing Lieber-DeCarli liquid diet or an isocaloric control diet for 5 weeks. Genomic and gene-specific hydroxymethylcytosine patterns were determined through hydroxymethyl DNA immunoprecipitation array in hepatic DNA. RESULTS: Hydroxymethylcytosine patterns were more perturbed by alcohol consumption in young mice than in old mice (431 differentially hydroxymethylated regions, DhMRs, in young vs 189 DhMRs in old). A CpG island ~2.5 kb upstream of the glucocorticoid receptor gene, Nr3c1, had increased hydroxymethylation as well as increased mRNA expression (p = 0.015) in young mice fed alcohol relative to the control group. Aging alone also altered hydroxymethylcytosine patterns, with 331 DhMRs, but alcohol attenuated this effect. Aging was associated with a decrease in hydroxymethylcytosine ~1 kb upstream of the leptin receptor gene, Lepr, and decreased transcription of this gene (p = 0.029). Nr3c1 and Lepr are both involved in hepatic lipid homeostasis and hepatosteatosis, which may create a carcinogenic environment. CONCLUSIONS: These results suggest that the location of hydroxymethylcytosine in the genome is site specific and not random, and that changes in hydroxymethylation may play a role in the liver's response to aging and alcohol. PMID- 26578531 TI - Green tea consumption and glutathione S-transferases genetic polymorphisms on the risk of adult leukemia. AB - PURPOSE: Green tea may have a beneficial role of inhibiting leukemia. Glutathione S-transferases (GSTs) are known to detoxify certain carcinogens. We investigated the roles of green tea consumption and polymorphisms of GSTM1, GSTT1 and GSTP1 on the risk of adult leukemia, and to determine whether the associations varied within GSTs genotypes. METHODS: A multicenter case-control study was conducted in China, 2008-2013. It comprised 442 incident, hematologically confirmed adult leukemia cases and 442 outpatient controls, individually matched to cases by gender, birth quinquennium and study site. Data were collected by face-to-face interview using a validated questionnaire. Genetic polymorphisms were assayed by PCR. RESULTS: An inverse association between green tea consumption and adult leukemia risk was observed. Compared with non-tea drinkers, the adjusted odds ratios (95 % confidence intervals) were 0.50 (0.27-0.93), 0.31 (0.17-0.55) and 0.53 (0.29-0.99) for those who, respectively, consumed green tea >20 years, >=2 cups daily and dried tea leaves >1000 g annually. In assessing the associations by GSTs genotypes, risk reduction associated with green tea consumption was stronger in individuals with the GSTT1-null genotype (OR 0.24; 95 % CI 0.11-0.53) than GSTT1-normal carriers (OR 0.67; 95 % CI 0.42-1.05; P interaction = 0.02). GSTM1 and GSTP1 did not significantly modify the inverse association of leukemia with green tea. CONCLUSIONS: The results suggest that regular daily green tea consumption may reduce leukemia risk in Chinese adults regardless of GSTM1 and GSTP1 polymorphic status. The association between green tea and adult leukemia risk varied with GSTT1 genotype and highlights further study. PMID- 26578532 TI - Modeling hemodynamic forces in carotid artery based on local geometric features. AB - Hemodynamic wall shear stress (WSS) plays an important role in the initiation and progression of carotid atherosclerosis. This study aims at developing a technique to model WSS distribution based on point-wise geometric features that can be efficiently computed. Computational fluid dynamic analysis was performed for ten subjects. Surface curvatures, vascular radius, rate of change of radius along the longitudinal direction and standardized longitudinal/circumferential coordinates were computed on a point-wise basis for the arteries. Each of these point-wise geometric parameters was transformed to maximize the adjusted correlation coefficient. The transformed geometric parameters subsequently served as input variables of a multiple regression model. Multiple regression analysis revealed a significant relationship ([Formula: see text]) between WSS and three geometric parameters in internal and external carotid arteries (ICA and ECA). These three geometric parameters include vascular radius (ICA: [Formula: see text], ECA: [Formula: see text]), standardized longitudinal/circumference coordinates (ICA: [Formula: see text], ECA: [Formula: see text]) and Gaussian curvature (ICA: [Formula: see text], ECA: [Formula: see text]). The results suggest that the proposed geometric parameters can serve as risk indicator in large-scale clinical studies aiming at elucidating the roles of local geometric risk of atherosclerosis. PMID- 26578533 TI - Clinical outcome of vertebral compression fracture after single fraction spine radiosurgery for spinal metastases. AB - Vertebral compression fracture (VCF) occurs after stereotactic body radiation therapy (SBRT) for spine metastasis. Recently, single fraction radiosurgery (sfSRS) is used more frequently. The aim of this study is to determine the clinical outcome of VCF after sfSRS. Spinal instability neoplastic score (SINS) criteria were used to retrospectively score 143 consecutive vertebral segments in 79 patients treated with SRS. Follow-up MRI, pain, and neurologic assessments obtained every 3-6 months. Pain also scored at 7, 14, and 30 days after sfSRS. Follow up was 16 +/- 18 months +/-SD, range 3-78. Long-term radiographic control occurred in 94 % of cases. Pain improvement resulted within 7 days in 100 % of cases with severe pain and sustained long-term in 95 %. VCF occurred in 21 % of segments: 30 % were de novo VCF. The overall 1 year fracture free probability (1yFFP) was 76 %. Pre-existing VCF resulted in higher probability to progress: 1yFFP 90 versus 60 %. Symptoms presented in 6 % of cases with de novo VCF and 39 % with progressive. The former were treated with vertebral augmentation (VA), the latter with open surgery. Surgery/VA prior to SRS did not change risk of progressive VCF. Univariate but not multivariate analysis identified histology (colorectal), pre-existing VCF, and pain (severe) as significant predictors of VCF. In conclusion, sfSRS compares favourably to SBRT for radiographic and pain control with similar VCF risk. Patients with pre-existing VCF have a higher probability to progress, become symptomatic, and require surgery. These results may help discussing risk and benefits with patients undergoing sfSRS for spinal metastasis and developing new treatment algorithms. PMID- 26578534 TI - The Rise and Fall of Universal Salt Iodization in Vietnam: Lessons Learned for Designing Sustainable Food Fortification Programs With a Public Health Impact. AB - BACKGROUND: In 2005, more than 90% of Vietnamese households were using adequately iodized salt, and urinary iodine concentration among women of reproductive age was in the optimal range. However, household coverage declined thereafter to 45% in 2011, and urinary iodine concentration levels indicated inadequate iodine intake. OBJECTIVE: To review the strengths and weaknesses of the Vietnamese universal salt iodization program from its inception to the current day and to discuss why achievements made by 2005 were not sustained. METHODS: Qualitative review of program documents and semistructured interviews with national stakeholders. RESULTS: National legislation for mandatory salt iodization was revoked in 2005, and the political importance of the program was downgraded with consequential effects on budget, staff, and authority. CONCLUSIONS: The Vietnamese salt iodization program, as it was initially designed and implemented, was unsustainable, as salt iodization was not practiced as an industry norm but as a government-funded activity. An effective and sustainable salt iodization program needs to be reestablished for the long-term elimination of iodine deficiency, building upon lessons learned from the past and programs in neighboring countries. The new program will need to include mandatory legislation, including salt for food processing; industry responsibility for the cost of fortificant; government commitment for enforcement through routine food control systems and monitoring of iodine status through existing health/nutrition assessments; and intersectoral collaboration and management of the program. Many of the lessons would apply equally to universal salt iodization programs in other countries and indeed to food fortification programs in general. PMID- 26578535 TI - Merging alcohol giants threaten global health. PMID- 26578536 TI - Herpes Zoster and Risk of Cancer in the Elderly U.S. Population. AB - BACKGROUND: Herpes zoster (HZ) arises in older people due to age-related decline in immunity. We assessed whether HZ, as a marker of immune suppression, is associated with increased cancer risk. METHODS: We conducted a case-control study in U.S. adults with ages >= 65 years using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. Cases (n = 1,108,986) were people with first cancers identified in cancer registries (1992-2005). Controls (n = 100,000) were cancer-free individuals frequency matched to cases on age, sex, and year of selection. We identified HZ diagnosis using Medicare claims. Logistic regression models were constructed to determine adjusted associations between cancer and HZ. RESULTS: HZ prevalence was modestly higher in cases than controls (1.4% vs. 1.2%). We identified significant associations between HZ and oral cavity/pharyngeal [adjusted OR (aOR) = 1.21], colon (aOR = 1.10), lung (aOR = 1.11), and non-melanoma skin (aOR = 1.46) cancers; myeloma (aOR = 1.38); diffuse large B-cell lymphoma (aOR = 1.30); lymphoplasmacytic lymphoma (aOR = 1.99); and chronic lymphocytic leukemia/small lymphocytic lymphoma (aOR = 1.55). Among solid cancers, HZ was mostly associated with regional and/or distant stage tumors. Associations were strongest when HZ was diagnosed 13 to 35 months before cancer diagnosis/selection; they were significant for some cancers in the 36 to 59 months period, and 60+ months for lymphoplasmacytic lymphoma (OR = 1.99). CONCLUSION: HZ is associated with modestly increased risk of a few cancers, particularly hematologic malignancies. Associations were strongest at short latency intervals for many cancers, and for regional/distant stages among solid cancers, perhaps reflecting reverse causality. IMPACT: Age-related immune decline does not play a major role in cancer development in older people, but it may be important for some lymphomas. PMID- 26578539 TI - Nature Contacts: Employee Wellness in Healthcare. AB - OBJECTIVE: This study was designed to ascertain the amount of outdoor, indoor, and indirect nature contact exposures hospital employees have in a workweek. BACKGROUND: Hospital employees have been found particularly vulnerable to work related stress. Increasing the nature contact exposure for hospital employees can reduce perceived stress; stress-related health behaviors; and stress-related health outcomes from outdoor, indoor, and indirect exposures to nature. METHODS: Staff on the fourth floor postsurgical unit of a large hospital (N = 42) were ask to participate in an employee questionnaire "nature contact questionnaire". This 16-item nature environment questionnaire measures the amount and types of nature contact exposures employees have during a workweek. RESULTS: Majority of employees reported few, if any, nature contact exposures, specifically in the area of outdoor nature contacts with limited indoor and indirect contacts. These results indicated that employees on the fourth floor postsurgical floor have limited ability to reduce stress through nature contact exposures which could impact their perceived levels of work stress and stress-related behaviors and health outcomes. CONCLUSIONS: Nature contact exposures are both a relatively easy and an inexpensive way to improve employee stress. These findings indicate limitations to employees' exposure to nature contacts. Healthcare environments would benefit from a concerted effort to provide increased outdoor, indoor, and indirect nature contact exposures for employees. PMID- 26578537 TI - Depression, Antidepressant Use, and Postmenopausal Breast Cancer Risk. AB - BACKGROUND: Whether depression and antidepressant (AD) use might influence breast cancer risk is unclear, and these exposures have not been evaluated together in a single, prospective cohort study of breast cancer risk. METHODS: Among 71,439 postmenopausal women in the Women's Health Initiative Observational Study (WHI OS), we estimated multivariable-adjusted HRs for the independent and joint effects of depressive symptoms and AD use on breast cancer risk using Cox proportional hazards regression. RESULTS: When analyzed separately, neither depressive symptoms nor AD use at baseline were associated with a significantly increased risk of total breast cancer (HR = 0.96, 95% CI, 0.85-1.08; HR = 1.04, 95% CI, 0.92-1.20, respectively) or invasive breast cancer (HR = 0.98, 95% CI, 0.86-1.12; HR = 1.00, 95% CI, 0.86-1.16, respectively). Current AD use was associated with a borderline-significant increase of in situ breast cancer (HR = 1.30, 95% CI, 0.99-1.75) after adjustment for depressive symptoms; however, this relationship was attenuated after adjustment for mammographic screening (HR = 1.08, 95% CI, 0.76-1.51). No significant variation in total breast cancer risk was observed when the separate and joint effects of depressive symptoms and AD use were explored (P for interaction = 0.14). CONCLUSION: We found no evidence that either depression or AD use influences breast cancer risk. An elevated risk of in situ disease among AD users could not be ruled out, though is likely due to increased screening in this subgroup. IMPACT: Given the high prevalence of these exposures, these results may provide reassurance to the millions of women who are depressed and/or use ADs each year. PMID- 26578538 TI - Effect of Condom Use on Per-act HSV-2 Transmission Risk in HIV-1, HSV-2 discordant Couples. AB - BACKGROUND: The efficacy of condoms for protection against transmission of herpes simplex virus type 2 (HSV-2) has been examined in a variety of populations with different effect measures. Often the efficacy has been assessed as change in hazard of transmission with consistent vs inconsistent use, independent of the number of acts. Condom efficacy has not previously measured on a per-act basis. METHODS: We examined the per-act HSV-2 transmission rates with and without condom use among 911 African HSV-2 and human immunodeficiency virus type 1 (HIV-1) serodiscordant couples followed for an average of 18 months in an HIV prevention study. Infectivity models were used to associate the log10 probability of HSV-2 transmission over monthly risk periods with reported numbers of protected and unprotected sex acts. Condom efficacy was computed as the proportionate reduction in transmission risk for protected relative to unprotected sex acts. RESULTS: Transmission of HSV-2 occurred in 68 couples, including 17 with susceptible women and 51 with susceptible men. The highest rate of transmission was from men to women: 28.5 transmissions per 1000 unprotected sex acts. We found that condoms were differentially protective against HSV-2 transmission by sex; condom use reduced per-act risk of transmission from men to women by 96% (P < .001) and marginally from women to men by 65% (P = .060). CONCLUSIONS: Condoms are recommended as an effective preventive method for heterosexual transmission of HSV-2. PMID- 26578540 TI - Identifying Challenging Job and Environmental Demands of Older Nurses Within the National Health Service. AB - OBJECTIVES: To explore the existing theoretical contexts of the job and environmental demands of the nursing profession in the National Health Service (NHS) and to investigate how these job and environmental demands impact on the personal constructs of older nurses within the NHS. BACKGROUND: Nursing is the single most widely practiced profession in the healthcare sector in the United Kingdom. However, nurses contend with challenging job and environmental demands on a daily basis, which deplete them of personal constructs (or resources) required to stay in the profession. METHODS: A multilevel exploratory qualitative research design was employed. Ten managers were interviewed for the preliminary study, based on which the three characteristics of an age-friendly NHS workplace were established: health, retirement, and flexibility. Then an in-depth literature review revealed that the most adversely affected job within the NHS was the nursing profession. Finally, a focus group study was undertaken with six older nurses working in the NHS. RESULTS: The most compelling finding of this study is that older nurses would generally not want to stay on the job if they had to work in the ward area. The physical, cognitive, and sensory constructs of older nurses are negatively affected by the job and environmental demands of the ward areas. CONCLUSIONS: Understanding how these job and environmental demands of the workplace affect an older nurse's personal constructs may help support a better design of nurse work and the wards and help extend the working lives of older nurses in the NHS. PMID- 26578542 TI - Economic Security, Social Cohesion, and Depression Disparities in Post-transition Societies: A Comparison of Older Adults in China and Russia. AB - Although both China and Russia have experienced several decades of market reform, initial evidence suggests that this structural change has compromised mental and physical health among the Russian population but not the Chinese population. Using data from the World Health Organization Study on Global AGEing and Adult Health (2007-2010), this study examines the factors associated with the disparity in depression between older adults in China and their Russian counterparts, all of whom experienced market transition in the prime of their lives (N = 10,896). Results show that the lower level of depression among Chinese respondents is attributable to higher levels of economic security and social cohesion as well as stronger effects of economic and social resources on depression, while health rating style is likely a minor factor. The study advances the sociological understanding of global/comparative mental health by considering the effects of macrolevel political, economic, social, and cultural conditions. PMID- 26578543 TI - Lifestyle Intervention for Weight Loss and Cardiometabolic Changes in the Setting of Glucokinase Regulatory Protein Inhibition: Glucokinase Regulatory Protein Leu446Pro Variant in Look AHEAD. AB - BACKGROUND: Glucokinase regulatory protein (GCKR) inhibitors offer a novel treatment approach for glucose control in diabetes mellitus; however, their cardiometabolic effects, particularly in relation to increased triglycerides and C-reactive protein (CRP) levels, are of concern. GCKR Leu446Pro is a common variant associated with reduced GCKR function, increased triglycerides, and CRP. METHODS AND RESULTS: We investigated whether a 1-year intensive lifestyle intervention (ILI) for weight loss would avert the unfavorable cardiometabolic effects associated with GCKR Leu446Pro when compared with a diabetes mellitus support and education arm in overweight/obese individuals with type 2 diabetes mellitus with triglyceride (n=3214) and CRP (n=1411) data participating in a randomized lifestyle intervention study for weight loss, Action for Health in Diabetes Mellitus (Look AHEAD). Once demographics, medication use and baseline adiposity, and fitness were accounted for, ILI did not modify the baseline association of GCKR-Leu446Pro with elevated triglycerides (beta+/-SE=0.067+/ 0.013, P=1.5*10(-7) and beta+/-SE=0.052+/-0.015, P=5*10(-4)) or with elevated CRP (beta+/-SE=0.136+/-0.034, P=5.1*10(-5)and beta+/-SE=0.903+/-0.038, P=0.015) in the overall sample and Non-Hispanic Whites, respectively. The lack of a protective effect from ILI at 1 year when compared with diabetes mellitus support and education (ILI versus diabetes mellitus support and education interaction for triglyceride and CRP change, respectively: P=0.64 and 0.37 in the overall sample; P=0.27 and 0.05 in Non-Hispanic Whites) persisted after additional adjustment for changes in adiposity and fitness. CONCLUSIONS: Moderate improvements in adiposity and fitness with ILI did not mitigate the adverse cardiometabolic effects of GCKR inhibition in overweight/obese individuals with diabetes mellitus. PMID- 26578545 TI - Usual and Dual-Task Walking Speed: Implications for Pedestrians Crossing the Road. AB - OBJECTIVE: In many countries, pedestrian light crossings require a minimum walking speed of 1.2 m/s. This study examined the proportion of adults in a nationally representative sample whose usual and dual-task walking speeds are <1.2 m/s. METHOD: Community-dwelling adults aged >=50 years in The Irish Longitudinal Study on Ageing (TILDA) completed walking speed tests on a GAITRite(r) walkway (N = 4,909). RESULTS: One third of Irish adults aged 65 to 74 years and 61% of adults aged >=75 years walked slower than 1.2 m/s. In dual-task walking, 54% of adults aged <65 years and 91% of adults aged >=75 years walked slower than 1.2 m/s. DISCUSSION: Based on these data, many older people would have insufficient time to cross the road at light-controlled pedestrian crossings. Increasing the time provided would be an advantage for many older pedestrians. PMID- 26578544 TI - CD36 Is a Matrix Metalloproteinase-9 Substrate That Stimulates Neutrophil Apoptosis and Removal During Cardiac Remodeling. AB - BACKGROUND: After myocardial infarction, the left ventricle undergoes a wound healing response that includes the robust infiltration of neutrophils and macrophages to facilitate removal of dead myocytes as well as turnover of the extracellular matrix. Matrix metalloproteinase (MMP)-9 is a key enzyme that regulates post-myocardial infarction left ventricular remodeling. METHODS AND RESULTS: Infarct regions from wild-type and MMP-9 null mice (n=8 per group) analyzed by glycoproteomics showed that of 541 N-glycosylated proteins quantified, 45 proteins were at least 2-fold upregulated or downregulated with MMP-9 deletion (all P<0.05). Cartilage intermediate layer protein and platelet glycoprotein 4 (CD36) were identified as having the highest fold increase in MMP 9 null mice. By immunoblotting, CD36 but not cartilage intermediate layer protein decreased steadily during the time course post-myocardial infarction, which identified CD36 as a candidate MMP-9 substrate. MMP-9 was confirmed in vitro and in vivo to proteolytically degrade CD36. In vitro stimulation of day 7 post myocardial infarction macrophages with MMP-9 or a CD36-blocking peptide reduced phagocytic capacity. Dual immunofluorescence revealed concomitant accumulation of apoptotic neutrophils in the MMP-9 null group compared with wild-type group. In vitro stimulation of isolated neutrophils with MMP-9 decreased neutrophil apoptosis, indicated by reduced caspase-9 expression. CONCLUSIONS: Our data reveal a new cell-signaling role for MMP-9 through CD36 degradation to regulate macrophage phagocytosis and neutrophil apoptosis. PMID- 26578541 TI - Mechanisms and therapeutic effectiveness of lactobacilli. AB - The gut microbiome is not a silent ecosystem but exerts several physiological and immunological functions. For many decades, lactobacilli have been used as an effective therapy for treatment of several pathological conditions displaying an overall positive safety profile. This review summarises the mechanisms and clinical evidence supporting therapeutic efficacy of lactobacilli. We searched Pubmed/Medline using the keyword 'Lactobacillus'. Selected papers from 1950 to 2015 were chosen on the basis of their content. Relevant clinical and experimental articles using lactobacilli as therapeutic agents have been included. Applications of lactobacilli include kidney support for renal insufficiency, pancreas health, management of metabolic imbalance, and cancer treatment and prevention. In vitro and in vivo investigations have shown that prolonged lactobacilli administration induces qualitative and quantitative modifications in the human gastrointestinal microbial ecosystem with encouraging perspectives in counteracting pathology-associated physiological and immunological changes. Few studies have highlighted the risk of translocation with subsequent sepsis and bacteraemia following probiotic administration but there is still a lack of investigations on the dose effect of these compounds. Great care is thus required in the choice of the proper Lactobacillus species, their genetic stability and the translocation risk, mainly related to inflammatory disease-induced gut mucosa enhanced permeability. Finally, we need to determine the adequate amount of bacteria to be delivered in order to achieve the best clinical efficacy decreasing the risk of side effects. PMID- 26578551 TI - Corrigendum. PMID- 26578546 TI - Which Features of the Environment Impact Community Participation of Older Adults? A Systematic Review and Meta-Analysis. AB - OBJECTIVE: The objective of this study is to identify features of the environment associated with community participation of older adults. METHOD: A systematic review of studies that examined associations between environment and community participation in older adults was conducted. Environmental features were extracted and grouped using the International Classification of Functioning, Disability, and Health's environmental categories. Meta-analysis of environmental categories was conducted by calculating combined effect size (ES) estimates. RESULTS: Significant, small to moderate, random ESs were found for six of seven environmental categories: neighborliness (ES = 0.52, 95% confidence interval [CI] = [0.18, 0.87]), social support (ES = 0.38, 95% CI = [0.13, 0.62]), land-use diversity (ES = 0.29, 95% CI = [0.16, 0.42]), transportation (ES = 0.29, 95% CI = [0.15, 0.43]), civil protection (e.g., safety; ES = 0.27, 95% CI = [0.0, 0.54]), and street connectivity/walkability (ES = 0.20, 95% CI = [0.15, 0.26]). DISCUSSION: Community initiatives that address specific features of the social environment and street-level environment may increase community participation of older adults. PMID- 26578552 TI - Listening to Our Patients: Learning About Suicide Risk and Protective Factors From Veterans With HIV/AIDS. AB - PURPOSE: We sought to gather perspectives of veterans with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) regarding suicide risk factors, warning signs, and protective factors. We also aimed to modify an existing Veterans Health Administration tool, the Suicide Risk Assessment Guide Pocket Card, for HIV/AIDS provider use. METHODS: Twenty male veterans participated in audio-recorded semistructured interviews that were transcribed and coded for themes. FINDINGS: Veterans highlighted personally relevant psychosocial stressors (i.e., poverty, social isolation and loneliness, and physical health). Although the concept of warning signs did not seem salient to participants, they named indicators of elevated imminent risk for self-directed violence (i.e., "relapse," "not take'n medications," and "miss'n appointments") and few protective factors. No themes emerged regarding recommended pocket card changes. CONCLUSIONS: This sample of veterans identified self-directed violence risks noted in the general population and others with HIV/AIDS, as well as proximal events associated with increased risk. Care providers are encouraged to explore the relevance of noted imminent and persistent indicators of increased risk with veterans seeking care. PMID- 26578553 TI - 'Birthgasm': A Literary Review of Orgasm as an Alternative Mode of Pain Relief in Childbirth. AB - Childbirth is a fundamental component of a woman's sexual cycle. The sexuality of childbirth is not well recognized in Western society despite research showing that some women experience orgasm(s) during labor and childbirth. Current thinking supports the view that labor and childbirth are perceived to be physically painful events, and more women are relying on medical interventions for pain relief in labor. This review explores the potential of orgasm as a mode of pain relief in childbirth and outlines the physiological explanations for its occurrence. Potential barriers to sexual expression during childbirth and labor, including the influence of deeply held cultural beliefs about sexuality, the importance of privacy and intimacy in facilitating orgasmic birth experiences, and the value of including prospective fathers in the birthing experience, are discussed. The role of midwives and their perceptions of the use of complementary and alternative therapies for pain relief in labor are examined. While there are indications of widespread use of complementary and alternative therapies such as hydrotherapy, herbal remedies, and breathing techniques for pain relief in childbirth, orgasm was not among those mentioned. Lack of recognition of the sexuality of childbirth, despite findings that orgasm can attenuate the effects of labor pain, suggests the need for greater awareness among expectant parents, educators, and health professionals of the potential of orgasm as a means of pain relief in childbirth. PMID- 26578554 TI - RNAi revised--target mRNA-dependent enhancement of gene silencing. AB - The discovery of RNA interference (RNAi) gave rise to the development of new nucleic acid-based technologies as powerful investigational tools and potential therapeutics. Mechanistic key details of RNAi in humans need to be deciphered yet, before such approaches take root in biomedicine and molecular therapy. We developed and validated an in silico-based model of siRNA-mediated RNAi in human cells in order to link in vitro-derived pre-steady state kinetic data with a quantitative and time-resolved understanding of RNAi on the cellular level. The observation that product release by Argonaute 2 is accelerated in the presence of an excess of target RNA in vitro inspired us to suggest an associative mechanism for the RNA slicer reaction where incoming target mRNAs actively promote dissociation of cleaved mRNA fragments. This novel associative model is compatible with high multiple turnover rates of RNAi-based gene silencing in living cells and accounts for target mRNA concentration-dependent enhancement of the RNAi machinery. PMID- 26578556 TI - The Saccharomyces Genome Database Variant Viewer. AB - The Saccharomyces Genome Database (SGD; http://www.yeastgenome.org) is the authoritative community resource for the Saccharomyces cerevisiae reference genome sequence and its annotation. In recent years, we have moved toward increased representation of sequence variation and allelic differences within S. cerevisiae. The publication of numerous additional genomes has motivated the creation of new tools for their annotation and analysis. Here we present the Variant Viewer: a dynamic open-source web application for the visualization of genomic and proteomic differences. Multiple sequence alignments have been constructed across high quality genome sequences from 11 different S. cerevisiae strains and stored in the SGD. The alignments and summaries are encoded in JSON and used to create a two-tiered dynamic view of the budding yeast pan-genome, available at http://www.yeastgenome.org/variant-viewer. PMID- 26578555 TI - SugarBindDB, a resource of glycan-mediated host-pathogen interactions. AB - The SugarBind Database (SugarBindDB) covers knowledge of glycan binding of human pathogen lectins and adhesins. It is a curated database; each glycan-protein binding pair is associated with at least one published reference. The core data element of SugarBindDB is a set of three inseparable components: the pathogenic agent, a lectin/adhesin and a glycan ligand. Each entity (agent, lectin or ligand) is described by a range of properties that are summarized in an entity dedicated page. Several search, navigation and visualisation tools are implemented to investigate the functional role of glycans in pathogen binding. The database is cross-linked to protein and glycan-relaled resources such as UniProtKB and UniCarbKB. It is tightly bound to the latter via a substructure search tool that maps each ligand to full structures where it occurs. Thus, a glycan-lectin binding pair of SugarBindDB can lead to the identification of a glycan-mediated protein-protein interaction, that is, a lectin-glycoprotein interaction, via substructure search and the knowledge of site-specific glycosylation stored in UniCarbKB. SugarBindDB is accessible at: http://sugarbind.expasy.org. PMID- 26578557 TI - LegumeIP 2.0--a platform for the study of gene function and genome evolution in legumes. AB - The LegumeIP 2.0 database hosts large-scale genomics and transcriptomics data and provides integrative bioinformatics tools for the study of gene function and evolution in legumes. Our recent updates in LegumeIP 2.0 include gene and protein sequences, gene models and annotations, syntenic regions, protein families and phylogenetic trees for six legume species: Medicago truncatula, Glycine max (soybean), Lotus japonicus, Phaseolus vulgaris (common bean), Cicer arietinum (chickpea) and Cajanus cajan (pigeon pea) and two outgroup reference species: Arabidopsis thaliana and Poplar trichocarpa. Moreover, the LegumeIP 2.0 features the following new data resources and bioinformatics tools: (i) an integrative gene expression atlas for four model legumes that include 550 array hybridizations from M. truncatula, 962 gene expression profiles of G. max, 276 array hybridizations from L. japonicas and 56 RNA-Seq-based gene expression profiles for C. arietinum. These datasets were manually curated and hierarchically organized based on Experimental Ontology and Plant Ontology so that users can browse, search, and retrieve data for their selected experiments. (ii) New functions/analytical tools to query, mine and visualize large-scale gene sequences, annotations and transcriptome profiles. Users may select a subset of expression experiments and visualize and compare expression profiles for multiple genes. The LegumeIP 2.0 database is freely available to the public at http://plantgrn.noble.org/LegumeIP/. PMID- 26578558 TI - Simultaneous characterization of sense and antisense genomic processes by the double-stranded hidden Markov model. AB - Hidden Markov models (HMMs) have been extensively used to dissect the genome into functionally distinct regions using data such as RNA expression or DNA binding measurements. It is a challenge to disentangle processes occurring on complementary strands of the same genomic region. We present the double-stranded HMM (dsHMM), a model for the strand-specific analysis of genomic processes. We applied dsHMM to yeast using strand specific transcription data, nucleosome data, and protein binding data for a set of 11 factors associated with the regulation of transcription.The resulting annotation recovers the mRNA transcription cycle (initiation, elongation, termination) while correctly predicting strand specificity and directionality of the transcription process. We find that pre initiation complex formation is an essentially undirected process, giving rise to a large number of bidirectional promoters and to pervasive antisense transcription. Notably, 12% of all transcriptionally active positions showed simultaneous activity on both strands. Furthermore, dsHMM reveals that antisense transcription is specifically suppressed by Nrd1, a yeast termination factor. PMID- 26578559 TI - VFDB 2016: hierarchical and refined dataset for big data analysis--10 years on. AB - The virulence factor database (VFDB, http://www.mgc.ac.cn/VFs/) is dedicated to providing up-to-date knowledge of virulence factors (VFs) of various bacterial pathogens. Since its inception the VFDB has served as a comprehensive repository of bacterial VFs for over a decade. The exponential growth in the amount of biological data is challenging to the current database in regard to big data analysis. We recently improved two aspects of the infrastructural dataset of VFDB: (i) removed the redundancy introduced by previous releases and generated two hierarchical datasets--one core dataset of experimentally verified VFs only and another full dataset including all known and predicted VFs and (ii) refined the gene annotation of the core dataset with controlled vocabularies. Our efforts enhanced the data quality of the VFDB and promoted the usability of the database in the big data era for the bioinformatic mining of the explosively growing data regarding bacterial VFs. PMID- 26578560 TI - Structural basis for RNA-genome recognition during bacteriophage Qbeta replication. AB - Upon infection of Escherichia coli by bacteriophage Qbeta, the virus-encoded beta subunit recruits host translation elongation factors EF-Tu and EF-Ts and ribosomal protein S1 to form the Qbeta replicase holoenzyme complex, which is responsible for amplifying the Qbeta (+)-RNA genome. Here, we use X-ray crystallography, NMR spectroscopy, as well as sequence conservation, surface electrostatic potential and mutational analyses to decipher the roles of the beta subunit and the first two oligonucleotide-oligosaccharide-binding domains of S1 (OB1-2) in the recognition of Qbeta (+)-RNA by the Qbeta replicase complex. We show how three basic residues of the beta subunit form a patch located adjacent to the OB2 domain, and use NMR spectroscopy to demonstrate for the first time that OB2 is able to interact with RNA. Neutralization of the basic residues by mutagenesis results in a loss of both the phage infectivity in vivo and the ability of Qbeta replicase to amplify the genomic RNA in vitro. In contrast, replication of smaller replicable RNAs is not affected. Taken together, our data suggest that the beta-subunit and protein S1 cooperatively bind the (+)-stranded Qbeta genome during replication initiation and provide a foundation for understanding template discrimination during replication initiation. PMID- 26578561 TI - Control of alternative end joining by the chromatin remodeler p400 ATPase. AB - Repair of DNA double-strand breaks occurs in a chromatin context that needs to be modified and remodeled to allow suitable access to the different DNA repair machineries. Of particular importance for the maintenance of genetic stability is the tight control of error-prone pathways, such as the alternative End Joining pathway. Here, we show that the chromatin remodeler p400 ATPase is a brake to the use of alternative End Joining. Using specific intracellular reporter susbstrates we observed that p400 depletion increases the frequency of alternative End Joining events, and generates large deletions following repair of double-strand breaks. This increase of alternative End Joining events is largely dependent on CtIP-mediated resection, indicating that it is probably related to the role of p400 in late steps of homologous recombination. Moreover, p400 depletion leads to the recruitment of poly(ADP) ribose polymerase (PARP) and DNA ligase 3 at DNA double-strand breaks, driving to selective killing by PARP inhibitors. All together these results show that p400 acts as a brake to prevent alternative End Joining-dependent genetic instability and underline its potential value as a clinical marker. PMID- 26578562 TI - Discover hidden splicing variations by mapping personal transcriptomes to personal genomes. AB - RNA-seq has become a popular technology for studying genetic variation of pre mRNA alternative splicing. Commonly used RNA-seq aligners rely on the consensus splice site dinucleotide motifs to map reads across splice junctions. Consequently, genomic variants that create novel splice site dinucleotides may produce splice junction RNA-seq reads that cannot be mapped to the reference genome. We developed and evaluated an approach to identify 'hidden' splicing variations in personal transcriptomes, by mapping personal RNA-seq data to personal genomes. Computational analysis and experimental validation indicate that this approach identifies personal specific splice junctions at a low false positive rate. Applying this approach to an RNA-seq data set of 75 individuals, we identified 506 personal specific splice junctions, among which 437 were novel splice junctions not documented in current human transcript annotations. 94 splice junctions had splice site SNPs associated with GWAS signals of human traits and diseases. These involve genes whose splicing variations have been implicated in diseases (such as OAS1), as well as novel associations between alternative splicing and diseases (such as ICA1). Collectively, our work demonstrates that the personal genome approach to RNA-seq read alignment enables the discovery of a large but previously unknown catalog of splicing variations in human populations. PMID- 26578563 TI - An ultra-dense library resource for rapid deconvolution of mutations that cause phenotypes in Escherichia coli. AB - With the wide availability of whole-genome sequencing (WGS), genetic mapping has become the rate-limiting step, inhibiting unbiased forward genetics in even the most tractable model organisms. We introduce a rapid deconvolution resource and method for untagged causative mutations after mutagenesis, screens, and WGS in Escherichia coli. We created Deconvoluter-ordered libraries with selectable insertions every 50 kb in the E. coli genome. The Deconvoluter method uses these for replacement of untagged mutations in the genome using a phage-P1-based gene replacement strategy. We validate the Deconvoluter resource by deconvolution of 17 of 17 phenotype-altering mutations from a screen of N-ethyl-N-nitrosourea induced mutants. The Deconvoluter resource permits rapid unbiased screens and gene/function identification and will enable exploration of functions of essential genes and undiscovered genes/sites/alleles not represented in existing deletion collections. This resource for unbiased forward-genetic screens with mapping-by-sequencing ('forward genomics') demonstrates a strategy that could similarly enable rapid screens in many other microbes. PMID- 26578564 TI - Hymenoptera Genome Database: integrating genome annotations in HymenopteraMine. AB - We report an update of the Hymenoptera Genome Database (HGD) (http://HymenopteraGenome.org), a model organism database for insect species of the order Hymenoptera (ants, bees and wasps). HGD maintains genomic data for 9 bee species, 10 ant species and 1 wasp, including the versions of genome and annotation data sets published by the genome sequencing consortiums and those provided by NCBI. A new data-mining warehouse, HymenopteraMine, based on the InterMine data warehousing system, integrates the genome data with data from external sources and facilitates cross-species analyses based on orthology. New genome browsers and annotation tools based on JBrowse/WebApollo provide easy genome navigation, and viewing of high throughput sequence data sets and can be used for collaborative genome annotation. All of the genomes and annotation data sets are combined into a single BLAST server that allows users to select and combine sequence data sets to search. PMID- 26578565 TI - PCOSKB: A KnowledgeBase on genes, diseases, ontology terms and biochemical pathways associated with PolyCystic Ovary Syndrome. AB - Polycystic ovary syndrome (PCOS) is one of the major causes of female subfertility worldwide and ~ 7-10% of women in reproductive age are affected by it. The affected individuals exhibit varying types and levels of comorbid conditions, along with the classical PCOS symptoms. Extensive studies on PCOS across diverse ethnic populations have resulted in a plethora of information on dysregulated genes, gene polymorphisms and diseases linked to PCOS. However, efforts have not been taken to collate and link these data. Our group, for the first time, has compiled PCOS-related information available through scientific literature; cross-linked it with molecular, biochemical and clinical databases and presented it as a user-friendly, web-based online knowledgebase for the benefit of the scientific and clinical community. Manually curated information on associated genes, single nucleotide polymorphisms, diseases, gene ontology terms and pathways along with supporting reference literature has been collated and included in PCOSKB (http://pcoskb.bicnirrh.res.in). PMID- 26578566 TI - The methyltransferase domain of dengue virus protein NS5 ensures efficient RNA synthesis initiation and elongation by the polymerase domain. PMID- 26578567 TI - Different genome stability proteins underpin primed and naive adaptation in E. coli CRISPR-Cas immunity. AB - CRISPR-Cas is a prokaryotic immune system built from capture and integration of invader DNA into CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) loci, termed 'Adaptation', which is dependent on Cas1 and Cas2 proteins. In Escherichia coli, Cascade-Cas3 degrades invader DNA to effect immunity, termed 'Interference'. Adaptation can interact with interference ('primed'), or is independent of it ('naive'). We demonstrate that primed adaptation requires the RecG helicase and PriA protein to be present. Genetic analysis of mutant phenotypes suggests that RecG is needed to dissipate R-loops at blocked replication forks. Additionally, we identify that DNA polymerase I is important for both primed and naive adaptation, and that RecB is needed for naive adaptation. Purified Cas1-Cas2 protein shows specificity for binding to and nicking forked DNA within single strand gaps, and collapsing forks into DNA duplexes. The data suggest that different genome stability systems interact with primed or naive adaptation when responding to blocked or collapsed invader DNA replication. In this model, RecG and Cas3 proteins respond to invader DNA replication forks that are blocked by Cascade interference, enabling DNA capture. RecBCD targets DNA ends at collapsed forks, enabling DNA capture without interference. DNA polymerase I is proposed to fill DNA gaps during spacer integration. PMID- 26578568 TI - dbPTM 2016: 10-year anniversary of a resource for post-translational modification of proteins. AB - Owing to the importance of the post-translational modifications (PTMs) of proteins in regulating biological processes, the dbPTM (http://dbPTM.mbc.nctu.edu.tw/) was developed as a comprehensive database of experimentally verified PTMs from several databases with annotations of potential PTMs for all UniProtKB protein entries. For this 10th anniversary of dbPTM, the updated resource provides not only a comprehensive dataset of experimentally verified PTMs, supported by the literature, but also an integrative interface for accessing all available databases and tools that are associated with PTM analysis. As well as collecting experimental PTM data from 14 public databases, this update manually curates over 12 000 modified peptides, including the emerging S-nitrosylation, S-glutathionylation and succinylation, from approximately 500 research articles, which were retrieved by text mining. As the number of available PTM prediction methods increases, this work compiles a non homologous benchmark dataset to evaluate the predictive power of online PTM prediction tools. An increasing interest in the structural investigation of PTM substrate sites motivated the mapping of all experimental PTM peptides to protein entries of Protein Data Bank (PDB) based on database identifier and sequence identity, which enables users to examine spatially neighboring amino acids, solvent-accessible surface area and side-chain orientations for PTM substrate sites on tertiary structures. Since drug binding in PDB is annotated, this update identified over 1100 PTM sites that are associated with drug binding. The update also integrates metabolic pathways and protein-protein interactions to support the PTM network analysis for a group of proteins. Finally, the web interface is redesigned and enhanced to facilitate access to this resource. PMID- 26578569 TI - Genome-wide binding studies reveal DNA binding specificity mechanisms and functional interplay amongst Forkhead transcription factors. AB - Transcription factors belonging to the same transcription factor families contain very similar DNA binding domains and hence have the potential to bind to related DNA sequences. However, subtle differences in binding specificities can be detected in vitro with the potential to direct specific responses in vivo. Here, we have examined the binding properties of three Forkhead (FOX) transcription factors, FOXK2, FOXO3 and FOXJ3 in vivo. Extensive overlap in chromatin binding is observed, although underlying differential DNA binding specificity can dictate the recruitment of FOXK2 and FOXJ3 to chromatin. However, functionally, FOXO3 dependent gene regulation is generally mediated not through uniquely bound regions but through regions occupied by both FOXK2 and FOXO3 where both factors play a regulatory role. Our data point to a model whereby FOX transcription factors control gene expression through dynamically binding and generating partial occupancy of the same site rather than mutually exclusive binding derived by stable binding of individual FOX proteins. PMID- 26578570 TI - PlanMine--a mineable resource of planarian biology and biodiversity. AB - Planarian flatworms are in the midst of a renaissance as a model system for regeneration and stem cells. Besides two well-studied model species, hundreds of species exist worldwide that present a fascinating diversity of regenerative abilities, tissue turnover rates, reproductive strategies and other life history traits. PlanMine (http://planmine.mpi-cbg.de/) aims to accomplish two primary missions: First, to provide an easily accessible platform for sharing, comparing and value-added mining of planarian sequence data. Second, to catalyze the comparative analysis of the phenotypic diversity amongst planarian species. Currently, PlanMine houses transcriptomes independently assembled by our lab and community contributors. Detailed assembly/annotation statistics, a custom developed BLAST viewer and easy export options enable comparisons at the contig and assembly level. Consistent annotation of all transcriptomes by an automated pipeline, the integration of published gene expression information and inter relational query tools provide opportunities for mining planarian gene sequences and functions. For inter-species comparisons, we include transcriptomes of, so far, six planarian species, along with images, expert-curated information on their biology and pre-calculated cross-species sequence homologies. PlanMine is based on the popular InterMine system in order to make the rich biology of planarians accessible to the general life sciences research community. PMID- 26578571 TI - DNA data bank of Japan (DDBJ) progress report. AB - The DNA Data Bank of Japan Center (DDBJ Center; http://www.ddbj.nig.ac.jp) maintains and provides public archival, retrieval and analytical services for biological information. The contents of the DDBJ databases are shared with the US National Center for Biotechnology Information (NCBI) and the European Bioinformatics Institute (EBI) within the framework of the International Nucleotide Sequence Database Collaboration (INSDC). Since 2013, the DDBJ Center has been operating the Japanese Genotype-phenotype Archive (JGA) in collaboration with the National Bioscience Database Center (NBDC) in Japan. In addition, the DDBJ Center develops semantic web technologies for data integration and sharing in collaboration with the Database Center for Life Science (DBCLS) in Japan. This paper briefly reports on the activities of the DDBJ Center over the past year including submissions to databases and improvements in our services for data retrieval, analysis, and integration. PMID- 26578572 TI - WormBase 2016: expanding to enable helminth genomic research. AB - WormBase (www.wormbase.org) is a central repository for research data on the biology, genetics and genomics of Caenorhabditis elegans and other nematodes. The project has evolved from its original remit to collect and integrate all data for a single species, and now extends to numerous nematodes, ranging from evolutionary comparators of C. elegans to parasitic species that threaten plant, animal and human health. Research activity using C. elegans as a model system is as vibrant as ever, and we have created new tools for community curation in response to the ever-increasing volume and complexity of data. To better allow users to navigate their way through these data, we have made a number of improvements to our main website, including new tools for browsing genomic features and ontology annotations. Finally, we have developed a new portal for parasitic worm genomes. WormBase ParaSite (parasite.wormbase.org) contains all publicly available nematode and platyhelminth annotated genome sequences, and is designed specifically to support helminth genomic research. PMID- 26578573 TI - Death of a dogma: eukaryotic mRNAs can code for more than one protein. AB - mRNAs carry the genetic information that is translated by ribosomes. The traditional view of a mature eukaryotic mRNA is a molecule with three main regions, the 5' UTR, the protein coding open reading frame (ORF) or coding sequence (CDS), and the 3' UTR. This concept assumes that ribosomes translate one ORF only, generally the longest one, and produce one protein. As a result, in the early days of genomics and bioinformatics, one CDS was associated with each protein-coding gene. This fundamental concept of a single CDS is being challenged by increasing experimental evidence indicating that annotated proteins are not the only proteins translated from mRNAs. In particular, mass spectrometry (MS) based proteomics and ribosome profiling have detected productive translation of alternative open reading frames. In several cases, the alternative and annotated proteins interact. Thus, the expression of two or more proteins translated from the same mRNA may offer a mechanism to ensure the co-expression of proteins which have functional interactions. Translational mechanisms already described in eukaryotic cells indicate that the cellular machinery is able to translate different CDSs from a single viral or cellular mRNA. In addition to summarizing data showing that the protein coding potential of eukaryotic mRNAs has been underestimated, this review aims to challenge the single translated CDS dogma. PMID- 26578574 TI - Ensembl Genomes 2016: more genomes, more complexity. AB - Ensembl Genomes (http://www.ensemblgenomes.org) is an integrating resource for genome-scale data from non-vertebrate species, complementing the resources for vertebrate genomics developed in the context of the Ensembl project (http://www.ensembl.org). Together, the two resources provide a consistent set of programmatic and interactive interfaces to a rich range of data including reference sequence, gene models, transcriptional data, genetic variation and comparative analysis. This paper provides an update to the previous publications about the resource, with a focus on recent developments. These include the development of new analyses and views to represent polyploid genomes (of which bread wheat is the primary exemplar); and the continued up-scaling of the resource, which now includes over 23 000 bacterial genomes, 400 fungal genomes and 100 protist genomes, in addition to 55 genomes from invertebrate metazoa and 39 genomes from plants. This dramatic increase in the number of included genomes is one part of a broader effort to automate the integration of archival data (genome sequence, but also associated RNA sequence data and variant calls) within the context of reference genomes and make it available through the Ensembl user interfaces. PMID- 26578575 TI - Binding dynamics of a monomeric SSB protein to DNA: a single-molecule multi process approach. AB - Single-stranded DNA binding proteins (SSBs) are ubiquitous across all organisms and are characterized by the presence of an OB (oligonucleotide/oligosaccharide/oligopeptide) binding motif to recognize single stranded DNA (ssDNA). Despite their critical role in genome maintenance, our knowledge about SSB function is limited to proteins containing multiple OB domains and little is known about single OB-folds interacting with ssDNA. Sulfolobus solfataricus SSB (SsoSSB) contains a single OB-fold and being the simplest representative of the SSB-family may serve as a model to understand fundamental aspects of SSB:DNA interactions. Here, we introduce a novel approach based on the competition between Forster resonance energy transfer (FRET), protein-induced fluorescence enhancement (PIFE) and quenching to dissect SsoSSB binding dynamics at single-monomer resolution. We demonstrate that SsoSSB follows a monomer-by-monomer binding mechanism that involves a positive-cooperativity component between adjacent monomers. We found that SsoSSB dynamic behaviour is closer to that of Replication Protein A than to Escherichia coli SSB; a feature that might be inherited from the structural analogies of their DNA-binding domains. We hypothesize that SsoSSB has developed a balance between high-density binding and a highly dynamic interaction with ssDNA to ensure efficient protection of the genome but still allow access to ssDNA during vital cellular processes. PMID- 26578576 TI - EMDataBank unified data resource for 3DEM. AB - Three-dimensional Electron Microscopy (3DEM) has become a key experimental method in structural biology for a broad spectrum of biological specimens from molecules to cells. The EMDataBank project provides a unified portal for deposition, retrieval and analysis of 3DEM density maps, atomic models and associated metadata (emdatabank.org). We provide here an overview of the rapidly growing 3DEM structural data archives, which include maps in EM Data Bank and map-derived models in the Protein Data Bank. In addition, we describe progress and approaches toward development of validation protocols and methods, working with the scientific community, in order to create a validation pipeline for 3DEM data. PMID- 26578578 TI - Structure and specificity of the RNA-guided endonuclease Cas9 during DNA interrogation, target binding and cleavage. PMID- 26578577 TI - The nucleosome landscape of Plasmodium falciparum reveals chromatin architecture and dynamics of regulatory sequences. AB - In eukaryotes, the chromatin architecture has a pivotal role in regulating all DNA-associated processes and it is central to the control of gene expression. For Plasmodium falciparum, a causative agent of human malaria, the nucleosome positioning profile of regulatory regions deserves particular attention because of their extreme AT-content. With the aid of a highly controlled MNase-seq procedure we reveal how positioning of nucleosomes provides a structural and regulatory framework to the transcriptional unit by demarcating landmark sites (transcription/translation start and end sites). In addition, our analysis provides strong indications for the function of positioned nucleosomes in splice site recognition. Transcription start sites (TSSs) are bordered by a small nucleosome-depleted region, but lack the stereotypic downstream nucleosome arrays, highlighting a key difference in chromatin organization compared to model organisms. Furthermore, we observe transcription-coupled eviction of nucleosomes on strong TSSs during intraerythrocytic development and demonstrate that nucleosome positioning and dynamics can be predictive for the functionality of regulatory DNA elements. Collectively, the strong nucleosome positioning over splice sites and surrounding putative transcription factor binding sites highlights the regulatory capacity of the nucleosome landscape in this deadly human pathogen. PMID- 26578580 TI - Assembly: a resource for assembled genomes at NCBI. AB - The NCBI Assembly database (www.ncbi.nlm.nih.gov/assembly/) provides stable accessioning and data tracking for genome assembly data. The model underlying the database can accommodate a range of assembly structures, including sets of unordered contig or scaffold sequences, bacterial genomes consisting of a single complete chromosome, or complex structures such as a human genome with modeled allelic variation. The database provides an assembly accession and version to unambiguously identify the set of sequences that make up a particular version of an assembly, and tracks changes to updated genome assemblies. The Assembly database reports metadata such as assembly names, simple statistical reports of the assembly (number of contigs and scaffolds, contiguity metrics such as contig N50, total sequence length and total gap length) as well as the assembly update history. The Assembly database also tracks the relationship between an assembly submitted to the International Nucleotide Sequence Database Consortium (INSDC) and the assembly represented in the NCBI RefSeq project. Users can find assemblies of interest by querying the Assembly Resource directly or by browsing available assemblies for a particular organism. Links in the Assembly Resource allow users to easily download sequence and annotations for current versions of genome assemblies from the NCBI genomes FTP site. PMID- 26578579 TI - Unique transposon landscapes are pervasive across Drosophila melanogaster genomes. AB - To understand how transposon landscapes (TLs) vary across animal genomes, we describe a new method called the Transposon Insertion and Depletion AnaLyzer (TIDAL) and a database of >300 TLs in Drosophila melanogaster (TIDAL-Fly). Our analysis reveals pervasive TL diversity across cell lines and fly strains, even for identically named sub-strains from different laboratories such as the ISO1 strain used for the reference genome sequence. On average, >500 novel insertions exist in every lab strain, inbred strains of the Drosophila Genetic Reference Panel (DGRP), and fly isolates in the Drosophila Genome Nexus (DGN). A minority (<25%) of transposon families comprise the majority (>70%) of TL diversity across fly strains. A sharp contrast between insertion and depletion patterns indicates that many transposons are unique to the ISO1 reference genome sequence. Although TL diversity from fly strains reaches asymptotic limits with increasing sequencing depth, rampant TL diversity causes unsaturated detection of TLs in pools of flies. Finally, we show novel transposon insertions negatively correlate with Piwi-interacting RNA (piRNA) levels for most transposon families, except for the highly-abundant roo retrotransposon. Our study provides a useful resource for Drosophila geneticists to understand how transposons create extensive genomic diversity in fly cell lines and strains. PMID- 26578581 TI - DBAASP v.2: an enhanced database of structure and antimicrobial/cytotoxic activity of natural and synthetic peptides. AB - Antimicrobial peptides (AMPs) are anti-infectives that may represent a novel and untapped class of biotherapeutics. Increasing interest in AMPs means that new peptides (natural and synthetic) are discovered faster than ever before. We describe herein a new version of the Database of Antimicrobial Activity and Structure of Peptides (DBAASPv.2, which is freely accessible at http://dbaasp.org). This iteration of the database reports chemical structures and empirically-determined activities (MICs, IC50, etc.) against more than 4200 specific target microbes for more than 2000 ribosomal, 80 non-ribosomal and 5700 synthetic peptides. Of these, the vast majority are monomeric, but nearly 200 of these peptides are found as homo- or heterodimers. More than 6100 of the peptides are linear, but about 515 are cyclic and more than 1300 have other intra-chain covalent bonds. More than half of the entries in the database were added after the resource was initially described, which reflects the recent sharp uptick of interest in AMPs. New features of DBAASPv.2 include: (i) user-friendly utilities and reporting functions, (ii) a 'Ranking Search' function to query the database by target species and return a ranked list of peptides with activity against that target and (iii) structural descriptions of the peptides derived from empirical data or calculated by molecular dynamics (MD) simulations. The three-dimensional structural data are critical components for understanding structure-activity relationships and for design of new antimicrobial drugs. We created more than 300 high-throughput MD simulations specifically for inclusion in DBAASP. The resulting structures are described in the database by novel trajectory analysis plots and movies. Another 200+ DBAASP entries have links to the Protein DataBank. All of the structures are easily visualized directly in the web browser. PMID- 26578582 TI - Enhanced annotations and features for comparing thousands of Pseudomonas genomes in the Pseudomonas genome database. AB - The Pseudomonas Genome Database (http://www.pseudomonas.com) is well known for the application of community-based annotation approaches for producing a high quality Pseudomonas aeruginosa PAO1 genome annotation, and facilitating whole genome comparative analyses with other Pseudomonas strains. To aid analysis of potentially thousands of complete and draft genome assemblies, this database and analysis platform was upgraded to integrate curated genome annotations and isolate metadata with enhanced tools for larger scale comparative analysis and visualization. Manually curated gene annotations are supplemented with improved computational analyses that help identify putative drug targets and vaccine candidates or assist with evolutionary studies by identifying orthologs, pathogen associated genes and genomic islands. The database schema has been updated to integrate isolate metadata that will facilitate more powerful analysis of genomes across datasets in the future. We continue to place an emphasis on providing high quality updates to gene annotations through regular review of the scientific literature and using community-based approaches including a major new Pseudomonas community initiative for the assignment of high-quality gene ontology terms to genes. As we further expand from thousands of genomes, we plan to provide enhancements that will aid data visualization and analysis arising from whole genome comparative studies including more pan-genome and population-based approaches. PMID- 26578583 TI - csaw: a Bioconductor package for differential binding analysis of ChIP-seq data using sliding windows. AB - Chromatin immunoprecipitation with massively parallel sequencing (ChIP-seq) is widely used to identify binding sites for a target protein in the genome. An important scientific application is to identify changes in protein binding between different treatment conditions, i.e. to detect differential binding. This can reveal potential mechanisms through which changes in binding may contribute to the treatment effect. The csaw package provides a framework for the de novo detection of differentially bound genomic regions. It uses a window-based strategy to summarize read counts across the genome. It exploits existing statistical software to test for significant differences in each window. Finally, it clusters windows into regions for output and controls the false discovery rate properly over all detected regions. The csaw package can handle arbitrarily complex experimental designs involving biological replicates. It can be applied to both transcription factor and histone mark datasets, and, more generally, to any type of sequencing data measuring genomic coverage. csaw performs favorably against existing methods for de novo DB analyses on both simulated and real data. csaw is implemented as a R software package and is freely available from the open source Bioconductor project. PMID- 26578584 TI - InsectBase: a resource for insect genomes and transcriptomes. AB - The genomes and transcriptomes of hundreds of insects have been sequenced. However, insect community lacks an integrated, up-to-date collection of insect gene data. Here, we introduce the first release of InsectBase, available online at http://www.insect-genome.com. The database encompasses 138 insect genomes, 116 insect transcriptomes, 61 insect gene sets, 36 gene families of 60 insects, 7544 miRNAs of 69 insects, 96,925 piRNAs of Drosophila melanogaster and Chilo suppressalis, 2439 lncRNA of Nilaparvata lugens, 22,536 pathways of 78 insects, 678,881 untranslated regions (UTR) of 84 insects and 160,905 coding sequences (CDS) of 70 insects. This release contains over 12 million sequences and provides search functionality, a BLAST server, GBrowse, insect pathway construction, a Facebook-like network for the insect community (iFacebook), and phylogenetic analysis of selected genes. PMID- 26578585 TI - Gene3D: expanding the utility of domain assignments. AB - Gene3D http://gene3d.biochem.ucl.ac.uk is a database of domain annotations of Ensembl and UniProtKB protein sequences. Domains are predicted using a library of profile HMMs representing 2737 CATH superfamilies. Gene3D has previously featured in the Database issue of NAR and here we report updates to the website and database. The current Gene3D (v14) release has expanded its domain assignments to ~ 20,000 cellular genomes and over 43 million unique protein sequences, more than doubling the number of protein sequences since our last publication. Amongst other updates, we have improved our Functional Family annotation method. We have also improved the quality and coverage of our 3D homology modelling pipeline of predicted CATH domains. Additionally, the structural models have been expanded to include an extra model organism (Drosophila melanogaster). We also document a number of additional visualization tools in the Gene3D website. PMID- 26578586 TI - GREENC: a Wiki-based database of plant lncRNAs. AB - Long non-coding RNAs (lncRNAs) are functional non-translated molecules greater than 200 nt. Their roles are diverse and they are usually involved in transcriptional regulation. LncRNAs still remain largely uninvestigated in plants with few exceptions. Experimentally validated plant lncRNAs have been shown to regulate important agronomic traits such as phosphate starvation response, flowering time and interaction with symbiotic organisms, making them of great interest in plant biology and in breeding. There is still a lack of lncRNAs in most sequenced plant species, and in those where they have been annotated, different methods have been used, so making the lncRNAs less useful in comparisons within and between species. We developed a pipeline to annotate lncRNAs and applied it to 37 plant species and six algae, resulting in the annotation of more than 120 000 lncRNAs. To facilitate the study of lncRNAs for the plant research community, the information gathered is organised in the Green Non-Coding Database (GreeNC, http://greenc.sciencedesigners.com/). PMID- 26578587 TI - BioGPS: building your own mash-up of gene annotations and expression profiles. AB - BioGPS (http://biogps.org) is a centralized gene-annotation portal that enables researchers to access distributed gene annotation resources. This article focuses on the updates to BioGPS since our last paper (2013 database issue). The unique features of BioGPS, compared to those of other gene portals, are its community extensibility and user customizability. Users contribute the gene-specific resources accessible from BioGPS ('plugins'), which helps ensure that the resource collection is always up-to-date and that it will continue expanding over time (since the 2013 paper, 162 resources have been added, for a 34% increase in the number of resources available). BioGPS users can create their own collections of relevant plugins and save them as customized gene-report pages or 'layouts' (since the 2013 paper, 488 user-created layouts have been added, for a 22% increase in the number of layouts). In addition, we recently updated the most popular plugin, the 'Gene expression/activity chart', to include ~ 6000 datasets (from ~ 2000 datasets) and we enhanced user interactivity. We also added a new 'gene list' feature that allows users to save query results for future reference. PMID- 26578589 TI - ORegAnno 3.0: a community-driven resource for curated regulatory annotation. AB - The Open Regulatory Annotation database (ORegAnno) is a resource for curated regulatory annotation. It contains information about regulatory regions, transcription factor binding sites, RNA binding sites, regulatory variants, haplotypes, and other regulatory elements. ORegAnno differentiates itself from other regulatory resources by facilitating crowd-sourced interpretation and annotation of regulatory observations from the literature and highly curated resources. It contains a comprehensive annotation scheme that aims to describe both the elements and outcomes of regulatory events. Moreover, ORegAnno assembles these disparate data sources and annotations into a single, high quality catalogue of curated regulatory information. The current release is an update of the database previously featured in the NAR Database Issue, and now contains 1 948 307 records, across 18 species, with a combined coverage of 334 215 080 bp. Complete records, annotation, and other associated data are available for browsing and download at http://www.oreganno.org/. PMID- 26578590 TI - RING1A and BMI1 bookmark active genes via ubiquitination of chromatin-associated proteins. AB - During mitosis the chromatin undergoes dramatic architectural changes with the halting of the transcriptional processes and evacuation of nearly all transcription associated machinery from genes and promoters. Molecular bookmarking of genes during mitosis is a mechanism of faithfully transmitting cell-specific transcription patterns through cell division. We previously discovered chromatin ubiquitination at active promoters as a potential mitotic bookmark. In this study, we identify the enzymes involved in the deposition of ubiquitin before mitosis. We find that the polycomb complex proteins BMI1 and RING1A regulate the ubiquitination of chromatin associated proteins bound to promoters, and this modification is necessary for the expression of marked genes once the cells enter G1. Depletion of RING1A, and thus inactivation of mitotic bookmarking by ubiquitination, is deleterious to progression through G1, cell survival and proliferation. Though the polycomb complex proteins are thought to primarily regulate gene expression by transcriptional repression, in this study, we discover that these two polycomb proteins regulate the transcription of active genes during the mitosis to G1 transition. PMID- 26578588 TI - Cellular localization of long non-coding RNAs affects silencing by RNAi more than by antisense oligonucleotides. AB - Thousands of long non-coding RNAs (lncRNAs) have been identified in mammalian cells. Some have important functions and their dysregulation can contribute to a variety of disease states. However, most lncRNAs have not been functionally characterized. Complicating their study, lncRNAs have widely varying subcellular distributions: some reside predominantly in the nucleus, the cytoplasm or in both compartments. One method to query function is to suppress expression and examine the resulting phenotype. Methods to suppress expression of mRNAs include antisense oligonucleotides (ASOs) and RNA interference (RNAi). Antisense and RNAi based gene-knockdown methods vary in efficacy between different cellular compartments. It is not known if this affects their ability to suppress lncRNAs. To address whether localization of the lncRNA influences susceptibility to degradation by either ASOs or RNAi, nuclear lncRNAs (MALAT1 and NEAT1), cytoplasmic lncRNAs (DANCR and OIP5-AS1) and dual-localized lncRNAs (TUG1, CasC7 and HOTAIR) were compared for knockdown efficiency. We found that nuclear lncRNAs were more effectively suppressed using ASOs, cytoplasmic lncRNAs were more effectively suppressed using RNAi and dual-localized lncRNAs were suppressed using both methods. A mixed-modality approach combining ASOs and RNAi reagents improved knockdown efficacy, particularly for those lncRNAs that localize to both nuclear and cytoplasmic compartments. PMID- 26578591 TI - SomamiR 2.0: a database of cancer somatic mutations altering microRNA-ceRNA interactions. AB - SomamiR 2.0 (http://compbio.uthsc.edu/SomamiR) is a database of cancer somatic mutations in microRNAs (miRNA) and their target sites that potentially alter the interactions between miRNAs and competing endogenous RNAs (ceRNA) including mRNAs, circular RNAs (circRNA) and long noncoding RNAs (lncRNA). Here, we describe the recent major updates to the SomamiR database. We expanded the scope of the database by including somatic mutations that impact the interactions between miRNAs and two classes of non-coding RNAs, circRNAs and lncRNAs. Recently, a large number of miRNA target sites have been discovered by newly emerged high-throughput technologies for mapping the miRNA interactome. We have mapped 388 247 somatic mutations to the experimentally identified miRNA target sites. The updated database also includes a list of somatic mutations in the miRNA seed regions, which contain the most important guiding information for miRNA target recognition. A recently developed webserver, miR2GO, was integrated with the database to provide a seamless pipeline for assessing functional impacts of somatic mutations in miRNA seed regions. Data and functions from multiple sources including biological pathways and genome-wide association studies were updated and integrated with SomamiR 2.0 to make it a better platform for functional analysis of somatic mutations altering miRNA-ceRNA interactions. PMID- 26578592 TI - PANTHER version 10: expanded protein families and functions, and analysis tools. AB - PANTHER (Protein Analysis THrough Evolutionary Relationships, http://pantherdb.org) is a widely used online resource for comprehensive protein evolutionary and functional classification, and includes tools for large-scale biological data analysis. Recent development has been focused in three main areas: genome coverage, functional information ('annotation') coverage and accuracy, and improved genomic data analysis tools. The latest version of PANTHER, 10.0, includes almost 5000 new protein families (for a total of over 12 000 families), each with a reference phylogenetic tree including protein-coding genes from 104 fully sequenced genomes spanning all kingdoms of life. Phylogenetic trees now include inference of horizontal transfer events in addition to speciation and gene duplication events. Functional annotations are regularly updated using the models generated by the Gene Ontology Phylogenetic Annotation Project. For the data analysis tools, PANTHER has expanded the number of different 'functional annotation sets' available for functional enrichment testing, allowing analyses to access all Gene Ontology annotations--updated monthly from the Gene Ontology database--in addition to the annotations that have been inferred through evolutionary relationships. The Prowler (data browser) has been updated to enable users to more efficiently browse the entire database, and to create custom gene lists using the multiple axes of classification in PANTHER. PMID- 26578593 TI - DNA-PK triggers histone ubiquitination and signaling in response to DNA double strand breaks produced during the repair of transcription-blocking topoisomerase I lesions. AB - Although defective repair of DNA double-strand breaks (DSBs) leads to neurodegenerative diseases, the processes underlying their production and signaling in non-replicating cells are largely unknown. Stabilized topoisomerase I cleavage complexes (Top1cc) by natural compounds or common DNA alterations are transcription-blocking lesions whose repair depends primarily on Top1 proteolysis and excision by tyrosyl-DNA phosphodiesterase-1 (TDP1). We previously reported that stabilized Top1cc produce transcription-dependent DSBs that activate ATM in neurons. Here, we use camptothecin (CPT)-treated serum-starved quiescent cells to induce transcription-blocking Top1cc and show that those DSBs are generated during Top1cc repair from Top1 peptide-linked DNA single-strand breaks generated after Top1 proteolysis and before excision by TDP1. Following DSB induction, ATM activates DNA-PK whose inhibition suppresses H2AX and H2A ubiquitination and the later assembly of activated ATM into nuclear foci. Inhibition of DNA-PK also reduces Top1 ubiquitination and proteolysis as well as resumption of RNA synthesis suggesting that DSB signaling further enhances Top1cc repair. Finally, we show that co-transcriptional DSBs kill quiescent cells. Together, these new findings reveal that DSB production and signaling by transcription-blocking Top1 lesions impact on non-replicating cell fate and provide insights on the molecular pathogenesis of neurodegenerative diseases such as SCAN1 and AT syndromes, which are caused by TDP1 and ATM deficiency, respectively. PMID- 26578594 TI - SEA: a super-enhancer archive. AB - Super-enhancers are large clusters of transcriptional enhancers regarded as having essential roles in driving the expression of genes that control cell identity during development and tumorigenesis. The construction of a genome-wide super-enhancer database is urgently needed to better understand super-enhancer directed gene expression regulation for a given biology process. Here, we present a specifically designed web-accessible database, Super-Enhancer Archive (SEA, http://sea.edbc.org). SEA focuses on integrating super-enhancers in multiple species and annotating their potential roles in the regulation of cell identity gene expression. The current release of SEA incorporates 83 996 super-enhancers computationally or experimentally identified in 134 cell types/tissues/diseases, including human (75 439, three of which were experimentally identified), mouse (5879, five of which were experimentally identified), Drosophila melanogaster (1774) and Caenorhabditis elegans (904). To facilitate data extraction, SEA supports multiple search options, including species, genome location, gene name, cell type/tissue and super-enhancer name. The response provides detailed (epi)genetic information, incorporating cell type specificity, nearby genes, transcriptional factor binding sites, CRISPR/Cas9 target sites, evolutionary conservation, SNPs, H3K27ac, DNA methylation, gene expression and TF ChIP-seq data. Moreover, analytical tools and a genome browser were developed for users to explore super-enhancers and their roles in defining cell identity and disease processes in depth. PMID- 26578595 TI - Hydroxymethyluracil modifications enhance the flexibility and hydrophilicity of double-stranded DNA. AB - Oxidation of a DNA thymine to 5-hydroxymethyluracil is one of several recently discovered epigenetic modifications. Here, we report the results of nanopore translocation experiments and molecular dynamics simulations that provide insight into the impact of this modification on the structure and dynamics of DNA. When transported through ultrathin solid-state nanopores, short DNA fragments containing thymine modifications were found to exhibit distinct, reproducible features in their transport characteristics that differentiate them from unmodified molecules. Molecular dynamics simulations suggest that 5 hydroxymethyluracil alters the flexibility and hydrophilicity of the DNA molecules, which may account for the differences observed in our nanopore translocation experiments. The altered physico-chemical properties of DNA produced by the thymine modifications may have implications for recognition and processing of such modifications by regulatory DNA-binding proteins. PMID- 26578596 TI - HPMCD: the database of human microbial communities from metagenomic datasets and microbial reference genomes. AB - The Human Pan-Microbe Communities (HPMC) database (http://www.hpmcd.org/) provides a manually curated, searchable, metagenomic resource to facilitate investigation of human gastrointestinal microbiota. Over the past decade, the application of metagenome sequencing to elucidate the microbial composition and functional capacity present in the human microbiome has revolutionized many concepts in our basic biology. When sufficient high quality reference genomes are available, whole genome metagenomic sequencing can provide direct biological insights and high-resolution classification. The HPMC database provides species level, standardized phylogenetic classification of over 1800 human gastrointestinal metagenomic samples. This is achieved by combining a manually curated list of bacterial genomes from human faecal samples with over 21000 additional reference genomes representing bacteria, viruses, archaea and fungi with manually curated species classification and enhanced sample metadata annotation. A user-friendly, web-based interface provides the ability to search for (i) microbial groups associated with health or disease state, (ii) health or disease states and community structure associated with a microbial group, (iii) the enrichment of a microbial gene or sequence and (iv) enrichment of a functional annotation. The HPMC database enables detailed analysis of human microbial communities and supports research from basic microbiology and immunology to therapeutic development in human health and disease. PMID- 26578597 TI - HGTree: database of horizontally transferred genes determined by tree reconciliation. AB - The HGTree database provides putative genome-wide horizontal gene transfer (HGT) information for 2472 completely sequenced prokaryotic genomes. This task is accomplished by reconstructing approximate maximum likelihood phylogenetic trees for each orthologous gene and corresponding 16S rRNA reference species sets and then reconciling the two trees under parsimony framework. The tree reconciliation method is generally considered to be a reliable way to detect HGT events but its practical use has remained limited because the method is computationally intensive and conceptually challenging. In this regard, HGTree (http://hgtree.snu.ac.kr) represents a useful addition to the biological community and enables quick and easy retrieval of information for HGT-acquired genes to better understand microbial taxonomy and evolution. The database is freely available and can be easily scaled and updated to keep pace with the rapid rise in genomic information. PMID- 26578598 TI - Nucleotide modifications within bacterial messenger RNAs regulate their translation and are able to rewire the genetic code. AB - Nucleotide modifications within RNA transcripts are found in every organism in all three domains of life. 6-methyladeonsine (m(6)A), 5-methylcytosine (m(5)C) and pseudouridine (Psi) are highly abundant nucleotide modifications in coding sequences of eukaryal mRNAs, while m(5)C and m(6)A modifications have also been discovered in archaeal and bacterial mRNAs. Employing in vitro translation assays, we systematically investigated the influence of nucleotide modifications on translation. We introduced m(5)C, m(6)A, Psi or 2'-O-methylated nucleotides at each of the three positions within a codon of the bacterial ErmCL mRNA and analyzed their influence on translation. Depending on the respective nucleotide modification, as well as its position within a codon, protein synthesis remained either unaffected or was prematurely terminated at the modification site, resulting in reduced amounts of the full-length peptide. In the latter case, toeprint analysis of ribosomal complexes was consistent with stalling of translation at the modified codon. When multiple nucleotide modifications were introduced within one codon, an additive inhibitory effect on translation was observed. We also identified the m(5)C modification to alter the amino acid identity of the corresponding codon, when positioned at the second codon position. Our results suggest a novel mode of gene regulation by nucleotide modifications in bacterial mRNAs. PMID- 26578599 TI - HMGB1 interacts with XPA to facilitate the processing of DNA interstrand crosslinks in human cells. AB - Many effective agents used in cancer chemotherapy cause DNA interstrand crosslinks (ICLs), which covalently link both strands of the double helix together resulting in cytotoxicity. ICLs are thought to be processed by proteins from a variety of DNA repair pathways; however, a clear understanding of ICL recognition and repair processing in human cells is lacking. Previously, we found that the high mobility group box 1 (HMGB1) protein bound to triplex-directed psoralen ICLs (TFO-ICLs) in vitro, cooperatively with NER damage recognition proteins, promoted removal of UVC-induced lesions and facilitated error-free repair of TFO-ICLs in mouse fibroblasts. Here, we demonstrate that HMGB1 recognizes TFO-ICLs in human cells, and its depletion increases ICL-induced mutagenesis in human cells without altering the mutation spectra. In contrast, HMGB1 depletion in XPA-deficient human cells significantly altered the ICL induced mutation spectrum from predominantly T->A to T->G transversions. Moreover, the recruitment of XPA and HMGB1 to the ICLs is co-dependent. Finally, we show that HMGB1 specifically introduces negative supercoils in ICL-containing plasmids in HeLa cell extracts. Taken together, our data suggest that in human cells, HMGB1 functions in association with XPA on ICLs and facilitates the formation of a favorable architectural environment for ICL repair processing. PMID- 26578600 TI - Mouse genome database 2016. AB - The Mouse Genome Database (MGD; http://www.informatics.jax.org) is the primary community model organism database for the laboratory mouse and serves as the source for key biological reference data related to mouse genes, gene functions, phenotypes and disease models with a strong emphasis on the relationship of these data to human biology and disease. As the cost of genome-scale sequencing continues to decrease and new technologies for genome editing become widely adopted, the laboratory mouse is more important than ever as a model system for understanding the biological significance of human genetic variation and for advancing the basic research needed to support the emergence of genome-guided precision medicine. Recent enhancements to MGD include new graphical summaries of biological annotations for mouse genes, support for mobile access to the database, tools to support the annotation and analysis of sets of genes, and expanded support for comparative biology through the expansion of homology data. PMID- 26578601 TI - Therapeutic target database update 2016: enriched resource for bench to clinical drug target and targeted pathway information. AB - Extensive drug discovery efforts have yielded many approved and candidate drugs targeting various targets in different biological pathways. Several freely accessible databases provide the drug, target and drug-targeted pathway information for facilitating drug discovery efforts, but there is an insufficient coverage of the clinical trial drugs and the drug-targeted pathways. Here, we describe an update of the Therapeutic Target Database (TTD) previously featured in NAR. The updated contents include: (i) significantly increased coverage of the clinical trial targets and drugs (1.6 and 2.3 times of the previous release, respectively), (ii) cross-links of most TTD target and drug entries to the corresponding pathway entries of KEGG, MetaCyc/BioCyc, NetPath, PANTHER pathway, Pathway Interaction Database (PID), PathWhiz, Reactome and WikiPathways, (iii) the convenient access of the multiple targets and drugs cross-linked to each of these pathway entries and (iv) the recently emerged approved and investigative drugs. This update makes TTD a more useful resource to complement other databases for facilitating the drug discovery efforts. TTD is accessible at http://bidd.nus.edu.sg/group/ttd/ttd.asp. PMID- 26578602 TI - The CSB chromatin remodeler and CTCF architectural protein cooperate in response to oxidative stress. AB - Cockayne syndrome is a premature aging disease associated with numerous developmental and neurological abnormalities, and elevated levels of reactive oxygen species have been found in cells derived from Cockayne syndrome patients. The majority of Cockayne syndrome cases contain mutations in the ATP-dependent chromatin remodeler CSB; however, how CSB protects cells from oxidative stress remains largely unclear. Here, we demonstrate that oxidative stress alters the genomic occupancy of the CSB protein and increases CSB occupancy at promoters. Additionally, we found that the long-range chromatin-structure regulator CTCF plays a pivotal role in regulating sites of genomic CSB occupancy upon oxidative stress. We show that CSB directly interacts with CTCF in vitro and that oxidative stress enhances the CSB-CTCF interaction in cells. Reciprocally, we demonstrate that CSB facilitates CTCF-DNA interactions in vitro and regulates CTCF-chromatin interactions in oxidatively stressed cells. Together, our results indicate that CSB and CTCF can regulate each other's chromatin association, thereby modulating chromatin structure and coordinating gene expression in response to oxidative stress. PMID- 26578603 TI - Multiple Cis-acting elements modulate programmed -1 ribosomal frameshifting in Pea enation mosaic virus. AB - Programmed -1 ribosomal frameshifting (-1 PRF) is used by many positive-strand RNA viruses for translation of required products. Despite extensive studies, it remains unresolved how cis-elements just downstream of the recoding site promote a precise level of frameshifting. The Umbravirus Pea enation mosaic virus RNA2 expresses its RNA polymerase by -1 PRF of the 5'-proximal ORF (p33). Three hairpins located in the vicinity of the recoding site are phylogenetically conserved among Umbraviruses. The central Recoding Stimulatory Element (RSE), located downstream of the p33 termination codon, is a large hairpin with two asymmetric internal loops. Mutational analyses revealed that sequences throughout the RSE and the RSE lower stem (LS) structure are important for frameshifting. SHAPE probing of mutants indicated the presence of higher order structure, and sequences in the LS may also adapt an alternative conformation. Long-distance pairing between the RSE and a 3' terminal hairpin was less critical when the LS structure was stabilized. A basal level of frameshifting occurring in the absence of the RSE increases to 72% of wild-type when a hairpin upstream of the slippery site is also deleted. These results suggest that suppression of frameshifting may be needed in the absence of an active RSE conformation. PMID- 26578604 TI - GEN1 promotes Holliday junction resolution by a coordinated nick and counter-nick mechanism. AB - Holliday junctions (HJs) that physically link sister chromatids or homologous chromosomes are formed as intermediates during DNA repair by homologous recombination. Persistent recombination intermediates are acted upon by structure selective endonucleases that are required for proper chromosome segregation at mitosis. Here, we have purified full-length human GEN1 protein and show that it promotes Holliday junction resolution by a mechanism that is analogous to that exhibited by the prototypic HJ resolvase E. coli RuvC. We find that GEN1 cleaves HJs by a nick and counter-nick mechanism involving dual co-ordinated incisions that lead to the formation of ligatable nicked duplex products. As observed with RuvC, cleavage of the first strand is rate limiting, while second strand cleavage is rapid. In contrast to RuvC, however, GEN1 is largely monomeric in solution, but dimerizes on the HJ. Using HJs containing non-cleavable phosphorothioate containing linkages in one strand, we show that the two incisions can be uncoupled and that the first nick occurs upon GEN1 dimerization at the junction. These results indicate that the mechanism of HJ resolution is largely conserved from bacteria to man, despite a lack of sequence homology between the resolvases. PMID- 26578606 TI - BubbleTree: an intuitive visualization to elucidate tumoral aneuploidy and clonality using next generation sequencing data. AB - Tumors are characterized by properties of genetic instability, heterogeneity, and significant oligoclonality. Elucidating this intratumoral heterogeneity is challenging but important. In this study, we propose a framework, BubbleTree, to characterize the tumor clonality using next generation sequencing (NGS) data. BubbleTree simultaneously elucidates the complexity of a tumor biopsy, estimating cancerous cell purity, tumor ploidy, allele-specific copy number, and clonality and represents this in an intuitive graph. We further developed a three-step heuristic method to automate the interpretation of the BubbleTree graph, using a divide-and-conquer strategy. In this study, we demonstrated the performance of BubbleTree with comparisons to similar commonly used tools such as THetA2, ABSOLUTE, AbsCN-seq and ASCAT, using both simulated and patient-derived data. BubbleTree outperformed these tools, particularly in identifying tumor subclonal populations and polyploidy. We further demonstrated BubbleTree's utility in tracking clonality changes from patients' primary to metastatic tumor and dating somatic single nucleotide and copy number variants along the tumor clonal evolution. Overall, the BubbleTree graph and corresponding model is a powerful approach to provide a comprehensive spectrum of the heterogeneous tumor karyotype in human tumors. BubbleTree is R-based and freely available to the research community (https://www.bioconductor.org/packages/release/bioc/html/BubbleTree.html). PMID- 26578607 TI - Establishing and Delivering Quality Radiation Therapy in Resource-Constrained Settings: The Story of Botswana. AB - There is a global cancer crisis, and it is disproportionately affecting resource constrained settings, especially in low- and middle-income countries (LMICs). Radiotherapy is a critical and cost-effective component of a comprehensive cancer control plan that offers the potential for cure, control, and palliation of disease in greater than 50% of patients with cancer. Globally, LMICs do not have adequate access to quality radiation therapy and this gap is particularly pronounced in sub-Saharan Africa. Although there are numerous challenges in implementing a radiation therapy program in a low-resource setting, providing more equitable global access to radiotherapy is a responsibility and investment worth prioritizing. We outline a systems approach and a series of key questions to direct strategy toward establishing quality radiation services in LMICs, and highlight the story of private-public investment in Botswana from the late 1990s to the present. After assessing the need and defining the value of radiation, we explore core investments required, barriers that need to be overcome, and assets that can be leveraged to establish a radiation program. Considerations addressed include infrastructure; machine choice; quality assurance and patient safety; acquisition, development, and retention of human capital; governmental engagement; public-private partnerships; international collaborations; and the need to critically evaluate the program to foster further growth and sustainability. PMID- 26578605 TI - Bioinformatic tools for microRNA dissection. AB - Recently, microRNAs (miRNAs) have emerged as important elements of gene regulatory networks. MiRNAs are endogenous single-stranded non-coding RNAs (~22 nt long) that regulate gene expression at the post-transcriptional level. Through pairing with mRNA, miRNAs can down-regulate gene expression by inhibiting translation or stimulating mRNA degradation. In some cases they can also up regulate the expression of a target gene. MiRNAs influence a variety of cellular pathways that range from development to carcinogenesis. The involvement of miRNAs in several human diseases, particularly cancer, makes them potential diagnostic and prognostic biomarkers. Recent technological advances, especially high throughput sequencing, have led to an exponential growth in the generation of miRNA-related data. A number of bioinformatic tools and databases have been devised to manage this growing body of data. We analyze 129 miRNA tools that are being used in diverse areas of miRNA research, to assist investigators in choosing the most appropriate tools for their needs. PMID- 26578608 TI - Global Health Equity: Cancer Care Outcome Disparities in High-, Middle-, and Low Income Countries. AB - Breakthroughs in our global fight against cancer have been achieved. However, this progress has been unequal. In low- and middle-income countries and for specific populations in high-income settings, many of these advancements are but an aspiration and hope for the future. This review will focus on health disparities in cancer within and across countries, drawing from examples in Kenya, Brazil, and the United States. Placed in context with these examples, the authors also draw basic recommendations from several initiatives and groups that are working on the issue of global cancer disparities, including the US Institute of Medicine, the Global Task Force on Expanded Access to Cancer Care and Control in Developing Countries, and the Union for International Cancer Control. From increasing initiatives in basic resources in low-income countries to rapid learning systems in high-income countries, the authors argue that beyond ethics and equity issues, it makes economic sense to invest in global cancer control, especially in low- and middle-income countries. PMID- 26578609 TI - Special Issue on Global Cancer Medicine. PMID- 26578610 TI - A Vision for Global Cancer Medicine: Pursuing the Equity of Chance. AB - At the turn of the century, some claimed that HIV/AIDS was a disease that could not be managed in low-income settings. It was argued that "poor people would not comply with treatment," and that treatment was too expensive and too complicated to deliver. But over the past two decades, data on outcomes have thoroughly disproved this myth. Similar arguments have more recently been made about cancer treatment: chemotherapy was said to be too toxic and too costly and that it required administration expertise beyond that available in low-income settings. We argue that these claims are similarly rooted in ideology rather than evidence. Fortunately, such claims are starting to be refuted by a diverse set of global cancer partnerships around the world that are documenting progress and positive results. In this review article, we provide examples of programs that can give us reason to hope that the treatment playing field is being leveled such that birthplace does not determine survival prognosis. We believe that through strong collaborative efforts and solidarity, the equity of chance can be achieved for patients with cancer worldwide. PMID- 26578611 TI - Infection and Cancer: The Case of Hepatitis B. AB - Infection is a well-described cause of cancer in humans. Being one of the most common infections worldwide, hepatitis B virus (HBV) is the leading cause of hepatocellular carcinoma (HCC), particularly in Asian countries. The etiological link between HBV and HCC provides an important opportunity for health care policy makers and clinicians to intervene with HBV infection to prevent cancer development and improve the outcomes of cancer. This review aims to use HBV as an example to illustrate the potential of tackling infection-related conditions to help improve cancer outcomes. This article is divided into four parts: In the first part, an overview is given on the epidemiologic data and risk factors of HCC development in patients with chronic hepatitis B. In the second part, recent progress on the anti-HBV strategies for preventing HCC is updated. In the third part, approaches to improve the outcomes of established HBV-related HCC are covered. These methods include surveillance strategies to identify asymptomatic HCC among patients with chronic HBV infection, and use of antiviral treatment to avoid HBV reactivation during treatment for HCC and reduce the recurrence of HCC after curative treatment. Finally, the status of the development of targeted drugs specifically for HBV-related HCC is discussed in the section on future development. PMID- 26578612 TI - Provision of Palliative Care in Low- and Middle-Income Countries: Overcoming Obstacles for Effective Treatment Delivery. AB - Despite being declared a basic human right, access to adult and pediatric palliative care for millions of individuals in need in low- and middle-income countries (LMICs) continues to be limited or absent. The requirement to make palliative care available to patients with cancer is increasingly urgent because global cancer case prevalence is anticipated to double over the next two decades. Fifty percent of these cancers are expected to occur in LMICs, where mortality figures are disproportionately greater as a result of late detection of disease and insufficient access to appropriate treatment options. Notable initiatives in many LMICs have greatly improved access to palliative care. These can serve as development models for service scale-up in these regions, based on rigorous evaluation in the context of specific health systems. However, a multipronged public health approach is needed to fulfill the humane and ethical obligation to make palliative care universally available. This includes health policy that supports the integration of palliative care and investment in systems of health care delivery; changes in legislation and regulation that inappropriately restrict access to opioid medications for individuals with life-limiting illnesses; education and training of health professionals; development of a methodologically rigorous data and research base specific to LMICs that encompasses health systems and clinical care; and shifts in societal and health professional attitudes to palliative and end-of-life care. International partnerships are valuable to achieve these goals, particularly in education and research, but leadership and health systems stewardship within LMICs are critical factors that will drive and implement change. PMID- 26578613 TI - Proposing Essential Medicines to Treat Cancer: Methodologies, Processes, and Outcomes. AB - PURPOSE: A great proportion of the world's cancer burden resides in low- and middle-income countries where cancer care infrastructure is often weak or absent. Although treatment of cancer is multidisciplinary, involving surgery, radiation, systemic therapies, pathology, radiology, and other specialties, selection of medicines that have impact and are affordable has been particularly challenging in resource-constrained settings. In 2014, at the invitation of the WHO, the Union for International Cancer Control convened experts to develop an approach to propose essential cancer medicines to be included in the WHO Model Essential Medicines Lists (EML) for Adults and for Children, as well as a resulting new list of cancer medicines. METHODS: Experts identified 29 cancer types with potential for maximal treatment impact, on the basis of incidence and benefit of systemic therapies. More than 90 oncology experts from all continents drafted and reviewed disease-based documents outlining epidemiology, diagnostic needs, treatment options, and benefits and toxicities. RESULTS: Briefing documents were created for each disease, along with associated standard treatment regimens, resulting in a list of 52 cancer medicines. A comprehensive application was submitted as a revision to the existing cancer medicines on the WHO Model Lists. In May 2015, the WHO announced the addition of 16 medicines to the Adult EML and nine medicines to the Children's EML. CONCLUSION: The list of medications proposed, and the ability to link each recommended medicine to specific diseases, should allow public officials to apply resources most effectively in developing and supporting nascent or growing cancer treatment programs. PMID- 26578614 TI - The American Society of Clinical Oncology's Efforts to Support Global Cancer Medicine. AB - Despite much progress in the management of malignant diseases, the number of new cases and cancer-related deaths continues to rise around the world. More than half of new cases occur in economically developing countries, where more than two thirds of cancer deaths are expected. However, implementation of all necessary steps to accomplish the dissemination of state-of-the-art prevention, diagnosis, and management will require increased allocation of resources, and, more importantly, harmonization of the efforts of hundreds of national and international public health agencies, policy-setting bodies, governments, pharmaceutical companies, and philanthropic organizations. More than 30% of the members of the American Society of Clinical Oncology (ASCO) reside and practice outside US borders, and more than half of attendees at all of the scientific congresses and symposia organized by ASCO are international. As cancer has become an increasingly global disease, ASCO has evolved as a global organization. The ASCO Board of Directors currently includes members from France, Brazil, and Canada. In 2013, the ASCO Board of Directors identified a number of strategic priorities for the future. Recognizing the importance of non-US members to the society, their first strategic priority was improving the society's service to non-US members and defining these members' identity in the international oncology community. This article reviews current ASCO activities in the international arena and its future plans in global oncology. PMID- 26578615 TI - Cancer Genomics: Diversity and Disparity Across Ethnicity and Geography. AB - Ethnic and geographic differences in cancer incidence, prognosis, and treatment outcomes can be attributed to diversity in the inherited (germline) and somatic genome. Although international large-scale sequencing efforts are beginning to unravel the genomic underpinnings of cancer traits, much remains to be known about the underlying mechanisms and determinants of genomic diversity. Carcinogenesis is a dynamic, complex phenomenon representing the interplay between genetic and environmental factors that results in divergent phenotypes across ethnicities and geography. For example, compared with whites, there is a higher incidence of prostate cancer among Africans and African Americans, and the disease is generally more aggressive and fatal. Genome-wide association studies have identified germline susceptibility loci that may account for differences between the African and non-African patients, but the lack of availability of appropriate cohorts for replication studies and the incomplete understanding of genomic architecture across populations pose major limitations. We further discuss the transformative potential of routine diagnostic evaluation for actionable somatic alterations, using lung cancer as an example, highlighting implications of population disparities, current hurdles in implementation, and the far-reaching potential of clinical genomics in enhancing cancer prevention, diagnosis, and treatment. As we enter the era of precision cancer medicine, a concerted multinational effort is key to addressing population and genomic diversity as well as overcoming barriers and geographical disparities in research and health care delivery. PMID- 26578616 TI - Medical Education and Training: Building In-Country Capacity at All Levels. AB - Poorly trained workers and limited workforce capacity contribute immensely to barriers in cancer control in low- and middle-income countries (LMICs). Because of an increasing disease burden and the gap in trained personnel, it is critical that LMICs must develop appropriate in-country training programs at all levels to adequately address their cancer-related outcomes. The training in LMICs of cancer health personnel should address priority cancer diseases in the specific country by developing caregivers, trainers, researchers, and administrators at all levels of health care and all cadres of staff, from the community level to the national level. The Academic Model of Providing Access to Health care is a representative model of how a public tertiary hospital like the Moi Teaching and Referral Hospital in an LMIC setting can leverage its resources, collaborate with partners from high-resource countries, and assist in the development of a training center to spearhead a sustainable education program. PMID- 26578617 TI - Implementation Science for Global Oncology: The Imperative to Evaluate the Safety and Efficacy of Cancer Care Delivery. AB - PURPOSE: The development of cancer care treatment facilities in resource constrained settings represents a challenge for many reasons. Implementation science-the assessment of how services are set up and delivered; contextual factors that affect delivery, treatment safety, toxicity, and efficacy; and where adaptations are needed-is essential if we are to understand the performance of a treatment program, know where the gaps in care exist, and design interventions in care delivery models to improve outcomes for patients. METHODS: The field of implementation science in relation to cancer care delivery is reviewed, and the experiences of the integrated implementation science program at the Butaro Cancer Center of Excellence in Rwanda are described as a practical application. Implementation science of HIV and tuberculosis care delivery in similar challenging settings offers some relevant lessons. RESULTS: Integrating effective implementation science into cancer care in resource-constrained settings presents many challenges, which are discussed. However, with carefully designed programs, it is possible to perform this type of research, on regular and ongoing bases, and to use the results to develop interventions to improve quality of care and patient outcomes and provide evidence for effective replication and scale-up. CONCLUSION: Implementation science is both critical and feasible in evaluating, improving, and supporting effective expansion of cancer care in resource-limited settings. In ideal circumstances, it should be a prospective program, established early in the lifecycle of a new cancer treatment program and should be an integrated and continual process. PMID- 26578618 TI - Structural Barriers to Diagnosis and Treatment of Cancer in Low- and Middle Income Countries: The Urgent Need for Scaling Up. AB - Noncommunicable diseases are now recognized by the United Nations and WHO as a major public health crisis. Cancer is a main part of this problem, and health care systems are facing a great challenge to improve cancer care, control costs, and increase systems efficiency. The disparity in access to care and outcomes between high-income countries and low- and middle-income countries is staggering. The reasons for this disparity include cost, access to care, manpower and training deficits, and a lack of awareness in the lay and medical communities. Diagnosis and treatment play an important role in this complex environment. In different regions and countries of the world, a variety of health care systems are in place, but most of them are fragmented or poorly coordinated. The need to scale up cancer care in the low- and middle-income countries is urgent, and this article reviews many of the structural mechanisms of the problem, describes the current situation, and proposes ways for improvement. The organization of cancer services is also included in the analysis. PMID- 26578619 TI - Oncologic Care and Pathology Resources in Africa: Survey and Recommendations. AB - The connection of a clinician who identifies a patient with signs and symptoms of malignancy to an oncologist who has the tools to treat a patient's cancer requires a diagnostic pathology laboratory to receive, process, and diagnose the tumor. Without an accurate classification, nothing is known of diagnosis, prognosis, or treatment by the clinical team, and most important, the patient is left scared, confused, and without hope. The vast majority of deaths from malignancies occur in sub-Saharan Africa primarily as a result of lack of public awareness of cancer and how it is diagnosed and treated in the setting of a severe lack of resources (physical and personnel) to actually diagnose tumors. To correct this massive health disparity, a plan of action is required across the continent of Africa to bring diagnostic medicine into the modern era and connect patients with the care they desperately need. We performed a survey of resources in Africa for tissue diagnosis of cancer and asked quantitative questions about tools, personnel, and utilization. We identified a strong correlation between pathology staffing and capacity to provide pathology services. On the basis of this survey and through a congress of concerned pathologists, we propose strategies that will catapult the continent into an era of high-quality pathology services with resultant improvement in cancer outcomes. PMID- 26578620 TI - Global Pediatric Oncology: Lessons From Partnerships Between High-Income Countries and Low- to Mid-Income Countries. AB - Partnerships between medical institutions in high-income countries (HICs) and low to mid-income countries (LMICs) have succeeded in initiating and expanding pediatric cancer control efforts. The long-term goal is consistently a sustainable national pediatric cancer program. Here, we review the elements required for successful implementation, development, and long-term sustainability of pediatric cancer programs in LMICs that first arise as partnerships with institutions in HICs. Although plans must be adapted to each country's resources, certain components are unfailingly necessary. First, an essential step is provision of treatment regardless of ability to pay. Second, financial support for program development and long-term sustainability must be sought from sources both international and local, public and private. A local leader, typically a well-trained pediatric oncologist who devotes full-time effort to the project, should direct medical care and collaborate with hospital, governmental, and community leadership and international agencies. Third, nurses must be trained in pediatric cancer care and allowed to practice this specialty full-time. It is also essential to develop a grassroots organization, such as a foundation, dedicated solely to pediatric oncology. Its members must be trained and educated to provide pediatric cancer advocacy, fundraising, and (in concert with government) program sustainability. Finally, a project mentor in the HIC is crucial and should explore the possibility of collaborative research in the LMIC, which may offer significant opportunities. Relationships between the partnership's leaders and influential individuals in the community, hospital, grassroots foundation, and government will lay the foundation for productive collaboration and a sustainable pediatric oncology program. PMID- 26578621 TI - Depressive Symptoms and Risk of Cardiovascular Events in Blacks: Findings From the Jackson Heart Study. AB - BACKGROUND: Most studies of depression and cardiovascular risk have been conducted in white populations. We investigated this association in a community based cohort of blacks. METHODS AND RESULTS: We used data from the Jackson Heart Study to investigate associations of baseline depressive symptoms between 2000 and 2004 with incident stroke and coronary heart disease (CHD) during 10 years. We used Kaplan-Meier estimates and Cox proportional hazards models to assess cardiovascular event risk using 3 exposure variables: any depressive symptoms (Center for Epidemiological Studies Depression score >=16); none (score <16), minor (score 16 to <21), and major depression (score>=21); and Center for Epidemiological Studies Depression score per 1-SD increase. Models were adjusted for a stroke or CHD risk score and behavioral risk factors. Of 3309 participants with no stroke history, 738 (22.3%) had baseline depressive symptoms. A similar proportion with no previous CHD had baseline depressive symptoms (21.8%). The unadjusted 10-year risk of stroke was similar among participants with any compared with no depressive symptoms (3.7% versus 2.6%; P=0.12). Unadjusted CHD rates were higher among participants with depressive symptoms (5.6% versus 3.6%; P=0.03), and differences persisted after adjustment for clinical and behavioral risk factors but not after adjustment for coping strategies. In adjusted models comparing major versus no depressive symptoms, patients with major depressive symptoms had a 2-fold greater hazard of stroke (hazard ratio, 1.95; 95% confidence interval, 1.02-3.71; P=0.04). In continuous models, a 1-SD increase in Center for Epidemiological Studies Depression score was associated with a 30% increase in adjusted incident stroke risk (P=0.04). Similar associations were observed for incident CHD in models adjusted for clinical and behavioral risk factors, but associations were not significant after adjustment for coping strategies. CONCLUSIONS: In a community-based cohort of blacks, major depressive symptoms were associated with greater risks of incident stroke and CHD after adjustment for clinical and behavioral risk factors. PMID- 26578623 TI - CD4+ T effector memory cell dysfunction is associated with the accumulation of granulocytic myeloid-derived suppressor cells in glioblastoma patients. AB - BACKGROUND: Myeloid-derived suppressor cells (MDSCs) comprise a heterogeneous population of myeloid cells that are significantly expanded in cancer patients and are associated with tumor progression. METHODS: Multicolor flow cytometry was used to study the frequency, phenotype, and function of MDSCs in peripheral blood and freshly resected tumors of 52 participants with primary glioblastoma (GBM). RESULTS: The frequency of CD14(high)CD15(pos) monocytic and CD14(low)CD15(pos) granulocytic MDSCs was significantly higher in peripheral blood of GBM participants compared with healthy donors. The majority of granulocytic MDSCs consisted of CD14(low)CD15(high) neutrophilic MDSCs with high T-cell suppressive capacities. At the tumor side, we found an increase in CD14(high)CD15(pos) monocytic MDSCs and high frequencies of CD14(low)CD15(pos) granulocytic MDSCs that displayed an activated phenotype with downregulation of CD16 and upregulation of HLA-DR molecules, which did not inhibit T-cell proliferative responses in vitro. However, a strong association between granulocytic MDSCs and CD4(+) effector memory T-cells (TEM) within the tumors was detected. Tumor derived CD4(+) TEM expressed high levels of PD-1 when compared with their blood derived counterparts and were functionally exhausted. The respective ligand, PD L1, was significantly upregulated on tumor-derived MDSCs, and T-cell co-culture experiments confirmed that glioma-infiltrating MDSCs can induce PD-1 expression on CD4(+) TEM. CONCLUSIONS: Our findings provide a detailed characterization of different MDSC subsets in GBM patients and indicate that both granulocytic MDSCs in peripheral blood and at the tumor site play a major role in GBM-induced T-cell suppression. PMID- 26578622 TI - Amino acid positron emission tomography to monitor chemotherapy response and predict seizure control and progression-free survival in WHO grade II gliomas. AB - BACKGROUND: Patients with WHO grade II glioma may respond to chemotherapy that is currently not standardized regarding timing and treatment duration. Metabolic changes during chemotherapy may precede structural tumor volume reductions. We therefore compared time courses of amino acid PET and MRI responses to temozolomide (TMZ) and assessed whether responses correlated with seizure control and progression-free survival (PFS). METHODS: PET and MRI were performed before and during TMZ chemotherapy. Tumor volumes were calculated using regions-of interest analysis. Amino acid uptake was also quantified as metabolically active tumor volume and tumor-to-cerebellum uptake ratio. RESULTS: One hundred twenty five PET and 125 MRI scans from 33 patients were analyzed. Twenty-five patients showed metabolic responses that exhibited an exponential time course with a 25% reduction of the active volume on average after 2.3 months. MRI responses followed a linear course with a 25% reduction after 16.8 months. Reduction of metabolically active tumor volumes, but not reduction of PET uptake ratios or MRI tumor volumes, correlated with improved seizure control following chemotherapy (P = .012). Receiver-operating-characteristic curve analysis showed that a decrease of the active tumor volume of >=80.5% predicts a PFS of >=60 months (P = .018) and a decrease of >=64.5% a PFS of >=48 months (P = .037). CONCLUSIONS: Amino acid PET is superior to MRI for evaluating TMZ responses in WHO grade II glioma patients. The response delay between both imaging modalities favors amino acid PET for individually tailoring the duration of chemotherapy. Additional studies should investigate whether this personalized approach is appropriate with regard to outcome. PMID- 26578626 TI - Functional Response of Four Syrphid Predators Associated With Green Apple Aphid (Hemiptera: Aphididae) in Laboratory. AB - Aphis pomi De Geer, the green apple aphid, is an economic pest of apple and other rosaceae throughout the world. In the present study, functional responses of the syrphids Episyrphus balteatus De Geer, Eristalis tenax(L.), Eristalis interruptus (Poda), and Sphaerophoria scripta (L.), to A. pomi were studied under laboratory conditions to determine their relative predatory potential. The second- and third instar larvae of the predators were exposed to increasing densities of similar sized A. pomi nymphs in Petri dishes. Ep. balteatus was found to possess the highest consumption rate followed by Er. tenax, Er. interruptus, and S. scripta. All predator species and stages exhibited a Type II functional response. The coefficients of attack rate and handling time showed an insignificant variation between species and preying stages, suggesting equal potential of the four syrphid species to regulate A. pomi colonies. PMID- 26578625 TI - Carbohydrate malabsorption in acutely malnourished children and infants: a systematic review. AB - CONTEXT: Severe acute malnutrition (SAM) accounts for approximately 1 million child deaths per year. High mortality is linked with comorbidities, such as diarrhea and pneumonia. OBJECTIVE: The aim of this systematic review was to determine the extent to which carbohydrate malabsorption occurs in children with SAM. DATA SOURCES: The PubMed and Embase databases were searched. Reference lists of selected articles were checked. DATA EXTRACTION: All observational and controlled intervention studies involving children with SAM in which direct or indirect measures of carbohydrate absorption were analyzed were eligible for inclusion. A total of 20 articles were selected for this review. DATA SYNTHESIS: Most studies reported carbohydrate malabsorption, particularly lactose malabsorption, and suggested an increase in diarrhea and reduced weight gain in children on a lactose-containing diet. As most studies reviewed were observational, there was no conclusive scientific evidence of a causal relationship between lactose malabsorption and a worse clinical outcome among malnourished children. CONCLUSION: The combined data indicate that carbohydrate malabsorption is prevalent in children with SAM. Additional well-designed intervention studies are needed to determine whether outcomes of SAM complicated by carbohydrate malabsorption could be improved by altering the carbohydrate/lactose content of therapeutic feeds and to elucidate the precise mechanisms involved. PMID- 26578627 TI - Feeding Behavior of Soybean Aphid (Hemiptera: Aphididae) Biotype 2 on Resistant and Susceptible Soybean. AB - Host plant resistance to the soybean aphid, Aphis glycines Matsumura, is an effective means of controlling populations of this introduced pest species in the United States. Rag (Resistance to Aphis glycines) genes identified in soybean germplasm have been incorporated into commercial cultivars, but differential responses by soybean aphid biotypes to the Rag genes have made understanding mechanisms underlying resistance associated with Rag genes increasingly important. We compared the behavior of biotype 2 aphids on the resistant soybean line PI243540, which is a source of Rag2, and the susceptible cultivar Wyandot. Scanning electron microscopy revealed that the abaxial surface of leaves from resistant plants had a higher density of both long and glandulartrichomes, which might repel aphids, on veins. Time-lapse animation also suggested a repellent effect of resistant plants on aphids. However, electropenatography (EPG) indicated that the time to first probe did not differ between aphids feeding on the resistant and susceptible lines. EPG also indicated that fewer aphids feeding on resistant plants reached the phloem, and the time before reaching the phloem was much longer relative to susceptible soybean. For aphids that reached the phloem, there was no difference in either number of feedings or their duration in phloem. However, aphids feeding on resistant soybean had fewer prolonged phases of active salivation (E1) and many more pathway activities and non-probing intervals. Together, the feeding behavior of aphids suggested that Rag2 resistance has strong antixenosis effects, in addition to previously reported antibiosis, and was associated with epidermal and mesophyll tissues. PMID- 26578628 TI - Demography and Consumption of Spodoptera litura (Lepidoptera: Noctuidae) Reared on Cabbage and Taro. AB - Spodoptera litura (F.) causes considerable economic damage to multiple agro-crops annually in many countries. In this study, the demography of S. litura reared on cabbage and taro was investigated using the age-stage, two-sex life table at 25+/ 1 degrees C, 60+/-10% relative humidity, and a photoperiod of 12: 12 (L:D) h. Our results showed that the net reproductive rate, intrinsic rate, and finite rate of population increase on cabbage (1893.1 offspring, 0.2374 d(-1), and 1.2679 d(-1)) were all not significantly different from those on taro (1361.0 offspring, 0.2298 d(-1), and 1.2584 d(-1)). The net consumption rate on cabbage (439.1 cm2) was, however, three times higher than that on taro (141.7 cm2). According to the population parameters, both cabbage and taro are suitable host plants for S. litura. When both the population growth rate and the consumption rate were taken into consideration, the finite consumption rate on cabbage (omega=3.8054) was significantly higher than that on taro (omega=1.3184). In Taiwan, taro and cabbage are commonly planted in adjacent farm plots, with taro being grown from March to November and cabbage from October to April. Because of the overlapping growth periods of the two crops, S. litura can easily propagate throughout the year by switching between the adjacent crops during the overlap periods. Pest management strategies for controlling S. litura must be thoroughly reevaluated based on ecological characteristics, including its life table and consumption rate on its major host plants. PMID- 26578633 TI - In Memoriam--Dr. Alexander Boroffka (1920-2014). PMID- 26578635 TI - In Memoriam--Professor Ajita Chakraborty. PMID- 26578636 TI - Regulatory Forum Opinion Piece*: Retrospective Evaluation of Doses in the 26-week Tg.rasH2 Mice Carcinogenicity Studies: Recommendation to Eliminate High Doses at Maximum Tolerated Dose in Future Studies. A Response to the Counterpoints. AB - We recently conducted a retrospective analysis of data collected from 29 Tg.rasH2 carcinogenicity studies conducted at our facility to determine how successful was the strategy of choosing the high dose of the 26-week studies based on an estimated maximum tolerated dose (MTD). As a result of our publication, 2 counterviews were expressed. Both counterviews illustrate very valid points in their interpretation of our data. In this article, we would like to highlight clarifications based on several points and issues they have raised in their papers, namely, the dose-level selection, determining if MTD was exceeded in 26 week studies, and a discussion on the number of dose groups to be used in the studies. PMID- 26578637 TI - Abdominal adipocyte populations in women with visceral obesity. AB - BACKGROUND: Visceral obesity is independently related to numerous cardiometabolic alterations, with adipose tissue dysfunction as a central feature. OBJECTIVE: To examine whether omental (OM) and subcutaneous (SC) adipocyte size populations in women relate to visceral obesity, cardiometabolic risk factors and adipocyte lipolysis independent of total adiposity. DESIGN AND METHODS: OM and SC fat samples were obtained during gynecological surgery in 60 women (mean age, 46.1+/ 5.9 years; mean BMI, 27.1+/-4.5 kg/m2 (range, 20.3-41. kg/m2)). Fresh samples were treated with osmium tetroxide and were analyzed with a Multisizer Coulter. Cell size distributions were computed for each sample with exponential and Gaussian function fits. RESULTS: Computed tomography-measured visceral fat accumulation was the best predictor of larger cell populations as well as the percentage of small cells in both OM and SC fat (P<0.0001 for all). Accordingly, women with visceral obesity had larger cells in the main population and higher proportion of small adipocytes independent of total adiposity (P<=0.05). Using linear regression analysis, we found that women characterized by larger-than predicted adipocytes in either OM or SC adipose tissue presented higher visceral adipose tissue area, increased percentage of small cells and homeostasis model assessment insulin resistance index as well as higher OM adipocyte isoproterenol , forskolin- and dbcAMP-stimulated lipolysis compared to women with smaller-than predicted adipocytes, independent of total adiposity (P<=0.05). CONCLUSION: Excess visceral adipose tissue accumulation is a strong marker of both adipocyte hypertrophy and increased number of small cells in either fat compartment, which relates to higher insulin resistance index and lipolytic response, independent of total adiposity. PMID- 26578638 TI - The USP8 mutational status may predict drug susceptibility in corticotroph adenomas of Cushing's disease. AB - CONTEXT: Somatic mutations in the ubiquitin-specific peptidase USP8 gene were recently detected in one- to two-third(s) of corticotroph adenomas of Cushing's disease (CD). These mutations may lead to the deubiquitination of EGFR, thereby increasing EGFR signaling, which has been implicated in ACTH hypersecretion. OBJECTIVE: Our objective was to determine the impact of USP8 mutations on the clinicopathological features of CD. SUBJECTS AND METHODS: USP8 mutations as well as clinicopathological characteristics were examined in 60 corticotroph adenomas including 15 Crooke's cell adenomas (CCAs), a rare histological variant presenting with generally aggressive behavior, using qRT-PCR and/or immunohistochemistry. RESULTS: USP8 mutations were exclusively detected in women, except for one case, with a prevalence of 42.2% in non-CCA and 13.3% in CCA (overall 35%). Clinically well-behaved presentations including microadenoma and curative resection were more common in mutated cases. The expression of EGFR was not associated with the mutation status. In contrast, mutated tumors expressed significantly higher levels of POMC, SSTR5, and MGMT. CONCLUSIONS: Microadenomas that strongly express POMC were common among mutated tumors, which may lead to the mechanisms by which very small adenomas secrete excess ACTH to present overt CD. While USP8 mutations were less likely to enhance tumorous ACTH hypersecretion via EGFR-mediated activation, the presence of USP8 mutations may predict favorable responses to the somatostatin analog pasireotide, which exhibits high affinity for SSTR5. In contrast, non-mutated aggressive tumors such as CCA may respond better to the alkylating agent temozolomide because of their significantly weak expression of MGMT. PMID- 26578639 TI - Increased circulating osteopontin levels in adult patients with type 1 diabetes mellitus and association with dysmetabolic profile. AB - OBJECTIVE: Osteopontin (OPN) is a sialoprotein implicated in different immunity and metabolic pathways. Capable of activating dendritic cells and inducing Th1 Th17-mediated tissue damage, OPN plays a significant role in the development/progression of several autoimmune diseases; interestingly, it was also shown that OPN participates in the acute pancreatic islets response to experimentally induced diabetes in non-obese diabetic (NOD) mice. Furthermore, OPN promotes adipose tissue dysfunction, systemic inflammation and insulin resistance. Our aims of this study were to evaluate circulating OPN levels in adult patients with type 1 diabetes mellitus (T1DM) compared to non-diabetic control participants and to unravel clinical and biochemical correlates of OPN concentration. DESIGN: Case-control study. METHODS: We enrolled 54 consecutive T1DM patients referred to our diabetes outpatient clinic at Sapienza University of Rome and 52 healthy sex and age-comparable controls. The study population underwent clinical evaluation, blood sampling for biochemistry and complete screening for diabetes complications. Serum OPN levels were measured by MILLIPLEX Multiplex Assays Luminex. RESULTS: T1DM patients had significantly higher serum OPN levels than controls (17.2+/-12.9 vs 10.5+/-11.6 mg/ml, P=0.009). OPN levels correlated with T1DM, higher blood pressure, BMI, creatinine, gamma-GT, ALP and lower HDL; the association between high OPN levels and T1DM was independent from all confounders. No correlation was shown between OPN and HbA1c, C-peptide, insulin requirement, co-medications and diabetes duration. CONCLUSIONS: This study demonstrates for the first time in a case-control study that adults with T1DM have increased serum OPN levels, and that higher OPN concentrations are associated with an unfavorable metabolic profile in these patients. PMID- 26578640 TI - MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature. AB - The fast technological development, particularly single nucleotide polymorphism array, array-comparative genomic hybridization, and whole exome sequencing, has led to the discovery of many novel genetic causes of growth failure. In this review we discuss a selection of these, according to a diagnostic classification centred on the epiphyseal growth plate. We successively discuss disorders in hormone signalling, paracrine factors, matrix molecules, intracellular pathways, and fundamental cellular processes, followed by chromosomal aberrations including copy number variants (CNVs) and imprinting disorders associated with short stature. Many novel causes of GH deficiency (GHD) as part of combined pituitary hormone deficiency have been uncovered. The most frequent genetic causes of isolated GHD are GH1 and GHRHR defects, but several novel causes have recently been found, such as GHSR, RNPC3, and IFT172 mutations. Besides well-defined causes of GH insensitivity (GHR, STAT5B, IGFALS, IGF1 defects), disorders of NFkappaB signalling, STAT3 and IGF2 have recently been discovered. Heterozygous IGF1R defects are a relatively frequent cause of prenatal and postnatal growth retardation. TRHA mutations cause a syndromic form of short stature with elevated T3/T4 ratio. Disorders of signalling of various paracrine factors (FGFs, BMPs, WNTs, PTHrP/IHH, and CNP/NPR2) or genetic defects affecting cartilage extracellular matrix usually cause disproportionate short stature. Heterozygous NPR2 or SHOX defects may be found in ~3% of short children, and also rasopathies (e.g., Noonan syndrome) can be found in children without clear syndromic appearance. Numerous other syndromes associated with short stature are caused by genetic defects in fundamental cellular processes, chromosomal abnormalities, CNVs, and imprinting disorders. PMID- 26578641 TI - Thrombospondin-1 is a glucocorticoid responsive protein in humans. AB - OBJECTIVE: Thrombospondin-1 (TSP1) is a matricellular protein whose gene expression has previously been shown to increase acutely after exposure to dexamethasone in vitro. The aim of this study was to determine if TSP1 is altered by acute and chronic states of glucocorticoid excess in human subjects. DESIGN AND METHODS: Three studies have been undertaken to assess the difference or change in TSP1 in response to altered glucocorticoid activity: i) an acute interventional study assessed the effects of a single 4 mg dose of dexamethasone in 20 healthy volunteers; ii) a cross-sectional study compared plasma TSP1 in 20 healthy volunteers and eight patients with Cushing's syndrome; iii) an interventional study assessed the effect on plasma TSP1 of an increase in hydrocortisone dose from <=20 mg/day to 30 mg/day for 7 days in 16 patients with secondary adrenal insufficiency. RESULTS: In healthy volunteers, 4 mg dexamethasone significantly increased peripheral blood mononuclear cell (PBMC) TSP1 mRNA levels (P<0.0001) and plasma TSP1 concentrations (P<0.0001), peaking at 12 h. Median (interquartile range) plasma TSP1 was higher in Cushing's, 638 (535 756) ng/ml, than in healthy volunteers, 272 (237-336) ng/ml (P<0.0001). Plasma TSP1 >400 ng/ml diagnosed Cushing's syndrome with sensitivity of 100% and specificity of 85%. The higher hydrocortisone dose increased plasma TSP1 from 139 (86-199) to 256 (133-516) ng/ml, (P<0.01) in patients with secondary adrenal insufficiency. CONCLUSIONS: TSP1 is a glucocorticoid responsive protein in humans. Further research is required to determine if plasma TSP1 has a role as a glucocorticoid biomarker. PMID- 26578642 TI - Segmental Analysis of Cardiac Short-Axis Views Using Lagrangian Radial and Circumferential Strain. AB - Accurate description of myocardial deformation in the left ventricle is a three dimensional problem, requiring three normal strain components along its natural axis, that is, longitudinal, radial, and circumferential strains. Although longitudinal strains are best estimated from long-axis views, radial and circumferential strains are best depicted in short-axis views. An algorithm that utilizes a polar grid for short-axis views previously developed in our laboratory for a Lagrangian description of tissue deformation is utilized for radial and circumferential displacement and strain estimation. Deformation of the myocardial wall, utilizing numerical simulations with ANSYS, and a finite-element analysis based canine heart model were adapted as the input to a frequency-domain ultrasound simulation program to generate radiofrequency echo signals. Clinical in vivo data were also acquired from a healthy volunteer. Local displacements estimated along and perpendicular to the ultrasound beam propagation direction are then transformed into radial and circumferential displacements and strains using the polar grid based on a pre-determined centroid location. Lagrangian strain variations demonstrate good agreement with the ideal strain when compared with Eulerian results. Lagrangian radial and circumferential strain estimation results are also demonstrated for experimental data on a healthy volunteer. Lagrangian radial and circumferential strain tracking provide accurate results with the assistance of the polar grid, as demonstrated using both numerical simulations and in vivo study. PMID- 26578643 TI - Forensic Pathology of Traumatic Brain Injury. AB - Traumatic brain injury constitutes a significant proportion of cases requiring forensic examination, and it encompasses (1) blunt, nonmissile head injury, especially involving motor vehicle accidents, and (2) penetrating, missile injury produced by a range of high- and lower-velocity projectiles. This review examines the complex pathophysiology and biomechanics of both types of neurotrauma and assesses the macroscopic and histologic features of component lesions, which may be used to determine the cause and manner of death resulting from an intentional assault or accident. Estimation of the survival time postinjury by pathologic examination is also important where malicious head injury is suspected, in an attempt to ascertain a time at which the traumatic event might have been committed, thereby evaluating the authenticity of statements made by the alleged perpetrator. PMID- 26578647 TI - Basophils are dispensable for the recovery of gross locomotion after spinal cord hemisection injury. AB - Basophils are the smallest population of granulocytes found in the circulation. They have crucial and nonredundant roles in allergic disorders, in protection from parasite infections, in autoimmunity, and in the regulation of type 2 immunity. They share phenotypic and functional properties with mast cells, which exert substantial protective effects after traumatic brain injury and spinal cord injury, although they are considered one of the most proinflammatory cell types in the body. In contrast, the in vivo functions of basophils in central nervous system trauma are still obscure and not well studied. In this study, we show that by comparing spinal cord injury in wild type vs. basophil-deficient Mcpt8Cre transgenic mice, the locomotor recovery is not affected in mice depleted in basophils. In addition, no substantial differences were observed in the lesion size and in the astrocytic and macrophage/microglia reaction between both mouse strains. Hence, despite the multiple properties shared with mast cells, these data show, for the first time, to our knowledge, that basophils are dispensable for the functional recovery process after hemisection injury to the spinal cord in mice. PMID- 26578648 TI - Platelet-neutrophil complex formation-a detailed in vitro analysis of murine and human blood samples. AB - Platelets form complexes with neutrophils during inflammatory processes. These aggregates migrate into affected tissues and also circulate within the organism. Several studies have evaluated platelet-neutrophil complexes as a marker of cardiovascular diseases in human and mouse. Although multiple publications have reported platelet-neutrophil complex counts, we noticed that different methods were used to analyze platelet-neutrophil complex formation, resulting in significant differences, even in baseline values. We established a protocol for platelet-neutrophil complex measurement with flow cytometry in murine and human whole blood samples. In vitro platelet-neutrophil complex formation was stimulated with ADP or PMA. We tested the effect of different sample preparation steps and cytometer settings on platelet-neutrophil complex detection and noticed false-positive counts with increasing acquisition speed. Platelet-neutrophil complex formation depends on platelet P-selectin expression, and antibody blocking of P-selectin consequently prevented ADP-induced platelet-neutrophil complex formation. These findings may help generating more comparable data among different research groups that examine platelet-neutrophil complexes as a marker for cardiovascular disease and novel therapeutic interventions. PMID- 26578649 TI - Role of interferon-gamma and cytotoxic T lymphocytes in intraocular tumor rejection. AB - The eye is normally an immunosuppressive environment. This condition is better known as immune privilege and protects the eye from immune-mediated inflammation of tissues that cannot regenerate. However, immune privilege creates a dilemma for the eye when intraocular neoplasms arise. In some cases, immune privilege is suspended, resulting in the immune rejection of intraocular tumors. This study employed a mouse model in which interferon-gamma-dependent intraocular tumor rejection occurs. We tested the hypothesis that this rejection requires interferon-gamma for the generation and functional capacity of cytotoxic T lymphocyte-mediated rejection of intraocular tumors. Tumors grew progressively in the eyes of interferon-gamma knockout mice, even though the mice generated tumor specific cytotoxic T lymphocyte responses in the periphery. However, interferon gamma knockout mice rejected tumors that were introduced into extraocular sites. Subcutaneous tumor immunization before intraocular challenge led to tumor rejection and preservation of the eye in wild-type mice. By contrast, tumors grew progressively in the eyes of interferon-gamma knockout mice despite their ability to generate peripheral tumor-specific cytotoxic T lymphocytes as well as the capacity of CD8(+) T cells to enter the eye as shown by the presence of CD8 and perforin message and CD3(+)CD8(+) leukocytes within the tumor-bearing eye. We found that cytotoxic T lymphocytes generated in wild-type mice and adoptively transferred into interferon-gamma knockout mice mediated the rejection of intraocular tumors in interferon-gamma knockout hosts. The results indicate that interferon-gamma is critical for the initial priming and differentiation of cytotoxic T lymphocytes residing in the periphery to produce the most effect antitumor function within the eye. PMID- 26578651 TI - Left ventricular asynchrony in early isolated cardiac sarcoidosis. PMID- 26578650 TI - TLR9 is required for MAPK/NF-kappaB activation but does not cooperate with TLR2 or TLR6 to induce host resistance to Brucella abortus. AB - Brucella abortus is a Gram-negative intracellular bacterial pathogen that causes a zoonosis of worldwide occurrence, leading to undulant fever in humans and abortion in domestic animals. B. abortus is recognized by several pattern recognition receptors triggering pathways during the host innate immune response. Therefore, here, we determined the cooperative role of TLR9 with TLR2 or TLR6 receptors in sensing Brucella Furthermore, we deciphered the host innate immune response against B. abortus or its DNA, emphasizing the role of TLR9-MAPK/NF kappaB signaling pathways in the production of proinflammatory cytokines. TLR9 is required for the initial host control of B. abortus, but this TLR was dispensable after 6 wk of infection. The susceptibility of TLR9(-/-)-infected animals to Brucella paralleled with lower levels of IFN-gamma produced by mouse splenocytes stimulated with this pathogen compared with wild-type cells. However, no apparent cooperative interplay was observed between TLR2-TLR9 or TLR6-TLR9 receptors to control infection. Moreover, B. abortus or its DNA induced activation of MAPK/NF kappaB pathways and production of IL-12 and TNF-alpha by macrophages partially dependent on TLR9 but completely dependent on MyD88. In addition, B. abortus derived CpG oligonucleotides required TLR9 to promote IL-12 and TNF-alpha production by macrophages. By confocal microscopy, we demonstrated that TLR9 redistributed and colocalized with lysosomal-associated membrane protein-1 upon Brucella infection. Thus, B. abortus induced TLR9 traffic, leading to cell signaling activation and IL-12 and TNF-alpha production. Although TLR9 recognized Brucella CpG motifs, our results suggest a new pathway of B. abortus DNA activating macrophages independent of TLR9. PMID- 26578652 TI - A familial cluster of left ventricular non-compaction and mitral valve prolapse. PMID- 26578653 TI - Anomalous origin of the left coronary artery from the right sinus of Valsalva: two abnormal courses in one patient. PMID- 26578654 TI - Role of perfusion imaging in diagnosing myxoma mimics. PMID- 26578655 TI - Enabling systematic interrogation of protein-protein interactions in live cells with a versatile ultra-high-throughput biosensor platform. AB - Large-scale genomics studies have generated vast resources for in-depth understanding of vital biological and pathological processes. A rising challenge is to leverage such enormous information to rapidly decipher the intricate protein-protein interactions (PPIs) for functional characterization and therapeutic interventions. While a number of powerful technologies have been employed to detect PPIs, a singular PPI biosensor platform with both high sensitivity and robustness in a mammalian cell environment remains to be established. Here we describe the development and integration of a highly sensitive NanoLuc luciferase-based bioluminescence resonance energy transfer technology, termed BRET(n), which enables ultra-high-throughput (uHTS) PPI detection in live cells with streamlined co-expression of biosensors in a miniaturized format. We further demonstrate the application of BRET(n) in uHTS format in chemical biology research, including the discovery of chemical probes that disrupt PRAS40 dimerization and pathway connectivity profiling among core members of the Hippo signaling pathway. Such hippo pathway profiling not only confirmed previously reported PPIs, but also revealed two novel interactions, suggesting new mechanisms for regulation of Hippo signaling. Our BRET(n) biosensor platform with uHTS capability is expected to accelerate systematic PPI network mapping and PPI modulator-based drug discovery. PMID- 26578656 TI - Spatial control of active CDC-42 during collective migration of hypodermal cells in Caenorhabditis elegans. AB - Collective epithelial cell migration requires the maintenance of cell-cell junctions while enabling the generation of actin-rich protrusions at the leading edge of migrating cells. Ventral enclosure of Caenorhabditis elegans embryos depends on the collective migration of anterior-positioned leading hypodermal cells towards the ventral midline where they form new junctions with their contralateral neighbours. In this study, we characterized the zygotic function of RGA-7/SPV-1, a CDC-42/Cdc42 and RHO-1/RhoA-specific Rho GTPase-activating protein, which controls the formation of actin-rich protrusions at the leading edge of leading hypodermal cells and the formation of new junctions between contralateral cells. We show that RGA-7 controls these processes in an antagonistic manner with the CDC-42's effector WSP-1/N-WASP and the CDC-42 binding proteins TOCA-1/2/TOCA1. RGA-7 is recruited to spatially distinct locations at junctions between adjacent leading cells, where it promotes the accumulation of clusters of activated CDC-42. It also inhibits the spreading of these clusters towards the leading edge of the junctions and regulates their accumulation and distribution at new junctions formed between contralateral leading cells. Our study suggests that RGA-7 controls collective migration and junction formation between epithelial cells by spatially restricting active CDC 42 within cell-cell junctions. PMID- 26578657 TI - Trajectories of Vasomotor Symptoms and Carotid Intima Media Thickness in the Study of Women's Health Across the Nation. AB - BACKGROUND AND PURPOSE: Emerging work has linked menopausal vasomotor symptoms (VMS) to subclinical cardiovascular disease (CVD) among women. However, VMS are dynamic over time. No studies have considered how temporal patterns of VMS may relate to subclinical CVD. We tested how temporal patterns of VMS assessed over 13 years were related to carotid intima media thickness (IMT) among midlife women. METHODS: The Study of Women's Health Across the Nation is a longitudinal cohort study of midlife women. Eight hundred and eleven white, black, Hispanic, and Chinese participants with a well-characterized final menstrual period completed measures of VMS, a blood draw, and physical measures approximately annually for 13 years. Women underwent a carotid artery ultrasound at study visit 12. RESULTS: Four trajectories of VMS were identified by trajectory analysis (consistently high, early-onset, late-onset, persistently low VMS) and tested in relation to carotid indices in linear regression models. Results indicated that women with early-onset VMS had both greater mean IMT (beta, b [standard error, SE]=0.03 [0.01], P=0.03) and greater maximal IMT (b [SE]=0.04 [0.01], P=0.008) than women with consistently low VMS, adjusting for demographics and CVD risk factors. CONCLUSIONS: This is the first study to test trajectories of VMS in relation to subclinical CVD. Women with VMS early in the menopause transition had higher mean IMT and maximal IMT than those with consistently low VMS across the transition. Associations were not accounted for by demographic factors nor by CVD risk factors. Results can signal to women in need of early CVD risk reduction. PMID- 26578658 TI - Positron Emission Tomographic Imaging in Stroke: Cross-Sectional and Follow-Up Assessment of Amyloid in Ischemic Stroke. AB - BACKGROUND AND PURPOSE: Cardiovascular risk factors significantly increase the risk of developing Alzheimer disease. A possible mechanism may be via ischemic infarction-driving amyloid deposition. We conducted a study to determine the presence of beta-amyloid in infarct, peri-infarct, and hemispheric areas after stroke. We hypothesized that an infarct would trigger beta-amyloid deposition, with deposition over time. METHODS: Patients were recruited within 40 days of acute ischemic stroke and imaged with computed tomographic or magnetic resonance imaging and Pittsburgh compound B (11C-PiB) positron emission tomographic scans. Follow-up positron emission tomographic scanning was performed in a subgroup <=18 months after the stroke event. Standardized uptake value ratios for regions of interest were analyzed after coregistration. RESULTS: Forty-seven patients were imaged with (11)C-PiB positron emission tomography. There was an increase in (11)C-PiB accumulation in the stroke area compared with a reference region in the contralesional hemisphere, which was not statistically significant (median difference in standardized uptake value ratio, 0.07 [95% confidence interval, 0.06 to 0.123]; P=0.452). There was no significant increase in the accumulation of (11)C-PiB in the peri-infarct region or in the ipsilesional hemisphere (median difference in standardized uptake value ratio, 0.04 [95% confidence interval, 0.02 to 0.10]; P=0.095). We repeated (11)C-PiB positron emission tomography in 21 patients and found a significant reduction in accumulation of (11)C-PiB between regions of interest (median difference in standardized uptake value ratio, -0.08 [95% confidence interval, -0.23 to -0.03]; P=0.04). CONCLUSIONS: There was no significant increase in (11)C-PiB accumulation in or around the infarct. There was no increase in ipsilesional hemispheric (11)C-PiB accumulation over time. We found no evidence that infarction leads to sustained or increased beta-amyloid deposition <=18 months after stroke. PMID- 26578659 TI - Predictors of Clinical Worsening in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy: Prospective Cohort Study. AB - BACKGROUND AND PURPOSE: Predictors of clinical worsening in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy remain unknown. This study aims to identify demographic, clinical, and magnetic resonance imaging predictors of incident strokes, incident dementia, clinical deterioration, and death in patients with this genetically proven disease. METHODS: Two hundred ninety subjects (mean age, 50.6+/-11.4 years) were assessed at baseline and followed up for 36 months. Incident clinical events were recorded, and clinical scores included the Mini Mental State Examination, Mattis Dementia Rating Scale, modified Rankin Scale, and Barthel index. The number of lacunes and microbleeds, the volume of white-matter hyperintensities, and brain parenchymal fraction were assessed on baseline magnetic resonance imaging. Data were analyzed by ANCOVA, multivariable logistic regression, and Cox proportional hazard models. RESULTS: Incident stroke occurred in 55 of 278 patients (19.8%). Moderate or severe disability developed in 19 of 210 (9%) nondisabled individuals, incident dementia in 49 of 231 (20%) nondemented subjects, and 4.8% of patients died. Active smoking, the number of lacunes, and brain parenchymal fraction independently predicted incident stroke during follow-up. Gait disturbance, dementia, and brain parenchymal fraction predicted progression toward moderate or severe disability. Active smoking, disability, and brain parenchymal fraction predicted incident dementia. Age was the only significant predictor of death. CONCLUSIONS: Clinical assessment and brain magnetic resonance imaging aid in predicting incident clinical events and clinical deterioration in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. There is a bidirectional relationship between dementia and moderate or severe disability in predicting each other's onset. Active smoking is a modifiable risk factor associated with clinical progression in Notch3 mutation carriers. PMID- 26578661 TI - Derivation and Validation of a Novel Prognostic Scale (Modified-Stroke Subtype, Oxfordshire Community Stroke Project Classification, Age, and Prestroke Modified Rankin) to Predict Early Mortality in Acute Stroke. AB - BACKGROUND AND PURPOSE: The stroke subtype, Oxfordshire Community Stroke Project classification, age, and prestroke modified Rankin (SOAR) score is a prognostic scale proposed for early mortality prediction after acute stroke. We aimed to evaluate whether including a measure of initial stroke severity (National Institutes of Health Stroke Scale and modified-SOAR [mSOAR] scores) would improve the prognostic accuracy. METHODS: Using Anglia Stroke and Heart Clinical Network data, 2008 to 2011, we assessed the performance of SOAR and mSOAR against in hospital mortality using area under the receiver operating curve statistics. We externally validated the prognostic utility of SOAR and mSOAR using an independent cohort data set from Glasgow. We described calibration using Hosmer Lemeshow goodness-of-fit test. RESULTS: A total of 1002 patients were included in the derivation cohort, and 105 (10.5%) died as inpatients. The area under the receiver operating curves for outcome of early mortality derived from the SOAR and mSOAR scores were 0.79 (95% confidence interval, 0.75-0.84) and 0.83 (95% confidence interval, 0.79-0.86), respectively (P=0.001). The external validation data set contained 1012 patients with stroke; of which, 121 (12.0%) patients died within 90 days. The mSOAR scores identified the risk of early mortality ranging from 3% to 42%. External validation of mSOAR score yielded an area under the receiver operating curve of 0.84 (95% confidence interval, 0.82-0.88) for outcome of early mortality. Calibration was good (P=0.70 for the Hosmer-Lemeshow test). CONCLUSIONS: Adding National Institutes of Health Stroke Scale data to create a modified-SOAR score improved prognostic utility in both derivation and validation data sets. The mSOAR may have clinical utility by using easily available data to predict mortality. PMID- 26578660 TI - Multilingual Validation of the Questionnaire for Verifying Stroke-Free Status in West Africa. AB - BACKGROUND AND PURPOSE: The Questionnaire for Verifying Stroke-Free Status (QVSFS), a method for verifying stroke-free status in participants of clinical, epidemiological, and genetic studies, has not been validated in low-income settings where populations have limited knowledge of stroke symptoms. We aimed to validate QVSFS in 3 languages, Yoruba, Hausa and Akan, for ascertainment of stroke-free status of control subjects enrolled in an on-going stroke epidemiological study in West Africa. METHODS: Data were collected using a cross sectional study design where 384 participants were consecutively recruited from neurology and general medicine clinics of 5 tertiary referral hospitals in Nigeria and Ghana. Ascertainment of stroke status was by neurologists using structured neurological examination, review of case records, and neuroimaging (gold standard). Relative performance of QVSFS without and with pictures of stroke symptoms (pictograms) was assessed using sensitivity, specificity, positive predictive value, and negative predictive value. RESULTS: The overall median age of the study participants was 54 years and 48.4% were males. Of 165 stroke cases identified by gold standard, 98% were determined to have had stroke, whereas of 219 without stroke 87% were determined to be stroke-free by QVSFS. Negative predictive value of the QVSFS across the 3 languages was 0.97 (range, 0.93-1.00), sensitivity, specificity, and positive predictive value were 0.98, 0.82, and 0.80, respectively. Agreement between the questionnaire with and without the pictogram was excellent/strong with Cohen k=0.92. CONCLUSIONS: QVSFS is a valid tool for verifying stroke-free status across culturally diverse populations in West Africa. PMID- 26578662 TI - Socio-economic environment, area facilities and obesity and physical inactivity among children. AB - BACKGROUND: To evaluate whether the relationship between socio-economic environment and obesity and physical inactivity in children can be explained by household socio-economic position and area facilities. METHODS: Two indicators of the socio-economic context of neighbourhood of residence based on wealth and deprivation were estimated in a sample of 727 children and adolescents residents in Madrid (Spain). Multilevel logit models were used to calculate the relationship between each indicator and obesity and physical inactivity. RESULTS: After adjusting for household socio-economic position, obesity prevalence was 3.79 times higher among subjects living in deprived areas than among those living in non-deprived areas (CI: 1.95-7.34), and 2.38 higher among subjects living in less wealthy areas than in those living in wealthier areas (CI: 0.85-6.65). Adjustment for the availability of retail shops in subjects' neighbourhood of residence failed to change the magnitude of the association. Neither neighbourhood socio-economic context nor availability of sports facilities was related to physical inactivity. CONCLUSION: In the city of Madrid, socio-economic context of neighbourhood of residence shows an inverse relationship with obesity but not with physical inactivity among children. The relationship observed with obesity is not explained by the availability of area facilities. PMID- 26578663 TI - Effectiveness of an active commuting school-based intervention at 6-month follow up. AB - BACKGROUND: Active commuting to school may provide a significant source of physical activity in youth. Previous school-based intervention studies have shown a positive effect on increasing the frequency of active commuting to school in the short-term. However, how the observed effects are after the intervention remains to be investigated. The objective of the present study was to investigate the effects of a school-based intervention on active commuting to school at 6 month follow-up. METHODS: A total of 494 children ages 8-11 years from 5 primary schools were invited to the study. The schools were non-randomly allocated into control or experimental group. The experimental group received a 6-month programme focused on increasing active commuting to school, while the control group received no intervention. Frequency and mode of commuting to school were measured using a questionnaire at pre-intervention, post-intervention and 6-month follow-up. Children with valid data on commuting to school and provided data for sex, age and distance from home were included in this study (n= 206). RESULTS: There was a significant difference in the change of number of walk and bike travels per week between groups at 6-month follow-up (Control-Group = -0.4 +/- 0.3; Experimental-Group = 0.6 +/- 0.2;p = 0.019). Regarding the frequency of mode of commuting, only a change in walking to school was significantly different between the groups at 6-month follow-up (Difference Follow-up-Post-intervention) (Control-Group = -0.6 +/- 0.3; Experimental-Group = 0.7 +/- 0.2;p = 0.004). CONCLUSIONS: A 6-month school-based intervention focused on increasing active commuting to school could be effective strategy for increasing the frequency of active commuting to school even beyond the period of intervention. PMID- 26578664 TI - Insights into the concept of vitality: associations with participation and societal costs. AB - BACKGROUND: In healthcare, the focus is currently shifting from someone's disabilities to someone's abilities, which is also evident from the increasing focus on vitality. Vitality (here defined as energy, motivation and resilience) is an often used concept, which also aims at someone's capabilities. However, little is known about vitality yet; in particular about its association with participation and societal costs. METHODS: Within a cross-sectional design, information regarding vitality, participation and societal costs was collected among 8015 Dutch adults aged 20 years and over. Vitality was measured using the validated Dutch Vitality Questionnaire (Vita-16). Information on economic (i.e. want/able to work, work absenteeism, work performance), societal (i.e. voluntary work, informal care giving) and social participation (i.e. quantity and quality of social contacts) and societal costs (i.e. healthcare and work-related costs) was collected using an internet survey. RESULTS: Significant associations were found between vitality and various economic (i.e.sustainable employability:want to work: beta = 1.21, 95% CI: 0.99-1.43,able to work:beta = 2.09, 95% CI: 1.79 2.38;work absenteeism: OR = 0.75, 95% CI: 0.71-0.79;work performance:beta = 0.49, 95% CI: 0.46-0.52), societal (i.e.voluntary work, informal care) and social (i.e.quantity and quality of social contacts) participation measures, as well as between vitality and societal costs (i.e.healthcare costs:beta = -213.73, 95% CI: ?-311.13 to ?-107.08),absenteeism costs: beta = -338.57, 95% CI: ?-465.36 to ? 214.14 and presenteeism costs:beta = -1293.31, 95% CI: ?-1492.69 to ?-1088.95). CONCLUSION: This study showed significant positive associations between vitality and economic, societal and social participation and negative associations between vitality and societal costs. This may stimulate research on interventions enhancing and maintaining vitality and thereby contributing to improved participation and reduced costs. PMID- 26578665 TI - Correction. PMID- 26578666 TI - Initiatives to close the gap in inequalities in abortion provision in a remote and rural UK setting. PMID- 26578667 TI - Myocardial Hypoxia in Dilated Cardiomyopathy: Is it Just a Matter of Supply and Demand? PMID- 26578669 TI - Relapsing Leukemia Infiltrating the Heart. PMID- 26578668 TI - Psychosocial Factors, Exercise Adherence, and Outcomes in Heart Failure Patients: Insights From Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION). AB - BACKGROUND: Psychosocial factors may influence adherence with exercise training for heart failure (HF) patients. We aimed to describe the association between social support and barriers to participation with exercise adherence and clinical outcomes. METHODS AND RESULTS: Of patients enrolled in Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION), 2279 (97.8%) completed surveys to assess social support and barriers to exercise, resulting in the perceived social support score (PSSS) and barriers to exercise score (BTES). Higher PSSS indicated higher levels of social support, whereas higher BTES indicated more barriers to exercise. Exercise time at 3 and 12 months correlated with PSSS (r= 0.09 and r= 0.13, respectively) and BTES (r=-0.11 and r= 0.12, respectively), with higher exercise time associated with higher PSSS and lower BTES (All P<0.005). For cardiovascular death or HF hospitalization, there was a significant interaction between the randomization group and BTES (P=0.035), which corresponded to a borderline association between increasing BTES and cardiovascular death or HF hospitalization in the exercise group (hazard ratio 1.25, 95% confidence interval 0.99, 1.59), but no association in the usual care group (hazard ratio 0.83, 95% confidence interval 0.66, 1.06). CONCLUSIONS: Poor social support and high barriers to exercise were associated with lower exercise time. PSSS did not impact the effect of exercise training on outcomes. However, for cardiovascular death or HF hospitalization, exercise training had a greater impact on patients with lower BTES. Given that exercise training improves outcomes in HF patients, assessment of perceived barriers may facilitate individualized approaches to implement exercise training therapy in clinical practice. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00047437. PMID- 26578670 TI - Isolated Severe Right Ventricle Endomyocardial Fibrosis in a Child: Vanishing Tropical Disease Revisited. PMID- 26578672 TI - Correction. PMID- 26578671 TI - Letter by Teerlink et al Regarding Article, "Myosin Activator Omecamtiv Mecarbil Increases Myocardial Oxygen Consumption and Impairs Cardiac Efficiency Mediated by Resting Myosin ATPase Activity". PMID- 26578673 TI - Development of Heptylmannoside-Based Glycoconjugate Antiadhesive Compounds against Adherent-Invasive Escherichia coli Bacteria Associated with Crohn's Disease. AB - The ileal lesions of Crohn's disease (CD) patients are colonized by adherent invasive Escherichia coli (AIEC) bacteria. These bacteria adhere to mannose residues expressed by CEACAM6 on host cells in a type 1 pilus-dependent manner. In this study, we investigated different antagonists of FimH, the adhesin of type 1 pili, for their ability to block AIEC adhesion to intestinal epithelial cells (IEC). Monovalent and multivalent derivatives of n-heptyl alpha-d-mannoside (HM), a nanomolar antagonist of FimH, were tested in vitro in IEC infected with the AIEC LF82 strain and in vivo by oral administration to CEACAM6-expressing mice infected with LF82 bacteria. In vitro, multivalent derivatives were more potent than the monovalent derivatives, with a gain of efficacy superior to their valencies, probably owing to their ability to form bacterial aggregates. Of note, HM and the multi-HM glycoconjugates exhibited lower efficacy in vivo in decreasing LF82 gut colonization. Interestingly, HM analogues functionalized with an isopropylamide (1A-HM) or beta-cyclodextrin pharmacophore at the end of the heptyl tail (1CD-HM) exerted beneficial effects in vivo. These two compounds strongly decreased the amount of LF82 bacteria in the feces of mice and that of bacteria associated with the gut mucosa when administered orally at a dose of 10 mg/kg of body weight after infection. Importantly, signs of colitis and intestinal inflammation induced by LF82 infection were also prevented. These results highlight the potential of the antiadhesive compounds to treat CD patients abnormally colonized by AIEC bacteria and point to an alternative to the current approach focusing on blocking proinflammatory mediators. IMPORTANCE: Current treatments for Crohn's disease (CD), including immunosuppressive agents, anti-tumor necrosis factor alpha (anti-TNF-alpha) and anti-integrin antibodies, focus on the symptoms but not on the cause of the disease. Adherent-invasive Escherichia coli (AIEC) bacteria abnormally colonize the ileal mucosa of CD patients via the interaction of the mannose-specific adhesin FimH of type 1 pili with CEACAM6 mannosylated proteins expressed on the epithelial cell surface. Thus, we decided to develop an antiadhesive strategy based on synthetic FimH antagonists specifically targeting AIEC bacteria that would decrease intestinal inflammation. Heptylmannoside (HM)-based glycocompounds strongly inhibit AIEC adhesion to intestinal epithelial cells in vitro. The antiadhesive effect of two of these compounds of relatively simple chemical structure was also observed in vivo in AIEC-infected CEACAM6-expressing mice and was associated with a reduction in the signs of colitis. These results suggest a new therapeutic approach for CD patients colonized by AIEC bacteria, based on the development of synthetic FimH antagonists. PMID- 26578674 TI - The Complete Genome Sequence of the Emerging Pathogen Mycobacterium haemophilum Explains Its Unique Culture Requirements. AB - Mycobacterium haemophilum is an emerging pathogen associated with a variety of clinical syndromes, most commonly skin infections in immunocompromised individuals. M. haemophilum exhibits a unique requirement for iron supplementation to support its growth in culture, but the basis for this property and how it may shape pathogenesis is unclear. Using a combination of Illumina, PacBio, and Sanger sequencing, the complete genome sequence of M. haemophilum was determined. Guided by this sequence, experiments were performed to define the basis for the unique growth requirements of M. haemophilum. We found that M. haemophilum, unlike many other mycobacteria, is unable to synthesize iron-binding siderophores known as mycobactins or to utilize ferri-mycobactins to support growth. These differences correlate with the absence of genes associated with mycobactin synthesis, secretion, and uptake. In agreement with the ability of heme to promote growth, we identified genes encoding heme uptake machinery. Consistent with its propensity to infect the skin, we show at the whole-genome level the genetic closeness of M. haemophilum with Mycobacterium leprae, an organism which cannot be cultivated in vitro, and we identify genes uniquely shared by these organisms. Finally, we identify means to express foreign genes in M. haemophilum. These data explain the unique culture requirements for this important pathogen, provide a foundation upon which the genome sequence can be exploited to improve diagnostics and therapeutics, and suggest use of M. haemophilum as a tool to elucidate functions of genes shared with M. leprae. IMPORTANCE: Mycobacterium haemophilum is an emerging pathogen with an unknown natural reservoir that exhibits unique requirements for iron supplementation to grow in vitro. Understanding the basis for this iron requirement is important because it is fundamental to isolation of the organism from clinical samples and environmental sources. Defining the molecular basis for M. haemophilium's growth requirements will also shed new light on mycobacterial strategies to acquire iron and can be exploited to define how differences in such strategies influence pathogenesis. Here, through a combination of sequencing and experimental approaches, we explain the basis for the iron requirement. We further demonstrate the genetic closeness of M. haemophilum and Mycobacterium leprae, the causative agent of leprosy which cannot be cultured in vitro, and we demonstrate methods to genetically manipulate M. haemophilum. These findings pave the way for the use of M. haemophilum as a model to elucidate functions of genes shared with M. leprae. PMID- 26578675 TI - Iron Modulates Butyrate Production by a Child Gut Microbiota In Vitro. AB - The aim of this study was to investigate the effect of iron (Fe) availability on butyrate production in the complex bacterial ecosystem of the human gut. Hence, different Fe availabilities were mimicked in an in vitro colonic fermentation model (the polyfermenter intestinal model called PolyFermS) inoculated with immobilized gut microbiota from a child and in batch cultures of the butyrate producer Roseburia intestinalis. Shifts in the microbial community (16S rRNA sequencing and quantitative PCR), metabolic activity (high-performance liquid chromatography), and expression of genes involved in butyrate production were assessed. In the PolyFermS, moderate Fe deficiency resulted in a 1.4-fold increase in butyrate production and a 5-fold increase in butyryl-coenzyme A (CoA):acetate CoA-transferase gene expression, while very strong Fe deficiency significantly decreased butyrate concentrations and butyrate-producing bacteria compared with the results under normal Fe conditions. Batch cultures of R. intestinalis grown in a low-Fe environment preferentially produced lactate and had reduced butyrate and hydrogen production, in parallel with upregulation of the lactate dehydrogenase gene and downregulation of the pyruvate:ferredoxin oxidoreductase gene. In contrast, under high-Fe conditions, R. intestinalis cultures showed enhanced butyrate and hydrogen production, along with increased expression of the corresponding genes, compared with the results under normal-Fe conditions. Our data reveal the strong regulatory effect of Fe on gut microbiota butyrate producers and on the concentrations of butyrate, which contributes to the maintenance of host gut health. IMPORTANCE: Fe deficiency is one of the most common nutritional deficiencies worldwide and can be corrected by Fe supplementation. In this in vitro study, we show that environmental Fe concentrations in a continuous gut fermentation model closely mimicking a child's gut microbiota strongly affect the composition of the gut microbiome and its metabolic activity, particularly butyrate production. The differential expression of genes involved in the butyrate production pathway under different Fe conditions and the enzyme cofactor role of Fe explain the observed modulation of butyrate production. Our data reveal that the level of dietary Fe reaching the colon affects the microbiome, and its essential function of providing the host with beneficial butyrate. PMID- 26578676 TI - Experimental Infection of Snakes with Ophidiomyces ophiodiicola Causes Pathological Changes That Typify Snake Fungal Disease. AB - Snake fungal disease (SFD) is an emerging skin infection of wild snakes in eastern North America. The fungus Ophidiomyces ophiodiicola is frequently associated with the skin lesions that are characteristic of SFD, but a causal relationship between the fungus and the disease has not been established. We experimentally infected captive-bred corn snakes (Pantherophis guttatus) in the laboratory with pure cultures of O. ophiodiicola. All snakes in the infected group (n = 8) developed gross and microscopic lesions identical to those observed in wild snakes with SFD; snakes in the control group (n = 7) did not develop skin infections. Furthermore, the same strain of O. ophiodiicola used to inoculate snakes was recovered from lesions of all animals in the infected group, but no fungi were isolated from individuals in the control group. Monitoring progression of lesions throughout the experiment captured a range of presentations of SFD that have been described in wild snakes. The host response to the infection included marked recruitment of granulocytes to sites of fungal invasion, increased frequency of molting, and abnormal behaviors, such as anorexia and resting in conspicuous areas of enclosures. While these responses may help snakes to fight infection, they could also impact host fitness and may contribute to mortality in wild snakes with chronic O. ophiodiicola infection. This work provides a basis for understanding the pathogenicity of O. ophiodiicola and the ecology of SFD by using a model system that incorporates a host species that is easy to procure and maintain in the laboratory. IMPORTANCE: Skin infections in snakes, referred to as snake fungal disease (SFD), have been reported with increasing frequency in wild snakes in the eastern United States. While most of these infections are associated with the fungus Ophidiomyces ophiodiicola, there has been no conclusive evidence to implicate this fungus as a primary pathogen. Furthermore, it is not understood why the infections affect different host populations differently. Our experiment demonstrates that O. ophiodiicola is the causative agent of SFD and can elicit pathological changes that likely impact fitness of wild snakes. This information, and the laboratory model we describe, will be essential in addressing unresolved questions regarding disease ecology and outcomes of O. ophiodiicola infection and helping to conserve snake populations threatened by the disease. The SFD model of infection also offers utility for exploring larger concepts related to comparative fungal virulence, host response, and host-pathogen evolution. PMID- 26578677 TI - RNA Futile Cycling in Model Persisters Derived from MazF Accumulation. AB - Metabolism plays an important role in the persister phenotype, as evidenced by the number of strategies that perturb metabolism to sabotage this troublesome subpopulation. However, the absence of techniques to isolate high-purity populations of native persisters has precluded direct measurement of persister metabolism. To address this technical challenge, we studied Escherichia coli populations whose growth had been inhibited by the accumulation of the MazF toxin, which catalyzes RNA cleavage, as a model system for persistence. Using chromosomally integrated, orthogonally inducible promoters to express MazF and its antitoxin MazE, bacterial populations that were almost entirely tolerant to fluoroquinolone and beta-lactam antibiotics were obtained upon MazF accumulation, and these were subjected to direct metabolic measurements. While MazF model persisters were nonreplicative, they maintained substantial oxygen and glucose consumption. Metabolomic analysis revealed accumulation of all four ribonucleotide monophosphates (NMPs). These results are consistent with a MazF catalyzed RNA futile cycle, where the energy derived from catabolism is dissipated through continuous transcription and MazF-mediated RNA degradation. When transcription was inhibited, oxygen consumption and glucose uptake decreased, and nucleotide triphosphates (NTPs) and NTP/NMP ratios increased. Interestingly, the MazF-inhibited cells were sensitive to aminoglycosides, and this sensitivity was blocked by inhibition of transcription. Thus, in MazF model persisters, futile cycles of RNA synthesis and degradation result in both significant metabolic demands and aminoglycoside sensitivity. IMPORTANCE: Metabolism plays a critical role in controlling each stage of bacterial persistence (shutdown, stasis, and reawakening). In this work, we generated an E. coli strain in which the MazE antitoxin and MazF toxin were artificially and independently inducible, and we used this strain to generate model persisters and study their metabolism. We found that even though growth of the model persisters was inhibited, they remained highly metabolically active. We further uncovered a futile cycle driven by continued transcription and MazF-mediated transcript degradation that dissipated the energy derived from carbon catabolism. Interestingly, the existence of this futile cycle acted as an Achilles' heel for MazF model persisters, rendering them vulnerable to killing by aminoglycosides. PMID- 26578678 TI - Lineage-Specific Methyltransferases Define the Methylome of the Globally Disseminated Escherichia coli ST131 Clone. AB - Escherichia coli sequence type 131 (ST131) is a clone of uropathogenic E. coli that has emerged rapidly and disseminated globally in both clinical and community settings. Members of the ST131 lineage from across the globe have been comprehensively characterized in terms of antibiotic resistance, virulence potential, and pathogenicity, but to date nothing is known about the methylome of these important human pathogens. Here we used single-molecule real-time (SMRT) PacBio sequencing to determine the methylome of E. coli EC958, the most-well characterized completely sequenced ST131 strain. Our analysis of 52,081 methylated adenines in the genome of EC958 discovered three (m6)A methylation motifs that have not been described previously. Subsequent SMRT sequencing of isogenic knockout mutants identified the two type I methyltransferases (MTases) and one type IIG MTase responsible for (m6)A methylation of novel recognition sites. Although both type I sites were rare, the type IIG sites accounted for more than 12% of all methylated adenines in EC958. Analysis of the distribution of MTase genes across 95 ST131 genomes revealed their prevalence is highly conserved within the ST131 lineage, with most variation due to the presence or absence of mobile genetic elements on which individual MTase genes are located. IMPORTANCE: DNA modification plays a crucial role in bacterial regulation. Despite several examples demonstrating the role of methyltransferase (MTase) enzymes in bacterial virulence, investigation of this phenomenon on a whole genome scale has remained elusive until now. Here we used single-molecule real time (SMRT) sequencing to determine the first complete methylome of a strain from the multidrug-resistant E. coli sequence type 131 (ST131) lineage. By interrogating the methylome computationally and with further SMRT sequencing of isogenic mutants representing previously uncharacterized MTase genes, we defined the target sequences of three novel ST131-specific MTases and determined the genomic distribution of all MTase target sequences. Using a large collection of 95 previously sequenced ST131 genomes, we identified mobile genetic elements as a major factor driving diversity in DNA methylation patterns. Overall, our analysis highlights the potential for DNA methylation to dramatically influence gene regulation at the transcriptional level within a well-defined E. coli clone. PMID- 26578680 TI - Cryptococcus gattii in the Age of Whole-Genome Sequencing. AB - Cryptococcus gattii, the sister species of Cryptococcus neoformans, is an emerging pathogen which gained importance in connection with the ongoing cryptococcosis outbreak on Vancouver Island. Many molecular studies have divided this species into for major lineages: VGI, VGII, VGIII, and VGIV. This commentary summarizes the whole-genome sequencing (WGS) studies that have been carried out with this species, re-emphasizing the phylogenetic relationships, showing chromosomal rearrangements between those four groups, and identifying VGII as ancestral population within C. gattii. In addition, WGS specific to VGII, containing the Vancouver Island outbreak genotypes and those from the Pacific Northwest region of the United States, has placed the origin of this lineage within South America and identified specific genes responsible for either brain or lung infection. It also showed, that many genotypes are spread across a number of different continents, as has been previously shown by multilocus sequence typing (MLST). In addition, it showed that recombination occurs more frequently between mitochondrial than nuclear genomes. PMID- 26578679 TI - DNA-Containing Immunocomplexes Promote Inflammasome Assembly and Release of Pyrogenic Cytokines by CD14+ CD16+ CD64high CD32low Inflammatory Monocytes from Malaria Patients. AB - High levels of circulating immunocomplexes (ICs) are found in patients with either infectious or sterile inflammation. We report that patients with either Plasmodium falciparum or Plasmodium vivax malaria have increased levels of circulating anti-DNA antibodies and ICs containing parasite DNA. Upon stimulation with malaria-induced ICs, monocytes express an NF-kappaB transcriptional signature. The main source of IC-induced proinflammatory cytokines (i.e., tumor necrosis factor alpha [TNF-alpha] and interleukin-1beta [IL-1beta])in peripheral blood mononuclear cells from acute malaria patients was found to be a CD14(+) CD16 (FcgammaRIIIA)(+) CD64 (FcgammaRI)(high) CD32 (FcgammaRIIB)(low) monocyte subset. Monocytes from convalescent patients were predominantly of the classical phenotype (CD14(+) CD16(-)) that produces high levels of IL-10 and lower levels of TNF-alpha and IL-1beta in response to ICs. Finally, we report a novel role for the proinflammatory activity of ICs by demonstrating their ability to induce inflammasome assembly and caspase-1 activation in human monocytes. These findings illuminate our understanding of the pathogenic role of ICs and monocyte subsets and may be relevant for future development of immunity-based interventions with broad applications to systemic inflammatory diseases. IMPORTANCE: Every year, there are approximately 200 million cases of Plasmodium falciparum and P. vivax malaria, resulting in nearly 1 million deaths, most of which are children. Decades of research on malaria pathogenesis have established that the clinical manifestations are often a consequence of the systemic inflammation elicited by the parasite. Recent studies indicate that parasite DNA is a main proinflammatory component during infection with different Plasmodium species. This finding resembles the mechanism of disease in systemic lupus erythematosus, where host DNA plays a central role in stimulating an inflammatory process and self-damaging reactions. In this study, we disclose the mechanism by which ICs containing Plasmodium DNA activate innate immune cells and consequently stimulate systemic inflammation during acute episodes of malaria. Our results further suggest that Toll-like receptors and inflammasomes have a central role in malaria pathogenesis and provide new insights toward developing novel therapeutic interventions for this devastating disease. PMID- 26578681 TI - Dual RNA-seq of Nontypeable Haemophilus influenzae and Host Cell Transcriptomes Reveals Novel Insights into Host-Pathogen Cross Talk. AB - The ability to adhere and adapt to the human respiratory tract mucosa plays a pivotal role in the pathogenic lifestyle of nontypeable Haemophilus influenzae (NTHi). However, the temporal events associated with a successful colonization have not been fully characterized. In this study, by reconstituting the ciliated human bronchial epithelium in vitro, we monitored the global transcriptional changes in NTHi and infected mucosal epithelium simultaneously for up to 72 h by dual RNA sequencing. The initial stage of colonization was characterized by the binding of NTHi to ciliated cells. Temporal profiling of host mRNA signatures revealed significant dysregulation of the target cell cytoskeleton elicited by bacterial infection, with a profound effect on the intermediate filament network and junctional complexes. In response to environmental stimuli of the host epithelium, NTHi downregulated its central metabolism and increased the expression of transporters, indicating a change in the metabolic regime due to the availability of host substrates. Concurrently, the oxidative environment generated by infected cells instigated bacterial expression of stress-induced defense mechanisms, including the transport of exogenous glutathione and activation of the toxin-antitoxin system. The results of this analysis were validated by those of confocal microscopy, Western blotting, Bio-plex, and real time quantitative reverse transcription-PCR (qRT-PCR). Notably, as part of our screening for novel signatures of infection, we identified a global profile of noncoding transcripts that are candidate small RNAs (sRNAs) regulated during human host infection in Haemophilus species. Our data, by providing a robust and comprehensive representation of the cross talk between the host and invading pathogen, provides important insights into NTHi pathogenesis and the development of efficacious preventive strategies. IMPORTANCE: Simultaneous monitoring of infection-linked transcriptome alterations in an invading pathogen and its target host cells represents a key strategy for identifying regulatory responses that drive pathogenesis. In this study, we report the progressive events of NTHi colonization in a highly differentiated model of ciliated bronchial epithelium. Genome-wide transcriptome maps of NTHi during infection provided mechanistic insights into bacterial adaptive responses to the host niche, with modulation of the central metabolism as an important signature of the evolving milieu. Our data indicate that infected epithelia respond by substantial alteration of the cytoskeletal network and cytokine repertoire, revealing a dynamic cross talk that is responsible for the onset of inflammation. This work significantly enhances our understanding of the means by which NTHi promotes infection on human mucosae and reveals novel strategies exploited by this important pathogen to cause invasive disease. PMID- 26578682 TI - Posttranslational Modification of HOIP Blocks Toll-Like Receptor 4-Mediated Linear-Ubiquitin-Chain Formation. AB - Linear ubiquitination is an atypical posttranslational modification catalyzed by the linear-ubiquitin-chain assembly complex (LUBAC), containing HOIP, HOIL-1L, and Sharpin. LUBAC facilitates NF-kappaB activation and inflammation upon receptor stimulation by ligating linear ubiquitin chains to critical signaling molecules. Indeed, linear-ubiquitination-dependent signaling is essential to prevent pyogenic bacterial infections that can lead to death. While linear ubiquitination is essential for intracellular receptor signaling upon microbial infection, this response must be measured and stopped to avoid tissue damage and autoimmunity. While LUBAC is activated upon bacterial stimulation, the mechanisms regulating LUBAC activity in response to bacterial stimuli have remained elusive. We demonstrate that LUBAC activity itself is downregulated through ubiquitination, specifically, ubiquitination of the catalytic subunit HOIP at the carboxyl-terminal lysine 1056. Ubiquitination of Lys1056 dynamically altered HOIP conformation, resulting in the suppression of its catalytic activity. Consequently, HOIP Lys1056-to-Arg mutation led not only to persistent LUBAC activity but also to prolonged NF-kappaB activation induced by bacterial lipopolysaccharide-mediated Toll-like receptor 4 (TLR4) stimulation, whereas it showed no effect on NF-kappaB activation induced by CD40 stimulation. This study describes a novel posttranslational regulation of LUBAC-mediated linear ubiquitination that is critical for specifically directing TLR4-mediated NF kappaB activation. IMPORTANCE: Posttranslational modification of proteins enables cells to respond quickly to infections and immune stimuli in a tightly controlled manner. Specifically, covalent modification of proteins with the small protein ubiquitin is essential for cells to initiate and terminate immune signaling in response to bacterial and viral infection. This process is controlled by ubiquitin ligase enzymes, which themselves must be regulated to prevent persistent and deleterious immune signaling. However, how this regulation is achieved is poorly understood. This paper reports a novel ubiquitination event of the atypical ubiquitin ligase HOIP that is required to terminate bacterial lipopolysaccharide (LPS)-induced TLR4 immune signaling. Ubiquitination causes the HOIP ligase to undergo a conformational change, which blocks its enzymatic activity and ultimately terminates LPS-induced TLR4 signaling. These findings provide a new mechanism for controlling HOIP ligase activity that is vital to properly regulate a proinflammatory immune response. PMID- 26578683 TI - A Single Human Cerebral Malaria Histopathologic Study Can Be Worth a Thousand Experiments. AB - Severe malaria is a density-dependent disease that comprises infected-erythrocyte sequestration, with or without monocytic infiltration, as seen in renal, placental, and lung tissues from severe malaria patients. HIV induces a chronic proinflammatory state with higher numbers of inflammasome-activated monocytes and platelets circulating. The epidemiological and pathological study of S. E. Hochman et al. that was published in a recent issue of mBio (Hochman SE, Madaline TF, Wassmer SC, Mbale E, Choi N, et al., mBio 6:e01390-15, 2015, doi:10.1128/mBio.01390-15) analyzes a large cohort of Malawian children and shows that cerebral malaria in younger HIV-negative children presents as an acute disease predominated by sequestered infected erythrocytes. In contrast, they show that case presentation in older HIV-positive children is as a more lethal acute on chronic disease marked by double the monocytic infiltrates and 5 times as many platelets. This study suggests that cerebral involvement in severe malaria is a pathology similar to that of other organ involvement of severe malaria, with a bias in HIV-positive individuals toward more monocytic infiltrates. The study also addresses the important association of severe malaria and HIV prevalence. PMID- 26578684 TI - KDR Amplification Is Associated with VEGF-Induced Activation of the mTOR and Invasion Pathways but does not Predict Clinical Benefit to the VEGFR TKI Vandetanib. AB - PURPOSE: VEGF pathway inhibitors have been investigated as therapeutic agents in the treatment of non-small cell lung cancer (NSCLC) because of its central role in angiogenesis. These agents have improved survival in patients with advanced NSCLC, but the effects have been modest. Although VEGFR2/KDRis typically localized to the vasculature, amplification ofKDRhas reported to occur in 9% to 30% of the DNA from different lung cancers. We investigated the signaling pathways activated downstream ofKDRand whetherKDRamplification is associated with benefit in patients with NSCLC treated with the VEGFR inhibitor vandetanib. METHODS: NSCLC cell lines with or withoutKDRamplification were studied for the effects of VEGFR tyrosine kinase inhibitors (TKI) on cell viability and migration. Archival tumor samples collected from patients with platinum refractory NSCLC in the phase III ZODIAC study of vandetanib plus docetaxel or placebo plus docetaxel (N= 294) were screened forKDRamplification by FISH. RESULTS: KDRamplification was associated with VEGF-induced activation of mTOR, p38, and invasiveness in NSCLC cell lines. However, VEGFR TKIs did not inhibit proliferation of NSCLC cell lines withKDRamplification. VEGFR inhibition decreased cell motility as well as expression of HIF1alpha inKDR-amplified NSCLC cells. In the ZODIAC study,KDRamplification was observed in 15% of patients and was not associated with improved progression-free survival, overall survival, or objective response rate for the vandetanib arm. CONCLUSIONS: Preclinical studies suggestKDRactivates invasion but not survival pathways inKDR-amplified NSCLC models. Patients with NSCLC whose tumor hadKDRamplification were not associated with clinical benefit for vandetanib in combination with docetaxel. PMID- 26578685 TI - LincRNA-Cox2 modulates TNF-alpha-induced transcription of Il12b gene in intestinal epithelial cells through regulation of Mi-2/NuRD-mediated epigenetic histone modifications. AB - Long intergenic noncoding RNAs (lincRNAs) can regulate the transcription of inflammatory genes and thus may represent a new group of inflammatory mediators with a potential pathogenic role in inflammatory diseases. Here, our genome-wide transcriptomic data show that TNF-alpha stimulation caused up-regulation of 171 lincRNAs and down-regulation of 196 lincRNAs in murine intestinal epithelial cells in culture. One of the up-regulated lincRNAs, lincRNA-Cox2, is an early responsive lincRNA induced by TNF-alpha through activation of the NF-KB signaling pathway. Knockdown of lincRNA-Cox2 resulted in reprogramming of the gene expression profile in intestinal epithelial cells in response to TNF-alpha stimulation. Specifically, lincRNA-Cox2 silencing significantly (P < 0.05) enhanced the transcription of Il12b, a secondary late-responsive gene induced by TNF-alpha. Mechanistically, lincRNA-Cox2 promoted the recruitment of the Mi 2/nucleosome remodeling and deacetylase (Mi-2/NuRD) repressor complex to the Il12b promoter region. Recruitment of the Mi-2/NuRD complex was associated with decreased H3K27 acetylation and increased H3K27 dimethylation at the Il12b promoter region, which might contribute to Il12b trans-suppression by lincRNA Cox2. Thus, our data demonstrate a novel mechanism of epigenetic modulation by lincRNA-Cox2 on Il12b transcription, supporting an important role for lincRNAs in the regulation of intestinal epithelial inflammatory responses. PMID- 26578686 TI - Phosphorylation of murine double minute-2 on Ser166 is downstream of VEGF-A in exercised skeletal muscle and regulates primary endothelial cell migration and FoxO gene expression. AB - We demonstrated in a previous study that murine double minute (Mdm)-2 is essential for exercise-induced skeletal muscle angiogenesis. In the current study, we investigated the mechanisms that regulate Mdm2 activity in response to acute exercise and identified VEGF-A as a key stimulator of Mdm2 phosphorylation on Ser(166) (p-Ser166-Mdm2). VEGF-A and p-Ser166-Mdm2 protein levels were measured in human and rodent muscle biopsy specimens after 1 bout of exercise. VEGF-A-dependent Mdm2 phosphorylation was demonstrated in vivo in mice harboring myofiber-specific deletion of VEGF-A (mVEGF(-/-)) and in vitro in primary human and rodent endothelial cells (ECs). Exercise increased VEGF-A and p-Ser166-Mdm2 protein levels respectively by 157 and 68% in human muscle vs. pre-exercise levels. Similar results were observed in exercised rodent muscles compared to sedentary controls; however, exercise-induced Mdm2 phosphorylation was significantly attenuated in mVEGF(-/-) mice. Recombinant VEGF-A elevated p-Ser166 Mdm2 by 50-125% and stimulated migration by 33% in ECs when compared to untreated cells, whereas the Mdm2 antagonist Nutlin-3a abrogated VEGF-driven EC migration. Finally, overexpression of a Ser166-Mdm2 phosphorylation mimetic increased EC migration, increased Mdm2 to FoxO1 binding (+55%), and decreased FoxO1-dependent gene expression compared with ECs overexpressing WT-Mdm2. Our results suggest that VEGF-mediated Mdm2 phosphorylation on Ser(166) is a novel proangiogenic pathway within the skeletal muscle. PMID- 26578687 TI - C1q/TNF-related protein-1 functions to protect against acute ischemic injury in the heart. AB - Obesity is associated with an increased risk of cardiovascular disease. C1q/TNF related protein (CTRP)-1 is a poorly characterized adipokine that is up-regulated in association with ischemic heart disease. We investigated the role of CTRP1 in myocardial ischemia injury. CTRP1-knockout mice showed increased myocardial infarct size, cardiomyocyte apoptosis, and proinflammatory gene expression after I/R compared with wild-type (WT) mice. In contrast, systemic delivery of CTRP1 attenuated myocardial damage after I/R in WT mice. Treatment of cardiomyocytes with CTRP1 led to reduction of hypoxia-reoxygenation-induced apoptosis and lipopolysaccharide-stimulated expression of proinflammatory cytokines, which was reversed by inhibition of sphingosine-1-phosphate (S1P) signaling. Treatment of cardiomyocytes with CTRP1 also resulted in the increased production of cAMP, which was blocked by suppression of S1P signaling. The antiapoptotic and anti inflammatory actions of CTRP1 were cancelled by inhibition of adenylyl cyclase or knockdown of adiponectin receptor 1. Furthermore, blockade of S1P signaling reversed CTRP1-mediated inhibition of myocardial infarct size, apoptosis, and inflammation after I/R in vivo. These data indicate that CTRP1 protects against myocardial ischemic injury by reducing apoptosis and inflammatory response through activation of the S1P/cAMP signaling pathways in cardiomyocytes, suggesting that CTRP1 plays a crucial role in the pathogenesis of ischemic heart disease. PMID- 26578689 TI - Cleaving for growth: threonine aspartase 1--a protease relevant for development and disease. AB - From the beginning of life, proteases are key to organismal development comprising morphogenesis, cellular differentiation, and cell growth. Regulated proteolytic activity is essential for the orchestration of multiple developmental pathways, and defects in protease activity can account for multiple disease patterns. The highly conserved protease threonine aspartase 1 is a member of such developmental proteases and critically involved in the regulation of complex processes, including segmental identity, head morphogenesis, spermatogenesis, and proliferation. Additionally, threonine aspartase 1 is overexpressed in numerous liquid as well as in solid malignancies. Although threonine aspartase 1 is able to cleave the master regulator mixed lineage leukemia protein as well as other regulatory proteins in humans, our knowledge of its detailed pathobiological function and the underlying molecular mechanisms contributing to development and disease is still incomplete. Moreover, neither effective genetic nor chemical inhibitors for this enzyme are available so far precluding the detailed dissection of the pathobiological functions of threonine aspartase 1. Here, we review the current knowledge of the structure-function relationship of threonine aspartase 1 and its mechanistic impact on substrate-mediated coordination of the cell cycle and development. We discuss threonine aspartase 1-mediated effects on cellular transformation and conclude by presenting a short overview of recent interference strategies. PMID- 26578688 TI - The beta2-adrenoceptor activates a positive cAMP-calcium feedforward loop to drive breast cancer cell invasion. AB - Activation of the sympathetic nervous system by stress increases breast cancer metastasis in vivo. Preclinical studies suggest that stress activates beta adrenoceptors (betaARs) to enhance metastasis from primary tumors and that beta blockers may be protective in breast cancer. However, the subtype of betaAR that mediates this effect, as well as the signaling mechanisms underlying increased tumor cell dissemination, remain unclear. We show that the beta2AR is the only functionally relevant betaAR subtype in the highly metastatic human breast cancer cell line MDA-MB-231HM. beta2AR activation results in elevated cAMP (formoterol pEC50 9.86 +/- 0.32), increased intracellular Ca(2+) (formoterol pEC50 8.20 +/- 0.33) and reduced phosphorylated ERK (pERK; formoterol pIC50 11.62 +/- 0.31). We demonstrate that a highly amplified positive feedforward loop between the cAMP and Ca(2+) pathways is responsible for efficient inhibition of basal pERK. Importantly, activation of the beta2AR increased invasion (formoterol area under the curve [AUC] relative to vehicle: 1.82 +/- 0.36), which was dependent on the cAMP/Ca(2+) loop (formoterol AUC in the presence of 2'5'-dideoxyadenosine 0.64 +/ 0.03, or BAPTA-AM 0.45 +/- 0.23) but independent of inhibition of basal pERK1/2 (vehicle AUC with U0126 0.60 +/- 0.30). Specifically targeting the positive feedforward cAMP/Ca(2+) loop may be beneficial for the development of therapeutics to slow disease progression in patients with breast cancer. PMID- 26578690 TI - LC-MS/MS Measurement of Parathyroid Hormone-Related Peptide. AB - INTRODUCTION: Parathyroid hormone-related peptide (PTHrP) is involved in activating pathways, allowing tumor cells to form bone metastases. Measurement of PTHrP is used for the diagnosis and clinical management of patients suspected of hypercalcemia of malignancy. We developed an LC-MS/MS method for measuring PTHrP, established sex-specific reference intervals, and assessed the method's performance. METHODS: PTHrP was enriched from plasma samples with rabbit polyclonal anti-PTHrP antibody conjugated to magnetic beads. Enriched PTHrP was digested with trypsin, and PTHrP-specific tryptic peptide was analyzed with 2 dimensional LC-MS/MS in multiple reaction monitoring mode. RESULTS: The lower limit of quantification was 0.6 pmol/L, and the upper limit of linearity was 600 pmol/L. Total imprecision was <10%. Very poor agreement was observed with the RIA (n = 207; Deming regression RIA = 0.059 * LC-MS/MS - 1.8, r = 0.483; Sy|x = 3.9). Evaluation of the clinical performance of the assay using samples from patients with and without hypercalcemia (n = 199) resulted in an area under the ROC curve of 0.874. In sets of consecutively analyzed routine samples of patients assessed for hypercalcemia, the PTHrP positivity rate by RIA (n = 1376) was 1.9%, and 26.6% by LC-MS/MS (n = 1705). Concentrations were below the lower limit of quantification in 95.6% of the samples by RIA and 2.0% by LC-MS/MS. CONCLUSIONS: PTHrP is a normal constituent in circulating blood and its concentrations are substantially underestimated by commercial RIAs, causing false-negative results in samples from patients suspected of hypercalcemia. Our observations suggest a link between increased concentrations of PTHrP in postmenopausal women with low body mass index and increased incidence of osteoporosis. PMID- 26578691 TI - Potential of Mass Spectrometry in Developing Clinical Laboratory Biomarkers of Nonvolatiles in Exhaled Breath. AB - BACKGROUND: Exhaled breath contains nonvolatile substances that are part of aerosol particles of submicrometer size. These particles are formed and exhaled as a result of normal breathing and contain material from distal airways of the respiratory system. Exhaled breath can be used to monitor biomarkers of both endogenous and exogenous origin and constitutes an attractive specimen for medical investigations. CONTENT: This review summarizes the present status regarding potential biomarkers of nonvolatile compounds in exhaled breath. The field of exhaled breath condensate is briefly reviewed, together with more recent work on more selective collection procedures for exhaled particles. The relation of these particles to the surfactant in the terminal parts of the respiratory system is described. The literature on potential endogenous low molecular weight compounds as well as protein biomarkers is reviewed. The possibility to measure exposure to therapeutic and abused drugs is demonstrated. Finally, the potential future role and importance of mass spectrometry is discussed. SUMMARY: Nonvolatile compounds exit the lung as aerosol particles that can be sampled easily and selectively. The clinical applications of potential biomarkers in exhaled breath comprise diagnosis of disease, monitoring of disease progress, monitoring of drug therapy, and toxicological investigations. PMID- 26578692 TI - Photosystem II Assembly Steps Take Place in the Thylakoid Membrane of the Cyanobacterium Synechocystis sp. PCC6803. AB - Thylakoid biogenesis is an intricate process requiring accurate and timely assembly of proteins, pigments and other cofactors into functional, photosynthetically competent membranes. PSII assembly is studied in particular as its core protein, D1, is very susceptible to photodamage and has a high turnover rate, particularly in high light. PSII assembly is a modular process, with assembly steps proceeding in a specific order. Using aqueous two-phase partitioning to separate plasma membranes (PM) and thylakoid membranes (TM), we studied the subcellular localization of the early assembly steps for PSII biogenesis in a Synechocystis sp. PCC6803 cyanobacterium strain lacking the CP47 antenna. This strain accumulates the early D1-D2 assembly complex which was localized in TM along with associated PSII assembly factors. We also followed insertion and processing of the D1 precursor (pD1) by radioactive pulse-chase labeling. D1 is inserted into the membrane with a C-terminal extension which requires cleavage by a specific protease, the C-terminal processing protease (CtpA), to allow subsequent assembly of the oxygen-evolving complex. pD1 insertion as well as its conversion to mature D1 under various light conditions was seen only in the TM. Epitope-tagged CtpA was also localized in the same membrane, providing further support for the thylakoid location of pD1 processing. However, Vipp1 and PratA, two proteins suggested to be part of the so-called 'thylakoid centers', were found to associate with the PM. Together, these results suggest that early PSII assembly steps occur in TM or specific areas derived from them, with interaction with PM needed for efficient PSII and thylakoid biogenesis. PMID- 26578693 TI - TENOR: Database for Comprehensive mRNA-Seq Experiments in Rice. AB - Here we present TENOR (Transcriptome ENcyclopedia Of Rice, http://tenor.dna.affrc.go.jp), a database that encompasses large-scale mRNA sequencing (mRNA-Seq) data obtained from rice under a wide variety of conditions. Since the elucidation of the ability of plants to adapt to various growing conditions is a key issue in plant sciences, it is of great interest to understand the regulatory networks of genes responsible for environmental changes. We used mRNA-Seq and performed a time-course transcriptome analysis of rice, Oryza sativa L. (cv. Nipponbare), under 10 abiotic stress conditions (high salinity; high and low phosphate; high, low and extremely low cadmium; drought; osmotic; cold; and flood) and two plant hormone treatment conditions (ABA and jasmonic acid). A large number of genes that were responsive to abiotic stresses and plant hormones were detected by differential expression analysis. Furthermore, several responsive genes were found to encode transcription factors that could control the transcriptional network of stress responses, but the timing of the induction of these genes was not uniform across conditions. A significant number of cis-regulatory elements were enriched in the promoter regions of the responsive genes and were shared among conditions. These data suggest that some key components of gene regulation networks are shared between different stress signaling pathways. All the resources (novel genes identified from mRNA-Seq data, expression profiles, co-expressed genes and cis-regulatory elements) can be searched for and are available in TENOR. PMID- 26578694 TI - Distinct Biochemical Properties of Arabidopsis thaliana Actin Isoforms. AB - Plants and animals express multiple actin isoforms in a manner that is dependent on tissues, organs and the stage of development. Previous genetic analyses suggested that individual actin isoforms have specific roles in cells, but there is little biochemical evidence to support this hypothesis. In this study, we purified four recombinant Arabidopsis actin isoforms, two major vegetative actin isoforms, ACT2 and ACT7, and two major reproductive isoforms, ACT1 and ACT11, and characterized them biochemically. Phalloidin bound normally to the filaments of the two reproductive actins as well as to the filaments of skeletal muscle actin. However, phalloidin bound only weakly to ACT7 filaments and hardly at all to ACT2 filaments, despite the conserved sequence of the phalloidin-binding site. Polymerization and phosphate release rates among these four actin isoforms were also significantly different. Moreover, interactions with profilin (PRF) were also different among the four Arabidopsis actin isoforms. PRF1 and PRF2 inhibited the polymerization of ACT1, ACT11 and ACT7, while ACT2 was only weakly affected. Plant actin isoforms have different biochemical properties. This result supports the idea that actin isoforms play specific roles to achieve multiple cell functions. PMID- 26578695 TI - Analysis of the Fine-Tuning of Cyanobacterial Circadian Phase by Monochromatic Light and Long-Day Conditions. AB - The cyanobacterial circadian-related protein, Pex, accumulates in the dark period of the diurnal light-dark cycle. After the diurnal cycle, an approximately 3 h advance in the phase of the circadian bioluminescence rhythm is observed in pex deficient mutants, as compared with the wild type. However, it is unclear what type of photosensing mechanism regulates the accumulation and the phase change. In monochromatic light irradiation experiments, Pex accumulation was strongly repressed under blue light conditions; however, only small reductions in Pex accumulation were observed under red or green light conditions. After the diurnal cycle of 12 h of white fluorescent light and 12 h of blue light, the phase advance was repressed more than that of the cycle of 12 h red (or green) light. The phase advance also occurred after 16 h light/8 h dark cycles (long-day cycles) but did not occur after 8 h light/16 h dark cycles (short-day cycles). While Pex is a unique winged helix transcription factor harboring secondary structures (alpha0 and alpha4 helices), the importance of the structures is not understood. In in vivo experiments with site-directed mutations in the alpha0 helix, the obtained mutants, in which Pex was missing the hydrophobic side chain at the 28th or 32nd amino acid residue, exhibited no phase delay after the light/dark cycle. In in vitro DNA binding assays, the mutant proteins showed no binding to the promoter region of the clock gene kaiA. From these results, we propose a molecular model which describes the phase delay in cyanobacteria. PMID- 26578696 TI - OryzaGenome: Genome Diversity Database of Wild Oryza Species. AB - The species in the genus Oryza, encompassing nine genome types and 23 species, are a rich genetic resource and may have applications in deeper genomic analyses aiming to understand the evolution of plant genomes. With the advancement of next generation sequencing (NGS) technology, a flood of Oryza species reference genomes and genomic variation information has become available in recent years. This genomic information, combined with the comprehensive phenotypic information that we are accumulating in our Oryzabase, can serve as an excellent genotype phenotype association resource for analyzing rice functional and structural evolution, and the associated diversity of the Oryza genus. Here we integrate our previous and future phenotypic/habitat information and newly determined genotype information into a united repository, named OryzaGenome, providing the variant information with hyperlinks to Oryzabase. The current version of OryzaGenome includes genotype information of 446 O. rufipogon accessions derived by imputation and of 17 accessions derived by imputation-free deep sequencing. Two variant viewers are implemented: SNP Viewer as a conventional genome browser interface and Variant Table as a text-based browser for precise inspection of each variant one by one. Portable VCF (variant call format) file or tab-delimited file download is also available. Following these SNP (single nucleotide polymorphism) data, reference pseudomolecules/scaffolds/contigs and genome-wide variation information for almost all of the closely and distantly related wild Oryza species from the NIG Wild Rice Collection will be available in future releases. All of the resources can be accessed through http://viewer.shigen.info/oryzagenome/. PMID- 26578698 TI - AMPK agonist AICAR delays the initial decline in lifetime-apex Vo2 peak, while voluntary wheel running fails to delay its initial decline in female rats. AB - There has never been an outcome measure for human health more important than peak oxygen consumption (Vo2 peak), yet little is known regarding the molecular triggers for its lifetime decline with aging. We examined the ability of physical activity or 5 wk of 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR) administration to delay the initial aging-induced decline in lifetime apex Vo2 peak and potential underlying molecular mechanisms. Experiment 1 consisted of female rats with (RUN) and without (NO RUN) running wheels, while experiment 2 consisted of female nonrunning rats getting the AMPK agonist AICAR (0.5 mg/g/day) subcutaneously for 5 wk beginning at 17 wk of age. All rats underwent frequent, weekly or biweekly Vo2 peak tests beginning at 10 wk of age. In experiment 1, lifetime-apex Vo2 peak occurred at 19 wk of age in both RUN and NO RUN and decreased thereafter. Vo2 peak measured across experiment 1 was ~25% higher in RUN than in NO RUN. In experiment 2, AICAR delayed the chronological age observed in experiment 1 by 1 wk, from 19 wk to 20 wk of age. RUN and NO RUN showed different skeletal muscle transcriptomic profiles both pre- and postapex. Additionally, growth and development pathways are differentially regulated between RUN and NO RUN. Angiomotin mRNA was downregulated postapex in RUN and NO RUN. Furthermore, strong significant correlations to Vo2 peak and trends for decreased protein concentration supports angiomotin's potential importance in our model. Contrary to our primary hypothesis, wheel running was not sufficient to delay the chronological age of lifetime-apex Vo2 peak decline, whereas AICAR delayed it 1 wk. PMID- 26578697 TI - Patterns of gene expression among murine models of hemorrhagic shock/trauma and sepsis. AB - Controversy remains whether the leukocyte genomic response to trauma or sepsis is dependent upon the initiating stimulus. Previous work illustrated poor correlations between historical models of murine trauma and sepsis (i.e., trauma hemorrhage and lipopolysaccharide injection, respectively). The aim of this study is to examine the early genomic response in improved murine models of sepsis [cecal ligation and puncture (CLP)] and trauma [polytrauma (PT)] with and without pneumonia (PT+Pp). Groups of naive, CLP, PT, and PT+Pp mice were killed at 2 h, 1 or 3 days. Total leukocytes were isolated for genome-wide expression analysis, and genes that were found to differ from control (false discovery rate adjusted P < 0.001) were assessed for fold-change differences. Spearman correlations were also performed. For all time points combined (CLP, PT, PT+Pp), there were 10,426 total genes that were found to significantly differ from naive controls. At 2 h, the transcriptomic changes between CLP and PT showed a positive correlation (rs) of 0.446 (P < 0.0001) but were less positive thereafter. Correlations were significantly improved when we limited the analysis to common genes whose expression differed by a 1.5 fold-change. Both pathway and upstream analyses revealed the activation of genes known to be associated with pathogen-associated and damage-associated molecular pattern signaling, and early activation patterns of expression were very similar between polytrauma and sepsis at the earliest time points. This study demonstrates that the early leukocyte genomic response to sepsis and trauma are very similar in mice. PMID- 26578699 TI - Strigolactones Regulate Plant Growth in Arabidopsis via Degradation of the DWARF53-Like Proteins SMXL6, 7, and 8. PMID- 26578701 TI - Drug Susceptibility of Genetically Engineered Trypanosoma cruzi Strains and Sterile Cure in Animal Models as a Criterion for Potential Clinical Efficacy of Anti-T. cruzi Drugs. PMID- 26578700 TI - The WRKY Transcription Factor WRKY71/EXB1 Controls Shoot Branching by Transcriptionally Regulating RAX Genes in Arabidopsis. AB - Plant shoot branching is pivotal for developmental plasticity and crop yield. The formation of branch meristems is regulated by several key transcription factors including REGULATOR OF AXILLARY MERISTEMS1 (RAX1), RAX2, and RAX3. However, the regulatory network of shoot branching is still largely unknown. Here, we report the identification of EXCESSIVE BRANCHES1 (EXB1), which affects axillary meristem (AM) initiation and bud activity. Overexpression of EXB1 in the gain-of-function mutant exb1-D leads to severe bushy and dwarf phenotypes, which result from excessive AM initiation and elevated bud activities. EXB1 encodes the WRKY transcription factor WRKY71, which has demonstrated transactivation activities. Disruption of WRKY71/EXB1 by chimeric repressor silencing technology leads to fewer branches, indicating that EXB1 plays important roles in the control of shoot branching. We demonstrate that EXB1 controls AM initiation by positively regulating the transcription of RAX1, RAX2, and RAX3. Disruption of the RAX genes partially rescues the branching phenotype caused by EXB1 overexpression. We further show that EXB1 also regulates auxin homeostasis in control of shoot branching. Our data demonstrate that EXB1 plays pivotal roles in shoot branching by regulating both transcription of RAX genes and auxin pathways. PMID- 26578702 TI - Reply to "Drug Susceptibility of Genetically Engineered Trypanosoma cruzi Strains and Sterile Cure in Animal Models as a Criterion for Potential Clinical Efficacy of Anti-T. cruzi Drugs". PMID- 26578703 TI - Erratum for Uda et al., Establishment of an In Vitro d-Cycloserine-Synthesizing System by Using O-Ureido-l-Serine Synthase and d-Cycloserine Synthetase Found in the Biosynthetic Pathway. PMID- 26578705 TI - New hopes in the fight against cancer: a special issue on targeted anti-cancer drug discovery and cell signaling. PMID- 26578706 TI - Targeting KRAS-mutant non-small cell lung cancer: challenges and opportunities. AB - Oncogenic mutations in Kirsten rat sarcoma viral oncogene homolog (KRAS) occur in 15%-30% of non-small cell lung cancer (NSCLC). However, despite decades of intensive research, there is still no direct KRAS inhibitor with clinically proven efficacy. Considering its association with poor treatment response and prognosis of lung cancer, developing an effective inhibitory approach is urgently needed. Here, we review different strategies currently being explored to target KRAS-mutant NSCLC, discuss opportunities and challenges, and also propose some novel methods and concepts with the promise of clinical application. PMID- 26578707 TI - Putrescine Alleviates Iron Deficiency via NO-Dependent Reutilization of Root Cell Wall Fe in Arabidopsis. AB - Plants challenged with abiotic stress show enhanced polyamines levels. Here, we show that the polyamine putrescine (Put) plays an important role to alleviate Fe deficiency. The adc2-1 mutant, which is defective in Put biosynthesis, was hypersensitive to Fe deficiency compared with wild type (Col-1 of Arabidopsis [Arabidopsis thaliana]). Exogenous Put decreased the Fe bound to root cell wall, especially to hemicellulose, and increased root and shoot soluble Fe content, thus alleviating the Fe deficiency-induced chlorosis. Intriguingly, exogenous Put induced the accumulation of nitric oxide (NO) under both Fe-sufficient (+Fe) and Fe-deficient (-Fe) conditions, although the ferric-chelate reductase (FCR) activity and the expression of genes related to Fe uptake were induced only under -Fe treatment. The alleviation of Fe deficiency by Put was diminished in the hemicellulose-level decreased mutant-xth31 and in the noa1 and nia1nia2 mutants, in which the endogenous NO levels are reduced, indicating that both NO and hemicellulose are involved in Put-mediated alleviation of Fe deficiency. However, the FCR activity and the expression of genes related to Fe uptake were still up regulated under -Fe+Put treatment compared with -Fe treatment in xth31, and Put induced cell wall Fe remobilization was abolished in noa1 and nia1nia2, indicating that Put-regulated cell wall Fe reutilization is dependent on NO. From our results, we conclude that Put is involved in the remobilization of Fe from root cell wall hemicellulose in a process dependent on NO accumulation under Fe deficient condition in Arabidopsis. PMID- 26578708 TI - RNA Recognition Motif-Containing Protein ORRM4 Broadly Affects Mitochondrial RNA Editing and Impacts Plant Development and Flowering. AB - Plant RNA editosomes modify cytidines (C) to uridines (U) at specific sites in plastid and mitochondrial transcripts. Members of the RNA-editing factor interacting protein (RIP) family and Organelle RNA Recognition Motif-containing (ORRM) family are essential components of the Arabidopsis (Arabidopsis thaliana) editosome. ORRM2 and ORRM3 have been recently identified as minor mitochondrial editing factors whose silencing reduces editing efficiency at ~6% of the mitochondrial C targets. Here we report the identification of ORRM4 (for organelle RRM protein 4) as a novel, major mitochondrial editing factor that controls ~44% of the mitochondrial editing sites. C-to-U conversion is reduced, but not eliminated completely, at the affected sites. The orrm4 mutant exhibits slower growth and delayed flowering time. ORRM4 affects editing in a site specific way, though orrm4 mutation affects editing of the entire transcript of certain genes. ORRM4 contains an RRM domain at the N terminus and a Gly-rich domain at the C terminus. The RRM domain provides the editing activity of ORRM4, whereas the Gly-rich domain is required for its interaction with ORRM3 and with itself. The presence of ORRM4 in the editosome is further supported by its interaction with RIP1 in a bimolecular fluorescence complementation assay. The identification of ORRM4 as a major mitochondrial editing factor further expands our knowledge of the composition of the RNA editosome and reveals that adequate mitochondrial editing is necessary for normal plant development. PMID- 26578710 TI - Body Mass Index, Weight Gain, and Hypertensive Disorders in Pregnancy. AB - BACKGROUND: This study examines the interrelationship between gestational weight gain, pre-pregnancy body mass index (BMI), race/ethnicity, and their association with hypertensive disorders during pregnancy (HDP). METHODS: Data from the 2004 2011 national Pregnancy Risk Assessment Monitoring System (PRAMS) were analyzed. Women with singleton live births were included in the analysis (N = 270,131). Gestational weight gain was categorized reflecting the Institute of Medicine (IOM) weight gain recommendation (no gain/weight loss; <=11, 12-14; 15-25; 26-35; >=36 pounds). Pre-pregnancy BMI (underweight; normal; overweight; obese) and race/ethnicity (non-Hispanic (NH) White, NH-Black, Hispanic, and NH-other) were examined. Hypertensive disorders during pregnancy were dichotomized (HDP; no HDP). Data were stratified by BMI and race/ethnicity, and multiple logistic regression analysis was conducted to generate odds ratios and 95% confidence intervals (CIs). RESULTS: Compared to normal and overweight women who gained the IOM recommended weight, higher odds of HDP was observed in those who gained >=36 pounds regardless of their race/ethnicity. Among obese NH-White (odds ratio (OR) = 1.29, 95% CI = 1.11, 1.50) and Hispanic women (OR = 1.64, 95% CI = 1.05, 2.54), the odds of HDP was higher among those who gained 25-35 pounds and those who gained >=36 pounds (OR = 1.59, 95% CI = 1.37, 1.85) and (OR = 2.20, 95% CI = 1.41, 3.44), respectively. However, for NH-Black obese women, higher odds of HDP was observed among those who gained >=36 pounds (OR = 1.34, 95% CI = 1.04, 1.73). CONCLUSIONS: Although there are some ethnic/racial variations, pregnant women who exceeded gestational weight gain recommendations are at increased risk of HDP. Health care providers should consider the interrelationship between pre-pregnancy gestational weight gain (GWG) and BMI when counseling patients regarding HDP. PMID- 26578709 TI - The Vacuolar Proton-Cation Exchanger EcNHX1 Generates pH Signals for the Expression of Secondary Metabolism in Eschscholzia californica. AB - Cell cultures of Eschscholzia californica react to a fungal elicitor by the overproduction of antimicrobial benzophenanthridine alkaloids. The signal cascade toward the expression of biosynthetic enzymes includes (1) the activation of phospholipase A2 at the plasma membrane, resulting in a peak of lysophosphatidylcholine, and (2) a subsequent, transient efflux of vacuolar protons, resulting in a peak of cytosolic H(+). This study demonstrates that one of the Na(+)/H(+) antiporters acting at the tonoplast of E. californica cells mediates this proton flux. Four antiporter-encoding genes were isolated and cloned from complementary DNA (EcNHX1-EcNHX4). RNA interference-based, simultaneous silencing of EcNHX1, EcNHX3, and EcNHX4 resulted in stable cell lines with largely diminished capacities of (1) sodium-dependent efflux of vacuolar protons and (2) elicitor-triggered overproduction of alkaloids. Each of the four EcNHX genes of E. californica reconstituted the lack of Na(+)-dependent H(+) efflux in a Deltanhx null mutant of Saccharomyces cerevisiae. Only the yeast strain transformed with and expressing the EcNHX1 gene displayed Na(+)-dependent proton fluxes that were stimulated by lysophosphatidylcholine, thus giving rise to a net efflux of vacuolar H(+). This finding was supported by three-dimensional protein homology models that predict a plausible recognition site for lysophosphatidylcholine only in EcNHX1. We conclude that the EcNHX1 antiporter functions in the elicitor-initiated expression of alkaloid biosynthetic genes by recruiting the vacuolar proton pool for the signaling process. PMID- 26578712 TI - The case for banning cigarettes. AB - Lifelong smokers lose on average a decade of life vis-a-vis non-smokers. Globally, tobacco causes about 5-6 million deaths annually. One billion tobacco related deaths are predicted for the 21st century, with about half occurring before the age of 70. In this paper, we consider a complete ban on the sale of cigarettes and find that such a ban, if effective, would be justified. As with many policy decisions, the argument for such a ban requires a weighing of the pros and cons and how they impact on different individuals, both current and future. The weightiest factor supporting a ban, we argue, is the often substantial well-being losses many individuals suffer because of smoking. These harms, moreover, disproportionally affect the disadvantaged. The potential gains in well-being and equality, we argue, outweigh the limits a ban places on individuals' freedom, its failure to respect some individuals' autonomous choice and the likelihood that it may, in individual cases, reduce well-being. PMID- 26578713 TI - p53 regulates expression of uncoupling protein 1 through binding and repression of PPARgamma coactivator-1alpha. AB - The tumor suppressor p53 (TRP53 in mice) is known for its involvement in carcinogenesis, but work during recent years has underscored the importance of p53 in the regulation of whole body metabolism. A general notion is that p53 is necessary for efficient oxidative metabolism. The importance of UCP1-dependent uncoupled respiration and increased oxidation of glucose and fatty acids in brown or brown-like adipocytes, termed brite or beige, in relation to energy balance and homeostasis has been highlighted recently. UCP1-dependent uncoupled respiration in classic interscapular brown adipose tissue is central to cold induced thermogenesis, whereas brite/beige adipocytes are of special importance in relation to diet-induced thermogenesis, where the importance of UCP1 is only clearly manifested in mice kept at thermoneutrality. We challenged wild-type and TRP53-deficient mice by high-fat feeding under thermoneutral conditions. Interestingly, mice lacking TRP53 gained less weight compared with their wild type counterparts. This was related to an increased expression of Ucp1 and other PPARGC1a and PPARGC1b target genes but not Ppargc1a or Ppargc1b in inguinal white adipose tissue of mice lacking TRP53. We show that TRP53, independently of its ability to bind DNA, inhibits the activity of PPARGC1a and PPARGC1b. Collectively, our data show that TRP53 has the ability to regulate the thermogenic capacity of adipocytes through modulation of PPARGC1 activity. PMID- 26578714 TI - Short-term muscle disuse lowers myofibrillar protein synthesis rates and induces anabolic resistance to protein ingestion. AB - Disuse leads to rapid loss of skeletal muscle mass and function. It has been hypothesized that short successive periods of muscle disuse throughout the lifespan play an important role in the development of sarcopenia. The physiological mechanisms underlying short-term muscle disuse atrophy remain to be elucidated. We assessed the impact of 5 days of muscle disuse on postabsorptive and postprandial myofibrillar protein synthesis rates in humans. Twelve healthy young (22 +/- 1 yr) men underwent a 5-day period of one-legged knee immobilization (full leg cast). Quadriceps cross-sectional area (CSA) of both legs was assessed before and after immobilization. Continuous infusions of l [ring-(2)H5]phenylalanine and l-[1-(13)C]leucine were combined with the ingestion of a 25-g bolus of intrinsically l-[1-(13)C]phenylalanine- and l-[1-(13)C]leucine labeled dietary protein to assess myofibrillar muscle protein fractional synthetic rates in the immobilized and nonimmobilized control leg. Immobilization led to a 3.9 +/- 0.6% decrease in quadriceps muscle CSA of the immobilized leg. Based on the l-[ring-(2)H5]phenylalanine tracer, immobilization reduced postabsorptive myofibrillar protein synthesis rates by 41 +/- 13% (0.015 +/- 0.002 vs. 0.032 +/- 0.005%/h, P < 0.01) and postprandial myofibrillar protein synthesis rates by 53 +/- 4% (0.020 +/- 0.002 vs. 0.044 +/- 0.003%/h, P < 0.01). Comparable results were found using the l-[1-(13)C]leucine tracer. Following protein ingestion, myofibrillar protein bound l-[1-(13)C]phenylalanine enrichments were 53 +/- 18% lower in the immobilized compared with the control leg (0.007 +/- 0.002 and 0.015 +/- 0.002 mole% excess, respectively, P < 0.05). We conclude that 5 days of muscle disuse substantially lowers postabsorptive myofibrillar protein synthesis rates and induces anabolic resistance to protein ingestion. PMID- 26578716 TI - Kazuo Ishiguro's Never Let Me Go: a model of 'completion' for the end of life. AB - Kazuo Ishiguro's remarkable novel, Never Let Me Go, is a potent critique of societal and medical inhumanity. However, it can also read as a study of psychosocial development across the life span, featuring age-specific milestones and acceptance of death as the fixed point towards which humans advance through the stages of maturation. Emphasising a developmental perspective based on Eriksonian and Jaquesian theory, Ishiguro's storyline is followed closely and retold in this article. At each critical point in the novel, the differing styles of preparation for death are considered. PMID- 26578715 TI - Canonical Notch activation in osteocytes causes osteopetrosis. AB - Activation of Notch1 in cells of the osteoblastic lineage inhibits osteoblast differentiation/function and causes osteopenia, whereas its activation in osteocytes causes a distinct osteopetrotic phenotype. To explore mechanisms responsible, we established the contributions of canonical Notch signaling (Rbpjkappa dependent) to osteocyte function. Transgenics expressing Cre recombinase under the control of the dentin matrix protein-1 (Dmp1) promoter were crossed with Rbpjkappa conditional mice to generate Dmp1-Cre(+/ );Rbpjkappa(Delta/Delta) mice. These mice did not have a skeletal phenotype, indicating that Rbpjkappa is dispensable for osteocyte function. To study the Rbpjkappa contribution to Notch activation, Rosa(Notch) mice, where a loxP flanked STOP cassette is placed between the Rosa26 promoter and the NICD coding sequence, were crossed with Dmp1-Cre transgenic mice and studied in the context (Dmp1-Cre(+/-);Rosa(Notch);Rbpjkappa(Delta/Delta)) or not (Dmp1-Cre(+/ );Rosa(Notch)) of Rbpjkappa inactivation. Dmp1-Cre(+/-);Rosa(Notch) mice exhibited increased femoral trabecular bone volume and decreased osteoclasts and bone resorption. The phenotype was reversed in the context of the Rbpjkappa inactivation, demonstrating that Notch canonical signaling was accountable for the phenotype. Notch activation downregulated Sost and Dkk1 and upregulated Axin2, Tnfrsf11b, and Tnfsf11 mRNA expression, and these effects were not observed in the context of the Rbpjkappa inactivation. In conclusion, Notch activation in osteocytes suppresses bone resorption and increases bone volume by utilization of canonical signals that also result in the inhibition of Sost and Dkk1 and upregulation of Wnt signaling. PMID- 26578718 TI - Comparison of Patellar Tendon and Hamstring Tendon Anterior Cruciate Ligament Reconstruction: A 15-Year Follow-up of a Randomized Controlled Trial. AB - BACKGROUND: Numerous studies have compared patellar tendon (PT) and hamstring tendon (HS) anterior cruciate ligament (ACL) reconstructions in the short to midterm, but fewer long-term results have been published. HYPOTHESIS: There will be no difference in functional outcome between ACL reconstruction performed with PT and HS grafts, but PT grafts will have more donor site morbidity. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: Sixty-five patients undergoing ACL reconstruction were randomized to receive either a PT graft or a 4-strand HS graft. Early results were reported at 4, 8, 12, 24, and 36 months. Forty-seven patients (22 of 31 PT and 25 of 34 HS) were reviewed at a mean of 15.3 years. RESULTS: Four graft ruptures (1 PT, 3 HS) and 6 contralateral ACL injuries (4 PT, 2 HS) occurred in the group that was reviewed. There was no statistically significant difference between the groups for any of the variables measured. There was a similar incidence of anterior knee pain and kneeling pain in both groups. The previously observed increased extension deficit in the PT group at 3 years was not present at 15 years, and there was no significant between-group difference in knee laxity. A higher proportion of patients in the PT group were participating in sport on a weekly basis (73% PT, 48% HS; P = .05). There was no difference in the degree of osteoarthritis between the groups. CONCLUSION: This randomized controlled trial showed that HS and PT ACL reconstructions have comparable results at an average 15-year follow-up. Contrary to the study hypothesis, some of the graft differences seen at earlier review were not present at 15 years, and patients with PT grafts were more active in sport participation. Overall, both graft types provided good long-term subjective and objective outcomes. PMID- 26578719 TI - Product Differences in Intra-articular Hyaluronic Acids for Osteoarthritis of the Knee. AB - BACKGROUND: Knee osteoarthritis (OA) is a common and often disabling joint disorder among adults that may result in impaired activity and daily function. A variety of treatment options are currently available and prescribed for knee OA depending on the severity of the disorder and physician preference. Intra articular hyaluronic acid (IA-HA) injection is a treatment for knee OA that reportedly provides numerous biochemical and biological benefits, including shock absorption, chondroprotection, and anti-inflammatory effects within the knee. Clarity is needed as to whether the available IA-HA products should be considered for therapy as a group or whether there are significant differences in the products that need to be considered in treatment of OA of the knee. PURPOSE: To determine whether there are differences in efficacy and safety with respect to intrinsic properties of available IA-HA injections for knee OA. STUDY DESIGN: Meta-analysis. METHODS: A comprehensive literature search of the Medline, EMBASE, and PubMed databases was conducted for all existing randomized trials of IA-HA. The primary outcome measure analyzed was the mean pain score at the reported follow-up nearest to 26 weeks after injection. Pooled efficacy and safety results were recorded for subgroupings of HA product characteristics. RESULTS: A total of 68 studies were included for analysis. Products with an average molecular weight >=3000 kDa provided favorable efficacy results when compared with products of an average molecular weight <3000 kDa. Products with a molecular weight >=3000 kDa demonstrated significantly fewer discontinuations due to treatment-related adverse events than did <=1500 kDa counterparts, while trial discontinuation rates were similar between biological fermentation-derived HA products and avian derived HA. The results did not demonstrate a significant difference in the occurrence of effusion across molecular weight subgroups. Additionally, biological fermentation-derived HA had a significantly smaller incidence of effusion than did avian-derived HA. Biological fermentation-derived HA demonstrated fewer acute flare-ups at the injection site than did avian-derived HA products, while high-molecular-weight products demonstrated the highest rate of injection site flare-up. CONCLUSION: Despite similarities, IA-HA products should not be treated as a group, as there are differences in IA-HA products that influence both efficacy and safety. In the available literature, IA-HA products with a molecular weight >=3000 kDa and those derived from biological fermentation relate to superior efficacy and safety-factors that may influence selection an IA HA product for OA of the knee. PMID- 26578717 TI - Laboratory Measures as Proxies for Primary Care Encounters: Implications for Quantifying Clinical Retention Among HIV-Infected Adults in North America. AB - Because of limitations in the availability of data on primary care encounters, patient retention in human immunodeficiency virus (HIV) care is often estimated using laboratory measurement dates as proxies for clinical encounters, leading to possible outcome misclassification. This study included 83,041 HIV-infected adults from 14 clinical cohorts in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) who had >=1 HIV primary care encounters during 2000-2010, contributing 468,816 person-years of follow-up. Encounter-based retention (REB) was defined as >=2 encounters in a calendar year, >=90 days apart. Laboratory-based retention (RLB) was defined similarly, using the dates of CD4-positive cell counts or HIV-1 RNA measurements. Percentage of agreement and the kappa statistic were used to characterize agreement between RLB and REB. Logistic regression with generalized estimating equations and stabilized inverse probability-of-selection weights was used to elucidate temporal trends and the discriminatory power of RLB as a predictor of REB, accounting for age, sex, race/ethnicity, primary HIV risk factor, and cohort site as potential confounders. Both REB and RLB increased from 2000 to 2010 (from 67% to 78% and from 65% to 77%, respectively), though REB was higher than RLB throughout (P < 0.01). RLB agreed well with REB (80%-86% agreement; kappa = 0.55-0.62, P < 0.01) and had a strong, imperfect ability to discriminate between persons retained and not retained in care by REB (C statistic: C = 0.81, P < 0.05). As a proxy for REB, RLB had a sensitivity and specificity of 84% and 77%, respectively, with misclassification error of 18%. PMID- 26578720 TI - Reproduction at the extremes: pseudovivipary, hybridization and genetic mosaicism in Posidonia australis (Posidoniaceae). AB - BACKGROUND AND AIMS: Organisms occupying the edges of natural geographical ranges usually survive at the extreme limits of their innate physiological tolerances. Extreme and prolonged fluctuations in environmental conditions, often associated with climate change and exacerbated at species' geographical range edges, are known to trigger alternative responses in reproduction. This study reports the first observations of adventitious inflorescence-derived plantlet formation in the marine angiosperm Posidonia australis, growing at the northern range edge (upper thermal and salinity tolerance) in Shark Bay, Western Australia. These novel plantlets are described and a combination of microsatellite DNA markers and flow cytometry is used to determine their origin. METHODS: Polymorphic microsatellite DNA markers were used to generate multilocus genotypes to determine the origin of the adventitious inflorescence-derived plantlets. Ploidy and genome size were estimated using flow cytometry. KEY RESULTS: All adventitious plantlets were genetically identical to the maternal plant and were therefore the product of a novel pseudoviviparous reproductive event. It was found that 87 % of the multilocus genotypes contained three alleles in at least one locus. Ploidy was identical in all sampled plants. The genome size (2 C value) for samples from Shark Bay and from a separate site much further south was not significantly different, implying they are the same ploidy level and ruling out a complete genome duplication (polyploidy). CONCLUSIONS: Survival at range edges often sees the development of novel responses in the struggle for survival and reproduction. This study documents a physiological response at the trailing edge, whereby reproductive strategy can adapt to fluctuating conditions and suggests that the lower-than-usual water temperature triggered unfertilized inflorescences to 'switch' to growing plantlets that were adventitious clones of their maternal parent. This may have important long-term implications as both genetic and ecological constraints may limit the ability to adapt or range-shift; this seagrass meadow in Shark Bay already has low genetic diversity, no sexual reproduction and no seedling recruitment. PMID- 26578721 TI - A comparison of floral integration between selfing and outcrossing species: a meta-analysis. AB - BACKGROUND AND AIMS: Floral integration is thought to be an adaptation to promote cross-fertilization, and it is often assumed that it increases morphological matching between flowers and pollinators, increasing the efficiency of pollen transfer. However, the evidence for this role of floral integration is limited, and recent studies have suggested a possible positive association between floral integration and selfing. Although a number of explanations exist to account for this inconsistency, to date there has been no attempt to examine the existence of an association between floral integration and mating system. This study hypothesized that if pollinator-mediated pollen movement among plants (outcrossing) is the main factor promoting floral integration, species with a predominantly outcrossing mating system should present higher levels of floral integration than those with a predominantly selfing mating system. METHODS: A phylogenetically informed meta-analysis of published data was performed in order to evaluate whether mating system (outcrossing vs. selfing) accounts for the variation in floral integration among 64 species of flowering plants. Morphometric floral information was used to compare intra-floral integration among traits describing sexual organs (androecium and gynoecium) and those corresponding to the perianth (calix and corolla). KEY RESULTS: The analysis showed that outcrossing species have lower floral integration than selfing species. This pattern was caused by significantly higher integration of sexual traits than perianth traits, as integration of the latter group remained unchanged across mating categories. CONCLUSIONS: The results suggest that the evolution of selfing is associated with concomitant changes in intra-floral integration. Thus, floral integration of sexual traits should be considered as a critical component of the selfing syndrome. PMID- 26578722 TI - Gene expression profiling identifies responsive patients with cancer of unknown primary treated with carboplatin, paclitaxel, and everolimus: NCCTG N0871 (alliance). AB - BACKGROUND: Carboplatin (C) and paclitaxel (P) are standard treatments for carcinoma of unknown primary (CUP). Everolimus, an mTOR inhibitor, exhibits activity in diverse cancer types. We did a phase II trial combining everolimus with CP for CUP. We also evaluated whether a gene expression profiling (GEP) test that predicts tissue of origin (TOO) could identify responsive patients. PATIENTS AND METHODS: A tumor biopsy was required for central confirmation of CUP and GEP. Patients with metastatic, untreated CUP received everolimus (30 mg weekly) with P (200 mg/m(2)) and C (area under the curve 6) every 3 weeks. The primary end point was response rate (RR), with 22% needed for success. The GEP test categorized patients into two groups: those having a TOO where CP is versus is not considered standard therapy. RESULTS: Of 45 assessable patients, the RR was 36% (95% confidence interval 22% to 51%), which met criteria for success. Grade >=3 toxicities were predominantly hematologic (80%). Adequate tissue for GEP was available in 38 patients and predicted 10 different TOOs. Patients with a TOO where platinum/taxane is a standard (n = 19) tended to have higher RR (53% versus 26%) and significantly longer PFS (6.4 versus 3.5 months) and OS (17.8 versus 8.3 months, P = 0.005), compared with patients (n = 19) with a TOO where platinum/taxane is not standard. CONCLUSIONS: Everolimus combined with CP demonstrated promising antitumor activity and an acceptable side-effect profile. A tumor biomarker identifying TOO may be useful to select CUP patients for specific antitumor regimens. CLINICALTRIALSGOV: NCT00936702. PMID- 26578723 TI - Reply to 'Plasma vemurafenib concentrations in advanced BRAFV600mut melanoma patients: impact on tumour response and tolerance' by Funck-Brentano et al. PMID- 26578724 TI - Reply to the letter to the editor 'KRT81 miR-SNP rs3660 is associated with risk and survival of NSCLC' by Robles et al. PMID- 26578725 TI - Reply to the letter to the editor 'Plasma vemurafenib concentrations in advanced BRAFV600mut melanoma patients: impact on tumor response and tolerance' by Funck Brentano et al. PMID- 26578726 TI - Strategies for clinical implementation of TNM-Immunoscore in resected nonsmall cell lung cancer. AB - Immunoscore is a prognostic tool defined to quantify in situ immune cell infiltrates and appears highly promising as a supplement to the tumor-node metastasis (TNM) classification of various tumors. In colorectal cancer, an international task force has initiated prospective multicenter studies aiming to implement TNM-Immunoscore (TNM-I) in a routine clinical setting. In breast cancer, recommendations for the evaluation of tumor-infiltrating lymphocytes (TILs) have been proposed by an international working group. Regardless of promising results, there are potential obstacles related to implementing TNM-I into the clinic. Diverse methods may be needed for different malignancies and even within each cancer entity. Nevertheless, a uniform approach across malignancies would be advantageous. In nonsmall-cell lung cancer (NSCLC), there are several previous reports indicating an apparent prognostic importance of TILs, but studies on TILs in a TNM-I setting are sparse and no general recommendations are made. However, recently published data is promising, evoking a realistic hope of a clinical useful NSCLC TNM-I. This review will focus on the TNM-I potential in NSCLC and propose strategies for clinical implementation of a TNM-I in resected NSCLC. PMID- 26578727 TI - Next-generation sequencing of the basal cell carcinoma miRNome and a description of novel microRNA candidates under neoadjuvant vismodegib therapy: an integrative molecular and surgical case study. AB - BACKGROUND: MicroRNAs (miRNAs) have been identified as key players in posttranscriptional gene regulation and have a significant impact on basal cell carcinoma (BCC) development. The Sonic hedgehog pathway inhibitor vismodegib has been approved for oral therapy of metastatic or advanced BCC. Here, a high throughput miRNA sequencing analysis was carried out to identify differentially expressed miRNAs and possible novel miRNA candidates in vismodegib-treated BCC tissue. Additionally, we described our surgical experience with neoadjuvant oral vismodegib therapy. PATIENTS AND METHODS: A punch biopsy (4 mm) from a patient with an extensive cranial BCC under oral vismodegib therapy and a corresponding nonlesional epithelial skin biopsy were harvested. Total RNA was isolated, after which a sequencing cDNA library was prepared, and cluster generation was carried out, which was followed by an ultra-high-throughput miRNA sequencing analysis to indicate the read number of miRNA expression based on miRBase 21. In addition to the identification of differentially expressed miRNAs from RNA sequencing data, additional novel miRNA candidates were determined with a tool for identifying new miRNA sequences (miRDeep2). RESULTS: We identified 33 up-regulated miRNAs (fold change >=2) and 39 potentially new miRNA candidates (miRDeep scores 0-43.6). A manual sequence analysis of the miRNA candidates on the genomic locus of chromosome 1 with provisional IDs of chr1_1913 and chr1_421 was further carried out and rated as promising (chr1_1913) and borderline (chr1_421). Histopathology revealed skip lesions in clinically healthy appearing skin at the tumor margins, which were the cause of seven re-excisions by micrographic controlled surgery to achieve tumor-free margins. CONCLUSION: miRNA sequencing revealed novel miRNA candidates that need to be further confirmed in functional Dicer knockout studies. Clinically, on the basis of our surgical experience described here, neoadjuvant vismodegib therapy in BCC appears to impede histopathologic evaluations with effects on surgical therapy. Thus, larger studies are necessary, but are not preferable at this time if other options are available. PMID- 26578728 TI - Challenges of phase 1 clinical trials evaluating immune checkpoint-targeted antibodies. AB - BACKGROUND: Immunostimulatory monoclonal antibodies (imAbs) targeting immune checkpoint molecules are revolutionizing oncology not only regarding cancer therapeutics and clinical care, but also from a drug development point of view. A handful of first-generation molecules have been approved so far based on their tremendous efficacy, after an expedited development phase that has challenged most paradigms established in the era of conventional cytotoxic therapy and to some extent molecularly targeted agents. A huge wave of second-generation imAbs is just entering into phase 1 trials now, in monotherapy or in combination. In order to maximize their chances of success in early phase trials, and eventually for patients' benefit, their clinical development has to benefit from lessons learnt from previous imAbs phase 1 trials. MATERIALS AND METHODS: We reviewed the early clinical development of anti-cytotoxic T-lymphocyte antigen 4 and anti programmed death-1 receptor/ligand. Particularities of each agent, including safety, dose--toxicity and dose--efficacy relationships, scheduling, pharmacokinetics (PK), pharmacodynamics (PD), trial design, biomarkers, response assessment and overall drug development strategies, are described and challenged. RESULTS: As opposed to conventional cytotoxic agents, dose of imAbs is not linearly associated with efficacy and toxicity. Therefore, the definition of a minimal immunologically active dose could be proposed. Traditional patient eligibility criteria might also be revisited as the toxicity profile and mechanism of toxicity--immune-related adverse events--are mostly known and their physiopathology somehow less unexpected than with molecularly targeted small molecules. Most challenging are the comprehensive investigation of complex PK and PD characteristics as well as the definition of patient selection biomarkers. Finally, the early focus on efficacy (and not only dose confirmation) in expansion cohorts challenges the traditional phase 1/2/3 drug development process. CONCLUSION: Several drug development paradigms have been challenged by imAbs. Here, we discuss novel approaches for an efficient and successful drug development of these agents. PMID- 26578729 TI - Home administration of bortezomib in multiple myeloma is cost-effective and is preferred by patients compared with hospital administration: results of a prospective single-center study. AB - BACKGROUND: Subcutaneous (s.c.) administration of bortezomib is the most widely used route of administration for the treatment of patients with multiple myeloma. No study has as yet prospectively evaluated home versus hospital administration of s.c. bortezomib with respect to patient preference and cost. PATIENTS AND METHODS: In this prospective trial, myeloma patients received the first administration of s.c. bortezomib of each cycle in the outpatient unit of the Department of Hematology. When possible, all subsequent doses of bortezomib within each cycle were provided at home. A cost analysis was carried out to compare the average cost of an injection of bortezomib in the outpatient unit and at home. In order to compare hospital and home administration of bortezomib for preference and satisfaction, patients had to complete 2 simple questionnaires analyzing 16 criteria, such as quality of life, well-being, social life, satisfaction, safety, quality of care, the reduction in personal transportation time, and personal anxiety. Each item was analyzed using a Likert scale. RESULTS: Fifty patients were studied. Overall, a total of 1043 s.c. injections of bortezomib were carried out, 655 (62.8%) at home, and 388 (35.2%) in the outpatient unit. The cost analysis showed that the total cost of one s.c. injection of bortezomib in the outpatient unit was ?1510.09 versus ?1224.57 for the home administration, which represents a reduction of ?285.52, i.e. 20% of the cost of the hospital administration. The evaluation of patient preference and satisfaction showed that home administration improved the quality of life in 84% of the patients, increased well-being in 78%, and improved the activities of daily living in 72% of the cases. Overall, 98% of the patients noted their preference for home administration over the hospital administration of bortezomib. CONCLUSION: Home administration of s.c. bortezomib is cost-effective and is preferred by myeloma patients compared with hospital administration. PMID- 26578730 TI - In real life, one-quarter of patients with hormone receptor-positive metastatic breast cancer receive chemotherapy as initial palliative therapy: a study of the Southeast Netherlands Breast Cancer Consortium. AB - BACKGROUND: The objective of this study was to present initial systemic treatment choices and the outcome of hormone receptor-positive (HR+) metastatic breast cancer. PATIENTS AND METHODS: All the 815 consecutive patients diagnosed with metastatic breast cancer in 2007-2009 in eight participating hospitals were identified. From the 611 patients with HR+ disease, a total of 520 patients with HER2-negative (HER2-) breast cancer were included. Initial palliative systemic treatment was registered. Progression-free survival (PFS) and overall survival (OS) per initial palliative systemic therapy were obtained using the Kaplan-Meier method and compared using the log-rank test. RESULTS: From the total of 520 patients with HR+/HER2- metastatic breast cancer, 482 patients (93%) received any palliative systemic therapy. Patients that received initial chemotherapy (n = 116) were significantly younger, had less comorbidity, had received more prior adjuvant systemic therapy and were less likely to have bone metastasis only compared with patients that received initial endocrine therapy (n = 366). Median PFS of initial palliative chemotherapy was 5.3 months [95% confidence interval (CI) 4.2-6.2] and of initial endocrine therapy 13.3 months (95% CI 11.3-15.5), with a median OS of 16.1 and 36.9 months, respectively. Initial chemotherapy was also associated with worse outcome in terms of PFS and OS after adjustment for prognostic factors. CONCLUSIONS: A high percentage of patients with HR+ disease received initial palliative chemotherapy, which was associated with worse outcome, even after adjustment of relevant prognostic factors. PMID- 26578731 TI - Conversion to resection of liver metastases from colorectal cancer with hepatic artery infusion of combined chemotherapy and systemic cetuximab in multicenter trial OPTILIV. AB - BACKGROUND: Systemic chemotherapy typically converts previously unresectable liver metastases (LM) from colorectal cancer to curative intent resection in ~15% of patients. This European multicenter phase II trial tested whether hepatic artery infusion (HAI) with triplet chemotherapy and systemic cetuximab could increase this rate to 30% in previously treated patients. PATIENTS AND METHODS: Participants had unresectable LM from wt KRAS colorectal cancer. Main non inclusion criteria were advanced extra hepatic disease, prior HAI and grade 3 neuropathy. Irinotecan (180 mg/m(2)), oxaliplatin (85 mg/m(2)) and 5-fluorouracil (2800 mg/m(2)) were delivered via an implanted HAI access port and combined with i.v. cetuximab (500 mg/m(2)) every 14 days. Multidisciplinary decisions to resect LM were taken after every three courses. The rate of macroscopic complete resections (R0 + R1) of LM, progression-free survival (PFS) and overall survival (OS) were computed according to intent to treat. RESULTS: The patient population consisted of 42 men and 22 women, aged 33-76 years, with a median of 10 LM involving a median of six segments. Up to 3 extrahepatic lesions of <1 cm were found in 41% of the patients. A median of six courses was delivered. The primary end point was met, with R0-R1 hepatectomy for 19 of the 64 previously treated patients, 29.7% (95% confidence interval 18.5-40.9). Grade 3-4 neutropenia (42.6%), abdominal pain (26.2%), fatigue (18%) and diarrhea (16.4%) were frequent. Objective response rate was 40.6% (28.6-52.3). Median PFS and OS reached 9.3 (7.8-10.9) and 25.5 months (18.8-32.1) respectively. Those with R0-R1 hepatectomy had a median OS of 35.2 months (32.6-37.8), with 37.4% (23.6-51.2) alive at 4 years. CONCLUSION: The coordination of liver-specific intensive chemotherapy and surgery had a high curative intent potential that deserves upfront randomized testing. PROTOCOL NUMBERS: EUDRACT 2007-004632-24, NCT00852228. PMID- 26578732 TI - Pre-treatment lymphocytopaenia is an adverse prognostic biomarker in muscle invasive and advanced bladder cancer. AB - BACKGROUND: Pre-treatment lymphocytopaenia may result from cytokines secreted by the tumour microenvironment in association with aggressive tumour biology. We sought to establish the prognostic significance of lymphocytopaenia in muscle invasive and advanced bladder cancer. PATIENTS AND METHODS: Seventy-four patients with muscle-invasive bladder cancer treated with radical chemoradiotherapy and 131 patients with advanced bladder cancer treated with palliative chemotherapy were included in the study. The absolute lymphocyte count on the first day of treatment was recorded. Invasive local or systemic recurrence in the muscle invasive bladder cancer cohort and all-cause mortality in the advanced bladder cancer cohort were defined as survival end points. Receiver operating characteristic (ROC) curve analysis was utilized to determine the cut-off for defining lymphocytopaenia in the muscle-invasive bladder cancer cohort followed by multivariable analysis in a model evaluating the following variables: anaemia, neutrophilia, tumour stage, hydronephrosis and neoadjuvant chemotherapy. Subsequently, lymphocytopaenia was assessed in a multivariable model of the advanced bladder cancer cohort analysing the following prognostic variables: neutrophilia, anaemia, performance status and presence of bone or visceral metastases. A further analysis was carried out evaluating absolute lymphocyte count as a continuous variable. RESULTS: An absolute lymphocyte count of 1.5 * 10(9)/l was determined as the cut-off on ROC curve analysis in the muscle invasive bladder cancer cohort, and multivariate analysis revealed that only lymphocytopaenia was predictive for inferior outcome in this cohort. In the advanced bladder cancer cohort, lymphocytopaenia [hazard ratio (HR) 1.6, 95% confidence interval (CI) 1.1-2.4; P = 0.02] and performance status (HR 1.7, 95% CI 1.0-2.7; P = 0.047) were adverse prognostic factors in the binary variable multivariate model. Absolute lymphocyte count was the sole significant factor when analysed as a continuous variable (HR 0.66, 95% CI 0.5-0.87; P = 0.003). CONCLUSION: Pre-treatment lymphocytopaenia is an independent adverse prognostic factor in both muscle-invasive and advanced bladder cancer. It may be a manifestation of cancer-induced immune suppression driving tumour progression. PMID- 26578733 TI - KRT81 miR-SNP rs3660 is associated with risk and survival of NSCLC. PMID- 26578734 TI - A randomized trial of intensive versus minimal surveillance of patients with resected Dukes B2-C colorectal carcinoma. AB - BACKGROUND: Colorectal cancer is the third most common and the third most lethal cancer in both men and women in developed countries. About 75% of cases are first diagnosed when the disease is classified as localized or regional, undergo potentially curative treatment and enter a post-treatment surveillance program. Although such programs drain significant resources from health systems, empirical evidence of their efficacy is scanty. PATIENTS AND METHODS: Dukes B2-C colorectal cancer patients who had no evidence of disease at the end of their front-line treatment (surgery and adjuvant radiochemotherapy, if indicated) were eligible for the trial and randomized to two different surveillance programs. These programs differed greatly in the frequency of diagnostic imaging. They had similar schedules of physical examinations and carcinoembryonic antigen (CEA) assessments. Patients received baseline and yearly health-related quality-of-life (HR-QoL) questionnaires. Primary outcomes were overall survival (OS) and QoL. RESULTS: From 1998 to 2006, 1228 assessable patients were randomized, 933 with colon cancer and 295 with rectal cancer. More than 90% of patients had the expected number of diagnostic procedures. Median follow-up duration was 62 months [interquartile range (IQR) 51-86] in the minimal surveillance group and 62 months (IQR 50-85) in the intensive group. At primary analysis, 250 patients had recurred and 218 had died. Intensive surveillance anticipated recurrence, as shown by a significant difference in mean disease-free survival of 5.9 months. Comparison of OS curves of the whole intention-to-treat population showed no statistically significant differences. HR-QoL of life scores did not differ between regimens. CONCLUSION: Our findings support the conclusions of other randomized clinical trials, which show that early diagnosis of cancer recurrence is not associated with OS benefit. CLINICALTRIALSGOV: NCT02409472. PMID- 26578735 TI - Efficacy and safety of enzalutamide in patients 75 years or older with chemotherapy-naive metastatic castration-resistant prostate cancer: results from PREVAIL. AB - BACKGROUND: Prostate cancer disproportionately affects older men. Because age affects treatment decisions, it is important to understand the efficacy and tolerability of therapies for advanced prostate cancer in elderly men. This analysis describes efficacy and safety outcomes in men aged >=75 years who received enzalutamide, an androgen receptor inhibitor, in the phase III PREVAIL trial. PATIENTS AND METHODS: PREVAIL was a randomised, double-blind, multinational study of oral enzalutamide 160 mg/day (N = 872) versus placebo (N = 845) in chemotherapy-naive men with metastatic castration-resistant prostate cancer. Overall survival (OS) and radiographic progression-free survival (rPFS) were coprimary end points. Subgroup analysis of men aged >=75 years (elderly) and men aged <75 years was pre-specified for the coprimary end points and adverse events (AEs). RESULTS: Among 609 elderly patients (35%) who participated in PREVAIL, median treatment duration was 16.6 and 5.0 months in the enzalutamide and placebo arms, respectively. In the elderly subgroup, OS was greater with enzalutamide than with placebo [32.4 months (95% confidence interval (CI) 27.7 not yet reached] versus 25.1 months (95% CI 22.6-28.0); hazard ratio (HR) = 0.61 (95% CI 0.47-0.79); P = 0.0001], as was rPFS [not yet reached (95% CI 12.3-not yet reached) versus 3.7 months (95% CI 3.6-5.3); HR = 0.17 (95% CI 0.12-0.24); P < 0.0001]. Irrespective of treatment assignment, incidence of AEs was similar between the two age groups, except for an overall higher incidence of falls among elderly patients than younger patients [84/609 (13.8%) versus 62/1106 (5.6%)] and among elderly patients receiving enzalutamide than those receiving placebo [61/317 (19.2%) versus 23/292 (7.9%)]. CONCLUSIONS: Elderly men benefited from treatment with enzalutamide in terms of OS and rPFS. Enzalutamide was well tolerated in the elderly subgroup and those aged <75 years. Age and enzalutamide treatment were associated with a higher incidence of falls. CLINICAL TRIAL IDENTIFIER: NCT01212991, ClinicalTrials.gov. PMID- 26578736 TI - Phase II study of medroxyprogesterone acetate plus metformin as a fertility sparing treatment for atypical endometrial hyperplasia and endometrial cancer. AB - BACKGROUND: Metformin, widely used in the treatment of type 2 diabetes mellitus, reduces the risk of cancer and relapse after treatment. Fertility-sparing treatment for endometrial cancer (EC) with progestin is associated with a high chance of disease regression, and the high relapse rate continues to be a problem. We assessed the efficacy of metformin in preventing recurrence after medroxyprogesterone acetate (MPA) as fertility-sparing treatment for atypical endometrial hyperplasia (AEH) and EC. PATIENTS AND METHODS: This phase II study enrolled 17 patients with AEH and 19 patients with EC limited to the endometrium (age, 20-40 years). MPA (400 mg/day) and metformin (750-2250 mg/day) were administered for 24-36 weeks to achieve a complete response (CR). Metformin was administered until conception, even after MPA discontinuation. The primary end point was relapse-free survival (RFS) after remission. We analyzed all efficacy end points in the full analysis set. RESULTS: The body mass index was >=25 kg/m(2) in 27 patients (mean, 31 kg/m(2); range, 19-51 kg/m(2)), and the homeostasis model assessment for insulin resistance index was >=2.5 in 24 patients (mean, 4.7; range, 0.7-21). Two patients showed progression at 12 weeks [6%; 95% confidence interval (CI) 2-18]. At 36 weeks, 29 (81%; 95% CI 65-90) patients achieved CR, and 5 (14%; 95% CI 6-29) patients achieved partial response. During a median follow-up of 38 months (range, 9-66 months) after remission, relapse was confirmed in three of the patients who had achieved CR (relapse rate, 10%). The 3-year estimated RFS rate was 89%. No patients experienced severe toxicity. CONCLUSIONS: Metformin inhibited disease relapse after MPA therapy. The combination of metformin and MPA in EC treatment should be studied further. TRIAL REGISTRATION NUMBER: UMIN 000002210. PMID- 26578737 TI - Implications of polygenic risk for personalised colorectal cancer screening. AB - BACKGROUND: We modelled the utility of applying a personalised screening approach for colorectal cancer (CRC) when compared with standard age-based screening. In this personalised screening approach, eligibility is determined by absolute risk which is calculated from age and polygenic risk score (PRS), where the PRS is relative risk attributable to common genetic variation. In contrast, eligibility in age-based screening is determined only by age. DESIGN: We calculated absolute risks of CRC from UK population age structure, incidence and mortality rate data, and a PRS distribution which we derived for the 37 known CRC susceptibility variants. We compared the number of CRC cases potentially detectable by personalised and age-based screening. Using Genome-Wide Complex Trait Analysis to calculate the heritability attributable to common variation, we repeated the analysis assuming all common CRC risk variants were known. RESULTS: Based on the known CRC variants, individuals with a PRS in the top 1% have a 2.9-fold increased CRC risk over the population median. Compared with age-based screening (aged 60: 10-year absolute risk 1.96% in men, 1.19% in women, as per the UK NHS National Bowel Screening Programme), personalised screening of individuals aged 55-69 at the same risk would lead to 16% fewer men and 17% fewer women being eligible for screening with 10% and 8%, respectively, fewer screen-detected cases. If all susceptibility variants were known, individuals with a PRS in the top 1% would have an estimated 7.7-fold increased risk. Personalised screening would then result in 26% fewer men and women being eligible for screening with 7% and 5% fewer screen-detected cases. CONCLUSION: Personalised screening using PRS has the potential to optimise population screening for CRC and to define those likely to maximally benefit from chemoprevention. There are however significant technical and operational details to be addressed before any such programme is introduced. PMID- 26578738 TI - Statistical controversies in clinical research: end points other than overall survival are vital for regulatory approval of anticancer agents. AB - There is an ongoing debate about the relative merits of overall survival (OS) and other metrics that can be used as primary end points in cancer clinical trials. Although survival time is arguably the most objective metric for assessing the efficacy of anticancer treatment, OS as a clinical-trial end point needs to be conceptually distinguished from increased survival time as a goal desired by patients, clinicians and public-health policy makers. OS presents several drawbacks as a primary end point that threatens to hamper further drug development, including the increase in the number of patients and the much longer follow-up required in a clinical trial. In many settings of first-line therapy for metastatic disease, median OS is currently two to four times longer than median progression-free survival. As a result, the analysis of OS may be increasingly confounded by the effect of salvage therapies used after disease progression. In this review, we use straightforward statistical reasoning and examples from the oncology literature to argue that OS should no longer be the primary end point of most future phase III cancer clinical trials that aim at assessing the efficacy of novel therapies in the setting of metastatic disease. PMID- 26578739 TI - Access to innovative oncology medicines in Europe. PMID- 26578740 TI - Prevalence of rare EGFR gene mutations in nonsmall-cell lung cancer: a multicenter study on 3856 Polish Caucasian patients. PMID- 26578741 TI - Vertebrate seed dispersers maintain the composition of tropical forest seedbanks. AB - The accumulation of seeds in the soil (the seedbank) can set the template for the early regeneration of habitats following disturbance. Seed dispersal is an important factor determining the pattern of seed rain, which affects the interactions those seeds experience. For this reason, seed dispersal should play an important role in structuring forest seedbanks, yet we know little about how that happens. Using the functional extirpation of frugivorous vertebrates from the island of Guam, together with two nearby islands (Saipan and Rota) that each support relatively intact disperser assemblages, we aimed to identify the role of vertebrate dispersers in structuring forest seedbanks. We sampled the seedbank on Guam where dispersers are absent, and compared this with the seedbank on Saipan and Rota where they are present. Almost twice as many species found in the seedbank on Guam, when compared with Saipan and Rota, had a conspecific adult within 2 m. This indicates a strong role of vertebrate dispersal in determining the identity of seeds in the seedbank. In addition, on Guam, a greater proportion of samples contained no seeds and overall species richness was lower than on Saipan. Differences in seed abundance and richness between Guam and Rota were less clear, as seedbanks on Rota also contained fewer species than Saipan, possibly due to increased post-dispersal seed predation. Our findings suggest that vertebrate seed dispersers can have a strong influence on the species composition of seedbanks. Regardless of post-dispersal processes, without dispersal, seedbanks no longer serve to increase the species pool of recruits during regeneration. PMID- 26578742 TI - Evolutionary site-number changes of ribosomal DNA loci during speciation: complex scenarios of ancestral and more recent polyploid events. AB - Several genome duplications have been identified in the evolution of seed plants, providing unique systems for studying karyological processes promoting diversification and speciation. Knowledge about the number of ribosomal DNA (rDNA) loci, together with their chromosomal distribution and structure, provides clues about organismal and molecular evolution at various phylogenetic levels. In this work, we aim to elucidate the evolutionary dynamics of karyological and rDNA site-number variation in all known taxa of subtribe Vellinae, showing a complex scenario of ancestral and more recent polyploid events. Specifically, we aim to infer the ancestral chromosome numbers and patterns of chromosome number variation, assess patterns of variation of both 45S and 5S rDNA families, trends in site-number change of rDNA loci within homoploid and polyploid series, and reconstruct the evolutionary history of rDNA site number using a phylogenetic hypothesis as a framework. The best-fitting model of chromosome number evolution with a high likelihood score suggests that the Vellinae core showing x = 17 chromosomes arose by duplication events from a recent x = 8 ancestor. Our survey suggests more complex patterns of polyploid evolution than previously noted for Vellinae. High polyploidization events (6x, 8x) arose independently in the basal clade Vella castrilensis-V. lucentina, where extant diploid species are unknown. Reconstruction of ancestral rDNA states in Vellinae supports the inference that the ancestral number of loci in the subtribe was two for each multigene family, suggesting that an overall tendency towards a net loss of 5S rDNA loci occurred during the splitting of Vellinae ancestors from the remaining Brassiceae lineages. A contrasting pattern for rDNA site change in both paleopolyploid and neopolyploid species was linked to diversification of Vellinae lineages. This suggests dynamic and independent changes in rDNA site number during speciation processes and a significant lack of correlation between 45S and 5S rDNA evolutionary pathways. PMID- 26578743 TI - Root aeration improves growth and nitrogen accumulation in rice seedlings under low nitrogen. AB - In wetland soils, changes in oxygen (O2) level in the rhizosphere are believed to influence the behaviour of nutrients and their usage by plants. However, the effect of aeration on nitrogen (N) acquisition under different N supply conditions remains largely unknown. In this study, the rice cultivars Yangdao 6 (YD6, with higher root aerenchyma abundance) and Nongken 57 (NK57, with lower root aerenchyma abundance) were used to evaluate the effects of aeration on rice growth and N accumulation. Our results showed that the number of adventitious roots and the root surface area increased significantly, and ethylene production and aerenchyma formation decreased in both cultivars after external aeration (EA). Five N treatments, including no N (-N), 0.125 mM NH4NO3 (LN), 1.25 mM Ca(NO3)2 (NO3-N), 1.25 mM (NH4)2SO4 (NH4-N) and 1.25 mM NH4NO3 (N/N), were applied to YD6 and NK57 for 2 days under internal aeration or EA conditions. External aeration increased the root biomass in both cultivars and the shoot biomass in NK57 by 18-50 %. The total N concentrations in roots of YD6 grown under -N and LN and of NK57 grown under NO3-N were increased by EA. Expression of OsPAD4, one of four putative genes regulating aerenchyma formation, showed a similar pattern alongside changes in the ethylene level in the EA-treated rice irrespective of the N treatments. Furthermore, expression of the high-affinity nitrate transporter gene OsNRT2.1 was increased by EA under -N, LN and NO3-N conditions. Our data provide evidence of an interaction between O2 and the supply of N in ethylene production, aerenchyma formation and N nutrition through modification of the expression of OsPAD4 and OsNRT2.1. PMID- 26578744 TI - Inbreeding effects in a mixed-mating vine: effects of mating history, pollen competition and stress on the cost of inbreeding. AB - Inbreeding depression is assumed to be a central factor contributing to the stability of plant mating systems. Predicting the fitness consequence of inbreeding in natural populations is complicated, however, because it may be affected by the mating histories of populations generating variation in the amount of purging of deleterious alleles. Furthermore, the level of inbreeding depression may depend on environmental conditions and the intensity of pollen competition. In a greenhouse experiment comparing four populations of the neotropical vine Dalechampia scandens (Euphorbiaceae), we tested whether inbreeding depression for early-life fitness depended on the inferred mating history of each population, as indicated by genetically determined differences in herkogamy and autofertility rates. We also tested whether the intensity of pollen competition and the level of stress encountered by the seeds and seedlings affected the amount of inbreeding depression observed. Herkogamy was a good predictor of autofertility in each population. However, we found only limited evidence for inbreeding depression in any population, and inbreeding depression varied independently of the intensity of pollen competition and amount of stress encountered by the seeds and seedlings. Thus, the population's rate of autofertility did not predict the amount of inbreeding depression. Overall, we found no evidence supporting the expectations that more inbred populations experience less inbreeding depression, and that pollen competition reduces the cost of inbreeding. These results suggest that additional factors may be responsible for the maintenance of the mixed mating systems of D. scandens populations. PMID- 26578745 TI - Bergamot versus beetle: evidence for intraspecific chemical specialization. AB - A large proportion of phytophagous insects show host plant specificity (monophagy or oligophagy), often determined by host secondary chemistry. Yet, even specialists can be negatively affected by host chemistry at high levels or with novel compounds, which may manifest itself if their host species is chemically variable. This study tested for reciprocal effects of a specialist tortoise beetle (Physonota unipunctata) feeding on a host plant (Monarda fistulosa) with two monoterpene chemotypes [thymol (T) and carvacrol (C)] using a controlled field experiment where larvae fed on caged plants of both chemotypes, haphazardly collected natural plants with and without beetle damage, and growth chamber experiments where larvae that hatched and briefly fed on one chemotype were reared on either chemotype. In the field experiment, plant chemotype did not affect larval weight or length, but did influence larval survival with almost 8.3 % more surviving on T plants. Herbivores reduced seed head area (86.5 % decrease), stem mass (41.2 %) and stem height (21.1 %) of caged plants, but this was independent of host chemotype. Natural plants experienced similar reductions in these variables (74.0, 41.4 and 8.7 %) and T chemotypes were more frequently damaged. In the growth chamber, larval relative growth rate (RGR) differed for both feeding history and year. Larvae from T natal plants reared on T hosts grew at almost twice the rate of those from C and reared on T. Larvae from either T or C natal plants reared on C plants showed intermediate growth rates. Additional analyses revealed natal plant chemotype as the most important factor, with the RGR of larvae from T natal plants almost one-third higher than that of those from C natal plants. These cumulative results demonstrate intraspecific variation in plant resistance that may lead to herbivore specialization on distinct host chemistry, which has implications for the evolutionary trajectory of both the insect and plant species. PMID- 26578746 TI - Coeliac disease in the ERA of the new ESPGHAN and BSPGHAN guidelines: a prospective cohort study. AB - OBJECTIVE: To evaluate the consequences of the last European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and British Society of Paediatric Gastroenterology, Hepatology and Nutrition (BSPGHAN) guidelines for the diagnosis of coeliac disease (CD) by means of a prospective study. DESIGN: Prospective cohort study. SETTING: Institute for Maternal and Child Health IRCCS Burlo Garofolo (Trieste, Italy). PATIENTS: Children diagnosed with CD without a duodenal biopsy (group 1), following the last ESPGHAN and BSPGHAN guidelines, and children diagnosed with a duodenal biopsy, matched for sex, age and year of diagnosis (group 2), were prospectively enrolled over a 3 year period. All patients were put on a gluten-free diet (GFD) and were followed up for clinical conditions and laboratory testing at 6 months every year since diagnosis (median follow up: 1.9 years). OUTCOME MEASURES: Resolution of symptoms, body mass index, laboratory testing (haemoglobin, anti-transglutaminase IgA), adherence to a GFD, quality of life, and supplementary post-diagnosis medical consultations. RESULTS: 51 out of 468 (11%) patients were diagnosed without a duodenal biopsy (group 1; median age 2.1 years) and matched to 92 patients diagnosed with a biopsy (group 2; median age 2.4 years). At the end of follow-up the two groups were statistically comparable in terms of clinical and nutritional status, anti-transglutaminase IgA antibody titres, quality of life, adherence to a GFD, and number of supplementary medical consultations. CONCLUSIONS: On the basis of this prospective study, diagnosis of CD can be reliably performed without a duodenal biopsy in approximately 11% of cases. At least during a medium-term follow-up, this approach has no negative consequences relating to clinical remission, adherence to diet, and quality of life of children with CD. PMID- 26578747 TI - Preoperative Risk Factors and Complication Rates in Facelift: Analysis of 11,300 Patients. AB - BACKGROUND: Facelift (rhytidectomy) is a prominent technique for facial rejuvenation with 126 713 performed in the United States in 2014. Current literature on facelift complications is inconclusive and derives from retrospective studies. OBJECTIVES: This study reports the incidence and risk factors of major complications following facelift in a large, prospective, multi center database. It compares complications of facelifts done alone or in combination with other cosmetic surgical procedures. METHODS: A prospective cohort of patients undergoing facelift between 2008 and 2013 was identified from the CosmetAssure database. Primary outcome was occurrence of major complications, defined as complications requiring emergency room (ER) visit, hospital admission, or reoperation within 30 days of the procedure. Univariate and multivariate analysis evaluated risk factors including age, gender, BMI, smoking, diabetes, combined procedures, and type of surgical facility. RESULTS: Of the 129 007 patients enrolled in CosmetAssure, 11 300 (8.8%) underwent facelifts. Facelift cohort had more males (8.8%), diabetics (2.7%), elderly (mean age 59.2 years) and obese (38.5%) induviduals, but fewer smokers (4.8%). Combined procedures accounted for 57.4% of facelifts. Facelifts had a 1.8% complication rate, similar to the rate of 2% associated to other cosmetic surgeries. Hematoma (1.1%) and infection (0.3%) were most common. Combined procedures had up to 3.7% complication rate compared to 1.5% in facelifts alone. Male gender (relative risk 3.9) and type of facility (relative risk 2.6) were independent predictors of hematoma. Combined procedures (relative risk 3.5) and BMI >= 25 (relative risk 2.8) increased infection risk. CONCLUSIONS: Rhytidectomy is a very safe procedure in the hands of board-certified plastic surgeons. Hematoma and infection are the most common major complications. Male gender, BMI >= 25, and combined procedures are independent risk factors. LEVEL OF EVIDENCE 2: Risk. PMID- 26578748 TI - Double-Loop Dermal Suture: A Technique for High-Tension Wound Closure. PMID- 26578749 TI - Bidirectional expression of long ncRNA/protein-coding gene pairs in cancer. AB - Bidirectional initiation of transcription by RNA polymerase II occurs prevalently at active promoters during protein-coding gene (PCG) expression. Upstream, antisense noncoding RNAs (ncRNAs) of differing lengths, stabilities and processings are being expressed from these promoters in concert with downstream, processive messenger RNA transcription. Although abundantly detected, the functional role and regulatory capacity of such transcripts have only been determined for individual cases. Long ncRNAs in general are reportedly able to regulate all steps of the gene expression process. Therefore, to get insight into the functionality of long ncRNAs transcribed bidirectionally from cancer associated PCGs is of interest, as expression changes of tumor suppressor genes and oncogenes are prevalent in cancer.Here, we review the sources and characteristics of antisense transcription occurring at PCG loci in the human genome, and focus on the functional impact of bidirectional long ncRNA expression at cancer-associated PCGs. PMID- 26578750 TI - Comments on Smith (2015)-'The past, present and future of mitochondrial genomics: have we sequenced enough mtDNAs'. PMID- 26578752 TI - Inner Workings: Climate change frees ancient artifacts. PMID- 26578751 TI - Feeding the brain and nurturing the mind: Linking nutrition and the gut microbiota to brain development. AB - The human gut contains a microbial community composed of tens of trillions of organisms that normally assemble during the first 2-3 y of postnatal life. We propose that brain development needs to be viewed in the context of the developmental biology of this "microbial organ" and its capacity to metabolize the various diets we consume. We hypothesize that the persistent cognitive abnormalities seen in children with undernutrition are related in part to their persistent gut microbiota immaturity and that specific regions of the brain that normally exhibit persistent juvenile (neotenous) patterns of gene expression, including those critically involved in various higher cognitive functions such as the brain's default mode network, may be particularly vulnerable to the effects of microbiota immaturity in undernourished children. Furthermore, we postulate that understanding the interrelationships between microbiota and brain metabolism in childhood undernutrition could provide insights about responses to injury seen in adults. We discuss approaches that can be used to test these hypotheses, their ramifications for optimizing nutritional recommendations that promote healthy brain development and function, and the potential societal implications of this area of investigation. PMID- 26578753 TI - Core Concept: Resting-state connectivity. PMID- 26578754 TI - Bill Paul: The heart of immunology. PMID- 26578756 TI - Path selection in the growth of rivers. AB - River networks exhibit a complex ramified structure that has inspired decades of studies. However, an understanding of the propagation of a single stream remains elusive. Here we invoke a criterion for path selection from fracture mechanics and apply it to the growth of streams in a diffusion field. We show that, as it cuts through the landscape, a stream maintains a symmetric groundwater flow around its tip. The local flow conditions therefore determine the growth of the drainage network. We use this principle to reconstruct the history of a network and to find a growth law associated with it. Our results show that the deterministic growth of a single channel based on its local environment can be used to characterize the structure of river networks. PMID- 26578757 TI - Kinetics methods for clinical epidemiology problems. AB - Calculating the probability of each possible outcome for a patient at any time in the future is currently possible only in the simplest cases: short-term prediction in acute diseases of otherwise healthy persons. This problem is to some extent analogous to predicting the concentrations of species in a reactor when knowing initial concentrations and after examining reaction rates at the individual molecule level. The existing theoretical framework behind predicting contagion and the immediate outcome of acute diseases in previously healthy individuals is largely analogous to deterministic kinetics of chemical systems consisting of one or a few reactions. We show that current statistical models commonly used in chronic disease epidemiology correspond to simple stochastic treatment of single reaction systems. The general problem corresponds to stochastic kinetics of complex reaction systems. We attempt to formulate epidemiologic problems related to chronic diseases in chemical kinetics terms. We review methods that may be adapted for use in epidemiology. We show that some reactions cannot fit into the mass-action law paradigm and solutions to these systems would frequently exhibit an antiportfolio effect. We provide a complete example application of stochastic kinetics modeling for a deductive meta-analysis of two papers on atrial fibrillation incidence, prevalence, and mortality. PMID- 26578758 TI - High-temperature in situ crystallographic observation of reversible gas sorption in impermeable organic cages. AB - Crystallographic observation of adsorbed gas molecules is a highly difficult task due to their rapid motion. Here, we report the in situ single-crystal and synchrotron powder X-ray observations of reversible CO2 sorption processes in an apparently nonporous organic crystal under varying pressures at high temperatures. The host material is formed by hydrogen bond network between 1,3,5 tris-(4-carboxyphenyl)benzene (H3BTB) and N,N-dimethylformamide (DMF) and by pi pi stacking between the H3BTB moieties. The material can be viewed as a well ordered array of cages, which are tight packed with each other so that the cages are inaccessible from outside. Thus, the host is practically nonporous. Despite the absence of permanent pathways connecting the empty cages, they are permeable to CO2 at high temperatures due to thermally activated molecular gating, and the weakly confined CO2 molecules in the cages allow direct detection by in situ single-crystal X-ray diffraction at 323 K. Variable-temperature in situ synchrotron powder X-ray diffraction studies also show that the CO2 sorption is reversible and driven by temperature increase. Solid-state magic angle spinning NMR defines the interactions of CO2 with the organic framework and dynamic motion of CO2 in cages. The reversible sorption is attributed to the dynamic motion of the DMF molecules combined with the axial motions/angular fluctuations of CO2 (a series of transient opening/closing of compartments enabling CO2 molecule passage), as revealed from NMR and simulations. This temperature-driven transient molecular gating can store gaseous molecules in ordered arrays toward unique collective properties and release them for ready use. PMID- 26578759 TI - Seasonal fluxes of carbonyl sulfide in a midlatitude forest. AB - Carbonyl sulfide (OCS), the most abundant sulfur gas in the atmosphere, has a summer minimum associated with uptake by vegetation and soils, closely correlated with CO2. We report the first direct measurements to our knowledge of the ecosystem flux of OCS throughout an annual cycle, at a mixed temperate forest. The forest took up OCS during most of the growing season with an overall uptake of 1.36 +/- 0.01 mol OCS per ha (43.5 +/- 0.5 g S per ha, 95% confidence intervals) for the year. Daytime fluxes accounted for 72% of total uptake. Both soils and incompletely closed stomata in the canopy contributed to nighttime fluxes. Unexpected net OCS emission occurred during the warmest weeks in summer. Many requirements necessary to use fluxes of OCS as a simple estimate of photosynthesis were not met because OCS fluxes did not have a constant relationship with photosynthesis throughout an entire day or over the entire year. However, OCS fluxes provide a direct measure of ecosystem-scale stomatal conductance and mesophyll function, without relying on measures of soil evaporation or leaf temperature, and reveal previously unseen heterogeneity of forest canopy processes. Observations of OCS flux provide powerful, independent means to test and refine land surface and carbon cycle models at the ecosystem scale. PMID- 26578760 TI - Formation and evolution of molecular products in alpha-pinene secondary organic aerosol. AB - Much of our understanding of atmospheric secondary organic aerosol (SOA) formation from volatile organic compounds derives from laboratory chamber measurements, including mass yield and elemental composition. These measurements alone are insufficient to identify the chemical mechanisms of SOA production. We present here a comprehensive dataset on the molecular identity, abundance, and kinetics of alpha-pinene SOA, a canonical system that has received much attention owing to its importance as an organic aerosol source in the pristine atmosphere. Identified organic species account for ~58-72% of the alpha-pinene SOA mass, and are characterized as semivolatile/low-volatility monomers and extremely low volatility dimers, which exhibit comparable oxidation states yet different functionalities. Features of the alpha-pinene SOA formation process are revealed for the first time, to our knowledge, from the dynamics of individual particle phase components. Although monomeric products dominate the overall aerosol mass, rapid production of dimers plays a key role in initiating particle growth. Continuous production of monomers is observed after the parent alpha-pinene is consumed, which cannot be explained solely by gas-phase photochemical production. Additionally, distinct responses of monomers and dimers to alpha-pinene oxidation by ozone vs. hydroxyl radicals, temperature, and relative humidity are observed. Gas-phase radical combination reactions together with condensed phase rearrangement of labile molecules potentially explain the newly characterized SOA features, thereby opening up further avenues for understanding formation and evolution mechanisms of alpha-pinene SOA. PMID- 26578761 TI - Fate of MgSiO3 melts at core-mantle boundary conditions. AB - One key for understanding the stratification in the deep mantle lies in the determination of the density and structure of matter at high pressures, as well as the density contrast between solid and liquid silicate phases. Indeed, the density contrast is the main control on the entrainment or settlement of matter and is of fundamental importance for understanding the past and present dynamic behavior of the deepest part of the Earth's mantle. Here, we adapted the X-ray absorption method to the small dimensions of the diamond anvil cell, enabling density measurements of amorphous materials to unprecedented conditions of pressure. Our density data for MgSiO3 glass up to 127 GPa are considerably higher than those previously derived from Brillouin spectroscopy but validate recent ab initio molecular dynamics simulations. A fourth-order Birch-Murnaghan equation of state reproduces our experimental data over the entire pressure regime of the mantle. At the core-mantle boundary (CMB) pressure, the density of MgSiO3 glass is 5.48 +/- 0.18 g/cm(3), which is only 1.6% lower than that of MgSiO3 bridgmanite at 5.57 g/cm(3), i.e., they are the same within the uncertainty. Taking into account the partitioning of iron into the melt, we conclude that melts are denser than the surrounding solid phases in the lowermost mantle and that melts will be trapped above the CMB. PMID- 26578762 TI - Collapse of the West Antarctic Ice Sheet after local destabilization of the Amundsen Basin. AB - The future evolution of the Antarctic Ice Sheet represents the largest uncertainty in sea-level projections of this and upcoming centuries. Recently, satellite observations and high-resolution simulations have suggested the initiation of an ice-sheet instability in the Amundsen Sea sector of West Antarctica, caused by the last decades' enhanced basal ice-shelf melting. Whether this localized destabilization will yield a full discharge of marine ice from West Antarctica, associated with a global sea-level rise of more than 3 m, or whether the ice loss is limited by ice dynamics and topographic features, is unclear. Here we show that in the Parallel Ice Sheet Model, a local destabilization causes a complete disintegration of the marine ice in West Antarctica. In our simulations, at 5-km horizontal resolution, the region disequilibrates after 60 y of currently observed melt rates. Thereafter, the marine ice-sheet instability fully unfolds and is not halted by topographic features. In fact, the ice loss in Amundsen Sea sector shifts the catchment's ice divide toward the Filchner-Ronne and Ross ice shelves, which initiates grounding line retreat there. Our simulations suggest that if a destabilization of Amundsen Sea sector has indeed been initiated, Antarctica will irrevocably contribute at least 3 m to global sea-level rise during the coming centuries to millennia. PMID- 26578763 TI - Twisted photon entanglement through turbulent air across Vienna. AB - Photons with a twisted phase front can carry a discrete, in principle, unbounded amount of orbital angular momentum (OAM). The large state space allows for complex types of entanglement, interesting both for quantum communication and for fundamental tests of quantum theory. However, the distribution of such entangled states over large distances was thought to be infeasible due to influence of atmospheric turbulence, indicating a serious limitation on their usefulness. Here we show that it is possible to distribute quantum entanglement encoded in OAM over a turbulent intracity link of 3 km. We confirm quantum entanglement of the first two higher-order levels (with OAM=+/- 1h and +/- 2h). They correspond to four additional quantum channels orthogonal to all that have been used in long distance quantum experiments so far. Therefore, a promising application would be quantum communication with a large alphabet. We also demonstrate that our link allows access to up to 11 quantum channels of OAM. The restrictive factors toward higher numbers are technical limitations that can be circumvented with readily available technologies. PMID- 26578764 TI - Teleportation of entanglement over 143 km. AB - As a direct consequence of the no-cloning theorem, the deterministic amplification as in classical communication is impossible for unknown quantum states. This calls for more advanced techniques in a future global quantum network, e.g., for cloud quantum computing. A unique solution is the teleportation of an entangled state, i.e., entanglement swapping, representing the central resource to relay entanglement between distant nodes. Together with entanglement purification and a quantum memory it constitutes a so-called quantum repeater. Since the aforementioned building blocks have been individually demonstrated in laboratory setups only, the applicability of the required technology in real-world scenarios remained to be proven. Here we present a free space entanglement-swapping experiment between the Canary Islands of La Palma and Tenerife, verifying the presence of quantum entanglement between two previously independent photons separated by 143 km. We obtained an expectation value for the entanglement-witness operator, more than 6 SDs beyond the classical limit. By consecutive generation of the two required photon pairs and space-like separation of the relevant measurement events, we also showed the feasibility of the swapping protocol in a long-distance scenario, where the independence of the nodes is highly demanded. Because our results already allow for efficient implementation of entanglement purification, we anticipate our research to lay the ground for a fully fledged quantum repeater over a realistic high-loss and even turbulent quantum channel. PMID- 26578765 TI - Filming the formation and fluctuation of skyrmion domains by cryo-Lorentz transmission electron microscopy. AB - Magnetic skyrmions are promising candidates as information carriers in logic or storage devices thanks to their robustness, guaranteed by the topological protection, and their nanometric size. Currently, little is known about the influence of parameters such as disorder, defects, or external stimuli on the long-range spatial distribution and temporal evolution of the skyrmion lattice. Here, using a large (7.3 * 7.3 MUm(2)) single-crystal nanoslice (150 nm thick) of Cu2OSeO3, we image up to 70,000 skyrmions by means of cryo-Lorentz transmission electron microscopy as a function of the applied magnetic field. The emergence of the skyrmion lattice from the helimagnetic phase is monitored, revealing the existence of a glassy skyrmion phase at the phase transition field, where patches of an octagonally distorted skyrmion lattice are also discovered. In the skyrmion phase, dislocations are shown to cause the emergence and switching between domains with different lattice orientations, and the temporal fluctuation of these domains is filmed. These results demonstrate the importance of direct-space and real-time imaging of skyrmion domains for addressing both their long-range topology and stability. PMID- 26578766 TI - Transition to farming more likely for small, conservative groups with property rights, but increased productivity is not essential. AB - Theories for the origins of agriculture are still debated, with a range of different explanations offered. Computational models can be used to test these theories and explore new hypotheses; Bowles and Choi [Bowles S, Choi J-K (2013) Proc Natl Acad Sci USA 110(22):8830-8835] have developed one such model. Their model shows the coevolution of farming and farming-friendly property rights, and by including climate variability, replicates the timings for the emergence of these events seen in the archaeological record. Because the processes modeled occurred a long time ago, it can be difficult to justify exact parameter values; hence, we propose a fitting to idealized outcomes (FIO) method to explore the model's parameter space in more detail. We have replicated the model of Bowles and Choi, and used the FIO method to identify complexities and interactions of the model previously unidentified. Our results indicate that the key parameters for the emergence of farming are group structuring, group size, conservatism, and farming-friendly property rights (lending further support to Bowles and Choi's original proposal). We also find that although advantageous, it is not essential that farming productivity be greater than foraging productivity for farming to emerge. In addition, we highlight how model behaviors can be missed when gauging parameter sensitivity via a fix-all-but-one variation approach. PMID- 26578767 TI - Gating mechanisms of a natural anion channelrhodopsin. AB - Anion channelrhodopsins (ACRs) are a class of light-gated channels recently identified in cryptophyte algae that provide unprecedented fast and powerful hyperpolarizing tools for optogenetics. Analysis of photocurrents generated by Guillardia theta ACR 1 (GtACR1) and its mutants in response to laser flashes showed that GtACR1 gating comprises two separate mechanisms with opposite dependencies on the membrane voltage and pH and involving different amino acid residues. The first mechanism, characterized by slow opening and fast closing of the channel, is regulated by Glu-68. Neutralization of this residue (the E68Q mutation) specifically suppressed this first mechanism, but did not eliminate it completely at high pH. Our data indicate the involvement of another, yet unidentified pH-sensitive group X. Introducing a positive charge at the Glu-68 site (the E68R mutation) inverted the channel gating so that it was open in the dark and closed in the light, without altering its ion selectivity. The second mechanism, characterized by fast opening and slow closing of the channel, was not substantially affected by the E68Q mutation, but was controlled by Cys-102. The C102A mutation reduced the rate of channel closing by the second mechanism by ~100-fold, whereas it had only a twofold effect on the rate of the first. The results show that anion conductance by ACRs has a fundamentally different structural basis than the relatively well studied conductance by cation channelrhodopsins (CCRs), not attributable to simply a modification of the CCR selectivity filter. PMID- 26578768 TI - Structural basis for the binding of tryptophan-based motifs by delta-COP. AB - Coatomer consists of two subcomplexes: the membrane-targeting, ADP ribosylation factor 1 (Arf1):GTP-binding betagammadeltazeta-COP F-subcomplex, which is related to the adaptor protein (AP) clathrin adaptors, and the cargo-binding alphabeta'epsilon-COP B-subcomplex. We present the structure of the C-terminal MU homology domain of the yeast delta-COP subunit in complex with the WxW motif from its binding partner, the endoplasmic reticulum-localized Dsl1 tether. The motif binds at a site distinct from that used by the homologous AP MU subunits to bind YxxPhi cargo motifs with its two tryptophan residues sitting in compatible pockets. We also show that the Saccharomyces cerevisiae Arf GTPase-activating protein (GAP) homolog Gcs1p uses a related WxxF motif at its extreme C terminus to bind to delta-COP at the same site in the same way. Mutations designed on the basis of the structure in conjunction with isothermal titration calorimetry confirm the mode of binding and show that mammalian delta-COP binds related tryptophan-based motifs such as that from ArfGAP1 in a similar manner. We conclude that delta-COP subunits bind Wxn(1-6)[WF] motifs within unstructured regions of proteins that influence the lifecycle of COPI-coated vesicles; this conclusion is supported by the observation that, in the context of a sensitizing domain deletion in Dsl1p, mutating the tryptophan-based motif-binding site in yeast causes defects in both growth and carboxypeptidase Y trafficking/processing. PMID- 26578769 TI - Single-molecule view of basal activity and activation mechanisms of the G protein coupled receptor beta2AR. AB - Binding of extracellular ligands to G protein-coupled receptors (GPCRs) initiates transmembrane signaling by inducing conformational changes on the cytoplasmic receptor surface. Knowledge of this process provides a platform for the development of GPCR-targeting drugs. Here, using a site-specific Cy3 fluorescence probe in the human beta2-adrenergic receptor (beta2AR), we observed that individual receptor molecules in the native-like environment of phospholipid nanodiscs undergo spontaneous transitions between two distinct conformational states. These states are assigned to inactive and active-like receptor conformations. Individual receptor molecules in the apo form repeatedly sample both conformations, with a bias toward the inactive conformation. Experiments in the presence of drug ligands show that binding of the full agonist formoterol shifts the conformational distribution in favor of the active-like conformation, whereas binding of the inverse agonist ICI-118,551 favors the inactive conformation. Analysis of single-molecule dwell-time distributions for each state reveals that formoterol increases the frequency of activation transitions, while also reducing the frequency of deactivation events. In contrast, the inverse agonist increases the frequency of deactivation transitions. Our observations account for the high level of basal activity of this receptor and provide insights that help to rationalize, on the molecular level, the widely documented variability of the pharmacological efficacies among GPCR-targeting drugs. PMID- 26578770 TI - High-resolution structures of the M2 channel from influenza A virus reveal dynamic pathways for proton stabilization and transduction. AB - The matrix 2 (M2) protein from influenza A virus is a proton channel that uses His37 as a selectivity filter. Here we report high-resolution (1.10 A) cryogenic crystallographic structures of the transmembrane domain of M2 at low and high pH. These structures reveal that waters within the pore form hydrogen-bonded networks or "water wires" spanning 17 A from the channel entrance to His37. Pore-lining carbonyl groups are well situated to stabilize hydronium via second-shell interactions involving bridging water molecules. In addition, room temperature crystallographic structures indicate that water becomes increasingly fluid with increasing temperature and decreasing pH, despite the higher electrostatic field. Complementary molecular dynamics simulations reveal a collective switch of hydrogen bond orientations that can contribute to the directionality of proton flux as His37 is dynamically protonated and deprotonated in the conduction cycle. PMID- 26578771 TI - Electron cryotomography reveals ultrastructure alterations in platelets from patients with ovarian cancer. AB - Thrombocytosis and platelet hyperreactivity are known to be associated with malignancy; however, there have been no ultrastructure studies of platelets from patients with ovarian cancer. Here, we used electron cryotomography (cryo-ET) to examine frozen-hydrated platelets from patients with invasive ovarian cancer (n = 12) and control subjects either with benign adnexal mass (n = 5) or free from disease (n = 6). Qualitative inspections of the tomograms indicate significant morphological differences between the cancer and control platelets, including disruption of the microtubule marginal band. Quantitative analysis of subcellular features in 120 platelet electron tomograms from these two groups showed statistically significant differences in mitochondria, as well as microtubules. These structural variations in the platelets from the patients with cancer may be correlated with the altered platelet functions associated with malignancy. Cryo ET of platelets shows potential as a noninvasive biomarker technology for ovarian cancer and other platelet-related diseases. PMID- 26578772 TI - Direct real-time detection of the structural and biochemical events in the myosin power stroke. AB - A principal goal of molecular biophysics is to show how protein structural transitions explain physiology. We have developed a strategic tool, transient time-resolved FRET [(TR)(2)FRET], for this purpose and use it here to measure directly, with millisecond resolution, the structural and biochemical kinetics of muscle myosin and to determine directly how myosin's power stroke is coupled to the thermodynamic drive for force generation, actin-activated phosphate release, and the weak-to-strong actin-binding transition. We find that actin initiates the power stroke before phosphate dissociation and not after, as many models propose. This result supports a model for muscle contraction in which power output and efficiency are tuned by the distribution of myosin structural states. This technology should have wide application to other systems in which questions about the temporal coupling of allosteric structural and biochemical transitions remain unanswered. PMID- 26578773 TI - PML IV/ARF interaction enhances p53 SUMO-1 conjugation, activation, and senescence. AB - Promyelocytic leukemia protein (PML) nuclear bodies (NBs) recruit multiple partners, including p53 and many of its regulators. NBs are believed to facilitate several posttranslational modifications and are key regulators of senescence. PML, the organizer of NBs, is expressed as a number of splice variants that all efficiently recruit p53 partners. However, overexpression of only one of them, PML IV, triggers p53-driven senescence. Here, we show that PML IV specifically binds ARF, a key p53 regulator. Similar to ARF, PML IV enhances global SUMO-1 conjugation, particularly that of p53, resulting in p53 stabilization and activation. ARF interacts with and stabilizes the NB-associated UBC9 SUMO-conjugating enzyme, possibly explaining PML IV-enhanced SUMOylation. These results unexpectedly link two key tumor suppressors, highlighting their convergence for global control of SUMO conjugation, p53 activation, and senescence induction. PMID- 26578774 TI - Persistent impacts of West Nile virus on North American bird populations. AB - Since its introduction to North America in 1999, West Nile virus (WNV) has had devastating impacts on native host populations, but to date these impacts have been difficult to measure. Using a continental-scale dataset comprised of a quarter-million birds captured over nearly two decades and a recently developed model of WNV risk, we estimated the impact of this emergent disease on the survival of avian populations. We find that populations were negatively affected by WNV in 23 of the 49 species studied (47%). We distinguished two groups of species: those for which WNV negatively impacted survival only during initial spread of the disease (n = 11), and those that show no signs of recovery since disease introduction (n = 12). Results provide a novel example of the taxonomic breadth and persistent impacts of this wildlife disease on a continental scale. Phylogenetic analyses further identify groups (New World sparrows, finches, and vireos) disproportionally affected by temporary or persistent WNV effects, suggesting an evolutionary dimension of disease risk. Identifying the factors affecting the persistence of a disease across host species is critical to mitigating its effects, particularly in a world marked by rapid anthropogenic change. PMID- 26578775 TI - Facilitation shifts paradigms and can amplify coastal restoration efforts. AB - Restoration has been elevated as an important strategy to reverse the decline of coastal wetlands worldwide. Current practice in restoration science emphasizes minimizing competition between out-planted propagules to maximize planting success. This paradigm persists despite the fact that foundational theory in ecology demonstrates that positive species interactions are key to organism success under high physical stress, such as recolonization of bare substrate. As evidence of how entrenched this restoration paradigm is, our survey of 25 restoration organizations in 14 states in the United States revealed that >95% of these agencies assume minimizing negative interactions (i.e., competition) between outplants will maximize propagule growth. Restoration experiments in both Western and Eastern Atlantic salt marshes demonstrate, however, that a simple change in planting configuration (placing propagules next to, rather than at a distance from, each other) results in harnessing facilitation and increased yields by 107% on average. Thus, small adjustments in restoration design may catalyze untapped positive species interactions, resulting in significantly higher restoration success with no added cost. As positive interactions between organisms commonly occur in coastal ecosystems (especially in more physically stressful areas like uncolonized substrate) and conservation resources are limited, transformation of the coastal restoration paradigm to incorporate facilitation theory may enhance conservation efforts, shoreline defense, and provisioning of ecosystem services such as fisheries production. PMID- 26578776 TI - Life and extinction of megafauna in the ice-age Arctic. AB - Understanding the population dynamics of megafauna that inhabited the mammoth steppe provides insights into the causes of extinctions during both the terminal Pleistocene and today. Our study area is Alaska's North Slope, a place where humans were rare when these extinctions occurred. After developing a statistical approach to remove the age artifacts caused by radiocarbon calibration from a large series of dated megafaunal bones, we compare the temporal patterns of bone abundance with climate records. Megafaunal abundance tracked ice age climate, peaking during transitions from cold to warm periods. These results suggest that a defining characteristic of the mammoth steppe was its temporal instability and imply that regional extinctions followed by population reestablishment from distant refugia were characteristic features of ice-age biogeography at high latitudes. It follows that long-distance dispersal was crucial for the long-term persistence of megafaunal species living in the Arctic. Such dispersal was only possible when their rapidly shifting range lands were geographically interconnected. The end of the last ice age was fatally unique because the geographic ranges of arctic megafauna became permanently fragmented after stable, interglacial climate engendered the spread of peatlands at the same time that rising sea level severed former dispersal routes. PMID- 26578778 TI - An anticomplement agent that homes to the damaged brain and promotes recovery after traumatic brain injury in mice. AB - Activation of complement is a key determinant of neuropathology and disability after traumatic brain injury (TBI), and inhibition is neuroprotective. However, systemic complement is essential to fight infections, a critical complication of TBI. We describe a targeted complement inhibitor, comprising complement receptor of the Ig superfamily (CRIg) fused with complement regulator CD59a, designed to inhibit membrane attack complex (MAC) assembly at sites of C3b/iC3b deposition. CRIg and CD59a were linked via the IgG2a hinge, yielding CD59-2a-CRIg dimer with increased iC3b/C3b binding avidity and MAC inhibitory activity. CD59-2a-CRIg inhibited MAC formation and prevented complement-mediated lysis in vitro. CD59-2a CRIg dimer bound C3b-coated surfaces with submicromolar affinity (KD). In experimental TBI, CD59-2a-CRIg administered posttrauma homed to sites of injury and significantly reduced MAC deposition, microglial accumulation, mitochondrial stress, and axonal damage and enhanced neurologic recovery compared with placebo controls. CD59-2a-CRIg inhibited MAC-induced inflammasome activation and IL-1beta production in microglia. Given the important anti-infection roles of complement opsonization, site-targeted inhibition of MAC should be considered to promote recovery postneurotrauma. PMID- 26578777 TI - Community rescue in experimental metacommunities. AB - The conditions that allow biodiversity to recover following severe environmental degradation are poorly understood. We studied community rescue, the recovery of a viable community through the evolutionary rescue of many populations within an evolving community, in metacommunities of soil microbes adapting to a herbicide. The metacommunities occupied a landscape of crossed spatial gradients of the herbicide (Dalapon) and a resource (glucose), whereas their constituent communities were either isolated or connected by dispersal. The spread of adapted communities across the landscape and the persistence of communities when that landscape was degraded were strongly promoted by dispersal, and the capacity to adapt to lethal stress was also related to community size and initial diversity. After abrupt and lethal stress, community rescue was most frequent in communities that had previously experienced sublethal levels of stress and had been connected by dispersal. Community rescue occurred through the evolutionary rescue of both initially common taxa, which remained common, and of initially rare taxa, which grew to dominate the evolved community. Community rescue may allow productivity and biodiversity to recover from severe environmental degradation. PMID- 26578779 TI - Role of vascular density and normalization in response to neoadjuvant bevacizumab and chemotherapy in breast cancer patients. AB - Preoperative bevacizumab and chemotherapy may benefit a subset of breast cancer (BC) patients. To explore potential mechanisms of this benefit, we conducted a phase II study of neoadjuvant bevacizumab (single dose) followed by combined bevacizumab and adriamycin/cyclophosphamide/paclitaxel chemotherapy in HER2 negative BC. The regimen was well-tolerated and showed a higher rate of pathologic complete response (pCR) in triple-negative (TN)BC (11/21 patients or 52%, [95% confidence interval (CI): 30,74]) than in hormone receptor-positive (HR)BC [5/78 patients or 6% (95%CI: 2,14)]. Within the HRBCs, basal-like subtype was significantly associated with pCR (P = 0.007; Fisher exact test). We assessed interstitial fluid pressure (IFP) and tissue biopsies before and after bevacizumab monotherapy and circulating plasma biomarkers at baseline and before and after combination therapy. Bevacizumab alone lowered IFP, but to a smaller extent than previously observed in other tumor types. Pathologic response to therapy correlated with sVEGFR1 postbevacizumab alone in TNBC (Spearman correlation 0.610, P = 0.0033) and pretreatment microvascular density (MVD) in all patients (Spearman correlation 0.465, P = 0.0005). Moreover, increased pericyte-covered MVD, a marker of extent of vascular normalization, after bevacizumab monotherapy was associated with improved pathologic response to treatment, especially in patients with a high pretreatment MVD. These data suggest that bevacizumab prunes vessels while normalizing those remaining, and thus is beneficial only when sufficient numbers of vessels are initially present. This study implicates pretreatment MVD as a potential predictive biomarker of response to bevacizumab in BC and suggests that new therapies are needed to normalize vessels without pruning. PMID- 26578780 TI - Role of HIV-1 matrix protein p17 variants in lymphoma pathogenesis. AB - Although in decline after successful anti-HIV therapy, B-cell lymphomas are still elevated in HIV-1-seropositive (HIV+) persons, and the mechanisms are obscure. The HIV-1 matrix protein p17 persists in germinal centers long after HIV-1 drug suppression, and some p17 variants (vp17s) activate Akt signaling and promote growth of transformed B cells. Here we show that vp17s derived from four of five non-Hodgkin lymphoma (NHL) tissues from HIV+ subjects display potent B-cell growth-promoting activity. They are characterized by amino acid insertions at position 117-118 (Ala-Ala) or 125-126 (Gly-Asn or Gly-Gln-Ala-Asn-Gln-Asn) among some other mutations throughout the sequence. Identical dominant vp17s are found in both tumor and plasma. Three of seven plasma samples from an independent set of NHL cases manifested multiple Ala insertions at position 117-118, and one with the Ala-Ala profile also promoted B-cell growth and activated Akt signaling. Ultradeep pyrosequencing showed that vp17s with C-terminal insertions are more frequently detected in plasma of HIV+ subjects with than without NHL. Insertion of Ala-Ala at position 117-118 into reference p17 (refp17) was sufficient to confer B-cell growth-promoting activity. In contrast, refp17 bearing the Gly-Asn insertion at position 125-126 did not, suggesting that mutations not restricted to the C terminus can also account for this activity. Biophysical analysis revealed that the Ala-Ala insertion mutant is destabilized compared with refp17, whereas the Gly-Asn form is stabilized. This finding provides an avenue for further exploration of structure function relationships and new treatment strategies in combating HIV-1-related NHL. PMID- 26578781 TI - Maternal testosterone exposure increases anxiety-like behavior and impacts the limbic system in the offspring. AB - During pregnancy, women with polycystic ovary syndrome (PCOS) display high circulating androgen levels that may affect the fetus and increase the risk of mood disorders in offspring. This study investigated whether maternal androgen excess causes anxiety-like behavior in offspring mimicking anxiety disorders in PCOS. The PCOS phenotype was induced in rats following prenatal androgen (PNA) exposure. PNA offspring displayed anxiety-like behavior in the elevated plus maze, which was reversed by flutamide [androgen receptor (AR) blocker] and tamoxifen [selective estrogen receptor (ER) modulator]. Circulating sex steroids did not differ between groups at adult age. The expression of serotonergic and GABAergic genes associated with emotional regulation in the amygdala was consistent with anxiety-like behavior in female, and partly in male PNA offspring. Furthermore, AR expression in amygdala was reduced in female PNA offspring and also in females exposed to testosterone in adult age. To determine whether AR activation in amygdala affects anxiety-like behavior, female rats were given testosterone microinjections into amygdala, which resulted in anxiety-like behavior. Together, these data describe the anxiety-like behavior in PNA offspring and adult females with androgen excess, an impact that seems to occur during fetal life, and is mediated via AR in amygdala, together with changes in ERalpha, serotonergic, and GABAergic genes in amygdala and hippocampus. The anxiety-like behavior following testosterone microinjections into amygdala demonstrates a key role for AR activation in this brain area. These results suggest that maternal androgen excess may underpin the risk of developing anxiety disorders in daughters and sons of PCOS mothers. PMID- 26578782 TI - Host target modification as a strategy to counter pathogen hijacking of the jasmonate hormone receptor. AB - In the past decade, characterization of the host targets of pathogen virulence factors took a center stage in the study of pathogenesis and disease susceptibility in plants and humans. However, the impressive knowledge of host targets has not been broadly exploited to inhibit pathogen infection. Here, we show that host target modification could be a promising new approach to "protect" the disease-vulnerable components of plants. In particular, recent studies have identified the plant hormone jasmonate (JA) receptor as one of the common targets of virulence factors from highly evolved biotrophic/hemibiotrophic pathogens. Strains of the bacterial pathogen Pseudomonas syringae, for example, produce proteinaceous effectors, as well as a JA-mimicking toxin, coronatine (COR), to activate JA signaling as a mechanism to promote disease susceptibility. Guided by the crystal structure of the JA receptor and evolutionary clues, we succeeded in modifying the JA receptor to allow for sufficient endogenous JA signaling but greatly reduced sensitivity to COR. Transgenic Arabidopsis expressing this modified receptor not only are fertile and maintain a high level of insect defense, but also gain the ability to resist COR-producing pathogens Pseudomonas syringae pv. tomato and P. syringae pv. maculicola. Our results provide a proof of-concept demonstration that host target modification can be a promising new approach to prevent the virulence action of highly evolved pathogens. PMID- 26578783 TI - Unique COPII component AtSar1a/AtSec23a pair is required for the distinct function of protein ER export in Arabidopsis thaliana. AB - Secretory proteins traffic from endoplasmic reticulum (ER) to Golgi via the coat protein complex II (COPII) vesicle, which consists of five cytosolic components (Sar1, Sec23-24, and Sec13-31). In eukaryotes, COPII transport has diversified due to gene duplication, creating multiple COPII paralogs. Evidence has accumulated, revealing the functional heterogeneity of COPII paralogs in protein ER export. Sar1B, the small GTPase of COPII machinery, seems to be specialized for large cargo secretion in mammals. Arabidopsis contains five Sar1 and seven Sec23 homologs, and AtSar1a was previously shown to exhibit different effects on alpha-amylase secretion. However, mechanisms underlying the functional diversity of Sar1 paralogs remain unclear in higher organisms. Here, we show that the Arabidopsis Sar1 homolog AtSar1a exhibits distinct localization in plant cells. Transgenic Arabidopsis plants expressing dominant-negative AtSar1a exhibit distinct effects on ER cargo export. Mutagenesis analysis identified a single amino acid, Cys84, as being responsible for the functional diversity of AtSar1a. Structure homology modeling and interaction studies revealed that Cys84 is crucial for the specific interaction of AtSar1a with AtSec23a, a distinct Arabidopsis Sec23 homolog. Structure modeling and coimmunoprecipitation further identified a corresponding amino acid, Cys484, on AtSec23a as being essential for the specific pair formation. At the cellular level, the Cys484 mutation affects the distinct function of AtSec23a on vacuolar cargo trafficking. Additionally, dominant-negative AtSar1a affects the ER export of the transcription factor bZIP28 under ER stress. We have demonstrated a unique plant pair of COPII machinery function in ER export and the mechanism underlying the functional diversity of COPII paralogs in eukaryotes. PMID- 26578784 TI - The human hippocampus contributes to both the recollection and familiarity components of recognition memory. AB - Despite a substantial body of work comprising theoretical modeling, the effects of medial temporal lobe lesions, and electrophysiological signal analysis, the role of the hippocampus in recognition memory remains controversial. In particular, it is not known whether the hippocampus exclusively supports recollection or both recollection and familiarity--the two latent cognitive processes theorized to underlie recognition memory. We studied recognition memory in a large group of patients undergoing intracranial electroencephalographic (iEEG) monitoring for epilepsy. By measuring high-frequency activity (HFA)--a signal associated with precise spatiotemporal properties--we show that hippocampal activity during recognition predicted recognition memory performance and tracked both recollection and familiarity. Through the lens of dual-process models, these results indicate that the hippocampus supports both the recollection and familiarity processes. PMID- 26578785 TI - An analysis of ozone damage to historical maize and soybean yields in the United States. AB - Numerous controlled experiments find that elevated ground-level ozone concentrations ([O3]) damage crops and reduce yield. There have been no estimates of the actual yield losses in the field in the United States from [O3], even though such estimates would be valuable for projections of future food production and for cost-benefit analyses of reducing ground-level [O3]. Regression analysis of historical yield, climate, and [O3] data for the United States were used to determine the loss of production due to O3 for maize (Zea mays) and soybean (Glycine max) from 1980 to 2011, showing that over that period production of rain fed fields of soybean and maize were reduced by roughly 5% and 10%, respectively, costing approximately $9 billion annually. Maize, thought to be inherently resistant to O3, was at least as sensitive as soybean to O3 damage. Overcoming this yield loss with improved emission controls or more tolerant germplasm could substantially increase world food and feed supply at a time when a global yield jump is urgently needed. PMID- 26578786 TI - Automatic classification of prostate cancer Gleason scores from multiparametric magnetic resonance images. AB - Noninvasive, radiological image-based detection and stratification of Gleason patterns can impact clinical outcomes, treatment selection, and the determination of disease status at diagnosis without subjecting patients to surgical biopsies. We present machine learning-based automatic classification of prostate cancer aggressiveness by combining apparent diffusion coefficient (ADC) and T2-weighted (T2-w) MRI-based texture features. Our approach achieved reasonably accurate classification of Gleason scores (GS) 6(3 + 3) vs. >=7 and 7(3 + 4) vs. 7(4 + 3) despite the presence of highly unbalanced samples by using two different sample augmentation techniques followed by feature selection-based classification. Our method distinguished between GS 6(3 + 3) and >=7 cancers with 93% accuracy for cancers occurring in both peripheral (PZ) and transition (TZ) zones and 92% for cancers occurring in the PZ alone. Our approach distinguished the GS 7(3 + 4) from GS 7(4 + 3) with 92% accuracy for cancers occurring in both the PZ and TZ and with 93% for cancers occurring in the PZ alone. In comparison, a classifier using only the ADC mean achieved a top accuracy of 58% for distinguishing GS 6(3 + 3) vs. GS >=7 for cancers occurring in PZ and TZ and 63% for cancers occurring in PZ alone. The same classifier achieved an accuracy of 59% for distinguishing GS 7(3 + 4) from GS 7(4 + 3) occurring in the PZ and TZ and 60% for cancers occurring in PZ alone. Separate analysis of the cancers occurring in TZ alone was not performed owing to the limited number of samples. Our results suggest that texture features derived from ADC and T2-w MRI together with sample augmentation can help to obtain reasonably accurate classification of Gleason patterns. PMID- 26578787 TI - Stochastic electrotransport selectively enhances the transport of highly electromobile molecules. AB - Nondestructive chemical processing of porous samples such as fixed biological tissues typically relies on molecular diffusion. Diffusion into a porous structure is a slow process that significantly delays completion of chemical processing. Here, we present a novel electrokinetic method termed stochastic electrotransport for rapid nondestructive processing of porous samples. This method uses a rotational electric field to selectively disperse highly electromobile molecules throughout a porous sample without displacing the low electromobility molecules that constitute the sample. Using computational models, we show that stochastic electrotransport can rapidly disperse electromobile molecules in a porous medium. We apply this method to completely clear mouse organs within 1-3 days and to stain them with nuclear dyes, proteins, and antibodies within 1 day. Our results demonstrate the potential of stochastic electrotransport to process large and dense tissue samples that were previously infeasible in time when relying on diffusion. PMID- 26578788 TI - Temperature compensation and temperature sensation in the circadian clock. AB - All known circadian clocks have an endogenous period that is remarkably insensitive to temperature, a property known as temperature compensation, while at the same time being readily entrained by a diurnal temperature oscillation. Although temperature compensation and entrainment are defining features of circadian clocks, their mechanisms remain poorly understood. Most models presume that multiple steps in the circadian cycle are temperature-dependent, thus facilitating temperature entrainment, but then insist that the effect of changes around the cycle sums to zero to enforce temperature compensation. An alternative theory proposes that the circadian oscillator evolved from an adaptive temperature sensor: a gene circuit that responds only to temperature changes. This theory implies that temperature changes should linearly rescale the amplitudes of clock component oscillations but leave phase relationships and shapes unchanged. We show using timeless luciferase reporter measurements and Western blots against TIMELESS protein that this prediction is satisfied by the Drosophila circadian clock. We also review evidence for pathways that couple temperature to the circadian clock, and show previously unidentified evidence for coupling between the Drosophila clock and the heat-shock pathway. PMID- 26578789 TI - Telomeric repeat-containing RNA (TERRA) constitutes a nucleoprotein component of extracellular inflammatory exosomes. AB - Telomeric repeat-containing RNA (TERRA) has been identified as a telomere associated regulator of chromosome end protection. Here, we report that TERRA can also be found in extracellular fractions that stimulate innate immune signaling. We identified extracellular forms of TERRA in mouse tumor and embryonic brain tissue, as well as in human tissue culture cell lines using RNA in situ hybridization. RNA-seq analyses revealed TERRA to be among the most highly represented transcripts in extracellular fractions derived from both normal and cancer patient blood plasma. Cell-free TERRA (cfTERRA) could be isolated from the exosome fractions derived from human lymphoblastoid cell line (LCL) culture media. cfTERRA is a shorter form (~200 nt) of cellular TERRA and copurifies with CD63- and CD83-positive exosome vesicles that could be visualized by cyro electron microscopy. These fractions were also enriched for histone proteins that physically associate with TERRA in extracellular ChIP assays. Incubation of cfTERRA-containing exosomes with peripheral blood mononuclear cells stimulated transcription of several inflammatory cytokine genes, including TNFalpha, IL6, and C-X-C chemokine 10 (CXCL10) Exosomes engineered with elevated TERRA or liposomes with synthetic TERRA further stimulated inflammatory cytokines, suggesting that exosome-associated TERRA augments innate immune signaling. These findings imply a previously unidentified extrinsic function for TERRA and a mechanism of communication between telomeres and innate immune signals in tissue and tumor microenvironments. PMID- 26578790 TI - JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age. AB - Chronic, low grade, sterile inflammation frequently accompanies aging and age related diseases. Cellular senescence is associated with the production of proinflammatory chemokines, cytokines, and extracellular matrix (ECM) remodeling proteases, which comprise the senescence-associated secretory phenotype (SASP). We found a higher burden of senescent cells in adipose tissue with aging. Senescent human primary preadipocytes as well as human umbilical vein endothelial cells (HUVECs) developed a SASP that could be suppressed by targeting the JAK pathway using RNAi or JAK inhibitors. Conditioned medium (CM) from senescent human preadipocytes induced macrophage migration in vitro and inflammation in healthy adipose tissue and preadipocytes. When the senescent cells from which CM was derived had been treated with JAK inhibitors, the resulting CM was much less proinflammatory. The administration of JAK inhibitor to aged mice for 10 wk alleviated both adipose tissue and systemic inflammation and enhanced physical function. Our findings are consistent with a possible contribution of senescent cells and the SASP to age-related inflammation and frailty. We speculate that SASP inhibition by JAK inhibitors may contribute to alleviating frailty. Targeting the JAK pathway holds promise for treating age-related dysfunction. PMID- 26578791 TI - Epidermal development, growth control, and homeostasis in the face of centrosome amplification. AB - As nucleators of the mitotic spindle and primary cilium, centrosomes play crucial roles in equal segregation of DNA content to daughter cells, coordination of growth and differentiation, and transduction of homeostatic cues. Whereas the majority of mammalian cells carry no more than two centrosomes per cell, exceptions to this rule apply in certain specialized tissues and in select disease states, including cancer. Centrosome amplification, or the condition of having more than two centrosomes per cell, has been suggested to contribute to instability of chromosomes, imbalance in asymmetric divisions, and reorganization of tissue architecture; however, the degree to which these conditions are a direct cause of or simply a consequence of human disease is poorly understood. Here we addressed this issue by generating a mouse model inducing centrosome amplification in a naturally proliferative epithelial tissue by elevating Polo like kinase 4 (Plk4) expression in the skin epidermis. By altering centrosome numbers, we observed multiciliated cells, spindle orientation errors, and chromosome segregation defects within developing epidermis. None of these defects was sufficient to impart a proliferative advantage within the tissue, however. Rather, impaired mitoses led to p53-mediated cell death and contributed to defective growth and stratification. Despite these abnormalities, mice remained viable and healthy, although epidermal cells with centrosome amplification were still appreciable. Moreover, these abnormalities were insufficient to disrupt homeostasis and initiate or enhance tumorigenesis, underscoring the powerful surveillance mechanisms in the skin. PMID- 26578792 TI - Chronic centrosome amplification without tumorigenesis. AB - Centrosomes are microtubule-organizing centers that facilitate bipolar mitotic spindle assembly and chromosome segregation. Recognizing that centrosome amplification is a common feature of aneuploid cancer cells, we tested whether supernumerary centrosomes are sufficient to drive tumor development. To do this, we constructed and analyzed mice in which centrosome amplification can be induced by a Cre-recombinase-mediated increase in expression of Polo-like kinase 4 (Plk4). Elevated Plk4 in mouse fibroblasts produced supernumerary centrosomes and enhanced the expected mitotic errors, but proliferation continued only after inactivation of the p53 tumor suppressor. Increasing Plk4 levels in mice with functional p53 produced centrosome amplification in liver and skin, but this did not promote spontaneous tumor development in these tissues or enhance the growth of chemically induced skin tumors. In the absence of p53, Plk4 overexpression generated widespread centrosome amplification, but did not drive additional tumors or affect development of the fatal thymic lymphomas that arise in animals lacking p53. We conclude that, independent of p53 status, supernumerary centrosomes are not sufficient to drive tumor formation. PMID- 26578793 TI - Fat, weather, and date affect migratory songbirds' departure decisions, routes, and time it takes to cross the Gulf of Mexico. AB - Approximately two thirds of migratory songbirds in eastern North America negotiate the Gulf of Mexico (GOM), where inclement weather coupled with no refueling or resting opportunities can be lethal. However, decisions made when navigating such features and their consequences remain largely unknown due to technological limitations of tracking small animals over large areas. We used automated radio telemetry to track three songbird species (Red-eyed Vireo, Swainson's Thrush, Wood Thrush) from coastal Alabama to the northern Yucatan Peninsula (YP) during fall migration. Detecting songbirds after crossing ~1,000 km of open water allowed us to examine intrinsic (age, wing length, fat) and extrinsic (weather, date) variables shaping departure decisions, arrival at the YP, and crossing times. Large fat reserves and low humidity, indicative of beneficial synoptic weather patterns, favored southward departure across the Gulf. Individuals detected in the YP departed with large fat reserves and later in the fall with profitable winds, and flight durations (mean = 22.4 h) were positively related to wind profit. Age was not related to departure behavior, arrival, or travel time. However, vireos negotiated the GOM differently than thrushes, including different departure decisions, lower probability of detection in the YP, and longer crossing times. Defense of winter territories by thrushes but not vireos and species-specific foraging habits may explain the divergent migratory behaviors. Fat reserves appear extremely important to departure decisions and arrival in the YP. As habitat along the GOM is degraded, birds may be limited in their ability to acquire fat to cross the Gulf. PMID- 26578794 TI - Genome-wide redistribution of H3K27me3 is linked to genotoxic stress and defective growth. AB - H3K9 methylation directs heterochromatin formation by recruiting multiple heterochromatin protein 1 (HP1)-containing complexes that deacetylate histones and methylate cytosine bases in DNA. In Neurospora crassa, a single H3K9 methyltransferase complex, called the DIM-5,-7,-9, CUL4, DDB1 Complex (DCDC), is required for normal growth and development. DCDC-deficient mutants are hypersensitive to the genotoxic agent methyl methanesulfonate (MMS), but the molecular basis of genotoxic stress is unclear. We found that both the MMS sensitivity and growth phenotypes of DCDC-deficient strains are suppressed by mutation of embryonic ectoderm development or Su-(var)3-9; E(z); Trithorax (set) 7, encoding components of the H3K27 methyltransferase Polycomb repressive complex 2 (PRC2). Trimethylated histone H3K27 (H3K27me3) undergoes genome-wide redistribution to constitutive heterochromatin in DCDC- or HP1-deficient mutants, and introduction of an H3K27 missense mutation is sufficient to rescue phenotypes of DCDC-deficient strains. Accumulation of H3K27me3 in heterochromatin does not compensate for silencing; rather, strains deficient for both DCDC and PRC2 exhibit synthetic sensitivity to the topoisomerase I inhibitor Camptothecin and accumulate gammaH2A at heterochromatin. Together, these data suggest that PRC2 modulates the response to genotoxic stress. PMID- 26578795 TI - Amino-terminal p53 mutations lead to expression of apoptosis proficient p47 and prognosticate better survival, but predispose to tumorigenesis. AB - Whereas most mutations in p53 occur in the DNA-binding domain and lead to its functional inactivation, their relevance in the amino-terminal transactivation domain is unclear. We show here that amino-terminal p53 (ATp53) mutations often result in the abrogation of full-length p53 expression, but concomitantly lead to the expression of the amino-terminally truncated p47 isoform. Using genetically modified cancer cells that only express p47, we demonstrate it to be up-regulated in response to various stimuli, and to contribute to cell death, through its ability to selectively activate a group of apoptotic target genes. Target gene selectivity is influenced by K382 acetylation, which depends on the amino terminus, and is required for recruitment of selective cofactors. Consistently, cancers capable of expressing p47 had a better overall survival. Nonetheless, retention of the apoptotic function appears insufficient for tumor suppression, because these mutations are also found in the germ line and lead to Li-Fraumeni syndrome. These data from ATp53 mutations collectively demonstrate that p53's apoptosis proficiency is dispensable for tumor suppression, but could prognosticate better survival. PMID- 26578798 TI - Correction for Futrell et al., Large-scale evidence of dependency length minimization in 37 languages. PMID- 26578796 TI - Reduced DOCK4 expression leads to erythroid dysplasia in myelodysplastic syndromes. AB - Anemia is the predominant clinical manifestation of myelodysplastic syndromes (MDS). Loss or deletion of chromosome 7 is commonly seen in MDS and leads to a poor prognosis. However, the identity of functionally relevant, dysplasia causing, genes on 7q remains unclear. Dedicator of cytokinesis 4 (DOCK4) is a GTPase exchange factor, and its gene maps to the commonly deleted 7q region. We demonstrate that DOCK4 is underexpressed in MDS bone marrow samples and that the reduced expression is associated with decreased overall survival in patients. We show that depletion of DOCK4 levels leads to erythroid cells with dysplastic morphology both in vivo and in vitro. We established a novel single-cell assay to quantify disrupted F-actin filament network in erythroblasts and demonstrate that reduced expression of DOCK4 leads to disruption of the actin filaments, resulting in erythroid dysplasia that phenocopies the red blood cell (RBC) defects seen in samples from MDS patients. Reexpression of DOCK4 in -7q MDS patient erythroblasts resulted in significant erythropoietic improvements. Mechanisms underlying F actin disruption revealed that DOCK4 knockdown reduces ras-related C3 botulinum toxin substrate 1 (RAC1) GTPase activation, leading to increased phosphorylation of the actin-stabilizing protein ADDUCIN in MDS samples. These data identify DOCK4 as a putative 7q gene whose reduced expression can lead to erythroid dysplasia. PMID- 26578797 TI - Deciphering tissue-induced Klebsiella pneumoniae lipid A structure. AB - The outcome of an infection depends on host recognition of the pathogen, hence leading to the activation of signaling pathways controlling defense responses. A long-held belief is that the modification of the lipid A moiety of the lipopolysaccharide could help Gram-negative pathogens to evade innate immunity. However, direct evidence that this happens in vivo is lacking. Here we report the lipid A expressed in the tissues of infected mice by the human pathogen Klebsiella pneumoniae. Our findings demonstrate that Klebsiella remodels its lipid A in a tissue-dependent manner. Lipid A species found in the lungs are consistent with a 2-hydroxyacyl-modified lipid A dependent on the PhoPQ-regulated oxygenase LpxO. The in vivo lipid A pattern is lost in minimally passaged bacteria isolated from the tissues. LpxO-dependent modification reduces the activation of inflammatory responses and mediates resistance to antimicrobial peptides. An lpxO mutant is attenuated in vivo thereby highlighting the importance of this lipid A modification in Klebsiella infection biology. Colistin, one of the last options to treat multidrug-resistant Klebsiella infections, triggers the in vivo lipid A pattern. Moreover, colistin-resistant isolates already express the in vivo lipid A pattern. In these isolates, LpxO dependent lipid A modification mediates resistance to colistin. Deciphering the lipid A expressed in vivo opens the possibility of designing novel therapeutics targeting the enzymes responsible for the in vivo lipid A pattern. PMID- 26578799 TI - Correction for Dequeant et al., Discovery of progenitor cell signatures by time series synexpression analysis during Drosophila embryonic cell immortalization. PMID- 26578800 TI - Correction for Samaha et al., Top-down control of the phase of alpha-band oscillations as a mechanism for temporal prediction. PMID- 26578801 TI - Three-dimensional organization of nascent rod outer segment disk membranes. AB - The vertebrate photoreceptor cell contains an elaborate cilium that includes a stack of phototransductive membrane disks. The disk membranes are continually renewed, but how new disks are formed remains poorly understood. Here we used electron microscope tomography to obtain 3D visualization of the nascent disks of rod photoreceptors in three mammalian species, to gain insight into the process of disk morphogenesis. We observed that nascent disks are invariably continuous with the ciliary plasma membrane, although, owing to partial enclosure, they can appear to be internal in 2D profiles. Tomographic analyses of the basal-most region of the outer segment show changes in shape of the ciliary plasma membrane indicating an invagination, which is likely a first step in disk formation. The invagination flattens to create the proximal surface of an evaginating lamella, as well as membrane protrusions that extend between adjacent lamellae, thereby initiating a disk rim. Immediately distal to this initiation site, lamellae of increasing diameter are evident, indicating growth outward from the cilium. In agreement with a previous model, our data indicate that mature disks are formed once lamellae reach full diameter, and the growth of a rim encloses the space between adjacent surfaces of two lamellae. This study provides 3D data of nascent and mature rod photoreceptor disk membranes at unprecedented z-axis depth and resolution, and provides a basis for addressing fundamental questions, ranging from protein sorting in the photoreceptor cilium to photoreceptor electrophysiology. PMID- 26578802 TI - SMARCAL1 maintains telomere integrity during DNA replication. AB - The SMARCAL1 (SWI/SNF related, matrix-associated, actin-dependent, regulator of chromatin, subfamily A-like 1) DNA translocase is one of several related enzymes, including ZRANB3 (zinc finger, RAN-binding domain containing 3) and HLTF (helicase-like transcription factor), that are recruited to stalled replication forks to promote repair and restart replication. These enzymes can perform similar biochemical reactions such as fork reversal; however, genetic studies indicate they must have unique cellular activities. Here, we present data showing that SMARCAL1 has an important function at telomeres, which present an endogenous source of replication stress. SMARCAL1-deficient cells accumulate telomere associated DNA damage and have greatly elevated levels of extrachromosomal telomere DNA (C-circles). Although these telomere phenotypes are often found in tumor cells using the alternative lengthening of telomeres (ALT) pathway for telomere elongation, SMARCAL1 deficiency does not yield other ALT phenotypes such as elevated telomere recombination. The activity of SMARCAL1 at telomeres can be separated from its genome-maintenance activity in bulk chromosomal replication because it does not require interaction with replication protein A. Finally, this telomere-maintenance function is not shared by ZRANB3 or HLTF. Our results provide the first identification, to our knowledge, of an endogenous source of replication stress that requires SMARCAL1 for resolution and define differences between members of this class of replication fork-repair enzymes. PMID- 26578803 TI - Defective histone supply causes changes in RNA polymerase II elongation rate and cotranscriptional pre-mRNA splicing. AB - RNA polymerase II (RNAPII) transcription elongation is a highly regulated process that greatly influences mRNA levels as well as pre-mRNA splicing. Despite many studies in vitro, how chromatin modulates RNAPII elongation in vivo is still unclear. Here, we show that a decrease in the level of available canonical histones leads to more accessible chromatin with decreased levels of canonical histones and variants H2A.X and H2A.Z and increased levels of H3.3. With this altered chromatin structure, the RNAPII elongation rate increases, and the kinetics of pre-mRNA splicing is delayed with respect to RNAPII elongation. Consistent with the kinetic model of cotranscriptional splicing, the rapid RNAPII elongation induced by histone depletion promotes the skipping of variable exons in the CD44 gene. Indeed, a slowly elongating mutant of RNAPII was able to rescue this defect, indicating that the defective splicing induced by histone depletion is a direct consequence of the increased elongation rate. In addition, genome wide analysis evidenced that histone reduction promotes widespread alterations in pre-mRNA processing, including intron retention and changes in alternative splicing. Our data demonstrate that pre-mRNA splicing may be regulated by chromatin structure through the modulation of the RNAPII elongation rate. PMID- 26578804 TI - Glycosylation inhibition reduces cholesterol accumulation in NPC1 protein deficient cells. AB - Lysosomes are lined with a glycocalyx that protects the limiting membrane from the action of degradative enzymes. We tested the hypothesis that Niemann-Pick type C 1 (NPC1) protein aids the transfer of low density lipoprotein-derived cholesterol across this glycocalyx. A prediction of this model is that cells will be less dependent upon NPC1 if their glycocalyx is decreased in density. Lysosome cholesterol content was significantly lower after treatment of NPC1-deficient human fibroblasts with benzyl-2-acetamido-2-deoxy-alpha-D-galactopyranoside, an inhibitor of O-linked glycosylation. Direct biochemical measurement of cholesterol showed that lysosomes purified from NPC1-deficient fibroblasts contained at least 30% less cholesterol when O-linked glycosylation was blocked. As an independent means to modify protein glycosylation, we used Chinese hamster ovary ldl-D cells defective in UDP-Gal/UDP-GalNAc 4-epimerase in which N- and O linked glycosylation can be controlled. CRISPR generated, NPC1-deficient ldl-D cells supplemented with galactose accumulated more cholesterol than those in which sugar addition was blocked. In the absence of galactose supplementation, NPC1-deficient ldl-D cells also transported more cholesterol from lysosomes to the endoplasmic reticulum, as monitored by an increase in cholesteryl [(14)C] oleate levels. These experiments support a model in which NPC1 protein functions to transfer cholesterol past a lysosomal glycocalyx. PMID- 26578805 TI - Fungal cryptochrome with DNA repair activity reveals an early stage in cryptochrome evolution. AB - DASH (Drosophila, Arabidopsis, Synechocystis, Human)-type cryptochromes (cry DASH) belong to a family of flavoproteins acting as repair enzymes for UV-B induced DNA lesions (photolyases) or as UV-A/blue light photoreceptors (cryptochromes). They are present in plants, bacteria, various vertebrates, and fungi and were originally considered as sensory photoreceptors because of their incapability to repair cyclobutane pyrimidine dimer (CPD) lesions in duplex DNA. However, cry-DASH can repair CPDs in single-stranded DNA, but their role in DNA repair in vivo remains to be clarified. The genome of the fungus Phycomyces blakesleeanus contains a single gene for a protein of the cryptochrome/photolyase family (CPF) encoding a cry-DASH, cryA, despite its ability to photoreactivate. Here, we show that cryA expression is induced by blue light in a Mad complex dependent manner. Moreover, we demonstrate that CryA is capable of binding flavin (FAD) and methenyltetrahydrofolate (MTHF), fully complements the Escherichia coli photolyase mutant and repairs in vitro CPD lesions in single-stranded and double stranded DNA with the same efficiency. These results support a role for Phycomyces cry-DASH as a photolyase and suggest a similar role for cry-DASH in mucoromycotina fungi. PMID- 26578806 TI - The extent of functional redundancy changes as species' roles shift in different environments. AB - Assessing the ecological impacts of environmental change requires knowledge of the relationship between biodiversity and ecosystem functioning. The exact nature of this relationship can differ considerably between ecosystems, with consequences for the efficacy of species diversity as a buffer against environmental change. Using a microbial model system, we show that the relationship can vary depending on environmental conditions. Shapes suggesting functional redundancy in one environment can change, suggesting functional differences in another environment. We find that this change is due to shifting species roles and interactions. Species that are functionally redundant in one environment may become pivotal in another. Thus, caution is advised in drawing conclusions about functional redundancy based on a single environmental situation. It also implies that species richness is important because it provides a pool of species with potentially relevant traits. These species may turn out to be essential performers or partners in new interspecific interactions after environmental change. Therefore, our results challenge the generality of functional redundancy. PMID- 26578807 TI - Genetic polymorphism directs IL-6 expression in fibroblasts but not selected other cell types. AB - Interleukin (IL)-6 blockade is an effective treatment for rheumatoid arthritis (RA), and synovial fibroblasts are a major IL-6 producer in the inflamed joint. We found that human RA and osteoarthritis (OA) synovial fibroblasts derived from independent donors reproducibly segregated into low, medium, and high IL-6 producers, independent of stimulus, cell passage, or disease state. IL-6 expression pattern correlated strongly with total mRNA expression, not mRNA stability, suggesting transcriptional rather than posttranscriptional regulation. High-fibroblast IL-6 expression was significantly associated with the IL-6 proximal promoter single nucleotide polymorphism (SNP) rs1800795 minor allele (CC) genotype. In contrast, no association between this SNP and IL-6 production was detected in CD14(+) monocytes, another major producer of synovial IL-6. Luciferase expression assays confirmed that this SNP was associated with differential IL-6 expression in fibroblasts. To date, several association studies examining rs1800795 allele frequency and disease risk have reported seemingly conflicting results ranging from no association to association with either the major or minor allele across a spectrum of conditions, including cancer and autoimmune, cardiovascular, infectious, and metabolic diseases. This study points to a prominent contribution from promoter genetic variation in fibroblast IL-6 regulation, but not in other IL-6-producing cell types. We propose that some of the heterogeneity in these clinical studies likely reflects the cellular source of IL-6 in specific diseases, much of which may be produced by nonhematopoietic cells. These results highlight that functional analysis of disease-associated SNPs on gene expression and pathologic processes must consider variation in diverse cell types. PMID- 26578808 TI - Managing variance: Key policy challenges for the Anthropocene. PMID- 26578809 TI - Imprinted X chromosome inactivation offers up a double dose of epigenetics. PMID- 26578810 TI - Rapid genome reshaping by multiple-gene loss after whole-genome duplication in teleost fish suggested by mathematical modeling. AB - Whole-genome duplication (WGD) is believed to be a significant source of major evolutionary innovation. Redundant genes resulting from WGD are thought to be lost or acquire new functions. However, the rates of gene loss and thus temporal process of genome reshaping after WGD remain unclear. The WGD shared by all teleost fish, one-half of all jawed vertebrates, was more recent than the two ancient WGDs that occurred before the origin of jawed vertebrates, and thus lends itself to analysis of gene loss and genome reshaping. Using a newly developed orthology identification pipeline, we inferred the post-teleost-specific WGD evolutionary histories of 6,892 protein-coding genes from nine phylogenetically representative teleost genomes on a time-calibrated tree. We found that rapid gene loss did occur in the first 60 My, with a loss of more than 70-80% of duplicated genes, and produced similar genomic gene arrangements within teleosts in that relatively short time. Mathematical modeling suggests that rapid gene loss occurred mainly by events involving simultaneous loss of multiple genes. We found that the subsequent 250 My were characterized by slow and steady loss of individual genes. Our pipeline also identified about 1,100 shared single-copy genes that are inferred to have become singletons before the divergence of clupeocephalan teleosts. Therefore, our comparative genome analysis suggests that rapid gene loss just after the WGD reshaped teleost genomes before the major divergence, and provides a useful set of marker genes for future phylogenetic analysis. PMID- 26578811 TI - Structural basis for antagonizing a host restriction factor by C7 family of poxvirus host-range proteins. AB - Human sterile alpha motif domain-containing 9 (SAMD9) protein is a host restriction factor for poxviruses, but it can be overcome by some poxvirus host range proteins that share homology with vaccinia virus C7 protein. To understand the mechanism of action for this important family of host-range factors, we determined the crystal structures of C7 and myxoma virus M64, a C7 family member that is unable to antagonize SAMD9. Despite their different functions and only 23% sequence identity, the two proteins have very similar overall structures, displaying a previously unidentified fold comprised of a compact 12-stranded antiparallel beta-sandwich wrapped in two short alpha helices. Extensive structure-guided mutagenesis of C7 identified three loops clustered on one edge of the beta sandwich as critical for viral replication and binding with SAMD9. The loops are characterized with functionally important negatively charged, positively charged, and hydrophobic residues, respectively, together forming a unique "three-fingered molecular claw." The key residues of the claw are not conserved in two C7 family members that do not antagonize SAMD9 but are conserved in distantly related C7 family members from four poxvirus genera that infect diverse mammalian species. Indeed, we found that all in the latter group of proteins bind SAMD9. Taken together, our data indicate that diverse mammalian poxviruses use a conserved molecular claw in a C7-like protein to target SAMD9 and overcome host restriction. PMID- 26578812 TI - Advanced neuroendocrine prostate tumors regress to stemness. PMID- 26578813 TI - Molecular basis for specific viral RNA recognition and 2'-O-ribose methylation by the dengue virus nonstructural protein 5 (NS5). AB - Dengue virus (DENV) causes several hundred million human infections and more than 20,000 deaths annually. Neither an efficacious vaccine conferring immunity against all four circulating serotypes nor specific drugs are currently available to treat this emerging global disease. Capping of the DENV RNA genome is an essential structural modification that protects the RNA from degradation by 5' exoribonucleases, ensures efficient expression of viral proteins, and allows escape from the host innate immune response. The large flavivirus nonstructural protein 5 (NS5) (105 kDa) has RNA methyltransferase activities at its N-terminal region, which is responsible for capping the virus RNA genome. The methyl transfer reactions are thought to occur sequentially using the strictly conserved flavivirus 5' RNA sequence as substrate (GpppAG-RNA), leading to the formation of the 5' RNA cap: G0pppAG-RNA -> (m7)G0pppAG-RNA ("cap-0")->(m7)G0pppAm2'-O-G-RNA ("cap-1"). To elucidate how viral RNA is specifically recognized and methylated, we determined the crystal structure of a ternary complex between the full-length NS5 protein from dengue virus, an octameric cap-0 viral RNA substrate bearing the authentic DENV genomic sequence (5'-(m7)G0pppA1G2U3U4G5U6U7-3'), and S-adenosyl-l homocysteine (SAH), the by-product of the methylation reaction. The structure provides for the first time, to our knowledge, a molecular basis for specific adenosine 2'-O-methylation, rationalizes mutagenesis studies targeting the K61 D146-K180-E216 enzymatic tetrad as well as residues lining the RNA binding groove, and offers previously unidentified mechanistic and evolutionary insights into cap-1 formation by NS5, which underlies innate immunity evasion by flaviviruses. PMID- 26578814 TI - Pentatricopeptide-repeat family protein RF6 functions with hexokinase 6 to rescue rice cytoplasmic male sterility. AB - Cytoplasmic male sterility (CMS) has been extensively used for hybrid seed production in many major crops. Honglian CMS (HL-CMS) is one of the three major types of CMS in rice and has contributed greatly to food security worldwide. The HL-CMS trait is associated with an aberrant chimeric mitochondrial transcript, atp6-orfH79, which causes pollen sterility and can be rescued by two nonallelic restorer-of-fertility (Rf) genes, Rf5 or Rf6. Here, we report the identification of Rf6, which encodes a novel pentatricopeptide repeat (PPR) family protein with a characteristic duplication of PPR motifs 3-5. RF6 is targeted to mitochondria, where it physically associates with hexokinase 6 (OsHXK6) and promotes the processing of the aberrant CMS-associated transcript atp6-orfH79 at nucleotide 1238, which ensures normal pollen development and restores fertility. The duplicated motif 3 of RF6 is essential for RF6-OsHXK6 interactions, processing of the aberrant transcript, and restoration of fertility. Furthermore, reductions in the level of OsHXK6 result in atp6-orfH79 transcript accumulation and male sterility. Together these results reveal a novel mechanism for CMS restoration by which RF6 functions with OsHXK6 to restore HL-CMS fertility. The present study also provides insight into the function of hexokinase 6 in regulating mitochondrial RNA metabolism and may facilitate further exploitation of heterosis in rice. PMID- 26578816 TI - BRICHOS binds to a designed amyloid-forming beta-protein and reduces proteasomal inhibition and aggresome formation. AB - The BRICHOS domain is associated with proliferative, degenerative and amyloid diseases, and it has been shown to inhibit fibril formation and toxicity of the Alzheimer's disease-associated amyloid beta-peptide. ProSP-C (prosurfactant protein C) BRICHOS binds to stretches of hydrophobic amino acid residues, which are unfolded or in beta-strand conformation, suggesting that it may have broad anti-amyloid activity. We have studied the effect of the proSP-C BRICHOS domain on the designed amyloidogenic beta-sheet proteins beta17 and beta23. beta17 expressed in the secretory pathway of HEK (human embryonic kidney)-293 cells forms intracellular inclusions, whereas beta23 is rapidly degraded. Co-expression of BRICHOS leads to a reduction in beta17 inclusion size and increased levels of soluble beta17 and beta23. Furthermore, BRICHOS interacts with the beta-proteins intracellularly, reduces their ubiquitination and decreases aggresome formation and proteasomal inhibition. Collectively, these data suggest that BRICHOS is capable of delaying the aggregation process and toxicity of amyloidogenic proteins in a generic manner. PMID- 26578815 TI - Unexpected features of the dark proteome. AB - We surveyed the "dark" proteome-that is, regions of proteins never observed by experimental structure determination and inaccessible to homology modeling. For 546,000 Swiss-Prot proteins, we found that 44-54% of the proteome in eukaryotes and viruses was dark, compared with only ~14% in archaea and bacteria. Surprisingly, most of the dark proteome could not be accounted for by conventional explanations, such as intrinsic disorder or transmembrane regions. Nearly half of the dark proteome comprised dark proteins, in which the entire sequence lacked similarity to any known structure. Dark proteins fulfill a wide variety of functions, but a subset showed distinct and largely unexpected features, such as association with secretion, specific tissues, the endoplasmic reticulum, disulfide bonding, and proteolytic cleavage. Dark proteins also had short sequence length, low evolutionary reuse, and few known interactions with other proteins. These results suggest new research directions in structural and computational biology. PMID- 26578817 TI - Biophysical characterization of laforin-carbohydrate interaction. AB - Laforin is a human dual-specificity phosphatase (DSP) involved in glycogen metabolism regulation containing a carbohydrate-binding module (CBM). Mutations in the gene coding for laforin are responsible for the development of Lafora disease, a progressive fatal myoclonus epilepsy with early onset, characterized by the intracellular deposition of abnormally branched, hyperphosphorylated insoluble glycogen-like polymers, called Lafora bodies. Despite the known importance of the CBM domain of laforin in the regulation of glycogen metabolism, the molecular mechanism of laforin-glycogen interaction is still poorly understood. Recently, the structure of laforin with bound maltohexaose was determined and despite the importance of such breakthrough, some molecular interaction details remained missing. We herein report a thorough biophysical characterization of laforin-carbohydrate interaction using soluble glycans. We demonstrated an increased preference of laforin for the interaction with glycans with higher order of polymerization and confirmed the importance of tryptophan residues for glycan interaction. Moreover, and in line with what has been described for other CBMs and lectins, our results confirmed that laforin-glycan interactions occur with a favourable enthalpic contribution counter-balanced by an unfavourable entropic contribution. The analysis of laforin-glycan interaction through the glycan side by saturation transfer difference (STD)-NMR has shown that the CBM-binding site can accommodate between 5 and 6 sugar units, which is in line with the recently obtained crystal structure of laforin. Overall, the work in the present study complements the structural characterization of laforin and sheds light on the molecular mechanism of laforin-glycan interaction, which is a pivotal requisite to understand the physiological and pathological roles of laforin. PMID- 26578818 TI - Upregulated Expression of SOX4 Is Associated with Tumor Growth and Metastasis in Nasopharyngeal Carcinoma. AB - SOX4, which belongs to the sex-determining region Y-related high-mobility group (SRY) box family, plays a critical role in embryonic development, cell fate decision, differentiation, and tumor development. Nasopharyngeal carcinoma (NPC) is one of the most common cancers in China and Southeast Asia. However, the molecular mechanisms of this disease remain unknown. In the present study, we used immunohistochemistry to investigate the correlation between the expression of SOX4 with clinicopathologic variables as well as patients prognosis of NPC. We found overexpression of SOX4 was correlated with clinical stages, lymph node metastasis, and Ki-67 expression in NPC (P < 0.05). Besides, patients who expressed higher levels of SOX4 had poorer survival rate (P < 0.05). Then, in vitro studies, we took serum starvation-refeeding experiment and knocked down the expression of SOX4 with siRNA to demonstrate that SOX4 could promote proliferation of NPC nonkeratinizing cell line CNE2. The regulation of SOX4 on cell migration was determined by the transwell migration assay and wounding healing assay. Besides, we also found SOX4 could promote epithelial-mesenchymal transition (EMT) of CNE2 cells and decrease their cisplatin sensitivity. Our data suggested that SOX4 might play an important role in regulating NPC progression and would provide a potential therapeutic strategy for NPC. PMID- 26578819 TI - NRAMP1 and VDR Gene Polymorphisms in Susceptibility to Tuberculosis in Venezuelan Population. AB - Natural resistance-associated macrophage protein (Nramp1) and the vitamin D receptor (VDR) are central components of the innate and adaptive immunity against Mycobacterium tuberculosis, and associations between susceptibility to tuberculosis and polymorphisms in the genes NRAMP and VDR have been sought in geographically diverse populations. We investigated associations of NRAMP1 and VDR gene polymorphisms with susceptibility to TB in the Venezuelan population. The results suggest the absence of any association between VDR variants FokI, ApaI, and TaqI and susceptibility to tuberculosis. In contrast, the NRAMP1 3'UTR variants were associated with susceptibility to M. tuberculosis infection, as seen in the comparisons between TST+ and TST- controls, and also with progression to TB disease, as shown in the comparisons between TB patients and TST+ controls. This study confirms the previously described association of the NRAMP1 3'UTR polymorphism with M. tuberculosis infection and disease progression. PMID- 26578820 TI - The Effects of Gender Differences in Patients with Depression on Their Emotional Working Memory and Emotional Experience. AB - A large amount of research has been conducted on the effects of sex hormones on gender differences in patients with depression, yet research on cognitive differences between male and female patients with depression is insufficient. This study uses emotion pictures to investigate the differences of the emotional working memory ability and emotional experience in male and female patients with depression. Despite identifying that the working memory of patients with depression is impaired, our study found no significant gender differences in emotional working memory. Moreover, the research results revealed that memory effects of mood congruence are produced in both men and women, which may explain why the depression state can be maintained. Furthermore, female patients have more emotional experiences than male patients, which is particularly significant in terms of negative emotional experiences. This result provides cognitive evidence to explain why women suffer from longer terms of depression, are more susceptible to relapse, and can more easily suffer from major depressive disorder in the future. PMID- 26578821 TI - Serum Osteocalcin Is Associated with Inflammatory Factors in Metabolic Syndrome: A Population-Based Study in Chinese Males. AB - Osteocalcin (OCN) was potentially associated with inflammatory factors, so we explored the metabolic role in this association in general population. Our findings suggest that OCN was positively associated with IgG while inversely associated with C3, both of which were probably mediated by obesity. Moreover, serum OCN was inversely associated with hsCRP in men with impaired fasting glucose, hyperglycemia, or metabolic syndrome, while its association with IgE was significantly observed in men with a normal metabolic profile. PMID- 26578822 TI - A Nomogram to Predict Prognostic Value of Red Cell Distribution Width in Patients with Esophageal Cancer. AB - OBJECTIVES: The prognostic value of inflammatory index in esophageal cancer (EC) was not established. In the present study, we initially used a nomogram to predict prognostic value of red cell distribution width (RDW) in patients with esophageal squamous cell carcinoma (ESCC). METHODS: A total of 277 ESCC patients were included in this retrospective study. Kaplan-Meier method was used to calculate the cancer-specific survival (CSS). A nomogram was established to predict the prognosis for CSS. RESULTS: The mean value of RDW was 14.5 +/- 2.3%. The patients were then divided into two groups: RDW >= 14.5% and RDW < 14.5%. Patients with RDW < 14.5% had a significantly better 5-year CSS than patients with RDW >= 14.5% (43.9% versus 23.3%, P < 0.001). RDW was an independent prognostic factor in patients with ESCC (P = 0.036). A nomogram could be more accurate for CSS. Harrell's c-index for CSS prediction was 0.68. CONCLUSION: RDW was a potential prognostic biomarker in patients with ESCC. The nomogram based on CSS could be used as an accurately prognostic prediction for patients with ESCC. PMID- 26578823 TI - Acute Median Neuropathy and Carpal Tunnel Release in Perilunate Injuries Can We Predict Who Gets a Median Neuropathy? AB - This study addressed the following null hypotheses: 1) There are no demographic differences between patients with perilunate dislocation (PLD) or fracture dislocation (PLFD); 2) There are no factors associated with the development of median nerve symptoms in the setting of a PLD or PLFD; and 3) There are no factors associated with carpal tunnel release. Using a retrospective search of a prospective trauma database, we identified all patients who had sustained a radiologically confirmed PLD or PLFD over a 10-year period at two trauma centers. From the medical records we identified median nerve symptoms and carpal tunnel release in addition to demographic and injury characteristics. Among the 71 patients treated for PLD or PLFD, acute median neuropathy was diagnosed in 33 patients (47 %). The only significant difference between PLD and PLFD was a younger age with PLFD. No demographic or injury factors were associated with symptoms of median neuropathy. Carpal tunnel release surgery during the initial operative management was related to the presence of median nerve symptoms and the trauma center. We report a high incidence of acute median neuropathy accompanying perilunate injuries. As there are no demographic or injury factors associated with symptoms of median neuropathy; all patients with PLD/PLFD merit equally high vigilance for acute median neuropathy. LEVEL OF EVIDENCE: Level III, prognostic study. PMID- 26578824 TI - A New "Trapdoor technique" for Fixation of Displaced Greater Tuberosity Fractures of the Shoulder. AB - Isolated greater tuberosity fractures of the proximal humerus are frequently displaced posteriorly and superiorly by the pull of the rotator cuff. This displacement can lead to a decline in function if left untreated. Traditionally these fractures have been treated surgically using screw fixation. On occasions this metalwork can remain prominent and potentially cause impingement. We present a new surgical "trapdoor" technique for fixation of isolated greater tuberosity fractures which can avoid these problems and be utilised either open or arthroscopically. Following reduction of the isolated greater tuberosity fragment, two double loaded metal screw in anchors are placed through stab incisions in the rotator cuff at the bone-tendon interface and secured into the humeral head. A suture from each of the anchors is tied together to secure the tuberosity fragment proximally and a suture-less anchor is inserted distal to the fracture site forming an inverted triangle. The remaining sutures are placed through the suture-less anchor and tensioned independently. As the sutures are tied and snugged tight, the distal aspect of the fracture reduces, thus closing the "trapdoor." This is a newly described versatile technique that can be used regardless of the size and comminution of the tuberosity fragment and can be performed either open or arthroscopically. It avoids the problems of metalwork prominence and irritation and the use of the suture-less anchor allows independent tensioning of the sutures to ensure adequate fracture reduction. PMID- 26578825 TI - Effect of Heparin on Post-Operative Adhesion in Flexor Tendon Surgery of the Hand. AB - Flexor tendon laceration is a common hand injury. Timely and correct diagnosis of this defect is an important factor for restoring hand function. Post-operative adhesion is a frequent problem after tendon repair and its prevention is difficult in some types of tendon lacerations. There have been some controversial studies on the positive effect of some materials and substances on prevention of these adhesions. This study aims to evaluate effects of the Heparin in postoperative tendon adhesions. In this clinical trial, 100 patients with laceration of flexor tendons in zone II of the hand were enrolled. The patients were randomly divided into two groups. In the first group, 0.5 cc Heparin (5000 IU/cc) was injected into each tendon ends before tendon repair. In the control group, repair was carried out without any heparin injection. After 3 months the total active range of motion (TAROM), mean extension gap (MEG) and mean flexion gap (MFG) were measured and compared between these two groups. The TAROM and MEGs were not significantly different between two groups; but MFGs were significantly better in Heparin treated group (P < 0.02). However rupture rate was significantly higher in heparin treated group (P = 0.003). Heparin may improve the tendons function and reduce the postoperative adhesions in zone II of the hand; however there is a significant risk of tendon rupture. PMID- 26578826 TI - Percutaneous Screw Fixation of Scaphoid Waist Fracture Non-Union Without Bone Grafting. AB - The aim of the study was to evaluate results of volar percutaneous headless compression screw fixation without bone grafting in 21 patients with scaphoid waist nonunion fractures. The inclusion criteria in this series were scaphoid waist fracture nonunion with intact cartilaginous envelope, minimal fracture line at nonunion interface, no cyst or sclerosis, no avascular necrosis and normal scapholunate angle without humpback deformity. There were 17 male and 4 female patients with an average age of 23 years (range 16-45 years). All patients had radiographic examinations that included Posteroanterior, lateral, oblique and scaphoid views. Preoperative MRI to assess the cartilaginous shill and vascularity of scaphoid was done. CT scans were performed postoperatively to confirm scaphoid fracture healing. The average clinical follow-up was at 25 months (range 18-35) postoperatively. All fractures united successfully with no additional procedures. The average DASH score (disabilities of the arm, shoulder, and hand) at final follow-up was 8 (range 0-16). Percutaneous fixation for selected scaphoid nonunion can avoid the morbidity of an open approach and bone grafting. PMID- 26578827 TI - Experimental Thromboprophylaxis with Low Molecular Weight Heparin After Microsurgical Revascularization. AB - There is great variability among microsurgeons as regards the use of prophylactic anticoagulant after revascularization and this is probably due to lack of comparative data. Also, there has been much debate regarding the benefit of anti thrombotic therapies versus the risk of complications such as systemic bleeding and hematoma formation. To evaluate the effectiveness of postoperative low molecular weight heparin (LMWH) as a prophylactic anticoagulant therapy after microsurgical repair of the femoral artery and vein in rats. Randomized, blinded study. The femoral artery and vein of 40 Sprague Dawley rats were sectioned and repaired with microsurgical sutures under general anesthesia. They were randomly divided into 2 groups: Group (A) in which the 20 rats were injected with Enoxaparin subcutaneously at a dose 1.5 mg/kg once daily for 3 successive days; Group (B), the control group, in which 20 rats were injected with isotonic sodium chloride 0.9 % subcutaneously in a blinded fashion. After 7 days, the femoral vessels were re-explored and patency of the femoral vessels was assessed with empty-and-refill test. There were a total of 12 vascular thrombosis among 74 microsurgical repair in both groups with percentage of 16.22 % including, 5 arterial anastomosis and 7 venous anastomosis. The incidence of thrombosis in the treatment group (A) was 18.4 % while the incidence of thrombosis in the control group (B) was 13.8 %. This difference was not statistically significant using Fisher exact test. Postoperative administration of LMWH did not provide the desired protection against thrombosis after microsurgical vascular repair. PMID- 26578828 TI - Exploring the Relation Between Impairment Rating by AMA Guide and Activity and Participation Based on ICF in the Patients with Hand Injuries. AB - The aim of this paper is to analyze the relation between components of disability with distinguished score of impairment, activity and participation questionnaire based on clinical data of persons with hand injuries. Impairment was evaluated by use of AMA guide 6th edition and disability by DASH questionnaire on Convenience sample of patients (N = 117), with chronic hand injuries. Linking and allocating items of the DASH were done based on the ICF Core Set for Hand Conditions and the opinions of a group of experts from different related fields. Data was analyses by using Kappa index, Chi square test and a set of Pearson, Part and Partial correlations coefficient. Most of the DASH items were allocated to the activity; one to four of the items could not be classified and 0 to 22 were classified as having overlap. Participation and activity scores correlated positively with each other (r > 0.80). Impairment had high correlation with activity and participation scores (>73). With controlling the effect of each or both construct, this relation between them with impairment diminished but still significant between activity and impairment. There is a huge overlap in definition of activity and participation. The most effecting item in relation of disability and impairment is activity restriction. Participation had no relation with impairment. PMID- 26578829 TI - Time from Booking Until Appointment and Healthcare Utilization in Hand Surgery Patients with Discretionary Conditions. AB - Delaying treatment for benign musculoskeletal conditions may allow patients to learn self-efficacy and develop coping strategies, leading to less medical intervention and reduced cost. We tested the hypothesis that time from booking until appointment is not associated with healthcare costs. We further tested the secondary hypothesis that time from booking to appointment is not associated with specific healthcare utilizations. We identified 16,750 patients (55 % women; mean age 50 years) making first clinic visits to hand surgeons at our hospital between January 1, 2003 and December 31, 2012. Booking time was defined as the time between the scheduling of an appointment and the actual visit. Imaging procedures, injections, nerve conduction studies, occupational therapy visits, surgery, and referrals were determined up until the patient's second visit with the surgeon, or 90 days. Costs were determined in Relative Value Units. Duration between booking and office visit was not associated with higher cost (regression coefficient [beta] 0.0023, P = 0.77). Duration between booking and office visit was associated with a higher rate of nerve conduction studies (odds ratio [OR] 1.02, P < 0.001) and a lower rate of occupational therapy (OR 0.98, P < 0.001). There was substantial variation between surgeons. Greater wait time was not therapeutic, but is associated with different diagnostic and treatment measures that suggest people that are willing to wait have different types of problems. The variation by surgeon may make variation based on other factors, including time between booking and appointment, difficult to discern. PMID- 26578830 TI - Ulnar Shortening Osteotomy: Are Complications Under Reported? AB - Ulnar shortening osteotomy is an accepted treatment for ulnar impaction syndrome and numerous techniques for have been described in the literature. We present our single surgeon case series over 10 years of oblique ulnar shortening osteotomy using a jig technique. A review of the current literature with reference to the risk of complications is included. All patients undergoing ulnar shortening osteotomy from 2001 to 2011 were identified and case-notes were reviewed retrospectively. Risks of complications included metalwork irritation (51 %), non union (6.3 %), refracture (1.6 %) and chronic regional pain syndrome (1.6 %). Oblique ulnar osteotomy using a jig technique is reliable and reproducible in shortening the ulna and maintaining alignment, rotation and compression at the osteotomy site. Symptoms improved in the majority of patients. However, the morbidity associated with the procedure may be underestimated as highlighted by our complication rates. Surgeons should counsel patients appropriately when offering ulnar shortening osteotomy. PMID- 26578831 TI - Early Patient Satisfaction with Different Treatment Pathways for Trigger Finger and Thumb. AB - Little is known about factors related to patient satisfaction with treatment for trigger digits. This study tested the null hypothesis that there are no factors associated with treatment satisfaction 2 months after completion of treatment (absence of triggering) or 4 months after the last visit for patients with a trigger thumb or finger. Secondary null hypotheses were: 1) There are no factors associated with a change in patients' preferred treatment before and after consultation with a hand surgeon; and 2) Initial treatment provided is not different from final received treatment. In an observational study, 63 English speaking adult patients were enrolled after being diagnosed with one or more new idiopathic trigger digits by one of two hand surgeons, but before the hand surgeon discussed treatment options. Patients were asked to fill out questionnaires at enrollment. Final evaluation was by phone. Satisfaction with treatment was not related to the initial treatment or other patient or disease factors. Twenty-three patients (37 %) had a different preference for treatment after talking with a hand surgeon. Involvement of the long and ring fingers were the only factors associated with staying with pre-visit treatment preferences. There was a significant difference in proportions of the various treatments provided at enrollment and final treatment recorded at the final phone evaluation, 14 patients (22 %) had a subsequent alternative form of treatment. Patients' preferences for trigger finger treatment often change after consulting with a hand surgeon and during treatment, but these choices do not affect treatment satisfaction. PMID- 26578832 TI - Histologic and Biomechanical Evaluation of the Effects of Social Stress and the Antidepressant Fluoxetine on Tendon Healing in Rats. AB - Impaired wound healing in humans under psychological stress and the positive effects of antidepressant drugs on wound healing were also shown in the literature. However, there are currently no studies regarding the effects of antidepressant drugs on tendon healing. The aim of this study was to compare tendon healing under normal conditions versus social stress. We also aimed to perform a histological and biomechanical analysis of the effects of the antidepressant drug fluoxetine on tendon healing. Sixty Sprague Dawley rats were divided into six groups. A social stress regimen was used to stress the rats. The use of fluoxetine in the social stress group yielded significantly better biomechanical results and the collagen organizations of the fluoxetine group were more similar to the normal tendon collagen organization. Fluoxetine seems to inhibit the negative effects of stress on tendon healing and seems to improve tendon healing. LEVELS OF EVIDENCE: Level 5. PMID- 26578833 TI - Factors Associated with Patient Delay in Scaphoid Nonunions. AB - Delay in seeking medical attention by patients, ?so-called patient delay, contributes to the relative high rate of delayed diagnosis and treatment in scaphoid nonunion cases. In this retrospective study we investigated the incidence of patients with a patient delay exceeding 6 months, thus by definition having an established nonunion. In addition to this, we investigated demographic, injury and patient related factors associated with this patient delay in scaphoid nonunion patients. We included 101 patients with established scaphoid nonunions treated surgically at our specialized hand surgery unit. Information regarding demographic and injury characteristics, and subjective patient related factors was obtained from medical records and a questionnaire-based survey. Sixty-four patients (63 %) responded to our survey. A quarter (25 %) of the patients showed a delay of more than 6 months. Demographic and injury characteristics were not related to this delay. In contrast to this, not attributing post-injury symptoms to a fracture but to e.g. a sprain instead, showed to be an independent predictor of patient delay. We report a high incidence of patients with an established scaphoid nonunion who delayed seeking medical attention. As there appears to be no demographic or injury characteristics associated with this patient delay, future developments of strategies to reduce patient delay should be targeted on all patients with a suspected scaphoid injury. PMID- 26578834 TI - Free Vascularized Medial Femoral Condyle Structural Flaps for Septic Terminal Digital Bone Loss. AB - A unique clinical problem exists when the majority of distal bone stock in a digit is destroyed by osteomyelitis, leaving a residual soft tissue envelope with tenuous, random perfusion surrounding a nidus of scar tissue. Pulp pinch is lost in the absence of bony support, and limited options exist. Apart from toe transfer or revision amputation with shortening, non-vascularized bone grafting inside the residual soft tissue envelope risks graft resorption and reactivation of infection. The purpose of this investigation was to evaluate the clinical outcomes of free vascularized medial femoral condyle structural bone flaps to restore lost pulp pinch in such cases. Nine patients (8 males, 1 female) with a mean age of 43 years sustained extensive terminal bone loss near digital tips following osteomyelitis. The mean length of bone defect was 28 mm (+/- 8.4). The patients were reconstructed at a mean of 12 weeks from initial trauma/infection, having undergone a mean of two prior surgeries. A structural block of vascularized bone from the medial femoral condyle replaced the missing bone at the digital tip defect, temporarily fixed with K-wires. The bone flap was encased by the residual soft tissue envelope after removing scar tissue from the prior trauma and infection. All bone flaps incorporated fully, restoring pulp pinch function to the respective digits with a mean time to union of 8.6 (+/- 2.1) weeks; range 6-11 weeks. With few alternative solutions able to address this unique and difficult problem, the structural block of vascularized bone proved able to resist resorption, nonunion, and reactivation of infection; the problems normally encountered under this scenario. PMID- 26578835 TI - Percutaneous Reduction and Fixation Using Two K-wires In Paediatric Angulated Radial Neck Fractures. AB - BACKGROUND: Fractures of the radial neck in children are usually seen at about the age of five years, after the appearance of the proximal radial epiphysis. They are usually caused by a fall on the outstretched hand which produces a valgus strain [1]. Minor degrees of angulation can be accepted and treated conservatively, but advice on the maximum acceptable angulation varies widely, up to as much as 45 degrees 0 [2] More severely angulated and displaced fractures have been variously treated by closed or open reduction, but the precise indications for each are not clear [3]. In a retrospective study Steele et al. found that open reduction generally had a poor result and that open reduction with internal fixation was even worse, as has been reported by others [4, 5]. METHODS: We describe a modified percutaneous technique using two (1.6 mm) K-wires for reduction (one wire for leverage and one wire for translation) and two K wires for rotationally stable fixation. RESULTS: Nine patients were included in the study. The median age of the patients was 9.6 years. There were six males and three females. The average follow up period was 23 months. The final results of the study included six patients with excellent results and one with a good result. Unfortunately, two patients were visitors and failed to attend for review. CONCLUSION: We have found this technique effective and easily reproducible. Level of evidence IV - Case series. PMID- 26578836 TI - A Simple Dressing Technique Following Dermofasciectomy and Full Thickness Skin Grafting of the Fingers in the Treatment of Severe Dupuytren's Contracture. AB - Dupuytren's disease with severe finger contractures and recurrent contractures following previous surgery often have extensive skin involvement. In these severe cases, excision of the diseased chord along with the involved skin is a good option to reduce the risk of recurrance. The resulting skin defect can be covered with a full thickness skin graft (FTSG) or a cross finger flap. Cross finger flaps have donor finger morbidity and hence a full thickness graft is usually preferred. The FTSG extending to the midlateral margins on both sides of the finger reduces the risk of joint contracture due to graft shrinkage. Once the FTSG is sutured in place, the standard practice is to compress and secure the graft to its recipient bed with a tie-over dressing and this can be time consuming. We present a simple dressing technique to secure the FTSG without the need for a tie-over dressing. PMID- 26578837 TI - Platelet-Rich-Plasma Injections in Treating Lateral Epicondylosis: a Review of the Recent Evidence. AB - Lateral epicondylosis is common, with various treatment modalities. Platelet-rich plasma injections from autologous blood have recently been used in centres worldwide for the treatment of tennis elbow. We review and present the recent published evidence on the effectiveness of PRP injections for lateral epicondylosis. Nine studies met our inclusion criteria including 6 RCT's for the purpose of analysis. PRP injections have an important and effective role in the treatment of this debilitating pathology, in cases where physiotherapy has been unsuccessful. PMID- 26578838 TI - Descending genicular vessels as recipient pedicle for free flap cover of complex defects around upper and mid-lower third junction of tibia. PMID- 26578839 TI - Upper Trunk Emerging From the Sixth and Seventh Cervical Roots - Case Report of an Incidental Finding of a Rare Anomaly of the Brachial Plexus. PMID- 26578840 TI - Solitary Myxoid Neurofibroma of the Palm. PMID- 26578841 TI - An Ulnar Neurofibroma: Management with Sural Graft Reconstruction. PMID- 26578842 TI - Hybrid Axial Ulnar Carpal and Perilunate Dislocation: A Case Report. PMID- 26578843 TI - Floating Index Metacarpal Associated with Multiple Carpometacarpal Fracture Dislocations: a Case Report. AB - The floating metacarpal bone is a result of simultaneous fracture-dislocation of both carpometacarpal and metacarpophalangeal joints. This rare entity may be associated with other hand injuries. Here we present a floating index metacarpal with concomitant 3rd-5th carpometacarpal fracture-dislocations. Excellent functional short-term result was achieved after open metacarpopha langeal reduction and closed carpometacarpal reduction and percutaneous pinning. PMID- 26578844 TI - Painful Metastasis in the Lunate Bone as the First Symptom of a Pancoast Tumor; a Case Report and Review of the Literature. PMID- 26578845 TI - Late Recurrence of Dermatofibrosarcoma Protuberans in a Previously Skin Grafted Forearm. PMID- 26578846 TI - Membranous CD24 expression as detected by the monoclonal antibody SWA11 is a prognostic marker in non-small cell lung cancer patients. AB - BACKGROUND: Lung cancer is one of the most common malignant neoplasms worldwide and has a high mortality rate. To enable individualized therapy regimens, a better understanding of the molecular tumor biology has still to be elucidated. The expression of the cell surface protein CD24 has already been claimed to be associated with shorter patient survival in non-small cell lung cancer (NSCLC), however, the prognostic value and applicability of CD24 immunostaining in paraffin embedded tissue specimens has been questioned due to the recent acknowledgement of restricted epitope specificity of the commonly used antibody SN3b. METHODS: A cohort of 137 primary NSCLC cases was immunostained with a novel CD24 antibody (clone SWA11), which specifically recognizes the CD24 protein core and the resulting expression data were compared with expression profiles based on the monoclonal antibody SN3b. Furthermore, expression data were correlated to clinico-pathological parameters. Univariate and multivariate survival analyses were conducted with Kaplan Meier estimates and Cox regression, respectively. RESULTS: CD24 positivity was found in 34 % resp. 21 % (SN3b) of NSCLC with a membranous and/or cytoplasmic staining pattern. Kaplan-Meier analyses revealed that membranous, but not cytoplasmic CD24 expression (clone SWA11) was associated with lympho-nodular spread and shorter overall survival times (both p < 0.05). CD24 expression established by SN3b antibodies did not reveal significant clinicopathological correlations with overall survival, neither for cytoplasmic nor membranous CD24 staining. CONCLUSIONS: Membranous CD24 immunoreactivity, as detected with antibody clone SWA11 may serve as a prognostic factor for lymphonodular spread and poorer overall survival. Furthermore, these results corroborate the importance of a careful distinction between membranous and cytoplasmic localisation, if CD24 is to be considered as a potential prognostic biomarker. PMID- 26578847 TI - The Professional Nurse Self-Assessment Scale: Psychometric testing in Norwegian long term and home care contexts. AB - BACKGROUND: Nurses' clinical competence is vital to ensure safe and high quality care, and the continuous assessment of nurses' clinical competence is of major concern. A validated instrument for the self-assessment of nurses' clinical competence at different educational levels across specialties and countries is lacking. The aim of this study was to test the reliability and construct validity of the new Professional Nurse Self-Assessment Scale (ProffNurse SAS) questionnaire in long term and home care contexts in Norway. The questionnaire is based on the Nordic Advanced Practice Nursing model, in which the nurse-patient relationship is central. METHODS: The study has a cross-sectional survey design. A purposive sample of 357 registered nurses who worked in long term and home care contexts in two geographical regions encompassing eight municipalities and three counties was included. The respondents completed the 74-item ProffNurse SAS questionnaire and demographic background data was collected. Data collection was conducted in two phases: first region autumn 2011 and second region spring 2012. Exploratory factor analyses (EFA) were used to test the psychometric properties of the questionnaire and included the following steps: assessment of the factorality of the data, factor extraction by Principal Component Analysis (PCA), oblimin (oblique) factor rotation, and interpretation. Cronbach's alpha was used to estimate the internal consistency. RESULTS: The PCA revealed a six-component structure, reducing the number of items in the questionnaire from 74 to 51. Based on the content of the highest-loading items, the six components were named: Direct Clinical Practice, Professional Development, Ethical Decision-Making, Clinical Leadership, Cooperation and Consultation, and Critical Thinking. The Cronbach's alpha values ranged from 0.940 (highest; Direct Clinical Practice) to 0.737 (lowest; Critical Thinking), leading to the estimation that the ProffNurse SAS is reliable. CONCLUSIONS: The six components support the study's theoretical framework. The ProffNurse SAS showed acceptable reliability and construct validity and may therefore be a promising instrument for the assessment of practicing nurses' clinical competence. However, we recommend further psychometric testing in other countries and contexts and the inclusion of larger samples of nurses at various levels of education, particularly master's level APNs. PMID- 26578848 TI - Long-term consequences of in utero irradiated mice indicate proteomic changes in synaptic plasticity related signalling. AB - BACKGROUND: The harmful consequences of in utero irradiation on learning and memory have been recognised but the molecular mechanisms behind the damage are still unknown. RESULTS: Using a mass spectrometry-based approach, we investigated the long-term changes in the global cortical and hippocampal proteome 6 months after 0.1, 0.5 and 1.0 Gy in utero X-ray irradiation delivered on embryonic day 11 in male C57Bl/6 J offspring. We noted alterations in several signalling pathways involved in cognition, the transcription factor cAMP response element binding protein (CREB) playing a central role. Immunoblotting of CREB and phosphorylated CREB (Ser133) showed an altered expression profile at all doses in the hippocampus and at 0.5 and 1.0 Gy in the cortex. The greatest reduction in the phospho-CREB level was seen at 1.0 Gy in the hippocampus. It was accompanied by enhanced expression of postsynaptic density protein 95 (PSD95), suggesting effect on synaptic plasticity in neuronal dendrites. CONCLUSIONS: As the CREB signalling pathway plays a crucial role in neuronal plasticity and long-term memory formation in the brain, the radiation-induced alterations of this pathway seen here are in good agreement with the cognitive dysfunction seen in in utero irradiated populations. These data contribute to a deeper biological understanding of molecular mechanisms behind the long-term damage induced by relatively low doses of ionising radiation during gestation. PMID- 26578849 TI - Oral dabigatran etexilate versus enoxaparin for venous thromboembolism prevention after total hip arthroplasty: pooled analysis of two phase 3 randomized trials. AB - BACKGROUND: Two phase 3 trials compared 28-35 days of treatment with oral dabigatran 220 mg or 150 mg (RE-NOVATE) or 220 mg (RE-NOVATE II) once daily with subcutaneous enoxaparin 40 mg once daily for prevention of venous thromboembolism (VTE) after elective total hip arthroplasty. METHODS: This prespecified pooled analysis compared the outcomes for the dabigatran 220 mg dose with enoxaparin, which included 4,374 patients. Total VTE (venographic and symptomatic) plus all cause mortality (primary efficacy), major VTE (proximal deep vein thrombosis [DVT] or non-fatal pulmonary embolism) plus VTE-related death, and bleeding events were evaluated. Efficacy analysis was based on the modified intention-to treat (ITT) population and safety analysis was based on all treated patients. The common risk difference (RD) for dabigatran versus enoxaparin was estimated using a fixed effects model. RESULTS: Total VTE and all-cause mortality occurred in 6.8 % (114/1,672) and 7.7 % (129/1,682) (RD:-0.8 %, 95 % confidence interval [CI] 2.6 to 0.9) for dabigatran and enoxaparin, respectively. Major VTE plus VTE related mortality occurred in 2.7 % (46/1,714) and 4.0 % (69/1,711) (RD: -1.4 %, 95 % CI -2.6 to -0.2) of patients receiving dabigatran 220 mg and enoxaparin, respectively. Major bleeding occurred in 1.7 % (37/2,156) and 1.3 % (27/2,157) (RD: 0.5 %, 95 % CI -0.2 to 1.2), for dabigatran and enoxaparin respectively. CONCLUSIONS: Extended prophylaxis with oral dabigatran 220 mg once daily was as effective as enoxaparin 40 mg once daily in reducing the risk of total VTE and all-cause mortality after total hip arthroplasty, with a similar bleeding profile. The clinically relevant outcome of major VTE and VTE-related death was significantly reduced with dabigatran versus enoxaparin. TRIAL REGISTRATION: NCT00657150 and NCT00168818. PMID- 26578851 TI - A Medium-Throughput Single Cell CRISPR-Cas9 Assay to Assess Gene Essentiality. AB - BACKGROUND: Target selection for oncology is a crucial step in the successful development of therapeutics. Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 editing of specific loci offers an alternative method to RNA interference and small molecule inhibitors for determining whether a cell line is dependent on a specific gene product for proliferation or survival. In our initial studies using CRISPR-Cas9 to verify the dependence on EZH2 activity for proliferation of a SMARCB1/SNF5/INI1 mutant malignant rhabdoid tumor (MRT) cell line, we noted that the initial reduction in proliferation was lost over time. We hypothesized that in the few cells that retain proliferative capacity, at least one allele of EZH2 remains functional. To verify this, we developed an assay to analyze 10s-100s of clonal cell populations for target gene disruption using restriction digest and fluorescent fragment length analyses. RESULTS: Our results clearly show that in cell lines in which EZH2 is essential for proliferation, at least one potentially functional allele of EZH2 is retained in the clones that survive. CONCLUSION: This assay clearly indicates whether or not a specific gene is essential for survival and/or proliferation in a given cell line. Such data can aid the development of more robust therapeutics by increasing confidence in target selection. PMID- 26578850 TI - Fractional flow reserve (FFR) versus angiography in guiding management to optimise outcomes in non-ST segment elevation myocardial infarction (FAMOUS NSTEMI) developmental trial: cost-effectiveness using a mixed trial- and model based methods. AB - BACKGROUND: In the Fractional flow reserve (FFR) versus angiography in guiding management to optimise outcomes in non-ST elevation myocardial infarction (FAMOUS) clinical trial, FFR was shown to significantly reduce coronary revascularisation, compared to visual interpretation of standard coronary angiography without FFR. We estimated the cost-effectiveness from a UK National Health Service perspective, based on the results of FAMOUS. METHODS: A mixed trial- and model-based approach using decision and statistical modelling was used. Within-trial (1-year) costs and QALYs were assembled at the individual level and then modelled on subsequent management strategy [coronary artery bypass graft (CABG), percutaneous coronary intervention (PCI) or medical therapy (MT)] and major adverse coronary events (death, MI, stroke and revascularisation). One year resource uses included: material, hospitalisation, medical, health professional service use and events. Utilities were derived from individual EQ5D responses. Unit costs were derived from the literature. Outcomes were extended to a lifetime on the basis of MACE during the 1st year. Costs and QALYs were modelled using generalized linear models whilst MACE was modelled using logistic regression. The analysis adopted a payer perspective. Costs and outcomes were discounted at 3.5 %. RESULTS: Costs were related to the subsequent management strategy and MACE whilst QALYs were not. FFR led to a modest cost increase, albeit an imprecise increase, over both the trial [L112 (-L129 to L357)] and lifetime horizons [L133 (-L199 to L499)]. FFR led to a small, albeit imprecise, increase in QALYs over both the trial [0.02 (-0.03 to 0.06)] and lifetime horizons [0.03 (-0.21 to 0.28)]. The mean ICER was L7516/QALY and L4290/QALY over the trial and lifetime horizons, respectively. Decision remained high; FFR had 64 and 59 % probability of cost-effectiveness over trial and lifetime horizons, respectively. CONCLUSIONS: FFR was cost-effective at the mean, albeit with considerable decision uncertainty. Uncertainty can be reduced with more information on long-term health events. PMID- 26578852 TI - Effects of powdered Montmorency tart cherry supplementation on an acute bout of intense lower body strength exercise in resistance trained males. AB - BACKGROUND: The purpose of this study was to examine whether short-term ingestion of a powdered tart cherry supplement prior to and following intense resistance exercise attenuates muscle soreness and recovery strength loss, while reducing markers of muscle damage, inflammation, and oxidative stress. METHODS: Twenty three healthy, resistance-trained men (20.9 +/- 2.6 yr, 14.2 +/- 5.4% body fat, 63.9 +/- 8.6 kg FFM) were matched based on relative maximal back squat strength, age, body weight, and fat free mass. Subjects were randomly assigned to ingest, in a double blind manner, capsules containing a placebo (P, n = 12) or powdered tart cherries [CherryPURE((r))] (TC, n = 11). Participants supplemented one time daily (480 mg/d) for 10-d including day of exercise up to 48-h post-exercise. Subjects performed ten sets of ten repetitions at 70% of a 1-RM back squat exercise. Fasting blood samples, isokinetic MVCs, and quadriceps muscle soreness ratings were taken pre-lift, 60-min, 24-h, and 48-h post-lift and analyzed by MANOVA with repeated measures. RESULTS: Muscle soreness perception in the vastus medialis (1/4) (p = 0.10) and the vastus lateralis (1/4) (p = 0.024) was lower in TC over time compared to P. Compared to pre-lift, TC vastus medialis (1/4) soreness was significantly attenuated up to 48-h post-lift with vastus lateralis (1/4) soreness significantly lower at 24-h post-lift compared to P. TC changes in serum creatinine (p = 0.03, delta p = 0.024) and total protein (p = 0.018, delta p = 0.006) were lower over time and smaller from pre-lift levels over time compared to P Significant TC group reductions from pre-lift levels were found for AST and creatinine 48-h post-lift, bilirubin and ALT 60-min and 48-h post-lift. No significant supplementation effects were observed for serum inflammatory or anti-inflammatory markers. None of the free radical production, lipid peroxidation, or antioxidant capacity markers (NT, TBARS, TAS, SOD) demonstrated significant changes with supplementation. Changes in TC whole blood lymphocyte counts (p = 0.013) from pre-lift were greater compared to P, but TC lymphocyte counts returned to pre-lift values quicker than P. CONCLUSION: Short-term supplementation of Montmorency powdered tart cherries surrounding a single bout of resistance exercise, appears to be an effective dietary supplement to attenuate muscle soreness, strength decrement during recovery, and markers of muscle catabolism in resistance trained individuals. PMID- 26578853 TI - Detecting the subtle shape differences in hemodynamic responses at the group level. AB - The nature of the hemodynamic response (HDR) is still not fully understood due to the multifaceted processes involved. Aside from the overall amplitude, the response may vary across cognitive states, tasks, brain regions, and subjects with respect to characteristics such as rise and fall speed, peak duration, undershoot shape, and overall duration. Here we demonstrate that the fixed-shape (FSM) or adjusted-shape (ASM) methods may fail to detect some shape subtleties (e.g., speed of rise or recovery, or undershoot). In contrast, the estimated shape method (ESM) through multiple basis functions can provide the opportunity to identify some subtle shape differences and achieve higher statistical power at both individual and group levels. Previously, some dimension reduction approaches focused on the peak magnitude, or made inferences based on the area under the curve (AUC) or interaction, which can lead to potential misidentifications. By adopting a generic framework of multivariate modeling (MVM), we showcase a hybrid approach that is validated by simulations and real data. With the whole HDR shape integrity maintained as input at the group level, the approach allows the investigator to substantiate these more nuanced effects through the unique HDR shape features. Unlike the few analyses that were limited to main effect, two- or three-way interactions, we extend the modeling approach to an inclusive platform that is more adaptable than the conventional GLM. With multiple effect estimates from ESM for each condition, linear mixed-effects (LME) modeling should be used at the group level when there is only one group of subjects without any other explanatory variables. Under other situations, an approximate approach through dimension reduction within the MVM framework can be adopted to achieve a practical equipoise among representation, false positive control, statistical power, and modeling flexibility. The associated program 3dMVM is publicly available as part of the AFNI suite. PMID- 26578854 TI - Markers for blood-brain barrier integrity: how appropriate is Evans blue in the twenty-first century and what are the alternatives? AB - In recent years there has been a resurgence of interest in brain barriers and various roles their intrinsic mechanisms may play in neurological disorders. Such studies require suitable models and markers to demonstrate integrity and functional changes at the interfaces between blood, brain, and cerebrospinal fluid. Studies of brain barrier mechanisms and measurements of plasma volume using dyes have a long-standing history, dating back to the late nineteenth century. Their use in blood-brain barrier studies continues in spite of their known serious limitations in in vivo applications. These were well known when first introduced, but seem to have been forgotten since. Understanding these limitations is important because Evans blue is still the most commonly used marker of brain barrier integrity and those using it seem oblivious to problems arising from its in vivo application. The introduction of HRP in the mid twentieth-century was an important advance because its reaction product can be visualized at the electron microscopical level, but it also has limitations. Advantages and disadvantages of these markers will be discussed together with a critical evaluation of alternative approaches. There is no single marker suitable for all purposes. A combination of different sized, visualizable dextrans and radiolabeled molecules currently seems to be the most appropriate approach for qualitative and quantitative assessment of barrier integrity. PMID- 26578855 TI - Hypothalamic tanycytes-masters and servants of metabolic, neuroendocrine, and neurogenic functions. AB - There is a resurgent interest in tanycytes, a radial glial-like cell population occupying the floor and ventro-lateral walls of the third ventricle (3V). Tanycytes reside in close proximity to hypothalamic neuronal nuclei that regulate appetite and energy expenditure, with a subset sending projections into these nuclei. Moreover, tanycytes are exposed to 3V cerebrospinal fluid and have privileged access to plasma metabolites and hormones, through fenestrated capillaries. Indeed, some tanycytes act as conduits for trafficking of these molecules into the brain parenchyma. Tanycytes can also act as neural stem/progenitor cells, supplying the postnatal and adult hypothalamus with new neurons. Collectively, these findings suggest that tanycytes regulate and integrate important trophic and metabolic processes and possibly endow functional malleability to neuronal circuits of the hypothalamus. Hence, manipulation of tanycyte biology could provide a valuable tool for modulating hypothalamic functions such as energy uptake and expenditure in order to tackle prevalent eating disorders such as obesity and anorexia. PMID- 26578856 TI - A dynamical model improves reconstruction of handwriting from multichannel electromyographic recordings. AB - In recent years, several assistive devices have been proposed to reconstruct arm and hand movements from electromyographic (EMG) activity. Although simple to implement and potentially useful to augment many functions, such myoelectric devices still need improvement before they become practical. Here we considered the problem of reconstruction of handwriting from multichannel EMG activity. Previously, linear regression methods (e.g., the Wiener filter) have been utilized for this purpose with some success. To improve reconstruction accuracy, we implemented the Kalman filter, which allows to fuse two information sources: the physical characteristics of handwriting and the activity of the leading hand muscles, registered by the EMG. Applying the Kalman filter, we were able to convert eight channels of EMG activity recorded from the forearm and the hand muscles into smooth reconstructions of handwritten traces. The filter operates in a causal manner and acts as a true predictor utilizing the EMGs from the past only, which makes the approach suitable for real-time operations. Our algorithm is appropriate for clinical neuroprosthetic applications and computer peripherals. Moreover, it is applicable to a broader class of tasks where predictive myoelectric control is needed. PMID- 26578857 TI - New aspects in fenestrated capillary and tissue dynamics in the sensory circumventricular organs of adult brains. AB - The blood-brain barrier (BBB) generally consists of endothelial tight junction barriers that prevent the free entry of blood-derived substances, thereby maintaining the extracellular environment of the brain. However, the circumventricular organs (CVOs), which are located along the midlines of the brain ventricles, lack these endothelial barriers and have fenestrated capillaries; therefore, they have a number of essential functions, including the transduction of information between the blood circulation and brain. Previous studies have demonstrated the extensive contribution of the CVOs to body fluid and thermal homeostasis, energy balance, the chemoreception of blood-derived substances, and neuroinflammation. In this review, recent advances have been discussed in fenestrated capillary characterization and dynamic tissue reconstruction accompanied by angiogenesis and neurogliogenesis in the sensory CVOs of adult brains. The sensory CVOs, including the organum vasculosum of the lamina terminalis (OVLT), subfornical organ (SFO), and area postrema (AP), have size-selective and heterogeneous vascular permeabilities. Astrocyte-/tanycyte like neural stem cells (NSCs) sense blood- and cerebrospinal fluid-derived information through the transient receptor potential vanilloid 1, a mechanical/osmotic receptor, Toll-like receptor 4, a lipopolysaccharide receptor, and Nax, a Na-sensing Na channel. They also express tight junction proteins and densely and tightly surround mature neurons to protect them from blood-derived neurotoxic substances, indicating that the NSCs of the CVOs perform BBB functions while maintaining the capacity to differentiate into new neurons and glial cells. In addition to neurogliogenesis, the density of fenestrated capillaries is regulated by angiogenesis, which is accompanied by the active proliferation and sprouting of endothelial cells. Vascular endothelial growth factor (VEGF) signaling may be involved in angiogenesis and neurogliogenesis, both of which affect vascular permeability. Thus, recent findings advocate novel concepts for the CVOs, which have the dynamic features of vascular and parenchymal tissues. PMID- 26578858 TI - Effects of alternating current stimulation on the healthy and diseased brain. AB - Cognitive and neurological dysfunctions can severely impact a patient's daily activities. In addition to medical treatment, non-invasive transcranial alternating current stimulation (tACS) has been proposed as a therapeutic technique to improve the functional state of the brain. Although during the last years tACS was applied in numerous studies to improve motor, somatosensory, visual and higher order cognitive functions, our knowledge is still limited regarding the mechanisms as to which type of ACS can affect cortical functions and altered neuronal oscillations seem to be the key mechanism. Because alternating current send pulses to the brain at predetermined frequencies, the online- and after-effects of ACS strongly depend on the stimulation parameters so that "optimal" ACS paradigms could be achieved. This is of interest not only for neuroscience research but also for clinical practice. In this study, we summarize recent findings on ACS-effects under both normal conditions and in brain diseases. PMID- 26578859 TI - ICA-based artifact removal diminishes scan site differences in multi-center resting-state fMRI. AB - Resting-state fMRI (R-fMRI) has shown considerable promise in providing potential biomarkers for diagnosis, prognosis and drug response across a range of diseases. Incorporating R-fMRI into multi-center studies is becoming increasingly popular, imposing technical challenges on data acquisition and analysis, as fMRI data is particularly sensitive to structured noise resulting from hardware, software, and environmental differences. Here, we investigated whether a novel clean up tool for structured noise was capable of reducing center-related R-fMRI differences between healthy subjects. We analyzed three Tesla R-fMRI data from 72 subjects, half of whom were scanned with eyes closed in a Philips Achieva system in The Netherlands, and half of whom were scanned with eyes open in a Siemens Trio system in the UK. After pre-statistical processing and individual Independent Component Analysis (ICA), FMRIB's ICA-based X-noiseifier (FIX) was used to remove noise components from the data. GICA and dual regression were run and non parametric statistics were used to compare spatial maps between groups before and after applying FIX. Large significant differences were found in all resting-state networks between study sites before using FIX, most of which were reduced to non significant after applying FIX. The between-center difference in the medial/primary visual network, presumably reflecting a between-center difference in protocol, remained statistically significant. FIX helps facilitate multi center R-fMRI research by diminishing structured noise from R-fMRI data. In doing so, it improves combination of existing data from different centers in new settings and comparison of rare diseases and risk genes for which adequate sample size remains a challenge. PMID- 26578860 TI - Cytoplasmic dynein and its regulatory proteins in Golgi pathology in nervous system disorders. AB - The Golgi apparatus is a dynamic organelle involved in processing and sorting of lipids and proteins. In neurons, the Golgi apparatus is important for the development of axons and dendrites and maintenance of their highly complex polarized morphology. The motor protein complex cytoplasmic dynein has an important role in Golgi apparatus positioning and function. Together, with dynactin and other regulatory factors it drives microtubule minus-end directed motility of Golgi membranes. Inhibition of dynein results in fragmentation and dispersion of the Golgi ribbon in the neuronal cell body, resembling the Golgi abnormalities observed in some neurodegenerative disorders, in particular motor neuron diseases. Mutations in dynein and its regulatory factors, including the dynactin subunit p150Glued, BICD2 and Lis-1, are associated with several human nervous system disorders, including cortical malformation and motor neuropathy. Here we review the role of dynein and its regulatory factors in Golgi function and positioning, and the potential role of dynein malfunction in causing Golgi apparatus abnormalities in nervous system disorders. PMID- 26578861 TI - Toward a neuromorphic microphone. AB - Neuromorphic systems are used in variety of circumstances: as parts of sensory systems, for modeling parts of neural systems and for analog signal processing. In the sensory processing domain, neuromorphic systems can be considered in three parts: pre-transduction processing, transduction itself, and post-transduction processing. Neuromorphic systems include transducers for light, odors, and touch but so far neuromorphic applications in the sound domain have used standard microphones for transduction. We discuss why this is the case and describe what research has been done on neuromorphic approaches to transduction. We make a case for a change of direction toward systems where sound transduction itself has a neuromorphic component. PMID- 26578862 TI - Golgi fragmentation in amyotrophic lateral sclerosis, an overview of possible triggers and consequences. AB - Amyotrophic Lateral Sclerosis (ALS) is an invariably fatal neurodegenerative disorder, which specifically targets motor neurons in the brain, brain stem and spinal cord. Whilst the etiology of ALS remains unknown, fragmentation of the Golgi apparatus is detected in ALS patient motor neurons and in animal/cellular disease models. The Golgi is a highly dynamic organelle that acts as a dispatching station for the vesicular transport of secretory/transmembrane proteins. It also mediates autophagy and maintains endoplasmic reticulum (ER) and axonal homeostasis. Both the trigger for Golgi fragmentation and the functional consequences of a fragmented Golgi apparatus in ALS remain unclear. However, recent evidence has highlighted defects in vesicular trafficking as a pathogenic mechanism in ALS. This review summarizes the evidence describing Golgi fragmentation in ALS, with possible links to other disease processes including cellular trafficking, ER stress, defective autophagy, and axonal degeneration. PMID- 26578863 TI - Olfaction, navigation, and the origin of isocortex. AB - There are remarkable similarities between the brains of mammals and birds in terms of microcircuit architecture, despite obvious differences in gross morphology and development. While in reptiles and birds the most expanding component (the dorsal ventricular ridge) displays an overall nuclear shape and derives from the lateral and ventral pallium, in mammals a dorsal pallial, six layered isocortex shows the most remarkable elaboration. Regardless of discussions about possible homologies between mammalian and avian brains, a main question remains in explaining the emergence of the mammalian isocortex, because it represents a unique phenotype across amniotes. In this article, we propose that the origin of the isocortex was driven by behavioral adaptations involving olfactory driven goal-directed and navigating behaviors. These adaptations were linked with increasing sensory development, which provided selective pressure for the expansion of the dorsal pallium. The latter appeared as an interface in olfactory-hippocampal networks, contributing somatosensory information for navigating behavior. Sensory input from other modalities like vision and audition were subsequently recruited into this expanding region, contributing to multimodal associative networks. PMID- 26578864 TI - Potential application of lithium in Parkinson's and other neurodegenerative diseases. AB - Lithium, the long-standing hallmark treatment for bipolar disorder, has recently been identified as a potential neuroprotective agent in neurodegeneration. Here we focus on introducing numerous in vitro and in vivo studies that have shown lithium treatment to be efficacious in reducing oxidative stress and inflammation, increasing autophagy, inhibiting apoptosis, and decreasing the accumulation of alpha-synulcein, with an emphasis on Parkinson's disease. A number of biological pathways have been shown to be involved in causing these neuroprotective effects. The inhibition of GSK-3beta has been the mechanism most studied; however, other modes of action include the regulation of apoptotic proteins and glutamate excitotoxicity as well as down-regulation of calpain. This review provides a framework of the neuroprotective effects of lithium in neurodegenerative diseases and the putative mechanisms by which lithium provides the protection. Lithium-only treatment may not be a suitable therapeutic option for neurodegenerative diseases due to inconsistent efficacy and potential side effects, however, the use of low dose lithium in combination with other potential or existing therapeutic compounds may be a promising approach to reduce symptoms and disease progression in neurodegenerative diseases. PMID- 26578866 TI - Brain-specific transcriptional regulator T-brain-1 controls brain wiring and neuronal activity in autism spectrum disorders. AB - T-brain-1 (TBR1) is a brain-specific T-box transcription factor. In 1995, Tbr1 was first identified from a subtractive hybridization that compared mouse embryonic and adult telencephalons. Previous studies of Tbr1 (-/-) mice have indicated critical roles for TBR1 in the development of the cerebral cortex, amygdala, and olfactory bulb. Neuronal migration and axonal projection are two important developmental features controlled by TBR1. Recently, recurrent de novo disruptive mutations in the TBR1 gene have been found in patients with autism spectrum disorders (ASDs). Human genetic studies have identified TBR1 as a high confidence risk factor for ASDs. Because only one allele of the TBR1 gene is mutated in these patients, Tbr1 (+/-) mice serve as a good genetic mouse model to explore the mechanism by which de novo TBR1 mutation leads to ASDs. Although neuronal migration and axonal projection defects of cerebral cortex are the most prominent phenotypes in Tbr1 (-/-) mice, these features are not found in Tbr1 (+/ ) mice. Instead, inter- and intra-amygdalar axonal projections and NMDAR expression and activity in amygdala are particularly susceptible to Tbr1 haploinsufficiency. The studies indicated that both abnormal brain wiring (abnormal amygdalar connections) and excitation/inhibition imbalance (NMDAR hypoactivity), two prominent models for ASD etiology, are present in Tbr1 (+/-) mice. Moreover, calcium/calmodulin-dependent serine protein kinase (CASK) was found to interact with TBR1. The CASK-TBR1 complex had been shown to directly bind the promoter of the Grin2b gene, which is also known as Nmdar2b, and upregulate Grin2b expression. This molecular function of TBR1 provides an explanation for NMDAR hypoactivity in Tbr1 (+/-) mice. In addition to Grin2b, cell adhesion molecules-including Ntng1, Cdh8, and Cntn2-are also regulated by TBR1 to control axonal projections of amygdala. Taken together, the studies of Tbr1 provide an integrated picture of ASD etiology at the cellular and circuit levels. PMID- 26578865 TI - Defects in the COG complex and COG-related trafficking regulators affect neuronal Golgi function. AB - The Conserved Oligomeric Golgi (COG) complex is an evolutionarily conserved hetero-octameric protein complex that has been proposed to organize vesicle tethering at the Golgi apparatus. Defects in seven of the eight COG subunits are linked to Congenital Disorders of Glycosylation (CDG)-type II, a family of rare diseases involving misregulation of protein glycosylation, alterations in Golgi structure, variations in retrograde trafficking through the Golgi and system-wide clinical pathologies. A troublesome aspect of these diseases are the neurological pathologies such as low IQ, microcephaly, and cerebellar atrophy. The essential function of the COG complex is dependent upon interactions with other components of trafficking machinery, such as Rab-GTPases and SNAREs. COG-interacting Rabs and SNAREs have been implicated in neurodegenerative diseases like Alzheimer's disease and Parkinson's disease. Defects in Golgi maintenance disrupts trafficking and processing of essential proteins, frequently associated with and contributing to compromised neuron function and human disease. Despite the recent advances in molecular neuroscience, the subcellular bases for most neurodegenerative diseases are poorly understood. This article gives an overview of the potential contributions of the COG complex and its Rab and SNARE partners in the pathogenesis of different neurodegenerative disorders. PMID- 26578867 TI - Generalized reconfigurable memristive dynamical system (MDS) for neuromorphic applications. AB - This study firstly presents (i) a novel general cellular mapping scheme for two dimensional neuromorphic dynamical systems such as bio-inspired neuron models, and (ii) an efficient mixed analog-digital circuit, which can be conveniently implemented on a hybrid memristor-crossbar/CMOS platform, for hardware implementation of the scheme. This approach employs 4n memristors and no switch for implementing an n-cell system in comparison with 2n (2) memristors and 2n switches of a Cellular Memristive Dynamical System (CMDS). Moreover, this approach allows for dynamical variables with both analog and one-hot digital values opening a wide range of choices for interconnections and networking schemes. Dynamical response analyses show that this circuit exhibits various responses based on the underlying bifurcation scenarios which determine the main characteristics of the neuromorphic dynamical systems. Due to high programmability of the circuit, it can be applied to a variety of learning systems, real-time applications, and analytically indescribable dynamical systems. We simulate the FitzHugh-Nagumo (FHN), Adaptive Exponential (AdEx) integrate and fire, and Izhikevich neuron models on our platform, and investigate the dynamical behaviors of these circuits as case studies. Moreover, error analysis shows that our approach is suitably accurate. We also develop a simple hardware prototype for experimental demonstration of our approach. PMID- 26578868 TI - Using a novel source-localized phase regressor technique for evaluation of the vascular contribution to semantic category area localization in BOLD fMRI. AB - Numerous studies have shown that gradient-echo blood oxygen level dependent (BOLD) fMRI is biased toward large draining veins. However, the impact of this large vein bias on the localization and characterization of semantic category areas has not been examined. Here we address this issue by comparing standard magnitude measures of BOLD activity in the Fusiform Face Area (FFA) and Parahippocampal Place Area (PPA) to those obtained using a novel method that suppresses the contribution of large draining veins: source-localized phase regressor (sPR). Unlike previous suppression methods that utilize the phase component of the BOLD signal, sPR yields robust and unbiased suppression of large draining veins even in voxels with no task-related phase changes. This is confirmed in ideal simulated data as well as in FFA/PPA localization data from four subjects. It was found that approximately 38% of right PPA, 14% of left PPA, 16% of right FFA, and 6% of left FFA voxels predominantly reflect signal from large draining veins. Surprisingly, with the contributions from large veins suppressed, semantic category representation in PPA actually tends to be lateralized to the left rather than the right hemisphere. Furthermore, semantic category areas larger in volume and higher in fSNR were found to have more contributions from large veins. These results suggest that previous studies using gradient-echo BOLD fMRI were biased toward semantic category areas that receive relatively greater contributions from large veins. PMID- 26578869 TI - Barbed channels enhance unidirectional connectivity between neuronal networks cultured on multi electrode arrays. AB - Cultured neurons on multi electrode arrays (MEAs) have been widely used to study various aspects of neuronal (network) functioning. A possible drawback of this approach is the lack of structure in these networks. At the single cell level, several solutions have been proposed to enable directed connectivity, and promising results were obtained. At the level of connected sub-populations, a few attempts have been made with promising results. First assessment of the designs' functionality, however, suggested room for further improvement. We designed a two chamber MEA aiming to create a unidirectional connection between the networks in both chambers ("emitting" and "receiving"). To achieve this unidirectionality, all interconnecting channels contained barbs that hindered axon growth in the opposite direction (from receiving to emitting chamber). Visual inspection showed that axons predominantly grew through the channels in the promoted direction. This observation was confirmed by spontaneous activity recordings. Cross correlation between the signals from two electrodes inside the channels suggested signal propagation at ~2 m/s from emitting to receiving chamber. Cross correlation between the firing patterns in both chambers indicated that most correlated activity was initiated in the emitting chamber, which was also reflected by a significantly lower fraction of partial bursts (i.e., a one chamber-only burst) in the emitting chamber. Finally, electrical stimulation in the emitting chamber induced a fast response in that chamber, and a slower response in the receiving chamber. Stimulation in the receiving chamber evoked a fast response in that chamber, but no response in the emitting chamber. These results confirm the predominantly unidirectional nature of the connecting channels from emitting to receiving chamber. PMID- 26578870 TI - Role of central vagal 5-HT3 receptors in gastrointestinal physiology and pathophysiology. AB - Vagal neurocircuits are vitally important in the co-ordination and modulation of GI reflexes and homeostatic functions. 5-hydroxytryptamine (5-HT; serotonin) is critically important in the regulation of several of these autonomic gastrointestinal (GI) functions including motility, secretion and visceral sensitivity. While several 5-HT receptors are involved in these physiological responses, the ligand-gated 5-HT3 receptor appears intimately involved in gut brain signaling, particularly via the afferent (sensory) vagus nerve. 5-HT is released from enterochromaffin cells in response to mechanical or chemical stimulation of the GI tract which leads to activation of 5-HT3 receptors on the terminals of vagal afferents. 5-HT3 receptors are also present on the soma of vagal afferent neurons, including GI vagal afferent neurons, where they can be activated by circulating 5-HT. The central terminals of vagal afferents also exhibit 5-HT3 receptors that function to increase glutamatergic synaptic transmission to second order neurons of the nucleus tractus solitarius within the brainstem. While activation of central brainstem 5-HT3 receptors modulates visceral functions, it is still unclear whether central vagal neurons, i.e., nucleus of the tractus solitarius (NTS) and dorsal motor nucleus of the vagus (DMV) neurons themselves also display functional 5-HT3 receptors. Thus, activation of 5-HT3 receptors may modulate the excitability and activity of gastrointestinal vagal afferents at multiple sites and may be involved in several physiological and pathophysiological conditions, including distention- and chemical-evoked vagal reflexes, nausea, and vomiting, as well as visceral hypersensitivity. PMID- 26578871 TI - I'll take the low road: the evolutionary underpinnings of visually triggered fear. AB - Although there is general agreement that the central nucleus of the amygdala (CeA) is critical for triggering the neuroendocrine response to visual threats, there is uncertainty about the role of subcortical visual pathways in this process. Primates in general appear to depend less on subcortical visual pathways than other mammals. Yet, imaging studies continue to indicate a role for the superior colliculus and pulvinar nucleus in fear activation, despite disconnects in how these brain structures communicate not only with each other but with the amygdala. Studies in fish and amphibians suggest that the neuroendocrine response to visual threats has remained relatively unchanged for hundreds of millions of years, yet there are still significant data gaps with respect to how visual information is relayed to telencephalic areas homologous to the CeA, particularly in fish. In fact ray finned fishes may have evolved an entirely different mechanism for relaying visual information to the telencephalon. In part because they lack a pathway homologous to the lateral geniculate-striate cortex pathway of mammals, amphibians continue to be an excellent model for studying how stress hormones in turn modulate fear activating visual pathways. Glucocorticoids, melanocortin peptides, and CRF all appear to play some role in modulating sensorimotor processing in the optic tectum. These observations, coupled with data showing control of the hypothalamus-pituitary-adrenal axis by the superior colliculus, suggest a fear/stress/anxiety neuroendocrine circuit that begins with first order synapses in subcortical visual pathways. Thus, comparative studies shed light not only on how fear triggering visual pathways came to be, but how hormones released as a result of this activation modulate these pathways. PMID- 26578873 TI - Cardinality as a highly descriptive feature in myoelectric pattern recognition for decoding motor volition. AB - Accurate descriptors of muscular activity play an important role in clinical practice and rehabilitation research. Such descriptors are features of myoelectric signals extracted from sliding time windows. A wide variety of myoelectric features have been used as inputs to pattern recognition algorithms that aim to decode motor volition. The output of these algorithms can then be used to control limb prostheses, exoskeletons, and rehabilitation therapies. In the present study, cardinality is introduced and compared with traditional time domain (Hudgins' set) and other recently proposed myoelectric features (for example, rough entropy). Cardinality was found to consistently outperform other features, including those that are more sophisticated and computationally expensive, despite variations in sampling frequency, time window length, contraction dynamics, type, and number of movements (single or simultaneous), and classification algorithms. Provided that the signal resolution is kept between 12 and 14 bits, cardinality improves myoelectric pattern recognition for the prediction of motion volition. This technology is instrumental for the rehabilitation of amputees and patients with motor impairments where myoelectric signals are viable. All code and data used in this work is available online within BioPatRec. PMID- 26578872 TI - Impaired neural structure and function contributing to autonomic symptoms in congenital central hypoventilation syndrome. AB - Congenital central hypoventilation syndrome (CCHS) patients show major autonomic alterations in addition to their better-known breathing deficiencies. The processes underlying CCHS, mutations in the PHOX2B gene, target autonomic neuronal development, with frame shift extent contributing to symptom severity. Many autonomic characteristics, such as impaired pupillary constriction and poor temperature regulation, reflect parasympathetic alterations, and can include disturbed alimentary processes, with malabsorption and intestinal motility dyscontrol. The sympathetic nervous system changes can exert life-threatening outcomes, with dysregulation of sympathetic outflow leading to high blood pressure, time-altered and dampened heart rate and breathing responses to challenges, cardiac arrhythmia, profuse sweating, and poor fluid regulation. The central mechanisms contributing to failed autonomic processes are readily apparent from structural and functional magnetic resonance imaging studies, which reveal substantial cortical thinning, tissue injury, and disrupted functional responses in hypothalamic, hippocampal, posterior thalamic, and basal ganglia sites and their descending projections, as well as insular, cingulate, and medial frontal cortices, which influence subcortical autonomic structures. Midbrain structures are also compromised, including the raphe system and its projections to cerebellar and medullary sites, the locus coeruleus, and medullary reflex integrating sites, including the dorsal and ventrolateral medullary nuclei. The damage to rostral autonomic sites overlaps metabolic, affective and cognitive regulatory regions, leading to hormonal disruption, anxiety, depression, behavioral control, and sudden death concerns. The injuries suggest that interventions for mitigating hypoxic exposure and nutrient loss may provide cellular protection, in the same fashion as interventions in other conditions with similar malabsorption, fluid turnover, or hypoxic exposure. PMID- 26578875 TI - Effects of thresholding on correlation-based image similarity metrics. AB - The computation of image similarity is important for a wide range of analyses in neuroimaging, from decoding to meta-analysis. In many cases the images being compared have empty voxels, but the effects of such empty voxels on image similarity metrics are poorly understood. We present a detailed investigation of the influence of different degrees of image thresholding on the outcome of pairwise image comparison. Given a pair of brain maps for which one of the maps is thresholded, we show that an analysis using the intersection of non-zero voxels across images at a threshold of Z = +/-1.0 maximizes accuracy for retrieval of a list of maps of the same contrast, and thresholding up to Z = +/ 2.0 can increase accuracy as compared to comparison using unthresholded maps. Finally, maps can be thresholded up to to Z = +/-3.0 (corresponding to 25% of voxels non-empty within a standard brain mask) and still maintain a lower bound of 90% accuracy. Our results suggest that a small degree of thresholding may improve the accuracy of image similarity computations, and that robust meta analytic image similarity comparisons can be obtained using thresholded images. PMID- 26578874 TI - Neuroinflammatory paradigms in lysosomal storage diseases. AB - Lysosomal storage diseases (LSDs) include approximately 70 distinct disorders that collectively account for 14% of all inherited metabolic diseases. LSDs are caused by mutations in various enzymes/proteins that disrupt lysosomal function, which impairs macromolecule degradation following endosome-lysosome and phagosome lysosome fusion and autophagy, ultimately disrupting cellular homeostasis. LSDs are pathologically typified by lysosomal inclusions composed of a heterogeneous mixture of various proteins and lipids that can be found throughout the body. However, in many cases the CNS is dramatically affected, which may result from heightened neuronal vulnerability based on their post-mitotic state. Besides intrinsic neuronal defects, another emerging factor common to many LSDs is neuroinflammation, which may negatively impact neuronal survival and contribute to neurodegeneration. Microglial and astrocyte activation is a hallmark of many LSDs that affect the CNS, which often precedes and predicts regions where eventual neuron loss will occur. However, the timing, intensity, and duration of neuroinflammation may ultimately dictate the impact on CNS homeostasis. For example, a transient inflammatory response following CNS insult/injury can be neuroprotective, as glial cells attempt to remove the insult and provide trophic support to neurons. However, chronic inflammation, as seen in several LSDs, can promote neurodegeneration by creating a neurotoxic environment due to elevated levels of cytokines, chemokines, and pro-apoptotic molecules. Although neuroinflammation has been reported in several LSDs, the cellular basis and mechanisms responsible for eliciting neuroinflammatory pathways are just beginning to be defined. This review highlights the role of neuroinflammation in select LSDs and its potential contribution to neuron loss. PMID- 26578876 TI - Dendritic targeting of short and long 3' UTR BDNF mRNA is regulated by BDNF or NT 3 and distinct sets of RNA-binding proteins. AB - Sorting of mRNAs in neuronal dendrites relies upon inducible transport mechanisms whose molecular bases are poorly understood. We investigated here the mechanism of inducible dendritic targeting of rat brain-derived neurotrophic factor (BDNF) mRNAs as a paradigmatic example. BDNF encodes multiple mRNAs with either short or long 3' UTR, both hypothesized to harbor inducible dendritic targeting signals. However, the mechanisms of sorting of the two 3' UTR isoforms are controversial. We found that dendritic localization of BDNF mRNAs with short 3' UTR was induced by depolarization and NT3 in vitro or by seizures in vivo and required CPEB-1, -2 and ELAV-2, -4. Dendritic targeting of long 3' UTR was induced by activity or BDNF and required CPEB-1 and the relief of soma-retention signals mediated by ELAV-1, -3, -4, and FXR proteins. Thus, long and short 3' UTRs, by using different sets of RNA-binding proteins provide a mechanism of selective targeting in response to different stimuli which may underlay distinct roles of BDNF variants in neuronal development and plasticity. PMID- 26578877 TI - An N-terminal deletion variant of HCN1 in the epileptic WAG/Rij strain modulates HCN current densities. AB - Rats of the Wistar Albino Glaxo/Rij (WAG/Rij) strain show symptoms resembling human absence epilepsy. Thalamocortical neurons of WAG/Rij rats are characterized by an increased HCN1 expression, a negative shift in I h activation curve, and an altered responsiveness of I h to cAMP. We cloned HCN1 channels from rat thalamic cDNA libraries of the WAG/Rij strain and found an N-terminal deletion of 37 amino acids. In addition, WAG-HCN1 has a stretch of six amino acids, directly following the deletion, where the wild-type sequence (GNSVCF) is changed to a polyserine motif. These alterations were found solely in thalamus mRNA but not in genomic DNA. The truncated WAG-HCN1 was detected late postnatal in WAG/Rij rats and was not passed on to rats obtained from pairing WAG/Rij and non-epileptic August Copenhagen Irish rats. Heterologous expression in Xenopus oocytes revealed 2.2 fold increased current amplitude of WAG-HCN1 compared to rat HCN1. While WAG-HCN1 channels did not have altered current kinetics or changed regulation by protein kinases, fluorescence imaging revealed a faster and more pronounced surface expression of WAG-HCN1. Using co-expression experiments, we found that WAG-HCN1 channels suppress heteromeric HCN2 and HCN4 currents. Moreover, heteromeric channels of WAG-HCN1 with HCN2 have a reduced cAMP sensitivity. Functional studies revealed that the gain-of-function of WAG-HCN1 is not caused by the N terminal deletion alone, thus requiring a change of the N-terminal GNSVCF motif. Our findings may help to explain previous observations in neurons of the WAG/Rij strain and indicate that WAG-HCN1 may contribute to the genesis of absence seizures in WAG/Rij rats. PMID- 26578878 TI - Selective potentiation of alpha 1 glycine receptors by ginkgolic acid. AB - Glycine receptors (GlyRs) belong to the superfamily of pentameric cys-loop receptor-operated channels and are involved in numerous physiological functions, including movement, vision, and pain. In search for compounds performing subunit specific modulation of GlyRs we studied action of ginkgolic acid, an abundant Ginkgo biloba product. Using patch-clamp recordings, we analyzed the effects of ginkgolic acid in concentrations from 30 nM to 25 MUM on alpha1-alpha3 and alpha1/beta, alpha2/beta configurations of GlyR and on GABAARs expressed in cultured CHO-K1 cells and mouse neuroblastoma (N2a) cells. Ginkgolic acid caused an increase in the amplitude of currents mediated by homomeric alpha1 and heteromeric alpha1/beta GlyRs and provoked a left-shift of the concentration dependent curves for glycine. Even at high concentrations (10-25 MUM) ginkgolic acid was not able to augment ionic currents mediated by alpha2, alpha2/beta, and alpha3 GlyRs, or by GABAAR consisting of alpha1/beta2/gamma2 subunits. Mutation of three residues (T59A/A261G/A303S) in the alpha2 GlyR subunit to the corresponding ones from the alpha1 converted the action of ginkgolic acid to potentiation with a distinct decrease in EC50 for glycine, suggesting an important role for these residues in modulation by ginkgolic acid. Our results suggest that ginkgolic acid is a novel selective enhancer of alpha1 GlyRs. PMID- 26578879 TI - Calretinin and parvalbumin in schizophrenia and affective disorders: a mini review, a perspective on the evolutionary role of calretinin in schizophrenia, and a preliminary post-mortem study of calretinin in the septal nuclei. AB - OBJECTIVE: The septal nuclei are important limbic regions that are involved in emotional behavior and connect to various brain regions such as the habenular complex. Both the septal nuclei and the habenular complex are involved in the pathology of schizophrenia and affective disorders. METHODS: We characterized the number and density of calretinin-immunoreactive neurons in the lateral, medial, and dorsal subregions of the septal nuclei in three groups of subjects: healthy control subjects (N = 6), patients with schizophrenia (N = 10), and patients with affective disorders (N = 6). RESULTS: Our mini-review of the combined role of calretinin and parvalbumin in schizophrenia and affective disorders summarizes 23 studies. We did not observe significant differences in the numbers of calretinin immunoreactive neurons or neuronal densities in the lateral, medial, and dorsal septal nuclei of patients with schizophrenia or patients with affective disorders compared to healthy control subjects. CONCLUSIONS: Most post-mortem investigations of patients with schizophrenia have indicated significant abnormalities of parvalbumin-immunoreactive neurons in various brain regions including the hippocampus, the anterior cingulate cortex, and the prefrontal cortex in schizophrenia. This study also provides an explanation from an evolutionary perspective for why calretinin is affected in schizophrenia. PMID- 26578880 TI - The established and emerging roles of astrocytes and microglia in amyotrophic lateral sclerosis and frontotemporal dementia. AB - Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two progressive, fatal neurodegenerative syndromes with considerable clinical, genetic and pathological overlap. Clinical symptoms of FTD can be seen in ALS patients and vice versa. Recent genetic discoveries conclusively link the two diseases, and several common molecular players have been identified (TDP-43, FUS, C9ORF72). The definitive etiologies of ALS and FTD are currently unknown and both disorders lack a cure. Glia, specifically astrocytes and microglia are heavily implicated in the onset and progression of neurodegeneration witnessed in ALS and FTD. In this review, we summarize the current understanding of the role of microglia and astrocytes involved in ALS and FTD, highlighting their recent implications in neuroinflammation, alterations in waste clearance involving phagocytosis and the newly described glymphatic system, and vascular abnormalities. Elucidating the precise mechanisms of how astrocytes and microglia are involved in ALS and FTD will be crucial in characterizing these two disorders and may represent more effective interventions for disease progression and treatment options in the future. PMID- 26578881 TI - The prion protein constitutively controls neuronal store-operated Ca(2+) entry through Fyn kinase. AB - The prion protein (PrP(C)) is a cell surface glycoprotein mainly expressed in neurons, whose misfolded isoforms generate the prion responsible for incurable neurodegenerative disorders. Whereas PrP(C) involvement in prion propagation is well established, PrP(C) physiological function is still enigmatic despite suggestions that it could act in cell signal transduction by modulating phosphorylation cascades and Ca(2+) homeostasis. Because PrP(C) binds neurotoxic protein aggregates with high-affinity, it has also been proposed that PrP(C) acts as receptor for amyloid-beta (Abeta) oligomers associated with Alzheimer's disease (AD), and that PrP(C)-Abeta binding mediates AD-related synaptic dysfunctions following activation of the tyrosine kinase Fyn. Here, use of gene encoded Ca(2+) probes targeting different cell domains in primary cerebellar granule neurons (CGN) expressing, or not, PrP(C), allowed us to investigate whether PrP(C) regulates store-operated Ca(2+) entry (SOCE) and the implication of Fyn in this control. Our findings show that PrP(C) attenuates SOCE, and Ca(2+) accumulation in the cytosol and mitochondria, by constitutively restraining Fyn activation and tyrosine phosphorylation of STIM1, a key molecular component of SOCE. This data establishes the existence of a PrP(C)-Fyn-SOCE triad in neurons. We also demonstrate that treating cerebellar granule and cortical neurons with soluble Abeta(1-42) oligomers abrogates the control of PrP(C) over Fyn and SOCE, suggesting a PrP(C)-dependent mechanizm for Abeta-induced neuronal Ca(2+) dyshomeostasis. PMID- 26578882 TI - Traction force and tension fluctuations in growing axons. AB - Actively generated mechanical forces play a central role in axon growth and guidance, but the mechanisms that underly force generation and regulation in growing axons remain poorly understood. We report measurements of the dynamics of traction stresses from growth cones of actively advancing axons from postnatal rat DRG neurons. By tracking the movement of the growth cone and analyzing the traction stress field from a reference frame that moves with it, we are able to show that there is a clear and consistent average stress field that underlies the complex spatial stresses present at any one time. The average stress field has strong maxima on the sides of the growth cone, directed inward toward the growth cone neck. This pattern represents a contractile stress contained within the growth cone, and a net force that is balanced by the axon tension. Using high time-resolution measurements of the growth cone traction stresses, we show that the stress field is composed of fluctuating local stress peaks, with a large number peaks that live for a short time, a population of peaks whose lifetime distribution follows an exponential decay, and a small number of very long-lived peaks. We show that the high time-resolution data also reveal that the tension appears to vary randomly over short time scales, roughly consistent with the lifetime of the stress peaks, suggesting that the tension fluctuations originate from stochastic adhesion dynamics. PMID- 26578883 TI - Acquired equivalence associative learning in GTC epileptic patients: experimental and computational study. AB - Previous cognitive behavioral studies based on Acquired Equivalence Associative learning Task (AEALT) showed a strong relation between hippocampus and basal ganglia in associative learning. However, experimental behavioral studies of patients with Generalized Tonic Clonic (GTC) epilepsy remained sparse. The aim of the present study is to integrate a classical behavioral cognitive analysis with a computational model approach to investigate cognitive associative learning impairments in patients with GTC epilepsy. We measured the accuracy of associative learning response performance in five GTC epileptic patients and five control subjects by using AEALT, all subjects were matched in age and gender. We ran the task using E-Prime, a neuropsychological software program, and SPSS for data statistical analysis. We tested whether GTC epileptic patients would have different learning performance than normal subjects, based on the degree and the location of impairment either in basal ganglia and/or hippocampus. With the number of patients that was available, our behavioral analysis showed no remarkable differences in learning performance of GTC patients as compared to their control subjects, both in the transfer and acquisition phases. In parallel, our simulation results confirmed strong connection and interaction between hippocampus and basal ganglia in our GTC and their control subjects. Nevertheless, the differences in neural firing rate of the connectionist model and weight update of basal ganglia were not significantly different between GTC and control subjects. Therefore, the behavioral analysis and the simulation data provided the same result, thus indicating that the computational model is likely to predict cognitive outcomes. PMID- 26578884 TI - Commentary: "Prdm13 regulates subtype specification of retinal amacrine interneurons and modulates visual sensitivity". PMID- 26578885 TI - Axonal protection by short-term hyperglycemia with involvement of autophagy in TNF-induced optic nerve degeneration. AB - Previous reports showed that short-term hyperglycemia protects optic nerve axons in a rat experimental hypertensive glaucoma model. In this study, we investigated whether short-term hyperglycemia prevents tumor necrosis factor (TNF)-induced optic nerve degeneration in rats and examined the role of autophagy in this axon change process. In phosphate-buffered saline (PBS)-treated rat eyes, no significant difference in axon number between the normoglycemic (NG) and streptozotocin (STZ)-induced hyperglycemic (HG) groups was seen at 2 weeks. Substantial degenerative changes in the axons were noted 2 weeks after intravitreal injection of TNF in the NG group. However, the HG group showed significant protective effects on axons against TNF-induced optic nerve degeneration compared with the NG group. This protective effect was significantly inhibited by 3-methyladenine (3-MA), an autophagy inhibitor. Immunoblot analysis showed that the LC3-II level in the optic nerve was increased in the HG group compared with the NG group. Increased p62 protein levels in the optic nerve after TNF injection was observed in the NG group, and this increase was inhibited in the HG group. Electron microscopy showed that autophagosomes were increased in optic nerve axons in the HG group. Immunohistochemical study showed that LC3 was colocalized with nerve fibers in the retina and optic nerve in both the NG and HG groups. Short-term hyperglycemia protects axons against TNF-induced optic nerve degeneration. This axonal-protective effect may be associated with autophagy machinery. PMID- 26578887 TI - Fast and reliable identification of axons, axon initial segments and dendrites with local field potential recording. AB - The axon initial segment (AIS) is an essential neuronal compartment. It is usually where action potentials are initiated. Recent studies demonstrated that the AIS is a plastic structure that can be regulated by neuronal activity and by the activation of metabotropic receptors. Studying the AIS in live tissue can be difficult because its identification is not always reliable. Here we provide a new technique allowing a fast and reliable identification of the AIS in live brain slice preparations. By simultaneous recording of extracellular local field potentials and whole-cell patch-clamp recording of neurons, we can detect sinks caused by inward currents flowing across the membrane. We determine the location of the AIS by comparing the timing of these events with the action potential. We demonstrate that this method allows the unequivocal identification of the AIS of different types of neurons from the brain. PMID- 26578888 TI - Mechanosensitive enteric neurons in the guinea pig gastric corpus. AB - For long it was believed that a particular population of enteric neurons, referred to as intrinsic primary afferent neuron (IPAN)s, encodes mechanical stimulation. We recently proposed a new concept suggesting that there are in addition mechanosensitive enteric neurons (MEN) that are multifunctional. Based on firing pattern MEN behaved as rapidly, slowly, or ultra-slowly adapting RAMEN, SAMEN, or USAMEN, respectively. We aimed to validate this concept in the myenteric plexus of the gastric corpus, a region where IPANs were not identified and existence of enteric sensory neurons was even questioned. The gastric corpus is characterized by a particularly dense extrinsic sensory innervation. Neuronal activity was recorded with voltage sensitive dye imaging after deformation of ganglia by compression (intraganglionic volume injection or von Fry hair) or tension (ganglionic stretch). We demonstrated that 27% of the gastric neurons were MEN and responded to intraganglionic volume injection. Of these 73% were RAMEN, 25% SAMEN, and 2% USAMEN with a firing frequency of 1.7 (1.1/2.2), 5.1 (2.2/7.7), and of 5.4 (5.0/15.5) Hz, respectively. The responses were reproducible and stronger with increased stimulus strength. Even after adaptation another deformation evoked spike discharge again suggesting a resetting mode of the mechanoreceptors. All MEN received fast synaptic input. Fifty five percent of all MEN were cholinergic and 45% nitrergic. Responses in some MEN significantly decreased after perfusion of TTX, low Ca(++)/high Mg(++) Krebs solution, capsaicin induced nerve defunctionalization and capsazepine indicating the involvement of TRPV1 expressing extrinsic mechanosensitive nerves. Half of gastric MEN responded to intraganglionic volume injection as well as to ganglionic stretch and 23% responded to stretch only. Tension-sensitive MEN were to a large proportion USAMEN (44%). In summary, we demonstrated for the first time compression and tension-sensitive MEN in the stomach; many of them responded to one stimulus modality only. Their proportions and the basic properties were similar to MEN previously identified by us in other intestinal region and species. Unlike in the intestine, the responsiveness of some gastric MEN is enhanced by extrinsic TRPV1 expressing visceral afferents. PMID- 26578886 TI - Role of TGFbeta signaling in the pathogenesis of Alzheimer's disease. AB - Aging is the main risk factor for Alzheimer's disease (AD); being associated with conspicuous changes on microglia activation. Aged microglia exhibit an increased expression of cytokines, exacerbated reactivity to various stimuli, oxidative stress, and reduced phagocytosis of beta-amyloid (Abeta). Whereas normal inflammation is protective, it becomes dysregulated in the presence of a persistent stimulus, or in the context of an inflammatory environment, as observed in aging. Thus, neuroinflammation can be a self-perpetuating deleterious response, becoming a source of additional injury to host cells in neurodegenerative diseases. In aged individuals, although transforming growth factor beta (TGFbeta) is upregulated, its canonical Smad3 signaling is greatly reduced and neuroinflammation persists. This age-related Smad3 impairment reduces protective activation while facilitating cytotoxic activation of microglia through several cellular mechanisms, potentiating microglia-mediated neurodegeneration. Here, we critically discuss the role of TGFbeta-Smad signaling on the cytotoxic activation of microglia and its relevance in the pathogenesis of AD. Other protective functions, such as phagocytosis, although observed in aged animals, are not further induced by inflammatory stimuli and TGFbeta1. Analysis in silico revealed that increased expression of receptor scavenger receptor (SR) A, involved in Abeta uptake and cell activation, by microglia exposed to TGFbeta, through a Smad3-dependent mechanism could be mediated by transcriptional co factors Smad2/3 over the MSR1 gene. We discuss that changes of TGFbeta-mediated regulation could at least partially mediate age-associated microglia changes, and, together with other changes on inflammatory response, could result in the reduction of protective activation and the potentiation of cytotoxicity of microglia, resulting in the promotion of neurodegenerative diseases. PMID- 26578889 TI - Role of brain glycogen in the response to hypoxia and in susceptibility to epilepsy. AB - Although glycogen is the only carbohydrate reserve of the brain, its overall contribution to brain functions remains unclear. It has been proposed that glycogen participates in the preservation of such functions during hypoxia. Several reports also describe a relationship between brain glycogen and susceptibility to epilepsy. To address these issues, we used our brain-specific Glycogen Synthase knockout (GYS1(Nestin-KO)) mouse to study the functional consequences of glycogen depletion in the brain under hypoxic conditions and susceptibility to epilepsy. GYS1(Nestin-KO) mice presented significantly different power spectra of hippocampal local field potentials (LFPs) than controls under hypoxic conditions. In addition, they showed greater excitability than controls for paired-pulse facilitation evoked at the hippocampal CA3-CA1 synapse during experimentally induced hypoxia, thereby suggesting a compensatory switch to presynaptic mechanisms. Furthermore, GYS1(Nestin-KO) mice showed greater susceptibility to hippocampal seizures and myoclonus following the administration of kainate and/or a brief train stimulation of Schaffer collaterals. We conclude that brain glycogen could play a protective role both in hypoxic situations and in the prevention of brain seizures. PMID- 26578890 TI - Automated measurement of fast mitochondrial transport in neurons. AB - There is growing recognition that fast mitochondrial transport in neurons is disrupted in multiple neurological diseases and psychiatric disorders. However, a major constraint in identifying novel therapeutics based on mitochondrial transport is that the large-scale analysis of fast transport is time consuming. Here we describe methodologies for the automated analysis of fast mitochondrial transport from data acquired using a robotic microscope. We focused on addressing questions of measurement precision, speed, reliably, workflow ease, statistical processing, and presentation. We used optical flow and particle tracking algorithms, implemented in ImageJ, to measure mitochondrial movement in primary cultured cortical and hippocampal neurons. With it, we are able to generate complete descriptions of movement profiles in an automated fashion of hundreds of thousands of mitochondria with a processing time of approximately one hour. We describe the calibration of the parameters of the tracking algorithms and demonstrate that they are capable of measuring the fast transport of a single mitochondrion. We then show that the methods are capable of reliably measuring the inhibition of fast mitochondria transport induced by the disruption of microtubules with the drug nocodazole in both hippocampal and cortical neurons. This work lays the foundation for future large-scale screens designed to identify compounds that modulate mitochondrial motility. PMID- 26578892 TI - Gating of tactile information through gamma band during passive arm movement in awake primates. AB - To make precise and prompt action in a dynamic environment, the sensorimotor system needs to integrate all related information. The inflow of somatosensory information to the cerebral cortex is regulated and mostly suppressed by movement, which is commonly referred to as sensory gating or gating. Sensory gating plays an important role in preventing redundant information from reaching the cortex, which should be considered when designing somatosensory neuroprosthetics. Gating can occur at several levels within the sensorimotor pathway, while the underlying mechanism is not yet fully understood. The average sensory evoked potential is commonly used to assess sensory information processing, however the assumption of a stereotyped response to each stimulus is still an open question. Event related spectral perturbation (ERSP), which is the power spectrum after time-frequency decomposition on single trial evoked potentials (total power), could overcome this limitation of averaging and provide additional information for understanding the underlying mechanism. To this aim, neural activities in primary somatosensory cortex (S1), primary motor cortex (M1), and ventral posterolateral (VPL) nucleus of thalamus were recorded simultaneously in two areas (S1 and M1 or S1 and VPL) during passive arm movement and rest in awake monkeys. Our results showed that neural activity at different recording areas demonstrated specific and unique response frequency characteristics. Tactile input induced early high frequency responses followed by low frequency oscillations within sensorimotor circuits, and passive movement suppressed these oscillations either in a phase-locked or non-phase-locked manner. Sensory gating by movement was non-phase-locked in M1, and complex in sensory areas. VPL showed gating of non-phase-locked at gamma band and mix of phase-locked and non-phase-locked at low frequency, while S1 showed gating of phase-locked and non-phase-locked at gamma band and an early phase-locked elevation followed by non-phase-locked gating at low frequency. Granger causality (GC) analysis showed bidirectional coupling between VPL and S1, while GC between M1 and S1 was not responsive to tactile input. Thus, these results suggest that tactile input is dominantly transmitted along the ascending direction from VPL to S1, and the sensory input is suppressed during movement through a bottom-up strategy within the gamma-band during passive movement. PMID- 26578891 TI - Plasticity of brain wave network interactions and evolution across physiologic states. AB - Neural plasticity transcends a range of spatio-temporal scales and serves as the basis of various brain activities and physiologic functions. At the microscopic level, it enables the emergence of brain waves with complex temporal dynamics. At the macroscopic level, presence and dominance of specific brain waves is associated with important brain functions. The role of neural plasticity at different levels in generating distinct brain rhythms and how brain rhythms communicate with each other across brain areas to generate physiologic states and functions remains not understood. Here we perform an empirical exploration of neural plasticity at the level of brain wave network interactions representing dynamical communications within and between different brain areas in the frequency domain. We introduce the concept of time delay stability (TDS) to quantify coordinated bursts in the activity of brain waves, and we employ a system-wide Network Physiology integrative approach to probe the network of coordinated brain wave activations and its evolution across physiologic states. We find an association between network structure and physiologic states. We uncover a hierarchical reorganization in the brain wave networks in response to changes in physiologic state, indicating new aspects of neural plasticity at the integrated level. Globally, we find that the entire brain network undergoes a pronounced transition from low connectivity in Deep Sleep and REM to high connectivity in Light Sleep and Wake. In contrast, we find that locally, different brain areas exhibit different network dynamics of brain wave interactions to achieve differentiation in function during different sleep stages. Moreover, our analyses indicate that plasticity also emerges in frequency specific networks, which represent interactions across brain locations mediated through a specific frequency band. Comparing frequency-specific networks within the same physiologic state we find very different degree of network connectivity and link strength, while at the same time each frequency-specific network is characterized by a different signature pattern of sleep-stage stratification, reflecting a remarkable flexibility in response to change in physiologic state. These new aspects of neural plasticity demonstrate that in addition to dominant brain waves, the network of brain wave interactions is a previously unrecognized hallmark of physiologic state and function. PMID- 26578893 TI - Broadband macroscopic cortical oscillations emerge from intrinsic neuronal response failures. AB - Broadband spontaneous macroscopic neural oscillations are rhythmic cortical firing which were extensively examined during the last century, however, their possible origination is still controversial. In this work we show how macroscopic oscillations emerge in solely excitatory random networks and without topological constraints. We experimentally and theoretically show that these oscillations stem from the counterintuitive underlying mechanism-the intrinsic stochastic neuronal response failures (NRFs). These NRFs, which are characterized by short term memory, lead to cooperation among neurons, resulting in sub- or several- Hertz macroscopic oscillations which coexist with high frequency gamma oscillations. A quantitative interplay between the statistical network properties and the emerging oscillations is supported by simulations of large networks based on single-neuron in-vitro experiments and a Langevin equation describing the network dynamics. Results call for the examination of these oscillations in the presence of inhibition and external drives. PMID- 26578895 TI - Corticofugal GABAergic projection neurons in the mouse frontal cortex. AB - Cortical projection neurons are classified by hodology in corticocortical, commissural and corticofugal subtypes. Although cortical projection neurons had been regarded as only glutamatergic neurons, recently corticocortical GABAergic projection neurons has been also reported in several species. Here, we demonstrate corticofugal GABAergic projection neurons in the mouse frontal cortex. We employed viral-vector-mediated anterograde tracing, classical retrograde tracing, and immunohistochemistry to characterize neocortical GABAergic projection neurons. Injections of the Cre-dependent adeno-associated virus into glutamate decarboxylase 67 (GAD67)-Cre knock-in mice revealed neocortical GABAergic projections widely to the forebrain, including the cerebral cortices, caudate putamen (CPu), ventral pallidum (VP), lateral globus pallidus (LGP), nucleus accumbens, and olfactory tubercle (Tu). Minor GABAergic projections were also found in the mediodorsal thalamic nucleus, diagonal band of Broca, medial globus pallidus, substantial nigra, and dorsal raphe nucleus. Retrograde tracing studies also demonstrated corticofugal GABAergic projection neurons in the mouse frontal cortex. Further immunohistochemical screening with neurochemical markers revealed the majority of corticostriatal GABAergic projection neurons were positive for somatostatin (SS)-immunoreactivity. In contrast, corticothalamic GABAergic projection neurons were not identified by representative neurochemical markers for GABAergic neurons. These findings suggest that corticofugal GABAergic projection neurons are heterogeneous in terms of their neurochemical properties and target nuclei, and provide axonal innervations mainly to the nuclei in the basal ganglia. PMID- 26578894 TI - Frequency-specific alternations in the amplitude of low-frequency fluctuations in chronic tinnitus. AB - Tinnitus, a phantom ringing, buzzing, or hissing sensation with potentially debilitating consequences, is thought to arise from aberrant spontaneous neural activity at one or more sites within the central nervous system; however, the location and specific features of these oscillations are poorly understood with respect to specific tinnitus features. Recent resting-state functional magnetic resonance imaging (fMRI) studies suggest that aberrant fluctuations in spontaneous low-frequency oscillations (LFO) of the blood oxygen level-dependent (BOLD) signal may be an important factor in chronic tinnitus; however, the role that frequency-specific components of LFO play in subjective tinnitus remains unclear. A total of 39 chronic tinnitus patients and 41 well-matched healthy controls participated in the resting-state fMRI scans. The LFO amplitudes were investigated using the amplitude of low-frequency fluctuation (ALFF) and fractional ALFF (fALFF) in two different frequency bands (slow-4: 0.027-0.073 Hz and slow-5: 0.01-0.027 Hz). We observed significant differences between tinnitus patients and normal controls in ALFF/fALFF in the two bands (slow-4 and slow-5) in several brain regions including the superior frontal gyrus (SFG), inferior frontal gyrus, middle temporal gyrus, angular gyrus, supramarginal gyrus, and middle occipital gyrus. Across the entire subject pool, significant differences in ALFF/fALFF between the two bands were found in the midbrain, basal ganglia, hippocampus and cerebellum (Slow 4 > Slow 5), and in the middle frontal gyrus, supramarginal gyrus, posterior cingulate cortex, and precuneus (Slow 5 > Slow 4). We also observed significant interaction between frequency bands and patient groups in the orbitofrontal gyrus. Furthermore, tinnitus distress was positively correlated with the magnitude of ALFF in right SFG and the magnitude of fALFF slow-4 band in left SFG, whereas tinnitus duration was positively correlated with the magnitude of ALFF in right SFG and the magnitude of fALFF slow-5 band in left SFG. Resting-state fMRI provides an unbiased method for identifying aberrant spontaneous LFO occurring throughout the central nervous system. Chronic tinnitus patients have widespread abnormalities in ALFF and fALFF slow-4 and slow-5 band which are correlated with tinnitus distress and duration. These results provide new insights on the neuropathophysiology of chronic tinnitus; therapies capable of reversing these aberrant patterns may reduce tinnitus distress. PMID- 26578896 TI - The neural elements in the lining of the ventricular-subventricular zone: making an old story new by high-resolution scanning electron microscopy. AB - The classical description of the neural elements that compose the lining of brain ventricles introduces us to the single layer of ependymal cells. However, new findings, especially in the lateral ventricle (LV)-the major niche for the generation of new neurons in the adult brain-have provided information about additional cell elements that influence the organization of this part of the ventricular system and produce important contributions to neurogenesis. To complement the cell neurochemistry findings, we present a three-dimensional in situ description that demonstrates the anatomical details of the different types of ciliated cells and the innervation of these elements. After processing adult rat brains for ultrastructural analysis by high-resolution scanning electron microscopy (HRSEM) and transmission electron microscopy, we observed a heterogeneous pattern of cilia distribution at the different poles of the LV surface. Furthermore, we describe the particular three-dimensional aspects of the ciliated cells of the LV, in addition the fiber bundles and varicose axons surrounding these cells. Therefore, we provide a unique ultrastructural description of the three-dimensional in situ organization of the LV surface, highlighting its innervation, to corroborate the available neurochemical and functional findings regarding the factors that regulate this neurogenic niche. PMID- 26578897 TI - LIM homeobox protein 5 (Lhx5) is essential for mamillary body development. AB - The mamillary body (MM) is a group of hypothalamic nuclei related to memory and spatial navigation that interconnects hippocampal, thalamic, and tegmental regions. Here we demonstrate that Lhx5, a LIM-HD domain transcription factor expressed early in the developing posterior hypothalamus, is required for the generation of the MM and its derived tracts. The MM markers Foxb1, Sim2, and Lhx1 are absent in Lhx5 knock-out mice from early embryonic stages, suggesting abnormal specification of this region. This was supported by the absence of Nkx2.1 and expansion of Shh in the prospective mamillary area. Interestingly, we also found an ectopic domain expressing Lhx2 and Lhx9 along the anterio-posterior hypothalamic axis. Our results suggest that Lhx5 controls early aspects of hypothalamic development by regulating gene expression and cellular specification in the prospective MM. PMID- 26578898 TI - A univocal definition of the neuronal soma morphology using Gaussian mixture models. AB - The definition of the soma is fuzzy, as there is no clear line demarcating the soma of the labeled neurons and the origin of the dendrites and axon. Thus, the morphometric analysis of the neuronal soma is highly subjective. In this paper, we provide a mathematical definition and an automatic segmentation method to delimit the neuronal soma. We applied this method to the characterization of pyramidal cells, which are the most abundant neurons in the cerebral cortex. Since there are no benchmarks with which to compare the proposed procedure, we validated the goodness of this automatic segmentation method against manual segmentation by neuroanatomists to set up a framework for comparison. We concluded that there were no significant differences between automatically and manually segmented somata, i.e., the proposed procedure segments the neurons similarly to how a neuroanatomist does. It also provides univocal, justifiable and objective cutoffs. Thus, this study is a means of characterizing pyramidal neurons in order to objectively compare the morphometry of the somata of these neurons in different cortical areas and species. PMID- 26578899 TI - Construction and application of human neonatal DTI atlases. AB - Atlas-based MRI analysis is one of many analytical methods and is used to investigate typical as well as abnormal neurodevelopment. It has been widely applied to the adult and pediatric populations. Successful applications of atlas based analysis (ABA) in those cohorts have motivated the creation of a neonatal atlas and parcellation map (PM). The purpose of this review is to discuss the various neonatal diffusion tensor imaging (DTI) atlases that are available for use in ABA, examine how such atlases are constructed, review their applications, and discuss future directions in DTI. Neonatal DTI atlases are created from a template, which can be study-specific or standardized, and merged with the corresponding PM. Study-specific templates can retain higher image registration accuracy, but are usually not applicable across different studies. However, standardized templates can be used to make comparisons among various studies, but may not accurately reflect the anatomies of the study population. Methods such as volume-based template estimation are being developed to overcome these limitations. The applications for ABA, including atlas-based image quantification and atlas-based connectivity analysis, vary from quantifying neurodevelopmental progress to analyzing population differences in groups of neonates. ABA can also be applied to detect pathology related to prematurity at birth or exposure to toxic substances. Future directions for this method include research designed to increase the accuracy of the image parcellation. Methods such as multi-atlas label fusion and multi-modal analysis applied to neonatal DTI currently comprise an active field of research. Moreover, ABA can be used in high-throughput analysis to efficiently process medical images and to assess longitudinal brain changes. The overarching goal of neonatal ABA is application to the clinical setting, to assist with diagnoses, monitor disease progression and, ultimately, outcome prediction. PMID- 26578900 TI - Perinatal asphyxia results in altered expression of the hippocampal acylethanolamide/endocannabinoid signaling system associated to memory impairments in postweaned rats. AB - Perinatal asphyxia (PA) is an obstetric complication that strongly affects the CNS. The endocannabinoid system (ECS) is a lipid transmitter system involved in several physiological processes including synaptic plasticity, neurogenesis, memory, and mood. Endocannabinoids, and other acylethanolamides (AEs) without endocannabinoid activity, have recently received growing attention due to their potential neuroprotective functions in neurological disorders, including cerebral ischemia. In the present study, we aimed to analyze the changes produced by PA in the major metabolic enzymes and receptors of the ECS/AEs in the hippocampus using a rodent model of PA. To induce PA, we removed uterine horns from ready-to deliver rats and immersed them into a water bath during 19 min. Animals delivered spontaneously or by cesarean section were employed as controls. At 1 month of age, cognitive functions were assessed and immunohistochemical procedures were carried out to determine the expression of NeuN and glial fibrillary acidic protein, enzymes responsible for synthesis (DAGLalpha and NAPE-PLD) and degradation (FAAH) of ECS/AEs and their receptors (CB1 and PPARalpha) in the hippocampus. Postweaned asphyctic rats showed impaired recognition and spatial reference memory that were accompanied by hippocampal astrogliosis and changes in the expression of enzymes and receptors. The most remarkable findings in asphyctic rats were a decrease in the expression of NAPE-PLD and PPARalpha in both hippocampal areas CA1 and CA3. In addition, postweaned cesarean delivery rats showed an increase in the immunolabeling for FAAH in the hippocampal CA3 area. Since, NAPE-PLD and PPARalpha are proteins that participate in the biochemical process of AEs, specially the neuroprotective oleoylethanolamide, these results suggest that PA dysregulates this system. These data encourage conducting future studies using AEs as potential neuroprotective compounds in animal models of PA. PMID- 26578901 TI - Differential contributions of dorsolateral and frontopolar cortices to working memory processes in the primate. AB - The ability to maintain and manipulate information across temporal delays is a fundamental requirement to bridge the gap between perception and action. In the case of higher-order behavior, the maintenance of rules and strategies is particularly helpful in bridging this gap. The prefrontal cortex (PFC) has long been considered critical for such processes, and research has focused on different subdivisions of PFC to gain an insight into their diverse contributions to these mechanisms. Substantial evidence indicates that dorsolateral PFC (dlPFC) is an important structure for maintaining information across delays, with cells actively firing across delays and lesions to this region causing deficits in tasks involving delayed responses and maintenance of rules online. Frontopolar cortex (FP), on the other hand, appears to show the opposite pattern of results, with cells not firing across delays and lesions to this region not affecting the same rule-based, delayed response tasks that are impaired following dlPFC lesions. The body of evidence therefore suggests that dlPFC and FP's contributions to working memory differ. In this article, we will provide a perspective on how these regions might implement distinct but complementary and interactive functions that contribute to more general temporally-extended processes and support flexible, dynamic behavior. PMID- 26578902 TI - Prefrontal-amygdala fear networks come into focus. AB - The ability to form associations between aversive threats and their predictors is fundamental to survival. However, fear and anxiety in excess are detrimental and are a hallmark of psychiatric diseases such as post-traumatic stress disorder (PTSD). PTSD symptomatology includes persistent and intrusive thoughts of an experienced trauma, suggesting an inability to downregulate fear when a corresponding threat has subsided. Convergent evidence from human and rodent studies supports a role for the medial prefrontal cortex (mPFC)-amygdala network in both PTSD and the regulation of fear memory expression. In particular, current models stipulate that the prelimbic (PL) and infralimbic (IL) subdivisions of the rodent mPFC bidirectionally regulate fear expression via differential recruitment of amygdala neuronal subpopulations. However, an array of recent studies that employ new technical approaches has fundamentally challenged this interpretation. Here we explore how a new emphasis on the contribution of inhibitory neuronal populations, subcortical structures and the passage of time is reshaping our understanding of mPFC-amygdala circuits and their control over fear. PMID- 26578904 TI - Editorial: Reward- and aversion-related processing in the brain: translational evidence for separate and shared circuits. PMID- 26578903 TI - A high-density EEG study of differences between three high speeds of simulated forward motion from optic flow in adult participants. AB - A high-density EEG study was conducted to investigate evoked and oscillatory brain activity in response to high speeds of simulated forward motion. Participants were shown an optic flow pattern consisting of a virtual road with moving poles at either side of it, simulating structured forward motion at different driving speeds (25, 50, and 75 km/h) with a static control condition between each motion condition. Significant differences in N2 latencies and peak amplitudes between the three speeds of visual motion were found in parietal channels of interest P3 and P4. As motion speed increased, peak latency increased while peak amplitude decreased which might indicate that higher driving speeds are perceived as more demanding resulting in longer latencies, and as fewer neurons in the motion sensitive areas of the adult brain appear to be attuned to such high visual speeds this could explain the observed inverse relationship between speed and amplitude. In addition, significant differences between alpha de-synchronizations for forward motion and alpha synchronizations in the static condition were found in the parietal midline (PM) source. It was suggested that the alpha de-synchronizations reflect an activated state related to the visual processing of simulated forward motion, whereas the alpha synchronizations in response to the static condition reflect a deactivated resting period. PMID- 26578905 TI - Commentary: On the possible role of stimulation duration for after-effects of transcranial alternating current stimulation. PMID- 26578906 TI - Methods, caveats and the future of large-scale microelectrode recordings in the non-human primate. AB - Cognitive processes play out on massive brain-wide networks, which produce widely distributed patterns of activity. Capturing these activity patterns requires tools that are able to simultaneously measure activity from many distributed sites with high spatiotemporal resolution. Unfortunately, current techniques with adequate coverage do not provide the requisite spatiotemporal resolution. Large scale microelectrode recording devices, with dozens to hundreds of microelectrodes capable of simultaneously recording from nearly as many cortical and subcortical areas, provide a potential way to minimize these tradeoffs. However, placing hundreds of microelectrodes into a behaving animal is a highly risky and technically challenging endeavor that has only been pursued by a few groups. Recording activity from multiple electrodes simultaneously also introduces several statistical and conceptual dilemmas, such as the multiple comparisons problem and the uncontrolled stimulus response problem. In this perspective article, we discuss some of the techniques that we, and others, have developed for collecting and analyzing large-scale data sets, and address the future of this emerging field. PMID- 26578908 TI - Analyzing 7000 texts on deep brain stimulation: what do they tell us? AB - The enormous increase in numbers of scientific publications in the last decades requires quantitative methods for obtaining a better understanding of topics and developments in various fields. In this exploratory study, we investigate the emergence, trends, and connections of topics within the whole text corpus of the deep brain stimulation (DBS) literature based on more than 7000 papers (title and abstracts) published between 1991 to 2014 using a network approach. Taking the co occurrence of basic terms that represent important topics within DBS as starting point, we outline the statistics of interconnections between DBS indications, anatomical targets, positive, and negative effects, as well as methodological, technological, and economic issues. This quantitative approach confirms known trends within the literature (e.g., regarding the emergence of psychiatric indications). The data also reflect an increased discussion about complex issues such as personality connected tightly to the ethical context, as well as an apparent focus on depression as important DBS indication, where the co-occurrence of terms related to negative effects is low both for the indication as well as the related anatomical targets. We also discuss consequences of the analysis from a bioethical perspective, i.e., how such a quantitative analysis could uncover hidden subject matters that have ethical relevance. For example, we find that hardware-related issues in DBS are far more robustly connected to an ethical context compared to impulsivity, concrete side-effects or death/suicide. Our contribution also outlines the methodology of quantitative text analysis that combines statistical approaches with expert knowledge. It thus serves as an example how innovative quantitative tools can be made useful for gaining a better understanding in the field of DBS. PMID- 26578907 TI - Hypothalamic control of brown adipose tissue thermogenesis. AB - It has long been known, in large part from animal studies, that the control of brown adipose tissue (BAT) thermogenesis is insured by the central nervous system (CNS), which integrates several stimuli in order to control BAT activation through the sympathetic nervous system (SNS). SNS-mediated BAT activity is governed by diverse neurons found in brain structures involved in homeostatic regulations and whose activity is modulated by various factors including oscillations of energy fluxes. The characterization of these neurons has always represented a challenging issue. The available literature suggests that the neuronal circuits controlling BAT thermogenesis are largely part of an autonomic circuitry involving the hypothalamus, brainstem and the SNS efferent neurons. In the present review, we recapitulate the latest progresses in regards to the hypothalamic regulation of BAT metabolism. We briefly addressed the role of the thermoregulatory pathway and its interactions with the energy balance systems in the control of thermogenesis. We also reviewed the involvement of the brain melanocortin and endocannabinoid systems as well as the emerging role of steroidogenic factor 1 (SF1) neurons in BAT thermogenesis. Finally, we examined the link existing between these systems and the homeostatic factors that modulate their activities. PMID- 26578909 TI - The social neuroscience and the theory of integrative levels. AB - The theory of integrative levels provides a general description of the evolution of matter through successive orders of complexity and integration. Along its development, material forms pass through different levels of organization, such as physical, chemical, biological or sociological. The appearance of novel structures and dynamics during this process of development of matter in complex systems has been called emergence. Social neuroscience (SN), an interdisciplinary field that aims to investigate the biological mechanisms that underlie social structures, processes, and behavior and the influences between social and biological levels of organization, has affirmed the necessity for including social context as an essential element to understand the human behavior. To do this, SN proposes a multilevel integrative approach by means of three principles: multiple determinism, nonadditive determinism and reciprocal determinism. These theoretical principles seem to share the basic tenets of the theory of integrative levels but, in this paper, we aim to reveal the differences among both doctrines. First, SN asserts that combination of neural and social variables can produce emergent phenomena that would not be predictable from a neuroscientific or social psychological analysis alone; SN also suggests that to achieve a complete understanding of social structures we should use an integrative analysis that encompasses levels of organization ranging from the genetic level to the social one; finally, SN establishes that there can be mutual influences between biological and social factors in determining behavior, accepting, therefore, a double influence, upward from biology to social level, and downward, from social level to biology. In contrast, following the theory of integrative levels, emergent phenomena are not produced by the combination of variables from two levels, but by the increment of complexity at one level. In addition, the social behavior and structures might be contemplated not as the result of mixing or summing social and biological influences, but as emergent phenomena that should be described with its own laws. Finally, following the integrative levels view, influences upward, from biology to social level, and downward, from social level to biology, might not be equivalent, since the bottom up processes are emergent and the downward causation (DC) is not. PMID- 26578910 TI - Delay discounting without decision-making: medial prefrontal cortex and amygdala activations reflect immediacy processing and correlate with impulsivity and anxious-depressive traits. AB - Humans value rewards less when these are delivered in the future as opposed to immediately, a phenomenon referred to as delay discounting. While delay discounting has been studied during the anticipation of rewards and in the context of intertemporal decision-making, little is known about its neural correlates in the outcome phase (during reward delivery) and their relation to personality. Personality traits that have been associated with increased delay discounting include impulsivity and, potentially, anxious-depressive traits. Here we performed functional magnetic resonance imaging (fMRI) in 72 healthy participants while they carried out a monetary incentive delay (MID) task with a delay manipulation. In sixty percent of the experimental trials, participants won rewards that differed in magnitude (0.05?, 0.50? or 1?) and delay until delivery (immediately, 10 days, or 100 days). A factor analysis on questionnaires yielded two factors reflecting Impulsivity and Anxiety/Depression, which we used to examine potential relationships between personality and delay discounting. When winning a reward, medial prefrontal cortex (mPFC) activation was higher for immediate compared to delayed rewards. Moreover, amygdala activation correlated with reward magnitude for immediate but not for delayed rewards. Amygdala activation to winning immediate rewards was higher in more impulsive participants, while mPFC activation to winning immediate rewards was higher in more anxious-depressed participants. Our results uncover neural correlates of delay discounting during reward delivery, and suggest that impulsivity and subclinical anxious-depressive traits are related to stronger neural responses for winning immediate relative to delayed rewards. PMID- 26578912 TI - ERP measures of math anxiety: how math anxiety affects working memory and mental calculation tasks? AB - There have been several attempts to account for the impact of Mathematical Anxiety (MA) on brain activity with variable results. The present study examines the effects of MA on ERP amplitude during performance of simple arithmetic calculations and working memory tasks. Data were obtained from 32 university students as they solved four types of arithmetic problems (one- and two-digit addition and multiplication) and a working memory task comprised of three levels of difficulty (1, 2, and 3-back task). Compared to the Low-MA group, High-MA individuals demonstrated reduced ERP amplitude at frontocentral (between 180-320 ms) and centroparietal locations (between 380-420 ms). These effects were independent of task difficulty/complexity, individual performance, and general state/trait anxiety levels. Results support the hypothesis that higher levels of self-reported MA are associated with lower cortical activation during the early stages of the processing of numeric stimuli in the context of cognitive tasks. PMID- 26578911 TI - Active training for amblyopia in adult rodents. AB - Amblyopia is the most diffused form of visual function impairment affecting one eye, with a prevalence of 1-5% in the total world population. Amblyopia is usually caused by an early functional imbalance between the two eyes, deriving from anisometropia, strabismus, or congenital cataract, leading to severe deficits in visual acuity, contrast sensitivity and stereopsis. While amblyopia can be efficiently treated in children, it becomes irreversible in adults, as a result of a dramatic decline in visual cortex plasticity which occurs at the end of the critical period (CP) in the primary visual cortex. Notwithstanding this widely accepted dogma, recent evidence in animal models and in human patients have started to challenge this view, revealing a previously unsuspected possibility to enhance plasticity in the adult visual system and to achieve substantial visual function recovery. Among the new proposed intervention strategies, non invasive procedures based on environmental enrichment, physical exercise or visual perceptual learning (vPL) appear particularly promising in terms of future applicability in the clinical setting. In this survey, we will review recent literature concerning the application of these behavioral intervention strategies to the treatment of amblyopia, with a focus on possible underlying molecular and cellular mechanisms. PMID- 26578913 TI - Narrative language competence in children and adolescents with Down syndrome. AB - This study was designed to examine the narrative language abilities of children and adolescents with Down syndrome (DS) in comparison to same-age peers with fragile X syndrome (FXS) and younger typically developing (TD) children matched by nonverbal cognitive ability levels. Participants produced narrative retells from a wordless picture book. Narratives were analyzed at the macrostructural (i.e., their internal episodic structure) and the microstructural (i.e., rate of use of specific word categories) levels. Mean length of utterance (MLU), a microstructural metric of syntactic complexity, was used as a control variable. Participants with DS produced fewer episodic elements in their narratives (i.e., their narratives were less fully realized) than the TD participants, although MLU differences accounted for the macrostructural differences between participant groups. At the microstructural level, participants with DS displayed a lower rate of verb use than the groups with FXS and typical development, even after accounting for MLU. These findings reflect both similarities and differences between individuals with DS or FXS and contribute to our understanding of the language phenotype of DS. Implications for interventions to promote language development and academic achievement are discussed. PMID- 26578914 TI - Cholinergic and ghrelinergic receptors and KCNQ channels in the medial PFC regulate the expression of palatability. AB - The medial prefrontal cortex (mPFC) is a key brain region for the control of consummatory behavior. Neuronal activity in this area is modulated when rats initiate consummatory licking and reversible inactivations eliminate reward contrast effects and reduce a measure of palatability, the duration of licking bouts. Together, these data suggest the hypothesis that rhythmic neuronal activity in the mPFC is crucial for the control of consummatory behavior. The muscarinic cholinergic system is known to regulate membrane excitability and control low-frequency rhythmic activity in the mPFC. Muscarinic receptors (mAChRs) act through KCNQ (Kv7) potassium channels, which have recently been linked to the orexigenic peptide ghrelin. To understand if drugs that act on KCNQ channels within the mPFC have effects on consummatory behavior, we made infusions of several muscarinic drugs (scopolamine, oxotremorine, physostigmine), the KCNQ channel blocker XE-991, and ghrelin into the mPFC and evaluated their effects on consummatory behavior. A consistent finding across all drugs was an effect on the duration of licking bouts when animals consume solutions with a relatively high concentration of sucrose. The muscarinic antagonist scopolamine reduced bout durations, both systemically and intra-cortically. By contrast, the muscarinic agonist oxotremorine, the cholinesterase inhibitor physostigmine, the KCNQ channel blocker XE-991, and ghrelin all increased the durations of licking bouts when infused into the mPFC. Our findings suggest that cholinergic and ghrelinergic signaling in the mPFC, acting through KCNQ channels, regulates the expression of palatability. PMID- 26578915 TI - Laterality enhances numerical skills in the guppy, Poecilia reticulata. AB - It has been hypothesized that cerebral lateralization can significantly enhance cognition and that this was one of the primary selective forces shaping its wide spread evolution amongst vertebrate taxa. Here, we tested this hypothesis by examining the link between cerebral lateralization and numerical discrimination. Guppies, Poecilia reticulata, were sorted into left, right and non-lateralized groups using a standard mirror test and their numerical discrimination abilities tested in both natural shoal choice and abstract contexts. Our results show that strongly lateralized guppies have enhanced numerical abilities compared to non lateralized guppies irrespective of context. These data provide further credence to the notion that cerebral lateralization can enhance cognitive efficiency. PMID- 26578916 TI - Investigating decision rules with a new experimental design: the EXACT paradigm. AB - In the decision-making field, it is important to distinguish between the perceptual process (how information is collected) and the decision rule (the strategy governing decision-making). We propose a new paradigm, called EXogenous ACcumulation Task (EXACT) to disentangle these two components. The paradigm consists of showing a horizontal gauge that represents the probability of receiving a reward at time t and increases with time. The participant is asked to press a button when they want to request a reward. Thus, the perceptual mechanism is hard-coded and does not need to be inferred from the data. Based on this paradigm, we compared four decision rules (Bayes Risk, Reward Rate, Reward/Accuracy, and Modified Reward Rate) and found that participants appeared to behave according to the Modified Reward Rate. We propose a new way of analysing the data by using the accuracy of responses, which can only be inferred in classic RT tasks. Our analysis suggests that several experimental findings such as RT distribution and its relationship with experimental conditions, usually deemed to be the result of a rise-to-threshold process, may be simply explained by the effect of the decision rule employed. PMID- 26578917 TI - Individual variability in behavioral flexibility predicts sign-tracking tendency. AB - Sign-tracking rats show heightened sensitivity to food- and drug-associated cues, which serve as strong incentives for driving reward seeking. We hypothesized that this enhanced incentive drive is accompanied by an inflexibility when incentive value changes. To examine this we tested rats in Pavlovian outcome devaluation or second-order conditioning prior to the assessment of sign-tracking tendency. To assess behavioral flexibility we trained rats to associate a light with a food outcome. After the food was devalued by pairing with illness, we measured conditioned responding (CR) to the light during an outcome devaluation probe test. The level of CR during outcome devaluation probe test correlated with the rats' subsequent tracking tendency, with sign-tracking rats failing to suppress CR to the light after outcome devaluation. To assess Pavlovian incentive learning, we trained rats on first-order (CS+, CS-) and second-order (SOCS+, SOCS ) discriminations. After second-order conditioning, we measured CR to the second order cues during a probe test. Second-order conditioning was observed across all rats regardless of tracking tendency. The behavioral inflexibility of sign trackers has potential relevance for understanding individual variation in vulnerability to drug addiction. PMID- 26578918 TI - Sex differences in the representation of call stimuli in a songbird secondary auditory area. AB - Understanding how communication sounds are encoded in the central auditory system is critical to deciphering the neural bases of acoustic communication. Songbirds use learned or unlearned vocalizations in a variety of social interactions. They have telencephalic auditory areas specialized for processing natural sounds and considered as playing a critical role in the discrimination of behaviorally relevant vocal sounds. The zebra finch, a highly social songbird species, forms lifelong pair bonds. Only male zebra finches sing. However, both sexes produce the distance call when placed in visual isolation. This call is sexually dimorphic, is learned only in males and provides support for individual recognition in both sexes. Here, we assessed whether auditory processing of distance calls differs between paired males and females by recording spiking activity in a secondary auditory area, the caudolateral mesopallium (CLM), while presenting the distance calls of a variety of individuals, including the bird itself, the mate, familiar and unfamiliar males and females. In males, the CLM is potentially involved in auditory feedback processing important for vocal learning. Based on both the analyses of spike rates and temporal aspects of discharges, our results clearly indicate that call-evoked responses of CLM neurons are sexually dimorphic, being stronger, lasting longer, and conveying more information about calls in males than in females. In addition, how auditory responses vary among call types differ between sexes. In females, response strength differs between familiar male and female calls. In males, temporal features of responses reveal a sensitivity to the bird's own call. These findings provide evidence that sexual dimorphism occurs in higher-order processing areas within the auditory system. They suggest a sexual dimorphism in the function of the CLM, contributing to transmit information about the self-generated calls in males and to storage of information about the bird's auditory experience in females. PMID- 26578919 TI - Pre-weaning dietary iron deficiency impairs spatial learning and memory in the cognitive holeboard task in piglets. AB - Iron deficiency is the most common nutritional deficiency in humans, affecting more than two billion people worldwide. Early-life iron deficiency can lead to irreversible deficits in learning and memory. The pig represents a promising model animal for studying such deficits, because of its similarities to humans during early development. We investigated the effects of pre-weaning dietary iron deficiency in piglets on growth, blood parameters, cognitive performance, and brain histology later in life. Four to six days after birth, 10 male sibling pairs of piglets were taken from 10 different sows. One piglet of each pair was given a 200 mg iron dextran injection and fed a control milk diet for 28 days (88 mg Fe/kg), whereas the other sibling was given a saline injection and fed an iron deficient (ID) milk diet (21 mg Fe/kg). Due to severely retarded growth of two of the ID piglets, only eight ID piglets were tested behaviorally. After dietary treatment, all piglets were fed a balanced commercial pig diet (190-240 mg Fe/kg). Starting at 7.5 weeks of age, piglets were tested in a spatial cognitive holeboard task. In this task, 4 of 16 holes contain a hidden food reward, allowing measurement of working (short-term) memory and reference (long-term) memory (RM) simultaneously. All piglets received 40-60 acquisition trials, followed by a 16-trial reversal phase. ID piglets showed permanently retarded growth and a strong decrease in blood iron parameters during dietary treatment. After treatment, ID piglets' blood iron values restored to normal levels. In the holeboard task, ID piglets showed impaired RM learning during acquisition and reversal. Iron staining at necropsy at 12 weeks of age showed that ID piglets had fewer iron-containing cells in hippocampal regions CA1 and dentate gyrus (DG). The number of iron-containing cells in CA3 correlated positively with the average RM score during acquisition across all animals. Our results support the hypothesis that early-life iron deficiency leads to lasting cognitive deficits. The piglet as a model animal, tested in the holeboard, can be useful in future research for assessing long-term cognitive effects of early-life diets or diet induced deficiencies. PMID- 26578920 TI - Is there a pilot in the brain? Contribution of the self-positioning system to spatial navigation. AB - Since the discovery of place cells, the hippocampus is thought to be the neural substrate of a cognitive map. The later discovery of head direction cells, grid cells and border cells, as well as of cells with more complex spatial signals, has led to the idea that there is a brain system devoted to providing the animal with the information required to achieve efficient navigation. Current questioning is focused on how these signals are integrated in the brain. In this review, we focus on the issue of how self-localization is performed in the hippocampal place cell map. To do so, we first shortly review the sensory information used by place cells and then explain how this sensory information can lead to two coding modes, respectively based on external landmarks (allothetic information) and self-motion cues (idiothetic information). We hypothesize that these two modes can be used concomitantly with the rat shifting from one mode to the other during its spatial displacements. We then speculate that sequential reactivation of place cells could participate in the resetting of self localization under specific circumstances and in learning a new environment. Finally, we provide some predictions aimed at testing specific aspects of the proposed ideas. PMID- 26578921 TI - Modulation of instrumental responding by a conditioned threat stimulus requires lateral and central amygdala. AB - Two studies explored the role of the amygdala in response modulation by an aversive conditioned stimulus (CS) in rats. Experiment 1 investigated the role of amygdala circuitry in conditioned suppression using a paradigm in which licking for sucrose was inhibited by a tone CS that had been previously paired with footshock. Electrolytic lesions of the lateral amygdala (LA) impaired suppression relative to sham-operated animals, and produced the same pattern of results when applied to central amygdala. In addition, disconnection of the lateral and central amygdala, by unilateral lesion of each on opposite sides of the brain, also impaired suppression relative to control subjects that received lesions of both areas on the same side. In each case, lesions were placed following Pavlovian conditioning and instrumental training, but before testing. This procedure produced within-subjects measures of the effects of lesion on freezing and between-group comparisons for the effects on suppression. Experiment 2 extended this analysis to a task where an aversive CS suppressed shuttling responses that had been previously food reinforced and also found effects of bilateral lesions of the central amygdala in a pre-post design. Together, these studies demonstrate that connections between the lateral and central amygdala constitute a serial circuit involved in processing aversive Pavlovian stimuli, and add to a growing body of findings implicating central amygdala in the modulation of instrumental behavior. PMID- 26578922 TI - Decreased modulation by the risk level on the brain activation during decision making in adolescents with internet gaming disorder. AB - Greater impulse and risk-taking and reduced decision-making ability were reported as the main behavioral impairments in individuals with internet gaming disorder (IGD), which has become a serious mental health issue worldwide. However, it is not clear to date how the risk level modulates brain activity during the decision making process in IGD individuals. In this study, 23 adolescents with IGD and 24 healthy controls (HCs) without IGD were recruited, and the balloon analog risk task (BART) was used in a functional magnetic resonance imaging experiment to evaluate the modulation of the risk level (the probability of balloon explosion) on brain activity during risky decision making in IGD adolescents. Reduced modulation of the risk level on the activation of the right dorsolateral prefrontal cortex (DLPFC) during the active BART was found in IGD group compared to the HCs. In the IGD group, there was a significant negative correlation between the risk-related DLPFC activation during the active BART and the Barratt impulsivity scale (BIS-11) scores, which were significantly higher in IGD group compared with the HCs. Our study demonstrated that, as a critical decision-making related brain region, the right DLPFC is less sensitive to risk in IGD adolescents compared with the HCs, which may contribute to the higher impulsivity level in IGD adolescents. PMID- 26578923 TI - The effect of sung speech on socio-communicative responsiveness in children with autism spectrum disorders. AB - There is emerging evidence to demonstrate the efficacy of music-based interventions for improving social functioning in children with Autism Spectrum Disorders (ASD). While this evidence lends some support in favor of using song over spoken directives in facilitating engagement and receptive intervention in ASD, there has been little research that has investigated the efficacy of such stimuli on socio-communicative responsiveness measures. Here, we present preliminary results from a pilot study which tested whether sung instruction, as compared to spoken directives, could elicit greater number of socio-communicative behaviors in young children with ASD. Using an adapted single-subject design, three children between the ages of 3 and 4 years, participated in a programme consisting of 18 sessions, of which 9 were delivered with spoken directives and 9 with sung. Sessions were counterbalanced and randomized for three play activities block matching, picture matching and clay play. All sessions were video-recorded for post-hoc observational coding of three behavioral metrics which included performance, frequency of social gesture and eye contact. Analysis of the videos by two independent raters indicated increased socio-communicative responsiveness in terms of frequency of social gesture as well as eye contact during sung compared to spoken conditions, across all participants. Our findings suggest that sung directives may play a useful role in engaging children with ASD and also serve as an effective interventional medium to enhance socio-communicative responsiveness. PMID- 26578925 TI - Impacts of coordinative training on normal weight and overweight/obese children's attentional performance. AB - This study investigated the efficacy of a physical activity (PA) program to improve the attention span in normal weight vs. overweight/obese children. The study was designed as a cluster-randomized controlled intervention. One hundred fifty-seven normal weight and overweight/obese primary school children were randomly divided in three cohorts: Traditional PA, Coordinative PA and a Control group (not attending any PA). Before and after 5 months of intervention, children were administered the d2-R test of attention. Results showed that participants' attentional performances were significantly affected by Time (pre vs. post; P < 0.01) and by Time * Group interaction (traditional vs. coordinative vs. control; P < 0.001), revealing significant different effects of intervention/exercise modality on children's attentional performance, independently of their weight status. These data suggest that a 5-month school-based PA intervention can improve the cognitive performance in children. Further, the Coordinative PA intervention resulted in the most significant improvement in children's attention. PMID- 26578924 TI - Increased striatal functional connectivity with auditory cortex in tinnitus. AB - Tinnitus is a common auditory perceptual disorder whose neural substrates are under intense debate. One physiologically based model posits the dorsal striatum to play a key role in gating auditory phantoms to perceptual awareness. Here, we directly test this model along with the roles of auditory and auditory-limbic networks in tinnitus non-invasively by comparing resting-state fMRI functional connectivity patterns in chronic tinnitus patients against matched control subjects without hearing loss. We assess resting-state functional connectivity of the caudate dorsal striatum (area LC), caudate head (CH), nucleus accumbens (NA), and primary auditory cortex (A1) to determine patterns of abnormal connectivity. In chronic tinnitus, increases in ipsilateral striatal-auditory cortical connectivity are found consistently only in area LC. Other patterns of increased connectivity are as follows: (1) right striatal area LC, A1, CH, and NA with parietal cortex, (2) left and right CHs with dorsal pre-frontal cortex, (3) NA and A1 with cerebellum, hippocampus, visual and ventral pre-frontal cortex. Those findings provide further support for a striatal gating model of tinnitus, where dysfunctionally permissive area LC enables auditory phantoms to reach perceptual awareness. PMID- 26578926 TI - Adolescent development of context-dependent stimulus-reward association memory and its neural correlates. AB - Expression of learned stimulus-reward associations based on context is essential for regulation of behavior to meet situational demands. Contextual regulation improves during development, although the developmental progression of relevant neural and cognitive processes is not fully specified. We therefore measured neural correlates of flexible, contextual expression of stimulus-reward associations in pre/early-adolescent children (ages 9-13 years) and young adults (ages 19-22 years). After reinforcement learning using standard parameters, a contextual reversal manipulation was used whereby contextual cues indicated that stimulus-reward associations were the same as previously reinforced for some trials (consistent trials) or were reversed on other trials (inconsistent trials). Subjects were thus required to respond according to original stimulus reward associations vs. reversed associations based on trial-specific contextual cues. Children and young adults did not differ in reinforcement learning or in relevant functional magnetic resonance imaging (fMRI) correlates. In contrast, adults outperformed children during contextual reversal, with better performance specifically for inconsistent trials. fMRI signals corresponding to this selective advantage included greater activity in lateral prefrontal cortex (LPFC), hippocampus, and dorsal striatum for young adults relative to children. Flexible expression of stimulus-reward associations based on context thus improves via adolescent development, as does recruitment of brain regions involved in reward learning and contextual expression of memory. HighlightsEarly adolescent children and young adults were equivalent in reinforcement learning.Adults outperformed children in contextual expression of stimulus-reward associations.Adult advantages correlated with increased activity of relevant brain regions.Specific neurocognitive developmental changes support better contextual regulation. PMID- 26578927 TI - Changes in brain connectivity related to the treatment of depression measured through fMRI: a systematic review. AB - Depression is a mental illness that presents alterations in brain connectivity in the Default Mode Network (DMN), the Affective Network (AN) and other cortical limbic networks, and the Cognitive Control Network (CCN), among others. In recent years the interest in the possible effect of the different antidepressant treatments on functional connectivity has increased substantially. The goal of this paper is to conduct a systematic review of the studies on the relationship between the treatment of depression and brain connectivity. Nineteen studies were found in a systematic review on this topic. In all of them, there was improvement of the clinical symptoms after antidepressant treatment. In 18 out of the 19 studies, clinical improvement was associated to changes in brain connectivity. It seems that both DMN and the connectivity between cortical and limbic structures consistently changes after antidepressant treatment. However, the current evidence does not allow us to assure that the treatment of depression leads to changes in the CCN. In this regard, some papers report a positive correlation between changes in brain connectivity and improvement of depressive symptomatology, particularly when they measure cortical-limbic connectivity, whereas the changes in DMN do not significantly correlate with clinical improvement. Finally, some papers suggest that changes in connectivity after antidepressant treatment might be partly related to the mechanisms of action of the treatment administered. This effect has been observed in two studies with stimulation treatment (one with rTMS and one with ECT), and in two papers that administered three different pharmacological treatments. Our review allows us to make a series of recommendations that might guide future researchers exploring the effect of anti-depression treatments on brain connectivity. PMID- 26578928 TI - Processing ambiguity in a linguistic context: decision-making difficulties in non aphasic patients with behavioral variant frontotemporal degeneration. AB - Some extent of ambiguity is ubiquitous in everyday conversations. For example, words have multiple meaning and very common pronouns, like "he" and "she" (anaphoric pronouns), have little meaning on their own and refer to a noun that has been previously introduced in the discourse. Ambiguity triggers a decision process that is not a subroutine of language processing but rather a more general domain resource. Therefore non-aphasic patients with limited decision-making capability can encounter severe limitation in language processing due to extra linguistic limitations. In the present study, we test patients with behavioral variant frontotemporal degeneration (bvFTD), focusing on anaphora as a paradigmatic example of ambiguity resolution in the linguistic domain. bvFTD is characterized by gray matter (GM) atrophy in prefrontal cortex, but relative sparing of peri-Sylvian cortex. A group of patients with parietal disease due to corticobasal syndrome (CBS) was also tested here in order to investigate the specific role of prefrontal cortex in the task employed in the current study. Participants were presented with a pair of sentences in which the first sentence contained two nouns while the second contained a pronoun. In the experimental (ambiguous) condition, both nouns are plausible referents of the pronoun, thus requiring decision-making resources. The results revealed that bvFTD patients are significantly less accurate than healthy seniors in identifying the correct referent of a pronoun in the ambiguous condition, although CBS patients were as accurate as healthy seniors. Imaging analyses related bvFTD patients' performance to GM atrophy in ventromedial prefrontal cortex (vmPFC). These results suggest that bvFTD patients have difficulties in decision processes that involve the resolution of an ambiguity. PMID- 26578929 TI - What is in the feedback? Effect of induced happiness vs. sadness on probabilistic learning with vs. without exploration. AB - According to dominant neuropsychological theories of affect, emotions signal salience of events and in turn facilitate a wide spectrum of response options or action tendencies. Valence of an emotional experience is pivotal here, as it alters reward and punishment processing, as well as the balance between safety and risk taking, which can be translated into changes in the exploration exploitation trade-off during reinforcement learning (RL). To test this idea, we compared the behavioral performance of three groups of participants that all completed a variant of a standard probabilistic learning task, but who differed regarding which mood state was actually induced and maintained (happy, sad or neutral). To foster a change from an exploration to an exploitation-based mode, we removed feedback information once learning was reliably established. Although changes in mood were successful, learning performance was balanced between the three groups. Critically, when focusing on exploitation-driven learning only, they did not differ either. Moreover, mood valence did not alter the learning rate or exploration per se, when titrated using complementing computational modeling. By comparing systematically these results to our previous study (Bakic et al., 2014), we found that arousal levels did differ between studies, which might account for limited modulatory effects of (positive) mood on RL in the present case. These results challenge the assumption that mood valence alone is enough to create strong shifts in the way exploitation or exploration is eventually carried out during (probabilistic) learning. In this context, we discuss the possibility that both valence and arousal are actually necessary components of the emotional mood state to yield changes in the use and exploration of incentives cues during RL. PMID- 26578931 TI - How native-like can you possibly get: fMRI evidence for processing accent. AB - INTRODUCTION: If ever attained, adopting native-like accent is achieved late in the learning process. Resemblance between L2 and mother tongue can facilitate L2 learning. In particular, cognates (phonologically and semantically similar words across languages), offer the opportunity to examine the issue of foreign accent in quite a unique manner. METHODS: Twelve Spanish speaking (L1) adults learnt French (L2) cognates and practiced their native-like pronunciation by means of a computerized method. After consolidation, they were tested on L1 and L2 oral picture- naming during fMRI scanning. RESULTS AND DISCUSSION: The results of the present study show that there is a specific impact of accent on brain activation, even if L2 words are cognates, and belong to a pair of closely related languages. Results point that the insula is a key component of accent processing, which is in line with reports from patients with foreign accent syndrome following damage to the insula (e.g., Katz et al., 2012; Moreno-Torres et al., 2013; Tomasino et al., 2013), and healthy L2 learners (Chee et al., 2004). Thus, the left insula has been consistently related to the integration of attentional and working memory abilities, together with fine-tuning of motor programming to achieve optimal articulation. PMID- 26578932 TI - Nothing new under the sun, or the moon, or both. PMID- 26578930 TI - Probabilistic atlases of default mode, executive control and salience network white matter tracts: an fMRI-guided diffusion tensor imaging and tractography study. AB - Diffusion tensor imaging (DTI) is a powerful MRI technique that can be used to estimate both the microstructural integrity and the trajectories of white matter pathways throughout the central nervous system. This fiber tracking (aka, "tractography") approach is often carried out using anatomically-defined seed points to identify white matter tracts that pass through one or more structures, but can also be performed using functionally-defined regions of interest (ROIs) that have been determined using functional MRI (fMRI) or other methods. In this study, we performed fMRI-guided DTI tractography between all of the previously defined nodes within each of six common resting-state brain networks, including the: dorsal Default Mode Network (dDMN), ventral Default Mode Network (vDMN), left Executive Control Network (lECN), right Executive Control Network (rECN), anterior Salience Network (aSN), and posterior Salience Network (pSN). By normalizing the data from 32 healthy control subjects to a standard template using high-dimensional, non-linear warping methods-we were able to create probabilistic white matter atlases for each tract in stereotaxic coordinates. By investigating all 198 ROI-to-ROI combinations within the aforementioned resting state networks (for a total of 6336 independent DTI tractography analyses), the resulting probabilistic atlases represent a comprehensive cohort of functionally defined white matter regions that can be used in future brain imaging studies to: (1) ascribe DTI or other white matter changes to particular functional brain networks, and (2) compliment resting state fMRI or other functional connectivity analyses. PMID- 26578933 TI - Anterior cingulate cortex-related connectivity in first-episode schizophrenia: a spectral dynamic causal modeling study with functional magnetic resonance imaging. AB - Understanding the neural basis of schizophrenia (SZ) is important for shedding light on the neurobiological mechanisms underlying this mental disorder. Structural and functional alterations in the anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DLPFC), hippocampus, and medial prefrontal cortex (MPFC) have been implicated in the neurobiology of SZ. However, the effective connectivity among them in SZ remains unclear. The current study investigated how neuronal pathways involving these regions were affected in first-episode SZ using functional magnetic resonance imaging (fMRI). Forty-nine patients with a first episode of psychosis and diagnosis of SZ-according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision-were studied. Fifty healthy controls (HCs) were included for comparison. All subjects underwent resting state fMRI. We used spectral dynamic causal modeling (DCM) to estimate directed connections among the bilateral ACC, DLPFC, hippocampus, and MPFC. We characterized the differences using Bayesian parameter averaging (BPA) in addition to classical inference (t-test). In addition to common effective connectivity in these two groups, HCs displayed widespread significant connections predominantly involved in ACC not detected in SZ patients, but SZ showed few connections. Based on BPA results, SZ patients exhibited anterior cingulate cortico-prefrontal-hippocampal hyperconnectivity, as well as ACC related and hippocampal-dorsolateral prefrontal-medial prefrontal hypoconnectivity. In summary, spectral DCM revealed the pattern of effective connectivity involving ACC in patients with first-episode SZ. This study provides a potential link between SZ and dysfunction of ACC, creating an ideal situation to associate mechanisms behind SZ with aberrant connectivity among these cognition and emotion-related regions. PMID- 26578934 TI - Episodes, events, and models. AB - We describe a novel computational theory of how individuals segment perceptual information into representations of events. The theory is inspired by recent findings in the cognitive science and cognitive neuroscience of event segmentation. In line with recent theories, it holds that online event segmentation is automatic, and that event segmentation yields mental simulations of events. But it posits two novel principles as well: first, discrete episodic markers track perceptual and conceptual changes, and can be retrieved to construct event models. Second, the process of retrieving and reconstructing those episodic markers is constrained and prioritized. We describe a computational implementation of the theory, as well as a robotic extension of the theory that demonstrates the processes of online event segmentation and event model construction. The theory is the first unified computational account of event segmentation and temporal inference. We conclude by demonstrating now neuroimaging data can constrain and inspire the construction of process-level theories of human reasoning. PMID- 26578935 TI - High visual demand following theta burst stimulation modulates the effect on visual cortex excitability. AB - Modulatory effects of repetitive transcranial magnetic stimulation (TMS) depend on the activity of the stimulated cortical area before, during, and even after application. In the present study, we investigated the effects of theta burst stimulation (TBS) on visual cortex excitability using phosphene threshold (PTs). In a between-group design either continuous or intermittent TBS was applied with 100% of individual PT intensity. We varied visual demand following stimulation in form of high demand (acuity task) or low demand (looking at the wall). No change of PTs was observed directly after TBS. We found increased PTs only if subjects had high visual demand following continuous TBS. With low visual demand following stimulation no change of PT was observed. Intermittent TBS had no effect on visual cortex excitability at all. Since other studies showed increased PTs following continuous TBS using subthreshold intensities, our results highlight the importance of stimulation intensity applying TBS to the visual cortex. Furthermore, the state of the neurons in the stimulated cortex area not only before but also following TBS has an important influence on the effects of stimulation, making it necessary to scrupulously control for activity during the whole experimental session in a study. PMID- 26578936 TI - Cognitive and neural plasticity in older adults' prospective memory following training with the Virtual Week computer game. AB - Prospective memory (PM) - the ability to remember and successfully execute our intentions and planned activities - is critical for functional independence and declines with age, yet few studies have attempted to train PM in older adults. We developed a PM training program using the Virtual Week computer game. Trained participants played the game in 12, 1-h sessions over 1 month. Measures of neuropsychological functions, lab-based PM, event-related potentials (ERPs) during performance on a lab-based PM task, instrumental activities of daily living, and real-world PM were assessed before and after training. Performance was compared to both no-contact and active (music training) control groups. PM on the Virtual Week game dramatically improved following training relative to controls, suggesting PM plasticity is preserved in older adults. Relative to control participants, training did not produce reliable transfer to laboratory based tasks, but was associated with a reduction of an ERP component (sustained negativity over occipito-parietal cortex) associated with processing PM cues, indicative of more automatic PM retrieval. Most importantly, training produced far transfer to real-world outcomes including improvements in performance on real world PM and activities of daily living. Real-world gains were not observed in either control group. Our findings demonstrate that short-term training with the Virtual Week game produces cognitive and neural plasticity that may result in real-world benefits to supporting functional independence in older adulthood. PMID- 26578937 TI - Beta activity in the premotor cortex is increased during stabilized as compared to normal walking. AB - Walking on two legs is inherently unstable. Still, we humans perform remarkable well at it, mostly without falling. To gain more understanding of the role of the brain in controlling gait stability we measured brain activity using electro encephalography (EEG) during stabilized and normal walking. Subjects walked on a treadmill in two conditions, each lasting 10 min; normal, and while being laterally stabilized by elastic cords. Kinematics of trunk and feet, electro myography (EMG) of neck muscles, as well as 64-channel EEG were recorded. To assess gait stability the local divergence exponent, step width, and trunk range of motion were calculated from the kinematic data. We used independent component (IC) analysis to remove movement, EMG, and eyeblink artifacts from the EEG, after which dynamic imaging of coherent sources beamformers were determined to identify cortical sources that showed a significant difference between conditions. Stabilized walking led to a significant increase in gait stability, i.e., lower local divergence exponents. Beamforming analysis of the beta band activity revealed significant sources in bilateral pre-motor cortices. Projection of sensor data on these sources showed a significant difference only in the left premotor area, with higher beta power during stabilized walking, specifically around push-off, although only significant around contralateral push-off. It appears that even during steady gait the cortex is involved in the control of stability. PMID- 26578938 TI - Cognitive tasks during expectation affect the congruency ERP effects to facial expressions. AB - Expectancy congruency has been shown to modulate event-related potentials (ERPs) to emotional stimuli, such as facial expressions. However, it is unknown whether the congruency ERP effects to facial expressions can be modulated by cognitive manipulations during stimulus expectation. To this end, electroencephalography (EEG) was recorded while participants viewed (neutral and fearful) facial expressions. Each trial started with a cue, predicting a facial expression, followed by an expectancy interval without any cues and subsequently the face. In half of the trials, participants had to solve a cognitive task in which different letters were presented for target letter detection during the expectancy interval. Furthermore, facial expressions were congruent with the cues in 75% of all trials. ERP results revealed that for fearful faces, the cognitive task during expectation altered the congruency effect in N170 amplitude; congruent compared to incongruent fearful faces evoked larger N170 in the non-task condition but the congruency effect was not evident in the task condition. Regardless of facial expression, the congruency effect was generally altered by the cognitive task during expectation in P3 amplitude; the amplitudes were larger for incongruent compared to congruent faces in the non-task condition but the congruency effect was not shown in the task condition. The findings indicate that cognitive tasks during expectation reduce the processing of expectation and subsequently, alter congruency ERP effects to facial expressions. PMID- 26578939 TI - Structural and functional plasticity specific to musical training with wind instruments. AB - Numerous neuroimaging studies have shown structural and functional changes resulting from musical training. Among these studies, changes in primary sensory areas are mostly related to motor functions. In this study, we looked for some similar functional and structural changes in other functional modalities, such as somatosensory function, by examining the effects of musical training with wind instruments. We found significant changes in two aspects of neuroplasticity, cortical thickness, and resting-state neuronal networks. A group of subjects with several years of continuous musical training and who are currently playing in university wind ensembles showed differences in cortical thickness in lip- and tongue-related brain areas vs. non-music playing subjects. Cortical thickness in lip-related brain areas was significantly thicker and that in tongue-related areas was significantly thinner in the music playing group compared with that in the non-music playing group. Association analysis of lip-related areas in the music playing group showed that the increase in cortical thickness was caused by musical training. In addition, seed-based correlation analysis showed differential activation in the precentral gyrus and supplementary motor areas (SMA) between the music and non-music playing groups. These results suggest that high-intensity training with specific musical instruments could induce structural changes in related anatomical areas and could also generate a new functional neuronal network in the brain. PMID- 26578940 TI - Neuronal correlates of voluntary facial movements. AB - Whereas the somatotopy of finger movements has been extensively studied with neuroimaging, the neural foundations of facial movements remain elusive. Therefore, we systematically studied the neuronal correlates of voluntary facial movements using the Facial Action Coding System (FACS, Ekman et al., 2002). The facial movements performed in the MRI scanner were defined as Action Units (AUs) and were controlled by a certified FACS coder. The main goal of the study was to investigate the detailed somatotopy of the facial primary motor area (facial M1). Eighteen participants were asked to produce the following four facial movements in the fMRI scanner: AU1+2 (brow raiser), AU4 (brow lowerer), AU12 (lip corner puller) and AU24 (lip presser), each in alternation with a resting phase. Our facial movement task induced generally high activation in brain motor areas (e.g., M1, premotor cortex, supplementary motor area, putamen), as well as in the thalamus, insula, and visual cortex. BOLD activations revealed overlapping representations for the four facial movements. However, within the activated facial M1 areas, we could find distinct peak activities in the left and right hemisphere supporting a rough somatotopic upper to lower face organization within the right facial M1 area, and a somatotopic organization within the right M1 upper face part. In both hemispheres, the order was an inverse somatotopy within the lower face representations. In contrast to the right hemisphere, in the left hemisphere the representation of AU4 was more lateral and anterior compared to the rest of the facial movements. Our findings support the notion of a partial somatotopic order within the M1 face area confirming the "like attracts like" principle (Donoghue et al., 1992). AUs which are often used together or are similar are located close to each other in the motor cortex. PMID- 26578941 TI - Controlled processing during sequencing. AB - Longstanding evidence has identified a role for the frontal cortex in sequencing within both linguistic and non-linguistic domains. More recently, neuropsychological studies have suggested a specific role for the left premotor prefrontal junction (BA 44/6) in selection between competing alternatives during sequencing. In this study, we used neuroimaging with healthy adults to confirm and extend knowledge about the neural correlates of sequencing. Participants reproduced visually presented sequences of syllables and words using manual button presses. Items in the sequence were presented either consecutively or concurrently. Concurrent presentation is known to trigger the planning of multiple responses, which might compete with one another. Therefore, we hypothesized that regions involved in controlled processing would show greater recruitment during the concurrent than the consecutive condition. Whole-brain analysis showed concurrent > consecutive activation in sensory, motor and somatosensory cortices and notably also in rostral-dorsal anterior cingulate cortex. Region of interest analyses showed increased activation within left BA 44/6 and correlation between this region's activation and behavioral response times. Functional connectivity analysis revealed increased connectivity between left BA 44/6 and the posterior lobe of the cerebellum during the concurrent than the consecutive condition. These results corroborate recent evidence and demonstrate the involvement of BA 44/6 and other control regions when ordering co activated representations. PMID- 26578942 TI - Editorial: Neurofeedback in ADHD. PMID- 26578943 TI - Neural substrates underlying reconcentration for the preparation of an appropriate cognitive state to prevent future mistakes: a functional magnetic resonance imaging study. AB - The ability to reconcentrate on the present situation by recognizing one's own recent errors is a cognitive mechanism that is crucial for safe and appropriate behavior in a particular situation. However, an individual may not be able to adequately perform a subsequent task even if he/she recognize his/her own error; thus, it is hypothesized that the neural mechanisms underlying the reconcentration process are different from the neural substrates supporting error recognition. The present study performed a functional magnetic resonance imaging (fMRI) analysis to explore the neural substrates associated with reconcentration related to achieving an appropriate cognitive state, and to dissociate these brain regions from the neural substrates involved in recognizing one's own mistake. This study included 44 healthy volunteers who completed an experimental procedure that was based on the Eriksen flanker task and included feedback regarding the results of the current trial. The hemodynamic response induced by each instance of feedback was modeled using a combination of the successes and failures of the current and subsequent trials in order to identify the neural substrates underlying the ability to reconcentrate for the next situation and to dissociate them from those involved in recognizing current errors. The fMRI findings revealed significant and specific activation in the dorsal aspect of the medial prefrontal cortex (MFC) when participants successfully reconcentrated on the task after recognizing their own error based on feedback. Additionally, this specific activation was clearly dissociated from the activation foci that occurred during error recognition. These findings indicate that the dorsal aspect of the MFC may be a distinct functional region that specifically supports the reconcentration process and that is associated with the prevention of successive errors when a human subject recognizes his/her own mistake. Furthermore, it is likely that this reconcentration mechanism acts as a trigger to perform successful post-error behavioral adjustments. PMID- 26578944 TI - Impact of stochastic fluctuations in the cell free layer on nitric oxide bioavailability. AB - A plasma stratum (cell free layer or CFL) generated by flowing blood interposed between the red blood cell (RBC) core and the endothelium affects generation, consumption, and transport of nitric oxide (NO) in the microcirculation. CFL width is a principal factor modulating NO diffusion and vessel wall shears stress development, thus significantly affecting NO bioavailability. Since the CFL is bounded by the surface formed by the chaotically moving RBCs and the stationary but spatially non-uniform endothelial surface, its width fluctuates randomly in time and space. We analyze how these stochastic fluctuations affect NO transport in the CFL and NO bioavailability. We show that effects due to random boundaries do not average to zero and lead to an increase of NO bioavailability. Since endothelial production of NO is significantly enhanced by temporal variability of wall shear stress, we posit that stochastic shear stress stimulation of the endothelium yields the baseline continual production of NO by the endothelium. The proposed stochastic formulation captures the natural continuous and microscopic variability, whose amplitude is measurable and is of the scale of cellular dimensions. It provides a realistic model of NO generation and regulation. PMID- 26578945 TI - Exploratory graphical models of functional and structural connectivity patterns for Alzheimer's Disease diagnosis. AB - Alzheimer's Disease (AD) is the most common neurodegenerative disease in elderly people. Its development has been shown to be closely related to changes in the brain connectivity network and in the brain activation patterns along with structural changes caused by the neurodegenerative process. Methods to infer dependence between brain regions are usually derived from the analysis of covariance between activation levels in the different areas. However, these covariance-based methods are not able to estimate conditional independence between variables to factor out the influence of other regions. Conversely, models based on the inverse covariance, or precision matrix, such as Sparse Gaussian Graphical Models allow revealing conditional independence between regions by estimating the covariance between two variables given the rest as constant. This paper uses Sparse Inverse Covariance Estimation (SICE) methods to learn undirected graphs in order to derive functional and structural connectivity patterns from Fludeoxyglucose (18F-FDG) Position Emission Tomography (PET) data and segmented Magnetic Resonance images (MRI), drawn from the ADNI database, for Control, MCI (Mild Cognitive Impairment Subjects), and AD subjects. Sparse computation fits perfectly here as brain regions usually only interact with a few other areas. The models clearly show different metabolic covariation patters between subject groups, revealing the loss of strong connections in AD and MCI subjects when compared to Controls. Similarly, the variance between GM (Gray Matter) densities of different regions reveals different structural covariation patterns between the different groups. Thus, the different connectivity patterns for controls and AD are used in this paper to select regions of interest in PET and GM images with discriminative power for early AD diagnosis. Finally, functional an structural models are combined to leverage the classification accuracy. The results obtained in this work show the usefulness of the Sparse Gaussian Graphical models to reveal functional and structural connectivity patterns. This information provided by the sparse inverse covariance matrices is not only used in an exploratory way but we also propose a method to use it in a discriminative way. Regression coefficients are used to compute reconstruction errors for the different classes that are then introduced in a SVM for classification. Classification experiments performed using 68 Controls, 70 AD, and 111 MCI images and assessed by cross-validation show the effectiveness of the proposed method. PMID- 26578946 TI - Complex network analysis of resting state EEG in amnestic mild cognitive impairment patients with type 2 diabetes. AB - PURPOSE: Diabetes is a great risk factor for dementia and mild cognitive impairment (MCI). This study investigates whether complex network-derived features in resting state EEG (rsEEG) could be applied as a biomarker to distinguish amnestic mild cognitive impairment (aMCI) from normal cognitive function in subjects with type 2 diabetes (T2D). METHOD: In this study, EEG was recorded in 28 patients with T2D (16 aMCI patients and 12 controls) during a no task eyes-closed resting state. Pair-wise synchronization of rsEEG signals were assessed in six frequency bands (delta, theta, lower alpha, upper alpha, beta, and gamma) using phase lag index (PLI) and grouped into long distance (intra- and inter-hemispheric) and short distance interactions. PLI-weighted connectivity networks were also constructed, and characterized by mean clustering coefficient and path length. The correlation of these features and Montreal Cognitive Assessment (MoCA) scores was assessed. RESULTS: Main findings of this study were as follows: (1) In comparison with controls, patients with aMCI had a significant decrease of global mean PLI in lower alpha, upper alpha, and beta bands. Lower functional connection at short and long intra-hemispheric distance mainly appeared on the left hemisphere. (2) In the lower alpha band, clustering coefficient was significantly lower in aMCI group, and the path length significantly increased. (3) Cognitive status measured by MoCA had a significant positive correlation with cluster coefficient and negative correlation with path length in lower alpha band. CONCLUSIONS: The brain network of aMCI patients displayed a disconnection syndrome and a loss of small-world architecture. The correlation between cognitive states and network characteristics suggested that the more in deterioration of the diabetes patients' cognitive state, the less optimal the network organization become. Hence, the complex network-derived biomarkers based on EEG could be employed to track cognitive function of diabetic patients and provide a new diagnosis tool for aMCI. PMID- 26578947 TI - Editorial: Neural plasticity for rich and uncertain robotic information streams. PMID- 26578948 TI - Probing astrocyte metabolism in vivo: proton magnetic resonance spectroscopy in the injured and aging brain. AB - Following a brain injury, the mobilization of reactive astrocytes is part of a complex neuroinflammatory response that may have both harmful and beneficial effects. There is also evidence that astrocytes progressively accumulate in the normal aging brain, increasing in both number and size. These astrocyte changes in normal brain aging may, in the event of an injury, contribute to the exacerbated injury response and poorer outcomes observed in older traumatic brain injury (TBI) survivors. Here we present our view that proton magnetic resonance spectroscopy ((1)H-MRS), a neuroimaging approach that probes brain metabolism within a defined region of interest, is a promising technique that may provide insight into astrocyte metabolic changes in the injured and aging brain in vivo. Although (1)H-MRS does not specifically differentiate between cell types, it quantifies certain metabolites that are highly enriched in astrocytes (e.g., Myo inositol, mlns), or that are involved in metabolic shuttling between astrocytes and neurons (e.g., glutamate and glutamine). Here we focus on metabolites detectable by (1)H-MRS that may serve as markers of astrocyte metabolic status. We review the physiological roles of these metabolites, discuss recent (1)H-MRS findings in the injured and aging brain, and describe how an astrocyte metabolite profile approach might be useful in clinical medicine and clinical trials. PMID- 26578949 TI - Lower Bone Mineral Density in Patients with Parkinson's Disease: A Cross Sectional Study from Chinese Mainland. AB - KEY POINTS: Significantly lower BMD in PD compared to healthy subjects in both genders.Less than 35 mg(2)/dl(2) of Ca-P product in >80% of PD patients.Significant correlations between BMD and severity of PD.Lower BMD at H&Y stage III/IV than that at H&Y stage I/II. OBJECTIVES: Although several lines of evidence have suggested that patients with Parkinson's disease (PD) have a higher risk of osteoporosis and fracture, the association between bone mineral density (BMD) and severity of PD patients is unknown. METHODS: We performed a cross sectional study of 54 patients with PD and 59 healthy age-matched controls. Multiple clinical scales were used to evaluate the severity of PD, and serum levels of calcium, phosphorus, and homocysteine were measured to determine BMD's association with PD severity. RESULTS: BMD in PD patients was significantly lower than that in healthy controls. The BMD scores of the spine, femoral neck (FN), and hip were lower in females than in males in the healthy group. In the PD group, BMD in the hip was significantly lower in females compared to males. There was a negative correlation between daily l-DOPA dosage and BMD in the spine and hip in the PD group, while BMD in the spine, neck, and hip was significantly correlated with severity of PD. Besides, we found that among the lumbar spine (LS), FN, and hip, bone loss in the LS was the most severe in PD patients based on the T-scores. CONCLUSION: Our findings support the hypothesis that patients with PD have a higher risk of osteoporosis, and that low BMD in the spine, FN, and hip may indirectly reflect the severity of PD. Our findings have prompted us to pay more attention to osteoporosis in the LS in Chinese PD patients. PMID- 26578950 TI - ADNP: in search for molecular mechanisms and innovative therapeutic strategies for frontotemporal degeneration. AB - Activity-dependent neuroprotective protein (ADNP) is deregulated in Alzheimer's disease (AD) and in schizophrenia and mutated in autism. In mice, ADNP is essential for brain formation and ADNP haploinsufficiency is associated with cognitive and social deficits and tauopathy. Tauopathy, a major pathology in AD, is also found in ~45% of frontotemporal dementias (FTDs). Tau transcript, a product of a single gene, undergoes alternative splicing. Tau splicing seems to be altered in FTD brain. In transgenic mice overexpressing a mutated tau in the cerebral cortex, significant increases in ADNP transcript expression were observed in the cerebral cortex of young transgenic mice (~disease onset) and a marked decrease with aging as compared to control littermates. ADNP is a member of the SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex also associated with alternative splicing, including tau transcript splicing. Further cellular interactions of ADNP include association with microtubules, with tau being a microtubule-associated protein. NAP (davundetide), a novel drug candidate derived from ADNP, increases ADNP-microtubule association and protects against tauopathy and cognitive deficiencies in mice. Although, NAP did not provide protection in progressive supranuclear palsy (PSP), a pure tauopathy, it increased cognitive scores in amnestic mild cognitively impaired patients and protected functional activity in schizophrenia patients. This mini-review focuses on ADNP in the context of FTD and tau/microtubules and proposes NAP as a novel drug target for future clinical evaluations. PMID- 26578951 TI - Behavioral and Neurochemical Deficits in Aging Rats with Increased Neonatal Iron Intake: Silibinin's Neuroprotection by Maintaining Redox Balance. AB - Aging is a critical risk factor for Parkinson's disease. Silibinin, a major flavonoid in Silybum marianum, has been suggested to display neuroprotective properties against various neurodegenerative diseases. In the present study, we observed that neonatal iron (120 MUg/g body weight) supplementation resulted in significant abnormality of behavior and depletion of striatal dopamine (DA) in the aging male and female rats while it did not do so in the young male and female rats. No significant change in striatal serotonin content was observed in the aging male and female rats with neonatal supplementation of the same dose of iron. Furthermore, we found that the neonatal iron supplementation resulted in significant increase in malondialdehyde (MDA) and decrease in glutathione (GSH) in the substantia nigra (SN) of the aging male and female rats. No significant change in content of MDA and GSH was observed in the cerebellum of the aging male and female rats with the neonatal iron supplementation. Interestingly, silibinin (25 and 50 mg/kg body weight) treatment significantly and dose-dependently attenuated depletion of striatal DA and improved abnormality of behavior in the aging male and female rats with the neonatal iron supplementation. Moreover, silibinin significantly reduced MDA content and increased GSH content in the SN of the aging male and female rats. Taken together, our results indicate that elevated neonatal iron supplementation may result in neurochemical and behavioral deficits in the male and female rats with aging and silibinin may exert dopaminergic neuroprotection by maintaining redox balance. PMID- 26578952 TI - Structural Connectivity is Differently Altered in Dementia with Lewy Body and Alzheimer's Disease. AB - The structural connectivity within cortical areas and between cortical and subcortical structures was investigated in dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). We hypothesized that white matter (WM) tracts, which are linked to visual, attentional, and mnemonic functions, would be differentially and selectively affected in DLB as compared to AD and age-matched control subjects. Structural tensor imaging and diffusion tensor imaging (DTI) were performed on 14 DLB patients, 14 AD patients, and 15 controls. DTI metrics related to WM damage were assessed within tracts reconstructed by FreeSurfer's TRActs Constrained by UnderLying Anatomy pipeline. Correlation analysis between WM and gray matter (GM) metrics was performed to assess whether the structural connectivity alteration in AD and DLB could be secondary to GM neuronal loss or a consequence of direct WM injury. Anterior thalamic radiation (ATR) and cingulum cingulate gyrus were altered in DLB, whereas cingulum-angular bundle (CAB) was disrupted in AD. In DLB patients, secondary axonal degeneration within ATR was found in relation to microstructural damage within medio-dorsal thalamus, whereas axonal degeneration within CAB was related to precuneus thinning. WM alteration within the uncinate fasciculus was present in both groups of patients and was related to frontal and to temporal thinning in DLB and AD, respectively. We found structural connectivity alterations within fronto-thalamic and fronto-parietal (precuneus) network in DLB whereas, in contrast, disruption of structural connectivity of mnemonic pathways was present in AD. Furthermore, the high correlation between GM and WM metrics suggests that the structural connectivity alteration in DLB could be linked to GM neuronal loss rather than by direct WM injury. Thus, this finding supports the key role of cortical and subcortical atrophy in DLB. PMID- 26578953 TI - C-Reactive Protein, Advanced Glycation End Products, and Their Receptor in Type 2 Diabetic, Elderly Patients with Mild Cognitive Impairment. AB - OBJECTIVE: The aim of the study was to evaluate serum levels of advanced glycation end products (AGEs), receptor for advanced glycation end products (RAGE), and C-reactive protein (CRP) in elderly patients with type 2 diabetes mellitus with and without mild cognitive impairment (MCI) and to determine the predictors (including AGEs, RAGE, and CRP levels) of having MCI in elderly patients with type 2 diabetes. METHODS: Two hundred seventy-six diabetics elders were screened for MCI (using the Montreal Cognitive Assessment: MoCA score). Data of biochemical parameters and biomarkers were collected. RESULTS: Serum AGEs, RAGE, and CRP levels were significantly increased in MCI patients compared to controls. In group of patients with MCI, serum RAGE level was positively correlated with AGEs level and with CRP level. RAGE, AGEs, and CRP concentrations were positively correlated with HbA1c levels and negatively correlated with MoCA score. The univariate logistic regression models revealed that variables, which increased the likelihood of diagnosis of MCI in elderly patients with type 2 diabetes were higher levels of HbA1c, RAGE, AGEs, CRP, TG, lower level of HDL cholesterol, previous CVD, HA, or use of HA drugs, hyperlipidemia, retinopathy, nephropathy, increased number of co-morbidities, older age, and less years of formal education. HA or use of HA drugs, previous CVD, higher level of RAGE and CRP, older age and less years of formal education are the factors increasing the likelihood of having MCI in elderly patients with type 2 diabetes in multivariable model. CONCLUSION: In summary, serum AGEs, RAGE, and CRP are increased in the circulation of MCI elderly diabetic patients compared to controls. A larger population-based prospective study needs to be performed to further confirm the relationship between AGEs, RAGE, and the cognitive decline or progress to dementia. PMID- 26578954 TI - Natural products and drug discovery: a survey of stakeholders in industry and academia. AB - CONTEXT: In recent decades, natural products have undisputedly played a leading role in the development of novel medicines. Yet, trends in the pharmaceutical industry at the level of research investments indicate that natural product research is neither prioritized nor perceived as fruitful in drug discovery programmes as compared with incremental structural modifications and large volume HTS screening of synthetics. AIM: We seek to understand this phenomenon through insights from highly experienced natural product experts in industry and academia. METHOD: We conducted a survey including a series of qualitative and quantitative questions related to current insights and prospective developments in natural product drug development. The survey was completed by a cross-section of 52 respondents in industry and academia. RESULTS: One recurrent theme is the dissonance between the perceived high potential of NP as drug leads among individuals and the survey participants' assessment of the overall industry and/or company level strategies and their success. The study's industry and academic respondents did not perceive current discovery efforts as more effective as compared with previous decades, yet industry contacts perceived higher hit rates in HTS efforts as compared with academic respondents. Surprisingly, many industry contacts were highly critical to prevalent company and industry-wide drug discovery strategies indicating a high level of dissatisfaction within the industry. CONCLUSIONS: These findings support the notion that there is an increasing gap in perception between the effectiveness of well established, commercially widespread drug discovery strategies between those working in industry and academic experts. This research seeks to shed light on this gap and aid in furthering natural product discovery endeavors through an analysis of current bottlenecks in industry drug discovery programmes. PMID- 26578955 TI - Ginseng pharmacology: a new paradigm based on gintonin-lysophosphatidic acid receptor interactions. AB - Ginseng, the root of Panax ginseng, is used as a traditional medicine. Despite the long history of the use of ginseng, there is no specific scientific or clinical rationale for ginseng pharmacology besides its application as a general tonic. The ambiguous description of ginseng pharmacology might be due to the absence of a predominant active ingredient that represents ginseng pharmacology. Recent studies show that ginseng abundantly contains lysophosphatidic acids (LPAs), which are phospholipid-derived growth factor with diverse biological functions including those claimed to be exhibited by ginseng. LPAs in ginseng form a complex with ginseng proteins, which can bind and deliver LPA to its cognate receptors with a high affinity. As a first messenger, gintonin produces second messenger Ca(2+) via G protein-coupled LPA receptors. Ca(2+) is an intracellular mediator of gintonin and initiates a cascade of amplifications for further intercellular communications by activation of Ca(2+)-dependent kinases, receptors, gliotransmitter, and neurotransmitter release. Ginsenosides, which have been regarded as primary ingredients of ginseng, cannot elicit intracellular [Ca(2+)]i transients, since they lack specific cell surface receptor. However, ginsenosides exhibit non-specific ion channel and receptor regulations. This is the key characteristic that distinguishes gintonin from ginsenosides. Although the current discourse on ginseng pharmacology is focused on ginsenosides, gintonin can definitely provide a mode of action for ginseng pharmacology that ginsenosides cannot. This review article introduces a novel concept of ginseng ligand-LPA receptor interaction and proposes to establish a paradigm that shifts the focus from ginsenosides to gintonin as a major ingredient representing ginseng pharmacology. PMID- 26578956 TI - The scale of the evidence base on the health effects of conventional yogurt consumption: findings of a scoping review. AB - BACKGROUND: The health effects of conventional yogurt have been investigated for over a century; however, few systematic reviews have been conducted to assess the extent of the health benefits of yogurt. OBJECTIVE: The aim of this scoping review was to assess the volume of available evidence on the health effects of conventional yogurt. METHODS: The review was guided by a protocol agreed a priori and informed by an extensive literature search conducted in November 2013. Randomized controlled trials were selected and categorized according to the eligibility criteria established in the protocol. RESULTS: 213 studies were identified as relevant to the scoping question. The number of eligible studies identified for each outcome were: bone health (14 studies), weight management and nutrition related health outcomes (81 studies), metabolic health (6 studies); cardiovascular health (57 studies); gastrointestinal health (24 studies); cancer (39 studies); diabetes (13 studies), Parkinson's disease risk (3 studies), all cause mortality (3 studies), skin complaints (3 studies), respiratory complaints (3 studies), joint pain/function (2 studies); the remaining 8 studies reported a variety of other outcomes. For studies of a similar design and which assessed the same outcomes in similar population groups, we report the potential for the combining of data across studies in systematic reviews. CONCLUSIONS: This scoping review has revealed the extensive evidence base for many outcomes which could be the focus of systematic reviews exploring the health effects of conventional yogurt consumption. PMID- 26578958 TI - Molecular features of interaction between VEGFA and anti-angiogenic drugs used in retinal diseases: a computational approach. AB - Anti-angiogenic agents are biological drugs used for treatment of retinal neovascular degenerative diseases. In this study, we aimed at in silico analysis of interaction of vascular endothelial growth factor A (VEGFA), the main mediator of angiogenesis, with binding domains of anti-angiogenic agents used for treatment of retinal diseases, such as ranibizumab, bevacizumab and aflibercept. The analysis of anti-VEGF/VEGFA complexes was carried out by means of protein protein docking and molecular dynamics (MD) coupled to molecular mechanics Poisson Boltzmann Surface Area (MM-PBSA) calculation. Molecular dynamics simulation was further analyzed by protein contact networks. Rough energetic evaluation with protein-protein docking scores revealed that aflibercept/VEGFA complex was characterized by electrostatic stabilization, whereas ranibizumab and bevacizumab complexes were stabilized by Van der Waals (VdW) energy term; these results were confirmed by MM-PBSA. Comparison of MM-PBSA predicted energy terms with experimental binding parameters reported in literature indicated that the high association rate (Kon) of aflibercept to VEGFA was consistent with high stabilizing electrostatic energy. On the other hand, the relatively low experimental dissociation rate (Koff) of ranibizumab may be attributed to lower conformational fluctuations of the ranibizumab/VEGFA complex, higher number of contacts and hydrogen bonds in comparison to bevacizumab and aflibercept. Thus, the anti-angiogenic agents have been found to be considerably different both in terms of molecular interactions and stabilizing energy. Characterization of such features can improve the design of novel biological drugs potentially useful in clinical practice. PMID- 26578957 TI - HDL as a drug and nucleic acid delivery vehicle. AB - This review is intended to evaluate the research findings and potential clinical applications of drug transport systems, developed based on the concepts of the structure/function and physiological role(s) of high density lipoprotein type nanoparticles. These macromolecules provide targeted transport of cholesteryl esters (a highly lipophilic payload) in their natural/physiological environment. The ability to accommodate highly water insoluble constituents in their core regions enables High density lipoproteins (HDL) type nanoparticles to effectively transport hydrophobic drugs subsequent to systemic administration. Even though the application of reconstituted HDL in the treatment of a number of diseases is reviewed, the primary focus is on the application of HDL type drug delivery agents in cancer chemotherapy. The use of both native and synthetic HDL as drug delivery agents is compared to evaluate their respective potentials for commercial and clinical development. The current status and future perspectives for HDL type nanoparticles are discussed, including current obstacles and future applications in therapeutics. PMID- 26578959 TI - S-thanatin functionalized liposome potentially targeting on Klebsiella pneumoniae and its application in sepsis mouse model. AB - S-thanatin (Ts) was a short antimicrobial peptide with selective antibacterial activity. In this study, we aimed to design a drug carrier with specific bacterial targeting potential. The positively charged Ts was modified onto the liposome surface by linking Ts to the constituent lipids via a PEG linker. The benefits of this design were evaluated by preparing a series of liposomes and comparing their biological effects in vitro and in vivo. The particle size and Zeta potential of the constructed liposomes were measured with a Zetasizer Nano ZS system and a confocal laser scanning microscope. The in vitro drug delivery potential was evaluated by measuring the cellular uptake of encapsulated levofloxacin using HPLC. Ts-linked liposome or its conjugates with quantum dots favored bacterial cells, and increased the bacterial uptake of levofloxacin. In antimicrobial assays, the Ts and levofloxacin combination showed a synergistic effect, and Ts-LPs-LEV exhibited excellent activity against the quality control stain Klebsiella pneumoniae ATCC 700603 and restored the susceptibility of multidrug-resistant K. pneumoniae clinical isolates to levofloxacin in vitro. Furthermore, Ts-LPs-LEV markedly reduced the lethality rate of the septic shock and resulted in rapid bacterial clearance in mouse models receiving clinical multidrug resistant (MDR) isolates. These results suggest that the Ts functionalized liposome may be a promising antibiotic delivery system for clinical infectious disorders caused by MDR bacteria, in particular the sepsis related diseases. PMID- 26578960 TI - Supramammillary serotonin reduction alters place learning and concomitant hippocampal, septal, and supramammillar theta activity in a Morris water maze. AB - Hippocampal theta activity is related to spatial information processing, and high frequency theta activity, in particular, has been linked to efficient spatial memory performance. Theta activity is regulated by the synchronizing ascending system (SAS), which includes mesencephalic and diencephalic relays. The supramamillary nucleus (SUMn) is located between the reticularis pontis oralis and the medial septum (MS), in close relation with the posterior hypothalamic nucleus (PHn), all of which are part of this ascending system. It has been proposed that the SUMn plays a role in the modulation of hippocampal theta frequency; this could occur through direct connections between the SUMn and the hippocampus or through the influence of the SUMn on the MS. Serotonergic raphe neurons prominently innervate the hippocampus and several components of the SAS, including the SUMn. Serotonin desynchronizes hippocampal theta activity, and it has been proposed that serotonin may regulate learning through the modulation of hippocampal synchrony. In agreement with this hypothesis, serotonin depletion in the SUMn/PHn results in deficient spatial learning and alterations in CA1 theta activity-related learning in a Morris water maze. Because it has been reported that SUMn inactivation with lidocaine impairs the consolidation of reference memory, we asked whether changes in hippocampal theta activity related to learning would occur through serotonin depletion in the SUMn, together with deficiencies in memory. We infused 5,7-DHT bilaterally into the SUMn in rats and evaluated place learning in the standard Morris water maze task. Hippocampal (CA1 and dentate gyrus), septal and SUMn EEG were recorded during training of the test. The EEG power in each region and the coherence between the different regions were evaluated. Serotonin depletion in the SUMn induced deficient spatial learning and altered the expression of hippocampal high-frequency theta activity. These results provide evidence in support of a role for serotonin as a modulator of hippocampal learning, acting through changes in the synchronicity evoked in several relays of the SAS. PMID- 26578961 TI - Effect of acute fentanyl treatment on synaptic plasticity in the hippocampal CA1 region in rats. AB - Postoperative cognitive dysfunction (POCD), mainly characterized by short-term decline of learning and memory, occurs after operations under anesthesia. However, the underlying mechanisms are poorly understood. The MU-opioid receptors (MOR) are highly expressed in interneurons of hippocampus, and is believed to be critical for the dysfunction of synaptic plasticity between hippocampal neurons. Therefore, we investigated the effect of fentanyl, a strong agonist of MOR and often used for anesthesia and analgesia in clinical settings, on hippocampal synaptic plasticity in the Schaffer-collateral CA1 pathway during acute exposure and washout in vitro. Our results revealed that acute fentanyl exposure (0.01, 0.1, 1 MUM) dose-dependently increased the field excitatory postsynaptic potentials (fEPSPs), which was prevented by pre-administration of picrotoxin (50 MUM) or MOR antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Phe-Thr-NH2 (CTOP, 10 MUM). While fentanyl exposure-increased fEPSPs amplitude was prevented by picrotoxin [an inhibitor of gamma-aminobutyric acid receptor (GABAR)] treatment or fentanyl washout, pretreatment of picrotoxin failed to prevent the fentanyl-impaired long term potentiation (LTP) of synaptic strength as well as the fentanyl-enhanced long-term depression (LTD). These results demonstrated that fentanyl acute exposure and washout increases hippocampal excitability in the Schaffer collateral CA1 pathway, depending on disinhibiting interneurons after MOR activation. In addition, fentanyl acute exposure and washout modulated synaptic plasticity, but the inhibitory activation was not critical. Elucidating the detailed mechanisms for synaptic dysfunction after fentanyl exposure and washout may provide insights into POCD generation after fentanyl anesthesia. PMID- 26578963 TI - Toward a European definition for a drug shortage: a qualitative study. AB - BACKGROUND: Drug shortages are currently on the rise. In-depth investigation of the problem is necessary, however, a variety of definitions for 'drug shortages' are formulated in legislations, by different organizations, authorities, and other initiatives. For international comparison, the underlying definition for drug shortages is important to allow appropriate interpretation of national databases and the results of scientific studies. The objective is to identify the different elements which should be considered in a uniform definition for drug shortages in the European Union (EU) and to detect the different conditions for reporting drug shortages. MATERIALS AND METHODS: Definitions of drug shortages were searched in the scientific databases as well as in the gray literature. Similar topics were identified and organizations were contacted to formulate the reasoning underlying the definitions. RESULTS: Over 20 different definitions for drug shortages were identified. A distinction is made between general definitions of drug shortages and definitions used for the reporting of drug shortages. Differences and similarities are observed in the elements within the definitions, e.g., when does a supply problem become a drug shortage, permanent and/or temporally shortages, the typology and time frame of a drug shortage. The moment a supply problem is considered as a shortage, can be defined at four levels: (i) demand side, (ii) supply side, (iii) delivery of a drug, and (iv) availability of a drug. Permanent discontinuations of drugs are not always covered in definitions for drug shortages. Some definitions only consider those drugs used for the treatment of serious diseases or drugs for which no alternative is available. Different time frames were observed, varying between 1 day and 20 days. CONCLUSION: Obtaining a uniform definition for drug shortages is important as well as identifying which conditions are preferable to report drug shortages in order to facilitate international benchmarking. This paper can be used as a guidance to point out all the different elements which should be considered to formulate a uniform definition to be applied in the EU. PMID- 26578962 TI - Original insights on thrombospondin-1-related antireceptor strategies in cancer. AB - Thrombospondin-1 (TSP-1) is a large matricellular glycoprotein known to be overexpressed within tumor stroma in several cancer types. While mainly considered as an endogenous angiogenesis inhibitor, TSP-1 exhibits multifaceted functionalities in a tumor context depending both on TSP-1 concentration as well as differential receptor expression by cancer cells and on tumor-associated stromal cells. Besides, the complex modular structure of TSP-1 along with the wide variety of its soluble ligands and membrane receptors considerably increases the complexity of therapeutically targeting interactions involving TSP-1 ligation of cell-surface receptors. Despite the pleiotropic nature of TSP-1, many different antireceptor strategies have been developed giving promising results in preclinical models. However, transition to clinical trials often led to nuanced outcomes mainly due to frequent severe adverse effects. In this review, we will first expose the intricate and even sometimes opposite effects of TSP-1-related signaling on tumor progression by paying particular attention to modulation of angiogenesis and tumor immunity. Then, we will provide an overview of current developments and prospects by focusing particularly on the cell-surface molecules CD47 and CD36 that function as TSP-1 receptors; including antibody-based approaches, therapeutic gene modulation and the use of peptidomimetics. Finally, we will discuss original approaches specifically targeting TSP-1 domains, as well as innovative combination strategies with a view to producing an overall anticancer response. PMID- 26578964 TI - Pharmacological profiling of zebrafish behavior using chemical and genetic classification of sleep-wake modifiers. AB - Sleep-wake states are impaired in various neurological disorders. Impairment of sleep-wake states can be an early condition that exacerbates these disorders. Therefore, treating sleep-wake dysfunction may prevent or slow the development of these diseases. Although many gene products are likely to be involved in the sleep-wake disturbance, hypnotics and psychostimulants clinically used are limited in terms of their mode of action and are not without side effects. Therefore, there is a growing demand for developing new hypnotics and psychostimulants with high efficacy and few side effects. Toward this end, animal models are indispensable for use in genetic and chemical screens to identify sleep-wake modifiers. As a proof-of-concept study, we performed behavioral profiling of zebrafish treated with chemical and genetic sleep-wake modifiers. We were able to demonstrate that behavioral profiling of zebrafish treated with hypnotics or psychostimulants from 9 to 10 days post-fertilization was sufficient to identify drugs with specific modes of action. We were also able to identify behavioral endpoints distinguishing GABA-A modulators and hypocretin (hcrt) receptor antagonists and between sympathomimetic and non-sympathomimetic psychostimulants. This behavioral profiling can serve to identify genes related to sleep-wake disturbance associated with various neuropsychiatric diseases and novel therapeutic compounds for insomnia and excessive daytime sleep with fewer adverse side effects. PMID- 26578965 TI - Syzygium cumini (L.) skeels: a prominent source of bioactive molecules against cardiometabolic diseases. AB - Syzygium cumini (Myrtaceae) is a worldwide medicinal plant traditionally used in herbal medicines due to its vaunted properties against cardiometabolic disorders, which include: antihyperglycemic, hypolipemiant, antiinflammatory, cardioprotective, and antioxidant activities. These properties have been attributed to the presence of bioactive compounds such as phenols, flavonoids, and tannins in different parts of the plant, albeit the knowledge on their mechanisms of action is scarce. This mini-review highlights the cardiometabolic properties of S. cumini by correlating its already identified phytochemicals with their described mechanisms of action. Data herein compiled show that some compounds target multiple metabolic pathways; thereby, becoming potential pharmacological tools. Moreover, the lack of clinical trials on S. cumini usage makes it a fruitful field of interest for both scientific community and pharmaceutical industry. PMID- 26578967 TI - Redox mechanisms of cardiomyocyte mitochondrial protection. AB - Oxidative and nitrosative stress are primary contributors to the loss of myocardial tissue in insults ranging from ischemia/reperfusion injury from coronary artery disease and heart transplantation to sepsis-induced myocardial dysfunction and drug-induced myocardial damage. This cell damage caused by oxidative and nitrosative stress leads to mitochondrial protein, DNA, and lipid modifications, which inhibits energy production and contractile function, potentially leading to cell necrosis and/or apoptosis. However, cardiomyocytes have evolved an elegant set of redox-sensitive mechanisms that respond to and contain oxidative and nitrosative damage. These responses include the rapid induction of antioxidant enzymes, mitochondrial DNA repair mechanisms, selective mitochondrial autophagy (mitophagy), and mitochondrial biogenesis. Coordinated cytoplasmic to nuclear cell-signaling and mitochondrial transcriptional responses to the presence of elevated cytoplasmic oxidant production, e.g., H2O2, allows nuclear translocation of the Nfe2l2 transcription factor and up-regulation of downstream cytoprotective genes such as heme oxygenase-1 which generates physiologic signals, such as CO that up-regulates Nfe212 gene transcription. Simultaneously, a number of other DNA binding transcription factors are expressed and/or activated under redox control, such as Nuclear Respiratory Factor-1 (NRF 1), and lead to the induction of genes involved in both intracellular and mitochondria-specific repair mechanisms. The same insults, particularly those related to vascular stress and inflammation also produce elevated levels of nitric oxide, which also has mitochondrial protein thiol-protective functions and induces mitochondrial biogenesis through cyclic GMP-dependent and perhaps other pathways. This brief review provides an overview of these pathways and interconnected cardiac repair mechanisms. PMID- 26578968 TI - The training intensity distribution among well-trained and elite endurance athletes. AB - Researchers have retrospectively analyzed the training intensity distribution (TID) of nationally and internationally competitive athletes in different endurance disciplines to determine the optimal volume and intensity for maximal adaptation. The majority of studies present a "pyramidal" TID with a high proportion of high volume, low intensity training (HVLIT). Some world-class athletes appear to adopt a so-called "polarized" TID (i.e., significant % of HVLIT and high-intensity training) during certain phases of the season. However, emerging prospective randomized controlled studies have demonstrated superior responses of variables related to endurance when applying a polarized TID in well trained and recreational individuals when compared with a TID that emphasizes HVLIT or threshold training. The aims of the present review are to: (1) summarize the main responses of retrospective and prospective studies exploring TID; (2) provide a systematic overview on TIDs during preparation, pre-competition, and competition phases in different endurance disciplines and performance levels; (3) address whether one TID has demonstrated greater efficacy than another; and (4) highlight research gaps in an effort to direct future scientific studies. PMID- 26578966 TI - Role of bioinformatics in establishing microRNAs as modulators of abiotic stress responses: the new revolution. AB - microRNAs (miRs) are a class of 21-24 nucleotide long non-coding RNAs responsible for regulating the expression of associated genes mainly by cleavage or translational inhibition of the target transcripts. With this characteristic of silencing, miRs act as an important component in regulation of plant responses in various stress conditions. In recent years, with drastic change in environmental and soil conditions different type of stresses have emerged as a major challenge for plants growth and productivity. The identification and profiling of miRs has itself been a challenge for research workers given their small size and large number of many probable sequences in the genome. Application of computational approaches has expedited the process of identification of miRs and their expression profiling in different conditions. The development of High-Throughput Sequencing (HTS) techniques has facilitated to gain access to the global profiles of the miRs for understanding their mode of action in plants. Introduction of various bioinformatics databases and tools have revolutionized the study of miRs and other small RNAs. This review focuses the role of bioinformatics approaches in the identification and study of the regulatory roles of plant miRs in the adaptive response to stresses. PMID- 26578970 TI - In vitro osteogenic and odontogenic differentiation of human dental pulp stem cells seeded on carboxymethyl cellulose-hydroxyapatite hybrid hydrogel. AB - Stem cells from human dental pulp have been considered as an alternative source of adult stem cells in tissue engineering because of their potential to differentiate into multiple cell lineages. Recently, polysaccharide based hydrogels have become especially attractive as matrices for the repair and regeneration of a wide variety of tissues and organs. The incorporation of inorganic minerals as hydroxyapatite nanoparticles can modulate the performance of the scaffolds with potential applications in tissue engineering. The aim of this study was to verify the osteogenic and odontogenic differentiation of dental pulp stem cells (DPSCs) cultured on a carboxymethyl cellulose-hydroxyapatite hybrid hydrogel. Human DPSCs were seeded on carboxymethyl cellulose hydroxyapatite hybrid hydrogel and on carboxymethyl cellulose hydrogel for 1, 3, 5, 7, 14, and 21 days. Cell viability assay and ultramorphological analysis were carried out to evaluate biocompatibility and cell adhesion. Real Time PCR was carried out to demonstrate the expression of osteogenic and odontogenic markers. Results showed a good adhesion and viability in cells cultured on carboxymethyl cellulose-hydroxyapatite hybrid hydrogel, while a low adhesion and viability was observed in cells cultured on carboxymethyl cellulose hydrogel. Real Time PCR data demonstrated a temporal up-regulation of osteogenic and odontogenic markers in dental pulp stem cells cultured on carboxymethyl cellulose-hydroxyapatite hybrid hydrogel. In conclusion, our in vitro data confirms the ability of DPSCs to differentiate toward osteogenic and odontogenic lineages in presence of a carboxymethyl cellulose-hydroxyapatite hybrid hydrogel. Taken together, our results provide evidence that DPSCs and carboxymethyl cellulose-hydroxyapatite hybrid hydrogel could be considered promising candidates for dental pulp complex and periodontal tissue engineering. PMID- 26578969 TI - Utilizing small nutrient compounds as enhancers of exercise-induced mitochondrial biogenesis. AB - Endurance exercise, when performed regularly as part of a training program, leads to increases in whole-body and skeletal muscle-specific oxidative capacity. At the cellular level, this adaptive response is manifested by an increased number of oxidative fibers (Type I and IIA myosin heavy chain), an increase in capillarity and an increase in mitochondrial biogenesis. The increase in mitochondrial biogenesis (increased volume and functional capacity) is fundamentally important as it leads to greater rates of oxidative phosphorylation and an improved capacity to utilize fatty acids during sub-maximal exercise. Given the importance of mitochondrial biogenesis for skeletal muscle performance, considerable attention has been given to understanding the molecular cues stimulated by endurance exercise that culminate in this adaptive response. In turn, this research has led to the identification of pharmaceutical compounds and small nutritional bioactive ingredients that appear able to amplify exercise responsive signaling pathways in skeletal muscle. The aim of this review is to discuss these purported exercise mimetics and bioactive ingredients in the context of mitochondrial biogenesis in skeletal muscle. We will examine proposed modes of action, discuss evidence of application in skeletal muscle in vivo and finally comment on the feasibility of such approaches to support endurance training applications in humans. PMID- 26578971 TI - Pathophysiological significance of the two-pore domain K(+) channel K2P5.1 in splenic CD4(+)CD25(-) T cell subset from a chemically-induced murine inflammatory bowel disease model. AB - The alkaline pH-activated, two-pore domain K(+) channel K2P5.1 (also known as TASK2/KCNK5) plays an important role in maintaining the resting membrane potential, and contributes to the control of Ca(2+) signaling in several types of cells. Recent studies highlighted the potential role of the K2P5.1 K(+) channel in the pathogenesis of autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. The aim of the present study was to elucidate the pathological significance of the K2P5.1 K(+) channel in inflammatory bowel disease (IBD). The degrees of colitis, colonic epithelial damage, and colonic inflammation were quantified in the dextran sulfate sodium-induced mouse IBD model by macroscopic and histological scoring systems. The expression and functional activity of K2P5.1 in splenic CD4(+) T cells were measured using real time PCR, Western blot, and fluorescence imaging assays. A significant increase was observed in the expression of K2P5.1 in the splenic CD4(+) T cells of the IBD model. Concomitant with this increase, the hyperpolarization response induced by extracellular alkaline pH was significantly larger in the IBD model with the corresponding intracellular Ca(2+) rises. The expression of K2P5.1 was higher in CD4(+)CD25(-) T cells than in CD4(+)CD25(+) regulatory T cells. The knockout of K2P5.1 in mice significantly suppressed the disease responses implicated in the IBD model. Alternations in intracellular Ca(2+) signaling following the dysregulated expression of K2P5.1 were associated with the disease pathogenesis of IBD. The results of the present study suggest that the K2P5.1 K(+) channel in CD4(+)CD25(-) T cell subset is a potential therapeutic target and biomarker for IBD. PMID- 26578972 TI - Attenuation of eccentric exercise-induced muscle damage conferred by maximal isometric contractions: a mini review. AB - Although, beneficial in determined contexts, eccentric exercise-induced muscle damage (EIMD) might be unwanted during training regimens, competitions and daily activities. There are a vast number of studies investigating strategies to attenuate EIMD response after damaging exercise bouts. Many of them consist of performing exercises that induce EIMD, consuming supplements or using equipment that are not accessible for most people. It appears that performing maximal isometric contractions (ISOs) 2-4 days prior to damaging bouts promotes significant attenuation of EIMD symptoms that are not related to muscle function. It has been shown that the volume of ISOs, muscle length in which they are performed, and interval between them and the damaging bout influence the magnitude of this protection. In addition, it appears that this protection is not long-lived, lasting no longer than 4 days. Although no particular mechanisms for these adaptations were identified, professionals should consider applying this non-damaging stimulus before submitting their patients to unaccustomed exercised. However, it seems not to be the best option for athletes or relatively trained individuals. Future, studies should focus on establishing if ISOs protect other populations (i.e., trained individuals) or muscle groups (i.e., knee extensors) against EIMD, as well as investigate different mechanisms for ISO-induced protection. PMID- 26578973 TI - Disentangling cardiovascular control mechanisms during head-down tilt via joint transfer entropy and self-entropy decompositions. AB - A full decomposition of the predictive entropy (PE) of the spontaneous variations of the heart period (HP) given systolic arterial pressure (SAP) and respiration (R) is proposed. The PE of HP is decomposed into the joint transfer entropy (JTE) from SAP and R to HP and self-entropy (SE) of HP. The SE is the sum of three terms quantifying the synergistic/redundant contributions of HP and SAP, when taken individually and jointly, to SE and one term conditioned on HP and SAP denoted as the conditional SE (CSE) of HP given SAP and R. The JTE from SAP and R to HP is the sum of two terms attributable to SAP or R plus an extra term describing the redundant/synergistic contribution to the JTE. All quantities were computed during cardiopulmonary loading induced by -25 degrees head-down tilt (HDT) via a multivariate linear regression approach. We found that: (i) the PE of HP decreases during HDT; (ii) the decrease of PE is attributable to a lessening of SE of HP, while the JTE from SAP and R to HP remains constant; (iii) the SE of HP is dominant over the JTE from SAP and R to HP and the CSE of HP given SAP and R is prevailing over the SE of HP due to SAP and R both in supine position and during HDT; (iv) all terms of the decompositions of JTE from SAP and R to HP and SE of HP due to SAP and R were not affected by HDT; (v) the decrease of the SE of HP during HDT was attributed to the reduction of the CSE of HP given SAP and R; (vi) redundancy of SAP and R is prevailing over synergy in the information transferred into HP both in supine position and during HDT, while in the HP information storage synergy and redundancy are more balanced. The approach suggests that the larger complexity of the cardiac control during HDT is unrelated to the baroreflex control and cardiopulmonary reflexes and may be related to central commands and/or modifications of the dynamical properties of the sinus node. PMID- 26578974 TI - Diagnostic ultrasound estimates of muscle mass and muscle quality discriminate between women with and without sarcopenia. AB - INTRODUCTION: Age-related changes in muscle mass and muscle tissue composition contribute to diminished strength in older adults. The objectives of this study are to examine if an assessment method using mobile diagnostic ultrasound augments well-known determinants of lean body mass (LBM) to aid sarcopenia staging, and if a sonographic measure of muscle quality is associated with muscle performance. METHODS: Twenty community-dwelling female subjects participated in the study (age = 43.4 +/- 20.9 years; BMI: 23.8, interquartile range: 8.5). Dual energy X-ray absorptiometry (DXA) and diagnostic ultrasound morphometry were used to estimate LBM. Muscle tissue quality was estimated via the echogenicity using grayscale histogram analysis. Peak force was measured with grip dynamometry and scaled for body size. Bivariate and multiple regression analyses were used to determine the association of the predictor variables with appendicular lean mass (aLM/ht(2)), and examine the relationship between scaled peak force values and muscle echogenicity. The sarcopenia LBM cut point value of 6.75 kg/m(2) determined participant assignment into the Normal LBM and Low LBM subgroups. RESULTS: The selected LBM predictor variables were body mass index (BMI), ultrasound morphometry, and age. Although BMI exhibited a significant positive relationship with aLM/ht(2) (adj. R (2) = 0.61, p < 0.001), the strength of association improved with the addition of ultrasound morphometry and age as predictor variables (adj. R (2) = 0.85, p < 0.001). Scaled peak force was associated with age and echogenicity (adj. R (2) = 0.53, p < 0.001), but not LBM. The Low LBM subgroup of women (n = 10) had higher scaled peak force, lower BMI, and lower echogenicity values in comparison to the Normal LBM subgroup (n = 10; p < 0.05). CONCLUSIONS: Diagnostic ultrasound morphometry values are associated with LBM, and improve the BMI predictive model for aLM/ht(2) in women. In addition, ultrasound proxy measures of muscle quality are more strongly associated with strength than muscle mass within the study sample. PMID- 26578975 TI - Naturalistic stimulation changes the dynamic response of action potential encoding in a mechanoreceptor. AB - Naturalistic signals were created from vibrations made by locusts walking on a Sansevieria plant. Both naturalistic and Gaussian noise signals were used to mechanically stimulate VS-3 slit-sense mechanoreceptor neurons of the spider, Cupiennius salei, with stimulus amplitudes adjusted to give similar firing rates for either stimulus. Intracellular microelectrodes recorded action potentials, receptor potential, and receptor current, using current clamp and voltage clamp. Frequency response analysis showed that naturalistic stimulation contained relatively more power at low frequencies, and caused increased neuronal sensitivity to higher frequencies. In contrast, varying the amplitude of Gaussian stimulation did not change neuronal dynamics. Naturalistic stimulation contained less entropy than Gaussian, but signal entropy was higher than stimulus in the resultant receptor current, indicating addition of uncorrelated noise during transduction. The presence of added noise was supported by measuring linear information capacity in the receptor current. Total entropy and information capacity in action potentials produced by either stimulus were much lower than in earlier stages, and limited to the maximum entropy of binary signals. We conclude that the dynamics of action potential encoding in VS-3 neurons are sensitive to the form of stimulation, but entropy and information capacity of action potentials are limited by firing rate. PMID- 26578977 TI - Flight control and landing precision in the nocturnal bee Megalopta is robust to large changes in light intensity. AB - Like their diurnal relatives, Megalopta genalis use visual information to control flight. Unlike their diurnal relatives, however, they do this at extremely low light intensities. Although Megalopta has developed optical specializations to increase visual sensitivity, theoretical studies suggest that this enhanced sensitivity does not enable them to capture enough light to use visual information to reliably control flight in the rainforest at night. It has been proposed that Megalopta gain extra sensitivity by summing visual information over time. While enhancing the reliability of vision, this strategy would decrease the accuracy with which they can detect image motion-a crucial cue for flight control. Here, we test this temporal summation hypothesis by investigating how Megalopta's flight control and landing precision is affected by light intensity and compare our findings with the results of similar experiments performed on the diurnal bumblebee Bombus terrestris, to explore the extent to which Megalopta's adaptations to dim light affect their precision. We find that, unlike Bombus, light intensity does not affect flight and landing precision in Megalopta. Overall, we find little evidence that Megalopta uses a temporal summation strategy in dim light, while we find strong support for the use of this strategy in Bombus. PMID- 26578978 TI - Multitasking roles of mosquito labrum in oviposition and blood feeding. AB - Reception of odorants by two main head appendages, antennae and maxillary palps, is essential for insects' survival and reproduction. There is growing evidence in the literature suggesting that the proboscis is also an olfactory appendage and its function as an additional "antenna" has been previously proposed. We surmised that movements of the labrum toward a blood vessel might be chemically oriented and, if so, there should be odorant receptors expressed in the labrum. To test this hypothesis, we first compared by quantitative PCR expression of odorant receptors (OR) from the Southern house mosquito, Culex quinquefasciatus in antennae and proboscis and, subsequently compared OR expression in various proboscis parts. Our data suggested that a receptor for the oviposition attractant, skatole, CquiOR21, was not expressed in proboscis, whereas a receptor for another oviposition attractant, 4EP (4-ethylphenol), CquiOR99, and a receptorf for the insect repellent DEET, CquiOR136, were expressed in the stylet of the proboscis, particularly in the tip of the labrum. In a dual-choice olfactometer, mosquitoes having the stylet coated with nail polish were attracted to 4EP in the same manner as the untreated mosquitoes. By contrast, in an oviposition assay, the stylet-treated mosquitoes did not discriminate 4EP from control oviposition cups, whereas the untreated mosquitoes (as well as mosquitoes having the labella coated) laid significantly more egg rafts in cups treated with 4EP. Ablation experiments confirmed that 4EP was sensed by the labrum where CquiOR99 is highly expressed. Stylet-coated, labella-coated, and untreated mosquitoes laid significantly more egg rafts in skatole-treated cups than in control cups. Likewise, coating of proboscis structures with nail polish had no effect on DEET-mediated oviposition deterrence. In a behavioral arena designed to mimic a human arm, mosquitoes showed significantly reduced probing time when blood was impregnated with 4EP, i.e., they engaged more rapidly in continuous blood feeding as compared to untreated blood. The time of engagement for feeding in skatole-containing blood vs. untreated blood did not differ significantly. Taken together, these data suggest that 4EP reception by the labrum is important not only for oviposition decisions, but also for reducing probing and initiation of blood feeding. PMID- 26578976 TI - Adipokines, diabetes and atherosclerosis: an inflammatory association. AB - Cardiovascular diseases can be considered the most important cause of death in diabetic population and diabetes can in turn increase the risk of cardiovascular events. Inflammation process is currently recognized as responsible for the development and maintenance of diverse chronic diseases, including diabetes and atherosclerosis. Considering that adipose tissue is an important source of adipokines, which may present anti and proinflammatory effects, the aim of this review is to explore the role of the main adipokines in the pathophysiology of diabetes and atherosclerosis, highlighting the therapeutic options that could arise from the manipulation of these signaling pathways both in humans and in translational models. PMID- 26578980 TI - Gas analyzer's drift leads to systematic error in maximal oxygen uptake and maximal respiratory exchange ratio determination. AB - The aim was to examine the drift in the measurements of fractional concentration of oxygen (FO2) and carbon dioxide (FCO2) of a Nafion-using metabolic cart during incremental maximal exercise in 18 young and 12 elderly males, and to propose a way in which the drift can be corrected. The drift was verified by comparing the pre-test calibration values with the immediate post-test verification values of the calibration gases. The system demonstrated an average downscale drift (P < 0.001) in FO2 and FCO2 of -0.18% and -0.05%, respectively. Compared with measured values, corrected average maximal oxygen uptakevalues were 5-6% lower (P < 0.001) whereas corrected maximal respiratory exchange ratio values were 8-9% higher (P < 0.001). The drift was not due to an electronic instability in the analyzers because it was reverted after 20 min of recovery from the end of the exercise. The drift may be related to an incomplete removal of water vapor from the expired gas during transit through the Nafion conducting tube. These data demonstrate the importance of checking FO2 and FCO2 values by regular pre-test calibrations and post-test verifications, and also the importance of correcting a possible shift immediately after exercise. PMID- 26578979 TI - Malformations of the tooth root in humans. AB - The most common root malformations in humans arise from either developmental disorders of the root alone or disorders of radicular development as part of a general tooth dysplasia. The aim of this review is to relate the characteristics of these root malformations to potentially disrupted processes involved in radicular morphogenesis. Radicular morphogenesis proceeds under the control of Hertwig's epithelial root sheath (HERS) which determines the number, length, and shape of the root, induces the formation of radicular dentin, and participates in the development of root cementum. Formation of HERS at the transition from crown to root development appears to be very insensitive to adverse effects, with the result that rootless teeth are extremely rare. In contrast, shortened roots as a consequence of impaired or prematurely halted apical growth of HERS constitute the most prevalent radicular dysplasia which occurs due to trauma and unknown reasons as well as in association with dentin disorders. While odontoblast differentiation inevitably stops when growth of HERS is arrested, it seems to be unaffected even in cases of severe dentin dysplasias such as regional odontodysplasia and dentin dysplasia type I. As a result radicular dentin formation is at least initiated and progresses for a limited time. The only condition affecting cementogenesis is hypophosphatasia which disrupts the formation of acellular cementum through an inhibition of mineralization. A process particularly susceptible to adverse effects appears to be the formation of the furcation in multirooted teeth. Impairment or disruption of this process entails taurodontism, single-rooted posterior teeth, and misshapen furcations. Thus, even though many characteristics of human root malformations can be related to disorders of specific processes involved in radicular morphogenesis, precise inferences as to the pathogenesis of these dysplasias are hampered by the still limited knowledge on root formation. PMID- 26578981 TI - Lipid storage changes in human skeletal muscle during detraining. AB - Exercise training is known to increase intramuscular triglyceride content in both trained and untrained legs. The purpose of the study was to determine the changes of intramyocellular lipids (IMCL) and extramyocellular lipids (EMCL) of both trained and untrained legs during detraining. We measured both IMCL and EMCL levels in previously trained vs. untrained legs during 4-weeks of detraining after 6-weeks of strength training. Eight young men (aged 21.4 +/- 1.4 years) trained their vastus lateralis muscle in one leg using a dynamometer, whereas the contralateral leg served as untrained control. Muscle cross-sectional area (CSA), IMCL, EMCL, total creatine (creatine + phophocreatine) of extensor (vastus lateralis) muscles were assessed using magnetic resonance imaging (MRI) and proton magnetic resonance spectra ((1)H-MRS) before training, 3 days after and 28 days after the last bout of training. CSA was increased in both legs by Day 3 after training, and was still high at Day 28 post-training; IMCL increased in both legs by Day 3 after training, then decreased at Day 28 post-training only in the untrained leg; EMCL shows no significant change by Day 3 after training, but at Day 28 post-training has increased in the trained leg and decreased in the untrained leg; total creatine did not change significantly. CONCLUSION: Decreases of IMCL and EMCL storages in previously untrained leg during detraining indicates an ectopic influence on tissue lipid storage by different metabolic demand among tissues in the same human body. PMID- 26578982 TI - Dexamethasone increases aquaporin-2 protein expression in ex vivo inner medullary collecting duct suspensions. AB - Aquaporin-2 (AQP2) is the vasopressin-regulated water channel that controls renal water reabsorption and plays an important role in the maintenance of body water homeostasis. Excessive glucocorticoid as often seen in Cushing's syndrome causes water retention. However, whether and how glucocorticoid regulates AQP2 remains unclear. In this study, we examined the direct effect of dexamethasone on AQP2 protein expression and activity. Dexamethasone increased AQP2 protein abundance in rat inner medullary collecting duct (IMCD) suspensions. This was confirmed in HEK293 cells transfected with AQP2 cDNA. Cell surface protein biotinylation showed an increase of dexamethasone-induced cell membrane AQP2 expression and this effect was blocked by glucocorticoid receptor antagonist RU486. Functionally, dexamethasone treatment of oocytes injected with an AQP2 cRNA increased water transport activity as judged by cell rupture time in a hypo osmotic solution (66 +/- 13 s in dexamethasone vs. 101 +/- 11 s in control, n = 15). We further found that dexamethasone treatment reduced AQP2 protein degradation, which could result in an increase of AQP2 protein. Interestingly, dexamethasone promoted cell membrane AQP2 moving to less buoyant lipid raft submicrodomains. Taken together, our data demonstrate that dexamethasone promotes AQP2 protein expression and increases water permeability mainly via inhibition of AQP2 protein degradation. The increase in AQP2 activity promotes water reabsorption, which may contribute to glucocorticoid-induced water retention and hypertension. PMID- 26578983 TI - Acute responses of circulating microRNAs to low-volume sprint interval cycling. AB - Low-volume high-intensity interval training is an efficient and practical method of inducing physiological responses in various tissues to develop physical fitness and may also change the expression of circulating microRNAs (miRNAs). The purpose of the present study was to examine whether miRNAs for muscle, heart, somatic tissue and metabolism were affected by 30-s intervals of intensive sprint cycling. We also examined the relationship of these miRNAs to conventional biochemical and performance indices. Eighteen healthy young males performed sprint interval cycling. Circulating miRNAs in plasma were detected using TaqMan based quantitative PCR and normalized to Let-7d/g/i. In addition, we determined the levels of insulin-like growth factor-I, testosterone and cortisol, and anaerobic capacity. Compared to plasma levels before exercise muscle-specific miR 1 (0.12 +/- 0.02 vs. 0.09 +/- 0.02), miR-133a (0.46 +/- 0.10 vs. 0.31 +/- 0.06), and miR-133b (0.19 +/- 0.02 vs. 0.10 +/- 0.01) decreased (all P < 0.05), while miR-206 and miR-499 remained unchanged. The levels of metabolism related miR-122 (0.62 +/- 0.07 vs. 0.34 +/- 0.03) and somatic tissues related miR-16 (1.74 +/- 0.27 vs. 0.94 +/- 0.12) also decreased (both P < 0.05). The post-exercise IGF-1 and cortisol concentrations were significantly increased, while testosterone concentrations did not. Plasma levels of miR-133b correlated to peak power (r = 0.712, P = 0.001) and miR-122 correlated to peak power ratio (r = 0.665, P = 0.003). In conclusion sprint exercise provokes genetic changes for RNA related to specific muscle or metabolism related miRNAs suggesting that miR-133b and miR-122 may be potential useful biomarkers for actual physiological strain or anaerobic capacity. Together, our findings on the circulating miRNAs may provide new insight into the physiological responses that are being performed during exercise and delineate mechanisms by which exercise confers distinct phenotypes and improves performance. PMID- 26578984 TI - Patterns of Substance Use Across the First Year of College and Associated Risk Factors. AB - Starting college is a major life transition. This study aims to characterize patterns of substance use across a variety of substances across the first year of college and identify associated factors. We used data from the first cohort (N = 2056, 1240 females) of the "Spit for Science" sample, a study of incoming freshmen at a large urban university. Latent transition analysis was applied to alcohol, tobacco, cannabis, and other illicit drug uses measured at the beginning of the fall semester and midway through the spring semester. Covariates across multiple domains - including personality, drinking motivations and expectancy, high school delinquency, peer deviance, stressful events, and symptoms of depression and anxiety - were included to predict the patterns of substance use and transitions between patterns across the first year. At both the fall and spring semesters, we identified three subgroups of participants with patterns of substance use characterized as: (1) use of all four substances; (2) alcohol, tobacco, and cannabis use; and (3) overall low substance use. Patterns of substance use were highly stable across the first year of college: most students maintained their class membership from fall to spring, with just 7% of participants in the initial low substance users transitioning to spring alcohol, tobacco, and cannabis users. Most of the included covariates were predictive of the initial pattern of use, but covariates related to experiences across the first year of college were more predictive of the transition from the low to alcohol, tobacco, and cannabis user groups. Our results suggest that while there is an overall increase in alcohol use across all students, college students largely maintain their patterns of substance use across the first year. Risk factors experienced during the first year may be effective targets for preventing increases in substance use. PMID- 26578985 TI - Involuntary Medication, Seclusion, and Restraint in German Psychiatric Hospitals after the Adoption of Legislation in 2013. AB - BACKGROUND: Involuntary medication in psychiatric treatment of inpatients is highly controversial. While laws regulating involuntary medication have been changed in Germany, no data have been available to date on how often involuntary medication is actually applied. Recently, our hospital group introduced specific routine documentation of legal status and application of involuntary medication in the patients' electronic records, which allows the assessment of the frequency of involuntary medication. METHOD: For the year 2014, we extracted aggregated data from the electronic database on age, sex, psychiatric diagnosis, legal status during admission, kind of coercive measure (mechanical restraint, seclusion, and involuntary medication) applied, and the number and duration of seclusion and restraint episodes for seven study sites. RESULTS: A total of 1,514 (9.6%) of 15,832 admissions were involuntary. At least one coercive measure was applied in 976 (6.2%) admissions. Seclusion was applied in 579 (3.7%) admissions, mechanical restraint was applied in 529 (3.3%) admissions, and involuntary medication was applied in 78 (0.5%) admissions. Two-thirds of involuntary medications were applied in cases of emergency; the remainder was applied after a formal decision by a judge. In 55 (70.5%) of the admissions with involuntary medication, at least one other coercive measure (seclusion, restraint, or both) was applied as well. CONCLUSION: Involuntary medication is rarely applied and less frequent than seclusion or mechanical restraint, possibly as a consequence of recent legal restrictions. PMID- 26578986 TI - Virtual Reality-Based Attention Bias Modification Training for Social Anxiety: A Feasibility and Proof of Concept Study. AB - Attention bias modification (ABM) programs have been considered as a promising new approach for the treatment of various disorders, including social anxiety disorder (SAD). However, previous studies yielded ambiguous results regarding the efficacy of ABM in SAD. The present proof-of-concept study investigates the feasibility of a newly developed virtual reality (VR)-based dot-probe training paradigm. It was designed to facilitate attentional disengagement from threatening stimuli in socially anxious individuals (N = 15). The following outcomes were examined: (a) self-reports of enjoyment, motivation, flow, and presence; (b) attentional bias for social stimuli; and (c) social anxiety symptoms. Results showed that ABM training is associated with high scores in enjoyment, motivation, flow, and presence. Furthermore, significant improvements in terms of attention bias and social anxiety symptoms were observed from pre- to follow-up assessment. The study suggests that VR is a feasible and presumably a promising new medium for ABM trainings. Controlled studies will need to be carried out. PMID- 26578987 TI - Eyeblink Classical Conditioning in Alcoholism and Fetal Alcohol Spectrum Disorders. AB - Alcoholism is a debilitating disorder that can take a significant toll on health and professional and personal relationships. Excessive alcohol consumption can have a serious impact on both drinkers and developing fetuses, leading to long term learning impairments. Decades of research in laboratory animals and humans have demonstrated the value of eyeblink classical conditioning (EBC) as a well characterized model system to study the neural mechanisms underlying associative learning. Behavioral EBC studies in adults with alcohol use disorders and in children with fetal alcohol spectrum disorders report a clear learning deficit in these two patient populations, suggesting alcohol-related damage to the cerebellum and associated structures. Insight into the neural mechanisms underlying these learning impairments has largely stemmed from laboratory animal studies. In this mini-review, we present and discuss exemplary animal findings and data from patient and neuroimaging studies. An improved understanding of the neural mechanisms underlying learning deficits in EBC related to alcoholism and prenatal alcohol exposure has the potential to advance the diagnoses, treatment, and prevention of these and other pediatric and adult disorders. PMID- 26578988 TI - Exercise and Alcohol Consumption: What We Know, What We Need to Know, and Why it is Important. AB - Exercise provides a wealth of benefits to brain and body, and is regarded as a protective factor against disease. Protective factors tend to cluster together - that is, people who engage in one healthy behavior, such as exercise, also engage in other healthy behaviors, such as maintaining a nutritious diet and getting sufficient sleep. In contrast to exercise, alcohol consumption is not typically regarded as a health-promoting behavior, although moderate intake has been associated with a lower risk of cardiovascular disease. Surprisingly, several large, population-based studies have shown a positive association between physical activity and alcohol intake. The present review focuses on what is known about this relationship, including potential neural bases as well as moderating factors, and discusses important directions for further study, such as a more thorough characterization of people who both drink and exercise. We focus on ramifications for intervening with people who have alcohol use disorders, as exercise has been assessed as both a treatment and preventive measure, with mixed results. We believe that, in order for such interventions to be effective, clinical trials must distinguish treatment-seeking populations from non-treatment seeking ones, as well as ensure that the use of exercise as a tool to decrease alcohol consumption is made explicit. We posit that a better understanding of the relationship between physical activity and alcohol intake will maximize intervention efforts by informing the design of clinical trials and research driven prevention strategies, as well as enable individuals to make educated decisions about their health behaviors. PMID- 26578989 TI - The physiology and psychophysics of the color-form relationship: a review. AB - The relationship between color and form has been a long standing issue in visual science. A picture of functional segregation and topographic clustering emerges from anatomical and electrophysiological studies in animals, as well as by brain imaging studies in human. However, one of the many roles of chromatic information is to support form perception, and in some cases it can do so in a way superior to achromatic (luminance) information. This occurs both at an early, contour detection stage, as well as in late, higher stages involving spatial integration and the perception of global shapes. Pure chromatic contrast can also support several visual illusions related to form-perception. On the other hand, form seems a necessary prerequisite for the computation and assignment of color across space, and there are several respects in which the color of an object can be influenced by its form. Evidently, color and form are mutually dependent. Electrophysiological studies have revealed neurons in the visual brain able to signal contours determined by pure chromatic contrast, the spatial tuning of which is similar to that of neurons carrying luminance information. It seems that, especially at an early stage, form is processed by several, independent systems that interact with each other, each one having different tuning characteristics in color space. At later processing stages, mechanisms able to combine information coming from different sources emerge. A clear interaction between color and form is manifested by the fact that color-form contingencies can be observed in various perceptual phenomena such as adaptation aftereffects and illusions. Such an interaction suggests a possible early binding between these two attributes, something that has been verified by both electrophysiological and fMRI studies. PMID- 26578990 TI - Cueing musical emotions: An empirical analysis of 24-piece sets by Bach and Chopin documents parallels with emotional speech. AB - Acoustic cues such as pitch height and timing are effective at communicating emotion in both music and speech. Numerous experiments altering musical passages have shown that higher and faster melodies generally sound "happier" than lower and slower melodies, findings consistent with corpus analyses of emotional speech. However, equivalent corpus analyses of complex time-varying cues in music are less common, due in part to the challenges of assembling an appropriate corpus. Here, we describe a novel, score-based exploration of the use of pitch height and timing in a set of "balanced" major and minor key compositions. Our analysis included all 24 Preludes and 24 Fugues from Bach's Well-Tempered Clavier (book 1), as well as all 24 of Chopin's Preludes for piano. These three sets are balanced with respect to both modality (major/minor) and key chroma ("A," "B," "C," etc.). Consistent with predictions derived from speech, we found major-key (nominally "happy") pieces to be two semitones higher in pitch height and 29% faster than minor-key (nominally "sad") pieces. This demonstrates that our balanced corpus of major and minor key pieces uses low-level acoustic cues for emotion in a manner consistent with speech. A series of post hoc analyses illustrate interesting trade-offs, with sets featuring greater emphasis on timing distinctions between modalities exhibiting the least pitch distinction, and vice versa. We discuss these findings in the broader context of speech-music research, as well as recent scholarship exploring the historical evolution of cue use in Western music. PMID- 26578992 TI - Influence of trait empathy on the emotion evoked by sad music and on the preference for it. AB - Some people experience pleasant emotion when listening to sad music. Therefore, they can enjoy listening to it. In the current study, we aimed to investigate such apparently paradoxical emotional mechanisms and focused on the influence of individuals' trait empathy, which has been reported to associate with emotional responses to sad music and a preference for it. Eighty-four elementary school children (42 males and 42 females, mean age 11.9 years) listened to two kinds of sad music and rated their emotional state and liking toward them. In addition, trait empathy was assessed using the Interpersonal Reactivity Index scale, which comprises four sub-components: Empathic Concern, Personal Distress, Perspective Taking, and Fantasy (FS). We conducted a path analysis and tested our proposed model that hypothesized that trait empathy and its sub-components would affect the preference for sad music directly or indirectly, mediated by the emotional response to the sad music. Our findings indicated that FS, a sub-component of trait empathy, was directly associated with liking sad music. Additionally, perspective taking ability, another sub-component of trait empathy, was correlated with the emotional response to sad music. Furthermore, the experience of pleasant emotions contributed to liking sad music. PMID- 26578991 TI - Impaired reasoning and problem-solving in individuals with language impairment due to aphasia or language delay. AB - The precise nature of the relationship between language and thought is an intriguing and challenging area of inquiry for scientists across many disciplines. In the realm of neuropsychology, research has investigated the inter dependence of language and thought by testing individuals with compromised language abilities and observing whether performance in other cognitive domains is diminished. One group of such individuals is patients with aphasia who have an impairment in speech and language arising from a brain injury, such as a stroke. Our previous research has shown that the degree of language impairment in these individuals is strongly associated with the degree of impairment on complex reasoning tasks, such as the Wisconsin Card Sorting Task (WCST) and Raven's Matrices. In the current study, we present new data from a large group of individuals with aphasia that show a dissociation in performance between putatively non-verbal tasks on the Wechsler Adult Intelligence Scale (WAIS) that require differing degrees of reasoning (Picture Completion vs. Picture Arrangement tasks). We also present an update and replication of our previous findings with the WCST showing that individuals with the most profound core language deficits (i.e., impaired comprehension and disordered language output) are particularly impaired on problem-solving tasks. In the second part of the paper, we present findings from a neurologically intact individual known as "Chelsea" who was not exposed to language due to an unaddressed hearing loss that was present since birth. At the age of 32, she was fitted with hearing aids and exposed to spoken and signed language for the first time, but she was only able to acquire a limited language capacity. Chelsea was tested on a series of standardized neuropsychological measures, including reasoning and problem-solving tasks. She was able to perform well on a number of visuospatial tasks but was disproportionately impaired on tasks that required reasoning, such as Raven's Matrices and the WAIS Picture Arrangement task. Together, these findings suggest that language supports complex reasoning, possibly due to the facilitative role of verbal working memory and inner speech in higher mental processes. PMID- 26578993 TI - The cultural transmission of cooperative norms. AB - Cooperative behavior depends on cultural environment, so what happens when people move from to a new culture governed by a new norm? The dynamics of culture induced cooperation has not been well understood. We expose lab participants to a sequence of different subject pools while playing a constrained Trust Game. We find prior exposure to different subject pools does in fact influence cooperative behavior; first impressions matter-the primacy effect plays a stronger role than the recency effect; and selfish first impressions matter more than cooperative first impressions-observing selfish behavior by others had a longer-lasting and greater influence on behaviors than observing cooperative behavior by others. Moreover, three consecutive exposures to cooperative environments were needed to neutralize one exposure to a selfish environment. PMID- 26578994 TI - Scientific integrity in research methods. PMID- 26578995 TI - Individual factors predicted to influence outcome in group CBT for psychosis (CBTp) and related therapies. PMID- 26578996 TI - The relation of general socio-emotional processing to parenting specific behavior: a study of mothers with and without posttraumatic stress disorder. AB - Socio-emotional information processing during everyday human interactions has been assumed to translate to social-emotional information processing when parenting a child. Yet, few studies have examined whether this is indeed the case. This study aimed to improve on this by connecting the functional neuroimaging data when seeing socio-emotional interactions that are not parenting specific to observed maternal sensitivity. The current study considered 45 mothers of small children (12-42 months of age). It included healthy controls (HC) and mothers with interpersonal violence-related posttraumatic stress disorder (IPV-PTSD), as well as mothers without PTSD, both with and without IPV exposure. We found that anterior cingulate cortex (ACC) and ventromedial prefrontal cortex (vmPFC) activity correlated negatively with observed maternal sensitivity when mothers watched videos of menacing vs. prosocial adult male female interactions. This relationship was independent of whether mothers were HC or had IPV-PTSD. We also found dorsolateral prefrontal cortex (dlPFC) activity to be correlated negatively with maternal sensitivity when mothers watched any kind of arousing adult interactions. With regards to ACC and vmPFC activity, we interpret our results to mean that the ease of general emotional information integration translates to parenting-specific behavior. Our dlPFC activity findings support the idea that the efficiency of top-down control of socio emotional processing in non-parenting specific contexts may be predictive of parenting behavior. PMID- 26578997 TI - Beyond mechanistic interaction: value-based constraints on meaning in language. AB - According to situated, embodied, and distributed approaches to cognition, language is a crucial means for structuring social interactions. Recent approaches that emphasize this coordinative function treat language as a system of replicable constraints on individual and interactive dynamics. In this paper, we argue that the integration of the replicable-constraints approach to language with the ecological view on values allows for a deeper insight into processes of meaning creation in interaction. Such a synthesis of these frameworks draws attention to important sources of structuring interactions beyond the sheer efficiency of a collective system in its current task situation. Most importantly, the workings of linguistic constraints will be shown as embedded in more general fields of values, which are realized on multiple timescales. Because the ontogenetic timescale offers a convenient window into the emergence of linguistic constraints, we present illustrations of concrete mechanisms through which values may become embodied in language use in development. PMID- 26578998 TI - A framework of psychological compensation in attention deficit hyperactivity disorder. AB - The term compensation is widely used in the context of attention deficit hyperactivity disorder (ADHD), yet, it is neither defined nor theory driven. Adapting a model of psychological compensation (Backman and Dixon, 1992) to fit ADHD research is the aim of this review: we will (1) introduce the existing theoretical framework of psychological compensation, (2) discuss its applicability to ADHD and adapt the model to fit ADHD research, and (3) set up requirements for research on psychological compensation in ADHD. According to the framework psychological compensation can be inferred if a deficit (i.e., a mismatch between skill and environmental demand) is counterbalanced by the investment of more effort, the utilization of latent skills, or the acquisition of new skills. The framework has to be adapted because ADHD deficits are developmental and in individuals with ADHD compensation can appear independent of awareness of the deficit. A better understanding of psychological compensation in ADHD could foster diagnosis and interventions. Therefore, we suggest that future studies should follow a research design incorporating independent measures of deficit, compensation, and outcome as well as include individuals who compensate for their ADHD related deficits. PMID- 26578999 TI - Emotions as pragmatic and epistemic actions. AB - This paper explores the idea that emotions in social contexts and their intentionality may be conceived of as pragmatic or epistemic actions. That is, emotions are often aimed at achieving certain goals within a social context, so that they resemble pragmatic actions; and in other cases emotions can be plausibly construed as acts of probing the social environment so as to extract or uncover important information, thus complying with the functions of epistemic actions (cf. Kirsh and Maglio, 1994). This view of emotions stands at odds with the wide-held conception that emotions' intentionality can be cashed out in terms of representations of value. On such a position, emotions' intentionality has only a mind-to-world direction of fit while any world-to-mind direction of fit is deemed secondary or is even outrightly denied. However, acknowledging that emotions (qua actions) also have a world-to-mind direction fit has several advantages over the typical rendition of emotions as representations of value, such as accounting for emotions' sensitivity to contextual factors, variations in emotion expression and, importantly, assessing the appropriateness of emotional reactions. To substantiate this claim, several cases of emotions in social contexts are discussed, as the social dimension of emotions highlights that emotions are inherently ways of interacting with one's social environment. In sum, the construal of emotions in social contexts as pragmatic or epistemic actions yields a more fine-grained and accurate understanding of emotions' intentionality and their roles in social contexts than the insistence on a purely mind-to-world direction of fit. PMID- 26579000 TI - Parent-child math anxiety and math-gender stereotypes predict adolescents' math education outcomes. AB - Two studies examined social determinants of adolescents' math anxiety including parents' own math anxiety and children's endorsement of math-gender stereotypes. In Study 1, parent-child dyads were surveyed and the interaction between parent and child math anxiety was examined, with an eye to same- and other-gender dyads. Results indicate that parent's math anxiety interacts with daughters' and sons' anxiety to predict math self-efficacy, GPA, behavioral intentions, math attitudes, and math devaluing. Parents with lower math anxiety showed a positive relationship to children's math outcomes when children also had lower anxiety. The strongest relationships were found with same-gender dyads, particularly Mother-Daughter dyads. Study 2 showed that endorsement of math-gender stereotypes predicts math anxiety (and not vice versa) for performance beliefs and outcomes (self-efficacy and GPA). Further, math anxiety fully mediated the relationship between gender stereotypes and math self-efficacy for girls and boys, and for boys with GPA. These findings address gaps in the literature on the role of parents' math anxiety in the effects of children's math anxiety and math anxiety as a mechanism affecting performance. Results have implications for interventions on parents' math anxiety and dispelling gender stereotypes in math classrooms. PMID- 26579001 TI - Shape of the self-concept clarity change during group psychotherapy predicts the outcome: an empirical validation of the theoretical model of the self-concept change. AB - BACKGROUND: Self-Concept Clarity (SCC) describes the extent to which the schemas of the self are internally integrated, well defined, and temporally stable. This article presents a theoretical model that describes how different shapes of SCC change (especially stable increase and "V" shape) observed in the course of psychotherapy are related to the therapy outcome. Linking the concept of Jean Piaget and the dynamic systems theory, the study postulates that a stable SCC increase is needed for the participants with a rather healthy personality structure, while SCC change characterized by a "V" shape or fluctuations is optimal for more disturbed patients. METHOD: Correlational study in a naturalistic setting with repeated measurements (M = 5.8) was conducted on the sample of 85 patients diagnosed with neurosis and personality disorders receiving intensive eclectic group psychotherapy under routine inpatient conditions. Participants filled in the Self-Concept Clarity Scale (SCCS), Symptoms' Questionnaire KS-II, and Neurotic Personality Questionnaire KON-2006 at the beginning and at the end of the course of psychotherapy. The SCCS was also administered every 2 weeks during psychotherapy. RESULTS: As hypothesized, among the relatively healthiest group of patients the stable SCC increase was related to positive treatment outcome, while more disturbed patients benefited from the fluctuations and "V" shape of SCC change. CONCLUSIONS: The findings support the idea that for different personality dispositions either a monotonic increase or transient destabilization of SCC is a sign of a good treatment prognosis. PMID- 26579002 TI - Comparing interval estimates for small sample ordinal CFA models. AB - Robust maximum likelihood (RML) and asymptotically generalized least squares (AGLS) methods have been recommended for fitting ordinal structural equation models. Studies show that some of these methods underestimate standard errors. However, these studies have not investigated the coverage and bias of interval estimates. An estimate with a reasonable standard error could still be severely biased. This can only be known by systematically investigating the interval estimates. The present study compares Bayesian, RML, and AGLS interval estimates of factor correlations in ordinal confirmatory factor analysis models (CFA) for small sample data. Six sample sizes, 3 factor correlations, and 2 factor score distributions (multivariate normal and multivariate mildly skewed) were studied. Two Bayesian prior specifications, informative and relatively less informative were studied. Undercoverage of confidence intervals and underestimation of standard errors was common in non-Bayesian methods. Underestimated standard errors may lead to inflated Type-I error rates. Non-Bayesian intervals were more positive biased than negatively biased, that is, most intervals that did not contain the true value were greater than the true value. Some non-Bayesian methods had non-converging and inadmissible solutions for small samples and non normal data. Bayesian empirical standard error estimates for informative and relatively less informative priors were closer to the average standard errors of the estimates. The coverage of Bayesian credibility intervals was closer to what was expected with overcoverage in a few cases. Although some Bayesian credibility intervals were wider, they reflected the nature of statistical uncertainty that comes with the data (e.g., small sample). Bayesian point estimates were also more accurate than non-Bayesian estimates. The results illustrate the importance of analyzing coverage and bias of interval estimates, and how ignoring interval estimates can be misleading. Therefore, editors and policymakers should continue to emphasize the inclusion of interval estimates in research. PMID- 26579003 TI - Role descriptions induce gender mismatch effects in eye movements during reading. AB - The present eye-tracking study investigates the effect of gender typicality on the resolution of anaphoric personal pronouns in English. Participants read descriptions of a person performing a typically male, typically female or gender neutral occupational activity. The description was followed by an anaphoric reference (he or she) which revealed the referent's gender. The first experiment presented roles which were highly typical for men (e.g., blacksmith) or for women (e.g., beautician), the second experiment presented role descriptions with a moderate degree of gender typicality (e.g., psychologist, lawyer). Results revealed a gender mismatch effect in early and late measures in the first experiment and in early stages in the second experiment. Moreover, eye-movement data for highly typical roles correlated with explicit typicality ratings. The results are discussed from a cross-linguistic perspective, comparing natural gender languages and grammatical gender languages. An interpretation of the cognitive representation of typicality beliefs is proposed. PMID- 26579004 TI - The Facial Expressive Action Stimulus Test. A test battery for the assessment of face memory, face and object perception, configuration processing, and facial expression recognition. AB - There are many ways to assess face perception skills. In this study, we describe a novel task battery FEAST (Facial Expressive Action Stimulus Test) developed to test recognition of identity and expressions of human faces as well as stimulus control categories. The FEAST consists of a neutral and emotional face memory task, a face and shoe identity matching task, a face and house part-to-whole matching task, and a human and animal facial expression matching task. The identity and part-to-whole matching tasks contain both upright and inverted conditions. The results provide reference data of a healthy sample of controls in two age groups for future users of the FEAST. PMID- 26579005 TI - The strength of a remorseful heart: psychological and neural basis of how apology emolliates reactive aggression and promotes forgiveness. AB - Apology from the offender facilitates forgiveness and thus has the power to restore a broken relationship. Here we showed that apology from the offender not only reduces the victim's propensity to react aggressively but also alters the victim's implicit attitude and neural responses toward the offender. We adopted an interpersonal competitive game which consisted of two phases. In the first, "passive" phase, participants were punished by high or low pain stimulation chosen by the opponents when losing a trial. During the break, participants received a note from each of the opponents, one apologizing and the other not. The second, "active" phase, involved a change of roles where participants could punish the two opponents after winning. Experiment 1 included an Implicit Association Test (IAT) in between the reception of notes and the second phase. Experiment 2 recorded participants' brain potentials in the second phase. We found that participants reacted less aggressively toward the apologizing opponent than the non-apologizing opponent in the active phase. Moreover, female, but not male, participants responded faster in the IAT when positive and negative words were associated with the apologizing and the non-apologizing opponents, respectively, suggesting that female participants had enhanced implicit attitude toward the apologizing opponent. Furthermore, the late positive potential (LPP), a component in brain potentials associated with affective/motivational reactions, was larger when viewing the portrait of the apologizing than the non-apologizing opponent when participants subsequently selected low punishment. Additionally, the LPP elicited by the apologizing opponents' portrait was larger in the female than in the male participants. These findings confirm the apology's role in reducing reactive aggression and further reveal that this forgiveness process engages, at least in female, an enhancement of the victim's implicit attitude and a prosocial motivational change toward the offender. PMID- 26579007 TI - Target definition for shipwreck hunting. AB - The research described in the present article was implemented to define the locations of two World War II shipwrecks, the German raider Kormoran, and the Australian light cruiser HMAS Sydney. The paper describes the long and complex trail that led through inefficient oceanographic prediction to ambiguous historical prediction involving a single report and on to precise cognitive prediction based on nine reports from more than 70 survivors, a process that yielded a single target position or "mean" just 2.7 NM (nautical miles) from the wreck of Kormoran. Prediction for the position of the wreck of Sydney opened with wishful thinking that she had somehow reached the coast more than 100 NM away when cognitive analysis of the survivor's reports actually provided the basis for accurate prediction in a position near to the wreck of Kormoran. In the account provided below, the focus on cognitive procedures emerged from, first, a review of a sample of the shipwreck hunts, and, second, growing awareness of the extraordinarily rich database available for this search, and the extent to which it was open to cognitive analysis. This review touches on both the trans disciplinary and the cognitive or intra-disciplinary issues that so challenged the political entities responsible for supervising of the search for the wrecks of Kormoran and Sydney. One of the theoretical questions that emerged from these debate concerns the model of expertise advanced by Collins (2013). The decomposability of alleged forms of expertise is revealed as a fundamental problem for research projects that might or might not benefit from trans disciplinary research. Where expertise can be decomposed for operational purposes, the traditional dividing lines between experts and novices, and fools for that matter, are much harder to discern, and require advanced and scientifically informed review. PMID- 26579006 TI - Neurobiological response to EMDR therapy in clients with different psychological traumas. AB - We assessed cortical activation differences in real-time upon exposure to traumatic memory between two distinct groups of psychologically traumatized clients also in comparison with healthy controls. We used electroencephalography (EEG) to compare neuronal activation throughout the bilateral stimulation phase of Eye Movement Desensitization and Reprocessing (EMDR) sessions. We compared activation between the first (T0) and the last (T1) session, the latter performed after processing the index trauma. The group including all clients showed significantly higher cortical activity in orbito-frontal cortex at T0 shifting at T1 toward posterior associative regions. However, the subgroup of clients with chronic exposure to the traumatic event showed a cortical firing at both stages which was closer to that of controls. For the first time EEG monitoring enabled to disclose neurobiological differences between groups of clients with different trauma histories during the reliving of the traumatic event. Cortical activations in clients chronically exposed to traumatic memories were moderate, suggesting an association between social and environmental contexts with the neurobiological response to trauma exposure and psychotherapy. PMID- 26579008 TI - Personality judgments from everyday images of faces. AB - People readily make personality attributions to images of strangers' faces. Here we investigated the basis of these personality attributions as made to everyday, naturalistic face images. In a first study, we used 1000 highly varying "ambient image" face photographs to test the correspondence between personality judgments of the Big Five and dimensions known to underlie a range of facial first impressions: approachability, dominance, and youthful-attractiveness. Interestingly, the facial Big Five judgments were found to separate to some extent: judgments of openness, extraversion, emotional stability, and agreeableness were mainly linked to facial first impressions of approachability, whereas conscientiousness judgments involved a combination of approachability and dominance. In a second study we used average face images to investigate which main cues are used by perceivers to make impressions of the Big Five, by extracting consistent cues to impressions from the large variation in the original images. When forming impressions of strangers from highly varying, naturalistic face photographs, perceivers mainly seem to rely on broad facial cues to approachability, such as smiling. PMID- 26579009 TI - Life is unfair, and so are racing sports: some athletes can randomly benefit from alerting effects due to inconsistent starting procedures. AB - The Olympics are the world's largest sporting events, attracting billions of viewers worldwide. Important parts are racing sports, such as running, swimming and speed skating. In these sports, athletes compete against each other in different heats to determine who wins the gold, or who is granted a place in the final. Of course, the gold goes to whoever is the most talented and has trained the hardest. Or does it? Here we argue that subtle differences between athletes' starts can bias the competition, and demonstrate this in the results of speed skating at the 2010 Winter Olympics. This bias could be removed by simple alterations to current starting procedures. The proposed change would greatly improve racing sport fairness, which currently suffers from an injustice that disadvantages not only athletes, but entire nations rooting for them. PMID- 26579010 TI - Levels of attention and task difficulty in the modulation of interval duration mismatch negativity. AB - Time perception has been described as a fundamental skill needed to engage in a number of higher level cognitive processes essential to successfully navigate everyday life (e.g., planning, sequencing, etc.) Temporal processing is often thought of as a basic neural process that impacts a variety of other cognitive processes. Others, however, have argued that timing in the brain can be affected by a number of variables such as attention and motivation. In an effort to better understand timing in the brain at a basic level with minimal attentional demands, researchers have often employed use of the mismatch negativity (MMN). MMN, specifically duration MMN (dMMN) and interval MMN (iMMN) have been popular methods for studying temporal processing in populations for which attention or motivation may be an issue (e.g., clinical populations, early developmental studies). There are, however, select studies which suggest that attention may in fact modify both temporal processing in general and the MMN event-related potential. It is unclear the degree to which attention affects MMN or whether the effects differ depending on the complexity or difficulty of the MMN paradigm. The iMMN indexes temporal processing and is elicited by introducing a deviant interval duration amid a series of standards. A greater degree of difference in the deviant from the standard elicits a heightened iMMN. Unlike past studies, in which attention was intentionally directed toward a closed-captioned move, the current study had participants partake in tasks involving varying degrees of attention (passive, low, and high) with varying degrees of deviants (small, medium, and large) to better understand the role of attention on the iMMN and to assess whether level of attention paired with changes in task difficulty differentially influence the iMMN electrophysiological responses. Data from 19 subjects were recorded in an iMMN paradigm. The amplitude of the iMMN waveform showed an increase with attention, particularly for intervals that were the most distinct from a standard interval (p < 0.02). Results suggest that the role of attention on the iMMN is complex. Both the degree of attention paid as well as the level of difficulty of the MMN task likely influence the neuronal response within a timing network. These results suggest that electrophysiological perception of time is modified by attention and that the design of the iMMN study is critical to minimize the possible confounding effects of attention. In addition, the implications of these results for future studies assessing interval duration-based MMN in clinical populations is also addressed. PMID- 26579011 TI - Culture moderates the relationship between interdependence and face recognition. AB - Recent theory suggests that face recognition accuracy is affected by people's motivations, with people being particularly motivated to remember ingroup versus outgroup faces. In the current research we suggest that those higher in interdependence should have a greater motivation to remember ingroup faces, but this should depend on how ingroups are defined. To examine this possibility, we used a joint individual difference and cultural approach to test (a) whether individual differences in interdependence would predict face recognition accuracy, and (b) whether this effect would be moderated by culture. In Study 1 European Canadians higher in interdependence demonstrated greater recognition for same-race (White), but not cross-race (East Asian) faces. In Study 2 we found that culture moderated this effect. Interdependence again predicted greater recognition for same-race (White), but not cross-race (East Asian) faces among European Canadians; however, interdependence predicted worse recognition for both same-race (East Asian) and cross-race (White) faces among first-generation East Asians. The results provide insight into the role of motivation in face perception as well as cultural differences in the conception of ingroups. PMID- 26579012 TI - The influence of math anxiety on symbolic and non-symbolic magnitude processing. AB - Deficits in basic numerical abilities have been investigated repeatedly as potential risk factors of math anxiety. Previous research suggested that also a deficient approximate number system (ANS), which is discussed as being the foundation for later math abilities, underlies math anxiety. However, these studies examined this hypothesis by investigating ANS acuity using a symbolic number comparison task. Recent evidence questions the view that ANS acuity can be assessed using a symbolic number comparison task. To investigate whether there is an association between math anxiety and ANS acuity, we employed both a symbolic number comparison task and a non-symbolic dot comparison task, which is currently the standard task to assess ANS acuity. We replicated previous findings regarding the association between math anxiety and the symbolic distance effect for response times. High math anxious individuals showed a larger distance effect than less math anxious individuals. However, our results revealed no association between math anxiety and ANS acuity assessed using a non-symbolic dot comparison task. Thus, our results did not provide evidence for the hypothesis that a deficient ANS underlies math anxiety. Therefore, we propose that a deficient ANS does not constitute a risk factor for the development of math anxiety. Moreover, our results suggest that previous interpretations regarding the interaction of math anxiety and the symbolic distance effect have to be updated. We suggest that impaired number comparison processes in high math anxious individuals might account for the results rather than deficient ANS representations. Finally, impaired number comparison processes might constitute a risk factor for the development of math anxiety. Implications for current models regarding the origins of math anxiety are discussed. PMID- 26579013 TI - Visual-auditory differences in duration discrimination of intervals in the subsecond and second range. AB - A common finding in time psychophysics is that temporal acuity is much better for auditory than for visual stimuli. The present study aimed to examine modality specific differences in duration discrimination within the conceptual framework of the Distinct Timing Hypothesis. This theoretical account proposes that durations in the lower milliseconds range are processed automatically while longer durations are processed by a cognitive mechanism. A sample of 46 participants performed two auditory and visual duration discrimination tasks with extremely brief (50-ms standard duration) and longer (1000-ms standard duration) intervals. Better discrimination performance for auditory compared to visual intervals could be established for extremely brief and longer intervals. However, when performance on duration discrimination of longer intervals in the 1-s range was controlled for modality-specific input from the sensory-automatic timing mechanism, the visual-auditory difference disappeared completely as indicated by virtually identical Weber fractions for both sensory modalities. These findings support the idea of a sensory-automatic mechanism underlying the observed visual auditory differences in duration discrimination of extremely brief intervals in the millisecond range and longer intervals in the 1-s range. Our data are consistent with the notion of a gradual transition from a purely modality specific, sensory-automatic to a more cognitive, amodal timing mechanism. Within this transition zone, both mechanisms appear to operate simultaneously but the influence of the sensory-automatic timing mechanism is expected to continuously decrease with increasing interval duration. PMID- 26579014 TI - Motor and cognitive growth following a Football Training Program. AB - Motor and cognitive growth in children may be influenced by football practice. Therefore the aim of this study was to assess whether a Football Training Program taken over 6 months would improve motor and cognitive performances in children. Motor skills concerned coordinative skills, running, and explosive legs strength. Cognitive abilities involved visual discrimination times and visual selective attention times. Forty-six children with chronological age of ~9.10 years, were divided into two groups: Group 1 (n = 24) attended a Football Exercise Program and Group 2 (n = 22) was composed of sedentary children. Their abilities were measured by a battery of tests including motor and cognitive tasks. Football Exercise Program resulted in improved running, coordination, and explosive leg strength performances as well as shorter visual discrimination times in children regularly attending football courses compared with their sedentary peers. On the whole these results support the thesis that the improvement of motor and cognitive abilities is related not only to general physical activity but also to specific ability related to the ball. Football Exercise Programs is assumed to be a "natural and enjoyable tool" to enhance cognitive resources as well as promoting and encouraging the participation in sport activities from early development. PMID- 26579015 TI - How automatic activation of emotion regulation influences experiencing negative emotions. PMID- 26579016 TI - Processing implicit control: evidence from reading times. AB - Sentences such as "The ship was sunk to collect the insurance" exhibit an unusual form of anaphora, implicit control, where neither anaphor nor antecedent is audible. The non-finite reason clause has an understood subject, PRO, that is anaphoric; here it may be understood as naming the agent of the event of the host clause. Yet since the host is a short passive, this agent is realized by no audible dependent. The putative antecedent to PRO is therefore implicit, which it normally cannot be. What sorts of representations subserve the comprehension of this dependency? Here we present four self-paced reading time studies directed at this question. Previous work showed no processing cost for implicit vs. explicit control, and took this to support the view that PRO is linked syntactically to a silent argument in the passive. We challenge this conclusion by reporting that we also find no processing cost for remote implicit control, as in: "The ship was sunk. The reason was to collect the insurance." Here the dependency crosses two independent sentences, and so cannot, we argue, be mediated by syntax. Our Experiments 1-4 examined the processing of both implicit (short passive) and explicit (active or long passive) control in both local and remote configurations. Experiments 3 and 4 added either "3 days ago" or "just in order" to the local conditions, to control for the distance between the passive and infinitival verbs, and for the predictability of the reason clause, respectively. We replicate the finding that implicit control does not impose an additional processing cost. But critically we show that remote control does not impose a processing cost either. Reading times at the reason clause were never slower when control was remote. In fact they were always faster. Thus, efficient processing of local implicit control cannot show that implicit control is mediated by syntax; nor, in turn, that there is a silent but grammatically active argument in passives. PMID- 26579017 TI - The moderator role of emotion regulation ability in the link between stress and well-being. AB - This article examined the moderating role of a central core dimension of emotional intelligence-emotion-regulation ability-in the relationship between perceived stress and indicators of well-being (depression and subjective happiness) in a sample from a community adult population. The relationships for males and females on these dimensions were also compared. Results revealed that emotion-regulation abilities moderated both the association between perceived stress and depression/happiness for the total sample. However, a gender-specific analysis showed that the moderation effect was only significant for males. In short, when males reported a high level of perceived stress, those with high scores in regulating emotions reported higher scores in subjective happiness and lower depression symptoms than those with low regulating emotions. However, no interaction effect of regulating emotions and stress for predicting subjective happiness and depression was found for females. In developing stress management programmes for reducing depression and increasing well-being, these findings suggest that training in emotional regulation may be more beneficial for males than females. Our findings are discussed in terms of the need for future research to understand the different gender associations and to consider these differences in further intervention programmes. PMID- 26579018 TI - Voluntary transition of the CEO: owner CEOs' sense of self before, during and after transition. AB - This inductive study explores how former business owner chief executive officers (CEOs) experience sense of self during voluntary separation and transition from their company. Our inquiry engaged 16 CEOs who ran companies ranging in size from 15 to 500 employees as they detailed their stories of walking away from roles as owner CEOs. We developed a coding scheme to analyze themes manifested in the narratives. We also analyzed the former CEOs' narratives using a stage and valence model depicting both the continuum of the separation experience and the characterization of each stage as a positive or negative state of being. The diverse yet synchronous stories resulted in three implications for current owner CEOs, professionals who advise CEOs, and future research on CEOs' careers. First, the CEOs often failed to allocate sufficient time and effort to prepare for an identity shift following the sale of their company or transition into retirement. Second, the CEOs experienced a diminished sense of self and dissatisfaction with the exit event. Third, the majority of the CEOs demonstrated an ability to work through the adverse and unanticipated states of being into a positive sense of self. PMID- 26579019 TI - Preliminary validation of FastaReada as a measure of reading fluency. AB - Fluent reading is characterized by speed and accuracy in the decoding and comprehension of connected text. Although a variety of measures are available for the assessment of reading skills most tests do not evaluate rate of text recognition as reflected in fluent reading. Here we evaluate FastaReada, a customized computer-generated task that was developed to address some of the limitations of currently available measures of reading skills. FastaReada provides a rapid assessment of reading fluency quantified as words read per minute for connected, meaningful text. To test the criterion validity of FastaReada, 124 mainstream school children with typical sensory, mental and motor development were assessed. Performance on FastaReada was correlated with the established Neale Analysis of Reading Ability (NARA) measures of text reading accuracy, rate and comprehension, and common single word measures of pseudoword (non-word) reading, phonetic decoding, phonological awareness (PA) and mode of word decoding (i.e., visual or eidetic versus auditory or phonetic). The results demonstrated strong positive correlations between FastaReada performance and NARA reading rate (r = 0.75), accuracy (r = 0.83) and comprehension (r = 0.63) scores providing evidence for criterion-related validity. Additional evidence for criterion validity was demonstrated through strong positive correlations between FastaReada and both single word eidetic (r = 0.81) and phonetic decoding skills (r = 0.68). The results also demonstrated FastaReada to be a stronger predictor of eidetic decoding than the NARA rate measure, with FastaReada predicting 14.4% of the variance compared to 2.6% predicted by NARA rate. FastaReada was therefore deemed to be a valid tool for educators, clinicians, and research related assessment of reading accuracy and rate. As expected, analysis with hierarchical regressions also highlighted the closer relationship of fluent reading to rapid visual word recognition than to phonological-based skills. Eidetic decoding was the strongest predictor of FastaReada performance (16.8%) followed by phonetic decoding skill (1.7%). PA did not make a unique contribution after eidetic decoding and phonetic decoding skills were accounted for. PMID- 26579020 TI - Visual processing in reading disorders and attention-deficit/hyperactivity disorder and its contribution to basic reading ability. AB - Whether visual processing deficits are common in reading disorders (RD), and related to reading ability in general, has been debated for decades. The type of visual processing affected also is debated, although visual discrimination and short-term memory (STM) may be more commonly related to reading ability. Reading disorders are frequently comorbid with ADHD, and children with ADHD often have subclinical reading problems. Hence, children with ADHD were used as a comparison group in this study. ADHD and RD may be dissociated in terms of visual processing. Whereas RD may be associated with deficits in visual discrimination and STM for order, ADHD is associated with deficits in visual-spatial processing. Thus, we hypothesized that children with RD would perform worse than controls and children with ADHD only on a measure of visual discrimination and a measure of visual STM that requires memory for order. We expected all groups would perform comparably on the measure of visual STM that does not require sequential processing. We found children with RD or ADHD were commensurate to controls on measures of visual discrimination and visual STM that do not require sequential processing. In contrast, both RD groups (RD, RD/ADHD) performed worse than controls on the measure of visual STM that requires memory for order, and children with comorbid RD/ADHD performed worse than those with ADHD. In addition, of the three visual measures, only sequential visual STM predicted reading ability. Hence, our findings suggest there is a deficit in visual sequential STM that is specific to RD and is related to basic reading ability. The source of this deficit is worthy of further research, but it may include both reduced memory for order and poorer verbal mediation. PMID- 26579021 TI - Visual exploration patterns of human figures in action: an eye tracker study with art paintings. AB - Art exploration is a complex process conditioned by factors at different levels and includes both basic visual principles and complex cognitive factors. The human figure is considered a critical factor attracting the attention in art painting. Using an eye-tracking methodology, the goal of this study was to explore different elements of the human figure performing an action (face and body parts in action) in complex social scenes characterized by different levels of social interaction between agents depicted in scenes (individual vs. social). The sample included 44 laypersons, and the stimuli consisted of 10 fine art paintings representing the figurative style of classical art. The results revealed different scanning patterns of the human figure elements related to the level of social interaction of agents depicted in the scene. The agents' face attracted eye movements in social interaction scenes while the agents' body parts attracted eye movements only when the agents were involved in individual actions. These processes were confirmed specifically in participants with high empathic abilities who became immediately fixated on faces to develop a mimetic engagement with other agents. Future studies integrating other measures would help confirm the results obtained and strengthen their implication for embodiment processes. PMID- 26579023 TI - Active search for antecedents in cataphoric pronoun resolution. AB - Cataphoric dependencies where a pronoun precedes its antecedent appear to call on different mechanisms in language comprehension from forward dependencies where the antecedent precedes the pronoun. Previous research has shown that the resolution of cataphoric dependencies involves predictive processes such as the active search mechanism, which hypothesizes the automatic search for an antecedent immediately after encountering a cataphoric pronoun. The current study employs gender mismatch to investigate whether the active search for an antecedent of a cataphoric pronoun is restricted only to grammatically licit positions. We present results from an event-related potential experiment on the reading comprehension of cataphoric dependencies in Dutch. Results show that gender mismatch gives rise to an anterior negativity at grammatically licit antecedent positions only. We hypothesize that this negativity reflects the prediction failure for an antecedent after encountering a pronoun, rather than a gender mismatch. We discuss the timing, topography and functionality of this negativity with respect to previous studies and how this relates to the ERPs elicited in the processing of structural constraints on pronoun resolution. PMID- 26579022 TI - Moral judgment as information processing: an integrative review. AB - How do humans make moral judgments about others' behavior? This article reviews dominant models of moral judgment, organizing them within an overarching framework of information processing. This framework poses two distinct questions: (1) What input information guides moral judgments? and (2) What psychological processes generate these judgments? Information Models address the first question, identifying critical information elements (including causality, intentionality, and mental states) that shape moral judgments. A subclass of Biased Information Models holds that perceptions of these information elements are themselves driven by prior moral judgments. Processing Models address the second question, and existing models have focused on the relative contribution of intuitive versus deliberative processes. This review organizes existing moral judgment models within this framework and critically evaluates them on empirical and theoretical grounds; it then outlines a general integrative model grounded in information processing, and concludes with conceptual and methodological suggestions for future research. The information-processing framework provides a useful theoretical lens through which to organize extant and future work in the rapidly growing field of moral judgment. PMID- 26579024 TI - Differential effects of white noise in cognitive and perceptual tasks. AB - Beneficial effects of noise on higher cognition have recently attracted attention. Hypothesizing an involvement of the mesolimbic dopamine system and its functional interactions with cortical areas, the current study aimed to demonstrate a facilitation of dopamine-dependent attentional and mnemonic functions by externally applying white noise in five behavioral experiments including a total sample of 167 healthy human subjects. During working memory, acoustic white noise impaired accuracy when presented during the maintenance period (Experiments 1-3). In a reward based long-term memory task, white noise accelerated perceptual judgments for scene images during encoding but left subsequent recognition memory unaffected (Experiment 4). In a modified Posner task (Experiment 5), the benefit due to white noise in attentional orienting correlated weakly with reward dependence, a personality trait that has been associated with the dopaminergic system. These results suggest that white noise has no general effect on cognitive functions. Instead, they indicate differential effects on perception and cognition depending on a variety of factors such as task demands and timing of white noise presentation. PMID- 26579025 TI - Stimulus devaluation induced by action stopping is greater for explicit value representations. AB - We recently showed that rapidly stopping an action in the face of a reward related stimulus reduces the subjective value of that stimulus (Wessel et al., 2014). In that study, there were three phases. In an initial learning phase, geometric shapes were associated with monetary value via implicit learning. In a subsequent treatment phase, half the shapes were paired with action stopping, and half were not. In a final auction phase, shapes that had been paired with stopping in the treatment phase were subjectively perceived as less valuable compared to those that were not. Exploratory post hoc analyses showed that the stopping-induced devaluation effect was larger for participants with greater explicit knowledge of stimulus values. Here, we repeated the study in 65 participants to systematically test whether the level of explicit knowledge influences the degree of devaluation. The results replicated the core result that action stopping reduces stimulus value. Furthermore, they showed that this effect was indeed significantly larger in participants with more explicit knowledge of the relative stimulus values in the learning phase. These results speak to the robustness of the stopping-induced devaluation effect, and furthermore imply that behavioral therapies using stopping could be successful in devaluing real-world stimuli, insofar as stimulus values are explicitly represented. Finally, to facilitate future investigations into the applicability of these findings, as well as the mechanisms underlying stopping-induced stimulus devaluation, we herein provide open source code for the behavioral paradigm. PMID- 26579027 TI - Supervision and MFT burnout: overcoming the challenges therapists face in the workplace. PMID- 26579026 TI - Evidence from paranoid schizophrenia for more than one component of theory of mind. AB - We previously reported finding that performance was impaired on four out of five theory of mind (ToM) tests in a group of 21 individuals diagnosed with paranoid schizophrenia (pScz), relative to a non-clinical group of 29 individuals (Scherzer et al., 2012). Only the Reading the Mind in the Eyes Test did not distinguish between groups. A principal components analysis revealed that the results on the ToM battery could be explained by one general ToM factor with the possibility of a latent second factor. As well, the tests were not equally sensitive to the pathology. There was also overmentalization in some ToM tests and under-mentalisation in others. These results led us to postulate that there is more than one component to ToM. We hypothesized that correlations between the different EF measures and ToM tests would differ sufficiently within and between groups to support this hypothesis. We considered the relationship between the performance on eight EF tests and five ToM tests in the same diagnosed and non clinical individuals as in the first study. The ToM tests shared few EF correlates and each had its own best EF predictor. These findings support the hypothesis of multiple ToM components. PMID- 26579028 TI - Making sense of (exceptional) causal relations. A cross-cultural and cross linguistic study. AB - In order to make sense of the world, humans tend to see causation almost everywhere. Although most causal relations may seem straightforward, they are not always construed in the same way cross-culturally. In this study, we investigate concepts of "chance," "coincidence," or "randomness" that refer to assumed relations between intention, action, and outcome in situations, and we ask how people from different cultures make sense of such non-law-like connections. Based on a framework proposed by Alicke (2000), we administered a task that aims to be a neutral tool for investigating causal construals cross-culturally and cross linguistically. Members of four different cultural groups, rural Mayan Yucatec and Tseltal speakers from Mexico and urban students from Mexico and Germany, were presented with a set of scenarios involving various types of causal and non causal relations and were asked to explain the described events. Three links varied as to whether they were present or not in the scenarios: Intention-to Action, Action-to-Outcome, and Intention-to-Outcome. Our results show that causality is recognized in all four cultural groups. However, how causality and especially non-law-like relations are interpreted depends on the type of links, the cultural background and the language used. In all three groups, Action-to Outcome is the decisive link for recognizing causality. Despite the fact that the two Mayan groups share similar cultural backgrounds, they display different ideologies regarding concepts of non-law-like relations. The data suggests that the concept of "chance" is not universal, but seems to be an explanation that only some cultural groups draw on to make sense of specific situations. Of particular importance is the existence of linguistic concepts in each language that trigger ideas of causality in the responses from each cultural group. PMID- 26579029 TI - Non-expert listeners show decreased heart rate and increased blood pressure (fear bradycardia) in response to atonal music. AB - Previous studies suggested that listening to different types of music may modulate differently psychological mood and physiological responses associated with the induced emotions. In this study the effect of listening to instrumental classical vs. atonal contemporary music was examined in a group of 50 non-expert listeners. The subjects' heart rate and diastolic and systolic blood pressure values were measured while they listened to music of different style and emotional typologies. Pieces were selected by asking a group of composers and conservatory professors to suggest a list of the most emotional music pieces (from Renaissance to present time). A total of 214 suggestions from 20 respondents were received. Then it was asked them to identify which pieces best induced in the listener feelings of agitation, joy or pathos and the number of suggested pieces per style was computed. Atonal pieces were more frequently indicated as agitating, and tonal pieces as joyful. The presence/absence of tonality in a musical piece did not affect the affective dimension of pathos (being touching). Among the most frequently cited six pieces were selected that were comparable for structure and style, to represent each emotion and style. They were equally evaluated as unfamiliar by an independent group of 10 students of the same cohort) and were then used as stimuli for the experimental session in which autonomic parameters were recorded. Overall, listening to atonal music (independent of the pieces' emotional characteristics) was associated with a reduced heart rate (fear bradycardia) and increased blood pressure (both diastolic and systolic), possibly reflecting an increase in alertness and attention, psychological tension, and anxiety. This evidence fits with the results of the esthetical assessment showing how, overall, atonal music is perceived as more agitating and less joyful than tonal one. PMID- 26579030 TI - Zooming into creativity: individual differences in attentional global-local biases are linked to creative thinking. AB - While recent studies have investigated how processes underlying human creativity are affected by particular visual-attentional states, we tested the impact of more stable attention-related preferences. These were assessed by means of Navon's global-local task, in which participants respond to the global or local features of large letters constructed from smaller letters. Three standard measures were derived from this task: the sizes of the global precedence effect, the global interference effect (i.e., the impact of incongruent letters at the global level on local processing), and the local interference effect (i.e., the impact of incongruent letters at the local level on global processing). These measures were correlated with performance in a convergent-thinking creativity task (the Remote Associates Task), a divergent-thinking creativity task (the Alternate Uses Task), and a measure of fluid intelligence (Raven's matrices). Flexibility in divergent thinking was predicted by the local interference effect while convergent thinking was predicted by intelligence only. We conclude that a stronger attentional bias to visual information about the "bigger picture" promotes cognitive flexibility in searching for multiple solutions. PMID- 26579031 TI - Factors affecting athletes' motor behavior after the observation of scenes of cooperation and competition in competitive sport: the effect of sport attitude. AB - AIM: This study delineated how observing sports scenes of cooperation or competition modulated an action of interaction, in expert athletes, depending on their specific sport attitude. METHOD: In a kinematic study, athletes were divided into two groups depending on their attitude toward teammates (cooperative or competitive). Participants observed sport scenes of cooperation and competition (basketball, soccer, water polo, volleyball, and rugby) and then they reached for, picked up, and placed an object on the hand of a conspecific (giving action). Mixed-design ANOVAs were carried out on the mean values of grasping reaching parameters. RESULTS: Data showed that the type of scene observed as well as the athletes' attitude affected reach-to-grasp actions to give. In particular, the cooperative athletes were speeded when they observed scenes of cooperation compared to when they observed scenes of competition. DISCUSSION: Participants were speeded when executing a giving action after observing actions of cooperation. This occurred only when they had a cooperative attitude. A match between attitude and intended action seems to be a necessary prerequisite for observing an effect of the observed type of scene on the performed action. It is possible that the observation of scenes of competition activated motor strategies which interfered with the strategies adopted by the cooperative participants to execute a cooperative (giving) sequence. PMID- 26579032 TI - Ratio dependence in small number discrimination is affected by the experimental procedure. AB - Adults, infants and some non-human animals share an approximate number system (ANS) to estimate numerical quantities, and are supposed to share a second, 'object-tracking,' system (OTS) that supports the precise representation of a small number of items (up to 3 or 4). In relative numerosity judgments, accuracy depends on the ratio of the two numerosities (Weber's Law) for numerosities >4 (the typical ANS range), while for numerosities <=4 (OTS range) there is usually no ratio effect. However, recent studies have found evidence for ratio effects for small numerosities, challenging the idea that the OTS might be involved for small number discrimination. Here we tested the hypothesis that the lack of ratio effect in the numbers 1-4 is largely dependent on the type of stimulus presentation. We investigated relative numerosity judgments in college students using three different procedures: a simultaneous presentation of intermingled and separate groups of dots in separate experiments, and a further experiment with sequential presentation. As predicted, in the large number range, ratio dependence was observed in all tasks. By contrast, in the small number range, ratio insensitivity was found in one task (sequential presentation). In a fourth experiment, we showed that the presence of intermingled distractors elicited a ratio effect, while easily distinguishable distractors did not. As the different ratio sensitivity for small and large numbers has been often interpreted in terms of the activation of the OTS and ANS, our results suggest that numbers 1-4 may be represented by both numerical systems and that the experimental context, such as the presence/absence of task-irrelevant items in the visual field, would determine which system is activated. PMID- 26579033 TI - Cross-cultural adjustment to the United States: the role of contextualized extraversion change. AB - Personality traits can predict how well-sojourners and expatriates adjust to new cultures, but the adjustment process remains largely unexamined. Based on recent findings that reveal personality traits predict as well as respond to life events and experiences, this research focuses on within-person change in contextualized extraversion and its predictive validity for cross-cultural adjustment in international students who newly arrived in US colleges. We proposed that the initial level as well as the rate of change in school extraversion (i.e., contextualized extraversion that reflects behavioral tendency in school settings) will predict cross-cultural adjustment, withdrawal cognitions, and school satisfaction. Latent growth modeling of three-wave longitudinal surveys of 215 new international students (54% female, M age = 24 years) revealed that the initial level of school extraversion significantly predicted cross-cultural adjustment, (lower) withdrawal cognitions, and satisfaction, while the rate of change (increase) in school extraversion predicted cross-cultural adjustment and (lower) withdrawal cognitions. We further modeled global extraversion and cross cultural motivation as antecedents and explored within-person change in school extraversion as a proximal factor that affects adjustment outcomes. The findings highlight the malleability of contextualized personality, and more importantly, the importance of understanding within-person change in contextualized personality in a cross-cultural adjustment context. The study points to more research that explicate the process of personality change in other contexts. PMID- 26579034 TI - Pattern glare: the effects of contrast and color. AB - AIM: To test a theory of visual stress by investigating the inter-relationships between (1) the threshold contrast/saturation at which individuals first report discomfort when viewing colored gratings of progressively increasing contrast and decreasing saturation; (2) the choice of a colored overlay for reading; (3) any increase in reading speed when the overlay is used. METHOD: Ninety-five young adults, with normal color vision, reported illusions from square-wave gratings (Pattern Glare Test), chose any colored overlays that improved clarity (Intuitive Color Overlays) and read aloud randomly ordered common words (Wilkins Rate of Reading Test). This was followed by an automated choice of tints for text using various screen colors on a tablet, and a test of discomfort from patterns of progressively increasing contrast and decreasing saturation, using software developed for this study. All participants wore their optimal refractive correction throughout the procedure. RESULTS: Fifty-eight participants chose a colored overlay and reported that it made text easier and more comfortable to read. On average, these individuals had a greater improvement in reading speed with their overlays (p = 0.003), a lower contrast threshold at which discomfort from achromatic gratings was first reported (p = 0.015), and a tendency to report more pattern glare (p = 0.052), compared to the other participants. Participants who chose both a most and least preferred tint for text using the automated procedure reported discomfort from colored gratings at a significantly higher contrast with their most preferred color compared to their least preferred color (p = 0.003). The choice of a colored tint was moderately consistent across tests. The most and least preferred colors tended to be complementary. CONCLUSION: Colored tints that improved reading speed reduced pattern glare both in terms of the illusion susceptibility and in terms of discomfort contrast threshold, supporting a theory of visual stress. An automated test that incorporates colored gratings and a choice of most and least preferred color might better identify individuals whose reading speed improves with colored overlays. PMID- 26579035 TI - Reliability and validity of the NeuroCognitive Performance Test, a web-based neuropsychological assessment. AB - The NeuroCognitive Performance Test (NCPT) is a brief, repeatable, web-based cognitive assessment platform that measures performance across several cognitive domains. The NCPT platform is modular and includes 18 subtests that can be arranged into customized batteries. Here we present normative data from a sample of 130,140 healthy volunteers for an NCPT battery consisting of 8 subtests. Participants took the NCPT remotely and without supervision. Factor structure and effects of age, education, and gender were evaluated with this normative dataset. Test-retest reliability was evaluated in a subset of participants who took the battery again an average of 78.8 days later. The eight NCPT subtests group into 4 putative cognitive domains, have adequate to good test-retest reliability, and are sensitive to expected age- and education-related cognitive effects. Concurrent validity to standard neuropsychological tests was demonstrated in 73 healthy volunteers. In an exploratory analysis the NCPT battery could differentiate those who self-reported Mild Cognitive Impairment or Alzheimer's disease from matched healthy controls. Overall these results demonstrate the reliability and validity of the NCPT battery as a measure of cognitive performance and support the feasibility of web-based, unsupervised testing, with potential utility in clinical and research settings. PMID- 26579036 TI - Long-lasting virtual motorcycle-riding trainer effectiveness. AB - This work aimed to test the long-lasting effects of learning acquired with a virtual motorcycle-riding trainer as a tool to improve hazard perception. During the simulation, the rider can interact with other road actors and experience the most common potential accident situations in order to learn to modify his or her behavior to anticipate hazards and avoid crashes. We compared performance to the riding simulator of the two groups of participants: the experimental group, which was trained with the same simulator one year prior, and the control group that had not received any type of training with a riding or driving simulator. All of the participants had ridden a moped in the previous 12 months. The experimental group showed greater abilities to avoid accidents and recognize hazards in comparison to their performance observed a year before, whereas the performance of the control group was similar to that of the experimental group 1 year before in the first two sessions, and even better in the third. We interpreted this latter result as a consequence of their prior on-road experience. Also, the fact that the performance of the experimental group at the beginning of the follow-up is better than that recorded at the end of the training-1 year before-is in line with the idea of a transfer from the on-road experience to the simulator. The present data confirm our main expectation that the effectiveness of the riding training simulator on the ability to cope with potentially dangerous situations persists over time and provides additional evidence in favor of the idea that simulators may be considered useful tools for training the ability to detect and react to hazards, leading to an improvement of this higher-order cognitive skill that persists over time. Implications for the reciprocal influence of the training with the simulator and the on-the road experience are discussed as well. PMID- 26579037 TI - Commentary: Yawning, acute stressors, and arousal reduction in Nazca booby adults and nestlings. PMID- 26579038 TI - Predictive coding in visual search as revealed by cross-frequency EEG phase synchronization. PMID- 26579039 TI - Aging and the optimal viewing position effect in Chinese. AB - Substantial evidence indicates that where readers fixate within a word affects the efficiency with which that word is recognized. Indeed, words in alphabetic languages (e.g., English, French) are recognized most efficiently when fixated at their optimal viewing position (OVP), which is near the word center. However, little is known about the effects of fixation location on word recognition in non alphabetic languages, such as Chinese. Moreover, studies to date have not investigated if effects of fixation location vary across adult age-groups, although it is well-established that older readers experience greater difficulty recognizing words due to visual and cognitive declines. Accordingly, the present research examined OVP effects by young and older adult readers when recognizing Chinese words presented in isolation. Most words in Chinese are formed from two or more logograms called characters and so the present experiment investigated the influence of fixation location on the recognition of 2-, 3-, and 4-character words (and nonwords). The older adults experienced generally greater word recognition difficulty. But whereas the young adults recognized words most efficiently when initially fixating the first character of 2-character words and second character of 3- and 4-character words, the older adults recognized words most efficiently when initially fixating the first character for words of each length. The findings therefore reveal subtle but potentially important adult age differences in the effects of fixation location on Chinese word recognition. Moreover, the similarity in effects for words and nonwords implies a more general age-related change in oculomotor strategy when processing Chinese character strings. PMID- 26579040 TI - Television and eating: repetition enhances food intake. AB - Some studies find that eating with TV increases food intake while others do not. Some of this variability may reflect the engagingness of what is being watched (i.e., content). To test this we varied engagingness by manipulating content familiarity. Female participants undertook two sessions. In the "Different" session they watched two different episodes of the comedy Friends, with snack food presented during the second episode. In the "Same" session they viewed another episode of Friends twice in succession, with snack food presented during the second repeat showing. The three episodes of Friends used here were fully counterbalanced, so overall the only difference between the "Same" and "Different" sessions was whether the content of the second show was familiar or novel. As expected, 14% less was eaten in the "Different" session, suggesting that novel and presumably more engaging content can reduce intake relative to watching familiar and presumably less engaging content. These findings are consistent with the idea that the engagingness of TV can differentially affect food intake, although boredom or irritability resulting from repeat viewing might also explain this effect. PMID- 26579041 TI - The long-term effectiveness of cognitive behavior therapy for psychosis within a routine psychological therapies service. AB - Randomised controlled trials (RCTs) have shown the efficacy of CBTp, however, few studies have considered its long-term effectiveness in routine services. This study reports the outcomes of clients seen in a psychological therapies clinic, set up following positive results obtained from an RCT (Peters et al., 2010). The aims were to evaluate the effectiveness of CBTp, using data from the service's routine assessments for consecutive referrals over a 12 years period, and assess whether gains were maintained at a 6+ months' follow-up. Of the 476 consenting referrals, all clients (N = 358) who received >=5 therapy sessions were offered an assessment at four time points (baseline, pre-, mid-, and end of therapy) on measures assessing current psychosis symptoms, emotional problems, general well being and life satisfaction. A sub-set (N = 113) was assessed at a median of 12 months after finishing therapy. Following the waiting list (median of 3 months) clients received individualized, formulation-based CBTp for a median number of 19 sessions from 121 therapists with a range of experience receiving regular supervision. Clients showed no meaningful change on any measure while on the waiting list (Cohen's d <= 0.23). In contrast, highly significant improvements following therapy, all of which were significantly greater than changes during the waiting list, were found on all domains assessed (Cohen's d: 0.44-0.75). All gains were maintained at follow-up (Cohen's d: 0.29-0.82), with little change between end of therapy and follow-up (Cohen's d <= 0.18). Drop-out rate from therapy was low (13%). These results demonstrate the positive and potentially enduring impact of psychological therapy on a range of meaningful outcomes for clients with psychosis. The follow-up assessments were conducted on only a sub set, which may not generalize to the full sample. Nevertheless this study is the largest of its kind in psychosis, and has important implications for the practice of CBTp in clinical services. PMID- 26579042 TI - The virtual hand illusion is moderated by context-induced spatial reference frames. AB - The tendency to perceive an artificial effector as part of one's own body is known to depend on temporal criteria, like the synchrony between stimulus events informing about the effector. The role of spatial factors is less well understood. Rather than physical distance, which has been manipulated in previous studies, we investigated the role of relative, context-induced distance between the participant's real hand and an artificial hand stimulated synchronously or asynchronously with the real hand. We replicated previously reported distance effects in a virtual reality setup: the perception of ownership increased with decreased distance, and the impact of synchrony was stronger for short distances. More importantly, we found that ownership perception and impact of synchrony were affected by previous distance: the same, medium distance between real and artificial hand induced more pronounced ownership after having experienced a far distance condition than after a near-distance condition. This suggests that subjective, context-induced spatial reference frames contribute to ownership perception, which does not seem to fit with the idea of fixed spatial criteria and/or permanent body representations as the sole determinants of perceived body ownership. PMID- 26579043 TI - Embodied cognition and circular causality: on the role of constitutive autonomy in the reciprocal coupling of perception and action. AB - The reciprocal coupling of perception and action in cognitive agents has been firmly established: perceptions guide action but so too do actions influence what is perceived. While much has been said on the implications of this for the agent's external behavior, less attention has been paid to what it means for the internal bodily mechanisms which underpin cognitive behavior. In this article, we wish to redress this by reasserting that the relationship between cognition, perception, and action involves a constitutive element as well as a behavioral element, emphasizing that the reciprocal link between perception and action in cognition merits a renewed focus on the system dynamics inherent in constitutive biological autonomy. Our argument centers on the idea that cognition, perception, and action are all dependent on processes focussed primarily on the maintenance of the agent's autonomy. These processes have an inherently circular nature-self organizing, self-producing, and self-maintaining-and our goal is to explore these processes and suggest how they can explain the reciprocity of perception and action. Specifically, we argue that the reciprocal coupling is founded primarily on their endogenous roles in the constitutive autonomy of the agent and an associated circular causality of global and local processes of self-regulation, rather than being a mutual sensory-motor contingency that derives from exogenous behavior. Furthermore, the coupling occurs first and foremost via the internal milieu realized by the agent's organismic embodiment. Finally, we consider how homeostasis and the related concept of allostasis contribute to this circular self-regulation. PMID- 26579044 TI - Complementary fMRI and EEG evidence for more efficient neural processing of rhythmic vs. unpredictably timed sounds. AB - The brain's fascinating ability to adapt its internal neural dynamics to the temporal structure of the sensory environment is becoming increasingly clear. It is thought to be metabolically beneficial to align ongoing oscillatory activity to the relevant inputs in a predictable stream, so that they will enter at optimal processing phases of the spontaneously occurring rhythmic excitability fluctuations. However, some contexts have a more predictable temporal structure than others. Here, we tested the hypothesis that the processing of rhythmic sounds is more efficient than the processing of irregularly timed sounds. To do this, we simultaneously measured functional magnetic resonance imaging (fMRI) and electro-encephalograms (EEG) while participants detected oddball target sounds in alternating blocks of rhythmic (e.g., with equal inter-stimulus intervals) or random (e.g., with randomly varied inter-stimulus intervals) tone sequences. Behaviorally, participants detected target sounds faster and more accurately when embedded in rhythmic streams. The fMRI response in the auditory cortex was stronger during random compared to random tone sequence processing. Simultaneously recorded N1 responses showed larger peak amplitudes and longer latencies for tones in the random (vs. the rhythmic) streams. These results reveal complementary evidence for more efficient neural and perceptual processing during temporally predictable sensory contexts. PMID- 26579045 TI - Is it time for a new measurement approach? A closer look at the assessment of cognitive adaptability in complex problem solving. PMID- 26579046 TI - Mirror neuron system based therapy for aphasia rehabilitation. AB - OBJECTIVE: To investigate the effect of hand action observation training, i.e., mirror neuron system (MNS) based training, on language function of aphasic patients after stroke. In addition, to reveal the tentative mechanism underlying this effect. METHODS: Six aphasic patients after stroke, meeting the criteria, undergo 3 weeks' training protocol (30 min per day, 6 days per week). Among them, four patients accepted an ABA training design, i.e., they implemented Protocol A (hand action observation combined with repetition) in the first and third weeks and carried out Protocol B (static object observation combined with repetition) in the second week. Conversely, for the other two patients, BAB training design was adopted, i.e., patients took Protocol B in the first and third weeks and accepted Protocol A in the second week. Picture naming test, western aphasia battery (WAB) and Token Test were applied to evaluate the changes of language function before and after each week's training. Furthermore, two subjects (one aphasic patient and one healthy volunteer) attended a functional MRI (fMRI) experiment, by which we tried to reveal the mechanism underlying possible language function changes after training. RESULTS: Compared with static object observation and repetition training (Protocol B), hand action observation and repetition training (Protocol A) effectively improved most aspects of the language function in all six patients, as demonstrated in the picture naming test, subtests of oral language and aphasia quotient (AQ) of WAB. In addition, the fMRI experiment showed that Protocol A induced more activations in the MNS of one patient and one healthy control when compared to Protocol B. CONCLUSION: The mirror neuron based therapy may facilitate the language recovery for aphasic patients and this, to some extent, provides a novel direction of rehabilitation for aphasia patients. PMID- 26579047 TI - When deception becomes easy: the effects of task switching and goal neglect on the truth proportion effect. AB - Lying is typically more cognitively demanding than truth telling. Yet, recent cognitive models of lying propose that lying can be just as easy as truth telling, depending on contextual factors. In line with this idea, research has shown that the cognitive cost of deception decreases when people frequently respond deceptively, while it increases when people rarely respond deceptively (i.e., the truth proportion effect). In the present study, we investigated two possible underlying mechanisms of the truth proportion effect. In Experiment 1 (N = 121), we controlled for the impact of switch costs by keeping the number of switches between deceptive and truthful responses constant. We found that people who often responded deceptively made fewer errors when responding deceptively than people who only occasionally responded deceptively, replicating the truth proportion effect. Thus, while the truth proportion effect in earlier studies may be partially driven by the cost of switching between truthful and deceptive responses, we still found evidence for the truth proportion effect while controlling for switch costs. In Experiment 2 (N = 68), we assessed whether the truth proportion effect is influenced by goal neglect. According to this view, the truth proportion effect should be reduced if participants are cued to maintain the task goals, while it should be larger when participants are allowed to neglect the task goals. In line with this hypothesis, we found a smaller truth proportion effect when participants were cued with the task goals compared to when they were not cued. This study shows that the truth proportion effect is influenced by goal neglect, implying that frequent deceptive responding strengthens the goal of responding deceptively. Our findings imply that the accuracy of lie detection tests could be increased by using a majority of truth items (i.e., induce the truth proportion effect), and that the truth proportion effect should be maximized by (1) increasing the number of truth-lie task switches and (2) inducing goal neglect. PMID- 26579048 TI - Arousal and exposure duration affect forward step initiation. AB - Emotion influences parameters of goal-directed whole-body movements in several ways. For instance, previous research has shown that approaching (moving toward) pleasant stimuli is easier compared to approaching unpleasant stimuli. However, some studies found that when emotional pictures are viewed for a longer time, approaching unpleasant stimuli may in fact be facilitated. The effect of viewing duration may have modulated whole-body approach movement in previous research but this has not been investigated to date. In the current study, participants initiated a step forward after viewing neutral, high-arousal pleasant and high arousal unpleasant stimuli. The viewing duration of the stimuli was set to seven different durations, varying from 100 to 4000 ms. Valence and arousal scores were collected for all stimuli. The results indicate that both viewing duration and the arousal of the stimuli influence kinematic parameters in forward gait initiation. Specifically, longer viewing duration, compared to shorter viewing duration, (a) diminished the step length and peak velocity in both neutral and emotional stimuli, (b) increased reaction time in neutral stimuli and, (c) decreased reaction time in pleasant and unpleasant stimuli. Strikingly, no differences were found between high-arousal pleasant and high-arousal unpleasant stimuli. In other words, the valence of the stimuli did not influence kinematic parameters of forward step initiation. Instead the arousal level (neutral: low; pleasant and unpleasant: high) explained the variance found in the results. The kinematics of forward gait initiation seemed to be reflected in the subjective arousal scores, but not the valence scores. So it seems arousal affects forward gait initiation parameters more strongly than valence. In addition, longer viewing duration seemed to cause diminished alertness, affecting GI parameters. These results shed new light on the prevailing theoretical interpretations regarding approach motivation in the literature, which warrants further examination in future research. PMID- 26579049 TI - The modality-switch effect: visually and aurally presented prime sentences activate our senses. AB - Verifying different sensory modality properties for concepts results in a processing cost known as the modality-switch effect. It has been argued that this cognitive cost is the result of a perceptual simulation. This paper extends this argument and reports an experiment investigating whether the effect is the result of an activation of sensory information which can also be triggered by perceptual linguistically described stimuli. Participants were first exposed to a prime sentence describing a light or a sound's perceptual property (e.g., "The light is flickering", "The sound is echoing"), then required to perform a property verification task on a target sentence (e.g., "Butter is yellowish", "Leaves rustle"). The content modalities of the prime and target sentences could be compatible (i.e., in the same modality: e.g., visual-visual) or not (i.e., in different modalities). Crucially, we manipulated the stimuli's presentation modality such that half of the participants was faced with written sentences while the other half was faced with aurally presented sentences. Results show a cost when two different modalities alternate, compared to when the same modality is repeated with both visual and aural stimuli presentations. This result supports the embodied and grounded cognition view which claims that conceptual knowledge is grounded into the perceptual system. Specifically, this evidence suggests that sensory modalities can be pre-activated through the simulation of either read or listened linguistic stimuli describing visual or acoustic perceptual properties. PMID- 26579050 TI - Distractor onset but not preparation time affects the frequency of task confusions in task switching. AB - When participants rapidly switch between tasks that share the same stimuli and responses, task confusions (i.e., the accidental application of the wrong task) can occur. The present study investigated whether these task confusions result from failures of endogenous control (i.e., from ineffective task preparation) or from failures of exogenous control (i.e., from stimulus-induced task conflicts). The frequency of task confusions was estimated by considering the relative proportion of distractor errors, that is, errors that result when participants erroneously respond to the distractor associated with the alternative task. In Experiment 1, the efficiency of exogenous control was manipulated by varying the temporal order of target and distractor presentation. In Experiment 2, the efficiency of endogenous control was manipulated by varying the time available for preparing the task in advance. It turned out that only the efficiency of exogenous control but not the efficiency of endogenous control influenced the proportion of distractor errors. Accordingly, task confusions are more related to failures in exogenous control. PMID- 26579051 TI - The power of simplicity: a fast-and-frugal heuristics approach to performance science. AB - Performance science is a fairly new multidisciplinary field that integrates performance domains such as sports, medicine, business, and the arts. To give its many branches a structure and its research a direction, it requires a theoretical framework. We demonstrate the applications of this framework with examples from sport and medicine. Because performance science deals mainly with situations of uncertainty rather than known risks, the needed framework can be provided by the fast-and-frugal heuristics approach. According to this approach, experts learn to rely on heuristics in an adaptive way in order to make accurate decisions. We investigate the adaptive use of heuristics in three ways: the descriptive study of the heuristics in the cognitive "adaptive toolbox;" the prescriptive study of their "ecological rationality," that is, the characterization of the situations in which a given heuristic works; and the engineering study of "intuitive design," that is, the design of transparent aids for making better decisions. PMID- 26579052 TI - Expert interpretation of bar and line graphs: the role of graphicacy in reducing the effect of graph format. AB - The distinction between informational and computational equivalence of representations, first articulated by Larkin and Simon (1987) has been a fundamental principle in the analysis of diagrammatic reasoning which has been supported empirically on numerous occasions. We present an experiment that investigates this principle in relation to the performance of expert graph users of 2 * 2 "interaction" bar and line graphs. The study sought to determine whether expert interpretation is affected by graph format in the same way that novice interpretations are. The findings revealed that, unlike novices-and contrary to the assumptions of several graph comprehension models-experts' performance was the same for both graph formats, with their interpretation of bar graphs being no worse than that for line graphs. We discuss the implications of the study for guidelines for presenting such data and for models of expert graph comprehension. PMID- 26579053 TI - The curvilinear relationship between work pressure and momentary task performance: the role of state and trait core self-evaluations. AB - Whereas several studies have demonstrated that core self-evaluations (CSE)-or one's appraisals about one's own self-worth, capabilities, and competences-relate to job outcomes, less is known about the mechanisms underlying these relationships. In the present study, we address this issue by examining the role of within- and between-person variation in CSE in the relationship between work pressure and task performance. We hypothesized that (a) work pressure relates to task performance in a curvilinear way, (b) state CSE mediates the curvilinear relationship between work pressure and task performance, and (c) the relationship between work pressure and state CSE is moderated by trait CSE. Our hypotheses were tested via a 10-day daily diary study with 55 employees in which trait CSE was measured at baseline, while work pressure, task performance, and state CSE were assessed on a daily basis. Bayesian multilevel path analysis showed that work pressure affects task performance via state CSE, with state CSE increasing as long as the employee feels that (s)he is able to handle the work pressure, while it decreases when the level of work pressure exceeds the employees' coping abilities. Moreover, we found that for people low on trait CSE, the depleting effect of work pressure via state CSE happens for low levels of work pressure, while for people high in trait CSE the depleting effect is located at high levels of work pressure. Together, our findings suggest that the impact of work pressure on task performance is driven by a complex interplay of between- and within person differences in CSE. PMID- 26579054 TI - Non-contact measurement of facial surface vibration patterns during singing by scanning laser Doppler vibrometer. AB - This paper presents a method of measuring the vibration patterns on facial surfaces by using a scanning laser Doppler vibrometer (LDV). The surfaces of the face, neck, and body vibrate during phonation and, according to Titze (2001), these vibrations occur when aerodynamic energy is efficiently converted into acoustic energy at the glottis. A vocalist's vibration velocity patterns may therefore indicate his or her phonatory status or singing skills. LDVs enable laser-based non-contact measurement of the vibration velocity and displacement of a certain point on a vibrating object, and scanning LDVs permit multipoint measurements. The benefits of scanning LDVs originate from the facts that they do not affect the vibrations of measured objects and that they can rapidly measure the vibration patterns across planes. A case study is presented herein to demonstrate the method of measuring vibration velocity patterns with a scanning LDV. The objective of the experiment was to measure the vibration velocity differences between the modal and falsetto registers while three professional soprano singers sang sustained vowels at four pitch frequencies. The results suggest that there is a possibility that pitch frequency are correlated with vibration velocity. However, further investigations are necessary to clarify the relationships between vibration velocity patterns and phonation status and singing skills. PMID- 26579055 TI - Differential effects of wakeful rest, music and video game playing on working memory performance in the n-back task. AB - The interruption of learning processes by breaks filled with diverse activities is common in everyday life. We investigated the effects of active computer gaming and passive relaxation (rest and music) breaks on working memory performance. Young adults were exposed to breaks involving (i) eyes-open resting, (ii) listening to music and (iii) playing the video game "Angry Birds" before performing the n-back working memory task. Based on linear mixed-effects modeling, we found that playing the "Angry Birds" video game during a short learning break led to a decline in task performance over the course of the task as compared to eyes-open resting and listening to music, although overall task performance was not impaired. This effect was associated with high levels of daily mind wandering and low self-reported ability to concentrate. These findings indicate that video games can negatively affect working memory performance over time when played in between learning tasks. We suggest further investigation of these effects because of their relevance to everyday activity. PMID- 26579056 TI - Visual scanning behavior is related to recognition performance for own- and other age faces. AB - It is well-established that our recognition ability is enhanced for faces belonging to familiar categories, such as own-race faces and own-age faces. Recent evidence suggests that, for race, the recognition bias is also accompanied by different visual scanning strategies for own- compared to other-race faces. Here, we tested the hypothesis that these differences in visual scanning patterns extend also to the comparison between own and other-age faces and contribute to the own-age recognition advantage. Participants (young adults with limited experience with infants) were tested in an old/new recognition memory task where they encoded and subsequently recognized a series of adult and infant faces while their eye movements were recorded. Consistent with findings on the other-race bias, we found evidence of an own-age bias in recognition which was accompanied by differential scanning patterns, and consequently differential encoding strategies, for own-compared to other-age faces. Gaze patterns for own-age faces involved a more dynamic sampling of the internal features and longer viewing time on the eye region compared to the other regions of the face. This latter strategy was extensively employed during learning (vs. recognition) and was positively correlated to discriminability. These results suggest that deeply encoding the eye region is functional for recognition and that the own-age bias is evident not only in differential recognition performance, but also in the employment of different sampling strategies found to be effective for accurate recognition. PMID- 26579057 TI - Perceptual representation and effectiveness of local figure-ground cues in natural contours. AB - A contour shape strongly influences the perceptual segregation of a figure from the ground. We investigated the contribution of local contour shape to figure ground segregation. Although previous studies have reported local contour features that evoke figure-ground perception, they were often image features and not necessarily perceptual features. First, we examined whether contour features, specifically, convexity, closure, and symmetry, underlie the perceptual representation of natural contour shapes. We performed similarity tests between local contours, and examined the contribution of the contour features to the perceptual similarities between the contours. The local contours were sampled from natural contours so that their distribution was uniform in the space composed of the three contour features. This sampling ensured the equal appearance frequency of the factors and a wide variety of contour shapes including those comprised of contradictory factors that induce figure in the opposite directions. This sampling from natural contours is advantageous in order to randomly pickup a variety of contours that satisfy a wide range of cue combinations. Multidimensional scaling analyses showed that the combinations of convexity, closure, and symmetry contribute to perceptual similarity, thus they are perceptual quantities. Second, we examined whether the three features contribute to local figure-ground perception. We performed psychophysical experiments to judge the direction of the figure along the local contours, and examined the contribution of the features to the figure-ground judgment. Multiple linear regression analyses showed that closure was a significant factor, but that convexity and symmetry were not. These results indicate that closure is dominant in the local figure-ground perception with natural contours when the other cues coexist with equal probability including contradictory cases. PMID- 26579059 TI - The role of psychological factors in the career of the independent dancer. AB - Previous research indicates that psychological factors such as motivation and mental skills play an important role in relation to performance and to negotiating talent development stages. However, little is known about these factors in dance, particularly with regard to the independent dancer whose career may involve multiple roles, varied work patterns, and periods of instability. The aim of this study was to explore dancers' motivation to work in an independent capacity, and the extent to which dancers' psychological characteristics and skills enabled them to navigate a career in this demanding sector. In-depth semi structured interviews were conducted with 14 dancers at different stages of their careers. Interviews were transcribed verbatim and content analyzed. Analysis revealed that the dancers were intrinsically motivated and highly committed to the profession. Working in the independent sector offered dancers opportunities for growth and fulfillment; they appreciated the autonomy, flexibility and freedom that the independent career afforded, as well as working with new people across roles and disciplines. In order to overcome the various challenges associated with the independent role, optimism, self-belief, social support, and career management skills were crucial. The mental skills reported by the participants had developed gradually in response to the demands that they faced. Therefore, mental skills training could be invaluable for dancers to help them successfully negotiate the independent sector. PMID- 26579058 TI - Event-related potentials (ERPs) and hemodynamic (functional near-infrared spectroscopy, fNIRS) as measures of schizophrenia deficits in emotional behavior. AB - Recent research evidences supported the significant role of multimethodological neuroscientific approach for the diagnosis and the rehabilitative intervention in schizophrenia. Indeed both electrophysiological and neuroimaging measures in integration each other appear able to furnish a deep overview of the cognitive and affective behavior in schizophrenia patients (SPs). The aim of the present review is focused on the emotional dysfunctional response taking into account the multimeasures for emotional behavior, i.e., the event-related potentials (ERPs) and the hemodynamic profile functional near-infrared spectroscopy (fNIRS). These measures may be considered as predictive measures of the SPs' deficits in emotional behavior. The integration between ERP and fNIRS may support both the prefrontal cortical localization anomaly and the attentional bias toward some specific emotional conditions (mainly negative). PMID- 26579060 TI - Causal explanations within weak and incomplete theories. PMID- 26579061 TI - The effect of loving-kindness meditation on positive emotions: a meta-analytic review. AB - While it has been suggested that loving-kindness meditation (LKM) is an effective practice for promoting positive emotions, the empirical evidence in the literature remains unclear. Here, we provide a systematic review of 24 empirical studies (N = 1759) on LKM with self-reported positive emotions. The effect of LKM on positive emotions was estimated with meta-analysis, and the influence of variations across LKM interventions was further explored with subgroup analysis and meta-regression. The meta-analysis showed that (1) medium effect sizes for LKM interventions on daily positive emotions in both wait-list controlled RCTs and non-RCT studies; and (2) small to large effect sizes for the on-going practice of LKM on immediate positive emotions across different comparisons. Further analysis showed that (1) interventions focused on loving-kindness had medium effect size, but interventions focused on compassion showed small effect sizes; (2) the length of interventions and the time spent on meditation did not influence the effect sizes, but the studies without didactic components in interventions had small effect sizes. A few individual studies reported that the nature of positive emotions and individual differences also influenced the results. In sum, LKM practice and interventions are effective in enhancing positive emotions, but more studies are needed to identify the active components of the interventions, to compare different psychological operations, and to explore the applicability in clinical populations. PMID- 26579062 TI - Figure-ground organization and the emergence of proto-objects in the visual cortex. AB - A long history of studies of perception has shown that the visual system organizes the incoming information early on, interpreting the 2D image in terms of a 3D world and producing a structure that provides perceptual continuity and enables object-based attention. Recordings from monkey visual cortex show that many neurons, especially in area V2, are selective for border ownership. These neurons are edge selective and have ordinary classical receptive fields (CRF), but in addition their responses are modulated (enhanced or suppressed) depending on the location of a 'figure' relative to the edge in their receptive field. Each neuron has a fixed preference for location on one side or the other. This selectivity is derived from the image context far beyond the CRF. This paper reviews evidence indicating that border ownership selectivity reflects the formation of early object representations ('proto-objects'). The evidence includes experiments showing (1) reversal of border ownership signals with change of perceived object structure, (2) border ownership specific enhancement of responses in object-based selective attention, (3) persistence of border ownership signals in accordance with continuity of object perception, and (4) remapping of border ownership signals across saccades and object movements. Findings 1 and 2 can be explained by hypothetical grouping circuits that sum contour feature signals in search of objectness, and, via recurrent projections, enhance the corresponding low-level feature signals. Findings 3 and 4 might be explained by assuming that the activity of grouping circuits persists and can be remapped. Grouping, persistence, and remapping are fundamental operations of vision. Finding these operations manifest in low-level visual areas challenges traditional views of visual processing. New computational models need to be developed for a comprehensive understanding of the function of the visual cortex. PMID- 26579063 TI - Memory behavior requires knowledge structures, not memory stores. PMID- 26579064 TI - How peer-review constrains cognition: on the frontline in the knowledge sector. AB - Peer-review is neither reliable, fair, nor a valid basis for predicting 'impact': as quality control, peer-review is not fit for purpose. Endorsing the consensus, I offer a reframing: while a normative social process, peer-review also shapes the writing of a scientific paper. In so far as 'cognition' describes enabling conditions for flexible behavior, the practices of peer-review thus constrain knowledge-making. To pursue cognitive functions of peer-review, however, manuscripts must be seen as 'symbolizations', replicable patterns that use technologically enabled activity. On this bio-cognitive view, peer-review constrains knowledge-making by writers, editors, reviewers. Authors are prompted to recursively re-aggregate symbolizations to present what are deemed acceptable knowledge claims. How, then, can recursive re-embodiment be explored? In illustration, I sketch how the paper's own content came to be re-aggregated: agonistic review drove reformatting of argument structure, changes in rhetorical ploys and careful choice of wordings. For this reason, the paper's knowledge claims can be traced to human activity that occurs in distributed cognitive systems. Peer-review is on the frontline in the knowledge sector in that it delimits what can count as knowing. Its systemic nature is therefore crucial to not only discipline-centered 'real' science but also its 'post-academic' counterparts. PMID- 26579065 TI - Retrospective Evaluation of Deep Transcranial Magnetic Stimulation as Add-On Treatment for Parkinson's Disease. AB - OBJECTIVE: To evaluate the safety and assess the different symptom improvements found after a combined low-frequency primary motor cortex and high-frequency prefrontal cortex (PFC) stimulation using the deep TMS (dTMS) H-coil, as an add on treatment for Parkinson's disease (PD). METHODS: Forty-five PD patients underwent 14 dTMS sessions; each consisting of 1 Hz stimulation of the primary motor cortex for 15 min, followed by 10 Hz stimulation of the PFC for 15 min. Clinical assessments were performed, BEFORE, at the MIDDLE, and END of therapy as well as at FOLLOW-UP after 30 days, using Movement Disorder Society-Unified Parkinson's Disease Rating Scale, TINETTI, UP&GO, SCOPA, HDRS21, Beck Depression Inventory, and self-applied daily motor assessment scales. RESULTS: Treatment was well-tolerated, without serious adverse effects. dTMS-induced significant PD symptom improvements at END and at FOLLOW-UP, in all subscales of the UPDRS, gait speed, depressive symptoms, balance, autonomic symptoms, and a 73% increase in daily ON time. CONCLUSION: In the cohort of PD patients treated, dTMS was well tolerated with only minor adverse effects. The dTMS-induced significant improvements in motor, postural, and motivational symptoms of PD patients and may potentiate concurrent levodopa treatment. SIGNIFICANCE: The present study demonstrates that dTMS may have a much wider spectrum of beneficial effects than previously reported for TMS, including enhancement of levodopa effects, suggesting that future clinical trials with dTMS should include a broader range of symptom measurements. PMID- 26579066 TI - Multi-Modal Imaging of Neural Correlates of Motor Speed Performance in the Trail Making Test. AB - The assessment of motor and executive functions following stroke or traumatic brain injury is a key aspect of impairment evaluation and used to guide further therapy. In clinical routine, such assessments are largely dominated by pen-and paper tests. While these provide standardized, reliable, and ecologically valid measures of the individual level of functioning, rather little is yet known about their neurobiological underpinnings. Therefore, the aim of this study was to investigate brain regions and their associated networks that are related to upper extremity motor function, as quantified by the motor speed subtest of the trail making test (TMT-MS). Whole-brain voxel-based morphometry and whole-brain tract based spatial statistics were used to investigate the association between TMT-MS performance with gray-matter volume (GMV) and white-matter integrity, respectively. While results demonstrated no relationship to local white-matter properties, we found a significant correlation between TMT-MS performance and GMV of the lower bank of the inferior frontal sulcus, a region associated with cognitive processing, as indicated by assessing its functional profile by the BrainMap database. Using this finding as a seed region, we further examined and compared networks as reflected by resting state connectivity, meta-analytic connectivity modeling, structural covariance, and probabilistic tractography. While differences between the different approaches were observed, all approaches converged on a network comprising regions that overlap with the multiple-demand network. Our data therefore indicate that performance may primarily depend on executive function, thus suggesting that motor speed in a more naturalistic setting should be more associated with executive rather than primary motor function. Moreover, results showed that while there were differences between the approaches, a convergence indicated that common networks can be revealed across highly divergent methods. PMID- 26579068 TI - Sleep Parameters, Functional Status, and Time Post-Stroke are Associated with Offline Motor Skill Learning in People with Chronic Stroke. AB - BACKGROUND: Mounting evidence demonstrates that individuals with stroke benefit from sleep to enhance learning of a motor task. While stage NREM2 sleep and REM sleep have been associated with offline motor skill learning in neurologically intact individuals, it remains unknown which sleep parameters or specific sleep stages are associated with offline motor skill learning in individuals with stroke. METHODS: Twenty individuals with chronic stroke (>6 months following stroke) and 10 control participants slept for three consecutive nights in a sleep laboratory with polysomnography. Participants practiced a tracking task the morning before the third night and underwent a retention test the morning following the third night. Offline learning on the tracking task was assessed. Pearson's correlations assessed for associations between the magnitude of offline learning and sleep variables, age, upper-extremity motor function, stroke severity, depression, and time since stroke occurrence. RESULTS: Individuals with stroke performed with significantly less error on the tracking task following a night of sleep (p = 0.006) while the control participants did not (p = 0.816). Increased sleep efficiency (r = -0.285), less time spent in stage NREM3 sleep (r = 0.260), and more time spent in stage REM sleep (r = -0.266) were weakly-to moderately associated with increased magnitude of offline motor learning. Furthermore, higher upper-extremity motor function (r = -0.400), lower stroke severity (r = 0.360), and less time since stroke occurrence (r = 0.311) were moderately associated with increased magnitude of offline motor learning. CONCLUSION: This study is the first study to provide insight into which sleep stages and individual characteristics may be associated with offline learning in people with stroke. Further research is needed to delineate which factors or combination of factors promote offline motor learning in people with neurologic injury to best promote motor recovery in these individuals. PMID- 26579067 TI - Modeling Chronic Traumatic Encephalopathy: The Way Forward for Future Discovery. AB - Despite the extensive media coverage associated with the diagnosis of chronic traumatic encephalopathy (CTE), our fundamental understanding of the disease pathophysiology remains in its infancy. Only recently have scientific laboratories and personnel begun to explore CTE pathophysiology through the use of preclinical models of neurotrauma. Some studies have shown the ability to recapitulate some aspects of CTE in rodent models, through the use of various neuropathological, biochemical, and/or behavioral assays. Many questions related to CTE development, however, remain unanswered. These include the role of impact severity, the time interval between impacts, the age at which impacts occur, and the total number of impacts sustained. Other important variables such as the location of impacts, character of impacts, and effect of environment/lifestyle and genetics also warrant further study. In this work, we attempt to address some of these questions by exploring work previously completed using single- and repetitive-injury paradigms. Despite some models producing some deficits similar to CTE symptoms, it is clear that further studies are required to understand the development of neuropathological and neurobehavioral features consistent with CTE like features in rodents. Specifically, acute and chronic studies are needed that characterize the development of tau-based pathology. PMID- 26579070 TI - Reducing Errors in Transition from Acute Stroke Hospitalization to Inpatient Rehabilitation. AB - OBJECTIVE: Effective stroke care does not end with acute treatment during hospitalization, but extends through rehabilitation and secondary stroke prevention. In transitions across care environments, stroke patients are vulnerable to errors in communication of diagnosis and treatment. This study aimed to demonstrate that formalized communication between the neurology team and the rehabilitation medicine team would promote secondary stroke prevention and minimize interruptions during rehabilitation. METHODS: The intervention was a standardized verbal handoff by phone between the discharging neurology resident and the admitting rehabilitation resident regarding each patient at transfer. This retrospective cohort study compared a pre-intervention control group (September 2012 to February 2013) and a post-intervention group transferred with the handoff (September 2013 to January 2014). The outcomes measured included errors in communication of stroke severity, stroke mechanism, medications, and recommended follow-up (appointments and tests) as well as emergent brain imaging, return to the acute care facility, and readmission. RESULTS: The pre- and post intervention groups were similar with respect to number of patients (50 vs. 52) and demographics including gender (52 vs. 54% female), age (65.8 vs. 64.0 years), severity of illness as measured by the National Institutes of Health Stroke Scale (NIHSS) (10 vs. 6.5), and stroke type (84 vs. 77% ischemic). Implementation of the handoff decreased errors in communication of diagnosis (NIHSS 92 vs. 74%, p = 0.02; stroke mechanism 54 vs. 30%, p = 0.02). Furthermore, the handoff decreased the proportion with errors in reconciliation of critical medications (42 vs. 23%, p = 0.04). However, the intervention did not significantly reduce interruptions of the rehabilitation program, such as emergent brain imaging (8 vs. 12%, p = 0.55), or transfers back to the acute care hospital (26 vs. 21%, p = 0.56). CONCLUSION: Standardized handoffs decreased errors in communication of diagnosis and critical medications for secondary stroke prevention. PMID- 26579071 TI - The Virtual Brain: Modeling Biological Correlates of Recovery after Chronic Stroke. AB - There currently remains considerable variability in stroke survivor recovery. To address this, developing individualized treatment has become an important goal in stroke treatment. As a first step, it is necessary to determine brain dynamics associated with stroke and recovery. While recent methods have made strides in this direction, we still lack physiological biomarkers. The Virtual Brain (TVB) is a novel application for modeling brain dynamics that simulates an individual's brain activity by integrating their own neuroimaging data with local biophysical models. Here, we give a detailed description of the TVB modeling process and explore model parameters associated with stroke. In order to establish a parallel between this new type of modeling and those currently in use, in this work we establish an association between a specific TVB parameter (long-range coupling) that increases after stroke with metrics derived from graph analysis. We used TVB to simulate the individual BOLD signals for 20 patients with stroke and 10 healthy controls. We performed graph analysis on their structural connectivity matrices calculating degree centrality, betweenness centrality, and global efficiency. Linear regression analysis demonstrated that long-range coupling is negatively correlated with global efficiency (P = 0.038), but is not correlated with degree centrality or betweenness centrality. Our results suggest that the larger influence of local dynamics seen through the long-range coupling parameter is closely associated with a decreased efficiency of the system. We thus propose that the increase in the long-range parameter in TVB (indicating a bias toward local over global dynamics) is deleterious because it reduces communication as suggested by the decrease in efficiency. The new model platform TVB hence provides a novel perspective to understanding biophysical parameters responsible for global brain dynamics after stroke, allowing the design of focused therapeutic interventions. PMID- 26579069 TI - A Review of Transcranial Magnetic Stimulation and Multimodal Neuroimaging to Characterize Post-Stroke Neuroplasticity. AB - Following stroke, the brain undergoes various stages of recovery where the central nervous system can reorganize neural circuitry (neuroplasticity) both spontaneously and with the aid of behavioral rehabilitation and non-invasive brain stimulation. Multiple neuroimaging techniques can characterize common structural and functional stroke-related deficits, and importantly, help predict recovery of function. Diffusion tensor imaging (DTI) typically reveals increased overall diffusivity throughout the brain following stroke, and is capable of indexing the extent of white matter damage. Magnetic resonance spectroscopy (MRS) provides an index of metabolic changes in surviving neural tissue after stroke, serving as a marker of brain function. The neural correlates of altered brain activity after stroke have been demonstrated by abnormal activation of sensorimotor cortices during task performance, and at rest, using functional magnetic resonance imaging (fMRI). Electroencephalography (EEG) has been used to characterize motor dysfunction in terms of increased cortical amplitude in the sensorimotor regions when performing upper limb movement, indicating abnormally increased cognitive effort and planning in individuals with stroke. Transcranial magnetic stimulation (TMS) work reveals changes in ipsilesional and contralesional cortical excitability in the sensorimotor cortices. The severity of motor deficits indexed using TMS has been linked to the magnitude of activity imbalance between the sensorimotor cortices. In this paper, we will provide a narrative review of data from studies utilizing DTI, MRS, fMRI, EEG, and brain stimulation techniques focusing on TMS and its combination with uni- and multimodal neuroimaging methods to assess recovery after stroke. Approaches that delineate the best measures with which to predict or positively alter outcomes will be highlighted. PMID- 26579072 TI - Pathogenic microRNAs Common to Brain and Retinal Degeneration; Recent Observations in Alzheimer's Disease and Age-Related Macular Degeneration. PMID- 26579073 TI - Affinity Chromatography of Native and Recombinant Proteins from Receptors for Insulin and IGF-I to Recombinant Single Chain Antibodies. AB - Affinity chromatography is an efficient method to isolate proteins by taking advantage of their affinities for specific molecules such as substrates, inhibitors, antigens, ligands, antibodies, and other interacting molecules, including subunits. Nowadays, we take the effectiveness and excellence of this technology for granted. This essay will mainly cover the use of affinity chromatography based on my experience. PMID- 26579074 TI - Geomicrobiology of sublacustrine thermal vents in Yellowstone Lake: geochemical controls on microbial community structure and function. AB - Yellowstone Lake (Yellowstone National Park, WY, USA) is a large high-altitude (2200 m), fresh-water lake, which straddles an extensive caldera and is the center of significant geothermal activity. The primary goal of this interdisciplinary study was to evaluate the microbial populations inhabiting thermal vent communities in Yellowstone Lake using 16S rRNA gene and random metagenome sequencing, and to determine how geochemical attributes of vent waters influence the distribution of specific microorganisms and their metabolic potential. Thermal vent waters and associated microbial biomass were sampled during two field seasons (2007-2008) using a remotely operated vehicle (ROV). Sublacustrine thermal vent waters (circa 50-90 degrees C) contained elevated concentrations of numerous constituents associated with geothermal activity including dissolved hydrogen, sulfide, methane and carbon dioxide. Microorganisms associated with sulfur-rich filamentous "streamer" communities of Inflated Plain and West Thumb (pH range 5-6) were dominated by bacteria from the Aquificales, but also contained thermophilic archaea from the Crenarchaeota and Euryarchaeota. Novel groups of methanogens and members of the Korarchaeota were observed in vents from West Thumb and Elliot's Crater (pH 5-6). Conversely, metagenome sequence from Mary Bay vent sediments did not yield large assemblies, and contained diverse thermophilic and nonthermophilic bacterial relatives. Analysis of functional genes associated with the major vent populations indicated a direct linkage to high concentrations of carbon dioxide, reduced sulfur (sulfide and/or elemental S), hydrogen and methane in the deep thermal ecosystems. Our observations show that sublacustrine thermal vents in Yellowstone Lake support novel thermophilic communities, which contain microorganisms with functional attributes not found to date in terrestrial geothermal systems of YNP. PMID- 26579075 TI - Genome reconstructions indicate the partitioning of ecological functions inside a phytoplankton bloom in the Amundsen Sea, Antarctica. AB - Antarctica polynyas support intense phytoplankton blooms, impacting their environment by a substantial depletion of inorganic carbon and nutrients. These blooms are dominated by the colony-forming haptophyte Phaeocystis antarctica and they are accompanied by a distinct bacterial population. Yet, the ecological role these bacteria may play in P. antarctica blooms awaits elucidation of their functional gene pool and of the geochemical activities they support. Here, we report on a metagenome (~160 million reads) analysis of the microbial community associated with a P. antarctica bloom event in the Amundsen Sea polynya (West Antarctica). Genomes of the most abundant Bacteroidetes and Proteobacteria populations have been reconstructed and a network analysis indicates a strong functional partitioning of these bacterial taxa. Three of them (SAR92, and members of the Oceanospirillaceae and Cryomorphaceae) are found in close association with P. antarctica colonies. Distinct features of their carbohydrate, nitrogen, sulfur and iron metabolisms may serve to support mutualistic relationships with P. antarctica. The SAR92 genome indicates a specialization in the degradation of fatty acids and dimethylsulfoniopropionate (compounds released by P. antarctica) into dimethyl sulfide, an aerosol precursor. The Oceanospirillaceae genome carries genes that may enhance algal physiology (cobalamin synthesis). Finally, the Cryomorphaceae genome is enriched in genes that function in cell or colony invasion. A novel pico-eukaryote, Micromonas related genome (19.6 Mb, ~94% completion) was also recovered. It contains the gene for an anti-freeze protein, which is lacking in Micromonas at lower latitudes. These draft genomes are representative for abundant microbial taxa across the Southern Ocean surface. PMID- 26579076 TI - Bacteria in a wood fungal disease: characterization of bacterial communities in wood tissues of esca-foliar symptomatic and asymptomatic grapevines. AB - Esca is a grapevine trunk disease (GTD) associated with different pathogenic fungi inhabiting the woody tissues. Bacteria can also be found in such tissues and they may interact with these fungal colonizers. Although such types of microbial interactions have been observed for wood diseases in many trees, this has never been studied for grapevine. In this study, the bacterial microflora of different vine status (esca-symptomatic and asymptomatic), different anatomical part (trunk and cordon) and different type of tissues (necrotic or not) have been studied. Based on Single Strand Conformation Polymorphism (SSCP) analyses, data showed that (i) specific complexes of bacterial microflora colonize the wood of both necrotic and non-necrotic tissues of esca-foliar symptomatic and asymptomatic vines, and also that (ii) depending on the anatomical part of the plant, cordon or trunk, differences could be observed between the bacterial communities. Such differences were also revealed through the community-level physiological profiling (CLPP) with Biolog Ecoplates(TM). Two hundred seventeen bacterial strains were also isolated from plant samples and then assigned to bacterial species based on the 16S rRNA genes. Although Bacillus sp. and Pantoea agglomerans were the two most commonly isolated species from all kinds of tissues, various other taxa were also isolated. Inoculation of vine cuttings with 14 different bacterial species, and one GTD fungus, Neofusicoccum parvum, showed no impact of these bacteria on the size of the wood necroses caused by N. parvum. This study showed, therefore, that bacterial communities differ according to the anatomical part (trunk or cordon) and/or the type of tissue (necrotic or non necrotic) of wood of grapevine plants showing external symptoms of esca disease. However, research into bacteria having a role in GTD development needs further studies. PMID- 26579079 TI - Growth and inactivation of Salmonella enterica and Listeria monocytogenes in broth and validation in ground pork meat during simulated home storage abusive temperature and home pan-frying. AB - Ground pork meat with natural microbiota and inoculated with low initial densities (1-10 or 10-100 CFU/g) of Salmonella enterica or Listeria monocytogenes was stored under abusive temperature at 10 degrees C and thermally treated by a simulated home pan-frying procedure. The growth and inactivation characteristics were also evaluated in broth. In ground pork meat, the population of S. enterica increased by less than one log after 12-days of storage at 10 degrees C, whereas L. monocytogenes increased by 2.3 to 2.8 log units. No unusual intrinsic heat resistance of the pathogens was noted when tested in broth at 60 degrees C although shoulders were observed on the inactivation curves of L. monocytogenes. After growth of S. enterica and L. monocytogenes at 10 degrees C for 5 days to levels of 1.95 log CFU/g and 3.10 log CFU/g, respectively, in ground pork meat, their inactivation in the burger subjected to a simulated home pan-frying was studied. After thermal treatment S. enterica was undetectable but L. monocytogenes was recovered in three out of six of the 25 g burger samples. Overall, the present study shows that data on growth and inactivation of broths are indicative but may underestimate as well as overestimate behavior of pathogens and thus need confirmation in food matrix conditions to assess food safety in reasonably foreseen abusive conditions of storage and usual home pan frying of meat burgers in Belgium. PMID- 26579078 TI - Metabolomic insights into the intricate gut microbial-host interaction in the development of obesity and type 2 diabetes. AB - Gut microbiota has recently been proposed as a crucial environmental factor in the development of metabolic diseases such as obesity and type 2 diabetes, mainly due to its contribution in the modulation of several processes including host energy metabolism, gut epithelial permeability, gut peptide hormone secretion, and host inflammatory state. Since the symbiotic interaction between the gut microbiota and the host is essentially reflected in specific metabolic signatures, much expectation is placed on the application of metabolomic approaches to unveil the key mechanisms linking the gut microbiota composition and activity with disease development. The present review aims to summarize the gut microbial-host co-metabolites identified so far by targeted and untargeted metabolomic studies in humans, in association with impaired glucose homeostasis and/or obesity. An alteration of the co-metabolism of bile acids, branched fatty acids, choline, vitamins (i.e., niacin), purines, and phenolic compounds has been associated so far with the obese or diabese phenotype, in respect to healthy controls. Furthermore, anti-diabetic treatments such as metformin and sulfonylurea have been observed to modulate the gut microbiota or at least their metabolic profiles, thereby potentially affecting insulin resistance through indirect mechanisms still unknown. Despite the scarcity of the metabolomic studies currently available on the microbial-host crosstalk, the data-driven results largely confirmed findings independently obtained from in vitro and animal model studies, putting forward the mechanisms underlying the implication of a dysfunctional gut microbiota in the development of metabolic disorders. PMID- 26579080 TI - Analysis of genes that are differentially expressed during the Sclerotinia sclerotiorum-Phaseolus vulgaris interaction. AB - The fungus Sclerotinia sclerotiorum (Lib.) de Bary, one of the most important plant pathogens, causes white mold on a wide range of crops. Crop yield can be dramatically decreased due to this disease, depending on the plant cultivar and environmental conditions. In this study, a suppression subtractive hybridization cDNA library approach was used for the identification of pathogen and plant genes that were differentially expressed during infection of the susceptible cultivar BRS Perola of Phaseolus vulgaris L. A total of 979 unigenes (430 contigs and 549 singletons) were obtained and classified according to their functional categories. The transcriptional profile of 11 fungal genes related to pathogenicity and virulence were evaluated by reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR). Additionally, the temporal expression profile obtained by RT-qPCR was evaluated for the following categories of plant defense-related genes: pathogenesis-related genes (PvPR1, PvPR2, and PvPR3), phenylpropanoid pathway genes (PvIsof, PvFPS1, and 4CL), and genes involved in defense and stress-related categories (PvLox, PvHiprp, PvGST, PvPod, and PvDox). Data obtained in this study provide a starting point for achieving a better understanding of the pathosystem S. sclerotiorum-P. vulgaris. PMID- 26579081 TI - Taxonomic and functional characteristics of microbial communities and their correlation with physicochemical properties of four geothermal springs in Odisha, India. AB - This study describes microbial diversity in four tropical hot springs representing moderately thermophilic environments (temperature range: 40-58 degrees C; pH: 7.2-7.4) with discrete geochemistry. Metagenome sequence data showed a dominance of Bacteria over Archaea; the most abundant phyla were Chloroflexi and Proteobacteria, although other phyla were also present, such as Acetothermia, Nitrospirae, Acidobacteria, Firmicutes, Deinococcus-Thermus, Bacteroidetes, Thermotogae, Euryarchaeota, Verrucomicrobia, Ignavibacteriae, Cyanobacteria, Actinobacteria, Planctomycetes, Spirochaetes, Armatimonadetes, Crenarchaeota, and Aquificae. The distribution of major genera and their statistical correlation analyses with the physicochemical parameters predicted that the temperature, aqueous concentrations of ions (such as sodium, chloride, sulfate, and bicarbonate), total hardness, dissolved solids and conductivity were the main environmental variables influencing microbial community composition and diversity. Despite the observed high taxonomic diversity, there were only little variations in the overall functional profiles of the microbial communities in the four springs. Genes involved in the metabolism of carbohydrates and carbon fixation were the most abundant functional class of genes present in these hot springs. The distribution of genes involved in carbon fixation predicted the presence of all the six known autotrophic pathways in the metagenomes. A high prevalence of genes involved in membrane transport, signal transduction, stress response, bacterial chemotaxis, and flagellar assembly were observed along with genes involved in the pathways of xenobiotic degradation and metabolism. The analysis of the metagenomic sequences affiliated to the candidate phylum Acetothermia from spring TB-3 provided new insight into the metabolism and physiology of yet-unknown members of this lineage of bacteria. PMID- 26579082 TI - Seasonal and spatial patterns of microbial diversity along a trophic gradient in the interconnected lakes of the Osterseen Lake District, Bavaria. AB - The Osterseen Lake District in Bavaria consists of 19 small interconnected lakes that exhibit a pronounced trophic gradient from eutrophic to oligotrophic. It therefore presents a unique model system to address ecological questions regarding niche adaptation and Baas Becking's long standing hypothesis of "everything is everywhere, but the environment selects." Here, we present the first assessment of the microbial diversity in these lakes. We sampled the lakes in August and December and used 454 pyrosequencing of 16S rRNA amplicons to analyze the microbial diversity. The diversity patterns between lakes and seasons were compared and the bacterial community composition was correlated with key chemical and physical parameters. Distinct patterns of bacterial diversity only emerged at the level of individual OTUs (operational taxonomic units), but not at the level of the major bacterial phyla. This emphasizes the high functional and physiological diversity among bacterial species within a phylum and calls for analysis of biodiversity at the level of OTUs in order to understand fine-scale biogeography. We were able to identify a number of cosmopolitan OTUs as well as specialist OTUs that were restricted to certain lakes or seasons, suggesting adaptation to specific ecological niches. PMID- 26579083 TI - Panamanian frog species host unique skin bacterial communities. AB - Vertebrates, including amphibians, host diverse symbiotic microbes that contribute to host disease resistance. Globally, and especially in montane tropical systems, many amphibian species are threatened by a chytrid fungus, Batrachochytrium dendrobatidis (Bd), that causes a lethal skin disease. Bd therefore may be a strong selective agent on the diversity and function of the microbial communities inhabiting amphibian skin. In Panama, amphibian population declines and the spread of Bd have been tracked. In 2012, we completed a field survey in Panama to examine frog skin microbiota in the context of Bd infection. We focused on three frog species and collected two skin swabs per frog from a total of 136 frogs across four sites that varied from west to east in the time since Bd arrival. One swab was used to assess bacterial community structure using 16S rRNA amplicon sequencing and to determine Bd infection status, and one was used to assess metabolite diversity, as the bacterial production of anti-fungal metabolites is an important disease resistance function. The skin microbiota of the three Panamanian frog species differed in OTU (operational taxonomic unit, ~bacterial species) community composition and metabolite profiles, although the pattern was less strong for the metabolites. Comparisons between frog skin bacterial communities from Panama and the US suggest broad similarities at the phylum level, but key differences at lower taxonomic levels. In our field survey in Panama, across all four sites, only 35 individuals (~26%) were Bd infected. There was no clustering of OTUs or metabolite profiles based on Bd infection status and no clear pattern of west-east changes in OTUs or metabolite profiles across the four sites. Overall, our field survey data suggest that different bacterial communities might be producing broadly similar sets of metabolites across frog hosts and sites. Community structure and function may not be as tightly coupled in these skin symbiont microbial systems as it is in many macro systems. PMID- 26579077 TI - HIV-1, methamphetamine and astrocytes at neuroinflammatory Crossroads. AB - As a popular psychostimulant, methamphetamine (METH) use leads to long-lasting, strong euphoric effects. While METH abuse is common in the general population, between 10 and 15% of human immunodeficiency virus-1 (HIV-1) patients report having abused METH. METH exacerbates the severity and onset of HIV-1-associated neurocognitive disorders (HAND) through direct and indirect mechanisms. Repetitive METH use impedes adherence to antiretroviral drug regimens, increasing the likelihood of HIV-1 disease progression toward AIDS. METH exposure also directly affects both innate and adaptive immunity, altering lymphocyte numbers and activity, cytokine signaling, phagocytic function and infiltration through the blood brain barrier. Further, METH triggers the dopamine reward pathway and leads to impaired neuronal activity and direct toxicity. Concurrently, METH and HIV-1 alter the neuroimmune balance and induce neuroinflammation, which modulates a wide range of brain functions including neuronal signaling and activity, glial activation, viral infection, oxidative stress, and excitotoxicity. Pathologically, reactive gliosis is a hallmark of both HIV-1- and METH-associated neuroinflammation. Significant commonality exists in the neurotoxic mechanisms for both METH and HAND; however, the pathways dysregulated in astroglia during METH exposure are less clear. Thus, this review highlights alterations in astrocyte intracellular signaling pathways, gene expression and function during METH and HIV-1 comorbidity, with special emphasis on HAND-associated neuroinflammation. Importantly, this review carefully evaluates interventions targeting astrocytes in HAND and METH as potential novel therapeutic approaches. This comprehensive overview indicates, without a doubt, that during HIV-1 infection and METH abuse, a complex dialog between all neural cells is orchestrated through astrocyte regulated neuroinflammation. PMID- 26579084 TI - Quorum-sensing regulation in staphylococci-an overview. AB - Staphylococci are frequent human commensals and some species can cause disease. Staphylococcus aureus in particular is a dangerous human pathogen. In staphylococci, the ability to sense the bacterial cell density, or quorum, and to respond with genetic adaptations is due to one main system, which is called accessory gene regulator (Agr). The extracellular signal of Agr is a post translationally modified peptide containing a thiolactone structure. Under conditions of high cell density, Agr is responsible for the increased expression of many toxins and degradative exoenzymes, and decreased expression of several colonization factors. This regulation is important for the timing of virulence factor expression during infection and the development of acute disease, while low activity of Agr is associated with chronic staphylococcal infections, such as those involving biofilm formation. Accordingly, drugs inhibiting Agr are being evaluated for their capacity to control acute forms of S. aureus infection. PMID- 26579085 TI - Genetically engineered microorganisms for the detection of explosives' residues. AB - The manufacture and use of explosives throughout the past century has resulted in the extensive pollution of soils and groundwater, and the widespread interment of landmines imposes a major humanitarian risk and prevents civil development of large areas. As most current landmine detection technologies require actual presence at the surveyed areas, thus posing a significant risk to personnel, diverse research efforts are aimed at the development of remote detection solutions. One possible means proposed to fulfill this objective is the use of microbial bioreporters: genetically engineered microorganisms "tailored" to generate an optical signal in the presence of explosives' vapors. The use of such sensor bacteria will allow to pinpoint the locations of explosive devices in a minefield. While no study has yet resulted in a commercially operational system, significant progress has been made in the design and construction of explosives sensing bacterial strains. In this article we review the attempts to construct microbial bioreporters for the detection of explosives, and analyze the steps that need to be undertaken for this strategy to be applicable for landmine detection. PMID- 26579086 TI - Milk kefir: composition, microbial cultures, biological activities, and related products. AB - In recent years, there has been a strong focus on beneficial foods with probiotic microorganisms and functional organic substances. In this context, there is an increasing interest in the commercial use of kefir, since it can be marketed as a natural beverage that has health promoting bacteria. There are numerous commercially available kefir based-products. Kefir may act as a matrix in the effective delivery of probiotic microorganisms in different types of products. Also, the presence of kefir's exopolysaccharides, known as kefiran, which has biological activity, certainly adds value to products. Kefiran can also be used separately in other food products and as a coating film for various food and pharmaceutical products. This article aims to update the information about kefir and its microbiological composition, biological activity of the kefir's microflora and the importance of kefiran as a beneficial health substance. PMID- 26579088 TI - Survey on antimicrobial resistance patterns in Vibrio vulnificus and Vibrio cholerae non-O1/non-O139 in Germany reveals carbapenemase-producing Vibrio cholerae in coastal waters. AB - An increase in the occurrence of potentially pathogenic Vibrio species is expected for waters in Northern Europe as a consequence of global warming. In this context, a higher incidence of Vibrio infections is predicted for the future and forecasts suggest that people visiting and living at the Baltic Sea are at particular risk. This study aimed to investigate antimicrobial resistance patterns among Vibrio vulnificus and Vibrio cholerae non-O1/non-O139 isolates that could pose a public health risk. Antimicrobial susceptibility of 141 V. vulnificus and 184 V. cholerae non-O1/non-O139 strains isolated from German coastal waters (Baltic Sea and North Sea) as well as from patients and retail seafood was assessed by broth microdilution and disk diffusion. Both species were susceptible to most of the agents tested (12 subclasses) and no multidrug resistance was observed. Among V. vulnificus isolates, non-susceptibility was exclusively found toward aminoglycosides. In case of V. cholerae, a noticeable proportion of strains was non-susceptible to aminopenicillins and aminoglycosides. In addition, resistance toward carbapenems, quinolones, and folate pathway inhibitors was sporadically observed. Biochemical testing indicated the production of carbapenemases with unusual substrate specificity in four environmental V. cholerae strains. Most antimicrobial agents recommended for treatment of V. vulnificus and V. cholerae non-O1/non-O139 infections were found to be effective in vitro. However, the occurrence of putative carbapenemase producing V. cholerae in German coastal waters is of concern and highlights the need for systematic monitoring of antimicrobial susceptibility in potentially pathogenic Vibrio spp. in Europe. PMID- 26579087 TI - Colonial vs. planktonic type of growth: mathematical modeling of microbial dynamics on surfaces and in liquid, semi-liquid and solid foods. AB - Predictive models are mathematical expressions that describe the growth, survival, inactivation, or biochemical processes of foodborne bacteria. During processing of contaminated raw materials and food preparation, bacteria are entrapped into the food residues, potentially transferred to the equipment surfaces (abiotic or inert surfaces) or cross-contaminate other foods (biotic surfaces). Growth of bacterial cells can either occur planktonically in liquid or immobilized as colonies. Colonies are on the surface or confined in the interior (submerged colonies) of structured foods. For low initial levels of bacterial population leading to large colonies, the immobilized growth differs from planktonic growth due to physical constrains and to diffusion limitations within the structured foods. Indeed, cells in colonies experience substrate starvation and/or stresses from the accumulation of toxic metabolites such as lactic acid. Furthermore, the micro-architecture of foods also influences the rate and extent of growth. The micro-architecture is determined by (i) the non-aqueous phase with the distribution and size of oil particles and the pore size of the network when proteins or gelling agent are solidified, and by (ii) the available aqueous phase within which bacteria may swarm or swim. As a consequence, the micro-environment of bacterial cells when they grow in colonies might greatly differs from that when they grow planktonically. The broth-based data used for modeling (lag time and generation time, the growth rate, and population level) are poorly transferable to solid foods. It may lead to an over-estimation or under estimation of the predicted population compared to the observed population in food. If the growth prediction concerns pathogen bacteria, it is a major importance for the safety of foods to improve the knowledge on immobilized growth. In this review, the different types of models are presented taking into account the stochastic behavior of single cells in the growth of a bacterial population. Finally, the recent advances in the rules controlling different modes of growth, as well as the methodological approaches for monitoring and modeling such growth are detailed. PMID- 26579089 TI - Shifts in the pelagic ammonia-oxidizing microbial communities along the eutrophic estuary of Yong River in Ningbo City, China. AB - Aerobic ammonia oxidation plays a key role in the nitrogen cycle, and the diversity of the responsible microorganisms is regulated by environmental factors. Abundance and composition of ammonia-oxidizing archaea (AOA) and ammonia oxidizing bacteria (AOB) were investigated in the surface waters along an environmental gradient of the Yong River in Ningbo, East China. Water samples were collected from three pelagic zones: (1) freshwaters in the urban canals of Ningbo, (2) brackish waters in the downstream Yong River, and (3) coastal marine water of Hangzhou Bay. Shifts in activity and diversity of the ammonia-oxidizing microorganisms occurred simultaneously with changes in environmental factors, among which salinity and the availabilities of ammonium and oxygen. The AOA abundance was always higher than that of AOB and was related to the ammonia oxidation activity. The ratios of AOA/AOB in the brackish and marine waters were significantly higher than those found in freshwaters. Both AOA and AOB showed similar community compositions in brackish and marine waters, but only 31 and 35% similarity, respectively, between these waters and the urban inland freshwaters. Most of AOA-amoA sequences from freshwater were affiliated with sequences obtained from terrestrial environments and those collected from brackish and coastal areas were ubiquitous in marine, coastal, and terrestrial ecosystems. All AOB from freshwaters belonged to Nitrosomonas, and the AOB from brackish and marine waters mainly belonged to Nitrosospira. PMID- 26579090 TI - The importance of chorismate mutase in the biocontrol potential of Trichoderma parareesei. AB - Species of Trichoderma exert direct biocontrol activity against soil-borne plant pathogens due to their ability to compete for nutrients and to inhibit or kill their targets through the production of antibiotics and/or hydrolytic enzymes. In addition to these abilities, Trichoderma spp. have beneficial effects for plants, including the stimulation of defenses and the promotion of growth. Here we study the role in biocontrol of the T. parareesei Tparo7 gene, encoding a chorismate mutase (CM), a shikimate pathway branch point leading to the production of aromatic amino acids, which are not only essential components of protein synthesis but also the precursors of a wide range of secondary metabolites. We isolated T. parareesei transformants with the Tparo7 gene silenced. Compared with the wild-type, decreased levels of Tparo7 expression in the silenced transformants were accompanied by reduced CM activity, lower growth rates on different culture media, and reduced mycoparasitic behavior against the phytopathogenic fungi Rhizoctonia solani, Fusarium oxysporum and Botrytis cinerea in dual cultures. By contrast, higher amounts of the aromatic metabolites tyrosol, 2-phenylethanol and salicylic acid were detected in supernatants from the silenced transformants, which were able to inhibit the growth of F. oxysporum and B. cinerea. In in vitro plant assays, Tparo7-silenced transformants also showed a reduced capacity to colonize tomato roots. The effect of Tparo7 silencing on tomato plant responses was examined in greenhouse assays. The growth of plants colonized by the silenced transformants was reduced and the plants exhibited an increased susceptibility to B. cinerea in comparison with the responses observed for control plants. In addition, the plants turned yellowish and were defective in jasmonic acid- and ethylene-regulated signaling pathways which was seen by expression analysis of lipoxygenase 1 (LOX1), ethylene insensitive protein 2 (EIN2) and pathogenesis-related protein 1 (PR-1) genes. PMID- 26579091 TI - A network-based approach to disturbance transmission through microbial interactions. AB - Microbes numerically dominate aquatic ecosystems and play key roles in the biogeochemistry and the health of these environments. Due to their short generations times and high diversity, microbial communities are among the first responders to environmental changes, including natural and anthropogenic disturbances such as storms, pollutant releases, and upwelling. These disturbances affect members of the microbial communities both directly and indirectly through interactions with impacted community members. Thus, interactions can influence disturbance propagation through the microbial community by either expanding the range of organisms affected or buffering the influence of disturbance. For example, interactions may expand the number of disturbance-affected taxa by favoring a competitor or buffer the impacts of disturbance when a potentially disturbance-responsive clade's growth is limited by an essential microbial partner. Here, we discuss the potential to use inferred ecological association networks to examine how disturbances propagate through microbial communities focusing on a case study of a coastal community's response to a storm. This approach will offer greater insight into how disturbances can produce community-wide impacts on aquatic environments following transient changes in environmental parameters. PMID- 26579092 TI - Rapid culture-based diagnosis of pulmonary tuberculosis in developed and developing countries. AB - Culturing Mycobacterium tuberculosis remains the gold standard for the laboratory diagnosis of pulmonary tuberculosis, with 9 million new cases and 1.5 million deaths mainly in developing countries. Reviewing data reported over 20 years yields a state-of-the-art procedure for the routine culture of M. tuberculosis in both developed and developing countries. Useful specimens include sputum, induced sputum, and stools collected in quaternary ammonium preservative-containing sterile cans. The usefulness of other non-invasive specimens remains to be evaluated. Specimens can be collected in a diagnosis kit also containing sampling materials, instructions, laboratory requests, and informed consent. Automated direct LED fluorescence microscopy after auramine staining precedes inoculation of an egg-lecithin-containing culture solid medium under microaerophilic atmosphere, inverted microscope reading or scanning video-imaging detection of colonies and colonies identification by recent molecular methods. This procedure should result in a diagnosis of pulmonary tuberculosis as fast as 5 days. It may be implemented in both developed and developing countries with automated steps replaceable by manual steps depending on local resources. PMID- 26579093 TI - Production of ergothioneine by Methylobacterium species. AB - Metabolomic analysis revealed that Methylobacterium cells accumulate a large amount of ergothioneine (EGT), which is a sulfur-containing, non-proteinogenic, antioxidative amino acid derived from histidine. EGT biosynthesis and its role in methylotrophy and physiology for plant surface-symbiotic Methylobacterium species were investigated in this study. Almost all Methylobacterium type strains can synthesize EGT. We selected one of the most productive strains (M. aquaticum strain 22A isolated from a moss), and investigated the feasibility of fermentative EGT production through optimization of the culture condition. Methanol as a carbon source served as the best substrate for production. The productivity reached up to 1000 MUg/100 ml culture (1200 MUg/g wet weight cells, 6.3 mg/g dry weight) in 38 days. Next, we identified the genes (egtBD) responsible for EGT synthesis, and generated a deletion mutant defective in EGT production. Compared to the wild type, the mutant showed better growth on methanol and on the plant surface as well as severe susceptibility to heat treatment and irradiation of ultraviolet (UV) and sunlight. These results suggested that EGT is not involved in methylotrophy, but is involved in their phyllospheric lifestyle fitness of the genus in natural conditions. PMID- 26579094 TI - Pestivirus infection in reindeer (Rangifer tarandus). AB - Reindeer species (Rangifer tarandus, Linnaeus, 1758) includes wild and semi domesticated ruminants belonging to Capreaolinae subfamily of Cervidae family reared in Eurasia (reindeer subspecies) and North America (caribou subspecies). Herding of reindeer has a great historical, socio-economic and ecological importance, especially to indigenous ethnic minorities. Infectious disease threats may therefore impact not solely the animal population driving it to further extinction and irreversible alterations to the wild environments of northern hemisphere, but also add to cultural changes observed as negative impact of globalization. Introduction of new technologies to control of reindeer migration between dwindling pasture areas and intensification of reindeer husbandry may facilitate the intra- and interspecies transmission of pathogens. The role of the reindeer as a potential BVDV reservoir has been studied, however, the number of publications is rather limited. The observed seroprevalences of the virus varied significantly between different geographical regions with different epidemiological situation. Most frequently limited number of animals studied and the differences in the sensitivities and specificities of the diagnostic test used could have also influenced on the differences between the studies. No pestivirus has been ever detected in free-ranging reindeer, however, a putative pestivirus strain named V60-Krefeld has been isolated from reindeer kept at a German Zoo in the 1990's. The virus was characterized as border disease virus type 2 (BDV-2) closely related to German ovine strains. The cross-neutralization studies of the semi-domesticated reindeer sera from Sweden suggested infection with a strain related to BDV-1 or BDV-2. The available data indicates that reindeer might be infected by a endemic species-specific BDV-like strain. However, the interspecies transmission of BVDV from domestic animals should not be excluded, since the susceptibility of reindeer to BVDV-1 has been confirmed under experimental conditions. PMID- 26579095 TI - Diversity and structure of soil bacterial communities in the Fildes Region (maritime Antarctica) as revealed by 454 pyrosequencing. AB - This study assessed the diversity and composition of bacterial communities in four different soils (human-, penguin-, seal-colony impacted soils and pristine soil) in the Fildes Region (King George Island, Antarctica) using 454 pyrosequencing with bacterial-specific primers targeting the 16S rRNA gene. Proteobacteria, Actinobacteria, Acidobacteria, and Verrucomicrobia were abundant phyla in almost all the soil samples. The four types of soils were significantly different in geochemical properties and bacterial community structure. Thermotogae, Cyanobacteria, Fibrobacteres, Deinococcus-Thermus, and Chlorobi obviously varied in their abundance among the 4 soil types. Considering all the samples together, members of the genera Gaiella, Chloracidobacterium, Nitrospira, Polaromonas, Gemmatimonas, Sphingomonas, and Chthoniobacter were found to predominate, whereas members of the genera Chamaesiphon, Herbaspirillum, Hirschia, Nevskia, Nitrosococcus, Rhodococcus, Rhodomicrobium, and Xanthomonas varied obviously in their abundance among the four soil types. Distance-based redundancy analysis revealed that pH (p < 0.01), phosphate phosphorus (p < 0.01), organic carbon (p < 0.05), and organic nitrogen (p < 0.05) were the most significant factors that correlated with the community distribution of soil bacteria. To our knowledge, this is the first study to explore the soil bacterial communities in human-, penguin-, and seal- colony impacted soils from ice-free areas in maritime Antarctica using high-throughput pyrosequencing. PMID- 26579097 TI - Proteomics of Neisseria gonorrhoeae: the treasure hunt for countermeasures against an old disease. AB - Neisseria gonorrhoeae is an exquisitely adapted, strictly human pathogen and the causative agent of the sexually transmitted infection gonorrhea. This ancient human disease remains a serious problem, occurring at high incidence globally and having a major impact on reproductive and neonatal health. N. gonorrhoeae is rapidly evolving into a superbug and no effective vaccine exists to prevent gonococcal infections. Untreated or inadequately treated gonorrhea can lead to severe sequelae, including pelvic inflammatory disease and infertility in women, epididymitis in men, and sight-threatening conjunctivitis in infants born to infected mothers. Therefore, there is an immediate need for accelerated research toward the identification of molecular targets for development of drugs with new mechanisms of action and preventive vaccine(s). Global proteomic approaches are ideally suited to guide these studies. Recent quantitative proteomics (SILAC, iTRAQ, and ICAT) have illuminated the pathways utilized by N. gonorrhoeae to adapt to different lifestyles and micro-ecological niches within the host, while comparative 2D SDS-PAGE analysis has been used to elucidate spectinomycin resistance mechanisms. Further, high-throughput examinations of cell envelopes and naturally released membrane vesicles have unveiled the ubiquitous and differentially expressed proteins between temporally and geographically diverse N. gonorrhoeae isolates. This review will focus on these different approaches, emphasizing the role of proteomics in the search for vaccine candidates. Although our knowledge of N. gonorrhoeae has been expanded, still far less is known about this bacterium than the closely related N. meningitidis, where genomics- and proteomics-driven studies have led to the successful development of vaccines. PMID- 26579098 TI - Metagenomic sequencing of marine periphyton: taxonomic and functional insights into biofilm communities. AB - Periphyton communities are complex phototrophic, multispecies biofilms that develop on surfaces in aquatic environments. These communities harbor a large diversity of organisms comprising viruses, bacteria, algae, fungi, protozoans, and metazoans. However, thus far the total biodiversity of periphyton has not been described. In this study, we use metagenomics to characterize periphyton communities from the marine environment of the Swedish west coast. Although we found approximately ten times more eukaryotic rRNA marker gene sequences compared to prokaryotic, the whole metagenome-based similarity searches showed that bacteria constitute the most abundant phyla in these biofilms. We show that marine periphyton encompass a range of heterotrophic and phototrophic organisms. Heterotrophic bacteria, including the majority of proteobacterial clades and Bacteroidetes, and eukaryotic macro-invertebrates were found to dominate periphyton. The phototrophic groups comprise Cyanobacteria and the alpha proteobacterial genus Roseobacter, followed by different micro- and macro-algae. We also assess the metabolic pathways that predispose these communities to an attached lifestyle. Functional indicators of the biofilm form of life in periphyton involve genes coding for enzymes that catalyze the production and degradation of extracellular polymeric substances, mainly in the form of complex sugars such as starch and glycogen-like meshes together with chitin. Genes for 278 different transporter proteins were detected in the metagenome, constituting the most abundant protein complexes. Finally, genes encoding enzymes that participate in anaerobic pathways, such as denitrification and methanogenesis, were detected suggesting the presence of anaerobic or low-oxygen micro-zones within the biofilms. PMID- 26579099 TI - Immunization with individual proteins of the Lrp/AsnC family induces protection against Brucella melitensis 16M challenges in mice. AB - Brucellosis is one of the most common zoonoses worldwide. Subunit vaccines are promising for the prevention of human brucellosis. In our previous protective antigen screening studies, we identified a new protective antigen, BMEI0357, which belongs to the Lrp/asnC protein family, a conserved transcriptional regulator in bacteria that is absent in eukaryotes. In the present study, the Brucella genome annotation was screened and a total of six proteins were identified as members of the Lrp/AsnC family. Lrp/AsnC proteins have two domains that are conserved among the family members. However, sequence similarities between these proteins ranged from 9 to 50%, indicating high sequence heterogeneity. To test whether proteins of this family have similar characteristics, all six proteins were cloned and expressed in Escherichia coli. The recombinant proteins were purified and their protective efficacy was evaluated in BALB/c mice challenged with Brucella melitensis 16M. The results show that all six Lrp/AsnC proteins could induce a protective immune response against Brucella melitensis 16M. Antibodies against the Lrp/AsnC proteins were detected in the immunized mice. However, levels of antibodies against these proteins were relatively variable in human brucellosis sera. Taken together, our results show that these six proteins of the Lrp/AsnC family in Brucella could induce protective immune responses in mice. PMID- 26579096 TI - Analyzing the molecular mechanism of lipoprotein localization in Brucella. AB - Bacterial lipoproteins possess diverse structure and functionality, ranging from bacterial physiology to pathogenic processes. As such many lipoproteins, originating from Brucella are exploited as potential vaccines to countermeasure brucellosis infection in the host. These membrane proteins are translocated from the cytoplasm to the cell membrane where they are anchored peripherally by a multifaceted targeting mechanism. Although much research has focused on the identification and classification of Brucella lipoproteins and their potential use as vaccine candidates for the treatment of Brucellosis, the underlying route for the translocation of these lipoproteins to the outer surface of the Brucella (and other pathogens) outer membrane (OM) remains mostly unknown. This is partly due to the complexity of the organism and evasive tactics used to escape the host immune system, the variation in biological structure and activity of lipoproteins, combined with the complex nature of the translocation machinery. The biosynthetic pathway of Brucella lipoproteins involves a distinct secretion system aiding translocation from the cytoplasm, where they are modified by lipidation, sorted by the lipoprotein localization machinery pathway and thereafter equipped for export to the OM. Surface localized lipoproteins in Brucella may employ a lipoprotein flippase or the beta-barrel assembly complex for translocation. This review provides an overview of the characterized Brucella OM proteins that form part of the OM, including a handful of other characterized bacterial lipoproteins and their mechanisms of translocation. Lipoprotein localization pathways in gram negative bacteria will be used as a model to identify gaps in Brucella lipoprotein localization and infer a potential pathway. Of particular interest are the dual topology lipoproteins identified in Escherichia coli and Haemophilus influenza. The localization and topology of these lipoproteins from other gram negative bacteria are well characterized and may be useful to infer a solution to better understand the translocation process in Brucella. PMID- 26579100 TI - Multiplex detection of nine food-borne pathogens by mPCR and capillary electrophoresis after using a universal pre-enrichment medium. AB - Routine microbiological quality analyses in food samples require, in some cases, an initial incubation in pre-enrichment medium. This is necessary in order to ensure that small amounts of pathogenic strains are going to be detected. In this work, a universal pre-enrichment medium has been developed for the simultaneous growth of Bacillus cereus, Campylobacter jejuni, Clostridium perfringens, Cronobacter sakazakii, Escherichia coli, Enterobacteriaceae family (38 species, 27 genera), Listeria monocytogenes, Staphylococcus aureus, Salmonella spp. (two species, 13 strains). Growth confirmation for all these species was achieved in all cases, with excellent enrichments. This was confirmed by plating on the corresponding selective agar media for each bacterium. This GVUM universal pre enrichment medium could be useful in food microbiological analyses, where different pathogenic bacteria must be detected after a pre-enrichment step. Following, a mPCR reaction for detection of all these pathogens was developed, after designing a set of nine oligonucleotide pairs from specific genetic targets on gDNA from each of these bacteria, covering all available strains already sequenced in GenBank for each pathogen type. The detection limits have been 1 Genome Equivalent (GE), with the exception of the Fam. Enterobacteriaceae (5 GEs). We obtained amplification for all targets (from 70 to 251 bp, depending on the bacteria type), showing the capability of this method to detect the most important industrial and sanitary food-borne pathogens from a universal pre enrichment medium. This method includes an initial pre-enrichment step (18 h), followed by a mPCR (2 h) and a capillary electrophoresis (30 min); avoiding the tedious and long lasting growing on solid media required in traditional analysis (1-4 days, depending on the specific pathogen and verification procedure). An external testing of this method was conducted in order to compare classical and mPCR methods. This evaluation was carried out on five types of food matrices (meat, dairy products, prepared foods, canned fish, and pastry products), which were artificially contaminated with each one of the microorganisms, demonstrating the equivalence between both methods (coincidence percentages between both methods ranged from 78 to 92%). PMID- 26579101 TI - Nordihydroguaiaretic acid enhances the activities of aminoglycosides against methicillin- sensitive and resistant Staphylococcus aureus in vitro and in vivo. AB - Infections caused by methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA) are prevalent. MRSA infections are difficult to treat and there are no new classes of antibiotics produced to the market to treat infections caused by the resistant bacteria. Therefore, using antibiotic enhancers to rescue existing classes of antibiotics is an attractive strategy. Nordihydroguaiaretic acid (NDGA) is an antioxidant compound found in extracts from plant Larrea Tridentata. It exhibits antimicrobial activity and may target bacterial cell membrane. Combination efficacies of NDGA with many classes of antibiotics were examined by chequerboard method against 200 clinical isolates of MRSA and MSSA. NDGA in combination with gentamicin, neomycin, and tobramycin was examined by time-kill assays. The synergistic combinations of NDGA and aminoglycosides were tested in vivo using a murine skin infection model. Calculations of the fractional inhibitory concentration index (FICI) showed that NDGA when combined with gentamicin, neomycin, or tobramycin displayed synergistic activities in more than 97% of MSSA and MRSA, respectively. Time kill analysis demonstrated that NDGA significantly augmented the activities of these aminoglycosides against MRSA and MSSA in vitro and in murine skin infection model. The enhanced activity of NDGA resides on its ability to damage bacterial cell membrane leading to accumulation of the antibiotics inside bacterial cells. We demonstrated that NDGA strongly revived the therapeutic potencies of aminoglycosides in vitro and in vivo. This combinational strategy could contribute major clinical implications to treat antibiotic resistant bacterial infections. PMID- 26579102 TI - Current and future resources for functional metagenomics. AB - Functional metagenomics is a powerful experimental approach for studying gene function, starting from the extracted DNA of mixed microbial populations. A functional approach relies on the construction and screening of metagenomic libraries-physical libraries that contain DNA cloned from environmental metagenomes. The information obtained from functional metagenomics can help in future annotations of gene function and serve as a complement to sequence-based metagenomics. In this Perspective, we begin by summarizing the technical challenges of constructing metagenomic libraries and emphasize their value as resources. We then discuss libraries constructed using the popular cloning vector, pCC1FOS, and highlight the strengths and shortcomings of this system, alongside possible strategies to maximize existing pCC1FOS-based libraries by screening in diverse hosts. Finally, we discuss the known bias of libraries constructed from human gut and marine water samples, present results that suggest bias may also occur for soil libraries, and consider factors that bias metagenomic libraries in general. We anticipate that discussion of current resources and limitations will advance tools and technologies for functional metagenomics research. PMID- 26579103 TI - The controversial nature of the Weissella genus: technological and functional aspects versus whole genome analysis-based pathogenic potential for their application in food and health. AB - Despite the use of several Weissella (W.) strains for biotechnological and probiotic purposes, certain species of this genus were found to act as opportunistic pathogens, while strains of W. ceti were recognized to be pathogenic for farmed rainbow trout. Herein, we investigated the pathogenic potential of weissellas based on in silico analyses of the 13 whole genome sequences available to date in the NCBI database. Our screening allowed us to find several virulence determinants such as collagen adhesins, aggregation substances, mucus-binding proteins, and hemolysins in some species. Moreover, we detected several antibiotic resistance-encoding genes, whose presence could increase the potential pathogenicity of some strains, but should not be regarded as an excluding trait for beneficial weissellas, as long as these genes are not present on mobile genetic elements. Thus, selection of weissellas intended to be used as starters or for biotechnological or probiotic purposes should be investigated regarding their safety aspects on a strain to strain basis, preferably also by genome sequencing, since nucleotide sequence heterogeneity in virulence and antibiotic resistance genes makes PCR-based screening unreliable for safety assessments. In this sense, the application of W. confusa and W. cibaria strains as starter cultures or as probiotics should be approached with caution, by carefully selecting strains that lack pathogenic potential. PMID- 26579104 TI - Phylogeography of Yersinia ruckeri reveals effects of past evolutionary events on the current strain distribution and explains variations in the global transmission of enteric redmouth (ERM) disease. AB - Phylogeographic patterns and population genetic structure of Yersinia ruckeri, the pathological agent of enteric redmouth disease (ERM) in salmonids, were investigated on the basis of concatenated multiloci sequences from isolates of different phenotypes obtained between 1965 and 2009 from diverse areas and hosts. Sequence analyses revealed genetic differentiation among subpopulations with the largest genetic distance occurring between subpopulations of Europe and Canada and/or South America. Bayesian analysis indicated the presence of three ancestral population clusters. Mismatch distribution displayed signatures characteristic of changes in size due to demographic and spatial expansions in the overall Y. ruckeri population, and also in the geographically separate subpopulations. Furthermore, a weak signal of isolation by distance was determined. A significant positive correlation between genetic and geographical distances was observed. These results revealed that the population of Y. ruckeri has undergone both ancient and recent population changes that were probably induced by biogeography forces in the past and, much more recently, by adaptive processes forced by aquaculture expansion. These findings have important implications for future studies on Y. ruckeri population dynamics, on the potential role of genetic structure to explain variations in ERM transmission, and on the effect of past evolutionary events on current estimations of gene flow. PMID- 26579105 TI - A detailed view of the intracellular transcriptome of Listeria monocytogenes in murine macrophages using RNA-seq. AB - Listeria monocytogenes is a bacterial pathogen and causative agent for the foodborne infection listeriosis, which is mainly a threat for pregnant, elderly, or immunocompromised individuals. Due to its ability to invade and colonize diverse eukaryotic cell types including cells from invertebrates, L. monocytogenes has become a well-established model organism for intracellular growth. Almost 10 years ago, we and others presented the first whole-genome microarray-based intracellular transcriptome of L. monocytogenes. With the advent of newer technologies addressing transcriptomes in greater detail, we revisit this work, and analyze the intracellular transcriptome of L. monocytogenes during growth in murine macrophages using a deep sequencing based approach. We detected 656 differentially expressed genes of which 367 were upregulated during intracellular growth in macrophages compared to extracellular growth in Brain Heart Infusion broth. This study confirmed ~64% of all regulated genes previously identified by microarray analysis. Many of the regulated genes that were detected in the current study involve transporters for various metals, ions as well as complex sugars such as mannose. We also report changes in antisense transcription, especially upregulations during intracellular bacterial survival. A notable finding was the detection of regulatory changes for a subset of temperate A118-like prophage genes, thereby shedding light on the transcriptional profile of this bacteriophage during intracellular growth. In total, our study provides an updated genome-wide view of the transcriptional landscape of L. monocytogenes during intracellular growth and represents a rich resource for future detailed analysis. PMID- 26579106 TI - Cross-biome comparison of microbial association networks. AB - Clinical and environmental meta-omics studies are accumulating an ever-growing amount of microbial abundance data over a wide range of ecosystems. With a sufficiently large sample number, these microbial communities can be explored by constructing and analyzing co-occurrence networks, which detect taxon associations from abundance data and can give insights into community structure. Here, we investigate how co-occurrence networks differ across biomes and which other factors influence their properties. For this, we inferred microbial association networks from 20 different 16S rDNA sequencing data sets and observed that soil microbial networks harbor proportionally fewer positive associations and are less densely interconnected than host-associated networks. After excluding sample number, sequencing depth and beta-diversity as possible drivers, we found a negative correlation between community evenness and positive edge percentage. This correlation likely results from a skewed distribution of negative interactions, which take place preferentially between less prevalent taxa. Overall, our results suggest an under-appreciated role of evenness in shaping microbial association networks. PMID- 26579108 TI - Potential effects of UV radiation on photosynthetic structures of the bloom forming cyanobacterium Cylindrospermopsis raciborskii CYRF-01. AB - Cyanobacteria are aquatic photosynthetic microorganisms. While of enormous ecological importance, they have also been linked to human and animal illnesses around the world as a consequence of toxin production by some species. Cylindrospermopsis raciborskii, a filamentous nitrogen-fixing cyanobacterium, has attracted considerable attention due to its potential toxicity and ecophysiological adaptability. We investigated whether C. raciborskii could be affected by ultraviolet (UV) radiation. Non-axenic cultures of C. raciborskii were exposed to three UV treatments (UVA, UVB, or UVA + UVB) over a 6 h period, during which cell concentration, viability and ultrastructure were analyzed. UVA and UVA + UVB treatments showed significant negative effects on cell concentration (decreases of 56.4 and 64.3%, respectively). This decrease was directly associated with cell death as revealed by a cell viability fluorescent probe. Over 90% of UVA + UVB- and UVA-treated cells died. UVB did not alter cell concentration, but reduced cell viability in almost 50% of organisms. Transmission electron microscopy (TEM) revealed a drastic loss of thylakoids, membranes in which cyanobacteria photosystems are localized, after all treatments. Moreover, other photosynthetic- and metabolic-related structures, such as accessory pigments and polyphosphate granules, were damaged. Quantitative TEM analyses revealed a 95.8% reduction in cell area occupied by thylakoids after UVA treatment, and reduction of 77.6 and 81.3% after UVB and UVA + UVB treatments, respectively. Results demonstrated clear alterations in viability and photosynthetic structures of C. raciborskii induced by various UV radiation fractions. This study facilitates our understanding of the subcellular organization of this cyanobacterium species, identifies specific intracellular targets of UVA and UVB radiation and reinforces the importance of UV radiation as an environmental stressor. PMID- 26579109 TI - Microbiome composition and geochemical characteristics of deep subsurface high pressure environment, Pyhasalmi mine Finland. AB - Pyhasalmi mine in central Finland provides an excellent opportunity to study microbial and geochemical processes in a deep subsurface crystalline rock environment through near-vertical drill holes that reach to a depth of more than two kilometers below the surface. However, microbial sampling was challenging in this high-pressure environment. Nucleic acid yields obtained were extremely low when compared to the cell counts detected (1.4 * 10(4) cells mL(-1)) in water. The water for nucleic acid analysis went through high decompression (60-130 bar) during sampling, whereas water samples for detection of cell counts by microscopy could be collected with slow decompression. No clear cells could be identified in water that went through high decompression. The high-pressure decompression may have damaged part of the cells and the nucleic acids escaped through the filter. The microbial diversity was analyzed from two drill holes by pyrosequencing amplicons of the bacterial and archaeal 16S rRNA genes and from the fungal ITS regions from both DNA and RNA fractions. The identified prokaryotic diversity was low, dominated by Firmicute, Beta- and Gammaproteobacteria species that are common in deep subsurface environments. The archaeal diversity consisted mainly of Methanobacteriales. Ascomycota dominated the fungal diversity and fungi were discovered to be active and to produce ribosomes in the deep oligotrophic biosphere. The deep fluids from the Pyhasalmi mine shared several features with other deep Precambrian continental subsurface environments including saline, Ca dominated water and stable isotope compositions positioning left from the meteoric water line. The dissolved gas phase was dominated by nitrogen but the gas composition clearly differed from that of atmospheric air. Despite carbon poor conditions indicated by the lack of carbon-rich fracture fillings and only minor amounts of dissolved carbon detected in formation waters, some methane was found in the drill holes. No dramatic differences in gas compositions were observed between different gas sampling methods tested. For simple characterization of gas composition the most convenient way to collect samples is from free flowing fluid. However, compared to a pressurized method a relative decrease in the least soluble gases may appear. PMID- 26579107 TI - Wolbachia and the insect immune system: what reactive oxygen species can tell us about the mechanisms of Wolbachia-host interactions. AB - Wolbachia are intracellular bacteria that infect a vast range of arthropod species, making them one of the most prevalent endosymbionts in the world. Wolbachia's stunning evolutionary success is mostly due to their reproductive parasitism but also to mutualistic effects such as increased host fecundity or protection against pathogens. However, the mechanisms underlying Wolbachia phenotypes, both parasitic and mutualistic, are only poorly understood. Moreover, it is unclear how the insect immune system is involved in these phenotypes and why it is not more successful in eliminating the bacteria. Here we argue that reactive oxygen species (ROS) are likely to be key in elucidating these issues. ROS are essential players in the insect immune system, and Wolbachia infection can affect ROS levels in the host. Based on recent findings, we elaborate a hypothesis that considers the different effects of Wolbachia on the oxidative environment in novel vs. native hosts. We propose that newly introduced Wolbachia trigger an immune response and cause oxidative stress, whereas in coevolved symbioses, infection is not associated with oxidative stress, but rather with restored redox homeostasis. Redox homeostasis can be restored in different ways, depending on whether Wolbachia or the host is in charge. This hypothesis offers a mechanistic explanation for several of the observed Wolbachia phenotypes. PMID- 26579110 TI - Prevalence of extended-spectrum cephalosporin-resistant Escherichia coli in a farrowing farm: ST1121 clone harboring IncHI2 plasmid contributes to the dissemination of bla CMY-2. AB - During a regular monitoring of antimicrobial resistance in a farrowing farm in Southern China, 117 Escherichia coli isolates were obtained from sows and piglets. Compared with the isolates from piglets, the isolates from sows exhibited higher resistance rates to the tested cephalosporins. Correspondingly, the total detection rate of the bla CMY-2/bla CTX-M genes in the sow isolates (34.2%) was also significantly higher than that of the piglet isolates (13.6%; p < 0.05). The bla CMY-2 gene had a relatively high prevalence (11.1%) in the E. coli isolates. MLST and PFGE analysis revealed the clonal spread of ST1121 E. coli in most (7/13) of the bla CMY-2-positive isolates. An indistinguishable IncHI2 plasmid harboring bla CMY-2 was also identified in each of the seven ST1121 E. coli isolates. Complete sequence analysis of this IncHI2 plasmid (pEC5207) revealed that pEC5207 may have originated through recombination of an IncHI2 plasmid with a bla CMY-2-carrying IncA/C plasmid like pCFSAN007427_01. In addition to bla CMY-2, pEC5207 also carried other resistance determinants for aminoglycosides (aacA7), sulfonamides (sul1), as well as heavy metals ions, such as Cu and Ag. The susceptibility testing showed that the pEC5207 can mediate both antibiotic and heavy metal resistance. This highlights the role of pEC5207 in co selection of bla CMY-2-positive isolates under the selective pressure of heavy metals, cephalosporins, and other antimicrobials. In conclusion, clonal spread of an ST1121 type E. coli strain harboring an IncHI2 plasmid contributed to the dissemination of bla CMY-2 in a farrowing farm in Southern China. We also have determined the first complete sequence analysis of a bla CMY-2-carrying IncHI2 plasmid. PMID- 26579111 TI - A fragrant neighborhood: volatile mediated bacterial interactions in soil. AB - There is increasing evidence that volatile organic compounds (VOCs) play essential roles in communication and competition between soil microorganisms. Here we assessed volatile-mediated interactions of a synthetic microbial community in a model system that mimics the natural conditions in the heterogeneous soil environment along the rhizosphere. Phylogenetic different soil bacterial isolates (Burkholderia sp., Dyella sp., Janthinobacterium sp., Pseudomonas sp., and Paenibacillus sp.) were inoculated as mixtures or monoculture in organic-poor, sandy soil containing artificial root exudates (ARE) and the volatile profile and growth were analyzed. Additionally, a two compartment system was used to test if volatiles produced by inter-specific interactions in the rhizosphere can stimulate the activity of starving bacteria in the surrounding, nutrient-depleted soil. The obtained results revealed that both microbial interactions and shifts in microbial community composition had a strong effect on the volatile emission. Interestingly, the presence of a slow growing, low abundant Paenibacillus strain significantly affected the volatile production by the other abundant members of the bacterial community as well as the growth of the interacting strains. Furthermore, volatiles released by mixtures of root-exudates consuming bacteria stimulated the activity and growth of starved bacteria. Besides growth stimulation, also an inhibition in growth was observed for starving bacteria exposed to microbial volatiles. The current work suggests that volatiles produced during microbial interactions in the rhizosphere have a significant long distance effect on microorganisms in the surrounding, nutrient-depleted soil. PMID- 26579112 TI - A rapid real-time quantitative PCR assay to determine the minimal inhibitory extracellular concentration of antibiotics against an intracellular Francisella tularensis Live Vaccine Strain. AB - Francisella tularensis is a highly virulent facultative intracellular bacterium. The lack of a safe and efficient vaccine makes antibiotics the preferred treatment. F. tularensis antibiotic susceptibility tests are based on the in vitro standard CLSI-approved microdilution method for determining the MIC. However, limited data are available regarding the minimal inhibitory extracellular concentration (MIEC) needed to eradicate intracellular bacteria. Here, we evaluated the MIEC values of various WHO-recommended antibiotics and compared the MIEC values to the established MICs. We describe a rapid 3-h quantitative PCR (qPCR) intracellular antibiogram assay, which yields comparable MIEC values to those obtained by the classical 72-h cfu assay. This rapid qPCR assay is highly advantageous in light of the slow growth rates of F. tularensis. Our results showed that the MIECs obtained for doxycycline, chloramphenicol and ciprofloxacin were indicative of intracellular activity. Gentamicin was not effective against intracellular bacteria for at least 32 h post treatment, raising the question of whether slow-penetrating gentamicin should be used for certain stages of the disease. We suggest that the qPCR intracellular antibiogram assay may be used to screen for potentially active antibiotics against intracellular F. tularensis as well as to detect strains with acquired resistance to recommended antibiotics. PMID- 26579113 TI - Hydrologic linkages drive spatial structuring of bacterial assemblages and functioning in alpine floodplains. AB - Microbial community assembly and microbial functions are affected by a number of different but coupled drivers such as local habitat characteristics, dispersal rates, and species interactions. In groundwater systems, hydrological flow can introduce spatial structure and directional dependencies among these drivers. We examined the importance of hydrology in structuring bacterial communities and their function within two alpine floodplains during different hydrological states. Piezometers were installed in stream sediments and surrounding riparian zones to assess hydrological flows and also were used as incubation chambers to examine bacterial community structures and enzymatic functions along hydrological flow paths. Spatial eigenvector models in conjunction with models based on physico-chemical groundwater characteristics were used to evaluate the importance of hydrologically-driven processes influencing bacterial assemblages and their enzymatic activities. Our results suggest a strong influence (up to 40% explained variation) of hydrological connectivity on enzymatic activities. The effect of hydrology on bacterial community structure was considerably less strong, suggesting that assemblages demonstrate large functional plasticity/redundancy. Effect size varied between hydrological periods but flow-related mechanisms always had the most power in explaining both bacterial structure and functioning. Changes in hydrology should be considered in models predicting ecosystem functioning and integrated into ecosystem management strategies for floodplains. PMID- 26579114 TI - Effects of new Torulaspora delbrueckii killer yeasts on the must fermentation kinetics and aroma compounds of white table wine. AB - Torulaspora delbrueckii is becoming widely recommended for improving some specific characteristics of wines. However, its impact on wine quality is still far from satisfactory at the winery level, mostly because it is easily replaced by Saccharomyces cerevisiae-like yeasts during must fermentation. New T. delbrueckii killer strains were here isolated and selected for winemaking. They killed S. cerevisiae yeasts and were able to dominate and complete the fermentation of sterile grape must. Sequential yeast inoculation of non-sterile white must with T. delbrueckii followed by S. cerevisiae did not ensure T. delbrueckii dominance or wine quality improvement. Only a single initial must inoculation at high cell concentrations allowed the T. delbrueckii killer strains to dominate and complete the must fermentation to reach above 11% ethanol, but not the non-killer strains. None of the wines underwent malolactic fermentation as long as the must had low turbidity and pH. Although no statistically significant differences were found in the wine quality score, the S. cerevisiae dominated wines were preferred over the T. delbrueckii-dominated ones because the former had high-intensity fresh fruit aromas while the latter had lower intensity, but nevertheless nice and unusual dried fruit/pastry aromas. Except for ethyl propanoate and 3-ethoxy-1-propanol, which were more abundant in the T. delbrueckii-dominated wines, most of the compounds with fresh fruit odor descriptors, including those with the greatest odor activity values (isoamyl acetate, ethyl hexanoate, and ethyl octanoate), were more abundant in the S. cerevisiae-dominated wines. The low relative concentrations of these fruity compounds made it possible to detect in the T. delbrueckii-dominated wines the low-relative-concentration compounds with dried fruit and pastry odors. An example was gamma-ethoxy-butyrolactone which was significantly more abundant in these wines than in those dominated by S. cerevisiae. PMID- 26579115 TI - Inhibition of Staphylococcus aureus cocktail using the synergies of oregano and rosemary essential oils or carvacrol and 1,8-cineole. AB - This study assessed the inhibitory effects of the essential oils (EOs) from Origanum vulgare L. (OVEO) and Rosmarinus officinalis L. (ROEO), as well as of the its majority individual constituents (ICs) carvacrol (CAR) and 1,8-cineole (CIN), respectively, combined at subinhibitory concentrations against a cocktail of Staphylococcus aureus. The Minimum inhibitory Concentration (MIC) of both OVEO and CAR against S. aureus cocktail was 1.25 MUL/mL, while for ROEO and CIN the MIC value was 10 MUL/mL. The Fractional Inhibitory Concentration Index of the combined EOs or ICs was <=0.5 indicating a synergic interaction. The incorporation of OVEO and ROEO or CAR and CIN at different combinations in cheese and meat broths caused a decrease (p <= 0.05) of initial counts of S. aureus. Combined application of 1/8 MIC OVEO and 1/4 MIC ROEO or 1/4 MIC CAR and 1/4 MIC CIN in meat and cheese samples reduced (p <= 0.05) the viable cells counts and caused morphological changes in S. aureus cells, such as cell shrinkage and appearance of blebbing-like structures on cell surfaces. However, in cheese and meat samples the decrease in viable cell counts was smaller (p <= 0.05) than that observed in cheese and meat broths. These findings reinforce the potential of the use of OVEO and ROEO or CAR and CIN in combination to control S. aureus in cheese and meat matrices. PMID- 26579117 TI - Corrigendum: Recreational drug use among individuals living with HIV in Europe: review of the prevalence, comparison with the general population and HIV guidelines recommendations. PMID- 26579116 TI - An insight into the isolation, enumeration, and molecular detection of Listeria monocytogenes in food. AB - Listeria monocytogenes, a foodborne pathogen that can cause listeriosis through the consumption of food contaminated with this pathogen. The ability of L. monocytogenes to survive in extreme conditions and cause food contaminations have become a major concern. Hence, routine microbiological food testing is necessary to prevent food contamination and outbreaks of foodborne illness. This review provides insight into the methods for cultural detection, enumeration, and molecular identification of L. monocytogenes in various food samples. There are a number of enrichment and plating media that can be used for the isolation of L. monocytogenes from food samples. Enrichment media such as buffered Listeria enrichment broth, Fraser broth, and University of Vermont Medium (UVM) Listeria enrichment broth are recommended by regulatory agencies such as Food and Drug Administration-bacteriological and analytical method (FDA-BAM), US Department of Agriculture-Food and Safety (USDA-FSIS), and International Organization for Standardization (ISO). Many plating media are available for the isolation of L. monocytogenes, for instance, polymyxin acriflavin lithium-chloride ceftazidime aesculin mannitol, Oxford, and other chromogenic media. Besides, reference methods like FDA-BAM, ISO 11290 method, and USDA-FSIS method are usually applied for the cultural detection or enumeration of L. monocytogenes. most probable number technique is applied for the enumeration of L. monocytogenes in the case of low level contamination. Molecular methods including polymerase chain reaction, multiplex polymerase chain reaction, real-time/quantitative polymerase chain reaction, nucleic acid sequence-based amplification, loop-mediated isothermal amplification, DNA microarray, and next generation sequencing technology for the detection and identification of L. monocytogenes are discussed in this review. Overall, molecular methods are rapid, sensitive, specific, time- and labor-saving. In future, there are chances for the development of new techniques for the detection and identification of foodborne with improved features. PMID- 26579118 TI - Regulation of B Cell Differentiation by Intracellular Membrane-Associated Proteins and microRNAs: Role in the Antibody Response. AB - B cells are central to adaptive immunity and their functions in antibody responses are exquisitely regulated. As suggested by recent findings, B cell differentiation is mediated by intracellular membrane structures (including endosomes, lysosomes, and autophagosomes) and protein factors specifically associated with these membranes, including Rab7, Atg5, and Atg7. These factors participate in vesicle formation/trafficking, signal transduction and induction of gene expression to promote antigen presentation, class switch DNA recombination (CSR)/somatic hypermutation (SHM), and generation/maintenance of plasma cells and memory B cells. Their expression is induced in B cells activated to differentiate and further fine-tuned by immune-modulating microRNAs, which coordinates CSR/SHM, plasma cell differentiation, and memory B cell differentiation. These short non-coding RNAs would individually target multiple factors associated with the same intracellular membrane compartments and collaboratively target a single factor in addition to regulating AID and Blimp-1. These, together with regulation of microRNA biogenesis and activities by endosomes and autophagosomes, show that intracellular membranes and microRNAs, two broadly relevant cell constituents, play important roles in balancing gene expression to specify B cell differentiation processes for optimal antibody responses. PMID- 26579119 TI - Opposing Roles of Interferon-Gamma on Cells of the Central Nervous System in Autoimmune Neuroinflammation. AB - Multiple sclerosis (MS) is the principal cause of autoimmune neuroinflammation in humans, and its animal model, experimental autoimmune encephalomyelitis (EAE), is widely used to gain insight about their immunopathological mechanisms for and the development of novel therapies for MS. Most studies on the role of interferon (IFN)-gamma in the pathogenesis and progression of EAE have focused on peripheral immune cells, while its action on central nervous system (CNS)-resident cells has been less explored. In addition to the well-known proinflammatory and damaging effects of IFN-gamma in the CNS, evidence has also endowed this cytokine both a protective and regulatory role in autoimmune neuroinflammation. Recent investigations performed in this research field have exposed the complex role of IFN-gamma in the CNS uncovering unexpected mechanisms of action that underlie these opposing activities on different CNS-resident cell types. The mechanisms behind these two-faced effects of IFN-gamma depend on dose, disease phase, and cell development stage. Here, we will review and discuss the dual role of IFN gamma on CNS-resident cells in EAE highlighting its protective functions and the mechanisms proposed. PMID- 26579121 TI - The Role of Latently Infected B Cells in CNS Autoimmunity. AB - The onset of multiple sclerosis (MS) is caused by both genetic and environmental factors. Among the environmental factors, it is believed that previous infection with Epstein-Barr virus (EBV) may contribute in the development of MS. EBV has been associated with other autoimmune diseases, such as systemic lupus erythematous, and cancers like Burkitt's lymphoma. EBV establishes a life-long latency in B cells with occasional reactivation of the virus throughout the individual's life. The role played by B cells in MS pathology has been largely studied, yet is not clearly understood. In MS patients, Rituximab, a novel treatment that targets CD20(+) B cells, has proven to have successful results in diminishing the number of relapses in remitting relapsing MS; however, the mechanism of how this drug acts has not been clearly established. In this review, we analyze the evidence of how B cells latently infected with EBV might be altering the immune system response and helping in the development of MS. We will also discuss how animal models, such as experimental autoimmune encephalomyelitis (EAE) and murine gammaherpesvirus-68 (gammaHV-68), can be used as powerful tools in the study of the relationship between EBV, MS, and B cells. PMID- 26579120 TI - Cetuximab Reconstitutes Pro-Inflammatory Cytokine Secretions and Tumor Infiltrating Capabilities of sMICA-Inhibited NK Cells in HNSCC Tumor Spheroids. AB - Immunosuppressive factors, such as soluble major histocompatibility complex class I chain-related peptide A (sMICA) and transforming growth factor beta 1 (TGF beta1), are involved in tumor immune escape mechanisms (TIEMs) exhibited by head and neck squamous cell carcinomas (HNSCCs) and may represent opportunities for therapeutic intervention. In order to overcome TIEMs, we investigated the antibody-dependent cellular cytotoxicity (ADCC), cytokine release and retargeted tumor infiltration of sMICA-inhibited patient NK cells expressing Fcgamma receptor IIIa (FcgammaRIIIa, CD16a) in the presence of cetuximab, an anti epidermal growth factor receptor (HER1) monoclonal antibody (mAb). Compared to healthy controls, relapsed HNSCC patients (n = 5), not currently in treatment revealed decreased levels of circulating regulatory NK cell subsets in relation to increased cytotoxic NK cell subpopulations. Elevated sMICA and TGF-beta1 plasma levels correlated with diminished TNFalpha and IFN-gamma release and decreased NKG2D (natural killer group 2 member D)-dependent killing of HNSCC cells by NK cells. Incubation of IL-2-activated patient NK cells with patient plasma containing elevated sMICA or sMICA analogs (shed MICA and recombinant MICA) significantly impaired NKG2D-mediated killing by down-regulation of NKG2D surface expression. Of note, CD16 surface expression levels, pro-apoptotic and activation markers, and viability of patient and healthy donor NK cell subpopulations were not affected by this treatment. Accordingly, cetuximab restored killing activity of sMICA-inhibited patient NK cells against cetuximab coated primary HNSCC cells via ADCC in a dose-dependent manner. Rapid reconstitution of anti-tumor recognition and enhanced tumor infiltration of treated NK cells was monitored by 24 h co-incubation of HNSCC tumor spheroids with cetuximab (1 MUg/ml) and was characterized by increased IFN-gamma and TNFalpha secretion. This data show that the impaired NK cell-dependent tumor surveillance in relapsed HNSCC patients could be reversed by the re-establishment of ADCC-mediated effector cell activity, thus supporting NK cell-based immunotherapy in combination with antineoplastic monoclonal mAbs. PMID- 26579122 TI - Measles Virus Epitope Presentation by HLA: Novel Insights into Epitope Selection, Dominance, and Microvariation. AB - Immunity to infections with measles virus (MV) can involve vigorous human leukocyte antigen (HLA) class I-restricted CD8(+) cytotoxic T cell (CTL) responses. MV, albeit regarded monotypic, is known to undergo molecular evolution across its RNA genome. To address which regions of the MV proteome are eligible for recognition by CD8(+) CTLs and how different HLA class I loci contribute to the epitope display, we interrogated the naturally processed and presented MV peptidome extracted from cell lines expressing in total a broad panel of 16 different common HLA-A, -B, and -C molecules. The repertoire and abundance of MV peptides were bona fide identified by nanoHPLC-MS/MS. -Eighty-nine MV peptides were discovered and assignment to an HLA-A, -B, or -C allele, based on HLA peptide affinity prediction, was in most cases successful. Length variation and presentation by multiple HLA class I molecules was common in the MV peptidome. More than twice as many unique MV epitopes were found to be restricted by HLA-B than by HLA-A, while MV peptides with supra-abundant expression rates (>5,000 cc) were rather associated with HLA-A and HLA-C. In total, 59 regions across the whole MV proteome were identified as targeted by HLA class I. Sequence coverage by epitopes was highest for internal proteins transcribed from the MV-P/V/C and M genes and for hemagglutinin. At the genome level, the majority of the HLA class I-selected MV epitopes represented codons having a higher non-synonymous mutation rate than silent mutation rate, as established by comparison of a set of 58 unique full length MV genomes. Interestingly, more molecular variation was seen for the epitopes expressed at rates >=1,000 cc. These data for the first time indicate that HLA class I broadly samples the MV proteome and that CTL pressure may contribute to the genomic evolution of MV. PMID- 26579123 TI - Editorial: History of Chemoattractant Research. PMID- 26579126 TI - Inflammatory Bowel Disease: Genetics, Epigenetics, and Pathogenesis. AB - Inflammatory bowel diseases (IBDs) are complex, multifactorial disorders characterized by chronic relapsing intestinal inflammation. Although etiology remains largely unknown, recent research has suggested that genetic factors, environment, microbiota, and immune response are involved in the pathogenesis. Epidemiological evidence for a genetic contribution is defined: 15% of patients with Crohn's Disease (CD) have an affected family member with IBD, and twin studies for CD have shown 50% concordance in monozygotic twins compared to <10% in dizygotics. The most recent and largest genetic association studies, which employed genome-wide association data for over 75,000 patients and controls, identified 163 susceptibility loci for IBD. More recently, a trans-ethnic analysis, including over 20,000 individuals, identified an additional 38 new IBD loci. Although most cases are correlated with polygenic contribution toward genetic susceptibility, there is a spectrum of rare genetic disorders that can contribute to early-onset IBD (before 5 years) or very early onset IBD (before 2 years). Genetic variants that cause these disorders have a wide effect on gene function. These variants are so rare in allele frequency that the genetic signals are not detected in genome-wide association studies of patients with IBD. With recent advances in sequencing techniques, ~50 genetic disorders have been identified and associated with IBD-like immunopathology. Monogenic defects have been found to alter intestinal immune homeostasis through many mechanisms. Candidate gene resequencing should be carried out in early-onset patients in clinical practice. The evidence that genetic factors contribute in small part to disease pathogenesis confirms the important role of microbial and environmental factors. Epigenetic factors can mediate interactions between environment and genome. Epigenetic mechanisms could affect development and progression of IBD. Epigenomics is an emerging field, and future studies could provide new insight into the pathogenesis of IBD. PMID- 26579124 TI - Regulation of Macrophage, Dendritic Cell, and Microglial Phenotype and Function by the SOCS Proteins. AB - Macrophages are innate immune cells of dynamic phenotype that rapidly respond to external stimuli in the microenvironment by altering their phenotype to respond to and to direct the immune response. The ability to dynamically change phenotype must be carefully regulated to prevent uncontrolled inflammatory responses and subsequently to promote resolution of inflammation. The suppressor of cytokine signaling (SOCS) proteins play a key role in regulating macrophage phenotype. In this review, we summarize research to date from mouse and human studies on the role of the SOCS proteins in determining the phenotype and function of macrophages. We will also touch on the influence of the SOCS on dendritic cell (DC) and microglial phenotype and function. The molecular mechanisms of SOCS function in macrophages and DCs are discussed, along with how dysregulation of SOCS expression or function can lead to alterations in macrophage/DC/microglial phenotype and function and to disease. Regulation of SOCS expression by microRNA is discussed. Novel therapies and unanswered questions with regard to SOCS regulation of monocyte-macrophage phenotype and function are highlighted. PMID- 26579127 TI - HLA Preferences for Conserved Epitopes: A Potential Mechanism for Hepatitis C Clearance. AB - Hepatitis C virus (HCV) infections affect more than 170 million people worldwide. Most of these individuals are chronically infected, but some clear the infection rapidly. Host factors seem to play a key role in HCV clearance, among them are the human leukocyte antigen (HLA) class I molecules. Certain HLA molecules, e.g., B*27 and B*57, are associated with viral clearance. To identify potential mechanisms for these associations, we assess epitope distribution differences between HLA molecules using experimentally verified and in silico predicted HCV epitopes. Specifically, we show that the NS5B protein harbors the largest fraction of conserved regions among all HCV proteins. Such conserved regions could be good targets for cytotoxic T-cell (CTL) responses. We find that the protective HLA-B*27 molecule preferentially presents cytotoxic T-cell (CTL) epitopes from NS5B and, in general, presents the most strongly conserved epitopes among the 23 HLA molecules analyzed. In contrast, HLA molecules known to be associated with HCV persistence do not have similar preferences and appear to target the variable P7 protein. Overall, our analysis suggests that by targeting highly constrained - and thereby conserved - regions of HCV, the protective HLA molecule HLA-B*27 reduces the ability of HCV to escape the cytotoxic T-cell response of the host. For visualizing the distribution of both experimentally verified and predicted epitopes across the HCV genome, we created the HCV epitope browser, which is available at theory.bio.uu.nl/ucqi/hcv. PMID- 26579125 TI - Pathogenic Inflammation and Its Therapeutic Targeting in Systemic Lupus Erythematosus. AB - Systemic lupus erythematosus (SLE, lupus) is a highly complex and heterogeneous autoimmune disease that most often afflicts women in their child-bearing years. It is characterized by circulating self-reactive antibodies that deposit in tissues, including skin, kidneys, and brain, and the ensuing inflammatory response can lead to irreparable tissue damage. Over many years, clinical trials in SLE have focused on agents that control B- and T-lymphocyte activation, and, with the single exception of an agent known as belimumab which targets the B-cell survival factor BAFF, they have been disappointing. At present, standard therapy for SLE with mild disease is the agent hydroxychloroquine. During disease flares, steroids are often used, while the more severe manifestations with major organ involvement warrant potent, broad-spectrum immunosuppression with cyclophosphamide or mycophenolate. Current treatments have severe and dose limiting toxicities and thus a more specific therapy targeting a causative factor or signaling pathway would be greatly beneficial in SLE treatment. Moreover, the ability to control inflammation alongside B-cell activation may be a superior approach for disease control. There has been a recent focus on the innate immune system and associated inflammation, which has uncovered key players in driving the pathogenesis of SLE. Delineating some of these intricate inflammatory mechanisms has been possible with studies using spontaneous mouse mutants and genetically engineered mice. These strains, to varying degrees, exhibit hallmarks of the human disease and therefore have been utilized to model human SLE and to test new drugs. Developing a better understanding of the initiation and perpetuation of disease in SLE may uncover suitable novel targets for therapeutic intervention. Here, we discuss the involvement of inflammation in SLE disease pathogenesis, with a focus on several key proinflammatory cytokines and myeloid growth factors, and review the known outcomes or the potential for targeting these factors in SLE. PMID- 26579128 TI - Effector and Central Memory Poly-Functional CD4(+) and CD8(+) T Cells are Boosted upon ZOSTAVAX((r)) Vaccination. AB - ZOSTAVAX((r)) is a live attenuated varicella-zoster virus (VZV) vaccine that is licensed for the protection of individuals >=50 years against shingles and its most common complication, postherpetic neuralgia. While IFNgamma responses increase upon vaccination, the quality of the T cell response has not been elucidated. By using polychromatic flow cytometry, we characterized the breadth, magnitude, and quality of ex vivo CD4(+) and CD8(+) T cell responses induced 3-4 weeks after ZOSTAVAX vaccination of healthy adults. We show, for the first time that the highest frequencies of VZV-specific CD4(+) T cells were poly-functional CD154(+)IFNgamma(+)IL-2(+)TNFalpha(+) cells, which were boosted upon vaccination. The CD4(+) T cells were broadly reactive to several VZV proteins, with immediate early (IE) 63 ranking the highest among them in the fold rise of poly-functional cells, followed by IE62, gB, open reading frame (ORF) 9, and gE. We identified a novel poly-functional ORF9-specific CD8(+) T cell population in 62% of the subjects, and these were boosted upon vaccination. Poly-functional CD4(+) and CD8(+) T cells produced significantly higher levels of IFNgamma, IL-2, and TNFalpha compared to mono-functional cells. After vaccination, a boost in the expression of IFNgamma by poly-functional IE63- and ORF9-specific CD4(+) T cells and IFNgamma, IL-2, and TNFalpha by ORF9-specific poly-functional CD8(+) T cells was observed. Responding poly-functional T cells exhibited both effector (CCR7( )CD45RA(-)CD45RO(+)), and central (CCR7(+)CD45RA(-)CD45RO(+)) memory phenotypes, which expressed comparable levels of cytokines. Altogether, our studies demonstrate that a boost in memory poly-functional CD4(+) T cells and ORF9 specific CD8(+) T cells may contribute toward ZOSTAVAX efficacy. PMID- 26579129 TI - Redirection of Epithelial Immune Responses by Short-Chain Fatty Acids through Inhibition of Histone Deacetylases. AB - Short-chain fatty acids (SCFAs) are products of microbial fermentation that are important for intestinal epithelial health. Here, we describe that SCFAs have rapid and reversible effects on toll-like receptor (TLR) responses in epithelial cells. Incubation of HEK293 or HeLa epithelial cells with the SCFAs butyrate or propionate at physiological concentrations enhanced NF-kappaB activation induced by TLR5, TLR2/1, TLR4, and TLR9 agonists. NF-kappaB activation in response to tumor necrosis factor alpha (TNFalpha) was also increased by SCFAs. Comparative transcript analysis of HT-29 colon epithelial cells revealed that SCFAs enhanced TLR5-induced transcription of TNFalpha but dampened or even abolished the TLR5 mediated induction of IL-8 and monocyte chemotactic protein 1. SCFAs are known inhibitors of histone deacetylases (HDACs). Butyrate or propionate caused a rapid increase in histone acetylation in epithelial cells, similar to the small molecule HDAC inhibitor trichostatin A (TSA). TSA also mimicked the effects of SCFAs on TLR-NF-kappaB responses. This study shows that bacterial SCFAs rapidly alter the epigenetic state of host cells resulting in redirection of the innate immune response and selective reprograming of cytokine/chemokine expression. PMID- 26579130 TI - Correlation of Hsp70 Serum Levels with Gross Tumor Volume and Composition of Lymphocyte Subpopulations in Patients with Squamous Cell and Adeno Non-Small Cell Lung Cancer. AB - Heat-shock protein 70 (Hsp70) is frequently found on the plasma membrane of a large number of malignant tumors including non-small cell lung cancer (NSCLC) and gets released into the blood circulation in lipid vesicles. On the one hand, a membrane (m)Hsp70-positive phenotype correlates with a high aggressiveness of the tumor; on the other hand, mHsp70 serves as a target for natural killer (NK) cells that had been pre-stimulated with Hsp70-peptide TKD plus low-dose interleukin-2 (TKD/IL-2). Following activation, NK cells show an up-regulated expression of activatory C-type lectin receptors, such as CD94/NKG2C, NKG2D, and natural cytotoxicity receptors (NCRs; NKp44, NKp46, and NKp30) and thereby gain the capacity to kill mHsp70-positive tumor cells. With respect to these results, the efficacy of ex vivo TKD/IL-2 stimulated, autologous NK cells is currently tested in a proof-of-concept phase II clinical trial in patients with squamous cell NSCLC after radiochemotherapy (RCT) at the TUM. Inclusion criteria are histological proven, non-resectable NSCLC in stage IIIA/IIIB, clinical responses to RCT and a mHsp70-positive tumor phenotype. The mHsp70 status is determined in the serum of patients using the lipHsp70 ELISA test, which enables the quantification of liposomal and free Hsp70. Squamous cell and adeno NSCLC patients had significantly higher serum Hsp70 levels than healthy controls. A significant correlation of serum Hsp70 levels with the gross tumor volume was shown for adeno and squamous cell NSCLC. However, significantly elevated ratios of activated CD69(+)/CD94(+) NK cells that are associated with low serum Hsp70 levels were observed only in patients with squamous cell lung cancer. These data might provide a first hint that squamous cell NSCLC is more immunogenic than adeno NSCLC. PMID- 26579131 TI - Convergence of External Crohn's Disease Risk Factors on Intestinal Bacteria. AB - Crohn's disease (CD) is an immune-mediated intestinal illness that significantly compromises health in many developed countries. Although definitive causes remain elusive, the required contribution of microbes in the progression of disease has become an accepted concept. Known CD risk factors, such as antibiotic use and acute infectious gastroenteritis, may impact the gut. This concept is now being explored with a view toward understanding the beneficial and unfavorable microbes that may be altered in numbers during such external insults. A comprehensive understanding of the microbial component to CD could be useful clinically as future therapies may focus on preventing risk exposures on susceptible individuals, eliminating harmful microbes, or restoring a protective gut microbiome. Here, we examine how acute infectious gastroenteritis and antibiotic exposure may impact the gut microbiota in the context of inflammation in CD. PMID- 26579132 TI - T Cell Motility as Modulator of Interactions with Dendritic Cells. AB - It is well established that the balance of costimulatory and inhibitory signals during interactions with dendritic cells (DCs) determines T cell transition from a naive to an activated or tolerant/anergic status. Although many of these molecular interactions are well reproduced in reductionist in vitro assays, the highly dynamic motility of naive T cells in lymphoid tissue acts as an additional lever to fine-tune their activation threshold. T cell detachment from DCs providing suboptimal stimulation allows them to search for DCs with higher levels of stimulatory signals, while storing a transient memory of short encounters. In turn, adhesion of weakly reactive T cells to DCs presenting peptides presented on major histocompatibility complex with low affinity is prevented by lipid mediators. Finally, controlled recruitment of CD8(+) T cells to cognate DC-CD4(+) T cell clusters shapes memory T cell formation and the quality of the immune response. Dynamic physiological lymphocyte motility therefore constitutes a mechanism to mitigate low avidity T cell activation and to improve the search for "optimal" DCs, while contributing to peripheral tolerance induction in the absence of inflammation. PMID- 26579133 TI - Comparing the Immunomodulatory Properties of Bone Marrow, Adipose Tissue, and Birth-Associated Tissue Mesenchymal Stromal Cells. AB - Mesenchymal stromal cells (MSC) have gained immense attraction in regenerative medicine, tissue engineering, and immunotherapy. This is based on their differentiation potential and the supply of pro-regenerative and immunomodulatory signals. MSC can be isolated from a multitude of tissue sources, but mainly bone marrow, adipose tissue, and birth-associated tissues (e.g., umbilical cord, cord blood, placenta) appear to be relevant for clinical translation in immune mediated disorders. However, only a few studies directly compared the immunomodulatory potency of MSC from different tissue sources. This review compiles the current literature regarding the similarities and differences between these three sources for MSCs with a special focus on their immunomodulatory effects on T-lymphocyte subsets and monocytes, macrophages, and dendritic cells. PMID- 26579134 TI - Resistance evaluation of Chinese wild Vitis genotypes against Botrytis cinerea and different responses of resistant and susceptible hosts to the infection. AB - The necrotrophic fungus Botrytis cinerea is a major threat to grapevine cultivation worldwide. A screen of 41 Vitis genotypes for leaf resistance to B. cinerea suggested species independent variation and revealed 18 resistant Chinese wild Vitis genotypes, while most investigated V. vinifera, or its hybrids, were susceptible. A particularly resistant Chinese wild Vitis, "Pingli-5" (V. sp. [Qinling grape]) and a very susceptible V. vinifera cultivar, "Red Globe" were selected for further study. Microscopic analysis demonstrated that B. cinerea growth was limited during early infection on "Pingli-5" before 24 h post inoculation (hpi) but not on Red Globe. It was found that reactive oxygen species (ROS) and antioxidative system were associated with fungal growth. O[Formula: see text] accumulated similarly in B. cinerea 4 hpi on both Vitis genotypes. Lower levels of O[Formula: see text] (not H2O2) were detected 4 hpi and ROS (H2O2 and O[Formula: see text]) accumulation from 8 hpi onwards was also lower in "Pingli 5" leaves than in "Red Globe" leaves. B. cinerea triggered sustained ROS production in "Red Globe" but not in "Pingli-5" with subsequent infection progresses. Red Globe displayed little change in antioxidative activities in response to B. cinerea infection, instead, antioxidative activities were highly and timely elevated in resistant "Pingli-5" which correlated with its minimal ROS increases and its high resistance. These findings not only enhance our understanding of the resistance of Chinese wild Vitis species to B. cinerea, but also lay the foundation for breeding B. cinerea resistant grapes in the future. PMID- 26579135 TI - Distribution of circular proteins in plants: large-scale mapping of cyclotides in the Violaceae. AB - During the last decade there has been increasing interest in small circular proteins found in plants of the violet family (Violaceae). These so-called cyclotides consist of a circular chain of approximately 30 amino acids, including six cysteines forming three disulfide bonds, arranged in a cyclic cystine knot (CCK) motif. In this study we map the occurrence and distribution of cyclotides throughout the Violaceae. Plant material was obtained from herbarium sheets containing samples up to 200 years of age. Even the oldest specimens contained cyclotides in the preserved leaves, with no degradation products observable, confirming their place as one of the most stable proteins in nature. Over 200 samples covering 17 of the 23-31 genera in Violaceae were analyzed, and cyclotides were positively identified in 150 species. Each species contained a unique set of between one and 25 cyclotides, with many exclusive to individual plant species. We estimate the number of different cyclotides in the Violaceae to be 5000-25,000, and propose that cyclotides are ubiquitous among all Violaceae species. Twelve new cyclotides from six phylogenetically dispersed genera were sequenced. Furthermore, the first glycosylated derivatives of cyclotides were identified and characterized, further increasing the diversity and complexity of this unique protein family. PMID- 26579136 TI - Species identity and neighbor size surpass the impact of tree species diversity on productivity in experimental broad-leaved tree sapling assemblages under dry and moist conditions. AB - Species diversity may increase the productivity of tree communities through complementarity (CE) and/or selection effects (SE), but it is not well known how this relationship changes under water limitation. We tested the stress-gradient hypothesis, which predicts that resource use complementarity and facilitation are more important under water-limited conditions. We conducted a growth experiment with saplings of five temperate broad-leaved tree species that were grown in assemblages of variable diversity (1, 3, or 5 species) and species composition under ample and limited water supply to examine effects of species richness and species identity on stand- and tree-level productivity. Special attention was paid to effects of neighbor identity on the growth of target trees in mixture as compared to growth in monoculture. Stand productivity was strongly influenced by species identity while a net biodiversity effect (NE) was significant in the moist treatment (mostly assignable to CE) but of minor importance. The growth performance of some of the species in the mixtures was affected by tree neighborhood characteristics with neighbor size likely being more important than neighbor species identity. Diversity and neighbor identity effects visible in the moist treatment mostly disappeared in the dry treatment, disproving the stress gradient hypothesis. The mixtures were similarly sensitive to drought-induced growth reduction as the monocultures, which may relate to the decreased CE on growth upon drought in the mixtures. PMID- 26579137 TI - Evolutionary transgenomics: prospects and challenges. AB - Many advances in our understanding of the genetic basis of species differences have arisen from transformation experiments, which allow us to study the effect of genes from one species (the donor) when placed in the genetic background of another species (the recipient). Such interspecies transformation experiments are usually focused on candidate genes - genes that, based on work in model systems, are suspected to be responsible for certain phenotypic differences between the donor and recipient species. We suggest that the high efficiency of transformation in a few plant species, most notably Arabidopsis thaliana, combined with the small size of typical plant genes and their cis-regulatory regions allow implementation of a screening strategy that does not depend upon a priori candidate gene identification. This approach, transgenomics, entails moving many large genomic inserts of a donor species into the wild type background of a recipient species and then screening for dominant phenotypic effects. As a proof of concept, we recently conducted a transgenomic screen that analyzed more than 1100 random, large genomic inserts of the Alabama gladecress Leavenworthia alabamica for dominant phenotypic effects in the A. thaliana background. This screen identified one insert that shortens fruit and decreases A. thaliana fertility. In this paper we discuss the principles of transgenomic screens and suggest methods to help minimize the frequencies of false positive and false negative results. We argue that, because transgenomics avoids committing in advance to candidate genes it has the potential to help us identify truly novel genes or cryptic functions of known genes. Given the valuable knowledge that is likely to be gained, we believe the time is ripe for the plant evolutionary community to invest in transgenomic screens, at least in the mustard family Brassicaceae where many species are amenable to efficient transformation. PMID- 26579138 TI - The structure of Medicago truncatula delta(1)-pyrroline-5-carboxylate reductase provides new insights into regulation of proline biosynthesis in plants. AB - The two pathways for proline biosynthesis in higher plants share the last step, the conversion of delta(1)-pyrroline-5-carboxylate (P5C) to L-proline, which is catalyzed by P5C reductase (P5CR, EC 1.5.1.2) with the use of NAD(P)H as a coenzyme. There is increasing amount of evidence to suggest a complex regulation of P5CR activity at the post-translational level, yet the molecular basis of these mechanisms is unknown. Here we report the three-dimensional structure of the P5CR enzyme from the model legume Medicago truncatula (Mt). The crystal structures of unliganded MtP5CR decamer, and its complexes with the products NAD(+), NADP(+), and L-proline were refined using x-ray diffraction data (at 1.7, 1.85, 1.95, and 2.1 A resolution, respectively). Based on the presented structural data, the coenzyme preference for NADPH over NADH was explained, and NADPH is suggested to be the only coenzyme used by MtP5CR in vivo. Furthermore, the insensitivity of MtP5CR to feed-back inhibition by proline, revealed by enzymatic analysis, was correlated with structural features. Additionally, a mechanism for the modulation of enzyme activity by chloride anions is discussed, as well as the rationale for the possible development of effective enzyme inhibitors. PMID- 26579139 TI - Beyond conservation agriculture. AB - Global support for Conservation Agriculture (CA) as a pathway to Sustainable Intensification is strong. CA revolves around three principles: no-till (or minimal soil disturbance), soil cover, and crop rotation. The benefits arising from the ease of crop management, energy/cost/time savings, and soil and water conservation led to widespread adoption of CA, particularly on large farms in the Americas and Australia, where farmers harness the tools of modern science: highly sophisticated machines, potent agrochemicals, and biotechnology. Over the past 10 years CA has been promoted among smallholder farmers in the (sub-) tropics, often with disappointing results. Growing evidence challenges the claims that CA increases crop yields and builds-up soil carbon although increased stability of crop yields in dry climates is evident. Our analyses suggest pragmatic adoption on larger mechanized farms, and limited uptake of CA by smallholder farmers in developing countries. We propose a rigorous, context-sensitive approach based on Systems Agronomy to analyze and explore sustainable intensification options, including the potential of CA. There is an urgent need to move beyond dogma and prescriptive approaches to provide soil and crop management options for farmers to enable the Sustainable Intensification of agriculture. PMID- 26579141 TI - Re-analysis of protein data reveals the germination pathway and up accumulation mechanism of cell wall hydrolases during the radicle protrusion step of seed germination in Podophyllum hexandrum- a high altitude plant. AB - Podophyllum hexandrum Royle is an important high-altitude plant of Himalayas with immense medicinal value. Earlier, it was reported that the cell wall hydrolases were up accumulated during radicle protrusion step of Podophyllum seed germination. In the present study, Podophyllum seed Germination protein interaction Network (PGN) was constructed by using the differentially accumulated protein (DAP) data set of Podophyllum during the radicle protrusion step of seed germination, with reference to Arabidopsis protein-protein interaction network (AtPIN). The developed PGN is comprised of a giant cluster with 1028 proteins having 10,519 interactions and a few small clusters with relevant gene ontological signatures. In this analysis, a germination pathway related cluster which is also central to the topology and information dynamics of PGN was obtained with a set of 60 key proteins. Among these, eight proteins which are known to be involved in signaling, metabolism, protein modification, cell wall modification, and cell cycle regulation processes were found commonly highlighted in both the proteomic and interactome analysis. The systems-level analysis of PGN identified the key proteins involved in radicle protrusion step of seed germination in Podophyllum. PMID- 26579142 TI - The development of quick, robust, quantitative phenotypic assays for describing the host-nonhost landscape to stripe rust. AB - Nonhost resistance is often conceptualized as a qualitative separation from host resistance. Classification into these two states is generally facile, as they fail to fully describe the range of states that exist in the transition from host to nonhost. This poses a problem when studying pathosystems that cannot be classified as either host or nonhost due to their intermediate status relative to these two extremes. In this study, we investigate the efficacy of the Poaceae stripe rust (Puccinia striiformis Westend.) interaction for describing the host nonhost landscape. First, using barley (Hordeum vulgare L.) and Brachypodium distachyon (L.) P. Beauv. We observed that macroscopic symptoms of chlorosis and leaf browning were associated with hyphal colonization by P. striiformis f. sp. tritici, respectively. This prompted us to adapt a protocol for visualizing fungal structures into a phenotypic assay that estimates the percent of leaf colonized. Use of this assay in intermediate host and intermediate nonhost systems found the frequency of infection decreases with evolutionary divergence from the host species. Similarly, we observed that the pathogen's ability to complete its life cycle decreased faster than its ability to colonize leaf tissue, with no incidence of pustules observed in the intermediate nonhost system and significantly reduced pustule formation in the intermediate host system as compared to the host system, barley-P. striiformis f. sp. hordei. By leveraging the stripe rust pathosystem in conjunction with macroscopic and microscopic phenotypic assays, we now hope to dissect the genetic architecture of intermediate host and intermediate nonhost resistance using structured populations in barley and B. distachyon. PMID- 26579140 TI - Salinity tolerance in plants. Quantitative approach to ion transport starting from halophytes and stepping to genetic and protein engineering for manipulating ion fluxes. AB - Ion transport is the fundamental factor determining salinity tolerance in plants. The Review starts from differences in ion transport between salt tolerant halophytes and salt-sensitive plants with an emphasis on transport of potassium and sodium via plasma membranes. The comparison provides introductory information for increasing salinity tolerance. Effects of salt stress on ion transport properties of membranes show huge opportunities for manipulating ion fluxes. Further steps require knowledge about mechanisms of ion transport and individual genes of ion transport proteins. Initially, the Review describes methods to measure ion fluxes, the independent set of techniques ensures robust and reliable basement for quantitative approach. The Review briefly summarizes current data concerning Na(+) and K(+) concentrations in cells, refers to primary thermodynamics of ion transport and gives special attention to individual ion channels and transporters. Simplified scheme of a plant cell with known transport systems at the plasma membrane and tonoplast helps to imagine the complexity of ion transport and allows choosing specific transporters for modulating ion transport. The complexity is enhanced by the influence of cell size and cell wall on ion transport. Special attention is given to ion transporters and to potassium and sodium transport by HKT, HAK, NHX, and SOS1 proteins. Comparison between non selective cation channels and ion transporters reveals potential importance of ion transporters and the balance between the two pathways of ion transport. Further on the Review describes in detail several successful attempts to overexpress or knockout ion transporters for changing salinity tolerance. Future perspectives are questioned with more attention given to promising candidate ion channels and transporters for altered expression. Potential direction of increasing salinity tolerance by modifying ion channels and transporters using single point mutations is discussed and questioned. An alternative approach from synthetic biology is to create new regulation networks using novel transport proteins with desired properties for transforming agricultural crops. The approach had not been widely used earlier; it leads also to theoretical and pure scientific aspects of protein chemistry, structure-function relations of membrane proteins, systems biology and physiology of stress and ion homeostasis. Summarizing, several potential ways are aimed at required increase in salinity tolerance of plants of interest. PMID- 26579144 TI - Effect of bacterial root symbiosis and urea as source of nitrogen on performance of soybean plants grown hydroponically for Bioregenerative Life Support Systems (BLSSs). AB - Soybean is traditionally grown in soil, where root symbiosis with Bradyrhizobium japonicum can supply nitrogen (N), by means of bacterial fixation of atmospheric N2. Nitrogen fertilizers inhibit N-fixing bacteria. However, urea is profitably used in soybean cultivation in soil, where urease enzymes of telluric microbes catalyze the hydrolysis to ammonium, which has a lighter inhibitory effect compared to nitrate. Previous researches demonstrated that soybean can be grown hydroponically with recirculating complete nitrate-based nutrient solutions. In Space, urea derived from crew urine could be used as N source, with positive effects in resource procurement and waste recycling. However, whether the plants are able to use urea as the sole source of N and its effect on root symbiosis with B. japonicum is still unclear in hydroponics. We compared the effect of two N sources, nitrate and urea, on plant growth and physiology, and seed yield and quality of soybean grown in closed-loop Nutrient Film Technique (NFT) in growth chamber, with or without inoculation with B. japonicum. Urea limited plant growth and seed yield compared to nitrate by determining nutrient deficiency, due to its low utilization efficiency in the early developmental stages, and reduced nutrients uptake (K, Ca, and Mg) throughout the whole growing cycle. Root inoculation with B. japonicum did not improve plant performance, regardless of the N source. Specifically, nodulation increased under fertigation with urea compared to nitrate, but this effect did not result in higher leaf N content and better biomass and seed production. Urea was not suitable as sole N source for soybean in closed-loop NFT. However, the ability to use urea increased from young to adult plants, suggesting the possibility to apply it during reproductive phase or in combination with nitrate in earlier developmental stages. Root symbiosis did not contribute significantly to N nutrition and did not enhance the plant ability to use urea, possibly because of ineffective infection process and nodule functioning in hydroponics. PMID- 26579143 TI - DNA maintenance in plastids and mitochondria of plants. AB - The DNA molecules in plastids and mitochondria of plants have been studied for over 40 years. Here, we review the data on the circular or linear form, replication, repair, and persistence of the organellar DNA (orgDNA) in plants. The bacterial origin of orgDNA appears to have profoundly influenced ideas about the properties of chromosomal DNA molecules in these organelles to the point of dismissing data inconsistent with ideas from the 1970s. When found at all, circular genome-sized molecules comprise a few percent of orgDNA. In cells active in orgDNA replication, most orgDNA is found as linear and branched-linear forms larger than the size of the genome, likely a consequence of a virus-like DNA replication mechanism. In contrast to the stable chromosomal DNA molecules in bacteria and the plant nucleus, the molecular integrity of orgDNA declines during leaf development at a rate that varies among plant species. This decline is attributed to degradation of damaged-but-not-repaired molecules, with a proposed repair cost-saving benefit most evident in grasses. All orgDNA maintenance activities are proposed to occur on the nucleoid tethered to organellar membranes by developmentally-regulated proteins. PMID- 26579145 TI - Natural variation and gene regulatory basis for the responses of asparagus beans to soil drought. AB - Asparagus bean (Vigna unguiculata ssp. sesquipedalis) is the Asian subspecies of cowpea, a drought-resistant legume crop native to Africa. In order to explore the genetic variation of drought responses in asparagus bean, we conducted multi-year phenotyping of drought resistance traits across the Chinese asparagus bean mini core. The phenotypic distribution indicated that the ssp. sesquipedalis subgene pool has maintained high natural variation in drought responses despite known domestic bottleneck. Thirty-nine SNP loci were found to show an association with drought resistance via a genome-wide association study (GWAS). Whole-plant water relations were compared among four genotypes by lysimetric assay. Apparent genotypic differences in transpiration patterns and the critical soil water threshold in relation to dehydration avoidance were observed, indicating a delicate adaptive mechanism for each genotype to its own climate. Microarray gene expression analyses revealed that known drought resistance pathways such as the ABA and phosphate lipid signaling pathways are conserved between different genotypes, while differential regulation of certain aquaporin genes and hormonal genes may be important for the genotypic differences. Our results suggest that divergent sensitivity to soil water content is an important mechanism configuring the genotypic specific responses to water deficit. The SNP markers identified provide useful resources for marker-assisted breeding. PMID- 26579146 TI - Deletion of Proton Gradient Regulation 5 (PGR5) and PGR5-Like 1 (PGRL1) proteins promote sustainable light-driven hydrogen production in Chlamydomonas reinhardtii due to increased PSII activity under sulfur deprivation. AB - Continuous hydrogen photo-production under sulfur deprivation was studied in the Chlamydomonas reinhardtii pgr5 pgrl1 double mutant and respective single mutants. Under medium light conditions, the pgr5 exhibited the highest performance and produced about eight times more hydrogen than the wild type, making pgr5 one of the most efficient hydrogen producer reported so far. The pgr5 pgrl1 double mutant showed an increased hydrogen burst at the beginning of sulfur deprivation under high light conditions, but in this case the overall amount of hydrogen produced by pgr5 pgrl1 as well as pgr5 was diminished due to photo-inhibition and increased degradation of PSI. In contrast, the pgrl1 was effective in hydrogen production in both high and low light. Blocking photosynthetic electron transfer by DCMU stopped hydrogen production almost completely in the mutant strains, indicating that the main pathway of electrons toward enhanced hydrogen production is via linear electron transport. Indeed, PSII remained more active and stable in the pgr mutant strains as compared to the wild type. Since transition to anaerobiosis was faster and could be maintained due to an increased oxygen consumption capacity, this likely preserves PSII from photo-oxidative damage in the pgr mutants. Hence, we conclude that increased hydrogen production under sulfur deprivation in the pgr5 and pgrl1 mutants is caused by an increased stability of PSII permitting sustainable light-driven hydrogen production in Chlamydomonas reinhardtii. PMID- 26579148 TI - Editorial: Natural diversity in the new millennium. PMID- 26579147 TI - Transcriptional regulation of drought response: a tortuous network of transcriptional factors. AB - Drought is one of the leading factors responsible for the reduction in crop yield worldwide. Due to climate change, in future, more areas are going to be affected by drought and for prolonged periods. Therefore, understanding the mechanisms underlying the drought response is one of the major scientific concerns for improving crop yield. Plants deploy diverse strategies and mechanisms to respond and tolerate drought stress. Expression of numerous genes is modulated in different plants under drought stress that help them to optimize their growth and development. Plant hormone abscisic acid (ABA) plays a major role in plant response and tolerance by regulating the expression of many genes under drought stress. Transcription factors being the major regulator of gene expression play a crucial role in stress response. ABA regulates the expression of most of the target genes through ABA-responsive element (ABRE) binding protein/ABRE binding factor (AREB/ABF) transcription factors. Genes regulated by AREB/ABFs constitute a regulon termed as AREB/ABF regulon. In addition to this, drought responsive genes are also regulated by ABA-independent mechanisms. In ABA-independent regulation, dehydration-responsive element binding protein (DREB), NAM, ATAF, and CUC regulons play an important role by regulating many drought-responsive genes. Apart from these major regulons, MYB/MYC, WRKY, and nuclear factor-Y (NF-Y) transcription factors are also involved in drought response and tolerance. Our understanding about transcriptional regulation of drought is still evolving. Recent reports have suggested the existence of crosstalk between different transcription factors operating under drought stress. In this article, we have reviewed various regulons working under drought stress and their crosstalk with each other. PMID- 26579151 TI - Novel evidence for within-species leaf economics spectrum at multiple spatial scales. AB - Leaf economics spectrum (LES), characterizing covariation among a suite of leaf traits relevant to carbon and nutrient economics, has been examined largely among species but hardly within species. In addition, very little attempt has been made to examine whether the existence of LES depends on spatial scales. To address these questions, we quantified the variation and covariation of four leaf economic traits (specific leaf area, leaf dry matter content, leaf nitrogen and phosphorus contents) in a cosmopolitan wetland species (Phragmites australis) at three spatial (inter-regional, regional, and site) scales across most of the species range in China. The species expressed large intraspecific variation in the leaf economic traits at all of the three spatial scales. It also showed strong covariation among the four leaf economic traits across the species range. The coordination among leaf economic traits resulted in LES at all three scales and the environmental variables determining variation in leaf economic traits were different among the spatial scales. Our results provide novel evidence for within-species LES at multiple spatial scales, indicating that resource trade-off could also constrain intraspecific trait variation mainly driven by climatic and/or edaphic differences. PMID- 26579150 TI - Surveying the potential of secreted antimicrobial peptides to enhance plant disease resistance. AB - Antimicrobial peptides (AMPs) are natural products found across diverse taxa as part of the innate immune system against pathogen attacks. Some AMPs are synthesized through the canonical gene expression machinery and are called ribosomal AMPs. Other AMPs are assembled by modular enzymes generating nonribosomal AMPs and harbor unusual structural diversity. Plants synthesize an array of AMPs, yet are still subject to many pathogen invasions. Crop breeding programs struggle to release new cultivars in which complete disease resistance is achieved, and usually such resistance becomes quickly overcome by the targeted pathogens which have a shorter generation time. AMPs could offer a solution by exploring not only plant-derived AMPs, related or unrelated to the crop of interest, but also non-plant AMPs produced by bacteria, fungi, oomycetes or animals. This review highlights some promising candidates within the plant kingdom and elsewhere, and offers some perspectives on how to identify and validate their bioactivities. Technological advances, particularly in mass spectrometry (MS) and nuclear magnetic resonance (NMR), have been instrumental in identifying and elucidating the structure of novel AMPs, especially nonribosomal peptides which cannot be identified through genomics approaches. The majority of non-plant AMPs showing potential for plant disease immunity are often tested using in vitro assays. The greatest challenge remains the functional validation of candidate AMPs in plants through transgenic experiments, particularly introducing nonribosomal AMPs into crops. PMID- 26579149 TI - Understanding nitrate assimilation and its regulation in microalgae. AB - Nitrate assimilation is a key process for nitrogen (N) acquisition in green microalgae. Among Chlorophyte algae, Chlamydomonas reinhardtii has resulted to be a good model system to unravel important facts of this process, and has provided important insights for agriculturally relevant plants. In this work, the recent findings on nitrate transport, nitrate reduction and the regulation of nitrate assimilation are presented in this and several other algae. Latest data have shown nitric oxide (NO) as an important signal molecule in the transcriptional and posttranslational regulation of nitrate reductase and inorganic N transport. Participation of regulatory genes and proteins in positive and negative signaling of the pathway and the mechanisms involved in the regulation of nitrate assimilation, as well as those involved in Molybdenum cofactor synthesis required to nitrate assimilation, are critically reviewed. PMID- 26579152 TI - NAC transcription factors in plant multiple abiotic stress responses: progress and prospects. AB - Abiotic stresses adversely affect plant growth and agricultural productivity. According to the current climate prediction models, crop plants will face a greater number of environmental stresses, which are likely to occur simultaneously in the future. So it is very urgent to breed broad-spectrum tolerant crops in order to meet an increasing demand for food productivity due to global population increase. As one of the largest families of transcription factors (TFs) in plants, NAC TFs play vital roles in regulating plant growth and development processes including abiotic stress responses. Lots of studies indicated that many stress-responsive NAC TFs had been used to improve stress tolerance in crop plants by genetic engineering. In this review, the recent progress in NAC TFs was summarized, and the potential utilization of NAC TFs in breeding abiotic stress tolerant transgenic crops was also be discussed. In view of the complexity of field conditions and the specificity in multiple stress responses, we suggest that the NAC TFs commonly induced by multiple stresses should be promising candidates to produce plants with enhanced multiple stress tolerance. Furthermore, the field evaluation of transgenic crops harboring NAC genes, as well as the suitable promoters for minimizing the negative effects caused by over-expressing some NAC genes, should be considered. PMID- 26579154 TI - Dynamic epigenetic states of maize centromeres. AB - The centromere is a specialized chromosomal region identified as the major constriction, upon which the kinetochore complex is formed, ensuring accurate chromosome orientation and segregation during cell division. The rapid evolution of centromere DNA sequence and the conserved centromere function are two contradictory aspects of centromere biology. Indeed, the sole presence of genetic sequence is not sufficient for centromere formation. Various dicentric chromosomes with one inactive centromere have been recognized. It has also been found that de novo centromere formation is common on fragments in which centromeric DNA sequences are lost. Epigenetic factors play important roles in centromeric chromatin assembly and maintenance. Non-disjunction of the supernumerary B chromosome centromere is independent of centromere function, but centromere pairing during early prophase of meiosis I requires an active centromere. This review discusses recent studies in maize about genetic and epigenetic elements regulating formation and maintenance of centromere chromatin, as well as centromere behavior in meiosis. PMID- 26579153 TI - Effect of temperature on the pathogenesis, accumulation of viral and satellite RNAs and on plant proteome in peanut stunt virus and satellite RNA-infected plants. AB - Temperature is an important environmental factor influencing plant development in natural and diseased conditions. The growth rate of plants grown at C27 degrees C is more rapid than for plants grown at 21 degrees C. Thus, temperature affects the rate of pathogenesis progression in individual plants. We have analyzed the effect of temperature conditions (either 21 degrees C or 27 degrees C during the day) on the accumulation rate of the virus and satellite RNA (satRNA) in Nicotiana benthamiana plants infected by peanut stunt virus (PSV) with and without its satRNA, at four time points. In addition, we extracted proteins from PSV and PSV plus satRNA-infected plants harvested at 21 dpi, when disease symptoms began to appear on plants grown at 21 degrees C and were well developed on those grown at 27 degrees C, to assess the proteome profile in infected plants compared to mock-inoculated plants grown at these two temperatures, using 2D-gel electrophoresis and mass spectrometry approaches. The accumulation rate of the viral RNAs and satRNA was more rapid at 27 degrees C at the beginning of the infection and then rapidly decreased in PSV-infected plants. At 21 dpi, PSV and satRNA accumulation was higher at 21 degrees C and had a tendency to increase further. In all studied plants grown at 27 degrees C, we observed a significant drop in the identified proteins participating in photosynthesis and carbohydrate metabolism at the proteome level, in comparison to plants maintained at 21 degrees C. On the other hand, the proteins involved in protein metabolic processes were all more abundant in plants grown at 27 degrees C. This was especially evident when PSV-infected plants were analyzed, where increase in abundance of proteins involved in protein synthesis, degradation, and folding was revealed. In mock-inoculated and PSV-infected plants we found an increase in abundance of the majority of stress-related differently-regulated proteins and those associated with protein metabolism. In contrast, in PSV plus satRNA infected plants the shift in the temperature barely increased the level of stress related proteins. PMID- 26579155 TI - Changes in the nuclear proteome of developing wheat (Triticum aestivum L.) grain. AB - Wheat grain end-use value is determined by complex molecular interactions that occur during grain development, including those in the cell nucleus. However, our knowledge of how the nuclear proteome changes during grain development is limited. Here, we analyzed nuclear proteins of developing wheat grains collected during the cellularization, effective grain-filling, and maturation phases of development, respectively. Nuclear proteins were extracted and separated by two dimensional gel electrophoresis. Image analysis revealed 371 and 299 reproducible spots in gels with first dimension separation along pH 4-7 and pH 6-11 isoelectric gradients, respectively. The relative abundance of 464 (67%) protein spots changed during grain development. Abundance profiles of these proteins clustered in six groups associated with the major phases and phase transitions of grain development. Using nano liquid chromatography-tandem mass spectrometry to analyse 387 variant and non-variant protein spots, 114 different proteins were identified that were classified into 16 functional classes. We noted that some proteins involved in the regulation of transcription, like HMG1/2-like protein and histone deacetylase HDAC2, were most abundant before the phase transition from cellularization to grain-filling, suggesting that major transcriptional changes occur during this key developmental phase. The maturation period was characterized by high relative abundance of proteins involved in ribosome biogenesis. Data are available via ProteomeXchange with identifier PXD002999. PMID- 26579156 TI - The Piriformospora indica effector PIIN_08944 promotes the mutualistic Sebacinalean symbiosis. AB - Pathogenic and mutualistic microbes actively suppress plant defense by secreting effector proteins to manipulate the host responses for their own benefit. Current knowledge about fungal effectors has been mainly derived from biotrophic and hemibiotrophic plant pathogenic fungi and oomycetes with restricted host range. We studied colonization strategies of the root endophytic basidiomycete Piriformospora indica that colonizes a wide range of plant species thereby establishing long-term mutualistic relationships. The release of P. indica's genome helped to identify hundreds of genes coding for candidate effectors and provides an opportunity to investigate the role of those proteins in a mutualistic symbiosis. We demonstrate that the candidate effector PIIN_08944 plays a crucial role during fungal colonization of Arabidopsis thaliana roots. PIIN_08944 expression was detected during chlamydospore germination, and fungal deletion mutants (PiDelta08944) showed delayed root colonization. Constitutive over-expression of PIIN_08944 in Arabidopsis rescued the delayed colonization phenotype of the deletion mutant. PIIN_08944-expressing Arabidopsis showed a reduced expression of flg22-induced marker genes of pattern-triggered immunity (PTI) and the salicylic acid (SA) defense pathway, and expression of PIIN_08944 in barley reduced the burst of reactive oxygen species (ROS) triggered by flg22 and chitin. These data suggest that PIIN_08944 contributes to root colonization by P. indica by interfering with SA-mediated basal immune responses of the host plant. Consistent with this, PIIN_08944-expressing Arabidopsis also supported the growth of the biotrophic oomycete Hyaloperonospora arabidopsidis while growth of the necrotrophic fungi Botrytis cinerea on Arabidopsis and Fusarium graminearum on barley was not affected. PMID- 26579158 TI - Peach MYB7 activates transcription of the proanthocyanidin pathway gene encoding leucoanthocyanidin reductase, but not anthocyanidin reductase. AB - Proanthocyanidins (PAs) are a group of natural phenolic compounds that have a great effect on both flavor and nutritious value of fruit. It has been shown that PA synthesis is regulated by R2R3-MYB transcription factors (TFs) via activation of PA-specific pathway genes encoding leucoanthocyanidin reductase and anthocyanidin reductase. Here, we report the isolation and characterization of a MYB gene designated PpMYB7 in peach. The peach PpMYB7 represents a new group of R2R3-MYB genes regulating PA synthesis in plants. It is able to activate transcription of PpLAR1 but not PpANR, and has a broader selection of potential bHLH partners compared with PpMYBPA1. Transcription of PpMYB7 can be activated by the peach basic leucine-zipper 5 TF (PpbZIP5) via response to ABA. Our study suggests a transcriptional network regulating PA synthesis in peach, with the results aiding the understanding of the functional divergence between R2R3-MYB TFs in plants. PMID- 26579157 TI - The female gametophyte: an emerging model for cell type-specific systems biology in plant development. AB - Systems biology, a holistic approach describing a system emerging from the interactions of its molecular components, critically depends on accurate qualitative determination and quantitative measurements of these components. Development and improvement of large-scale profiling methods ("omics") now facilitates comprehensive measurements of many relevant molecules. For multicellular organisms, such as animals, fungi, algae, and plants, the complexity of the system is augmented by the presence of specialized cell types and organs, and a complex interplay within and between them. Cell type-specific analyses are therefore crucial for the understanding of developmental processes and environmental responses. This review first gives an overview of current methods used for large-scale profiling of specific cell types exemplified by recent advances in plant biology. The focus then lies on suitable model systems to study plant development and cell type specification. We introduce the female gametophyte of flowering plants as an ideal model to study fundamental developmental processes. Moreover, the female reproductive lineage is of importance for the emergence of evolutionary novelties such as an unequal parental contribution to the tissue nurturing the embryo or the clonal production of seeds by asexual reproduction (apomixis). Understanding these processes is not only interesting from a developmental or evolutionary perspective, but bears great potential for further crop improvement and the simplification of breeding efforts. We finally highlight novel methods, which are already available or which will likely soon facilitate large-scale profiling of the specific cell types of the female gametophyte in both model and non-model species. We conclude that it may take only few years until an evolutionary systems biology approach toward female gametogenesis may decipher some of its biologically most interesting and economically most valuable processes. PMID- 26579159 TI - Bacteriocins from the rhizosphere microbiome - from an agriculture perspective. AB - Bacteria produce and excrete a versatile and dynamic suit of compounds to defend against microbial competitors and mediate local population dynamics. These include a wide range of broad-spectrum non-ribosomally synthesized antibiotics, lytic enzymes, metabolic by-products, proteinaceous exotoxins, and ribosomally produced antimicrobial peptides (bacteriocins). Most bacteria produce at least one bacteriocin. Bacteriocins are of interest in the food industry as natural preservatives and in the probiotics industry, leading to extensive studies on lactic acid bacteria (colicin produced by Escherichia coli is a model bacteriocin). Recent studies have projected use of bacteriocins in veterinary medicine and in agriculture, as biostimulants of plant growth and development and as biocontrol agents. For example, bacteriocins such as Cerein 8A, Bac-GM17, putidacin, Bac 14B, amylocyclicin have been studied for their mechanisms of anti microbial activity. Bac IH7 promotes tomato and musk melon plant growth. Thuricin 17 (Th17) is the only bacteriocin studied extensively for plant growth promotion, including at the molecular level. Th17 functions as a bacterial signal compound, promoting plant growth in legumes and non-legumes. In Arabidopsis thaliana and Glycine max Th17 increased phytohormones IAA and SA at 24 h post treatment. At the proteome level Th17 treatment of 3-week-old A. thaliana rosettes led to >2 fold changes in activation of the carbon and energy metabolism pathway proteins, 24 h post treatment. At 250 mM NaCl stress, the control plants under osmotic shock shut down most of carbon-metabolism and activated energy-metabolism and antioxidant pathways. Th17 treated plants, at 250 mM NaCl, retained meaningful levels of the light harvesting complex, photosystems I and II proteins and energy and antioxidant pathways were activated, so that rosettes could better withstand the salt stress. In Glycine max, Th17 helped seeds germinate in the presence of NaCl stress, and was most effective at 100 mM NaCl. The 48 h post germination proteome suggested efficient and speedier partitioning of storage proteins, activation of carbon, nitrogen and energy metabolisms in Th17 treated seeds both under optimal and 100 mM NaCl. This review focuses on the bacteriocins produced by plant-rhizosphere colonizers and plant-pathogenic bacteria, that might have uses in agriculture, veterinary, and human medicine. PMID- 26579160 TI - Atypical centromeres in plants-what they can tell us. AB - The centromere, visible as the primary constriction of condensed metaphase chromosomes, is a defined chromosomal locus essential for genome stability. It mediates transient assembly of a multi-protein complex, the kinetochore, which enables interaction with spindle fibers and thus faithful segregation of the genetic information during nuclear divisions. Centromeric DNA varies in extent and sequence composition among organisms, but a common feature of almost all active eukaryotic centromeres is the presence of the centromeric histone H3 variant cenH3 (a.k.a. CENP-A). These typical centromere features apply to most studied species. However, a number of species display "atypical" centromeres, such as holocentromeres (centromere extension along almost the entire chromatid length) or neocentromeres (ectopic centromere activity). In this review, we provide an overview of different atypical centromere types found in plants including holocentromeres, de novo formed centromeres and terminal neocentromeres as well as di-, tri- and metapolycentromeres (more than one centromere per chromosomes). We discuss their specific and common features and compare them to centromere types found in other eukaryotic species. We also highlight new insights into centromere biology gained in plants with atypical centromeres such as distinct mechanisms to define a holocentromere, specific adaptations in species with holocentromeres during meiosis or various scenarios leading to neocentromere formation. PMID- 26579161 TI - Genome-wide gene phylogeny of CIPK family in cassava and expression analysis of partial drought-induced genes. AB - Cassava is an important food and potential biofuel crop that is tolerant to multiple abiotic stressors. The mechanisms underlying these tolerances are currently less known. CBL-interacting protein kinases (CIPKs) have been shown to play crucial roles in plant developmental processes, hormone signaling transduction, and in the response to abiotic stress. However, no data is currently available about the CPK family in cassava. In this study, a total of 25 CIPK genes were identified from cassava genome based on our previous genome sequencing data. Phylogenetic analysis suggested that 25 MeCIPKs could be classified into four subfamilies, which was supported by exon-intron organizations and the architectures of conserved protein motifs. Transcriptomic analysis of a wild subspecies and two cultivated varieties showed that most MeCIPKs had different expression patterns between wild subspecies and cultivatars in different tissues or in response to drought stress. Some orthologous genes involved in CIPK interaction networks were identified between Arabidopsis and cassava. The interaction networks and co-expression patterns of these orthologous genes revealed that the crucial pathways controlled by CIPK networks may be involved in the differential response to drought stress in different accessions of cassava. Nine MeCIPK genes were selected to investigate their transcriptional response to various stimuli and the results showed the comprehensive response of the tested MeCIPK genes to osmotic, salt, cold, oxidative stressors, and ABA signaling. The identification and expression analysis of CIPK family suggested that CIPK genes are important components of development and multiple signal transduction pathways in cassava. The findings of this study will help lay a foundation for the functional characterization of the CIPK gene family and provide an improved understanding of abiotic stress responses and signaling transduction in cassava. PMID- 26579162 TI - Identification of transcriptional regulatory nodes in soybean defense networks using transient co-transactivation assays. AB - Plant responses to major environmental stressors, such as insect feeding, not only occur via the functions of defense genes but also involve a series of regulatory factors. Our previous transcriptome studies proposed that, in addition to two defense-related genes, GmVSPbeta and GmN:IFR, a high proportion of transcription factors (TFs) participate in the incompatible soybean-common cutworm interaction networks. However, the regulatory mechanisms and effects of these TFs on those induced defense-related genes remain unknown. In the present work, we isolated and identified 12 genes encoding MYB, WRKY, NAC, bZIP, and DREB TFs from a common cutworm-induced cDNA library of a resistant soybean line. Sequence analysis of the promoters of three co-expressed genes, including GmVSPalpha, GmVSPbeta, and GmN:IFR, revealed the enrichment of various TF-binding sites for defense and stress responses. To further identify the regulatory nodes composed of these TFs and defense gene promoters, we performed extensive transient co-transactivation assays to directly test the transcriptional activity of the 12 TFs binding at different levels to the three co-expressed gene promoters. The results showed that all 12 TFs were able to transactivate the GmVSPbeta and GmN:IFR promoters. GmbZIP110 and GmMYB75 functioned as distinct regulators of GmVSPalpha/beta and GmN:IFR expression, respectively, while GmWRKY39 acted as a common central regulator of GmVSPalpha/beta and GmN:IFR expression. These corresponding TFs play crucial roles in coordinated plant defense regulation, which provides valuable information for understanding the molecular mechanisms involved in insect-induced transcriptional regulation in soybean. More importantly, the identified TFs and suitable promoters can be used to engineer insect-resistant plants in molecular breeding studies. PMID- 26579163 TI - Boron deficiency in woody plants: various responses and tolerance mechanisms. AB - Boron (B) is an essential microelement for higher plants, and its deficiency is widespread around the world and constrains the productivity of both agriculture and forestry. In the last two decades, numerous studies on model or herbaceous plants have contributed greatly to our understanding of the complex network of B deficiency responses and mechanisms for tolerance. In woody plants, however, fewer studies have been conducted and they have not well been recently synthesized or related to the findings on model species on B transporters. Trees have a larger body size, longer lifespan and more B reserves than do herbaceous plants, indicating that woody species might undergo long-term or mild B deficiency more commonly and that regulation of B reserves helps trees cope with B deficiency. In addition, the highly heterozygous genetic background of tree species suggests that they may have more complex mechanisms of response and tolerance to B deficiency than do model plants. Boron-deficient trees usually exhibit two key visible symptoms: depression of growing points (root tip, bud, flower, and young leaf) and deformity of organs (root, shoot, leaf, and fruit). These symptoms may be ascribed to B functioning in the cell wall and membrane, and particularly to damage to vascular tissues and the suppression of both B and water transport. Boron deficiency also affects metabolic processes such as decreased leaf photosynthesis, and increased lignin and phenol content in trees. These negative effects will influence the quality and quantity of wood, fruit and other agricultural products. Boron efficiency probably originates from a combined effect of three processes: B uptake, B translocation and retranslocation, and B utilization. Root morphology and mycorrhiza can affect the B uptake efficiency of trees. During B translocation from the root to shoot, differences in B concentration between root cell sap and xylem exudate, as well as water use efficiency, may play key roles in tolerance to B deficiency. In addition, B retranslocation efficiency primarily depends on the extent of xylem-to-phloem transfer and the variety and amount of cis-diol moieties in the phloem. The B requirement for cell wall construction also contribute to the B use efficiency in trees. The present review will provide an update on the physiological and molecular responses and tolerance mechanisms to B deficiency in woody plants. Emphasis is placed on the roles of B reserves that are more important for tolerance to B deficiency in trees than in herbaceous plants and the possible physiological and molecular mechanisms of differential B efficiency in trees. We propose that B may be used to study the relationship between the cell wall and the membrane via the B-bridge. Transgenic B-efficient tree cultivars have considerable potential for forestry or fruit rootstock production on low B soils in the future. PMID- 26579164 TI - Validation of molecular markers associated with boron tolerance, powdery mildew resistance and salinity tolerance in field peas. AB - Field pea (Pisum sativum L.) is an important grain legume consumed both as human food and animal feed. However, productivity in low rainfall regions can be significantly reduced by inferior soils containing high levels of boron and/or salinity. Furthermore, powdery mildew (PM) (Erysiphe pisi) disease also causes significant yield loss in warmer regions. Breeding for tolerance to these abiotic and biotic stresses are major aims for pea breeding programs and the application of molecular markers for these traits could greatly assist in developing improved germplasm at a faster rate. The current study reports the evaluation of a near diagnostic marker, PsMlo, associated with PM resistance and boron (B) tolerance as well as linked markers associated with salinity tolerance across a diverse set of pea germplasm. The PsMlo1 marker predicted the PM and B phenotypic responses with high levels of accuracy (>80%) across a wide range of field pea genotypes, hence offers the potential to be widely adapted in pea breeding programs. In contrast, linked markers for salinity tolerance were population specific; therefore, application of these markers would be suitable to relevant crosses within the program. Our results also suggest that there are possible new sources of salt tolerance present in field pea germplasm that could be further exploited. PMID- 26579165 TI - Genome-wide survey and comprehensive expression profiling of Aux/IAA gene family in chickpea and soybean. AB - Auxin plays a central role in many aspects of plant growth and development. Auxin/Indole-3-Acetic Acid (Aux/IAA) genes cooperate with several other components in the perception and signaling of plant hormone auxin. An investigation of chickpea and soybean genomes revealed 22 and 63 putative Aux/IAA genes, respectively. These genes were classified into six subfamilies on the basis of phylogenetic analysis. Among 63 soybean Aux/IAA genes, 57 (90.5%) were found to be duplicated via whole genome duplication (WGD)/segmental events. Transposed duplication played a significant role in tandem arrangements between the members of different subfamilies. Analysis of Ka/Ks ratio of duplicated Aux/IAA genes revealed purifying selection pressure with restricted functional divergence. Promoter sequence analysis revealed several cis-regulatory elements related to auxin, abscisic acid, desiccation, salt, seed, and endosperm, indicating their role in development and stress responses. Expression analysis of chickpea and soybean Aux/IAA genes in various tissues and stages of development demonstrated tissue/stage specific differential expression. In soybean, at least 16 paralog pairs, duplicated via WGD/segmental events, showed almost indistinguishable expression pattern, but eight pairs exhibited significantly diverse expression patterns. Under abiotic stress conditions, such as desiccation, salinity and/or cold, many Aux/IAA genes of chickpea and soybean revealed differential expression. qRT-PCR analysis confirmed the differential expression patterns of selected Aux/IAA genes in chickpea. The analyses presented here provide insights on putative roles of chickpea and soybean Aux/IAA genes and will facilitate elucidation of their precise functions during development and abiotic stress responses. PMID- 26579166 TI - Yeast functional screen to identify genes conferring salt stress tolerance in Salicornia europaea. AB - Salinity is a critical environmental factor that adversely affects crop productivity. Halophytes have evolved various mechanisms to adapt to saline environments. Salicornia europaea L. is one of the most salt-tolerant plant species. It does not have special salt-secreting structures like a salt gland or salt bladder, and is therefore a good model for studying the common mechanisms underlying plant salt tolerance. To identify candidate genes encoding key proteins in the mediation of salt tolerance in S. europaea, we performed a functional screen of a cDNA library in yeast. The library was screened for genes that allowed the yeast to grow in the presence of 1.3 M NaCl. We obtained three full-length S. europaea genes that confer salt tolerance. The genes are predicted to encode (1) a novel protein highly homologous to thaumatin-like proteins, (2) a novel coiled-coil protein of unknown function, and (3) a novel short peptide of 32 residues. Exogenous application of a synthetic peptide corresponding to the 32 residues improved salt tolerance of Arabidopsis. The approach described in this report provides a rapid assay system for large-scale screening of S. europaea genes involved in salt stress tolerance and supports the identification of genes responsible for such mechanisms. These genes may be useful candidates for improving crop salt tolerance by genetic transformation. PMID- 26579167 TI - Methylation of miRNA genes in the response to temperature stress in Populus simonii. AB - DNA methylation and miRNAs provide crucial regulation of the transcriptional and post-transcriptional responses to abiotic stress. In this study, we used methylation-sensitive amplification polymorphisms to identify 1066 sites that were differentially methylated in response to temperature stress in Populus simonii. Among these loci, BLAST searches of miRBase identified seven miRNA genes. Expression analysis by quantitative real-time PCR suggested that the methylation pattern of these miRNA genes probably influences their expression. Annotation of these miRNA genes in the sequenced genome of Populus trichocarpa found three target genes (Potri.007G090400, Potri.014G042200, and Potri.010G176000) for the miRNAs produced from five genes (Ptc-MIR396e and g, Ptc MIR156i and j, and Ptc-MIR390c) respectively. The products of these target genes function in lipid metabolism to deplete lipid peroxide. We also constructed a network based on the interactions between DNA methylation and miRNAs, miRNAs and target genes, and the products of target genes and the metabolic factors that they affect, including H2O2, malondialdehyde, catalase (CAT), and superoxide dismutase. Our results suggested that DNA methylation probably regulates the expression of miRNA genes, thus affecting expression of their target genes, likely through the gene-silencing function of miRNAs, to maintain cell survival under abiotic stress conditions. PMID- 26579169 TI - Different roles of cyclic electron flow around photosystem I under sub-saturating and saturating light intensities in tobacco leaves. AB - In higher plants, the generation of proton gradient across the thylakoid membrane (DeltapH) through cyclic electron flow (CEF) has mainly two functions: (1) to generate ATP and balance the ATP/NADPH energy budget, and (2) to protect photosystems I and II against photoinhibition. The intensity of light under which plants are grown alters both CEF activity and the ATP/NADPH demand for primary metabolic processes. However, it is unclear how the role of CEF is affected by the level of irradiance that is applied during the growth and measurement periods. We studied the role of CEF at different light intensities in leaves from sun- and shade-grown plants. At 849 MUmol photons m(-2) s(-1), both types of leaves had nearly the same degree of CEF activation. Modeling of the ATP/NADPH demand revealed that, at this light intensity, the contribution of CEF toward supplying ATP was much higher in the sun leaves. Meanwhile, the shade leaves showed higher levels of non-photochemical quenching and the P700 oxidation ratio. Therefore, at 849 MUmol photons m(-2) s(-1), CEF mainly helped in the synthesis of ATP in the sun leaves, but functioned in photoprotection for the shade leaves. When the light intensity increased to 1976 MUmol photons m(-2) s(-1), CEF activation was greatly enhanced in the sun leaves, but its contribution to supplying ATP changed slightly. These results indicate that the main role of CEF is altered flexibly in response to light intensity. In particular, CEF mainly contributes to balancing the ATP/NADPH energy budget under sub-saturating light intensities. When exposed to saturating light intensities, CEF mainly protects photosynthetic apparatus against photoinhibition. PMID- 26579168 TI - Impacts of high ATP supply from chloroplasts and mitochondria on the leaf metabolism of Arabidopsis thaliana. AB - Chloroplasts and mitochondria are the major ATP producing organelles in plant leaves. Arabidopsis thaliana purple acid phosphatase 2 (AtPAP2) is a phosphatase dually targeted to the outer membranes of both organelles and it plays a role in the import of selected nuclear-encoded proteins into these two organelles. Overexpression (OE) of AtPAP2 in A. thaliana accelerates plant growth and promotes flowering, seed yield, and biomass at maturity. Measurement of ADP/ATP/NADP(+)/NADPH contents in the leaves of 20-day-old OE and wild-type (WT) lines at the end of night and at 1 and 8 h following illumination in a 16/8 h photoperiod revealed that the ATP levels and ATP/NADPH ratios were significantly increased in the OE line at all three time points. The AtPAP2 OE line is therefore a good model to investigate the impact of high energy on the global molecular status of Arabidopsis. In this study, transcriptome, proteome, and metabolome profiles of the high ATP transgenic line were examined and compared with those of WT plants. A comparison of OE and WT at the end of the night provide valuable information on the impact of higher ATP output from mitochondria on plant physiology, as mitochondrial respiration is the major source of ATP in the dark in leaves. Similarly, comparison of OE and WT following illumination will provide information on the impact of higher energy output from chloroplasts on plant physiology. OE of AtPAP2 was found to significantly affect the transcript and protein abundances of genes encoded by the two organellar genomes. For example, the protein abundances of many ribosomal proteins encoded by the chloroplast genome were higher in the AtPAP2 OE line under both light and dark conditions, while the protein abundances of multiple components of the photosynthetic complexes were lower. RNA-seq data also showed that the transcription of the mitochondrial genome is greatly affected by the availability of energy. These data reflect that the transcription and translation of organellar genomes are tightly coupled with the energy status. This study thus provides comprehensive information on the impact of high ATP level on plant physiology, from organellar biology to primary and secondary metabolism. PMID- 26579170 TI - Atmospheric H2S and SO2 as sulfur source for Brassica juncea and Brassica rapa: impact on the glucosinolate composition. AB - The impact of sulfate deprivation and atmospheric H2S and SO2 nutrition on the content and composition of glucosinolates was studied in Brassica juncea and B. rapa. Both species contained a number of aliphatic, aromatic and indolic glucosinolates. The total glucosinolate content was more than 5.5-fold higher in B. juncea than in B. rapa, which could solely be attributed to the presence of high levels of sinigrin, which was absent in the latter species. Sulfate deprivation resulted in a strong decrease in the content and an altered composition of the glucosinolates of both species. Despite the differences in patterns in foliarly uptake and metabolism, their exposure hardly affected the glucosinolate composition of the shoot, both at sulfate-sufficient and sulfate deprived conditions. This indicated that the glucosinolate composition in the shoot was hardly affected by differences in sulfur source (viz., sulfate, sulfite and sulfide). Upon sulfate deprivation, where foliarly absorbed H2S and SO2 were the sole sulfur source for growth, the glucosinolate composition of roots differed from sulfate-sufficient B. juncea and B. rapa, notably the fraction of the indolic glucosinolates was lower than that observed in sulfur-sufficient roots. PMID- 26579171 TI - Alleviation of cold damage to photosystem II and metabolisms by melatonin in Bermudagrass. AB - As a typical warm-season grass, Bermudagrass [Cynodon dactylon (L).Pers.] is widely applied in turf systems and animal husbandry. However, cold temperature is a key factor limiting resource utilization for Bermudagrass. Therefore, it is relevant to study the mechanisms by which Burmudagrass responds to cold. Melatonin is a crucial animal and plant hormone that is responsible for plant abiotic stress responses. The objective of this study was to investigate the role of melatonin in cold stress response of Bermudagrass. Wild Bermudagrass pre treated with 100 MUM melatonin was subjected to different cold stress treatments (-5 degrees C for 8 h with or without cold acclimation). The results showed lower malondialdehyde (MDA) and electrolyte leakage (EL) values, higher levels of chlorophyll, and greater superoxide dismutase and peroxidase activities after melatonin treatment than those in non-melatonin treatment under cold stress. Analysis of chlorophyll a revealed that the chlorophyll fluorescence transient (OJIP) curves were higher after treatment with melatonin than that of non melatonin treated plants under cold stress. The values of photosynthetic fluorescence parameters increased after treatment with melatonin under cold stress. The analysis of metabolism showed alterations in 46 metabolites in cold stressed plants after melatonin treatment. Among the measured metabolites, five sugars (arabinose, mannose, glucopyranose, maltose, and turanose) and one organic acid (propanoic acid) were significantly increased. However, valine and threonic acid contents were reduced in melatonin-treated plants. In summary, melatonin maintained cell membrane stability, increased antioxidant enzymes activities, improved the process of photosystem II, and induced alterations in Bermudagrass metabolism under cold stress. PMID- 26579173 TI - Corrigendum: How and why do root apices sense light under the soil surface? AB - [This corrects the article on p. 775 in vol. 6, PMID: 26442084.]. PMID- 26579172 TI - Role of ethylene in responses of plants to nitrogen availability. AB - Ethylene is a plant hormone involved in several physiological processes and regulates the plant development during the whole life. Stressful conditions usually activate ethylene biosynthesis and signaling in plants. The availability of nutrients, shortage or excess, influences plant metabolism and ethylene plays an important role in plant adaptation under suboptimal conditions. Among the plant nutrients, the nitrogen (N) is one the most important mineral element required for plant growth and development. The availability of N significantly influences plant metabolism, including ethylene biology. The interaction between ethylene and N affects several physiological processes such as leaf gas exchanges, roots architecture, leaf, fruits, and flowers development. Low plant N use efficiency (NUE) leads to N loss and N deprivation, which affect ethylene biosynthesis and tissues sensitivity, inducing cell damage and ultimately lysis. Plants may respond differently to N availability balancing ethylene production through its signaling network. This review discusses the recent advances in the interaction between N availability and ethylene at whole plant and different organ levels, and explores how N availability induces ethylene biology and plant responses. Exogenously applied ethylene seems to cope the stress conditions and improves plant physiological performance. This can be explained considering the expression of ethylene biosynthesis and signaling genes under different N availability. A greater understanding of the regulation of N by means of ethylene modulation may help to increase NUE and directly influence crop productivity under conditions of limited N availability, leading to positive effects on the environment. Moreover, efforts should be focused on the effect of N deficiency or excess in fruit trees, where ethylene can have detrimental effects especially during postharvest. PMID- 26579174 TI - Conservation of the abscission signaling peptide IDA during Angiosperm evolution: withstanding genome duplications and gain and loss of the receptors HAE/HSL2. AB - The peptide INFLORESCENCE DEFICIENT IN ABSCISSION (IDA), which signals through the leucine-rich repeat receptor-like kinases HAESA (HAE) and HAESA-LIKE2 (HSL2), controls different cell separation events in Arabidopsis thaliana. We hypothesize the involvement of this signaling module in abscission processes in other plant species even though they may shed other organs than A. thaliana. As the first step toward testing this hypothesis from an evolutionarily perspective we have identified genes encoding putative orthologs of IDA and its receptors by BLAST searches of publically available protein, nucleotide and genome databases for angiosperms. Genes encoding IDA or IDA-LIKE (IDL) peptides and HSL proteins were found in all investigated species, which were selected as to represent each angiosperm order with available genomic sequences. The 12 amino acids representing the bioactive peptide in A. thaliana have virtually been unchanged throughout the evolution of the angiosperms; however, the number of IDL and HSL genes varies between different orders and species. The phylogenetic analyses suggest that IDA, HSL2, and the related HSL1 gene, were present in the species that gave rise to the angiosperms. HAE has arisen from HSL1 after a genome duplication that took place after the monocot-eudicots split. HSL1 has also independently been duplicated in the monocots, while HSL2 has been lost in gingers (Zingiberales) and grasses (Poales). IDA has been duplicated in eudicots to give rise to functionally divergent IDL peptides. We postulate that the high number of IDL homologs present in the core eudicots is a result of multiple whole genome duplications (WGD). We substantiate the involvement of IDA and HAE/HSL2 homologs in abscission by providing gene expression data of different organ separation events from various species. PMID- 26579176 TI - The receptor-like kinase SOBIR1 interacts with Brassica napus LepR3 and is required for Leptosphaeria maculans AvrLm1-triggered immunity. AB - The fungus Leptosphaeria maculans (L. maculans) is the causal agent of blackleg disease of canola/oilseed rape (Brassica napus) worldwide. We previously reported cloning of the B. napus blackleg resistance gene, LepR3, which encodes a receptor like protein. LepR3 triggers localized cell death upon recognition of its cognate Avr protein, AvrLm1. Here, we exploited the Nicotiana benthamiana model plant to investigate the recognition mechanism of AvrLm1 by LepR3. Co-expression of the LepR3/AvrLm1 gene pair in N. benthamiana resulted in development of a hypersensitive response (HR). However, a truncated AvrLm1 lacking its indigenous signal peptide was compromised in its ability to induce LepR3-mediated HR, indicating that AvrLm1 is perceived by LepR3 extracellularly. Structure-function analysis of the AvrLm1 protein revealed that the C-terminal region of AvrLm1 was required for LepR3-mediated HR in N. benthamiana and for resistance to L. maculans in B. napus. LepR3 was shown to be physically interacting with the B. napus receptor like kinase, SOBIR1 (BnSOBIR1). Silencing of NbSOBIR1 or NbSERK3 (BAK1) compromised LepR3-AvrLm1-dependent HR in N. benthamiana, suggesting that LepR3-mediated resistance to L. maculans in B. napus requires SOBIR1 and BAK1/SERK3. Using this model system, we determined that BnSOBIR1 and SERK3/BAK1 are essential partners in the LepR3 signaling complex and were able to define the AvrLm1 effector domain. PMID- 26579175 TI - De novo transcriptome profiling of cold-stressed siliques during pod filling stages in Indian mustard (Brassica juncea L.). AB - Low temperature is a major abiotic stress that impedes plant growth and development. Brassica juncea is an economically important oil seed crop and is sensitive to freezing stress during pod filling subsequently leading to abortion of seeds. To understand the cold stress mediated global perturbations in gene expression, whole transcriptome of B. juncea siliques that were exposed to sub optimal temperature was sequenced. Manually self-pollinated siliques at different stages of development were subjected to either short (6 h) or long (12 h) durations of chilling stress followed by construction of RNA-seq libraries and deep sequencing using Illumina's NGS platform. De-novo assembly of B. juncea transcriptome resulted in 133,641 transcripts, whose combined length was 117 Mb and N50 value was 1428 bp. We identified 13,342 differentially regulated transcripts by pair-wise comparison of 18 transcriptome libraries. Hierarchical clustering along with Spearman correlation analysis identified that the differentially expressed genes segregated in two major clusters representing early (5-15 DAP) and late stages (20-30 DAP) of silique development. Further analysis led to the discovery of sub-clusters having similar patterns of gene expression. Two of the sub-clusters (one each from the early and late stages) comprised of genes that were inducible by both the durations of cold stress. Comparison of transcripts from these clusters led to identification of 283 transcripts that were commonly induced by cold stress, and were referred to as "core cold-inducible" transcripts. Additionally, we found that 689 and 100 transcripts were specifically up-regulated by cold stress in early and late stages, respectively. We further explored the expression patterns of gene families encoding for transcription factors (TFs), transcription regulators (TRs) and kinases, and found that cold stress induced protein kinases only during early silique development. We validated the digital gene expression profiles of selected transcripts by qPCR and found a high degree of concordance between the two analyses. To our knowledge this is the first report of transcriptome sequencing of cold-stressed B. juncea siliques. The data generated in this study would be a valuable resource for not only understanding the cold stress signaling pathway but also for introducing cold hardiness in B. juncea. PMID- 26579177 TI - Overexpression of the CC-type glutaredoxin, OsGRX6 affects hormone and nitrogen status in rice plants. AB - Glutaredoxins (GRXs) are small glutathione dependent oxidoreductases that belong to the Thioredoxin (TRX) superfamily and catalyze the reduction of disulfide bonds of their substrate proteins. Plant GRXs include three different groups based on the motif sequence, namely CPYC, CGFS, and CC-type proteins. The rice CC type proteins, OsGRX6 was identified during the screening for genes whose expression changes depending on the level of available nitrate. Overexpression of OsGRX6 in rice displayed a semi-dwarf phenotype. The OsGRX6 overexpressors contain a higher nitrogen content than the wild type, indicating that OsGRX6 plays a role in homeostatic regulation of nitrogen use. Consistent with this, OsGRX6 overexpressors displayed delayed chlorophyll degradation and senescence compared to the wild type plants. To examine if the growth defect of these transgenic lines attribute to disturbed plant hormone actions, plant hormone levels were measured. The levels of two cytokinins (CKs), 2-isopentenyladenine and trans-zeatin, and gibberellin A1 (GA1) were increased in these lines. We also found that these transgenic lines were less sensitive to exogenously applied GA, suggesting that the increase in GA1 is a result of the feedback regulation. These data suggest that OsGRX6 affects hormone signaling and nitrogen status in rice plants. PMID- 26579178 TI - 2-Deoxy-2-fluoro-d-glucose metabolism in Arabidopsis thaliana. AB - 2-Deoxy-2-fluoro-d-glucose (FDG) is glucose analog routinely used in clinical and animal radiotracer studies to trace glucose uptake but it has rarely been used in plants. Previous studies analyzed FDG translocation and distribution pattern in plants and proposed that FDG could be used as a tracer for photoassimilates in plants. Elucidating FDG metabolism in plants is a crucial aspect for establishing its application as a radiotracer in plant imaging. Here, we describe the metabolic fate of FDG in the model plant species Arabidopsis thaliana. We fed FDG to leaf tissue and analyzed leaf extracts using MS and NMR. On the basis of exact mono-isotopic masses, MS/MS fragmentation, and NMR data, we identified 2-deoxy-2 fluoro-gluconic acid, FDG-6-phosphate, 2-deoxy-2-fluoro-maltose, and uridine diphosphate-FDG as four major end products of FDG metabolism. Glycolysis and starch degradation seemed to be the important pathways for FDG metabolism. We showed that FDG metabolism in plants is considerably different than animal cells and goes beyond FDG-phosphate as previously presumed. PMID- 26579179 TI - Eocene Podocarpium (Leguminosae) from South China and its biogeographic implications. AB - Podocarpium A. Braun ex Stizenberger is one of the most common legumes in the Neogene of Eurasia, including fossil fruits, seeds, leaves, and possible flower and pollen grains. This genus is not completely consistent with any extant genera according to gross morphological characters and poorly preserved cuticular structures reported in previous studies. The fossil pods collected from the coal bearing series of the Changchang Basin of Hainan Island and Maoming Basin of Guangdong, South China, are examined by morphologically comparative work, with special reference to venation patterns and placental position. These distinctive features, as well as the ovule development of pods from different developmental stages and the epidermal structure of the pods, as distinguished from previous records lead to the conclusion that these fossils can be recognized as a new species of Podocarpium, P. eocenicum sp. nov. This new discovery indicates that Podocarpium had arrived in South China by the Eocene. Investigation on the fossil records of this extinct genus shows that P. eocenicum is the earliest and lowest latitude fossil data. The possible occurrence pattern of this genus is revealed as follows: Podocarpium had distributed in the South China at least in the middle Eocene, and then migrated to Europe during the Oligocene; in the Miocene this genus reached its peak in Eurasia, spreading extensively across subtropical areas to warm temperate areas; finally, Podocarpium shrank rapidly and became extinct in Eurasia during the Pliocene. PMID- 26579180 TI - On flavonoid accumulation in different plant parts: variation patterns among individuals and populations in the shore campion (Silene littorea). AB - The presence of anthocyanins in flowers and fruits is frequently attributed to attracting pollinators and dispersers. In vegetative organs, anthocyanins and other non-pigmented flavonoids such as flavones and flavonols may serve protective functions against UV radiation, cold, heat, drought, salinity, pathogens, and herbivores; thus, these compounds are usually produced as a plastic response to such stressors. Although, the independent accumulation of anthocyanins in reproductive and vegetative tissues is commonly postulated due to differential regulation, the accumulation of flavonoids within and among populations has never been thoroughly compared. Here, we investigated the shore campion (Silene littorea, Caryophyllaceae) which exhibits variation in anthocyanin accumulation in its floral and vegetative tissues. We examined the in situ accumulation of flavonoids in floral (petals and calyxes) and vegetative organs (leaves) from 18 populations representing the species' geographic distribution. Each organ exhibited considerable variability in the content of anthocyanins and other flavonoids both within and among populations. In all organs, anthocyanin and other flavonoids were correlated. At the plant level, the flavonoid content in petals, calyxes, and leaves was not correlated in most of the populations. However, at the population level, the mean amount of anthocyanins in all organs was positively correlated, which suggests that the variable environmental conditions of populations may play a role in anthocyanin accumulation. These results are unexpected because the anthocyanins are usually constitutive in petals, yet contingent to environmental conditions in calyxes and leaves. Anthocyanin variation in petals may influence pollinator attraction and subsequent plant reproduction, yet the amount of anthocyanins may be a direct response to environmental factors. In populations on the west coast, a general pattern of increasing accumulation of flavonoids toward southern latitudes was observed in calyxes and leaves. This pattern corresponds to a gradual increase of UV-B radiation and temperature, and a decrease of rainfall toward the south. However, populations along the southern coast exposed to similar climatic stressors showed highly variable flavonoid contents, implying that other factors may play a role in flavonoid accumulation. PMID- 26579181 TI - Cellular reprogramming through mitogen-activated protein kinases. AB - Mitogen-activated protein kinase (MAPK) cascades are conserved eukaryote signaling modules where MAPKs, as the final kinases in the cascade, phosphorylate protein substrates to regulate cellular processes. While some progress in the identification of MAPK substrates has been made in plants, the knowledge on the spectrum of substrates and their mechanistic action is still fragmentary. In this focused review, we discuss the biological implications of the data in our original paper (Sustained mitogen-activated protein kinase activation reprograms defense metabolism and phosphoprotein profile in Arabidopsis thaliana; Frontiers in Plant Science 5: 554) in the context of related research. In our work, we mimicked in vivo activation of two stress-activated MAPKs, MPK3 and MPK6, through transgenic manipulation of Arabidopsis thaliana and used phosphoproteomics analysis to identify potential novel MAPK substrates. Here, we plotted the identified putative MAPK substrates (and downstream phosphoproteins) as a global protein clustering network. Based on a highly stringent selection confidence level, the core networks highlighted a MAPK-induced cellular reprogramming at multiple levels of gene and protein expression-including transcriptional, post transcriptional, translational, post-translational (such as protein modification, folding, and degradation) steps, and also protein re-compartmentalization. Additionally, the increase in putative substrates/phosphoproteins of energy metabolism and various secondary metabolite biosynthesis pathways coincides with the observed accumulation of defense antimicrobial substances as detected by metabolome analysis. Furthermore, detection of protein networks in phospholipid or redox elements suggests activation of downstream signaling events. Taken in context with other studies, MAPKs are key regulators that reprogram cellular events to orchestrate defense signaling in eukaryotes. PMID- 26579182 TI - Does gibberellin biosynthesis play a critical role in the growth of Lolium perenne? Evidence from a transcriptional analysis of gibberellin and carbohydrate metabolic genes after defoliation. AB - Global meat and milk production depends to a large extent on grazed pastures, with Lolium perenne being the major forage grass in temperate regions. Defoliation and subsequent regrowth of leaf blades is a major and essential event with respect to L. perenne growth and productivity. Following defoliation, carbohydrates (mainly fructans and sucrose) have to be mobilized from heterotrophic tissues to provide energy and carbon for regrowth of photosynthetic tissues. This mobilization of reserve carbohydrates requires a substantial change in the expression of genes coding for enzymes involved in carbohydrate metabolism. Here we tested the hypothesis that gibberellins (GA) are at the core of the processes regulating the expression of these genes. Thus, we examined the transcript profiles of genes involved in carbohydrate and GA metabolic pathways across a time course regrowth experiment. Our results show that following defoliation, the immediate reduction of carbohydrate concentrations in growing tissues is associated with a concomitant increase in the expression of genes encoding carbohydrate mobilizing invertases, and was also associated with a strong decrease in the expression of fructan synthesizing fructosyltransferase genes. We also show that the decrease in fructan levels is preceded by increased expression of the GA activating gene GA 3-oxidase and decreased expression of the GA inactivating gene GA 2 -oxidase in sheaths. GA 3-oxidase expression was negatively, while GA 2 -oxidase positively linked to sucrose concentrations. This study provides indicative evidence that gibberellins might play a role in L. perenne regrowth following defoliation and we hypothesize that there is a link between gibberellin regulation and sugar metabolism in L. perenne. PMID- 26579183 TI - Quantitative genetic analysis of agronomic and morphological traits in sorghum, Sorghum bicolor. AB - The productivity in sorghum is low, owing to various biotic and abiotic constraints. Combining insect resistance with desirable agronomic and morphological traits is important to increase sorghum productivity. Therefore, it is important to understand the variability for various agronomic traits, their heritabilities and nature of gene action to develop appropriate strategies for crop improvement. Therefore, a full diallel set of 10 parents and their 90 crosses including reciprocals were evaluated in replicated trials during the 2013 14 rainy and postrainy seasons. The crosses between the parents with early- and late-flowering flowered early, indicating dominance of earliness for anthesis in the test material used. Association between the shoot fly resistance, morphological, and agronomic traits suggested complex interactions between shoot fly resistance and morphological traits. Significance of the mean sum of squares for GCA (general combining ability) and SCA (specific combining ability) of all the studied traits suggested the importance of both additive and non-additive components in inheritance of these traits. The GCA/SCA, and the predictability ratios indicated predominance of additive gene effects for majority of the traits studied. High broad-sense and narrow-sense heritability estimates were observed for most of the morphological and agronomic traits. The significance of reciprocal combining ability effects for days to 50% flowering, plant height and 100 seed weight, suggested maternal effects for inheritance of these traits. Plant height and grain yield across seasons, days to 50% flowering, inflorescence exsertion, and panicle shape in the postrainy season showed greater specific combining ability variance, indicating the predominance of non-additive type of gene action/epistatic interactions in controlling the expression of these traits. Additive gene action in the rainy season, and dominance in the postrainy season for days to 50% flowering and plant height suggested G X E interactions for these traits. PMID- 26579184 TI - Gene-to-metabolite network for biosynthesis of lignans in MeJA-elicited Isatis indigotica hairy root cultures. AB - Root and leaf tissue of Isatis indigotica shows notable anti-viral efficacy, and are widely used as "Banlangen" and "Daqingye" in traditional Chinese medicine. The plants' pharmacological activity is attributed to phenylpropanoids, especially a group of lignan metabolites. However, the biosynthesis of lignans in I. indigotica remains opaque. This study describes the discovery and analysis of biosynthetic genes and AP2/ERF-type transcription factors involved in lignan biosynthesis in I. indigotica. MeJA treatment revealed differential expression of three genes involved in phenylpropanoid backbone biosynthesis (IiPAL, IiC4H, Ii4CL), five genes involved in lignan biosynthesis (IiCAD, IiC3H, IiCCR, IiDIR, and IiPLR), and 112 putative AP2/ERF transcription factors. In addition, four intermediates of lariciresinol biosynthesis were found to be induced. Based on these results, a canonical correlation analysis using Pearson's correlation coefficient was performed to construct gene-to-metabolite networks and identify putative key genes and rate-limiting reactions in lignan biosynthesis. Over expression of IiC3H, identified as a key pathway gene, was used for metabolic engineering of I. indigotica hairy roots, and resulted in an increase in lariciresinol production. These findings illustrate the utility of canonical correlation analysis for the discovery and metabolic engineering of key metabolic genes in plants. PMID- 26579185 TI - MPK3/MPK6 are involved in iron deficiency-induced ethylene production in Arabidopsis. AB - Iron (Fe) is an essential micronutrient that participates in various biological processes important for plant growth. Ethylene production induced by Fe deficiency plays important roles in plant tolerance to stress induced by Fe deficiency. However, the activation and regulatory mechanisms of 1 Aminocyclopropane-1-carboxylic acid synthase (ACS) genes in this response are not clear. In this study, we demonstrated that Fe deficiency increased the abundance of ACS2, ACS6, ACS7, and ACS11 transcripts in both leaves and roots as well as the abundance of ACS8 transcripts in leaves and ACS9 transcripts in roots. Furthermore, we investigated the role of mitogen-activated protein kinase 3 and 6 (MPK3/MPK6)-regulated ACS2/6 activation in Fe deficiency-induced ethylene production. Our results showed that MPK3/MPK6 transcript abundance and MPK3/MPK6 phosphorylation are elevated under conditions of Fe deficiency. Furthermore, mpk3 and mpk6 mutants show a lesser induction of ethylene production under Fe deficiency and a greater sensitivity to Fe deficiency. Finally, in mpk3, mpk6, and acs2 mutants under conditions of Fe deficiency, induction of transcript expression of the Fe-deficiency response genes FRO2, IRT1, and FIT is partially compromised. Taken together, our results suggest that the MPK3/MPK6 and ACS2 are part of the Fe starvation-induced ethylene production signaling pathway. PMID- 26579186 TI - Arabidopsis LEAFY COTYLEDON1 controls cell fate determination during post embryonic development. AB - Arabidopsis LEAFY COTYLEDON1 (LEC1) transcription factor is a master regulator that shapes plant embryo development and post-embryonic seedling establishment. Loss-of-function of LEC1 alters the cotyledon identity, causing the formation of ectopic trichomes, which does not occur in wild-type seedlings, implying that LEC1 might regulate embryonic cell fate determination during post-embryonic development. To test this hypothesis, we compared the expression of trichome development-related genes between the wild-type and the lec1 mutant. We observed that transcripts of GLABROUS1 (GL1), GL2, and GL3, genes encoding the positive regulators in trichome development, were significantly upregulated, while the TRICHOMELESS1 (TCL2), ENHANCER OF TRY AND CPC1 (ETC1), and ETC2 genes, encoding the negative regulators in trichome development, were downregulated in the lec1 mutant. Furthermore, overexpression of LEC1 activated the expressions of TCL2, CAPPICE (CPC), and ETC1, resulting in production of cotyledonary leaves with no or fewer trichomes during vegetative development. In addition, we demonstrated that LEC1 interacts with TCL2 in yeast and in vitro. A genetic experiment showed that loss-of-function of GL2 rescued the ectopic trichome formation in the lec1 mutant. These findings strongly support that LEC1 regulates trichome development, providing direct evidence for the role of LEC1 in cell fate determination during post-embryonic development. PMID- 26579187 TI - Gladiolus hybridus ABSCISIC ACID INSENSITIVE 5 (GhABI5) is an important transcription factor in ABA signaling that can enhance Gladiolus corm dormancy and Arabidopsis seed dormancy. AB - The phytohormone abscisic acid (ABA) regulates plant development and is crucial for abiotic stress response. In this study, cold storage contributes to reducing endogenous ABA content, resulting in dormancy breaking of Gladiolus. The ABA inhibitor fluridone also promotes germination, suggesting that ABA is an important hormone that regulates corm dormancy. Here, we report the identification and functional characterization of the Gladiolus ABI5 homolog (GhABI5), which is a basic leucine zipper motif transcriptional factor (TF). GhABI5 is expressed in dormant vegetative organs (corm, cormel, and stolon) as well as in reproductive organs (stamen), and it is up-regulated by ABA or drought. Complementation analysis reveals that GhABI5 rescues the ABA insensitivity of abi5-3 during seed germination and induces the expression of downstream ABA response genes in Arabidopsis thaliana (EM1, EM6, and RD29B). Down regulation of GhABI5 in dormant cormels via virus induced gene silence promotes sprouting and reduces the expression of downstream genes (GhLEA and GhRD29B). The results of this study reveal that GhABI5 regulates bud dormancy (vegetative organ) in Gladiolus in addition to its well-studied function in Arabidopsis seeds (reproductive organ). PMID- 26579188 TI - The key factor limiting plant growth in cold and humid alpine areas also plays a dominant role in plant carbon isotope discrimination. AB - Many environmental factors affect carbon isotope discrimination in plants, yet the predominant factor influencing this process is generally assumed to be the key growth-limiting factor. However, to our knowledge this hypothesis has not been confirmed. We therefore determined the carbon isotope composition (delta(13)C) of plants growing in two cold and humid mountain regions where temperature is considered to be the key growth-limiting factor. Mean annual temperature (MAT) showed a significant impact on variation in carbon isotope discrimination value (Delta) irrespective of study area or plant functional type with either partial correlation or regression analysis, but the correlation between Delta and soil water content (SWC) was usually not significant. In multiple stepwise regression analysis, MAT was either the first or the only variable selected into the prediction model of Delta against MAT and SWC, indicating that the effect of temperature on carbon isotope discrimination was predominant. The results therefore provide evidence that the key growth-limiting factor is also crucial for plant carbon isotope discrimination. Changes in leaf morphology, water viscosity and carboxylation efficiency with temperature may be responsible for the observed positive correlation between Delta and temperature. PMID- 26579189 TI - Emerging roles of protein kinase CK2 in abscisic acid signaling. AB - The phytohormone abscisic acid (ABA) regulates many aspects of plant growth and development as well as responses to multiple stresses. Post-translational modifications such as phosphorylation or ubiquitination have pivotal roles in the regulation of ABA signaling. In addition to the positive regulator sucrose non fermenting-1 related protein kinase 2 (SnRK2), the relevance of the role of other protein kinases, such as CK2, has been recently highlighted. We have recently established that CK2 phosphorylates the maize ortholog of open stomata 1 OST1, ZmOST1, suggesting a role of CK2 phosphorylation in the control of ZmOST1 protein degradation (Vilela et al., 2015). CK2 is a pleiotropic enzyme involved in multiple developmental and stress-responsive pathways. This review summarizes recent advances that taken together suggest a prominent role of protein kinase CK2 in ABA signaling and related processes. PMID- 26579190 TI - Sequenced genomes and rapidly emerging technologies pave the way for conifer evolutionary developmental biology. AB - Conifers, Ginkgo, cycads and gnetophytes comprise the four groups of extant gymnosperms holding a unique position of sharing common ancestry with the angiosperms. Comparative studies of gymnosperms and angiosperms are the key to a better understanding of ancient seed plant morphologies, how they have shifted over evolution to shape modern day species, and how the genes governing these morphologies have evolved. However, conifers and other gymnosperms have been notoriously difficult to study due to their long generation times, inaccessibility to genetic experimentation and unavailable genome sequences. Now, with three draft genomes from spruces and pines, rapid advances in next generation sequencing methods for genome wide expression analyses, and enhanced methods for genetic transformation, we are much better equipped to address a number of key evolutionary questions relating to seed plant evolution. In this mini-review we highlight recent progress in conifer developmental biology relevant to evo-devo questions. We discuss how genome sequence data and novel techniques might allow us to explore genetic variation and naturally occurring conifer mutants, approaches to reduce long generation times to allow for genetic studies in conifers, and other potential upcoming research avenues utilizing current and emergent techniques. Results from developmental studies of conifers and other gymnosperms in comparison to those in angiosperms will provide information to trace core molecular developmental control tool kits of ancestral seed plants, but foremost they will greatly improve our understanding of the biology of conifers and other gymnosperms in their own right. PMID- 26579192 TI - Cryptic relatedness in epidemiologic collections accessed for genetic association studies: experiences from the Epidemiologic Architecture for Genes Linked to Environment (EAGLE) study and the National Health and Nutrition Examination Surveys (NHANES). AB - Epidemiologic collections have been a major resource for genotype-phenotype studies of complex disease given their large sample size, racial/ethnic diversity, and breadth and depth of phenotypes, traits, and exposures. A major disadvantage of these collections is they often survey households and communities without collecting extensive pedigree data. Failure to account for substantial relatedness can lead to inflated estimates and spurious associations. To examine the extent of cryptic relatedness in an epidemiologic collection, we as the Epidemiologic Architecture for Genes Linked to Environment (EAGLE) study accessed the National Health and Nutrition Examination Surveys (NHANES) linked to DNA samples ("Genetic NHANES") from NHANES III and NHANES 1999-2002. NHANES are population-based cross-sectional surveys conducted by the National Center for Health Statistics at the Centers for Disease Control and Prevention. Genome-wide genetic data is not yet available in NHANES, and current data use agreements prohibit the generation of GWAS-level data in NHANES samples due issues in maintaining confidentiality among other ethical concerns. To date, only hundreds of single nucleotide polymorphisms (SNPs) genotyped in a variety of candidate genes are available for analysis in NHANES. We performed identity-by-descent (IBD) estimates in three self-identified subpopulations of Genetic NHANES (non Hispanic white, non- Hispanic black, and Mexican American) using PLINK software to identify potential familial relationships from presumed unrelated subjects. We then compared the PLINKidentified relationships to those identified by an alternative method implemented in Kinship-based INference for Genome-wide association studies (KING). Overall, both methods identified familial relationships in NHANES III and NHANES 1999-2002 for all three subpopulations, but little concordance was observed between the two methods due in major part to the limited SNP data available in Genetic NHANES. Despite the lack of genome-wide data, our results suggest the presence of cryptic relatedness in this epidemiologic collection and highlight the limitations of restricted datasets such as NHANES in the context of modern day genetic epidemiology studies. PMID- 26579191 TI - Sorbitol treatment extends lifespan and induces the osmotic stress response in Caenorhabditis elegans. AB - The response to osmotic stress is a highly conserved process for adapting to changing environmental conditions. Prior studies have shown that hyperosmolarity by addition of sorbitol to the growth medium is sufficient to increase both chronological and replicative lifespan in the budding yeast, Saccharomyces cerevisiae. Here we report a similar phenomenon in the nematode Caenorhabditis elegans. Addition of sorbitol to the nematode growth medium induces an adaptive osmotic response and increases C. elegans lifespan by about 35%. Lifespan extension from 5% sorbitol behaves similarly to dietary restriction in a variety of genetic backgrounds, increasing lifespan additively with mutation of daf 2(e1370) and independently of daf-16(mu86), sir-2.1(ok434), aak-2(ok524), and hif 1(ia04). Dietary restriction by bacterial deprivation or mutation of eat 2(ad1113) fails to further extend lifespan in the presence of 5% sorbitol. Two mutants with constitutive activation of the osmotic response, osm-5(p813) and osm 7(n1515), were found to be long-lived, and lifespan extension from sorbitol required the glycerol biosynthetic enzymes GPDH-1 and GPDH-2. Taken together, these observations demonstrate that exposure to sorbitol at levels sufficient to induce an adaptive osmotic response extends lifespan in worms and define the osmotic stress response pathway as a longevity pathway conserved between yeast and nematodes. PMID- 26579193 TI - Trends in substitution models of molecular evolution. AB - Substitution models of evolution describe the process of genetic variation through fixed mutations and constitute the basis of the evolutionary analysis at the molecular level. Almost 40 years after the development of first substitution models, highly sophisticated, and data-specific substitution models continue emerging with the aim of better mimicking real evolutionary processes. Here I describe current trends in substitution models of DNA, codon and amino acid sequence evolution, including advantages and pitfalls of the most popular models. The perspective concludes that despite the large number of currently available substitution models, further research is required for more realistic modeling, especially for DNA coding and amino acid data. Additionally, the development of more accurate complex models should be coupled with new implementations and improvements of methods and frameworks for substitution model selection and downstream evolutionary analysis. PMID- 26579195 TI - Mammary epithelial cells isolated from milk are a valuable, non-invasive source of mammary transcripts. AB - Milk is produced in the udder by mammary epithelial cells (MEC). Milk contains MEC, which are gradually exfoliated from the epithelium during lactation. Isolation of MEC from milk using immunomagnetic separation may be a useful non invasive method to investigate transcriptional regulations in ruminants' udder. This review aims to describe the process of isolating MEC from milk, to provide an overview on the studies that use this method to analyze gene expression by qRT PCR and to evaluate the validity of this method by analyzing and comparing the results between studies. In several goat and cow studies, consistent reductions in alpha-lactalbumin mRNA levels during once-daily milking (ODM) and in SLC2A1 mRNA level during feed restriction are observed. The effect of ODM on alpha lactalbumin mRNA level was similarly observed in milk isolated MEC and mammary biopsy. Moreover, we and others showed decreasing alpha-lactalbumin and increasing BAX mRNA levels with advanced stages of lactation in dairy cows and buffalo. The relevance of using the milk-isolated MEC method to analyze mammary gene expression is proven, as the transcript variations were also consistent with milk yield and composition variations under the effect of different factors such as prolactin inhibition or photoperiod. However, the RNA from milk-isolated MEC is particularly sensitive to degradation. This could explain the differences obtained between milk-isolated MEC and mammary biopsy in two studies where gene expression was compared using qRT-PCR or RNA Sequencing analyses. As a conclusion, when the RNA quality is conserved, MEC isolated from milk are a valuable, non-invasive source of mammary mRNA to study various factors that impact milk yield and composition (ODM, feeding level, endocrine status, photoperiod modulation, and stage of lactation). PMID- 26579194 TI - Mechanisms of mutational robustness in transcriptional regulation. AB - Robustness is the invariance of a phenotype in the face of environmental or genetic change. The phenotypes produced by transcriptional regulatory circuits are gene expression patterns that are to some extent robust to mutations. Here we review several causes of this robustness. They include robustness of individual transcription factor binding sites, homotypic clusters of such sites, redundant enhancers, transcription factors, redundant transcription factors, and the wiring of transcriptional regulatory circuits. Such robustness can either be an adaptation by itself, a byproduct of other adaptations, or the result of biophysical principles and non-adaptive forces of genome evolution. The potential consequences of such robustness include complex regulatory network topologies that arise through neutral evolution, as well as cryptic variation, i.e., genotypic divergence without phenotypic divergence. On the longest evolutionary timescales, the robustness of transcriptional regulation has helped shape life as we know it, by facilitating evolutionary innovations that helped organisms such as flowering plants and vertebrates diversify. PMID- 26579196 TI - Phenotypic variance explained by local ancestry in admixed African Americans. AB - We surveyed 26 quantitative traits and disease outcomes to understand the proportion of phenotypic variance explained by local ancestry in admixed African Americans. After inferring local ancestry as the number of African-ancestry chromosomes at hundreds of thousands of genotyped loci across all autosomes, we used a linear mixed effects model to estimate the variance explained by local ancestry in two large independent samples of unrelated African Americans. We found that local ancestry at major and polygenic effect genes can explain up to 20 and 8% of phenotypic variance, respectively. These findings provide evidence that most but not all additive genetic variance is explained by genetic markers undifferentiated by ancestry. These results also inform the proportion of health disparities due to genetic risk factors and the magnitude of error in association studies not controlling for local ancestry. PMID- 26579197 TI - Long-Term Ultrasonography Follow-Up of Thyroid Colloid Cysts at the Health Center: A Single-Center Study. AB - Objective. No previous study has employed long-term follow-up ultrasonography (US) examinations for evaluating thyroid colloid cysts (TCCs) in the general population. This study aimed to assess the interval changes of TCCs at the health center by evaluating long-term US follow-up examinations. Methods. For evaluation of the thyroid gland at our health center from 2006 to 2010, 3692 individuals underwent 4 or more thyroid US examinations at an interval of 1 year or 2 years. We assessed the interval changes of TCCs >= 5 mm on US follow-up examinations. Results. Of the 3692 subjects, only 115 (3.1%) showed TCCs >= 5 mm on one or more thyroid US examinations. The interval changes in TCCs, as shown by the thyroid US examinations performed during the study period, were classified as follows: no interval change (n = 60), gradual increase (n = 37), gradual decrease (n = 6), positive fluctuation (n = 10), negative fluctuation (n = 0), and disappearance (n = 2). No subject reported any relevant symptom pertaining to TCCs. Conclusions. Overall, follow-up US examinations showed various interval changes in TCCs, but a majority of TCCs showed no interval change or a gradual increase in size. PMID- 26579198 TI - "The Great Mimicker": An Unusual Etiology of Cytopenia, Diffuse Lymphadenopathy, and Massive Splenomegaly. AB - Sarcoidosis is an idiopathic multisystem disease characterized by the formation of noncaseating granulomas. It frequently presents with pulmonary infiltrates and bilateral hilar and mediastinal lymphadenopathy. Splenic involvement is common, but massive splenomegaly is a rare occurrence. Sarcoidosis is known as "the great mimicker" (or "the great imitator") since it exhibits a myriad of symptoms, mimicking other inflammatory, infectious, and neoplastic conditions, including lymphoma. Herein, we report the case of a 44-year-old male patient who was found to have bicytopenia, hypercalcemia, diffuse lymphadenopathy, and massive splenomegaly, a constellation of findings suggestive of underlying lymphoma. Interestingly, lymph node biopsy showed noncaseating granulomas suggestive of sarcoidosis, without evidence of malignancy. PMID- 26579199 TI - Linking environmental exposure with public health: dichlorodiphenyltrichloroethane extracted from soils and water of recently exposed communities of selected locations in Zambia. AB - BACKGROUND: In 2000, a Zambian private mining company reintroduced the use of dichlorodiphenyltrichloroethane (DDT) to control malaria in two districts. From 2000 to 2010, DDT had been applied in homes without any studies conducted to ascertain its fate in the environment. We aimed to quantify the presence of DDT and its metabolites in the soil and water around communities where it was recently used. METHODS: We collected superficial soil and water samples from drinking sources of three study areas. DDT was extracted by QuEChERS method and solid phase extraction for soils and water, respectively. Analysis was by gas chromatography-mass spectrometry. A revalidated method with limits of detection ranging from 0.034 to 0.04 ppb was used. RESULTS: Median levels of total DDT were found at 100.4 (IQR 90.9-110) and 725.4 ng/L (IQR 540-774.5) for soils and water, respectively. No DDT above detection limits was detected in the reference area. These results are clinically significant given the persistent characteristics of DDT. CONCLUSION: DDT presence in these media suggests possible limitations in the environmental safeguards during IRS. Such occurrence could have potential effects on humans, especially children; hence, there is a need to further examine possible associations between this exposure and humans. PMID- 26579200 TI - Effects of Lower-Leg Kinesiology Taping on Balance Ability in Stroke Patients with Foot Drop. AB - Objective. The purpose of this study was to observe the effects of lower-leg kinesiology taping on balance ability in stroke patients with foot drop. Design. Randomized controlled trial study. Method. Thirty stroke patients with foot drop were randomly divided into two groups. The experimental group underwent kinesiology taping, and the control group underwent placebo taping. Balance ability was assessed before and after taping in both groups. Results. No difference was observed over time in the Berg Balance Scale score between the two groups, and a significant difference in the Berg Balance Scale score was observed only in the experimental group. Additionally, there were significant differences in the center of pressure area and limits of stability over time. Conclusion. Kinesiology taping temporarily improved static balance ability in stroke patients. However, its effect on dynamic balance was not verified. Therefore, further research on the influence of long-term kinesiology taping on dynamic balance and gait ability is suggested. PMID- 26579201 TI - Protective Effect of Calculus Bovis Sativus on Dextran Sulphate Sodium-Induced Ulcerative Colitis in Mice. AB - Calculus Bovis Sativus (CBS) is a commonly used traditional Chinese medicine, which has been reported to exhibit antispasmodic, fever-reducing, anti inflammatory, and gallbladder-repairing effects. The present study aims to investigate the protective effect of CBS on dextran sulphate sodium- (DSS-) induced ulcerative colitis (UC) in mice. C57BL/6 male mice were exposed to 5% DSS in drinking water. CBS was given orally at 50 and 150 mg/kg once per day for 7 days. Body weight, disease activity index (DAI), colon length, colonic myeloperoxidase (MPO) activity, superoxide dismutase (SOD) activity, and malondialdehyde (MDA) and nitric oxide (NO) levels were measured. Administration of CBS significantly reserved these changes, decreased the MPO activity and MDA and NO level, and increased the SOD activity in the colon tissue. Histological observation suggested that CBS alleviated edema, mucosal damage, and inflammatory cells infiltration induced by DSS in the colon. Moreover, CBS significantly downregulated the mRNA expression of tumor necrosis factor-alpha (TNF-alpha), interleukin- (IL-) 1beta and IL-6 in the colon tissue. Our data suggested that CBS exerted protective effect on DSS-induced UC partially through the antioxidant and anti-inflammatory activities. PMID- 26579202 TI - Preliminary Phytochemical Screening and Biological Activities of Bulbine abyssinica Used in the Folk Medicine in the Eastern Cape Province, South Africa. AB - Bulbine abyssinica A. Rich. is used in traditional medicine to treat rheumatism, dysentery, bilharzia, cracked lips, back pain, infertility, diabetes mellitus, and gastrointestinal, vaginal, and bladder infections. Therefore, preliminary phytochemical screening, antioxidant, anti-inflammatory, and antibacterial properties of the whole plant (acetone and aqueous extracts) were determined using standard procedures. The in vitro antioxidant model assays revealed that the plant possesses free radical scavenging potential varying with free radical species. The species showed significant protein denaturation inhibitory activity with good protection against erythrocyte membrane lysis indicating anti inflammatory potential. The results also showed that the species was active against the growth of all the selected eight diabetic status opportunistic bacteria except one. Moreover, the species is characterized by appreciable amounts of total phenols, flavonoids, flavanols, proanthocyanidins, and alkaloids. Traces amounts of saponins and tannins were also observed. Amongst the identified phytochemicals present, empirical searches identified them being antioxidant, anti-inflammatory, and antimicrobial agents. The identification of these phytochemical constituents with their known pharmacological properties indicates that this plant is a good source of the free radical scavenging, anti inflammatory, and antimicrobial agents. These findings also account for the multipharmacological use of B. abyssinica in fork medicine. PMID- 26579203 TI - Evaluation of the Anxiolytic and Antidepressant Activities of the Aqueous Extract from Camellia euphlebia Merr. ex Sealy in Mice. AB - Camellia euphlebia Merr. ex Sealy is a traditional Chinese medicine that has been widely used for improvement of human emotions in the Guangxi Province of southern China. However, there are no studies about the anxiolytic and antidepressant activities of Camellia euphlebia. This study evaluated the anxiolytic and antidepressant activities of the aqueous extract from Camellia euphlebia (CEE) in mice. We found that administration of 400 mg/kg CEE or 20 mg/kg fluoxetine for 7 days significantly reduced the immobility time in both TST and FST. Oral administration of 100 mg/kg extract or 4 mg/kg diazepam for 7 days significantly increased the percentage of time spent and the number of entries into the open arms of the EPMT. In addition, the time spent by mice in the illuminated side of the LDBT was increased. Furthermore, pretreatment with 400 mg/kg CEE for 7 days significantly elevated the level of 5-HT and DA in the whole brain of mice. These results provide support for the potential anxiolytic and antidepressant activity of Camellia euphlebia and contribute towards validation of the traditional use of Camellia euphlebia in the treatment of emotional disorders. PMID- 26579204 TI - A Novel Korean Red Ginseng Compound Gintonin Inhibited Inflammation by MAPK and NF-kappaB Pathways and Recovered the Levels of mir-34a and mir-93 in RAW 264.7 Cells. AB - The beneficial health promoting effects of ginseng from vitalizing the body to enhancing long life have been well explored very rapidly in the past few years. Up till now many ginsenosides have been discovered for their marvelous therapeutic effects. However during past three years, a novel ginseng compound has been discovered, called gintonin, that differs from other ginsenosides on the basis of its signal transduction and chemical nature. Gintonin has been widely studied for its anti-Alzheimer's disease activities and other neuropathies. However, its anti-inflammatory activity remained unexplored. In our study we have reported for the first time the anti-inflammatory activity of gintonin on RAW 264.7 cells. We found that gintonin potently suppresses the nitric oxide production without any cytotoxicity at given doses and also efficiently suppressed the levels of proinflammatory cytokines. Moreover, it mediaes its signal transduction via MAPK and NF-kappaB pathways and revives the levels of mir 34a and mir-93. These findings are valuable for the anti-inflammatory effects of this new compound with particular reference to microRNA involvement in the ginseng family. PMID- 26579205 TI - Actinobacteria from Termite Mounds Show Antiviral Activity against Bovine Viral Diarrhea Virus, a Surrogate Model for Hepatitis C Virus. AB - Extracts from termite-associated bacteria were evaluated for in vitro antiviral activity against bovine viral diarrhea virus (BVDV). Two bacterial strains were identified as active, with percentages of inhibition (IP) equal to 98%. Both strains were subjected to functional analysis via the addition of virus and extract at different time points in cell culture; the results showed that they were effective as posttreatments. Moreover, we performed MTT colorimetric assays to identify the CC50, IC50, and SI values of these strains, and strain CDPA27 was considered the most promising. In parallel, the isolates were identified as Streptomyces through 16S rRNA gene sequencing analysis. Specifically, CDPA27 was identified as S. chartreusis. The CDPA27 extract was fractionated on a C18-E SPE cartridge, and the fractions were reevaluated. A 100% methanol fraction was identified to contain the compound(s) responsible for antiviral activity, which had an SI of 262.41. GC-MS analysis showed that this activity was likely associated with the compound(s) that had a peak retention time of 5 min. Taken together, the results of the present study provide new information for antiviral research using natural sources, demonstrate the antiviral potential of Streptomyces chartreusis compounds isolated from termite mounds against BVDV, and lay the foundation for further studies on the treatment of HCV infection. PMID- 26579206 TI - Dietary fat and carbohydrate modulate the effect of the ATP-binding cassette A1 (ABCA1) R230C variant on metabolic risk parameters in premenopausal women from the Genetics of Atherosclerotic Disease (GEA) Study. AB - BACKGROUND: Although the R230C-ATP-binding cassette A1 (ABCA1) variant has been consistently associated with HDL-C levels, its association with diabetes and other metabolic parameters is unclear. Estrogen and dietary factors are known to regulate ABCA1 expression in different tissues. Thus, we aimed to explore whether gender, menopausal status and macronutrient proportions of diet modulate the effect of this variant on various metabolic parameters. METHODS: One thousand five hundred ninety-eight controls from the GEA study were included (787 men, 363 premenopausal women and 448 menopausal women), previously assessed for anthropometric and biochemical measurements and visceral to subcutaneous abdominal fat (VAT/SAT) ratio on computed tomography. Taqman assays were performed for genotyping. Diet macronutrient proportions were assessed using a food frequency questionnaire validated for the Mexican population. Multivariate regression models were constructed to assess the interaction between the proportion of dietary macronutrients and the R230C polymorphism on metabolic parameters. RESULTS: All significant interactions were observed in premenopausal women. Those carrying the risk allele and consuming higher carbohydrate/lower fat diets showed an unfavorable metabolic pattern [lower HDL-C and adiponectin levels, higher VAT/SAT ratio, homeostasis model assessment for insulin resistance (HOMA-IR) and higher gamma-glutamyl transpeptidase (GGT) and alkaline phosphatase (ALP) levels]. Conversely, premenopausal women carrying the risk allele and consuming lower carbohydrate/higher fat diets showed a more favorable metabolic pattern (higher HDL-C and adiponectin levels, and lower VAT/SAT ratio, HOMA-IR, GGT and ALP levels). CONCLUSION: This is the first study reporting a gender specific interaction between ABCA1/R230C variant and dietary carbohydrate and fat percentages affecting VAT/SAT ratio, GGT, ALP, adiponectin levels and HOMA index. Our study confirmed the previously reported gender-specific ABCA1-diet interaction affecting HDL-C levels observed in an independent study. Our results show how gene-environment interactions may help further understand how certain gene variants confer metabolic risk, and may provide information useful to design diet intervention studies. PMID- 26579207 TI - NMFBFS: A NMF-Based Feature Selection Method in Identifying Pivotal Clinical Symptoms of Hepatocellular Carcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is a highly aggressive malignancy. Traditional Chinese Medicine (TCM), with the characteristics of syndrome differentiation, plays an important role in the comprehensive treatment of HCC. This study aims to develop a nonnegative matrix factorization- (NMF-) based feature selection approach (NMFBFS) to identify potential clinical symptoms for HCC patient stratification. METHODS: The NMFBFS approach consisted of three major steps. Firstly, statistics-based preliminary feature screening was designed to detect and remove irrelevant symptoms. Secondly, NMF was employed to infer redundant symptoms. Based on NMF-derived basis matrix, we defined a novel similarity measurement of intersymptoms. Finally, we converted each group of redundant symptoms to a new single feature so that the dimension was further reduced. RESULTS: Based on a clinical dataset consisting of 407 patient samples of HCC with 57 symptoms, NMFBFS approach detected 8 irrelevant symptoms and then identified 16 redundant symptoms within 6 groups. Finally, an optimal feature subset with 39 clinical features was generated after compressing the redundant symptoms by groups. The validation of classification performance shows that these 39 features obviously improve the prediction accuracy of HCC patients. CONCLUSIONS: Compared with other methods, NMFBFS has obvious advantages in identifying important clinical features of HCC. PMID- 26579208 TI - MOtoNMS: A MATLAB toolbox to process motion data for neuromusculoskeletal modeling and simulation. AB - BACKGROUND: Neuromusculoskeletal modeling and simulation enable investigation of the neuromusculoskeletal system and its role in human movement dynamics. These methods are progressively introduced into daily clinical practice. However, a major factor limiting this translation is the lack of robust tools for the pre processing of experimental movement data for their use in neuromusculoskeletal modeling software. RESULTS: This paper presents MOtoNMS (matlab MOtion data elaboration TOolbox for NeuroMusculoSkeletal applications), a toolbox freely available to the community, that aims to fill this lack. MOtoNMS processes experimental data from different motion analysis devices and generates input data for neuromusculoskeletal modeling and simulation software, such as OpenSim and CEINMS (Calibrated EMG-Informed NMS Modelling Toolbox). MOtoNMS implements commonly required processing steps and its generic architecture simplifies the integration of new user-defined processing components. MOtoNMS allows users to setup their laboratory configurations and processing procedures through user friendly graphical interfaces, without requiring advanced computer skills. Finally, configuration choices can be stored enabling the full reproduction of the processing steps. MOtoNMS is released under GNU General Public License and it is available at the SimTK website and from the GitHub repository. Motion data collected at four institutions demonstrate that, despite differences in laboratory instrumentation and procedures, MOtoNMS succeeds in processing data and producing consistent inputs for OpenSim and CEINMS. CONCLUSIONS: MOtoNMS fills the gap between motion analysis and neuromusculoskeletal modeling and simulation. Its support to several devices, a complete implementation of the pre processing procedures, its simple extensibility, the available user interfaces, and its free availability can boost the translation of neuromusculoskeletal methods in daily and clinical practice. PMID- 26579209 TI - FlexDM: Simple, parallel and fault-tolerant data mining using WEKA. AB - BACKGROUND: With the continued exponential growth in data volume, large-scale data mining and machine learning experiments have become a necessity for many researchers without programming or statistics backgrounds. WEKA (Waikato Environment for Knowledge Analysis) is a gold standard framework that facilitates and simplifies this task by allowing specification of algorithms, hyper parameters and test strategies from a streamlined Experimenter GUI. Despite its popularity, the WEKA Experimenter exhibits several limitations that we address in our new FlexDM software. RESULTS: FlexDM addresses four fundamental limitations with the WEKA Experimenter: reliance on a verbose and difficult-to-modify XML schema; inability to meta-optimise experiments over a large number of algorithm hyper-parameters; inability to recover from software or hardware failure during a large experiment; and failing to leverage modern multicore processor architectures. Direct comparisons between the FlexDM and default WEKA XML schemas demonstrate a 10-fold improvement in brevity for a specification that allows finer control of experimental procedures. The stability of FlexDM has been tested on a large biological dataset (approximately 450 k attributes by 150 samples), and automatic parallelisation of tasks yields a quasi-linear reduction in execution time when distributed across multiple processor cores. CONCLUSION: FlexDM is a powerful and easy-to-use extension to the WEKA package, which better handles the increased volume and complexity of data that has emerged during the 20 years since WEKA's original development. FlexDM has been tested on Windows, OSX and Linux operating systems and is provided as a pre-configured virtual reference environment for trivial usage and extensibility. This software can substantially improve the productivity of any research group conducting large scale data mining or machine learning tasks, in addition to providing non programmers with improved control over specific aspects of their data analysis pipeline via a succinct and simplified XML schema. PMID- 26579210 TI - Coping among trauma-affected youth: a qualitative study. AB - BACKGROUND: Eastern Democratic Republic of Congo has endured decades of conflict resulting in widespread experiences of conflict related trauma and destruction to health and social infrastructure. The aim of this qualitative study was to provide a context specific understanding of youth exposure to violence (ages 10 15 years) and use of cognitive and behavioral coping strategies. METHODS: A purposive sampling strategy based on age, gender and exposure to traumatic events was used to identify eligible youth in an ongoing parent study from four villages in the Walungu Territory, Eastern Democratic Republic of Congo. These four villages were selected from a total of 10 participating in the parent study because of the reported high exposure to conflict-related trauma. The interview guide consisted of broad open-ended questions related to the following topics, 1) identification of traumatic experiences, 2) methods for coping and changes in coping behavior 3) gender and age differences in coping, 4) sources of psychosocial support. A grounded theory approach was used to identify emergent themes. RESULTS: Of the 48 eligible participants identified, 30 youth completed the interview, 53 % were female (n = 16) and 47 % were male (n = 14). Youth ranged in age from 10-15 (mean age = 13.07). Exposures to different forms of violence and stress were reported among youth participants. Exposures to traumatic stressors occur at the individual, family and community level. In response to traumatic stress, youth reported both cognitive and behavioral coping strategies. Cognitive coping strategies included trying to forget and praying. Behavioral coping strategies included social support seeking and risk-taking behavior. These strategies may be used in mutually reinforcing ways, with youth employing more than one coping strategy. CONCLUSION: This qualitative research provides important, culturally grounded information on coping strategies used by youth in rural post-conflict settings where limited psychosocial support services are available. Understanding use of cognitive and behaviors coping strategies may inform local community and international development programs to support youth mental health along adaptive trajectories resulting in promotion of well-being and reduced risk taking behaviors. PMID- 26579211 TI - RNA:DNA hybrids in the human genome have distinctive nucleotide characteristics, chromatin composition, and transcriptional relationships. AB - BACKGROUND: RNA:DNA hybrids represent a non-canonical nucleic acid structure that has been associated with a range of human diseases and potential transcriptional regulatory functions. Mapping of RNA:DNA hybrids in human cells reveals them to have a number of characteristics that give insights into their functions. RESULTS: We find RNA:DNA hybrids to occupy millions of base pairs in the human genome. A directional sequencing approach shows the RNA component of the RNA:DNA hybrid to be purine-rich, indicating a thermodynamic contribution to their in vivo stability. The RNA:DNA hybrids are enriched at loci with decreased DNA methylation and increased DNase hypersensitivity, and within larger domains with characteristics of heterochromatin formation, indicating potential transcriptional regulatory properties. Mass spectrometry studies of chromatin at RNA:DNA hybrids shows the presence of the ILF2 and ILF3 transcription factors, supporting a model of certain transcription factors binding preferentially to the RNA:DNA conformation. CONCLUSIONS: Overall, there is little to indicate a dependence for RNA:DNA hybrids forming co-transcriptionally, with results from the ribosomal DNA repeat unit instead supporting the intriguing model of RNA generating these structures in trans. The results of the study indicate heterogeneous functions of these genomic elements and new insights into their formation and stability in vivo. PMID- 26579213 TI - An in silico MS/MS library for automatic annotation of novel FAHFA lipids. AB - BACKGROUND: A new lipid class named 'fatty acid esters of hydroxyl fatty acids' (FAHFA) was recently discovered in mammalian adipose tissue and in blood plasma and some FAHFAs were found to be associated with type 2 diabetes. To facilitate the automatic annotation of FAHFAs in biological specimens, a tandem mass spectra (MS/MS) library is needed. Due to the limitation of the commercial available standard compounds, we proposed building an in silico MS/MS library to extend the coverage of molecules. RESULTS: We developed a computer-generated library with 3267 tandem mass spectra (MS/MS) for 1089 FAHFA species. FAHFA spectra were generated based on authentic standards with negative mode electrospray ionization and 10, 20, and 40 V collision induced dissociation at 4 spectra/s as used in in ultra-high performance liquid chromatography-QTOF mass spectrometry studies. However, positional information of the hydroxyl group is only obtained either at lower QTOF spectra acquisition rates of 1 spectrum/s or at the MS(3) level in ion trap instruments. Therefore, an additional set of 4290 fragment-rich MS/MS spectra was created to enable distinguishing positional FAHFA isomers. The library was generated based on ion fragmentations and ion intensities of FAHFA external reference standards, developing a heuristic model for fragmentation rules and extending these rules to large swaths of computer-generated structures of FAHFAs with varying chain lengths, degrees of unsaturation and hydroxyl group positions. Subsequently, we validated the new in silico library by discovering several new FAHFA species in egg yolk, showing that this library enables high throughput screening of FAHFA lipids in various biological matrices. CONCLUSIONS: The developed library and templates are freely available for commercial or noncommercial use at http://fiehnlab.ucdavis.edu/staff/yanma/fahfa-lipid-library. This in silico MS/MS library allows users to annotate FAHFAs from accurate mass tandem mass spectra in an easy and fast manner with NIST MS Search or PepSearch software. The developing template is provided for advanced users to modify the parameters and export customized libraries according to their instrument features. Graphical abstractExample of experimental and in silico MS/MS spectra for FAHFA lipids. PMID- 26579212 TI - Remodeling of nuclear landscapes during human myelopoietic cell differentiation maintains co-aligned active and inactive nuclear compartments. AB - BACKGROUND: Previous studies of higher order chromatin organization in nuclei of mammalian species revealed both structural consistency and species-specific differences between cell lines and during early embryonic development. Here, we extended our studies to nuclear landscapes in the human myelopoietic lineage representing a somatic cell differentiation system. Our longterm goal is a search for structural features of nuclei, which are restricted to certain cell types/species, as compared to features, which are evolutionary highly conserved, arguing for their basic functional roles in nuclear organization. RESULTS: Common human hematopoietic progenitors, myeloid precursor cells, differentiated monocytes and granulocytes analyzed by super-resolution fluorescence microscopy and electron microscopy revealed profound differences with respect to global chromatin arrangements, the nuclear space occupied by the interchromatin compartment and the distribution of nuclear pores. In contrast, we noted a consistent organization in all cell types with regard to two co-aligned networks, an active (ANC) and an inactive (INC) nuclear compartment delineated by functionally relevant hallmarks. The ANC is enriched in active RNA polymerase II, splicing speckles and histone signatures for transcriptionally competent chromatin (H3K4me3), whereas the INC carries marks for repressed chromatin (H3K9me3). CONCLUSIONS: Our findings substantiate the conservation of the recently published ANC-INC network model of mammalian nuclear organization during human myelopoiesis irrespective of profound changes of the global nuclear architecture observed during this differentiation process. According to this model, two spatially co-aligned and functionally interacting active and inactive nuclear compartments (ANC and INC) pervade the nuclear space. PMID- 26579214 TI - Ambiguity of non-systematic chemical identifiers within and between small molecule databases. AB - BACKGROUND: A wide range of chemical compound databases are currently available for pharmaceutical research. To retrieve compound information, including structures, researchers can query these chemical databases using non-systematic identifiers. These are source-dependent identifiers (e.g., brand names, generic names), which are usually assigned to the compound at the point of registration. The correctness of non-systematic identifiers (i.e., whether an identifier matches the associated structure) can only be assessed manually, which is cumbersome, but it is possible to automatically check their ambiguity (i.e., whether an identifier matches more than one structure). In this study we have quantified the ambiguity of non-systematic identifiers within and between eight widely used chemical databases. We also studied the effect of chemical structure standardization on reducing the ambiguity of non-systematic identifiers. RESULTS: The ambiguity of non-systematic identifiers within databases varied from 0.1 to 15.2 % (median 2.5 %). Standardization reduced the ambiguity only to a small extent for most databases. A wide range of ambiguity existed for non-systematic identifiers that are shared between databases (17.7-60.2 %, median of 40.3 %). Removing stereochemistry information provided the largest reduction in ambiguity across databases (median reduction 13.7 percentage points). CONCLUSIONS: Ambiguity of non-systematic identifiers within chemical databases is generally low, but ambiguity of non-systematic identifiers that are shared between databases, is high. Chemical structure standardization reduces the ambiguity to a limited extent. Our findings can help to improve database integration, curation, and maintenance. PMID- 26579215 TI - Transposable element polymorphisms recapitulate human evolution. AB - BACKGROUND: The human genome contains several active families of transposable elements (TE): Alu, L1 and SVA. Germline transposition of these elements can lead to polymorphic TE (polyTE) loci that differ between individuals with respect to the presence/absence of TE insertions. Limited sets of such polyTE loci have proven to be useful as markers of ancestry in human population genetic studies, but until this time it has not been possible to analyze the full genomic complement of TE polymorphisms in this way. RESULTS: For the first time here, we have performed a human population genetic analysis based on a genome-wide polyTE data set consisting of 16,192 loci genotyped in 2,504 individuals across 26 human populations. PolyTEs are found at very low frequencies, > 93 % of loci show < 5 % allele frequency, consistent with the deleteriousness of TE insertions. Nevertheless, polyTEs do show substantial geographic differentiation, with numerous group-specific polymorphic insertions. African populations have the highest numbers of polyTEs and show the highest levels of polyTE genetic diversity; Alu is the most numerous and the most diverse polyTE family. PolyTE genotypes were used to compute allele sharing distances between individuals and to relate them within and between human populations. Populations and continental groups show high coherence based on individuals' polyTE genotypes, and human evolutionary relationships revealed by these genotypes are consistent with those seen for SNP-based genetic distances. The patterns of genetic diversity encoded by TE polymorphisms recapitulate broad patterns of human evolution and migration over the last 60-100,000 years. The utility of polyTEs as ancestry informative markers is further underscored by their ability to accurately predict both ancestry and admixture at the continental level. A genome-wide list of polyTE loci, along with their population group-specific allele frequencies and FST values, is provided as a resource for investigators who wish to develop panels of TE-based ancestry markers. CONCLUSIONS: The genetic diversity represented by TE polymorphisms reflects known patterns of human evolution, and ensembles of polyTE loci are suitable for both ancestry and admixture analyses. The patterns of polyTE allelic diversity suggest the possibility that there may be a connection between TE-based genetic divergence and population-specific phenotypic differences. Graphical Abstract?. PMID- 26579216 TI - Cytoplasm-predominant Pten associates with increased region-specific brain tyrosine hydroxylase and dopamine D2 receptors in mouse model with autistic traits. AB - BACKGROUND: Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by impairment in social communication/interaction and inflexible/repetitive behavior. Several lines of evidence support genetic factors as a predominant cause of ASD. Among those autism susceptibility genes that have been identified, the PTEN tumor suppressor gene, initially identified as predisposing to Cowden heritable cancer syndrome, was found to be mutated in a subset of ASD patients with extreme macrocephaly. However, the ASD-relevant molecular mechanism mediating the effect of PTEN mutations remains elusive. METHODS: We developed a Pten knock-in murine model to study the effects of Pten germline mutations, specifically altering subcellular localization, in ASD. Proteins were isolated from the hemispheres of the male littermates, and Western blots were performed to determine protein expression levels of tyrosine hydroxylase (TH). Immunohistochemical stains were carried out to validate the localization of TH and dopamine D2 receptors (D2R). PC12 cells ectopically expressing either wild-type or missense mutant PTEN were then compared for the differences in TH expression. RESULTS: Mice carrying Pten mutations have high TH and D2R in the striatum and prefrontal cortex. They also have increased phosphorylation of cAMP response element-binding protein (CREB) and TH. Mechanistically, PTEN downregulates TH production in PC12 cells via inhibiting the phosphoinositide 3-kinase (PI3K)/CREB signaling pathway, while PTEN reduces TH phosphorylation via suppressing MAPK pathway. Unlike wild-type PTEN but similar to the mouse knock-in mutant Pten, three naturally occurring missense mutations of PTEN that we previously identified in ASD patients, H93R, F241S, and D252G, were not able to suppress TH when overexpressed in PC12 cells. In addition, two other PTEN missense mutations, C124S (pan phosphatase dead) and G129E (lipid phosphatase dead), failed to suppress TH when ectopically expressed in PC12 cells. CONCLUSIONS: Our data reveal a non-canonical PTEN-TH pathway in the brain that may work as a core regulator of dopamine signaling, which when dysfunctional is pathogenic in ASD. PMID- 26579217 TI - Sex differences in psychophysical and neurophysiological responses to pain in older adults: a cross-sectional study. AB - BACKGROUND: Neuroimaging studies in younger adults have demonstrated sex differences in brain processing of painful experimental stimuli. Such differences may contribute to findings that women suffer disproportionately from pain. It is not known whether sex-related differences in pain processing extend to older adults. METHODS: This cross-sectional study investigated sex differences in pain reports and brain response to pain in 12 cognitively healthy older female adults and 12 cognitively healthy age-matched older male adults (age range 65-81, median = 67). Participants underwent psychophysical assessments of thermal pain responses, functional MRI, and psychosocial assessment. RESULTS: When compared to older males, older females reported experiencing mild and moderate pain at lower stimulus intensities (i.e., exhibited greater pain sensitivity; Cohen's d = 0.92 and 0.99, respectively, p < 0.01) yet did not report greater pain-associated unpleasantness. Imaging results indicated that, despite the lower stimulus intensities required to elicit mild pain detection in females, they exhibited less deactivations than males in regions associated with the default mode network (DMN) and in regions associated with pain affect (bilateral dorsolateral prefrontal cortex, somatomotor area, rostral anterior cingulate cortex (rACC), and dorsal ACC). Conversely, at moderate pain detection levels, males exhibited greater activation than females in several ipsilateral regions typically associated with pain sensation (e.g., primary (SI) and secondary somatosensory cortices (SII) and posterior insula). Sex differences were found in the association of brain activation in the left rACC with pain unpleasantness. In the combined sample of males and females, brain activation in the right secondary somatosensory cortex was associated with pain unpleasantness. CONCLUSIONS: Cognitively healthy older adults in the sixth and seventh decades of life exhibit similar sex differences in pain sensitivity compared to those reported in younger individuals. However, older females did not find pain to be more unpleasant. Notably, increased sensitivity to mild pain in older females was reflected via less brain deactivation in regions associated with both the DMN and in pain affect. Current findings elevate the rACC as a key region associated with sex differences in reports of pain unpleasantness and brain deactivation in older adults. Also, pain affect may be encoded in SII in both older males and females. PMID- 26579218 TI - Reduced voluntary running performance is associated with impaired coordination as a result of muscle satellite cell depletion in adult mice. AB - BACKGROUND: Satellite cells, or muscle stem cells, have been thought to be responsible for all muscle plasticity, but recent studies using genetically modified mouse models that allow for the conditional ablation of satellite cells have challenged this dogma. Results have confirmed the absolute requirement of satellite cells for muscle regeneration but surprisingly also showed that they are not required for adult muscle growth. While the function of satellite cells in muscle growth and regeneration is becoming better defined, their role in the response to aerobic activity remains largely unexplored. The purpose of the current study was to assess the involvement of satellite cells in response to aerobic exercise by evaluating the effect of satellite cell depletion on wheel running performance. RESULTS: Four-month-old female Pax7/DTA mice (n = 8-12 per group) were satellite cell depleted via tamoxifen administration; at 6 months of age, mice either remained sedentary or were provided with running wheels for 8 weeks. Plantaris muscles were significantly depleted of Pax7+cells (>=90 % depleted), and 8 weeks of wheel running did not result in an increase in Pax7+ cells, or in myonuclear accretion. Interestingly, satellite cell-depleted animals ran ~27 % less distance and were 23 % slower than non-depleted animals. Wheel running was associated with elevated succinate dehydrogenase activity, muscle vascularization, lipid accumulation, and a significant shift toward more oxidative myosin heavy chain isoforms, as well as an increase in voltage dependent anion channel abundance, a marker of mitochondrial density. Importantly, these changes were independent of satellite cell content. Interestingly, depletion of Pax7+ cells from intra- as well as extrafusal muscle fibers resulted in atrophy of intrafusal fibers, thickening of muscle spindle associated extracellular matrix, and a marked reduction of functional outcomes including grip strength, gait fluidity, and balance, which likely contributed to the impaired running performance. CONCLUSIONS: Depletion of Pax7-expressing cells in muscle resulted in reduced voluntary wheel running performance, without affecting markers of aerobic adaptation; however, their absence may perturb proprioception via disruption of muscle spindle fibers resulting in loss of gross motor coordination, indicating that satellite cells have a yet unexplored role in muscle function. PMID- 26579220 TI - A dataset describing brooding in three species of South African brittle stars, comprising seven high-resolution, micro X-ray computed tomography scans. AB - BACKGROUND: Brooding brittle stars have a special mode of reproduction whereby they retain their eggs and juveniles inside respiratory body sacs called bursae. In the past, studying this phenomenon required disturbance of the sample by dissecting the adult. This caused irreversible damage and made the sample unsuitable for future studies. Micro X-ray computed tomography (MUCT) is a promising technique, not only to visualise juveniles inside the bursae, but also to keep the sample intact and make the dataset of the scan available for future reference. FINDINGS: Seven MUCT scans of five freshly fixed (70 % ethanol) individuals, representing three differently sized brittle star species, provided adequate image quality to determine the numbers, sizes and postures of internally brooded young, as well as anatomy and morphology of adults. No staining agents were necessary to achieve high-resolution, high-contrast images, which permitted visualisations of both calcified and soft tissue. The raw data (projection and reconstruction images) are publicly available for download from GigaDB. CONCLUSIONS: Brittle stars of all sizes are suitable candidates for MUCT imaging. This explicitly adds a new technique to the suite of tools available for studying the development of internally brooded young. The purpose of applying the technique was to visualise juveniles inside the adult, but because of the universally good quality of the dataset, the images can also be used for anatomical or comparative morphology-related studies of adult structures. PMID- 26579221 TI - Perspectives of clinical microbiologists on antimicrobial stewardship programmes within NHS trusts in England. AB - BACKGROUND: The Antimicrobial Self-Assessment Toolkit for NHS Trusts (ASAT) was developed in England by a National Pharmacist Reference Group of an Advisory Non Departmental Public Body on Antimicrobial Resistance and Healthcare Associated Infections (ARHAI), in conjunction with the Department of Health. It is intended to identify and evaluate interventions for the promotion and implementation hospital-based antimicrobial stewardship programmes (ASPs). ASAT v16 was produced by iterative validity testing with end-users utilising a sequential exploratory strategy. It was highlighted that there was a need for the inclusion of the domain which targeted the role of clinical microbiologists due to their substantial roles in hospital-based ASP development and implementation. METHODS: This study aimed to investigate the content validity of ASAT v16 and a proposed draft domain for clinical microbiologists and hence produce ASAT v17. From June to September 2011, semi-structured interviews were conducted with ten consultant clinical microbiologists from secondary and tertiary care National Health Service (NHS) Trusts within England. Interviews were conducted until no novel themes were identified i.e., data saturation was achieved. Each interview was digitally recorded and transcribed verbatim and then analysed using a thematic framework that facilitated the identification of emergent themes and sub-themes. RESULTS: Nine emergent themes were identified which included common enablers and challenges associated with the implementation of effective and sustainable hospital-based ASPs. Key themes included formal governmental mandates, IT infrastructure and also prescribers' knowledge base of antimicrobial chemotherapy and infectious diseases. Most respondents agreed with the content of ASATv16 and the proposed draft section however they suggested that minor modifications were required to improve question sensitivity and hence reduce measurement error. CONCLUSIONS: Although, the ASAT been through multiple iterations and content validity testing, further modifications were required to produce the next iteration, ASAT v17. Question merging and other minor modifications were conducted as indicated by study findings. This study reinforces the need for stakeholder engagement during the development and implementation of tools that evaluate hospital-based implementation strategies. PMID- 26579219 TI - NF-kappaB in inflammation and renal diseases. AB - Nuclear factor kappaB (NF-kappaB) is a family of inducible transcription factors that plays a vital role in different aspects of immune responses. NF-kappaB is normally sequestered in the cytoplasm as inactive complexes via physical association with inhibitory proteins termed IkappaBs. In response to immune and stress stimuli, NF-kappaB members become activated via two major signaling pathways, the canonical and noncanonical pathways, and move to the nucleus to exert transcriptional functions. NF-kappaB is vital for normal immune responses against infections, but deregulated NF-kappaB activation is a major cause of inflammatory diseases. Accumulated studies suggest the involvement of NF-kappaB in the pathogenesis of renal inflammation caused by infection, injury, or autoimmune factors. In this review, we discuss the current understanding regarding the activation and function of NF-kappaB in different types of kidney diseases. PMID- 26579222 TI - Respiratory consequences of N95-type Mask usage in pregnant healthcare workers-a controlled clinical study. AB - BACKGROUND: Outbreaks of emerging infectious diseases have led to guidelines recommending the routine use of N95 respirators for healthcare workers, many of whom are women of childbearing age. The respiratory effects of prolonged respirator use on pregnant women are unclear although there has been no definite evidence of harm from past use. METHODS: We conducted a two-phase controlled clinical study on healthy pregnant women between 27 to 32 weeks gestation. In phase I, energy expenditure corresponding to the workload of routine nursing tasks was determined. In phase II, pulmonary function of 20 subjects was measured whilst at rest and exercising to the predetermined workload while breathing ambient air first, then breathing through N95-mask materials. RESULTS: Exercising at 3 MET while breathing through N95-mask materials reduced mean tidal volume (TV) by 23.0 % (95 % CI -33.5 % to -10.5 %, p < 0.001) and lowered minute ventilation (VE) by 25.8 % (95 % CI -34.2 % to -15.8 %, p < 0.001), with no significant change in breathing frequency compared to breathing ambient air. Volumes of oxygen consumption (VO2) and carbon dioxide expired (VCO2) were also significantly reduced; VO2 by 13.8 % (95 % CI -24.2 % to -3 %, p = 0.013) and VCO2 by 17.7 %, (95 % CI -28.1 % to -8.6 %, p = 0.001). Although no changes in the inspired oxygen and carbon dioxide concentrations were demonstrated, breathing through N95-mask materials during low intensity work (3 MET) reduced expired oxygen concentration by 3.2 % (95 % CI: -4.1 % to -2.2 %, p < 0.001), and increased expired carbon dioxide by 8.9 % (95 % CI: 6.9 % to 13.1 %; p <0.001) suggesting an increase in metabolism. There were however no changes in the maternal and fetal heart rates, finger-tip capillary lactate levels and oxygen saturation and rating of perceived exertion at the work intensity investigated. CONCLUSIONS: Breathing through N95 mask materials have been shown to impede gaseous exchange and impose an additional workload on the metabolic system of pregnant healthcare workers, and this needs to be taken into consideration in guidelines for respirator use. The benefits of using N95 mask to prevent serious emerging infectious diseases should be weighed against potential respiratory consequences associated with extended N95 respirator usage. TRIAL REGISTRATION: The study was registered at clinicaltrials.gov, identifier NCT00265926. PMID- 26579224 TI - Quantitative real-time PCR assisted cell counting (qPACC) for epigenetic - based immune cell quantification in blood and tissue. AB - A novel form of immune cell quantification in blood and tissue is described using epigenetic - based, quantitative real-time PCR assisted cell counting (qPACC). The methylation status of the chromatin structure of either actively expressed or silenced genes is the basis of the epigenetic-based cell identification and quantification technology. Discovery of cell type specific removal of methyl groups (demethylation) from the 5'-carbon of the cytosine base in the dinucleotide cytosine phosphate guanine permits precise and robust quantification of immune cells from only small amounts of human blood or tissue samples. These epigenetic biomarkers located on genomic DNA are stably associated with a cell type of interest. PMID- 26579223 TI - Transcranial magnetic stimulation to understand pathophysiology and as potential treatment for neurodegenerative diseases. AB - Common neurodegenerative diseases include Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD). Transcranial magnetic stimulation (TMS) is a noninvasive and painless method to stimulate the human brain. Single- and paired-pulse TMS paradigms are powerful ways to study the pathophysiological mechanisms of neurodegenerative diseases. Motor evoked potential studied with single-pulse TMS is increased in PD, AD and ALS, but is decreased in HD. Changes in motor cortical excitability in neurodegenerative diseases may be related to functional deficits in cortical circuits or to compensatory mechanisms. Reduction or even absence of short interval intracortical inhibition induced by paired-pulse TMS is common in neurodegenerative diseases, suggesting that there are functional impairments of inhibitory cortical circuits. Decreased short latency afferent inhibition in AD, PD and HD may be related to the cortical cholinergic deficits in these conditions. Cortical plasticity tested by paired associative stimulation or theta burst stimulation is impaired in PD, AD and HD. Repetitive TMS (rTMS) refers to the application of trains of regularly repeating TMS pulses. High-frequency facilitatory rTMS may improve motor symptoms in PD patients whereas low-frequency inhibitory stimulation is a potential treatment for levodopa induced dyskinesia. rTMS delivered both to the left and right dorsolateral prefrontal cortex improves memory in AD patients. Supplementary motor cortical stimulation in low frequency may be useful for HD patients. However, the effects of treatment with multiple sessions of rTMS for neurodegenerative diseases need to be tested in large, sham controlled studies in the future before they can be adopted for routine clinical practice. PMID- 26579225 TI - A quantitative analysis of therapeutic cancer vaccines in phase 2 or phase 3 trial. AB - Despite the progress that has been made in other forms of cancer therapy, Provenge(r) (Sipuleucel-T) is the only FDA-approved vaccine for the treatment of cancer. To understand the current landscape of therapeutic oncology vaccines we performed a quantitative analysis of phase 2 and phase 3 therapeutic cancer vaccine trials. We highlight shifts in trends for the vaccine platforms examined, common adjuvant use, target indications, antibody or treatment combinations between past and recent trials as well as discuss the relationship between these trends and ratio between the number of phase 3: phase 2 for different vaccine platforms. Despite the poor success rate in vaccine approvals, registration of phase 3 trials between 2010 and 2014 were stable indicating continued investment and efforts towards development of immunotherapeutic vaccines. PMID- 26579226 TI - Inhibition of the angiopoietin/Tie2 axis induces immunogenic modulation, which sensitizes human tumor cells to immune attack. AB - BACKGROUND: The angiopoietin/Tie2 pathway is an attractive target for cancer therapy due to its well-known role in regulating angiogenesis. Trebananib, a recombinant peptide-Fc fusion protein, or peptibody, that binds to angiopoietin-1 (Ang1) and Ang2 to block their interaction with the Tie2 receptor, is under active clinical investigation. We investigated whether suppressing the angiopoietin/Tie2 pathway, using the preclinical version of Trebananib (mL4-3 and L1-7(N)), could increase the sensitivity of human tumor cells to immune-mediated lysis through immunogenic modulation, which would make Trebananib a promising candidate for combination with immunotherapy. METHODS: We assessed human carcinoma cells for expression and activation of Ang1 and Ang2 and their receptor tyrosine kinase Tie2. In vitro, we exposed tumor cell lines expressing Tie2 to the peptibodies mL4-3 and L1-7(N), which inhibit the binding of Ang1 and Ang2 to Tie2, and assessed the cells for changes in viability, proliferation, surface phenotype, and sensitivity to attack by antigen-specific cytotoxic T lymphocytes (CTLs). RESULTS: Suppression of the angiopoietin/Tie2 pathway using mL4-3 and L1 7(N) had no effect on the proliferation or viability of tumor cells. However, these inhibitors markedly altered tumor cell phenotype, rendering tumor cells significantly more sensitive to antigen-specific CTL killing. ICAM-1 was shown to be mechanistically involved in these inhibitors' ability to sensitize tumor cells to immune-mediated attack by functional blocking studies. CONCLUSION: Our findings provide a rationale for the combination of agents targeting the angiopoietin/Tie2 pathway with cancer immunotherapies. PMID- 26579227 TI - Cetuximab ameliorates suppressive phenotypes of myeloid antigen presenting cells in head and neck cancer patients. AB - BACKGROUND: Myeloid-derived suppressor cells (MDSC) and M2 monocytes/macrophages are two types of suppressive myeloid antigen presenting cells that have been shown to promote tumor progression and correlate with poor prognosis in cancer patients. Tumor antigen specific monoclonal antibodies (mAb) have emerged as important agents for cancer therapy. In addition to the direct inhibition of tumor growth, the Fc portions of the therapeutic mAbs, such as the IgG1 portion of the anti-epidermal growth factor receptor (EGFR) mAb cetuximab, might interact with the Fc-gamma receptors (FcgammaR) on myeloid cells and modulate their suppressive activity. METHODS: Patients with locally advanced head and neck squamous cell carcinoma (HNSCC) on the UPCI 08-013 NCT01218048 trial were treated with single-agent cetuximab before surgery. Blood were collected pre- and post cetuximab treatment to analyze frequency of monocytic MDSC (CD11b(+)CD14(+)HLA DR(lo/-)), granulocytic MDSC (LIN(-)CD11b(+)CD15(+)) and CD11b(+)CD14(+)HLA DR(hi) monocytes by flow cytometry. Besides, CD11b(+)CD14(+)HLA-DR(hi) monocytes were sorted for qPCR analysis of IL-10 and IL-12B transcripts. MDSC were generated in vitro with or without coated hIgG1 and tested for suppressive activity in mixed leukocyte reaction (MLR). Naive monocytes from HNSCC patients co-cultured with tumor cell lines in the presence of cetuximab or hIgG1 were analyzed for M1/2 surface markers and cytokines. RESULTS: We observed significantly increased monocytic MDSC in non-responders and decreased granulocytic MDSC in responders after cetuximab treatment. In addition, circulating CD11b(+)CD14(+)HLA-DR(hi) monocytes of cetuximab responders displayed attenuated M2 polarization, with decreased CD163(+) expression and IL-10 transcripts after cetuximab treatment. This beneficial effect appeared to be FcgammaR dependent, since CD16 ligation reproduced the reversal of suppressive activity of MDSC in vitro. CD14(+) naive monocytes from the co-cultures of tumor cells, cetuximab and HNSCC patient PBMC or purified monocytes were skewed to an M1-like phenotype, with increased expression of HLA-DR, CD86 and production of IL 12 p70. Likewise, reduced M2 features (expression of CD163 and production of IL 10) were found after crosslinking CD16 on the surface of monocytes to cetuximab coated tumor cells. CONCLUSION: Our studies demonstrate a novel function of cetuximab in ameliorating suppressive phenotypes of FcgammaR bearing myeloid cells in cancer patients, which is associated with better clinical outcome of cetuximab-treated patients. CLINICAL TRIAL REGISTRY: #NCT01218048. Registered 7 October 2010. PMID- 26579228 TI - Erratum to: Immune monitoring technology primer. AB - [This corrects the article DOI: 10.1186/s40425-015-0086-9.]. PMID- 26579229 TI - T-5224, a selective inhibitor of c-Fos/activator protein-1, improves survival by inhibiting serum high mobility group box-1 in lethal lipopolysaccharide-induced acute kidney injury model. AB - BACKGROUND: Sepsis is a potentially fatal syndrome mediated by an early [e.g., tumor necrosis factor-alpha (TNF-alpha)] and late [high mobility group box-1 (HMGB-1)] proinflammatory cytokine response to infection. Sepsis-induced acute kidney injury (AKI) is associated with a high mortality. C-Fos/activator protein 1 (AP-1) controls the transactivation of proinflammatory cytokines via AP-1 binding in the promoter region. T-5224 is a de novo small molecule inhibitor of c Fos/AP-1 that controls gene expression of multiple proinflammatory cytokines. We investigated whether T-5224, a selective inhibitor of c-Fos/AP-1, improves survival in lethal lipopolysaccharide (LPS)-induced AKI by inhibiting early (TNF alpha) and late (HMGB-1) proinflammatory cytokine response. METHODS: Mice were divided into four groups (control, LPS, LPS + T-5224, and T-5224 only). Control mice were administered polyvinylpyrrolidone (PVP) solution orally, immediately after intraperitoneal (i.p.) saline injection. LPS mice were administered PVP solution orally immediately after i.p. LPS (10 mg/kg) injection. LPS + T-5224 mice were administered T-5224 orally (300 mg/kg) immediately after i.p. LPS injection. T-5224 mice were administered T-5224 orally (300 mg/kg) after i.p. saline injection. Serum concentrations of TNF-alpha, HMBG-1, and interleukin (IL) 10 were measured by enzyme-linked immunosorbent assay (ELISA). Serum blood urea nitrogen (BUN) and creatinine concentrations were commercially analyzed. Finally, histological examination was performed on the kidney. RESULTS: Treatment with T 5224 decreased serum TNF-alpha and HMGB-1 levels and increased survival after LPS injection. Furthermore, T-5224 treatment decreased serum BUN and creatinine concentrations but increased serum IL-10 concentration. LPS-induced pathological changes in kidney were attenuated by T-5224 treatment. CONCLUSIONS: These results suggest that T-5224, a selective inhibitor of c-Fos/AP-1, inhibits expression of early and late proinflammatory cytokines, protecting mice from LPS-induced lethality. T-5224 is a potential approach for decreasing lethality in sepsis induced AKI. PMID- 26579230 TI - Sonoelectrochemical mineralization of perfluorooctanoic acid using Ti/PbO 2 anode assessed by response surface methodology. AB - BACKGROUND: Perfluorocarboxylic acids (PFCAs) are emerging pollutant and classified as fully fluorinated hydrocarbons containing a carboxylic group. PFCAs show intensively resistance against chemical and biological degradation due to their strong C-F bond. The Sonoelectrochemical mineralization of the synthetic aqueous solution of the perfluorooctanoic acid (PFOA) on Ti/PbO2 anode was investigated using the response surface methodology based on a central composite design with three variables: current density, pH, and supporting electrolyte concentration. METHODS: The defluorination ratio of PFOA was determined as an indicator of PFOA mineralization. Fluoride ion concentration was measured with an ion chromatograph unit. The Ti/PbO2 electrode was prepared using the electrochemical deposition method. The ultrasonic frequency was 20 kHz. RESULTS: The optimum conditions for PFOA mineralization in synthetic solution were electrolyte concentration, pH, and current density of 94 mM, 2, and 83.64 mA/cm(2), respectively. The results indicated that the most effective factor for PFOA mineralization was current density. Furthermore, the PFOA defluorination efficiency significantly enhanced with increasing current density. Under optimum conditions, the maximum mineralization of PFOA was 95.48 % after 90 min of sonoelectrolysis. CONCLUSIONS: Sonoelectrolysis was found to be a more effective technique for mineralization of an environmentally persistent compound. PMID- 26579231 TI - Rational Risk-Benefit Decision-Making in the Setting of Military Mefloquine Policy. AB - Mefloquine is an antimalarial drug that has been commonly used in military settings since its development by the US military in the late 1980s. Owing to the drug's neuropsychiatric contraindications and its high rate of inducing neuropsychiatric symptoms, which are contraindications to the drug's continued use, the routine prescribing of mefloquine in military settings may be problematic. Due to these considerations and to recent concerns of chronic and potentially permanent psychiatric and neurological sequelae arising from drug toxicity, military prescribing of mefloquine has recently decreased. In settings where mefloquine remains available, policies governing prescribing should reflect risk-benefit decision-making informed by the drug's perceived benefits and by consideration both of the risks identified in the drug's labeling and of specific military risks associated with its use. In this review, these risks are identified and recommendations are made for the rational prescribing of the drug in light of current evidence. PMID- 26579232 TI - Effectiveness Evaluation of Levamisole, Albendazole, Ivermectin, and Vernonia amygdalina in West African Dwarf Goats. AB - Anthelmintic drug resistance has led to the search for alternatives in controlling helminth infections. Fifty West African Dwarf goats without history of anthelmintic treatment were divided equally into five groups. Group A was treated with ivermectin injection subcutaneously, group B with levamisole subcutaneously, group C with albendazole orally, and group D with aqueous extract of Vernonia amygdalina and group E was untreated control. Faecal samples were collected before treatment from each animal and larval culture was carried out. Faecal egg count reduction (FECR) test was carried out for each group and the data analysed using FECR version 4 to calculate percent reduction in faecal egg count. Predominant helminth infections from larval culture were Haemonchus contortus (70%), Trichostrongylus spp. (61%), and Oesophagostomum spp. (56%). Mixed infection was present in all the animals. From the FECR test Vernonia amygdalina extract was more effective against helminths (100%), compared to ivermectin 96%, levamisole 96%, and albendazole 99%. The lower 95% confidence limit was 89 for ivermectin and levamisole and 91 for albendazole. There is low resistance to ivermectin and levamisole and susceptibility to albendazole while V. amygdalina has great potentials that could be explored for the treatment of helminth diseases in goats. PMID- 26579233 TI - Iris from Iridectomy Used as Spacer underneath the Scleral Flap: The Iridenflip Trabeculectomy Technique. AB - Purpose. We describe a modified trabeculectomy technique in which the iris is used to prevent fibrosis of the scleral flap. Material and Methods. A retrospective case series of patients with medically uncontrolled open angle glaucoma underwent trabeculectomy. Instead of performing a classical iridectomy, the iris was used as spacer underneath the scleral flap. Postoperative management was identical to classical trabeculectomy, with suture removal and needling if necessary. Five of the patients underwent simultaneous phacoemulsification through a separate temporal corneal incision. Patients should have two-year follow-up. Results. Data of ten patients were analysed, two had a previous failed trabeculectomy, two had LTP, and one had a corneal transplantation. In 3 patients MMC 0,1 mg/mL was used. After one and two years mean IOP was, respectively, 13,1 and 12,1 mmHg. IOP <= 16 mmHg was reached in 90% of patients without pressure lowering medication. No major complications were seen; no abnormal inflammatory reaction and no deformation or dislocation of the pupil occurred. Conclusion. By using the iris from the iridectomy as spacer under the scleral flap, fibrosis of the scleral flap is no longer possible. This iridenflip trabeculectomy technique gives an excellent complete success rate (IOP <= 16 mmHg) of 90%. A larger study is currently being done. PMID- 26579234 TI - Photoreceptor Inner and Outer Segment Junction Reflectivity after Vitrectomy for Macula-Off Rhegmatogenous Retinal Detachment. AB - Purpose. To evaluate the spatial distribution of photoreceptor inner and outer segment junction (IS/OS) reflectivity changes after successful vitrectomy for macula-off retinal detachment (PPV-mOFF) using spectral domain optical coherence tomography (SdOCT). Methods. Twenty eyes after successful PPV-mOFF were included in the study. During a mean follow-up period of 15.3 months, SdOCT was performed four times. To evaluate the IS/OS reflectivity a four-grade scale was used. Results. At the first follow-up visit the IS/OS had very similar reflectivity in entire length of the central scan with total average value of 1,05. At the second visit the most significant increase of the reflectivity was observed in temporal and nasal parafovea with average values of 2,17 and 2,22, respectively. The third region of increased reflectivity of an average value of 2,33 appeared during the third follow-up visit and was located in the foveola. At the last follow-up visit in entire central cross section the IS/OS reflectivity exceeded grade 2 reaching the highest average values in nasal and temporal parafovea and foveola. Conclusions. A gradual increase of the IS/OS reflectivity was observed in eyes after PPV-mOFF. The process is not random and starts independently in the peripheral and central part of the macula which may be attributed to the variable regenerative potential of cones and rods. PMID- 26579235 TI - Design and Characterization of Buccoadhesive Liquisolid System of an Antihypertensive Drug. AB - Nifedipine is an antihypertensive BCS class II drug which has poor bioavailability when given orally. The objective of the present study was to increase the bioavailability of nifedipine, by formulation and evaluation of a buccoadhesive liquisolid system using magnesium aluminium silicate (Neusilin) as both carrier and coating material and dissolution media were selected based on the solubility studies. A mixture of carboxymethylcellulose sodium and carbomer was used as mucoadhesive polymers. Buccoadhesive tablets were prepared by direct compression. FTIR studies confirmed no interaction between drug and excipients. XRD studies indicated change/reduction in crystallinity of drug. The powder characteristics were evaluated by different flow parameters to comply with pharmacopoeial specifications. The dissolution studies for liquisolid compacts and tablet formulations were carried out and it was found that nifedipine liquisolid tablets formulated from bioadhesive polymers containing 49% liquisolid system, 17.5% carbomer, and 7.5% carboxymethylcellulose sodium showed the best results in terms of dissolution properties. Prepared formulation batches were evaluated for swelling, bioadhesion strength, ex vivo residence time, and permeability studies. The optimized batch was showing promising features of the system. Formulating nifedipine as a buccoadhesive tablet allows reduction in dose and offers better control over the plasma levels. PMID- 26579236 TI - A Simple and Safe Technique for CT Guided Lung Nodule Marking prior to Video Assisted Thoracoscopic Surgical Resection Revisited. AB - Aim. We describe our experience of a simple, safe, and reproducible technique for lung nodule marking prethoracoscopic metastasectomy. Thoracoscopic lung nodule resection reduces patient discomfort, complications, higher level of care, hospital stay, and cost; however, small deeply placed lung nodules are difficult to locate and resect thoracoscopically. Materials and Methods. We describe and review the success of our novel technique, where nodules are identified on a low dose CT and marked with methylene blue using CT fluoroscopy guidance immediately prior to surgery. Results. 30 nodules were marked with a mean size of 8 mm (4-18 mm) located at a mean depth of 17 mm, distributed through both lungs. Dye was detected at the pleural surface in 97% of the patients and at the nodule in 93%. There were no major complications. Thoracoscopic resection was possible in 90%. Conclusion. This is a simple and safe method of lung nodule marking to facilitate thoracoscopic resection in cases where this may not be technically possible due to nodule location. PMID- 26579237 TI - The management of moderate and severe congenital penile torsion associated with hypospadias: Urethral mobilisation is not a panacea against torsion. AB - OBJECTIVES: To evaluate the effectiveness of urethral mobilisation for correcting moderate and severe penile torsion associated with distal hypospadias. PATIENTS AND METHODS: Nineteen patients with distal hypospadias and congenital moderate and severe penile torsion were treated surgically. The hypospadias was at the distal shaft, coronal and glanular in seven, eight and four patients, respectively, and six had mild chordee. The mean (SD, range) angle of torsion was 94.7 (19.9, 75-160) degrees . The urethra was mobilised down to the perineum. If the urethral mobilisation was insufficient the right border of the tunica albuginea was anchored to the pubic periosteum. The hypospadias was repaired using the urethral mobilisation and advancement technique, with a triangular plate flap for meatoplasty. The patients were followed up for 12-18 months. RESULTS: All patients had a successful functional and cosmetic outcome, with no residual torsion. Two patients had a small subcutaneous haematoma that resolved after conservative treatment. Massive oedema occurred in three patients and was treated conservatively. Urethral mobilisation did not correct the penile torsion completely. Although the mean (SD, range) angle of torsion was reduced to 86.1 (14.3, 65-130) degrees , statistically significantly different (P = 0.001), it was not clinically important. The presence of chordee had no significant correlation with the reduction of penile torsion. CONCLUSION: Urethral mobilisation cannot completely correct moderate and severe penile torsion but it might only partly decrease the angle of torsion. Periosteal anchoring of the tunica albuginea might be the most reliable manoeuvre for the complete correction of penile torsion. PMID- 26579238 TI - Primary vesico-ureteric reflux: The need for individualised risk stratification. AB - The management of paediatric primary vesico-ureteric reflux (VUR) has undergone serial changes over the last decade. As this disorder is extremely heterogeneous, and high-quality prospective data are limited, the treatment strategies vary among centres. Current treatment options include observation only, continuous antibiotic prophylaxis, and surgery. Surgical intervention is indicated if a child has a breakthrough urinary tract infection (UTI) while on continuous antibiotic prophylaxis or if there are renal scars present. After excluding a secondary cause of VUR the physician should consider the risk factors affecting the severity of VUR and manage the child accordingly. Those factors include demographic factors (age at presentation, gender, ethnicity) and clinical factors (VUR grade, unilateral vs. bilateral, presence of renal scars, initial presentation, the number of UTIs, and presence of any voiding or bowel dysfunction). In this review we summarise the major controversial issues in current reports on VUR and highlight the importance of individualised patient management according to their risk stratification. PMID- 26579239 TI - Can evidence-based medicine change toilet-training practice? AB - OBJECTIVES: To assess the evidence showing that a specific method of toilet training (TT) is more effective than others, as any method of TT recommended by a physician faces obstacles because parents rarely request advice on TT from physicians, and TT practices vary tremendously across cultures and socioeconomic levels. METHODS: Reports on the natural course of urinary incontinence in children and different methods of TT, published in English between 1946 and 2012, were reviewed. Specifically investigated were historical recommendations on TT, the prevalence of urinary incontinence during childhood, the outcome of TT methods, and the effect of culture and socioeconomic status on the choice of TT method and timing. RESULTS: TT now occurs at later ages than it did previously. This progression reflects changing ideas about normal childhood physiology and psychology. The prevalence of urinary incontinence in European countries progressively decreased in children aged between 6-7 years and 16-17 years old. TT methods change with increasing socioeconomic levels to 'child-centred' techniques applied at older ages, but the prevalence of urinary incontinence after 'parent-centred' techniques of TT at younger ages has not been studied. There is currently no evidence that a specific timing or method of TT is more effective or prevents voiding dysfunction. CONCLUSIONS: Follow-up studies of urinary continence in children toilet trained at 6-12 months of age might provide evidence for whether a given method or timing of TT is beneficial to prevent voiding dysfunction. The recommendations of physicians might be more readily adopted if they fit culturally accepted ideas of good parenting techniques. PMID- 26579240 TI - Disorders of sexual differentiation: I. Genetics and pathology. AB - OBJECTIVES: To provide a summary of the recent major advances in the field of molecular genetics and understanding of psychosexual development, as these developments have resulted in changes in terminology and classification of disorders of sexual differentiation (DSD)/intersex; and to provide a quick and simplified review of the basic information. METHODS: Recent publications (over the last 10 years) were identified by a PubMed search, as were relevant previous studies, using the keywords; 'sex chromosomes', 'psychosexual development', 'classifications', 'disorders of sexual differentiation', 'Chicago consensus', 'gonadal malignancy', 'intersex' and 'ambiguous genitalia'. RESULTS: The newly proposed terminology and classification has eliminated some confusion for both patient and family, as well as among health professionals. The new advances have facilitated the categorisation of gonadal malignancy in patients with DSD into high-, intermediate- and low-risk groups. CONCLUSIONS: The major changes in terminology and classification of DSD should be considered as the first steps on a long road of research effort. The current available data remain far from sufficient. More molecular genetics studies will allow a better understanding of the causes of each condition of DSD. PMID- 26579241 TI - Disorders of sexual differentiation: II. Diagnosis and treatment. AB - OBJECTIVES: To provide a review and summary of recent advances in the diagnosis and management of disorder(s) of sexual differentiation (DSD), an area that has developed over recent years with implications for the management of children with DSD; and to assess the refinements in the surgical techniques used for genital reconstruction. METHODS: Recent publications (in the previous 10 years) were identified using PubMed, as were relevant previous studies, using following keywords; 'diagnosis and management', 'ambiguous genitalia', 'intersex', 'disorders of sexual differentiation', 'genitogram', 'endocrine assessment', 'gender assignment', 'genitoplasty', and 'urogenital sinus'. The findings were reviewed. RESULTS: Arbitrary criteria have been developed to select patients likely to have DSD. Unnecessary tests, especially those that require anaesthesia or are associated with radiation exposure, should be limited to situations where a specific question needs to be answered. Laparoscopy is an important diagnostic tool in selected patients. The routine use of multidisciplinary diagnostic and expert surgical teams has become standard. Full disclosure of different therapeutic approaches and their timing is recommended. CONCLUSIONS: Diagnostic tests should be tailored according to the available information. Parents and/or patients should be made aware of the paucity of well-designed studies, as these conditions are rare. Unnecessary irreversible surgery should be postponed until a multidisciplinary experienced team, with the parents' and or patients' approval, can make a well-judged decision. PMID- 26579242 TI - Disorders of sexual development in a cultural context. AB - BACKGROUND: Disorders of sexual development (DSD) are congenital conditions in which the development of the chromosomal, gonadal or anatomical sex can be deemed atypical. The external genitalia should appear 'normal' in size and shape from birth, with no question of abnormality, and the individual must receive appropriate social-environmental feedback in the course of the sexual maturation process. METHODS: We review regional differences in the variables considered important for gender assignment in individuals with DSD. Various approaches to certain forms of DSD are analysed within their cultural context. RESULTS: The decision to leave the sex of rearing undisturbed or to change it is difficult. It depends on the patient's age and the extent to which the gender identity has been established with parental gender preference, social, cultural and religious factors. Severe forms of genetically female congenital adrenal hyperplasia, androgen insensitivity syndrome, 17beta-hydroxysteroid dehydrogenase-3, 5alpha reductase and cytochrome P450 oxidoreductase deficiencies are found to be the most difficult cases to diagnose and/or manage. CONCLUSION: Gender assignment in children with DSD is a subject of intense debate. Each case of DSD must be evaluated individually and on its merits and potentials. Although early admission and appropriate diagnostic facilities could provide the correct diagnosis, this is not the case in some cultures. It is seen that 'gender panic', social and religious concepts affect the decision-making process in gender assignment, especially in delayed cases. PMID- 26579244 TI - Editorial comment on: The surgical management of paediatric bladder and prostate rhabdomyosarcoma. PMID- 26579243 TI - The surgical management of paediatric bladder and prostate rhabdomyosarcoma. AB - BACKGROUND: The surgical management of paediatric bladder/prostate rhabdomyosarcoma (B/P RMS) continues to develop, with the goal of maximising organ preservation while achieving successful cancer control. The timing of radiotherapy and surgical excision to improve event-free survival (EFS) and overall survival (OS) remains controversial. METHODS: Previous reports in English on B/P RMS over the past 15 years were identified and reviewed, focusing on studies comparing the effects of radiotherapy and surgery for local control, the effect of local control on OS, and improved means of diagnosing viable tumour after chemotherapy. RESULTS: The concept of lowering the 'cost of cure' drives current protocols. Bladder-sparing surgery is possible for 80% of patients after initial chemotherapy, with a mean 5-year OS of 85%. Overall, half of the patients are continent of urine, and adding radiotherapy might increase the risk of incontinence. Previous studies suggesting that early radiotherapy achieved better EFS than delayed radiotherapy did not control for stage and size of the tumour, which are the primary determinants of EFS. Improved local control does not automatically translate into improved OS. CONCLUSIONS: The current role for the surgical management in B/P RMS is to achieve local control of tumours that do not respond to chemotherapy and radiotherapy. An improved means of detecting viable tumour after initial chemotherapy would improve the ability to decide when local therapy is necessary. The continuing challenge for urologists managing these children is knowing when bladder-sparing surgery would be the best therapy. PMID- 26579245 TI - Unusual presentations of prostate cancer: A review and case reports. AB - OBJECTIVE: To report our institutional experience with some rare presentations of prostate cancer, as prostate cancer is a common problem and affects a large group of men during their lifetime, but a few studies report unusual presentations of metastatic prostate cancer. METHODS: All possible clinical and pathological data were collected for six relevant patients with prostate cancer and unusual metastases who were identified at our institution. PubMed was searched for unusual presentations of prostate cancer in the last 20 years (1982-2012) and all relevant publications were assessed. The authors discussed the reports and selected those articles of major clinical significance to include in a review. RESULTS: We identified 19 reports of major clinical significance and reviewed them. As in the cases from our institution, supraclavicular lymphadenopathy, isolated upper ureteric obstruction and severe obstructing constipation were some of the rare presentations encountered at other institutions, and reported mostly as sporadic case-reports. CONCLUSION: Prostate cancer should be always considered in the differential diagnosis of elderly men presenting with supraclavicular lymphadenopathy, hydroureteronephrosis or constipation, even in the presence of a normal digital rectal examination and low serum total prostate-specific antigen (PSA) levels. PSA immunohistochemical staining should be used in doubtful cases. PMID- 26579246 TI - Bladder leiomyoma: Presentation, evaluation and treatment. AB - BACKGROUND: Bladder leiomyomas are benign mesenchymal neoplasms and very rare urinary tumours that represent <0.5% of all bladder tumours, with only 250 cases reported worldwide to date. The importance of recognising their characteristic features, leading to their correct treatment, is fundamental. Therefore, we reviewed reports of leiomyomas of the urinary bladder, their causes, clinical presentations, imaging methods and surgical management, updated to 2012. METHODS: We retrospectively reviewed articles published in the USA, Europe and Asia, from 1953 to date, using PubMed, Medscape, Medline and the several major journals. We report areas of controversies and well-established guidelines. RESULTS: We reviewed 36 articles that confirmed, with a high level of evidence-based medicine, that the male to female ratio is equal, the cause of bladder leiomyomas remains unknown, and their most common presentation is obstructive uropathy; endovesical tumours are the most common. Their radiological diagnosis can be made by ultrasonography, computed tomography or magnetic resonance imaging. Complete surgical resection is a very effective treatment, associated with almost no recurrence. CONCLUSION: In symptomatic patients a complete surgical resection can give a very good outcome, with almost no recurrence. PMID- 26579247 TI - Percutaneous nephrolithotomy in the supine position: Safety and outcomes in a single-centre experience. AB - OBJECTIVES: To assess the feasibility of performing percutaneous nephrolithotomy (PCNL) with the patient supine. Although PCNL with the patient prone is the standard technique for treating large (>2 cm) renal stones including staghorn stones, we evaluated the safety and efficacy of supine PCNL for managing large renal stones, with special attention to evaluating the complications. PATIENTS AND METHOD: In a prospective study between January 2010 and December 2011, 54 patients with large and staghorn renal stones underwent cystoscopy with a ureteric catheter inserted, followed by puncture of the collecting system while they were supine. Tract dilatation to 30 F was followed by nephroscopy, stone disintegration using pneumatic lithotripsy, and retrieval using a stone forceps. All patients had a nephrostomy tube placed at the end of the procedure. The results were compared with those from recent large series of supine PCNL. RESULTS: The median (range) operative duration was 130 (90-210) min, and the mean (SD) volume of irrigant was 22.2 (3.7) L. One puncture was used to enter the collecting system in 51 renal units (94%), while three units (6%) with a staghorn stone needed two punctures. The stone clearance rate was 91%, and five patients had an auxiliary procedure. There were complications in 15 patients (28%). All patients were stone-free at a 3-month follow-up. CONCLUSION: Supine PCNL is technically feasible; it has several advantages to patients, urologists and anaesthesiologists. It gives stone-free rates and a low incidence of organ injury comparable to those in standard prone PCNL. PMID- 26579248 TI - Percutaneous endoscopic nephropexy with a percutaneous suture passed through the kidney. AB - OBJECTIVES: To report a technique of percutaneous endoscopic nephropexy, using a polyglactin suture passed through the kidney, in patients with nephroptosis. PATIENTS AND METHODS: Four women presenting with symptomatic right nephroptosis underwent a percutaneous endoscopic nephropexy. An upper-pole calyx was accessed percutaneously and a 24-F working sheath was placed. Another needle access was made through a lower-pole calyx and a #2 polyglactin suture was passed into the renal pelvis. It was then pulled out through the upper-pole tract using the nephroscope. A retroperitoneoscopy was performed and the tip of the nephroscope was used to cause nephrolysis. After inserting the nephrostomy tube the polyglactin suture was passed into the subcutaneous tissue and then tied without too much tension, to avoid cutting the parenchyma. RESULTS: The operative duration was 33 min and the hospital stay after surgery was 3.5 days. The nephrostomy catheter was removed 5 days after surgery. There were no complications, especially no haemorrhagic, infectious, lithiasic or thoracic complications. The four patients were relieved of their initial symptoms, with a mean follow-up of 28 months. Ultrasonography and/or intravenous urography showed the kidney at a higher location with the patient standing. CONCLUSIONS: This technique combines the nephrostomy tract used in percutaneous techniques with the suture and nephrolysis used in laparoscopic techniques. Moreover, this procedure seems to be safe, with satisfactory anatomical and clinical results and a lower morbidity. However, a larger series will be necessary to establish its long-term morbidity and success rate. PMID- 26579249 TI - Editorial comment to "Percutaneous endoscopic nephropexy with a percutaneous suture passed through the kidney". PMID- 26579250 TI - Free-flank modified supine vs. prone position in percutaneous nephrolithotomy: A prospective randomised trial. AB - OBJECTIVE: To compare the technical aspects, operative time, safety and effectiveness of percutaneous nephrolithotomy (PCNL) in the free-flank modified supine position (FFMSP) vs. the standard prone position (SPP). PATIENTS AND METHODS: Seventy-seven patients (47 men and 30 women) with renal stones were enrolled and systematically randomised into two groups, A (39 patients) treated using the FFMSP, and B (38 patients) in the SPP. The outcome was considered as a cure (successful procedure) if the patient became stone-free or had residual fragments of <4 mm in diameter. The operative time (from the induction of anaesthesia to the removal of the endotracheal tube) was measured and any operative complications or conflicts were recorded. The different variables were compared and analysed between the groups. RESULTS: Patients in both groups had comparable preoperative clinical data and there were no significant differences in the preoperative clinical characteristics. The procedure was successful in 84.6% and 84% of group A and B, respectively. The operative time was significantly longer in group B (SPP) than A (FFMSP). There was no significant difference between the groups in fluoroscopy time and patients' outcome. CONCLUSIONS: The FFMSP (with a cushion under the ipsilateral shoulder) has similar efficacy and safety as the SPP for PCNL and is associated with a significantly quicker operation. PMID- 26579251 TI - The use of a biological model for comparing two techniques of fluoroscopy-guided percutaneous puncture: A randomised cross-over study. AB - OBJECTIVES: To develop a new and inexpensive model for training in fluoroscopic puncture into the pelvicalyceal system, and to use this model to compare the learning curve of two fluoroscopic techniques, the 'eye of the needle' (EN) and triangulation techniques. MATERIALS AND METHODS: For the trial we used a commercial plastic model (a shop-window mannequin) in which a bovine kidney, embedded in sponge with a spatial orientation similar to the human, was inserted into the model. The ureter of the animal kidney was connected to contrast fluid. Ten residents and interns were randomised into two groups; group A started the puncture using the EN technique, each member making five attempts, and then five attempts using the triangulation technique, and group B started with triangulation and then used the EN technique. RESULTS: There was no statistically significant difference between the techniques for the mean (SD) number of trials to make a correct puncture, at 2.68 (1.00) in the EN technique and 2.86 (1.05) in the triangulation technique, or for the duration of each trial, at 523 (189) s for the EN technique and 578 (175) s for the triangulation technique. The fluoroscopy time was less in the EN technique, at 113.9 (48.9) s than for the triangulation method, at 135.8 (42.4) (P < 0.005). CONCLUSIONS: The model was easy to construct and feasible for training. Both techniques had a similar learning curve, with higher fluoroscopy exposure for the triangulation technique. PMID- 26579252 TI - Thermo-expandable metallic urethral stents for managing recurrent bulbar urethral strictures: To use or not? AB - OBJECTIVES: To assess the role of temporary thermally expandable urethral stents in maintaining urethral patency in patients with a recurrent bulbar urethral stricture. PATIENTS AND METHODS: Twenty-three men with a recurrent bulbar urethral stricture after several attempts at direct visual internal urethrotomy (DVIU) and/or failed urethroplasty were managed with a thermally expandable, biocompatible nickel-titanium alloy urethral stent (Memokath(r) MK044, Pnn Medical, Kvistgaard, Denmark). The stents were applied by a special mounting device via a rigid urethroscope after DVIU. All patients were followed using plain radiography, uroflowmetry and urine analysis every 3 months for 1 year, and then every 6 months. RESULTS: The mean (SD) age of the patients was 55.4 (7.3) years and the mean (SD) stricture length was 3.6 (1.2) cm. All patients tolerated the stent, with minimal discomfort in some patients. Four patients (17%) had urinary tract infections, three (13%) had haematuria, three (13%) had obstructed stents due to encrustation, in five (22%) the stent migrated, and two patients had no delayed complications. The mean (SD) follow-up was 17.4 (6.1) months. CONCLUSION: Urethral stenting with nickel-titanium alloy thermally expandable stents can be an acceptable temporary procedure for patients with recurrent bulbar urethral strictures who are unfit for or who refuse urethroplasty. However, they have limitations; the search for an ideal urethral stent continues. PMID- 26579253 TI - The validity of testicular aspirate cytology and DNA image-analysis of the aspirate in the assessment of infertile men. AB - OBJECTIVE: To assess the possibility of using cytological examination and DNA image-analysis of testicular fine-needle aspirates instead of open surgical biopsy in the investigation of infertile men, as testicular biopsy has long been used for investigating infertility but the interpretation of histological slides is usually subjective. PATIENTS AND METHODS: Thirty-three men (aged 22-36 years) were evaluated for infertility and underwent both open biopsy and fine-needle aspiration of their testes. Subsequently, the needle aspirates were assessed histopathologically and cytologically, and by DNA image cytometry. The percentages of haploid, diploid and tetraploid cells were determined for each patient. RESULTS: The cases were divided into four categories: (1) Complete spermatogenesis, with a DNA pattern of 1n > 2n > 4n; (2) Maturation arrest, with a DNA pattern of 2n > 4n with no haploid cells; (3) Sertoli cell-only syndrome, with a DNA pattern of only 2n, with no haploid or tetraploid cells; (4) Hypospermatogenesis, with a variable DNA pattern, i.e. mild with 1n > 2n, moderate with 2n > 1n > 4n, and marked where the DNA pattern was 2n > 4n > 1n. From the cytological and DNA image-analysis of the aspirate a diagnosis was possible that had a strong correlation with the histological diagnosis of the same case. From image analysis we could exclude interstitial cells, Sertoli cells and sperms on the static image, and differentiate between spermatozoa and spermatids based on morphological characteristics in the cytological smear. This technique can therefore be used to quantitatively determine the percentages of various cell types within the seminiferous tubules. By coupling image ploidy analysis and cytological examination of a cytological smear, spermatogenesis can be assessed accurately. CONCLUSION: Image cytometry could be used to exclude interstitial cells, Sertoli cells and sperms on the static image and so produce an accurate assessment of spermatogenesis. A combination of ploidy and cell morphology characteristics in cytological smears provides an accurate, reproducible and easily used alternative to open testicular biopsy. PMID- 26579254 TI - Effect of noise stress on male rat fertility, and the protective effect of vitamins C and E on its potential effect. AB - OBJECTIVE: To evaluate the effect of noise on the fertility of male rats, and to assess the effect of vitamins C and E on its potential effect. MATERIALS AND METHODS: Forty adult male rats were randomly divided into five equal groups. Group 1 (control) was not exposed to noise. Groups 2-5 were exposed to noise of 90-130 dB and 300-350 Hz from 19.00 to 07.00 h every day for 50 days; group 2 received vitamin C and group 3 received vitamin E. Group 4 received vitamins C and E concomitantly and group 5 received no vitamins. After 50 days, the serum levels of follicle-stimulating hormone (FSH), luteinising hormone (LH) and testosterone were measured. Each rat was then left for 1 week with three female rats, for mating. Pregnant females were killed humanely after 19 days of pregnancy and evaluated for the presence and number of viable, dead and absorbed fetuses. RESULTS: The mean serum FSH level was statistically significantly different between the control and groups 2 (P < 0.05) and 5 (P < 0.001). The mean serum LH level differed significantly between the control and groups 2 (P = 0.05), 3 (P < 0.05) and 5 (P < 0.001). The mean serum testosterone level was significantly different between the control and group 5 (P < 0.001). Serum FSH, LH and testosterone levels in group 5 were significantly different from all the others (P < 0.001). The pregnancy rates in females mated with groups 1 and 5 were statistically different (P < 0.05). Comparing groups 1-4, there was no difference in the occurrence of abnormal pregnancy (P > 0.05), but group 5 values were significantly different from the others (P < 0.001). CONCLUSION: These data strongly suggest that noise stress has a significant effect on the fertility of male rats. PMID- 26579256 TI - Welcome from the Editor. PMID- 26579257 TI - The scope of urological interaction: Endless open sky. PMID- 26579258 TI - Collaboration and education. PMID- 26579255 TI - The expression of p63 in bladder cancer vs. chronic bilharzial bladder. AB - OBJECTIVE: To investigate the immunohistochemical expression of p63 in bladder cancer and the variation of expression in relation to histological type, grade and stage of the tumour, and whether bilharziasis (endemic in Egypt) has an effect on its expression, in an attempt to better understand the tumour behaviour and the possibility of using p63 as a prognostic marker. PATIENTS AND METHODS: In a prospective study, biopsies were taken from the bladders of 70 patients, who were divided into three groups; group A comprised 10 with a normal urothelium, group B comprised 20 with chronic cystitis (bilharzial and non-bilharzial) and group C contained 40 with bladder cancer. The biopsies were examined for the expression of p63, using immunohistochemical techniques. RESULTS: The mean (SD) ages of groups A, B and C were 45.2 (9.5), 50.5 (11.7) and 60.5 (9.9) years, respectively. There was a statistically significant decrease in the expression and immunoreactivity in group C (P < 0.05), and a significant decrease with advancing tumour stage and grade (P < 0.01). In cases of squamous cell carcinoma there was a statistically significant lower immunoreactivity than in transitional cell carcinoma (P < 0.05). There was a tendency for a statistically significant decrease in the immunoreactivity in bilharzial cystitis (P < 0.05), but in the malignant group, bilharziasis had no apparent effect on the pattern of expression. CONCLUSION: p63 might be a helpful biomarker and adjunct in predicting the biological behaviour and progression of tumours. Further studies are recommended to elucidate more clearly its role as a prognostic indicator and its utility as a tumour marker. PMID- 26579259 TI - Is 'second-look' (re-staging) transurethral resection of bladder tumours a new standard of care? PMID- 26579260 TI - The role of biopsy in incidental renal tumours. AB - PURPOSE: Historically, the biopsy of renal masses was not advocated, and to date there remains some controversy on the role of biopsy for renal masses in making treatment decisions. With the widespread use of imaging methods, the incidental diagnosis of renal masses has increased, necessitating renal biopsies to better plan the management of these tumours. Here I review previous reports to define the role of biopsy in incidental renal tumours. METHODS: Data were obtained from English-language studies listed in PubMed on the use of renal biopsy for evaluating incidental solid small renal tumours. RESULTS: The biopsy of small renal tumours is increasingly accepted due to: the increase in the incidence of small renal tumours; the finding that a significant number of these tumours are benign; the availability of new management options, such as ablative therapy and surveillance strategies; that imaging alone is unable to predict the biological behaviour of these tumours; and advances in the pathological evaluation of the biopsies. The biopsy procedure has an acceptable complication rate but is not free of limitations. The current recommendations for the use of renal biopsy in small renal tumours are: to help in differentiating benign from malignant renal tumours; before or during ablative therapies and during the follow-up after ablative therapies, for defining treatment success or failure; and to exclude nonrenal cell primary tumours (metastasis and lymphoma) or benign conditions (abscess), which may not require surgery. CONCLUSIONS: The biopsy of small renal tumours is a safe and accurate procedure, and can help in the planning of definitive patient management. PMID- 26579261 TI - Incidental vs symptomatic renal tumours: Survival outcomes. AB - PURPOSE: Currently there is an increase in the incidental diagnosis of renal cell carcinoma (RCC). Our aim was to assess the survival of patients with incidental and symptomatic renal tumours who had undergone nephrectomy. PATIENTS AND METHODS: We retrospectively assessed 604 patients who underwent renal surgery for RCC between 1983 and 2005. Patients were divided in two groups; group 1 had incidental and group 2 had symptomatic tumours. The median follow-up was 4 and 3.3 years for groups 1 and 2, respectively. All patients had surgery in the form of radical or partial nephrectomy. Sex, age, tumour size, type of surgery, pathological characteristics and patient survival in both groups were evaluated. The statistical analysis included the log-rank, Kaplan-Meier and Cox regression tests. RESULTS: There were 85 patients (14%) in group 1 (mean age 49.6 years) and 519 (86%) in group 2 (mean age 50 years). The mean (SEM, range) tumour size was 7.4 (0.4, 1.5-20) cm in group 1 and 9.7 (0.2, 2-38) cm in group 2 (P < 0.001). The most common stage was T1 (52%) and T2 (44%) in groups 1 and 2, respectively, with a predominance of G2 grade and the conventional type histology in both the groups. There was a significant difference in cancer-specific survival (CSS) between the groups (log-rank, P = 0.017). The 5- and 10-year CSS was 94% and 94% for group 1, and 82.5% and 79.5% for group 2. Cox regression analysis showed that in group 1, only the tumour mid-zonal location (P = 0.093), tumour stage pT (P < 0.001), grade 1 (P = 0.03), grade 2 (P = 0.01), grade 4 (P = 0.01) and the papillary histological type (P = 0.019) had significant effects on CSS. In group 2, only tumour size (P = 0.022) and stage pN (P = 0.003) had significant effects on CSS. The tumour recurrence rate was 18% and 29% for groups 1 and 2, respectively. CONCLUSIONS: This large study supports the findings of other smaller studies published previously, confirming that at presentation incidental renal tumours are smaller and their diagnosis provides a better prognosis and longer CSS. PMID- 26579262 TI - Updated counselling for the patient with prostate cancer. PMID- 26579263 TI - From 'stone cutting' to high-technology methods: The changing face of stone surgery. PMID- 26579264 TI - Shock-wave lithotripsy in the elderly: Safety, efficacy and special considerations. AB - PURPOSE: Shock-wave lithotripsy (SWL) for elderly patients can be challenging. Patients often have a long-standing complex stone burden and significant comorbidities. We report a cohort of patients aged ?70 years who were treated by SWL, with special attention to treatment outcomes, complications and the need for adjuvant procedures. PATIENTS AND METHODS: Over a period of 4 years, 2311 patients were treated with SWL in a tertiary referral centre. Among these patients, 137 were aged ?70 years (5.9%). Patient and stone data were obtained from an electronic database and the patients' electronic medical records were reviewed. RESULTS: During the pre-procedural assessment, 29 patients (21.2%) were considered to be at high anaesthetic risk, due their comorbidities (American Society of Anesthesiology score 3+). In terms of stone burden, 16 stones (11.7%) were located in the distal ureter (mean stone diameter 7.9 mm) and 28 (20.4%) were in the proximal ureter (mean diameter 10.1 mm). In the kidney, 54 stones (39.4%) were in the renal pelvis, upper or mid calyx (mean diameter 10.6 mm), while 39 stones (28.5%) were in the lower calyx (mean diameter 10.1 mm). The median (range) number of SWL sessions per patient was 2.0 (1-3). The overall stone-free rate achieved by SWL alone was 63.5% (65.9% for ureteric stones and 62.4% for renal stones). In total, 38 patients (27.7%) had an adjuvant procedure to achieve stone clearance (ureteroscopy in 23, PCNL in 14 and laparoscopic ureterolithotomy in one case). Apart from six cases (4.3%) of ureteric obstruction due to steinstrasse, there were no severe complications noted. CONCLUSIONS: The management of elderly patients presenting with urolithiasis is challenging, due to the presence of significant comorbidities. Careful assessment of an integrated management plan for geriatric patients with urolithiasis is essential, and SWL still remains a safe and efficient first-line tool in well selected cases. PMID- 26579265 TI - Extracorporeal shock wave lithotripsy of lower ureteric stones: Outcome and criteria for success. AB - OBJECTIVE: To evaluate the efficacy of extracorporeal shock wave lithotripsy (ESWL) for distal ureteric calculi (DUC) and to determine variables that could affect the outcome results. PATIENTS AND METHODS: Between April 2004 and February 2008, 100 patients with a solitary DUC were treated with in situ ESWL using a lithotripter (Lithostar Plus, Siemens, Erlangen, Germany). The outcome of treatment was evaluated after 3 months. The patients' clinical and radiological findings, as well as stone characteristics, were reviewed and correlated with the stone-free rate (SFR). RESULTS: After in situ ESWL, 84 patients (84%) were stone free (after one session in 57 and after two in 27). From a univariate analysis only three factors had a significant impact on the SFR, i.e. the body mass index (BMI), stone length and stone width. The SFR was significantly lower in obese patients than in normal and overweight patients (P = 0.019). Stone width ?8 mm was associated with a SFR of 64% (14/22), compared with 89.7% (70/78) for those with a stone width of <8 mm (P = 0.007). The SFR was 86.8% (66/76) for a stone length of ?10 mm and 71% (17/24) for a stone length of >10 mm (P = 0.016). On multivariate analysis, BMI, stone width and stone length maintained their statistical significance. CONCLUSION: Primary in situ ESWL remains an effective and safe form of treatment for DUC. The length and transverse diameter of the stone, together with the BMI of the patient, were the only significant predictors of the overall success of ESWL. PMID- 26579266 TI - Novel technologies in flexible ureterorenoscopy. PMID- 26579267 TI - The 'Elephant in the Room'. PMID- 26579268 TI - Reversion of penile fibrosis: Current information and a new horizon. AB - Ageing has a detrimental effect on cavernous tissue and the tunica albuginea of the penis. Furthermore, atherosclerosis of the penile vessels that occurs with ageing causes a decrease in penile oxygen tension. A reduction in smooth muscle cells (SMCs) was shown in relation to diminution of oxygen tension. Chronic ischaemia is therefore not only associated with fibrosis but also with nitric oxide-cyclic guanosine monophosphate reduction. The sensitivity of the alpha adrenoceptors on the SMCs increases with ageing. The decrease in penile elasticity and compliance are explained by the changes in the ratio of penile collagen that occur with ageing. Contradictory to the view that testosterone is only necessary for sexual desire, numerous recent studies showed that androgen deprivation produces penile tissue atrophy, alterations in dorsal nerve structure, alterations in endothelial morphology, reduction in trabecular SM content, increase in deposition of extracellular matrix and accumulation of fat containing cells (adipocytes) in the subtunical region of corpus cavernosum. The aim of the current review is to shed some light on the underlying aetiology of corporal fibrosis especially ageing, cavernous nerve damage, androgen deprivation and tunical fibrosis. Ultimately I will address the proposed prevention of erectile dysfunction associated with penile fibrosis. PMID- 26579269 TI - The role of the urologist in the prevention and early detection of cardiovascular disease. AB - In this review we identify whether problems encountered in urology, such as erectile dysfunction, have a bearing on general health, in particular cardiovascular health. Testosterone, traditionally regarded as the hormone subserving male reproductive and sexual functioning, appears to have a much wider role. Recent findings show that testosterone is involved in the metabolic control of glucose and lipids, of strength of bone and muscle, and psychological aspects such as mood and energy. Serum testosterone levels decline with ageing, free testosterone levels more so than total testosterone. At least 10 publications have shown that low testosterone levels are associated with an increased risk of death. The metabolic syndrome is a clustering of risk factors predisposing to diabetes mellitus type 2, atherosclerosis, and cardiovascular morbidity and mortality. There is a direct correlation between plasma testosterone and insulin sensitivity, and low testosterone levels are associated with an increased risk of type 2 diabetes mellitus, dramatically illustrated by androgen deprivation in men with prostate carcinoma. Lower total testosterone and sex hormone-binding globulin levels predict a higher incidence of the metabolic syndrome. Administration of testosterone to hypogonadal men reverses part of the unfavourable risk profile for the development of diabetes and atherosclerosis, thus also improving risk factors for erectile dysfunction. We conclude that urologists diagnosing and treating erectile problems are in a unique position to include general aspects of men's health in their work, and thus contribute to general health and to cardiovascular health in particular. PMID- 26579270 TI - The use (and misuse) of English in urological papers. PMID- 26579271 TI - Recoverability of renal function after relief of chronic partial unilateral ureteric obstruction: The effect of an angiotensin-converting enzyme inhibitor (enalapril). AB - OBJECTIVES: We evaluated the effect of an angiotensin-converting enzyme inhibitor (enalapril) on renal function during and after the relief of partial unilateral ureteric obstruction (UUO). MATERIALS AND METHODS: Thirty-two male mongrel dogs were classified into three groups: sham (eight), control (12; left partial UUO + no medication) and study (12; left partial UUO + enalapril). Dogs in the study and control groups were subjected to 4 weeks of partial UUO. After that, the dogs were re-opened and subjected to Lich-Gregoir vesico-ureteric re-implantation, and were killed humanely by the end of the eighth week after relief of obstruction. The study and control groups were evaluated at baseline, after 4 weeks of obstruction and at 4 and 8 weeks after relief of obstruction, by measuring selective creatinine clearance (CCr), selective renographic clearance (RCr) and renal resistive index (RI). The sham group had sham surgery at 4 and 8 weeks and was evaluated as the other two groups. RESULTS: Sham surgery showed no significant effect on any of the evaluated variables. Compared with the control, enalapril offset the reductions of CCr and RCr by an extra 11% and 12% of the basal values by the end of the fourth week of obstruction, respectively. Moreover, compared with the control, enalapril enhanced the recovery of CCr by an extra 10% and of RCr by an extra 23% of the basal values at 8 weeks after relief of the 4-week obstruction. In addition, the increase in RI was significantly less in the enalapril group. CONCLUSION: Enalapril decreases the deterioration of renal function in partial UUO and enhances the recoverability of renal function after relief of obstruction. PMID- 26579272 TI - Laparo-endoscopic single-site radical prostatectomy: Feasibility and technique. AB - BACKGROUND: As laparoscopy becomes a standard approach in many urological procedures, researchers strive to make minimally invasive surgery less invasive. Our objective was to apply recent innovations in equipment and surgical approaches to develop the technique and perform laparo-endoscopic single site radical prostatectomy (LESS-RP). METHODS: The technique for LESS-RP was derived by combining existing techniques of standard laparoscopic RP and developing techniques of urological LESS. This incorporated newly available low-profile trocars, flexible instruments and a flexible-tip laparoscope. The procedure was performed through a single 3-cm transverse infra-umbilical incision. LESS-RP was completed successfully via a single operative site without auxiliary needles or trocars. Perioperative variables and postoperative outcomes were recorded and measured. RESULTS: The operative time was 424 min and the hospital stay was 10 days because of a vesicourethral leak and ileus. The anastomotic leak resolved and the urethral catheter was removed at 4 weeks after surgery. The final pathology showed negative margins and Gleason 3 + 4 pT2c prostatic adenocarcinoma. CONCLUSIONS: LESS-RP is feasible by replicating laparoscopic RP techniques and incorporating the LESS technique with the advent of flexible-tip laparoscopes and flexible instruments. After a learning curve has been overcome, this should be further tested prospectively to compare oncological and functional outcomes with laparoscopic and robotic-assisted RP. PMID- 26579273 TI - Long-term outcomes of kidney donors. AB - As the demand for kidney transplantation, particularly from living donors, continues to rise, there is increasing and much needed interest in accurately quantifying the long-term risks of kidney donation. We review the outcomes of kidney donors in the domains of survival, perioperative mortality, risk of end stage renal disease, quality of life, course of diabetes mellitus in donors, pregnancy after donation, obesity, and prevalence of other health conditions. PMID- 26579274 TI - Effect of donor and recipient variables on the long-term live-donor renal allograft survival in children. AB - OBJECTIVE: We aimed to analyse donor and recipient predictors of graft survival in children who received live-donor renal grafts. PATIENTS AND METHODS: The study comprised 273 children who received live-donor renal transplants at our center between March 1976 and October 2010. The follow-up ranged from 6 months to 25 years. Donor variables included donor age, gender, donor/recipient body weight ratio (DR BWR), ABO blood groups, human leukocyte antigen, and DR mismatching. Donor-specific problems, e.g., ischemia time during surgery and number of renal arteries, were included. Recipient variables included recipient age, sex, original kidney disease, ischemia time, acute tubular necrosis (ATN) after transplantation, immunosuppression, number of acute rejection episodes, re transplantation, and development of hypertension. RESULTS: Independent variables with a sustained effect on the 5- and 10-year graft survival on multivariate analysis were: ATN after transplant, number of acute rejections, hypertension, and DR BWR. At the last follow-up, 185 patients (67.8%) had a functioning graft, while 82 (30.0%) had graft failure. Only six patients (0.02%) were lost to follow up. CONCLUSION: Donor and recipient variables that affect short- and long-term graft survival in children with a live-donor renal allograft are DR BWR, number of acute rejections, ATN and hypertension after transplant. Considering these variables provides a better outcome. PMID- 26579275 TI - Retrograde balloon dilation >10 weeks after renal transplantation for transplant ureter stenosis - our experience and review of the literature. AB - OBJECTIVE: Despite many efforts to prevent ureteric stenosis in a transplanted kidney, this complication occurs in 3-5% of renal transplant recipients. Balloon dilatation (BD) is a possible minimally invasive approach for treatment, but reports to date refer only to the antegrade approach; we analysed our experience with retrograde BD (RBD) and reviewed previous reports. PATIENTS AND METHODS: From October 2008 to February 2011, eight patients after renal transplantation (RTX) underwent RBD for transplant ureteric stenosis at our hospital. We retrospectively analysed the outcome and reviewed previous reports. RESULTS: The eight recipients (five men and three women; median age 55 years, range 38-69) were treated with one or two RBDs for transplant ureteric stenosis. There were no complications. The median (range) time after RTX was 4.5 (2.5-11) months. Long term success was only achieved in one recipient, while five patients were re operated on (three with a new implant, two by replacement of transplanted ureter with ileum) after a median (range) of 2.8 (0.7-7.0) months after unsuccessful RBD(s). For two recipients the success remained unclear (one graft loss due to other reasons, one result pending). When the first RBD was unsuccessful there was no improvement with a second. CONCLUSION: RBD is technically feasible, but our findings and the review of previous reports on antegrade ureteric dilatation suggest that the success rate is low when the ureter is dilated at ?10 weeks after RTX. From our results we cannot recommend RBD for transplant ureteric stenosis at ?10 weeks after RTX, while previous reports show favourable results of antegrade BD in the initial 3 months after RTX. PMID- 26579276 TI - Clinical experience with shock-wave lithotripsy using the Siemens Modularis Vario lithotripter. AB - PURPOSE: To assess the effectiveness of a lithotripter (Modularis Vario; Siemens, AG Healthcare, Munich, Germany) in the management of renal and ureteric stones. PATIENTS AND METHODS: In all, 1146 adult patients with renal or ureteric stones were treated at one urological centre using the latest model of the Modularis Vario lithotripter. The effectiveness of lithotripsy and re-treatment rate were assessed. Data were obtained on stone location, stone size, shock wave usage, success rate, and complications. RESULTS: Between May 2007 and November 2009, 698 patients with renal stones and 448 with ureteric stones underwent extracorporeal shock-wave lithotripsy (ESWL). The mean (SD) renal stone size was 12.8 (3.8) mm; a mean of 1.36 sessions was required, with a mean (SD) number of 3744 (1961) shocks delivered per renal stone. After 3 months, the success rate defined as the patient being stone-free or with residual fragments of <4 mm; for renal stones the rate was 91.1%, with a 6.9% complication rate in the form of steinstrasse and severe renal colic. The mean (SD) ureteric stone size was 10.4 (2.7) mm. A mean of 1.37 sessions was required, with a mean (SD) of 4551 (2467) shocks delivered for each ureteric stone. The success rate for ureteric stones was 89.5%, with a 5.6% complication rate. The overall efficiency quotient was 0.66. CONCLUSION: The Siemens Modularis Vario lithotripter is a safe and effective machine for treating renal and ureteric stones. PMID- 26579277 TI - Prostate-sparing cystectomy: Potential functional advantages and objective oncological risks; a case series and review. AB - OBJECTIVES: Prostate-sparing cystectomy (PSC) has been debated over the last decade; our aim was to assess the functional results and to evaluate the oncological outcome after PSC, to judge the value of this technique. PATIENTS AND METHODS: Twenty-six men (median age 62 years) who were candidates for radical cystectomy were operated between 2004 and 2009 in the urology departments of Foch Hospital, Suresnes, France, and Theodor Bilharz Research Institute, Giza, Egypt. They all underwent a PSC with orthotopic bladder substitution. The functional results were assessed at 1, 3 and 6 months, with the final results evaluated at 1 year. Incontinence was classified according to pads used per day, and erectile function after PSC was assessed using the International Index of Erectile Function questionnaire. There was a strict follow-up for oncological failure, with special attention given to the remnant of the prostate and prostatic urethra. RESULTS: The final functional results were assessed at 1 year, with daytime continence achieved in 22 patients (95%) and nocturnal leak in four (13%). At 1 year, 18 patients (83%) reported having erections on sexual stimulation. The median follow-up was 43 months, with an overall incidence of recurrence of 30% and a median time to metastasis of 30 months. At 36 months, the overall survival rate was 81%, with a tumour-free survival rate of 70%. CONCLUSION: PSC was no better than standard radical cystectomy, and should only be offered to patients who prefer preservation of their sexual function and continence over appropriate tumour control. PMID- 26579278 TI - Prostate sparing cystectomy: A procedure with limited indications. PMID- 26579279 TI - Aesthetic neo-glans reconstruction after penis-sparing surgery for benign, premalignant or malignant penile lesions. AB - PURPOSE: To describe the technique and results of penis-sparing surgery combined with a cosmetic neo-glans reconstruction for benign, pre-malignant or malignant penile lesions. PATIENTS AND METHODS: Twenty-one patients (mean age 61 years) with penile lesions with a broad spectrum of histopathology underwent organ sparing surgery with neo-glans reconstruction, using a free split-thickness skin graft harvested from the thigh. Three patients were treated by glans-skinning and glans-resurfacing, 10 by glansectomy and neo-glans reconstruction, four by partial penectomy and a neo-glans reconstruction, and four by neo-glans reconstruction after a traditional partial penectomy. RESULTS: The mean follow-up was 45 months; all patients were free of primary local disease. All patients were satisfied with the appearance of the penis after surgery, and recovered their sexual ability, although sensitivity was reduced as a consequence of glans/penile amputation. CONCLUSION: In benign, premalignant or malignant penile lesions, penis-sparing surgery combined with a cosmetic neo-glans reconstruction can be used to assure a normally appearing and functional penis, while fully eradicating the primary local disease. PMID- 26579280 TI - Current concepts of organ-sparing surgery in penile cancer. PMID- 26579281 TI - Penile cosmetic preservation in the management of the invasive penile cancer. PMID- 26579282 TI - Interposition of dartos flaps to prevent fistula after tubularized incised-plate repair of hypospadias. AB - OBJECTIVE: To evaluate the effect of urethral coverage by a single- or double layered dorsal dartos flap after tubularized incised-plate (TIP) repair of hypospadias on fistula formation. PATIENTS AND METHODS: In this retrospective study we evaluated sequential patients with hypospadias who underwent TIP urethroplasty with a dorsal dartos interpositional flap between April 2008 and December 2009. We reviewed their medical records for the site of hypospadias, previous hypospadias repair, single- or double-layered dartos flap and postoperative complications. The patients were divided into two groups; in group A the urethra was covered by a single layer of dartos fascia, and in group B the urethra was covered by double layers of dartos flap. RESULTS: Of 91 patients who opted for hypospadias repair during the time of the study, 62 had a TIP urethroplasty with a dorsal dartos flap; of these 62, three did not fulfil the requirement of the minimum follow-up, so 59 were eligible for the study (32 in group A and 27 in group B). Preoperative clinical data were comparable in both groups. At a mean of 12.2 months of follow-up, there was no reported fistula in group B, while two patients in group A developed a urethrocutaneous fistula (P = 0.19). Meatal stenosis occurred in two patients in group A and one in group B (P = 0.66). CONCLUSION: There was no significant difference in subsequent urethrocutaneous fistula between a double-layered dorsal dartos flap and single layer for covering the urethra as a part of TIP urethroplasty for repairing hypospadias. PMID- 26579283 TI - Tissue interposition in hypospadias repair: A mechanical barrier or healing promoter? PMID- 26579284 TI - The role of synthetic slings in male stress incontinence. AB - OBJECTIVE: Our primary aim was to compare the outcomes of synthetic bone-anchored male slings (BAMS) and transobturator male slings (TOMS), to identify preoperative risk factors for failure, and to evaluate patient satisfaction with each procedure. PATIENTS AND METHODS: Charts were reviewed retrospectively of patients who underwent synthetic BAMS or TOMS from 2000 to 2011. Data were categorised into groups based on outcomes of 'dry', 'improved' and 'failure'. Success was defined as completely dry or an improvement by >50% in daily pad use. The data analysed included demographics, daily pad use before and after surgery, previous urethral insult, type of prostatectomy, and urodynamic study variables. Data were analysed using logistical regression, the t-test and chi-square analysis, where appropriate. RESULTS: Sixty-eight men were analysed (30 in each group; eight patients were excluded). Daily pad use for the TOMS group changed from 3.5 before to 1.5 after surgery (P = 0.001), whilst the BAMS group was unchanged from 3.9 to 3.5 (P = 0.747). The TOMS group had a success rate of 23/30 (77%) and a mean (SD) patient global impression of improvement score of 1.67 (0.90), whilst the BAMS group had a success rate of 11/30 (37%) and mean (SD) score of 2.64 (1.12). Urethral insult (P = 0.001) and preoperative pad use (P = 0.047) were significant predictors of failure. CONCLUSION: TOMS gave better outcomes than BAMS in both performance and patient satisfaction. Patients with a greater severity of incontinence and evidence of urethral insult before surgery should be counselled about the likelihood of suboptimal outcomes with any type of sling placement. PMID- 26579285 TI - Repair of vesicovaginal fistula: Single-centre experience and analysis of outcome predictors. AB - OBJECTIVES: Data from 80 patients with a vesicovaginal fistula (VVF) were collected and analysed, to define the probable factors affecting the outcome of surgery. PATIENTS AND METHODS: In a retrospective study, the records of 80 women with a mean (SD) age of 35.8 (9) year were assessed; 40% of the VVF occurred after abdominal hysterectomy, 30% after Caesarean section, 15% after difficult vaginal delivery and 11.25% after forceps vaginal delivery. Fifteen women (18%) had a previous failed repair. The median duration of the VVF was 11.5 months. RESULTS: Of the 80 VVF, 41 were high, 30 were low, four combined high and low and five were at the bladder neck. Nine cases had multiple openings on pan-endoscopy. An abdominal approach was used in 54 patients, vaginal in 20 and a combined approach in six. The median (SD) catheter duration was 14 (3.9) days. Ureteric stents were left in 59 patients. At a mean (SD) follow-up of 33.02 (65.7) months, the VVF was cured in 65 (81%) patients. Univariate analysis of variables possibly affecting the success of surgery showed that the duration of VVF, surgical approach, previous repair and position of the VVF were significant factors. Only previous intervention and surgical approach maintained significance in multivariate analysis. CONCLUSION: An abdominal approach seems to give superior results. Previous failed repair had a significant negative effect on success. An earlier repair (<6 months) is associated with higher success rates. PMID- 26579286 TI - The effect of adipose-derived stem cells on augmentation ileocystoplasty: A pilot study. AB - OBJECTIVES: Incorporation of intestinal tissue into urinary tract elicits many metabolic and mechanical complications due to anatomical and physiological differences. Adipose-derived stem cells (ADSCs) improve vascularity and functional outcomes by a paracrine mechanism. In a pilot study we investigated whether ADSCs can survive in the augmented bladder and improve its function. MATERIALS AND METHODS: Autologous ADSCs were harvested from rat paragonadal fat and cultured before injection into a rat model of augmentation ileocystoplasty (study group). Control augmented bladders were injected with cell-free saline. Eight weeks later, rats underwent abdominal ultrasonography for upper tract changes and were examined by conscious cystometry to determine bladder function. After extirpation, augmented bladders were examined using Masson trichrome staining for connective tissue and muscle content, immunohistochemistry for alpha smooth muscle actin, and rat endothelial cell antigen staining for endothelial cells. Changes in the extracellular matrix were assessed by determining the elastin content. ADSCs were labelled and tracked by 5-ethynyl-2-deoxyuridine nuclear staining. RESULTS: Abdominal ultrasonography showed better preservation of upper tract function in the ADSC group than in the saline-treated group (P = 0.007). After 2 months there were no differences in the variables assessed by conscious cystometry between the ADSC and saline-treated groups. However, the bladder weight was significantly greater in the ADSC-treated group. On immunohistochemistry, the implanted ADSCs survived up to 8 weeks but did not transdifferentiate into smooth muscle or endothelial cells. CONCLUSION: These results suggested a potential role of ADSCs in modifying the intestinal segment in augmented bladders; this role has to be further elucidated. PMID- 26579287 TI - Effects of testosterone on the lower urinary tract go beyond the prostate: New insights, new treatment options. AB - The traditional assumption that the prostate is an organ exquisitely sensitive to androgen action still holds true, but with lower-than-normal circulating levels of testosterone, all androgen receptors are saturated and a further increase in circulating levels of testosterone has no effect on the prostate (saturation model). Prostate disease (prostate cancer and benign prostatic hyperplasia, BPH) usually occur at an age when circulating levels of testosterone are declining, so it is unlikely that they are to be attributed to an excess of testosterone. The bother of BPH is presently subsumed under 'pathology of the lower urinary tract'. Surprisingly, these structures have androgen receptors, and depend for their relaxation on nitric oxide, for which the mechanism, in turn, is aided by androgens. This explains why phosphodiesterase type-5 inhibitors also benefit erectile function and symptoms of the lower urinary tract. Normalisation of testosterone in hypogonadal men favours this action. During the development of the prostate, epithelium and mesenchyme are under the control of testicular androgens, and interact to form an organised secretory organ. Furthermore, many of the disease processes of the prostate have been attributed to androgen action, and consequently, therapies have been aimed at manipulating androgen activity. PMID- 26579288 TI - Combined intracavernous vasoactive drugs and sildenafil citrate in treatment of severe erectile dysfunction not responding to on-demand monotherapy. AB - OBJECTIVE: To investigate the effect of chronic use of sildenafil and intracavernous injection (ICI) with trimix in men not responding to on-demand monotherapy with sildenafil or ICI with prostaglandin-E1 (PGE1). PATIENTS AND METHODS: The study included 40 patients with erectile dysfunction (ED), with a mean (SD) age of 50.7 (11.3) years and unresponsive to on-demand sildenafil or ICI with PGE1 as monotherapy. They were assessed using the Sexual Health in Men (SHIM)-5 score for ED severity, penile colour Doppler ultrasonography (CDUS) for peak systolic velocity (PSV), end-diastolic velocity (EDV) and resistance index (RI) with an ICI test using 0.25 mL of trimix of papaverine, PGE1 and phentolamine. Testosterone, prolactin and cholesterol levels were assessed. Patients received 25 mg sildenafil daily for 8 weeks, combined with twice weekly ICI with 0.25 mL of trimix. After treatment, the Erection Hardness Score (EHS), penile CDUS with ICI and ED Inventory of Treatment Satisfaction were assessed. RESULTS: The mean (SD) SHIM-5 score before treatment was 8.3 (0.5) in 15 of the 40 men and 6.3 (0.4) in 25. Penile haemodynamics were normal in five (13%), showed arterial insufficiency in five (13%), venous occlusive disease in 26 (65%) and mixed vascular in four (10%). There was an improved SHIM-5 score in 28 (70%) patients, as shown by their haemodynamic values, duration of erection and EHS with therapy, and 66% satisfaction with treatment. Adverse effects (penile pain, headache, facial flushing, dyspepsia, nasal congestion, dizziness) were reported in 17 patients (43%). CONCLUSION: Chronic use of trimix plus daily low-dose sildenafil improved penile haemodynamics in these patients with ED not responding to on-demand phosphodiesterase-5 inhibitors or ICI with PGE1 monotherapy. PMID- 26579289 TI - Does size matter? The significance of prostate size on pathologic and functional outcomes in patients undergoing robotic prostatectomy. AB - BACKGROUND: We examined the effect of prostate weight on perioperative data, and the pathological and functional outcomes of robotic-assisted laparoscopic prostatectomy (RALP). PATIENTS AND METHODS: Data were available from 716 consecutive patients before, during and after undergoing RALP at one institution. Prostate size was arbitrarily stratified by recorded prostate weight into <50, 50 80 and >80 g, corresponding to small, moderate and large glands, respectively. Perioperative data and the histopathological and functional outcomes were compared across these groups by both univariable and multivariable-adjusted analyses. RESULTS: Increased prostate size was associated with increased age, preoperative prostate-specific antigen levels, body mass index, operative duration, blood loss, lower biopsy and pathological Gleason scores, and lower pathological staging (P < 0.05). The incidence of extensive positive surgical margins was 14.8%, 9.7%, and 5.3% in small, moderate and large prostates, respectively (P < 0.001). However, after multivariable adjustment, only Gleason score and pathological stage were significantly associated with the incidence of positive margins (P < 0.05); prostate weight was not significantly associated. Overall, 78% and 92% of patients were potent and continent at 12 months, respectively, which was not affected by prostate size. CONCLUSION: Patients with larger prostates had favourable pathological outcomes after RALP. When controlling for pathological stage, prostate size was not associated with margin positivity. Functionally, neither continence nor potency at 12 months was affected by prostate size. PMID- 26579290 TI - Endourological management of ureteric strictures after kidney transplantation: Stenting the stent. AB - The incidence of ureteric obstruction after kidney transplantation is 3-12.4%, and the most common cause is ureteric stenosis. The standard treatment remains open surgical revision, but this is associated with significant morbidity and potential complications. By contrast, endourological approaches such as balloon dilatation of the ureter, ureterotomy or long-term ureteric stenting are minimally invasive treatment alternatives. Here we discuss the available minimally invasive treatment options to treat transplant ureteric strictures, with an emphasis on long-term stenting. Using an example patient, we describe the use of a long-term new-generation ureteric metal stent to treat a transplant ureter where a mesh wire stent had been placed 5 years previously. The mesh wire stent was heavily encrusted throughout, overgrown by urothelium and impossible to remove. Because the patient had several previous surgeries, we first considered endourological solutions. After re-canalising the ureter and mesh wire stent by a minimally invasive procedure, we inserted a Memokath(r) (PNN Medical, Kvistgaard, Denmark) through the embedded mesh wire stent. This illustrates a novel method for resolving the currently rare but existing problem of ureteric mesh wire stents becoming dysfunctional over time, and for treating complex transplant ureteric strictures. PMID- 26579291 TI - Long-term outcome of grafts with multiple arteries in live-donor renal allotransplantation: Analysis of 2100 consecutive patients. AB - PURPOSE: To analyse the long-term outcome in relation to multiple graft arteries (MGA) in live-donor renal transplantation, and assess its effect on graft and patient survival. PATIENTS AND METHODS: Between March 1976 and November 2009, a total of 2100 live-donor renal transplants were carried out at our centre. Patients were stratified according to the number of graft arteries into two groups, i.e. MGA (two or more arteries; 237 patients) and single-graft artery (SGA; 1863 patients). Variables assessed included patient demographics, site of vascular anastomosis, ischaemia time, onset of diuresis, delayed graft function, acute tubular necrosis (ATN), acute rejection, vascular and urological complications. Moreover, long-term patient and graft survival were compared among both groups. Patients were followed up for a mean (SD) of 112 (63) months. RESULTS: Grafts with MGA were associated with a prolonged ischaemia time (P = 0.001) and ATN (P = 0.005). Vascular thrombosis (arterial and venous) had a higher incidence in MGA (2.5%) than SGA (0.6%) (P = 0.01). Both groups were not significantly different for the onset of diuresis, acute rejection and urological complications (P = 0.16, 0.23 and 0.85, respectively). Graft and patient survival were comparable in both groups. The mean (SD) 1-, 5-, 10- and 20-year graft survival rates (%) for MGA were 96.1 (1.26), 86.6 (2.39), 61.3 (4.42) and 33.8 (7.23), and 97.5 (0.36), 86.8 (0.84), 66.0 (1.35) and 37.3 (2.76) for SGA (P = 0.54). CONCLUSIONS: Although there was a higher incidence of prolonged ischaemia time, ATN and vascular thrombosis in live-donor renal transplants with MGA, it did not adversely affect patient or graft survival. The early, intermediate- and long-term follow-up showed an outcome comparable to that in patients with SGA. PMID- 26579292 TI - Management of calcular anuria in adults caused by ureteric stones: By using of ureteroscopy and holmium laser. AB - PURPOSE: To present our clinical outcomes in the management of anuria in adult patients caused by ureteral calculi by using of ureteroscopy and holmium laser. MATERIALS AND METHODS: Nineteen patients presented with calcular anuria with ages between 19 and 48 years. The presentation was anuria with serum creatinine levels of 2-5.5 mg% (mean 3.5) and hyperkalemia in nine patients (5.2-6.1 mmol/L). There were bilateral ureteric stones in 14 (73.7%) and unilateral in five (26.3%) with single functioning kidney. Thirty-three ureteroscopic procedures were performed for 19 patients including bilateral ureteroscopy in 14. Laser lithotripsy was delivered using holmium laser via 356 MUm laser fibre, with energy (1-1.2 J) and pulse rate (10 Hz). Post-operatively, monitoring of urine output, serum creatinine and K levels was done until normal values were obtained. RESULTS: Ureteroscopy was performed for all 19 patients (33 procedures), but laser lithotripsy was done successfully in 30 procedures. The operative time was 46 min (25-70). The successful fragmentation rate was (100%). The stone-free rate was 90.9%. There were mucosal abrasions in 6 (31.5%), and mild to moderate haematuria in 9 (47.4%), and high fever in two patients (10.5%). Serum creatinine and potassium levels returned to normal within 7-10 days. Urine output gradually reached normal level within a week. CONCLUSIONS: Ureteroscopy and holmium laser lithotripsy represent an effective and safe modality for the treatment of anuria caused by ureteral calculi. PMID- 26579293 TI - Editorial. PMID- 26579294 TI - Kidney preservation protocol for management of emphysematous pyelonephritis: Treatment modalities and follow-up. AB - OBJECTIVES: To present treatments for kidney preservation in the management of emphysematous pyelonephritis (EPN), and to evaluate the functional outcome of preserved kidneys during the follow-up. PATIENTS AND METHODS: The computerized files of patients with EPN from 2000 to 2010 were reviewed. After initial resuscitation, ultrasonography-guided percutaneous tubes were placed for drainage of infected fluid and gas. A radio-isotopic renal scan was done after stabilization of the patients' condition. Preservation of the affected kidney was attempted when the differential function was >10%. A renal isotopic scan was taken during the follow-up to evaluate renographic changes in preserved kidneys. RESULTS: The study included 33 kidneys in 30 consecutive patients (mean age 51.7 years, SD 10.9). Kidney preservation was applicable for 23 kidneys (20 patients). Preservation methods included percutaneous nephrostomy for 12, percutaneous tube drain for two and conservative treatment for nine kidneys (six patients). Nephrectomy was performed for 10 kidneys (emergency in three and delayed in seven). The frequency of post-treatment septic shock after kidney preservation (10%) was significantly lower than after nephrectomy (20%, P = 0.005). The overall mortality rate was 7% (two patients). The follow-up was completed for 13 patients with 15 preserved kidneys for a mean duration of 21 months. During the follow-up, differential renographic clearance of the affected kidney was stable in 13 of 15 while two kidneys showed improvement. CONCLUSIONS: Kidney preservation should be the primary goal in the treatment of EPN when the differential renal clearance is >10%. It was associated with fewer complications than nephrectomy and the follow-up showed a favourable functional outcome of the preserved kidneys. PMID- 26579295 TI - Classification of pelvic fracture urethral injuries: Is there an effect on the type of delayed urethroplasty? AB - The posterior urethral injury due to pelvic fracture is a challenging problem. Because pelvic fractures are widely varying in severity, direction and mechanism, a wide spectrum of pelvic fracture urethral injuries (PFUIs) is clinically identified. Previously published data indicate that the proposed classifications of PFUIs are neither ideal nor universally acceptable. Moreover, these classifications might not have a significant effect on the delayed definitive techniques of urethral reconstruction. The currently available classifications and management strategies of PFUIs lack consensus and are based on accumulated surgical experience and clinical case studies. In the current era of evidence based medicine there should be clear and appropriate guidelines for managing PFUIs, based on meta-analysis of well-designed controlled studies and evidence based surgical science. In this way several controversies in the management of PFUIs will be resolved and the quality of life of patients who have sustained PFUIs will be improved. PMID- 26579296 TI - Simplification of classification and surgical expertise in the delayed treatment of traumatic posterior urethral injuries. PMID- 26579297 TI - Trends of genitourinary cancer among Saudis. AB - INTRODUCTION: Saudi Arabia has a low incidence of cancer; the age-standardized rate of cancer is only 83/100,000, compared to the world rate of 181/100,000. Recent reports confirm a yearly increase in cancer in general, and of genitourinary cancer (GUC) in particular. The aim of the study was to assess the trends of GUC among Saudi nationals. METHODS: All available annual reports of the Saudi Cancer Registry (SCR) from 1994 to 2006 were analysed and compared with worldwide data. RESULTS: Over a period of 13 years, 7132 GUCs were identified among Saudis, comprising 8.9% of all cancers reported, compared to 12.7% worldwide. The incidence rate of GUC increased over the study period, with the greatest increase in prostate and kidney cancer, at 48% and 33%, respectively. Summary stage data (Surveillance, Epidemiology and End Results programme) showed late presentation of GUC at the time of diagnosis. An improvement in stage was only found in testicular and prostate cancer, at 79% and 50%, respectively. While prostate and bladder cancer ranked sixth and ninth in the male population, penile cancer continued to be a rare disease. CONCLUSIONS: The incidence of GUC in Saudi Arabia is still low, but there was a significant increase in prostate and kidney cancer. More effort is needed to detect GUC at an earlier stage. A national cancer control programme is suggested. PMID- 26579298 TI - Closure of bladder exstrophy with a bilateral anterior pubic osteotomy: Revival of an old technique. AB - OBJECTIVE: To evaluate the results of simple closure using bilateral anterior pubic osteotomy to achieve a tension-free approximation of the pubis and abdominal wall in patients with bladder exstrophy. PATIENTS AND METHODS: A prospective study carried out between 2006 and 2009 included 15 patients (13 boys and 2 girls; age range 3-47 months). Of these patients, three had recurrent exstrophy while 10 were operated primarily. An elective surgical technique was used for all patients, which included dissection of the exstrophic bladder from the abdominal wall, closure of the bladder and reconstruction of the urethra, then dissection of the rectus muscle and sheath lateral to the attachment of muscle to pubic bone, which makes osteotomy of the superior pubic ramus easy, thus facilitating closure. RESULTS: For closure of the bladder and anterior abdominal wall the results were excellent for all patients soon after surgery, but there was soft-tissue infection in two patients. Of all 15 patients, one had incomplete bladder dehiscence and another had a vesico-cutaneous fistula; both needed surgical intervention later. CONCLUSIONS: Simple closure with anterior pubic osteotomy is a feasible and effective means to facilitate both bladder and abdominal closure for patients with bladder exstrophy. It is advantageous in being a rapid procedure, and can be completed by the paediatric urologist. PMID- 26579299 TI - Editorial comment. PMID- 26579300 TI - Assessment of noninvasive predictors of bladder outlet obstruction and acute urinary retention secondary to benign prostatic enlargement. AB - PURPOSE: To prospectively compare the diagnostic accuracy of intravesical prostatic protrusion (IPP), detrusor wall thickness (DWT), prostate volume (PV) and serum prostate specific antigen (PSA) levels for detecting bladder outlet obstruction (BOO) and predicting acute urinary retention (AUR) secondary to benign prostatic obstruction. PATIENTS AND METHODS: In all, 135 men who presented with lower urinary tract symptoms due to benign prostatic enlargement were enrolled in the study; among them, 50 presented with AUR. Thirty normal men in the same age group were included and represented a control group for normative data. Their evaluation included a digital rectal examination, International Prostate Symptom Score and quality-of-life question, uroflowmetry and serum total PSA assay. Transabdominal ultrasonography was used to measure the PV, IPP DWT and post-void residual urine volume. Pressure-flow urodynamic studies were used as the reference standard test for BOO, differentiating obstructed from unobstructed bladders. DWT, IPP, PV and total PSA level served as index tests. To compare the usefulness of the various indices, the area under the curve (AUC) of receiver operator characteristic curves was calculated for each index. RESULTS: According to presentation and urodynamic studies, patients were classified into three groups: Group 1 (no BOO), 50 patients with a BOO index (BOOI) of <40; group 2 (BOO), 35 with a BOOI of >40; and group 3 (AUR), 50 who presented with AUR. The IPP, DWT, PV and PSA levels differed significantly between obstructed and unobstructed patients, with a significant correlation with the BOOI. The AUC for IPP, DWT, PSA and PV were 0.885, 0.783, 0.745 and 0.678, respectively. The IPP threshold at 8 mm provided the best diagnostic accuracy (80%) for detecting BOO, followed by combined DWT and IPP (77.6%). Between patients with and without AUR, there was a highly significant difference in IPP, DWT and PSA; a combined IPP threshold of >8 mm and DWT >2 mm detected AUR in 45 of 50 patients (90%). CONCLUSION: All four noninvasive indices were correlated significantly with BOOI. The IPP as a single variable and combined with DWT predicted BOO and AUR better than PSA or PV. PMID- 26579301 TI - Renoprotective effect of Linum usitatissimum seeds through haemodynamic changes and conservation of antioxidant enzymes in renal ischaemia-reperfusion injury in rats. AB - OBJECTIVE: To evaluate an ethanolic extract of seeds of Linum usitatissimum (Linn.) (EELU) for its renoprotective role in rats through its antihypertensive effect and conservation of biological oxidation enzymes. MATERIALS AND METHODS: Male Wistar rats (200-250 g) underwent uninephrectomy on day 0; after 2 weeks of recovery, the nephrectomised rats were divided into four groups of eight each: (I) sham (II); renal ischaemia reperfusion (RIR); (III) RIR + EELU 200 mg/kg; and (IV) RIR + EELU 400 mg/kg. In group II, III and IV the renal artery was occluded for 45 min and reperfused for 4 weeks; the sham group did not undergo RIR. RESULTS: EELU (400 mg/kg) significantly decreased the haemodynamic changes after 4 weeks of RIR injury. EELU treatment significantly restored the levels of renal endogenous antioxidant enzymes and membrane-bound enzymes. EELU 400 mg/kg restored the levels of blood urea nitrogen and serum creatinine. EELU also decreased the levels of tumour necrosis factor-alpha and myeloperoxidase activity. A flow-cytometric study confirmed a significant decrease in cellular necrosis and increase in viability after RIR in EELU-treated rats. The anti apoptotic role of EELU was evident from the decrease in DNA fragmentation. Renal tissue damage as assessed by histopathology was decreased in groups III and IV (200 and 400 mg/kg EELU). CONCLUSION: We conclude that EELU protected the kidney against RIR-induced renal injury, probably by inhibiting reactive oxygen species that have a causal role in such cases. It also inhibits apoptotic cell death and inflammation, and improves haemodynamic changes. PMID- 26579302 TI - A visit to the Endourology and Stone Service at St. Bartholomew's Hospital (Barts), London, UK. PMID- 26579304 TI - Hyperechogenic renal parenchyma in potential live related kidney donors: Does it justify exclusion? AB - OBJECTIVES: To assess the predictive importance of ultrasonic grade 1 hyperechogenicity in potential live related kidney donors in the absence of urinary abnormalities and with perfect renal function. SUBJECTS AND METHODS: The study included 34 potential living related kidney donors with this abnormality; their mean (SD, range) age was 32.7 (8.45, 23-48) years. Ten matched healthy donors with normal ultrasonographic appearance of the kidneys were studied as controls. All cases were thoroughly investigated, including measuring glomerular filtration rate by isotopic scintigraphy. The renal reserve was estimated by dopamine and amino-acid infusion in all subjects (study and control groups). A percutaneous renal biopsy was taken from 17 subjects in the abnormal echogenicity group and open renal biopsy was taken from eight of the control subjects. RESULTS: The renal reserve was comparable in both groups. Abnormal histopathological changes were found in seven subjects (41%) of the abnormal echogenicity group, i.e. partial glomerulosclerosis in one, mesangial thickening in two, interstitial fibrosis in one, focal tubular atrophy in one, immunoglobulin (Ig M) immune deposits in three and IgA in one. Only one subject in the control group showed mild mesangial thickening. CONCLUSION: Grade 1 echogenicity might be a sign of unrecognized kidney disease. Renal biopsy is mandatory when such related donors are the only available ones. Abnormal histopathology contraindicates donation. PMID- 26579303 TI - Controversies related to living kidney donors. AB - BACKGROUND: Increasing the living-donor pool by accepting donors with an isolated medical abnormality (IMA) can significantly decrease the huge gap between limited supply and rising demand for organs. There is a wide range of variation among different centres in dealing with these categories of donors. We reviewed studies discussing living kidney donors with IMA, including greater age, obesity, hypertension, microscopic haematuria and nephrolithiasis, to highlight the effect of these abnormalities on both donor and recipient sides from medical and surgical perspectives. METHODS: We systematically searched MEDLINE, ISI Science Citation Index expanded, and Google scholar, from the inception of each source to January 2011, using the terms 'kidney transplant', 'renal', 'graft', 'living donor', 'old', 'obesity', 'nephrolithiasis', 'haematuria' and 'hypertension'. In all, 58 studies were found to be relevant and were reviewed comprehensively. RESULTS: Most of the reviewed studies confirmed the safety of using elderly, moderately obese and well-controlled hypertensive donors. Also, under specific circumstances, donors with nephrolithiasis can be accepted. However, persistent microscopic haematuria should be considered seriously and renal biopsy is indicated to exclude underlying renal disease. CONCLUSION: Extensive examination and cautious selection with tailored immunosuppressive protocols for these groups can provide a satisfactory short- and medium-term outcome. Highly motivated elderly, obese, controlled hypertensive and the donor with a unilateral small stone (<1.5 cm, with normal metabolic evaluation) could be accepted. Donors with dysmorphic and persistent haematuria should not be accepted. A close follow-up after donation is crucial, especially for obese donors who developed microalbuminuria. PMID- 26579305 TI - Laparoscopic management of primary pelvi-ureteric junction obstruction: Single centre experience. AB - OBJECTIVE: To evaluate the effect and safety of laparoscopic pyeloplasty in the treatment of pelvi-ureteric junction obstruction (PUJO). PATIENTS AND METHODS: In 34 patients, laparoscopic dismembered pyeloplasty was used to treat primary PUJO. Information was obtained for symptoms, results of a nuclear scan before and after surgery, intraoperative blood loss, operative duration, stenting method, and hospital stay. Under general anaesthesia and in the flank position, a 10 mm trocar was first placed above the umbilicus; three 5 mm working ports were then placed. The ureter and pelvis were freed from surrounding adhesions. The obstructive pelvi-ureteric segment was then excised, and the opened point of the ureter spatulated. Ureteropyeloplasty between the lower pole, pelvis and spatulated ureter was made using a 4-0 polyglactin suture around a JJ stent. RESULTS: The mean (SD) preoperative nuclear scan result was 23.6 (6.4) mL/min, with retention of tracer. The median operative duration was 200 min, and the median blood loss 120 mL. All patients were stented with a JJ stent. The mean hospital stay was 5 days. The final results were assessed at 6 months after surgery, when the mean (SD) nuclear scan result was 30 (7.4) mL/min. CONCLUSION: Laparoscopic pyeloplasty is a safe and effective option which can produce satisfactory results both clinically and radiologically. PMID- 26579306 TI - Familial prostatic calcification in childhood associated with cranial-bone thickening: Review of literature and report of three cases. AB - OBJECTIVES: To review the few published cases of prostatic calculi, a rare condition in children, and to report three further cases. METHODS: The databases PUBMED and HINARI were searched using the keywords 'childhood' and 'prostatic calculi'; the search included reports from 1956 to the present. Further cases from three families with children having prostatic calculi are reported here. RESULTS: Four cases were recorded previously but no association was stated between the presence of calculi and cranial-bone abnormality. CONCLUSIONS: Prostatic calculi in childhood are rare; the condition requires further study and clarification. PMID- 26579307 TI - Use of a long-term metal stent in complex uretero-ileal anastomotic stricture. AB - Uretero-ileal anastomotic stricture is a potentially serious late complication after ileal conduit formation, with a reported incidence of 3-9%. The standard management technique is open surgical revision of the anastomosis with reimplantation of the affected ureter. This is technically challenging and has potential significant morbidity for the patient. Advances in endourological techniques now offer a variety of less-invasive treatment options, like balloon dilatation or laser ureterotomy followed by stent insertion. What happens when such open and minimally invasive techniques fail? Recently, using a combined antegrade and retrograde approach, we inserted a novel, semi-permanent, dual expansion thermo-expandable metallic alloy stent across a recurrent ileal ureteric stricture. We describe the technique and potential advantages of this minimally invasive method. This minimally invasive treatment option is of interest, as in contrast to other stents, it does not require routine change, and is resistant to corrosion and urothelial ingrowth, hence ensuring ease of exchange or removal if required. PMID- 26579308 TI - Percutaneous unroofing of renal simple cysts: Experience from one centre. AB - OBJECTIVE: To assess the efficacy of percutaneous unroofing (PU) for treating simple renal cysts, compared with laparoscopic decortication and open surgery. PATIENTS AND METHODS: From November 2009 to October 2010, 11 patients with 12 simple cysts in renal units were managed by PU. All cysts were evaluated with ultrasonography and abdominal computed tomography. A standard transurethral resectoscope was used to resect the cyst wall, and the parenchymal portion of the cyst was subsequently cauterised. A drain was left in place for 2 days. Success was defined as a >50% reduction in cyst diameter. RESULTS: At the 5-month follow up, patients were asked about their symptoms and assessed by ultrasonography. Of the 12 cyst units, eight were completely resolved, three were reduced to <50% in diameter and one was persistent, close to the original size. CONCLUSION: Simple renal cysts can be managed safely by PU, with a success rate of >90%. This technique offers several advantages over open surgery, with a shorter hospital stay, improved convalescence and reduced risk of complications. PU also avoids the multiple trocar sites, extensive dissection, and technical difficulty associated with laparoscopy. PMID- 26579309 TI - Myelolipomas and other fatty tumours of the adrenals. AB - BACKGROUND: Lipomatous tumours of the adrenals are almost always benign. The importance of recognising their characteristic radiological features, leading to their correct treatment, is fundamental, as there has been an increase in the identification of these lesions. Our goal was to review all lipomatous tumours of the adrenal glands, particularly myelolipomas, their imaging methods and surgical management, updated in 2011. METHODS: This was a retrospective review of articles published in the USA and Europe, from 1979 to date. The sites from which information was retrieved covered PubMed, Medscape, Clinical Imaging, Histopathology, Urologia Internationalis, Archives of Surgery, JACS, the American Urological Association, BMJ, Medline, and Springer Link. We report areas of controversies in addition to well established guidelines. RESULTS: We reviewed 45 articles, that confirmed, with a high level of evidence-based medicine, that the diagnosis of a lipomatous adrenal tumour is made by various imaging procedures, particularly computed tomography (CT). We emphasise the importance to their management of the initial size of the adrenal mass, its increase in size over time, in addition to the presence of symptoms. CONCLUSION: Lipomatous tumours of the adrenals are most frequently benign. The diagnosis is usually made by various techniques, in particular CT. The fundamental characteristics indicating the necessity of surgical intervention are the symptoms presented, volume of the tumoral mass (>5 cm), and the increase in size of the tumour as shown in two consecutive imaging studies. PMID- 26579310 TI - Orthotopic diversion after cystectomy in women: A single-centre experience with a 10-year follow-up. AB - OBJECTIVE: To evaluate and update the clinical and surgical outcome of orthotopic diversion in an eligible cohort of women with bladder carcinoma. PATIENTS AND METHODS: From 1999 to 2010, 78 women (mean age 42.4 years) had a radical cystectomy (RC) with orthotopic diversion using ileal neobladder reconstruction to treat invasive bladder carcinoma. The mean (SD) follow-up was 62 (25) months. RESULTS: The histopathological pattern was squamous cell carcinoma in 52 (67%) patients, transitional cell carcinoma in 17 (22%), mixed in four (5%) and undifferentiated carcinoma in five (6%). Three patients were completely incontinent day and night. Stress urinary incontinence after this surgery was reported in 11 (14%) patients, with daytime continence reported in 64 (82%); 59 (76%) patients were completely continent day and night. Chronic retention developed in nine (12%) patients. There was pouch prolapse through the vaginal stump in five (6%) patients, and a pouch-vaginal fistula in seven (9%). Sexual dysfunction was reported in 45 (69%) patients of 65 sexually active women. Stones formed in the pouch in five (6%) patients, while there were renal stones in four renal units. Oncological recurrence was reported in 15 (19%) patients, which was local in 11 (14%) and distant in four (5%). CONCLUSION: The long-term results showed that orthotopic neobladder construction after RC in women provides oncological safety and is functionally effective with proper surgical technique. Removal of the gynaecological organs during RC in women might be unnecessary for low-grade, low-stage tumour. PMID- 26579311 TI - Age-specific reference ranges of serum prostate-specific antigen in Iraqi men. AB - BACKGROUND: Different races have their own reference ranges of serum prostate specific antigen (PSA) because of the influence of geographical and ethnic differences. In this study we determined the distribution of serum PSA levels in Iraqi men with no prostate cancer, to our knowledge the first such study from Iraq. SUBJECTS AND METHODS: From January 2003 to May 2004, in a prospectively designed study, we included 130 Iraqi men aged 20-79 years. The criteria of an elevated PSA level, abnormal ultrasonography results and/or abnormal findings on a digital rectal examination were used to exclude patients from the study. Ethnicity was not recorded, as Iraq has a multi-ethnic status. The results were analysed using descriptive statistics, statistical tables, the arithmetic mean, standard error, standard deviation, and by two extremes. RESULTS: The PSA values in different age groups (20-29, 30-39, 40-49, 50-59 and 60-79) were, respectively, ?0.55 to ?1.3, ?1.6, ?2.0, ?4.6 and ?4.8 ng/mL. There was a significant increase between the third and fourth group, and all these results were significant at P < 0.001, with the last being more significant. CONCLUSION: Serum PSA measurements should be standardized according to country and ethnic groups. Our result of a PSA maximum at 4.8 ng/mL is slightly more than the international standard threshold of 4.0 ng/mL. PMID- 26579312 TI - The psychosexual aspects of hypospadias repair: A review. AB - OBJECTIVE: To review the psychosexual effects on men after hypospadias repair. METHODS: We reviewed all English-language publications in the MEDLINE database from the US National Library of Medicine with the search terms 'hypospadias adult', 'psychosexual hypospadias', 'psychosocial hypospadias', and 'social hypospadias'. Each term returned 1036, 35, 19 and 68 results, respectively, which were reviewed. RESULTS: While improvements in surgical techniques have improved function, the abnormality and repair still causes a disruption in perceived quality of life for many men. After repair, many men suffer from a negative view of their genitals and some degree of sexual inhibition. However, they still maintain a satisfactory sex life. CONCLUSIONS: Psychosexual effects of hypospadias repair they endure in adulthood, although affected men maintain satisfaction with their sexual life. PMID- 26579314 TI - Editorial comment. PMID- 26579313 TI - Evaluation of transvaginal slings using different materials in the management of female stress urinary incontinence. AB - PURPOSE: To evaluate tailored polypropylene (prolene) mesh, anterior rectus sheath, and vaginal wall slings positioned under the mid-urethra, to treat stress urinary incontinence (SUI) in women, as SUI is a common pathological condition causing considerable distress and compromising social, physical, psychological, and sexual health, and for which surgical treatment remains controversial. PATIENTS AND METHODS: This prospective randomised study included 32 patients with SUI, evaluated by SEAPI (Stress, Emptying, Anatomy, Protection, and Instability) symptom score and urodynamics. According to sling material, 12 patients had tailored prolene mesh, 12 had anterior rectus sheath and eight had anterior vaginal wall slings. Operative variables (intraoperative bleeding, duration, complications and hospital stay) were documented, and postoperative complications and continence status were assessed. The follow-up was 12-18 months. RESULTS: Patients who received tailored prolene mesh slings had a lower operative duration and hospital stay, and less intraoperative bleeding. Postoperative complications, e.g. urinary retention and urgency, were <12%, with no significant differences. There was no significant difference among the three studied groups in the success rate (75%, 67% and 75%). CONCLUSIONS: Tailored prolene mesh, anterior rectus sheath and the vaginal wall sling are good alternatives to treat SUI in women, with comparable results in a short-term follow up. The surgeon's experience and the patient's clinical circumstances should be considered when choosing a sling material, as success rates are comparable, being slightly better for the prolene sling in operative duration, bleeding and hospital stay. PMID- 26579315 TI - A 'Hybrid Fellowship'. PMID- 26579316 TI - Management of Inflammatory Internal Root Resorption with Biodentine and Thermoplasticised Gutta-Percha. AB - Internal root resorption is a chronic inflammatory process initiated within the pulp space with the loss of dentin. This condition demands a comprehensive understanding of the pathologic process, so as to identify the cause and arrest the resorptive phenomena. It is a rare occurrence, asymptomatic, with slow progression, detected through routine radiographic examination, where it appears as a radiolucent lesion. This paper reports a clinical case of inflammatory internal root resorption in the premolar tooth. Because it is asymptomatic, internal root resorption needs an early diagnosis in order to institute the endodontic treatment before the process compromises the remaining mineralized structures of the tooth. Biodentine was used to reinforce the weaker structures in the root. Thermoplasticised gutta-percha was used to completely obturate the defect. Ten-month follow-up showed arrest of internal root resorption. PMID- 26579317 TI - Cystic Adenomatoid Odontogenic Tumor. AB - Adenomatoid Odontogenic Tumor (AOT) is a well-established benign epithelial lesion of odontogenic origin. Rightfully called "the master of disguise," this lesion has been known for its varied clinical and histoarchitectural patterns. Not only does AOT predominantly present radiologically as a unilocular cystic lesion enclosing the unerupted tooth (which is commonly mistaken as a dentigerous cyst) but the lesion also presents rarely with a cystic component histopathologically. We present one such unusual case of cystic AOT associated with an impacted canine, mimicking a dentigerous cyst. The present case aims to highlight the difference between cystic AOT and dentigerous cyst radiographically. The exact histogenesis of AOT and its variants still remains obscure. An attempt has been made to hypothesize the new school of thought regarding the origin of AOT. PMID- 26579318 TI - Heparin-Induced Thrombocytopenia in a Patient with Essential Thrombocythemia: A Case Based Update. AB - Vascular thrombosis is a common clinical feature of both essential thrombocythemia (ET) and heparin-induced thrombocytopenia (HIT). The development of HIT in a patient with ET is rare and underrecognized. We report the case of a 77-year-old woman with preexisting ET, who was admitted with acute coronary syndrome, and IV heparin was started. She was exposed to unfractionated heparin (UFH) 5 days prior to this admission. Decrease in platelet count was noted, and HIT panel was sent. Heparin was discontinued. Patient developed atrial fibrillation, and Dabigatran was started. On day three, patient also developed multiple tiny cerebral infarctions and acute right popliteal DVT. On day ten of admission, HIT panel was positive, and Dabigatran was changed to Lepirudin. Two days later, Lepirudin was also discontinued because patient developed pseudoaneurysm on the right common femoral artery at the site of cardiac catheterization access. A progressive increase in the platelet count was noted after discontinuing heparin. Physicians should be aware of the coexistence of HIT and ET, accompanied challenges of the prompt diagnosis, and initiation of appropriate treatment. PMID- 26579319 TI - A Potential Role for Felbamate in TSC- and NF1-Related Epilepsy: A Case Report and Review of the Literature. AB - A 15-year-old girl with maternal inheritance of neurofibromatosis type 1 (NF1) and paternal inheritance of tuberous sclerosis complex (TSC) developed intractable epilepsy at age 5. Her seizures were refractory to adequate doses of four antiepileptic medications until felbamate was initiated at age 7. She has since remained seizure-free on felbamate monotherapy. Although felbamate has multiple mechanisms of action, it is thought to have its most potent antiepileptic effects through inhibition of the N-methyl-D-aspartate receptor (NMDAR). Previous studies have shown that the NMDAR is altered in varying epilepsy syndromes and notably in the cortical tubers found in TSC. The aim of this paper is to examine how felbamate monotherapy was able to achieve such robust antiepileptic effects in a unique patient and possibly offer a novel therapeutic approach to patients suffering from TSC- and NF-related epilepsy. PMID- 26579320 TI - Ascites in the Puerperium in the Context of a Woman with Turner Syndrome Who Conceived through Assisted Reproductive Technology. AB - The case is about a young female who delivered twins by caesarean section (CS). On the 4th postoperative day, she presented with ascites which was resistant to empirical antibiotic and diuretic treatment. The woman was affected by Turner syndrome (TS); she had a medical background of chronic use of hormonal medication since puberty and conceived through ART- (assisted reproduction techniques-) IVF oocyte donation. It is important to exhibit high suspicion for clot formation in the hepatic vasculature during the puerperium, especially in the case of history of chronic hormone treatment. Ascites albumin gradient and Doppler values lead to the diagnosis of thrombosis and the administration of high doses of anticoagulants is considered to be fundamental. PMID- 26579321 TI - Medial Patellofemoral Ligament Reconstruction in a Below-Knee Amputee. AB - Patellar instability is a common finding in patients with below-knee amputation and yet management options are not commonly described in the literature. We describe the first reported case of a medial patellofemoral ligament reconstruction using allograft in a patient with a below-knee amputation. Clinical outcome at two-year follow-up remains very good. PMID- 26579322 TI - Calcinosis Universalis of the Elbow: A Rare Case with Classical Presentation. AB - Juvenile Dermatomyositis (JDM) is a rare autoimmune disease in children and adolescents. In these patients calcinosis might be the most characteristic symptom. However there are only few reported cases of intramuscular calcinosis in Dermatomyositis. We report a case of calcinosis universalis (CU) of the elbow in JDM successfully treated with broaching. The patient, a 24-year-old woman, suffered from a long history of JDM. On examination she presented with a fistula lateral to the olecranon and pain of the right elbow joint. Plain X-rays displayed a diffuse pattern of multiple periarticular, subcutaneous, and intramuscular calcifications. The patient underwent surgery for histological and microbiological sampling as well as broaching. Intraoperatively sinus formation and subfascial hard calcium deposition were found. Due to the risk of collateral tissue damage, incomplete broaching was performed. A local infection with Staphylococcus was diagnosed and treated with antibiotics. On six-week and 30 month follow-up the patient was free of pain and had very good function. Calcifications on standard radiographs had almost resolved entirely. This case report gives a summary on calcinosis in Dermatomyositis and adds a new case of recalcitrant CU to the literature. Broaching surgery proved to be a reliable treatment option in symptomatic calcinosis. PMID- 26579323 TI - A Rare Case of Erdheim-Chester Disease and Langerhans Cell Histiocytosis Overlap Syndrome. AB - A 48-year-old woman with a past medical history of seizures and end-stage renal disease secondary to obstructive uropathy from retroperitoneal fibrosis presented to the emergency department with seizures and altered mental status. A Glasgow Coma Scale of 4 prompted intubation, and she was subsequently admitted to the intensive care unit. Magnetic resonance imaging of the brain performed to elucidate the aetiology of her seizure showed a dural-based mass within the left temporoparietal lobe as well as mass lesions within the orbits. Further imaging showed extensive retroperitoneal fibrosis extending to the mediastinum with involvement of aorta and posterior pleural space. Imaging of the long bones showed bilateral sclerosis and cortical thickening of the diaphyses. Imaging of the maxillofacial structures showed osseous destructive lesions involving the mandible. These clinical and radiological features were consistent with a diagnosis of Erdheim-Chester disease; however, the patient's skin biopsy was consistent with Langerhans cell histiocytosis. PMID- 26579324 TI - Update Review and Clinical Presentation in Congenital Insensitivity to Pain and Anhidrosis. AB - Introduction. Congenital insensitivity to pain and anhidrosis (CIPA) or hereditary sensory and autonomic neuropathy type IV is an extremely rare syndrome. Three clinical findings define the syndrome: insensitivity to pain, impossibility to sweat, and mental retardation. This pathology is caused by a genetic mutation in the NTRK1 gene, which encodes a tyrosine receptor (TrkA) for nerve growth factor (NGF). Methods. The consultation of a child female in our center with CIPA and a tibia fracture in pseudoarthrosis encouraged us to carefully review literature and examine the therapeutic possibilities. A thorough review of literature published in Pubmed was done about CIPA and other connected medical issues mentioned in the paper. Conclusions. The therapeutic approach of CIPA remains unclear. The preventive approach remains the only possible treatment of CIPA. We propose two new important concepts in the therapeutic approach for these patients: (1) early surgical treatment for long bone fractures to prevent pseudoarthrosis and to allow early weight bearing, decreasing the risk of further osteopenia, and (2) bisphosphonates to avoid the progression of osteopenia and to reduce the number of consecutive fractures. PMID- 26579325 TI - 17-Week Delay Surgery after Chemoradiation in Rectal Cancer with Complete Pathological Response. AB - Neoadjuvant chemoradiation (CRT) followed by curative surgery still remains the standard of care for locally advanced rectal cancer (LARC). The main purpose of this multimodal treatment is to achieve a complete pathological tumor response (ypCR), with better survival. The surgery delay after CRT completion seems to increase tumor response and ypCR rate. Usually, time intervals range from 8 to 12 weeks, but the maximum tumor regression may not be seen in rectal adenocarcinomas until several months after CRT. About this issue, we report a case of a 52-year old man with LARC treated with neoadjuvant CRT who developed, one month after RT completion, an acute myocardial infarction. The need to increase the interval between CRT and surgery for 17 weeks allowed a curative surgery without morbidity and an unexpected complete tumor response in the resected specimen (given the parameters presented in pelvic magnetic resonance imaging (MRI) performed 11 weeks after radiotherapy completion). PMID- 26579326 TI - The Forgotten Complication of Recurrent Nephrolithiasis: "Squamous Cell Carcinoma of the Renal Pelvis"-A Case and Review of the Literature. AB - Squamous cell carcinoma (SCC) of the renal pelvis is an aggressive tumor with insidious onset of unspecific symptoms and advanced stages at diagnosis. It is a rare entity, accounting for 0.5-8% of renal tumors. In this paper, we describe the case of a patient with a history of recurrent nephrolithiasis that presented with an aggressive form of SCC of the renal pelvis with rapid relapse after resection. PMID- 26579327 TI - Femoral Metastasis from Penile Carcinoma: Report of 2 Cases. AB - Purpose. Penile cancer rarely gives symptomatic skeletal metastases. Methods. We present 2 patients with squamous carcinoma of the penis who were surgically treated for metastases in the femur. Results. Both patients had pathological fractures and were operated on. In one case, the skeletal metastasis preceded any lymphatic spread of the disease, suggesting early haematogenous dissemination. Conclusions. Endoprosthetic reconstruction resulted in pain relief and restored the ambulatory capacity. Clinicians should be aware of the possibility for symptomatic bone metastases with a risk for pathological fracture in patients with penile cancer. PMID- 26579328 TI - Clinical Outcomes from Unselected "Real-World" Patients with Long Coronary Lesion Receiving 40 mm Biodegradable Polymer Coated Sirolimus-Eluting Stent. AB - Background. Long lesions being implanted with drug-eluting stents (DES) are associated with relatively high restenosis rates and higher incidences of adverse events. Objectives. We aimed to examine the safety and efficacy of the long (40 mm) biodegradable polymer coated Indolimus sirolimus-eluting stent (SES) in real world patients with long coronary lesions. Methods. This study was observational, nonrandomized, retrospective, and carried out in real-world patients. A total of 258 patients were enrolled for the treatment of long coronary lesions, with 40 mm Indolimus. The primary endpoints in the study were incidence of major adverse cardiac events (MACE), a miscellany of cardiac death, myocardial infarction (MI), target lesion revascularization (TLR) or target vessel revascularization (TVR), and stent thrombosis (ST) up to 6-month follow-up. Results. The study population included higher proportion of males (74.4%) and average age was 53.2 +/- 11.0 years. A total of 278 lesions were intervened successfully with 280 stents. The observed MACE at 6-month follow-up was 2.0%, which included 0.8% cardiac death and 1.2% MI. There were no TLR or TVR and ST observed during 6-month follow-up. Conclusions. The long (40 mm) Indolimus stent demonstrated low MACE rate and was proven to be safe and effective treatment for long lesions in "real-world" patients. PMID- 26579329 TI - An Analysis of the Relationship Between the Heat Index and Arrivals in the Emergency Department. AB - BACKGROUND: Heatwaves are one of the most deadly weather-related events in the United States and account for more deaths annually than hurricanes, tornadoes, floods, and earthquakes combined. However, there are few statistically rigorous studies of the effect of heatwaves on emergency department (ED) arrivals. A better understanding of this relationship can help hospitals plan better and provide better care for patients during these types of events. METHODS: A retrospective review of all ED patient arrivals that occurred from April 15 through August 15 for the years 2008 through 2013 was performed. Daily patient arrival data were combined with weather data (temperature and humidity) to examine the potential relationships between the heat index and ED arrivals as well as the length of time patients spend in the ED using generalized additive models. In particular the effect the 2012 heat wave that swept across the United States, and which was hypothesized to increase arrivals was examined. RESULTS: While there was no relationship found between the heat index and arrivals on a single day, a non-linear relationship was found between the mean three-day heat index and the number of daily arrivals. As the mean three-day heat index initially increased, the number of arrivals significantly declined. However, as the heat index continued to increase, the number of arrivals increased. It was estimated that there was approximately a 2% increase in arrivals when the mean heat index for three days approached 100 degrees F. This relationship was strongest for adults aged 18-64, as well as for patients arriving with lower acuity. Additionally, a positive relationship was noted between the mean three day heat index and the length of stay (LOS) for patients in the ED, but no relationship was found for the time from which a patient was first seen to when a disposition decision was made. No significant relationship was found for the effect of the 2012 heat wave on ED arrivals, though it did have an effect on patient LOS. CONCLUSION: A single hot day has only a limited effect on ED arrivals, but continued hot weather has a cumulative effect. When the heat index is high (~90 degrees F) for a number of days in a row, this curtails peoples activities, but if the heat index is very hot (~100 degrees F) this likely results in an exacerbation of underlying conditions as well as heat-related events that drives an increase in ED arrivals. Periods of high heat also affects the length of stay of patients either by complicating care or by making it more difficult to discharge patients. PMID- 26579330 TI - Enhanced Reprogramming Efficiency and Kinetics of Induced Pluripotent Stem Cells Derived from Human Duchenne Muscular Dystrophy. AB - The generation of disease-specific induced pluripotent stem cells (iPSCs) holds a great promise for understanding disease mechanisms and for drug screening. Recently, patient-derived iPSCs, containing identical genetic anomalies of the patient, have offered a breakthrough approach to studying Duchenne muscular dystrophy (DMD), a fatal disease caused by the mutation in the dystrophin gene. However, development of scalable and high fidelity DMD-iPSCs is hampered by low reprogramming efficiency, the addition of expensive growth factors and slow kinetics of disease-specific fibroblasts. Here, we show an efficient generation of DMD-iPSCs on bFGF secreting human foreskin fibroblast feeders (I-HFF) by employing single polycistronic lentiviral vector for delivering of transcription factors to DMD patient-specific fibroblast cells. Using this method, DMD-iPSCs generated on I-HFF feeders displayed pluripotent characteristics and disease genotype with improved reprogramming efficiency and kinetics over to mouse feeders. Moreover, we were able to maintain disease-specific iPSCs without additional supplementation of bFGF on I-HFF feeders. Our findings offer improvements in the generation of DMD-iPSCs and will facilitate in understanding of pathological mechanisms and screening of safer drugs for clinical intervention. KEY WORDS: Duchenne Muscular Dystrophy, Reprogramming, Induced pluripotent Stem Cells, Immortalized Human Feeder, Basic Fibroblast Growth Factor, Stem Cell Cassette. PMID- 26579331 TI - 2011 Joplin, Missouri Tornado Experience, Mental Health Reactions, and Service Utilization: Cross-Sectional Assessments at Approximately 6 Months and 2.5 Years Post-Event. AB - Introduction. On May 22, 2011 the deadliest tornado in the United States since 1947 struck Joplin, Missouri killing 161 people, injuring approximately 1,150 individuals, and causing approximately $2.8 billion in economic losses. Methods. This study examined the mental health effects of this event through a random digit dialing sample (N = 380) of Joplin adults at approximately 6 months post disaster (Survey 1) and a purposive convenience sample (N = 438) of Joplin adults at approximately 2.5 years post-disaster (Survey 2). For both surveys we assessed tornado experience, posttraumatic stress, depression, mental health service utilization, and sociodemographics. For Survey 2 we also assessed social support and parent report of child strengths and difficulties. Results. Probable PTSD relevance was 12.63% at Survey 1 and 26.74% at Survey 2, while current depression prevalence was 20.82% at Survey 1 and 13.33% at Survey 2. Less education and more tornado experience was generally related to greater likelihood of experiencing probable PTSD and current depression for both surveys. Men and younger participants were more likely to report current depression at Survey 1. Low levels of social support (assessed only at Survey 2) were related to more probable PTSD and current depression. For both surveys, we observed low rates of mental health service utilization, and these rates were also low for participants reporting probable PTSD and current depression. At Survey 2 we assessed parent report of child (ages 4 to 17) strengths and difficulties and found that child difficulties were more frequent for younger children (ages 4 to 10) than older children (ages 11 to 17), and that parents reporting probable PTSD reported a greater frequency of children with borderline or abnormal difficulties. Discussion. Overall our results indicate that long-term (multi-year) community disaster mental health monitoring, assessment, referral, outreach, and services are needed following a major disaster like the 2011 Joplin tornado. PMID- 26579332 TI - Dysferlinopathy Fibroblasts Are Defective in Plasma Membrane Repair. AB - BACKGROUND: Dysferlin is a sarcolemmal protein that is defective in Miyoshi myopathy and limb-girdle muscular dystrophy type 2B, and is involved in sarcolemmal repair. Primary cultured myoblasts and myotubes established from patient muscle biopsies have been widely utilized to explore the molecular mechanism of dysferlinopathy. OBJECTIVES: The purpose of this study was to explore the possible utility of dermal fibroblasts from dysferlin-deficient patients and SJL mice as a tool for studying dysferlinopathy. METHODS: Dysferlin protein expression in fibroblasts from dysferlin-deficient patients and SJL mice was analyzed by immunoblotting and immunocytochemistry. The membrane wound-repair assay was performed on the fibroblasts using a confocal microscope equipped with a UV-laser. The membrane blebbing assay using hypotonic shock, in which normal membrane blebbing is detected only in the presence of dysferlin, was also performed using human and mouse fibroblasts. RESULTS: Mis-sense mutated dysferlin was expressed at a very low level in fibroblasts from a dysferlinopathy patient, and lower expression level of truncated dysferlin was observed in SJL mouse fibroblast. Fibroblasts from patients with dysferlinopathy and SJL mice showed attenuated membrane repair and did not form membrane blebs in response to hypoosmotic shock. Proteosomal inhibitior increased mis-sense mutated or truncated dysferlin levels, and restored membrane blebbing, however, proteosomal inhibition failed to improve levels of dysferlin with non-sense or frame-shift mutation. CONCLUSION: Fibroblasts from dysferlinopathy patients and SJL mice showed attenuated plasma membrane repair, and could be a tool for studying dysferlinopathy. PMID- 26579333 TI - Postreduction Breast Augmentation. AB - Most breast reduction patients are highly satisfied after surgery. However, there is a subset of women who seek breast augmentation years later to restore lost volume chiefly associated with weight loss and postpartum changes. Breast shape and overall aesthetics are often revised at the same time. METHODS: A retrospective review was performed of 2 surgeons' experiences with post-reduction breast augmentation. Twenty patients were identified between 2002 and 2014. An in depth chart review was conducted to determine patient motivation and to examine the operative techniques employed. Implant variables, a reduction specimen weight to implant volume comparison (where available), and complications are reported. RESULTS: The average age was 37.1 years and average body mass index was 21.8 kg/m(2). Most patients waited over a decade to have their breasts revised. Weight loss was the motivating factor in 8 patients and pregnancy changes in 11. Nineteen patients wished to stay with the same bra size or 1 cup size larger. Although all patients elected to have an implant placed, 19 patients wished to have an improved breast shape, not specifically a larger volume. The average breast implant was 203.5 cm(3) (range, 120-340 cm(3)). Complications from implant placement included a seroma treated by aspiration and a Baker class III capsular contracture that required surgical correction. CONCLUSIONS: A small subset of reduction mammaplasty patients seek breast augmentation many years later primarily to improve breast contour, not to restore their prereduction breast volumes. Conservative augmentation combined with revision of breast shape and areolar aesthetics yields good results with minimal complications. PMID- 26579334 TI - Solitary Fibrous Tumor of the Lower Leg: A Rare and Difficult Diagnosis. AB - Solitary fibrous tumor (SFT) is a rare neoplasm that commonly originates in the pleura. Extrapleural locations are rare and for this reason sometimes difficult to diagnose. Malignant forms with local recurrence or distant metastases have been reported, also as a consequence of inappropriate treatment. In this article, we report the case of an SFT of the lower leg in a 37-year-old man. Leg SFT is a rare occurrence, and differential diagnosis may be difficult because they can mimic a variety of benign and malignant mesenchymal tumors; immunohistochemical analysis for CD34, CD99, vimentin, and Bcl-2 is necessary. Misdiagnosis carries a significant risk of inadequate removal with subsequent increased risk of recurrence and distant metastases. PMID- 26579335 TI - Skin Necrosis in a Patient with Factor V Leiden Mutation following Nipple Sparing Mastectomy. AB - Nipple-sparing mastectomy (NSM) and immediate breast reconstruction have replaced radical surgical interventions for the treatment of selected patients with breast cancer undergoing prophylactic mastectomy. NSM is technically a difficult procedure. After dissection, the remaining breast skin and nipple-areola complex (NAC) must be thin enough to be free of tumor tissue and thick enough to preserve tissue perfusion. Factor V Leiden mutation is the most common cause of hereditary thrombophilia; thrombosis almost always develops in the venous system. The literature includes only a few case series of arterial thrombosis. The present study aimed to describe for the first time a patient with Factor V Leiden mutation that developed nipple-areola complex and skin necrosis, and multiple embolisms in the upper extremity arteries following NSM. PMID- 26579336 TI - A Review of the Use of Medicare Claims Data in Plastic Surgery Outcomes Research. AB - With a growing national emphasis in data transparency and reporting of public health data, it is essential for researchers to know more about Medicare claims data, the largest and most reliable source of health-care utilization and expenditure for individuals older than 65 years in the United States. This article provides an overview of Medicare claims data for plastic surgery outcomes research. We highlight essential information on various files included in Medicare claims data, strengths and limitations of the data, and ways to expand the use of existing data for research purposes. As of now, Medicare data are limited in providing adequate information regarding severity of diagnosed conditions, health status of individuals, and health outcomes after certain procedures. However, the data contain all health-care utilization and expenditures for services that are covered by Medicare Parts A, B, and D (inpatient, outpatient, ambulatory-based and physician-based services, and prescription drugs). Additionally, Medicare claims data can be used for longitudinal analysis of variations in utilization and cost of health-care services at the patient level and provider level. Linking Medicare claims data with other national databases and utilizing the ICD-10 coding system would further expand the use of these datasets in health services research. PMID- 26579337 TI - Flexible Curved V-Y Subcutaneous Flap for Facial Skin Defects. AB - We devised an improved type of the V-Y subcutaneous pedicle flap with the elements of both advancement and rotation flaps. This flexible curved V-Y subcutaneous flap was used for facial skin defect reconstruction in 15 patients. Curved flaps were designed according to the elasticity of the surrounding skin and the postoperative scar direction. RESULTS: In all the 15 patients, the flap survived without circulatory impairment, and follow-up for more than 1 year indicated an inconspicuous scar and good course. CONCLUSIONS: With elements of both advancement and rotation flaps, transfer and wound closure of the flexible curved V-Y subcutaneous flap are easy. In addition, the postoperative scar can be positioned along natural wrinkle lines and relaxed skin tension lines. This may be a useful local flap for facial and general plastic surgery. PMID- 26579338 TI - Skin Excision as an Adjunctive Technique to Rhinoplasty in Middle-Aged and Elderly Patients. AB - Rhinoplasty in middle-aged and elderly patients comes with its own set of challenges. There is relative lengthening of the nose with drooping of the nasal tip. With aging, the skin loses its elasticity, and the combination of nasal skeletal reduction along with overlying inelastic skin provides a setup for skin redundancy and poor postoperative outcome. We describe a surgical technique involving lenticular skin excision as a part of rhinoplasty in 12 patients older than 50 years to improve the aesthetic outcome. Skin width up to 1.6 cm was excised. Included is a literature review of skin excision in rhinoplasty. In elderly patients with thin, inelastic skin and long nose with a drooping tip, a reduction rhinoplasty technique might result in skin redundancy. Lenticular skin excision along the radix of the nose in these 12 patients improved the aesthetic outcome by decreasing the redundancy and preventing nasal tip ptosis. The wound from the skin resection healed in all the patients with minimal scar, and no complication was noted after at least 1 year of follow-up for each patient. PMID- 26579339 TI - Psychosocial Outcomes after Bilateral Hand Transplantation. AB - Since the first successful hand transplantation in 1998, there have been multiple reports about surgical technique, transplant survival, and immunosuppression. However, very limited published data exist on psychosocial outcomes following hand transplantation. METHODS: We report psychosocial outcomes in a patient with bilateral hand transplants at the midforearm level with serial follow-ups over 3.5 years. Different metrics used to study psychosocial outcomes included the following: SF-12, CES-D, Dyadic Adjustment Scale, Rosenberg SE, and EQ-5D. RESULT: Preoperatively, our patient did not have any evidence of depression (CES D = 3), had a nonstressful relationship with his spouse (Dyadic Adjustment Scale = 100), and self-esteem was in the normal range (Rosenberg SE = 21). These metrics and his additional scales (SF-12 MCS, EQ-5D, and EQ-VAS) did not change appreciably and were within the normal range for the entire duration of 3.5-year follow-up at all different time points. CONCLUSION: With the increasing popularity of hand transplantation and the increasing awareness of the importance of psychosocial parameters in overall success, appropriate, comprehensive, and standardized measurements are important. These should be an integral part of patients' screening and follow-up. PMID- 26579340 TI - Treatment of Skin Depression with Combined Upward Suture Traction and Percutaneous Subcision. AB - Scar retraction and soft-tissue depression may compromise aesthetics and cause social embarrassment. The purpose of this study was to evaluate the results of treating soft-tissue depressions or retractions at varied anatomy regions with combined upward suture traction and percutaneous subcision. METHODS: There were 40 patients (age: mean, 39 years; range, 22-55 years; 39 women and 1 man) (total, 77 soft-tissue lesions) who had treatment with the present technique from 1996 to 2013. Postoperative follow-up was from 6 months to 2 years. The treated anatomic areas were evaluated in 5 groups: (1) face (8 patients; 8 lesions); (2) gluteal (16 patients; 46 lesions); (3) breast (7 patients; 10 lesions); (4) abdomen (7 patients; 7 lesions); and (5) lower limb (2 patients; 6 lesions). The technique included placing a 2-0 nylon monofilament suture deep at the core of the depression, pulling vertically up with the suture, and using a needle or miniblade (placed percutaneously or through a small incision) to release the adhesions. RESULTS: The depressions were released successfully in all patients. Bruises around treated areas persisted for 2-3 weeks. Moderate induration persisted until 3 months. In the gluteal region, 6 patients who had retracted areas with diameter >5 cm developed seroma after treatment; the seromas resolved after needle aspiration or placement of a Penrose drain for 2 weeks (2 patients). CONCLUSION: The present results confirmed the efficacy of the combined subcision method with upward traction at diverse body sites as previously reported for inverted nipple in the breast. PMID- 26579341 TI - Beautif(o)ul. PMID- 26579342 TI - Oleogranulomatous Mastitis: A Topical Subject. AB - Paraffin and petrolatum have been known for more than 100 years as volumizing products. Certain countries still use them despite important complications. The authors report the case of a 39-year-old patient presenting a bilateral oleogranulomatous mastitis. An injection of petrolatum had been realized 2 years ago in Chechnya for cosmetic reasons. Clinically, she presented dense, erythemic, and painful breasts. The radiological examination found diffuse oily cysts. After first abdominal expansion, a bilateral mastectomy with immediate reconstruction was performed. The authors present a literature review about the clinical and radiological data and the possible treatments, and underline the numerous risks of this procedure, which should be strictly forbidden. PMID- 26579343 TI - Asian Outcomes of Primary Breast Augmentation in 162 Consecutive Cases by a Single Surgeon. AB - In 162 Asian patients, primary breast augmentation was performed by a single surgeon during 5 years. The purpose of this study evaluates Asian outcomes in primary breast augmentation using single antibiotic breast irrigation by a single surgeon's practice and examines the comparison of Asian and Western outcomes in primary breast augmentation. METHODS: A retrospective chart review was performed to examine a total of 162 patients who received the same brand of implants for primary breast augmentation under sedative anesthesia (propofol infusion) in a single surgeon's practice. Asian patients' demographics, preoperative and postoperative measurements, surgical technique (single antibiotic breast irrigation), implant type, size, texture, soft tissue coverage, implant placement, incision approach, complications, and incidence of reoperation were documented. RESULTS: This study presents data for 162 primary breast augmentation who received a total of 324 implants. The mean length of follow-up for all patients was 25.1 months (range, 6-60 months). The difference between Tebbetts and Adams' reoperation proportion (rho0 = 0.028) and this article's reoperation proportion (rho0 = 0.0185) is not statistically significant (P value = 0.3707). Reoperation rate and complications are not related with implant type, implant placement, body mass index, and incision approach. CONCLUSIONS: By comparison, the reoperation rates between Asian and Western patients are equal due to adequate preoperative evaluation and surgical procedure. The differences are found somewhat in the average measurements of age, body mass index, and implant size. The technique of the use of blunt dissection with fingers under tumescent infiltration and single antibiotics irrigation provides an alternative way to surgeons for breast augmentation. PMID- 26579344 TI - The Nipple-Areola Preserving Mastectomy: A Multistage Procedure Aiming to Improve Reconstructive Outcomes following Mastectomy. AB - Ischemia of the nipple-areola complex (NAC) and periareolar tissue is commonly seen following tissue-preserving mastectomies for small invasive and noninvasive cancers. The nipple-areola preserving mastectomy is a multistage procedure in which the NAC and central mastectomy flap tissue is surgically delayed to improve the survivability in patients undergoing mastectomies followed by reconstruction. METHODS: We conducted a retrospective chart review of 20 patients undergoing the 2-stage nipple-areola preserving mastectomy: the first stage comprised undermining the NAC and raising the breast skin flaps, with placement of a silicone sheet in the dissected pocket. The second stage followed 2-3 weeks after the NAC delay, with patients undergoing nipple-sparing mastectomies. RESULTS: Mean age was 46.2 years (range, 23-59 years). Indications included breast cancer in 18 patients and BRCA gene mutation prophylaxis in 2 patients. None were actively smoking. Mean time between delay of flaps and breast reconstructions was 16 days (range, 10-35 days). One patient underwent bilateral nipple resection at the time of mastectomies due to a subareolar nipple biopsy positive for ductal carcinoma in situ. One patient underwent left nipple excision after a skin nipple biopsy was positive for metaplasia. No signs of NAC vascular compromise were observed in any of the cases. CONCLUSIONS: Our 2-stage approach benefits patients undergoing nipple-sparing mastectomy, especially those at high-risk, by safely increasing survivability of the native breast skin envelope and NAC, while improving oncologic outcomes by identification of subareolar malignancies and sentinel node status before mastectomy and reconstruction. PMID- 26579345 TI - Scalp Surgery: Quantitative Analysis of Follicular Unit Growth. AB - Over the years, different kinds of hair transplantation have been compared in an attempt to overcome male pattern alopecia and, at the same time, maximize both the survival and growth rate of grafted hair. In this study, we have assessed the survival and growth rate of follicular units (FU) in an in vitro model, as compared with that of conventional hair micrografts, to experimentally evaluate and elaborate on the differences between these 2 approaches in hair transplantation procedures. METHODS: Group A (control; n = 100 follicles) was composed of hair micrografts, whereas FUs were assigned to Group B (experimental; n = 100 follicles, n = 35 FUs). Each group was cultured for a period of 10 days; the total stretch of follicles was measured soon after the harvest and 10 days later. The Kruskal-Wallis one-way analysis of variance on ranks test was used to perform statistical analysis. RESULTS: The growth rate of follicles from Group A (mean 10-day shaft growth rate = 0.30 mm) proved to be statistically different compared with that of Group B (mean 10-day shaft growth rate = 0.23 mm). Conversely, our data did not show any significant difference between the survival rate of hair grafts from these 2 groups. CONCLUSIONS: Our data highlighted a reduced FU shaft growth compared with that of hair micrografts, corroborating, to a certain extent, the hypothesis that a significant amount of adipose tissue surrounding the follicle included in the graft may result in an inadequate nourishment supply to follicular cells. PMID- 26579346 TI - Delayed Mammoplasty with Silicone Gel Implants following DIEP Flap Breast Reconstruction. AB - The deep inferior epigastric artery perforator (DIEP) flap is a state-of-the-art option for breast reconstruction. However, thin patients with medium- to large size native breasts are not ideal candidates due to the limited amount of available tissue. We reviewed our experience utilizing the DIEP flap in combination with prosthetic implants. METHODS: We conducted a retrospective chart review of 7 patients, totaling 11 implants, who underwent breast reconstruction with the DIEP flap and subsequent mammoplasty. All cases underwent previous mastectomies. No implant placement was offered at the time of their DIEP flap reconstruction. Immediate breast reconstruction with the DIEP flap was performed in 9 cases, whereas 2 required delayed reconstruction secondary to postmastectomy radiotherapy. No patients received postreconstruction radiotherapy. Breast asymmetry and inadequate volume were the primary indications for mammoplasty. For all cases, we used smooth, round silicone gel implants, which were placed in the subpectoral region. RESULTS: Mean age was 43 years. One patient was actively smoking. Four patients underwent bilateral implant placement. The mean time of delay between breast reconstruction and mammoplasty was 61 weeks. Average volume of silicone implants was 229 mL. A medial pedicle vertical mastopexy was performed in 1 patient on a nonreconstructed breast to achieve symmetry. Five patients underwent nipple reconstruction. All patients underwent delayed mammoplasty without intraoperative complications and good aesthetic results. CONCLUSIONS: Delayed mammoplasty following DIEP flap breast reconstruction is a safe and feasible procedure for patients who seek an aesthetic and natural looking breast but lack adequate abdominal tissue. PMID- 26579347 TI - Combined Use of Anterolateral Thigh and Gluteal Fold Flaps for Complex Groin Reconstruction. AB - We present a case of an epithelioid sarcoma of the right groin in which wide resection resulted in a complex groin defect involving the full thickness of the abdominal wall and the perineum. We reconstructed the defect using a combination of pedicled anterolateral thigh (ALT) flap and gluteal fold flap. The functional and aesthetic results were satisfactory. The ALT flap with a robust iliotibial tract is the flap of choice for abdominal wall reconstruction; however, the area covered by the skin island of the flap is restricted because the skin island is tethered to the iliotibial tract. In such cases, a gluteal fold flap is ideal for an ALT flap. Therefore, using a combination of a pedicled ALT flap and a gluteal fold flap could be a reliable option for the reconstruction of a complex groin defect. PMID- 26579348 TI - Evolutionary Reasons for Male Preferences Regarding the Female Breast Shape. PMID- 26579349 TI - Experience of Raising Flaps Using Cadavers Embalmed by Saturated Salt Solution Method. PMID- 26579350 TI - Differential Reanimation of the Upper and Lower Face Using 2 Interpositional Nerve Grafts in Total Facial Nerve Reconstruction. AB - Radical parotidectomy often results in complex facial nerve defects involving the main nerve trunk and multiple distal nerve branches. Although cable nerve grafting often leads to good nerve regeneration, severe synkinesis due to aberrant axonal regrowth is inevitable. In such situations, the use of 2 motor sources to differentially reanimate the upper and lower face could minimize synkinesis. Here we describe a method of total facial nerve reconstruction in which the upper and lower face are differentially reconstructed with the hypoglossal nerve and facial nerve, respectively, using 2 interpositional nerve grafts. Reconstruction of the lower face with the facial nerve restored voluntary and coordinated animation, and reconstruction of the upper face with the hypoglossal nerve restored frontalis muscle tone and eye closure. These results suggest that our method could serve as an alternative to conventional techniques that use only the facial or hypoglossal nerve. PMID- 26579351 TI - Does Radiofrequency Assistance Improve Skin Contraction after Liposuction? PMID- 26579352 TI - A Rapid, Simple, Effective, and Inexpensive Reconstructed Nipple Flap Guard. AB - Nipple reconstruction is a commonly performed component of breast reconstruction. A nipple reconstructed using local skin flaps requires protection from trauma. Here we describe a novel, effective, simple, rapid, inexpensive, and convenient method to protect a reconstructed nipple in the early postoperative period. PMID- 26579353 TI - Reproducible Volume Restoration and Efficient Long-term Volume Retention after Point-of-care Standardized Cell-enhanced Fat Grafting in Breast Surgery. AB - Lipoaspirated fat grafts are used to reconstruct volume defects in breast surgery. Although intraoperative treatment decisions are influenced by volume changes observed immediately after grafting, clinical effect and patient satisfaction are dependent on volume retention over time. The study objectives were to determine how immediate breast volume changes correlate to implanted graft volumes, to understand long-term adipose graft volume changes, and to study the "dose" effect of adding autologous stromal vascular fraction (SVF) cells to fat grafts on long-term volume retention. METHODS: A total of 74 patients underwent 77 cell-enhanced fat grafting procedures to restore breast volume deficits associated with cosmetic and reconstructive indications. Although all procedures used standardized fat grafts, 21 of the fat grafts were enriched with a low dose of SVF cells and 56 were enriched with a high SVF cell dose. Three dimensional imaging was used to quantify volume retention over time. RESULTS: For each milliliter of injected fat graft, immediate changes in breast volume were shown to be lower than the actual volume implanted for all methods and clinical indications treated. Long-term breast volume changes stabilize by 90-120 days after grafting. Final volume retention in the long-term was higher with high cell enhanced fat grafts. CONCLUSIONS: Intraoperative immediate breast volume changes do not correspond with implanted fat graft volumes. In the early postoperative period (7-21 days), breast volume increases more than the implanted volume and then rapidly decreases in the subsequent 30-60 days. High-dose cell-enhanced fat grafts decrease early postsurgical breast edema and significantly improve long term volume retention. PMID- 26579355 TI - Hardware Location and Clinical Outcome in Ulna Shortening Osteotomy. AB - The purpose of this study was to investigate the influence of plate location during ulna shortening osteotomy on the incidence of hardware irritation and clinical outcome. METHODS: Forty patients (17 women, 23 men; mean age, 47 years) who underwent a shortening osteotomy of the ulna due to idiopathic ulna impaction syndrome were examined after a mean of 36 months. All complications and secondary procedures were extracted from the patients' records. RESULTS: The rate of hardware removal was higher in patients who had a dorsal placement of the plate in comparison with ulnar or palmar placements, although this difference was not statistically significant. Apart from hardware irritation, there were 4 nonunions, 1 secondary osteoarthritis of the distal radioulnar joint, and 1 case of chronic irritation of the dorsal branch of the ulnar nerve, which required secondary surgery. The incidence of secondary surgery other than hardware removal was not significantly related to the original location of the plate. CONCLUSIONS: Secondary surgery after ulnar shortening osteotomy is common. However, we found no difference in clinical outcomes based on plate location. PMID- 26579354 TI - Chemical Burn Injury in Kumasi: The Trend and Complications following and Their Management. AB - A chemical burn refers to irritation and destruction of human tissue caused by exposure to a chemical, usually by direct contact with the chemical or its fumes. The study investigated the trend and complications following chemical burns and their management. METHODS: The study involved a retrospective review of Burns Registry at the Burns Intensive Care Unit of the Komfo Anokye Teaching Hospital on patients who were admitted for burns from May 1, 2009 to April 30, 2013. RESULTS: Chemical burns admissions accounted for 3.5% (n = 17) out of the total 487 burns cases, consisting of 12 males (70.6%) and 5 females (29.4%). Mean total burns surface area was 21.9%; mean length of stay in Burns Intensive Care Unit was 9.5 days. The etiological agents for the chemical burns included the following: hot caustic soda 1 (5.9%); acid 9 (53.9%)-the most common; hot ethanol 3 (17.6%); and other chemicals such as other bases, oxidizers, solvents, etc. accounted for 4 (23.5%) etiological agents. Outcome included 11 discharges (64.7%), 6 transferred out to other wards (35.3%), and 0 deaths (0.0%). The complications included severe scar contractures in 5 patients (29.4%), loss of vision: partial/total = 2 (11.8%), gross keloidal/hypertrophic scars = 10 (58.8%). CONCLUSIONS: Chemical burns are severe and often cause severe debilitating sequelae including partial/total loss of vision. But the current study showed that only a small population (3.5%) were affected by chemical burns and no death was recorded; society has to be continually conscious of chemicals, especially caustic agents, and hence take the necessary precautions so as to prevent these avoidable complications. PMID- 26579357 TI - Cover story. PMID- 26579356 TI - Editor profile: Guest editor of special issue "Drug Delivery System and Pharmaceutical Technology". PMID- 26579358 TI - Editorial. PMID- 26579359 TI - Can formulation and drug delivery reduce attrition during drug discovery and development-review of feasibility, benefits and challenges. AB - Drug discovery and development has become longer and costlier process. The fear of failure and stringent regulatory review process is driving pharmaceutical companies towards "me too" drugs and improved generics (505(b) (2)) fillings. The discontinuance of molecules at late stage clinical trials is common these years. The molecules are withdrawn at various stages of discovery and development process for reasons such as poor ADME properties, lack of efficacy and safety reasons. Hence this review focuses on possible applications of formulation and drug delivery to salvage molecules and improve the drugability. The formulation and drug delivery technologies are suitable for addressing various issues contributing to attrition are discussed in detail. PMID- 26579360 TI - Fundamental aspects of solid dispersion technology for poorly soluble drugs. AB - The solid dispersion has become an established solubilization technology for poorly water soluble drugs. Since a solid dispersion is basically a drug-polymer two-component system, the drug-polymer interaction is the determining factor in its design and performance. In this review, we summarize our current understanding of solid dispersions both in the solid state and in dissolution, emphasizing the fundamental aspects of this important technology. PMID- 26579361 TI - Crosslinked hydrogels-a promising class of insoluble solid molecular dispersion carriers for enhancing the delivery of poorly soluble drugs. AB - Water-insoluble materials containing amorphous solid dispersions (ASD) are an emerging category of drug carriers which can effectively improve dissolution kinetics and kinetic solubility of poorly soluble drugs. ASDs based on water insoluble crosslinked hydrogels have unique features in contrast to those based on conventional water-soluble and water-insoluble carriers. For example, solid molecular dispersions of poorly soluble drugs in poly(2-hydroxyethyl methacrylate) (PHEMA) can maintain a high level of supersaturation over a prolonged period of time via a feedback-controlled diffusion mechanism thus avoiding the initial surge of supersaturation followed by a sharp decline in drug concentration typically encountered with ASDs based on water-soluble polymers. The creation of both immediate- and controlled-release ASD dosage forms is also achievable with the PHEMA based hydrogels. So far, ASD systems based on glassy PHEMA have been shown to be very effective in retarding precipitation of amorphous drugs in the solid state to achieve a robust physical stability. This review summarizes recent research efforts in investigating the potential of developing crosslinked PHEMA hydrogels as a promising alternative to conventional water-soluble ASD carriers, and a related finding that the rate of supersaturation generation does affect the kinetic solubility profiles implications to hydrogel based ASDs. PMID- 26579362 TI - Kidney-targeted drug delivery systems. AB - Kidney-targeted drug delivery systems represent a promising technology to improve drug efficacy and safety in the treatment of renal diseases. In this review, we summarize the strategies that have been employed to develop kidney-targeted drug delivery systems. We also describe how macromolecular carriers and prodrugs play crucial roles in targeting drugs to particular target cells in the kidney. New technologies render it possible to create renal targeting conjugates and other delivery systems including nanoparticles and liposomes present promising strategies to achieve the goal of targeting drugs to the kidney. PMID- 26579363 TI - Evaluation of percutaneous permeation of repellent DEET and sunscreen oxybenzone from emulsion-based formulations in artificial membrane and human skin. AB - Insect repellent DEET and sunscreen ingredient oxybenzone play an essential role in minimizing vector-borne diseases and skin cancers. The purpose of this study was to investigate the effects of emulsion type, addition of thickening agent and droplet size in three emulsion-based lotions on percutaneous permeation of DEET and oxybenzone using in vitro diffusion experiments, in order to minimize overall systemic permeation of the substances. Formulation C (water-in-oil emulsion) significantly increased overall permeation of DEET through human skin (56%) compared to Formulation A (oil-in-water emulsion). Formulation B (oil-in-water emulsion with thickening agent xanthan gum) significantly decreased the size of oil droplet containing DEET (16%), but no effect on oil droplets containing oxybenzone. Adding xanthan gum also increased overall permeation of DEET and oxybenzone (21% and 150%) when compared to Formulation A; presence of both ingredients in Formulation B further increased their permeation (36% and 23%) in comparison to its single counterparts. Overall permeation of oxybenzone through LDPE was significantly higher by 26%-628% than that through human skin; overall permeation of DEET through human skin was significantly higher by 64%-338% than that through LDPE. PMID- 26579364 TI - Three-dimensional DEM-CFD analysis of air-flow-induced detachment of API particles from carrier particles in dry powder inhalers. AB - Air flow and particle-particle/wall impacts are considered as two primary dispersion mechanisms for dry powder inhalers (DPIs). Hence, an understanding of these mechanisms is critical for the development of DPIs. In this study, a coupled DEM-CFD (discrete element method-computational fluid dynamics) is employed to investigate the influence of air flow on the dispersion performance of the carrier-based DPI formulations. A carrier-based agglomerate is initially formed and then dispersed in a uniformed air flow. It is found that air flow can drag API particles away from the carrier and those in the downstream air flow regions are prone to be dispersed. Furthermore, the influence of the air velocity and work of adhesion are also examined. It is shown that the dispersion number (i.e., the number of API particles detached from the carrier) increases with increasing air velocity, and decreases with increasing the work of adhesion, indicating that the DPI performance is controlled by the balance of the removal and adhesive forces. It is also shown that the cumulative Weibull distribution function can be used to describe the DPI performance, which is governed by the ratio of the fluid drag force to the pull-off force. PMID- 26579365 TI - Bio-mimetic drug delivery systems designed to help the senior population reconstruct melatonin plasma profiles similar to those of the healthy younger population. AB - The secretion of melatonin (MT) is obviously different in the younger and the senior sectors of the population, and the maximum plasma concentration of seniors is only half of that in the younger population group. If exogenous MT can be supplied to senior citizens based on the secretion rate and amount of endogenous MT in the younger population by a bio-mimetic drug delivery system (DDS), an improved therapeutic effect and reduced side effects can be expected. Based upon this hypothesis, the pharmacokinetic parameters of MT, namely, the absorption rate constant (k a), the elimination rate constant (k e), and the ratio of absorption rate (F) to the apparent volume of distribution (V) were obtained by a residual method depending on the plasma concentration curve of immediate release preparations in the healthy younger population. The dose-division method was applied to calculate the cumulative release profiles of MT achieved by oral administration of a controlled release drug delivery system (DDS) to generate plasma MT profiles similar to the physiological level-time profiles. The in vivo release of MT deduced from the healthy younger population physiological MT profiles as the pharmacokinetic output of the bio-mimetic DDS showed a two-phase profile with two different zero order release rates, namely, 4.919 MUg/h during 0 4 h (r=0.9992), and 11.097 MUg/h during 4-12 h (r=0.9886), respectively. Since the osmotic pump type of DDS generally exhibits a good correlation between in vivo and in vitro release behaviors, an osmotic pump controlled delivery system was designed in combination with dry coating technology targeting on the cumulative release characteristics to mimic the physiological MT profiles in the healthy younger population. The high similarity between the experimental drug release profiles and the theoretical profiles (similarity factor f 2>50) and the high correlation between the predicted plasma concentration profiles and the theoretical plasma concentration profiles (r=0.9366, 0.9163, 0.9264) indicated that a prototype bio-mimetic drug delivery system of MT was established. The similarity factors between the experimental drug release profiles and the theoretical release profile were all larger than 50 both in periods of 0-4 h and 4-12 h, namely, 68.8 and 57.3 for the first batch (Batch No. 20131031), 76.7 and 50.2 for the second batch (Batch No. 20131101), and 73.7 and 51.1 for the third batch (Batch No. 20131126), respectively. The correlation coefficients between the predicted plasma concentration profiles based on the release profiles of the bio-mimetic DDS and physiological profiles were 0.9366 (Batch No. 20131031), 0.9163 (Batch No. 20131101), 0.9264 (Batch No. 20131126), respectively. Since the pharmacokinetic profile of MT in any kind of animal differs markedly from that of human beings, it is impossible to test the bio-mimetic DDS in animals directly. Therefore, the predicted pharmacokinetic profile based upon the in vitro release kinetics is an acceptable surrogate for the conventional animal test. In this research, a bio-mimetic DDS for replacement of MT was designed with in silico evaluation. PMID- 26579366 TI - A detachable coating of cholesterol-anchored PEG improves tumor targeting of cell penetrating peptide-modified liposomes. AB - Cell-penetrating peptides (CPPs) have been widely used to enhance the membrane translocation of various carriers for many years, but the non-specificity of CPPs seriously limits their utility in vivo. In this study, cholesterol-anchored, reduction-sensitive PEG (first synthesized by our laboratory) was applied to develop a co-modified liposome with improved tumor targeting. Following optimization of the formulation, the in vitro and in vivo properties of the co modified liposome were evaluated. The co-modified liposome had a much lower cellular uptake and tumor spheroid uptake, but a much higher tumor accumulation compared to CPP-modified liposome, indicating the non-specific penetration of CPPs could be attenuated by the outer PEG coating. With the addition of exogenous reducing agent, both the in vitro and in vivo cellular uptake was markedly increased, demonstrating that the reduction-sensitive PEG coating achieved a controllable detachment from the surface of liposomes and did not affect the penetrating abilities of CPPs. The present results demonstrate that the combination of cholestervsitive PEG and CPPs is an ideal alternative for the application of CPP-modified carriers in vivo. PMID- 26579367 TI - Comparative pharmacokinetics of tetramethylpyrazine phosphate in rat plasma and extracellular fluid of brain after intranasal, intragastric and intravenous administration. AB - The purpose of this study was to compare the pharmacokinetic profiles of tetramethylpyrazine phosphate (TMPP) in plasma and extracellular fluid of the cerebral cortex of rats via three delivery routes: intranasal (i.n.), intragastric (i.g.) and intravenous (i.v.) administration. After i.n., i.g. and i.v. administration of a single-dose at 10 mg/kg, cerebral cortex dialysates and plasma samples drawn from the carotid artery were collected at timed intervals. The concentration of TMPP in the samples was analyzed by HPLC. The area under the concentration-time curve (AUC) and the ratio of the AUCbrain to the AUCplasma (drug targeting efficiency, DTE) was calculated to evaluate the brain targeting efficiency of the drug via these different routes of administration. After i.n. administration, TMPP was rapidly absorbed to reach its peak plasma concentration within 5 min and showed a delayed uptake into cerebral cortex (t max=15 min). The ratio of the AUCbrain dialysates value between i.n. route and i.v. injection was 0.68, which was greater than that obtained after i.g. administration (0.43). The systemic bioavailability obtained with i.n. administration was greater than that obtained by the i.g. route (86.33% vs. 50.39%), whereas the DTE of the nasal route was 78.89%, close to that of oral administration (85.69%). These results indicate that TMPP is rapidly absorbed from the nasal mucosa into the systemic circulation, and then crosses the blood-brain barrier (BBB) to reach the cerebral cortex. Intranasal administration of TMPP could be a promising alternative to intravenous and oral approaches. PMID- 26579368 TI - An aerosol formulation of R-salbutamol sulfate for pulmonary inhalation. AB - An aerosol formulation containing 7.5 mg of R-salbutamol sulfate was developed. The aerosol was nebulized with an air-jet nebulizer, and further assessed according to the new European Medicines Agency (EMA) guidelines. A breath simulator was used for studies of delivery rate and total amount of the active ingredient at volume of 3 mL. A next generation impactor (NGI) with a cooler was used for analysis of the particle size and in vitro lung deposition rate of the active ingredient at 5 degrees C. The anti-asthmatic efficacy of the aerosol formulation was assessed in guinea pigs with asthma evoked by intravenous injection of histamine compared with racemic salbutamol. Our results show that this aerosol formulation of R-salbutamol sulfate met all the requirements of the new EMA guidelines for nebulizer. The efficacy of a half-dose of R-salbutamol equaled that of a normal dose of racemic salbutamol. PMID- 26579369 TI - Preparation and evaluation of sustained-release solid dispersions co-loading gastrodin with borneol as an oral brain-targeting enhancer. AB - Borneol is a traditional Chinese medicine that can promote drug absorption from the gastrointestinal tract and distribution to the brain. However, stomach irritation may occur when high doses of borneol are used. In the present work, gastrodin, the main bioactive ingredient of the traditional Chinese drug "Tianma" (Rhizoma Gastrodiae) was used as a model drug to explore reasonable application of borneol. Sustained-release solid dispersions (SRSDs) for co-loading gastrodin and borneol were prepared using ethylcellulose as a sustained release matrix and hydroxy-propyl methylcellulose as a retarder. The dispersion state of drug within the SRSDs was analyzed by using scanning electron microscopy, differential scanning calorimetry, and powder X-ray diffractometry. The results indicated that both gastrodin and borneol were molecularly dispersed in an amorphous form. Assay of in vitro drug release demonstrated that the dissolution profiles of gastrodin and borneol from the SRSDs both fitted the Higuchi model. Subsequently, gastric mucosa irritation and the brain targeting of the SRSDs were evaluated. Compared with the free mixture of gastrodin and borneol, brain targeting of SRSDs was slightly weaker (brain targeting index: 1.83 vs. 2.09), but stomach irritation obviously reduced. Sustained-release technology can be used to reduce stomach irritation caused by borneol while preserving sufficient transport capacity for oral brain-targeting drug delivery. PMID- 26579370 TI - Enhanced delivery of hydrophilic peptides in vitro by transdermal microneedle pretreatment. AB - The aims of this study were to investigate the utility of solid microneedle arrays (150 um in length) in enhancing transdermal delivery of peptides and to examine the relationship between peptide permeation rates and D2O flux. Four model peptides were used (Gly-Gln-Pro-Arg [tetrapeptide-3, 456.6 Da], Val-Gly-Val Ala-Pro-Gly [hexapeptide, 498.6 Da], AC-Glu-Glu-Met-Gln-Arg-Arg-NH2 [acetyl hexapeptide-3, 889 Da] and Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly-NH2 [oxytocin, 1007.2 Da]). The influence of microneedle pretreatment on skin permeation was evaluated using porcine ear skin with Franze diffusion cell. Peptide permeation across the skin was significantly enhanced by microneedle pretreatment, and permeation rates were dependent on peptide molecular weights. A positive correlation between D2O flux and acetyl hexapeptide-3 clearances suggests that convective solvent flow contributes to the enhanced transdermal peptide delivery. It is concluded that solid microneedle arrays are effective devices to enhance skin delivery of peptides. PMID- 26579372 TI - Research and development in drug innovation: reflections from the 2013 bioeconomy conference in China, lessons learned and future perspectives. AB - The enormous progress biotechnology, bioinformatics and nanotechnology made in recent years provides opportunities and scientific framework for development of biomedicine and constitutes a paradigm shift in pharmaceutical R&D and drug innovation. By analyzing the data and related information at R&D level over the past decades, developmental tendency and R&D patterns were summarized. We found that a growing number of biologics in the pipeline of pharma companies with successful products already in the market though, small molecular entities have primarily dominated drug innovation. Additionally, small/medium size companies will continue to play a key role in the development of small molecule drugs and biologics in a multi-channel integrated process. More importantly, modern and effective R&D strategies in biomedicine development to predict and evaluate efficacy and/or safety of 21st century therapeutics are urgently needed. To face new challenges, developmental strategies were proposed, in terms of molecular targeted medicine, generic drugs, new drug delivery system and protein-based drugs. Under the current circumstances, interdisciplinary cooperation mode and policy related to drug innovation in China were deeply discussed as well. PMID- 26579371 TI - The pharmacological impact of ATP-binding cassette drug transporters on vemurafenib-based therapy. AB - Melanoma is the most serious type of skin cancer and one of the most common cancers in the world. Advanced melanoma is often resistant to conventional therapies and has high potential for metastasis and low survival rates. Vemurafenib is a small molecule inhibitor of the BRAF serine-threonine kinase recently approved by the United States Food and Drug Administration to treat patients with metastatic and unresectable melanomas that carry an activating BRAF (V600E) mutation. Many clinical trials evaluating other therapeutic uses of vemurafenib are still ongoing. The ATP-binding cassette (ABC) transporters are membrane proteins with important physiological and pharmacological roles. Collectively, they transport and regulate levels of physiological substrates such as lipids, porphyrins and sterols. Some of them also remove xenobiotics and limit the oral bioavailability and distribution of many chemotherapeutics. The overexpression of three major ABC drug transporters is the most common mechanism for acquired resistance to anticancer drugs. In this review, we highlight some of the recent findings related to the effect of ABC drug transporters such as ABCB1 and ABCG2 on the oral bioavailability of vemurafenib, problems associated with treating melanoma brain metastases and the development of acquired resistance to vemurafenib in cancers harboring the BRAF (V600E) mutation. PMID- 26579373 TI - Smart polymers for the controlled delivery of drugs - a concise overview. AB - Smart polymers have enormous potential in various applications. In particular, smart polymeric drug delivery systems have been explored as "intelligent" delivery systems able to release, at the appropriate time and site of action, entrapped drugs in response to specific physiological triggers. These polymers exhibit a non-linear response to a small stimulus leading to a macroscopic alteration in their structure/properties. The responses vary widely from swelling/contraction to disintegration. Synthesis of new polymers and crosslinkers with greater biocompatibility and better biodegradability would increase and enhance current applications. The most fascinating features of the smart polymers arise from their versatility and tunable sensitivity. The most significant weakness of all these external stimuli-sensitive polymers is slow response time. The versatility of polymer sources and their combinatorial synthesis make it possible to tune polymer sensitivity to a given stimulus within a narrow range. Development of smart polymer systems may lead to more accurate and programmable drug delivery. In this review, we discuss various mechanisms by which polymer systems are assembled in situ to form implanted devices for sustained release of therapeutic macromolecules, and we highlight various applications in the field of advanced drug delivery. PMID- 26579374 TI - RasGAP-derived peptide GAP159 enhances cisplatin-induced cytotoxicity and apoptosis in HCT116 cells. AB - To increase the efficacy of currently used anti-cancer genotoxins, one of the current efforts is to find agents that can sensitize cancer cells to genotoxins so that the efficacious doses of genotoxins can be lowered to reduce deleterious side-effects. In this study, we reported that a synthetic RasGAP-derived peptide GAP159 could enhance the effect of chemotherapeutic agent cisplatin (CDDP) in human colon carcinoma HCT116 cells. Our results showed that GAP159 significantly increased the CDDP-induced cytotoxicity and apoptosis in HCT116 cells. This synergistic effect was associated with the inhibitions of phospho-AKT, phospho ERK and NF-kappaB. In mouse colon tumor CT26 animal models, GAP159 combined with CDDP significantly suppressed CT26 tumor growth, and GAP159 alone showed slight inhibitory effect. Our data suggests that co-treatment of GAP159 and chemotherapeutics will become a potential therapeutic strategy for colon cancers. PMID- 26579375 TI - Establishment of a selective evaluation method for DPP4 inhibitors based on recombinant human DPP8 and DPP9 proteins. AB - Dipeptidyl peptidase 4 (DPP4) is recognised as an attractive anti-diabetic drug target, and several DPP4 inhibitors are already on the market. As members of the same gene family, dipeptidyl peptidase 8 (DPP8) and dipeptidyl peptidase 9 (DPP9) share high sequence and structural homology as well as functional activity with DPP4. However, the inhibition of their activities was reported to cause severe toxicities. Thus, the development of DPP4 inhibitors that do not have DPP8 and DPP9 inhibitory activity is critical for safe anti-diabetic therapy. To achieve this goal, we established a selective evaluation method for DPP4 inhibitors based on recombinant human DPP8 and DPP9 proteins expressed by Rosetta cells. In this method, we used purified recombinant 120 kDa DPP8 or DPP9 protein from the Rosetta expression system. The optimum concentrations of the recombinant DPP8 and DPP9 proteins were 30 ng/mL and 20 ng/mL, respectively, and the corresponding concentrations of their substrates were both 0.2 mmol/L. This method was highly reproducible and reliable for the evaluation of the DPP8 and DPP9 selectivity for DPP4 inhibitor candidates, which would provide valuable guidance in the development of safe DPP4 inhibitors. PMID- 26579376 TI - Inhibition of tyrosinase activity and melanine pigmentation by 2-hydroxytyrosol. AB - 2-Hydroxytyrosol (2-HT), originally reported as a synthetic compound, was isolated for the first time as a fungal metabolite. 2-HT was found to inhibit mushroom tyrosinase with an IC50 value of 13.0 umol/L. Furthermore, 2-HT dose dependently inhibited tyrosinase activity (IC50, 32.5 umol/L) in the cell-free extract of B16 melanoma cells and alpha-melanocyte stimulating hormone (alpha MSH)-stimulated melanin formation in intact B16 melanoma cells. PMID- 26579377 TI - Comparative pharmacokinetics of zolpidem tartrate in five ethnic populations of China. AB - The objective of this study was to evaluate the difference in the pharmacokinetics of zolpidem tatrate in subjects from five Chinese ethnicities (Han, Mongolian, Uigur, Korean and Hui). Healthy subjects (10 Hans, 10 Mongolians, 10 Uigurs, 10 Koreans and 9 Huis) were recruited and each received a 10 mg tablet-dose of zolpidem tatrate. A total of 12 plasma samples were collected over a 12 h period after administration. The concentrations of zolpidem in plasma were determined by an HPLC-FLU method, after which the pharmacokinetic parameters were determined using DAS 2.0 software and analyzed by SPSS 16.0 software. After normalization by weight, no differences were noted in the pharmacokinetic parameters of zolpidem tatrate among the five ethnic groups (P>0.05). However, there were statistically significant differences between males and females for the pharmacokinetic parameters (P<0.05). The metabolism of zolpidem tatrate in males was faster than in females. Results indicate that ethnicity has no significant impact on the pharmacokinetics of zolpidem tatrate after a single oral dose in healthy Chinese subjects. However, an effect of gender on the pharmacokinetics of zolpidem tatrate can be noted. PMID- 26579378 TI - Role of mucoadhesive polymers in enhancing delivery of nimodipine microemulsion to brain via intranasal route. AB - Intranasal drug administration is receiving increased attention as a delivery method for bypassing the blood-brain barrier and rapidly targeting therapeutics to the CNS. However, rapid mucociliary clearance in the nasal cavity is a major hurdle. The purpose of this study was to evaluate the effect of mucoadhesive polymers in enhancing the delivery of nimodipine microemulsion to the brain via the intranasal route. The optimized mucoadhesive microemulsion was characterized, and the in vitro drug release and in vivo nasal absorption of drug from the new formulation were evaluated in rats. The optimized formulation consisted of Capmul MCM as oil, Labrasol as surfactant, and Transcutol P as co-surfactant, with a particle size of 250 nm and zeta potential value of -15 mV. In vitro and ex vivo permeation studies showed an initial burst of drug release at 30 min and sustained release up to 6 h, attributable to the presence of free drug entrapped in the mucoadhesive layer. In vivo pharmacokinetic studies in rats showed that the use of the mucoadhesive microemulsion enhanced brain and plasma concentrations of nimodipine. These results suggest that incorporation of a mucoadhesive agent in a microemulsion intranasal delivery system can increase the retention time of the formulation and enhance brain delivery of drugs. PMID- 26579379 TI - Enhancing production of ergosterol in Pichia pastoris GS115 by over-expression of 3-hydroxy-3-methylglutaryl CoA reductase from Glycyrrhiza uralensis. AB - The rate-limiting enzyme in the mevalonic acid (MVA) pathway which can lead to triterpenoid saponin glycyrrhizic acid (GA) is 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR). In order to reveal the effect of copy number variation in the HMGR gene on the MVA pathway, the HMGR gene from Glycyrrhiza uralensis Fisch. (GuHMGR) was cloned and over-expressed in Pichia pastoris GS115. Six recombinant P. pastoris strains containing different copy numbers of the GuHMGR gene were obtained and the content of ergosterol was analyzed by HPLC. The results showed that all the recombinant P. pastoris strains contained more ergosterol than the negative control and the strains with 8 and 44 copies contained significantly more ergosterol than the other strains. However, as the copy number increased, the content of ergosterol showed an increasing-decreasing-increasing pattern. This study provides a rationale for increasing the content of GA through over expressing the GuHMGR gene in cultivars of G. uralensis. PMID- 26579380 TI - Electronic circular dichroism behavior of chiral Phthiobuzone. AB - Phthiobuzone is a bis(thiosemicarbazone) derivative with a single chiral center which has been used as a racemate in the clinical treatment of herpes and trachoma diseases. In this study, its two enantiomers were prepared from chiral amino acids and their absolute configurations were investigated by electronic circular dichroism (ECD) combined with modern quantum-chemical calculations using time-dependent density functional theory. It was found that solvation changed both the conformational distribution and the ECD spectrum of each conformer. The theoretical ECD spectra of the two enantiomers were in good agreement with the experimentally determined spectra of the corresponding isomers in dimethyl sulfoxide. The ECD behavior of the bis(thiosemicarbazone) chromophore in a chiral environment is also discussed. Our results indicate that ECD spectroscopy may be a useful tool for the stereochemical evaluation of chiral drugs. PMID- 26579381 TI - Nutraceuticals as potential therapeutic agents for colon cancer: a review. AB - Colon cancer is a world-wide health problem and the second-most dangerous type of cancer, affecting both men and women. The modern diet and lifestyles, with high meat consumption and excessive alcohol use, along with limited physical activity has led to an increasing mortality rate for colon cancer worldwide. As a result, there is a need to develop novel and environmentally benign drug therapies for colon cancer. Currently, nutraceuticals play an increasingly important role in the treatment of various chronic diseases such as colon cancer, diabetes and Alzheimer's disease. Nutraceuticals are derived from various natural sources such as medicinal plants, marine organisms, vegetables and fruits. Nutraceuticals have shown the potential to reduce the risk of colon cancer and slow its progression. These dietary substances target different molecular aspects of colon cancer development. Accordingly, this review briefly discusses the medicinal importance of nutraceuticals and their ability to reduce the risk of colorectal carcinogenesis. PMID- 26579382 TI - Application of near infrared spectroscopy to the analysis and fast quality assessment of traditional Chinese medicinal products. AB - Near infrared spectroscopy (NIRS) has been widely applied in both qualitative and quantitative analysis. There is growing interest in its application to traditional Chinese medicine (TCM) and a review of recent developments in the field is timely. To present an overview of recent applications of NIRS to the identification, classification and analysis of TCM products, studies describing the application of NIRS to TCM products are classified into those involving qualitative and quantitative analysis. In addition, the application of NIRS to the detection of illegal additives and the rapid assessment of quality of TCMs by fast inspection are also described. This review covers over 100 studies emphasizing the application of NIRS in different fields. Furthermore, basic analytical principles and specific examples are used to illustrate the feasibility and effectiveness of NIRS in pattern identification. NIRS provides an effective and powerful tool for the qualitative and quantitative analysis of TCM products. PMID- 26579383 TI - Brain tumor-targeted drug delivery strategies. AB - Despite the application of aggressive surgery, radiotherapy and chemotherapy in clinics, brain tumors are still a difficult health challenge due to their fast development and poor prognosis. Brain tumor-targeted drug delivery systems, which increase drug accumulation in the tumor region and reduce toxicity in normal brain and peripheral tissue, are a promising new approach to brain tumor treatments. Since brain tumors exhibit many distinctive characteristics relative to tumors growing in peripheral tissues, potential targets based on continuously changing vascular characteristics and the microenvironment can be utilized to facilitate effective brain tumor-targeted drug delivery. In this review, we briefly describe the physiological characteristics of brain tumors, including blood-brain/brain tumor barriers, the tumor microenvironment, and tumor stem cells. We also review targeted delivery strategies and introduce a systematic targeted drug delivery strategy to overcome the challenges. PMID- 26579384 TI - PD173074, a selective FGFR inhibitor, reverses MRP7 (ABCC10)-mediated MDR. AB - Multidrug resistance protein 7 (MRP7, ABCC10) is a recently identified member of the ATP-binding cassette (ABC) transporter family, which adequately confers resistance to a diverse group of antineoplastic agents, including taxanes, vinca alkaloids and nucleoside analogs among others. Clinical studies indicate an increased MRP7 expression in non-small cell lung carcinomas (NSCLC) compared to a normal healthy lung tissue. Recent studies revealed increased paclitaxel sensitivity in the Mrp7(-/-) mouse model compared to their wild-type counterparts. This demonstrates that MRP7 is a key contributor in developing drug resistance. Recently our group reported that PD173074, a specific fibroblast growth factor receptor (FGFR) inhibitor, could significantly reverse P glycoprotein-mediated MDR. However, whether PD173074 can interact with and inhibit other MRP members is unknown. In the present study, we investigated the ability of PD173074 to reverse MRP7-mediated MDR. We found that PD173074, at non toxic concentration, could significantly increase the cellular sensitivity to MRP7 substrates. Mechanistic studies indicated that PD173074 (1 MUmol/L) significantly increased the intracellular accumulation and in-turn decreased the efflux of paclitaxel by inhibiting the transport activity without altering expression levels of the MRP7 protein, thereby representing a promising therapeutic agent in the clinical treatment of chemoresistant cancer patients. PMID- 26579385 TI - Alkaloid profiling of the traditional Chinese medicine Rhizoma corydalis using high performance liquid chromatography-tandem quadrupole time-of-flight mass spectrometry. AB - Since alkaloids are the major active constituents of Rhizoma corydalis (RC), a convenient and accurate analytical method is needed for their identification and characterization. Here we report a method to profile the alkaloids in RC based on liquid chromatography-tandem quadrupole time-of-flight mass spectrometry (LC-Q TOF-MS/MS). A total of 16 alkaloids belonging to four different classes were identified by comparison with authentic standards. The fragmentation pathway of each class of alkaloid was clarified and their differences were elucidated. Furthermore, based on an analysis of fragmentation pathways and alkaloid profiling, a rapid and accurate method for the identification of unknown alkaloids in RC is proposed. The method could also be useful for the quality control of RC. PMID- 26579386 TI - Combined use of phospholipid complexes and self-emulsifying microemulsions for improving the oral absorption of a BCS class IV compound, baicalin. AB - The aim of this study was to develop a formulation to improve the oral absorption of baicalin (BA) by combining a phospholipid complex (PC) and self-emulsifying microemulsion drug delivery system (SMEDDS), termed BA-PC-SMEDDS. BA-PC was prepared by a solvent evaporation method and evaluated by complexation percentage (CP). The physicochemical properties of BA-PC were determined. The synergistic effect of PC and SMEDDS on permeation of BA was studied in vitro with Caco-2 cells and in situ with a single pass intestinal perfusion model. The improved bioavailability of BA in BA-PC-SMEDDS was confirmed in an in vivo rat model. The CP of BA-PC reached 100% when the molar ratio of drug to phospholipid (PP) was >=1:1. The solubility of BA-PC increased in both water and octanol, and the log P o/w of BA-PC was increased significantly. BA-PC-SMEDDS could be dispersed more evenly in water, compared to BA and BA-PC. Both the Caco-2 cell uptake and single pass intestinal perfusion models illustrated that transport of BA in BA-PC was lower than that of free BA, while improved significantly in BA-PC-SMEDDS. The relative bioavailability of BA-PC(1:2)-SMEDDS was 220.37%. The combination system of PC and SMEDDS had a synergistic effect on improving the oral absorption of BA. PMID- 26579388 TI - Editor Profile: Guest editor of special issue "Research Progress of Anti infective Drugs". PMID- 26579389 TI - Editorial. PMID- 26579387 TI - Commercialized non-Camellia tea: traditional function and molecular identification. AB - Non-Camellia tea is a part of the colorful Chinese tea culture, and is also widely used as beverage and medicine in folk for disease prevention and treatment. In this study, 37 samples were collected, including 33 kinds of non Camellia teas and 4 kinds of teas (Camellia). Traditional functions of non Camellia teas were investigated. Furthermore, non-Camellia teas of original plants were characterized and identified by molecular methods. Four candidate regions (rbcL, matK, ITS2, psbA-trnH) were amplified by polymerase chain reaction. In addition, DNA barcodes were used for the first time to discriminate the commercial non-Camellia tea and their adulterants, and to evaluate their safety. This study showed that BLASTN and the relevant phylogenetic tree are efficient tools for identification of the commercial non-Camellia tea and their adulterants. However, some sequences from original plants have not been found and there is a limitation of sequence number of original plants in GenBank. Submitting more original plant sequences to the GenBank will be helpful for evaluating the safety of non-Camellia teas. PMID- 26579390 TI - Cover story. PMID- 26579391 TI - Recent advances in the anti-HCV mechanisms of interferon. AB - Interferon (IFN) in combination with ribavirin has been the standard of care (SOC) for chronic hepatitis C for the past few decades. Although the current SOC lacks the desired efficacy, and 4 new direct-acting antiviral agents have been recently approved, interferons are still likely to remain the cornerstone of therapy for some time. Moreover, as an important cytokine system of innate immunity, host interferon signaling provides a powerful antiviral response. Nevertheless, the mechanisms by which HCV infection controls interferon production, and how interferons, in turn, trigger anti-HCV activities as well as control the outcome of HCV infection remain to be clarified. In this report, we review current progress in understanding the mechanisms of IFN against HCV, and also summarize the knowledge of induction of interferon signaling by HCV infection. PMID- 26579392 TI - Therapeutic strategies for a functional cure of chronic hepatitis B virus infection. AB - Treatment of chronic hepatitis B virus (HBV) infection with the viral DNA polymerase inhibitors or pegylated alpha-interferon has led to a significant retardation in HBV-related disease progression and reduction in mortality related to chronic hepatitis B associated liver decompensation and hepatocellular carcinoma. However, chronic HBV infection remains not cured. The reasons for the failure to eradicate HBV infection by long-term antiviral therapy are not completely understood. However, clinical studies suggest that the intrinsic stability of the nuclear form of viral genome, the covalently closed circular (ccc) DNA, sustained low level viral replication under antiviral therapy and homeostatic proliferation of hepatocytes are the critical virological and pathophysiological factors that affect the persistence and therapeutic outcomes of HBV infection. More importantly, despite potent suppression of HBV replication in livers of the treated patients, the dysfunction of HBV-specific antiviral immunity persists. The inability of the immune system to recognize cells harboring HBV infection and to cure or eliminate cells actively producing virus is the biggest challenge to finding a cure. Unraveling the complex virus-host interactions that lead to persistent infection should facilitate the rational design of antivirals and immunotherapeutics to cure chronic HBV infection. PMID- 26579394 TI - Replication priority of hepatitis C virus genotype 2a in a Chinese cohort. AB - HCV genotypes have been documented in clinical practice. The aim of this study was to determine the replication priority of different HCV genotypes in a Chinese HCV positive cohort. Serum samples from 491 apparently healthy Chinese blood donors testing positive for HCV antibodies and naive to antiviral drug therapy were tested. Genotyping analysis showed that genotypes 1b and 2a were predominant and accounted for 77.6% of the HCV infections. Among the genotype groups, individuals infected with genotype 2a had an HCV RNA viral load (10(8) copies/mL) about 200-fold (lg, 2.3) greater than those infected with other genotypes (10(4) 10(5) copies/mL) indicating a replication priority of genotype 2a. However, there was no correlation between HCV genotype and antibody response suggesting that the amplification advantage of genotype 2a results from a favorable interaction with the host cellular environment. In conclusion, HCV genotypes 1b and 2a are the predominant genotypes in China and genotype 2a possesses a significant replication priority compared with the other genotypes. This suggests the existence of host cellular factors that may act as drug-targets for entirely clearing HCV infection in the future. PMID- 26579393 TI - Antibiotic drugs targeting bacterial RNAs. AB - RNAs have diverse structures that include bulges and internal loops able to form tertiary contacts or serve as ligand binding sites. The recent increase in structural and functional information related to RNAs has put them in the limelight as a drug target for small molecule therapy. In addition, the recognition of the marked difference between prokaryotic and eukaryotic rRNA has led to the development of antibiotics that specifically target bacterial rRNA, reduce protein translation and thereby inhibit bacterial growth. To facilitate the development of new antibiotics targeting RNA, we here review the literature concerning such antibiotics, mRNA, riboswitch and tRNA and the key methodologies used for their screening. PMID- 26579395 TI - Establishment of drug-resistant HBV small-animal models by hydrodynamic injection. AB - In antiviral therapy of hepatitis B virus (HBV) infection, drug resistance remains a huge obstacle to the long-term effectiveness of nucleoside/tide analogs (NAs). Primary resistance mutation (rtM204V) contributes to lamivudine (LAM) resistance, and compensatory mutations (rtL180M and rtV173L) restore viral fitness and increase replication efficiency. The evaluation of new anti-viral agents against drug-resistant HBV is limited by the lack of available small animal models. We established LAM-resistance HBV replication mice models based on clinical LAM-resistant HBV mutants. Double (rtM204V+rtL180M) or triple (rtM204V+rtL180M+rtV173L) lamivudine-resistant mutations were introduced into HBV expression vector, followed by hydrodynamic injection into tail vein of NOD/SCID mice. Viremia was detected on days 5, 9, 13 and 17 and liver HBV DNA was detected on day 17 after injection. The serum and liver HBV DNA levels in LAM-resistant model carrying triple mutations are the highest among the models. Two NAs, LAM and entecavir (ETV), were used to test the availability of the models. LAM and ETV inhibited viral replication on wild-type model. LAM was no longer effective on LAM-resistant models, but ETV retains a strong activity. Therefore, these models can be used to evaluate anti-viral agents against lamivudine-resistance, affording new opportunities to establish other drug-resistant HBV small-animal models. PMID- 26579396 TI - The antiviral effect of jiadifenoic acids C against coxsackievirus B3. AB - Coxsackievirus B type 3 (CVB3) is one of the major causative pathogens associated with viral meningitis and myocarditis, which are widespread in the human population and especially prevalent in neonates and children. These infections can result in dilated cardiomyopathy (DCM) and other severe clinical complications. There are no vaccines or drugs approved for the prevention or therapy of CVB3-induced diseases. During screening for anti-CVB3 candidates in our previous studies, we found that jiadifenoic acids C exhibited strong antiviral activities against CVB3 as well as other strains of Coxsackie B viruses (CVBs). The present studies were carried out to evaluate the antiviral activities of jiadifenoic acids C. Results showed that jiadifenoic acids C could reduce CVB3 RNA and proteins synthesis in a dose-dependent manner. Jiadifenoic acids C also had a similar antiviral effect on the pleconaril-resistant variant of CVB3. We further examined the impact of jiadifenoic acids C on the synthesis of viral structural and non-structural proteins, finding that jiadifenoic acids C could reduce VP1 and 3D protein production. A time-course study with Vero cells showed that jiadifenoic acids C displayed significant antiviral activities at 0-6 h after CVB3 inoculation, indicating that jiadifenoic acids C functioned at an early step of CVB3 replication. However, jiadifenoic acids C had no prophylactic effect against CVB3. Taken together, we show that jiadifenoic acids C exhibit strong antiviral activities against all strains of CVB, including the pleconaril resistant variant. Our study could provide a significant lead for anti-CVB3 drug development. PMID- 26579398 TI - Genetic basis of high level aminoglycoside resistance in Acinetobacter baumannii from Beijing, China. AB - The objective of this study was to investigate the genetic basis of high level aminoglycoside resistance in Acinetobacter baumannii clinical isolates from Beijing, China. 173 A. baumannii clinical isolates from hospitals in Beijing from 2006 to 2009 were first subjected to high level aminoglycoside resistance (HLAR, MIC to gentamicin and amikacin>512 ug/mL) phenotype selection by broth microdilution method. The strains were then subjected to genetic basis analysis by PCR detection of the aminoglycoside modifying enzyme genes (aac(3)-I, aac(3) IIc, aac(6')-Ib, aac(6')-II, aph(4)-Ia, aph(3')-I, aph(3')-IIb, aph(3')-IIIa, aph(3')-VIa, aph(2")-Ib, aph(2")-Ic, aph(2")-Id, ant(2")-Ia, ant(3")-I and ant(4')-Ia) and the 16S rRNA methylase genes (armA, rmtB and rmtC). Correlation analysis between the presence of aminoglycoside resistance gene and HLAR phenotype were performed by SPSS. Totally 102 (58.96%) HLAR isolates were selected. The HLAR rates for year 2006, 2007, 2008 and 2009 were 52.63%, 65.22%, 51.11% and 70.83%, respectively. Five modifying enzyme genes (aac(3)-I, detection rate of 65.69%; aac(6')-Ib, detection rate of 45.10%; aph(3')-I, detection rate of 47.06%; aph(3')-IIb, detection rate of 0.98%; ant(3")-I, detection rate of 95.10%) and one methylase gene (armA, detection rate of 98.04%) were detected in the 102 A. baumannii with aac(3)-I+aac(6')-Ib+ant(3")-I+armA (detection rate of 25.49%), aac(3)-I+aph(3')-I+ant(3")-I+armA (detection rate of 21.57%) and ant(3") I+armA (detection rate of 12.75%) being the most prevalent gene profiles. The values of chi-square tests showed correlation of armA, ant(3")-I, aac(3)-I, aph(3')-I and aac(6')-Ib with HLAR. armA had significant correlation (contingency coefficient 0.685) and good contingency with HLAR (kappa 0.940). The high rates of HLAR may cause a serious problem for combination therapy of aminoglycoside with beta-lactams against A. baumannii infections. As armA was reported to be able to cause high level aminoglycoside resistance to most of the clinical important aminoglycosides (gentamicin, amikacin, tobramycin, etc), the function of aminoglycoside modifying enzyme gene(s) in A. baumannii carrying armA deserves further investigation. PMID- 26579397 TI - Curcumin inhibits the replication of enterovirus 71 in vitro. AB - Human enterovirus 71 (EV71) is the main causative pathogen of hand, foot, and mouth disease (HFMD) in children. The epidemic of HFMD has been a public health problem in Asia-Pacific region for decades, and no vaccine and effective antiviral medicine are available. Curcumin has been used as a traditional medicine for centuries to treat a diversity of disorders including viral infections. In this study, we demonstrated that curcumin showed potent antiviral effect again EV71. In Vero cells infected with EV71, the addition of curcumin significantly suppressed the synthesis of viral RNA, the expression of viral protein, and the overall production of viral progeny. Similar with the previous reports, curcumin reduced the production of ROS induced by viral infection. However, the antioxidant property of curcumin did not contribute to its antiviral activity, since N-acetyl-l-cysteine, the potent antioxidant failed to suppress viral replication. This study also showed that extracellular signal-regulated kinase (ERK) was activated by either viral infection or curcumin treatment, but the activated ERK did not interfere with the antiviral effect of curcumin, indicating ERK is not involved in the antiviral mechanism of curcumin. Unlike the previous reports that curcumin inhibited protein degradation through ubiquitin proteasome system (UPS), we found that curcumin had no impact on UPS in control cells. However, curcumin did reduce the activity of proteasomes which was increased by viral infection. In addition, the accumulation of the short-lived proteins, p53 and p21, was increased by the treatment of curcumin in EV71 infected cells. We further probed the antiviral mechanism of curcumin by examining the expression of GBF1 and PI4KB, both of which are required for the formation of viral replication complex. We found that curcumin significantly reduced the level of both proteins. Moreover, the decreased expression of either GBF1 or PI4KB by the application of siRNAs was sufficient to suppress viral replication. We also demonstrated that curcumin showed anti-apoptotic activity at the early stage of viral infection. The results of this study provide solid evidence that curcumin has potent anti-EV71 activity. Whether or not the down regulated GBF1 and PI4KB by curcumin contribute to its antiviral effect needs further studies. PMID- 26579399 TI - A cell-based high-throughput approach to identify inhibitors of influenza A virus. AB - Influenza is one of the most common infections threatening public health worldwide and is caused by the influenza virus. Rapid emergence of drug resistance has led to an urgent need to develop new anti-influenza inhibitors. In this study we established a 293T cell line that constitutively synthesizes a virus-based negative strand RNA, which expresses Gaussia luciferase upon influenza A virus infection. Using this cell line, an assay was developed and optimized to search for inhibitors of influenza virus replication. Biochemical studies and statistical analyses presented herein demonstrate the sensitivity and reproducibility of the assay in a high-throughput format (Z' factor value>0.8). A pilot screening provides further evidence for validation of the assay. Taken together, this work provides a simple, convenient, and reliable HTS assay to identify compounds with anti-influenza activity. PMID- 26579400 TI - Synthesis and biological evaluation of sophocarpinic acid derivatives as anti-HCV agents. AB - Chronic hepatitis C virus (HCV) infection has become a major public health burden worldwide. Twenty-two sophocarpinic acid or matrine derivatives were synthesized and their anti-HCV activities were evaluated in vitro. The structure-activity analysis revealed that (i) sophocarpinic acids with a D-seco 3-ring structure scaffold were more favorable than matrines with a 4-ring scaffold; (ii) the introduction of an electron-withdrawing group on the phenyl ring in 12-N benzenesulfonyl Delta (betagamma) sophocarpinic acids was beneficial for the antiviral activity against HCV. Among them, compounds 9h and 9j exhibited the most potent inhibitory activities on HCV replication with selectivity indies of 70.3 and 30.9, respectively. Therefore, both were selected as antiviral candidates for further investigation. PMID- 26579401 TI - Synthesis and antiviral activity of some novel indole-2-carboxylate derivatives. AB - A series of novel indole-2-carboxylate derivatives were synthesized and assayed to determine their in vitro broad-spectrum antiviral activities. The biological results showed that some of the synthesized compounds exhibited potent broad spectrum antiviral activity. Notably, compound 8f showed the highest SI value (17.1) to Cox B3 virus. Compound 14f showed both potent inhibitory activity against influenza A (IC50=7.53 MUmol/L) and the highest SI value (12.1). SAR results showed that the alkyloxy at the 4-position of indole ring was not crucial to the antiviral activities. Incorporation of an acetyl substituent at the amino group disfavored antiviral activity towards RNA viruses. PMID- 26579402 TI - Characterization of impurities in cefpodoxime proxetil using LC-MS (n). AB - Reversed-phase liquid chromatography coupled with electrospray ionization tandem mass spectrometry (ESI-MS/MS) was used to characterize impurities in cefpodoxime proxetil, an ester-modified prodrug. Based on the mechanisms by which cephalosporins are degraded, stress tests were designed and performed. The bulk material and capsule were eluted through a C18 column with formic acid-methanol water as the mobile phase. In total, 15 impurities were characterized in commercial samples, including 7 known impurities and 8 new impurities. The structures of these unknown compounds were deduced via comparison with the fragmentation patterns of cefpodoxime proxetil. Data from this systematic study will help improve the safety and quality of cefpodoxime proxetil. PMID- 26579403 TI - Pharmacokinetic aspects and in vitro-in vivo correlation potential for lipid based formulations. AB - Lipid-based formulations have been an attractive choice among novel drug delivery systems for enhancing the solubility and bioavailability of poorly soluble drugs due to their ability to keep the drug in solubilized state in the gastrointestinal tract. These formulations offer multiple advantages such as reduction in food effect and inter-individual variability, ease of preparation, and the possibility of manufacturing using common excipients available in the market. Despite these advantages, very few products are available in the present market, perhaps due to limited knowledge in the in vitro tests (for prediction of in vivo fate) and lack of understanding of the mechanisms behind pharmacokinetic and biopharmaceutical aspects of lipid formulations after oral administration. The current review aims to provide a detailed understanding of the in vivo processing steps involved after oral administration of lipid formulations, their pharmacokinetic aspects and in vitro in vivo correlation (IVIVC) perspectives. Various pharmacokinetic and biopharmaceutical aspects such as formulation dispersion and lipid digestion, bioavailability enhancement mechanisms, impact of excipients on efflux transporters, and lymphatic transport are discussed with examples. In addition, various IVIVC approaches towards predicting in vivo data from in vitro dispersion/precipitation, in vitro lipolysis and ex vivo permeation studies are also discussed in detail with help of case studies. PMID- 26579404 TI - Three new shRNA expression vectors targeting the CYP3A4 coding sequence to inhibit its expression. AB - RNA interference (RNAi) is useful for selective gene silencing. Cytochrome P450 3A4 (CYP3A4), which metabolizes approximately 50% of drugs in clinical use, plays an important role in drug metabolism. In this study, we aimed to develop a short hairpin RNA (shRNA) to modulate CYP3A4 expression. Three new shRNAs (S1, S2 and S3) were designed to target the coding sequence (CDS) of CYP3A4, cloned into a shRNA expression vector, and tested in different cells. The mixture of three shRNAs produced optimal reduction (55%) in CYP3A4 CDS-luciferase activity in both CHL and HEK293 cells. Endogenous CYP3A4 expression in HepG2 cells was decreased about 50% at both mRNA and protein level after transfection of the mixture of three shRNAs. In contrast, CYP3A5 gene expression was not altered by the shRNAs, supporting the selectivity of CYP3A4 shRNAs. In addition, HepG2 cells transfected with CYP3A4 shRNAs were less sensitive to Ginkgolic acids, whose toxic metabolites are produced by CYP3A4. These results demonstrate that vector-based shRNAs could modulate CYP3A4 expression in cells through their actions on CYP3A4 CDS, and CYP3A4 shRNAs may be utilized to define the role of CYP3A4 in drug metabolism and toxicity. PMID- 26579405 TI - Antiulcerogenic activity of Scutia buxifolia on gastric ulcers induced by ethanol in rats. AB - Gastric ulcers affect many people around the world and their development is a result of the imbalance between aggressive and protective factors in the gastric mucosa. Scutia buxifolia, commonly known as coronilha, has attracted the interest of the scientific community due to its pharmacological properties and its potential therapeutic applications. In this study, the preventive effects of the crude extract of Scutia buxifolia (ceSb) against gastric ulcer induced by 70% ethanol were evaluated in male Wistar rats. In addition, the composition of ceSb was clarified by high-performance liquid chromatography (HPLC). S. buxifolia extract (100, 200 and 400 mg/kg body weight) attenuated oxidative and histopathological features induced by ethanol. Moreover, all evaluated doses of ceSb caused significant (P<0.001 and P<0.0001) and dose-dependent increase in sulfhydryl groups (NPSH) levels, catalase (CAT) and superoxide dismutase (SOD) activities. Furthermore, the administration of ceSb reversed the increase in lipid peroxidation produced by ethanol. The protective effect of the extract could be attributed to antioxidant compounds present in the ceSb, such as flavonoids and phenolic acids, which were quantified by HPLC. Thus, an antioxidant effect of the extract leads to a protection on gastric tissue. These results indicate that S. buxifolia could have a beneficial role against ethanol toxicity by preventing oxidative stress and gastric tissue injury. PMID- 26579406 TI - Novel coumarin-benzimidazole derivatives as antioxidants and safer anti inflammatory agents. AB - Inspired from occurrence of anti-inflammatory activity of 3-substituted coumarins and antiulcer activity of various 2-substituted benzimidazoles, novel compounds have been designed by coupling coumarin derivatives at 3-position directly or through amide linkage with benzimidazole nucleus at 2-position. The resultant compounds are expected to exhibit both anti-inflammatory and antioxidant activities along with less gastric toxicity profile. Two series of coumarin benzimidazole derivatives (4a-e and 5a-e) were synthesized and evaluated for anti inflammatory activity and antioxidant activity. Compounds 4c, 4d and 5a displayed good anti-inflammatory (45.45%, 46.75% and 42.85% inhibition, respectively, versus 54.54% inhibition by indomethacin) and antioxidant (IC50 of 19.7, 13.9 and 1.2 umol/L, respectively, versus 23.4 umol/L for butylatedhydroxytoluene) activities. Evaluation of ulcer index and in vivo biochemical estimations for oxidative stress revealed that compounds 4d and 5a remain safe on gastric mucosa and did not induce oxidative stress in tissues. Calculation of various molecular properties suggests the compounds to be sufficiently bioavailable. PMID- 26579407 TI - Transmission FTIR derivative spectroscopy for estimation of furosemide in raw material and tablet dosage form. AB - A Fourier transform infrared derivative spectroscopy (FTIR-DS) method has been developed for determining furosemide (FUR) in pharmaceutical solid dosage form. The method involves the extraction of FUR from tablets with N,N-dimethylformamide by sonication and direct measurement in liquid phase mode using a reduced path length cell. In general, the spectra were measured in transmission mode and the equipment was configured to collect a spectrum at 4 cm(-1) resolution and a 13 s collection time (10 scans co-added). The spectra were collected between 1400 cm( 1) and 450 cm(-1). Derivative spectroscopy was used for data processing and quantitative measurement using the peak area of the second order spectrum of the major spectral band found at 1165 cm(-1) (SO2 stretching of FUR) with baseline correction. The method fulfilled most validation requirements in the 2 mg/mL and 20 mg/mL range, with a 0.9998 coefficient of determination obtained by simple calibration model, and a general coefficient of variation <2%. The mean recovery for the proposed assay method resulted within the (100+/-3)% over the 80%-120% range of the target concentration. The results agree with a pharmacopoeial method and, therefore, could be considered interchangeable. PMID- 26579408 TI - Simultaneous determination of nineteen major components in Qi She Pill by ultra high-performance liquid chromatography-tandem mass spectrometry. AB - Qi She Pill (QSP) is a traditional Chinese medicine (TCM) prescription that has been used in treating cervical spondylosis radiculopathy for many years. In this study, a simple and sensitive method using ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) on a reverse-phase C18 column was developed for the simultaneous determination of the 19 major components in QSP. We found that the optimum mobile phase for gradient elution was 0.1% formic acid and methanol. The correlation coefficients of all calibration curves were greater than 0.99. Recoveries measured at three concentration levels varied from 95.43% to 102.35%. Relative standard deviations of intra- and inter-day precisions were less than 4.45%. After successfully validating our method, we then applied it to the quantification of 19 components in QSP products to show that this method provides a new standard in quality assessment of TCM prescriptions containing multiple bioactive components. PMID- 26579409 TI - Preclinical investigation of the pharmacokinetics, metabolism, and protein and red blood cell binding of DRDE-07: a prophylactic agent against sulphur mustard. AB - DRDE-07, a newly synthesized amifostine analog currently under clinical investigation in a phase I trial, is a potent antidote against sulfur mustard toxicity. The purpose of this research was to evaluate the pharmacokinetic profile of DRDE-07 in female Swiss Albino mice after a single oral dose of 400 or 600 mg/kg. The physicochemical properties of DRDE-07, including solubility, pK a, Log P, plasma protein binding and plasma/blood partitioning, were determined to support the pharmacokinetic characterization. DRDE-07 concentration was determined by an HPLC-UV method. The profile of plasma concentration versus time was analyzed using a non-compartmental model. Plasma protein binding was assessed using ultrafiltration. DRDE-07 appeared rapidly in plasma after oral administration with peak plasma levels (C max) observed in less than 15 min. There was a rapid decline in the plasma levels followed by a smaller second peak about 90 min after dosing. The plasma protein binding of DRDE-07 was found to be less than 25% at all concentrations studied. Plasma clearance of DRDE-07 is expected to be ~1.5 fold higher than the blood clearance of DRDE-07. The probable metabolite of DRDE-07 was identified as phenyl-S-ethyl amine. PMID- 26579410 TI - Pharmacokinetics of levosulpiride after single and multiple intramuscular administrations in healthy Chinese volunteers. AB - The main purpose of this study was to evaluate the pharmacokinetics of levosulpiride in humans after single and multiple intramuscular injections. Six males and six females received single dose of either 25 mg or 50 mg levosulpiride, or multiple doses of 25 mg every 12 h for 5 consecutive days. In the single 25 mg study, the mean peak plasma concentration (C max) was 441 ng/mL, the mean area under the concentration-time curve from 0 to 36 h (AUC0-36) was 1724 ng h/mL, and the mean elimination half-life (t 1/2) was 7.0 h. In the single 50 mg study, the mean C max was 823 ng/mL, the mean AUC0-36 was 3748 ng.h/mL, and the mean t 1/2 was 6.8 h. After multiple doses of 25 mg levosulpiride, the average plasma concentration (C av) was 136 ng/mL, the fluctuation index (DF) was 3.60, and the accumulation ratio (R) was 1.2. Levosulpiride injections appeared to be well tolerated by the subjects, and can be used for successive administration. PMID- 26579411 TI - Development and in vitro/in vivo evaluation of controlled release provesicles of a nateglinide-maltodextrin complex. AB - The aim of this study was to characterize the provesicle formulation of nateglinide (NTG) to facilitate the development of a novel controlled release system of NTG with improved efficacy and oral bioavailability compared to the currently marketed NTG formulation (GlinateTM 60). NTG provesicles were prepared by a slurry method using the non-ionic surfactant, Span 60 (SP), and cholesterol (CH) as vesicle forming agents and maltodextrin as a coated carrier. Multilamellar niosomes with narrow size distribution were shown to be successfully prepared by means of dynamic laser scattering (DLS) and field emission scanning electron microscopy (FESEM). The absence of drug-excipient interactions was confirmed by Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC) and X-ray diffraction (XRD) studies. In vitro release of NTG in different dissolution media was improved compared to pure drug. A goat intestinal permeation study revealed that the provesicular formulation (F4) with an SP:CH ratio of 5:5 gave higher cumulative amount of drug permeated at 48 h compared to GlinateTM 60 and control. A pharmacodynamic study in streptozotocin-induced diabetic rats confirmed that formulation F4 significantly (P<0.05) reduced blood glucose levels in comparison to Glinate 60. Overall the results show that controlled release NTG provesicles offer a useful and promising oral delivery system for the treatment of type II diabetes. PMID- 26579412 TI - Recent advances in the study of (-)clausenamide: chemistry, biological activities and mechanism of action. AB - Clausenamide (clau) is one of seven novel compounds isolated from Clausena lansium (Lour) skeels. Clau is unusual in that it contains 4 chiral centers yielding 8 pairs of enantiomers. After identification of the configuration of these enantiomers, the synthesis of 16 enantiomers, including optically active clau and (+) and (-)clau was carried out. During this study, many stereochemical and synthetic difficulties were solved and the Baldwin principle was updated. Production scale is now sufficient to meet the needs of clinical practice. In a pharmacological study numerous models and indicators showed that (-)clau is the active enantiomer, while (+)clau is inactive and elicits greater toxicity than ( )clau. The principal pharmacological effects of (-)clau are to increase cognition, demonstrated in ten models of memory impairment, as well as to inhibit beta-amyloid (Abeta) toxicity, blocking neurofibrillary tangle formation by inhibiting the phosphorylation of tau protein. This anti-dementia effect is characterized by increased synaptic plasticity both in efficacy and in structure and provides new support for the theory that synaptic loss is the main cause of dementia. (-)Clau is considered to be a promising drug candidate for treatment of Alzheimer's disease and other neurodegenerative disorders. PMID- 26579413 TI - ETME, a novel beta-elemene derivative, synergizes with arsenic trioxide in inducing apoptosis and cell cycle arrest in hepatocarcinoma cells via a p53 dependent pathway. AB - Arsenic trioxide (ATO) has been identified as an effective treatment for acute promyelocytic leukemia (APL) but is much less effective against solid tumors such as hepatocellular carcinoma (HCC). In the search for ways to enhance its therapeutic efficacy against solid tumors, we have examined its use in combination with a novel derivative of beta-elemene, N-(beta-elemene-13 yl)tryptophan methyl ester (ETME). Here we report the effects of the combination on cell viability, apoptosis, the cell cycle and mitochondria membrane potential (MMP) in HCC SMMC-7721 cells. We found that the two compounds acted synergistically to enhance antiproliferative activity and apoptosis. The combination also decreased the MMP, down-regulated Bcl-2 and pro-proteins of the caspase family, and up-regulated Bax and BID, all of which were reversed by the p53 inhibitor, pifithrin-alpha. In addition, the combination induced cell cycle arrest at the G2/M phase and reduced tumor volume and weight in an xenograft model of nude mice. Overall, the results suggest that ETME in combination with ATO may be useful in the treatment of HCC patients particularly those unresponsive to ATO alone. PMID- 26579415 TI - Assessment by HPLC of the degradation behavior of acitretin under hydrolytic, oxidative, photolytic and thermal stress conditions. AB - Acitretin is a photosensitive oral retinoid with very limited data available on its degradation. The official HPLC method for acitretin determination was insufficient to resolve the degradation products generated during stability studies. Therefore, an isocratic RP-HPLC-UV method was developed for the determination of acitretin in the presence of its related impurities and degradation products. Efficient chromatographic separation was achieved on a Thermo beta-basic column C18 (100 mm*4.6 mm, 5 MUm) with mobile phase containing 0.3% (v/v) glacial acetic acid with acetonitrile (ACN) and isopropyl alcohol (IPA) in an isocratic ratio of 70:30 at a flow rate of 1.0 mL/min with the eluent monitored at 360 nm. The method was validated for specificity, linearity, precision, accuracy and robustness. The calibration plot was linear over the concentration range of 50-150 MUg/mL with a correlation coefficient (r (2)) of 0.999. The proposed method was used to investigate the degradation kinetics of acitretin under the different degradative conditions. The degradation rate constant (K), half-life (t 1/2), and t 90 were calculated. Degradation of acitretin followed pseudo-first-order kinetics. The drug was found to be less stable under acidic and photolytic degradation conditions: the photolytic degradation constants for acitretin in sunlight and UV light were 0.002698% and 0.0008402% min(-1), respectively. The LOD for acitretin and the known impurities were at a level below 0.02%. The method shows consistent recoveries for ACTR (99.8%-101.2%) and also for its known impurities (97.2-101.3%). The method was found to be accurate, precise, linear, specific, sensitive, rugged, robust, and useful for characterizing the stability of this chemical. PMID- 26579414 TI - Inhibition of acetylcholinesterase by two genistein derivatives: kinetic analysis, molecular docking and molecular dynamics simulation. AB - In this study two genistein derivatives (G1 and G2) are reported as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), and differences in the inhibition of AChE are described. Although they differ in structure by a single methyl group, the inhibitory effect of G1 (IC50=264 nmol/L) on AChE was 80 times stronger than that of G2 (IC50=21,210 nmol/L). Enzyme-kinetic analysis, molecular docking and molecular dynamics (MD) simulations were conducted to better understand the molecular basis for this difference. The results obtained by kinetic analysis demonstrated that G1 can interact with both the catalytic active site and peripheral anionic site of AChE. The predicted binding free energies of two complexes calculated by the molecular mechanics/generalized born surface area (MM/GBSA) method were consistent with the experimental data. The analysis of the individual energy terms suggested that a difference between the net electrostatic contributions (DeltaE ele+DeltaG GB) was responsible for the binding affinities of these two inhibitors. Additionally, analysis of the molecular mechanics and MM/GBSA free energy decomposition revealed that the difference between G1 and G2 originated from interactions with Tyr124, Glu292, Val294 and Phe338 of AChE. In conclusion, the results reveal significant differences at the molecular level in the mechanism of inhibition of AChE by these structurally related compounds. PMID- 26579416 TI - Synthesis of taurine-fluorescein conjugate and evaluation of its retina-targeted efficiency in vitro. AB - In this work, retinal penetration of fluorescein was achieved in vitro by covalent attachment of taurine to fluorescein, yielding the F-Tau conjugate. Nuclear magnetic resonance (NMR) and high resolution mass spectrometry (HRMS) were used to confirm the successful synthesis of F-Tau. The cellular uptake of F Tau in adult retinal pigment epithelial cells (ARPE-19) and human retinal microvascular endothelial cells (hRMECs) was visualized via confocal scanning microscopy. The results indicated an improvement of solubility and a reduction of logP of F-Tau compared with fluorescein. As compared with fluorescein, F-Tau showed little toxicity, and was retained longer by cells in uptake experiments. F Tau also displayed higher transepithelial permeabilities than fluorescein in ARPE 19 and hRMECs monolayer cells (P<0.05). These results showed that taurine may be a useful ligand for targeting small-molecule hydrophobic pharmaceuticals into the retina. PMID- 26579417 TI - Solid lipid nanoparticles for nose to brain delivery of haloperidol: in vitro drug release and pharmacokinetics evaluation. AB - In the present study, haloperidol (HP)-loaded solid lipid nanoparticles (SLNs) were prepared to enhance the uptake of HP to brain via intranasal (i.n.) delivery. SLNs were prepared by a modified emulsification-diffusion technique and evaluated for particle size, zeta potential, drug entrapment efficiency, in vitro drug release, and stability. All parameters were found to be in an acceptable range. In vitro drug release was found to be 94.16+/-4.78% after 24 h and was fitted to the Higuchi model with a very high correlation coefficient (R (2)=0.9941). Pharmacokinetics studies were performed on albino Wistar rats and the concentration of HP in brain and blood was measured by high performance liquid chromatography. The brain/blood ratio at 0.5 h for HP-SLNs i.n., HP sol. i.n. and HP sol. i.v. was 1.61, 0.17 and 0.031, respectively, indicating direct nose-to-brain transport, bypassing the blood-brain barrier. The maximum concentration (C max) in brain achieved from i.n. administration of HP-SLNs (329.17+/-20.89 ng/mL, T max 2 h) was significantly higher than that achieved after i.v. (76.95+/-7.62 ng/mL, T max 1 h), and i.n. (90.13+/-6.28 ng/mL, T max 2 h) administration of HP sol. The highest drug-targeting efficiency (2362.43%) and direct transport percentage (95.77%) was found with HP-SLNs as compared to the other formulations. Higher DTE (%) and DTP (%) suggest that HP-SLNs have better brain targeting efficiency as compared to other formulations. PMID- 26579418 TI - Preferential expression of cytochrome CYP CYP2R1 but not CYP1B1 in human cord blood hematopoietic stem and progenitor cells. AB - Cytochrome P450 (CYP) enzymes metabolize numerous endogenous substrates, such as retinoids, androgens, estrogens and vitamin D, that can modulate important cellular processes, including proliferation, differentiation and apoptosis. The aim of this study is to characterize the expression of CYP genes in CD34+ human cord blood hematopoietic stem and early progenitor cells (CBHSPCs) as a first step toward assessment of the potential biological functions of CYP enzymes in regulating the expansion or differentiation of these cells. CD34+ CBHSPCs were purified from umbilical cord blood via antibody affinity chromatography. Purity of CD34+ CBHSPCs was assessed using fluorescence-activated cell sorting. RNA was isolated from purified CD34+ CBHSPCs and total mononuclear cells (MNCs) for RNA PCR analysis of CYP expression. Fourteen human CYPs were detected in the initial screening with qualitative RT-PCR in CD34+ CBHSPCs. Further quantitative RNA-PCR analysis of the detected CYP transcripts yielded evidence for preferential expression of CYP2R1 in CD34+ CBHSPCs relative to MNCs; and for greater expression of CYP1B1 in MNCs relative to CD34+ CBHSPCs. These findings provide the basis for further studies on possible functions of CYP2R1 and CYP1B1 in CBHSPCs' proliferation and/or differentiation and their potential utility as targets for drugs designed to modulate CD34+ CBHSPC expansion or differentiation. PMID- 26579419 TI - S-palmitoylation regulates AMPA receptors trafficking and function: a novel insight into synaptic regulation and therapeutics. AB - Glutamate acting on AMPA-type ionotropic glutamate receptor (AMPAR) mediates the majority of fast excitatory synaptic transmission in the mammalian central nervous system. Dynamic regulation of AMPAR by post-translational modifications is one of the key elements that allow the nervous system to adapt to environment stimulations. S-palmitoylation, an important lipid modification by post translational addition of a long-chain fatty acid to a cysteine residue, regulates AMPA receptor trafficking, which dynamically affects multiple fundamental brain functions, such as learning and memory. In vivo, S palmitoylation is controlled by palmitoyl acyl transferases and palmitoyl thioesterases. In this review, we highlight advances in the mechanisms for dynamic AMPA receptors palmitoylation, and discuss how palmitoylation affects AMPA receptors function at synapses in recent years. Pharmacological regulation of S-palmitoylation may serve as a novel therapeutic strategy for neurobiological diseases. PMID- 26579422 TI - Alectinib: a novel second generation anaplastic lymphoma kinase (ALK) inhibitor for overcoming clinically-acquired resistance. AB - The development of inhibitors for the tyrosine anaplastic lymphoma kinase (ALK) has advanced rapidly, driven by biology and medicinal chemistry. The first generation ALK inhibitor crizotinib was granted US FDA approval with only four years of preclinical and clinical testing. Although this drug offers significant clinical benefit to the ALK-positive patients, resistance has been developed through a variety of mechanisms. In addition to ceritinib, alectinib is another second-generation ALK inhibitor launched in 2014 in Japan. This drug has a unique chemical structure bearing a 5H-benzo[b]carbazol-11(6H)-one structural scaffold with an IC50 value of 1.9 nmol/L, and is highly potent against ALK bearing the gatekeeper mutation L1196M with an IC50 of 1.56 nmol/L. In the clinic, alectinib is highly efficacious in treatment of ALK-positive non-small cell lung cancer (NSCLC), and retains potency to combat crizotinib-resistant ALK mutations L1196M, F1174L, R1275Q and C1156Y. PMID- 26579420 TI - Ameliorating effects of traditional Chinese medicine preparation, Chinese materia medica and active compounds on ischemia/reperfusion-induced cerebral microcirculatory disturbances and neuron damage. AB - Ischemic stroke and ischemia/reperfusion (I/R) injury induced by thrombolytic therapy are conditions with high mortality and serious long-term physical and cognitive disabilities. They have a major impact on global public health. These disorders are associated with multiple insults to the cerebral microcirculation, including reactive oxygen species (ROS) overproduction, leukocyte adhesion and infiltration, brain blood barrier (BBB) disruption, and capillary hypoperfusion, ultimately resulting in tissue edema, hemorrhage, brain injury and delayed neuron damage. Traditional Chinese medicine (TCM) has been used in China, Korea, Japan and other Asian countries for treatment of a wide range of diseases. In China, the usage of compound TCM preparation to treat cerebrovascular diseases dates back to the Han Dynasty. Even thousands of years earlier, the medical formulary recorded many classical prescriptions for treating cerebral I/R-related diseases. This review summarizes current information and underlying mechanisms regarding the ameliorating effects of compound TCM preparation, Chinese materia medica, and active components on I/R-induced cerebral microcirculatory disturbances, brain injury and neuron damage. PMID- 26579421 TI - Near-infrared fluorescent probes for imaging of amyloid plaques in Alzheimer's disease. AB - One of the early pathological hallmarks of Alzheimer's disease (AD) is the deposition of amyloid-beta (Abeta) plaques in the brain. There has been a tremendous interest in the development of Abeta plaques imaging probes for early diagnosis of AD in the past decades. Optical imaging, particularly near-infrared fluorescence (NIRF) imaging, has emerged as a safe, low cost, real-time, and widely available technique, providing an attractive approach for in vivo detection of Abeta plaques among many different imaging techniques. In this review, we provide a brief overview of the state-of-the-art development of NIRF Abeta probes and their in vitro and in vivo applications with special focus on design strategies and optical, binding, and brain-kinetic properties. PMID- 26579423 TI - Safety issues and new rapid detection methods in traditional Chinese medicinal materials. AB - The safety of traditional Chinese medicine (TCM) is a major strategic issue that involves human health. With the continuous improvement in disease prevention and treatment, the export of TCM and its related products has increased dramatically in China. However, the frequent safety issues of Chinese medicine have become the 'bottleneck' impeding the modernization of TCM. It was proved that mycotoxins seriously affect TCM safety; the pesticide residues of TCM are a key problem in TCM international trade; adulterants have also been detected, which is related to market circulation. These three factors have greatly affected TCM safety. In this study, fast, highly effective, economically-feasible and accurate detection methods concerning TCM safety issues were reviewed, especially on the authenticity, mycotoxins and pesticide residues of medicinal materials. PMID- 26579424 TI - Quercetin protects human brain microvascular endothelial cells from fibrillar beta-amyloid1-40-induced toxicity. AB - Amyloid beta-peptides (Abeta) are known to undergo active transport across the blood-brain barrier, and cerebral amyloid angiopathy has been shown to be a prominent feature in the majority of Alzheimer's disease. Quercetin is a natural flavonoid molecule and has been demonstrated to have potent neuroprotective effects, but its protective effect on endothelial cells under Abeta-damaged condition is unclear. In the present study, the protective effects of quercetin on brain microvascular endothelial cells injured by fibrillar Abeta 1-40 (fAbeta 1-40) were observed. The results show that fAbeta 1-40-induced cytotoxicity in human brain microvascular endothelial cells (hBMECs) can be relieved by quercetin treatment. Quercetin increases cell viability, reduces the release of lactate dehydrogenase, and relieves nuclear condensation. Quercetin also alleviates intracellular reactive oxygen species generation and increases superoxide dismutase activity. Moreover, it strengthens the barrier integrity through the preservation of the transendothelial electrical resistance value, the relief of aggravated permeability, and the increase of characteristic enzyme levels after being exposed to fAbeta 1-40. In conclusion, quercetin protects hBMECs from fAbeta 1-40-induced toxicity. PMID- 26579426 TI - Chromopeptide A, a highly cytotoxic depsipeptide from the marine sediment-derived bacterium Chromobacterium sp. HS-13-94. AB - A bicyclic depsipeptide, chromopeptide A (1), was isolated from a deep-sea derived bacterium Chromobacterium sp. HS-13-94. Its structure was determined by extensive spectroscopic analysis and by comparison with a related known compound. The absolute configuration of chromopeptide A was established by X-ray diffraction analysis employing graphite monochromated Mo K alpha radiation (lambda=0.71073 A) with small Flack parameter 0.03. Chromopeptide A suppressed the proliferation of HL-60, K-562, and Ramos cells with average IC50 values of 7.7, 7.0, and 16.5 nmol/L, respectively. PMID- 26579425 TI - Effects of fluoxetine on protein expression of potassium ion channels in the brain of chronic mild stress rats. AB - The purpose of this study is to investigate the expression of major potassium channel subtypes in the brain of chronical mild stress (CMS) rats and reveal the effects of fluoxetine on the expression of these channels. Rats were exposed to a variety of unpredictable stress for three weeks and induced anhedonia, lower sucrose preference, locomotor activity and lower body weight. The protein expressions were determined by Western blot. CMS significantly increased the expression of Kv2.1 channel in frontal cortex but not in hippocampus, and the expression level was normalized after fluoxetine treatment. The expression of TREK-1 channel was also obviously increased in frontal cortex in CMS rats. Fluoxetine treatment might prevent this increase. However, the expression of Kv3.1 and Kv4.2 channels was considerably decreased in hippocampus after CMS, and was not affected by fluoxetine. These results suggest that different subtypes of potassium channels are associated with the pathophysiology of depression and that the therapeutical effects of fluoxetine may relate to Kv2.1 and TREK-1 potassium channels. PMID- 26579427 TI - Design, synthesis and evaluation of genistein-polyamine conjugates as multi functional anti-Alzheimer agents. AB - A series of genistein-polyamine conjugates (4a-4h) were designed, synthesized and evaluated as multi-functional anti-Alzheimer agents. The results showed that these compounds had significant cholinesterases (ChEs) inhibitory activity. Compound 4b exhibited the strongest inhibition to acetylcholinesterase (AChE) with an IC50 value of 2.75 MUmol/L, which was better than that of rivastigmine (5.60 MUmol/L). Lineweaver-Burk plot and molecular modeling study showed that compound 4b targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Besides, compound 4b showed potent metal-chelating ability. In addition, it was found that 4a-4h did not affect HepG-2 cell viability at the concentration of 10 MUmol/L. PMID- 26579428 TI - Pharmacokinetics of propafenone hydrochloride sustained-release capsules in male beagle dogs. AB - This paper describes the development and validation of a liquid chromatography mass spectrometric assay for propafenone and its application to a pharmacokinetic study of propafenone administered as a new propafenone hydrochloride sustained release capsule (SR-test), as an instant-release tablet (IR-reference) and as the market leader sustained-release capsule (Rythmol, SR-reference) in male beagle dogs (n=8). In Study A comparing SR-test with IR-reference in a crossover design T max and t 1/2 of propafenone for SR-test were significantly higher than those for IR-reference while C max and AUC were lower demonstrating the sustained release properties of the new formulation. In Study B comparing SR-test with SR reference the observed C max and AUC of propafenone for SR-test (124.5+/-140.0 ng/mL and 612.0+/-699.2 ng.h/mL, respectively) were higher than for SR-reference (78.52+/-72.92 ng/mL and 423.6+/-431.6 ng.h/mL, respectively) although the differences were not significant. Overall, the new formulation has as good if not better sustained release characteristics to the market leader formulation. PMID- 26579430 TI - Editorial. PMID- 26579431 TI - Cover story. PMID- 26579429 TI - In vitro and in vivo evaluation of cubosomes containing 5-fluorouracil for liver targeting. AB - The objective of this study was to prepare cubosomal nanoparticles containing a hydrophilic anticancer drug 5-fluorouracil (5-FU) for liver targeting. Cubosomal dispersions were prepared by disrupting a cubic gel phase of monoolein and water in the presence of Poloxamer 407 as a stabilizer. Cubosomes loaded with 5-FU were characterized in vitro and in vivo. In vitro, 5-FU-loaded cubosomes entrapped 31.21% drug and revealed nanometer-sized particles with a narrow particle size distribution. In vitro 5-FU release from cubosomes exhibited a phase of rapid release of about half of the entrapped drug during the first hour, followed by a relatively slower drug release as compared to 5-FU solution. In vivo biodistribution experiments indicated that the cubosomal formulation significantly (P<0.05) increased 5-FU liver concentration, a value approximately 5-fold greater than that observed with a 5-FU solution. However, serum serological results and histopathological findings revealed greater hepatocellular damage in rats treated with cubosomal formulation. These results demonstrate the successful development of cubosomal nanoparticles containing 5-FU for liver targeting. However, further studies are required to evaluate hepatotoxicity and in vivo antitumor activity of lower doses of 5-FU cubosomal formulation in treatment of liver cancer. PMID- 26579432 TI - Editor profile: Guest editor of special issue "Bile Acids and Nuclear Receptors in Digestive System and Therapy". PMID- 26579433 TI - Farnesoid X receptor, the bile acid sensing nuclear receptor, in liver regeneration. AB - The liver is unique in regenerative potential, which could recover the lost mass and function after injury from ischemia and resection. The underlying molecular mechanisms of liver regeneration have been extensively studied in the past using the partial hepatectomy (PH) model in rodents, where 2/3 PH is carried out by removing two lobes. The whole process of liver regeneration is complicated, orchestrated event involving a network of connected interactions, which still remain fully elusive. Bile acids (BAs) are ligands of farnesoid X receptor (FXR), a nuclear receptor of ligand-activated transcription factor. FXR has been shown to be highly involved in liver regeneration. BAs and FXR not only interact with each other but also regulate various downstream targets independently during liver regeneration. Moreover, recent findings suggest that tissue-specific FXR also contributes to liver regeneration significantly. These novel findings suggest that FXR has much broader role than regulating BA, cholesterol, lipid and glucose metabolism. Therefore, these researches highlight FXR as an important pharmaceutical target for potential use of FXR ligands to regulate liver regeneration in clinic. This review focuses on the roles of BAs and FXR in liver regeneration and the current underlying molecular mechanisms which contribute to liver regeneration. PMID- 26579434 TI - The human gut sterolbiome: bile acid-microbiome endocrine aspects and therapeutics. AB - The human body is now viewed as a complex ecosystem that on a cellular and gene level is mainly prokaryotic. The mammalian liver synthesizes and secretes hydrophilic primary bile acids, some of which enter the colon during the enterohepatic circulation, and are converted into numerous hydrophobic metabolites which are capable of entering the portal circulation, returned to the liver, and in humans, accumulating in the biliary pool. Bile acids are hormones that regulate their own synthesis, transport, in addition to glucose and lipid homeostasis, and energy balance. The gut microbial community through their capacity to produce bile acid metabolites distinct from the liver can be thought of as an "endocrine organ" with potential to alter host physiology, perhaps to their own favor. We propose the term "sterolbiome" to describe the genetic potential of the gut microbiome to produce endocrine molecules from endogenous and exogenous steroids in the mammalian gut. The affinity of secondary bile acid metabolites to host nuclear receptors is described, the potential of secondary bile acids to promote tumors, and the potential of bile acids to serve as therapeutic agents are discussed. PMID- 26579435 TI - Epigenetic regulation of drug metabolism and transport. AB - The drug metabolism is a biochemical process on modification of pharmaceutical substances through specialized enzymatic systems. Changes in the expression of drug-metabolizing enzyme genes can affect drug metabolism. Recently, epigenetic regulation of drug-metabolizing enzyme genes has emerged as an important mechanism. Epigenetic regulation refers to heritable factors of genomic modifications that do not involve changes in DNA sequence. Examples of such modifications include DNA methylation, histone modifications, and non-coding RNAs. This review examines the widespread effect of epigenetic regulations on genes involved in drug metabolism, and also suggests a network perspective of epigenetic regulation. The epigenetic mechanisms have important clinical implications and may provide insights into effective drug development and improve safety of drug therapy. PMID- 26579437 TI - Bile acid signaling and biliary functions. AB - This review focuses on various components of bile acid signaling in relation to cholangiocytes. Their roles as targets for potential therapies for cholangiopathies are also explored. While many factors are involved in these complex signaling pathways, this review emphasizes the roles of transmembrane G protein coupled receptor (TGR5), farnesoid X receptor (FXR), ursodeoxycholic acid (UDCA) and the bicarbonate umbrella. Following a general background on cholangiocytes and bile acids, we will expand the review and include sections that are most recently known (within 5-7 years) regarding the field of bile acid signaling and cholangiocyte function. These findings all demonstrate that bile acids influence biliary functions which can, in turn, regulate the cholangiocyte response during pathological events. PMID- 26579436 TI - Circadian rhythms in liver metabolism and disease. AB - Mounting research evidence demonstrates a significant negative impact of circadian disruption on human health. Shift work, chronic jet lag and sleep disturbances are associated with increased incidence of metabolic syndrome, and consequently result in obesity, type 2 diabetes and dyslipidemia. Here, these associations are reviewed with respect to liver metabolism and disease. PMID- 26579438 TI - Metabolic effects of intestinal absorption and enterohepatic cycling of bile acids. AB - The classical functions of bile acids include acting as detergents to facilitate the digestion and absorption of nutrients in the gut. In addition, bile acids also act as signaling molecules to regulate glucose homeostasis, lipid metabolism and energy expenditure. The signaling potential of bile acids in compartments such as the systemic circulation is regulated in part by an efficient enterohepatic circulation that functions to conserve and channel the pool of bile acids within the intestinal and hepatobiliary compartments. Changes in hepatobiliary and intestinal bile acid transport can alter the composition, size, and distribution of the bile acid pool. These alterations in turn can have significant effects on bile acid signaling and their downstream metabolic targets. This review discusses recent advances in our understanding of the inter relationship between the enterohepatic cycling of bile acids and the metabolic consequences of signaling via bile acid-activated receptors, such as farnesoid X nuclear receptor (FXR) and the G-protein-coupled bile acid receptor (TGR5). PMID- 26579439 TI - Bile acid nuclear receptor FXR and digestive system diseases. AB - Bile acids (BAs) are not only digestive surfactants but also important cell signaling molecules, which stimulate several signaling pathways to regulate some important biological processes. The bile-acid-activated nuclear receptor, farnesoid X receptor (FXR), plays a pivotal role in regulating bile acid, lipid and glucose homeostasis as well as in regulating the inflammatory responses, barrier function and prevention of bacterial translocation in the intestinal tract. As expected, FXR is involved in the pathophysiology of a wide range of diseases of gastrointestinal tract, including inflammatory bowel disease, colorectal cancer and type 2 diabetes. In this review, we discuss current knowledge of the roles of FXR in physiology of the digestive system and the related diseases. Better understanding of the roles of FXR in digestive system will accelerate the development of FXR ligands/modulators for the treatment of digestive system diseases. PMID- 26579440 TI - Emerging role of microRNAs in lipid metabolism. AB - microRNAs (miRNAs or miRs) are small non-coding RNAs that are involved in post transcriptional regulation of their target genes in a sequence-specific manner. Emerging evidence demonstrates that miRNAs are critical regulators of lipid synthesis, fatty acid oxidation and lipoprotein formation and secretion. Dysregulation of miRNAs disrupts gene regulatory network, leading to metabolic syndrome and its related diseases. In this review, we introduced epigenetic and transcriptional regulation of miRNAs expression. We emphasized on several representative miRNAs that are functionally involved into lipid metabolism, including miR-33/33(*), miR122, miR27a/b, miR378/378(*), miR-34a and miR-21. Understanding the function of miRNAs in lipid homeostasis may provide potential therapeutic strategies for fatty liver disease. PMID- 26579441 TI - Bile acids and sphingosine-1-phosphate receptor 2 in hepatic lipid metabolism. AB - The liver is the central organ involved in lipid metabolism. Dyslipidemia and its related disorders, including non-alcoholic fatty liver disease (NAFLD), obesity and other metabolic diseases, are of increasing public health concern due to their increasing prevalence in the population. Besides their well-characterized functions in cholesterol homoeostasis and nutrient absorption, bile acids are also important metabolic regulators and function as signaling hormones by activating specific nuclear receptors, G-protein coupled receptors, and multiple signaling pathways. Recent studies identified a new signaling pathway by which conjugated bile acids (CBA) activate the extracellular regulated protein kinases (ERK1/2) and protein kinase B (AKT) signaling pathway via sphingosine-1-phosphate receptor 2 (S1PR2). CBA-induced activation of S1PR2 is a key regulator of sphingosine kinase 2 (SphK2) and hepatic gene expression. This review focuses on recent findings related to the role of bile acids/S1PR2-mediated signaling pathways in regulating hepatic lipid metabolism. PMID- 26579443 TI - Nanocarrier-mediated co-delivery of chemotherapeutic drugs and gene agents for cancer treatment. AB - The efficacy of chemotherapeutic drug in cancer treatment is often hampered by drug resistance of tumor cells, which is usually caused by abnormal gene expression. RNA interference mediated by siRNA and miRNA can selectively knock down the carcinogenic genes by targeting specific mRNAs. Therefore, combining chemotherapeutic drugs with gene agents could be a promising strategy for cancer therapy. Due to poor stability and solubility associated with gene agents and drugs, suitable protective carriers are needed and have been widely researched for the co-delivery. In this review, we summarize the most commonly used nanocarriers for co-delivery of chemotherapeutic drugs and gene agents, as well as the advances in co-delivery systems. PMID- 26579444 TI - Antagonism of toll-like receptor 2 attenuates the formation and progression of abdominal aortic aneurysm. AB - Abdominal aortic aneurysm (AAA) is an inflammatory vascular disorder with high mortality. Accumulating evidence shows that toll-like receptor 2 (TLR2) plays a critical role in the regulation of wound-repairing process after tissue injury. We wondered if TLR2 signaling contributed to the pathogenesis of AAA and that targeting TLR2 would attenuate AAA development and progression. In this study, enhanced expression of TLR2 and its ligands were observed in human AAA tissue. Neutralization of TLR2 protected against AAA development and caused established AAA to regress in mouse models of AAA. In addition, TLR2-deficient mice also failed to develop AAA. The prophylactic and therapeutic effects of blocking TLR2 were accompanied by a significant resolution of inflammation and vascular remodeling, as indicated by the decreased expression or activity of MMP-2/9, alpha-SMA, inflammatory cytokines, and transcription factors NF-kappaB, AP-1 and STAT1/3 in AAA tissue. Mechanistically, blocking TLR2 decreased the expression and interaction of TLR2 and several endogenous ligands, which diminished chronic inflammation and vascular remodeling in the vascular tissue of AAA. Our studies indicate that the interactions between TLR2 and its endogenous ligands contribute to the pathogenesis of AAA and that targeting TLR2 offers great potential toward the development of therapeutic agents against AAA. PMID- 26579442 TI - Role of farnesoid X receptor and bile acids in alcoholic liver disease. AB - Alcoholic liver disease (ALD) is one of the major causes of liver morbidity and mortality worldwide. Chronic alcohol consumption leads to development of liver pathogenesis encompassing steatosis, inflammation, fibrosis, cirrhosis, and in extreme cases, hepatocellular carcinoma. Moreover, ALD may also associate with cholestasis. Emerging evidence now suggests that farnesoid X receptor (FXR) and bile acids also play important roles in ALD. In this review, we discuss the effects of alcohol consumption on FXR, bile acids and gut microbiome as well as their impacts on ALD. Moreover, we summarize the findings on FXR, FoxO3a (forkhead box-containing protein class O3a) and PPARalpha (peroxisome proliferator-activated receptor alpha) in regulation of autophagy-related gene transcription program and liver injury in response to alcohol exposure. PMID- 26579445 TI - DZNep inhibits the proliferation of colon cancer HCT116 cells by inducing senescence and apoptosis. AB - EZH2 is over-expressed in human colon cancer and is closely associated with tumor proliferation, metastasis and poor prognosis. Targeting and inhibiting EZH2 may be an effective therapeutic strategy for colon cancer. 3-Deazaneplanocin A (DZNep), as an EZH2 inhibitor, can suppress cancer cell growth. However, the anti cancer role of DZNep in colon cancer cells has been rarely studied. In this study, we demonstrate that DZNep can inhibit the growth and survival of colon cancer HCT116 cells by inducing cellular senescence and apoptosis. The study provides a novel view of anti-cancer mechanisms of DZNep in human colon cancer cells. PMID- 26579446 TI - Kallistatin, a new and reliable biomarker for the diagnosis of liver cirrhosis. AB - Kallistatin, which protects organs and cells against inflammation, fibrosis and oxidative stress, is mainly synthesized and secreted in liver. However, its relationship to human liver disease remains unclear. The purpose of this study was to explore the relationship between serum kallistatin and clinical evidence of both cirrhosis and hepatocellular carcinoma (HCC), and to determine if serum kallistatin levels could be used as a diagnostic indicator of hepatic health status, especially human liver cirrhosis (LC). Our cohort consisted of 115 patients with clinically proven liver fibrosis (LF), LC, or HCC by liver biopsies, and 31 healthy controls (CON). Serum kallistatin levels were quantified by ELISA. Results of the present study demonstrated that irrespective of the underlying etiology, serum kallistatin levels were significantly lower in the LF/LC group when compared with the CON group. A decrease in serum kallistatin levels appeared to reflect the extent of cirrhosis, with the lowest levels associated with higher grades of cirrhosis. Patients with LC had a noticeable correlation between serum kallistatin levels and other serum biochemical indicators. The area under the curve (AUC) for LC, viral liver cirrhosis (VLC) and alcoholic liver cirrhosis (ALC) was 0.845, 0.757 and 0.931, respectively. In conclusion, our findings demonstrated that kallistatin, a plasma protein produced by the liver, can be a useful and reliable diagnostic indicator of hepatic health status, especially for LC. PMID- 26579447 TI - Synthesis and antiviral activity of a series of novel N-phenylbenzamide and N phenylacetophenone compounds as anti-HCV and anti-EV71 agents. AB - A series of novel N-phenylbenzamide and N-phenylacetophenone compounds were synthesized and evaluated for their antiviral activity against HCV and EV71 (strain SZ-98). The biological results showed that three compounds (23, 25 and 41) exhibited considerable anti-HCV activity (IC50=0.57-7.12 MUmol/L) and several compounds (23, 28, 29, 30, 31 and 42) displayed potent activity against EV71 with the IC50 values lower than 5.00 MUmol/L. The potency of compound 23 (IC50=0.57 MUmol/L) was superior to that of reported compounds IMB-1f (IC50=1.90 MUmol/L) and IMB-1g (IC50=1.00 MUmol/L) as anti-HCV agents, and compound 29 possessed the highest anti-EV71 activity, comparable to the comparator drug pirodavir. The efficacy in vivo and antiviral mechanism of these compounds warrant further investigations. PMID- 26579448 TI - Glucosylated caffeoylquinic acid derivatives from the flower buds of Lonicera japonica. AB - Three new glucosylated caffeoylquinic acid isomers (1-3), along with six known compounds, have been isolated from an aqueous extract of the flower buds of Lonicera japonica. Structures of the new compounds were determined by spectroscopic and chemical methods as (-)-4-O-(4-O-beta-d glucopyranosylcaffeoyl)quinic acid (1), (-)-3-O-(4-O-beta-d glucopyranosylcaffeoyl)quinic acid (2), and (-)-5-O-(4-O-beta-d glucopyranosylcaffeoyl)quinic acid (3), respectively. In the preliminary in vitro assays, two known compounds methyl caffeate and 2'-O-methyladenosine showed inhibitory activity against Coxsackie virus B3 with IC50 values of 3.70 MUmol/L and 6.41 MUmol/L and SI values of 7.8 and 12.1, respectively. PMID- 26579449 TI - Acetylenes and fatty acids from Codonopsis pilosula. AB - Four new acetylenes (1-4) and one new unsaturated omega-hydroxy fatty acid (5), together with 5 known analogues, were isolated from an aqueous extract of Codonopsis pilosula roots. Their structures were determined by spectroscopic and chemical methods. The new acetylenes are categorized as an unusual cyclotetradecatrienynone (1), tetradecenynetriol (2), and rare octenynoic acids (3 and 4), respectively, and 3 and 4 are possibly derived from oxidative metabolic degradation of 1 and/or 2. The absolute configuration of 1 was assigned by comparison of the experimental circular dichroism (CD) spectrum with the calculated electronic circular dichroism (ECD) spectra of stereoisomers based on the quantum-mechanical time-dependent density functional theory, while the configuration of 2 was assigned by using modified Mosher's method based on the MPA determination rule of Deltadelta RS values for diols. PMID- 26579450 TI - Effects of antibiotic antitumor drugs on nucleotide levels in cultured tumor cells: an exploratory method to distinguish the mechanisms of antitumor drug action based on targeted metabolomics. AB - Nucleotide pools in mammalian cells change due to the influence of antitumor drugs, which may help in evaluating the drug effect and understanding the mechanism of drug action. In this study, an ion-pair RP-HPLC method was used for a simple, sensitive and simultaneous determination of the levels of 12 nucleotides in mammalian cells treated with antibiotic antitumor drugs (daunorubicin, epirubicin and dactinomycin D). Through the use of this targeted metabolomics approach to find potential biomarkers, UTP and ATP were verified to be the most appropriate biomarkers. Moreover, a holistic statistical approach was put forward to develop a model which could distinguish 4 categories of drugs with different mechanisms of action. This model can be further validated by evaluating drugs with different mechanisms of action. This targeted metabolomics study may provide a novel approach to predict the mechanism of action of antitumor drugs. PMID- 26579451 TI - Development of a new ferulic acid certified reference material for use in clinical chemistry and pharmaceutical analysis. AB - This study compares the results of three certified methods, namely differential scanning calorimetry (DSC), the mass balance (MB) method and coulometric titrimetry (CT), in the purity assessment of ferulic acid certified reference material (CRM). Purity and expanded uncertainty as determined by the three methods were respectively 99.81%, 0.16%; 99.79%, 0.16%; and 99.81%, 0.26% with, in all cases, a coverage factor (k) of 2 (P=95%). The purity results are consistent indicating that the combination of DSC, the MB method and CT provides a confident assessment of the purity of suitable CRMs like ferulic acid. PMID- 26579452 TI - Study on pharmacokinetics and tissue distribution of the isocorydine derivative (AICD) in rats by HPLC-DAD method. AB - A simple and effective high-performance liquid chromatography with diode-array detection method coupled with a liquid-liquid extraction pretreatment has been developed for determining the pharmacokinetics and tissue distribution of a novel structurally modified derivative (8-acetamino-isocorydine) of isocorydine. According to the in vivo experiments data calculations by DAS 2.0 software, a two compartment metabolic model was suitable for describing the pharmacokinetic of 8 acetamino-isocorydine in rats. 8-Acetamino-isocorydine was absorbed well after oral administration, and the absolute bioavailability was 76.5%. The half-life of 8-acetamino-isocorydine after intravenous and oral administration was 2.2 h and 2.0 h, respectively. In vivo, 8-acetamino-isocorydine was highly distributed in the lungs, kidney and liver; however, relatively little entered the brain, suggesting that 8-acetamino-isocorydine could not easily pass through the blood brain barrier. Our work describes the first characterization of the pharmacokinetic parameters and tissue distribution of 8-acetamino-isocorydine. The acquired data will provide useful information for the in vivo pharmacology of 8-acetamino-isocorydine, and can be applied to new drug research. PMID- 26579453 TI - Pharmacokinetic study of salvianolic acid D after oral and intravenous administration in rats. AB - A sensitive, specific and rapid LC-MS method was developed and validated for the determination of salvianolic acid D (SalD) in rat plasma. This method used a single quadrupole mass spectrometer with an electrospray ionization (ESI) source. A single ion monitoring scanning (SIM) mode was employed. It showed good linearity over the concentration range from 3.3 to 666.7 ng/mL for the determination of SalD. The R.S.D.% of intra-day and inter-day precision values were no more than 7.69%, and the accuracy was within 91%-104% at all quality control levels. This LC-MS method was applied to the pharmacokinetic study of SalD in rats. A two-compartmental model analysis was employed. The plasma concentrations at 2 min (C 2min) were 5756.06+/-719.61, 11,073.01+/-1783.46 and 21,077.58+/-5581.97 MUg/L for 0.25, 0.5 and 1 mg/kg intravenous injection, respectively. The peak plasma concentration (C max) was 333.08+/-61.21 MUg/L for 4 mg/kg oral administration. The area under curve (AUC0-t ) was 14,384.379+/ 8443.184, 22,813.369+/-11,860.823, 46,406.122+/-27,592.645 and 8201.740+/ 4711.961 MUg/L.h for intravenous injection (0.25, 0.5 and 1 mg/kg) and oral administration (4 mg/kg), respectively. The bioavailability of SalD was calculated to be 4.159%+/-0.517%. PMID- 26579454 TI - Pharmacokinetic analysis and tissue distribution of Vam3 in the rat by a validated LC-MS/MS method. AB - Vam3 is a potential pharmacologically active ingredient isolated from Vitis amurensis Rupr. A rapid, simple and sensitive method to determine Vam3 levels in rat plasma and tissue was developed based on LC-MS/MS. Vam3 and an internal standard (IS) were chromatographed on a C18 short column with acetonitrile-0.1% formic acid in water by gradient elution. MS detection was performed by electrospray ionization in negative ion multiple reaction-monitoring modes. This method monitored the transitions m/z 451.0->345.0 and m/z 301.0->164.0 for Vam3 and IS, respectively. The calibration curve was linear over a concentration range of 1.64-1000 ng/mL. The inter-day and intra-day variabilities in precision was less than 12.8%, while the inter-day and intra-day accuracies ranged from -10.60% to 9.08% in plasma and tissue homogenates. This method was applied to investigate the pharmacokinetics and tissue distribution of Vam3 in rats. The results indicated that Vam3 had poor absorption into systemic circulation and extensive tissue distribution after oral administration, and the absolute bioavailability was low (0.79%). Vam3 had a relatively long terminal elimination half-life in lung, and the highest concentration was found in small intestinal tissue. The developed method and the pharmacokinetic data can provide a basis for further studies on the bioactivity of Vam3. PMID- 26579455 TI - Site-specific PEGylation of lidamycin and its antitumor activity. AB - In this study, N-terminal site-specific mono-PEGylation of the recombinant lidamycin apoprotein (rLDP) of lidamycin (LDM) was prepared using a polyethyleneglycol (PEG) derivative (M w 20 kDa) through a reactive terminal aldehyde group under weak acidic conditions (pH 5.5). The biochemical properties of mPEG-rLDP-AE, an enediyne-integrated conjugate, were analyzed by SDS-PAGE, RP HPLC, SEC-HPLC and MALDI-TOF. Meanwhile, in vitro and in vivo antitumor activity of mPEG-rLDP-AE was evaluated by MTT assays and in xenograft model. The results indicated that mPEG-rLDP-AE showed significant antitumor activity both in vitro and in vivo. After PEGylation, mPEG-rLDP still retained the binding capability to the enediyne AE and presented the physicochemical characteristics similar to that of native LDP. It is of interest that the PEGylation did not diminish the antitumor efficacy of LDM, implying the possibility that this derivative may function as a payload to deliver novel tumor-targeted drugs. PMID- 26579456 TI - Synchrotron radiation-based Fourier-transform infrared spectromicroscopy for characterization of the protein/peptide distribution in single microspheres. AB - The present study establishes a visualization method for the measurement of the distribution and localization of protein/peptide constituents within a single poly-lactide-co-glycolide (PLGA) microsphere using synchrotron radiation-based Fourier-transform infrared spectromicroscopy (SR-FTIR). The representative infrared wavenumbers specific for protein/peptide (Exenatide) and excipient (PLGA) were identified and chemical maps at the single microsphere level were generated by measuring and plotting the intensity of these specific bands. For quantitative analysis of the distribution within microspheres, Matlab software was used to transform the map file into a 3D matrix and the matrix values specific for the drug and excipient were extracted. Comparison of the normalized SR-FTIR maps of PLGA and Exenatide indicated that PLGA was uniformly distributed, while Exenatide was relatively non-uniformly distributed in the microspheres. In conclusion, SR-FTIR is a rapid, nondestructive and sensitive detection technology to provide the distribution of chemical constituents and functional groups in microparticles and microspheres. PMID- 26579457 TI - Ginsenoside Rg1 protects against transient focal cerebral ischemic injury and suppresses its systemic metabolic changes in cerabral injury rats. AB - Ginsenoside Rg1 (GR), a major bioactive compound of traditional Chinese medicine, such as Panax ginseng or Radix Notoginseng, has been shown to exert neuroprotective effects against ischemic stroke. However, pharmacokinetic studies have suggested that GR could not be efficiently transported through the blood brain barrier. The mechanism by which GR attenuates cerebral ischemic injury in vivo remains largely unknown. Therefore, this study explored potential neuro protective effects of GR through its systemic metabolic regulating mechanism by using mass spectrometry-based metabolomic profiling. Rats with middle cerebral artery occlusion (MCAO) were treated with GR intravenously. Their metabolic profiles in serum were measured by gas chromatography coupled with mass spectrometry on 1 and 3 days after MCAO. GR exhibited a potent neuro-protective effect by significantly decreasing the neurological scores and infarct volume in the MCAO rats. Moreover, 18 differential metabolites were tentatively identified, all of which appeared to correlate well with these disease indices. Our findings suggested that GR carries a therapeutic potential in stroke possibly through a feed-back mechanism by regulating systematic metabolic mediation. PMID- 26579459 TI - Current developments in pharmacological therapeutics for chronic constipation. AB - Chronic constipation is a common gastrointestinal disease severely affecting the patient's quality of life. The traditional treatment of constipation is the use of laxatives. Recently, several new drugs including lubiprostone, linaclotide and prucalopride have been approved for treatment of chronic constipation. However, a significant unmet medical need still remains, particularly among those patients achieving poor results by current therapies. The 5-HT4 receptor modulators velusetrag and naronapride, the guanylate cyclase C agonist plecanatide and the ileal bile acid transporter inhibitor elobixibat are recognized as the most promising drugs under investigation. Herein, we give a comprehensive review on the pharmacological therapeutics for the treatment of chronic constipation, with the purpose of reflecting the drug development trends in this field. PMID- 26579460 TI - The antiviral and antimicrobial activities of licorice, a widely-used Chinese herb. AB - Licorice is a common herb which has been used in traditional Chinese medicine for centuries. More than 20 triterpenoids and nearly 300 flavonoids have been isolated from licorice. Recent studies have shown that these metabolites possess many pharmacological activities, such as antiviral, antimicrobial, anti inflammatory, antitumor and other activities. This paper provides a summary of the antiviral and antimicrobial activities of licorice. The active components and the possible mechanisms for these activities are summarized in detail. This review will be helpful for the further studies of licorice for its potential therapeutic effects as an antiviral or an antimicrobial agent. PMID- 26579461 TI - Development of a C3c-based ELISA method for the determination of anti complementary potency of Bupleurum polysaccharides. AB - Traditionally, determination of inhibitory potency of complement inhibitors is performed by the hemolytic assay. However, this assay is not applicable to the lectin pathway, thus impeding the understanding of complement inhibitors against the overall function of the complement system. The main objective of our study was to develop a specific enzyme-linked immunosorbent assay (ELISA) as an alternative method to assess the anti-complement activity, particularly against the lectin pathway. By using respective coating substrates against different activation pathways, followed by capturing the stable C3c fragments, our ELISA method can be used to screen complement inhibitors against the classical pathway and the lectin pathway. The inhibitory effect of suramin on the classical pathway, as measured by our hemolytic assay is consistent with previous reports. Further assessment of suramin and Bupleurum polysaccharides against the lectin pathway showed a good reproducibility of the method. Comparison of the lectin pathway IC50 between Bupleurum smithii var. parvifolium polysaccharides (1.055 mg/mL) and Bupleurum chinense polysaccharides (0.98 mg/mL) showed that, similar to the classical and alterative pathway, these two Bupleurum polysaccharides had comparable anti-complementary properties against the lectin pathway. The results demonstrate that the described ELISA assay can compensate for the shortcomings of the hemolytic assay in lectin pathway. PMID- 26579462 TI - Neocryptotanshinone inhibits lipopolysaccharide-induced inflammation in RAW264.7 macrophages by suppression of NF-kappaB and iNOS signaling pathways. AB - Neocryptotanshinone (NCTS) is a natural product isolated from traditional Chinese herb Salvia miltiorrhiza Bunge. In this study, we investigated its anti inflammatory effects in lipopolysaccharide (LPS)-stimulated mouse macrophage (RAW264.7) cells. MTT results showed that NCTS partly reversed LPS-induced cytotoxicity. Real-time PCR results showed that NCTS suppressed LPS-induced mRNA expression of inflammatory cytokines, including tumor necrosis factor alpha (TNFalpha), interleukin-6 (IL-6) and interleukin-1beta (IL-1beta). Moreover, NCTS could decrease LPS-induced nitric oxide (NO) production. Western blotting results showed that NCTS could down-regulate LPS-induced expression of inducible nitric oxide synthase (iNOS), p-IkappaBalpha, p-IKKbeta and p-NF-kappaB p65 without affecting cyclooxygenase-2 (COX-2). In addition, NCTS inhibited LPS-induced p-NF kappaB p65 nuclear translocation. In conclusion, these data demonstrated that NCTS showed anti-inflammatory effect by suppression of NF-kappaB and iNOS signaling pathways. PMID- 26579458 TI - Discovery of direct inhibitors of Keap1-Nrf2 protein-protein interaction as potential therapeutic and preventive agents. AB - The Keap1-Nrf2-ARE pathway is an important antioxidant defense mechanism that protects cells from oxidative stress and the Keap1-Nrf2 protein-protein interaction (PPI) has become an important drug target to upregulate the expression of ARE-controlled cytoprotective oxidative stress response enzymes in the development of therapeutic and preventive agents for a number of diseases and conditions. However, most known Nrf2 activators/ARE inducers are indirect inhibitors of Keap1-Nrf2 PPI and they are electrophilic species that act by modifying the sulfhydryl groups of Keap1's cysteine residues. The electrophilicity of these indirect inhibitors may cause "off-target" side effects by reacting with cysteine residues of other important cellular proteins. Efforts have recently been focused on the development of direct inhibitors of Keap1-Nrf2 PPI. This article reviews these recent research efforts including the development of high throughput screening assays, the discovery of peptide and small molecule direct inhibitors, and the biophysical characterization of the binding of these inhibitors to the target Keap1 Kelch domain protein. These non-covalent direct inhibitors of Keap1-Nrf2 PPI could potentially be developed into effective therapeutic or preventive agents for a variety of diseases and conditions. PMID- 26579463 TI - DMH1 (4-[6-(4-isopropoxyphenyl)pyrazolo[1,5-a]pyrimidin-3-yl]quinoline) inhibits chemotherapeutic drug-induced autophagy. AB - Our previous work found that DMH1 (4-[6-(4-isopropoxyphenyl)pyrazolo [1,5 a]pyrimidin-3-yl]quinoline) was a novel autophagy inhibitor. Here, we aimed to investigate the effects of DMH1 on chemotherapeutic drug-induced autophagy as well as the efficacy of chemotherapeutic drugs in different cancer cells. We found that DMH1 inhibited tamoxifen- and cispcis-diaminedichloroplatinum (II) (CDDP)-induced autophagy responses in MCF-7 and HeLa cells, and potentiated the anti-tumor activity of tamoxifen and CDDP for both cells. DMH1 inhibited 5 fluorouracil (5-FU)-induced autophagy responses in MCF-7 and HeLa cells, but did not affect the anti-tumor activity of 5-FU for these two cell lines. DMH1 itself did not induce cell death in MCF-7 and HeLa cells, but inhibited the proliferation of these cells. In conclusion, DMH1 inhibits chemotherapeutic drug induced autophagy response and the enhancement of efficacy of chemotherapeutic drugs by DMH1 is dependent on the cell sensitivity to drugs. PMID- 26579464 TI - Benzimidazole derivatives: search for GI-friendly anti-inflammatory analgesic agents. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) have been successfully used for the alleviation of pain and inflammation in the past and continue to be used daily by millions of patients worldwide. However, gastrointestinal (GI) toxicity associated with NSAIDs is an important medical and socioeconomic problem. Local generation of various reactive oxygen species plays a significant role in the formation of gastric ulceration associated with NSAIDs therapy. Co-medication of antioxidants along with NSAIDs has been found to be beneficial in the prevention of GI injury. This paper describes the synthesis and biological evaluation of N-1 (phenylsulfonyl)-2-methylamino-substituted-1H-benzimidazole derivatives as anti inflammatory analgesic agents with lower GI toxicity. Studies in vitro and in vivo demonstrated that the antioxidant activity of the test compounds decreased GI toxicity. PMID- 26579465 TI - Synthesis, potential anticonvulsant and antidepressant effects of 2-(5-methyl-2,3 dioxoindolin-1-yl)acetamide derivatives. AB - A new series of 2-(5-methyl-2,3-dioxoindolin-1-yl)acetamide derivatives were synthesized and evaluated for their anticonvulsive activity in a pentylenetetrazole (PTZ)-evoked convulsion model and antidepressant activity in the forced swimming test (FST) model. Eleven synthesized compounds were found to be protective against PTZ-induced seizure and showed the anticonvulsant activity. In addition, four of the synthesized compounds (4l, 4m, 4p and 4q) showed potent antidepressant-like activity. Among these compounds, compound 4l was found to have the most potent antidepressant-like activity, and significantly reduced the duration of immobility time at 100 mg/kg dose level when compared to the vehicle control, which is similar to the reference drug fluoxetine. PMID- 26579466 TI - 4-Hydroxybenzyl-substituted amino acid derivatives from Gastrodia elata. AB - Seven new 4-hydroxybenzyl-substituted amino acid derivatives (1-7), together with 11 known compounds, were isolated from an aqueous extract of the rhizomes of Gastrodia elata Blume. Their structures were determined by spectroscopic and chemical methods. Compounds 1-3 are pyroglutamate derivatives containing 4 hydroxybenzyl units at the N atom and 4-7 are the first examples of natural products with the 4-hydroxybenzyl unit linked via a thioether bond to 2-hydroxy-3 mercaptopropanoic acid (4-6) and 2-hydroxy-4-mercaptobutanoic acid (7), which would be biogenetically derived from cysteine and homocysteine, respectively. The structures of 1 and 2 were verified by synthesis, while the absolute configurations of 4, 5 and 7 were assigned using Mosher's method based on the MPA determination rule of Deltadelta RS values. The known compound 4-(hydroxymethyl) 5-nitrobenzene-1,2-diol (8) exhibited activity against Fe(2+)-cysteine induced rat liver microsomal lipid peroxidation with IC50 values of 9.99*10(-6) mol/L. PMID- 26579467 TI - Morphological and microscopic characterization of five commonly-used testacean traditional Chinese medicines. AB - Testacean traditional Chinese medicine (TTCM), derived from the outer shell of sea or freshwater mollusks, is a special and important category of Chinese medicinal materials. To ensure the effective use of TTCM, a comparative identification study was performed on five commonly-used testacean drugs, including Haliotidis Concha, Arcae Concha, Meretricis Concha, Ostreae Concha and Margaritifera Concha (Shijueming, Walengzi, Geqiao, Muli and Zhenzhumu in Chinese, respectively). Typical morphological photographs of the crude drugs were acquired, and the key microscopic characteristics of the derived powders under normal light microscope and polarized light microscope were summarized. The major results can be concluded as follows: (1) the original species involved in the five TTCMs could be distinguished by their respective interspecies morphological characteristics; (2) the key identification characteristics of the five powdered crude drugs were mainly crystal fragments, with the fragment features under both normal light and polarized light microscope providing powerful points for differentiating the five commonly-used testacean drugs. This study demonstrated that it is feasible to provide authentication for these five kinds of TTCMs by the combination of morphology with microscopy. PMID- 26579468 TI - Hydrogen sulfide prodrugs-a review. AB - Hydrogen sulfide (H2S) is recognized as one of three gasotransmitters together with nitric oxide (NO) and carbon monoxide (CO). As a signaling molecule, H2S plays an important role in physiology and shows great potential in pharmaceutical applications. Along this line, there is a need for the development of H2S prodrugs for various reasons. In this review, we summarize different H2S prodrugs, their chemical properties, and some of their potential therapeutic applications. PMID- 26579469 TI - HIF-1alpha pathway: role, regulation and intervention for cancer therapy. AB - Hypoxia-inducible factor-1 (HIF-1) has been recognized as an important cancer drug target. Many recent studies have provided convincing evidences of strong correlation between elevated levels of HIF-1 and tumor metastasis, angiogenesis, poor patient prognosis as well as tumor resistance therapy. It was found that hypoxia (low O2 levels) is a common character in many types of solid tumors. As an adaptive response to hypoxic stress, hypoxic tumor cells activate several survival pathways to carry out their essential biological processes in different ways compared with normal cells. Recent advances in cancer biology at the cellular and molecular levels highlighted the HIF-1alpha pathway as a crucial survival pathway for which novel strategies of cancer therapy could be developed. However, targeting the HIF-1alpha pathway has been a challenging but promising progresses have been made in the past twenty years. This review summarizes the role and regulation of the HIF-1alpha in cancer, and recent therapeutic approaches targeting this important pathway. PMID- 26579471 TI - Cancer metastases: challenges and opportunities. AB - Cancer metastasis is the major cause of cancer morbidity and mortality, and accounts for about 90% of cancer deaths. Although cancer survival rate has been significantly improved over the years, the improvement is primarily due to early diagnosis and cancer growth inhibition. Limited progress has been made in the treatment of cancer metastasis due to various factors. Current treatments for cancer metastasis are mainly chemotherapy and radiotherapy, though the new generation anti-cancer drugs (predominantly neutralizing antibodies for growth factors and small molecule kinase inhibitors) do have the effects on cancer metastasis in addition to their effects on cancer growth. Cancer metastasis begins with detachment of metastatic cells from the primary tumor, travel of the cells to different sites through blood/lymphatic vessels, settlement and growth of the cells at a distal site. During the process, metastatic cells go through detachment, migration, invasion and adhesion. These four essential, metastatic steps are inter-related and affected by multi-biochemical events and parameters. Additionally, it is known that tumor microenvironment (such as extracellular matrix structure, growth factors, chemokines, matrix metalloproteinases) plays a significant role in cancer metastasis. The biochemical events and parameters involved in the metastatic process and tumor microenvironment have been targeted or can be potential targets for metastasis prevention and inhibition. This review provides an overview of these metastasis essential steps, related biochemical factors, and targets for intervention. PMID- 26579470 TI - Mechanisms of resistance to EGFR tyrosine kinase inhibitors. AB - Since the discovery that non-small cell lung cancer (NSCLC) is driven by epidermal growth factor receptor (EGFR) mutations, the EGFR tyrosine kinase inhibitors (EGFR-TKIs, e.g., gefitinib and elrotinib) have been effectively used for clinical treatment. However, patients eventually develop drug resistance. Resistance to EGFR-TKIs is inevitable due to various mechanisms, such as the secondary mutation (T790M), activation of alternative pathways (c-Met, HGF, AXL), aberrance of the downstream pathways (K-RAS mutations, loss of PTEN), impairment of the EGFR-TKIs-mediated apoptosis pathway (BCL2-like 11/BIM deletion polymorphism), histologic transformation, ATP binding cassette (ABC) transporter effusion, etc. Here we review and summarize the known resistant mechanisms to EGFR-TKIs and provide potential targets for development of new therapeutic strategies. PMID- 26579473 TI - Adenine: an important drug scaffold for the design of antiviral agents. AB - Adenine derivatives, in particular the scaffold bearing the acyclic nucleoside phosphonates (ANPS), possess significant antiviral and cytostatic activity. Till now, several effective adenine derivatives have been marketed for the treatment of HIV, HBV, CMV and other virus-infected diseases. These compounds are represented by tenofovir (PMPA), a medicine for both HIV and HBV, and adefovir as an anti-HBV agent. More than this, other analogs, such as GS9148, GS9131, and GS7340, are also well-known anti-viral agents that have been progressed to the clinical studies for their excellent activity. In general, the structures of these compounds include an adenine nucleobase linked to a phosphonate side chain. Considerable structural modifications on the scaffold itself and the peripheral sections were made. The structure-activity relationships (SARs) of this skeleton will provide valuable clues to identify more effective adenine derivatives as antiviral drugs. Here, we systematically summarized the SARs of the adenine derivatives, and gave important information for further optimizing this template. PMID- 26579472 TI - New small-molecule drug design strategies for fighting resistant influenza A. AB - Influenza A virus is the major cause of seasonal or pandemic flu worldwide. Two main treatment strategies-vaccination and small molecule anti-influenza drugs are currently available. As an effective vaccine usually takes at least 6 months to develop, anti-influenza small molecule drugs are more effective for the first line of protection against the virus during an epidemic outbreak, especially in the early stage. Two major classes of anti-influenza drugs currently available are admantane-based M2 protein blockers (amantadine and rimantadine) and neuraminidase (NA) inhibitors (oseltamivir, zanamivir, and peramivir). However, the continuous evolvement of influenza A virus and the rapid emergence of resistance to current drugs, particularly to amantadine, rimantadine, and oseltamivir, have raised an urgent need for developing new anti-influenza drugs against resistant forms of influenza A virus. In this review, we first give a brief introduction of the molecular mechanisms behind resistance, and then discuss new strategies in small-molecule drug development to overcome influenza A virus resistance targeting mutant M2 proteins and neuraminidases, and other viral proteins not associated with current drugs. PMID- 26579474 TI - Insoluble drug delivery strategies: review of recent advances and business prospects. AB - The emerging trends in the combinatorial chemistry and drug design have led to the development of drug candidates with greater lipophilicity, high molecular weight and poor water solubility. Majority of the failures in new drug development have been attributed to poor water solubility of the drug. Issues associated with poor solubility can lead to low bioavailability resulting in suboptimal drug delivery. About 40% of drugs with market approval and nearly 90% of molecules in the discovery pipeline are poorly water-soluble. With the advent of various insoluble drug delivery technologies, the challenge to formulate poorly water soluble drugs could be achieved. Numerous drugs associated with poor solubility and low bioavailabilities have been formulated into successful drug products. Several marketed drugs were reformulated to improve efficacy, safety and patient compliance. In order to gain marketing exclusivity and patent protection for such products, revitalization of poorly soluble drugs using insoluble drug delivery technologies have been successfully adopted by many pharmaceutical companies. This review covers the recent advances in the field of insoluble drug delivery and business prospects. PMID- 26579475 TI - Calycosin-7-O-beta-d-glucopyranoside stimulates osteoblast differentiation through regulating the BMP/WNT signaling pathways. AB - The isoflavone calycosin-7-O-beta-d-glucopyranoside (CG) is a principal constituent of Astragalus membranaceus (AR) and has been reported to inhibit osteoclast development in vitro and bone loss in vivo. The aim of this study was to investigate the osteogenic effects of CG and its underlying mechanism in ST2 cells. The results show that exposure of cells to CG in osteogenic differentiation medium increases ALP activity, osteocalcin (Ocal) mRNA expression and the osteoblastic mineralization process. Mechanistically, CG treatment increased the expression of bone morphogenetic protein 2 (BMP-2), p-Smad 1/5/8, beta-catenin and Runx2, all of which are regulators of the BMP- or wingless-type MMTV integration site family (WNT)/beta-catenin-signaling pathways. Moreover, the osteogenic effects of CG were inhibited by Noggin and DKK-1 which are classical inhibitors of the BMP and WNT/beta-catenin-signaling pathways, respectively. Taken together, the results indicate that CG promotes the osteoblastic differentiation of ST2 cells through regulating the BMP/WNT signaling pathways. On this basis, CG may be a useful lead compound for improving the treatment of bone-decreasing diseases and enhancing bone regeneration. PMID- 26579476 TI - Determination of ginsenoside compound K in human plasma by liquid chromatography tandem mass spectrometry of lithium adducts. AB - Ginsenoside compound K (GCK), the main metabolite of protopanaxadiol constituents of Panax ginseng, easily produces alkali metal adduct ions during mass spectrometry particularly with lithium. Accordingly, we have developed a rapid and sensitive liquid chromatography-tandem mass spectrometric method for analysis of GCK in human plasma based on formation of a lithium adduct. The analyte and paclitaxel (internal standard) were extracted from 50 uL human plasma using methyl tert-butyl ether. Chromatographic separation was performed on a Phenomenex Gemini C18 column (50 mm*2.0 mm; 5 MUm) using stepwise gradient elution with acetonitrile-water and 0.2 mmol/L lithium carbonate at a flow rate of 0.5 mL/min. Detection was performed in the positive ion mode using multiple reaction monitoring of the transitions at m/z 629->449 for the GCK-lithium adduct and m/z 860->292 for the adduct of paclitaxel. The assay was linear in the concentration range 1.00-1000 ng/mL (r (2)>0.9988) with intra- and inter-day precision of +/ 8.4% and accuracy in the range of -4.8% to 6.5%. Recovery, stability and matrix effects were all satisfactory. The method was successfully applied to a pharmacokinetic study involving administration of a single GCK 50 mg tablet to healthy Chinese volunteers. PMID- 26579477 TI - Validated LC--MS/MS method for determination of YH-8, a novel PKnB inhibitor, in rat plasma and its application to pharmacokinetic study. AB - (E)-Methyl-4-aryl-4-oxabut-2-enoate (YH-8) is a novel PKnB protein kinase inhibitor with good anti-tuberculosis activity. To evaluate its pharmacokinetics in rats, a sensitive and selective high performance liquid chromatography-tandem mass spectrometric (LC--MS/MS) method has been developed and validated for the quantification of YH-8 in rat plasma for the first time. Samples were pre-treated using a liquid--liquid extraction with ethyl acetate and the chromatographic separation was performed on a C18 column by gradient elution with methanol--water as the mobile phase. YH-8 was detected using a tandem mass spectrometer in positive selected reaction monitoring (SRM) mode. Method validation revealed good linearity over the range of 1-500 ng/mL for YH-8 with a lower limit of quantification (LLOQ) of 1 ng/mL. Intra- and inter-day precision of YH-8 assay in rat plasma samples were 2.0%-6.8%, with accuracy of the method being 100.69% 106.18%. Stability test showed that when spiked into rat plasma, YH-8 was stable for 12 h at room temperature, for up to 15 days at -70 degrees C, and after three freeze-thaw cycles. Extracted samples were found to be stable over 12 h in an auto-sampler. The method was successfully applied to the pharmacokinetic study of YH-8 in rats after oral administration at 100 mg/kg and 200 mg/kg. PMID- 26579478 TI - Cloning, expression and characterization of COI1 gene (AsCOI1) from Aquilaria sinensis (Lour.) Gilg. AB - Aquilaria sinensis, a kind of typically wounding-induced medicinal plant with a great economical value, is widely used in the production of traditional Chinese medicine, perfume and incense. Coronatine-insensitive protein 1 (COI1) acts as a receptor in jasmonate (JA) signaling pathway, and regulates the expression of JA responsive genes in plant defense. However, little is known about the COI1 gene in A. sinensis. Here, based on the transcriptome data, a full-length cDNA sequence of COI1 (termed as AsCOI1) was firstly cloned by RT-PCR and rapid amplification of cDNA ends (RACE) strategies. AsCOI1 is 2330 bp in length (GenBank accession No. KM189194), and contains a complete open frame (ORF) of 1839 bp. The deduced protein was composed of 612 amino acids, with a predicted molecular weight of 68.93 kDa and an isoelectric point of 6.56, and was predicted to possess F-box and LRRs domains. Combining bioinformatics prediction with subcellular localization experiment analysis, AsCOI1 was appeared to locate in nucleus. AsCOI1 gene was highly expressed in roots and stems, the major organs of agarwood formation. Methyl jasmonate (MeJA), mechanical wounding and heat stress could significantly induce the expression level of AsCOI1 gene. AsCOI1 is an early wound-responsive gene, and it likely plays some role in agarwood formation. PMID- 26579479 TI - Simultaneous determination of 3-chlorotyrosine and 3-nitrotyrosine in human plasma by direct analysis in real time-tandem mass spectrometry. AB - A novel method for the simultaneous determination of 3-nitrotyrosine (NT) and 3 chlorotyrosine (CT) in human plasma has been developed based on direct analysis in real time-tandem mass spectrometry (DART-MS/MS). Analysis was performed in the positive ionization mode using multiple reaction monitoring (MRM) of the ion transitions at m/z 216.2/170.1 for CT, m/z 227.2/181.1 for NT and m/z 230.2/184.2 for the internal standard, d (3)-NT. The assay was linear in the ranges 0.5-100 MUg/mL for CT and 4-100 MUg/mL for NT with corresponding limits of detection of 0.2 and 2 MUg/mL. Intra- and inter-day precisions and accuracies were respectively <15% and +/-15%. Matrix effects were also evaluated. The method is potentially useful for high throughput analysis although sensitivity needs to be improved before it can be applied in clinical research. PMID- 26579480 TI - Interactions among SARS-CoV accessory proteins revealed by bimolecular fluorescence complementation assay. AB - The accessory proteins (3a, 3b, 6, 7a, 7b, 8a, 8b, 9b and ORF14), predicted unknown proteins (PUPs) encoded by the genes, are considered to be unique to the severe acute respiratory syndrome coronavirus (SARS-CoV) genome. These proteins play important roles in various biological processes mediated by interactions with their partners. However, very little is known about the interactions among these accessory proteins. Here, a EYFP (enhanced yellow fluorescent protein) bimolecular fluorescence complementation (BiFC) assay was used to detect the interactions among accessory proteins. 33 out of 81 interactions were identified by BiFC, much more than that identified by the yeast two-hybrid (Y2H) system. This is the first report describing direct visualization of interactions among accessory proteins of SARS-CoV. These findings attest to the general applicability of the BiFC system for the verification of protein-protein interactions. PMID- 26579481 TI - Quality of life after palliative radiotherapy in bone metastases: A literature review. AB - OBJECTIVE: To investigate the quality of life (QOL) following palliative radiotherapy for painful bone metastases. METHODS: A literature search was conducted in OvidSP Medline (1946-Jan Week 4 2014), Embase (1947-Week 5 2014), and the Cochrane Central Register of Controlled Trials (Dec 2013) databases. The search was limited to English. Subject headings and keywords included 'palliative radiation', 'cancer palliative therapy', 'bone metastases', 'quality of life', and 'pain'. All studies (prospective or retrospective) reporting change in QOL before and after palliative radiotherapy for painful bone metastases were included. RESULTS: Eighteen articles were selected from a total of 1730. The most commonly used tool to evaluate QOL was the Brief Pain Inventory. Seventeen studies collected data prospectively. An improvement in symptoms and functional interference scores following radiotherapy was observed in all studies. The difference in changes in QOL between responders and non responders was inconsistently reported. CONCLUSION: QOL improves in patients who respond to palliative radiotherapy for painful bone metastases. PMID- 26579482 TI - Socioeconomic and demographic factors contributing to outcomes in patients with primary lymphoma of bone. AB - BACKGROUND: Primary lymphoma of bone (PLB) is a rare disease, comprising a malignant lymphoid infiltrate of bone. The goal of this study was to identify socioeconomic, demographic, and anatomic factors as prognostic indicators of survival for this disease using the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: The SEER database was used to identify a study population of 692 patients diagnosed with PLB in the United States from 1989 to 2003. Survival was analyzed using the Kaplan-Meier method, with effects of potential prognostic factors on survival analyzed using the log-rank test. Multivariable analysis was performed by Cox proportional hazards regression. RESULTS: The overall 5-year survival rate was 49.6%, with a 10-year survival rate of 30.2%. Median overall survival was 4.9 years (95% CI: 3.9, 6.1). In multivariable analysis, age (p<0.0001), marital status (p=0.006), and appendicular vs. axial tumor location (p=0.004) were found to be independent predictors of survival. CONCLUSIONS: This population-based study of PLB identified age, marital status, and tumor location as independent indicators of prognosis. This finding supports the clinical suspicion that an appendicular tumor location confers a better prognosis than an axial tumor location. PMID- 26579484 TI - A definition of "uncomplicated bone metastases" based on previous bone metastases radiation trials comparing single-fraction and multi-fraction radiation therapy. AB - The most recent systematic review of randomized trials in patients with bone metastases has shown equal efficacy of single fraction (SF) and multiple fraction (MF) palliative radiation therapy in pain relief. It is important to determine the patient population to which the evidence applies. This study aims to examine the eligibility criteria of the studies included in the systematic review to define characteristics of "uncomplicated" bone metastases. Inclusion and exclusion criteria of 21 studies included in the systematic review were compared. Common eligibility criteria were documented in hopes of defining the specific features of a common patient population representative of those in the studies. More than half of the studies included patients with cytological or histological evidence of malignancy. Patients with impending and/or existing pathological fracture, spinal cord compression or cauda equina compression were excluded in most studies. Most studies also excluded patients receiving retreatment to the same site. "Uncomplicated" bone metastases can be defined as: presence of painful bone metastases unassociated with impending or existing pathologic fracture or existing spinal cord or cauda equina compression. Therefore, MF and SF have equal efficacy in patients with such bone metastases. PMID- 26579485 TI - Use of urinary markers in cancer setting: A literature review. AB - INTRODUCTION: In bone metastases, the disruption of normal bone processes results in increased resorption and formation rates, which can often be quantitatively measured by biomarkers in the urine and blood. The purpose of this review is to summarize relevant studies of urinary markers used as a diagnostic and/or prognostic tool, as well as its potential and advances in directing therapy. METHODS: A literature search was conducted using Ovid MEDLINE (1950 to July 2014), EMBASE (1950 to 2014 week 30) and Cochrane Central Register of Controlled Trials (3rd Quarter 2014) to identify studies that detailed the use of urinary markers in the cancer setting, specifically involving markers for bone metastases. Search terms included "urinary markers", "cancer", and "bone metastases". RESULTS: A total of 35 articles, with 24 original studies, were identified. In general, urinary markers can be used to detect early signs of bone metastases prior to skeletal imaging, but still must be used in conjunction with imaging to avoid false positive results. The use of urinary markers, such as N telopeptide, as a prognostic tool remains controversial, but can provide information on the relative risk of skeletal related events (SREs), disease progression, as well as death. Finally, while urinary markers have shown to be potentially useful in confirming the efficacy of bone metastases treatments, exploring the appropriate dosages for treatment, and directing therapy, it is still unclear to what extent urinary markers should be reduced by. CONCLUSION: The potential use of urinary markers in the management of bone metastases is promising as it can allow for earlier and more convenient detection of bone metastases in comparison to other techniques. However, additional studies involving prospective clinical trials are suggested to further examine the potential of urinary markers in developing appropriate treatment strategies and endpoints, especially in developing a clearer protocol on the extent urinary markers should be reduced by to correlate with achievement of clinical benefit. PMID- 26579483 TI - Receptor tyrosine kinases: Characterisation, mechanism of action and therapeutic interests for bone cancers. AB - Bone cancers are characterised by the development of tumour cells in bone sites, associated with a dysregulation of their environment. In the last two decades, numerous therapeutic strategies have been developed to target the cancer cells or tumour niche. As the crosstalk between these two entities is tightly controlled by the release of polypeptide mediators activating signalling pathways through several receptor tyrosine kinases (RTKs), RTK inhibitors have been designed. These inhibitors have shown exciting clinical impacts, such as imatinib mesylate, which has become a reference treatment for chronic myeloid leukaemia and gastrointestinal tumours. The present review gives an overview of the main molecular and functional characteristics of RTKs, and focuses on the clinical applications that are envisaged and already assessed for the treatment of bone sarcomas and bone metastases. PMID- 26579486 TI - Benign tumours of the bone: A review. AB - Benign tumours of the bone are not cancerous and would not metastasise to other regions of the body. However, they can occur in any part of the skeleton, and can still be dangerous as they may grow and compress healthy bone tissue. There are several types of benign tumours that can be classified by the type of matrix that the tumour cells produce; such as bone, cartilage, fibrous tissue, fat or blood vessel. Overall, 8 different types can be distinguished: osteochondroma, osteoma, osteoid osteoma, osteoblastoma, giant cell tumour, aneurysmal bone cyst, fibrous dysplasia and enchondroma. The incidence of benign bone tumours varies depending on the type. However, they most commonly arise in people less than 30 years old, often triggered by the hormones that stimulate normal growth. The most common type is osteochondroma. This review discusses the different types of common benign tumours of the bone based on information accumulated from published literature. PMID- 26579487 TI - Gorham-Stout disease of the proximal fibula treated with radiotherapy and zoledronic acid. AB - Gorham-Stout disease is a rare disease characterized by anarchic lymphovascular proliferation causing resorption of bone sometimes leading to disastrous complications. Bone tissue is progressively replaced by angiomatic and lymphangiomatic tissue and finally by fibrous tissue. This disease is known to be ubiquitous and of complex etiology. We present a case of Gorham-Stout disease of the proximal fibula invading the proximal tibia and soft tissues of the popliteal space that was successfully treated with radiotherapy and zoledronic acid. PMID- 26579488 TI - Correlation of baseline biomarkers with clinical outcomes and response to fulvestrant with vandetanib or placebo in patients with bone predominant metastatic breast cancer: An OCOG ZAMBONEY sub-study. AB - BACKGROUND: Bone metastases are common in women with breast cancer and often result in skeletal related events (SREs). As the angiogenic factor vascular endothelial growth factor (VEGF) regulates osteoclast activity and is associated with more extensive bone metastases and SRE risk in metastatic breast cancer, we hypothesized that blockade of VEGF signaling could be a therapeutic strategy for inhibiting bone metastases progression and possibly prolonging overall (OS) or progression-free survival (PFS). The Zamboney trial was a randomized placebo controlled study designed to assess whether patients with bone predominant metastatic breast cancer benefited from addition of the VEGF receptor (VEGFR) targeting agent, vandetanib, to endocrine therapy with fulvestrant. As a companion study, evaluation of biomarkers and their potential association with response to vandetanib or SRE risk was performed. METHODS: Baseline overnight fasted serum from enrolled patients was analyzed for levels of various putative biomarkers including; VEGF-A, soluble (s)VEGFR2, sVEGFR3, transforming growth factor (TGF)-beta1 and activinA by ELISA. Spearman correlation coefficients and Wilcoxon rank sum tests were used to investigate potential relationships between biomarker values and baseline clinical parameters. Prognostic and predictive ability of each marker was investigated using Cox proportional hazards regression with adjustments for treatment and baseline strata of serum CTx (<400 versus >=400 ng/L). RESULTS: Of 129 enrolled patients, serum was available for analysis in 101; 51 in vandetanib and 50 in placebo arm. Mean age amongst consenting patients was 59.8 years. Clinical characteristics were not significantly different between patients with or without serum biomarker data and serum markers were similar for patients by treatment arm. Baseline sVEGFR2 was prognostic for OS (HR=0.77, 95% CI=0.61-0.96, p=0.020), and although a modest association was observed, it was not significant for PFS (HR=0.90, 95% CI=0.80-1.01, p=0.085) nor time to first SRE (HR=0.82, 95% CI=0.66-1.02, p=0.079). When interaction terms were evaluated, sVEGFR2 was not found to be predictive of response to vandetanib, although a modest association remained with respect to PFS (interaction p=0.085). No other marker showed any significant prognostic or predictive ability with any measured outcome. CONCLUSIONS: In this clinical trial, sVEGFR2 appeared prognostic for OS, hence validation of sVEGFR2 should be conducted. Moreover, the role of sVEGFR2 in breast cancer bone metastasis progression should be elucidated. PMID- 26579489 TI - Are adjuvant bisphosphonates now standard of care of women with early stage breast cancer? A debate from the Canadian Bone and the Oncologist New Updates meeting. AB - The 9th Bone and the Oncologist New Updates conference was held in Ottawa, Canada during 2014. This annual meeting focuses on innovative research into the mechanisms and consequences of treatment-induced and metastatic bone disease. Given the recent presentation of the Oxford overview's "Effects of bisphosphonate treatment on recurrence and cause-specific mortality in women with early breast cancer: A meta-analysis of individual patient data from randomized trials" at the San Antonio Breast Cancer Symposium, a debate as to the pro's and con's of adjuvant bisphosphonate use in early stage breast cancer was undertaken. As bisphosphonate treatment in post-menopausal women appeared to demonstrate a similar magnitude of benefit to that of other commonly used adjuvant strategies the debate assessed whether or not there was sufficient data to incorporate adjuvant bisphosphonates into standard practice and if so, in which patient populations. PMID- 26579490 TI - Hyperspectral Imaging as an Early Biomarker for Radiation Exposure and Microcirculatory Damage. AB - BACKGROUND: Radiation exposure can lead to detrimental effects in skin microcirculation. The precise relationship between radiation dose received and its effect on cutaneous perfusion still remains controversial. Previously, we have shown that hyperspectral imaging (HSI) is able to demonstrate long-term reductions in cutaneous perfusion secondary to chronic microvascular injury. This study characterizes the changes in skin microcirculation in response to varying doses of ionizing radiation and investigates these microcirculatory changes as a possible early non-invasive biomarker that may correlate with the extent of long term microvascular damage. METHODS: Immunocompetent hairless mice (n = 66) were exposed to single fractions of superficial beta-irradiation in doses of 0, 5, 10, 20, 35, or 50 Gy. A HSI device was utilized to measure deoxygenated hemoglobin levels in irradiated and control areas. HSI measurements were performed at baseline before radiation exposure and for the first 3 days post-irradiation. Maximum macroscopic skin reactions were graded, and histological assessment of cutaneous microvascular densities at 4 weeks post-irradiation was performed in harvested tissue by CD31 immunohistochemistry. RESULTS: CD31 immunohistochemistry demonstrated a significant correlation (r = 0.90, p < 0.0001) between dose and vessel density reduction at 4 weeks. Using HSI analysis, early changes in deoxygenated hemoglobin levels were observed during the first 3 days post irradiation in all groups. These deoxygenated hemoglobin changes varied proportionally with dose (r = 0.98, p < 0.0001) and skin reactions (r = 0.98, p < 0.0001). There was a highly significant correlation (r = 0.91, p < 0.0001) between these early changes in deoxygenated hemoglobin and late vascular injury severity assessed at the end of 4 weeks. CONCLUSION: Radiation dose is directly correlated with cutaneous microvascular injury severity at 4 weeks in our model. Early post-exposure measurement of cutaneous deoxygenated hemoglobin levels may be a useful biomarker for radiation dose reconstruction and predictor for chronic microvascular injury. PMID- 26579491 TI - Cervical Cancer in Botswana: Current State and Future Steps for Screening and Treatment Programs. AB - Botswana has a high burden of cervical cancer due to a limited screening program and high HIV prevalence. About 60% of the cervical cancer patients are HIV positive; most present with advanced cervical disease. Through initiatives by the Botswana Ministry of Health and various strategic partnerships, strides have been made in treatment of pre-invasive and invasive cancer. The See and Treat program for cervical cancer is expanding throughout the country. Starting in 2015, school going girls will be vaccinated against HPV. In regards to treatment of invasive cancer, a multidisciplinary clinic has been initiated at the main oncology hospital to streamline care. However, challenges remain such as delays in treatment, lack of trained human personnel, limited follow-up care, and little patient education. Despite improvements in the care of pre-invasive and invasive cervical cancer patients, for declines in cervical cancer-related morbidity and mortality to be achieved, Botswana needs to continue to invest in decreasing the burden of disease and improving patient outcomes of patients with cervical cancer. PMID- 26579492 TI - Preventing Damage Limitation: Targeting DNA-PKcs and DNA Double-Strand Break Repair Pathways for Ovarian Cancer Therapy. AB - Platinum-based chemotherapy is the cornerstone of ovarian cancer treatment, and its efficacy is dependent on the generation of DNA damage, with subsequent induction of apoptosis. Inappropriate or aberrant activation of the DNA damage response network is associated with resistance to platinum, and defects in DNA repair pathways play critical roles in determining patient response to chemotherapy. In ovarian cancer, tumor cell defects in homologous recombination - a repair pathway activated in response to double-strand DNA breaks (DSB) - are most commonly associated with platinum-sensitive disease. However, despite initial sensitivity, the emergence of resistance is frequent. Here, we review strategies for directly interfering with DNA repair pathways, with particular focus on direct inhibition of non-homologous end joining (NHEJ), another DSB repair pathway. DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a core component of NHEJ and it has shown considerable promise as a chemosensitization target in numerous cancer types, including ovarian cancer where it functions to promote platinum-induced survival signaling, via AKT activation. The development of pharmacological inhibitors of DNA-PKcs is on going, and clinic-ready agents offer real hope to patients with chemoresistant disease. PMID- 26579495 TI - Editorial: Psychosocial Advances in Neuro-Oncology. PMID- 26579493 TI - Unconventional Functions of Mitotic Kinases in Kidney Tumorigenesis. AB - Human tumors exhibit a variety of genetic alterations, including point mutations, translocations, gene amplifications and deletions, as well as aneuploid chromosome numbers. For carcinomas, aneuploidy is associated with poor patient outcome for a large variety of tumor types, including breast, colon, and renal cell carcinoma. The Renal cell carcinoma (RCC) is a heterogeneous carcinoma consisting of different histologic types. The clear renal cell carcinoma (ccRCC) is the most common subtype and represents 85% of the RCC. Central to the biology of the ccRCC is the loss of function of the Von Hippel-Lindau gene, but is also associated with genetic instability that could be caused by abrogation of the cell cycle mitotic spindle checkpoint and may involve the Aurora kinases, which regulate centrosome maturation. Aneuploidy can also result from the loss of cell cell adhesion and apical-basal cell polarity that also may be regulated by the mitotic kinases (polo-like kinase 1, casein kinase 2, doublecortin-like kinase 1, and Aurora kinases). In this review, we describe the "non-mitotic" unconventional functions of these kinases in renal tumorigenesis. PMID- 26579494 TI - Immunostimulation by OX40 Ligand Transgenic Ewing Sarcoma Cells. AB - Interleukin-2 (IL-2) transgenic Ewing sarcoma cells can induce tumor specific T and NK cell responses and reduce tumor growth in vivo and in vitro. Nevertheless, the efficiency of this stimulation is not high enough to inhibit tumor growth completely. In addition to recognition of the cognate antigen, optimal T-cell stimulation requires signals from so-called co-stimulatory molecules. Several members of the tumor necrosis factor superfamily have been identified as co stimulatory molecules that can augment antitumor immune responses. OX40 (CD134) and OX40 ligand (OX40L = CD252; also known as tumor necrosis factor ligand family member 4) is one example of such receptor/ligand pair with co-stimulatory function. In the present investigation, we generated OX40L transgenic Ewing sarcoma cells and tested their immunostimulatory activity in vitro. OX40L transgenic Ewing sarcoma cells showed preserved expression of Ewing sarcoma associated (anti)gens including lipase member I, cyclin D1 (CCND1), cytochrome P450 family member 26B1 (CYP26B1), and the Ewing sarcoma breakpoint region 1 friend leukemia virus integration 1 (EWSR1-FLI1) oncogene. OX40L-expressing tumor cells showed a trend for enhanced immune stimulation against Ewing sarcoma cells in combination with IL-2 and stimulation of CD137. Our data suggest that inclusion of the OX40/OX40L pathway of co-stimulation might improve immunotherapy strategies for the treatment of Ewing sarcoma. PMID- 26579496 TI - Putative Breast Cancer Driver Mutations in TBX3 Cause Impaired Transcriptional Repression. AB - The closely related T-box transcription factors TBX2 and TBX3 are frequently overexpressed in melanoma and various types of human cancers, in particular, breast cancer. The overexpression of TBX2 and TBX3 can have several cellular effects, among them suppression of senescence, promotion of epithelial mesenchymal transition, and invasive cell motility. In contrast, loss of function of TBX3 and most other human T-box genes causes developmental haploinsufficiency syndromes. Stephens and colleagues (1), by exome sequencing of breast tumor samples, identified five different mutations in TBX3, all affecting the DNA binding T-domain. One in-frame deletion of a single amino acid, p.N212delN, was observed twice. Due to the clustering of these mutations to the T-domain and for statistical reasons, TBX3 was inferred to be a driver gene in breast cancer. Since mutations in the T-domain generally cause loss of function and because the tumorigenic action of TBX3 has generally been attributed to overexpression, we determined whether the putative driver mutations had loss- or gain-of-function properties. We tested two in-frame deletions, one missense, and one frameshift mutant protein for DNA-binding in vitro, and for target gene repression in cell culture. In addition, we performed an in silico analysis of somatic TBX mutations in breast cancer, collected in The Cancer Genome Atlas (TCGA). Both the experimental and the in silico analysis indicate that the observed mutations predominantly cause loss of TBX3 function. PMID- 26579498 TI - Disease-Free Survival at 2 and 3 Years is a Significant Early Surrogate Marker Predicting the 5-Year Overall Survival in Patients Treated with Radical Cystectomy for Urothelial Carcinoma of the Bladder: External Evaluation and Validation in a Cohort of Korean Patients. AB - PURPOSE: We aimed to externally validate the association of 2- and 3-year disease free survival (DFS) with 5-year overall survival (OS) in patients treated with radical cystectomy (RC) for urothelial carcinoma (UC) of the bladder. MATERIALS AND METHODS: We reviewed the clinical data of 422 patients who underwent RC for UC of the bladder in our institution between 1991 and 2012. Survival curves were plotted with the Kaplan-Meier method. The Kappa statistic and Kendall tau-b test were used to assess the agreements between 2- and 3-year DFS and 5-year OS. RESULTS: In the entire study population, 2- and 3-year DFS and 5-year OS rates were 76.4, 71.5, and 67.4%, respectively. All Kappa and Kendall's tau-b test values for agreements between 2- and 3-year DFS and 5-year OS were more than 0.40, indicating moderate agreement for all patients and in each patient subgroup selected according to specific variables (all p-values <0.05). Kaplan-Meier analysis for DFS and Cox-proportional hazard models for landmark analysis at each time point indicated that most recurrences occurred within 3 years after surgery. The 5-year OS rates of patients who were recurrence-free at each time point gradually increased to more than 95% in an extended recurrence-free interval of 12-36 months. CONCLUSION: Our external validation results support the existing finding that 2- and 3-year DFS can be a valid early surrogate end point to predict 5-year OS after RC in patients with UC of the bladder. PMID- 26579499 TI - Thoracic Wall Reconstruction after Tumor Resection. AB - INTRODUCTION: Surgical treatment of malignant thoracic wall tumors represents a formidable challenge. In particular, locally advanced tumors that have already infiltrated critical anatomic structures are associated with a high surgical morbidity and can result in full-thickness defects of the thoracic wall. Plastic surgery can reduce this surgical morbidity by reconstructing the thoracic wall through various tissue transfer techniques. Sufficient soft-tissue reconstruction of the thoracic wall improves quality of life and mitigates functional impairment after extensive resection. The aim of this article is to illustrate the various plastic surgery treatment options in the multimodal therapy of patients with malignant thoracic wall tumors. MATERIALS AND METHODS: This article is based on a review of the current literature and the evaluation of a patient database. RESULTS: Several plastic surgical treatment options can be implemented in the curative and palliative therapy of patients with malignant solid tumors of the chest wall. Large soft-tissue defects after tumor resection can be covered by local, pedicled, or free flaps. In cases of large full-thickness defects, flaps can be combined with polypropylene mesh to improve chest wall stability and to maintain pulmonary function. The success of modern medicine has resulted in an increasing number of patients with prolonged survival suffering from locally advanced tumors that can be painful, malodorous, or prone to bleeding. Resection of these tumors followed by thoracic wall reconstruction with viable tissue can substantially enhance the quality of life of these patients. DISCUSSION: In curative treatment regimens, chest wall reconstruction enables complete resection of locally advanced tumors and subsequent adjuvant radiotherapy. In palliative disease treatment, plastic surgical techniques of thoracic wall reconstruction provide palliation of tumor-associated morbidity and can therefore improve patients' quality of life. PMID- 26579501 TI - Editorial: Frontiers in Autoimmune Disease: Rheumatic Fever and Rheumatic Heart Disease. PMID- 26579497 TI - The Extracellular Matrix in Epithelial Ovarian Cancer - A Piece of a Puzzle. AB - Epithelial ovarian cancer is the fifth leading cause of cancer-related deaths in women and the most lethal gynecological malignancy. Extracellular matrix (ECM) is an integral component of both the normal and tumor microenvironment. ECM composition varies between tissues and is crucial for maintaining normal function and homeostasis. Dysregulation and aberrant deposition or loss of ECM components is implicated in ovarian cancer progression. The mechanisms by which tumor cells induce ECM remodeling to promote a malignant phenotype are yet to be elucidated. A thorough understanding of the role of the ECM in ovarian cancer is needed for the development of effective biomarkers and new therapies. PMID- 26579502 TI - Streptococcus bovis Bacteremia in Neonates in a Predominantly Hispanic Population. AB - BACKGROUND: Streptococcus bovis bacteremia has been associated with gastrointestinal diseases, especially colon cancer, neoplastic colon polyps, and other malignancies of the GI tract in adults. Sporadic cases of S. bovis disease have also been reported in neonates and young infants. Although uncommon, S. bovis infection can cause fulminant neonatal sepsis and meningitis. OBJECTIVES: We report a series of pediatric patients with S. bovis bacteremia in a county hospital in a United States-Mexico border city in order to examine the demographic and clinical associations. METHODS: We characterized the demographic and clinical features in all pediatric patients with blood cultures positive for S. bovis at University Medical Center in El Paso, TX, USA between January 2000 and December 2010. Hospital records were systematically reviewed by using a standardized protocol. RESULTS: A total of seven episodes of S. bovis bacteremia were documented in seven pediatric patients (four female and three male). Mean age was 1.2 days (range 1-3 days), all were Hispanic, average birth weight (3.25 kg). Mode of delivery was spontaneous vaginal delivery (five) and Caesarian section (two). All of our patients developed early (<1 week) onset disease and presented with signs of respiratory distress. Five out of seven babies presented with abdominal distention and diarrhea. Six had clinical evidence of sepsis at presentation. Respiratory distress was the most common manifestation of sepsis (seven). Aspiration pneumonia was diagnosed in two of them. Most patients were treated with a combination of antibiotics (six), either ampicillin and gentamicin or ampicillin and cefotaxime, and one with ampicillin alone. None of the pediatric patients had endoscopy and none of them died. CONCLUSION: Streptococcus bovis is considered as an uncommon pathogen in the newborn, but can be associated with substantial morbidity and mortality if not identified and treated early. Physicians should be alert to the less common presentation of neonatal bacteremia due to S. bovis. PMID- 26579503 TI - True Precocious Puberty Following Treatment of a Leydig Cell Tumor: Two Case Reports and Literature Review. AB - Leydig cell testicular tumors are a rare cause of precocious pseudopuberty in boys. Surgery is the main therapy and shows good overall prognosis. The physical signs of precocious puberty are expected to disappear shortly after surgical removal of the mass. We report two children, 7.5 and 7.7 year-old boys, who underwent testis-sparing surgery for a Leydig cell testicular tumor causing precocious pseudopuberty. During follow-up, after an immediate clinical and laboratory regression, both boys presented signs of precocious puberty and ultimately developed central precocious puberty. They were successfully treated with gonadotropin-releasing hormone (GnRH) analogs. Only six other cases have been described regarding the development of central precocious puberty after successful treatment of a Leydig cell tumor causing precocious pseudopuberty. Gonadotropin-dependent precocious puberty should be considered in children treated for a Leydig cell tumor presenting persistent or recurrent physical signs of puberty activation. In such cases, therapy with GnRH analogs appears to be the most effective medical treatment. PMID- 26579500 TI - Pathogenesis of cerebral malaria: new diagnostic tools, biomarkers, and therapeutic approaches. AB - Cerebral malaria is a severe neuropathological complication of Plasmodium falciparum infection. It results in high mortality and post-recovery neuro cognitive disorders in children, even after appropriate treatment with effective anti-parasitic drugs. While the complete landscape of the pathogenesis of cerebral malaria still remains to be elucidated, numerous innovative approaches have been developed in recent years in order to improve the early detection of this neurological syndrome and, subsequently, the clinical care of affected patients. In this review, we briefly summarize the current understanding of cerebral malaria pathogenesis, compile the array of new biomarkers and tools available for diagnosis and research, and describe the emerging therapeutic approaches to tackle this pathology effectively. PMID- 26579504 TI - Monitoring Oxygenation and Gas Exchange in Neonatal Intensive Care Units: Current Practice in the Netherlands. AB - BACKGROUND: Although recommendations in oxygenation and gas exchange monitoring in the neonatal intensive care unit (NICU) are available, little is known of the current practice. AIM: To evaluate the current practice in oxygenation and gas exchange monitoring of the NICUs in the Netherlands. METHODS: An online survey based questionnaire concerning preferences and current practice of monitoring oxygenation and gas exchange was sent out to all 107 neonatal staff members (neonatologists, neonatal fellows, and physician assistants) of the 10 NICUs in the Netherlands. RESULTS: The response rate was 42%. Pulse oximetry (PO), partial pressure of oxygen in arterial blood gas (paO2), and oxygen saturation in arterial blood gas (saO2) was used by, respectively, 100, 80, and 27% of the staff members for monitoring oxygenation. Of all staff members, 76% considered PO as the best parameter for monitoring oxygenation, 22% paO2, and 2% saO2. Blood gas, transcutaneous gas monitoring, endotracheal gas monitoring, and near infrared spectroscopy was used by, respectively, 100, 82, 40, and 18% of the staff members for monitoring gas exchange. During endotracheal ventilation, 67% of the caregivers would exclusively accept arterial blood gas for gas exchange monitoring. In contrast, during non-invasive ventilation, 68% of the caregivers did not prefer arterial or capillary blood gas (CBG). CBG is found reliable in infants with warm extremities by 76% of the caregivers. Venous blood gas would be accepted by 60% of the caregivers, independent of the mode of respiratory support, and only when venous blood sample was needed for other reasons. CONCLUSION: This survey identified a wide variation in preference in monitoring oxygenation and gas exchange monitoring among Dutch neonatal staff members. PMID- 26579505 TI - Compliance Audit of Processed Complementary Foods in Urban Ghana. AB - BACKGROUND AND OBJECTIVES: Although processed complementary foods (PCFs) can contribute to meeting dietary needs of infants and young children, it has been associated with unethical marketing practices, which undermine practice of exclusive breastfeeding for 6 months. The current study assessed PCF labeling compliance to the International Code of Marketing of Breast Milk Substitutes (CMBMS) and the National Breastfeeding Promotion Regulation (NBPR) in Ghana. METHODS: A variety of PCF were purchased from child welfare clinics, fuel station shops, supermarkets, "mother/baby" care shops, and pharmacies in the La and Osu Klottey sub-metropolitan areas in Accra. The labels were evaluated against the best practice indicators proposed by the Maternal, Infant, and Young Child Nutrition Working Group based on the international CMBMS, and also indicators based on the NBPR. An overall compliance estimate was determined based on intensity of compliance to the indicators. RESULTS: The PCF purchased included cereal-based products, fruit juices, fruit and vegetable purees, milk-based products, and combination meals; 75% of PCF were imported. One hundred of the 108 products identified were labeled in English and thus included in analysis. None of the products complied with all labeling requirements of CMBMS or NBPR; 84 and 17% of product labels complied with at least 50% of NBPR and 50% of CMBMS indicators, respectively. Only 5% of labels had content indicating importance of exclusive breastfeeding for 6 months. Additionally, only 5% of labels warned against the hazard of introducing PCF earlier than 6 months as required by the NBPR. CONCLUSION: Labeling of most PCF sold by selected retailers in Accra did not comply with NBPR and CMBMS labeling requirements. Enforcement of local law on labeling of PCF is urgently needed. PMID- 26579506 TI - Low Virologic Failure and Drug Resistance among HIV-Infected Patients Receiving Hospital-Based ART While Care and Outreach through Community in Guangxi, China. AB - OBJECTIVES: To investigate human immunodeficiency virus (HIV) virologic suppression and drug resistance among HIV-infected patients receiving first-line antiretroviral treatment (ART) in hospitals while community care and outreach through local health workers in Guangxi, China. DESIGN: This was a series of cross-sectional surveys from 2004 to 2012 in Guangxi, supported by the Chinese National HIVDR Surveillance and Monitoring Network Working Group. SETTINGS: Guangxi, China. METHODS: Demographic, ART, and laboratory data (CD4(+) cell count, viral load, and drug resistance) were analyzed. Factors associated with virologic suppression were identified by logistic regression analysis. RESULTS: A total of 780 patients were included in this study. The median treatment duration was 20.6 months (IQR 6.6-35.9). Of 780 study participants, 95.4% of patients (744/780) had HIV virologic suppression. Among these, of the 143 patients who were infected through drug injection, only 10 (7.0%) experienced virologic failure, and the overall prevalence of HIV drug resistance was 2.8% (22/789). Factors associated with virologic suppression in the final multivariate models included self-reported missing doses in the past month (compared to not missing doses in the past month, AOR = 0.2, 95% CI: 0.1-0.6) and initial ART regimen without 3TC (compared to initial ART regimen with 3TC, AOR = 0.2, 95% CI: 0.1 0.4). Moreover, the trend chi-square test showed that the proportion of virologic suppression increased over time from 2004 to 2012 (P = 0.002). CONCLUSION: This study first demonstrated that HIV patients infected through various transmission routes can achieve an excellent treatment outcome in hospitals at or above the county level for free first-line ART in Guangxi. It is an important of ART education and adherence to intervention for achieving better treatment outcomes. PMID- 26579507 TI - Issues of Unequal Access to Public Health in India. PMID- 26579508 TI - Frailty in Community-Dwelling Older People in Abu Dhabi, United Arab Emirates: A Cross-Sectional Study. AB - BACKGROUND: Frailty describes the aging-associated loss of physiological and psychological reserves, leading to an increased risk of adverse health outcomes. Many developed countries view frailty as a major priority for their health and social care systems. Less is known about frailty in less-developed countries. The purpose of this study was to determine the prevalence of frailty in a sample of community-dwelling older people in the United Arab Emirates (UAE). METHODS: This was a cross-sectional study of community-dwelling Emirati adults aged 55 years and older (n = 160) in Abu Dhabi, UAE. Data were collected at interview by questionnaire and physical measurements. Frailty was defined according to the criteria of the Fried Frailty Index. The prevalence of frailty and its association with selected independent variables were assessed. RESULTS: The overall prevalence of frailty (95% CI) was 47% (39-55). Higher levels of frailty were seen in older age groups, women, those who were non-married, those with recent hospital admission, those with comorbid conditions, those on more than five medications, and those with lower forced expiratory volume and mini-mental state examination score. After adjustment in a multiple logistic regression model, only age and gender were found to be independently associated with frailty. CONCLUSION: A high prevalence of frailty was found among older Emiratis. Given that frailty is associated with adverse health outcomes and can be a means of identifying opportunities for intervention in clinical practice and health policy, further attention and consideration within professional and public health policy circles are needed. PMID- 26579510 TI - Suberin: the biopolyester at the frontier of plants. AB - Suberin is a lipophilic macromolecule found in specialized plant cell walls, wherever insulation or protection toward the surroundings is needed. Suberized cells form the periderm, the tissue that envelops secondary stems as part of the bark, and develop as the sealing tissue after wounding or leaf abscission. Suberin is a complex polyester built from poly-functional long-chain fatty acids (suberin acids) and glycerol. The suberin acids composition of a number of plant tissues and species is now established, but how the polyester macromolecule is assembled within the suberized cell walls is not known. In the last years contributions from several areas have however significantly enriched our understanding of suberin. The primary structure of the polyester, i.e., how the suberin acids and glycerol are sequentially linked was revealed, together with the stereochemistry of the mid-chain functional groups some suberin acids have; solid-state NMR studies showed the presence of methylene chains spatially separated and with different molecular mobility; biophysical studies showed the membrane behavior of suberin acids derivatives, allowing new insights on structure-properties relationships; and a number of candidate genes were conclusively related to suberin biosynthesis. The comprehension of suberin as a macromolecule will be essential to understand its vital protective roles in plants and how they will deal with eventual environmental changes. Suberin is also expected to be a source for high-performing bio-based chemicals, taking advantage of the structural uniqueness of their constituent suberin acids. PMID- 26579509 TI - Carbon nanotube biosensors. AB - Nanomaterials possess unique features which make them particularly attractive for biosensing applications. In particular, carbon nanotubes (CNTs) can serve as scaffolds for immobilization of biomolecules at their surface, and combine several exceptional physical, chemical, electrical, and optical characteristics properties which make them one of the best suited materials for the transduction of signals associated with the recognition of analytes, metabolites, or disease biomarkers. Here we provide a comprehensive review on these carbon nanostructures, in which we describe their structural and physical properties, functionalization and cellular uptake, biocompatibility, and toxicity issues. We further review historical developments in the field of biosensors, and describe the different types of biosensors which have been developed over time, with specific focus on CNT-conjugates engineered for biosensing applications, and in particular detection of cancer biomarkers. PMID- 26579511 TI - Use of Nanostructure-Initiator Mass Spectrometry to Deduce Selectivity of Reaction in Glycoside Hydrolases. AB - Chemically synthesized nanostructure-initiator mass spectrometry (NIMS) probes derivatized with tetrasaccharides were used to study the reactivity of representative Clostridium thermocellum beta-glucosidase, endoglucanases, and cellobiohydrolase. Diagnostic patterns for reactions of these different classes of enzymes were observed. Results show sequential removal of glucose by the beta glucosidase and a progressive increase in specificity of reaction from endoglucanases to cellobiohydrolase. Time-dependent reactions of these polysaccharide-selective enzymes were modeled by numerical integration, which provides a quantitative basis to make functional distinctions among a continuum of naturally evolved catalytic properties. Consequently, our method, which combines automated protein translation with high-sensitivity and time-dependent detection of multiple products, provides a new approach to annotate glycoside hydrolase phylogenetic trees with functional measurements. PMID- 26579512 TI - Characterization of Protein-Protein Interfaces through a Protein Contact Network Approach. AB - Anthrax toxin comprises three different proteins, jointly acting to exert toxic activity: a non-toxic protective agent (PA), toxic edema factor (EF), and lethal factor (LF). Binding of PA to anthrax receptors promotes oligomerization of PA, binding of EF and LF, and then endocytosis of the complex. Homomeric forms of PA, complexes of PA bound to LF and to the endogenous receptor capillary morphogenesis gene 2 (CMG2) were analyzed. In this work, we characterized protein protein interfaces (PPIs) and identified key residues at PPIs of complexes, by means of a protein contact network (PCN) approach. Flexibility and global and local topological properties of each PCN were computed. The vulnerability of each PCN was calculated using different node removal strategies, with reference to specific PCN topological descriptors, such as participation coefficient, contact order, and degree. The participation coefficient P, the topological descriptor of the node's ability to intervene in protein inter-module communication, was the key descriptor of PCN vulnerability of all structures. High P residues were localized both at PPIs and other regions of complexes, so that we argued an allosteric mechanism in protein-protein interactions. The identification of residues, with key role in the stability of PPIs, has a huge potential in the development of new drugs, which would be designed to target not only PPIs but also residues localized in allosteric regions of supramolecular complexes. PMID- 26579513 TI - Modifications in Wheelchair Propulsion Technique with Speed. AB - OBJECTIVE: Repetitive loading of the upper limb joints during manual wheelchair (WC) propulsion (WCP) has been identified as a factor that contributes to shoulder pain, leading to loss of independence and decreased quality of life. The purpose of this study was to determine how individual manual WC users with paraplegia modify propulsion mechanics to accommodate expected increases in reaction forces (RFs) generated at the pushrim with self-selected increases in WCP speed. METHODS: Upper extremity kinematics and pushrim RFs were measured for 40 experienced manual WC users with paraplegia while propelling on a stationary ergometer at self-selected free and fast propulsion speeds. Upper extremity kinematics and kinetics were compared within subject between propulsion speeds. Between group and within-subject differences were determined (alpha = 0.05). RESULTS: Increased propulsion speed was accompanied by increases in RF magnitude (22 of 40, >10 N) and shoulder net joint moment (NJM, 15 of 40, >10 Nm) and decreases in pushrim contact duration. Within-subject comparison indicated that 27% of participants modified their WCP mechanics with increases in speed by regulating RF orientation relative to the upper extremity segments. CONCLUSIONS: Reorientation of the RF relative to the upper extremity segments can be used as an effective strategy for mitigating rotational demands (NJM) imposed on the shoulder at increased propulsion speeds. Identification of propulsion strategies that individuals can use to effectively accommodate for increases in RFs is an important step toward preserving musculoskeletal health of the shoulder and improving health-related quality of life. PMID- 26579514 TI - Prediction of Genetic Interactions Using Machine Learning and Network Properties. AB - A genetic interaction (GI) is a type of interaction where the effect of one gene is modified by the effect of one or several other genes. These interactions are important for delineating functional relationships among genes and their corresponding proteins, as well as elucidating complex biological processes and diseases. An important type of GI - synthetic sickness or synthetic lethality - involves two or more genes, where the loss of either gene alone has little impact on cell viability, but the combined loss of all genes leads to a severe decrease in fitness (sickness) or cell death (lethality). The identification of GIs is an important problem for it can help delineate pathways, protein complexes, and regulatory dependencies. Synthetic lethal interactions have important clinical and biological significance, such as providing therapeutically exploitable weaknesses in tumors. While near systematic high-content screening for GIs is possible in single cell organisms such as yeast, the systematic discovery of GIs is extremely difficult in mammalian cells. Therefore, there is a great need for computational approaches to reliably predict GIs, including synthetic lethal interactions, in these organisms. Here, we review the state-of-the-art approaches, strategies, and rigorous evaluation methods for learning and predicting GIs, both under general (healthy/standard laboratory) conditions and under specific contexts, such as diseases. PMID- 26579516 TI - Effect of Porosity of Alumina and Zirconia Ceramics toward Pre-Osteoblast Response. AB - It is acknowledged that cellular responses are highly affected by biomaterial porosity. The investigation of this effect is important for the development of implanted biomaterials that integrate with bone tissue. Zirconia and alumina ceramics exhibit outstanding mechanical properties and are among the most popular implant materials used in orthopedics, but few data exist regarding the effect of porosity on cellular responses to these materials. The present study investigates the effect of porosity on the attachment and proliferation of pre-osteoblastic cells on zirconia and alumina. For each composition, ceramics of three different porosities are fabricated by sintering, and characterized using scanning electron microscopy, energy dispersive X-ray spectroscopy and X-ray powder diffraction. Cell proliferation is quantified, and microscopy is employed to qualitatively support the proliferation results and evaluate cell morphology. Cell adhesion and metabolic activity are found comparable among low porosity zirconia and alumina. In contrast, higher porosity favors better cell spreading on zirconia and improves growth, but does not significantly affect cell response on alumina. Between the highest porosity materials, cell response on zirconia is found superior to alumina. Results show that an average pore size of ~150 MUm and ~50% porosity can be considered beneficial to cellular growth on zirconia ceramics. PMID- 26579515 TI - Immunological Approaches to Biomass Characterization and Utilization. AB - Plant biomass is the major renewable feedstock resource for sustainable generation of alternative transportation fuels to replace fossil carbon-derived fuels. Lignocellulosic cell walls are the principal component of plant biomass. Hence, a detailed understanding of plant cell wall structure and biosynthesis is an important aspect of bioenergy research. Cell walls are dynamic in their composition and structure, varying considerably among different organs, cells, and developmental stages of plants. Hence, tools are needed that are highly efficient and broadly applicable at various levels of plant biomass-based bioenergy research. The use of plant cell wall glycan-directed probes has seen increasing use over the past decade as an excellent approach for the detailed characterization of cell walls. Large collections of such probes directed against most major cell wall glycans are currently available worldwide. The largest and most diverse set of such probes consists of cell wall glycan-directed monoclonal antibodies (McAbs). These McAbs can be used as immunological probes to comprehensively monitor the overall presence, extractability, and distribution patterns among cell types of most major cell wall glycan epitopes using two mutually complementary immunological approaches, glycome profiling (an in vitro platform) and immunolocalization (an in situ platform). Significant progress has been made recently in the overall understanding of plant biomass structure, composition, and modifications with the application of these immunological approaches. This review focuses on such advances made in plant biomass analyses across diverse areas of bioenergy research. PMID- 26579517 TI - Growth of Novel Ceramic Layers on Metals via Chemical and Heat Treatments for Inducing Various Biological Functions. AB - The present authors' systematic studies on growth of novel ceramic layers on Ti metal and its alloys by chemical and heat treatments for inducing bone-bonding bioactivity and some other biological functions are reviewed. Ti metal formed an apatite on its surface in a simulated body fluid, when heat-treated after exposure to strong acid solutions to form rutile surface layer, or to strong alkali solutions to form sodium titanate surface layer. Both types of Ti metal tightly bonded to the living bone. The alkali and heat treatment was applied to the surface Ti metal of an artificial hip joint and successfully used in the clinic since 2007. The acid and heat treatments was applied to porous Ti metal to induce osteoconductivity as well as osteoinductivity. The resulting product was successfully used in clinical trials for spinal fusion devices. For the Ti-based alloys, the alkali and heat treatment was little modified to form calcium titanate surface layer. Bone-growth promoting Mg, Sr, and Zn ions as well as the antibacterial Ag ion were successfully incorporated into the calcium titanate layer. PMID- 26579518 TI - Planning the Surgical Correction of Spinal Deformities: Toward the Identification of the Biomechanical Principles by Means of Numerical Simulation. AB - In decades of technical developments after the first surgical corrections of spinal deformities, the set of devices, techniques, and tools available to the surgeons has widened dramatically. Nevertheless, the rate of complications due to mechanical failure of the fixation or the instrumentation remains rather high. Indeed, basic and clinical research about the principles of deformity correction and the optimal surgical strategies (i.e., the choice of the fusion length, the most appropriate instrumentation, and the degree of tolerable correction) did not progress as much as the implantable devices and the surgical techniques. In this work, a software approach for the biomechanical simulation of the correction of patient-specific spinal deformities aimed to the identification of its biomechanical principles is presented. The method is based on three-dimensional reconstructions of the spinal anatomy obtained from biplanar radiographic images. A user-friendly graphical user interface allows for the planning of the desired deformity correction and to simulate the implantation of pedicle screws. Robust meshing of the instrumented spine is provided by using consolidated computational geometry and meshing libraries. Based on a finite element simulation, the program is able to predict the loads and stresses acting in the instrumentation as well as those in the biological tissues. A simple test case (reduction of a low-grade spondylolisthesis at L3-L4) was simulated as a proof of concept, and showed plausible results. Despite the numerous limitations of this approach which will be addressed in future implementations, the preliminary outcome is promising and encourages a wide effort toward its refinement. PMID- 26579521 TI - Hypoxic pre-conditioning increases the infiltration of endothelial cells into scaffolds for dermal regeneration pre-seeded with mesenchymal stem cells. AB - Many therapies using mesenchymal stem cells (MSC) rely on their ability to produce and release paracrine signals with chemotactic and pro-angiogenic activity. These characteristics, however, are mostly studied under standard in vitro culture conditions. In contrast, various novel cell-based therapies imply pre-seeding MSC into bio-artificial scaffolds. Here we describe human bone marrow derived MSC seeded in Integra matrices, a common type of scaffold for dermal regeneration (SDR). We show and measured the distribution of MSC within the SDR, where cells clearly establish physical interactions with the scaffold, exhibiting constant metabolic activity for at least 15 days. In the SDR, MSC secrete VEGF and SDF-1alpha and induce transwell migration of CD34(+) hematopoietic/endothelial progenitor cells, which is inhibited in the presence of a CXCR4/SDF-1alpha antagonist. MSC in SDR respond to hypoxia by altering levels of angiogenic signals such as Angiogenin, Serpin-1, uPA, and IL-8. Finally, we show that MSC-containing SDR that have been pre-incubated in hypoxia show higher infiltration of endothelial cells after implantation into immune deficient mice. Our data show that MSC are fully functional ex vivo when implanted into SDR. In addition, our results strongly support the notion of hypoxic pre-conditioning MSC containing SDR, in order to promote angiogenesis in the wounds. PMID- 26579519 TI - Transcriptional regulators of Na,K-ATPase subunits. AB - The Na,K-ATPase classically serves as an ion pump creating an electrochemical gradient across the plasma membrane that is essential for transepithelial transport, nutrient uptake and membrane potential. In addition, Na,K-ATPase also functions as a receptor, a signal transducer and a cell adhesion molecule. With such diverse roles, it is understandable that the Na,K-ATPase subunits, the catalytic alpha-subunit, the beta-subunit and the FXYD proteins, are controlled extensively during development and to accommodate physiological needs. The spatial and temporal expression of Na,K-ATPase is partially regulated at the transcriptional level. Numerous transcription factors, hormones, growth factors, lipids, and extracellular stimuli modulate the transcription of the Na,K-ATPase subunits. Moreover, epigenetic mechanisms also contribute to the regulation of Na,K-ATPase expression. With the ever growing knowledge about diseases associated with the malfunction of Na,K-ATPase, this review aims at summarizing the best characterized transcription regulators that modulate Na,K-ATPase subunit levels. As abnormal expression of Na,K-ATPase subunits has been observed in many carcinoma, we will also discuss transcription factors that are associated with epithelial-mesenchymal transition, a crucial step in the progression of many tumors to malignant disease. PMID- 26579522 TI - Desflurane Allows for a Faster Emergence When Compared to Sevoflurane without Affecting the Baseline Cognitive Recovery Time. AB - AIMS: We compared the effect of desflurane and sevoflurane on anesthesia recovery time in patients undergoing urological cystoscopic surgery. The Short Orientation Memory-Concentration Test (SOMCT) measured and compared cognitive impairment between groups and coughing was assessed throughout the anesthetic. METHODS AND MATERIALS: This investigation included 75 ambulatory patients. Patients were randomized to receive either desflurane or sevoflurane. Inhalational anesthetics were discontinued after removal of the cystoscope and once repositioning of the patient was final. Coughing assessment and awakening time from anesthesia were assessed by a blinded observer. STATISTICAL ANALYSIS USED: Statistical analysis was performed by using t-test for parametric variables and Mann-Whitney U test for non-parametric variables. RESULTS: The primary endpoint, mean time to eye opening, was 5.0 +/- 2.5 min for desflurane and 7.9 +/- 4.1 min for sevoflurane (p < 0.001). There were no significant differences in time to SOMCT recovery (p = 0.109), overall time spent in the post-anesthesia care unit (PACU) (p = 0.924) or time to discharge (p = 0.363). Median time until readiness for discharge was 9 min in the desflurane group, while the sevoflurane group had a median time of 20 min (p = 0.020). The overall incidence of coughing during the perioperative period was significantly higher in the desflurane (p = 0.030). CONCLUSION: We re confirmed that patients receiving desflurane had a faster emergence and met the criteria to be discharged from the PACU earlier. No difference was found in time to return to baseline cognition between desflurane and sevoflurane. PMID- 26579520 TI - beta cell ER stress and the implications for immunogenicity in type 1 diabetes. AB - Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by hyperglycemia due to progressive immune-mediated destruction of insulin-producing pancreatic islet beta cells. Although many elegant studies have identified beta cell autoantigens that are targeted by the autoimmune response, the mechanisms by which these autoantigens are generated remain poorly understood. Normal beta cell physiology includes a high demand for insulin production and secretion in response to dynamic glucose sensing. This secretory function predisposes beta cells to significantly higher levels of endoplasmic reticulum (ER) stress compared to nonsecretory cells. In addition, many environmental triggers associated with T1D onset further augment this inherent ER stress in beta cells. ER stress may increase abnormal post-translational modification (PTM) of endogenous beta cell proteins. Indeed, in other autoimmune disorders such as celiac disease, systemic lupus erythematosus, multiple sclerosis, and rheumatoid arthritis, abnormally modified neo-antigens are presented by antigen presenting cells (APCs) in draining lymph nodes. In the context of genetic susceptibility to autoimmunity, presentation of neo-antigens activates auto-reactive T cells and pathology ensues. Therefore, the ER stress induced by normal beta cell secretory physiology and environmental triggers may be sufficient to generate neo-antigens for the autoimmune response in T1D. This review summarizes what is currently known about ER stress and protein PTM in target organs of other autoimmune disease models, as well as the data supporting a role for ER stress-induced neo antigen formation in beta cells in T1D. PMID- 26579523 TI - Immune Thrombocytopenic Purpura Secondary to Cytomegalovirus Infection: A Case Report. AB - Immune thrombocytopenic purpura (ITP) is defined as an acquired thrombocytopenia with antibodies detected against platelet surface antigens, and it is the most common form of thrombocytopenia in otherwise asymptomatic adults. ITP secondary to an underlying condition is a diagnosis of exclusion that is essential to establish for treatment efficacy. Secondary thrombocytopenia caused by cytomegalovirus (CMV) is common; however, case reports associated with diagnosis in immunocompetent adults are rare, and to the best of our knowledge only 20 publications have been associated with this diagnosis. Our report is based on a clinical presentation of a 37-year-old female complaining of petechiae, heavy menses, shortness of breath, and a platelet count of 1 * 10(9)/L. Treatment with IVIG and steroids failed to improve platelet count. Subsequently, an infectious laboratory workup was performed, detecting CMV infection, and treatment with antiviral agents was initiated, causing platelet count to increase as viral load decreased. PMID- 26579524 TI - The Effects of a "Health at Every Size((r))"-Based Approach in Obese Women: A Pilot-Trial of the "Health and Wellness in Obesity" Study. AB - This study explored the effects of Health at Every Size((r))-based intervention on obese women by qualitatively evaluating participants' perception toward the program and quantitatively evaluating changes related to psychological, behavioral, and body composition assessments. A prospective 1-year quasi experimental mixed-method trial was conducted. The mixed-method design was characterized by a spiral method, and quantitative and qualitative findings were combined during the interpretation phase. The qualitative data involved three focus groups; and quantitative data comprised physiological, psychological, and behavioral assessments. Initially, 30 participants were recruited; 14 concluded the intervention. From the focus groups, the following interpretative axes were constructed: the intervention as a period of discoveries; shifting parameters: psychological, physical, and behavioral changes; eating changes, and; redefining success. Body weight, body mass index, total body fat mass, and body fat percentage were significantly decreased after the intervention (-3.6, -3.2, 13.0, and -11.1%, respectively; p <= 0.05, within-time effect). Participants reported to be more physically active and perceiving better their bodies. Eating wise, participants reported that the hunger and satiety cues and the consumption of more frequent meals facilitated their eating changes. Finally, participants reported that they could identify feelings with eating choices and refrain from the restrained behavior. These qualitative improvements were accompanied by modest but significant improvements in quantitative assessments. Clinicaltrials.gov registration: NCT02102061. PMID- 26579525 TI - Validation of the Comprehensive Feeding Practices Questionnaire among Brazilian Families of School-Aged Children. AB - INTRODUCTION: Children's eating behaviors are influenced by parents, who are the first nutritional educators. The comprehensive feeding practices questionnaire (CFPQ) was developed to measure feeding practices among parents, but has not yet been validated in Brazil, where child obesity rates are steeply increasing. The aim of the study was to test the validity of the CFPQ among Brazilian parents of school-aged children and propose a new version of the instrument. METHODS: Transcultural adaptation included translation into Portuguese, back translation, content validity, testing for semantic equivalence, and piloting. Questionnaire data were obtained for 659 parents of 5- to 9-year olds. Confirmatory and exploratory factor analyses and psychometric analyses (tests for internal consistency, factor correlations, item-discriminant and convergent validity, and test-retest reliability) were conducted. RESULTS: Confirmatory factor analysis demonstrated a poor fit of the data to the original 12-factor model. Exploratory factor analysis generated a 6-factor model composed of 42 items: healthy eating guidance, monitoring, restriction for weight control, restriction for health, emotion regulation/food as reward, and pressure. This factor solution was supported by internal consistency tests (alpha = 0.71-0.91) and factor correlations (rho = -0.16 to 0.32). Item-discriminant and convergent validity tests showed that parents who used coercive practices had more overweight children and were more concerned about their child's weight (rho = 0.09-0.40). Test-retest reliability was acceptable (intraclass correlation coefficient = 0.45 0.77). CONCLUSION: Since parental practices are highly culturally and age group sensitive, it is essential to conduct careful evaluations of questionnaires when introduced into specific age groups within new cultural settings. This modified six-factor model of the CFPQ is valid to measure parental feeding behaviors of school-aged children in urban Brazilian settings. PMID- 26579526 TI - Decision Making in Double-Pedicled DIEP and SIEA Abdominal Free Flap Breast Reconstructions: An Algorithmic Approach and Comprehensive Classification. AB - INTRODUCTION: The deep inferior epigastric artery perforator free flap is the gold standard for autologous breast reconstruction. However, using a single vascular pedicle may not yield sufficient tissue in patients with midline scars or insufficient lower abdominal pannus. Double-pedicled free flaps overcome this problem using different vascular arrangements to harvest the entire lower abdominal flap. The literature is, however, sparse regarding technique selection. We therefore reviewed our experience in order to formulate an algorithm and comprehensive classification for this purpose. METHODS: All patients undergoing unilateral double-pedicled abdominal perforator free flap breast reconstruction (AFFBR) by a single surgeon (CMM) over 40 months were reviewed from a prospectively collected database. RESULTS: Of the 112 consecutive breast free flaps performed, 25 (22%) utilised two vascular pedicles. The mean patient age was 45 years (range = 27-54). All flaps, but one (which used the thoracodorsal system), were anastomosed to the internal mammary vessels using the rib preservation technique. The surgical duration was 656 min (range = 468-690 min). The median flap weight was 618 g (range = 432-1275 g) and the mastectomy weight was 445 g (range = 220-896 g). All flaps were successful and only three patients requested minor liposuction to reduce and reshape their reconstructed breasts. CONCLUSION: Bipedicled free abdominal perforator flaps, employed in a fifth of all our AFFBRs, are a reliable and safe option for unilateral breast reconstruction. They, however, necessitate clear indications to justify the additional technical complexity and surgical duration. Our algorithm and comprehensive classification facilitate technique selection for the anastomotic permutations and successful execution of these operations. LEVELS OF EVIDENCE: Therapeutic level IV. PMID- 26579527 TI - Proteomic and epigenomic markers of sepsis-induced delirium (SID). AB - In elderly population sepsis is one of the leading causes of intensive care unit (ICU) admissions in the United States. Sepsis-induced delirium (SID) is the most frequent cause of delirium in ICU (Martin et al., 2010). Together delirium and SID represent under-recognized public health problems which place an increasing financial burden on the US health care system, currently estimated at 143-152 billion dollars per year (Leslie et al., 2008). The interest in SID was recently reignited as it was demonstrated that, contrary to prior beliefs, cognitive deficits induced by this condition may be irreversible and lead to dementia (Pandharipande et al., 2013; Brummel et al., 2014). Conversely, it is construed that diagnosing SID early or mitigating its full blown manifestations may preempt geriatric cognitive disorders. Biological markers specific for sepsis and SID would facilitate the development of potential therapies, monitor the disease process and at the same time enable elderly individuals to make better informed decisions regarding surgeries which may pose the risk of complications, including sepsis and delirium. This article proposes a battery of peripheral blood markers to be used for diagnostic and prognostic purposes in sepsis and SID. Though each individual marker may not be specific enough, we believe that together as a battery they may achieve the necessary accuracy to answer two important questions: who may be vulnerable to the development of sepsis, and who may develop SID and irreversible cognitive deficits following sepsis? PMID- 26579528 TI - P2X and P2Y receptor signaling in red blood cells. AB - Purinergic signaling involves the activation of cell surface P1 and P2 receptors by extracellular nucleosides and nucleotides such as adenosine and adenosine triphosphate (ATP), respectively. P2 receptors comprise P2X and P2Y receptors, and have well-established roles in leukocyte and platelet biology. Emerging evidence indicates important roles for these receptors in red blood cells. P2 receptor activation stimulates a number of signaling pathways in progenitor red blood cells resulting in microparticle release, reactive oxygen species formation, and apoptosis. Likewise, activation of P2 receptors in mature red blood cells stimulates signaling pathways mediating volume regulation, eicosanoid release, phosphatidylserine exposure, hemolysis, impaired ATP release, and susceptibility or resistance to infection. This review summarizes the distribution of P2 receptors in red blood cells, and outlines the functions of P2 receptor signaling in these cells and its implications in red blood cell biology. PMID- 26579529 TI - A proposal for a dipole-generated BLUF domain mechanism. AB - The resting and signaling structures of the blue-light sensing using flavin (BLUF) photoreceptor domains are still controversially debated due to differences in the molecular models obtained by crystal and NMR structures. Photocycles for the given preferred structural framework have been established, but a unifying picture combining experiment and theory remains elusive. We summarize present work on the AppA BLUF domain from both experiment and theory. We focus on IR and UV/vis spectra, and to what extent theory was able to reproduce experimental data and predict the structural changes upon formation of the signaling state. We find that the experimental observables can be theoretically reproduced employing any structural model, as long as the orientation of the signaling essential Gln63 and its tautomer state are a choice of the modeler. We also observe that few approaches are comparative, e.g., by considering all structures in the same context. Based on recent experimental findings and a few basic calculations, we suggest the possibility for a BLUF activation mechanism that only relies on electron transfer and its effect on the local electrostatics, not requiring an associated proton transfer. In this regard, we investigate the impact of dispersion correction on the interaction energies arising from weakly bound amino acids. PMID- 26579530 TI - Corrigendum to "Toxicity of Graphene Shells, Graphene Oxide, and Graphene Oxide Paper Evaluated with Escherichia coli Biotests". PMID- 26579532 TI - Sexy Mouth Odour? Male Oral Gland Pheromone in the Grain Beetle Parasitoid Lariophagus distinguendus (Forster) (Hymenoptera: Pteromalidae). AB - Throughout the animal kingdom, sexual pheromones are used for the attraction of mates and as courtship signals but also enable sexual isolation between species. In the parasitic wasp Lariophagus distinguendus, male courtship behaviour consisting of wing fanning, antennal stroking of the female antenna, and head nodding stimulates female receptivity leading to copulation. Recently L. distinguendus was reported to consist of two different lineages, which are sexually isolated because males fail to elicit receptivity in foreign females. It is unclear, however, which part of the courtship behaviour triggers female receptivity and therefore could be a mechanism causing sexual isolation. Here we show that in L. distinguendus a nonvolatile male oral pheromone is essential to release the female receptivity signal. In contrast, male wing fanning and antennal contact play a minor role. Additionally, the composition of the oral pheromone depends on the developmental host and females learn the composition upon emergence from the host substrate. These results will enable more detailed work on oral sexual pheromones to answer the question of how they are involved in the speciation process of L. distinguendus and other parasitoid species, for a better understanding of the huge biodiversity in this group. PMID- 26579531 TI - Mechanism of Action of Bortezomib and the New Proteasome Inhibitors on Myeloma Cells and the Bone Microenvironment: Impact on Myeloma-Induced Alterations of Bone Remodeling. AB - Multiple myeloma (MM) is characterized by a high capacity to induce alterations in the bone remodeling process. The increase in osteoclastogenesis and the suppression of osteoblast formation are both involved in the pathophysiology of the bone lesions in MM. The proteasome inhibitor (PI) bortezomib is the first drug designed and approved for the treatment of MM patients by targeting the proteasome. However, recently novel PIs have been developed to overcome bortezomib resistance. Interestingly, several preclinical data indicate that the proteasome complex is involved in both osteoclast and osteoblast formation. It is also evident that bortezomib either inhibits osteoclast differentiation induced by the receptor activator of nuclear factor kappa B (NF-kappaB) ligand (RANKL) or stimulates the osteoblast differentiation. Similarly, the new PIs including carfilzomib and ixazomib can inhibit bone resorption and stimulate the osteoblast differentiation. In a clinical setting, PIs restore the abnormal bone remodeling by normalizing the levels of bone turnover markers. In addition, a bone anabolic effect was described in responding MM patients treated with PIs, as demonstrated by the increase in the osteoblast number. This review summarizes the preclinical and clinical evidence on the effects of bortezomib and other new PIs on myeloma bone disease. PMID- 26579533 TI - Establishment of the MethyLight Assay for Assessing Aging, Cigarette Smoking, and Alcohol Consumption. AB - The environmental factors such as aging, smoking, and alcohol consumption have been reported to influence DNA methylation (DNAm). However, the versatility of DNAm measurement by DNAm array systems is low in clinical use. Thus, we developed the MethyLight assay as a simple method to measure DNAm. In the present study, we isolated peripheral blood DNA from 33 healthy volunteers and selected cg25809905, cg02228185, and cg17861230 as aging, cg23576855 as smoking, and cg02583484 as alcohol consumption biomarkers. The predicted age by methylation rates of cg25809905 and cg17861230 significantly correlated with chronological age. In immortalized B-cells, DNAm rates of two sites showed a younger status than the chronological age of donor. On the other hand, the predicted age of the patients with myocardial infarction (MI) was not accelerated. The methylation rate of cg23576855 was able to discriminate the groups based on the smoking status. The DNAm rate of cg02583484 was reduced in subjects with habitual alcohol consumption compared to that of subjects without habitual alcohol consumption. In conclusion, our MethyLight assay system reconfirms that aging, smoking, and alcohol consumption influenced DNAm in peripheral blood in the Japanese. This MethyLight system will facilitate DNAm measurement in epidemiological and clinical studies. PMID- 26579534 TI - 3,3'-Diindolylmethane: A Promising Sensitizer of gamma-Irradiation. AB - PURPOSE: Radiotherapy is an effective treatment modality in the clinical treatment of breast cancer. The present work investigated the effect of 3,3' diindolylmethane (DIM) on gamma-irradiation sensitizing human breast carcinoma. METHODS: Cell survival, intracellular ROS levels, cell cycle distribution, cell apoptosis, and expression of proteins related to apoptosis were measured with MTT assays, flow cytometry, and Western blot analysis, respectively. RESULTS: In vitro DIM plus gamma-irradiation arrested the activity of G2/M phase cell cycle, increased intracellular ROS level, significantly suppressed PARP (poly ADP-ribose polymerase), and enhanced gamma-irradiation-induced apoptosis, thereby inhibiting the proliferation of MCF-7 cells. CONCLUSION: These data provide a rationale for the use of DIM as a promising sensitizer of gamma-irradiation. PMID- 26579535 TI - Quantitative Image Analysis of Epithelial and Stromal Area in Histological Sections of Colorectal Cancer: An Emerging Diagnostic Tool. AB - In colorectal cancer (CRC), an increase in the stromal (S) area with the reduction of the epithelial (E) parts has been suggested as an indication of tumor progression. Therefore, an automated image method capable of discriminating E and S areas would allow an improved diagnosis. Immunofluorescence staining was performed on paraffin-embedded sections from colorectal tumors (16 samples from patients with liver metastasis and 18 without). Noncancerous tumor adjacent mucosa (n = 5) and normal mucosa (n = 4) were taken as controls. Epithelial cells were identified by an anti-keratin 8 (K8) antibody. Large tissue areas (5-63 mm(2)/slide) including tumor center, tumor front, and adjacent mucosa were scanned using an automated microscopy system (TissueFAXS). With our newly developed algorithms, we showed that there is more K8-immunoreactive E in the tumor center than in tumor adjacent and normal mucosa. Comparing patients with and without metastasis, the E/S ratio decreased by 20% in the tumor center and by 40% at tumor front in metastatic samples. The reduction of E might be due to a more aggressive phenotype in metastasis patients. The novel software allowed a detailed morphometric analysis of cancer tissue compartments as tools for objective quantitative measurements, reduced analysis time, and increased reproducibility of the data. PMID- 26579536 TI - Comparison of Antibiotic Resistance and Virulence Factors among Escherichia coli Isolated from Conventional and Free-Range Poultry. AB - Microbiological contamination in commercial poultry production has caused concerns for human health because of both the presence of pathogenic microorganisms and the increase in antimicrobial resistance in bacterial strains that can cause treatment failure of human infections. The aim of our study was to analyze the profile of antimicrobial resistance and virulence factors of E. coli isolates from chicken carcasses obtained from different farming systems (conventional and free-range poultry). A total of 156 E. coli strains were isolated and characterized for genes encoding virulence factors described in extraintestinal pathogenic E. coli (ExPEC). Antimicrobial susceptibility testing was performed for 15 antimicrobials, and strains were confirmed as extended spectrum of beta-lactamases- (ESBLs-) producing E. coli by phenotypic and genotypic tests. The results indicated that strains from free-range poultry have fewer virulence factors than strains from conventional poultry. Strains from conventionally raised chickens had a higher frequency of antimicrobial resistance for all antibiotics tested and also exhibited genes encoding ESBL and AmpC, unlike free-range poultry isolates, which did not. Group 2 CTX-M and CIT were the most prevalent ESBL and AmpC genes, respectively. The farming systems of poultries can be related with the frequency of virulence factors and resistance to antimicrobials in bacteria. PMID- 26579537 TI - Molecular Imaging with MRI: Potential Application in Pancreatic Cancer. AB - Despite the variety of approaches that have been improved to achieve a good understanding of pancreatic cancer (PC), the prognosis of PC remains poor, and the survival rates are dismal. The lack of early detection and effective interventions is the main reason. Therefore, considerable ongoing efforts aimed at identifying early PC are currently being pursued using a variety of methods. In recent years, the development of molecular imaging has made the specific targeting of PC in the early stage possible. Molecular imaging seeks to directly visualize, characterize, and measure biological processes at the molecular and cellular levels. Among different imaging technologies, the magnetic resonance (MR) molecular imaging has potential in this regard because it facilitates noninvasive, target-specific imaging of PC. This topic is reviewed in terms of the contrast agents for MR molecular imaging, the biomarkers related to PC, targeted molecular probes for MRI, and the application of MRI in the diagnosis of PC. PMID- 26579538 TI - Exercise and BMI in Overweight and Obese Children and Adolescents: A Systematic Review and Trial Sequential Meta-Analysis. AB - OBJECTIVE: Determine the effects of exercise on body mass index (BMI in kg . m( 2)) among overweight and obese children and adolescents. METHODS: Trial sequential meta-analysis of randomized controlled exercise intervention trials >= 4 weeks and published up to November 11, 2014. RESULTS: Of the 5,436 citations screened, 20 studies representing 971 boys and girls were included. Average length, frequency, and duration of training were 13 weeks, 3 times per week, for 46 minutes per session. Overall, random-effects models showed that exercise decreased BMI by 3.6% (mean: -1.08; 95% CI: -0.52 to -1.64; Q = 231.4; p < 0.001; I (2) = 90.9%; 95% CI: 87.6% to 93.4%; D (2) = 91.5%). Trial sequential meta analysis showed that changes in BMI crossed the monitoring boundary for a type 1 error in 2010, remaining stable thereafter. The number needed to treat was 5 while the percentile improvement was 26.9. It was estimated that approximately 2.5 million overweight and obese children in the US and 22.0 million overweight and obese children worldwide could reduce their BMI by participating in a regular exercise program. Overall quality of evidence was rated as moderate. CONCLUSIONS: Exercise is associated with improvements in BMI among overweight and obese children and adolescents. This trial is registered with PROSPERO Trial Registration #CRD42015017586. PMID- 26579540 TI - Availability of Software-Based Correction of Mandibular Plane for the Vertical Measurement of the Mandible in Cone Beam Computed Tomography. AB - OBJECTIVES: To investigate the availability of correction of mandibular plane using software for vertical measurements in cone beam computed tomography (CBCT) according to the sites of the mandible. METHODS: CBCT scans of six dry mandibles were performed at 0-, 5-, 10-, 15-, and 20-degree angles relative to CBCT scanning table. Using the imaging software, mandibular planes of the different angles were corrected to that of 0-degree angle on the CBCT images. Before and after correction of the mandibular planes, the distance from the mandibular canal to the alveolar crest was measured at M1, M2, and M3 areas of the mandible and vertical measurements were statistically compared with those of 0-angle location using the paired t-test. RESULTS: Prior to correction, the vertical measurements increased as the angle increased. The greatest differences of measurements were observed in M3 areas (P < 0.05). After correction, a strong correlation was found in measurements between the 0-degree angle and the other angles in all sites of the mandible (P > 0.05). CONCLUSIONS: The vertical measurements of CBCT were significantly influenced by mandibular positioning. When CBCT scans are performed at angles other than 0-degree angle, software-based correction of the mandibular plane can be a reliable tool for the accurate vertical measurements in CBCT. PMID- 26579539 TI - Computational and Pharmacological Target of Neurovascular Unit for Drug Design and Delivery. AB - The blood-brain barrier (BBB) is a dynamic and highly selective permeable interface between central nervous system (CNS) and periphery that regulates the brain homeostasis. Increasing evidences of neurological disorders and restricted drug delivery process in brain make BBB as special target for further study. At present, neurovascular unit (NVU) is a great interest and highlighted topic of pharmaceutical companies for CNS drug design and delivery approaches. Some recent advancement of pharmacology and computational biology makes it convenient to develop drugs within limited time and affordable cost. In this review, we briefly introduce current understanding of the NVU, including molecular and cellular composition, physiology, and regulatory function. We also discuss the recent technology and interaction of pharmacogenomics and bioinformatics for drug design and step towards personalized medicine. Additionally, we develop gene network due to understand NVU associated transporter proteins interactions that might be effective for understanding aetiology of neurological disorders and new target base protective therapies development and delivery. PMID- 26579541 TI - Pentraxin-3 Predicts Long-Term Cardiac Events in Patients with Chronic Heart Failure. AB - The aim of this study was to investigate the long-term prognostic value of pentraxin-3 (PTX3) in patients with chronic heart failure (CHF). 377 patients were prospectively followed up for 3 years to determine cardiac events including cardiac death or rehospitalization for worsening heart failure. The plasma PTX3 levels were significantly higher in CHF patients than in healthy subjects (p < 0.001), and they increased with advancing New York Heart Association (NYHA) Functional Classification (p < 0.001). Plasma PTX3 levels in CHF patients with cardiac events were significantly higher than in event-free patients (p < 0.001). We determined the normal upper limit of plasma PTX3 levels from the mean + 2 SD value of 64 control subjects (3.64 ng/mL). A Kaplan-Meier analysis revealed that patients with increased PTX3 (>= 3.64 ng/mL) were at a higher risk for cardiac events than those without increased PTX3 (p < 0.01). A multifactorial Cox proportional hazards model showed that increased PTX3 ( >= 3.64 ngImL) was an independent risk factor for cardiac events in CHF patients (hazard ratio (HR) = 4.224, p < 0.01; 95% CI: 1.130-15.783). Plasma PTX3 levels are a long-term independent predictor of prognosis in patients with CHF. PMID- 26579542 TI - Association between Micronutrient Levels and Chronic Spontaneous Urticaria. AB - Previous reports have suggested a possible role for vitamin D in the etiology of chronic spontaneous urticaria (CSU); however, little information is available regarding the role of other micronutrients. We, therefore, analyzed vitamin D, vitamin B12, and ferritin levels in CSU patients (n = 282) from a preexisting database at Southampton General Hospital. Data were compared against mean micronutrient levels of the general population of the UK, obtained from the National Diet and Nutrition Survey. Vitamin D levels of CSU patients were found to be higher than those of the general UK population (P = 0.001). B12 levels were lower in patients with CSU (P < 0.001) than in the general population. Ferritin levels were found to be lower in male CSU patients than in the general male population (P = 0.009). This association between low B12 and iron levels and CSU might indicate a causal link, with micronutrient replacement as a potential therapeutic option. PMID- 26579543 TI - Mechanisms and Clinical Applications of Genome Instability in Multiple Myeloma. AB - Ongoing genomic instability represents a hallmark of multiple myeloma (MM) cells, which manifests largely as whole chromosome- or translocation-based aneuploidy. Importantly, although it supports tumorigenesis, progression and, response to treatment in MM patients, it remains one of the least understood components of malignant transformation in terms of molecular basis. Therefore these aspects make the comprehension of genomic instability a pioneering strategy for novel therapeutic and clinical speculations to use in the management of MM patients. Here we will review mechanisms mediating genomic instability in MM cells with an emphasis placed on pathogenic mutations affecting DNA recombination, replication and repair, telomere function and mitotic regulation of spindle attachment, centrosome function, and chromosomal segregation. We will discuss the mechanisms by which genetic aberrations give rise to multiple pathogenic events required for myelomagenesis and conclude with a discussion of the clinical applications of these findings in MM patients. PMID- 26579544 TI - A Series of Imidazole Derivatives: Synthesis, Two-Photon Absorption, and Application for Bioimaging. AB - A new series of D-pi-A type imidazole derivatives have been synthesized and characterized. Two corresponding imidazolium salts (iodine and hexafluorophosphate) were prepared from the imidazole compound. Their electron withdrawing ability can be largely tunable by salt formation reaction or ion exchange. UV-vis absorption and single-photon fluorescence spectra have been systematically investigated in different solvents. The two-photon cross sections (delta 2PA) of the imidazole derivatives are measured by two-photon excited fluorescence (2PEF) method. Compared with those of T-1 (107 GM) and T-3 (96 GM), T-2 (imidazolium iodine salt) has a large two-photon absorption (2PA) cross section value of 276 GM. Furthermore, the cytotoxicity and applications in bioimaging for the imidazole derivatives were carried out. The results showed that T-1 can be used as a lysosomal tracker with high stability and water solubility within pHs of 4-6, while T-2 and T-3 can be used as probes for cell cytoplasm. PMID- 26579545 TI - Strategies and Advancements in Harnessing the Immune System for Gastric Cancer Immunotherapy. AB - In cancer biology, cells and molecules that form the fundamental components of the tumor microenvironment play a major role in tumor initiation, and progression as well as responses to therapy. Therapeutic approaches that would enable and harness the immune system to target tumor cells mark the future of anticancer therapy as it could induce an immunological memory specific to the tumor type and further enhance tumor regression and relapse-free survival in cancer patients. Gastric cancer is one of the leading causes of cancer-related mortalities that has a modest survival benefit from existing treatment options. The advent of immunotherapy presents us with new approaches in gastric cancer treatment where adaptive cell therapies, cancer vaccines, and antibody therapies have all been used with promising outcomes. In this paper, we review the current advances and prospects in the gastric cancer immunotherapy. Special focus is laid on new strategies and clinical trials that attempt to enhance the efficacy of various immunotherapeutic modalities in gastric cancer. PMID- 26579546 TI - HIV Vaccine: Recent Advances, Current Roadblocks, and Future Directions. AB - HIV/AIDS is a leading cause of mortality and morbidity worldwide. In spite of successful interventions and treatment protocols, an HIV vaccine would be the ultimate prevention and control strategy. Ever since identification of HIV/AIDS, there have been meticulous efforts for vaccine development. The specific aim of this paper is to review recent vaccine efficacy trials and associated advancements and discuss the current challenges and future directions. Recombinant DNA technologies greatly facilitated development of many viral products which were later incorporated into vectors for effective vaccines. Over the years, a number of scientific approaches have gained popularity and include the induction of neutralizing antibodies in late 1980s, induction of CD8 T cell in early 1990s, and combination approaches currently. Scientists have hypothesized that stimulation of right sequences of somatic hypermutations could induce broadly reactive neutralizing antibodies (bnAbs) capable of effective neutralization and viral elimination. Studies have shown that a number of host and viral factors affect these processes. Similarly, eliciting specific CD8 T cells immune responses through DNA vaccines hold future promises. In summary, future studies should focus on the continuous fight between host immune responses and ever-evasive viral factors for effective vaccines. PMID- 26579548 TI - Microfluidics and cancer analysis: cell separation, cell/tissue culture, cell mechanics, and integrated analysis systems. AB - Among the growing number of tools available for cancer studies, microfluidic systems have emerged as a promising analytical tool to elucidate cancer cell and tumor function. Microfluidic methods to culture cells have created approaches to provide a range of environments from single-cell analysis to complex three dimensional devices. In this review we discuss recent advances in tumor cell culture, cancer cell analysis, and advanced studies enabled by microfluidic systems. PMID- 26579547 TI - Regulation of Neutrophil Degranulation and Cytokine Secretion: A Novel Model Approach Based on Linear Fitting. AB - Neutrophils participate in the maintenance of host integrity by releasing various cytotoxic proteins during degranulation. Due to recent advances, a major role has been attributed to neutrophil-derived cytokine secretion in the initiation, exacerbation, and resolution of inflammatory responses. Because the release of neutrophil-derived products orchestrates the action of other immune cells at the infection site and, thus, can contribute to the development of chronic inflammatory diseases, we aimed to investigate in more detail the spatiotemporal regulation of neutrophil-mediated release mechanisms of proinflammatory mediators. Purified human neutrophils were stimulated for different time points with lipopolysaccharide. Cells and supernatants were analyzed by flow cytometry techniques and used to establish secretion profiles of granules and cytokines. To analyze the link between cytokine release and degranulation time series, we propose an original strategy based on linear fitting, which may be used as a guideline, to (i) define the relationship of granule proteins and cytokines secreted to the inflammatory site and (ii) investigate the spatial regulation of neutrophil cytokine release. The model approach presented here aims to predict the correlation between neutrophil-derived cytokine secretion and degranulation and may easily be extrapolated to investigate the relationship between other types of time series of functional processes. PMID- 26579549 TI - A strategy for enhanced antibacterial activity against Staphylococcus aureus by the assembly of alamethicin with a thermo-sensitive polymeric carrier. AB - We demonstrate here a strategy for enhanced antibacterial activity against microbial strains by the assembly of antimicrobial peptides with a temperature responsive polymeric carrier. The assembly complex was less toxic to human cells and more stable to enzymatic cleavage. This work may provide a promising drug delivery system for antimicrobial peptides. PMID- 26579550 TI - Visualization of ion transport in Nafion using electrochemical strain microscopy. AB - The electromechanical response of a Nafion membrane immersed in water was probed using electrochemical strain microscopy (ESM) to redistribute protons and measure the resulting local strain that is caused by the movement of protons. We also measured the relaxation of protons from the surface resulting from proton diffusion. Using this technique, we can visualize and analyze the local strain change resulting from the redistribution and relaxation of hydrated protons. PMID- 26579551 TI - Synthesis of highly white-fluorescent Cu-Ga-S quantum dots for solid-state lighting devices. AB - The synthesis of highly efficient, white-emitting Cu-Ga-S quantum dots (QDs), which possess not only sufficiently wide spectral coverage of blue-to-red but an exceptional quantum yield as high as 75%, is demonstrated. These QDs are further applied as down-converters with a near-UV light-emitting diode (LED) for the fabrication of white QD-LEDs. PMID- 26579552 TI - Rational design of SnO2@C nanocomposites for lithium ion batteries by utilizing adsorption properties of MOFs. AB - A facile synthetic strategy is developed to prepare mono-dispersed SnO2 particles within three-dimensional porous carbon frameworks by utilizing the adsorption properties of metal-organic frameworks. This composite exhibits a high reversible capacity of 900 mA h g(-1) at 100 mA g(-1) after 50 cycles, with a stable capacity retention of 880 mA h g(-1) at 100 mA g(-1) even after 200 cycles. PMID- 26579554 TI - Low-Temperature Synthesis of a TiO2/Si Heterojunction. AB - The classical SiO2/Si interface, which is the basis of integrated circuit technology, is prepared by thermal oxidation followed by high temperature (>800 degrees C) annealing. Here we show that an interface synthesized between titanium dioxide (TiO2) and hydrogen-terminated silicon (H:Si) is a highly efficient solar cell heterojunction that can be prepared under typical laboratory conditions from a simple organometallic precursor. A thin film of TiO2 is grown on the surface of H:Si through a sequence of vapor deposition of titanium tetra(tert-butoxide) (1) and heating to 100 degrees C. The TiO2 film serves as a hole-blocking layer in a TiO2/Si heterojunction solar cell. Further heating to 250 degrees C and then treating with a dilute solution of 1 yields a hole surface recombination velocity of 16 cm/s, which is comparable to the best values reported for the classical SiO2/Si interface. The outstanding performance of this heterojunction is attributed to Si-O-Ti bonding at the TiO2/Si interface, which was probed by angle resolved X-ray photoelectron spectroscopy. Attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) showed that Si-H bonds remain even after annealing at 250 degrees C. The ease and scalability of the synthetic route employed and the quality of the interface it provides suggest that this surface chemistry has the potential to enable fundamentally new, efficient silicon solar cell devices. PMID- 26579553 TI - SR2067 Reveals a Unique Kinetic and Structural Signature for PPARgamma Partial Agonism. AB - Synthetic full agonists of PPARgamma have been prescribed for the treatment of diabetes due to their ability to regulate glucose homeostasis and insulin sensitization. While the use of full agonists of PPARgamma has been hampered due to severe side effects, partial agonists have shown promise due to their decreased incidence of such side effects in preclinical models. No kinetic information has been forthcoming in regard to the mechanism of full versus partial agonism of PPARgamma to date. Here, we describe the discovery of a partial agonist, SR2067. A co-crystal structure obtained at 2.2 A resolution demonstrates that interactions with the beta-sheet are driven exclusively via hydrophobic interactions mediated through a naphthalene group, an observation that is unique from other partial agonists. Surface plasmon resonance revealed that SR2067 binds to the receptor with higher affinity (KD = 513 nM) as compared to that of full agonist rosiglitazone, yet it has a much slower off rate compared to that of rosiglitazone. PMID- 26579555 TI - Pressure-Induced Oriented Attachment Growth of Large-Size Crystals for Constructing 3D Ordered Superstructures. AB - Oriented attachment (OA), a nonclassical crystal growth mechanism, provides a powerful bottom-up approach to obtain ordered superstructures, which also demonstrate exciting charge transmission characteristic. However, there is little work observably pronouncing the achievement of 3D OA growth of crystallites with large size (e.g., submicrometer crystals). Here, we report that SnO2 3D ordered superstructures can be synthesized by means of a self-limited assembly assisted by OA in a designed high-pressure solvothermal system. The size of primary building blocks is 200-250 nm, which is significantly larger than that in previous results (normally <10 nm). High pressure plays the key role in the formation of 3D configuration and fusion of adjacent crystals. Furthermore, this high-pressure strategy can be readily expanded to additional materials. We anticipate that the welded structures will constitute an ideal system with relevance to applications in optical responses, lithium ion battery, solar cells, and chemical sensing. PMID- 26579556 TI - LDA-Promoted Synthesis of 3-Amino Furans by Selective Lithiation of Enaminones. AB - An efficient cascade beta-metalation/addition/cyclization reaction promoted by LDA is described in which 3-amino furans were constructed from enaminones and aldehydes. A broad range of substituents on the starting compounds was tolerated, and the polysubstituted furans were gained with moderate to excellent yields within 2 h. PMID- 26579557 TI - Is High Sexual Desire a Risk for Women's Relationship and Sexual Well-Being? AB - Historically, women's sexual desire has been deemed socially problematic. The growing popularity of the concept of hypersexuality-which lists high sexual desire among its core components-poses a risk of re-pathologizing female sexual desire. Data from a 2014 online survey of 2,599 Croatian women aged 18-60 years was used to examine whether high sexual desire is detrimental to women's relationship and sexual well-being. Based on the highest scores on an indicator of sexual desire, 178 women were classified in the high sexual desire (HSD) group; women who scored higher than one standard deviation above the Hypersexual Disorder Screening Inventory mean were categorized in the hypersexuality (HYP) group (n = 239). Fifty-seven women met the classification criteria for both groups (HYP&HSD). Compared to other groups, the HSD was the most sexually active group. Compared to controls, the HYP and HYP&HSD groups-but not the HSD group reported significantly more negative consequences associated with their sexuality. Compared to the HYP group, women with HSD reported better sexual function, higher sexual satisfaction, and lower odds of negative behavioral consequences. The findings suggest that, at least among women, hypersexuality should not be conflated with high sexual desire and frequent sexual activity. PMID- 26579558 TI - Desulfovibrio vulgaris Growth Coupled to Formate-Driven H2 Production. AB - Formate is recognized as a superior substrate for biological H2 production by several bacteria. However, the growth of a single organism coupled to this energetic pathway has not been shown in mesophilic conditions. In the present study, a bioreactor with gas sparging was used, where we observed for the first time that H2 production from formate can be coupled with growth of the model sulfate-reducing bacterium Desulfovibrio vulgaris in the absence of sulfate or a syntrophic partner. In these conditions, D. vulgaris had a maximum growth rate of 0.078 h(-1) and a doubling time of 9 h, and the DeltaG of the reaction ranged between -21 and -18 kJ mol(-1). This is the first report of a single mesophilic organism that can grow while catalyzing the oxidation of formate to H2 and bicarbonate. Furthermore, high volumetric and specific H2 production rates (125 mL L(-1) h(-1) and 2500 mL gdcw(-1) h(-1)) were achieved in a new bioreactor designed and optimized for H2 production. This high H2 production demonstrates that the nonconventional H2-producing organism D. vulgaris is a good biocatalyst for converting formate to H2. PMID- 26579559 TI - Centrifugation-Assisted Single-Cell Trapping in a Truncated Cone-Shaped Microwell Array Chip for the Real-Time Observation of Cellular Apoptosis. AB - Microfluidic devices have been extensively used in single-cell assays. However, most of them have complicated structures (multiple layers, valves, and channels) and require the assistance of a pump or pressure-controlling system. In this paper, we present a facile centrifugation-assisted single-cell trapping (CAScT) approach based on a truncated cone-shaped microwell array (TCMA) chip for real time observation of cellular apoptosis. Our method requires neither a pump nor a pressure-controlling system, and it greatly reduces the complexity of other cell trapping devices. This method is so fast and efficient that single-cell occupancy could reach approximately 90% within a few seconds. Combined with modern fluorescence microscopy, CAScT makes the highly ordered and addressable TCMA a high-throughput platform (10(4)-10(5) single-cell trapping sites per cm(2)) for single-cell analysis. Cells trapped in it could be exposed to various chemicals by directly immersing it in bulk solutions without the significant loss of cells due to the truncated cone shape of the microwells. As a proof of concept, we demonstrated the ability of our chip for the real-time observation of the apoptosis of single HeLa cells induced by the common anticancer drug doxorubicin. This simple, robust, and efficient approach possesses great potential in diverse applications, such as drug screening, biosensing, and fundamental biological research. PMID- 26579560 TI - N-MOSFETs Formed on Solid Phase Epitaxially Grown GeSn Film with Passivation by Oxygen Plasma Featuring High Mobility. AB - Solid phase epitaxially grown GeSn was employed as the platform to assess the eligibility of direct O2 plasma treatment on GeSn surface for passivation of GeSn N-MOSFETs. It has been confirmed that O2 plasma treatment forms a GeSnO(x) film on the surface and the GeSnO(x) topped by in situ Al2O3 constitutes the gate stack of GeSn MOS devices. The capability of the surface passivation was evidenced by the low interface trap density (D(it)) of 1.62 * 10(11) cm(-2) eV( 1), which is primarily due to the formation of Ge-O and Sn-O bonds at the surface by high density/reactivity oxygen radicals that effectively suppress dangling bonds and decrease gap states. The good D(it) not only makes tiny frequency dispersion in the characterization of GeSn MOS capacitors, but results in GeSn N MOSFETs with outstanding peak electron mobility as high as 518 cm(2)/(V s) which outperforms other devices reported in the literature due to reduced undesirable carrier scattering. In addition, the GeSn N-MOSFETs also exhibit promising characteristics in terms of acceptable subthreshold swing of 156 mV/dec and relatively large I(ON)/I(OFF) ratio more than 4 orders. Moreover, the robust reliability in terms small V(t) variation against high field stress attests the feasibility of using the O2 plasma-treated passivation to advanced GeSn technology. PMID- 26579561 TI - Economic evaluation of schema therapy and clarification-oriented psychotherapy for personality disorders: a multicenter, randomized controlled trial. AB - PURPOSE: To compare from a societal perspective the cost-effectiveness and cost utility of schema therapy, clarification-oriented psychotherapy, and treatment as usual for patients with avoidant, dependent, obsessive-compulsive, paranoid, histrionic, and/or narcissistic personality disorder. METHOD: A multicenter, randomized controlled trial, single-blind parallel design, was conducted between May 2006 and December 2011 in 12 Dutch mental health institutes. Data from 320 patients (diagnosed according to DSM-IV criteria) randomly assigned to schema therapy (n = 145), treatment as usual (n = 134), or clarification-oriented psychotherapy (n = 41) were analyzed. Costs were repeatedly measured during 36 months by interview and patient registries. Primary outcome measures were proportion of recovered patients as measured with the Structured Clinical Interview for DSM-IV Axis II Personality Disorders for the cost-effectiveness analysis, and quality-adjusted life-years (QALYs) for the cost-utility analysis. Bootstrap replications in the cost-effectiveness and the cost-utility planes were used to estimate the probability that one treatment was more cost-effective than the other. Mixed gamma regression on net monetary benefit for different levels of willingness to pay for extra effects was used as sensitivity analysis. Additional sensitivity analyses were done to assess robustness of the results. RESULTS: Due to higher clinical effects and lower costs, schema therapy was dominant over the other treatments in the cost-effectiveness analyses. Schema therapy has the probability of being the most cost-effective treatment (78% at ?0 to 96% at ?37,500 [$27,375] willingness to pay per extra recovery). Treatment as usual was more cost-effective than clarification-oriented psychotherapy due to lower costs. In the cost-utility analysis, schema therapy had a stable 75% probability of being cost-effective. Sensitivity analyses confirmed these findings. CONCLUSIONS: The results support the cost-effectiveness of schema therapy but not of clarification-oriented psychotherapy. TRIAL REGISTRATION: Netherlands Trial Register NTR566. PMID- 26579562 TI - Dexamethasone Suppression FDG PET/CT for Differentiating between True- and False Positive Pulmonary and Mediastinal Lymph Node Metastases in Non-Small Cell Lung Cancer: A Pilot Study of FDG PET/CT after Oral Administration of Dexamethasone. AB - PURPOSE: To examine whether dexamethasone suppression can reduce fluorine 18 fluorodeoxyglucose (FDG) uptake in false-positive (FP) findings in pulmonary and mediastinal lymph nodes in non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Institutional ethics review board approved this prospective study with written informed consent. The study population was composed of 17 patients with NSCLC who underwent both baseline and dexamethasone suppression (24 hours after oral administration of 8 mg dexamethasone) FDG positron emission tomography/computed tomography and surgery. FDG uptake was evaluated by using a five-point visual scoring system (negative findings, score of 0-1; positive findings, score of 2-4) and maximum standardized uptake value (SUVmax). The Mann Whitney U, Wilcoxon signed-rank, Kruskal-Wallis, or Spearman rank correlation tests were used as necessary for statistical evaluations. RESULTS: In 17 primary lesions, no significant difference was noted in visual score between baseline (mean, 3.4 +/- 1.2) and dexamethasone suppression scans (mean, 3.3 +/- 1.2; P = .16), although SUVmax was significantly lower on dexamethasone suppression scans (mean, 7.1 +/- 5.2) than on baseline scans (mean, 8.6 +/- 6.6; P = .005). In eight nodes with true-positive (TP) findings, there were no significant differences in visual score (mean for both, 3.8 +/- 0.5) and SUVmax (mean, 5.3 +/ 2.3 vs 5.5 +/- 2.5, respectively; P = .81) between baseline and dexamethasone suppression scans. In 19 nodes with FP findings at baseline, dexamethasone suppression resulted in significantly lowered visual score (mean, 3.4 +/- 0.6 vs 2.4 +/- 0.8, respectively; P < .001) and SUVmax (mean, 3.5 +/- 0.8 vs 2.7 +/- 0.7, respectively; P < .001), and four nodes with FP findings were rated as true negative findings on dexamethasone suppression scans, which resulted in a significant difference in SUVmax between nodal lesions with TP and FP findings (P = .014). CONCLUSION: Oral dexamethasone has the potential to reduce FDG uptake in pulmonary and mediastinal nodes with FP findings in NSCLC. PMID- 26579563 TI - Effect of Radiofrequency Transmit Field Correction on Quantitative Dynamic Contrast-enhanced MR Imaging of the Breast at 3.0 T. AB - PURPOSE: To investigate the effects of radiofrequency transmit field (B1(+)) correction on (a) the measured T1 relaxation times of normal breast tissue and malignant lesions and (b) the pharmacokinetically derived parameters of malignant breast lesions at 3 T. MATERIALS AND METHODS: Ethics approval and informed consent were obtained. Between May 2013 and January 2014, 30 women (median age, 58 years; range, 32-83 years) with invasive ductal carcinoma of at least 10 mm were recruited to undergo dynamic contrast material-enhanced magnetic resonance (MR) imaging before surgery. B1(+) and T1 mapping sequences were performed to determine the effect of B1(+) correction on the native tissue relaxation time (T10) of fat, parenchyma, and malignant lesions in both breasts. Pharmacokinetic parameters were calculated before and after correction for B1(+) variations. Results were correlated with histologic grade by using the Kruskal-Wallis test. RESULTS: Measurements showed a mean 37% flip angle difference between the right and left breast, which resulted in a 61% T10 difference in fat and a 41.5% difference in parenchyma between the two breasts. The T1 of lesions in the right breast increased by 58%, whereas that of lesions in the left breast decreased by 30% after B1(+) correction. The whole-tumor transendothelial permeability across the vascular compartment(K(trans)) of lesions in the right breast decreased by 41%, and that of lesions in the left breast increased by 46% after correction. A systematic increase in K(trans) was observed, with significant differences found across the histologic grades (P < .001). The effect size of B1(+) correction on K(trans) calculation was large for lesions in the right breast and moderate for lesions in the left breast (Cohen effect size, d = 0.86 and d = 0.59, respectively). CONCLUSION: B1(+) correction demonstrates a substantial effect on the results of quantitative dynamic contrast-enhanced analysis of breast tissue at 3 T, which propagates into the pharmacokinetic analysis of tumors that is dependent on whether the tumor is located in the right or left breast. PMID- 26579564 TI - MR Perfusion-derived Hemodynamic Parametric Response Mapping of Bevacizumab Efficacy in Recurrent Glioblastoma. AB - PURPOSE: To better understand the effect of bevacizumab therapy on tumor blood flow and oxygenation status in patients with recurrent glioblastoma. MATERIALS AND METHODS: Retrospective data evaluation was approved by the local ethics committee of the University of Heidelberg (ethics approval number, S-320/2012), and informed consent was waived. A total of 71 patients who received a diagnosis of recurrent glioblastoma underwent conventional anatomic magnetic resonance (MR) imaging and dynamic susceptibility contrast material-enhanced MR imaging at baseline and at the first follow-up examination after initiation of bevacizumab therapy. Parametric response maps (PRMs) were created with multistep (nonlinear) registration of patients' post- to pretreatment images and voxel-wise subtraction between Gaussian-normalized relative cerebral blood volume (nrCBV) and Gaussian normalized relative cerebral blood flow (nrCBF) maps. Intratumor voxels were stratified as being increased (PRM[+]) or decreased (PRM[-]) if they exceeded a threshold that represented the 95% confidence interval in the normal-appearing brain. Correlation with progression-free and overall survival was performed with Cox proportional hazards models. RESULTS: The risks for disease progression and death significantly increased with (a) higher baseline nrCBV (hazard ratio [HR] = 1.86, P < .01; HR = 1.52, P < .01) and nrCBF (HR = 1.78, P < .01; HR = 1.86, P < .01) values and (b) higher PRM(-) of nrCBV (HR = 1.03, P = .01; HR = 1.02, P = .03) and nrCBF (HR = 1.04, P < .01; HR = 1.03, P < .01), but not with higher PRM(+) of nrCBV and nrCBF, and not for the relative change in mean nrCBV and nrCBF, confirming the superiority of the PRM approach. The magnitude of PRM(-) for both nrCBV and nrCBF significantly increased for higher baseline values (P < .01). CONCLUSION: Pretreatment hemodynamic parameters are the principal determinant of response to bevacizumab therapy in patients with recurrent glioblastoma. Although the magnitude of PRM(-) is a function of the corresponding pretreatment parameter, the finding of higher PRM(-) and a lack of change in PRM(+) in nonresponders to bevacizumab therapy implies that tumors with a high degree of angiogenesis before bevacizumab therapy retain a higher level of angiogenesis during therapy, despite a greater antiangiogenic effect of bevacizumab, such that a reversal of the biologic behavior and relative prognosis of these tumors does not occur. PMID- 26579565 TI - Ordering in Polymer Micelle-Directed Assemblies of Colloidal Nanocrystals. AB - Assembly of presynthesized nanocrystals by block copolymer micelles can be rationalized by the incorporation of nanocrystals into micellar coronas of constant width. As determined by quantitative analysis using small-angle X-ray scattering, high loading of small nanocrystals yields composites exhibiting order on two length scales, whereas intermediate loading of nanocrystals larger than the coronal width produces single nanocrystal networks. The resulting structures obey expectations of thermodynamically driven assembly on the nanocrystal length scale, whereas kinetically frozen packing principles dictate order on the polymer micelle length scale. PMID- 26579566 TI - Co-localization of glutamic acid decarboxylase and vesicular GABA transporter in cytochrome oxidase patches of macaque striate cortex. AB - The patches in primary visual cortex constitute hot spots of metabolic activity, manifested by enhanced levels of cytochrome oxidase (CO) activity. They are also labeled preferentially by immunostaining for glutamic acid decarboxylase (GAD), gamma-aminobutyric acid (GABA), and parvalbumin. However, calbindin shows stronger immunoreactivity outside patches. In light of this discrepancy, the distribution of the vesicular GABA transporter (VGAT) was examined in striate cortex of two normal macaques. VGAT immunoreactivity was strongest in layers 4B, 4Calpha, and 5. In tangential sections, the distribution of CO, GAD, and VGAT was compared in layer 2/3. There was a close match between all three labels. This finding indicates that GABA synthesis is enriched in patches, and that inhibitory synapses are more active in patches than interpatches. PMID- 26579567 TI - Enhanced stability and dermal delivery of hydroquinone using solid lipid nanoparticles. AB - Hydroquinone (HQ), a well-known anti-hyperpigmentation agent suffers from (a) instability due to rapid oxidation, (b) insufficient skin penetration because of hydrophilic structure, and (c) severe side effects as a results of systemic absorption. This study aimed to load HQ into solid lipid nanoparticles (SLNs) to overcome the mentioned drawbacks for the efficient treatment of hyperpigmentation. The optimized SLN formulation was prepared by hot melt homogenization method and fully characterized by various techniques. The ability of SLNs in dermal delivery of HQ was assessed through the excised rat skin. The optimized HQ-loaded SLNs (particle size of 86 nm, encapsulation efficiency% of 89.5% and loading capacity% of 11.2%) exhibited a good physicochemical stability during a period of five months. XRD and DSC results showed that HQ was dispersed in an amorphous state, confirming uniform drug dispersion in the SLNs structure and embedment of drug in the solid lipid matrix. In vitro penetration studies showed almost 3 times higher drug accumulation in the skin and 6.5 times lower drug entrance to receiving compartment of Franz diffusion cell from HQ-loaded SLN hydrogel compared with HQ Carbopol made hydrogel. These results indicated the better HQ localization in the skin and its lower systemic absorption. It was concluded that SLN is a promising colloidal drug carrier for topical administration of HQ in the treatment of hyperpigmentation due to suitable HQ loading value in spite of its hydrophilic structure, high stability against oxidation and appropriate skin penetration along with the low systemic absorption. PMID- 26579568 TI - New aspects of pathogenesis of atrial fibrillation: remodelling of intercalated discs. AB - This review deals with the understanding of the role of key factors of ageing, oxidative stress and inflammation, in relation to development of age-related cardiovascular disease, atrial fibrillation. Increased production of reactive oxygen species and systemic inflammation promote cardiac structural and electrophysiologic remodeling that is crucial with respect to development and sustaining of atrial fibrillation. Data suggest that alterations in atrial connexin-43 and/or connexin-40 expression, phosphorylation and distribution affect cell-to-cell electrical coupling and molecular signalling that is proarrhythmogenic. However, studies showing causal relationship in the context of pathogenesis of atrial fibrillation are still scarce. Nevertheless, gap junctional connexin channels are considered as targets for arrhythmia prevention and therapeutic interventions aimed at mitochondria-related reactive oxygen species appear to be challenging. In addition, ageing is accompanied by abnormalities in adhesive junctions that most likely promote asynchronous contraction and arrhythmias. It is consistent with recent data that highlight a new perspective in regulation of intercalated disc function via adhesive junctions, fascia adherens and desmosomes. The crosstalk between adhesive and gap junctions is suggested to be implicated in pathogenesis of arrhythmias. On the other hand, modulation of adhesive proteins, N-cadherin and catenin may be promising tool aimed to synchronize heart function. Despite the progress in this field many questions remain to be answered by further research. PMID- 26579569 TI - Involvement of microRNAs in the inflammatory pathways of pulmonary sarcoidosis. AB - Sarcoidosis is a multi-organ disease in which affected tissues are invaded with non-necrotizing granulomatous structures, mostly consisted of T helper 1 (Th1) cells and multinucleate giant cells. However, the etiology and pathogenesis of sarcoidosis is not known and the diagnosis is usually based on clinical examination involving radiography and histopathological analysis of biopsies of affected organs. Although the knowledge on the molecular background of sarcoidosis is limited, it seems that the important pathways involve transforming growth factor-beta (TGF-beta) and JAK/STAT, which may influence the interferon gamma (IFN-gamma)-mediated signaling. Additionally, recently the role of microRNAs (miRNAs), the small non-coding RNA molecules, has been emphasized in different pathological conditions including autoimmune diseases. This review summarizes the current knowledge on the molecular pathways in the pathogenesis of sarcoidosis with a special emphasis on cytokines and miRNAs controlling immune cells proliferation and differentiation. Moreover, the possible role of T regulatory cells (CD4(+) CD25(+) FoxP3(+)) in this disease has been discussed. PMID- 26579570 TI - Melatonin in the thyroid gland: regulation by thyroid-stimulating hormone and role in thyroglobulin gene expression. AB - Melatonin is an indoleamine with multiple functions in both plant and animal species. In addition to data in literature describing many other important roles for melatonin, such as antioxidant, circadian rhythm controlling, anti-aging, antiproliferative or immunomodulatory activities, our group recently reported that thyroid C-cells synthesize melatonin and suggested a paracrine role for this molecule in the regulation of thyroid activity. To discern the role played by melatonin at thyroid level and its involvement in the hypothalamic-pituitary thyroid axis, in the present study we have analyzed the effect of thyrotropin in the regulation of the enzymatic machinery for melatonin biosynthesis in C cells as well as the effect of melatonin in the regulation of thyroid hormone biosynthesis in thyrocytes. Our results show that the key enzymes for melatonin biosynthesis (AANAT and ASMT) are regulated by thyroid-stimulating hormone. Furthermore, exogenous melatonin increases thyroglobulin expression at mRNA and protein levels on cultured thyrocytes and this effect is not strictly mediated by the upregulation of TTF1 or, noteworthy, PAX8 transcription factors. The present data show that thyroid C-cells synthesize melatonin under thyroid-stimulating hormone control and, consistently with previous data, support the hypothesis of a paracrine role for C-cell-synthesised melatonin within the thyroid gland. Additionally, in the present study we show evidence for the involvement of melatonin in thyroid function by directly-regulating thyroglobulin gene expression in follicular cells. PMID- 26579571 TI - The assessment of serum concentration of adiponectin, leptin and serum carbohydrate antigen-19.9 in patients with pancreatic cancer and chronic pancreatitis. AB - Pancreatic cancer and chronic pancreatitis are still significant diagnostic and clinical problems. The clinical impact of preoperative serum carbohydrate antygen 19-9 (CA 19-9) levels have been disscussed. The aim of this study was a comparative analysis of the concentrations in serum of adipocytokines: adiponectin and leptin and CA 19-9 in patients with pancreatic cancer (PC), chronic pancreatitis (CP) and control group (CG). The study was performed in a group of 90 patients. Group 1 consisted of 30 patients with PC, group 2 consisted of 30 patients with CP. There was no coincidence of pancreatic cancer in CP group. Group 3 (CG) consisted of 30 persons and were recruited among patients operated for cholelithiasis. The serum samples were taken from patients and the concentration of adiponectin, leptin, CA 19-9 and CEA were evaluated. The revealed concentrations levels of the adiponectin were significantly higher in the PC serum samples compared to the CP and CG. There was no significant correlation between increased adiponectin concentration and body fat mass in the PC group. The concentration of leptin was significantly lower in CP serum samples compared to PC and CG. The concentration of leptin was similar in the PC and CG. The concentration of leptin was mainly dependent on body fat mass and fat distribution. Additionally, measurement of waist circumference and body composition was recorded using bioelectrical impedance analysis. CONCLUSIONS: significantly higher concentration levels of adiponectin in the PC group, independent of body fat mass, may play a potential role as a new tumor marker in PC and might be useful in the differential diagnosis between PC and CP, but this statement needs further investigation. To our knowledge, this was the first study evaluating not only body mass index but also the content and distribution of body fat in patients with PC and CP. PMID- 26579572 TI - Effects of fluoxetine and melatonin on mood, sleep quality and body mass index in postmenopausal women. AB - Frequent mood and sleep disorders and increased appetite leading to obesity are observed in postmenopausal women. Due to the limitations of hormone replacement therapy the researchers look for other treatment regimes. The aim of the study was to evaluate the efficacy of fluoxetine and melatonin in the treatment of these disorders. The study included 64 overweight postmenopausal women, aged 54 - 65 years, with increased appetite. They were randomly assigned in 2 groups. In group I (n = 30) fluoxetine (20 mg in the morning) and placebo (in the evening) were administered for 24 weeks. Group II (n = 34) received fluoxetine (20 mg in the morning) and melatonin (5 mg in the evening) in the same period of time. Hamilton anxiety rating scale (HARS), Beck depression scale (BDI), the insomnia severity index (ISI) and body mass index (BMI) were used to assess the health status and the treatment efficacy. After 24 weeks, comparable and statistically significant reduction in the level of anxiety and depression was obtained in both groups. In group I, the ISI decreased from 14.9 +/- 2.5 points to 10.9 +/- 1.9 points (P < 0.05) and in group II from 15.8 +/- 2.4 points to 7.7 +/- 1.5 points (P < 0.001). In group I no reduction in BMI was achieved whereas in group II this index decreased from 30.9 +/- 3.1 to 26.3 +/- 3.2 (P < 0.05). We conclude that combined administration of fluoxetine and melatonin was useful option to treat mood, sleep and appetite disorders in postmenopausal women. PMID- 26579573 TI - Total and high molecular weight adiponectin levels in the rat model of post myocardial infarction heart failure. AB - Adiponectin is a protein secreted primarily by adipose tissue. It has been suggested that adiponectin plays a protective role in the early phase following myocardial infarction. Our primary aim was to investigate the effects of post myocardial infarction heart failure well-characterized by left ventricular hemodynamic parameters on the total and high molecular weight adiponectin concentrations in plasma, fat and cardiac tissue. Eight weeks after myocardial infarction or sham operation, total and high molecular weight adiponectin concentrations in plasma, fat, and cardiac tissues were assayed in rats. In addition, hemodynamic parameters and expression of the genes encoding atrial natriuretic peptide and brain natriuretic peptide in left ventricle were evaluated. Atrial natriuretic peptide and brain natriuretic peptide mRNA levels in left ventricle tissue were higher in rats with myocardial infarction-induced heart failure compared with the controls. Similarly, total adiponectin concentration was increased in left ventricle (but not in right ventricle) in rats with post-myocardial infarction heart failure. In contrast, adiponectin levels in plasma and cardiac adipose tissue in rats with post-myocardial infarction heart failure were lower than in sham-operated animals. Furthermore, there were no significant differences in levels of high molecular weight adiponectin in plasma, cardiac tissue or adipose tissue between these two groups. We conclude that in the rat model of post-myocardial infarction heart failure, adiponectin level is increased in left ventricle tissue. This is accompanied by decreased adiponectin levels in plasma and cardiac adipose tissue. PMID- 26579574 TI - Impact of obesity and nitric oxide synthase gene G894T polymorphism on essential hypertension. AB - Hypertension is a multifactorial disease caused by environmental, metabolic and genetic factors, but little is currently known on the complex interplay between these factors and blood pressure. The aim of the present study was to assess the potential impact of obesity, and angiotensin-converting enzyme (ACE) I/D polymorphism and endothelial nitric oxide synthase gene (NOS3) 4a/4b, G894T and T786C variants on the essential hypertension. The study group consisted of 1,027 Caucasian adults of Polish nationality (45.5 +/- 13.6 years old), of which 401 met the criteria for hypertension. Body weight, height and blood pressure were measured and data on self-reported smoking status were collected. Fasting blood glucose, total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides were determined by standard procedures. The ACE I/D polymorphism and three polymorphisms in NOS3 gene (4a/4b, G894T, -T786C) were detected by the PCR method. Multivariable logistic regression demonstrated that age above 45 years, diabetes, dyslipidemia, smoking and male sex are important risk factors for hypertension and no significant influence of variants in ACE and NOS3 genes on this risk was recognized. Obese subjects had a 3.27-times higher risk (OR = 3.27, 95% CI: 2.37 - 4.52) of hypertension than non-obese, and in obese the NOS3 894T allele was associated with 1.37 fold higher risk of hypertension (P = 0.031). The distribution of NOS3 G894T genotypes supported the co-dominant (OR = 1.35, P = 0.034, Pfit = 0.435) or recessive (OR = 2.00, P = 0.046, Pfit = 0.286), but not dominant model of inheritance (P = 0.100). The study indicates that in obese NOS3 G894T polymorphism may enhance hypertension risk. However, in the presence of such strong risk factors as age, diabetes and smoking, the impact of this genetic variant seems to be attenuated. Further studies are needed to reveal the usefulness of G894T polymorphism in hypertension risk assessment in obese. PMID- 26579575 TI - Effect of tachycardia on lipid metabolism and expression of fatty acid transporters in heart ventricles of the rat. AB - Tachycardia increases oxidation of the plasma-borne long chain fatty acids in the heart. The aim of the present study was to examine effect of tachycardia on: 1) the total level of free fatty acids, diacylglycerols, triacylglycerols and phospholipids in both heart ventricles; 2) (14)C-palmitate incorporation in the lipid fractions; 3) expression of fatty acid and glucose transporters in the ventricles. Tachycardia was induced in anesthetized rats by electrical atrial pacing at the rate of 600/min. Samples of the left (LV) and right (RV) ventricle were taken after 30 and 60 min pacing. The level free fatty acids, diacylglycerols, triacylglycerols and phospholipids was determined by means of gas-liquid chromatography and (14)C-palmitate incorporation by liquid scintillation counting, respectively. Expression of fatty acid- and glucose transporters was determined using Western blot technique. In LV, 30min pacing increased the content of diacylglycerols whereas the content of other lipids remained stable. After 60 min of pacing the levels of the examined lipid fractions did not differ from the respective control values. In RV, the content of diacylglycerols and triacylglycerols was reduced both after 30 and 60 min pacing. Tachycardia also affected incorporation of (14)C-palmitate in lipid fractions of goth ventricles. 30 min pacing up-regulated plasmalemmal expression of FAT/CD36 (fatty acid translocase) in both ventricles and reduced its microsomal expression in LV. After 60 min pacing they did not differ from the respective control values. Plasmalemmal expression of FATP-1 (fatty acid transport protein 1) increased and its microsomal expression decreased in RV after 30 min pacing. After 60 min pacing the plasmalemmal FATP-1 expression remained elevated whereas the microsomal expression did not differ from the control value. Pacing did not affect or expression of FABPpm (plasma membrane associated fatty acid binding protein) in either plasma membranes and microsomal compartments. Thirty min pacing increased plasmalemmal and reduced microsomal expression of GLUT-4 (glucotransporter 4) in both ventricles. It increased plasmalemmal expression of GLUT-1 (glucotransporter 1) in RV. It returned to normal after 60 min pacing. It is concluded that tachycardia induces numerous changes in metabolism of myocardial lipids as well as expression of fatty acid and glucose transporters in both heart ventricles. PMID- 26579576 TI - Akt1 binds focal adhesion kinase via the Akt1 kinase domain independently of the pleckstrin homology domain. AB - Akt1 and focal adhesion kinase (FAK) are protein kinases that play key roles in normal cell signaling. Individually, aberrant expression of these kinases has been linked to a variety of cancers. Together, Akt1/FAK interactions facilitate cancer metastasis by increasing cell adhesion under conditions of increased extracellular pressure. Pathological and iatrogenic sources of pressure arise from tumor growth against constraining stroma or direct perioperative manipulation. We previously reported that 15 mmHg increased extracellular pressure causes Akt1 to both directly interact with FAK and to phosphorylate and activate it. We investigated the nature of the Akt1/FAK binding by creating truncations of recombinant FAK, conjugated to glutathione S-transferase (GST), to pull down full-length Akt1. Western blots probing for Akt1 showed that FAK/Akt1 binding persisted in FAK truncations consisting of only amino acids 1-126, FAK(NT1), which contains the F1 subdomain of its band 4.1, ezrin, radixin, and moesin (FERM) domain. Using FAK(NT1) as bait, we then pulled down truncated versions of recombinant Akt1 conjugated to HA (human influenza hemagglutinin). Probes for GST-FAK(NT1) showed Akt1-FAK binding to occur in the absence of the both the Akt1 (N)-terminal pleckstrin homology (PH) domain and its adjacent hinge region. The Akt1 (C)-terminal regulatory domain was equally unnecessary for Akt1/FAK co-immunoprecipitation. Truncations involving the Akt1 catalytic domain showed that the domain by itself was enough to pull down FAK. Additionally, a fragment spanning from the PH domain to half way through the catalytic domain demonstrated increased FAK binding compared to full length Akt1. These results begin to delineate the Akt1/FAK interaction and can be used to manipulate their force-activated signal interactions. Furthermore, the finding that the N-terminal half of the Akt1 catalytic domain binds so strongly to FAK when cleaved from the rest of the protein may suggest a means for developing novel inhibitors that target this specific Akt1/FAK interaction. PMID- 26579577 TI - Kynuramines induce overexpression of heat shock proteins in pancreatic cancer cells via 5-hydroxytryptamine and MT1/MT2 receptors. AB - Kynuramines, metabolites of melatonin and L-tryptophan, are synthesized endogenously by oxygenases or in spontaneous reaction by an interaction with free radicals. We have reported previously that melatonin stimulates expression and phosphorylation of heat shock protein (HSP) 27, as well as production of HSP70 and HSP90alphabeta in pancreatic carcinoma cells (PANC-1). Based on those results, we hypothesized that above processes could have been involved in the interruption of intrinsic proapoptotic pathway. Herein, we report that incubation of PANC-1 cells with N(1)-acetyl-N(2)-formyl-5-methoxykynuramine (AFMK) or with L kynurenine (L-KYN) lead to the overexpression of heat shock protein synthesis and these effects are partially reversed by 5-HT3 or MT1/MT2 receptor antagonists. PANC-1 cells in culture were treated with AFMK or L-KYN, with non selective MT1/MT2 receptor antagonist (luzindole), with 5-HT2 and 5-HT3 receptor antagonists (ketanserin and MDL72222), or combination of these substances. Both AFMK and L-KYN significantly decreased cytoplasmic HSP27 and this effect was presumably due to increased of its phosphorylation and consequent nuclear translocation, confirmed by immunoprecipitation of phosphorylated form of HSP27. These changes were accompanied by marked augmentation of HSP70 and HSP90alphabeta in the cytosolic fraction. Pretreatment of cell cultures with luzindole or MDL72222 followed by the addition of AFMK or L-KYN reversed the stimulatory effects of these substances on HSP expression in PANC-1 cells, whereas ketanserin failed to influence mentioned above phenomenon. We conclude that activation of HSPs in pancreatic carcinoma cells seems to be dependent on an interaction of AFMK or L-KYN with MT1/MT2 or/and 5-HT3 receptors. PMID- 26579578 TI - A mutein of human basic fibroblast growth factor TGP-580 accelerates colonic ulcer healing by stimulating angiogenesis in the ulcer bed in rats. AB - Previously, we reported that TGP-580, a mutein of human basic fibroblast growth factor (bFGF), accelerated the healing of gastric and duodenal ulcers in rats. In the present study, we examined the effect of TGP-580 on the healing of colonic ulcers. In male Sprague Dawley rats, ulcers were induced in the colon 6 cm from the anus by enema of 50 MUl of 3% N-ethylmaleimide, a sulfhydryl alkylator. The lesions were examined under a dissecting microscope (x10). The concentration of bFGF in the ulcerated colon was measured by enzyme immunoassay, and both the distribution of bFGF and the density of microvessels in the ulcer bed were examined by immunohistochemical staining. The content of bFGF in the ulcerated colon was markedly increased associated with ulcer healing, and ulcer healing was significantly delayed by intravenous administration of a monoclonal antibody for bFGF (MAb 3H3) once daily for 10 days. In the ulcer bed, many cells such as fibroblasts, vascular endothelial cells and macrophages were positively stained with bFGF antiserum. TGP-580, human bFGF or dexamethasone was given intracolonally twice daily for 10 days, starting the day after ulcer induction. TGP-580 (0.2 - 20 MUg/ml, 200 MUl/rat) dose-dependently accelerated ulcer healing, and its effect was more than 10 times stronger than that of human bFGF. Density (MUm/0.01 mm(2)) of microvessels in the ulcer bed was significantly increased by treatment with TGP-580, and there was a good correlation between the density of microvessels and the decrease of ulcerated area (R(2) = 0.633). On the other hand dexamethasone (20 MUg/ml) inhibited angiogenesis in the ulcer bed and delayed ulcer healing. These results suggest that angiogenesis in the ulcer bed plays an important role in ulcer healing, and that bFGF mutein TGP-580 accelerated colonic ulcer healing, at least in part, by stimulating angiogenesis, whereas glucocorticoids may delay the healing by inhibiting angiogenesis. PMID- 26579579 TI - Pretreatment with low doses of acenocoumarol inhibits the development of acute ischemia/reperfusion-induced pancreatitis. AB - Coagulative disorders are known to occur in acute pancreatitis and are related to the severity of this disease. Various experimental and clinical studies have shown protective and therapeutic effect of heparin in acute pancreatitis. Aim of the present study was to determine the influence of acenocoumarol, a vitamin K antagonist, on the development of acute pancreatitis. Studies were performed on male Wistar rats weighing 250 - 270 g. Acenocoumarol at the dose of 50, 100 or 150 MUg/kg/dose or vehicle were administered once a day for 7 days before induction of acute pancreatitis. Acute pancreatitis was induced in rats by pancreatic ischemia followed by reperfusion. The severity of acute pancreatitis was assessed after 5-h reperfusion. Pretreatment with acenocoumarol given at the dose of 50 or 100 MUg/kg/dose reduced morphological signs of acute pancreatitis. These effects were accompanied with a decrease in the pancreatitis-evoked increase in serum activity of lipase and serum concentration of pro-inflammatory interleukin-1beta. Moreover, the pancreatitis-evoked reductions in pancreatic DNA synthesis and pancreatic blood flow were partially reversed by pretreatment with acenocoumarol given at the dose of 50 and 100 MUg/kg/dose. Administration of acenocoumarol at the dose of 150 MUg/kg/dose did not exhibit any protective effect against ischemia/reperfusion-induced pancreatitis. We concluded that pretreatment with low doses of acenocoumarol reduces the severity of ischemia/reperfusion-induced acute pancreatitis. PMID- 26579580 TI - Anti-inflammatory effects of nesfatin-1 in rats with acetic acid - induced colitis and underlying mechanisms. AB - Mucosal balance impairment, bacterial over-proliferation, cytokines, inflammatory mediators are known as responsible for inflammatory bowel disease. Besides known anorexigenic, neuroprotective, and anti-apoptotic effects, the major effect of nesfatin-1 on colitis is unknown. Our aim was to investigate the possible anti inflammatory effects of nesfatin-1 in acetic acid induced colitis model and potential underlying mechanisms. Male Spraque-Dawley rats were anesthetized by intraperitoneal ketamine (100 mg/kg) and chlorpromazine (0.75 mg/kg). For nesfatin-1 and antagonist applications some of the rats were intracerebroventricularly (i.c.v.) cannulated. In colitis group, intrarectally (i.r.) 4% acetic acid solution (1 ml) and 10 minutes later i.c.v. nesfatin-1 (0.05 MUg/5 MUl) or vehicle (5 MUl) were administered. Treatments continued for 3 days. In control group, physiological saline solution was used intrarectally. To identify the underlying effective mechanism of nesfatin-1, rats were divided into 3 subgroups, 5 minutes following colitis induction; i.c.v. atosiban (oxytocin receptor antagonist), SHU9119 (melanocortin receptor antagonist) or GHSR-1a antagonist (ghrelin receptor antagonist) were administered, 5 minutes later nesfatin-1 was administered for 3 days. On the fourth day, rats were decapitated, and colon tissues were sampled. Macroscopic and microscopic damage scores of distal colon, and colonic tissue malondialdehyde, glutathione, myeloperoxidase, superoxide dismutase, catalase, luminol and lucigenin chemiluminescence measurements were analysed. The increased myeloperoxidase activity, malondialdehyde levels, luminol and lucigenin chemiluminescence measurements, macroscopic and microscopic damage scores with colitis induction (P < 0.05 - 0.001) were decreased with nesfatin-1 treatment (P < 0.05 - 0.001). Nesfatin-1 may show this effect by inhibiting neutrophil infiltration through tissues and by decreasing formation of free oxygen radicals. Atosiban and GHSR-1a administration alleviated the protective effect of nesfatin-1 from microscopic and oxidant damage parameters and lipid peroxidation (P < 0.05 - 0.001). The results of the study suggest that nesfatin-1 had a protective effect from colitis induction, and the anti-inflammatory and antioxidant effects of nesfatin-1 on colitis might occur via oxytocin and ghrelin receptors. PMID- 26579581 TI - Genetic and environmental predictors of chronic kidney disease in patients with type 2 diabetes and diabetic foot ulcer: a pilot study. AB - Chronic kidney disease (CKD) is often observed among patients with type 2 diabetes mellitus (T2DM) and diabetic foot (DF) leading to end stage renal disease. The aim of this pilot study was to determine genetic and environmental factors involved in the etiology of CKD among patients with DF. The following polymorphisms were studied: rs1800469, rs759853, rs1553005, rs1799983, rs1801133, rs3134069, rs2073618, rs8192678, rs6330, rs11466112, rs121917832 in terms of alleles distribution in patients with DF and T2DM, with or without CKD. The study includes 101 patients with T2DM and DF. Studied groups were divided into 39 individuals with CKD (cases) and 62 controls, depending on the presence of kidney failure defined as eGFR < 60ml/min/1.73m(2) and coexistence of microalbuminuria > 30 mg/dl in at least 3 urine samples. Cases and controls were matched according to mean age, gender, mean duration of T2DM, mean duration of insulin therapy, mean duration of DF cholesterol levels and smoking frequencies. The study showed that CKD risk factors were the following variables: creatinine level, body weight, hips circumference, ischemic heart disease, hypertension and diabetic retinopathy. Moreover, the results suggest the protective role of the allele C of rs3134069 polymorphism in CKD development in patients with T2DM and DF in the following allelic variants: [AA] vs. [AC] and [AA] vs. [AC + CC]. The allele C was observed to be less frequent than the allele A in patients with T2DM and DF. None of the other following polymorphisms was observed to be a potential risk factor of CKD in T2DM and DF population: rs6330, rs759853, rs1553005, rs1799983, rs1801133, rs1800469, rs8192678, rs11466112, rs121917832. We concluded that the rs3134069 polymorphism seems to be the most likely protective genetic factor in CKD development in patients with T2DM and DF. PMID- 26579582 TI - Popular species of edible mushrooms as a good source of zinc to be released to artificial digestive juices. AB - Because fruiting bodies of edible mushrooms accumulate elements very effectively, in this study for the first time we aimed at determining the degree of the release of zinc(II) ions to artificial digestive juices imitating the human gastrointestinal tract from freeze-dried popular edible mushroom fruiting bodies, such as Agaricus bisporus, Boletus badius and Cantharellus cibarius. For the analysis, anodic stripping voltammetry method was used. The amount of zinc released to artificial saliva within 1 minute ranged from 0.03 to 1.14 mg/100 g d.w. In gastric juice, the amounts were higher and ranged from 0.75 to 2.07 mg/100 g d.w. depending on the incubation time. After incubation of the freeze dried edible mushroom fruiting bodies for 1 minute in artificial saliva, 15 in artificial gastric juice and then 150 minutes in artificial intestinal juice, it was found that the concentration of the released zinc in artificial intestinal juice was the highest and amounted to 6.44 mg/100 g d.w. The total average amount of zinc released from Boletus badius was the highest and this was estimated at 4.13 mg/100 g d.w. For the remaining two investigated species of A. bisporus and C. cibarius, the total amounts of zinc released into artificial digestive juices were only slightly lower and were estimated at 2.23 and 3.29 mg/100 g d.w. on average, respectively. It was demonstrated for the first time that mushrooms release zinc to artificial digestive juices imitating conditions in the human digestive tract and are a good source of this element. PMID- 26579583 TI - From Spill to Sequestration: The Molecular Journey of Contamination via Comprehensive Multiphase NMR. AB - Comprehensive multiphase NMR is a novel NMR technique that permits all components (solutions, gels, and solids) to be studied in unaltered natural samples. In this study a wide range of CMP-NMR interaction and editing-based experiments are combined to follow contaminants (pentafluorophenol (PFP) and perfluorooctanoic acid (PFOA)) from the solution state (after a spill) through the gel-state and finally into the true solid-state (sequestered) in an intact water-swollen soil. Kinetics experiments monitoring each phase illustrate PFOA rapidly transfers from solution to the solid phase while for PFP the process is slower with longer residence times in the solution and gel phase. Interaction-based experiments reveal that PFOA enters the soil via its hydrophobic tails and selectively binds to soil microbial protein. PFP sorption shows less specificity exhibiting interactions with a range of gel and solid soil components with a preference toward aromatics (mainly lignin). The results indicate that in addition to more traditional measurements such as Koc, other factors including the influence of the contaminant on the soil-water interface, specific biological interactions, soil composition (content of lignin, protein, etc.) and physical accessibility/swellability of soil organic components will likely be central to better explaining and predicting the true behavior of contaminants in soil. PMID- 26579584 TI - Female Sexual Function Improves After Endometrial Ablation. AB - BACKGROUND: Many women have heavy menstrual bleeding during perimenopause that may interfere with overall quality of life and contribute to sexual dysfunction. We aimed to determine whether sexual function in women improves after endometrial ablation for heavy menstrual periods. METHODS: Validated surveys (Female Sexual Function Index [FSFI], Female Sexual Distress Scale [FSDS], and Short-Form Health Survey [SF-12]) were administered to 136 women before and after endometrial ablation from August 2008 through June 2013. Scores at baseline and 6 months after surgery were compared using the paired t test. RESULTS: A total of 97 women completed the FSFI and FSDS surveys at baseline and 6 months after ablation. Mean full-scale FSFI score increased from 26.5 to 28.8 (p < .001), with improvement in 5 of 6 FSFI domains. Mean FSDS score decreased from 13.6 to 9.7 (p < .001), showing decreased personal distress regarding sexual function. In assessing quality of life, SF-12 scores improved for global physical function (p < .001) and mental function (p = .002). CONCLUSIONS: Female sexual function improved and personal distress associated with sexual function decreased after endometrial ablation for heavy menstrual cycles. PMID- 26579585 TI - A Green's-Function Approach to Exchange Spin Coupling As a New Tool for Quantum Chemistry. AB - Exchange spin coupling is usually evaluated in quantum chemistry from the energy difference between a high-spin determinant and a Broken-Symmetry (BS) determinant in combination with Kohn-Sham density functional theory (KS-DFT), based on the work of Noodleman. As an alternative, an efficient approximate approach relying on Green's functions has been developed by one of the authors. This approach stems from solid-state physics and has never been systematically tested for molecular systems. We rederive a version of the Green's-function approach originally suggested by Han, Ozaki, and Yu. This new derivation employs local projection operators as common in quantum chemistry for defining local properties such as partial charges, rather than using a dual basis as in the Han-Ozaki-Yu approach. The result is a simple postprocessing procedure for KS-DFT calculations, which in contrast to the BS energy-difference approach requires the electronic structure of only one spin state. We show for several representative small molecules, diradicals, and dinuclear transition metal complexes that this method gives qualitatively consistent results with the BS energy-difference approach as long as it is applied to high-spin determinants and as long as structural relaxation effects in different spin states do not play an important role. PMID- 26579586 TI - Society of Biomolecular Imaging and Informatics Special Issue, November 2015. PMID- 26579587 TI - Colloquium: SBI(2) HCS/HCA Informatics and Data Analysis--Best Practices and Unmet Needs September 15, 2015. PMID- 26579588 TI - Two-level Anterior Cervical Discectomy and Fusion: An Outpatient Surgery? PMID- 26579589 TI - Results of Yet Another Antibiotics vs Appendectomy Randomized Trial: Still Not Enough to Change My Practice. PMID- 26579590 TI - "The Heart Game": Using Gamification as Part of a Telerehabilitation Program for Heart Patients. AB - OBJECTIVE: The aim of this article is to describe the development and testing of a prototype application ("The Heart Game") using gamification principles to assist heart patients in their telerehabilitation process in the Teledialog project. MATERIALS AND METHODS: A prototype game was developed via user-driven innovation and tested on 10 patients 48-89 years of age and their relatives for a period of 2 weeks. The application consisted of a series of daily challenges given to the patients and relatives and was based on several gamification principles. A triangulation of data collection techniques (interviews, participant observations, focus group interviews, and workshop) was used. Interviews with three healthcare professionals and 10 patients were carried out over a period of 2 weeks in order to evaluate the use of the prototype. RESULTS: The heart patients reported the application to be a useful tool as a part of their telerehabilitation process in everyday life. Gamification and gameful design principles such as leaderboards, relationships, and achievements engaged the patients and relatives. The inclusion of a close relative in the game motivated the patients to perform rehabilitation activities. CONCLUSIONS: "The Heart Game" concept presents a new way to motivate heart patients by using technology as a social and active approach to telerehabilitation. The findings show the potential of using gamification for heart patients as part of a telerehabilitation program. The evaluation indicated that the inclusion of the patient's spouse in the rehabilitation activities could be an effective strategy. A major challenge in using gamification for heart patients is avoiding a sense of defeat while still adjusting the level of difficulty to the individual patient. PMID- 26579591 TI - FANCONI ANEMIA PRESENTING AS BILATERAL DIFFUSE RETINAL OCCLUSIVE VASCULOPATHY. AB - PURPOSE: To describe the ocular findings and subsequent workup of a 21-year-old woman with previously undiagnosed Fanconi anemia. METHODS: Observational case report and literature review. RESULTS: A 21-year-old healthy woman presented with bilateral retinal hemorrhages, telangiectasia, and severe ischemia with vascular leak. Systemic workup revealed anemia and thrombocytopenia. A diepoxybutane chromosomal breakage test confirmed the diagnosis of Fanconi anemia. CONCLUSION: Ocular complications are common in patients with Fanconi anemia and may be the presenting manifestation of the disease. PMID- 26579592 TI - HLA-A29-POSITIVE BIRDSHOT CHORIORETINOPATHY IN AN AFRICAN AMERICAN PATIENT. AB - PURPOSE: To report the first documented case of HLA-A29-positive birdshot chorioretinopathy in an African American patient. METHODS: A 51-year-old African American woman presented with a 10-year history of photopsia, progressive decrease in visual acuity, metamorphopsia, and new nyctalopia. Both fundi showed evidence of periphlebitis, arterial attenuation, macular edema, and diffuse chorioretinal atrophy. RESULTS: Fluorescein angiography revealed diffuse vascular leakage, and indocyanine green showed evenly distributed and symmetrical hypofluorescent spots, which were difficult to appreciate on fundoscopy. Workup revealed a positive HLA-A29 and was negative for sarcoid, tuberculosis, and syphilis. CONCLUSION: Birdshot chorioretinopathy overwhelmingly affects non Hispanic Caucasians, but there have been rare reported cases in other ethnicities including Hispanics and African Americans. This patient's ethnicity may have contributed to the 10-year delay in diagnosis. To our knowledge, this is the first documented HLA-A29 positive case of birdshot chorioretinopathy in an African American. HLA-A29 may be a useful supportive test in cases with classic clinical presentation in non-Caucasian patients to enable the correct diagnose in a timely manner. PMID- 26579593 TI - CENTRAL RETINAL VEIN OCCLUSION IN HEREDITARY SPHEROCYTOSIS. AB - PURPOSE: To investigate and identify hereditary spherocytosis as a possible risk factor for the development of a central retinal vein occlusion in a young, otherwise healthy, adult. METHOD: This study is a retrospective case description of a single female patient. RESULTS: A 31-year-old white woman with hereditary spherocytosis after splenectomy was found to have a central retinal vein occlusion. She had no atherosclerotic risk factors and a negative hypercoaguable workup. Her course was complicated by macular edema. She was treated with intravitreal ranibizumab injections with resultant improvement of her vision and resolution of her macular edema. CONCLUSION: Hereditary spherocytosis is an inherited deficiency in erythrocyte membrane proteins that should be considered in younger patients with central retinal vein occlusions because of the disease's impact on hematologic factors. Furthermore, intravitreal antivascular endothelial growth factor injections may improve macular edema in this population. PMID- 26579594 TI - GRANULOMATOSIS WITH POLYANGIITIS (GPA) PRESENTING WITH FROSTED BRANCH ANGIITIS. AB - PURPOSE: To report a case of frosted branch angiitis in a patient with granulomatosis with polyangiitis. METHODS: Clinical case report. Imaging was obtained with pseudo-color scanning laser ophthalmoscope photographs, fluorescein angiography, spectral domain optical coherence tomography, and B-scan ultrasound. RESULTS: A 24-year-old woman with a clinical history of granulomatosis with polyangiitis who presented with acute vision loss was found to have frosted branch angiitis with concurrent posterior scleritis and orbital inflammation. These findings improved rapidly after initiation of high-dose intravenous solumedrol. CONCLUSION: This is a unique case of frosted branch angiitis associated with granulomatosis with polyangiitis. The authors are not aware of a previous report of this association. Although rare, retinal vasculitis should be recognized as a potential complication of granulomatosis with polyangiitis and can respond rapidly to prompt initiation of therapy. PMID- 26579595 TI - BILATERAL OPTIC NERVE COLOBOMAS IN INFANT WITH TETRAPLOIDY. AB - PURPOSE: To describe the previously unreported ocular anomalies in the rare condition of tetraploidy. METHODS: This study is a retrospective case report of a 23-day-old male infant with tetraploidy. RetCam fundus photography and neuroimaging were performed. RESULTS: This 23-day-old male infant was born at full term and found to have tetraploidy with numerous congenital anomalies including bilateral optic nerve colobomas, left microphthalmia, vitreous hemorrhage, and septo-optic dysplasia. CONCLUSION: Infants with tetraploidy can present with ocular anomalies and while hospitalized should be examined by an ophthalmologist. PMID- 26579597 TI - High performance volume-of-intersection projectors for 3D-PET image reconstruction based on polar symmetries and SIMD vectorisation. AB - For high-resolution, iterative 3D PET image reconstruction the efficient implementation of forward-backward projectors is essential to minimise the calculation time. Mathematically, the projectors are summarised as a system response matrix (SRM) whose elements define the contribution of image voxels to lines-of-response (LORs). In fact, the SRM easily comprises billions of non-zero matrix elements to evaluate the tremendous number of LORs as provided by state-of the-art PET scanners. Hence, the performance of iterative algorithms, e.g. maximum-likelihood-expectation-maximisation (MLEM), suffers from severe computational problems due to the intensive memory access and huge number of floating point operations. Here, symmetries occupy a key role in terms of efficient implementation. They reduce the amount of independent SRM elements, thus allowing for a significant matrix compression according to the number of exploitable symmetries. With our previous work, the PET REconstruction Software TOolkit (PRESTO), very high compression factors (>300) are demonstrated by using specific non-Cartesian voxel patterns involving discrete polar symmetries. In this way, a pre-calculated memory-resident SRM using complex volume-of intersection calculations can be achieved. However, our original ray-driven implementation suffers from addressing voxels, projection data and SRM elements in disfavoured memory access patterns. As a consequence, a rather limited numerical throughput is observed due to the massive waste of memory bandwidth and inefficient usage of cache respectively. In this work, an advantageous symmetry driven evaluation of the forward-backward projectors is proposed to overcome these inefficiencies. The polar symmetries applied in PRESTO suggest a novel organisation of image data and LOR projection data in memory to enable an efficient single instruction multiple data vectorisation, i.e. simultaneous use of any SRM element for symmetric LORs. In addition, the calculation time is further reduced by using simultaneous multi-threading (SMT). A global speedup factor of 11 without SMT and above 100 with SMT has been achieved for the improved CPU-based implementation while obtaining equivalent numerical results. PMID- 26579596 TI - Central tolerance to self revealed by the autoimmune regulator. AB - The autoimmune regulator (Aire) was initially identified as the gene causing multiorgan system autoimmunity in humans, and deletion of this gene in mice also resulted in organ-specific autoimmunity. Aire regulates the expression of tissue specific antigens (TSAs) in medullary thymic epithelial cells (mTECs), which play a critical role in the negative selection of autoreactive T cells and the generation of regulatory T cells. More recently, the role of Aire in the development of mTECs has helped elucidate its ability to present the spectrum of TSAs needed to prevent autoimmunity. Molecular characterization of the functional domains of Aire has revealed multiple binding partners that assist Aire's function in altering gene transcription and chromatin remodeling. These recent advances have further highlighted the importance of Aire in central tolerance. PMID- 26579598 TI - Impaired cortical neurogenesis in plexin-B1 and -B2 double deletion mutant. AB - Mammalian cortical expansion is tightly controlled by fine-tuning of proliferation and differentiation of neural progenitors in a region-specific manner. How extrinsic cues interface with cell-intrinsic programs to balance proliferative versus neurogenic decisions remains an unsolved question. We examined the function of Semaphorin receptors Plexin-B1 and -B2 in corticogenesis by generating double mutants, whereby Plexin-B2 was conditionally ablated in the developing brain in a Plexin-B1 null mutant background. Absence of both Plexin-Bs resulted in cortical thinning, particularly in the caudomedial cortex. Plexin B1/B2 double, but not single, mutants exhibited a reduced neural progenitor pool, attributable to decreased proliferation and an altered division mode favoring cell cycle exit. This resulted in deficient production of neurons throughout the neurogenic period, proportionally affecting all cortical laminae. Consistent with the in vivo data, cultured neural progenitors lacking both Plexin-B1 and -B2 displayed decreased proliferative capacity and increased spontaneous differentiation. Our study therefore defines a novel function of Plexin-B1 and B2 in transmitting extrinsic signals to maintain proliferative and undifferentiated states of neural progenitors. As single mutants displayed no apparent cortical defects, we conclude that Plexin-B1 and -B2 play redundant or compensatory roles during forebrain development to ensure proper neuronal production and neocortical expansion. (c) 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 882-899, 2016. PMID- 26579599 TI - Structural and electronic properties of photoexcited TiO2 nanoparticles from first principles. AB - The structure and energetics of excitons and individual electron and hole polarons in a model anatase TiO2 nanoparticle (NP) are investigated by means of Density Functional Theory (DFT) and Time Dependent (TD)-DFT calculations. The effect of the Hartree-Fock exchange (HF-exc) contribution in the description of TiO2 NPs with unpaired electrons is examined by comparing the results from semilocal and hybrid DFT functionals with different HF-exc percentages, including a long-range corrected hybrid functional. The performances of TD-DFT and ground state (SCF) DFT approaches in the description of the photoexcited polaron states in TiO2 NPs are also analyzed. Our results confirm that the HF-exc contribution is essential to properly describe the self-trapping of the charge carriers. They also suggest that long-range corrected functionals are needed to properly describe excited state relaxation in TiO2 NPs. TD-DFT geometry optimization of the lowest excited singlet and triplet states deliver photoluminescence values in close agreement with the experimental data. PMID- 26579600 TI - X-ray absorption in insulators with non-Hermitian real-time time-dependent density functional theory. AB - Non-Hermitian real-time time-dependent density functional theory was used to compute the Si L-edge X-ray absorption spectrum of alpha-quartz using an embedded finite cluster model and atom-centered basis sets. Using tuned range-separated functionals and molecular orbital-based imaginary absorbing potentials, the excited states spanning the pre-edge to ~20 eV above the ionization edge were obtained in good agreement with experimental data. This approach is generalizable to TDDFT studies of core-level spectroscopy and dynamics in a wide range of materials. PMID- 26579601 TI - Carotenoids and light-harvesting: from DFT/MRCI to the Tamm-Dancoff approximation. AB - Carotenoids are known to play a fundamental role in photosynthetic light harvesting (LH) complexes; however, an accurate quantum-mechanical description of that is still missing. This is due to the multideterminant nature of the involved electronic states combined with an extended conjugation which limits the applicability of many of the most advanced approaches. In this study, we apply a multireference configuration interaction extension of density functional theory (DFT/MRCI) to describe transition energies and densities as well as the corresponding excitonic couplings, for the three lowest singlet excited states of nine carotenoids present in three different LH complexes of algae and plants. These benchmark results are used to find an approximated computational approach, which could be used to quantitatively reproduce the key quantities at a reduced computational cost. To this end, we tested the Tamm-Dancoff approximation (TDA) to time-dependent density functional theory in combination with different functionals. By analyzing the errors with respect to DFT/MRCI-TDA results for the full set of electronic properties, we conclude that TDA-TPSS with small basis sets indeed represents an effective approach to investigate LH processes that involve carotenoids. PMID- 26579602 TI - Systematic procedure to parametrize force fields for molecular fluids. AB - A new strategy to develop force fields for molecular fluids is presented. The intermolecular parameters are fitted to reproduce experimental values of target properties at ambient conditions and also the critical temperature. The partial charges are chosen to match the dielectric constant. The Lennard-Jones parameters, epsilonii and sigmaii, are fitted to reproduce the surface tension at the vapor-liquid interface and the liquid density, respectively. The choice of those properties allows obtaining systematically the final parameters using a small number of simulations. It is shown that the use of surface tension as a target property is better than the choice of heat of vaporization. The method is applied to molecules, from all atoms to a coarse-grained level, such as pyridine, dichloromethane, methanol, and 1-ethyl-3-methylimidazolium tetrafluoroborate (EMIM-BF4) at different temperatures and pressures. The heat of vaporization, radial distribution functions, and self-diffusion coeficient are also calculated. PMID- 26579603 TI - Achieving linear scaling in computational cost for a fully polarizable MM/continuum embedding. AB - In this paper, we present a new, efficient implementation of a fully polarizable QM/MM/continuum model based on an induced-dipoles polarizable force field and on the Conductor-like Screening Model as a polarizable continuum in combination with a self-consistent field QM method. The paper focuses on the implementation of the MM/continuum embedding, where the two polarizable methods are fully coupled to take into account their mutual polarization. With respect to previous implementations, we achieve for the first time a linear scaling with respect to both the computational cost and the memory requirements without limitations on the molecular cavity shape. This is achieved thanks to the use of the recently developed ddCOSMO model for the continuum and the Fast Multipole Method for the force field, together with an efficient iterative procedure. Therefore, it becomes possible to include in the classical layer as much as several tens of thousands of atoms with a limited computational effort. PMID- 26579604 TI - High-level QM/MM calculations support the concerted mechanism for Michael addition and covalent complex formation in thymidylate synthase. AB - Thymidylate synthase (TS) is a promising cancer target, due to its crucial function in thymine synthesis. It performs the reductive methylation of 2' deoxyuridine-5'-phosphate (dUMP) to thymidine-5'-phosphate (dTMP), using N-5,10 methylene-5,6,7,8-tetrahydrofolate (mTHF) as a cofactor. After the formation of the dUMP/mTHF/TS noncovalent complex, and subsequent conformational activation, this complex has been proposed to react via nucleophilic attack (Michael addition) by Cys146, followed by methylene-bridge formation to generate the ternary covalent intermediate. Herein, QM/MM (B3LYP-D/6-31+G(d)-CHARMM27) methods are used to model the formation of the ternary covalent intermediate. A two dimensional potential energy surface reveals that the methylene-bridged intermediate is formed via a concerted mechanism, as indicated by a single transition state on the minimum energy pathway and the absence of a stable enolate intermediate. A range of different QM methods (B3LYP, MP2 and SCS-MP2, and different basis sets) are tested for the calculation of the activation energy barrier for the formation of the methylene-bridged intermediate. We test convergence of the QM/MM results with respect to size of the QM region. Inclusion of Arg166, which interacts with the nucleophilic thiolate, in the QM region is important for reliable results; the MM model apparently does not reproduce energies for distortion of the guanidinium side chain correctly. The spin component scaled-Moller-Plessett perturbation theory (SCS-MP2) approach was shown to be in best agreement (within 1.1 kcal/mol) while the results obtained with MP2 and B3LYP also yielded acceptable values (deviating by less than 3 kcal/mol) compared with the barrier derived from experiment. Our results indicate that using a dispersion-corrected DFT method, or a QM method with an accurate treatment of electron correlation, increases the agreement between the calculated and experimental activation energy barriers, compared with the semiempirical AM1 method. These calculations provide important insight into the reaction mechanism of TS and may be useful in the design of new TS inhibitors. PMID- 26579605 TI - Designing peptide sequences in flexible chain conformations to bind RNA: a search algorithm combining Monte Carlo, self-consistent mean field and concerted rotation techniques. AB - A search algorithm combining Monte Carlo, self-consistent mean field, and concerted rotation techniques was developed to discover peptide sequences that are reasonable HIV drug candidates due to their exceptional binding to human tRNAUUU(Lys3), the primer of HIV replication. The search algorithm allows for iteration between sequence mutations and conformation changes during sequence evolution. Searches conducted for different classes of peptides identified several potential peptide candidates. Analysis of the energy revealed that the asparagine and cysteine at residues 11 and 12 play important roles in "recognizing" tRNA(Lys3) via van der Waals interactions, contributing to binding specificity. Arginines preferentially attract the phosphate linkage via charge charge interaction, contributing to binding affinity. Evaluation of the RNA/peptide complex's structure revealed that adding conformation changes to the search algorithm yields peptides with better binding affinity and specificity to tRNA(Lys3) than a previous mutation-only algorithm. PMID- 26579606 TI - Free-energy calculations reveal the subtle differences in the interactions of DNA bases with alpha-hemolysin. AB - Next generation DNA sequencing methods that utilize protein nanopores have the potential to revolutionize this area of biotechnology. While the technique is underpinned by simple physics, the wild-type protein pores do not have all of the desired properties for efficient and accurate DNA sequencing. Much of the research efforts have focused on protein nanopores, such as alpha-hemolysin from Staphylococcus aureus. However, the speed of DNA translocation has historically been an issue, hampered in part by incomplete knowledge of the energetics of translocation. Here we have utilized atomistic molecular dynamics simulations of nucleotide fragments in order to calculate the potential of mean force (PMF) through alpha-hemolysin. Our results reveal specific regions within the pore that play a key role in the interaction with DNA. In particular, charged residues such as D127 and K131 provide stabilizing interactions with the anionic DNA and therefore are likely to reduce the speed of translocation. These regions provide rational targets for pore optimization. Furthermore, we show that the energetic contributions to the protein-DNA interactions are a complex combination of electrostatics and short-range interactions, often mediated by water molecules. PMID- 26579607 TI - Double hybrid functionals and the Pi-system bond length alternation challenge: rivaling accuracy of post-HF methods. AB - Predicting accurate bond length alternations (BLAs) in long conjugated oligomers has been a significant challenge for electronic-structure methods for many decades, made particularly important by the close relationships between BLA and the rich optoelectronic properties of pi-delocalized systems. Here, we test the accuracy of recently developed, and increasingly popular, double hybrid (DH) functionals, positioned at the top of Jacobs Ladder of DFT methods of increasing sophistication, computational cost, and accuracy, due to incorporation of MP2 correlation energy. Our test systems comprise oligomeric series of polyacetylene, polymethineimine, and polysilaacetylene up to six units long. MP2 calculations reveal a pronounced shift in BLAs between the 6-31G(d) basis set used in many studies of BLA to date and the larger cc-pVTZ basis set, but only modest shifts between cc-pVTZ and aug-cc-pVQZ results. We hence perform new reference CCSD(T)/cc-pVTZ calculations for all three series of oligomers against which we assess the performance of several families of DH functionals based on BLYP, PBE, and TPSS, along with lower-rung relatives including global- and range-separated hybrids. Our results show that DH functionals systematically improve the accuracy of BLAs relative to single hybrid functionals. xDH-PBE0 (N(4) scaling using SOS MP2) emerges as a DH functional rivaling the BLA accuracy of SCS-MP2 (N(5) scaling), which was found to offer the best compromise between computational cost and accuracy the last time the BLA accuracy of DFT- and wave function-based methods was systematically investigated. Interestingly, xDH-PBE0 (XYG3), which differs to other DHs in that its MP2 term uses PBE0 (B3LYP) orbitals that are not self-consistent with the DH functional, is an outlier of trends of decreasing average BLA errors with increasing fractions of MP2 correlation and HF exchange. PMID- 26579608 TI - Correction to variational, self-consistent implementation of the Perdew-Zunger self-interaction correction with complex optimal orbitals. PMID- 26579609 TI - Carbamoyl anion-initiated cascade reaction for stereoselective synthesis of substituted alpha-hydroxy-beta-amino amides. AB - A carbamoyl anion-initiated cascade reaction with acylsilanes and imines has been used to rapidly construct substituted alpha-hydroxy-beta-amino amides. The Brook rearrangement-mediated cascade allows the formation of two C-C bonds and one O-Si bond in a single pot. Using this approach, a range of alpha-aryl alpha-hydroxy beta-amino amides has been synthesized in high yields with excellent diastereoselectivities. PMID- 26579611 TI - Twitter-Augmented Journal Club: Educational Engagement and Experience So Far. AB - Social media is a nascent medical educational technology. The benefits of Twitter include (1) easy adoption; (2) access to experts, peers, and patients across the globe; (3) 24/7 connectivity; (4) creation of virtual, education-based communities using hashtags; and (5) crowdsourcing information using retweets. We report on a novel Twitter-augmented journal club for anesthesia residents: its design, implementation, and impact. Our inaugural anesthesia Twitter-augmented journal club succeeded in engaging the anesthesia community and increasing residents' professional use of Twitter. Notably, our experience suggests that anesthesia residents are willing to use social media for their education. PMID- 26579612 TI - An Uncommon Complication with a Supraglottic Airway: The King LT. AB - General anesthesia was administered in an 18-year-old man for removal of hardware from his right knee using a King Laryngeal Tube supraglottic airway. An hour after extubation, he reported inability to swallow with no respiratory distress. Examination showed an edematous uvula, which took 3 days to subside with anti inflammatory medication. During the positioning of the King Laryngeal Tube, it was pulled back to ensure adequate ventilation. The inflated cuff could have dragged the uvula and folded it on itself, leading to venous congestion and edema. PMID- 26579610 TI - Associations of Alcohol Availability and Neighborhood Socioeconomic Characteristics With Drinking: Cross-Sectional Results From the Multi-Ethnic Study of Atherosclerosis (MESA). AB - BACKGROUND: Living in neighborhoods with a high density of alcohol outlets and socioeconomic disadvantage may increase residents' alcohol use. Few researchers have studied these exposures in relation to multiple types of alcohol use, including beverage-specific consumption, and how individual demographic factors influence these relationships. OBJECTIVE: To examine the relationships of alcohol outlet density and neighborhood disadvantage with alcohol consumption, and to investigate differences in these associations by race/ethnicity and income. METHODS: Using cross-sectional data (N = 5,873) from the Multi-ethnic Study of Atherosclerosis in 2002, we examine associations of residential alcohol outlet density and neighborhood socioeconomic disadvantage with current, total weekly and heaviest daily alcohol use in gender-specific regression models, as well as moderation by race/ethnicity and income. RESULTS: Drinking men living near high densities of alcohol outlets had 23%-29% more weekly alcohol use than men in low density areas. Among women who drank, those living near a moderate density of alcohol outlets consumed approximately 40% less liquor each week than those in low density areas, but higher outlet densities were associated with more wine consumption (35%-49%). Living in highly or moderately disadvantaged neighborhoods was associated with a lower probability of being a current drinker, but with higher rates of weekly beer consumption. Income moderated the relationship between neighborhood context and weekly alcohol use. CONCLUSIONS/IMPORTANCE: Neighborhood disadvantage and alcohol outlet density may influence alcohol use with effects varying by gender and income. Results from this research may help target interventions and policy to groups most at risk for greater weekly consumption. PMID- 26579613 TI - Anesthetic Implications of an Obstetric Patient with Blue Rubber Bleb Nevus Syndrome. AB - Blue rubber bleb nevus syndrome, a syndrome of multifocal venous malformations, has been reported rarely during pregnancy. This syndrome has been associated with airway lesions in some patients and neuraxial abnormalities in other patients. We report the anesthetic and obstetric management of a patient with an extensive distribution of both airway and neuraxial lesions. PMID- 26579614 TI - Anesthesia for Potts Shunt in a Child with Severe Refractory Idiopathic Pulmonary Arterial Hypertension. AB - Childhood idiopathic pulmonary arterial hypertension is a progressive and fatal disease. When pulmonary artery pressures become suprasystemic and refractory to medical management, atrial septostomy can be recommended for bridging patients to lung transplantation. Recently, a surgical Potts shunt has been recommended as an alternative rescue therapy, and initial outcome data are promising. The placement of a Potts shunt converts the child to Eisenmenger physiology, which is anticipated to provide an improved quality and duration of life. We present the first description of anesthetic management of a child undergoing surgical Potts shunt for pulmonary arterial hypertension and summarize the multiple, unique intraoperative considerations. PMID- 26579615 TI - ERIC-PCR Genotyping of Some Campylobacter jejuni Isolates of Chicken and Human Origin in Egypt. AB - The public health importance of the genus Campylobacter is attributed to several species causing diarrhea in consumers. Poultry and their meat are considered the most important sources of human campylobacteriosis. In this study, 287 samples from chicken (131 cloacal swabs, 39 chicken skin, 78 chicken meat, and 39 cecal parts) obtained from retail outlets as well as 246 stool swabs from gastroenteritis patients were examined. A representative number of the biochemically identified Campylobacter jejuni isolates were identified by real time PCR, confirming the identification of the isolates as C. jejuni. Genotyping of the examined isolates (n = 31) by enterobacterial repetitive intergenic consensus PCR (ERIC-PCR) revealed a high discriminatory index of ERIC-PCR (D = 0.948), dividing C. jejuni isolates of chicken and human origins into 18 profiles and four clusters. The 18 profiles obtained indicated the heterogeneity of C. jejuni. Dendrogram analysis showed that four clusters were generated; all human isolates fell into clusters I and III. These observations further support the existence of a genetic relationship between human and poultry isolates examined in the present study. In conclusion, the results obtained support the speculation that poultry and poultry meat have an important role as sources of infection in the acquisition of Campylobacter infection in humans. PMID- 26579616 TI - Engineered Carbon-Nanomaterial-Based Electrochemical Sensors for Biomolecules. AB - The study of electrochemical behavior of bioactive molecules has become one of the most rapidly developing scientific fields. Biotechnology and biomedical engineering fields have a vested interest in constructing more precise and accurate voltammetric/amperometric biosensors. One rapidly growing area of biosensor design involves incorporation of carbon-based nanomaterials in working electrodes, such as one-dimensional carbon nanotubes, two-dimensional graphene, and graphene oxide. In this review article, we give a brief overview describing the voltammetric techniques and how these techniques are applied in biosensing, as well as the details surrounding important biosensing concepts of sensitivity and limits of detection. Building on these important concepts, we show how the sensitivity and limit of detection can be tuned by including carbon-based nanomaterials in the fabrication of biosensors. The sensing of biomolecules including glucose, dopamine, proteins, enzymes, uric acid, DNA, RNA, and H2O2 traditionally employs enzymes in detection; however, these enzymes denature easily, and as such, enzymeless methods are highly desired. Here we draw an important distinction between enzymeless and enzyme-containing carbon nanomaterial-based biosensors. The review ends with an outlook of future concepts that can be employed in biosensor fabrication, as well as limitations of already proposed materials and how such sensing can be enhanced. As such, this review can act as a roadmap to guide researchers toward concepts that can be employed in the design of next generation biosensors, while also highlighting the current advancements in the field. PMID- 26579617 TI - Hydrophosphination reactions with transition metal ferrocenylphosphine complexes. AB - The group 6 metal mono-, bis- and tris-ferrocenylphosphine complexes [M(CO)5(PH2Fc)] (1a, M = Cr; 1b, M = Mo; 1c, M = W), cis-[M(CO)4(PH2Fc)2] (2a, M = Cr; 2b, M = Mo; 2c, M = W) and fac-[M(CO)3(PH2Fc)3] (3a, M = Cr; 3b, M = Mo; 3c, M = W) [Fc = Fe(eta(5)-C5H4)(eta(5)-C5H5)] were prepared and fully characterised. IR and NMR spectroscopy and single-crystal X-ray diffraction analysis indicate that FcPH2 is as good a sigma donor as PhPH2 but is easier to handle and furthermore has a redox-active ferrocenyl group. Complex 1c was employed in the hydrophosphination of acrylonitrile and methyl acrylate in the presence of catalytic amounts of KOtBu giving the secondary phosphine complexes [W(CO)5{PH(Fc)(CH2CH2CN)}] (4a) and [W(CO)5{PH(Fc)(CH2CH2C(O)OMe)}] (4b). In addition, FcP(CH2CH2CN)2 (5) was prepared by a similar method from FcPH2 and acrylonitrile. These hydrophosphination products represent a convenient method for the modification of phosphines. PMID- 26579618 TI - Calcium Sensing Receptor Function Supports Osteoblast Survival and Acts as a Co Factor in PTH Anabolic Actions in Bone. AB - Anabolic actions of PTH in bone involve increased deposition of mineralizing matrix. Regulatory feedback of the process may be important to maintain calcium homeostasis and, in turn, calcium may inform the process. This investigation clarified the role of calcium availability and the calcium sensing receptor (CaSR) in the anabolic actions of PTH. CaSR function promoted osteoblastic cell numbers, with lower cell numbers in post-confluent cultures of primary calvarial cells from Col1-CaSR knock-out (KO) mice, and for calvarial cells from wild-type (WT) mice treated with a calcilytic. Increased apoptosis of calvarial cells with calcilytic treatment suggested CaSR is critical for protection against stage dependent cell death. Whole and cortical, but not trabecular, bone parameters were significantly lower in Col1-CaSR KO mice versus WT littermates. Intact Col1 CaSR KO mice had lower serum P1NP levels relative to WT. PTH treatment displayed anabolic actions in WT and, to a lesser degree, KO mice, and rescued the lower P1NP levels in KO mice. Furthermore, PTH effects on whole tibiae were inhibited by osteoblast-specific CaSR ablation. Vertebral body implants (vossicles) from untreated Col1-CaSR KO and WT mice had similar bone volumes after 4 weeks of implantation in athymic mice. These findings suggest that trabecular bone formation can occur independently of the CaSR, and that the CaSR plays a collaborative role in the PTH anabolic effects on bone. J. Cell. Biochem. 117: 1556-1567, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26579619 TI - In silico and in vitro screening to identify structurally diverse non-azole CYP51 inhibitors as potent antifungal agent. AB - The problem of resistance to azole class of antifungals is a serious cause of concern to the medical fraternity and thus there is an urgent need to identify non-azole scaffolds with high affinity for lanosterol 14alpha-demethylase (CYP51). In view of this we have attempted to identify novel non-azole CYP51 inhibitors through the application of pharmacophore based virtual screening and in vitro evaluation. A rigorously validated pharmacophore model comprising of 2 hydrogen bond acceptor and 2 hydrophobic features has been developed and used to mine NCI database. Out of 265 retrieved hits, NSC 1215 and 1520 have been chosen on the basis of Lipinski's rule of five, fit and estimated values. Both the hits were docked into the active site of CYP51. In view of high fit value and CDocker score, NSC 1215 and 1520 have been subjected to in vitro microbiological assay. The result reveals that NSC 1215 and 1520 are active against Candida albicans, Candida parapsilosis, Candida tropicalis, and Aspergillus niger. In addition to this the absorption characteristics of both the hits have also been determined using the rat sac technique and permeation in order of NSC 1520>NSC 1215 has been observed. PMID- 26579620 TI - Thai Silk Fibroin/Gelatin Sponges for the Dual Controlled Release of Curcumin and Docosahexaenoic Acid for Anticancer Treatment. AB - In this study, curcumin and/or docosahexaenoic acid (DHA) were encapsulated in Thai silk fibroin/gelatin (SF/G) sponges, prepared at different blending ratios, aimed to be applied as a controlled release system for localized cancer therapy. The SF/G sponges were fabricated by freeze-drying and glutaraldehyde cross linking techniques. Physicochemical properties of the SF/G sponges were characterized. Then, curcumin and/or DHA were loaded in the sponges by physical adsorption. The encapsulation efficiency and the in vitro release of curcumin and/or DHA from the sponges were evaluated. SF/G sponges could encapsulate curcumin and/or DHA at high encapsulation efficiency. The highly cross-linked and slowly degrading SF/G (50/50) sponge released curcumin and/or DHA at the slowest rate. The in vitro cytotoxicity of the sponges against noncancer cells (L929 mouse fibroblast) and anticancer of curcumin and/or DHA released from the sponges against cervical cancer cells (CaSki) were tested. All sponges were not toxic to L929 mouse fibroblast. The mixed curcumin-DHA at the ratio of 1:4 had the highest inhibiting effect on the growth of CaSki, comparing with the release of curcumin or DHA alone. SF/G sponges could be a potential carrier for dual release of curcumin and DHA for anticancer effect. PMID- 26579622 TI - Size-controlled large-diameter and few-walled carbon nanotube catalysts for oxygen reduction. AB - We demonstrate a new strategy for tuning the size of large-diameter and few walled nitrogen-doped carbon nanotubes (N-CNTs) from 50 to 150 nm by varying the transition metal (TM = Fe, Co, Ni or Mn) used to catalyze graphitization of dicyandiamide. Fe yielded the largest tubes, followed by Co and Ni, while Mn produced a clot-like carbon morphology. We show that morphology is correlated with electrocatalytic activity for the oxygen reduction reaction (ORR). A clear trend of Fe > Co > Ni > Mn for the ORR catalytic activity was observed, in both alkaline media and more demanding acidic media. The Fe-derived N-CNTs exhibited the highest BET (~870 m(2) g(-1)) and electrochemically accessible (~450 m(2) g( 1)) surface areas and, more importantly, the highest concentration of nitrogen incorporated into the carbon planes. Thus, in addition to the intrinsic high activity of Fe-derived catalysts, the high surface area and nitrogen doping contribute to high ORR activity. This work, for the first time, demonstrates size controlled synthesis of large-diameter N-doped carbon tube electrocatalysts by varying the metal used in N-CNT generation. Electrocatalytic activity of the Fe derived catalyst is already the best among studied metals, due to the high intrinsic activity of possible Fe-N coordination. This work further provides a promising route to advanced Fe-N-C nonprecious metal catalysts by generating favorable morphology with more active sites and improved mass transfer. PMID- 26579621 TI - Endohelminths in Bird Hosts from Northern California and an Analysis of the Role of Life History Traits on Parasite Richness. AB - The life history characteristics of hosts often influence patterns of parasite infection either by affecting the likelihood of parasite exposure or the probability of infection after exposure. In birds, migratory behavior has been suggested to affect both the composition and abundance of parasites within a host, although whether migratory birds have more or fewer parasites is unclear. To help address these knowledge gaps, we collaborated with airports, animal rescue/rehabilitation centers, and hunter check stations in the San Francisco Bay Area of California to collect 57 raptors, egrets, herons, ducks, and other waterfowl for parasitological analysis. After dissections of the gastrointestinal tract of each host, we identified 64 taxa of parasites: 5 acanthocephalans, 24 nematodes, 8 cestodes, and 27 trematodes. We then used a generalized linear mixed model to determine how life history traits influenced parasite richness among bird hosts, while controlling for host phylogeny. Parasite richness was greater in birds that were migratory with larger clutch sizes and lower in birds that were herbivorous. The effects of clutch size and diet are consistent with previous studies and have been linked to immune function and parasite exposure, respectively, whereas the effect of migration supports the hypothesis of "migratory exposure" rather than that of "migratory escape." PMID- 26579624 TI - The Feasibility of Using Large-Scale Text Mining to Detect Adverse Childhood Experiences in a VA-Treated Population. AB - Free text in electronic health records resists large-scale analysis. Text records facts of interest not found in encoded data, and text mining enables their retrieval and quantification. The U.S. Department of Veterans Affairs (VA) clinical data repository affords an opportunity to apply text-mining methodology to study clinical questions in large populations. To assess the feasibility of text mining, investigation of the relationship between exposure to adverse childhood experiences (ACEs) and recorded diagnoses was conducted among all VA treated Gulf war veterans, utilizing all progress notes recorded from 2000-2011. Text processing extracted ACE exposures recorded among 44.7 million clinical notes belonging to 243,973 veterans. The relationship of ACE exposure to adult illnesses was analyzed using logistic regression. Bias considerations were assessed. ACE score was strongly associated with suicide attempts and serious mental disorders (ORs = 1.84 to 1.97), and less so with behaviorally mediated and somatic conditions (ORs = 1.02 to 1.36) per unit. Bias adjustments did not remove persistent associations between ACE score and most illnesses. Text mining to detect ACE exposure in a large population was feasible. Analysis of the relationship between ACE score and adult health conditions yielded patterns of association consistent with prior research. PMID- 26579623 TI - Successful Retreatment of a Child with a Refractory Brainstem Ganglioglioma with Vemurafenib. AB - A child with brainstem ganglioglioma underwent subtotal resection and focal radiation. Magnetic resonance imaging confirmed tumor progression 6 months later. Another partial resection revealed viable BRAF V600E-positive residual tumor. Vemurafenib (660 mg/m(2) /dose) was administered twice daily, resulting in >70% tumor reduction with sustained clinical improvement for 1 year. Vemurafenib was then terminated, but significant tumor progression occurred 3 months later. Vemurafenib was restarted, resulting in partial response. Toxicities included Grade I pruritus and Grade II rash. Vemurafenib was effectively crushed and administered in solution via nasogastric tube. We demonstrate benefit from restarting vemurafenib therapy. PMID- 26579625 TI - [Effects of Reactive Jump Training in Handball Players Regarding Jump Height and Power Development in the Triceps Surae Muscle]. AB - BACKGROUND: Studies have shown changes in the technical and physical demands in modern handball. The game has increased considerably in speed, power and dynamics. Jump training has, therefore, become ever more important in the training of the athletes. These developments contribute to the fact that handball is now one of the most injury-prone types of sport, with the lower extremities being most frequently affected. Reactive jump training is not only used in training by now, but also increasingly in injury prevention. The aim of this study was to investigate the effectiveness of reactive jump training with handball players. MATERIAL AND METHODS: 21 regional league handball players were randomly divided into an intervention group (n = 12) and a control group (n = 9). The intervention group completed a six-week reactive jump training programme while the control group went through a non-specific training programme. Jump height (squat and counter movement jump), isokinetic and isometric maximum power as well as muscle activity served as measuring parameters. RESULTS: A comparison of the intervention and control groups revealed that the reactive jump training led to significant improvements in jump height. The isometric and isokinetic maximum power measurements and the electromyographic activities of the triceps surae muscle demonstrated an improvement in the values within the intervention group. However, this improvement was not significant compared with the control group. Likewise both jumps correlated with the muscle activity of the soleus muscle as shown by electromyography. A moderate correlation was noticed between the isokinetic maximum power measurement and the electromyographic activity of the soleus and gastrocnemius medialis muscles. Furthermore, the correlations of the isometric and isokinetic maximum power meas-urements resulted in a strong correlation coefficient. CONCLUSION: This study revealed a significant increase in jump height after reactive jump training. There was no significant difference in power development between the two groups. However, we were able to demonstrate correlations which would make it seem reasonable and interesting to investigate the question more closely. An interesting field of research could be the question of the effectiveness of reactive jump training in the areas of rehabilitation and injury prevention. PMID- 26579628 TI - From the Editor-in-Chief's Desk. PMID- 26579629 TI - Refining Clinical Judgment of Treatment Response and Symptom Remission Identification in Childhood Anxiety Using a Signal Detection Analysis on the Pediatric Anxiety Rating Scale. AB - OBJECTIVE: The purpose of this study was to determine guidelines for delineating treatment response and symptom remission for children with anxiety disorder based on the five item and Pediatric Anxiety Rating Scale (PARS5), and replicate guidelines using the six item PARS (PARS6). METHODS: Participants were 73 children 7-13 years of age with a primary anxiety disorder who received computer assisted cognitive behavioral therapy for anxiety. Signal detection analyses utilizing receiver operating curve procedures were used to determine optimal guidelines for defining treatment response and symptom remission for youth with anxiety disorders on the PARS5 and PARS6. The percent reduction in anxiety severity was used to predict treatment responder status. The percent reduction in symptoms and posttreatment raw score were used to predict remission status. RESULTS: Optimal prediction of treatment response based on gold standard criteria was achieved at 15-20% reduction in symptoms on the PARS5 (with 20% reduction achieving marginally higher accuracy), and 20% reduction on the PARS6. A 25% reduction in symptoms on the PARS5 or a posttreatment raw score cutoff of 9 optimally predicted remission status. For the PARS6, a cutoff of 35% reduction or a posttreatment score of 11, was considered optimal for determining remission in clinical settings, whereas a 30% reduction or score of 12 was considered optimal for research settings. CONCLUSIONS: With different scoring options available for the PARS, these results provide guidelines for determining response and remission based on the PARS5 and PARS6 scores. Guidelines have implications for use in clinical trials, as well as for assessment of change in clinical practice. PMID- 26579630 TI - The Impact of Psychosocial Stressors on Treatment of a Teenage Girl with Obsessive Compulsive Disorder, Trichotillomania, and Anxiety. PMID- 26579632 TI - Toll/IL-1 domain-containing adaptor inducing IFN-beta (TRIF) mediates innate immune responses in murine peritoneal mesothelial cells through TLR3 and TLR4 stimulation. AB - Mesothelial cells are composed of monolayer of the entire surface of serosal cavities including pleural, pericardial, and peritoneal cavity. Although mesothelial cells are known to express multiple Toll-like receptors (TLRs) which contribute to trigger innate immune responses against infections, the precise molecular mechanism remains still unclear. In the present study, we investigated the role of Toll/IL-1 domain-containing adaptor inducing IFN-beta (TRIF), one of the two major TLRs-adaptor molecules, on innate immune response induced by TLR3 and TLR4 stimulation in murine peritoneal mesothelial cells (PMCs). TRIF was strongly expressed in PMCs and its deficiency led to impaired production of cytokines and chemokines by poly I:C and LPS in the cells. Activation of NF kappaB or MAPKs through poly I:C and LPS stimulation was reduced in TRIF deficient PMCs as compared to the WT cells. TRIF was also necessary for optimal nitric oxide synthesis and gene expression of inducible nitric oxide synthase (iNOS) and IFN-beta in PMCs in response to poly I:C and LPS. Furthermore, both Escherichia coli and Pseudomonas aeruginosa induced high level of IL-6, CXCL1, and CCL2 production in PMCs, which was significantly impaired by TRIF deficiency. These results demonstrated that TRIF is required for optimal activation of innate immune responses in mesothelial cells against microbial infections. PMID- 26579633 TI - Combination of low producer AA-genotypes in IFN-gamma and IL-10 genes makes a high risk genetic variant for HIV disease progression. AB - Rate of HIV disease progression varies considerably among individuals, host genetic makeup be one of the possible reasons. We aimed to determine association of functional single nucleotide polymorphism (SNPs), (-179G/T and +874T/A) in IFN gamma and (-1082A/G, -819C/T and -592C/A) in IL-10 genes, with the rate of disease progression or susceptibility to HIV infection. Therapy naive HIV infected individuals from North India, categorized as slow progressors or fast progressors and HIV exposed seronegative individuals were recruited for this study. Genotyping results revealed significantly higher frequencies of low producer AA genotype at +874T/A in IFN-gamma gene and -592C/A position in IL-10 gene in FPs (p<0.002). Multifactor dimensional reduction (MDR) analysis revealed this to be a high risk combination for faster disease progression in HIV-1 infected individuals. Low producer AA genotype carriers at +874T/A in IFN-gamma gene produced significantly low amounts of cellular IFN-gamma. Low producing haplotype 'ATA' at -1082, -819 and -592 loci in IL-10 gene was significantly over represented in FPs as compared to SPs (p<0.01) and these individuals showed poor response to therapy in terms of CD4 count gains after one year of ART, compared to high producing haplotype (GCC) carriers. Thus, a combination of genetic variations in IFN-gamma and IL-10 cytokine genes in a single host associate with HIV disease progression and may help clinicians to better manage the HIV disease if known earlier. PMID- 26579634 TI - Hydrodynamic function of biomimetic shark skin: effect of denticle pattern and spacing. AB - The structure of shark skin has been the subject of numerous studies and recently biomimetic shark skin has been fabricated with rigid denticles (scales) on a flexible substrate. This artificial skin can bend and generate thrust when attached to a mechanical controller. The ability to control the manufacture of biomimetic shark skin facilitates manipulation of surface parameters and understanding the effects of changing denticle patterns on locomotion. In this paper we investigate the effect of changing the spacing and arrangement of denticles on the surface of biomimetic shark skin on both static and dynamic locomotor performance. We designed 3D-printed flexible membranes with different denticle patterns and spacings: (1) staggered-overlapped, (2) linear-overlapped, and (3) linear-non-overlapped, and compared these to a 3D-printed smooth-surfaced control. These 3D printed shark skin models were then tested in a flow tank with a mechanical flapping device that allowed us to either hold the models in a stationary position or move them dynamically. We swam the membranes at a frequency of 1 Hz with different heave amplitudes (from +/-1 cm to +/-3 cm) while measuring forces, torques, self-propelled swimming speed, and cost of transport (COT). Static tests revealed drag reduction of denticle patterns compared to a smooth control at low speeds, but increased drag at speeds above 25 cm s(-1). However, during dynamic (swimming) tests, the staggered-overlapped pattern produced the fastest swimming speeds with no significant increase in the COT at lower heave values. For instance, at a heave frequency of 1 Hz and amplitude of +/-1 cm, swimming speed of the staggered-overlapped pattern increased by 25.2% over the smooth control. At higher heave amplitudes, significantly faster self propelled swimming speeds were achieved by the staggered-overlapped pattern, but with higher COT. Only the staggered-overlapped pattern provides a significant swimming performance advantage over the smooth control and the other two denticle patterns. Quantitative hydrodynamic comparisons among skin models where control over manufacture allows alteration of design parameters provides a useful experimental tool for future work on the considerable natural diversity of shark skin denticles both among species and on different body locations. PMID- 26579635 TI - Vitreomacular Attachment Ultrastructure and Histopathological Correlation. AB - PURPOSE: The ultrastructural anatomy of the vitreomacular interface in young human donor eyes and animal eyes is explored using scanning electron microscopy (SEM) to determine its relationship with the formation of the perimacular ridge from abusive head trauma, as well as macular hole formation, vitreomacular traction syndrome, and preretinal hemorrhage. MATERIALS AND METHODS: SEM is used to image the posterior poles of 23 human donor eyes, as well as several cow, dog, monkey, pig, and rabbit eyes for vitreomacular interface anatomy. We examined autopsy eyes from abusive head trauma histopathologically. RESULTS: Two rings of thick, circumferential, vitreous attachment at the area centralis are found. An inner ring at the fovea, R1, and an outer ring at the perifoveal region, R2, are both observed in eyes from donors < 30 years of age; comparatively, in eyes from donors > 30 years, only R2 is present (p<0.001). R2 is found with unique elliptical shape in Cynomolgus monkey. Macula, R1, and R2 are not detected in cow, dog, pig, or rabbit eyes. CONCLUSIONS: The vitreomacular ring attachments found in donor eyes correspond anatomically with the perimacular ridge found histopathologically in abusive head trauma, and likely correlates with the macular hole, vitreomacular traction syndrome, and preretinal hemorrhage. Vitreomacular interface anatomy in the monkey, but not the cow, dog, pig, or rabbit, demonstrates some anatomical similarity to that of the human, consistent with species differences regarding the area centralis. PMID- 26579637 TI - Negative Pressure Pulmonary Edema after Electroconvulsive Therapy. PMID- 26579636 TI - Nomogram for Preoperative Estimation of Microvascular Invasion Risk in Hepatitis B Virus-Related Hepatocellular Carcinoma Within the Milan Criteria. AB - IMPORTANCE: The presence of microvascular invasion (MVI) decreases surgical outcomes of hepatocellular carcinoma (HCC). An accurate preoperative prediction of MVI can help surgeons to better choose surgical procedures, but accuracy is still difficult to achieve. OBJECTIVE: To develop a nomogram to predict MVI presence before liver resection for hepatitis B virus (HBV)-related HCC within the Milan criteria (solitary nodule <=5 cm; <=3 nodules, none >3 cm; and no macrovascular invasion). DESIGN, SETTING, AND PARTICIPANTS: Data on 1004 consecutive patients who underwent liver resection for HBV-related HCC within the Milan criteria at the Eastern Hepatobiliary Surgery Hospital between April 6, 2004, and February 22, 2011, were prospectively collected. Of these, patients who underwent surgery in an earlier period formed the training cohort (n = 707) for nomogram development, and those who underwent surgery thereafter formed the validation cohort (n = 297) to confirm the model's performance. Data analysis was conducted from August 1 to November 11, 2014. EXPOSURES: Liver resection for HCC. MAIN OUTCOMES AND MEASURES: Overall survival and time to recurrence after liver resection were measured. Multivariate logistic regression was used to identify the independent risk factors associated with MVI that then were incorporated into the nomogram. RESULTS: Histopathologically identified MVI was found in 211 of 707 patients (29.8%) and 89 of 297 patients (30.0%) in the training and validation cohorts, respectively. In the training cohort, the 5-year recurrence and overall survival rates were 78.5% and 46.9%, respectively, in patients with MVI and 58.4%, and 70.9%, respectively, in patients without MVI (both P < .001). The preoperative factors associated with MVI were large tumor diameter, multiple nodules, incomplete capsule, alpha-fetoprotein level greater than 20 ng/mL, platelet count less than 100 * 103/uL, hepatitis B virus DNA load greater than 104 IU/mL, and a typical dynamic pattern of tumors on contrast-enhanced magnetic resonance imaging. Incorporating these 7 factors, the nomogram achieved good concordance indexes of 0.81 (95% CI, 0.78-0.85) and 0.80 (95% CI, 0.75-0.86) in predicting MVI in the training and validation cohorts, respectively, and had well fitted calibration curves. The positive and negative predictive values (95% CIs) of the nomogram were calculated, resulting in positive predictive values of 57.2% (52.0%-64.9%) and 57.9% (49.2%-68.5%) and negative predictive values of 87.2% (83.2%-89.4%) and 83.2% (76.0%-87.7%) for the training and validation cohorts, respectively. Patients who had a nomogram score of less than 200 or 200 or greater were considered to have low or high risks of MVI presence, respectively. CONCLUSIONS AND RELEVANCE: The nomogram achieved an optimal preoperative prediction of MVI in HBV-related HCC within the Milan criteria. Using the model, the risk for an individual patient to harbor MVI can be determined, which can lead to a rational therapeutic choice. PMID- 26579638 TI - Anti-mullerian hormone and insulin-like 3 levels in healthy normal-weight ovulatory and anovulatory eumenorrheic late adolescent females: potential early biomarkers of ovarian dysfunction? AB - OBJECTIVE: The aim of this study was to evaluate differences in anti-mullerian hormone (AMH) and insulin-like 3 (INSL3) levels and their association with gonadotropin and ovarian steroid hormones, as expression of ovarian function, between healthy normal-weight ovulatory and anovulatory eumenorrheic late adolescent females. STUDY DESIGN: This study analyzed AMH and INSL3 levels in forty healthy eumenorrheic late adolescent females (aged 16-19 ys), selected from a cross-sectional epidemiological study performed on the prevalence of hyperandrogenic states. The subjects were divided into ovulatory (n: 28) and anovulatory (n: 12) groups in accordance to a previous cluster analysis based on progesterone (P) distribution measured once in the latter part of the cycle. Both groups were compared for anthropometric, biochemical and hormonal parameters. RESULTS: INSL3 and AMH were detectable in all samples. Testosterone (P=0.01), the free-androgen index (FAI) (P=0.051), gonadotropins (LH: P=0.02; FSH: P=0.004) and AMH (P=0.02) levels were significantly higher in the anovulatory group with respect to their ovulatory counterpart. A trend toward significantly higher INSL3 concentrations (P=0.08) was also shown in the anovulatory group. A positive correlation between INSL3 levels and androgens such as androstenedione (r=0.38; P=0.02), testosterone (r=0.44; P=0.004) and FAI (r=0.42; P=0.006) and a negative borderline significant correlation (r=-0.30; P=0.055) between AMH and P were shown in all subjects. CONCLUSION: Healthy eumenorrheic late adolescent females with sporadic anovulation display higher AMH and INSL-3 blood concentrations in association with higher androgen levels compared with age- and BMI-matched subjects with ovulatory cycle, suggesting evidence of an earlier ovarian dysfunction. PMID- 26579639 TI - A Positive Study Despite Negative Results. PMID- 26579640 TI - Don't Blame the Messenger. PMID- 26579641 TI - The Efficacy and Utility of Acute Normovolemic Hemodilution. PMID- 26579642 TI - Isovaline: Is It the Next Analgesic? PMID- 26579643 TI - Cardiac Bulldozers, Backhoes, and Blood Pressure. PMID- 26579644 TI - Refining the Odds. PMID- 26579645 TI - Strain Assessment of Myocardial Function: A Better Approach or Just Fun and Games? PMID- 26579646 TI - Quality Improvement Demands Quality Data. PMID- 26579647 TI - Anesthesiology Graduate Medical Education: Best Approaches for the Learner, Best Approaches for the Teacher. PMID- 26579648 TI - Alpha, Beta, Meta: Guidelines for Assessing Power and Type I Error in Meta Analyses. PMID- 26579649 TI - What Is an Acute Care Anesthesiologist? PMID- 26579650 TI - Time Has Come for the Acute Care Anesthesiologist. PMID- 26579651 TI - Screening for High Blood Pressure in the Perioperative Setting: The Role of Anesthesiologists in Future Cardiovascular Risk Management. PMID- 26579652 TI - Intraoperative, Real-Time Three-Dimensional Transesophageal Echocardiography for the Transcatheter Placement of an Edwards SAPIEN Aortic Valve in the Mitral Position for Severe Mitral Stenosis. PMID- 26579653 TI - The Sudden Appearance of a Mobile Mass in the Ascending Aorta on Transesophageal Echocardiography After Transcatheter Aortic Valve Replacement. PMID- 26579654 TI - Three-Dimensional Transesophageal Echocardiography in the Excision of a Myocardial Pseudoaneurysm. PMID- 26579655 TI - Associated Roles of Perioperative Medical Directors and Anesthesia: Hospital Agreements for Operating Room Management. AB - As reviewed previously, decision making can be made systematically shortly before the day of surgery based on reducing the hours of overutilized operating room (OR) time and tardiness of case starts (i.e., patient waiting). We subsequently considered in 2008 that such decision making depends on rational anesthesia hospital agreements specifying anesthesia staffing. Since that prior study, there has been a substantial increase in understanding of the timing of decision making to reduce overutilized OR time. Most decisions substantively influencing overutilized OR time are those made within 1 workday before the day of surgery and on the day of surgery, because only then are ORs sufficiently full that case scheduling and staff assignment decisions affect overutilized OR time. Consequently, anesthesiologists can easily be engaged in such decisions, because generally they must be involved to ensure that the corresponding anesthesia staff assignments are appropriate. Despite this, at hospitals with >8 hours of OR time used daily in each OR, computerized recommendations are superior to intuition because of cognitive biases. Decisions need to be made by a Perioperative Medical Director who has knowledge of the principles of perioperative managerial decision making published in the scientific literature rather than by a committee lacking this competency. Education in the scientific literature, and when different analytical methods should be used, is important. The addition that we make in this article is to show that an agreement between an anesthesia group and a hospital can both reduce overutilized OR time and patient waiting: The anesthesia group and hospital will ensure, hourly, that, when there are case(s) waiting to start, the number of ORs in use for each service will be at least the number that maximizes the efficiency of use of OR time. Neither the anesthesia group nor the hospital will be expected to run more than that number of ORs without mutual agreement. Agreements assure that processes mutually beneficial to organizations, but not necessarily to individuals at each point in time, are performed as designed, especially in the setting of cognitive biases. PMID- 26579656 TI - The Efficacy and Safety of the Novel Peripheral Analgesic Isovaline as an Adjuvant to Propofol for General Anesthesia and Conscious Sedation: A Proof-of Principle Study in Mice. AB - BACKGROUND: The combination of propofol and an opioid analgesic is widely used for procedural sedation, as well as total IV anesthesia. However, opioids produce respiratory depression, a primary cause of death due to these agents. We recently reported on the antinociceptive actions of isovaline, a small nonbiogenic amino acid that does not readily cross the blood-brain barrier and acts on peripheral gamma-aminobutyric acid type B receptors. Here, we explored the possibility that isovaline may be an effective and safe alternative to opioids as an adjunct to propofol for producing anesthesia. METHODS: With approval from our Animal Care Committee, we conducted an in vivo study in adult female CD-1 mice using Dixon's "up-and-down" method for dose assessment. Animals received intraperitoneal saline, propofol, isovaline, fentanyl, or coadministration of propofol with isovaline or fentanyl. We assessed hypnosis by a loss of righting reflex and immobility by an absence of motor response to tail clip application. General anesthesia was defined as the presence of both hypnosis and immobility. We assessed conscious sedation as a decrease in time on a rotarod. The maximal dose without respiratory rates of <4 per minute, apnea, or death was defined as the maximal tolerated dose. RESULTS: Either isovaline or fentanyl coadministered with propofol at its half-maximal effective dose (ED50) for hypnosis produced general anesthesia (isovaline ED50, 96 mg/kg [95% confidence interval {CI}, 88-124 mg/kg]; fentanyl ED50, 0.12 mg/kg [95% CI, 0.08-3.5 mg/kg]). Propofol produced hypnosis (ED50, 124 mg/kg [95% CI, 84-3520 mg/kg]) but did not block responses to tail clip application. Neither isovaline nor fentanyl produced hypnosis at doses which produced immobility (isovaline ED50, 350 mg/kg [95% CI, 286-1120 mg/kg]; fentanyl ED50, 0.35 mg/kg [95% CI, 0.23-0.51 mg/kg]). Isovaline at its analgesic ED50, coadministered with a subhypnotic dose of propofol (40 mg/kg), did not exacerbate propofol-induced deficits in rotarod performance. The median maximal tolerated dose of fentanyl coadministered with the hypnotic ED50 of propofol was 11 mg/kg (95% CI, 8-18 mg/kg). Isovaline at a maximal deliverable (soluble) dose of 5000 mg/kg produced no apparent respiratory depression or other adverse effects. CONCLUSIONS: The novel analgesic, isovaline, coadministered with propofol, produced general anesthesia and conscious sedation in mice. The margin of safety for propofol-isovaline was considerably higher than that for propofol fentanyl. This study's results show that propofol-based sedation and general anesthesia can be effectively and safely produced by replacing the conventional opioid component with a brain-impermeant peripherally acting gamma-aminobutyric acid type B receptor agonist. The results provide proof of the principle of combining a peripheral analgesic with a centrally acting hypnotic to produce general anesthesia. This principle suggests a novel approach to clinical general anesthesia and conscious sedation. PMID- 26579657 TI - Occupational Chronic Sevoflurane Exposure in the Everyday Reality of the Anesthesia Workplace. AB - BACKGROUND: Although sevoflurane is one of the most commonly used volatile anesthetics in clinical practice, anesthesiologists are hardly aware of their individual occupational chronic sevoflurane exposure. Therefore, we studied sevoflurane concentrations in the anesthesiologists' breathing zones, depending on the kind of induction for general anesthesia, the used airway device, and the type of airflow system in the operating room. Furthermore, sevoflurane baselines and typical peaks during general anesthesia were determined. METHODS: Measurements were performed with the LumaSense Photoacoustic Gas Monitor. As we detected the gas monitor's cross-sensitivity reactions between sevoflurane and disinfectants, regression lines for customarily used disinfectants during surgery (Cutasept(r), Octeniderm(r)) and their alcoholic components were initially analyzed. Hospital sevoflurane concentrations were thereafter measured during elective surgery in 119 patients. The amount of inhaled sevoflurane by anesthesiologists was estimated according to mVA = cVA * V * t * rhoVA aer. RESULTS: Induction of general anesthesia stopped after tracheal intubation with the patient's expiratory sevoflurane concentration of 1.5%. Thereby, inhalational inductions (INH) caused higher sevoflurane concentrations than IV inductions (mean [SD]: (Equation is included in full-text article.)[ppm] INH 2.43 +/- 1.91 versus IV 0.62 +/- 0.33, P < 0.001; mVA [mg] INH 1.95 +/- 1.54 versus IV 0.30 +/- 0.22, P < 0.001). The use of laryngeal mask airway (LMATM) led to generally higher sevoflurane concentrations in the anesthesiologists' breathing zones than tracheal tubes ((Equation is included in full-text article.)[ppm] tube 0.37 +/- 0.16 versus LMATM 0.79 +/- 0.53, P = 0.009; (Equation is included in full-text article.)[ppm] tube 1.91 +/- 0.91 versus LMATM 2.91 +/- 1.81, P = 0.057; mVA [mg] tube 1.47 +/- 0.64 versus LMATM 2.73 +/- 1.81, P = 0.019). Sevoflurane concentrations were trended higher during surgery in operating rooms with turbulent flow (TF) air-conditioning systems compared with laminar flow (LF) air conditioning systems ((Equation is included in full-text article.)[ppm] TF 0.29 +/- 0.12 versus LF 0.13 +/- 0.06, P = 0.012; mVA [mg/h] TF 1.16 +/- 0.50 versus LF 0.51 +/- 0.25, P = 0.007). CONCLUSIONS: Anesthesiologists are chronically exposed to trace concentrations of sevoflurane during work. Inhalational inductions, LMATM, and TF air-conditioning systems in particular are associated with higher sevoflurane exposure. However, the amount of inhaled sevoflurane per day was lower than expected, perhaps because concentrations in previous measurements could be overestimated (10%-15%) because of the cross-sensitivity reaction. PMID- 26579658 TI - Caring for the Jehovah's Witness Parturient. AB - Caring for the Jehovah's Witness parturient is a complex task that presents a number of ethical, medical, and legal concerns because many Jehovah's Witnesses refuse allogeneic blood transfusion. Childbirth and its surrounding events may be associated with significant blood loss. Given their significant role in the intraoperative administration of blood products, anesthesia providers should be familiar with factors that must be considered in the perioperative care of Jehovah's Witness parturients. Several pharmacologic therapies, anesthetic techniques, and operative interventions aimed at blood conservation may be useful in the care of such patients. Aside from their refusal of transfusion, each Witness makes a personal decision on the acceptability of derivatives of plasma or cellular blood components and autologous blood management. Therefore, the patient-physician relationship must ensure that the individual patient's desires are accurately communicated, respected, and documented in the patient's medical record. The Perioperative Surgical Home model is appropriate for use in caring for Jehovah's Witness patients because it allows for the early and continuing coordination of care and communication between the patient and a multidisciplinary team. In this article, we present a focused review of concepts important to the provision of anesthetic care of parturients who are Jehovah's Witnesses and introduce an algorithmic perioperative approach that may be applied to the care of the Jehovah's Witness parturient undergoing an operative procedure. PMID- 26579659 TI - Obstetric Neuraxial Drug Administration Errors: A Quantitative and Qualitative Analytical Review. AB - BACKGROUND: Drug administration errors in obstetric neuraxial anesthesia can have devastating consequences. Although fully recognizing that they represent "only the tip of the iceberg," published case reports/series of these errors were reviewed in detail with the aim of estimating the frequency and the nature of these errors. METHODS: We identified case reports and case series from MEDLINE and performed a quantitative analysis of the involved drugs, error setting, source of error, the observed complications, and any therapeutic interventions. We subsequently performed a qualitative analysis of the human factors involved and proposed modifications to practice. RESULTS: Twenty-nine cases were identified. Various drugs were given in error, but no direct effects on the course of labor, mode of delivery, or neonatal outcome were reported. Four maternal deaths from the accidental intrathecal administration of tranexamic acid were reported, all occurring after delivery of the fetus. A range of hemodynamic and neurologic signs and symptoms were noted, but the most commonly reported complication was the failure of the intended neuraxial anesthetic technique. Several human factors were present; most common factors were drug storage issues and similar drug appearance. Four practice recommendations were identified as being likely to have prevented the errors. CONCLUSIONS: The reported errors exposed latent conditions within health care systems. We suggest that the implementation of the following processes may decrease the risk of these types of drug errors: (1) Careful reading of the label on any drug ampule or syringe before the drug is drawn up or injected; (2) labeling all syringes; (3) checking labels with a second person or a device (such as a barcode reader linked to a computer) before the drug is drawn up or administered; and (4) use of non-Luer lock connectors on all epidural/spinal/combined spinal-epidural devices. Further study is required to determine whether routine use of these processes will reduce drug error. PMID- 26579660 TI - The Cognitive Science of Learning: Concepts and Strategies for the Educator and Learner. AB - Education is the fundamental process used to develop and maintain the professional skills of physicians. Medical students, residents, and fellows are expected to learn considerable amounts of information as they progress toward board certification. Established practitioners must continue to learn in an effort to remain up-to-date in their clinical realm. Those responsible for educating these populations endeavor to teach in a manner that is effective, efficient, and durable. The study of learning and performance is a subdivision of the field of cognitive science that focuses on how people interpret and process information and how they eventually develop mastery. A deeper understanding of how individuals learn can empower both educators and learners to be more effective in their endeavors. In this article, we review a number of concepts found in the literature on learning and performance. We address both the theoretical principles and the practical applications of each concept. Cognitive load theory, constructivism, and analogical transfer are concepts particularly beneficial to educators. An understanding of goal orientation, metacognition, retrieval, spaced learning, and deliberate practice will primarily benefit the learner. When these concepts are understood and incorporated into education and study, the effectiveness of learning is significantly improved. PMID- 26579661 TI - The National Anesthesia Clinical Outcomes Registry. AB - The Anesthesia Quality Institute (AQI) was chartered in 2008 by the American Society of Anesthesiologists to develop the National Anesthesia Clinical Outcomes Registry (NACOR). In this Technical Communication, we will describe how data enter NACOR, how they are authenticated, and how they are analyzed and reported. NACOR accepts case-level administrative, clinical, and quality capture data from voluntarily participating anesthesia practices and health care facilities in the United States. All data are transmitted to the AQI in summary electronic files generated by billing, quality capture, and electronic health care record software, typically on a monthly basis. All data elements are mapped to fields in the NACOR schema in accordance with a publicly available data dictionary. Incoming data are loaded into NACOR by AQI technologists and are subject to both manual and automated review to identify systematically missing elements, miscoding, and inadvertent corruption. Data are deidentified in compliance with Health Insurance Portability and Accountability Act regulations. The database server of AQI, which houses the NACOR database, is protected by 2 firewalls within the American Society of Anesthesiologists' network infrastructure; this system has not been breached. The NACOR Participant User File, a deidentified case-level dataset of information from NACOR, is available to researchers at participating institutions. NACOR architecture and the nature of the Participant User File include both strengths and weaknesses. PMID- 26579662 TI - Systematic Reviews of Anesthesiologic Interventions Reported as Statistically Significant: Problems with Power, Precision, and Type 1 Error Protection. AB - BACKGROUND: The GRADE Working Group assessment of the quality of evidence is being used increasingly to inform clinical decisions and guidelines. The assessment involves explicit consideration of all sources of uncertainty. One of these sources is imprecision or random error. Many published meta-analyses are underpowered and likely to be updated in the future. When data are sparse and there are repeated updates, the risk of random error is increased. Trial Sequential Analysis (TSA) is one of several methodologies that estimates this increased risk (and decreased precision) in meta-analyses. With nominally statistically significant meta-analyses of anesthesiologic interventions, we used TSA to estimate power and imprecision in the context of sparse data and repeated updates. METHODS: We conducted a search to identify all systematic reviews with meta-analyses that investigated an intervention that may be implemented by an anesthesiologist during the perioperative period. We randomly selected 50 meta analyses that reported a statistically significant dichotomous outcome in their abstract. We applied TSA to these meta-analyses by using 2 main TSA approaches: relative risk reduction 20% and relative risk reduction consistent with the conventional 95% confidence limit closest to null. We calculated the power achieved by each included meta-analysis, by using each TSA approach, and we calculated the proportion that maintained statistical significance when allowing for sparse data and repeated updates. RESULTS: From 11,870 titles, we found 682 systematic reviews that investigated anesthesiologic interventions. In the 50 sampled meta-analyses, the median number of trials included was 8 (interquartile range [IQR], 5-14), the median number of participants was 964 (IQR, 523-1736), and the median number of participants with the outcome was 202 (IQR, 96-443). By using both of our main TSA approaches, only 12% (95% CI, 5%-25%) of the meta analyses had power >= 80%, and only 32% (95% CI, 20%-47%) of the meta-analyses preserved the risk of type 1 error <5%. CONCLUSIONS: Most nominally statistically significant meta-analyses of anesthesiologic interventions are underpowered, and many do not maintain their risk of type 1 error <5% if TSA monitoring boundaries are applied. Consideration of the effect of sparse data and repeated updates is needed when assessing the imprecision of meta-analyses of anesthesiologic interventions. PMID- 26579663 TI - Caroline B. Palmer: Pioneer Physician Anesthetist and First Chair of Anesthesia at Stanford. AB - Caroline B. Palmer was appointed as Chief of Anesthesia at Cooper Medical College (soon renamed as Stanford Medical School) in 1909. For the next 28 years, she was an innovative leader, a clinical researcher, and a strong advocate for recognition of anesthesiology as a medical specialty. To honor her accomplishments, the operating room suite in the new Stanford Hospital will be named after this pioneering woman anesthesiologist. PMID- 26579664 TI - Data, Big Data, and Metadata in Anesthesiology. AB - The last decade has seen an explosion in the growth of digital data. Since 2005, the total amount of digital data created or replicated on all platforms and devices has been doubling every 2 years, from an estimated 132 exabytes (132 billion gigabytes) in 2005 to 4.4 zettabytes (4.4 trillion gigabytes) in 2013, and a projected 44 zettabytes (44 trillion gigabytes) in 2020. This growth has been driven in large part by the rise of social media along with more powerful and connected mobile devices, with an estimated 75% of information in the digital universe generated by individuals rather than entities. Transactions and communications including payments, instant messages, Web searches, social media updates, and online posts are all becoming part of a vast pool of data that live "in the cloud" on clusters of servers located in remote data centers. The amount of accumulating data has become so large that it has given rise to the term Big Data. In many ways, Big Data is just a buzzword, a phrase that is often misunderstood and misused to describe any sort of data, no matter the size or complexity. However, there is truth to the assertion that some data sets truly require new management and analysis techniques. PMID- 26579665 TI - Trauma, Critical Care, and Emergency Care Anesthesiology: A New Paradigm for the "Acute Care" Anesthesiologist? PMID- 26579666 TI - Has the Emperor Been Wearing Clothes? (The Value of the Pediatric Perioperative Surgical Home). PMID- 26579667 TI - Prevention of Peri-Induction Hypertension in Pre-Eclamptic Patients. PMID- 26579668 TI - The Future of Physician Anesthesiologists. PMID- 26579669 TI - In Response. PMID- 26579670 TI - Methodologic Concerns Regarding a Study Concluding That Epidural Labor Analgesia Is Associated with a Decreased Risk of Postpartum Depression. PMID- 26579671 TI - In Response. PMID- 26579674 TI - Priscilla Kincaid-Smith (1926-2015). PMID- 26579676 TI - Replenishment of the podocyte compartment by parietal epithelial cells. AB - While progressive podocytopenia is a characteristic feature of chronic glomerular disease, the visceral epithelial niche can be replenished from the parietal epithelium. Two new reports demonstrate this process in genetically engineered mice, using fate mapping, and in human renal biopsies manifesting segmental glomerulosclerosis in diverse settings, using cellular and extracellular matrix markers. PMID- 26579677 TI - Vitamin D: can you have too much of a good thing in chronic kidney disease? AB - Recommendation of vitamin D supplements is common although there is little information regarding the definition of the upper limit of safety. Kusunoki et al. now publish interesting data of a novel mechanism by which excess 25 hydroxyvitamin D exerts adverse effects on the kidney, using unilateral ureteral obstruction in the mouse as a model of kidney disease. Their report provides a new mechanism to be assessed as a surrogate measure of vitamin D toxicity that may be clinically relevant. PMID- 26579678 TI - What is myeloperoxidase doing in ANCA-associated glomerulonephritis? AB - O'Sullivan et al. describe glomerular localization of myeloperoxidase (MPO) in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and correlate the amount of deposition with severity of injury. MPO is the antigen against which anti-MPO ANCAs are directed, the antigen to which pathogenic T cells that can induce antibody-independent AAV are directed, and MPO can induce glomerular injury directly by interacting with H2O2 and a halide to halogenate glomerular structures. All three of these roles are likely involved in human disease. PMID- 26579679 TI - Is hemodiafiltration ready for broader use? AB - Hemodiafiltration is practiced throughout Europe and in a few additional countries but, because of regulatory restrictions, is not currently available in the United States. Hemodiafiltration removes uremic species more broadly than is achieved by diffusion dialysis, perhaps explaining its better outcome profile. PMID- 26579680 TI - Initiation of dialysis: Trigger or cause of cardiovascular events? AB - Initiation of dialysis is associated with increased morbidity and mortality. However, a question could be asked whether these events are caused by initiation of dialysis or whether dialysis serves as a trigger unveiling or worsening underlying preexisting cardiovascular comorbidities that could be pre-treated. PMID- 26579681 TI - Uromodulin, kidney function, cardiovascular disease, and mortality. AB - Uromodulin (Tamm-Horsfall protein) is exclusively produced by the kidney and is the most abundant protein excreted in normal urine. The level of uromodulin in urine could represent a useful biomarker for renal tubular function. The study of Garimella et al. adds elements into the debate, by suggesting that, in elderly adults, low urinary uromodulin concentrations in spot urine identify people at risk of progressive kidney disease and mortality above and beyond established markers of kidney disease. PMID- 26579682 TI - Supplemental iron via dialysate: a novel mode of delivery for hemodialysis patients. AB - Gupta et al. describe a novel strategy for iron administration to hemodialysis patients, giving ferric pyrophosphate citrate via the dialysate. PRIME, a randomized controlled study comparing this technology against placebo, shows a 35% reduction in prescribed erythropoiesis-stimulating agent dose. The findings may be explained in part by a restrictive protocol for intravenous iron administration in the placebo group, producing lower ferritin levels. There were no obvious safety concerns. The general applicability of this technology, and its cost-effectiveness, are unclear at the present time. PMID- 26579683 TI - Assessing the protective effect of remote ischemic preconditioning on acute kidney injury after coronary artery bypass graft surgery. PMID- 26579684 TI - The Authors Reply. PMID- 26579685 TI - Cell-based immunosuppression in kidney transplantation: the value of non-human primate studies. PMID- 26579686 TI - Circulating progranulin but not renal progranulin expression is increased in renal dysfunction. PMID- 26579687 TI - The Authors Reply. PMID- 26579688 TI - Serial monitoring of anti-PLA2R in initial PLA2R-negative patients with primary membranous nephropathy. PMID- 26579689 TI - Renal dysfunction after endovascular abdominal aortic aneurysm repair: time to use the correct outcome measures. PMID- 26579690 TI - Severe skeletal deformities in inappropriately treated distal renal tubular acidosis. PMID- 26579691 TI - Multiple osteolytic lesions in a hemodialysis patient. PMID- 26579692 TI - Hypercalcemia in testicular tuberculosis. PMID- 26579693 TI - The Case | An unusual case of intoxication. PMID- 26579694 TI - The Case | Hypercalcemia in a renal transplant recipient. PMID- 26579695 TI - Case complexity in patients with chronic nonspecific musculoskeletal pain: a Delphi and feasibility study. AB - Assessment of case complexity in patients with chronic nonspecific musculoskeletal pain (CMP) is currently clinician based, not transparent, and with low reliability. The objective of this study was to explore case complexity and to initiate the development of a case complexity index (CCI). A three-round Delphi study among clinicians involved in multidisciplinary Pain Rehabilitation Programs was performed to identify important factors that are assumed to influence functioning in patients with CMP. The 10 most important factors were used to initiate the development of a CCI, with mean ratings of importance per factor as weights. The feasibility of the CCI was tested in a pilot study on 16 patients with CMP. In the first round, 166 factors were identified; in the second round, the 10 most important factors were selected; in the third round, relative weights of each factor were calculated, ranging from 1.75 (features of complaints) to 3.56 (psychiatric disorders) on a scale from 0 (no weight) to 4 (very heavy weight). The assessments for the factors were mainly based on clinical examination and reasoning. Clinicians could rate all patients using the CCI, which confirmed feasibility of the CCI. Ten, mainly psychosocial, factors were identified, which were assumed to be most important for the assessment of case complexity in a patient with CMP. With these factors, a CCI was created, for which feasibility was established. This CCI is transparent, easy to use, and might provide a basis for further development of a structured assessment of case complexity, which may have scientific and clinical relevance. PMID- 26579696 TI - Predictors of static balance in ambulatory persons with multiple sclerosis. AB - People with multiple sclerosis (MS) experience a high rate of falls and have decreased static and dynamic balance. The purpose of this study was to determine best predictors of static standing balance, as measured by a single limb stance (SLS) timed test, in ambulatory persons with MS (PwMS) from among commonly used medical and rehabilitation clinical tests. Ambulatory PwMS participated in a single test session. Medical exam data gathered included the Function System (FS) neurologic exam and Expanded Disability Status Score (EDSS). A variety of commonly administered rehabilitation clinical tests addressing static balance, dynamic balance, gait endurance, functional lower extremity strength, abdominal and respiratory muscle strength were completed. Descriptive statistics, Pearson product moment correlations, and forward step-wise linear regressions were calculated. Twenty-eight ambulatory PwMS completed this study. Mean age was 54.74 years. Mean SLS score was 14.6 s. Pyramidal, sensory, bowel/bladder, and visual FS scores and the EDSS were significantly correlated with SLS. Maximal step length scores were significantly correlated with SLS at P less than 0.05 and the Functional Stair Test (FST) and 6-min walk test were correlated with SLS at P less than 0.10. Medical exam data EDSS and FS sensory explain 72.1% of the variance in SLS scores. Rehabilitation exam data FS sensory and FST explain 68.8% of the variance. The FS sensory, EDSS, and FST together explain 73.3% of the variance. PMID- 26579697 TI - Loneliness during inpatient rehabilitation: results of a qualitative study. AB - The current study provides evidence of patient loneliness during inpatient rehabilitation, an incidental, yet important finding from a qualitative study. Patients, staff and community volunteers in our rehabilitation centre completed semistructured in-depth interviews that were subjected to a thematic analysis. Results indicated that some patients had unmet social needs and experienced profound loneliness despite being surrounded by staff and patients. Further investigation to quantify the prevalence, intensity and effects of loneliness during inpatient rehabilitation is warranted. PMID- 26579698 TI - Patients with obesity-related comorbidities have higher disability compared with those without obesity-related comorbidities: results from a cross-sectional study. AB - The aim of the present study was to describe disability in adult obese patients with obesity-related comorbidities, and to compare it with that of patients without obesity-related comorbidities. Two groups of obese patients were administered a set of 166 International Classification of Functioning, Disability and Health (ICF) categories; on the basis of this set, count-based indexes were developed for each ICF component and difference between patients with and without comorbidities were assessed with independent-sample t-test and Cohen's d as a measure of effect size. ICF categories in which at least 20% of patients reported a problem were considered relevant for describing functioning of obese patients; for each of them, the risk of having obesity-related comorbidities was calculated using odds ratio and 95% confidence interval. A total of 106 inpatients were enrolled in the study: 68 ICF categories reached the 20% threshold, and 31 of them were relevant only among patients with comorbidities. The presence of obesity-related comorbidities was associated with an increased risk of bodily impairments and limitations in performing daily activities. Compared with patients without obesity-related comorbidities, those with comorbidities showed higher disability. Comorbidities contribute to obesity-related disability, and our results support the importance of early rehabilitation interventions to reduce disability. PMID- 26579699 TI - Bimanual dexterity assessment: validation of a revised form of the turning subtest from the Minnesota Dexterity Test. AB - Bimanual coordination underlies many daily activities. It is tested by various versions of the old Minnesota Dexterity Test (dating back to 1931, 'turning' subtest). This, however, is ill standardized, may be time-consuming, and has poor normative data. A timed-revised form of the turning subtest (MTTrf) is presented. Age-related norms and test-retest reliability were computed. Sixty-four healthy individuals, 24-79 years, comprising 34 women, were required to pick up 60 small plastic disks from wells, rotate each disk, and transfer it to the other hand, which must replace it, as quickly as possible. Two trials were requested for each hand (ABBA sequence). The average time (seconds) across the 4 trials gave the test score. Participants were grouped (CART algorithm) into 3 statistically distinct (P<0.05) age*score strata, with cutoff 53+ and 73+ years, and tested at baseline and after 1 week. Test-retest reliability was measured both as consistency [intraclass correlation coefficient (ICCs) model 2.1] and as agreement (Bland-Altman plot). From the ICCs, the individual test-retest minimal real difference (in seconds) was computed. The whole MTTrf took less than 4 min to administer. Baseline scores ranged from 40 to 78 s. The ICCs ranged from 0.45 to 0.81 and the minimal real difference ranged from 6.68 to 13.40 s across the age groups. Fifty-nine out of 64 observations (92%) fell within the confidence limits of the Bland-Altman plot. The MTTrf is a reliable and practical test of bimanual coordination. It may be a useful addition to protocols of manual testing in occupational therapy. PMID- 26579700 TI - An ultra scale-down approach identifies host cell protein differences across a panel of mAb producing CHO cell line variants. AB - During the manufacture of biopharmaceutical products, the final product must lie within strict pre-set specifications, for example the host cell protein (HCP) content. A number of specific HCPs have been identified in particular products and the interactions between product/HCPs have also been recently investigated; however, a comparison of the HCP dynamics between related cell lines and their response to early downstream processing to aid process development and cell line selection has not been published. We have utilised a proteomic approach coupled with an ultra scale-down study to determine the HCP profile dynamics, at harvest and during early downstream processing, across a panel of recombinant GS-CHOK1SV antibody producing cell lines. The results reveal that cell culture viability upon harvest has the greatest impact upon shear sensitivity and HCP concentration. Whilst the general HCP population/profile was broadly similar across the cell lines, the actual amounts of some specific HCPs in the supernatant differed and a number of cell line specific differences in the response to early downstream processing were observed. We anticipate that such knowledge can now be applied to cell line selection and downstream processing development to target reduction/removal of general and specific problematic HCPs before and during downstream processing. PMID- 26579701 TI - Electrospray-printed nanostructured graphene oxide gas sensors. AB - We report low-cost conductometric gas sensors that use an ultrathin film made of graphene oxide (GO) nanoflakes as transducing element. The devices were fabricated by lift-off metallization and near-room temperature, atmospheric pressure electrospray printing using a shadow mask. The sensors are sensitive to reactive gases at room temperature without requiring any post heat treatment, harsh chemical reduction, or doping with metal nanoparticles. The sensors' response to humidity at atmospheric pressure tracks that of a commercial sensor, and is linear with changes in humidity in the 10%-60% relative humidity range while consuming <6 MUW. Devices with GO layers printed by different deposition recipes yielded nearly identical response characteristics, suggesting that intrinsic properties of the film control the sensing mechanism. The gas sensors successfully detected ammonia at concentrations down to 500 ppm (absolute partial pressure of ~5 * 10(-4) T) at ~1 T pressure, room temperature conditions. The sensor technology can be used in a great variety of applications including air conditioning and sensing of reactive gas species in vacuum lines and abatement systems. PMID- 26579702 TI - Examining the association between musculoskeletal injuries and carpal tunnel syndrome in manual laborers. AB - INTRODUCTION: The association between musculoskeletal injuries and carpal tunnel syndrome (CTS) has not been investigated in a large, population-based study. METHODS: Latino manual laborers were recruited as part of a study of work-related health conditions. Each had a clinical examination, completed a hand diagram, and had nerve conduction studies. RESULTS: A total of 512 individuals completed all testing. An association was found between rotator cuff syndrome and CTS, with an adjusted odds ratio of 2.25 (P = 0.01) for the right arm, 2.08 (P = 0.03) for the left arm, and 1.84 (P = 0.03) for all individuals. Associations between epicondylitis and CTS did not reach statistical significance. CONCLUSIONS: Individuals with rotator cuff syndrome have a higher prevalence of CTS. Further investigations will be needed to examine for causation and to determine if 1 condition typically occurs first and leads to the other. Muscle Nerve 54: 31-35, 2016. PMID- 26579703 TI - Correlation of Inflammation in Frozen Sections With Site of Nonmelanoma Skin Cancer. AB - IMPORTANCE: During Mohs micrographic surgery of nonmelanoma skin cancer (NMSC), inflammation in histologic frozen sections has been found to occasionally presage the detection of tumors in frozen sections of adjacent excision specimens. OBJECTIVE: To quantify the correlation between the location of inflammation without visible tumor in histologic frozen sections and the location of subsequently detected NMSC. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study of 3148 cases pertaining to frozen sections associated with the staged excision of NMSC was performed from September 8, 2008, to September 18, 2009, at an urban academic medical center, with the collected data analyzed on May 9, 2013. EXPOSURES: Consecutive cases of Mohs micrographic surgery performed at an academic medical center. MAIN OUTCOMES AND MEASURES: For each wedge-shaped tissue segment corresponding with 1 hour of time on a clock face, the proportion of patients with inflammation at the source location of the segment who subsequently had a tumor at this same location; the proportion of patients who had neither inflammation nor subsequent tumor at the source location of the segment; the probability of subsequent tumor at this location given the prior finding of inflammation at the same location; and the probability that a location was without tumor in the absence of preexisting inflammation at that location. RESULTS: Of the medical records of 3148 cases of NMSC that were reviewed, 60 showed inflammation in histologic frozen sections from an excision specimen that was followed by tumor in the subsequent excision specimen. Of these 60, 39 (65%) were b asal cel carcinoma and 21 (35%) were squamous cell carcinomas; 53 (88%) were Mohs stage 1. In 7 of 12 segments, a significant positive correlation was found between the presence of inflammation and the presence of nearby tumor with correlation coefficients ranging from 0.196 to 0.384 (P < .05) . The probability that tumor was absent when inflammation was not seen at a particular location (ie, clock-face segment) in preceding sections from that location was 91%, with segment-specific probability values ranging from 82% to 96%. CONCLUSIONS AND RELEVANCE: During Mohs micrographic surgery of NMSC with the examination of frozen sections, histologic inflammation is modestly predictive of adjacent tumor whereas lack of inflammation strongly predicts that no additional tumor will be found. PMID- 26579704 TI - Anxiety reduction on atomoxetine and methylphenidate medication in children with ADHD. AB - BACKGROUND: Atomoxetine and methylphenidate are widely used to treat attention deficit-hyperactivity disorder (ADHD) with similar effectiveness after 8 weeks of treatment, when atomoxetine has reached its a full effect. Both drugs have also been shown to have an effect on comorbid anxiety. To the best of our knowledge, no study has compared their effect on the dynamics of anxiety symptom reduction. The aim of this study was to compare the medication effect on core and comorbid anxiety symptom dynamics in children with ADHD. METHODS: Sixty-nine patients participated in the study: 36 patients were taking atomoxetine and 33 patients, methylphenidate. Therapeutic effect on core symptoms of ADHD was measured on the ADHD-rating scale IV, and symptoms of anxiety were measured using the Conners Parent Rating Scale (CPRS). Symptoms were measured prior to and every 2 weeks during 8 weeks of treatment. RESULTS: There was a significant decrease in CPRS anxiety subscale score in both medication groups. Anxiety subscale score was significantly lower in the atomoxetine group in the fourth week, and lasted through to 8 weeks of medication. CONCLUSION: Both atomoxetine and methylphenidate reduced the symptoms of ADHD and anxiety. Atomoxetine was more effective in anxiety symptom reduction from the fourth week of treatment. PMID- 26579705 TI - Light-controlled propulsion, aggregation and separation of water-fuelled TiO2/Pt Janus submicromotors and their "on-the-fly" photocatalytic activities. AB - In this work, water-fuelled TiO2/Pt Janus submicromotors with light-controlled motions have been developed by utilizing the asymmetrical photocatalytic water redox reaction over TiO2/Pt Janus submicrospheres under UV irradiation. The motion state, speed, aggregation and separation behaviors of the TiO2/Pt Janus submicromotor can be reversibly, wirelessly and remotely controlled at will by regulating the "on/off" switch, intensity and pulsed/continuous irradiation mode of UV light. The motion of the water-fuelled TiO2/Pt Janus submicromotor is governed by light-induced self-electrophoresis under the local electrical field generated by the asymmetrical water oxidation and reduction reactions on its surface. The TiO2/Pt Janus submicromotors can interact with each other through the light-switchable electrostatic forces, and hence continuous and pulsed UV irradiation can make the TiO2/Pt Janus submicromotors aggregate and separate at will, respectively. Because of the enhanced mass exchange between the environment and active submicromotors, the separated TiO2/Pt Janus submicromotors powered by the pulsed UV irradiation show a much higher activity for the photocatalytic degradation of the organic dye than the aggregated TiO2/Pt submicromotors. The water-fuelled TiO2/Pt Janus submicromotors developed here have some outstanding advantages as "swimming" photocatalysts for organic pollutant remediation in the macro or microenvironment (microchannels and microwells in microchips) because of their small size, long-term stability, wirelessly controllable motion behaviors and long life span. PMID- 26579706 TI - Behavior and Sensory Interests Questionnaire: Validation in a sample of children with autism spectrum disorder and other developmental disability. AB - Repetitive behaviors, restricted interests and other unusual sensory behaviors often significantly impact the lives of many individuals with developmental disabilities, including Autism Spectrum Disorder (ASD). Identifying specific patterns of atypical behaviors across different disorders allows for improved specificity of diagnoses, monitoring response to treatment and elucidating the genetic and neurobiological underpinnings of these disorders. The Behavior and Sensory Interests Questionnaire (BSIQ) is a newly designed, continuous dimensional instrument that comprehensively assesses the type, frequency, intensity, age of onset, and duration of these behaviors. The BSIQ takes 15-40 min to administer to a caregiver in an interview format. Using a large sample of children with either ASD, intellectual disabilities or who were typically developing, the construct validity of the BSIQ was confirmed using a series of multi-group confirmatory factor analysis models. Configural and metric invariance were satisfied, but not scalar invariance, as expected. The BSIQ showed acceptable internal consistency, excellent inter-rater reliability and excellent test-retest reliability. PMID- 26579707 TI - MiR130b-Regulation of PPARgamma Coactivator- 1alpha Suppresses Fat Metabolism in Goat Mammary Epithelial Cells. AB - Fat metabolism is a complicated process regulated by a series of factors. microRNAs (miRNAs) are a class of negative regulator of proteins and play crucial roles in many biological processes; including fat metabolism. Although there have been some researches indicating that miRNAs could influence the milk fat metabolism through targeting some factors, little is known about the effect of miRNAs on goat milk fat metabolism. Here we utilized an improved miRNA detection assay, S-Poly-(T), to profile the expression of miRNAs in the goat mammary gland in different periods, and found that miR-130b was abundantly and differentially expressed in goat mammary gland. Additionally, overexpressing miR-130b impaired adipogenesis while inhibiting miR-130b enhanced adipogenesis in goat mammary epithelial cells. Utilizing 3'-UTR assay and Western Blot analusis, the protein peroxisome proliferator-activated receptor coactivator-1alpha (PGC1alpha), a major regulator of fat metabolism, was demonstrated to be a potential target of miR-130b. Interestingly, miR-130b potently repressed PGC1alpha expression by targeting both the PGC1alpha mRNA coding and 3' untranslated regions. These findings have some insight of miR-130b in mediating adipocyte differentiation by repressing PGC1alpha expression and this contributes to further understanding about the functional significance of miRNAs in milk fat synthesis. PMID- 26579708 TI - Application of Network Scale Up Method in the Estimation of Population Size for Men Who Have Sex with Men in Shanghai, China. AB - BACKGROUND: Men who have sex with men (MSM) are at high risk of HIV infection. For developing proper interventions, it is important to know the size of MSM population. However, size estimation of MSM populations is still a significant public health challenge due to high cost, hard to reach and stigma associated with the population. OBJECTIVES: We aimed to estimate the social network size (c value) in general population and the size of MSM population in Shanghai, China by using the net work scale-up method. METHODS: A multistage random sampling was used to recruit participants aged from 18 to 60 years who had lived in Shanghai for at least 6 months. The "known population method" with adjustment of backward estimation and regression model was applied to estimate the c value. And the MSM population size was further estimated using an adjusted c value taking into account for the transmission effect through social respect level towards MSM. RESULTS: A total of 4017 participants were contacted for an interview, and 3907 participants met the inclusion criterion. The social network size (c value) of participants was 236 after adjustment. The estimated size of MSM was 36354 (95% CI: 28489-44219) for the male Shanghaies aged 18 to 60 years, and the proportion of MSM among the total male population aged 18 to 60 years in Shanghai was 0.28%. CONCLUSIONS: We employed the network scale-up method and used a wide range of data sources to estimate the size of MSM population in Shanghai, which is useful for HIV prevention and intervention among the target population. PMID- 26579709 TI - IDO Downregulation Induces Sensitivity to Pemetrexed, Gemcitabine, FK866, and Methoxyamine in Human Cancer Cells. AB - Indoleamine 2,3-dioxygenase-1 (IDO) is an immune regulatory enzyme expressed by most human tumors. IDO levels in tumor cells correlate with increased metastasis and poor patient outcome and IDO is linked to tumor cell resistance to immunotherapy, radiation therapy, and chemotherapy. Knowledge of tumor cell autonomous effects of IDO, independent of its well-known role in regulating and suppressing anti-tumor immune responses, is limited. Clonal populations of A549 human lung adenocarcinoma cells stably transfected with anti-IDO shRNA or scrambled control shRNA were used to study IDO effects on drug sensitivity and resistance. IFNgamma was used to induce IDO in those cells. We show, for the first time, that IDO mediates human tumor cell resistance to the candidate anticancer drugs FK866 (an NAD+ inhibitor), methoxyamine (MX, a base excision repair [BER] inhibitor) and approved anticancer drugs pemetrexed (a folate anti metabolite) and gemcitabine (a nucleoside analogue), and combined treatment with pemetrexed and MX, in the absence of immune cells. Concurrent knockdown of IDO and thymidylate synthase (TS, a key rate-limiting enzyme in DNA synthesis and repair) sensitizes human lung cancer cells to pemetrexed and 5FUdR to a greater degree than knockdown of either target alone. We conclude that BER in IDO expressing A549 cells plays a major role in mediating resistance to a range of approved and candidate anticancer drugs. IDO inhibitors are undergoing clinical trials primarily to improve antitumor immune responses. We show that targeting IDO alone or in combination with TS is a potentially valuable therapeutic strategy for cancer treatment, independent of immune activity and in combination with conventional chemotherapy. PMID- 26579710 TI - Breast and Bottle Feeding as Risk Factors for Dental Caries: A Systematic Review and Meta-Analysis. AB - Understanding the role that breastfeeding and bottle feeding play in the development of dental caries during childhood is essential in helping dentists and parents and care providers prevent the disease, and also for the development of effective public health policies. However, the issue is not yet fully understood. The aim of this systematic review and meta-analysis was to search for scientific evidence in response to the question: Do bottle fed children have more dental caries in primary dentition than breastfed children? Seven electronic databases and grey literature were used in the search. The protocol number of the study is PROSPERO CRD 42014006534. Two independent reviewers selected the studies, extracted data and evaluated risk of bias by quality assessment. A random effect model was used for meta-analysis, and the summary effect measure were calculated by odds ratio (OR) and 95% CI. Seven studies were included: five cross-sectional, one case-control and one cohort study. A meta-analysis of cross sectional studies showed that breastfed children were less affected by dental caries than bottle fed children (OR: 0.43; 95%CI: 0.23-0.80). Four studies showed that bottle fed children had more dental caries (p<0.05), while three studies found no such association (p>0.05). The scientific evidence therefore indicated that breastfeeding can protect against dental caries in early childhood. The benefits of breastfeeding until age two is recommended by WHO/UNICEF guidelines. Further prospective observational cohort studies are needed to strengthen the evidence. PMID- 26579711 TI - Coevolution Analysis of HIV-1 Envelope Glycoprotein Complex. AB - The HIV-1 Env spike is the main protein complex that facilitates HIV-1 entry into CD4+ host cells. HIV-1 entry is a multistep process that is not yet completely understood. This process involves several protein-protein interactions between HIV-1 Env and a variety of host cell receptors along with many conformational changes within the spike. HIV-1 Env developed due to high mutation rates and plasticity escape strategies from immense immune pressure and entry inhibitors. We applied a coevolution and residue-residue contact detecting method to identify coevolution patterns within HIV-1 Env protein sequences representing all group M subtypes. We identified 424 coevolving residue pairs within HIV-1 Env. The majority of predicted pairs are residue-residue contacts and are proximal in 3D structure. Furthermore, many of the detected pairs have functional implications due to contributions in either CD4 or coreceptor binding, or variable loop, gp120 gp41, and interdomain interactions. This study provides a new dimension of information in HIV research. The identified residue couplings may not only be important in assisting gp120 and gp41 coordinate structure prediction, but also in designing new and effective entry inhibitors that incorporate mutation patterns of HIV-1 Env. PMID- 26579712 TI - Ontogenetic Tooth Reduction in Stenopterygius quadriscissus (Reptilia: Ichthyosauria): Negative Allometry, Changes in Growth Rate, and Early Senescence of the Dental Lamina. AB - We explore the functional, developmental, and evolutionary processes which are argued to produce tooth reduction in the extinct marine reptile Stenopterygius quadriscissus (Reptilia: Ichthyosauria). We analyze the relationship between mandible growth and tooth size, shape, and count, to establish an ontogenetic trend. The pattern in S. quadriscissus is consistent with hypotheses of tooth size reduction by neutral selection, and this unusual morphology (a functionally edentulous rostrum) was produced by a series of different evolutionary developmental changes that are known for other taxa showing tooth reduction and loss. Specifically, this species evolved functional edentulism by evolutionary changes in the growth allometry of the dentition and by altering growth rates through ontogeny. This observation supports previous hypotheses that S. quadriscissus underwent ontogenetic tooth reduction. Tooth reduction in S. quadriscissus may be caused by unique selective pressures resulting from prey choice and feeding behavior, expanding our current understanding of the mechanisms producing tooth reduction. PMID- 26579713 TI - Ernst Rudin and the State of Science. PMID- 26579714 TI - Investigating DNA Binding and Conformational Variation in Temperature Sensitive p53 Cancer Mutants Using QM-MM Simulations. AB - The tp53 gene is found to be mutated in 50% of all the cancers. The p53 protein, a product of tp53 gene, is a multi-domain protein. It consists of a core DNA binding domain (DBD) which is responsible for its binding and transcription of downstream target genes. The mutations in p53 protein are responsible for creating cancerous conditions and are found to be occurring at a high frequency in the DBD region of p53. Some of these mutations are also known to be temperature sensitive (ts) in nature. They are known to exhibit partial or strong binding with DNA in the temperature range (298-306 K). Whereas, at 310 K and above they show complete loss in binding. We have analyzed the changes in binding and conformational behavior at 300 K and 310 K for three of the ts-mutants viz., V143A, R249S and R175H. QM-MM simulations have been performed on the wild type and the above mentioned ts-mutants for 30 ns each. The optimal estimate of free energy of binding for a particular number of interface hydrogen bonds was calculated using the maximum likelihood method as described by Chodera et. al (2007). This parameter has been observed to be able to mimic the binding affinity of the p53 ts-mutants at 300 K and 310 K. Thus the correlation between MM-GBSA free energy of binding and hydrogen bonds formed by the interface residues between p53 and DNA has revealed the temperature dependent nature of these mutants. The role of main chain dihedrals was obtained by performing dihedral principal component analysis (PCA). This analysis, suggests that the conformational variations in the main chain dihedrals (phi and psi) of the p53 ts mutants may have caused reduction in the overall stability of the protein. The solvent exposure of the side chains of the interface residues were found to hamper the binding of the p53 to the DNA. Solvent Accessible Surface Area (SASA) also proved to be a crucial property in distinguishing the conformers obtained at 300 K and 310 K for the three ts-mutants from the wild type at 300 K. PMID- 26579715 TI - A Systematic Review of Changes in Marine Mammal Health in North America, 1972 2012: The Need for a Novel Integrated Approach. AB - Marine mammals are often cited as "sentinels of ocean health" yet accessible, synthesized data on their health changes that could effectively warn of ocean health changes are rare. The objectives of this study were to 1) perform a systematic review of published cases of marine mammal disease to determine spatial and temporal trends in disease from 1972-2012, including changes in regions and taxa affected and specific causes; and 2) compare numbers of published cases of neoplasia with known, hospital-based neoplasia records to explore the causes of discrepancy between numbers of published cases and true disease trends. Peer-reviewed literature was compiled, and data were collected from The Marine Mammal Center database in Sausalito, California for comparison of numbers of neoplasia cases. Toxicoses from harmful algal blooms appear to be increasing. Viral epidemics are most common along the Atlantic U.S. coastline, while bacterial epidemics, especially leptospirosis, are most common along the Pacific coast. Certain protozoal and fungal zoonoses appear to be emerging, such as Toxoplasma gondii in southern sea otters in California, and Cryptococcus gattii in cetaceans in the Pacific Northwest. Disease reports were most common from California where pinniped populations are large, but increased effort also occurs. Anthropogenic trauma remains a large threat to marine mammal health, through direct mortality and indirect chronic disease. Neoplasia cases were under reported from 2003-2012 when compared to true number of cases, and over-reported in several years due to case duplication. Peer-reviewed literature greatly underestimates the true magnitude of disease in marine mammals as it focuses on novel findings, fails to reflect etiology of multifactorial diseases, rarely reports prevalence rather than simple numbers of cases, and is typically presented years after a disease first occurs. Thus literature cannot guide management actions adequately, nor inform indices of ocean health. A real-time, nationally centralized system for reporting marine mammal disease data is needed to be able to understand how marine mammal diseases are changing with ecosystem changes, and before these animals can truly be considered 'sentinels of ocean health'. PMID- 26579716 TI - Application of 5-Fluorouracil-Polycaprolactone Sustained-Release Film in Ahmed Glaucoma Valve Implantation Inhibits Postoperative Bleb Scarring in Rabbit Eyes. AB - This study was designed to investigate whether 5-fluorouracil (5-Fu) polycaprolactone sustained-release film in Ahmed glaucoma valve implantation inhibits postoperative bleb scarring in rabbit eyes. Eighteen New Zealand white rabbits were randomly divided into three groups (A, B and C; n = 6 per group). Group A received combined 5-Fu-polycaprolactone sustained-release film application and Ahmed glaucoma valve implantation, group B received local infiltration of 5-Fu and Ahmed glaucoma valve implantation, and group C received Ahmed glaucoma valve implantation. Postoperative observations were made of the anterior segment, intraocular pressure, central anterior chamber depth, blebs, drainage tube, and accompanying ciliary body detachment. The pathology of the blebs and surrounding tissues were observed at month 3 postoperatively. We revealed that the 5-Fu-polycaprolactone sustained-release film maintained a release concentration range of 13.7 +/- 0.12 to 37.41 +/- 0.47 MUg/ml over three months in vitro. Postoperatively, diffuse blebs with ridges were found in all eyes in group A, two blebs were observed in group B, and no bleb formation was present in group C. The postoperative central anterior chamber depth in group A was significantly less than that of the other two groups. The postoperative intraocular pressure of group A stabilized at 6.33-8.67 mmHg, whereas that of group C gradually remained at 7.55-10.02 mmHg. The histopathology showed that the fibrous tissue thickness of the blebs in group A was significantly thinner than that of the other groups. We conclude that the 5-Fu-polycaprolactone sustained release film had a sustained drug release effect, which promoted the inhibition of bleb scarring after Ahmed glaucoma valve implantation. PMID- 26579717 TI - A Cross-Reactive Human Single-Chain Antibody for Detection of Major Fish Allergens, Parvalbumins, and Identification of a Major IgE-Binding Epitope. AB - Fish allergy is associated with moderate to severe IgE-mediated reactions to the calcium binding parvalbumins present in fish muscle. Allergy to multiple fish species is caused by parvalbumin-specific cross-reactive IgE recognizing conserved epitopes. In this study, we aimed to produce cross-reactive single chain variable fragment (scFv) antibodies for the detection of parvalbumins in fish extracts and the identification of IgE epitopes. Parvalbumin-specific phage clones were isolated from the human ETH-2 phage display library by three rounds of biopanning either against cod parvalbumin or by sequential biopanning against cod (Gad m 1), carp (Cyp c 1) and rainbow trout (Onc m 1) parvalbumins. While biopanning against Gad m 1 resulted in the selection of clones specific exclusively for Gad m 1, the second approach resulted in the selection of clones cross-reacting with all three parvalbumins. Two clones, scFv-gco9 recognizing all three parvalbumins, and scFv-goo8 recognizing only Gad m 1 were expressed in the E. coli non-suppressor strain HB2151 and purified from the periplasm. scFv-gco9 showed highly selective binding to parvalbumins in processed fish products such as breaded cod sticks, fried carp and smoked trout in Western blots. In addition, the scFv-gco9-AP produced as alkaline phosphatase fusion protein, allowed a single-step detection of the parvalbumins. In competitive ELISA, scFv-gco9 was able to inhibit binding of IgE from fish allergic patients' sera to all three beta-parvalbumins by up to 80%, whereas inhibition by scFv-goo8 was up to 20%. 1H/15N HSQC NMR analysis of the rGad m 1:scFv-gco9 complex showed participation of amino acid residues conserved among these three parvalbumins explaining their cross-reactivity on a molecular level. In this study, we have demonstrated an approach for the selection of cross-reactive parvalbumin-specific antibodies that can be used for allergen detection and for mapping of conserved epitopes. PMID- 26579719 TI - Impact of Collateral Status on Successful Revascularization in Endovascular Treatment: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Pre-treatment collateral status may be associated with the rates of successful revascularization in acute ischemic stroke patients receiving endovascular treatment (EVT). We conducted a systematic review and meta-analysis to synthesize relevant evidence currently available. METHODS: Relevant full-text articles published in English since January 1, 2000, reporting associations between collateral status and successful reperfusion and/or recanalization in acute ischemic stroke patients receiving EVT in cohort or case-control studies, or randomized clinical trials, were retrieved through search of PubMed. Study selection, data extraction and study quality assessment were carried out by 2 investigators. Risk ratios (RR) were pooled for good vs. poor collaterals for the outcomes of successful reperfusion and recanalization, based on random-effects models. Subgroup analyses were conducted to explore for potential factors that might interfere with the effects of pre-treatment collateral status on reperfusion by EVT. RESULTS: In total, 27 studies (2,366 subjects) were included in qualitative analysis, among which 24 studies (2,239 subjects) were quantitatively analyzed. Overall, good pre-treatment collaterals significantly increased the rate of both successful reperfusion (RR 1.28, 95% CI 1.17-1.40; p < 0.001) and recanalization (RR 1.23, 95% CI 1.06-1.42; p = 0.006), as compared with poor collaterals. Subgroup analyses revealed that the effects of collateral status on successful reperfusion by EVT might be different between populations with different ethnicities. CONCLUSIONS: Good pre-treatment collaterals may enhance the rates of successful reperfusion and recanalization in EVT for acute ischemic stroke. This may partly explain the favorable effects of good pre treatment collaterals on clinical outcomes of stroke patients receiving EVT. Thus, it would be valuable to assess the collateral status prior to EVT in acute ischemic stroke. But studies are needed to further verify if the positive effects of good collaterals on revascularization by EVT are restricted to certain subgroups of patients. PMID- 26579718 TI - A Role for Reactive Oxygen Species Produced by NADPH Oxidases in the Embryo and Aleurone Cells in Barley Seed Germination. AB - Reactive oxygen species (ROS) promote the germination of several seeds, and antioxidants suppress it. However, questions remain regarding the role and production mechanism of ROS in seed germination. Here, we focused on NADPH oxidases, which produce ROS. After imbibition, NADPH oxidase mRNAs were expressed in the embryo and in aleurone cells of barley seed; these expression sites were consistent with the sites of ROS production in the seed after imbibition. To clarify the role of NADPH oxidases in barley seed germination, we examined gibberellic acid (GA) / abscisic acid (ABA) metabolism and signaling in barley seeds treated with diphenylene iodonium chloride (DPI), an NADPH oxidase inhibitor. DPI significantly suppressed germination, and suppressed GA biosynthesis and ABA catabolism in embryos. GA, but not ABA, induced NADPH oxidase activity in aleurone cells. Additionally, DPI suppressed the early induction of alpha-amylase by GA in aleurone cells. These results suggest that ROS produced by NADPH oxidases promote GA biosynthesis in embryos, that GA induces and activates NADPH oxidases in aleurone cells, and that ROS produced by NADPH oxidases induce alpha-amylase in aleurone cells. We conclude that the ROS generated by NADPH oxidases regulate barley seed germination through GA / ABA metabolism and signaling in embryo and aleurone cells. PMID- 26579720 TI - Structural Aspects of the Antiparallel and Parallel Duplexes Formed by DNA, 2'-O Methyl RNA and RNA Oligonucleotides. AB - This study investigated the influence of the nature of oligonucleotides on the abilities to form antiparallel and parallel duplexes. Base pairing of homopurine DNA, 2'-O-MeRNA and RNA oligonucleotides with respective homopyrimidine DNA, 2'-O MeRNA and RNA as well as chimeric oligonucleotides containing LNA resulted in the formation of 18 various duplexes. UV melting, circular dichroism and fluorescence studies revealed the influence of nucleotide composition on duplex structure and thermal stability depending on the buffer pH value. Most duplexes simultaneously adopted both orientations. However, at pH 5.0, parallel duplexes were more favorable. Moreover, the presence of LNA nucleotides within a homopyrimidine strand favored the formation of parallel duplexes. PMID- 26579721 TI - Correction: Risk Factors for Acquired Rifamycin and Isoniazid Resistance: A Systematic Review and Meta-Analysis. PMID- 26579722 TI - Structural Diversity of Bacterial Communities Associated with Bloom-Forming Freshwater Cyanobacteria Differs According to the Cyanobacterial Genus. AB - The factors and processes driving cyanobacterial blooms in eutrophic freshwater ecosystems have been extensively studied in the past decade. A growing number of these studies concern the direct or indirect interactions between cyanobacteria and heterotrophic bacteria. The presence of bacteria that are directly attached or immediately adjacent to cyanobacterial cells suggests that intense nutrient exchanges occur between these microorganisms. In order to determine if there is a specific association between cyanobacteria and bacteria, we compared the bacterial community composition during two cyanobacteria blooms of Anabaena (filamentous and N2-fixing) and Microcystis (colonial and non-N2 fixing) that occurred successively within the same lake. Using high-throughput sequencing, we revealed a clear distinction between associated and free-living communities and between cyanobacterial genera. The interactions between cyanobacteria and bacteria appeared to be based on dissolved organic matter degradation and on N recycling, both for N2-fixing and non N2-fixing cyanobacteria. Thus, the genus and potentially the species of cyanobacteria and its metabolic capacities appeared to select for the bacterial community in the phycosphere. PMID- 26579723 TI - Assessing the Reliability and Validity of the Sheehan Irritability Scale in Patients With Major Depressive Disorder. AB - OBJECTIVE: Irritability is a significant component in the clinical manifestation of major depressive disorder (MDD). The Sheehan Irritability Scale (SIS) was developed to assess irritability-related symptoms in patients with psychiatric disorders. Data from a phase 2 clinical trial (June 2008-July 2009) was utilized to evaluate the psychometric properties of the SIS. The trial population included patients diagnosed with MDD, according to DSM-IV and confirmed via the MINI diagnostic scale, who had inadequate response to citalopram. METHOD: The secondary analyses included 586 patients from the United States and India. Data from the SIS, depression severity measures (17-item Hamilton Depression Rating Scale [HDRS-17], Montgomery-Asberg Depression Rating Scale [MADRS], Quick Inventory of Depressive Symptomatology-Self-Report [QIDS-SR]), and other measures (Sheehan Disability Scale [SDS], Clinical Global Impressions-Severity of Illness scale [CGI-S]) were used in the psychometric evaluation. All statistical tests used a significance level of .05 unless otherwise noted. RESULTS: Internal consistency (0.92-0.99) and test-retest reliability (0.83 to 0.98) were excellent. Concurrent validity was demonstrated through strong correlations between the SIS total score and HDRS-17, QIDS-SR, SDS, CGI-S, and MADRS scores. SIS total scores were significantly different by clinical severity level (P < .001). Minimally important difference estimates suggest that a 7- to 8-point change in the SIS total score may be clinically meaningful. CONCLUSIONS: The SIS has excellent reliability, acceptable validity, and good responsiveness, making the SIS appropriate for use in clinical research and practice. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00692445. PMID- 26579724 TI - Modulating the Electron-Hole Interaction in a Hybrid Lead Halide Perovskite with an Electric Field. AB - Despite rapid developments in both photovoltaic and light-emitting device performance, the understanding of the optoelectronic properties of hybrid lead halide perovskites is still incomplete. In particular, the polarizability of the material, the presence of molecular dipoles, and their influence on the dynamics of the photoexcitations remain an open issue to be clarified. Here, we investigate the effect of an applied external electric field on the photoexcited species of CH3NH3PbI3 thin films, both at room temperature and at low temperature, by monitoring the photoluminescence (PL) yield and PL decays. At room temperature we find evidence for electric-field-induced reduction of radiative bimolecular carrier recombination together with motion of charged defects that affects the nonradiative decay rate of the photoexcited species. At low temperature (190 K), we observe a field-induced enhancement of radiative free carrier recombination rates that lasts even after the removal of the field. We assign this to field-induced alignment of the molecular dipoles, which reduces the vibrational freedom of the lattice and the associated local screening and hence results in a stronger electron-hole interaction. PMID- 26579725 TI - Copper and Zinc Ions Specifically Promote Nonamyloid Aggregation of the Highly Stable Human gamma-D Crystallin. AB - Cataract is the leading cause of blindness in the world. It results from aggregation of eye lens proteins into high-molecular-weight complexes, causing light scattering and lens opacity. Copper and zinc concentrations in cataractous lens are increased significantly relative to a healthy lens, and a variety of experimental and epidemiological studies implicate metals as potential etiological agents for cataract. The natively monomeric, beta-sheet rich human gammaD (HgammaD) crystallin is one of the more abundant proteins in the core of the lens. It is also one of the most thermodynamically stable proteins in the human body. Surprisingly, we found that both Cu(II) and Zn(II) ions induced rapid, nonamyloid aggregation of HgammaD, forming high-molecular-weight light scattering aggregates. Unlike Zn(II), Cu(II) also substantially decreased the thermal stability of HgammaD and promoted the formation of disulfide-bridged dimers, suggesting distinct aggregation mechanisms. In both cases, however, metal induced aggregation depended strongly on temperature and was suppressed by the human lens chaperone alphaB-crystallin (HalphaB), implicating partially folded intermediates in the aggregation process. Consistently, distinct site-specific interactions of Cu(II) and Zn(II) ions with the protein and conformational changes in specific hinge regions were identified by nuclear magnetic resonance. This study provides insights into the mechanisms of metal-induced aggregation of one of the more stable proteins in the human body, and it reveals a novel and unexplored bioinorganic facet of cataract disease. PMID- 26579727 TI - Chemo- and Enantioselective Addition and beta-Hydrogen Transfer Reduction of Carbonyl Compounds with Diethylzinc Reagent in One Pot Catalyzed by a Single Chiral Organometallic Catalyst. AB - Using a single chiral phosphoramide-Zn(II) complex as the catalyst, the asymmetric beta-H transfer reduction of aromatic alpha-trifluoromethyl ketones and enantioselective addition of aromatic aldehydes with Et2Zn in one pot were successfully realized, affording the corresponding additive products of secondary alcohols in high yields (up to 99%) with excellent enantioselectivities (up to 98% ee) and the reduction products of alpha-trifluoromethyl alcohols in good to excellent yields with up to 77% ee. PMID- 26579726 TI - Two-Dimensional Potentials of Mean Force of Nile Red in Intact and Damaged Model Bilayers. Application to Calculations of Fluorescence Spectra. AB - Fluorescent dyes revolutionized and expanded our understanding of biological membranes. The interpretation of experimental fluorescence data in terms of membrane structure, however, requires detailed information about the molecular environment of the dyes. Nile red is a fluorescent molecule whose excitation and emission maxima depend on the polarity of the solvent. It is mainly used as a probe to study lipid microenvironments, for example in imaging the progression of damage to the myelin sheath in multiple sclerosis. In this study, we determine the position and orientation of Nile red in lipid bilayers by calculating two dimensional Potential of Mean Force (2D-PMF) profiles in a defect-free 1 palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayer and in damaged bilayers containing two mixtures of the oxidized lipid 1-palmitoyl-2-(9'-oxo nonanoyl)-sn-glycero-3-phosphocholine and POPC. From 2D-PMF simulations we obtain positions and orientations of Nile Red corresponding to the minimum on the binding free energy surface in three different membrane environments with increasing amounts of water, mimicking damage in biological tissue. Using representative snapshots from the simulations, we use combined quantum mechanical/molecular mechanical (QM/MM) models to calculate the emission spectrum of Nile red as a function of its local solvation environment. The results of QM and QM/MM computations are in qualitative agreement with the experimentally observed shift in fluorescence for the dye moving from aqueous solution to the more hydrophobic environment of the lipid interiors. The range of the conformation dependent values of the computed absorption-emission spectra and the lack of solvent relaxation effects in the QM/MM calculations made it challenging to delineate specific differences between the intact and damaged bilayers. PMID- 26579728 TI - Hydroquinone-Mediated Redox Cycling of Iron and Concomitant Oxidation of Hydroquinone in Oxic Waters under Acidic Conditions: Comparison with Iron-Natural Organic Matter Interactions. AB - Interactions of 1,4-hydroquinone with soluble iron species over a pH range of 3-5 in the air-saturated and partially deoxygenated solution are examined here. Our results show that 1,4-hydroquinone reduces Fe(III) in acidic conditions, generating semiquinone radicals (Q(*-)) that can oxidize Fe(II) back to Fe(III). The oxidation rate of Fe(II) by Q(*-)increases with increase in pH due to the speciation change of Q(*-) with its deprotonated form (Q(*-)) oxidizing Fe(II) more rapidly than the protonated form (HQ(*)). Although the oxygenation of Fe(II) is negligible at pH < 5, O2 still plays an important role in iron redox transformation by rapidly oxidizing Q(*-) to form benzoquinone (Q). A kinetic model is developed to describe the transformation of quinone and iron under all experimental conditions. The results obtained here are compared with those obtained in our previous studies of iron-Suwannee River fulvic acid (SRFA) interactions in acidic solutions and support the hypothesis that hydroquinone moieties can reduce Fe(III) in natural waters. However, the semiquinone radicals generated in pure hydroquinone solution are rapidly oxidized by dioxygen, while the semiquinone radicals generated in SRFA solution are resistant to oxidation by dioxygen, with the result that steady-state semiquinone concentrations in SRFA solutions are 2-3 orders of magnitude greater than in solutions of 1,4 hydroquinone. As a result, semiquinone moieties in SRFA play a much more important role in iron redox transformations than is the case in solutions of simple quinones such as 1,4-hydroquinone. This difference in the steady-state concentration of semiquinone species has a dramatic effect on the cycling of iron between the +II and +III oxidation states, with iron turnover frequencies in solutions containing SRFA being 10-20 times higher than those observed in solutions of 1,4-hydroquinone. PMID- 26579729 TI - Field-Induced Slow Magnetic Relaxation and Gas Adsorption Properties of a Bifunctional Cobalt(II) Compound. AB - A new compound, {[Co(bmzbc)2] . 2DMF}n (JXNU-1, JXNU denotes Jiangxi Normal University), based on the 4-(benzimidazole-1-yl)benzoate (bmzbc(-)) ligand has been synthesized and structurally characterized. The Co(II) ions are bridged by the rod-like bmzbc(-) ligands to give a two-dimensional (2D) sheet wherein the Co(II) ions are spatially separated from each other by the long bmzbc(-) rods. The 2D sheets are further stacked into a 3D framework with 1D channels occluding the guest DMF molecules. Detailed magnetic studies show that the individual octahedral Co(II) ions in JXNU-1 exhibit field-induced slow magnetic relaxation, which is characteristic behavior of single-ion magnets (SIMs). The rarely observed positive value of zero-field splitting (ZFS) parameter D for the Co(II) ion in JXNU-1 demonstrates that JXNU-1 is a unique example of Co(II)-based SIMs with easy-plane anisotropy, which is also confirmed by the calculations. The microporous nature of JXNU-1 was established by measuring CO2 sorption isotherms. The abrupt changes observed in the C3H8 and C2H6 adsorption isotherms indicate that a structural transformation occurred in the gas-loading process. The long connection between the magnetic metal centers in JXNU-1 meets the requirements for construction of porosity and SIM in a well-defined network, harmoniously providing a good candidate of functional molecular materials exhibiting SIM and porosity. PMID- 26579730 TI - Skp Trimer Formation Is Insensitive to Salts in the Physiological Range. AB - Biogenesis of the Gram-negative outer membrane involves the chaperone seventeen kilodalton protein (Skp). A Skp trimer is currently thought to bind its unfolded outer membrane protein (uOMP) substrates. Using sedimentation equilibrium, we discovered that Skp is not an obligate trimer under physiological conditions and that Na(+), Cl(-), Mg(2+), and PO4(3-) ions are not linked to Skp trimerization. These findings suggest that electrostatics play a negligible role in Skp assembly. Our results demonstrate that Skp monomers are populated at biologically relevant concentrations, which raises the idea that kinetic formation of Skp-uOMP complexes likely involves Skp monomer assembly around its substrate. In addition, van't Hoff analysis of Skp self-association does not support a previously proposed coupled folding and trimerization of Skp. PMID- 26579731 TI - Globally Optimized Targeted Mass Spectrometry: Reliable Metabolomics Analysis with Broad Coverage. AB - Targeted detection is one of the most important methods in mass spectrometry (MS) based metabolomics; however, its major limitation is the reduced metabolome coverage that results from the limited set of targeted metabolites typically used in the analysis. In this study we describe a new approach, globally optimized targeted (GOT)-MS, that combines many of the advantages of targeted detection and global profiling in metabolomics analysis, including the capability to detect unknowns, broad metabolite coverage, and excellent quantitation. The key step in GOT-MS is a global search of precursor and product ions using a single liquid chromatography-triple quadrupole (LC-QQQ) mass spectrometer. Here, focused on measuring serum metabolites, we obtained 595 precursor ions and 1 890 multiple reaction monitoring (MRM) transitions, under positive and negative ionization modes in the mass range of 60-600 Da. For many of the MRMs/metabolites under investigation, the analytical performance of GOT-MS is better than or at least comparable to that obtained by global profiling using a quadrupole-time-of-flight (Q-TOF) instrument of similar vintage. Using a study of serum metabolites in colorectal cancer (CRC) as a representative example, GOT-MS significantly outperformed a large targeted MS assay containing ~160 biologically important metabolites and provided a complementary approach to traditional global profiling using Q-TOF-MS. GOT-MS thus expands and optimizes the detection capabilities for QQQ-MS through a novel approach and should have the potential to significantly advance both basic and clinical metabolic research. PMID- 26579732 TI - Interfacial Study To Suppress Charge Carrier Recombination for High Efficiency Perovskite Solar Cells. AB - We report effects of an interface between TiO2-perovskite and grain-grain boundaries of perovskite films prepared by single step and sequential deposited technique using different annealing times at optimum temperature. Nanoscale kelvin probe force microscopy (KPFM) measurement shows that charge transport in a perovskite solar cell critically depends upon the annealing conditions. The KPFM results of single step and sequential deposited films show that the increase in potential barrier suppresses the back-recombination between electrons in TiO2 and holes in perovskite. Spatial mapping of the surface potential within perovskite film exhibits higher positive potential at grain boundaries compared to the surface of the grains. The average grain boundary potential of 300-400 mV is obtained upon annealing for sequentially deposited films. X-ray diffraction (XRD) spectra indicate the formation of a PbI2 phase upon annealing which suppresses the recombination. Transient analysis exhibits that the optimum device has higher carrier lifetime and short carrier transport time among all devices. An optimum grain boundary potential and proper band alignment between the TiO2 electron transport layer (ETL) and the perovskite absorber layer help to increase the overall device performance. PMID- 26579734 TI - Relationship between central behavioral effects and peripheral sympathetic neurotransmission functionality during acute cocaine withdrawal syndrome in adult rats. AB - BACKGROUND: Acute cocaine withdrawal syndrome (ACWS) is characterized as a set of organic alterations triggered by abrupt discontinuation of chronic cocaine consumption, usually occurring at 24-40 hours after withdrawal. However, little is known about the relationship between central and peripheral sympathetic neurotransmission during ACWS. OBJECTIVE AND METHODS: We investigated the mechanisms involved in central and peripheral sympathetic neurotransmission and how ACWS affects the sympathetic functionality. Cocaine was administered twice daily for 5 days in Wistar rats (at least 5 in each group): on the first and second day, 15 mg/kg/i.p.; third day, 20 mg/kg/i.p.; and finally in the last two days, 30 mg/kg/i.p. Subsequently, at 1, 24, 48 and 120 h after cocaine administration the following experiments were done: (i) at the central level, behavioral tests of open-field and elevated plus maze; and (ii) at the peripheral level, tests of catecholamine release, function of alpha2-adrenergic receptors (alpha2-ARs), imidazoline receptors (I(1,2)-Rs), L-type voltage-gated (Ca(v1.2)) Ca(2+) channels and alpha1-ARs. RESULTS: During ACWS, rats showed hypolocomotion and exacerbation of anxiogenic-effects 24 h after cocaine withdrawal. Likewise, a decrease in the catecholamine release and activity of alpha2-ARs/I(1,2)-Rs at 24 48 h after cocaine withdrawal was observed. A decrease in Ca(v1.2) channels and alpha1-ARs function at 48 h after cocaine withdrawal was observed. CONCLUSIONS: The relationship of central and peripheral sympathetic neurotransmission during ACWS possibly due to a failure in activation and/or inactivation of presynaptic alpha2-ARs/I(1,2)-Rs, may offer a potential target for attenuating ACWS. PMID- 26579733 TI - Radiomics: Images Are More than Pictures, They Are Data. AB - In the past decade, the field of medical image analysis has grown exponentially, with an increased number of pattern recognition tools and an increase in data set sizes. These advances have facilitated the development of processes for high throughput extraction of quantitative features that result in the conversion of images into mineable data and the subsequent analysis of these data for decision support; this practice is termed radiomics. This is in contrast to the traditional practice of treating medical images as pictures intended solely for visual interpretation. Radiomic data contain first-, second-, and higher-order statistics. These data are combined with other patient data and are mined with sophisticated bioinformatics tools to develop models that may potentially improve diagnostic, prognostic, and predictive accuracy. Because radiomics analyses are intended to be conducted with standard of care images, it is conceivable that conversion of digital images to mineable data will eventually become routine practice. This report describes the process of radiomics, its challenges, and its potential power to facilitate better clinical decision making, particularly in the care of patients with cancer. PMID- 26579735 TI - Racial/Ethnic Differences Affecting Adherence to Cancer Screening Guidelines Among Women. AB - BACKGROUND: Race/ethnicity has been shown to modify the effects between obesity and cancer screening among women. The purpose of this article is to update the literature with recent data to examine how the association between different characteristics, including body mass index (BMI), and cancer screening compliance varies by race/ethnicity in a national sample of women. MATERIALS AND METHODS: Three cycles of the Health Information National Trends Survey (HINTS) were combined for this cross-sectional study. Weighted descriptive statistics were evaluated using chi-square tests. Multivariable logistic regression evaluated associations between women with underweight or normal (<25), overweight (25 29.9), and obese (>30) BMIs and cancer screening concordant with guidelines (Papanicolaou [Pap] testing <=3 years, ages 21+ years; mammography <=2 years, ages 40+ years) in analyses stratified by race/ethnicity. We also assessed variance between racial/ethnic groups in how age, income, and insurance status were associated with cancer screening compliance. RESULTS: This study included 4992 women who were evaluated for Pap testing and 3773 for mammography. In analyses stratified by race/ethnicity, whites with a higher household income were more likely to report having a Pap test (adjusted prevalence ratio [aPR] 2.16, 95% confidence interval [95% CI] 1.38-3.40) and a mammogram (aPR 1.63, 95% CI 1.04-2.55) compared to lower income white women. Black women with BMIs between 25 and 30 were less likely to receive a Pap test (aPR 0.38, 95% CI 0.19-0.76) than black women with BMIs <25, while no association was observed among the other groups. Insurance was associated with increased likelihood of Pap testing among white and black women. Insurance coverage was positively associated with mammography only among white and Hispanic women. CONCLUSIONS: We found variations in adherence to cancer screening guidelines by age, insurance coverage, and income between racial/ethnic groups. Little evidence was observed for variations in screening by BMI. PMID- 26579736 TI - Collaborative regression-based anatomical landmark detection. AB - Anatomical landmark detection plays an important role in medical image analysis, e.g. for registration, segmentation and quantitative analysis. Among the various existing methods for landmark detection, regression-based methods have recently attracted much attention due to their robustness and efficiency. In these methods, landmarks are localised through voting from all image voxels, which is completely different from the classification-based methods that use voxel-wise classification to detect landmarks. Despite their robustness, the accuracy of regression-based landmark detection methods is often limited due to (1) the inclusion of uninformative image voxels in the voting procedure, and (2) the lack of effective ways to incorporate inter-landmark spatial dependency into the detection step. In this paper, we propose a collaborative landmark detection framework to address these limitations. The concept of collaboration is reflected in two aspects. (1) Multi-resolution collaboration. A multi-resolution strategy is proposed to hierarchically localise landmarks by gradually excluding uninformative votes from faraway voxels. Moreover, for informative voxels near the landmark, a spherical sampling strategy is also designed at the training stage to improve their prediction accuracy. (2) Inter-landmark collaboration. A confidence-based landmark detection strategy is proposed to improve the detection accuracy of 'difficult-to-detect' landmarks by using spatial guidance from 'easy to-detect' landmarks. To evaluate our method, we conducted experiments extensively on three datasets for detecting prostate landmarks and head & neck landmarks in computed tomography images, and also dental landmarks in cone beam computed tomography images. The results show the effectiveness of our collaborative landmark detection framework in improving landmark detection accuracy, compared to other state-of-the-art methods. PMID- 26579737 TI - Disfavoring Mechanochemical Reactions by Stress-Induced Steric Hindrance. AB - Mechanochemical activation of covalent bonds using sonication, force spectroscopy, or molecular force probes usually lowers activation energies and thus accelerates reactions. However, applying mechanical forces to complex molecules is known to not only stretch covalent bonds but also to distort the molecular skeleton that hosts the activated bonds-leading to nonmonotonous behavior as a function of force. Here, the Bell-Taft model is introduced and validated which both rationalizes and quantifies such nonlinear effects on activation energies, including the transition from catch bonds at low forces to slip binding, in terms of steric hindrance caused by force-induced conformational distortions. The fully parametrized version of the model relies exclusively on readily accessible zero-force data and thus allows one to qualitatively explore mechanically induced reactivity changes in complex setups. PMID- 26579738 TI - Excited-State Vibrations of Solvated Molecules: Going Beyond the Linear-Response Polarizable Continuum Model. AB - In this work we compare the excited-state vibrational patterns computed in gas and condensed phases, the latter being modeled with the Polarizable Continuum Model. For the first time we compare the results of two alternative theoretical approaches that is a standard linear-response approximation and a state-specific description, within the corrected linear-response formulation. Using five test molecules, we show that the point group symmetry of the excited-state geometry might differ with the linear and corrected linear-response models. The vibrational frequencies obtained with the latter model are often rather close to their gas counterparts, whereas the linear-response model tends to overestimate solvation effects. The differences in zero-point vibrational energies between the excited and ground states have also been evaluated, and the impact of the selected solvent model is generally limited for this average parameter. PMID- 26579740 TI - Applicability of Quantum Thermal Baths to Complex Many-Body Systems with Various Degrees of Anharmonicity. AB - The semiclassical method of quantum thermal baths by colored noise thermostats has been used to simulate various atomic systems in the molecular and bulk limits, at finite temperature and in moderately to strongly anharmonic regimes. In all cases, the method performs relatively well against alternative approaches in predicting correct energetic properties, including in the presence of phase changes, provided that vibrational delocalization is not too strong-neon appearing already as an upper limiting case. In contrast, the dynamical behavior inferred from global indicators such as the root-mean-square bond length fluctuation index or the vibrational spectrum reveals more marked differences caused by zero-point energy leakage, except in the case of isolated molecules with well separated vibrational modes. To correct for such deficiencies and reduce the undesired transfer among modes, empirical modifications of the noise power spectral density were attempted to better describe thermal equilibrium but still failed when used as semiclassical preparation for microcanonical trajectories. PMID- 26579739 TI - Independent Metrics for Protein Backbone and Side-Chain Flexibility: Time Scales and Effects of Ligand Binding. AB - Conformational dynamics are central for understanding biomolecular structure and function, since biological macromolecules are inherently flexible at room temperature and in solution. Computational methods are nowadays capable of providing valuable information on the conformational ensembles of biomolecules. However, analysis tools and intuitive metrics that capture dynamic information from in silico generated structural ensembles are limited. In standard work flows, flexibility in a conformational ensemble is represented through residue wise root-mean-square fluctuations or B-factors following a global alignment. Consequently, these approaches relying on global alignments discard valuable information on local dynamics. Results inherently depend on global flexibility, residue size, and connectivity. In this study we present a novel approach for capturing positional fluctuations based on multiple local alignments instead of one single global alignment. The method captures local dynamics within a structural ensemble independent of residue type by splitting individual local and global degrees of freedom of protein backbone and side-chains. Dependence on residue type and size in the side-chains is removed via normalization with the B factors of the isolated residue. As a test case, we demonstrate its application to a molecular dynamics simulation of bovine pancreatic trypsin inhibitor (BPTI) on the millisecond time scale. This allows for illustrating different time scales of backbone and side-chain flexibility. Additionally, we demonstrate the effects of ligand binding on side-chain flexibility of three serine proteases. We expect our new methodology for quantifying local flexibility to be helpful in unraveling local changes in biomolecular dynamics. PMID- 26579741 TI - Stalking Higher Energy Conformers on the Potential Energy Surface of Charged Species. AB - Combined theoretical DFT-MD and RRKM methodologies and experimental spectroscopic infrared predissociation (IRPD) strategies to map potential energy surfaces (PES) of complex ionic clusters are presented, providing lowest and high energy conformers, thresholds to isomerization, and cluster formation pathways. We believe this association not only represents a significant advance in the field of mapping minima and transition states on the PES but also directly measures dynamical pathways for the formation of structural conformers and isomers. Pathways are unraveled over picosecond (DFT-MD) and microsecond (RRKM) time scales while changing the amount of internal energy is experimentally achieved by changing the loss channel for the IRPD measurements, thus directly probing different kinetic and isomerization pathways. Demonstration is provided for Li(+)(H2O)3,4 ionic clusters. Nonstatistical formation of these ionic clusters by both direct and cascade processes, involving isomerization processes that can lead to trapping of high energy conformers along the paths due to evaporative cooling, has been unraveled. PMID- 26579742 TI - Multiple-Time Step Ab Initio Molecular Dynamics Based on Two-Electron Integral Screening. AB - A multiple-timestep ab initio molecular dynamics scheme based on varying the two electron integral screening method used in Hartree-Fock or density functional theory calculations is presented. Although screening is motivated by numerical considerations, it is also related to separations in the length- and timescales characterizing forces in a molecular system: Loose thresholds are sufficient to describe fast motions over short distances, while tight thresholds may be employed for larger length scales and longer times, leading to a practical acceleration of ab initio molecular dynamics simulations. Standard screening approaches can lead, however, to significant discontinuities in (and inconsistencies between) the energy and gradient when the screening threshold is loose, making them inappropriate for use in dynamics. To remedy this problem, a consistent window-screening method that smooths these discontinuities is devised. Further algorithmic improvements reuse electronic-structure information within the dynamics step and enhance efficiency relative to a naive multiple timestepping protocol. The resulting scheme is shown to realize meaningful reductions in the cost of Hartree-Fock and B3LYP simulations of a moderately large system, the protonated sarcosine/glycine dipeptide embedded in a 19-water cluster. PMID- 26579743 TI - Photodissociation Dynamics of Homonuclear Diatomic Molecules in Helium Nanodroplets. The Case of Cl2@(4He)N. AB - To investigate the photodissociation dynamics of diatomic homonuclear molecules in helium nanodroplets, a hybrid quantum mechanical theoretical method that combines time dependent density functional theory (helium) and quantum dynamics (molecule) has been developed. This method has been applied to investigate the Cl2 photodissociation arising from the B <- X electronic transition, considering Cl2(v = 0,X)@((4)He)N nanodroplets with N = 50, 100, 200, 300, and 500 (initial configuration for the dynamics). A time scale of a few picoseconds has been determined, and the time required for the dissociating atoms to reach the nanodroplet surface increases with N. Moreover, at the high velocities involved (orders of magnitude above the Landau's critical velocity), an efficient energy exchange between the chlorine atoms and the helium takes place, releasing up to 91% of the energy of the excited diatomics for the bigger nanodroplet considered; and the energy exchange mechanism is the same for all the nanodroplets. Finally, simple (linear) relations for the average Cl final velocity and the (small) number of evaporated He atoms with respect to the radius of the droplets have been reported, together with the existence of confinement resonances. We hope that these results will encourage the experimentalists to investigate this kind of systems. PMID- 26579744 TI - Diffusion Monte Carlo Study of Para-Diiodobenzene Polymorphism Revisited. AB - We revisit our investigation of the diffusion Monte Carlo (DMC) simulation of para-diiodobenzene (p-DIB) molecular crystal polymorphism. [See J. Phys. Chem. Lett. 2010, 1, 1789-1794.] We perform, for the first time, a rigorous study of finite-size effects and choice of nodal surface on the prediction of polymorph stability in molecular crystals using fixed-node DMC. Our calculations are the largest that are currently feasible using the resources of the K-computer and provide insights into the formidable challenge of predicting such properties from first principles. In particular, we show that finite-size effects can influence the trial nodal surface of a small (1 * 1 * 1) simulation cell considerably. Therefore, we repeated our DMC simulations with a 1 * 3 * 3 simulation cell, which is the largest such calculation to date. We used a density functional theory (DFT) nodal surface generated with the PBE functional, and we accumulated statistical samples with ~6.4 * 10(5) core hours for each polymorph. Our final results predict a polymorph stability that is consistent with experiment, but they also indicate that the results in our previous paper were somewhat fortuitous. We analyze the finite-size errors using model periodic Coulomb (MPC) interactions and kinetic energy corrections, according to the CCMH scheme of Chiesa, Ceperley, Martin, and Holzmann. We investigate the dependence of the finite-size errors on different aspect ratios of the simulation cell (k-mesh convergence) in order to understand how to choose an appropriate ratio for the DMC calculations. Even in the most expensive simulations currently possible, we show that the finite size errors in the DMC total energies are much larger than the energy difference between the two polymorphs, although error cancellation means that the polymorph prediction is accurate. Finally, we found that the T move scheme is essential for these massive DMC simulations in order to circumvent population explosions and large time-step biases. PMID- 26579745 TI - Preselective Screening for Linear-Scaling Exact Exchange-Gradient Calculations for Graphics Processing Units and General Strong-Scaling Massively Parallel Calculations. AB - We present an extension of our recently presented PreLinK scheme (J. Chem. Phys. 2013, 138, 134114) for the exact exchange contribution to nuclear forces. The significant contributions to the exchange gradient are determined by preselection based on accurate shell-pair contributions to the SCF exchange energy prior to the calculation. Therefore, our method is highly suitable for massively parallel electronic structure calculations because of an efficient load balancing of the significant contributions only and an unhampered control flow. The efficiency of our method is shown for several illustrative calculations on single GPU servers, as well as for hybrid MPI/CUDA parallel calculations with the largest system comprising 3369 atoms and 26952 basis functions. PMID- 26579746 TI - Coupled-Perturbed SCF Approach for Calculating Static Polarizabilities and Hyperpolarizabilities with Nonorthogonal Localized Molecular Orbitals. AB - Coupled-perturbed self-consistent-field (CPSCF) approach has been broadly used for polarizabilities and hyperpolarizabilities computation. To extend this application to large systems, we have reformulated the CPSCF equations with nonorthogonal localized molecular orbitals (NOLMOs). NOLMOs are the most localized representation of electronic degrees of freedom. Methods based on NOLMOs are potentially ideal for investigating large systems. In atomic orbital representation, with a static external electric field added, the wave function and SCF operator of unperturbed NOLMO-SCF wave function/orbitals are expanded to different orders of perturbations. We have derived the corresponding equations up to the third order, which are significantly different from those of a conventional CPSCF method because of the release of the orthogonal restrictions on MOs. The solution to these equations has been implemented. Several chemical systems are used to verify our method. This work represents the first step toward efficient calculations of molecular response and excitation properties with NOLMOs. PMID- 26579747 TI - Accurate Treatment of Large Supramolecular Complexes by Double-Hybrid Density Functionals Coupled with Nonlocal van der Waals Corrections. AB - In this work, we present a thorough assessment of the performance of some representative double-hybrid density functionals (revPBE0-DH-NL and B2PLYP-NL) as well as their parent hybrid and GGA counterparts, in combination with the most modern version of the nonlocal (NL) van der Waals correction to describe very large weakly interacting molecular systems dominated by noncovalent interactions. Prior to the assessment, an accurate and homogeneous set of reference interaction energies was computed for the supramolecular complexes constituting the L7 and S12L data sets by using the novel, precise, and efficient DLPNO-CCSD(T) method at the complete basis set limit (CBS). The correction of the basis set superposition error and the inclusion of the deformation energies (for the S12L set) have been crucial for obtaining precise DLPNO-CCSD(T)/CBS interaction energies. Among the density functionals evaluated, the double-hybrid revPBE0-DH-NL and B2PLYP-NL with the three-body dispersion correction provide remarkably accurate association energies very close to the chemical accuracy. Overall, the NL van der Waals approach combined with proper density functionals can be seen as an accurate and affordable computational tool for the modeling of large weakly bonded supramolecular systems. PMID- 26579748 TI - The Energy Difference between the Triply-Bridged and All-Terminal Structures of Co4(CO)12, Rh4(CO)12, and Ir4(CO)12: A Difficult Test for Conventional Density Functional Methods. AB - The M4(CO)12 molecules Co4(CO)12, Rh4(CO)12, and Ir4(CO)12 have two low-lying structures, the all-terminal structure with Td symmetry and the triply bridged structure with C3v symmetry. A total of 45 density functional theory (DFT) methods have been used to predict structures and vibrational frequencies for Co4(CO)12, Rh4(CO)12, and Ir4(CO)12. The different DFT methods show a broad range of energy differences DeltaE = E(Td) - E(C3v). For Rh4(CO)12, none of the 45 DFT predictions is within 11 kcal/mol of the 2005 experimental value of 5.1 +/- 0.6 kcal/mol reported by Allian and Garland (Dalton Trans. 2005, 1957 - 1965). For the challenging Ir4(CO)12 molecule, 21 DFT methods predict the correct Td structure, while 24 DFT methods predict the C3v structure to lie lower in energy. This research reveals many peculiar problems in the computation of the vibrational frequencies for the all-terminal structure. PMID- 26579749 TI - Evaluation of Energy Gradients and Infrared Vibrational Spectra through Molecules in-Molecules Fragment-Based Approach. AB - Molecules-in-Molecules (MIM) is a general hybrid fragment-based extrapolation approach for calculating accurate total energies of large molecules, similar in spirit to the popular ONIOM methodology. In this work, the MIM model is extended for the precise evaluation of the energy gradients and infrared (IR) vibrational spectra of large molecules. The overlapping subsystems in this work are constructed from nonoverlapping fragments using a number-based scheme, and the dangling bonds are saturated with link-hydrogen atoms. Independent fragment calculations are performed to evaluate the energies and its gradients. Subsequently, the link-atom energy gradient components are projected back onto the corresponding host and supporting atoms, through the Jacobian projection method, as in the ONIOM approach. After geometry optimization, the Jacobian link atom projection method is also employed for the precise evaluation of the force constants and dipole derivatives of the full molecule. The performance of the MIM model is benchmarked on 25 small-to-large peptides, with inevitable weak long range intramolecular interactions. Upon accounting these long-range interactions through a second layer, at an inexpensive low-level of theory (MIM2), the energy accuracy improve by 80%, compared to MIM with one layer (MIM1). The MIM2 IR frequencies and intensities have an ~75% improvement, compared to the corresponding values at the MIM1 level of theory. A similar improvement is also observed for anion, cation, and radical systems constructed from the neutral benchmark molecules. The accuracy and performance of the benchmark systems validate the MIM model for exploring the vibrational infrared spectra of large molecules. PMID- 26579750 TI - Third-Order Incremental Dual-Basis Set Zero-Buffer Approach for Large High-Spin Open-Shell Systems. AB - The third-order incremental dual-basis set zero-buffer approach (inc3-db-B0) is an efficient, accurate, and black-box quantum chemical method for obtaining correlation energies of large systems, and it has been successfully applied to many real chemical problems. In this work, we extend this approach to high-spin open-shell systems. In the open-shell approach, we will first decompose the occupied orbitals of a system into several domains by a K-means clustering algorithm. The essential part is that we preserve the active (singly occupied) orbitals in all the calculations of the domain correlation energies. The duplicated contributions of the active orbitals to the correlation energy are subtracted from the incremental expansion. All techniques of truncating the virtual space such as the B0 approximation can be applied. This open-shell inc3 db-B0 approach is combined with the CCSD and CCSD(T) methods and applied to the computations of a singlet-triplet gap and an electron detachment process. Our approach exhibits an accuracy better than 0.6 kcal/mol or 0.3 eV compared with the standard implementation, while it saves a large amount of the computational time and can be efficiently parallelized. PMID- 26579751 TI - One-Electron Energies from the Two-Component GW Method. AB - The two-component extension of the G0W0 method for closed-shell systems based on the previously implemented one-component version in TURBOMOLE that uses localized basis functions is presented. In this way, it is possible to account for spin orbit effects on one-electron energies of isolated molecular systems at the G0W0 level. We briefly sketch the derivation of the underlying equations, give details about the implementation, and apply the method to several atomic and diatomic systems. The influence of spin-orbit coupling changes calculated first ionization energies by up to 0.7 eV, leading to maximum errors smaller than 0.3 eV. Virtually the same results are obtained with an economic extrapolation scheme based on the one-component G0W0 and the two-component reference state calculation. Furthermore, for binding energies of core levels, two-component G0W0 is very accurate, as demonstrated for mercury and zinc atoms as well as for ZnF2. PMID- 26579752 TI - Excitation Energies from Real-Time Propagation of the Four-Component Dirac-Kohn Sham Equation. AB - We report the first implementation of real-time time-dependent density functional theory (RT-TDDFT) at the relativistic four-component level of theory. In contrast to the perturbative linear-response TDDFT approach (LR-TDDFT), the RT-TDDFT approach performs an explicit time propagation of the Dirac-Kohn-Sham density matrix, offering the possibility to simulate molecular spectroscopies involving strong electromagnetic fields while, at the same time, treating relativistic scalar and spin-orbit corrections variationally. The implementation is based on the matrix representation of the Dirac-Coulomb Hamiltonian in the basis of restricted kinetically balanced Gaussian-type functions, exploiting the noncollinear Kramers unrestricted formalism implemented in the program ReSpect. We also present an analytic form for the delta-type impulse commonly used in RT TDDFT calculations, as well as a dipole-weighted transition matrix analysis, facilitating the interpretation of spectral transitions in terms of ground-state molecular orbitals. The possibilities offered by the methodology are illustrated by investigating vertical excitation energies and oscillator strengths for ground state to excited-state transitions in the Group 12 atoms and in heavy-element hydrides. The accuracy of the method is assessed by comparing the excitation energies obtained with earlier relativistic linear response TDDFT results and available experimental data. PMID- 26579753 TI - Spin Adapted versus Broken Symmetry Approaches in the Description of Magnetic Coupling in Heterodinuclear Complexes. AB - The performance of a series of wave function and density functional theory based methods in predicting the magnetic coupling constant of a family of heterodinuclear magnetic complexes has been studied. For the former, the accuracy is similar to other simple cases involving homodinuclear complexes, the main limitation being a sufficient inclusion of dynamical correlation effects. Nevertheless, these series of calculations provide an appropriate benchmark for density functional theory based methods. Here, the usual broken symmetry approach provides a convenient framework to predict the magnetic coupling constants but requires deriving the appropriate mapping. At variance with simple dinuclear complexes, spin projection based techniques cannot recover the corresponding (approximate) spin adapted solution. Present results also show that current implementation of spin flip techniques leads to unphysical results. PMID- 26579754 TI - Calculated Nuclear Magnetic Resonance Spectra of Polytwistane and Related Hydrocarbon Nanorods. AB - Polytwistane is an intriguing hydrocarbon nanorod that has not been experimentally realized to date. To facilitate its identification in complex reaction mixtures, the (1)H and (13)C nuclear magnetic resonance (NMR) spectra of idealized polytwistane were calculated using two distinct quantum chemical approaches. In addition, the NMR spectra of related hydrocarbon nanorods were determined. On the basis of these data, we speculate whether polytwistane and its congeners correspond to a crystalline one-dimensional sp(3) carbon nanomaterial formed by high-pressure solid-state polymerization of benzene. PMID- 26579755 TI - Co-C Bond Dissociation Energies in Cobalamin Derivatives and Dispersion Effects: Anomaly or Just Challenging? AB - Accurate Co-C bond dissociation energies (BDEs) of large cobalamin derivatives in the gas phase and solution are crucial for understanding bond activation mechanisms in various enzymatic reactions. However, they are challenging for both experiment and theory as indicated by an obvious discrepancy between experimental and theoretical gas phase data for adenosylcobinamide. State-of-the-art dispersion-corrected DFT and LPNO-CCSD calculations are conducted for the Co-C BDEs of some neutral and positively charged cobalamin derivatives with adenosyl and methyl ligands and compared with available experimental gas phase and solution data to resolve the controversy. Our results from various levels of electronic structure theory are fully consistent with chemical and physical reasoning. We show undoubtedly that the Co-C bonds in complexes with the bulky adenosyl ligand are indirectly enhanced by many ligand-host noncovalent interactions and that the overall BDE are larger than those with the small methyl ligand in the gas phase. The additional intramolecular dispersion and hydrogen bond interactions are significantly but not fully quenched in aqueous solution. The theoretical results including standard continuum solvation and dispersion corrections to DFT are in full accordance with experimental solution data. This is in agreement with several successful joined experimental/theoretical studies in recent years employing similar quantum chemical methodology. We see therefore no empirical basis for questioning the reliability of current dispersion corrections like D3 or VV10 to standard density functional approximations neither for these compounds nor for organometallic chemistry in general. PMID- 26579757 TI - Removing External Degrees of Freedom from Transition-State Search Methods using Quaternions. AB - In finite systems, such as nanoparticles and gas-phase molecules, calculations of minimum energy paths (MEPs) connecting initial and final states of transitions as well as searches for saddle points are complicated by the presence of external degrees of freedom, such as overall translation and rotation. A method based on quaternion algebra for removing the external degrees of freedom is described here and applied in calculations using two commonly used methods: the nudged elastic band (NEB) method for MEPs and the DIMER method for finding the minimum mode in minimum mode following searches of first-order saddle points. With the quaternion approach, fewer images in the NEB are needed to represent MEPs accurately. In both NEB and DIMER calculations of finite systems, the number of iterations required to reach convergence is significantly reduced. The algorithms have been implemented in the Atomic Simulation Environment (ASE) open source software. PMID- 26579756 TI - Acidic C-H Bond as a Proton Donor in Excited State Intramolecular Proton Transfer Reactions. AB - An unprecedented type of excited state intramolecular proton transfer in a series of benzo[h]quinoline (BHQ) derivatives substituted at position 10 with strong CH acid character is described using density functional theory/time-dependent density functional theory computational approaches with a hybrid functional and the 6-311++G(d,p) triple-xi quality basis set. Our results show that for 10 malononitrile-substituted BHQ (2CNBHQ) the excited state intramolecular proton transfer C-H...N reaction is a barrierless process. Calculations also reveal that the reaction profiles of the 4-amino-substituted 2CNBHQ show a large dependence on the polarity of the environment. PMID- 26579758 TI - Probing the Unfolded Configurations of a beta-Hairpin Using Sketch-Map. AB - This work examines the conformational ensemble involved in beta-hairpin folding by means of advanced molecular dynamics simulations and dimensionality reduction. A fully atomistic description of the protein and the surrounding solvent molecules is used, and this complex energy landscape is sampled by means of parallel tempering metadynamics simulations. The ensemble of configurations explored is analyzed using the recently proposed sketch-map algorithm. Further simulations allow us to probe how mutations affect the structures adopted by this protein. We find that many of the configurations adopted by a mutant are the same as those adopted by the wild-type protein. Furthermore, certain mutations destabilize secondary-structure-containing configurations by preventing the formation of hydrogen bonds or by promoting the formation of new intramolecular contacts. Our analysis demonstrates that machine-learning techniques can be used to study the energy landscapes of complex molecules and that the visualizations that are generated in this way provide a natural basis for examining how the stabilities of particular configurations of the molecule are affected by factors such as temperature or structural mutations. PMID- 26579760 TI - Comparison of Real-Time and Linear-Response Time-Dependent Density Functional Theories for Molecular Chromophores Ranging from Sparse to High Densities of States. AB - We assess the performance of real-time time-dependent density functional theory (RT-TDDFT) for the calculation of absorption spectra of 12 organic dye molecules relevant to photovoltaics and dye-sensitized solar cells with 8 exchange correlation functionals (3 traditional, 3 global hybrids, and 2 range-separated hybrids). We compare the calculations with traditional linear-response (LR) TDDFT and experimental spectra. In addition, we demonstrate the efficacy of the RT TDDFT approach to calculate wide absorption spectra of two large chromophores relevant to photovoltaics and molecular switches. RT-TDDFT generally requires longer simulation times, compared to LR-TDDFT, for absorption spectra of small systems. However, it becomes more effective for the calculation of wide absorption spectra of large molecular complexes and systems with very high densities of states. PMID- 26579759 TI - Conserve Water: A Method for the Analysis of Solvent in Molecular Dynamics. AB - Molecular dynamics with explicit solvent is favored for its ability to more correctly simulate aqueous biological processes and has become routine thanks to increasingly powerful computational resources. However, analysis techniques including Markov state models (MSMs) ignore solvent atoms and focus solely on solute coordinates despite solvent being implicated in myriad biological phenomena. We present a unified framework called "solvent-shells featurization" for including solvent degrees of freedom in analysis and show that this method produces better models. We apply this method to simulations of dewetting in the two-domain protein BphC to generate a predictive MSM and identify functional water molecules. Furthermore, the proposed methodology could be easily extended for building MSMs of any systems with indistinguishable components. PMID- 26579761 TI - Calculating High Energy Charge Transfer States Using Optimally Tuned Range Separated Hybrid Functionals. AB - Recently developed optimally tuned range-separated hybrid (OT-RHS) functionals within time-dependent density functional theory have been shown to address existing limitations in calculating charge transfer excited state energies. The RSH success in improving the calculation of CT states stems from enforcing the correspondence of the frontier molecular orbitals (FMOs) to physical properties, where the highest occupied MO energy relates to the ionization potential and the lowest unoccupied MO energy relates to the electron affinity. However, in this work, we show that a less accurate description of CT states that involves non FMOs is afforded by the RSH approach. In order to achieve a high quality description of such higher energy CT states, the parameter tuning procedure, which lies at the foundation of the RSH approach, needs to be generalized to consider the CT process. We demonstrate the need for improved description of such CT states in donor-acceptor systems, where the optimal tuning parameter is accounting for the state itself. PMID- 26579762 TI - Early Events in the Nonadiabatic Relaxation Dynamics of 4-(N,N Dimethylamino)benzonitrile. AB - 4-(N,N-Dimethylamino)benzonitrile (DMABN) is the archetypal system for dual fluorescence. Several past studies, both experimental and theoretical, have examined the mechanism of its relaxation in the gas phase following photoexcitation to the S2 state, without converging to a single description. In this contribution, we report first-principles simulations of the early events involved in this process performed using the nonadiabatic trajectory surface hopping (TSH) approach in combination with the ADC(2) electronic structure method. ADC(2) is verified to reproduce the ground- and excited-state structures of DMABN in reasonably close agreement with previous theoretical benchmarks. The TSH simulations predict that internal conversion from the S2 state to the S1 takes place as early as 8.5 fs, on average, after the initial photoexcitation, and with no significant torsion of the dimethylamino group relative to the aromatic ring. As evidenced by supporting EOM-CCSD calculations, the population transfer from S2 to S1 can be attributed to the skeletal deformation modes of the aromatic ring and the stretching of the ring-dimethylamino nitrogen bond. The non or slightly twisted locally excited structure is the predominant product of the internal conversion, and the twisted intramolecular charge transfer structure is formed through equilibration with the locally excited structure with no change of adiabatic state. These findings point toward a new interpretation of data from previous time-resolved experiments. PMID- 26579763 TI - Infrared and Raman Spectroscopy of Liquid Water through "First-Principles" Many Body Molecular Dynamics. AB - Vibrational spectroscopy is a powerful technique to probe the structure and dynamics of water. However, deriving an unambiguous molecular-level interpretation of the experimental spectral features remains a challenge due to the complexity of the underlying hydrogen-bonding network. In this contribution, we present an integrated theoretical and computational framework (named many-body molecular dynamics or MB-MD) that, by systematically removing uncertainties associated with existing approaches, enables a rigorous modeling of vibrational spectra of water from quantum dynamical simulations. Specifically, we extend approaches used to model the many-body expansion of interaction energies to develop many-body representations of the dipole moment and polarizability of water. The combination of these "first-principles" representations with centroid molecular dynamics simulations enables the simulation of infrared and Raman spectra of liquid water under ambient conditions that, without relying on any ad hoc parameters, are in good agreement with the corresponding experimental results. Importantly, since the many-body energy, dipole, and polarizability surfaces employed in the simulations are derived independently from accurate fits to correlated electronic structure data, MB-MD allows for a systematic analysis of the calculated spectra in terms of both electronic and dynamical contributions. The present analysis suggests that, while MB-MD correctly reproduces both the shifts and the shapes of the main spectroscopic features, an improved description of quantum dynamical effects possibly combined with a dissociable water potential may be necessary for a quantitative representation of the OH stretch band. PMID- 26579764 TI - Density-Difference-Driven Optimized Embedding Potential Method To Study the Spectroscopy of Br2 in Water Clusters. AB - A variant of the density difference driven optimized embedding potential (DDD OEP) method, proposed by Roncero et al. (J. Chem. Phys. 2009, 131, 234110), has been applied to the calculation of excited states of Br2 within small water clusters. It is found that the strong interaction of Br2 with the lone electronic pair of the water molecules makes necessary to optimize specific embedding potentials for ground and excited electronic states, separately and using the corresponding densities. Diagnosis and convergence studies are presented with the aim of providing methods to be applied for the study of chromophores in solution. Also, some preliminary results obtained for the study of electronic states of Br2 in clathrate cages are presented. PMID- 26579765 TI - Reassessment of the Thermodynamic, Kinetic, and Spectroscopic Features of Cyanomethanimine Derivatives: A Full Anharmonic Perturbative Treatment. AB - Herein we report a full thermodynamic and vibrational investigation of C cyanomethanimine isomers rooted into the Density Functional Theory (DFT) and the second-order vibrational perturbation theory (VPT2). We show that an anharmonic treatment affects dramatically the vibrational behavior of the molecules, especially thanks to the inclusion of interaction terms between the various modes. Furthermore, the equilibrium constant between the isomers, as well as the rate constant, have been obtained at both harmonic and anharmonic levels showing, as expected, slight but non-negligible differences. To support our investigation, dispersion effects have been employed. PMID- 26579766 TI - A Kinetic Monte Carlo Study of Fullerene Adsorption within a Pc-PBBA Covalent Organic Framework and Implications for Electron Transport. AB - Two-dimensional covalent organic frameworks (COFs), with their predictable assembly into ordered porous crystalline materials, tunable composition, and high charge carrier mobility, offer the possibility of creating ordered bulk heterojunction solar cells given a suitable electron-transporting material to fill the pores. The photoconductive (hole-transporting) properties of many COFs have been reported, including the recent creation of a TT-COF/PCBM solar cell by Dogru et al. Although a prototype device has been fabricated, its poor solar efficiency suggests a potential issue with electron transport caused by the interior packing of the fullerenes. Such packing information is absent and cannot be obtained experimentally. In this paper, we use Kinetic Monte Carlo (KMC) simulations to understand the dominant pore-filling mechanisms and packing configurations of C60 molecules in a Pc-PBBA COF that are similar to the COF fabricated experimentally. The KMC simulations thus offer more realistic filling conditions than our previously used Monte Carlo (MC) techniques. We found persistently large separation distances between C60 molecules that are absent in the more tractable MC simulations and which are likely to hinder electron transport significantly. We attribute the looser fullerene packing to the existence of stable motifs with pairwise distances that are mismatched with the underlying adsorption lattice of the COF. We conclude that larger pore COFs may be necessary to optimize electron transport and hence produce higher efficiency devices. PMID- 26579767 TI - Why is Benzene Soluble in Water? Role of OH/pi Interaction in Solvation. AB - The XH/pi interaction (X = C, N, or O) plays an essential role in a variety of fundamental processes in condensed phase, and it attracts broad interests in the fields of chemistry and biochemistry in recent years. This issue has a direct relevance to an intriguing phenomenon that a benzene molecule exhibits a negative solvation free energy of -0.87 kcal/mol in ambient water though it is a typical nonpolar organic solute. In this work, we developed a novel method to analyze the free energy deltaMU due to the electron density fluctuation of a solute in solution to clarify the mechanism responsible for the affinity of benzene to bulk water. Explicitly, the free energy deltaMU is decomposed into contributions from sigma and pi electrons in pi-conjugated systems on the basis of the QM/MM method combined with a theory of solutions. With our analyses, the free energy deltaMU(pi) arising from the fluctuation of pi electrons in benzene was obtained as -0.94 kcal/mol and found to be the major source of the affinity of benzene to water. Thus, the role of pi electrons in hydration is quantified for the first time with our analyses. Our method was applied to phenyl methyl ether (PME) in water solution to examine the substituent effects of the electron donating group (EDG) on the hydration of a pi-conjugated system. The delocalization effect of the pi electrons on hydration was also investigated performing the decomposition analyses for ethene and 1,3-butadiene molecules in water solutions. It was revealed that the stabilization due to deltaMU(pi) for butadiene (-0.76 kcal/mol) is about three times as large as that for ethene (-0.26 kcal/mol), which suggests the importance of the delocalization effect of the pi electrons in mediating the affinity to polar solvent. PMID- 26579768 TI - Understanding the epsilon and zeta High-Pressure Solid Phases of Oxygen. Systematic Periodic Density Functional Theory Studies Using Localized Atomic Basis. AB - The experimentally characterized epsilon and zeta phases of solid oxygen are studied by periodic Hartree-Fock (HF) and Density Functional Theory calculations at pressures from 10 to 160 GPa using different types of exchange-correlation functionals with Gaussian atomic basis sets. Full geometry optimizations of the monoclinic C2/m (O2)4 unit cell were done to study the evolution of the structural and electronic properties with pressure. Vibrational calculations were performed at each pressure. While periodic HF does not predict the epsilon-zeta phase transition in the considered range, Local Density approximation and Generalized Gradient approximation methods predict too low transition pressures. The performance of hybrid functional methods is dependent on the amount of non local HF exchange. PBE0, M06, B3PW91, and B3LYP approaches correctly predict the structural and electronic changes associated with the phase transition. GGA and hybrid functionals predict a pressure range where both phases coexist, but only the latter type of methods yield results in agreement with experiment. Using the optimized (O2)4 unit cell at each pressure we show, through CASSCF(8,8) calculations, that the greater accuracy of the optimized geometrical parameters with increasing pressure is due to a decreasing multireference character of the unit cell wave function. The mechanism of the transition from the non-conducting to the conducting zeta phase is explained through the Electron Pair Localization Function, which clearly reveals chemical bonding between O2 molecules in the ab crystal planes belonging to different unit cells due to much shorter intercell O2 O2 distances. PMID- 26579769 TI - Opsin Effect on the Electronic Structure of the Retinylidene Chromophore in Rhodopsin. AB - Direct examination of experimental NMR parameters combined with electronic structure analysis was used to provide a first-principle interpretation of NMR experiments and give a precise evaluation of how the electronic perturbation of the protein environment affects the electronic properties of the retinylidene chromophere in rhodopsin. To this end, we pursued a theoretical analysis using a combination of tools including quantum mechanics/molecular mechanics (QM/MM) at the Density Functional Theory (DFT) level, in conjunction with gauge independent atomic orbital (GIAO) calculations of (13)C NMR chemical shieldings and (1)J(CC) spin-spin coupling constants obtained with the Coupled Perturbed DFT (CPDFT) method. The opsin effect on the retinylidene chromophere is interpreted as an inductive effect of Glu-113 which readjusts the weighting factors of resonance substructures of the conjugated chain of the chromophere. These changes give a rationalization to the alternating effect of the (13)C chemical shifts magnitudes when comparing the retinylidene chromophere in the presence and absence of the protein environment. Conversely, perturbation of pi orbitals has little to no effect over (1)J (13)C-(13)C spin-spin coupling constants, as they are mainly dominated by the Fermi contact term, and hence the counteraion effect is restricted to the vicinity of the perturbation. Thus, the apparent contradiction between experimental findings based on chemical shifts (deep penetration) and one bond J-couplings (localized effects of the protonated Schiff base at the chain terminus) is in fact a consequence of different properties responding differently to the same external perturbation. PMID- 26579770 TI - Can We Execute Stable Microsecond-Scale Atomistic Simulations of Protein-RNA Complexes? AB - We report over 30 MUs of unrestrained molecular dynamics simulations of six protein-RNA complexes in explicit solvent. We utilize the AMBER ff99bsc0chi(OL3) RNA force field combined with the ff99SB protein force field and its more recent ff12SB version with reparametrized side-chain dihedrals. The simulations show variable behavior, ranging from systems that are essentially stable to systems with progressive deviations from the experimental structure, which we could not stabilize anywhere close to the starting experimental structure. For some systems, microsecond-scale simulations are necessary to achieve stabilization after initial sizable structural perturbations. The results show that simulations of protein-RNA complexes are challenging and every system should be treated individually. The simulations are affected by numerous factors, including properties of the starting structures (the initially high force field potential energy, resolution limits, conformational averaging, crystal packing, etc.), force field imbalances, and real flexibility of the studied systems. These factors, and thus the simulation behavior, differ from system to system. The structural stability of simulated systems does not correlate with the size of buried interaction surface or experimentally determined binding affinities but reflects the type of protein-RNA recognition. Protein-RNA interfaces involving shape-specific recognition of RNA are more stable than those relying on sequence specific RNA recognition. The differences between the protein force fields are considerably smaller than the uncertainties caused by sampling and starting structures. The ff12SB improves description of the tyrosine side-chain group, which eliminates some problems associated with tyrosine dynamics. PMID- 26579771 TI - High-Resolution Coarse-Grained Modeling Using Oriented Coarse-Grained Sites. AB - We introduce a method to bring nearly atomistic resolution to coarse-grained models, and we apply the method to proteins. Using a small number of coarse grained sites (about one per eight atoms) but assigning an independent three dimensional orientation to each site, we preferentially integrate out stiff degrees of freedom (bond lengths and angles, as well as dihedral angles in rings) that are accurately approximated by their average values, while retaining soft degrees of freedom (unconstrained dihedral angles) mostly responsible for conformational variability. We demonstrate that our scheme retains nearly atomistic resolution by mapping all experimental protein configurations in the Protein Data Bank onto coarse-grained configurations and then analytically backmapping those configurations back to all-atom configurations. This roundtrip mapping throws away all information associated with the eliminated (stiff) degrees of freedom except for their average values, which we use to construct optimal backmapping functions. Despite the 4:1 reduction in the number of degrees of freedom, we find that heavy atoms move only 0.051 A on average during the roundtrip mapping, while hydrogens move 0.179 A on average, an unprecedented combination of efficiency and accuracy among coarse-grained protein models. We discuss the advantages of such a high-resolution model for parametrizing effective interactions and accurately calculating observables through direct or multiscale simulations. PMID- 26579772 TI - Potential Application of Alchemical Free Energy Simulations to Discriminate GPCR Ligand Efficacy. AB - G protein-coupled receptors (GPCRs) play fundamental roles in physiological processes by modulating diverse signaling pathways and thus have been one of the most important drug targets. Based on the fact that GPCR-mediated signaling is modulated in a ligand-specific manner such as agonist, inverse agonist, and neutral antagonist (termed ligand efficacy), quantitative characterization of the ligand efficacy is essential for rational design of selective modulators for GPCR targets. As experimental approaches for this purpose are time-, cost-, and labor intensive, computational tools that can systematically predict GPCR ligand efficacy can have a big impact on GPCR drug design. Here, we have performed free energy perturbation molecular dynamics simulations to calculate absolute binding free energy of an inverse agonist, a neutral antagonist, and an agonist to beta2 adrenergic receptor (beta2-AR) active and inactive states, respectively, in explicit lipid bilayers. Relatively short alchemical free energy calculations reveal that both the time-series of the total binding free energy and decomposed energy contributions can be used as relevant physical properties to discriminate beta2-AR ligand efficacy. This study illustrates a merit of the current approach over simple, fast docking calculations or highly expensive millisecond-time scale simulations. PMID- 26579774 TI - Bottom-Up Coarse-Graining of Peptide Ensembles and Helix-Coil Transitions. AB - This work investigates the capability of bottom-up methods for parametrizing minimal coarse-grained (CG) models of disordered and helical peptides. We consider four high-resolution peptide ensembles that demonstrate varying degrees of complexity. For each high-resolution ensemble, we parametrize a CG model via the multiscale coarse-graining (MS-CG) method, which employs a generalized Yvon Born-Green (g-YBG) relation to determine potentials directly (i.e., without iteration) from the high-resolution ensemble. The MS-CG method accurately describes high-resolution models that fluctuate about a single conformation. However, given the minimal resolution and simple molecular mechanics potential, the MS-CG method provides a less accurate description for a high-resolution peptide model that samples a disordered ensemble with multiple distinct conformations. We employ an iterative g-YBG method to develop a CG model that more accurately describes the relevant distribution functions and free energy surfaces for this disordered ensemble. Nevertheless, this more accurate model does not reproduce the cooperative helix-coil transition that is sampled by the high resolution model. By comparing the different models, we demonstrate that the errors in the MS-CG model primarily stem from the lack of cooperative interactions afforded by the minimal representation and molecular mechanics potential. This work demonstrates the potential of the MS-CG method for accurately modeling complex biomolecular structures, but also highlights the importance of more complex potentials for modeling cooperative transitions with a minimal CG representation. PMID- 26579773 TI - Biasing Potential Replica Exchange Multisite lambda-Dynamics for Efficient Free Energy Calculations. AB - Traditional free energy calculation methods are well-known for their drawbacks in scalability and speed in converging results particularly for calculations with large perturbations. In the present work, we report on the development of biasing potential replica exchange multisite lambda-dynamics (BP-REX MSlambdaD), which is a free energy method that is capable of performing simultaneous alchemical free energy transformations, including perturbations between flexible moieties. BP-REX MSlambdaD and the original MSlambdaD are applied to a series of symmetrical 2,5 benzoquinone derivatives covering a diverse chemical space and range of conformational flexibility. Improved lambda-space sampling is observed for the BP REX MSlambdaD simulations, yielding a 2-5-fold increase in the number of transitions between substituents compared to traditional MSlambdaD. We also demonstrate the efficacy of varying the value of c, the parameter that controls the ruggedness of the landscape mediating the sampling of lambda-states, based on the flexibility of the fragment. Finally, we developed a protocol for maximizing the transition frequency between fragments. This protocol reduces the "kinetic barrier" for alchemically transforming fragments by grouping and ordering based on volume. These findings are applied to a challenging test set involving a series of geldanamycin-based inhibitors of heat shock protein 90 (Hsp90). Even though the perturbations span volume changes by as large as 60 A(3), the values for the free energy change achieve an average unsigned error (AUE) of 1.5 kcal/mol relative to experimental Kd measurements with a reasonable correlation (R = 0.56). Our results suggest that the BP-REX MSlambdaD algorithm is a highly efficient and scalable free energy method, which when utilized will enable routine calculations on the order of hundreds of compounds using only a few simulations. PMID- 26579775 TI - A Collective Variable for the Rapid Exploration of Protein Druggability. AB - An efficient molecular simulation methodology has been developed for the evaluation of the druggability (ligandability) of a protein. Previously proposed techniques were designed to assess the druggability of crystallographic structures and cannot be tightly coupled to molecular dynamics (MD) simulations. By contrast, the present approach, JEDI (Just Exploring Druggability at protein Interfaces), features a druggability potential made of a combination of empirical descriptors that can be collected "on-the-fly" during MD simulations. Extensive validation studies indicate that JEDI analyses discriminate druggable and nondruggable protein binding site conformations with accuracy similar to alternative methodologies, and at a fraction of the computational cost. Since the JEDI function is continuous and differentiable, the druggability potential can be used as collective variable to rapidly detect cryptic druggable binding sites in proteins with a variety of MD free energy methods. Protocols for applications to flexible docking problems are outlined. PMID- 26579776 TI - Decoding the Mobility and Time Scales of Protein Loops. AB - The flexible nature of protein loops and the time scales of their dynamics are critical for many biologically important events at the molecular level, such as protein interaction and recognition processes. In order to obtain a predictive understanding of the dynamic properties of loops, 500 ns molecular dynamics (MD) computer simulations of 38 different proteins were performed and validated using NMR chemical shifts. A total of 169 loops were analyzed and classified into three types, namely fast loops with correlation times <10 ns, slow loops with correlation times between 10 and 500 ns, and loops that are static over the course of the whole trajectory. Chemical and biophysical loop descriptors, such as amino-acid sequence, average 3D structure, charge distribution, hydrophobicity, and local contacts were used to develop and parametrize the ToeLoop algorithm for the prediction of the flexibility and motional time scale of every protein loop, which is also implemented as a public Web server (http://spin.ccic.ohio-state.edu/index.php/loop). The results demonstrate that loop dynamics with their time scales can be predicted rapidly with reasonable accuracy, which will allow the screening of average protein structures to help better understand the various roles loops can play in the context of protein protein interactions and binding. PMID- 26579777 TI - Molecular Dynamics Simulations of 441 Two-Residue Peptides in Aqueous Solution: Conformational Preferences and Neighboring Residue Effects with the Amber ff99SB ildn-NMR Force Field. AB - Understanding the intrinsic conformational preferences of amino acids and the extent to which they are modulated by neighboring residues is a key issue for developing predictive models of protein folding and stability. Here we present the results of 441 independent explicit-solvent MD simulations of all possible two-residue peptides that contain the 20 standard amino acids with histidine modeled in both its neutral and protonated states. (3)J(HNHalpha) coupling constants and delta(Halpha) chemical shifts calculated from the MD simulations correlate quite well with recently published experimental measurements for a corresponding set of two-residue peptides. Neighboring residue effects (NREs) on the average (3)J(HNHalpha) and delta(Halpha) values of adjacent residues are also reasonably well reproduced, with the large NREs exerted experimentally by aromatic residues, in particular, being accurately captured. NREs on the secondary structure preferences of adjacent amino acids have been computed and compared with corresponding effects observed in a coil library and the average beta-turn preferences of all amino acid types have been determined. Finally, the intrinsic conformational preferences of histidine, and its NREs on the conformational preferences of adjacent residues, are both shown to be strongly affected by the protonation state of the imidazole ring. PMID- 26579778 TI - Hierarchical Biomolecular Dynamics: Picosecond Hydrogen Bonding Regulates Microsecond Conformational Transitions. AB - Biomolecules exhibit structural dynamics on a number of time scales, including picosecond (ps) motions of a few atoms, nanosecond (ns) local conformational transitions, and microsecond (MUs) global conformational rearrangements. Despite this substantial separation of time scales, fast and slow degrees of freedom appear to be coupled in a nonlinear manner; for example, there is theoretical and experimental evidence that fast structural fluctuations are required for slow functional motion to happen. To elucidate a microscopic mechanism of this multiscale behavior, Aib peptide is adopted as a simple model system. Combining extensive molecular dynamics simulations with principal component analysis techniques, a hierarchy of (at least) three tiers of the molecule's free energy landscape is discovered. They correspond to chiral left- to right-handed transitions of the entire peptide that happen on a MUs time scale, conformational transitions of individual residues that take about 1 ns, and the opening and closing of structure-stabilizing hydrogen bonds that occur within tens of ps and are triggered by sub-ps structural fluctuations. Providing a simple mechanism of hierarchical dynamics, fast hydrogen bond dynamics is found to be a prerequisite for the ns local conformational transitions, which in turn are a prerequisite for the slow global conformational rearrangement of the peptide. As a consequence of the hierarchical coupling, the various processes exhibit a similar temperature behavior which may be interpreted as a dynamic transition. PMID- 26579779 TI - Correction to Small Molecule Hydration Free Energies in Explicit Solvent: An Extensive Test of Fixed-Charge Atomistic Simulations. PMID- 26579780 TI - Statewide Administration of the CRAFFT Screening Tool: Highlighting the Spectrum of Substance Use. AB - BACKGROUND: Adolescent alcohol and drug use in the United States are associated with negative consequences spanning multiple domains. Much of the public health surveillance of these behaviors relies on self-report survey data. These data frequently takes the form of frequency or prevalence data for specific substances, which may not provide a complete picture of use. OBJECTIVES: This study analyzes a state-level survey that includes the CRAFFT screening tool. The study's goal is to elucidate the spectrum of substance use severity across a large segment of substance-using adolescents attending schools in the state of Indiana and to assess the contribution of a variety of predictor variables to the variance between users falling into each category of use severity. METHODS: Data were collected in 2011 from 168,801 adolescents, of whom 25,204 met the inclusion criteria for this study. The authors utilize multinomial logit analyses to highlight variables, including sociodemographic data, poly-drug use, and risk/protective behavior scales, associated with each category of use. RESULTS: Seriousness of use is not uniform across substance-using adolescents; 49% were categorized as nonproblem users, 33% as problem users, and 18% as dependent users. Risk and protective factors predict adolescents' severity of substance use, but do not do so uniformly. Poly-drug use is a significant predictor of problem use and dependent use as well. CONCLUSIONS: The CRAFFT may provide a more nuanced perspective of adolescent substance use than frequency/prevalence data alone; the authors describe the implications derived from these data and analyses to the adolescent prevention and treatment systems. PMID- 26579781 TI - A Personal Reflection on Measurement from Three Decades Away. PMID- 26579782 TI - Highly Pathogenic Leptospira Found in Urban Brown Rats (Rattus norvegicus) in the Largest Cities of Sweden. AB - Leptospirosis is an emerging zoonosis of global concern; however, its contemporary occurrence in Sweden, a European country partly located north of the Arctic Circle, is poorly known. Four out of 30 brown rats, captured within urban districts in Sweden, were found to be positive for antibodies to Leptospira interrogans serovar Icterohaemorrhagiae. This serovar causes Weil's disease in humans, a severe infection with jaundice, renal failure, and hemorrhage. Our study is the first finding of this highly pathogenic serovar in Swedish rats since the 1930s. PMID- 26579783 TI - Highly Ordered Single Crystalline Nanowire Array Assembled Three-Dimensional Nb3O7(OH) and Nb2O5 Superstructures for Energy Storage and Conversion Applications. AB - Three-dimensional (3D) metal oxide superstructures have demonstrated great potentials for structure-dependent energy storage and conversion applications. Here, we reported a facile hydrothermal method for direct growth of highly ordered single crystalline nanowire array assembled 3D orthorhombic Nb3O7(OH) superstructures and their subsequent thermal transformation into monoclinic Nb2O5 with well preserved 3D nanowire superstructures. The performance of resultant 3D Nb3O7(OH) and Nb2O5 superstructures differed remarkably when used for energy conversion and storage applications. The thermally converted Nb2O5 superstructures as anode material of lithium-ion batteries (LiBs) showed higher capacity and excellent cycling stability compared to the Nb3O7(OH) superstructures, while directly hydrothermal grown Nb3O7(OH) nanowire superstructure film on FTO substrate as photoanode of dye-sensitized solar cells (DSSCs) without the need for further calcination exhibited an overall light conversion efficiency of 6.38%, higher than that (5.87%) of DSSCs made from the thermally converted Nb2O5 film. The high energy application performance of the niobium-based nanowire superstructures with different chemical compositions can be attributed to their large surface area, superior electron transport property, and high light utilization efficiency resulting from a 3D superstructure, high crystallinity, and large sizes. The formation process of 3D nanowire superstructures before and after thermal treatment was investigated and discussed based on our theoretical and experimental results. PMID- 26579784 TI - The New Designer Drug Wave: A Clinical, Toxicological, and Legal Analysis. AB - This article reviews clinical, toxicological, and legal issues related to designer drug abuse, with a focus on synthetic cathinones (bath salts). Synthetic cathinones are amphetamine-type central nervous system (CNS) stimulants that produce similar effects to amphetamine. Like amphetamine, synthetic cathinones can also result in neurological and cardiovascular side-effects consistent with sympathomimetic toxicity. The differential for a patient presenting with the signs and symptoms of synthetic cathinone toxicity is broad, and laboratory testing for synthetic cathinones is of limited value in acute management. If a diagnosis of cathinone-induced delirium is suspected, treatment efforts should focus on controlling agitation and then treating medical complications such as metabolic acidosis. Physicians should be aware of these new drugs, not only to optimally treat patients, but also to raise awareness of the dangers of designer drug use through patient counseling and community outreach programs. PMID- 26579785 TI - Diagnostic Impact of Peritoneal Fluid Cytology in the Setting of Pediatric Uterine Adnexal Biopsy or Resection. AB - Peritoneal fluid sampling has been recommended during surgery to resect an ovarian or fallopian tube mass, particularly for its staging relevance in ovarian carcinoma. Guidelines specifically for children are not well established, partly because of incomplete knowledge of the test characteristics in this age group. We sought to determine whether peritoneal fluid cytology sampling aids in diagnosis or staging of pediatric uterine adnexal masses. Children who underwent adnexal mass biopsy or excision from 1993 to 2014 were identified via archival review. Accompanying peritoneal fluid (washings or ascites) was assessed to determine whether it provided information beyond that in the accompanying surgical pathology specimen. Of 656 patients who underwent adnexal mass resection, 350 had concurrent cytologic sampling of peritoneal fluid. Median age at surgery was 14 years. Adnexal mass histologic examination showed tumors with malignant potential in 54 (8%) patients. Malignancy was identified in 3 cytology specimens (2 dysgerminomas and 1 mixed germ cell tumor). By today's guidelines, the malignant cytology specimens would have upstaged 1 of the 3 patients, and her therapy may not have changed. Cytology findings did not refine the histologic diagnosis in any benign or malignant case. Our findings demonstrated a low rate of malignancy (<1%) in peritoneal washing/ascites samples accompanying resection of a pediatric adnexal mass. Influencing staging or treatment by cytology sampling was rare in our cohort. Our findings provided benchmark data in an area dominated by adult studies. Furthermore, they may guide recommendations for cytologic fluid collection and processing tailored for pediatric populations. PMID- 26579786 TI - Biogeochemical Approaches to Assess PAH Pollution in an Urban Waterway. AB - Biogeochemical approaches were applied to enhance the study on polycyclic aromatic hydrocarbon (PAH) pollution in an urban waterway. Chemical characterizations of PAHs in the studied area were identified, geochemical factors were revealed, and related mechanisms were discussed. It was found that, during summer, an early diagenetic process in the sediment could play a major role for the existence of high PAH concentrations, especially high molecular weight PAHs (>= 4 rings), in the water column and sediment porewater. This effect could vary with tidal cycling, and higher PAH concentration in the water column would be expected during low tide. Other potential pollution sources were also evaluated in the studied creek. Results showed that pyrogenic sources dominated in the creek, generally. Nevertheless, petroleum products from a metal recycling plant could be an important point source to the waterway during wet weather. Comparing with previous studies in other waterways of the same watershed and published literature suggested that the limited toxicity to the ecosystem was only detected in sediments. More information needs to be collected during low tide for a more objective evaluation of PAH toxicity in the creek. PMID- 26579787 TI - NUTRITIONAL SUPPLEMENTATION IN AGE-RELATED MACULAR DEGENERATION. AB - PURPOSE: To evaluate the rate of adherence to prescribed nutritional supplementation in patients affected by age-related macular degeneration, in an Italian tertiary referral tertiary center. METHODS: Patients with age-related macular degeneration, age-related eye disease study Categories 3 and 4, were recruited and underwent an 11-item questionnaire. RESULTS: The study included a total of 193 patients meeting the age-related eye disease study nutritional supplementation criteria (174 patients with age-related eye disease study Category 4 and 19 with Category 3). Seventy-seven (40%) were taking oral supplementation, 70 of whom (90%) 1 tablet/day. Oral supplementation was recommended by the personal ophthalmologist in 85 patients (44%), including all those currently receiving it. Eight patients of 85 (9.4%) rejected supplementation despite it being recommended, mostly because they were already taking other medicines. Ninety-four patients (48%) claimed they had not received any information from their ophthalmologist. CONCLUSION: Our data reveal that Italian patients with age-related eye disease study Categories 3 and 4 have a low adherence to nutritional supplementation. In 65% of cases, patients were not adequately informed by their ophthalmologist of the potential benefits of oral supplementation for age-related macular degeneration; indeed, 108 patients (56%) were not even aware such nutritional treatments are available. Ophthalmologists should be aware of the importance of giving advice to persons with age-related macular degeneration regarding the benefits of oral supplements. PMID- 26579788 TI - 25-GAUGE PARS PLANA VITRECTOMY AND SF6 GAS FOR THE REPAIR OF PRIMARY INFERIOR RHEGMATOGENOUS RETINAL DETACHMENT. AB - PURPOSE: To compare anatomical and functional outcomes of 25-gauge pars plana vitrectomy (PPV) and sulfur hexafluoride gas between inferior and superior rhegmatogenous retinal detachment (RRD). METHODS: A retrospective cohort study of patients with RRD who underwent 25-gauge PPV. Group A consisted of patients with an identified inferior retinal break (4-8 o'clock hours). Group B consisted of patients with an identified superior retinal break. RESULTS: Overall, 59 eyes of 59 patients with a mean age of 60.0 +/- 12.3 years were included, with 57.6% being males; 25 with inferior breaks (Group A) and 34 with superior breaks (Group B). The mean follow-up time was 4 months (range 2-16 months). Single-surgery anatomical success was achieved in 96% (24/25) of Group A and 82.4% (28/34) of Group B patients (P = 0.22) with final anatomical success achieved in all cases. In regression analysis, break location (superior versus inferior) did not significantly account for the variation in single-surgery success or visual outcomes. CONCLUSION: Favorable results were achieved using 25-gauge vitrectomy and sulfur hexafluoride gas for primary RRD treatment. No differences in anatomical and functional success rates were observed between inferior and superior retinal break-associated RRD. PMID- 26579789 TI - Correspondence. PMID- 26579790 TI - 577-NM YELLOW LASER PHOTOCOAGULATION FOR COATS DISEASE. AB - PURPOSE: To describe the outcomes of children with Coats disease treated with 577 nm yellow laser indirect ophthalmoscopy. METHODS: A retrospective consecutive case series of pediatric patients with Coats disease treated at a single institution between 2011 and 2014. Laser indirect ophthalmoscopy was performed under anesthesia. Full treatment was defined as complete ablation of all visible telangiectasias and resolution of subretinal fluid. No patients were treated with cryotherapy or bevacizumab. RESULTS: Seventeen eyes of 16 patients were consecutively treated. At the time of diagnosis, the eye was classified as Stage 1 (telangiectasias only) in 1 case, Stage 2A (extra-foveal exudation) in 2 cases, Stage 2B (fovea-involving exudation) in 6 cases, Stage 3A1 (extra-foveal exudative retinal detachment) in 2 cases, Stage 3A2 (subtotal foveal-involving detachment) in 1 case, and Stage 3B (total exudative retinal detachment) in 5 cases. The mean age at initial treatment was 71.2 months. Mean length of follow up was 20.8 months (median 18.5 months, range 3.7-37.3 months). Patients underwent an average of 2.5 laser treatments. Sixteen of 17 eyes achieved full treatment (94.1%) with a mean time-to-full-treatment of 11.2 months. One eye developed glaucoma and end-stage disease. CONCLUSION: 577-nm yellow wavelength laser indirect ophthalmoscopy is an effective treatment for Coats disease including cases of exudative retinal detachment. PMID- 26579791 TI - Reply. PMID- 26579792 TI - Discovering Innovation at the Intersection of Undergraduate Medical Education, Human Factors, and Collaboration: The Development of a Nasogastric Tube Safety Pack. AB - PROBLEM: Significant deficiencies exist in the knowledge and skills of medical students and residents around health care quality and safety. The theory and practice of quality and safety should be embedded into undergraduate medical practice so that health care professionals are capable of developing interventions and innovations to effectively anticipate and mitigate errors. APPROACH: Since 2011, Leeds Medical School in the United Kingdom has used case study examples of nasogastric (NG) tube patient safety incidents within the undergraduate patient safety curriculum. In 2012, a medical undergraduate student approached a clinician with an innovative idea after undertaking an NG tubes root cause analysis case study. Simultaneously, a separate local project demonstrated low compliance (11.6%) with the United Kingdom's National Patient Safety Agency NG tubes guideline for use of the correct method to check tube position. These separate endeavors led to interdisciplinary collaboration between a medical student, health care professionals, researchers, and industry to develop the Initial Placement Nasogastric Tube Safety Pack. OUTCOMES: Human factors engineering was used to inform pack design to allow guideline recommendations to be accessible and easy to follow. A timeline of product development, mapped against key human factors and medical device design principles used throughout the process, is presented. The safety pack has since been launched in five UK National Health Service (NHS) hospitals, and the pack has been introduced into health care professional staff training for NG tubes. NEXT STEPS: A mixed-methods evaluation is currently under way in five NHS organizations. PMID- 26579793 TI - Variability in Implementation of Interventions Aimed at Reducing Readmissions Among Patients With Heart Failure: A Survey of Teaching Hospitals. AB - PURPOSE: To highlight teaching hospitals' efforts to reduce readmissions by describing interventions implemented to improve care transitions for heart failure (HF) patients and the variability in implemented HF-specific and care transition interventions. METHOD: In 2012, the authors surveyed a network of 17 teaching hospitals to capture information about the number, type, stage of implementation, and structure of 4 HF-specific and 21 care transition (predischarge, bridging, and postdischarge) interventions implemented to reduce readmissions among patients with HF. The authors summarized data using descriptive statistics, including the mean number of interventions implemented and the frequency and stage of specific interventions, and descriptive plots of the structure of two common interventions (multidisciplinary rounds and follow-up telephone calls). RESULTS: Sixteen hospitals (94%) responded. The number and stage of implementation of the HF-specific and care transition interventions implemented varied across institutions. The mean number of interventions at an advanced stage of implementation (i.e., implemented for >= 75% of HF patients on the cardiology service or on all services) was 10.9 (standard deviation = 4.3). Overall, predischarge interventions were more common than bridging or postdischarge interventions. There was variability in the personnel involved in multidisciplinary rounds and in the processes/content of follow-up telephone calls. CONCLUSIONS: Teaching hospitals have implemented a wide range of interventions aimed at reducing hospital readmissions, but there is substantial variability in the types, stages, and structure of their interventions. This heterogeneity highlights the need for collaborative efforts to improve understanding of intervention effectiveness. PMID- 26579794 TI - Opening Residents' Notes to Patients: A Qualitative Study of Resident and Faculty Physician Attitudes on Open Notes Implementation in Graduate Medical Education. AB - PURPOSE: OpenNotes is a growing national initiative inviting patients to read clinician progress notes (open notes) through a secure electronic portal. The goals of this study were to (1) identify resident and faculty preceptor attitudes about sharing notes with patients, and (2) assess specific educational needs, policy recommendations, and approaches to facilitate open notes implementation. METHOD: This was a qualitative study using focus groups with residents and faculty physicians who supervise residents, representing primary care, general surgery, surgical and procedural specialties, and nonprocedural specialties, from Beth Israel Deaconess Medical Center and Geisinger Health System in spring 2013. Data were audio recorded and transcribed verbatim, then coded and organized into themes. RESULTS: Thirty-six clinicians (24 [66.7%] residents and 12 [33.3%] faculty physicians) participated. Four main themes emerged: (1) implications of full transparency, (2) note audiences and ideology, (3) trust between patients and doctors, and (4) time pressures. Residents and faculty discussed how open notes might yield more engaged patients and better notes but were concerned about the time needed to edit notes and respond to patient inquiries. Residents were uncertain how much detail they should share with patients and were concerned about the potential to harm the patient-doctor relationship. Residents and faculty offered several recommendations for open notes implementation. CONCLUSIONS: Overall, participants were ambivalent about resident participation in open notes. Residents and faculty identified clinical and educational benefits to open notes but were concerned about potential effects on the patient-doctor relationship, requirements for oversight, and increased workload and burnout. PMID- 26579795 TI - Resident Role Modeling: "It Just Happens". AB - PURPOSE: Role modeling by staff physicians is a significant component of the clinical teaching of students and residents. However, the importance of resident role modeling has only recently emerged, and residents' understanding of themselves as role models has yet to be explored. This study sought to understand residents' perceptions of themselves as role models, describe how residents learn about role modeling, and identify ways to improve resident role modeling. METHOD: Fourteen semistructured interviews were conducted with residents in internal medicine, general surgery, and pediatrics at the McGill University Faculty of Medicine between April and September 2013. Interviews were audio-recorded and subsequently transcribed for analysis; iterative analysis followed principles of qualitative description. RESULTS: Four primary themes were identified through data analysis: residents perceived role modeling as the demonstration of "good" behaviors in the clinical context; residents believed that learning from their role modeling "just happens" as long as learners are "watching"; residents did not equate role modeling with being a role model; and residents learned about role modeling from watching their positive and negative role models. CONCLUSIONS: While residents were aware that students and junior colleagues learned from their modeling, they were often not aware of role modeling as it was occurring; they also believed that learning from role modeling "just happens" and did not always see themselves as role models. Helping residents view effective role modeling as a deliberate process rather than something that "just happens" may improve clinical teaching across the continuum of medical education. PMID- 26579796 TI - Genetic Association Between CDKN1B rs2066827 Polymorphism and Susceptibility to Cancer. AB - Much attention has been directed to the association between cancer risk and rs2066827 polymorphism of the CDKN1B gene. However, the results are indefinitive and inconclusive. This study was devised to evaluate the hypothesis that rs2066827 polymorphism is associated with the risk of cancer.Computer-based databases (EMBASE, PubMed, and CNKI) were used to seek all case-control studies evaluating rs2066827 polymorphism and susceptibility to cancer. The genetic risk was assessed by calculating pooled odds ratio (OR) with its corresponding 95% confidence interval (CI). Fixed-effects pooled ORs were calculated by the Mantel Haenszel method (Ph > 0.05), and random-effects pooled ORs were estimated by the DerSimonian-Laird method (Ph < 0.05).Data on rs2066827 polymorphism and cancer risk were available for 9038 cancer cases and 11,596 controls participating in 17 studies. Carriage of a TG genotype was associated with a minor but significant decrease in the risk of cancer (pooled OR 0.92, 95% CI: 0.86-0.99; model, TG vs. TT). We observed a moderately decreased risk of ovarian cancer based on 1829 cases and 2868 controls (pooled OR 0.85, 95% CI: 0.74-0.97; model, TG vs. TT). A slightly deceased risk of cancer was also indicated in Caucasians consisting of 6707 cases and 8279 controls (pooled OR 0.91, 95% CI: 0.85-0.98; model, TG vs. TT).These data suggest that carriage of a TG genotype at rs2066827 polymorphism may be associated with decreased susceptibility to cancer, ovarian cancer in particular. PMID- 26579797 TI - Effect of Functional Bread Rich in Potassium, gamma-Aminobutyric Acid and Angiotensin-Converting Enzyme Inhibitors on Blood Pressure, Glucose Metabolism and Endothelial Function: A Double-blind Randomized Crossover Clinical Trial. AB - Because it has been suggested that food rich in gamma-aminobutyric acid (GABA) or angiotensin-converting enzyme inhibitor (ACEI) peptides have beneficial effects on blood pressure (BP) and other cardiovascular risk factors, we tested the effects of low-sodium bread, but rich in potassium, GABA, and ACEI peptides on 24 hour BP, glucose metabolism, and endothelial function.A randomized, double-blind, crossover trial was conducted in 30 patients with pre or mild-to-moderate hypertension, comparing three 4-week nutritional interventions separated by 2 week washout periods. Patients were randomly assigned to consume 120 g/day of 1 of the 3 types of bread for each nutritional intervention: conventional wheat bread (CB), low-sodium wheat bread enriched in potassium (LSB), and low-sodium wheat bread rich in potassium, GABA, and ACEI peptides (LSB + G). For each period, 24-hour BP measurements, in vivo endothelial function, and biochemical samples were obtained.After LSB + G consumption, 24-hour ambulatory BP underwent a nonsignificant greater reduction than after the consumption of CB and LSB (0.26 mm Hg in systolic BP and -0.63 mm Hg in diastolic BP for CB; -0.71 mm Hg in systolic BP and -1.08 mm Hg in diastolic BP for LSB; and -0.75 mm Hg in systolic BP and -2.12 mm Hg in diastolic BP for LSB + G, respectively). Diastolic BP at rest decreased significantly during the LSB + G intervention, although there were no significant differences in changes between interventions. There were no significant differences between interventions in terms of changes in in vivo endothelial function, glucose metabolism, and peripheral inflammatory parameters.Compared with the consumption of CB or LSB, no greater beneficial effects on 24-hour BP, endothelial function, or glucose metabolism were demonstrated after the consumption of LSB + G in a population with pre or mild-to moderate hypertension. Further studies are warranted to clarify the effect of GABA on BP, preferably using a specific design for noninferiority trials and ambulatory BP monitoring as a measure of BP.This study was registered at Current Controlled Trials as ISRCTN31436822. PMID- 26579798 TI - An Atypically Large, Free-Floating Thrombus Extending From the Lung to the Left Atrium via a Pulmonary Vein: A Case Report. AB - An atypically large, free-floating thrombus extending from primary pulmonary malignancy into the left atrium (LA) is a rare phenomenon. Here, we report a 61 year-old man presenting with a large mass in the lower lobe of the left lung, extending to LA via the left inferior pulmonary vein.The thrombus remained clinically silent and was detected by computed tomography (CT) and transthoracic echocardiography. To prevent life-threatening complications including systemic embolism and sudden death, the patient underwent surgical excision of the mass under cardiopulmonary bypass. Pathology of the tumor and the embolus was confirmed as moderately differentiated squamous cell carcinoma. Furthermore, immunohistochemical studies demonstrated consistency of the tumor cells in this pathological category.The patient tolerated the surgery well and his condition began to improve gradually after the operation. PMID- 26579799 TI - Drug Fever Induced by Piperacillin/Tazobactam in a Scoliosis Patient: A Case Report. AB - Drug fever is frequently underrecognized by clinicians despite its common occurrence. Fever induced by piperacillin/tazobactam has not been reported in scoliosis correction surgery.Drug fever caused by piperacillin/tazobactam in a scoliosis patient was described.A 36-year-old woman with adult scoliosis undergoing correction surgery was reported. She developed a fever after an intake of piperacillin/tazobactam for 3 days. Eosinophil count, erythrocyte sedimentation rate, and C-reactive proteins were increased in her blood examination. Thorough history, chest radiography, blood cultures, physical examination, and urinalysis revealed no evidences of fever. A drug fever is therefore considered. The fever lasted for 2 weeks and her body temperature come back to normal 4 days after piperacillin/tazobactam cessation.Fever could be caused by piperacillin/tazobactam. The drug fever's diagnosis is easily confounded by a co-occurring infection. Therefore, it is crucial for clinicians to doubt drugs as a reason when no other origin of fever could be identified in a patient. PMID- 26579800 TI - Correlation Between Bladder Pain Syndrome/Interstitial Cystitis and Pelvic Inflammatory Disease. AB - Pelvic inflammatory disease (PID) has been investigated in Western countries and identified to be associated with chronic pelvic pain and inflammation. Bladder pain syndrome/interstitial cystitis (BPS/IC) is a complex syndrome that is significantly more prevalent in women than in men. Chronic pelvic pain is a main symptom of BPS/IC, and chronic inflammation is a major etiology of BPS/IC. This study aimed to investigate the correlation between BPS/IC and PID using a population-based dataset.We constructed a case-control study from the Taiwan National Health Insurance program. The case cohort comprised 449 patients with BPS/IC, and 1796 randomly selected subjects (about 1:4 matching) were used as controls. A Multivariate logistic regression model was constructed to estimate the association between BPS/IC and PID.Of the 2245 sampled subjects, a significant difference was observed in the prevalence of PID between BPS/IC cases and controls (41.7% vs 15.4%, P < 0.001). Multivariate logistic regression analysis revealed that the odds ratio (OR) for PID among cases was 3.69 (95% confidence interval [CI]: 2.89-4.71). Furthermore, the ORs for PID among BPS/IC cases were 4.52 (95% CI: 2.55-8.01), 4.31 (95% CI: 2.91-6.38), 3.00 (95% CI: 1.82 4.94), and 5.35 (95% CI: 1.88-15.20) in the <35, 35-49, 50-64, and >65 years age groups, respectively, after adjusting for geographic region, irritable bowel syndrome, and hypertension. Joint effect was also noted, specifically when patients had both PID and irritable bowel disease with OR of 10.5 (95% CI: 4.88 22.50).This study demonstrated a correlation between PID and BPS/IC. Clinicians treating women with PID should be alert to BPS/IC-related symptoms in the population. PMID- 26579801 TI - Correlation Between CASC8, SMAD7 Polymorphisms and the Susceptibility to Colorectal Cancer: An Updated Meta-Analysis Based on GWAS Results. AB - Genome-wide association studies (GWASs) and a number of case-control studies have suggested that several single nucleotide polymorphisms (SNPs), rs7837328, rs7014346, rs6983267, rs10505477 on CASC8 gene and rs4939827, rs4464148, rs12953717 on SMAD7 gene are significantly correlated with the susceptibility to colorectal cancer (CRC). For the sake of clarifying the association, a meta analysis was conducted and population heterogeneity was considered in the study.A total of 34 articles including 90 studies (168,471 cases and 163,223 controls) that evaluated the relationship between the CASC8, SMAD7 genes and the risk of CRC under the allelic model were reviewed. Also subgroup analysis was performed by ethnicity (Caucasian, Asian, and African) and all of the analyses were implemented in R 3.2.1 software.Pooled data from the meta-analysis revealed that the A allele of rs7837328, the A allele of rs7014346, the G allele of rs6983267, the A allele of rs10505477, the T allele of rs4939827, the T of rs4464148, and the T of rs12953717 were significantly associated with an increased risk of CRC under the allelic model. Additionally, subgroup analyses of 6 SNPs by ethnicity (rs4464148 excepted) witnessed that the A allele of rs7837328, the G allele of rs6983267, and the T of rs12953717 were notably associated with an increased risk of CRC among Caucasian and Asian. Furthermore, the A allele of rs7014346, the A allele of rs10505477, and the T allele of rs4939827 were significantly related with an elevated risk of CRC only among Caucasian.Our study suggested that for CASC8 gene, SNP of rs7837328 and rs6983267 are risk factors for CRC among both Caucasian and Asian whereas rs7014346 and rs10505477 are risky gene polymorphisms only among Caucasian. For SMAD7 gene, rs4939827 and rs4464148 are risk factors for CRC among Caucasian whereas rs12953717 could elevate the susceptibility to CRC in both Caucasian and Asian. PMID- 26579802 TI - Efficacy of Pregabalin in Acute Postoperative Pain Under Different Surgical Categories: A Meta-Analysis. AB - The efficacy of pregabalin in acute postsurgical pain has been demonstrated in numerous studies; however, the analgesic efficacy and adverse effects of using pregabalin in various surgical procedures remain uncertain. We aim to assess the postsurgical analgesic efficacy and adverse events after pregabalin administration under different surgical categories using a systematic review and meta-analysis of randomized controlled trials.A search of the literature was performed between August 2014 to April 2015, using PubMed, Ovid via EMBASE, Google Scholar, and ClinicalTrials.gov with no limitation on publication year or language. Studies considered for inclusion were randomized controlled trials, reporting on relevant outcomes (2-, 24-hour pain scores, or 24 hour morphine equivalent consumption) with treatment with perioperative pregabalin.Seventy-four studies were included. Pregabalin reduced pain scores at 2 hours in all categories: cardiothoracic (Hedge's g and 95%CI, -0.442 [-0.752 to -0.132], P = 0.005), ENT (Hedge g and 95%CI, -0.684 [-1.051 to -0.316], P < 0.0001), gynecologic (Hedge g, 95%CI, -0.792 [-1.235 to -0.350], P < 0.0001), laparoscopic cholecystectomy (Hedge g, 95%CI, -0.600 [-0.989 to -0.210], P = 0.003), orthopedic (Hedge g, 95%CI, -0.507 [-0.812 to -0.202], P = 0.001), spine (Hedge g, 95%CI, -0.972 [-1.537 to -0.407], P = 0.001), and miscellaneous procedures (Hedge g, 95%CI, -1.976 [-2.654 to -1.297], P < 0.0001). Pregabalin reduced 24 hour morphine consumption in gynecologic (Hedge g, 95%CI, -1.085 [-1.582 to 0.441], P = 0.001), laparoscopic cholecystectomy (Hedge g, 95%CI, -0.886 [-1.652 to -0.120], P = 0.023), orthopedic (Hedge g, 95%CI, -0.720 [-1.118 to -0.323], P < 0.0001), spine (Hedge g, 95%CI, -1.016 [-1.732 to -0.300], P = 0.005), and miscellaneous procedures (Hedge g, 95%CI, -1.329 [-2.286 to -0.372], P = 0.006). Pregabalin resulted in significant sedation in all surgical categories except ENT, laparoscopic cholecystectomy, and gynecologic procedures. Postoperative nausea and vomiting was only significant after pregabalin in miscellaneous procedures.Analgesic effects and incidence of adverse effects of using pregabalin are not equal in different surgical categories. PMID- 26579803 TI - Functional Inducible Nitric Oxide Synthase Gene Variants Associate With Hypertension: A Case-Control Study in a Finnish Population-The TAMRISK Study. AB - Increased inducible nitric oxide synthase (iNOS) activity and expression has been associated with hypertension, but less is known whether the 2 known functional polymorphic sites in the iNOS gene (g.-1026 C/A (rs2779249), g.2087 G/A (rs2297518)) affect susceptibility to hypertension. The objective of this study was to investigate the association between the genetic variants of iNOS and diagnosed hypertension in a Finnish cohort.This study included 320 hypertensive cases and 439 healthy controls. All participants were 50-year-old men and women and the data were collected from the Tampere adult population cardiovascular risk study (TAMRISK). DNA was extracted from buccal swabs and iNOS single nucleotide polymorphisms (SNPs) were analyzed using KASP genotyping PCR. Data analysis was done by logistic regression.At the age of 50 years, the SNP rs2779249 (C/A) associated significantly with hypertension (P = 0.009); specifically, subjects carrying the A-allele had higher risk of hypertension compared to those carrying the CC genotype (OR = 1.47; CI = 1.08-2.01; P = 0.015). In addition, a 15-year follow-up period (35, 40, and 45 years) of the same individuals showed that carriers of the A-allele had more often hypertension in all of the studied age groups. The highest risk for developing hypertension was obtained among 35-year old subjects (odds ratio [OR] 3.83; confidence interval [CI] = 1.20-12.27; P = 0.024). Those carrying variant A had also significantly higher readings of both systolic (P = 0.047) and diastolic (P = 0.048) blood pressure during the follow up. No significant associations between rs2297518 (G/A) variants alone and hypertension were found. However, haplotype analysis of rs2779249 and rs2297518 revealed that individuals having haplotype H3 which combines both A alleles (CA GA, 19.7% of individuals) was more commonly found in the hypertensive group than in the normotensive group (OR = 2.01; CI = 1.29-3.12; P = 0.002).In conclusion, there was a significant association between iNOS genetic variant (rs2779249) and hypertension in the genetically homogenous Finnish population. Those who carried the rare A-allele of the gene had higher risk for hypertension already at the age of 35 years. PMID- 26579804 TI - Computed Tomography-Derived Fractional Flow Reserve in the Detection of Lesion Specific Ischemia: An Integrated Analysis of 3 Pivotal Trials. AB - Invasive fractional flow reserve (FFR) is the gold standard for the determination of physiologic stenosis severity and the need for revascularization. FFR computed from standard acquired coronary computed tomographic angiography datasets (FFRCT) is an emerging technology which allows calculation of FFR using resting image data from coronary computed tomographic angiography (CCTA). However, the diagnostic accuracy of FFRCT in the evaluation of lesion-specific myocardial ischemia remains to be confirmed, especially in patients with intermediate coronary stenosis. We performed an integrated analysis of data from 3 prospective, international, and multicenter trials, which assessed the diagnostic performance of FFRCT using invasive FFR as a reference standard. Three studies evaluating 609 patients and 1050 vessels were included. The total calculated sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of FFRCT were 82.8%, 77.7%, 60.8%, 91.6%, and 79.2%, respectively, for the per-vessel analysis, and 89.4%, 70.5%, 69.7%, 89.7%, and 78.7%, respectively, for the per-patient analysis. Compared with CCTA alone, FFRCT demonstrated significantly improved accuracy (P < 0.001) in detecting lesion specific ischemia. In patients with intermediate coronary stenosis, FFRCT remained both highly sensitive and specific with respect to the diagnosis of ischemia. In conclusion, FFRCT appears to be a reliable noninvasive alternative to invasive FFR, as it demonstrates high accuracy in the determination of anatomy and lesion-specific ischemia, which justifies the performance of additional randomized controlled trials to evaluate both the clinical benefits and the cost effectiveness of FFRCT-guided coronary revascularization. PMID- 26579805 TI - Bevacizumab to Treat Cholangiopathy in Hereditary Hemorrhagic Telangiectasia: Be Cautious: A Case Report. AB - Hereditary hemorrhagic telangiectasia (HHT) is an inherited vascular dysplasia characterized by mucocutaneous telangiectasia and visceral arteriovenous malformations. Hepatic involvement with vascular malformations may lead to portal hypertension, biliary ischemia, and high-output cardiac failure. There is no curative treatment for the disease. Liver transplantation is indicated for life threatening complications, but it carries significant risk due to surgery and immunosuppressive treatment. Some case reports or small open studies suggest that bevacizumab, a recombinant humanized anti-VEGF monoclonal antibody, should be efficient in limiting bleeding and in reducing liver disease in HHT.We report a case of a 63-year-old woman with HHT presenting with ischemic cholangiopathy. Liver transplant was indicated, but given a previous encouraging report showing a regression of biliary disease with bevacizumab in 3 patients with HHT this drug was proposed. No significant efficacy but a severe adverse effect was observed after 3 months: bilateral pulmonary embolisms, thrombosis in the right atrial cavity, and thrombosis of the right hepatic vein were evidenced. Bevacizumab was stopped; anticoagulant started. Four months later, the patient received a transplanted liver. She feels well 1 year later.This case report intends to provide the information for clinicians to consider the use of bevacizumab in HHT. Whereas several uncontrolled series and case reports have suggested the efficacy of this drug in reducing bleeding and liver disease, no severe side effects were mentioned to date. For the first time in HHT we report a life-threatening side effect of this drug and no efficacy. Moreover, systemic thrombosis, the observed complication, may preclude transplantation. To date, caution seems still indispensable when considering the use of bevacizumab in HHT. PMID- 26579806 TI - Preoperative Enteral Nutritional Support in Patients Undergoing Hepatectomy for Hepatocellular Carcinoma: A Strengthening the Reporting of Observational Studies in Epidemiology Article. AB - To compare the short-term outcomes between hepatocellular carcinoma (HCC) patients with and those without preoperative nutrition on the basis of postoperative enteral nutrition.HCC patients with postoperative enteral nutrition who underwent liver resection between February 2010 and December 2014 in Nanjing Drum Tower Hospital were considered for the study: 43 patients with and 36 patients without preoperative nutrition. Primary endpoint was the incidence of overall complications. Secondary endpoints were infectious and major complications.In the preoperative enteral nutrition group, shorter length of postoperative hospital stay (10.5 +/- 2.7 versus 13.7 +/- 6.3 days, P = 0.007), less exogenous albumin infusion (10.2 +/- 22.4 versus 47.8 +/- 97.7 g, P = 0.030), earlier first exhaust time (2.7 +/- 0.8 versus 3.0 +/- 0.9 days, P = 0.043), and first defection time (3.5 +/- 0.9 versus 4.4 +/- 1.4 days, P = 0.001) were observed. No significant differences were observed in the incidence of overall complications (32.6% versus 52.8%, P = 0.070), infectious complications (7.0% versus 8.3%, P = 1), and major complications (14.0% versus 11.1%, P = 0.969) between the preoperative enteral nutrition and control group.Preoperative enteral nutrition could improve short-term outcomes of HCC patients via accelerating the recovery of gastrointestinal function and shortening the length of postoperative hospital stay. PMID- 26579807 TI - Dilated Cardiomyopathy Revealing Cushing Disease: A Case Report and Literature Review. AB - Cardiovascular impairments are frequent in Cushing's syndrome and the hypercortisolism can result in cardiac structural and functional changes that lead in rare cases to dilated cardiomyopathy (DCM). Such cardiac impairment may be reversible in response to a eucortisolaemic state.A 43-year-old man with a medical past of hypertension and history of smoking presented to the emergency department with global heart failure. Coronary angiography showed a significant stenosis of a marginal branch and cardiac MRI revealed a nonischemic DCM. The left ventricular ejection fraction (LVEF) was estimated as 28% to 30%. Clinicobiological features and pituitary imaging pointed toward Cushing's disease and administration of adrenolytic drugs (metyrapone and ketoconazole) was initiated. Despite the normalization of cortisol which had been achieved 2 months later, the patient presented an acute heart failure. A massive mitral regurgitation secondary to posterior papillary muscle rupture was diagnosed as a complication of the occlusion of the marginal branch. After 6 months of optimal pharmacological treatment for systolic heart failure, as well as treatment with inhibitors of steroidogenesis, there was no improvement of LVEF. The percutaneous mitral valve was therefore repaired and a defibrillator implanted. The severity of heart failure contraindicated pituitary surgery and the patient was instead treated by stereotaxic radiotherapy.This is the first case reporting a Cushing's syndrome DCM without improvement of LVEF despite normalization of serum cortisol levels. PMID- 26579808 TI - Bisphosphonates in the Treatment of Patients With Metastatic Breast, Lung, and Prostate Cancer: A Meta-Analysis. AB - The purpose of this meta-analysis was to investigate whether bisphosphonates are a key therapy for bone metastases in lung cancer, breast cancer, and prostate cancer by comparing all randomized controlled trials that appraised the effects of bisphosphonates on risk of skeletal-related events (SREs).PubMed, Embase, and Medline databases (up to December 2014) were used to search all related articles. Using the data from 19 available publications, the authors examined the efficacy in treating or reducing the risk of SREs in lung cancer, breast cancer, and prostate cancer by meta-analysis.Bisphosphonates have demonstrated efficacy in treating or reducing the risk of SREs in lung cancer [odds ratio (OR) = 0.81, 95% confidence interval (CI) = 0.69-0.95, P = 0.008], breast cancer (OR = 0.62, 95% CI = 0.54-0.71, P = 0.000), and prostate cancer (OR = 0.62, 95% CI = 0.45-0.86, P = 0.004).This meta-analysis suggests that bisphosphonates have demonstrated efficacy in treating or reducing the risk of SREs in lung cancer, breast cancer, and prostate cancer. PMID- 26579809 TI - Use of SSRI, But Not SNRI, Increased Upper and Lower Gastrointestinal Bleeding: A Nationwide Population-Based Cohort Study in Taiwan. AB - Selective serotonin receptor inhibitor (SSRI) and serotonin-noradrenaline reuptake inhibitor (SNRI) users have been reported to have an increased risk of upper gastrointestinal bleeding (UGIB), but their association with lower gastrointestinal bleeding (LGIB) is less studied. This study aimed to analyze the incidence of UGIB and LGIB among SSRI users, SNRI users, and controls.Using the National Health Insurance Research Database of Taiwan, 9753 subjects who were taking serotonin reuptake inhibitors (8809 with SSRIs, and 944 with SNRIs), and 39,012 age, sex, and enrollment time-matched controls were enrolled at a 1:4 ratio. The log-rank test was used to analyze differences in the cumulative hazard of UGIB and LGIB between groups. Cox proportional hazard regression analysis was used to evaluate the independent risk factors for UGIB and LGIB.During the 10 year follow-up period from 2000 to 2010, SSRI users, but not SNRI users, had significantly higher incidences of UGIB and LGIB than the controls (P < 0.001; log-rank test). The use of SSRIs, but not SNRIs, was independently associated with an increased risk of UGIB (hazard ratio [HR]:1.97; 95% confidence interval [CI]: 1.67-2.31) and LGIB (HR: 2.96, 95% CI: 2.46-3.57) after adjusting for age, sex, underlying comorbidities, and medications.The long-term use of SSRIs significantly increased the risk of UGIB and LGIB, and caused more LGIB than UGIB in the general population after adjusting for possible confounding factors, but the association between SNRIs and GIB is insignificant. Further prospective studies are needed to clarify this important issue. PMID- 26579810 TI - Hospitalization Incidence, Mortality, and Seasonality of Common Respiratory Viruses Over a Period of 15 Years in a Developed Subtropical City. AB - Information on respiratory viruses in subtropical region is limited.Incidence, mortality, and seasonality of influenza (Flu) A/B, respiratory syncytial virus (RSV), adenovirus (ADV), and parainfluenza viruses (PIV) 1/2/3 in hospitalized patients were assessed over a 15-year period (1998-2012) in Hong Kong.Male predominance and laterally transversed J-shaped distribution in age-specific incidence was observed. Incidence of Flu A, RSV, and PIV decreased sharply from infants to toddlers; whereas Flu B and ADV increased slowly. RSV conferred higher fatality than Flu, and was the second killer among hospitalized elderly. ADV and PIV were uncommon, but had the highest fatality. RSV, PIV 2/3 admissions increased over the 15 years, whereas ADV had decreased significantly. A "high season," mainly contributed by Flu, was observed in late-winter/early-spring (February-March). The "medium season" in spring/summer (April-August) was due to Flu and RSV. The "low season" in late autumn/winter (October-December) was due to PIV and ADV. Seasonality varied between viruses, but predictable distinctive pattern for each virus existed, and temperature was the most important associating meteorological variable.Respiratory viruses exhibit strong sex- and age-predilection, and with predictable seasonality allowing strategic preparedness planning. Hospital-based surveillance is crucial for real-time assessment on severity of new variants. PMID- 26579811 TI - The Association Between Apolipoprotein E and Functional Outcome After Traumatic Brain Injury: A Meta-Analysis. AB - Traumatic brain injury (TBI) is a leading cause of death and disability. Previous studies have investigated the association of apolipoprotein E (APOE) epsilon4 with functional outcome after TBI and reported inconsistent results.The purpose of this study was to perform a systematic literature search and conduct meta analyses to examine whether APOE epsilon4 is associated with poorer functional outcome in patients with TBI.We performed a systematic literature search in PubMed, Cochrane Library, Embase, Google Scholar, and HuGE.The eligibility criteria of this study included the following: Patients had TBI; the studies reported APOE genotype data or provided odds ratios (ORs) and the corresponding 95% confidence intervals (CIs); the functional outcome was assessed using the Glasgow Outcome Scale (GOS) or the Glasgow Outcome Scale Extended (GOSE); and patients were followed for at least 3 months after TBI.In all meta-analyses, we used random-effects models to calculate the odds ratio as a measure of association. We examined the association of APOE epsilon4 with functional outcome at different time points after TBI.A total of 12 studies met the eligibility criteria and were included in the meta-analyses. We did not find a significant association between APOE epsilon4 and functional outcome at 6 (P = 0.23), 12 (P = 0.44), and 24 months (P = 0.85) after TBI. However, APOE epsilon4 was associated with an increased risk of unfavorable long-term (>=6 months) functional outcome after TBI (OR = 1.36, 95% CI: 1.07-1.74, P = 0.01).Limitations of this study include The sample size was limited; the initial severity of TBI varied within and across studies; we could not control for potential confounding factors, such as age at injury and sex; a meta-analysis of the genotype dosage effect was not feasible; and we could not examine the association with specific factors such as neurobehavioral or specific cognitive functions.Our meta-analysis indicates APOE epsilon4 is associated with the long-term functional outcome of patients with TBI. Future studies that control for confounding factors, with large sample sizes and more homogeneous initial TBI severity levels, are needed to validate the findings from this study. PMID- 26579812 TI - Risk of Acute Kidney Injury and Long-Term Outcome in Patients With Acetaminophen Intoxication: A Nationwide Population-Based Retrospective Cohort Study. AB - Acetaminophen (APAP) intoxication is a common cause of hepatic toxicity and life threatening hepatic failure. However, few studies have investigated the possible association between APAP intoxication and acute kidney injury (AKI). We constructed a retrospective cohort study to clarify the relationship between APAP intoxication and the risk of AKI.We identified patients with APAP intoxication and selected a comparison cohort that was 1:4 frequency matched according to age, sex, and year of APAP intoxication diagnosis from the Taiwan National Health Insurance Research Database from 1998 to 2010. We analyzed the risks of AKI for patients with APAP intoxication by using Cox proportional hazards regression models.In this study, 2914 patients with APAP intoxication and 11,656 controls were included. The overall risks of developing AKI were 2.41-fold in the patients with APAP intoxication compared with the comparison cohort. After we excluded APAP intoxication patients with coexisting AKI and hepatic failure/hepatitis, the overall risks of developing AKI were still 2.22-fold in the patients with APAP intoxication. There were 2 patients who had end-stage renal disease (ESRD) following APAP intoxication-related AKI. Limitations include retrospective review, selection bias, and absence of data on detail medications used, laboratory investigations and dosage of APAP intoxication.Our long-term cohort study results showed that AKI is a possible adverse effect among patients with APAP intoxication, regardless of whether patients have presented with hepatic toxicity. However, additional studies are necessary to clarify whether such patients can progress to ESRD. PMID- 26579813 TI - Risk of Periodontal Diseases in Patients With Chronic Obstructive Pulmonary Disease: A Nationwide Population-based Cohort Study. AB - Several studies have reported an association between chronic obstructive pulmonary disease (COPD) and periodontal diseases. However, a large-scale population-based cohort study was previously absent from the literature. Therefore, we evaluated the risk of periodontal diseases in patients with COPD in a nationwide population.From the National Health Insurance claims data of Taiwan, we identified 22,332 patients with COPD who were newly diagnosed during 2000 to 2010. For each case, two individuals without COPD were randomly selected and frequency matched by age, sex, and diagnosis year. Both groups were followed up till the end of 2011.The overall incidence of periodontal diseases was 1.19-fold greater in the COPD group than in the comparison group (32.2 vs 26.4 per 1000 person-years; 95% confidence interval [CI] 1.15-1.24). Compared with non-COPD patients, the adjusted hazard ratios of patients with COPD increased with the number of emergency room visits (from 1.14 [95% CI 1.10-1.19] to 5.09 [95% CI 4.53-5.72]) and admissions (from 1.15 [95% CI 1.10-1.20] to 3.17 [95% CI 2.81 3.57]). In addition, the adjusted hazard ratios of patients with COPD treated with inhaled corticosteroids (1.22, 95% CI 1.11-1.34) and systemic corticosteroids (1.15, 95% CI 1.07-1.23) were significantly higher than those of patients not treated with corticosteroids.Patient with COPD are at a higher risk of developing periodontal diseases than the general population. Our results also support that the risk of periodontal diseases is proportional to COPD control. In addition, patients who receive corticosteroid treatment are at a higher risk of developing periodontal diseases. PMID- 26579814 TI - ANCA-Associated Systemic Vasculitis Presenting With Hypertrophic Spinal Pachymeningitis: A Report of 2 Cases and Review of Literature. AB - Reports of hypertrophic pachymeningitis associated with myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA) localized exclusively in the spine were quite rare. Two cases of ANCA-associated systemic vasculitis (AASV) presenting with hypertrophic spinal pachymeningitis (HSP) causing low back pain and numbness are described. Two patients showed prominent systemic and local inflammatory reactions manifested as fever, elevated levels of erythrocyte sedimentation rate and C-reactive protein, and markedly increased levels of total protein of cerebrospinal fluid. The gadolinium (Gd)-enhanced T1-weighted magnetic resonance imaging scan of spinal cord demonstrated diffuse spinal dura matter thickening. Additionally, simple microscopic hematuria was found in 1 case suggestive of renal involvement and the other 1 complicated with interstitial lung disease. Then, a diagnosis of HSP secondary to AASV was made. Combination therapy of corticosteroids and cyclophosphamide produced a rapid improvement in the clinical symptoms and laboratory parameters. Followed up for 6 months, 1 case relapsed when the dosage of prednisone was tapered to 10 mg daily. Since the patient refused rituximab-based regimen, an immunosuppressive triple-therapy (corticosteroid, cyclophosphamide, and azathioprine) was initiated and brought control of the disease during the subsequent 6 months of follow-up.HSP is a relatively rare form of central nervous system involvement of AASV. Early recognition and intervention are of great significance since the pathogenesis of HSP starts with an inflammatory and fibrosing process. PMID- 26579815 TI - Nomogram to Predict Occult N2 Lymph Nodes Metastases in Patients With Squamous Nonsmall Cell Lung Cancer. AB - For nonsmall cell lung cancer (NSCLC) patients without distant metastases, occult involvement of N2 lymph nodes would be of the utmost importance in determining both treatment and survival. The key to optimal treatment strategies relied on accurate diagnosis, in particular accurate clinical tumor staging. Patients with clinical N0 or N1 staging preoperatively had a sizeable risk to have occult N2 lymph nodes metastases.From November 2004 to March 2007, the entire database in a tertiary hospital of all patients with a pathologic diagnosis of squamous NSCLC underwent anatomical pulmonary resection and systematic mediastinal lymph node dissection were retrospectively collected and reviewed. A nomogram was developed on the basis of a multivariable logistic regression model with a combination of all potential variables. In order to surmount the potential of overestimating predictive performance, both bootstrapping for internal validation and an independent external validation set were employed.A nomogram incorporating the significant risk factors was created to predict the probability of occult N2 lymph nodes metastases. The calibration plot for the probability of occult N2 lymph nodes metastases showed an optimal agreement between the predicted probabilities by nomogram and actual observed probabilities. An objective and accurate nomogram predictive model for occult N2 lymph nodes metastases was drawn up and validated internally and externally in patients with squamous NSCLC.The nomogram model, as a robust tool in predicting occult N2 lymph nodes involvement, could be involved in a cost-effective application of specific diagnostic and therapeutic strategies. PMID- 26579816 TI - Evaluation of the Clinical Performance of a Novel Chemiluminescent Immunoassay for Detection of Anticardiolipin and Anti-Beta2-Glycoprotein 1 Antibodies in the Diagnosis of Antiphospholipid Syndrome. AB - Detection of antiphospholipid antibodies represents the first-line approach for diagnosis of antiphospholipid syndrome (APS). In this study, we evaluated the clinical performance of a novel chemiluminescence assay (CIA) in detection of IgG/IgM/IgA anti-cardiolipin (aCL) and IgG/IgM/IgA anti-beta2 glycoprotein 1 (abeta2GP1) antibodies and to compare it with commercial enzyme-linked immunosorbent assay (ELISA) kits from the same manufacturer.A total of 227 sera were tested in this study, including 84 samples from patients with APS, 104 samples from patients with non-APS diseases as disease controls, and 39 healthy controls. Serum IgG/IgM/IgA aCL and IgG/IgM/IgA abeta2GP1 were determined by both ELISA (QUANTA LiteTM ELISA) and CIA (QUANTA Flash(r)assays).Significant quantitative correlations were identified between ELISA and CIA in IgG/IgM/IgA aCL and IgG/IgM/IgA abeta2GP1 autoantibodies detection (P < 0.001), with the rho value ranging from 0.51 to 0.87. In addition, ELISA and CIA demonstrated good qualitative agreements in IgG/IgM/IgA aCL and IgM/IgA abeta2GP1 autoantibodies determination with kappa coefficient ranged from 0.52 to 0.77. In contrast, ELISA and CIA showed a moderate qualitative agreement in IgG abeta2GP1 detection with a kappa value of 0.2. Notably, significantly higher IgG abeta2GP1 positive sera were detected by CIA, compared to those detected by ELISA in both primary APS (52.9% vs. 8.8%) and APS associated to other diseases sera (70.0% vs. 8.0%). For diagnosis of APS, IgG abeta2GP1 detection by CIA (IgG abeta2GP1 CIA) demonstrated the highest sensitivity (63.1%), followed by IgG aCL CIA (48.8%). More importantly, IgG abeta2GP1 CIA demonstrated the highest ability to predict the thrombotic events in patients with APS, with an OR of 3 (95% CI: 1.1-7.9).Our data suggest that this novel CIA assay had good performance in detecting aCL and abeta2GP1 antibodies, especially in the detection of IgG abeta2GP1 antibodies. Our findings could shed insight on the application of CIA in the laboratory diagnosis of APS in China. PMID- 26579817 TI - It Is Not Mandatory to Use Triple Rather Than Dual Anti-Platelet Therapy After a Percutaneous Coronary Intervention With a Second-Generation Drug-Eluting Stent. AB - It has been shown that triple antiplatelet therapy with cilostazol results in better clinical outcomes than dual therapy in patients treated with a first generation drug-eluting stent (DES); however, it is unclear whether triple antiplatelet therapy has a similar efficacy after the implantation of second generation DES.In the COACT (Cath Olic medical center percutAneous Coronary in Tervention) registry, 1248 study subjects who underwent percutaneous coronary intervention with an everolimus- or zotarolimus-eluting stent (Endeavor, Xience V, or Promus) were analyzed. The patients were divided into 2 groups after propensity score matching (n = 724; M = 422 [58.3%]; mean age = 66.1 +/- 11.0 years): Group 1: patients treated with dual antiplatelet drugs (aspirin and clopidogrel; n = 362; M = 213 [58.8%]; mean age = 65.6 +/- 11.7 years); Group 2: patients treated with triple antiplatelet drugs (aspirin, clopidogrel, and cilostazol; n = 362; M = 209 [57.7%]; mean age = 65.6 +/- 11.7 years). The mean follow-up duration was 13 +/- 10 months, and the cumulative incidence of major cardiovascular events (MACE) was 6.3% in Group 1 and 7.7% in Group 2. There were no significant differences in MACE (death, nonfatal myocardial infarction, and stroke) between the 2 groups (OR, 1.210; 95% CI: 0.772-1.898; P = 0.406). Kaplan Meier curves for MACE did not show any survival benefit for triple antiplatelet therapy, even in patients with acute coronary syndrome.In patients treated with a second-generation DES implantation, there is no added clinical benefit to using triple rather than dual antiplatelet therapy. PMID- 26579818 TI - Kikuchi Disease-Like Inflammatory Pattern in Cutaneous Inflammatory Infiltrates Without Lymph Node Involvement: A New Clue for the Diagnosis of Lupus? AB - Kikuchi-Fujimoto disease (KFD) is a rare and benign disorder that usually occurs in young adults with enlarged lymph nodes containing infiltrate of cytotoxic T cells and nuclear debris. It can be a manifestation of systemic lupus erythematosus (SLE) although the strength of this association has varied among studies. Although specific KFD cutaneous lesions are well described, pure cutaneous lesions have never been reported. We studied a series of patients prospectively entered into a database between 2007 and 2014 with skin biopsies showing diffuse or localized inflammatory infiltrates reminiscent of cutaneous KFD, without lymph-node-related KFD. We called these skin lesions "Kikuchi disease-like inflammatory pattern" (KLIP). Twenty-nine patients, whose median age was 49 years at the time of skin biopsy, were selected and retrospectively analyzed using standardized clinical and histology charts. In skin biopsies, KLIP was localized to restricted areas within the inflammatory infiltrate (17%) or diffuse (83%), and was the only histological finding (45%) or accompanied interface dermatitis with or without dermal mucinosis (55%). Clinical dermatological findings varied widely. A definite diagnosis could be established for 24 patients: 75% had connective tissue diseases or vasculitis, mainly cutaneous lupus erythematosus (CLE) (n = 16, 67%), including 5 SLE with satisfying American College of Rheumatology criteria; 3 of the remaining patients had malignant hemopathies. CLE patients were mostly young females with acute (n = 5), subacute (n = 4), or chronic CLE (n = 6) or lupus tumidus (n = 1). Two were classified as having anti-tumor necrosis factor-alpha-induced lupus. Because two thirds of these patients were finally diagnosed with CLE, we think that KLIP may represent a new histopathological clue for the diagnosis of lupus based on skin biopsy, requiring clinical-immunological comparison to make the correct diagnosis. KLIP should not be considered a variant of classical KFD, but rather as an elementary pattern of cutaneous inflammation, that might be the expression of the same cytotoxic process within skin infiltrates as that involved in KFD. This lesion might reflect a particular T-cell-mediated autoimmune process directed against mononuclear cells within cutaneous lupus infiltrates. PMID- 26579819 TI - Prognostic Significance of Single Progesterone Receptor Positivity: A Comparison Study of Estrogen Receptor Negative/Progesterone Receptor Positive/Her2 Negative Primary Breast Cancer With Triple Negative Breast Cancer. AB - Single progesterone receptor positive (PgR+), especially in form of ER-/PgR+/HER2 , is a nonnegligible phenomenon. Little is known about the characteristics and the role of single PgR positive in this phenotype. Therefore, we explore the significance of single PgR positivity by comparing ER-/PgR+/HER2- breast cancers with triple negative breast cancers (TNBCs).Three thousand nine hundred sixty-six cases of primary invasive breast carcinoma operated consecutively from January 2005 to May 2008 in Cancer Hospital, Chinese Academy of Medical Sciences were examined. Two hundred forty (6%) cases were identified as ER-/PgR+/HER2- breast cancers and 348 (8.8%) cases as TNBCs. Clinicopathological characteristics and survivals were analyzed respectively and then compared between 2 subtypes.Compared with patients with TNBCs, ER-/PgR+/HER2- tumor tended to have lower tumor grade (Grade 3: 45.7% vs. 37.5%, P = 0.051) and smaller tumor size (P = 0.036). However, no differences were found between ER-/PgR+/HER2- and TNBC patients in relapse-free survival (RFS) and OS. The 5-year RFS rates were 80.7% and 77.4%, respectively (P = 0.330) and the 5-year OS rates were 88.0% and 85.2%, respectively (P = 0.290). ER-/PgR+/HER2- patients receiving adjuvant endocrine treatment had better RFS (P = 0.016) and overall survival (OS) (P < 0.0001) than patients receiving no endocrine therapy.This exclusive analysis of patients with ER-/PgR+/HER2- breast cancers showed that this subtype exhibited an aggressive behavior as TNBC, suggesting that it should also be regarded as biologically distinctive group and single PgR positive itself is not a good prognostic factor. However, adjuvant endocrine therapy could still benefit this group of patients. Further investigations should be done to elucidate the underlying mechanism. PMID- 26579820 TI - The Impact of Admission Diagnosis on Recurrent or Frequent Hospitalizations in 3 Dementia Subtypes: A Hospital-Based Cohort in Taiwan with 4 Years Longitudinal Follow-Ups. AB - Increasing numbers of patients with different types of dementia have resulted in the increasing medical care loads. It is not known whether explanatory factors for recurrent or prolong hospitalization were driven by the subtypes of dementia. We analyzed 203 dementia patients aged >65-year-old with a clinical diagnosis of Alzheimer disease (AD), vascular dementia (VaD), or Parkinsonism-related dementia (PRD). With a 4-year follow-up period, logistic regression analyses were used to identify predictors of dementia diagnosis, cerebrovascular risk factors, chronic systemic diseases, and the etiology for admission for recurrent (>4 times/4 years) or prolonged hospitalization stay (>14 days per hospitalization). There were 48 AD, 96 VaD, and 59 PRD patients that completed the 4-year study. The average length of hospital stay was significant, the shortest in AD and the longest in PRD (P = 0.01), whereas the frequency of hospitalization was not different among 3 dementia subtypes. Although delirium is the most common etiology for admission in the patients, diabetes mellitus (Odds ratio, OR = 2.79, P = 0.02), pneumonia (OR = 11.21, P < 0.001), and fall-related hip fracture (OR = 4.762, P = 0.029) were significantly associated with prolong hospitalization. Patients with coronary artery disease (OR = 9.87, P = 0.02), pneumonia (OR = 84.48, P < 0.001), urinary tract infection (OR = 55.09, P < 0.001), and fall related fracture (OR = 141.7, P < 0.001) predict recurrent hospitalization. Dementia subtypes did not influence directly on the hospitalization courses. The etiologies for admission carried higher clinical significance, compared with the coexisted systemic diseases. PMID- 26579821 TI - Polymorphisms and Plasma Levels of Tissue Inhibitor of Metalloproteinase-3: Impact on Genetic Susceptibility and Clinical Outcome of Oral Cancer. AB - Oral cancer, the fourth most common cancer among men in Taiwan, is associated with environmental carcinogens. Tissue inhibitor of metalloproteinase-3 (TIMP3), a member of the TIMP family, is the only protein that binds to the extracellular matrix for suppressing cancer cell growth, angiogenesis, migration, and invasion. The association of TIMP3 polymorphism with oral cancer susceptibility, however, has not yet been reported. In this study, 1947 participants-1200 healthy male controls and 747 male patients with oral cancer-were recruited. Allelic discrimination of TIMP3 -1296 T > C (rs9619311), TIMP3 C > T (rs9862), and TIMP3 C > T (rs11547635) polymorphisms were assessed through real-time polymerase chain reaction. The authors discovered that individuals carrying the polymorphic rs9862 allele are more susceptible to oral cancer [odds ratio (OR), 1.5; 95% confidence interval (CI), 1.2-1.9; adjusted OR (AOR), 1.6; 95% CI, 1.2-2.1] after adjustment for betel quid chewing, alcohol, and tobacco consumption. Among 601 betel quid chewers, the TIMP3 polymorphism rs9862 T/T carriers had a 32.2-fold (95% CI, 20.2 51.3) increased oral cancer risk compared with those carrying C/C and not chewing betel quid. In addition, the authors observed a significant association between rs9862 variants and large tumors (OR, 1.5; 95% CI, 1.0-2.3) development. Moreover, TIMP3 plasma levels significantly increased in oral cancer patients who have large tumor or carry T allele rs9862 polymorphism. In conclusion, these results suggest that gene-environment interactions between the TIMP3 rs9862 polymorphisms and betel quid may alter oral cancer susceptibility and tumor growth in Taiwanese men. PMID- 26579822 TI - Centralized HIV Program Oversight: An Investigation of a Case Series of New HIV Infections among US Army Soldiers, 2012 to 2013. AB - Centralized HIV program oversight and repeal of the Department of Defense policy "Don't Ask Don't Tell" permitted characterization of HIV transmission among soldiers assigned to a large US Army base continental United States from 2012 to 2013. An investigation of a greater than expected number of new HIV infections among soldiers was initiated to characterize transmission and identify opportunities to disrupt transmission and deliver services.All soldiers who were assigned to the base at the time of their first positive HIV test and who had their first positive HIV test in 2012 or in the first 6 months of 2013 and who had a clinical genotype available for analysis were eligible for inclusion in the investigation.All patients (n = 19) were men; most were black (52%) and less than 30 years old (64%). Fifteen of the 19 patients participated in in-depth interviews. Eighty percent were men who have sex with men who reported multiple sex partners having met through social and electronic networks. All were subtype B infections. Significant knowledge gaps and barriers to accessing testing and care in the military healthcare system were identified. Most (58%) belonged to transmission networks involving other soldiers.This investigation represents an important step forward in on-going efforts to develop a comprehensive understanding of transmission networks in the Army that can inform delivery of best practices combination prevention services. The Army is developing plans to directly engage individuals in key affected populations most at risk for HIV infection to identify and address unmet needs and expand delivery and uptake of prevention services. Further investigation is underway and will determine whether these findings are generalizable to the Army. PMID- 26579823 TI - Case Report: Renal Sympathetic Denervation as a Tool for the Treatment of Refractory Inappropriate Sinus Tachycardia. AB - Inappropriate sinus tachycardia is defined as sinus tachycardia at rest (heart rate >=100 bpm) in sitting position or/and as an average heart rate >=90 bpm during 24-hour Holter monitoring. The most common symptoms are palpitation, dizziness, chest discomfort, orthostatic intolerance, and fatigue. Sometimes, the symptoms can be severe and debilitating, and its etiology is not well understood. Pharmacological approaches present limitation because of their relatively small effectiveness, intolerance, or side effects.In this series of cases of inappropriate sinus tachycardia, the authors report 3 cases refractory to conventional pharmacological therapy, in which the authors were not tempted for ablation of the sinus node. The authors, however, use another therapeutic approach, which was renal sympathetic denervation, to reduce sympathetic activity in the sinus node, and consequently reduce tachycardia with improvement of symptoms.Three months after renal sympathetic denervation, all patients were not using any type of medication, and reported no more symptoms. The authors know that this is the first report using the renal sympathetic denervation for the treatment of inappropriate sinus tachycardia. Studies with a larger number of patients, a longer time of follow-up, and a control group, however, should be performed. PMID- 26579824 TI - Inverse Association of Parkinson Disease With Systemic Lupus Erythematosus: A Nationwide Population-based Study. AB - The effects of the inflammatory mediators involved in systemic lupus erythematous (SLE) on subsequent Parkinson disease have been reported, but no relevant studies have focused on the association between the 2 diseases. This nationwide population-based study evaluated the risk of Parkinson disease in patients with SLE.We identified 12,817 patients in the Taiwan National Health Insurance database diagnosed with SLE between 2000 and 2010 and compared the incidence rate of Parkinson disease among these patients with that among 51,268 randomly selected age and sex-matched non-SLE patients. A Cox multivariable proportional hazards model was used to evaluate the risk factors of Parkinson disease in the SLE cohort.We observed an inverse association between a diagnosis of SLE and the risk of subsequent Parkinson disease, with the crude hazard ratio (HR) being 0.60 (95% confidence interval 0.45-0.79) and adjusted HR being 0.68 (95% confidence interval 0.51-0.90). The cumulative incidence of Parkinson disease was 0.83% lower in the SLE cohort than in the non-SLE cohort. The adjusted HR of Parkinson disease decreased as the follow-up duration increased and was decreased among older lupus patients with comorbidity.We determined that patients with SLE had a decreased risk of subsequent Parkinson disease. Further research is required to elucidate the underlying mechanism. PMID- 26579825 TI - Trends of Antibiotic Consumption in Korea According to National Reimbursement Data (2008-2012): A Population-Based Epidemiologic Study. AB - This study determined the trends in the quantities and patterns of nationwide antibiotic consumption in the Republic of Korea (ROK).This nationwide descriptive epidemiological study was conducted in the ROK between 2008 and 2012. The quantities and patterns of total systemic antibiotic prescriptions were analyzed using National Health Insurance claims data collected through the Health Insurance Review and Assessment service. Data concerning systemic antibiotics were collected using measurement units of the defined daily dose (DDD) per 1000 people per day according to the Anatomical Therapeutic Chemical classification.Over the 5-year study period, the annual consumption of systemic antibiotics ranged from 21.68 to 23.12 DDD per 1000 people per day. Outpatient antibiotic use accounted for 80.9% of total consumption. A regression model with autoregressive errors showed significant increased consumption of major antibiotic subgroups, including 3rd-generation cephalosporins, carbapenems, and glycopeptides (P < 0.001). However, the antibiotic use of 1st- (P = 0.003), 2nd- (P = 0.004), and 3rd-generation (P = 0.018) cephalosporins among patients who underwent surgery under monitoring by the antimicrobial stewardship programs for perioperative prescription was significantly lower than in those who underwent surgery without monitoring programs. In time-series analysis, total antibiotic consumption demonstrated significant seasonality (P < 0.001).The consumption of broad-spectrum antibiotics was noted to have increased in the ROK from 2008 to 2012, providing a possible explanation for the changing epidemiology of multidrug resistance. Larger prospective studies are needed to investigate the impact on public health of monitoring programs of perioperative antibiotic usage. PMID- 26579826 TI - Blisters and Loss of Epidermis in Patients With Lupus Erythematosus: A Clinicopathological Study of 22 Patients. AB - The nosology of bullous lesions or equivalents (vesicles, erosions, and crusts) in patients with lupus erythematosus (LE) is rarely addressed.The primary aim of this study was to draw up a precise phenotypic inventory of such skin lesions; the secondary objective was to assess a potential relationship between the different types of loss of epidermis and extracutaneous lupus manifestations.We conducted a retrospective multicenter study including 22 patients with definite LE and bullous lesions or equivalents. All biopsies were reviewed. Patients were recruited in the dermatology departments of 6 centers. Patients were included if they met the diagnosis of systemic LE according to American College of Rheumatology and/or Systemic Lupus International Collaborating Clinics criteria or diagnosis of cutaneous LE based on classic clinical criteria and/or histological ascertainment of LE. Patients were recruited through clinician's memory and photographic collections.Three clinico-pathological patterns could be individualized. First, toxic epidermal necrolysis (TEN)-like, sheet-like, skin detachment; sun-exposure, mild mucosal involvement, and dermal mucin deposition allow differential diagnosis with classical Lyell syndrome. Second, vesiculo bullae and/or crusting occurring on typical lesions of subacute cutaneous lupus erythematosus or chronic cutaneous lupus erythematosus. Third, tense vesicles and/or blisters with an underlying neutrophilic dermatosis and a usual response to dapsone.A careful analysis of 22 LE patients with epidermal detachment reveals 2 main pathomechanisms: a classic LE interface dermatitis, which can be hyperacute and lead to TEN-like skin detachment; and a neutrophilic dermatosis, with tense vesicles and/or blisters, including classic bullous LE. PMID- 26579827 TI - Risk of Restless Legs Syndrome Following Tension-Type Headache: A Nationwide Population-Based Cohort Study. AB - Migraine and restless legs syndrome (RLS) appear to be associated, but the relationship between tension-type headache (TTH) and RLS is unknown. This nationwide, population-based, retrospective cohort study explored the potential association between TTH and RLS.We identified 15,504 patients with newly diagnosed TTH from 2000 to 2007 and 62,016 individuals without TTH who were selected by frequency matched based on sex, age, and the index year. The study participants were followed until diagnosed with RLS, withdrawal from the NHI program, or the end of 2011. Cox proportional hazard models were used to identify risk factors for RLS in TTH patients.After adjusting for sex, age, comorbidity, and medications, TTH was significantly associated with an increased risk of RLS (hazard ratio [HR] = 1.57, 95% confidence interval [CI] = 1.22-2.02). The risk was most prominent in patients aged 20 to 39 years in the TTH group, which exhibited a 2.60-fold higher risk (95% confidence interval = 1.53-4.42) of RLS compared with the non-TTH group. The TTH group had a higher risk of RLS than that of the non-TTH group regardless of sex.Tension-type headache appears to be associated with an increased risk of developing RLS. This similarity to migraines may indicate that headache and RLS have a coincident pathophysiological mechanism, a possibility requiring further study. Clinicians should be more attentive to RLS as a possible comorbidity in patients with TTH. PMID- 26579828 TI - Antiretroviral Therapy Fails to Restore Levels of HIV-1 Restriction miRNAs in PBMCs of HIV-1-infected MSM. AB - A number of cellular microRNAs (miRNAs) have been identified to have the ability to inhibit HIV-1 replication. In this study, we examined the impact of combination antiretroviral therapy (cART) on the expression of HIV-1 restriction miRNAs in peripheral blood mononuclear cells of HIV-1-infected men who have sex with men (MSM). Compared with male healthy donors, HIV-infected MSM had significantly lower levels of 9 HIV-1 restriction miRNAs. The treatment of HIV-1 infected MSM with cART, however, failed to restore the levels of these miRNAs in peripheral blood mononuclear cells. These observations suggest that the suppression of the cellular restriction miRNAs by HIV-1 may attribute to the virus latency during cART. PMID- 26579829 TI - Increased Expression of the Autocrine Motility Factor is Associated With Poor Prognosis in Patients With Clear Cell-Renal Cell Carcinoma. AB - Glucose-6-phosphate isomerase (GPI), also known as phosphoglucose isomerase, was initially identified as the second glycolytic enzyme that catalyzes the interconversion of glucose-6-phosphate to fructose-6-phosphate. Later studies demonstrated that GPI was the same as the autocrine motility factor (AMF), and that it mediates its biological effects through the interaction with its surface receptor (AMFR/gp78). In this study, we assessed the role of GPI/AMF as a prognostic factor for clear cell renal cell carcinoma (ccRCC) cancer-specific (CSS) and progression-free survival (PFS). In addition, we evaluated the expression and localization of GPI/AMF and AMFR, using tissue microarray-based immunohistochemistry (TMA-IHC), indirect immunofluorescence (IF), and confocal microscopy analysis.Primary renal tumor and nonneoplastic tissues were collected from 180 patients who underwent nephrectomy for ccRCC. TMA-IHC and IF staining showed an increased signal for both GPI and AMFR in cancer cells, and their colocalization on plasma membrane. Kaplan-Meier curves showed significant differences in CSS and PFS among groups of patients with high versus low GPI expression. In particular, patients with high tissue levels of GPI had a 5-year survival rate of 58.8%, as compared to 92.1% for subjects with low levels (P < 0.0001). Similar findings were observed for PFS (56.8% vs 93.3% at 5 years). At multivariate analysis, GPI was an independent adverse prognostic factor for CSS (HR = 1.26; P = 0.001), and PFS (HR = 1.16; P = 0.01).In conclusion, our data suggest that GPI could serve as a marker of ccRCC aggressiveness and a prognostic factor for CSS and PFS. PMID- 26579830 TI - Risk of Peripheral Arterial Occlusive Disease in Patients With Systemic Lupus Erythematosus: A Nationwide Population-Based Cohort Study. AB - Systemic lupus erythematosus (SLE) is associated with atherosclerosis, but the relationship between SLE and peripheral arterial occlusive disease (PAOD) remains unclear. We sought to investigate this relationship by comparing cardiovascular complications in patients with and without SLE.Data on patients from 2000 to 2011 were collected from the National Health Insurance Research Database of Taiwan. The SLE cohort was frequency-matched according to age, sex, and history of diabetes mellitus (DM) with patients without SLE (control cohort). We evaluated the risk of cardiovascular complications, including hypertension, DM, stroke, chronic obstructive pulmonary disease, heart failure, coronary artery disease, and hyperlipidemia.The study included 10,144 patients with SLE and 10,144 control patients. The incidence of PAOD was 9.39-fold higher (95% confidence interval [CI] = 7.70-11.15) in the SLE cohort than in the non-SLE cohort. Moreover, SLE was an independent risk factor for PAOD. The adjusted risk of PAOD was highest in patients with SLE who were aged <=34 years (hazard ratio = 47.6, 95% CI = 26.8 84.4). The risk of PAOD was highest during the first year of follow-up and decreased over time.Patients with SLE exhibit a higher incidence and an independently higher risk of PAOD compared with the general population. The PAOD risk is markedly elevated in patients with SLE who are young and in whom the disease is at an early stage. PMID- 26579831 TI - Increased Risk of Intracerebral Hemorrhage Among Patients With Hepatitis C Virus Infection. AB - This research explored whether hepatitis C virus (HCV) infection leads to the development of intracerebral hemorrhage (ICH).Using Taiwan National Health Insurance claims data, 9023 patients newly diagnosed with HCV infection between 2000 and 2010 were identified, and 36,092 age- and sex-frequency-matched patients without HCV infection were selected randomly as the control group. The risk of ICH for patients with HCV infection and comorbidities of diabetes, hypertension, ischemic heart disease, hyperlipidemia, atrial fibrillation, alcoholic liver disorder, and head injury was evaluated at the end of 2011.The risk of ICH was higher in the HCV cohort than in the control group, with an adjusted hazard ratio (aHR) of 1.60 (95% confidence interval [CI]: 1.24-2.06), estimated using a multivariate Cox regression model. Age-specific analysis revealed that the risk of ICH in the HCV patients was higher in the younger groups, with aHRs of 1.92 (95% CI: 1.18-3.11) and 2.45 (95% CI: 1.52-3.98) in the <=55 and 56 to 64 years age groups, respectively. The risk of ICH increased with the severity of HCV infection, from an aHR of 1.66 (95% CI: 1.21-2.30) in mild HCV patients to 2.12 (95% CI: 1.47-3.06) in severe HCV patients. For patients without comorbidities, the risk of ICH was 2.33 (95% CI: 1.36-3.98) higher in the HCV cohort than in the control group.We found that HCV infection is associated with an increased risk to develop ICH, particularly in the patients with relatively younger ages. PMID- 26579832 TI - Erratum: EFSUMB Guidelines on Interventional Ultrasound (INVUS), Part VI - Ultrasound-Guided Vascular Interventions. PMID- 26579833 TI - Direct Conversion of Equine Adipose-Derived Stem Cells into Induced Neuronal Cells Is Enhanced in Three-Dimensional Culture. AB - The ability to culture neurons from horses may allow further investigation into equine neurological disorders. In this study, we demonstrate the generation of induced neuronal cells from equine adipose-derived stem cells (EADSCs) using a combination of lentiviral vector expression of the neuronal transcription factors Brn2, Ascl1, Myt1l (BAM) and NeuroD1 and a defined chemical induction medium, with betaIII-tubulin-positive induced neuronal cells displaying a distinct neuronal morphology of rounded and compact cell bodies, extensive neurite outgrowth, and branching of processes. Furthermore, we investigated the effects of dimensionality on neuronal transdifferentiation, comparing conventional two dimensional (2D) monolayer culture against three-dimensional (3D) culture on a porous polystyrene scaffold. Neuronal transdifferentiation was enhanced in 3D culture, with evenly distributed cells located on the surface and throughout the scaffold. Transdifferentiation efficiency was increased in 3D culture, with an increase in mean percent conversion of more than 100% compared to 2D culture. Additionally, induced neuronal cells were shown to transit through a Nestin positive precursor state, with MAP2 and Synapsin 2 expression significantly increased in 3D culture. These findings will help to increase our understanding of equine neuropathogenesis, with prospective roles in disease modeling, drug screening, and cellular replacement for treatment of equine neurological disorders. PMID- 26579834 TI - Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus from Latin America. AB - OBJECTIVE: This post hoc analysis evaluated the efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus (T2DM) from Latin America. RESEARCH DESIGN AND METHODS: Analyses were performed in subgroups of patients from Latin America based on data from three individual, 26-week, placebo-controlled studies of canagliflozin (monotherapy [n = 116/584], add-on to metformin [n = 199/918], and add-on to metformin plus sulfonylurea [n = 76/469]) and three individual, 52-week, active controlled studies of canagliflozin (add-on to metformin versus sitagliptin [n = 240/1101], add-on to metformin versus glimepiride [n = 155/1450], and add-on to metformin plus sulfonylurea versus sitagliptin [n = 156/755]). MAIN OUTCOME MEASURES: Changes from baseline in HbA1c, body weight, and systolic blood pressure (BP) with canagliflozin 100 and 300 mg versus placebo or active comparator (i.e., sitagliptin or glimepiride) were evaluated in the overall study populations and Latin American subgroups. Safety was assessed based on adverse event (AE) reports. RESULTS: Canagliflozin 100 and 300 mg provided reductions in HbA1c, body weight, and systolic BP across studies in patients from Latin America that were generally similar to those seen in the overall populations of patients with T2DM. The AE profile in patients from Latin America was equivalent to that in the overall populations; higher rates of genital mycotic infections and osmotic diuresis-related AEs were seen with canagliflozin versus comparators. Limitations of this study include the post hoc analysis of data and the small sample size of patients from Latin America. CONCLUSION: Canagliflozin improved glycemic control, reduced body weight and systolic BP, and was generally well tolerated in patients with T2DM from Latin America. CLINICAL TRIAL REGISTRATION: NCT01081834; NCT01106677; NCT01106625; NCT00968812; NCT01137812. PMID- 26579836 TI - Unraveling Special Structures and Properties of Gold-Covered Gold-Core Cage on Au33-42 Nanoparticles. AB - New low-energy atomic structures and properties of medium-size gold nanoparticles (Au33-42) are studied, where the atomic positions of gold atoms are obtained on the basis of the generic formulation of shell and core concept. Hollow cage, tube like, double-layered flat, fcc-like, and close-packed configurations are predicted. Relativistic density functional theory optimization indicated that low symmetry stuffed configurations are all lower in energy than the others. Further analysis of the optimized structures of Au33-42 nanoparticles shows that these gold cores are all four-atom tetrahedral structures and similar to each other; only the number and positions of gold atoms at the surface of gold core are different. Compared with structure and electronic properties, Au33-42 nanoparticles have different structure stabilities and chemical activities. But they are all hybridizations of sp and d electrons. The obtained information forms the basis for future chemisorption studies to unravel the catalytic effects of gold nanoparticles. PMID- 26579835 TI - Supervised learning for neural manifold using spatiotemporal brain activity. AB - OBJECTIVE: Determining the means by which perceived stimuli are compactly represented in the human brain is a difficult task. This study aimed to develop techniques for the construction of the neural manifold as a representation of visual stimuli. APPROACH: We propose a supervised locally linear embedding method to construct the embedded manifold from brain activity, taking into account similarities between corresponding stimuli. In our experiments, photographic portraits were used as visual stimuli and brain activity was calculated from magnetoencephalographic data using a source localization method. MAIN RESULTS: The results of 10 * 10-fold cross-validation revealed a strong correlation between manifolds of brain activity and the orientation of faces in the presented images, suggesting that high-level information related to image content can be revealed in the brain responses represented in the manifold. SIGNIFICANCE: Our experiments demonstrate that the proposed method is applicable to investigation into the inherent patterns of brain activity. PMID- 26579837 TI - Speaking the Same Language: Using Standardized Terminology. PMID- 26579838 TI - Physicians' Awareness, Attitudes, and Experiences Regarding Imiquimod Treatment of Vaginal and Cervical Intraepithelial Neoplasia. AB - OBJECTIVE: The aim of the study was to assess awareness, attitudes, and current clinical experiences of gynecologists regarding imiquimod as a potential treatment modality for vaginal intraepithelial neoplasia (VAIN) and cervical intraepithelial neoplasia (CIN). MATERIALS AND METHODS: A 37-item questionnaire consisting of both multiple choice and open questions was sent to all Dutch gynecologists who regularly perform colposcopies in all 87 Dutch hospitals, in December 2014. The outcomes were assessed using descriptive statistics. RESULTS: Gynecologists from 52 hospitals (60%) completed the questionnaire. Of the 77 respondents, 79% and 58% were aware of imiquimod for treating VAIN and CIN, respectively. Twelve and 5 respondents had used imiquimod to treat VAIN and CIN, respectively; most treatments were for intractable VAIN lesions and recurrent lesions and to avoid surgical treatment for CIN in patients with a future pregnancy wish. Most respondents reported successful treatment outcomes but frequent adverse effects. Most (96%) stated that they would consider using imiquimod to treat high-grade CIN in selected patients, but only upon additional evidence and inclusion into treatment guidelines. CONCLUSIONS: The awareness of imiquimod as a potential treatment for VAIN and CIN was limited, possibly because of the paucity of evidence regarding vaginal imiquimod efficacy, the lack of inclusion into guidelines, and the high frequency of adverse effects. Imiquimod was applied off-label in a limited number of selected patients, with good treatment results. The respondents generally had a positive attitude toward treating VAIN and CIN with imiquimod. Additional evidence on treatment efficacy and inclusion in treatment guidelines is necessary before application in clinical practice. PMID- 26579839 TI - The Effect of Country of Birth on the Pattern of Disease and Survival From Cervical Cancer. AB - OBJECTIVE: The aim of the study was to investigate the impact of country of birth on the pattern of disease and survival from cervical cancer in women living in the United Kingdom. MATERIALS AND METHODS: A retrospective database evaluation study was performed to review all cases of cervical cancer diagnosed in the Pan Birmingham Cancer Network between 2005 and 2009. Population characteristics and survival data were obtained from the West Midlands Cancer Registry and National Health Authority Information System, United Kingdom. Women's country of birth was classified as being high- (including patients born in the United Kingdom and Ireland), middle-, or low-income countries according to the World Bank country classification. Screening histories data were obtained from the West Midlands Cancer Screening Quality Assurance Reference Centre. Overall survival data were analyzed using the nonparametric Kaplan-Meier method with log-rank tests to compare between groups. RESULTS: Four hundred eighty-four cases were identified. A country of birth was available for 459 cases (94.8%). Cancers detected through screening or interval cancers accounted for 140 (28.9%) of cases compared with 226 (46.7%) where women had not complied with screening. Of the women born outside of the United Kingdom/Ireland, 40 (59.7%) originated from low-income, 23 (34.3%) from middle-income, and 4 (6.0%) from high-income countries. Multivariate analysis identified age (p < .001) and stage (p < .001) at diagnosis as having a significant effect on survival, but no effect was seen from social deprivation (p = .18) or economic status of country of birth (p = .30). DISCUSSION: Country of birth is not an independent prognostic indicator for cervical cancer survival. PMID- 26579840 TI - Lesions and Neoplasms of the Penis: A Review. AB - In addition to practitioners who care for male patients, with the increased use of high-resolution anoscopy, practitioners who care for women are seeing more men in their practices as well. Some diseases affecting the penis can impact on their sexual partners. Many of the lesions and neoplasms of the penis occur on the vulva as well. In addition, there are common and rare lesions unique to the penis. A review of the scope of penile lesions and neoplasms that may present in a primary care setting is presented to assist in developing a differential diagnosis if such a patient is encountered, as well as for practitioners who care for their sexual partners. A familiarity will assist with recognition, as well as when consultation is needed. PMID- 26579841 TI - Clinical Utility of Molecular Biomarkers in Cervical Squamous Intraepithelial Lesions in a Young Adult Population. AB - OBJECTIVE: Although human papillomavirus (HPV) infection is necessary for cervical squamous intraepithelial lesion (SIL/CIN) and cancer to develop, exposure to HPV is not predictive of which women will develop SIL/CIN and cancer. This study examines mRNA expression of several potential biomarkers in exfoliated cervical cells collected from college-aged women. MATERIALS AND METHODS: Freshman female students were recruited into the Carolina Women's Care Study, which was designed to prospectively evaluate factors that contribute to persistent HPV infections. One component of this study was to extract mRNA from exfoliated cervical cells. In this study, mRNA expression of Frizzled (FZD), growth differentiating factor 15, interleukin 1 beta (IL1beta), and N-cadherin was assessed through real-time polymerase chain reaction. Statistical analysis was performed with a Student t test; all results were standardized with glyceraldehyde 3-phosphate dehydrogenase. RESULTS: Fifty samples were selected that reflected the demographics of the Carolina Women's Care Study participants. IL1beta mRNA expression was 9.4-fold higher in cervical cells from women with abnormal Pap tests (p = .0018); low-grade squamous intraepithelial lesion had 12.7-fold higher expression than negatives (p = .0011). The FZD mRNA expression was 5.7-fold higher in CIN 2 as compared with CIN 1 (p = .0041) and 8.5-fold higher compared with cytology/pathology negative (p = .0014). Other differences in mRNA expression showed trends but not reaching statistical significance for each condition. CONCLUSIONS: It seems that several biomarkers involved in the cytokine/inflammatory pathway (IL1beta), cell adhesion pathway (N-cadherin), growth factor (growth differentiating factor 15), and Wingless (WNT) signaling pathway (FZD) may be potential biomarkers in conjunction with the Pap test and HPV that help predict which women are at highest risk for developing CIN 3 and cervical cancer. PMID- 26579843 TI - Ternary NiFeMn layered double hydroxides as highly-efficient oxygen evolution catalysts. AB - Layered double hydroxides (LDHs) are a family of layer materials that receive heightened attention. Herein a ternary NiFeMn-LDH is investigated with superior oxygen evolution activity, which is attributed to the Mn(4+) doping in the intralayer, which modifies the electronic structure and improves the conductivity of the electrocatalyst. PMID- 26579842 TI - An Insight Into Cervical Cancer Screening and Treatment Capacity in Sub Saharan Africa. AB - OBJECTIVE: Approximately 85% of cervical cancer cases and deaths occur in resource-constrained countries where best practices for prevention, particularly for women with HIV infection, still need to be developed. The aim of this study was to assess cervical cancer prevention capacity in select HIV clinics located in resource-constrained countries. MATERIALS AND METHODS: A cross-sectional survey of sub-Saharan African sites of 4 National Institutes of Health-funded HIV/AIDS networks was conducted. Sites were surveyed on the availability of cervical cancer screening and treatment among women with HIV infection and without HIV infection. Descriptive statistics and chi or Fisher exact test were used as appropriate. RESULTS: Fifty-one (65%) of 78 sites responded. Access to cervical cancer screening was reported by 49 sites (96%). Of these sites, 39 (80%) performed screening on-site. Central African sites were less likely to have screening on-site (p = .02) versus other areas. Visual inspection with acetic acid and Pap testing were the most commonly available on-site screening methods at 31 (79%) and 26 (67%) sites, respectively. High-risk HPV testing was available at 29% of sites with visual inspection with acetic acid and 50% of sites with Pap testing. Cryotherapy and radical hysterectomy were the most commonly available on site treatment methods for premalignant and malignant lesions at 29 (74%) and 18 (46%) sites, respectively. CONCLUSIONS: Despite limited resources, most sites surveyed had the capacity to perform cervical cancer screening and treatment. The existing infrastructure of HIV clinical and research sites may provide the ideal framework for scale-up of cervical cancer prevention in resource-constrained countries with a high burden of cervical dysplasia. PMID- 26579844 TI - An Analysis of 34,218 Pediatric Outpatient Controlled Substance Prescriptions. AB - BACKGROUND: Prescription errors are among the most common types of iatrogenic errors. Because of a previously reported 82% error rate in handwritten discharge narcotic prescriptions, we developed a computerized, web-based, controlled substance prescription writer that includes weight-based dosing logic and alerts to reduce the error rate to (virtually) zero. Over the past 7 years, >34,000 prescriptions have been created by hospital providers using this platform. We sought to determine the ongoing efficacy of the program in prescription error reduction and the patterns with which providers prescribe controlled substances for children and young adults (ages 0-21 years) at hospital discharge. METHODS: We examined a database of 34,218 controlled substance discharge prescriptions written by our institutional providers from January 1, 2007 to February 14, 2014, for demographic information, including age and weight, type of medication prescribed based on patient age, formulation of dispensed medication, and amount of drug to be dispensed at hospital discharge. In addition, we randomly regenerated 2% (700) of prescriptions based on stored data and analyzed them for errors using previously established error criteria. Weights that were manually entered into the prescription writer by the prescriber were compared with the patient's weight in the hospital's electronic medical record. RESULTS: Patients in the database averaged 9 +/- 6.1 (range, 0-21) years of age and 36.7 +/- 24.9 (1-195) kg. Regardless of age, the most commonly prescribed opioid was oxycodone (73%), which was prescribed as a single agent uncombined with acetaminophen. Codeine was prescribed to 7% of patients and always in a formulation containing acetaminophen. Liquid formulations were prescribed to 98% of children <6 years of age and to 16% of children >12 years of age (the remaining 84% received tablet formulations). Regardless of opioid prescribed, the amount of liquid dispensed averaged 106 +/- 125 (range, 2-3240) mL, and the number of tablets dispensed averaged 51 +/- 51 (range, 1-1080). Of the subset of 700 regenerated prescriptions, all were legible (drug, amount dispensed, dose, patient demographics, and provider name) and used best prescribing practice (e.g., no trailing zero after a decimal point, leading zero for doses <1). Twenty-five of the 700 (3.6%) had incorrectly entered weights compared with the most recent weight in the chart. Of these, 14 varied by 10% or less and only 2 varied by >15%. Of these, 1 resulted in underdosing (true weight 80 kg prescribed for a weight of 50 kg) and the other in overdosing (true weight 10 kg prescribed for a weight of 30 kg). CONCLUSIONS: A computerized prescription writer eliminated most but not all the errors common to handwritten prescriptions. Oxycodone has supplanted codeine as the most commonly prescribed oral opioid in current pediatric pain practice and, independent of formulation, is dispensed in large quantities. This study underscores the need for liquid opioid formulations in the pediatric population and, because of their abuse potential, the urgent need to determine how much of the prescribed medication is actually used by patients. PMID- 26579845 TI - Awake Craniotomy: A New Airway Approach. AB - Awake craniotomies have been performed regularly at the University of Pennsylvania since 2004. Varying approaches to airway management are described for this procedure, including intubation with an endotracheal tube and use of a laryngeal mask airway, simple facemask, or nasal cannula. In this case series, we describe the successful use (i.e., no need for endotracheal intubation related to inadequate gas exchange) of bilateral nasopharyngeal airways in 90 patients undergoing awake craniotomies. The use of nasopharyngeal airways can ease the transition between the asleep and awake phases of the craniotomy without the need to stimulate the airway. Our purpose was to describe our experience and report adverse events related to this technique. PMID- 26579846 TI - Blood Bupivacaine Concentrations After Transversus Abdominis Plane Block in Neonates: A Prospective Observational Study. AB - BACKGROUND: Untreated pain can have instant and prolonged consequences to behavioral and neurologic outcomes in neonates. Although the use of transversus abdominis plane (TAP) block to minimize postsurgical pain has been demonstrated in neonates, no data regarding the safety of this procedure are available for this patient population. For instance, it is unknown whether plasma levels of local anesthetics are safe in neonates after TAP blocks. The main objective of the current investigation was to evaluate plasma bupivacaine concentrations in neonates having an ultrasound-guided TAP block. METHODS: The study was a prospective, observational study. After general anesthesia was induced, neonates received an ultrasound-guided TAP block with 0.125% bupivacaine and a total volume of 1 mL/kg. Dried blood spot samples were obtained and analyzed for bupivacaine levels at 0, 5, 15, 30, 60, 120 minutes, 4, and 24 hours after the TAP block. RESULTS: Ten neonates were included in the study. The highest 99% upper prediction limit for blood concentration, 0.38 ug/mL, occurred at the 30 minute interval, but it was significantly lower than potentially toxic plasma levels (1.5-2.0 ug/mL). The highest individual concentration was 0.26 ug/mL and occurred at the 30-minute interval. None of the patients demonstrated any potential signs of local anesthetic toxicity. CONCLUSIONS: Our results suggest a low risk of local anesthetic toxicity in neonates after a TAP block. Future studies to determine the efficacy of the TAP block to minimize postsurgical pain in this patient population are warranted. PMID- 26579848 TI - Refinements to the structure of graphite oxide: absolute quantification of functional groups via selective labelling. AB - Chemical modification and functionalization of inherent functional groups within graphite oxide (GO) are essential aspects of graphene-based nano-materials used in wide-ranging applications. Despite extensive research, there remains some discrepancy in its structure, with current knowledge limited primarily to spectroscopic data from XPS, NMR and vibrational spectroscopies. We report herein an innovative electrochemistry-based approach. Four electroactive labels are chosen to selectively functionalize groups in GO, and quantification of each group is achieved by voltammetric analysis. This allows for the first time quantification of absolute amounts of each group, with a further advantage of distinguishing various carbonyl species: namely ortho- and para-quinones from aliphatic ketones. Intrinsic variations in the compositions of permanganate versus chlorate-oxidized GOs were thus observed. Principal differences include permanganate-GO exhibiting substantial quinonyl content, in comparison to chlorate-GO with the vast majority of its carbonyls as isolated ketones. The results confirm that carboxylic groups are rare in actuality, and are in fact entirely absent from chlorate-GO. These observations refine and advance our understanding of GO structure by addressing certain disparities in past models resulting from employment of different oxidation routes, with the vital implication that GO production methods cannot be used interchangeably in the manufacture of graphene-based devices. PMID- 26579847 TI - First-Attempt Intubation Success of Video Laryngoscopy in Patients with Anticipated Difficult Direct Laryngoscopy: A Multicenter Randomized Controlled Trial Comparing the C-MAC D-Blade Versus the GlideScope in a Mixed Provider and Diverse Patient Population. AB - BACKGROUND: Intubation success in patients with predicted difficult airways is improved by video laryngoscopy. In particular, acute-angle video laryngoscopes are now frequently chosen for endotracheal intubation in these patients. However, there is no evidence concerning whether different acute-angle video laryngoscopes can be used interchangeably in this scenario and would allow endotracheal intubation with the same success rate. We therefore tested whether first-attempt intubation success is similar when using a newly introduced acute-angle blade, that is an element of an extended airway management system (C-MAC D-Blade) compared with a well-established acute-angle video laryngoscope (GlideScope). METHODS: In this large multicentered prospective randomized controlled noninferiority trial, patients requiring general anesthesia for elective surgery and presenting with clinical predictors of difficult laryngoscopy were randomly assigned to intubation using either the C-MAC D-Blade or the GlideScope video laryngoscope. The hypothesis was that first-attempt intubation success using the new device (D-Blade) is no >4% less than the established device (GlideScope), which would determine noninferiority of the new instrument versus the established instrument. The secondary outcomes we observed included intubation success with multiple attempts and airway-related complications within 7 days of enrollment. RESULTS: Eleven hundred patients were randomly assigned to either video laryngoscope. Intubation success rate on first attempt was 96.2% in the GlideScope group and 93.4% in the C-MAC D-Blade group. Although the absolute difference between the 2 groups was only 2.8%, the 90.35% upper confidence limit of the difference exceeded the predefined margin (4.98%), indicating a rejection of the noninferiority hypothesis for first-attempt intubation success. For attending anesthesiologists, and upon multiple attempts, intubation success did not differ between systems. Pharyngeal injury was noted in 1% of the patients, and the incidence did not differ between interventional groups. CONCLUSIONS: Head to-head comparison in this large multicenter trial revealed that the newly introduced C-MAC D-Blade does not yield the same first-attempt intubation success as the GlideScope in patients with predicted difficult laryngoscopy except in the hands of attending anesthesiologists. Additional research would be necessary to identify potential causes for this difference. Intubation success rates were very high with both systems, indicating that acute-angle video laryngoscopy is an exceptionally successful strategy for the initial approach to endotracheal intubation in patients with predicted difficult laryngoscopy. PMID- 26579849 TI - Unusual stability of dyads during photochemical hydrogen production. AB - Dyads for photochemical water splitting often suffer from instability during irradiation with visible light. However, the use of bis(bidentate) phosphines forming a five-membered ring enhances their stability. The coordination of these phosphor based chelates to soft metals like Pd(ii) prolongs the photocatalytic activity to 1000 hours. To avoid contribution to hydrogen production by colloidal metal, a small amount of Hg is added to the reaction mixture. In the course of our investigations, it turned out that colloidal palladium was not able to produce hydrogen under our irradiation conditions. As soon as metallic palladium emerged in our reaction vessels, no further hydrogen production was detected. This is confirmed by the observation that the hydrogen production depends on the kind of ancillary ligands present in the dyads. The first dyads of the type [MI(bpy)2(dppcb)MII(bpy)](4+) are presented (MI = Os, MII = Pd (1); MI = Ru, MII = Pd (2); MI = Os, MII = Pt (3); MI = Ru, MII = Pt (4)). In [Os(bpy)2(dppcb)Pd(dppm)](PF6)4 (5) the ancillary ligand is varied. Furthermore, it is also possible to produce hydrogen in an intermolecular way. Using different bidentate diphosphines instead of a bis(bidentate) tetraphosphine leads to this intermolecular approach, where the chromophore and the water reduction catalyst (WRC) belong now to two molecules. In this case the TON is sensitive to the type of diphosphine, which is only possible if intact molecules act as catalysts and no free palladium(0) is formed. PMID- 26579850 TI - Three-Year Clinical and Radiographic Implant Follow-up in Sinus-Lifted Maxilla With Lateral Window Technique. AB - INTRODUCTION: The aim of this study was to evaluate retrospectively the 3-year outcome of implants placed in augmented maxillary sinuses with minimal residual alveolar bone heights (<=3 mm). MATERIALS AND METHOD: A total of 28 sinus floors were augmented with xenograft, and 58 implants were placed. The outcome measures were implant success based on implant stability and the absence of periimplantitis, and marginal and apical bone resorption on periapical radiograph and prosthesis survival. RESULTS: Fifty-seven of 58 implants with their prostheses remained functional with a success rate of 98.28%. None of the implants showed any signs of mobility or periimplantitis. Both apical and cervical bone resorption around the implants were highest by the end of the first year. CONCLUSIONS: The success rate of the implants placed with staged approach in augmented maxillary sinuses with the residual alveolar bone height of <=3 mm was high in a 3-year term. Bio-Oss is an acceptable substitute autogenous bone and can be used as an augmentation material during the maxillary sinus lift procedure. PMID- 26579852 TI - In situ studies of growth of carbon nanotubes on a local metal microheater. AB - Using electron microscopy and in situ Raman spectroscopy we investigate carbon nanotube growth from ethylene on iron catalyst islands patterned on top of Mo electrodes, using a highly localized resistive on-chip-heating technique. A clear transition is observed between multi-walled and single-walled nanotube growth as the local temperature of the heater is increased. This can be rationalized in terms of the balance between incoming carbon flux and diffusion through the catalyst particle. The observed changes in heater performance on exposure to the hydrocarbon gas are explored and related to the formation of molybdenum carbide, leading to a rapid change in resistivity and heating power that increases the local temperature of the heater by up to 100 degrees C. This provides optimum conditions for nanotube growth after an incubation time that depends on the carbon flux. PMID- 26579851 TI - Comparing 2 Cone Beam Computed Tomography Devices for the Transfer Accuracy of a Laboratory-Based Guided Surgery System In Vitro. AB - PURPOSE: Using surgical templates for guided placement increases accuracy and decreases patient's discomfort, therefore optimizing the functional, aesthetic, and prosthetic outcomes. Cone Beam computed tomography (CBCT) devices differ in their resolution and geometric accuracies and have been recently demonstrated to influence the measurements of guided surgery. The study aim is to investigate the potential influence of CBCT device selection on the transfer accuracy of guided surgery. MATERIALS AND METHODS: Thirty-two Straumann implants placed in 8 acrylic models were implanted using digital planning and guided surgery. Preoperative and postoperative CBCT scans of 2 different devices (AccuiTomo 170, Morita and NewTom 5G; QR Verona) were made. Post-op implant position was compared with the digital planning and linear and angular deviations at the implant tip and base were compared between both devices. RESULTS: Mean linear and angular deviations were (0.53 mm/0.96 degree) and (0.66 mm/1.04 degree) for the Newtom and AccuiTomo, respectively. The differences were statistically insignificant (P = 0.615). CONCLUSION: In our sample, CBCT device selection did not influence the transfer accuracy of guided surgery. More research is needed to evaluate the accuracy of other systems. PMID- 26579853 TI - Antibiotics vs Surgery for Acute Appendicitis: Toward a Patient-Centered Treatment Approach. PMID- 26579855 TI - Outcome Disparities in Pancreatic Cancer: Need for Improved Regionalization of Care. PMID- 26579854 TI - Safety and Efficacy of Anakinra in Severe Hidradenitis Suppurativa: A Randomized Clinical Trial. AB - IMPORTANCE: Hidradenitis suppurativa (HS) is a common skin disorder in which excessive inflammation is believed to have an important role. There is no specific therapy for HS. OBJECTIVE: To investigate the safety and efficacy of the anti-inflammatory biological therapy anakinra in HS. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, randomized, placebo-controlled clinical trial with a 12-week treatment phase and a 12-week follow-up phase. The setting was Attikon University General Hospital, a tertiary care institution in Athens, Greece. Participants were 20 patients with Hurley stage II or III HS. The study and the analysis were conducted between March 1, 2012, and February 28, 2014. INTERVENTIONS: Patients were randomized to receive injections from identical syringes containing placebo or anakinra subcutaneously once daily for 12 weeks. Peripheral blood mononuclear cells were isolated and stimulated for cytokine production before the beginning of treatment and at week 12 (the end of treatment) and week 24. MAIN OUTCOMES AND MEASURES: The primary end point was the effect of anakinra on HS disease severity. Secondary end points were the time to a new exacerbation and the production of cytokines. RESULTS: Among the 20 trial participants, 10 each were randomized to the group to receive anakinra or the placebo group. The mean (SD) ages were 42.8 (13.8) and 36 (11.3) years in the anakinra and placebo groups, respectively. The disease activity score was decreased at the end of treatment in 20% (2 of 10) of the placebo arm compared with 67% (6 of 9) of the anakinra arm (P = .04). Hidradenitis suppurativa clinical response at 12 weeks was achieved in 30% (3 of 10) of the placebo arm and in 78% (7 of 9) of the anakinra arm (P = .04). The production of interferon gamma by peripheral blood mononuclear cells in the anakinra arm was decreased, and the production of interleukin 22 was increased. The time to a new HS exacerbation was prolonged in the anakinra arm by log-rank test (log rank, 6.137; P = .01). No serious adverse events were reported. CONCLUSIONS AND RELEVANCE: Anakinra has the potential to be an effective and well-tolerated treatment for HS. Inhibition of interleukin 1 is a promising treatment strategy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01558375. PMID- 26579856 TI - A ligand-controlled switch of regioselectivity in ring-opening coupling of diarylmethylenecyclopropa[b]naphthalenes with Grignard reagents. AB - A ligand-controlled regioselectivity switch of ring-opening coupling reaction of diarylmethylenecyclopropa[b]naphthalenes with Grignard reagents providing differently substituted beta-vinylic naphthalenes in moderate to excellent yields was reported: when Pd(OAc)2 was used, the aromatic group from the Grignard reagent regioselectively coupled to the naphthyl ring after the ring-opening of three-membered cycle, which is different from the Pd(PPh3)2Cl2-catalyzed reaction. Based on a careful NMR study, we concluded that it may be explained by the ligand effect. PMID- 26579857 TI - The Facial Profile. PMID- 26579858 TI - The Facial Profile in the Context of Facial Aesthetics. AB - Beauty has been an intriguing issue since the evolving of a culture in mankind. Even the Neanderthals are believed to have applied makeover to enhance facial structures and thus underline beauty. The determinants of beauty and aesthetics have been defined by artists and scientists alike. This article will give an overview of the evolvement of a beauty concept and the significance of the facial profile. It aims at sharpening the senses of the facial plastic surgeon for analyzing the patient's face, consulting the patient on feasible options, planning, and conducting surgery in the most individualized way. PMID- 26579859 TI - Fast and Accurate Digital Morphometry of Facial Expressions. AB - Facial surgery deals with a part of the human body that is of particular importance in everyday social interactions. The perception of a person's natural, emotional, and social appearance is significantly influenced by one's expression. This is why facial dynamics has been increasingly studied by both artists and scholars since the mid-Renaissance. Currently, facial dynamics and their importance in the perception of a patient's identity play a fundamental role in planning facial surgery. Assistance is needed for patient information and communication, and documentation and evaluation of the treatment as well as during the surgical procedure. Here, the quantitative assessment of morphological features has been facilitated by the emergence of diverse digital imaging modalities in the last decades. Unfortunately, the manual data preparation usually needed for further quantitative analysis of the digitized head models (surface registration, landmark annotation) is time-consuming, and thus inhibits its use for treatment planning and communication. In this article, we refer to historical studies on facial dynamics, briefly present related work from the field of facial surgery, and draw implications for further developments in this context. A prototypical stereophotogrammetric system for high-quality assessment of patient-specific 3D dynamic morphology is described. An individual statistical model of several facial expressions is computed, and possibilities to address a broad range of clinical questions in facial surgery are demonstrated. PMID- 26579860 TI - The Nose Influences Visual and Personality Perception. AB - Nasal deformities are known to attract attention, are felt to be stigmatizing, and are known to affect negatively the perception of personalities. These effects have not been studied on profile views. The objective of this study was the quantification of visual attention directed toward nasal deformities and its impact on the perception of personality traits. Forty observers were divided into two groups and their visual scanpaths were recorded. Both groups observed a series of photographs displaying profile views of 20 adult patients' faces with one or more nasal deformities or computer-morphed corrected noses. Photographs were chosen from a consecutive sample of patients (range: 17-68 years, median: 45) who requested a rhinoplasty at the Department of Otolaryngology, Head and Neck Surgery, Facial Plastic Surgery of the Cantonal Hospital Sankt Gallen, Switzerland. Patients' photographs showed a nasal deformity in one series and a computer-morphed nose in the other series and vice versa. Visual fixation times on the noses were compared between the photographs with and without a nasal deformity. Observers subsequently rated personality traits using visual analog scales. The nasal profile with a deformity received more visual attention in 17 of 20 patients (85%). The mean relative fixation duration of all nasal deformities was significantly larger compared with all computer-simulated noses (17.3 +/- 6.9 [SD] vs. 10.6 +/- 2.5%; p < 0.001). Cumulative personality questionnaire scores and the score for satisfaction were significantly lower for faces with nasal deformities compared with computer-morphed noses (27.8 +/- 6.0 vs. 29.1 +/- 6.0, p = 0.040, and 5.3 +/- 1.59 vs. 5.7 +/- 1.53, p = 0.017, respectively). For deformed noses, the mean relative fixation duration did not correlate with the cumulative personality score (R = - 0.399; p = 0.082). To the best knowledge of the authors, an attention-drawing potential of nasal deformities on a profile view has been quantified for the first time. This seems to lead to a more negative perception of personality traits. PMID- 26579861 TI - Computational Planning in Facial Surgery. AB - This article reflects the research of the last two decades in computational planning for cranio-maxillofacial surgery. Model-guided and computer-assisted surgery planning has tremendously developed due to ever increasing computational capabilities. Simulators for education, planning, and training of surgery are often compared with flight simulators, where maneuvers are also trained to reduce a possible risk of failure. Meanwhile, digital patient models can be derived from medical image data with astonishing accuracy and thus can serve for model surgery to derive a surgical template model that represents the envisaged result. Computerized surgical planning approaches, however, are often still explorative, meaning that a surgeon tries to find a therapeutic concept based on his or her expertise using computational tools that are mimicking real procedures. Future perspectives of an improved computerized planning may be that surgical objectives will be generated algorithmically by employing mathematical modeling, simulation, and optimization techniques. Planning systems thus act as intelligent decision support systems. However, surgeons can still use the existing tools to vary the proposed approach, but they mainly focus on how to transfer objectives into reality. Such a development may result in a paradigm shift for future surgery planning. PMID- 26579862 TI - Navigation in Orthognathic Surgery: 3D Accuracy. AB - This article aims to determine the absolute accuracy of maxillary repositioning during orthognathic surgery according to simulation-guided navigation, that is, the combination of navigation and three-dimensional (3D) virtual surgery. We retrospectively studied 15 patients treated for asymmetric dentofacial deformities at the Oral and Maxillofacial Surgery Unit of the S.Orsola-Malpighi University Hospital in Bologna, Italy, from January 2010 to January 2012. Patients were scanned with a cone-beam computed tomography before and after surgery. The virtual surgical simulation was realized with a dedicated software and loaded on a navigation system to improve intraoperative reproducibility of the preoperative planning. We analyzed the outcome following two protocols: (1) planning versus postoperative 3D surface analysis; (2) planning versus postoperative point-based analysis. For 3D surface comparison, the mean Hausdorff distance was measured, and median among cases was 0.99 mm. Median reproducibility < 1 mm was 61.88% and median reproducibility < 2 mm was 85.46%. For the point based analysis, with sign, the median distance was 0.75 mm in the frontal axis, 0.05 mm in the caudal-cranial axis, -0.35 mm in the lateral axis. In absolute value, the median distance was 1.19 mm in the frontal axis, 0.59 mm in the caudal cranial axis, and 1.02 mm in the lateral axis. We suggest that simulation-guided navigation makes accurate postoperative outcomes possible for maxillary repositioning in orthognathic surgery, if compared with the surgical computer designed project realized with a dedicated software, particularly for the vertical dimension, which is the most challenging to manage. PMID- 26579863 TI - Computer-Designed Splints for Surgical Transfer of 3D Orthognathic Planning. AB - Advances in computers and imaging have permitted the adoption of three dimensional (3D) planning protocols in orthognathic surgery, which may allow a paradigm shift when the computer-assisted planning can be transferred properly. The purpose of this investigation was to introduce an innovative clinical protocol using computer-aided designed and computer-aided manufactured (CAD/CAM) surgical splints for surgical transfer of 3D orthognathic planning compared with the classic technique using arbitrary occlusal splints. The clinical protocols consisted of computed tomography (CT) or cone-beam CT (CBCT) maxillofacial imaging, bone segmentation, 3D diagnosis, computer-assisted surgical treatment planning, and CAD/CAM surgical splints (group A) and manufacture of arbitrary occlusal splints (group B) for intraoperative surgical planning transfer. The observed patients underwent bimaxillary osteotomies and, if necessary, an additional genioplasty. Both techniques were evaluated by applying 13 hard tissue parameters to compare the 3D orthognathic planning (T0) with the postoperative result (T1) using 3D cephalometry. The CAD/CAM splints showed significant better precision for the maxilla (DeltaT < 0.23 mm) and mandible (DeltaT < 0.33 mm) compared with a maxillary deviation of 1.3 mm and a mandibular deviation of 1.8 mm when using the arbitrary splints. Computer-assisted diagnosis and preoperative surgical planning provide clinicians with valuable tools and allow 3D imagination. CAD/CAM splints provide a reliable, innovative, and precise approach for the transfer of 3D orthognathic planning, which is more precise compared with the conventional arbitrary occlusal splints. PMID- 26579864 TI - Facelift 2015. AB - Among the current topics, one that is more commonly discussed is that of the mini invasive or "soft" techniques that seem to attract doctors and patients more than real surgery. We instead propose a relatively aggressive technique that can really rejuvenate the faces and necks of our patients. Are we not in step with the times? The problem is, unfortunately, that until now there is nothing that, without anesthesia, swelling, bruising, and so forth, can magically bring about the result of a well-done facelift. There are no "thread lifts" or fillings or endopeels or weird devices using radiofrequency, ultrasound, or shock waves-the list could go on forever-that can compare with a properly performed facelift. But how should a good facelift be done? For many years, we have been using the protocol described in this article, and the request for facelifts has not dropped, despite never having used advertising in our practice. We want to give our patients natural and long-lasting results, and for this purpose we must use an effective and individualized technique, even if it implies a relatively long down time. In this article, we describe the technical choices that we have made based on a long clinical experience and on detailed anatomical studies. Most difficulties that are encountered with this type of surgery concern finding the proper dissection plane and the proper amount of traction to be applied to the different tissue layers. It is indeed not at all easy, especially for a beginner, to be sure that one has reached the proper depth of dissection, which will allow the elevation of the superficial musculo-aponeurotic system (SMAS) in a risk-free manner even in the area which is medial to the anterior border of the parotid gland where the facial nerve is no longer protected by the gland itself. We will nevertheless try to provide precise indications concerning every important detail needed to perform the operation safely. PMID- 26579865 TI - Dentofacial Composition: An Entire Aesthetic Concept. AB - The aesthetic appearance of the mouth region, in addition to the eye and nose area, is the impressive element for facial aesthetics. Therefore, the reconstruction of the intraoral region is very important for the facial aesthetics in the case of genetic dysplasia, trauma, or even in cases for rejuvenating purposes only. The entire region is complex so that in many patient cases only the team work of restorative dentists, surgeons, and orthodontists will be effective. A key role is played here by the dental technician. Besides the frequent necessity of osseous augmentation, the mucogingival complex needs to be, in most cases, harmonized and reconstructed, respectively. There is often a lack of keratinized gingiva and disturbing cicatrice tracks. Quite frequently the mucogingival appearance is also unsatisfactory due to preceding operations and attempted plastic coverages. The aim of this report is to describe the successful surgical and prosthetic treatment of aesthetically and functionally impaired intraoral hard and soft tissue. For surgeons who are interested in aesthetics, it is advisable to learn from experiences of a specialized restorative dentist, oral surgeon, and orthodontist. PMID- 26579866 TI - Genioplasty. AB - With increasing aesthetic awareness, in addition to the forehead, nose, and cheekbone prominence, the chin nowadays is seen as one of the most important parts of the facial skeleton. The size and location of these areas of the skeleton in relation to the skull base and their three-dimensional positional relationship to each other are essential and contribute the individuality of a human face. The position of the chin has a strong influence on the assessment of the facial harmony; its different types and forms dominate the appearance. Furthermore, the expression of the chin is equated with character traits and thus it is an important component of the profile forms. Genioplasty is a routine procedure for the correction of aesthetic and functional deformity of the chin region. It is therefore one of the contour-enhancing surgical methods. PMID- 26579867 TI - Comparison of Two Kinds of Lasers in the Treatment of Acne Scars. AB - Acne scars are common and stigmatizing for the affected patients. Besides surgery, chemical peels, microdermabrasion, and microneedling, the treatment with fractional laser is a standard therapy. The results of reducing acne scars treated either with a fractional Er:YAG (erbium-doped yttrium-aluminum-garnet [Er:Y3Al5O1]) or a carbon dioxide (CO 2 ) laser at different wavelengths were compared and evaluated in the pilot study presented here. Fourteen patients with severe scars on both cheeks were treated four times in a random split-face approach: on one side with Er:YAG laser and on the contralateral side with CO2 laser following a standardized protocol. Therapeutic success was evaluated through the use of a high-resolution, 3D small-field capture system (PRIMOS), digital photography, and the Patient and Observer Scar Assessment Scale (POSAS) questionnaire. The evaluation was performed by a blinded investigator. Treatment results displayed a higher efficacy of the fractional CO2 laser compared with the Er:YAG laser as displayed by digital photographs. Additionally, objective (high resolution, 3D small-field capture; PRIMOS) and subjective (POSAS) measuring results correlated positively in certain qualities (color, stiffness, thickness, surface, overall opinion). Using a novel scientific approach, we evaluated the therapeutic efficacy of different fractional lasers on acne scars using a rater blinded approach. Compared with an Er:YAG laser, better skin smoothening was achieved by fractional CO2 laser treatment. PMID- 26579868 TI - A Rare Late Complication of Rhinoplasty: Dorsal Nasal Cyst. PMID- 26579869 TI - Prefabricated Composite Graft for Eyelid Reconstruction. AB - The authors propose a prefabricated chondromucosal composite graft to reconstruct full-thickness defects of the lower eyelid. The technique was used in a patient suffering from a locally invasive basal cell carcinoma of the lower eyelid, who had previously undergone an extensive submucosal nasal septum resection. One week prior to the eyelid resection, the anterior skin surface of the auricular concha was replaced with a full-thickness oral mucosa graft. One week later, a full thickness excision of the right lower eyelid was performed and the prefabricated chondromucosal auricular graft was used to restore the posterior lamella. The anterior lamella was reconstructed with a bipedicled myocutaneous flap from the upper eyelid. Because of the patient's scheduling needs, the medial pedicle of the flap was divided 28 days later and the lateral one after further 37 days. All the procedures were performed under local anesthesia. This technique adds a simple key detail to other time-honored reliable techniques, thus outlining an extremely convenient sequence for full-thickness eyelid reconstruction. The easily prepared prefabricated chondromucosal graft might be associated with any of the previously described flaps, thus providing a versatile and reliable method of posterior lamella reconstruction. PMID- 26579870 TI - Rhinoplasty in Clefts: An 18-Year Retrospective Review. AB - Cleft rhinoplasty has spurred much interest in literature because of the difficult task in obtaining a normal nasal form, function, and development. The pursuit of perfection has resulted in myriad techniques, modifications, and innovations to optimize results, but no one protocol or algorithm was proved to be completely satisfactory. Controversies still exist in timing, surgical approach, nonsurgical techniques, and outcome assessment. This article submits a humble contribution that might hopefully help in reaching consensus. Throughout a period of 18 years, 800 patients with different ages and types of clefts were managed by single surgeon using various procedures to correct their nasal deformities. These procedures included preoperative naso-alveolar molding, gingivoperiosteoplasty, primary closed or open rhinoplasty, postoperative nasal stents and nasal molding, and secondary open septorhinoplasty. The outcome was judged by panel assessment and computer-assisted anthropometry. Clinical results were satisfactory for most patients, parents, and surgeon panel. Computer assisted anthropometry proved helpful in outcome assessment and analysis. Cleft rhinoplasty is neither optional nor separable from cleft lip repair. It requires clear perception of the complex pathogenesis and the governing dynamics of the cleft deformity. A perfect nose with no deformity is unusual, but a reasonably good result is attainable when the principles of nasal repair are fully grasped and faithfully applied. PMID- 26579871 TI - Similar Fracture Patterns in Human Nose and Gothic Cathedral. AB - This study proposes that the bony anatomy of the human nose and masonry structure of the Gothic cathedral are geometrically similar, and have common fracture patterns. We also aim to correlate the fracture patterns observed in patients' midface structures with those seen in the Gothic cathedral using computational approach. CT scans of 33 patients with facial fractures were examined and compared with computer simulations of both the Gothic cathedral and human nose. Three similar patterns were found: (1) Cracks of the nasal arch with crumpling of the vertical buttresses akin to the damage seen during minor earthquakes; (2) lateral deviation of the central nasal arch and collapse of the vertical buttresses akin to those due to lateral forces from wind and in major earthquakes; and (3) Central arch collapse seen as a result of collapse under excessive dead weight. Interestingly, the finding of occult nasal and septal fractures in the mandible fractures with absence of direct nasal trauma highlights the possibility of transmission of forces from the foundation to the arch leading to structural failure. It was also found that the structural buttresses of the Gothic cathedral delineate the vertical buttresses in the human midface structure. These morphologic similarities between the human nose and Gothic cathedral will serve as a basis to study the biomechanics of nasal fractures. Identification of structural buttresses in a skeletal structure has important implications for reconstruction as reestablishment of structural continuity restores normal anatomy and architectural stability of the human midface structure. PMID- 26579872 TI - Lmo4 and Other LIM domain only factors are necessary and sufficient for multiple retinal cell type development. AB - Understanding the molecular basis by which distinct cell types are specified is a central issue in retinogenesis and retinal disease development. Here we examined the role of LIM domain only 4 (Lmo4) in retinal development using both gain-of function and loss-of-function approaches. By immunostaining, Lmo4 was found to be expressed in mouse retina from E10.5 to mature stages. Retroviral delivery of Lmo4 into retinal progenitor cells could promote the amacrine, bipolar and Muller cell fates at the expense of photoreceptors. It also inhibited the fate of early born retinal ganglion cells. Using a dominant-negative form of Lmo4 which suppresses transcriptional activities of all LIM domain only factors, we demonstrated that LIM domain only factors are both necessary and sufficient for promoting amacrine and bipolar cell development, but not for the differentiation of ganglion, horizontal, Muller, or photoreceptor cells. Taken together, our study uncovers multiple roles of Lmo4 during retinal development and demonstrates the importance of LIM domain only factors in ensuring proper retinal cell specification and differentiation. (c) 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 900-915, 2016. PMID- 26579873 TI - Water exposure--challenging differences between occupations. AB - BACKGROUND: Few studies have compared water exposure between different occupations in the general population. OBJECTIVES: To investigate and compare the extent of occupational water exposure, with a focus on service, healthcare and production occupations previously classified as involving a high risk for hand eczema. METHODS: In two public health surveys (2006 and 2010), a validated question regarding occupational water exposure was answered by 18 342 and 15,736 gainfully employed individuals, respectively. RESULTS: Exposure for >= 0.5 h/day was reported by 17.5% and 16.3% (p = 0.020) for the respective years, and exposure for > 2 h/day by 7.8% and 7.7% (p = 0.73). Exposure in women was almost twice as high as in men for both years (p <= 0.001) and exposure levels (p < 0.001). Exposure for > 2 h/day was more common in high-risk occupations in service and healthcare than in non-high-risk occupations [prevalence proportion ratios of 16.7 (95%CI: 14.0-20.0) and 8.3 (95%CI: 6.9-9.9), respectively]. Exposure was highest in service occupations, where 44.6% reported exposure for > 2 h/day in 2010, and kitchen work, cleaning and hairdressing dominated. In healthcare, the corresponding figure was 22.0%. CONCLUSIONS: Challenging differences in water exposure between occupational groups were found, and extensive water exposure was reported in a number of occupations previously classified as involving a high risk for hand eczema. PMID- 26579874 TI - Preparation and Characterization of Amylose Inclusion Complexes for Drug Delivery Applications. AB - Amylose complexes with nimesulide (NMS) and praziquantel (PZQ) were prepared by a simple and low cost method, so that high yield (>57%) and drug content (up to 68.16%) were achieved. The influence of drug:polymer ratio, temperature, and presence of palmitic acid on the complexes properties was evaluated. Differential scanning calorimetry, X-ray diffraction, and nuclear magnetic resonance data evidenced the drug-polymer interaction and the formation of inclusion complexes with semi-crystalline structures related to type II complexes. The drug release rates from complexes were lowered in acid media (pH 1.2) and phosphate buffer (pH 6.9). The presence of pancreatin promoted a significant acceleration of the release rates of both drugs, evidencing the enzymatic degradability of these complexes. The highest enzymatic resistance of PZQ1:30PA60 degrees C complex makes the release time longer and the full release of PZQ in phosphate buffer with pancreatin occurred at 240 min, whereas the complexes with NMS and PZQ1:5PA90 degrees C did it in 60 min. According to the Weibull model, the drug release process in media without enzyme occurred by complex mechanisms involving diffusion, swelling, and erosion. In media containing pancreatin, generally, the better correlation was with the first order, evidencing the acceleration of the release rates of drugs in the early stages of the test, due to enzymatic degradation. PMID- 26579875 TI - Strong metal-support interaction in novel core-shell Au-CeO2 nanostructures induced by different pretreatment atmospheres and its influence on CO oxidation. AB - Yolk-shell Au/CeO2 (Y-Au/CeO2) and encapsulated Au/CeO2 (E-Au/CeO2) nanocatalysts were prepared by using silica templates. A strong metal-support interaction (SMSI) in the Au/CeO2 nanostructures induced by different pretreatment atmospheres and its influence on CO oxidation were studied. E-Au/CeO2 pretreated in O2 had the best performance, followed by Y-Au/CeO2 pretreated in O2, Y-Au/CeO2 pretreated in H2, and E-Au/CeO2 pretreated in H2. The reasons for the different activities were discussed. There were two kinds of strong metal-support interactions (SMSI) between Au and CeO2 termed as R-SMSI (pretreated in reductive atmosphere) and O-SMSI (pretreated in oxidation atmosphere). Because of the smaller size of the Au and the larger contact area, both the R-SMSI and O-SMSI of E-Au/CeO2 were larger than those of Y-Au/CeO2. The O-SMSI was accompanied by the formation of cationic Au species that were beneficial to the enhancing of activity. As expected, the activity of E-Au/CeO2 pretreated in O2 with a Au size less than 5 nm was higher than that of Y-Au/CeO2 pretreated in O2 with 25 nm Au. However, it is surprisingly found that the activity of Y-Au/CeO2 pretreated in H2 with 25 nm Au was higher than that of E-Au/CeO2 pretreated in H2 with a Au size less than 5 nm. R-SMSI resulted in the formation of a AuCe alloy that had a negative effect on the activity. Compared with E-Au/CeO2 pretreated in H2, Y Au/CeO2 pretreated in H2 exhibited a smaller relative content of the AuCe alloy, leading to a better activity of Y-Au/CeO2 pretreated in H2. PMID- 26579876 TI - The naming game: A discrepancy among the medical community. AB - As anatomists we rely on the nomenclature of structures in order to describe them appropriately, particularly their orientation in respect to their surrounding. The terminology used by the anatomist to describe an organ, muscle, or nerve within the body is taught to medical students as law. Students learn to describe structures in the "anatomical position", which has been accepted in the literature since the original Latin Nomina Anatomica. They therefore familiarize themselves with the use of terms such as superior, inferior, posterior and anterior to describe all anatomical structures, except in respect of the heart. The heart is still described in the original Valentine position. As anatomists we owe it to the medical and research community to correct the nomenclature to minimize confusion, and to describe the heart properly in respect to its surrounding structures. PMID- 26579877 TI - Compositional Factors that Influence Lipid Peroxidation in Beef Juice and Standard Sausages. AB - In order to identify how different additives influenced lipid peroxidation formation, a sausage only using beef juice as pigment source and a standard beef pork meat sausage were studied. The effects of different additives, including fish oil, myoglobin, nitrite, clove extract, and calcium sources on oxidation and sensory properties were examined. Both sausage systems were stored in 3 different manners prior to testing: (1) frozen immediately at -80 degrees C; (2) chilled stored for 2.5 weeks followed by fluorescent light illumination at 4 degrees C for another 2 wk; (3) frozen at -20 degrees C for 5 mo. The frozen group 3 showed the highest peroxide formation and thiobarbituric acid reactive substances (TBARS) for both sausage systems. Unpolar peroxides dominated in both systems. The clove extract could offset the peroxide formation from myoglobin/beef juice and/or fish oil, but the addition of clove flavor was recognized by the sensory panelists. Calcium addition reduced lipid peroxide formation. Added nitrite and fish oil seemed to interact to stimulate nitroso-myoglobin formation. Nitrite was identified to interact with clove addition and thereby, relatively speaking, increased TBARS. The 2 sausage systems generally ranked the additives similarly as pro- and antioxidants. PMID- 26579878 TI - Rapid skeletal muscle wasting predicts worse survival in patients with liver cirrhosis. AB - AIM: Sarcopenia impairs the outcome of patients with liver cirrhosis independently of liver function reserves. The aim of this study was to investigate whether the rate of skeletal muscle wasting predicts mortality in cirrhotic patients. METHODS: This retrospective study evaluated 149 cirrhotic patients who visited our hospital between March 2004 and September 2012. The skeletal muscle cross-sectional area at the level of the third lumbar vertebra was measured by computed tomography, from which the skeletal muscle index was obtained for diagnosis of sarcopenia. The relative change in skeletal muscle area per year (DeltaSMA/y) was calculated in each patient. Cox proportional hazards regression analysis was performed to evaluate risk factors for mortality. RESULTS: Of the 149 cirrhotic patients, 94 (63%) were diagnosed with sarcopenia. The median of DeltaSMA/y in all patients was -2.2%. For patients in Child-Pugh class A, B and C, DeltaSMA/y was -1.3%, -3.5% and -6.1%, respectively. During a median follow-up period of 39 months (range, 1-110), 45 patients (30%) died. The optimal cut-off value of DeltaSMA/y for predicting mortality was -3.1%; the survival rate in patients with DeltaSMA/y of -3.1% or less was significantly lower than in patients with DeltaSMA/y of more than -3.1% (P < 0.0001). The multivariate Cox proportional hazards model found DeltaSMA/y of -3.1% or less to be significantly associated with mortality in cirrhotic patients (hazard ratio = 2.73, 95% confidence interval = 1.43-5.44, P < 0.01). CONCLUSION: DeltaSMA/y is useful for predicting mortality in patients with liver cirrhosis. Management of skeletal muscle may contribute toward improving the outcome of cirrhotic patients. PMID- 26579880 TI - Non-monotonic course of protein solubility in aqueous polymer-salt solutions can be modeled using the sol-mxDLVO model. AB - Protein purification is often performed using cost-intensive chromatographic steps. To discover economic alternatives (e.g., crystallization), knowledge on protein solubility as a function of temperature, pH, and additives in solution as well as their concentration is required. State-of-the-art models for predicting protein solubility almost exclusively consider aqueous salt systems, whereas "salting-in" and "salting-out" effects induced by the presence of an additional polymer are not considered. Thus, we developed the sol-mxDLVO model. Using this newly developed model, protein solubility in the presence of one salt and one polymer, especially the non-monotonic course of protein solubility, could be predicted. Systems considered included salts (NaCl, Na-p-Ts, (NH(4))(2) SO(4)) and the polymer polyethylene glycol (MW: 2000 g/mol, 12000 g/mol) and proteins lysozyme from chicken egg white (pH 4 to 5.5) and D-xylose ketol-isomerase (pH 7) at 298.15 K. The results show that by using the sol-mxDLVO model, protein solubility in polymer-salt solutions can be modeled in good agreement with the experimental data for both proteins considered. The sol-mxDLVO model can describe the non-monotonic course of protein solubility as a function of polymer concentration and salt concentration, previously not covered by state-of-the-art models. PMID- 26579879 TI - Pilot Study of Adding Vincristine, Topotecan, and Cyclophosphamide to Interval Compressed Chemotherapy in Newly Diagnosed Patients With Localized Ewing Sarcoma: A Report From the Children's Oncology Group. AB - BACKGROUND: The combination of topotecan and cyclophosphamide is active in relapsed Ewing sarcoma family of tumors (ESFT). The feasibility of adding these agents combined with vincristine (vincristine-topotecan-cyclophosphamide [VTc]) to standard five-drug chemotherapy with vincristine-doxorubicin-cyclophosphamide (VDC) and ifosfamide-etoposide (IE) administered in an interval-compressed (2 week instead of 3-week intervals) schedule was investigated. PROCEDURE: Newly diagnosed patients with localized ESFT < 31 years, with good performance status and adequate organ function were eligible. Seventeen alternating cycles of chemotherapy with VTc, VDC, and IE were administered at 2-week intervals. Local control (LC) of the primary tumor occurred following six cycles. Primary endpoints were the ability to deliver chemotherapy in an interval-compressed schedule, and the rate of grade 3 or greater nonhematologic toxicity and grade 4 hematologic toxicity, which delayed chemotherapy by >=2 weeks. Secondary endpoints were event-free survival (EFS) and overall survival (OS). RESULTS: Thirty-five patients with a median age of 11 years were enrolled. The mean time to last dose of chemotherapy prior to LC was 12.6 +/- 1.4 weeks and 45.5% of patients received intended chemotherapy without any delay prior to LC. There were no toxic deaths or unexpected toxicities. Five-year EFS was 79.6% (95% confidence interval [CI]: 61.8-89.7%) and 5-year OS was 88% (95% CI: 71.4-95.3%). CONCLUSIONS: The addition of VTc to standard therapy was tolerable with sufficient interval compression compared to historical standard 3-week cycles. PMID- 26579881 TI - Oxidative stress and antioxidant parameters in patients with major depressive disorder compared to healthy controls before and after antidepressant treatment: results from a meta-analysis. AB - OBJECTIVE: To investigate the role of oxidative stress and antioxidants in depression. DATA SOURCES: We searched the literature without language restrictions through MEDLINE/PubMed, Cochrane Library, Fisterra, and Galenicom from database inception until December 31, 2013, supplemented by a hand search of relevant articles. Search terms included (1) oxidative stress, antioxidant*, nitrosative stress, nitrative stress, nitro-oxidative stress, free radical*, and names of individual oxidative stress markers/antioxidants and (2) depression and related disorders and antidepressant. STUDY SELECTION: Included were studies in patients with depression comparing antioxidant or oxidative stress markers with those in healthy controls before and after antidepressant treatment. DATA EXTRACTION: Two authors independently extracted the data for antioxidant or oxidative stress markers. Standardized mean differences (SMDs) +/- 95% confidence intervals (CIs) for results from >= 3 studies were calculated. DATA SYNTHESIS: Altogether, 29 studies (N = 3,961; patients with depression = 2,477, healthy controls = 1,484) reported on the oxidative stress marker malondialdehyde (MDA) and total nitrites, the antioxidants uric acid and zinc, or the antioxidant enhancing enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX). When patients with depression were compared with healthy controls, depression was associated with higher oxidative stress MDA levels (8 studies; n = 916; SMD = 1.34; 95% CI, 0.57 to 2.11; P < .001), lower antioxidant uric acid (4 studies; n = 512; SMD = -0.64; 95% CI, -1.22 to -0.06; P = .030) and zinc levels (13 studies; n = 2,002; SMD = -0.66; 95% CI, -0.98 to -0.34; P < .0001), and higher antioxidant-enhancing enzyme SOD levels (11 studies; n = 902; SMD = 0.62; 95% CI, 0.07 to 1.17; P = .028), while differences in total nitrites and CAT and GPX were nonsignificant. Antidepressant treatment, which significantly reduced Hamilton Depression Rating Scale scores (24.6 +/- 0.7 to 16.2 +/- 1.6; SMD = 2.65; 95% CI, 1.13 to 4.15; P = .00065), reduced MDA (4 studies; n = 194; SMD = -1.45; 95% CI, -2.43 to -0.47; P = .004) and increased uric acid (3 studies; n = 212; SMD = 0.76; 95% CI, 0.03 to 1.49; P = .040) and zinc levels (3 studies; n = 65; SMD = 1.22; 95% CI, 0.40 to 2.04, P = .004), without differences in MDA (P = .60), uric acid (P = .10), and zinc (P = .163) levels compared to healthy controls. CONCLUSIONS: Results suggest that oxidative stress plays a role in depression and that antidepressant activity may be mediated via improving oxidative stress/antioxidant function. PMID- 26579882 TI - Multitriggered Shape-Memory Acrylamide-DNA Hydrogels. AB - Acrylamide-acrylamide nucleic acids are cross-linked by two cooperative functional motives to form shaped acrylamide-DNA hydrogels. One of the cross linking motives responds to an external trigger, leading to the dissociation of one of the stimuli-responsive bridges, and to the transition of the stiff shaped hydrogels into soft shapeless states, where the residual bridging units, due to the chains entanglement, provide an intrinsic memory for the reshaping of the hydrogels. Subjecting the shapeless states to counter stimuli restores the dissociated bridges, and regenerates the original shape of the hydrogels. By the cyclic dissociation and reassembly of the stimuli-responsive bridges, the reversible switchable transitions of the hydrogels between stiff shaped hydrogel structures and soft shapeless states are demonstrated. Shaped hydrogels bridged by K(+)-stabilized G-quadruplexes/duplex units, by i-motif/duplex units, or by two different duplex bridges are described. The cyclic transitions of the hydrogels between shaped and shapeless states are stimulated, in the presence of appropriate triggers and counter triggers (K(+) ion/crown ether; pH = 5.0/8.0; fuel/antifuel strands). The shape-memory hydrogels are integrated into shaped two hydrogel or three-hydrogel hybrid structures. The cyclic programmed transitions of selective domains of the hybrid structures between shaped hydrogel and shapeless states are demonstrated. The possible applications of the shape-memory hydrogels for sensing, inscription of information, and controlled release of loads are discussed. PMID- 26579883 TI - Surface Dipoles: A Growing Body of Evidence Supports Their Impact and Importance. AB - Surface dipoles arise from differences in the distribution of electron density of interfacial molecular structures as expressed by charge separation. The direction and magnitude of the associated dipole moments directly impact a variety of interfacial phenomena. For example, the wettability of thin film-coated solid surfaces toward polar contacting liquids can be systematically adjusted by reorienting the direction of an array of interfacial dipoles, while the vector sum total of all of the dipole moments associated with such thin films can be used to tune the work function of a metal. One method of producing such dipole arrays is by coating a surface with a self-assembled monolayer (SAM), which is a thin organic film of amphiphilic adsorbates that spontaneously assemble on a surface. The interfacial properties of SAMs can be menu-selected by choice of adsorbate structure using omega-terminated thiols on gold surfaces as a convenient system for studying and utilizing these properties. In this Account, we describe the impact of an array of oriented surface dipoles upon the interfacial energy of the thin film bearing such an array. Our analysis of these films divides the subject of surface dipole arrays into three types: (1) those directing a well-defined electronegative pole toward the interface, (2) those incorporating an invertable polar group, and (3) those directing a well-defined electropositive pole toward the interface. With regard to the first category, we analyze the impact of permanent dipoles on the wettability of alkanethiolate SAMs generated from adsorbates possessing well-defined transitions between terminal fluorocarbon and underlying hydrocarbon chain segments. The second category covers recent reports of light-responsive SAMs formed from azobenzene-based adsorbates. Finally, the third category explores a unique example of a dipole array that exposes the positive ends of the interfacial dipoles formed from CH3 terminated fluorocarbon tailgroups. Our analysis of the SAMs formed from these carefully crafted adsorbates encompassing several series of fluorocarbon containing thiols provides support for a conclusion that oriented surface dipoles exert a significant influence on interfacial energetics and wettability. In contrast to the limited distance from the interface that a surface dipole array will have upon contacting liquids, the work function of a thin film reflects the influence of all the polar groups within the film. Therefore, we also explore the change in the substrate work function for n-alkanethiol-modified gold surfaces as a function of molecular length and for other adsorbates as a function of their chemical composition. PMID- 26579884 TI - Iron-Catalyzed Divergent Tandem Radical Annulation of Aldehydes with Olefins toward Indolines and Dihydropyrans. AB - Iron-catalyzed divergent tandem radical annulations of aldehydes with olefins are reported. The new strategy allows the rapid and efficient construction of various multifunctionlized indolines (R = Ar) and dihydropyrans (R = Me), which are significant skeletons in bioactive natural products and pharmaceuticals. The substituents of tertiary amines play vital roles to facilitate the desired transformation. Mechanistic studies on indoline formation disclose that the homolytic cleavage of the carbonyl C-H bond might be involved in the rate determining step, while dissociation of the aromatic C-H bond was most likely included in the product-determining step. PMID- 26579885 TI - On the optimum resolution of transmission-electron backscattered diffraction (t EBSD). AB - The work presented aims at determining the optimum physical resolution of the transmission-electron backscattered diffraction (t-EBSD) technique. The resolution depends critically on intrinsic factors such as the density, atomic number and thickness of the specimen but also on the extrinsic experimental set up of the electron beam voltage, specimen tilt and detector position. In the present study, the so-called physical resolution of a typical t-EBSD set-up was determined with the use of Monte Carlo simulations and confronted to experimental findings. In the case of a thin Au film of 20 nm, the best resolution obtained was 9 nm whereas for a 100 nm Au film the best resolution was 66 nm. The precise dependence of resolution on thickness was found to vary differently depending on the specific elements involved. This means that the resolution of each specimen should be determined individually. Experimentally the median probe size of the t EBSD for a 140 nm thick AuAg specimen was measured to be 87 nm. The first and third quartiles of the probe size measurements were found to be 60 nm and 118 nm. Simulation of this specimen resulted in a resolution of 94 nm which fits between these quartiles. PMID- 26579886 TI - Microstructure-Dependent Gas Adsorption: Accurate Predictions of Methane Uptake in Nanoporous Carbons. AB - We present a framework for rapidly predicting gas adsorption properties based on van der Waals density functional calculations and thermodynamic modeling. Utilizing this model and experimentally determined pore size distributions, we are able to accurately predict uptakes in five activated carbon materials without empirical potentials or lengthy simulations. Our results demonstrate that materials with smaller pores and higher heats of adsorption can still have poor adsorption characteristics due to relatively low densities of highly adsorbent pores. PMID- 26579887 TI - Molecular Dynamics Studies of Liposomes as Carriers for Photosensitizing Drugs: Development, Validation, and Simulations with a Coarse-Grained Model. AB - Liposomes are proposed as drug delivery systems and can in principle be designed so as to cohere with specific tissue types or local environments. However, little detail is known about the exact mechanisms for drug delivery and the distributions of drug molecules inside the lipid carrier. In the current work, a coarse-grained (CG) liposome model is developed, consisting of over 2500 lipids, with varying degrees of drug loading. For the drug molecule, we chose hypericin, a natural compound proposed for use in photodynamic therapy, for which a CG model was derived and benchmarked against corresponding atomistic membrane bilayer model simulations. Liposomes with 21-84 hypericin molecules were generated and subjected to 10 microsecond simulations. Distribution of the hypericins, their orientations within the lipid bilayer, and the potential of mean force for transferring a hypericin molecule from the interior aqueous "droplet" through the liposome bilayer are reported herein. PMID- 26579889 TI - Prediction of Small Molecule Hydration Thermodynamics with Grid Cell Theory. AB - An efficient methodology has been developed to quantify water energetics by analysis of explicit solvent molecular simulations of organic and biomolecular systems. The approach, grid cell theory (GCT), relies on a discretization of the cell theory methodology on a three-dimensional grid to spatially resolve the density, enthalpy, and entropy of water molecules in the vicinity of solute(s) of interest. Entropies of hydration are found to converge more efficiently than enthalpies of hydration. GCT predictions of free energies of hydration on a data set of small molecules are strongly correlated with thermodynamic integration predictions. Agreement with the experiment is comparable for both approaches. A key advantage of GCT is its ability to provide from a single simulation insightful graphical analyses of spatially resolved components of the enthalpies and entropies of hydration. PMID- 26579888 TI - Nonadiabatic Ensemble Simulations of cis-Stilbene and cis-Azobenzene Photoisomerization. AB - Structurally, stilbene and azobenzene molecules exist in closed and open cis and trans forms, which are able to transform into each other under the influence of light (photoisomerization). To accurately simulate the photoisomerization processes, one must go beyond ground-state (Born-Oppenheimer) calculations and include nonadiabatic coupling between the electronic and vibrational states. We have successfully implemented nonadiabatic couplings and a surface-hopping algorithm within a density functional theory approach that utilizes local orbitals. We demonstrate the effectiveness of our approach by performing molecular dynamics simulations of the cis-trans photoisomerization in both azobenzene and stilbene upon excitation into the S1 state. By generating an ensemble of trajectories, we can gather characteristic transformation times and quantum yields that we will discuss and compare with ultrafast spectroscopic experiments. PMID- 26579890 TI - Comparing Counterpoise-Corrected, Uncorrected, and Averaged Binding Energies for Benchmarking Noncovalent Interactions. PMID- 26579891 TI - Dimers of Dimers (DOD): A New Fragment-Based Method Applied to Large Water Clusters. AB - We have developed a dimer-based two-body interaction model, denoted "dimers of dimers" (DOD), for the study of water clusters using a fragmentation approach. By including a second layer at a lower level of theory (e.g., Hartree-Fock), our DOD2 model accurately reproduces the total energies of water clusters ranging in size from 16 to 100 molecules using the MP2 method with a variety of basis sets. The mean absolute error in the calculated DOD2 total energy for a broad range of calculations is only 0.83 kcal/mol. The size of the fragments is independent of the cluster size, and the number of fragments grows fairly slowly with the cluster size. Our results suggest that our method should be applicable for the study of large water clusters. PMID- 26579892 TI - Reactive Many-Body Expansion for a Protonated Water Cluster. AB - We generalize the standard many-body expansion technique that is used to approximate the total energy of a molecular system to enable the treatment of chemical reactions by quantum chemical techniques. By considering all possible assignments of atoms to monomer units of the many-body expansion and associating suitable weights with each, we construct a potential energy surface that is a smooth function of the nuclear positions. We derive expressions for this reactive many-body expansion energy and describe an algorithm for its evaluation, which scales polynomially with system size, and therefore will make the method feasible for future condensed phase simulations. We demonstrate the accuracy and smoothness of the resulting potential energy surface on a molecular dynamics trajectory of the protonated water hexamer, using the Hartree-Fock method for the many-body term and Moller-Plesset theory for the low order terms of the many-body expansion. PMID- 26579893 TI - Benchmark Assessment of Density Functional Methods on Group II-VI MX (M = Zn, Cd; X = S, Se, Te) Quantum Dots. AB - In this work, we build a benchmark data set of geometrical parameters, vibrational normal modes, and low-lying excitation energies for MX quantum dots, with M = Cd, Zn, and X = S, Se, Te. The reference database has been constructed by ab initio resolution-of-identity second-order approximate coupled cluster RI CC2/def2-TZVPP calculations on (MX)6 model molecules in the wurtzite structure. We have tested 26 exchange-correlation density functionals, ranging from local generalized gradient approximation (GGA) and hybrid GGA to meta-GGA, meta-hybrid, and long-range corrected. The best overall functional is the hybrid PBE0 that outperforms all other functionals, especially for excited state energies, which are of particular relevance for the systems studied here. Among the DFT methodologies with no Hartree-Fock exchange, the M06-L is the best one. Local GGA functionals usually provide satisfactory results for geometrical structures and vibrational frequencies but perform rather poorly for excitation energies. Regarding the CdSe cluster, we also present a test of several basis sets that include relativistic effects via effective core potentials (ECPs) or via the ZORA approximation. The best basis sets in terms of computational efficiency and accuracy are the SBKJC and def2-SV(P). The LANL2DZ basis set, commonly employed nowadays on these types of nanoclusters, performs very disappointingly. Finally, we also provide some suggestions on how to perform calculations on larger systems keeping a balance between computational load and accuracy. PMID- 26579894 TI - Assessment of Perturbative Explicitly Correlated Methods for Prototypes of Multiconfiguration Electronic Structure. PMID- 26579895 TI - Density Functional Theory of Open-Shell Systems. The 3d-Series Transition-Metal Atoms and Their Cations. AB - The 3d-series transition metals (also called the fourth-period transition metals), Sc to Zn, are very important in industry and biology, but they provide unique challenges to computing the electronic structure of their compounds. In order to successfully describe the compounds by theory, one must be able to describe their components, in particular the constituent atoms and cations. In order to understand the ingredients required for successful computations with density functional theory, it is useful to examine the performance of various exchange-correlation functionals; we do this here for 4s(N)3d(N') transition metal atoms and their cations. We analyze the results using three ways to compute the energy of the open-shell states: the direct variational method, the weighted averaged broken symmetry (WABS) method, and a new broken-symmetry method called the reinterpreted broken symmetry (RBS) method. We find the RBS method to be comparable in accuracy with the WABS method. By examining the overall accuracy in treating 18 multiplicity-changing excitations and 10 ionization potentials with the RBS method, 10 functionals are found to have a mean-unsigned error of <5 kcal/mol, with omegaB97X-D topping the list. For local density functionals, which are more practical for extended systems, the M06-L functional is the most accurate. And by combining the results with our previous studies of p-block and 4d-series elements as well as databases for alkyl bond dissociation, main-group atomization energies, and pi-pi noncovalent interactions, we find five functionals, namely, PW6B95, MPW1B95, M08-SO, SOGGA11-X, and MPWB1K, to be highly recommended. We also studied the performance of PW86 and C09 exchange functionals, which have drawn wide interest in recent studies due to their claimed ability to reproduce Hartree-Fock exchange at long distance. By combining them with four correlation functionals, we find the performance of the resulting functionals disappointing both for 3d transition-metal chemistry and in broader tests, and thus we do not recommend PW86 and C09 as components of generalized gradient approximations for general application. PMID- 26579896 TI - Sensitivity of ab Initio vs Empirical Methods in Computing Structural Effects on NMR Chemical Shifts for the Example of Peptides. AB - The structural sensitivity of NMR chemical shifts as computed by quantum chemical methods is compared to a variety of empirical approaches for the example of a prototypical peptide, the 38-residue kaliotoxin KTX comprising 573 atoms. Despite the simplicity of empirical chemical shift prediction programs, the agreement with experimental results is rather good, underlining their usefulness. However, we show in our present work that they are highly insensitive to structural changes, which renders their use for validating predicted structures questionable. In contrast, quantum chemical methods show the expected high sensitivity to structural and electronic changes. This appears to be independent of the quantum chemical approach or the inclusion of solvent effects. For the latter, explicit solvent simulations with increasing number of snapshots were performed for two conformers of an eight amino acid sequence. In conclusion, the empirical approaches neither provide the expected magnitude nor the patterns of NMR chemical shifts determined by the clearly more costly ab initio methods upon structural changes. This restricts the use of empirical prediction programs in studies where peptide and protein structures are utilized for the NMR chemical shift evaluation such as in NMR refinement processes, structural model verifications, or calculations of NMR nuclear spin relaxation rates. PMID- 26579897 TI - Isotropic Periodic Sum Treatment of Long-Range Electrostatic Interactions in Combined Quantum Mechanical and Molecular Mechanical Calculations. AB - The isotropic periodic sum (IPS) method was extended to describe long-range electrostatic interactions in combined quantum mechanical and molecular mechanical (QM/MM) calculations. The resulting method, designated QM/MM-IPS, was tested for two ion association processes and a model SN2 reaction in aqueous solution. Potential of mean force (PMF) profiles and radial distribution functions computed from the QM/MM-IPS simulations were compared with those obtained by using the existing QM/MM-Ewald sum and cutoff (QM/MM-Cutoff) methods. In contrast to the QM/MM-Cutoff method, with which PMFs of ion separation tend to display a spurious linear drift, the QM/MM-IPS method successfully eliminates such artifacts, in excellent agreement with the QM/MM-Ewald results. The PMF obtained with the QM/MM-IPS method for the SN2 reaction that transfers an NH3 group between two chloride anions closely resembles that from the QM/MM-Ewald simulations. Compared with QM/MM-Ewald, the QM/MM-IPS method reduces the computational cost by 60-70% when a local region of 12 to 14 A is used. These results suggest that the QM/MM-IPS method can be used as a reliable and efficient alternative to the QM/MM-Ewald method to incorporate long-range electrostatic effects in simulating solution-phase chemical reactions. PMID- 26579898 TI - Systematic Study of Locally Dense Basis Sets for NMR Shielding Constants. AB - This paper presents a systematic study of partitioning schemes for locally dense basis sets in the context of NMR shielding calculations. The partitionings explored were based exclusively on connectivity and utilized the basis sets from the pcS-n series. Deviations from pcS-4 shieldings were calculated for a set of 28 organic molecules at the HF, B3LYP, and KT3 levels of theory, with the primary goal being the determination of an efficient scheme that achieves maximal deviations of 0.1 ppm for (1)H and 1 ppm for (13)C. Both atom based and group based divisions of basis sets were examined, with the latter providing the most promising results. It is demonstrated that for the systems studied, at least pcS 1 is required for all parts of the molecule. This, coupled with pcS-3 on the group of interest and pcS-2 on the adjacent groups, is sufficient to achieve the desired level of accuracy at a minimal computational expense. In addition, the suitability of the pcS-n basis sets for post-SCF methods was confirmed through a comparison with other standard basis sets at the MP2 level. PMID- 26579899 TI - Ab Initio Path Integral Molecular Dynamics Study of the Nuclear Quantum Effect on Out-of-Plane Ring Deformation of Hydrogen Maleate Anion. AB - Ab initio path integral molecular dynamics (PIMD) simulation was performed to understand the nuclear quantum effect on the out-of-plane ring deformation of hydrogen maleate anion and investigate the existence of a stable structure with ring deformation, which was suggested in experimental observation (Fillaux et al., Chem. Phys. 1999, 120, 387-403). The isotope effect and the temperature effect are studied as well. We first investigated the nuclear quantum effect on the proton transfer. In static calculation and classical ab initio molecular dynamics simulations, the proton in the hydrogen bond is localized to either oxygen atom. On the other hand, the proton is located at the center of two oxygen atoms in quantum ab initio PIMD simulations. The nuclear quantum effect washes out the barrier of proton transfer. We next examined the nuclear quantum effect on the motion of hydrogen maleate anion. Principal component analysis revealed that the out-of-plane ring bending modes have dominant contribution to the entire molecular motion. In quantum ab initio PIMD simulations, structures with ring deformation were the global minimum for the deuterated isotope at 300 K. We analyzed the out-of-plane ring bending mode further and found that there are three minima along a ring distortion mode. We successfully found a stable structure with ring deformation of hydrogen maleate for the first time, to our knowledge, using theoretical calculation. The structures with ring deformation found in quantum simulation of the deuterated isotope allowed the proton transfer to occur more frequently than the planar structure. Static ab initio electronic structure calculation found that the structures with ring deformation have very small proton transfer barrier compared to the planar structure. We suggest that the "proton transfer driven" mechanism is the origin of stabilization for the structure with out-of-plane ring deformation. PMID- 26579900 TI - Laplacian-Level Kinetic Energy Approximations Based on the Fourth-Order Gradient Expansion: Global Assessment and Application to the Subsystem Formulation of Density Functional Theory. AB - We tested Laplacian-level meta-generalized gradient approximation (meta-GGA) noninteracting kinetic energy functionals based on the fourth-order gradient expansion (GE4). We considered several well-known Laplacian-level meta-GGAs from the literature (bare GE4, modified GE4, and the MGGA functional of Perdew and Constantin (Phys. Rev. B 2007,75, 155109)), as well as two newly designed Laplacian-level kinetic energy functionals (L0.4 and L0.6). First, a general assessment of the different functionals is performed to test them for model systems (one-electron densities, Hooke's atom, and different jellium systems) and atomic and molecular kinetic energies as well as for their behavior with respect to density-scaling transformations. Finally, we assessed, for the first time, the performance of the different functionals for subsystem density functional theory (DFT) calculations on noncovalently interacting systems. We found that the different Laplacian-level meta-GGA kinetic functionals may improve the description of different properties of electronic systems, but no clear overall advantage is found over the best GGA functionals. Concerning the subsystem DFT calculations, the here-proposed L0.4 and L0.6 kinetic energy functionals are competitive with state-of-the-art GGAs, whereas all other Laplacian-level functionals fail badly. The performance of the Laplacian-level functionals is rationalized thanks to a two-dimensional reduced-gradient and reduced-Laplacian decomposition of the nonadditive kinetic energy density. PMID- 26579901 TI - Analytical First-Order Molecular Properties and Forces within the Adiabatic Connection Random Phase Approximation. AB - The random phase approximation (RPA) is an increasingly popular method for computing molecular ground-state correlation energies within the adiabatic connection fluctuation-dissipation theorem framework of density functional theory. We present an efficient analytical implementation of first-order RPA molecular properties and nuclear forces using the resolution-of-the-identity (RI) approximation and imaginary frequency integration. The centerpiece of our approach is a variational RPA energy Lagrangian invariant under unitary transformations of occupied and virtual reference orbitals, respectively. Its construction requires the solution of a single coupled-perturbed Kohn-Sham equation independent of the number of perturbations. Energy gradients with respect to nuclear displacements and other first-order properties such as one particle densities or dipole moments are obtained from partial derivatives of the Lagrangian. Our RPA energy gradient implementation exhibits the same [Formula: see text] scaling with system size N as a single-point RPA energy calculation. In typical applications, the cost for computing the entire gradient vector with respect to nuclear displacements is ~5 times that of a single-point RPA energy calculation. Derivatives of the quadrature nodes and weights used for frequency integration are essential for RPA gradients with an accuracy consistent with RPA energies and can be included in our approach. The quality of RPA equilibrium structures is assessed by comparison to accurate theoretical and experimental data for covalent main group compounds, weakly bonded dimers, and transition metal complexes. RPA outperforms semilocal functionals as well as second-order Moller-Plesset (MP2) theory, which fails badly for the transition metal compounds. Dipole moments of polarizable molecules and weakly bound dimers show a similar trend. RPA harmonic vibrational frequencies are nearly of coupled cluster singles, doubles, and perturbative triples quality for a set of main group compounds. Compared to the ring-coupled cluster based implementation of Rekkedal et al. [J. Chem. Phys. 2013, 139, 081101.], our method scales better by two powers of N and supports a semilocal Kohn-Sham reference. The latter is essential for the good performance of RPA in small-gap systems. PMID- 26579902 TI - Insights into the Perplexing Nature of the Bonding in C2 from Generalized Valence Bond Calculations. AB - Diatomic carbon, C2, has been variously described as having a double, triple, or quadruple bond. In this article, we report full generalized valence bond (GVB) calculations on C2. The GVB wave function-more accurate than the Hartree-Fock wave function and easier to interpret than traditional multiconfiguration wave functions-is well-suited for characterizing the bonding in C2. The GVB calculations show that the electronic wave function of C2 is not well described by a product of singlet-coupled, shared electron pairs (perfect pairing), which is the theoretical basis for covalent chemical bonds. Rather, C2 is best described as having a traditional covalent sigma bond with the electrons in the remaining orbitals of the two carbon atoms antiferromagnetically coupled. However, even this description is incomplete as the perfect pairing spin function also makes a significant contribution to the full GVB wave function. The complicated structure of the wave function of C2 is the source of the uncertainty about the nature of the bonding in this molecule. PMID- 26579903 TI - How to Compute the Fukui Matrix and Function for Systems with (Quasi-)Degenerate States. AB - A system in a spatially (quasi-)degenerate ground state responds in a qualitatively different way to a change in the external potential. Consequently, the usual method for computing the Fukui function, namely, taking the difference between the electron densities of the N- and N +/- 1 electron systems, cannot be applied directly. It is shown how the Fukui matrix, and thus also the Fukui function, depends on the nature of the perturbation. One thus needs to use degenerate perturbation theory for the given perturbing potential to generate the density matrix whose change with respect to a change in the number of electrons equals the Fukui matrix. Accounting for the degeneracy in the case of nitrous oxide reveals that an average over the degenerate states differs significantly from using the proper density matrix. We further show the differences in Fukui functions depending on whether a Dirac delta perturbation is used or an interaction with a true point charge (leading to the Fukui potential). PMID- 26579904 TI - Hydration Energy from a Composite Method for Implicit Representation of Solvent. AB - The CMIRS1.0 (composite method for implicit representation of solvent, Version 1.0) model is introduced for efficacious and inexpensive computation of hydration free energies. The method collects together several disparate models designed to describe short-range dispersion, exchange, and hydrogen bonding interactions as well as long-range electrostatic interactions. All the interactions are formulated as functionals of the solute charge density. The model uses only six adjustable parameters to determine the various short-range terms. In conjunction with an isodensity criterion that uses one parameter to determine the solute cavity size and shape, the model is tested on a large database of neutral and ionic solutes in water. The mean unsigned error compared to experiment is found to be as low as 0.8 kcal/mol for neutral solutes and 2.4 kcal/mol for ionic solutes, which is comparable to or better than other analogous approaches in the literature that invoke many more fitting parameters. PMID- 26579905 TI - On the Innocence of Bipyridine Ligands: How Well Do DFT Functionals Fare for These Challenging Spin Systems? AB - The electronic structures of a number of iron, cobalt, vanadium, and titanium complexes with the 2,2'-bipyridine (bpy) ligand were considered using the multireference CASSCF and NEVPT2 methods. Many of these systems have been studied in the past using B3LYP and were then found to contain the bpy ligand as a radical anion. For many of the cases, this is contradicted by our multireference calculations. While there are instances where the ligand is indeed a radical anion, in many cases it remains neutral and is involved in backbonding from the metal center. For those cases where CASSCF is too costly, a number of DFT functionals, including the newer double-hybrid functionals, were evaluated against the CASSCF data. It was found that nonhybrid functionals, especially those containing the kinetic energy density tau, were the best at predicting the electronic nature of the complexes. The tau-HCTH and HCTH functionals were the top performers, correctly predicting eleven out of eleven test cases and with the lowest mean unsigned errors (MUE, 7.6 and 7.8 kcal.mol(-1), respectively); the M06-L, N12, BLYP, PBE, and TPSS functionals also did well, while B3LYP had significant problems. PMID- 26579906 TI - Computation of Nonlinear Optical Properties of Molecules with Large Amplitude Anharmonic Motions. III. Arbitrary Double-Well Potentials. PMID- 26579907 TI - Calculations of One-Electron Redox Potentials of Oxoiron(IV) Porphyrin Complexes. AB - Density functional theory calculations have been performed to calculate the one electron redox potential for a series of oxoiron(IV) porphyrin complexes of the form [(TMP)Fe(IV)(O)(L)] (TMP = 5,10,15,20-tetramesitylporphyrinate). Different axial ligands were chosen (L = none, Im, ClO4(-), CH3CO2(-), Cl(-), F(-), SCH3( )) in order to compare the results with recent electrochemical experiments. The redox potentials were calculated with a Born-Haber cycle and the use of an internal reference, i.e. the absolute redox potential of ferrocene. Diverse methodologies were tested and show that the computed redox potentials depend strongly on the functional, the basis set, and the continuum models used to compute the solvation energies. Globally, BP86 gives better results for the geometries of the complexes than B3LYP and M06-L as well as more consistent values for the redox potentials. Although the results fit the experimental data for L = Im and L = ClO4(-), the addition of the other anionic axial ligands to the oxoiron(IV) porphyrin complex strongly lowers the redox potential, which is in disagreement with experimental observations. This important discrepancy is discussed. PMID- 26579908 TI - Can the Counterpoise Correction for Basis Set Superposition Effect Be Justified? AB - The basis set superposition effect (BSSE) is a simple concept, and its validity is almost universally accepted. So is the counterpoise method to correct for it. The idea is that the basis set is biased toward the dimer because each monomer in the dimer can "use" the basis functions on the other monomer, which it cannot in a simple monomer calculation. This hypothesis can only be tested if basis set free benchmark numbers are available for monomers and dimer. We are testing the hypothesis on a few systems (in this paper Be2) that are small enough that sufficiently accurate benchmark numbers (basis set free, or close to basis set limit; full CI or close to full CI) are available or can be obtained. We find that the answer to the title question is negative: the standard basis sets of quantum chemistry appear to be biased toward the atom in the sense that basis set errors are larger for the dimer than the monomer. Applying the counterpoise correction increases the imbalance by reducing the already smaller basis set error of the monomer even further. Counterpoise corrected bond energies then deviate more from the basis set limit numbers than uncorrected bond energies. These conclusions hold both at the Hartree-Fock level and (much stronger) at the correlated (CCSD(T), full CI) levels. So the answer to the title question is No. PMID- 26579909 TI - Energy Diagrams for Water Oxidation in Photosystem II Using Different Density Functionals. AB - The full sequence of intermediates in the water oxidation process in photosystem II has recently been characterized by model calculations, in good agreement with experiments. In the present paper, the energy diagram obtained is used as a benchmark test for several density functionals. Only the results using B3LYP with 15% or 20% show good agreement with experiments. The other functionals tried show errors for some energy levels as large as 20-30 kcal/mol. The reason for these large errors is that the error for three consecutive oxidations of Mn(III) to Mn(IV) accumulates as the cluster is oxidized. PMID- 26579910 TI - Optimizing Protein-Protein van der Waals Interactions for the AMBER ff9x/ff12 Force Field. AB - The quality of molecular dynamics (MD) simulations relies heavily on the accuracy of the underlying force field. In recent years, considerable effort has been put into developing more accurate dihedral angle potentials for MD force fields, but relatively little work has focused on the nonbonded parameters, many of which are two decades old. In this work, we assess the accuracy of protein-protein van der Waals interactions in the AMBER ff9x/ff12 force field. Across a test set of 44 neat organic liquids containing the moieties present in proteins, we find root mean-square (RMS) errors of 1.26 kcal/mol in enthalpy of vaporization and 0.36 g/cm(3) in liquid densities. We then optimize the van der Waals radii and well depths for all of the relevant atom types using these observables, which lowers the RMS errors in enthalpy of vaporization and liquid density of our validation set to 0.59 kcal/mol (53% reduction) and 0.019 g/cm(3) (46% reduction), respectively. Limitations in our parameter optimization were evident for certain atom types, however, and we discuss the implications of these observations for future force field development. PMID- 26579911 TI - Monte Carlo Free Ligand Diffusion with Markov State Model Analysis and Absolute Binding Free Energy Calculations. AB - Obtaining absolute binding free energies from unbiased ligand diffusion has attracted a significant amount of attention due to its implications in drug design. Several studies have used special purpose computers and software to achieve microsecond molecular dynamics which, combined with a Markov state model analysis, are capable of providing absolute binding free energies. We have recently developed a Monte Carlo based technique, PELE, capable of performing a dynamical exploration of the protein-ligand energy landscape including free ligand diffusion into the active site, at a fraction of the computational cost of molecular dynamics techniques. We demonstrate here the capabilities of our Monte Carlo technique in obtaining absolute binding free energies for a series of benzamidine like inhibitors into trypsin. Our results are in good agreement with experimental data and other molecular dynamics simulations, indicating that PELE can be a useful tool for quick estimates of binding free energies and mechanisms. PMID- 26579912 TI - Toward an Optomechanical Control of Photoswitches by Tuning Their Spectroscopical Properties: Structural and Dynamical Insights into Azobenzene. AB - A new methodology to calculate efficiently the absorption spectrum of a single molecule when subjected to mechanical stress is presented. As example, the developed methodology was applied to cis- and trans-azobenzene, commonly used as photoswitch in a wide variety of applications. The results show that both (1)(n,pi*) and (1)(pi,pi*) optical transitions can be efficiently modulated by applying an external force. A structural analysis was performed to evaluate the role of each internal coordinate in the excitation process, taking into account the application of external forces at different positions of azobenzene. Moreover, stress-strain curves were calculated in order to determine the maximum applicable forces within the elastic region, highlighting notable differences between the mechanical properties of cis- and trans-azobenzene conformers. The optomechanical work obtained by elongation and compression steps is calculated for a single azobenzene molecule and compared to available experimental data. Finally, the implications derived from the application of azobenzene as main chain component of a linear polymer acting as a photoinduced motor are discussed. PMID- 26579913 TI - Electronic Structure Study of Singlet Fission in Tetracene Derivatives. AB - A detailed theoretical study of the singlet fission process in tetracene and two of its derivatives, that is 5,12-diphenyltetracene (DPT) and rubrene, is presented. This work aims to unravel the intricacies and the differences of their singlet fission mechanism by means of electronic structure calculations using molecular and cluster models and a variety of computational tools. Although the electronic structure at the molecular level is very similar for the three compounds, their different crystal packing has important consequences in their ability to produce two triplet states from a single exciton. The results obtained indicate that the lowest singlet is found to delocalize at least over seven molecules. Computed relative energies rule out the presence of charge transfer (CT) states as intermediates in a two-step mechanism in all cases. On the other hand, CT states do play a role as mediators, specially in tetracene. They decisively participate in the coupling between single and multiexcitonic states through second-order contributions. Finally, the present study pinpoints that the transition from the optically allowed exciton to the dark multiexciton state might be facilitated by intramolecular motion toward the lowest excited singlet geometry. PMID- 26579914 TI - The Triplet-Singlet Gap in the m-Xylylene Radical: A Not So Simple One. AB - Meta-benzoquinodimethane (MBQDM) or m-xylylene provides a model for larger organic diradicals, the triplet-singlet gap being the key property. In the present work this energy difference has been the object of a systematic study by means of several density functional theory-based methods including B3LYP, M06, M06-2X, HSE and LC-omegaPBE potentials and a variety of wave function-based methods such as complete active space self consistent field (CASSCF), Multireference second-order Moller-Plesset (MRMP), difference dedicated configuration interaction (DDCI), and Multireference configuration interaction (MRCI). In each case various basis sets of increasing quality have been explored, and the effect of the molecular geometry is also analyzed. The use of the triplet and broken symmetry (BS) solutions for the corresponding optimized geometries obtained from B3LYP and especially M06-2X functionals provide the value of the adiabatic triplet-singlet gap closer to experiment when compared to the reported value of Wenthold, Kim, and Lineberger, (J. Am. Chem. Soc. 1997, 119, 1354) and also for the electron affinity. The agreement further improves using the full pi valence CASSCF(8,8) optimized geometry as an attempt to correct for the spin contamination effects on the geometry of the BS state. The CASSCF, MRMP, and MRCI, even with the full pi valence CAS(8,8) as reference and relatively large basis set, systematically overestimate the experimental value indicating either that an accurate description must go beyond this level of theory, including sigma electrons and higher order polarization functions, or perhaps that the measured value is affected by the experimental conditions. PMID- 26579915 TI - An Effective Two-Orbital Quantum Chemical Model for Organic Photovoltaic Materials. AB - We present a coarse-grained quantum chemical model of organic photovoltaic materials, which is based on the classic idea that the main physical processes involve the electrons occupying the frontier orbitals (HOMO and LUMO) of each molecule or "site". This translates into an effective electronic Hamiltonian with two electrons and two orbitals per site. The on-site parameters (one- and two electron integrals) can be rigorously related to the ionization energy, electron affinity, and singlet and triplet first excitation energies of that site. The intersite Hamiltonian parameters are introduced in a way that is consistent with classical electrostatics, and for the one-electron part, we use a simple approximation that could be refined using information from atomistic quantum chemical calculations. The model has been implemented within the GAMESS-US package. This allows the exploration of the physics of these materials using state-of-the art quantum chemical methods on relatively large systems (hundreds of electron-donor and electron-acceptor sites). To illustrate this point, we present ground- and excited-state calculations on dimers and two-dimensional arrays of sites using the Hartree-Fock, configuration interaction, and coupled cluster methods. The calculations provide evidence for the possibility of low energy, long-range electron transfer in donor-acceptor heterojunctions characterized by a moderate degree of disorder. PMID- 26579916 TI - Effects of Edge Oxidation on the Structural, Electronic, and Magnetic Properties of Zigzag Boron Nitride Nanoribbons. AB - The effects of edge chemistry on the relative stability and electronic properties of zigzag boron nitride nanoribbons (ZBNNRs) are investigated. Among all functional groups considered, fully hydroxylated ZBNNRs are found to be the most energetically stable. When an in-plane external electric field is applied perpendicular to the axis of both hydrogenated and hydroxylated ZBNNRs, a spin polarized half-metallic state is induced, whose character is different than that predicted for zigzag graphene nanoribbons. The onset field for achieving the half metallic state is found to mainly depend on the width of the ribbon. Our results indicate that edge functionalization of ZBNNRs may open the way for the design of new nanoelectronic and nanospintronic devices. PMID- 26579917 TI - Quantifying Artifacts in Ewald Simulations of Inhomogeneous Systems with a Net Charge. AB - Ewald summation, which has become the de facto standard for computing electrostatic interactions in biomolecular simulations, formally requires that the simulation box is neutral. For non-neutral systems, the Ewald algorithm implicitly introduces a uniform background charge distribution that effectively neutralizes the simulation box. Because a uniform distribution of counter charges typically deviates from the spatial distribution of counterions in real systems, artifacts may arise, in particular in systems with an inhomogeneous dielectric constant. Here, we derive an analytical expression for the effect of using an implicit background charge instead of explicit counterions, on the chemical potential of ions in heterogeneous systems, which (i) provides a quantitative criterium for deciding if the background charge offers an acceptable trade-off between artifacts arising from sampling problems and artifacts arising from the homogeneous background charge distribution, and (ii) can be used to correct this artifact in certain cases. Our model quantifies the artifact in terms of the difference in charge density between the non-neutral system with a uniform neutralizing background charge and the real neutral system with a physically correct distribution of explicit counterions. We show that for inhomogeneous systems, such as proteins and membranes in water, the artifact manifests itself by an overstabilization of ions inside the lower dielectric by tens to even hundreds kilojoules per mole. We have tested the accuracy of our model in molecular dynamics simulations and found that the error in the calculated free energy for moving a test charge from water into hexadecane, at different net charges of the system and different simulation box sizes, is correctly predicted by the model. The calculations further confirm that the incorrect distribution of counter charges in the simulation box is solely responsible for the errors in the PMFs. PMID- 26579918 TI - On the Sensitivity of Peptide Nucleic Acid Duplex Formation and Crystal Dissolution to a Variation of Force-Field Parameters. AB - The technique of one-step perturbation to explore the relation between particular force-field parameters on the one hand and particular properties of a biomolecular system on the other hand from one or a few molecular dynamics simulations is applied to investigate the dependence of the free enthalpy of dimer formation and of crystal dissolution of a self-complementary fragment (H CGTACG-NH2) of peptide nucleic acid, PNA, a mimic of DNA. The simulations show that PNA dimer formation in aqueous solution is favored by a decrease in the base charges with respect to values of the GROMOS 45A4 force field, while it is disfavored by a decrease in the backbone charges. In contrast, crystal dissolution of the PNA dimer is favored by a decrease in base charges, while a variation of backbone charges has a minor effect on this free enthalpy change. These opposite effects in a crystalline versus aqueous solution environment can be understood from the different water contents for these systems and have consequences for biomolecular force-field development. PMID- 26579919 TI - Are Waters around RNA More than Just a Solvent? - An Insight from Molecular Dynamics Simulations. AB - Hydrating water molecules are believed to be an inherent part of the RNA structure and have a considerable impact on RNA conformation. However, the magnitude and mechanism of the interplay between water molecules and the RNA structure are still poorly understood. In principle, such hydration effects can be studied by molecular dynamics (MD) simulations. In our recent MD studies, we observed that the choice of water model has a visible impact on the predicted structure and structural dynamics of RNA and, in particular, has a larger effect than type, parametrization, and concentration of the ions. Furthermore, the water model effect is sequence dependent and modulates the sequence dependence of A-RNA helical parameters. Clearly, the sensitivity of A-RNA structural dynamics to the water model parametrization is a rather spurious effect that complicates MD studies of RNA molecules. These results nevertheless suggest that the sequence dependence of the A-RNA structure, usually attributed to base stacking, might be driven by the structural dynamics of specific hydration. Here, we present a systematic MD study that aimed to (i) clarify the atomistic mechanism of the water model sensitivity and (ii) discover whether and to what extent specific hydration modulates the A-RNA structural variability. We carried out an extended set of MD simulations of canonical A-RNA duplexes with TIP3P, TIP4P/2005, TIP5P, and SPC/E explicit water models and found that different water models provided a different extent of water bridging between 2'-OH groups across the minor groove, which in turn influences their distance and consequently also inclination, roll, and slide parameters. Minor groove hydration is also responsible for the sequence dependence of these helical parameters. Our simulations suggest that TIP5P is not optimal for RNA simulations. PMID- 26579920 TI - Generalized QM/MM Force Matching Approach Applied to the 11-cis Protonated Schiff Base Chromophore of Rhodopsin. AB - We extended a previously developed force matching approach to systems with covalent QM/MM boundaries and describe its user-friendly implementation in the publicly available software package CPMD. We applied this approach to the challenging case of the retinal protonated Schiff base in dark state bovine rhodopsin. We were able to develop a highly accurate force field that is able to capture subtle structural changes within the chromophore that have a pronounced influence on the optical properties. The optical absorption spectrum calculated from configurations extracted from a MD trajectory using the new force field is in excellent agreement with QM/MM and experimental references. PMID- 26579921 TI - Highly Scalable and Memory Efficient Ultra-Coarse-Grained Molecular Dynamics Simulations. AB - The use of coarse-grained (CG) models can significantly increase the time and length scales accessible to computational molecular dynamics (MD) simulations. To address very large-scale phenomena, however, requires a careful consideration of memory requirements and parallel MD load balancing in order to make efficient use of current supercomputers. In this work, a CG-MD code is introduced which is specifically designed for very large, highly parallel simulations of systems with markedly non-uniform particle distributions, such as those found in highly CG models having an implicit solvent. The CG-MD code uses an unorthodox combination of sparse data representations with a Hilbert space-filling curve (SFC) to provide dynamic topological descriptions, reduced memory overhead, and advanced load-balancing characteristics. The results of representative large-scale simulations indicate that our approach can offer significant advantages over conventional MD techniques, and should enable new classes of CG-MD systems to be investigated. PMID- 26579922 TI - Conformational Entropies and Order Parameters: Convergence, Reproducibility, and Transferability. AB - Conformational entropy provides major contributions to protein folding and functions, such as ligand binding, making it a potentially important driver of biologically relevant processes. NMR spectroscopy is a unique technique to estimate conformational entropy changes at atomic resolution, an approach that can be favorably augmented by comparisons with results from molecular dynamics (MD) simulations, for example, by generating an order-parameter-to-entropy dictionary. Here, we address critical issues pertaining to such an approach, including reproducibility, convergence, and transferability by analyzing long (380 ns -1 ms) MD trajectories obtained for five different proteins. We observe that order parameters and conformational entropies calculated over 10-100 ns windows are typically well converged among individual MD trajectories and reproducible between pairs of independent trajectories, when calculated on a per residue level. However, significant discrepancies sometimes arise for the total conformational entropy evaluated as the sum of the residue-specific entropies, especially in cases that involve rare transitions to alternative conformational states. Furthermore, we find that the order-parameter-to-entropy dictionary depends strongly on the protein and the sampling frequency, but much less so on the molecular dynamics force field. Thus, the transferability of the dictionary is poor between proteins but relatively good between different states (e.g., different ligand-bound complexes) of the same protein, provided that a protein specific dictionary has been derived. PMID- 26579923 TI - Energy-Driven Undocking (EDU-HREM) in Solute Tempering Replica Exchange Simulations. AB - We present a new computational strategy for calculating the absolute binding free energy for protein ligand association in the context of atomistic simulation in explicit solvent. The method is based on an appropriate definition of a solute tempering scheme enforced via Hamilton replica exchange method (HREM). The definition of "solute" includes both the ligand and the active site, with the remainder of the systems defined as "solvent". The hydrophilicity of the solute and the solute torsional plus nonbonded intrasolute interactions are increased and decreased, respectively, along the replica progression, thus favoring the extrusion of the drug form the active site in the scaled states of the generalized ensemble. The proposed technique, named "Energy Driven Undocking" (EDU-HREM), completely bypasses the need for defining and/or identifying the relevant reaction coordinates in a ligand receptor interactions and allows the calculation of the absolute binding free energy in one single generalized simulation of the drug-receptor system. The methodology is applied, with encouraging results, to the calculation of the absolute binding free energy of some FK506-related ligands of the peptidyl prolyl cis-trans isomerase protein (FKBP12) with known dissociation constants. Aspects of the binding/inhibition mechanism in FKBP12 are also analyzed and discussed. PMID- 26579924 TI - Energies and 2'-Hydroxyl Group Orientations of RNA Backbone Conformations. Benchmark CCSD(T)/CBS Database, Electronic Analysis, and Assessment of DFT Methods and MD Simulations. AB - Sugar-phosphate backbone is an electronically complex molecular segment imparting RNA molecules high flexibility and architectonic heterogeneity necessary for their biological functions. The structural variability of RNA molecules is amplified by the presence of the 2'-hydroxyl group, capable of forming multitude of intra- and intermolecular interactions. Bioinformatics studies based on X-ray structure database revealed that RNA backbone samples at least 46 substates known as rotameric families. The present study provides a comprehensive analysis of RNA backbone conformational preferences and 2'-hydroxyl group orientations. First, we create a benchmark database of estimated CCSD(T)/CBS relative energies of all rotameric families and test performance of dispersion-corrected DFT-D3 methods and molecular mechanics in vacuum and in continuum solvent. The performance of the DFT-D3 methods is in general quite satisfactory. The B-LYP-D3 method provides the best trade-off between accuracy and computational demands. B3-LYP-D3 slightly outperforms the new PW6B95-D3 and MPW1B95-D3 and is the second most accurate density functional of the study. The best agreement with CCSD(T)/CBS is provided by DSD-B-LYP-D3 double-hybrid functional, although its large-scale applications may be limited by high computational costs. Molecular mechanics does not reproduce the fine energy differences between the RNA backbone substates. We also demonstrate that the differences in the magnitude of the hyperconjugation effect do not correlate with the energy ranking of the backbone conformations. Further, we investigated the 2'-hydroxyl group orientation preferences. For all families, we conducted a QM and MM hydroxyl group rigid scan in gas phase and solvent. We then carried out set of explicit solvent MD simulations of folded RNAs and analyze 2'-hydroxyl group orientations of different backbone families in MD. The solvent energy profiles determined primarily by the sugar pucker match well with the distribution data derived from the simulations. The QM and MM energy profiles predict the same 2'-hydroxyl group orientation preferences. Finally, we demonstrate that the high energy of unfavorable and rarely sampled 2'-hydroxyl group orientations can be attributed to clashes between occupied orbitals. PMID- 26579925 TI - Evaluation of Proteins' Rotational Diffusion Coefficients from Simulations of Their Free Brownian Motion in Volume-Occupied Environments. AB - We have investigated the rotational dynamics of hen egg white lysozyme in monodisperse aqueous solutions of concentrations up to 250 mg/mL, using a rigid body Brownian dynamics method that accurately accounts for anisotropies of diffusing objects. We have examined the validity of the free diffusion concept in the analysis of computer simulations of volume-occupied molecular solutions. We have found that, when as the only intermolecular interaction, the excluded volume effect is considered, rotational diffusion of molecules adheres to the free diffusion model. Further, we present a method based on the exact (in the case of the free diffusion) analytic forms of autocorrelation functions of particular vectors rigidly attached to diffusing objects, which allows one to obtain from results of molecular simulations the three principal rotational diffusion coefficients characterizing rotational Brownian motion of an arbitrarily shaped rigid particle for an arbitrary concentration of crowders. We have applied this approach to trajectories resulting from Brownian dynamics simulations of hen egg white lysozyme solutions. We show that the apparent anisotropy of proteins' rotational motions increases with an increasing degree of crowding. Finally, we demonstrate that even if the hydrodynamic anisotropy of molecules is neglected and molecules are simulated using their average translational and rotational diffusion coefficients, excluded volume effects still lead to their anisotropic rotational dynamics. PMID- 26579926 TI - Development of a novel computerised version of the Month Backwards Test: A comparison of performance in hospitalised elderly patients and final year medical students. AB - BACKGROUND AND AIMS: The Months Backwards Test (MBT) is a commonly used bedside test of cognitive function, but there is uncertainty as to optimal testing procedures. We examined performance among hospitalised elderly patients and cognitively intact young persons with verbal and computerised versions of the test. PARTICIPANTS AND METHODS: Fifty acute elderly medical inpatients and fifty final year medical students completed verbal (MBTv) and computerised (MBTc) versions of the MBT and the Montreal Cognitive Assessment (MoCA). Completion time and errors were compared. RESULTS: Thirty four participants scored <26 on the MoCA indicating significant cognitive impairment. The mean MoCA scores in the elderly medical group (23.6+/-3.4; range 13-28) were significantly lower than for the medical students (29.2+/-0.6; range 28-30: p<0.01). For the verbal months backwards test (MBTv), there were significantly more errors and longer completion times in the elderly medical patients (25.1+/-20.9 vs. 10.5+/-4.5; p<0.05). Completion times were 2-3 times longer for the MBTc compared to the MBTv (patients: 63.5+/-43.9 vs. students 20.3+/-4.4; p<0.05). There was high correlation between the two versions of the MBT (r=0.84) and also between the MBTc and the MoCA (r=0.85). The MBTc had higher correlation with visuospatial function (MBTc r=0.70, MBTv r=0.57). An MBTc cut-off time of 30s for distinguishing performance (pass/fail) had excellent sensitivity (100%) with modest specificity (44%) for cognitive impairment in elderly medical patients. CONCLUSION: The computerised MBT allows accurate and efficient testing of attention and general cognition in clinical populations. PMID- 26579927 TI - Electron transfer dissociation of doubly charged ions with different cationizing agents. AB - Electron transfer dissociation (ETD) studies have been performed on a peptide and a synthetic polysaccharide doubly charged by different cationization agents. The ETD of protonated-sodiated bombesin gave rise to contiguous series of abundant c- and z-type ions that identified the complete sequence. ETD of the doubly protonated peptide produced a different fragment distribution, which also allowed for complete sequence coverage, but the relative intensities of some sequence ions were very small. Collisionally activated dissociation (CAD) of either precursor rendered limited sequence information. ETD of the sodiated-ammoniated pentamer of a starch-derived linear polysaccharide caused extensive fragmentation through cross-ring cleavages that revealed the possible position of a hydroxyethyl substituent on the saccharide ring. In contrast, ETD of the di sodiated pentasaccharide did not produce a structure-revealing fragmentation pattern. On the other hand, CAD resulted in efficient glycosidic bond cleavages, either directly (from the sodiated-ammoniated precursor) or via multi-stage fragmentation (from the di-sodiated precursor), which indicated that hydroxyethylation occurs randomly at any saccharide repeat unit along the chain. Overall, the use of different cationizing agents complements the information available by using identical charge sites and opens or enhances ETD pathways that unveil valuable sequence or positional information. PMID- 26579928 TI - Prediction of adducts on positive mode electrospray ionization mass spectrometry: proton/sodium selectivity in methanol solutions. AB - We used positive mode electrospray ionization (ESI) mass spectrometry to examine 540 in-house high-resolution mass spectrometry (HRMS) samples that formed an adducted positive ion. Of the 540 samples, the sodium adduct ([M+Na]+) was detected in 480 samples, and the protonated molecule ([M+H]+) was detected in 92 samples; both [M+Na]+ and [M+H]+ were detected in 32 samples. No other adduct ions were predominant. The selectivities of these adducts were evaluated by a two dimensional plot using topological polar surface area (tPSA) and molecular weight. Two predominant trends were observed: [M+H]+ converged around tPSA (A2) = 20 and molecular weight = 250, and the selectivity for [M+Na]+ correlated with the tPSA value. These observations were found to be related to the elemental composition of the sample compounds. From the results obtained by positive mode ESI mass spectroscopy under our experimental conditions, predominant trends were observed with respect to adduct selectivity: compounds containing oxygen atom(s) form [M+Na]+, and compounds containing nitrogen but not oxygen atom(s) form [M+H]2. Based on these trends, we developed the "Nitrogen-Oxygen rule" (NO rule) to predict the adduct formed by a given compound on positive mode ESI. This NO rule provides a guideline to estimate elemental composition using ESI-HRMS with methanol as mobile phase. PMID- 26579929 TI - "Dilute-and-shoot" rapid-separation liquid chromatography tandem mass spectrometry method for fast detection of thiodiglycolic acid in urine. AB - A new sensitive rapid-separation liquid chromatography tandem mass spectrometry approach for the determination of thiodiglycolic acid (TDGA) in urine has been developed. The use of the "dilute-and-shoot" method helps to shorten the sample preparation stage and provides a sensitive and direct approach for TDGA determination in urine. Chromatographic separation of the analyte and other urine compounds was achieved using a reverse-phase liquid chromatography column with mobile phases consisting of 0.1% formic acid in water and acetonitrile in a gradient elution mode. For the identification and quantification of TDGA electrospray ionization-tandem mass spectrometry monitoring, two precursor-to product ion transitions were used. The method demonstrates good linearity and has a detection limit of 50 ng mL-1 in urine. PMID- 26579930 TI - Structure characterization of phospholipids and lipid A of Pseudomonas putida KT2442. AB - Pseudomonas putida KT2442 is an important bacterium for producing various types of polyhydroxyalkanoate polymers. Phospholipids and lipid A in membranes of P. putida play important roles in stress responses, but detailed structural information of these lipids is not known. In this study, phospholipids and lipid A were isolated from P. putida KT2442, and their structures were analyzed using thin layer chromatography, high performance liquid chromatography, and electrospray ionization/mass spectrometry. Major phospholipids in P. putida KT2442 were phosphatidylethanolamine (79.9%), phosphatidylglycero1 (12.7%), and cardiolipin (7.4%), with C16:1 and/or C18:1 acyl chains. Four lipid A species were found in P. putida KT2442: two are hexa-acylated, and the other two are penta-acylated. Compared with lipid A of P. aeruginosa, P. putida lipid A has less hydroxylation on the secondary acyl chains and less modification. Therefore, P. putida lipid A could be used as a base structure to investigate lipid A modification of P. aeruginosa for understanding its pathogenesis. PMID- 26579931 TI - Letter: The potential of amine-containing dendrimer mass standards for internal calibration of peptides. AB - In order to ensure accurate mass determinations, MALDI-TOF mass spectrometers must be calibrated regularly. While peptides and proteins represent the most widely used calibration standards due to their monodispersity, known masses and availability, their limited shelf-life complicates their use. Recently, polyester dendrimer calibrants have been introduced as an alternative because, in addition to monodispersity and relative molecular masses as high as 30,000, they exhibit vastly improved stability and broad compatibility with both matrices and solvents. However, the use of these initially reported polyester dendrimers as internal calibrants for the analysis of peptides or proteins presents a unique problem because these dendrimers typically require ionization with metal cations, while amino acid-based compounds preferentially ionize via protonation of an amine. To address this complication, dendrimers bearing a single amine were prepared which demonstrate the ability to easily ionize via protonation with either acidic matrices or dilute solutions of trifluoroacetic acid. This class of amine-containing dendrimers shows promise as a calibrant system specifically designed for the internal calibration of peptides. PMID- 26579932 TI - Letter: Fast detection of polycyclic aromatic hydrocarbons in complex mixtures of organic compounds based on gas chromatography-mass spectrometry with atmospheric pressure photoionization. AB - The research is devoted to the investigation of the selectivity detection of 16 polycyclic aromatic hydrocarbons (PAHs) using gas chromatography-mass spectrometry (GC-MS), electron ionization (EI) GC-MS with atmospheric pressure photoionization (APPhI) and GC-MS atmospheric pressure photochemical ionization (APPhCI) when vapors of different substances (benzene, toluene, and naphthalene) were used as gas reagents. Capillary columns of different lengths were used for the separation of the components of the mixture of 44 semivolatile organic compounds. It was shown that the most-selective detection of 16 PAHs in a 44- component mixture was possible when GC-MS APPhCI was used. Only 16 PAHs were registered on the respective mass chromatograms and a fast detection of them was possible. The respective APPhI and APPhCI mass spectra consisted of only peak of the respective molecular ion, M++ - the radical cation. Detection limits were 3 pg MUL-1 to 15 pg MUL. PMID- 26579933 TI - In Vitro and in Silico Analyses for Predicting Hepatic Cytochrome P450-Dependent Metabolic Potencies of Polychlorinated Biphenyls in the Baikal Seal. AB - The aim of this study was to understand the cytochrome P450 (CYP)-dependent metabolic pathway and potency of polychlorinated biphenyls (PCBs) in the Baikal seal (Pusa sibirica). In vitro metabolism of 62 PCB congener mixtures was investigated by using liver microsomes of this species. A decreased ratio of over 20% was observed for CB3, CB4, CB8, CB15, CB19, CB22, CB37, CB54, CB77, and CB105, suggesting the preferential metabolism of low-chlorinated PCBs by CYPs. The highly activated metabolic pathways in Baikal seals that were predicted from the decreased PCBs and detected hydroxylated PCBs (OH-PCBs) were CB22 to 4'OH CB20 and CB77 to 4'OH-CB79. The total amount of OH-PCBs detected as identified and unidentified congeners accounted for only a 3.8 +/- 1.7 mol % of loaded PCBs, indicating many unknown PCB metabolic pathways. To explore factors involved in CYP-dependent PCB metabolism, we examined the relationships among the structural and physicochemical properties of PCBs, the in silico PCB-CYP docking parameters, and the in vitro PCB decreased ratios by principal component analysis. Statistical analysis showed that the decreased PCB ratio was at least partly accounted for by the substituted chlorine number of PCBs and the distance from the Cl-unsubstituted carbon of docked PCBs to the heme Fe in CYP2A and 2B. PMID- 26579934 TI - Electrochemical lactate biosensor based upon chitosan/carbon nanotubes modified screen-printed graphite electrodes for the determination of lactate in embryonic cell cultures. AB - l-lactate is an essential metabolite present in embryonic cell culture. Changes of this important metabolite during the growth of human embryo reflect the quality and viability of the embryo. In this study, we report a sensitive, stable, and easily manufactured electrochemical biosensor for the detection of lactate within embryonic cell cultures media. Screen-printed disposable electrodes are used as electrochemical sensing platforms for the miniaturization of the lactate biosensor. Chitosan/multi walled carbon nanotubes composite have been employed for the enzymatic immobilization of the lactate oxidase enzyme. This novel electrochemical lactate biosensor analytical efficacy is explored towards the sensing of lactate in model (buffer) solutions and is found to exhibit a linear response towards lactate over the concentration range of 30.4 and 243.9 uM in phosphate buffer solution, with a corresponding limit of detection (based on 3-sigma) of 22.6 uM and exhibits a sensitivity of 3417 +/- 131 uAM(-1) according to the reproducibility study. These novel electrochemical lactate biosensors exhibit a high reproducibility, with a relative standard deviation of less than 3.8% and an enzymatic response over 82% after 5 months stored at 4 degrees C. Furthermore, high performance liquid chromatography technique has been utilized to independently validate the electrochemical lactate biosensor for the determination of lactate in a commercial embryonic cell culture medium providing excellent agreement between the two analytical protocols. PMID- 26579935 TI - Screen-printed carbon electrode-based electrochemical immunosensor for rapid detection of microalbuminuria. AB - A urinary microalbumin test is used to detect early signs of kidney damage in people who have a risk of chronic kidney disease, such as those with diabetes or hypertension. In this study, we developed a screen-printed carbon electrode-based immunosensor for the detection of microalbumin in urine. Anti-human albumin antibodies were immobilized on the screen-printed sensor surface by the covalent immobilization method. Cyclic voltammetry (CV) and scanning electron microscopy with an energy dispersive spectroscopical (SEM-EDS) analysis demonstrated that the modification process was well performed. Chronoamperometric (CA) electrochemical measurement technique was employed for the quantitative detection of albumin. The electrochemical measurements performed with some possible interfering compounds normally present in urine (ascorbic acid, uric acid, glucose and creatinine samples) demonstrated a high specificity and selectivity of this immunosensor in albumin detection. Under optimum conditions, the immunosensor can detect urinary albumin in a wide linear range from 10 ug/ml to 300 ug/ml with a detection limit of 9.7 ug/ml. The excellent performance of this immunosensor was confirmed by analyzing microalbumin in urine samples; the results were in good agreement with those obtained by the standard immunoturbidimetric method. The biosensor proposed herein is easy to prepare and can be used for low-cost, rapid, and sensitive screening of microalbuminuria. This approach provides a promising platform for developing clinical point-of-care diagnostic applications. PMID- 26579936 TI - Electronic Coupling in [Mo2]-Bridge-[Mo2] Systems with Twisted Bridges. AB - In order to evaluate the impact of bridge conformation on electronic coupling in donor-bridge-acceptor triad systems, two Mo2 dimers, [Mo2(DAniF)3]2[MU-1,4 {C(O)NH}2-Naph] (1, DAniF = N,N'-di(p-anisyl)formamidinate and Naph = naphthalenyl) and [Mo2(DAniF)3]2[MU-1,4-(CS2)2-2,5-Me2C6H2] (2), have been synthesized and structurally characterized. These two compounds feature a large dihedral angle (>60 degrees ) between the central aromatic ring and the plane defined by the Mo-Mo bond vectors, which is distinct from the previously reported phenylene bridged analogues [Mo2(DAniF)3]2[MU-1,4-{C(O)NH}2-ph] (I) and [Mo2(DAniF)3]2[MU-1,4-(CS2)2-C6H4] (II), respectively. Unusual optical behaviors are observed for the mixed-valence (MV) species (1(+) and 2(+)), generated by single-electron oxidation. While 2(+) exhibits a weak intervalence charge transfer (IVCT) absorption band in the near-IR region, the IVCT band is absent in the spectrum of 1(+), which is quite different from what observed for I(+) and II(+). Optical analyses, based on superexchange formalism and Hush model, indicate that, in terms of Robin-Day classification, mixed-valence species 1(+) belongs to the electronically uncoupled Class I and complex 2(+), with Hab = 220 cm(-1), is assigned to the weakly coupled Class II. Together with I(+) and II(+), the four MV complexes complete a transition from Class I to Class II-III borderline as a result of manipulating the geometric topology of the bridge. Given the structural and electronic features for the molecular systems, the impacts of electrostatic interaction (through-space) and electron resonance (through-bond) on electronic coupling are discussed. PMID- 26579937 TI - Nucleosomes Inhibit Cas9 Endonuclease Activity in Vitro. AB - During Cas9 genome editing in eukaryotic cells, the bacterial Cas9 enzyme cleaves DNA targets within chromatin. To understand how chromatin affects Cas9 targeting, we characterized Cas9 activity on nucleosome substrates in vitro. We find that Cas9 endonuclease activity is strongly inhibited when its target site is located within the nucleosome core. In contrast, the nucleosome structure does not affect Cas9 activity at a target site within the adjacent linker DNA. Analysis of target sites that partially overlap with the nucleosome edge indicates that the accessibility of the protospacer-adjacent motif (PAM) is the critical determinant of Cas9 activity on a nucleosome. PMID- 26579938 TI - Intron 4 of the RH Gene in Han Chinese, Tibetan, and Mongol Populations. AB - AIMS: This study aimed to compare the intron 4 sequence of the RHD and RHCE genes from Han Chinese, Tibetans, and Mongols, and explore its polymorphisms. MATERIALS AND METHODS: To investigate the distinction in the RHD and RHCE intron 4, polymerase chain reaction (PCR) was performed by a set of primers: Intron4F and Intron4R. Primer Intron4F for a sequence located in exon 4 and primer Intron4R for a sequence located in exon 5, respectively. RHD and RHCE intron 4 of all the samples from 26 cases of random unrelated Hans (13 RhD-positive donors and 13 RhD negative donors), 25 cases of random unrelated Tibetans (18 RhD-positive donors and 7 RhD-negative donors), and 4 cases of random unrelated Mongols (1 RhD positive donor and 3 RhD-negative donors) were amplified with PCR. The PCR products were then sequenced. RESULTS: A 576-bp product was detected in all the Han, Tibetan, and Mongol RhD-positive donors, whereas a 1228-bp product was detected in RhD-negative donors. The sequences of RHCE gene intron 4 were identical to each other in all Han, Tibetan, and Mongol RhD-negative donors, including 335 bp of Alu element, with a whole length of 1078 bp. By contrast, a 426-bp product was detected in all Han, Tibetan, and Mongol RhD-positive donors. Compared with the RHCE gene, a 652-bp deletion was noted in the RHD gene of Chinese, including the whole Alu element. The results were similar to the findings of Caucasians, whereas the lengths of RHD gene deletion fragments of Japanese and French were 649 and 654 or 651 bp, respectively. CONCLUSIONS: The RHCE gene intron 4 of Han Chinese, Tibetans, and Mongols differs from the RHD gene intron 4 in the presence of a 652-bp fragment. The RHCE gene intron 4 in Chinese has its own structural characteristics and differs among various ethnicities and regions. PMID- 26579939 TI - Designed Synthesis of In2O3 Beads@TiO2-In2O3 Composite Nanofibers for High Performance NO2 Sensor at Room Temperature. AB - Porous single crystal In2O3 beads@TiO2-In2O3 composite nanofibers (TINFs) have been prepared via a facile electrospinning method. The beads were formed because of the existence of hemimicelles in pecursor solution. The formation of hemimicelles was attributed to the synergy of tetrabutyl titanate (TBT) and polyvinylpyrrolidone (PVP). Abundant In(3+) ions were drawn toward the ketonic oxygen of PVP resulting in In(3+) ions aggregation. Compared with pristine In2O3 nanofibers (INFs), the as-prepared TINFs exhibited excellent properties for sensing NO2 gas at room temperature (25 degrees C). The enhanced sensing property was due to much absorbed oxygen and Schottky junctions between the porous single crystal In2O3 beads and the Au electrode of the sensor. The strategy for combining the unique In2O3 beads@TiO2-In2O3 nanofibers structure which possessed superior conductivity and sufficient electrons with the addition of TiO2 offered an innovation to enhance the gas sensing performance. PMID- 26579940 TI - Can Wi-Fi Affect Brain Function? PMID- 26579941 TI - (56)Fe Irradiation Alters Spine Density and Dendritic Complexity in the Mouse Hippocampus. AB - A unique feature of the space radiation environment is the presence of high energy charged particles, which can be significantly hazardous to space flight crews who are exposed during a mission. Health risks associated with high-LET radiation exposure include cognitive injury. The pathogenesis of this injury is unknown but may involve modifications to dendritic structure and/or alterations in dendritic spine density and morphology. In this study, 24 two-month-old C57BL6/J male mice were either whole-body irradiated with 0.5 Gy (56)Fe (600 MeV/n; n = 12) or sham irradiated (n = 12). Three months postirradiation animals were tested for locomotor activity and habituation. After behavioral testing, animals were euthanized and the brains were flash frozen. Compared to sham irradiated mice, irradiated mice moved less when first introduced to the environment, although they did recognize the environment when re-exposed to it one day later. Exposure to (56)Fe radiation significantly compromised the dendritic architecture and reduced spine density throughout the hippocampal tri synaptic network. To our knowledge, these data represents the first reported evidence that high-LET radiation has deleterious effects on mature neurons associated with hippocampal learning and memory. PMID- 26579942 TI - Role of Pro-inflammatory Cytokines in Radiation-Induced Genomic Instability in Human Bronchial Epithelial Cells. AB - Inflammatory cytokines have been implicated in the regulation of radiation induced genomic instability in the hematopoietic system and have also been shown to induce chronic DNA damage responses in radiation-induced senescence. We have previously shown that human bronchial epithelial cells (HBEC3-KT) have increased genomic instability and IL-8 production persisting at day 7 after exposure to high-LET (600 MeV/nucleon (56)Fe ions) compared to low-LET (320 keV X rays) radiation. Thus, we investigated whether IL-8 induction is part of a broader pro inflammatory response produced by the epithelial cells in response to damage, which influences genomic instability measured by increased micronuclei and DNA repair foci frequencies. We found that exposure to radiation induced the release of multiple inflammatory cytokines into the media, including GM-CSF, GROalpha, IL 1alpha, IL-8 and the inflammation modulator, IL-1 receptor antagonist (IL-1RA). Our results suggest that this is an IL-1alpha-driven response, because an identical signature was induced by the addition of recombinant IL-1alpha to nonirradiated cells and functional interference with recombinant IL-1RA (Anakinra) or anti-IL-1alpha function-blocking antibody, decreased IL-8 production induced by radiation exposure. However, genomic instability was not influenced by this pathway as addition of recombinant IL-1alpha to naive or irradiated cells or the presence of IL-1 RA under the same conditions as those that interfered with the function of IL-8, did not affect micronuclei or DNA repair foci frequencies measured at day 7 after exposure. While dose-response studies revealed that genomic instability and IL-8 production are the consequences of targeted effects, experiments employing a co-culture transwell system revealed the propagation of pro-inflammatory responses but not genomic instability from irradiated to nonirradiated cells. Collectively, these results point to a cell-autonomous mechanism sustaining radiation-induced genomic instability in this model system and suggest that while molecules associated with these mechanisms could be markers for persisting damage, they reflect two different outcomes. PMID- 26579943 TI - Atorvastatin Ameliorates Radiation-Induced Cardiac Fibrosis in Rats. AB - Radiation-induced heart injury is one of the major side effects of radiotherapy for thoracic malignancies. Previous studies have shown that radiotherapy induced myocardial fibrosis and intensified myocardial remodeling. In this study, we investigated whether atorvastatin could inhibit radiation-induced heart fibrosis in Sprague-Dawley rats, which were randomly divided into six groups: control; radiation only; and four treatment groups receiving atorvastatin plus radiation (E1, E2, E3 and E4). All rats, except the control group, received local heart irradiation in 7 daily fractions of 3 Gy for a total of 21 Gy. Rats in groups E1 (10 mg/kg/day) and E2 (20 mg/kg/day) received atorvastatin and radiation treatment until week 12 after exposure. Rats in groups E3 (10 mg/kg/day) and E4 (20 mg/kg/day) received atorvastatin treatment from 3 months before irradiation to week 12 after irradiation. The expressions of TGF-beta1, Smad2, Smad3, fibronectin, ROCK I and p-Akt in heart tissues were evaluated using real-time PCR or Western blot analyses. Atorvastatin significantly reduced the expression of TGF-beta1, Smad3/P-Smad3, ROCK I and p-Akt in rats of the E1-E4 groups and in a dose-dependent manner. Fibronectin exhibited a similar pattern of expression changes. In addition, echocardiography showed that atorvastatin treatment can inhibit the increase of left ventricular end-diastolic dimension, left ventricular end-systolic diameter and left ventricular posterior wall thickness, and prevent the decrease of ejection fraction and fraction shortening in E1-E4 groups compared with the radiation only group. This study demonstrated that radiation exposure increased the expression of fibronectin in cardiac fibroblasts and induced cardiac fibrosis through activation of the TGF-beta1/Smad3, RhoA/ROCK, and PI3K/AKT signaling pathways. Statins ameliorated radiation-induced cardiac fibrosis in Sprague-Dawley rats. Our results suggest that atorvastatin is effective for the treatment of radiation-induced cardiac fibrosis, especially with longer and higher dose atorvastatin treatment, as demonstrated in experimental group E4. PMID- 26579944 TI - Organ Dose Estimates for Hyperthyroid Patients Treated with (131)I: An Update of the Thyrotoxicosis Follow-Up Study. AB - The Thyrotoxicosis Therapy Follow-up Study (TTFUS) is comprised of 35,593 hyperthyroid patients treated from the mid-1940s through the mid-1960s. One objective of the TTFUS was to evaluate the long-term effects of high-dose iodine 131 ((131)I) treatment (1-4). In the TTFUS cohort, 23,020 patients were treated with (131)I, including 21,536 patients with Graves disease (GD), 1,203 patients with toxic nodular goiter (TNG) and 281 patients with unknown disease. The study population constituted the largest group of hyperthyroid patients ever examined in a single health risk study. The average number (+/- 1 standard deviation) of (131)I treatments per patient was 1.7 +/- 1.4 for the GD patients and 2.1 +/- 2.1 for the TNG patients. The average total (131)I administered activity was 380 +/- 360 MBq for GD patients and 640 +/- 550 MBq for TNG patients. In this work, a biokinetic model for iodine was developed to derive organ residence times and to reconstruct the radiation-absorbed doses to the thyroid gland and to other organs resulting from administration of (131)I to hyperthyroid patients. Based on (131)I data for a small, kinetically well-characterized sub-cohort of patients, multivariate regression equations were developed to relate the numbers of disintegrations of (131)I in more than 50 organs and tissues to anatomical (thyroid mass) and clinical (percentage thyroid uptake and pulse rate) parameters. These equations were then applied to estimate the numbers of (131)I disintegrations in the organs and tissues of all other hyperthyroid patients in the TTFUS who were treated with (131)I. The reference voxel phantoms adopted by the International Commission on Radiological Protection (ICRP) were then used to calculate the absorbed doses in more than 20 organs and tissues of the body. As expected, the absorbed doses were found to be highest in the thyroid (arithmetic means of 120 and 140 Gy for GD and TNG patients, respectively). Absorbed doses in organs other than the thyroid were much smaller, with arithmetic means of 1.6 Gy, 1.5 Gy and 0.65 Gy for esophagus, thymus and salivary glands, respectively. The arithmetic mean doses to all other organs and tissues were more than 100 times less than those to the thyroid gland. To our knowledge, this work represents the most comprehensive study to date of the doses received by persons treated with (131)I for hyperthyroidism. PMID- 26579945 TI - Genetic and pharmacological intervention of the p75NTR pathway alters morphological and behavioural recovery following traumatic brain injury in mice. AB - PRIMARY OBJECTIVE: Neurotrophin levels are elevated after TBI, yet there is minimal regeneration. It was hypothesized that the pro-neurotrophin/p75NTR pathway is induced more than the mature neurotrophin/Trk pathway and that interfering with p75 signalling improves recovery following TBI. RESEARCH DESIGN: Lateral Fluid Percussion (LFP) injury was performed on wildtype and p75 mutant mice. In addition, TrkB agonist 7,8 Dihydroxyflavone or p75 antagonist TAT-Pep5 were tested. Western blot and immunohistochemistry revealed biochemical and cellular changes. Morris Water Maze and Rotarod tests demonstrated cognitive and vestibulomotor function. MAIN OUTCOMES AND RESULTS: p75 was up-regulated and TrkB was down-regulated 1 day post-LFP. p75 mutant mice as well as mice treated with the p75 antagonist or the TrkB agonist exhibited reduced neuronal death and degeneration and less astrocytosis. The cells undergoing apoptosis appear to be neurons rather than glia. There was improved motor function and spatial learning in p75 mutant mice and mice treated with the p75 antagonist. CONCLUSIONS: Many of the pathological and behavioural consequences of TBI might be due to activation of the pro-neurotrophin/p75 toxic pathway overriding the protective mechanisms of the mature neurotrophin/Trk pathway. Targeting p75 can be a novel strategy to counteract the damaging effects of TBI. PMID- 26579946 TI - Water equivalent phantom materials for 192Ir brachytherapy. AB - Several solid phantom materials have been tested regarding their suitability as water substitutes for dosimetric measurements in brachytherapy with (192)Ir as a typical high energy photon emitter. The radial variations of the spectral photon fluence, of the total, primary and scattered photon fluence and of the absorbed dose to water in the transversal plane of the tested cylindrical phantoms surrounding a centric and coaxially arranged Varian GammaMed afterloading (192)Ir brachytherapy source were Monte-Carlo simulated in EGSnrc. The degree of water equivalence of a phantom material was evaluated by comparing the radial dose-to water profile in the phantom material with that in water. The phantom size was varied over a large range since it influences the dose contribution by scattered photons with energies diminished by single and multiple Compton scattering. Phantom axis distances up to 10 cm were considered as clinically relevant. Scattered photons with energies reaching down into the 25 keV region dominate the photon fluence at source distances exceeding 3.5 cm. The tested phantom materials showed significant differences in the degree of water equivalence. In phantoms with radii up to 10 cm, RW1, RW3, Solid Water, HE Solid Water, Virtual Water, Plastic Water DT, and Plastic Water LR phantoms show excellent water equivalence with dose deviations from a water phantom not exceeding 0.8%, while Original Plastic Water (as of 2015), Plastic Water (1995), Blue Water, polyethylene, and polystyrene show deviations up to 2.6%. For larger phantom radii up to 30 cm, the deviations for RW1, RW3, Solid Water, HE Solid Water, Virtual Water, Plastic Water DT, and Plastic Water LR remain below 1.4%, while Original Plastic Water (as of 2015), Plastic Water (1995), Blue Water, polyethylene, and polystyrene produce deviations up to 8.1%. PMMA plays a separate role, with deviations up to 4.3% for radii not exceeding 10 cm, but below 1% for radii up to 30 cm. As suggested by the results of the dose simulations and the values of the linear attenuation coefficient, MU, over a large energy range, the balanced content of inorganic additives in a phantom material is regarded as the key feature, providing water equivalence with regard to the attenuation of the primary photons, the release of low-energy photons by Compton scattering, and their attenuation by a combination of the photoelectric and Compton effects. PMID- 26579947 TI - The effects of 8 weeks of motor skill training on cardiorespiratory fitness and endurance performance in children with developmental coordination disorder. AB - Interventions based on everyday motor skills have been developed to be effective in children with developmental coordination disorder (DCD). The purpose of the present study was to examine the effects of motor skill training on exercise tolerance and cardiorespiratory fitness in children with DCD. Children were assigned to 3 groups: an experimental training group comprising 14 children with DCD, a control nontraining group comprising 13 children with DCD, and a control nontraining group comprising 14 typically developed children. All participants were tested twice with an interval of 8-weeks on a cardiopulmonary exercise test, pulmonary function testing, and a 6-min walk test. After the training program the maximal power output was significantly increased for DCD group at anaerobic threshold (p < 0.05) and at peak level (maximal oxygen uptake, p < 0.001). Improvement in power output was more pronounced at the anaerobic threshold (t (13) = -5.21, p < 0.001) than at the maximal intensity (maximal oxygen uptake, t (13) = -3.08, p < 0.01) in the DCD training group. Children with DCD that participated in the training program improved their walking distance (t (13) = 9.08, p < 0.001), had a higher maximum heart rate (t (13) = -3.41, p < 0.01), and reduced perceived exertion (t (13) = 2.75, p < 0.05). The DCD nontraining group and the typically developed group did not change on any of the measures. In conclusion, training delayed reaching the anaerobic threshold and improved aerobic endurance and exercise tolerance in children with DCD. PMID- 26579948 TI - Dietary HMB and beta-alanine co-supplementation does not improve in situ muscle function in sedentary, aged male rats. AB - This study evaluated the effects of dietary beta-hydroxy-beta-methylbutyrate (HMB) combined with beta-alanine (beta-Ala) in sedentary, aged male rats. It has been suggested that dietary HMB or beta-Ala supplementation may mitigate age related declines in muscle strength and fatigue resistance. A total of 20 aged Sprague-Dawley rats were studied. At age 20 months, 10 rats were administered a control, purified diet and 10 rats were administered a purified diet supplemented with both HMB and beta-Ala (HMB+beta-Ala) for 8 weeks (approximately equivalent to 3 and 2.4 g per day human dose). We measured medial gastrocnemius (MG) size, force, fatigability, and myosin composition. We also evaluated an array of protein markers related to muscle mitochondria, protein synthesis and breakdown, and autophagy. HMB+beta-Ala had no significant effects on body weight, MG mass, force or fatigability, myosin composition, or muscle quality. Compared with control rats, those fed HMB+beta-Ala exhibited a reduced (41%, P = 0.039) expression of muscle RING-finger protein 1 (MURF1), a common marker of protein degradation. Muscle from rats fed HMB+beta-Ala also exhibited a 45% reduction (P = 0.023) in p70s6K phosphorylation following fatiguing stimulation. These data suggest that HMB+beta-Ala at the dose studied may reduce muscle protein breakdown by reducing MURF1 expression, but has minimal effects on muscle function in this model of uncomplicated aging. They do not, however, rule out potential benefits of HMB+beta-Ala co-supplementation at other doses or durations of supplementation in combination with exercise or in situations where extreme muscle protein breakdown and loss of mass occur (e.g., bedrest, cachexia, failure-to-thrive). PMID- 26579949 TI - High prevalence of suboptimal vitamin B12 status in young adult women of South Asian and European ethnicity. AB - Suboptimal vitamin B12 (B12) status has been associated with an increased risk of congenital anomalies, preterm birth, and childhood insulin resistance. South Asians - Canada's largest minority group - and women of reproductive age are vulnerable to B12 deficiency. This study aimed to assess the prevalence of and factors associated with B12 deficiency and suboptimal B12 status in a convenience sample of young adult women of South Asian and European descent in Metro Vancouver. We measured serum B12, holotranscobalamin, plasma methylmalonic acid, red blood cell and plasma folate, and hematologic parameters in 206 nonpregnant, healthy women aged 19-35 years. Categorization for B12 status adhered to serum B12 cutoffs for deficiency (<148 pmol/L) and suboptimal B12 status (148-220 pmol/L). We collected demographic, lifestyle, and dietary intake data and conducted genotyping for common genetic variants linked to B-vitamin metabolism. The prevalence of deficiency and suboptimal B12 status were 14% and 20%, respectively. Serum vitamin B12 concentrations were negatively associated with oral contraceptive use and first-generation immigrant status, and positively with dietary B12 intake and B12 supplement use. The prevalence of B12 inadequacy in this sample of highly educated women is higher than in the general Canadian population. In light of maternal and fetal health risks associated with B12 inadequacy in early-pregnancy, practitioners should consider monitoring B12 status before and during early pregnancy, especially in immigrants and women with low dietary B12 intakes including non-users of vitamin supplements. PMID- 26579950 TI - Multichannel Detection and Differentiation of Explosives with a Quantum Dot Array. AB - The sensing and differentiation of explosive molecules is key for both security and environmental monitoring. Single fluorophores are a widely used tool for explosives detection, but a fluorescent array is a more powerful tool for detecting and differentiating such molecules. By combining array elements into a single multichannel platform, faster results can be obtained from smaller amounts of sample. Here, five explosives are detected and differentiated using quantum dots as luminescent probes in a multichannel platform: 2,4-dinitrotoluene (DNT), 2,4,6-trinitrotoluene (TNT), tetryl (2,4,6-trinitrophenylmethylnitramine), cyclotrimethylenetrinitramine (RDX), and pentaerythritol tetranitrate (PETN). The sharp, variable emissions of the quantum dots, from a single excitation wavelength, make them ideal for such a system. Each color quantum dot is functionalized with a different surface receptor via a facile ligation process. These receptors undergo nonspecific interactions with the explosives, inducing variable fluorescence quenching of the quantum dots. Pattern analysis of the fluorescence quenching data allows for explosive detection and identification with limits-of-detection in the ppb range. PMID- 26579951 TI - Mapping Physiological Suitability Limits for Malaria in Africa Under Climate Change. AB - We mapped current and future temperature suitability for malaria transmission in Africa using a published model that incorporates nonlinear physiological responses to temperature of the mosquito vector Anopheles gambiae and the malaria parasite Plasmodium falciparum. We found that a larger area of Africa currently experiences the ideal temperature for transmission than previously supposed. Under future climate projections, we predicted a modest increase in the overall area suitable for malaria transmission, but a net decrease in the most suitable area. Combined with human population density projections, our maps suggest that areas with temperatures suitable for year-round, highest-risk transmission will shift from coastal West Africa to the Albertine Rift between the Democratic Republic of Congo and Uganda, whereas areas with seasonal transmission suitability will shift toward sub-Saharan coastal areas. Mapping temperature suitability places important bounds on malaria transmissibility and, along with local level demographic, socioeconomic, and ecological factors, can indicate where resources may be best spent on malaria control. PMID- 26579953 TI - Fatal Disseminated Aspergillus penicillioides Infection in a 3-Month-Old Infant with Suspected Cystic Fibrosis: Autopsy Case Report with Review of Literature. AB - Patients with cystic fibrosis (CF) often are colonized by Aspergillus species in their respiratory tract, but invasive aspergillosis is a rare complication. We describe the autopsy findings of an infant with cystic fibrosis who had fatal disseminated aspergillosis. The causative agent was identified as A. penicillioides by molecular technique. To our knowledge, this is the first report of disseminated aspergillosis caused by A. penicillioides in any type of patient. The literature on invasive aspergillosis in patients with cystic fibrosis also is reviewed. PMID- 26579952 TI - Can Postpartum Depression Be Managed in Pediatric Primary Care? AB - BACKGROUND: Postpartum depression is prevalent among women who have had a baby within the last 12 months. Depression can compromise parenting practices, child development, and family stability. Effective treatments are available, but access to mental healthcare is challenging. Routine infant healthcare visits represent the most regular contact mothers have with the healthcare system, making pediatric primary care (PPC) an ideal venue for managing postpartum depression. METHODS: We conducted a review of the published literature on postpartum depression programs. This was augmented with a Google search of major organizations' websites to identify relevant programs. Programs were included if they focused on clinical care practices, for at-risk or depressed women during the first year postpartum, which were delivered within the primary care setting. RESULTS: We found that 18 programs focused on depression care for mothers of infants; 12 were developed for PPC. All programs used a screening tool. Psychosocial risk assessments were commonly used to guide care strategies, which included brief counseling, motivating help seeking, engaging social supports, and facilitating referrals. Available outcome data suggest the importance of addressing postpartum depression within primary care and providing staff training and support. The evidence is strongest in family practices and community-based health settings. More outcome data are needed in pediatric practices. CONCLUSION: Postpartum depression can be managed within PPC. Psychosocial strategies can be integrated as part of anticipatory guidance. Critical supports for primary care clinicians, especially in pediatric practices, are needed to improve access to timely nonstigmatizing care. PMID- 26579955 TI - The Psychopharmacology of +/-3,4 Methylenedioxymethamphetamine and its Role in the Treatment of Posttraumatic Stress Disorder. AB - Prior to 1985, +/-3,4-methylenedioxymethamphetamine (MDMA) was readily used as a psychotherapeutic adjunct. As MDMA became popular in treating various psychiatric illnesses by mental health professionals, the public started to abuse the MDMA containing recreational drug "ecstasy." This alarmed the DEA, which led to emergency scheduling of MDMA as a Schedule I drug. Due to its scheduling in 1985, human research and clinical use has been limited. The majority of research on MDMA has been focused on the drug's potential harmful effects rather than its possible therapeutic effects. The limitations on retrospective human studies and preclinical animal models of MDMA neurotoxicity are examined in this analysis. New research has shown that MDMA, used as a catalyst in psychotherapy, is effective in treating posttraumatic stress disorder (PTSD). This review also examines the psychopharmacological basis for the efficacy of MDMA-assisted psychotherapy. Specifically, the brain regions involved with both PTSD and those activated by MDMA (i.e., amygdala, anterior cingulate cortex, and hippocampus) are examined. Also, the possible neurochemical mechanisms involved in MDMA's efficacy in treating PTSD are reviewed. PMID- 26579954 TI - Chemically Modified Interleukin-6 Aptamer Inhibits Development of Collagen Induced Arthritis in Cynomolgus Monkeys. AB - Interleukin-6 (IL-6) is a potent mediator of inflammatory and immune responses, and a validated target for therapeutic intervention of inflammatory diseases. Previous studies have shown that SL1026, a slow off-rate modified aptamer (SOMAmer) antagonist of IL-6, neutralizes IL-6 signaling in vitro. In the present study, we show that SL1026 delays the onset and reduces the severity of rheumatoid symptoms in a collagen-induced arthritis model in cynomolgus monkeys. SL1026 (1 and 10 mg/kg), administered q.i.d., delayed the progression of arthritis and the concomitant increase in serum IL-6 levels compared to the untreated control group. Furthermore, SL1026 inhibited IL-6-induced STAT3 phosphorylation ex vivo in T lymphocytes from human blood and IL-6-induced C reactive protein and serum amyloid A production in human primary hepatocytes. Importantly, SOMAmer treatment did not elicit an immune response, as evidenced by the absence of anti-SOMAmer antibodies in plasma of treated monkeys. These results demonstrate that SOMAmer antagonists of IL-6 may be attractive agents for the treatment of IL-6-mediated diseases, including rheumatoid arthritis. PMID- 26579956 TI - Scoliosis and the Subsequent Risk of Depression: A Nationwide Population-based Cohort Study in Taiwan. AB - STUDY DESIGN: A retrospective cohort study by using the Taiwanese National Health Insurance Research Database (NHIRD). OBJECTIVE: The purpose of this study is to conduct a large-scale cohort study to investigate the relationship between scoliosis and depression. SUMMARY OF BACKGROUND DATA: The association between scoliosis and depression has rarely been studied in Asian populations. METHODS: The study cohort consisted of patients with diagnosis of scoliosis between 2003 and 2005 (N = 1409). A comparison cohort was constructed from five age- and gender-matched control subjects selected via random sampling (N = 7045). Data on adjusted hazard ratios (AHRs) of depression, 5-year freedom from depression rates, and risk factors for depression for the two cohorts were compared. All subjects were tracked for 5 years from the date of cohort entry to identify the development of depression. Cox proportional hazard regressions were performed to evaluate the 5-year freedom from depression rates. This study is supported by the University research grant without any study-specific conflicts. RESULTS: During the 5-year follow-up period, 116 and 307 depression patients belonged to the scoliosis cohort and the comparison cohort, respectively. The AHRs of depression in patients with scoliosis was higher [AHR 1.95; 95% confidence interval (95% CI) 1.58-2.42; P < 0.001] than that of the controls during the 5-year follow-up. The risk of depression also demonstrated to be age-dependent for scoliosis patients. The middle-age (41-65 years old) and young adults (18-40 years old) scoliosis patients had higher AHRs (middle-age: AHR 2.45; 95% CI 1.67-3.59; P < 0.05; young adult: AHR 1.99; 95% CI 1.41-2.82; P < 0.05). CONCLUSION: The population-based study indicated that patients with scoliosis may have an increased risk of depression. Health care professionals should consider designing and planning effective psychological prevention and treatment for scoliosis patients. LEVEL OF EVIDENCE: 4. PMID- 26579957 TI - Can Intraoperative Text Messages Reduce Parental Anxiety of Children Undergoing Posterior Spinal Fusion Surgery for Adolescent Idiopathic Scoliosis? AB - STUDY DESIGN: A prospective, nonrandomized study. OBJECTIVE: To evaluate the effectiveness of periodic intraoperative text messages (SMS) in reducing parental anxiety level during posterior spinal fusion (PSF) surgery for adolescent idiopathic scoliosis (AIS) patients. SUMMARY OF BACKGROUND DATA: No studies have reported the use of intraoperative SMS to reduce level of anxiety in parents of patients who are undergoing AIS corrective surgery. METHODS: Parents of 50 AIS patients were studied at two centers. Group 1 did not receive any SMS whereas those in Group 2 received periodic SMS. Parents' anxiety were assessed using a validated Visual Analog Scale for anxiety (VAS-A) and the anxiety component of the Hospital Anxiety Depression Score (HADS). The assessment was carried out at five different periods: (P1) 6 hours before the surgery; (P2) at separation in the operation theatre; (P3) 1 hour after commencement of surgery; (P4) immediately after completion of surgery; (P5) 1 day postsurgery. RESULTS: A total of 96 parents (47 fathers, 49 mothers) were involved in this study. Both groups were comparable in terms of demographics and education level. The mean VAS for Group 1 peaked at P2 and the HADS scores peaked at P3. The anxiety level of Group 1 remained high at P2, P3, and P4. There was a steady decline in parental anxiety in Group 2 from P1 to P5. There were significantly lower mean VAS score and HADS score for both father and mother in Group 2 during P3 and P4. The mean HADS scores for parents in Group 1 at P2 and P3 were higher than 8, which indicate abnormal anxiety. CONCLUSION: The anxiety levels of parents receiving the SMS were significantly lower than parents who did not receive any messages. Thus, intraoperative SMS is an effective intervention to decrease parental anxiety of AIS patients undergoing PSF surgery. LEVEL OF EVIDENCE: 3. PMID- 26579958 TI - Replication of Association Between 53 Single-Nucleotide Polymorphisms in a DNA Based Diagnostic Test and AIS Progression in Chinese Han Population. AB - STUDY DESIGN: A case-only study. OBJECTIVE: The aim of this study was to evaluate the association of the 53 single-nucleotide polymorphisms (SNPs) in a prognostic test with curve progression in Chinese adolescent idiopathic scoliosis (AIS) patients. SUMMARY OF BACKGROUND DATA: "ScoliScore" was the first diagnostic kit developed for curve progression of AIS in the white population. To date, there is still a paucity of validation of ScoliScore in Chinese Han population. METHODS: A total of 670 AIS patients were included in the study, with 313 patients assigned to the nonprogression group and the other 357 patients assigned to the progression group. A panel of 53 SNPs encompassed in ScoliScore were genotyped using the PCR-based Invader assay. The allele frequencies were compared between AIS patients with progressive curve and those with nonprogressive curve. RESULTS: SNP rs9945359 and rs17044552 are the only 2 SNPs that had significantly different allele frequencies between the 2 groups. Allele A of rs9945359 was significantly higher in the progression group than in the nonprogression group (25.7% vs 19.5%, P = 0.01), and allele A of rs17044552 was significantly lower in the progression group (11.5% vs 16.4%, P = 0.01). The odds ratio (OR) of these 2 SNPs were 1.42 [95% confidence interval (95% CI) 1.09-1.88] and 0.65 (95% CI 0.47-0.91), respectively. As for the allele frequencies of the other 51 SNPs, no significant difference was found between the 2 groups. CONCLUSION: ScoliScore could not be able to predict the curve progression of AIS in Chinese Han population. However, the role of this test in other populations cannot be totally excluded, and additional replication studies in other ethnic groups are warranted to evaluate the significance of these SNPs. LEVEL OF EVIDENCE: 4. PMID- 26579959 TI - Spinal Fracture in Patients With Ankylosing Spondylitis: Cohort Definition, Distribution of Injuries, and Hospital Outcomes. AB - STUDY DESIGN: A retrospective cohort. OBJECTIVE: The aim of this study was to characterize spinal fractures in patients with ankylosing spondylitis. SUMMARY OF BACKGROUND DATA: Patients with ankylosing spondylitis are susceptible to fractures of the spinal column, even from minor trauma. However, the literature describing patients with ankylosing spondylitis and spinal fractures consists largely of case reports and small case series. The purpose of this study is to better characterize fractures of the ankylosed spine, including the patient population, locations of fracture, and outcomes in a large, nationally representative sample. METHODS: All patients with diagnoses of both fracture of the spinal column and ankylosing spondylitis admitted between 2005 and 2011 were identified in the National Inpatient Sample (NIS). Patient demographics, fracture regions, and complications were characterized with descriptive statistics. The associations between injury characteristics and outcomes were assessed using Poisson regression. RESULTS: A total of 939 patients with ankylosing spondylitis admitted with a spinal fracture were identified in NIS. The average age was 68.4 +/- 14.7 years, and 85% of patients were male. Cervical fractures were the most common (53.0%), followed by thoracic (41.9%), lumbar (18.2%), and sacral (1.5%). Spinal cord injury was present in 27.5% of cervical fractures, 16.0% of thoracic fractures, and 21.1% of cases overall. Fractures involving more than 1 region of the spine occurred in 13.1% of patients. Patients were treated with fusion in 49.9% of cases. In-hospital adverse events occurred in 29.4% of patients, and 6.6% of patients died during their admission. CONCLUSION: More than 10% of patients had fractures in more than 1 region of the spine. There is a high risk of adverse events in this population, and 6.6% of patients died during their inpatient stay. These results provide clinicians with a better understanding of the distribution and the high morbidity and mortality of fractures in the ankylosed spine. LEVEL OF EVIDENCE: 3. PMID- 26579960 TI - Spondylectomy for Giant Cell Tumor After Denosumab Therapy. AB - STUDY DESIGN: A case report. OBJECTIVE: To report a case of the lumbar giant cell tumor (GCT) utilizing a new clinical treatment modality (denosumab therapy), which showed a massive tumor reduction combined with the L4 spondylectomy. SUMMARY OF BACKGROUND DATA: There are some controversies about spinal GCT treatments. Denosumab has provided good clinical results in terms of tumor shrinkage, and local control in a short-time follow-up clinical study phase 2, although for spinal lesions, it has not been described. Nonetheless, "en bloc" spondylectomy has been accepted as being the best treatments modalities in terms of oncological control. METHODS: A case study with follow-up examination and series radiological assessments 6 months after therapy started, followed by a complex spine surgery. RESULTS: The denosumab therapy showed on the lumbar computed tomography scans follow-up 6 months later, a marked tumor regression around 90% associated to vertebral body calcification, facilitating a successful L4 spondylectomy with an anterior and posterior reconstruction. The patient recovered without neurological deficits. CONCLUSION: A new therapeutic modality for spinal GCT is available and showing striking clinical results; however, it is necessary for well-designed studies to answer the real role of denosumab therapy avoiding or facilitating complex spine surgeries as spondylectomies for spinal GCT. LEVEL OF EVIDENCE: 5. PMID- 26579961 TI - Reliability Analysis of Spino-Pelvic Parameters in Adult Spinal Deformity: A Comparison of Whole Spine and Pelvic Radiographs. AB - STUDY DESIGN: Retrospective study. OBJECTIVE: To examine the reliabilities of sagittal spino-pelvic alignment measurements using whole spine-pelvic and local pelvic radiographs and to determine whether spinal deformity affects these reliabilities. SUMMARY OF BACKGROUND DATA: Sagittal spino-pelvic alignment is important in adult spinal deformity patients (ASD). Spino-pelvic parameters are closely related to health-related quality of life and indispensable for surgical planning. However, few studies have focused on the reliability of these measurements. METHODS: Three spino-pelvic parameters, pelvic incidence (PI), pelvic tilt (PT), and sacral slope (SS) were measured in 2 patient groups: 33 adult scoliosis (AS) and 33 nondeformity (ND) patients, using whole spine-pelvic lateral radiographs (whole spine radiographs) and local pelvic lateral radiographs (local pelvic radiographs), by 5 experienced spine surgeons. Intra- and interobserver reliabilities for each procedure were evaluated by intraclass correlation coefficients (ICC). The interobserver reliability differences between the 2 procedures were statistically evaluated. The difference between the largest and smallest measurements among the 5 observers was also evaluated in the AS and ND groups. RESULTS: Measurement of the 3 parameters using whole spine or local pelvic radiographs showed good to excellent intraobserver reliability (range of ICC: 0.820-0.935). The interobserver reliabilities of PI and PT from local pelvic radiographs were significantly higher than those from whole spine radiographs (P < 0.002). The intraobserver reliabilities of PI and PT from pelvic radiographs tended to be higher than those from whole spine radiographs, but the differences were not statistically significant. The reliability of SS was comparable between the 2 methods. The differences between the highest and lowest PI and PT measurements were smaller with the pelvic compared to whole spine radiographs. These findings were consistent in the AS and ND groups. CONCLUSION: Local pelvic radiography is more reliable than whole spine radiography for determining spino pelvic parameters, and we recommend its use for evaluating ASD patients. LEVEL OF EVIDENCE: 3. PMID- 26579962 TI - The Regionalization of Lumbar Spine Procedures in New York State: A 10-Year Analysis. AB - STUDY DESIGN: A retrospective review of an administrative database. OBJECTIVE: The purpose of this study is to determine the current extent of regionalization by mapping lumbar spine procedures according to hospital and patient zip code, as well as examine the rate of growth of lumbar spine procedures performed at high-, medium-, and low-volume institutions in New York State. SUMMARY OF BACKGROUND DATA: The association between hospital and spine surgeon volume and improved patient outcomes is well established. There is no study investigating the actual process of patient migration to high-volume hospitals. METHODS: New York Statewide Planning and Research Cooperative System (SPARCS) administrative data were used to identify 228,695 lumbar spine surgery patients from 2005 to 2014. The data included the patients' zip code, hospital of operation, and year of discharge. The volume of lumbar spine surgery in New York State was mapped according to patient and hospital 3-digit zip code. New York State hospitals were categorized as low, medium, and high volume and descriptive statistics were used to determine trends in changes in hospital volume. RESULTS: Lumbar spine surgery recipients are widely distributed throughout the state. Procedures are regionalized on a select few metropolitan centers. The total number of procedures grew 2.5% over the entire 10-year-period. High-volume hospital caseload increased 50%, from 7253 procedures in 2005 to 10,915 procedures in 2014. The number of procedures at medium and low-volume hospitals decreased 30% and 13%, respectively. CONCLUSIONS: Despite any concerted effort aimed at moving orthopedic patients to high-volume hospitals, migration to high-volume centers occurred. Public interest in quality outcomes and cost, as well as financial incentives among medical centers to increase market share, potentially influence the migration of patients to high-volume centers. Further regionalization has the potential to exacerbate the current level of disparities among patient populations at low and high-volume hospitals. LEVEL OF EVIDENCE: 3. PMID- 26579963 TI - Cervical Sagittal Imbalance is a Predictor of Kyphotic Deformity After Laminoplasty in Cervical Spondylotic Myelopathy Patients Without Preoperative Kyphotic Alignment. AB - STUDY DESIGN: A retrospective cohort study. OBJECTIVE: The aim of this study is to investigate the preoperative factors for postlaminoplasty kyphotic deformity in cervical spondylotic myelopathy (CSM) patients without preoperative kyphotic alignment focused on the cervical sagittal balance. SUMMARY OF BACKGROUND DATA: After laminoplasty (LAMP), appropriate decompression may be obtained when cervical lordosis is maintained to allow the posterior shift of the spinal cord. Therefore, LAMP is not suitable for patients with preoperative cervical kyphosis. However, we sometimes encounter patients who developed postoperative kyphosis despite normal preoperative alignment. The risk factors of postlaminoplasty kyphotic deformity for the patients without preoperative kyphotic alignment are not well known. METHODS: A total of 174 consecutive patients who received a double-door LAMP for CSM without preoperative kyphotic alignment and completed a 1-year follow-up were enrolled. Cervical lateral X-ray images obtained in the standing position were measured at the preoperative stage and during a 1-year follow-up visit. The radiographic measurements included the following: (1) C2-7 lordotic angle (C2-7 angle), (2) C2-7 range of motion (C2-7 ROM), (3) CGH (center of gravity of the head)-C7 SVA, and (4) C7 slope. The clinical results were evaluated using the Japanese Orthopedic Association score system for cervical myelopathy (C-JOA score). RESULTS: Postoperative kyphotic deformity was observed in 9 patients (5.2%). The recovery rates of the C-JOA scores at the 1-year follow up period in the kyphotic deformity (+) group were inferior to those of the kyphotic deformity (-) group. The CGH-C7 SVA and advanced age were detected as preoperative risk factors using multivariate analysis. Cutoff values for predicting postlaminoplasty kyphotic deformity were a CGH-C7 SVA = 42 mm and an age of 75 years. CONCLUSION: Cervical sagittal imbalance and advanced age were the preoperative risk factors for kyphotic deformity after LAMP for CSM in patients without preoperative cervical kyphotic alignment. LEVEL OF EVIDENCE: 4. PMID- 26579964 TI - Cumulative Intracranial Tumor Volume (CITV) Enhances the Prognostic Value of the Lung-Specific Graded Prognostic Assessment (GPA) Model. AB - BACKGROUND: Management of patients afflicted with brain metastasis requires tailoring of therapeutic strategies based on survival expectations. Therefore, the development of prognostic indices is of critical importance in this patient population. OBJECTIVE: To determine whether the cumulative intracranial tumor volume (CITV) of brain metastasis augments the prognostic value of the lung specific Graded Prognostic Assessment (GPA) index. METHODS: Patient data were derived from 365 lung cancer patients with brain metastasis who were consecutively treated with stereotactic radiosurgery at the University of California, San Diego/San Diego Gamma Knife Center. CITV was analyzed to determine the volume cutoff that maximized sensitivity and specificity for 1-year survival. Multivariate Cox proportional hazard modeling was performed, and overall survival was estimated by the Kaplan-Meier method risk stratifying with or without this optimal CITV. The prognostic value of these models (lung-specific GPA +/- CITV) was quantitatively compared with the use of net reclassification improvement (>0) and integrated discrimination improvement. RESULTS: For the University of California, San Diego/San Diego Gamma Knife Center cohort, the CITV cutoff that had the greatest survival discrimination at 1 year was 4 cm. The addition of CITV to the lung-specific GPA indexes significantly improved the prognostic value of lung-specific GPA, with net reclassification improvement >0 of 0.430 (95% confidence interval, 0.228-0.629) and integrated discrimination improvement of 0.029 (95% confidence interval, 0.004-0.073). These findings were validated in an independent cohort of 1638 lung cancer patients with brain metastasis who were treated with stereotactic radiosurgery at the Katsuta Hospital Mito Gamma House in Japan. CONCLUSION: In independent cohorts, the addition of CITV to the lung-specific GPA index significantly improved the prognostic value of this index. ABBREVIATIONS: AUC, area under the receiver operating characteristic curveBM, brain metastasisCITV, cumulative intracranial tumor volumeds-GPA, disease-specific Graded Prognostic AssessmentGPA, Graded Prognostic AssessmentIDI, integrated discrimination improvementKHMGH, Katsuta Hospital Mito Gamma HouseKPS, Karnofsky Performance StatusNRI, net reclassification improvementROC, receiver-operating characteristic curveSRS, stereotactic radiosurgeryUCSD/SDGKC, University of California, San Diego/San Diego Gamma Knife Center. PMID- 26579965 TI - Internal Auditory Canal Decompression for Hearing Maintenance in Neurofibromatosis Type 2 Patients. AB - BACKGROUND: In neurofibromatosis type 2 (NF2), multiple therapeutic options are available to prevent bilateral hearing loss that significantly affects the quality of life of patients. OBJECTIVE: To evaluate the morbidity and functional results of internal auditory canal (IAC) decompression in NF2 patients with an only hearing ear. METHODS: Twenty-one NF2 patients operated on for IAC decompression in a 3-year period with a minimum follow-up of 1 year were included in this retrospective study. They presented unilateral deafness due to previous contralateral vestibular schwannoma removal in 16 patients or contralateral hearing loss due to the tumor in 5 patients. Hearing level was of class A (American Academy of Otolaryngology-Head and Neck Surgery classification) in 7 patients, B in 8 patients, C in 1 patient, and D in 5 patients. Pure-tone average and speech discrimination score evaluations were performed at 6 days, 1 year, and during the follow-up. Eight patients had postoperative chemotherapy. RESULTS: No case of facial nerve palsy was observed. In the early postoperative period; all patients maintained the hearing class of the preoperative period. At 1-year follow-up, all but 3 patients maintained their hearing scores; at last follow-up (mean follow-up, 23 +/- 8 months; range, 12-44 months), hearing classes remained stable with only 1 patient worsening from class B to C and 1 patient improving from class D to B. CONCLUSION: Decompression of IAC seems to be a useful procedure for hearing maintenance in NF2 patients, with very low morbidity. Ideal timing and association with chemotherapy should be evaluated in the future. ABBREVIATIONS: FN, facial nerveIAC, internal auditory canalNF2, neurofibromatosis type 2PTA, pure tone averageSDS, speech discrimination scoreVS, vestibular schwannoma. PMID- 26579966 TI - Outcomes of Operative and Nonoperative Treatment for Adult Spinal Deformity: A Prospective, Multicenter, Propensity-Matched Cohort Assessment With Minimum 2 Year Follow-up. AB - BACKGROUND: High-quality studies that compare operative and nonoperative treatment for adult spinal deformity (ASD) are needed. OBJECTIVE: To compare outcomes of operative and nonoperative treatment for ASD. METHODS: This is a multicenter, prospective analysis of consecutive ASD patients opting for operative or nonoperative care. Inclusion criteria were age >18 years and ASD. Operative and nonoperative patients were propensity matched with the baseline Oswestry Disability Index, Scoliosis Research Society-22r, thoracolumbar/lumbar Cobb angle, pelvic incidence-to-lumbar lordosis mismatch (PI-LL), and leg pain score. Analyses were confined to patients with a minimum of 2 years of follow-up. RESULTS: Two hundred eighty-six operative and 403 nonoperative patients met the criteria, with mean ages of 53 and 55 years, 2-year follow-up rates of 86% and 55%, and mean follow-up of 24.7 and 24.8 months, respectively. At baseline, operative patients had significantly worse health-related quality of life (HRQOL) based on all measures assessed (P < .001) and had worse deformity based on pelvic tilt, pelvic incidence-to-lumbar lordosis mismatch, and sagittal vertical axis (P <= .002). At the minimum 2-year follow-up, all HRQOL measures assessed significantly improved for operative patients (P < .001), but none improved significantly for nonoperative patients except for modest improvements in the Scoliosis Research Society-22r pain (P = .04) and satisfaction (P < .001) domains. On the basis of matched operative-nonoperative cohorts (97 in each group), operative patients had significantly better HRQOL at follow-up for all measures assessed (P < .001), except Short Form-36 mental component score (P = .06). At the minimum 2-year follow-up, 71.5% of operative patients had >=1 complications. CONCLUSION: Operative treatment for ASD can provide significant improvement of HRQOL at a minimum 2-year follow-up. In contrast, nonoperative treatment on average maintains presenting levels of pain and disability. ABBREVIATIONS: ASD, adult spinal deformityHRQOL, health-related quality of lifeLL, lumbar lordosisMCID, minimal clinically important differenceNRS, numeric rating scaleODI, Oswestry Disability IndexPI, pelvic incidenceSF-36, Short Form 36SRS-22r, Scoliosis Research Society-22rSVA, sagittal vertical axis. PMID- 26579967 TI - Treatment of Distal Anterior Circulation Aneurysms With the Pipeline Embolization Device: A US Multicenter Experience. AB - BACKGROUND: Utilization of the Pipeline embolization device (PED) to treat distal carotid circulation aneurysms has not been well studied. OBJECTIVE: To report the collective experience of using PED to treat distal anterior circulation aneurysms. METHODS: We retrospectively reviewed clinical and radiographic records of all patients who underwent Pipeline embolization of distal anterior circulation aneurysms at 10 US neurosurgical centers between 2011 and 2013. RESULTS: Twenty-eight patients (mean age 51.7 years; 18 women) with 28 aneurysms were included in the analyses. Fifteen aneurysms were fusiform, 5 dissecting, and 8 saccular. Average aneurysm size was 12.3 mm; 7 were giant. Twenty aneurysms were located along the middle cerebral artery, 6 along the anterior cerebral artery, and 2 along the anterior communicating artery. PED deployment was successful in 27 patients, with coils utilized in 6 cases. Clinical follow-up was available for an average of 10.7 months (range 3-26). Twenty-seven patients had follow-up neurovascular imaging: 21 aneurysms had complete occlusion, 4 had residual neck filling, and 2 had residual dome filling. Periprocedural complications (<30 days) occurred in 3 patients (10.7%), including 1 case of device failure resulting in stroke. Outcomes were good (modified Rankin Scale score 0 to 2) in 27 patients (96.4%) and fair (modified Rankin Scale 3) in 1. CONCLUSION: PED can be utilized in the treatment of distal anterior circulation aneurysms with difficult anatomy for conventional surgical or endovascular techniques. Larger-scale studies with long-term follow-up are needed to further elucidate the durability of PED treatment and its effect on perforator-rich vascular segments. ABBREVIATIONS: ACA, anterior cerebral arteryAcomA, anterior communicating arteryDSA, digital subtraction angiographyMCA, middle cerebral arterymRS, modified Rankin scalePED, Pipeline embolization device. PMID- 26579968 TI - Benefit of Transforaminal Lumbar Interbody Fusion vs Posterolateral Spinal Fusion in Lumbar Spine Disorders: A Propensity-Matched Analysis From the National Neurosurgical Quality and Outcomes Database Registry. AB - BACKGROUND: Despite increasing use and potential benefits of transforaminal lumbar interbody fusion (TLIF) compared with posterolateral spinal fusion (PSF), previous studies have not documented improved clinical outcomes with TLIF vs PSF. OBJECTIVE: To compare the outcomes of TLIF with PSF in patients with spondylolisthesis, spinal stenosis, and adjacent level disease. METHODS: The National Neurosurgical Quality and Outcomes Database was queried for patients who had a lumbar fusion. Eighty-five percent (1722) of enrolled cases had 12-month follow-up data. There were 306 PSF patients and 1230 TLIF patients. PSF cases within each diagnostic subgroup were propensity-matched to patients who had TLIF. Sufficient propensity-matched controls were available for patients with spondylolisthesis (109), spinal stenosis (63), and adjacent segment disease (47). RESULTS: Operating room time, estimated blood loss, and length of stay were similar between PSF and TLIF in all 3 propensity-matched groups. In the spondylolisthesis group, there was a greater improvement in Oswestry Disability Index (ODI) with TLIF vs PSF at 3 months (19.4 vs 26.0, P = .009), 12 months (20.8 vs 29.3, P = .001), and in percentage reaching minimal clinically important difference at 12 months (80% vs 62%, P = .007). There were no differences in ODI improvement between PSF and TLIF in the stenosis or adjacent segment disease groups. CONCLUSION: TLIF generated more favorable ODI outcomes than PSF for patients with spondylolisthesis, but not for patients with spinal stenosis or adjacent segment disease. There was also equivalence in operating room time and estimated blood loss between TLIF and PSF, potentially altering the long-standing assumption that PSF is a simpler procedure. ABBREVIATIONS: ASA, American Society of AnesthesiologistsEBL, estimated blood lossEQ-5D, EuroQOL-5DHRQOL, health related quality of lifeMCID, minimal clinically important differenceNQOD, National Neurosurgery Quality and Outcomes DatabaseNRS, numeric rating scaleODI, Oswestry Disability IndexOR, operating roomPSF, posterolateral spinal fusionTLIF, transforaminal lumbar interbody fusion. PMID- 26579969 TI - Genetic engineering strategies to prevent the effects of antibody and complement on xenogeneic chondrocytes. AB - Advances in animal transgenesis may allow using xenogeneic chondrocytes in tissue engineering applications for clinical cartilage repair. Porcine cartilage is rejected by humoral and cellular mechanisms that could be overcome by identifying key molecules triggering rejection and developing effective genetic-engineering strategies. Accordingly, high expression of alpha1,2-fucosyltransferase (HT) in xenogeneic cartilage protects from galactose alpha1,3-galactose (Gal)-mediated antibody responses. Now, we studied whether expression of a complement inhibitor provides further protection. First, porcine articular chondrocytes (PAC) were isolated from non-transgenic, single and double transgenic pigs expressing HT and moderate levels of human CD59 (hCD59) and their response to human serum was assessed. High recombinant expression of human complement regulatory molecules hCD59 and hDAF was also attained by retroviral transduction of PAC for further analyses. Complement activation on PAC after exposure to 20 % human serum for 24 hours mainly triggered the release of pro-inflammatory cytokines IL-6 and IL-8. Transgenic expression of HT and hCD59 did not suffice to fully counteract this effect. Nevertheless, the combination of blocking anti-Gal antibodies (or C5a) and high hCD59 levels conferred very high protection. On the contrary, high hDAF expression attained the most dramatic reduction in IL-6/IL-8 secretion by a single strategy, but the additional inhibition of anti-Gal antibodies or C5a did not provide further improvement. Notably, we demonstrate that both hCD59 and hDAF inhibit anaphylatoxin release in this setting. In conclusion, our study identifies genetic-engineering approaches to prevent humoral rejection of xenogeneic chondrocytes for use in cartilage repair. PMID- 26579971 TI - Pharmacotherapy for premature ejaculation. AB - INTRODUCTION: Four premature ejaculation (PE) subtypes are distinguished on the basis of the duration of the intravaginal ejaculation latency time (IELT), its course in life, and frequency of complaints. Since the 1930s oral drug treatment and local anesthetics have been used to treat PE. Apart from dapoxetine, all currently available drugs to treat PE (SSRIs, clomipramine, and local anesthetics) are off-label. Not only men with lifelong and acquired PE, but also men with normal IELT values may want to postpone their ejaculation time. AREAS COVERED: The guideline of the International Society for Sexual Medicine for the treatment of PE has provided evidence-based recommendations for the pharmacotherapy of lifelong and acquired PE. Selective serotonin reuptake inhibitors (SSRIs) delay ejaculation by interfering with the serotonin (5-HT) neurotransmission system in the central nervous system. Attention is given not only to the well-known but also to the recently published, very rare side effects of SSRIs. EXPERT OPINION: Men with normal IELT values who want to postpone ejaculation do not need "drugs for the treatment of PE" but "ejaculation delaying drugs." Pharmacological research of these ejaculation-delaying drugs ought to be investigated in men with normal IELT values, such as in men with subjective PE, variable PE, and in male volunteers. PMID- 26579970 TI - Derivation of Rabbit Embryonic Stem Cells from Vitrified-Thawed Embryos. AB - The rabbit is a useful animal model for regenerative medicine. We previously developed pluripotent rabbit embryonic stem cell (rbESC) lines using fresh embryos. We also successfully cryopreserved rabbit embryos by vitrification. In the present work, we combined these two technologies to derive rbESCs using vitrified-thawed (V/T) embryos. We demonstrate that V/T blastocysts (BLs) can be used to derive pluripotent rbESCs with efficiencies comparable to those using fresh BLs. These ESCs are undistinguishable from the ones derived from fresh embryos. We tested the developmental capacity of rbESCs derived from V/T embryos by BL injection experiments and produced chimeric kits. Our work adds cryopreservation to the toolbox of rabbit stem cell research and applications and will greatly expand the available research materials for regenerative medicine in a clinically relevant animal model. PMID- 26579972 TI - Classification of mouth movements using 7 T fMRI. AB - OBJECTIVE: A brain-computer interface (BCI) is an interface that uses signals from the brain to control a computer. BCIs will likely become important tools for severely paralyzed patients to restore interaction with the environment. The sensorimotor cortex is a promising target brain region for a BCI due to the detailed topography and minimal functional interference with other important brain processes. Previous studies have shown that attempted movements in paralyzed people generate neural activity that strongly resembles actual movements. Hence decodability for BCI applications can be studied in able-bodied volunteers with actual movements. APPROACH: In this study we tested whether mouth movements provide adequate signals in the sensorimotor cortex for a BCI. The study was executed using fMRI at 7 T to ensure relevance for BCI with cortical electrodes, as 7 T measurements have been shown to correlate well with electrocortical measurements. Twelve healthy volunteers executed four mouth movements (lip protrusion, tongue movement, teeth clenching, and the production of a larynx activating sound) while in the scanner. Subjects performed a training and a test run. Single trials were classified based on the Pearson correlation values between the activation patterns per trial type in the training run and single trials in the test run in a 'winner-takes-all' design. MAIN RESULTS: Single trial mouth movements could be classified with 90% accuracy. The classification was based on an area with a volume of about 0.5 cc, located on the sensorimotor cortex. If voxels were limited to the surface, which is accessible for electrode grids, classification accuracy was still very high (82%). Voxels located on the precentral cortex performed better (87%) than the postcentral cortex (72%). SIGNIFICANCE: The high reliability of decoding mouth movements suggests that attempted mouth movements are a promising candidate for BCI in paralyzed people. PMID- 26579973 TI - Rotational Excitation of the OH(+) Radical by Collision with H at Low Temperature. AB - A ro-vibrationally inelastic close coupling study of the rotational excitation of OH(+)(X(3)Sigma(-)) by collisions with H((2)S) is presented. The two lowest potential energy surfaces of doublet and quadruplet spin multiplicity are involved. The former is the one we developed recently, and the latter is a modified version of the quadruplet surface of Martinez et al. to include the long range charge-induced-dipole potential. The details of the modification of this surface are presented as well as the comparison of the rotational excitation resulting from collisions with hydrogen on these two surfaces. The effect of the coupling between vibration and rotation on the rotational excitation rate is also discussed, as the potential well depth of the doublet surface is quite large and allows the coupling between many vibrational channels of OH(+). As the hydrogen exchange reaction can occur for both potential energy surfaces, we discuss the reliability of the approximation made by the calculation of the cross sections with a quantum dynamics limited to the inelastic process. The relative importance of the collisions on the doublet or quadruplet surface within a given rotational transition is also discussed. PMID- 26579974 TI - The Relationship Between Nurse Staffing and 30-Day Readmission for Adults With Heart Failure. AB - OBJECTIVE: The purpose of this study was to better understand the relationship between nurse staffing and 30-day excess readmission ratios for patients with heart failure in the top US adult cardiology and heart surgery hospitals. BACKGROUND: Heart failure is the most common cause of hospitalization for patients older than 65 years and is the most frequent diagnosis associated with 30-day hospital readmission in the United States. METHODS: A secondary data analysis was conducted using nurse staffing data from 661 cardiology and heart surgery hospitals from the 2013 US News & World Report "Best Hospitals" survey. These data were combined with excess readmission ratios from the Centers for Medicare & Medicaid Services Hospital Compare database from 2013. An independent samples t test was used to compare staffing (low/high) and excess hospital readmissions rates. RESULTS: A significant difference (P = .021) was found between the low nurse staffing group (n = 358) and the high nurse staffing group (n = 303). Hospitals with a lower nurse staffing index had a significantly higher excess readmission rate. CONCLUSION: These data provide further support to the body of research showing a positive relationship between nurse staffing and positive outcomes. PMID- 26579975 TI - Quantum interferences in the photodissociation of Cl2(B) in superfluid helium nanodroplets ((4)He)N. AB - Quantum interferences are probably one of the most fascinating phenomena in chemical physics and, particularly, in reaction dynamics, where they are often very elusive from an experimental perspective. Here, we have theoretically investigated, using a hybrid method recently proposed by us, the dynamics of the formation of confinement quantum interferences in the photodissociation of a Cl2 molecule (B <- X electronic excitation) embedded in a superfluid helium nanodroplet of different sizes (50-500 (4)He atoms), which is to the best of our knowledge the first time that this type of interference is described in reaction dynamics. Thus, we have widely extended a recent contribution of our group, where interferences were not the main target, identifying the way they are formed and lead to the production of strongly oscillating velocity distributions in the Cl dissociating atoms, and also paying attention to the energy transfer processes involved. This probably corresponds to a rather general behavior in the photodissociation of molecules in helium nanodroplets. We hope that the present study will encourage the experimentalists to investigate this captivating phenomenon, although the technical difficulties involved are very high. PMID- 26579976 TI - Clinical Outcomes of Advanced Heart Failure Patients with Cardiogenic Shock Treated with Temporary Circulatory Support Before Durable LVAD Implant. AB - Temporary circulatory support (TCS) is used to improve hemodynamics in patients with cardiogenic shock as a bridge to durable ventricular assist device (dVAD). Data from dVAD recipients with or without TCS (extracorporeal membranous oxygenation [ECMO], n = 14; TandemHeart [TH], n = 26) were evaluated. Clinical characteristics and hemodynamics were analyzed for patients before and after TCS and compared with profile 1 (n = 29) or profile 2-3 (n = 269) patients without TCS before dVAD. Extracorporeal membranous oxygenation patients had the highest use of preoperative mechanical ventilation, vasopressors, and the highest HeartMate II risk score before dVAD (p < 0.01). Patients receiving TCS before dVAD implant had hemodynamics comparable with patients in Profiles 2-3 and superior to that of Profile 1 patients without TCS. Operative survival after dVAD was lower in patients receiving ECMO (57%) compared with Profile 1 patients receiving TH (88%), Profile 1 without TCS (82%), or Profile 2-3 patients (97%; all p < 0.01). Despite improved clinical stability with TCS, patients bridged to a dVAD have event-free survival that parallels patients in profile 1 without TCS. Our data suggest that patients requiring TCS before dVAD implant should be still classified Interagency Registry for Mechanically Assisted Circulatory Support profile 1. PMID- 26579977 TI - Clinical Durability of the CARMEDA BioActive Surface in EXCOR Ventricular Assist Device Pumps. AB - The durability of CBAS Heparin Surface on EXCOR pumps retrieved after clinical use for varying periods of time was studied by analyzing samples for surface heparin density and bioactivity. The mean time of clinical use of the investigated 14 EXCOR pumps was 178 days (range, 15-461 days). Mean heparin density was 3.1 +/- 0.6 MUg/cm2 (range, 2.2-4.8 MUg/cm2), and the measured mean heparin bioactivity was 14 +/- 5 rhomol/cm2 (range: 7-27 rhomol/cm2). There was no detectable degradation or loss of function of CBAS Heparin Surface over time. Samples from the housing and the membrane of the EXCOR pump showed no significant difference in heparin bioactivity or density. The CBAS Heparin Surface stays on the surface and remains bioactive on the EXCOR pump at least up until 1 year. This is an important demonstration of coating durability and supports the mid term and long-term clinical use as bridge-to-heart transplantation or to myocardial recovery. PMID- 26579978 TI - The Use of Extracorporeal Membrane Oxygenation Systems in Severe Accidental Hypothermia After Drowning: A Centre Experience. AB - Cardiopulmonary failure because of drowning with accidental hypothermia (AH) remains a major task for emergency care physicians. In this case series, we describe our experience in nine patients with cardiopulmonary failure after drowning with AH less than 35 degrees C, who were provided on an emergency basis with extracorporeal life support (ECLS) system or extracorporeal membrane oxygenation (ECMO). Conservative rewarming methods are not considered for this study. Preclinical conditions and protocols were gathered. Surgical reports and clinical data sets were collected. Median age was 24 years (range, 6-75 years). Six patients were male. Climatic conditions mostly showed cold to frosty weather. All cases had different preclinical rescue procedures. They reached the emergency department under cardiopulmonary resuscitation (CPR). Indications for ECLS were cardiac arrest, and in one case, pulmonary failure. Mean CPR duration was 60 min (range: 15-120 min). Before implantation, the median pH value was 6.9. Two patients could be successfully weaned from the systems. Cause of death was severe neurologic damage in six patients and cardiac failure in one patient. The use of ECLS/ECMO is a therapy option for a small range of patients with cardiopulmonary failure because of drowning with AH. Nevertheless, the interval of preclinical rescue remains extensively long. PMID- 26579979 TI - Phosphorus Removal in Low-Flux Hemodialysis, High-Flux Hemodialysis, and Hemodiafiltration. AB - Phosphorus removal by hemoelimination procedure is a important mechanism to maintain phosphorus level in acceptable level in patients on dialysis. Phosphorus is removed by both diffusion and convection, but in clinical practice, it is not possible to differentiate the contribution of this two transport modalities. We used Gutzwiller formula to quantify the amount of removed phosphorus and compared it in low-flux hemodialysis (LFHD), high-flux hemodialysis (HFHD), and on-line hemodiafiltration (HDF). There were no significant differences in phosphorus predialysis concentration, duration of procedure, processed blood volume and ultrafiltration, e.g., factors, which could possibly influence phosphorus elimination. All three tested dialysis modes also did not differ in urea dialysis dose (Kt/V) as a parameter of small molecular weight removal (LFHD, 1.50 +/- 0.04 vs HFHD, 1.5 +/- 0.06 vs HDF, 1.5 +/- 0.05). The amount of removed phosphorus in LFHD, HFHD, and HDF was 34.0 +/- 1.2, 37.8 +/- 1.6, and 38.3 +/- 1.4 mmol, respectively. Statistically significant increase in phosphorus removal was seen only with use of high-flux membrane (HFHD and HDF) when compared with the low flux one. No difference was, however, found between HFHD and HDF. It can thus be concluded that phosphorus removal in all three dialysis modes is a predominantly diffusive issue and contribution of convection to it is minor to negligible. PMID- 26579980 TI - Infections and Extracorporeal Membrane Oxygenation: Incidence, Therapy, and Outcome. AB - The objective is to assess the influence of infections and the microbiological spectrum on the general outcome of patients undergoing therapy with extracorporeal devices (ECDs), extracorporeal membrane oxygenation, extracorporeal life support, and pumpless extracorporeal lung assist. We performed a single-center, retrospective analysis of 99 patients receiving ECD. Infections requiring ECD, nosocomial infections occurring during treatment, the use of guideline-based antiinfective therapies, and patient outcomes were described and statistically analyzed. We analyzed 88 patients-survivors and nonsurvivors-and subdivided the infections into primary and nosocomial infections. The median patient age was 54.0 years, 85.2% were men, and 45 (51.1%) survived. Surviving ECD patients had a higher risk of nosocomial infection because of their prolonged hospital stay. Our results indicated that early, focused, antiinfective therapy was important to avoid severe infection complications. Infections causing sepsis and multiorgan dysfunction were negatively associated with outcome and successful weaning of ECD. The percentages and types of pathogens in the ECD cohort did not differ from the general colonization of intensive care units. Because a significant correlation between pathogens, infections, and outcome was not detected, we recommend focusing on clinical parameters to decide whether patients will benefit from ECD support. PMID- 26579981 TI - Selective nanomanipulation of fluorescent polystyrene nano-beads and single quantum dots at gold nanostructures based on the AC-dielectrophoretic force. AB - We introduced the selective manipulation of polystyrene (PS) nano-beads and single quantum dots (QDs) at a gold nanostructure by using the AC dielectrophoretic (DEP) force. Manipulation in three degrees of freedom (end facet, side, and position-selective manipulation) was accomplished in gold nanostructures between microelectrodes. A 10 MUm gap between the microelectrodes, which has a 100 nm-wide nanowire and 200 nm-wide vortex nanostructures at the inside of the gap, was fabricated, and nanostructures were not connected with the electrodes. We also performed theoretical calculations to verify the selective manipulation through the floating AC-DEP force. A sufficiently high gradient of the square of the electric field (?|E|(2), ~10(19) V(2) m(-3)) was accomplished and controlled for achieving a strong attaching force of nanoparticles using the gap between microelectrodes and nanostructures as well as the rotation of structures. Fluorescent PS nano-beads and QDs were attached at the designed end facet, side, and position of nanostructures with high selectivity. A single QD attachment was also realized at gold nanostructures, and the attached QDs were verified as single using optical "blinking" measurements. PMID- 26579982 TI - Chiral modification of copper exchanged zeolite-Y with cinchonidine and its application in the asymmetric Henry reaction. AB - Chirally modified Cu(2+) exchanged zeolite-Y was synthesized by direct adsorption of cinchonidine under ambient conditions. The chirally modified materials were characterized using various spectrochemical and physicochemical techniques viz. BET, FTIR, MAS ((1)H and (13)C NMR), XPS, SEM, cyclic voltammetry and PXRD. Characteristic peaks of cinchonidine observed in the supported materials confirmed the adsorption of cinchonidine and its coordination with the Cu(2+) active site on copper exchanged zeolite-Y. (13)C SSNMR and XPS analysis however confirmed for the half encapsulation process, only the quinoline ring of cinchonidine gets coordinated to the internal metal sites via the N atom while the quinuclidine moiety extends out of the host surface. Cinchonidine supported Cu(2+)-Y zeolites were found to exhibit good catalytic performance in the asymmetric Henry reaction. (1)H SSNMR studies also confirmed the protonation of the N atom of the quinuclidine ring during the course of the Henry reaction. Heterogeneous chiral catalysts were effective for up to two consecutive cycles. Leaching of cinchonidine after the second cycle was found to have a negative result in the catalytic performance. PMID- 26579983 TI - Ordered arrays of Au catalysts by FIB assisted heterogeneous dewetting. AB - Synthesizing Au0.8Si0.2 nanocatalysts that are homogeneous in size and have controlled position is becoming a challenging and crucial prequisite for the fabrication of ordered semiconductor nanowires. In this study, Au0.8Si0.2 nanocatalysts are synthesized via dewetting of Au layers on Si(111) during thermal annealing in an ultra-high vacuum. In the first part of the paper, the mechanism of homogeneous dewetting is analyzed as a function of the Au-deposited thickness (h Au). We distinguish three different dewetting regimes: (I) for a low thickness ([Formula: see text]), a submonolyer coverage of Au is stabilized and there is no dewetting. (II) For an intermediate thickness ([Formula: see text]), there is both dewetting and Au0.8Si0.2 phase formation. The size and density of the Au0.8Si0.2 clusters are directly related to h Au. When cooling down to room temperature, the clusters decompose and reject the Si at the Au/Si substrate interface. (III) For a large thickness ([Formula: see text]), only dewetting takes place, without forming AuSi clusters. In this regime, the dewetting is kinetically controlled by the self-diffusion of Au (activation energy ~0.43 eV) without evidence of an Si-alloying effect. As a practical consequence, when relying solely on the homogeneous dewetting of Au/Si(111) to form the Au0.8Si0.2 catalysts (without a supply of Si atoms from vapor), regime II should be used to obtain good size and density control. In the second part of the paper, a process for ordering the catalysts using focused ion beam-(FIB) assisted dewetting (heterogeneous dewetting) is developed. We show that no matter what the FIB milling conditions and the Au nominal thickness are, dewetting is promoted by ion beam irradiation and is accompanied by the formation of Au0.8Si0.2 droplets. The droplets preferentially form on the patterned areas, while in similar annealing conditions, they do not form on the unpatterned areas. This behavior is attributed to the larger Au-Si interdiffusion in the patterned areas, which results from the Si amorphization induced by the FIB. A systematic analysis of the position of the nanodroplets shows their preferential nucleation inside the patterns, while thicker platelets of almost pure Au are observed between the patterns. The evolutions of the size homogeneity and the occupancy rate of the patterns are quantified as a function of the FIB dose and annealing temperature. Nice arrays of perfectly ordered AuSi catalysts are obtained after optimizing the FIB and dewetting conditions. PMID- 26579984 TI - The Incidence Rates and Standardized Incidence Ratios of Cancer in Hemophilic HIV/AIDS Patients in Taiwan. PMID- 26579985 TI - Neurocognitive Function at the First-Line Failure and on the Second-Line Antiretroviral Therapy in Africa: Analyses From the EARNEST Trial. AB - OBJECTIVE: To assess neurocognitive function at the first-line antiretroviral therapy failure and change on the second-line therapy. DESIGN: Randomized controlled trial was conducted in 5 sub-Saharan African countries. METHODS: Patients failing the first-line therapy according to WHO criteria after >12 months on non-nucleoside reverse transcriptase inhibitors-based regimens were randomized to the second-line therapy (open-label) with lopinavir/ritonavir (400 mg/100 mg twice daily) plus either 2-3 clinician-selected nucleoside reverse transcriptase inhibitors, raltegravir, or as monotherapy after 12-week induction with raltegravir. Neurocognitive function was tested at baseline, weeks 48 and 96 using color trails tests 1 and 2, and the Grooved Pegboard test. Test results were converted to an average of the 3 individual test z-scores. RESULTS: A total of 1036 patients (90% of those >18 years enrolled at 13 evaluable sites) had valid baseline tests (58% women, median: 38 years, viral load: 65,000 copies per milliliter, CD4 count: 73 cells per cubic millimeter). Mean (SD) baseline z-score was -2.96 (1.74); lower baseline z-scores were independently associated with older age, lower body weight, higher viral load, lower hemoglobin, less education, fewer weekly working hours, previous central nervous system disease, and taking fluconazole (P < 0.05 in multivariable model). Z-score was increased by mean (SE) of +1.23 (0.04) after 96 weeks on the second-line therapy (P < 0.001; n = 915 evaluable), with no evidence of difference between the treatment arms (P = 0.35). CONCLUSIONS: Patients in sub-Saharan Africa failing the first line therapy had low neurocognitive function test scores, but performance improved on the second-line therapy. Regimens with more central nervous system penetrating drugs did not enhance neurocognitive recovery indicating this need not be a primary consideration in choosing a second-line regimen. PMID- 26579986 TI - Atherosclerosis is Evident in Treated HIV-Infected Subjects With Low Cardiovascular Risk by Carotid Cardiovascular Magnetic Resonance. AB - OBJECTIVE: Premature atherosclerosis has been observed among HIV-infected individuals with high cardiovascular risk using one-dimensional ultrasound carotid intima-media thickness. We evaluated the assessment of HIV-infected individuals with low traditional cardiovascular disease risk using cardiovascular magnetic resonance, which allows three-dimensional assessment of the carotid artery wall. METHODS: Carotid cardiovascular magnetic resonance was performed in 33 HIV-infected individuals (cases) (19 male, 14 female), and 35 HIV-negative controls (20 male, 15 female). Exclusion criteria included smoking, hypertension, hyperlipidemia (total cholesterol/HDL ratio > 5) or family history of premature atherosclerosis. Cases were stable on combination antiretroviral therapy with plasma HIV-1 RNA <50 copies per milliliter. Using computer modeling, the arterial wall, lumen, and total vessel volumes were calculated for a 4-cm length of each carotid artery centered on the bifurcation. The wall/outer-wall ratio (W/OW), an index of vascular thickening, was compared between the groups. RESULTS: Cases had a median CD4 cell count of 690 cells per microliter. Mean (+/-SD) age and 10-year Framingham coronary risk scores were similar for cases and controls (45.2 +/- 9.7 years versus 46.9 +/- 11.6 years and 3.97% +/- 3.9% versus 3.72% +/- 3.5%, respectively). W/OW was significantly increased in cases compared with controls (36.7% versus 32.5%, P < 0.0001); this was more marked in HIV-infected females. HIV status was significantly associated with increased W/OW after adjusting for age (P < 0.0001). No significant association between antiretroviral type and W/OW was found-W/OW lowered comparing abacavir to zidovudine (P = 0.038), but statistical model fits poorly. CONCLUSIONS: In a cohort of treated HIV-infected individuals with low measurable cardiovascular risk, we have observed evidence of premature subclinical atherosclerosis. PMID- 26579987 TI - Authors' Reply: Is Genotype Testing Really Cost-Effective for Primary Resistance in Brazil? PMID- 26579988 TI - Inflammation and Specific Symptoms of Depression. PMID- 26579990 TI - Microvascular Invasion in Hepatitis B Virus-Related Hepatocellular Carcinoma: Another Step Toward Preoperative Evaluation? PMID- 26579989 TI - Who Receives Speech/Language Services by 5 Years of Age in the United States? AB - PURPOSE: We sought to identify factors predictive of or associated with receipt of speech/language services during early childhood. We did so by analyzing data from the Early Childhood Longitudinal Study-Birth Cohort (ECLS-B; Andreassen & Fletcher, 2005), a nationally representative data set maintained by the U.S. Department of Education. We addressed two research questions of particular importance to speech-language pathology practice and policy. First, do early vocabulary delays increase children's likelihood of receiving speech/language services? Second, are minority children systematically less likely to receive these services than otherwise similar White children? METHOD: Multivariate logistic regression analyses were performed for a population-based sample of 9,600 children and families participating in the ECLS-B. RESULTS: Expressive vocabulary delays by 24 months of age were strongly associated with and predictive of children's receipt of speech/language services at 24, 48, and 60 months of age (adjusted odds ratio range = 4.32-16.60). Black children were less likely to receive speech/language services than otherwise similar White children at 24, 48, and 60 months of age (adjusted odds ratio range = 0.42-0.55). Lower socioeconomic status children and those whose parental primary language was other than English were also less likely to receive services. Being born with very low birth weight also significantly increased children's receipt of services at 24, 48, and 60 months of age. CONCLUSION: Expressive vocabulary delays at 24 months of age increase children's risk for later speech/language services. Increased use of culturally and linguistically sensitive practices may help racial/ethnic minority children access needed services. PMID- 26579991 TI - Preparation of porous aromatic framework/ionic liquid hybrid composite coated solid-phase microextraction fibers and their application in the determination of organochlorine pesticides combined with GC-ECD detection. AB - A novel hybrid material incorporating porous aromatic frameworks and an ionic liquid, 1-(triethoxy silyl)propyl-3-aminopropyl imidazole hexafluorophosphate, was prepared as solid-phase microextraction coating and employed for the extraction of organochlorine pesticides. Combining the advantages of porous aromatic frameworks and an ionic liquid, the fiber exhibited a high adsorption capacity for organochlorine pesticides. Under optimized experimental conditions, enhancement factors of 247-1696 were obtained with good linearity in the range of 1-500 MUg L(-1). The detection limits and quantification limits were determined to be in the range of 0.11-0.29 MUg L(-1) and 0.35-0.93 MUg L(-1). The relative standard deviations for six replicates of organochlorine pesticides were in the range of 4.4%-7.2% and 5.7%-10.1% for one fiber and fiber-to-fiber, respectively. By coupling with a gas chromatography-electron capture detector, the novel fiber was successfully used for the determination of organochlorine pesticides in juice and milk samples with recoveries of 76.1%-121.3%. PMID- 26579992 TI - Morphometric Characteristics of the Humerus and Ulna in Limbs Bearing the Supratrochlear Aperture (STA). AB - The supratrochlear aperture (STA) is a perforation of the septum found between the olecranon and coronoid fossae of the humerus. Its prevalence is population specific and varies by sex. There is no consensus on the etiology of this feature despite decades of investigation. Two aspects of the mechanical theory, which states that the STA is formed when the ulnar olecranon and coronoid processes impinge upon the septum separating the olecranon and coronoid fossae, were investigated. First, osteometric measures of bone size were used to test the proposition that larger humeri are less prone to STA formation. We compared the dimensions of STA bearing humeri with those lacking STAs and investigated which skeletal features discriminate among South African populations. To specifically evaluate the mechanical theory that articulation with the olecranon and coronoid fossae may result in STA formation, dimensions of the olecranon and coronoid processes were compared. Our results verified that smaller individuals are prone to STA formation and that a significantly longer olecranon process is associated with the aperture. The olecranon process length and olecranon-coronoid distance were the main contributors to STA presence. Variables that contributed the most towards discrimination among the South African populations were the olecranon fossa depth and right humeral head circumference. An inverse relationship between the olecranon process length and olecranon fossa depth was also associated with presence of the STA. PMID- 26579993 TI - Probing Submicron Aggregation Kinetics of an IgG Protein by Asymmetrical Flow Field-Flow Fractionation. AB - A lack of reliable analytical methods has hindered the quantification of submicron protein aggregates and a detailed understanding of their formation kinetics. In this study, a simple asymmetrical flow field-flow fractionation (AF4) method with good size selectivity (>0.5) is used to investigate nanometer (<0.1 MUm) and submicron (0.1-1 MUm) aggregates of heat-stressed anti streptavidin (anti-SA) IgG1. The Lumry-Eyring nucleated polymerization (LENP) model for non-native protein aggregation is fit to the AF4 data, and kinetic analysis shows that aggregates are formed via slow nucleation and aggregate condensation at long stress times. Comparison of centrifuged and uncentrifuged heat-stressed anti-SA IgG1 AF4 results show the removal of high molar mass submicron aggregates and large material (>20 MUm) and suggests that centrifugation may influence the aggregation kinetics. Furthermore, qualitative LENP model analysis of centrifuged and uncentrifuged samples suggests that significant aggregate-aggregate condensation occurs even at early stress times and highlights the potential of AF4 to determine aggregation kinetics for species greater than 1 MUm. PMID- 26579994 TI - Two sensitizing oxidation products of p-phenylenediamine patch tested in patients allergic to p-phenylenediamine. AB - BACKGROUND: The results from a previous study indicated the presence of several possible sensitizers formed during oxidation of the potent sensitizer p phenylenediamine (PPD) to which PPD-sensitized patients might react, in various patterns. OBJECTIVES: To extract and analyse a yellow spot from a thin-layer chromatogram with oxidized PPD, to which 6 of 14 (43%) PPD-positive patients had reacted in a previous study, in order to identify potential sensitizer(s) and to patch test this/these substance(s) in the 14 PPD-positive patients. METHODS: The yellow spot was extracted from a thin-layer chromatogram of oxidized PPD, and two substances, suspected to be allergens, were identified by analysis with gas chromatography mass spectrometry (GCMS). The 14 PPD-positive patients, who had been previously tested with the thin-layer chromatogram of oxidized PPD, participated in the investigation, and were tested with dilutions of the two substances. RESULTS: GCMS analysis identified 4-nitroaniline and 4,4' azodianiline in the yellow spot. Of the 14 PPD-positive test patients, 5 (36%) reacted to 4-nitroaniline and 9 (64%) reacted to 4,4'-azodianiline. CONCLUSION: The results show that 4-nitroaniline and 4,4'-azodianiline, formed during oxidation of PPD, are potent sensitizers. PPD-sensitized patients react to a high extent to concentrations equimolar to PPD of 4-nitroaniline and 4,4' azodianiline. PMID- 26579995 TI - Topography and landmarks for the nerve supply to the levator ani and its relevance to pelvic floor pathologies. AB - The aim of this study was to explore the anatomical variations of the nerve to the levator ani (LA) and to relate these findings to LA dysfunction. One hundred fixed human female cadavers were dissected using transabdominal, gluteal, and perineal approaches, resulting in two hundred dissections of the sacral plexus. The pudendal nerve and the sacral nerve roots were traced from their origin at the sacral foramina to their termination. All nerves contributing to the innervation of the LA were considered to be the nerve to the LA. Based on the spinal nerve components, the nerve to the LA was classified into the following categories: 50% (n = 100) originated from S4 and S5 (type I); 19% (n = 38) originated from S5 (type II); 16% (n = 32) originated from S4 (type III); 11% (n = 22) originated from S3 and S4 (type IV); 4% (n = 8) originated from S3, S4, and S5 (type V). Two patterns of nerve termination were observed. In 42% of specimens, the nerve to the LA penetrated the coccygeus muscle and assumed an external position along the inferior surface of the LA muscle. In the remaining 58% of specimens, the nerve crossed the superior surface of the coccygeus muscle and continued along the superior surface of the iliococcygeus muscle. Damage to the nerve to LA has been associated with various pathologies. In order to minimize injuries during surgical procedures, a thorough understanding of the course and variations of the nerve to the LA is extremely important. PMID- 26579996 TI - Impact of Radio Frequency, Microwaving, and High Hydrostatic Pressure at Elevated Temperature on the Nutritional and Antinutritional Components in Black Soybeans. AB - In this study, the effects of high hydrostatic pressure (HHP) at elevated temperature (60 degrees C) and 2 dielectric heating (DH) methods (radio frequency [RF], and microwaving [MW]) on the nutritional compositions and removal of antinutritional factors in black soybeans were studied. Each treatment caused <2% reduction in protein, and 3.3% to 7.0% decline in total amino acid content. However, the proportion of essential amino acid slightly increased in DH treated samples. The treatment decreased fat content (14.0% to 35.7%), but had small influence on fatty acid proportion. Antinutritional factors including trypsin inhibitor, tannins, saponins, and phytic acid were all declined by the 3 treatments, and DH treatment was generally more efficient. The most abundant saponins was decreased >22% in DH treated samples. MW and HHP led to higher in vitro protein digestibility, RF and MW promoted protein aggregation from atomic force microscope topography, but HHP caused more damages on protein subunits as seen from SDS-PAGE image. PMID- 26579997 TI - Early Integration of Palliative Care for Children with High-Risk Cancer and Their Families. AB - Despite increasing data to support pediatric palliative care (PPC) as an integral component of high-quality care for children with life-threatening conditions and their families, timely integration of PPC is offered inconsistently to children with high-risk cancer. In this review, we summarize the growing body of literature in support of early integration of PPC for children with high-risk cancer and their families, advocating that PPC principles and resources are imperative to holistic cancer-directed care and rooted in evidence-based medicine. Finally, we offer possible strategies for optimizing integration of PPC into holistic cancer care for children and families. PMID- 26579998 TI - An HPLC method for the determination of a novel anti-hypertension agent 6,7 dimethoxy-3-(4-(4-fluorobenzyloxy)-3-methoxyphenylmethyl)quinazolin-4(3H)-one in rat plasma: application to pharmacokinetic study. AB - : 6,7-dimethoxy-3-(4-(4-fluorobenzyloxy)-3-methoxyphenylmethyl) quinazolin-4(3H) one (DFMQ-19), a novel analogue of 3-benzylquinazolin-4(3H)-ones, may be considered as a drug candidate for the treatment of hypertension. The aim of this study was to develop and validate a reverse-phase high-performance liquid chromatography to determine the DFMQ-19 in plasma and demonstrate its application in pharmacokinetic study. Separation of DFMQ-19 and I.S (structural analog of DFMQ-19) was performed using Shim-Pack VP-ODS column and a mixture of acetonitrile and water as mobile phase. The HPLC method was validated according to the ICH guidelines. The limit of detection and lower limit of quantitation were 0.05 ug/ml and 0.1 ug/ml respectively. The recovery rate of DFMQ-19 from blood samples was >81% of the spiked amount. The RSD of the intra- and inter-day precisions was within 7.5%, and RE of accuracy was between -14.4% and 4.5%. This method was successfully applied to the pharmacokinetic study after administration of DFMQ-19. The pharmacokinetic parameters, such as half-life (t1/2 ), mean residence time (MRT), maximum concentration (Cmax ) were determined. Based on these pharmacokinetic parameters, the oral bioavailability of DFMQ-19 was calculated to be 13.42% in rat. This article is protected by copyright. All rights reserved. HIGHLIGHTS: HPLC method was validated to quantify DFMQ-19 in rat plasma I.S is one of the structural analogs of the analyte The HPLC method was validated according to the ICH guidelines The oral bioavailability of DFMQ-19 was 13.42% in rat. PMID- 26579999 TI - Eucalyptus hairy roots, a fast, efficient and versatile tool to explore function and expression of genes involved in wood formation. AB - Eucalyptus are of tremendous economic importance being the most planted hardwoods worldwide for pulp and paper, timber and bioenergy. The recent release of the Eucalyptus grandis genome sequence pointed out many new candidate genes potentially involved in secondary growth, wood formation or lineage-specific biosynthetic pathways. Their functional characterization is, however, hindered by the tedious, time-consuming and inefficient transformation systems available hitherto for eucalypts. To overcome this limitation, we developed a fast, reliable and efficient protocol to obtain and easily detect co-transformed E. grandis hairy roots using fluorescent markers, with an average efficiency of 62%. We set up conditions both to cultivate excised roots in vitro and to harden composite plants and verified that hairy root morphology and vascular system anatomy were similar to wild-type ones. We further demonstrated that co transformed hairy roots are suitable for medium-throughput functional studies enabling, for instance, protein subcellular localization, gene expression patterns through RT-qPCR and promoter expression, as well as the modulation of endogenous gene expression. Down-regulation of the Eucalyptus cinnamoyl-CoA reductase1 (EgCCR1) gene, encoding a key enzyme in lignin biosynthesis, led to transgenic roots with reduced lignin levels and thinner cell walls. This gene was used as a proof of concept to demonstrate that the function of genes involved in secondary cell wall biosynthesis and wood formation can be elucidated in transgenic hairy roots using histochemical, transcriptomic and biochemical approaches. The method described here is timely because it will accelerate gene mining of the genome for both basic research and industry purposes. PMID- 26580000 TI - In vivo amyloid aggregation kinetics tracked by time-lapse confocal microscopy in real-time. AB - Amyloid polymerization underlies an increasing number of human diseases. Despite this process having been studied extensively in vitro, aggregation is a difficult process to track in vivo due to methodological limitations and the slow kinetics of aggregation reactions in cells and tissues. Herein we exploit the amyloid properties of the inclusions bodies (IBs) formed by amyloidogenic proteins in bacteria to address the kinetics of in vivo amyloid aggregation. To this aim we used time-lapse confocal microscopy and a fusion of the amyloid-beta peptide (A beta42) with a fluorescent reporter. This strategy allowed us to follow the intracellular kinetics of amyloid-like aggregation in real-time and to discriminate between variants exhibiting different in vivo aggregation propensity. Overall, the approach opens the possibility to assess the impact of point mutations as well as potential anti-aggregation drugs in the process of amyloid formation in living cells. PMID- 26580001 TI - Florida Best Practice Psychotherapeutic Medication Guidelines for Adults With Bipolar Disorder: A Novel, Practical, Patient-Centered Guide for Clinicians. AB - OBJECTIVE: This report describes the 2014 update of the Florida Best Practice Psychotherapeutic Medication Guidelines for Adults With Bipolar Disorder, intended to provide frontline clinicians with a simple, evidence-based approach to treatments for 3 phases of bipolar disorder: acute depression, acute mania, and maintenance. PARTICIPANTS: The consensus meeting included representatives from the Florida Agency for Health Care Administration, pharmacists, health care policy experts, mental health clinicians, and experts in bipolar disorder. The effort was funded by the Florida Agency for Health Care Administration. EVIDENCE: The available published and nonpublished data from trials in the treatment of bipolar I disorder were reviewed. Evidence for efficacy and harm from replicated randomized clinical trials, systematic reviews and meta-analyses, or non replicated randomized clinical trials was included. No recommendations were made with evidence from other sources. CONSENSUS PROCESS: Decisions regarding the structure of the guidelines were made during a stakeholder meeting in Tampa, Florida, on September 20 and 21, 2013. Better proven and safer/more efficacious treatments were to be utilized before using those with less evidence and/or greater risk. Safety and risk of harm were balanced against potential benefit. Lower-quality evidence was recommended only if higher-level treatments were found to be ineffective or not tolerated, because of patient preference, or because of past treatment success. While respecting patient and clinician choice, the guidelines are structured to encourage evidence-based, safe prescribing first. CONCLUSIONS: This iteration of the Florida guidelines for the treatment of bipolar disorder is a practical, simple, patient-focused guide to treatment for acute mania and acute bipolar depression and maintenance treatment that considers safety and harm in the hierarchy of treatment choices. While using strict evidence-based criteria for inclusion in recommendations, it eliminates expert opinion as a level of evidence while respecting clinician and patient choice in treatment decision-making. PMID- 26580002 TI - Chemistry of Covalent Organic Frameworks. AB - Linking organic molecules by covalent bonds into extended solids typically generates amorphous, disordered materials. The ability to develop strategies for obtaining crystals of such solids is of interest because it opens the way for precise control of the geometry and functionality of the extended structure, and the stereochemical orientation of its constituents. Covalent organic frameworks (COFs) are a new class of porous covalent organic structures whose backbone is composed entirely of light elements (B, C, N, O, Si) that represent a successful demonstration of how crystalline materials of covalent solids can be achieved. COFs are made by combination of organic building units covalently linked into extended structures to make crystalline materials. The attainment of crystals is done by several techniques in which a balance is struck between the thermodynamic reversibility of the linking reactions and their kinetics. This success has led to the expansion of COF materials to include organic units linked by these strong covalent bonds: B-O, C-N, B-N, and B-O-Si. Since the organic constituents of COFs, when linked, do not undergo significant change in their overall geometry, it has been possible to predict the structures of the resulting COFs, and this advantage has facilitated their characterization using powder X-ray diffraction (PXRD) techniques. It has also allowed for the synthesis of COF structures by design and for their formation with the desired composition, pore size, and aperture. In practice, the modeled PXRD pattern for a given expected COF is compared with the experimental one, and depending on the quality of the match, this is used as a starting point for solving and then refining the crystal structure of the target COF. These characteristics make COFs an attractive class of new porous materials. Accordingly, they have been used as gas storage materials for energy applications, solid supports for catalysis, and optoelectronic devices. A large and growing library of linkers amenable to the synthesis of COFs is now available, and new COFs and topologies made by reticular synthesis are being reported. Much research is also directed toward the development of new methods of linking organic building units to generate other crystalline COFs. These efforts promise not only new COF chemistry and materials, but also the chance to extend the precision of molecular covalent chemistry to extended solids. PMID- 26580003 TI - C3-OH of Amphotericin B Plays an Important Role in Ion Conductance. AB - Amphotericin B (AmB) is the archetype for small molecules that form ion channels in living systems and has recently been shown to replace a missing protein ion transporter and thereby restore physiology in yeast. Molecular modeling studies predict that AmB self-assembles in lipid membranes with the polyol region lining a channel interior that funnels to its narrowest region at the C3-hydroxyl group. This model predicts that modification of this functional group would alter conductance of the AmB ion channel. To test this hypothesis, the C3-hydroxyl group was synthetically deleted, and the resulting derivative, C3deoxyAmB (C3deOAmB), was characterized using multidimensional NMR experiments and single ion channel electrophysiology recordings. C3deOAmB possesses the same macrocycle conformation as AmB and retains the capacity to form transmembrane ion channels, yet the conductance of the C3deOAmB channels is 3-fold lower than that of AmB channels. Thus, the C3-hydroxyl group plays an important role in AmB ion channel conductance, and synthetic modifications at this position may provide an opportunity for further tuning of channel functions. PMID- 26580004 TI - Downregulation of microRNA-586 Inhibits Proliferation, Invasion and Metastasis and Promotes Apoptosis in Human Osteosarcoma U2-OS Cell Line. AB - In this study, we aim to examine the association of microRNA-586 (miR-586) with osteosarcoma (OS) cell proliferation, apoptosis, invasion, and metastasis. U2-OS cell lines were divided into 4 groups: an miR-586 group, anti-miR-586 group, control group (empty plasmid) and blank group (no plasmid). qRT-PCR was used to detect miR-586 expression, cell counting kit-8 and EdU assays to detect cell proliferation, flow cytometry to detect cell cycle distribution, Annexin V/PI double staining to detect cell apoptosis, and the Transwell assay to detect cell invasion and metastasis. miR-586 expression was significantly higher in the miR 586 group but significantly lower in the anti-miR-586 group compared with the control and blank groups. Cell proliferation at 2-5 days after cell transfection and the EdU-positive cell number increased obviously in the miR-586 group but decreased clearly in the anti-miR-586 group. In the miR-586 group, cells at G0/G1 stage and apoptosis cells significantly decreased, while cells at G2/M and S stages and invasive and metastatic cells significantly increased compared to the control and blank groups; however, opposite trends were found in the anti-miR-586 group. Downregulation of miR-586 expression in OS may inhibit cell proliferation, invasion and metastasis, and promote cell apoptosis. PMID- 26580005 TI - Quantifying "Softness" of Organic Coatings on Gold Nanoparticles Using Correlated Small-Angle X-ray and Neutron Scattering. AB - Small-angle X-ray and neutron scattering provide powerful tools to selectively characterize the inorganic and organic components of hybrid nanomaterials. Using hydrophobic gold nanoparticles coated with several commercial and dendritic thiols, the size of the organic layer on the gold particles is shown to increase from 1.2 to 4.1 nm. A comparison between solid-state diffraction from self assembled lattices of nanoparticles and the solution data from neutron scattering suggests that engineering softness/deformability in nanoparticle coatings is less straightforward than simply increasing the organic size. The "dendritic effect" in which higher generations yield increasingly compact molecules explains changes in the deformability of organic ligand shells. PMID- 26580006 TI - Comparison of national ZP equations for lean meat percentage assessment in SEUROP pig classification. AB - The objectives of the present work were (1) to compare pig carcass classification using different ZP ("Zwei-Punkt-Messverfahren") equations approved in the EU, applied on the same dataset, and to discuss the origin of differences between member states; (2) to evaluate the effect of a possible common ZP equation from the combined dataset and analyse how do the different subsets perform; and (3) to discuss the consequences of different national equations within the EU in view of the harmonization of pig carcass classification. A dataset of 951 carcasses from Belgium, France, Germany, Slovenia and Spain was used, 12 approved ZP equations in Europe were applied and the results were compared. Observed differences can be due not only to differences in genetics and sexes, but also to differences in the ZP measurement and dissection trials performed to obtain national equations. Important differences between some equations (up to almost 5 lean meat percentage) indicate a low harmonization among them and a need for improvements. PMID- 26580008 TI - Circadian clocks: A receptor for subtle temperature changes. PMID- 26580007 TI - Therapeutic antibodies reveal Notch control of transdifferentiation in the adult lung. AB - Prevailing dogma holds that cell-cell communication through Notch ligands and receptors determines binary cell fate decisions during progenitor cell divisions, with differentiated lineages remaining fixed. Mucociliary clearance in mammalian respiratory airways depends on secretory cells (club and goblet) and ciliated cells to produce and transport mucus. During development or repair, the closely related Jagged ligands (JAG1 and JAG2) induce Notch signalling to determine the fate of these lineages as they descend from a common proliferating progenitor. In contrast to such situations in which cell fate decisions are made in rapidly dividing populations, cells of the homeostatic adult airway epithelium are long lived, and little is known about the role of active Notch signalling under such conditions. To disrupt Jagged signalling acutely in adult mammals, here we generate antibody antagonists that selectively target each Jagged paralogue, and determine a crystal structure that explains selectivity. We show that acute Jagged blockade induces a rapid and near-complete loss of club cells, with a concomitant gain in ciliated cells, under homeostatic conditions without increased cell death or division. Fate analyses demonstrate a direct conversion of club cells to ciliated cells without proliferation, meeting a conservative definition of direct transdifferentiation. Jagged inhibition also reversed goblet cell metaplasia in a preclinical asthma model, providing a therapeutic foundation. Our discovery that Jagged antagonism relieves a blockade of cell-to cell conversion unveils unexpected plasticity, and establishes a model for Notch regulation of transdifferentiation. PMID- 26580009 TI - Neonicotinoid pesticide exposure impairs crop pollination services provided by bumblebees. AB - Recent concern over global pollinator declines has led to considerable research on the effects of pesticides on bees. Although pesticides are typically not encountered at lethal levels in the field, there is growing evidence indicating that exposure to field-realistic levels can have sublethal effects on bees, affecting their foraging behaviour, homing ability and reproductive success. Bees are essential for the pollination of a wide variety of crops and the majority of wild flowering plants, but until now research on pesticide effects has been limited to direct effects on bees themselves and not on the pollination services they provide. Here we show the first evidence to our knowledge that pesticide exposure can reduce the pollination services bumblebees deliver to apples, a crop of global economic importance. Bumblebee colonies exposed to a neonicotinoid pesticide provided lower visitation rates to apple trees and collected pollen less often. Most importantly, these pesticide-exposed colonies produced apples containing fewer seeds, demonstrating a reduced delivery of pollination services. Our results also indicate that reduced pollination service delivery is not due to pesticide-induced changes in individual bee behaviour, but most likely due to effects at the colony level. These findings show that pesticide exposure can impair the ability of bees to provide pollination services, with important implications for both the sustained delivery of stable crop yields and the functioning of natural ecosystems. PMID- 26580010 TI - Metabolism: Inflammation keeps old mice healthy. PMID- 26580011 TI - Corrigendum: The 'obligate diploid' Candida albicans forms mating-competent haploids. PMID- 26580013 TI - Corrigendum: Mutant IDH inhibits HNF-4alpha to block hepatocyte differentiation and promote biliary cancer. PMID- 26580012 TI - Hemichordate genomes and deuterostome origins. AB - Acorn worms, also known as enteropneust (literally, 'gut-breathing') hemichordates, are marine invertebrates that share features with echinoderms and chordates. Together, these three phyla comprise the deuterostomes. Here we report the draft genome sequences of two acorn worms, Saccoglossus kowalevskii and Ptychodera flava. By comparing them with diverse bilaterian genomes, we identify shared traits that were probably inherited from the last common deuterostome ancestor, and then explore evolutionary trajectories leading from this ancestor to hemichordates, echinoderms and chordates. The hemichordate genomes exhibit extensive conserved synteny with amphioxus and other bilaterians, and deeply conserved non-coding sequences that are candidates for conserved gene-regulatory elements. Notably, hemichordates possess a deuterostome-specific genomic cluster of four ordered transcription factor genes, the expression of which is associated with the development of pharyngeal 'gill' slits, the foremost morphological innovation of early deuterostomes, and is probably central to their filter feeding lifestyle. Comparative analysis reveals numerous deuterostome-specific gene novelties, including genes found in deuterostomes and marine microbes, but not other animals. The putative functions of these genes can be linked to physiological, metabolic and developmental specializations of the filter-feeding ancestor. PMID- 26580014 TI - Depletion of fat-resident Treg cells prevents age-associated insulin resistance. AB - Age-associated insulin resistance (IR) and obesity-associated IR are two physiologically distinct forms of adult-onset diabetes. While macrophage-driven inflammation is a core driver of obesity-associated IR, the underlying mechanisms of the obesity-independent yet highly prevalent age-associated IR are largely unexplored. Here we show, using comparative adipo-immune profiling in mice, that fat-resident regulatory T cells, termed fTreg cells, accumulate in adipose tissue as a function of age, but not obesity. Supporting the existence of two distinct mechanisms underlying IR, mice deficient in fTreg cells are protected against age associated IR, yet remain susceptible to obesity-associated IR and metabolic disease. By contrast, selective depletion of fTreg cells via anti-ST2 antibody treatment increases adipose tissue insulin sensitivity. These findings establish that distinct immune cell populations within adipose tissue underlie ageing- and obesity-associated IR, and implicate fTreg cells as adipo-immune drivers and potential therapeutic targets in the treatment of age-associated IR. PMID- 26580015 TI - Sweet and bitter taste in the brain of awake behaving animals. AB - Taste is responsible for evaluating the nutritious content of food, guiding essential appetitive behaviours, preventing the ingestion of toxic substances, and helping to ensure the maintenance of a healthy diet. Sweet and bitter are two of the most salient sensory percepts for humans and other animals; sweet taste allows the identification of energy-rich nutrients whereas bitter warns against the intake of potentially noxious chemicals. In mammals, information from taste receptor cells in the tongue is transmitted through multiple neural stations to the primary gustatory cortex in the brain. Recent imaging studies have shown that sweet and bitter are represented in the primary gustatory cortex by neurons organized in a spatial map, with each taste quality encoded by distinct cortical fields. Here we demonstrate that by manipulating the brain fields representing sweet and bitter taste we directly control an animal's internal representation, sensory perception, and behavioural actions. These results substantiate the segregation of taste qualities in the cortex, expose the innate nature of appetitive and aversive taste responses, and illustrate the ability of gustatory cortex to recapitulate complex behaviours in the absence of sensory input. PMID- 26580016 TI - Drosophila Ionotropic Receptor 25a mediates circadian clock resetting by temperature. AB - Circadian clocks are endogenous timers adjusting behaviour and physiology with the solar day. Synchronized circadian clocks improve fitness and are crucial for our physical and mental well-being. Visual and non-visual photoreceptors are responsible for synchronizing circadian clocks to light, but clock-resetting is also achieved by alternating day and night temperatures with only 2-4 degrees C difference. This temperature sensitivity is remarkable considering that the circadian clock period (~24 h) is largely independent of surrounding ambient temperatures. Here we show that Drosophila Ionotropic Receptor 25a (IR25a) is required for behavioural synchronization to low-amplitude temperature cycles. This channel is expressed in sensory neurons of internal stretch receptors previously implicated in temperature synchronization of the circadian clock. IR25a is required for temperature-synchronized clock protein oscillations in subsets of central clock neurons. Extracellular leg nerve recordings reveal temperature- and IR25a-dependent sensory responses, and IR25a misexpression confers temperature-dependent firing of heterologous neurons. We propose that IR25a is part of an input pathway to the circadian clock that detects small temperature differences. This pathway operates in the absence of known 'hot' and 'cold' sensors in the Drosophila antenna, revealing the existence of novel periphery-to-brain temperature signalling channels. PMID- 26580017 TI - Corrigendum: The formation and fate of internal waves in the South China Sea. PMID- 26580019 TI - Genomics: Acorn worms in a nutshell. PMID- 26580018 TI - The ontogeny of fairness in seven societies. AB - A sense of fairness plays a critical role in supporting human cooperation. Adult norms of fair resource sharing vary widely across societies, suggesting that culture shapes the acquisition of fairness behaviour during childhood. Here we examine how fairness behaviour develops in children from seven diverse societies, testing children from 4 to 15 years of age (n = 866 pairs) in a standardized resource decision task. We measured two key aspects of fairness decisions: disadvantageous inequity aversion (peer receives more than self) and advantageous inequity aversion (self receives more than a peer). We show that disadvantageous inequity aversion emerged across all populations by middle childhood. By contrast, advantageous inequity aversion was more variable, emerging in three populations and only later in development. We discuss these findings in relation to questions about the universality and cultural specificity of human fairness. PMID- 26580020 TI - Potential sea-level rise from Antarctic ice-sheet instability constrained by observations. AB - Large parts of the Antarctic ice sheet lying on bedrock below sea level may be vulnerable to marine-ice-sheet instability (MISI), a self-sustaining retreat of the grounding line triggered by oceanic or atmospheric changes. There is growing evidence that MISI may be underway throughout the Amundsen Sea embayment (ASE), which contains ice equivalent to more than a metre of global sea-level rise. If triggered in other regions, the centennial to millennial contribution could be several metres. Physically plausible projections are challenging: numerical models with sufficient spatial resolution to simulate grounding-line processes have been too computationally expensive to generate large ensembles for uncertainty assessment, and lower-resolution model projections rely on parameterizations that are only loosely constrained by present day changes. Here we project that the Antarctic ice sheet will contribute up to 30 cm sea-level equivalent by 2100 and 72 cm by 2200 (95% quantiles) where the ASE dominates. Our process-based, statistical approach gives skewed and complex probability distributions (single mode, 10 cm, at 2100; two modes, 49 cm and 6 cm, at 2200). The dependence of sliding on basal friction is a key unknown: nonlinear relationships favour higher contributions. Results are conditional on assessments of MISI risk on the basis of projected triggers under the climate scenario A1B (ref. 9), although sensitivity to these is limited by theoretical and topographical constraints on the rate and extent of ice loss. We find that contributions are restricted by a combination of these constraints, calibration with success in simulating observed ASE losses, and low assessed risk in some basins. Our assessment suggests that upper-bound estimates from low-resolution models and physical arguments (up to a metre by 2100 and around one and a half by 2200) are implausible under current understanding of physical mechanisms and potential triggers. PMID- 26580021 TI - Synthesis of Perfluorinated Isoquinolinediones through Visible-Light-Induced Cyclization of Alkenes. AB - A novel visible-light-induced carboperfluoroalkylation of alkenes using perfluoroalkyl iodides and bromides as Rf sources, leading to isoquinoline-1,3 diones, was developed. This method offers rapid entry to perfluorinated isoquinoline-1,3(2H,4H)-diones from N-alkyl-N-methacryloyl benzamides under mild reaction conditions, allowing for the incorporation of a wide variety of perfluorinated groups such as CF3, C3F7, C4F9, C6F13, C8F17, C10F21, and CF2CO2Et. PMID- 26580022 TI - Development of Ti-C-N coatings with improved tribological behavior and antibacterial properties. AB - In artificial metallic joint implants, the failure is provoked by two effects in most of the cases: mass loss and wear debris removed due to tribological corrosive effects on the implant alloy, and infections due to the presence of bacteria. In this work, several Ti-C-N corrosion and wear protective coatings were developed by Physical Vapour Deposition technology, and deposited on Ti6Al4V alloy. In order to provide the implant antibacterial properties, an additional silver top coating has been deposited. Tribological behavior was characterized through tribocorrosion and fretting tests. On the other hand, wettability tests were performed to study the grade of hydrophilicity/hydrophobia. Additionally, antibacterial properties were evaluated by means of bacterial adhesion tests. As a result of these characterization studies, the coating with the best performance was selected. The as-coated material includes excellent protection against tribocorrosion and fretting effects (in relation to the uncoated one) and the silver layer has been confirmed to exhibit antibacterial properties. PMID- 26580023 TI - The cardiac torsion as a sensitive index of heart pathology: A model study. AB - The torsional behaviour of the heart (i.e. the mutual rotation of the cardiac base and apex) was proved to be sensitive to alterations of some cardiovascular parameters, i.e. preload, afterload and contractility. Moreover, pathologies which affect the fibers architecture and cardiac geometry were proved to alter the cardiac torsion pattern. For these reasons, cardiac torsion represents a sensitive index of ventricular performance. The aim of this work is to provide further insight into physiological and pathological alterations of the cardiac torsion by means of computational analyses, combining a structural model of the two ventricles with simple lumped parameter models of both the systemic and the pulmonary circulations. Starting from diagnostic images, a 3D anatomy based geometry of the two ventricles was reconstructed. The myocytes orientation in the ventricles was assigned according to literature data and the myocardium was modelled as an anisotropic hyperelastic material. Both the active and the passive phases of the cardiac cycle were modelled, and different clinical conditions were simulated. The results in terms of alterations of the cardiac torsion in the presence of pathologies are in agreement with experimental literature data. The use of a computational approach allowed the investigation of the stresses and strains in the ventricular wall as well as of the global hemodynamic parameters in the presence of the considered pathologies. Furthermore, the model outcomes highlight how for specific pathological conditions, an altered torsional pattern of the ventricles can be present, encouraging the use of the ventricular torsion in the clinical practice. PMID- 26580024 TI - The improved mechanical properties of beta-CaSiO3 bioceramics with Si3N4 addition. AB - The motivation of this study is to investigate the effect of Si3N4 addition on the sinterability of beta-CaSiO3 ceramics. beta-CaSiO3 ceramics with different content of Si3N4 were prepared at the sintering temperature ranging from 1000 degrees C to 1150 degrees C. The results showed that Si3N4 can be successfully used as sintering additive by being oxidized to form SiO2. The beta-CaSiO3 ceramics with 3wt% Si3N4 sintered at 1100 degrees C revealed flexural strength, hardness and fracture toughness of 157.2MPa, 4.4GPa and 2.3MPam(1/2) respectively, which was much higher than that of pure beta-CaSiO3 ceramics (41.1MPa, 1.0GPa, 1.1MPam(1/2)). XRD analysis and SEM observation indicated that the main phase maintained to be beta-phase after sintering. PMID- 26580025 TI - Sex-related mercury bioaccumulation in fish from the Madeira River, Amazon. AB - Sex plays an important role in the kinetics and dynamics of methylmercury in some animals. Although fish is the main source of mercury exposure to consumers, the role of sex in fish-Hg bioaccumulation is less known. We studied total Hg (THg) concentrations in 2538 samples (males=1052, females=1486) of fish from different trophic levels (herbivorous, planctivorous, detritivorous, omnivorous, carnivorous, piscivorous); for each species we made a post hoc estimation of the minimum number of samples required to detect variance-based differences between sexes. Only five of the 41 studied species showed significant difference between sexes; but, no consistent dominant pattern of THg concentrations favored either sex. When grouped by trophic levels, overall mean difference in THg concentrations between males and females were not statistically significant. Correlation analysis showed sex-dependent THg bio-accumulation as a function of condition factor was statistically significant and negative for all trophic levels (detritivorous, herviborous, omnivorous, planctivorous, carnivorous, and piscivorous). CONCLUSIONS: Sex is not the main driver of Hg bioaccumulation in most Amazonian fish species; however, studies have to consider the minimum number of samples required to ascertain sex effects on THg bioaccumulation. Therefore, neither the surveillance of environmental pollution nor the current food advisories based on muscle THg need to change because of fish sex. PMID- 26580026 TI - Elevated childhood exposure to arsenic despite reduced drinking water concentrations--A longitudinal cohort study in rural Bangladesh. AB - OBJECTIVES: The aim of this study was to evaluate the massive efforts to lower water arsenic concentrations in Bangladesh. METHODS: In our large mother-child cohort in rural Matlab, we measured the arsenic concentrations (and other elements) in drinking water and evaluated the actual exposure (urinary arsenic), from early gestation to 10 years of age (n=1017). RESULTS: Median drinking water arsenic decreased from 23 (2002-2003) to <2 MUg/L (2013), and the fraction of wells exceeding the national standard (50 MUg/L) decreased from 58 to 27%. Still, some children had higher water arsenic at 10 years than earlier. Installation of deeper wells (>50 m) explained much of the lower water arsenic concentrations, but increased the manganese concentrations. The highest manganese concentrations (~900 MUg/L) appeared in 50-100 m wells. Low arsenic and manganese concentrations (17% of the children) occurred mainly in >100 m wells. The decrease in urinary arsenic concentrations over time was less apparent, from 82 to 58 MUg/L, indicating remaining sources of exposure, probably through food (mean 133 MUg/kg in rice). CONCLUSION: Despite decreased water arsenic concentrations in rural Bangladesh, the children still have elevated exposure, largely from food. Considering the known risks of severe health effects in children, additional mitigation strategies are needed. PMID- 26580027 TI - Ab Initio Geometry and Bright Excitation of Carotenoids: Quantum Monte Carlo and Many Body Green's Function Theory Calculations on Peridinin. AB - In this letter, we report the singlet ground state structure of the full carotenoid peridinin by means of variational Monte Carlo (VMC) calculations. The VMC relaxed geometry has an average bond length alternation of 0.1165(10) A, larger than the values obtained by DFT (PBE, B3LYP, and CAM-B3LYP) and shorter than that calculated at the Hartree-Fock (HF) level. TDDFT and EOM-CCSD calculations on a reduced peridinin model confirm the HOMO-LUMO major contribution of the Bu(+)-like (S2) bright excited state. Many Body Green's Function Theory (MBGFT) calculations of the vertical excitation energy of the Bu(+)-like state for the VMC structure (VMC/MBGFT) provide an excitation energy of 2.62 eV, in agreement with experimental results in n-hexane (2.72 eV). The dependence of the excitation energy on the bond length alternation in the MBGFT and TDDFT calculations with different functionals is discussed. PMID- 26580028 TI - Ionic Liquids Can Selectively Change the Conformational Free-Energy Landscape of Sugar Rings. AB - We investigated the conformational free energy landscape of glucose solvated in water and in the ionic liquids (ILs) 1-butyl-3-methylimidazolium chloride ([Bmim][Cl]) and 1-butyl-3-methylimidazoulim boron tetrafluoride ([Bmim][BF4]). To quantify equilibrium thermodynamic solvent effects, molecular dynamics simulations in conjunction with enhanced sampling based on the metadynamics framework were used. The results show that the solvent choice induces significant differences in the equilibrium ring structures, which may help further resolve the molecular mechanism governing IL-mediated cellulose dissolution. PMID- 26580029 TI - Comparison between Mean Forces and Swarms-of-Trajectories String Methods. AB - The original formulation of the string method in collective variable space is compared with a recent variant called string method with swarms-of-trajectories. The assumptions made in the original method are revisited and the significance of the minimum free energy path (MFEP) is discussed in the context of reactive events. These assumptions are compared to those made in the string method with swarms-of-trajectories, and shown to be equivalent in a certain regime: in particular an expression for the path identified by the swarms-of-trajectories method is given and shown to be closely related to the MFEP. Finally, the algorithmic aspects of both methods are compared. PMID- 26580030 TI - Rigorous Error Bounds for Ewald Summation of Electrostatics at Planar Interfaces. AB - We present a rigorous Ewald summation formula to evaluate the electrostatic interactions in two-dimensionally periodic planar interfaces of three-dimensional systems. By rewriting the Fourier part of the summation formula of the original Ewald2D expression with an explicit order N(2) complexity to a closed form Fourier integral, we find that both the previously developed electrostatic layer correction term and the boundary correction term naturally arise from the expression of a rigorous trapezoidal summation of the Fourier integral part. We derive the exact corrections to the trapezoidal summation in a form of contour integrals offering precise error bounds with given parameter sets of mesh size and system length. Numerical calculations of Madelung constants in model ionic crystals of slab geometry have been performed to support our analytical results. PMID- 26580031 TI - Robust Estimation of Diffusion-Optimized Ensembles for Enhanced Sampling. AB - The multicanonical, or flat-histogram, method is a common technique to improve the sampling efficiency of molecular simulations. The idea is that free-energy barriers in a simulation can be removed by simulating from a distribution where all values of a reaction coordinate are equally likely, and subsequently reweight the obtained statistics to recover the Boltzmann distribution at the temperature of interest. While this method has been successful in practice, the choice of a flat distribution is not necessarily optimal. Recently, it was proposed that additional performance gains could be obtained by taking the position-dependent diffusion coefficient into account, thus placing greater emphasis on regions diffusing slowly. Although some promising examples of applications of this approach exist, the practical usefulness of the method has been hindered by the difficulty in obtaining sufficiently accurate estimates of the diffusion coefficient. Here, we present a simple, yet robust solution to this problem. Compared to current state-of-the-art procedures, the new estimation method requires an order of magnitude fewer data to obtain reliable estimates, thus broadening the potential scope in which this technique can be applied in practice. PMID- 26580032 TI - Calculation of Lipid-Bilayer Permeabilities Using an Average Force. AB - Calculations of lipid bilayer permeabilities from first principles, using molecular simulations, would be valuable to rapidly assess the bioavailability of drug candidates, as well as to decipher, at the atomic level, the mechanisms that underlie the translocation of permeants. The most common theoretical approach, the solubility-diffusion model, requires determination of the free energy and the diffusivity as functions of the position of the permeant. Quantitative predictions of permeability have, however, been stymied by acute difficulties in calculating the diffusivity, inadequate sampling, and, most insidiously, systematic biases due to imperfections in the force field, simulation parameters, and the inherent limitations of the diffusive model. In the present work, we combine importance-sampling simulations employing an adaptive biasing force with a Bayesian-inference algorithm to determine the free energy and diffusivity with noteworthy precision and spatial resolution. In multimicrosecond simulations, we probe the sensitivity of the permeability estimates to different aspects of the methodology, including the truncation of short-range interactions, the thermostat, the force-field parameters of the permeant, the time scale over which the diffusivity is estimated, and the size of the simulated system. The force field parameters and time scale dependence of the diffusivities impose the greatest uncertainties on the permeability estimates. Our simulations highlight the importance of membrane distortion due to the presence of the permeant, which may be partially suppressed if the bilayer patch is not large enough. We suggest that improvements to force fields and more robust kinetic models may be needed to reduce systematic errors below a factor of two. PMID- 26580033 TI - Benchmarking Hydrogen and Carbon NMR Chemical Shifts at HF, DFT, and MP2 Levels. AB - An extensive study of error distributions for calculating hydrogen and carbon NMR chemical shifts at Hartree-Fock (HF), density functional theory (DFT), and Moller Plesset second-order perturbation theory (MP2) levels is presented. Our investigation employs accurate CCSD(T)/cc-pVQZ calculations for providing reference data for 48 hydrogen and 40 carbon nuclei within an extended set of chemical compounds covering a broad range of the NMR scale with high relevance to chemical applications, especially in organic chemistry. Besides the approximations of HF, a variety of DFT functionals, and conventional MP2, we also present results with respect to a spin component-scaled MP2 (GIAO-SCS-MP2) approach. For each method, the accuracy is analyzed in detail for various basis sets, allowing identification of efficient combinations of method and basis set approximations. PMID- 26580034 TI - Performance of Density Functionals for Activation Energies of Re-Catalyzed Organic Reactions. AB - By employing high-level coupled cluster CCSD(T)-F12 calculations as reference, we herein systematically assessed the performance of 16 popular density functional theory (DFT) approximations for typical rhenium-catalyzed reactions. The reactions under study cover those catalyzed by low-valent rhenium(I)/(III) carbonyl complexes as well as high-valent organorhenium(VII) bisperoxo complex. Without DFT dispersion correction, the four best-performing functionals for the barrier heights are B2GP-PLYP, TPSSh, B3LYP, and PBE0 with the mean unsigned deviations (MUDs) under 1.6 kcal/mol. Among these four functionals, B2GP-PLYP generates more accurate barrier heights, while B3LYP and TPSSh behave more reliably in the barrier trend description for these Re-catalyzed reactions. In general, herein the hybrid functionals are better choices than pure GGA or pure meta-GGA functionals. DFT empirical dispersion corrections were found to have beneficial effects on MUDs only for four tested functionals of BMK, CAM-B3LYP, LC omegaPBE, and omegaB97X. Often associated with very large errors up to about 15 kcal/mol in barrier height for many tested functionals, the reaction catalyzed by high-valent rhenium(VII) bisperoxo is apparently different from the ones catalyzed by low-valent rhenium(I)/(III) carbonyl complexes. For reactions catalyzed by Re(I)/(III) carbonyl complexes, omegaB97XD with dispersion correction performs excellently (MUD = 0.63 kcal/mol) and hence is highly recommended for these Re(I)/Re(III)-mediated reactions. PMID- 26580035 TI - A Quasidegenerate Second-Order Perturbation Theory Approximation to RAS-nSF for Excited States and Strong Correlations. AB - We present a modification of the recently developed Restricted Active Space with n Spin Flips method (RAS-nSF), which provides significant efficiency advantages. In the RAS-nSF configuration interaction wave function, an arbitrary number of spin-flips are performed within an orbital active space (often simply the singly occupied orbitals), with state-specific orbital relaxation being described by single excitations into and out of the active space (termed hole and particle states, respectively). As the number of hole and particle states dominates the cost of the calculation, we present an attractive simplification in which the orbital relaxation effects (via hole and particle states) are treated perturbatively rather than variationally. The physical justification for this simplification stems from the spin-flip methodology itself, which suggests that the underlying molecular orbitals (high-spin ROHF) are capable of providing a decent description of the target (spin-flipped) electronic states. The current approach termed SF-CAS(h,p)n (Spin-Flip Complete Active-Space with perturbative Hole and Particle states) yields spin-pure energies and eigenfunctions due to the spin-free formulation. A description of the theory is presented, and a number of numerical examples are investigated to determine the accuracy of the approximation. Computational speedups of over 100 times were demonstrated on a 254 electron, 358 basis function calculation on a Cu(II) porphyrin derivatized with a verdazyl group. PMID- 26580036 TI - New Experimental NMR Shielding Scales Mapped Relativistically from NSR: Theory and Application. AB - The recently proposed relativistic mapping between nuclear magnetic resonance (NMR) shielding and nuclear spin-rotation (NSR) coupling tensors [J. Chem. Phys. 2013, 138, 134104] is employed to establish new experimental (more precisely, experimentally derived) absolute shielding constants for H and X in HX (X = F, Cl, Br, and I). The results are much more accurate than the old "experimental" values that were based on the well-known nonrelativistic mapping. The relativistic mapping is very robust in the sense that it is rather insensitive to the quality of one-particle basis sets and the treatment of electron correlation. Relativistic effects in the NSR coupling constants are also elucidated in depth. PMID- 26580037 TI - Benchmarking the Electron Affinity of Uracil. AB - The Weizmann Bruecker doubles composite method W1BD has been applied in a benchmark study of electron attachment to the nucleobase uracil. The largest computations involved the BD method with a basis set of 760 contracted Gaussian functions, namely augh-cc-pVQZ+2df. The predictions demonstrate that the adiabatic electron affinity (AEA) of uracil is definitely positive. The most relable value for the AEA of uracil should be 0.024 +/- 0.013 eV. Other high level methods such as CASPT2 and G4 theory also predict the AEA of uracil with reasonable accuracy. Both the Hartree-Fock and MP2 approaches severely underestimate the AEA. The latter two methods are not recommended for the study of electron attachment to the DNA/RNA bases. On the other hand, some commonly used Density functional theory approaches, especially, M06-2X, are promising candidates for the study of electron-DNA/RNA interactions. PMID- 26580038 TI - Jahn-Teller Instability of Icosahedral [W@Au12](.). AB - The anionic state of the icosahedral W@Au12 cluster offers a rare example of a Jahn-Teller (JT) instability in an icosahedral fourfold degenerate Gamma8 spinor level. The JT energy splittings of the ground Gamma8 and excited sixfold degenerate Gamma9 splittings in the vicinity of the degeneracy point are calculated with relativistic density functional theory. The results are very well explained by a first-order coupling model, based on the orbital instability of the spherical d-shell of the cluster. In addition the pentagonal JT minimum has been determined. It presents a remarkable example of an auro-sandwich type compound. PMID- 26580039 TI - Correlation Energies from the Two-Component Random Phase Approximation. AB - The correlation energy within the two-component random phase approximation accounting for spin-orbit effects is derived. The resulting plasmon equation is rewritten-analogously to the scalar relativistic case-in terms of the trace of two Hermitian matrices for (Kramers-restricted) closed-shell systems and then represented as an integral over imaginary frequency using the resolution of the identity approximation. The final expression is implemented in the TURBOMOLE program suite. The code is applied to the computation of equilibrium distances and vibrational frequencies of heavy diatomic molecules. The efficiency is demonstrated by calculation of the relative energies of the Oh-, D4h-, and C5v symmetric isomers of Pb6. Results within the random phase approximation are obtained based on two-component Kohn-Sham reference-state calculations, using effective-core potentials. These values are finally compared to other two component and scalar relativistic methods, as well as experimental data. PMID- 26580040 TI - Characterization and Quantification of Polyradical Character. AB - The decomposition of ?S(2)? into atomic and diatomic contributions (local spin analysis) is used to detect and quantify the polyradical character of molecular systems. A model triradical system is studied in detail, and the local spin analysis is used to distinguish several patterns of local spin distributions and spin-spin interactions that can be found for different electronic states. How close a real molecular system is to an ideal system of k perfectly localized spin centers is utilized to define a measure of its k-radical character. The spin properties and triradical character of the lowest-lying electronic states of a number of all sigma, all pi, and sigma-pi organic triradicals are discussed in detail. The local spin contributions exhibit good correlation with experimental triradical stabilization energies. PMID- 26580041 TI - Pipek-Mezey Orbital Localization Using Various Partial Charge Estimates. AB - The Pipek-Mezey scheme for generating chemically intuitive, localized molecular orbitals is generalized to incorporate various ways of estimating the atomic charges, instead of the ill-defined Mulliken charges used in the original formulation, or Lowdin charges, which have also been used. Calculations based on Bader, Becke, Voronoi, Hirshfeld, and Stockholder partial charges, as well as intrinsic atomic orbital charges, are applied to orbital localization for a variety of molecules. While the charges obtained with these various estimates differ greatly, the resulting localized orbitals are found to be quite similar and properly separate sigma and pi orbitals, as well as core and valence orbitals. The calculated results are only weakly dependent on the basis set, unlike those based on Mulliken or Lowdin charges. The effect of varying the penalty exponent on the charge in the objective function was studied briefly and was found to lead to some changes in the localized orbitals when degeneracies are present. The various localization methods have been implemented in ERKALE, an open source program for electronic structure calculations. PMID- 26580042 TI - Assessing the Performance of CASPT2 and DFT Methods for the Description of Long, Multicenter Bonding in Dimers between Radical Ions. AB - The performance of a wide variety of density functionals for the description of long, multicenter bonding in dimers between radical ions has been addressed in this work. Results on interaction energies and equilibrium distances have been evaluated through pure GGA and meta-GGA, hybrid, RSH, and double hybrid functionals. Grimme's dispersion corrections have also been assessed. All results are systematically analyzed and compared for the pi-[TCNE]2(2-), pi-[TTF]2(2+), pi-[TCNB]2(2-), and pi-[TCNP]2(2-) dimers. The DFT results are benchmarked against RASPT2 calculations based on large active spaces. It is shown that small active spaces do not quantitatively describe the interaction energy curves of these dimers. B97-D3(BJ) turns to be the functional that best reproduces the finest RASPT2 results, while PBE-D3(BJ), B3LYP-D3(BJ), and M06-L also provide satisfactory results. PMID- 26580043 TI - Transmission Coefficients, Committors, and Solvent Coordinates in Ion-Pair Dissociation. AB - From a hypothetical perfect dividing surface, all trajectories commit to opposite basins in forward and backward time without recrossing, transition state theory is exact, the transmission coefficient is one, and the committor distribution is perfectly focused at 1/2. However, chemical reactions in solution and other real systems often have dynamical trajectories that recross the dividing surface. To separate true dynamical effects from effects of a nonoptimal dividing surface, the dividing surface and/or reaction coordinate should be optimized before computing transmission coefficients. For NaCl dissociation in TIP3P water, we show that recrossing persists even when the 1/2-committor surface itself is used as the dividing surface, providing evidence that recrossing cannot be fully eliminated from the dynamics for any configurational coordinate. Consistent with this finding, inertial likelihood maximization finds a combination of ion-pair distance and two solvent coordinates that improves the committor distribution and increases the transmission coefficient relative to those for ion-pair distance alone, but recrossing is not entirely eliminated. Free energy surfaces for the coordinates identified by inertial likelihood maximization show that the intrinsic recrossing stems from anharmonicity and shallow intermediates that remain after dimensionality reduction to the dynamically important variables. PMID- 26580044 TI - Excited-State Proton Transfer Controls Irreversibility of Photoisomerization in Mononuclear Ruthenium(II) Monoaquo Complexes: A DFT Study. AB - The detailed DFT investigation clears the working mechanism of the irreversible photoisomerization of trans-[Ru(tpy)(pynp)(OH2)](2+) (TA) and cis [Ru(tpy)(pynp)(OH2)](2+) (CA) complexes. Both TA and CA complexes present two types of low lying triplet states, one resulting from a triplet metal-ligand charge-transfer (TMLCT) and the other from a triplet metal-centered d-d transition (TMC). The vertical excitation of the singlet ground state of the complexes leads to a singlet excited state, which undergoes ultrafast decay to the corresponding TMLCT. For TA, this TMLCT transforms with a low barrier to a TMC state. The dissociative nature of the TMC state leads to easy water removal to produce a five-coordinate intermediate that can isomerize via rotation of a pynp ligand and proceed towards the CA product. For CA, however, during this excitation and intersystem crossing process, an excited-state proton transfer (ESPT) occurs and the resultant TMLCT is very much stabilized with a very strong Ru(II)-OH bond; the high barrier from this TMLCT blocks conversion to a TMC state and thus prevents isomerization from the cis to the trans isomer. This high barrier also prevents the possibility of the isomerization process from TA to CA solely on the adiabatic triplet pathway. Instead, crossing points (XMC-CB, XMC CA) near the minimum of the triplet metal-centered state of the cis isomer provide nonadiabatic decay channels to the ground-state S0--CA, which completes the photoisomerization pathway from TA to CA. PMID- 26580045 TI - Going Backward: A Flexible Geometric Approach to Reverse Transformation from Coarse Grained to Atomistic Models. AB - The conversion of coarse-grained to atomistic models is an important step in obtaining insight about atomistic scale processes from coarse-grained simulations. For this process, called backmapping or reverse transformation, several tools are available, but these commonly require libraries of molecule fragments or they are linked to a specific software package. In addition, the methods are usually restricted to specific molecules and to a specific force field. Here, we present an alternative method, consisting of geometric projection and subsequent force-field based relaxation. This method is designed to be simple and flexible, and offers a generic solution for resolution transformation. For simple systems, the conversion only requires a list of particle correspondences on the two levels of resolution. For special cases, such as nondefault protonation states of amino acids and virtual sites, a target particle list can be specified. The mapping uses simple building blocks, which list the particles on the different levels of resolution. For conversion to higher resolution, the initial model is relaxed with several short cycles of energy minimization and position-restrained MD. The reconstruction of an atomistic backbone from a coarse grained model is done using a new dedicated algorithm. The method is generic and can be used to map between any two particle based representations, provided that a mapping can be written. The focus of this work is on the coarse-grained MARTINI force field, for which mapping definitions are written to allow conversion to and from the higher-resolution force fields GROMOS, CHARMM, and AMBER, and to and from a simplified three-bead lipid model. Together, these offer the possibility to simulate mesoscopic membrane structures, to be transformed to MARTINI and subsequently to an atomistic model for investigation of detailed interactions. The method was tested on a set of systems ranging from a simple, single-component bilayer to a large protein-membrane-solvent complex. The results demonstrate the efficiency and the efficacy of the new approach. PMID- 26580046 TI - Importance of Force Decomposition for Local Stress Calculations in Biomembrane Molecular Simulations. AB - Local stress fields are routinely computed from molecular dynamics trajectories to understand the structure and mechanical properties of lipid bilayers. These calculations can be systematically understood with the Irving-Kirkwood-Noll theory. In identifying the stress tensor, a crucial step is the decomposition of the forces on the particles into pairwise contributions. However, such a decomposition is not unique in general, leading to an ambiguity in the definition of the stress tensor, particularly for multibody potentials. Furthermore, a theoretical treatment of constraints in local stress calculations has been lacking. Here, we present a new implementation of local stress calculations that systematically treats constraints and considers a privileged decomposition, the central force decomposition, that leads to a symmetric stress tensor by construction. We focus on biomembranes, although the methodology presented here is widely applicable. Our results show that some unphysical behavior obtained with previous implementations (e.g. nonconstant normal stress profiles along an isotropic bilayer in equilibrium) is a consequence of an improper treatment of constraints. Furthermore, other valid force decompositions produce significantly different stress profiles, particularly in the presence of dihedral potentials. Our methodology reveals the striking effect of unsaturations on the bilayer mechanics, missed by previous stress calculation implementations. PMID- 26580047 TI - Adaptive Biasing Combined with Hamiltonian Replica Exchange to Improve Umbrella Sampling Free Energy Simulations. AB - The accurate calculation of potentials of mean force for ligand-receptor binding is one of the most important applications of molecular simulation techniques. Typically, the separation distance between ligand and receptor is chosen as a reaction coordinate along which a PMF can be calculated with the aid of umbrella sampling (US) techniques. In addition, restraints can be applied on the relative position and orientation of the partner molecules to reduce accessible phase space. An approach combining such phase space reduction with flattening of the free energy landscape and configurational exchanges has been developed, which significantly improves the convergence of PMF calculations in comparison with standard umbrella sampling. The free energy surface along the reaction coordinate is smoothened by iteratively adapting biasing potentials corresponding to previously calculated PMFs. Configurations are allowed to exchange between the umbrella simulation windows via the Hamiltonian replica exchange method. The application to a DNA molecule in complex with a minor groove binding ligand indicates significantly improved convergence and complete reversibility of the sampling along the pathway. The calculated binding free energy is in excellent agreement with experimental results. In contrast, the application of standard US resulted in large differences between PMFs calculated for association and dissociation pathways. The approach could be a useful alternative to standard US for computational studies on biomolecular recognition processes. PMID- 26580048 TI - RESPAC: Method to Determine Partial Charges in Coarse-Grained Protein Model and Its Application to DNA-Binding Proteins. AB - While coarse-grained (CG) molecular simulations for large biomolecular complexes have become popular, their electrostatic treatment is often rather simplistic. Here, for Calpha-based CG models of globular proteins, we developed a method to obtain an optimal partial charge set and applied it to 17 proteins that bind to DNA. The method follows the restrained electrostatic potential (RESP) fitting method widely used for determination of atomic partial charges in all-atom (AA) molecular mechanics. The proposed method, called the RESPAC method, finds optimal partial charges on surface Calpha CG beads so that these charges best approximate the electrostatic potential of the AA model under a restraint term. Comparison of the AA and CG electrostatic potentials showed that the RESPAC charges outperformed simplistic integer-valued charges. Then, the RESPAC method was applied to lac repressor binding to a nonspecific DNA sequence. We found that the CG simulations correlated well with AA molecular dynamics simulations. We also performed CG simulations of 16 other transcription factors. The differences in binding interfaces between nonspecific and specific DNAs were, on average, reduced by using the RESPAC charges. Yet, for several proteins, the nonspecific DNA binding interface was quite different from that of the specific binding interface, which is in accord with a previous report. PMID- 26580049 TI - Thermal Gradients on Graphene to Drive Nanoflake Motion. AB - Thermophoresis has been emerging as a novel technique for manipulating nanoscale particles. Materials with good thermal conductivity and low surface friction, such as graphene, are best suited to serve as a platform for solid-solid transportations or manipulations. Here we employ nonequilibrium molecular dynamics simulations to explore the feasibility of utilizing a thermal gradient on a large graphene substrate to control the motion of a small graphene nanoflake on it. Attempts to systematically investigate the mechanism of graphene-graphene transportation have centered on the fundamental driving mechanism of the motion and the quantitative effect of significant parameters such as temperature gradient and geometry of graphene on the motion of the nanoflake. Simulation results have demonstrated that temperature gradient plays the pivotal role in the evolution of the motion of the nanoflake on the graphene surface. Also, the geometry of nanoflakes has presented an intriguing signature on the motion of the nanoflake, which shows the nanoflakes with a circular shape move slower but rotate faster than other shapes with the identical area. It reveals that edge effects can stabilize the angular motion of thermophoretically driven particles. An interesting relation between the effective initial driving force and temperature gradient has been quantitatively captured by employing the steered molecular dynamics. These findings will provide fundamental insights into the motion of nanodevices on a solid surface due to thermophoresis, and will offer the novel view for manipulating nanoscale particles on a solid surface in techniques such as cell separation, water purification, and chemical extraction. PMID- 26580050 TI - Analytical Harmonic Vibrational Frequencies for the Green Fluorescent Protein Computed with ONIOM: Chromophore Mode Character and Its Response to Environment. AB - A systematic comparison of different environmental effects on the vibrational modes of the 4-hydroxybenzylidene-2,3-dimethylimidazolinone (HBDI) chromophore using the ONIOM method allows us to model how the molecule's spectroscopic transitions are modified in the Green Fluorescent Protein (GFP). ONIOM(QM:MM) reduces the expense of normal mode calculations when computing the majority of second derivatives only at the MM level. New developments described here for the efficient solution of the CPHF equations, including contributions from electrostatic interactions with environment charges, mean that QM model systems of ~100 atoms can be embedded within a much larger MM environment of ~5000 atoms. The resulting vibrational normal modes, their associated frequencies, and dipole derivative vectors have been used to interpret experimental difference spectra (GFPI2-GFPA), chromophore vibrational Stark shifts, and changes in the difference between electronic and vibrational transition dipoles (mode angles) in the protein environment. PMID- 26580051 TI - Computational Investigation on the Spectroscopic Properties of Thiophene Based Europium beta-Diketonate Complexes. AB - The adiabatic transition energies from the lowest triplet states of four Europium tris beta-diketonate/phenantroline complexes have been determined in vacuo and in dicholomethane solution by the DeltaSCF approach at the density functional theory level, using the PBE1PBE and the CAM-B3LYP hybrid functionals. The calculated adiabatic transition energies have been compared with the experimental 0-0 transitions of each complex determined from phosphorescence spectra of the corresponding Gd(3+) complexes and followed by direct comparison between simulated and experimental spectra line shapes. For compound 1, the Eu(TTA)3Phen system, triplet states other than the lowest one and conformational isomers other than the one present in the crystallographic structure have been considered. In the crystallographic structure, this compound presents three quasi-degenerate low energy triplet states, differing for the TTA ligand where the two unpaired electrons are localized and showing close adiabatic transition energies. For compound 1, the lowest triplet states of the four investigated conformational isomers show similar characteristics and close adiabatic transition energies. On the basis of these results, an investigation of compounds 2-4 (Eu(Br-TTA)3Phen, Eu(DTDK)3Phen, and Eu(MeT-TTA)3) has been performed by considering only the isomer present in the crystallographic structure and only the lowest triplet state of each compound. For compounds 1-3, the energies of the lowest triplet states calculated by both functionals in solution including zero-point energy corrections well reproduce the experimental trends as well as the values of the adiabatic transition energies: CAM-B3LYP, the best performing functional, provides energies of the lowest triplet state with deviations from experiments lower than 1200 cm(-1). Also, the calculated vibrationally resolved phosphorescence spectra and UV-vis absorptions well reproduce the main features of their experimental counterparts. Significant differences between calculated and experimental results are observed for compound 4, for which difficulties in the experimental determination of the triplet state energy were encountered: our results show that the negligible photoluminescence quantum yield of this compound is due to the fact that the energy of the most stable triplet state is significantly lower than that of the resonance level of the Europium ion, and thus the energy transfer process is prevented. These results confirm the reliability of the adopted computational approach in calculating the energy of the lowest triplet state energy of these systems, a key parameter in the design of new ligands for lanthanide complexes presenting large photoluminescence quantum yields. PMID- 26580052 TI - Chelation-Induced Quenching of Two-Photon Absorption of Azacrown Ether Substituted Distyryl Benzene for Metal Ion Sensing. AB - Imaging of metal ion concentration, distribution, and dynamics can pave the way to diagnose a number of diseases and to identify the normal functioning of the human body. Recently, two-photon microscopy-based imaging of metal ions has become popular due to several favorable factors as compared to fluorescence-based imaging. However, much has to be investigated in order to design probes with large two-photon absorption cross sections and yet with selective binding affinity toward metal ions. In particular, it is crucial to recognize the mechanisms of metal ion-induced changes of the two-photon absorption intensity. The present paper contributes to this effort and reports on the results of extensive studies carried out to define a reliable computational protocol that can account for sampling, solvent, and finite temperature effects for one- and two-photon properties of metal probes, using azacrown ether substituted distyrylbenzene embedded in solvents as a testbed. We employ a selection of theoretical approaches to model the structure of the probe alone and in the presence of Mg(2+) ion in acetonitrile solvent, including static quantum-chemical calculations, rigid- and flexible-body molecular dynamics, and hybrid QM/MM molecular dynamics. For a set of solute-solvent configurations, the one- and the two-photon properties are computed using the recently developed polarizable embedding response approach. It is found that the hybrid QM/MM molecular dynamics based approach is the most successful one among other employed computational strategies, viz. reproduction of the metal ion-induced blue shift in the absorption wavelength and decrease in the two-photon absorption cross section, which actually is in excellent agreement with experimental data. The mechanism for such metal ion-induced changes in the optical properties is put forward using a few-state model. Possible design principles to tune the two-photon absorption properties of probes are also discussed. PMID- 26580053 TI - Advanced Capabilities of the PYXAID Program: Integration Schemes, Decoherence Effects, Multiexcitonic States, and Field-Matter Interaction. AB - In our previous work [J. Chem. Theory Comput. 2013, 9, 4959], we introduced the PYXAID program, developed for the purpose of performing nonadiabatic molecular dynamics simulations in large-scale condensed matter systems. The methodological aspects and the basic capabilities of the program have been extensively discussed. In the present work, we perform a thorough investigation of advanced capabilities of the program, namely, the advanced integration techniques for the time-dependent Schrodinger equation (TD-SE), the decoherence corrections via decoherence-induced surface hopping, the use of multiexciton basis configurations, and the direct simulation of photoexcitation via explicit light matter interaction. We demonstrate the importance of the mentioned features by studying the electronic dynamics in a variety of systems. In particular, we demonstrate that the advanced integration techniques for solving TD-SE may lead to a significant speedup of the calculations and provide more stable solutions. We show that decoherence is necessary for accurate description of slow relaxation processes such as electron-hole recombination in solid C60. By using multiexciton configurations and direct, nonperturbative treatment of field-matter interactions, we found nontrivial optimality conditions for the multiple exciton generation in a small silicon cluster. PMID- 26580054 TI - Optical Signatures of OBO Fluorophores: A Theoretical Analysis. AB - Dioxaborines dyes, based on the OBO atomic sequence, constitute one promising series of molecules for both organic electronics and bioimaging applications. Using Time-Dependent Density Functional Theory, we have simulated the optical signatures of these fluoroborates. In particular, we have computed the 0-0 energies and shapes of both the absorption and the emission bands. To assess the importance of solvent effects three polarization schemes have been applied within the Polarizable Continuum Model: the linear-response (LR), the corrected linear response (cLR), and the state-specific (SS). We show that the SS approach is unable to yield consistent chemical trends for these challenging compounds that combine charge-transfer and cyanine characters. On the contrary, LR and cLR are more effective in reproducing chemical trends in OBO dyes. We have applied our computational protocol not only to analyze the signatures of existing dyes but also to design structures with red-shifted absorption and emission bands. PMID- 26580055 TI - Nuclear Quantum Effects in Water: A Multiscale Study. AB - We outline a method to investigate the role of nuclear quantum effects in liquid water making use of a force field derived from ab initio simulations. Starting from a first-principles molecular dynamics simulation, we obtain an effective force field for bulk liquid water using the force-matching technique. After validating that our effective model reproduces the key structural and dynamic properties of the reference system, we use it to perform path integral simulations to investigate the role played by nuclear quantum effects on bulk water, probing radial distribution functions, vibrational spectra, and hydrogen bond fluctuations. Our approach offers a practical route to derive ab initio quality molecular models to study quantum effects at a low computational cost. PMID- 26580056 TI - In Silico Design of Monomolecular Drug Carriers for the Tyrosine Kinase Inhibitor Drug Imatinib Based on Calix- and Thiacalix[n]arene Host Molecules: A DFT and Molecular Dynamics Study. AB - The use of functionalized calix- and thia-calix[n]arenes is proposed as the basis for our in silico design of a suitable drug carrier for the tyrosine kinase inhibitor, Imatinib. Their mutual electronic properties and interaction energies, Eint, were assessed with the use of Density Functional Theory (DFT) methods under the NBODel methodology. Three structural variables for the host molecules were considered: R = {SO3H (1), t-Bu (2), i-Pr (3), COOH (4), (CH2)2OH (5), (CH2)2NH2 (6)}; b = {CH2, S}; n = {5, 6, 8}, and two possible orientations for the insertion of Imatinib within the macrocycle cavity: pyridine moiety pointing inward (N1) and piperazine pointing inward (N2). In total, we explored 72 different assemblies. Initial molecular mechanics geometry optimizations with the UFF potential were undertaken for every host-guest complex, with further optimization at the B97D/6-31G(d,p) level of theory. Using the same optimized structures, Molecular Dynamics (MD) simulations were carried out on all 72 assemblies using the General Amber Force Field and the AMBER 12 MD package. Electronic parameters were fitted using the RESP method, and the complexes were run for 100 ns. Potential of mean force was obtained for the most stable systems using umbrella sampling and the Weighted Histogram Analysis Method. Calix[n]arenes families 1 and 5 (R = SO3H and (CH2)2OH, respectively) with n = 6 constitute the most promising candidates to become drug carriers within our parameter space due to their more negative Eint values and increased flexibility to allow the inclusion of the drug. PMID- 26580057 TI - Anisotropic Contributions to Protein-Protein Interactions. AB - The anisotropy of shape and functionality of proteins complicates the prediction of protein-protein interactions. We examine the distribution of electrostatic and nonelectrostatic contributions to these interactions for two globular proteins, lysozyme and chymosin B, which differ in molecular weight by about a factor of 2. The interaction trends for these proteins are computed in terms of contributions to the osmotic second virial coefficient that are evaluated using atomistic models of the proteins. Our emphasis is on identifying the orientational configurations that contribute most strongly to the overall interactions due to high-complementarity interactions, and on calculating the effect of ionic strength on such interactions. The results emphasize the quantitative importance of several features of protein interactions, notably that despite differences in their frequency of occurrence, configurations differing appreciably in interaction energy can contribute meaningfully to overall interactions. However, relatively small effects due to charge anisotropy or specific hydration can affect the overall interaction significantly only if they contribute to strongly attractive configurations. The results emphasize the necessity of accounting for detailed anisotropy to capture actual experimental trends, and the sensitivity of even very detailed atomistic models to subtle solution contributions. PMID- 26580058 TI - Sampling the Denatured State of Polypeptides in Water, Urea, and Guanidine Chloride to Strict Equilibrium Conditions with the Help of Massively Parallel Computers. AB - The denatured state of polypeptides and proteins, stabilized by chemical denaturants like urea and guanidine chloride, displays residual secondary structure when studied by nuclear-magnetic-resonance spectroscopy. However, these experimental techniques are weakly sensitive, and thus molecular-dynamics simulations can be useful to complement the experimental findings. To sample the denatured state, we made use of massively-parallel computers and of a variant of the replica exchange algorithm, in which the different branches, connected with unbiased replicas, favor the formation and disruption of local secondary structure. The algorithm is applied to the second hairpin of GB1 in water, in urea, and in guanidine chloride. We show with the help of different criteria that the simulations converge to equilibrium. It results that urea and guanidine chloride, besides inducing some polyproline-II structure, have different effect on the hairpin. Urea disrupts completely the native region and stabilizes a state which resembles a random coil, while guanidine chloride has a milder effect. PMID- 26580060 TI - Erratum: Method for Visualizing and Quantifying the Nonvalence Character of Excess Electrons. PMID- 26580059 TI - Extension of the Universal Force Field to Metal-Organic Frameworks. AB - The Universal Force Field (UFF) (Rappe et al., J. Am. Chem. Soc. 1992) provides a general approach to molecular mechanics for molecules and materials composed of elements throughout the periodic table. Though the method is tunable by the specification of bond orders and the introduction of effective charges, the presently available list of atom types is insufficient to treat various systems containing transition metals, including metal-organic frameworks (MOFs). As MOFs are composite materials built of a combination of individually stable building blocks, a plethora of MOF structures are possible, and the prediction of their structure with a low-cost method is important. We have extended the UFF parameter set to include transition metal elements Zn, Cu, Ni, Co, Fe, Mn, Cr, V, Ti, Sc, and Al, as they occur in MOFs, and have proposed additional O parameters that provide reliable structures of the metal oxide clusters of the connectors. We have benchmarked the performance of the MOF extension to UFF (UFF4MOF) with respect to experimentally available data and to DFT calculations. The parameters are available in various well-spread programs, including GULP, deMonNano, and ADF, and all information is provided to include them in other molecular mechanics codes. PMID- 26580061 TI - Addendum: Assessment of Coupled Cluster Theory and more Approximate Methods for Hydrogen Bonded Systems. PMID- 26580062 TI - Determination of NH proton chemical shift anisotropy with (14)N-(1)H heteronuclear decoupling using ultrafast magic angle spinning solid-state NMR. AB - The extraction of chemical shift anisotropy (CSA) tensors of protons either directly bonded to (14)N nuclei (I=1) or lying in their vicinity using rotor synchronous recoupling pulse sequence is always fraught with difficulty due to simultaneous recoupling of (14)N-(1)H heteronuclear dipolar couplings and the lack of methods to efficiently decouple these interactions. This difficulty mainly arises from the presence of large (14)N quadrupolar interactions in comparison to the rf field that can practically be achieved. In the present work it is demonstrated that the application of on-resonance (14)N-(1)H decoupling with rf field strength ~30 times weaker than the (14)N quadrupolar coupling during (1)H CSA recoupling under ultrafast MAS (90kHz) results in CSA lineshapes that are free from any distortions from recoupled (14)N-(1)H interactions. With the use of extensive numerical simulations we have shown the applicability of our proposed method on a naturally abundant l-Histidine HCl.H2O sample. PMID- 26580063 TI - Local T2 measurement employing longitudinal Hadamard encoding and adiabatic inversion pulses in porous media. AB - Band selective adiabatic inversion radio frequency pulses were employed for multi slice T2 distribution measurements in porous media samples. Multi-slice T2 measurement employing longitudinal Hadamard encoding has an inherent sensitivity advantage over slice-by-slice local T2 measurements. The slice selection process is rendered largely immune to B1 variation by employing hyperbolic secant adiabatic inversion pulses, which simultaneously invert spins in several well defined slices. While Hadamard encoding is well established for local spectroscopy, the current work is the first use of Hadamard encoding for local T2 measurement. PMID- 26580064 TI - Proton-detected solid-state NMR spectroscopy of fully protonated proteins at slow to moderate magic-angle spinning frequencies. AB - (1)H-detection offers a substitute to the sensitivity-starved experiments often used to characterize biomolecular samples using magic-angle spinning solid-state NMR spectroscopy (MAS-ssNMR). To mitigate the effects of the strong (1)H-(1)H dipolar coupled network that would otherwise severely broaden resonances, high MAS frequencies (>40kHz) are often employed. Here, we have explored the alternative of stroboscopic (1)H-detection at moderate MAS frequencies of 5-30kHz using windowed version of supercycled-phase-modulated Lee-Goldburg homonuclear decoupling. We show that improved resolution in the (1)H dimension, comparable to that obtainable at high spinning frequencies of 40-60kHz without homonuclear decoupling, can be obtained in these experiments for fully protonated proteins. Along with detailed analysis of the performance of the method on the standard tri peptide f-MLF, experiments on micro-crystalline GB1 and amyloid-beta aggregates are used to demonstrate the applicability of these pulse-sequences to challenging biomolecular systems. With only two parameters to optimize, broadbanded performance of the homonuclear decoupling sequence, linear dependence of the chemical-shift scaling factor on resonance offset and a straightforward implementation under experimental conditions currently used for many biomolecular studies (viz. spinning frequencies and radio-frequency amplitudes), we expect these experiments to complement the current (13)C-detection based methods in assignments and characterization through chemical-shift mapping. PMID- 26580065 TI - Identification of an Immune-Neuroendocrine Biomarker Panel for Detection of Depression: A Joint Effects Statistical Approach. AB - BACKGROUND/AIMS: Less than half of depression patients are correctly diagnosed within the primary care setting. Previous proteomic studies have identified numerous immune and neuroendocrine changes in patients. However, few studies have considered the joint effects of biological molecules and their diagnostic potential. Our aim was to develop and validate a diagnostic serum biomarker panel identified through joint effects analysis of multiplex immunoassay profiling data from 1,007 clinical samples. METHODS: In stage 1, we conducted a meta-analysis of two independent cohorts of 78 first-/recent-onset drug-naive/drug-free depression patients and 156 controls and applied the 10-fold cross-validation with least absolute shrinkage and selection operator regression to identify an optimal diagnostic prediction model (biomarker panel). In stage 2, we tested the discriminatory performance of this biomarker panel using the naturalistic Netherlands Study of Depression and Anxiety (NESDA) cohort of 468 depression patients and 305 controls. RESULTS: An optimal panel of 33 immune-neuroendocrine biomarkers and gender was selected in the meta-analysis. Testing this biomarker gender panel using the NESDA cohort resulted in a moderate to good performance to differentiate patients from controls (0.69 < AUC < 0.86), particularly the first episode patients free of chronic non-psychiatric diseases or medications and following incorporation of sociodemographic covariates (0.76 < AUC < 0.92). CONCLUSION: Despite the need for additional validation studies, we demonstrated that a blood-based biomarker-sociodemographic panel can detect depression in naturalistic healthcare settings with good discriminatory power. Further refinements of blood biomarker panels aiding in the diagnosis of depression may provide a cost-effective means to increase accuracy of clinical diagnosis within the primary care setting. PMID- 26580066 TI - Does Chronic Unpredictable Stress during Adolescence Affect Spatial Cognition in Adulthood? AB - Spatial abilities allow animals to retain and cognitively manipulate information about their spatial environment and are dependent upon neural structures that mature during adolescence. Exposure to stress in adolescence is thought to disrupt neural maturation, possibly compromising cognitive processes later in life. We examined whether exposure to chronic unpredictable stress in adolescence affects spatial ability in late adulthood. We evaluated spatial learning, reference and working memory, as well as long-term retention of visuospatial cues using a radial arm water maze. We found that stress in adolescence decreased the rate of improvement in spatial learning in adulthood. However, we found no overall performance impairments in adult reference memory, working memory, or retention caused by adolescent-stress. Together, these findings suggest that adolescent-stress may alter the strategy used to solve spatial challenges, resulting in performance that is more consistent but is not refined by incorporating available spatial information. Interestingly, we also found that adolescent-stressed rats showed a shorter latency to begin the water maze task when re-exposed to the maze after an overnight delay compared with control rats. This suggests that adolescent exposure to reoccurring stressors may prepare animals for subsequent reoccurring challenges. Overall, our results show that stress in adolescence does not affect all cognitive processes, but may affect cognition in a context-dependent manner. PMID- 26580067 TI - Association between Serum Alkaline Phosphatase Level and Cerebral Small Vessel Disease. AB - BACKGROUND: Serum alkaline phosphatase (ALP) is a marker of vascular calcification. A high serum ALP level is associated with an increase in cardiovascular events, and predicts poor functional outcome in patients with stroke. We investigated whether serum ALP was associated with cerebral small vessel disease (cSVD) and large cerebral artery stenosis (LCAS). METHODS: We evaluated vascular risk factors, brain magnetic resonance images (MRIs), and MR angiograms from 1,011 neurologically healthy participants. The presence of silent lacunar infarction (SLI) and moderate-to-severe cerebral white matter hyperintensities (MS-cWMH) were evaluated as indices of cSVD on brain MRIs. Findings of extracranial arterial stenosis (ECAS) or intracranial arterial stenosis (ICAS) were considered to be indices of LCAS on MR angiograms. RESULTS: Subjects with SLI (odds ratio [OR]: 2.09; 95% confidence interval [CI]: 1.27 3.42; p = 0.004) and MS-cWMH (OR: 1.48; 95% CI; 1.03-2.13, p = 0.036) were significantly more likely to have ALP levels in the third tertile (ALP >= 195 IU/L) than the first tertile (ALP <= 155 IU/L), after adjusting for cardiovascular risk factors. The mean serum ALP level was significantly higher in patients with SLI or MS-cWMH compared to patients without those findings. After adjustment for confounding factors, the multivariate model found that the statistical significance of serum ALP remained when the presence of SLI (OR: 1.05 per 10 IU/L increase in ALP; 95% CI: 1.02-1.08; p = 0.003) or MS-cWMH (OR: 1.03 per 10 IU/L increase in ALP; 95% CI: 1.00-1.06; p = 0.025) were added to the model. There were no differences in the proportions of patients with LCAS, ICAS, and ECAS across the serum ALP tertiles. CONCLUSIONS: Our study of neurologically healthy participants found a positive association between serum ALP level and indicators of cSVD, but no association between serum ALP level and the indicators of LCAS. PMID- 26580068 TI - The Vestibular-Evoked Postural Response of Adolescents with Idiopathic Scoliosis Is Altered. AB - Adolescent idiopathic scoliosis is a multifactorial disorder including neurological factors. A dysfunction of the sensorimotor networks processing vestibular information could be related to spine deformation. This study investigates whether feed-forward vestibulomotor control or sensory reweighting mechanisms are impaired in adolescent scoliosis patients. Vestibular evoked postural responses were obtained using galvanic vestibular stimulation while participants stood with their eyes closed and head facing forward. Lateral forces under each foot and lateral displacement of the upper body of adolescents with mild (n = 20) or severe (n = 16) spine deformation were compared to those of healthy control adolescents (n = 16). Adolescent idiopathic scoliosis patients demonstrated greater lateral displacement and net lateral forces than controls both during and immediately after vestibular stimulation. Altered sensory reweighting of vestibular and proprioceptive information changed balance control of AIS patients during and after vestibular stimulation. Therefore, scoliosis onset could be related to abnormal sensory reweighting, leading to altered sensorimotor processes. PMID- 26580069 TI - Analysis of Stage-Specific Gene Expression Profiles in the Uterine Endometrium during Pregnancy in Pigs. AB - The uterine endometrium plays a critical role in regulating the estrous cycle and the establishment and maintenance of pregnancy in mammalian species. Many studies have investigated the expression and function of genes in the uterine endometrium, but the global expression pattern of genes and relationships among genes differentially expressed in the uterine endometrium during gestation in pigs remain unclear. Thus, this study investigated global gene expression profiles using microarray in pigs. Diverse transcriptome analyses including clustering, network, and differentially expressed gene (DEG) analyses were performed to detect endometrial gene expression changes during the different gestation stages. In total, 6,991 genes were found to be differentially expressed by comparing genes expressed on day (D) 12 of pregnancy with those on D15, D30, D60, D90 and D114 of pregnancy, and clustering analysis of detected DEGs distinguished 8 clusters. Furthermore, several pregnancy-related hub genes such as ALPPL2, RANBP17, NF1B, SPP1, and CST6 were discovered through network analysis. Finally, detected hub genes were technically validated by quantitative RT-PCR. These results suggest the complex network characteristics involved in uterine endometrial gene expression during pregnancy and indicate that diverse patterns of stage-specific gene expression and network connections may play a critical role in endometrial remodeling and in placental and fetal development to establish and maintenance of pregnancy in pigs. PMID- 26580070 TI - The Expression of TALEN before Fertilization Provides a Rapid Knock-Out Phenotype in Xenopus laevis Founder Embryos. AB - Recent advances in genome editing using programmable nucleases have revolutionized gene targeting in various organisms. Successful gene knock-out has been shown in Xenopus, a widely used model organism, although a system enabling less mosaic knock-out in founder embryos (F0) needs to be explored in order to judge phenotypes in the F0 generation. Here, we injected modified highly active transcription activator-like effector nuclease (TALEN) mRNA to oocytes at the germinal vesicle (GV) stage, followed by in vitro maturation and intracytoplasmic sperm injection, to achieve a full knock-out in F0 embryos. Unlike conventional injection methods to fertilized embryos, the injection of TALEN mRNA into GV oocytes allows expression of nucleases before fertilization, enabling them to work from an earlier stage. Using this procedure, most of developed embryos showed full knock-out phenotypes of the pigmentation gene tyrosinase and/or embryonic lethal gene pax6 in the founder generation. In addition, our method permitted a large 1 kb deletion. Thus, we describe nearly complete gene knock-out phenotypes in Xenopus laevis F0 embryos. The presented method will help to accelerate the production of knock-out frogs since we can bypass an extra generation of about 1 year in Xenopus laevis. Meantime, our method provides a unique opportunity to rapidly test the developmental effects of disrupting those genes that do not permit growth to an adult able to reproduce. In addition, the protocol shown here is considerably less invasive than the previously used host transfer since our protocol does not require surgery. The experimental scheme presented is potentially applicable to other organisms such as mammals and fish to resolve common issues of mosaicism in founders. PMID- 26580071 TI - Human MAMLD1 Gene Variations Seem Not Sufficient to Explain a 46,XY DSD Phenotype. AB - MAMLD1 is thought to cause disordered sex development in 46,XY patients. But its role is controversial because some MAMLD1 variants are also detected in normal individuals, several MAMLD1 mutations have wild-type activity in functional tests, and the male Mamld1-knockout mouse has normal genitalia and reproduction. Our aim was to search for MAMLD1 variations in 108 46,XY patients with disordered sex development, and to test them functionally. We detected MAMDL1 variations and compared SNP frequencies in controls and patients. We tested MAMLD1 transcriptional activity on promoters involved in sex development and assessed the effect of MAMLD1 on androgen production. MAMLD1 expression in normal steroid producing tissues and mutant MAMLD1 protein expression were also assessed. Nine MAMLD1 mutations (7 novel) were characterized. In vitro, most MAMLD1 variants acted similarly to wild type. Only the L210X mutation showed loss of function in all tests. We detected no effect of wild-type or MAMLD1 variants on CYP17A1 enzyme activity in our cell experiments, and Western blots revealed no significant differences for MAMLD1 protein expression. MAMLD1 was expressed in human adult testes and adrenals. In conclusion, our data support the notion that MAMLD1 sequence variations may not suffice to explain the phenotype in carriers and that MAMLD1 may also have a role in adult life. PMID- 26580072 TI - Helicobacter pylori Eradication Prevents Metachronous Gastric Neoplasms after Endoscopic Resection of Gastric Dysplasia. AB - PURPOSE: There is insufficient data about the role of eradication of H. pylori after endoscopic resection (ER) for gastric dysplasia. The aim was to investigate the benefit of H. pylori eradication after ER in patients with gastric dysplasia to prevent metachronous gastric neoplasms. MATERIALS AND METHODS: We retrospectively reviewed 1872 patients who underwent ER of gastric dysplasia. We excluded patients with a follow-up period of <2 years or who had not undergone tests for active H. pylori infection. A total of 282 patients were enrolled. The patients were categorized into those without active H. pylori infection (H. pylori-negative group, n = 124), those who successfully underwent H. pylori eradication (eradicated group, n = 122), and those who failed or did not undergo H. pylori eradication (persistent group, n = 36). RESULTS: Metachronous recurrence was diagnosed in 36 patients, including 19 in the H. pylori-negative group, 10 in the eradicated group, and 7 in the persistent group. The cumulative incidence of metachronous recurrence was significantly lower in the H. pylori eradicated group in comparison with either of the H. pylori-persistent (non eradicated or failed) groups (p = 0.039). Similarly, the incidence of metachronous recurrence was significantly lower in the H. pylori-eradicated group compared with the H. pylori-negative group (p = 0.041). CONCLUSION: Successful H. pylori eradication may reduce the development of metachronous gastric neoplasms after ER in patients with gastric dysplasia. PMID- 26580073 TI - Comparison of Different Buffers for Protein Extraction from Formalin-Fixed and Paraffin-Embedded Tissue Specimens. AB - We determined the best extraction buffer for proteomic investigation using formalin-fixation and paraffin-embedded (FFPE) specimens. A Zwittergent 3-16 based buffer, sodium dodecyl sulfate (SDS)-containing buffer with/without polyethylene glycol 20000 (PEG20000), urea-containing buffer, and FFPE-FASP protein preparation kit were compared for protein extraction from different types of rat FFPE tissues, including the heart, brain, liver, lung, and kidney. All of the samples were divided into two groups of laser microdissected (LMD) and non LMD specimens. For both kinds of specimens, Zwittergent was the most efficient buffer for identifying peptides and proteins, was broadly applicable to different tissues without impairing the enzymatic digestion, and was well compatible with mass spectrometry analysis. As a high molecular weight carrier substance, PEG20000 improved the identification of peptides and proteins; however, such an advantage is limited to tissues containing submicrograms to micrograms of protein. Considering its low lytic strength, urea-containing buffer would not be the first alternative for protein recovery. In conclusion, Zwittergent 3-16 is an effective buffer for extracting proteins from FFPE specimens for downstream proteomics analysis. PMID- 26580075 TI - Genetic Interaction of Aspergillus nidulans galR, xlnR and araR in Regulating D Galactose and L-Arabinose Release and Catabolism Gene Expression. AB - In Aspergillus nidulans, the xylanolytic regulator XlnR and the arabinanolytic regulator AraR co-regulate pentose catabolism. In nature, the pentose sugars D xylose and L-arabinose are both main building blocks of the polysaccharide arabinoxylan. In pectin and arabinogalactan, these two monosaccharides are found in combination with D-galactose. GalR, the regulator that responds to the presence of D-galactose, regulates the D-galactose catabolic pathway. In this study we investigated the possible interaction between XlnR, AraR and GalR in pentose and/or D-galactose catabolism in A. nidulans. Growth phenotypes and metabolic gene expression profiles were studied in single, double and triple disruptant A. nidulans strains of the genes encoding these paralogous transcription factors. Our results demonstrate that AraR and XlnR not only control pentose catabolic pathway genes, but also genes of the oxido-reductive D galactose catabolic pathway. This suggests an interaction between three transcriptional regulators in D-galactose catabolism. Conversely, GalR is not involved in regulation of pentose catabolism, but controls only genes of the oxido-reductive D-galactose catabolic pathway. PMID- 26580074 TI - Molecular Characterisation of Chikungunya Virus Infections in Trinidad and Comparison of Clinical and Laboratory Features with Dengue and Other Acute Febrile Cases. AB - Local transmission of Chikungunya virus (CHIKV) was first documented in Trinidad and Tobago (T&T) in July 2014 preceding a large epidemic. At initial presentation, it is difficult to distinguish chikungunya fever (CHIKF) from other acute undifferentiated febrile illnesses (AUFIs), including life-threatening dengue disease. We characterised and compared dengue virus (DENV) and CHIKV infections in 158 patients presenting with suspected dengue fever (DF) and CHIKF at a major hospital in T&T, and performed phylogenetic analyses on CHIKV genomic sequences recovered from 8 individuals. The characteristics of patients with and without PCR-confirmed CHIKV were compared using Pearson's chi2 and student's t tests, and adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were determined using logistic regression. We then compared signs and symptoms of people with RT-qPCR-confirmed CHIKV and DENV infections using the Mann-Whitney U, Pearson's chi2 and Fisher's exact tests. Among the 158 persons there were 8 (6%) RT-qPCR-confirmed DENV and 30 (22%) RT-qPCR-confirmed CHIKV infections. Phylogenetic analyses showed that the CHIKV strains belonged to the Asian genotype and were most closely related to a British Virgin Islands strain isolated at the beginning of the 2013/14 outbreak in the Americas. Compared to persons who were RT-qPCR-negative for CHIKV, RT-qPCR-positive individuals were significantly more likely to have joint pain (aOR: 4.52 [95% CI: 1.28-16.00]), less likely to be interviewed at a later stage of illness (days post onset of fever--aOR: 0.56 [0.40-0.78]) and had a lower white blood cell count (aOR: 0.83 [0.71-0.96]). Among the 38 patients with RT-qPCR-confirmed CHIKV or DENV, there were no significant differences in symptomatic presentation. However when individuals with serological evidence of recent DENV or CHIKV infection were included in the analyses, there were key differences in clinical presentation between CHIKF and other AUFIs including DF, which can be used to triage patients for appropriate care in the clinical setting. PMID- 26580076 TI - Use of Antimalarial in the Management of Fever during a Community Survey in the Kintampo Districts of Ghana. AB - BACKGROUND: Epidemiology of malaria and related fevers in most parts of Africa is changing due to scale up of interventions such as appropriate use of ACTs in the effort towards sustained control and eventual elimination of malaria. The use of ACTs in the management of malaria-associated fever was evaluated in the Kintampo districts of Ghana. METHODS: Household survey was conducted between October 2009 and February, 2011. A random selection of 370 households was generated from 25,000 households existing within the Health and Demographic Surveillance Systems in Kintampo, Ghana at the time. All household members present at the time of survey in the eligible households were interviewed based on a two weeks reported fever recall and the use of antimalarial for the management of fever. A finger prick blood sample was also obtained from each member of the household present and later examined for malaria parasites using microscopy. Descriptive analysis was performed, with univariate and multivariate analysis used to identify predictors of fever and malaria parasitemia. RESULTS: A total of 1436 individuals were interviewed from 370 households. Overall, fever prevalence was 23.8% (341/1436) and was 38.8% (77/198) in children < 5 years, 21.3% (264/1238) in older children plus adults. Participants who sought treatment for fever were 84% (285/341) with 47.7% (136/285) using any anti-malarial. Artemisinin-based Combination Therapy use was in 69.1% (94/136) of cases while 30.9% used mono therapies. Malaria parasitaemia rate was 28.2% (397/1407). CONCLUSION: The study reports high community fever prevalence, frequent use of antimalarials for fever treatment and relatively high use of mono-therapies especially in children < 5 years in an area with high malaria parasite prevalence in Ghana. PMID- 26580077 TI - Subject Based Registration for Individualized Analysis of Diffusion Tensor MRI. AB - Registration of subject and control brains to a common anatomical space or template is the basis for quantitatively delineating regions of abnormality in an individual brain. Normally, a brain atlas is chosen as the template. Limitations in the registration process result in persistent differences between individual subject brains and template, which can be a source of error in an analysis. We propose a new approach to the registration process where the subject of interest is the registration template. Through this change, we eliminate errors due to differences between a brain template and a subject's brain. We applied this method to the analysis of FA values derived from DTI data of 20 individual mTBI patients as compared to 48 healthy controls. Subject-centered analysis resulted in identification of significantly fewer regions of abnormally low FA compared to two separate atlas-centered analyses, with subject-centered abnormalities essentially representing the common subset of abnormal low FA regions detected by the two atlas-centered methods. Whereas each atlas-centered approach demonstrated abnormalities in nearly every subject (19/20 and 20/20), the subject-centered approach demonstrated abnormalities in fewer than half the subjects (9/20). This reduction of diffusion abnormalities observed using the subject-centered approach is due to elimination of misregistration errors that occur when registering the subject of interest to a template. Evaluation of atlas-centered analyses demonstrated that 9.8% to 13.3% of subject GM and CSF was misregistered onto the WM of the brain atlas, resulting in the observation of additional low FA clusters compared to the subject-centered approach. Without careful evaluation, these misregistrations could be misinterpreted as pathology. An additional benefit of the subject-centered approach is that diffusion abnormalities can now be visualized directly in the subject's anatomical space, rather than interpolating results from the brain atlas space, and can thereby enhance correlation with other components of an imaging protocol. PMID- 26580080 TI - Are we really delivering evidence-based treatments for eating disorders? How eating-disordered patients describe their experience of cognitive behavioral therapy. AB - Psychotherapists report routinely not practising evidence-based treatments. However, there is little research examining the content of therapy from the patient perspective. This study examined the self-reported treatment experiences of individuals who had been told that they had received cognitive-behavior therapy (CBT) for their eating disorder. One hundred and fifty-seven such sufferers (mean age = 25.69 years) were recruited from self-help organisations. Participants completed an online survey assessing demographics, clinical characteristics, and therapy components. The use of evidence-based CBT techniques varied widely, with core elements for the eating disorders (e.g., weighing and food monitoring) used at well below the optimum level, while a number of unevidenced techniques were reported as being used commonly. Cluster analysis showed that participants received different patterns of intervention under the therapist label of 'CBT', with evidence-based CBT being the least common. Therapist age and patient diagnosis were related to the pattern of intervention delivered. It appears that clinicians are not subscribing to a transdiagnostic approach to the treatment of eating disorders. Patient recollections in this study support the conclusion that evidence-based practice is not routinely undertaken with this client group, even when the therapy offered is described as such. PMID- 26580079 TI - Metabolic Interplay between the Asian Citrus Psyllid and Its Profftella Symbiont: An Achilles' Heel of the Citrus Greening Insect Vector. AB - 'Candidatus Liberibacter asiaticus' (CLas), the bacterial pathogen associated with citrus greening disease, is transmitted by Diaphorina citri, the Asian citrus psyllid. Interactions among D. citri and its microbial endosymbionts, including 'Candidatus Profftella armatura', are likely to impact transmission of CLas. We used quantitative mass spectrometry to compare the proteomes of CLas(+) and CLas(-) populations of D. citri, and found that proteins involved in polyketide biosynthesis by the endosymbiont Profftella were up-regulated in CLas(+) insects. Mass spectrometry analysis of the Profftella polyketide diaphorin in D. citri metabolite extracts revealed the presence of a novel diaphorin-related polyketide and the ratio of these two polyketides was changed in CLas(+) insects. Insect proteins differentially expressed between CLas(+) and CLas(-) D. citri included defense and immunity proteins, proteins involved in energy storage and utilization, and proteins involved in endocytosis, cellular adhesion, and cytoskeletal remodeling which are associated with microbial invasion of host cells. Insight into the metabolic interdependence between the insect vector, its endosymbionts, and the citrus greening pathogen reveals novel opportunities for control of this disease, which is currently having a devastating impact on citrus production worldwide. PMID- 26580078 TI - Modulation of Human Macrophage Responses to Mycobacterium tuberculosis by Silver Nanoparticles of Different Size and Surface Modification. AB - Exposure to silver nanoparticles (AgNP) used in consumer products carries potential health risks including increased susceptibility to infectious pathogens. Systematic assessments of antimicrobial macrophage immune responses in the context of AgNP exposure are important because uptake of AgNP by macrophages may lead to alterations of innate immune cell functions. In this study we examined the effects of exposure to AgNP with different particle sizes (20 and 110 nm diameters) and surface chemistry (citrate or polyvinlypyrrolidone capping) on cellular toxicity and innate immune responses against Mycobacterium tuberculosis (M.tb) by human monocyte-derived macrophages (MDM). Exposures of MDM to AgNP significantly reduced cellular viability, increased IL8 and decreased IL10 mRNA expression. Exposure of M.tb-infected MDM to AgNP suppressed M.tb induced expression of IL1B, IL10, and TNFA mRNA. Furthermore, M.tb-induced IL 1beta, a cytokine critical for host resistance to M.tb, was inhibited by AgNP but not by carbon black particles indicating that the observed immunosuppressive effects of AgNP are particle specific. Suppressive effects of AgNP on the M.tb induced host immune responses were in part due to AgNP-mediated interferences with the TLR signaling pathways that culminate in the activation of the transcription factor NF-kappaB. AgNP exposure suppressed M.tb-induced expression of a subset of NF-kappaB mediated genes (CSF2, CSF3, IFNG, IL1A, IL1B, IL6, IL10, TNFA, NFKB1A). In addition, AgNP exposure increased the expression of HSPA1A mRNA and the corresponding stress-induced Hsp72 protein. Up-regulation of Hsp72 by AgNP can suppress M.tb-induced NF-kappaB activation and host immune responses. The observed ability of AgNP to modulate infectious pathogen-induced immune responses has important public health implications. PMID- 26580081 TI - Interpretation modification training reduces social anxiety in clinically anxious children. AB - The present study was designed to examine the effects of training in positive interpretations in clinically anxious children. A total of 87 children between 7 and 12 years of age were randomly assigned to either a positive cognitive bias modification training for interpretation (CMB-I) or a neutral training. Training included 15 sessions in a two-week period. Children with an interpretation bias prior to training in the positive training group showed a significant reduction in interpretation bias on the social threat scenarios after training, but not children in the neutral training group. No effects on interpretation biases were found for the general threat scenarios or the non-threat scenarios. Furthermore, children in the positive training did not self-report lower anxiety than children in the neutral training group. However, mothers and fathers reported a significant reduction in social anxiety in their children after positive training, but not after neutral training. This study demonstrated that clinically anxious children with a prior interpretation bias can be trained away from negative social interpretation biases and there is some evidence that this corresponds to reductions in social anxiety. This study also highlights the importance of using specific training stimuli. PMID- 26580082 TI - Trypanorhynch cestodes (Eutetrarhynchidae) from batoids along the coast of Argentina, including the description of new species in Dollfusiella Campbell et Beveridge, 1994 and Mecistobothrium Heinz et Dailey, 1974. AB - During a recent parasitological survey of elasmobranchs along the coast of Argentina, two new species of eutetrarhynchid cestodes of the genera Dollfusiella Campbell et Beveridge, 1994 and Mecistobothrium Heinz et Dailey, 1974 were collected from batoids. Dollfusiella acuta sp. n. was found in four arhynchobatid skates, i.e. Sympterygia acuta Garman (type host), Sympterygia bonapartii Muller et Henle, Atlantoraja castelnaui (Miranda Ribeiro) and Atlantoraja platana (Gunther), and Mecistobothrium oblongum sp. n. in the eagle ray Myliobatis goodei Garman. Dollfusiella acuta sp. n. has a tentacular armature consisting of basal rows of uncinate hooks, a distinct basal swelling with uncinate, falcate and bill hooks, and a heteroacanthous metabasal armature with heteromorphous hooks (bothrial uncinate hooks and antibothrial falcate hooks), hooks 1(1') not separated, testes in two columns and an internal seminal vesicle. The tentacular armature of M. oblongum sp. n. is characterised by basal rows of uncinate hooks, a basal swelling with uncinate and falcate hooks, a typical heteroacanthous metabasal armature with heteromorphous hooks (uncinate and falcate to spiniform), and hooks 1(1') separated and of a constant size along the tentacle. It also possesses an elongate scolex, numerous testes arranged in 5-6 irregular columns, and an internal seminal vesicle. The discovery of M. oblongum in M. goodei represents the first record of species of Mecistobothrium in the southwestern Atlantic Ocean. An amended description of Dollfusiella cortezensis (Friggens et Duszynski, 2005) is also provided to clarify details of the scolex and tentacular armature. Members of Dollfusiella in the southwestern Atlantic are specific to a single host species or to a particular host family, while M. oblongum was found in a single host species. Although globally some plerocerci of eutetrarhynchids have been found in teleosts, extensive examination of teleosts off the coast of Argentina suggests that the transmission pathways of these species are exclusively based on invertebrates as intermediate or paratenic hosts. PMID- 26580083 TI - Universal Stress Protein Regulates Electron Transfer and Superoxide Generation Activities of the Cytochrome bc1 Complex from Rhodobacter sphaeroides. AB - Interactions between Rhodobacter sphaeroides cytochrome bc1 complex (Rsbc1) and soluble cytosolic proteins were studied by a precipitation pull-down technique. After being purified, detergent-dispersed Rsbc1 complex was incubated with soluble cytosolic fraction and then dialyzed in the absence of detergent; the interacting proteins were coprecipitated with Rsbc1 complex upon centrifugation. One of the cytosolic proteins pulled down by Rsbc1 complex was identified by liquid chromatography-coupled tandem mass spectrometry (LC/MS/MS) to be the reported R. sphaeroides universal stress protein (UspA). Incubating purified UspA with the detergent dispersed bc1 complex resulted in an increase in the Rsbc1 complex activity by 60% and a decrease in superoxide generation activity by the complex by more than 70%. These UspA effects were only observed with Rsbc1 complexes containing subunit IV and assayed under aerobic conditions. These results suggest that the interaction between UspA and Rsbc1 complex may play an important role in R. sphaeroides cells during oxidative stress. Using a biotin label transfer technique, cytochrome c1 of the Rsbc1 complex was identified as the interacting site for UspA. PMID- 26580084 TI - An Ultrasensitive (Parts-Per-Quadrillion) and SPE-Free Method for the Quantitative Analysis of Estrogens in Surface Water. AB - An analytical method is presented here that is sensitive to the parts-per quadrillion (pg/L) for estrogens in surface water. The estrogens included for study were estrone, 17beta-estradiol, estriol, 17alpha-ethinylestradiol, and equilin. The method consisted of the small-scale liquid-liquid extraction of surface water followed by derivation with dansyl chloride. Analyte separation and detection were performed by high-pressure liquid-chromatography and tandem mass spectrometry. A large volume (100 MUL) of the sample was injected on-column to increase the analyte mass sent to the detector. The detection limits of the method were 0.045 ng/L for estrone, 0.086 ng/L for 17beta-estradiol, 0.030 ng/L for estriol, 0.049 ng/L for 17alpha-ethinylestradiol, and 0.13 ng/L for equilin. The whole-method accuracy ranged from 93 +/- 5.8% to 105 +/- 4.5% for all the analytes at two different spike levels. Similarly, the precision of the method was less than 8.0% relative standard deviation. The final method was used to analyze a series of samples from the Mississippi River spanning 51 river miles. Estrone was detected in all of the samples and 17beta-estradiol was detected in one. Concentrations of estrone ranged from between the detection and quantification limits up to 0.63 ng/L. Increases in the concentration of estrone could be observed downstream from potential sources including a drinking water treatment plant. 17beta-estradiol was detected below its quantitation limit in a sample taken downstream from a wastewater treatment plant. PMID- 26580085 TI - Perchlorate formation during the electro-peroxone treatment of chloride containing water: Effects of operational parameters and control strategies. AB - This study investigated the degradation of clofibric acid and formation of perchlorate during the electro-peroxone (E-peroxone) treatment of chloride containing (26.1-100 mg L(-1)) water (Na2SO4 electrolytes and secondary effluents). The E-peroxone process involves sparging O2 and O3 gas mixture into an electrolysis reactor where a carbon-based cathode is used to electrochemically convert the sparged O2 to H2O2. The electro-generated H2O2 then reacts with sparged O3 to produce OH, which can rapidly oxidize pollutants in the bulk solution. When boron-doped diamond (BDD) electrodes were used as the anode, perchlorate concentrations increased significantly from undetectable levels to ~15-174 mg L(-1) in the different water samples as the applied current density was increased from 4 to 32 mA cm(-2). In contrast, no ClO4(-) was detected when Pt/Ti anodes were used in the E-peroxone process operated under similar reaction conditions. In addition, when sufficient O3 was sparged to maximize OH production from its peroxone reaction with electro-generated H2O2, the E-peroxone process with Pt/Ti anodes achieved comparable clofibric acid degradation and total organic carbon (TOC) removal yields as that with BDD anodes, but did not generate detectable ClO4(-). These results indicate that by optimizing operational parameters and using Pt/Ti anodes, the E-peroxone process can achieve the goal of both fast pollutant degradation and ClO4(-) prevention during the treatment of chloride-containing wastewater. PMID- 26580086 TI - Quantification and kinetic characterization of soluble microbial products from municipal wastewater treatment plants. AB - Soluble microbial products (SMP) formed by microorganisms in wastewater treatment plants (WWTPs) adversely affect final effluent quality and treatment efficiency. It is difficult to distinguish SMP from residual proteins, lipids and carbohydrates present in the influent that may persist during treatment. No method is currently available to determine quantitatively the extent to which SMP contribute to organic discharges from municipal WWTPs. In this work a modeling approach is presented which allows the SMP fraction of the effluent of a municipal WWTP to be quantified and described. The model is validated, in terms of utilization-associated products, biomass-associated products and extracellular polymeric substances, using influent from a municipal WWTP. SMP was found to account for, on average, 27 mg/L of chemical oxygen demand (COD), or 61% of the total COD in the WWTP effluent. Over 90% of the SMP was comprised of biomass associated products. Five main factors influencing SMP formation in WWTP were evaluated. Neither wastewater composition nor mixed liquor suspended solids concentration was found to affect SMP production. On the other hand, a positive correlation was observed for SMP formation with both solids retention time and influent COD concentration, and a negative correlation with hydraulic retention time. Thus, operating or designing WWTPs with short solids retention and long hydraulic retention times could be considered as solutions for minimizing SMP production. PMID- 26580088 TI - Enhanced Reaction Kinetics and Structure Integrity of Ni/SnO2 Nanocluster toward High-Performance Lithium Storage. AB - SnO2 is regarded as one of the most promising anodes via conversion-alloying mechanism for advanced lithium ion batteries. However, the sluggish conversion reaction severely degrades the reversible capacity, Coulombic efficiency and rate capability. In this paper, through constructing porous Ni/SnO2 composite electrode composed of homogeneously distributed SnO2 and Ni nanoparticles, the reaction kinetics of SnO2 is greatly enhanced, leading to full conversion reaction, superior cycling stability and improved rate capability. The uniformly distributed Ni nanoparticles provide a fast charge transport pathway for electrochemical reactions, and restrict the direct contact and aggregation of SnO2 nanoparticles during cycling. In the meantime, the void space among the nanoclusters increases the contact area between the electrolyte and active materials, and accommodates the huge volume change during cycling as well. The Ni/SnO2 composite electrode possesses a high reversible capacity of 820.5 mAh g( 1) at 1 A g(-1) up to 100 cycles. More impressively, large capacity of 841.9, 806.6, and 770.7 mAh g(-1) can still be maintained at high current densities of 2, 5, and 10 A g(-1) respectively. The results demonstrate that Ni/SnO2 is a high performance anode for advanced lithium-ion batteries with high specific capacity, excellent rate capability, and cycling stability. PMID- 26580089 TI - Are "classical" tests of repeated-sprint ability in football externally valid? A new approach to determine in-game sprinting behaviour in elite football players. AB - The aim of this study was to investigate the occurrence of repeated sprinting bouts in elite football. Furthermore, the construct validity of current tests assessing repeated-sprint ability (RSA) was analysed using information of sprinting sequences as they actually occurred during match-play. Sprinting behaviour in official competition was analysed for 19 games of the German national team between August 2012 and June 2014. A sprinting threshold was individually calculated based on the peak velocity reached during in-game sprinting. Players performed 17.2 +/- 3.9 sprints per game and during the entire 19 games a total of 35 bouts of repeated sprinting (a minimum of three consecutive sprints with a recovery duration <30 s separating efforts). This averages one bout of repeated sprinting per player every 463 min. No general decrement in maximal sprinting speed was observed during bouts with up to five consecutive sprints. Results of the present study question the importance of RSA as it is classically defined. They indicate that shorter accelerations are more important in game-specific situations which do not reach speeds necessary to qualify them as sprints. The construct validity of classic tests of RSA in football is not supported by these observations. PMID- 26580090 TI - S100B serum protein cannot predict secondary intracranial haemorrhage after mild head injury in patients with low-dose acetylsalicylic acid prophylaxis. AB - INTRODUCTION: The goal of this study was to investigate if S100B serum protein could predict secondary intracranial haemorrhagic events (SIHEs) after mild head injury (mHI) in patients taking low-dose acetylsalicylic acid (LDA), making routinely repeated head computed tomography (RRHCT) scans unnecessary. METHODS: Three hundred and eight-two patients with mHI, older than 60 years and taking LDA prophylaxis were enrolled. Primary head CT and RRHCT scans within 3 and 48 hours to trauma were performed. Additionally, S100B serum protein levels were evaluated at admission and predictive power for SIHEs was analysed. RESULTS: Fifty-nine per cent were female and the mean age of all included patients was 81.8 +/- 8.9 years. In four patients SIHEs were diagnosed. Sensitivity and the negative predictive value of S100B serum protein (cut-off value 0.10 ug l(-1)) were 75.0% and 98.6%, respectively. Specificity was 19.0% and the positive predictive value 1.0% (306 false positive values). In patients without bleeding, the median S100B value was 0.18 (IQR = 0.12-0.34) and in the ones with SIHEs, the median was 0.11 (IQR = 0.10-1.16) (p > 0.05). The discriminatory power of S100B in the ROC analysis was 0.399 (95% CI = 0.079-0.720; p > 0.05). CONCLUSION: S100B cannot be considered as an effective diagnostic tool in the prediction or exclusion of SIHE in older patients with mHIs taking LDA prophylaxis. PMID- 26580091 TI - Systematic Study of the Glutathione (GSH) Reactivity of N-Arylacrylamides: 1. Effects of Aryl Substitution. AB - Success in the design of targeted covalent inhibitors depends in part on a knowledge of the factors influencing electrophile reactivity. In an effort to further develop an understanding of structure-reactivity relationships among N arylacrylamides, we determined glutathione (GSH) reaction rates for a family of N arylacrylamides independently substituted at ortho-, meta-, and para-positions with 11 different groups common to inhibitor design. We find that substituent effects on reaction rates show a linear Hammett correlation for ortho-, meta-, and para-substitution. In addition, we note a correlation between (1)H and (13)C NMR chemical shifts of the acrylamide with GSH reaction rates, suggesting that NMR chemical shifts may be a convenient surrogate measure of relative acrylamide reactivity. Density functional theory calculations reveal a correlation between computed activation parameters and experimentally determined reaction rates, validating the use of such methodology for the screening of synthetic candidates in a prospective fashion. PMID- 26580092 TI - Chemical Mass Production of Graphene Nanoplatelets in ~100% Yield. AB - Successful application of graphene is hampered by the lack of cost-effective methods for its production. Here, we demonstrate a method of mass production of graphene nanoplatelets (GNPs) by exfoliation of flake graphite in the tricomponent system made by a combination of ammonium persulfate ((NH4)2S2O8), concentrated sulfuric acid, and fuming sulfuric acid. The resulting GNPs are tens of microns in diameter and 10-35 nm in thickness. When in the liquid phase of the tricomponent media, graphite completely loses its interlayer registry. This provides a ~100% yield of GNPs from graphite in 3-4 h at room temperature or in 10 min at 120 degrees C. PMID- 26580094 TI - Low Seroprevalence of Leishmania infantum and Toxoplasma gondii in the Horse Population in Israel. AB - A cross-sectional investigation was done on the seroprevalence of Leishmania infantum and Toxoplasma gondii infection among apparently healthy horses in Israel. This survey included 383 horses distributed in 22 farms throughout Israel during the years 2011-2013. Serum samples were tested for the presence of immunoglobulin G (IgG) antibodies using the direct agglutination test (DAT) specific to Leishmania and by the modified agglutination test (MAT) for the presence of IgG antibodies to T. gondii. Low seroprevalences were detected for both L. infantum and T. gondii in the horse population in Israel; of the 338 horses tested, 6 (1.4%) were found to be seropositive for L. infantum and 11 (2.5%) for T. gondii, with no significant association between seroprevalence and demographic/environmental factors. An ongoing geographical expansion of L. infantum, previously reported in humans and dogs in Israel, was also supported by our results in horses. Here we present evidence of exposure of horses to L. infantum and T. gondii in Israel. Continuous seroprevalence surveillance in horses, such as the one performed in this study, might further elucidate the eco epidemiology of these two important zoonotic parasites in this country. PMID- 26580093 TI - Safety, immune lot-to-lot consistency and non-inferiority of a fully liquid pentavalent DTwp-HepB-Hib vaccine in healthy Indian toddlers and infants. AB - Pentavalent combination vaccines are important tools to strengthen the immunization programs in numerous countries throughout the world. A large number of countries have recognized the value of combination vaccines and have introduced whole cell pentavalent vaccines into their immunization programs. A phase III, multi-center, randomized, single blinded study of a fully liquid pentavalent DTwP-HepB-Hib investigational vaccine (Shan5TM) was conducted across India in 2 cohorts: 15 toddlers were evaluated for safety and immunogenicity following a single booster dose (Cohort 1) followed by 1085 infants (Cohort 2) evaluated for immunogenicity and safety following 3-dose primary immunization of the investigational vaccine or a locally licensed comparator vaccine (Pentavac SD). Immune consistency analysis among 3 lots of the investigational vaccine, and immune non-inferiority analysis of pooled (3 lots) data of investigational vaccine vs. comparator vaccine were carried out in cohort 2. The vaccines demonstrated comparable safety and immune responses in cohort 1. In cohort 2, equivalent immune consistency among 3 lots was observed for all antigens except whole cell pertussis antigens, where a marginal variation was observed which was linked to the low power of the test and concluded to not have any clinical significance. Immune non-inferiority against the comparator vaccine was demonstrated for all 5 antigens. Safety results were comparable between vaccine groups. This investigational, fully-liquid, whole-cell pertussis (wP) containing new pentavalent vaccine was found to be safe and immunologically non-inferior to the licensed comparator vaccine. PMID- 26580095 TI - Is Identification of Lupus Erythematosus Cells Still Useful? A Case Report. AB - A 13-year-old girl presented with significant weight loss, depression, anemia, and neutropenia. The preliminary diagnosis was anorexia nervosa combined with depression. Due to peripheral cytopenia, a bone marrow biopsy was performed to rule out leukemia. Lupus erythematosus (LE) cells were found in the bone marrow aspirate, which prompted autoantibody testing, although clinically it was not suspected the patient had systemic lupus erythematosus (SLE). Further testing demonstrated very high levels of antinuclear antibodies (ANA) (>12 U) and anti double strand DNA (dsNDA) (>1000 IU/mL), which confirmed the diagnosis of SLE. The patient was treated with steroids for SLE, and symptoms improved quickly. In conclusion, although the identification of LE cells as one of the diagnostic criteria for SLE has been obsolete, careful examination of bone marrow to identify LE cells is still very important in the diagnosis of unsuspected SLE. PMID- 26580096 TI - Defining Why Cancer Develops in Children. PMID- 26580097 TI - MicroRNA-192-5p Promote the Proliferation and Metastasis of Hepatocellular Carcinoma Cell by Targeting SEMA3A. AB - Side population (SP) cells are a small subset of cells isolated from a cultured cancer cell line with characteristics similar to those of cancer stem cells, such as high metastatic and tumorigenic potentials. However, the molecular mechanisms remain unclear for the malignant properties of SP cells. In this study, SP cells were isolated by staining cultured HCCLM3 cells with fluorescent DNA-binding dye Hoechst 33342 and sorted by flow cytometry. The proportion of SP cells was 2.79%+/-0.19% in the HCCLM3 cell line. Compared with non-SP cells, SP cells possessed stronger capability of sphere formation and tumorigenicity, and expressed higher levels of CD133 and CD90. Then, we found that SP cells possessed 25 upregulated and 34 downregulated microRNAs with differences of >3-fold. As one of the upregulated microRNAs, miR-192-5p was computationally predicted to target semaphorin 3A (SEMA3A), a potent suppressor of tumor angiogenesis in various cancer models. Luciferase reporter assay showed that SEMA3A was a direct target of miR-192-5p. Overexpression of miR-192-5p promoted cell proliferation and metastasis targeting SEMA3A in HCCLM3 cells. Immunohistochemical staining revealed that SEMA3A expression was significantly reverse associated with metastasis in hepatocellular carcinoma tissues. The results indicate that miR-192 5p contributes to targeting SEMA3A in HCCLM3 cells, and this may be used as a target in targeted therapy and a marker for cancer behavior and prognosis. PMID- 26580098 TI - Human Papillomavirus (HPV) Detection in Cytologic Specimens: Similarities and Differences of Available Methodology. AB - Accumulating evidence regarding the causative role of human papillomavirus (HPV) in a wide range of malignant and nonmalignant diseases highlights the importance of HPV testing. This study describes and discusses the efficacy and characteristics of 4 well-established and commercially available tests. Here, 181 cytologic specimens from cervical smears were analyzed using the HPV SIGN PQ (Diatech) and the Linear Array (Roche) method. Discrepant results were further studied with the Real Time High-Risk HPV (Abbott) method and the INNO-LiPA (Fujirebio) method. Of 181 cytologic specimens, 61 (34%) showed discrepant results. High-risk HPV was not detected in 9 cases by HPV SIGN PQ, in 16 cases by Linear Array, in 10 cases by Real Time High-Risk HPV, and in 6 cases by INNO LiPA, respectively. Lack of DNA detection or problems in interpreting the result were seen in 9 cases with HPV SIGN PQ, 8 cases with Linear Array, 3 cases with Real Time High-Risk HPV, and 3 cases with INNO-LiPA, respectively. This study indicates that the choice of HPV detection method has a substantial influence on the HPV risk classification of tested PAP smears and clinical follow-up decisions. PMID- 26580099 TI - Population Pharmacokinetics of High-Dose Oxazepam in Alcohol-Dependent Patients: Is There a Risk of Accumulation? AB - BACKGROUND: According to the guidelines, benzodiazepines with a short half-life are the reference medication to treat alcohol withdrawal syndrome. The doses of oxazepam used in this population may reach up to 300 mg per day, significantly higher than usual doses. Its use in these patients deserves further information to confirm that the half-life remains constant and that no accumulation appears. The objective of this study was to investigate the pharmacokinetics of high doses of oxazepam in alcohol-dependent patients treated for alcohol withdrawal syndrome. METHODS: Overall, 63 outpatients [weight, 71.1 kg (45.0-118.0); age, 47.6 years (31-67)] followed in the addictology unit, were studied. Total mean dose of 96.0 mg per day (range, 20-300 mg/d) was administered by oral route. Therapeutic drug monitoring allowed the measurement of 96 plasma concentrations. The following covariates were evaluated: demographic data (age, body weight, height, gender) and biological data (creatinine, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transferase). Pharmacokinetic analysis was performed using a nonlinear mixed-effect population model. RESULTS: Data were modeled with a 1-compartment pharmacokinetic model. The population typical mean 90% confidence interval values for clearance, apparent volume of distribution (V), and duration of absorption (D1) were 6.8 L/h (range, 3.9-8.0 L/h), 159 L (range, 98.0-282 L), and 2 hours (fixed), respectively. The interindividual variability of clearance and V, and residual variability (90% confidence interval) were 74% (44%-96%), 69% (40%-89%), and 32% (20%-41%), respectively. The elimination half-life was 16 hours (range, 3-42 hours). CONCLUSIONS: Oxazepam exhibited a linear pharmacokinetics with a proportional relationship from 20 to 300 mg per day, the dose range currently used in alcohol dependent patients treated for alcohol withdrawal syndrome. We did not find any evidence of drug accumulation with these doses. PMID- 26580100 TI - Vigabatrin versus carbamazepine monotherapy for epilepsy. AB - BACKGROUND: This is an update of a Cochrane review first published in 2012 (Cochrane Database of Systematic Reviews 2012, Issue 1).The efficacy and safety of vigabatrin (VGB) as an add-on therapy for refractory epilepsy have been well established. However, this information needs to be weighed against the risk of development of visual field defects. Whether VGB monotherapy is an effective and safe treatment compared with the standard antiepileptic drug carbamazepine (CBZ) as monotherapy for epilepsy has not been systematically reviewed. OBJECTIVES: To investigate the efficacy and safety of VGB versus CBZ monotherapy for epilepsy in children and adults. SEARCH METHODS: For the latest update, we searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 3 of 4), MEDLINE (1948 to July 2015), EMBASE (1974 to July 2015) and the Chinese Biomedical Database (CBM) (1979 to July 2015). We searched trial registers and contacted the manufacturer of VGB and authors of included studies for additional information. We applied no language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing VGB versus CBZ monotherapy for epilepsy. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. The primary outcome was time to treatment withdrawal. Secondary outcomes were time to achieve six-month and 12-month remission after randomisation, time to first seizure after randomisation and adverse events. We presented results as hazard ratios (HRs) with 95% confidence intervals (CIs) (time to event data) or as risk ratios (RRs) with 95% CIs (adverse events). MAIN RESULTS: Five studies involving a total of 734 participants were eligible for inclusion. We assessed only one study as good quality and the other four as poor quality. However, it was difficult to perform a meta-analysis by extracting aggregate data to synthesise the results as originally planned, mainly because not all studies reported the same outcomes as those chosen for this review. No significant differences favoured VGB or CBZ in terms of time to treatment withdrawal and time to achieve six-month remission after dose stabilisation from randomisation, but results did show a disadvantage for VGB on time to first seizure after randomisation. Compared with CBZ, VGB was associated with more occurrences of weight gain and fewer occurrences of skin rash and drowsiness. No differences in visual field defects and visual disturbances were noted. AUTHORS' CONCLUSIONS: Data are currently insufficient to address the risk-benefit balance of VGB versus CBZ monotherapy for epilepsy. Given the high prevalence of visual field defects reported in an existing systematic review of observational studies (Maguire 2010), VGB monotherapy should be prescribed with caution for epilepsy and should not be considered a first-line choice. If necessary, the visual field should be frequently assessed. Future research should focus on investigating the reasons for visual field defects and exploring potential prevention strategies. Moreover, future monotherapy studies of epilepsy should report results according to the recommendations of the International League Against Epilepsy (ILAE) Commission, and methodological quality should be improved. PMID- 26580101 TI - Nurse, interrupted. PMID- 26580104 TI - Recognizing reversible posterior leukoencephalopathy syndrome. PMID- 26580105 TI - Code Comfort: Prompt symptom relief in end-of-life care. PMID- 26580106 TI - Making an impact with service learning. PMID- 26580107 TI - How nurses can collaborate with EHR design. PMID- 26580111 TI - Silent Sam. PMID- 26580112 TI - Low back pain. PMID- 26580113 TI - The ethics of peer review: What to know before saying "yes". PMID- 26580114 TI - Head-to-toe: Organizing your baseline patient physical assessment. PMID- 26580115 TI - Cinema verite: Envisioning a nursing career. PMID- 26580116 TI - Finding the balance for a culture of safety. PMID- 26580117 TI - Understanding new cholesterol-lowering agents. PMID- 26580120 TI - Towards a symbiotic brain-computer interface: exploring the application-decoder interaction. AB - OBJECTIVE: State of the art brain-computer interface (BCI) research focuses on improving individual components such as the application or the decoder that converts the user's brain activity to control signals. In this study, we investigate the interaction between these components in the P300 speller, a BCI for communication. We introduce a synergistic approach in which the stimulus presentation sequence is modified to enhance the machine learning decoding. In this way we aim for an improved overall BCI performance. APPROACH: First, a new stimulus presentation paradigm is introduced which provides us flexibility in tuning the sequence of visual stimuli presented to the user. Next, an experimental setup in which this paradigm is compared to other paradigms uncovers the underlying mechanism of the interdependence between the application and the performance of the decoder. MAIN RESULTS: Extensive analysis of the experimental results reveals the changing requirements of the decoder concerning the data recorded during the spelling session. When few data is recorded, the balance in the number of target and non-target stimuli shown to the user is more important than the signal-to-noise rate (SNR) of the recorded response signals. Only when more data has been collected, the SNR becomes the dominant factor. SIGNIFICANCE: For BCIs in general, knowing the dominant factor that affects the decoder performance and being able to respond to it is of utmost importance to improve system performance. For the P300 speller, the proposed tunable paradigm offers the possibility to tune the application to the decoder's needs at any time and, as such, fully exploit this application-decoder interaction. PMID- 26580119 TI - Roles of p53 and ASF1A in the Reprogramming of Sheep Kidney Cells to Pluripotent Cells. AB - Since the first report of induced pluripotent stem cells (iPSCs) by Takahashi and Yamanaka, numerous attempts have been made to derive iPSCs from other species via the ectopic expression of defined factors. Sheep iPSCs (siPSCs) have significant potential for biotechnology and agriculture. Although several groups have described siPSCs, the reprogramming efficiency was extremely low. The exogenous transgenes could be not silenced in the iPSCs, which hampered their development and application. Here, we report that p53 knockdown and antisilencing function 1A (ASF1A) overexpression promoted iPSC generation from sheep kidney cells (SKCs). Compared with transduction with eight human defined transcription factors (Oct4, Sox2, Klf4, c-Myc, Nanog, Lin28, hTERT, and SV40LT), the additional introduction of p53 RNA interference (RNAi) and/or ASF1A in the presence of small-molecule compounds [vitamin C (Vc) and valproic acid (VPA)] greatly improved the efficiency of sheep iPSC generation. The siPSCs exhibited morphological features similar to mouse embryonic stem cells (ESCs) and were positive for alkaline phosphatase and, pluripotent marker genes (Oct4, Nanog, Sox2, Rex1, TRA-1-60, TRA 1-81, and E-cadherin). Furthermore, these cells exhibited a normal karyotype of 54 chromosomes and were able to differentiate into all three germ layers both in vitro and in vivo. Moreover, the exogenous genes were silenced in siPSCs when p53 small hairpin RNA (shRNA) and ASF1A were added. Our results may help to reveal the role of p53 and ASF1A in sheep somatic cell reprogramming and provide an efficient approach to reprogramming sheep somatic cells. PMID- 26580121 TI - Anharmonic Effects on Vibrational Spectra Intensities: Infrared, Raman, Vibrational Circular Dichroism, and Raman Optical Activity. AB - The aim of this paper is 2-fold. First, we want to report the extension of our virtual multifrequency spectrometer (VMS) to anharmonic intensities for Raman optical activity (ROA) with the full inclusion of first- and second-order resonances for both frequencies and intensities in the framework of the generalized second-order vibrational perturbation theory (GVPT2) for all kinds of vibrational spectroscopies. Then, from a more general point of view, we want to present and validate the performance of VMS for the parallel analysis of different vibrational spectra for medium-sized molecules (IR, Raman, VCD, ROA) including both mechanical and electric/magnetic anharmonicity. For the well-known methyloxirane benchmark, careful selection of density functional, basis set, and resonance thresholds permitted us to reach qualitative and quantitative agreement between experimental and computed band positions and shapes. Next, the whole series of halogenated azetidinones is analyzed, showing that it is now possible to interpret different spectra in terms of mass, electronegativity, polarizability, and hindrance variation between closely related substituents, chiral spectroscopies being particular effective in this connection. PMID- 26580122 TI - Exploration of gated ligand binding recognizes an allosteric site for blocking FABP4-protein interaction. AB - Fatty acid binding protein 4 (FABP4), reversibly binding to fatty acids and other lipids with high affinities, is a potential target for treatment of cancers. The binding site of FABP4 is buried in an interior cavity and thereby ligand binding/unbinding is coupled with opening/closing of FABP4. It is a difficult task both experimentally and computationally to illuminate the entry or exit pathway, especially with the conformational gating. In this report we combine extensive computer simulations, clustering analysis, and the Markov state model to investigate the binding mechanism of FABP4 and troglitazone. Our simulations capture spontaneous binding and unbinding events as well as the conformational transition of FABP4 between the open and closed states. An allosteric binding site on the protein surface is recognized for the development of novel FABP4 inhibitors. The binding affinity is calculated and compared with the experimental value. The kinetic analysis suggests that ligand residence on the protein surface may delay the binding process. Overall, our results provide a comprehensive picture of ligand diffusion on the protein surface, ligand migration into the buried cavity, and the conformational change of FABP4 at an atomic level. PMID- 26580123 TI - Equiosmolar Solutions of Hypertonic Saline and Mannitol Do Not Impair Blood Coagulation During Elective Intracranial Surgery. AB - BACKGROUND: The authors investigated the effect of equiosmolar, equivolemic solutions of 3% hypertonic saline (HS) and 20% mannitol on blood coagulation assessed by rotational thromboelastometry (ROTEM) and standard coagulation tests during elective craniotomy. METHODS: In a prospective, randomized, double-blind trial, 40 patients undergoing elective craniotomy were randomized to receive 5 mL/kg of either 20% mannitol or 3% HS for intraoperative brain relaxation. Fibrinogen, activated partial thromboplastin time, prothrombin time, hemoglobin, hematocrit, and platelet count were simultaneously measured intraoperatively with ROTEM for EXTEM, INTEM, and FIBTEM analysis. ROTEM parameters were: clotting time (CT), clot formation time (CFT), maximum clot firmness (MCF), and alpha-angle. RESULTS: No significant differences between groups were found in ROTEM variables CT, CFT, MCF, alpha-angle (EXTEM and INTEM), and MCF (FIBTEM) nor standard coagulation tests. ROTEM parameters did not show changes after administration of hyperosmolar solutions relating to basal values, except for an increase of CFT EXTEM (118+/-28 vs. 128+/-26 s) and decrease of CT INTEM (160+/-18 vs. 148+/-15 s) with values within normal range. Significant decreases from baseline levels were observed for hematocrit (-7%), platelet count (-10%), and fibrinogen (-13%) after HS infusion, and hematocrit (-9%), platelet count (-13%), and fibrinogen ( 9%) after mannitol infusion, but remaining normal. CONCLUSIONS: The use of 5 mL/kg of equiosmolar solutions of 3% HS and 20% mannitol applied to reach a brain relaxation during elective craniotomy does not induce coagulation impairment as evidenced by ROTEM and standard coagulation tests. PMID- 26580124 TI - Intraoperative Monitoring of Diaphragm Neural Pathways During Cervical Surgery by Electrical Stimulation and Recordings of Ventilator Waveforms: Physiological Bases and Pilot Study. AB - BACKGROUND: Surgery on the cervical spine entails the risk of damaging the neural structures responsible for diaphragmatic innervation, namely (C3)-C4-(C5) roots. In some "difficult" cases, anatomic identification of these structures may be hard to achieve. Therefore, monitoring of the diaphragm through the ventilation waveforms displayed on the anesthesia machine can be of practical help. According to literature review, very few publications have reported such monitoring. METHODS: The present work aimed at investigating the feasibility and reliability of identifying cervical root(s) responsible for diaphragmatic innervation, by observing the changes on the recorded waveforms, indicating diaphragmatic responses to direct radicular electrical stimulation. In this study, the events not only on the capnography curve but also on pressure-time and flow-time waveforms were analyzed. Eight patients undergoing cervical Microsurgical DREZotomy (MDT) were enrolled in the study, as this surgical modality allows easy access to the C4 root, known to be prominent in diaphragmatic innervation. The technique did not require any harmful additional maneuver to the current anesthesia and surgical protocols. RESULTS: Stimulation resulted in specific patterns of changes in the 3 waveforms in all 8 patients and proved "easy" to interpret, provided that close cooperation exists between the anesthesiologist and the surgeon. CONCLUSION: Intraoperative monitoring of the diaphragmatic responses to stimulation can be advocated in surgery at the cervical spine level, and also more widely in surgery in the supraclavicular region, when neural structures responsible for diaphragmatic function are at risk. PMID- 26580125 TI - Comparison of Intra-Abdominal Pressure Among 3 Prone Positional Apparatuses After Changing From the Supine to the Prone Position and Applying Positive End Expiratory Pressure in Healthy Euvolemic Patients: A Prospective Observational Study. AB - BACKGROUND: Positional apparatuses used for the prone position can affect intra abdominal pressure (IAP). In this study, we compared the IAP after changing to the prone position and applying various positive end-expiratory pressure (PEEP) levels among 3 prone positional apparatuses. METHODS: A total of 108 healthy euvolemic patients undergoing elective prone spinal surgery were divided into 3 groups based on the positional apparatus used: the Jackson spinal table was used in group J (n=36), the Wilson frame in group W (n=36), and chest rolls in group C (n=36). The IAP was measured 2 minutes after application of 0, 3, 6, and 9 cm H2O of PEEP. RESULTS: The IAP in the supine position was 6.4+/-3.0, 5.9+/-2.8, and 7.1+/-2.5 mm Hg in groups J, C, and W, respectively. After the supine-to-prone positional change, the IAP in the prone position was significantly lower in group J than in groups C and W (2.7+/-2.9 vs. 8.9+/-4.0 and 12.9+/-4.3 mm Hg, P<0.01). In the prone position, a PEEP of 9 cm H2O increased the IAP from baseline (zero PEEP) by 1.5+/-1.3, 1.6+/-1.3, and 1.7+/-1.0 mm Hg in groups J, C, and W, respectively. CONCLUSIONS: The IAP in the prone position was significantly lower using the Jackson table compared with the Wilson frame and chest rolls. A PEEP up to 9 cm H2O can be safely used in healthy euvolemic patients undergoing prone spinal surgery without a clinically significant increase in IAP, irrespective of the type of prone positional apparatus. PMID- 26580126 TI - Hyperventilation, Sympathetic and Metabolic Derangements After Endoscopic Third Ventriculostomy. PMID- 26580127 TI - Acute Subdural Hematoma Causing Neurogenic Pulmonary Edema Following Lumbar Spine Surgery. PMID- 26580128 TI - Red-green-blue laser emission from cascaded polymer membranes. AB - Red-green-blue polymer laser emission is achieved in a free-standing membrane device consisting of three distributed feedback cavities. The polymer membrane is fabricated via interference lithography and a simple lift-off process. Multilayer structures can be assembled by cascading several polymer membranes. Thus optically pumped, simultaneous, red-green-blue laser emission is obtained from a three-layer cascaded membrane structure. This simple and low-cost fabrication technique can be used for compact, integrated laser sources. PMID- 26580129 TI - Microwave-assisted FLP-catalyzed hydrogenations. AB - FLP-catalyzed hydrogenations of 15 substrates were compared using microwave irradiation and conventional heating. The direct comparison revealed that a rate acceleration of up to 2.5 was achieved in the presence of microwaves. This heating method is particularly promising for the hydrogenation of nitrogen containing heterocycles. Acridine, quinines and especially 1-methyl indole were reduced very efficiently under mild conditions and only 4 bar hydrogen pressure in high yields. PMID- 26580130 TI - The effects of PDE10 inhibition on attentional set-shifting do not depend on the activation of dopamine D1 receptors. AB - Inhibitors of phosphodiesterase 10A (PDE10A) represent a novel class of potential antipsychotic compounds. These principles increase the level of cAMP and cGMP in the medium spiny neurons of the striatum and resemble the neurochemical consequences of dopamine D2 receptor inhibition and dopamine D1 receptor stimulation. Cognitive dysfunctions, including an impaired ability to shift perceptual attentional set, are core features of schizophrenia. In the present study, we investigated the involvement of D1 receptors in the procognitive action of the PDE10A inhibitor using the attentional set-shifting task in rats. The performance of the rats in the extradimensional shift stage of the attentional set-shifting task was taken as an index of cognitive flexibility. We first assessed the effects of the D1 agonist in otherwise untreated animals and in animals pretreated with the D1 receptor antagonist. We then investigated the procognitive effects of the PDE10A inhibitor, MP-10, in otherwise untreated animals and in animals pretreated with the D1 receptor antagonist. The dopamine D1 receptor antagonist SCH-23390 produced cognitive impairment at the dose of 0.0125 mg/kg, but not at 0.0063 mg/kg. The D1 receptor agonist, SKF-81,297, produced a procognitive effect that was abolished by 0.0063 mg/kg of SCH-23390. The compound MP-10 produced a procognitive effect at the dose of 0.3 mg/kg, but not at 0.1 mg/kg. Rat pretreatment with 0.0063 mg/kg of SCH-23390 did not block the procognitive effect of 0.3 mg/kg of MP-10. The present study demonstrates that the blockade of dopamine D1 receptors is unlikely to affect the procognitive effects of PDE10A inhibition. PMID- 26580132 TI - From genetic studies to precision medicine in alcohol dependence. AB - Genetic factors contribute to more than 50% of the variation in the vulnerability to alcohol dependence (AD). Although significant advances have been made in medications for AD, these medications do not work for all people. Precise tailoring of medicinal strategies for individual alcoholic patients is needed to achieve optimal outcomes. This review updates the most promising information on genetic variants in AD, which may be useful for improving diagnostic, therapeutic, and monitoring strategies. We describe genetic candidates of various neurotransmitter and enzyme systems. In addition to biological and allelic associations with AD, genetic effects on AD-related phenotypes and treatment responses have also been described. Gene-gene and gene-environment interactions have been considered. Potential applications of genomewide and epigenetic approaches for identifying genetic biomarkers of AD have been discussed. Overall, the application of genetic findings in precision medicine for AD will likely involve an integrated approach that distinguishes effect sizes of specific genetic predictors with regard to sex, pharmacotherapy, ethnicity, and AD-related aspects and considers gene-gene and gene-environment interactions. Our work may pave the way toward more precise treatment for AD that could ultimately improve clinical management and interventions. PMID- 26580133 TI - A phase-field study of the scaling law in free-standing ferroelectric thin films. AB - The scaling law for ferroelectric stripe domains is investigated in free-standing BaTiO3 and PbTiO3 thin films via phase-field simulations. The results agree with the Kittel law, where the square of the domain width is found to be proportional to the thin film thickness. After being rescaled by the corresponding domain wall thickness, the generalized scaling law is also demonstrated, with the dimensionless scaling constant M estimated to be ~3.3 in two ferroelectric materials. Moreover, we predict the effect of the exchange constant which is incorporated in Ginzburg-Landau theory on the equilibrium domain width and the critical thickness of the ferroelectric thin films. PMID- 26580131 TI - Effects of sex and remifentanil dose on rats' acquisition of responding for a remifentanil-conditioned reinforcer. AB - Opioid-conditioned reinforcement is thought to exacerbate opioid abuse and dependence. Sex/gender can influence opioid abuse behaviors, but the effects of sex/gender on opioid-conditioned reinforcement, specifically, are unclear. In this study, we compared new-response acquisition with opioid-conditioned reinforcement in male and female rats. First, separate groups received response independent remifentanil injections (0.0-32.0 MUg/kg, intravenous) and presentations of a light-noise stimulus. In the experimental groups, injections and stimulus presentations always co-occurred [paired Pavlovian conditioning (PAV)]; in the control groups, the two occurred independently of each other (random PAV). Next, in the instrumental acquisition (ACQ) sessions, two novel nose-poke manipulanda were introduced. All animals (regardless of sex, dose, and PAV type) could respond in the active nose-poke, which produced the stimulus alone, or in the inactive nose-poke. Both males and females dose-dependently acquired nose-poke responding (active>inactive) after paired PAV, but not after random PAV. Therefore, the stimulus was a conditioned reinforcer. We identified three sex differences. First, only females acquired responding after paired PAV with 32.0 MUg/kg remifentanil. Second, using a progressive ratio schedule for ACQ, both sexes acquired responding, but females made significantly more active responses. Third, when a single session of PAV was conducted, only males acquired responding. Thus, rats' sex interacts with pharmacological and environmental factors to determine opioid-conditioned reinforcement. PMID- 26580134 TI - Autophagy: An Exposing Therapeutic Target in Atherosclerosis. AB - Autophagy is an evolutionarily conserved catabolic process whereby the cytoplasmic contents of a cell are sequestered within autophagosomes through a lysosome-dependent pathway. Increasing evidence shows that this process is of great importance in a wide range of diseases, including atherosclerosis (AS). Autophagy can be modulated in advanced AS plaques by cytokines, reactive lipids, lipopolysaccharides, advanced glycation end products, and microRNAs. Autophagy exerts both protective and detrimental functions in vascular disorders. However, despite an increasing interest in autophagy, it remains an underestimated and overlooked phenomenon in AS. Therefore, the precise role of autophagy and its relationship with apoptosis need to be described. This review highlights recent findings on the autophagy activities and signaling pathways in endothelial cells, macrophages, and smooth muscle cells that are accompanied by apoptosis in AS. We conclude with recent studies on autophagy modulation as a new therapeutic approach to treat AS. PMID- 26580135 TI - Comparison of African American Children's Performances on a Minimal Competence Core for Morphosyntax and the Index of Productive Syntax. AB - PURPOSE: This study is a response to the need for evidence-based measures of spontaneous oral language to assess African American children under the age of 4 years. We determined if pass/fail status on a minimal competence core for morphosyntax (MCC-MS) was more highly related to scores on the Index of Productive Syntax (IPSyn)-the measure of convergent criterion validity-than to scores on 3 measures of divergent validity: number of different words (Watkins, Kelly, Harbers, & Hollis, 1995), Percentage of Consonants Correct-Revised (Shriberg, Austin, Lewis, McSweeney, & Wilson, 1997), and the Leiter International Performance Scale-Revised (Roid & Miller, 1997). METHOD: Archival language samples for 68 African American 3-year-olds were analyzed to determine MCC-MS pass/fail status and the scores on measures of convergent and divergent validity. RESULTS: Higher IPSyn scores were observed for 60 children who passed the MCC-MS than for 8 children who did not. A significant positive correlation, rpb = .73, between MCC-MS pass/fail status and IPSyn scores was observed. This coefficient was higher than MCC-MS correlations with measures of divergent validity: rpb = .13 (Leiter International Performance Scale-Revised), rpb = .42 (number of different words in 100 utterances), and rpb = .46 (Percentage of Consonants Correct-Revised). CONCLUSION: The MCC-MS has convergent criterion validity with the IPSyn. Although more research is warranted, both measures can be potentially used in oral language assessments of African American 3-year-olds. PMID- 26580137 TI - Hg(2+) detection using a phosphorothioate RNA probe adsorbed on graphene oxide and a comparison with thymine-rich DNA. AB - Mercury is a highly toxic heavy metal and many DNA-based biosensors have been recently developed for Hg(2+) detection in water. Among them, thymine-rich DNA is the most commonly used for designing Hg(2+) sensors. However, the thymine-Hg(2+) interaction is strongly affected by the buffer conditions. We recently reported a molecular beacon containing phosphorothioate (PS)-modified RNA linkages that can be cleaved by Hg(2+). In this work, the fluorescence quenching and DNA adsorption properties of nano-sized graphene oxide (NGO) were used to develop a new sensor using the PS-RNA chemistry. Three DNA probes, containing one, three and five PS RNA linkages, respectively, were tested. Finally, a fluorophore-labeled poly-A DNA with five PS-RNA linkages was selected and adsorbed by NGO. In the presence of Hg(2+), the fluorophore was released from NGO due to the cleavage reaction, resulting in a fluorescence enhancement. This sensor is highly selective for Hg(2+) with a detection limit of 8.5 nM Hg(2+). For comparison, a fluorophore labeled poly-T DNA was also tested, which responded to Hg(2+) more slowly and was inhibited by high NaCl concentrations, while the PS-RNA probe was more tolerant to different buffer conditions. This work indicates a new method for interfacing DNA with NGO for Hg(2+) detection. PMID- 26580136 TI - Epidemiology of DSM-5 Drug Use Disorder: Results From the National Epidemiologic Survey on Alcohol and Related Conditions-III. AB - IMPORTANCE: Current information on the prevalence and sociodemographic and clinical profiles of individuals in the general population with DSM-5 drug use disorder (DUD) is limited. Given the present societal and economic context in the United States and the new diagnostic system, up-to-date national information is needed from a single uniform data source. OBJECTIVE: To present nationally representative findings on the prevalence, correlates, psychiatric comorbidity, disability, and treatment of DSM-5 DUD diagnoses overall and by severity level. DESIGN, SETTING, AND PARTICIPANTS: In-person interviews were conducted with 36,309 adults in the 2012-2013 National Epidemiologic Survey on Alcohol and Related Conditions-III, a cross-sectional representative survey of the United States. The household response rate was 72%; person-level response rate, 84%; and overall response rate, 60.1%. Data were collected April 2012 through June 2013 and analyzed from February through March 2015. MAIN OUTCOMES AND MEASURES: Twelve month and lifetime DUD, based on amphetamine, cannabis, club drug, cocaine, hallucinogen, heroin, nonheroin opioid, sedative/tranquilizer, and/or solvent/inhalant use disorders. RESULTS: Prevalences of 12-month and lifetime DUD were 3.9% and 9.9%, respectively. Drug use disorder was generally greater among men, white and Native American individuals, younger and previously or never married adults, those with lower education and income, and those residing in the West. Significant associations were found between 12-month and lifetime DUD and other substance use disorders. Significant associations were also found between any 12-month DUD and major depressive disorder (odds ratio [OR], 1.3; 95% CI, 1.09-1.64), dysthymia (OR, 1.5; 95% CI, 1.09-2.02), bipolar I (OR, 1.5; 95% CI, 1.06-2.05), posttraumatic stress disorder (OR, 1.6; 95% CI, 1.27-2.10), and antisocial (OR, 1.4; 95% CI, 1.11-1.75), borderline (OR, 1.8; 95% CI, 1.41-2.24), and schizotypal (OR, 1.5; 95% CI, 1.18-1.87) personality disorders. Similar associations were found for any lifetime DUD with the exception that lifetime DUD was also associated with generalized anxiety disorder (OR, 1.3; 95% CI, 1.06 1.49), panic disorder (OR, 1.3; 95% CI, 1.06-1.59), and social phobia (OR, 1.3; 95% CI, 1.09-1.64). Twelve-month DUD was associated with significant disability, increasing with DUD severity. Among respondents with 12-month and lifetime DUD, only 13.5% and 24.6% received treatment, respectively. CONCLUSIONS AND RELEVANCE: DSM-5 DUD is a common, highly comorbid, and disabling disorder that largely goes untreated in the United States. These findings indicate the need for additional studies to understand the broad relationships in more detail; estimate present day economic costs of DUDs; investigate hypotheses regarding etiology, chronicity, and treatment use; and provide information to policy makers about allocation of resources for service delivery and research. Findings also indicate an urgent need to destigmatize DUD and educate the public, clinicians, and policy makers about its treatment to encourage affected individuals to obtain help. PMID- 26580138 TI - Addition of Statins to Treatment With beta-Blockers to Improve Outcomes for Cardiac Surgery Patients: Beyond the Surgical Care Improvement Project. PMID- 26580139 TI - Effect of surgical delay on bacterial colonization in proximal humeral fractures. AB - Postoperative infection is a severe complication after proximal humeral fracture surgical treatment. The aim of this study was to determine if the surgical delay could modify the number and type of bacteria on the surgical site. A two stages study was set up. In the first stage the effect of delay was simulated in 20 patients affected by proximal humeral fracture treated conservatively. In a second stage, the effect of delay was measured in 20 patients that underwent surgery. In stage 1, three skin culture swabs were taken in correspondence of the deltopectoral approach, the day of the fracture (day 0), the day after (day 1), and five days after fracture (day 5). In stage 2, skin swab cultures were taken the day of trauma and immediately before surgery and cultured on various media suitable for aerobic and anaerobic bacteria. The number of bacteria increased over the course of the study, from day 0 to day 5, both considering the total number of colony-forming units and individual species of pathogen bacteria. The second stage of the study confirmed these data. An increasing number of bacteria was observed in patients that underwent surgery later than 2 days from trauma. The delay of surgery increased bacterial colonization of the skin in the deltopectoral approach area including common pathogenic bacteria such as Staphylococcus aureus, coagulase-negative staphylococci and Propionibacterium acnes. This might justify the correlation between delay to surgery and risk of infection. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:942-948, 2016. PMID- 26580140 TI - Freeze-Drying Above the Glass Transition Temperature in Amorphous Protein Formulations While Maintaining Product Quality and Improving Process Efficiency. AB - This study explored the ability to conduct primary drying during lyophilization at product temperatures above the glass transition temperature of the maximally freeze-concentrated solution (Tg') in amorphous formulations for four proteins from three different classes. Drying above Tg' resulted in significant reductions in lyophilization cycle time. At higher protein concentrations, formulations freeze dried above Tg' but below the collapse temperature yielded pharmaceutically acceptable cakes. However, using an immunoglobulin G type 4 monoclonal antibody as an example, we found that as protein concentration decreased, minor extents of collapse were observed in formulations dried at higher temperatures. No other impacts to product quality, physical stability, or chemical stability were observed in this study among the different drying conditions for the different proteins. Drying amorphous formulations above Tg', particularly high protein concentration formulations, is a viable means to achieve significant time and cost savings in freeze-drying processes. PMID- 26580141 TI - How the distinctive cultures of osteopathic and allopathic medical schools affect the careers, perceptions, and institutional efforts of their anatomy faculties: A qualitative case study of two schools. AB - Anatomy faculties are integral to basic science instruction in medical schools, particularly given the preponderance of anatomic instruction in the preclinical curriculum. Recent years have witnessed major curricular restructuring and other emerging national trends that pose significant challenges to anatomists. An examination of anatomy faculty perceptions at two philosophically distinct medical schools within this shifting climate provides an indicator of how different institutional characteristics may impact anatomy instruction and other faculty responsibilities. Semistructured interviews of anatomy faculty from a large, well-established allopathic medical school (Indiana University School of Medicine) and a small, new osteopathic medical school (Marian University College of Osteopathic Medicine) were explored using qualitative thematic analysis. Four overarching themes were identified: (1) Institutional philosophies, such as affiliation with osteopathic versus allopathic medicine, have minimal impact on how the anatomical sciences are taught. (2) Differences in anatomy faculty experiences at these two institutions are largely driven by the institution's size and history. There is a disparity between institutions in the relative importance of teaching and research, but an ability to do research is important for both faculties. (3) Anatomy instruction and research agendas are driven by personal philosophies and interests rather than institutional philosophy. (4) Autonomy is highly valued by anatomists at both institutions. All the participants share a devotion to educating future physicians. In fact, this study identified more similarities than differences in these two faculties. Finally, we argue that shared educational resources and research collaborations can improve anatomy education and faculty development at both institutions. Anat Sci Educ 9: 255-264. (c) 2015 American Association of Anatomists. PMID- 26580142 TI - Highly selective, sensitive and fluorescent sensing of dimeric G-quadruplexes by a dimeric berberine. AB - This paper describes the highly selective, sensitive and topology-specific fluorescent sensing of dimeric G-quadruplexes by a polyether-tethered dimeric berberine 1. Compound 1 displays high selectivity for dimeric G-quadruplexes over monomeric ones, and can be lit up by dimeric G-quadruplexes, in particular by the one linked with one TTA subunit. In addition, it shows no effect on the topology or thermal stability of the G-quadruplexes. PMID- 26580143 TI - Dissecting the proteome dynamics of the early heat stress response leading to plant survival or death in Arabidopsis. AB - In many plant species, an exposure to a sublethal temperature triggers an adaptative response called acclimation. This response involves an extensive molecular reprogramming that allows the plant to further survive to an otherwise lethal increase of temperature. A related response is also launched under an abrupt and lethal heat stress that, in this case, is unable to successfully promote thermotolerance and therefore ends up in plant death. Although these molecular programmes are expected to have common players, the overlapping degree and the specific regulators of each process are currently unknown. We have carried out a high-throughput comparative proteomics analysis during acclimation and during the early stages of the plant response to a severe heat stress that lead Arabidopsis seedlings either to survival or death. This analysis dissects these responses, unravels the common players and identifies the specific proteins associated with these different fates. Thermotolerance assays of mutants in genes with an uncharacterized role in heat stress demonstrate the relevance of this study to uncover both positive and negative heat regulators and pinpoint a pivotal role of JR1 and BAG6 in heat tolerance. PMID- 26580144 TI - Relationships Heal. PMID- 26580146 TI - The Stories Clinicians Tell: Achieving High Reliability and Improving Patient Safety. AB - The patient safety movement has been deeply affected by the stories patients have shared that have identified numerous opportunities for improvements in safety. These stories have identified system and/or human inefficiencies or dysfunctions, possibly even failures, often resulting in patient harm. Although patients' stories tell us much, less commonly heard are the stories of clinicians and how their personal observations regarding the environments they work in and the circumstances and pressures under which they work may degrade patient safety and lead to harm.If the health care industry is to function like a high-reliability industry, to improve its processes and achieve the outcomes that patients rightly deserve, then leaders and managers must seek and value input from those on the front lines-both clinicians and patients. Stories from clinicians provided in this article address themes that include incident identification, disclosure and transparency, just culture, the impact of clinical workload pressures, human factors liabilities, clinicians as secondary victims, the impact of disruptive and punitive behaviors, factors affecting professional morale, and personal failings. PMID- 26580145 TI - Association of Dental Care with Adherence to HEDIS Measures. AB - CONTEXT: The dental setting represents an unrealized opportunity to increase adherence to preventive services and improve health outcomes. OBJECTIVE: To compare adherence to a subset of Healthcare Effectiveness Data and Information Set (HEDIS) measures among a population that received dental care with a population that did not receive dental care. DESIGN: Using a retrospective cohort design, we identified 5216 adults who received regular dental care and 5216 persons who did not. The groups were matched on propensity scores, were followed for 3 years, and retained medical and dental benefits. Receipt of dental care was defined as 1 or more dental visits in each 12-month period. MAIN OUTCOME MEASURES: Outcome measures were assessed in a subpopulation that qualified for 1 of 5 HEDIS denominator groups (dental = 4184 patients; nondental = 3871 patients). They included 3 preventive measures (cervical, colorectal, and breast cancer screening), 4 chronic disease management services (hemoglobin A1c and low density lipoprotein cholesterol testing, and nephropathy and retinopathy screening among the diabetes mellitus [DM] population), and 4 health outcome measures (poor glycemic control, low-density lipoprotein cholesterol control, blood pressure control in the DM population, and blood pressure control in the hypertensive population). RESULTS: Dental care was associated with higher adherence to all three cancer screening measures, one of four disease management services (higher retinopathy screening), and three of four health outcomes (better glycemic control in the DM population and better blood pressure control in the DM and hypertensive populations). CONCLUSIONS: Dental care was associated with improved adherence to 7 of 11 HEDIS measures. PMID- 26580147 TI - Disseminated granuloma annulare responding to narrowband UVB phototherapy. PMID- 26580148 TI - Effects of SNF1 on Maltose Metabolism and Leavening Ability of Baker's Yeast in Lean Dough. AB - Maltose metabolism of baker's yeast (Saccharomyces cerevisiae) in lean dough is negatively influenced by glucose repression, thereby delaying the dough fermentation. To improve maltose metabolism and leavening ability, it is necessary to alleviate glucose repression. The Snf1 protein kinase is well known to be essential for the response to glucose repression and required for transcription of glucose-repressed genes including the maltose-utilization genes (MAL). In this study, the SNF1 overexpression and deletion industrial baker's yeast strains were constructed and characterized in terms of maltose utilization, growth and fermentation characteristics, mRNA levels of MAL genes (MAL62 encoding the maltase and MAL61 encoding the maltose permease) and maltase and maltose permease activities. Our results suggest that overexpression of SNF1 was effective to glucose derepression for enhancing MAL expression levels and enzymes (maltase and maltose permease) activities. These enhancements could result in an 18% increase in maltose metabolism of industrial baker's yeast in LSMLD medium (the low sugar model liquid dough fermentation medium) containing glucose and maltose and a 15% increase in leavening ability in lean dough. These findings provide a valuable insight of breeding industrial baker's yeast for rapid fermentation. PMID- 26580149 TI - Long-term safety and activity of cladribine in patients with extranodal B-cell marginal zone lymphoma of the mucosa-associated lymphoid tissue (MALT) lymphoma. AB - The purine analogue 2-chloro-deoxyadenosine (2-CDA, cladribine) +/- rituximab has been successfully tested in mucosa-associated lymphoid tissue lymphoma (MALT lymphoma) patients. However, studies using cladribine in other indications have reported the potential for prolonged hematological side effects and secondary hematologic and non-hematologic malignancies. To date, there have been no data on long-term effects of cladribine in MALT lymphoma patients. We have analyzed a large number of 49 patients treated with cladribine at our institution 1997-2011. All patients were treated within clinical trials and had undergone a standardized follow-up protocol minimizing a potential bias in the detection of late sequels and relapses. After a median follow-up time of 61 months (interquartile range: 43 72) for 49 analyzed patients, 35 (71%) are alive, while 14 (29%) have died. In the entire collective, three cases (6%) of prolonged pancytopenia including manifest myelodysplastic syndrome in one patient (2%), three cases (6%) of secondary lymphoid malignancies, and five cases (10%) of non-hematologic cancers were documented. In terms of outcome, 42/49 (86%) patients responded to cladribine-containing treatment, and only 10/42 (24%) responding patients needed further treatment after a median time to progression of 14 months (interquartile range, 8-34). Currently, 25/35 (71%) patients being alive are in ongoing complete remission and 2/35 (6%) in ongoing stable disease, respectively. Eight patients (23%) are free of lymphoma after second-line therapy, with the median overall survival not having been reached. Our data suggest that cladribine might be safely applied in patients with MALT lymphoma, also in terms of long-term toxicities. These data also confirm the potential of cladribine to induce durable remissions. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26580150 TI - A New Empirical Definition of Major Depressive Episode Recovery and Its Positive Impact on Future Course of Illness. AB - OBJECTIVE: To provide the first head-to-head test of the predictive validity of 2 resolution levels included in the current consensus definition of major depressive episode (MDE) recovery and provide an empirically based, clinically useful definition of the end of an MDE. METHOD: 322 participants entering the National Institute of Mental Health Collaborative Depression Study with MDE (diagnosed by Research Diagnostic Criteria) in 1978-1981, and followed thereafter for up to 31 years, were divided into those with 8 consecutive weeks of asymptomatic MDE recovery or residual subsyndromal depressive symptom (SSD) resolution of their index MDE. These 2 levels of recovery were defined based on weekly symptom status on all depressive conditions, assessed by Longitudinal Interval Follow-Up Evaluation (LIFE) interviews conducted every 6 months. Primary measures of validity of these 2 alternative definitions were first well interval duration and long-term depressive illness burden. Groups were also compared on clinical variables, antidepressant treatment, and psychosocial function. RESULTS: 61.2% of subjects recovered asymptomatically from their index MDE. By survival analysis, they remained free of a depressive episode relapse or recurrence 4.2 times longer than those with SSD resolution (median = 135 vs 32 weeks; chi2 = 70.65; P < .0001). This was not attributable to a difference in intensity of antidepressant medication. Compared to asymptomatic recovery, SSD resolution was associated with significantly longer and more severe index MDEs, with more miscellaneous psychopathology as well as increased long-term psychosocial dysfunction and a greater depressive illness burden during the ensuing 10 or 20 years. Asymptomatic MDE resolution was a stronger predictor of time well than any of 18 other predictors, singly or combined. Eight consecutive weeks of asymptomatic recovery had 93% overlap with a 4-week definition and conferred little benefit over 4 weeks. CONCLUSIONS: Four consecutive weeks of asymptomatic recovery defines the end of an MDE and the beginning of a stable well state with improved psychosocial function. Residual symptom resolution is a continuation of an active state of the episode, not the end of an MDE. PMID- 26580151 TI - Exploring omega-3 fatty acids, enzymes and biodiesel producing thraustochytrids from Australian and Indian marine biodiversity. AB - The marine environment harbours a vast diversity of microorganisms, many of which are unique, and have potential to produce commercially useful materials. Therefore, marine biodiversity from Australian and Indian habitat has been explored to produce novel bioactives, and enzymes. Among these, thraustochytrids collected from Indian habitats were shown to be rich in saturated fatty acids (SFAs) and monounsaturated fatty acids (MUFAs), together constituting 51-76% of total fatty acids (TFA). Indian and Australian thraustochytrids occupy separate positions in the dendrogram, showing significant differences exist in the fatty acid profiles in these two sets of thraustochytrid strains. In general, Australian strains had a higher docosahexaenoic acid (DHA) content than Indian strains with DHA at 17-31% of TFA. A range of enzyme activities were observed in the strains, with Australian strains showing overall higher levels of enzyme activity, with the exception of one Indian strain (DBTIOC-1). Comparative analysis of the fatty acid profile of 34 strains revealed that Indian thraustochytrids are more suitable for biodiesel production since these strains have higher fatty acids content for biodiesel (FAB, 76%) production than Australian thraustochytrids, while the Australian strains are more suitable for omega-3 (40%) production. PMID- 26580152 TI - Selective Silylative Reduction of Pyridines Leading to Structurally Diverse Azacyclic Compounds with the Formation of sp3 C-Si Bonds. AB - Tris(pentafluorophenyl)borane-catalyzed silylative reduction of pyridines has been developed giving rise to the formation of sp(3) C-Si bonds selectively beta to the nitrogen atom of azacyclic products. Depending on the position and nature of pyridine substituents, structurally diverse azacycles are obtained with high selectivity under the borane catalysis. Mechanistic studies elucidated the sequence of hydrosilylation in this multiple reduction cascade: 1,2- or 1,4 hydrosilylation as an initial step depending on the substituent position, followed by selective hydrosilylation of enamine double bonds eventually affording beta-silylated azacyclic compounds. PMID- 26580153 TI - Probing Redox Reactions at the Nanoscale with Electrochemical Tip-Enhanced Raman Spectroscopy. AB - A fundamental understanding of electrochemical processes at the nanoscale is crucial to solving problems in research areas as diverse as electrocatalysis, energy storage, biological electron transfer, and plasmon-driven chemistry. However, there is currently no technique capable of directly providing chemical information about molecules undergoing heterogeneous charge transfer at the nanoscale. Tip-enhanced Raman spectroscopy (TERS) uniquely offers subnanometer spatial resolution and single-molecule sensitivity, making it the ideal tool for studying nanoscale electrochemical processes with high chemical specificity. In this work, we demonstrate the first electrochemical TERS (EC-TERS) study of the nanoscale redox behavior of Nile Blue (NB), and compare these results with conventional cyclic voltammetry (CV). We successfully monitor the disappearance of the 591 cm(-1) band of NB upon reduction and its reversible reappearance upon oxidation during the CV. Interestingly, we observe a negative shift of more than 100 mV in the onset of the potential response of the TERS intensity of the 591 cm(-1) band, compared to the onset of faradaic current in the CV. We hypothesize that perturbation of the electrical double-layer by the TERS tip locally alters the effective potential experienced by NB molecules in the tip-sample junction. However, we demonstrate that the tip has no effect on the local charge transfer kinetics. Additionally, we observe step-like behavior in some TERS voltammograms corresponding to reduction and oxidation of single or few NB molecules. We also show that the coverage of NB is nonuniform across the ITO surface. We conclude with a discussion of methods to overcome the perturbation of the double-layer and general considerations for using TERS to study nanoscale electrochemical processes. PMID- 26580154 TI - Breast cancer. PMID- 26580155 TI - A tumour through time. PMID- 26580156 TI - Perspective: The risks of overdiagnosis. PMID- 26580157 TI - Immunology: Another shot at cancer. PMID- 26580158 TI - Genetics: Big hopes for big data. PMID- 26580159 TI - Medicine: Eyes on the target. PMID- 26580160 TI - Molecular biology: Marked progress. PMID- 26580161 TI - Genetics: Relative risk. PMID- 26580162 TI - Screening: Don't look now. PMID- 26580163 TI - Breast cancer: 4 big questions. PMID- 26580164 TI - Human Endogenous Retrovirus Expression in Primary Cutaneous T-Cell Lymphomas. AB - BACKGROUND: Mycosis fungoides (MF) and Sezary syndrome (SS) are the most frequent cutaneous T-cell lymphomas (CTCL). Human endogenous retroviruses (HERVs) were reverse transcribed and integrated into primate chromosomal DNA, becoming noninfectious, although various stimuli may reactivate them. HERV expression seems to be impaired in several human diseases but limited data regarding CTCL are available. OBJECTIVE: To evaluate the endogenous retroviral transcription profile in CTCL and their expression among disease clinical stages. METHODS: Peripheral blood mononuclear cells from 42 MF/SS patients were analyzed. Total RNA was extracted and amplified with reverse transcription polymerase chain reaction. Results were compared with those obtained in a cohort of 20 healthy donors. RESULTS: HERVs were significantly overexpressed in MF/SS patients compared with healthy donors. No differences were found between early and advanced CTCL stages. CONCLUSION: HERVs can act as promoters in MF/SS pathogenesis. It remains to link HERV hyperexpression to the outcome in CTCL patients. PMID- 26580165 TI - Beyond DP4: an Improved Probability for the Stereochemical Assignment of Isomeric Compounds using Quantum Chemical Calculations of NMR Shifts. AB - The DP4 probability is one of the most sophisticated and popular approaches for the stereochemical assignment of organic molecules using GIAO NMR chemical shift calculations when only one set of experimental data is available. In order to improve the performance of the method, we have developed a modified probability (DP4+), whose main differences from the original DP4 are the inclusion of unscaled data and the use of higher levels of theory for the NMR calculation procedure. With these modifications, a significant improvement in the overall performance was achieved, providing accurate and confident results in establishing the stereochemistry of 48 challenging isomeric compounds. PMID- 26580167 TI - Developments in Theoretical Chemistry. PMID- 26580166 TI - The membrane-associated MUC1 improves adhesion of salivary MUC5B on buccal cells. Application to development of an in vitro cellular model of oral epithelium. AB - OBJECTIVES: The mucosal pellicle is a thin layer of salivary proteins, mostly MUC5B mucins, anchored to epithelial oral cells. This pellicle is involved in protection of oral mucosae against abrasion, pathogenic microorganisms or chemical xenobiotics. The present study aimed at studying the involvement of MUC1 in mucosal pellicle formation and more specifically in salivary MUC5B binding using a cell-based model of oral epithelium. DESIGN: MUC1 mRNAs were not detected in TR146 cells, and therefore a stable cell line named TR146/MUC1 expressing this protein was developed by transfection. TR146 and TR146/MUC1 were incubated with human saliva in order to evaluate retention of MUC5B by epithelial cells. RESULTS: The cell surface of both TR146 and TR146/MUC1 was typical of a squamous non-keratinized epithelium, with the presence of numerous microplicae. After incubation for 2h with saliva diluted in culture medium (1:1) and two washes with PBS, saliva deposits on cells appeared as a loose filamentous thin network. MUC5B fluorescent immunostaining evidenced a heterogeneous lining of confluent cell cultures by this salivary mucin but with higher fluorescence on TR146/MUC1 cells. Semi-quantification of MUC5B bound to cells confirmed a better retention by TR146/MUC1, evaluated by Dot Blot (+34.1%, p<0.05) or by immunocytochemistry (+44%, p<0.001). CONCLUSION: The membrane-bound mucin MUC1 is a factor enhancing the formation of the mucosal pellicle by increasing the binding of salivary MUC5B to oral epithelial cells. An in vitro model suitable to study specifically the function and properties of the mucosal pellicle is proposed. PMID- 26580168 TI - Complex Chemical Reaction Networks from Heuristics-Aided Quantum Chemistry. AB - While structures and reactivities of many small molecules can be computed efficiently and accurately using quantum chemical methods, heuristic approaches remain essential for modeling complex structures and large-scale chemical systems. Here, we present a heuristics-aided quantum chemical methodology applicable to complex chemical reaction networks such as those arising in cell metabolism and prebiotic chemistry. Chemical heuristics offer an expedient way of traversing high-dimensional reactive potential energy surfaces and are combined here with quantum chemical structure optimizations, which yield the structures and energies of the reaction intermediates and products. Application of heuristics-aided quantum chemical methodology to the formose reaction reproduces the experimentally observed reaction products, major reaction pathways, and autocatalytic cycles. PMID- 26580169 TI - Quantum Chemical Calculations Using Accelerators: Migrating Matrix Operations to the NVIDIA Kepler GPU and the Intel Xeon Phi. AB - Increasingly, modern computer systems comprise a multicore general-purpose processor augmented with a number of special purpose devices or accelerators connected via an external interface such as a PCI bus. The NVIDIA Kepler Graphical Processing Unit (GPU) and the Intel Phi are two examples of such accelerators. Accelerators offer peak performances that can be well above those of the host processor. How to exploit this heterogeneous environment for legacy application codes is not, however, straightforward. This paper considers how matrix operations in typical quantum chemical calculations can be migrated to the GPU and Phi systems. Double precision general matrix multiply operations are endemic in electronic structure calculations, especially methods that include electron correlation, such as density functional theory, second order perturbation theory, and coupled cluster theory. The use of approaches that automatically determine whether to use the host or an accelerator, based on problem size, is explored, with computations that are occurring on the accelerator and/or the host. For data-transfers over PCI-e, the GPU provides the best overall performance for data sizes up to 4096 MB with consistent upload and download rates between 5-5.6 GB/s and 5.4-6.3 GB/s, respectively. The GPU outperforms the Phi for both square and nonsquare matrix multiplications. PMID- 26580170 TI - Fate of a Graphene Flake: A New Route toward Fullerenes Disclosed with Ab Initio Simulations. AB - The top-down formation of a fullerene from a graphene flake is investigated via extensive ab initio molecular dynamics simulations in the range 300-3000 K, accelerated by metadynamics. Topological (SPRINT) coordinates are used to ensure a prejudice-free exploration of the free-energy surface and path collective variables to provide reliable free-energy barriers. The low-barrier zipping of the 2D nanoflake into a 3D nanocone is revealed as the early key transformation, mediated by a four-membered ring. Multiple-step pathways lead it toward different but always fully tricoordinated 0D closed cages. This scenario comprises several key chemical reactions characteristic of carbon at the nanoscale, as known from diverse experiments. PMID- 26580171 TI - Accelerate Sampling in Atomistic Energy Landscapes Using Topology-Based Coarse Grained Models. AB - We describe a multiscale enhanced sampling (MSES) method where efficient topology based coarse-grained models are coupled with all-atom ones to enhance the sampling of atomistic protein energy landscape. The bias from the coupling is removed by Hamiltonian replica exchange, thus allowing one to benefit simultaneously from faster transitions of coarse-grained modeling and accuracy of atomistic force fields. The method is demonstrated by calculating the conformational equilibria of several small but nontrivial beta-hairpins with varied stabilities. PMID- 26580172 TI - Anchor Points Reactive Potential for Bond-Breaking Reactions. AB - We present a new method for fitting potential energy surfaces in molecular mechanics-like internal coordinates based on data from electronic structure calculations. The method should be applicable to chemical reactions involving either bond dissociation or isomerization and is illustrated here for bond dissociation, in particular the breaking of an O-H bond in methanol and the breaking of an N-H bond in dimethylamine. As compared to previously available systematic methods for fitting global potential energy surfaces, it extends the maximum size of the system than can be treated by at least an order of magnitude. PMID- 26580173 TI - A Comparison of Advanced Monte Carlo Methods for Open Systems: CFCMC vs CBMC. AB - Two state-of-the-art simulation methods for computing adsorption properties in porous materials like zeolites and metal-organic frameworks are compared: the configurational bias Monte Carlo (CBMC) method and the recently proposed continuous fractional component Monte Carlo (CFCMC) method. We show that CFCMC is a very significant improvement over CBMC, and we can recommend it as our preferred method of choice. It is faster, more reliable, and (in contrast to CBMC) provides insight on whether or not the results are properly equilibrated. We also show that it is possible to combine the methods in a new CB/CFCMC hybrid method and derive the acceptance rules. This method achieves even higher insertion acceptance ratios. PMID- 26580174 TI - Convective Replica-Exchange in Ergodic Regimes. AB - In a recent article (J. Comput. Chem. 2013, 34, 132-140), convective replica exchange (convective-RE) has been presented as an alternative to the standard even-odd transition scheme. Computations on systems of various complexity have shown that convective-RE may increase the number of replica round-trips in temperature space with respect to the standard exchange scheme, leading to a more effective sampling of energy basins. Moreover, it has been shown that the method may prevent the formation of bottlenecks in the diffusive walk of replicas through the space of temperature states. By using an ideal temperature-RE model and a classical harmonic-oscillator RE scheme, we study the performances of convective-RE when ergodicity is not broken and convergence of acceptance probabilities is attained. In this dynamic regime, the round-trip ratio between convective and standard-RE is at maximum ~ 1.5, a value much smaller than that observed in nonergodic simulations. For large acceptance probabilities, the standard-RE outperforms convective-RE. Our observations suggest that convective RE can safely be used in either ergodic or non-ergodic regimes; however, convective-RE is advantageous only when bottlenecks occur in the state-space diffusion of replicas, or when acceptance probabilities are globally low. We also show that decoupling of the state-space dynamics of the stick replica from the dynamics of the remaining replicas improves the efficiency of convective-RE at low acceptance probability regimes. PMID- 26580175 TI - GPU Accelerated Implementation of Density Functional Theory for Hybrid QM/MM Simulations. AB - The hybrid simulation tools (QM/MM) evolved into a fundamental methodology for studying chemical reactivity in complex environments. This paper presents an implementation of electronic structure calculations based on density functional theory. This development is optimized for performing hybrid molecular dynamics simulations by making use of graphic processors (GPU) for the most computationally demanding parts (exchange-correlation terms). The proposed implementation is able to take advantage of modern GPUs achieving acceleration in relevant portions between 20 to 30 times faster than the CPU version. The presented code was extensively tested, both in terms of numerical quality and performance over systems of different size and composition. PMID- 26580176 TI - How Do DFT-DCP, DFT-NL, and DFT-D3 Compare for the Description of London Dispersion Effects in Conformers and General Thermochemistry? AB - The dispersion-core-potential corrected B3LYP-DCP method (Torres and DiLabio J. Phys. Chem. Lett. 2012, 3, 1738) is for the first time thoroughly assessed and compared with the B3LYP-NL (Hujo and Grimme J. Chem. Theory Comput. 2011, 7, 3866) and B3LYP-D3 (Grimme et al. J. Comput. Chem. 2011, 32, 1456) methods for a broad range of chemical problems that particularly shed light on intramolecular London-dispersion effects in conformers and general thermochemistry. The analysis is based on a compilation of 473 reference cases, the majority of which are taken from the GMTKN30 database (Goerigk and Grimme J. Chem. Theory Comput. 2010, 6, 107; 2011, 7, 291). The results confirm previous findings that B3LYP-DCP indeed predicts very good binding energies for noncovalently bound complexes, particularly with small basis sets. However, problems are identified for the description of intramolecular effects in some conformers and chemical reactions, for which B3LYP-DCP sometimes gives results similar or worse than uncorrected B3LYP. Surprisingly large errors for total atomization energies reveal an unwanted influence of the DCPs on the short-range electronic structure of the investigated systems. However, a recently modified carbon potential for B3LYP-DCP (DiLabio et al. Theor. Chem. Acc. 2013, 132, 1389) was additionally tested that seems to solve most of those problems and provides improved results. An overall comparison between all tested methods shows that B3LYP-NL is the most robust and accurate approach, closely followed by B3LYP-D3. This is also true when small basis sets of double-zeta quality are applied for which those methods have not been parametrized. However, binding energies of noncovalently bound complexes can be more strongly influenced by basis-set superposition-error effects than for B3LYP-DCP. Finally, it is noted that the DFT-D3 and DFT-NL schemes are readily applicable to a large range of chemical elements and they are therefore particularly recommended for more general applications. PMID- 26580177 TI - Nuclear Magnetic Shielding Constants from Quantum Mechanical/Molecular Mechanical Calculations Using Polarizable Embedding: Role of the Embedding Potential. AB - We present NMR shielding constants obtained through quantum mechanical/molecular mechanical (QM/MM) embedding calculations. Contrary to previous reports, we show that a relatively small QM region is sufficient, provided that a high-quality embedding potential is used. The calculated averaged NMR shielding constants of both acrolein and acetone solvated in water are based on a number of snapshots extracted from classical molecular dynamics simulations. We focus on the carbonyl chromophore in both molecules, which shows large solvation effects, and we study the convergence of shielding constants with respect to total system size and size of the QM region. By using a high-quality embedding potential over standard point charge potentials, we show that the QM region can be made at least 2 A smaller without any loss of quality, which makes calculations on ensembles tractable by conventional density functional theory calculations. PMID- 26580178 TI - A Hybrid Density Functional Theory/Molecular Mechanics Approach for Linear Response Properties in Heterogeneous Environments. AB - We introduce a density functional theory/molecular mechanical approach for computation of linear response properties of molecules in heterogeneous environments, such as metal surfaces or nanoparticles embedded in solvents. The heterogeneous embedding environment, consisting from metallic and nonmetallic parts, is described by combined force fields, where conventional force fields are used for the nonmetallic part and capacitance-polarization-based force fields are used for the metallic part. The presented approach enables studies of properties and spectra of systems embedded in or placed at arbitrary shaped metallic surfaces, clusters, or nanoparticles. The capability and performance of the proposed approach is illustrated by sample calculations of optical absorption spectra of thymidine absorbed on gold surfaces in an aqueous environment, where we study how different organizations of the gold surface and how the combined, nonadditive effect of the two environments is reflected in the optical absorption spectrum. PMID- 26580179 TI - The Variationally Orbital-Adapted Configuration Interaction Singles (VOA-CIS) Approach to Electronically Excited States. AB - For chemically accurate excited state energies, one is forced to include electron electron correlation at a level of theory significantly higher than configuration interaction singles (CIS). Post-CIS corrections do exist, but most often, if they are computationally inexpensive, these methods rely on perturbation theory. At the same time, inexpensive variational post-CIS methods would be ideal since modeling electronic relaxation usually requires globally smooth potential energy surfaces (PESs) and there will inevitably be regions of near electronic degeneracy. With that goal in mind, we now present a new method entitled variationally orbital adapted CIS (VOA-CIS). On the one hand, we show that in the ground-state geometry, VOA-CIS performs comparably to CIS(D) at predicting relative excited state energies. On the other hand, far beyond CIS(D) or any other perturbative method, VOA-CIS correctly rebalances the energy of charge transfer (CT) states versus non-CT states, while simultaneously producing smooth PESs-including the important case of avoided crossings. In fact, through localized diabatization of VOA-CIS excited states, one can find a set of reasonable diabatic states modeling CT chemical dynamics. After significant benchmarking, we are now confident VOA-CIS and VOA-CIS-like methods should play a major role in future excited state calculations. PMID- 26580181 TI - Electronic Energy Gaps for pi-Conjugated Oligomers and Polymers Calculated with Density Functional Theory. AB - In varying contexts, the terms "energy gap" (energy difference) or "band gap" may refer to different experimentally observable quantities or to calculated values that may or may not represent observable quantities. This work discusses various issues related to calculations of electronic energy gaps for organic pi conjugated oligomers and linear polymers by density functional theory (DFT). Numerical examples are provided, juxtaposing systematic versus fortuitous agreement of orbital energy gaps with observable fundamental (ionization vs electron attachment) or optical (electronic excitation) energy gaps. Successful applications of DFT using nonempirically tuned hybrid density functionals with range-separated exchange (RSE) for calculations of optical gaps, fundamental gaps, and electron attachment/detachment energies are demonstrated. The extent of "charge-transfer like" character in the longest-wavelength singlet electronic excitations is investigated. PMID- 26580180 TI - An ab Initio Benchmark and DFT Validation Study on Gold(I)-Catalyzed Hydroamination of Alkynes. AB - High level ab initio calculations have been carried out on an archetypal gold(I) catalyzed reaction: hydroamination of ethyne. We studied up to 12 structures of possible gold(I)-coordinated species modeling different intermediates potentially present in a catalytic cycle for the addition of a protic nucleophile to an alkyne. The benchmark is used to evaluate the performances of some popular density functionals for describing geometries and relative energies of stationary points along the reaction profile. Most functionals (including hybrid or meta hybrid) give accurate structures but large nonsystematic errors (4-12 kcal/mol) along the reaction energy profile. The double hybrid functional B2PLYP outperforms all considered functionals and compares very nicely with our reference ab initio benchmark energies. Moreover, we present an assessment of the accuracy of commonly used approaches to include relativistic effects, such as relativistic effective potentials and a scalar ZORA Hamiltonian, by a comparison with the results obtained using a relativistic all-electron four-component Dirac Kohn-Sham method. The contribution of nonscalar relativistic effects in gold(I) catalyzed reactions, as we investigated here, is expected to be on the order of 1 kcal/mol. PMID- 26580182 TI - Static and Dynamical Correlation in Diradical Molecules by Quantum Monte Carlo Using the Jastrow Antisymmetrized Geminal Power Ansatz. AB - Diradical molecules are essential species involved in many organic and inorganic chemical reactions. The computational study of their electronic structure is often challenging, because a reliable description of the correlation, and in particular of the static one, requires multireference techniques. The Jastrow correlated antisymmetrized geminal power (JAGP) is a compact and efficient wave function ansatz, based on the valence-bond representation, which can be used within quantum Monte Carlo (QMC) approaches. The AGP part can be rewritten in terms of molecular orbitals, obtaining a multideterminant expansion with zero seniority number. In the present work we demonstrate the capability of the JAGP ansatz to correctly describe the electronic structure of two diradical prototypes: the orthogonally twisted ethylene, C2H4, and the methylene, CH2, representing respectively a homosymmetric and heterosymmetric system. In the orthogonally twisted ethylene, we find a degeneracy of pi and pi* molecular orbitals, as correctly predicted by multireference procedures, and our best estimates of the twisting barrier, using respectively the variational Monte Carlo (VMC) and the lattice regularized diffusion Monte Carlo (LRDMC) methods, are 71.9(1) and 70.2(2) kcal/mol, in very good agreement with the high-level MR CISD+Q value, 69.2 kcal/mol. In the methylene we estimate an adiabatic triplet singlet (X(3)B1-a(1)A1) energy gap of 8.32(7) and 8.64(6) kcal/mol, using respectively VMC and LRDMC, consistently with the experimental-derived finding for Te, 9.363 kcal/mol. On the other hand, we show that the simple ansatz of a Jastrow correlated single determinant (JSD) wave function is unable to provide an accurate description of the electronic structure in these diradical molecules, both at variational level (VMC torsional barrier of C2H4 of 99.3(2) kcal/mol, triplet-singlet energy gap of CH2 of 13.45(10) kcal/mol) and, more remarkably, in the fixed-nodes projection schemes (LRDMC torsional barrier of 97.5(2) kcal/mol, triplet-singlet energy gap of 13.36(8) kcal/mol) showing that a poor description of the static correlation yields an inaccurate nodal surface. The suitability of JAGP to correctly describe diradicals with a computational cost comparable with that of a JSD calculation, in combination with a favorable scalability of QMC algorithms with the system size, opens new perspectives in the ab initio study of large diradical systems, like the transition states in cycloaddition reactions and the thermal isomerization of biological chromophores. PMID- 26580184 TI - Unifying General and Segmented Contracted Basis Sets. Segmented Polarization Consistent Basis Sets. AB - We propose a method, denoted P-orthogonalization, for converting a general contracted basis set to a computationally more efficient segmented contracted basis set, while inheriting the full accuracy of the general contracted basis set. The procedure can be used for any general contracted basis set to remove the redundancies between general contracted functions in terms of primitive functions. The P-orthogonalization procedure is used to construct a segmented contracted version of the polarization consistent basis sets, which are optimized for density functional theory calculations. Benchmark calculations show that the new pcs-n basis sets provide uniform error control of the basis set incompleteness for molecular systems composed of atoms from the first three rows in the periodic table (H-Kr) and for different exchange-correlation functionals. The basis set errors at a given zeta quality level are lower than other existing basis sets, and the pcs-n basis sets are furthermore shown to be among the computationally most efficient. The pcs-n basis sets are available in qualities ranging from (unpolarized) double-zeta to pentuple zeta quality and should therefore be well suited for both routine and benchmark calculations using density functional theory methods in general. PMID- 26580183 TI - Theoretical Study of One-Electron Oxidized Mn(III)- and Ni(II)-Salen Complexes: Localized vs Delocalized Ground and Excited States in Solution. AB - One-electron oxidized Mn(III)- and Ni(II)-salen complexes exhibit unique mixed valence electronic structures and charge transfer (CT) absorption spectra. We theoretically investigated them to elucidate the reason why the Mn(III)-salen complex takes a localized electronic structure (class II mixed valence compound by Robin-Day classification) and the Ni(II)-analogue has a delocalized one (class III) in solution, where solvation effect was taken into consideration either by the three-dimensional reference interaction site model self-consistent field (3D RISM-SCF) method or by the mean-field (MF) QM/MM-MD simulation. The geometries of these complexes were optimized by the 3D-RISM-SCF-U-DFT/M06. The vertical excitation energy and the oscillator strength of the first excited state were evaluated by the general multiconfiguration reference quasi-degenerate perturbation theory (GMC-QDPT), including the solvation effect based on either 3D RISM-SCF- or MF-QM/MM-MD-optimized solvent distribution. The computational results well agree with the experimentally observed absorption spectra and the experimentally proposed electronic structures. The one-electron oxidized Mn(III) salen complex with a symmetrical salen ligand belongs to the class II, as experimentally reported, in which the excitation from the phenolate anion to the phenoxyl radical moiety occurs. In contrast, the one-electron oxidized Ni(II) salen complex belongs to the class III, in which the excitation occurs from the doubly occupied delocalized pi1 orbital of the salen radical to the singly occupied delocalized pi2 orbital; the pi1 is a bonding combination of the HOMOs of two phenolate moieties and the pi2 is an antibonding combination. Solvation effect is indispensable for correctly describing the mixed-valence character, the geometrical distortion, and the intervalence CT absorption spectra of these complexes. The number of d electrons and the d orbital energy level play crucial roles to provide the localization/delocalization character of these complexes. PMID- 26580185 TI - Mechanism of Olefin Asymmetric Hydrogenation Catalyzed by Iridium Phosphino Oxazoline: A Pair Natural Orbital Coupled Cluster Study. AB - Since the development of chiral phosphino-oxazoline iridium catalysts, which hydrogenate unfunctionalized alkenes enantioselectively, the asymmetric hydrogenation of prochiral olefins has become important in the production of chiral compounds. For the last 10 years, details of the mechanism, including formal oxidation state assignment of the metal center and the nature of intermediates and transition states have been debated. Various contributions have been given from a theoretical point of view, but due to the size of the structures, these have been forced to rely on density functional theory (DFT) methods. In our investigation of the catalytic cycle, we employ both DFT and a correlated ab initio method, namely, the newly implemented domain-based local pair natural orbital coupled-cluster theory with single and double excitations and the inclusion of perturbative triples correction (DLPNO-CCSD(T)). Our results show that the most likely active paths involve the formation of an intermediate Ir(V) species. Furthermore, we have been able to predict the absolute configuration of the major products, and where comparison to experiment is possible, the results of our calculations agree with the enantiomeric excess obtained from hydrogenating five prochiral substrates. This work also shows that it is now possible to study catalytic reactions with untruncated models (having up to 88 atoms) at the CCSD(T) level of theory. PMID- 26580186 TI - Concerted Cyclization of Lanosterol C-Ring and D-Ring Under Human Oxidosqualene Cyclase Catalysis: An ab Initio QM/MM MD Study. AB - Human oxidosqualene cyclase (OSC) is one key enzyme in the biosynthesis of cholesterol. It can catalyze the linear-chain 2,3-oxidosqualene to form lanosterol, the tetracyclic (6-6-6-5 members for A-B-C-D rings) cholesterol precursor. It also has been treated as a novel antihyperlipidemia target. In addition, the structural diversity of cyclic terpenes in plants originates from the cyclization of 2,3-oxidosqualene. The enzyme catalytic mechanism is considered to be one of the most complicated ones in nature, and there are a lot of controversies about the mechanism in the past half a century. Herein, state-of the-art ab initio QM/MM MD simulations are employed to investigate the detailed cyclization mechanism of C-ring and D-ring formation. Our study reveals that the C and D rings are formed near-synchronously from a stable "6-6-5" ring intermediate. Interestingly, the transition state of this concerted reaction presents a "6-6-6" structure motif, while this unstable "6-6-6" structure in our simulations is thought to be a stable intermediate state in most previous hypothetical mechanisms. Furthermore, as the tailed side chain of 2,3 oxidosqualene shows a beta conformation while it is alpha conformation in lanosterol, finally, it is observed that the rotatable "tail" chain prefers to transfer beta conformation to alpha conformation at the "6-6-5" intermediate state. PMID- 26580187 TI - Divided Saddle Theory: A New Idea for Rate Constant Calculation. AB - We present a theory of rare events and derive an algorithm to obtain rates from postprocessing the numerical data of a free energy calculation and the corresponding committor analysis. The formalism is based on the division of the saddle region of the free energy profile of the rare event into two adjacent segments called saddle domains. The method is built on sampling the dynamics within these regions: auxiliary rate constants are defined for the saddle domains and the absolute forward and backward rates are obtained by proper reweighting. We call our approach divided saddle theory (DST). An important advantage of our approach is that it requires only standard computational techniques which are available in most molecular dynamics codes. We demonstrate the potential of DST numerically on two examples: rearrangement of alanine-dipeptide (CH3CO-Ala-NHCH3) conformers and the intramolecular Cope reaction of the fluxional barbaralane molecule. PMID- 26580188 TI - Linear Basis Function Approach to Efficient Alchemical Free Energy Calculations. 1. Removal of Uncharged Atomic Sites. AB - We present a general approach to transform between molecular potential functions during free energy calculations using a variance minimized linear basis functional form. This approach splits the potential energy function into a sum of pairs of basis functions, which depend on coordinates, and 'alchemical' switches, which depend only on the coupling variable. The power of this approach is that, first, the calculation of the coupling parameter dependent terms is removed from inner loop force calculation routines, second, the flexibility in specifying basis functions and alchemical switches allows users to choose transformation pathways that maximize statistical efficiency, and third, it is possible to predict entirely in postprocessing, without any additional energy evaluations, the thermodynamic properties along any alchemical path with moderate overlap from an initial simulation that uses the same basis functions. This allows construction of optimized, minimum variance alchemical switches from a single simulation with fixed basis functions and trial alchemical switching functions. We describe how to construct these linear basis potentials for real molecular systems of different sizes and shapes, considering particularly the problems of eliminating singularities and minimizing variance of particle removal in dense fluids. The statistical error in free energy calculations using the optimized basis functions is lower than standard soft core models, and approach the minimum variance possible over all pair potentials. We recommend an optimized set of basis functions and alchemical switches for standard molecular free energy calculations. PMID- 26580190 TI - First Principle Calculations of the Potential Energy Curves for Electronic States of the Lithium Dimer. AB - A multireference coupled cluster (CC) approach formulated in the (2,0) sector of the Fock space (FS) is applied to study electronic states of the Li2 molecule. The CC model including single (S) and double (D) excitations from the reference configuration is considered. The FS-CCSD(2,0) method is applicable to the description of the double electron attached states, which implies that in the neutral molecule studies the doubly ionized reference should be adopted. The results of this study include potential energy curves (PECs) and selected spectroscopic constants for 34 electronic states correlating to five lowest dissociation limits of Li2. Both the PECs and the computed spectroscopic constants agree very well with the experimental data wherever the latter are available. This indicates that the rigorous ab initio method can be successfully applied to study the energetics and molecular properties of the alkali metal diatomics. PMID- 26580189 TI - Damped Response Theory in Combination with Polarizable Environments: The Polarizable Embedding Complex Polarization Propagator Method. AB - We present a combination of the polarizable embedding (PE) scheme with the complex polarization propagator (CPP) method with the aim of calculating response properties including relaxation for large and complex systems. This new approach, termed PE-CPP, will benefit from the highly advanced description of the environmental electrostatic potential and polarization in the PE method as well as the treatment of near-resonant effects in the CPP approach. The PE-CPP model has been implemented in a Kohn-Sham density functional theory approach, and we present pilot calculations exemplifying the implementation for the UV/vis and carbon K-edge X-ray absorption spectra of the protein plastocyanin. Furthermore, technical details associated with a PE-CPP calculation are discussed. PMID- 26580191 TI - Fast and Accurate Electronic Excitations in Cyanines with the Many-Body Bethe Salpeter Approach. AB - The accurate prediction of the optical signatures of cyanine derivatives remains an important challenge in theoretical chemistry. Indeed, up to now, only the most expensive quantum chemical methods (CAS-PT2, CC, DMC, etc.) yield consistent and accurate data, impeding the applications on real-life molecules. Here, we investigate the lowest lying singlet excitation energies of increasingly long cyanine dyes within the GW and Bethe-Salpeter Green's function many-body perturbation theory. Our results are in remarkable agreement with available coupled-cluster (exCC3) data, bringing these two single-reference perturbation techniques within a 0.05 eV maximum discrepancy. By comparison, available TD-DFT calculations with various semilocal, global, or range-separated hybrid functionals, overshoot the transition energies by a typical error of 0.3-0.6 eV. The obtained accuracy is achieved with a parameter-free formalism that offers similar accuracy for metallic or insulating, finite size or extended systems. PMID- 26580192 TI - Cooperative Contributions of the Intermolecular Charge Fluxes and Intramolecular Polarizations in the Far-Infrared Spectral Intensities of Liquid Water. AB - The main factors that determine the infrared and far-infrared (terahertz) spectral features of liquid water in the frequency region below 1000 cm(-1) are examined theoretically. By analyzing the modulations of electron populations induced by molecular translations in water clusters, it is shown that there is an approximate linear relation between the derivative of intermolecular electron population transfer (?rhoD<-A/?rO...H) and the hydrogen-bond length (rO...H). This relation is used to incorporate the effects of hydrogen-bond fluctuations and defects into the intensity generation mechanisms in the spectral simulations of liquid water based on classical molecular dynamics, showing that intermolecular charge fluxes and intramolecular polarizations contribute cooperatively to the intensity of the band at ~200 cm(-1) (6 THz). It is also shown that the intensity of the band at ~700 cm(-1) is reduced by the libration polarization cross term, in accord with the reduced magnitude of dynamical dipole. The dependence of the calculated spectral profiles on the temperature and potential model is also discussed. PMID- 26580193 TI - Singlet Exciton Diffusion in Organic Crystals Based on Marcus Transfer Rates. AB - Exciton diffusion is a critical step for energy conversion in optoelectronic devices. This spawns the desire for theoretical approaches that allow for fast but reliable determinations of the material-dependent exciton transport parameters. For this purpose, the Marcus theory, which is widely used in the context of charge transport, is adapted to exciton diffusion. In contrast to the common approach of calculating the exciton hopping rate via the coupling and the spectral overlap, this alternative approach is less costly, because, instead of the spectral overlap, only the reorganization energy is needed. To demonstrate the capability of the approach, the diffusion constants for naphthalene, anthracene, and diindenoperylene crystals are calculated and compared with both calculations conducted with the well-established exciton hopping rate, including coupling and spectral overlap, and with experimental data. These test calculations show that Marcus-based exciton diffusion properties tend to be too small but are qualitatively correct (i.e., they seem to be useful to predict trends). Nevertheless, for reliable results, high-level quantum chemical approaches are necessary for the computation of the reorganization energies. However, they have to be calculated only once. Coupling constants, which are needed for all pairs of monomers, have a considerably smaller influence, i.e., they can be computed by a lower level approach, which makes the method even less costly. PMID- 26580194 TI - Configurational Entropy in Ice Nanosystems: Tools for Structure Generation and Screening. AB - Recently, a number of experimental and theoretical studies of low-temperature ice and water in nanoscale systems have emerged. Any theoretical study trying to model such systems will encounter the proton-disorder problem, i.e., there exist many configurations differing by water-molecule rotations for a fixed oxygen atom structure. An extensive search within the allowed proton-disorder space should always be perfomed to ensure a reasonable low-energy isomer and to address the effect of proton-configurational entropy that may affect experimental observables. In the present work, an efficient general-purpose program for finite, semiperiodic, and periodic systems of hydrogen-bonded molecules is presented, which can be used in searching and enumerating the proton configurational ensemble. Benchmarking tests are performed for ice nanotubes and finite slabs. Finally, the program is applied to experimentally appropriate ice nanosystems. A boron nitride film supported ice nanodot is studied in detail. Using a systematic generation of its proton-configurational ensemble, we find an isomer that is ~1 eV lower in total energy than one previously studied. The present isomer features a considerable dipole moment and implies that ice nanodots are inherently ferroelectric parallel to the surface. We conclude by demonstrating how the so-called hydrogen-bond connectivity parameters can be used to screen low-energy isomers. PMID- 26580195 TI - Self-Modulated Band Structure Engineering in C4F Nanosheets: First-Principles Insights. AB - Density functional theory (DFT) computations with van der Waals (vdw) correction revealed the existence of considerable C(delta+)F(delta-)...C(delta+)F(delta-) dipole-dipole interactions between two experimentally realized C4F monolayers. The dipole-dipole interactions induce a subtle interlayer polarization, which results in a significantly reduced band gap for C4F bilayer as compared to the individual C4F monolayer. With increasing the number of stacked layers, the band gap of C4F nanosheets can be further reduced, leading to a semiconducting metallic transition. Moreover, the band gap of C4F nanosheets can be feasibly modulated by applying an external electric field. Our results provide new insights on taking advantage of nonbonding interactions to tune the electronic properties of graphene materials. PMID- 26580196 TI - Electronic Excited States in Amorphous MEH-PPV Polymers from Large-Scale First Principles Calculations. AB - The electronic excited states of amorphous polymeric semiconductor MEH-PPV are investigated by first principles quantum chemical calculations based on trajectories from classical molecular dynamics simulations. We inferred an average conjugation length of ~5-7 monomers for lowest vertical excitations of amorphous MEH-PPV at room temperature and verified that the normal definition of a chromophore in a polymer based on purely geometric "conjugation breaks" is not always valid in amorphous polymers and a rigorous definition can be only on the basis of the evaluation of the polymer excited state wave function. The charge transfer character is observed to be nearly invariant for all excited states in low energy window while the exciton delocalization extent is found to increase with energy. The interchain excitonic couplings for amorphous MEH-PPV are shown to be usually smaller than 10 meV suggesting that the transport mechanism across chain can be described by incoherent hopping. All these observations about the energetic and spatial distribution of the excitons in polymer as well as their couplings provide important qualitative insights and useful quantitative information for constructing a realistic model for exciton migration dynamics in amorphous polymer materials. PMID- 26580197 TI - Ion Binding to Quadruplex DNA Stems. Comparison of MM and QM Descriptions Reveals Sizable Polarization Effects Not Included in Contemporary Simulations. AB - Molecular mechanical (MM) force fields are commonly employed for biomolecular simulations. Despite their success, the nonpolarizable nature of contemporary additive force fields limits their performance, especially in long simulations and when strong polarization effects are present. Guanine quadruplex D(R)NA molecules have been successfully studied by MM simulations in the past. However, the G-stems are stabilized by a chain of monovalent cations that create sizable polarization effects. Indeed, simulation studies revealed several problems that have been tentatively attributed to the lack of polarization. Here, we provide a detailed comparison between quantum chemical (QM) DFT-D3 and MM potential energy surfaces of ion binding to G-stems and assess differences that may affect MM simulations. We suggest that MM describes binding of a single ion to the G-stem rather well. However, polarization effects become very significant when a second ion is present. We suggest that the MM approximation substantially limits accuracy of description of energy and dynamics of multiple ions inside the G stems and binding of ions at the stem-loop junctions. The difference between QM and MM descriptions is also explored using symmetry-adapted perturbation theory and quantum theory of atoms in molecules analyses, which reveal a delicate balance of electrostatic and induction effects. PMID- 26580198 TI - Nature Utilizes Unusual High London Dispersion Interactions for Compact Membranes Composed of Molecular Ladders. AB - London dispersion interactions play a key role in nature, in particular, in membranes that constitute natural barriers. Here we demonstrate that the spatial alignment of "molecular ladders" ([n]ladderanes), i.e., highly unusual and strained all-trans-fused cyclobutane moieties, leads to much larger attractive dispersion interactions as compared to alkyl chains of the same length. This provides a rationale for the occurrence of peculiar ladderane fatty acids in the dense cell walls of anammox bacteria. Despite the energetic penalty paid for the assembly of such strained polycycles, the advantage lies in significantly higher, dispersion-dominated interaction energies as compared to straight-chain hydrocarbon moieties commonly found in fatty acids. We discern the dispersion contributions to the total interaction energies using a variety of computational methods including modern dispersion-corrected density functional theory and high level ab initio approaches. Utilizing larger assemblies, we also show that the intermolecular interactions behave additively. PMID- 26580199 TI - Erratum to "S66: A Well-balanced Database of Benchmark Interaction Energies Relevant to Biomolecular Structures". PMID- 26580200 TI - Peptide signaling in pollen tube guidance. AB - Fertilization is an important life event for sexually reproductive plants. Part of this process involves precise regulation of a series of complicated cell-cell communications between male and female tissues. Through genetic and omics approaches, many genes and proteins involved in this process have been identified. Here we review our current understanding of signaling components during fertilization. We will especially focus on LURE peptides and related signaling events that are required for micropylar pollen tube guidance. We will also summarize signaling events required for termination of micropylar pollen tube guidance after fertilization. PMID- 26580201 TI - The Distribution of Substance P and Kisspeptin in the Mediobasal Hypothalamus of the Male Rhesus Monkey and a Comparison of Intravenous Administration of These Peptides to Release GnRH as Reflected by LH Secretion. AB - Substance P (SP) was recently reported to be expressed in human kisspeptin/neurokinin B/dynorphin (KNDy) neurons and to enhance KNDy neuron excitability in the mouse hypothalamus. We therefore examined (1) interactions of SP and kisspeptin in the mediobasal hypothalamus of adult male rhesus monkeys using immunofluorescence, and (2) the ability of SP to induce LH release in GnRH primed, agonadal juvenile male monkeys. SP cell bodies were observed only occasionally in the arcuate nucleus (Arc), but more frequently dorsal to the Arc in the region of the premammillary nucleus. Castration resulted in an increase in the number of SP cell bodies in the Arc but not in the other regions. SP fibers innervated the Arc, where they were found in close apposition with kisspeptin perikarya in the periphery of this nucleus. Beaded SP axons projected to the median eminence, where they terminated in the external layer and intermingled with beaded kisspeptin axons. Colocalization of the two peptides, however, was not observed. Although close apposition between SP fibers and kisspeptin neurons suggest a role for SP in modulating GnRH pulse generator activity, i.v. injections of SP failed to elicit release of GnRH (as reflected by LH) in the juvenile monkey. Although the finding of structural interactions between SP and kisspeptin neurons is consistent with the notion that this tachykinin may be involved in regulating pulsatile GnRH release, the apparent absence of expression of SP in KNDy neurons suggests that this peptide is unlikely to be a fundamental component of the primate GnRH pulse generator. PMID- 26580202 TI - New Archaeological Evidence for an Early Human Presence at Monte Verde, Chile. AB - Questions surrounding the chronology, place, and character of the initial human colonization of the Americas are a long-standing focus of debate. Interdisciplinary debate continues over the timing of entry, the rapidity and direction of dispersion, the variety of human responses to diverse habitats, the criteria for evaluating the validity of early sites, and the differences and similarities between colonization in North and South America. Despite recent advances in our understanding of these issues, archaeology still faces challenges in defining interdisciplinary research problems, assessing the reliability of the data, and applying new interpretative models. As the debates and challenges continue, new studies take place and previous research reexamined. Here we discuss recent exploratory excavation at and interdisciplinary data from the Monte Verde area in Chile to further our understanding of the first peopling of the Americas. New evidence of stone artifacts, faunal remains, and burned areas suggests discrete horizons of ephemeral human activity in a sandur plain setting radiocarbon and luminescence dated between at least ~18,500 and 14,500 cal BP. Based on multiple lines of evidence, including sedimentary proxies and artifact analysis, we present the probable anthropogenic origins and wider implications of this evidence. In a non-glacial cold climate environment of the south-central Andes, which is challenging for human occupation and for the preservation of hunter-gatherer sites, these horizons provide insight into an earlier context of late Pleistocene human behavior in northern Patagonia. PMID- 26580203 TI - PKD2 and RSK1 Regulate Integrin beta4 Phosphorylation at Threonine 1736. AB - The integrin alpha6beta4, a major component of hemidesmosomes (HDs), stabilizes keratinocyte cell adhesion to the epidermal basement membrane through binding to the cytoskeletal linker protein plectin and association with keratin filaments. Disruption of the alpha6beta4-plectin interaction through phosphorylation of the beta4 subunit results in a reduction in adhesive strength of keratinocytes to laminin-332 and the dissolution of HDs. Previously, we have demonstrated that phosphorylation of T1736 in the C-terminal end of the beta4 cytoplasmic domain disrupts the interaction of beta4 with the plakin domain of plectin. Furthermore, we showed that beta4-T1736 can be phosphorylated by PKD1 in vitro, and although both PMA and EGF induced T1736 phosphorylation, only PMA was able to activate PKD1. Here, we show that depletion of [Ca2+]i augments PMA- and EGF-induced phosphorylation of beta4-T1736 and that this is caused by inhibition of the calcium-sensitive protein phosphatase calcineurin and augmentation of ERK1/2 activation. We also show that in keratinocytes the PMA-stimulated phosphorylation of beta4-T1736 primarily is mediated by PKD2 activation downstream of PKCdelta. On the other hand, both the EGF-stimulated phosphorylation of T1736 and the EGF induced dissolution of HDs are dependent on a functional MAPK signaling pathway, and treatment with the RSK inhibitor BI-D1870 prevented EGF-stimulated phosphorylation of beta4-T1736. Moreover, phosphorylation of beta4-T1736 is enhanced by overexpression of wild-type RSK1, while it is reduced by the expression of kinase-inactive RSK1 or by siRNA-mediated depletion of RSK1. In summary, our data indicate that different stimuli can lead to the phosphorylation of beta4-T1736 by either PKD2 or RSK1. PMID- 26580205 TI - Correction: Attitudes in China about Crops and Foods Developed by Biotechnology. PMID- 26580204 TI - Comparison of Equivalence between Two Commercially Available S499-Phosphorylated FMRP Antibodies in Mice. AB - Fragile X syndrome (FXS) develops from excessive trinucleotide CGG repeats in the 5'-untranslated region at Xq27.3 of the Fmr-1 gene, which functionally silences its expression and prevents transcription of its protein. This disorder is the most prominent form of heritable intellectual deficiency, affecting roughly 1 in 5,000 males and 1 in 10,000 females globally. Antibody specificity and selectivity are essential for investigating changes in intracellular protein signaling and phosphorylation status of the Fragile X Mental Retardation Protein (FMRP). Currently, both PhosphoSolutions(r) and abcam(r) produce commercially available S499-phosphorylated FMRP specific antibodies. The antibody from PhosphoSolutions(r) has been validated in previous studies; however, the antibody from abcam(r) antibody has yet to receive similar validation. This study aims to determine whether these two antibodies are true equivalents through western blot analysis of both NS-Pten knockout (KO) and Fmr-1 KO mice strains. We prepared hippocampal synaptosomal preparations and probed the samples using total FMRP, abcam(r) phosphorylated FMRP, and PhosphoSolutions(r) phosphorylated FMRP antibodies. We found that there was a significant increase in phosphorylated FMRP levels using the abcam(r) and PhosphoSolutions(r) antibodies in the NS-Pten KO mice compared to wildtype mice. However, there was much more variability using the abcam(r) antibody. Furthermore, there was a band present in the Fmr-1 KO for the phosphorylated FMRP site using the abcam(r) antibody for western blotting but not for the PhosphoSolutions(r) antibody. Our findings strongly suggest that the antibody from abcam(r) is neither specific nor selective for its advertised targeted substrate, S499-phosphorylated FMRP. PMID- 26580206 TI - Seed-Specific Expression of the Arabidopsis AtMAP18 Gene Increases both Lysine and Total Protein Content in Maize. AB - Lysine is the most limiting essential amino acid for animal nutrition in maize grains. Expression of naturally lysine-rich protein genes can increase the lysine and protein contents in maize seeds. AtMAP18 from Arabidopsis thaliana encoding a microtubule-associated protein with high-lysine content was introduced into the maize genome with the seed-specific promoter F128. The protein and lysine contents of different transgenic offspring were increased prominently in the six continuous generations investigated. Expression of AtMAP18 increased both zein and non-zein protein in the transgenic endosperm. Compared with the wild type, more protein bodies were observed in the endosperm of transgenic maize. These results implied that, as a cytoskeleton binding protein, AtMAP18 facilitated the formation of protein bodies, which led to accumulation of both zein and non-zein proteins in the transgenic maize grains. Furthermore, F1 hybrid lines with high lysine, high protein and excellent agronomic traits were obtained by hybridizing T6 transgenic offspring with other wild type inbred lines. This article provides evidence supporting the use of cytoskeleton-associated proteins to improve the nutritional value of maize. PMID- 26580207 TI - Thrombotic Role of Blood and Endothelial Cells in Uremia through Phosphatidylserine Exposure and Microparticle Release. AB - The mechanisms contributing to an increased risk of thrombosis in uremia are complex and require clarification. There is scant morphological evidence of membrane-dependent binding of factor Xa (FXa) and factor Va (FVa) on endothelial cells (EC) in vitro. Our objectives were to confirm that exposed phosphatidylserine (PS) on microparticle (MP), EC, and peripheral blood cell (PBC) has a prothrombotic role in uremic patients and to provide visible and morphological evidence of PS-dependent prothrombinase assembly in vitro. We found that uremic patients had more circulating MP (derived from PBC and EC) than controls. Additionally, patients had more exposed PS on their MPs and PBCs, especially in the hemodialysis group. In vitro, EC exposed more PS in uremic toxins or serum. Moreover, reconstitution experiments showed that at the early stages, PS exposure was partially reversible. Using confocal microscopy, we observed that PS-rich membranes of EC and MP provided binding sites for FVa and FXa. Further, exposure of PS in uremia resulted in increased generation of FXa, thrombin, and fibrin and significantly shortened coagulation time. Lactadherin, a protein that blocks PS, reduced 80% of procoagulant activity on PBC, EC, and MP. Our results suggest that PBC and EC in uremic milieu are easily injured or activated, which exposes PS and causes a release of MP, providing abundant procoagulant membrane surfaces and thus facilitating thrombus formation. Blocking PS binding sites could become a new therapeutic target for preventing thrombosis. PMID- 26580208 TI - Automatic Counting of Microglial Cells in Healthy and Glaucomatous Mouse Retinas. AB - Proliferation of microglial cells has been considered a sign of glial activation and a hallmark of ongoing neurodegenerative diseases. Microglia activation is analyzed in animal models of different eye diseases. Numerous retinal samples are required for each of these studies to obtain relevant data of statistical significance. Because manual quantification of microglial cells is time consuming, the aim of this study was develop an algorithm for automatic identification of retinal microglia. Two groups of adult male Swiss mice were used: age-matched controls (naive, n = 6) and mice subjected to unilateral laser induced ocular hypertension (lasered; n = 9). In the latter group, both hypertensive eyes and contralateral untreated retinas were analyzed. Retinal whole mounts were immunostained with anti Iba-1 for detecting microglial cell populations. A new algorithm was developed in MATLAB for microglial quantification; it enabled the quantification of microglial cells in the inner and outer plexiform layers and evaluates the area of the retina occupied by Iba 1+ microglia in the nerve fiber-ganglion cell layer. The automatic method was applied to a set of 6,000 images. To validate the algorithm, mouse retinas were evaluated both manually and computationally; the program correctly assessed the number of cells (Pearson correlation R = 0.94 and R = 0.98 for the inner and outer plexiform layers respectively). Statistically significant differences in glial cell number were found between naive, lasered eyes and contralateral eyes (P<0.05, naive versus contralateral eyes; P<0.001, naive versus lasered eyes and contralateral versus lasered eyes). The algorithm developed is a reliable and fast tool that can evaluate the number of microglial cells in naive mouse retinas and in retinas exhibiting proliferation. The implementation of this new automatic method can enable faster quantification of microglial cells in retinal pathologies. PMID- 26580210 TI - Distribution and Potential Indicators of Hospitalized Cases of Neurocysticercosis and Epilepsy in Ecuador from 1996 to 2008. AB - BACKGROUND: Epilepsy is one of the most common signs of Neurocysticercosis (NCC). In this study, spatial and temporal variations in the incidence of hospitalized cases (IHC) of epilepsy and NCC in Ecuadorian municipalities were analyzed. Additionally, potential socio-economic and landscape indicators were evaluated in order to understand in part the macro-epidemiology of the Taenia solium taeniasis/cysticercosis complex. METHODOLOGY: Data on the number of hospitalized epilepsy and NCC cases by municipality of residence were obtained from morbidity hospital systems in Ecuador. SatScan software was used to determine whether variations in the IHC of epilepsy and NCC in space and time. In addition, several socio-economic and landscape variables at municipality level were used to study factors intervening in the macro-epidemiology of these diseases. Negative Binomial regression models through stepwise selection and Bayesian Model Averaging (BMA) were used to explain the variations in the IHC of epilepsy and NCC. PRINCIPAL FINDINGS: Different clusters were identified through space and time. Traditional endemic zones for NCC and epilepsy, recognized in other studies were confirmed in our study. However, for both disorders more recent clusters were identified. Among municipalities, an increasing tendency for IHC of epilepsy, and a decreasing tendency for the IHC of NCC were observed over time. In contrast, within municipalities a positive linear relationship between both disorders was found. An increase in the implementation of systems for eliminating excrements would help to reduce the IHC of epilepsy by 1.00% (IC95%; 0.2%-1.8%) and by 5.12% (IC95%; 3.63%-6.59%) for the IHC of NCC. The presence of pig production was related to IHC of NCC. CONCLUSION/SIGNIFICANCE: Both disorders were related to the lack of an efficient system for eliminating excrements. Given the appearance of recent epilepsy clusters, these locations should be studied in depth to discriminate epilepsies due to NCC from epilepsies due to other causes. Field studies are needed to evaluate the true prevalence of cysticercosis in humans and pigs in different zones of the country in order to better implement and manage prevention and/or control campaigns. PMID- 26580211 TI - Ictal epileptic headache in adult life: Electroclinical patterns and spectrum of related syndromes. AB - OBJECTIVES: Both headache and epilepsy are frequent paroxysmal disorders that often co-occur or are related in numerous ways. Although ictal epileptic headache has become the focus of several studies, this remains a very rare and not well known phenomenon. Electroclinical features, pathophysiology, and syndromic context are heterogeneous. We investigated the electroclinical and neuroimaging findings in a population of adult patients with ictal epileptic headache. METHODS: We retrospectively examined 8800 EEG recordings of almost 4800 patients admitted to our video-EEG laboratory from 2010 to 2013 with a history of well documented epilepsy. We selected patients who reported headache closely related to a seizure documented by video-EEG or 24-hour ambulatory EEG. We analyzed ictal electroclinical features of headache, and we defined the related epileptic syndromes. RESULTS: We identified five patients with ictal epileptic headache. Two patients described tension headache during an epileptic seizure. In three patients, the headache was accompanied by other "minor" neurological symptoms mimicking a migrainous aura. In all cases, the headache stopped with the end of the epileptic activity. Three patients had a history of partial symptomatic epilepsy with cerebral lesions (low grade glioma, astrocytoma, porencephalic cyst) in the left posterior regions, whereas two patients were affected by idiopathic generalized epilepsy. CONCLUSION: This study confirms the rarity of ictal epileptic headache. To date, well-documented video-EEG cases remain as exceptional reports, especially in cases of idiopathic generalized epilepsies. Moreover, we confirm the main involvement of posterior regions in patients with ictal epileptic headache affected by partial symptomatic epilepsies. PMID- 26580212 TI - Transcutaneous vagus nerve stimulation (tVNS) protocol for the treatment of major depressive disorder: A case study assessing the auricular branch of the vagus nerve. PMID- 26580213 TI - Outcome of psychogenic nonepileptic seizures (PNES) in children: A 2-year follow up study. AB - OBJECTIVE: The objective of this study was to determine the outcome of psychogenic nonepileptic seizures (PNES) in children seen at a level 4 epilepsy center. METHODS: We retrospectively analyzed patients under the age of 18 years who were diagnosed with PNES based on evaluation in the epilepsy monitoring unit and had a follow-up of at least 2 years postdiagnosis. Remission of events was noted at 6 months, 12 months, and 24 months of follow-up, and patient and disease variables affecting outcome were studied. RESULTS: Ninety patients met inclusion criteria (58 females; mean age: 14.03 +/- 3.3 years). Thirty-two out of ninety (36%) patients had early (within 6 months) and sustained remission (until 2 years of follow-up) of their events ("favorable outcome"), while 30/90 patients (33%) never achieved remission during the study period ("unfavorable outcome"). The factors that were associated with "unfavorable outcome" included the presence of comorbid epilepsy [12/30 (40%) vs 0/32, p<0.0001] and prolonged duration of symptoms before establishment of the diagnosis (median 365 days vs 60 days, p<0.0001). Patient's age, gender, frequency of events, the presence of major psychosocial stressors, and comorbid psychiatric conditions had no significant impact on the disease outcome. CONCLUSIONS: About a third of children with PNES achieve early and sustained remission of symptoms, while another third continue to manifest seizure-like events until at least two years after the diagnosis. The presence of comorbid epilepsy and prolonged duration of PNES are associated with a poor two-year outcome. Early suspicion and diagnosis of PNES, especially in patients with epilepsy, is essential. PMID- 26580209 TI - Deficient Event-Related Theta Oscillations in Individuals at Risk for Alcoholism: A Study of Reward Processing and Impulsivity Features. AB - BACKGROUND: Individuals at high risk to develop alcoholism often manifest neurocognitive deficits as well as increased impulsivity. Event-related oscillations (EROs) have been used to effectively measure brain (dys)function during cognitive tasks in individuals with alcoholism and related disorders and in those at risk to develop these disorders. The current study examines ERO theta power during reward processing as well as impulsivity in adolescent and young adult subjects at high risk for alcoholism. METHODS: EROs were recorded during a monetary gambling task (MGT) in 12-25 years old participants (N = 1821; males = 48%) from high risk alcoholic families (HR, N = 1534) and comparison low risk community families (LR, N = 287) from the Collaborative Study on the Genetics of Alcoholism (COGA). Impulsivity scores and prevalence of externalizing diagnoses were also compared between LR and HR groups. RESULTS: HR offspring showed lower theta power and decreased current source density (CSD) activity than LR offspring during loss and gain conditions. Younger males had higher theta power than younger females in both groups, while the older HR females showed more theta power than older HR males. Younger subjects showed higher theta power than older subjects in each comparison. Differences in topography (i.e., frontalization) between groups were also observed. Further, HR subjects across gender had higher impulsivity scores and increased prevalence of externalizing disorders compared to LR subjects. CONCLUSIONS: As theta power during reward processing is found to be lower not only in alcoholics, but also in HR subjects, it is proposed that reduced reward-related theta power, in addition to impulsivity and externalizing features, may be related in a predisposition to develop alcoholism and related disorders. PMID- 26580214 TI - Risk factors for reading disability in families with rolandic epilepsy. AB - OBJECTIVE: The high prevalence and impact of neurodevelopmental comorbidities in childhood epilepsy are now well known, as are the increased risks and familial aggregation of reading disability (RD) and speech sound disorder (SSD) in rolandic epilepsy (RE). The risk factors for RD in the general population include male sex, SSD, and ADHD, but it is not known if these are the same in RE or whether there is a contributory role of seizure and treatment-related variables. METHODS: An observational study of 108 probands with RE (age range: 3.6-22 years) and their 159 siblings (age range: 1-29 years; 83 with EEG data) were singly ascertained in the US or UK through a proband affected by RE. We used a nested case-control design, multiple logistic regression, and generalized estimating equations to test the hypothesis of an association between RD and seizure variables or antiepileptic drug treatment in RE; we also assessed an association between EEG focal sharp waves and RD in siblings. RESULTS: Reading disability was reported in 42% of probands and 22% of siblings. Among probands, RD was strongly associated with a history of SSD (OR: 9.64, 95% CI: 2.45-37.21), ADHD symptoms (OR: 10.31, 95% CI: 2.15-49.44), and male sex (OR: 3.62, 95% CI: 1.11-11.75) but not with seizure or treatment variables. Among siblings, RD was independently associated only with SSD (OR: 4.30, 95% CI: 1.42-13.0) and not with the presence of interictal EEG focal sharp waves. SIGNIFICANCE: The principal risk factors for RD in RE are SSD, ADHD, and male sex, the same risk factors as for RD without epilepsy. Seizure or treatment variables do not appear to be important risk factors for RD in probands with RE, and there was no evidence to support interictal EEG focal sharp waves as a risk factor for RD in siblings. Future studies should focus on the precise neuropsychological characterization of RD in families with RE and on the effectiveness of standard oral-language and reading interventions. PMID- 26580215 TI - Language and central temporal auditory processing in childhood epilepsies. AB - Because of the relationship between rolandic, temporoparietal, and centrotemporal areas and language and auditory processing, the aim of this study was to investigate language and central temporal auditory processing of children with epilepsy (rolandic epilepsy and temporal lobe epilepsy) and compare these with those of children without epilepsy. Thirty-five children aged between eight and 14 years old were studied. Two groups of children participated in this study: a group with childhood epilepsy (n=19), and a control group without epilepsy or linguistic changes (n=16). There was a significant difference between the two groups, with the worst performance in children with epilepsy for the gaps-in noise test, right ear (p<0.001) and left ear (p<0.001) tests, and duration pattern test--naming (p=0.002) and humming (p=0.002). In auditory P300, there was no significant difference in latency (p=0.343) and amplitude (p=0.194) between the groups. There was a significant difference between the groups, with the worst performance in children with epilepsy, for the auditory-receptive vocabulary (PPVT) (p<0.001) and phonological working memory (nonwords repetition task) tasks (p=0.001). We conclude that the impairment of central temporal auditory processing and language skills may be comorbidities in children with rolandic epilepsy and temporal lobe epilepsy. PMID- 26580216 TI - Physiologic Status Monitoring via the Gastrointestinal Tract. AB - Reliable, real-time heart and respiratory rates are key vital signs used in evaluating the physiological status in many clinical and non-clinical settings. Measuring these vital signs generally requires superficial attachment of physically or logistically obtrusive sensors to subjects that may result in skin irritation or adversely influence subject performance. Given the broad acceptance of ingestible electronics, we developed an approach that enables vital sign monitoring internally from the gastrointestinal tract. Here we report initial proof-of-concept large animal (porcine) experiments and a robust processing algorithm that demonstrates the feasibility of this approach. Implementing vital sign monitoring as a stand-alone technology or in conjunction with other ingestible devices has the capacity to significantly aid telemedicine, optimize performance monitoring of athletes, military service members, and first responders, as well as provide a facile method for rapid clinical evaluation and triage. PMID- 26580218 TI - Regularization of languages by adults and children: A mathematical framework. AB - The fascinating ability of humans to modify the linguistic input and "create" a language has been widely discussed. In the work of Newport and colleagues, it has been demonstrated that both children and adults have some ability to process inconsistent linguistic input and "improve" it by making it more consistent. In Hudson Kam and Newport (2009), artificial miniature language acquisition from an inconsistent source was studied. It was shown that (i) children are better at language regularization than adults and that (ii) adults can also regularize, depending on the structure of the input. In this paper we create a learning algorithm of the reinforcement-learning type, which exhibits patterns reported in Hudson Kam and Newport (2009) and suggests a way to explain them. It turns out that in order to capture the differences between children's and adults' learning patterns, we need to introduce a certain asymmetry in the learning algorithm. Namely, we have to assume that the reaction of the learners differs depending on whether or not the source's input coincides with the learner's internal hypothesis. We interpret this result in the context of a different reaction of children and adults to implicit, expectation-based evidence, positive or negative. We propose that a possible mechanism that contributes to the children's ability to regularize an inconsistent input is related to their heightened sensitivity to positive evidence rather than the (implicit) negative evidence. In our model, regularization comes naturally as a consequence of a stronger reaction of the children to evidence supporting their preferred hypothesis. In adults, their ability to adequately process implicit negative evidence prevents them from regularizing the inconsistent input, resulting in a weaker degree of regularization. PMID- 26580217 TI - Gonadal Transcriptome Analysis in Sterile Double Haploid Japanese Flounder. AB - Sterility is a serious problem that can affect all bionts. In teleosts, double haploids (DHs) induced by mitogynogenesis are often sterile. This sterility severely restricts the further application of DHs for production of clones, genetic analysis, and breeding. However, sterile DH individuals are good source materials for investigation of the molecular mechanisms of gonad development, especially for studies into the role of genes that are indispensable for fish reproduction. Here, we used the Illumina sequencing platform to analyze the transcriptome of sterile female DH Japanese flounder in order to identify major genes that cause sterility and to provide a molecular basis for an intensive study of gonadal development in teleosts. Through sequencing, assembly, and annotation, we obtained 52,474 contigs and found that 60.7% of these shared homologies with existing sequences. A total of 1225 differentially expressed unigenes were found, including 492 upregulated and 733 downregulated genes. Gene Ontology and KEGG analyses showed that genes showing significant upregulation, such as CYP11A1, CYP11B2, CYP17, CYP21, HSD3beta, bcl2l1, and PRLR, principally correlated with sterol metabolic process, steroid biosynthetic process, and the Jak-stat signaling pathway. The significantly downregulated genes were primarily associated with immune response, antigen processing and presentation, cytokine cytokine receptor interaction, and protein digestion and absorption. Using a co expression network analysis, we conducted a comprehensive comparison of gene expression in the gonads of fertile and sterile female DH Japanese flounder. Identification of genes showing significantly different expression will provide further insights into DH reproductive dysfunction and oocyte maturation processes in teleosts. PMID- 26580219 TI - Techno-Cultural Characterization of the MIS 5 (c. 105 - 90 Ka) Lithic Industries at Blombos Cave, Southern Cape, South Africa. AB - Blombos Cave is well known as an important site for understanding the evolution of symbolically mediated behaviours among Homo sapiens during the Middle Stone Age, and during the Still Bay in particular. The lower part of the archaeological sequence (M3 phase) contains 12 layers dating to MIS 5 with ages ranging from 105 to 90 ka ago (MIS 5c to 5b) that provide new perspectives on the technological behaviour of these early humans. The new data obtained from our extensive technological analysis of the lithic material enriches our currently limited knowledge of this time period in the Cape region. By comparing our results with previously described lithic assemblages from sites south of the Orange River, we draw new insights on the extent of the techno-cultural ties between these sites and the M3 phase at Blombos Cave and highlight the importance of this phase within the Middle Stone Age cultural stratigraphy. PMID- 26580220 TI - First-In-Class Small Molecule ONC201 Induces DR5 and Cell Death in Tumor but Not Normal Cells to Provide a Wide Therapeutic Index as an Anti-Cancer Agent. AB - We previously identified ONC201 (TIC10) as a first-in-class orally active small molecule with robust antitumor activity that is currently in clinical trials in advanced cancers. Here, we further investigate the safety characteristics of ONC201 in preclinical models that reveal an excellent safety profile at doses that exceed efficacious doses by 10-fold. In vitro studies indicated a strikingly different dose-response relationship when comparing tumor and normal cells where maximal effects are much stronger in tumor cells than in normal cells. In further support of a wide therapeutic index, investigation of tumor and normal cell responses under identical conditions demonstrated large apoptotic effects in tumor cells and modest anti-proliferative effects in normal cells that were non apoptotic and reversible. Probing the underlying mechanism of apoptosis indicated that ONC201 does not induce DR5 in normal cells under conditions that induce DR5 in tumor cells; DR5 is a pro-apoptotic TRAIL receptor previously linked to the anti-tumor mechanism of ONC201. GLP toxicology studies in Sprague-Dawley rats and beagle dogs at therapeutic and exaggerated doses revealed no dose-limiting toxicities. Observations in both species at the highest doses were mild and reversible at doses above 10-fold the expected therapeutic dose. The no observed adverse event level (NOAEL) was >=42 mg/kg in dogs and >=125 mg/kg in rats, which both correspond to a human dose of approximately 1.25 g assuming standard allometric scaling. These results provided the rationale for the 125 mg starting dose in dose escalation clinical trials that began in 2015 in patients with advanced cancer. PMID- 26580221 TI - Immune Depletion in Combination with Allogeneic Islets Permanently Restores Tolerance to Self-Antigens in Diabetic NOD Mice. AB - The destruction of beta cells in type 1 diabetes (T1D) results in loss of insulin production and glucose homeostasis. Treatment of non-obese diabetic (NOD) mice with immune-depleting/modulating agents (e.g., anti-CD3, murine anti-thymocyte globulin (mATG)) can lead to diabetes reversal. However, for preclinical studies with these and other agents seeking to reverse disease at onset, the necessity for exogenous insulin administration is debated. Spontaneously diabetic NOD mice were treated with a short-course of mATG and insulin provided as drug therapy or by way of allogeneic islet implants. Herein we demonstrate that exogenous insulin administration is required to achieve disease reversal with mATG in NOD mice. Unexpectedly, we also observed that provision of insulin by way of allogeneic islet implantation in combination with mATG leads to a pronounced reversal of diabetes as well as restoration of tolerance to self-islets. Expansion/induction of regulatory cells was observed in NOD mice stably cured with mATG and allogeneic islets. These data suggest that transient provision of allogeneic insulin-producing islets might provide a temporary window for immune depletion to be more effective and instilling stable tolerance to endogenous beta cells. These findings support the use of a never before explored approach for preserving beta cell function in patients with recent onset T1D. PMID- 26580222 TI - Gene Flow of a Forest-Dependent Bird across a Fragmented Landscape. AB - Habitat loss and fragmentation can affect the persistence of populations by reducing connectivity and restricting the ability of individuals to disperse across landscapes. Dispersal corridors promote population connectivity and therefore play important roles in maintaining gene flow in natural populations inhabiting fragmented landscapes. In the prairies, forests are restricted to riparian areas along river systems which act as important dispersal corridors for forest dependent species across large expanses of unsuitable grassland habitat. However, natural and anthropogenic barriers within riparian systems have fragmented these forested habitats. In this study, we used microsatellite markers to assess the fine-scale genetic structure of a forest-dependent species, the black-capped chickadee (Poecile atricapillus), along 10 different river systems in Southern Alberta. Using a landscape genetic approach, landscape features (e.g., land cover) were found to have a significant effect on patterns of genetic differentiation. Populations are genetically structured as a result of natural breaks in continuous habitat at small spatial scales, but the artificial barriers we tested do not appear to restrict gene flow. Dispersal between rivers is impeded by grasslands, evident from isolation of nearby populations (~ 50 km apart), but also within river systems by large treeless canyons (>100 km). Significant population genetic differentiation within some rivers corresponded with zones of different cottonwood (riparian poplar) tree species and their hybrids. This study illustrates the importance of considering the impacts of habitat fragmentation at small spatial scales as well as other ecological processes to gain a better understanding of how organisms respond to their environmental connectivity. Here, even in a common and widespread songbird with high dispersal potential, small breaks in continuous habitats strongly influenced the spatial patterns of genetic variation. PMID- 26580223 TI - Two new species of Urocleidoides Mizelle et Price, 1964 (Monogenoidea) from the gill lamellae of profundulids and poeciliids from Central America and southern Mexico. AB - During investigations of gill ectoparasites (Platyhelminthes) parasitising freshwater fish from Central America (Guatemala, Honduras, El Salvador and Panama) and southeastern Mexico (Guerrero, Oaxaca and Chiapas), the following dactylogyrid monogenoidean were found: Urocleidoides simonae sp. n. from Profundulus punctatus (Gunther) (type host), Profundulus balsanus Ahl, Profundulus guatemalensis (Gunther), Profundulus kreiseri Matamoros, Shaefer, Hernandez et Chakrabarty, Profundulus labialis (Gunther), Profundulus oaxacae (Meek), Profundulus sp. 1 and Profundulus sp. 2 (all Profundulidae); Urocleidoides vaginoclaustroides sp. n. from Pseudoxiphophorus bimaculata (Heckel) (type host) and Poeciliopsis retropinna (Regan) (both Poeciliidae); and Urocleidoides vaginoclaustrum Jogunoori, Kritsky et Venkatanarasaiah, 2004 from P. labialis, Profundulus portillorum Matamoros et Shaefer and Xiphophorus hellerii Heckel (Poeciliidae). Urocleidoides simonae sp. n. differs from all other congeneric species in having anchors with well-differentiated roots, curved elongate shaft and short point. Urocleidoides vaginoclaustroides sp. n. most closely resembles U. vaginoclaustrum, but differs from this species mainly in the shape of its anchors (i.e. evenly curved shaft and short point vs curved shaft and elongate point extending just past the tip of the superficial anchor root). The complexity of potential hosts for species of Urocleidoides and their effect on its distribution on profundulid and poeciliid fishes are briefly discussed. PMID- 26580224 TI - Antimicrobial Contact-Active Oligo(2-oxazoline)s-Grafted Surfaces for Fast Water Disinfection at the Point-of-Use. AB - Water is one of the most valuable resources today and its purity is crucial to health and society well-being. The access to safe drinking water is decreasing in the world, which can have a huge socio-economic impact especially in developing countries, more prone to water-associated diseases. The goal of this work was to develop an innovative, fast, and cost-effective 3D material capable of decontaminating water. We have used an eco-friendly strategy, combining plasma surface activation and supercritical fluid technology to produce, for the first time, a 2-oxazoline-grafted 3D surface with broad-spectrum contact-active antimicrobial properties. Oligo(2-methyl-2-oxazoline) quaternized with N,N dimethyldodecylamine and grafted to a chitosan (CHT) scaffold (CHT-OMetOx-DDA) efficiently and quickly (<3 min) killed >99.999% of Staphylococcus aureus and Escherichia coli cells upon direct contact and avoided bacterial adhesion to the materials surface, which is important for the prevention of biofilm formation. As a proof of concept, CHT-OMetOx-DDA scaffold was demonstrated to be suitable for water purification efficiently killing the microorganisms present in different water samples within minutes of contact and without leaching to the water. Additionally, we report for the first time a new method to clearly distinguish two mechanisms of action of bioactive surfaces: contact-active and releasing systems. PMID- 26580225 TI - Formation of cyanogen iodide by lactoperoxidase. AB - The haem protein lactoperoxidase (LPO) is an important component of the anti microbial immune defence in external secretions and is also applied as preservative in food, oral care and cosmetic products. Upon oxidation of SCN(-) and I(-) by the LPO-hydrogen peroxide system, oxidised species are formed with bacteriostatic and/or bactericidal activity. Here we describe the formation of the inter(pseudo)halogen cyanogen iodide (ICN) by LPO. This product is formed when both, thiocyanate and iodide, are present together in the reaction mixture. Using (13)C nuclear magnetic resonance spectroscopy and gas chromatography-mass spectrometry we could identify this inter(pseudo)halogen after applying iodide in slight excess over thiocyanate. The formation of ICN is based on the reaction of oxidised iodine species with thiocyanate. Further, we could demonstrate that ICN is also formed by the related haem enzyme myeloperoxidase and, in lower amounts, in the enzyme-free system. As I(-) is not competitive for SCN(-) under physiologically relevant conditions, the formation of ICN is not expected in secretions but may be relevant for LPO-containing products. PMID- 26580226 TI - Kinetic and structural studies reveal a unique binding mode of sulfite to the nickel center in urease. AB - Urease is the most efficient enzyme known to date, and catalyzes the hydrolysis of urea using two Ni(II) ions in the active site. Urease is a virulence factor in several human pathogens, while causing severe environmental and agronomic problems. Sporosarcina pasteurii urease has been used extensively in the structural characterization of the enzyme. Sodium sulfite has been widely used as a preservative in urease solutions to prevent oxygen-induced oxidation, but its role as an inhibitor has also been suggested. In the present study, isothermal titration microcalorimetry was used to establish sulfite as a competitive inhibitor for S. pasteurii urease, with an inhibition constant of 0.19mM at pH7. The structure of the urease-sulfite complex, determined at 1.65A resolution, shows the inhibitor bound to the dinuclear Ni(II) center of urease in a tridentate mode involving bonds between the two Ni(II) ions in the active site and all three oxygen atoms of the inhibitor, supporting the observed competitive inhibition kinetics. This coordination mode of sulfite has never been observed, either in proteins or in small molecule complexes, and could inspire synthetic coordination chemists as well as biochemists to develop urease inhibitors based on this chemical moiety. PMID- 26580228 TI - Emerging Technologies for Environmental Remediation: Integrating Data and Judgment. AB - Emerging technologies present significant challenges to researchers, decision makers, industry professionals, and other stakeholder groups due to the lack of quantitative risk, benefit, and cost data associated with their use. Multi criteria decision analysis (MCDA) can support early decisions for emerging technologies when data is too sparse or uncertain for traditional risk assessment. It does this by integrating expert judgment with available quantitative and qualitative inputs across multiple criteria to provide relative technology scores. Here, an MCDA framework provides preliminary insights on the suitability of emerging technologies for environmental remediation by comparing nanotechnology and synthetic biology to conventional remediation methods. Subject matter experts provided judgments regarding the importance of criteria used in the evaluations and scored the technologies with respect to those criteria. The results indicate that synthetic biology may be preferred over nanotechnology and conventional methods for high expected benefits and low deployment costs but that conventional technology may be preferred over emerging technologies for reduced risks and development costs. In the absence of field data regarding the risks, benefits, and costs of emerging technologies, structuring evidence-based expert judgment through a weighted hierarchy of topical questions may be helpful to inform preliminary risk governance and guide emerging technology development and policy. PMID- 26580227 TI - Direct Analysis of Gene Synthesis Reactions Using Solid-State Nanopores. AB - Synthetic nucleic acids offer rich potential to understand and engineer new cellular functions, yet an unresolved limitation in their production and usage is deleterious products, which restrict design complexity and add cost. Herein, we employ a solid-state nanopore to differentiate molecules of a gene synthesis reaction into categories of correct and incorrect assemblies. This new method offers a solution that provides information on gene synthesis reactions in near real time with higher complexity and lower costs. This advance can permit insights into gene synthesis reactions such as kinetics monitoring, real-time tuning, and optimization of factors that drive reaction-to-reaction variations as well as open venues between nanopore-sensing, synthetic biology, and DNA nanotechnology. PMID- 26580229 TI - Conjugated Polymer Nanoparticles for the Amplified Detection of Nitro-explosive Picric Acid on Multiple Platforms. AB - Spontaneously formed conjugated polymer nanoparticles (CPNs) or polymer dots displayed remarkable fluorescence response toward nitroexplosive-picric acid (PA) in multiple environments including 100% aqueous media, solid support using portable paper strips and vapor phase detection via two terminal device. This new cationic conjugated polyelectrolyte (CPE) poly(3,3'-((2-phenyl-9H-fluorene-9,9 diyl)bis(hexane-6,1-diyl))bis(1-methyl-1H-imidazol-3-ium)bromide) (PFMI) was synthesized by Suzuki coupling polymerization followed by post functionalization method without employing any hectic purification technique. Highest quenching constant value (K(sv)) of 1.12 * 10(8) M(-1) and a very low detection limit of 30.9 pM/7.07 ppt were obtained exclusively for PA in 100% aqueous environment which is rare and unique for any CPE/CPNs. Contact mode detection of PA was also performed using simple, cost-effective and portable fluorescent paper strips for achieving on-site detection. Furthermore, the two terminal sensor device fabricated with nanoparticles of PFMI (PFMI-NPs) provides an exceptional and unprecedented platform for the vapor mode detection of PA under ambient conditions. The mechanism for the ultrasensitivity of PFMI-NPs probe to detect PA is attributed to the "molecular-wire effect", electrostatic interaction, photoinduced electron transfer (PET), and possible resonance energy transfer (RET). PMID- 26580230 TI - Climate Change, Health, and Communication: A Primer. AB - Climate change is one of the most serious and pervasive challenges facing us today. Our changing climate has implications not only for the ecosystems upon which we depend, but also for human health. Health communication scholars are well-positioned to aid in the mitigation of and response to climate change and its health effects. To help theorists, researchers, and practitioners engage in these efforts, this primer explains relevant issues and vocabulary associated with climate change and its impacts on health. First, this primer provides an overview of climate change, its causes and consequences, and its impacts on health. Then, the primer describes ways to decrease impacts and identifies roles for health communication scholars in efforts to address climate change and its health effects. PMID- 26580231 TI - Electron Microscopy of Living Cells During in Situ Fluorescence Microscopy. AB - We present an approach toward dynamic nanoimaging: live fluorescence of cells encapsulated in a bionanoreactor is complemented with in situ scanning electron microscopy (SEM) on an integrated microscope. This allows us to take SEM snapshots on-demand, that is, at a specific location in time, at a desired region of interest, guided by the dynamic fluorescence imaging. We show that this approach enables direct visualization, with EM resolution, of the distribution of bioconjugated quantum dots on cellular extensions during uptake and internalization. PMID- 26580232 TI - Association of the Aldose Reductase-106TT Genotype with Increased Risk for Diabetic Retinopathy in the Chinese Han Population: An Updated Meta-Analysis. AB - PURPOSE: A meta-analysis was conducted to assess the effects of the aldose reductase (ALR) C-106T polymorphism on the risk for development of diabetic retinopathy (DR) in the Chinese population. MATERIALS AND METHODS: Relevant studies were identified using PubMed, Springer Link, Ovid, Chinese Wanfang Data Knowledge Service Platform, Chinese National Knowledge Infrastructure (CNKI), and Chinese Biology Medicine (CBM) through 21 March 2015. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the associations. RESULTS: This meta-analysis identified 11 studies, including 1386 DR cases, 1594 diabetes mellitus (DM) control cases, and 472 healthy control cases. In the overall analysis, a non-significant association between the ALR C( 106)T polymorphism and DR was found in the Chinese population. In subgroups stratified by ethnicity, significantly increased risks for DR in association with ALR C(-106)T variants were found in the Chinese Han population. When compared with healthy controls, we found the following associations: T versus C (OR, 1.63; 95%CI, 1.23-2.17), TT versus CC (OR, 2.04; 95%CI, 1.03-4.02), and TT + CT versus CC (OR, 1.82; 95%CI, 1.28-2.57). CONCLUSIONS: Our meta-analysis showed that ALR C 106T variants appear to influence the risk for DR in Chinese Han persons. Studies with larger sample sizes and wider population spectra are warranted to verify this finding. PMID- 26580233 TI - RNA sequencing uncovers antisense RNAs and novel small RNAs in Streptococcus pyogenes. AB - Streptococcus pyogenes is a human pathogen responsible for a wide spectrum of diseases ranging from mild to life-threatening infections. During the infectious process, the temporal and spatial expression of pathogenicity factors is tightly controlled by a complex network of protein and RNA regulators acting in response to various environmental signals. Here, we focus on the class of small RNA regulators (sRNAs) and present the first complete analysis of sRNA sequencing data in S. pyogenes. In the SF370 clinical isolate (M1 serotype), we identified 197 and 428 putative regulatory RNAs by visual inspection and bioinformatics screening of the sequencing data, respectively. Only 35 from the 197 candidates identified by visual screening were assigned a predicted function (T-boxes, ribosomal protein leaders, characterized riboswitches or sRNAs), indicating how little is known about sRNA regulation in S. pyogenes. By comparing our list of predicted sRNAs with previous S. pyogenes sRNA screens using bioinformatics or microarrays, 92 novel sRNAs were revealed, including antisense RNAs that are for the first time shown to be expressed in this pathogen. We experimentally validated the expression of 30 novel sRNAs and antisense RNAs. We show that the expression profile of 9 sRNAs including 2 predicted regulatory elements is affected by the endoribonucleases RNase III and/or RNase Y, highlighting the critical role of these enzymes in sRNA regulation. PMID- 26580234 TI - Evaluation of Bone Mineral Density and Bone Biomarkers in Patients With Type 2 Diabetes Treated With Canagliflozin. AB - CONTEXT: Canagliflozin is a sodium glucose cotransporter 2 inhibitor developed to treat type 2 diabetes mellitus (T2DM). OBJECTIVE: Our objective is to describe the effects of canagliflozin on bone mineral density (BMD) and bone biomarkers in patients with T2DM. DESIGN: This was a randomized study, consisting of a 26-week, double-blind, placebo-controlled period and a 78-week, double-blind, placebo controlled extension. SETTING: This study was undertaken in 90 centers in 17 countries. PATIENTS: Patients were aged 55-80 years (N = 716) and whose T2DM was inadequately controlled on a stable antihyperglycemic regimen. INTERVENTIONS: Canagliflozin 100 or 300 mg or placebo were administered once daily. OUTCOME AND MEASURES: BMD was assessed using dual-energy x-ray absorptiometry at weeks 26, 52, and 104. Bone strength was assessed using quantitative computed tomography and finite element analysis at week 52. Serum collagen type 1 beta-carboxy telopeptide, osteocalcin, and estradiol were assessed at weeks 26 and 52. RESULTS: Canagliflozin doses of 100 and 300 mg were associated with a decrease in total hip BMD over 104 weeks, (placebo-subtracted changes: -0.9% and -1.2%, respectively), but not at other sites measured (femoral neck, lumbar spine, or distal forearm). No meaningful changes in bone strength were observed. At week 52, canagliflozin was associated with an increase in collagen type 1 beta-carboxy telopeptide that was significantly correlated with a reduction in body weight, an increase in osteocalcin, and, in women, a decrease in estradiol. CONCLUSIONS: In older patients with T2DM, canagliflozin showed small but significant reductions in total hip BMD and increases in bone formation and resorption biomarkers, due at least in part to weight loss. PMID- 26580235 TI - Link Between Increased Satiety Gut Hormones and Reduced Food Reward After Gastric Bypass Surgery for Obesity. AB - CONTEXT: Roux-en-Y gastric bypass (RYGB) surgery is an effective long-term intervention for weight loss maintenance, reducing appetite, and also food reward, via unclear mechanisms. OBJECTIVE: To investigate the role of elevated satiety gut hormones after RYGB, we examined food hedonic-reward responses after their acute post-prandial suppression. DESIGN: These were randomized, placebo controlled, double-blind, crossover experimental medicine studies. PATIENTS: Two groups, more than 5 months after RYGB for obesity (n = 7-11), compared with nonobese controls (n = 10), or patients after gastric banding (BAND) surgery (n = 9) participated in the studies. INTERVENTION: Studies were performed after acute administration of the somatostatin analog octreotide or saline. In one study, patients after RYGB, and nonobese controls, performed a behavioral progressive ratio task for chocolate sweets. In another study, patients after RYGB, and controls after BAND surgery, performed a functional magnetic resonance imaging food picture evaluation task. MAIN OUTCOME MEASURES: Octreotide increased both appetitive food reward (breakpoint) in the progressive ratio task (n = 9), and food appeal (n = 9) and reward system blood oxygen level-dependent signal (n = 7) in the functional magnetic resonance imaging task, in the RYGB group, but not in the control groups. RESULTS: Octreotide suppressed postprandial plasma peptide YY, glucagon-like peptide-1, and fibroblast growth factor-19 after RYGB. The reduction in plasma peptide YY with octreotide positively correlated with the increase in brain reward system blood oxygen level-dependent signal in RYGB/BAND subjects, with a similar trend for glucagon-like peptide-1. CONCLUSIONS: Enhanced satiety gut hormone responses after RYGB may be a causative mechanism by which anatomical alterations of the gut in obesity surgery modify behavioral and brain reward responses to food. PMID- 26580236 TI - Social Jetlag, Chronotype, and Cardiometabolic Risk. AB - CONTEXT: Shift work, which imposes a habitual disruption in the circadian system, has been linked to increased incidence of cardiometabolic diseases, and acute circadian misalignment alters various metabolic processes. However, it remains unclear whether day-to-day circadian dysregulation contributes to these risks beyond poor sleep and other behavioral characteristics. OBJECTIVE: Individuals differ in circadian phase preference, known as chronotype, but may be constrained by modern work obligations to specific sleep schedules. Individuals experience social jetlag (SJL) due to a habitual discrepancy between their endogenous circadian rhythm and actual sleep times imposed by social obligations. Here, we examined whether chronotype and/or SJL associate with components of cardiovascular disease risk beyond the known effects of sleep disturbances, poor health behaviors, and depressive symptomatology. DESIGN: Participants were healthy, midlife adults who worked part- or full-time day shifts (n = 447; mean age, 42.7 [range, 30-54] y; 53% female; 83% white). Chronotype was assessed with the Composite Scale of Morningness. SJL was quantified as the difference (in minutes) between the midpoints of actigraphy-derived sleep intervals before work vs non-workdays. RESULTS: Multiple regression analyses showed that SJL related to a lower high-density lipoprotein-cholesterol level, higher triglycerides, higher fasting plasma insulin, insulin resistance, and adiposity (P < .05), even after adjustment for subjective sleep quality, actigraphy-derived sleep characteristics, depressive symptomatology, and health behaviors. Evening chronotype associated with lower high-density lipoprotein-cholesterol after adjustment for covariates. CONCLUSION: Our findings suggest that a misalignment of sleep timing is associated with metabolic risk factors that predispose to diabetes and atherosclerotic cardiovascular disease. PMID- 26580237 TI - Effects of Canagliflozin on Fracture Risk in Patients With Type 2 Diabetes Mellitus. AB - CONTEXT: Canagliflozin is a sodium glucose cotransporter 2 inhibitor developed to treat type 2 diabetes mellitus (T2DM). OBJECTIVE: The purpose of this study was to describe the effects of canagliflozin on bone fracture risk. DESIGN AND SETTING: This was a randomized phase 3 study in patients with T2DM. PATIENTS AND INTERVENTIONS: Canagliflozin doses of 100 and 300 mg were evaluated in the overall population of patients from 9 placebo- and active-controlled studies (N = 10 194), as well as in separate analyses of a single trial enriched with patients with a prior history/risk of cardiovascular disease (ie, the CANagliflozin cardioVascular Assessment Study [CANVAS]; N = 4327) and a pooled population of 8 non-CANVAS studies (N = 5867). OUTCOME MEASURES: The incidence of adjudicated fracture adverse events (AEs), fall-related AEs, and volume depletion-related AEs was assessed. RESULTS: The incidence of fractures was similar with canagliflozin (1.7%) and noncanagliflozin (1.5%) in the pooled non-CANVAS studies. In CANVAS, a significant increase in fractures was seen with canagliflozin (4.0%) vs placebo (2.6%) that was balanced between the upper and lower limbs. The incidence of fractures was higher with canagliflozin (2.7%) vs noncanagliflozin (1.9%) in the overall population, which was driven by the increase of fractures in CANVAS. The incidence of reported fall-related AEs was low, but significantly higher with canagliflozin in CANVAS, potentially related to volume depletion-related AEs, but not significantly different in the pooled non-CANVAS studies and the overall population. CONCLUSIONS: Fracture risk was increased with canagliflozin treatment, driven by CANVAS patients, who were older, with a prior history/risk of cardiovascular disease, and with lower baseline estimated glomerular filtration rate and higher baseline diuretic use. The increase in fractures may be mediated by falls; however, the cause of increased fracture risk with canagliflozin is unknown. PMID- 26580238 TI - Case Report: Nodule Development From Subcapsular Aldosterone-Producing Cell Clusters Causes Hyperaldosteronism. AB - CONTEXT: We previously reported that the human adrenal cortex remodels to form subcapsular aldosterone-producing cell clusters (APCCs). Some APCCs were recently found to carry aldosterone-producing adenoma (APA)-associated somatic mutations in ion channel/pump genes, which implied that APCCs produce aldosterone autonomously and are an origin of APA. However, there has been no report describing an APCC-to-APA transitional lesion. CASE DESCRIPTION: A histological examination revealed unilateral multiple adrenocortical micronodules in the adrenals of two patients with primary aldosteronism (PA). Based on immunohistochemistry for aldosterone synthase, some of the micronodules were identified as possible APCC-to-APA transitional lesions (pAATLs; a tentative term used in this manuscript), which consisted of a subcapsular APCC-like portion and an inner micro-APA-like (mAPA-like) portion without an apparent histological border. Genomic DNA samples prepared from pAATL histological sections were analyzed by next-generation sequencing for the known APA-associated mutations. The mAPA-like portions from two of the three large pAATLs examined harbored mutations (KCNJ5 [p.G151R] in pAATL 3 and ATP1A1 [p.L337M] in pAATL 7), whereas their corresponding APCC-like portions did not, suggesting their role in the formation of mAPA. Another lesion carried novel mutations in ATP1A1 (p.Ile322_Ile325del and p.Ile327Ser) in both the mAPA-like and APCC-like portions, thereby supporting these portions having a clonal origin. CONCLUSION: A novel aldosterone-producing pathology, pAATL that causes unilateral PA, was detected in the adrenals of two patients. Next-generation sequencing analyses of the large pAATLs suggested that the introduction of APA-associated mutations in the ion channel/pump genes may be involved in the development of mAPA from existing APCCs. PMID- 26580239 TI - Effect of Valvular Surgery in Carcinoid Heart Disease: An Observational Cohort Study. AB - CONTEXT: Carcinoid heart disease (NET-CHD) is associated with the development of symptom-limited exercise capacity and high rates of morbidity and mortality. OBJECTIVE: This study sought to determine the survival, cardiac function, and functional class following surgery. DESIGN AND SETTING, AND PATIENTS: This was a retrospective observational cohort study between 2005 and 2015 at a European Centre of Excellence for Neuroendocrine Tumours, Queen Elizabeth Hospital Birmingham. England consisting of 62 consecutive patients referred to the NET Cardiology Service. INTERVENTIONS: Subjects were assessed at referral using transthoracic echocardiography (with saline contrast) and transesophageal echocardiography, and 77% with confirmed NET-CHD underwent cardiovascular magnetic resonance imaging. Symptomatic patients with concomitant severe valvular dysfunction were referred for surgery with stable NET disease. MAIN OUTCOME MEASURE: Survival of patients with proven NET-CHD following medical and surgical treatments was measure. RESULTS: In total, 47/62 patients were diagnosed with NET CHD. Thirty-two patients (68%) underwent surgery with bioprosthetic valve replacements in all subjects; tricuspid, n = 31; pulmonary, n = 30; mitral, n = 3; and aortic, n = 3. Four patients underwent concomitant coronary artery bypass grafting. There were 4 (13%) early post-operative deaths. One- and 2-y survival rates after surgery were 75 and 69% compared with 45 and 15% in un-operated patients. Post-operatively, functional class was improved (pre-New York Heart Association Classification [NYHA], 2.6 [0.5] vs post-NYHA, 1.7 [1.1]), P < .05, right-ventricular (RV) size was reduced (136 ml/m(2) [25] vs 71 ml/m(2) [7]; P < .01) with preserved RV ejection fraction (61% +/- 9 vs 55% +/- 10; P = .26). CONCLUSION: Valve surgery improved functional class and resulted in RV reverse remodelling with improved survival rates at 2 y compared with those not proceeding to operation. These data highlight the importance of close collaboration between NET clinicians, cardiology, and cardiothoracic surgery teams. Early referral can improve functional capacity but more research is needed to define the selection of appropriate candidates and randomized data are needed to define the effect of surgery on prognosis. PMID- 26580241 TI - Prolonged and Severe Gestational Thyrotoxicosis Due to Enhanced hCG Sensitivity of a Mutant Thyrotropin Receptor. AB - CONTEXT: Gestational thyrotoxicosis, whether associated with hyperemesis gravidarum or not, is thought to be due to excessive human chorionic gonadotropin (hCG) secretion. CASE DESCRIPTION: We report here the second case of gestational thyrotoxicosis associated with hyperemesis gravidarum due to a mutation of the TSH receptor, providing thyroid hypersensitivity to hCG. CONCLUSION: Severe and lasting gestational thyrotoxicosis with normal hCG concentration should lead to sequencing of the TSH receptor gene. PMID- 26580243 TI - Value-Based Cancer Care. PMID- 26580240 TI - Treatment with Sildenafil Improves Insulin Sensitivity in Prediabetes: A Randomized, Controlled Trial. AB - CONTEXT: Sildenafil increases insulin sensitivity in mice. In humans, phosphodiesterase 5 inhibition improves disposition index, but the mechanism of this effect has not been elucidated and may depend on duration. In addition, increasing cyclic GMP without increasing nitric oxide could have beneficial effects on fibrinolytic balance. OBJECTIVE: The objective was to test the hypothesis that chronic phosphodiesterase 5 inhibition with sildenafil improves insulin sensitivity and secretion without diminishing fibrinolytic function. DESIGN: This was a randomized, double-blind, placebo-controlled study. SETTING: This trial was conducted at Vanderbilt Clinical Research Center. PARTICIPANTS: Participants included overweight individuals with prediabetes. INTERVENTIONS: Subjects were randomized to treatment with sildenafil 25 mg three times a day or matching placebo for 3 months. Subjects underwent a hyperglycemic clamp prior to and at the end of treatment. MAIN OUTCOME MEASURES: The primary outcomes of the study were insulin sensitivity and glucose-stimulated insulin secretion. RESULT: Twenty-one subjects completed each treatment arm. After 3 months, the insulin sensitivity index was significantly greater in the sildenafil group compared to the placebo group by 1.84 mg/kg/min per MUU/mL*100 (95% confidence interval, 0.01 to 3.67 mg/kg/min per MUU/mL*100; P = .049), after adjusting for baseline insulin sensitivity index and body mass index. In contrast, there was no effect of 3 month treatment with sildenafil on acute- or late-phase glucose-stimulated insulin secretion (P > .30). Sildenafil decreased plasminogen activator inhibitor 1 (P = .01), without altering tissue-plasminogen activator. In contrast to placebo, sildenafil also decreased the urine albumin-to-creatinine ratio from 12.67 +/- 14.67 to 6.84 +/- 4.86 MUg/mg Cr. This effect persisted 3 months after sildenafil discontinuation. CONCLUSIONS: Three-month phosphodiesterase 5 inhibition enhances insulin sensitivity and improves markers of endothelial function. PMID- 26580245 TI - Impact of Genetic Mutations and Health Plan Access to Therapies on Treatment Response and Drug Costs Related to Tyrosine Kinase Inhibitor Treatment Among Patients With Chronic Myelogenous Leukemia. AB - OBJECTIVES: This study assessed treatment responses and economic consequences of limiting access to the second-generation BCR-ABL1 tyrosine kinase inhibitors (2G TKI), dasatinib and nilotinib, for treatment of chronic myelogenous leukemia, while taking into account frequencies of genetic mutations that exhibit different sensitivities to the 2G-TKIs. METHODS: Frequencies of BCR-ABL1 mutations and the impact of mutations on responses to 2G-TKIs were obtained from published literature and used as inputs in a decision analytics model. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were estimated after 12 months of 2G-TKI treatment. Total annual 2G-TKI drug costs per CHR and MCyR were estimated and compared among 3 2G-TKI access scenarios: (1) open access to both 2G-TKIs; (2) access restricted to dasatinib (DASA-only); and (3) access restricted to nilotinib (NILO-only). RESULTS: Among a hypothetical cohort of 1000 2G-TKI-treated chronic myelogenous leukemia patients, the percentage of patients with CHR and MCyR were greatest for the open access plan (CHR: 93%, MCyR: 56%), followed by DASA-only (88%, 53%) and NILO-only (67%, 47%). Compared with the 2G TKI costs per CHR in open access ($120,706/CHR), the costs were 5% higher ($126,753/CHR) in DASA-only and 41% higher ($169,990/CHR) in NILO-only. Likewise, compared with the 2G-TKI costs per MCyR in open access ($198,284/MCyR), the costs were 6% higher ($209,259/MCyR) in DASA-only and 22% higher ($241,515/MCyR) in NILO-only. CONCLUSION: Open access to both 2G-TKIs is associated with improved clinical and economic outcomes: greater treatment response rates (CHR and MCyR) and lower drug costs compared with restricted access to 2G-TKIs. PMID- 26580244 TI - Use of In Vivo and In Vitro Data to Derive a Chronic Reference Value for Crotonaldehyde Based on Relative Potency to Acrolein. AB - The Texas Commission on Environmental Quality (TCEQ) conducted a chronic inhalation noncancer toxicity assessment for crotonaldehyde (CRO). Since there were limited toxicity data for CRO, a reference value (ReV) was derived using a relative potency factor (RPF) approach with acrolein as the index chemical. Both CRO and acrolein are alpha,beta-unsaturated carbonyls and share common steps in their mode of action (MOA). Only studies that investigated the effects of CRO and acrolein in the same study were used to calculate a CRO:acrolein RPF. In vivo findings measuring both 50% respiratory depression in rats and two species of mice and subcutaneous 50% lethality in rats and mice were used to calculate an RPF of 3 (rounded to one significant figure). In vitro data were useful to compare the MOA of CRO and acrolein and to support the RPF determined using in vivo data. In vitro cell culture studies investigating cytotoxicity in normal human lung fibroblast cultures using the propidium iodide cytotoxicity assay and in mouse lymphocyte cultures using the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) cytotoxicity assay were used to calculate an in vitro RPF of 3, which supports the in vivo RPF. The chronic ReV for acrolein of 1.2 ppb derived by TCEQ was multiplied by the RPF of 3 to calculate the ReV for CRO of 3.6 ppb (10 MUg/m(3)). The ReV for CRO was developed to protect the general public from adverse health effects from chronic exposure to CRO in ambient air. PMID- 26580246 TI - The Orphan Drug Act: Restoring the Mission to Rare Diseases. AB - The Orphan Drug Act has fostered drug development for patients with rare cancers and other diseases; however, current data suggest that companies are gaming the system to use the law for mainstream drugs. We identify a pattern of pharmaceutical companies submitting drugs to the Food and Drug Administration (FDA) as orphan drugs but once approved, the drugs are used broadly off-label with the lucrative orphan drug protections and exclusivity benefits. Since the law was passed, the proportion of new FDA-approved drugs that were submitted as orphan drugs has increased with a peak last year of 41% of all FDA-approved drugs approved as orphan drugs. On the basis of the current data, we suggest that patients with rare cancers and other diseases may suffer due to dilution of the incentives and benefits. We propose reform to increase submission scrutiny, decrease benefits based on off-label use, and increase price transparency. PMID- 26580247 TI - Secondary cervical spine injury during airway management: beyond a 'one-size-fits all' approach. PMID- 26580248 TI - Too much blood pressure? PMID- 26580250 TI - Ouroboros. PMID- 26580249 TI - Timing of reversal with respect to three nerve stimulator end-points from cisatracurium-induced neuromuscular block. AB - After elective ear surgery with cisatracurium neuromuscular blockade, 48 adults were randomly assigned to receive neostigmine: (a) at appearance of the fourth twitch of a 'train-of-four'; (b) at loss of fade to train-of-four; or (c) at loss of fade to double-burst stimulation, all monitored using a TOF-Watch SX(r) on one arm. For each of these conditions, the recovery from train-of-four (TOF) ratio was measured in parallel objectively using a TOF-Watch SX placed on the contralateral arm. The median (IQR [range]) time from administration of reversal to a train-of-four ratio >= 0.9 was 11 (9-15.5 [2-28]) min, 8 (4-13.5 [1-25]) min and 7 (4-10 [2-15]) min in the three groups, respectively. This recovery time was significantly shorter when reversal was given at loss of fade to double-burst stimulation (c), than when given at the appearance of the fourth twitch (a), p = 0.046. However, the total time to extubation may be unaffected as it takes longer for fade to be lost after double-burst stimulation than for four twitches subjectively to appear. PMID- 26580251 TI - Awake nasotracheal intubation using videolaryngoscopy or fibreoptic bronchoscopy. PMID- 26580252 TI - Awake nasal intubation and topical anaesthesia: how and how much? PMID- 26580253 TI - Awake nasal intubation: the gag reflex and failure of videolaryngoscopy. PMID- 26580254 TI - Awake nasal intubation: were patients' tracheas intubated 'blindly'? PMID- 26580255 TI - Awake nasal intubation: from darkness into light, or a leap into the unknown? PMID- 26580256 TI - A reply. PMID- 26580257 TI - Dexmedetomidine and emergence agitation. PMID- 26580258 TI - A reply. PMID- 26580259 TI - Auditing safe sedation practice nationally. PMID- 26580260 TI - Death of the anaesthetic room IV. PMID- 26580261 TI - Death of the anaesthetic room III. PMID- 26580262 TI - Emergency airway management in obstetric general anaesthesia. PMID- 26580263 TI - First use of thiopental in obstetric anaesthesia. PMID- 26580264 TI - Use of the skin pinch test before elective caesarean section. PMID- 26580265 TI - A reply. PMID- 26580266 TI - Wrong about Wright. PMID- 26580267 TI - Bromage, or not Bromage? PMID- 26580268 TI - A reply. PMID- 26580269 TI - Exhaustion by design. PMID- 26580270 TI - Roll Out the Old: Welcome in the New. PMID- 26580271 TI - Design and Clinical Evaluation of a Handheld Wavefront Autorefractor. AB - PURPOSE: To introduce a novel autorefractor design that is intended to be manufacturable at low cost and evaluate its performance in measuring refractive errors. METHODS: We developed a handheld, open-view autorefractor (the "QuickSee" [QS]) that uses a simplified approach to wavefront sensing that forgoes moving parts and expensive components. Adult subjects (n = 41) were recruited to undergo noncycloplegic refraction with three methods: (1) a QS prototype, (2) a Grand Seiko WR-5100K (GS) autorefractor, and (3) subjective refraction (SR). Agreements between the QS and GS were evaluated using a Bland-Altman analysis. The accuracy of both autorefractors was evaluated using SR as the clinical gold standard. RESULTS: The spherical equivalent powers measured from both autorefractors correlate well with SR, with identical correlation coefficients of r = 0.97. Both autorefractors also agree well with each other, with a spherical equivalent power 95% confidence interval of +/-0.84 diopters (D). The difference between the accuracy of each objective device is not statistically significant for any component of the power vector (p = 0.55, 0.41, and 0.18, for M, J0, and J45, respectively). The spherical and cylindrical powers measured by the GS agree within 0.25 D of the SR in 49 and 82% of the eyes, respectively, whereas the spherical and cylindrical powers measured by the QS agree within 0.25 D of the SR in 74 and 87% of the eyes, respectively. CONCLUSIONS: The prototype autorefractor exhibits equivalent performance to the GS autorefractor in matching power vectors measured by SR. PMID- 26580274 TI - Understanding Academic Clinicians' Decision Making for the Treatment of Childhood Obesity. AB - BACKGROUND: Although most clinicians agree that obesity is a major problem, treatment rates remain low. We conducted this discrete choice experiment (DCE) to understand academic clinicians' decisions in treating childhood obesity. METHODS: A total of 198 academic pediatric surgeons, pediatricians, family physicians, and allied health professionals were recruited from 15 teaching hospitals across Canada to participate in this DCE. Participants completed 15 tasks choosing between three obesity treatment scenarios to identify the scenario in which they would most likely treat pediatric obesity. RESULTS: Latent class analysis revealed two classes with early intervention and late intervention preferences. Participants in the early intervention group (30%) were sensitive to variations in patient and family support. They would likely intervene if patients were obese, with normal lipid levels, were prediabetic, had high blood pressure, and when obesity was lifestyle associated. Late intervention clinicians (70%) were more likely to intervene if patients were morbidly obese, had abnormal lipid levels, required insulin for diabetes, had very high blood pressure, or when obesity impacted the patient's mental health. Simulations predicted that increasing colleague support for intervention, providing expert consultation, and mobilizing multidisciplinary support would increase the likelihood of treating pediatric obesity earlier from 16.1% to 81.5%. CONCLUSIONS: This DCE was implemented to understand the factors clinicians use in making decisions. Most academic clinicians choose to intervene late in the clinical course when more severe obesity-related morbidities are present. Increased support from colleagues, expert consultation, and multidisciplinary support are likely to lead to earlier treatment of obesity among academic clinicians caring for children. PMID- 26580275 TI - Isonatric Dialysis Biofeedback in Hemodiafiltration with Online Regeneration of Ultrafiltrate in Hypertensive Hemodialysis Patients: A Randomized Controlled Study. AB - Dialysis biofeedback in hemodiafiltration with online regeneration of ultrafiltrate (HFR) could help to improve arterial hypertension. We evaluated the impact of isonatric HFR (HFR-iso) on hypertension control compared to conventional HFR. Forty-seven hemodialysis patients were included and randomized (ratio 2/1) HFR-iso versus HFR during 24 dialysis sessions. In the HFR-iso group (32 patients, 768 dialysis sessions), the predialytic systolic blood pressure (BP) decreased from S1 to S24 of 9 +/- 20 mm Hg and increased of 5 +/- 24 mm Hg in the HFR group (15 patients, 360 dialysis sessions), variation that differed between the 2 groups (x0394;S1-S24, p = 0.035; interaction group*time, p = 0.012). The diastolic BP (HFR-iso -3 +/- 14 mm Hg vs. HFR 5 +/- 13 mm Hg; p = 0.088), the DDD of antihypertensive treatment and the dry weight did not vary significantly during the study. Number of sessions complicated by symptomatic hypotension was similar in the 2 groups. HFR-iso improved BP control without increasing dialysis hypotension episodes. SHORT SUMMARY: In this multicenter, open-label, controlled, randomized study, we evaluated the impact of dialysis biofeedback in HFR on arterial hypertension compared to conventional HFR. We observed that HFR-iso improved arterial BP control without increasing dialysis hypotension episodes. PMID- 26580276 TI - Genome-wide Association Study to Identify Quantitative Trait Loci for Meat and Carcass Quality Traits in Berkshire. AB - Meat and carcass quality attributes are of crucial importance influencing consumer preference and profitability in the pork industry. A set of 400 Berkshire pigs were collected from Dasan breeding farm, Namwon, Chonbuk province, Korea that were born between 2012 and 2013. To perform genome wide association studies (GWAS), eleven meat and carcass quality traits were considered, including carcass weight, backfat thickness, pH value after 24 hours (pH24), Commission Internationale de l'Eclairage lightness in meat color (CIE L), redness in meat color (CIE a), yellowness in meat color (CIE b), filtering, drip loss, heat loss, shear force and marbling score. All of the 400 animals were genotyped with the Porcine 62K SNP BeadChips (Illumina Inc., USA). A SAS general linear model procedure (SAS version 9.2) was used to pre-adjust the animal phenotypes before GWAS with sire and sex effects as fixed effects and slaughter age as a covariate. After fitting the fixed and covariate factors in the model, the residuals of the phenotype regressed on additive effects of each single nucleotide polymorphism (SNP) under a linear regression model (PLINK version 1.07). The significant SNPs after permutation testing at a chromosome-wise level were subjected to stepwise regression analysis to determine the best set of SNP markers. A total of 55 significant (p<0.05) SNPs or quantitative trait loci (QTL) were detected on various chromosomes. The QTLs explained from 5.06% to 8.28% of the total phenotypic variation of the traits. Some QTLs with pleiotropic effect were also identified. A pair of significant QTL for pH24 was also found to affect both CIE L and drip loss percentage. The significant QTL after characterization of the functional candidate genes on the QTL or around the QTL region may be effectively and efficiently used in marker assisted selection to achieve enhanced genetic improvement of the trait considered. PMID- 26580277 TI - Effect of a c-MYC Gene Polymorphism (g.3350G>C) on Meat Quality Traits in Berkshire. AB - c-MYC (v-myelocytomatosis viral oncogene homologue) is a transcription factor that plays important role in many biological process including cell growth and differentiation, such as myogenesis and adipogenesis. In this study, we aimed to detect MYC gene polymorphisms, their genotype frequencies and to determine associations between these polymorphisms and meat quality traits in Berkshire pigs. We identified a single nucleotide polymorphism (SNP) in intron 2 of MYC gene by Sanger sequencing, i.e., g.3350G>C (rs321898326), that is only found in Berkshire pigs, but not in other breeds including Duroc, Landrace, and Yorkshire pigs that were used in this study. Genotypes of total 378 Berkshire pigs (138 sows and 240 boars) were determined using Hha I restriction enzyme digestion after polymerase chain reaction. Observed allele frequencies of GG, GC, and CC genotypes were 0.399, 0.508, and 0.093 respectively. Statistical analysis indicated that the g.3350G>C polymorphism was significantly associated with pH45min and cooking loss (p<0.05), suggesting that g.3350G>C SNP can be used for pre-selection of pH45min and cooking loss traits in Berkshire pigs. PMID- 26580278 TI - Genome-wide Association Study (GWAS) and Its Application for Improving the Genomic Estimated Breeding Values (GEBV) of the Berkshire Pork Quality Traits. AB - The missing heritability has been a major problem in the analysis of best linear unbiased prediction (BLUP). We introduced the traditional genome-wide association study (GWAS) into the BLUP to improve the heritability estimation. We analyzed eight pork quality traits of the Berkshire breeds using GWAS and BLUP. GWAS detects the putative quantitative trait loci regions given traits. The single nucleotide polymorphisms (SNPs) were obtained using GWAS results with p value <0.01. BLUP analyzed with significant SNPs was much more accurate than that with total genotyped SNPs in terms of narrow-sense heritability. It implies that genomic estimated breeding values (GEBVs) of pork quality traits can be calculated by BLUP via GWAS. The GWAS model was the linear regression using PLINK and BLUP model was the G-BLUP and SNP-GBLUP. The SNP-GBLUP uses SNP-SNP relationship matrix. The BLUP analysis using preprocessing of GWAS can be one of the possible alternatives of solving the missing heritability problem and it can provide alternative BLUP method which can find more accurate GEBVs. PMID- 26580279 TI - Physiological Responses and Lactation to Cutaneous Evaporative Heat Loss in Bos indicus, Bos taurus, and Their Crossbreds. AB - Cutaneous evaporative heat loss in Bos indicus and Bos taurus has been well documented. Nonetheless, how crossbreds with different fractional genetic proportions respond to such circumstances is of interest. A study to examine the physiological responses to cutaneous evaporative heat loss, also lactation period and milk yield, were conducted in Sahiwal (Bos indicus, n = 10, 444+/-64.8 kg, 9+/-2.9 years), Holstein Friesian (Bos taurus, HF100% (n = 10, 488+/-97.9 kg, 6+/ 2.8 years)) and the following crossbreds: HF50% (n = 10, 355+/-40.7 kg, 2+/-0 years) and HF87.5% (n = 10, 489+/-76.8 kg, 7+/-1.8 years). They were allocated so as to determine the physiological responses of sweating rate (SR), respiration rate (RR), rectal temperature (RT), and skin temperature (ST) with and without hair from 06:00 h am to 15:00 h pm. And milk yield during 180 days were collected at days from 30 to 180. The ambient temperature-humidity-index (THI) increased from less than 80 in the early morning to more than 90 in the late afternoon. The interaction of THI and breed were highly affected on SR, RR, RT, and ST (p<0.01). The SR was highest in Sahiwal (595 g/m(2)/h) compared to HF100% (227 g/m(2)/h), and their crossbreds both HF50% (335 g/m(2)/h) and HF87.5% (299 g/m(2)/h). On the other hand, RR was higher in HF87.5% (54 bpm) and both HF100% (48 bpm) and HF50% (42 bpm) than Sahiwal (25 bpm) (p<0.01). The RT showed no significant differences as a result of breed (p>0.05) but did change over time. The ST with and without hair were similar, and was higher in HF100% (37.4 degrees C; 38.0 degrees C) and their crossbred HF50% (35.5 degrees C; 35.5 degrees C) and HF87.5% (37.1 degrees C; 37.9 degrees C) than Sahiwal (34.8 degrees C; 34.8 degrees C) (p<0.01). Moreover, the early lactation were higher at HF100% (25 kg) and 87.5% (25 kg) than HF50% (23 kg) which were higher than Sahiwal (18 kg) while the peak period of lactation was higher at HF100% (35 kg) than crossbreds both HF87.5% and HF50% (32 kg) which was higher than Sahiwal (26 kg) (p<0.05). In conclusion, sweating and respiration were the main vehicle for dissipating excess body heat for Sahiwal, HF and crossbreds, respectively. The THI at 76 to 80 were the critical points where the physiological responses to elevated temperature displayed change. PMID- 26580280 TI - Embryo Aggregation Promotes Derivation Efficiency of Outgrowths from Porcine Blastocysts. AB - Porcine embryonic stem cells (pESCs) have become an advantageous experimental tool for developing therapeutic applications and producing transgenic animals. However, despite numerous reports of putative pESC lines, deriving validated pESC lines from embryos produced in vitro remains difficult. Here, we report that embryo aggregation was useful for deriving pESCs from in vitro-produced embryos. Blastocysts derived from embryo aggregation formed a larger number of colonies and maintained cell culture stability. Our derived cell lines demonstrated expression of pluripotent markers (alkaline phosphatase, Oct4, Sox2, and Nanog), an ability to form embryoid bodies, and the capacity to differentiate into the three germ layers. A cytogenetic analysis of these cells revealed that all lines derived from aggregated blastocysts had normal female and male karyotypes. These results demonstrate that embryo aggregation could be a useful technique to improve the efficiency of deriving ESCs from in vitro-fertilized pig embryos, studying early development, and deriving pluripotent ESCs in vitro in other mammals. PMID- 26580281 TI - Effect of Soyabean Isoflavones Exposure on Onset of Puberty, Serum Hormone Concentration and Gene Expression in Hypothalamus, Pituitary Gland and Ovary of Female Bama Miniature Pigs. AB - This study was to investigate the effect of soyabean isoflavones (SIF) on onset of puberty, serum hormone concentration, and gene expression in hypothalamus, pituitary and ovary of female Bama miniature pigs. Fifty five, 35-days old pigs were randomly assigned into 5 treatment groups consisting of 11 pigs per treatment. Results showed that dietary supplementation of varying dosage (0, 250, 500, and 1,250 mg/kg) of SIF induced puberty delay of the pigs with the age of puberty of pigs fed basal diet supplemented with 1,250 mg/kg SIF was significantly higher (p<0.05) compared to control. Supplementation of SIF or estradiol valerate (EV) reduced (p<0.05) serum gonadotrophin releasing hormone and luteinizing hormone concentration, but increased follicle-stimulating hormone concentration in pigs at 4 months of age. The expression of KiSS-1 metastasis suppressor (KISS1), steroidogenic acute regulatory protein (StAR) and 3-beta hydroxysteroid dehydrogenase/delta-5-delta-4 isomerase (3beta-HSD) was reduced (p<0.01) in SIF-supplemented groups. Expression of gonadotropin-releasing hormone receptor in the pituitary of miniature pigs was reduced (p<0.05) compared to the control when exposed to 250, 1,250 mg/kg SIF and EV. Pigs on 250 mg/kg SIF and EV also showed reduced (p<0.05) expression of cytochrome P450 19A1 compared to the control. Our results indicated that dietary supplementation of SIF induced puberty delay, which may be due to down-regulation of key genes that play vital roles in the synthesis of steroid hormones. PMID- 26580283 TI - Effect of Feeding a Mixed Microbial Culture Fortified with Trace Minerals on the Performance and Carcass Characteristics of Late-fattening Hanwoo Steers: A Field Study. AB - This study was conducted to determine the effects of feeding a trace minerals fortified microbial culture (TMC) on the performance and carcass characteristics of late-fattening Hanwoo steers. A mixture of microbes (0.6% [v/w] of Enterobacter sp., Bacillus sp., Lactobacillus sp., and Saccharomyces sp.) was cultured with 99% feedstuff for ensiling and 0.4% trace minerals (zinc, selenium, copper, and cobalt). Sixteen late-fattening steers (mean age, 21.8 months) were allocated to two diets: a control diet (concentrate mix and rice straw) and a treated diet (control diet+3.3% TMC). At a mean age of 31.1 months, all the steers were slaughtered. The addition of TMC to the diet did not affect the average daily weight gain of the late fattening steers, compared with that of control steers. Moreover, consuming the TMC-supplemented diet did not affect cold carcass weight, yield traits such as back fat thickness, longissimus muscle area, yield index or yield grade, or quality traits such as meat color, fat color, texture, maturity, marbling score, or quality grade. However, consumption of a TMC-supplemented diet increased the concentrations of zinc, selenium, and sulfur (p<0.05) in the longissimus muscle. With respect to amino acids, animals consuming TMC showed increased (p<0.05) concentrations of lysine, leucine, and valine among essential amino acids and a decreased (p<0.05) concentration of proline among non-essential amino acids. In conclusion, the consumption of a TMC supplemented diet during the late-fattening period elevated the concentrations of certain trace minerals and essential amino acids in the longissimus muscle, without any deleterious effects on performance and other carcass characteristics of Hanwoo steers. PMID- 26580282 TI - Effect of Lipid Sources with Different Fatty Acid Profiles on Intake, Nutrient Digestion and Ruminal Fermentation of Feedlot Nellore Steers. AB - The present study was conducted to determine the effect of lipid sources with different fatty acid profiles on nutrient digestion and ruminal fermentation. Ten rumen and duodenal fistulated Nellore steers (268 body weight+/-27 kg) were distributed in a duplicated 5*5 Latin square. Dietary treatments were as follows: without fat (WF), palm oil (PO), linseed oil (LO), protected fat (PF; Lactoplus), and whole soybeans (WS). The roughage feed was corn silage (600 g/kg on a dry matter [DM] basis) plus concentrate (400 g/kg on a DM basis). The higher intake of DM and organic matter (OM) (p<0.001) was found in animals on the diet with PF and WF (around 4.38 and 4.20 kg/d, respectively). Treatments with PO and LO decreased by around 10% the total digestibility of DM and OM (p<0.05). The addition of LO decreased by around 22.3% the neutral detergent fiber digestibility (p = 0.047) compared with other diets. The higher microbial protein synthesis was found in animals on the diet with LO and WS (33 g N/kg OM apparently digested in the rumen; p = 0.040). The highest C18:0 and linolenic acid intakes occurred in animals fed LO (p<0.001), and the highest intake of oleic (p = 0.002) and C16 acids (p = 0.022) occurred with the diets with LO and PF. Diet with PF decreased biohydrogenation extent (p = 0.05) of C18:1 n9,c, C18:2 n6,c, and total unsaturated fatty acids (UFA; around 20%, 7%, and 13%, respectively). The diet with PF and WF increased the concentration of NH3-N (p<0.001); however, the diet did not change volatile fatty acids (p>0.05), such as the molar percentage of acetate, propionate, butyrate and the acetate:propionate ratio. Treatments PO, LO and with WS decreased by around 50% the concentration of protozoa (p<0.001). Diets with some type of protection (PF and WS) decreased the effects of lipid on ruminal fermentation and presented similar outflow of benefit UFA as LO. PMID- 26580284 TI - Effects of Supplemental Mannanoligosaccharides on Growth Performance, Faecal Characteristics and Health in Dairy Calves. AB - Twenty Holstein calves were used to investigate the effects of mannanoligosaccharides (MOS) supplementation in the whole milk on growth performance, faecal score, faecal pH, selected faecal bacterial populations and health during the preweaning period. Healthy calves selected by clinical examination were allocated to one of the two groups (control [CG] and experimental [EG]) at 5 days old. Each group consisted of 5 male and 5 female calves. Each calf in EG was supplemented with 7 g/d of a MOS product (Celmanax) from 5 days to 56 days of age. MOS supplement was mixed with the whole milk once in the morning and administered to the calves in EG via nipple bottle, whereas the calves in CG were fed the whole milk without MOS. Calves were weaned at 56 days of age. The final body weight, average daily weight gain (ADG) and average daily feed intake (ADFI) were statistically similar (p>0.05) but were higher by 3.70%, 6.66%, and 10.97%, respectively, in MOS than in control calves. Feed efficiency (ADG/ADFI) was also similar in two calves group. While faecal scores did not differ on day 5, 7, 14, 21, 28, 42, 49, and 56 between groups, EG had a higher faecal score (p = 0.05) than CG on day 35. Faecal concentration of Lactobacillus was lower (p<0.05) in EG compared with CG. No differences (p>0.05) in faecal concentrations of Bifidobacterium, Clostridium perfringens, and Escherichia coli were found between groups. Although there were no significant differences (p>0.05) in the incidence of diarrhoea, treatment days for diarrhoea and the costs associated with diarrhoea treatments between groups, collectively, the observed reductions in treatment days and the cost of diarrhoea treatments accompanying increases in final body weight, ADG and ADFI for EG may indicate potential benefit of MOS in treatment of diarrhoea. PMID- 26580285 TI - The Effect of Yerba Mate (Ilex Paraguariensis) Supplementation on Nutrient Degradability in Dairy Cows: An In sacco and In vitro Study. AB - This study was carried out to investigate the effects of Yerba Mate (YM) supplementation on nutrients' degradation, in vitro dry matter disappearance, gas production and rumen ammonia concentration. Three rumen-fistulated Holstein Friesian cows were used for the in situ incubations and provided rumen liquor for in vitro incubations. The inclusion of YM in a control diet (pasture+pellets) affected some in sacco degradation parameters. YM supplementation decreased the effective degradability and degradation rate of pasture crude protein (CP), and it seems to slow down the degradation of pasture neutral detergent fiber. A significant increase of degradation of pasture acid detergent fiber (ADF) was detected after YM inclusion in the control diet. YM supplementation reduced in vitro gas production of pasture and ammonia concentration of pellets. The addition of YM in ruminant diet could decrease ammonia production and increase protein availability for productive purposes. The moderate presence of tannins in YM could have affected the degradation kinetics of pasture CP and ADF and the ammonia production of pellets. PMID- 26580286 TI - Dietary Protein Sources Affect Internal Quality of Raw and Cooked Shell Eggs under Refrigerated Conditions. AB - This study was conducted to evaluate the effects of various protein sources (soybean meal, SBM; cottonseed protein, CSP; double-zero rapeseed meal, DRM) on the internal quality of refrigerated eggs. A total of 360 laying hens (32 wk of age) were randomly allotted to six treatment groups (five replicates per treatment) and fed diets containing SBM, CSP, or DRM individually or in combination with equal crude protein content (SBM-CSP, SBM-DRM, and CSP-DRM) as the protein ingredient(s). A 6*3 factorial arrangement was employed with dietary types and storage time (0 d, 2 wk, and 4 wk) as the main effects. After 12 wk of diet feeding, a total of 270 eggs were collected for egg quality determination. The egg Haugh unit (HU) in the CSP, SBM-DRM, and DRM groups were significantly lower than those in the SBM and SBM-CSP groups. The hardness and springiness of the cooked yolk in the CSP group were significantly higher than those in the other treatment groups. A lower HU, lower yolk index and higher albumen pH were observed in the DRM group compared to the SBM and SBM-CSP groups when the eggs were stored to 4 wk, and the HU was improved in the CSP-DRM group compared to the DRM group (p<0.05). Higher yolk hardness was observed in the CSP group compared to the other groups during storage (p<0.05), but the hardness of the cooked yolk in the SBM-CSP and CSP-DRM groups showed no difference in comparison to the SBM group. In conclusion, CSP may ameliorate the negative effects of DRM on the HU of refrigerated eggs, and SBM or DRM may alleviate the adverse effects of CSP on yolk hardness. PMID- 26580287 TI - Monitoring of Chicken RNA Integrity as a Function of Prolonged Postmortem Duration. AB - Gene expression profiling has offered new insights into postmortem molecular changes associated with meat quality. To acquire reliable transcript quantification, high quality RNA is required. The objective of this study was to analyze integrity of RNA isolated from chicken skeletal muscle (pectoralis major) and its capability of serving as the template in quantitative real-time polymerase chain reaction (qPCR) as a function of postmortem intervals representing the end-points of evisceration, carcass chilling and aging stages in chicken abattoirs. Chicken breast muscle was dissected from the carcasses (n = 6) immediately after evisceration, and one-third of each sample was instantly snap frozen and labeled as 20 min postmortem. The remaining muscle was stored on ice until the next rounds of sample collection (1.5 h and 6 h postmortem). The delayed postmortem duration did not significantly affect A260/A280 and A260/A230 (p>=0.05), suggesting no altered purity of total RNA. Apart from a slight decrease in the 28s:18s ribosomal RNA ratio in 1.5 h samples (p<0.05), the value was not statistically different between 20 min and 6 h samples (p>=0.05), indicating intact total RNA up to 6 h. Abundance of reference genes encoding beta actin (ACTB), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), hypoxanthine guanine phosphoribosyltransferase (HPRT), peptidylprolylisomerase A (PPIA) and TATA box-binding protein (TBP) as well as meat-quality associated genes (insulin like growth factor 1 (IGF1), pyruvate dehydrogenase kinase isozyme 4 (PDK4), and peroxisome proliferator-activated receptor delta (PPARD) were investigated using qPCR. Transcript abundances of ACTB, GAPDH, HPRT, and PPIA were significantly different among all postmortem time points (p<0.05). Transcript levels of PDK4 and PPARD were significantly reduced in the 6 h samples (p<0.05). The findings suggest an adverse effect of a prolonged postmortem duration on reliability of transcript quantification in chicken skeletal muscle. For the best RNA quality, chicken skeletal muscle should be immediately collected after evisceration or within 20 min postmortem, and rapidly preserved by deep freezing. PMID- 26580288 TI - Heterophil Phagocytic Activity Stimulated by Lactobacillus salivarius L61 and L55 Supplementation in Broilers with Salmonella Infection. AB - Newborn chicks are susceptible to Salmonella enterica serovar Enteritidis (SE). The objective of this study was to evaluate the effect of Lactobacillus probiotic isolated from chicken feces on heterophil phagocytosis in broiler chicks. A total of 150 newborn broiler chicks were divided into 5 groups (30 chicks per group) as follows: group 1 (normal control), given feed and water only, group 2 (positive control) given feed, water and SE infection, group 3 (L61 treated) given feed, water, SE infection followed by Lactobacillus salivarius L61 treatment, group 4 (L55 treated) given feed, water, SE infection followed by L. salivarius L55 treatment, and group 5 given feed, water, SE infection followed by L. salivarius L61 + L55 combination treatment. After SE infection, L. salivarius treatment lasted for 7 days. The results showed that L. salivarius L61 and L. salivarius L55 treatment, either alone or combination of both, increased the survival rate after SE infection, and upregulated heterophil phagocytosis and phagocytic index (PI). Conversely, chick groups treated with Lactobacillus showed lower SE recovery rate from cecal tonsils than that of the positive control group. The PI values of the chicken group with SE infection, followed by the combination of L. salivarius L61 and L. salivarius L55 were the highest as compared to either positive control or normal control group. Two Lactobacillus strains supplementation group showed significantly (p<0.05) higher PI value at 48 h than 24 h after treatment. PMID- 26580289 TI - Effect of Suckling Systems on Serum Oxytocin and Cortisol Concentrations and Behavior to a Novel Object in Beef Calves. AB - We investigated differences between effects of natural- and bucket-suckling methods on basal serum oxytocin (OT) and cortisol concentrations, and the effect of OT concentration on affiliative and investigative behavior of calves to a novel object. Ten Japanese Black calves, balanced with birth order, were allocated evenly to natural-suckling (NS) and bucket suckling (BS) groups. Blood samples were collected at the ages of 1 and 2 months (1 week after weaning) calves, and serum OT and cortisol concentrations were measured using enzyme linked immunosorbent assay and enzymeimmunoassay tests, respectively. Each calf at the age of 2 months (2 weeks after weaning) was released into an open-field with a calf decoy, and its investigative and affiliative behaviors were recorded for 20 minutes. In 1-month-old calves, the basal serum OT concentration (25.5+/ 4.9 [mean+/-standard deviation, pg/mL]) of NS was significantly higher than that of BS (16.9+/-6.7) (p<0.05), whereas the basal cortisol concentration (5.8+/-2.5 [mean+/-standard deviation, ng/mL]) of NS was significantly lower than that in BS (10.0+/-2.8) (p<0.05). Additionally, a negative correlation was noted between serum OT and cortisol concentrations in 1-month-old calves (p = 0.06). Further, the higher serum OT concentration the calves had at 1 month old, the more investigative the calves were at 2 months old but not affiliative in the open field with a calf decoy. Thus, we concluded that the natural suckling method from a dam elevates the basal serum OT concentration in calves, and high serum OT concentrations induce investigative behavior and attenuate cortisol concentrations. PMID- 26580290 TI - Spin-orbit coupling at surfaces and 2D materials. AB - Spin-orbit interaction gives rise to a splitting of surface states via the Rashba effect, and in topological insulators it leads to the existence of topological surface states. The resulting k(//) momentum separation between states with the opposite spin underlies a wide range of new phenomena at surfaces and interfaces, such as spin transfer, spin accumulation, spin-to-charge current conversion, which are interesting for fundamental science and may become the basis for a breakthrough in the spintronic technology. The present review summarizes recent theoretical and experimental efforts to reveal the microscopic structure and mechanisms of spin-orbit driven phenomena with the focus on angle and spin resolved photoemission and scanning tunneling microscopy. PMID- 26580291 TI - Molecular Structure of Cyclopropyl (Isocyanato) Silane: A Combined Microwave Spectral and Theoretical Study. AB - The molecular equilibrium structures of two conformers (cis and gauche) of C3H5 SiH2-NCO have been deduced by a combination of microwave (MW) spectra at natural abundance including data from (13)C and (29,30)Si isotopomers and ab initio calculations. The MW rotational constants (RCs) for the most abundant isotopes are cis: A = 4216.3617(64), B = 1225.76654(91), and C = 1037.31468(77) MHz and gauche: A = 4955.55(79), B = 1094.9276(81), and C = 942.7031(80) MHz. The symmetric quartic centrifugal distortion constants have been evaluated for the cis conformer, using the I(r) representation for CS symmetry. Only partial substitution structures (PSSs) could be derived from the spectra after inclusion of the above isotopic combinations at each center. Using the PSSs, the full structures were determined by ab initio calculation of the equilibrium structures using coupled-cluster singles and doubles with selected triples configuration calculations (CCSD(T)); the two conformers have an energy difference of 228 cm( 1) (cis lower than gauche). The similarity of the calculated and MW RC results confirms the identities of the two compounds. The more interesting cis conformer has bond lengths C2-Si3, 1.9072(73), C2-C9 1.464(22), and C9-C10 1.4944(33) A and angles Si3-C2-C10 119.4(12) degrees and C9-C2-C10 57.1(12) degrees , with similar results for the gauche conformer. The Si3N4C5 angle is wide in the cis conformer (145 degrees ) and nearly linear in the gauche conformer (179 degrees ). New physical insights into the bonding of cis conformers of this type have led the identification of an attractive force between the relatively crowded cyclopropyl and isocyanato groups in the cis conformation. This is demonstrated by three methods: Comparing electronic charges (both AIMALL and Mulliken analyses) in the pair of conformers shows a relative shift of density between these groups in the cis compound. Comparison of the highest occupied molecular orbitals (HOMOs) shows major mixing of density, exemplified by HOMO-1 in these structural units for the cis conformer but which is absent for the gauche conformer. Finally, the nearly linear isocyanate moiety (and the molecular dipole moment) of the cis conformer points closely toward the connected C atom of the cyclopropyl ring, while the gauche conformer dipole moment is significantly different in direction and points toward the midpoint of the C2Si3 bond. Both the HCSiN torsional and Si-N?C bending surfaces connecting these conformers were explored at the Moller-Plesset second-order perturbation theory level (MP2), which led to the exclusion of other conformers. The bending surface shows a very high amount of quartic potential function. PMID- 26580292 TI - Key roles of carbon solubility in single-walled carbon nanotube nucleation and growth. AB - Elucidating the roles played by carbon solubility in catalyst nanoparticles is required to better understand the growth mechanisms of single-walled carbon nanotubes (SWNTs). Here, we highlight that controlling the level of dissolved carbon is of key importance to enable nucleation and growth. We first performed tight binding based atomistic computer simulations to study carbon incorporation in metal nanoparticles with low solubilities. For such metals, carbon incorporation strongly depends on their structures (face centered cubic or icosahedral), leading to different amounts of carbon close to the nanoparticle surface. Following this idea, we then show experimentally that Au nanoparticles effectively catalyze SWNT growth when in a face centered cubic structure, and fail to do so when icosahedral. Both approaches emphasize that the presence of subsurface carbon in the nanoparticles is necessary to enable the cap lift-off, making the nucleation of SWNTs possible. PMID- 26580293 TI - Cerium oxide as a promoter for the electro-oxidation reaction of ethanol: in situ XAFS characterization of the Pt nanoparticles supported on CeO2 nanoparticles and nanorods. AB - In this study we probe the electrocatalytic activity of Pt nanoparticles supported on ceria nanoparticles (NPs) and nanorods (NRs) in the ethanol oxidation reaction (EOR) in alkaline media. The goal of this study was to relate morphology, support structure and composition to the EOR catalytic activity by using in situ X-ray absorption fine structure (XAFS) studies. Cyclic voltammetry experiments showed that both ceria supported catalysts (NP vs. NR) had similar peak current densities at fast scan rates, however at slow scan rates, the ceria NR catalyst showed superior catalytic activity. In situ XAFS studies in KOH showed that both ceria supported catalysts had more electron density in their d band (with the ceria NR having more electron density overall) than ceria - free Pt/Vulcan standard. However, in an ethanol solution the ceria NR catalyst had the least electron density. We propose that this change is due to the increased charge transfer efficiency between the ceria nanorod support and platinum. In the KOH solution, the increased electron density makes the platinum less electrophilic and hinders Pt-OH bond formation. In the EtOH solution, platinum's increased nucleophilicity facilitates the bond formation between Pt and the electron deficient carbon in ethanol which in turn withdraws the electron density from platinum and increases the white line intensity as observed in the XAS measurements. PMID- 26580294 TI - Research highlights: challenges in the characterization, storage, and isolation of natural organic matter. AB - Dissolved organic matter (DOM) is a critical component of natural waters, providing an important nutrient source for the microbial community, binding and interacting with metals and pollutants, and serving as a major reservoir of carbon in the global carbon cycle. Differences in organic material origin as well as biotic and abiotic transformation processes produce DOM of varying composition. These highly complex mixtures are difficult to characterize due to the diversity of compounds found in DOM. This Highlight examines three recent publications that study the methods used to characterize DOM and how storage and handling of DOM samples may affect its composition. Collectively, these publications underscore the challenges that researchers face when working with natural organic matter and offer important considerations for natural organic matter handling and analysis. PMID- 26580295 TI - The Optic Canal Size Is Associated With the Severity of Papilledema and Poor Visual Function in Idiopathic Intracranial Hypertension. AB - BACKGROUND: To determine whether the size of the bony optic canal is associated with the severity of papilledema and poor visual function in idiopathic intracranial hypertension (IIH). METHODS: We performed a retrospective review of definite patients with IIH with requisite brain magnetic resonance imaging allowing for optic canal measurement. Clinical characteristics and automated (Humphrey) visual field results were reviewed; papilledema was graded according to the modified Frisen scale. Cross-sectional area of the optic canals was measured independently by 2 readers and averaged for each canal. Logistic regression modeling was applied. RESULTS: Sixty-nine patients with IIH were included (mean age: 33; 91% women; 65% black). Controlling for age, sex, body mass index, race, and cerebrospinal fluid (CSF) opening pressure, each mm increase in canal size was associated with a 0.50 dB reduction in Humphrey visual field mean deviation (P = 0.006); this was likely mediated by the increased odds of Grade 4-5 papilledema or optic atrophy in patients with larger canals (odds ratio: 1.30 [95% CI: 1.10-1.55; P = 0.003] for Grade 4-5 papilledema or atrophy vs grade <4 papilledema per mm increase in canal size). CONCLUSIONS: Poor visual function and severe papilledema or optic atrophy were associated with a larger optic canal. Potential mechanisms include alteration of local CSF flow or bony remodeling at the optic canals. PMID- 26580296 TI - Head-locking durability of fixed and variable angle locking screws under repetitive loading. AB - Polyaxial locking screws are increasingly applied in fracture fixation. To investigate the durability of the head-locking mechanism, the removal torque of variable angle (VA) and fixed angle (FA) stainless steel and titanium locking screws was investigated without and after a cyclic loading test. Stainless steel (St) and titanium (Ti) 2.4 mm orthogonally inserted FA screws and 2.4 mm VA screws inserted in different inclinations (0 degrees -15 degrees ) (n = 6 per group) were locked at 0.8 Nm. Removal torque was determined without (W) and after (A) cyclic loading (sinusoidal load, 5 Hz, constant amplitude of 25 N, up to 10'000 cycles, or failure). Significant differences in-between the groups were detected by Student's t-test (p < 0.05). Except VA Ti in 0deg and FA, all groups exhibited a drop in removal torque below the insertion torque without and after cyclic testing. The removal torque was (St: FA W:0.81 Nm +/- 0.04 A:0.72Nm +/- 0.04; VA0deg W:0.73 Nm +/- 0.04 A:0.65 Nm +/- 0.05; VA15deg W:0.51 Nm +/- 0.05 A:0.50 Nm +/- 0.08; Ti: FA W:0.82 Nm +/- 0.03 A:0.70 Nm +/- 0.04; VA0deg W:0.80 Nm +/- 0.02 A:0.72 Nm +/- 0.05; VA15deg W:0.55 Nm +/- 0.03 A:0.54 Nm +/- 0.06). In all groups, the removal torque after cyclic testing did not drop below 16% of the removal torque without cyclic testing. No head loosening was observed after cyclic testing. Stainless steel and titanium 2.4 mm fixed and variable angle locking screws provide a stable and lasting head-locking mechanism. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:949-952, 2016. PMID- 26580297 TI - Ground state of bilayer halpha-silica: mechanical and electronic properties. AB - The family of two-dimensional (2D) crystals was recently joined by silica, one of the most abundant resources on earth. So far two different polymorphs of this material, namely a tetrahedra-shaped monolayer and a fully saturated bilayer structure, have been synthesized on various metal substrates and their fascinating properties enable 2D silica to hold promise in nanoelectronic device applications. In this paper a new ground state of bilayer-AAr-stacking halpha silica-has been discovered by first principles calculations. The new structure is featured with a formation of Si-Si bonds between all sp(3) hybridized SiO3 triangular pyramids, lying respectively in different silica layers, with an intrinsic rotational angle of about 12.5 degrees along the out-of-plane Si-Si bond. Due to the doubled number of Si-Si bonds in the new structure, the system energy is lowered by nearly three times more than that reported recently in literature (0.8 eV) (Ozcelik et al 2014 Phys. Rev. Lett. 112 246803), when compared with the single layer halpha-silica. A mechanical property investigation shows that the AAr-stacking bilayer halpha-silica possesses high in-plane stiffness and a negative Poisson's ratio, which stems from the intrinsic rotational angle of the SiO3 triangular pyramids. Strikingly, the negative Poisson's ratio evolves into positive at a critical tensile strain epsilon ~ 1.2%. Such negative-to-positive evolvement is associated with the adaptation of the rotational angle to the applied strain and the structure transition into the nearby valley of the energy landscape. The detailed transition process has been thoroughly analyzed. The electronic properties of the new ground state are also calculated, along with their response to the external strain. Our new ground state structure introduces a new member to the family of 2D bilayer silica materials and is expected to facilitate experimental studies identifying the related structures and exploring further physical and chemical properties of nanoscale systems. PMID- 26580298 TI - English Language Learners' Nonword Repetition Performance: The Influence of Age, L2 Vocabulary Size, Length of L2 Exposure, and L1 Phonology. AB - PURPOSE: This study examined individual differences in English language learners' (ELLs) nonword repetition (NWR) accuracy, focusing on the effects of age, English vocabulary size, length of exposure to English, and first-language (L1) phonology. METHOD: Participants were 75 typically developing ELLs (mean age 5;8 [years;months]) whose exposure to English began on average at age 4;4. Children spoke either a Chinese language or South Asian language as an L1 and were given English standardized tests for NWR and receptive vocabulary. RESULTS: Although the majority of ELLs scored within or above the monolingual normal range (71%), 29% scored below. Mixed logistic regression modeling revealed that a larger English vocabulary, longer English exposure, South Asian L1, and older age all had significant and positive effects on ELLs' NWR accuracy. Error analyses revealed the following L1 effect: onset consonants were produced more accurately than codas overall, but this effect was stronger for the Chinese group whose L1s have a more limited coda inventory compared with English. CONCLUSION: ELLs' NWR performance is influenced by a number of factors. Consideration of these factors is important in deciding whether monolingual norm referencing is appropriate for ELL children. PMID- 26580299 TI - Robust NMR water signal suppression for demanding analytical applications. AB - We describe the design and application of robust, general-purpose water signal suppression pulse sequences well suited to chemometric work. Such pulse sequences need to deal well with pulse mis-calibrations, radiation damping, chemical exchange, and the presence of sample inhomogeneities, as well as with significant variations in sample characteristics such as pH, ionic strength, relaxation characteristics and molecular weight. Of course, such pulse sequences should produce un-distorted lineshapes and baselines and work well both under automation and in the hands of non-experts. As an example, one such pulse sequences, Robust 5, will be presented. This new pulse sequence meets those criteria and is able to reduce a 50 M proteo water signal down to a 0.9 mM level, without fine tuning, and under automation, and it is therefore well suited to the most demanding of analytical applications. PMID- 26580300 TI - Safety and efficacy of a second-generation coronary sirolimus-eluting stent with biodegradable polymers in daily clinical practice: a 12-month follow-up of the ALEX registry. AB - BACKGROUND: Second-generation drug-eluting stents (DESs) have shown higher safety and efficacy compared with first-generation DESs. This effect was achieved by improving biocompatibility using an interalia cobalt-chromium construction, thinner stent struts and biodegradable polymers. OBJECTIVES: To assess clinical and angiographic outcomes of patients receiving a novel second-generation cobalt chromium sirolimus-eluting stent. MATERIALS AND METHODS: A total of 424 consecutive patients who received an Alex stent were enrolled in the registry from January to December 2012. The primary outcome measure was the occurrence of 12-month major cardiac adverse events, defined as cases of death, nonfatal myocardial infarction and target lesion revascularization. Quantitative coronary angiography for 240 randomly selected patients was performed by an independent Corelab. RESULTS: The primary endpoint occurred in 31 of 424 patients (7.3%). The rates of death, nonfatal myocardial infarction and target lesion revascularization were 3.3, 2.6 and 3.5%, respectively. According to the definition established by the Academic Research Foundation, definitive and probable stent thrombosis (ST) occurred in 1.6% (7/424) of patients, including six cases of early ST and one case of late ST. The acute device success rate was 98.5%. CONCLUSION: The ALEX Registry provides evidence for the safety and effectiveness of the study device in a relevant population. Quantitative analysis showed a satisfactory performance of the study device for complex coronary lesions. The 12-month rates of major cardiac adverse event and ST were similar to those of other second-generation DES registries. PMID- 26580301 TI - Altered expression of lysosomal hydrolase, acid alpha-glucosidase, gene in coronary artery disease. AB - BACKGROUND: Coronary artery disease (CAD) is a common complex disease caused by atherosclerosis. Autophagy is a cellular degradation process that delivers long lived macromolecules and dysfunctional organelles into lysosomes for digestion. Autophagy regulates lipid and cholesterol metabolism. We have previously shown that expression of autophagic and lysosomal genes is altered in CAD patients. In this study, we investigated gene expression of a lysosomal hydrolase, acid alpha glucosidase (GAA), in CAD patients and controls. METHODS: GAA gene expression was examined in large cohorts of CAD patients (n=248) and ethnically matched controls (n=208). GAA enzymatic activity, protein levels, and transcript levels were determined and compared between CAD patients and controls. RESULTS: GAA activities in CAD patients were significantly elevated (P<0.05) compared with controls. Consistently, GAA transcription levels were also significantly increased in CAD patients (P<0.01). Multivariate logistic regression analyses (GAA transcript level, hypertension, diabetes, and smoking) revealed that GAA transcript levels were strongly associated with CAD (odds ratio 5.93, 95% confidence interval 2.98-11.78, P=3.89*10(-7)). GAA protein levels were insignificantly increased in CAD patients (P>0.05), likely due to assay insensitivity. CONCLUSION: Compared with controls, GAA gene expression levels in CAD patients were significantly increased, suggesting that GAA may be involved in the CAD development. PMID- 26580302 TI - Measuring the Quality of Care for Patients With Traumatic Brain Injury. PMID- 26580303 TI - Distribution of single-nucleotide variants on protein-protein interaction sites and its relationship with minor allele frequency. AB - Recent advances in DNA sequencing techniques have identified rare single nucleotide variants with less than 1% minor allele frequency. Despite the growing interest and physiological importance of rare variants in genome sciences, less attention has been paid to the allele frequency of variants in protein sciences. To elucidate the characteristics of genetic variants on protein interaction sites, from the viewpoints of the allele frequency and the structural position of variants, we mapped about 20,000 human SNVs onto protein complexes. We found that variants are less abundant in protein interfaces, and specifically the core regions of interfaces. The tendency to "avoid" the interfacial core is stronger among common variants than rare variants. As amino acid substitutions, the trend of mutating amino acids among rare variants is consistent in different interfacial regions, reflecting the fact that rare variants result from random mutations in DNA sequences, whereas amino acid changes of common variants vary between the interfacial core and rim regions, possibly due to functional constraints on proteins. This study illustrated how the allele frequency of variants relates to the protein structural regions and the functional sites in general and will lead to deeper understanding of the potential deleteriousness of rare variants at the structural level. Exceptional cases of the observed trends will shed light on the limitations of structural approaches to evaluate the functional impacts of variants. PMID- 26580304 TI - A Real-World Study of Switching From Allopurinol to Febuxostat in a Health Plan Database. AB - OBJECTIVE: The objective of this study was to assess the real-world comparative effectiveness of continuing on allopurinol versus switching to febuxostat. METHODS: In a retrospective claims data study of enrollees in health plans affiliated with Optum, we evaluated patients from February 1, 2009, to May 31, 2012, with a gout diagnosis, a pharmacy claim for allopurinol or febuxostat, and at least 1 serum uric acid (SUA) result available during the follow-up period. Univariate and multivariable-adjusted analyses (controlling for patient demographics and clinical factors) assessed the likelihood of SUA lowering and achievement of target SUA of less than 6.0 mg/dL or less than 5.0 mg/dL in allopurinol continuers versus febuxostat switchers. RESULTS: The final study population included 748 subjects who switched to febuxostat from allopurinol and 4795 continuing users of allopurinol. The most common doses of allopurinol were 300 mg/d or less in 95% of allopurinol continuers and 93% of febuxostat switchers (prior to switching); the most common dose of febuxostat was 40 mg/d, in 77% of febuxostat switchers (after switching). Compared with allopurinol continuers, febuxostat switchers had greater (1) mean preindex SUA, 8.0 mg/dL versus 6.6 mg/dL (P < 0.001); (2) likelihood of postindex SUA of less than 6.0 mg/dL, 62.2% versus 58.7% (P = 0.072); (3) likelihood of postindex SUA of less than 5.0 mg/dL, 38.9% versus 29.6% (P < 0.001); and (4) decrease in SUA, 1.8 (SD, 2.2) mg/dL versus 0.4 (SD, 1.7) mg/dL (P < 0.001). In multivariable-adjusted analyses, compared with allopurinol continuers, febuxostat switchers had significantly higher likelihood of achieving SUA of less than 6.0 mg/dL (40% higher) and SUA of less than 5.0 mg/dL (83% higher). CONCLUSIONS: In this "real-world" setting, many patients with gout not surprisingly were not treated with maximum permitted doses of allopurinol. Patients switched to febuxostat were more likely to achieve target SUA levels than those who continued on generally stable doses of allopurinol. PMID- 26580305 TI - Magnetically Actuated Wormlike Nanomotors for Controlled Cargo Release. AB - Magnetically actuated nanomotor, which swims under externally applied magnetic fields, shows great promise for controlled cargo delivery and release in biological fluids. Here, we report an on-demand release of 6-carboxyfluoresceins (FAM), a green fluorescein, from G-quadruplex DNA functionalized magnetically actuated wormlike nanomotors by applying an alternating magnetic field. This field-triggered FAM releasing process can be easily controlled by multiple parameters such as magnetic field, frequency, and exposure time. In addition, the experimental results and the theoretical simulation demonstrate that both a thermal and a nonthermal mechanism are involved in the cargo releasing process. PMID- 26580306 TI - Prediction of periapical status and tooth extraction. AB - AIM: To describe and analyse risk factors associated with prediction of periapical status, assessed using the full-scale Periapical Index (PAI) supplemented with extraction as outcome variable. METHODOLOGY: In 1997-1998, 616 randomly selected individuals from Aarhus County, Denmark, underwent a full-mouth radiographic survey. All 616 were re-invited in 2003-2004 and in 2008-2009, when 473 and 363 persons, respectively, consented and attended a new radiographic examination. The study population of the present investigation included 330 persons who had participated in all three examinations, and 143 persons who had participated in the first and second examination only. Using the full-mouth radiographic survey and interview information, the following variables were assessed: on person level - age, gender, smoking habits and number of teeth; on tooth level - presence of tooth, PAI, root filling, caries, marginal bone level, restoration, jaw and tooth group. The outcome variable was the 5 score PAI supplemented with extraction. The observation period was 5 years. Ordered logistic regression analyses were carried out for root filled and non-root filled teeth separately. The Regional Committee of Ethics approved the study. RESULTS: For both root filled teeth and non-root filled teeth, the baseline PAI score was the most important predictive factor of periapical status and extraction (P < 0.0001). Non-root filled teeth had in general a better outcome than root filled teeth. However, in non-root filled teeth, several other factors had a significant influence on the outcome, and the risk estimates were larger and showed a more pronounced variation between the different categories of predictive factors. For root filled teeth few variables, other than baseline PAI score, influenced the outcome significantly. CONCLUSION: The full-scale PAI was the strongest predictive factor of periapical status or extraction even when adjusted for additional factors, such as marginal bone level. A high baseline PAI score increased the risk for an impaired outcome. The large difference in risk estimates for non-root filled compared to root filled teeth documents the importance of separate analyses/studies for identification and quantification of predictive factors associated with periapical status and extraction of a tooth. PMID- 26580307 TI - Efficacy of Bright Light Treatment, Fluoxetine, and the Combination in Patients With Nonseasonal Major Depressive Disorder: A Randomized Clinical Trial. AB - IMPORTANCE: Bright light therapy is an evidence-based treatment for seasonal depression, but there is limited evidence for its efficacy in nonseasonal major depressive disorder (MDD). OBJECTIVE: To determine the efficacy of light treatment, in monotherapy and in combination with fluoxetine hydrochloride, compared with a sham-placebo condition in adults with nonseasonal MDD. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo- and sham controlled, 8-week trial in adults (aged 19-60 years) with MDD of at least moderate severity in outpatient psychiatry clinics in academic medical centers. Data were collected from October 7, 2009, to March 11, 2014. Analysis was based on modified intent to treat (randomized patients with >=1 follow-up rating). INTERVENTIONS: Patients were randomly assigned to (1) light monotherapy (active 10,000-lux fluorescent white light box for 30 min/d in the early morning plus placebo pill); (2) antidepressant monotherapy (inactive negative ion generator for 30 min/d plus fluoxetine hydrochloride, 20 mg/d); (3) combination light and antidepressant; or (4) placebo (inactive negative ion generator plus placebo pill). MAIN OUTCOMES AND MEASURES: Change score on the Montgomery-Asberg Depression Rating Scale (MADRS) from baseline to the 8-week end point. Secondary outcomes included response (>=50% reduction in MADRS score) and remission (MADRS score <=10 at end point). RESULTS: A total of 122 patients were randomized (light monotherapy, 32; fluoxetine monotherapy, 31; combination therapy, 29; placebo, 30). The mean (SD) changes in MADRS score for the light, fluoxetine, combination, and placebo groups were 13.4 (7.5), 8.8 (9.9), 16.9 (9.2), and 6.5 (9.6), respectively. The combination (effect size [d] = 1.11; 95% CI, 0.54 to 1.64) and light monotherapy (d = 0.80; 95% CI, 0.28 to 1.31) were significantly superior to placebo in the MADRS change score, but fluoxetine monotherapy (d = 0.24; 95% CI, 0.27 to 0.74) was not superior to placebo. For the respective placebo, fluoxetine, light, and combination groups at the end point, response was achieved by 10 (33.3%), 9 (29.0%), 16 (50.0%), and 22 (75.9%) and remission was achieved by 9 (30.0%), 6 (19.4%), 14 (43.8%), and 17 (58.6%). Combination therapy was superior to placebo in MADRS response (beta = 1.70; df = 1; P = .005) and remission (beta = 1.33; df = 1; P = .02), with numbers needed to treat of 2.4 (95% CI, 1.6 to 5.8) and 3.5 (95% CI, 2.0 to 29.9), respectively. All treatments were generally well tolerated, with few significant differences in treatment emergent adverse events. CONCLUSIONS AND RELEVANCE: Bright light treatment, both as monotherapy and in combination with fluoxetine, was efficacious and well tolerated in the treatment of adults with nonseasonal MDD. The combination treatment had the most consistent effects. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00958204. PMID- 26580308 TI - The Impact of Carvacrol on Ammonia and Biogenic Amine Production by Common Foodborne Pathogens. AB - The impact of carvacrol at different levels (0.1%, 0.5%, and 1%) on ammonia (AMN) and biogenic amines (BAs) production by 8 common foodborne pathogens (FBPs) (Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Enterococcus faecalis, Pseudomonas aeruginosa, Listeria monocytogenes, Aeromonas hydrophila, and Salmonella Paratyphi A) was studied using a rapid high-performance liquid chromatography method. Significant differences among bacteria (P < 0.05) in AMN and BA production were observed using a tyrosine decarboxylase broth. Tyramine, dopamine, agmatine, spermine, and putrescine were the main amines produced by the bacteria. Tyramine production by P. aeruginosa was the highest (967 mg/L), whereas K. pneumoniae was the poorest tyramine producer (6.42 mg/L). AMN and BA production varied significantly depending on carvacrol levels and the specific bacterial strains. Tyramine production for all bacterial strains was significantly suppressed by addition of carvacrol at levels of 0.5% and 1%, but not 0.1%. Consequently, the effect of carvacrol on BA and AMN formation by FBP was dependent on bacterial strain as well as carvacrol level. PMID- 26580309 TI - Practical session assessments in human anatomy: Weightings and performance. AB - Assessment weighting within a given module can be a motivating factor for students when deciding on their commitment level and time given to study a specific topic. In this study, an analysis of assessment performances of second year anatomy students was performed over four years to determine if (1) students performed better when a higher weighting was given to a set of practical session assessments and (2) whether an improved performance in the practical session assessments had a carry-over effect on other assessment tasks within that anatomy module and/or other anatomy modules that follow. Results showed that increasing the weighting of practical session assessments improved the average mark in that assessment and also improved the percentage of students passing that assessment. Further, it significantly improved performance in the written end-semester examination within the same module and had a carry-over effect on the anatomy module taught in the next teaching period, as students performed better in subsequent practical session assessments as well as subsequent end-semester examinations. It was concluded that the weighting of assessments had significant influences on a student's performance in that, and subsequent, assessments. It is postulated that practical session assessments, designed to develop deep learning skills in anatomy, improved efficacy in student performance in assessments undertaken in that and subsequent anatomy modules when the weighting of these assessments was greater. These deep learning skills were also transferable to other methods of assessing anatomy. Anat Sci Educ 9: 330-336. (c) 2015 American Association of Anatomists. PMID- 26580310 TI - Extracted tooth roots used for lateral alveolar ridge augmentation: a proof-of concept study. AB - OBJECTIVES: To assess the efficacy of tooth roots used as autografts for lateral ridge augmentation and two-stage early osseointegration of titanium implants. MATERIAL & METHODS: The maxillary premolars were randomly assigned to either endodontic therapy (PM-E) or were left untreated (PM-C). Retromolar cortical autogenous bone (AB) blocks served as controls. PM-E/PM-C and AB were used for ridge augmentation at chronic-type defects in both lower quadrants (n = 8 foxhounds). At 12 weeks, titanium implants were inserted and left to heal for another 3 weeks. Histological analyses considered crestal ridge width (CW); augmented area (AA) and bone-to-implant contact (BIC). RESULTS: Both PM and AB grafts (exposures: AB = 3; PM-C = 4; PM-E = 7) were gradually involved in the bone remodelling process and associated with a replacement resorption. Median CW (PM-C: 2.70 versus AB: 3.30 mm; PM-E: 2.96 versus AB: 3.35 mm), AA (PM-C: 7.55 versus AB: 8.56 mm(2) ; PM-E: 11.20 versus AB: 6.60 mm(2) ) and BIC (PM-C: 36.96 mm versus AB: 64.10%; PM-E: 50.79 versus AB: 32.53%) values were comparable in both PM and AB groups (p > 0.05, respectively). CONCLUSIONS: Extracted tooth roots revealed a structural and biological potential to serve as an alternative autograft to autogenous bone. A higher exposure rate may be expected when using endodontically treated teeth. PMID- 26580311 TI - Determination of sperm concentration using flow cytometry with simultaneous analysis of sperm plasma membrane integrity in zebrafish Danio rerio. AB - Control of sperm concentration is required to ensure consistent and reproducible results for cryopreservation and in vitro fertilization protocols. Determination of sperm concentration is traditionally performed with a counting chamber (e.g., hemocytometer), or more recently with a spectrophotometer. For small-sized biomedical model fishes, the availability of sperm sample is limited to microliters, so it is desirable to develop fast and accurate approaches for concentration determination that also minimize sample use. In this study, a new approach was developed for sperm concentration determination using a flow cytometer (Accuri C6, BD Biosciences, San Jose, CA) with simultaneous measurement of sperm membrane integrity after fluorescent staining with SYBR((r)) -14 and propidium iodide (PI) in sperm from Zebrafish Danio rerio. The goal was to develop a protocol for simultaneous determination of sperm quality and quantity by flow cytometry. The objectives were to (1) determine the effects of sample volume (250 and 500 ul) and analysis volume (10 and 50 ul) on the accuracy of particle counting using standard volumetric validation beads; (2) identify the effective range of sperm concentrations that flow cytometry can measure; (3) test the precision and reproducibility of the sperm concentration measurements; and (4) verify the flow cytometry approach by comparison with measurement with a hemocytometer and a microspectrophotometer. Sample volumes of 250 and 500 ul and analysis volumes of 10 and 50 ul did not affect bead count with the factory-set flow rates of "medium" or "fast," and the precision and accuracy was retained across a concentration range of 1 * 10(3) -1 * 10(7) cells/ml. The approach developed in this study was comparable to traditional methodologies such as hemocytometer or microspectrophotometer. This study provides an efficient, accurate, and rapid method for determination of sperm concentration using flow cytometry while providing simultaneous assessment of sperm membrane integrity. Such approaches can reduce the time needed for quantity assessment and maximize the use of valuable sperm samples. (c) 2015 International Society for Advancement of Cytometry. PMID- 26580312 TI - The Skin Safety Model: Reconceptualizing Skin Vulnerability in Older Patients. AB - PURPOSE: To develop a unique skin safety model (SSM) that offers a new and unified perspective on the diverse yet interconnected antecedents that contribute to a spectrum of potential iatrogenic skin injuries in older hospitalized adults. ORGANIZING CONSTRUCT: Discussion paper. METHODS: A literature search of electronic databases was conducted for published articles written in English addressing skin integrity and iatrogenic skin injury in elderly hospital patients between 1960 and 2014. FINDINGS: There is a multiplicity of literature outlining the etiology, prevention, and management of specific iatrogenic skin injuries. Complex and interrelated factors contribute to iatrogenic skin injury in the older adult, including multiple comorbidities, factors influencing healthcare delivery, and acute situational stressors. A range of injuries can result when these factors are complicated by skin irritants, pressure, shear, or friction; however, despite skin injuries sharing multiple antecedents, no unified overarching skin safety conceptual model has been published. CONCLUSIONS: The SSM presented in this article offers a new, unified framework that encompasses the spectrum of antecedents to skin vulnerability as well as the spectrum of iatrogenic skin injuries that may be sustained by older acute care patients. Current skin integrity frameworks address prevention and management of specific skin injuries. In contrast, the SSM recognizes the complex interplay of patient and system factors that may result in a range of iatrogenic skin injuries. Skin safety is reconceptualized into a single model that has the potential for application at the individual patient level, as well as healthcare systems and governance levels. CLINICAL RELEVANCE: Skin safety is concerned with keeping skin safe from any iatrogenic skin injury, and remains an ongoing challenge for healthcare providers. A conceptual framework that encompasses all of the factors that may contribute to a range of iatrogenic skin injuries is essential, and guides the clinician in maintaining skin integrity in the vulnerable older patient. PMID- 26580313 TI - Antibiotic exposure and the risk for depression, anxiety, or psychosis: a nested case-control study. AB - OBJECTIVE: Changes in the microbiota (dysbiosis) were suggested to increase the risk of several psychiatric conditions through neurologic, metabolic, and immunologic pathways. Our aim was to assess whether exposure to specific antibiotic groups increases the risk for depression, anxiety, or psychosis. METHOD: We conducted 3 nested case-control studies during the years 1995-2013 using a large population-based medical record database from the United Kingdom. The study included 202,974 patients with depression, 14,570 with anxiety, and 2,690 with psychosis and 803,961, 57,862, and 10,644 matched controls, respectively. Cases were defined as individuals aged 15-65 years with any medical Read code for depression, anxiety, or psychosis. Subjects with diagnosis-specific psychotropic prescriptions > 90 days before index date were excluded. For every case, 4 controls were selected using incidence density sampling, matching on age, sex, practice site, calendar time, and duration of follow-up before index date. The primary exposure of interest was therapy with 1 of 7 antibiotic classes > 1 year before index date. Odds ratios (ORs) and 95% CIs were calculated for the association between each psychiatric disorder and exposure to individual classes of antibiotics using conditional logistic regression analysis. The risk was adjusted for obesity, smoking history, alcohol consumption, socioeconomic status, and number of infectious events before diagnosis. RESULTS: Treatment with a single antibiotic course was associated with higher risk for depression with all antibiotic groups, with an adjusted OR (AOR) of 1.23 for penicillins (95% CI, 1.18-1.29) and 1.25 (95% CI, 1.15-1.35) for quinolones. The risk increased with recurrent antibiotic exposures to 1.40 (95% CI, 1.35-1.46) and 1.56 (95% CI, 1.46 1.65) for 2-5 and > 5 courses of penicillin, respectively. Similar association was observed for anxiety and was most prominent with exposures to penicillins and sulfonamides, with an AOR of 1.17 (95% CI, 1.01-1.36) for a single course of penicillin and 1.44 (95% CI, 1.18-1.75) for > 5 courses. There was no change in risk for psychosis with any antibiotic group. There was a mild increase in the risk of depression and anxiety with a single course of antifungals; however, there was no increase in risk with repeated exposures. CONCLUSION: Recurrent antibiotic exposure is associated with increased risk for depression and anxiety but not for psychosis. PMID- 26580314 TI - Pro-region engineering for improved yeast display and secretion of brain derived neurotrophic factor. AB - Brain derived neurotrophic factor (BDNF) is a promising therapeutic candidate for a variety of neurological diseases. However, it is difficult to produce as a recombinant protein. In its native mammalian context, BDNF is first produced as a pro-protein with subsequent proteolytic removal of the pro-region to yield mature BDNF protein. Therefore, in an attempt to improve yeast as a host for heterologous BDNF production, the BDNF pro-region was first evaluated for its effects on BDNF surface display and secretion. Addition of the wild-type pro region to yeast BDNF production constructs improved BDNF folding both as a surface-displayed and secreted protein in terms of binding its natural receptors TrkB and p75, but titers remained low. Looking to further enhance the chaperone like functions provided by the pro-region, two rounds of directed evolution were performed, yielding mutated pro-regions that further improved the display and secretion properties of BDNF. Subsequent optimization of the protease recognition site was used to control whether the produced protein was in pro- or mature BDNF forms. Taken together, we have demonstrated an effective strategy for improving BDNF compatibility with yeast protein engineering and secretion platforms. PMID- 26580315 TI - STD NMR and molecular modelling insights into interaction of novel mannose-based ligands with DC-SIGN. AB - Study of interaction of mannose-based ligands with receptor DC-SIGN using high resolution NMR in combination with molecular modelling showed that four alpha-d mannoside ligands interact with the binding site predominantly through the mannose moiety. The other two aromatic groups that are bound to alpha-d-mannose through a glycerol linker demonstrate interaction that can be related to their substitution pattern. Ligand with naphthyl and meta-substituted phenyl ring exhibited the most favourable binding characteristics. In addition to the predicted hydrophobic interactions of aromatic moieties our results propose new contacts of substituted phenyl moiety in the more polar area of the flat binding site of DC-SIGN and thus offer new possibilities in further designing of novel, more potent DC-SIGN antagonists. PMID- 26580316 TI - Cyclopropanation/Carboboration Reactions of Enynes with B(C6F5)3. AB - Stoichiometric reaction of B(C6F5)3 with 1,6-enynes is shown to proceed via initial cyclopropanation and formal 1,1-carboboration. Depending on the substitution on the alkene moiety, subsequent ring-opening of the cyclopropane affords either cyclopentane or cyclohexane derivatives in which the C6F5 and B(C6F5)2 adopt a 1,4-positioning. Mechanistically, this transformation involves pi-activation of the alkyne moiety, which triggers cyclopropanation, followed by carboboration. Both the cyclopropanation and subsequent ring-opening are shown to be stereospecific. Both cyclopropanation and 1,4-carboborated products were employed as Lewis acid components in frustrated Lewis pair activation of H2 and CO2. PMID- 26580317 TI - 7-Chloro-5-(furan-3-yl)-3-methyl-4H-benzo[e][1,2,4]thiadiazine 1,1-Dioxide as Positive Allosteric Modulator of alpha-Amino-3-hydroxy-5-methyl-4 isoxazolepropionic Acid (AMPA) Receptor. The End of the Unsaturated-Inactive Paradigm? AB - 5-Arylbenzothiadiazine type compounds acting as positive allosteric modulators of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-PAMs) have received particular attention in the past decade for their nootropic activity and lack of the excitotoxic side effects of direct agonists. Recently, our research group has published the synthesis and biological activity of 7 chloro-5-(3-furanyl)-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide (1), one of the most active benzothiadiazine-derived AMPA-PAMs in vitro to date. However, 1 exists as two stereolabile enantiomers, which rapidly racemize in physiological conditions, and only one isomer is responsible for the pharmacological activity. In the present work, experiments carried out with rat liver microsomes show that 1 is converted by hepatic cytochrome P450 to the corresponding unsaturated derivative 2 and to the corresponding pharmacologically inactive benzenesulfonamide 3. Surprisingly, patch-clamp experiments reveal that 2 displays an activity comparable to that of the parent compound. Molecular modeling studies were performed to rationalize these results. Furthermore, mice cerebral microdialysis studies suggest that 2 is able to cross the blood-brain barrier and increases acetylcholine and serotonin levels in the hippocampus. The experimental data disclose that the achiral hepatic metabolite 2 possesses the same pharmacological activity of its parent compound 1 but with an enhanced chemical and stereochemical stability, as well as an improved pharmacokinetic profile compared with 1. PMID- 26580318 TI - Copper-Promoted Tandem Reaction of Azobenzenes with Allyl Bromides via N?N Bond Cleavage for the Regioselective Synthesis of Quinolines. AB - A copper-promoted tandem reaction of a variety of azobenzenes and allyl bromides via N?N bond cleavage to regioselectively construct quinoline derivatives has been developed. The azobenzenes act as not only construction units but also an oxidant for quinoline formation. PMID- 26580319 TI - Brain disorders across the lifespan. PMID- 26580320 TI - Brain and other nervous system disorders across the lifespan - global challenges and opportunities. AB - This is an exciting time for scientific discovery that aims to reduce the frequency and impact of neurological, mental health and substance-use disorders. As it became increasingly clear that low- and middle-income countries have a disproportionate share of these disorders, and that many of the problems are best addressed by indigenous researchers who can seek context-sensitive solutions, the US National Institutes of Health and other research funders began to invest more in low- and middle-income country-focused research and research capacity-building to confront this significant public health challenge. In an effort to identify existing information, knowledge gaps, and emerging research and research capacity building opportunities that are particularly relevant to low- and middle-income countries, in February 2014 the Center for Global Health Studies at the National Institutes of Health Fogarty International Center held a workshop to explore these issues with scientific experts from low- and middle-income countries and the United States. This evolved into the preparation of the Reviews in this supplement, which is designed to highlight opportunities and challenges associated with topical areas in brain-disorders research over the coming decade. This Introduction highlights some of the over-arching and intersecting priorities for addressing causes, prevention, treatment and rehabilitation as well as best practices to promote overall nervous system health. We review some brain disorders in low- and middle-income countries, while the Reviews describe relevant issues and the epidemiology of particular conditions in greater depth. PMID- 26580321 TI - Reducing neurodevelopmental disorders and disability through research and interventions. AB - We define neurodevelopment as the dynamic inter-relationship between genetic, brain, cognitive, emotional and behavioural processes across the developmental lifespan. Significant and persistent disruption to this dynamic process through environmental and genetic risk can lead to neurodevelopmental disorders and disability. Research designed to ameliorate neurodevelopmental disorders in low- and middle-income countries, as well as globally, will benefit enormously from the ongoing advances in understanding their genetic and epigenetic causes, as modified by environment and culture. We provide examples of advances in the prevention and treatment of, and the rehabilitation of those with, neurodevelopment disorders in low- and middle-income countries, along with opportunities for further strategic research initiatives. Our examples are not the only possibilities for strategic research, but they illustrate problems that, when solved, could have a considerable impact in low-resource settings. In each instance, research in low- and middle-income countries led to innovations in identification, surveillance and treatment of a neurodevelopmental disorder. These innovations have also been integrated with genotypic mapping of neurodevelopmental disorders, forming important preventative and rehabilitative interventions with the potential for high impact. These advances will ultimately allow us to understand how epigenetic influences shape neurodevelopmental risk and resilience over time and across populations. Clearly, the most strategic areas of research opportunity involve cross-disciplinary integration at the intersection between the environment, brain or behaviour neurodevelopment, and genetic and epigenetic science. At these junctions a robust integrative cross disciplinary scientific approach is catalysing the creation of technologies and interventions for old problems. Such approaches will enable us to achieve and sustain the United Nations moral and legal mandate for child health and full development as a basic global human right. PMID- 26580322 TI - A focus on adolescence to reduce neurological, mental health and substance-use disability. AB - Globally, there is a crucial need to prioritize research directed at reducing neurological, mental health and substance-use disorders in adolescence, which is a pivotal age for the development of self-control and regulation. In adolescence, behaviour optimally advances towards adaptive long-term goals and suppresses conflicting maladaptive short-lived urges to balance impulsivity, exploration and defiance, while establishing effective societal participation. When self-control fails to develop, violence, injury and neurological, mental health and substance use disorders can result, further challenging the development of self-regulation and impeding the transition to a productive adulthood. Adolescent outcomes, positive and negative, arise from both a life-course perspective and within a socioecological framework. Little is known about the emergence of self-control and regulation in adolescents in low- and middle-income countries where enormous environmental threats are more common (for example, poverty, war, local conflicts, sex trafficking and slavery, early marriage and/or pregnancy, and the absence of adequate access to education) than in high-income countries and can threaten optimal neurodevelopment. Research must develop or adapt appropriate assessments of adolescent ability and disability, social inclusion and exclusion, normative development, and neurological, mental health and substance-use disorders. Socioecological challenges in low- and middle-income countries require innovative strategies to prevent mental health, neurological and substance-use disorders and develop effective interventions for adolescents at risk, especially those already living with these disorders and the consequent disability. PMID- 26580323 TI - Nervous system disorders across the life course in resource-limited settings. AB - The resiliency of the adult nervous system is markedly affected by the environment and the circumstances during infant and child development. As such, adults in resource-limited settings who may have experienced early deprivation are particularly vulnerable to subsequent neurological disorders. Adult populations in countries with relatively recent advances in economic development may still have a higher susceptibility to neurological illness or injury that is reflective of the socioeconomic environment that was present during that population's infancy and childhood. Brain and peripheral nervous system research conducted over the past decade in resource-limited settings has led to an impressive and growing body of knowledge that informs our understanding of neurological function and dysfunction, independent of geography. Neurological conditions feature prominently in the burgeoning epidemic of non-communicable diseases facing low- and middle-income countries. Neurological research in these countries is needed to address this burden of disease. Although the burden of more prevalent and severe neurological disease poses public health and clinical challenges in settings with limited neurological expertise, the same factors, along with genetic heterogeneity and the relative absence of ingrained clinical care practices, offer circumstances well-suited for the conduct of crucial future research that is globally relevant. PMID- 26580324 TI - Global research challenges and opportunities for mental health and substance-use disorders. AB - The research agenda for global mental health and substance-use disorders has been largely driven by the exigencies of high health burdens and associated unmet needs in low- and middle-income countries. Implementation research focused on context-driven adaptation and innovation in service delivery has begun to yield promising results that are improving the quality of, and access to, care in low resource settings. Importantly, these efforts have also resulted in the development and augmentation of local, in-country research capacities. Given the complex interplay between mental health and substance-use disorders, medical conditions, and biological and social vulnerabilities, a revitalized research agenda must encompass both local variation and global commonalities in the impact of adversities, multi-morbidities and their consequences across the life course. We recommend priorities for research - as well as guiding principles for context driven, intersectoral, integrative approaches - that will advance knowledge and answer the most pressing local and global mental health questions and needs, while also promoting a health equity agenda and extending the quality, reach and impact of scientific enquiry. PMID- 26580325 TI - Global research priorities for infections that affect the nervous system. AB - Infections that cause significant nervous system morbidity globally include viral (for example, HIV, rabies, Japanese encephalitis virus, herpes simplex virus, varicella zoster virus, cytomegalovirus, dengue virus and chikungunya virus), bacterial (for example, tuberculosis, syphilis, bacterial meningitis and sepsis), fungal (for example, cryptococcal meningitis) and parasitic (for example, malaria, neurocysticercosis, neuroschistosomiasis and soil-transmitted helminths) infections. The neurological, cognitive, behavioural or mental health problems caused by the infections probably affect millions of children and adults in low- and middle-income countries. However, precise estimates of morbidity are lacking for most infections, and there is limited information on the pathogenesis of nervous system injury in these infections. Key research priorities for infection related nervous system morbidity include accurate estimates of disease burden; point-of-care assays for infection diagnosis; improved tools for the assessment of neurological, cognitive and mental health impairment; vaccines and other interventions for preventing infections; improved understanding of the pathogenesis of nervous system disease in these infections; more effective methods to treat and prevent nervous system sequelae; operations research to implement known effective interventions; and improved methods of rehabilitation. Research in these areas, accompanied by efforts to implement promising technologies and therapies, could substantially decrease the morbidity and mortality of infections affecting the nervous system in low- and middle-income countries. PMID- 26580326 TI - A global perspective on the influence of environmental exposures on the nervous system. AB - Economic transitions in the era of globalization warrant a fresh look at the neurological risks associated with environmental change. These are driven by industrial expansion, transfer and mobility of goods, climate change and population growth. In these contexts, risk of infectious and non-infectious diseases are shared across geographical boundaries. In low- and middle-income countries, the risk of environmentally mediated brain disease is augmented several fold by lack of infrastructure, poor health and safety regulations, and limited measures for environmental protection. Neurological disorders may occur as a result of direct exposure to chemical and/or non-chemical stressors, including but not limited to, ultrafine particulate matters. Individual susceptibilities to exposure-related diseases are modified by genetic, epigenetic and metagenomic factors. The existence of several uniquely exposed populations, including those in the areas surrounding the Niger Delta or north western Amazon oil operations; those working in poorly regulated environments, such as artisanal mining industries; or those, mostly in sub-Saharan Africa, relying on cassava as a staple food, offers invaluable opportunities to advance the current understanding of brain responses to environmental challenges. Increased awareness of the brain disorders that are prevalent in low- and middle-income countries and investments in capacity for further environmental health-related research are positive steps towards improving human health. PMID- 26580327 TI - Global neurotrauma research challenges and opportunities. AB - Traumatic injury to the brain or spinal cord is one of the most serious public health problems worldwide. The devastating impact of 'trauma', a term used to define the global burden of disease related to all injuries, is the leading cause of loss of human potential across the globe, especially in low- and middle-income countries. Enormous challenges must be met to significantly advance neurotrauma research around the world, specifically in underserved and austere environments. Neurotrauma research at the global level needs to be contextualized: different regions have their own needs and obstacles. Interventions that are not considered a priority in some regions could be a priority for others. The introduction of inexpensive and innovative interventions, including mobile technologies and e health applications, focused on policy management improvement are essential and should be applicable to the needs of the local environment. The simple transfer of a clinical question from resource-rich environments to those of low- and middle-income countries that lack sophisticated interventions may not be the best strategy to address these countries' needs. Emphasis on promoting the design of true 'ecological' studies that include the evaluation of human factors in relation to the process of care, analytical descriptions of health systems, and how leadership is best applied in medical communities and society as a whole will become crucial. PMID- 26580329 TI - Building global capacity for brain and nervous system disorders research. AB - The global burden of neurological, neuropsychiatric, substance-use and neurodevelopmental disorders in low- and middle-income countries is worsened, not only by the lack of targeted research funding, but also by the lack of relevant in-country research capacity. Such capacity, from the individual to the national level, is necessary to address the problems within a local context. As for many health issues in these countries, the ability to address this burden requires development of research infrastructure and a trained cadre of clinicians and scientists who can ask the right questions, and conduct, manage, apply and disseminate research for practice and policy. This Review describes some of the evolving issues, knowledge and programmes focused on building research capacity in low- and middle-income countries in general and for brain and nervous system disorders in particular. PMID- 26580330 TI - Formation of Amides from Imines via Cyanide-Mediated Metal-Free Aerobic Oxidation. AB - A new protocol for the direct formation of amides from imines derived from aromatic aldehydes via metal-free aerobic oxidation in the presence of cyanide is described. This protocol was applicable to various aldimines, and the desired amides were obtained in moderate to good yields. Mechanistic studies suggested that this aerobic oxidative amidation might proceed via the addition of cyanide to imines followed by proton transfer from carbon to nitrogen in the original imines, leading to carbanions of alpha-amino nitriles, which undergo subsequent oxidation with molecular oxygen in air to provide the desired amide compounds. PMID- 26580328 TI - Regional research priorities in brain and nervous system disorders. AB - The characteristics of neurological, psychiatric, developmental and substance-use disorders in low- and middle-income countries are unique and the burden that they have will be different from country to country. Many of the differences are explained by the wide variation in population demographics and size, poverty, conflict, culture, land area and quality, and genetics. Neurological, psychiatric, developmental and substance-use disorders that result from, or are worsened by, a lack of adequate nutrition and infectious disease still afflict much of sub-Saharan Africa, although disorders related to increasing longevity, such as stroke, are on the rise. In the Middle East and North Africa, major depressive disorders and post-traumatic stress disorder are a primary concern because of the conflict-ridden environment. Consanguinity is a serious concern that leads to the high prevalence of recessive disorders in the Middle East and North Africa and possibly other regions. The burden of these disorders in Latin American and Asian countries largely surrounds stroke and vascular disease, dementia and lifestyle factors that are influenced by genetics. Although much knowledge has been gained over the past 10 years, the epidemiology of the conditions in low- and middle-income countries still needs more research. Prevention and treatments could be better informed with more longitudinal studies of risk factors. Challenges and opportunities for ameliorating nervous-system disorders can benefit from both local and regional research collaborations. The lack of resources and infrastructure for health-care and related research, both in terms of personnel and equipment, along with the stigma associated with the physical or behavioural manifestations of some disorders have hampered progress in understanding the disease burden and improving brain health. Individual countries, and regions within countries, have specific needs in terms of research priorities. PMID- 26580331 TI - The prevalence and odds of suicidal thoughts, behaviours and deaths among people with painful comorbidities: An updated meta-analysis accounting for publication bias. PMID- 26580332 TI - An Analysis of Surgical Treatment for the Spontaneous Rupture of Hepatocellular Carcinoma. AB - BACKGROUND/AIMS: The prognosis of spontaneous rupture of hepatocellular carcinoma (HCC) remains unclear. We investigated the prognosis of patients with ruptured HCC based on the treatments and prognostic factors associated with long-term survival. METHODS: The prognoses of 64 consecutive patients treated for ruptured HCC from 1986 to 2013 were analyzed according to their methods of treatment. The prognostic factors of 16 surgical patients were identified, and their overall survival (OS) and recurrence rates were compared to 1,157 surgical patients who underwent surgery for non-ruptured HCC. The surgical outcomes were also compared using a propensity score matching method. RESULTS: Surgery was associated with a better OS. Curative resection was the only independent prognostic factor in surgical patients with ruptured HCC (p = 0.040). Although the OS of surgical patients with non-ruptured HCC was found to be significantly better than that of the patients with ruptured HCC, no significant difference in OS was observed after propensity score matching. CONCLUSION: A curative resection should be the objective of treatment, assuming the suitability of the patient's clinical condition. When the liver function reserve and tumor extension of patients with ruptured and non-ruptured HCC are similar, then their surgical outcomes may not be significantly different. PMID- 26580333 TI - A fifteen years old left ventricular pseudoaneurysm. PMID- 26580334 TI - Calcium sensitizers: What have we learned over the last 25 years? AB - The use of inotropes for correcting hemodynamic dysfunction in patients with congestive heart failure has been described over many decades. Drugs such as cardiac glycosides, cathecolamines, phosphodiestherase inhibitors, and calcium sensitizers have been in turn proposed. However, the number of new chemical entities in this therapeutic field has been surprisingly low, and the current selection of drugs is limited. One of the paradigm shifts in the discovery for new inotropes was to focus on 'calcium sensitizers' instead of 'calcium mobilizers'. This was designed to lead to the development of safer inotropes, devoid of the complications that arise due to increased intracellular calcium levels. However, only three such calcium sensitizers have been fully developed over the latest 30 years. Moreover, two of these, levosimendan and pimobendan, have multiple molecular targets and other pharmacologic effects in addition to inotropy, such as peripheral vasodilation. More recently, omecamtiv mecarbil was described, which is believed to have a pure inotropy action that is devoid of pleiotropic effects. When the clinical data of these three calcium sensitizers are compared, it appears that the less pure inotropes have the cutting edge over the purer inotrope, due to additional effects during the treatment of a complex syndrome such as acute congested heart failure. This review aims to answer the question whether calcium sensitization per se is a sufficient strategy for bringing required clinical benefits to patients with heart failure. This review is dedicated to the memory of Heimo Haikala, a true and passionate innovator in this challenging field. PMID- 26580335 TI - Pulmonary vascular remodeling in mitral valve disease: An optical coherence tomography study. PMID- 26580336 TI - Electrocardiographic predictors of coronary microvascular dysfunction in patients with non-obstructive coronary artery disease: Utility of a novel T wave analysis program. AB - BACKGROUND: Coronary microvascular dysfunction (CMD) is linked to adverse cardiovascular events. Definitive diagnosis of CMD requires invasive provocative testing during angiography. We developed and tested a novel computerized T wave analysis tool to identify electrocardiographic signatures of CMD. METHODS: 1552 patients underwent an invasive assessment of coronary microvascular function. Patients with interpretable pre-procedural ECGs were divided into 2 age and sex matched groups (n=261 in each group, 75% female): normal microvascular function, CFR>2.5 (CFR+), and abnormal microvascular function, CFR <= 2.5 (CFR-). ECGs were evaluated using a novel T wave program that quantified subtle changes in T wave morphology. RESULTS: T wave repolarization parameters were significantly different between patients with normal and abnormal microvascular function. The top 3 features in males comprised of T wave area in V6 (CFR+: 10091.4 mV(2) vs. CFR-: 8152.3 mV(2), p<0.05); T1 Y-center of gravity in lead II (CFR+: 17.8 mV vs. CFR-: 22.4, p<0.005) and T Peak-T End in lead II (CFR+: 97.6 msec vs. CFR-: 91.1 msec, p<0.05). These could identify the presence of an abnormal CFR with 74 +/- 0.2% accuracy. In females, the top 3 features were T wave right slope lead V6 (CFR+: -2489.1 mV/msec vs. CFR-: -2352.3 mV/msec, p<0.005); Amplitude in V6 (CFR+: 190.4 mV vs. 172.7 mV, p=0.05) and Y-center of gravity in lead V1 (CFR+: 33.3 vs. CFR-: 40.0, p=0.001). These features could identify the presence of an abnormal CFR with 67 +/- 0.3% accuracy. CONCLUSION: Our data demonstrates that a computer-based repolarization measurement tool may identify electrocardiographic signatures of CMD. PMID- 26580337 TI - Length of hospital stay is shorter in South Asian patients with transient ischemic attack. PMID- 26580338 TI - Predictors of independent walking at hospital discharge in elderly heart failure patients. PMID- 26580339 TI - Incidence and prevalence of pulmonary arterial hypertension in Germany. PMID- 26580340 TI - The Chinese herb extract Wenxin Keli: A promising agent for the management of atrial fibrillation. PMID- 26580341 TI - Stress from myasthenic crisis triggers Takotsubo (broken heart) syndrome. PMID- 26580342 TI - Effects of skiing on cardiorespiratory and metabolic responses in middle-aged subjects with increased cardiovascular risk. PMID- 26580343 TI - Association between peripheral plasma markers and left atrial anatomy in patients with atrial fibrillation. PMID- 26580344 TI - Is hyperuricemia a recognizable biomarker for low risk of stroke in patients with atrial fibrillation? PMID- 26580345 TI - Transcatheter aortic valve implantation in the young. PMID- 26580346 TI - Comparison of surgical repair and percutaneous stent implantation for native coarctation of the aorta in patients >= 15 years of age. PMID- 26580347 TI - Contrast-induced acute kidney injury in patients with non-ST-segment elevation myocardial infarction undergoing early versus delayed invasive strategy. PMID- 26580348 TI - ADMA, subclinical changes and atrial fibrillation in the general population. AB - BACKGROUND: Pathways of oxidative stress, nitric oxide bioavailability and L arginine derivatives are hypothesized to be related to atrial fibrillation (AF). Circulating methylated L-arginine metabolites can be assessed in the general population and may show an association with AF. METHODS: We determined L-arginine and its metabolites asymmetric dimethylarginine (ADMA), L-N(omega) monomethylarginine (NMMA) and symmetric dimethylarginine (SDMA) in the population based Gutenberg Health Study (n=5000), mean age 55 +/- 11 years, 51% men, in association with clinical variables of AF such as electrocardiographic and echocardiographic measures and manifest AF. RESULTS: Individuals with AF (N=161), 71% men, were older, mean age 64.9 +/- 8.3 years. In Bonferroni-corrected multivariable-adjusted regression analyses we observed moderate inverse associations for L-arginine, SDMA, and L-arginine/ADMA ratio with ventricular heart rate, and for L-arginine and L-arginine/ADMA ratio with QTc interval. L arginine was correlated with QRS duration. In echocardiographic analyses, SDMA was related to left atrial diameter and deceleration time, ADMA and NMMA were correlated with left ventricular mass. ADMA (odds ratio [OR] 1.21, 95% confidence interval [CI] 1.11-1-32; p=0.013) and NMMA (OR 1.17, 95% CI 1.09-1.26, p=0.014) were related to prevalent AF. L-arginine/ADMA ratio was inversely associated (OR 0.8, 95% CI 0.71-0.90, p=0.0082). Results were similar after adjustment for creatinine. CONCLUSIONS: In our large, population-based cohort, we observed moderate associations of l-arginine metabolites and intermediate electrocardiographic and echocardiographic variables and AF. Our findings support further investigations to define the role of L-arginine derivatives in AF and their clinical utility. PMID- 26580349 TI - Clinical-pharmacist intervention reduces clinically relevant drug-drug interactions in patients with heart failure: A randomized, double-blind, controlled trial. AB - BACKGROUND: Incidence of drug-drug interactions (DDIs) increases with complexity of treatment and comorbidities, as in heart failure (HF). This randomized, double blind study evaluated the intervention of the pharmacist on prevalence of clinically relevant DDIs (NCT01855165). METHODS: Patients admitted with HF were screened for clinically relevant DDIs, and randomized to control or intervention. All attending physicians received standard advice about pharmacological therapy; those in the intervention group also received alerts about clinically relevant DDIs. Primary endpoint was DDI at discharge and secondary were re-hospitalization or death during follow-up. RESULTS: Of 213 patients, 51 (mean age, 79 +/- 6 years; male, 47%) showed 66 clinically relevant DDIs and were randomized. For intervention (n=26) versus control (n=25), the number of patients with and the number of DDIs were significantly lower at discharge: 8 vs. 18 and 10 vs. 31; p=0.003 and 0.0049, respectively. Over a 6 month follow-up period, 11 control and 9 intervention patients were re-hospitalized or died (p>0.2 for all). No significant differences were seen between control and intervention for patients with eGFR <60 mL/min/1.73 m(2) (78%) for re-hospitalization or death (10 vs. 7; p=0.74). CONCLUSIONS: Pharmacist intervention significantly reduces the number of patients with clinically relevant DDIs, but not clinical endpoints 6 months from discharge. PMID- 26580350 TI - Diagnosis of adventitial cystic disease of the popliteal artery by optical coherence tomography. PMID- 26580351 TI - Atrial fibrillation and heart failure due to reduced versus preserved ejection fraction: A systematic review and meta-analysis of death and adverse outcomes. AB - BACKGROUND: Atrial fibrillation (AF) and heart failure frequently coexist, commonly resulting in serious adverse events. With both conditions increasing in prevalence and justified concerns about treatment efficacy, it is vital to understand how the type of heart failure impacts on prognosis. METHODS: We performed a systematic review of studies examining cardiovascular outcomes in AF patients with heart failure and reduced ejection fraction (AF-HFrEF) compared to those with preserved ejection fraction (AF-HFpEF). The primary outcome was all cause mortality, meta-analyzed using a random-effects model. Prospective registration: PROSPERO-CRD42014007305. RESULTS: Thirteen studies were included in the systematic review (n=54,587) with 10 suitable for meta-analysis, including retrospective/prospective cohorts and sub-group analyses of randomized trials. AF HFrEF was present in 49% and these patients were younger, more often male and with higher NYHA class than AF-HFpEF. Oral anticoagulation use was 55% versus 50% respectively (p<0.001). All-cause mortality was significantly higher in AF-HFrEF; risk ratio (RR) 1.24, 95% CI 1.12-1.36, p<0.001 (n=45,100), with absolute death rates of 24% compared to 18% in AF-HFpEF over 2 years. There were no significant differences in incident stroke (RR 0.85, 95% CI 0.70-1.03, p=0.094; n=33,773) or heart failure hospitalization (RR 1.21, 95% CI 0.96-1.53, p=0.115; n=31,583). The risk of bias was generally low, but heterogeneity was substantial. CONCLUSIONS: All-cause mortality is significantly higher in AF patients with HFrEF compared to HFpEF, although stroke risk and heart failure hospitalization are similar. Further studies are needed to address the prevention of adverse outcomes in all AF patients with heart failure, regardless of ejection fraction. PMID- 26580353 TI - Bilateral coronary obstruction in high-risk transcatheter aortic valve-in-valve implantation: When procedural strategy counts. PMID- 26580352 TI - Predicting ischemic mitral regurgitation in patients with acute ST-elevation myocardial infarction: Does time to reperfusion really matter and what is the role of collateral circulation? AB - BACKGROUND/OBJECTIVES: Ischemic mitral regurgitation (MR) is an adverse prognostic factor. We aimed to assess the role of time delay from symptom onset to reperfusion, and the impact of collateral circulation to incidence of MR in relation to established echocardiographic and clinical risk factors. METHODS: Patients with STEMI presenting within 12 h from symptom onset and treated with primary percutaneous coronary intervention (PPCI) at Hospital of Lithuanian University of Health Sciences were enrolled. Echocardiography was performed after PPCI. Based on MR grade, patients were divided into no significant MR (NMR, grade 0-I MR, N = 102) and ischemic MR (IMR, grade >= 2 MR, N = 71) groups. Well developed collaterals were defined as grade >= 2 by Rentrop classification. Continuous variables were compared by independent samples Student's T-test. Multivariate logistic regression analysis was used to identify independent predictors of ischemic MR. RESULTS: Time to reperfusion, MI localization, TIMI flow before/after PCI was similar between the groups. IMR group patients were elder, more often females and non-smokers, had lower body mass index, higher prevalence of multi-vessel coronary artery disease (CAD), better-developed collateral supply, greater left ventricular end-diastolic diameter index, left atrial index, pulmonary artery systolic pressure and lower ejection fraction. Multivariate logistic regression analysis revealed that ischemic MR is predicted by female gender, well-developed collateral supply, presence of multi-vessel CAD, and lower EF. CONCLUSION: In acute STEMI significant MR is unrelated to ischemic time and is predicted by female gender, lower EF, multi-vessel CAD and well developed collateral supply to the infarct region. PMID- 26580354 TI - To what do psychiatric diagnoses refer? A two-dimensional semantic analysis of diagnostic terms. AB - In somatic medicine, diagnostic terms often refer to the disease processes that are the causes of patients' symptoms. The language used in some clinical textbooks and health information resources suggests that this is also sometimes assumed to be the case with diagnoses in psychiatry. However, this seems to be in tension with the ways in which psychiatric diagnoses are defined in diagnostic manuals, according to which they refer solely to clusters of symptoms. This paper explores how theories of reference in the philosophy of language can help to resolve this tension. After the evaluation of descriptive and causal theories of reference, I put forward a conceptual framework based on two-dimensional semantics that allows the causal analysis of diagnostic terms in psychiatry, while taking seriously their descriptive definitions in diagnostic manuals. While the framework is presented as a solution to a problem regarding the semantics of psychiatric diagnoses, it can also accommodate the analysis of diagnostic terms in other medical disciplines. PMID- 26580355 TI - GEM*: A Molecular Electronic Density-Based Force Field for Molecular Dynamics Simulations. AB - GEM*, a force field that combines Coulomb and Exchange terms calculated with Hermite Gaussians with the polarization, bonded, and modified van der Waals terms from AMOEBA is presented. GEM* is tested on an initial water model fitted at the same level as AMOEBA. The integrals required for the evaluation of the intermolecular Coulomb interactions are efficiently evaluated by means of reciprocal space methods. The GEM* water model is tested by comparing energies and forces for a series of water oligomers and MD simulations. Timings for GEM* compared to AMOEBA are presented and discussed. PMID- 26580356 TI - Multisurface Adiabatic Reactive Molecular Dynamics. AB - Adiabatic reactive molecular dynamics (ARMD) simulation method is a surface crossing algorithm for modeling chemical reactions in classical molecular dynamics simulations using empirical force fields. As the ARMD Hamiltonian is time dependent during crossing, it allows only approximate energy conservation. In the current work, the range of applicability of conventional ARMD is explored, and a new multisurface ARMD (MS-ARMD) method is presented, implemented in CHARMM and applied to the vibrationally induced photodissociation of sulfuric acid (H2SO4) in the gas phase. For this, an accurate global potential energy surface (PES) involving 12 H2SO4 and 4 H2O + SO3 force fields fitted to MP2/6 311G++(2d,2p) reference energies is employed. The MS-ARMD simulations conserve total energy and feature both intramolecular H-transfer reactions and water elimination. An analytical treatment of the dynamics in the crossing region finds that conventional ARMD can approximately conserve total energy for limiting cases. In one of them, the reduced mass of the system is large, which often occurs for simulations of solvated biomolecular systems. On the other hand, MS ARMD is a general approach for modeling chemical reactions including gas-phase, homogeneous, heterogeneous, and enzymatic catalytic reactions while conserving total energy in atomistic simulations. PMID- 26580357 TI - Exploring the Conformational Dynamics of Alanine Dipeptide in Solution Subjected to an External Electric Field: A Nonequilibrium Molecular Dynamics Simulation. AB - In this paper, we investigate the conformational dynamics of alanine dipeptide under an external electric field by nonequilibrium molecular dynamics simulation. We consider the case of a constant and of an oscillatory field. In this context, we propose a procedure to implement the temperature control, which removes the irrelevant thermal effects of the field. For the constant field different time scales are identified in the conformational, dipole moment, and orientational dynamics. Moreover, we prove that the solvent structure only marginally changes when the external field is switched on. In the case of oscillatory field, the conformational changes are shown to be as strong as in the previous case, and nontrivial nonequilibrium circular paths in the conformation space are revealed by calculating the integrated net probability fluxes. PMID- 26580358 TI - Audibilization: Data Analysis by Ear. AB - As molecular dynamics simulations continue to grow in size and complexity, new techniques are needed to rapidly identify regions of data likely to benefit from further analysis. Audibilization, the conversion of data to sound, facilitates this task by taking advantage of the user's innate ability to identify anomalies in patterns of sound. Audibilization also complements visualization of a molecular simulation by allowing the user to easily correlate changes in numerical quantities with changes in the overall structure of the molecular system. Here we present three examples highlighting the utility of audibilization in the analysis of three different molecular simulations. First, we present a simulation of liquid water in which the lengths of the O-H bonds are calculated at each time step and audibilized. Interestingly, we find that anomalies in the pattern of bond vibration are due to intermolecular interactions but do not correlate with the formation of hydrogen bonds. Next, we present a simulation of the rupture of a gold nanowire. Here we audibilize the nanowire potential energy and illustrate that sharp changes in this value coincide with important structural events such as the formation of monatomic chains and dislocations. Finally, we present a simulation of single-stranded DNA passing through a nanogap. Here the bond angle is audibilized and used to illustrate the conformational changes of each base as it passes through the nanogap. This simulation also illustrates the use of more advanced audibilization techniques such as the multiplexing of audibilized signals and the weighting of certain segments of data relative to others. PMID- 26580359 TI - Surface Hopping Dynamics with Correlated Single-Reference Methods: 9H-Adenine as a Case Study. AB - Surface hopping dynamics methods using the coupled cluster to approximated second order (CC2), the algebraic diagrammatic construction scheme to second order (ADC(2)), and the time-dependent density functional theory (TDDFT) were developed and implemented into the program system Newton-X. These procedures are especially well-suited to simulate nonadiabatic processes involving various excited states of the same multiplicity and the dynamics in the first excited state toward an energetic minimum or up to the region where a crossing with the ground state is found. 9H-adenine in the gas phase was selected as the test case. The results showed that dynamics with ADC(2) is very stable, whereas CC2 dynamics fails within 100 fs, because of numerical instabilities present in the case of quasi degenerate excited states. ADC(2) dynamics correctly predicts the ultrafast character of the deactivation process. It predicts that C2-puckered conical intersections should be the preferential pathway for internal conversion for low energy excitation. C6-puckered conical intersection also contributes appreciably to internal conversion, becoming as important as C2-puckered for high-energy excitations. In any case, H-elimination plays only a minor role. TDDFT based on a long-range corrected functional fails to predict the ultrafast deactivation. In the comparison with several other methods previously used for dynamics simulations of adenine, ADC(2) has the best performance, providing the most consistent results so far. PMID- 26580360 TI - Assessing the Reliability of the Dynamics Reconstructed from Metadynamics. AB - Sampling a molecular process characterized by an activation free energy significantly larger than kBT is a well-known challenge in molecular dynamics simulations. In a recent work [Tiwary and Parrinello, Phys. Rev. Lett. 2013, 111, 230602], we have demonstrated that the transition times of activated molecular transformations can be computed from well-tempered metadynamics provided that no bias is deposited in the transition state region and that the set of collective variables chosen to enhance sampling does not display hysteresis. Ensuring though that these two criteria are met may not always be simple. Here we build on the fact that the times of escape from a long-lived metastable state obey Poisson statistics. This allows us to identify quantitative measures of trustworthiness of our calculation. We test our method on a few paradigmatic examples. PMID- 26580361 TI - General Multiobjective Force Field Optimization Framework, with Application to Reactive Force Fields for Silicon Carbide. AB - First-principles-based force fields prepared from large quantum mechanical data sets are now the norm in predictive molecular dynamics simulations for complex chemical processes, as opposed to force fields fitted solely from phenomenological data. In principle, the former allow improved accuracy and transferability over a wider range of molecular compositions, interactions, and environmental conditions unexplored by experiments. That is, assuming they have been optimally prepared from a diverse training set. The trade-off has been force field engines that are functionally complex, with a large number of nonbonded and bonded analytical forms that give rise to rather large parameter search spaces. To address this problem, we have developed GARFfield (genetic algorithm-based reactive force field optimizer method), a hybrid multiobjective Pareto-optimal parameter development scheme based on genetic algorithms, hill-climbing routines and conjugate-gradient minimization. To demonstrate the capabilities of GARFfield we use it to develop two very different force fields: (1) the ReaxFF reactive force field for modeling the adiabatic reactive dynamics of silicon carbide growth from an methyltrichlorosilane precursor and (2) the SiC electron force field with effective core pseudopotentials for modeling nonadiabatic dynamic phenomena with highly excited electronic states. The flexible and open architecture of GARFfield enables efficient and fast parallel optimization of parameters from quantum mechanical data sets for demanding applications like ReaxFF, electronic fast forward (or electron force field), and others including atomistic reactive charge-optimized many-body interatomic potentials, Morse, and coarse-grain force fields. PMID- 26580362 TI - Efficient Calculation of Free Energy Differences Associated with Isotopic Substitution Using Path-Integral Molecular Dynamics. AB - The problem of computing free energy differences due to isotopic substitution in chemical systems is discussed. The shift in the equilibrium properties of a system upon isotopic substitution is a purely quantum mechanical effect that can be quantified using the Feynman path integral approach. In this paper, we explore two developments that lead to a highly efficient path integral scheme. First, we employ a mass switching function inspired by the work of Ceriotti and Markland [ J. Chem. Phys. 2013, 138, 014112] that is based on the inverse square root of the mass and which leads to a perfectly constant free energy derivative with respect to the switching parameter in the harmonic limit. We show that even for anharmonic systems, this scheme allows a single-point thermodynamic integration approach to be used in the construction of free energy differences. In order to improve the efficiency of the calculations even further, however, we derive a set of free energy derivative estimators based on the fourth-order scheme of Takahashi and Imada [ J. Phys. Soc. Jpn. 1984, 53, 3765]. The Takahashi-Imada procedure generates a primitive fourth-order estimator that allows the number of imaginary time slices in the path-integral approach to be reduced substantially. However, as with all primitive estimators, its convergence is plagued by numerical noise. In order to alleviate this problem, we derive a fourth-order virial estimator based on a transferring of the difference between second- and fourth-order primitive estimators, which remains relatively constant as a function of the number of configuration samples, to the second-order virial estimator. We show that this new estimator converges as smoothly as the second order virial estimator but requires significantly fewer imaginary time points. PMID- 26580363 TI - Static Dielectric Constant from Simulations Revisited: Fluctuations or External Field? AB - We compare two methods-the fluctuation formula and the application of an external electric field-for determining the static relative permittivity (static dielectric constant) from molecular simulations in the Ewald dielectric boundary conditions. We express both the systematic and statistical errors in terms of a dimensionless saturation (dielectric polarization reduced by its maximum) and show that both methods possess the same efficiency. Saturation in the fluctuation route depends on the number of particles and the permittivity of the surrounding medium, where a value of infinity (tinfoil) for the latter is usually reasonable but not necessarily optimum. Saturation in the external field route is easily controlled by the field intensity; hence, we develop an extrapolation scheme and apply it to several water models, specifically, nonpolarizable (SPC/E, TIP4P/2005, NE6) and polarizable (POL3, DC97, BK3). In addition, we discuss the Clausius-Mossotti approximation for the optical permittivity; this quantity is needed in the fluctuation formula for polarizable models. PMID- 26580364 TI - Force-Field Development from Electronic Structure Calculations with Periodic Boundary Conditions: Applications to Gaseous Adsorption and Transport in Metal Organic Frameworks. AB - We present a systematic and efficient methodology to derive accurate (nonpolarizable) force fields from periodic density functional theory (DFT) calculations for use in classical molecular simulations. The methodology requires reduced computation cost compared with other conventional ways. Moreover, the whole process is performed self-consistently in a fully periodic system. The force fields derived by using this methodology nicely predict the CO2 and H2O adsorption isotherms inside Mg-MOF-74, and is transferable to Zn-MOF-74; by replacing the Mg-CO2 interactions with the corresponding Zn-CO2 interactions, we obtain an accurate prediction of the corresponding isotherm. We have applied this methodology to address the effect of water on the separation of flue gases in these materials. In general, the mixture isotherms of CO2 and H2O calculated with these derived force fields show a significant reduction in CO2 uptake with the existence of trace amounts of water vapor. The effect of water, however, is found to be quantitatively different between Mg- and Zn-MOF-74. PMID- 26580365 TI - Mechanism of Spin-Orbit Effects on the Ligand NMR Chemical Shift in Transition Metal Complexes: Linking NMR to EPR. AB - Relativistic effects play an essential role in understanding the nuclear magnetic resonance (NMR) chemical shifts in heavy-atom compounds. Particularly interesting from the chemical point of view are the relativistic effects due to heavy atom (HA) on the NMR chemical shifts of the nearby light atoms (LA), referred to as the HALA effects. The effect of Spin-Orbit (SO) interaction originating from HA on the nuclear magnetic shielding at a neighboring LA, sigma(SO), is explored here in detail for a series of d(6) complexes of iridium. Unlike the previous findings, the trends in sigma(SO) observed in this study can be fully explained neither in terms of the s-character of the HA-LA bonding nor by trends in the energy differences between occupied and virtual molecular orbitals (MOs). Rather, the sigma(SO) contribution to the total NMR shielding is found to be modulated by the d-orbital participation of the heavy atom (Ir) in the occupied and virtual spin-orbit active MOs, i.e., those which contribute significantly to the sigma(SO). The correlation between the d-character of sigma(SO)-active MOs and the size of the corresponding SO contribution to the nuclear magnetic shielding constant at LA is so tight that the magnitude of sigma(SO) can be predicted in a given class of compounds on the basis of d-orbital character of relevant MO with relative error smaller than 15%. This correspondence is supported by an analogy between the perturbation theory expressions for the spin-orbit induced NMR sigma tensor and those for the EPR g-tensor as well as the A-tensor of the ligand. This correlation is demonstrated on a series of d(5) complexes of iridium. Thus, known qualitative relationships between electronic structure and EPR parameters can be newly applied to reproduce, predict, and understand the SO-induced contributions to NMR shielding constants of light atoms in heavy-atom compounds. PMID- 26580366 TI - Solv-ccCA: Implicit Solvation and the Correlation Consistent Composite Approach for the Determination of pKa. AB - Direct theoretical methods are advantageous for the prediction of pKa, as relative methods rely upon the experimental values of reference acid molecules that can limit application of the method to well-characterized systems. Here, a direct route is introduced, which incorporates the SMD universal solvation model1 within the correlation consistent Composite Approach (ccCA). This Solv-ccCA methodology has been used for the prediction of theoretical pKa values for nitrogen-containing species to within a mean absolute deviation (MAD) of 1.0 pKa unit from experimental values by utilizing a thermodynamic cycle that combines gas-phase and solution-phase calculations. Several density functionals, including B3LYP, B97-1, B97-2, B98, BMK, M06, and M06-2X, were also evaluated for use with SMD and for comparison to Solv-ccCA. PMID- 26580367 TI - How Small Can a Catenane Be? AB - Catenanes are playing an increasingly important role in supramolecular chemistry. In attempting to identify the minimum number of carbon atoms in a viable catenane, the B3LYP, BP86, M06-2X, MM3, and MM4 methods were applied to study representative [2]catenane models, which consist of two mechanically interlocked saturated n-cycloalkanes ([CnH2n]2). The structures, energy variations, and electron density differences vary nearly monotonically from n = 18 to 11. For example, the B3LYP/DZP++ dissociation energies [CnH2n]2 -> 2CnH2n are 101, 121, 159, 191, 222, 252, 290, and 323 kcal/mol from n = 18 to 11, respectively. However, there is much variation among the energetic predictions with the B3LYP, BP86, M06-2X, MM3, and MM4 methods. The distances of the longest C-C single bond in each catenane are 1.593 (n = 18), 1.604 (n = 17), 1.631 (n = 16), 1.640 (n = 15), 1.667 (n = 14), 1.669 (n = 13), 1.680 (n = 12), and 1.689 A (n = 11). These results display something of a shoulder in the vicinity of n = 14. This may suggest that [C15H30]2 is the smallest catenane that will resist fragmentation under specified laboratory conditions. PMID- 26580368 TI - Generalized Energy-Based Fragmentation CCSD(T)-F12a Method and Application to the Relative Energies of Water Clusters (H2O)20. AB - The generalized energy-based fragmentation (GEBF) approach has been implemented for the explicitly correlated F12a of coupled-cluster with the noniterative triples corrections [CCSD(T)-F12a] method for medium- and large-sized systems. By combining the canonical Hartree-Fock (HF) total energies and the GEBF-X correlation energies, the GEBF-X/HF method is illustrated to be more accurate than the origin GEBF-X method, where X could be any electron correlation method, such as second-order Moller-Plesset perturbation theory (MP2), MP2-F12, CCSD(T), and CCSD(T)-F12a. By combining the GEBF-X/HF results at the MP2-F12 and CCSD(T) F12a levels, we can approximately achieve the CCSD(T) complete basis set (CBS) limit. Our test calculations for 10 low-energy isomers of water 20-mers show that for the relative energies of large water clusters, both the basis set and high level electron correlation effects should be taken into account, in which the former is even more important. In addition, the GEBF-CCSD(T)/HF method at the CBS limit is used to evaluate 32 levels of density functional theory (DFT) methods. The results show that the DFT methods are difficult to predict the relative energies between the isomers of water 20-mers. The GEBF-CCSD(T)/HF method at the CBS limit is expected to be a benchmark for DFT and other electron correlation methods for medium- and large-sized systems with complex structures, in which both the basis set and electron correlation effects are important. PMID- 26580369 TI - Origin of the Red Shift for the Lowest Singlet pi -> pi* Charge-Transfer Absorption of p-Nitroaniline in Supercritical CO2. AB - The origin of the unusual solvatochromic shift of p-nitroaniline (PNA) in supercritical carbon dioxide (SCCO2) is theoretically investigated on the basis of experimental data. Ab initio quantum chemistry calculations have been employed to unveil the interaction of CO2 with this archetypical molecule. It is demonstrated that the nitro group of PNA works as an electron-donating site binding to the electron-deficient carbon atom of CO2, most probably via a Lewis acid-base interaction. Moreover, a cooperative C-H...O hydrogen bond seems to act as an additional stabilizing source during the solvation process of PNA in SCCO2. To support the influence of solute-solvent specific interactions on the lowest singlet pi -> pi* charge-transfer excitation, we perform a sequential Monte Carlo time-dependent density functional theory simulation to evaluate the excited states of PNA in SCCO2 (T = 315 K, rho = 0.81 g/cm(3)). A critical assessment of this simulation, compared to calculations carried out within the polarized continuum model, gives strong evidence that our proposed complexes are important in describing the solvatochromic shift of PNA in SCCO2. The calculated red shift from the gas phase accounts for 66% to 80% (depending on the degree of complexation) of the experimental data. Finally, these results also alleviate possible failures commonly attributed to long-range corrected functionals in reproducing the solvatochromism of PNA. PMID- 26580370 TI - The R(-7) Dispersion Interaction in the General Effective Fragment Potential Method. AB - The R(-7) term (E7) in the dispersion expansion is developed in the framework of the general effective fragment potential (EFP2) method, formulated with the dynamic anisotropic Cartesian polarizability tensors over the imaginary frequency range. The E7 formulation is presented in terms of both the total molecular polarizability and the localized molecular orbital (LMO) contributions. An origin transformation from the center of mass to the LMO centroids is incorporated for the computation of the LMO dipole-quadrupole polarizability. The two forms considered for the damping function for the R(-7) dispersion interaction, the overlap-based and Tang-Toennies damping functions, are extensions of the existing damping functions for the R(-6) term in the dispersion expansion. The R(-7) dispersion interaction is highly orientation dependent: it can be either attractive or repulsive, and its magnitude can change substantially as the relative orientation of two interacting molecules changes. Although the R(-7) dispersion energy rotationally averages to zero, it may be significant for systems in which rotational averaging does not occur, such as rotationally rigid molecular systems as in molecular solids or constrained surface reactions. PMID- 26580371 TI - Geometry Optimization in Polarizable QM/MM Models: The Induced Dipole Formulation. AB - We present the mathematical derivation and the computational implementation of the analytical geometry derivatives for a polarizable QM/MM model (QM/MMPol). In the adopted QM/MMPol model, the focused part is treated at QM level of theory, while the remaining part (the environment) is described classically as a set of fixed charges and induced dipoles. The implementation is performed within the ONIOM procedure, resulting in a polarizable embedding scheme, which can be applied to solvated and embedded systems and combined with different polarizable force fields available in the literature. Two test cases characterized by strong hydrogen-bond and dipole-dipole interactions, respectively, are used to validate the method with respect to the nonpolarizable one. Finally, an application to geometry optimization of the chromophore of Rhodopsin is presented to investigate the impact of including mutual polarization between the QM and the classical parts in conjugated systems. PMID- 26580372 TI - Development of a "First Principles" Water Potential with Flexible Monomers. II: Trimer Potential Energy Surface, Third Virial Coefficient, and Small Clusters. AB - A full-dimensional potential energy function (MB-pol) for simulations of water from the dimer to bulk phases is developed entirely from "first principles" by building upon the many-body expansion of the interaction energy. Specifically, the MB-pol potential is constructed by combining a highly accurate dimer potential energy surface [J. Chem. Theory Comput. 2013, 9, 5395] with explicit three-body and many-body polarization terms. The three-body contribution, expressed as a combination of permutationally invariant polynomials and classical polarizability, is derived from a fit to more than 12000 three-body energies calculated at the CCSD(T)/aug-cc-pVTZ level of theory, imposing the correct asymptotic behavior as predicted from "first principles". Here, the accuracy of MB-pol is demonstrated through comparison of the calculated third virial coefficient with the corresponding experimental data as well as through analysis of the relative energy differences of small clusters. PMID- 26580373 TI - Comparison of ab Initio, DFT, and Semiempirical QM/MM Approaches for Description of Catalytic Mechanism of Hairpin Ribozyme. AB - We have analyzed the capability of state-of-the-art multiscale computational approaches to provide atomic-resolution electronic structure insights into possible catalytic scenarios of the hairpin ribozyme by evaluating potential and free energy surfaces of the reactions by various hybrid QM/MM methods. The hairpin ribozyme is a unique catalytic RNA that achieves rate acceleration similar to other small self-cleaving ribozymes but without direct metal ion participation. Guanine 8 (G8) and adenine 38 (A38) have been identified as the catalytically essential nucleobases. However, their exact catalytic roles are still being investigated. In line with the available experimental data, we considered two reaction scenarios involving protonated A38H(+) as a general acid which is further assisted by either canonical G8 or deprotonated G8(-) forms. We used the spin-component scaled Moller-Plesset (SCS-MP2) method at the complete basis set limit as the reference method. The semiempirical AM1/d-PhoT and SCC DFTBPR methods provided acceptable activation barriers with respect to the SCS MP2 data but predicted significantly different reaction pathways. DFT functionals (BLYP and MPW1K) yielded the same reaction pathway as the SCS-MP2 method. The activation barriers were slightly underestimated by the GGA BLYP functional, although with accuracy comparable to the semiempirical methods. The SCS-MP2 method and hybrid MPW1K functional gave activation barriers that were closest to those derived from experimentally measured rate constants. PMID- 26580374 TI - Application of Automated Reaction Path Search Methods to a Systematic Search of Single-Bond Activation Pathways Catalyzed by Small Metal Clusters: A Case Study on H-H Activation by Gold. AB - A new theoretical approach to find metal-cluster-catalyzed single bond activation pathways is introduced. The proposed approach combines two automated reaction path search techniques: the anharmonic downward distortion following (ADDF) and the artificial force induced reaction (AFIR) methods, developed in our previous works [Maeda, S.; Ohno, K.; Morokuma, K. Phys. Chem. Chem. Phys. 2013, 15, 3683 3701]. A simple model reaction of the H-H bond activation catalyzed by Aun (n = 7, 8) clusters is considered as an example. We have automatically found 33 and 20 transition-state (TS) structures for H2 dissociation on Au7 and Au8 clusters, respectively, and successfully identified the best dissociation pathways with the lowest barrier. Systematic analysis of the structure-dependent reactivity of small gold clusters is performed. It is demonstrated that the most stable structures of the gold clusters are not always highly reactive and several isomeric structures must be taken into account for adequate description of the reaction rates at finite temperatures. The proposed approach can serve as a promising tool for investigation of the chemical reactions catalyzed by small metal clusters. PMID- 26580375 TI - Nonadiabatic and Time-Resolved Photoelectron Spectroscopy for Molecular Systems. AB - We quantify the nonadiabatic contributions to the vibronic sidebands of equilibrium and explicitly time-resolved nonequilibrium photoelectron spectra for a vibronic model system of trans-polyacetylene. Using exact diagonalization, we directly evaluate the sum-over-states expressions for the linear-response photocurrent. We show that spurious peaks appear in the Born-Oppenheimer approximation for the vibronic spectral function, which are not present in the exact spectral function of the system. The effect can be traced back to the factorized nature of the Born-Oppenheimer initial and final photoemission states and also persists when either only initial or final states are replaced by correlated vibronic states. Only when correlated initial and final vibronic states are taken into account are the spurious spectral weights of the Born Oppenheimer approximation suppressed. In the nonequilibrium case, we illustrate for an initial Franck-Condon excitation and an explicit pump-pulse excitation how the vibronic wavepacket motion of the system can be traced in the time-resolved photoelectron spectra as a function of the pump-probe delay. PMID- 26580376 TI - Performance of an Optimally Tuned Range-Separated Hybrid Functional for 0-0 Electronic Excitation Energies. AB - Using a set of 40 conjugated molecules, we assess the performance of an "optimally tuned" range-separated hybrid functional in reproducing the experimental 0-0 energies. The selected protocol accounts for the impact of solvation using a corrected linear-response continuum approach and vibrational corrections through calculations of the zero-point energies of both ground and excited-states and provides basis set converged data thanks to the systematic use of diffuse-containing atomic basis sets at all computational steps. It turns out that an optimally tuned long-range corrected hybrid form of the Perdew-Burke Ernzerhof functional, LC-PBE*, delivers both the smallest mean absolute error (0.20 eV) and standard deviation (0.15 eV) of all tested approaches, while the obtained correlation (0.93) is large but remains slightly smaller than its M06-2X counterpart (0.95). In addition, the efficiency of two other recently developed exchange-correlation functionals, namely SOGGA11-X and omegaB97X-D, has been determined in order to allow more complete comparisons with previously published data. PMID- 26580377 TI - Data Filtering for Effective Analysis of Crystal-Solution Interface Molecular Dynamics Simulations. AB - Analysis of processes occurring at the solid-solution interface during crystal growth and dissolution simulations requires an effective way to detect rare, uncorrelated transitions from the liquid to the solid state or vice versa. Because of the oscillatory behavior of molecules, this is not a trivial problem. Usually, to take the thermal vibration and rotational flexibility of the molecules into account, the data (e.g., orientation, center of mass position) needed to determine the molecular state are averaged over some time interval. Then they are evaluated using some order parameters to classify the individual molecules as being either crystalline or in solution. In this case, the results can be very sensitive to the time interval, which is mostly chosen in some heuristic way. To suppress the problem of fast non-Markovian dynamics and to make the identification of the molecular state more reliable and robust, the application of a Kalman filter, optionally combined with a hysteretic approach, is proposed in this contribution. A scheme to estimate the filter parameters is introduced. To demonstrate the approach, simple and widely used order parameters based on the structural features of molecules are taken. The obtained results are clearly superior to those based on the data averaging technique and are important for the effective transition rates calculation as well as for the general analysis of the time evolution of interfaces. PMID- 26580378 TI - First Multireference Correlation Treatment of Bulk Metals. AB - Existence of the sp-d hybridization of the valence band states of the fcc Ca and Sr in the vicinity of the Fermi level indicates that their electronic wave function can have a multireference (MR) character. We performed a wave-function based correlation treatment for these materials by means of the method of increments. As opposed to the single-reference correlation treatment (here, coupled cluster), which fails to describe cohesive properties in both cases, employing the MR averaged coupled pair functional, one can achieve almost 100% of the experimental correlation energy. PMID- 26580379 TI - Enthalpy-Entropy Tuning in the Adsorption of Nucleobases at the Au(111) Surface. AB - The interaction of DNA molecules with hard substrates is of paramount importance both for the study of DNA itself and for the variety of possible technological applications. Interaction with inorganic surfaces strongly modifies the helical shape of DNA. Hence, an accurate understanding of DNA structure and function at interfaces is a fundamental question with enormous impact in science and society. This work sets the fundamentals for the simulation of entire DNA oligomers on gold surfaces in dry and wet conditions. Thanks to the new GolDNA-AMBER force field, which was derived from first principles and includes dispersion interactions and polarization effects, we simulated self-assembled guanine and adenine monolayers on Au(111) in vacuo and the adsorption of all nucleobases on the same substrate in aqueous conditions. The periodic monolayers obtained from classical simulations match very well those from first principle calculations and experiments, assessing the robustness of the force field and motivating the application to more complex systems for which quantum calculations are not affordable and experiments are elusive. The energetics of nucleobases on Au(111) in solution reveal fundamental physicochemical effects: we find that the adsorption paradigm shifts from purely enthalpic to dominantly entropic by changing the environment and aggregation phase. PMID- 26580380 TI - Transmembrane Permeation Mechanism of Charged Methyl Guanidine. AB - The mechanism of transmembrane ion permeation is studied using charged methyl guanidine as a model ion. With a widely applied reaction coordinate, our umbrella sampling results reveal a significant finite-size effect in small simulation systems and a serious hysteresis in large systems. Therefore, it is important to re-examine the simulation techniques for studying transmembrane permeation mechanism of ions suggested in previous works. In this work, two novel collective variables are designed to acquire a continuous trajectory of the permeation process and small statistical errors through umbrella sampling. A water-bridge mechanism is discussed in detail. In this mechanism, a continuous water chain (or a chain of water molecules and lipid head groups) is formed across the membrane to conduct the transmembrane permeation of charged methyl guanidine. We obtain a continuous transition trajectory by combining the two-dimensional umbrella sampling in the local region of the saddle state and a one-dimensional sampling in the out region. Our free energy analysis shows that, with the presence of the water bridge, the energy barrier of the transmembrane permeation of ions is reduced significantly. Our analysis suggests that the water-bridge mechanism is common for permeation of ions across thick membranes, including palmitoyloleoyl phosphocholine and dipalmitoylphosphatidylcholine membranes. PMID- 26580381 TI - Simple Link Atom Saccharide Hybrid (SLASH) Treatment for Glycosidic Bonds at the QM/MM Boundary. AB - We investigated link atom approaches for treating the polar C-O bond with particular reference to the glycosidic bond found in complex carbohydrates. We show that cutting this bond after the oxygen in the QM region and saturating the QM system with a hydrogen link atom leads to greater conformational and configurational accuracy at the boundary compared with cutting the bond before oxygen and saturating the QM system with a halogen link atom to represent the oxygen. Furthermore, we find that balancing the MM atom charges and redistributing the boundary atom charges at the QM/MM boundary minimizes the effect of the link atom, both energetically and structurally. This is illustrated via a series of calculations on a set of carbohydrate and carbohydrate-like model compounds. Finally, we confirm the validity of our model by performing molecular dynamics simulations for a typical disaccharide model compound in water. Our postsimulation conformational and configurational analyses show that the oxygen to-water hydrogen pair distribution functions and the Phi,Psi distributions at the glycosidic boundary between the quantum and classical regions compare favorably with results obtained from complete QM and complete MM treatments of the saccharide. PMID- 26580382 TI - Variational Approach to Molecular Kinetics. AB - The eigenvalues and eigenvectors of the molecular dynamics propagator (or transfer operator) contain the essential information about the molecular thermodynamics and kinetics. This includes the stationary distribution, the metastable states, and state-to-state transition rates. Here, we present a variational approach for computing these dominant eigenvalues and eigenvectors. This approach is analogous to the variational approach used for computing stationary states in quantum mechanics. A corresponding method of linear variation is formulated. It is shown that the matrices needed for the linear variation method are correlation matrices that can be estimated from simple MD simulations for a given basis set. The method proposed here is thus to first define a basis set able to capture the relevant conformational transitions, then compute the respective correlation matrices, and then to compute their dominant eigenvalues and eigenvectors, thus obtaining the key ingredients of the slow kinetics. PMID- 26580383 TI - Mechanism of Stapled Peptide Binding to MDM2: Possible Consequences for Peptide Design. AB - MDM2 is a negative regulator of p53. The N terminal domain of MDM2 interacts with a helical region of the transcriptional activation domain of p53. Stapled peptides have been designed to mimic this interaction, in order to inhibit p53 MDM2 binding and thereby activate the p53 response. Here, we studied how the helical segment of p53 or a stapled peptide (re)binds to MDM2 as it is systematically displaced from the MDM2 binding pocket. Depending on its sequence, presence of staple, and/or a C-terminal tail, the peptide approaches MDM2 differently and not exclusively via the crack propagation mechanism proposed previously for p53. The presence of an interacting staple appears to reduce the peptide's sensitivity to mutations of key hydrophobic residues of p53, and this could pave the way for increased diversity in sequence design of stapled peptides used in inhibiting the p53-MDM2 interaction. We further found that the presence of a hydrophobic staple in the peptide-MDM2 interface tends to trap a network of water molecules prior to binding. The release of these structured waters would then reduce the entropic penalty upon peptide binding. PMID- 26580384 TI - Determination of Signaling Pathways in Proteins through Network Theory: Importance of the Topology. AB - Network theory methods are being increasingly applied to proteins to investigate complex biological phenomena. Residues that are important for signaling processes can be identified by their condition as critical nodes in a protein structure network. This analysis involves modeling the protein as a graph in which each residue is represented as a node and edges are drawn between nodes that are deemed connected. In this paper, we show that the results obtained from this type of network analysis (i.e., signaling pathways, key residues for signal transmission, etc.) are profoundly affected by the topology of the network, with normally used determination of network edges by geometrical cutoff schemes giving rise to substantial statistical errors. We propose a method of determining protein structure networks by calculating inter-residue interaction energies and show that it gives an accurate and reliable description of the signal-propagation properties of a known allosteric enzyme. We also show that including covalent interactions in the network topology is essential for accurate results to be obtained. PMID- 26580385 TI - Protocol To Make Protein NMR Structures Amenable to Stable Long Time Scale Molecular Dynamics Simulations. AB - A robust protocol for the treatment of NMR protein structures is presented that makes them amenable to long time scale molecular dynamics (MD) simulations that are stable. The protocol embeds an NMR structure in a native low energy region of the recently developed ff99SB_phipsi(g24;CS) molecular mechanics force field. Extended MD trajectories that start from these structures show good consistency with proton-proton nuclear Overhauser effect data, and they reproduce NMR chemical shift data better than the original NMR structures as is demonstrated for four protein systems. Moreover, for all proteins studied here the simulations spontaneously approach the X-ray crystal structures, thereby improving the effective resolution of the initial structural models. PMID- 26580386 TI - Toward QM/MM Simulation of Enzymatic Reactions with the Drude Oscillator Polarizable Force Field. AB - The polarization of the environment can influence the results from hybrid quantum mechanical/molecular mechanical (QM/MM) simulations of enzymatic reactions. In this article, we address several technical aspects in the development of polarizable QM/MM embedding using the Drude Oscillator (DO) force field. We propose a stable and converging update of the DO polarization state for geometry optimizations and a suitable treatment of the QM/MM-DO boundary when the QM and MM regions are separated by cutting through a covalent bond. We assess the performance of our approach by computing binding energies and geometries of three selected complexes relevant to biomolecular modeling, namely the water trimer, the N-methylacetamide dimer, and the cationic bis(benzene)sodium sandwich complex. Using a recently published MM-DO force field for proteins, we evaluate the effect of MM polarization on the QM/MM energy profiles of the enzymatic reactions catalyzed by chorismate mutase and by p-hydroxybenzoate hydroxylase. We find that inclusion of MM polarization affects the computed barriers by about 10%. PMID- 26580387 TI - Energy Landscapes and Global Optimization of Self-Assembling Cyclic Peptides. AB - Self-assembled cyclic peptide nanotubes have attracted much attention because of their antimicrobial properties. Here, we present calculations on the formation of cyclic peptide dimers using basin-hopping and discrete path sampling. We present an analysis of the basin-hopping move sets that most efficiently explore the conformations of cyclic peptides. Group rotation moves, in which sections of the ring are rotated as a rigid body, are the most effective for cyclic peptides containing up to 20 residues. For cyclic peptide dimers, we find that a combination of group rotation intramolecular moves and rigid body intermolecular moves performs well. Discrete path sampling calculations on the cyclic peptide dimers show significant differences in the dimerization of hexa- and octapeptides. PMID- 26580388 TI - Cooperativity Assisted Shortening of Hydrogen Bonds in Crystalline Oxalic Acid Dihydrate: DFT and NBO Model Studies. AB - The distance of ~2.49 A separating the carboxylic OH oxygen from the water oxygen atom in the alpha-polymorph of crystalline oxalic acid dihydrate is by ~0.1 A shorter than the average distance in carboxylic acid monohydrates. It is also by ~0.2 A shorter than the corresponding distance presently calculated for the heterotrimer consisting of one acid and two water molecules. The large difference between RO...O in the heterotrimer and in the crystal is attributed to the cooperative effect in the latter; this is supported by calculations carried out on clusters constituted of an increasing number of acid and water molecules. The present DFT calculations with geometry optimization include seven isolated model clusters, the largest of which contains five acid and eight water molecules. The RO...O of the short hydrogen bond shortens progressively with increasing the number of cluster constituents; in the largest cluster, it reaches 2.50 A. This is remarkably close to both the experimental distance as well as to the distance obtained by the periodic DFT calculation. The electronic effects were studied by Natural Bond Orbital analysis, revealing an enhancement of hydrogen bonding on extending the network by increased polarization of the carbonyl group and by the increased delocalization interaction between the lone electron pair on the acceptor oxygen atom and the OH antibond orbital. The formation of circular motifs appears to be the most important factor in the cooperative shortening of the hydrogen bonds. In agreement with the measured hydrogen bond distances, inspection of the electron density reveals a notable difference in hydrogen bond shrinking tendency between the two known polymorphs of the title system. PMID- 26580389 TI - A Practical Computational Approach to Study Molecular Instability Using the Pseudo-Jahn-Teller Effect. AB - Vibronic coupling theory shows that the cause for spontaneous instability in systems presenting a nondegenerate ground state is the so-called pseudo-Jahn Teller effect, and thus its study can be extremely helpful to understand the structure of many molecules. While this theory, based on the mixing of the ground and excited states with a distortion, has been long studied, there are two obscure points that we try to clarify in the present work. First, the operators involved in both the vibronic and nonvibronic parts of the force constant take only into account electron-nuclear and nuclear-nuclear interactions, apparently leaving electron-electron repulsions and the electron's kinetic energy out of the chemical picture. Second, a fully quantitative computational appraisal of this effect has been up to now problematic. Here, we present a reformulation of the pseudo-Jahn-Teller theory that explicitly shows the contributions of all operators in the molecular Hamiltonian and allows connecting the results obtained with this model to other chemical theories relating electron distribution and geometry. Moreover, we develop a practical approach based on Hartree-Fock and density functional theory that allows quantification of the pseudo-Jahn-Teller effect. We demonstrate the usefulness of our method studying the pyramidal distortion in ammonia and its absence in borane, revealing the strong importance of the kinetic energy of the electrons in the lowest a2" orbital to trigger this instability. The present tool opens a window for exploring in detail the actual microscopic origin of structural instabilities in molecules and solids. PMID- 26580390 TI - Erratum to Molecular Dynamics Simulations of Highly Crowded Amino Acid Solutions: Comparisons of Eight Different Force Field Combinations with Experiment and with Each Other. PMID- 26580391 TI - Erratum: "The Variationally Orbital-Adapted Configuration Interaction Singles (VOA-CIS) Approach to Electronically Excited States". PMID- 26580393 TI - Honeybee Colony Vibrational Measurements to Highlight the Brood Cycle. AB - Insect pollination is of great importance to crop production worldwide and honey bees are amongst its chief facilitators. Because of the decline of managed colonies, the use of sensor technology is growing in popularity and it is of interest to develop new methods which can more accurately and less invasively assess honey bee colony status. Our approach is to use accelerometers to measure vibrations in order to provide information on colony activity and development. The accelerometers provide amplitude and frequency information which is recorded every three minutes and analysed for night time only. Vibrational data were validated by comparison to visual inspection data, particularly the brood development. We show a strong correlation between vibrational amplitude data and the brood cycle in the vicinity of the sensor. We have further explored the minimum data that is required, when frequency information is also included, to accurately predict the current point in the brood cycle. Such a technique should enable beekeepers to reduce the frequency with which visual inspections are required, reducing the stress this places on the colony and saving the beekeeper time. PMID- 26580394 TI - Effect of Temperature-Sensitive Poloxamer Solution/Gel Material on Pericardial Adhesion Prevention: Supine Rabbit Model Study Mimicking Cardiac Surgery. AB - OBJECTIVE: We investigated the mobility of a temperature-sensitive poloxamer/Alginate/CaCl2 mixture (PACM) in relation to gravity and cardiac motion and the efficacy of PACM on the prevention of pericardial adhesion in a supine rabbit model. METHODS: A total of 50 rabbits were randomly divided into two groups according to materials applied after epicardial abrasion: PACM and dye mixture (group PD; n = 25) and saline as the control group (group CO; n = 25). In group PD, rabbits were maintained in a supine position with appropriate sedation, and location of mixture of PACM and dye was assessed by CT scan at the immediate postoperative period and 12 hours after surgery. The grade of adhesions was evaluated macroscopically and microscopically two weeks after surgery. RESULTS: In group PD, enhancement was localized in the anterior pericardial space, where PACM and dye mixture was applied, on immediate post-surgical CT scans. However, the volume of the enhancement was significantly decreased at the anterior pericardial space 12 hours later (P < .001). Two weeks after surgery, group PD had significantly lower macroscopic adhesion score (P = .002) and fibrosis score (P = .018) than did group CO. Inflammation score and expression of anti macrophage antibody in group PD were lower than those in group CO, although the differences were not significant. CONCLUSIONS: In a supine rabbit model study, the anti-adhesion effect was maintained at the area of PACM application, although PACM shifted with gravity and heart motion. For more potent pericardial adhesion prevention, further research and development on the maintenance of anti-adhesion material position are required. PMID- 26580395 TI - von Willebrand Factor-Rich Platelet Thrombi in the Liver Cause Sinusoidal Obstruction Syndrome following Oxaliplatin-Based Chemotherapy. AB - Oxaliplatin-based chemotherapy is widely used to treat advanced colorectal cancer (CRC). Sinusoidal obstruction syndrome (SOS) due to oxaliplatin is a serious type of chemotherapy-associated liver injury (CALI) in CRC patients. SOS is thought to be caused by the sinusoidal endothelial cell damage, which results in the release of unusually-large von Willebrand factor multimers (UL-VWFMs) from endothelial cells. To investigate the pathophysiology of CALI after oxaliplatin-based chemotherapy, we analyzed plasma concentration of von Willebrand factor (VWF) and the distribution of VWFMs in CRC patients. Twenty-three patients with advanced CRC who received oxaliplatin-based chemotherapy with (n = 6) and without (n = 17) bevacizumab were analyzed. CALI (n = 6) and splenomegaly (n = 9) were found only in patients who did not treated with bevacizumab. Plasma VWF antigen (VWF:Ag) and serum aspartate aminotransferase (AST) levels increased after chemotherapy only in patients without bevacizumab. VWFM analysis in patients who did not receive bevacizumab showed the presence of UL-VWFMs and absence of high molecular weight VWFMs during chemotherapy, especially in those with CALI. In addition, plasma VWF:Ag and AST levels increased after chemotherapy in patients with splenomegaly (n = 9), but not in patients without splenomegaly (n = 14). Histological findings in the liver tissue of patients who did not receive bevacizumab included sinusoidal dilatation and microthrombi in the sinusoids. Many microthrombi were positive for both anti-IIb/IIIa and anti-VWF antibodies. Plasma UL-VWFM levels might be increased by damage to endothelial cells as a result of oxaliplatin based chemotherapy. Bevacizumab could prevent CALI and splenomegaly through inhibition of VWF-rich platelet thrombus formation. PMID- 26580396 TI - Age-Related Macular Degeneration and Incident Stroke: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Age-related macular degeneration (AMD) is the leading cause of vision loss and blindness in people over 65 years old in the United States and has been associated with cardiovascular risk and decreased survival. There is conflicting data, however, regarding the contribution of AMD to the prediction of stroke. AIM: To determine whether AMD is a risk indicator for incident stroke in a meta analysis of available prospective and retrospective cohort studies published in the English literature. METHODS: We performed a systematic literature search of all studies published in English with Pub Med and other databases from 1966 to August 2014, reporting stroke incidence in patients with macular degeneration. Two investigators independently extracted the data. A random effects model was used to report Odds ratios (OR), with corresponding 95% confidence intervals (CI). Meta-regression using a mixed linear model was used to understand potential heterogeneity amongst studies. RESULTS: We identified 9 studies that reported stroke incidence in patients with and without early AMD (N = 1,420,978). No significant association was found between early AMD with incident stroke. Combined, these 9 studies demonstrated random effects (OR, 1.12; CI, 0.86-1.47; I2 = 96%). Meta-regression on baseline covariates of age, sex, and year of publication did not significantly relate to heterogeneity. CONCLUSIONS: We found no significant relationship between AMD and incident stroke. Further studies are needed to clarify other causes of decreased survival in patients with AMD. PMID- 26580397 TI - Prediction of Severe Acute Pancreatitis Using a Decision Tree Model Based on the Revised Atlanta Classification of Acute Pancreatitis. AB - OBJECTIVE: To develop a model for the early prediction of severe acute pancreatitis based on the revised Atlanta classification of acute pancreatitis. METHODS: Clinical data of 1308 patients with acute pancreatitis (AP) were included in the retrospective study. A total of 603 patients who were admitted to the hospital within 36 hours of the onset of the disease were included at last according to the inclusion criteria. The clinical data were collected within 12 hours after admission. All the patients were classified as having mild acute pancreatitis (MAP), moderately severe acute pancreatitis (MSAP) and severe acute pancreatitis (SAP) based on the revised Atlanta classification of acute pancreatitis. All the 603 patients were randomly divided into training group (402 cases) and test group (201 cases). Univariate and multiple regression analyses were used to identify the independent risk factors for the development of SAP in the training group. Then the prediction model was constructed using the decision tree method, and this model was applied to the test group to evaluate its validity. RESULTS: The decision tree model was developed using creatinine, lactate dehydrogenase, and oxygenation index to predict SAP. The diagnostic sensitivity and specificity of SAP in the training group were 80.9% and 90.0%, respectively, and the sensitivity and specificity in the test group were 88.6% and 90.4%, respectively. CONCLUSIONS: The decision tree model based on creatinine, lactate dehydrogenase, and oxygenation index is more likely to predict the occurrence of SAP. PMID- 26580398 TI - A Double Negative Loop Comprising ETV6/RUNX1 and MIR181A1 Contributes to Differentiation Block in t(12;21)-Positive Acute Lymphoblastic Leukemia. AB - Childhood acute lymphoblastic leukemia (ALL) with t(12;21), which results in expression of the ETV6/RUNX1 fusion gene, is the most common chromosomal lesion in precursor-B (pre-B) ALL. We identified 17 microRNAs that were downregulated in ETV6/RUNX1+ compared with ETV6/RUNX1- clinical samples. Among these microRNAs, miR-181a-1 was the most significantly reduced (by ~75%; P < 0.001). Using chromatin immunoprecipitation, we demonstrated that ETV6/RUNX1 directly binds the regulatory region of MIR181A1, and knockdown of ETV6/RUNX1 increased miR-181a-1 level. We further showed that miR-181a (functional counterpart of miR-181a-1) could target ETV6/RUNX1 and cause a reduction in the level of the oncoprotein ETV6/RUNX1, cell growth arrest, an increase in apoptosis, and induction of cell differentiation in ETV6/RUNX1+ cell line. Moreover, ectopic expression of miR 181a also resulted in decreased CD10 hyperexpression in ETV6/RUNX1+ primary patient samples. Taken together, our results demonstrate that MIR181A1 and ETV6/RUNX1 regulate each other, and we propose that a double negative loop involving MIR181A1 and ETV6/RUNX1 may contribute to ETV6/RUNX1-driven arrest of differentiation in pre-B ALL. PMID- 26580400 TI - Catalytic Gas-Phase Glycerol Processing over SiO2-, Cu-, Ni- and Fe- Supported Au Nanoparticles. AB - In this study, we investigated different metal pairings of Au nanoparticles (NPs) as potential catalysts for glycerol dehydration for the first time. All of the systems preferred the formation of hydroxyacetone (HYNE). Although the bimetallics that were tested, i.e., Au NPs supported on Ni, Fe and Cu appeared to be more active than the Au/SiO2 system, only Cu supported Au NPs gave high conversion (ca. 63%) and selectivity (ca. 70%) to HYNE. PMID- 26580399 TI - Expression Profile of Genes Related to Drug Metabolism in Human Brain Tumors. AB - BACKGROUND: Endogenous and exogenous compounds as well as carcinogens are metabolized and detoxified by phase I and II enzymes, the activity of which could be crucial to the inactivation and hence susceptibility to carcinogenic factors. The expression of these enzymes in human brain tumor tissue has not been investigated sufficiently. We studied the association between tumor pathology and the expression profile of seven phase I and II drug metabolizing genes (CYP1A1, CYP1B1, ALDH3A1, AOX1, GSTP1, GSTT1 and GSTM3) and some of their proteins. METHODS: Using qRT-PCR and western blotting analysis the gene and protein expression in a cohort of 77 tumors were investigated. The major tumor subtypes were meningioma, astrocytoma and brain metastases, -the later all adenocarcinomas from a lung primary. RESULTS: Meningeal tumors showed higher expression levels for AOX1, CYP1B1, GSTM3 and GSTP1. For AOX1, GSTM and GSTP1 this could be verified on a protein level as well. A negative correlation between the WHO degree of malignancy and the strength of expression was identified on both transcriptional and translational level for AOX1, GSTM3 and GSTP1, although the results could have been biased by the prevalence of meningiomas and glioblastomas in the inevitably bipolar distribution of the WHO grades. A correlation between the gene expression and the protein product was observed for AOX1, GSTP1 and GSTM3 in astrocytomas. CONCLUSIONS: The various CNS tumors show different patterns of drug metabolizing gene expression. Our results suggest that the most important factor governing the expression of these enzymes is the histological subtype and to a far lesser extent the degree of malignancy itself. PMID- 26580402 TI - Identification of a New Hesperornithiform from the Cretaceous Niobrara Chalk and Implications for Ecologic Diversity among Early Diving Birds. AB - The Smoky Hill Member of the Niobrara Chalk in Kansas (USA) has yielded the remains of numerous members of the Hesperornithiformes, toothed diving birds from the late Early to Late Cretaceous. This study presents a new taxon of hesperornithiform from the Smoky Hill Member, Fumicollis hoffmani, the holotype of which is among the more complete hesperornithiform skeletons. Fumicollis has a unique combination of primitive (e.g. proximal and distal ends of femur not expanded, elongate pre-acetabular ilium, small and pyramidal patella) and derived (e.g. dorsal ridge on metatarsal IV, plantarly-projected curve in the distal shaft of phalanx III:1) hesperornithiform characters, suggesting it was more specialized than small hesperornithiforms like Baptornis advenus but not as highly derived as the larger Hesperornis regalis. The identification of Fumicollis highlights once again the significant diversity of hesperornithiforms that existed in the Late Cretaceous Western Interior Seaway. This diversity points to the existence of a complex ecosystem, perhaps with a high degree of niche partitioning, as indicated by the varying degrees of diving specializations among these birds. PMID- 26580401 TI - Infants' Peripheral Blood Lymphocyte Composition Reflects Both Maternal and Post Natal Infection with Plasmodium falciparum. AB - Maternal parasitoses modulate fetal immune development, manifesting as altered cellular immunological activity in cord blood that may be linked to enhanced susceptibility to infections in early life. Plasmodium falciparum typifies such infections, with distinct placental infection-related changes in cord blood exemplified by expanded populations of parasite antigen-specific regulatory T cells. Here we addressed whether such early-onset cellular immunological alterations persist through infancy. Specifically, in order to assess the potential impacts of P. falciparum infections either during pregnancy or during infancy, we quantified lymphocyte subsets in cord blood and in infants' peripheral blood during the first year of life. The principal age-related changes observed, independent of infection status, concerned decreases in the frequencies of CD4+, NKdim and NKT cells, whilst CD8+, Treg and Teff cells' frequencies increased from birth to 12 months of age. P. falciparum infections present at delivery, but not those earlier in gestation, were associated with increased frequencies of Treg and CD8+ T cells but fewer CD4+ and NKT cells during infancy, thus accentuating the observed age-related patterns. Overall, P. falciparum infections arising during infancy were associated with a reversal of the trends associated with maternal infection i.e. with more CD4+ cells, with fewer Treg and CD8+ cells. We conclude that maternal P. falciparum infection at delivery has significant and, in some cases, year-long effects on the composition of infants' peripheral blood lymphocyte populations. Those effects are superimposed on separate and independent age- as well as infant infection-related alterations that, respectively, either match or run counter to them. PMID- 26580404 TI - Influence of life history traits on the population genetic structure of parasitic helminths: a minireview. AB - Parasite life history traits influence the rate of gene flow between populations and the effective population size, both of which determine the levels of genetic variability and the geographic distribution of such variability. In this short review targeted to parasitologists, we summarise how life history traits influence the population genetic structure of parasitic helminths. These organisms are characterised by a wide variety of life cycles and are ecologically different from microparasites, which have been studied in more detail. In order to provide the reader a concise review that illustrates key aspects of the subject matter, we have limited ourselves to studying examples selected for their clarity and relevance. PMID- 26580403 TI - Development and Internal Validation of a Predictive Model Including Pulse Oximetry for Hospitalization of Under-Five Children in Bangladesh. AB - BACKGROUND: The reduction in the deaths of millions of children who die from infectious diseases requires early initiation of treatment and improved access to care available in health facilities. A major challenge is the lack of objective evidence to guide front line health workers in the community to recognize critical illness in children earlier in their course. METHODS: We undertook a prospective observational study of children less than 5 years of age presenting at the outpatient or emergency department of a rural tertiary care hospital between October 2012 and April 2013. Study physicians collected clinical signs and symptoms from the facility records, and with a mobile application performed recordings of oxygen saturation, heart rate and respiratory rate. Facility physicians decided the need for hospital admission without knowledge of the oxygen saturation. Multiple logistic predictive models were tested. FINDINGS: Twenty-five percent of the 3374 assessed children, with a median (interquartile range) age of 1.02 (0.42-2.24), were admitted to hospital. We were unable to contact 20% of subjects after their visit. A logistic regression model using continuous oxygen saturation, respiratory rate, temperature and age combined with dichotomous signs of chest indrawing, lethargy, irritability and symptoms of cough, diarrhea and fast or difficult breathing predicted admission to hospital with an area under the receiver operating characteristic curve of 0.89 (95% confidence interval -CI: 0.87 to 0.90). At a risk threshold of 25% for admission, the sensitivity was 77% (95% CI: 74% to 80%), specificity was 87% (95% CI: 86% to 88%), positive predictive value was 70% (95% CI: 67% to 73%) and negative predictive value was 91% (95% CI: 90% to 92%). CONCLUSION: A model using oxygen saturation, respiratory rate and temperature in combination with readily obtained clinical signs and symptoms predicted the need for hospitalization of critically ill children. External validation of this model in a community setting will be required before adoption into clinical practice. PMID- 26580405 TI - Vertical Movements and Patterns in Diving Behavior of Whale Sharks as Revealed by Pop-Up Satellite Tags in the Eastern Gulf of Mexico. AB - The whale shark (Rhincodon typus) is a wide-ranging, filter-feeding species typically observed at or near the surface. This shark's sub-surface habits and behaviors have only begun to be revealed in recent years through the use of archival and satellite tagging technology. We attached pop-up satellite archival transmitting tags to 35 whale sharks in the southeastern Gulf of Mexico off the Yucatan Peninsula from 2003-2012 and three tags to whale sharks in the northeastern Gulf off Florida in 2010, to examine these sharks' long-term movement patterns and gain insight into the underlying factors influencing their vertical habitat selection. Archived data were received from 31 tags deployed on sharks of both sexes with total lengths of 5.5-9 m. Nine of these tags were physically recovered facilitating a detailed long-term view into the sharks' vertical movements. Whale sharks feeding inshore on fish eggs off the northeast Yucatan Peninsula demonstrated reverse diel vertical migration, with extended periods of surface swimming beginning at sunrise followed by an abrupt change in the mid-afternoon to regular vertical oscillations, a pattern that continued overnight. When in oceanic waters, sharks spent about 95% of their time within epipelagic depths (<200 m) but regularly undertook very deep ("extreme") dives (>500 m) that largely occurred during daytime or twilight hours (max. depth recorded 1,928 m), had V-shaped depth-time profiles, and comprised more rapid descents (0.68 m sec-1) than ascents (0.50 m sec-1). Nearly half of these extreme dives had descent profiles with brief but conspicuous changes in vertical direction at a mean depth of 475 m. We hypothesize these stutter steps represent foraging events within the deep scattering layer, however, the extreme dives may have additional functions. Overall, our results demonstrate complex and dynamic patterns of habitat utilization for R. typus that appear to be in response to changing biotic and abiotic conditions influencing the distribution and abundance of their prey. PMID- 26580406 TI - Engaging the Public to Identify Opportunities to Improve Critical Care: A Qualitative Analysis of an Open Community Forum. AB - OBJECTIVE: To engage the public to understand how to improve the care of critically ill patients. DESIGN: A qualitative content analysis of an open community forum (Cafe Scientifique). SETTING: Public venue in Calgary, Alberta, Canada. PARTICIPANTS: Members of the general public including patients, families of patients, health care providers, and members of the community at large. METHODS: A panel of researchers, decision-makers, and a family member led a Cafe Scientifique, an informal dialogue between the populace and experts, over three hours to engage the public to understand how to improve the care of critically ill patients. Conventional qualitative content analysis was used to analyze the data. The inductive analysis occurred in three phases: coding, categorizing, and developing themes. RESULTS: Thirty-eight members of the public (former ICU patients, family members of patients, providers, community members) attended. Participants focused the discussion and provided concrete suggestions for improvement around communication (family as surrogate voice, timing of conversations, decision tools) and provider well-being and engagement, as opposed to medical interventions in critical care. CONCLUSIONS: Cafe participants believe patient and family centered care is important to ensure high-quality care in the ICU. A Cafe Scientifique is a valuable forum to engage the public to contribute to priority setting areas for research in critical care, as well as a platform to share lived experience. Research stakeholders including health care organizations, governments, and funding organizations should provide more opportunities for the public to engage in meaningful conversations about how to best improve healthcare. PMID- 26580407 TI - Adenovirus species C detection in children under four years of age with acute bronchiolitis or recurrent wheezing. AB - BACKGROUND: Lower respiratory tract viral infection is an important cause of morbidity and mortality in children worldwide. Among viral etiological agents the human Adenovirus (AdV) has been associated to mild or severe respiratory tract infection. OBJECTIVE: To detect the presence of human Adenovirus (AdV) in children with acute bronchiolitis or recurrent wheezing, describing their clinical features and determining Adenovirus species and AdV association to Respiratory Syncytial Virus (RSV), Human Metapneumovirus (MPV) and Parainfluenza virus (PIV). STUDY DESIGN: A total of 155 children bellow 48 months of age with acute bronchiolitis or recurrent wheezing were investigated for the presence of AdV, RSV, MPV and PIV in nasopharyngeal aspirate, by real-time PCR method. RESULTS: AdV, predominantly of species C, has been detected as the unique pathogen (AdVi) or in association to other pathogens (AdVa.), in 39/155 samples. Crackles were more frequent in children with AdV. RSVi was detected predominantly in children with acute bronchiolitis while AdVi and AdVa were detected more frequently in patients with recurrent wheezing. CONCLUSION: A small outbreak of AdV species C was observed in 2012 and 2013. AdV was detected more frequently in children with recurrent wheezing while RSVi was more frequent in infants with acute bronchiolitis. PMID- 26580408 TI - Test based on subtype-specific MU-capture IgM immunoassay can distinguish between infections of European and Siberian subtypes of tick-borne encephalitis virus. AB - BACKGROUND: In many European countries (including Finland, Estonia, Latvia and Russia) two subtypes of tick-borne encephalitis virus (TBEV) occur with overlapping geographic distribution yet with apparently different severity and persistence of symptoms. However, it has not usually been possible to distinguish these infections in the laboratory, as TBEV RNA or sequences have rarely been retrieved from patients seeking medical care in the second phase of infection when the neurological symptoms occur, and serological tests have so far not been able to discriminate between the subtype-specific responses. OBJECTIVES: The aim of this study was to assess the applicability of a MU-capture enzyme immunoassay (EIA) based on TBEV prME subviral particles produced in mammalian cells from Semliki-Forest virus replicons (SFV-prME EIA) to distinguish reactivity to European and Siberian strains of TBEV. STUDY DESIGN: Altogether 54 TBEV IgM positive acute human serum samples and 6 positive cerebrospinal fluid (CSF) samples from different regions of Finland were tested in EIA with subtype specific antigens and TBEV-IgM subtype-specific index ratios were determined. RESULTS: All 30 samples from patients whose transmission had occurred in foci where only Siberian subtype of TBEV is occurring had an index ratio of more than 1.8, whereas all 30 acute TBE samples from an area where only European subtype circulates had an index ratio below 1.5. CONCLUSIONS: We conclude that the assay is a useful tool to distinguish between acute infections of European and Siberian strains of TBEV, and should help in further studies of the clinical outcome of these two subtypes. PMID- 26580409 TI - Rapid genome sequencing and characterization of novel avian-origin influenza A H7N9 virus directly from clinical sample by semiconductor sequencing. AB - BACKGROUND: Recent outbreaks of severe pneumonia or acute respiratory distress syndrome have attracted much public interest. Rapid and accurate diagnosis of the causative agent is key for an adequate response to suspected outbreaks. OBJECTIVES: We report a case that highlights the potential of semiconductor sequencing to rapidly determine the novel virus genome sequences. STUDY DESIGN: We have developed a method for rapid de novo assembly of the novel influenza A H7N9 virus genome directly from the tracheal aspirate of a patient using semiconductor sequencer without culture and prior sequence information. Further, characteristic amino acids were analyzed and phylogenetic analysis were done for key genes of the influenza A virus. RESULTS: Deep sequencing yielded 435,239 reads assigned to H7N9 viruses, with an average length of 172 bp, accounting for 18.6% of total reads (2,339,680). Complete genome of the virus was obtained by de novo assembly method within 2 days. Genomic average depth of coverage of the Ion Torrent PGM was up to 5679 fold. Selected characteristic amino acids were observed, and phylogenetic analyses showed that the novel H7 virus was genetically close to 2011 duck H7N3 viruses in Zhejiang. The novel N9 sequences were most closely related to gene sequences of N9 derived from ducks H11N9 in 2011 in Jiangxi and H2N9 sequences from Hong Kong in 2010, in China, and therefore they may share a common ancestor. CONCLUSIONS: The sequence-independent semiconductor sequencing is a powerful tool to investigate outbreak of a novel pathogen. PMID- 26580410 TI - Studies of Highly-Ordered Heterodiantennary Mannose/Glucose-Functionalized Polymers and Concanavalin A Protein Interactions Using Isothermal Titration Calorimetry. AB - Preparations of the highly ordered monoantennary, homofunctional diantennary, and heterofunctional diantennary neoglycopolymers of alpha-d-mannose and beta-d glucose residues were achieved via ring-opening metathesis polymerization. Isothermal titration calorimetry measurements of these synthetic neoglycopolymers with Concanavalin A (Con A), revealed that heterofunctional diantennary architectures bearing both alpha-mannose and nonbinding beta-glucose units, poly(Man-Glc), binds to Con A (Ka = 16.1 * 10(6) M(-1)) comparably to homofunctional diantennary neoglycopolymer (Ka = 30 * 10(6) M(-1)) bearing only alpha-mannose unit, poly(Man-Man). In addition, poly(Man-Glc) neoglycopolymer shows a nearly 5-fold increasing in binding affinity compared to monoantennary neoglycopolymer, poly(Man). Although the exact mechanism for the high binding affinity of poly(Man-Glc) to Con A is unclear, we hypothesize that the alpha mannose bound to Con A might facilitate interaction of beta-glucose with the extended binding site of Con A due to the close proximity of beta-glucose to alpha-mannose residues in the designed polymerizable scaffold. PMID- 26580412 TI - Citizen Science Program Shows Urban Areas Have Lower Occurrence of Frog Species, but Not Accelerated Declines. AB - Understanding the influence of landscape change on animal populations is critical to inform biodiversity conservation efforts. A particularly important goal is to understand how urban density affects the persistence of animal populations through time, and how these impacts can be mediated by habitat provision; but data on this question are limited for some taxa. Here, we use data from a citizen science monitoring program to investigate the effect of urbanization on patterns of frog species richness and occurrence over 13 years. Sites surrounded by a high proportion of bare ground (a proxy for urbanization) had consistently lower frog occurrence, but we found no evidence that declines were restricted to urban areas. Instead, several frog species showed declines in rural wetlands with low quality habitat. Our analysis shows that urban wetlands had low but stable species richness; but also that population trajectories are strongly influenced by vegetation provision in both the riparian zone and the wider landscape. Future increases in the extent of urban environments in our study area are likely to negatively impact populations of several frog species. However, existing urban areas are unlikely to lose further frog species in the medium term. We recommend that landscape planning and management focus on the conservation and restoration of rural wetlands to arrest current declines, and the revegetation of urban wetlands to facilitate the re-expansion of urban-sensitive species. PMID- 26580413 TI - Potentiometric in Situ Monitoring of Anions in the Synthesis of Copper and Silver Nanoparticles Using the Polyol Process. AB - Potentiometric sensors, such as polymeric membrane, ion-selective electrodes (ISEs), have been used in the past to monitor a variety of chemical processes. However, the use of these sensors has traditionally been limited to aqueous solutions and moderate temperatures. Here we present an ISE with a high-capacity ion-exchange sensing membrane for measurements of nitrate and nitrite in the organic solvent propylene glycol at 150 degrees C. It is capable of continuously measuring under these conditions for over 180 h. We demonstrate the usefulness of this sensor by in situ monitoring of anion concentrations during the synthesis of copper and silver nanoparticles in propylene glycol using the polyol method. Ion chromatography and a colorimetric method were used to independently confirm anion concentrations measured in situ. In doing so, it was shown that in this reaction the co-ion nitrate is reduced to nitrite. PMID- 26580411 TI - Chronic Conductive Hearing Loss Leads to Cochlear Degeneration. AB - Synapses between cochlear nerve terminals and hair cells are the most vulnerable elements in the inner ear in both noise-induced and age-related hearing loss, and this neuropathy is exacerbated in the absence of efferent feedback from the olivocochlear bundle. If age-related loss is dominated by a lifetime of exposure to environmental sounds, reduction of acoustic drive to the inner ear might improve cochlear preservation throughout life. To test this, we removed the tympanic membrane unilaterally in one group of young adult mice, removed the olivocochlear bundle in another group and compared their cochlear function and innervation to age-matched controls one year later. Results showed that tympanic membrane removal, and the associated threshold elevation, was counterproductive: cochlear efferent innervation was dramatically reduced, especially the lateral olivocochlear terminals to the inner hair cell area, and there was a corresponding reduction in the number of cochlear nerve synapses. This loss led to a decrease in the amplitude of the suprathreshold cochlear neural responses. Similar results were seen in two cases with conductive hearing loss due to chronic otitis media. Outer hair cell death was increased only in ears lacking medial olivocochlear innervation following olivocochlear bundle cuts. Results suggest the novel ideas that 1) the olivocochlear efferent pathway has a dramatic use-dependent plasticity even in the adult ear and 2) a component of the lingering auditory processing disorder seen in humans after persistent middle-ear infections is cochlear in origin. PMID- 26580414 TI - Addressing Methodological Challenges in Large Communication Data Sets: Collecting and Coding Longitudinal Interactions in Home Hospice Cancer Care. AB - In this article, we present strategies for collecting and coding a large longitudinal communication data set collected across multiple sites, consisting of more than 2000 hours of digital audio recordings from approximately 300 families. We describe our methods within the context of implementing a large scale study of communication during cancer home hospice nurse visits, but this procedure could be adapted to communication data sets across a wide variety of settings. This research is the first study designed to capture home hospice nurse caregiver communication, a highly understudied location and type of communication event. We present a detailed example protocol encompassing data collection in the home environment, large-scale, multisite secure data management, the development of theoretically-based communication coding, and strategies for preventing coder drift and ensuring reliability of analyses. Although each of these challenges has the potential to undermine the utility of the data, reliability between coders is often the only issue consistently reported and addressed in the literature. Overall, our approach demonstrates rigor and provides a "how-to" example for managing large, digitally recorded data sets from collection through analysis. These strategies can inform other large-scale health communication research. PMID- 26580415 TI - Fabrication of Oxidation-Resistant Metal Wire Network-Based Transparent Electrodes by a Spray-Roll Coating Process. AB - Roll and spray coating methods have been employed for the fabrication of highly oxidation resistant transparent and conducting electrodes (TCEs) by a simple solution process using crackle lithography technique. We have spray-coated a crackle paint-based precursor to produce highly interconnected crackle network on PET roll mounted on a roll coater with web speed of 0.6 m/min. Ag TCE with a transmittance of 78% and sheet resistance of ~20 Omega/? was derived by spraying Ag precursor ink over the crackle template followed by lift-off and annealing under ambient conditions. The Ag wire mesh was stable toward bending and sonication tests but prone to oxidation in air. When electrolessly coated with Pd, its robustness toward harsh oxidation conditions was enhanced. A low-cost transparent electrode has also been realized by using only small amounts of Ag as seed layer and growing Cu wire mesh by electroless method. Thus, made Ag/Cu meshes are found to be highly stable for more than a year even under ambient atmosphere. PMID- 26580417 TI - Evaluation of the New "SAVE" Protocol in Diabetic Macular Edema Over the Course of Anti-VEGF Treatment. AB - BACKGROUND: To evaluate a recently established grading protocol for diabetic macular edema (DME) over the course of intravitreal anti-VEGF treatment with ranibizumab. METHODS: Fluorescein angiography images and optical coherence tomography scans before treatment and after 3 monthly applied intravitreal ranibizumab injections were retrospectively graded for each included study eye according to the recently introduced "SAVE" grading protocol ("S"= subretinal fluid; "A"= "area of retinal thickening"; "V"="vitreo-retinal abnormalities"; "E"="etiology of leakage focal versus non-focal") and correlated with best corrected visual acuity (BCVA) in letters (lett). RESULTS: Five of the 39 included study eyes had subretinal fluid ("S") before treatment which resolved during treatment. BCVA of study eyes with an initial retinal thickening smaller than one disc diameter ("A") was non-significantly higher compared to patients with a retinal thickening greater than one disc diameter (34.0 +/- 17.9 lett versus 25.3 +/- 13.3 lett, p=0.236) but became significant during treatment (40.5 +/- 10.0 lett versus 28.3 +/- 13.1 lett, p=0.004). No difference in BCVA was observed between patients with or without vitreo-retinal abnormalities ("V") before and during therapy. BCVA in patients with focal leakage ("E") was significantly higher than in patients with non-focal leakage before (33.1 +/- 12.3 lett versus 23.3 +/- 13.3 lett, p=0.017) and during (38.9 +/- 10.9 lett versus 26.3 +/- 12.6 lett, p=0.002) therapy. CONCLUSIONS: Applying the grading protocol "SAVE", focal leakage ("E") was the only retrospectively observed parameter which significantly correlated with a better BCVA before therapy and over the course of treatment in patients with fovea-involving DME. PMID- 26580416 TI - Chlamydial polymorphic membrane proteins: regulation, function and potential vaccine candidates. AB - Pmps (Polymorphic Membrane Proteins) are a group of membrane bound surface exposed chlamydial proteins that have been characterized as autotransporter adhesins and are important in the initial phase of chlamydial infection. These proteins all contain conserved GGA (I, L, V) and FxxN tetrapeptide motifs in the N-terminal portion of each protein. All chlamydial species express Pmps. Even in the chlamydia-related bacteria Waddlia chondrophila, a Pmp-like adhesin has been identified, demonstrating the importance of Pmps in Chlamydiales biology. Chlamydial species vary in the number of pmp genes and their differentially regulated expression during the infectious cycle or in response to stress. Studies have also demonstrated that Pmps are able to induce innate immune functional responses in infected cells, including production of IL-8, IL-6 and MCP-1, by activating the transcription factor NF-kappaB. Human serum studies have indicated that although anti-Pmp specific antibodies are produced in response to a chlamydial infection, the response is variable depending on the Pmp protein. In C. trachomatis, PmpB, PmpC, PmpD and PmpI were the proteins eliciting the strongest immune response among adolescents with and without pelvic inflammatory disease (PID). In contrast, PmpA and PmpE elicited the weakest antibody response. Interestingly, there seems to be a gender bias for Pmp recognition with a stronger anti-Pmp reactivity in male patients. Furthermore, anti-PmpA antibodies might contribute to adverse pregnancy outcomes, at least among women with PID. In vitro studies indicated that dendritic cells infected with C. muridarum were able to present PmpG and PmpF on their MHC class II receptors and T cells were able to recognize the MHC class-II bound peptides. In addition, vaccination with PmpEFGH and Major Outer Membrane Protein (MOMP) significantly protected mice against a genital tract C. muridarum infection, suggesting that Pmps may be an important component of a multi-subunit chlamydial vaccine. Thus, Pmps might be important not only for the pathogenesis of chlamydial infection, but also as potential candidate vaccine proteins. PMID- 26580418 TI - Surface-Mediated Protein Unfolding as a Search Process for Denaturing Sites. AB - Surface-induced protein denaturation has important implications for the development of materials that are resistant and/or innocuous to biomolecules. Here, we studied the mechanism of lysozyme (T4L) unfolding on fused silica (FS) using single-molecule methods that provided direct insight into the cause of denaturation. Unfolding of T4L was monitored by Forster resonance energy transfer while simultaneously tracking the adsorption, diffusion, and desorption of individual molecules at the solid-solution interface. Results of high-throughput single-molecule analysis suggested that the unfolding of T4L on FS was mediated by surface diffusion and occurred on isolated nanoscale sites, which were relatively rare and distinct from the majority of the surface. These observations suggest that surface-mediated protein unfolding is a search process that is based on the exploration for denaturing sites by the protein. Ultimately, these findings have important implications for the design of protein-compatible surfaces. PMID- 26580419 TI - The sxt Gene and Paralytic Shellfish Poisoning Toxins as Markers for the Monitoring of Toxic Alexandrium Species Blooms. AB - Paralytic shellfish poisoning (PSP) is a serious human illness caused by the ingestion of seafood contaminated with saxitoxin and its derivatives (STXs). These toxins are produced by some species of marine dinoflagellates within the genus Alexandrium. In the Mediterranean Sea, toxic Alexandrium spp. blooms, especially of A. minutum, are frequent and intense with negative impact to coastal ecosystem, aquaculture practices and other economic activities. We conducted a large scale study on the sxt gene and toxin distribution and content in toxic dinoflagellate A. minutum of the Mediterranean Sea using both quantitative PCR (qPCR) and HILIC-HRMS techniques. We developed a new qPCR assay for the estimation of the sxtA1 gene copy number in seawater samples during a bloom event in Syracuse Bay (Mediterranean Sea) with an analytical sensitivity of 2.0 * 10 degrees sxtA1 gene copy number per reaction. The linear correlation between sxtA1 gene copy number and microalgal abundance and between the sxtA1 gene and STX content allowed us to rapidly determine the STX-producing cell concentrations of two Alexandrium species in environmental samples. In these samples, the amount of sxtA1 gene was in the range of 1.38 * 10(5) - 2.55 * 10(8) copies/L and the STX concentrations ranged from 41-201 nmol/L. This study described a potential PSP scenario in the Mediterranean Sea. PMID- 26580420 TI - An Orally Bioavailable, Indole-3-glyoxylamide Based Series of Tubulin Polymerization Inhibitors Showing Tumor Growth Inhibition in a Mouse Xenograft Model of Head and Neck Cancer. AB - A number of indole-3-glyoxylamides have previously been reported as tubulin polymerization inhibitors, although none has yet been successfully developed clinically. We report here a new series of related compounds, modified according to a strategy of reducing aromatic ring count and introducing a greater degree of saturation, which retain potent tubulin polymerization activity but with a distinct SAR from previously documented libraries. A subset of active compounds from the reported series is shown to interact with tubulin at the colchicine binding site, disrupt the cellular microtubule network, and exert a cytotoxic effect against multiple cancer cell lines. Two compounds demonstrated significant tumor growth inhibition in a mouse xenograft model of head and neck cancer, a type of the disease which often proves resistant to chemotherapy, supporting further development of the current series as potential new therapeutics. PMID- 26580421 TI - Effect of Rumex Aquaticus Herba Extract Against Helicobacter pylori-Induced Inflammation in Gastric Epithelial Cells. AB - The purposes of this study were to examine the characteristics of Helicobacter pylori and the effect of Rumex Aquaticus Herba extract on the expression of cytokines in H. pylori-infected gastric epithelial cells. Cultured human adenocarcinoma gastric cells (AGS) were infected by H. pylori in RPMI 1640 media. Cell growth was measured by trypan blue assay. Western blot analysis was performed to investigate effect of extract containing Quercetin-3-O-beta-d glucuronopyranoside (ECQ) on the expression of inflammatory factors and the inhibition on cell growth. Furthermore, we compared the inhibitory effects with various combinations of clarithromycin, amoxicillin, omeprazole, and ECQ. The urease test with Christensen's Urea Agar was performed to identify the urease activity of H. pylori and the effect ECQ has on urease activity. When the cells were exposed to H. pylori, the trypan blue assay revealed a decrease in the rate of cell growth. Western blot analysis showed that H. pylori-infected cells had increased levels of degraded IkappaB-alpha and inflammatory factors. Pretreatment with ECQ inhibited interleukin expression induced by H. pylori in a dose dependent manner. A combination of ECQ and antibiotics inhibited cytokine expression more effectively than other treatments. H. pylori displayed significant urease activity. ECQ did not significantly inhibit urease activity. These data suggest that H. pylori infection has cytotoxic effects against AGS cells, and ECQ may inhibit the production of proinflammatory cytokines in H. pylori-infected AGS cells. PMID- 26580422 TI - Lateral Thalamic Infarction and the Vascular Geometry of the Posterior Cerebral Artery. AB - BACKGROUND: The geometric properties of the parental artery affect the development of local atherosclerosis and perforator infarction. In this study, we aimed at investigating the association between vascular geometry of the posterior cerebral artery (PCA) and the development of isolated lateral thalamic infarction (LTI), the most frequent type of thalamic infarction. METHODS: The geometric properties of the corresponding PCA in LTI patients were assessed and they include the diameters of the distal basilar artery (BA) and proximal PCA, distal BA - PCA angle, first PCA angle (angle between P1 and P2), and the presence of the posterior communicating artery (Pcom). These parameters obtained from the ipsilesional PCA were compared with the contralesional PCA and the corresponding PCA in age- and sex-matched controls. RESULTS: Forty-five LTI patients were enrolled. The ipsilesional PCA in LTI patients demonstrated a greater ipsilesional P1 - P2 angle (81.4 +/- 22.6 vs. 71.3 +/- 23.2 degrees , respectively; p = 0.04) and a higher prevalence of Pcom (42.2 vs. 13.3%; p = 0.002) when compared to control subjects. In comparison with the contralesional PCA, ipsilesional PCA demonstrated a smaller diameter, larger angle between P1 and P2 segment, and a higher prevalence of Pcom. The presence of hyperlipidemia (OR 3.548 (1.283-9.811); p = 0.02) and Pcom (OR 3.507 (1.104-11.135); p = 0.03) was a factor that was independently associated with LTI. CONCLUSIONS: Local hemodynamics in the PCA may be influenced by the P1 - P2 angle and the presence of Pcom, which are associated with the development of LTI. PMID- 26580423 TI - [Research in nursing ethics - looking back and looking forward]. PMID- 26580424 TI - Research in Nursing Ethics--Looking Back & Looking Forward. PMID- 26580425 TI - [Acute care nurses' ethical reasoning: a thematic analysis]. AB - BACKGROUND: In the day-to-day course of nursing, ethical issues are being openly articulated to a growing extent. However, nurses only rarely systematically address these issues. This subject was explored in interviews with professionals who have a particular focus on ethics. OBJECTIVE: Gain input for further developing the skills of nursing staff in ethical reasoning. METHOD: In two focus groups and four individual interviews, we questioned 14 professionals, including nine nurses, who have a special interest in ethics. RESULTS: Nurses find it ethically problematic when the wishes of patients are not respected or something is forced on them, creating the impression that the care being given is exacerbating rather than alleviating the patient's suffering. These problematic aspects are often overlooked because the consequences of the action in question are not immediately apparent. Ethical issues in nursing are often addressed in informal, non-systematic discussions among nursing staff. Nurses actively and confidently engage in discussions on treatment goals, and the teamwork with doctors is usually experienced as being based on mutual respect and partnership. The inherent hierarchical role differences between nursing and medical staff nevertheless manifest in ethical issues. CONCLUSION: Through the practical application of ethical reasoning in day-to-day nursing, structured discussions of the ethical aspects of cases and dedicated further education, nurses should learn to better recognise ethical issues in nursing and effectively analyse them and find solutions. PMID- 26580426 TI - [Decision-making processes in nursing and activities at the end of life in intensive care-An international comparative study]. AB - BACKGROUND: Intensive care units (ICUs) are traditionally settings that offer high technologically advanced treatment for those who are in critical situations due to an illness or accident. Questions regarding the withdrawal and withholding as well as the ending of life sustaining treatment are related to ethical dilemmas. Nurses' decision-making processes and nursing activities in different countries are scarcely studied. QUESTION: Which end-of-life decision-making processes and activities that are performed by nurses can be identified and described? AIM: The objective is the identification of a nursing terrain regarding decision-making and activities in patient end-of-life care on the intensive care unit. METHOD: Semi-structured interviews were conducted with 51 experienced nurses in university or hospital premises: 10 in Brazil, 9 in England, 10 in Germany, 10 in Ireland and 12 nurses in Palestine. The study used grounded theory to inform data collection and analysis. RESULTS: The finding of the study is the identification of a dynamic process in which activities with a focus on cure shift to activities with a focus on end-of-life care. The core category that emerged was 'negotiated reorienting': The shift of activities implies negotiations between nurses and physicians, relatives as well as with oneself. Moreover the process is characterized by a constant re-orientation that is induced by changing patient data and the realisation of the whole situation. Nurses' core practices are 'consensus seeking' and 'emotional holding' (sub categories). CONCLUSIONS: In all countries a nursing terrain of activities in end of-life care could be identified and described. However, it is unclear whether nursing activities connected to relatives of the patient are dominant in such a way that relations to dying patients and respect for their autonomy are put into the background. A field study could give answers to this question possible. PMID- 26580427 TI - [Effects of care experience to the attitude of active euthanasia among the Austrian population-a cross sectional study]. AB - BACKGROUND: Attitudes towards active euthanasia by request of competent patients who are seriously or incurable ill people are common in public debates. There is still a lack of knowledge on how people with care experience differ in their attitudes towards active euthanasia from those without. AIM: The aim of this study is to find out if and how care experience has an effect on the attitude toward voluntary active euthanasia. METHOD: In spring 2014 a cross-sectional survey was conducted among the Austrian population by a self-developed questionnaire (on basis of a qualitative pilot study). An online-survey was distributed among persons aged 16 to 65 years and a postal survey among those aged 65 years and older (n=725). Descriptive data was analysed with IBM SPSS Version 2.0. Ethical approval has been provided by the Medical University Graz. RESULTS: 48% of the respondents have experience with care, 8.6% as physicians or nurses, 43.7% as family caregiver and 50% as not caring relatives. Multiple answers were possible. People with caring experience-as nurses or family caregiver-show a significantly lower approval of voluntary active euthanasia (p=0.04). CONCLUSIONS: Care experiences have an impact on the attitude towards voluntary active euthanasia. Thus, experiences of caring should be better included in end-of-life debates. PMID- 26580428 TI - [Proxy decision about long-term gastrostomy tubes (PEG catheters) in patients with dementia in long-term nursing care: reducing decision uncertainty in health related taboo topics]. PMID- 26580431 TI - Synthesis aided design: The biological design-build-test engineering paradigm? PMID- 26580432 TI - Effect of Antimicrobial Use in Agricultural Animals on Drug-resistant Foodborne Campylobacteriosis in Humans: A Systematic Literature Review. AB - Controversy continues concerning antimicrobial use in food animals and its relationship to drug-resistant infections in humans. We systematically reviewed published literature for evidence of a relationship between antimicrobial use in agricultural animals and drug-resistant foodborne campylobacteriosis in humans. Based on publications from the United States (U.S.), Canada and Denmark from 2010 to July 2014, 195 articles were retained for abstract review, 50 met study criteria for full article review with 36 retained for which data are presented. Two publications reported increase in macrolide resistance of Campylobacter coli isolated from feces of swine receiving macrolides in feed, and one of these described similar findings for tetracyclines and fluoroquinolones. A study in growing turkeys demonstrated increased macrolide resistance associated with therapeutic dosing with Tylan(r) in drinking water. One publication linked tetracycline-resistant C. jejuni clone SA in raw cow's milk to a foodborne outbreak in humans. No studies that identified farm antimicrobial use also traced antimicrobial-resistant Campylobacter from farm to fork. Recent literature confirms that on farm antibiotic selection pressure can increase colonization of animals with drug-resistant Campylobacter spp. but is inadequately detailed to establish a causal relationship between use of antimicrobials in agricultural animals and prevalence of drug-resistant foodborne campylobacteriosis in humans. PMID- 26580433 TI - Potential of Using Maize Cobs in Pig Diets - A Review. AB - The quest to broaden the narrow range of feed ingredients available to pig producers has prompted research on the use of low cost, unconventional feedstuffs, which are typically fibrous and abundant. Maize cobs, a by-product of a major cereal grown worldwide, have potential to be used as a pig feed ingredient. Presently, maize cobs are either dumped or burnt for fuel. The major challenge in using maize cobs in pig diets is their lignocellulosic nature (45% to 55% cellulose, 25% to 35% hemicellulose, and 20% to 30% lignin) which is resistant to pigs' digestive enzymes. The high fiber in maize cobs (930 g neutral detergent fiber/kg dry matter [DM]; 573 g acid detergent fiber/kg DM) increases rate of passage and sequestration of nutrients in the fiber reducing their digestion. However, grinding, heating and fermentation can modify the structure of the fibrous components in the maize cobs and improve their utilization. Pigs can also extract up to 25% of energy maintenance requirements from fermentation products. In addition, dietary fiber improves pig intestinal health by promoting the growth of lactic acid bacteria, which suppress proliferation of pathogenic bacteria in the intestines. This paper reviews maize cob composition and the effect on digestibility of nutrients, intestinal microflora and growth performance and proposes the use of ensiling using exogenous enzymes to enhance utilization in diets of pigs. PMID- 26580434 TI - Molecular Characterization and Expression Analysis of Creatine Kinase Muscle (CK M) Gene in Horse. AB - Since ancient days, domestic horses have been closely associated with human civilization. Today, horse racing is an important industry. Various genes involved in energy production and muscle contraction are differentially regulated during a race. Among them, creatine kinase (CK) is well known for its regulation of energy preservation in animal cells. CK is an iso-enzyme, encoded by different genes and expressed in skeletal muscle, heart, brain and leucocytes. We confirmed that the expression of CK-M significantly increased in the blood after a 30 minute exercise period, while no considerable change was observed in skeletal muscle. Analysis of various tissues showed an ubiquitous expression of the CK-M gene in the horse; CK-M mRNA expression was predominant in the skeletal muscle and the cardiac muscle compared to other tissues. An evolutionary study by synonymous and non-synonymous single nucleotide polymorphism ratio of CK-M gene revealed a positive selection that was conserved in the horse. More studies are warranted in order to develop the expression of CK-M gene as a biomarker in blood of thoroughbred horses. PMID- 26580436 TI - Genetic Parameters of Pre-adjusted Body Weight Growth and Ultrasound Measures of Body Tissue Development in Three Seedstock Pig Breed Populations in Korea. AB - The objective of this study was to compare the effects of body weight growth adjustment methods on genetic parameters of body growth and tissue among three pig breeds. Data collected on 101,820 Landrace, 281,411 Yorkshire, and 78,068 Duroc pigs, born in Korean swine breeder farms since 2000, were analyzed. Records included body weights on test day and amplitude (A)-mode ultrasound carcass measures of backfat thickness (BF), eye muscle area (EMA), and retail cut percentage (RCP). Days to 90 kg body weight (DAYS90), through an adjustment of the age based on the body weight at the test day, were obtained. Ultrasound measures were also pre-adjusted (ABF, EMA, AEMA, ARCP) based on their test day measures. The (co)variance components were obtained with 3 multi-trait animal models using the REMLF90 software package. Model I included DAYS90 and ultrasound traits, whereas model II and III accounted DAYS90 and pre-adjusted ultrasound traits. Fixed factors were sex (sex) and contemporary groups (herd-year-month of birth) for all traits among the models. Additionally, model I and II considered a linear covariate of final weight on the ultrasound measure traits. Heritability (h(2)) estimates for DAYS90, BF, EMA, and RCP ranged from 0.36 to 0.42, 0.34 to 0.43, 0.20 to 0.22, and 0.39 to 0.45, respectively, among the models. The h(2) estimates of DAYS90 from model II and III were also somewhat similar. The h(2) for ABF, AEMA, and ARCP were 0.35 to 0.44, 0.20 to 0.25, and 0.41 to 0.46, respectively. Our heritability estimates varied mostly among the breeds. The genetic correlations (rG) were moderately negative between DAYS90 and BF (-0.29 to -0.38), and between DAYS90 and EMA (-0.16 to -0.26). BF had strong rG with RCP (-0.87 to -0.93). Moderately positive rG existed between DAYS90 and RCP (0.20 to 0.28) and between EMA and RCP (0.35 to 0.44) among the breeds. For DAYS90, model II and III, its correlations with ABF, AEMA, and ARCP were mostly low or negligible except the rG between DAYS90 and AEMA from model III (0.27 to 0.30). The rG between AEMA and ABF and between AEMA and ARCP were moderate but with negative and positive signs, respectively; also reflected influence of pre adjustments. However, the rG between BF and RCP remained non-influential to trait pre-adjustments or covariable fits. Therefore, we conclude that ultrasound measures taken at a body weight of about 90 kg as the test final should be adjusted for body weight growth. Our adjustment formulas, particularly those for BF and EMA, should be revised further to accommodate the added variation due to different performance testing endpoints with regard to differential growth in body composition. PMID- 26580435 TI - Association of Chicken Growth Hormones and Insulin-like Growth Factor Gene Polymorphisms with Growth Performance and Carcass Traits in Thai Broilers. AB - Molecular marker selection has been an acceptable tool in the acceleration of the genetic response of desired traits to improve production performance in chickens. The crossbreds from commercial parent stock (PS) broilers with four Thai synthetic breeds; Kaen Thong (KT), Khai Mook Esarn (KM), Soi Nin (SN), and Soi Pet (SP) were used to study the association among chicken growth hormones (cGH) and the insulin-like growth factor (IGF-I) genes for growth and carcass traits; for the purpose of developing a suitable terminal breeding program for Thai broilers. A total of 408 chickens of four Thai broiler lines were genotyped, using polymerase chain reaction-restriction fragment length polymorphism methods. The cGH gene was significantly associated with body weight at hatching; at 4, 6, 8, 10 weeks of age and with average daily gain (ADG); during 2 to 4, 4 to 6, 0 to 6, 0 to 8, and 0 to 10 weeks of age in PS*KM chickens. For PS*KT populations, cGH gene showed significant association with body weight at hatching, and ADG; during 8 to 10 weeks of age. The single nucleotide polymorphism variant confirmed that allele G has positive effects for body weight and ADG. Within carcass traits, cGH revealed a tentative association within the dressing percentage. For the IGF-I gene polymorphism, there were significant associations with body weight at hatching; at 2, 4, and 6 weeks of age and ADG; during 0 to 2, 4 to 6, and 0 to 6 weeks of age; in all of four Thai broiler populations. There were tentative associations of the IGF-I gene within the percentages of breast muscles and wings. Thus, cGH gene may be used as a candidate gene, to improve growth traits of Thai broilers. PMID- 26580437 TI - Subcellular Characterization of Porcine Oocytes with Different Glucose-6 phosphate Dehydrogenase Activities. AB - The in vitro maturation (IVM) efficiency of porcine embryos is still low because of poor oocyte quality. Although brilliant cresyl blue positive (BCB+) oocytes with low glucose-6-phosphate dehydrogenase (G6PDH) activity have shown superior quality than BCB negative (-) oocytes with high G6PDH activity, the use of a BCB staining test before IVM is still controversial. This study aimed to shed more light on the subcellular characteristics of porcine oocytes after selection using BCB staining. We assessed germinal vesicle chromatin configuration, cortical granule (CG) migration, mitochondrial distribution, the levels of acetylated lysine 9 of histone H3 (AcH3K9) and nuclear apoptosis features to investigate the correlation between G6PDH activity and these developmentally related features. A pattern of chromatin surrounding the nucleoli was seen in 53.0% of BCB+ oocytes and 77.6% of BCB+ oocytes showed peripherally distributed CGs. After IVM, 48.7% of BCB+ oocytes had a diffused mitochondrial distribution pattern. However, there were no significant differences in the levels of AcH3K9 in the nuclei of blastocysts derived from BCB+ and BCB- oocytes; at the same time, we observed a similar incidence of apoptosis in the BCB+ and control groups. Although this study indicated that G6PDH activity in porcine oocytes was correlated with several subcellular characteristics such as germinal vesicle chromatin configuration, CG migration and mitochondrial distribution, other features such as AcH3K9 level and nuclear apoptotic features were not associated with G6PDH activity and did not validate the BCB staining test. In using this test for selecting porcine oocytes, subcellular characteristics such as the AcH3K9 level and apoptotic nuclear features should also be considered. Adding histone deacetylase inhibitors or apoptosis inhibitors into the culture medium used might improve the efficiency of IVM of BCB+ oocytes. PMID- 26580438 TI - The Usefulness of Selected Physicochemical Indices, Cell Membrane Integrity and Sperm Chromatin Structure in Assessments of Boar Semen Sensitivity. AB - The present work describes experiments undertaken to evaluate the usefulness of selected physicochemical indices of semen, cell membrane integrity and sperm chromatin structure for the assessment of boar semen sensitivity to processes connected with pre-insemination procedures. The experiments were carried out on 30 boars: including 15 regarded as providers of sensitive semen and 15 regarded as providers of semen that is little sensitive to laboratory processing. The selection of boars for both groups was based on sperm morphology analyses, assuming secondary morphological change incidence in spermatozoa as the criterion. Two ejaculates were manually collected from each boar at an interval of 3 to 4 months. The following analyses were carried out for each ejaculate: sperm motility assessment, sperm pH measurement, sperm morphology assessment, sperm chromatin structure evaluation and cell membrane integrity assessment. The analyses were performed three times. Semen storage did not cause an increase in the incidence of secondary morphological changes in the group of boars considered to provide sperm of low sensitivity. On the other hand, with continued storage there was a marked increase in the incidence of spermatozoa with secondary morphological changes in the group of boars regarded as producing more sensitive semen. Ejaculates of group I boars evaluated directly after collection had an approximately 6% smaller share of spermatozoa with undamaged cell membranes than the ejaculates of boars in group II (p<=0.05). In the process of time the percentage of spermatozoa with undamaged cell membranes decreased. The sperm of group I boars was characterised with a lower sperm motility than the semen of group II boars. After 1 hour of storing diluted semen, the sperm motility of boars producing highly sensitive semen was already 4% lower (p<=0.05), and after 24 hours of storage it was 6.33% lower than that of the boars that produced semen with a low sensitivity. Factors that confirm the accuracy of insemination male selection can include a low rate of sperm motility decrease during the storage of diluted semen, low and contained incidence of secondary morphological changes in spermatozoa during semen storage and a high frequency of spermatozoa with undamaged cell membranes. PMID- 26580439 TI - Characterization of Bovine NANOG5'-flanking Region during Differentiation of Mouse Embryonic Stem Cells. AB - Embryonic stem cells (ESCs) have been used as a powerful tool for research including gene manipulated animal models and the study of developmental gene regulation. Among the critical regulatory factors that maintain the pluripotency and self-renewal of undifferentiated ESCs, NANOG plays a very important role. Nevertheless, because pluripotency maintaining factors and specific markers for livestock ESCs have not yet been probed, few studies of the NANOG gene from domestic animals including bovine have been reported. Therefore, we chose mouse ESCs in order to understand and compare NANOG expression between bovine, human, and mouse during ESCs differentiation. We cloned a 600 bp (-420/+181) bovine NANOG 5'-flanking region, and tagged it with humanized recombinant green fluorescent protein (hrGFP) as a tracing reporter. Very high GFP expression for bovine NANOG promoter was observed in the mouse ESC line. GFP expression was monitored upon ESC differentiation and was gradually reduced along with differentiation toward neurons and adipocyte cells. Activity of bovine NANOG ( 420/+181) promoter was compared with already known mouse and human NANOG promoters in mouse ESC and they were likely to show a similar pattern of regulation. In conclusion, bovine NANOG 5-flanking region functions in mouse ES cells and has characteristics similar to those of mouse and human. These results suggest that bovine gene function studied in mouse ES cells should be evaluated and extrapolated for application to characterization of bovine ES cells. PMID- 26580440 TI - Effect of Medicinal Plant By-products Supplementation to Total Mixed Ration on Growth Performance, Carcass Characteristics and Economic Efficacy in the Late Fattening Period of Hanwoo Steers. AB - This study was conducted to evaluate the effect of medicinal plant by-products (MPB) supplementation to a total mixed ration (TMR) on growth, carcass characteristics and economic efficacy in the late fattening period of Hanwoo steers. Twenty seven steers (body weight [BW], 573+/-57 kg) were assigned to 3 treatment groups so that each treatment based on BW contained 9 animals. All groups received ad libitum TMR throughout the feeding trial until slaughter (from 24 to 30 months of age) and treatments were as follows: control, 1,000 g/kg TMR; treatment 1 (T1), 970 g/kg TMR and 30 g/kg MPB; treatment 2 (T2), 950 g/kg TMR and 50 g/kg MPB. Initial and final BW were not different among treatments. Resultant data were analyzed using general linear models of SAS. Average daily gain and feed efficiency were higher (p<0.05) for T1 than control, but there was no difference between control and T2. Plasma albumin showed low-, intermediate- and high-level (p<0.05) for control, T1 and T2, whereas non-esterified fatty acid was high-, intermediate- and high-level (p<0.05) for control, T1 and T2, respectively. Carcass weight, carcass rate, backfat thickness and rib eye muscle area were not affected by MPB supplementation, whereas quality and yield grades were highest (p<0.05) for T1 and T2, respectively. Daily feed costs were decreased by 0.5% and 0.8% and carcass prices were increased by 18.1% and 7.6% for T1 and T2 compared to control, resulting from substituting TMR with 30 and 50 g/kg MPB, respectively. In conclusion, the substituting TMR by 30 g/kg MPB may be a potential feed supplement approach to improve economic efficacy in the late fattening period of Hanwoo steers. PMID- 26580441 TI - Effects of Forage:Concentrate Ratio on Growth Performance, Ruminal Fermentation and Blood Metabolites in Housing-feeding Yaks. AB - The objective of this study was to determine the effect of forage: concentrate ratio (F:C) on growth performance, ruminal fermentation and blood metabolites of housing-feeding yaks. Thirty-two Maiwa male yaks (initial body weight = 207.99+/ 3.31 kg) were randomly assigned to four dietary treatments (8 yaks per treatment). Experimental diets were: A, B, C, D which contained 70:30, 60:40, 50:50 and 40:60 F:C ratios, respectively. Dry matter intake and average daily gain in yaks fed the C and D diets were greater (p<0.05) than yaks fed the A and B diets. No differences were found in ruminal NH3-N, total volatile fatty acids, acetate, butyrate, valerate, and isovalerate concentrations. The propionate concentration was increased (p<0.05) in the C and D groups compared with the A and B diets. In contrast, the acetate to propionate ratio was decreased and was lowest (p<0.05) in the C group relative to the A and B diets, but was similar with the D group. For blood metabolites, no differences were found in serum concentrations of urea-N, albumin, triglyceride, cholesterol, low density lipoprotein, alanine aminotransferase, and aspartate aminotransferase (p>0.05) among treatments. Treatment C had a higher concentration of total protein and high density lipoprotein (p<0.05) than A and B groups. In addition, there was a trend that the globulin concentration of A group was lower than other treatments (p = 0.079). Results from this study suggest that increasing the level of concentrate from 30% to 50% exerted a positive effect on growth performance, rumen fermentation and blood metabolites in yaks. PMID- 26580442 TI - Branched-chain Amino Acids are Beneficial to Maintain Growth Performance and Intestinal Immune-related Function in Weaned Piglets Fed Protein Restricted Diet. AB - As a novel approach for disease control and prevention, nutritional modulation of the intestinal health has been proved. However, It is still unknown whether branched-chain amino acid (BCAA) is needed to maintain intestinal immune-related function. The objective of this study was to determine whether BCAA supplementation in protein restricted diet affects growth performance, intestinal barrier function and modulates post-weaning gut disorders. One hundred and eight weaned piglets (7.96+/-0.26 kg) were randomly fed one of the three diets including a control diet (21% crude protein [CP], CON), a protein restricted diet (17% CP, PR) and a BCAA diet (BCAA supplementation in the PR diet) for 14 d. The growth performance, plasma amino acid concentrations, small intestinal morphology and intestinal immunoglobulins were tested. First, average daily gain (ADG) (p<0.05) and average daily feed intake (ADFI) (p<0.05) of weaned pigs in PR group were lower, while gain:feed ratio was lower than the CON group (p<0.05). Compared with PR group, BCAA group improved ADG (p<0.05), ADFI (p<0.05) and feed:gain ratio (p<0.05) of piglets. The growth performance data between CON and BCAA groups was not different (p>0.05). The PR and BCAA treatments had a higher (p<0.05) plasma concentration of methionine and threonine than the CON treatment. The level of some essential and functional amino acids (such as arginine, phenylalanine, histidine, glutamine etc.) in plasma of the PR group was lower (p<0.05) than that of the CON group. Compared with CON group, BCAA supplementation significantly increased BCAA concentrations (p<0.01) and decreased urea concentration (p<0.01) in pig plasma indicating that the efficiency of dietary nitrogen utilization was increased. Compared with CON group, the small intestine of piglets fed PR diet showed villous atrophy, increasing of intra-epithelial lymphocytes (IELs) number (p<0.05) and declining of the immunoglobulin concentration, including jejunal immunoglobulin A (IgA) (p = 0.04), secreted IgA (sIgA) (p = 0.03) and immunoglobulin M (p = 0.08), and ileal IgA (p = 0.01) and immunoglobulin G (p = 0.08). The BCAA supplementation increased villous height in the duodenum (p<0.01), reversed the trend of an increasing IELs number. Notably, BCAA supplementation increased levels of jejunal and ileal immunoglobulin mentioned above. In conclusion, BCAA supplementation to protein restricted diet improved intestinal immune defense function by protecting villous morphology and by increasing levels of intestinal immunoglobulins in weaned piglets. Our finding has the important implication that BCAA may be used to reduce the negative effects of a protein restricted diet on growth performance and intestinal immunity in weaned piglets. PMID- 26580443 TI - The Effect of Inclusion Level of Soybean Oil and Palm Oil on Their Digestible and Metabolizable Energy Content Determined with the Difference and Regression Method When Fed to Growing Pigs. AB - This experiment was conducted to determine the effects of inclusion level of soybean oil (SO) and palm oil (PO) on their digestible and metabolism energy (DE and ME) contents when fed to growing pigs by difference and regression method. Sixty-six crossbred growing barrows (Duroc*Landrace*Yorkshire and weighing 38.1+/ 2.4 kg) were randomly allotted to a 2*5 factorial arrangement involving 2 lipid sources (SO and PO), and 5 levels of lipid (2%, 4%, 6%, 8%, and 10%) as well as a basal diet composed of corn and soybean meal. The barrows were housed in individual metabolism crates to facilitate separate collection of feces and urine, and were fed the assigned test diets at 4% of initial body weight per day. A 5-d total collection of feces and urine followed a 7-d diet adaptation period. The results showed that the DE and ME contents of SO and PO determined by the difference method were not affected by inclusion level. The DE and ME determined by the regression method for SO were greater compared with the corresponding respective values for PO (DE: 37.07, ME: 36.79 MJ/kg for SO; DE: 34.11, ME: 33.84 MJ/kg for PO, respectively). These values were close to the DE and ME values determined by the difference method at the 10% inclusion level (DE: 37.31, ME: 36.83 MJ/kg for SO; DE: 34.62, ME: 33.47 MJ/kg for PO, respectively). A similar response for the apparent total tract digestibility of acid-hydrolyzed ether extract (AEE) in lipids was observed. The true total tract digestibility of AEE in SO was significantly (p<0.05) greater than that for PO (97.5% and 91.1%, respectively). In conclusion, the DE and ME contents of lipid was not affected by its inclusion level. The difference method can substitute the regression method to determine the DE and ME contents in lipids when the inclusion level is 10%. PMID- 26580444 TI - Proximate Composition, and l-Carnitine and Betaine Contents in Meat from Korean Indigenous Chicken. AB - This study investigated the proximate composition and l-carnitine and betaine content of meats from 5 lines of Korean indigenous chicken (KIC) for developing highly nutritious meat breeds with health benefits from the bioactive compounds such as l-carnitine and betaine in meat. In addition, the relevance of gender (male and female) and meat type (breast and thigh meat) was examined. A total of 595 F1 progeny (black [B], grey-brown [G], red-brown [R], white [W], and yellow brown [Y]) from 70 full-sib families were used. The moisture, protein, fat, and ash contents of the meats were significantly affected by line, gender, and meat type (p<0.05). The males in line G and females in line B showed the highest protein and the lowest fat content of the meats. l-carnitine and betaine content showed effects of meat type, line, and gender (p<0.05). The highest l-carnitine content was found in breast and thigh meats from line Y in both genders. The breast meat from line G and the thigh meat from line R had the highest betaine content in males. The female breast and thigh meats showed the highest betaine content in line R. These data could be valuable for establishing selection strategies for developing highly nutritious chicken meat breeds in Korea. PMID- 26580445 TI - Effects of Water-misting Sprays with Forced Ventilation after Transport during Summer on Meat Quality, Stress Parameters, Glycolytic Potential and Microstructures of Muscle in Broilers. AB - Effects of water-misting sprays with forced ventilation after transport during summer on meat quality, stress parameters, glycolytic potential and microstructures of muscle in broilers were investigated. A total of 105 mixed-sex Arbor Acres broilers were divided into three treatment groups: i) 45-min transport without rest (T group), ii) 45-min transport with 1-h rest (TR group), iii) 45-min transport with 15-min water-misting sprays with forced ventilation and 45-min rest (TWFR group). The results showed the TWFR group significantly increased (p<0.05) initial muscle pH (pHi) and ultimate pH (pHu) and significantly reduced L* (p<0.05), drip loss, cook loss, creatine kinase, lactate dehydrogenase activity, plasma glucose content, lactate and glycolytic potential when compared with other groups. Microstructure of the muscle from TWFR group broilers under light microscopy showed smaller intercellular spaces among muscle fibers and bundles compared with T group. In conclusion this study indicated water-misting sprays with forced ventilation after transport could relieve the stress caused by transport under high temperature, which was favorable for the broilers' welfare. Furthermore, water-misting sprays with forced ventilation after transport slowed down the postmortem glycolysis rate and inhibited the occurrence of PSE-like meat in broilers. Although rest after transport could also improve the meat quality, the effect was not as significant as water-misting sprays with forced ventilation after transport. PMID- 26580446 TI - Molecular Cloning and Characterization of a New C-type Lysozyme Gene from Yak Mammary Tissue. AB - Milk lysozyme is the ubiquitous enzyme in milk of mammals. In this study, the cDNA sequence of a new chicken-type (c-type) milk lysozyme gene (YML), was cloned from yak mammary gland tissue. A 444 bp open reading frames, which encodes 148 amino acids (16.54 kDa) with a signal peptide of 18 amino acids, was sequenced. Further analysis indicated that the nucleic acid and amino acid sequences identities between yak and cow milk lysozyme were 89.04% and 80.41%, respectively. Recombinant yak milk lysozyme (rYML) was produced by Escherichia coli BL21 and Pichia pastoris X33. The highest lysozyme activity was detected for heterologous protein rYML5 (M = 1,864.24 U/mg, SD = 25.75) which was expressed in P. pastoris with expression vector pPICZalphaA and it clearly inhibited growth of Staphylococcus aureus. Result of the YML gene expression using quantitative polymerase chain reaction showed that the YML gene was up-regulated to maximum at 30 day postpartum, that is, comparatively high YML can be found in initial milk production. The phylogenetic tree indicated that the amino acid sequence was similar to cow kidney lysozyme, which implied that the YML may have diverged from a different ancestor gene such as cow mammary glands. In our study, we suggest that YML be a new c-type lysozyme expressed in yak mammary glands that plays a role as host immunity. PMID- 26580447 TI - Effects of Tributyrin on Intestinal Energy Status, Antioxidative Capacity and Immune Response to Lipopolysaccharide Challenge in Broilers. AB - This study was carried out to investigate the effects of tributyrin (TB) on the growth performance, pro-inflammatory cytokines, intestinal morphology, energy status, disaccharidase activity, and antioxidative capacity of broilers challenged with lipopolysaccharide (LPS). A total of 160 one-day-old Cobb broilers were allocated to 1 of 4 treatments, with 4 replicated pens per treatment and 10 birds per pen. The experiment consisted of a 2*2 factorial arrangements of treatments with TB supplementation (0 or 500 mg/kg) and LPS challenge (0 or 500 MUg/kg body weight [BW]). On days 22, 24, and 26 of the trial, broilers received an intraperitoneal administration of 500 MUg/kg BW LPS or saline. Dietary TB showed no effect on growth performance. However, LPS challenge decreased the average daily gain of broilers from day 22 to day 26 of the trial. Dietary TB supplementation inhibited the increase of interleukin-1beta (in the jejunum and ileum), interleukin-6 (in the duodenum and jejunum), and prostaglandin E2 (in the duodenum) of LPS-challenged broilers. Similar inhibitory effects of TB in the activities of total nitric oxide synthase (in the ileum) and inducible nitric oxide synthase (in the jejunum) were also observed in birds challenged with LPS. Additionally, TB supplementation mitigated the decrease of ileal adenosine triphosphate, adenosine diphosphate and total adenine nucleotide and the reduction of jejunal catalase activity induced by LPS. Taken together, these results suggest that the TB supplementation was able to reduce the release of pro-inflammatory cytokines and improve the energy status and anti-oxidative capacity in the small intestine of LPS-challenged broilers. PMID- 26580448 TI - Germline Mutations in Predisposition Genes in Pediatric Cancer. AB - BACKGROUND: The prevalence and spectrum of predisposing mutations among children and adolescents with cancer are largely unknown. Knowledge of such mutations may improve the understanding of tumorigenesis, direct patient care, and enable genetic counseling of patients and families. METHODS: In 1120 patients younger than 20 years of age, we sequenced the whole genomes (in 595 patients), whole exomes (in 456), or both (in 69). We analyzed the DNA sequences of 565 genes, including 60 that have been associated with autosomal dominant cancer predisposition syndromes, for the presence of germline mutations. The pathogenicity of the mutations was determined by a panel of medical experts with the use of cancer-specific and locus-specific genetic databases, the medical literature, computational predictions, and second hits identified in the tumor genome. The same approach was used to analyze data from 966 persons who did not have known cancer in the 1000 Genomes Project, and a similar approach was used to analyze data from an autism study (from 515 persons with autism and 208 persons without autism). RESULTS: Mutations that were deemed to be pathogenic or probably pathogenic were identified in 95 patients with cancer (8.5%), as compared with 1.1% of the persons in the 1000 Genomes Project and 0.6% of the participants in the autism study. The most commonly mutated genes in the affected patients were TP53 (in 50 patients), APC (in 6), BRCA2 (in 6), NF1 (in 4), PMS2 (in 4), RB1 (in 3), and RUNX1 (in 3). A total of 18 additional patients had protein-truncating mutations in tumor-suppressor genes. Of the 58 patients with a predisposing mutation and available information on family history, 23 (40%) had a family history of cancer. CONCLUSIONS: Germline mutations in cancer-predisposing genes were identified in 8.5% of the children and adolescents with cancer. Family history did not predict the presence of an underlying predisposition syndrome in most patients. (Funded by the American Lebanese Syrian Associated Charities and the National Cancer Institute.). PMID- 26580451 TI - A new medium for triplet-triplet annihilated upconversion and photocatalytic application. AB - Since the triplet-triplet annihilated upconversion (TTA-UC) materials work efficiently only in degassing organic solvents, it is of significance to find a new medium without toxicity and volatility and that promotes TTA-UC. Here, we firstly reported the effect of an OH-containing medium on low power upconversion and found that in alcohol solvent containing beta-cyclodextrin (beta-CD), the phosphorescence lifetime (taup) of the sensitizer (PdTPP) and the fluorescence quantum yield (Phif) of the acceptor (DPA) were enhanced with the increase in the number of OH-groups of the medium. A large triplet-triplet quenching constant (kq, 1.91 * 10(9) M(-1) s(-1)) and high upconversion efficiency (PhiUC, ~ 36%) of PdTPP/DPA were obtained under the excitation of a diode laser (532 nm, 60 mW cm( 2)). Under our green-to-blue upconversion irradiation, in a demonstration experiment the photocurrent was recorded at 0.09 MUA cm(-2), resulting from photocatalytic water splitting by a Cd0.7Zn0.3S photoanode and a Pt counter electrode in a photoelectrochemical cell. The importance of this study suggests that upconversion-powered photoelectrochemistry possesses potential application for hydrogen generation from water under excitation of sun energy. PMID- 26580450 TI - The Importance of Hand Exposures to Absorbed Dosage of Hand Harvesters. AB - Fruit harvesters' primary pesticide exposure results from direct dermal and clothing contact with foliar residues. The transfer of pesticide residues from foliage to strawberry harvesters' hands and their subsequent dissipation under normal occupational conditions in the field was examined. The effectiveness of latex gloves as sampling dosimeters was evaluated and compared with bare-handed harvester exposures. After application of malathion and fenpropathrin insecticides on strawberry fields, resulting harvester exposures using four independent methods were studied. Between d 4 (preharvest interval, PHI) and d 7 after pesticide application, (1) dislodgeable foliar residues, (2) pesticide residues accumulating on the gloves, and (3) end-of-shift harvester hand-wash residues decreased by 90, 75, and 85%, respectively. In contrast, the 7-d decline in excreted urine metabolites was only 43% for gloved harvesters and 29% for barehanded ones. In addition, gloved harvesters displayed 23% lower biomonitored exposures than barehanded ones, demonstrating that latex gloves are an effective protective barrier against surface residues. Since malathion and its metabolites are readily excreted, data indicated that there were likely other sources of excreted malathion breakdown products present on foliar surfaces after dissipation of malathion itself. PMID- 26580449 TI - Correlates of misperception of breast cancer risk among Korean-American Women. AB - In this study, the authors investigate the factors associated with misperception of breast cancer risk, including unrealistic optimism and unrealistic pessimism, among Korean-American women (KAW). Baseline data were collected between March 2010 and October 2011 from 421 KAW aged 40-65 years who participated in a community-based randomized intervention trial designed to promote breast and cervical cancer screening. Multivariate multinomial regression was performed to identify correlates of misperception of breast cancer risk among KAW. A total of 210 KAW (49.9%) had breast cancer risk perception consistent with their objective risk, whereas 50.1% of KAW in the study had some form of misperception of risk. Specifically, 167 participants (39.7%) were unrealistically optimistic about their own breast cancer risk; 44 (10.5%) were unrealistically pessimistic. In multivariate multinomial logistic regression analysis, living with a partner and higher education were significantly associated with higher odds of having unrealistic optimism. High social support is associated with a lower likelihood of having a pessimistic risk perception. Higher worry is associated with a higher likelihood of having unrealistic pessimism. Misperception of breast cancer risk among KAW and related factors must be considered when developing behavioral interventions for this population. PMID- 26580452 TI - Translational Insights Into Peroxisome Proliferator-Activated Receptors in Experimental Acute Pancreatitis. AB - Acute pancreatitis (AP) is an inflammatory disorder of the exocrine pancreas frequently associated with metabolic causes, contributing factors, or consequences, including hypertriglyceridemia, obesity, and disorders of intermediary metabolism, respectively. To date, there is no specific therapy for this disease. Future optimal therapy should correct both inflammatory and metabolic components of the disease. Peroxisome proliferator-activated receptors (PPARs) are lipid-sensing nuclear receptors that control inflammatory and metabolic pathways via ligand-dependent and ligand-independent mechanisms. There are 3 known subtypes, PPAR-alpha, PPAR-beta/delta, and PPAR-gamma, which are differentially expressed in various tissues. The PPARs interact closely with other transcription factors such as nuclear factor kappaB and signal tranducers and activators of transcription that have pivotal roles in the pathobiology of AP. In this comprehensive review, we summarize the role of PPARs in AP, highlighting important in vitro and in vivo experimental findings. Finally, we propose future research directions as well as potential translational use of PPAR agonists in the treatment of AP. PMID- 26580453 TI - The Prognostic Significance of Lymph Node Ratio in Carcinoid Tumors. AB - OBJECTIVES: Nodal metastases are an important prognostic factor in survival for patients with carcinoid tumors. However, it is unclear if the current American Joint Committee on Cancer's gastrointestinal carcinoid staging guidelines, which look only at presence or absence of regional metastases (N1/N0), are fully utilizing lymph node data. Some research has indicated that lymph node ratios (LNRs) are powerful predictors of survival. In our study, we evaluated LNR in carcinoid tumors. METHODS: Eleven thousand one hundred eighty-nine carcinoid tumors recorded in the Surveillance, Epidemiology, and End Results database between 1988 and 2011 were evaluated. Receiver operating characteristic curves and the area under the receiver operating characteristic curve (AUC) were used to evaluate the ability of nodal involvement or LNR to predict 10-year survival. All analyses were performed using STATA and SAS version 9.3. RESULTS: Receiver operating characteristic curve analysis indicated that LNR and node positivity were both predictive of 10-year survival, AUC = 0.734, P < 0.0001; AUC = 0.7048, P < 0.0001. Lymph node ratio was 88% specific and 50% sensitive in predicting 10 year survival. N1 was 88% specific and 49% sensitive in predicting 10-year survival. CONCLUSIONS: Our study indicated that LNR is an independent predictor of survival for patients with carcinoid tumors but was no better than N1/N0 for 10-year survival. PMID- 26580454 TI - Success of Extracorporeal Shock Wave Lithotripsy in Chronic Calcific Pancreatitis Management: A Meta-Analysis and Systematic Review. AB - OBJECTIVES: This is a meta-analysis and systematic review to assess the overall utility and safety of Extracorporeal shock wave lithotripsy (ESWL) in chronic calcific pancreatitis. Primary outcomes are pain relief, narcotic usage, ductal clearance, quality of life, and pancreatic exocrine and endocrine function. METHODS: Studies involving ESWL in chronic calcific pancreatitis with main pancreatic duct stones greater than 5 mm and patients that failed conservative pain management were included. Fixed and random effects models were used to calculate the pooled proportions. RESULTS: Initial search identified 1471 reference articles, in which 184 articles were selected and reviewed. Data were extracted from 27 studies (N = 3189) which met the inclusion criterion. The pooled proportion of patients with absence of pain at follow-up was 52.7% (95% confidence interval [95% CI], 50.85-54.56) and mild to moderate pain at follow-up was 33.43% (95% CI, 31.40-35.50). Quality of life improved in 88.21% (95% CI, 85.43-90.73) and complete ductal clearance was 70.69% (95% CI, 68.97-72.38) in the pooled patients. CONCLUSIONS: The ESWL is an effective and safe management option in patients with chronic calcific pancreatitis patients with main pancreatic duct stone size greater than 5 mm who did not get adequate pain relief with conservative management. PMID- 26580455 TI - Characterization of Insulin-Immunoreactive Cells and Endocrine Cells Within the Duct System of the Adult Human Pancreas. AB - OBJECTIVE: The adult pancreatic duct system accommodates endocrine cells that have the potential to produce insulin. Here we report the characterization and distribution of insulin-immunoreactive cells and endocrine cells within the ductal units of adult human pancreas. METHODS: Sequential pancreas sections from 12 nondiabetic adults were stained with biomarkers of ductal epithelial cells (cytokeratin 19), acinar cells (amylase), endocrine cells (chromogranin A; neuron specific enolase), islet hormones (insulin, glucagon, somatostatin, pancreatic polypeptide), cell proliferation (Ki-67), and neogenesis (CD29). RESULTS: The number of islet hormone-immunoreactive cells increased from large ducts to the terminal branches. The insulin-producing cells outnumbered endocrine cells reactive for glucagon, somatostatin, or pancreatic polypeptide. The proportions of insulin-immunoreactive count compared with local islets (100% as a baseline) were 1.5% for the main ducts, 7.2% for interlobular ducts, 24.8% for intralobular ducts, 67.9% for intercalated ducts, and 348.9% for centroacinar cells. Both Ki 67- and CD29-labeled cells were predominantly localized in the terminal branches around the islets. The terminal branches also showed cells coexpressing islet hormones and cytokeratin 19. CONCLUSIONS: The adult human pancreatic ducts showed islet hormone-producing cells. The insulin-reactive cells predominantly localized in terminal branches where they may retain potential capability for beta-cell neogenesis. PMID- 26580456 TI - What is needed to incorporate clinical pharmacogenetic tests into the practice of psychopharmacotherapy? AB - This editorial considers two questions in psychopharmacotherapy: 1) What is needed to market pharmacogenetic tests in the US, since the US appears to lead other countries? and 2) What is needed for US-marketed pharmacogenetic tests to be incorporated by prescribers into long-term practice? US marketing of pharmacogenetic tests requires 1) understanding the pharmacological complexity of drug response, 2) modifying the oversight of non-FDA regulatory agencies, 3) clarifying the FDA's role and 4) promoting innovative marketing. The incorporation of pharmacogenetic tests into long-term practice requires 1) not jeopardizing pharmacogenetic testing by short-sighted marketing of non-validated tests, 2) educating prescribers about benefits, 3) educating patients about limitations and 4) considering the differences between isolated testing and generalized testing incorporating big data. PMID- 26580457 TI - Electromechanical coupling and design considerations in single-layer MoS2 suspended-channel transistors and resonators. AB - We report on the analysis of electromechanical coupling effects in suspended doubly-clamped single-layer MoS2 structures, and the designs of suspended-channel field-effect transistors (FETs) and vibrating-channel nanoelectromechanical resonators. In DC gating scenario, signal transduction processes including electrostatic actuation, deflection, straining on bandgap, mobility, carrier density and their intricate cross-interactions, have been analyzed considering strain-enhanced mobility (by up to 4 times), to determine the transfer characteristics. In AC gating scenario and resonant operations (using 100 MHz and 1 GHz devices as relevant targets), we demonstrate that the vibrating-channel MoS2 devices can offer enhanced signals (than the zero-bandgap graphene counterparts), thanks to the resonant straining effects on electron transport of the semiconducting channel. We also show dependence of signal intensity and signal-to-background ratio (SBR) on device geometries and scaling effects, with SBR enhancement by a factor of ~8 for resonance signal, which provide guidelines toward designing future devices with desirable parameters. PMID- 26580458 TI - Preferences of Bulgarian consumers for quality, access and price attributes of healthcare services-result of a discrete choice experiment. AB - OBJECTIVE: The aim of the study is to determine the preferences of Bulgarian citizens regarding the provision of healthcare services. METHOD: A survey was carried out in Bulgaria among a nationally representative sample of 1003 respondents. Both a discrete choice experiment and a self-explicated ranking of outpatient and inpatient service attributes were included in the survey. The data are analyzed to elicit the preferences of Bulgarian healthcare consumers for service attributes and to compare them with previous studies in Bulgaria and other countries in Central and Eastern Europe. RESULTS: The reputation and skills of the care provider appear to be relatively most important to the respondents, followed by the state of the equipment, the condition of the facility and the attitude of the staff. The fee-level and access-related attributes (waiting and traveling time) emerged as less important. Overall, consumers in Bulgaria value the quality of healthcare provision very highly. Yet, there are some statistically significant differences between socio-demographic groups. CONCLUSION: In general, Bulgarian healthcare consumers are willing to accept higher prices for the services they use, when this comes with improved quality of services. These findings comply with findings in previous studies in Bulgaria and in the region. Given the quality problems in the Bulgarian healthcare sector, our findings indicate that priority has to be given to the improvement of healthcare quality when the Bulgarian government invests in this sector. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26580459 TI - Swift heavy ion-beam induced amorphization and recrystallization of yttrium iron garnet. AB - Pure and (Ca and Si)-substituted yttrium iron garnet (Y3Fe5O12 or YIG) epitaxial layers and amorphous films on gadolinium gallium garnet (Gd3Ga5O12, or GGG) single crystal substrates were irradiated by 50 MeV (32)Si and 50 MeV (or 60 MeV) (63)Cu ions for electronic stopping powers larger than the threshold value (~4 MeV MUm(-1)) for amorphous track formation in YIG crystals. Conductivity data of crystalline samples in a broad ion fluence range (10(11)-10(16) cm(-2)) are modeled with a set of rate equations corresponding to the amorphization and recrystallization induced in ion tracks by electronic excitations. The data for amorphous layers confirm that a recrystallization process takes place above ~10(14) cm(-2). Cross sections for both processes deduced from this analysis are discussed in comparison to previous determinations with reference to the inelastic thermal-spike model of track formation. Micro-Raman spectroscopy was also used to follow the related structural modifications. Raman spectra show the progressive vanishing and randomization of crystal phonon modes in relation to the ion-induced damage. For crystalline samples irradiated at high fluences (?10(14) cm(-2)), only two prominent broad bands remain like for amorphous films, thereby reflecting the phonon density of states of the disordered solid, regardless of samples and irradiation conditions. The main band peaked at ~660 cm(-1) is assigned to vibration modes of randomized bonds in tetrahedral (FeO4) units. PMID- 26580460 TI - Photoinduced Electron Transfer from Various Aniline Derivatives to Graphene Quantum Dots. AB - The present study utilizes the luminescence nature of the graphene quantum dots (GQDs) to analyze the mechanistic aspects of the photoinduced electron transfer (PET) processes between GQDs and aniline derivatives. A systematic investigation of PET from various aniline derivatives to GQDs has been presented. Solution processable GQDs have been synthesized from graphene oxide (GO) at 200 degrees C. The as-synthesized GQDs exhibit a strong green luminescence at 510 nm, upon photoexcitation at 440 nm. Various aniline derivatives (aniline, N-methylaniline, N,N'-dimethylaniline, N-ethylaniline, N,N'-diethylaniline, and N,N' diphenylaniline) have been utilized as electron donors to probe the PET process. Results from UV-visible absorption and steady-state and time-resolve luminescence spectroscopy suggest that the GQDs interact with the aniline derivatives in the excited state, which results in a significant luminescence quenching of the GQDs. The bimolecular rate constants of the dynamic quenching have been deduced for various donor-acceptor systems, and the values are in the range of (1.06-2.68) * 10(9) M(-1) s(-1). The negative values of the free energy change of the electron transfer process suggest that PET from aniline derivatives to GQDs is feasible and could be responsible for the luminescence quenching. The PET has been confirmed by detecting radical cations for certain aniline derivatives, using a nanosecond laser flash photolysis setup. The present study shows that among the various types of graphene systems, GQDs are better candidates for understanding the mechanism of PET in graphene-based donor-acceptor systems. PMID- 26580461 TI - Lessons Learned and Unlearned. PMID- 26580462 TI - A Systematic Review on Interventions Supporting Preceptor Development. AB - Increases in newly licensed nurses and experienced nurses changing specialties create a challenge for nursing professional development specialists (NPDS). The NPDS must use the best available evidence in designing programs. A systematic review of interventions for developing preceptors is needed to inform the NPDS in best practice. A search was conducted for full-text, quantitative, and mixed methods articles published after the year 2000. Over 4000 titles were initially identified, which yielded 12 research studies for evaluation and syntheses. Results identified a limited body of evidence reflecting a need for NPDS to increase efforts in measuring the effectiveness of preceptor development initiatives.(See CE Video, Supplemental Digital Content 1, http://links.lww.com/JNPD/A9). PMID- 26580463 TI - Team Huddle Implementation in a General Pediatric Clinic. AB - Teamwork and communication are critical to ensure safe and quality patient care. However, the ability to affect these constructs within well-established healthcare settings is challenging. Using a quality improvement approach, staff development educators collaborated with clinical nursing staff to implement a daily team huddle. When incorporated into the workflow, a team huddle can promote communication and positively influence how teams function within a clinical area.(See CE Video, Supplemental Digital Content 1, http://links.lww.com/JNPD/A9). PMID- 26580464 TI - Tasks and Technology Versus Compassion and Caring in Nursing: Are they Mutually Exclusive? PMID- 26580465 TI - Interprofessional Simulation: Debriefing From the Learner's Point of View. PMID- 26580466 TI - Interprofessionalism and Relationship Building. PMID- 26580467 TI - Direct Influence: Past and Present. PMID- 26580468 TI - Comparison of Online and Traditional Basic Life Support Renewal Training Methods for Registered Professional Nurses. AB - Basic Life Support certification for nursing staff is achieved through various training methods. This study compared three American Heart Association training methods for nurses seeking Basic Life Support renewal: a traditional classroom approach and two online options. Findings indicate that online methods for Basic Life Support renewal deliver cost and time savings, while maintaining positive learning outcomes, satisfaction, and confidence level of participants. PMID- 26580469 TI - Using a Mock Trial Method to Enhance Effectiveness of Teaching Evidence-Based Practice in Nursing. AB - Traditional teaching methodologies may deter adult learning because of passive the exchange of knowledge. Teaching to the "evidence" substantiating best practice requires a systematic approach to transfer knowledge into clinical inquiry. A mock trial simulated role-play activity was selected to show the value of learning through active engagement. The nurse "defendant" was challenged to substantiate practice based on the evidence. Seminar participants (the jury) scrutinized testimony through deliberation before delivering the final verdict. PMID- 26580470 TI - Bringing in the "CIA": A New Process to Improve Staff Communication. AB - Nurses consistently express dissatisfaction with the overwhelming amount and rate of change in health care today. Nurse educators identified this as a problem at a 475-bed hospital and developed a process to present changes in information in a new and exciting method. This article reports on the identification and implementation of the new communication model and the lessons learned during the process. A new method for communication dissemination was designed utilizing a "Coordinator Information Advisory Group" concept. PMID- 26580472 TI - Motion compensation for PET image reconstruction using deformable tetrahedral meshes. AB - Respiratory-induced organ motion is a technical challenge to PET imaging. This motion induces displacements and deformation of the organs tissues, which need to be taken into account when reconstructing the spatial radiation activity. Classical image-based methods that describe motion using deformable image registration (DIR) algorithms cannot fully take into account the non reproducibility of the respiratory internal organ motion nor the tissue volume variations that occur during breathing. In order to overcome these limitations, various biomechanical models of the respiratory system have been developed in the past decade as an alternative to DIR approaches. In this paper, we describe a new method of correcting motion artefacts in PET image reconstruction adapted to motion estimation models such as those based on the finite element method. In contrast with the DIR-based approaches, the radiation activity was reconstructed on deforming tetrahedral meshes. For this, we have re-formulated the tomographic reconstruction problem by introducing a time-dependent system matrix based calculated using tetrahedral meshes instead of voxelized images. The MLEM algorithm was chosen as the reconstruction method. The simulations performed in this study show that the motion compensated reconstruction based on tetrahedral deformable meshes has the capability to correct motion artefacts. Results demonstrate that, in the case of complex deformations, when large volume variations occur, the developed tetrahedral based method is more appropriate than the classical DIR-based one. This method can be used, together with biomechanical models controlled by external surrogates, to correct motion artefacts in PET images and thus reducing the need for additional internal imaging during the acquisition. PMID- 26580473 TI - Does Game Participation Impact Cognition and Symptoms in Elite Football Players? AB - OBJECTIVE: To measure neurocognitive functioning in college and professional football players after game participation. STUDY DESIGN: Retrospective, cross sectional cohort design. PARTICIPANTS: Ninety-four male university and professional football players. INTERVENTION: All participants completed Immediate Postconcussion Assessment and Cognitive Testing (ImPACT) testing at baseline, and either at postconcussion (group 1) or postgame (group 2) participation. MAIN OUTCOME MEASURES: Results from the 5 ImPACT composite scores (Verbal Memory, Visual Memory, Visual Motor Speed, Reaction Time and Impulse Control) and Total Symptom Score. RESULTS: Repeated-measures analysis of variance demonstrated a significant main effect for time (improvements) in 3 of 5 domains for the postconcussion group, but no improvements in the postgame group. The postconcussion group presented with significantly improved results on 4 of 5 ImPACT domains compared with the postgame group at the follow-up time interval. CONCLUSIONS: Participation in a football game with potential cumulative head contacts did not yield increased symptoms or cognitive impairment. However, the absence of improvement in cognitive functioning in noninjured football players, which was found in those players who were returned to play after an injury, may suggest that there is a measureable impact as a result of playing football. PMID- 26580474 TI - The Clinical Utility of a Concussion Rebaseline Protocol After Concussion Recovery. AB - OBJECTIVE: To evaluate the clinical utility of "rebaseline" testing (ie, new baseline) before the season after an athlete's concussion recovery by (1) determining differences between baseline and rebaseline scores, and (2) comparing differences to clinical reliable change indices (RCIs). DESIGN: Retrospective cohort. SETTING: Clinical research center. PATIENTS: Thirty-four Division I collegiate athletes (16 females, 18 males; baseline age = 18.38 +/- 0.78 years). INTERVENTIONS: Neurocognitive, balance, and symptom testing was conducted at 3 times: (1) original baseline, (2) final postinjury before return-to-play, and (3) rebaseline completed before the next competitive season. Physicians diagnosed concussions, and all concussed athletes' returned-to-play during the same season. MAIN OUTCOME MEASURES: Dependent variables included all neurocognitive domains, balance composite, and total symptom scores. Mean differences between sessions were compared with 80% RCIs to clinically interpret statistical findings. RESULTS: Statistically significant improvements in neurocognitive performance were observed between baseline and rebaseline sessions: psychomotor speed (F1,33 = 13.79, P = 0.001), cognitive flexibility (F1,33 = 7.99, P = 0.008), processing speed (F1,32 = 15.93, P < 0.001), executive functioning (F1,33 = 9.61, P = 0.004), and reasoning (F1,32 = 7.63, P = 0.009). We observed significant improvement in balance (F1,29 = 22.26, P < 0.001), but no difference in total symptom score (P = 0.719). Participants performed statistically better at last postinjury compared with rebaseline in visual memory (F1,29 = 5.64, P = 0.024) and complex attention (F1,31 = 11.38, P = 0.002), but worse in processing speed (F1,30 = 8.92, P = 0.006). Participants reported more symptoms (F1.28 = 10.83, P = 0.003) at rebaseline than last postinjury. No observed mean differences exceeded RCIs. CONCLUSIONS: All between-session improvements were within RCIs and therefore within expected test-retest variation. Our results suggest limited clinical utility for rebaseline assessments in the collegiate setting. CLINICAL RELEVANCE: Despite statistically significant differences between test sessions, no differences exceeded RCIs, suggesting the differences were of little clinical utility in the interpretation of neurocognitive, balance, and symptom scoring. PMID- 26580476 TI - Target identification of natural products and bioactive compounds using affinity based probes. AB - Covering: 2010 to 2014.Advances in isolation, synthesis and screening strategies have made many bioactive substances available. However, in most cases their putative biological targets remain unknown. Herein, we highlight recent advances in target identification of natural products and bioactive compounds by using affinity-based probes. Aided by photoaffinity labelling, this strategy can capture potential cellular targets (on and off) of a natural product or bioactive compound in live cells directly, even when the compound-target interaction is reversible with moderate affinity. The knowledge of these targets may help uncover molecular pathways and new therapeutics for currently untreatable diseases. In this highlight, we will introduce the development of various photoactivatable groups, their synthesis and applications in target identification of natural products and bioactive compounds, with a focus on work done in recent years and from our laboratory. We will further discuss the strengths and weaknesses of each group and the outlooks for this novel proteome wide profiling strategy. PMID- 26580475 TI - Factors associated with the sensitivity of fine-needle aspiration cytology for the diagnosis of follicular variant papillary thyroid carcinoma. AB - BACKGROUND: The purpose of this study was to evaluate the factors associated with diagnostic accuracy of preoperative fine-needle aspiration (FNA) for follicular variant papillary thyroid carcinoma (FVPTC). METHODS: The patients with FVPTC who underwent thyroidectomy were divided into 2 groups: "group A" (Bethesda category II, III, or IV) versus "group B" (category V or VI). RESULTS: A total of 225 patients (117 in group A and 108 in group B) were included. Group B was associated with older age, malignant ultrasonographic features, smaller tumor size, extrathyroidal extension, higher stage, and B-type Raf (BRAF)(V600E) mutation compared with group A. In multivariable analysis, malignant ultrasonographic features and tumor size <=3.0 cm were independent predictive factors for group B. CONCLUSION: FVPTCs >3.0 cm are unlikely to be diagnosed as category V or VI. Clinicians should keep FVPTC in mind and consider diagnostic lobectomy for the nodules regardless of FNA or ultrasonographic findings. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E1467-E1471, 2016. PMID- 26580477 TI - Nanostructures for protein drug delivery. AB - Use of nanoscale devices as carriers for drugs and imaging agents has been extensively investigated and successful examples can already be found in therapy. In parallel, recombinant DNA technology together with molecular biology has opened up numerous possibilities for the large-scale production of many proteins of pharmaceutical interest, reflecting in the exponentially growing number of drugs of biotechnological origin. When we consider protein drugs, however, there are specific criteria to take into account to select adequate nanostructured systems as drug carriers. In this review, we highlight the main features, advantages, drawbacks and recent developments of nanostructures for protein encapsulation, such as nanoemulsions, liposomes, polymersomes, single-protein nanocapsules and hydrogel nanoparticles. We also discuss the importance of nanoparticle stabilization, as well as future opportunities and challenges in nanostructures for protein drug delivery. PMID- 26580478 TI - Measuring the Quality of Care for Patients With Traumatic Brain Injury. PMID- 26580479 TI - Automated Detection of Glaucoma From Topographic Features of the Optic Nerve Head in Color Fundus Photographs. AB - OBJECTIVE: To describe and evaluate the performance of an automated CAD system for detection of glaucoma from color fundus photographs. DESIGN AND SETTING: Color fundus photographs of 2252 eyes from 1126 subjects were collected from 2 centers: Aravind Eye Hospital, Madurai and Coimbatore, India. The images of 1926 eyes (963 subjects) were used to train an automated image analysis-based system, which was developed to provide a decision on a given fundus image. A total of 163 subjects were clinically examined by 2 ophthalmologists independently and their diagnostic decisions were recorded. The consensus decision was defined to be the clinical reference (gold standard). Fundus images of eyes with disagreement in diagnosis were excluded from the study. The fundus images of the remaining 314 eyes (157 subjects) were presented to 4 graders and their diagnostic decisions on the same were collected. The performance of the system was evaluated on the 314 images, using the reference standard. The sensitivity and specificity of the system and 4 independent graders were determined against the clinical reference standard. RESULTS: The system achieved an area under receiver operating characteristic curve of 0.792 with a sensitivity of 0.716 and specificity of 0.717 at a selected threshold for the detection of glaucoma. The agreement with the clinical reference standard as determined by Cohen kappa is 0.45 for the proposed system. This is comparable to that of the image-based decisions of 4 ophthalmologists. CONCLUSIONS AND RELEVANCE: An automated system was presented for glaucoma detection from color fundus photographs. The overall evaluation results indicated that the presented system was comparable in performance to glaucoma classification by a manual grader solely based on fundus image examination. PMID- 26580480 TI - Parent Reports of Young Spanish-English Bilingual Children's Productive Vocabulary: A Development and Validation Study. AB - PURPOSE: This 2-phase study aims to extend research on parent report measures of children's productive vocabulary by investigating the development (n = 38) of the Spanish Vocabulary Extension and validity (n = 194) of the 100-item Spanish and English MacArthur-Bates Communicative Development Inventories Toddler Short Forms and Upward Extension (Fenson et al., 2000, 2007; Jackson-Maldonado, Marchman, & Fernald, 2013) and the Spanish Vocabulary Extension for use with parents from low income homes and their 24- to 48-month-old Spanish-English bilingual children. METHOD: Study participants were drawn from Early Head Start and Head Start collaborative programs in the Northeastern United States in which English was the primary language used in the classroom. All families reported Spanish or Spanish English as their home language(s). The MacArthur Communicative Development Inventories as well as the researcher-designed Spanish Vocabulary Extension were used as measures of children's English and Spanish productive vocabularies. RESULTS: Findings revealed the forms' concurrent and discriminant validity, on the basis of standardized measures of vocabulary, as measures of productive vocabulary for this growing bilingual population. CONCLUSION: These findings suggest that parent reports, including our researcher-designed form, represent a valid, cost-effective mechanism for vocabulary monitoring purposes in early childhood education settings. PMID- 26580481 TI - Predictors of functional and clinical outcome in early-onset first-episode psychosis: the child and adolescent first episode of psychosis (CAFEPS) study. AB - OBJECTIVE: The objective of this study was to study baseline clinical and biological predictors of 2-year outcome in a cohort of children and adolescents with a first episode of psychosis. METHOD: Standard instruments were used to evaluate symptoms and functioning in 110 children and adolescents (mean age = 15.47 years) with first episode of psychosis at admission (between 2003 and 2005) and after 2-year follow-up. Clinical assessments included diagnostic assessment to yield DSM-IV diagnosis, developmental, premorbid, and past-year data, together with structural neuroimaging and other biological parameters (genetics and oxidative stress). Eighty-three subjects had assessments at baseline (including the Strauss-Carpenter Outcome Scale [SCOS]) and at 2-year follow-up. Association and multistep regression analyses were conducted to show correlates and predictors of primary outcome measures: functional outcome (Children's Global Assessment Scale [CGAS]), improvement (CGAS change), and primary negative symptoms (Proxy for the Deficit Syndrome Scale). RESULTS: The SCOS predicted 27.46% (P < .001) of the variance in CGAS score at 2 years. Baseline severity (measured by CGAS) predicted 30.9% (P < .001) of CGAS improvement after 2 years, and SCOS total score predicted an added 24.1% (P < .001). A diagnosis of nonaffective psychosis, primary negative symptoms, and less white matter at baseline predicted more primary negative symptoms at follow-up. The prediction of functional outcome was not increased by genetic, oxidative stress, or neurostructural markers. CONCLUSIONS: Baseline clinical assessments have a better predictive value than biological assessments for 2-year follow-up functioning of children and adolescents with a first episode of psychosis. Patients with primary negative symptoms at baseline continue to have negative symptoms 2 years later, and neurostructural markers predict these. Clinicians must still rely on clinical variables to judge the functional prognosis of early-onset first psychotic episodes. PMID- 26580482 TI - Multifunctional Ultrathin PdxCu(1-x) and Pt~PdxCu(1-x) One-Dimensional Nanowire Motifs for Various Small Molecule Oxidation Reactions. AB - Developing novel electrocatalysts for small molecule oxidation processes, including formic acid oxidation (FAOR), methanol oxidation reaction (MOR), and ethanol oxidation reaction (EOR), denoting the key anodic reactions for their respective fuel cell configurations, is a significant and relevant theme of recent efforts in the field. Herein, in this report, we demonstrated a concerted effort to couple and combine the benefits of small size, anisotropic morphology, and tunable chemical composition in order to devise a novel "family" of functional architectures. In particular, we have fabricated not only ultrathin 1 D Pd(1-x)Cu(x) alloys but also Pt-coated Pd(1-x)Cu(x) (i.e., Pt~Pd(1-x)Cu(x); herein the ~ indicates an intimate association, but not necessarily actual bond formation, between the inner bimetallic core and the Pt outer shell) core-shell hierarchical nanostructures with readily tunable chemical compositions by utilizing a facile, surfactant-based, wet chemical synthesis coupled with a Cu underpotential deposition technique. Our main finding is that our series of as prepared nanowires are functionally flexible. More precisely, we demonstrate that various examples within this "family" of structural motifs can be tailored for exceptional activity with all 3 of these important electrocatalytic reactions. In particular, we note that our series of Pd(1-x)Cu(x) nanowires all exhibit enhanced FAOR activities as compared with not only analogous Pd ultrathin nanowires but also commercial Pt and Pd standards, with Pd9Cu representing the "optimal" composition. Moreover, our group of Pt~Pd(1-x)Cu(x) nanowires consistently outperformed not only commercial Pt NPs but also ultrathin Pt nanowires by several fold orders of magnitude for both the MOR and EOR reactions in alkaline media. The variation of the MOR and EOR performance with the chemical composition of our ultrathin Pt~Pd(1-x)Cu(x) nanowires was also discussed. PMID- 26580483 TI - Pain following foraminal enlargement in mandibular molars with necrosis and apical periodontitis: A randomized controlled trial. AB - AIM: This randomized controlled trial was conducted to evaluate the effect of foraminal enlargement during chemomechanical root canal preparation on postoperative pain. METHODOLOGY: Seventy mandibular first molars with asymptomatic pulp necrosis and chronic apical periodontitis were randomized into two groups - foraminal enlargement (FE) and conventional nonforaminal enlargement (NFE). Canals were prepared according to the respective protocols, and the teeth were restored temporarily. Postoperatively, the patients were prescribed ibuprofen 400 mg, to be taken if required. Pain experience and analgesic intake were recorded for 7 days following chemomechanical preparation. The data were analysed using Mann-Whitney U-test and chi-square tests. RESULTS: Pain experience was higher with foraminal enlargement than when using a conventional technique. A significant difference was observed in postoperative pain during the first 4 days and the sixth day (P < 0.05), with greater pain in the FE as compared to the NFE group. There was no significant difference in prevalence of analgesic intake and number of doses between the experimental groups (P > 0.05). CONCLUSION: Enlargement of the apical foramen during root canal treatment increased the incidence and intensity of postoperative pain. PMID- 26580485 TI - Localized Hair Repigmentation in a 91-Year-Old Woman. PMID- 26580486 TI - Formation of 4(5)-Methylimidazole in Aqueous d-Glucose-Amino Acids Model System. AB - The International Agency for Research on Cancer (IRAC) has classified 4(5) methylimidazole (4-MeI) as a group 2B possible human carcinogen. Thus, how 4-MeI forms in a D-glucose (Glu) amino acids (AA) model system is important, as it is how browning is affected. An aqueous solution of Glu was mixed individually in equimolar amounts at 3 concentrations (0.05, 0.1, and 0.15 M) with aqueous solutions of L-Alanine (Ala), L-Arginine (Arg), Glycine (Gly), L-Lysine (Lys), and L-Serine (Ser). The Glu-AA mixtures were reacted at 60, 120, and 160 degrees C for 1 h. The 4-MeI levels were measured by gas chromatography-mass spectrometry after derivatization with isobutylchloroformate. No 4-MeI was formed at 60 degrees C for any treatment combination; however, at 120 degrees C and 0.05 M, Glu-Arg and Glu-Lys produced 0.13 and 0.14 mg/kg of 4-MeI. At 160 degrees C and 0.05 M all treatment combinations formed 4-MeI. At 160 degrees C and 0.15 M, the observed levels of Glu-Ala, Glu-Arg, Glu-Gly, Glu-Lys, and Glu-Ser were 0.21, 1.00, 0.15, 0.22, and 0.16 mg/kg. The AA type, reactant concentrations, and temperature significantly affected (P < 0.001) formation of 4-MeI as well as browning. Glu-Lys treatment in all combinations produced the most browning, but Glu-Arg produced the most 4-MeI. This method showed that foods processed using low temperatures may have reduced levels of 4-MeI. PMID- 26580484 TI - Compromised blood-brain barrier permeability: novel mechanism by which circulating angiotensin II signals to sympathoexcitatory centres during hypertension. AB - Angiotensin II (AngII) is a pivotal peptide implicated in the regulation of blood pressure. In addition to its systemic vascular and renal effects, AngII acts centrally to modulate the activities of neuroendocrine and sympathetic neuronal networks, influencing in turn sympatho-humoral outflows to the circulation. Moreover, a large body of evidence supports AngII signalling dysregulation as a key mechanism contributing to exacerbated sympathoexcitation during hypertension. Due to its hydrophilic actions, circulating AngII does not cross the blood-brain barrier (BBB), signalling to the brain via the circumventricular organs which lack a tight BBB. In this review, we present and discuss recent studies from our laboratory showing that elevated circulating levels of AngII during hypertension result in disruption of the BBB integrity, allowing access of circulating AngII to critical sympathoexcitatory brain centres such as the paraventricular nucleus of the hypothalamus and the rostral ventrolateral medulla. We propose the novel hypothesis that AngII-driven BBB breakdown constitutes a complementary mechanism by which circulating AngII, working in tandem with the central renin-angiotensin system, further exacerbates sympatho-humoral activation during hypertension. These results are discussed within the context of a growing body of evidence in the literature supporting AngII as a pro-inflammatory signal, and brain microglia as key cell targets mediating central AngII actions during hypertension. PMID- 26580487 TI - Novel polyol-responsive monoclonal antibodies against extracellular beta-D glucans from Pleurotus ostreatus. AB - beta-D-glucans from mushroom strains play a major role as biological response modifiers in several clinical disorders. Therefore, a specific assay method is of critical importance to find useful and novel sources of beta-d-glucans with anti tumor activity. Hybridoma technology was used to raise monoclonal antibodies (Mabs) against extracellular beta-d-glucans (EBG) from Pleurotus ostreatus. Two of these hybridoma clones (3F8_3H7 and 1E6_1E8_B3) secreting Mabs against EBG from P. ostreatus were selected and 3F8_3H7 was used to investigate if they are polyol-responsive Mabs (PR-Mabs) by using ELlSA-elution assay. This hybridoma cell line secreted Mab of IgM class, which was purified in a single step by gel filtration chromatography on Sephacryl S-300HR, which revealed a protein band on native PAGE with Mr of 917 kDa. Specificity studies of Mab 3F8_3H7 revealed that it recognized a common epitope on several beta-d-glucans from different basidiomycete strains as determined by indirect ELlSA and Western blotting under native conditions. This Mab exhibited high apparent affinity constant (KApp) for beta-d-glucans from several mushroom strains. However, it revealed differential reactivity to some heat-treated beta-d-glucans compared with the native forms suggesting that it binds to a conformation-sensitive epitope on beta-d-glucan molecule. Epitope analysis of Mab 3F8_3H7 and 1E6_1E8_B3 was investigated by additivity index parameter, which revealed that they bound to the same epitope on some beta-d-glucans and to different epitopes in other antigens. Therefore, these Mab can be used to assay for beta-d-glucans as well as to act as powerful probes to detect conformational changes in these biopolymers. PMID- 26580488 TI - Calibration of interphase fluorescence in situ hybridization cutoff by mathematical models. AB - Fluorescence in situ hybridization (FISH) continues to play an important role in clinical investigations. Laboratories may create their own cutoff, a percentage of positive nuclei to determine whether a specimen is positive or negative, to eliminate false positives that are created by signal overlap in most cases. In some cases, it is difficult to determine the cutoff value because of differences in both the area of nuclei and the number of signals. To address these problems, we established two mathematical models using probability theory. To verify these two models, normal disomy cells from healthy individuals were used to simulate cells with different numbers of signals by hybridization with different probes. We used an X/Y probe to obtain the average distance between two signals and the probability of signal overlap in different nuclei area. Frequencies of all signal patterns were scored and compared with theoretical frequencies, and models were assessed using a goodness of fit test. We used five BCR/ABL1-positive samples, 20 BCR/ABL1-negative samples and two samples with ambiguous results to verify the cutoff calibrated by these two models. The models were in agreement with experimental results. The dynamic cutoff can classify cases in routine analysis correctly, and it can also correct for influences from nuclei area and the number of signals in some ambiguous cases. The probability models can be used to assess the effect of signal overlap and calibrate the cutoff. PMID- 26580490 TI - Factors of Resilience in Emergency Department Nurses Who Have Experienced Workplace Violence in Taiwan. AB - PURPOSE: This study investigated the relationship among personality traits, social network integration (SNI), and resilience in emergency department (ED) nurses who had suffered from physical or verbal violence by patients or their families. DESIGN AND METHODS: A cross-sectional study with convenience sampling was conducted for exploring the related factors of resilience on abused nurses. A total of 187 participants met our inclusion criteria and completed all questionnaires. FINDINGS: Higher degrees of extraversion and peer support were associated with greater resilience among all abused nurses, whereas neuroticism was inversely associated with their resilience. CONCLUSIONS: Among all forms of SNI, only peer support was shown to enhance an individual's resilience. In addition, personality traits were associated with resilience, and religions did not play an important role in enhancing resilience among our participants. CLINICAL RELEVANCE: Through a clearer understanding of the role of peer support in resilience among ED nurses, healthcare managers should provide and enhance their peer support to intensify their resilience for prevention of consequences of workplace violence. PMID- 26580489 TI - Pharmacokinetics and pharmacodynamics of everolimus in patients with renal angiomyolipoma and tuberous sclerosis complex or lymphangioleiomyomatosis. AB - AIMS: The purpose was to determine the exposure-response relationship of everolimus in patients with angiomyolipoma from the EXIST-2 trial and to analyze the correlation between exposure and plasma concentrations of angiogenic biomarkers in these patients. METHODS: One hundred and eighteen patients with angiomyolipoma associated with tuberous sclerosis complex (TSC) or sporadic lymphangioleiomyomatosis (sLAM) were randomly assigned 2 : 1 to receive everolimus 10 mg (n = 79) or placebo (n = 39) once daily. Blood samples for determining everolimus concentration were collected at weeks 2, 4, 12, 24 and 48 during double-blind treatment. Plasma samples for biomarker analysis were collected at baseline and weeks 4, 12, 24, 36, 48 and at the end of treatment. Concentrations of eight angiogenic biomarkers associated with tumour growth were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: Peak and trough concentrations of everolimus in blood remained stable over time and similar to those reported in other indications. Substantial pharmacodynamic effects were observed in the everolimus, but not placebo, arm for three biomarkers: After 24 weeks of treatment, reduction of vascular endothelial growth factor D (VEGF-D) and collagen type IV (COL-IV) (mean fold-changes with 95% confidence intervals [CI] were 0.36 [0.33, 0.40], and 0.54 [0.51, 0.57], respectively, P < 0.001 for both), along with increased VEGF-A (mean fold-change of 1.59 [1.39, 1.80], P < 0.001), were seen. Furthermore, baseline VEGF-D and COL-IV levels were associated with angiomyolipoma size at baseline and with angiomyolipoma response to everolimus. CONCLUSIONS: These findings suggest that plasma angiogenic markers may provide an objective measure of patient response to everolimus. PMID- 26580491 TI - Correction: CAPS-1 promotes fusion competence of stationary dense-core vesicles in presynaptic terminals of mammalian neurons. PMID- 26580492 TI - Fighting Fenton Chemistry: A Highly Active Iron(III) Tetracarbene Complex in Epoxidation Catalysis. AB - Organometallic Fe complexes with exceptionally high activities in homogeneous epoxidation catalysis are reported. The compounds display Fe(II) and Fe(III) oxidation states and bear a tetracarbene ligand. The more active catalyst exhibits activities up to 183 000 turnovers per hour at room temperature and turnover numbers of up to 4300 at -30 degrees C. For the Fe(III) complex, a decreased Fenton-type reactivity is observed compared with Fe(II) catalysts reported previously as indicated by a substantially lower H2 O2 decomposition and higher (initial) turnover frequencies. The dependence of the catalyst performance on the catalyst loading, substrate, water addition, and the oxidant is investigated. Under all applied conditions, the advantageous nature of the use of the Fe(III) complex is evident. PMID- 26580493 TI - Selective recognition of neutral guests in an aqueous medium by a biomimetic calix[6]cryptamide receptor. AB - The design of artificial receptors that can efficiently work in water is a challenging research area. A possible biomimetic approach for the elaboration of such receptors consists of associating a hydrophobic cavity with a polar polyfunctional binding site. On this basis, a hydrophilic calix[6]cryptamide decorated with oligo(ethylene glycol) units (i.e. 8) was synthesized through an efficient [1 + 1] macrocyclization reaction as the key-step. The complexation of neutral molecules was evaluated by NMR spectroscopy through competition experiments either in apolar or aqueous media. In both media, host 8 can bind neutral species that display H-bonding acceptor and donor groups such as amides or ureas. Interestingly, the most polar and acidic molecule is the best guest in chloroform and the worst one in an aqueous medium, highlighting the importance of the environment. As shown by NMR and X-ray diffraction data, the mode of recognition involves a complementary DAAAD-ADDDA quintuple H-bonding array between the binding partners as well as multiple CH-pi interactions. A comparison of this calix[6]arene-based host-guest system with the binding site of biotin binding proteins shows strong similarities. Besides, the acid-base control of the binding properties of receptor 8 in aqueous media is highly reminiscent of allosteric processes encountered in natural systems. PMID- 26580494 TI - Target-Based Drug Repositioning Using Large-Scale Chemical-Protein Interactome Data. AB - Drug repositioning, or the identification of new indications for known drugs, is a useful strategy for drug discovery. In this study, we developed novel computational methods to predict potential drug targets and new drug indications for systematic drug repositioning using large-scale chemical-protein interactome data. We explored the target space of drugs (including primary targets and off targets) based on chemical structure similarity and phenotypic effect similarity by making optimal use of millions of compound-protein interactions. On the basis of the target profiles of drugs, we constructed statistical models to predict new drug indications for a wide range of diseases with various molecular features. The proposed method outperformed previous methods in terms of interpretability, applicability, and accuracy. Finally, we conducted a comprehensive prediction of the drug-target-disease association network for 8270 drugs and 1401 diseases and showed biologically meaningful examples of newly predicted drug targets and drug indications. The predictive model is useful to understand the mechanisms of the predicted drug indications. PMID- 26580495 TI - Indium-Catalyzed Amide Allylation of N-Carbonyl Imides: Formation of Azaspiro gamma-lactones via Ring Opening-Reclosure. AB - A novel and facile synthesis of azaspiro-gamma-lactones with a methylene-lactam framework from N-carbonyl imides is described. Mechanistic investigations provide evidence for a two-step reaction process involving ZnCl(2)-promoted addition of beta-amido allylindium species followed by an unexpectedly molecular-sieves mediated ring opening-reclosure concomitantly with the loss of an N-carbonyl unit. PMID- 26580496 TI - Casein Kinase 2 Is a Novel Regulator of the Human Organic Anion Transporting Polypeptide 1A2 (OATP1A2) Trafficking. AB - Human organic anion transporting polypeptides (OATPs) mediate the influx of many important drugs into cells. Casein kinase 2 (CK2) is a critical protein kinase that phosphorylates >300 protein substrates and is dysregulated in a number of disease states. Among the CK2 substrates are several transporters, although whether this includes human OATPs has not been evaluated. The current study was undertaken to evaluate the regulation of human OATP1A2 by CK2. HEK-239T cells in which OATP1A2 was overexpressed were treated with CK2 specific inhibitors or transfected with CK2 specific siRNA, and the activity, expression, and subcellular trafficking of OATP1A2 was evaluated. CK2 inhibition decreased the uptake of the prototypic OATP1A2 substrate estrone-3-sulfate (E3S). Kinetic studies revealed that this was due to a decrease in the maximum velocity (Vmax) of E3S uptake, while the Michaelis constant was unchanged. The cell surface expression, but not the total cellular expression of OATP1A2, was impaired by CK2 inhibition and knockdown of the catalytic alpha-subunits of CK2. CK2 inhibition decreased the internalization of OATP1A2 via a clathrin-dependent pathway, decreased OATP1A2 recycling, and likely impaired OATP1A2 targeting to the cell surface. Consistent with these findings, CK2 inhibition also disrupted the colocalization of OATP1A2 and Rab GTPase (Rab)4-, Rab8-, and Rab9-positive endosomal and secretory vesicles. Taken together, CK2 has emerged as a novel regulator of the subcellular trafficking and stability of OATP1A2. Because OATP1A2 transports many molecules of physiological and pharmacological importance, the present data may inform drug selection in patients with diseases in which CK2 and OATP1A2 are dysregulated. PMID- 26580497 TI - The Anancomeric Character of the Pharmacophore 1,3,4-Thiadiazoline Framework in Chiral Spiro-Cyclohexyl Derivatives: Effects on Stereochemistry and Spiro Junction Lability. Thermodynamic Aspects. AB - Three new and easily accessible chiral compounds, containing the pharmacophore 1,3,4-thiadiazoline nucleus joined by a spiro center to a monoalkyl (methyl or t butyl) substituted cyclohexyl fragment, have been synthesized and fully characterized from the structural and stereochemical point of view. The formation of a spiro-cyclohexyl-thiadiazoline system (sCT) offered the rare opportunity to generate at room temperature both anancomeric structures, displaying alkyl groups bound to the cyclohexyl ring in equatorial position, and other quite stable stereoisomers in which the same alkyl moieties are, instead, inserted in axial position, even for the extreme case represented by the really bulky t-butyl group. DFT calculations led to a clear rationalization of such stereochemical behaviors, pointing out that in all cases they arise from the unexpected strong anancomeric character possessed by the sCT framework in its 4-acetyl substituted version. In consideration of the large number of substances in which the 1,3,4 thiadiazoline heterocycle has been found as the active pharmacophore, the results discussed in this work may provide solid bases to allow a rational design of new chiral bioactive spiro-thiadiazolines characterized by well-defined stereochemical structures and single anancomeric geometries. PMID- 26580498 TI - William E. Paul 1936-2015. PMID- 26580499 TI - A 'rule of 3' to revive Greek science, research and innovation. PMID- 26580500 TI - Biological sensors shed light on ligand geography. PMID- 26580501 TI - Nr4a1 discloses the sympathetic side of monocytes. PMID- 26580508 TI - Corrigendum: The receptor NLRP3 is a transcriptional regulator of TH2 differentiation. PMID- 26580509 TI - Corrigendum: The RIP1-RIP3 complex initiates mitochondrial fission to fuel NLRP3. PMID- 26580510 TI - Interactions of zinc octacarboxyphthalocyanine with selected amino acids and with albumin. AB - Effect of selected amino acids (glycine, l-histidine, l-cysteine, l-serine, l tryptophan) and albumin on the spectroscopic properties and photostability of zinc octacarboxyphthalocyanine (ZnPcOC) was explored in the phosphate buffer at a pH of 7.0. The photodegradation of ZnPcOC alone and in the presence of amino acids or albumin has been investigated in aqueous phase using UV-366nm and daylight irradiation. Kinetic analysis showed that the interaction with amino acids or albumin enhances the photostability of ZnPcOC. To answer the question of how zinc phthalocyanine interacts with amino acids extensive DFT calculations were performed. Analysis of the optimized geometry features of ZnPcOC: amino acids complexes in the gas phase and in water environment as well as the BSSE corrected interaction energies indicates that the more likely is the formation of equatorial complexes in which H-bonds are formed between the COOH groups of the phthalocyanine and carboxyl or amino groups of amino acids. UV-Vis spectra calculated by employing time dependent density functional theory (TD-DFT) are also consistent with this conclusion. PMID- 26580511 TI - Structure, spectra and antioxidant action of ascorbic acid studied by density functional theory, Raman spectroscopic and nuclear magnetic resonance techniques. AB - Structure, vibrational and nuclear magnetic resonance spectra, and antioxidant action of ascorbic acid towards hydroxyl radicals have been studied computationally and in vitro by ultraviolet-visible, nuclear magnetic resonance and vibrational spectroscopic techniques. Time dependant density functional theory calculations have been employed to specify various electronic transitions in ultraviolet-visible spectra. Observed chemical shifts and vibrational bands in nuclear magnetic resonance and vibrational spectra, respectively have been assigned with the help of calculations. Changes in the structure of ascorbic acid in aqueous phase have been examined computationally and experimentally by recording Raman spectra in aqueous medium. Theoretical calculations of the interaction between ascorbic acid molecule and hydroxyl radical predicted the formation of dehydroascorbic acid as first product, which has been confirmed by comparing its simulated spectra with the corresponding spectra of ascorbic acid in presence of hydrogen peroxide. PMID- 26580512 TI - An optical sensing composite for cysteine detection using up-conversion nanoparticles and a rhodamine-derived chemosensor: Construction, characterization, photophysical feature and sensing performance. AB - In this paper, we reported an optical sensing composite for cysteine detection. A chemosensor derived from rhodamine 6G was synthesized and characterized. To minimize its photobleaching, up-conversion nanocrystals beta-NaYF4:Yb(3+)/Er(3+) were prepared and modified with alpha-cyclodextrin, serving as excitation host. Under 980nm laser excitation, emission of these up-conversion nanocrystals overlapped well with the absorption of our chemosensor. Energy transfer between them was analyzed and confirmed by emission decay analysis. Job's analysis suggested that the complexation equilibrium between our chemosensor and cysteine was a simple one with binding stoichiometry of 1:1. A sensing system was constructed with up-conversion nanocrystals (modified with alpha-cyclodextrin) and this chemosensor. Emission "turn-on" effect was observed only for cysteine but immune to other competing amino acids and thiols, showing a good selectivity. PMID- 26580514 TI - Construction of the B88 Exchange-Energy Functional in Two Dimensions. AB - We construct a generalized-gradient approximation for the exchange-energy density of finite two-dimensional systems. Guided by nonempirical principles, we include the proper small-gradient limit and the proper tail for the exchange-hole potential. The observed performance is superior to that of the two-dimensional local-density approximation, which underlines the usefulness of the approach in practical applications. PMID- 26580515 TI - Molecular Dynamics in the Multicanonical Ensemble: Equivalence of Wang-Landau Sampling, Statistical Temperature Molecular Dynamics, and Metadynamics. AB - We show a direct formal relationship between the Wang-Landau iteration [PRL 86, 2050 (2001)], metadynamics [PNAS 99, 12562 (2002)], and statistical temperature molecular dynamics (STMD) [PRL 97, 050601 (2006)] that are the major work-horses for sampling from generalized ensembles. We demonstrate that STMD, itself derived from the Wang-Landau method, can be made indistinguishable from metadynamics. We also show that Gaussian kernels significantly improve the performance of STMD, highlighting the practical benefits of this improved formal understanding. PMID- 26580513 TI - Phosphorylation of mouse SAMHD1 regulates its restriction of human immunodeficiency virus type 1 infection, but not murine leukemia virus infection. AB - Human SAMHD1 (hSAMHD1) restricts HIV-1 infection in non-dividing cells by depleting intracellular dNTPs to limit viral reverse transcription. Phosphorylation of hSAMHD1 at threonine (T) 592 by cyclin-dependent kinase (CDK) 1 and CDK2 negatively regulates HIV-1 restriction. Mouse SAMHD1 (mSAMHD1) restricts HIV-1 infection in non-dividing cells, but whether its phosphorylation regulates retroviral restriction is unknown. Here we identified six phospho-sites of mSAMHD1, including T634 that is homologous to T592 of hSAMHD1 and phosphorylated by CDK1 and CDK2. We found that wild-type (WT) mSAMHD1 and a phospho-ablative mutant, but not a phospho-mimetic mutant, restricted HIV-1 infection in differentiated U937 cells. Murine leukemia virus (MLV) infection of dividing NIH3T3 cells was modestly restricted by mSAMHD1 WT and phospho-mutants, but not by a dNTPase-defective mutant. Our results suggest that phosphorylation of mSAMHD1 at T634 by CDK1/2 negatively regulates its HIV-1 restriction in differentiated cells, but does not affect its MLV restriction in dividing cells. PMID- 26580516 TI - Excited-State Geometries of Solvated Molecules: Going Beyond the Linear-Response Polarizable Continuum Model. AB - The theoretical determination of excited-state structures remains an active field of research, as these data are hardly accessible by experimental approaches. In this contribution, we investigate excited-state geometries obtained with Time Dependent Density Functional Theory, using both linear-response and, for the first time, corrected linear-response approaches of the Polarizable Continuum Model. Several chromophores representative of key dye families are used. In most cases, the corrected linear-response approach provides bond distances in between the gas and linear-response data, the latter model providing larger medium induced structural changes than the corrected linear-response model. However, in a few cases, the solvation effects predicted by the two continuum approaches present opposite directions compared to the gas phase reference. PMID- 26580517 TI - Electronic Quenching in N((2)D) + N2 Collisions: A State-Specific Analysis via Surface Hopping Dynamics. AB - The electronic quenching reaction N((2)D) + N2 -> N((4)S) + N2 is studied using the trajectory surface hopping method and employing two doublet and one quartet accurate potential energy surfaces. State-specific properties are analyzed, such as the dependence of the cross section on the initial quantum state of the reactants, vibrational energy transfer, and rovibrational distribution of the product N2 molecule in thermalized conditions. It is found that rotational energy on the reactant N2 molecule is effective in promoting the reaction, whereas vibrational excitation tends to reduce the reaction probability. For initial states and collision energy thermalized in an initial bath, it is found that the products are "hotter", both vibration and rotation wise. PMID- 26580518 TI - A Method for Creating Thermal and Angular Momentum Fluxes in Nonperiodic Simulations. AB - We present a new reverse nonequilibrium molecular dynamics method that can be used with nonperiodic simulation cells. This method applies thermal and/or angular momentum fluxes between two arbitrary regions of the simulation and is capable of creating stable temperature and angular velocity gradients while conserving total energy and angular momentum. One particularly useful application is the exchange of kinetic energy between two concentric spherical regions, which can be used to generate thermal transport between nanoparticles and the solvent that surrounds them. The rotational couple to the solvent (a measure of interfacial friction) is also available via this method. As tests of the new method, we have computed the thermal conductivities of gold nanoparticles and water clusters, the interfacial thermal conductivity (G) of a solvated gold nanoparticle, and the interfacial friction of a variety of solvated gold nanostructures. PMID- 26580519 TI - Quantitative Predictions of the Interfacial Tensions of Liquid-Liquid Interfaces through Atomistic and Coarse Grained Models. AB - We report molecular simulations of oil-water liquid-liquid interfaces by using atomistic and coarse grained (CG) MARTINI force fields. We also apply the electronic continuum (EC) model to the MARTINI force field for the calculation of the interfacial tension of oil/water-salt systems. In a first step, we propose to calculate the interfacial tensions using thermodynamic and mechanical definitions of hydrocarbon-water interfacial systems modified by the addition of salts and alcohol. We also establish here the order of magnitude of the long-range corrections to the interfacial tension in fluid-fluid interfaces. Whereas the atomistic models are able to reproduce quantitatively the interfacial tension and the coexisting densities of oil-water systems, the coarse-description shows some deviations in the prediction of the interfacial tensions. Nevertheless, the physical features of these liquid-liquid interfaces are well-captured by this CG description. The CG force field offers then a very challenging alternative that will require however a more developed calibration of the parameters on the basis of liquid-liquid properties. PMID- 26580520 TI - Density of States Guided Moller-Plesset Perturbation Theory. AB - An integral formalism using a density-of-state framework has been developed for Moller-Plesset perturbation theory. This method is designed to compute the correlation energy correction for large systems with high density of states, such as polymers and nanostructures. The framework has the potential to lower the computational cost of perturbation theory, and such perspectives are discussed in this paper. This method has been implemented for the second- and third-order perturbation theory. Applications of the new methods to test cases of conjugated molecules show very good accuracy and significant savings in computational cost. PMID- 26580521 TI - Symmetry Breaking and Broken Ergodicity in Full Configuration Interaction Quantum Monte Carlo. AB - The initiator full configuration interaction quantum Monte Carlo method (i FCIQMC) is applied to the binding curve of N2 in Slater-determinant Hilbert spaces formed of both canonical restricted Hartree-Fock (RHF) and symmetry-broken unrestricted Hartree-Fock (UHF) orbitals. By explicit calculation, we demonstrate that the technique yields the same total energy for both types of orbital but that as the bond is stretched, FCI expansions expressed in unrestricted orbitals are substantially more compact than their restricted counterparts and more compact than those expressed in split-localized orbitals. These unrestricted Hilbert spaces, however, become nonergodic toward the dissociation limit, and the total wave function may be thought of as the sum of two weakly coupled, spin impure, functions whose energies are nonetheless very close to the exact energy. In this limit, it is a challenge for i-FCIQMC to resolve a spin-pure wave function. The use of unrestricted natural orbitals is a promising remedy for this problem, as their expansions are more strongly weighted toward lower excitations of the reference, and they provide stronger coupling to higher excitations than do UHF orbitals. PMID- 26580522 TI - Partitioned EOMEA-MBPT(2): An Efficient N(5) Scaling Method for Calculation of Electron Affinities. AB - We present an N(5) scaling modification to the standard EOMEA-CCSD method, based on the matrix partitioning technique and perturbative approximations. The method has lower computational scaling and smaller storage requirements than the standard EOMEA-CCSD method and, therefore, can be used to calculate electron affinities of large molecules and clusters. The performance and capabilities of the new method have been benchmarked with the standard EOMEA-CCSD method, for a test set of 20 small molecules, and the average absolute deviation is only 0.03 eV. The method is further used to investigate electron affinities of DNA and RNA nucleobases, and the results are in excellent agreement with the experimental values. PMID- 26580523 TI - Toward Reliable Prediction of Hyperfine Coupling Constants Using Ab Initio Density Matrix Renormalization Group Method: Diatomic (2)Sigma and Vinyl Radicals as Test Cases. AB - The density matrix renormalization group (DMRG) method is used in conjunction with the complete active space (CAS) procedure, the CAS configuration interaction (CASCI), and the CAS self-consistent field (CASSCF) to evaluate hyperfine coupling constants (HFCCs) for a series of diatomic (2)Sigma radicals (BO, CO(+), CN, and AlO) and vinyl (C2H3) radical. The electron correlation effects on the computed HFCC values were systematically investigated using various levels of active space, which were increasingly extended from single valence space to large size model space entailing double valence and at least single polarization shells. In addition, the core correlation was treated by including the core orbitals in active space. Reasonably accurate results were obtained by the DMRG CASSCF method involving orbital optimization, while DMRG-CASCI calculations with Hartree-Fock orbitals provided poor agreement of the HFCCs with the experimental values. To achieve further insights into the accuracy of HFCC calculations, the orbital contributions to the total spin density were analyzed at a given nucleus, which is directly related to the FC term and is numerically sensitive to the level of correlation treatment and basis sets. The convergence of calculated HFCCs with an increasing number of renormalized states was also assessed. This work serves as the first study on the performance of the ab initio DMRG method for HFCC prediction. PMID- 26580524 TI - Analytical Energy Gradients in Range-Separated Hybrid Density Functional Theory with Random Phase Approximation. AB - Analytical forces have been derived in the Lagrangian framework for several random phase approximation (RPA) correlated total energy methods based on the range separated hybrid (RSH) approach, which combines a short-range density functional approximation for the short-range exchange-correlation energy with a Hartree-Fock-type long-range exchange and RPA long-range correlation. The RPA correlation energy has been expressed as a ring coupled cluster doubles (rCCD) theory. The resulting analytical gradients have been implemented and tested for geometry optimization of simple molecules and intermolecular charge transfer complexes, where intermolecular interactions are expected to have a non negligible effect even on geometrical parameters of the monomers. PMID- 26580525 TI - Quantum Monte Carlo Study of the Protonated Water Dimer. AB - We report an extensive theoretical study of the protonated water dimer H5O2(+) (Zundel ion) by means of the highly correlated variational Monte Carlo and lattice regularized Monte Carlo approaches. This system represents the simplest model for proton transfer (PT), and a correct description of its properties is essential in order to understand the PT mechanism in more complex aqueous systems. Our Jastrow correlated AGP wave function ensures an accurate treatment of electron correlation. By exploiting the advantage of contracting the primitive basis set over atomic hybrid orbitals, we are able to limit dramatically the number of variational parameters with a systematic control on the numerical precision, a crucial ingredient in order to simulate larger systems. For both energetics and geometrical properties, our QMC results are found to be in excellent agreement with state-of-the-art coupled cluster CCSD(T) techniques. A comparison with density functional theory in the PBE approximation points to the crucial role of electron correlation for a correct description of the PT in the dimer. We prove that the QMC framework used in this work is able to resolve the tiny energy differences (~0.3 kcal/mol) and structural variations involved in proton transfer reactions. Our approach combines these features and a favorable N(4) scaling with the number of particles which paves the way to the simulation of more realistic PT models. A test calculation on a larger protonated water cluster is carried out. The QMC approach used here represents a promising candidate to provide the first high-level ab initio description of PT in water. PMID- 26580526 TI - Accurate Coulomb Potentials for Periodic and Molecular Systems through Density Fitting. AB - We present a systematically improvable density fitting scheme designed for accurate Coulomb potential evaluation of periodic and molecular systems. The method does not depend on the way the density is calculated, allowing for a basis set expansion as well as a numerical representations of the orbitals. The scheme is characterized by a partitioning of the density into local contributions that are expanded by means of cubic splines. For three-dimensional periodic systems, the long-range contribution to the Coulomb potential is treated with the usual reciprocal space representation of the multipole moments, while in one- and two dimensional systems, it is calculated via a new algorithm based on topological extrapolation. The efficiency and numerical robustness of the scheme is assessed for a number of periodic and nonperiodic systems within the framework of density functional theory. PMID- 26580527 TI - Accurate Prediction of Hyperfine Coupling Constants in Muoniated and Hydrogenated Ethyl Radicals: Ab Initio Path Integral Simulation Study with Density Functional Theory Method. AB - We performed ab initio path integral molecular dynamics (PIMD) simulations with a density functional theory (DFT) method to accurately predict hyperfine coupling constants (HFCCs) in the ethyl radical (CbetaH3-CalphaH2) and its Mu-substituted (muoniated) compound (CbetaH2Mu-CalphaH2). The substitution of a Mu atom, an ultralight isotope of the H atom, with larger nuclear quantum effect is expected to strongly affect the nature of the ethyl radical. The static conventional DFT calculations of CbetaH3-CalphaH2 find that the elongation of one Cbeta-H bond causes a change in the shape of potential energy curve along the rotational angle via the imbalance of attractive and repulsive interactions between the methyl and methylene groups. Investigation of the methyl-group behavior including the nuclear quantum and thermal effects shows that an unbalanced CbetaH2Mu group with the elongated Cbeta-Mu bond rotates around the Cbeta-Calpha bond in a muoniated ethyl radical, quite differently from the CbetaH3 group with the three equivalent Cbeta-H bonds in the ethyl radical. These rotations couple with other molecular motions such as the methylene-group rocking motion (inversion), leading to difficulties in reproducing the corresponding barrier heights. Our PIMD simulations successfully predict the barrier heights to be close to the experimental values and provide a significant improvement in muon and proton HFCCs given by the static conventional DFT method. Further investigation reveals that the Cbeta-Mu/H stretching motion, methyl-group rotation, methylene-group rocking motion, and HFCC values deeply intertwine with each other. Because these motions are different between the radicals, a proper description of the structural fluctuations reflecting the nuclear quantum and thermal effects is vital to evaluate HFCC values in theory to be comparable to the experimental ones. Accordingly, a fundamental difference in HFCC between the radicals arises from their intrinsic molecular motions at a finite temperature, in particular the methyl-group behavior. PMID- 26580528 TI - Generalized Gradient Approximation Correlation Energy Functionals Based on the Uniform Electron Gas with Gap Model. AB - We studied uniform electron gas with a gap model in the context of density functional theory. On the basis of this analysis, we constructed two local gap models that are used in generalized gradient approximation (GGA) correlation functionals that satisfy numerous exact constraints for correlation energy. The first one, named GAPc, fulfills the full second-order correlation gradient expansion at any density regime and is very accurate for jellium surfaces, comparable to state-of-the-art GGAs for atomic systems and molecular systems, and is well compatible with known semilocal exchanges. The second functional, named GAPloc, satisfies the same exact conditions, except that the second-order gradient expansion is sacrificed for a better behavior under the Thomas-Fermi scaling and a more realistic correlation energy density of the helium atom. The GAPloc functional displays a high accuracy for atomic correlation energies, still preserving a reasonable behavior for jellium surfaces. Moreover, it shows a higher compatibility with the Hartree-Fock exchange than other semilocal correlation functionals. This feature is explained in terms of the real-space analysis of the GAPloc correlation energy. PMID- 26580529 TI - Coupled Cluster Valence Bond Method: Efficient Computer Implementation and Application to Multiple Bond Dissociations and Strong Correlations in the Acenes. AB - We describe an efficient implementation of the coupled cluster valence bond (CCVB) model. CCVB captures a certain essential part of the description of molecules with strong correlations (SC), which allows it to achieve correct energy profiles when covalent bonds are broken, while maintaining proper spin symmetry and size extensivity. To illustrate treatment of SC in bond breaking, we examine the symmetric dissociation of the sulfur allotropes S6 and S8 into triplet S atoms. To show applicability to larger systems and to explore whether CCVB can capture aspects of SC that arise in extended pi systems, we report results for a series of acenes up to 12 fused benzene rings, with active spaces of up to 228 correlated electrons. The lowest-energy CCVB solutions found for two of the largest acenes show signatures consistent with multi-electron SC and partial delocalization. PMID- 26580530 TI - Accurate Electron Affinities from the Extended Koopmans' Theorem Based on Orbital Optimized Methods. AB - The extended Koopmans' theorem (EKT) provides a systematic way to compute electron affinities (EAs) from any level of theory. Although, it is widely applied to ionization potentials, the EKT approach has not been extensively applied to computations of electron affinities. We present the first benchmarking study to investigate the performances of the EKT methods for predictions of EAs. We assess the performances of the EKT approaches based on orbital-optimized methods [Bozkaya, U. J. Chem. Phys. 2013, 139, 154105], such as the orbital optimized third-order Moller-Plesset perturbation theory and the orbital optimized coupled-electron pair theory [OCEPA(0)], and their standard counterparts for EAs of the selected atoms, closed- and open-shell molecules. Especially, results of the OCEPA(0) method (with the aug-cc-pVQZ basis set) for EAs of the considered atoms and molecules are very promising, the corresponding mean absolute errors are 0.14 and 0.17 eV, respectively. PMID- 26580531 TI - Comparison of Smooth Hartree-Fock Pseudopotentials. AB - The accuracy of two widely used scalar relativistic Hartree-Fock pseudopotentials, the Trail-Needs-Dirac-Fock (TNDF) and the Burkatzki-Filippi Dolg (BFD) pseudopotentials, is assessed. The performance of the pseudopotentials is tested for a chemically representative set of 34 first-row molecules. All comparisons are made at the Hartree-Fock level of theory, and both sets of pseudopotentials give good results. The all-electron equilibrium geometries, molecular dissociation energies, and zero-point vibrational energies are reproduced a little more accurately by the TNDF pseudopotentials than the BFD ones. PMID- 26580532 TI - Achieving High-Accuracy Intermolecular Interactions by Combining Coulomb Attenuated Second-Order Moller-Plesset Perturbation Theory with Coupled Kohn-Sham Dispersion. AB - The dispersion-corrected second-order Moller-Plesset perturbation theory (MP2C) approach accurately describes intermolecular interactions in many systems. MP2C, however, expends much computational effort to compute the long-range correlation with MP2, only to discard and replace those contributions with a simpler long range dispersion correction based on intermolecular perturbation theory. Here, we demonstrate that one can avoid calculating the long-range MP2 correlation by attenuating the Coulomb operator, allowing the dispersion correction to handle the long-range interactions inexpensively. With relatively modest Coulomb attenuation, one obtains results that are very similar to those from conventional MP2C. With more aggressive attenuation, one can remove just enough short-range repulsive exchange-dispersion interactions to compensate for finite basis set errors. Doing so makes it possible to approach complete basis set limit quality results with only an aug-cc-pVTZ basis, resulting in substantial computational savings. Further computational savings could be achieved by reformulating the MP2C algorithm to exploit the increased sparsity of the two-electron integrals. PMID- 26580533 TI - On-the-Fly Learning and Sampling of Ligand Binding by High-Throughput Molecular Simulations. AB - High-throughput molecular dynamics (MD) simulations are a computational method consisting of using multiple short trajectories, instead of few long ones, to cover slow biological time scales. Compared to long trajectories this method offers the possibility to start the simulations in successive batches, building a knowledgeable model of the available data to inform subsequent new simulations iteratively. Here, we demonstrate an automatic, iterative, on-the-fly method for learning and sampling molecular simulations in the context of ligand binding for the case of trypsin-benzamidine binding. The method uses Markov state models to learn a simplified model of the simulations and decide where best to sample from, achieving a converged binding affinity in approximately one microsecond, 1 order of magnitude faster than classical sampling. This method demonstrates for the first time the potential of adaptive sampling schemes in the case of ligand binding. PMID- 26580534 TI - Testing Noncollinear Spin-Flip, Collinear Spin-Flip, and Conventional Time Dependent Density Functional Theory for Predicting Electronic Excitation Energies of Closed-Shell Atoms. AB - Conventional time-dependent density functional theory (TDDFT) is based on a closed-shell Kohn-Sham (KS) singlet ground state with the adiabatic approximation, using either linear response (KS-LR) or the Tamm-Dancoff approximation (KS-TDA); these methods can only directly predict singly excited states. This deficiency can be overcome by using a triplet state as the reference in the KS-TDA approximation and "exciting" the singlet by a spin flip (SF) from the triplet; this is the method suggested by Krylov and co-workers, and we abbreviate this procedure as SF-KS-TDA. SF-KS-TDA can be applied either with the original collinear kernel of Krylov and co-workers or with a noncollinear kernel, as suggested by Wang and Ziegler. The SF-KS-TDA method does bring some new practical difficulties into play, but it can at least formally model doubly excited states and states with double-excitation character, so it might be more useful than conventional TDDFT (both KS-LR and KS-TDA) for photochemistry if these additional difficulties can be surmounted and if it is accurate with existing approximate exchange-correlation functionals. In the present work, we carried out calculations specifically designed to understand better the accuracy and limitations of the conventional TDDFT and SF-KS-TDA methods; we did this by studying closed-shell atoms and closed-shell monatomic cations because they provide a simple but challenging testing ground for what we might expect in studying the photochemistry of molecules with closed-shell ground states. To test their accuracy, we applied conventional KS-LR and KS-TDA and 18 versions of SF-KS TDA (nine collinear and nine noncollinear) to the same set of vertical excitation energies (including both Rydberg and valence excitations) of Be, B(+), Ne, Na(+), Mg, and Al(+). We did this for 10 exchange-correlation functionals of various types, both local and nonlocal. We found that the GVWN5 and M06 functionals with nonlocal kernels in spin-flip calculations can both have accuracy competitive to CASPT2 calculations. When the results were averaged over all 36 test energy differences, seven (GVWN5, M06, B3PW91, LRC-omegaPBE, LRC-omegaPBEh, PBE, and M06 2X) of the 10 studied density functionals had smaller mean unsigned errors for noncollinear calculations than the mean unsigned error of the best functional (M06-2X) for either conventional KS-TDA or KS-LR. PMID- 26580535 TI - Assessment of CCSD(T)-F12 Approximations and Basis Sets for Harmonic Vibrational Frequencies. AB - We consider basis set convergence and the effect of various approximations to CCSD(T)-F12 for a representative sample of harmonic frequencies (the HFREQ2014 set). CCSD(T*)(F12*)/cc-pVDZ-F12 offers a particularly favorable compromise between accuracy and computational cost: its RMSD <3 cm(-1) from the valence CCSD(T) limit is actually less than the remaining discrepancy with the experimental value at the valence CCSD(T) limit (about 5 cm(-1) RMSD). CCSD(T) F12a and CCSD(T)-F12b appear to benefit from error compensation between CCSD and (T). PMID- 26580536 TI - Electrochemical Solvent Reorganization Energies in the Framework of the Polarizable Continuum Model. AB - Electron transfer reactions at electrochemical interfaces play a critical role in a wide range of catalytic processes. A key parameter in the rate constant expressions for such processes is the reorganization energy, which reflects the energetic cost of the solute and solvent rearrangements upon electron transfer. In this paper, we present dielectric continuum methods for calculating the solvent reorganization energy for electrochemical processes. We develop a method for calculating the electrochemical solvent reorganization energies with molecular-shaped cavities within the framework of the polarizable continuum model (PCM). The electronic and inertial responses of the solvent are separated according to their respective time scales, and two limiting cases of the relation between the solute and solvent electrons are examined. The effects of the electrode are included with the integral equations formalism PCM (IEF-PCM), in which the molecule-solvent boundary is treated explicitly, but the effects of the electrode-solvent boundary are included through an external Green's function. This approach accounts for the effects of detailed molecular charge redistribution in a molecular-shaped cavity, as well as the electronic and inertial solvent responses and the effects of the electrode. The calculated total reorganization energies are in reasonable agreement with experimental measurements for a series of electrochemical systems. Inclusion of the effects of the electrode is found to be essential for obtaining even qualitatively accurate solvent reorganization energies. These approaches are applicable to a wide range of systems and can be extended to include other types of boundaries, such as a self-assembled monolayer or double layer separating the electrode and the molecule. PMID- 26580537 TI - Quasiparticle Level Alignment for Photocatalytic Interfaces. AB - Electronic level alignment at the interface between an adsorbed molecular layer and a semiconducting substrate determines the activity and efficiency of many photocatalytic materials. Standard density functional theory (DFT)-based methods have proven unable to provide a quantitative description of this level alignment. This requires a proper treatment of the anisotropic screening, necessitating the use of quasiparticle (QP) techniques. However, the computational complexity of QP algorithms has meant a quantitative description of interfacial levels has remained elusive. We provide a systematic study of a prototypical interface, bare and methanol-covered rutile TiO2(110) surfaces, to determine the type of many body theory required to obtain an accurate description of the level alignment. This is accomplished via a direct comparison with metastable impact electron spectroscopy (MIES), ultraviolet photoelectron spectroscopy (UPS), and two-photon photoemission (2PP) spectroscopy. We consider GGA DFT, hybrid DFT, and G0W0, scQPGW1, scQPGW0, and scQPGW QP calculations. Our results demonstrate that G0W0, or our recently introduced scQPGW1 approach, are required to obtain the correct alignment of both the highest occupied and lowest unoccupied interfacial molecular levels (HOMO/LUMO). These calculations set a new standard in the interpretation of electronic structure probe experiments of complex organic molecule/semiconductor interfaces. PMID- 26580538 TI - Evaluation of the Linear and Second-Order NLO Properties of Molecular Crystals within the Local Field Theory: Electron Correlation Effects, Choice of XC Functional, ZPVA Contributions, and Impact of the Geometry in the Case of 2 Methyl-4-nitroaniline. AB - The linear [chi((1))] and second-order nonlinear [chi((2))] optical susceptibilities of the 2-methyl-4-nitroaniline (MNA) crystal are calculated within the local field theory, which consists of first computing the molecular properties, accounting for the dressing effects of the surroundings, and then taking into account the local field effects. Several aspects of these calculations are tackled with the aim of monitoring the convergence of the chi((1)) and chi((2)) predictions with respect to experiment by accounting for the effects of (i) the dressing field within successive approximations, of (ii) the first-order ZPVA corrections, and of (iii) the geometry. With respect to the reference CCSD-based results, besides double hybrid functionals, the most reliable exchange-correlation functionals are LC-BLYP for the static chi((1)) and CAM-B3LYP (and M05-2X, to a lesser extent) for the dynamic chi((1)) but they strongly underestimate chi((2)). Double hybrids perform better for chi((2)) but not necessarily for chi((1)), and, moreover, their performances are much similar to MP2, which is known to slightly overestimate beta, with respect to high-level coupled-clusters calculations and, therefore, chi((2)). Other XC functionals with less HF exchange perform poorly with overestimations/underestimations of chi((1))/chi((2)), whereas the HF method leads to underestimations of both. The first-order ZPVA corrections, estimated at the B3LYP level, are usually small but not negligible. Indeed, after ZPVA corrections, the molecular polarizabilities and first hyperpolarizabilities increase by 2% and 5%, respectively, whereas their impact is magnified on the macroscopic responses with enhancements of chi((1)) by up to 5% and of chi((2)) by as much as 10%-12% at lambda = 1064 nm. The geometry plays also a key role in view of predicting accurate susceptibilities, particularly for push-pull pi-conjugated compounds such as MNA. So, the geometry optimized using periodic boundary conditions is characterized by an overestimated bond length alternation, which gives larger molecular properties and even larger macroscopic responses, because of the local field factor amplification effects. Our best estimates based on experimental geometries, charge dressing field, ZPVA correction, and CCSD molecular properties lead to an overestimation of chi((1)) by 12% in the static limit and 7% at lambda = 1064 nm. For chi((2)), the difference, with respect to the experiment, is satisfactory and of the order of one standard deviation. PMID- 26580539 TI - Cob(II)alamin: Relativistic DFT Analysis of the EPR Parameters. AB - Relativistic density functional theory (DFT) has been applied to explore electron paramagnetic resonance (EPR) parameters as well as ground-state spin properties of cob(II)alamin. Cob(II)alamin is an intermediate which participates in many reactions catalyzed by derivatives of vitamin B12 and that can be detected by EPR spectroscopy due to the presence of the paramagnetic Co(II)(d(7)) center. The full structure of cob(II)alamin and its truncated analogues were examined. Three different DFT functionals, B3LYP, BP86, and PBE, have been applied to obtain the g- and A-tensors. Both tensors are axially symmetric and can provide useful insight into specific axial ligand interactions. Of the functionals tested, the hybrid B3LYP functional, was found to overestimate the axial bond length, whereas the GGA-type functionals, BP86 and PBE, produced geometries consistent with experimental data. The reliability of nonrelativistic and approximate relativistic methods for the calculation of EPR parameters has also been tested against a fully relativistic four-component approach. Since the EPR parameters are very sensitive to the local environment surrounding Co(II), a theoretical (DFT-BP86) estimate of the dependence of the g- and A-tensors on the metal-to axial ligand interatomic distance can be directly correlated with EPR measurements. The usefulness of such an approach has been demonstrated for the methionine synthase enzyme where the reduction of cob(II)alamin takes place during the reactivation cycle. PMID- 26580540 TI - Efficient Characterization of Protein Cavities within Molecular Simulation Trajectories: trj_cavity. AB - Protein cavities and tunnels are critical in determining phenomena such as ligand binding, molecular transport, and enzyme catalysis. Molecular dynamics (MD) simulations enable the exploration of the flexibility and conformational plasticity of protein cavities, extending the information available from static experimental structures relevant to, for example, drug design. Here, we present a new tool (trj_cavity) implemented within the GROMACS ( www.gromacs.org ) framework for the rapid identification and characterization of cavities detected within MD trajectories. trj_cavity is optimized for usability and computational efficiency and is applicable to the time-dependent analysis of any cavity topology, and optional specialized descriptors can be used to characterize, for example, protein channels. Its novel grid-based algorithm performs an efficient neighbor search whose calculation time is linear with system size, and a comparison of performance with other widely used cavity analysis programs reveals an orders-of-magnitude improvement in the computational cost. To demonstrate its potential for revealing novel mechanistic insights, trj_cavity has been used to analyze long-time scale simulation trajectories for three diverse protein cavity systems. This has helped to reveal, respectively, the lipid binding mechanism in the deep hydrophobic cavity of a soluble mite-allergen protein, Der p 2; a means for shuttling carbohydrates between the surface-exposed substrate-binding and catalytic pockets of a multidomain, membrane-proximal pullulanase, PulA; and the structural basis for selectivity in the transmembrane pore of a voltage-gated sodium channel (NavMs), embedded within a lipid bilayer environment. trj_cavity is available for download under an open-source license ( http://sourceforge.net/projects/trjcavity ). A simplified, GROMACS-independent version may also be compiled. PMID- 26580542 TI - Protonation of DMPC in a Bilayer Environment Using a Linear Response Approximation. AB - pH is a very important property, influencing all important biomolecules such as proteins, nucleic acids, and lipids. The effect of pH on proteins has been the subject of many computational works in recent years. However, the same has not been done for lipids, especially in their most biologically relevant environment: the bilayer. A reason for this is the inherent technical difficulty in dealing with this type of periodic systems. Here, we tackle this problem by developing a Poisson-Boltzmann-based method that takes in consideration the periodic boundary conditions of lipid bilayer patches. We used this approach with a linear response approximation to calculate the pKa value of a DMPC molecule when diluted in zwitterionic lipids. Our results show that DMPC protonation only becomes relevant at quite low pH values (2-3). However, when it happens, it has a strong impact on lipid conformations, leading to significant heterogeneity in the membrane. PMID- 26580541 TI - Sidekick for Membrane Simulations: Automated Ensemble Molecular Dynamics Simulations of Transmembrane Helices. AB - The interactions of transmembrane (TM) alpha-helices with the phospholipid membrane and with one another are central to understanding the structure and stability of integral membrane proteins. These interactions may be analyzed via coarse grained molecular dynamics (CGMD) simulations. To obtain statistically meaningful analysis of TM helix interactions, large (N ca. 100) ensembles of CGMD simulations are needed. To facilitate the running and analysis of such ensembles of simulations, we have developed Sidekick, an automated pipeline software for performing high throughput CGMD simulations of alpha-helical peptides in lipid bilayer membranes. Through an end-to-end approach, which takes as input a helix sequence and outputs analytical metrics derived from CGMD simulations, we are able to predict the orientation and likelihood of insertion into a lipid bilayer of a given helix of a family of helix sequences. We illustrate this software via analyses of insertion into a membrane of short hydrophobic TM helices containing a single cationic arginine residue positioned at different positions along the length of the helix. From analyses of these ensembles of simulations, we estimate apparent energy barriers to insertion which are comparable to experimentally determined values. In a second application, we use CGMD simulations to examine the self-assembly of dimers of TM helices from the ErbB1 receptor tyrosine kinase and analyze the numbers of simulation repeats necessary to obtain convergence of simple descriptors of the mode of packing of the two helices within a dimer. Our approach offers a proof-of-principle platform for the further employment of automation in large ensemble CGMD simulations of membrane proteins. PMID- 26580543 TI - fireball/amber: An Efficient Local-Orbital DFT QM/MM Method for Biomolecular Systems. AB - In recent years, quantum mechanics/molecular mechanics (QM/MM) methods have become an important computational tool for the study of chemical reactions and other processes in biomolecular systems. In the QM/MM technique, the active region is described by means of QM calculations, while the remainder of the system is described using a MM approach. Because of the complexity of biomolecules and the desire to achieve converged sampling, it is important that the QM method presents a good balance between accuracy and computational efficiency. Here, we report on the implementation of a QM/MM technique that combines a DFT approach specially designed for the study of complex systems using first-principles molecular dynamics simulations (fireball) with the amber force fields and simulation programs. We also present examples of the application of this QM/MM approach to three representative biomolecular systems: the analysis of the effect of electrostatic embedding in the behavior of a salt bridge between an aspartic acid and a lysine residue, a study of the intermediate states for the triosephosphate isomerase catalyzed conversion of dihydroxyacetone phosphate into glyceraldehyde 3-phosphate, and the detailed description, using DFT QM/MM molecular dynamics, of the cleavage of a phosphodiester bond in RNA catalyzed by the enzyme RNase A. PMID- 26580544 TI - Computational Screening of Weak Hydrogen Bond Networks: Predicting Stable Structures for Difluoromethane Oligomers. AB - The stability and the structure of small difluoromethane oligomers are studied by combining classical Monte Carlo and quantum mechanical calculations. A hierarchical procedure was adopted to validate the accuracy of the whole protocol: the force field used in Monte Carlo simulations is parametrized on the basis of dimer intermolecular energies computed with density functional theory. The density functional is similarly chosen by comparing the interaction energies with reference values, purposely computed at a coupled cluster level, extrapolated at the complete basis set. The structures of dimers, trimers, and tetramers identified by the screening as local minima are first characterized by some geometrical parameters and by their dipole moment and eventually validated by comparison with results of microwave spectroscopy. The results are found in very good agreement with the experiment for all considered structures. PMID- 26580545 TI - Erratum: Development of a "First-Principles" Water Potential with Flexible Monomers: Dimer Potential Energy Surface, VRT Spectrum, and Second Virial Coefficient. PMID- 26580546 TI - Twin Anemia-Polycythemia Sequence: Perinatal Management and Outcome. AB - OBJECTIVE: To determine the perinatal outcome of monochorionic twin pregnancies complicated by twin anemia-polycythemia sequence (TAPS). METHODS: All monochorionic twins diagnosed with TAPS between 2011 and 2014 were included. Each twin pair with TAPS (study group) was compared with 2 uncomplicated monochorionic twin pairs who were matched for gestational age at delivery (control group). Neonatal morbidity and mortality were evaluated. RESULTS: During the study period, 179 monochorionic twins were followed at our center, of whom 46 underwent laser ablation due to twin-to-twin transfusion syndrome. TAPS was diagnosed in 10 cases; 8 of them were spontaneous, and 2 occurred following laser surgery. Out of 7 patients diagnosed prenatally with TAPS, 5 cases were managed expectantly, and 2 cases were treated with intrauterine blood transfusion. The rates of severe and mild central nervous system lesions on postnatal ultrasound were similar in the TAPS group and control group (5.0 vs. 2.5%, p = 0.61, and 5.0 vs. 12.5%, p = 0.25, respectively). Additionally, severe neonatal morbidity was comparable between the groups. All neonates were alive at 1 month of age. CONCLUSION: The neonatal outcome of monocohorionic twins affected by TAPS is favorable and comparable to gestational age-matched uncomplicated monochorionic twins. PMID- 26580547 TI - High Innate Immune Specificity through Diversified C-Type Lectin-Like Domain Proteins in Invertebrates. AB - A key question in current immunity research is how the innate immune system can generate high levels of specificity. Evidence is accumulating that invertebrates, which exclusively rely on innate defense mechanisms, can differentiate between pathogens on the species and even strain level. In this review, we identify and discuss the particular potential of C-type lectin-like domain (CTLD) proteins to generate high immune specificity. Whilst several CTLD proteins are known to act as pattern recognition receptors in the vertebrate innate immune system, the exact role of CTLD proteins in invertebrate immunity is much less understood. We show that CTLD genes are highly abundant in most metazoan genomes and summarize the current state of knowledge on CTLD protein function in insect, crustacean and nematode immune systems. We then demonstrate extreme CTLD gene diversification in the genomes of Caenorhabditis nematodes and provide an update of data from CTLD gene function studies in C. elegans, which indicate that the diversity of CTLD genes could contribute to immune specificity. In spite of recent achievements, the exact functions of the diversified invertebrate CTLD genes are still largely unknown. Our review therefore specifically discusses promising research approaches to rectify this knowledge gap. PMID- 26580548 TI - A Newly Developed Shear Wave Elastography Modality: With a Unique Reliability Index. AB - OBJECTIVE: The aim of this study was to prospectively assess the usefulness of the reliability index, namely the percentage of the net amount of effective shear wave velocity (VsN). METHODS: One hundred and sixty-eight patients with chronic liver disease, who underwent ultrasound elastography, were consecutively enrolled. Shear wave measurement (SWM), FibroScan, virtual touch quantification, and shear wave elastography were performed for all patients, and the variations in the measurement results were compared with VsN. The absolute average value of the difference between SWM_Vs and Vs measured using other elastography devices is termed |DeltaVs|. VsN was classified into three groups: >=50, <50, and 0 (failure measurement). In these groups, there was a significant difference in abdominal circumference, body mass index, the distance between the ultrasound probe surface and the liver, and |DeltaVs|. When the distance between the ultrasound probe surface and the liver was >2 cm, VsN tended to be significantly lower (p < 0.001). RESULTS: When VsN was <50, |DeltaVs| became high, and there was variation in the results between each device. CONCLUSIONS: The results of this study show that VsN is a useful value to decide whether Vs is appropriate or not. PMID- 26580549 TI - The Effect of Novel Research Activities on Long-term Survival of Temporarily Captive Steller Sea Lions (Eumetopias jubatus). AB - Two novel research approaches were developed to facilitate controlled access to, and long-term monitoring of, juvenile Steller sea lions for periods longer than typically afforded by traditional fieldwork. The Transient Juvenile Steller sea lion Project at the Alaska SeaLife Center facilitated nutritional, physiological, and behavioral studies on the platform of temporary captivity. Temporarily captive sea lions (TJs, n = 35) were studied, and were intraperitoneally implanted with Life History Transmitters (LHX tags) to determine causes of mortality post-release. Our goal was to evaluate the potential for long-term impacts of temporary captivity and telemetry implants on the survival of study individuals. A simple open-population Cormack-Jolly-Seber mark-recapture model was built in program MARK, incorporating resightings of uniquely branded study individuals gathered by several contributing institutions. A priori models were developed to weigh the evidence of effects of experimental treatment on survival with covariates of sex, age, capture age, cohort, and age class. We compared survival of experimental treatment to a control group of n = 27 free-ranging animals (FRs) that were sampled during capture events and immediately released. Sex has previously been show to differentially affect juvenile survival in Steller sea lions. Therefore, sex was included in all models to account for unbalanced sex ratios within the experimental group. Considerable support was identified for the effects of sex, accounting for over 71% of total weight for all a priori models with delta AICc <5, and over 91% of model weight after removal of pretending variables. Overall, most support was found for the most parsimonious model based on sex and excluding experimental treatment. Models including experimental treatment were not supported after post-hoc considerations of model selection criteria. However, given the limited sample size, alternate models including effects of experimental treatments remain possible and effects may yet become apparent in larger sample sizes. PMID- 26580550 TI - Parental Effect of Long Acclimatization on Thermal Tolerance of Juvenile Sea Cucumber Apostichopus japonicus. AB - To evaluate the thermal resistance of marine invertebrates to elevated temperatures under scenarios of future climate change, it is crucial to understand parental effect of long acclimatization on thermal tolerance of offspring. To test whether there is parental effect of long acclimatization, adult sea cucumbers (Apostichopus japonicus) from the same broodstock were transplanted southward and acclimatized at high temperature in field mesocosms. Four groups of juvenile sea cucumbers whose parents experienced different durations of high temperature acclimatization were established. Upper thermal limits, oxygen consumption and levels of heat shock protein mRNA of juveniles was determined to compare thermal tolerance of individuals from different groups. Juvenile sea cucumbers whose parents experienced high temperature could acquire high thermal resistance. With the increase of parental exposure duration to high temperature, offspring became less sensitive to high temperature, as indicated by higher upper thermal limits (LT50), less seasonal variations of oxygen consumption, and stable oxygen consumption rates between chronic and acute thermal stress. The relatively high levels of constitutive expression of heat shock proteins should contribute to the high thermal tolerance. Together, these results indicated that the existence of a parental effect of long acclimatization would increase thermal tolerance of juveniles and change the thermal sensitivity of sea cucumber to future climate change. PMID- 26580551 TI - Phospholipid Binding Protein C Inhibitor (PCI) Is Present on Microparticles Generated In Vitro and In Vivo. AB - Protein C inhibitor is a secreted, non-specific serine protease inhibitor with broad protease reactivity. It binds glycosaminoglycans and anionic phospholipids, which can modulate its activity. Anionic phospholipids, such as phosphatidylserine are normally localized to the inner leaflet of the plasma membrane, but are exposed on activated and apoptotic cells and on plasma membrane derived microparticles. In this report we show by flow cytometry that microparticles derived from cultured cells and activated platelets incorporated protein C inhibitor during membrane blebbing. Moreover, protein C inhibitor is present in/on microparticles circulating in normal human plasma as judged from Western blots, ELISAs, flow cytometry, and mass spectrometry. These plasma microparticles are mainly derived from megakaryocytes. They seem to be saturated with protein C inhibitor, since they do not bind added fluorescence-labeled protein C inhibitor. Heparin partially removed microparticle-bound protein C inhibitor, supporting our assumption that protein C inhibitor is bound via phospholipids. To assess the biological role of microparticle-bound protein C inhibitor we performed protease inhibition assays and co-precipitated putative binding partners on microparticles with anti-protein C inhibitor IgG. As judged from amidolytic assays microparticle-bound protein C inhibitor did not inhibit activated protein C or thrombin, nor did microparticles modulate the activity of exogenous protein C inhibitor. Among the proteins co-precipitating with protein C inhibitor, complement factors, especially complement factor 3, were most striking. Taken together, our data do not support a major role of microparticle associated protein C inhibitor in coagulation, but rather suggest an interaction with proteins of the complement system present on these phospholipid vesicles. PMID- 26580552 TI - Brief report: Explaining differences in depressive symptoms between African American and European American adolescents. AB - African American adolescents report more depressive symptoms than their European American peers, but the reasons for these differences are poorly understood. This study examines whether risk factors in individual, family, school, and community domains explain these differences. African American and European American adolescents participating in the Birmingham Youth Violence Study (N = 594; mean age 13.2 years) reported on their depressive symptoms, pubertal development, aggressive and delinquent behavior, connectedness to school, witnessing violence, and poor parenting. Primary caregivers provided information on family income and their education level, marital status, and depression, and the adolescents' academic performance. African American adolescents reported more depressive symptoms than European American participants. Family socioeconomic factors reduced this difference by 29%; all risk factors reduced it by 88%. Adolescents' exposure to violence, antisocial behavior, and low school connectedness, as well as lower parental education and parenting quality, emerged as significant mediators of the group differences in depressive symptoms. PMID- 26580553 TI - Humor style similarity and difference in friendship dyads. AB - This study assessed the concurrent and prospective (fall to spring) associations between four different humor styles to assess the degree to which stable friendships are characterized by similarity, and to assess whether best friends' humor styles influence each other's later use of humor. Participants were aged 11 13 years, with 87 stable, reciprocal best friend dyads. Self-report assessments of humor styles were completed on both occasions. Results indicated that there was no initial similarity in dyads' levels of humor. However, dyads' use of humor that enhances interpersonal relationships (Affiliative humor) became positively correlated by spring. Additionally, young people's use of this humor style was positively associated with their best friend's later use of the same. No such effects were present for humor which was aggressive, denigrating toward the self, or used to enhance the self. These results have clear implications for theories of humor style development, highlighting an important role for Affiliative humor within stable friendship dyads. PMID- 26580555 TI - Correction: Perturbing the Cellular Levels of Steroid Receptor Coactivator-2 Impairs Murine Endometrial Function. PMID- 26580554 TI - Assessment of Interactions between Cisplatin and Two Histone Deacetylase Inhibitors in MCF7, T47D and MDA-MB-231 Human Breast Cancer Cell Lines - An Isobolographic Analysis. AB - Histone deacetylase inhibitors (HDIs) are promising anticancer drugs, which inhibit proliferation of a wide variety of cancer cells including breast carcinoma cells. In the present study, we investigated the influence of valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA, vorinostat), alone or in combination with cisplatin (CDDP) on proliferation, induction of apoptosis and cell cycle progression in MCF7, T47D and MDA-MB-231 human breast carcinoma cell lines. The type of interaction between HDIs and CDDP was determined by an isobolographic analysis. The isobolographic analysis is a very precise and rigorous pharmacodynamic method, to determine the presence of synergism, addition or antagonism between different drugs with using variety of fixed dose ratios. Our experiments show that the combinations of CDDP with SAHA or VPA at a fixed ratio of 1:1 exerted additive interaction in the viability of MCF7 cells, while in T47D cells there was a tendency to synergy. In contrast, sub-additive (antagonistic) interaction was observed for the combination of CDDP with VPA in MDA-MB-231 "triple-negative" (i.e. estrogen receptor negative, progesterone receptor negative, and HER-2 negative) human breast cancer cells, whereas combination of CDDP with SAHA in the same MDA-MB-231 cell line yielded additive interaction. Additionally, combined HDIs/CDDP treatment resulted in increase in apoptosis and cell cycle arrest in all tested breast cancer cell lines in comparison with a single therapy. In conclusion, the additive interaction of CDDP with SAHA or VPA suggests that HDIs could be combined with CDDP in order to optimize treatment regimen in some human breast cancers. PMID- 26580556 TI - Amplitude Manipulation Evokes Upper Limb Freezing during Handwriting in Patients with Parkinson's Disease with Freezing of Gait. AB - BACKGROUND: Recent studies show that besides freezing of gait (FOG), many people with Parkinson's disease (PD) also suffer from freezing in the upper limbs (FOUL). Up to now, it is unclear which task constraints provoke and explain upper limb freezing. OBJECTIVE: To investigate whether upper limb freezing and other kinematic abnormalities during writing are provoked by (i) gradual changes in amplitude or by (ii) sustained amplitude generation in patients with and without freezing of gait. METHODS: Thirty-four patients with PD, including 17 with and 17 without FOG, performed a writing task on a touch-sensitive writing tablet requiring writing at constant small and large size as well as writing at gradually increasing and decreasing size. Patients of both groups were matched for disease severity, tested while 'on' medication and compared to healthy age matched controls. RESULTS: Fifty upper limb freezing episodes were detected in 10 patients, including 8 with and 2 without FOG. The majority of the episodes occurred when participants had to write at small or gradually decreasing size. The occurrence of FOUL and the number of FOUL episodes per patient significantly correlated with the occurrence and severity of FOG. Patients with FOUL also showed a significantly smaller amplitude in the writing parts outside the freezing episodes. CONCLUSIONS: Corroborating findings of gait research, the current study supports a core problem in amplitude control underlying FOUL, both in maintaining as well as in flexibly adapting the cycle size. PMID- 26580557 TI - Sexual segregation of Echinorhynchus borealis von Linstow, 1901 (Acanthocephala) in the gut of burbot (Lota lota Linnaeus). AB - Helminths often occupy defined niches in the gut of their definitive hosts. In the dioecious acanthocephalans, adult males and females usually have similar gut distributions, but sexual site segregation has been reported in at least some species. We studied the intestinal distribution of the acanthocephalan Echinorhynchus borealis von Linstow, 1901 (syn. of E. cinctulus Porta, 1905) in its definitive host, burbot (Lota lota Linnaeus). Over 80% of female worms were found in the pyloric caeca, whereas the majority of males were in the anterior two-thirds of the intestine. This difference was relatively consistent between individual fish hosts. Worms from different parts of the gut did not differ in length, so site segregation was not obviously related to worm growth or age. We found proportionally more males in the caeca when a larger fraction of the females were found there, suggesting mating opportunities influence gut distribution. However, this result relied on a single parasite infrapopulation and is thus tentative. We discuss how mating strategies and/or sexual differences in life history might explain why males and females occupy different parts of the burbot gut. PMID- 26580558 TI - Growth and Reproduction of Glyphosate-Resistant and Susceptible Populations of Kochia scoparia. AB - Evolution of glyphosate-resistant kochia is a threat to no-till wheat-fallow and glyphosate-resistant (GR) cropping systems of the US Great Plains. The EPSPS (5 enol-pyruvylshikimate-3-phosphate synthase) gene amplification confers glyphosate resistance in the tested Kochia scoparia (L.) Schrad populations from Montana. Experiments were conducted in spring to fall 2014 (run 1) and summer 2014 to spring 2015 (run 2) to investigate the growth and reproductive traits of the GR vs. glyphosate-susceptible (SUS) populations of K. scoparia and to determine the relationship of EPSPS gene amplification with the level of glyphosate resistance. GR K. scoparia inbred lines (CHES01 and JOP01) exhibited 2 to 14 relative copies of the EPSPS gene compared with the SUS inbred line with only one copy. In the absence of glyphosate, no differences in growth and reproductive parameters were evident between the tested GR and SUS inbred lines, across an intraspecific competition gradient (1 to 170 plants m-2). GR K. scoparia plants with 2 to 4 copies of the EPSPS gene survived the field-use rate (870 g ha-1) of glyphosate, but failed to survive the 4,350 g ha-1 rate of glyphosate (five-times the field use rate). In contrast, GR plants with 5 to 14 EPSPS gene copies survived the 4,350 g ha-1 of glyphosate. The results from this research indicate that GR K. scoparia with 5 or more EPSPS gene copies will most likely persist in field populations, irrespective of glyphosate selection pressure. PMID- 26580559 TI - An Exploration of the Factors Considered When Forming Expectations for Returning to Work following Sickness Absence Due to a Musculoskeletal Condition. AB - INTRODUCTION: Workers' own expectations for returning to work following a period of sickness absence have been found to be one of the best predictors of future work status; however, there is a limited understanding of why people expect what they do. The current study was undertaken with the aim of determining what people take into consideration when forming their expectations for returning to work. METHODS: Thirty-four people (8 women, 26 men), who were off work due to a musculoskeletal condition, participated in one of 14 focus groups. Participants were aged 25 to 65 (M = 45, SD = 12.6), and all had been out of work for 3 months or less. RESULTS: All participants reported expecting to return to work, with the most common timeframe being approximately 30 days (Range = 1 day-12 months). When explaining what they thought about when forming their expectations, participants referenced numerous considerations. Much of what was spoken about could be compartmentalized to reflect features of themselves, their condition, or their broader environmental contexts. Participant's subjective experience of these features influenced his or her expectations. Prominent themes included concerns about employability, a desire to get back to normal, no job to go back to, mixed emotions, re-injury concerns, the judgments of workplace stakeholders, being needed by their employer, waiting for input, until the money runs out, and working out what was in their best interest. CONCLUSIONS: Indications are that many of the reported considerations are amenable to intervention, suggesting opportunities to assist workers in the process of returning to work. PMID- 26580560 TI - Contemporary Land Change Alters Fish Communities in a San Francisco Bay Watershed, California, U.S.A. AB - Urbanization is one of the leading threats to freshwater biodiversity, and urban regions continue to expand globally. Here we examined the relationship between recent urbanization and shifts in stream fish communities. We sampled fishes at 32 sites in the Alameda Creek Watershed, near San Francisco, California, in 1993 1994 and again in 2009, and we quantified univariate and multivariate changes in fish communities between the sampling periods. Sampling sites were classified into those downstream of a rapidly urbanizing area ("urbanized sites"), and those found in less impacted areas ("low-impacted sites"). We calculated the change from non-urban to urban land cover between 1993 and 2009 at two scales for each site (the total watershed and a 3km buffer zone immediately upstream of each site). Neither the mean relative abundance of native fish nor nonnative species richness changed significantly between the survey periods. However, we observed significant changes in fish community composition (as measured by Bray-Curtis dissimilarity) and a decrease in native species richness between the sampling periods at urbanized sites, but not at low-impacted sites. Moreover, the relative abundance of one native cyprinid (Lavinia symmetricus) decreased at the urbanized sites but not at low-impacted sites. Increased urbanization was associated with changes in the fish community, and this relationship was strongest at the smaller (3km buffer) scale. Our results suggest that ongoing land change alters fish communities and that contemporary resurveys are an important tool for examining how freshwater taxa are responding to recent environmental change. PMID- 26580562 TI - Reproductive Hormone and Transcriptomic Responses of Pituitary Tissue in Anestrus Gilts Induced by Nutrient Restriction. AB - The onset of estrus is a critical sign of female sexual maturity. The pituitary plays a vital role in this process by the secretion of reproductive hormones. To investigate the effects of nutrient restriction on reproductive function and the underlying mechanisms involved, deep RNA sequencing of pituitary gland tissue was carried out to determine the differentially expressed genes (DEGs) between gilts in normal estrus, and gilts in which anestrus was induced by nutrient restriction. Gilts which had gone through two estrus cycles were fed a normal (CON, 2.86kg/d, n = 10) or nutrient restricted (NR, 1kg/d, n = 10) diet. The NR gilts experienced another three estrus cycles, but did not express estrus symptoms at the anticipated 6th and 7th cycles. Body weight gain in NR gilts was significantly decreased by nutrient restriction. Gilts were considered as anestrus when blood progesterone concentrations lower than 1.0 ng/mL from three consecutive blood samples were recorded. Circulating concentrations of progesterone (< 1.0 ng/mL vs. 2.1 ng/mL) and estradiol (208.6 ng/mL vs. 371.8 ng/mL) were significantly lower in the NR gilts than in the CON gilts. Between 5,360,000 and 5,370,000 sequence reads per sample from the CON and NR gilts' pituitaries were obtained and mapped to the porcine genome. Analysis of read counts revealed 185 DEGs. Expression of selected genes was validated by the use of quantitative real-time RT-PCR. Bioinformatic analysis identified that the genes identified were enriched in the GO terms "neuroactive ligand-receptor interaction", "GnRH signaling pathway" and "immune response system". Our findings provide a new perspective for understanding the nutrient restriction-induced reproductive impairment at the pituitary transcriptional level, and how this is linked to hormone secretion. Moreover, the transcriptomic changes in anestrus gilts associated with nutrient restriction could be a resource for targeted studies of genes and pathways potentially involved in the regulation of reproductive function and animal health. PMID- 26580563 TI - In silico investigation of new binding pocket for mitogen activated kinase kinase (MEK): Development of new promising inhibitors. AB - It has been previously shown that the inhibition of mitogen activated protein kinase kinase (MEK) contributes to apoptosis and suppression of different cancer cells. Correspondingly, a number of MEK1/2 inhibitors have been designed and evaluated since 2001. However, they did not satisfy essential pharmacokinetic (PK) and pharmacodynamic (PD) properties thus, almost most of them were terminated in pre-clinical or clinical studies. This study aims to design new specific MEK1/2 inhibitors with improved PK/PD profiles to be used as alternative cancer medications. In first part of this study, a comprehensive screening, for the first time, was done on well-known MEK1/2 inhibitors using a number of computational programs such as AutoDock Tools 4.2 (ADT) and AutoDock Vina. Therefore a valuable training dataset as well as a reliable pharmacophore model were provided which were then used to design new inhibitors. According to the results of training dataset, Trametinib was determined as the best inhibitor provided, so far. So, Trametinib was used as the lead structure to design new inhibitors in this study. In second part of this investigation, a set of new allosteric MEK1/2 inhibitors were designed significantly improving the binding energy as well as the ADMET properties, suggesting more specific and stable ligand-receptor complexes. Consequently, the structures 14 and 15 of our inhibitors, as the most potent structures, are great substituents for Trametinib to be used and evaluated in clinical trials as alternative cancer drugs. PMID- 26580561 TI - Suppression of the Arboviruses Dengue and Chikungunya Using a Dual-Acting Group-I Intron Coupled with Conditional Expression of the Bax C-Terminal Domain. AB - In portions of South Asia, vectors and patients co-infected with dengue (DENV) and chikungunya (CHIKV) are on the rise, with the potential for this occurrence in other regions of the world, for example the United States. Therefore, we engineered an antiviral approach that suppresses the replication of both arboviruses in mosquito cells using a single antiviral group I intron. We devised unique configurations of internal, external, and guide sequences that permit homologous recognition and splicing with conserved target sequences in the genomes of both viruses using a single trans-splicing Group I intron, and examined their effectiveness to suppress infections of DENV and CHIKV in mosquito cells when coupled with a proapoptotic 3' exon, DeltaN Bax. RT-PCR demonstrated the utility of these introns in trans-splicing the DeltaN Bax sequence downstream of either the DENV or CHIKV target site in transformed Aedes albopictus C6/36 cells, independent of the order in which the virus specific targeting sequences were inserted into the construct. This trans-splicing reaction forms DENV or CHIKV DeltaN Bax RNA fusions that led to apoptotic cell death as evidenced by annexin V staining, caspase, and DNA fragmentation assays. TCID50-IFA analyses demonstrate effective suppression of DENV and CHIKV infections by our anti arbovirus group I intron approach. This represents the first report of a dual acting Group I intron, and demonstrates that we can target DENV and CHIKV RNAs in a sequence specific manner with a single, uniquely configured CHIKV/DENV dual targeting group I intron, leading to replication suppression of both arboviruses, and thus providing a promising single antiviral for the transgenic suppression of multiple arboviruses. PMID- 26580564 TI - A Psychological Exploration of Engagement in Geek Culture. AB - Geek culture is a subculture of enthusiasts that is traditionally associated with obscure media (Japanese animation, science fiction, video games, etc.). However, geek culture is becoming increasingly mainstream; for example, in the past year alone, Dragon*Con, a major Geek convention in Atlanta, Georgia, attracted an attendance of over 57,000 members. The present article uses an individual differences approach to examine three theoretical accounts of geek culture. Seven studies (N = 2354) develop the Geek Culture Engagement Scale (GCES) to quantify geek engagement and assess its relationships to theoretically relevant personality and individual differences variables. These studies present evidence that individuals may engage in geek culture in order to maintain narcissistic self-views (the great fantasy migration hypothesis), to fulfill belongingness needs (the belongingness hypothesis), and to satisfy needs for creative expression (the need for engagement hypothesis). Geek engagement is found to be associated with elevated grandiose narcissism, extraversion, openness to experience, depression, and subjective well-being across multiple samples. These data lay the groundwork for further exploration of geek culture as well as provide a foundation for examining other forms of subculture participation. PMID- 26580565 TI - Survival Analysis of Faculty Retention and Promotion in the Social Sciences by Gender. AB - BACKGROUND: Recruitment and retention of talent is central to the research performance of universities. Existing research shows that, while men are more likely than women to be promoted at the different stages of the academic career, no such difference is found when it comes to faculty retention rates. Current research on faculty retention, however, focuses on careers in science, technology, engineering, and mathematics (STEM). We extend this line of inquiry to the social sciences. METHODS: We follow 2,218 tenure-track assistant professors hired since 1990 in seven social science disciplines at nineteen U.S. universities from time of hire to time of departure. We also track their time to promotion to associate and full professor. Using survival analysis, we examine gender differences in time to departure and time to promotion. Our methods account for censoring and unobserved heterogeneity, as well as effect heterogeneity across disciplines and cohorts. RESULTS: We find no statistically significant differences between genders in faculty retention. However, we do find that men are more likely to be granted tenure than women. When it comes to promotion to full professor, the results are less conclusive, as the effect of gender is sensitive to model specification. CONCLUSIONS: The results corroborate previous findings about gender patterns in faculty retention and promotion. They suggest that advances have been made when it comes to gender equality in retention and promotion, but important differences still persist. PMID- 26580566 TI - Digital Gene Expression Analysis Based on De Novo Transcriptome Assembly Reveals New Genes Associated with Floral Organ Differentiation of the Orchid Plant Cymbidium ensifolium. AB - Cymbidium ensifolium belongs to the genus Cymbidium of the orchid family. Owing to its spectacular flower morphology, C. ensifolium has considerable ecological and cultural value. However, limited genetic data is available for this non-model plant, and the molecular mechanism underlying floral organ identity is still poorly understood. In this study, we characterize the floral transcriptome of C. ensifolium and present, for the first time, extensive sequence and transcript abundance data of individual floral organs. After sequencing, over 10 Gb clean sequence data were generated and assembled into 111,892 unigenes with an average length of 932.03 base pairs, including 1,227 clusters and 110,665 singletons. Assembled sequences were annotated with gene descriptions, gene ontology, clusters of orthologous group terms, the Kyoto Encyclopedia of Genes and Genomes, and the plant transcription factor database. From these annotations, 131 flowering-associated unigenes, 61 CONSTANS-LIKE (COL) unigenes and 90 floral homeotic genes were identified. In addition, four digital gene expression libraries were constructed for the sepal, petal, labellum and gynostemium, and 1,058 genes corresponding to individual floral organ development were identified. Among them, eight MADS-box genes were further investigated by full-length cDNA sequence analysis and expression validation, which revealed two APETALA1/AGL9 like MADS-box genes preferentially expressed in the sepal and petal, two AGAMOUS like genes particularly restricted to the gynostemium, and four DEF-like genes distinctively expressed in different floral organs. The spatial expression of these genes varied distinctly in different floral mutant corresponding to different floral morphogenesis, which validated the specialized roles of them in floral patterning and further supported the effectiveness of our in silico analysis. This dataset generated in our study provides new insights into the molecular mechanisms underlying floral patterning of Cymbidium and supports a valuable resource for molecular breeding of the orchid plant. PMID- 26580568 TI - 2014: WHO's 25th World No Tobacco Day Global Campaign. AB - BACKGROUND: Since 1988, WHO have celebrated and supported World No Tobacco Day (WNTD), linking each year to a different tobacco-related theme. New technologies and creative design have been used by WHO in order to adapt to the current trends and needs providing the public with visually attractive posters and brochures. METHODS: A review of World Health Organization (WHO) material on WNTD was made, every year themes and posters were collected and analysed to be presented in a comprehensive way. RESULTS: A systematic timeline and an infographic were designed, enclosing the themes of WNTD across the years. The evolution of WNTD themes was commented on with a historical approach. CONCLUSIONS: WNTD has evolved adapting to the current scenarios, and is a good example of a global communication campaign on public health awareness and prevention. PMID- 26580567 TI - High Fat High Cholesterol Diet (Western Diet) Aggravates Atherosclerosis, Hyperglycemia and Renal Failure in Nephrectomized LDL Receptor Knockout Mice: Role of Intestine Derived Lipopolysaccharide. AB - A high fat meal, frequently known as western diet (WD), exacerbates atherosclerosis and diabetes. Both these diseases are frequently associated with renal failure. Recent studies have shown that lipopolysaccharide (LPS) leaks into the circulation from the intestine in the setting of renal failure and after WD. However, it is not clear how renal function and associated disorders are affected by LPS. This study demonstrates that circulatory LPS exacerbates renal insufficiency, atherosclerosis and glucose intolerance. Renal insufficiency was induced by 2/3 nephrectomy in LDL receptor knockout mice. Nx animals were given normal diet (Nx) or WD (Nx+WD). The controls were sham operated animals on normal diet (control) and WD (WD). To verify if LPS plays a role in exaggerating renal insufficiency, polymyxin (PM), a known LPS antagonist, and curcumin (CU), a compound known to ameliorate chronic kidney disease (CKD), was given to Nx animals on western diet (Nx+WD+PM and Nx+WD+CU, respectively). Compared to control, all other groups displayed increased circulatory LPS. The Nx+WD cohort had the highest levels of LPS. Nx group had significant renal insufficiency and glucose intolerance but not atherosclerosis. WD had intense atherosclerosis and glucose intolerance but it did not show signs of renal insufficiency. Compared to other groups, Nx+WD had significantly higher cytokine expression, macrophage infiltration in the kidney, renal insufficiency, glucose intolerance and atherosclerosis. PM treatment blunted the expression of cytokines, deterioration of renal function and associated disorders, albeit not to the levels of Nx, and was significantly inferior to CU. PM is a non-absorbable antibiotic with LPS binding properties, hence its beneficial effect can only be due to its effect within the GI tract. We conclude that LPS may not cause renal insufficiency but can exaggerate kidney failure and associated disorders following renal insufficiency. PMID- 26580569 TI - Bipolar Conductance Switching of Single Anthradithiophene Molecules. AB - Single molecular switches are basic device elements in organic electronics. The pentacene analogue anthradithiophene (ADT) shows a fully reversible binary switching between different adsorption conformations on a metallic surface accompanied by a charge transfer. These transitions are activated locally in single molecules in a low-temperature scanning tunneling microscope . The switching induces changes between bistable orbital structures and energy level alignment at the interface. The most stable geometry, the "off" state, which all molecules adopt upon evaporation, corresponds to a short adsorption distance at which the electronic interactions of the acene rings bend the central part of the molecule toward the surface accompanied by a significant charge transfer from the metallic surface to the ADT molecules. This leads to a shift of the lowest unoccupied molecular orbital down to the Fermi level (EF). In the "on" state the molecule has a flat geometry at a larger distance from the surface; consequently the interaction is weaker, resulting in a negligible charge transfer with an orbital structure resembling the highest occupied molecular orbital when imaged close to EF. The potential barrier between these two states can be overcome reversibly by injecting charge carriers locally into individual molecules. Voltage-controlled current traces show a hysteresis characteristic of a bipolar switching behavior. The interpretation is supported by first-principles calculations. PMID- 26580571 TI - Reactive and Nonreactive Feshbach Resonances Accessed by Photodetachment of FH2O( ). AB - The photodetachment of the FH2O(-) anion is investigated quantum mechanically on accurate full-dimensional potential energy surfaces of the two lowest-lying electronic states of FH2O. The calculated photoelectron spectrum possesses both broad and sharp features, corresponding to reactive and nonreactive Feshbach resonances. The former extend to both reactant and product channels over the transition state, while the latter are supported by a hydrogen bonded HO-HF well in the product channel. Many of the resonances are assignable with quantum numbers for the stretching and bending modes of the HO-HF complex as well as the H-F vibration. The implications of these resonances in the F + H2O <-> HF + HO reaction are discussed. PMID- 26580570 TI - Cortical inhibitory and excitatory correlates of depression severity in children and adolescents. AB - OBJECTIVES: Neurophysiologic correlates of depression severity potentially have great utility in diagnosis and treatment planning. Transcranial magnetic stimulation (TMS) measures of cortical inhibition and excitability have shown promise as biomarkers in psychiatry, but no prior work has examined correlates of illness severity in pediatric mood disorders. This study sought to examine the relationship between depression severity and TMS measures of cortical inhibition and excitability in children and adolescents. METHODS: Twenty-four depressed and 22 healthy control youth underwent TMS testing (cortical silent period [CSP], short-interval intracortical inhibition at 2-ms and 4-ms interstimulus intervals (ISIs) [SICI-2,-4], resting motor threshold [RMT] and intracortical facilitation at 10-, 15-, and 20-ms ISIs [ICF-10,-15,-20]). Symptom severity was assessed with the Quick Inventory of Depressive Symptomatology (QIDS-A17-SR) and the Children's Depression Rating Scale-Revised (CDRS-R). RESULTS: In the overall sample, the following significant negative correlations were observed: CDRS-R and CSP (right hemisphere, rho=-0.35, p=0.021); QIDS-A17-SR and CSP (left, rho=-0.33, p=0.031; right, rho=-0.42, p=0.004); and CDRS-R and SICI-4 (right, rho=-0.30, p=0.042). Among healthy control participants, additional significant negative correlations were observed between QIDS-A17-SR and right ICF-10; QIDS-A17-SR and right ICF-15; and QIDS-A17-SR and left ICF-20. Among depressed participants, significant negative correlations were observed between QIDS-A17-SR and bilateral CSP; CDRS-R and bilateral ICF-10; CDRS-R and bilateral ICF-15; QIDS-A17-SR and left ICF-10; and QIDS-A17-SR and bilateral ICF-15. LIMITATIONS: Small sample, potential developmental/age- and sex-related effects. CONCLUSIONS: These preliminary results provide evidence for a relationship between depression severity and dysfunction in GABAergic and glutamatergic cortical processes in a pediatric population. PMID- 26580572 TI - Change of Retinal Nerve Layer Thickness in Non-Arteritic Anterior Ischemic Optic Neuropathy Revealed by Fourier Domain Optical Coherence Tomography. AB - PURPOSE: To examine the changes of non-arteritic anterior ischemic optic neuropathy (NAION) by serial morphometry using Fourier domain optical coherence tomography (FD-OCT). MATERIALS AND METHODS: Retrospective study in patients with newly diagnosed NAION (n=33, all unilateral) and controls (n=75 unilateral NAION patients with full contralateral eye vision) who underwent FD-OCT of the optic disk, optic nerve head (ONH), and macula within 1 week of onset and again 1, 3, 6, and 12 months later. The patients showed no improvement in vision during follow-up. RESULTS: Within 1 week of onset, all NAION eyes exhibited severe ONH fiber crowding and peripapillary retinal nerve fiber layer (RNFL) edema. Four had subretinal fluid accumulation and 12 had posterior vitreous detachment (PVD) at the optic disc surface. Ganglion cell complex (GCC) and RNFL thicknesses were reduced at 1 and 3 months (p < 0.05), with no deterioration thereafter. Initial RNFL/GCC contraction magnitude in the superior hemisphere correlated with the severity of inferior visual field deficits. CONCLUSIONS: NAION progression is characterized by an initial phase of accelerated RNFL and GCC deterioration. These results reveal that the kinetic change of neural retina in NAION and may have implication on the time window for treatment of NAION. FD-OCT is useful in the evaluation of NAION. PMID- 26580573 TI - Nitrogen-Doped Reduced Graphene Oxide Prepared by Simultaneous Thermal Reduction and Nitrogen Doping of Graphene Oxide in Air and Its Application as an Electrocatalyst. AB - Graphene is considered to be one of the most interesting materials because of its unique two-dimensional structure and properties. However, commercialization and large-scale production of graphene still face great challenges at the moment. Thermal reduction of graphene oxide (GO) can be an effective method to fabricate graphene in large scale, but the need for inert gas protection and high reaction temperature leads to high cost of production, thus limiting the production capacity of graphene. In this paper, for the first time we report a facile, safe, and scalable method to achieve simultaneous thermal reduction and nitrogen doping of GO in air at much lower reaction temperature while upholding a high-quality end product. The reduction and nitrogen doping of GO are evidenced by ultraviolet visible absorption spectroscopy, X-ray diffraction, Raman spectroscopy, Fourier transform infrared spectroscopy, and X-ray photoelectron spectroscopy. The nitrogen-doped reduced GO (NrGO) fabricated via this method has a high carbon/oxygen ratio of 15 and a nitrogen content of 11.87 atom %. The NrGO is also investigated by applying it as an electrocatalyst for the oxygen reduction reaction. As a result, the catalytic activity has presented itself as much higher than that of the undoped rGO. PMID- 26580574 TI - Ingestion of Nanoplastics and Microplastics by Pacific Oyster Larvae. AB - Plastic debris is a prolific contaminant effecting freshwater and marine ecosystems across the globe. Of growing environmental concern are "microplastics"and "nanoplastics" encompassing tiny particles of plastic derived from manufacturing and macroplastic fragmentation. Pelagic zooplankton are susceptible to consuming microplastics, however the threat posed to larvae of commercially important bivalves is currently unknown. We exposed Pacific oyster (Crassostrea gigas) larvae (3-24 d.p.f.) to polystyrene particles spanning 70 nm 20 MUm in size, including plastics with differing surface properties, and tested the impact of microplastics on larval feeding and growth. The frequency and magnitude of plastic ingestion over 24 h varied by larval age and size of polystyrene particle (ANOVA, P < 0.01), and surface properties of the plastic, with aminated particles ingested and retained more frequently (ANOVA, P < 0.01). A strong, significant correlation between propensity for plastic consumption and plastic load per organism was identified (Spearmans, r = 0.95, P < 0.01). Exposure to 1 and 10 MUm PS for up to 8 days had no significant effect on C. gigas feeding or growth at <100 microplastics mL(-1). In conclusion, whil micro- and nanoplastics were readily ingested by oyster larvae, exposure to plastic concentrations exceeding those observed in the marine environment resulted in no measurable effects on the development or feeding capacity of the larvae over the duration of the study. PMID- 26580575 TI - 25(th) Anniversary State-of-the-Art Expert Discussion With David W. Rattner, MD, on NOTES. PMID- 26580576 TI - Multifunctional Bioconjugate for Cancer Cell-Targeted Theranostics. AB - Cancer cell-targeted imaging and drug delivery remain a challenge for precise cancer theranostics. MUC1 is a large transmembrane glycoprotein that may potentially serve as a target for cancer theranostics. Herein, using a MUC1 targeting aptamer (APT) as the "warhead", we rationally designed and constructed a hybrid nanoparticle 1-NPs-QDs-hAPT (Vehicle) that could be applied for MUC1 targeted cell uptake and imaging. By intercalating different Vehicle amounts with the anticancer drug doxorubicin (DOX), we obtained the multifunctional bioconjugate Vehicle-DOX with a maximized drug payload and DOX fluorescence quenching capability. Confocal microscopy cell imaging indicated that Vehicle-DOX could be used to track MUC1-targeted drug release. A cytotoxicity study indicated that Vehicle-DOX could be applied for MUC1-targeted cytotoxicity. We anticipate that our multifunctional bioconjugate Vehicle-DOX could be applied for in vivo tumor-targeted theranostics. PMID- 26580577 TI - Hierarchical Layered Heterogeneous Graphene-poly(N-isopropylacrylamide)-clay Hydrogels with Superior Modulus, Strength, and Toughness. AB - Biological composites are renowned for their elaborate heterogeneous architectures at multiple scales, which lead to a unique combination of modulus, strength, and toughness. Inspired by biological composites, mimicking the heterogeneous structural design principles of biological composites is a powerful strategy to construct high-performance structural composites. Here, we creatively transfer some heterogeneous principles of biological composites to the structural design of nanocomposite hydrogels. Unique heterogeneous conductive graphene PNIPAM-clay hydrogels are prepared through a combination of inhomogeneous water removal processes, in situ free-radical polymerization, and chemical reduction of graphene oxide. The nanocomposite hydrogels exhibit hierarchical layered heterogeneous architectures with alternate stacking of dense laminated layers and loose porous layers. Under tensile load, the stiff dense laminated layers serve as sacrificial layers that fracture at a relatively low strain, while the stretchable loose porous layers serve as energy dissipation layers by large extension afterward. Such local inhomogeneous deformation of the two heterogeneous layers enables the nanocomposite hydrogels to integrate superior modulus, strength, and toughness (9.69 MPa, 0.97 MPa, and 5.60 MJ/m(3), respectively). The study might provide meaningful enlightenments for rational structural design of future high-performance nanocomposite hydrogels. PMID- 26580578 TI - Synthesis of the 16S,17S-Epoxyprotectin Intermediate in the Biosynthesis of Protectins by Human Macrophages. AB - The n-3 polyunsaturated fatty acids act as substrates during the resolution phase of acute inflammation for the biosynthesis of specialized pro-resolving lipid mediators. One premier example is the C22-dihydroxy-polyunsaturated fatty acid protectin D1 (1). The human 15-lipoxygenase type I, via stereoselective processes and with docosahexaenoic acid as the substrate, enables the formation of this specialized pro-resolving lipid mediator. Herein, based on results from LC/MS-MS metabololipidomics, support is presented for the apprehended biosynthesis of 1 in human macrophages occurring via the intermediate 16S,17S-epoxyprotectin (5). Stereochemically pure 5 was obtained using the Katsuki-Sharpless epoxidation protocol, establishing the chirality at the C16 and C17 atoms, one Z-selective reduction, and E- and Z-stereoselective Wittig reactions. In addition, information on the nonenzymatic aqueous hydrolysis products and the half-life of 16S,17S-epoxyprotectin (5) is presented. PMID- 26580579 TI - Changes in Pupil Size Following Panretinal and Focal/Grid Retinal Photocoagulation: Automatic Infrared Pupillometry Study. AB - PURPOSE: To evaluate possible changes in pupil size subsequent to panretinal and focal/grid laser photocoagulation. METHODS: Sixty-four eyes of 64 participants were included. Thirty-two eyes with planned panretinal photocoagulation formed Group 1, and 32 eyes with planned focal retinal photocoagulation formed Group 2. The participants underwent full ophthalmologic examination at baseline. Automated infrared pupillometry was performed at baseline and month 1. RESULTS: The mean pupillary measurements (in millimeters) for Group 1 (in order photopic, mesopic, scotopic) were 3.09 +/- 0.69 mm, 3.66 +/- 0.85 mm, and 3.87 +/- 1.01 mm and changed to 3.34 +/- 0.74 mm, 3.82 +/- 0.92 mm, and 4.03 +/- 1.02 mm. There was a significant increase in pupil size at month 1 (P = 0.001, P = 0.001, P = 0.003). For Group 2, they were 2.65 +/- 0.87 mm, 3.08 +/- 1.08 mm, and 3.18 +/- 1.19 mm and changed to 2.92 +/- 0.72 mm, 3.45 +/- 0.76 mm, and 3.57 +/- 0.88 mm. There was no significant difference in pupil size at month 1 (P = 0.151, P = 0.106, P = 0.095). CONCLUSION: We have demonstrated through automated infrared pupillary measurements that panretinal laser photocoagulation may significantly influence pupil size and focal/grid laser photocoagulation may not. PMID- 26580580 TI - Effect of Circadian Rhythm Disruption and Alcohol on the Oxidative Stress Level in Rat Brain. AB - Alcohol abuse is often associated with disrupted circadian rhythms and sleep, and the link seems to be bidirectional. In addition, it has been shown that exposure to constant illumination may increase lipid peroxidation in tissues. In this study, we investigated the effects of circadian rhythm disruption (CRD) and chronic alcohol intake (A) alone and in combination (CRD+A), on the oxidative stress in total rat brain homogenate. Our results demonstrated that lipid peroxidation was increased in the brain samples of all experimental animals compared with the control ones. The oxidative stress levels increased in the order: C 1H STDre(19)F-NMR technique, we here demonstrate its applicability to measure anomeric selectivity of binding in a model system using the plant lectin concanavalin A (ConA) and 2-deoxy-2-fluoro-d-mannose. Indeed, it is also possible to account for the mutual inhibition between the anomers on binding to the lectin by means of a kinetic model. The monitoring of (19)F-NMR signal perturbation disclosed the relative activities of the anomers in solution and thus enabled the calculation of their binding affinity towards ConA. The obtained data show a preference for the alpha anomer that increases with temperature. This experimental approach can be extended to others systems of biomedical interest by testing human lectins with suitably tailored glycan derivatives. PMID- 26580667 TI - High-Intensity Signal in Carotid Plaque on Routine 3D-TOF-MRA Is a Risk Factor of Ischemic Stroke. AB - BACKGROUND: Carotid atherosclerotic disease is recognized as an important risk factor for brain ischemic events. However, high-grade stenosis does not always cause ischemic strokes, whereas moderate-grade stenosis may often cause ischemic strokes. It has been reported that there is an association between carotid intraplaque hemorrhage (IPH) and new cerebral ischemic events. The purpose of this study was to elucidate the relationship between high-intensity signals (HIS) on maximum intensity projection (MIP) images from routine 3-dimensional time-of flight magnetic resonance angiography (3D-TOF-MRA) and prior ischemic strokes in the patients with moderate carotid stenosis. MATERIALS AND METHODS: Sixty-one patients with moderate carotid artery stenosis (50-69% stenosis based on North American Symptomatic Carotid Endarterectomy Trial criteria) were included. Carotid IPH was defined as the presence of HIS in carotid plaques on MIP images detected by 3D-TOF-MRA using criteria we previously reported. We analyzed the relationship between the presence of HIS in plaques and prior ischemic strokes defined as ischemic lesions on diffusion-weighted brain images. RESULTS: HIS in carotid plaques were present in 27 (44%) of 61 patients. Prior ipsilateral ischemic strokes occurred more frequently in the HIS-positive group than the HIS negative group (67 vs. 9%, p < 0.001). Furthermore, there were more smokers in the group with ischemic stroke than without it (62 vs. 25%, p = 0.005). In multivariate logistic regression analysis, HIS in carotid plaque (OR 23.4, 95% CI 4.62-118.3, p < 0.001) and smoking (OR 5.44, 95% CI 1.20-24.6, p = 0.028) were independent determinants of prior ischemic strokes after adjustment for age. CONCLUSIONS: HIS in carotid plaques on 3D-TOF-MRA MIP images are independent determinants of prior ischemic strokes in patients with moderate carotid artery stenosis, and they can potentially provide a reliable risk stratification of patients with moderate carotid artery stenosis. PMID- 26580668 TI - Short-Term Effect of Coarse Particles on Daily Mortality Rate in A Tropical City, Kaohsiung, Taiwan. AB - Many studies examined the short-term effects of air pollution on frequency of daily mortality over the past two decades. However, information on the relationship between exposure to levels of coarse particles (PM(2.5-10)) and daily mortality rate is relatively sparse due to limited availability of monitoring data and findings are inconsistent. This study was undertaken to determine whether an association exists between PM(2.5-10) levels and rate of daily mortality in Kaohsiung, Taiwan, a large industrial city with a tropical climate. Daily mortality rate, air pollution parameters, and weather data for Kaohsiung were obtained for the period 2006-2008. The relative risk (RR) of daily mortality occurrence was estimated using a time-stratified case-crossover approach, controlling for (1) weather variables, (2) day of the week, (3) seasonality, and (4) long-term time trends. For the single-pollutant model without adjustment for other pollutants, PM(2.5-10) exposure levels showed significant correlation with total mortality rate both on warm and cool days, with an interquartile range increase associated with a 14% (95% CI = 5-23%) and 12% (95% CI = 5-20%) rise in number of total deaths, respectively. In two pollutant models, PM(2.5-10) exerted significant influence on total mortality frequency after inclusion of sulfur dioxide (SO(2)) on warm days. On cool days, PM(2.5-10) induced significant elevation in total mortality rate when SO(2) or ozone (O(3)) was added in the regression model. There was no apparent indication of an association between PM(2.5-10) exposure and deaths attributed to respiratory and circulatory diseases. This study provided evidence of correlation between short-term exposure to PM(2.5-10) and increased risk of death for all causes. PMID- 26580669 TI - Very fast bulk Li ion diffusivity in crystalline Li(1.5)Al(0.5)Ti(1.5)(PO4)3 as seen using NMR relaxometry. AB - The realization of large powerful all-solid-state batteries is still hampered by the availability of environmentally friendly and low-cost Li ion conductors that can easily be produced on a large scale and with high reproducibility. Advanced solid electrolytes benefit from fast ion-selective transport and non flammability, but they may have low electrochemical stability with respect to Li metal. Sol-gel-synthesized lithium titanium aluminum phosphate Li(1.5)Al(0.5)Ti(1.5)(PO4)3 (LATP), which was prepared via a new synthesis route taking advantage of an annealing step at relatively low temperatures, has the potential to become one of the major players in this field although it may suffer from reduction upon direct contact with metallic lithium. Its ion dynamics is, however, as yet poorly understood. In the present study, (7)Li nuclear magnetic resonance (NMR) spectroscopy was used to monitor the key Li jump processes on the atomic scale. NMR relaxation clearly reveals heterogeneous dynamics comprising distinct ultra-fast and slower diffusion processes. The high Li ion self diffusion coefficients deduced originate from a rapid Li exchange with activation energies as low as 0.16 eV which means that sol-gel synthesized LATP is superior to other solid electrolytes. Our NMR results fully support recent theoretical investigations on the underlying diffusion mechanism, indicating that to rapidly jump from site to site, the ions use interstitial sites connected by low-energy barriers in LATP. PMID- 26580670 TI - Effects of the selected cytochrome P450 oxidoreductase genetic polymorphisms on cytochrome P450 2B6 activity as measured by bupropion hydroxylation. AB - BACKGROUND/AIM: Cytochrome P450 oxidoreductase (POR) is required for drug metabolism by all microsomal cytochrome P450 (CYP) enzymes. The aim of this study was to investigate whether single-nucleotide polymorphisms in the POR gene were correlated with interindividual variations in CYP2B6 activity, as measured by bupropion hydroxylation. METHODS: Thirty-five healthy individuals with selected CYP2B6 and POR polymorphisms were involved in the clinical study. The activity of CYP2B6 was evaluated on the basis of the area under the time-concentration curve (AUC) ratio of hydroxybupropion versus bupropion (AUC_hyd/AUC_bup). RESULTS: Individuals carrying CYP2B6*1/*1 showed a significantly higher mean AUC_hyd/AUC_bup than individuals carrying the CYP2B6*1/*6 and CYP2B6*6/*6 variants (17.1 +/- 6.23 vs. 10.3 +/- 4.53, P = 0.003 and 17.1 +/- 6.23 vs. 9.41 +/- 2.84, P = 0.002, respectively). POR g.6593A>G (rs2868177) AA homozygotes showed a significantly lower mean AUC_hyd/AUC_bup than POR g.6593A>G AG heterozygotes or GG homozygotes (8.54 +/- 2.65 vs. 14.9 +/- 6.06, P = 0.005 and 8.54 +/- 2.65 vs. 16.8 +/- 6.45, P = 0.002, respectively). Moreover, POR g.6593A>G AA homozygotes had a significantly lower mean AUC_hyd/AUC_bup than the POR g.6593A>G AG/GG genotypes in the CYP2B6*1/*1, CYP2B6*1/*6 and CYP2B6*6/*6 groups (10.9 +/- 1.82 vs. 19.7 +/- 5.53, P < 0.001; 6.18 +/- 0.284 vs. 12.1 +/- 4.31, P = 0.011; and 6.94 +/- 1.48 vs. 10.9 +/- 2.39, P = 0.043, respectively). There was no significant difference in the mean AUC_hyd/AUC_bup among different POR c.1508C>T (*28 or rs1057868) genotypes, even after the effect of CYP2B6*6 was excluded. CONCLUSION: These results indicate, for the first time, that the POR g.6593A>G polymorphism significantly influences CYP2B6 activity, as measured by bupropion hydroxylation, in humans, and the CYP2B6*6 and POR g.6593A>G polymorphisms might be considered simultaneously for the individualized therapy with CYP2B6 substrate drugs such as bupropion. PMID- 26580672 TI - Regulatory T-cells and preeclampsia: an overview of literature. AB - Regulatory T-cells (Tregs) are key players in successful pregnancy and their deficiencies are implicated in pregnancy complications such as preeclampsia (PE), but the results are inconsistent among studies. This study aims to compile an overview of the studies about the associations of Tregs and PE risk and to provide recommendations for future research. A sensitive search of three databases including PubMed, Scopus and Google scholar (from 1995 to January 9, 2015) identified 636 unique titles. An accurate process of study selection, data extraction and method qualification were independently conducted by authors on retrieved papers. Seventeen papers met the inclusion criteria and were included in quality assessment. Regarding the source of Tregs, 14 studies assessed Tregs in peripheral blood, 2 studies in peripheral blood and decidua and one study in peripheral blood and umbilical cord blood. Despite variation in the combinations of markers and other aspects of the studies designs, remarkable constancy in the results of studies that measured Tregs as CD4+FoxP3+ or CD4+CD25+FoxP3+ cells (but not CD4+CD25(high/low)FoxP3+ markers) was found, which in broad terms showed a shift towards fewer Treg cells in PE. This review revealed an association between lower percentage of circulating CD4+FoxP3+ or CD4+CD25+FoxP3+ Tregs and the risk of PE. Given the above issue and regarding the high consistency of studies on reduction of suppressive activity of Tregs in PE, we have proposed a model in which the Tregs deficiency is a reflection of immune endocrine imbalance, which reverses maternal tolerance and results in development of preeclampsia. PMID- 26580671 TI - Myostatin Attenuation In Vivo Reduces Adiposity, but Activates Adipogenesis. AB - A potentially novel approach for treating obesity includes attenuating myostatin as this increases muscle mass and decreases fat mass. Notwithstanding, conflicting studies report that myostatin stimulates or inhibits adipogenesis and it is unknown whether reduced adiposity with myostatin attenuation results from changes in fat deposition or adipogenesis. We therefore quantified changes in the stem, transit amplifying and progenitor cell pool in white adipose tissue (WAT) and brown adipose tissue (BAT) using label-retaining wild-type and mstn(-/-) (Jekyll) mice. Muscle mass was larger in Jekyll mice, WAT and BAT mass was smaller and label induction was equal in all tissues from both wild-type and Jekyll mice. The number of label-retaining cells, however, dissipated quicker in WAT and BAT of Jekyll mice and was only 25% and 17%, respectively, of wild-type cell counts 1 month after induction. Adipose cell density was significantly higher in Jekyll mice and increased over time concomitant with label-retaining cell disappearance, which is consistent with enhanced expansion and differentiation of the stem, transit amplifying and progenitor pool. Stromal vascular cells from Jekyll WAT and BAT differentiated into mature adipocytes at a faster rate than wild-type cells and although Jekyll WAT cells also proliferated quicker in vitro, those from BAT did not. Differentiation marker expression in vitro, however, suggests that mstn(-/-) BAT preadipocytes are far more sensitive to the suppressive effects of myostatin. These results suggest that myostatin attenuation stimulates adipogenesis in vivo and that the reduced adiposity in mstn(-/-) animals results from nutrient partitioning away from fat and in support of muscle. PMID- 26580674 TI - Surface effects in metal oxide-based nanodevices. AB - As devices shrink to the nanoscale, surface-to-volume ratio increases and the surface-environment interaction becomes a major factor for affecting device performance. The variation of electronic properties, including the surface band bending, gas chemisorption or photodesorption, native surface defects, and surface roughness, is called "surface effects". Such effects are ambiguous because they can be either negative or beneficial effects, depending on the environmental conditions and device application. This review provides an introduction to the surface effects on different types of nanodevices, offering the solutions to respond to their benefits and negative effects and provides an outlook on further applications regarding the surface effect. This review is beneficial for designing nano-enabled photodetectors, harsh electronics, memories, sensors and transistors via surface engineering. PMID- 26580673 TI - Smart CareTM versus respiratory physiotherapy-driven manual weaning for critically ill adult patients: a randomized controlled trial. AB - INTRODUCTION: A recent meta-analysis showed that weaning with SmartCareTM (Drager, Lubeck, Germany) significantly decreased weaning time in critically ill patients. However, its utility compared with respiratory physiotherapist protocolized weaning is still a matter of debate. We hypothesized that weaning with SmartCareTM would be as effective as respiratory physiotherapy-driven weaning in critically ill patients. METHODS: Adult critically ill patients mechanically ventilated for more than 24 hours in the adult intensive care unit of the Albert Einstein Hospital, Sao Paulo, Brazil, were randomly assigned to be weaned either by progressive discontinuation of pressure support ventilation (PSV) with SmartCareTM. Demographic data, respiratory function parameters, level of PSV, tidal volume (VT), positive end-expiratory pressure (PEEP), inspired oxygen fraction (FIO2), peripheral oxygen saturation (SpO2), end-tidal carbon dioxide concentration (EtCO2) and airway occlusion pressure at 0.1 second (P0.1) were recorded at the beginning of the weaning process and before extubation. Mechanical ventilation time, weaning duration and rate of extubation failure were compared. RESULTS: Seventy patients were enrolled 35 in each group. There was no difference between the two groups concerning age, sex or diagnosis at study entry. There was no difference in maximal inspiratory pressure, maximal expiratory pressure, forced vital capacity or rapid shallow breathing index at the beginning of the weaning trial. PEEP, VT, FIO2, SpO2, respiratory rate, EtCO2 and P0.1 were similar between the two groups, but PSV was not (median: 8 vs. 10 cmH2O; p =0.007). When the patients were ready for extubation, PSV (8 vs. 5 cmH2O; p =0.015) and PEEP (8 vs. 5 cmH2O; p <0.001) were significantly higher in the respiratory physiotherapy-driven weaning group. Total duration of mechanical ventilation (3.5 [2.0-7.3] days vs. 4.1 [2.7-7.1] days; p =0.467) and extubation failure (2 vs. 2; p =1.00) were similar between the two groups. Weaning duration was shorter in the respiratory physiotherapy-driven weaning group (60 [50-80] minutes vs. 110 [80-130] minutes; p <0.001). CONCLUSION: A respiratory physiotherapy-driven weaning protocol can decrease weaning time compared with an automatic system, as it takes into account individual weaning difficulties. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT02122016 . Date of Registration: 27 August 2013. PMID- 26580675 TI - Antitumor activity and systemic effects of PVM/MA-shelled selol nanocapsules in lung adenocarcinoma-bearing mice. AB - Selol is a semi-synthetic compound containing selenite that is effective against cancerous cells and safer for clinical applications in comparison with other inorganic forms of selenite. Recently, we have developed a formulation of poly(methyl vinyl ether-co-maleic anhydride)-shelled selol nanocapsules (SPN), which reduced the proliferative activity of lung adenocarcinoma cells and presented little deleterious effects on normal cells in in vitro studies. In this study, we report on the antitumor activity and systemic effects induced by this formulation in chemically induced lung adenocarcinoma-bearing mice. The in vivo antitumor activity of the SPN was verified by macroscopic quantification, immunohistochemistry and morphological analyses. Toxicity analyses were performed by evaluations of the kidney, liver, and spleen; analyses of hemogram and plasma levels of alanine aminotransferase, aspartate transaminase, urea, and creatinine; and DNA fragmentation and cell cycle activity of the bone marrow cells. Furthermore, we investigated the potential of the SPN formulation to cause hemolysis, activate the complement system, provoke an inflammatory response and change the conformation of the plasma proteins. Our results showed that the SPN reduced the area of the surface tumor nodules but not the total number of tumor nodules. The biochemical and hematological findings were suggestive of the low systemic toxicity of the SPN formulation. The surface properties of the selol nanocapsules point to characteristics that are consistent with the treatment of the tumors in vivo: low hemolytic activity, weak inflammatory reaction with no activation of the complement system, and mild or absent conformational changes of the plasma proteins. In conclusion, this report suggests that the SPN formulation investigated herein exhibits anti-tumoral effects against lung adenocarcinoma in vivo and is associated with low systemic toxicity and high biocompatibility. PMID- 26580676 TI - Rapid metabolizer genotype of CYP2C19 is a risk factor of being refractory to proton pump inhibitor therapy for reflux esophagitis. AB - BACKGROUND: Proton pump inhibitors (PPIs) are mainly metabolized by cytochrome P450 2C19 (CYP2C19) and used as the first-line therapy for gastroesophageal reflux disease (GERD). However, while several studies have examined the influence of CYP2C19 polymorphism on GERD treatment with PPIs, most have had small sample sizes and were conducted in a single center. Here, we used meta-analysis to investigate whether or not the CYP2C19 rapid metabolizer (RM) genotype is a risk factor for GERD patients being refractory to PPI therapy. METHODS: PubMed and other electronic databases were systematically searched up to August 2014 using the following terms: "GERD and CYP2C19", "esophagitis and CYP2C19", and "non erosive reflux disease and CYP2C19." Searches were limited to publications in English, and two investigators evaluated eligible studies and extracted data. RESULTS: The total efficacy rate of PPIs for GERD, including reflux esophagitis (RE) and non-erosive reflux disease, was 56.4% (95% confidence interval [CI]; 53.9-58.9%, 870/1543) in intention-to-treat analysis and 63.8% (95%CI; 61.3 66.2%, 950/1489) in per-protocol analysis. Efficacy rates varied significantly between CYP2C19 genotypes (intention-to-treat analysis: RMs, 52.2% [315/604]; intermediate metabolizers, 56.7% [298/526]; poor metabolizers [PMs], 61.3% [138/225]; P = 0.047). Among RE patients, CYP2C19 RMs had an increased risk of being refractory to PPI therapy compared with PMs (odds ratio: 1.661, 95% CI: 1.023-2.659, P = 0.040). CONCLUSIONS: The present meta-analysis demonstrates that CYP2C19 RMs with RE have an increased risk of being refractory to PPI therapy compared with PMs. Individualized dosing regimen with PPIs based on CYP2C19 genotype might be a valid therapeutic strategy for overcoming insufficient gastric acid inhibition. PMID- 26580677 TI - Heavy Water as a Probe of the Free Radical Nature and Electrical Conductivity of Melanin. AB - Melanins are pigmentary macromolecules found in many locations throughout nature including plants and vertebrate animals. It was recently proposed that the predominant brown-black pigment eumelanin is a mixed ionic-electronic conductor which has led to renewed interest in its basic properties as a model bioelectronic material. This exotic hybrid electrical behavior is strongly dependent upon hydration and is closely related to the free radical content of melanin which is believed to be a mixed population of two species: the semiquinone (SQ) and a carbon-centered radical (CCR). The predominant charge carrier is the proton that is released during the formation of the SQ radical and controlled by a comproportionation equilibrium reaction. In this paper we present a combined solid-state electron paramagnetic resonance (EPR), adsorption, and hydrated conductivity study using D2O as a probe. We make specific predictions as to how the heavy isotope effect, in contrast to H2O, should perturb the comproportionation equilibrium and the related outcome as far as the electrical conductivity is concerned. Our EPR results confirm the proposed two-spin mechanism and clearly demonstrate the power of combining macroscopic measurements with observations from mesoscopic probes for the study of bioelectronic materials. PMID- 26580678 TI - Diversity of composition and function of sodium channels in peripheral sensory neurons. PMID- 26580679 TI - Quality assurance for Quantitative Sensory Testing laboratories: development and validation of an automated evaluation tool for the analysis of declared healthy samples. AB - Quantitative Sensory Testing (QST) is a psychophysical method assessing the somatosensory nervous system. A premise for comparable results between laboratories is standardized testing. Its quality can be proven by analyzing healthy subjects, because their results should lie within confidence intervals estimated from large database samples. However, it is unclear how many abnormal values can be tolerated. Based on a binomial distribution, a tool for assessing samples of healthy subjects was developed to detect inclusion errors (inclusion of nonhealthy subjects) or measuring errors (inaccuracies in single QST parameters). Sensitivity and specificity of detecting inclusion errors were assessed in 431 healthy subjects and 833 patients with neuropathic pain syndromes from the German Research Network on Neuropathic Pain (DFNS) database. Measuring errors were simulated by raising all absolute values in a single parameter by 0.5 SD. We calculated optimal cutoff values for group sizes of 16 healthy subjects, as implemented in the DFNS certification procedures. The algorithm was applied in the certification process of 18 European QST laboratories. With a specificity of 95% and a sensitivity of 60%, inclusion errors can be assumed for >=4 abnormal values per subject, whereas >=6 abnormal values per QST parameter and laboratory indicate measuring errors. Subsequently, in the certification process of 5 of 18 centers, inclusion or measuring errors were detected. In most cases, inclusion errors were verified and reasons for measuring errors were illuminated by the centers. This underlines the usefulness and validity of our tool in quality assurance of QST laboratories using the DFNS protocol. PMID- 26580680 TI - Construct validity and reliability of a real-time multidimensional smartphone app to assess pain in children and adolescents with cancer. AB - We evaluated the construct validity (including responsiveness), reliability, and feasibility of the Pain Squad multidimensional smartphone-based pain assessment application (app) in children and adolescents with cancer, using 2 descriptive studies with repeated measures. Participants (8-18 years) undergoing cancer treatment were drawn from 4 pediatric cancer centers. In study 1, 92 participants self-reported their level of pain twice daily for 2 weeks using the Pain Squad app to assess app construct validity and reliability. In study 2, 14 participants recorded their level of pain twice a day for 1 week before and 2 weeks after cancer-related surgery to determine app responsiveness. Participants in both studies completed multiple measures to determine the construct validity and feasibility of the Pain Squad app. Correlations between average weekly pain ratings on the Pain Squad app and recalled least, average, and worst weekly pain were moderate to high (0.43-0.68). Correlations with health-related quality of life and pain coping (measured with PedsQL Inventory 4.0, PedsQL Cancer Module, and Pain Coping Questionnaire) were -0.46 to 0.29. The app showed excellent internal consistency (alpha = 0.96). Pain ratings changed because of surgery with large effect sizes between baseline and the first week postsurgery (>0.85) and small effect sizes between baseline and the second week postsurgery (0.13-0.32). These findings provide evidence of the construct validity, reliability, and feasibility of the Pain Squad app in children and adolescents with cancer. Use of real-time data capture approaches should be considered in future studies of childhood cancer pain. A video accompanying this abstract is available online as Supplemental Digital Content at http://links.lww.com/PAIN/A169. PMID- 26580681 TI - Importance of quantifying indirect effects from mediation analyses. PMID- 26580682 TI - Further verification by bootstrapped mediation analyses that pain catastrophizing modulates pain report but not spinal nociception: a reply to Lee, Hubscher, and McAuley. PMID- 26580683 TI - Erratum. PMID- 26580684 TI - A method to determine the detector locations of the cone-beam projection of the balls' centers. AB - In geometric calibration of cone-beam computed tomography (CBCT), sphere-like objects such as balls are widely imaged, the positioning information of which is obtained to determine the unknown geometric parameters. In this process, the accuracy of the detector location of CB projection of the center of the ball, which we call the center projection, is very important, since geometric calibration is sensitive to errors in the positioning information. Currently in almost all the geometric calibration using balls, the center projection is invariably estimated by the center of the support of the projection or the centroid of the intensity values inside the support approximately. Clackdoyle's work indicates that the center projection is not always at the center of the support or the centroid of the intensity values inside, and has given a quantitative analysis of the maximum errors in evaluating the center projection by the centroid. In this paper, an exact method is proposed to calculate the center projection, utilizing both the detector location of the ellipse center and the two axis lengths of the ellipse. Numerical simulation results have demonstrated the precision and the robustness of the proposed method. Finally there are some comments on this work with non-uniform density balls, as well as the effect by the error occurred in the evaluation for the location of the orthogonal projection of the cone vertex onto the detector. PMID- 26580685 TI - Novel homozygous mutations in the EVC and EVC2 genes in two consanguineous families segregating autosomal recessive Ellis-van Creveld syndrome. AB - Ellis-van Creveld syndrome (EVC) is a rare developmental disorder characterized by short limbs, short ribs, postaxial polydactyly, dysplastic nails, teeth, oral and cardiac abnormalities. It is caused by biallelic mutations in the EVC or EVC2 gene, separated by 2.6 kb of genomic sequence on chromosome 4p16. In the present study, we have investigated two consanguineous families of Pakistani origin, segregating EVC in autosomal recessive manner. Linkage in the families was established to chromosome 4p16. Subsequently, sequence analysis identified a novel nonsense mutation (p.Trp234*) in exon 8 of the EVC2 gene and 15 bp duplication in exon 14 of the EVC gene in the two families. This further expands the mutations in the EVC or EVC2 genes resulting in the EVC syndrome. PMID- 26580686 TI - Maternal dietary imbalance between omega-6 and omega-3 polyunsaturated fatty acids impairs neocortical development via epoxy metabolites. AB - Omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids (PUFAs) are essential nutrients. Although several studies have suggested that a balanced dietary n-6:n 3 ratio is essential for brain development, the underlying cellular and molecular mechanism is poorly understood. Here, we found that feeding pregnant mice an n-6 excess/n-3 deficient diet, which reflects modern human diets, impairsed neocortical neurogenesis in the offspring. This impaired neurodevelopment occurs through a precocious fate transition of neural stem cells from the neurogenic to gliogenic lineage. A comprehensive mediator lipidomics screen revealed key mediators, epoxy metabolites, which were confirmed functionally using a neurosphere assay. Importantly, although the offspring were raised on a well balanced n-6:n-3 diet, they exhibited increased anxiety-related behavior in adulthood. These findings provide compelling evidence that excess maternal consumption of n-6 PUFAs combined with insufficient intake of n-3 PUFAs causes abnormal brain development that can have long-lasting effects on the offspring's mental state. PMID- 26580687 TI - Double Fano resonances in plasmonic nanocross molecules and magnetic plasmon propagation. AB - Double Fano resonances in optical frequency are investigated in an artificial plasmonic molecule consisting of seven identical nanocrosses. These two Fano resonances are found to originate from different physical mechanisms. One is caused by the excitation of the inherent quadrupole dark mode supported by a single nanocross, and the other is attributed to the magnetic plasmon mode due to the generation of antiphase ring currents in adjacent fused tetramers. The two Fano resonances can either be tuned simultaneously or independently within a wide spectral range by adjusting the geometrical parameters of the nanocrosses. The excitation of the magnetic plasmon in a chain made of coupled nanoparticles allows for subwavelength guiding of optical energy with low radiative losses. The field decay length is as long as 2.608 MUm, which is comparable to that of the magnetic plasmon waveguides and far surpasses the value achieved in electric plasmon counterparts. Because of the special shape of the nanocross, a Mach Zehnder interferometer can be built to steer optical beams. These results show that the proposed plasmonic nanostructures have potential applications in biochemical sensing, narrow line-shape engineering and on-chip optical signal propagation in nanoscale integrated optics. PMID- 26580688 TI - Measuring the Quality of Care for Patients With Traumatic Brain Injury--Reply. PMID- 26580689 TI - A Longitudinal Examination of Postural Impairments in Children With Mild Traumatic Brain Injury: Implications for Acute Testing. AB - OBJECTIVE: To examine how postural control changes following pediatric mild traumatic brain injury. SETTING: Urban pediatric emergency department. PARTICIPANTS: Children 11 to 16 years old who presented within 6 hours of sustaining mild traumatic brain injury. DESIGN: Prospective observational cohort followed for 1 month. MAIN MEASURES: Total center of pressure path velocity and path velocity within distinct frequency bands, ranging from moderate to ultralow, were recorded by the Nintendo Wii Balance Board during a 2-legged stance. Measurements were recorded in 2 separate tests with eyes open and closed. The scores of the 2 tests were compared, and a Romberg quotient was computed. RESULTS: Eleven children were followed for 1 month postinjury. The ultralow frequency, which reflects slow postural movements associated with exploring stability boundaries, was lower (p = .02) during the eyes closed stance acutely following injury. The Romberg quotient for this frequency was also significantly lower acutely following injury (p = .007) than at 1 month. CONCLUSION: Following mild traumatic brain injury, children acutely demonstrate significantly more rigid sway patterns with eyes closed than with eyes open, which were highlighted by the Romberg quotient. The Romberg quotient could allow for accurate identification and tracking of postural instability without requiring knowledge of preinjury balance ability. PMID- 26580690 TI - The Application of the CRASH-CT Prognostic Model for Older Adults With Traumatic Brain Injury: A Population-Based Observational Cohort Study. AB - OBJECTIVE: To examine the performance of the Corticosteroid Randomization After Significant Head injury (CRASH) trial prognostic model in older patients with traumatic brain injury. SETTING: The National Study on Costs and Outcomes of Trauma cohort, established at 69 hospitals in the United States in 2001 and 2002. PARTICIPANTS: Adults with traumatic brain injury and an initial Glasgow Coma Scale score of 14 or less. DESIGN: The CRASH-CT model predicting death within 14 days was deployed in all patients. Model performance in older patients (aged 65 84 years) was compared with that in younger patients (aged 18-64 years). MAIN MEASURES: Model discrimination (as defined by the c-statistic) and calibration (as defined by the Hosmer-Lemeshow P value). RESULTS: CRASH-CT model discrimination was not significantly different between the older (n = 356; weighted n = 524) and younger patients (n = 981; weighted n = 2602) and was generally adequate (c-statistic 0.83 vs 0.87, respectively; P = .11). CRASH-CT model calibration was adequate for the older patients and inadequate for younger patients (Hosmer-Lemeshow P values .12 and .001, respectively), possibly reflecting differences in sample size. Calibration-in-the-large showed no systematic under- or overprediction in either stratum. CONCLUSION: The CRASH-CT model may be valid for use in a geriatric population. PMID- 26580691 TI - Feasibility of a Cognitive Behavioral Intervention to Manage Fatigue in Individuals With Traumatic Brain Injury: A Pilot Study. AB - OBJECTIVE: To evaluate the feasibility of conducting a randomized clinical trial of an Internet-based manualized intervention to teach individuals with traumatic brain injury to manage their fatigue. SETTING: Community dwelling. PARTICIPANTS: Forty-one participants randomized to Maximizing Energy (MAX) intervention group (n = 20) and Health Education group (n = 21). INTERVENTION: The experimental group (MAX intervention) received an 8-week program that combined education and Problem-Solving Therapy to teach individuals to manage fatigue-related problems. The attention control group received health education. MEASURES: Primary outcome measures pertained to the feasibility of conducting the trial. Secondary outcomes were fatigue impact and fatigue severity assessed at baseline and postintervention. RESULTS: Of the 65 participants referred, 41 were enrolled (63% recruitment rate), of which 3 withdrew (92% retention rate). Participants in the experimental and control groups completed their homework 75% and 85% of the time, respectively, and were equally engaged in the sessions. Participants in the experimental group were able to learn and implement the MAX intervention steps. Effect sizes for all measures ranged from small (-0.17) to medium (-0.58) in favor of the intervention group. CONCLUSION: Findings from the study suggest that the MAX intervention is feasible to administer to individuals with post-traumatic brain injury fatigue. PMID- 26580693 TI - The Nature and Clinical Significance of Preinjury Recall Bias Following Mild Traumatic Brain Injury. AB - OBJECTIVE: Patients with mild traumatic brain injury (MTBI) often underestimate their preinjury symptoms. This study aimed to clarify the mechanism underlying this recall bias and its contribution to MTBI outcome. SETTING: Level I trauma center. PARTICIPANTS: Patients with uncomplicated MTBI (N = 88) and orthopedic injury (N = 67). DESIGN: Prospective longitudinal. MAIN MEASURES: Current and retrospective ratings on the British Columbia Postconcussion Symptom Inventory, completed at 6 weeks and 1 year postinjury. RESULTS: Preinjury symptom reporting was comparable across groups, static across time, and associated with compensation-seeking. High preinjury symptom reporting was related to high postinjury symptom reporting in the orthopedic injury group but less so in the MTBI group, indicating a stronger positive recall bias in highly symptomatic MTBI patients. Low preinjury symptom reporting was not a risk factor for poor MTBI outcome. CONCLUSION: The recall bias was stronger and more likely clinically significant in MTBI patients with high postinjury symptoms. Multiple mechanisms appear to contribute to recall bias after MTBI, including the reattribution of preexisting symptoms to MTBI as well as processes that are not specific to MTBI (eg, related to compensation-seeking). PMID- 26580692 TI - Self-Reported Sleep Disturbance Mediates the Relationship Between PTSD and Cognitive Outcome in Blast-Exposed OEF/OIF Veterans. AB - OBJECTIVES: To examine the contribution of sleep disturbance to cognitive performance following blast exposure. DESIGN: Correlational research evaluating self-reported sleep disturbance as a mediator of the association between the primary blast-related comorbidities of mild traumatic brain injury (mTBI) and posttraumatic stress disorder and cognitive outcome. PARTICIPANTS: One hundred sixty Operation Enduring Freedom/Operation Iraqi Freedom Veterans with a history of blast exposure assigned to 1 of 3 groups (no TBI, mTBI without loss of consciousness, and mTBI with loss of consciousness). MAIN OUTCOME MEASURES: Neuropsychological measures and self-report of sleep disturbance. RESULTS: Increased posttraumatic stress disorder symptomatology was associated with worse performance in multiple cognitive domains. This association was mediated in part by self-reported sleep disturbance. Traumatic brain injury with loss of consciousness was associated with lower manual dexterity, but this association was not mediated by sleep disturbance. CONCLUSIONS: Our results highlight the importance of sleep disturbance as a factor contributing to cognitive outcome in individuals with posttraumatic stress disorder symptoms. They point to the importance of considering sleep problems in the diagnosis and treatment of cognitive deficits in veterans with blast exposure. PMID- 26580694 TI - A Dopamine Pathway Gene Risk Score for Cognitive Recovery Following Traumatic Brain Injury: Methodological Considerations, Preliminary Findings, and Interactions With Sex. AB - OBJECTIVES: With evidence of sexual dimorphism involving the dopamine (DA) pathway, and the importance of DA pathways in traumatic brain injury (TBI) recovery, we hypothesized that sex * DA-gene interactions may influence cognition post-TBI. PARTICIPANTS: Adult survivors of severe TBI (n = 193) consecutively recruited from a level 1 trauma center. DESIGN: Risk allele assignments were made for multiple DA pathway genes using a sex-specific stratified approach. Genetic risk alleles, and their impacts on cognition, were assessed at 6 and 12 months postinjury using unweighted, semiweighted, and weighted gene risk score (GRS) approaches. MAIN MEASURES: A cognitive composite score generated from 8 standardized neuropsychological tests targeting multiple cognitive domains. RESULTS: A significant sex * gene interaction was observed at 6 and 12 months for ANKK1 rs1800497 (6M: P = .002, 12M: P = .001) and COMT rs4680 (6M: P = .048; 12M: P = .004); DRD2 rs6279 (P = .001) and VMAT rs363226 (P = .043) genotypes were independently associated with cognition at 6 months, with trends for a sex * gene interaction at 12 months. All GRS methods were significant predictors of cognitive performance in multivariable models. Weighted GRS multivariate models captured the greatest variance in cognition: R = 0.344 (6 months); R = 0.441 (12 months), significantly increasing the variance captured from the base prediction models. CONCLUSIONS: A sex-specific DA-pathway GRS may be a valuable tool when predicting cognitive recovery post-TBI. Future work should validate these findings and explore how DA-pathway genetics may guide therapeutic intervention. PMID- 26580695 TI - Cognitive Intervention for Attention and Executive Function Impairments in Children With Traumatic Brain Injury: A Pilot Study. AB - OBJECTIVE: To test the effectiveness of the Attention Improvement and Management (AIM) program, a cognitive intervention for improving impairments in attention and executive functions (EFs) after pediatric traumatic brain injury (TBI). SETTING: Tertiary care children's hospital. PARTICIPANTS: A total of 13 children with complicated mild-to-severe TBI (average of 5 years postinjury) and 11 healthy comparison children aged 9 to 15 years completed the study. DESIGN: Open label pilot study with a nontreated control group. MAIN MEASURES: Subtests from the Test of Everyday Attention-for Children (TEA-Ch) and the Delis-Kaplan Executive Function System (D-KEFS), the self- and parent-report from the Behavior Rating Inventory of Executive Function (BRIEF), and the Goal Attainment Scale (GAS). RESULTS: Relative to the healthy comparison group, children with TBI demonstrated significant improvement postintervention on a neuropsychological measure of sustained attention, as well as on parent-reported EFs. The majority of families also reported expected or more-than-expected personalized goal attainment. CONCLUSIONS: The study provides preliminary evidence for the effectiveness of AIM in improving parent-reported EFs and personalized real-world goal attainment in children with TBI. PMID- 26580696 TI - Consistency of Recall for Deployment-Related Traumatic Brain Injury. AB - OBJECTIVE: To examine the temporal consistency of self-reported deployment related traumatic brain injury (TBI) and its association with posttraumatic stress disorder (PTSD) symptom severity. SETTING: In-person interviews at US Army installations (postdeployment); phone interviews (long-term follow-up). PARTICIPANTS: A total of 378 US Army soldiers and veterans deployed to Iraq; 14.3% (n = 54) reported TBI with loss of consciousness during an index deployment. DESIGN: Participants were evaluated after returning from deployment and again 5 to 9 years later. MAIN MEASURES: Temporal consistency of TBI endorsement based on TBI screening interviews; PTSD Checklist, Civilian Version. RESULTS: The concordance of deployment-related TBI endorsement from the postdeployment to long-term follow-up assessment was moderate (kappa = 0.53). Of the 54 participants reporting (predominantly mild) TBI occurring during an index deployment, 32 endorsed TBI inconsistently over time. More severe PTSD symptoms at postdeployment assessment were independently associated with discordant reporting (P = .0004); each 10-point increase in PCL scores increasing odds of discordance by 69% (odds ratio = 1.69; 95% confidence interval, 1.26-2.26). CONCLUSIONS: Deployment-related TBI may not be reported reliably over time, particularly among war-zone veterans with greater PTSD symptoms. Results of screening evaluations for TBI history should be viewed with caution in the context of PTSD symptom history. PMID- 26580697 TI - Integrated femtosecond stimulated Raman scattering and two-photon fluorescence imaging of subcellular lipid and vesicular structures. AB - The primary goal of this study is to demonstrate that stimulated Raman scattering (SRS) as a new imaging modality can be integrated into a femtosecond (fs) nonlinear optical (NLO) microscope system. The fs sources of high pulse peak power are routinely used in multimodal nonlinear microscopy to enable efficient excitation of multiple NLO signals. However, with fs excitations, the SRS imaging of subcellular lipid and vesicular structures encounters significant interference from proteins due to poor spectral resolution and a lack of chemical specificity, respectively. We developed a unique NLO microscope of fs excitation that enables rapid acquisition of SRS and multiple two-photon excited fluorescence (TPEF) signals. In the in vivo imaging of transgenic C. elegans animals, we discovered that by cross-filtering false positive lipid signals based on the TPEF signals from tryptophan-bearing endogenous proteins and lysosome-related organelles, the imaging system produced highly accurate assignment of SRS signals to lipid. Furthermore, we demonstrated that the multimodal NLO microscope system could sequentially image lipid structure/content and organelles, such as mitochondria, lysosomes, and the endoplasmic reticulum, which are intricately linked to lipid metabolism. PMID- 26580698 TI - Application of the Laplace transform in time-domain optical spectroscopy and imaging. PMID- 26580699 TI - Interventional multispectral photoacoustic imaging with a clinical ultrasound probe for discriminating nerves and tendons: an ex vivo pilot study. AB - Accurate and efficient identification of nerves is an essential component of peripheral nerve blocks. While ultrasound (US) imaging is increasingly used as a guidance modality, it often provides insufficient contrast for identifying nerves from surrounding tissues such as tendons. Electrical nerve stimulators can be used in conjunction with US imaging for discriminating nerves from surrounding tissues, but they are insufficient to reliably prevent neural punctures, so that alternative methods are highly desirable. In this study, an interventional multispectral photoacoustic (PA) imaging system was used to directly compare the signal amplitudes and spectra acquired from nerves and tendons ex vivo, for the first time. The results indicate that the system can provide significantly higher image contrast for discriminating nerves and tendons than that provided by US imaging. As such, photoacoustic imaging could be valuable as an adjunct to US for guiding peripheral nerve blocks. PMID- 26580700 TI - Oral cancer screening: serum Raman spectroscopic approach. AB - Serum Raman spectroscopy (RS) has previously shown potential in oral cancer diagnosis and recurrence prediction. To evaluate the potential of serum RS in oral cancer screening, premalignant and cancer-specific detection was explored in the present study using 328 subjects belonging to healthy controls, premalignant, disease controls, and oral cancer groups. Spectra were acquired using a Raman microprobe. Spectral findings suggest changes in amino acids, lipids, protein, DNA, and beta-carotene across the groups. A patient-wise approach was employed for data analysis using principal component linear discriminant analysis. In the first step, the classification among premalignant, disease control (nonoral cancer), oral cancer, and normal samples was evaluated in binary classification models. Thereafter, two screening-friendly classification approaches were explored to further evaluate the clinical utility of serum RS: a single four group model and normal versus abnormal followed by determining the type of abnormality model. Results demonstrate the feasibility of premalignant and specific cancer detection. The normal versus abnormal model yields better sensitivity and specificity rates of 64 and 80%; these rates are comparable to standard screening approaches. Prospectively, as the current screening procedure of visual inspection is useful mainly for high-risk populations, serum RS may serve as a useful adjunct for early and specific detection of oral precancers and cancer. PMID- 26580701 TI - Continuous 1D-Metallic Microfibers Web for Flexible Organic Solar Cells. AB - We report the use of a continuous 1D-metallic microfibers web (MFW) as transparent electrode for organic solar cells (OSCs). The MFW electrode can be produced with a process that involves simple electrospinning and wet etching of metal thin film. Au MFW exhibits a maximum optical transmittance of 90.8% (at 15 Omega/sq of the sheet resistance) and excellent mechanical flexibility. The MFW structure has an average width in the range from 4 to 6 MUm and a junction-free structure, resulting in very smooth surface roughness. The OSCs with Au MFW electrode exhibited a higher power conversion efficiency (PCE) of 3.50% than the device with an indium tin oxide electrode (PCE = 3.20%). The optical modeling calculation showed that the Au MFW electrode induced light scattering and improved the light absorption in the active layer, resulting in an improved PCE in the OSCs. PMID- 26580703 TI - Nevus Anemicus and Bier Spots in Tuberous Sclerosis Complex. PMID- 26580702 TI - Antidepressants are not overprescribed for mild depression. AB - OBJECTIVE: To evaluate overprescribing of antidepressant medication for minimal or mild depression. METHOD: Electronic records data from 4 large health care systems identified outpatients aged 18 years or older starting a new episode of antidepressant treatment in 2011 with an ICD-9 diagnosis of depressive disorder (296.2, 296.3, 311, or 300.4). Patient Health Questionnaire-9 (PHQ-9) depression severity scores at time of treatment initiation were used to examine the distribution of baseline severity and the association between baseline severity and patients' demographic and clinical characteristics. RESULTS: Of 19,751 adults beginning treatment in 2011, baseline PHQ-9 scores were available for 7,051. In those with a baseline score, 85% reported moderate or severe symptoms (PHQ-9 score of 10 or more), 12% reported mild symptoms (PHQ-9 score of 5 to 9), and 3% reported minimal symptoms (PHQ-9 score of less than 5). The proportion reporting minimal or mild symptoms when starting treatment increased with age, ranging from 11% in those under age 65 years to 26% in those aged 65 and older. The proportion with minimal or mild symptoms was also moderately higher among patients living in wealthier neighborhoods and those treated by psychiatrists. Nevertheless, across all subgroups defined by sex, race/ethnicity, prescriber specialty, and treatment history, the proportions with minimal or mild symptoms did not exceed 18%. Secondary analyses, including weighting and subgroup analyses, found no evidence that estimates of baseline severity were biased by missing PHQ-9 scores. CONCLUSIONS: In these health systems, prescribing of antidepressant medication for minimal or mild depression is much less common than suggested by previous reports. Given that this practice may sometimes be clinically appropriate, our findings indicate that overprescribing of antidepressants for mild depression is not a significant public health concern. PMID- 26580704 TI - Thermosensitive Hydrogel System With Paclitaxel Liposomes Used in Localized Drug Delivery System for In Situ Treatment of Tumor: Better Antitumor Efficacy and Lower Toxicity. AB - Intratumoral delivery of chemotherapeutic agents may provide drug localization within the tumor and divert the drug from nontarget organs to improve toxicity and increase efficacy. Thermosensitive injectable hydrogel system may be suitable for the treatment of pancreatic cancer. A study was carried out to examine the efficacy and toxicity of paclitaxel (PTX) liposome gel as a local chemotherapy system against pancreatic cancer in tumor-bearing mice model. The thermosensitive hydrogel we prepared had an appropriate sol-to-gel transition temperature and particle size and morphology study showed this new dosage form possessed physical stability of drug without precipitation and particle size growth of liposome. PTX lip-gel release in vitro showed a much more slowly release than PTX-lip. The PTX lip-gel system was proven to have a good retention inside of tumor tissue by intratumoral retention experiments. The in vivo trials showed a better balance between antitumor efficacy and systemic safety in PTX-lip-gel group than in other groups at the equal drug dose. In conclusion, the PTX-lip-gel we prepared in this study provided a high local PTX concentration, sustained and stable drug release, extend drug retention inside of tumor, and low toxicity to normal tissues. PMID- 26580705 TI - Effective Stabilization of a High-Loading Sulfur Cathode and a Lithium-Metal Anode in Li-S Batteries Utilizing SWCNT-Modulated Separators. AB - A custom single-wall carbon nanotube (SWCNT)-modulated separator is employed to directly suppress the polysulfide migration and indirectly protect the lithium metal anode from severe polysulfide contamination. The conductive sp(2) -carbon scaffold continuously reactivates and reutilizes the trapped active material, so the SWCNT-modulated separator provides a facile way to facilitate the implementation of pure sulfur cathodes with high sulfur contents and loadings. PMID- 26580707 TI - Centrality of Body and Embodiment in Nursing Care: A Scoping Study of the Italian Literature. AB - PURPOSE: Nursing has based its practical work on contact and a relationship with the patient's body and embodiment; however, the international theoretical and empirical researches on these concepts are still neglected. The purpose of this scoping study is to map the breadth and depth with which body and embodiment are addressed in the Italian nursing literature, identifying the key concepts and the main sources and types of evidence available. ORGANIZING CONSTRUCT: Scoping study with qualitative content analysis. It was conducted in accordance with the framework outlined by Arksey and O'Malley and following the recommendations by Levac, Colquhoun, and O'Brien. The qualitative content analysis process was conducted according to Elo and Kyngas. Lincoln and Guba's technique was followed to ensure trustworthiness. METHODS: Searches were conducted within seven electronic databases of peer-reviewed literature, one electronic Italian database, six electronic database searches of grey literature, four free online nursing journals, four Internet search engines, and 10 key hard-copy Italian nursing journals. FINDINGS: Through these searches, 2,536 records were identified, from which 18 were selected for the final review. Three generic categories emerged from qualitative content analysis: the conceptual category, the nursing care category, and the education category, each including eight, seven, and two subcategories, respectively. CONCLUSIONS: The central nursing concepts of body and embodiment definitely require greater and more continuous efforts of theoretical study and empirical research within the nursing discipline, both in Italy and internationally. CLINICAL RELEVANCE: A greater awareness of body and embodiment should guide nursing practice in caring for and supporting patients and also guide approaches to teaching and learning. Moreover, body and embodiment are concepts firmly rooted in nursing practice, and they are also ripe for future research and able to generate more holistic and complex ways of understanding patients. PMID- 26580706 TI - Rivaroxaban compared with standard thromboprophylaxis after major orthopaedic surgery: co-medication interactions. AB - AIM: The aim of the present study was to analyse concomitant drug use and its association with outcome in patients (N = 17 701) receiving rivaroxaban or standard of care (SOC) for the prevention of venous thromboembolism after major orthopaedic surgery in the non-interventional, phase IV XAMOS (Xarelto(r) in the prophylaxis of post-surgical venous thromboembolism after elective major orthopaedic surgery of hip or knee) study. METHODS: Concomitant drug use was at the discretion of the treating physician. Prespecified co-medications of interest were cytochrome P450 (CYP) 3A4/P-glycoprotein inhibitors/inducers, platelet aggregation inhibitors (PAIs) and nonsteroidal anti-inflammatory drugs (NSAIDs). Crude event incidences were compared between rivaroxaban and SOC groups. RESULTS: CYP3A4/P-glycoprotein inhibitor/inducer use was infrequent, in contrast to PAI (~7%) and NSAID (~52%) use. Rivaroxaban was associated with a lower incidence of overall symptomatic thromboembolic events compared with SOC, regardless of co medication use. In both treatment groups, PAI users, with higher age and prevalence of cardiovascular co-morbidities, had similar higher (>7-fold) incidences of symptomatic arterial but not venous thromboembolic events compared with non-users. NSAID use had no influence on thromboembolic events. However, odds ratios (ORs) for major bleeding events (European Medicines Agency definition) were higher in NSAID users compared with non-users in rivaroxaban [OR = 1.50; 95% confidence interval (CI) 1.06, 2.13] and SOC (OR = 1.70; CI 1.16, 2.49) groups. In PAI users, ORs for major bleeding events were no different from those of non-users in both the rivaroxaban (OR = 1.49; CI 0.84, 2.65) and SOC (OR = 1.46; CI 0.82, 2.62) groups. CONCLUSIONS: Use of NSAIDs in XAMOS was frequent and associated with a higher frequency of bleeding events in patients receiving rivaroxaban or SOC, although the benefit-risk profile of rivaroxaban compared with SOC was maintained. PMID- 26580708 TI - Outcomes of percutaneous cholecystostomy and predictors of eventual cholecystectomy. AB - BACKGROUND: Percutaneous cholecystostomy (PC) is an established treatment for high surgical risk patients with acute cholecystitis. This paper studies factors predictive of mortality and eventual cholecystectomy. METHODS: A retrospective review of all patients who underwent PC from March 2005 to March 2015 was performed. Patient demographics, clinical features, comorbidity profile, grade of cholecystitis, interval between cholecystitis diagnosis and PC, and method of PC were studied. Length of stay, complications, readmission rate, mortality and eventual cholecystectomy were studied. For patients with eventual cholecystectomy, operative data and perioperative outcomes were studied. RESULTS: One hundred and three patients with median age of 80 years (range 43-105) underwent PC. Median interval to PC was 2 days (range 0-15). 9.7% of patients had complications. Median length of stay was 19 days (range 3-206). 41% underwent eventual cholecystectomy. 30-day mortality rate was 10.7%. Higher APACHE II scores (P = 0.004), higher Charlson comorbidity index (CCI) (P = 0.009), and longer interval from diagnosis to PC (P = 0.037) were associated with in-hospital mortality. Younger age (P = 0.015), lower APACHE II scores (P = 0.043) and lower CCI (P = 0.002) were associated with eventual cholecystectomy. CONCLUSION: Percutaneous cholecystostomy is safe and effective in treatment of acute cholecystitis. Prompt PC improves survival in high risk surgical patients. Comorbidity severity is associated with mortality. Patients with lesser comorbidity are likely to receive eventual cholecystectomy. PMID- 26580709 TI - Chemistry of xylopyranosides. AB - Xylose is one of the few monosaccharidic building blocks that are used by mammalian cells. In comparison with other monosaccharides, xylose is rather unusual and, so far, only found in two different mammalian structures, i.e. in the Notch receptor and as the linker between protein and glycosaminoglycan (GAG) chains in proteoglycans. Interestingly, simple soluble xylopyranosides can not only initiate the biosynthesis of soluble GAG chains but also function as inhibitors of important enzymes in the biosynthesis of proteoglycans. Furthermore, xylose is a major constituent of hemicellulosic xylans and thus one of the most abundant carbohydrates on Earth. Altogether, this has spurred a strong interest in xylose chemistry. The scope of this review is to describe synthesis of xylopyranosyl donors, as well as protective group chemistry, modifications, and conformational analysis of xylose. PMID- 26580710 TI - Theory of the milieu dependent isomerisation dynamics of reducing sugars applied to d-erythrose. AB - Quantitative (1)H selective saturation transfer NMR spectroscopy ((1)H SST qNMR) was used to fully describe the milieu dependent dynamics of the isomeric system of d-erythrose. Thermodynamic activation parameters are calculated for acidic as well as for basic catalysis combining McConnell's modified Bloch equations for the chemical exchange solved for the constraint of saturating the non-hydrated acyclic isomer, the Eyring equation and Hudson's equation for pH dependent catalysis. A detailed mathematical examination describing the milieu dependent dynamics of sugar isomerisation is provided. Thermodynamic data show evidence that photo-catalysed sugar isomerisation as well as degradation has to be considered. Approximations describing the pH and temperature dependence of thermodynamic activation parameters are derived that indicate the possibility of photo-affecting equilibrium constants. Moreover, the results show that isomerisation dynamics are closely related to degradation kinetics and that sugars' reactivities are altered by the concentration of acyclic carbonyl isomer and the sum of its ring closing rate constants. Additionally, it is concluded that sugar solutions show a limited self-stabilising behaviour. PMID- 26580711 TI - A new method testing the orthogonality of different protecting groups. AB - A new test was elaborated to identify a new set of orthogonal protecting groups. With the developed method eight different protecting groups were tested under various deprotection conditions and the complex reaction mixtures were analysed by HPLC. The developed method allows for quick identification of orthogonality using simple model structures. PMID- 26580712 TI - Correction: Formation of lipid/peptide tubules by IAPP and temporin B on supported lipid membranes. AB - Correction for 'Formation of lipid/peptide tubules by IAPP and temporin B on supported lipid membranes' by Paavo K. J. Kinnunen et al., Soft Matter, 2015, DOI: 10.1039/b925228b. PMID- 26580713 TI - Investigating Molecular Kinetics by Variationally Optimized Diffusion Maps. AB - Identification of the collective coordinates that describe rare events in complex molecular transitions such as protein folding has been a key challenge in the theoretical molecular sciences. In the Diffusion Map approach, one assumes that the molecular configurations sampled have been generated by a diffusion process, and one uses the eigenfunctions of the corresponding diffusion operator as reaction coordinates. While diffusion coordinates (DCs) appear to provide a good approximation to the true dynamical reaction coordinates, they are not parametrized using dynamical information. Thus, their approximation quality could not, as yet, be validated, nor could the diffusion map eigenvalues be used to compute relaxation rate constants of the system. Here we combine the Diffusion Map approach with the recently proposed Variational Approach for Conformation Dynamics (VAC). Diffusion Map coordinates are used as a basis set, and their optimal linear combination is sought using the VAC, which employs time correlation information on the molecular dynamics (MD) trajectories. We have applied this approach to ultra-long MD simulations of the Fip35 WW domain and found that the first DCs are indeed a good approximation to the true reaction coordinates of the system, but they could be further improved using the VAC. Using the Diffusion Map basis, excellent approximations to the relaxation rates of the system are obtained. Finally, we evaluate the quality of different metric spaces and find that pairwise minimal root-mean-square deviation performs poorly, while operating in the recently introduced kinetic maps based on the time-lagged independent component analysis gives the best performance. PMID- 26580714 TI - Enantioselective Synthesis of Homoallylic Azides and Nitriles via Palladium Catalyzed Decarboxylative Allylation. AB - Azides and nitriles are important building blocks for the synthesis of nitrogen containing bioactive compounds. The first example of enantioselective palladium catalyzed decarboxylative allylation of alpha-azido and cyano beta-ketoesters is reported. Indanone derivatives were obtained in 50-88% yield/77-97% ee and 46-98% yield/78-93% ee for azide and nitrile substituents, respectively. The required starting materials were synthesized in one step from ketoesters via electrophilic azidation and cyanation using benziodoxole hypervalent iodine reagents. The products could be easily converted into useful nitrogen-containing building blocks, such as triazoles, amides, or alpha- and beta- amino ketones. PMID- 26580715 TI - beta-Functionalized Push-Pull opp-Dibenzoporphyrins. AB - The synthesis of a series of beta-functionalized push-pull dibenzoporphyrins was realized. These porphyrins display subtle push-pull effects, demonstrating the exceptional tunability of their electronic and electrochemical properties. The UV vis spectra of these porphyrins show unique absorption patterns with shouldered Soret bands and extra absorptions in the Q-band region. Stronger electron withdrawing groups display more significant bathochromic shifts of the Soret bands. The fluorescence spectra of these porphyrins show strong near-IR emission bands (600-850 nm). In particular, fluorescence quenching effect was observed for pyridyl carrying push-pull porphyrin 4c in the presence of an acid. TFA titration study of 4c using UV-vis and fluorescence spectroscopy reveals that the fluorescence quenching can be mainly attributed to the protonation of the pyridyl groups of 4c. The versatile synthetic methods developed in this work may open a door to access a large number of functionalized organic materials that are currently unavailable. The structure-property studies provided in this work may provide useful guidelines for the design of new generations of materials in dye sensitized solar cells, in nonlinear optical applications, as fluorescence probes, as well as sensitizers for photodynamic therapy. PMID- 26580718 TI - Assessing the suitability of the OECD 29 guidance document to investigate the transformation and dissolution of silver nanoparticles in aqueous media. AB - The OECD guidance document No. 29 was designed to determine the rate and extend to which metals can produce soluble available ionic metal species. This transformation/dissolution protocol was applied to silver nanomaterials. The results prove that concentrations of released Ag(+) at pH 8 were nearly similar at all three different loadings. At pH 6, the concentration of Ag(+) was almost the same at loadings of 10 and 100 mg L(-1) AgNPs. However, the study showed changes in concentrations of nanoparticles and aggregates (operationally defined as the fraction passing a 0.2 um filter). At the higher pH both the concentrations in the test medium of Ag(+) and of AgNPs (fraction < 0.2 um) decreased. After 7 days of test duration, 71 ug L(-1) of Ag(+) was found in pH 6 medium (initial loading of 100 mg L(-1)). In pH 8 medium a maximum concentration of 29 ug L(-1) Ag(+) was measured (initial loading of 10 mg L(-1)). The maximum transformation from AgNPs to Ag(+) was 2.7% (27 ug L(-1)) in pH 8 medium (loading of 1 mg L(-1)) after 7 days. At an initial loading of 100 mg L(-1) AgNPs in medium at pH 8, only 0.03% (30 ug L(-1)) were transformed to Ag(+) after 7 days. At the loading of 1 mg L(-1) AgNPs all silver concentrations remain relatively constant for the duration of the test after 7 until 28 days. The results reveal that only low concentrations of Ag(+) are released from AgNPs under the applied conditions. PMID- 26580717 TI - Plant vascular development: from early specification to differentiation. AB - Vascular tissues in plants are crucial to provide physical support and to transport water, sugars and hormones and other small signalling molecules throughout the plant. Recent genetic and molecular studies have identified interconnections among some of the major signalling networks that regulate plant vascular development. Using Arabidopsis thaliana as a model system, these studies enable the description of vascular development from the earliest tissue specification events during embryogenesis to the differentiation of phloem and xylem tissues. Moreover, we propose a model for how oriented cell divisions give rise to a three-dimensional vascular bundle within the root meristem. PMID- 26580719 TI - Theoretical study on the OH-initiated oxidation mechanism of polyfluorinated dibenzo-p-dioxins under the atmospheric conditions. AB - Density functional theory (DFT) calculations at the B3LYP/6-311++G(2df,p) level of theory have been carried out to investigate the atmospheric oxidation mechanisms of some polyfluorinated dibenzo-p-dioxins (PFDDs), initiated by OH radical. The computed results show that all OH addition reactions of PFDDs are thermodynamically spontaneous processes and the branch ratio of the PFDD-OH adducts is determined by the magnitude of the Gibbs free energies of activation (Delta(r)G(?)) and hence rate constants (k) for addition reactions. The OH reactions with all studied PFDDs are dominated by Cgamma-addition and the total rate constants for OH addition decrease with increasing the number of fluorine atom substituting at alpha positions. Under the atmospheric conditions, the subsequent O2 addition reactions of PFDD-OH adducts occur hardly thermodynamically and are slow kinetically. For PFDD-alpha(beta)-OH adducts without F atom at same positions the main reaction pathway is H abstraction by O2, while PFDD-gamma-OH adducts will undergo fused-ring C-O bond cleavage, affording the substituted phenoxy radicals. PMID- 26580716 TI - Beyond beta-catenin: prospects for a larger catenin network in the nucleus. AB - beta-catenin is widely regarded as the primary transducer of canonical WNT signals to the nucleus. In most vertebrates, there are eight additional catenins that are structurally related to beta-catenin, and three alpha-catenin genes encoding actin-binding proteins that are structurally related to vinculin. Although these catenins were initially identified in association with cadherins at cell-cell junctions, more recent evidence suggests that the majority of catenins also localize to the nucleus and regulate gene expression. Moreover, the number of catenins reported to be responsive to canonical WNT signals is increasing. Here, we posit that multiple catenins form a functional network in the nucleus, possibly engaging in conserved protein-protein interactions that are currently better characterized in the context of actin-based cell junctions. PMID- 26580720 TI - On the consequence of substituting maximum likelihood estimates for the observations below the limit of detection. AB - Use of maximum likelihood estimation procedures with multiple imputations to replace observations below the limit of detection (LOD) has been recommended. There is concern that the use of multiple imputations may introduce variability in the data resulting in different conclusions every time the same data are statistically analyzed. We analyzed data from National Health and Nutrition Examination Survey for 7 perfluorinated and 7 polybrominated diphenyl ethers to address these concerns. Data for each variable were subjected to 10 different iterations of statistical analysis. All observations below LOD were replaced by maximum likelihood estimation procedures with 5 imputations. The maximum variation in computing unadjusted geometric means over 10 iterations of analysis was about 2.5%. Unless the percent observations below LOD was more than 40%, maximum variation in computing adjusted geometric means was less than 1.5%. Maximum variation for computing adjusted geometric standard deviation was less than 6%. Except for border line comparisons, significance probabilities for pairwise comparisons did not vary enough to render contrasts from being statistically significant to statistically non-significant or vice versa. Similar conclusions applied to significance probabilities for regression slopes. The use of more than one multiply imputed variable in a regression model was not found to be of concern. The results show that the use of multiple imputations does not generate additional variabilities in the estimates of these statistics beyond tolerable statistical noise. However, when the percent observations in the data are relatively high, there is some possibility of obtaining disparate results. PMID- 26580721 TI - Polybrominated diphenyl ethers in sediments from the Southern Yellow Sea: Concentration, composition profile, source identification and mass inventory. AB - The Southern Yellow Sea (SYS) is believed to be influenced by the contaminants from mainland China and the Korean peninsula. Here we report the first record about concentrations of polybrominated diphenyl ethers (PBDEs) in the sediments of the SYS. The concentrations of ?(7)PBDEs (BDE-28, 47, 99, 100, 153, 154, 183) and BDE-209 were 0.064-0.807 ng g(-1) (dry weight) and 0.067-1.961 ng g(-1) with a mean value of 0.245 ng g(-1) and 0.652 ng g(-1), respectively. These are distinctively low compared with the PBDE levels previously reported in other regions of the world. PBDE concentrations gradually increased from the coastal areas to the central mud area. BDE-209 was the dominant congener, accounting for 70.2-91.6% of the total PBDEs. Congener profiles of PBDEs were similar to those in sediments from the Bohai Sea (BS), Laizhou Bay and modern Yellow River, which might be a tentative indication that they shared similar sources. Principal component analysis (PCA) revealed that PBDEs in the SYS were mainly from continental runoff (69.0%) and atmospheric deposition (31.0%). Depth profile of PBDEs in a sediment core collected from the edge of the central mud area showed that concentration of BDE-209 rapidly increased in recent years, which is in accordance with the replacement in demand and consumption of Penta- and Octa-BDEs by the Deca-BDE. Compared with BS, East China Sea, Erie and Ontario, the SYS was a relatively weak sink of PBDEs (0.102-1.288 t yr(-1) for ?(7)PBDEs and 0.107 3.129 t yr(-1) for BDE-209) in the world. PMID- 26580722 TI - Sudden unexpected death from natural diseases: Fifteen years' experience with 484 cases in Seychelles. AB - The aim of this study is to identify and subclassify sudden natural death (sudden death from natural diseases) cases in Seychelles. A total of 484 sudden natural death cases with autopsy at the Clinical Pathology Laboratory, Victoria Hospital, Seychelles between 1997 through 2012 were retrospectively reviewed. Among them, 363 cases (75%) were male and 121 (25%) were female. The most frequent sudden deaths were attributed to cardiovascular diseases (78.5%), and then followed by infectious diseases (9.9%), and gastrointestinal diseases (9.1%). This is the largest population-based study on sudden natural deaths in Seychelles. PMID- 26580723 TI - Survey of medico-legal investigation of homicide in the region of Epirus (Northwest Greece). AB - This study analyzed the forensic features of homicides in North-West Greece (Epirus) from 1998 to 2013, a borderland area between Greece and Albania. Although Greece is critically influenced by both the increasing flow of refugees and the current socioeconomic crisis, very little information has been published regarding the patterns of homicide in the country. Fifty-eight autopsied victims (36 males; 22 females) were investigated. The median age was 37 years old. The average annual homicide rate was 0.85 per 100,000 inhabitants and showed remarkable fluctuation, with largest increase during Greek financial downturn. Sixteen victims were not Greek citizens. The most common method of commitment was the use of firearm (40%). The main motives were economical causes (26%) and passion (14%). Four cases were categorized as matricide (7%), 3 as homicide suicide (5%), 2 as patricide (3%) and 1 as infanticide (2%). Toxicological analysis proved negative for ethanol and other psychotropic substances in the majority of the victims (50%). There is an urgent need for public actions both in Epirus and in Greece, with the application of effective strategies against criminality. PMID- 26580724 TI - Baluchi and Pakhtun population data of 9 X-chromosomal short tandem repeat loci. AB - Baluchistan is the largest province of Pakistan in terms of area, constituting approximately 44% of the country's total land mass, and the smallest in terms of population, being home to less than 5% of the country's population. Khyber Pakhtunkhwa (KPK) formerly called North-West Frontier Province is located in the north-west of Pakistan having an estimated 13.4% of total population of Pakistan in which Pakhtuns are the major ethnic group. A total of 250 samples from Baluchi population and 250 samples from Pakhtun population were typed for 9 X-chromosomal STR markers: DXS101, DXS6789, DXS7132, DXS7423, DXS7424, DXS8378, GATA31E08, GATA172D05 and HPRTB along with sex typing locus, Amelogenin. A total of 59 alleles were found in Baluchi population while 61 alleles were found in Pakhtun population. This is the first study of the two populations based on these markers and the population data can be used as reference database for Baluchi and Pakhtun populations. PMID- 26580725 TI - Urine specimen collection following consensual intercourse - A forensic evidence collection method for Y-DNA and spermatozoa. AB - The purpose of the prospective research was to evaluate the benefit of urine specimen as a collection technique for biological forensic evidence in adult volunteers following consensual intercourse. For detecting Y-chromosomal material Buccal Swab Spin Protocol((r)) was used in DNA extraction and purification and samples were analysed with Quantifiler Y Human Male DNA Quantification Kit((r)). The time frame for positive Y-DNA was evaluated. Immediate microscopy for detection of spermatozoa was performed. Y-DNA was detected in 173/205 (84.4%) urine samples. Of the 86 first post-coital void urine samples available, Y-DNA was detected in 83 (96.5%) specimens. Of the 119 urine samples from volunteers with post-coital activities Y-DNA was still measurable in 70 (58.8%) urine specimens. The male DNA amount was below 0.023 ng/MUl in 28/153 (18.3%) urine samples. Of the 22 urine samples obtained after 24 post-coital hours, 9 (40.9%) were still Y-DNA positive. No associations were found between coital durance, coital frequency during the past two weeks prior to the study intercourse, post coital activities, and the urine sample Y-DNA positivity. Of the 111 urine samples where the immediate microscopy was performed, in 66 (59.5%) samples spermatozoa were verified and one sample even contained motile spermatozoa. Microscopy detected 66 (67.3%) and failed to detect spermatozoa in 32 (32.7%) of Y-DNA positive samples. In addition to conventional invasive swab techniques, urine samples seem to be an effective biological trace collection method for Y DNA and spermatozoa within 24 h following penile-vaginal penetration. Furthermore, it may be considered as a non-invasive collection method in suspected acute child sexual abuse cases to diminish time delay in forensic evidence collection and to improve patients' positive attitudes towards evidence collection. PMID- 26580726 TI - Improved automation of dissolved organic carbon sampling for organic-rich surface waters. AB - In-situ UV-Vis spectrophotometers offer the potential for improved estimates of dissolved organic carbon (DOC) fluxes for organic-rich systems such as peatlands because they are able to sample and log DOC proxies automatically through time at low cost. In turn, this could enable improved total carbon budget estimates for peatlands. The ability of such instruments to accurately measure DOC depends on a number of factors, not least of which is how absorbance measurements relate to DOC and the environmental conditions. Here we test the ability of a S::can Spectro::lyserTM for measuring DOC in peatland streams with routinely high DOC concentrations. Through analysis of the spectral response data collected by the instrument we have been able to accurately measure DOC up to 66 mg L(-1), which is more than double the original upper calibration limit for this particular instrument. A linear regression modelling approach resulted in an accuracy >95%. The greatest accuracy was achieved when absorbance values for several different wavelengths were used at the same time in the model. However, an accuracy >90% was achieved using absorbance values for a single wavelength to predict DOC concentration. Our calculations indicated that, for organic-rich systems, in-situ measurement with a scanning spectrophotometer can improve fluvial DOC flux estimates by 6 to 8% compared with traditional sampling methods. Thus, our techniques pave the way for improved long-term carbon budget calculations from organic-rich systems such as peatlands. PMID- 26580727 TI - The association of annual air pollution exposure with blood pressure among patients with sleep-disordered breathing. AB - While sleep-disordered breathing (SDB), high blood pressure (BP) and air pollution exposure have separately been associated with increased risk of cardiopulmonary mortality, the association linking air pollution exposure to BP among patients with sleep-disordered breathing is still unclear. We collected 3762 participants' data from the Taipei Medical University Hospital's Sleep Center and air pollution data from the Taiwan Environmental Protection Administration. Associations of 1-year mean criteria air pollutants [particulate matter with aerodynamic diameters <=10 MUm (PM10), particulate matter with aerodynamic diameters <=2.5 MUm (PM2.5), nitrogen dioxide (NO2) and ozone (O3)] with systolic BP (SBP) and diastolic BP (DBP) were investigated by generalized additive models. After controlling for age, sex, body mass index (BMI), temperature and relative humidity, we observed that increases in air pollution levels were associated with decreased SBP and increased DBP. We also found that patients with apnea-hypopnea index (AHI) >=30 showed a stronger BP response to increased levels of air pollution exposure than those with AHI<30. Stronger effects of air pollution exposure on BP were found in overweight participants than in participants with normal BMI. We concluded that annual exposure to air pollution was associated with change of BP among patients with sleep-disordered breathing. The association between annual air pollution exposure and BP could be modified by AHI and BMI. PMID- 26580728 TI - Phosphite flux at the sediment-water interface in northern Lake Taihu. AB - Phosphite (H2PO3(-), HPO3(2-), +3 valence), a reduced form of phosphorus (P), has been widely detected in water environments. The role of phosphite in the P biogeochemical cycle has not been investigated systematically and quantitative results on phosphite fluxes are lacking. In this study, intact sediment core simulation was employed to measure the flux of phosphite at the sediment-water interface in northern Lake Taihu. Phosphite fluxes (MUmol m(-2) d(-1)) ranged from -38.21+/-1.14 to 7.10+/-2.18, with an annual average of -4.72+/-10.40. On the whole, phosphite migrated from water into sediment and the sediment was primarily a sink. The highest seasonal negative phosphite fluxes (MUmol m(-2) d( 1)) occurred in winter (-10.44+/-18.63), followed by summer (-8.04+/-5.61) and spring (-2.61+/-4.17). In autumn, phosphite flux was 2.20+/-4.07. Higher annual average negative fluxes of phosphite (MUmol m(-2) d(-1)) appeared in site ZSB ( 12.70+/-17.96), which contained the highest content of total soluble P. The average yearly migration of phosphite in Lake Taihu from water to sediment was estimated to be (4.04+/-8.88)*10(6) mol y(-1). The transfer of phosphite from water into sediment usually occurs in winter may due to the season's natural tendency to create more favorable conditions for phosphite biogeochemical reactions. Phosphite fluxes showed significant negative correlations with the original phosphite concentration in water (r=-0.840, p<0.01), as well as organic matter (r=-0.720, p<0.01) and phosphate bound to Ca (Ca-Ps) (r=-0.632, p<0.05) in sediment. These results indicate that microbiological processes and P species bound to Ca may play an important role in the P redox cycle. No significant correlations between phosphite fluxes and dissolved oxygen or oxidation-reduction potential were observed. PMID- 26580729 TI - The effect of ambient temperature on diabetes mortality in China: A multi-city time series study. AB - Few multi-city studies have been conducted to investigate the acute health effects of low and high temperatures on diabetes mortality worldwide. We aimed to examine effects of ambient temperatures on city-/gender-/age-/education-specific diabetes mortality in nine Chinese cities using a two-stage analysis. Distributed lag non-linear model was first applied to estimate the city-specific non-linear and delayed effects of temperatures on diabetes mortality. Pooled effects of temperatures on diabetes mortality were then obtained using meta-analysis, based on restricted maximum likelihood. We found that heat effects were generally acute and followed by a period of mortality displacement, while cold effects could last for over two weeks. The pooled relative risks of extreme high (99th percentile of temperature) and high temperature (90th percentile of temperature) were 1.29 (95%CI: 1.11-1.47) and 1.11 (1.03-1.19) over lag 0-21 days, compared with the 75th percentile of temperature. In contrast, the pooled relative risks over lag 0 21 days were 1.44 (1.25-1.66) for extreme low (1st percentile of temperature) and 1.20 (1.12-1.30) for low temperature (10th percentile of temperature), compared to 25th percentile of temperature. The estimate of heat effects was relatively higher among females than that among males, with opposite trend for cold effects, and the estimates of heat and cold effects were particularly higher among the elderly and those with low education, although the differences between these subgroups were not statistically significant (P>0.05). These findings have important public health implications for protecting diabetes patients from adverse ambient temperatures. PMID- 26580730 TI - Microbial transport into groundwater from irrigation: Comparison of two irrigation practices in New Zealand. AB - Rising demand on food is leading to an increase in irrigation worldwide to improve productivity. Irrigation, for pastoral agriculture (beef, dairy and sheep), is the largest consumptive use of water in New Zealand. There is a potential risk of leaching of microbial contaminants from faecal matter through the vadose zone into groundwater. Management of irrigation is vital for protection of groundwater from these microbial contaminants and maintain efficient irrigation practices. Our research investigated flood and spray irrigation, two practices common in New Zealand. The aim was to identify the risk of microbial transport and mitigation practices to reduce or eliminate the risk of microbial transport into groundwater. Cowpats were placed on lysimeters over a typical New Zealand soil (Lismore silt loam) and vadose zone and the leachate collected after irrigation events. Samples of both cowpats and leachate were analysed for the microbial indicator Escherichia coli and pathogen Campylobacter species. A key driver to the microbial transport derived from the model applied was the volume of leachate collected: doubling the leachate volume more than doubled the total recovery of E. coli. The persistence of E. coli in the cowpats during the experiment is an important factor as well as the initial environmental conditions, which were more favourable for survival and growth of E. coli during the spray irrigation compared with the flood irrigation. The results also suggest a reservoir of E. coli surviving in the soil. Although the same was potentially true for Campylobacter, little difference in the transport rates between irrigation practices could be seen due to the poor survival of Campylobacter during the experiment. Effective irrigation practices include monitoring the irrigation rates to minimise leachate production, delaying irrigation until 14days post-cowpat deposition and only irrigating when risk of transport to the groundwater is minimal. AIM: To compare the risk of microbial contamination of groundwater from cowpats using two irrigation practices onto pasture. PMID- 26580731 TI - Towards the standardization of nanoecotoxicity testing: Natural organic matter 'camouflages' the adverse effects of TiO2 and CeO2 nanoparticles on green microalgae. AB - In the last few years, the emission of CeO2 and TiO2 nanoparticles (NPs) into the environment has been raising concerns about their potential adverse effects on wildlife and human health. Aquatic organisms constitute one of the most important pathways for the entrance of these NPs and transfer throughout the food web, but divergences exist in the experimental data published on their aquatic toxicity. The pressing need for standardization of methods to analyze their ecotoxicity requires aquatic media representing realistic environmental conditions. The present study aimed to determine the usefulness of Suwannee River natural organic matter (SR-NOM) in the assessment of the agglomeration kinetics and ecotoxicity of CeO2 and TiO2 NPs towards green microalgae Pseudokirchneriella subcapitata. SR NOM alleviated the adverse effects of NPs on algal growth, completely in the case of TiO2 NPs and partially in the case of CeO2 NPs, suggesting a 'camouflage' of toxicity. This behavior has been observed also for other algal species and types of natural organic matter in the literature. Furthermore, SR-NOM markedly increased the stability of the NPs in algal medium, which led to a better reproducibility of the toxicity test results, and provided an electrophoretic mobility similar to that previously reported in various river and groundwaters. Thus, SR-NOM can be a representative sample of what is found in many different ecosystems, and the observed 'camouflage' of the effects of CeO2 and TiO2 NPs on algal cells might be considered as a natural interaction occurring in their standardized ecotoxicological assessment. PMID- 26580732 TI - Heavy metal enrichments in the Changjiang (Yangtze River) catchment and on the inner shelf of the East China Sea over the last 150 years. AB - Compositions of heavy metals including Cu, Zn, Cr and Pb in three sediment cores recovered from the lower basin of the Changjiang (Yangtze River) and the inner shelf mud of the East China Sea were analyzed by traditional X-ray florescence (XRF) and XRF Core Scanner. This study aims to investigate the accumulation of heavy metals in the fluvial sediments and to decipher the influence of anthropogenic activities within the large catchment over the last 150 years. The data suggest that the heavy metals, especially Pb and Zn, show obvious enrichments in concentrations since 1950s, and the small and consistent variations of heavy metal concentrations before 1950s can represent geochemical background values. After removing the grain size effect on elemental concentrations, we infer that the sources of heavy metals predominantly come from natural weathering detritus, while human contamination has increased over the last half century. The calculations of both enrichment factor and geoaccumulation index, however, indicate that the pollution of these heavy metals in the fluvial and shelf environments is not significant. The rapid increase in human activities and fast socioeconomic development in the Changjiang catchment and East China over the last five decades accounts for the enrichments of heavy metals in the river and marine sediments. The inner shelf of the East China Sea, as the major sink of the Changjiang-derived fine sediments, provides a high-resolution sediment archive for tracing the anthropogenic impacts on the catchment. PMID- 26580733 TI - Assessment of the environmental fate of cycloxaprid in flooded and anaerobic soils by radioisotopic tracing. AB - Cycloxaprid (CYC) is a novel broad-spectrum neonicotinoid insecticide that has been developed for agricultural pest control. The fate of the (14)C-labeled racemic and enantio-pure CYC isomers in flooded and anaerobic soil was investigated using radioisotope tracing techniques. After 100 d of incubation, only a minor portion (<1%) of the applied CYC isomers is mineralized by each of the four tested soil types. The fraction of initially applied radioactive CYC dissipated into the bound or non-extractable residues (BR) increases with increase in the length of the incubation period, reaching up to 53.0-81.6%. The dissipation of the CYC through mineralization or formation of BR is strongly influenced by soil properties, such as humic content, pH value, and retained microbial activity. Amongst the soils studied, the fluvio-marine yellow loamy soil displayed the highest tendency to mineralize CYC while the coastal saline soil exhibited the strongest tendency to form BR. The observation that the water phase retained the large portion(>60%) of the radioactivity attributed to the total extractable residue suggested that under the experimental condition, the initially applied (14)C-labeled CYC residues were readily available for leaching or offsite transport. Additionally, no enantiomer-specific behaviors are observed. The results from this study provide a framework for assessing the environmental impact resulting from the use of this pesticide. PMID- 26580734 TI - Benthic macroinvertebrates in lake ecological assessment: A review of methods, intercalibration and practical recommendations. AB - Legislation in Europe has been adopted to determine and improve the ecological integrity of inland and coastal waters. Assessment is based on four biotic groups, including benthic macroinvertebrate communities. For lakes, benthic invertebrates have been recognized as one of the most difficult organism groups to use in ecological assessment, and hitherto their use in ecological assessment has been limited. In this study, we review and intercalibrate 13 benthic invertebrate-based tools across Europe. These assessment tools address different human impacts: acidification (3 methods), eutrophication (3 methods), morphological alterations (2 methods), and a combination of the last two (5 methods). For intercalibration, the methods were grouped into four intercalibration groups, according to the habitat sampled and putative pressure. Boundaries of the 'good ecological status' were compared and harmonized using direct or indirect comparison approaches. To enable indirect comparison of the methods, three common pressure indices and two common biological multimetric indices were developed for larger geographical areas. Additionally, we identified the best-performing methods based on their responsiveness to different human impacts. Based on these experiences, we provide practical recommendations for the development and harmonization of benthic invertebrate assessment methods in lakes and similar habitats. PMID- 26580735 TI - Micro-computed tomography (MUCT) as a novel method in ecotoxicology- determination of morphometric and somatic data in rainbow trout (Oncorhynchus mykiss). AB - Fish are important sentinel organisms for the assessment of water quality and play a central role in ecotoxicological research. Of particular importance to the assessment of health and fitness of fish stocks in response to environmental conditions or pollution are morphometric (e.g. Fulton's condition index) and somatic indices (e.g. hepatosomatic, and gonadosomatic index). Standard measurements of somatic indices are invasive and require, by definition, the sacrifice of examined animals, thus prohibiting longitudinal studies and relocation of animals captured in the field. As a potential solution, in the present study, we propose the use of micro-computed tomography (MUCT) as imaging modality to non-invasively tomographically image rainbow trout (Oncorhynchus mykiss) exposed to different sediment suspensions. We here demonstrate that MUCT can be used as a tool to reliably measure the volumes of different organs, which could then be applied as a substitute of their weights in calculation of somatic indices. To the best of our knowledge, this study is the first to report the results of MUCT analyses in the context of ecotoxicological research in rainbow trout. It has the potential to greatly increase the information value of experiments conducted with fish and also to potentially reduce the number of animals required for studying temporal effects through facilitating longitudinal studies within the same individuals. PMID- 26580736 TI - Assessing bisphenol A (BPA) exposure risk from long-term dietary intakes in Taiwan. AB - Dietary intake is the major bisphenol A (BPA) exposure route in humans, and is a cause of BPA-related adverse effects. The large-scale exposure risk of humans to BPA through dietary sources in Taiwan is less well studied. The aim of this study was to assess the average daily dose (ADD) and hazardous quotient (HQ) of BPA exposure risk from long-term dietary intake of BPA, as well as BPA concentrations in different age-sex groups in Taiwan. We reanalyzed the BPA concentrations of regular daily food sources (rice, poultry, livestock, seafood, protein, fruits, and vegetables) and used a national dietary survey to estimate the contribution of variance to ADDs and potential human health effect for different age-sex groups. This study found that the daily consumption of chicken, pork/beef, and seafood were estimated to be 33.77 (Male)/22.65 (Female), 91.70 (M)/66.35 (F), and 54.15 (M)/40.78 (F) g/day, respectively. The highest BPA ADD was found in the 6-9 years age group (95% CI=0.0006-0.0027 mg/kg-bw/day), whereas the lowest BPA ADD was in the >=65 years age group (0.0002-0.0020 mg/kg-bw/day). Based on the latest EFSA guidelines (0.004 mg/kg-bw/day), the 97.5 percentile HQ of BPA intake in different age-sex groups in Taiwan posed no risks through dietary intake. However, a combination of multiple exposure routes and long-term exposure in specific populations may be of concern in the future. PMID- 26580737 TI - Toxicological and chemical assessment of arsenic-contaminated groundwater after electrochemical and advanced oxidation treatments. AB - Owing to its proven toxicity and mutagenicity, arsenic is regarded a principal pollutant in water used for drinking. The objective of this study was the toxicological and chemical evaluation of groundwater samples obtained from arsenic enriched drinking water wells before and after electrochemical and ozone UV-H2O2-based advanced oxidation processes (EAOP). For this purpose, acute toxicity test with Daphnia magna and chronic toxicity test with Lemna minor L. were employed as well as in vitro bioassays using human peripheral blood lymphocytes (HPBLs). Several oxidative stress parameters were estimated in L.minor. Physicochemical analysis showed that EAOP treatment was highly efficient in arsenic but also in ammonia and organic compound removal from contaminated groundwater. Untreated groundwater caused only slight toxicity to HPBLs and D. magna in acute experiments. However, 7-day exposure of L. minor to raw groundwater elicited genotoxicity, a significant growth inhibition and oxidative stress injury. The observed genotoxicity and toxicity of raw groundwater samples was almost completely eliminated by EAOP treatment. Generally, the results obtained with L. minor were in agreement with those obtained in the chemical analysis suggesting the sensitivity of the model organism in monitoring of arsenic-contaminated groundwater. In parallel to chemical analysis, the implementation of chronic toxicity bioassays in a battery is recommended in the assessment of the toxic and genotoxic potential of such complex mixtures. PMID- 26580738 TI - Glyphosate effects on soil rhizosphere-associated bacterial communities. AB - Glyphosate is one of the most widely used herbicides in agriculture with predictions that 1.35 million metric tons will be used annually by 2017. With the advent of glyphosate tolerant (GT) cropping more than 10 years ago, there is now concern for non-target effects on soil microbial communities that has potential to negatively affect soil functions, plant health, and crop productivity. Although extensive research has been done on short-term response to glyphosate, relatively little information is available on long-term effects. Therefore, the overall objective was to investigate shifts in the rhizosphere bacterial community following long-term glyphosate application on GT corn and soybean in the greenhouse. In this study, rhizosphere soil was sampled from rhizoboxes following 4 growth periods, and bacterial community composition was compared between glyphosate treated and untreated rhizospheres using next-generation barcoded sequencing. In the presence or absence of glyphosate, corn and soybean rhizospheres were dominated by members of the phyla Proteobacteria, Acidobacteria, and Actinobacteria. Proteobacteria (particularly gammaproteobacteria) increased in relative abundance for both crops following glyphosate exposure, and the relative abundance of Acidobacteria decreased in response to glyphosate exposure. Given that some members of the Acidobacteria are involved in biogeochemical processes, a decrease in their abundance could lead to significant changes in nutrient status of the rhizosphere. Our results also highlight the need for applying culture-independent approaches in studying the effects of pesticides on the soil and rhizosphere microbial community. PMID- 26580739 TI - Potential utilization for the evaluation of particulate and gaseous pollutants at an urban site near a major highway. AB - Works of particle number and mass concentration variability have a great importance since they may indicate better the influence of vehicle emissions in an urban region. Moreover, the importance of this work lies in the fact that there are few studies in Brazil, where the fuel used has unique characteristics. Consequently, this paper presents measurements of particle number (size range 0.3 10 MUm), particle mass (PM10, PM2.5, PM1), O3 and NOx (NO, NO2), in a site near a major highway at the Metropolitan Area of Porto Alegre, south Brazil. Measurements were carried out during two years: 2012 and 2013. Particle number and mass concentrations were measured using an optical counter with a PM10 analyzer. Results showed that concentrations of N0.3-1 (0.3-1 MUm) were the highest, although similar to N1-2.5 (1-2.5 MUm). Daily variability of the analyzed pollutants followed the traffic pattern. Moreover, NO2, O3, and particle number were higher during the day, whereas NO, NOx, and particle matter showed higher concentrations during nighttime. Traffic influence was evidenced by the mean concentrations of weekends and weekdays, being higher for the latter. Correlation of particles and gases with meteorological variables, together with the application of PCA confirmed the influence of vehicle exhaust discharges. PMID- 26580740 TI - Characterization and quantification of suspended sediment sources to the Manawatu River, New Zealand. AB - Knowledge of sediment movement throughout a catchment environment is essential due to its influence on the character and form of our landscape relating to agricultural productivity and ecological health. Sediment fingerprinting is a well-used tool for evaluating sediment sources within a fluvial catchment but still faces areas of uncertainty for applications to large catchments that have a complex arrangement of sources. Sediment fingerprinting was applied to the Manawatu River Catchment to differentiate 8 geological and geomorphological sources. The source categories were Mudstone, Hill Subsurface, Hill Surface, Channel Bank, Mountain Range, Gravel Terrace, Loess and Limestone. Geochemical analysis was conducted using XRF and LA-ICP-MS. Geochemical concentrations were analysed using Discriminant Function Analysis and sediment un-mixing models. Two mixing models were used in conjunction with GRG non-linear and Evolutionary optimization methods for comparison. Discriminant Function Analysis required 16 variables to correctly classify 92.6% of sediment sources. Geological explanations were achieved for some of the variables selected, although there is a need for mineralogical information to confirm causes for the geochemical signatures. Consistent source estimates were achieved between models with optimization techniques providing globally optimal solutions for sediment quantification. Sediment sources was attributed primarily to Mudstone, ~38-46%; followed by the Mountain Range, ~15-18%; Hill Surface, ~12-16%; Hill Subsurface, ~9-11%; Loess, ~9-15%; Gravel Terrace, ~0-4%; Channel Bank, ~0-5%; and Limestone, ~0%. Sediment source apportionment fits with the conceptual understanding of the catchment which has recognized soft sedimentary mudstone to be highly susceptible to erosion. Inference of the processes responsible for sediment generation can be made for processes where there is a clear relationship with the geomorphology, but is problematic for processes which occur within multiple terrains. PMID- 26580741 TI - Mercury levels assessment and its relationship with oxidative stress biomarkers in children from three localities in Yucatan, Mexico. AB - Mercury (Hg) is a global pollutant that is released into the environment from geologic and anthropogenic sources. Once it enters an organism, it generates several toxicity mechanisms and oxidative stress has been proposed as the main one. Metal susceptibility is greater in children, which is a result of their physiology and behavior. In Yucatan, Mexico, burning of unregulated garbage dumps and household trash, ingestion of top marine predators, and pottery manufacturing are among the conditions that could promote Hg exposure. However, for Yucatan, there are no published studies that report Hg levels and associated oxidative stress status in children. Therefore, this study aimed to assess Hg levels in blood and urine and oxidative stress biomarkers levels in a sample of 107 healthy children from three localities in Yucatan, Mexico, as well as investigate the relationship between these parameters. Hg was detected in 11 (10.28%) of blood samples and 38 (35.51%) of urine samples collected from the participating children. Fourteen subjects showed Hg above recommended levels. The oxidative stress biomarkers were slightly elevated in comparison with other studies and were statistically different between the sampling sites. No linear correlation between Hg levels and oxidative stress biomarkers was found. Nevertheless, exploratory univariate and multivariate analysis showed non-linear relations among the measured variables. Globally, the study provides, for the first time, information regarding Hg levels and their relationship with oxidative stress biomarkers in a juvenile population from Mexico's southeast (Yucatan) region. In agreement with worldwide concern about Hg, this study should stimulate studies on metal monitoring in humans (especially children) among scientists working in Mexico, the establishment of polices for its regulation, and the reduction of human health risks. PMID- 26580743 TI - The effect of gamma-tACS on working memory performance in healthy controls. AB - Transcranial Direct Current Stimulation (tDCS) has been widely investigated for its potential to enhance cognition, and in particular working memory, however to date standard approaches to stimulation have shown only modest effects. Alternative, more specialised, forms of current delivery may be better suited to cognitive enhancement. One such method is transcranial Alternating Current Stimulation (tACS) which delivers stimulation at a specific frequency and has been shown to entrain endogenous cortical oscillations which underlie cognitive functioning. To date there has been no comparison of the effects of tACS to those of tDCS on cognitive enhancement. In a randomised repeated-measures study design we assessed the effect of gamma (gamma)-tACS, tDCS and sham tDCS on working memory in 18 healthy participants who attended three sessions held at least 72h apart. Pre- and post-stimulation working memory performance was assessed using the 2 and 3-back. Our findings indicated the presence of a selective improvement in performance on the 3-back task following gamma-tACS compared with tDCS and sham stimulation. The current findings provide support for further and more detailed investigation of the role of gamma-tACS as a more specialised approach to neuromodulation. PMID- 26580744 TI - Effects of Repetitive Transcranial Magnetic Stimulation in the Rehabilitation of Communication and Deglutition Disorders: Systematic Review of Randomized Controlled Trials. AB - OBJECTIVE: To systematically review randomized controlled trials that evaluate the effects of repetitive transcranial magnetic stimulation (rTMS) on rehabilitation aspects related to communication and swallowing functions. METHODS: A search was conducted on PubMed, Clinical Trials, Cochrane Library, and ASHA electronic databases. Studies were judged according to the eligibility criteria and analyzed by 2 independent and blinded researchers. RESULTS: We analyzed 9 studies: 4 about aphasia, 3 about dysphagia, 1 about dysarthria in Parkinson's disease and 1 about linguistic deficits in Alzheimer's disease. All aphasia studies used low-frequency rTMS to stimulate Broca's homologous area. High-frequency rTMS was applied over the pharyngoesophageal cortex from the left and/or right hemisphere in the dysphagia studies and over the left dorsolateral prefrontal cortex in the Parkinson's and Alzheimer's studies. Two aphasia and all dysphagia studies showed a significant improvement of the disorder, compared to the sham group. The other 2 studies related to aphasia found a benefit restricted to subgroups with a severe case or injury on the anterior portion of the language cortical area, respectively, whereas the Alzheimer's study demonstrated positive effects specific to auditory comprehension. There were no changes for vocal function in the Parkinson's study. CONCLUSION: The benefits of the technique and its applicability in neurogenic disorders related to communication and deglutition are still uncertain. Therefore, other randomized controlled trials are needed to clarify the optimal stimulation protocol for each disorder studied and its real effects. PMID- 26580745 TI - Rapid Sampling of Folding Equilibria of beta-Peptides in Methanol Using a Supramolecular Solvent Model. AB - Molecular dynamics simulation of biomolecules in solvent using an atomic model for both the biomolecules and the solvent molecules is still computationally rather demanding considering the time scale of the biomolecular motions. The use of a supramolecular coarse-grained (CG) model can speed up the simulation considerably, but it also reduces the accuracy inevitably. Combining an atomic fine-grained (FG) level of modeling for the biomolecules and a supramolecular CG level for the solvent into a hybrid system, the increased computational efficiency may outweigh the loss of accuracy with respect to the biomolecular properties in the hybrid FG/CG simulation. Here, a previously published CG methanol model is reparametrized, and then a 1:1 mixture of FG and CG methanol is used to calibrate the FG-CG interactions using thermodynamic and dielectric screening data for liquid methanol. The FG-CG interaction parameter set is applied in hybrid FG/CG solute/solvent simulations of the folding equilibria of three beta-peptides that adopt different folds. The properties of the peptides are compared with those obtained in FG solvent simulations and with experimental NMR data. The comparison shows that the folding equilibria in the pure CG solvent simulations are different from those in the FG solvent simulations because of the lack of hydrogen-bonding partners in the supramolecular CG solvent. Next, we introduced an FG methanol layer around the peptides in CG solvent to recover the hydrogen-bonding pattern of the FG solvent simulations. The result shows that with the FG methanol layer, the folding equilibria of the three beta-peptides are very similar to those in the FG solvent simulations, while the computational efficiency is at least 3 times higher and the cutoff radius for nonbonded interactions could be increased from 1.4 to 2.0 nm. PMID- 26580742 TI - Interspecific differences in growth response and tolerance to the antibiotic sulfadiazine in ten clonal wetland plants in South China. AB - Pollution caused by residual antibiotics is a worldwide environmental issue. Antibiotic residues often occur in aquatic ecosystems, posing threats to the health of aquatic organisms. The effects of antibiotic residues on the growth of crop plants and on human health are reasonably well known. However, less is known about antibiotic effects on wetland plants. Therefore, we studied the response and tolerance of ten clonal wetland plants grown in soil spiked with sulfadiazine at 10 mg kg(-1) (an environmentally relevant concentration) and 100 mg kg(-1). At 10 mg kg(-1), ramet number was the least affected trait, while root number was the most affected among plant species. Plant shoot and total biomass were reduced in all species except in Cyperus malaccensis var. brevifolius and Panicum repens. Chlorophyll content was reduced in Alocasia macrorrhiza, Saururus chinensis, and Commelina diffusa. In general, Panicum paludosum and C. malaccensis var. brevifolius showed the least reduction of growth parameters, whereas growth of both A. macrorrhiza and S. chinensis was severely reduced. At 100 mg kg(-1), negative responses occurred in all species. Comprehensive tolerance analysis revealed that P. paludosum and C. malaccensis var. brevifolius were the species most resistant to sulfadiazine. These species are potential candidates for sulfadiazine polluted wetland restoration. A. macrorrhiza and S. chinensis were the most susceptible species and they should be protected from sulfadiazine pollution. Relative plant shoot biomass and height were the most useful indicators for evaluating plant tolerance to sulfadiazine. Plant tolerance to sulfadiazine was associated with the differences of plants in height and shoot biomass. PMID- 26580746 TI - Mechanism of Folding and Binding of an Intrinsically Disordered Protein As Revealed by ab Initio Simulations. AB - A complex of the phosphorylated kinase-inducible domain (pKID) with its interacting domain (KIX) is a model system for studies of mechanisms by which intrinsically unfolded proteins perform their functions. These mechanisms are not fully understood. Using an efficient coarse-grained model, ab initio simulations were performed of the coupled folding and binding of the pKID to the KIX. The simulations start from an unbound, randomly positioned and disordered pKID structure. During the simulations the pKID chain and its position remain completely unrestricted, while the KIX backbone is limited to near-native fluctuations. Ab initio simulations of such large-scale conformational transitions, unaffected by any knowledge about the bound pKID structure, remain inaccessible to classical simulations. Our simulations recover an ensemble of transient encounter complexes in good agreement with experimental results. We find that a key folding and binding step is linked to the formation of weak native interactions between a preformed nativelike fragment of a pKID helix and KIX surface. Once that nucleus forms, the pKID chain may condense from a largely disordered encounter ensemble to a natively bound and ordered conformation. The observed mechanism is reminiscent of a nucleation-condensation model, a common scenario for folding of globular proteins. PMID- 26580747 TI - The MoSGrid Science Gateway - A Complete Solution for Molecular Simulations. AB - The MoSGrid portal offers an approach to carry out high-quality molecular simulations on distributed compute infrastructures to scientists with all kinds of background and experience levels. A user-friendly Web interface guarantees the ease-of-use of modern chemical simulation applications well established in the field. The usage of well-defined workflows annotated with metadata largely improves the reproducibility of simulations in the sense of good lab practice. The MoSGrid science gateway supports applications in the domains quantum chemistry (QC), molecular dynamics (MD), and docking. This paper presents the open-source MoSGrid architecture as well as lessons learned from its design. PMID- 26580748 TI - Mechanism of the All-alpha to All-beta Conformational Transition of RfaH-CTD: Molecular Dynamics Simulation and Markov State Model. AB - The C-terminal domain of the bacterial transcription antiterminator RfaH undergoes a dramatic all-alpha-helix to all-beta-barrel transition when released from its N-terminal domain. These two distinct folding patterns correspond to different functions: the all-alpha state acts as an essential regulator of transcription to ensure RNA polymerase binding, whereas the all-beta state operates as an activator of translation by interacting with the ribosomal protein S10 and recruits ribosomal mRNA. Accordingly, this drastic conformational change enables RfaH to physically couple the transcription and translation processes in gene expression. To understand the mechanism behind this extraordinary functionally relevant structural transition, we constructed Markov state models using an adaptive seeding method. The constructed models highlight several parallel folding pathways with heterogeneous molecular mechanisms, which reveal the folding kinetics and atomic details of the conformational transition. PMID- 26580749 TI - Vibrational Properties of Hydrogen-Bonded Systems Using the Multireference Generalization to the "On-the-Fly" Electronic Structure within Quantum Wavepacket ab Initio Molecular Dynamics (QWAIMD). AB - We discuss a multiconfigurational treatment of the "on-the-fly" electronic structure within the quantum wavepacket ab initio molecular dynamics (QWAIMD) method for coupled treatment of quantum nuclear effects with electronic structural effects. Here, multiple single-particle electronic density matrices are simultaneously propagated with a quantum nuclear wavepacket and other classical nuclear degrees of freedom. The multiple density matrices are coupled through a nonorthogonal configuration interaction (NOCI) procedure to construct the instantaneous potential surface. An adaptive-mesh-guided set of basis functions composed of Gaussian primitives are used to simplify the electronic structure calculations. Specifically, with the replacement of the atom-centered basis functions positioned on the centers of the quantum-mechanically treated nuclei by a mesh-guided band of basis functions, the two-electron integrals used to compute the electronic structure potential surface become independent of the quantum nuclear variable and hence reusable along the entire Cartesian grid representing the quantum nuclear coordinates. This reduces the computational complexity involved in obtaining a potential surface and facilitates the interpretation of the individual density matrices as representative diabatic states. The parametric nuclear position dependence of the diabatic states is evaluated at the initial time-step using a Shannon-entropy-based sampling function that depends on an approximation to the quantum nuclear wavepacket and the potential surface. This development is meant as a precursor to an on-the-fly fully multireference electronic structure procedure embedded, on-the-fly, within a quantum nuclear dynamics formalism. We benchmark the current development by computing structural, dynamic, and spectroscopic features for a series of bihalide hydrogen-bonded systems: FHF(-), ClHCl(-), BrHBr(-), and BrHCl(-). We find that the donor-acceptor structural features are in good agreement with experiments. Spectroscopic features are computed using a unified velocity/flux autocorrelation function and include vibrational fundamentals and combination bands. These agree well with experiments and other theories. PMID- 26580750 TI - What Dominates the Error in the CaO Diatomic Bond Energy Predicted by Various Approximate Exchange-Correlation Functionals? AB - In order to understand what governs the accuracy of approximate exchange correlation functionals for intrinsically multiconfigurational systems containing metal atoms, the properties of the ground electronic state of CaO have been studied in detail. We first applied the T1, TAE(T), B1, and M diagnostics to CaO and confirmed that CaO is an intrinsically multiconfigurational system. Then, we compared the bond dissociation energies (BDEs) of CaO as calculated by 49 exchange-correlation functionals, three exchange-only functionals, and the HF method. To analyze the error in the BDEs for the various functionals, we decomposed each calculated BDE into four components, in particular the ionization potential, the electron affinity, the atomic excitation energy of the metal cation to prepare the valence state, and the interaction energy between prepared states. We found that the dominant error occurs in the calculated atomic excitation energy of the cation. Third, we compared dipole moments of CaO as calculated by the 53 methods, and we analyzed the dipole moments in terms of partial atomic charges to understand the contribution of ionic bonding and how it is affected by errors in the calculated ionization potential of the metal atom. We then analyzed the dipole moment in terms of the charge distribution among orbitals, and we found that the orbital charge distribution does not correlate well with the difference between the calculated ionization potential and electron affinity. Fourth, we examined the potential curves and internuclear distance dependence of the orbital energies of the lowest-energy CaO singlet and triplet states to analyze the near-degeneracy aspect of the correlation energy. The most important conclusion is that the error tends to be dominated by the error in the relative energies of s and d orbitals in Ca(+), and the most popular density functionals predict this excitation energy poorly. Thus, even if they were to predict the BDE reasonably well, it would be due to cancellation of errors. The effect of the cation excitation energy can be understood in terms of an orbital picture, as follows. For most functionals the predicted cation excitation energy is too small, so it is too easy to delocalize charge from the oxygen 2p orbital to the Ca(+) d orbital; this overestimates the covalency and explains why most functionals overestimate the bond energy. PMID- 26580751 TI - Spin-State Energetics of Heme-Related Models from DFT and Coupled Cluster Calculations. AB - Spin-state energetics of metalloporphyrins and heme groups is elucidated by performing high-level coupled cluster calculations for their simplified mimics. An efficient computational protocol is proposed-based on the mix of extrapolation to complete basis set and explicitly correlated (F12) methodology-which retains the high accuracy of the CCSD(T) method at a cost that makes it applicable also to relatively large models, e.g., FeP and FeP(Cl) (P = porphin). Adequacy of CCSD(T) is supported by analysis of multireference character and comparison with the completely renormalized CR-CC(2,3) method. The high-level coupled cluster results are used for assessment of density functional theory (DFT) methods, for which an accurate description of the spin-state energetics is recognized as a major challenge. Although the DFT results are highly functional-dependent, it is shown that the spin-state energetics of a full heme model and its simplified mimic remain in a good linear correlation. This makes it possible to estimate the spin-state energetics of full heme models based on the accurate CCSD(T) results for their mimics, as illustrated for porphyrin complexes of Fe(II), Mn(II), and Co(II); pentacoordinate heme complexes of Fe(II) and Fe(III); and a ferryl heme model. Comparison with the available experimental data is also presented. PMID- 26580752 TI - Description of Polar Chemical Bonds from the Quantum Mechanical Interference Perspective. AB - The Generalized Product Function Energy Partitioning (GPF-EP) method has been applied to a set of molecules, AH (A = Li, Be, B, C, N, O, F), CO and LiF with quite different dipole moments, in order to investigate the role played by the quantum interference effect in the formation of polar chemical bonds. The calculations were carried out with GPF wave functions treating all the core electrons as a single Hartree-Fock group and the bonding electrons at the Generalized Valence Bond Perfect-Pairing (GVB-PP) level, with the cc-pVTZ basis set. The results of the energy partitioning into interference and quasi-classical contributions along the respective Potential Energy Surfaces (PES) show that the main contribution to the depth of the potential wells comes from the interference term, which is an indication that all the molecules mentioned above form typical covalent bonds. In all cases, the stabilization promoted by the interference term comes from the kinetic contribution, in agreement with previous results. The analysis of the effect of quantum interference on the electron density reveals that while polarization effects (quasi-classical) tend to displace electronic density from the most polarizable atom toward the less polarizable one, interference (quantum effects) counteracts by displacing electronic density to the bond region, giving rise to the right electronic density and dipole moment. PMID- 26580753 TI - Reliability of Density Functional and Perturbation Theories for Calculating Core Ionization Spectra of Free Radicals. AB - The C 1s, N 1s, and O 1s ionization energies were calculated for the three stable nitroxide free radicals, viz., tempo and its two analogues, and compared to their most recent high-resolution core photoelectron spectra. We compare the performance of unrestricted and restricted open shell based DeltaHF, DeltaMP2, and DeltaB3LYP methods. A mixed basis set is employed in all cases, which consists of the core-valence correlation-consistent triple-zeta basis set (cc pCVTZ or cc-pwCVTZ) on the atom whose core-electron binding energy is calculated, model core potentials on the remaining first row atoms, and the cc-pVDZ basis set on the hydrogen atoms. The best overall performance for the three free radicals is offered by the restricted open shell based DeltaB3LYP method. Surprisingly, both the restricted open and unrestricted second-order perturbation theories perform relatively poorly and typically do not warrant additional computational effort over the reference DeltaHF methods. This is particularly true of the DeltaZAPT method, which exhibits a number of grave failures that render it unsuitable for calculating the core-ionization spectra. PMID- 26580754 TI - A Sparse Self-Consistent Field Algorithm and Its Parallel Implementation: Application to Density-Functional-Based Tight Binding. AB - We present an algorithm and its parallel implementation for solving a self consistent problem as encountered in Hartree-Fock or density functional theory. The algorithm takes advantage of the sparsity of matrices through the use of local molecular orbitals. The implementation allows one to exploit efficiently modern symmetric multiprocessing (SMP) computer architectures. As a first application, the algorithm is used within the density-functional-based tight binding method, for which most of the computational time is spent in the linear algebra routines (diagonalization of the Fock/Kohn-Sham matrix). We show that with this algorithm (i) single point calculations on very large systems (millions of atoms) can be performed on large SMP machines, (ii) calculations involving intermediate size systems (1000-100 000 atoms) are also strongly accelerated and can run efficiently on standard servers, and (iii) the error on the total energy due to the use of a cutoff in the molecular orbital coefficients can be controlled such that it remains smaller than the SCF convergence criterion. PMID- 26580755 TI - Quantum Monte Carlo Benchmark of Exchange-Correlation Functionals for Bulk Water. AB - The accurate description of the thermodynamic and dynamical properties of liquid water from first-principles is a very important challenge to the theoretical community. This represents not only a critical test of the predictive capabilities of first-principles methods, but it will also shed light into the microscopic properties of such an important substance. Density Functional Theory, the main workhorse in the field of first-principles methods, has been so far unable to properly describe water and its unusual properties in the liquid state. With the recent introduction of exact exchange and an improved description of dispersion interaction, the possibility of an accurate description of the liquid is finally within reach. Unfortunately, there is still no way to systematically improve exchange-correlation functionals, and the number of available functionals is very large. In this article we use highly accurate quantum Monte Carlo calculations to benchmark a selection of exchange-correlation functionals typically used in Density Functional Theory simulations of bulk water. This allows us to test the predictive capabilities of these functionals in water, giving us a way to choose optimal functionals for first-principles simulations. We compare and contrast the importance of different features of functionals, including the hybrid component, the vdW component, and their importance within different aspects of the PES. In addition, in order to correct the inaccuracies in the description of short-range interactions in the liquid, we test a recently introduced scheme that combines Density Functional Theory with Coupled Cluster calculations through a Many-Body expansion of the energy. PMID- 26580756 TI - Symbolic Algebra Development for Higher-Order Electron Propagator Formulation and Implementation. AB - Through the use of symbolic algebra, implemented in a program, the algebraic expression of the elements of the self-energy matrix for the electron propagator to different orders were obtained. In addition, a module for the software package Lowdin was automatically generated. Second- and third-order electron propagator results have been calculated to test the correct operation of the program. It was found that the Fortran 90 modules obtained automatically with our algorithm succeeded in calculating ionization energies with the second- and third-order electron propagator in the diagonal approximation. The strategy for the development of this symbolic algebra program is described in detail. This represents a solid starting point for the automatic derivation and implementation of higher-order electron propagator methods. PMID- 26580757 TI - Orbital-Optimized Second-Order Perturbation Theory with Density-Fitting and Cholesky Decomposition Approximations: An Efficient Implementation. AB - An efficient implementation of the orbital-optimized second-order perturbation theory with the density-fitting (DF-OMP2) and Cholesky decomposition (CD-OMP2) approaches is presented. The DF-OMP2 method is applied to a set of alkanes, conjugated dienes, and noncovalent interaction complexes to compare the computational cost with the conventional orbital-optimized MP2 (OMP2) [Bozkaya, U.; Turney, J. M.; Yamaguchi, Y.; Schaefer, H. F.; Sherrill, C. D. J. Chem. Phys. 2011, 135, 104103] and the orbital-optimized MP2 with the resolution of the identity approach (OO-RI-MP2) [Neese, F.; Schwabe, T.; Kossmann, S.; Schirmer, B.; Grimme, S. J. Chem. Theory Comput. 2009, 5, 3060-3073]. Our results demonstrate that the DF-OMP2 method provides substantially lower computational costs than OMP2 and OO-RI-MP2. Further application results show that the orbital optimized methods are very beneficial for the computation of open-shell noncovalent interactions. Considering both computational efficiency and the accuracy of the DF-OMP2 method, we conclude that DF-OMP2 is very promising for the study of weak interactions in open-shell molecular systems. PMID- 26580758 TI - Theoretical Study of the Local and Charge-Transfer Excitations in Model Complexes of Pentacene-C60 Using Tuned Range-Separated Hybrid Functionals. AB - The characteristics of the electronic excited states and the charge-transfer processes at organic-organic interfaces play an important role in organic electronic devices. However, charge-transfer excitations have proven challenging to describe with conventional density functional theory (DFT) methodologies due to the local nature of the exchange-correlation potentials often employed. Here, we examine the excited states of model pentacene-C60 complexes using time dependent DFT with, on one hand, one of the most popular standard hybrid functionals (B3LYP) and, on the other hand, several long-range corrected hybrid functionals for which we consider both default and nonempirically tuned range separation parameters. The DFT results based on the tuned functionals are found to agree well with the available experimental data. The results also underline that the interface geometry of the complex has a strong effect on the energies and ordering of the singlet and triplet charge-transfer states. PMID- 26580759 TI - Benchmark Study of Density Cumulant Functional Theory: Thermochemistry and Kinetics. AB - We present an extensive benchmark study of density cumulant functional theory (DCFT) for thermochemistry and kinetics of closed- and open-shell molecules. The performance of DCFT methods (DC-06, DC-12, ODC-06, and ODC-12) is compared to that of coupled-electron pair methods (CEPA0 and OCEPA0) and coupled-cluster theory (CCSD and CCSD(T)) for the description of noncovalent interactions (A24 database), barrier heights of hydrogen-transfer reactions (HTBH38), radical stabilization energies (RSE30), adiabatic ionization energies (AIE), and covalent bond stretching in diatomic molecules. Our results indicate that out of four DCFT methods the ODC-12 method is the most reliable and accurate DCFT formulation to date. Compared to CCSD, ODC-12 shows superior results for all benchmark tests employed in our study. With respect to coupled-pair theories, ODC-12 outperforms CEPA0 and shows similar accuracy to the orbital-optimized CEPA0 variant (OCEPA0) for systems at equilibrium geometries. For covalent bond stretching, ODC-12 is found to be more reliable than OCEPA0. For the RSE30 and AIE data sets, ODC-12 shows competitive performance with CCSD(T). In addition to benchmark results, we report new reference values for the RSE30 data set computed using coupled cluster theory with up to perturbative quadruple excitations. PMID- 26580760 TI - Explanation of the Source of Very Large Errors in Many Exchange-Correlation Functionals for Vanadium Dimer. AB - Vanadium dimer is a notoriously difficult case for Kohn-Sham (KS) density functional theory with currently available approximations to the exchange correlation (xc) functionals, and many approximate xc functionals yield an exceedingly large error in the calculated bond energy. In this paper, we first test the bond energies estimated by 43 xc functionals and the Hartree-Fock (HF) method. The results further confirm the large errors and show that, with the experimental bond energy being 64.2 kcal/mol, the KS calculations give predictions all over the map with errors ranging from -61.5 to +60.5 kcal/mol, and the HF method performs much worse with an error of -124.4 kcal/mol! The reason for these very large errors is examined in this article by analyzing the atomic and molecular orbital energies calculated by various xc functionals. The results show that the errors in estimates of the bond energy of vanadium dimer can primarily be related to the calculated energy gap between the 4s and 3dz2 atomic orbitals of the vanadium atom and especially to the 3dz2 orbital energy. This interesting relation between the errors in the calculated bond energy and the magnitudes of the single-particle orbital energies provides a constructive alternative to the common but more sterile explanation that it is the static correlation energy due to multicenter left-right correlation that makes the vanadium dimer and many other transition metal compounds so difficult for Kohn Sham calculations. One of the most important factors in determining the critical atomic orbital energy is the amount of nonlocal HF exchange that is included in the xc functional, but it is still difficult to explain why different local functionals (functionals with no HF exchange) yield quite different results. We conclude that improving calculations of orbital energies of atoms may provide a route to improving the accuracy of theoretical predictions of molecular bond energies for systems containing metal atoms. PMID- 26580761 TI - Charge-Shift Bonding Emerges as a Distinct Electron-Pair Bonding Family from Both Valence Bond and Molecular Orbital Theories. AB - The charge-shift bonding (CSB) concept was originally discovered through valence bond (VB) calculations. Later, CSB was found to have signatures in atoms-in molecules and electron-localization-function and in experimental electron density measurements. However, the CSB concept has never been derived from a molecular orbital (MO)-based theory. We now provide a proof of principle that an MO-based approach enables one to derive the CSB family alongside the distinctly different classical family of covalent bonds. In this bridging energy decomposition analysis, the covalent-ionic resonance energy, RECS, of a bond is extracted by cloning an MO-based purely covalent reference state, which is a constrained two configuration wave function. The energy gap between this reference state and the variational TCSCF ground state yields numerical values for RECS, which correlate with the values obtained at the VBSCF level. This simple MO-based method, which only takes care of static electron correlation, is already sufficient for distinguishing the classical covalent or polar-covalent bonds from charge-shift bonds. The equivalence of the VB and MO-based methods is further demonstrated when both methods are augmented by dynamic correlation. Thus, it is shown from both MO and VB perspectives that the bonding in the CSB family does not arise from electron correlation. Considering that the existence of the CSB family is associated also with quite a few experimental observations that we already reviewed ( Shaik , S. , Danovich , D. , Wu , W. , and Hiberty , P. C. Nat. Chem. , 2009 , 1 , 443 - 449 ), the new bonding concept has passed by now two stringent tests. This derivation, on the one hand, supports the new concept and on the other, it creates bridges between the two main theories of electronic structure. PMID- 26580762 TI - Efficient Basin-Hopping Sampling of Reaction Intermediates through Molecular Fragmentation and Graph Theory. AB - Basin-hopping sampling has been widely used for searching local minima on a potential energy surface. Reaction intermediates including reactants and products are also local minima composed of a reaction path, but their brute-force sampling is too demanding because of large degrees of freedom. We developed an efficient Monte Carlo basin-hopping method to sample reaction intermediates through the fragmentation of molecules and a postanalysis scheme using the graph theory with a matrix representation of molecular structures. The former greatly reduces the dimension of a given potential energy surface, while the latter offers not only the effective screening of resulting local minima toward desirable intermediates but also their automatic ordering along a reaction path. We combined it with the density functional tight binding method for rapid calculations and tested its performance for organic reactions. PMID- 26580763 TI - Stereoselectivity in Asymmetric Catalysis: The Case of Ruthenium-Catalyzed Ketone Hydrogenation. AB - The ruthenium-catalyzed asymmetric hydrogenation of simple ketones to generate enantiopure alcohols is an important process widely used in the fine chemical, pharmaceutical, fragrance, and flavor industries. Chiral diphosphine-RuCl2-1,2 diamine complexes are effective catalysts for the reaction giving high chemo- and enantioselectivity. However, no diphosphine-RuCl2-1,2-diamine complex has yet been discovered that is universal for all kinds of ketone substrates, and the ligands must be carefully chosen for each substrate. The procedure of finding the best ligands for a specific substrate can be facilitated by using virtual screening as a complement to the traditional experimental screening of catalyst libraries. We have generated a transition state force field (TSFF) for the ruthenium-catalyzed asymmetric hydrogenation of simple ketones using an improved Q2MM method. The developed TSFF can predict the enantioselectivity for 13 catalytic systems taken from the literature, with a mean unsigned error of 2.7 kJ/mol. PMID- 26580764 TI - Photoexcitation of Light-Harvesting C-P-C60 Triads: A FLMO-TD-DFT Study. AB - The recently proposed linear-scaling time-dependent density functional theory (TD DFT) [ J. Chem. THEORY: Comput. 2011 , 7 , 3643 ] is employed to capture more than 300 low-lying excited states for three light-harvesting C-P-C60 triads composed of beta-carotenoid polyene (C), diaryl-based porphyrin (P), and pyrrole fullerene (C60). The simulated optical absorption spectra are grossly in good agreement with experimental observations. To gain insights on the structure property relations, both top-down and bottom-up analyses of the excited states are made in terms of the underlying fragment localized molecular orbitals (FLMO). A maximum occupation method is further proposed for finding excited-state solutions of self-consistent-field equations and is applied to long-range charge transfer states that cannot be described by TD-DFT with pure density functionals. PMID- 26580765 TI - Efficient Calculations of Molecular Linear Response Properties for Spectral Regions. AB - Molecular spectra can be determined from molecular response functions, by solving the so-called damped response equations using the complex polarization propagator approach. The overall structure of response equations is identical for variational wave functions such as the Hartree-Fock, multiconfiguration self consistent field, and Kohn-Sham density functional theory, and the key program module is the linear response equation solver. We present an implementation of the solver using the algorithm with symmetrized vectors, optimized for addressing spectral regions of a width of some 5-10 eV and a resolution below 0.1 eV. The work is illustrated by the consideration of UV-vis as well as near carbon K -edge absorption spectra of the C60 fullerene. We demonstrate that it is possible to converge tightly response equations for hundreds of optical frequencies in resonance regions of the spectrum at a cost not much exceeding the solution of a single response equation in the nonresonant region. Our work is implemented in the molecular orbital based module of the Dalton program and serves as a documentation of the code distributed in the Dalton2013 release version. PMID- 26580766 TI - Solute-Solvent Charge-Transfer Excitations and Optical Absorption of Hydrated Hydroxide from Time-Dependent Density-Functional Theory. AB - The electronic structure of simple hydrated ions represents one of the most challenging problems in electronic-structure theory. Spectroscopic experiments identified the lowest excited state of the solvated hydroxide as a charge transfer-to-solvent (CTTS) state. In the present work we report computations of the absorption spectrum of the solvated hydroxide ion, treating both solvent and solute strictly at the same level of theory. The average absorption spectrum up to 25 eV has been computed for samples taken from periodic ab initio molecular dynamics simulations. The experimentally observed CTTS state near the onset of the absorption threshold has been analyzed at the generalized-gradient approximation (GGA) and with a hybrid density-functional. Based on results for the lowest excitation energies computed with the HSE hybrid functional and a Davidson diagonalization scheme, the CTTS transition has been found 0.6 eV below the first absorption band of liquid water. The transfer of an electron to the solvent can be assigned to an excitation from the solute 2ppi orbitals, which are subject to a small energetic splitting due to the asymmetric solvent environment, to the significantly delocalized lowest unoccupied orbital of the solvent. The distribution of the centers of the excited state shows that CTTS along the OH(-) axis of the hydroxide ion is avoided. Furthermore, our simulations indicate that the systematic error arising in the calculated spectrum at the GGA originates from a poor description of the valence band energies in the solution. PMID- 26580767 TI - Interactions of Alkanolamines with Water: Excess Enthalpies and Hydrogen Bonding. AB - We report a transferable force field to describe the interactions of alkanolamines based on the N-C-C-O backbone with water, derived from a comparison with experimental excess enthalpies. This force field is tested on 2-aminoethan-1 ol (MEA), 2-amino-2-methylpropan-1-ol, 2-aminobutan-1-ol (ABU), and 1-aminopropan 2-ol. These alkanolamines are derivatives of MEA obtained by substitution with methyl and ethyl groups on the carbon atoms of the N-C-C-O backbone. A specific cross interaction site corresponding to the hydrogen bond between the hydroxyl group of the alkanolamine and the oxygen atom of water was introduced in order to reproduce quantitatively experimental excess enthalpies. The transferability of this specific site was assessed by predictions on alkanolamines that were not included in the parametrization data set. New data on enthalpy of mixing for ABU with water are reported, since they were not available in the literature. From the molecular simulations, several microscopic quantities of the alkanolamine water mixtures were analyzed in order to improve our understanding of these systems. The structure of the solvation shells at varying compositions, statistics of hydrogen bonds, conformations, and energy decompositions served as bases for an interpretation of the molecular reasons underlying the behavior of the excess enthalpy. The prominent result is that water-water interactions play a major role in differentiating alkanolamine-water mixtures, which is a manifestation of the hydrophobic effect. Both the structural and energetic effects observed at the molecular level point to phenomena that have strong composition dependence, in particular, the interplay between the intramolecular hydrogen bond in the alkanolamine and the intermolecular hydrogen bonds with water. PMID- 26580768 TI - Effect of Anharmonicity on Adsorption Thermodynamics. AB - The effect of anharmonic corrections to the vibrational energies of extended systems is explored. Particular attention is paid to the thermodynamics of adsorption of small molecules on catalytically relevant systems typically affected by anharmonicity. The implemented scheme obtains one-dimensional anharmonic model potentials by distorting the equilibrium structure along the normal modes using both rectilinear (Cartesian) or curvilinear (internal) representations. Only in the latter case, the modes are decoupled also at higher order of the potential and the thermodynamic functions change in the expected directions. The method is applied to calculate ab initio enthalpies, entropies, and Gibbs free energies for the adsorption of methane in acidic chabazite (H-CHA) and on MgO(001) surface. The values obtained for the adsorption of methane in H CHA (273.15 K, 0.1 MPa, theta = 0.5) are DeltaH = -19.3, -TDeltaS = 11.9, and DeltaG = -7.5 kJ/mol. For methane on the MgO(001) (47 K, 1.3 * 10(-14) MPa, theta = 1) DeltaH = -14.4, -TDeltaS = 16.6, and DeltaG = 2.1 kJ/mol are obtained. The calculated desorption temperature is 44 K, and the desorption prefactor is 4.26 * 10(12) s(-1). All calculated results agree within chemical accuracy limits with experimental data. PMID- 26580769 TI - Outer Membrane Remodeling: The Structural Dynamics and Electrostatics of Rough Lipopolysaccharide Chemotypes. AB - Lipopolysaccharides (LPS) are the primary constituent of the outer membrane of Gram-negative bacteria such as Pseudomonas aeruginosa. Gram-negative bacteria can synthesize modified forms of LPS in response to environmental stimuli or due to genetic mutations, a process known as outer membrane remodeling. Chemical modifications of the LPS modulate the integrity and antibiotic susceptibility of bacterial outer membranes. It also governs microbial adhesion to tissues and artificial material surfaces. We have extended a previous model of the rough LPS to include four novel chemotypes rmlC, galU, LPS Re, and Lipid-A. Atomistic molecular dynamics (MD) simulations were performed for outer membrane models constituted of each LPS chemotypes and 1,2-dipalmitoyl-3 phosphatidylethanolamine. It is shown that the decrease in the LPS polysaccharide chain length leads to a significant increase in the diffusion coefficients for the Ca(2+) counterions, increase in acyl chain packing (decrease in membrane fluidity), and attenuation of the negative potential across the LPS surface as positive counterions becomes more exposed to the solvent. The electrostatic potential on the LPS surfaces reflects heterogeneous charge distributions with increasingly larger patches of positive and negative potentials as the polysaccharide chain length decreases. Such a pattern originates from the spatial arrangement of charged phosphate-Ca(2+) clusters in the LPS inner-core that becomes exposed in the membrane surface as monosaccharide units are lost in the shortest chemotypes LPS Re and Lipid-A. These MD-derived conformational ensembles reproduce experimental trends and provide atom-level structural information on the rough LPS chemotypes that can help to rationalize antibiotic resistance and bacterial adhesion processes. PMID- 26580770 TI - Low Scaling Algorithms for the Random Phase Approximation: Imaginary Time and Laplace Transformations. AB - In this paper, we determine efficient imaginary frequency and imaginary time grids for second-order Moller-Plesset (MP) perturbation theory. The least-squares and Minimax quadratures are compared for periodic systems, finding that the Minimax quadrature performs slightly better for the considered materials. We show that the imaginary frequency grids developed for second order also perform well for the correlation energy in the direct random phase approximation. Furthermore, we show that the polarizabilities on the imaginary time axis can be Fourier transformed to the imaginary frequency domain, since the time and frequency Minimax grids are dual to each other. The same duality is observed for the least squares grids. The transformation from imaginary time to imaginary frequency allows one to reduce the time complexity to cubic (in system size), so that random phase approximation (RPA) correlation energies become accessible for large systems. PMID- 26580771 TI - Parametrization of Extended Gaussian Disorder Models from Microscopic Charge Transport Simulations. AB - Simulations of organic semiconducting devices using drift-diffusion equations are vital for the understanding of their functionality as well as for the optimization of their performance. Input parameters for these equations are usually determined from experiments and do not provide a direct link to the chemical structures and material morphology. Here we demonstrate how such a parametrization can be performed by using atomic-scale (microscopic) simulations. To do this, a stochastic network model, parametrized on atomistic simulations, is used to tabulate charge mobility in a wide density range. After accounting for finite-size effects at small charge densities, the data is fitted to the uncorrelated and correlated extended Gaussian disorder models. Surprisingly, the uncorrelated model reproduces the results of microscopic simulations better than the correlated one, compensating for spatial correlations present in a microscopic system by a large lattice constant. The proposed method retains the link to the material morphology and the underlying chemistry and can be used to formulate structure-property relationships or optimize devices prior to compound synthesis. PMID- 26580772 TI - Systematic Method for Thermomechanically Consistent Coarse-Graining: A Universal Model for Methacrylate-Based Polymers. AB - We present a versatile systematic two-bead-per-monomer coarse-grain modeling strategy for simulating the thermomechanical behavior of methacrylate polymers at length and time scales far exceeding atomistic simulations. We establish generic bonded interaction parameters via Boltzmann inversion of probability distributions obtained from the common coarse-grain bead center locations of five different methacrylate polymers. Distinguishing features of each monomer side chain group are captured using Lennard-Jones nonbonded potentials with parameters specified to match the density and glass-transition temperature values obtained from all-atomistic simulations. The developed force field is validated using Flory-Fox scaling relationships, self-diffusion coefficients of monomers, and modulus of elasticity for p(MMA). Our approach establishes a transferable, efficient, and accurate scale-bridging strategy for investigating the thermomechanics of copolymers, polymer blends, and nanocomposites. PMID- 26580773 TI - Resolution-Adapted All-Atomic and Coarse-Grained Model for Biomolecular Simulations. AB - We develop here an adaptive multiresolution method for the simulation of complex heterogeneous systems such as the protein molecules. The target molecular system is described with the atomistic structure while maintaining concurrently a mapping to the coarse-grained models. The theoretical model, or force field, used to describe the interactions between two sites is automatically adjusted in the simulation processes according to the interaction distance/strength. Therefore, all-atomic, coarse-grained, or mixed all-atomic and coarse-grained models would be used together to describe the interactions between a group of atoms and its surroundings. Because the choice of theory is made on the force field level while the sampling is always carried out in the atomic space, the new adaptive method preserves naturally the atomic structure and thermodynamic properties of the entire system throughout the simulation processes. The new method will be very useful in many biomolecular simulations where atomistic details are critically needed. PMID- 26580774 TI - Role of Deprotonation Free Energies in pKa Prediction and Molecule Ranking. AB - A computationally efficient classical molecular simulation technique is derived for ranking the pKa values of a set of chemically similar congeneric molecules in an implicit solvent model of water. This uses the deprotonation free energy of the titratable group in the gas and aqueous phases obtained by thermodynamic integration (TI). For a series of alcohols and acids a strong linear correlation is demonstrated between the experimental pKa and the deprotonation free energy difference in the gas and liquid phases. These calculations also show that classical TI is more efficient than slow-growth TI in calculating deprotonation free energies for the series of molecules considered herein. PMID- 26580775 TI - Quantifying Environmental Effects on the Decay of Hole Transfer Couplings in Biosystems. AB - In the past two decades, many research groups worldwide have tried to understand and categorize simple regimes in the charge transfer of such biological systems as DNA. Theoretically speaking, the lack of exact theories for electron-nuclear dynamics on one side and poor quality of the parameters needed by model Hamiltonians and nonadiabatic dynamics alike (such as couplings and site energies) on the other are the two main difficulties for an appropriate description of the charge transfer phenomena. In this work, we present an application of a previously benchmarked and linear-scaling subsystem density functional theory (DFT) method for the calculation of couplings, site energies, and superexchange decay factors (beta) of several biological donor-acceptor dyads, as well as double stranded DNA oligomers composed of up to five base pairs. The calculations are all-electron and provide a clear view of the role of the environment on superexchange couplings in DNA-they follow experimental trends and confirm previous semiempirical calculations. The subsystem DFT method is proven to be an excellent tool for long-range, bridge-mediated coupling and site energy calculations of embedded molecular systems. PMID- 26580776 TI - Describing the Conformational Landscape of Small Organic Molecules through Gaussian Mixtures in Dihedral Space. AB - Due to the well-known structure-function paradigm, conformational equilibrium plays a major role in molecular recognition. Therefore, a deep understanding of the conformational profile of small organic molecules is an essential prerequisite to modern computer-assisted drug design. However, a thorough analysis and a meaningful representation of the conformational landscape of drug like molecules remains a challenge. The thermodynamic equilibrium of conformational states can be described in terms of probability density function (PDF) defined in the space of the relevant degrees of freedom of the system. In principle, this PDF could be estimated by traditional histogram methods, which are, however, hampered by several limitations when the variables forming the space are more than two or three. Here, we present an unsupervised parametric fitting procedure based on cluster analysis, aimed at estimating the PDF in the conformational space of small drug-like molecules with low sensitivity to data dimensionality. Indeed, data are represented in the dihedral space of the molecule and clustered using a simple adaptation of the standard k-means algorithm for periodic data. In the final step of the analysis, the PDF is derived as a linear combination of multivariate circular Gaussian distributions. We show that exploiting the analytic properties of Gaussian distributions, the proposed approach makes it possible to analyze the conformational ensemble in higher dimensional spaces with several advantages over the histogram-based methods. The posterior analysis of the PDF also helps identify a minimal subset of variables able to provide a meaningful representation of the conformational space. We tested our approach on alanine dipeptide, alanine tetrapeptide, and rilpivirine with satisfactory results compared to standard histogram-based methods and to those based on chemical intuition. PMID- 26580777 TI - Universal Method for Embedding Proteins into Complex Lipid Bilayers for Molecular Dynamics Simulations. AB - The growing interest toward membrane protein simulations calls for a universal and efficient protocol for embedding multiple proteins simultaneously into asymmetric many-component lipid membranes. To this end, here, we present a new and simple technique based on pushing proteins into a lipid membrane from its side by applying a high lateral pressure on the system. This approach is compatible with most (if not all) simulation software packages, and it is independent of external program codes. Most importantly, our protocol does not alter the lipid composition or the transmembrane lipid distribution of the host bilayer membrane. It can be employed with both atomistic and coarse-grained models, and it allows multiple proteins to be embedded into a membrane at the same time. It is shown that the protein structure is unaffected by the pressure applied to the system during the procedure, and the simulation resources required for protein insertion are shown to be modest, regarding both atomistic and coarse grained simulation models. PMID- 26580778 TI - Transient Effects of Excluded Volume Interactions on the Translational Diffusion of Hydrodynamically Anisotropic Molecules. AB - We have investigated effects of excluded volume interactions on the translational diffusion of hydrodynamically anisotropic molecules. For that, we have performed rigid-body Brownian dynamics simulations of aqueous solutions of hen egg-white lysozyme (HEWL), at concentrations ranging from 1.25 mg/mL to 250 mg/mL and evaluated the lysozyme's self-diffusion. In the long time limit (above 1 MUs), the protein's translational diffusion is isotropic, regardless the solution concentration. However, on the time scale of the order of up to hundreds of nanoseconds, the anisotropic translational diffusion is observed, with the transition time from the anisotropic to isotropic translational diffusion depending on the lysozyme concentration. The magnitude of the translational diffusion anisotropy in this transient regime is also concentration-dependent and steric interactions enhance the anisotropy. Moreover, steric interactions cause the anisotropy to be a nonmonotonic function of time. When the hydrodynamic anisotropy of the protein is neglected in Brownian dynamics simulations and its diffusion tensor is replaced with average translational and rotational diffusion coefficients, the lysozyme's translational dynamics in the long-time limit is similar to that in the case of the corresponding hydrodynamically anisotropic object. However, such a similarity is not observed below 1 MUs and in this time regime the translational dynamics of lysozyme molecules modeled with isotropic diffusion coefficients substantially deviates from that derived from Brownian dynamics simulations of their hydrodynamically anisotropic counterparts. PMID- 26580779 TI - Adaptive Resolution Simulation of MARTINI Solvents. AB - We present adaptive resolution molecular dynamics simulations of aqueous and apolar solvents using coarse-grained molecular models that are compatible with the MARTINI force field. As representatives of both classes of solvents we have chosen liquid water and butane, respectively, at ambient temperature. The solvent molecules change their resolution back and forth between the atomistic and coarse grained representations according to their positions in the system. The difficulties that arise from coupling to a coarse-grained model with a multimolecule mapping, for example, 4-to-1 mapping in the case of the Simple Point Charge (SPC) and MARTINI water models, could be successfully circumvented by using bundled water models. We demonstrate that the presented multiscale approach faithfully reproduces the structural and dynamical properties computed by reference fully atomistic molecular dynamics simulations. Our approach is general and can be used with any atomistic force field to be linked with the MARTINI force field. PMID- 26580780 TI - NMR Order Parameter Determination from Long Molecular Dynamics Trajectories for Objective Comparison with Experiment. AB - Functional protein motions covering a wide range of time scales can be studied, among other techniques, by NMR and by molecular dynamics (MD) computer simulations. MD simulations of proteins now routinely extend into the hundreds of nanoseconds time scale range exceeding the overall tumbling correlation times of proteins in solution by several orders of magnitude. This provides a unique opportunity to rigorously validate these simulations by quantitative comparison with model-free order parameters derived from NMR relaxation experiments. However, presently there is no consensus on how such a comparison is best done. We address here how this can be accomplished in a way that is both efficient and objective. For this purpose, we analyze (15)N R1 and R2 and heteronuclear {(1)H} (15)N NOE NMR relaxation parameters computed from 500 ns MD trajectories of 10 different protein systems using the model-free analysis. The resulting model-free S(2) order parameters are then used as targets for S(2) values computed directly from the trajectories by the iRED method by either averaging over blocks of variable lengths or by using exponentially weighted snapshots (wiRED). We find that the iRED results are capable of reproducing the target S(2) values with high accuracy provided that the averaging window is chosen 5 times the length of the overall tumbling correlation time. These results provide useful guidelines for the derivation of NMR order parameters from MD for a meaningful comparison with their experimental counterparts. PMID- 26580781 TI - Relationship between Protein Flexibility and Binding: Lessons for Structure-Based Drug Design. AB - Conceptually, the simplistic lock and key model has been superseded by more realistic views of molecular recognition that take into account the intrinsic dynamics of biological macromolecules. However, it is still common for structure based drug discovery methods to represent the receptor as static structures. The practical advantages of this approximation, the notable success attained over the past few decades with such simple models and the absence of clear guidelines for weighing the pros and cons of accounting for flexibility may prompt some investigators to stretch the rigid model beyond its scope. Here, we investigate the relationship between protein flexibility and binding free energy and present some useful hints for understanding when, and to what extent, flexibility should be considered. Using molecular dynamics simulations of hen egg-white lysozyme (HEWL) with explicit aqueous/organic solvent mixtures and a range of restraint conditions, we find out how artificially restricted mobility affects binding hot spots. Barring sampling errors or an inappropriate choice of reference structure, we find that decreased mobility (measured as B-factors) leads to artifactually more negative binding free energies, but a logarithmic relationship between both terms attenuates the errors. Consequently, ignoring flexibility may be an acceptable approximation for intrinsically rigid regions (such as the active site of enzymes) but may lead to larger errors elsewhere. For the same reason, local conformational sampling yields very accurate predictions and, owing to its practical advantages, may be preferable to full conformational sampling for many applications. PMID- 26580782 TI - QM Computations on Complete Nucleic Acids Building Blocks: Analysis of the Sarcin Ricin RNA Motif Using DFT-D3, HF-3c, PM6-D3H, and MM Approaches. AB - A set of conformations obtained from explicit solvent molecular dynamics (MD) simulations of the Sarcin-Ricin internal loop (SRL) RNA motif is investigated using quantum mechanical (QM, TPSS-D3/def2-TZVP DFT-D3) and molecular mechanics (MM, AMBER parm99bsc0+chiol3 force field) methods. Solvent effects are approximated using implicit solvent methods (COSMO for DFT-D3; GB and PB for MM). Large-scale DFT-D3 optimizations of the full 11-nucleotide motif are compared to MM results and reveal a higher flexibility of DFT-D3 over the MM in the optimization procedure. Conformational energies of the SRL motif expose significant differences in the DFT-D3 and MM energy descriptions that explain difficulties in MD simulations of the SRL motif. The TPSS-D3 data are in excellent agreement with results obtained by the hybrid functionals PW6B95-D3 and M06-2X. Computationally more efficient methods such as PM6-D3H and HF-3c show promising but partly inconsistent results. It is demonstrated that large-scale DFT-D3 computations on complete nucleic acids building blocks are a viable tool to complement the picture obtained from MD simulations and can be used as benchmarks for faster computational methods. Methodological challenges of large scale QM computations on nucleic acids such as missing solvent-solute interactions and the truncation of the studied systems are discussed. PMID- 26580783 TI - Intracranial Procedures and Expected Frequency of Creutzfeldt-Jakob Disease. AB - BACKGROUND/AIMS: To assess the frequency and characteristics of intracranial procedures (ICPs) performed and the number of U.S. residents living with a history of ICP. These data are used to calculate the expected annual number of sporadic Creutzfeldt-Jakob disease (CJD) cases among U.S. residents with a history of ICP. METHODS: The Nationwide Inpatient Sample provided data on the frequency and types of ICPs, and data from the National Center for Health Statistics was used to produce age-adjusted mortality rates. A model was constructed, which estimated long-term survival and sporadic CJD rates among ICP patients based on procedure type and age. RESULTS: There were an estimated 2,070,488 ICPs in the United States from 1998 to 2007, an average of over 200,000 per year. There were an estimated 2,023,726 U.S. residents in 2013 with a history of ICP in the previous 30 years. In 2013, there was expected to be 4.1 sporadic CJD cases (95% CI 1-8) among people with a history of ICP in the past 30 years. CONCLUSIONS: The considerable proportion of U.S. residents living with a history of ICP is important information for retrospective assessments of CJD or any other suspected long-term outcome of ICPs. PMID- 26580785 TI - Hydrogels functionalized with N-cadherin mimetic peptide enhance osteogenesis of hMSCs by emulating the osteogenic niche. AB - N-cadherin is considered to be the key factor in directing cell-cell interactions during mesenchymal condensation, which is essential to osteogenesis. In this study, hyaluronic acid (HA) hydrogels are biofunctionalized with an N-cadherin mimetic peptide to mimic the pro-osteogenic niche in the endosteal space to promote the osteogenesis of human mesenchymal stem cells (hMSCs). Results show that the conjugation of the N-cadherin peptide in the HA hydrogels enhances the expression of the osteogenic marker genes in the seeded hMSCs. Furthermore, the biofunctionalized HA hydrogels promote the alkaline phosphatase activity, type I collagen deposition, and matrix mineralization by the seeded hMSCs under both in vitro and in vivo condition. We postulate that the biofunctionalized hydrogels emulates the N-cadherin-mediated homotypic cell-cell adhesion among MSCs and the "orthotypic" interaction between the osteoblasts and MSCs. These findings demonstrate that the biofunctionalized HA hydrogels provide a supportive niche microenvironment for the osteogenesis of hMSCs. PMID- 26580786 TI - Fatal Asphyxiation in Two Long-Finned Pilot Whales (Globicephala melas) Caused by Common Soles (Solea solea). AB - Long-finned pilot whales (Globicephala melas) are rare visitors to the southern North Sea, but recently two individual strandings occurred on the Dutch coast. Both animals shared the same, unusual cause of death: asphyxiation from a common sole (Solea solea) stuck in their nasal cavity. This is a rare cause of death in cetaceans. Whilst asphyxiation has been reported in smaller odontocetes, there are no recent records of this occurring in Globicephala species. Here we report the stranding, necropsy and diet study results as well as discuss the unusual nature of this phenomenon. Flatfish are not a primary prey species for pilot whales and are rarely eaten by other cetaceans, such as harbour porpoises (Phocoena phocoena), in which there are several reports of asphyxiation due to airway obstruction by soles. This risk may be due to the fish's flexible bodies which can enter small cavities either actively in an attempt to escape or passively due to the whale 'coughing' or 'sneezing' to rid itself of the blockage of the trachea. It is also possible that the fish enter the airways whilst the whale is re-articulating the larynx after trying to ingest large, oddly shaped prey. It is unlikely that the soles entered the airways after the death of the whales and we believe therefore that they are responsible for the death of these animals. PMID- 26580788 TI - [Seminar on the Elimination of Measles and Rubella in Spain]. PMID- 26580787 TI - The Expression of the Ubiquitin Ligase SIAH2 (Seven In Absentia Homolog 2) Is Increased in Human Lung Cancer. AB - OBJECTIVES: Lung cancer is the leading cause of cancer-related deaths worldwide. Overall 5-year survival has shown little improvement over the last decades. Seven in absentia homolog (SIAH) proteins are E3 ubiquitin ligases that mediate proteasomal protein degradation by poly-ubiquitination. Even though SIAH proteins play a key role in several biological processes, their role in human cancer remains controversial. The aim of the study was to document SIAH2 expression pattern at different levels (mRNA, protein level and immunohistochemistry) in human non-small cell lung cancer (NSCLC) samples compared to surrounding healthy tissue from the same patient, and to analyse the association with clinicopathological features. MATERIALS AND METHODS: One hundred and fifty-two samples from a patient cohort treated surgically for primary lung cancer were obtained for the study. Genic and protein expression levels of SIAH2 were analysed and compared with clinic-pathologic variables. RESULTS: The present study is the first to analyze the SIAH2 expression pattern at different levels (RNA, protein expression and immunohistochemistry) in non-small cell lung cancer (NSCLC). We found that SIAH2 protein expression is significantly enhanced in human lung adenocarcinoma (ADC) and squamous cell lung cancer (SCC). Paradoxically, non-significant changes at RNA level were found, suggesting a post traductional regulatory mechanism. More importantly, an increased correlation between SIAH2 expression and tumor grade was detected, suggesting that this protein could be used as a prognostic biomarker to predict lung cancer progression. Likewise, SIAH2 protein expression showed a strong positive correlation with fluorodeoxyglucose (2-deoxy-2(18F)fluoro-D-glucose) uptake in primary NSCLC, which may assist clinicians in stratifying patients at increased overall risk of poor survival. Additionally, we described an inverse correlation between the expression of SIAH2 and the levels of one of its substrates, the serine/threonine kinase DYRK2. CONCLUSIONS: Our results provide insight into the potential use of SIAH2 as a novel target for lung cancer treatment. PMID- 26580789 TI - [The State of Measles and Rubella in the WHO European region]. AB - The long-standing and widespread use of vaccines against measles has resulted in a dramatic decline in cases and measles mortality worldwide compared with the pre vaccination era.All regions of the World Health Organization (WHO) have measles elimination goals and the WHO regions of the Americas, Europe and Western Pacific also have rubella elimination goals. This article aims to report on progress toward elimination of measles and rubella in the WHO European Region based on the latest available data. We also discuss current challenges and actions needed to reach this goal in the Region. Despite substantial progress made towards controlling measles and rubella, the countries of the WHO European Region continue to face challenges in interrupting endemic transmission of these diseases. Widespread outbreaks and endemic transmission of measles and rubella persisted in some countries of the Region in 2014 and have continued in 2015. Interrupting endemic transmission in each and every country is necessary to declare elimination for the entire Region. High population immunity and high quality surveillance are the cornerstones to eliminate measles and rubella. In the absence of sustained political commitment and implementation of the required strategies by all countries, the goal of eliminating these diseases in the WHO European Region is at stake. PMID- 26580790 TI - [Verifying the Elimination of Measles and Rubella in the WHO European region: the Case of Spain]. AB - Like some other countries in the Region, Spain has recently experienced multiple but small measles outbreaks resulting from several importations and in which health care professionals were also infected. The European Regional Verification Commission (RVC) for Measles and Rubella Elimination, an independent panel of experts, conducted an annual review of the reports submitted by the National Verification Committees (NVC) and a country visit to assess the status of interruption of endemic transmission of these diseases in Spain. Essential criteria supporting interruption included absence of endemic transmission in the presence of high-quality surveillance system and genotyping evidence. High vaccination coverage with the first dose of measles -and rubella-containing vaccine (MRCV1) has been maintained above 95% at national level. The figure is based on the number of doses administered to children aged 12-24 months. However, there are two autonomous regions, namely Cataluna and Castilla y Leon with low (<90%) vaccination coverage. In the autonomous regions of Murcia and Melilla, although the coverage with MRCV1 was above 95%, that of the second dose of measles -and rubella-containing vaccine was below 90. On the basis of the evidence provided, with only two imported cases of rubella in 2013, the RVC concluded that endemic transmission of rubella had been interrupted in Spain, but there is a risk of re-establishing transmission due to the sub-optimal population immunity in at least four regions as the coverage with two doses of measles- and rubella- containing vaccines was below the required minimum of 95%. PMID- 26580791 TI - [Immunization Programme and Coverage against Measles and Rubella in Spain. Challenges for Achieving their Elimination]. AB - The World Health Organization had established the achievement and sustainability of very high coverage with two doses of vaccine against measles and at least one against rubella as one of the key strategies for the elimination of both measles and rubella. The current immunization programme in Spain includes the immunization with two doses of combined vaccine against measles, mumps and rubella at 12 months and 3-4 years of age. Since 2000 coverage with first dose is over the target of 95% but the coverage with the second dose remains between 90 and 95%. In 2014, at subnational level three regions had coverage below the objective and only eight regions achieved the objective for the second dose. The challenges and some activities to strengthen the immunization programme in order to achieve the elimination of measles and rubella are discussed. PMID- 26580792 TI - [Epidemiologic Surveillance on Measles, Rubella and Congenital Rubella Syndrome. Spain]. AB - To achieve the goal of eliminating measles and rubella two key strategies have been defined: sustain very low level of population susceptibility and strengthen surveillance system by rigorous case investigation and rapid control measures implementation. Surveillance of measles, rubella and CRS are included into the Spanish Surveillance System (RENAVE); surveillance is mandatory, passive, nationwide and case-based with laboratory information integrated. Information flows from sub national to national level (National Centre for Epidemiology) and then, to the WHO-Europe through ECDC. In the final phase of elimination, good surveillance and documented evidences are keys. Information on epidemiology of measles, rubella and CRS cases and outbreaks, pattern of importation, genotypes circulating and performance of measles and rubella surveillance are required at national and international level. Also all investigated and discarded measles or rubella cases should be reported. Currently the system faces some challenges gathering needed information for documenting the elimination. As long as the disease incidence declines, increases difficulties in identifying clinical measles and rubella because of non-specific prodromal signs and atypical cases. Differential diagnosis for fever and rash including measles and rubella should be performed in all clinical settings. Three clinical specimens must be collected to confirm or discard cases and to allow the virus characterization in order to know the pattern of importation of measles and rubella. PMID- 26580793 TI - [Microbiological Surveillance of Measles and Rubella in Spain. Laboratory Network]. AB - The Laboratory is a fundamental component on the surveillance of measles and rubella. Cases need to be properly confirmed to ensure an accurate estimation of the incidence. Strains should be genetically characterized to know the transmission pattern of these viruses and frequently, outbreaks and transmission chains can be totally discriminated only after that. Finally, the susceptibility of the population is estimated on the basis of sero-prevalence surveys. Detection of specific IgM response is the base of the laboratory diagnosis of these diseases. It should be completed with genomic detection by RT-PCR to reach an optimal efficiency, especially when sampling is performed early in the course of the disease. Genotyping is performed by genomic sequencing according to reference protocols of the WHO. Laboratory surveillance of measles and rubella in Spain is organized as a net of regional laboratories with different capabilities. The National Center of Microbiology as National Reference Laboratory (NRL), supports regional laboratories ensuring the availability of all required techniques in the whole country and watching for the quality of the results. The NRL is currently working in the implementation of new molecular techniques based on the analysis of genomic hypervariable regions for the strain characterization at sub-genotypic levels and use them in the surveillance. PMID- 26580794 TI - [Plan for the Elimination of Measles and Rubella in Spain]. AB - The current Plan for the elimination of measles and rubella is made of the Plan for the elimination of measles in Spain, set up in 2001, and the Surveillance protocol of rubella and congenital rubella syndrome in the phase of elimination, established in 2007. The monitoring of the elimination of both diseases conducted from the European Region of World Health Organization (WHO) has been reinforced since 2010. An annual report with information on the situation of measles and rubella in The Member Estates is being requested since 2013. The Ministry of Health, Social Services and Equality nominated a National Committee for Verification of Measles and Rubella Elimination in 2013, for the review and delivery of the requested information. The strategies and activities currently recommended from the WHO European Region, the verification process in Spain, and the steps to follow for the updating of the Plan for the elimination of measles and rubella in Spain are mentioned in this article. PMID- 26580795 TI - [Surveillance Plan on Recent Outbreak of Measles and Rubella in Catalonia, Spain]. AB - Measles and rubella are two immuno-preventive illnesses. In Catalonia, since 1988 all children are given two doses of measles and rubella vaccine with high levels of vaccination coverage. The measles elimination programme has been carried out since 1990 in Catalonia. This programme includes achieving and keeping high immunization levels among population with high vaccination coverage, intense epidemiological surveillance and an immediate response to the appearance of a case or outbreak. In 2014, the measles incidence rate was 1.9 cases/ 100,000 inhabitants. There were 4 recent outbreaks in 2006, 2011, 2013 and 2014 that affected 381, 289, 31 and 124 people respectively. All outbreaks were triggered by an imported case. In 2011 and 2014 measles outbreaks, 6% and 5.5% of affected people were health care workers. All outbreaks presented a great variety of measles genotypes. Concerning rubella elimination programme, since 2002, 68 cases of postnatal rubella and 5 cases of congenital rubella were confirmed. Regarding measles and rubella surveillance and control, in addition to strengthen vaccination coverage, it is essential immediate notification, within the first 24 hours since suspicion and laboratory confirmation. In addition there is a need to enforce vaccination among health care workers as well as in other susceptible and unvaccinated people. It is recommended to vaccinate all people who were born after 1966 and who have not been vaccinated with two doses of trivalent measles mumps-rubella vaccine. Furthermore, we have to emphasize that the progress concerning genotypes study allows identifying various imported cases from other European countries with active outbreaks, aspect that makes easier the surveillance of these illnesses. PMID- 26580796 TI - [Outbreaks of Measles in Andalusia, Spain, during the Period 2010-2015]. AB - The Andalusian Surveillance Epidemiological System (SVEA) controls and investigates any notification of measles or any other communicable disease. The aim of this article is to describe the epidemiological characteristics of measles outbreaks occurred in Andalusia in the last five years (2010-2015) and their control measures. In this period three outbreaks were reported: the first one started in Granada in 2010 in a community of objectors to vaccination. Control measures of measles protocol of SVEA were adopted (case isolation, identification and contacts immunization), including judicial measures among the group who refused the vaccination. The second outbreak started in Seville in 2011 in an "area in need of social transformation" and it spread throughout the region. The routine vaccination coverage review was introduced within the surveillance system after those outbreaks, identifying the most vulnerable people. During the first six months of 2015, a small outbreak, of 15 cases, occurred in Granada. The outbreak was controlled mainly due to the early intervention, the health measures adopted in the schools and health centres involved and the high vaccination coverage achieved in the population. PMID- 26580797 TI - [Activities to catch up and Vaccinate the Susceptible Population in Valencian Community, Spain]. AB - Eliminating measles and rubella and preventing congenital rubella infection plan of WHO highlighted the need to assess vaccination coverage and develop strategies to improve it and eliminate pockets of low immunization coverage. It exists evidence about the potential role of immunization information systems to improve coverage. The aim of this article is to describe the actions taken from the Vaccine Information System of Valencian Community addressed to improve the vaccination coverage. The Vaccine Information System is a comprehensive information system that allows the management of vaccination programs. It is connected to other systems so that decisions related to vaccinations as clinical and epidemiological management is facilitated. Regarding the role in improving vaccination coverage, the Vaccine Information System facilitates the implementation of all alternatives that have been proven effective: calculate coverage and feedback of results, active recruitment, cooperate with the epidemiological surveillance and logistics management of vaccines. We can conclude, therefore, that the Vaccine Information System is a useful tool to improve vaccination coverage and thus contribute to the elimination of measles and rubella. PMID- 26580799 TI - Correction: Developmental Changes in Composition and Morphology of Cuticular Waxes on Leaves and Spikes of Glossy and Glaucous Wheat (Triticum aestivum L.). PMID- 26580798 TI - LEF-1 Regulates Tyrosinase Gene Transcription In Vitro. AB - TYR, DCT and MITF are three important genes involved in maintaining the mature phenotype and producing melanin; they therefore participate in neural crest cell development into melanocytes. Previous studies have revealed that the Wnt signaling factor lymphoid enhancer-binding factor (LEF-1) can enhance DCT and MITF gene expression. However, whether LEF-1 also affects TYR gene expression remains unclear. In the present study, we found that LEF-1 regulated TYR transcription in vitro. LEF-1 overexpression increased TYR gene promoter activity, whereas LEF-1 knockdown by RNA interference significantly decreased TYR expression. Moreover, the core GTTTGAT sequence (-56 to -50) within the TYR promoter is essential for the effect of LEF-1 on TYR expression, and chromatin immunoprecipitation (ChIP) assay indicated that endogenous LEF-1 interacts with the TYR promoter. In addition, we observed a synergistic transactivation of the TYR promoter by LEF-1 and MITF. These data suggest that Wnt signaling plays an important role in regulating melanocyte development and differentiation. PMID- 26580800 TI - Long-Term Cultures of Human Cornea Limbal Explants Form 3D Structures Ex Vivo - Implications for Tissue Engineering and Clinical Applications. AB - Long-term cultures of cornea limbal epithelial stem cells (LESCs) were developed and characterized for future tissue engineering and clinical applications. The limbal tissue explants were cultivated and expanded for more than 3 months in medium containing serum as the only growth supplement and without use of scaffolds. Viable 3D cell outgrowth from the explants was observed within 4 weeks of cultivation. The outgrowing cells were examined by immunofluorescent staining for putative markers of stemness (ABCG2, CK15, CK19 and Vimentin), proliferation (p63alpha, Ki-67), limbal basal epithelial cells (CK8/18) and differentiated cornea epithelial cells (CK3 and CK12). Morphological and immunostaining analyses revealed that long-term culturing can form stratified 3D tissue layers with a clear extracellular matrix deposition and organization (collagen I, IV and V). The LESCs showed robust expression of p63alpha, ABCG2, and their surface marker fingerprint (CD117/c-kit, CXCR4, CD146/MCAM, CD166/ALCAM) changed over time compared to short-term LESC cultures. Overall, we provide a model for generating stem cell-rich, long-standing 3D cultures from LESCs which can be used for further research purposes and clinical transplantation. PMID- 26580801 TI - State-Space Modelling of the Drivers of Movement Behaviour in Sympatric Species. AB - Understanding animal movement behaviour is key to furthering our knowledge on intra- and inter-specific competition, group cohesion, energy expenditure, habitat use, the spread of zoonotic diseases or species management. We used a radial basis function surface approximation subject to minimum description length constraint to uncover the state-space dynamical systems from time series data. This approximation allowed us to infer structure from a mathematical model of the movement behaviour of sheep and red deer, and the effect of density, thermal stress and vegetation type. Animal movement was recorded using GPS collars deployed in sheep and deer grazing a large experimental plot in winter and summer. Information on the thermal stress to which animals were exposed was estimated using the power consumption of mechanical heated models and meteorological records of a network of stations in the plot. Thermal stress was higher in deer than in sheep, with less differences between species in summer. Deer travelled more distance than sheep, and both species travelled more in summer than in winter; deer travel distance showed less seasonal differences than sheep. Animal movement was better predicted in deer than in sheep and in winter than in summer; both species showed a swarming behaviour in group cohesion, stronger in deer. At shorter separation distances swarming repulsion was stronger between species than within species. At longer separation distances inter specific attraction was weaker than intra-specific; there was a positive density dependent effect on swarming, and stronger in deer than in sheep. There was not clear evidence which species attracted or repelled the other; attraction between deer at long separation distances was stronger when the model accounted for thermal stress, but in general the dynamic movement behaviour was hardly affected by the thermal stress. Vegetation type affected intra-species interactions but had little effect on inter-species interactions. Our modelling approach is useful in interpreting animal interactions, in order to unravel complex cooperative or competitive behaviours, and to the best of our knowledge is the first modelling attempt to make predictions of multi-species animal movement under different habitat mosaics and abiotic environmental conditions. PMID- 26580803 TI - Multilocus genotyping of Giardia duodenalis (Lambl, 1859) from symptomatic human infections in Slovenia. AB - Giardiasis is a common gastrointestinal infection of humans and animals with a worldwide distribution. Eight genetic groups (known as assemblages A to H) are currently recognised within the species complex of Giardia duodenalis (Lambl, 1859), of which assemblages A and B are responsible for infection of humans and other mammalian hosts. Genotyping data on giardiasis are not available from Slovenia. In this work, we have characterised isolates of G. duodenalis from 85 human symptomatic cases collected during 2002-2013. Genomic DNAs were first tested by a real-time (rt) PCR assay and then by conventional PCR at three loci (beta-giardin, bg; triose phosphate isomerase, tpi; and glutamate dehydrogenase, gdh). We found that the threshold cycle (Ct) values in rt-PCR testing were higher for samples collected during 2002-2005 and that this was paralleled by a low amplification rate in conventional PCR (6 of 32, i.e. 19%). In contrast, lower Ct values and higher amplification rate (45 of 53; 85%) were observed for samples collected during 2006-2013, suggesting an adverse effect of prolonged freezing of stools. Assemblages A and B were found with an almost identical frequency in the 51 genotyped samples. In agreement with previous studies, sequences from assemblage B isolates were characterised by larger genetic variability and by the presence of heterogeneous positions, which made assignment to specific genotypes difficult. Less variability was observed in sequences from assemblage A isolates, which belonged to the human-specific subassemblage AII. These data showed that the genotypes of G. duodenalis that circulate in humans in Slovenia are similar to those previously identified in Europe. PMID- 26580802 TI - An Interactive Text Message Intervention to Reduce Binge Drinking in Young Adults: A Randomized Controlled Trial with 9-Month Outcomes. AB - BACKGROUND: Binge drinking is associated with numerous negative consequences. The prevalence and intensity of binge drinking is highest among young adults. This randomized trial tested the efficacy of a 12-week interactive text message intervention to reduce binge drinking up to 6 months after intervention completion among young adults. METHODS AND FINDINGS: Young adult participants (18 25 y; n = 765) drinking above the low-risk limits (AUDIT-C score >3/4 women/men), but not seeking alcohol treatment, were enrolled from 4 Emergency Departments (EDs) in Pittsburgh, PA. Participants were randomized to one of three conditions in a 2:1:1 allocation ratio: SMS Assessments + Feedback (SA+F), SMS Assessments (SA), or control. For 12 weeks, SA+F participants received texts each Thursday querying weekend drinking plans and prompting drinking limit goal commitment and each Sunday querying weekend drinking quantity. SA+F participants received tailored feedback based on their text responses. To contrast the effects of SA+F with self-monitoring, SA participants received texts on Sundays querying drinking quantity, but did not receive alcohol-specific feedback. The control arm received standard care. Follow-up outcome data collected through web-based surveys were provided by 78% of participants at 3- months, 63% at 6-months and 55% at 9 months. Multiple imputation-derived, intent-to-treat models were used for primary analysis. At 9-months, participants in the SA+F group reported greater reductions in the number of binge drinking days than participants in the control group (incident rate ratio [IRR] 0.69; 95% CI .59 to.79), lower binge drinking prevalence (odds ratio [OR] 0.52; 95% CI 0.26 to 0.98]), less drinks per drinking day (beta -.62; 95% CI -1.10 to -0.15) and lower alcohol-related injury prevalence (OR 0.42; 95% CI 0.21 to 0.88). Participants in the SA group did not reduce drinking or alcohol-related injury relative to controls. Findings were similar using complete case analyses. CONCLUSIONS: An interactive text-message intervention was more effective than self-monitoring or controls in reducing alcohol consumption and alcohol-related injury prevalence up to 6 months after intervention completion. These findings, if replicated, suggest a scalable approach to help achieve sustained reductions in binge drinking and accompanying injuries among young adults. TRIAL REGISTRATION: ClinicalTrials.gov NCT01688245. PMID- 26580804 TI - Implementation of Motor Imagery during Specific Aerobic Training Session in Young Tennis Players. AB - The aim of this study was to investigate the effects of implementing motor imagery (MI) during specific tennis high intensity intermittent training (HIIT) sessions on groundstroke performance in young elite tennis players. Stroke accuracy and ball velocity of forehand and backhand drives were evaluated in ten young tennis players, immediately before and after having randomly performed two HIIT sessions. One session included MI exercises during the recovery phases, while the other included verbal encouragements for physical efforts and served as control condition. Results revealed that similar cardiac demand was observed during both sessions, while implementing MI maintained groundstroke accuracy. Embedding MI during HIIT enabled the development of physical fitness and the preservation of stroke performance. These findings bring new insight to tennis and conditioning coaches in order to fulfil the benefits of specific playing HIIT sessions, and therefore to optimise the training time. PMID- 26580805 TI - Plasma Metabolic Profiles in Women are Menopause Dependent. AB - Menopause is an endocrinological transition that greatly affects health and disease susceptibility in middle-aged and elderly women. To gain new insights into the metabolic process of menopause, plasma metabolic profiles in 115 pre- and post-menopausal women were systematically analyzed by ultra-performance liquid chromatography/mass spectrometry in conjunction with univariate and multivariate statistical analysis. Metabolic signatures revealed considerable differences between pre- and post-menopausal women, and clear separations were observed between the groups in partial least-squares discriminant analysis score plots. In total, 28 metabolites were identified as potential metabolite markers for menopause, including up-regulated acylcarnitines, fatty acids, lysophosphatidylcholines, lysophosphatidylethanolamines, and down-regulated pregnanediol-3-glucuronide, dehydroepiandrosterone sulfate, p-hydroxyphenylacetic acid and dihydrolipoic acid. These differences highlight that significant alterations occur in fatty acid beta-oxidation, phospholipid metabolism, hormone metabolism and amino acid metabolism in post-menopausal women. In conclusion, our plasma metabolomics study provides novel understanding of the metabolic profiles related to menopause, and will be useful for investigating menopause-related diseases and assessing metabolomic confounding factors. PMID- 26580806 TI - Global Habitat Suitability and Ecological Niche Separation in the Phylum Placozoa. AB - The enigmatic placozoans, which hold a key position in the metazoan Tree of Life, have attracted substantial attention in many areas of biological and biomedical research. While placozoans have become an emerging model system, their ecology and particularly biogeography remain widely unknown. In this study, we use modelling approaches to explore habitat preferences, and distribution pattern of the placozoans phylum. We provide hypotheses for discrete ecological niche separation between genetic placozoan lineages, which may also help to understand biogeography patterns in other small marine invertebrates. We, here, used maximum entropy modelling to predict placozoan distribution using 20 environmental grids of 9.2 km2 resolution. In addition, we used recently developed metrics of niche overlap to compare habitat suitability models of three genetic clades. The predicted distributions range from 55 degrees N to 44 degrees S and are restricted to regions of intermediate to warm sea surface temperatures. High concentrations of salinity and low nutrient concentrations appear as secondary factors. Tests of niche equivalency reveal the largest differences between placozoan clades I and III. Interestingly, the genetically well-separated clades I and V appear to be ecologically very similar. Our habitat suitability models predict a wider latitudinal distribution for placozoans, than currently described, especially in the northern hemisphere. With respect to biogeography modelling, placozoans show patterns somewhere between higher metazoan taxa and marine microorganisms, with the first group usually showing complex biogeographies and the second usually showing "no biogeography." PMID- 26580808 TI - Acylhydrazones as Widely Tunable Photoswitches. AB - Molecular photoswitches have attracted much attention in biological and materials contexts. Despite the fact that existing classes of these highly interesting functional molecules have been heavily investigated and optimized, distinct obstacles and inherent limitations remain. Considerable synthetic efforts and complex structure-property relationships render the development and exploitation of new photoswitch families difficult. Here, we focus our attention on acylhydrazones: a novel, yet underexploited class of photochromic molecules based on the imine structural motif. We optimized the synthesis of these potent photoswitches and prepared a library of over 40 compounds, bearing different substituents in all four crucial positions of the backbone fragment, and conducted a systematic study of their photochromic properties as a function of structural variation. This modular family of organic photoswitches offers a unique combination of properties and the compounds are easily prepared on large scales within hours, through an atom-economic synthesis, from commercially available starting materials. During our thorough spectroscopic investigations, we identified photoswitches covering a wide range of thermal half-lives of their (Z)-isomers, from short-lived T-type to thermally stable P-type derivatives. By proper substitution, excellent band separation between the absorbance maxima of (E)- and (Z)-isomers in the UV or visible region could be achieved. Our library furthermore includes notable examples of rare negative photochromic systems, and we show that acylhydrazones are highly fatigue resistant and exhibit good quantum yields. PMID- 26580807 TI - Quantitative Shear-Wave Elastography of the Liver in Preterm Neonates with Intra Uterine Growth Restriction. AB - The feasibility and reproducibility of liver stiffness measurements using Supersonic Shear-wave Imaging (SSI) in preterm neonate have not been reported. Our aim was to determine if liver stiffness differs between intra-uterine growth restriction (IUGR) and appropriate for gestational age (AGA) preterm infants with/without cholestasis. We measured liver stiffness (in kPa) in 45 AGA and 18 IUGR preterm infants, and assessed reproducibility in 26 preterms using Intraclass Correlation Coefficients (ICC) and Bland-Altman tests. Liver stiffness values were compared between AGA and IUGR with and without cholestasis and correlated with birth weight. Measurements showed high reproducibility (ICC = 0.94-0.98 for intra-operator, 0.86 for inter-operator) with good agreement (95% limits: -1.24 to 1.24 kPa). During the first postnatal week, liver stiffness was higher in IUGR (7.50 +/-1.53 kPa) than in AGA infants (5.11 +/-0.80 kPa, p<0.001). After day 8, liver stiffness remained unchanged in AGA but increased progressively in IUGR infants (15.57 +/-6.49 kPa after day 21). Liver stiffness was higher in IUGR neonates with cholestasis (19.35 +/- 9.80 kPa) than without cholestasis (7.72 +/- 1.27 kPa, p<0.001). In conclusion, quantitative liver SSI in preterms is feasible and reproducible. IUGR preterms who will develop cholestasis present high liver stiffness even at birth, before biological cholestasis occurs. PMID- 26580809 TI - Increased Land Use by Chukchi Sea Polar Bears in Relation to Changing Sea Ice Conditions. AB - Recent observations suggest that polar bears (Ursus maritimus) are increasingly using land habitats in some parts of their range, where they have minimal access to their preferred prey, likely in response to loss of their sea ice habitat associated with climatic warming. We used location data from female polar bears fit with satellite radio collars to compare land use patterns in the Chukchi Sea between two periods (1986-1995 and 2008-2013) when substantial summer sea-ice loss occurred. In both time periods, polar bears predominantly occupied sea-ice, although land was used during the summer sea-ice retreat and during the winter for maternal denning. However, the proportion of bears on land for > 7 days between August and October increased between the two periods from 20.0% to 38.9%, and the average duration on land increased by 30 days. The majority of bears that used land in the summer and for denning came to Wrangel and Herald Islands (Russia), highlighting the importance of these northernmost land habitats to Chukchi Sea polar bears. Where bears summered and denned, and how long they spent there, was related to the timing and duration of sea ice retreat. Our results are consistent with other studies supporting increased land use as a common response of polar bears to sea-ice loss. Implications of increased land use for Chukchi Sea polar bears are unclear, because a recent study observed no change in body condition or reproductive indices between the two periods considered here. This result suggests that the ecology of this region may provide a degree of resilience to sea ice loss. However, projections of continued sea ice loss suggest that polar bears in the Chukchi Sea and other parts of the Arctic may increasingly use land habitats in the future, which has the potential to increase nutritional stress and human-polar bear interactions. PMID- 26580810 TI - Synthesis of Low-Density, Carbon-Doped, Porous Hexagonal Boron Nitride Solids. AB - Here, we report the scalable synthesis and characterization of low-density, porous, three-dimensional (3D) solids consisting of two-dimensional (2D) hexagonal boron nitride (h-BN) sheets. The structures are synthesized using bottom-up, low-temperature (~300 degrees C), solid-state reaction of melamine and boric acid giving rise to porous and mechanically stable interconnected h-BN layers. A layered 3D structure forms due to the formation of h-BN, and significant improvements in the mechanical properties were observed over a range of temperatures, compared to graphene oxide or reduced graphene oxide foams. A theoretical model based on Density Functional Theory (DFT) is proposed for the formation of h-BN architectures. The material shows excellent, recyclable absorption capacity for oils and organic solvents. PMID- 26580811 TI - Neotropical Copestylum Macquart (Diptera: Syrphidae) Breeding in Fruits and Flowers, Including 7 New Species. AB - Ten species of Copestylum (Diptera: Syrphidae) were reared from fruits and flowers in Costa Rica, Ecuador and Trinidad. Seven were new and in this paper, we describe them, their development sites and the third stage larva and/or the puparium of all ten species. One new synonym is proposed, Copestylum pinkusi (Curran) [= Copestylum cinctiventre (Curran)]. Similarities and differences between these new and other Copestylum species, suggest they separate into two groups, referred to as the Vagum and Cinctiventre species groups. Features characterising these groups for both adult and early stages are assessed. Each species was also distinguished using adult and early stage characters. Within the Vagum group, adults were more disparate morphologically than the larval stage; this was reversed in the Cinctiventre group. Adult colour patterns are probably cryptic in function and for disguise. Vagum species have disruptive marks, while the Cinctiventre species have reflective colours. Biologically, the groups are almost distinguished by larval development sites. Vagum species use predominantly fruits and have a larval stage that is relatively generalised in form and habit. Cinctiventre species are confined to developing in flowers and the larva is more specialised. A key to both adult and early stages of all ten species is provided. PMID- 26580812 TI - Comprehensive Analysis of a Yeast Lipase Family in the Yarrowia Clade. AB - Lipases are currently the subject of intensive studies due to their large range of industrial applications. The Lip2p lipase from the yeast Yarrowia lipolytica (YlLIP2) was recently shown to be a good candidate for different biotechnological applications. Using a combination of comparative genomics approaches based on sequence similarity, synteny conservation, and phylogeny, we constructed the evolutionary scenario of the lipase family for six species of the Yarrowia clade. RNA-seq based transcriptome analysis revealed the primary role of LIP2 homologues in the assimilation of different substrates. Once identified, these YlLIP2 homologues were expressed in Y. lipolytica. The lipase Lip2a from Candida phangngensis was shown to naturally present better activity and enantioselectivity than YlLip2. Enantioselectivity was further improved by site directed mutagenesis targeted to the substrate binding site. The mono-substituted variant V232S displayed enantioselectivity greater than 200 and a 2.5 fold increase in velocity. A double-substituted variant 97A-V232F presented reversed enantioselectivity, with a total preference for the R-enantiomer. PMID- 26580813 TI - Sex Partner Type, Drug Use and Condom Use Self-Efficacy Among African Americans from Disadvantaged Neighborhoods: Are Associations with Consistent Condom Use Moderated by Gender? AB - Gender inequalities in sexual behavior are explored from the perspective of the theory of gender and power. This study focused on the effect of sex partner type (steady versus casual), drug use, and condom use self-efficacy regarding consistent condom use (CCU) among a community-based sample of adults. The sample included 1,357 African American men and women (M age 37.0, SD 13.1 years; 44% women, 66% men) from 61 disadvantaged census block groups in Atlanta, GA as part of a study of individual and neighborhood characteristics and HIV risk-taking. Having a steady partner decreased the odds of CCU, while higher condom use self efficacy increased the odds of CCU. Among non-drug users, having a drug-using partner was associated with decreased odds of condom use for women only. Women with drug-using partners, especially a steady partner, were least likely to report CCU. Therefore, interventions intended to empower CCU among women need to expand beyond acknowledging the reduced control that women who use drugs demonstrate to also consider those who have drug-using sexual partners. PMID- 26580814 TI - The Devil We Don't Know: Investigating Habitat and Abundance of Endangered Giant Devil Rays in the North-Western Mediterranean Sea. AB - The giant devil ray Mobula mobular, the only Mediterranean mobulid, is subject to mortality caused by directed and accidental captures in fisheries throughout the region. Whilst the combination of human impacts, limited range and a low reproductive potential is not inconsistent with its endangered listing, there are insufficient data to enable a quantitative assessment of trends. Without this, it is difficult to assess and prioritise threats and develop effective conservation actions. Using results from aerial surveys conducted between 2009 and 2014 over the Ligurian, Corsican, Sardinian, northern and central Tyrrhenian seas (626,228 km2), this study provides the first quantitative information on giant devil ray abundance and habitat choice in the western Mediterranean. Devil rays were observed in all seasons except winter, with their estimated abundance in the study area peaking in summer. The overall uncorrected mean density in the study area during summer was estimated at 0.0257 individuals km-2 (range: 0.017-0.044), resulting in a total abundance estimate of 6,092 (12.7%CV) individuals at the surface; once corrected for availability bias, this estimate indicates a summer presence of >12,700 devil rays in the study area. Rays were mostly observed alone even if occasionally, larger aggregations up to a maximum of 18 individuals were observed. Although observed throughout the study area, spatial modelling identified their preferred habitat to be over a broad strip connecting the Tuscan Archipelago to Eastern Sardinia, over a wide range of water depths ranging from 10 to 2000m. The observed seasonal changes in giant devil ray distribution in this study, combined with similar evidence from other areas in the Mediterranean, support the hypothesis that the species undertakes latitudinal migrations across the region, taking advantage of highly productive waters in the north during summer, and warmer southern waters during winter. PMID- 26580815 TI - Influence of Lithium Solutes on Double-Layer Structure of Ionic Liquids. AB - The ionic liquid-electrode interface has attracted much recent interest owing to its importance for development of energy storage devices; however, the important step of adding electro-active ions is not yet well understood at the molecular level. Using direct force measurements across confined electrolyte films, we study the effect of added lithium-ion solute on the double-layer structure of an ionic liquid electrolyte with molecular resolution. We find anionic clusters involving lithium can persist adjacent to the surfaces, and in many cases, this inhibits direct adsorption of lithium ions to the negative surface. Two apparently similar ionic liquid solvents show diverging properties, with one facilitating and the other preventing direct Li-ion adsorption onto the negative surface. The results have implications for the selection of ionic liquids as electrolytes in lithium-ion batteries. PMID- 26580816 TI - Effects of Intravitreal Ranibizumab in the Treatment of Retinopathy of Prematurity in Chinese Infants. AB - PURPOSE: To evaluate the efficacy associated with intravitreal ranibizumab in the treatment of retinopathy of prematurity (ROP). METHODS: A retrospective case series study. Infants diagnosed with Type 1 ROP, or aggressive posterior ROP (AP ROP) were enrolled in the study. All infants in the study received intravitreal ranibizumab (0.25 mg/0.025 ml) as the initial treatment. Follow-up examinations were performed the day after treatment, then weekly for 1 month, bi-monthly for two additional months, then monthly until vascularization of zone III occurred. Additional treatments were initiated in cases of disease recurrence. RESULTS: Thirty-three premature infants (a total of 66 eyes) receiving intravitreal ranibizumab were included. The mean birth weight was 1291 +/- 211 g (range: 650 1650 g) and the mean gestational age was 29.8 +/- 1.6 weeks (range: 27.0-33.6 weeks). The mean gestational age at the time of the first injection was 35.8 +/- 1.6 weeks (range: 32.7-38.4 weeks). The mean follow-up time was 12.9 +/- 4.9 months (range: 6-22 months). Single injections were administered to 58 eyes (87.9%), whereas eight eyes (12.1%) received additional treatments. Recurrence was observed in eight eyes (12.1%), with a mean time to recurrence of 6.9 +/- 1.8 weeks (range: 4-8 weeks). CONCLUSION: Intravitreal ranibizumab is effective for the treatment of retinopathy of prematurity, although a small amount of patients recurred. Compared with intravitreal bevacizumab, a higher incidence and shorter time to recurrence were observed after intravitreal ranibizumab treatment, thus longer and more frequent follow-ups are needed. PMID- 26580817 TI - Single Site Discrimination of Cytosine, 5-Methylcytosine, and 5 Hydroxymethylcytosine in Target DNA Using Anthracene-Tagged Fluorescent Probes. AB - The ability to discriminate between epigenetic variants in DNA is a necessary tool if we are to increase our understanding of the roles that they play in various biological processes and medical conditions. Herein, it is demonstrated how a simple two-step fluorescent probe assay can be used to differentiate all three major epigenetic variants of cytosine at a single locus site in a target strand of DNA. PMID- 26580818 TI - Experimental Assessment of NOx Emissions from 73 Euro 6 Diesel Passenger Cars. AB - Controlling nitrogen oxides (NOx) emissions from diesel passenger cars during real-world driving is one of the major technical challenges facing diesel auto manufacturers. Three main technologies are available for this purpose: exhaust gas recirculation (EGR), lean-burn NOx traps (LNT), and selective catalytic reduction (SCR). Seventy-three Euro 6 diesel passenger cars (8 EGR only, 40 LNT, and 25 SCR) were tested on a chassis dynamometer over both the European type approval cycle (NEDC, cold engine start) and the more realistic Worldwide harmonized light-duty test cycle (WLTC version 2.0, hot start) between 2012 and 2015. Most vehicles met the legislative limit of 0.08 g/km of NOx over NEDC (average emission factors by technology: EGR-only 0.07 g/km, LNT 0.04 g/km, and SCR 0.05 g/km), but the average emission factors rose dramatically over WLTC (EGR only 0.17 g/km, LNT 0.21 g/km, and SCR 0.13 g/km). Five LNT-equipped vehicles exhibited very poor performance over the WLTC, emitting 7-15 times the regulated limit. These results illustrate how diesel NOx emissions are not properly controlled under the current, NEDC-based homologation framework. The upcoming real-driving emissions (RDE) regulation, which mandates an additional on-road emissions test for EU type approvals, could be a step in the right direction to address this problem. PMID- 26580819 TI - Simultaneous determination and pharmacokinetic study of eight components in rat plasma by UHPLC-MS/MS after oral administration of Hypericum japonicum Thunb extract. AB - A rapid and sensitive assay based on ultra high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) was established and validated for the simultaneous determination of gallic acid, protocatechuic acid, vanillic acid, caffeic acid, epicatechin, isoquercitrin, vincetoxicoside B and quercetin in rat plasma using catechin and daidzein as the internal standards (IS). Plasma samples added internal standards were acidified with formic acid then pretreated by direct protein precipitation with acetonitrile. The separation of eight constituents was achieved on a C18 column with gradient elution using methanol and 0.2% acetic acid aqueous solution as the mobile phase and detected by multiple reaction monitoring using electrospray ionization source in the positive negative ionization mode. The method was validated for sufficient specificity, precision, accuracy, and sensitivity over the concentration range of 10-6000 ng mL(-1) for gallic acid, 1.5-3000 ng mL(-1) for protocatechuic acid, 10-15000 ng mL(-1) for vanillic acid, 2-3600 ng mL(-1) for caffeic acid, 1.5-3600 ng mL(-1) for epicatechin, 4-6000 ng mL(-1) for isoquercitrin, 2-9000 ng mL(-1) for vincetoxicoside B, and 20-18000 ng mL(-1) for quercetin. The overall intra-run precision and the inter-run precision were showed in the range of 1.0-14.2% and 2.8-12.9%, respectively, and the accuracy was no more than 12.8%. This analytical method was successfully applied to investigate the pharmacokinetics of eight ingredients in rats after oral administration of Hypericum japonicum Thunb extract. PMID- 26580820 TI - Isolation and characterization of a tadalafil analogue, N-cyclopentyl nortadalafil in health supplement. AB - A tadalafil analogue was detected for the first time during the screening of a health supplement for undeclared sexual enhancement drugs. The compound had been isolated and purified by preparative high-pressure liquid chromatography (HPLC). Its chemical structure was elucidated using high-resolution mass spectrometry (HRMS), electrospray ionization tandem mass spectrometry (ESI-MS/MS) and nuclear magnetic resonance (NMR) spectroscopy. The compound had a protonated molecular ion at m/z 444 with a chemical formula of C26H25N3O4. The data obtained from the MS analysis of the compound suggested that the N-methyl group on the piperazinedione moiety of tadalafil was substituted with a -C5H9 group. Analysis using NMR was performed and the -C5H9 group was characterized as a cyclopentyl moiety. The analogue was named N-cyclopentyl nortadalafil. PMID- 26580821 TI - Development and validation of a hydrophilic interaction chromatography method coupled with a charged aerosol detector for quantitative analysis of nonchromophoric alpha-hydroxyamines, organic impurities of metoprolol. AB - The European Pharmacopeia (EP) metoprolol impurities M and N are polar, nonchromophoric alpha-hydroxyamines, which are poorly retained in a conventional reversed-phase chromatographic system and are invisible for UV detection. Impurities M and N are currently analyzed by TLC methods in the EP as specified impurities and in the United States Pharmacopeia-National Formulary (USP-NF) as unspecified impurities. In order to modernize the USP monographs of metoprolol drug substances and related drug products, a hydrophilic interaction chromatography (HILIC) method coupled with a charged aerosol detector (CAD) was explored for the analysis of the two impurities. A comprehensive column screening that covers a variety of HILIC stationary phases (underivatized silica, amide, diol, amino, zwitterionic, polysuccinimide, cyclodextrin, and mixed-mode) and optimization of HPLC conditions led to the identification of a Halo Penta HILIC column (4.6 * 150 mm, 5 MUm) and a mobile phase comprising 85% acetonitrile and 15% ammonium formate buffer (100 mM, pH 3.2). Efficient separations of metoprolol, succinic acid, and EP metoprolol impurities M and N were achieved within a short time frame (<8 min). The HILIC-CAD method was subsequently validated per USP validation guidelines with respect to specificity, robustness, linearity, accuracy, and precision, and could be incorporated into the current USP-NF monographs to replace the outdated TLC methods. Furthermore, the developed method was successfully applied to determine organic impurities in metoprolol drug substance (metoprolol succinate) and drug products (metoprolol tartrate injection and metoprolol succinate extended release tablets). PMID- 26580822 TI - Detection and quantification of the selective EP4 receptor antagonist CJ-023423 (grapiprant) in canine plasma by HPLC with spectrofluorimetric detection. AB - Grapiprant, a novel pharmacologically active ingredient, acts as a selective EP4 receptor antagonist whose physiological ligand is prostaglandin E2 (PGE2). It is currently under development for use in humans and dogs for the control of pain and inflammation associated with osteoarthritis. The aim of the present study was to develop an easy and sensitive method to quantify grapiprant in canine plasma and to apply the method in a canine patient. Several parameters, both in the extraction and detection method were evaluated. The final mobile phase consisted of ACN:AcONH4 (20 mM) solution, pH 4 (70:30, v/v) at a flow rate of 1 mL/min. The elution of grapiprant and IS (metoclopramide) was carried out in isocratic mode through a Synergi Polar-RP 80A analytical column (150 mm * 4.6 mm). The best excitation and emission wavelengths were 320 and 365 nm, respectively. Grapiprant was extracted from the plasma using CHCl3, which gave a recovery of 88.1 +/- 10.22% and a lower limit of quantification (LLOQ) of 10 ng/mL. The method was validated in terms of linearity, limit of detection (LOD), LLOQ, selectivity, accuracy and precision, extraction recovery, stability, and inter-laboratory cross validation, according to international guidelines. The chromatographic runs were specific with no interfering peaks at the retention times of the analyte and IS, as confirmed by HPLC-MS experiments. In conclusion, this was a simple and effective method using HPLC-FL to detect grapiprant in plasma, which may be useful for future pharmacokinetic studies. PMID- 26580823 TI - On-line monitoring of blend uniformity in continuous drug product manufacturing process--The impact of powder flow rate and the choice of spectrometer: Dispersive vs. FT. AB - One of the commonly acknowledged issues in continuous manufacturing of drug products is how to provide a representative sampling on flowing powder to assure its blend uniformity. An investigation was conducted to improve understanding on the impact of powder flow rate under different continuous manufacturing conditions and the impact of optical parameters (such as resolution, co-adds, and integration time) on NIR spectral quality with respect to a dispersive and a Fourier transform instrument. A partial least squares (PLS)-based spectral pretreatment was found useful to tackle the impact of different flow rates on NIR spectral signals. Multivariate figures of merit (FOM) were used to evaluate performances across different instruments and optical settings and discover the advantageous selectivity and sensitivity on the Fourier transform than the dispersive instrument regardless of the use of co-adds. PMID- 26580824 TI - Preparation of a novel starch-derived three-dimensional ordered macroporous carbon for improving the dissolution rate and oral bioavailability of water insoluble drugs. AB - In our study, soluble starch was applied as a novel carbon source for preparing three-dimensional ordered macroporous carbon (3DOMC) using monodisperse silica nanospheres as the hard template. The 3DOMC was used as an insoluble drug carrier when it was found that it could markedly improve the water solubility of felodipine (FDP). The structural features of 3DOMC were characterized by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The 3DOMC structure was found to have a higher drug loading than microporous and mesoporous structures, and the interconnected nanostructure effectively inhibited the formation of drug crystals. FDP, belonging to the Biopharmaceutics Classification System II (BCSII), was chosen as the model drug and was loaded into the 3DOMC structure by solvent evaporation. The state of FDP in the 3DOMC structure was characterized by powder X-ray diffractometry (PXRD), differential scanning calorimetry (DSC) and Fourier-transform infrared spectroscopy (FTIR). The results obtained showed that FDP was present in the pores in an amorphous or microcrystalline state. In vivo and in vitro experiments indicated that 3DOMC could significantly improve the drug dissolution rate, but the FDP-3DOMC self made common tablets had the disadvantage of a burst effect. For this reason, osmotic pump technology was used to control the drug release rate. We developed a potentially useful insoluble drug carrier for pharmaceutical applications. PMID- 26580825 TI - Quantitation of sulfobutyl ether-beta-cyclodextrin (CaptisolTM) in Vestipitant IV solution by liquid chromatography with ultraviolet (UV) detection. AB - This work describes a simple, sensitive and fast liquid chromatographic method using ultraviolet (UV) detection for the quantitation of CaptisolTM (sulfobutyl ether-beta-cyclodextrin, SBE-beta-CD) in Vestipitant (GW597599) IV formulation. The chromatographic system consists of a cyano-modified silica stationary phase column with 0.5mM copper(II) acetate in 50/50 (v/v) water/acetonitrile and 0.05% (v/v) of trifluoroacetic acid as the mobile phase. Due to the fact that SBE-beta CD does not possess a chromophore suitable for UV detection, copper(II) acetate is used as a detection reagent. At low pH copper(II) acetate interacts with SBE beta-CD and produces mixed copper(II) [Cu(2+)] chelate and copper(II) mono acetate [CuOAc(+)] complexes, while displacing sodium ions [Na(+)] from the sulfobutyl ether (SBE) group. The copper(II)-SBE-beta-CD interaction has optical properties that allow its detection by UV. This novel method is highly reproducible and reliable for accurate quantitation of SBE-beta-CD content in the Vestipitant IV solution, and in the solution without the Vestipitant matrix. PMID- 26580826 TI - Determination of irinotecan and SN38 in human plasma by TurboFlowTM liquid chromatography-tandem mass spectrometry. AB - Irinotecan is a cytotoxic agent used in the treatment of metastatic colorectal cancer. Irinotecan is a prodrug when is converted in vivo to an active metabolite SN38, which has potent pharmacological activity. SN38 is then inactivated and excreted as SN38-glucuronide. High-performance liquid chromatography-mass spectrometry is a widely used bioanalysis technique that can be coupled to the turbulent-flow extraction line to shorten preparation time. A technique was developed to quantify irinotecan and its metabolite by liquid chromatography tandem mass spectrometry coupled with a turbulent-flow online extraction method. Assays were performed on 100 MUL of plasma after protein precipitation. The supernatant is injected directly into the extraction column, transferred to the chromatographic column, and analyzed by tandem mass spectrometry. Linearity, reproducibility and repeatability of the method were validated on a concentration range of 25-2500 ng/mL for irinotecan and 5-500 ng/mL for SN38. For the low limit of quantification of irinotecan and SN38, precision is 6.31% and 8.73%, and accuracy is 84.0% and 91.8%, respectively. The SN38-glucuronide determination protocol included a hydrolyzation step. This method was successfully used to quantify irinotecan, SN38 and SN38-G in human plasma in a clinical trial. PMID- 26580827 TI - Development of analytical methods for functional analysis of intracellular protein using signal-responsive silica or organic nanoparticles. AB - Because proteins control cellular function, intracellular protein analysis is needed to gain a better understanding of life and disease. However, in situ protein analysis still faces many difficulties because proteins are heterogeneously located within the cell and the types and amount of proteins within the cell are ever changing. Recently, nanotechnology has received increasing attention and multiple protein-containing nanoparticles have been developed. Nanoparticles offer a promising tool for intracellular protein analysis because (1) they can permeate the cellular membrane after modification or changing composition, (2) the stability of various proteins is improved by encapsulation within nanoparticles, and (3) protein release and activity can be controlled. In this review, we discuss the development of analytical methods for intracellular functional protein analysis using signal-responsive silica and organic nanoparticles. PMID- 26580828 TI - Comparison of two enzymatic immunoassays, high resolution mass spectrometry method and radioimmunoassay for the quantification of human plasma histamine. AB - Histamine (HA) is one of the main immediate mediators involved in allergic reactions. HA plasma concentration is well correlated with the severity of vascular and respiratory signs of anaphylaxis. Consequently, plasma quantification of HA is useful to comfort the diagnosis of anaphylaxis. Currently, radioimmunoassay (RIA) is the gold standard method to quantify HA due to its high sensitivity, but it is time consuming, implicates specific formations and cautions for technicians, and produces hazardous radioactive wastes. The aim of this study was to compare two enzymatic immunoassays (EIA) and one in-house liquid chromatography high-resolution mass spectrometry method (LC-HRMS) with the gold standard method for HA quantification in plasma samples of patients suspected of anaphylaxis reactions. Ninety-two plasma samples were tested with the 4 methods (RIA, 2 EIA and LC-HRMS) for HA quantification. Fifty-eight samples displayed HA concentrations above the positive cut-off of 10nM evaluated by RIA, including 18 highly positive samples (>100 nM). This study shows that Immunotech((r)) EIA and LC-HRMS concentrations were highly correlated with RIA values, in particular for samples with a HA concentration around the positive cut off. In our hands, plasma concentrations obtained with the Demeditec Diagnostics((r)) EIA correlated less with results obtained by RIA, and an underestimation of plasma HA levels led to a lack of sensitivity. In conclusion, this study demonstrates that Immunotech((r)) EIA and LC-HRMS method could be used instead of RIA to assess plasma HA in human diagnostic use. PMID- 26580829 TI - Robotic Single- and Multisite Cholecystectomy in Children. AB - BACKGROUND: Elective cholecystectomy is a high-volume, simple procedure, well suited for the development of a pediatric robotic surgery program. Surgical robot software, by "reversing" the surgeon's hands, simplifies single-site cholecystectomy through a single incision at the umbilicus. MATERIALS AND METHODS: Data were reviewed on the first nine children who had robotic cholecystectomy, with the Da Vinci(r) Surgical System (Intuitive Surgical Inc., Sunnyvale, CA) device, at our institution. All cases were performed by a single surgeon, proctored by an experienced robotic general surgeon. RESULTS: There were 9 patients: the first 4 patients had robotic multiport cholecystectomy, and the last 5 had robotic single-site cholecystectomy. Eight were girls. They were 10-18 years of age (median, 14 years). Diagnoses were biliary dyskinesia (n = 5) and symptomatic cholelithiasis (n = 4). Median body mass index was 24.9 (range, 20.2 43.8) kg/m(2). Median anesthesia time for multiport cholecystectomy was 139 (range, 120-162) minutes; median anesthesia time for single-site cholecystectomy was 169 (range 122-180) minutes. Median console time for multiport cholecystectomy was 47 (range, 44-58) minutes; median console time for single site cholecystectomy was 69 (range, 66-86) minutes. Eight of the 9 patients went home on the day of surgery, and 1 stayed overnight. Patients were seen at 13-20 days after surgery (median, 14 days). There were no complications. There were no conversions to open surgery and none from single-site to multiport surgery. CONCLUSIONS: Robotic cholecystectomy is safe and efficacious and is a suitable introductory procedure for pediatric surgeons considering a robotic surgery program. Single-site robotic cholecystectomy is a cosmetically attractive option but takes longer than multiport robotic cholecystectomy. PMID- 26580830 TI - How To Light Special Hot Spots in Multiparticle-Film Configurations. AB - The precise control over the locations of hot spots in a nanostructured ensemble is of great importance in plasmon-enhanced spectroscopy, chemical sensing, and super-resolution optical imaging. However, for multiparticle configurations over metal films that involve localized and propagating surface plasmon modes, the locations of hot spots are difficult to predict due to complex plasmon competition and synergistic effects. In this work, theoretical simulations based on multiparticle-film configurations predict that the locations of hot spots can be efficiently controlled in the particle-particle gaps, the particle-film junctions, or in both, by suppressing or promoting specific plasmonic coupling effects in specific wavelength ranges. These findings offer an avenue to obtain strong Raman signals from molecules situated on single crystal surfaces and simultaneously avoid signal interference from particle-particle gaps. PMID- 26580831 TI - The Effect of Topical Glycerol Trinitrate on Laser-Aided Facial Hair Removal: A Triple-Blinded Randomized Clinical Trial. AB - OBJECTIVE: Our purpose in this study was to assess the effect of topical glyceryl trinitrate on the efficacy of long-term white hair removal aided by laser therapy in hirsute women. BACKGROUND DATA: Nitric oxide (NO) induces vasorelaxation and augmented perfusion when released from endothelial cells or from an alternatively provided exogenous source. Separately, vascular endothelial growth factor (VEGF) mediated angiogenesis during the anagen phase, the phase most susceptible to laser elimination, and modulation of VEGF by NO, has been discussed previously, but there are limited data regarding an efficient method for long-term white hair removal. METHODS AND MATERIALS: We conducted a triple-blinded randomized controlled clinical trial. Hirsute women with excess facial hair without a known allergy to nitroglycerin derivatives were recruited, and randomly allocated to receive either premedication with 2 g glycerol trinitrate 3 days before the laser sessions once a day, or placebo. All the participants underwent six laser sessions with 1-month intervals. Baseline hair numbers were counted before, 3, 6, and 12 months after the first session. Data were analyzed with repeated measures ANOVA test. RESULTS: A total of 83 patients were enrolled in control (43) and case (40) groups. The trends for hair reduction in both studied groups were significant (p < 0.001), but there were no significant differences between the case and control groups during the study period. CONCLUSIONS: According to our findings, all patients, regardless of whether or not they used trinitrate, had significant success with hair removal. This study could not differentiate hair removal efficacy between the study groups. Studies with other laser types and larger sample sizes are suggested to investigate the effect of NO on hair production. PMID- 26580833 TI - Cerebrospinal Fluid Biomarker for Alzheimer Disease Predicts Postoperative Cognitive Dysfunction. AB - BACKGROUND: Postoperative cognitive dysfunction (POCD) affects 16 to 21% of the elderly 3 months after anesthesia and surgery and is associated with adverse outcomes. The exact cause of POCD remains unknown. The authors hypothesized that elderly individuals with Alzheimer disease (AD) neuropathology, identified by cerebrospinal fluid (CSF) analysis, would have increased the risk for POCD. METHODS: CSF samples were collected from 59 patients 60 yr or older who received combined spinal and general anesthesia for elective total hip replacement. Patients underwent neuropsychological testing preoperatively and at 7 days, 3 months, and 12 months postoperatively. POCD at 3 months and cognitive decline at 12 months were calculated by using the reliable change index. CSF amyloid beta1 42 (Abeta1-42), total-tau, phosphorylated-tau, and neurofilament light were assayed with enzyme-linked immunosorbent assay methods. RESULTS: POCD was identified in 5 of 57 patients (8.8%) at 3 months. For Abeta1-42, 11 patients were below the cut-point for AD neuropathology of whom 3 were classified with POCD (27.3%; 95% CI, 6.0 to 61%), whereas of the 46 patients above the cut-point, 2 were classified with POCD (4.3%; 95% CI, 0.5 to 14.8%) (P = 0.01). There was no significant difference in the incidence of POCD in relation to the cut-points for any of the other analytes. CONCLUSIONS: Low CSF Abeta1-42 may be a significant predictor of POCD at 3 months. This indicates that patients with AD neuropathology even in the absence of clinically detectable AD symptoms may be susceptible to POCD. PMID- 26580832 TI - The Role of Kv1.2 Channel in Electrotaxis Cell Migration. AB - Voltage-gated potassium Kv1.2 channels play pivotal role in maintaining of resting membrane potential and, consequently, regulation of cellular excitability of neurons. Endogenously generated electric field (EF) have been proven as an important regulator for cell migration and tissue repair. The mechanisms of ion channel involvement in EF-induced cell responses are extensively studied but largely are poorly understood. In this study we generated three COS-7 clones with different expression levels of Kv1.2 channel, and confirmed their functional variations with patch clamp analysis. Time-lapse imaging analysis showed that EF induced cell migration response was Kv1.2 channel expression level depended. Inhibition of Kv1.2 channels with charybdotoxin (ChTX) constrained the sensitivity of COS-7 cells to EF stimulation more than their motility. Immunocytochemistry and pull-down analyses demonstrated association of Kv1.2 channels with actin-binding protein cortactin and its re-localization to the cathode-facing membrane at EF stimulation, which confirms the mechanism of EF induced directional migration. This study displays that Kv1.2 channels represent an important physiological link in EF-induced cell migration. The described mechanism suggests a potential application of EF which may improve therapeutic performance in curing injuries of neuronal and/or cardiac tissue repair, post operational therapy, and various degenerative syndromes. PMID- 26580834 TI - We Need More Reports of Global Health Anesthesia Articles. PMID- 26580835 TI - An Anesthesiologist's Perspective on the History of Basic Airway Management: The "Preanesthetic" Era-1700 to 1846. AB - Basic airway management modern history starts in the early 18th century in the context of resuscitation of the apparently dead. History saw the rise and fall of the mouth-to-mouth and then of the instrumental positive-pressure ventilation generated by bellows. Pulmonary ventilation had a secondary role to external and internal organ stimulation in resuscitation of the apparently dead. Airway access for the extraglottic technique was to the victim's nose. The bellows-to-nose technique was the "basic airway management technique" applicable by both medical and nonmedical personnel. Although the techniques had been described at the time, very few physicians practiced glottic (intubation) and subglottic (tracheotomy) techniques. Before the anesthetic era, positive-pressure ventilation was discredited and replaced by manual negative-pressure techniques. In the middle of the 19th century, physicians who would soon administer anesthetic gases were unfamiliar with the positive-pressure ventilation concept. PMID- 26580836 TI - Practice Guidelines for Obstetric Anesthesia: An Updated Report by the American Society of Anesthesiologists Task Force on Obstetric Anesthesia and the Society for Obstetric Anesthesia and Perinatology. PMID- 26580837 TI - A genome-wide association study on amyotrophic lateral sclerosis in the Taiwanese Han population. AB - Identification of mutations in patients with amyotrophic lateral sclerosis (ALS) in a genome-wide association study can reveal possible biomarkers of such a rapidly progressive and fatal neurodegenerative disease. It was observed that significant single nucleotide polymorphisms vary when the tested population changes from one ethnic group to another. To identify new loci associated with ALS susceptibility in the Taiwanese Han population, we performed a genome-wide association study on 94 patients with sporadic ALS and 376 matched controls. We uncovered two new susceptibility loci at 13q14.3 (rs2785946) and 11q25 (rs11224052). In addition, we analyzed the functions of all the associated genes among 54 significant single nucleotide polymorphisms using Gene Ontology annotations, and the results showed several statistically significant neural- and muscle-related Gene Ontology terms and the associated diseases. PMID- 26580838 TI - Attacks on Health Care in Syria--Normalizing Violations of Medical Neutrality? PMID- 26580840 TI - From globules to crystals: a spectral study of poly(2-isopropyl-2-oxazoline) crystallization in hot water. AB - One easy strategy to comprehend the complex folding/crystallization behaviors of proteins is to study the self-assembly process of their synthetic polymeric analogues with similar properties owing to their simple structures and easy access to molecular design. Poly(2-isopropyl-2-oxazoline) (PIPOZ) is often regarded as an ideal pseudopeptide with similar two-step crystallization behavior to proteins, whose aqueous solution experiences successive lower critical solution temperature (LCST)-type liquid-liquid phase separation upon heating and irreversible crystallization when annealed above LCST for several hours. In this paper, by microscopic observations, IR and Raman spectroscopy in combination with 2D correlation analysis, we show that the second step of PIPOZ crystallization in hot water can be further divided into two apparent stages, i.e., nucleation and crystal growth, and perfect crystalline PIPOZ chains are found to only develop in the second stage. While all the groups exhibit changes in initial nucleation, only methylene groups on the backbone participate in the crystal growth stage. During nucleation, a group motion transfer is found from the side chain to the backbone, and nucleation is assumed to be mainly driven by the cleavage of bridging C=O...D-O-D...O=C hydrogen bonds followed by chain arrangement due to amide dipolar orientation. Nevertheless, during crystal growth, a further chain ordering process occurs resulting in the final formation of crystalline PIPOZ chains with partial trans conformation of backbones and alternative side chains on the two sides. The underlying crystallization mechanism of PIPOZ in hot water we present here may provide very useful information for understanding the crystallization of biomacromolecules in biological systems. PMID- 26580839 TI - Effect of miR-503 Down-Regulation on Growth and Invasion of Esophagus Carcinoma and Related Immune Function. AB - BACKGROUND MicroRNA (miR) has been proved to be an important biomarker for tumors because it can regulate occurrence, progression, invasion, and metastasis of cancer. A previous study has shown the involvement of miR-503 in multiple gastrointestinal tumors. Its detailed role and immune regulatory function in esophagus carcinoma, however, remains unknown. This study thus investigated the effect of miR-503 in regulating growth, proliferation, and invasion of esophagus cancer and its influence on cytokine secretion. MATERIAL AND METHODS Esophagus carcinoma cell line EC9706 and normal esophageal epithelial cell line HEEC were transfected with miR-503 inhibitor. MTT assay was used to quantify the cell proliferation, and a Transwell chamber was used to evaluate cell invasion. Release of cytokines, including interleukin-2 (IL-2), IL-4, IL-10, and interferon gamma (IFN-gamma), was measured by enzyme-linked immunosorbent assay (ELISA). RESULTS MiR-503 expression was significantly elevated in esophagus carcinoma cells (p<0.05). The specific inhibition of miR-503 expression remarkably suppressed proliferation and invasion of tumor cells. It can also down-regulated IL-2 and IFN-gamma expression and facilitate secretion of IL-4 and IL-10 when compared to the control group (p<0.05 in all ceases). CONCLUSIONS The inhibition of miR-503 can effectively inhibit tumor progression and improve immune function, suggesting its potency as a novel drug target for esophagus cancer treatment. PMID- 26580841 TI - Quality of Life during the First Two Years Post Stroke: The Restore4Stroke Cohort Study. AB - BACKGROUND: Little information is available about the course of quality of life (QoL) post stroke and how dependency on activities of daily living (ADL) influences this course. The aim of this study was therefore to describe the course of QoL from 2 months up to 2 years post stroke and to study the influence of ADL dependency in the first week post stroke. METHODS: This is a multicenter prospective longitudinal cohort study in which 368 stroke patients were included and data were collected at 1 week, 2 months, 6 months, 12 months and 24 months post stroke. QoL assessment included measures of health-related quality of life (HRQoL) (short stroke-specific Quality of Life Scale), emotional functioning (Hospital Anxiety and Depression Scale), participation (Utrecht Scale for Evaluation of Rehabilitation-Participation), and life satisfaction (2LS). Dependency on ADL was defined as having a Barthel Index score <= 17 four days post stroke. Generalized Estimating Equations analyses were performed to examine the course of the 4 domains of QoL. Furthermore, the possible confounding effect of age, gender, marital status, level of education and discharge destination was examined. RESULTS: Results showed that HRQoL, participation and life satisfaction improved during the first year post stroke, with most changes occurring in the first 6 months. Furthermore, patients dependent in ADL scored consistently lower on all 4 QoL domains and test occasions compared to ADL-independent patients. In both patient groups separately, no changes over time were found in emotional functioning. ADL-independent patients improved in HRQoL (p = 0.002), participation (p < 0.001) and life satisfaction (p = 0.020) between 2 and 6 months and in life satisfaction (p = 0.003) between 6 and 12 months also. ADL dependent patients improved in HRQoL (p = 0.009) between 2 and 6 months and in participation between 2 and 6 months (p = 0.001) and between 6 and 12 months (p = 0.031). Furthermore, they experienced no changes in life satisfaction. No confounding effect was found after adding age, gender, marital status, level of education and discharge destination. CONCLUSIONS: Most improvement in QoL occurred up to 6 months post stroke and showed different patterns for specific domains of QoL and for patients with and without dependency in ADL in the first week post stroke. It is therefore important to differentiate between these different domains of QoL when the long-term perspective is considered. Furthermore, patients dependent in ADL consistently scored lower on all QoL domains and did not reach the level of QoL of patients independent of QoL. PMID- 26580842 TI - Three-dimensionally grown thorn-like Cu nanowire arrays by fully electrochemical nanoengineering for highly enhanced hydrazine oxidation. AB - This communication reports fully electrochemical nanoengineering toward three dimensionally grown thorn-like Cu nanowire arrays (CNWAs) as a highly efficient and durable electrocatalyst for hydrazine oxidation. Characterized by substantial negative shifting of the onset potential and an enlarged catalytic current density, the CNWAs afforded greatly enhanced hydrazine oxidation activity, even transcending that of the Pt/C catalyst at a higher reaction rate. The parameters of the electrochemical engineering and metallization methods were found to be essentially influential on the microstructure, and thus the electrocatalytic activity of the CNWAs. The present work typifies a flexible and expandible route toward integrated electrodes of metallic 1D nanostructures which are of interest in advancing the performance of cutting-edge electrochemical applications. PMID- 26580843 TI - Responsive neurostimulation in epilepsy. AB - Various neurostimulation modalities have emerged in the field of epilepsy. Despite the fact that delivery of an electrical current to the hyperexcitable epileptic brain might, at first, seem contradictory, neurostimulation has become an established therapeutic option with a promising efficacy and adverse effects profile. In "responsive" neurostimulation the strategy is to interfere as early as possible with the accumulation of seizure activity to prematurely abort or even prevent an upcoming seizure. The design of technology required for responsive stimulation is more challenging compared with devices for open-loop neurostimulation. The achievement of therapeutic success is dependent on adequate sensing and stimulation algorithms and a fast coupling between both. The benefits of delivering current only at the time of an approaching seizure merit further investigation. Current experience with responsive neurostimulation in epilepsy is still limited, but seems promising. PMID- 26580845 TI - Atomically thin spherical shell-shaped superscatterers based on a Bohr model. AB - Graphene monolayers can be used for atomically thin three-dimensional shell shaped superscatterer designs. Due to the excitation of the first-order resonance of transverse magnetic (TM) graphene plasmons, the scattering cross section of the bare subwavelength dielectric particle is enhanced significantly by five orders of magnitude. The superscattering phenomenon can be intuitively understood and interpreted with a Bohr model. In addition, based on the analysis of the Bohr model, it is shown that contrary to the TM case, superscattering is hard to achieve by exciting the resonance of transverse electric (TE) graphene plasmons due to their poor field confinements. PMID- 26580844 TI - Anger and Posttraumatic Stress Disorder Symptom Severity in a Trauma-Exposed Military Population: Differences by Trauma Context and Gender. AB - Studies have found a stronger association between anger and posttraumatic stress disorder (PTSD) severity in military populations than in nonmilitary populations. Two hypotheses have been proposed to explain this difference: Military populations are more prone to anger than nonmilitary populations, and traumas experienced on deployment create more anger than nondeployment traumas. To examine these hypotheses, we evaluated the association between anger and PTSD severity among never-deployed military service members with nondeployment traumas (n = 226) and deployed service members with deployment traumas (n = 594) using linear regression. We further examined these associations stratified by gender. Bivariate associations between anger and PTSD severity were similar for nondeployment and deployment events; however, gender modified this association. For men, the association for deployment events was stronger than for nondeployment events (beta = .18, r = .53 vs. beta = .16, r = .37, respectively), whereas the reverse was true for women (deployment: beta = .20, r = .42 vs. nondeployment: beta = .25, r = .65). Among men, findings supported the hypothesis that deployment traumas produce stronger associations between PTSD and anger and are inconsistent with hypothesized population differences. In women, however, there was not a clear fit with either hypothesis. PMID- 26580846 TI - Application of an adapted Fano cavity test for Monte Carlo simulations in the presence of B-fields. AB - With the advent of MR guided radiotherapy the relevance of Monte Carlo radiation transport simulations in the presence of strong magnetic fields (B-fields) is increasing. While new tests are available to benchmark these simulation algorithms for internal consistency, their application to known codes such as EGSnrc, PENELOPE, and GEANT4 is yet to be provided. In this paper a method is provided to apply the Fano cavity test as a benchmark for a generic implementation of B-field effects in PENELOPE. In addition, it is investigated whether violation of the conditions for the Fano test can partially explain the change in the response of ionization chambers in the presence of strong B-fields. In the present paper it is shown that the condition of isotropy of the secondary particle field (Charged Particle Isotropy, CPI) is an essential requirement to apply the Fano test in the presence of B-fields. Simulations in PENELOPE are performed with (B = 0.0 T) and (B = 1.5 T) for cylindrical cavity geometry. The secondary particle field consists of electrons generated from a mono energetic source (E = 0.5-4.0 MeV) with a uniform source density and different angular distributions; isotropic, mono-directional, and Compton. In realistic photon fields the secondary radiation field has a non-isotropic angular distribution due to the Compton process. Based on the simulations for the Compton angular distribution (non-CPI), the response change of the cavity model in a uniform radiation field in the presence of B-fields is investigated. For the angular distributions that violate the CPI condition and B = 1.5 T, the deviations from 1 are considerable, which emphasizes the requirement of CPI. For the isotropic angular distributions obeying this requirement, both the results for B = 0.0 T and B = 1.5 T shows deviations from the predictions for E ? 1.5 MeV with values up to 1.0% for E = 4.0 MeV. Nevertheless, due to the high correlation in the deviation for B = 0.0 T and B = 1.5 T, the accuracy of the PENELOPE code for the simulation of the change in detector response in the presence of B-fields is within 0.3%. The effect of the B-field on the detector response for non-isotropic angular distributions suggests that violation of CPI is a major contribution to the response change of ionization chambers in the presence of B-fields. PMID- 26580847 TI - Eruptive Keratoacanthomas After Photodynamic Therapy. PMID- 26580848 TI - Unbinding forces and energies between a siRNA molecule and a dendrimer measured by force spectroscopy. AB - We have measured the intermolecular forces between small interference RNA (siRNA) and polyamidoamine dendrimers at the single molecular level. A single molecule force spectroscopy approach has been developed to measure the unbinding forces and energies between a siRNA molecule and polyamidoamine dendrimers deposited on a mica surface in a buffer solution. We report three types of unbinding events which are characterized by forces and free unbinding energies, respectively, of 28 pN, 0.709 eV; 38 pN, 0.722 eV; and 50 pN, 0.724 eV. These events reflect different possible electrostatic interactions between the positive charges of one or two dendrimers and the negatively charged phosphate groups of a single siRNA. We have evidence of a high binding affinity of siRNA towards polyamidoamine dendrimers that leads to a 45% probability of measuring specific unbinding events. PMID- 26580849 TI - IMPAIRED EXECUTIVE FUNCTIONING IN PEDIATRIC TRICHOTILLOMANIA (HAIR PULLING DISORDER). AB - BACKGROUND: No neurocognitive examinations of pediatric trichotillomania (hair pulling disorder; HPD) have taken place. As a result, science's understanding of the underlying pathophysiology associated with HPD in youths is greatly lacking. The present study seeks to begin to address this gap in the literature via examination of executive functioning in a stimulant-free sample of children with HPD. METHODS: Sixteen and 23 children between 9 and 17 years of age meeting DSM-5 diagnostic criteria for HPD or classified as a healthy control, respectively, were recruited (N = 39) to complete structured interviews, self-reports, and a subset of tests from the Cambridge Automatic Neurocognitive Test Assessment Battery (CANTAB) assessing cognitive flexibility/reversal learning (intradimensional/extradimensional; IED), working memory (spatial span; SSP), and planning and organization (Stocking of Cambridge; SOC). RESULTS: Hierarchical regression analyses indicated that, after controlling for appropriate covariates, diagnostic status predicted impaired performance on both the IED (reversal learning only) and SOC (planning and organization) but failed to predict cognitive flexibility or working memory capacity. Correlational analyses revealed that pulling severity was strongly related to working memory capacity, while disparate relationships between pulling styles (automatic, focused pulling) were evident with respect to working memory and planning and organization. CONCLUSIONS: Children with HPD performed more poorly on tasks of executive functioning as compared to controls. Correlational analyses suggest potentially distinct pathophysiology underlying automatic and focused pulling warranting further research. Limitations and future areas of inquiry are discussed. PMID- 26580851 TI - Current Biomedicine and Pharmaceutics: Research and Applications. PMID- 26580852 TI - Visual Pathways in Humans With Ephrin-B1 Deficiency Associated With the Cranio Fronto-Nasal Syndrome. AB - PURPOSE: Numerous animal studies demonstrated the importance of components of the ephrin/Eph system for correct visual system development. Analogous investigations in humans are entirely missing. Here, we examined the visual system in humans with ephrin-B1 deficiency, which is x-linked and associated with the cranio fronto-nasal syndrome (CFNS) in heterozygous females. METHODS: For one male hemizygous for ephrin-B1 deficiency and three affected heterozygous females with molecular-genetically confirmed mutations, the integrity of the partial decussation of the optic nerves was assessed with visual evoked potentials (VEPs) and compared with albinotic, achiasmic, and control participants with healthy vision. Further, retinal morphology and function and the gross-retinotopic representation of the primary visual cortex were examined with spectral-domain optical coherence tomography (SD-OCT), ERG, and multifocal (mf) VEPs for the male participant and part of the carriers. RESULTS: Strabismus and lack of stereovision was evident in the male and two of the females. Other characteristics of the visual system organization and function were normal: (1) retina: SD-OCT and funduscopy indicated normal foveal and optic nerve head morphology. Electroretinograms indicated normal retinal function, (2) optic chiasm: conventional (c)VEP showed no evidence for misrouting and mfVEPs were only suggestive of, if any, very minor local misrouting, and (3) visual cortex: mfVEP characteristics indicated normal retinotopic gross-representations of the contralateral visual hemifield in each hemisphere. CONCLUSIONS: While ephrin-B1 deficiency leads to abnormal visual pathways in mice, it leaves the human visual system, apart from deficits in binocular vision, largely normal. We presume that other components of the ephrin-system can substitute the lack of ephrin-B1 in humans. PMID- 26580853 TI - Retinal Vascular Fractals Correlate With Early Neurodegeneration in Patients With Type 2 Diabetes Mellitus. AB - PURPOSE: To investigate the correlation between the retinal vascular fractal dimension (Fd) and neurodegenerative changes in patients with no or mild diabetic retinopathy (DR). METHODS: In this cross-sectional study we examined 103 patients with type 2 diabetes mellitus (T2DM) with no or mild DR. In a randomly selected eye of each patient, Fd was calculated using SIVA-Fractal, a specialized semiautomatic software. Retinal neurodegeneration was evaluated by Topcon 3D OCT 2000 spectral-domain optical coherence tomography (OCT) and by a RETI-scan multifocal ERG (mf-ERG) system in rings one to six. Level of DR was determined by a single trained grader in seven-field fundus photos according to the Early Treatment Diabetic Retinopathy Study (ETDRS) scale. RESULTS: Mean age and duration of T2DM were 62.3 and 11.6 years, respectively; 46.6% were men. Mean Fd was 1.413 (range, 1.278-1.509) and ETDRS levels were 10 (42.7%), 20 (35.0%), and 35 (22.3%), respectively. Fd correlated inversely with mf-ERG implicit time of ring one (r = -0.25, P = 0.01) and present diabetic neuropathy (P = 0.02), and positively with OCT ganglion cell layer (GCL) thickness (r = 0.20, P = 0.04). In a multivariable linear regression model, Fd was associated with mf-ERG implicit time of ring one (coefficient -0.0021/ms, P = 0.040) and the presence of diabetic neuropathy (coefficient -0.0209 for neuropathy present versus absent, P = 0.041). CONCLUSIONS: In patients with T2DM and no or minimal DR, independent correlations were found between early vascular and neurogenic changes. Thus, retinal vascular fractal analysis might be considered as a tool to identify patients with early neurodegenerative retinal changes. PMID- 26580850 TI - Antibiotic Duration After Laparoscopic Appendectomy for Acute Complicated Appendicitis. AB - IMPORTANCE: Optimal duration of antibiotic treatment to reduce infectious complications after an appendectomy for acute complicated appendicitis remains unclear. OBJECTIVE: To investigate the effect of antibiotic duration on infectious complications after laparoscopic appendectomy for acute complicated appendicitis. DESIGN, SETTING, AND PARTICIPANTS: National multicenter prospective, observational, surgical resident-led cohort study conducted in June and July 2014. This study involved academic teaching hospitals (n = 8), community teaching hospitals (n = 38), and community nonteaching hospitals (n = 16), and all consecutive patients (n = 1975) who underwent surgery for suspected acute appendicitis. EXPOSURES: Patients treated laparoscopically for whom the antibiotic regimens were prolonged postoperatively because of complicated appendicitis. MAIN OUTCOMES AND MEASURES: Receiving either 3 or 5 days of antibiotic treatment as planned and additional variables were explored as risk factors for infectious complications using regression analyses. RESULTS: A total of 1975 patients were included in 62 participating Dutch hospitals; 1901 (96.3%) of these underwent an appendectomy for acute appendicitis and laparoscopy was used in 74.4% of these patients (n = 1415). In 415 laparoscopically treated patients, antibiotic treatment was continued for more than 24 hours because of acute complicated appendicitis (29.3%). The prescribed antibiotic duration varied between 2 and 6 days in all of these patients. In 123 patients (29.6%), the length of treatment was adjusted. A shorter duration of antibiotic treatment (3 days instead of 5) had no significant effect on any infectious complication (odds ratio [OR], 0.93; 95% CI, 0.38-2.32; P = .88) or on intra-abdominal abscess development (OR, 0.89; 95% CI, 0.34-2.35; P = .81). Perforation of the appendix was the only independent risk factor for the development of an infectious complication (OR, 4.90; 95% CI, 1.41-17.06; P = .01) and intra-abdominal abscess (OR, 7.46; 95% CI, 1.65-33.66; P = .009) in multivariable regression analysis. CONCLUSIONS AND RELEVANCE: Lengthening of postoperative antibiotic treatment to 5 days was not associated with a reduction in infectious complications. Further restriction of antibiotic treatment can be considered in nonperforated complicated appendicitis. PMID- 26580855 TI - Serological markers of hepatitis B and C in patients with HIV/AIDS and active tuberculosis. AB - Infection with hepatitis B virus (HBV) and C virus (HCV) are common in patients with HIV/AIDS and tuberculosis (TB). This is a cross-sectional study with patients infected with HIV/AIDS and active TB in Recife, Brazil, aiming to verify the prevalence of markers for HBV: antibody to hepatitis B core antigen (anti HBc); and HCV: antibody to hepatitis C virus (anti-HCV) by chemiluminescence, and to identify the frequency of associated factors. Data were collected through questionnaires, and blood was drawn from patients for analysis. We used the chi square test and the Fisher exact test when necessary. We conducted a bivariate logistic regression analysis and the magnitude of the associations was expressed as odds ratio (OR) with a confidence interval of 95%. Among 166 patients studied with HIV/AIDS and active TB, anti-HBc was positive in 61 patients [36.7%; 95%CI (29.4-44.6%)] and anti-HCV in 11[6.6%; 95%CI (3.4-11.5%)]. In the logistic regression analysis, male sex, and age >=40 years were independent factors associated with the occurrence of anti-HBc. In conclusion, we verified a high frequency of HBV contact marker and a low frequency of HCV markers in patients with HIV/AIDS and TB in Recife. PMID- 26580856 TI - Near-Infrared Light-Responsive Poly(N-isopropylacrylamide)/Graphene Oxide Nanocomposite Hydrogels with Ultrahigh Tensibility. AB - Novel near-infrared (NIR) light-responsive poly(N-isopropylacrylamide)/graphene oxide (PNIPAM-GO) nanocomposite hydrogels with ultrahigh tensibility are prepared by incorporating sparse chemical cross-linking of small molecules with physical cross-linking of graphene oxide (GO) nanosheets. Combination of the GO nanosheets and thermoresponsive poly(N-isopropylacrylamide) (PNIPAM) polymeric networks provides the hydrogels with an excellent NIR light-responsive property. The ultrahigh tensibility of PNIPAM-GO nanocomposite hydrogels is achieved by simply using a very low concentration of N,N'-methylenebis(acrylamide) (BIS) molecules as chemical cross-linkers to generate a relatively homogeneous structure with flexible long polymer chains and rare chemically cross-linked dense clusters. Moreover, the oxidized groups of GO nanosheets enable the formation of a hydrogen bond interaction with the amide groups of PNIPAM chains, which could physically cross-link the PNIPAM chains to increase the toughness of the hydrogel networks. The prepared PNIPAM-GO nanocomposite hydrogels with ultrahigh tensibility exhibit rapid, reversible, and repeatable NIR light-responsive properties, which are highly promising for fabricating remote light-controlled devices, smart actuators, artificial muscles, and so on. PMID- 26580854 TI - The bHLH Transcription Factor NeuroD Governs Photoreceptor Genesis and Regeneration Through Delta-Notch Signaling. AB - PURPOSE: Photoreceptor genesis in the retina requires precise regulation of progenitor cell competence, cell cycle exit, and differentiation, although information around the mechanisms that govern these events currently is lacking. In zebrafish, the basic helix-loop-helix (bHLH) transcription factor NeuroD governs photoreceptor genesis, but the signaling pathways through which NeuroD functions are unknown. The purpose of this study was to identify these pathways, and during photoreceptor genesis, Notch signaling was investigated as the putative mediator of NeuroD function. METHODS: In embryos, genetic mosaic analysis was used to determine if NeuroD functions is cell- or non-cell autonomous. Morpholino-induced NeuroD knockdown, CRISPR/Cas9 mutation, and pharmacologic and transgenic approaches were used, followed by in situ hybridization, immunocytochemistry, and quantitative RT-PCR (qRT-PCR), to identify mechanisms through which NeuroD functions. In adults, following photoreceptor ablation and NeuroD knockdown, similar methods as above were used to identify NeuroD function during photoreceptor regeneration. RESULTS: In embryos, NeuroD function is non-cell-autonomous, NeuroD knockdown increases Notch pathway gene expression, Notch inhibition rescues the NeuroD knockdown-induced deficiency in cell cycle exit but not photoreceptor maturation, and Notch activation and CRISPR/Cas9 mutation of neurod recapitulate NeuroD knockdown. In adults, NeuroD knockdown prevents cell cycle exit and photoreceptor regeneration and increases Notch pathway gene expression, and Notch inhibition rescues this phenotype. CONCLUSIONS: These data demonstrate that during embryonic development, NeuroD governs photoreceptor genesis via non-cell-autonomous mechanisms and that, during photoreceptor development and regeneration, Notch signaling is a mechanistic link between NeuroD and cell cycle exit. In contrast, during embryonic development, NeuroD governs photoreceptor maturation via mechanisms that are independent of Notch signaling. PMID- 26580857 TI - Fat distribution and major depressive disorder in late adolescence. AB - OBJECTIVE: Substantial evidence exists to indicate bidirectional relationships between obesity and depressive disorders and the importance of fat distribution to this relationship. This analysis used a well-characterized sample of individuals in late adolescence to determine the association between depressive illness and fat distribution. METHOD: Medically healthy 15- to 20-year-olds, one half of whom had recently begun treatment with a selective serotonin reuptake inhibitor, underwent a comprehensive psychiatric evaluation that resulted in diagnostic classification and weekly psychiatric disorder ratings over the prior 4 months using the Longitudinal Interval Follow-Up Evaluation. A whole-body scan, using dual-energy x-ray absorptiometry, allowed estimations of total body less head (TBLH), total mass, fat mass, and visceral adipose tissue (VAT) mass. Assessments occurred between September 2010 and April 2014. Multivariable linear regression analyses, adjusted for relevant covariates, examined the association between DSM-IV-TR-diagnosed major depressive disorder (MDD) and VAT, the primary outcome of interest. These procedures also determined whether significant associations were confined to overweight/obese participants. RESULTS: The analysis included data from 200 participants (71% female; mean age = 19.0 +/- 1.6 years), of whom 128 had current MDD. The presence of MDD was associated with increased fat mass among overweight/obese participants (Cohen d = 0.79, P < .02), but not normal weight participants. This was true of both visceral and nonvisceral fat mass measures. Accounting for the presence of generalized anxiety disorder (GAD) did not alter the findings. CONCLUSION: In adolescents, relationships between central adiposity and MDD may be confined to those who are overweight/obese. Despite the high comorbidity of GAD and depressive disorders, only the latter appeared to be significantly associated with central adiposity. PMID- 26580858 TI - Genome mining of astaxanthin biosynthetic genes from Sphingomonas sp. ATCC 55669 for heterologous overproduction in Escherichia coli. AB - As a highly valued keto-carotenoid, astaxanthin is widely used in nutritional supplements and pharmaceuticals. Therefore, the demand for biosynthetic astaxanthin and improved efficiency of astaxanthin biosynthesis has driven the investigation of metabolic engineering of native astaxanthin producers and heterologous hosts. However, microbial resources for astaxanthin are limited. In this study, we found that the alpha-Proteobacterium Sphingomonas sp. ATCC 55669 could produce astaxanthin naturally. We used whole-genome sequencing to identify the astaxanthin biosynthetic pathway using a combined PacBio-Illumina approach. The putative astaxanthin biosynthetic pathway in Sphingomonas sp. ATCC 55669 was predicted. For further confirmation, a high-efficiency targeted engineering carotenoid synthesis platform was constructed in E. coli for identifying the functional roles of candidate genes. All genes involved in astaxanthin biosynthesis showed discrete distributions on the chromosome. Moreover, the overexpression of exogenous E. coli idi in Sphingomonas sp. ATCC 55669 increased astaxanthin production by 5.4-fold. This study described a new astaxanthin producer and provided more biosynthesis components for bioengineering of astaxanthin in the future. PMID- 26580859 TI - Safe Use of Therapeutic-Dose Oral Isotretinoin in Patients With a History of Pseudotumor Cerebri. PMID- 26580860 TI - A Review: Pharmaceutical and Pharmacokinetic Aspect of Nanocrystalline Suspensions. AB - Nanocrystals have emerged as a potential formulation strategy to eliminate the bioavailability-related problems by enhancing the initial dissolution rate and moderately super-saturating the thermodynamic solubility. This review contains an in-depth knowledge of, the processing method for formulation, an accurate quantitative assessment of the solubility and dissolution rates and their correlation to observe pharmacokinetic data. Poor aqueous solubility is considered the major hurdle in the development of pharmaceutical compounds. Because of a lack of understanding with regard to the change in the thermodynamic and kinetic properties (i.e., solubility and dissolution rate) upon nanosizing, we critically reviewed the literatures for solubility determination to understand the significance and accuracy of the implemented analytical method. In the latter part, we reviewed reports that have quantitatively studied the effect of the particle size and the surface area change on the initial dissolution rate enhancement using alternative approaches besides the sink condition dissolution. The lack of an apparent relationship between the dissolution rate enhancement and the observed bioavailability are discussed by reviewing the reported in vivo data on animal models along with the particle size and food effect. The review will provide comprehensive information to the pharmaceutical scientist in the area of nanoparticulate drug delivery. PMID- 26580861 TI - Social Support and Women Living With Breast Cancer in the South of Thailand. AB - PURPOSE: To discuss social support among women with breast cancer in rural communities in southern Thailand. DESIGN: Qualitative research that allowed researchers to understand the lived experiences of women living with breast cancer and social support. METHODS: In-depth interviewing and drawing methods were adopted with 20 women with breast cancer. Thematic analysis was employed to analyze the data. FINDINGS: Most women with breast cancer received three types of social support: emotional support, tangible support, and informational support. Most support came from family members and relatives. Religion was also a form of social support for women. Many women, however, received insufficient social support from healthcare providers. This reduced their capacity to manage their illness, thus impacting their well-being. CONCLUSIONS: Various forms of support are essential for women with breast cancer so that they can better cope with their condition. CLINICAL RELEVANCE: Nurses and other health professionals are an important source of social support for women with breast cancer. Through having an understanding of and being sensitive to these women's experiences, culture, and challenges, nurses and healthcare professionals can provide more individualized support and care to women during a vulnerable period of their life. We contend that the cultural perspectives of patients are crucial in nursing science. Nurses need to appreciate the importance of culture for the support of patients with breast cancer. PMID- 26580862 TI - Tranexamic acid-associated seizures: Causes and treatment. AB - Antifibrinolytic drugs are routinely used worldwide to reduce the bleeding that results from a wide range of hemorrhagic conditions. The most commonly used antifibrinolytic drug, tranexamic acid, is associated with an increased incidence of postoperative seizures. The reported increase in the frequency of seizures is alarming, as these events are associated with adverse neurological outcomes, longer hospital stays, and increased in-hospital mortality. However, many clinicians are unaware that tranexamic acid causes seizures. The goal of this review is to summarize the incidence, risk factors, and clinical features of these seizures. This review also highlights several clinical and preclinical studies that offer mechanistic insights into the potential causes of and treatments for tranexamic acid-associated seizures. This review will aid the medical community by increasing awareness about tranexamic acid-associated seizures and by translating scientific findings into therapeutic interventions for patients. PMID- 26580863 TI - Pathological spectrum of bile duct lesions from chronic bile duct injury to invasive cholangiocarcinoma corresponding to bile duct imaging findings of occupational cholangiocarcinoma. AB - BACKGROUND: We aimed to identify the pathological characteristics of occupational cholangiocarcinoma. METHODS: We examined the location and distribution of the carcinomas: atypical epithelium including biliary intraepithelial neoplasia (BilIN) and intraductal papillary neoplasm of the bile duct (IPNB); and chronic bile duct injuries in operative or autopsy liver specimens from 16 patients. We examined the detailed pathological findings and diagnostic imaging of three patients. Immunohistochemical analysis using primary antibodies against gammaH2AX and S100P was performed. RESULTS: BilIN and chronic bile duct injury were observed in 16 patients, and IPNB or invasive IPNB was observed in 11 patients. BilIN, IPNB, and/or chronic bile duct injury were observed in almost all the large bile ducts. Regional dilatation of the bile ducts without tumor-induced obstruction revealed such pathological changes. Highly positive results for the gammaH2AX and S100P markers were noted in invasive carcinoma, BilIN, and IPNB, whereas positive results for gammaH2AX and negative results for S100P were noted in non-neoplastic biliary epithelium. CONCLUSIONS: The carcinogenic process of occupational cholangiocarcinoma comprised chronic bile duct injury and DNA damage in almost all the large bile ducts, along with induction of precancerous lesions and development of invasive carcinoma. Such pathological findings reflected radiological changes on diagnostic imaging. PMID- 26580865 TI - Wave Science in Dermatologic Therapy. PMID- 26580864 TI - Latent developmental and evolutionary shapes embedded within the grapevine leaf. AB - Across plants, leaves exhibit profound diversity in shape. As a single leaf expands, its shape is in constant flux. Plants may also produce leaves with different shapes at successive nodes. In addition, leaf shape varies among individuals, populations and species as a result of evolutionary processes and environmental influences. Because leaf shape can vary in many different ways, theoretically, the effects of distinct developmental and evolutionary processes are separable, even within the shape of a single leaf. Here, we measured the shapes of > 3200 leaves representing > 270 vines from wild relatives of domesticated grape (Vitis spp.) to determine whether leaf shapes attributable to genetics and development are separable from each other. We isolated latent shapes (multivariate signatures that vary independently from each other) embedded within the overall shape of leaves. These latent shapes can predict developmental stages independent from species identity and vice versa. Shapes predictive of development were then used to stage leaves from 1200 varieties of domesticated grape (Vitis vinifera), revealing that changes in timing underlie leaf shape diversity. Our results indicate that distinct latent shapes combine to produce a composite morphology in leaves, and that developmental and evolutionary contributions to shape vary independently from each other. PMID- 26580866 TI - Randomized, Double-Blind, Split-Face Study Evaluating Fractional Ablative Erbium:YAG Laser-Mediated Trans-Epidermal Delivery of Cosmetic Actives and a Novel Acoustic Pressure Wave Ultrasound Technology for the Treatment of Skin Aging, Melasma, and Acne Scars. AB - BACKGROUND: Fractional laser resurfacing enhances trans-epidermal delivery (TED), however laser penetration depths >250- MUm fail to substantively increase drug delivery. AIM: Evaluate the safety and efficacy of a novel acoustic pressure wave ultrasound device following fractional ablative Er:YAG 2940-nm laser (FELR) and topical agents for rhytids, melasma, and acne scars. STUDY DESIGN: Randomized, blinded, parallel group split-face side-by-side, controlled study evaluating FELR and topical anti-aging and anti-pigment agents to entire face succeeded by ultrasound to randomized side. Fifteen subjects were enrolled to three treatment arms:rhytids, melasma, and acne scars. Two monthly treatments were administered with 1, 3, and 6 month follow-up. Efficacy was assessed by Comprehensive Grading Scale of Rhytids, Laxity, and Photoaging by Investigator and two blinded physician evaluators. Subject assessments, digital photographs, and reflectance spectroscopic analyses were obtained. RESULTS: Rhytid severity was reduced from a mean of 3.25 to 2.60 on the 4-point grading scale. Spectrophotometric analysis demonstrated increases in lightness (L*) and reductions in redness (a*) and pigment (b*), with greater improvements on the ultrasound side as compared to FELR and topicals alone. Moderate erythema post-treatment resolved in 7 days and no serious adverse events were observed. CONCLUSION: In this randomized, paired split-face clinical study, FELR-facilitated TED of topical anti-aging actives with ultrasound treatment is safe and effective with improvement in rhytids, melasma, and acne scars. Statistically significant greater improvement in pigment levels was observed on the ultrasound side as compared to FELR-TED and topical agents alone. PMID- 26580867 TI - Clinical Improvement and Safety of Ablative Fractional Laser Therapy for Post Surgical Scars: A Systematic Review of Randomized Controlled Trials. AB - BACKGROUND: Ablative fractional laser (AFL) therapy for scars is an area of increasing interest. While the enthusiasm for these treatments is high, a systematic review of their use on surgical scars has not been done. OBJECTIVE: To identify randomized trials that study the efficacy of ablative fractionated laser therapy for treatment of surgical scars. METHODS AND MATERIALS: EMBASE, Web of Science, and Pubmed databases were searched for randomized trials with 10 or more surgical wounds. No restrictions were placed on the language of the publications. RESULTS: Three randomized trials were identified that met the criteria for the review. One study found superior efficacy of ablative fractionated laser treatment of surgical scars compared to pulsed dye laser while the others found equivalent efficacy when compared to dermabrasion or pulsed dye laser. One study found a superior safety profile for ablative fractionated laser treatment over dermabrasion. No studies compared fractionated laser therapy to sham therapy or observation. CONCLUSIONS: AFL compares well with the scar amelioration techniques of dermabrasion and pulsed dye laser. Additional studies are needed to further contrast AFL to these and other modalities as well as to observation alone. PMID- 26580868 TI - The Use of a Fractional Ablative Micro-Plasma Radiofrequency Device in Treatment of Striae. AB - OBJECTIVE: To evaluate the efficacy of a fractional ablative micro-plasma radiofrequency (RF) device in the reduction of the appearance of abdominal striae. METHODS: Five female patients (age range, 30-60) with abdomen striae alba (n=4) and striae rubra (n=1) were enrolled in the study. Skin type distribution among the 5 patients was two type II, one type III, and two type IVs. The device (Accent XL, Alma Lasers Inc.) is a radiofrequency fractional platform (40.68 MhZ) that deploys multiple conical pin electrodes on a moving handheld 6 cogs roller. Four treatments were performed every two weeks with settings based on test spots performed two weeks prior to a full treatment session. Assessment of striae was based on clinical severity of the lesions on a 1-4 scale, with "4" being the most severe. A questionnaire was administered to patients with possible subjective responses ranging from 0-4, with 0 being no improvement and quartiles from 1-4 (1= mild improvement, 2= fair improvement, 3= moderate improvement, and 4= marked improvement, respectively). RESULTS: Three months after 4 treatments, a mean improvement of 20% was achieved (mean severity score changed from 2.9 to 2.5). Micro-wounds were approximately 200 MUm wide on the surface, initially presenting as small gray "dots" and evolving into black dots lasting about 2 weeks. Mean pain was 2/10. Erythema and edema persisted for about one day. No pigmentation abnormalities were observed at the final evaluation. The results from the patient questionnaire revealed a mean score of 2.4/4, thus falling in the range of good to very good. CONCLUSION: A fractional ablative micro-plasma RF roller device can improve improvement in the appearance of abdomen striae. PMID- 26580869 TI - Pulsed Dye Laser for Early Treatment of Scars After Dermatological Surgery. AB - BACKGROUND: Wound healing is a complex process; during the process angiogenesis takes place, that presents clinically as erythema, telangiectasia and edema. Pulsed dye laser (PDL) has a wavelength of 585-595 nm, which targets the chromophore hemoglobin. OBJECTIVE: Determine the level of improvement of post dermatological surgery scars. METHODS: Thirty patients attending for excision lesion were recruited. They were randomized to 1 of 2 groups. Group 1 scar was randomly divided into 2 parts, one half received PDL 595 nm on 3 occasions; the first after suture removal, 15 and 45 days. Group 2 in one half laser application was simulated while the other was left untreated. The Vancouver scar scale (VSS) was used by an external evaluator to assess the scars. Two skin biopsies were also obtained one before and one after laser treatment. RESULTS: The VSS at 45 days decreased in a significant way in the treatment group from 4 to 1 (P = .005). In the control group decreased from 2 to 1.3 (P = .056). No significant difference was found between the presence of inflammatory infiltrate of patients in the placebo group. CONCLUSION: This study confirmed the usefulness of pulsed dye laser for improving the appearance of scars. PMID- 26580870 TI - Synergistic Approaches to Neck Rejuvenation and Lifting. AB - There is an increasing trend shifting the aesthetic focus downward from the face with a significant number of new treatments aimed at the aging neck and below. Clinical characteristics of neck youth include clear skin texture and tone without laxity or fat, in addition to a well-defined cervicomental angle and distinct mandibular border. Similarly to treating facial aging, the neck requires a comprehensive assessment of all factors involved in the aging process--loss of volume, increased skin laxity, worsening texture and clarity, and crepe skin/wrinkling--as each requires a combination approach for improvement. It is essential to address each above factors for more than minimal improvement. A multitude of options including neuromodulators, energy based devices, surgery, and injectable agents for fat reduction are available in our armamentarium and understanding these options solo, or ideally in combination, is essential for best practice and optimal results. Herein, we describe synergic approaches to the treatment of neck aging. PMID- 26580871 TI - Radiofrequency in Cosmetic Dermatology: An Update. AB - Treatment options for cosmetic improvement of the skin and body continue to grow more numerous with each passing year. The decline in utilization of invasive surgical treatments for aging and body contour correlates with the recent rise in laser and light devices. These light based technologies transmit either a single or broad wavelength of amplified light to the skin, resulting in volumetric tissue heating. Depending on the chromophore targeted and wavelength applied, varied applications exist to treat numerous cosmetic concerns. Radiofrequency (RF) devices have become more popular recently as science has advanced and brought new, safer, and better therapies. PMID- 26580872 TI - A Controlled Comparison Study of Topical Fluourouracil 5% Cream Pre-Treatment of Aminolevulinic Acid/Photodynamic Therapy for Actinic Keratosis. AB - INTRODUCTION: Topical Fluorouracil 5% cream (5-FU) and 20% aminolevulinic acid (ALA)/ photodynamic therapy (PDT) are both FDA approved for the treatment of Actinic Keratosis (AK). We have studied the use of these 2 agents alone and in a sequential manner. We have also used a 5-FU re-challenge 3 months after treatment to highlight the efficacy of these treatments. METHODS: This was an investigator blinded randomized study in which 30 patients were randomized 1:1:1 into the following groups: Group 1 patients pretreated for 6-7 days with 5-FU, ALA applied with incubation of 2 hours, ALA removed with wet gauze, illuminated treated areas with 10 J/cm(2) with Blu-U device; Group 2 patients treated with 5-FU BID for 6-7 days and no ALA/PDT; Group 3 patients received no pretreatment, ALA applied with incubation of 2 hours, ALA removed with wet gauze, illuminated treated areas with 10 J.cm2 with Blu-U device. Patients were seen at screening/baseline, treatment for ALA/PDT, 24 hours post treatment, 1 week post treatment and 3 months post treatment. All subjects were then given a re-challenge course of 5-FU for 6 days and reassessed. RESULTS: AK counts in all groups were dramatically decreased and similar at 1 and 3 months post treatment. The re-challenge brought a significant difference with many subclinical lesions in the area of activity in the ALA and 5 FU alone groups. CONCLUSIONS: All three arms appeared equal in treating visible AKs. These data strongly suggests a synergistic role of 5-FU with ALA/PDT over ALA/PDT or 5-FU alone in treating the subclinical lesions demonstrated on a 5-FU re-challenge. Treatment of these subclinical lesions should result in a longer remission. The data also suggests that a 5-FU re-challenge could be a clinical tool to judge the efficacy of treatment for AK if these subclinical lesions are proven to be an AK precursor. PMID- 26580873 TI - Analysis of Depth of Ablation,Thermal Damage, Wound Healing, and Wound Contraction With Erbium YAG Laser in a Yorkshire Pig Model. AB - BACKGROUND AND OBJECTIVES: The erbium YAG laser is commonly used for skin resurfacing. It is known that varying the pulse duration can influence residual thermal damage and wound healing. Our study used a porcine model to evaluate a broad range of settings in a comparison of depth of ablation, depth of residual thermal damage (RTD), and wound contraction employing both a full coverage and fractional hand piece with an erbium YAG laser. MATERIALS AND METHODS: The laser delivered an ablative pulse followed by a heating pulse of variable duration using either the full coverage or fractional hand piece. Pulse durations for specific coagulation depths were selected based on existing heat transfer models. The bilateral flanks of a single Yorkshire pig were irradiated. There were 14 treatment groups. 3 sites were treated per group for a total of 42 sites. Two of the 3 sites were for observational assessments and the 3rd site served as a reservoir for biopsies. Biopsy specimens were collected on days 0, 1, 3, 7, 14, and 28. Bleeding, erythema, wound healing, and wound contraction (in the fractional hand piece groups) were assessed. CONCLUSION: Wound healing is faster for fractional laser skin resurfacing compared with traditional contiguous resurfacing as demonstrated by textural changes and degree of erythema. The laser operator can be confident that the depth of ablation displayed on this system accurately reflects what is occurring in vivo for both confluent and fractional modes. Likewise, the measured degree of coagulation was consistent with panel display settings for the confluent mode. However, the degree of coagulation, as measured by the thickness of residual thermal damage, did not vary significantly between the fractional groups. In other words, the pulse duration of the second (heating) pulse did not impact the degree of coagulation in the fractional mode. There was a 2.3% wound contraction between some groups and a 6.5% wound contraction between other groups. A two way analysis of variance found a statistically significant difference in wound contraction based on ablation depth ( P = 0.012) but the degree of coagulation did not prove to be statistically significant for wound contraction (P = 0.66). PMID- 26580874 TI - Intense Pulsed Light Pulse Configuration Manipulation Can Resolve the Classic Conflict Between Safety and Efficacy. AB - The widely used intense pulse light (IPL) technology was first commercially launched to the medical market in 1994 and similar to lasers, is based on the basic principle of selective photothermolysis. The main conflict during treatments with light-based technologies is between safety and efficacy of the treatment. The aim of this study was to evaluate new IPL technology, which integrates three different pulse configurations, with specific attention on the safety and efficacy of the treatment. 101 volunteers (with Fitzpatrick skin types I-VI) were treated as follows: 9 patients underwent 8 bi-weekly acne clearance treatments, 51 patients underwent 6-12 hair removal treatments, 11 patients were treated for general skin rejuvenation, 15 patients were treated for pigmentation lesions, and 15 patients were treated for vascular lesions. No serious adverse events were recorded. All patients that were treated for hair removal achieved significant hair clearance. The patients with facial rosacea responded the fastest to the treatment. Eight of nine patients that were treated for acne clearance achieved significant reduction in acne appearance. The results represented in this study support the approach that when taking into consideration both efficacy of the treatment and safety of the patients, the system should be "flexible" enough to allow exact treatment settings profile for each patient, according to their skin type and the symptom's biophysical characteristics. < PMID- 26580875 TI - Evaluation of a Low Energy, Low Density, Non-Ablative Fractional 1927 nm Wavelength Laser for Facial Skin Resurfacing. AB - OBJECTIVE: We investigated the safety, tolerability and efficacy of a low energy low density, non-ablative fractional 1,927-nm laser in the treatment of facial photodamage, melasma, and post inflammatory hyperpigmentation. DESIGN: Prospective non-randomized trial. SETTING: Single center, private practice with a dedicated research department. PARTICIPANTS: Subjects with clinically diagnosed facial photodamage, melasma, or post inflammatory hyperpigmentation. INTERVENTIONS: Subjects received four to six treatments at 14-day intervals (+/- 3 days) with a low energy low density non-ablative fractional 1,927-nm laser (Solta Hayward, CA) with an energy level of 5 mJ, and density coverage of either 5%, 7.5%, or 10%, with a total of up to 8 passes. MAIN OUTCOME AND MEASURES: Blinded assessment of clinical photos for overall improvement at one and three months post final treatment. Investigator improvement scores, and subject pain and satisfaction scores for overall improvement were recorded as well. RESULTS: We enrolled 23 subjects, average age 45.0 years (range, 25-64 years), 22 with Fitzpatrick Skin Types I-IV and 1 with Type VI, with facial photodamage, melasma, or post inflammatory hyperpigmentation. Approximately 55% of subjects reported marked to very significant improvement at one and three months post final treatment. Blinded assessment of photography of 20 subjects revealed an average of moderate improvement at one-month follow up and mild to moderate improvement at three months. Average subject pain score was 3.4/10 during treatment. CONCLUSIONS AND RELEVANCE: Favorable outcomes were demonstrated using the low energy low density, non-ablative fractional 1,927-nm laser in facial resurfacing for photodamage, melasma, and post inflammatory hyperpigmentation. Results were maintained at the 3-month follow up, as demonstrated by investigator and subject assessments, as well as blinded evaluations by three independent dermatologists utilizing photographs obtained from a standardized facial imaging device. PMID- 26580876 TI - A Retrospective Study of Patient Satisfaction Following a Trial of Nano fractional RF Treatment. AB - Traditional techniques used to treat dermatological conditions have typically involved surgery or full ablation of tissue. With the emergence of fractional radiofrequency (RF) technology, treatment for various skin conditions no longer requires surgery or full ablation. Instead, these treatment techniques deliver thermal energy, derived from fractional RF energy, in a highly targeted manner through multiple micro-needles, referred to as pins. This technique hastens recovery time and leads to less reported side effects associated with traditional methods of tissue augmentation. While the efficacy of this treatment has been demonstrated, patient satisfaction has not been assessed and documented thoroughly. The current study examined patient-reported satisfaction following treatment with the Venus Viva(TM) as assessed across five separate domains of self-reported satisfaction; degree of comfort during treatment procedures, recovery time following treatment, convenience and efficiency of treatment appointments, treatment results, and whether the patient would recommend the treatment to a friend. Participants included 43 healthy adult volunteers who reported varying degrees of facial dermatological conditions, such as rhytides, hyperpigmentation, or the redness associated with acne vulgaris. Participants received between one and three treatments with the Venus Viva(TM) device. Patient satisfaction was assessed three months following the last treatment. Results indicated that patients are highly satisfied with treatments received from the Venus Viva(TM) device and are highly likely to recommend the procedure to a friend. PMID- 26580877 TI - A Preliminary Study of a Transdermal Radiofrequency Device for Body Slimming. AB - BACKGROUND: The use and potential of radiofrequency energy for tissue contracture and body contouring has been established in the literature. Maximum reduction of laxity can be achieved by simultaneously tightening surface tissue and reducing unwanted fat below by the transdermal application of heat to reach and maintain tissue temperature targets within a well-defined range, inducing collagen remodeling in skin as well as apoptosis of fat cells and creating an overall slimming effect. A novel device utilizes transcutaneous monopolar RF for body slimming in this manner, employing a thermistor feedback control mechanism to safely manage energy delivery and tissue temperature. METHODS: Subjects (n=14) presenting with abdominal laxity were treated up to four times using the transcutaneous monopolar RF device at one or two zones in the abdominal region (at operator's discretion). Non-expert blinded graders rated correction on an arbitrary scale (0=no laxity, 4=maximum laxity) after choosing the order of the before-and-after photo sets. A patient satisfaction survey was also administered. RESULTS AND DISCUSSION: The two graders correctly ordered 10 of 14 photo sets in agreement. Average rated improvement was 0.75 and 0.80 for graders 1 and 2, respectively. Patient survey results revealed average perceived tightening of 2.14 points on a 0 to 4 scale (0=lowest tightening result, 4=highest tightening), and 8 of 14 subjects would recommend treatment to others. CONCLUSION: Transdermal monopolar RF is a safe and effective modality for non-invasive body slimming. PMID- 26580878 TI - Excellent Aesthetic and Functional Outcome After Fractionated Carbon Dioxide Laser Skin Graft Revision Surgery: Case Report and Review of Laser Skin Graft Revision Techniques. AB - Skin grafts are utilized in dermatology to reconstruct a defect secondary to surgery or trauma of the skin. Common indications for skin grafts include surgical removal of cutaneous malignancies, replacement of tissue after burns or lacerations, and hair transplantation in alopecia. Skin grafts may be cosmetically displeasing, functionally limiting, and significantly impact patient's quality-of-life. There is limited published data regarding skin graft revision to enhance aesthetics and function. Here, we present a case demonstrating excellent aesthetic and functional outcome after fractionated carbon dioxide (CO2) laser skin graft revision surgery and review of the medical literature on laser skin graft revision techniques. PMID- 26580879 TI - A Prospective, Neurophysiologic Comparative Study to Assess the Efficacy and Duration of Effect of IncobotulinumtoxinA and AbobotulinumtoxinA in the Treatment of Crow's Feet. AB - This randomized, rater-blind, split-face study compared the safety and efficacy of incobotulinumtoxinA and abobotulinumtoxinA for the treatment of crow's feet. Nine units of incobotulinumtoxinA were administered to the lateral periorbital region of one side of the face and 27 units of abobotulinumtoxinA to the other in healthy subjects (aged 35-55 years) with moderate-to-severe crow's feet at rest (2-3 points on the 5-point Merz Aesthetics Scale [MAS]). Investigators assessed efficacy using the MAS, while subjects assessed using a 9-point global assessment scale. Secondary objectives included electromyography to assess muscle activity before injection and at 2 weeks, 4 months, and 6 months afterwards. Twenty women were enrolled and 18 completed the study. At rest and maximum smile, at each time point, the mean wrinkle scores were significantly lower (P <= 0.05) than baseline for both treatments. No differences were noted between treatments. Responder (>= 1-point improvement from baseline) rates for both products were 100% and 83% at 2 weeks and 4 months post-treatment, respectively. At 6 months post-treatment, responder rates were 67% and 61% for incobotulinumtoxinA and abobotulinumtoxinA, respectively. For both, the maximum changes in electromyography parameters were observed 2 weeks post-treatment. A response was maintained for 6 months (P <= 0.05 vs baseline). Both treatments were well tolerated; only mild adverse events were reported. In conclusion, for treatment of crow's feet, incobotulinumtoxinA and abobotulinumtoxinA (1:3 dose) demonstrated comparable efficacy in terms of magnitude and longevity of effect. Both products demonstrated a high responder rate, with the response being maintained for 6 months in the majority. PMID- 26580880 TI - Expanding the Clinical Application of Fractional Radiofrequency Treatment: Findings on Rhytides, Hyperpigmentation, Rosacea, and Acne Redness. AB - While radiofrequency has been used medically for decades to treat a wide variety of conditions, its use therapeutically to target conditions affecting the skin is relatively new. With the development of fractional radiofrequency, which allows for the heat energy to be delivered in a more targeted manner through the use of needles as electrodes, this technique is now the preferred medical treatment option for many skin conditions given the reduction in recovery time and fewer number of reported side effects. The current study examined the clinical effectiveness of SmartScan(TM) Nano-Fractional RFTM treatment. Participants included 12 healthy female volunteers who reported varying degrees of rhytides, hyperpigmentation, or acne redness. Participants each received one treatment of SmartScan Nano-Fractional RF. The areas receiving treatment were photographed in a standardized way, using high-resolution macrophotography, at baseline (prior to receiving the treatment) and one month after treatment. Baseline and post treatment photographs were then visually compared for treatment effects and analyzed through software-assisted quantification of variation in pigmentation and skin texture. The results indicated that this SmartScan technique for Nano Fractional RF is effective in improving skin texture, and pigmentation. PMID- 26580881 TI - An Evaluation of Efficacy and Tolerability of Novel Enzyme Exfoliation Versus Glycolic Acid in Photodamage Treatment. AB - BACKGROUND: Glycolic acid acts by chemical destruction of adhesions between skin cells to exfoliate superficial skin layers and excess pigmentation. It is well known to improve the appearance of photoaged skin, but is associated with varying degrees of skin irritation. Hydrolyzed salmon roe proteins destroy cell adhesions enzymatically with potentially less irritation than acid treatments. This double blind prospective study assesses the efficacy and tolerability of hydrolyzed roe versus glycolic acid, and glycolic acid with citric acid. METHODS: 75 female subjects with mild to moderate photodamage, all skin types, and ages 31-70 years, were enrolled. In this 12 week study of twice daily self-treatments, patients were assigned to one of 3 groups; Group 1 (n-19) was assigned hydrolyzed roe cream, Group 2 (n=17), 4% glycolic acid, or Group 3 (n-16), 8% glycolic acid plus 2% citric acid. All patients used the same mild face wash and SPF 30 sunscreen throughout the study. Patients were evaluated at weeks 0, 8 and 12 for objective and subjective tolerability, improvement in photodamage by VISIA Complexion Analysis, modified Packman and Gans method, Visual Analog Scale (VAS), and answered an opinion questionnaire. RESULTS: Group 1 improved in skin clarity from a VAS 44.1 to 55.7 (P=0.0317) at week 12. VISIA mean scores correlated with office evaluation showing improvement in brown spots from 453 to 417 (P = 0.0115) at 12 weeks. Group 2 improved in superficial fine lines at week 8 (-5.9, P=0.0428) and week 12 (-9.1, P=0.0019). Group 3 improved at week 12 in skin clarity (11.5, P = 0.0469) and skin roughness (-13.3, P = 0.0426), and in hyperpigmentation at week 8 (-9.4, P = 0.0462) and week 12 (-14.6, P= 0.0019). CONCLUSION: Topical hydrolyzed roe protein used twice daily improves skin clarity. It has good tolerability with fewer instances of stinging and burning than the other glycolic acid containing creams. Patient's opinions of the 3 products were similar. PMID- 26580882 TI - Bensal HP Treatment for Burn and Excision Wounds: An In-Vivo Assessment of Wound Healing Efficacy and Immunological Impact. AB - Natural ingredients are of increasing interest within the field of dermatology. Bensal HP, an ointment containing 3% oak bark extract, 3% salicylic acid, and 6% benzoic acid, is believed to be efficacious against a variety of inflammatory and infectious dermatidites. Here we evaluate Bensal HP's ability to influence wound healing, which has yet to be studied in this setting. Bensal HP applied to burn wounds on the dorsal surface of BALB/c mice significantly attenuated wound expansion in the first few days post-injury as compared to controls. Histological analysis mirrored these findings with accelerated maturation of the wound bed and increased collagen deposition by the end of the study period. Cytokine analysis revealed decreased IL-6 and TNFalpha secretion in the Bensal HP-treated burns as compared to controls. Similarly, excisional wounds treated with Bensal HP demonstrated comparable wound healing as compared to controls with positive histologic features and increased collagen deposition. Furthermore, IL-6 production was attenuated in the Bensal-HP treated wounds at day 3, with no differences appreciated in IL-6 at day 7 or in TNFalpha at either time point. While Bensal-HP represents a therapeutic strategy to enhance the histologic and immunologic milieu in burn and excisional wounds, further study is needed to fully elucidate the full potential of this treatment. PMID- 26580883 TI - New Methods for the Clinical Enhancement of Photodynamic Therapy. AB - The prolonged incubation time of Photodynamic Therapy (PDT) as well as the need for two treatments to achieve high efficacy have motivated physicians to experiment with treatment parameters and PDT enhancements in order to maximize results and practicality. This review explores recent published strategies including occlusion, temperature elevation, pretreatment with topical 5-FU, and microneedle or laser-assisted reduction of the stratum corneum barrier. All of these innovations improve efficacy, reduce the need for multiple treatments or both, although there are concomitant increases in post-procedure side effects. PMID- 26580884 TI - A Split-Face Study of Dual-Wavelength Laser on Neck and Facial Port-Wine Stains in Chinese Patients. AB - BACKGROUND: Although pulsed dye laser (PDL) has long been regarded as the gold standard in treating port-wine stain (PWS), advanced PWS with deeper coloration may display resistance because of limited penetration depth of 585 or 595-nm light. Recently, a dual-wavelength laser system has been reported to achieve pronounced fading in many patients. OBJECTIVE: The objective was to evaluate the efficacy and safety of a dual-wavelength laser device in treatment of neck and facial PWS in a direct side-by-side comparison. METHODS: Sixteen Chinese patients with neck and/or facial PWSs were enrolled in the study. All lesions were randomly divided into two area, treated area and adjacent untreated area. Five successive treatments using a dual-wavelength laser system (595-nm PDL combined with 1,064-nm Nd:YAG laser) were delivered on treated areas at 4- to 6-week intervals. The adjacent area was not treated as self control. Two blinded dermatologists evaluated the clinical changes by comparing the before and after photos. Erythema index (EI) values were measured with a non-invasive instrument. RESULTS: After five sessions of treatment, over 62.5% (10/16) patients achieved more than 50% (moderate or significant) improvement. The efficacy maintained at the 3-month follow-up visit. The values of EI on treated area showed a significant decrease. Adverse effects of treated area were limited. CONCLUSION: Using this split-face module, the dual-wavelength laser system is proved to be effective and well tolerated in treating neck and facial PWSs in Chinese patients. Adverse effects were minimal and acceptable. PMID- 26580885 TI - Neocollagenesis in Deep and Superficial Dermis by Combining Fractionated Q Switched ND:YAG 1,064-nm With Topical Plant Stem Cell Extract and N-Acetyl Glucosamine: Open Case Series. AB - INTRODUCTION: As we enter a new age of increasing demand in novel cosmetic therapies, we are challenged to provide excellent results with minimal downtime and safety in all skin types. In this open case series we are studying the improvement in rhytides by combining a novel, FDA-approved, non-ablative fractionated Q-switched ND: YAG 1,064-nm laser that acts in the deep dermis, with a topical containing plant stem cell extract and N-acetyl glucosamine (NAG) that acts in the superficial dermis. METHOD: Six healthy females (Skin types III - V) were selected for the study with mean average age of 56 years +/- 11 years. The rhytides on the face and neck were assessed using a comprehensive grading scale. Patients were then divided into two groups, one received only laser treatment with the fractionated QSW 1,064 nm laser and the other group received combined treatment with the laser and topical. Patients were assessed again at 4 and 8 weeks. RESULTS: We observed an enhanced anti-aging effect of the laser in the patients with combined treatment. DISCUSSION: Understanding the effect of this novel laser therapy on human stem cells and investigating the basis of its synergistic effect with plant stem cell extract and NAG will lead us to better understand stem cell activity. Non-ablative tissue regeneration is the next step in providing optimal anti-aging treatments. PMID- 26580886 TI - Daylight-Photodynamic Therapy for the Treatment of Actinic Keratosis in Different Seasons. AB - BACKGROUND: non-melanoma skin cancer (NMSC) is the most common malignancy, whose public health significance is often unrecognized. Its incidence continues to grow at an alarming rate, becoming an occupational disease. Available treatments alternative to surgery include: photodynamic therapy, electrochemiotherapy, cryotherapy, ablative lasers, 5-fluorouracil, imiquimod, ingenol mebutate, and diclofenac. Each of these options has its advantages and disadvantages. Photodynamic therapy (PDT), using topically applied photosensitizer precursors such as methylaminolaevulinate (MAL), is a useful nonsurgical treatment, well accepted by patients, but the main limitation is pain. Recently, in order to overcome this limit, visible light irradiation photherapy was considered. AIM: we report our experience comparing conventional PDT (406 patients) with daylight mediated PDT (D-PDT) 240 patients with multiple actinic keratoses (AK), afferent to our photodynamic outpatients clinic from September 2013 to June 2014. MATERIALS AND METHODS: to establish predictors for the clinical response to conventional PDT and daylight PDT (DPDT), a retrospective study on 646 patients was performed. The following parameters have been evaluated: sex, age, anatomic site of the primary tumor and local skin reactions. We used the Spearmen's coefficient between the clinical response and the predictors analyzed; while Odds Ratio (OR) was performed to evaluate general clinical response and local skin reaction between PDT and D-PDT patients. Subsequently, we performed a sub analysis, focusing to the anatomical sites, and we subdivided anatomical sites in face and scalp, nose, trunk, and extremities. RESULTS: a total of 406 patients treated with PDT and 240 patients treated with D-PDT, were enrolled in the current report. The median age was 71 years in PDT and 73 years in D-PDT. The mean clinical response in PDT was of 74.4% and 95% in D-PDT. Performing OR between PDT and D-PDT, according to the clinical response, we found a better behavior in patients treated with D-PDT (P < 0.03); the same significance was maintained according to the presence or absence of local skin reaction (P < 0.0002). Using no parametric Spearman's Coefficient test among predictive factors and the therapeutical response we found that D-PDT showed a better clinical response in patients with AK size >= 0.6 mm (P < 0.03), while this evidence was not present in PDT. The nose remained in both PDT and DPDT the main anatomical site with a better clinical response to the treatment. CONCLUSION: Since efficacy of D-PDT is comparable or superior to conventional type, but is simpler and better appreciated by patients, in our opinion it may be used routinely to treat sun exposed multiple AKs especially in sun damaged skin also for aesthetic purposes. PMID- 26580887 TI - Fractionated Carbon Dioxide Laser Treatment of Fibroelastolytic Papulosis With Excellent Cosmetic Result and Resolution of Pruritus. AB - Fibroelastolytic papulosis (FEP) consists of two dermatological conditions with clinical and histological similarities: pseudoxanthoma elasticum (PXE)-like papillary dermal elastolysis (PXE-PDE) and white fibrous papulosis of neck (WFPN). There is no effective documented treatment of FEP that we found in the published medical literature. We present a case of a Caucasian man with FEP who underwent fractionated carbon dioxide (CO2) laser treatment and achieved excellent cosmetic results and resolution of pruritus after three treatment sessions with no recurrence six-months post treatment. PMID- 26580888 TI - Doxycycline-Induced Solar Urticaria: A Report of Two Cases. AB - We report two cases of doxycycline-induced solar urticaria that developed shortly after initiation of therapy with persistence despite discontinuation. Consequently, dermatologists should be aware of the association between doxycycline and solar urticaria and counsel their patients on the potential for this side effect when prescribing doxycycline. PMID- 26580889 TI - Treatment of Periorbital Veins With Long-Pulse Nd:YAG Laser. AB - Periorbital veins (POVs) are a common cosmetic concern. Anatomically, POVs are formed by superficial facial veins that start from the bridge of the nose, travel as supraorbital and infraorbital veins, and join venous branches from the lateral forehead and scalp. In patients with fair skin, or in patients whose facial skin is atrophied, POVs can become prominent. This can lead to a fatigued appearance, with perceived "dark circles" around the patients' eyes. Previously described surgical therapies for prominent POVs are invasive and can leave unsightly scars, and sclerotherapy has been reported to lead to embolization that could lead to blindness. Here, we give examples of the use of 1,064 nm neodymium-doped yttrium aluminum garnet (Nd:YAG) laser to non-invasively treat or at least minimize prominent POVs. We discuss various techniques, and review treatment schedules to achieve the optimal cosmetic outcome. Furthermore, potential pitfalls, such as local site reaction and laser-specific tissue damage, are explored. Overall, Nd:YAG laser does appear to be a safe and effective treatment for POVs that requires minimal post-treatment care. PMID- 26580890 TI - Perioral Rejuvenation With Ablative Erbium Resurfacing. AB - BACKGROUND AND OBJECTIVE: Since the introduction of the scanning full-field erbium laser, misconceptions regarding ablative erbium resurfacing have resulted in its being largely overshadowed by ablative fractional resurfacing. This case report illustrates the appropriateness of full-field erbium ablation for perioral resurfacing. METHODS: A patient with profoundly severe perioral photodamage etched-in lines underwent full-field ablative perioral resurfacing with an erbium laser (Contour TRL, Sciton Inc., Palo Alto, CA) that allows separate control of ablation and coagulation. The pre-procedure consultations included evaluation of the severity of etched-in lines, and discussion of patient goals, expectations, and appropriate treatment options, as well as a review of patient photos and post treatment care required. The author generally avoids full-field erbium ablation in patients with Fitzpatrick type IV and above. For each of 2 treatment sessions (separated by approximately 4 months), the patient received (12 cc plain 2% lidodaine) sulcus blocks before undergoing 4 passes with the erbium laser at 150 MU ablation, no coagulation, and then some very focal 30 MU ablation to areas of residual lines still visualized through the pinpoint bleeding. Similarly, full field ablative resurfacing can be very reliable for significant wrinkles and creping in the lower eyelid skin--where often a single treatment of 80 MU ablation, 50 MU coagulation can lead to a nice improvement. RESULTS: Standardized digital imaging revealed significant improvement in deeply etched rhytides without significant adverse events. CONCLUSION: For appropriately selected patients requiring perioral (or periorbital) rejuvenation, full-field ablative erbium resurfacing is safe, efficacious and merits consideration. PMID- 26580892 TI - Employment of High-Performance Thin-Layer Chromatography for the Quantification of Oleuropein in Olive Leaves and the Selection of a Suitable Solvent System for Its Isolation with Centrifugal Partition Chromatography. AB - A high-performance thin-layer chromatographic methodology was developed and validated for the isolation and quantitative determination of oleuropein in two extracts of Olea europaea leaves. OLE_A was a crude acetone extract, while OLE_AA was its defatted residue. Initially, high-performance thin-layer chromatography was employed for the purification process of oleuropein with fast centrifugal partition chromatography, replacing high-performance liquid-chromatography, in the stage of the determination of the distribution coefficient and the retention volume. A densitometric method was developed for the determination of the distribution coefficients, KC = CS/CM. The total concentrations of the target compound in the stationary phase (CS) and in the mobile phase (CM) were calculated by the area measured in the high-performance thin-layer chromatogram. The estimated Kc was also used for the calculation of the retention volume, VR, with a chromatographic retention equation. The obtained data were successfully applied for the purification of oleuropein and the experimental results confirmed the theoretical predictions, indicating that high-performance thin-layer chromatography could be an important counterpart in the phytochemical study of natural products. The isolated oleuropein (purity > 95%) was subsequently used for the estimation of its content in each extract with a simple, sensitive and accurate high-performance thin-layer chromatography method. The best fit calibration curve from 1.0 ug/track to 6.0 ug/track of oleuropein was polynomial and the quantification was achieved by UV detection at lambda 240 nm. The method was validated giving rise to an efficient and high-throughput procedure, with the relative standard deviation % of repeatability and intermediate precision not exceeding 4.9% and accuracy between 92% and 98% (recovery rates). Moreover, the method was validated for robustness, limit of quantitation, and limit of detection. The amount of oleuropein for OLE_A, OLE_AA, and an aqueous extract of olive leaves was estimated to be 35.5% +/- 2.7, 51.5% +/- 1.4, and 12.5% +/- 0.12, respectively. Statistical analysis proved that the method is repeatable and selective, and can be effectively applied for the estimation of oleuropein in olive leaves' extracts, and could potentially replace high-performance liquid chromatography methodologies developed so far. Thus, the phytochemical investigation of oleuropein could be based on high-performance thin-layer chromatography coupled with separation processes, such as fast centrifugal partition chromatography, showing efficacy and credibility. PMID- 26580891 TI - Large-Scale Analysis of 48 DNA and 48 RNA Tetranucleotides Studied by 1 MUs Explicit-Solvent Molecular Dynamics Simulations. AB - An understanding of how the conformational behavior of single-stranded DNAs and RNAs depend on sequence is likely to be important for attempts to rationalize the thermodynamics of nucleic acid folding. In an attempt to further our understanding of such sequence dependences, we report here the results of 192 (1 MUs) explicit-solvent molecular dynamics (MD) simulations of 48 DNA and 48 RNA tetranucleotide sequences performed using recently reported modifications to the AMBER force field. Each tetranucleotide was simulated starting from two different conformations, a fully natively stacked and a completely unstacked conformation, and populations of the various possible base stacking arrangements were analyzed. The simulations indicate that, for both DNA and RNA, the populations of fully natively stacked conformations increase linearly with increasing numbers of purines in the sequence, while the conformational entropies, computed by two complementary methods, decrease. Despite the comparatively short simulation times, the computed free energies of stacking of the 16 possible combinations of bases in the middle of the sequences are found to be in good correspondence with values reported recently from simulations of dinucleoside monophosphates using the same force field. Finally, consistent with recent reports from other groups, non-native stacking interactions, i.e., between bases that are not adjacent in sequence, are shown to be a recurring feature of the simulations; in particular, stacking interactions of bases in a i:i+2 relationship are shown to occur significantly more frequently when the intervening base is a pyrimidine. Given that the high prevalence of non-native stacking interactions is thought to be unrealistic, it appears that further parametrization work will be required before accurate conformational descriptions of single-stranded nucleic acids can be obtained with current force fields. PMID- 26580893 TI - Chiral Pyridoxal-Catalyzed Asymmetric Biomimetic Transamination of alpha-Keto Acids. AB - A series of chiral pyridoxals 8 and 9 have been developed from commercially available pyridoxine and (S)-alpha,alpha-diarylprolinols. The pyridoxals exhibited good catalytic activity in an asymmetric transamination of alpha-keto acids with 2,2-diphenylglycine (7f) as the amine source to give various alpha amino acids in 29-85% yields with 53-80% ee's. The current asymmetric transamination has successfully mimicked a complete biological transamination process characterized by two half-transaminations, a small chiral pyridoxal molecule acting as the catalyst, and enantioselective control. PMID- 26580894 TI - Cellulitis and erysipelas: prevention. AB - INTRODUCTION: Cellulitis is a common problem caused by spreading bacterial inflammation of the skin, with redness, pain, and lymphangitis. Up to 40% of affected people have systemic illness. Erysipelas is a form of cellulitis with marked superficial inflammation, typically affecting the lower limbs and the face. The most common pathogens in adults are streptococci and Staphylococcus aureus. Cellulitis and erysipelas can result in local necrosis and abscess formation. Around one quarter of affected people have more than one episode of cellulitis within 3 years. METHODS AND OUTCOMES: We conducted a systematic overview, aiming to answer the following clinical question: What are the effects of treatments to prevent recurrence of cellulitis and erysipelas? We searched: Medline, Embase, The Cochrane Library, and other important databases up to February 2015 (Clinical Evidence overviews are updated periodically; please check our website for the most up-to-date version of this overview). RESULTS: At this update, searching of electronic databases retrieved 323 studies. After deduplication and removal of conference abstracts, 184 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 170 studies and the further review of 14 full publications. Of the 14 full articles evaluated, one systematic review was added at this update. We performed a GRADE evaluation for one PICO combination. CONCLUSIONS: In this systematic overview, we categorised the efficacy for two interventions based on information about to the effectiveness and safety of antibiotics and treatment of predisposing factors. PMID- 26580895 TI - Nitrogen limitation, oxygen limitation, and lipid accumulation in Lipomyces starkeyi. AB - Lipid production by oleaginous yeasts is optimal at high carbon-to-nitrogen ratios. In the current study, nitrogen and carbon consumption by Lipomyces starkeyi were directly measured in defined minimal media with nitrogen content and agitation rates as variables. Shake flask cultures with an initial C:N ratio of 72:1 cultivated at 200rpm resulted in a lipid output of 10g/L, content of 55%, yield of 0.170g/g, and productivity of 0.06g/L/h. All of these values decreased by ~50-60% when the agitation rate was raised to 300rpm or when the C:N ratio was lowered to 24:1, demonstrating the importance of these parameters. Under all conditions, L. starkeyi cultures tolerated acidified media (pH~2.6) without difficulty, and produced considerable amounts of alcohols; including ethanol, mannitol, arabitol, and 2,3-butanediol. L. starkeyi also produced lipids from a corn stover hydrolysate, showing its potential to produce biofuels from renewable agricultural feedstocks. PMID- 26580896 TI - Effect of fuel origin on synergy during co-gasification of biomass and coal in CO2. AB - The effect of fuel origin on synergy in coal/biomass blends during co gasification has been assessed using a congruent-mass thermogravimetry analysis (TGA) method. Results revealed that synergy occurs when ash residuals are formed, followed by an almost complete gasification of biomass. Potassium species in biomass ash play a catalytic role in promoting gasification reactivity of coal char, which is a direct consequence of synergy during co-gasification. The SEM EDS spectra provided conclusive evidence that the transfer of potassium from biomass to the surface of coal char occurs during co-pyrolysis/gasification. Biomass ash rich in silica eliminated synergy in coal/biomass blends but not to the extent of inhibiting the reaction rate of the blended chars to make it slower than that of separated ones. The best result in terms of synergy was concluded to be the combination of low-ash coal and K-rich biomass. PMID- 26580897 TI - PCB153 (2,2',4,4',5,5'-hexachlorobiphenyl) differentially affects the VEGF/VEGFR system depending on photoperiod in the ovine choroid plexus. AB - Ortho-substituted polychlorinated biphenyls (PCBs) preferentially accumulate in the brain and cerebrospinal fluid (CSF) compared with other PCBs. We previously demonstrated in ewes that an identical dose of PCB153, the most environmentally prevalent congener, resulted in a higher plasma concentration during short days (SD: 1200pg/ml) than during long days (LD: 200pg/ml). Moreover, PCB153 treatment only reduced the SD tight junction protein content in the choroid plexus (CP), which was followed by a significant increase of the PCB153 concentration in the CSF. The aim of the present study was to evaluate how PCB153 treatment affects the VEGF/VEGFR system that maintains CSF homoeostasis and CP function. To do so, we collected CPs from ovariectomised, oestradiol-replaced adult ewes maintained under artificial LD or SD and treated them per os with low doses of PCB153 (0.3mg/kg, 3 times a week for 3 weeks). Exposure to PCB153 significantly affected (P<0.05) the VEGF/VEGFR system during the SD period, provoking increases in VEGF164 mRNA and protein levels and decreases in VEGFR-1 mRNA levels and VEGFR-2 mRNA and protein levels. These results suggest that exposure to environmentally relevant dose of PCB153 affects the VEGF/VEGFR system, which is involved in the fenestration of the CP endothelium and therefore in CSF production. PMID- 26580898 TI - A vote taking place on 2 December 2015 (EUCOMED) that will definitely influence our profession and continuing medical education. PMID- 26580899 TI - Performance of combined sodium persulfate/H2O2 based advanced oxidation process in stabilized landfill leachate treatment. AB - A combination of persulfate and hydrogen peroxide (S2O8(2-)/H2O2) was used to oxidizelandfill leachate. The reaction was performed under varying S2O8(2-)/H2O2 ratio (g/g), S2O8(2-)/H2O2 dosages (g/g), pH, and reaction time (minutes), so as to determine the optimum operational conditions. Results indicated that under optimum operational conditions (i.e. 120 min of oxidation using a S2O8(2-)/H2O2 ratio of 1 g/1.47 g at a persulfate and hydrogen peroxide dosage of 5.88 g/50 ml and8.63 g/50 ml respectively, at pH 11) removal of 81% COD and 83% NH3-N was achieved. In addition, the biodegradability (BOD5/COD ratio) of the leachate was improved from 0.09 to 0.17. The results obtained from the combined use of (S2O8(2 )/H2O2) were compared with those obtained with sodium persulfate only, hydrogen peroxide only and sodium persulfate followed by hydrogen peroxide. The combined method (S2O8(2-)/H2O2) achieved higher removal efficiencies for COD and NH3-N compared with the other methods using a single oxidizing agent. Additionally, the study has proved that the combination of S2O8(2-)/H2O2 is more efficient than the sequential use of sodium persulfate followed by hydrogen peroxide in advanced oxidation processes aiming at treatingstabilizedlandfill leachate. PMID- 26580901 TI - Thermodynamic-ensemble independence of solvation free energy. AB - Solvation free energy is the fundamental thermodynamic quantity in solution chemistry. Recently, it has been suggested that the partial molar volume correction is necessary to convert the solvation free energy determined in different thermodynamic ensembles. Here, we demonstrate ensemble-independence of the solvation free energy on general thermodynamic grounds. Theoretical estimates of the solvation free energy based on the canonical or grand-canonical ensemble are pertinent to experiments carried out under constant pressure without any conversion. PMID- 26580900 TI - Characterization of the three-dimensional free energy manifold for the uracil ribonucleoside from asynchronous replica exchange simulations. AB - Replica exchange molecular dynamics has emerged as a powerful tool for efficiently sampling free energy landscapes for conformational and chemical transitions. However, daunting challenges remain in efficiently getting such simulations to scale to the very large number of replicas required to address problems in state spaces beyond two dimensions. The development of enabling technology to carry out such simulations is in its infancy, and thus it remains an open question as to which applications demand extension into higher dimensions. In the present work, we explore this problem space by applying asynchronous Hamiltonian replica exchange molecular dynamics with a combined quantum mechanical/molecular mechanical potential to explore the conformational space for a simple ribonucleoside. This is done using a newly developed software framework capable of executing >3,000 replicas with only enough resources to run 2,000 simultaneously. This may not be possible with traditional synchronous replica exchange approaches. Our results demonstrate 1.) the necessity of high dimensional sampling simulations for biological systems, even as simple as a single ribonucleoside, and 2.) the utility of asynchronous exchange protocols in managing simultaneous resource requirements expected in high dimensional sampling simulations. It is expected that more complicated systems will only increase in computational demand and complexity, and thus the reported asynchronous approach may be increasingly beneficial in order to make such applications available to a broad range of computational scientists. PMID- 26580902 TI - Parameterizing complex reactive force fields using multiple objective evolutionary strategies (MOES). Part 1: ReaxFF models for cyclotrimethylene trinitramine (RDX) and 1,1-diamino-2,2-dinitroethene (FOX-7). AB - ReaxFF (van Duin, A.C.T.; Dasgupta, S.; Lorant, F.; Goddard, W.A. J. Phys. Chem. A, 2001, 105, 9396-9409) reactive potentials are parametrized for cyclotrimethylene trinitramine (RDX) and 1,1-diamino-2,2-dinitroethene (FOX-7) in a novel application combining data envelopment analysis and a modern self adaptive evolutionary algorithm to optimize multiple objectives simultaneously and map the entire family of solutions. In order to correct the poor crystallographic parameters predicted by ReaxFF using its base parametrization (Strachan, A.; van Duin, A. C. T.; Chakraborty, D.; Dasgupta S.; Goddard, W. A. Phys. Rev. Lett., 2003, 91, 098301), we augmented the existing training set data used for parametrization with additional (SAPT)DFT calculations of RDX and FOX-7 dimer interactions. By adjusting a small subset of the ReaxFF parameters that govern long-range interactions, the evolutionary algorithm approach converges on a family of solutions that best describe crystallographic parameters through simultaneous optimization of the objective functions. Molecular dynamics calculations of RDX and FOX-7 are conducted to assess the quality of the force fields, resulting in parametrizations that improve the overall prediction of the crystal structures. PMID- 26580903 TI - Parameterizing complex reactive force fields using multiple objective evolutionary strategies (MOES): Part 2: transferability of ReaxFF models to C-H-N O energetic materials. AB - The Multiple Objective Evolutionary Strategies (MOES) algorithm was used to parametrize force fields having the form of the reactive models ReaxFF (van Duin, A. C. T.; Dasgupta, S.; Lorant, F.; Goddard, W. A. J. Phys. Chem. A 2001, 105, 9396) and ReaxFF-lg (Liu, L.; Liu, Y.; Zybin, S. V.; Sun, H.; Goddard, W. A. J. Phys. Chem. A 2011, 115, 11016) in an attempt to produce equal or superior ambient state crystallographic structural results for cyclotrimethylene trinitramine (RDX). Promising candidates were then subjected to molecular dynamics simulations of five other well-known conventional energetic materials to assess the degree of transferability of the models. Two models generated through the MOES search were shown to have performance better than or as good as ReaxFF lg in describing the six energetic systems modeled. This study shows that MOES is an effective and efficient method to develop complex force fields. PMID- 26580904 TI - Quantum dynamics of radiationless electronic transitions including normal modes displacements and Duschinsky rotations: a second-order cumulant approach. AB - An analytical expression for the population dynamics of electronic radiationless transitions has been derived from the second order expansion of the quantum evolution operator in the Liouville space and the cumulant theory. The expression includes the effect of both normal mode displacements and Duschinsky rotations and allows to take into account both equilibrium and nonequilibrium initial conditions. The methodology has been applied to model the electron-transfer process between the accessory bacteriochlorophyll and the bacteriopheophytine in bacterial reactions centers, providing a rate in good agreement with experimental findings. PMID- 26580905 TI - Efficient nonequilibrium method for binding free energy calculations in molecular dynamics simulations. AB - We introduce an effective technique for the calculation of the binding free energy in drug-receptor systems using nonequilibrium molecular dynamics and application of the Jarzynski theorem. In essence, this novel methodology constitutes the nonequilibrium adaptation of an ancient free energy perturbation technique called Double Annihilation Method, invented more than 25 years ago [J. Chem. Phys. 1988, 89, 3742-3746] and upon which modern approaches of binding free energy computation in drug-receptor systems are heavily based. The proposed computational approach, termed Fast Switching Double Annihilation Methods (FS DAM) in honor of its ancient ancestor, is applied to a prototypical example system with multiple binding sites, proving its computational potential and versatility in unraveling multiple site or allosteric binding processes. PMID- 26580906 TI - Effect of heterojunction on exciton binding energy and electron-hole recombination probability in CdSe/ZnS quantum dots. AB - Presence of heterojunctions is important for generation of free charge carriers and the dissociation of bound electron-hole pairs in semiconductor nanoparticles. This work presents a theoretical investigation of the effect of core/shell heterojunction on electron-hole interaction in CdSe/ZnS quantum dots. The excitonic wave function in the CdSe/ZnS dots was calculated using the electron hole explicitly correlated Hartree-Fock (eh-XCHF) method and the effect of successive addition of the ZnS shell on exciton binding energy, electron-hole recombination probability, and the electron-hole separation distance was investigated. It was found that the scaling of all the three quantities as a function of dot diameter did not follow conventional volume scaling laws of core only dots, and the scaling laws were significantly altered due to the presence of the heterojunction. The spatial localization of the quasiparticles in the core/shell quantum dot was analyzed by calculating the 1-particle reduced density from the eh-XCHF wave function and partitioning the density spatially into core and shell regions. It was found that in the 15 nm CdSe/ZnS dot, the relative probability of the electron localization in the shell region was higher than the hole by a factor of 3. The degree of spatial localization of the quasiparticles was found to depend strongly on the initial size of the CdSe core in the core/shell quantum dot. It was found that a reduction in the CdSe core diameter by a factor of 1.7 resulted in an enhancement of the preferential localization of the electron in the shell region by a factor of 11.3. The results demonstrate that large CdSe/ZnS quantum dots with a small CdSe core have the necessary characteristics for efficient exciton dissociation and generation of free charge carriers. PMID- 26580907 TI - Diagonalization of large matrices: a new parallel algorithm. AB - On the basis of a dressed matrices formalism, a new algorithm has been devised for obtaining the lowest eigenvalue and the corresponding eigenvector of large real symmetric matrices. Given an N * N matrix, the proposed algorithm consists in the diagonalization of (N - 1)2 * 2 dressed matrices. Both sequential and parallel versions of the proposed algorithm have been implemented. Tests have been performed on a Hilbert matrix, and the results show that this algorithm is up 340 times faster than the corresponding LAPACK routine for N = 10(4) and about 10% faster than the Davidson method. The parallel MPI version has been tested using up to 512 nodes. The speed-up for a N = 10(6) matrix is fairly lineal until 64 cores. The time necessary to obtain the lowest eigenvalue and eigenvector is nearly 5.5 min with 512 cores. For an N = 10(7) matrix, the speed-up is nearly linear to 256 cores and the calculation time is 5.2 h with 512 nodes. Finally, in order to test the new algorithm on MRCI matrices, we have calculated the ground state and the pi -> pi* excited state of the butadiene molecule, starting from both SCF and CASSCF wave functions. In all the cases considered, correlation energies and wave functions are the same as obtained with the Davidson algorithm. PMID- 26580908 TI - Scalable electron correlation methods I.: PNO-LMP2 with linear scaling in the molecular size and near-inverse-linear scaling in the number of processors. AB - We propose to construct electron correlation methods that are scalable in both molecule size and aggregated parallel computational power, in the sense that the total elapsed time of a calculation becomes nearly independent of the molecular size when the number of processors grows linearly with the molecular size. This is shown to be possible by exploiting a combination of local approximations and parallel algorithms. The concept is demonstrated with a linear scaling pair natural orbital local second-order Moller-Plesset perturbation theory (PNO-LMP2) method. In this method, both the wave function manifold and the integrals are transformed incrementally from projected atomic orbitals (PAOs) first to orbital specific virtuals (OSVs) and finally to pair natural orbitals (PNOs), which allow for minimum domain sizes and fine-grained accuracy control using very few parameters. A parallel algorithm design is discussed, which is efficient for both small and large molecules, and numbers of processors, although true inverse linear scaling with compute power is not yet reached in all cases. Initial applications to reactions involving large molecules reveal surprisingly large effects of dispersion energy contributions as well as large intramolecular basis set superposition errors in canonical MP2 calculations. In order to account for the dispersion effects, the usual selection of PNOs on the basis of natural occupation numbers turns out to be insufficient, and a new energy-based criterion is proposed. If explicitly correlated (F12) terms are included, fast convergence to the MP2 complete basis set (CBS) limit is achieved. For the studied reactions, the PNO-LMP2-F12 results deviate from the canonical MP2/CBS and MP2-F12 values by <1 kJ mol(-1), using triple-zeta (VTZ-F12) basis sets. PMID- 26580909 TI - pi-Conjugation in trans-1,3-butadiene: static and dynamical electronic correlations described through quantum Monte Carlo. AB - We investigate the effects of the static and dynamical electronic correlations on the level of conjugation of the trans-1,3-butadiene molecule through Quantum Monte Carlo methods applied to an Antisymmetrized Geminal Power (AGP) wave function, with a Jastrow factor similar to the Gutzwiller ansatz. The degree of conjugation is measured through the convergence of the structural properties of 1,3-butadiene and in particular of the Bond Length Alternation (BLA), that is the difference between the lengths of the single and double carbon bonds. After verifying the different roles of the Fermionic AGP part of our wave function and of the Jastrow factor in recovering electronic correlation, we study the effects of a constrained Active Space AGP (AGPAS), similar to that used in the Complete Active Space (CAS) representation. Through this AGPAS, we are able to identify the effect of the limited active space on the degree of conjugation, showing that in the limit of infinite active space the structural properties converge exactly to those of the atomic AGP, giving a BLA for 1,3-butadiene around 0.1244(5) A. PMID- 26580910 TI - Robust, basis-set independent method for the evaluation of charge-transfer energy in noncovalent complexes. AB - Separation of the energetic contribution of charge transfer to interaction energy in noncovalent complexes would provide important insight into the mechanisms of the interaction. However, the calculation of charge-transfer energy is not an easy task. It is not a physically well-defined term, and the results might depend on how it is described in practice. Commonly, the charge transfer is defined in terms of molecular orbitals; in this framework, however, the charge transfer vanishes as the basis set size increases toward the complete basis set limit. This can be avoided by defining the charge transfer in terms of the spatial extent of the electron densities of the interacting molecules, but the schemes used so far do not reflect the actual electronic structure of each particular system and thus are not reliable. We propose a spatial partitioning of the system, which is based on a charge transfer-free reference state, namely superimposition of electron densities of the noninteracting fragments. We show that this method, employing constrained DFT for the calculation of the charge transfer energy, yields reliable results and is robust with respect to the strength of the charge transfer, the basis set size, and the DFT functional used. Because it is based on DFT, the method is applicable to rather large systems. PMID- 26580911 TI - Effects from spin-orbit coupling on electron-nucleus hyperfine coupling calculated at the restricted active space level for Kramers doublets. AB - Calculations of electron-nucleus hyperfine coupling were implemented at the restricted active space state interaction (RASSI) level to treat spin-orbit (SO) coupling, based on scalar relativistic restricted active space wave functions. The current implementation is suitable for light atomic systems, for light ligand atoms in heavy metal complexes, and for spin-orbit coupling-induced hyperfine coupling of heavy atoms if the unpaired electrons are described by orbitals with high angular momentum. Spin polarization is reasonably well treated by allowing one hole and one electron in a window of active orbitals ('ras1', 'ras3') surrounding the principal active space ('ras2'). A benchmark set of Kramers doublet states of molecules with light and heavy atoms is used to evaluate the approach and verify the implementation. For NpF6, the impact of SO coupling on the Np and F hyperfine coupling tensors is investigated in detail. It is demonstrated that the Np hyperfine coupling is strongly dominated by SO effects, that there is a large SO effect on the F hyperfine tensor components, and that SO coupling causes the fluorine dipolar term to acquire an isotropic component. PMID- 26580912 TI - Accuracy of embedded fragment calculation for evaluating electron interactions in mixed valence magnetic systems: study of 2e-reduced lindqvist polyoxometalates. AB - Accurate quantum chemical calculations on real-world magnetic systems are challenging, the inclusion of electron correlation being the bottleneck of such task. One method proposed to overcome this difficulty is the embedded fragment approach. It tackles a chemical problem by dividing it into small fragments, which are treated in a highly accurate way, surrounded by an embedding included at an approximate level. For the vast family of medium-to-large sized polyoxometalates, two-electron-reduced systems are habitual and their magnetic properties are interesting. In this paper, we aim at assessing the quality of embedded fragment calculations by checking their ability to reproduce the electronic spectra of a complete system, here the mixed-metal series [MoxW6 xO19](4-) (x = 0-6). The microscopic parameters extracted from fragment calculations (electron hopping, intersite electrostatic repulsion, local orbital energy, etc.) have been used to reproduce the spectra through model Hamiltonian calculations. These energies are compared to the results of the highly accurate ab initio difference dedicated configuration interaction (DDCI) method on the complete system. In general, the model Hamiltonian calculations using parameters extracted from embedded fragments nearly exactly reproduce the DDCI spectra. This is quite an important result since it can be generalized to any inorganic magnetic system. Finally, the occurrence of singlet or triplet ground states in the series of molecules studied is rationalized upon the interplay of the parameters extracted. PMID- 26580913 TI - QM/QM approach to model energy disorder in amorphous organic semiconductors. AB - It is an outstanding challenge to model the electronic properties of organic amorphous materials utilized in organic electronics. Computation of the charge carrier mobility is a challenging problem as it requires integration of morphological and electronic degrees of freedom in a coherent methodology and depends strongly on the distribution of polaron energies in the system. Here we represent a QM/QM model to compute the polaron energies combining density functional methods for molecules in the vicinity of the polaron with computationally efficient density functional based tight binding methods in the rest of the environment. For seven widely used amorphous organic semiconductor materials, we show that the calculations are accelerated up to 1 order of magnitude without any loss in accuracy. Considering that the quantum chemical step is the efficiency bottleneck of a workflow to model the carrier mobility, these results are an important step toward accurate and efficient disordered organic semiconductors simulations, a prerequisite for accelerated materials screening and consequent component optimization in the organic electronics industry. PMID- 26580914 TI - Embedded mean-field theory. AB - We introduce embedded mean-field theory (EMFT), an approach that flexibly allows for the embedding of one mean-field theory in another without the need to specify or fix the number of particles in each subsystem. EMFT is simple, is well-defined without recourse to parameters, and inherits the simple gradient theory of the parent mean-field theories. In this paper, we report extensive benchmarking of EMFT for the case where the subsystems are treated using different levels of Kohn Sham theory, using PBE or B3LYP/6-31G* in the high-level subsystem and LDA/STO-3G in the low-level subsystem; we also investigate different levels of density fitting in the two subsystems. Over a wide range of chemical problems, we find EMFT to perform accurately and stably, smoothly converging to the high-level of theory as the active subsystem becomes larger. In most cases, the performance is at least as good as that of ONIOM, but the advantages of EMFT are highlighted by examples that involve partitions across multiple bonds or through aromatic systems and by examples that involve more complicated electronic structure. EMFT is simple and parameter free, and based on the tests provided here, it offers an appealing new approach to a multiscale electronic structure. PMID- 26580915 TI - Catalytic role of dinuclear sigma,pi-acetylide gold(I) complexes in the hydroamination of terminal alkynes: theoretical insights. AB - A detailed density functional theory (DFT) investigation of the hydroamination of 1-octyne with aniline mediated by a sigma,pi-digold(I) bulky phosphine-based complex was undertaken in order to shed light on the mechanistic aspects of such processes. With the purpose to probe whether the performance that the cationic digold complexes exhibit is superior to those of mononuclear complexes, the same hydroamination reaction was explored by considering separately the reaction of aniline with both the monogold(I) complexes formed by pi- and sigma-coordination of 1-octyne to the dialkylbiarylphosphine Au(I) precatalyst. The outcomes of the computational analysis presented here show that, when the sigma,pi-digold alkynide complex can be formed, the reaction is not necessarily assisted by such a complex, as the computed energy barrier is almost equal to that found when the pi-coordinated alkyne mononuclear gold complex is involved in the hydroamination process. The catalytic assistance of the Au(I)-sigma-alkynyl complex, instead, can be surely excluded as the hydroamination product is formed by overcoming an energy barrier significantly higher than that computed when both sigma,pi-digold and pi-coordinated alkyne monogold complexes assist the reaction. Moreover, regardless of the implicated gold(I) species, the investigated mechanism accounts for the Markovnikov selectivity of the reaction, confirming the experimental evidence. The proposed mechanisms for the conversion of Au(I) pi-coordinated alkyne complexes into the corresponding sigma,pi-digold alkynide complexes were also explored. PMID- 26580916 TI - Mechanistic insight into marine bioluminescence: photochemistry of the chemiexcited Cypridina (sea firefly) lumophore. AB - Cypridina hilgendorfii (sea firefly) is a bioluminescent crustacean whose bioluminescence (BL) reaction is archetypal for a number of marine organisms, notably other bioluminescent crustaceans and coelenterates. Unraveling the mechanism of its BL is paramount for future applications of its strongly emissive lumophore. Cypridina produces light in a three-step reaction: First, the cypridinid luciferin is activated by an enzyme to produce a peroxide intermediate, cypridinid dioxetanone (CDO), which then decomposes to generate excited oxyluciferin (OxyCLnH*). Finally, OxyCLnH* deexcites to its ground state along with emission of bright blue light. Unfortunately, the detailed mechanism of the critical step, the thermolysis of CDO, remains unknown, and it is unclear whether the light emitter is generated from a neutral form (CDOH) or anionic form (CDO(-)) of the CDO precursor. In this work, we investigated the key step in the process by modeling the thermal decompositions of both CDOH and CDO(-). The calculated results indicate that the decomposition of CDO(-) occurs via the gradually reversible charge transfer (CT)-initiated luminescence (GRCTIL) mechanism, whereas CDOH decomposes through an entropic trapping mechanism without an obvious CT process. The thermolysis of CDO(-) is sensitive to solvent effects and is energetically favorable in polar environments compared with the thermolysis of CDOH. The thermolysis of CDO(-) produces the excited oxyluciferin anion (OxyCLn(-)*), which combines with a proton from the environment to form OxyCLnH*, the actual light emitter for the natural system. PMID- 26580917 TI - Pretreatment Factors Associated with Recurrence for Patients with Cervical Cancer International Federation of Gynecology and Obstetrics Stage IB1 Disease. AB - BACKGROUND: Pretreatment prognostic information is lacking for patients with cervical cancer International Federation of Gynecology and Obstetrics (FIGO) stage IB1 disease. Thus, we attempted to identify a high-risk subgroup among them prior to treatment. METHODS: Cervical cancer FIGO stage IB1 patients who had received curative treatment with various modalities in our institute between January 2004 and December 2010 were enrolled. Pretreatment clinical parameters including age, squamous cell carcinoma antigen (SCC-Ag), carcinoembryonic antigen, hemoglobin (Hb) level, platelet count, histological type, and treatment modality were analyzed for treatment outcomes. RESULTS: One hundred ninety-seven patients were included with a median follow-up of 66 months (range 6-119 months). In Cox regression analysis, only SCC histology (HR 0.457, 95% CI 0.241-0.967, p = 0.017) was an independent factor predicting better disease-free survival (DFS). Among SCC histology, patients with an Hb level less than 12 g/dl and a SCC-Ag level more than 3 ng/ml had worse treatment outcomes. The 5-year DFS rates were 89.2, 69.3, and 44.4% for the patients at low-risk (SCC, Hb >12 g/dl, SCC-Ag <=3 ng/ml), intermediate-risk (non-SCC), and high-risk (SCC, Hb <=12 g/dl, SCC-Ag >3 ng/ml), respectively (p < 0.001). CONCLUSION: Non-SCC and SCC histology with both anemia and high pretreatment SCC-Ag level were associated with recurrence. Further validation studies are warranted for clarification. PMID- 26580918 TI - Exposing native cyprinid (Barbus plebejus) juveniles to river sediments leads to gonadal alterations, genotoxic effects and thyroid disruption. AB - Juveniles (50 days post hatch) of a native cyprinid fish (Barbus plebejus) were exposed for 7 months to sediments from the River Lambro, a polluted tributary impairing the quality of the River Po for tens of kilometers from their confluence. Sediments were collected upstream of the city of Milan and downstream at the closure of the drainage basin of the River Lambro. Chemical analyses revealed the presence of a complex mixture of bioavailable endocrine-active chemicals, with higher exposure levels in the downstream section of the tributary. Mainly characterized by brominated flame retardants, alkylphenols, polychlorinated biphenyls, and minor co-occurring personal care products and natural hormones, the sediment contamination induced reproductive disorders, as well as other forms of endocrine disruption and toxicity. In particular, exposed male barbel exhibited higher biliary PAH-like metabolites, overexpression of the cyp1a gene, vitellogenin production in all specimens, the presence of oocytes (up to 22% intersex), degenerative alterations in their testis, liver fat vacuolization, a marked depression of total thyroxine (T4) and triiodothyronine (T3) plasma levels, and genotoxic damages determined as hepatic DNA adducts. These results clearly demonstrate that Lambro sediments alone are responsible for recognizable changes in the structure and function of the reproductive and, in general, the endocrine system of a native fish species. In the real environment, exposure to waterborne and food-web sources of chemicals are responsible for additional toxic loads, and the present findings thus provide evidence for a causal role of this tributary in the severe decline observed in barbel in recent decades and raise concern that the fish community of the River Po is exposed to endocrine-mediated health effects along tens of kilometres of its course. PMID- 26580919 TI - The Epidemiology of Migraine Headache in General Population of Tehran, Iran. AB - BACKGROUND: Migraine as one of the most common types of headache is known to cause serious intervention with routine activities of affected individuals due to the devastating nature of attacks. The aim of this study was to provide epidemiological data of migraine in Iranian general population. METHODS: In this cross-sectional general population study, migraine diagnoses (both episodic and chronic) were based on the International Classification of Headache Disorders. Face-to-face interviews were performed by 5 trained medical interns on a sample size of 2,300 people aged 12-65 years. RESULTS: A total number of 2,076 subjects were enrolled for final analysis. The mean age of the subjects at the time of the study was 36.27 +/- 14.56 years (age range 12-65 years). The 1-year prevalence of migraine was 27.6%. The prevalence of migraine among female subjects was significantly higher than among male subjects (36.7 vs. 21.6%, p < 0.001). The mean age of the subjects with migraine was 35.9 +/- 12.96 years. Totally, 49.9% of migraine sufferers experienced at least one episode of aura. The most prevalent type of aura was numbness reported in 32.4% of migraine subjects. CONCLUSIONS: Despite the higher prevalence of migraine among Iranian general population compared to most of the other populations investigated by previous studies, these individuals experience a less severe course of disease. PMID- 26580920 TI - [Early childhood development in Peru]. PMID- 26580921 TI - [Revista Peruana de Medicina Experimental y salud publica: His importance in the dissemination of science from Peru]. PMID- 26580922 TI - [Epidemiological characteristics of neonatal mortality in Peru, 2011-2012]. AB - OBJECTIVES: Describe the epidemiological characteristics of neonatal deaths in Peru. MATERIALS AND METHODS: Descriptive study based on notifications to the Perinatal and Neonatal National Epidemiological Surveillance Subsystem (PNNESS) made in 2011-2012. The capture-recapture method was used to calculate the registration of the notification and estimate the neonatal mortality rate (NMR) nationally and by regions. Responses were made to the questions: where, when, who and why the newborns died. RESULTS: 6,748 neonatal deaths were reported to PNNESS, underreport 52.9%. A national NMR of 12.8 deaths/1,000 live births was estimated. 16% of deaths occurred at home and 74.2% of these were in the highlands region, predominantly in rural areas and poor districts. 30% died in the first 24 hours and 42% between 1 and 7 days of life. 60.6% were preterm infants and 39.4% were term infants. 37% had normal weight, 29.4% low weight, and 33.6% very low weight. Preventable neonatal mortality was 33%, being higher in urban and highland areas. 25.1% died of causes related with prematurity immaturity; 23.5% by infections; 14.1% by asphyxiation and causes related to care during childbirth and 11% by lethal congenital malformation. CONCLUSIONS: Neonatal mortality in Peru is differentiated by setting; harms related to prematurity-immaturity dominated on the coast, while the highlands and jungle recorded more preventable neonatal mortality with a predominance of asphyxia and infections. PMID- 26580923 TI - [Characterization of anemia in children under five years of age from urban areas of Huancavelica and Ucayali, Peru]. AB - OBJECTIVES: Characterize anemia in children aged between 12 and 59 months from urban areas in the provinces of Coronel Portillo and Huancavelica in Peru. MATERIALS AND METHODS: Cross-sectional study carried out in two stages: a) population-based study to identify children with anemia using multistage probability sampling, and b) characterization of the serum levels of ferritin, vitamin B12, intraerythrocytic folic acid and presence of parasitosis in children with anemia. For the statistical analysis, expansion factors calculated from the sampling plan were applied. RESULTS: The prevalence of anemia was 55.9% in Huancavelica and 36.2% in Coronel Portillo. In Huancavelica, the coexistence of anemia with iron deficiency was 22.8% and anemia with vitamin B12 deficiency was 11%. In Coronel Portillo, the coexistence of anemia with iron deficiency and vitamin B12 deficiency was 15.2% and 29.7%, respectively. The most common types of anemia in Huancavelica were anemia with concurrent parasitosis (50.9%), iron deficiency anemia and parasitosis (12.3%), and iron deficiency alone (6.4%). In Coronel Portillo, it was anemia and parasitosis (54.4%), vitamin B12 deficiency and parasitosis (18.4%), and iron deficiency anemia and parasitosis (6.3%). CONCLUSIONS: The prevalence of anemia is higher than the national average, with anemia concurrent with parasitosis and anemia concurrent with two or more causes as the most common type. Consideration should be given to different causes other than iron deficiency in the programs of anemia contol for Peruvian children. PMID- 26580924 TI - [Mother?s strategies in the feeding process of children aged 6 to 24 months in two rural communities of Lima, Peru]. AB - OBJECTIVES: To know the strategies of mothers during the feeding process in children aged 6 to 24 months in two communities of Lima. MATERIALS AND METHODS: Qualitative study in which 18 primiparous or multiparous mothers of children aged 6-24 months participated. We used intentional sampling by age and parity of the mother, and conducted 36 direct observations and 12 in-depth interviews. Inductive data analysis was conducted, categories were grouped by subject and technique, reaching a consensus of the themes among the authors. RESULTS: Verbal communication was markedly greater in multiparous mothers. Three major themes were found. Verbal mother-child communication, multiparous mothers were those who used affectionate words during the meal. Involvement and strategies in the feeding process was seen as characterized by encouraging the child to finish the meal with games and singing that multiparous mothers performed sometimes with help from other family members. However these results were not obtained by primiparous mothers, they usually became withdrawn upon the rejection of food. The context during eating favors whether a child will finish the meal. CONCLUSIONS: The strategies used during meal time were varied and biased, predominantly by multiparous mothers, acting in a more active and responsive way. However primiparous mothers may act in an authoritarian manner when the child gets dirty, plays and/or refuses food. PMID- 26580925 TI - [Risk factors of small for the gestational age neonates in a hospital of Lima, Peru]. AB - OBJECTIVES: Identify risk factors for at-term small for gestational age newborns. MATERIALS AND METHODS: Retrospective cohort study using data from the Maternal Perinatal Information System of the Maria Auxiliadora Hospital of Lima, from the period 2000-2010. Maternal age, parity, education level, marital status, pregestational body mass index, number of prenatal care visits, presence of conditions such as preeclampsia, eclampsia, urinary tract infection and gestational diabetes as risk factors in small for gestational age newborns were evaluated. The weight for gestational age was calculated based on Peruvian percentiles. Crude relative risk (RR) and adjusted (ARR) were calculated with confidence intervals of 95% using log-binomial generalized linear models. RESULTS: 64,670 pregnant women were included. The incidence for small for gestational age was 7.2%. Preeclampsia (ARR 2.0, 95% CI: 1.86 to 2.15), eclampsia (ARR 3.22, 95% CI: 2.38 to 4.35), low maternal weight (ARR 1.38; 95% CI: 1.23 to 1.54), nulliparity (ARR 1.32, 95% CI: 1.23 to 1.42), age >=35 years (ARR 1.16, 95% CI: 1.04 -1.29), having prenatal care visits from 0 to 2 (ARR 1.43, 95% CI: 1.32 to 1.55) and 3 to 5 (ARR 1.22, 95% CI: 1.14 to 1.32) were risk factors for small for gestational age. CONCLUSIONS: It is necessary to identify pregnant women with risk factors such as those found to decrease the condition of small for gestational age. Actions should emphasize modifiable factors, such as the frequency of prenatal care visits. PMID- 26580926 TI - [Antiteratogenic capacity of resveratrol in streptozotocin-induced diabetes in rats]. AB - OBJECTIVES: To evaluate the anti-hyperglycemic and anti-teratogenic capacity of resveratrol in streptozotocin-induced diabetic rats. MATERIAL AND METHODS: Experimental study. There were three groups, of five rats each; two groups were treated with a single dose of 50 mg/Kg of streptozotocin (STZ), in citrate buffer, at the 4th day of gestation, and the third group was considered the control, and were administered with citrate buffer only. One of the two STZ induced groups was administered with 100 mg/Kg resveratrol the days 8th to 12th, when neurulation occurs. Fetuses were obtained the 19th gestational day, and were subjected to morphologic analysis; and in fetal liver the activities of scavenging enzymes catalase, superoxide dismutase and gluthathione peroxidase were measured. RESULTS: Resveratrol can decrease the teratogenic effect of STZ induced diabetes, and scavenging activities were beneficed by the administration of this antioxidant. CONCLUSION: Resveratrol shown embryoprotective properties mediated by amelioration of oxidative stress produced by maternal hyperglycemia. PMID- 26580927 TI - [Utilization of outpatient health services in the Peruvian population]. AB - OBJECTIVES: Describe the profile of need and patterns of use of outpatient health services in populations who are enrolled and non-enrolled in a health insurance program in Peru. MATERIALS AND METHODS: Descriptive cross-sectional study using data from the 2011 National Household Survey. The data were divided into five groups: persons enrolled in the Social Health Insurance (ESSALUD), Integral Health Insurance (SIS), Health Insurance of the Armed Forces and Police Force (AF PF), Private Health Insurances (SPS) and the uninsured. RESULTS: People insured and enrolled in ESSALUD were more likely to use outpatient services than uninsured people and those enrolled in SIS. SIS members mainly attended health centers and small health posts (47.1%), while other insurance members mainly used hospitals and private hospitals. The uninsured used as their first choice pharmacies and drugstores (46.7%) in order to solve their health problems. In all insurances, out-of-pocket payment was made for the consultation, medications and tests. The perception of "not serious" was the main reason for not seeking care in the insured (40.0%) and uninsured (41.4%); however the lack of money showed an important difference between insured (10.6%) and uninsured (16.3%). CONCLUSIONS: The outpatient health services utilization profile of the Peruvian population expresses differences that relate to enrollment in and type of insurance. PMID- 26580928 TI - [Microsurgical resection of glioblastoma guided with intraoperative fluorescein: a Retrospective evaluation]. AB - OBJECTIVES: To evaluate the influence of the use of sodium fluorescein (FLS-Na) in surgery of glioblastoma (GB) on the degree of tumor resection and survival in patients treated at the National Institute of Neoplastic Diseases. MATERIALS AND METHODS: A total of 238 cases of GB treated between 2008 and 2013 were reviewed and 150 cases of GB who underwent surgical resection with clinicopathological information and adequate follow-up were selected. RESULTS: The mean age was 51 years, 58.7% of the cases presented a Karnofsky score of at least 90. FLS-Na was administered in 80 cases (53.3%) and a subtotal and total resection was obtained in 69 (46%) and 81 (54%) cases, respectively. The group that received FLS-Na obtained higher rates of total resection than the group operated with white light alone (77.5 vs 27.1%, p<0.001). The median overall survival (OS) was higher in the group subject to total compared to subtotal resection (17 vs 7 months, p<0.001). The median OS in those who received FLS-Na was higher than in those who did not (15.0 vs 8 months, p=0.003). Other factors affecting OS were age (p=0.002), the Karnofsky score (p=0.052) and radiation therapy (p=0.016) and chemotherapy (p=0.011). CONCLUSIONS: The microsurgical technique with administration of FLS-Na was associated with an increase in the rate of total resection and survival. PMID- 26580929 TI - [Factors associated with in hospital deaths in a hemodialysis population in Peru]. AB - OBJECTIVES: To determine the factors associated with mortality during the first hospitalization of patients admitted to a hemodialysis unit. MATERIALS AND METHODS: Observational and retrospective study of patients admitted to "Dos de Mayo" National Hospital between January 2012 and December 2013. For the survival analysis we used the Kaplan-Meier method. A multivariate logistic regression was performed to evaluate the factors associated with hospital mortality. RESULTS: 216 patients with a mean age of 56.9 +/- 15.5 years were studied. 24% of patients (n = 51) died during their hospital stay. The mortality rate was 9.3 deaths/100 person-weeks (95% CI: 7.0 to 12.3). We found a tendency of less risk of death in patients with between 1 and 6 months from chronic kidney disease diagnosis (OR 0.84, 95% CI: 0.32 to 2.26) and in those with more than six months from chronic kidney disease diagnosis compared with those who had less than a month from chronic kidney disease diagnosis (OR 0.55, 95% CI: 0.19 to 1.57). Previous care by a nephrologist was not associated with differences in lower mortality (OR 1.14, 95% CI: 0.39 to 3.31). CONCLUSIONS: There is poor prior care among hemodialysis patients that form part of an inadequate health care structure and this is associated with high inhospital mortality. PMID- 26580930 TI - [Evaluation of enzyme-linked immunoelectrotransfer blot test using purified native antigen mix from cisticercus fluid of Taenia solium for diagnosis of human cysticercosis]. AB - OBJECTIVES: Evaluate the efficiency of the enzyme-linked immunoelectrotransfer blot test (EITB) for the detection of human cysticercosis using purified native antigen mix from cysticercus fluid of Taenia solium. MATERIAL AND METHODS: Observational study of the evaluation of the diagnostic test. The purified native antigen mix was extracted from the fluid of cysticercus from naturally parasitized pigs from areas considered endemic. Four purification methods were evaluated and one was selected: ammonium sulfate, lentil lectin-Sepharose, Sephadex G-75 and Electro-elution. The sensitivity of the purified antigen was determined with EITB and was evaluated with 50 sera positive for cysticercosis and the specificity with 50 sera negative for cysticercosis (20 free of parasitic infection and 30 positive for different parasites). RESULTS: The optimal concentration of the purified native antigen mix to prepare the EITB strips was 0.82 ug/mm. By affinity chromatography with Lentil Lectin- Sepharose we visualized and purified 8 specific antigenic glycoproteins, their relative masses being: 13, 14, 17, 18, 23, 24, 31 and 35 kDa. The purified antigens obtained by the other methods were not evaluated by EITB because they did not correspond to the specific antigenic proteins considered between 13 and 35 kDa. The EITB test using purified native antigen mix showed 100% sensitivity and 100% specificity. CONCLUSIONS: The purified antigen native mix improved the diagnostic efficiency of the EITB test. We recommend the preparation of an in-house kit and field validation so that it can be transferred and implemented in laboratories in endemic areas of Peru. PMID- 26580931 TI - [Traditional andean healers in the context of change: the case of Churcampa in Peru]. AB - OBJECTIVES: Describe the diversity of traditional healers, their links with the formal health system and changes in their therapeutic resources in two rural Andean communities in Churcampa, in the region of Huancavelica, Peru. MATERIALS AND METHODS: Qualitative study which combined three ethnographic techniques: in depth interviews, observations and accompaniments to traditional healers and health care personnel. RESULTS: 58 traditional healers, classified as healers, midwives and bonesetters were identified. Most healers interviewed learned their work while young and few had a teacher or mentor. The vast majority have objections to linking with health care facilities beyond referrals. There was no coordinated work among health personnel and traditional healers. However, when it happened, health personnel preferred those healers who have the willingness to adapt to the needs of the health services. We found that most of the healers were changing their practices due to the influence of evangelical churches. No healer had disciples to transmit their knowledge and practices. CONCLUSIONS: There is great diversity of traditional healers. This diversity is decreasing, among other factors, by the advance of the evangelical churches. Traditional healers refer some patients to the health facility; while health personnel establish hierarchical working relationships with the healers. It is necessary to work on these attitudes of the health care personnel, since the basis of an intercultural approach is to have coordinated and horizontal working relationships between both systems. PMID- 26580933 TI - [Evaluation of tuberculosis detection indicators in a region with high risk of transmission in Peru]. AB - An operational study was conducted to evaluate the tuberculosis detection indicators established in the Technical Standard for Comprehensive Care of Persons Affected by Tuberculosis. Three networks of first level of care facilities with very high risk of tuberculosis transmission from the Tacna region were selected. Using the registry of respiratory symptomatic patients, we analyzed 14,595 respiratory symptomatic subjects (RSS), of which we examined (ExRSS) 14,486 (99.3%). Of the total of ExRSS, 1.5% were BK (+).The average direct smears per RSS was 2.0 and search intensity (ratio between RSS and number of health care visits in more than 15 years) was 2.8%. Males were more likely to have at least one positive smear compared to women, OR 2.0 (95% CI: 1.5 to 2.6). It is concluded that the diagnostic performance of direct smears in respiratory symptomatic subjects is low. PMID- 26580932 TI - [Frequency of hepatitis a in children and adolescents from five cities of Peru]. AB - In order to determine the frequency of hepatitis A in children and adolescents in the cities of Lima, Arequipa, Piura, Cajamarca and Iquitos, a descriptive cross sectional study which measured serum anti-hepatitis A antibodies from 1,721 children and adolescents aged 1-15 years was performed. The overall frequency of positive serology was 50.5% (95% CI: 48.1 to 52.9), with lower rates for Lima at 37.4% (95% CI: 35.1 to 39.8) and higher rates for Iquitos at 68.7% (95% CI: 63.6 to 73.4). Seropositivity was higher in the group of 10-15 year-olds with 66.1% and in the socioeconomic status group E with 64.6%. We concluded that the cities studied have a pattern of intermediate endemicity. The frequency of hepatitis A was greater in children and adolescents of lower socioeconomic status and older age. PMID- 26580934 TI - [Demographic characteristics of human papillomavirus detected by PCR-RFLP in peruvian women]. AB - In order to determine the sociodemographic characteristics of human papillomavirus (HPV) in patients referred to the National Institute of Neoplastic Diseases (INEN) between 2012-2014, the detection of HPV in cervical cells was performed by polymerase chain reaction (PCR). In 465 cervical samples, 151 (32.5%) cases were HPV positive. The most common genotypes were HPV-16 (23.8%) and HPV-6 (11.9%). The presence of HPV was higher in women aged 17-29 years (OR = 2.64, 95% CI 1.14 to 6.13) and single women (OR = 2.31, 95% CI 1.37 to 3.91). The presence of genotypes of high-risk HPV was higher in single women (OR = 2.19, 95% CI 1.04 to 4.62). In conclusion, young and single women had a higher frequency of HPV-positive cases. Therefore participation by these groups should be emphasized in screening programs with combined molecular and cytological methods in order to detect the risk of developing cervical cancer in a timely manner. PMID- 26580935 TI - [Experimental evaluation of Ulomoides dermestoides (tenebrionidae) as an intermediate host of Hymenolepis diminuta]. AB - The aim of the study was to determine if Ulomoides dermestoides behaves as an intermediate host of Hymenolepis diminuta, therefore one hundred of them were experimentally infected with tapeworm eggs. As a result, it was found that in 92% of the insects formed cysticercoids which, inoculated in laboratory rats, developed the adult stage. These adults produced eggs with which the infection process was repeated, obtaining the same results. Therefore it can be said that U. dermestoides experimentally acts as an intermediate host. PMID- 26580936 TI - [How to produce a video to promote HIV testing in men who have sex with men?]. AB - The aim of the study was to describe the process of designing and producing a video to promote HIV testing in Peruvian men who have sex with men (MSM). The process involved the following steps: identification of the theories of behavior change; identifying key messages and video features; developing a script that would captivate the target audience; working with an experienced production company; and piloting the video. A video with everyday situations of risk associated with HIV infection was the one preferred by participants. Key messages identified, and theoretical constructs models chosen were used to create the video scenes. Participants identified with the main, 9 minute video which they considered to be clear and dynamic. It is necessary to work with the target population to design a video according to their preferences. PMID- 26580937 TI - [Notification of accidents and occupational diseases to the ministry of labor. Peru 2010-2014]. AB - In order to determine trends in accidents and illnesses reported to the Ministry of Labor of Peru, a descriptive study of secondary data from the reports of monthly newsletters from September 2010 to December 2014 was performed. At the national level, 54,596 non-fatal accidents were reported. The rates of non-fatal accidents increased in 2011-2013 (296.5 in 2011, 955.9 in 2012 and 1176.3 in 2013), decreasing in 2014 (878.9). There were 674 fatal accidents whose rates increased between 2011 and 2012 and were reduced between 2013 and 2014. 346 occupational diseases were reported; the most frequent were cases of hearing loss (77), illness by inadequate postures (57) and allergic dermatitis (44). Reports declined from 6.9 in 2011 to 2.3 in 2014. Reports of occupational diseases were declining, which could indicate significant underreporting. PMID- 26580938 TI - [Systematic review of the efectiveness of community-based interventions to decrease neonatal mortality]. AB - We evaluated the efficacy/effectiveness of community-based interventions to decrease neonatal mortality. A systematic review of randomized controlled trials, cluster randomized trials and cohort studies of interventions on pregnant women, neonates (up to 28 days after birth) or both was made. Thirty four studies were evaluated (n=844,989): 20 in pregnant women (n=406,172), 6 in neonates (n=24,994), and 8 in both (n=413,823). Risk of bias was generally low. There was heterogeneity among interventions. Interventions such as maternal health education and maternal and neonatal home care were associated to a decrease in neonatal mortality in half of the 6 studies of each group. Supplementation with multiple micronutrients, kangaroo mother care, and maternal supplementation with vitamin A did not decrease neonatal mortality. A few heterogeneous community based interventions demonstrated a decrease in neonatal mortality. PMID- 26580939 TI - [HIV in indigenous pregnant women: a challenge for peruvian public health]. AB - This narrative review addresses the issue of indigenous pregnant women with HIV, recounting the main findings on the issue at the international level and then reviewing the status of research in Peru. Research at the international level on indigenous pregnant women focuses on the health of the unborn and the prevention of vertical transmission. There is little information about their conceptions of the disease, care practices and prevention of vertical transmission, and their perceptions of Highly Active Antiretroviral Therapy (HAART) and the role of traditional medicine in the care of their health condition. At the national level only one bibliographic reference was found. There is evidence for the need of an urgent medical anthropological focus to investigate and deal with cases of HIV in pregnant women and women of reproductive age in indigenous communities in the Peruvian Amazon. PMID- 26580940 TI - [Melanoma immunotherapy: dendritic cell vaccines]. AB - This is a narrative review that shows accessible information to the scientific community about melanoma and immunotherapy. Dendritic cells have the ability to participate in innate and adaptive immunity, but are not unfamiliar to the immune evasion of tumors. Knowing the biology and role has led to generate in vitro several prospects of autologous cell vaccines against diverse types of cancer in humans and animal models. However, given the low efficiency they have shown, we must implement strategies to enhance their natural capacity either through the coexpression of key molecules to activate or reactivate the immune system, in combination with biosimilars or chemotherapeutic drugs. The action of natural products as alternative or adjuvant immunostimulant should not be ruled out. All types of immunotherapy should measure the impact of myeloid suppressor cells, which can attack the immune system and help tumor progression, respectively. This can reduce the activity of cellular vaccines and/or their combinations, that could be the difference between success or not of the immunotherapy. Although for melanoma there exist biosimilars approved by the Food and Drug Administration (FDA), not all have the expected success. Therefore it is necessary to evaluate other strategies including cellular vaccines loaded with tumor antigenic peptides expressed exclusively or antigens from tumor extracts and their respective adjuvants. PMID- 26580941 TI - [Child neurodevelopment: normal characteristics and warning signs in children under five years]. AB - The development of the nervous system is a complex process that results in the maturation of structures, the acquisition of skills and finally the formation of the individual as a unique person. This review contains information about the main characteristics of the processes of brain development, the characteristics of normal neurological development in different areas: gross and fine motor, language, sensory and socialization; and it is also accompanied by a description of the major changes in the development, identifiable in the daily clinical work of pediatricians. Our goal is to enhance knowledge in this key area of assessment of early childhood to detect problems sufficiently in advance for their timely intervention. PMID- 26580942 TI - [Early childhood growth and development]. AB - This article describes and discusses issues related to the process of childhood growth and development, with emphasis on the early years, a period in which this process reaches critical speed on major structures and functions of the human economy. We reaffirm that this can contribute to the social availability of a generation of increasingly better adults, which in turn will be able to contribute to building a better world and within it a society that enjoys greater prosperity. In the first chapter, we discuss the general considerations on the favorable evolution of human society based on quality of future adults, meaning the accomplishments that today?s children will gain. A second chapter mentions the basics of growth and development in the different fields and the various phenomena that occur in it. In the third we refer to lost opportunities and negative factors that can affect delaying the process and thereby result in not obtaining the expected accomplishments. In the fourth, conclusions and recommendations are presented confirming the initial conception that good early child care serves to build a better society and some recommendations are formulated to make it a good practice. PMID- 26580943 TI - [National congenital hypothyroidism screening in Peru: a broken program]. AB - Congenital hypothyroidism (CH) is the most important cause of preventable mental retardation. The prevalence of CH varies by geographic region, race and ethnicity. In the countries of the Northern hemisphere, the prevalence has been reported as 1:4,000 live newborns. The prevalence is remarkably different among the countries of Latin America not only because of their different races and ethnicities but also because of the heterogeneous social-economic development. The prevalence of CH in 1984 in Peru was reported as 1:1250. In 2007, the reported incidence by the Instituto Nacional Materno Perinatal was 1:1638. A recent retrospective study performed by the Instituto Nacional de Salud del Nino in Lima, Peru described the average age of diagnosis of CH as 5,9 months +/- 5,28. This late age of CH diagnosis certainly suggests the poor efficiency of the current neonatal CH screening programs in Peru. Every Peruvian infant deserves a timely newborn screening and treatment for CH. The Peruvian government is responsible for ensuring this mandatory goal is achieved promptly. PMID- 26580944 TI - [Transpacific partnership: when the cure is worse than the disease]. AB - Peru is negotiating the Transpacific Partnership Agreement, a commercial treaty that could have deleterious implications for the health systems of the included partners. Transparency and Intellectual Property chapters are the most controversial elements. The first mostly because it opens the possibility for groups of interest to refuse decisions being taken by the sanitary authorities concerning the incorporation of health technologies to the public health systems. The second because it poses restrictions to the entrance of generic medical products, widening the period of data exclusivity and implementing mechanisms of opposition to their registry. Other chapters include strategies to block the states from regulating the consumption of alcohol, tobacco and processed foods. We ought to create surveillance systems to evaluate the impact of the agreement if it is signed, and generate mechanisms that prevent the little resources we already have devoted for health to be deviated to top technology that will not necessarily have a positive impact at a population level. PMID- 26580945 TI - [Amebiasis of the central nervous system: report of six cases in Peru]. AB - Six cases of amoebic encephalitis admitted to the National Institute of Neoplastic Diseases between the years 1994-2010 in Peru are reported. These cases were admitted for clinical suspicion of malignant primary brain tumor and one orbital-nasal sarcoma. All cases came from coastal regions; three were less than 24 years of age and four were male. The most common symptoms were headache and seizures. Three cases had more than one brain lesion. Stereotactic biopsy was performed in three patients and the differential pathological diagnosis in two cases was glioma of high and low grade. It was possible to confirm the diagnosis using molecular techniques in paraffin-embedded samples in three cases. All patients died within 15 days of admission to the institution. Amoebic encephalitis may be erroneously interpreted as a cerebral neoplasm, causing delay in the management of the infection. PMID- 26580946 TI - [Heterotopic pancreas as a cause of intussusception: first case reported in Peru]. AB - The heterotopic pancreas (HP) is a rare condition in the pediatric population. HP cases involving an ileal intussusception are rare in children and very rarely reported, usually presenting with symptoms of intestinal obstruction. We report the case of a one year old male patient with a chronic history of anorexia, irritability, abdominal pain, accompanied by intermittent episodes of "currant jelly" stools that evolved to rectal bleeding. The patient presented a concomitant diagnosis of allergic colitis, which prolonged the effective surgical treatment at an external health center. In the abdominal CT scan, the classic "target" sign was found. In the exploratory laparotomy an ileoileal intussusception was confirmed, a mass was found that the histopathology laboratory confirmed as HP. To our knowledge, it is the first case of pediatric intussusception by HP reported in Peru. PMID- 26580947 TI - [Law of healthy eating promotion: playing politics with the health of children?]. PMID- 26580948 TI - [Neglect of oral health in children as a public health problem in Peru]. PMID- 26580949 TI - [Increase of isolation of extended spectrum beta-lactamase-producing Salmonella spp. in pediatric patients from the Instituto Nacional de Salud del Nino]. PMID- 26580950 TI - [Dengue in Ica: an opportunity for effective interventions]. PMID- 26580951 TI - [What do we know about the lack of respect and abuse during childbirth care in Peru?]. PMID- 26580952 TI - [Eduardo Pretell and the fight against iodine deficiency in Peru]. PMID- 26580953 TI - [Comments to the article: iodine concentrations in urine and salt consumption in women between the ages of 12 to 49 in Peru]. PMID- 26580954 TI - [Reply: iodine concentration in urine and salt consumption in women between 12 to 49 years of age in Peru]. PMID- 26580955 TI - [Comments to the article: effects of a lipid-based nutrient supplement on hemoglobin levels and anthropometric indicators in children from five districts in Huanuco, Peru]. PMID- 26580956 TI - [Reply: effects of a lipid-based nutrient supplement on hemoglobin levels and anthropometric indicators in children from five districts in Huanuco, Peru]. PMID- 26580957 TI - Neuromechanical model of praying mantis explores the role of descending commands in pre-strike pivots. AB - Praying mantises hunt by standing on their meso- and metathoracic legs and using them to rotate and translate (together, 'pivot') their bodies toward prey. We have developed a neuromechanical software model of the praying mantis Tenodera sinensis to use as a platform for testing postural controllers that the animal may use while hunting. Previous results showed that a feedforward model was insufficient for capturing the diversity of posture observed in the animal (Szczecinski et al 2014 Biomimetic and Biohybrid Syst. 3 296-307). Therefore we have expanded upon this model to make a flexible controller with feedback that more closely mimics the animal. The controller actuates 24 joints in the legs of a dynamical model to orient the head and translate the thorax toward prey. It is controlled by a simulation of nonspiking neurons assembled as a highly simplified version of networks that may exist in the mantid central complex and thoracic ganglia. Because of the distributed nature of these networks, we hypothesize that descending commands that orient the mantis toward prey may be simple direction-of intent signals, which are turned into motor commands by the structure of low level networks in the thoracic ganglia. We verify this through a series of experiments with the model. It captures the speed and range of mantid pivots as reported in other work (Yamawaki et al 2011 J. Insect Physiol. 57 1010-6). It is capable of pivoting toward prey from a variety of initial postures, as seen in the animal. Finally, we compare the model's joint kinematics during pivots to preliminary 3D kinematics collected from Tenodera. PMID- 26580958 TI - Determinants of the Efficacy of Cardiac Ischemic Preconditioning: A Systematic Review and Meta-Analysis of Animal Studies. AB - BACKGROUND: Ischemic preconditioning (IPC) of the heart is a protective strategy in which a brief ischemic stimulus immediately before a lethal ischemic episode potently limits infarct size. Although very promising in animal models of myocardial infarction, IPC has not yet been successfully translated to benefit for patients. OBJECTIVE: To appraise all preclinical evidence on IPC for myocardial infarction and identify factors hampering translation. METHODS AND RESULTS: Using systematic review and meta-analysis, we identified 503 animal studies reporting infarct size data from 785 comparisons between IPC-treated and control animals. Overall, IPC reduced myocardial infarction by 24.6% [95%CI 23.5, 25.6]. Subgroup analysis showed that IPC efficacy was reduced in comorbid animals and non-rodents. Efficacy was highest in studies using 2-3 IPC cycles applied <45 minutes before myocardial infarction. Local and remote IPC were equally effective. Reporting of study quality indicators was low: randomization, blinding and a sample size calculation were reported in 49%, 11% and 2% of publications, respectively. CONCLUSIONS: Translation of IPC to the clinical setting may be hampered by the observed differences between the animals used in preclinical IPC studies and the patient population, regarding comorbidity, sex and age. Furthermore, the IPC protocols currently used in clinical trials could be optimized in terms of timing and the number of ischemic cycles applied. In order to inform future clinical trials successfully, future preclinical studies on IPC should aim to maximize both internal and external validity, since poor methodological quality may limit the value of the preclinical evidence. PMID- 26580960 TI - Regulatory Mode and Risk-Taking: The Mediating Role of Anticipated Regret. AB - We propose that decision maker's regulatory mode affects risk-taking through anticipated regret. In the Study 1 either a locomotion or an assessment orientation were experimentally induced, and in the Studies 2 and 3 these different orientations were assessed as chronic individual differences. To assess risk-taking we used two behavioral measures of risk: BART and hot-CCT. The results show that experimentally induced assessment orientation--compared to locomotion--leads to decreased risk-taking through increased anticipated regret (Study 1). People chronically predisposed to be in the assessment state take less risk through increased anticipated regret (Study 2 and Study 3). Study 2 results also show a marginally non-significant indirect effect of chronic locomotion mode on BART through anticipated regret. Differently, Study 3 shows that people chronically predisposed to be in the locomotion state take greater risk through decreased anticipated regret, when play a dynamic risk task triggering stronger emotional arousal. Through all three studies, the average effect size for the relationship of assessment with anticipated regret was in the moderate-large range, whereas for risk-taking was in the moderate range. The average effect size for the relationship of locomotion with anticipated regret was in the moderate range, whereas for risk-taking was in the small-moderate range. These results increase our understanding of human behavior under conditions of risk obtaining novel insights into regulatory mode theory and decision science. PMID- 26580961 TI - Correction: Understanding Heroin Overdose: A Study of the Acute Respiratory Depressant Effects of Injected Pharmaceutical Heroin. PMID- 26580959 TI - Sphingosine Kinase 2 and Ceramide Transport as Key Targets of the Natural Flavonoid Luteolin to Induce Apoptosis in Colon Cancer Cells. AB - The plant flavonoid luteolin exhibits different biological effects, including anticancer properties. Little is known on the molecular mechanisms underlying its actions in colorectal cancer (CRC). Here we investigated the effects of luteolin on colon cancer cells, focusing on the balance between ceramide and sphingosine-1 phosphate (S1P), two sphingoid mediators with opposite roles on cell fate. Using cultured cells, we found that physiological concentrations of luteolin induce the elevation of ceramide, followed by apoptotic death of colon cancer cells, but not of differentiated enterocytes. Pulse studies revealed that luteolin inhibits ceramide anabolism to complex sphingolipids. Further experiments led us to demonstrate that luteolin induces an alteration of the endoplasmic reticulum (ER) Golgi flow of ceramide, pivotal to its metabolic processing to complex sphingolipids. We report that luteolin exerts its action by inhibiting both Akt activation, and sphingosine kinase (SphK) 2, with the consequent reduction of S1P, an Akt stimulator. S1P administration protected colon cancer cells from luteolin-induced apoptosis, most likely by an intracellular, receptor-independent mechanism. Overall this study reveals for the first time that the dietary flavonoid luteolin exerts toxic effects on colon cancer cells by inhibiting both S1P biosynthesis and ceramide traffic, suggesting its dietary introduction/supplementation as a potential strategy to improve existing treatments in CRC. PMID- 26580962 TI - The Peripheral Blood Neutrophil-To-Lymphocyte Ratio Is Superior to the Lymphocyte To-Monocyte Ratio for Predicting the Long-Term Survival of Triple-Negative Breast Cancer Patients. AB - PURPOSE: The peripheral hematologic parameters of patients can be prognostic for many malignant tumors, including breast cancer, although their value has not been investigated among the different molecular subtypes of breast cancer. The purpose of this study was to examine the prognostic significance of the neutrophil-to lymphocyte ratio (NLR) and the lymphocyte-to-monocyte ratio (LMR) in different molecular subtypes of breast cancer. METHODS: A retrospective cohort of 1570 operable breast cancer patients was recruited between January 2000 and December 2010. The counts of peripheral neutrophils, lymphocytes, monocytes and platelets were collected and applied to calculate the NLR and the LMR. Univariate and multivariate Cox proportional hazard analyses were used to assess the relationship of the NLR and the LMR with disease-free survival (DFS) and overall survival (OS) in all patients and triple negative breast cancer (TNBC) patients. RESULTS: Univariate analysis revealed that lower NLR (<=2.0) and higher LMR (>4.8) were significantly associated with superior DFS in all patients (NLR, P = 0.005; LMR, P = 0.041) and in TNBC patients (NLR, p = 0.007; LMR, P = 0.011). However, multivariate analysis revealed that only lower NLR was a significant independent predictor of superior DFS and OS in all breast cancer patients (DFS, HR = 1.50 95% CI: 1.14-1.97, P = 0.004; OS, HR = 1.63, 95% CI: 1.07-2.49, P = 0.022) and in TNBC patients (DFS, HR = 2.58, 95% CI: 1.23-5.42, P = 0.012; OS, HR = 3.05, 95% CI: 1.08-8.61, P = 0.035). Both univariate and multivariate analysis revealed that neither the NLR nor the LMR significantly predicted DFS and OS among the patients with other molecular subtypes of breast cancer. CONCLUSIONS: A higher pretreatment peripheral NLR significantly and independently indicated a poor prognosis for breast cancer and TNBC, and this measurement exhibited greater prognostic value than a lower LMR. The NLR was not a prognostic factor for other breast cancer subtypes. PMID- 26580963 TI - Cryptanalysis and Improvement of "A Secure Password Authentication Mechanism for Seamless Handover in Proxy Mobile IPv6 Networks". AB - Proxy Mobile IPv6 is a network-based localized mobility management protocol that supports mobility without mobile nodes' participation in mobility signaling. The details of user authentication procedure are not specified in this standard, hence, many authentication schemes have been proposed for this standard. In 2013, Chuang et al., proposed an authentication method for PMIPv6, called SPAM. However, Chuang et al.'s Scheme protects the network against some security attacks, but it is still vulnerable to impersonation and password guessing attacks. In addition, we discuss other security drawbacks such as lack of revocation procedure in case of loss or stolen device, and anonymity issues of the Chuang et al.'s scheme. We further propose an enhanced authentication method to mitigate the security issues of SPAM method and evaluate our scheme using BAN logic. PMID- 26580964 TI - MET Gene Amplification and MET Receptor Activation Are Not Sufficient to Predict Efficacy of Combined MET and EGFR Inhibitors in EGFR TKI-Resistant NSCLC Cells. AB - Epidermal growth factor receptor (EGFR), member of the human epidermal growth factor receptor (HER) family, plays a critical role in regulating multiple cellular processes including proliferation, differentiation, cell migration and cell survival. Deregulation of the EGFR signaling has been found to be associated with the development of a variety of human malignancies including lung, breast, and ovarian cancers, making inhibition of EGFR the most promising molecular targeted therapy developed in the past decade against cancer. Human non small cell lung cancers (NSCLC) with activating mutations in the EGFR gene frequently experience significant tumor regression when treated with EGFR tyrosine kinase inhibitors (TKIs), although acquired resistance invariably develops. Resistance to TKI treatments has been associated to secondary mutations in the EGFR gene or to activation of additional bypass signaling pathways including the ones mediated by receptor tyrosine kinases, Fas receptor and NF-kB. In more than 30-40% of cases, however, the mechanisms underpinning drug-resistance are still unknown. The establishment of cellular and mouse models can facilitate the unveiling of mechanisms leading to drug-resistance and the development or validation of novel therapeutic strategies aimed at overcoming resistance and enhancing outcomes in NSCLC patients. Here we describe the establishment and characterization of EGFR TKI-resistant NSCLC cell lines and a pilot study on the effects of a combined MET and EGFR inhibitors treatment. The characterization of the erlotinib-resistant cell lines confirmed the association of EGFR TKI resistance with loss of EGFR gene amplification and/or AXL overexpression and/or MET gene amplification and MET receptor activation. These cellular models can be instrumental to further investigate the signaling pathways associated to EGFR TKI-resistance. Finally the drugs combination pilot study shows that MET gene amplification and MET receptor activation are not sufficient to predict a positive response of NSCLC cells to a cocktail of MET and EGFR inhibitors and highlights the importance of identifying more reliable biomarkers to predict the efficacy of treatments in NSCLC patients resistant to EGFR TKI. PMID- 26580965 TI - Simple, Low-Cost Detection of Candida parapsilosis Complex Isolates and Molecular Fingerprinting of Candida orthopsilosis Strains in Kuwait by ITS Region Sequencing and Amplified Fragment Length Polymorphism Analysis. AB - Candida parapsilosis has now emerged as the second or third most important cause of healthcare-associated Candida infections. Molecular studies have shown that phenotypically identified C. parapsilosis isolates represent a complex of three species, namely, C. parapsilosis, C. orthopsilosis and C. metapsilosis. Lodderomyces elongisporus is another species phenotypically closely related to the C. parapsilosis-complex. The aim of this study was to develop a simple, low cost multiplex (m) PCR assay for species-specific identification of C. parapsilosis complex isolates and to study genetic relatedness of C. orthopsilosis isolates in Kuwait. Species-specific amplicons from C. parapsilosis (171 bp), C. orthopsilosis (109 bp), C. metapsilosis (217 bp) and L. elongisporus (258 bp) were obtained in mPCR. Clinical isolates identified as C. parapsilosis (n = 380) by Vitek2 in Kuwait and an international collection of 27 C. parapsilosis complex and L. elongisporus isolates previously characterized by rDNA sequencing were analyzed to evaluate mPCR. Species-specific PCR and DNA sequencing of internal transcribed spacer (ITS) region of rDNA were performed to validate the results of mPCR. Fingerprinting of 19 clinical C. orthopsilosis isolates (including 4 isolates from a previous study) was performed by amplified fragment length polymorphism (AFLP) analysis. Phenotypically identified C. parapsilosis isolates (n = 380) were identified as C. parapsilosis sensu stricto (n = 361), C. orthopsilosis (n = 15), C. metapsilosis (n = 1) and L. elongisporus (n = 3) by mPCR. The mPCR also accurately detected all epidemiologically unrelated C. parapsilosis complex and L. elongisporus isolates. The 19 C. orthopsilosis isolates obtained from 16 patients were divided into 3 haplotypes based on ITS region sequence data. Seven distinct genotypes were identified among the 19 C. orthopsilosis isolates by AFLP including a dominant genotype (AFLP1) comprising 11 isolates recovered from 10 patients. A rapid, low-cost mPCR assay for detection and differentiation of C. parapsilosis, C. orthopsilosis, C. metapsilosis and L. elongisporus has been developed. PMID- 26580966 TI - Passive Acoustic Monitoring the Diel, Lunar, Seasonal and Tidal Patterns in the Biosonar Activity of the Indo-Pacific Humpback Dolphins (Sousa chinensis) in the Pearl River Estuary, China. AB - A growing demand for sustainable energy has led to an increase in construction of offshore windfarms. Guishan windmill farm will be constructed in the Pearl River Estuary, China, which sustains the world's largest known population of Indo Pacific humpback dolphins (Sousa chinensis). Dolphin conservation is an urgent issue in this region. By using passive acoustic monitoring, a baseline distribution of data on this species in the Pearl River Estuary during pre construction period had been collected. Dolphin biosonar detection and its diel, lunar, seasonal and tidal patterns were examined using a Generalized Linear Model. Significant higher echolocation detections at night than during the day, in winter-spring than in summer-autumn, at high tide than at flood tide were recognized. Significant higher echolocation detections during the new moon were recognized at night time. The diel, lunar and seasonal patterns for the echolocation encounter duration also significantly varied. These patterns could be due to the spatial-temporal variability of dolphin prey and illumination conditions. The baseline information will be useful for driving further effective action on the conservation of this species and in facilitating later assessments of the effects of the offshore windfarm on the dolphins by comparing the baseline to post construction and post mitigation efforts. PMID- 26580967 TI - Multi-allele genotyping platform for the simultaneous detection of mutations in the Wilson disease related ATP7B gene. AB - Wilson's disease is an inherited disorder of copper transport in the hepatocytes with a wide range of genotype and phenotype characteristics. Mutations in the ATP7B gene are responsible for the disease. Approximately, over 500 mutations in the ATP7B gene have been described to date. We report a method for the simultaneous detection of the ten most common ATP7B gene mutations in Greek patients. The method comprises 3 simple steps: (i) multiplex PCR amplification of fragments in the ATP7B gene flanking the mutations (ii) multiplex primer extension reaction of the unpurified amplification products using allele-specific primers and (iii) visual detection of the primer extension reaction products within minutes by means of dry-reagent multi-allele dipstick assay using anti biotin conjugated gold nanoparticles. Optimization studies on the efficiency and specificity of the PEXT reaction were performed. The method was evaluated by genotyping 46 DNA samples of known genotype and 34 blind samples. The results were fully concordant with those obtained by reference methods. The method is simple, rapid, cost-effective and it does not require specialized instrumentation or highly qualified personnel. PMID- 26580969 TI - Self-Assembled Microdisk Lasers of Perylenediimides. AB - Organic solid-state lasers (OSSLs) have been a topic of intensive investigations. Perylenediimide (PDI) derivatives are widely used in organic thin-film transistors and solar cells. However, OSSLs based on neat PDIs have not been achieved yet, owing to the formation of H-aggregates and excimer trap-states. Here, we demonstrated the first PDI-based OSSL from whispering-gallery mode (WGM) hexagonal microdisk (hMD) microcavity of N,N'-bis(1-ethylpropyl)-2,5,8,11 tetrakis(p-methyl-phenyl)-perylenediimide (mp-PDI) self-assembled from solution. Single-crystal data reveal that mp-PDI molecules stack into a loosely packed twisted brickstone arrangement, resulting in J-type aggregates that exhibit a solid-state photoluminescence (PL) efficiency phi > 15%. Moreover, we found that exciton-vibration coupling in J-aggregates leads to an exceptional ultrafast radiative decay, which reduces the exciton diffusion length, in turn, suppresses bimolecular exciton annihilation (bmEA) process. These spectral features, plus the optical feedback provided by WGM-hMD microcavity, enable the observation of multimode lasing as evidenced by nonlinear output, spectral narrowing, and temporal coherence of laser emission. With consideration of high carrier-mobility associated with PDIs, hMDs of mp-PDI are attractive candidates on the way to achieve electrically driven OSSL. PMID- 26580968 TI - Time Trends in Incidence and Mortality of Acute Myocardial Infarction, and All Cause Mortality following a Cardiovascular Prevention Program in Sweden. AB - BACKGROUND: In 1988, a cardiovascular prevention program which combined an individual and a population-based strategy was launched within primary health care in Sollentuna, a municipality in Stockholm County. The aim of this study was to investigate time trends in the incidence of and mortality from acute myocardial infarction and all-cause mortality in Sollentuna compared with the rest of Stockholm County during a period of two decades following the implementation of a cardiovascular prevention program. MATERIALS AND METHODS: The average population in Sollentuna was 56,589 (49% men) and in Stockholm County (Sollentuna included) 1,795,504 (49% men) during the study period of 1987-2010. Cases of hospitalized acute myocardial infarction and death were obtained for the population of Sollentuna and the rest of Stockholm County using national registries of hospital discharges and deaths. Acute myocardial infarction incidence and mortality were estimated using the average population of Sollentuna and Stockholm in 1987-2010. RESULTS: During the observation period, the incidence of acute myocardial infarction decreased more in Sollentuna compared with the rest of Stockholm County in women (-22% vs. -7%; for difference in slope <0.05). There was a trend towards a greater decline in Sollentuna compared to the rest of Stockholm County in the incidence of acute myocardial infarction (in men), acute myocardial mortality, and all-cause mortality but the differences were not significant. CONCLUSION: During a period of steep decline in acute myocardial infarction incidence and mortality in Stockholm County the municipality of Sollentuna showed a stronger trend in women possibly compatible with favorable influence of a cardiovascular prevention program. TRIAL REGISTRATION: ClinicalTrials.gov NCT02212145. PMID- 26580970 TI - Covalent Functionalization of Boron Nitride Nanotubes via Reduction Chemistry. AB - Boron nitride nanotubes (BNNTs) exhibit a range of properties that hold great potential for many fields of science and technology; however, they have inherently low chemical reactivity, making functionalization for specific applications difficult. Here we propose that covalent functionalization of BNNTs via reduction chemistry could be a highly promising and viable strategy. Through density functional theory calculations of the electron affinity of BNNTs and their binding energies with various radicals, we reveal that their chemical reactivity can be significantly enhanced via reducing the nanotubes (i.e., negatively charging). For example, a 5.5-fold enhancement in reactivity of reduced BNNTs toward NH2 radicals was predicted relative to their neutral counterparts. The localization characteristics of the BNNT pi electron system lead the excess electrons to fill the empty p orbitals of boron sites, which promote covalent bond formation with an unpaired electron from a radical molecule. In support of our theoretical findings, we also experimentally investigated the covalent alkylation of BNNTs via reduction chemistry using 1 bromohexane. The thermogravimetric measurements showed a considerable weight loss (12-14%) only for samples alkylated using reduced BNNTs, suggesting their significantly improved reactivity over neutral BNNTs. This finding will provide an insight in developing an effective route to chemical functionalization of BNNTs. PMID- 26580972 TI - Circulating microRNAs and Outcome in Patients with Acute Heart Failure. AB - BACKGROUND: The biomarker value of circulating microRNAs (miRNAs) has been extensively addressed in patients with acute coronary syndrome. However, prognostic performances of miRNAs in patients with acute heart failure (AHF) has received less attention. METHODS: A test cohort of 294 patients with acute dyspnea (236 AHF and 58 non-AHF) and 44 patients with stable chronic heart failure (CHF), and an independent validation cohort of 711 AHF patients, were used. Admission levels of miR-1/-21/-23/-126/-423-5p were assessed in plasma samples. RESULTS: In the test cohort, admission levels of miR-1 were lower in AHF and stable CHF patients compared to non-AHF patients (p = 0.0016). Levels of miR 126 and miR-423-5p were lower in AHF and in non-AHF patients compared to stable CHF patients (both p<0.001). Interestingly, admission levels of miR-423-5p were lower in patients who were re-admitted to the hospital in the year following the index hospitalization compared to patients who were not (p = 0.0001). Adjusted odds ratio [95% confidence interval] for one-year readmission was 0.70 [0.53 0.93] for miR-423-5p (p = 0.01). In the validation cohort, admission levels of miR-423-5p predicted 1-year mortality with an adjusted odds ratio [95% confidence interval] of 0.54 [0.36-0.82], p = 0.004. Patients within the lowest quartile of miR-423-5p were at high risk of long-term mortality (p = 0.02). CONCLUSIONS: In AHF patients, low circulating levels of miR-423-5p at presentation are associated with a poor long-term outcome. This study supports the value of miR-423-5p as a prognostic biomarker of AHF. PMID- 26580973 TI - In Situ Ammonium Profiling Using Solid-Contact Ion-Selective Electrodes in Eutrophic Lakes. AB - A promising profiling setup for in situ measurements in lakes with potentiometric solid-contact ion-selective electrodes (SC-ISEs) and a data processing method for sensor calibration and drift correction are presented. The profiling setup consists of a logging system, which is equipped with a syringe sampler and sensors for the measurement of standard parameters including temperature, conductivity, oxygen and photosynthetically active radiation (PAR). The setup was expanded with SC-ISEs in galvanically separated amplifiers. The potential for high-resolution profiling is investigated by deploying the setup in the eutrophic Lake Rotsee (Lucerne, Switzerland), using two different designs of ammonium sensing SC-ISEs. Ammonium was chosen as a target analyte, since it is the most common reduced inorganic nitrogen species involved in various pathways of the nitrogen cycle and is therefore indicative of numerous biogeochemical processes that occur in lakes such as denitrification and primary production. One of the designs, which uses a composite carbon-nanotube-PVC-based membrane, suffered from sulfide poisoning in the deeper, sulfidic regions of the lake. In contrast, electrodes containing a plasticizer-free methacrylate copolymer-based sensing layer on top of a conducting polymer layer as a transducer did not show this poisoning effect. The syringe samples drawn during continuous profiling were utilized to calibrate the electrode response. Reaction hotspots and steep gradients of ammonium concentrations were identified on-site by monitoring the electrode potential online. Upon conversion to high-resolution concentration profiles, fine scale features between the calibration points were displayed, which would have been missed by conventional limnological sampling and subsequent laboratory analyses. Thus, the presented setup with SC-ISEs tuned to analytes of interest can facilitate the study of biogeochemical processes that occur at the centimeter scale. PMID- 26580971 TI - Mechanisms of Egg Yolk Formation and Implications on Early Life History of White Perch (Morone americana). AB - The three white perch (Morone americana) vitellogenins (VtgAa, VtgAb, VtgC) were quantified accurately and precisely in the liver, plasma, and ovary during pre-, early-, mid-, and post-vitellogenic oocyte growth using protein cleavage-isotope dilution mass spectrometry (PC-IDMS). Western blotting generally mirrored the PC IDMS results. By PC-IDMS, VtgC was quantifiable in pre-vitellogenic ovary tissues and VtgAb was quantifiable in pre-vitellogenic liver tissues however, neither protein was detected by western blotting in these respective tissues at this time point. Immunohistochemistry indicated that VtgC was present within pre vitellogenic oocytes and localized to lipid droplets within vitellogenic oocytes. Affinity purification coupled to tandem mass spectrometry using highly purified VtgC as a bait protein revealed a single specific interacting protein (Y-box binding protein 2a-like [Ybx2a-like]) that eluted with suramin buffer and confirmed that VtgC does not bind the ovary vitellogenin receptors (LR8 and Lrp13). Western blotting for LR8 and Lrp13 showed that both receptors were expressed during vitellogenesis with LR8 and Lrp13 expression highest in early- and mid-vitellogenesis, respectively. The VtgAa within the ovary peaked during post-vitellogenesis, while VtgAb peaked during early-vitellogenesis in both white perch and the closely related striped bass (M. saxatilis). The VtgC was steadily accumulated by oocytes beginning during pre-vitellogenesis and continued until post-vitellogenesis and its composition varies widely between striped bass and white perch. In striped bass, the VtgC accounted for 26% of the vitellogenin derived egg yolk, however in the white perch it comprised only 4%. Striped bass larvae have an extended developmental window and these larvae have yolk stores that may enable them to survive in the absence of food for twice as long as white perch after hatch. Thus, the VtgC may play an integral role in providing nutrients to late stage fish larvae prior to the onset of exogenous feeding and its composition in the egg yolk may relate to different early life histories among this diverse group of animals. PMID- 26580975 TI - Drawing the Line: The Development of a Comprehensive Assessment of Infidelity Judgments. AB - Infidelity is a leading cause of relationship discord and dissolution, and couples generally report expectations to maintain monogamy. However, a majority of men and women report engaging in some form of infidelity at least once in their lives. Research assessing judgments of the behaviors that constitute infidelity is lacking. The three studies reported here advanced the literature by developing and validating the Definitions of Infidelity Questionnaire (DIQ), a comprehensive measure examining infidelity judgments. Exploratory and confirmatory factor analyses indicated four factors to the scale: sexual/explicit behaviors, technology/online behaviors, emotional/affectionate behaviors, and solitary behaviors. Investigation of the psychometric properties demonstrated the DIQ to be reliable and valid. Participants agreed that sexual/explicit behaviors comprised infidelity to the largest extent, whereas other types of behaviors (technology/online behaviors, emotional/affectionate behaviors, and solitary behaviors) were judged as comprising infidelity to a lesser extent. Men reported more permissive judgments than did women. This study provides insights regarding operationalizing infidelity and identifying areas of ambiguity and consensus. Implications of the findings for educators and practitioners working with individuals in intimate relationships are discussed. PMID- 26580974 TI - IL6 Inhibits HBV Transcription by Targeting the Epigenetic Control of the Nuclear cccDNA Minichromosome. AB - The HBV covalently closed circular DNA (cccDNA) is organized as a mini-chromosome in the nuclei of infected hepatocytes by histone and non-histone proteins. Transcription from the cccDNA of the RNA replicative intermediate termed pre genome (pgRNA), is the critical step for genome amplification and ultimately determines the rate of HBV replication. Multiple evidences suggest that cccDNA epigenetic modifications, such as histone modifications and DNA methylation, participate in regulating the transcriptional activity of the HBV cccDNA. Inflammatory cytokines (TNFalpha, LTbeta) and the pleiotropic cytokine interleukin-6 (IL6) inhibit hepatitis B virus (HBV) replication and transcription. Here we show, in HepG2 cells transfected with linear HBV monomers and HBV-infected NTCP-HepG2 cells, that IL6 treatment leads to a reduction of cccDNA-bound histone acetylation paralleled by a rapid decrease in 3.5kb/pgRNA and subgenomic HBV RNAs transcription without affecting cccDNA chromatinization or cccDNA levels. IL6 repressive effect on HBV replication is mediated by a loss of HNF1alpha and HNF4alpha binding to the cccDNA and a redistribution of STAT3 binding from the cccDNA to IL6 cellular target genes. PMID- 26580976 TI - Orientation-Controlled Electrocatalytic Efficiency of an Adsorbed Oxygen-Tolerant Hydrogenase. AB - Protein immobilization on electrodes is a key concept in exploiting enzymatic processes for bioelectronic devices. For optimum performance, an in-depth understanding of the enzyme-surface interactions is required. Here, we introduce an integral approach of experimental and theoretical methods that provides detailed insights into the adsorption of an oxygen-tolerant [NiFe] hydrogenase on a biocompatible gold electrode. Using atomic force microscopy, ellipsometry, surface-enhanced IR spectroscopy, and protein film voltammetry, we explore enzyme coverage, integrity, and activity, thereby probing both structure and catalytic H2 conversion of the enzyme. Electrocatalytic efficiencies can be correlated with the mode of protein adsorption on the electrode as estimated theoretically by molecular dynamics simulations. Our results reveal that pre-activation at low potentials results in increased current densities, which can be rationalized in terms of a potential-induced re-orientation of the immobilized enzyme. PMID- 26580977 TI - Occupation Dynamics and Impacts of Damselfish Territoriality on Recovering Populations of the Threatened Staghorn Coral, Acropora cervicornis. AB - Large-scale coral reef restoration is needed to help recover structure and function of degraded coral reef ecosystems and mitigate continued coral declines. In situ coral propagation and reef restoration efforts have scaled up significantly in past decades, particularly for the threatened Caribbean staghorn coral, Acropora cervicornis, but little is known about the role that native competitors and predators, such as farming damselfishes, have on the success of restoration. Steep declines in A. cervicornis abundance may have concentrated the negative impacts of damselfish algal farming on a much lower number of coral prey/colonies, thus creating a significant threat to the persistence and recovery of depleted coral populations. This is the first study to document the prevalence of resident damselfishes and negative effects of algal lawns on A. cervicornis along the Florida Reef Tract (FRT). Impacts of damselfish lawns on A. cervicornis colonies were more prevalent (21.6% of colonies) than those of other sources of mortality (i.e., disease (1.6%), algal/sponge overgrowth (5.6%), and corallivore predation (7.9%)), and damselfish activities caused the highest levels of tissue mortality (34.6%) among all coral stressors evaluated. The probability of damselfish occupation increased as coral colony size and complexity increased and coral growth rates were significantly lower in colonies with damselfish lawns (15.4 vs. 29.6 cm per year). Reduced growth and mortality of existing A. cervicornis populations may have a significant effect on population dynamics by potentially reducing important genetic diversity and the reproductive potential of depleted populations. On a positive note, however, the presence of resident damselfishes decreased predation by other corallivores, such as Coralliophila and Hermodice, and may offset some negative impacts caused by algal farming. While most negative impacts of damselfishes identified in this study affected large individual colonies and <50% of the A. cervicornis population along the FRT, the remaining wild staghorn population, along with the rapidly increasing restored populations, continue to fulfill important functional roles on coral reefs by providing essential habitat and refuge to other reef organisms. Although the effects of damselfish predation are, and will continue to be, pervasive, successful restoration efforts and strategic coral transplantation designs may help overcome damselfish damage by rapidly increasing A. cervicornis cover and abundance while also providing important information to educate future conservation and management decisions. PMID- 26580978 TI - Dexamethasone Disodium Phosphate Penetration Into the Human Aqueous Humor After Topical Application. AB - PURPOSE: To study the amount of steroids that is found in the aqueous humor after topical administration of dexamethasone solution eye-drops and dexamethasone suspension eye-drops. MATERIALS AND METHODS: One hundred seventeen consecutive patients of both genders 18 years or older, candidates for cataract surgery were randomly assigned to one of three groups. Fifty-one patients (group A) received a single instillation of a suspension containing tobramicin 0.3% mg/ml + dexamethasone 0.1% mg/ml; 56 patients (group B) received a single instillation of a solution containing tobramicin 0.3% mg/ml + dexamethasone 0.1% mg/ml; 10 patients (group C), control group, did not receive any drops. Samples were taken immediately before surgery from the anterior chamber and dexamethasone levels were measured using gas chromatography/mass spectrometry. RESULTS: The mean dexamethasone concentrations were 0.56 MUM (min 0.00, max 3.25) in group A and 0.15 MUM (min 0.00, max 2.93) in group B. Dexamethasone was not detected in samples from group C. CONCLUSIONS: Dexamethasone suspension gives concentrations of steroids in the aqueous humor approximately three times higher than with dexamethasone solution drops. PMID- 26580979 TI - Synthesis, antimycobacterial screening and ligand-based molecular docking studies on novel pyrrole derivatives bearing pyrazoline, isoxazole and phenyl thiourea moieties. AB - We report here the synthesis, antibacterial and antitubercular evaluation of 61 novel pyrrolyl derivatives bearing pyrazoline, isoxazole and phenyl thiourea moieties. Molecular docking was carried out on enoyl ACP reductase from Mycobacterium tuberculsosis using Surflex-Dock, which is one of the key enzymes involved in type II fatty acid biosynthetic pathway of Mycobacterium tuberculosis, an attractive target for designing novel antitubercular agents. Docking analysis of the crystal structure of ENR performed using Surflex-Dock in Sybyl-X 2.0 software indicates the occupation of substituted pyrrolyl derivatives into hydrophobic pocket of InhA enzyme. Compounds 9b and 9d exhibited the highest antitubercular activity almost close to isoniazid (0.4 MUg/mL) with a MIC value of 0.8 MUg/mL. All other compounds showed the good activity with a MIC value of 6.25-100 MUg/mL. The compounds were further tested for mammalian cell toxicity using human lung cancer cell-line (A549) and were nontoxic. Some compounds exhibited inhibition activities against InhA. PMID- 26580981 TI - Interrogating Endogenous Protein Phosphatase Activity with Rationally Designed Chemosensors. AB - We introduce a versatile approach for repurposing protein kinase chemosensors, containing the phosphorylation-sensitive sulfonamido-oxine fluorophore termed Sox, for the specific determination of endogenous protein phosphatase activity from whole cell lysates and tissue homogenates. As a demonstration of this approach, we design and evaluate a direct chemosensor for protein tyrosine phosphatase-1B (PTP1B), an established signaling node in human disease. The optimal sensor design is capable of detecting as little as 6 pM (12 pg) full length recombinant PTP1B and is remarkably selective for PTP1B among a panel of highly homologous tyrosine phosphatases. Coupling this robust activity probe with the specificity of antibodies allowed for the temporal analysis of endogenous PTP1B activity dynamics in lysates generated from HepG2 cells after stimulation with insulin. Lastly, we leveraged this assay format to profile PTP1B activity perturbations in a rat model of nonalcoholic fatty liver disease (NAFLD), providing direct evidence for elevated PTP1B catalytic activity in this disease state. Given the modular nature of this assay, we anticipate that this approach will have broad utility in monitoring phosphatase activity dynamics in human disease states. PMID- 26580980 TI - Design of alpha7 nicotinic acetylcholine receptor ligands using the (het)Aryl 1,2,3-triazole core: Synthesis, in vitro evaluation and SAR studies. AB - We report here the synthesis of a large library of 1,2,3-triazole derivatives which were in vitro tested as alpha7 nAchR ligands. The SAR study revealed that several crucial factors are involved in the affinity of these compounds for alpha7 nAchR such as a (R) quinuclidine configuration and a mono C-3 quinuclidine substitution. The triazole ring was substituted by a phenyl ring bearing small OMe/CH2F groups or fluorine atom and by several heterocycles such as thiophenes, furanes, benzothiophenes or benzofuranes. Among the 30 derivatives tested, the two derivatives 10 and 39 with Ki in the nanomolar range were identified (2.3 and 3 nM respectively). They exhibited a strict selectivity toward the alpha4beta2 nicotinic receptor (up to 1 MUM) but interacted with the 5HT3 receptors with Ki around 3 nM. Synthesis, SAR studies and a full description of the derivatives are reported. PMID- 26580982 TI - Speciation Analysis of Labile and Total Silver(I) in Nanosilver Dispersions and Environmental Waters by Hollow Fiber Supported Liquid Membrane Extraction. AB - Hollow fiber supported liquid membrane (HFSLM) extraction was coupled with ICP-MS for speciation analysis of labile Ag(I) and total Ag(I) in dispersions of silver nanoparticles (AgNPs) and environmental waters. Ag(I) in aqueous samples was extracted into the HFSLM of 5%(m/v) tri-n-octylphosphine oxide in n-undecane, and stripped in the acceptor of 10 mM Na2S2O3 and 1 mM Cu(NO3)2 prepared in 5 mM NaH2PO4-Na2HPO4 buffer (pH 7.5). Negligible depletion and exhaustive extraction were conducted under static and 250 rpm shaking to extract the labile Ag(I) and total Ag(I), respectively. The extraction equilibration was reached in 8 h for both extraction modes. The extraction efficiency and detection limit were (2.97 +/- 0.25)% and 0.1 MUg/L for labile Ag(I), and (82.3 +/- 2.0)% and 0.5 MUg/L for total Ag(I) detection, respectively. The proposed method was applied to determine labile Ag(I) and total Ag(I) in different sized AgNP dispersions and real environmental waters, with spiked recoveries of total Ag(I) in the range of 74.0 98.1%. With the capability of distinguishing labile and total Ag(I), our method offers a new approach for evaluating the bioavailability and understanding the fate and toxicity of AgNPs in aquatic systems. PMID- 26580983 TI - A microfluidic platform for transcription- and amplification-free detection of zepto-mole amounts of nucleic acid molecules. AB - Here we report the development of a device for the transcription- and amplification-free detection of DNA and RNA molecules down to the zepto-mole range. A microfluidic chip with a built-in microarray was used for manipulation of nano-liter sample volumes. Specific staining and immobilization of the target molecules was achieved via a double hybridization approach thereby avoiding bias due to enzymatic processes like reverse transcription and PCR amplification. Therefore, target molecules were indirectly labeled by pre-hybridization to complementary Cy5-labeled probes. The remaining single-stranded portion of each target molecule could subsequently hybridize to complementary capture probes of a microarray. Thus a target-mediated immobilization of labeled DNA took place. By means of an ultra-sensitive fluorescence readout, all molecules hybridized to the microarray could be detected. The combination of minimized sample volume and single molecule detection yielded a detection limit of 39 fM (831 molecules in 35.4 nl assay volume) for target DNA and 16 fM (338 molecules) for target RNA after 1h on-chip hybridization. PMID- 26580984 TI - The Safety and Efficacy of Laparoscopic Percutaneous Extraperitoneal Closure for Inguinal Hernia in Neonates and Infants Younger Than 1 Year of Age in Comparison to Older Patients. AB - PURPOSE: Laparoscopic percutaneous extraperitoneal closure (LPEC) has been performed in Japan for the repair of the pediatric inguinal hernias for over a decade. However, the safety and efficacy of LPEC in neonates and infants under 1 year of age remain unknown. The aim of the present study is to elucidate the safety and efficacy of LPEC in the treatment of inguinal hernia in patients who are younger than 1 year of age. PATIENTS AND METHODS: The medical records of the patients who underwent LPEC at Saga-Ken Medical Center Koseikan (Saga, Japan) between August 2007 and November 2012 were collected. The intraoperative findings and postoperative outcomes were retrospectively investigated. The data of the patients who were younger than 1 year of age (Group A) were compared with the data of patients who were older than 1 year of age (Group B). RESULTS: During the study period, 150 LPEC procedures were performed in 112 Group A patients, whereas 607 LPEC procedures were performed in 456 Group B patients. There were no serious complications in either group. After a mean follow-up period of 50.4 +/- 15.6 months (range, 28-91 months), there were no significant differences between the two groups in the operating time or the incidence of intraoperative or postoperative complications. Postoperative testicular ascent and recurrence were observed in some cases of each group. CONCLUSIONS: LPEC is a safe and effective procedure for the repair of an inguinal hernia, even in neonatal and infant patients who are younger than 1 year of age. PMID- 26580985 TI - Ultralight, Strong, Three-Dimensional SiC Structures. AB - Ultralight and strong three-dimensional (3D) silicon carbide (SiC) structures have been generated by the carbothermal reduction of SiO with a graphene foam (GF). The resulting SiC foams have an average height of 2 mm and density ranging between 9 and 17 mg cm(-3). They are the lightest reported SiC structures. They consist of hollow struts made from ultrathin SiC flakes and long 1D SiC nanowires growing from the trusses, edges, and defect sites between layers. AFM results revealed an average flake thickness of 2-3 nm and lateral size of 2 MUm. In-situ compression tests in the scanning electron microscope (SEM) show that, compared with most of the existing lightweight foams, the present 3D SiC exhibited superior compression strengths and significant recovery after compression strains of about 70%. PMID- 26580987 TI - Patent injunctions in Europe: the return of the pan-European injunction--or how can you get a decision from one court effective in more than one country? PMID- 26580986 TI - Pain Rating in Women with Provoked Vestibulodynia: Evaluating Influence of Race. AB - BACKGROUND: Chronic pain may be perceived differently according to gender and race, which may affect physical health and psychological wellbeing. We evaluated daily pain ratings in black women as compared to white women with provoked vestibulodynia (PVD). METHODS: Seventy-one women (44 black, 27 white) rated pain severity with tampon insertion and sexual intercourse and recorded daily vulvar pain level on a visual analogue scale (0 = no pain to 10 = worst pain imaginable). In addition, they completed the Brief Pain Inventory (BPI) Interference Scale and Hamilton Anxiety Depression Scale (HADS). Multivariate analysis was performed to determine the effect of race on pain intensity after adjusting for functional impairment, affective distress and demographic characteristics. RESULTS: Pain ratings from tampon insertion (6.37 +/- 1.89 vs. 5.61 +/- 1.98, p = .12) and sexual intercourse (6.28 +/- 2.11 vs. 5.29 +/- 2.50, p = 0.24) were similar, but daily vulvar pain (4.57 +/- 2.27 vs 2.74 +/- 2.43, p = <.01) was significantly higher in black women. BPI-interference scores were associated with small, but significant increases in tampon insertion pain (p = <.01, beta = .06 units) and daily pain (p < .01, beta = .10 units) and to a lesser degree with sexual intercourse pain when corrected for multiple comparisons (p = .05, beta = .06 units). Race had no effect on pain after adjusting for other variables. CONCLUSION: While race was associated with functional impairment, after accounting for this, race was not associated with level of vulvar pain with PVD. PMID- 26580988 TI - Korea: the new first battleground for the high stakes poker game of pharmaceutical patent litigation. PMID- 26580989 TI - Personalized medicine: its implications and its impact on patents. PMID- 26580992 TI - Strategies for stem cell patent applications in the light of recent court cases. AB - Stem cells offer the prospect of treatments for diseases and injuries that are currently beyond medical science. Although development of these potential medical marvels has been dogged by their controversial origin, technological developments and guidance from recent judicial decisions have answered and overcome many of these difficulties. In particular, the European Patent Office, United States Patent and Trademark Office, Japan Patent Office and State Intellectual Property Office of China have published guidelines covering patenting of stem cell technologies in the light of recent decisions. We now see a patent landscape where stem cell technologies and related therapies can, with very few exceptions, be protected via patents, provided the appropriate form of claim wording is used. PMID- 26580993 TI - FFA4/GPR120 agonists: a survey of the recent patent literature. AB - FFA4/GPR120, a member of the rhodopsin family of G-protein-coupled receptors (GPCRs), is becoming an important target for therapeutic intervention in several areas of disease, including metabolic diseases, inflammation and cancer. In the last few years several patents on original chemotypes have been generated by different companies. In this review an analysis of the patents in the FFA4 agonism field is presented, with an emphasis on the documents published between 2013 and mid-2015. A discussion of the biological methods used in the patents is included. The general interest in this area is growing fast as half of the existing patents on FFA4 agonists have been issued after 2013. There is, however, a need of further diversifying new chemical classes away form the current substrate-like, carboxylic acid-containing agonists. PMID- 26580994 TI - Gastroretentive carrier systems in the delivery of therapeutic actives: an updated patent review. AB - Gastroretentive drug-delivery systems have the potential to prolong the gastric retention time and provide controlled/sustained release of a drug at the absorption site, thereby improving the bioavailability. Advantageous features include reduction in dose, side effects and dosing frequency. Research inputs have led to exploration of novel gastroretentive systems. The present review explores various patents issued on gastroretentive drug delivery on the basis of the therapeutic category of drugs. It traces US, EP and WIPO patents issued in the last 10 years. Various patents have revealed that gastrocarriers can effectively enhance therapeutic activity of a drug. Drugs acting on the CNS have been prominently investigated, followed by antimicrobials and locally acting drugs. Areas of future research can be drugs acting on the cardiovascular system. PMID- 26580995 TI - Autophagy as a Potential Target for Sarcopenia. AB - Sarcopenia is an aging-related disease with a significant reduction in mass and strength of skeletal muscle due to the imbalance between protein synthesis and protein degradation. The loss of skeletal muscle is an inevitable event during aging process, which can result in the significant impact on the quality of life, and also can increase the risk for other aging-associated diseases in the elderly. However, the underlying molecular mechanism of aging-related skeletal muscle loss is still poorly understood. Autophagy is a degradation pathway for the clearance of dysfunctional organelles and damaged macromolecules during aging process. Appropriate induction or accurate regulation of autophagic process and improved quality control of mitochondria through autophagy or other strategies are required for the maintenance of skeletal muscle mass. In this article, we have summarized the current understanding of autophagic pathways in sarcopenia, and discussed the functional status of autophagy and autophagy-associated quality control of mitochondria in the pathogenesis of sarcopenia. Moreover, this article will provide some theoretical references for the exploration of scientific and optimal intervention strategies such as exercise and caloric restriction for the prevention and treatment of sarcopenia through the regulation of autophagic pathways. PMID- 26580996 TI - Graduate Medical Education in the Freddie Gray Era. PMID- 26580998 TI - CLINICAL PRACTICE. Generalized Anxiety Disorder. PMID- 26580997 TI - Activity of Oral ALS-008176 in a Respiratory Syncytial Virus Challenge Study. AB - BACKGROUND Respiratory syncytial virus (RSV) infection is a cause of substantial morbidity and mortality. There is no known effective therapy. METHODS We conducted a randomized, double-blind, clinical trial in healthy adults inoculated with RSV. Participants received the oral nucleoside analogue ALS-008176 or placebo 12 hours after confirmation of RSV infection or 6 days after inoculation. Treatment was administered every 12 hours for 5 days. Viral load, disease severity, resistance, and safety were measured throughout the 28-day study period, with measurement beginning before inoculation. The primary end point was the area under the curve (AUC) for viral load, which was assessed immediately before administration of the first dose through the 12th day after inoculation in participants infected with RSV. RESULTS A total of 62 participants received placebo or one of three ALS-008176 dosing regimens: 1 loading dose of 750 mg followed by 9 maintenance doses of 500 mg (group 1), 1 loading dose of 750 mg followed by 9 maintenance doses of 150 mg (group 2), or 10 doses of 375 mg (group 3). In the 35 infected participants (23 of whom were treated with ALS-008176), the AUCs for viral load for groups 1, 2, and 3 and the placebo group were 59.9, 73.7, 133.4, and 500.9 log10 plaque-forming-unit equivalents * hours per milliliter, respectively (P<=0.001). The time to nondetectability on polymerase chain-reaction assay (P<0.001), the peak viral load (P<=0.001), the AUC for symptom score (P<0.05), and the AUC for mucus weight were lower in all groups receiving ALS-008176 than in the placebo group. Antiviral activity was greatest in the two groups that received a loading dose--viral clearance was accelerated (P<=0.05), and the AUC for viral load decreased by 85 to 88% as compared with the placebo group. Within this small trial, no viral rebound or resistance was identified. There were no serious adverse events, and there was no need for premature discontinuation of the study drug. CONCLUSIONS In this RSV challenge study, more rapid RSV clearance and a greater reduction of viral load, with accompanying improvements in the severity of clinical disease, were observed in the groups treated with ALS-008176 than in the placebo group. (Funded by Alios BioPharma; ClinicalTrials.gov number, NCT02094365.). PMID- 26580999 TI - IMAGES IN CLINICAL MEDICINE. Treponema pallidum--The Great Imitator. PMID- 26581000 TI - CASE RECORDS of the MASSACHUSETTS GENERAL HOSPITAL. Case 36-2015. A 27-Year-Old Woman with a Lesion of the Ear Canal. PMID- 26581001 TI - HABP2 Mutation and Nonmedullary Thyroid Cancer. PMID- 26581002 TI - HABP2 Mutation and Nonmedullary Thyroid Cancer. PMID- 26581003 TI - HABP2 Mutation and Nonmedullary Thyroid Cancer. PMID- 26581004 TI - HABP2 Mutation and Nonmedullary Thyroid Cancer. PMID- 26581005 TI - HABP2 Mutation and Nonmedullary Thyroid Cancer. PMID- 26581006 TI - Long-Term Outcomes of Abdominal Aortic Aneurysm Repair. PMID- 26581007 TI - Long-Term Outcomes of Abdominal Aortic Aneurysm Repair. PMID- 26581008 TI - Long-Term Outcomes of Abdominal Aortic Aneurysm Repair. PMID- 26581009 TI - Long-Term Outcomes of Abdominal Aortic Aneurysm Repair. PMID- 26581010 TI - Healthy Babies after Intrauterine Transfer of Mosaic Aneuploid Blastocysts. PMID- 26581011 TI - IMAGES IN CLINICAL MEDICINE. Tension Pneumoperitoneum. PMID- 26581012 TI - In a retrospective international study, circulating miR-148b and let-7b were found to be serum markers for detecting primary IgA nephropathy. AB - Immunoglobulin A nephropathy (IgAN) is a worldwide disease characterized by the presence of galactose-deficient IgA1 deposits in the glomerular mesangium. A kidney biopsy for diagnosis is required. Here, we measured two miRNAs (let-7b and miR-148b), previously identified as regulators of the O-glycosylation process of IgA1, in serum samples from patients with IgAN and healthy blood donors (controls) recruited in an international multicenter study. Two predictive models, based on these miRNAs, were developed and the diagnostic accuracy of the combined biomarkers was assessed by the area under the receiver operating characteristic (ROC) curve (AUC) carried out in three steps. In a training study, the combined miRNAs were able to discriminate between 100 patients with IgAN and 119 controls (AUC, 0.82). A validation study confirmed the model in an independent cohort of 145 patients with IgAN and 64 controls (AUC, 0.78). Finally, in a test study, the combined biomarkers were able to discriminate patients with IgAN from 105 patients affected by other forms of primary glomerulonephritis, supporting the specificity (AUC, 0.76). Using the same study design, we also performed two subgroup analyses (one for Caucasians and one for East Asians) and found that race-specific models were the best fit to distinguish IgAN patients from controls. Thus, serum levels of the combined miRNA biomarker, let-7b and miR-148b, appears to be a novel, reliable, and noninvasive test to predict the probability of having IgAN. PMID- 26581013 TI - Low Seroprevalence of West Nile Virus in Blood Donors from Catalonia, Spain. AB - West Nile virus (WNV) is an emerging arbovirus first recognized in Europe in the 1950s. Since then, outbreaks have been reported in several European countries. In 2010, the first WNV outbreak was recorded in Spain, affecting the southern part of the country. We conducted a seroprevalence study in the Catalonia region (northeastern Spain), an area considered at high risk of arbovirus transmission. A total of 800 serum samples from blood donors were collected and screened for antibodies against WNV by enzyme-linked immunosorbent assay (ELISA) and confirmed by a microneutralization assay. More than 50 samples tested positive by ELISA, but only one sample contained neutralizing antibodies against WNV and was obtained from a donor native of Pakistan. The low seroprevalence detected may serve as reference baseline data for monitoring WNV activity in our region in future years. PMID- 26581014 TI - Gallium(III)corrole-BODIPY hybrid: novel photophysical properties and first observation of B-F???F interactions. AB - Anchoring a BODIPY onto Ga(III)corrole via a meso-beta linkage facilitated PeT in polar solvents, which quenched the fluorescence, and is further confirmed by electrochemical studies. The triad exhibits unprecedented crystal emission, which is not known for a corrole derivative, due to unique packing. Compound 4 hosts the first example of a novel B-F???F interaction as well. PMID- 26581015 TI - Open Issues in Evolutionary Robotics. AB - One of the long-term goals in evolutionary robotics is to be able to automatically synthesize controllers for real autonomous robots based only on a task specification. While a number of studies have shown the applicability of evolutionary robotics techniques for the synthesis of behavioral control, researchers have consistently been faced with a number of issues preventing the widespread adoption of evolutionary robotics for engineering purposes. In this article, we review and discuss the open issues in evolutionary robotics. First, we analyze the benefits and challenges of simulation-based evolution and subsequent deployment of controllers versus evolution on real robotic hardware. Second, we discuss specific evolutionary computation issues that have plagued evolutionary robotics: (1) the bootstrap problem, (2) deception, and (3) the role of genomic encoding and genotype-phenotype mapping in the evolution of controllers for complex tasks. Finally, we address the absence of standard research practices in the field. We also discuss promising avenues of research. Our underlying motivation is the reduction of the current gap between evolutionary robotics and mainstream robotics, and the establishment of evolutionary robotics as a canonical approach for the engineering of autonomous robots. PMID- 26581016 TI - How Crossover Speeds up Building Block Assembly in Genetic Algorithms. AB - We reinvestigate a fundamental question: How effective is crossover in genetic algorithms in combining building blocks of good solutions? Although this has been discussed controversially for decades, we are still lacking a rigorous and intuitive answer. We provide such answers for royal road functions and OneMax, where every bit is a building block. For the latter, we show that using crossover makes every ([Formula: see text]+[Formula: see text]) genetic algorithm at least twice as fast as the fastest evolutionary algorithm using only standard bit mutation, up to small-order terms and for moderate [Formula: see text] and [Formula: see text]. Crossover is beneficial because it can capitalize on mutations that have both beneficial and disruptive effects on building blocks: crossover is able to repair the disruptive effects of mutation in later generations. Compared to mutation-based evolutionary algorithms, this makes multibit mutations more useful. Introducing crossover changes the optimal mutation rate on OneMax from [Formula: see text] to [Formula: see text]. This holds both for uniform crossover and k-point crossover. Experiments and statistical tests confirm that our findings apply to a broad class of building block functions. PMID- 26581017 TI - Multi-dimensional construction of a novel active yolk@conductive shell nanofiber web as a self-standing anode for high-performance lithium-ion batteries. AB - A novel active yolk@conductive shell nanofiber web with a unique synergistic advantage of various hierarchical nanodimensional objects including the 0D monodisperse SiO2 yolks, the 1D continuous carbon shell and the 3D interconnected non-woven fabric web has been developed by an innovative multi-dimensional construction method, and thus demonstrates excellent electrochemical properties as a self-standing LIB anode. PMID- 26581018 TI - Advances in multiplex nucleic acid diagnostics for blood-borne pathogens: promises and pitfalls. AB - The large number of blood-borne viruses, bacteria and parasites currently of concern, as well as many newly emerging pathogens, presents a daunting challenge to protection of the safety of blood for transfusion and diagnosing infectious diseases. Focusing on nucleic acid diagnostic tests, multiplex devices are coming into use with many more in various developmental stages that promise to offer solutions to the clinical need. The characteristics, advantages and disadvantages of platforms in clinical use and at the research and development stage are examined here. The presence of multiple assays and associated reagents operating simultaneously on one platform, implementation in traditional clinical laboratories and regulatory review will present special challenges. Fortunately, clinical laboratories have made dramatic technical progress in the last two decades and regulatory agencies have publicly expressed support for development of multiplex devices. PMID- 26581019 TI - Borderline Personality Disorder and Posttraumatic Stress Disorder at Psychiatric Discharge Predict General Hospital Admission for Self-Harm. AB - We investigated whether posttraumatic stress disorder (PTSD) was predictor of suicidal behavior even when adjusting for comorbid borderline personality disorder (BPD) and other salient risk factors. To study this, we randomly selected 308 patients admitted to a psychiatric hospital because of suicide risk. Baseline interviews were performed within the first days of the stay. Information concerning the number of self-harm admissions to general hospitals over the subsequent 6 months was retrieved through linkage with the regional hospital registers. A censored regression analysis of hospital admissions for self-harm indicated significant associations with both PTSD (beta = .21, p < .001) and BPD (beta = .27, p < .001). A structural model comprising two latent BPD factors, dysregulation and relationship problems, as well as PTSD and several other variables, demonstrated that PTSD was an important predictor of the number of self-harm admissions to general hospitals(B = 1.52, p < .01). Dysregulation predicted self-harm directly (B = 0.28, p < .05), and also through PTSD [corrected]. These results suggested that PTSD and related dysregulation problems could be important treatment targets for a reduction in the risk of severe self harm in high-risk psychiatric patients. PMID- 26581020 TI - Unconventional but tunable phase transition above the percolation threshold by two-layer conduction in electroless-deposited Au nanofeatures on silicon substrate. AB - Previous research has shown that disorder, dislocation, and carrier concentration are the main factors impacting transitions in the traditional metal-insulator transition (MIT) and metal-semiconductor transition (MST). In this study, it is demonstrated that a non-traditional metal-semiconductor transition governed by two-layer conduction is possible by tuning the conducting channel of one layer of the two-layer conduction system. By means of the electroless deposition method we produced Au nanofeatures (AuNFs) on p-type silicon (p-Si) as the two-layer conduction system, controlling AuNF coverage (Au%) below and above the percolation threshold (p c). Even when the AuNF coverage percentage is larger than p c, the resistivities of the AuNFs on p-Si show MST as the temperature increases. To demonstrate this finding, we present a conduction model based upon two predominant parallel conductions by AuNFs and p-Si in the present paper. In the results, we show how the temperature of the MST (T MST) is tuned from 145 to 232 K as Au% is changed from 82.7 to 54.3%. PMID- 26581021 TI - An Anatomic Study on Whether the Immature Patella is Centered on an Anteroposterior Radiograph. AB - BACKGROUND: In the operating room, after first obtaining a proper lateral radiograph with the condyles superimposed, a 90-degree rotation of the intraoperative fluoroscopy unit does not always produce an anteroposterior (AP) image with the patella centered. The orthogonality of these 2 views has not been well determined in children. METHODS: This study was comprised of a radiographic group (35 knees) and a cadaveric group (59 knees). Both cadaveric and clinical images were obtained by resting or positioning the femur with the posterior condyles overlapped, and then taking an orthogonal AP image. Centering of the patella was calculated and multiple regression analysis was performed to determine the relationship between patellar centering and age, sex, ethnicity, mechanical lateral distal femoral angle (mLDFA), medial proximal tibial angle (MPTA), and contralateral centering. RESULTS: Mean patellar centering, expressed as the lateral position of the patella with respect to the total condylar width, was 0.08+/-0.10 in the radiographic group and 0.06+/-0.03 in the cadaveric group. Positive (lateral) patellar centering in 1 knee had a statistically significant correlation with positive patellar centering in the contralateral knee in both the radiographs and the cadavers. In the radiographic group, there was a statistically significant correlation between femoral varus and valgus deformities and positive patellar centering. In the cadaveric group, there was a statistically significant correlation between tibial valgus and negative (medial) patellar centering. CONCLUSION: The patella in an immature knee is rarely perfectly centered on a true AP image, and is usually seated slightly laterally within the femoral condyles. CLINICAL RELEVANCE: Obtaining a true AP intraoperative radiograph is critical to analyzing and correcting valgus and varus deformities, and in the proper placement of implants. When addressing knee deformity one should consider obtaining an AP view orthogonal either to a perfect lateral of the knee or orthogonal to the flexion axis of the knee, particularly when evaluating distal femoral deformity. PMID- 26581022 TI - Monte Carlo study on the sensitivity of prompt gamma imaging to proton range variations due to interfractional changes in prostate cancer patients. AB - Proton range verification based on prompt gamma imaging is increasingly considered in proton therapy. Tissue heterogeneity normal to the beam direction or near the end of range may considerably degrade the ability of prompt gamma imaging to detect proton range shifts. The goal of this study was to systematically investigate the accuracy and precision of range detection from prompt gamma emission profiles for various fractions for intensity modulated proton therapy of prostate cancer, using a comprehensive clinical dataset of 15 different CT scans for 5 patients. Monte Carlo simulations using Geant4 were performed to generate spot-by-spot dose distributions and prompt gamma emission profiles for prostate treatment plans. The prompt gammas were scored at their point of emission. Three CT scans of the same patient were used to evaluate the impact of inter-fractional changes on proton range. The range shifts deduced from the comparison of prompt gamma emission profiles in the planning CT and subsequent CTs were then correlated to the corresponding range shifts deduced from the dose distributions for individual pencil beams. The distributions of range shift differences between prompt gamma and dose were evaluated in terms of precision (defined as half the 95% inter-percentile range IPR) and accuracy (median). In total about 1700 individual proton pencil beams were investigated. The IPR of the relative range shift differences between the dose profiles and the prompt gamma profiles varied between +/-1.4 mm and +/-2.9 mm when using the more robust profile shifting analysis. The median was found smaller than 1 mm. Methods to identify and reject unreliable spots for range verification due to range mixing were derived and resulted in an average 10% spot rejection, clearly improving the prompt gamma-dose correlation. This work supports that prompt gamma imaging can offer a reliable indicator of range changes due to anatomical variations and tissue heterogeneity in scanning proton treatment of prostate cancer patients when considering prompt gamma emission profiles. PMID- 26581023 TI - Malignant MCA Infarction: Pathophysiology and Imaging for Early Diagnosis and Management Decisions. AB - BACKGROUND: Malignant middle cerebral artery infarction is a devastating condition, with up to 80% mortality in conservatively treated patients. The pathophysiology of this stroke is characterized by a large core of severe ischemia and only a relatively small rim of penumbra. Due to the fast development of irreversible morphological damage, cytotoxic edema occurs immediately in a large portion of the ischemic territory. The subsequent damage of the tight junctions leads to the breakdown of the blood brain barrier and vasogenic brain edema, resulting in space-occupying brain swelling. The progressive vasogenic edema reaches its maximum after 1 to several days and exerts a mechanical force on surrounding tissue structures leading to midline shift and transtentorial herniation and finally brain stem compression and death. SUMMARY: Early severe neurological symptoms--hemiparesis, gaze deviation, higher cortical signs- followed by headache, vomiting, papillo edema and reduced consciousness may predict the deleterious course. Imaging supports the suspected diagnosis with hypodense changes on CT extending beyond 50% of the MCA territory. The size of the probably infarcted tissue and a midline shift on CT as well as the size of the lesion on diffusion-weighted MRI are predictive of a malignant course. Reduction of cerebral blood flow below a critical value and volume of irreversible tissue damage detected by positron emission tomography in the early hours after the stroke are indicative of progression to malignant infarction with increased intracranial pressure (ICP) and decreased tissue oxygen tension observed by multimodal neuromonitoring in the later course. Treatment options of malignant infarction include general measures to limit the extent of space occupying edema, but these therapies have not been efficacious. Only surgical intervention with decompressive hemicraniectomy (DHC) was successful in relieving the effects of increased ICP and of the deleterious shifts of brain tissue. Several controlled clinical trials have proven the efficacy of DHC with a significant decrease in mortality and improved functional outcome. However, DHC must be performed early and with a large diameter, regardless of the age of patients, but in patients beyond 60 years, the higher likelihood of resulting severe disability should be taken into consideration. KEY MESSAGES: Malignant MCA infarction can be predicted early with a high sensitivity by neuroimaging. The early diagnosis is mandatory for DHC, which was shown to reduce mortality and improve functional outcome in several controlled clinical trials. PMID- 26581024 TI - A highly efficient thermo-optic microring modulator assisted by graphene. AB - Graphene's remarkable electrical and optical properties afford great potential for constructing various optoelectronic devices, including modulators, photodetectors and pulse lasers. In particular, graphene-based optical modulators were demonstrated to be featured with a broadband response, small footprint, ultrafast speed and CMOS-compatibility, which may provide an alternative architecture for light-modulation in integrated photonic circuits. While on-chip graphene modulators have been studied in various structures, most of them are based on a capacitance-like configuration subjected to complicated fabrication processes and providing a low yield of working devices. Here, we experimentally demonstrate a new type of graphene modulator by employing graphene's electrical and thermal properties, which can be achieved with a simple fabrication flow. On a graphene-coated microring resonator with a small active area of 10 MUm(2), we have obtained an effective optical modulation via thermal energy electrically generated in a graphene layer. The resonant wavelength of the ring resonator shifts by 2.9 nm under an electrical power of 28 mW, which enables a large modulation depth of 7 dB and a broad operating wavelength range of 6.2 nm with 3 dB modulation. Due to the extremely high electrical and thermal conductivity in graphene, the graphene thermo-optical modulator operates at a very fast switching rate compared with the conventional silicon thermo-optic modulator, i.e. 10%-90% rise (90%-10% fall) time of 750 ns (800 ns). The results promise a novel architecture for massive on-chip modulation of optical interconnects compatible with CMOS technology. PMID- 26581025 TI - Associations of Socioeconomic Variables With Resection, Stage, and Survival in Patients With Early-Stage Pancreatic Cancer. AB - IMPORTANCE: Socioeconomic variables including sex, race, ethnicity, marital status, and insurance status are associated with survival in pancreatic cancer. It remains unknown exactly how these variables influence survival, including whether they affect stage at presentation or receipt of treatment or are independently associated with outcomes. OBJECTIVES: To investigate the relationship between socioeconomic factors and odds of resection in early-stage, resectable pancreatic adenocarcinoma and to determine whether these same factors were independently associated with survival in patients who underwent resection. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective cohort study of patients diagnosed as having T1 through T3 M0 pancreatic adenocarcinoma between January 1, 2004, and December 31, 2011, identified from the Surveillance, Epidemiology, and End Results database. MAIN OUTCOMES AND MEASURES: Socioeconomic and geographic variables associated with utilization of resection and disease specific survival. RESULTS: A total of 17,530 patients with localized, nonmetastatic pancreatic cancer were identified. The resection rate among these patients was 45.4% and did not change over time. Utilization of resection was independently associated with white vs African American race (odds ratio [OR] = 0.76; 95% CI, 0.65-0.88; P < .001), non-Hispanic ethnicity (for Hispanic, OR = 0.72; 95% CI, 0.60-0.85; P < .001), married status (OR = 1.42; 95% CI, 1.30-1.57; P < .001), insurance coverage (OR = 1.63; 95% CI, 1.22-2.18; P = .001), and the Northeast region (vs Southeast, OR = 1.67; 95% CI, 1.44-1.94; P < .001). Stage at presentation correlated with sex, race, ethnicity, marital status, and geographic region (ethnicity, P = .003; all others, P < .001); however, the factors associated with increased resection correlated with more advanced stage. Patients who underwent resection had significantly improved disease-specific survival compared with those who did not undergo resection (median, 21 vs 6 months; hazard ratio [HR] for disease-specific death = 0.32; 95% CI, 0.31-0.33; P < .001). Disease-specific survival among the patients who underwent surgical resection was independently associated with geographic region, with patients in the Pacific West (HR for death = 0.706; 95% CI, 0.628-0.793), Northeast (HR for death = 0.766; 95% CI, 0.667-0.879), and Midwest (HR for death = 0.765; 95% CI, 0.640 0.913) having improved survival in comparison with those in the Southeast (all P < .001). CONCLUSIONS AND RELEVANCE: Disparities in the utilization of surgical resection for patients with early-stage, resectable pancreatic cancer are associated with socioeconomic variables including race, ethnicity, marital status, insurance status, and geographic location. Of these factors, only geographic location is independently associated with survival in patients undergoing resection. PMID- 26581026 TI - Evaluation of chikungunya virus infection in children from India during 2009 2010: A cross sectional observational study. AB - Chikungunya virus, a small (about 60-70 nm diameter), spherical, enveloped, positive, single stranded RNA virus is transmitted by Aedes mosquitoes. After a short period of incubation (3-5 days) symptoms like fever with joint pains and others start appearing. After a gap of 20 years, this virus re-emerged during 2006-2008 in India causing a major outbreak of CHIKV in India. This study was conducted subsequent to the major outbreak in order to evaluate the proportion of chikungunya virus infection in children with suggestive symptoms at three geographical locations of India. Lineage of circulating strains and changes in the E1 structural polypeptide were also determined. Blood samples were collected (in Sodium citrate vacutainer tubes) during 1st June 2009 to 31st May 2010 from children (age 0 <= 18 years) suspected to have chikungunya infection, that is, those who presented with sudden onset of fever and/or joint pain, myalgia, and headache from three regions of India, All India Institute of Medical Sciences (AIIMS) in New Delhi, Karnataka Institute of Medical Sciences (KIMS) in Hubli and Sawai Mansingh Medical College (SMS) in Jaipur. Detection of CHIKV antibodies in all acute-phase patient plasma samples was done by IgM ELISA and for samples within <=5 days of fever, a one-step RT-PCR was carried out on a block thermo cycler targeting 294 bp region of E1 gene that codes for the viral envelope protein. Comparison of nucleotide and amino acid sequences from few positive samples of two regions was done with African S-27 reference strain using BioEdit. A phylogenetic tree was constructed using MEGA 6 by using the Maximum Likelihood method based on the Kimura 2-parameter model. Out of the 723 acute phase samples tested from three geographical locations of India, Chikungunya virus infection was detected in 249/723 (34.44%) subjects by either IgM Elisa (180/723) or RT-PCR (69/412). RT-PCR was employed in samples collected from children with <=5 days of fever. Maximum positive cases were from KIMS center, Hubli. Seasonally, positivity varied with number of enrolled cases at KIMS and SMS. Joint pain was significantly associated with CHIKV positivity (P = 0.0156). Presence/absence of certain clinical features varied with age (P < 0.05). Sequence analysis revealed four amino acid changes. Phylogenetic analysis with partial sequences of E1 gene from KIMS (n = 12) and SMS (n = 5) showed that the study isolates clustered with Indian Ocean Lineage strains (IOL) of East, Central and South African (ECSA) type. Evaluation of chikungunya virus infection in children from India during 2009-2010 showed high proportion of CHIKV infection in Southern region of India compared to Northern region. The circulating CHIKV strains were of Indian Ocean Lineage (IOL) group within the East, Central, and South African (ECSA) genotype. However few amino acid changes were observed in E1 polypeptide with reference to African strain S-27 (AF369024). Further studies are needed to know the implications of these changes in vector-pathogen compatibility and host-pathogen interactivity. As a whole, this study highlighted the proportion of CHIKV cases, lineage of causative strain and evolutionary pattern of circulating strain in terms of amino acid changes in the structural protein. PMID- 26581027 TI - Adsorptive Separation of Methanol-Acetone on Isostructural Series of Metal Organic Frameworks M-BTC (M = Ti, Fe, Cu, Co, Ru, Mo): A Computational Study of Adsorption Mechanisms and Metal-Substitution Impacts. AB - The adsorptive separation properties of M-BTC isostructural series (M = Ti, Fe, Cu, Co, Ru, Mo) for methanol-acetone mixtures were investigated by using various computational procedures of grand canonical Monte Carlo simulations (GCMC), density functional theory (DFT), and ideal adsorbed solution theory (IAST), following with comprehensive understanding of adsorbate-metal interactions on the adsorptive separation behaviors. The obtained results showed that the single component adsorptions were driven by adsorbate-framework interactions at low pressures and by framework structures at high pressures, among which the mass effects, electrostatics, and geometric accessibility of the metal sites also played roles. In the case of methanol-acetone separation, the selectivity of methanol on M-BTCs decreased with rising pressures due to the pressure-dependent separation mechanisms: the cooperative effects between methanol and acetone hindered the separation at low pressures, whereas the competitive effects of acetone further resulted in the lower selectivity at high pressures. Among these M-BTCs, Ti and Fe analogues exhibited the highest thermodynamic methanol/acetone selectivity, making them promising for adsorptive methanol/acetone separation processes. The investigation provides mechanistic insights on how the nature of metal centers affects the adsorption properties of MOFs, and will further promote the rational design of new MOF materials for effective gas mixture separation. PMID- 26581029 TI - Co-production of hydrogen and ethanol from glucose by modification of glycolytic pathways in Escherichia coli - from Embden-Meyerhof-Parnas pathway to pentose phosphate pathway. AB - Hydrogen (H2) production from glucose by dark fermentation suffers from the low yield. As a solution to this problem, co-production of H2 and ethanol, both of which are good biofuels, has been suggested. To this end, using Escherichia coli, activation of pentose phosphate (PP) pathway, which can generate more NADPH than the Embden-Meyhof-Parnas (EMP) pathway, was attempted. Overexpression of two key enzymes in the branch nodes of the glycolytic pathway, Zwf and Gnd, significantly improved the co-production of H2 and ethanol with concomitant reduction of pyruvate secretion. Gene expression analysis and metabolic flux analysis (MFA) showed that, upon overexpression of Zwf and Gnd, glucose assimilation through the PP pathway, compared with that of the EMP or Entner-Doudoroff (ED) pathway, was greatly enhanced. The maximum co-production yields were 1.32 mol H2 mol(-1) glucose and 1.38 mol ethanol mol(-1) glucose, respectively. It is noteworthy that the glycolysis and the amount of NAD(P)H formed under anaerobic conditions could be altered by modifying (the activity of) several key enzymes. Our strategy could be applied for the development of industrial strains for biological production of reduced chemicals and biofuels which suffers from lack of reduced co-factors. PMID- 26581028 TI - Prognostic subgroups for remission, response, and treatment continuation in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) trial. AB - OBJECTIVE: Identify moderators of treatment outcome from antipsychotic pharmacotherapy in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) trial. Specifically, we used logistic regression and receiver operating characteristic (ROC) analysis to explore the association between baseline characteristics and treatment outcomes in the CATIE trial. METHOD: This is a secondary analysis of the CATIE trial in which 1,460 adults with a DSM-IV diagnosis of schizophrenia were randomly assigned to olanzapine, perphenazine, quetiapine, risperidone, or ziprasidone treatment for up to 18 months or until discontinuation between January 2001 and December 2004. Logistic regression was used to examine baseline characteristics associated with remission, response, and treatment continuation at 3 and 6 months of treatment. ROC analyses identified subgroups associated with similar likelihood of treatment outcome. Remission was defined by scores of selected items on psychoticism, disorganization, and negative symptoms. Response was defined as a 50% or greater improvement on the Positive and Negative Syndrome Scale. RESULTS: The most consistent predictors of poor outcome on all variables were low scores on neurocognitive tests (in particular verbal memory) (OR = 1.13-1.49, P< .05); previous reported side effects (OR = 0.49-0.69, P < .05); negative attitude to medication (OR = 1.03-1.10, P < .05); comorbid depression (OR = 0.47-0.51, P < .05); psychosocial factors such as unemployment (OR = 0.74-0.75, P <.05), homelessness (OR = 0.54, P <.05), and living alone (OR = 1.58-1.94, P < .01); and random assignment to a medication other than olanzapine (OR = 1.54-2.04, P < .01). ROC analysis demonstrated prognostic subgroups with large differences in response likelihood. CONCLUSION: Baseline characteristics in schizophrenia are informative regarding clinically important treatment outcomes with respect to antipsychotic pharmacotherapy. Further research should examine whether interventions that target improvement of patients' deficits in neuropsychological function and attitude toward medication as well as decreasing patients' social isolation can improve treatment outcomes with antipsychotic treatment in schizophrenia. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00014001. PMID- 26581030 TI - Rapid Clearance of Necrolytic Migratory Erythema Following Intravenous Administration of Amino Acids. PMID- 26581032 TI - Distinction Between Cell Proliferation and Apoptosis Signals Regulated by Brain Derived Neurotrophic Factor in Human Periodontal Ligament Cells and Gingival Epithelial Cells. AB - Previously, we reported that brain-derived neurotrophic factor (BDNF) enhances periodontal tissue regeneration by inducing periodontal ligament cell proliferation in vivo. In addition, the down growth of gingival epithelial cells, which comprises a major obstacle to the regeneration, was not observed. However, the underlying molecular mechanism is still unclear. Therefore, this study aimed to investigate the effect of BDNF on cell proliferation and apoptosis in human periodontal ligament (HPL) cells and human gingival epithelial cells (OBA9 cells) and to explore the molecular mechanism in vitro. HPL cells dominantly expressed a BDNF receptor, TrkB, and BDNF increased cell proliferation and ERK phosphorylation. However, its proliferative effect was diminished by a MEK1/2 inhibitor (U0126) and TrkB siRNA transfection. Otherwise, OBA9 cells showed a higher expression level of p75, which is a pan-neurotrophin receptor, than that of HPL cells. BDNF facilitated not cell proliferation but cell apoptosis and JNK phosphorylation in OBA9 cells. A JNK inhibitor (SP600125) and p75 siRNA transfection attenuated the BDNF-induced cell apoptosis. Moreover, OBA9 cells pretreated with SP600125 or p75 siRNA showed cell proliferation by BDNF stimulation, though it was reduced by U0126 and TrkB siRNA. Interestingly, overexpression of p75 in HPL cells upregulated cell apoptosis and JNK phosphorylation by BDNF treatment. These results indicated that TrkB-ERK signaling regulates BDNF-induced cell proliferation, whereas p75-JNK signaling plays roles in cell apoptotic and cytostatic effect of BDNF. Overall, BDNF activates periodontal ligament cells proliferation and inhibits the gingival epithelial cells growth via the distinct pathway. J. Cell. Biochem. 117: 1543 1555, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26581033 TI - Tangential migration of glutamatergic neurons and cortical patterning during development: Lessons from Cajal-Retzius cells. AB - Tangential migration is a mode of cell movement, which in the developing cerebral cortex, is defined by displacement parallel to the ventricular surface and orthogonal to the radial glial fibers. This mode of long-range migration is a strategy by which distinct neuronal classes generated from spatially and molecularly distinct origins can integrate to form appropriate neural circuits within the cortical plate. While it was previously believed that only GABAergic cortical interneurons migrate tangentially from their origins in the subpallial ganglionic eminences to integrate in the cortical plate, it is now known that transient populations of glutamatergic neurons also adopt this mode of migration. These include Cajal-Retzius cells (CRs), subplate neurons (SPs), and cortical plate transient neurons (CPTs), which have crucial roles in orchestrating the radial and tangential development of the embryonic cerebral cortex in a noncell autonomous manner. While CRs have been extensively studied, it is only in the last decade that the molecular mechanisms governing their tangential migration have begun to be elucidated. To date, the mechanisms of SPs and CPTs tangential migration remain unknown. We therefore review the known signaling pathways, which regulate parameters of CRs migration including their motility, contact redistribution and adhesion to the pial surface, and discuss this in the context of how CR migration may regulate their signaling activity in a spatial and temporal manner. (c) 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 847-881, 2016. PMID- 26581031 TI - Identification and function probing of an antithrombin IIIbeta conformation specific antibody. AB - ESSENTIALS: Antithrombin III (AT)beta binds heparin with higher affinity than ATalpha. A conformation-specific antibody against ATbeta, TPP2009, was made to investigate ATbeta in hemostasis. TPP2009 bound specifically to heparin-ATbeta and greatly reduced the anticoagulant effect of AT. This antibody was effective in elucidating the importance of ATbeta in hemostasis. BACKGROUND: Antithrombin III (AT)beta is an isoform of AT that lacks the post-translational carbohydrate modification at Asn135. This isoform binds heparin with greater affinity than ATalpha, and has been shown to target antithrombotic function to the extracellular vascular endothelial injury site. OBJECTIVES: To characterize a conformation-specific antibody against ATbeta and begin to investigate the role of ATbeta in maintaining hemostasis. METHODS: Surface plasmon resonance (SPR), antigen binding and functional assays were conducted to characterize the mode of action of antibodies generated against heparin-bound ATbeta (ATbeta*H) by the use of phage display. RESULTS: SPR and binding studies showed that one of the antibodies, TPP2009, bound specifically to ATbeta*H and glycosaminoglycan associated ATbeta on endothelial cells. In diluted prothrombin and activated factor X (FXa)-induced clotting assays, TPP2009 dose-dependently reduced the anticoagulant effect of heparin in non-hemophilic and FVIII-deficient human plasma, with half-maximal effective concentrations (EC50 ) of 10.5 nm and 4.7 nm, respectively. In AT-deficient human plasma, TPP2009 dose-dependently inhibited the effects of exogenously added ATbeta and heparin. In purified systems with ATbeta and pentasaccharide, TPP2009 restored > 91% of FXa activity. TPP2009 dose dependently reversed the effects of heparin in rabbit (EC50 , 25.7 nm) and cynomolgus monkey (EC50 , 21.5 nm) plasma, but not in mouse plasma. TPP2009 was also effective in partially restoring FXa activity in rabbit and cynomolgus monkey plasma treated with FVIII function-neutralizing antibodies. CONCLUSIONS: TPP2009 specifically targets a unique conformational epitope on ATbeta*H and blocks ATbeta-mediated anticoagulation. It effectively promotes coagulation in plasma, indicating the importance of ATbeta in hemostasis. PMID- 26581034 TI - Urinary di-(2-ethylhexyl) phthalate metabolites for detecting transfusion of autologous blood stored in plasticizer-free bags. AB - BACKGROUND: Autologous blood transfusion (ABT) efficiently increases sport performance and is the most challenging doping method to detect. Current methods for detecting this practice center on the plasticizer di(2-ethlyhexyl) phthalate (DEHP), which enters the stored blood from blood bags. Quantification of this plasticizer and its metabolites in urine can detect the transfusion of autologous blood stored in these bags. However, DEHP-free blood bags are available on the market, including n-butyryl-tri-(n-hexyl)-citrate (BTHC) blood bags. Athletes may shift to using such bags to avoid the detection of urinary DEHP metabolites. STUDY DESIGN AND METHODS: A clinical randomized double-blinded two-phase study was conducted of healthy male volunteers who underwent ABT using DEHP-containing or BTHC blood bags. All subjects received a saline injection for the control phase and a blood donation followed by ABT 36 days later. Kinetic excretion of five urinary DEHP metabolites was quantified with liquid chromatography coupled with tandem mass spectrometry. RESULTS: Surprisingly, considerable levels of urinary DEHP metabolites were observed up to 1 day after blood transfusion with BTHC blood bags. The long-term metabolites mono-(2-ethyl-5-carboxypentyl) phthalate and mono-(2-carboxymethylhexyl) phthalate were the most sensitive biomarkers to detect ABT with BTHC blood bags. Levels of DEHP were high in BTHC bags (6.6%), the tubing in the transfusion kit (25.2%), and the white blood cell filter (22.3%). CONCLUSIONS: The BTHC bag contained DEHP, despite being labeled DEHP-free. Urinary DEHP metabolite measurement is a cost-effective way to detect ABT in the antidoping field even when BTHC bags are used for blood storage. PMID- 26581036 TI - Reproductive Outcome of Infertile Patients with Fibroids Based on the Patient and Fibroid Characteristics; Optimal and Personalized Management. AB - AIMS: To analyze the detailed clinical course of infertile patients with uterine fibroids and to identify optimal and personalized treatment based on the patient or fibroid characteristics. METHODS: Retrospective analysis of a case series was performed on 176 infertile patients with fibroids. The patients were classified into different groups according to different treatments (conservative infertility treatment, myomectomy and non-myomectomy surgery). Patient or fibroid characteristics for different groups were analyzed for a possible correlation with the reproductive outcome. RESULTS: The cumulative pregnancy rates by conservative treatment plateaued in 1 year. Myomectomy improved the reproductive outcome in patients who did not conceive with conservative infertility treatments. The most important determinant of the reproductive outcome in patients by conservative treatment prior to surgery was a past patient history of pregnancy. The most important determinant of the reproductive outcome after myomectomy was patient age. CONCLUSION: Myomectomy should be considered when infertile patients with fibroids do not conceive within 1 year of conservative infertility treatments. The most important determinant of reproductive outcome after myomectomy is patient age. Therefore, for patients younger than 40, the treatment schedule should be carefully considered so that the patients can sufficiently benefit from myomectomy and assisted reproductive technology. PMID- 26581035 TI - Quantifying the Determinants of Evolutionary Dynamics Leading to Drug Resistance. AB - The emergence of drug resistant pathogens is a serious public health problem. It is a long-standing goal to predict rates of resistance evolution and design optimal treatment strategies accordingly. To this end, it is crucial to reveal the underlying causes of drug-specific differences in the evolutionary dynamics leading to resistance. However, it remains largely unknown why the rates of resistance evolution via spontaneous mutations and the diversity of mutational paths vary substantially between drugs. Here we comprehensively quantify the distribution of fitness effects (DFE) of mutations, a key determinant of evolutionary dynamics, in the presence of eight antibiotics representing the main modes of action. Using precise high-throughput fitness measurements for genome wide Escherichia coli gene deletion strains, we find that the width of the DFE varies dramatically between antibiotics and, contrary to conventional wisdom, for some drugs the DFE width is lower than in the absence of stress. We show that this previously underappreciated divergence in DFE width among antibiotics is largely caused by their distinct drug-specific dose-response characteristics. Unlike the DFE, the magnitude of the changes in tolerated drug concentration resulting from genome-wide mutations is similar for most drugs but exceptionally small for the antibiotic nitrofurantoin, i.e., mutations generally have considerably smaller resistance effects for nitrofurantoin than for other drugs. A population genetics model predicts that resistance evolution for drugs with this property is severely limited and confined to reproducible mutational paths. We tested this prediction in laboratory evolution experiments using the "morbidostat", a device for evolving bacteria in well-controlled drug environments. Nitrofurantoin resistance indeed evolved extremely slowly via reproducible mutations-an almost paradoxical behavior since this drug causes DNA damage and increases the mutation rate. Overall, we identified novel quantitative characteristics of the evolutionary landscape that provide the conceptual foundation for predicting the dynamics of drug resistance evolution. PMID- 26581037 TI - [Short-Term Psychodynamic Therapy in Depression - An Evidence-Based Unified Protocol]. AB - With a lifetime prevalence of about 17% depression is the most common mental disorder. Psychotherapy is efficacious in the treatment of depression, with no significant differences between different forms of psychotherapies. For psychodynamic therapy (PDT) various models proved to be efficacious in randomized controlled trials (RCTs). As a consequence the evidence for PDT is scattered between different forms or orientations of PDT entailing problems regarding psychotherapy training and the transfer of research into clinical practice. Thus, our aim was to develop a unified protocol for the dynamic treatment of depression that is based on those models of PDT that proved efficacious in randomized controlled trials (RCTs). As a first step we conducted a systematic search of RCTs investigating manualized or manual-based individual psychodynamic therapy for depressive disorders in adults that proved to be efficacious compared to comparison conditions. 11 studies fulfilled our inclusion criteria. In a second step we systematically reviewed the studies with regard to the treatment concepts they had applied. 7 highly consistent treatment components could be identified. We conceptualized them in the form of 7 interrelated treatment modules which constitute the unified psychodynamic protocol for depression. The protocol may enhance the empirical status of PDT and facilitate both psychotherapy training as well as the transfer of research to clinical practice. Through the focused use of techniques that proofed efficacious it is expected to bring more benefit to depressed patients and therefore also have a positive impact on the health care system. PMID- 26581038 TI - Mothers' Views on Longer Storage of Neonatal Dried Blood Spots for Specific Secondary Uses. AB - BACKGROUND: Neonatal dried blood spots (DBS) present a wealth of data. Currently, many countries discuss DBS storage, management and use. We collected data in the Netherlands on the awareness and views of an unheard stakeholder: mothers (-to be). METHODS: A survey was conducted on an Amsterdam pregnancy fair website in 2011. We included 1,272 women who were pregnant and/or had at least one child <=5 years old. A descriptive analysis was used to score the awareness of and views on policies regarding the length of storage and secondary use. RESULTS: 18.9% of mothers (n = 1,272) were aware of all five current DBS screening, storage and use policies. The views were positive for all ten potential specific secondary uses. Most support was given to etiology research, while test development by a company was least supported. Extending the DBS storage beyond the 5-year status quo was approved by 67.8% of the respondents, indefinite storage was approved by 54.7%. CONCLUSION: Mothers indicate support of several secondary uses and prolonged storage of DBS but report a low awareness of current storage and secondary use policies. Efforts must be made to involve parents as key stakeholders in DBS policies. This could be achieved through a parent-led advisory structure. PMID- 26581039 TI - Incidence and Prognosis of Spinal Hemangioblastoma: A Surveillance Epidemiology and End Results Study. AB - OBJECTIVE: Intradural spinal hemangioblastoma are infrequent, vascular, pathologically benign tumors occurring either sporadically or in association with von Hippel-Lindau disease along the neural axis. Described in fewer than 1,000 cases, literature is variable with respect to epidemiological factors associated with spinal hemangioblastoma and their treatment. The objective of this study was to evaluate the epidemiology of intradural spinal hemangioblastoma with the Surveillance, Epidemiology and End Results (SEER) database while also presenting an illustrative case. METHODS: The SEER database was queried for cases of spinal hemangioblastoma between 2000 and 2010 with the use of SEER*Stat software. Incidence was evaluated as a function of age, sex and race. Survival was evaluated with the Cox proportionate hazards ratio using IBM SPSS software evaluating age, sex, location, treatment modality, pathology and number of primaries (p = 0.05). Descriptive statistics of the same factors were also calculated. The case of a 43-year-old patient with a surgical upper cervical intramedullary hemangioblastoma is also presented. RESULTS: In the data set between 2000 and 2010, there were 133 cases with an age-adjusted incidence of 0.014 (0.012-0.017) per 100,000 to the standard USA population. Hemangioblastoma was the tenth most common intradural spinal tumor type representing 2.1% (133 of 6,156) of all spinal tumors. There was no difference in incidence between men and women with an female:male rate ratio of 1.05 (0.73-1.50) with p = 0.86. The average age of patients was 48.0 (45.2-50.9) years, and a lower incidence was noted in patients <15 years compared to all other age groups (p < 0.05). There was no difference in incidence amongst the different races. Treatment included surgical resection in 106 (79.7%) cases, radiation with surgery in 7 (5.3%) cases, and radiation alone was used in only 1 (0.8%) case, and no treatment was performed in 17 (12.8%) cases. Mortality was noted in 12 (9%) cases, and median survival of 27.5 months (range 1-66 months) over the 10-year period. Mortality was attributable to the malignancy in 3 (2%) cases. There was no statistically significant different in Cox hazard ratios for mortality for sex, race, treatment modality, pathology or number of primaries. CONCLUSIONS: Spinal hemangioblastoma represent a small fraction of primary intradural spinal tumors, and this study did not identify any difference in incidence between genders. Surgical treatment alone was the most common treatment modality. Overall prognosis is good, with 9% observed mortality over the 10-year period, with 2% mortality attributable to the malignancy. PMID- 26581040 TI - Controversies about the visual areas located at the anterior border of area V2 in primates. AB - Anatomical and electrophysiological studies have provided us with detailed information regarding the extent and topography of the primary (V1) and secondary (V2) visual areas in primates. The consensus about the V1 and V2 maps, however, is in sharp contrast with controversies regarding the organization of the cortical areas lying immediately rostral to V2. In this review, we address the contentious issue of the extent of the third visual area (V3). Specifically, we will argue for the existence of both ventral (V3v) and dorsal (V3d) segments of V3, which are located, respectively, adjacent to the anterior border of ventral and dorsal V2. V3v and V3d would together constitute a single functional area with a complete representation of both upper and lower visual hemifields. Another contentious issue is the organization of the parietal-occipital (PO) area, which also borders the rostral edge of the medial portion of dorsal V2. Different from V1, V2, and V3, which exhibit a topography based on the defined lines of isoeccentricity and isopolar representation, area PO only has a systematic representation of polar angles, with an emphasis on the peripheral visual field (isoeccentricity lines are not well defined). Based on the connectivity patterns of area PO with distinct cytochrome oxidase modules in V2, we propose a subdivision of the dorsal stream of visual information processing into lateral and medial domains. In this model, area PO constitutes the first processing instance of the dorsal-medial stream, coding for the full-field flow of visual cues during navigation. Finally, we compare our findings with those in other species of Old and New World monkeys and argue that larger animals, such as macaque and capuchin monkeys, have similar organizations of the areas rostral to V2, which is different from that in smaller New World monkeys. PMID- 26581041 TI - Black Tea Extract and Its Theaflavin Derivatives Inhibit the Growth of Periodontopathogens and Modulate Interleukin-8 and beta-Defensin Secretion in Oral Epithelial Cells. AB - Over the years, several studies have brought evidence suggesting that tea polyphenols, mostly from green tea, may have oral health benefits. Since few data are available concerning the beneficial properties of black tea and its theaflavin derivatives against periodontal disease, the objective of this study was to investigate their antibacterial activity as well as their ability to modulate interleukin-8 and human beta-defensin (hBD) secretion in oral epithelial cells. Among the periodontopathogenic bacteria tested, Porphyromonas gingivalis was found to be highly susceptible to the black tea extract and theaflavins. Moreover, our data indicated that the black tea extract, theaflavin and theaflavin-3,3'-digallate can potentiate the antibacterial effect of metronidazole and tetracycline against P. gingivalis. Using lipopolysaccharide stimulated oral epithelial cells, the black tea extract (100 MUg/ml), as well as theaflavin and theaflavin-3,3'-digallate (50 MUg/ml) reduced interleukin-8 (IL-8) secretion by 85%, 79%, and 86%, respectively, thus suggesting an anti inflammatory property. The ability of the black tea extract and its theaflavin derivatives to induce the secretion of the antimicrobial peptides hBD-1, hBD-2 and hBD-4 by oral epithelial cells was then evaluated. Our results showed that the black tea extract as well as theaflavin-3,3'-digallate were able to increase the secretion of the three hBDs. In conclusion, the ability of a black tea extract and theaflavins to exert antibacterial activity against major periodontopathogens, to attenuate the secretion of IL-8, and to induce hBD secretion in oral epithelial cells suggest that these components may have a beneficial effect against periodontal disease. PMID- 26581042 TI - Food Security Monitoring via Mobile Data Collection and Remote Sensing: Results from the Central African Republic. AB - The Central African Republic is one of the world's most vulnerable countries, suffering from chronic poverty, violent conflicts and weak disaster resilience. In collaboration with Doctors without Borders/Medecins Sans Frontieres (MSF), this study presents a novel approach to collect information about socio-economic vulnerabilities related to malnutrition, access to resources and coping capacities. The first technical test was carried out in the North of the country (sub-prefecture Kabo) in May 2015. All activities were aimed at the investigation of technical feasibility, not at operational data collection, which requires a random sampling strategy. At the core of the study is an open-source Android application named SATIDA COLLECT that facilitates rapid and simple data collection. All assessments were carried out by local MSF staff after they had been trained for one day. Once a mobile network is available, all assessments can easily be uploaded to a database for further processing and trend analysis via MSF in-house software. On one hand, regularly updated food security assessments can complement traditional large-scale surveys, whose completion can take up to eight months. Ideally, this leads to a gain in time for disaster logistics. On the other hand, recording the location of every assessment via the smart phones' GPS receiver helps to analyze and display the coupling between drought risk and impacts over many years. Although the current situation in the Central African Republic is mostly related to violent conflict it is necessary to consider information about drought risk, because climatic shocks can further disrupt the already vulnerable system. SATIDA COLLECT can easily be adapted to local conditions or other applications, such as the evaluation of vaccination campaigns. Most importantly, it facilitates the standardized collection of information without pen and paper, as well as straightforward sharing of collected data with the MSF headquarters or other aid organizations. PMID- 26581043 TI - Correction: Viewpoints on Factors for Successful Employment for Adults with Autism Spectrum Disorder. PMID- 26581044 TI - Nitric Oxide-Related Biological Pathways in Patients with Major Depression. AB - BACKGROUND: Major depression is a well-known risk factor for cardiovascular diseases and increased mortality following myocardial infarction. However, biomarkers of depression and increased cardiovascular risk are still missing. The aim of this prospective study was to evaluate, whether nitric-oxide (NO) related factors for endothelial dysfunction, such as global arginine bioavailability, arginase activity, L-arginine/ADMA ratio and the arginine metabolites asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) might be biomarkers for depression-induced cardiovascular risk. METHODS: In 71 in-patients with major depression and 48 healthy controls the Global Arginine Bioavailability Ratio (GABR), arginase activity (arginine/ornithine ratio), the L-arginine/ADMA ratio, ADMA, and SDMA were determined by high-pressure liquid chromatography. Psychiatric and laboratory assessments were obtained at baseline at the time of in-patient admittance and at the time of hospital discharge. RESULTS: The ADMA concentrations in patients with major depression were significantly elevated and the SDMA concentrations were significantly decreased in comparison with the healthy controls. Even after a first improvement of depression, ADMA and SDMA levels remained nearly unchanged. In addition, after a first improvement of depression at the time of hospital discharge, a significant decrease in arginase activity, an increased L-arginine/ADMA ratio and a trend for increased global arginine bioavailability were observed. CONCLUSIONS: Our study results are evidence that in patients with major depression ADMA and SDMA might be biomarkers to indicate an increased cardiovascular threat due to depression-triggered NO reduction. GABR, the L-arginine/ADMA ratio and arginase activity might be indicators of therapy success and increased NO production after remission. PMID- 26581045 TI - Genome-wide identification and expression profiling of the copper transporter gene family in Populus trichocarpa. AB - Copper transporters (COPT/Ctr) have important roles in the transport of copper (Cu) across the cell membrane in many different species. A comprehensive phylogeny and a molecular structure analysis of the COPT/Ctr family in plants and animals are presented, with an emphasis and bioinformatic analysis of the copper transporter family in Populus trichocarpa (PtCOPT). Structural analyses of PtCOPTs showed that most have 3 transmembrane domains (TMDs), with an exception of PtCOPT4 (2 TMDs). Gene structure, gene chromosomal location, and synteny analyses of PtCOPTs demonstrated that tandem and segmental duplications have likely contributed to the expansion and evolution of the PtCOPTs. Additionally, promoter analyses showed that the function of PtCOPTs is related to Cu and ferrum (Fe) transport. Tissue-specific expression of PtCOPT genes showed that most had relatively high transcript levels in roots and leaves. Quantitative real-time RT PCR (qRT-PCR) analysis revealed that the expression of PtCOPT genes were induced not only in limited and excessive Cu, Fe, zinc (Zn) and manganese (Mn) stress, but also in lead (Pb), and cadmium (Cd) stress. PMID- 26581046 TI - Cadmium and zinc partitioning and accumulation during grain filling in two near isogenic lines of durum wheat. AB - Plants can readily accumulate cadmium (Cd), transferring this element to edible leaves, fruits, and seeds. Rice and wheat are among the top crop sources of Cd. Toxic heavy metals like Cd have chemical properties similar to essential micronutrients such as zinc (Zn) and are generally transported in plants by the same transporters as those essential micronutrients. Unfortunately our knowledge of Cd translocation and accumulation in seeds is still unclear. We conducted a partitioning study to assess both the whole plant Cd distribution and accumulation and potential source-sink remobilization during grain filling period in two near-isogenic lines of durum wheat that differ in root to shoot translocation and grain Cd content. We also assessed the role of Zn fertilization in Cd translocation and accumulation in the grains. There was no remobilization of Cd in both lines during grain filling. Although majority of Cd partitioned to the roots in both lines, root to shoot translocation of Cd differed in both lines. In contrast, there were no significant differences in Zn partitioning between the lines and remobilization was observed in different tissues. Although there was some remobilization of Zn, the main source of Cd and Zn is continued uptake and translocation to sources during grain fill. PMID- 26581047 TI - Apelin: A novel inhibitor of vascular calcification in chronic kidney disease. AB - BACKGROUND: Vascular calcification (VC) is closely related to cardiovascular events in chronic kidney disease (CKD). Apelin has emerged as a potent regulator of cardiovascular function, but its role in VC during CKD remains unknown. We determined whether apelin plays a role in phosphate-induced mineralization of human aortic smooth muscle cells (HASMCs) and in adenine-induced CKD rats with aortic calcification. METHODS AND RESULTS: In vitro, apelin-13 was found to inhibit calcium deposition in HASMCs (Pi(+) Apelin(+) group vs Pi(+) Apelin(-) group: 50.1 +/- 6.21 ug/mg vs 146.67 +/- 10.02 ug/mg protein, p = 0.012) and to suppress the induction of the osteoblastic transformation genes BMP-2, osteoprotegerin (OPG) and Cbfa1. This effect was mediated by interference of the sodium-dependent phosphate cotransporter (Pit-1) expression and phosphate uptake. In vivo, decreased plasma apelin levels (adenine(+) apelin(-) vs vehicle: 0.37 +/ 0.09 ng/ml vs 0.68 +/- 0.16 ng/ml, p = 0.003) and downregulation of APJ in the aorta were found in adenine-induced CKD rats with hyperphosphatemia (adenine(+) apelin(-) vs vehicle: 6.91 +/- 0.23 mmoL/L vs 2.3 +/- 0.07 mmoL/L, p = 0.001) and aortic calcification. Exogenous supplementation of apelin-13 normalized the level of the apelin/APJ system and significantly ameliorated aortic calcification, as well as the suppression of Runx2, OPG and Pit-1 expression. CONCLUSIONS: Apelin ameliorates VC by suppressing osteoblastic differentiation of VSMCs through downregulation of Pit-1. These results suggest apelin may have potential therapeutic value for treatment of VC in CKD. PMID- 26581049 TI - [Educational inequalities in mortality and survival of women and men in the Americas, 1990-2010]. AB - OBJECTIVE: Analyze magnitude and trends in educational inequality in mortality and survival of women and men in countries of the Americas. METHODS: Gap and gradient metrics were used to calculate inequality between countries in adult mortality, average age of death, life expectancy, and healthy life expectancy, according to educational level in men and women for 1990 and 2010. RESULTS: Between 1990 and 2010, the average number of years of education increased from 8 to 10 with no difference between sexes. Adult mortality (15-59 years) did not change: 1.9 per 1 000 women and 3.7 per 1 000 men. The slope index of inequality (SII) increased from -1.0 to -2.0 per 1 000 women and from -1.2 to -4.4 per 1 000 men. Life expectancy increased from 75.6 to 78.7 years in women and from 68.9 to 72.4 in men; absolute inequality decreased from 7.8 to 7.2 years in women and increased from 7.2 to 9.2 years in men. Healthy life expectancy increased from 63.7 to 65.9 years in women and from 59.5 to 62.5 years in men; the SII declined from 6.9 to 5.8 years in women and increased from 6.9 to 7.8 years in men. CONCLUSIONS: In the countries of the Americas, men are at greater risk of dying, die earlier, and live fewer disease- and disability-free years than women; educational level is a determinant of mortality and survival in both sexes, and educational inequalities are more pronounced and increasing among men, and are disproportionately concentrated in the most socially disadvantaged populations. PMID- 26581048 TI - Lipid metabolism in patients infected with Nef-deficient HIV-1 strain. AB - BACKGROUND: HIV protein Nef plays a key role in impairing cholesterol metabolism in both HIV infected and bystander cells. The existence of a small cohort of patients infected with Nef-deficient strain of HIV presented a unique opportunity to test the effect of Nef on lipid metabolism in a clinical setting. METHODS: Here we report the results of a study comparing six patients infected with Nef deficient strain of HIV (DeltaNefHIV) with six treatment-naive patients infected with wild-type HIV (WT HIV). Lipoprotein profile, size and functionality of high density lipoprotein (HDL) particles as well as lipidomic and microRNA profiles of patient plasma were analyzed. RESULTS: We found that patients infected with DeltaNefHIV had lower proportion of subjects with plasma HDL-C levels <1 mmol/l compared to patients infected with WT HIV. Furthermore, compared to a reference group of HIV-negative subjects, there was higher abundance of smaller under lipidated HDL particles in plasma of patients infected with WT HIV, but not in those infected with DeltaNefHIV. Lipidomic analysis of plasma revealed differences in abundance of phosphatidylserine and sphingolipids between patients infected with DeltaNefHIV and WT HIV. MicroRNA profiling revealed that plasma abundance of 24 miRNAs, many of those involved in regulation of lipid metabolism, was differentially regulated by WT HIV and DeltaNefHIV. CONCLUSION: Our findings are consistent with HIV protein Nef playing a significant role in pathogenesis of lipid-related metabolic complications of HIV disease. PMID- 26581050 TI - Assessing equitable care for Indigenous and Afrodescendant women in Latin America. AB - OBJECTIVE: To identify and understand the barriers to equitable care within health care settings that women of ethnic minorities encounter in Latin America and to examine possible strategies for mitigating the issues. METHODS: This was a comprehensive review of the literature from 2000-2015 available from the online databases PubMed, Google Scholar, EBSCOhost, and SciELO in Spanish, English, and Portuguese, using a keyword search that included the Region and country names. RESULTS: Health provider discrimination against Indigenous and Afrodescendant women is a primary barrier to quality health care access in Latin America. Discrimination is driven by biases against ethnic minority populations, women, and the poor in general. Discriminatory practices can manifest as patient blaming, purposeful neglect, verbal or physical abuse, disregard for traditional beliefs, and the non-use of Indigenous languages for patient communication. These obstacles prevent delivery of appropriate and timely clinical care, and also produce fear of shame, abuse, or ineffective treatment, which, in addition to financial barriers, deter women from seeking care. CONCLUSIONS: To ensure optimal health outcomes among Indigenous and Afrodescendant women in Latin America, the issue of discrimination in health care settings needs to be understood and addressed as a key driver of inequitable health outcomes. Strategies that target provider behavior alone have limited impact because they do not address women's needs and the context of socioeconomic inequality in which intra-hospital relations are built. PMID- 26581051 TI - A Spanish-language patient safety questionnaire to measure medical and nursing students' attitudes and knowledge. AB - OBJECTIVE: To design and validate a questionnaire for assessing attitudes and knowledge about patient safety using a sample of medical and nursing students undergoing clinical training in Spain and four countries in Latin America. METHODS: In this cross-sectional study, a literature review was carried out and total of 786 medical and nursing students were surveyed at eight universities from five countries (Chile, Colombia, El Salvador, Guatemala, and Spain) to develop and refine a Spanish-language questionnaire on knowledge and attitudes about patient safety. The scope of the questionnaire was based on five dimensions (factors) presented in studies related to patient safety culture found in PubMed and Scopus. Based on the five factors, 25 reactive items were developed. Composite reliability indexes and Cronbach's alpha statistics were estimated for each factor, and confirmatory factor analysis was conducted to assess validity. After a pilot test, the questionnaire was refined using confirmatory models, maximum-likelihood estimation, and the variance-covariance matrix (as input). Multiple linear regression models were used to confirm external validity, considering variables related to patient safety culture as dependent variables and the five factors as independent variables. RESULTS: The final instrument was a structured five-point Likert self-administered survey (the "Latino Student Patient Safety Questionnaire") consisting of 21 items grouped into five factors. Compound reliability indexes (Cronbach's alpha statistic) calculated for the five factors were about 0.7 or higher. The results of the multiple linear regression analyses indicated good model fit (goodness-of-fit index: 0.9). Item-total correlations were higher than 0.3 in all cases. The convergent-discriminant validity was adequate. CONCLUSIONS: The questionnaire designed and validated in this study assesses nursing and medical students' attitudes and knowledge about patient safety. This instrument could be used to indirectly evaluate whether or not students in health disciplines are acquiring and thus likely to put into practice the professional skills currently considered most appropriate for patient safety. PMID- 26581052 TI - [Musculoskeletal pain in Central American workers: results of the First Survey on Working Conditions and Health in Central America]. AB - OBJECTIVE: Examine the prevalence of musculoskeletal pain (MSP) in the six Spanish-speaking countries of Central America using a single standardized instrument, the First Survey on Working Conditions and Health in Central America in workers from all manual and non-manual labor sectors, using social security coverage as an indicator of formal versus informal employment. METHODS: The workers (n = 12 024) were surveyed in their homes. The age-adjusted prevalence of MSP during the previous month was calculated for pain in the back (upper, or cervical; middle, or thoracic; and lower, or lumbar) and arm joints (shoulder, elbow, and wrist). Prevalence was estimated by sex, occupation (manual or non manual), economic sector (agriculture, industry, or services), and social security coverage. Poisson regression models were used to calculate the prevalence rates and 95% confidence intervals, with stratification by country and anatomical site. RESULTS: By sites, the age-adjusted prevalence of cervical dorsal MSP was the highest, especially in El Salvador (47.8%) and Nicaragua (45.9%), and lumbar MSP was less prevalent, especially in Panama (12.8%) and Guatemala (14.8%). After additional adjustments, the prevalence of MSP was higher in women and manual workers for all the sites and in all the countries. There were no differences in MSP in terms of social security coverage or sector of economic activity. CONCLUSIONS: The high prevalence of MSP in Central America, regardless of sector of activity or social security coverage, indicates that the prevention of MSP should be a priority in occupational health programs in low- and middle-income countries, especially for women and manual workers. PMID- 26581053 TI - [Design and semantic validation of a new instrument to assess policy transfer of directly observed treatment for tuberculosis]. AB - OBJECTIVE: To design and semantically validate an instrument to evaluate the transfer of directly observed therapy (DOT) as a policy for tuberculosis control taking into consideration the experience of mid- and higher level health care workers. METHODS: This methodological investigation was developed in two stages: literature review to design the first draft of the instrument; and semantic validation of the first draft using questionnaires adapted from the DISABKIDS(r) project. The information obtained was analyzed using quantitative (descriptive statistics) or qualitative (content theme analysis) methods. RESULTS: Twenty-four mid- and higher level health care workers engaged in tuberculosis control participated in the study. The instrument was considered important for the work of study participants. The answers provided by participants led to changes in both the structure and content of the instrument. The process resulted in a final, semantically validated questionnaire. CONCLUSIONS: Semantic validation is important to ensure the applicability of assessment instruments, as shown by the contributions provided by participants. The instrument whose semantic validation was described in this study will now be assessed in terms of psychometric characteristics and usefulness to measure the transfer of DOT to health professionals as a tuberculosis control policy. PMID- 26581054 TI - [Prevalence of cardiovascular risk factors in an urban ambulatory adult population: AsuRiesgo study, Paraguay]. AB - OBJECTIVE: Cardiovascular diseases are the leading cause of mortality in the world. Although most of them are preventable, their prevalence continues to increase. The objective of this study was to estimate the prevalence of cardiovascular risk factors in an urban ambulatory adult hospital population in Asuncion, Paraguay. METHODS: A cross-sectional study was undertaken in the population of patients enrolled in the AsuRiesgo prospective study on the prevention of cardiovascular disease, which focuses on promoting a healthy lifestyle. Patients 18 years of age or older who were encountered in doctors' waiting rooms in a tertiary care hospital were invited to participate. Each patient's clinical history, body measurements, and laboratory test results were obtained. RESULTS: A total of 18 287 patients aged 51 +/- 16 years were recruited. Of this group, 67.5% were female, with an average bodyweight of 77.5 +/- 16.2 kg and a body mass index 29.7 +/- 5.9 kg/m2. The prevalence rates of a history of myocardial infarction, stroke, diabetes mellitus, and hypertension were 2.6%, 3%, 13.3%, and 53%, respectively, and the rates of smoking, unhealthy diet, sedentary lifestyle, and psychological stress were 29.3%, 41.2%, 58.2%, and 56.6%. The overall prevalence of obesity and overweight was 79.6%; the rates of prehypertension and systemic hypertension were 39% and 25%, respectively; and the prevalence of metabolic syndrome was 34.7%. CONCLUSIONS: Although the prevalence rates of smoking, systemic hypertension, and diabetes mellitus were low, those for obesity, sedentary lifestyle, psychological stress, unhealthy diet, and metabolic syndrome were very high. This finding demonstrates the need for global action to prevent disability and death from ischemic heart and cerebrovascular disease. It is urgent to implement programs to address these challenges on a national scale. PMID- 26581055 TI - Formative evaluation of a proposed mHealth program for childhood illness management in a resource-limited setting in Peru. AB - OBJECTIVE: To conduct a formative evaluation of a proposed mobile health (mHealth) program designed to educate caregivers about management of common childhood illnesses. METHODS: A cluster-randomized sample (n = 220) of mothers in Cono Norte, Arequipa, Peru with at least one child under five completed an iPad based survey. This descriptive study examined trends in mobile phone ownership and feasibility of and interest in mHealth across sociodemographic categories. Fisher's exact tests were used to evaluate associations. Univariate logistic regression models were fitted to calculate odds ratios and 95% confidence intervals. RESULTS: Of 220 participants, 82.3% and 95.0% reported mobile phone ownership and access, respectively. Ownership was significantly associated with educational level (P = 0.031); however, even among mothers with the lowest education, ownership approached 80%. Educational level and age, respectively, were associated with the ability to open (P < 0.001; P < 0.001), read (P < 0.001; P < 0.001), write (P < 0.001; P < 0.001), and send (P = 0.006; P = 0.047) text messages. Over 85% of mothers were interested in using their mobile phones to receive health advice for their child and to seek help during illness. Regression analyses revealed that ability to use a mobile phone was positively associated with the mother's intention to participate in the mHealth program. CONCLUSIONS: The study findings confirm widespread access to mobile phones and sufficient ability to utilize text messaging within this population of caregivers. In addition to access and feasibility, high levels of interest in using mobile phones for health-related purposes suggest the potential value associated with an mHealth program designed to improve childhood illness management in this community. PMID- 26581056 TI - [Role of the UNASUR national institutes of health in generating evidence on the social determinants of health]. AB - The present article analyzes the role of the Union of South American Nations (UNASUR) national institutes of health since their creation at the beginning of the 20th century up until the present time. It postulates that the national institutes of health are in a position to play a strategic role in generating knowledge and evidence to facilitate decision-making through monitoring and research on the social determinants of health and health inequities. To explore this hypothesis, the national institutes of health are analyzed in the context of the current global scenario, which is generating increased social inequalities, thus leading in turn to serious inequities in health conditions. The article proposes a new model of health promotion, disease prevention, and health care, where necessary, as well as policies and intersectoral actions that address these social determinants. In this new stage, the UNASUR national institutes of health should play a significant strategic role in identifying and analyzing correlations between patterns of production and consumption, social divisions that exist in the territory, conditions of development, and the health of their populations. These national institutes of health are members of the UNASUR Network of National Institutes of Health (RINS-UNASUR). The literature on their creation, drawn from the Network's websites and the proceedings of its meetings and seminars, is reviewed. Given that the current globalized development model is generating enormous social inequalities, by definition, the proposed hypothesis is that the national institutes of health should assume a much broader role in addressing the consequent inequities in the health of the population, complementing their traditional activities with this new strategic role. Without a major reduction in the existing social inequalities and economic inequities, it will be impossible to make significant improvements in health in a democratic manner. PMID- 26581057 TI - Social stressors, social support, and mental health among Haitian migrants in the Dominican Republic. AB - This mixed-method study explored the social world of Haitian migrants, examining forms of social support and social stress, as well as their relationship to mental health. Among six Haitian migrant communities in the Cibao Valley of the Dominican Republic, a community-based survey (n = 127) was conducted to assess migration experiences, current stressors, mental health, and functioning. In addition, to explore perceptions and experiences of migration, social interactions, and mental health, the study drew upon in-depth interviews and free listing activities among Haitian migrants, as well as cognitive interviews with select survey participants. Depressive, anxiety, and mental distress survey scores were associated with 1) negative social interactions (including interrogation or deportation, perceived mistreatment by Dominicans, and overcrowding) and 2) lack of social support, including migrating alone. Mental distress scores were higher among women, and being married was associated with higher anxiety scores, potentially reflecting unmet social expectations. In qualitative data, participants emphasized a lack of social support, often referred to as tet ansanm (literally meaning "heads together" in Haitian Creole or Kreyol and roughly defined as solidarity or reciprocal social collaboration). The authors of the study propose that the practice of tet ansanm-also termed konbit, and, in the Dominican Republic, convite-could be used as a means of facilitating positive-contact events among Haitians and Dominicans. These interactions could help counteract social stress and build social capital in settings similar to those of the study. PMID- 26581058 TI - Paving pathways: Brazil's implementation of a national human papillomavirus immunization campaign. AB - In 2014, Brazil introduced an HPV immunization program for girls 9-13 years of age as part of the Unified Health System's (SUS) National Immunization Program. The first doses were administered in March 2014; the second ones, in September 2014. In less than 3 months more than 3 million girls received the first dose of quadrivalent HPV vaccine, surpassing the target rate of 80%. This paper examines three elements that may influence the program's long-term success in Brazil: sustaining effective outreach, managing a large technology-transfer collaboration, and developing an electronic immunization registry, with a focus on the State of Sao Paulo. If these three factors are managed, the Government of Brazil is primed to serve as a model of success for other countries interested in implementing a national HPV vaccination program to decrease HPV-related morbidity and mortality. PMID- 26581059 TI - [Unraveling R0: considerations for public health applications]. AB - We assessed public health use of R0, the basic reproduction number, which estimates the speed at which a disease is capable of spreading in a population. These estimates are of great public health interest, as evidenced during the 2009 influenza A (H1N1) virus pandemic. We reviewed methods commonly used to estimate R0, examined their practical utility, and assessed how estimates of this epidemiological parameter can inform mitigation strategy decisions. In isolation, R0 is a suboptimal gauge of infectious disease dynamics across populations; other disease parameters may provide more useful information. Nonetheless, estimation of R0 for a particular population is useful for understanding transmission in the study population. Considered in the context of other epidemiologically important parameters, the value of R0 may lie in better understanding an outbreak and in preparing a public health response. PMID- 26581061 TI - Topography and nanostructural evaluation of chemically and thermally modified titanium substrates. AB - In this research, the effects of chemical and thermal treatment on the morphological and compositional aspects of titanium substrates and so, potentially, on development of biomimetic bone like layers formation during simulated body fluid (SBF) soaking was investigated. The HF, HF/HNO3 and NaOH solutions were used for chemical treatment and some of alkali-treated samples followed a heat treatment at 600 degrees C. The treated samples before and after soaking were subjected to material characterization tests using scanning electron microscopy (SEM), X-ray diffraction (XRD) and atomic force microscopy (AFM). White light interferometry (WLI) was used to determine the roughness parameters such as Ra, Rq, RKu and Rsk. The significance of the obtained data was assessed using ANOVA variance analysis between all samples. It was observed that the reaction at grain boundaries and sodium titanate intermediate layers play a great role in the nucleation of calcium phosphate layers. Based on the obtained results in this work, the calcium phosphate microstructure deposited on titanium substrates was more affected by chemical modification than surface topography. PMID- 26581060 TI - The Safety of a Conservative Fluid Replacement Strategy in Adults Hospitalised with Malaria. AB - BACKGROUND: A conservative approach to fluid resuscitation improves survival in children with severe malaria; however, this strategy has not been formally evaluated in adults with the disease. METHODS: Adults hospitalised with malaria at two tertiary referral hospitals in Myanmar received intravenous fluid replacement with isotonic saline, administered at a maintenance rate using a simple weight-based algorithm. Clinical and biochemical indices were followed sequentially. RESULTS: Of 61 adults enrolled, 34 (56%) had Plasmodium falciparum mono-infection, 17 (28%) Plasmodium vivax mono-infection and 10 (16%) mixed infection; 27 (44%) patients were at high risk of death (P. falciparum infection and RCAM score >= 2). In the first six hours of hospitalisation patients received a mean 1.7 ml/kg/hour (range: 1.3-2.2) of intravenous fluid and were able to drink a mean of 0.8 ml/kg/hour (range: 0-3). Intravenous fluid administration and oral intake were similar for the remainder of the first 48 hours of hospitalisation. All 61 patients survived to discharge. No patient developed Adult Respiratory Distress Syndrome, a requirement for renal replacement therapy or hypotension (mean arterial pressure < 60 mmHg). Plasma lactate was elevated (> 2 mmol/L) on enrolment in 26 (43%) patients but had declined by 6 hours in 25 (96%) and was declining at 24 hours in the other patient. Plasma creatinine was elevated (> 120 MUmol/L) on enrolment in 17 (28%) patients, but was normal or falling in 16 (94%) at 48 hours and declining in the other patient by 72 hours. There was no clinically meaningful increase in plasma lactate or creatinine in any patient with a normal value on enrolment. Patients receiving fluid replacement with the conservative fluid replacement algorithm were more likely to survive than historical controls in the same hospitals who had received fluid replacement guided by clinical judgement in the year prior to the study (p = 0.03), despite having more severe disease (p < 0.001). CONCLUSIONS: A conservative fluid resuscitation strategy appears safe in adults hospitalised with malaria. PMID- 26581062 TI - Ultrasonographic assessment of cervical length in pregnancies scheduled for a cesarean delivery: prediction of early spontaneous onset of labor. AB - AIM: To investigate whether the cervical length measured by transvaginal ultrasound at 35 to 36 weeks of gestation is predictive of spontaneous early onset of labor in pregnancies scheduled for elective cesarean section (CS). STUDY DESIGN: This was a prospective observational study on 167 women scheduled for elective CS at 39 weeks of gestation. The cervical length was measured ultrasonographycally at 35 to 36 weeks of gestation and the pregnancies characteristics were recorded. The presence or absence of spontaneous onset of labor before the time scheduled for elective CS was related to cervical length and pregnancies characteristics. RESULTS: Of the 167 pregnancies enrolled, 25 (14.97%) underwent early spontaneous onset of labor before the time scheduled for the elective CS. The cervical length was significantly shorter in these women when compared with those delivering with an elective CS (21 vs. 30 mm z=5.49 P<0.0001). The presence of >=2 previous CS as an indicator for elective CS resulted a significant predictor of early onset of labor in univariate analysis (P=0.01). Multivariate logistic regression analysis showed that cervical length (adjusted odds ratio 1.40; 95% confidence interval (CI) 1.22-1.61; P<=0.0001) was the only predictor for the early onset of labor. The area under the receiver operating characteristics curve for the prediction of early onset of labor was 0.844 (95% CI 0.738-0.950) for cervical length as test variable. Kaplan-Meier analysis demonstrated that a cervical length <24 mm was significantly associated with a short time interval to delivery (log rank test chi2=99,98; P<=0.0001). CONCLUSION: Cervical length at 35-36 weeks of gestation provides information about the likelihood of spontaneous early onset of labor in pregnancies scheduled for CS and may be useful in individualizing the gestational age for elective CS. PMID- 26581063 TI - Contraception: a questionnaire on knowledge and attitude of adolescents, distributed on Facebook. AB - BACKGROUND: The contraceptive pill is widely used. An accurate knowledge is necessary for correct use. OBJECTIVE: This study sheds light on adolescents' knowledge, attitude and behavior in regard to contraceptive use, in the year 2014. The goal is to provide general practitioners (GP) with information about the potential gaps in knowledge concerning contraceptive use in order to give better counseling and prevent high-risk behavior in adolescents. METHODS: A quantitative descriptive study was carried out among 14-25-year-old female and male adolescents. Data were collected through a web-based survey using the online survey software Qualtrics (Qualtrics, Provo, UT, USA) and was distributed via the social networking site Facebook. RESULTS: The survey was started by 1185 participants. The most popular contraceptive method among females is the oral contraceptive pill (63.7%). Four out of ten females (42.6%) do not know that when using an emergency pill, they must still take their regular contraceptive pill on the same day. The majority of female respondents (80.0%) go to their general practitioner for a prescription for the pill. Ninety-five percent (95.1%) of the females would feel comfortable asking their GP for extra information about the drug. The sex of the GP does not influence the likelihood of female patients seeking more information. The Internet also seems to serve as an important source of information. We defined a female subgroup, called "vulnerable". The majority of females in the non-vulnerable group (70.4%) protected themselves before their first sexual contact instead of only half of the members in the vulnerable group (51.0%). CONCLUSION: The level of knowledge among adolescents about contraception is not alarming, but there are a few blind spots. Eliminating these gaps should be the aim of the doctor and pharmacologist. PMID- 26581064 TI - Passive smoking: knowledge, exposure and responses among adolescents in a rural setting in Sri Lanka. AB - BACKGROUND: Passive smoking adversely affects the health of those exposed to it. Exposure to passive smoking among adolescents is also associated with early initiation to smoking. OBJECTIVE: This study aimed at determining the knowledge, exposure and response to passive smoking among adolescents in a rural setting in Sri Lanka. SUBJECT: Adolescents studying in grade 10 in seven rural schools in Polonnaruwa district. METHODS: A cross-sectional study, using a self-administered questionnaire, was conducted among 498 adolescents selected proportionate to the size of the student population using a multi-stage cluster sampling method. RESULTS: The response rate was 99.6% (498/500). Only 69.3%, (n=345) had heard of the term passive smoking. Of those who had heard of the term, 83.2%, (n=287) was accurate about what the term meant. Only 2.4% (n=12) of the study population was categorized as having a good level of knowledge on passive smoking. Self reported exposure levels to passive smoking was low among a majority (81%, n=406). On inquiring how they had reacted or will react to a situation of exposure to passive smoking, a majority (92.2%, n=459) indicated that they had/will rescind from the situation. CONCLUSION: The level of knowledge on passive smoking was poor among the adolescents in the rural setting in Sri Lanka. Despite the low level of exposure, the adolescents indicated that they were/will be assertive when faced with a situation of exposure to passive smoking. The study recommends that knowledge of adolescents on passive smoking be improved. PMID- 26581065 TI - Remission of congenital hyperinsulinism following conservative treatment: an exploratory study in patients with KATP channel mutations. AB - BACKGROUND: During conservative treatment, congenital hyperinsulinism (CHI) can resolve spontaneously. This study describes the hormonal and metabolic profiles in three patients with ABCC8/KCNJ11 mutations in clinical remission. METHODS: An age-adapted fasting and oral glucose tolerance test (OGTT) were performed. RESULTS: All patients (aged 6-9 years) tolerated age-adapted fasting durations (20, respectively 24 h), without reaching glucose concentrations <=2.5 mmol/L, nor developing hypoglycemia-related symptoms. Nevertheless, insulin concentrations from all patients exceeded the 90th reference percentile at the end of the fasting test (range: 4.2-15.8 mU/L). During the OGTT, one patient (patient 2; BMI: 23.4 kg/m2; age: 7 years) reached a glucose concentration of 11.4 mmol/L after 2 h (concomitant insulin concentration: 148.3 mU/L). CONCLUSIONS: The insulin concentration profiles in CHI patients in apparent clinical remission range from almost complete normalization to persistent, yet attenuated, hypersecretion. The hyperglycemia, detected during the OGTT, must be further monitored. PMID- 26581066 TI - Isolated methylmalonic acidemia with unusual presentation mimicking diabetic ketoacidosis. AB - BACKGROUND: Hyperglycemic ketoacidosis is an acute, life threatening condition requiring early etiologic recognition and management to prevent serious morbidity/mortality. The most common cause is diabetic ketoacidosis (DKA). Organic acidemias (OAs) are inheritable disorders caused by defects in protein metabolism resulting in acid accumulation. Patients with metabolic decompensation usually present with acidosis, with/without hypoglycemia. Hyperglycemia is a very rare manifestation. At least 16 cases of OAs presenting with hyperglycemia have been reported. Six of the 16 were diagnosed with isolated methylmalonic academia (MMA) and three of the six passed away from late diagnosis. CASE DESCRIPTION: We describe a 2-year-old Thai girl who presented with hyperglycemia, acidosis and ketosis. She has underlying delayed development, seizures, optic atrophy and poor growth. An initial diagnosis of DKA was made and standard treatment was started. After 4 h of treatment, the patient partially responded to treatment; blood sugar decreased but acidosis and ketonemia persisted. HbA1c was normal. Investigations to rule out OAs were performed. Markedly elevated urinary methylmalonic acid consistent with MMA was observed. Molecular and enzyme analyses confirmed the diagnosis with isolated MMA. Specific treatment for MMA including protein restriction, high caloric fluid, carnitine and vitamin B12 was promptly started. Clinical improvement was seen 4 days after initiating specific treatment. CONCLUSIONS: Inherited metabolic disorders should be included in differential diagnosis in hyperglycemia ketoacidosis patients who respond poorly to standard DKA treatment. Unusual findings, e.g. hyperammonemia, lactic acidosis, pancytopenia, abnormal basal ganglia in MRI or underlying delayed development may indicate underlying OAs. Determining the etiology of hyperglycemic ketoacidosis is important and can lead to good outcomes. PMID- 26581067 TI - Epileptogenesis following experimentally induced traumatic brain injury - a systematic review. AB - Traumatic brain injury (TBI) is a complex neurotrauma in civilian life and the battlefield with a broad spectrum of symptoms, long-term neuropsychological disability, as well as mortality worldwide. Posttraumatic epilepsy (PTE) is a common outcome of TBI with unknown mechanisms, followed by posttraumatic epileptogenesis. There are numerous rodent models of TBI available with varying pathomechanisms of head injury similar to human TBI, but there is no evidence for an adequate TBI model that can properly mimic all aspects of clinical TBI and the first successive spontaneous focal seizures follow a single episode of neurotrauma with respect to epileptogenesis. This review aims to provide current information regarding the various experimental animal models of TBI relevant to clinical TBI. Mossy fiber sprouting, loss of dentate hilar neurons along with recurrent seizures, and epileptic discharge similar to human PTE have been studied in fluid percussion injury, weight-drop injury, and cortical impact models, but further refinement of animal models and functional test is warranted to better understand the underlying pathophysiology of posttraumatic epileptogenesis. A multifaceted research approach in TBI model may lead to exploration of the potential treatment measures, which are a major challenge to the research community and drug developers. With respect to clinical setting, proper patient data collection, improved clinical trials with advancement in drug delivery strategies, blood-brain barrier permeability, and proper monitoring of level and effects of target drug are also important. PMID- 26581068 TI - Cannabinoids in the management of chronic pain: a front line clinical perspective. AB - Chronic pain is an escalating public health problem. Currently available treatments are inadequate to control chronic pain conditions, and there is a critical need for novel treatments. Over a half century of elegant preclinical research has identified the presence of a sophisticated endocannabinoid system that is part of our natural pain and immune defense network. Convergent work has supported the significant potential to exploit this system to decrease pain and inflammation. Although the clinical research remains in its infancy, recent systematic reviews have found that 25 of 30 randomized controlled trials have demonstrated a significant analgesic effect. The authors concluded that cannabinoids currently available for clinical use demonstrate a modest analgesic effect and are safe for the management of chronic pain. There is a critical need for more translational research so that the excellent work of Dr. Itai Bab and our basic science colleagues around the world can move forward in providing novel cannabinoid-based medicines. This should include more potent analgesics that are limited in side effects with several routes of delivery. Our patients deserve additional agents for pain control with a novel mechanism of action, and cannabinoids are the new frontier. PMID- 26581069 TI - New patterns of relapse in multiple myeloma: a case of "light chain escape" in which FLC predicted relapse earlier than urine and serum immunofixation. AB - Multiple myeloma (MM) is characterized, in about 80% of cases, by the production of monoclonal intact immunoglobulin and more than 95% of them have elevated concentrations of involved (i.e. of the same class of intact immunoglobulin) free light chain (FLC). The introduction of novel therapeutic strategies has changed the natural history of the disease, leading to new manifestations of relapse. Light chain escape (LCE) is a pattern of relapse in which the FLC increase is not accompanied by a concomitant raise of the original monoclonal component (MC). Here we present a case of a 55-year-old man with an IgG kappa MM stage III diagnosed in September 2007. At presentation an IgG kappa MC and urine Bence Jones protein (BJP) kappa were present. Bone marrow biopsy (BMB) showed the presence of 80% monotypic kappa plasma cells (PCs). The patient received bortezomib, thalidomide, dexamethasone before undergoing a double autologous stem cell transplantation (ASCT) in October 2008 and April 2009. In May 2011 he relapsed showing the same pattern of presentation and treatment with lenalidomide and dexamethasone was started. ln May 2013 serum and urine immunofixation and FLC became negative. In September 2014, an increase of kappa FLC was observed, while serum and urine immunofixations remained negative until January 2015, when urine immunofixation became positive. Eventually, in February 2015, serum immunofixation revealed the presence of a free kappa MC. After a new BMB showing 80% of monotypic kappa PCs, a LCE relapse was diagnosed and the patient started the treatment with bendamustine, bortezomib and dexamethasone. In the present case, the increase of kappa FLC has indicated relapse 4 and 5 months earlier than urine and serum IFE, respectively. Our observation confirms that it is advisable to routinely perform FLC or BJP during follow up of MM patients undergoing ASCT and/or treatment with biological drugs to ensure that LCE is not missed. PMID- 26581070 TI - HAND1 loss-of-function mutation associated with familial dilated cardiomyopathy. AB - BACKGROUND: The basic helix-loop-helix transcription factor HAND1 is essential for cardiac development and structural remodeling, and mutations in HAND1 have been causally linked to various congenital heart diseases. However, whether genetically compromised HAND1 predisposes to dilated cardiomyopathy (DCM) in humans remains unknown. METHODS: The whole coding region and splicing junctions of the HAND1 gene were sequenced in 140 unrelated patients with idiopathic DCM. The available family members of the index patient carrying an identified mutation and 260 unrelated ethnically matched healthy individuals used as controls were genotyped for HAND1. The functional effect of the mutant HAND1 was characterized in contrast to its wild-type counterpart by using a dual-luciferase reporter assay system. RESULTS: A novel heterozygous HAND1 mutation, p.R105X, was identified in a family with DCM transmitted as an autosomal dominant trait, which co-segregated with DCM in the family with complete penetrance. The nonsense mutation was absent in 520 control chromosomes. Functional analyses unveiled that the mutant HAND1 had no transcriptional activity. Furthermore, the mutation abolished the synergistic activation between HAND1 and GATA4, another crucial cardiac transcription factors that has been associated with various congenital cardiovascular malformations and DCM. CONCLUSIONS: This study firstly reports the association of HAND1 loss-of-function mutation with increased susceptibility to DCM in humans, which provides novel insight into the molecular mechanisms underpinning DCM. PMID- 26581071 TI - The importance of angiogenic markers in the differential diagnosis of HELLP syndrome vs. non-HELLP thrombocytopenia. PMID- 26581072 TI - Total error vs. measurement uncertainty: the match continues. PMID- 26581073 TI - A comparison of the effects of reflexology and relaxation on pain in women with multiple sclerosis. AB - BACKGROUND: Pain is a common and significant symptom in many individuals with multiple sclerosis (MS). The presence and severity of pain in individuals with MS has also been shown to be associated with higher levels of depression, functional impairment, and fatigue. It is common for MS patients and their caregivers to worry about narcotic addiction in the management of chronic pain. Therefore, this study aimed to determine and compare the effects of reflexology and relaxation on pain in women suffering from MS. METHODS: This study was a single-blind randomized clinical trial performed on 75 patients with MS referred to the MS Clinic of Ayatollah Kashani Hospital (Isfahan, Iran). After simple non-random sampling, using the minimization method, participants were randomly assigned to the three groups of reflexology, relaxation, and control. In the experimental groups, foot reflexology and relaxation interventions (Jacobson and Benson) were performed within 4 weeks, twice a week for 40 min. The control group received routine care and medical treatment as directed by a doctor. Data were collected using the Numerical Rating Scale before, immediately after, and 2 months after interventions in all three groups. Data analysis was performed using SPSS version 18 and descriptive and inferential statistical tests. RESULTS: Findings obtained from analysis of variance (ANOVA) showed no significant differences between mean pain intensity scores in the three groups preintervention and 2 months after interventions (p > 0.05). However, this difference was statistically significant immediately after the study (p < 0.05). Findings obtained from repeated measures ANOVA showed that the severity of pain significantly differed during different times in reflexology and relaxation (p < 0.05); however, this difference was not significant in the control group (p > 0.05). Furthermore, Fisher's least significant difference (LSD) revealed a significantly higher reduction in pain intensity scores in the reflexology group after the intervention, compared with the two other groups, but showed no significant differences between relaxation and control groups. There were no significant differences between the three groups 2 months after the interventions (p > 0.05). CONCLUSIONS: The results showed that both interventions are effective on relieving pain in women with MS; however, it appears that the effect of reflexology on pain reduction is greater than that of relaxation. Hence, these two methods can be recommended as effective techniques. PMID- 26581074 TI - Metabolism and metabolite profiles in vitro and in vivo of ospemifene in humans and preclinical species. AB - BACKGROUND: Metabolite profiles of ospemifene, a novel nonsteroidal selective estrogen receptor modulator, were surveyed as part of its development. METHODS: The pharmacokinetics of ospemifene and its two major, pharmacologically active metabolites 4-hydroxyospemifene and 4'-hydroxyospemifene, was elucidated in studies of volunteer humans given various doses of ospemifene and in experiments of several animal species (rat, mouse, dog, and cynomolgus monkey), which had been used either for pharmacological or toxicological studies of ospemifene. Metabolites produced in in vitro human and animal liver preparations were compared between species and with the metabolite profiles in the in vivo investigations. RESULTS: Considerable interspecies differences were observed in the metabolite profiles and quantities. The major human metabolite, 4 hydroxyospemifene, was produced in substantial amounts both in vitro and in vivo in most animal species, except dog, and thus the exposure to this metabolite seems adequate in the most important toxicology species, the rat and the cynomolgus monkey. 4'-Hydroxyospemifene was equally abundant in vitro and in vivo metabolite in mice and dogs, and consequently, its contribution to the total exposure of ospemifene-related activity would be adequately covered in animal experiments. Other ospemifene metabolites were variably detected in different species, but probably they are not of consequence to pharmacology or toxicology of ospemifene. CONCLUSIONS: Overall, there are quantitative and also some qualitative differences in the metabolism of ospemifene in different species. Generally, in vitro metabolite profiles were predictive for in vivo profiles. The contribution of two major hydroxyl metabolites to activity and toxicity of ospemifene is adequately covered by at least some animal species. PMID- 26581075 TI - Human genetics: international projects and personalized medicine. AB - In this article, we present the progress driven by the recent technological advances and new revolutionary massive sequencing technologies in the field of human genetics. We discuss this knowledge in relation with drug response prediction, from the germline genetic variation compiled in the 1000 Genomes Project or in the Genotype-Tissue Expression project, to the phenome-genome archives, the international cancer projects, such as The Cancer Genome Atlas or the International Cancer Genome Consortium, and the epigenetic variation and its influence in gene expression, including the regulation of drug metabolism. This review is based on the lectures presented by the speakers of the Symposium "Human Genetics: International Projects & New Technologies" from the VII Conference of the Spanish Pharmacogenetics and Pharmacogenomics Society, held on the 20th and 21st of April 2015. PMID- 26581076 TI - The consumer welfare implications of governmental policies and firm strategy in markets for medicines. AB - This paper empirically examines the consumer welfare implications of changes in government policies related to patent protection and compulsory licensing in the Indian market for oral anti-diabetic (OAD) medicines. In contrast to previous studies on the impact of pharmaceutical patents in India, we observe, and estimate the welfare effects accruing from differential pricing and voluntary licensing strategies of patent-holding innovator firms. Three novel molecules belonging to the dipeptidyl peptidase-4 (DPP-4) inhibitor class of OADs have been launched in India by the patent holders, at lower prices than those prevailing in the developed countries. Using aggregate market transaction data, we structurally estimate demand and supply and use the parameter estimates in our model to simulate consumer welfare under various counterfactual scenarios. Our results suggest that the introduction of DPP-4 inhibitors generated a consumer surplus gain of around 7.6 cents per day for a typical DPP-4 inhibitor user under the existing differential pricing and voluntary licensing strategies. If the innovators decide to price at developed-country levels, this surplus is eliminated almost entirely. The issuance of compulsory licensing does not always improve consumer welfare because if innovators defer or delay the introduction of new drugs in response, the loss in consumer welfare could be substantial. PMID- 26581077 TI - A "White" Anthocyanin-less Pomegranate (Punica granatum L.) Caused by an Insertion in the Coding Region of the Leucoanthocyanidin Dioxygenase (LDOX; ANS) Gene. AB - Color is an important determinant of pomegranate fruit quality and commercial value. To understand the genetic factors controlling color in pomegranate, chemical, molecular and genetic characterization of a "white" pomegranate was performed. This unique accession is lacking the typical pomegranate color rendered by anthocyanins in all tissues of the plant, including flowers, fruit (skin and arils) and leaves. Steady-state gene-expression analysis indicated that none of the analyzed "white" pomegranate tissues are able to synthesize mRNA corresponding to the PgLDOX gene (leucoanthocyanidin dioxygenase, also called ANS, anthocyanidin synthase), which is one of the central structural genes in the anthocyanin-biosynthesis pathway. HPLC analysis revealed that none of the "white" pomegranate tissues accumulate anthocyanins, whereas other flavonoids, corresponding to biochemical reactions upstream of LDOX, were present. Molecular analysis of the "white" pomegranate revealed the presence of an insertion and an SNP within the coding region of PgLDOX. It was found that the SNP does not change amino acid sequence and is not fully linked with the "white" phenotype in all pomegranate accessions from the collection. On the other hand, genotyping of pomegranate accessions from the collection and segregating populations for the "white" phenotype demonstrated its complete linkage with the insertion, inherited as a recessive single-gene trait. Taken together, the results indicate that the insertion in PgLDOX is responsible for the "white" anthocyanin-less phenotype. These data provide the first direct molecular, genetic and chemical evidence for the effect of a natural modification in the LDOX gene on color accumulation in a fruit-bearing woody perennial deciduous tree. This modification can be further utilized to elucidate the physiological role of anthocyanins in protecting the tree organs from harmful environmental conditions, such as temperature and UV radiation. PMID- 26581078 TI - Mechanical Stimulation by Postnasal Drip Evokes Cough. AB - Cough affects all individuals at different times, and its economic burden is substantial. Despite these widespread adverse effects, cough research relies on animal models, which hampers our understanding of the fundamental cause of cough. Postnasal drip is speculated to be one of the most frequent causes of chronic cough; however, this is a matter of debate. Here we show that mechanical stimuli by postnasal drip cause chronic cough. We distinguished human cough from sneezes and expiration reflexes by airflow patterns. Cough and sneeze exhibited one-peak and two-peak patterns, respectively, in expiratory airflow, which were also confirmed by animal models of cough and sneeze. Transgenic mice with ciliary dyskinesia coughed substantially and showed postnasal drip in the pharynx; furthermore, their cough was completely inhibited by nasal airway blockade of postnasal drip. We successfully reproduced cough observed in these mice by injecting artificial postnasal drip in wild-type mice. These results demonstrated that mechanical stimulation by postnasal drip evoked cough. The findings of our study can therefore be used to develop new antitussive drugs that prevent the root cause of cough. PMID- 26581079 TI - Transparency of Outcome Reporting and Trial Registration of Randomized Controlled Trials Published in the Journal of Consulting and Clinical Psychology. AB - BACKGROUND: Confidence that randomized controlled trial (RCT) results accurately reflect intervention effectiveness depends on proper trial conduct and the accuracy and completeness of published trial reports. The Journal of Consulting and Clinical Psychology (JCCP) is the primary trials journal amongst American Psychological Association (APA) journals. The objectives of this study were to review RCTs recently published in JCCP to evaluate (1) adequacy of primary outcome analysis definitions; (2) registration status; and, (3) among registered trials, adequacy of outcome registrations. Additionally, we compared results from JCCP to findings from a recent study of top psychosomatic and behavioral medicine journals. METHODS: Eligible RCTs were published in JCCP in 2013-2014. For each RCT, two investigators independently extracted data on (1) adequacy of outcome analysis definitions in the published report, (2) whether the RCT was registered prior to enrolling patients, and (3) adequacy of outcome registration. RESULTS: Of 70 RCTs reviewed, 12 (17.1%) adequately defined primary or secondary outcome analyses, whereas 58 (82.3%) had multiple primary outcome analyses without statistical adjustment or undefined outcome analyses. There were 39 (55.7%) registered trials. Only two trials registered prior to patient enrollment with a single primary outcome variable and time point of assessment. However, in one of the two trials, registered and published outcomes were discrepant. No studies were adequately registered as per Standard Protocol Items: Recommendation for Interventional Trials guidelines. Compared to psychosomatic and behavioral medicine journals, the proportion of published trials with adequate outcome analysis declarations was significantly lower in JCCP (17.1% versus 32.9%; p = 0.029). The proportion of registered trials in JCCP (55.7%) was comparable to behavioral medicine journals (52.6%; p = 0.709). CONCLUSIONS: The quality of published outcome analysis definitions and trial registrations in JCCP is suboptimal. Greater attention to proper trial registration and outcome analysis definition in published reports is needed. PMID- 26581080 TI - Plantecophys--An R Package for Analysing and Modelling Leaf Gas Exchange Data. AB - Here I present the R package 'plantecophys', a toolkit to analyse and model leaf gas exchange data. Measurements of leaf photosynthesis and transpiration are routinely collected with portable gas exchange instruments, and analysed with a few key models. These models include the Farquhar-von Caemmerer-Berry (FvCB) model of leaf photosynthesis, the Ball-Berry models of stomatal conductance, and the coupled leaf gas exchange model which combines the supply and demand functions for CO2 in the leaf. The 'plantecophys' R package includes functions for fitting these models to measurements, as well as simulating from the fitted models to aid in interpreting experimental data. Here I describe the functionality and implementation of the new package, and give some examples of its use. I briefly describe functions for fitting the FvCB model of photosynthesis to measurements of photosynthesis-CO2 response curves ('A-Ci curves'), fitting Ball-Berry type models, modelling C3 photosynthesis with the coupled photosynthesis-stomatal conductance model, modelling C4 photosynthesis, numerical solution of optimal stomatal behaviour, and energy balance calculations using the Penman-Monteith equation. This open-source package makes technically challenging calculations easily accessible for many users and is freely available on CRAN. PMID- 26581081 TI - Laparoscopic treatment for inguinal hernia combined with cryptorchidism: Totally extraperitoneal repair with orchiectomy under the same operative view. AB - INTRODUCTION: Approximately 7% of child patients with inguinal hernias also present with cryptorchidism. On the other hand, combined adult cases are uncommon. Here we report two adult cases of inguinal hernia combined with intra canalicular cryptorchidism who underwent totally extraperitoneal (TEP) repair with orchiectomy under the same operative view. PRESENTATION OF CASES: We treated two patients (49- and 38-year-old men) with right indirect inguinal hernias and cryptorchidism. Both patients underwent TEP repair with orchiectomy. In operative findings, an atrophic testis was drawn out with a hernia sac from the internal inguinal ring. After the testis was separated from the sac and cord structure was sheared, it was removed. The procedure did not require special techniques and devices. In both patients, the postoperative courses were satisfactory. DISCUSSION: To our knowledge, there has been only one such reported case till date which demonstrated the feasibility of TEP repair accompanied by orchiectomy. CONCLUSIONS: TEP repair with orchiectomy under the same operative view could be safely performed in adults with an inguinal hernia combined with extra-abdominal cryptorchidism. This procedure could be an option for the treatment of such adult patients. PMID- 26581082 TI - Is it really an abscess? An unusual case of metastatic stromal cell sarcoma of the prostate. AB - INTRODUCTION: Prostatic stromal sarcomas account for about 0.1% of all prostatic malignancies. Local recurrence into bladder, seminal vesicles and rectum has been documented. Distal metastasis, has so far only been reported in lung and bone. PRESENTATION OF CASE: We report the case of a 42 year old man with a subcutaneous metastatic deposit of a prostatic stromal cell sarcoma 5 years after radical prostatectomy. Additional staging with CT- and PET-scan showed lymph node involvement in the neck and left axilla. A core biopsy of the skin lesion was undertaken, of which the histology revealed a low grade spindle cell tumour that was morphologically identical to a previously diagnosed prostatic stromal sarcoma. DISCUSSION: In literature distant metastases to the lung and bone have been documented before. This is the first documented case of a subcutaneous metastasis of prostatic stromal cell sarcoma. CONCLUSION: The preferred treatment for prostatic stromal cell sarcoma is surgery by radical prostatectomy or cystoprostatectomy. There is currently not enough literature on the topic to elucidate the role of chemo- or radiotherapy in loco-regional or distant spread. PMID- 26581083 TI - Laparoscopic repair of an incarcerated femoral hernia. AB - INTRODUCTION: A femoral hernia is a rare, acquired condition, which has been reported in less than 5% of all abdominal wall hernias, with a female to male ratio of 4:1. PRESENTATION OF CASE: We report a case in a female patient who had a previous open inguinal herniorrhaphy three years previously. She presented with right sided groin pain of one month duration. Ultrasound gave a differential diagnosis of a recurrent inguinal hernia or a femoral hernia. A transabdominal preperitoneal repair was performed and the patient made an uneventful recovery. DISCUSSION: Laparoscopic repair of a femoral hernia is still in its infancy and even though the outcomes are superior to an open repair, open surgery remains the standard of care. The decision to perform a laparoscopic trans abdominal preperitoneal (TAPP) repair was facilitated by the patient having previous open hernia surgery. The learning curve for laparoscopic femoral hernia repair is steep and requires great commitment from the surgeon. Once the learning curve has been breached this is a feasible method of surgical repair. This is demonstrated by the fact that this case report is from a rural hospital in Canada. CONCLUSION: Laparoscopic femoral hernia repair involves more time and specialized laparoscopic skills. The advantages are a lower recurrence rate and lower incidence of inguinodynia. PMID- 26581084 TI - Transcriptator: An Automated Computational Pipeline to Annotate Assembled Reads and Identify Non Coding RNA. AB - RNA-seq is a new tool to measure RNA transcript counts, using high-throughput sequencing at an extraordinary accuracy. It provides quantitative means to explore the transcriptome of an organism of interest. However, interpreting this extremely large data into biological knowledge is a problem, and biologist friendly tools are lacking. In our lab, we developed Transcriptator, a web application based on a computational Python pipeline with a user-friendly Java interface. This pipeline uses the web services available for BLAST (Basis Local Search Alignment Tool), QuickGO and DAVID (Database for Annotation, Visualization and Integrated Discovery) tools. It offers a report on statistical analysis of functional and Gene Ontology (GO) annotation's enrichment. It helps users to identify enriched biological themes, particularly GO terms, pathways, domains, gene/proteins features and protein-protein interactions related informations. It clusters the transcripts based on functional annotations and generates a tabular report for functional and gene ontology annotations for each submitted transcript to the web server. The implementation of QuickGo web-services in our pipeline enable the users to carry out GO-Slim analysis, whereas the integration of PORTRAIT (Prediction of transcriptomic non coding RNA (ncRNA) by ab initio methods) helps to identify the non coding RNAs and their regulatory role in transcriptome. In summary, Transcriptator is a useful software for both NGS and array data. It helps the users to characterize the de-novo assembled reads, obtained from NGS experiments for non-referenced organisms, while it also performs the functional enrichment analysis of differentially expressed transcripts/genes for both RNA-seq and micro-array experiments. It generates easy to read tables and interactive charts for better understanding of the data. The pipeline is modular in nature, and provides an opportunity to add new plugins in the future. Web application is freely available at: http://www labgtp.na.icar.cnr.it/Transcriptator. PMID- 26581085 TI - Erythropoietin for the Treatment of Subarachnoid Hemorrhage: A Feasible Ingredient for a Successful Medical Recipe. AB - Subarachnoid hemorrhage (SAH) following aneurysm bleeding accounts for 6% to 8% of all cerebrovascular accidents. Although an aneurysm can be effectively managed by surgery or endovascular therapy, delayed cerebral ischemia is diagnosed in a high percentage of patients resulting in significant morbidity and mortality. Cerebral vasospasm occurs in more than half of all patients after aneurysm rupture and is recognized as the leading cause of delayed cerebral ischemia after SAH. Hemodynamic strategies and endovascular procedures may be considered for the treatment of cerebral vasospasm. In recent years, the mechanisms contributing to the development of vasospasm, abnormal reactivity of cerebral arteries and cerebral ischemia following SAH, have been investigated intensively. A number of pathological processes have been identified in the pathogenesis of vasospasm, including endothelial injury, smooth muscle cell contraction from spasmogenic substances produced by the subarachnoid blood clots, changes in vascular responsiveness and inflammatory response of the vascular endothelium. To date, the current therapeutic interventions remain ineffective as they are limited to the manipulation of systemic blood pressure, variation of blood volume and viscosity and control of arterial carbon dioxide tension. In this scenario, the hormone erythropoietin (EPO) has been found to exert neuroprotective action during experimental SAH when its recombinant form (rHuEPO) is administered systemically. However, recent translation of experimental data into clinical trials has suggested an unclear role of recombinant human EPO in the setting of SAH. In this context, the aim of the current review is to present current evidence on the potential role of EPO in cerebrovascular dysfunction following aneurysmal subarachnoid hemorrhage. PMID- 26581087 TI - Elementary School Children Contribute to Environmental Research as Citizen Scientists. AB - Research benefits increasingly from valuable contributions by citizen scientists. Mostly, participating adults investigate specific species, ecosystems or phenology to address conservation issues, but ecosystem functions supporting ecosystem health are rarely addressed and other demographic groups rarely involved. As part of a project investigating seed predation and dispersal as ecosystem functions along an urban-rural gradient, we tested whether elementary school children can contribute to the project as citizen scientists. Specifically, we compared data estimating vegetation cover, measuring vegetation height and counting seeds from a seed removal experiment, that were collected by children and scientists in schoolyards. Children counted seeds similarly to scientists but under- or overestimated vegetation cover and measured different heights. We conclude that children can be involved as citizen scientists in research projects according to their skill level. However, more sophisticated tasks require specific training to become familiarized with scientific experiments and the development of needed skills and methods. PMID- 26581086 TI - Biomarkers for Bone Tumors: Discovery from Genomics and Proteomics Studies and Their Challenges. AB - Diagnosis of bone tumor currently relies on imaging and biopsy, and hence, the need to find less invasive ways for its accurate detection. More recently, numerous promising deoxyribonucleic acid (DNA) and protein biomarkers with significant prognostic, diagnostic and/or predictive abilities for various types of bone tumors have been identified from genomics and proteomics studies. This article reviewed the putative biomarkers for the more common types of bone tumors (that is, osteosarcoma, Ewing sarcoma, chondrosarcoma [malignant] and giant cell tumor [benign]) that were unveiled from the studies. The benefits and drawbacks of these biomarkers, as well as the technology platforms involved in the research, were also discussed. Challenges faced in the biomarker discovery studies and the problems in their translation from the bench to the clinical settings were also addressed. PMID- 26581088 TI - Modified STOP-Bang Tool for Stratifying Obstructive Sleep Apnea Risk in Adolescent Children. AB - PURPOSE: Obstructive sleep apnea (OSA) is prevalent in children and diagnostic polysomnography is costly and not readily available in all areas. We developed a pediatric modification of a commonly used adult clinical prediction tool for stratifying the risk of OSA and the need for polysomnography. METHODS: A total of 312 children (age 9-17 years) from phase 2 of the Tucson Children's Assessment of Sleep Apnea cohort study, with complete anthropomorphic data, parent questionnaires, and home polysomnograms were included. An adolescent modification of STOP-Bang (teen STOP-Bang) was developed and included snoring, tired, observed apnea, blood pressure >= 95th percentile, BMI > 95th percentile, academic problems, neck circumference >95th percentile for age, and male gender. An apnea hypopnea index >= 1.5 events/hour was considered diagnostic of OSA. RESULTS: Receiver Operator Characteristic (ROC) curves for parent-reported STOP-Bang scores were generated for teenage and pre-teen children. A STOP-Bang score of < 3 in teenagers was associated with a negative predictive value of 0.96. ROC curves were also generated based upon child-reported sexual maturity rating (SMR; n = 291). The ability of teen STOP-Bang to discriminate the presence or absence of OSA as measured by the AUC for children with SMR >= 4 (0.83; 95%CI 0.71-0.95) was better than children with SMR < 4 (0.63; 95%CI 0.46-0.81; p = 0.048). CONCLUSIONS: In community dwelling adolescents, teen STOP-Bang may be useful in stratifying the risk of OSA. PMID- 26581089 TI - Does a Novel-Developed Product of Wheelchair Incorporating Pelvic Support Prevent Forward Head Posture during Prolonged Sitting? AB - Disabled elderly individuals with kyphosis or loss of muscle strength often display forward head posture (FHP). This study aimed to determine the utility of a wheelchair incorporating pelvic support in preventing FHP in disabled elderly individuals. In this study, 14 disabled elderly individuals (87.1 +/- 8.1 years) were selected. A wheelchair incorporating pelvic support (RX_ABS Lo) and a basic wheelchair (RX-1) were used. Each individual sat on both wheelchairs for 30 minutes. RX_ABS Lo has two belts to support the pelvic and thorax. Postures were recorded in the sagittal plane using a video camera. Cervical and trunk angles from horizontal were measured every 5 minutes. Simultaneously, contact areas and total pressures applied to the wheelchair seats and back supports were measured every 5 minutes. Comparisons of area under the curve values between the wheelchairs were performed using the paired t-test. Comparisons of time-dependent parameters for each wheelchair were performed using repeated one-way ANOVA. Cervical angles were greater when using RX_ABS Lo than RX-1. Although cervical angles were unchanged during 30 minutes when using RX_ABS Lo, the angles were significantly decreased after 30 minutes of using RX-1. Back support pressures and contact areas were greater for RX_ABS Lo than for RX-1. No significant difference in back support pressure distributions was observed during 30 minutes in the wheelchairs. The RX_ABS Lo may have utility in improving FHP by increasing cervical angles and improving stability with a back support to the upper thorax, lower thorax, and pelvis during prolonged sitting. PMID- 26581090 TI - Skin Commensal Staphylococci May Act as Reservoir for Fusidic Acid Resistance Genes. AB - We analyzed the occurrence and mechanisms of fusidic acid resistance present in staphylococci isolated from 59 healthy volunteers. The fingers of the volunteers were screened for the presence of staphylococci, and the collected isolates were tested for resistance to fusidic acid. A total of 34 fusidic acid resistant staphylococcal strains (all were coagulase-negative) were isolated from 22 individuals (22/59, 37.3%). Examination of the resistance genes revealed that acquired fusB or fusC was present in Staphylococcus epidermidis, Staphylococcus capitis subsp. urealyticus, Staphylococcus hominis subsp. hominis, Staphylococcus warneri and Staphylococcus haemolyticus. Resistance islands (RIs) carrying fusB were found in S. epidermidis and S. capitis subsp. urealyticus, while staphylococcal chromosome cassette (SCC)-related structures harboring fusC were found in S. hominis subsp. hominis. Genotypic analysis of S. epidermidis and S. hominis subsp. hominis indicated that the fus elements were disseminated in diverse genetic strain backgrounds. The fusC elements in S. hominis subsp. hominis strains were highly homologous to SCCfusC in the epidemic sequence type (ST) 239/SCCmecIII methicillin-resistant S. aureus (MRSA) or the pseudo SCCmec in ST779 MRSA. The presence of acquired fusidic acid resistance genes and their genetic environment in commensal staphylococci suggested that the skin commensal staphylococci may act as reservoir for fusidic acid resistance genes. PMID- 26581091 TI - Pigeons (Columba livia) as Trainable Observers of Pathology and Radiology Breast Cancer Images. AB - Pathologists and radiologists spend years acquiring and refining their medically essential visual skills, so it is of considerable interest to understand how this process actually unfolds and what image features and properties are critical for accurate diagnostic performance. Key insights into human behavioral tasks can often be obtained by using appropriate animal models. We report here that pigeons (Columba livia)-which share many visual system properties with humans-can serve as promising surrogate observers of medical images, a capability not previously documented. The birds proved to have a remarkable ability to distinguish benign from malignant human breast histopathology after training with differential food reinforcement; even more importantly, the pigeons were able to generalize what they had learned when confronted with novel image sets. The birds' histological accuracy, like that of humans, was modestly affected by the presence or absence of color as well as by degrees of image compression, but these impacts could be ameliorated with further training. Turning to radiology, the birds proved to be similarly capable of detecting cancer-relevant microcalcifications on mammogram images. However, when given a different (and for humans quite difficult) task namely, classification of suspicious mammographic densities (masses)-the pigeons proved to be capable only of image memorization and were unable to successfully generalize when shown novel examples. The birds' successes and difficulties suggest that pigeons are well-suited to help us better understand human medical image perception, and may also prove useful in performance assessment and development of medical imaging hardware, image processing, and image analysis tools. PMID- 26581092 TI - Does acute stress disorder predict subsequent posttraumatic stress disorder in pediatric burn survivors? AB - OBJECTIVE: This study examined the prevalence of posttraumatic stress disorder (PTSD) in pediatric burn survivors who had been treated for acute stress disorder (ASD) symptoms during their initial hospitalization and compared them to patients who had been asymptomatic for ASD symptoms. METHOD: Participants were identified from electronic medical records from 1995 to 2008 and data were collected from 2006 to 2008. Participants were primarily matched on total body surface area burned and gender, and as close as possible on age at time of burn and number of years postburn. Pediatric burn survivors completed a semistructured clinical interview, the Missouri Assessment of Genetics Interview for Children-PTSD section, which is based on criteria from the DSM-IV for evaluating lifetime PTSD. RESULTS: There were 183 participants in the study, and from this sample 85 matched pairs were identified. Most were 5 years postburn. The prevalence of PTSD at the time of follow-up was 8.24% (7 of 85) for the ASD group and 4.71% (4 of 85) for the non-ASD comparison group. No significant differences were found between these groups at P value >= .05. A logistic regression analysis was conducted to determine if prior ASD diagnosis, burn size, gender, ethnicity, age at time of study participation, and number of years postburn predicted subsequent PTSD. None of the variables were significant predictors. CONCLUSION: The prevalence of PTSD was similar in children who had ASD symptoms and those without ASD symptoms. The lifetime prevalence of PTSD was lower than reported in other studies. A possible explanation for this finding is that children received timely pharmacotherapy and psychotherapy during their acute hospitalization. PMID- 26581093 TI - Graphene Oxide Regulated Tin Oxide Nanostructures: Engineering Composition, Morphology, Band Structure, and Photocatalytic Properties. AB - A facile, one-step hydrothermal method has been developed to fabricate tin oxide reduced graphene oxide (Sn-RGO) nanocomposites with tunable composition, morphology, and energy band structure by utilizing graphene oxide (GO) as a multifunctional two-dimensional scaffold. By adjusting the GO concentration during synthesis, a variety of tin oxide nanomaterials with diverse composition and morphology are obtained. Simultaneously, the varying of GO concentration can also narrow the bandgap and tune the band edge positions of the Sn-RGO nanocomposites. As a result, the Sn-RGO nanocomposites with controllable composition, morphology, and energy band structure are obtained, which exhibit efficient photoactivities toward methyl orange (MO) degradation under visible light irradiation. It is expected that our work would point to the new possibility of using GO for directing synthesis of semiconductor nanomaterials with tailored structure and physicochemical properties. PMID- 26581095 TI - Building a comprehensive system of services to support adults living with long term mechanical ventilation. PMID- 26581096 TI - Left Renal Cortical Thickness Measured by Ultrasound Can Predict Early Progression of Chronic Kidney Disease. AB - AIMS: The kidney becomes atrophic in advanced chronic kidney disease, and renal size and parenchymal volume correlate with renal function. However, alterations in renal parenchymal volume have not been adequately studied in terms of the renal cortex and medulla. We investigated the relationship between the changes in the renal cortex and medulla and renal function. METHODS: Renal ultrasound (US) parameters including renal length, parenchymal thickness, cortical thickness and medullary thickness were assessed in 176 subjects, who were categorized into 4 groups based on the estimated glomerular filtration rate (ml/min/1.73 m2): group 1, >= 90; group 2, >= 60 but < 90; group 3, >= 30 but < 60; and group 4, < 30. Renal US parameters in both kidneys were compared among the 4 groups. RESULTS: We found stepwise associations in renal length, cortical thickness and parenchymal thickness with decreased renal function. Medullary thickness showed no changes among groups 1-3. Multiple linear regression analysis including sex, age and renal US parameters showed that only renal length was an independent predictor of renal function. When analyzed in groups 1-3, cortical thickness was the strongest associated parameter. Lower cortical left/right ratio (left cortical thickness/right cortical thickness) showed a stepwise association with a decrease in renal function. CONCLUSION: Renal length and cortical thickness measured by US were correlated with renal function. In particular, left cortical thickness could help to detect early changes in renal function. PMID- 26581094 TI - Ectodysplasin/NF-kappaB Promotes Mammary Cell Fate via Wnt/beta-catenin Pathway. AB - Mammary gland development commences during embryogenesis with the establishment of a species typical number of mammary primordia on each flank of the embryo. It is thought that mammary cell fate can only be induced along the mammary line, a narrow region of the ventro-lateral skin running from the axilla to the groin. Ectodysplasin (Eda) is a tumor necrosis factor family ligand that regulates morphogenesis of several ectodermal appendages. We have previously shown that transgenic overexpression of Eda (K14-Eda mice) induces formation of supernumerary mammary placodes along the mammary line. Here, we investigate in more detail the role of Eda and its downstream mediator transcription factor NF kappaB in mammary cell fate specification. We report that K14-Eda mice harbor accessory mammary glands also in the neck region indicating wider epidermal cell plasticity that previously appreciated. We show that even though NF-kappaB is not required for formation of endogenous mammary placodes, it is indispensable for the ability of Eda to induce supernumerary placodes. A genome-wide profiling of Eda-induced genes in mammary buds identified several Wnt pathway components as potential transcriptional targets of Eda. Using an ex vivo culture system, we show that suppression of canonical Wnt signalling leads to a dose-dependent inhibition of supernumerary placodes in K14-Eda tissue explants. PMID- 26581098 TI - Replaying Evolution to Test the Cause of Extinction of One Ecotype in an Experimentally Evolved Population. AB - In a long-term evolution experiment with Escherichia coli, bacteria in one of twelve populations evolved the ability to consume citrate, a previously unexploited resource in a glucose-limited medium. This innovation led to the frequency-dependent coexistence of citrate-consuming (Cit+) and non-consuming (Cit-) ecotypes, with Cit-bacteria persisting on the exogenously supplied glucose as well as other carbon molecules released by the Cit+ bacteria. After more than 10,000 generations of coexistence, however, the Cit-lineage went extinct; cells with the Cit-phenotype dropped to levels below detection, and the Cit-clade could not be detected by molecular assays based on its unique genotype. We hypothesized that this extinction was a deterministic outcome of evolutionary change within the population, specifically the appearance of a more-fit Cit+ ecotype that competitively excluded the Cit-ecotype. We tested this hypothesis by re-evolving the population from a frozen population sample taken within 500 generations of the extinction and from another sample taken several thousand generations earlier, in each case for 500 generations and with 20-fold replication. To our surprise, the Cit-type did not go extinct in any of these replays, and Cit-cells also persisted in a single replicate that was propagated for 2,500 generations. Even more unexpectedly, we showed that the Cit-ecotype could reinvade the Cit+ population after its extinction. Taken together, these results indicate that the extinction of the Cit-ecotype was not a deterministic outcome driven by competitive exclusion by the Cit+ ecotype. The extinction also cannot be explained by demographic stochasticity alone, as the population size of the Cit ecotype should have been many thousands of cells even during the daily transfer events. Instead, we infer that the extinction must have been caused by a rare chance event in which some aspect of the experimental conditions was inadvertently perturbed. PMID- 26581097 TI - Improved Detection of Invasive Pulmonary Aspergillosis Arising during Leukemia Treatment Using a Panel of Host Response Proteins and Fungal Antigens. AB - Invasive pulmonary aspergillosis (IPA) is an opportunistic fungal infection in patients undergoing chemotherapy for hematological malignancy, hematopoietic stem cell transplant, or other forms of immunosuppression. In this group, Aspergillus infections account for the majority of deaths due to mold pathogens. Although early detection is associated with improved outcomes, current diagnostic regimens lack sensitivity and specificity. Patients undergoing chemotherapy, stem cell transplantation and lung transplantation were enrolled in a multi-site prospective observational trial. Proven and probable IPA cases and matched controls were subjected to discovery proteomics analyses using a biofluid analysis platform, fractionating plasma into reproducible protein and peptide pools. From 556 spots identified by 2D gel electrophoresis, 66 differentially expressed post-translationally modified plasma proteins were identified in the leukemic subgroup only. This protein group was rich in complement components, acute-phase reactants and coagulation factors. Low molecular weight peptides corresponding to abundant plasma proteins were identified. A candidate marker panel of host response (9 plasma proteins, 4 peptides), fungal polysaccharides (galactomannan), and cell wall components (beta-D glucan) were selected by statistical filtering for patients with leukemia as a primary underlying diagnosis. Quantitative measurements were developed to qualify the differential expression of the candidate host response proteins using selective reaction monitoring mass spectrometry assays, and then applied to a separate cohort of 57 patients with leukemia. In this verification cohort, a machine learning ensemble based algorithm, generalized pathseeker (GPS) produced a greater case classification accuracy than galactomannan (GM) or host proteins alone. In conclusion, Integration of host response proteins with GM improves the diagnostic detection of probable IPA in patients undergoing treatment for hematologic malignancy. Upon further validation, early detection of probable IPA in leukemia treatment will provide opportunities for earlier interventions and interventional clinical trials. PMID- 26581099 TI - Identification of Key Factors Involved in the Biosorption of Patulin by Inactivated Lactic Acid Bacteria (LAB) Cells. AB - The purpose of this study was to identify the key factors involved in patulin adsorption by heat-inactivated lactic acid bacteria (LAB) cells. For preventing bacterial contamination, a sterilization process was involved in the adsorption process. The effects of various physical, chemical, and enzymatic pre-treatments, simultaneous treatments, and post-treatments on the patulin adsorption performances of six LAB strains were evaluated. The pre-treated cells were characterized by scanning electron microscopy (SEM). Results showed that the removal of patulin by viable cells was mainly based on adsorption or degradation, depending on the specific strain. The adsorption abilities were widely increased by NaOH and esterification pre-treatments, and reduced by trypsin, lipase, iodate, and periodate pre-treatments. Additionally, the adsorption abilities were almost maintained at pH 2.2-4.0, and enhanced significantly at pH 4.0-6.0. The effects of sodium and magnesium ions on the adsorption abilities at pH 4 were slight and strain-specific. A lower proportion of patulin was released from the strain with higher adsorption ability. Analyses revealed that the physical structure of peptidoglycan was not a principal factor. Vicinal OH and carboxyl groups were not involved in patulin adsorption, while alkaline amino acids, thiol and ester compounds were important for patulin adsorption. Additionally, besides hydrophobic interaction, electrostatic interaction also participated in patulin adsorption, which was enhanced with the increase in pH (4.0-6.0). PMID- 26581100 TI - Immunomodulatory Effects of Four Leishmania infantum Potentially Excreted/Secreted Proteins on Human Dendritic Cells Differentiation and Maturation. AB - Leishmania parasites and some molecules they secrete are known to modulate innate immune responses through effects on dendritic cells (DCs) and macrophages. Here, we characterized four Leishmania infantum potentially excreted/secreted recombinant proteins (LipESP) identified in our laboratory: Elongation Factor 1 alpha (LiEF-1alpha), a proteasome regulatory ATPase (LiAAA-ATPase) and two novel proteins with unknown functions, which we termed LiP15 and LiP23, by investigating their effect on in vitro differentiation and maturation of human DCs and on cytokine production by DCs and monocytes. During DCs differentiation, LipESP led to a significant decrease in CD1a. LiP23 and LiEF-1alpha, induced a decrease of HLA-DR and an increase of CD86 surface expression, respectively. During maturation, an up-regulation of HLA-DR and CD80 was found in response to LiP15, LiP23 and LiAAA-ATPase, while an increase of CD40 expression was only observed in response to LiP15. All LipESP induced an over-expression of CD86 with significant differences between proteins. These proteins also induced significant IL-12p70 levels in immature DCs but not in monocytes. The LipESP-induced IL-12p70 production was significantly enhanced by a co-treatment with IFN-gamma in both cell populations. TNF-alpha and IL-10 were induced in DCs and monocytes with higher levels observed for LiP15 and LiAAA-ATPase. However, LPS-induced cytokine production during DC maturation or in monocyte cultures was significantly down regulated by LipESP co-treatment. Our findings suggest that LipESP strongly interfere with DCs differentiation suggesting a possible involvement in mechanisms established by the parasite for its survival. These proteins also induce DCs maturation by up-regulating several costimulatory molecules and by inducing the production of proinflammatory cytokines, which is a prerequisite for T cell activation. However, the reduced ability of LipESP-stimulated DCs and monocytes to respond to lipopolysaccharide (LPS) that can be observed during human leishmaniasis, suggests that under certain circumstances LipESP may play a role in disease progression. PMID- 26581101 TI - The Wide Potential Trophic Niche of the Asiatic Fruit Fly Drosophila suzukii: The Key of Its Invasion Success in Temperate Europe? AB - The Asiatic fruit fly Drosophila suzukii has recently invaded Europe and North and South America, causing severe damage to fruit production systems. Although agronomic host plants of that fly are now well documented, little is known about the suitability of wild and ornamental hosts in its exotic area. In order to study the potential trophic niche of D. suzukii with relation to fruit characteristics, fleshy fruits from 67 plant species were sampled in natural and anthropic ecosystems (forests, hedgerows, grasslands, coastal areas, gardens and urban areas) of the north of France and submitted to experimental infestations. A set of fruit traits (structure, colour, shape, skin texture, diameter and weight, phenology) potentially interacting with oviposition choices and development success of D. suzukii was measured. Almost half of the tested plant species belonging to 17 plant families allowed the full development of D. suzukii. This suggests that the extreme polyphagy of the fly and the very large reservoir of hosts producing fruits all year round ensure temporal continuity in resource availability and contribute to the persistence and the exceptional invasion success of D. suzukii in natural habitats and neighbouring cultivated systems. Nevertheless, this very plastic trophic niche is not systematically beneficial to the fly. Some of the tested plants attractive to D. suzukii gravid females stimulate oviposition but do not allow full larval development. Planted near sensitive crops, these "trap plants" may attract and lure D. suzukii, therefore contributing to the control of the invasive fly. PMID- 26581103 TI - Effects of Prey Presence and Scale on Bobcat Resource Selection during Winter. AB - Factors relevant to resource selection in carnivores may vary across spatial and temporal scales, both in magnitude and rank. Understanding relationships among carnivore occupancy, prey presence, and habitat characteristics, as well as their interactions across multiple scales, is necessary to improve our understanding of resource selection and predict population changes. We used a multi-scale dynamic hierarchical co-occurrence model with camera data to study bobcat and snowshoe hare occupancy in the Upper Peninsula of Michigan during winter 2012-2013. Bobcat presence was influenced at the local scale by snowshoe hare presence, and by road density at the local and larger scale when hare were absent. Hare distribution was related primarily to vegetation cover types, and detectability varied in space and time. Bobcat occupancy dynamics were influenced by different factors depending on the spatial scale considered and the resource availability context. Moreover, considering observed co-occurrence, we suggest that bobcat presence had a greater effect on hare occupancy than hare presence on bobcat occupancy. Our results highlight the importance of studying carnivore distributions in the context of predator-prey relationships and its interactions with environmental covariates at multiple spatial scales. Our approach can be applied to other carnivore species to provide insights beneficial for management and conservation. PMID- 26581102 TI - Metabolic Characterization of the Common Marmoset (Callithrix jacchus). AB - High-resolution metabolomics has created opportunity to integrate nutrition and metabolism into genetic studies to improve understanding of the diverse radiation of primate species. At present, however, there is very little information to help guide experimental design for study of wild populations. In a previous non targeted metabolomics study of common marmosets (Callithrix jacchus), Rhesus macaques, humans, and four non-primate mammalian species, we found that essential amino acids (AA) and other central metabolites had interspecies variation similar to intraspecies variation while non-essential AA, environmental chemicals and catabolic waste products had greater interspecies variation. The present study was designed to test whether 55 plasma metabolites, including both nutritionally essential and non-essential metabolites and catabolic products, differ in concentration in common marmosets and humans. Significant differences were present for more than half of the metabolites analyzed and included AA, vitamins and central lipid metabolites, as well as for catabolic products of AA, nucleotides, energy metabolism and heme. Three environmental chemicals were present at low nanomolar concentrations but did not differ between species. Sex and age differences in marmosets were present for AA and nucleotide metabolism and warrant additional study. Overall, the results suggest that quantitative, targeted metabolomics can provide a useful complement to non-targeted metabolomics for studies of diet and environment interactions in primate evolution. PMID- 26581104 TI - Annual Acoustic Presence of Fin Whale (Balaenoptera physalus) Offshore Eastern Sicily, Central Mediterranean Sea. AB - In recent years, an increasing number of surveys have definitively confirmed the seasonal presence of fin whales (Balaenoptera physalus) in highly productive regions of the Mediterranean Sea. Despite this, very little is yet known about the routes that the species seasonally follows within the Mediterranean basin and, particularly, in the Ionian area. The present study assesses for the first time fin whale acoustic presence offshore Eastern Sicily (Ionian Sea), throughout the processing of about 10 months of continuous acoustic monitoring. The recording of fin whale vocalizations was made possible by the cabled deep-sea multidisciplinary observatory, "NEMO-SN1", deployed 25 km off the Catania harbor at a depth of about 2,100 meters. NEMO-SN1 is an operational node of the European Multidisciplinary Seafloor and water-column Observatory (EMSO) Research Infrastructure. The observatory was equipped with a low-frequency hydrophone (bandwidth: 0.05 Hz-1 kHz, sampling rate: 2 kHz) which continuously acquired data from July 2012 to May 2013. About 7,200 hours of acoustic data were analyzed by means of spectrogram display. Calls with the typical structure and patterns associated to the Mediterranean fin whale population were identified and monitored in the area for the first time. Furthermore, a background noise analysis within the fin whale communication frequency band (17.9-22.5 Hz) was conducted to investigate possible detection-masking effects. The study confirms the hypothesis that fin whales are present in the Ionian Sea throughout all seasons, with peaks in call detection rate during spring and summer months. The analysis also demonstrates that calls were more frequently detected in low background noise conditions. Further analysis will be performed to understand whether observed levels of noise limit the acoustic detection of the fin whales vocalizations, or whether the animals vocalize less in the presence of high background noise. PMID- 26581105 TI - Bone-Eating Worms Spread: Insights into Shallow-Water Osedax (Annelida, Siboglinidae) from Antarctic, Subantarctic, and Mediterranean Waters. AB - Osedax, commonly known as bone-eating worms, are unusual marine annelids belonging to Siboglinidae and represent a remarkable example of evolutionary adaptation to a specialized habitat, namely sunken vertebrate bones. Usually, females of these animals live anchored inside bone owing to a ramified root system from an ovisac, and obtain nutrition via symbiosis with Oceanospirillales gamma-proteobacteria. Since their discovery, 26 Osedax operational taxonomic units (OTUs) have been reported from a wide bathymetric range in the Pacific, the North Atlantic, and the Southern Ocean. Using experimentally deployed and naturally occurring bones we report here the presence of Osedax deceptionensis at very shallow-waters in Deception Island (type locality; Antarctica) and at moderate depths near South Georgia Island (Subantarctic). We present molecular evidence in a new phylogenetic analysis based on five concatenated genes (28S rDNA, Histone H3, 18S rDNA, 16S rDNA, and cytochrome c oxidase I-COI-), using Maximum Likelihood and Bayesian inference, supporting the placement of O. deceptionensis as a separate lineage (Clade VI) although its position still remains uncertain. This phylogenetic analysis includes a new unnamed species (O. 'mediterranea') recently discovered in the shallow-water Mediterranean Sea belonging to Osedax Clade I. A timeframe of the diversification of Osedax inferred using a Bayesian framework further suggests that Osedax diverged from other siboglinids during the Middle Cretaceous (ca. 108 Ma) and also indicates that the most recent common ancestor of Osedax extant lineages dates to the Late Cretaceous (ca. 74.8 Ma) concomitantly with large marine reptiles and teleost fishes. We also provide a phylogenetic framework that assigns newly-sequenced Osedax endosymbionts of O. deceptionensis and O. 'mediterranea' to ribospecies Rs1. Molecular analysis for O. deceptionensis also includes a COI-based haplotype network indicating that individuals from Deception Island and the South Georgia Island (ca. 1,600 km apart) are clearly the same species, confirming the well developed dispersal capabilities reported in other congeneric taxa. In addition, we include a complete description of living features and morphological characters (including scanning and transmission electron microscopy) of O. deceptionensis, a species originally described from a single mature female, and compare it to information available for other congeneric OTUs. PMID- 26581106 TI - Functional Characterization of IPSC-Derived Brain Cells as a Model for X-Linked Adrenoleukodystrophy. AB - X-ALD is an inherited neurodegenerative disorder where mutations in the ABCD1 gene result in clinically diverse phenotypes: the fatal disorder of cerebral childhood ALD (cALD) or a milder disorder of adrenomyeloneuropathy (AMN). The various models used to study the pathobiology of X-ALD disease lack the appropriate presentation for different phenotypes of cALD vs AMN. This study demonstrates that induced pluripotent stem cells (IPSC) derived brain cells astrocytes (Ast), neurons and oligodendrocytes (OLs) express morphological and functional activities of the respective brain cell types. The excessive accumulation of saturated VLCFA, a "hallmark" of X-ALD, was observed in both AMN OLs and cALD OLs with higher levels observed in cALD OLs than AMN OLs. The levels of ELOVL1 (ELOVL Fatty Acid Elongase 1) mRNA parallel the VLCFA load in AMN and cALD OLs. Furthermore, cALD Ast expressed higher levels of proinflammatory cytokines than AMN Ast and control Ast with or without stimulation with lipopolysaccharide. These results document that IPSC-derived Ast and OLs from cALD and AMN fibroblasts mimic the respective biochemical disease phenotypes and thus provide an ideal platform to investigate the mechanism of VLCFA load in cALD OLs and VLCFA-induced inflammatory disease mechanisms of cALD Ast and thus for testing of new therapeutics for AMN and cALD disease of X-ALD. PMID- 26581107 TI - Internet-Based Cognitive Behavioral Therapy for Insomnia (ICBT-i) Improves Comorbid Anxiety and Depression-A Meta-Analysis of Randomized Controlled Trials. AB - As the internet has become popularized in recent years, cognitive behavioral therapy for insomnia (CBT-i) has shifted from a face-to-face approach to delivery via the internet (internet-based CBT-i, ICBT-i). Several studies have investigated the effects of ICBT-i on comorbid anxiety and depression; however, the results remain inconclusive. Thus, a meta-analysis was conducted to determine the effects of ICBT-i on anxiety and depression. Electronic databases, including PubMed, EMBASE, PsycINFO and the Cochrane Library (throughout May 28, 2015), were systematically searched for randomized controlled trials (RCTs) of ICBT-i. Data were extracted from the qualified studies and pooled together. The standardized mean difference (SMD) and 95% confidence interval (95% CI) were calculated to assess the effects of ICBT-i on comorbid anxiety and depression. Nine records that included ten studies were ultimately qualified. The effect sizes (ESs) were 0.35 [-0.46, -0.25] for anxiety and -0.36 [-0.47, -0.26] for depression, which were stable using a between-group or within-group comparison and suggest positive effects of ICBT-i on both comorbid disorders. Although positive results were identified in this meta-analysis, additional high-quality studies with larger sample sizes are needed in the future. PMID- 26581108 TI - Weathering a Dynamic Seascape: Influences of Wind and Rain on a Seabird's Year Round Activity Budgets. AB - How animals respond to varying environmental conditions is fundamental to ecology and is a question that has gained impetus due to mounting evidence indicating negative effects of global change on biodiversity. Behavioural plasticity is one mechanism that enables individuals and species to deal with environmental changes, yet for many taxa information on behavioural parameters and their capacity to change are lacking or restricted to certain periods within the annual cycle. This is particularly true for seabirds where year-round behavioural information is intrinsically challenging to acquire due to their reliance on the marine environment where they are difficult to study. Using data from over 13,000 foraging trips throughout the annual cycle, acquired using new-generation automated VHF technology, we described sex-specific, year-round activity budgets in Cape gannets. Using these data we investigated the role of weather (wind and rain) on foraging activity and time allocated to nest attendance. Foraging activity was clearly influenced by wind speed, wind direction and rainfall during and outside the breeding season. Generally, strong wind conditions throughout the year resulted in relatively short foraging trips. Birds spent longer periods foraging when rainfall was moderate. Nest attendance, which was sex-specific outside of the breeding season, was also influenced by meteorological conditions. Large amounts of rainfall (> 2.5 mm per hour) and strong winds (> 13 m s-1) resulted in gannets spending shorter amounts of time at their nests. We discuss these findings in terms of life history strategies and implications for the use of seabirds as bio-indicators. PMID- 26581110 TI - Nature and Age of Neighbours Matter: Interspecific Associations among Tree Species Exist and Vary across Life Stages in Tropical Forests. AB - Detailed information about interspecific spatial associations among tropical tree species is scarce, and hence the ecological importance of those associations may have been underestimated. However, they can play a role in community assembly and species diversity maintenance. This study investigated the spatial dependence between pairs of species. First, the spatial associations (spatial attraction and spatial repulsion) that arose between species were examined. Second, different sizes of trees were considered in order to evaluate whether the spatial relationships between species are constant or vary during the lifetime of individuals. Third, the consistency of those spatial associations with the species-habitat associations found in previous studies was assessed. Two different tropical ecosystems were investigated: a montane cloud forest and a lowland moist forest. The results showed that spatial associations among species exist, and these vary among life stages and species. The rarity of negative spatial interactions suggested that exclusive competition was not common in the studied forests. On the other hand, positive interactions were common, and the results of this study strongly suggested that habitat associations were not the only cause of spatial attraction among species. If this is true, habitat associations and density dependence are not the only mechanisms that explain species distribution and diversity; other ecological interactions, such as facilitation among species, may also play a role. These spatial associations could be important in the assembly of tropical tree communities and forest succession, and should be taken into account in future studies. PMID- 26581109 TI - Molecular Characterization of the Elaeis guineensis Medium-Chain Fatty Acid Diacylglycerol Acyltransferase DGAT1-1 by Heterologous Expression in Yarrowia lipolytica. AB - Diacylglycerol acyltransferases (DGAT) are involved in the acylation of sn-1,2 diacylglycerol. Palm kernel oil, extracted from Elaeis guineensis (oil palm) seeds, has a high content of medium-chain fatty acids mainly lauric acid (C12:0). A putative E. guineensis diacylglycerol acyltransferase gene (EgDGAT1-1) is expressed at the onset of lauric acid accumulation in the seed endosperm suggesting that it is a determinant of medium-chain triacylglycerol storage. To test this hypothesis, we thoroughly characterized EgDGAT1-1 activity through functional complementation of a Yarrowia lipolytica mutant strain devoid of neutral lipids. EgDGAT1-1 expression is sufficient to restore triacylglycerol accumulation in neosynthesized lipid droplets. A comparative functional study with Arabidopsis thaliana DGAT1 highlighted contrasting substrate specificities when the recombinant yeast was cultured in lauric acid supplemented medium. The EgDGAT1-1 expressing strain preferentially accumulated medium-chain triacylglycerols whereas AtDGAT1 expression induced long-chain triacylglycerol storage in Y. lipolytica. EgDGAT1-1 localized to the endoplasmic reticulum where TAG biosynthesis takes place. Reestablishing neutral lipid accumulation in the Y. lipolytica mutant strain did not induce major reorganization of the yeast microsomal proteome. Overall, our findings demonstrate that EgDGAT1-1 is an endoplasmic reticulum DGAT with preference for medium-chain fatty acid substrates, in line with its physiological role in palm kernel. The characterized EgDGAT1-1 could be used to promote medium-chain triacylglycerol accumulation in microbial-produced oil for industrial chemicals and cosmetics. PMID- 26581111 TI - Safety, tolerability and pharmacokinetics of a novel phosphodiesterase inhibitor, E6005 ointment, in healthy volunteers and in patients with atopic dermatitis. AB - OBJECTIVES: The purpose of the present studies was to assess the safety, tolerability and pharmacokinetics of topical application of a novel phosphodiesterase inhibitor, E6005, in healthy volunteers and in patients with atopic dermatitis (AD). METHODS: In two randomized, investigator-blind, vehicle controlled studies, we evaluated the topical application of E6005 ointment at concentrations ranging from 0.01% to 0.2% in healthy volunteers (Study 001) and in patients with AD (Study 101). RESULTS: Thirty-six subjects were enrolled in Study 001 and 40 in Study 101. Neither skin irritation nor photosensitization was observed with application of E6005 in Study 001. Four subjects receiving E6005 in Study 001 experienced a treatment-emergent adverse event (application site edema, increased alanine aminotransferase or erythema); three of these subjects discontinued the study. Two subjects receiving E6005 in Study 101 experienced an adverse event (gout or enterocolitis); one discontinued the study. Plasma concentrations of E6005 were below the limit of quantification (1 ng/ml) in both studies. CONCLUSION: E6005 ointment exhibited acceptable safety and tolerability. Topical application of E6005 ointment resulted in very low systemic exposure to E6005 in healthy volunteers and in patients with AD. PMID- 26581112 TI - Molecular Dynamics Simulation of Na(+)-Cl(-) Ion-Pair in Water-Methanol Mixtures under Supercritical and Ambient Conditions. AB - Constrained molecular dynamics simulations have been performed to investigate the structure and thermodynamics of Na(+)-Cl(-) ion-pair association in water methanol mixtures under supercritical and ambient conditions in dilute solutions. From the computed potentials of mean force (PMFs) we find that contact ion pairs (CIPs) are more stable than all other associated states of the ion pairs in both ambient and supercritical conditions. Stabilities of CIPs increase with increase in the mole fraction of methanol. In supercritical conditions, major changes in PMFs occur as we go from x(methanol) = 0.00 to x(methanol) = 0.50. The stable solvent shared ion pair (SShIP) which occurs in x(methanol) = 0.00 and 0.25, vanishes when x(methanol) is 0.50 or greater. The stabilities of these ion pairs increase with increasing temperature. Local structures around the ions are studied using the radial distribution functions, density profiles, angular distribution functions, running coordination numbers and excess coordination numbers. Preferential solvation analysis shows that both Na(+) and Cl(-) ions are preferentially solvated by water. From the calculation of enthalpies and entropies, we find that Na(+)-Cl(-) ion-pair association in water-methanol binary mixtures is endothermic and driven by entropy both in ambient as well as under supercritical conditions. PMID- 26581113 TI - Generality of the 18-n Rule: Intermetallic Structural Chemistry Explained through Isolobal Analogies to Transition Metal Complexes. AB - Intermetallic phases exhibit a vast structural diversity in which electron count is known to be one controlling factor. However, chemical bonding theory has yet to establish how electron counts and structure are interrelated for the majority of these compounds. Recently, a simple bonding picture for transition metal (T) main group (E) intermetallics has begun to take shape based on isolobal analogies to molecular T complexes. This bonding picture is summarized in the 18-n rule: each T atom in a T-E intermetallic phase will need 18-n electrons to achieve a closed-shell 18-electron configuration, where n is the number of electron pairs it shares with other T atoms in multicenter interactions isolobal to T-T bonds. In this Article, we illustrate the generality of this rule with a survey over a wide range of T-E phases. First, we illustrate how three structural progressions with changing electron counts can be accounted for, both geometrically and electronically, with the 18-n rule: (1) the transition between the fluorite and complex beta-FeSi2 types for TSi2 phases; (2) the sequence from the marcasite type to the arsenopyrite type and back to the marcasite type for TSb2 compounds; and (3) the evolution from the AuCu3 type to the ZrAl3 and TiAl3 types for TAl3 phases. We then turn to a broader survey of the applicability of the 18-n rule through a study of the following 34 binary structure types: PtHg4, CaF2 (fluorite), Fe3C, CoGa3, Co2Al5, Ru2B3, beta-FeSi2, NiAs, Ni2Al3, Rh4Si5, CrSi2, Ir3Ga5, Mo3Al8, MnP, TiSi2, Ru2Sn3, TiAl3, MoSi2, CoSn, ZrAl3, CsCl, FeSi, AuCu3, ZrSi2, Mn2Hg5, FeS2 (oP6, marcasite), CoAs3 (skutterudite), PdSn2, CoSb2, Ir3Ge7, CuAl2, Re3Ge7, CrP2, and Mg2Ni. Through these analyses, the 18-n rule is established as a framework for interpreting the stability of 341 intermetallic phases and anticipating their properties. PMID- 26581114 TI - Chronology for the Cueva Victoria fossil site (SE Spain): Evidence for Early Pleistocene Afro-Iberian dispersals. AB - Cueva Victoria has provided remains of more than 90 species of fossil vertebrates, including a hominin phalanx, and the only specimens of the African cercopithecid Theropithecus oswaldi in Europe. To constrain the age of the vertebrate remains we used paleomagnetism, vertebrate biostratigraphy and (230)Th/U dating. Normal polarity was identified in the non-fossiliferous lowest and highest stratigraphic units (red clay and capping flowstones) while reverse polarity was found in the intermediate stratigraphic unit (fossiliferous breccia). A lower polarity change occurred during the deposition of the decalcification clay, when the cave was closed and karstification was active. A second polarity change occurred during the capping flowstone formation, when the upper galleries were filled with breccia. The mammal association indicates a post Jaramillo age, which allows us to correlate this upper reversal with the Brunhes Matuyama boundary (0.78 Ma). Consequently, the lower reversal (N-R) is interpreted as the end of the Jaramillo magnetochron (0.99 Ma). These ages bracket the age of the fossiliferous breccia between 0.99 and 0.78 Ma, suggesting that the capping flowstone was formed during the wet Marine Isotopic Stage 19, which includes the Brunhes-Matuyama boundary. Fossil remains of Theropithecus have been only found in situ ~1 m below the B/M boundary, which allows us to place the arrival of Theropithecus to Cueva Victoria at ~0.9-0.85 Ma. The fauna of Cueva Victoria lived during a period of important climatic change, known as the Early-Middle Pleistocene Climatic Transition. The occurrence of the oldest European Acheulean tools at the contemporaneous nearby site of Cueva Negra suggest an African dispersal into SE Iberia through the Strait of Gibraltar during MIS 22, when sea-level was ~100 m below its present position, allowing the passage into Europe of, at least, Theropithecus and Homo bearing Acheulean technology. PMID- 26581115 TI - A single nucleotide TDP-43 mutation within a Taiwanese family: A multifaceted demon. PMID- 26581116 TI - Serum level of microRNA-147 as diagnostic biomarker in human non-small cell lung cancer. AB - Objectives In this study, we intended to examine the gene expression level and the clinical significance of microRNA-147 (miR-147) in cancer tissues and sera of patients with non-small cell lung cancer (NSCLC). Methods Quantitative real-time PCR (qRT-PCR) was used to investigate the expression levels of miR-147 in 32 paired NSCLC tissues and their adjacent normal lung tissues, sera of 122 control and 87 NSCLC patients. The correlation of serum miR-147 expression level with clinicopathological characteristics, and the prognosis of NSCLC patients was statistically evaluated. Results MiR-147 was significantly down-regulated in NSCLC tissues than in paired adjacent normal tissues, and in sera of NSCLC patients than in sera of control patients. In addition, serum miR-147 was markedly down-regulated in advanced NSCLC patients and the patients with lymph node metastasis (LNM). Low serum miR-147 expression level was found to be significantly correlated with tumor, lymph node, metastasis stage, LNM, and tumor size. Statistical analysis showed that patients with low serum miR-147 had much worse overall survival, and low serum miR-147 expression level was an independent prognostic factor for poor prognosis for NSCLC. Conclusion Low serum miR-147 expression level may be a useful biomarker for patients with NSCLC. PMID- 26581117 TI - Living with an implantable cardioverter defibrillator: The patients' experience. AB - OBJECTIVES: To explore the lived experiences of implantable cardioverter defibrillator (ICD) recipients. BACKGROUND: Previous research suggests ICD recipients experience significant psychological distress with a focus on shock anxiety. In response, avoidant behaviors are often used which can lead to reduced quality of life, cardiac fitness and increased risk of arrhythmia. METHODS: A qualitative study using semi-structured interviews with a purposive sample of 18 recipients who had either received or not received an ICD shock was conducted. Data were analyzed using a thematic approach. RESULTS: Three themes with sub themes were defined: (i) physical consequences; (ii) emotional consequences (feeling vulnerable and uncertain; anxiety and depression); and (iii) coping with the ICD (avoidance/restrictive behaviors; acceptance; concealment). CONCLUSION: ICD recipients might be helped by a psycho-social intervention that corrects false beliefs about exercise and offers some simple stress management techniques. Additional elements might include helping recipients to re-evaluate goals and find a valued sense of self which this study found aided ICD acceptance. PMID- 26581118 TI - Apolipoprotein E epsilon4 is positively related to spatial performance but unrelated to hippocampal volume in healthy young adults. AB - The apolipoprotein E (APOE) epsilon4 allele is known to be a major genetic risk factor for Alzheimer's disease (AD). It has been linked to especially episodic memory decline and hippocampal atrophy in both healthy and demented elderly populations. In young adults, epsilon4 carriers have shown better performance in episodic memory compared to non-carriers. Spatial memory, however, has not been thoroughly assessed in relation to APOE in spite of its dependence on the hippocampus. In this study, we assessed the effect of APOE genotype on a variety of spatial and episodic memory tasks as well as hippocampal volume assessed through manual tracing in a sample of young adults (N=123). We also assessed whether potential effects were modulated by sex. The presence of one or more epsilon4 alleles had positive effects on spatial function and memory and object location memory, but no effect on word recognition. Men were superior to women in spatial function and memory but there were no sex differences in the other tasks. In spite of APOE epsilon4 carriers having superior performance in several memory tasks, no difference was found as a function of APOE genotype in hippocampal volume. To our knowledge, this study is the first to show that APOE epsilon4 has a positive effect on spatial ability in young adults. PMID- 26581119 TI - High-throughput profiling for discovery of non-coding RNA biomarkers of lung disease. AB - In respiratory medicine there is a need for clinical biomarkers for diagnosis, prognosis and assessment of response to therapy. Noncoding RNA (ncRNA) is expressed in all human cells; two major classes--long ncRNA and microRNA--are detectable extracellularly in the circulation and other biofluids. Altered ncRNA expression is associated with lung disease; collectively this indicates that ncRNA represents a potential biomarker class. This article presents and compares existing platforms for detection and quantification of ncRNA, specifically hybridization, qRT-PCR and RNA sequencing, and outlines methods for data interpretation and normalization. Each approach has merits and shortcomings, which can affect the choice of method when embarking on a biomarker study. Biomarker properties and pre-analytical considerations for ncRNA profiling are also presented. Since a variety of profiling approaches are available, careful study and experimental design are important. Finally, challenges and goals for reliable, standardized high-throughput ncRNA profiling in biofluids as lung disease biomarkers are reviewed. PMID- 26581120 TI - Graphene Based Waveguide Polarizers: In-Depth Physical Analysis and Relevant Parameters. AB - Optical polarizing devices exploiting graphene embedded in waveguides have been demonstrated in the literature recently and both the TE- and TM-pass behaviors were reported. The determination of the passing polarization is usually attributed to graphene's Fermi level (and, therefore, doping level), with, however, no direct confirmation of this assumption provided. Here we show, through numerical simulation, that rather than graphene's Fermi level, the passing polarization is determined by waveguide parameters, such as the superstrate refractive index and the waveguide's height. The results provide a consistent explanation for experimental results reported in the literature. In addition, we show that with an accurate graphene modeling, a waveguide cannot be switched between TE pass and TM pass via Fermi level tuning. Therefore, the usually overlooked contribution of the waveguide design is shown to be essential for the development of optimized TE- or TM-pass polarizers, which we show to be due to the control it provides on the fraction of the electric field that is tangential to graphene. PMID- 26581121 TI - Antiviral sesquiterpenes from leaves of Nicotiana tabacum. AB - Three unreported sesquiterpenes possessing two new skeletons, tabasesquiterpenes A-C (1-3), together with three known sesquiterpenes (3-6) were isolated from the leaves of Nicotiana tabacum. Their structures were determined mainly by spectroscopic methods, including extensive 1D- and 2D-NMR techniques. Compounds 1 6 were evaluated for their anti-tobacco mosaic virus (anti-TMV) activities. The results showed that compound 2 exhibited high anti-TMV activity with inhibition rate of 35.2%, which were higher than that of positive control (ningnanmycin). The other compounds also showed potential anti-TMV activity with inhibition rates in the range of 20.5-28.6%. PMID- 26581122 TI - Activation of brain serotonergic system by repeated intracerebral administration of 5-hydroxytryptophan (5-HTP) decreases the expression and activity of liver cytochrome P450. AB - Our recent studies suggest that brain serotonergic system may be involved in the neuroendocrine regulation of cytochrome P450 expression. Intracerebral injection of the serotonergic neurotoxin 5,7-dihydroxytryptamine affected serum hormone concentration and increased the expression and activity of the hormone-dependent isoforms CYP1A1/2, CYP2C11 and CYP3A1. Therefore, the aim of the present study was to investigate the effect of stimulation of brain serotonergic system on cytochrome P450 expression in the liver. The serotonin precursor 5 hydroxytryptophan (5-HTP) was injected for 5 days to the lateral ventricles of rat brain. Afterwards, the brain concentrations of serotonin and its metabolite 5 hydroxyindoleacetic acid 5-HIAA, serum hormone levels and liver cytochrome P450 expression and activity were measured. 5-HTP potently increased the concentration of serotonin and its metabolite 5-HIAA in all the brain structures studied including the hypothalamus. The brain concentrations of noradrenaline or dopamine and its metabolites were not changed in that structure. At the same time, a significant decrease in the serum concentration of the growth hormone and an increase in that of thyroxine were observed. In the liver, the activity of CYP1A, CYP2A, CYP2B, CYP2C11 and CYP3A was diminished, which positively correlated with a decrease in the respective CYP protein levels and a reduction in the mRNA levels of CYP1A2, CYP2A2, CYP2C11, CYP3A1 and CYP3A2. The obtained results provide evidence to prove that brain serotonergic system negatively regulates liver cytochrome P450 expression via endocrine system and suggest mechanisms by which this enzyme may be regulated by drugs with a serotonergic profile such as antidepressants. PMID- 26581123 TI - Quantification of adenosine A(1) receptor biased agonism: Implications for drug discovery. AB - Adenosine A1 receptor (A1AR) stimulation is a powerful protective mechanism in cerebral and cardiac ischemia-reperfusion injury. Despite this, therapeutic targeting of the A1AR for the treatment of ischemia-reperfusion injury has been largely unsuccessful, as high concentrations of prototypical A1AR agonists impart significant hemodynamic effects, particularly pronounced bradycardia, atrioventricular block and hypotension. Exploiting the phenomenon of biased agonism to develop ligands that promote A1AR cytoprotection in the absence of adverse hemodynamic effects remains a relatively unexplored, but exciting, approach to overcome current limitations. In native systems, the atypical A1AR agonists VCP746 and capadenoson retain cytoprotective signaling in the absence of bradycardia, a phenomenon suggestive of biased agonism. The current study used pharmacological inhibitors to investigate A1AR mediated cytoprotective signal transduction in a CHO FlpIn cell background, thus identifying candidate pathways for quantitative bias profiling, including cAMP, extracellular signal-regulated kinases 1 and 2 and Akt1/2/3. Subsequently, effects on cell survival and the bias profile of VCP746 and capadenoson were determined and compared to that of the prototypical A1AR agonists, NECA, R-PIA, MeCCPA and CPA. We found that prototypical agonists do not display significant bias for any of the pathways assessed. In contrast, VCP746 and capadenoson show significant bias away from calcium mobilization relative to all pathways tested. These studies demonstrate that quantitative "fingerprinting" of biased agonism within a model system can enable ligands to be clustered by their bias profile, which in turn may be predictive of preferential physiologically relevant in vivo pharmacology. PMID- 26581124 TI - A novel bioaugmentation treatment approach using a confined microbial environment: a case study in a Membrane Bioreactor wastewater treatment plant. AB - A novel bioaugmentation treatment approach, the Small-Bioreactor Platform (SBP) technology, was developed to increase the biological stabilization process in the treatment of wastewater in order to improve wastewater processing effectiveness. The SBP microfiltration membrane provides protection against the natural selection forces that target exogenous bacterial cultures within wastewater. As a result, the exogenous microorganisms culture adapt and proliferate, thus providing a successful bioaugmentation process in wastewater treatment. The new bioaugmentation treatment approach was studied in a full configuration Membrane Bioreactor (MBR) plant treating domestic wastewater. Our results present the potential of this innovative technology to eliminate, or reduce, the intensity of stress events, as well as shortening the recovery time after stress events, consequently elevating the treatment effectiveness. The effective dose of SBP capsules per cubic metre per day of wastewater was achieved during the addition of 3000 SBP capsules (1.25 SBP capsules per cubic metre per day), which provided approximately 4.5 L of high concentration exogenous biomass culture within the SBP capsules internal medium. This study demonstrates an innovative treatment capability which provides an effective bioaugmentation treatment in an MBR domestic wastewater treatment plant. PMID- 26581125 TI - On the Stability and Abundance of Single Walled Carbon Nanotubes. AB - Many nanotechnological applications, using single-walled carbon nanotubes (SWNTs), are only possible with a uniform product. Thus, direct control over the product during chemical vapor deposition (CVD) growth of SWNT is desirable, and much effort has been made towards the ultimate goal of chirality-controlled growth of SWNTs. We have used density functional theory (DFT) to compute the stability of SWNT fragments of all chiralities in the series representing the targeted products for such applications, which we compare to the chiralities of the actual CVD products from all properly analyzed experiments. From this comparison we find that in 84% of the cases the experimental product represents chiralities among the most stable SWNT fragments (within 0.2 eV) from the computations. Our analysis shows that the diameter of the SWNT product is governed by the well-known relation to size of the catalytic nanoparticles, and the specific chirality is normally determined by the product's relative stability, suggesting thermodynamic control at the early stage of product formation. Based on our findings, we discuss the effect of other experimental parameters on the chirality of the product. Furthermore, we highlight the possibility to produce any tube chirality in the context of recent published work on seeded-controlled growth. PMID- 26581126 TI - Development and validation of an LC/MS/MS method for simultaneous determination of shionone and epi-friedelinol in rat plasma for pharmacokinetic study after oral administration of Aster tataricus extract. AB - A rapid and sensitive liquid chromatography tandem mass spectrometry (LC/MS/MS) method was developed and validated using spinasterol as the internal standard (IS) for the simultaneous determination of shionone and epi-friedelinol in rat plasma. Plasma samples were pretreated using liquid-liquid extraction with ethyl ether. Chromatographic separation was achieved on a C18 column (100 * 2.1 mm, 5 MUm) with an isocratic elution consisting of acetonitrile-0.1% formic acid water (75:25, v/v) at a flow rate of 0.30 mL/min. Detection was performed under the selected reaction monitoring scan using an electrospray ionization in the positive ion mode. The mass transitions were as follows: m/z 427.4 -> 95.1 for shionone, m/z 411.4 -> 205.2 for epi-friedelinol and m/z 395.3 -> 105.2 for IS. All calibration curves exhibited good linearity (r > 0.995) over the concentration range for both components. The intra- and inter-day precisions at three QC and lower limit of quantitation levels were both <10.21% in terms of relative standard deviation, and the accuracy ranged from -7.13 to 8.02% in terms of relative error. The extraction recoveries of the compounds ranged from 82.07 to 89.81%. The developed method was successfully applied to the pharmacokinetic study of shionone and epi-friedelinol after oral administration of Aster tataricus extract to rats. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26581127 TI - Anogenital Human Papillomavirus Prevalence is Unaffected by Therapeutic Tumour Necrosis Factor-alpha Inhibition. AB - Patients receiving tumour necrosis factor alpha (TNF-alpha) inhibitors are at increased risk of exacerbation of (myco-)bacterial and some viral infections. However, information on anogenital human papillomavirus (HPV) infection in these patients is sparse or conflicting. In this study 222 patients with psoriasis or inflammatory bowel disease (IBD), who received either anti-TNF-alpha inhibitors or alternatives (purine-, folic acid analogues, phototherapy, fumaric ester, mesalazine) continuously for at least 6 months, were evaluated for the presence of anogenital HPV-induced lesions, mucosal HPV DNA, and serological status of mucosal low-risk HPV6 and high-risk HPV16/HPV18. Hallmarks of anogenital HPV infection were more frequently detected in patients with psoriasis than in those with IBD. HPV-induced lesions, viral DNA, and seroprevalence were not elevated in participants with psoriasis or IBD, who received TNF-alpha inhibitors for a mean duration of 31.4 months (range 6-96 months) compared with recipients of alternative or no treatment. TNF-alpha blockade for a mean period of 31.4 months does not increase detectable anogenital HPV infection or disease. PMID- 26581128 TI - Lack of Impact of Robotic Assisted Laparoscopic Radical Prostatectomy on Intraoperative Levels of Prostate Cancer Circulating Tumor Cells. AB - PURPOSE: While the significance of circulating tumor cells in clinically localized cancer remains controversial, it has been reported that surgical tumor manipulation can increase circulating tumor cells, including during open prostatectomy. To our knowledge it is unknown whether this cell shedding also occurs during minimally invasive prostatectomy, which minimizes tumor palpation and uses earlier vascular control. We tested the impact of robotic assisted laparoscopic radical prostatectomy on intraoperative circulating tumor cell levels. MATERIALS AND METHODS: Circulating tumor cell counts were compared in peripheral blood specimens from 25 patients treated with robotic assisted laparoscopic radical prostatectomy preoperatively vs intraoperatively after prostate excision, in addition to 11 healthy blood donors. Circulating tumor cell detection was performed using EpCAM immunomagnetic enrichment and multiparametric flow cytometry quantification of viable EpCAM positive/prostate specific membrane antigen positive/CD45 negative cells. Intraoperative cell counts and increases were tested in univariable analyses for associations with perioperative variables, histopathology and postoperative progression. RESULTS: Circulating tumor cells were detected in 0% of healthy controls compared to 48% and 52% of prostatectomy cases preoperatively and intraoperatively, respectively (range 1 to 8 cells). There was no difference in the incidence or mean number of circulating tumor cells preoperatively vs intraoperatively. Of the patients 60% had no intraoperative change from preoperative levels. Intraoperative cell increases vs decreases were equally infrequent (each 20%) with no intraoperative increase greater than 1 circulating tumor cell. Intraoperative circulating tumor cell detection was not significantly associated with prostatectomy operative characteristics, histopathology or early postoperative progression at a median 21 month followup. CONCLUSIONS: Robotic assisted laparoscopic radical prostatectomy does not cause significant intraoperative increases in circulating tumor cells in contrast to historical reports of open prostatectomy. These findings may aid urologists in counseling candidates for robotic assisted laparoscopic radical prostatectomy regarding the possibility of intraoperative tumor cell shedding. PMID- 26581129 TI - Taking "the Game" Out of The Match: A Simple Proposal. PMID- 26581130 TI - Looking Ahead: Practicing Radiation Oncology in the Era of ICD-10. PMID- 26581131 TI - Physics: The Use of Magnetic Resonance Imaging for Radiation Therapy is Accelerating in Utility and Novelty. PMID- 26581132 TI - Education and Training Needs in Radiation Oncology in India: Opportunities for Indo-US Collaborations. AB - PURPOSE: To conduct a survey of radiation oncologists in India, to better understand specific educational needs of radiation oncology in India and define areas of collaboration with US institutions. METHODS AND MATERIALS: A 20-question survey was distributed to members of the Association of Indian Radiation Oncologists and the Indian Brachytherapy Society between November 2013 and May 2014. RESULTS: We received a total of 132 responses. Over 50% of the physicians treat more than 200 patients per day, use 2-dimensional or 3-dimensional treatment planning techniques, and approximately 50% use image guided techniques. For education needs, most respondents agreed that further education in intensity modulated radiation therapy, image guided radiation therapy, stereotactic radiation therapy, biostatistics, and research methods for medical residents would be useful areas of collaboration with institutions in the United States. Other areas of collaboration include developing a structured training module for nursing, physics training, and developing a second-opinion clinic for difficult cases with faculty in the United States. CONCLUSION: Various areas of potential collaboration in radiation oncology education were identified through this survey. These include the following: establishing education programs focused on current technology, facilitating exchange programs for trainees in India to the United States, promoting training in research methods, establishing training modules for physicists and oncology nurses, and creating an Indo-US. Tumor Board. It would require collaboration between the Association of Indian Radiation Oncologists and the American Society for Radiation Oncology to develop these educational initiatives. PMID- 26581133 TI - Radiation Oncology Solutions in Tanzania. PMID- 26581134 TI - The Case for Elective International Residency Rotations. PMID- 26581135 TI - Phase 2 Trial of De-intensified Chemoradiation Therapy for Favorable-Risk Human Papillomavirus-Associated Oropharyngeal Squamous Cell Carcinoma. AB - PURPOSE: To perform a prospective, multi-institutional, phase 2 study of a substantial decrease in concurrent chemoradiation therapy (CRT) intensity as primary treatment for favorable-risk, human papillomavirus-associated oropharyngeal squamous cell carcinoma. METHODS AND MATERIALS: The major inclusion criteria were: (1) T0 to T3, N0 to N2c, M0; (2) human papillomavirus or p16 positive; and (3) minimal/remote smoking history. Treatment was limited to 60 Gy intensity modulated radiation therapy with concurrent weekly intravenous cisplatinum (30 mg/m(2)). The primary study endpoint was pathologic complete response (pCR) rate based on required biopsy of the primary site and dissection of pretreatment positive lymph node regions, regardless of radiographic response. Power computations were performed for the null hypothesis that the pCR rate is 87% and n=40, resulting in a type 1 error of 14.2%. Secondary endpoint measures included physician-reported toxicity (Common Toxicity Terminology for Adverse Events, CTCAE), patient-reported symptoms (PRO-CTCAE), and modified barium swallow studies. RESULTS: The study population was 43 patients. The pCR rate was 86% (37 of 43). The incidence of CTCAE grade 3/4 toxicity and PRO-CTCAE severe/very severe symptoms was as follows: mucositis 34%/45%, general pain 5%/48%, nausea 18%/52%, vomiting 5%/34%, dysphagia 39%/55%, and xerostomia 2%/75%. Grade 3/4 hematologic toxicities were 11%. Thirty-nine percent of patients required a feeding tube for a median of 15 weeks (range, 5-22 weeks). There were no significant differences in modified barium swallow studies before and after CRT. CONCLUSIONS: The pCR rate with decreased intensity of therapy with 60 Gy of IMRT and weekly low-dose cisplatinum is very high in favorable-risk oropharyngeal squamous cell carcinoma, with evidence of decreased toxicity compared with standard therapies. ClinicalTrials.gov ID: NCT01530997. PMID- 26581136 TI - Dose De-escalation in Human Papillomavirus-Associated Oropharyngeal Cancer: First Tracks on Powder. PMID- 26581137 TI - Prospective Trial of Stereotactic Body Radiation Therapy for Both Operable and Inoperable T1N0M0 Non-Small Cell Lung Cancer: Japan Clinical Oncology Group Study JCOG0403. AB - PURPOSE: To evaluate, in Japan Clinical Oncology Group study 0403, the safety and efficacy of stereotactic body radiation therapy (SBRT) in patients with T1N0M0 non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: Eligibility criteria included histologically or cytologically proven NSCLC, clinical T1N0M0. Prescribed dose was 48 Gy at the isocenter in 4 fractions. The primary endpoint was the percent (%) 3-year overall survival. The threshold % 3-year survival to be rejected was set at 35% for inoperable patients, whereas the expected % 3-year survival was 80% for operable patients. RESULTS: Between July 2004 and November 2008, 169 patients from 15 institutions were registered. One hundred inoperable and 64 operable patients (total 164) were eligible. Patients' characteristics were 122 male, 47 female; median age 78 years (range, 50-91 years); adenocarcinomas, 90; squamous cell carcinomas, 61; others, 18. Of the 100 inoperable patients, the % 3-year OS was 59.9% (95% confidence interval 49.6% 68.8%). Grade 3 and 4 toxicities were observed in 10 and 2 patients, respectively. No grade 5 toxicity was observed. Of the 64 operable patients, the % 3-year OS was 76.5% (95% confidence interval 64.0%-85.1%). Grade 3 toxicities were observed in 5 patients. No grade 4 and 5 toxicities were observed. CONCLUSIONS: Stereotactic body radiation therapy for stage I NSCLC is effective, with low incidences of severe toxicity. This treatment can be considered a standard treatment for inoperable stage I NSCLC. This treatment is promising as an alternative to surgery for operable stage I NSCLC. PMID- 26581138 TI - Phase 1 Dose Escalation Study of Accelerated Radiation Therapy With Concurrent Chemotherapy for Locally Advanced Lung Cancer. AB - PURPOSE: To determine the maximum tolerated dose of radiation therapy (RT) given in an accelerated fashion with concurrent chemotherapy using intensity modulated RT. METHODS AND MATERIALS: Patients with locally advanced lung cancer (non-small cell and small cell) with good performance status and minimal weight loss received concurrent cisplatin and etoposide with RT. Intensity modulated RT with daily image guidance was used to facilitate esophageal avoidance and delivered using 6 fractions per week (twice daily on Fridays with a 6-hour interval). The dose was escalated from 58 Gy to a planned maximum dose of 74 Gy in 4 Gy increments in a standard 3 + 3 trial design. Dose-limiting toxicity (DLT) was defined as acute grade 3-5 nonhematologic toxicity attributed to RT. RESULTS: A total of 24 patients were enrolled, filling all dose cohorts, all completing RT and chemotherapy as prescribed. Dose-limiting toxicity occurred in 1 patient at 58 Gy (grade 3 esophagitis) and 1 patient at 70 Gy (grade 3 esophageal fistula). Both patients with DLTs had large tumors (12 cm and 10 cm, respectively) adjacent to the esophagus. Three additional patients were enrolled at both dose cohorts without further DLT. In the final 74-Gy cohort, no DLTs were observed (0 of 6). CONCLUSIONS: Dose escalation and acceleration to 74 Gy with intensity modulated RT and concurrent chemotherapy was tolerable, with a low rate of grade >=3 acute esophageal reactions. PMID- 26581139 TI - Prospective, Multicenter Validation Study of Magnetic Resonance Volumetry for Response Assessment After Preoperative Chemoradiation in Rectal Cancer: Can the Results in the Literature be Reproduced? AB - PURPOSE: To review the available literature on tumor size/volume measurements on magnetic resonance imaging for response assessment after chemoradiotherapy, and validate these cut-offs in an independent multicenter patient cohort. METHODS AND MATERIALS: The study included 2 parts. (1) Review of the literature: articles were included that assessed the accuracy of tumor size/volume measurements on magnetic resonance imaging for tumor response assessment. Size/volume cut-offs were extracted; (2) Multicenter validation: extracted cut-offs from the literature were tested in a multicenter cohort (n=146). Accuracies were calculated and compared with reported results from the literature. RESULTS: The review included 14 articles, in which 3 different measurement methods were assessed: (1) tumor length; (2) 3-dimensonial tumor size; and (3) whole volume. Study outcomes consisted of (1) complete response (ypT0) versus residual tumor; (2) tumor regression grade 1 to 2 versus 3 to 5; and (3) T-downstaging (ypT=2008, non-adenocarcinoma histology, and LN+. Use of CRT improved OS among the entire cohort on MVA (HR 0.76, CI 0.601-0.962; P=.022). On MVA, CRT improved OS in patients with LN+ as their sole Peter's criteria (HR 0.58, CI 0.413-0.814; P=.002). Chemoradiation therapy did not improve OS in patients with only positive margins (P=.73), only parametrial invasion (P=.95), or any combination of these 2 factors without LN+ (P=.63). CONCLUSIONS: The use of adjuvant CRT after hysterectomy improves OS in patients with high-risk cervical cancer compared with EBRT alone, but this benefit seems to be restricted to patients with LN+. The benefits of adjuvant CRT over EBRT alone in patients with parametrial invasion and/or positive margins (without nodal involvement) are unknown. PMID- 26581142 TI - Survival Outcomes of Whole-Pelvic Versus Prostate-Only Radiation Therapy for High Risk Prostate Cancer Patients With Use of the National Cancer Data Base. AB - PURPOSE/OBJECTIVES: The addition of whole pelvic (WP) compared with prostate-only (PO) radiation therapy (RT) for clinically node-negative prostate cancer remains controversial. The purpose of our study was to evaluate the survival benefit of adding WPRT versus PO-RT for high-risk, node-negative prostate cancer, using the National Cancer Data Base (NCDB). METHODS AND MATERIALS: Patients with high-risk prostate cancer treated from 2004 to 2006, with available data for RT volume, coded as prostate and pelvis (WPRT) or prostate alone (PO-RT) were included. Multivariate analysis (MVA) and propensity-score matched analysis (PSM) were performed. Recursive partitioning analysis (RPA) based on overall survival (OS) using Gleason score (GS), T stage, and pretreatment prostate-specific antigen (PSA) was also conducted. RESULTS: A total of 14,817 patients were included: 7606 (51.3%) received WPRT, and 7211 (48.7%) received PO-RT. The median follow-up time was 81 months (range, 2-122 months). Under MVA, the addition of WPRT for high risk patients had no OS benefit compared with PO-RT (HR 1.05; P=.100). On subset analysis, patients receiving dose-escalated RT also did not benefit from WPRT (HR 1.01; P=.908). PSM confirmed no survival benefit with the addition of WPRT for high-risk patients (HR 1.05; P=.141). In addition, RPA was unable to demonstrate a survival benefit of WPRT for any subset. Other prognostic factors for inferior OS under MVA included older age (HR 1.25; P<.001), increasing comorbidity scores (HR 1.46; P<.001), higher T stage (HR 1.17; P<.001), PSA (HR 1.81; P<.001), and GS (HR 1.29; P<.001), and decreasing median county household income (HR 1.15; P=.011). Factors improving OS included the addition of androgen deprivation therapy (HR 0.92; P=.033), combination external beam RT plus brachytherapy boost (HR 0.71; P<.001), and treatment at an academic/research institution (HR 0.84; P=.002). CONCLUSION: In the largest reported analysis of WPRT for patients with high-risk prostate cancer treated in the dose-escalated era, the addition of WPRT demonstrated no survival advantage compared with PO-RT. PMID- 26581143 TI - Radical Prostatectomy Versus Radiation and Androgen Deprivation Therapy for Clinically Localized Prostate Cancer: How Good Is the Evidence? AB - PURPOSE: The optimal treatment of clinically localized prostate cancer is controversial. Most studies focus on biochemical (PSA) failure when comparing radical prostatectomy (RP) with radiation therapy (RT), but this endpoint has not been validated as predictive of overall survival (OS) or cause-specific survival (CSS). We analyzed the available literature to determine whether reliable conclusions could be made concerning the effectiveness of RP compared with RT with or without androgen deprivation therapy (ADT), assuming current treatment standards. METHODS: Articles published between February 29, 2004, and March 1, 2015, that compared OS and CSS after RP or RT with or without ADT were included. Because the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) system emphasis is on randomized controlled clinical trials, a reliability score (RS) was explored to further understand the issues associated with the study quality of observational studies, including appropriateness of treatment, source of data, clinical characteristics, and comorbidity. Lower RS values indicated lower reliability. RESULTS: Fourteen studies were identified, and 13 were completely evaluable. Thirteen of the 14 studies (93%) were observational studies with low-quality evidence. The median RS was 12 (range, 5 18); the median difference in 10-year OS and CSS favored RP over RT: 10% and 4%, respectively. In studies with a RS <=12 (average RS 9) the 10-year OS and CSS median differences were 17% and 6%, respectively. For studies with a RS >12 (average RS 15.5), the 10-year OS and CSS median differences were 5.5% and 1%, respectively. Thus, we observed an association between low RS and a higher percentage difference in OS and CSS. CONCLUSIONS: Reliable evidence that RP provides a superior CSS to RT with ADT is lacking. The most reliable studies suggest that the differences in 10-year CSS between RP and RT are small, possibly <1%. PMID- 26581145 TI - Total Skin Electron Beam for Primary Cutaneous T-cell Lymphoma. AB - PURPOSE: Recent trials with low-dose total skin electron beam (TSEB) therapy demonstrated encouraging results for treating primary cutaneous T-cell lymphoma (PCTCL). In this study, we assessed the feasibility of different radiation doses and estimated survival rates of different pathologic entities and stages. METHODS AND MATERIALS: We retrospectively identified 45 patients with PCTCL undergoing TSEB therapy between 2000 and 2015. Clinical characteristics, treatment outcomes, and toxicity were assessed. RESULTS: A total of 49 courses of TSEB therapy were administered to the 45 patients. There were 26 pathologically confirmed cases of mycosis fungoides (MF) lymphoma, 10 cases of Sezary syndrome (SS), and 9 non MF/SS PCTCL patients. In the MF patients, the overall response rate (ORR) was 92% (50% complete remission [CR]), 70% ORR in SS patients (50% CR), and 89% ORR in non-MF/SS patients (78% CR). The ORR for MF/SS patients treated with conventional dose (30-36 Gy) regimens was 92% (63% CR) and 75% (25% CR) for low-dose (<30-Gy) regimens (P=.09). In MF patients, the overall survival (OS) was 77 months with conventional dose regimens versus 14 months with low-dose regimens (P=.553). In SS patients, the median OS was 48 versus 16 months (P=.219), respectively. Median event-free survival (EFS) for MF in conventional dose patients versus low-dose patients was 15 versus 8 months, respectively (P=.264) and 19 versus 3 months for SS patients (P=.457). Low-dose regimens had shorter treatment time (P=.009) and lower grade 2 adverse events (P=.043). A second TSEB course was administered in 4 MF patients with 100% ORR. There is a possible prognostic impact of supplemental/boost radiation (P<.001); adjuvant treatment (P<.001) and radiation tolerability (P=.021) were detected. CONCLUSIONS: TSEB therapy is an efficacious treatment modality in the treatment of several forms of cutaneous T-cell lymphoma. There is a nonsignificant trend to higher and longer clinical benefit for MF and SS patients receiving conventional dose. Low-dose TSEB regimens are well tolerated and achieve short-term palliation. PMID- 26581144 TI - Local Control for Intermediate-Risk Rhabdomyosarcoma: Results From D9803 According to Histology, Group, Site, and Size: A Report From the Children's Oncology Group. AB - PURPOSE: To determine local control according to clinical variables for patients with intermediate-risk rhabdomyosarcoma (RMS) treated on Children's Oncology Group protocol D9803. PATIENTS AND METHODS: Of 702 patients enrolled, we analyzed 423 patients with central pathology-confirmed group III embryonal (n=280) or alveolar (group III, n=102; group I-II, n=41) RMS. Median age was 5 years. Patients received 42 weeks of VAC (vincristine, dactinomycin, cyclophosphamide) or VAC alternating with VTC (T = topotecan). Local therapy with 50.4 Gy radiation therapy with or without delayed primary excision began at week 12 for group III patients. Patients with group I/II alveolar RMS received 36-41.4 Gy. Local failure (LF) was defined as local progression as a first event with or without concurrent regional or distant failure. RESULTS: At a median follow-up of 6.6 years, patients with clinical group I/II alveolar RMS had a 5-year event-free survival rate of 69% and LF of 10%. Among patients with group III RMS, 5-year event-free survival and LF rates were 70% and 19%, respectively. Local failure rates did not differ by histology, nodal status, or primary site, though there was a trend for increased LF for retroperitoneal (RP) tumors (P=.12). Tumors >=5 cm were more likely to fail locally than tumors <5 cm (25% vs 10%, P=.0004). Almost all (98%) RP tumors were >=5 cm, with no difference in LF by site when the analysis was restricted to tumors >=5 cm (P=.86). CONCLUSION: Local control was excellent for clinical group I/II alveolar RMS. Local failure constituted 63% of initial events in clinical group III patients and did not vary by histology or nodal status. The trend for higher LF in RP tumors was related to tumor size. There has been no clear change in local control over RMS studies, including IRS III and IRS-IV. Novel approaches are warranted for larger tumors (>=5 cm). PMID- 26581146 TI - In the Modern Treatment Era, Is Breast Conservation Equivalent to Mastectomy in Women Younger Than 40 Years of Age? A Multi-Institution Study. AB - PURPOSE: Mastectomy is often recommended for women <=40 years of age with breast cancer, as young women were under-represented in the landmark trials comparing breast conservation therapy (BCT) to mastectomy. We hypothesized that, in the modern treatment era, BCT and mastectomy result in equivalent local control rates in young women. METHODS AND MATERIALS: Breast cancer cases arising between 1975 and 2013 in women <=40 years old were collected from the tumor registries of 2 large healthcare systems in Utah. Kaplan-Meier estimates and Cox proportional hazards models were used to analyze freedom from locoregional recurrence (FFLR), overall survival (OS), and relapse-free survival (RFS). RESULTS: This analysis identified 853 BCT candidates. A comparison of BCT to mastectomy after 2000 showed FFLR, RFS, and OS were all similar. Rate for FFLR at 10 years was 94.9% versus 92.1% for BCT and mastectomy, respectively (P=.57). For women whose cancer was diagnosed after 2000, who received BCT, FFLR and RFS rates were improved compared to those whose cancer was diagnosed prior to 2000 (P<.05), whereas OS (P=.46) rates were similar. Among those who underwent mastectomy, FFLR, OS, and RFS were significantly improved (P<.05) with diagnosis after 2000. CONCLUSIONS: FFLR rates for young women, <=40 years of age, have significantly improved for BCT and mastectomy over time. If patients were treated after 2000, BCT appears to be safe and equivalent to mastectomy at 10 years in terms of FFLR, OS, and RFS. PMID- 26581147 TI - MicroRNA-Related DNA Repair/Cell-Cycle Genes Independently Associated With Relapse After Radiation Therapy for Early Breast Cancer. AB - PURPOSE: Local recurrence and distant failure after adjuvant radiation therapy for breast cancer remain significant clinical problems, incompletely predicted by conventional clinicopathologic markers. We had previously identified microRNA-139 5p and microRNA-1274a as key regulators of breast cancer radiation response in vitro. The purpose of this study was to investigate standard clinicopathologic markers of local recurrence in a contemporary series and to establish whether putative target genes of microRNAs involved in DNA repair and cell cycle control could better predict radiation therapy response in vivo. METHODS AND MATERIALS: With institutional ethics board approval, local recurrence was measured in a contemporary, prospectively collected series of 458 patients treated with radiation therapy after breast-conserving surgery. Additionally, independent publicly available mRNA/microRNA microarray expression datasets totaling >1000 early-stage breast cancer patients, treated with adjuvant radiation therapy, with >10 years of follow-up, were analyzed. The expression of putative microRNA target biomarkers--TOP2A, POLQ, RAD54L, SKP2, PLK2, and RAG1--were correlated with standard clinicopathologic variables using 2-sided nonparametric tests, and to local/distant relapse and survival using Kaplan-Meier and Cox regression analysis. RESULTS: We found a low rate of isolated local recurrence (1.95%) in our modern series, and that few clinicopathologic variables (such as lymphovascular invasion) were significantly predictive. In multiple independent datasets (n>1000), however, high expression of RAD54L, TOP2A, POLQ, and SKP2 significantly correlated with local recurrence, survival, or both in univariate and multivariate analyses (P<.001). Low RAG1 expression significantly correlated with local recurrence (multivariate, P=.008). Additionally, RAD54L, SKP2, and PLK2 may be predictive, being prognostic in radiation therapy-treated patients but not in untreated matched control individuals (n=107; P<.05). CONCLUSIONS: Biomarkers of DNA repair and cell cycle control can identify patients at high risk of treatment failure in those receiving radiation therapy for early breast cancer in independent cohorts. These should be further investigated prospectively, especially TOP2A and SKP2, for which targeted therapies are available. PMID- 26581148 TI - Radiation Sensitivity and Radiation Necrosis in the Short Telomere Syndromes. PMID- 26581149 TI - Machine Learning Approaches for Predicting Radiation Therapy Outcomes: A Clinician's Perspective. AB - Radiation oncology has always been deeply rooted in modeling, from the early days of isoeffect curves to the contemporary Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) initiative. In recent years, medical modeling for both prognostic and therapeutic purposes has exploded thanks to increasing availability of electronic data and genomics. One promising direction that medical modeling is moving toward is adopting the same machine learning methods used by companies such as Google and Facebook to combat disease. Broadly defined, machine learning is a branch of computer science that deals with making predictions from complex data through statistical models. These methods serve to uncover patterns in data and are actively used in areas such as speech recognition, handwriting recognition, face recognition, "spam" filtering (junk email), and targeted advertising. Although multiple radiation oncology research groups have shown the value of applied machine learning (ML), clinical adoption has been slow due to the high barrier to understanding these complex models by clinicians. Here, we present a review of the use of ML to predict radiation therapy outcomes from the clinician's point of view with the hope that it lowers the "barrier to entry" for those without formal training in ML. We begin by describing 7 principles that one should consider when evaluating (or creating) an ML model in radiation oncology. We next introduce 3 popular ML methods--logistic regression (LR), support vector machine (SVM), and artificial neural network (ANN)--and critique 3 seminal papers in the context of these principles. Although current studies are in exploratory stages, the overall methodology has progressively matured, and the field is ready for larger-scale further investigation. PMID- 26581150 TI - Automatic Substitute Computed Tomography Generation and Contouring for Magnetic Resonance Imaging (MRI)-Alone External Beam Radiation Therapy From Standard MRI Sequences. AB - PURPOSE: To validate automatic substitute computed tomography CT (sCT) scans generated from standard T2-weighted (T2w) magnetic resonance (MR) pelvic scans for MR-Sim prostate treatment planning. PATIENTS AND METHODS: A Siemens Skyra 3T MR imaging (MRI) scanner with laser bridge, flat couch, and pelvic coil mounts was used to scan 39 patients scheduled for external beam radiation therapy for localized prostate cancer. For sCT generation a whole-pelvis MRI scan (1.6 mm 3 dimensional isotropic T2w SPACE [Sampling Perfection with Application optimized Contrasts using different flip angle Evolution] sequence) was acquired. Three additional small field of view scans were acquired: T2w, T2*w, and T1w flip angle 80 degrees for gold fiducials. Patients received a routine planning CT scan. Manual contouring of the prostate, rectum, bladder, and bones was performed independently on the CT and MR scans. Three experienced observers contoured each organ on MRI, allowing interobserver quantification. To generate a training database, each patient CT scan was coregistered to their whole-pelvis T2w using symmetric rigid registration and structure-guided deformable registration. A new multi-atlas local weighted voting method was used to generate automatic contours and sCT results. RESULTS: The mean error in Hounsfield units between the sCT and corresponding patient CT (within the body contour) was 0.6 +/- 14.7 (mean +/- 1 SD), with a mean absolute error of 40.5 +/- 8.2 Hounsfield units. Automatic contouring results were very close to the expert interobserver level (Dice similarity coefficient): prostate 0.80 +/- 0.08, bladder 0.86 +/- 0.12, rectum 0.84 +/- 0.06, bones 0.91 +/- 0.03, and body 1.00 +/- 0.003. The change in monitor units between the sCT-based plans relative to the gold standard CT plan for the same dose prescription was found to be 0.3% +/- 0.8%. The 3-dimensional gamma pass rate was 1.00 +/- 0.00 (2 mm/2%). CONCLUSIONS: The MR-Sim setup and automatic sCT generation methods using standard MR sequences generates realistic contours and electron densities for prostate cancer radiation therapy dose planning and digitally reconstructed radiograph generation. PMID- 26581151 TI - Assessing the Dosimetric Accuracy of Magnetic Resonance-Generated Synthetic CT Images for Focal Brain VMAT Radiation Therapy. AB - PURPOSE: The purpose of this study was to assess the dosimetric accuracy of synthetic CT (MRCT) volumes generated from magnetic resonance imaging (MRI) data for focal brain radiation therapy. METHODS AND MATERIALS: A study was conducted in 12 patients with gliomas who underwent both MR and CT imaging as part of their simulation for external beam treatment planning. MRCT volumes were generated from MR images. Patients' clinical treatment planning directives were used to create 12 individual volumetric modulated arc therapy (VMAT) plans, which were then optimized 10 times on each of their respective CT and MRCT-derived electron density maps. Dose metrics derived from optimization criteria, as well as monitor units and gamma analyses, were evaluated to quantify differences between the imaging modalities. RESULTS: Mean differences between planning target volume (PTV) doses on MRCT and CT plans across all patients were 0.0% (range: -0.1 to 0.2%) for D(95%); 0.0% (-0.7 to 0.6%) for D(5%); and -0.2% (-1.0 to 0.2%) for D(max). MRCT plans showed no significant changes in monitor units (-0.4%) compared to CT plans. Organs at risk (OARs) had average D(max) differences of 0.0 Gy (-2.2 to 1.9 Gy) over 85 structures across all 12 patients, with no significant differences when calculated doses approached planning constraints. CONCLUSIONS: Focal brain VMAT plans optimized on MRCT images show excellent dosimetric agreement with standard CT-optimized plans. PTVs show equivalent coverage, and OARs do not show any overdose. These results indicate that MRI derived synthetic CT volumes can be used to support treatment planning of most patients treated for intracranial lesions. PMID- 26581152 TI - In Regard to Bauman et al. PMID- 26581153 TI - In Reply to Kishan et al. PMID- 26581154 TI - In Regard to Dilmanian et al. PMID- 26581155 TI - In Reply to Sahadevan. PMID- 26581156 TI - A Resident's Perspective on Global Health Rotations in Radiation Oncology. PMID- 26581157 TI - In Regard to Onimaru et al. PMID- 26581158 TI - Commentary: SPG7 is an essential and conserved component of the mitochondrial permeability transition pore. PMID- 26581159 TI - Early Outcomes With HeartWare HVAD as Bridge to Transplant in Children: A Single Institution Experience. AB - The HeartWare HVAD has been used as a bridge to cardiac transplantation in the pediatric population. We describe outcomes following HeartWare HVAD implantation at a single center. A retrospective chart review was performed of all HeartWare HVAD implants performed at our institution between May 2013 and March 2015. Eight children between the ages of 9 and 17 years underwent HVAD implantation as a bridge to transplant (N = 7 cardiomyopathy, N = 1 complex single ventricle). There was one operative death in the complex single ventricle patient. Seven patients (87%) were successfully bridged to transplant. Median time of support was 24.5 days (range, 6-91 days). All transplanted patients are alive and well at a median follow-up of 448 days. Our results demonstrated that mechanical support with HeartWare HVAD is feasible in patients of varying sizes (from older children to adolescents). PMID- 26581160 TI - Increased Valency of Conserved-mosaic Vaccines Enhances the Breadth and Depth of Epitope Recognition. AB - The biggest roadblock in development of effective vaccines against human immunodeficiency virus type 1 (HIV-1) is the virus genetic diversity. For T-cell vaccine, this can be tackled by focusing the vaccine-elicited T-cells on the highly functionally conserved regions of HIV-1 proteins, mutations in which typically cause a replicative fitness loss, and by computing multivalent mosaic proteins, which maximize the coverage of potential 9-mer T-cell epitopes of the input viral sequences. Our first conserved region vaccines HIVconsv employed clade alternating consensus sequences and showed promise in the initial clinical trials in terms of magnitude and breadth of elicited CD8(+) T-cells. Here, monitoring T-cells restricted by HLA-A*02:01 in transgenic mice, we assessed whether or not the tHIVconsv design (HIVconsv with a tissue plasminogen activator leader sequence) benefits from combining with a complementing conserved mosaic immunogen tHIVcmo, and compared the bivalent immunization to that with trivalent conserved mosaic vaccines. A hierarchy of tHIVconsv <= tHIVconsv+tHIVcmo < tCmo1+tCmo2+tCmo3 vaccinations for induction of CD8(+) T-cell responses was observed in terms of recognition of tested peptide variants. Thus, our HLA A*02:01-restricted epitope data concur with previously published mouse and macaque observations and suggest that even conserved region vaccines benefit from oligovalent mosaic design. PMID- 26581161 TI - SET1A Cooperates With CUDR to Promote Liver Cancer Growth and Hepatocyte-like Stem Cell Malignant Transformation Epigenetically. AB - Long noncoding RNA CUDR plays an important role during tumorigenesis. Herein, we demonstrate that SET1A cooperates with CUDR to accelerate hepatocarcinogenesis and promote malignant transformation of hepatocyte-like stem cells. Mechanistically, CUDR enhances the phosphorylation of RB1, C-myc expression, and the interplay between the SET1A and pRB1. Notably, CUDR acts as a sponge cushion that shows a link between SET1A and pRB1, producing a activated pRB1-SET1A complex. On the other hand, the pRB1-SET1A complex may carry methyls(me) to occupy the position of H3K4, resulting in specific tri-methylation of forth lysine of histone H3 (H3K4me3). Thereby, the H3K4me3 loads on the TRF2 promoter region which causes the TRF2 overexpression. Ultimately, the excessive TRF2 binds to telomere repeat DNA, prolonging the telomere length. These findings provide the first demonstration that SET1A cooperates with CUDR to play a positive potential role during hepatocarcinogenesis and hepatocyte-like stem cells' malignant transformation epigenetically. PMID- 26581162 TI - Potent and Targeted Activation of Latent HIV-1 Using the CRISPR/dCas9 Activator Complex. AB - HIV-1 provirus integration results in a persistent latently infected reservoir that is recalcitrant to combined antiretroviral therapy (cART) with lifelong treatment being the only option. The "shock and kill" strategy aims to eradicate latent HIV by reactivating proviral gene expression in the context of cART treatment. Gene-specific transcriptional activation can be achieved using the RNA guided CRISPR-Cas9 system comprising single guide RNAs (sgRNAs) with a nuclease deficient Cas9 mutant (dCas9) fused to the VP64 transactivation domain (dCas9 VP64). We engineered this system to target 23 sites within the long terminal repeat promoter of HIV-1 and identified a "hotspot" for activation within the viral enhancer sequence. Activating sgRNAs transcriptionally modulated the latent proviral genome across multiple different in vitro latency cell models including T cells comprising a clonally integrated mCherry-IRES-Tat (LChIT) latency system. We detected consistent and effective activation of latent virus mediated by activator sgRNAs, whereas latency reversal agents produced variable activation responses. Transcriptomic analysis revealed dCas9-VP64/sgRNAs to be highly specific, while the well-characterized chemical activator TNFalpha induced widespread gene dysregulation. CRISPR-mediated gene activation represents a novel system which provides enhanced efficiency and specificity in a targeted latency reactivation strategy and represents a promising approach to a "functional cure" of HIV/AIDS. PMID- 26581163 TI - A Recombinant Bispecific CD20*CD95 Antibody With Superior Activity Against Normal and Malignant B-cells. AB - Monoclonal antibodies directed to the B-cell-specific CD20-antigen are successfully used for the treatment of lymphomas and autoimmune diseases. Here, we compare the anti-B-cell activity of three different antibodies directed to CD20: (i) a chimeric, monospecific antibody, (ii) an Fc-optimized variant thereof, and (iii) a bispecific CD20*CD95-antibody in a newly developed recombinant format, termed Fabsc. The bispecific antibody specifically triggers the CD95 death receptor on malignant, as well as activated, normal B-cells. We found that the capability of this antibody to suppress the growth of malignant B cells in vitro and in vivo and to specifically deplete normal, activated B-cells from peripheral blood mononuclear cell (PBMC) cultures was superior to that of the Fc-optimized monospecific antibody. This antibody in turn was more effective than its nonoptimized variant. Moreover, the bispecific antibody was the only reagent capable of significantly suppressing antibody production in vitro. Our findings imply that the bispecific CD20*CD95-antibody might become a new, prototypical reagent for the treatment of B-cell-mediated autoimmune disease. PMID- 26581164 TI - A Cross-Sectional Study of Pesticide Use and Knowledge of Smallholder Potato Farmers in Uganda. AB - In response to increased pest and disease problems, potato farmers use pesticides, which could raise environmental and health concerns. This study sought to promote proper and safe pesticide-handling practices by providing data needed to guide pesticide regulation policy and training for extension staff and farmers. A household survey was conducted in three major potato-growing agroecological zones of Uganda. Two hundred and four potato farmers were interviewed about the type and source of pesticides they use in potato cultivation, the frequency of applications, the use of protective clothing, and cases of pesticide poisoning. The types of pesticides used in potato were fungicides (72%), insecticides (62%), and herbicides (3%). Overall, use of personal protective equipment was low, that is, gumboots (73%), gloves (7%), face masks (16%), and long sleeve shirts (42%). Forty-three percent of farmers who applied pesticides reported having experienced skin itching, 25% skin burning sensation, 43% coughing, 60% a runny nose, 27% teary eyes, and 42% dizziness. An IPM approach involving only moderately to slightly hazardous pesticides when pest and disease incidence has reached economic injury levels and by considering all safety measures during application and storage would be environmentally recommendable and result in reduced health risks. PMID- 26581165 TI - IVIG therapy in pemphigus vulgaris has corticosteroid-sparing and immunomodulatory effects. AB - BACKGROUND: Intravenous immunoglobulin (IVIG) is a biological agent composed of polyclonal antibodies prepared from a large cohort of human plasma pools. IVIG is increasingly used for the treatment of various antibody-mediated diseases, including pemphigus vulgaris (PV). OBJECTIVE: The aim of the study was to evaluate the benefit and safety profiles of high dose IVIG therapy in PV patients determined by clinical remission, corticosteroid-sparing and immunomodulatory effects, and adverse events at 12 months' follow up. METHODS: Ten PV patients underwent 3-8 monthly cycles of IVIG therapy at a dose of 2 g/kg per cycle. The pemphigus disease area index (PDAI) score, direct immunofluorescence (DIF), indirect immunofluorescence (IIF), and corticosteroid dosage were evaluated before IVIG therapy, after each cycle, and at 6 and 12 months' follow up. RESULTS: The baseline PDAI score was 75.70 +/- 21.0 and baseline prednisone dosage was 201.60 +/- 71.7 mg/day. The PDAI score reduction of 98% was achieved at 12 months' follow up and a corticosteroid dose reduction of 90% corresponded to clinical improvement. The decrease in both values was statistically significant (P = 0.002, respectively). At 12 months' follow up, seven patients were shown to be negative on IIF, of whom three proved to be negative on DIF. Adverse events were mild and transient and did not require the cessation of IVIG therapy. CONCLUSION: IVIG induced long-term clinical remission, while displaying a corticocorticosteroid-sparing effect and evoking a long-standing immunomodulatory effect in PV patients. The safety profile of IVIG therapy was assessed as good. PMID- 26581167 TI - High susceptibility and low resistance allele frequency of Chrysodeixis includens (Lepidoptera: Noctuidae) field populations to Cry1Ac in Brazil. AB - BACKGROUND: The soybean looper (SBL), Chrysodeixis includens (Walker), is one of the most important soybean pests in Brazil. MON 87701 * MON 89788 soybean expressing Cry1Ac has been recently deployed in Brazil, providing high levels of control against the primary lepidopteran pests. To support insect resistance management (IRM) programmes, the baseline susceptibility of SBL to Cry1Ac was assessed, and the resistance allele frequency was estimated on the basis of an F2 screen. RESULTS: The toxicity (LC50 ) of Cry1Ac ranged from 0.39 to 2.01 ug mL( 1) diet among all SBL field populations collected from crop seasons 2008/09 to 2012/13, which indicated approximately fivefold variation. Cry1Ac diagnostic concentrations of 5.6 and 18 ug mL(-1) diet were established for monitoring purposes, and no shift in mortality was observed. A total of 626 F2 family lines derived from SBL collected from locations across Brazil during crop season 2014/15 were screened for the presence of Cry1Ac resistance alleles. None of the 626 families survived on MON 87701 * MON 89788 soybean leaf tissue (joint frequency 0.0004). CONCLUSIONS: SBL showed high susceptibility and low resistance allele frequency to Cry1Ac across the main soybean-producing regions in Brazil. These findings meet important criteria for effective IRM strategy. (c) 2015 Society of Chemical Industry. PMID- 26581166 TI - Linker histone H1.2 establishes chromatin compaction and gene silencing through recognition of H3K27me3. AB - Linker histone H1 is a protein component of chromatin and has been linked to higher-order chromatin compaction and global gene silencing. However, a growing body of evidence suggests that H1 plays a gene-specific role, regulating a relatively small number of genes. Here we show that H1.2, one of the H1 subtypes, is overexpressed in cancer cells and contributes to gene silencing. H1.2 gets recruited to distinct chromatin regions in a manner dependent on EZH2-mediated H3K27me3, and inhibits transcription of multiple growth suppressive genes via modulation of chromatin architecture. The C-terminal tail of H1.2 is critical for the observed effects, because mutations of three H1.2-specific amino acids in this domain abrogate the ability of H1.2 to bind H3K27me3 nucleosomes and inactivate target genes. Collectively, these results provide a molecular explanation for H1.2 functions in the regulation of chromatin folding and indicate that H3K27me3 is a key mechanism governing the recruitment and activity of H1.2 at target loci. PMID- 26581168 TI - Continuous succinic acid production by Actinobacillus succinogenes on xylose enriched hydrolysate. AB - BACKGROUND: Bio-manufacturing of high-value chemicals in parallel to renewable biofuels has the potential to dramatically improve the overall economic landscape of integrated lignocellulosic biorefineries. However, this will require the generation of carbohydrate streams from lignocellulose in a form suitable for efficient microbial conversion and downstream processing appropriate to the desired end use, making overall process development, along with selection of appropriate target molecules, crucial to the integrated biorefinery. Succinic acid (SA), a high-value target molecule, can be biologically produced from sugars and has the potential to serve as a platform chemical for various chemical and polymer applications. However, the feasibility of microbial SA production at industrially relevant productivities and yields from lignocellulosic biorefinery streams has not yet been reported. RESULTS: Actinobacillus succinogenes 130Z was immobilised in a custom continuous fermentation setup to produce SA on the xylose enriched fraction of a non-detoxified, xylose-rich corn stover hydrolysate stream produced from deacetylation and dilute acid pretreatment. Effective biofilm attachment, which serves as a natural cell retention strategy to increase cell densities, productivities and resistance to toxicity, was accomplished by means of a novel agitator fitting. A maximum SA titre, yield and productivity of 39.6 g L(-1), 0.78 g g(-1) and 1.77 g L(-1) h(-1) were achieved, respectively. Steady states were obtained at dilution rates of 0.02, 0.03, 0.04, and 0.05 h(-1) and the stirred biofilm reactor was stable over prolonged periods of operation with a combined fermentation time of 1550 h. Furthermore, it was found that a gradual increase in the dilution rate was required to facilitate adaptation of the culture to the hydrolysate, suggesting a strong evolutionary response to the toxic compounds in the hydrolysate. Moreover, the two primary suspected fermentation inhibitors, furfural and HMF, were metabolised during fermentation with the concentration of each remaining at zero across all steady states. CONCLUSIONS: The results demonstrate that immobilised A. succinogenes has the potential for effective conversion of an industrially relevant, biomass-derived feed stream to succinic acid. Furthermore, due to the attractive yields, productivities and titres achieved in this study, the process has the potential to serve as a means for value-added chemical manufacturing in the integrated biorefinery. PMID- 26581171 TI - Exploring preferred amino acid mutations in cancer genes: Applications to identify potential drug targets. AB - Somatic mutations developed with missense, silent, insertions and deletions have varying effects on the resulting protein and are one of the important reasons for cancer development. In this study, we have systematically analysed the effect of these mutations at protein level in 41 different cancer types from COSMIC database on different perspectives: (i) Preference of residues at the mutant positions, (ii) probability of substitutions, (iii) influence of neighbouring residues in driver and passenger mutations, (iv) distribution of driver and passenger mutations around hotspot site in five typical genes and (v) distribution of silent and missense substitutions. We observed that R->H substitution is dominant in drivers followed by R->Q and R->C whereas E->K has the highest preference in passenger mutations. A set of 17 mutations including R >Y, W->A and V->R are specific to driver mutations and 31 preferred substitutions are observed only in passenger mutations. These frequencies of driver mutations vary across different cancer types and are selective to specific tissues. Further, driver missense mutations are mainly surrounded with silent driver mutations whereas the passenger missense mutations are surrounded with silent passenger mutations. This study reveals the variation of mutations at protein level in different cancer types and their preferences in cancer genes and provides new insights for understanding cancer mutations and drug development. PMID- 26581169 TI - Cellular miR-130b inhibits replication of porcine reproductive and respiratory syndrome virus in vitro and in vivo. AB - MicroRNAs (miRNAs) can impact viral infections by binding to sequences with partial complementarity on viral RNA transcripts, usually resulting in the repression of virus replication. In the present study, we identified a potential binding site for miR-130 in the 5' untranslated region (bps 155-162) of the porcine reproductive and respiratory syndrome virus (PRRSV) genome. We found that the delivery of multiple miR-130 family mimics, especially miR-130b, resulted in inhibition of PRRSV replication in vitro. miR-130 was effective in inhibiting the replication of multiple type 2 PRRSV strains, but not against vSHE, a classical type 1 strain. miR-130 over-expression did not induce IFN-alpha or TNF-alpha expression in either uninfected or PRRSV-infected porcine alveolar macrophages. Results from luciferase reporter assays indicated that miR-130 directly targeted the PRRSV 5' UTR. Intranasal inoculation of piglets with miR-130b exhibited antiviral activity in vivo and partially protected piglets from an otherwise lethal challenge with HP-PRRSV strain vJX143. Overall, these results demonstrate the importance of the miR-130 family in modulating PRRSV replication and also provide a scientific basis for using cellular miRNAs in anti-PRRSV therapies. PMID- 26581172 TI - Ribonuclease 5 coordinates signals for the regulation of intraocular pressure and inhibits neural apoptosis as a novel multi-functional anti-glaucomatous strategy. AB - Glaucoma is a vision-threatening disorder characterized by progressive death of retinal ganglion cells (RGCs), although little is known about therapeutic milestones. Due to its complex and multifactorial pathogenesis, multipronged therapeutic approach is needed. Angiogenin (ANG), now called ribonuclease (RNase) 5, has been previously known as angiogenic factor and more recently its biologic activity is extended to promoting cell survival via its ribonucleolytic activity. Here, we revealed the defect of ANG in human glaucomatous trabecular meshwork (TM) cells and identified novel multiple functions of ANG as an anti-glaucomatous strategy. ANG was highly expressed in normal eyes and normal TM cells compared to glaucomatous TM cells. ANG induced intraocular pressure (IOP) lowering in rat models of both normal and elevated IOP, and as a possible mechanism, activated Akt-mediated signals for nitric oxide (NO) production, an important regulator of IOP in glaucomatous TM cell. Moreover, we demonstrated ANG-induced production of matrix metalloproteinase (MMP)-1 and -3 and rho-kinase inhibition for TM remodeling. For anti-glaucomatous defense optimization, ANG not only elicited immune-modulative pathways via indolamine 2,3-dioxygenase (IDO) activation in TM cells and suppression of Jurkat T cells, but also rescued neural stem cells (NSCs) from apoptosis induced by glaucomatous stress. These results demonstrate that novel multi-functional effects of ANG may have benefits against glaucoma in ocular tissues. PMID- 26581173 TI - Sampling and analyzing alveolar exhaled breath condensate in mechanically ventilated patients: a feasibility study. AB - Recent studies in spontaneously breathing subjects indicate the possibility of obtaining the alveolar fraction of exhaled breath condensate (aEBC). In critically ill mechanically ventilated patients, in whom microbial colonization of the upper airways is constant, collection of aEBC could considerably add to the ability of monitoring alveolar inflammation. We designed this study to test the feasibility of collecting aEBC in mechanically ventilated critically ill patients through a dedicated apparatus, i.e. a CO2 valve combined with a condenser placed in the expiratory limb of the ventilator circuit. We also aimed to assess the adequacy of the samples obtained by measuring different markers of oxidative stress and inflammation. We enrolled 40 mechanically ventilated patients, 20 with and 20 without acute respiratory distress syndrome (ARDS). Measurements of respiratory mechanics, gas exchange and hemodynamics were obtained with a standard ventilator circuit after 30 min of aEBC collection and after inserting the dedicated collecting apparatus. Data showed that intrinsic positive end-expiratory pressure, peak and plateau pressure, static compliance and airway resistance (Raw) were similar before and after adding the collecting apparatus in both ARDS and controls. Similarly, gas exchange and hemodynamic variables did not change and 30 min collection provided a median aEBC volume of 2.100 and 2.300 ml for ARDS and controls, respectively. aEBC pH showed a trend toward a slight reduction in the ARDS group of patients, as opposed to controls (7.83 (7.62-8.03) versus 7.98 (7.87-8.12), respectively, p = 0.055)). H2O2 was higher in patients with ARDS, compared to controls (0.09 (0.06-0.12) MUM versus 0.03 (0.01-0.09) MUM, p = 0.043), while no difference was found in proteins content, 8-isoprostane, 4-hydroxy-2-nonhenal. In conclusion, we demonstrate, in patients receiving controlled mechanical ventilation, that aEBC collection is feasible without detrimental effects on ventilator functioning, respiratory mechanics and gas exchange. In addition, we show that the sample obtained is appropriate for compounds analysis. PMID- 26581174 TI - Optical diagnostic systems for assessing head and neck lesions. AB - Novel optical-based diagnostic systems are promising technologies that can be used in the clinic providing the clinician with an adjunct to histopathological assessment and facilitating rapid diagnosis for patients. Aided by the use of differing wavelengths of light, these systems are capable of detecting changes within tissues and provide immediate results. We reviewed the most common optical biopsy systems to detect oral and head and neck lesions and discussed their clinical applications. PMID- 26581175 TI - Exotic stable cesium polynitrides at high pressure. AB - New polynitrides containing metastable forms of nitrogen are actively investigated as potential high-energy-density materials. Using a structure search method based on the CALYPSO methodology, we investigated the stable stoichiometries and structures of cesium polynitrides at high pressures. Along with the CsN3, we identified five new stoichiometric compounds (Cs3N, Cs2N, CsN, CsN2, and CsN5) with interesting structures that may be experimentally synthesizable at modest pressures (i.e., less than 50 GPa). Nitrogen species in the predicted structures have various structural forms ranging from single atom (N) to highly endothermic molecules (N2, N3, N4, N5, N6) and chains (Ninfinity). Polymeric chains of nitrogen were found in the high-pressure C2/c phase of CsN2. This structure contains a substantially high content of single N-N bonds that exceeds the previously known nitrogen chains in pure forms, and also exhibit metastability at ambient conditions. We also identified a very interesting CsN crystal that contains novel N4(4-) anion. To our best knowledge, this is the first time a charged N4 species being reported. Results of the present study suggest that it is possible to obtain energetic polynitrogens in main-group nitrides under high pressure. PMID- 26581176 TI - The self as capital in the narrative economy: how biographical testimonies move activism in the Global South. AB - This article analyses and theorises the practice of biographical storytelling of HIV-positive AIDS activists in South Africa. Combining research in illness narratives, studies of emotions in social activism and analysis of global health institutions in Africa, I explore how biographical self-narrations are deployed to facilitate access to resources and knowledge and thus acquire material and symbolic value. I illustrate my argument through the analysis of the case of an AIDS activist who became a professional biographical storyteller. Based on the analysis which I claim to represent wider dynamics in human-rights-based health activism in the Global South, I propose the concept of narrative economies by which I mean the set of exchange relationships within which biographical self narrations circulate and produce social value for individuals and organisations. PMID- 26581177 TI - Two-dimensional membrane as elastic shell with proof on the folds revealed by three-dimensional atomic mapping. AB - The great application potential for two-dimensional (2D) membranes (MoS2, WSe2, graphene and so on) aroused much effort to understand their fundamental mechanical properties. The out-of-plane bending rigidity is the key factor that controls the membrane morphology under external fields. Herein we provide an easy method to reconstruct the 3D structures of the folded edges of these 2D membranes on the atomic scale, using high-resolution (S)TEM images. After quantitative comparison with continuum mechanics shell model, it is verified that the bending behaviour of the studied 2D materials can be well explained by the linear elastic shell model. And the bending rigidities can thus be derived by fitting with our experimental results. Recall almost only theoretical approaches can access the bending properties of these 2D membranes before, now a new experimental method to measure the bending rigidity of such flexible and atomic thick 2D membranes is proposed. PMID- 26581178 TI - An Increase of Plasma Advanced Oxidation Protein Products Levels Is Associated with Cardiovascular Risk in Incident Peritoneal Dialysis Patients: A Pilot Study. AB - Advanced oxidation protein products (AOPPs) are considered as markers and even mediators of the proinflammatory effect of oxidative stress in uremia. We hypothesized that an increase of oxidative stress associated with peritoneal dialysis (PD), estimated by the variation of plasma AOPPs over time, might be associated with cardiovascular (CV) risk and overall prognosis. In 48 PD patients, blood samples were collected on two occasions: the first one in the first six months after starting PD therapy and the second one, one year after. The plasma AOPPs level variation over the first year on PD was significantly associated with CV antecedents and also with CV prognosis. In those patients in whom the AOPPs levels increased more than 50% above the baseline value, a significant association with past and future CV disease was confirmed. These patients had 4.7 times greater risk of suffering later CV disease than those with a smaller increase, even after adjusting for previous CV history. Our data suggest that the increase of AOPPs plasma level over the first year on PD is conditioned by CV antecedents but also independently predicts CV prognosis. AOPPs plasma levels seem to represent the CV status of PD patients with sufficient sensitivity to identify those with a clearly sustained higher CV risk. PMID- 26581179 TI - A novel fluorescence assay for inorganic pyrophosphatase based on modulated aggregation of graphene quantum dots. AB - A simple and highly sensitive fluorometric method has been developed for inorganic pyrophosphatase (PPase) activity detection based on the disaggregation and aggregation of graphene quantum dots (GQDs). Copper ions can trigger the severe aggregation of GQDs with rich carboxyl groups, which results in effective fluorescence quenching. While, with the addition of pyrophosphate (PPi), the quenched fluorescence is effectively recovered owing to the strong interaction between PPi and Cu(2+). Furthermore, under the catalytic hydrolysis of PPase, the complex of PPi-Cu(2+)-PPi is rapidly disassembled, and the fluorescence is re quenched. This method is highly sensitive and selective for PPase detection, with a linear correlation between the fluorescence intensity and the PPase concentration in the range from 1 to 200 mU mL(-1) with a detection limit down to 1 mU mL(-1) (S/N = 3). Additionally, the inhibition effect of NaF on the PPase activity is also studied. Thus, the proposed method may hold a potential application in the diagnosis of PPase-related diseases and screening of PPase inhibitors, to evaluate the function and inhibition of PPase in biological systems. PMID- 26581181 TI - Developing a Research Agenda to Optimize Diagnostic Imaging in the Emergency Department: An Executive Summary of the 2015 Academic Emergency Medicine Consensus Conference. AB - The 2015 Academic Emergency Medicine (AEM) consensus conference, "Diagnostic Imaging in the Emergency Department: A Research Agenda to Optimize Utilization," was held on May 12, 2015, with the goal of developing a high-priority research agenda on which to base future research. The specific aims of the conference were to: 1) understand the current state of evidence regarding emergency department (ED) diagnostic imaging utilization and identify key opportunities, limitations, and gaps in knowledge; 2) develop a consensus-driven research agenda emphasizing priorities and opportunities for research in ED diagnostic imaging; and 3) explore specific funding mechanisms available to facilitate research in ED diagnostic imaging. Over a 2-year period, the executive committee and other experts in the field convened regularly to identify specific areas in need of future research. Six content areas within emergency diagnostic imaging were identified prior to the conference and served as the breakout groups on which consensus was achieved: clinical decision rules; use of administrative data; patient-centered outcomes research; training, education, and competency; knowledge translation and barriers to imaging optimization; and comparative effectiveness research in alternatives to traditional computed tomography use. The executive committee invited key stakeholders to assist with planning and to participate in the consensus conference to generate a multidisciplinary agenda. There were 164 individuals involved in the conference spanning various specialties, including emergency medicine (EM), radiology, surgery, medical physics, and the decision sciences. This issue of AEM is dedicated to the proceedings of the 16th annual AEM consensus conference as well as original research related to emergency diagnostic imaging. PMID- 26581180 TI - Mutant cohesin affects RNA polymerase II regulation in Cornelia de Lange syndrome. AB - In addition to its role in sister chromatid cohesion, genome stability and integrity, the cohesin complex is involved in gene transcription. Mutations in core cohesin subunits SMC1A, SMC3 and RAD21, or their regulators NIPBL and HDAC8, cause Cornelia de Lange syndrome (CdLS). Recent evidence reveals that gene expression dysregulation could be the underlying mechanism for CdLS. These findings raise intriguing questions regarding the potential role of cohesin mediated transcriptional control and pathogenesis. Here, we identified numerous dysregulated genes occupied by cohesin by combining the transcriptome of CdLS cell lines carrying mutations in SMC1A gene and ChIP-Seq data. Genome-wide analyses show that genes changing in expression are enriched for cohesin-binding. In addition, our results indicate that mutant cohesin impairs both RNA polymerase II (Pol II) transcription initiation at promoters and elongation in the gene body. These findings highlight the pivotal role of cohesin in transcriptional regulation and provide an explanation for the typical gene dysregulation observed in CdLS patients. PMID- 26581182 TI - Ethical, legal, and societal issues and recommendations for controlled and uncontrolled DCD. AB - This report deals with organ retrieval procedures in both controlled and uncontrolled DCD, looking at the ethical, legal, and psychosocial aspects during the different phases of the process. A recently published report by the UK Donation Ethics Committee (UKDEC) has served as an important reference document to outline the steps in the controlled DCD patient-donor pathway (Academy of Medical Royal Colleges. UK Donation Ethics Committee. An ethical framework for controlled donation after circulatory death. December 2011). For uncontrolled DCD, the UKDEC pathway description was adapted. At the 6th International Conference in Organ Donation held in Paris in 2013, an established expert European Working Group reviewed the UKDEC reports, which were then considered along with the available published literature. Along this pathway, the crucial ethical, legal, and psychosocial aspects have been flagged, and relevant recommendations have been formulated based on a consensus of the working group. PMID- 26581183 TI - Exome Sequencing and Clot Lysis Experiments Demonstrate the R458C Mutation of the Alpha Chain of Fibrinogen to be Associated with Impaired Fibrinolysis in a Family with Thrombophilia. AB - AIM: We report the study of a familial rare disease with recurrent venous thromboembolic events that remained undiagnosed for many years using standard coagulation and hemostasis techniques. METHODS: Exome sequencing was performed in three familial cases with venous thromboembolic disease and one familial control using NimbleGen exome array. Clot lysis experiments were performed to analyze the reasons of the altered fibrinolytic activity caused by the mutation found. RESULTS: We found a mutation that consists of a R458C substitution on the fibrinogen alpha chain (FGA) gene confirmed in 13 new familial subjects that causes a rare subtype of dysfibrinogenemia characterized by venous thromboembolic events. The mutation was already reported to be associated with a fibrinogen variant called fibrinogen Bordeaux. Clot-lysis experiments showed a decreased and slower fibrinolytic activity in carriers of this mutation as compared to normal subjects, thus demonstrating an impaired fibrinolysis of fibrinogen Bordeaux. CONCLUSIONS: The exome sequencing and clot-lysis experiments might be powerful tools to diagnose idiopathic thrombophilias after an unsuccessful set of biochemical laboratory tests. Fibrinogen Bordeaux is associated with impaired fibrinolysis in this family with idiopathic thrombophilia. PMID- 26581184 TI - Prediction of Molecular Interaction between Platelet Glycoprotein Ibalpha and von Willebrand Factor using Molecular Dynamics Simulations. AB - AIM: The molecular mechanism of the unique interaction between platelet membrane glycoprotein Ibalpha (GPIbalpha) and von Willebrand Factor (VWF), necessary for platelet adhesion under high shear stress, is yet to be clarified. METHODS: The molecular dynamics simulation using NAMD (Nanoscale Molecular Dynamics) package with the CHARMM 22 (Chemistry at Harvard Macromolecular Mechanics) force field were used to predict dynamic structural changes occurring in the binding site of A1 domain of VWF and N terminus domain of GPIbalpha under water soluble condition. RESULTS: The mean distance between the mass center of A1 domain of VWF and GPIbalpha in the stable form was predicted as 27.3 A. The potential of mean force between the A1 domain of VWF and GPIbalpha were calculated in conditions of various distances of the mass center between them. All the calculated values were fitted to the Morse potential energy function curve. The maximum adhesive force between A1 domain of VWF and GPIbalpha was predicted as 62.3 pN by differentiating the potential of mean force with respect to the molecular distance. CONCLUSIONS: The molecular dynamics simulation is useful for predicting the dynamic structure changes of protein bonds involved in platelet adhesion and for predicting the adhesive forces generated between their interactions. PMID- 26581185 TI - Double-Chambered Right Ventricle with Ventricular Septal Defect and Subaortic Membrane- Three-Dimensional Echocardiographic Evaluation. AB - Double-chambered right ventricle (DCRV) is a rare congenital anomaly in which the right ventricle is divided into two compartments with varying pressures due to an anomalous muscle bundle. Here, we describe a case of an adolescent male with DCRV with associated ventricular septal defect and subaortic membrane. Two-dimensional and three-dimensional transthoracic echocardiography with color flow clearly outlined all the three cardiac anomalies as well as their relationship with each other. The diagnosis was confirmed by cardiac catheterization. The patient underwent successful surgical resection of the anomalous muscle bundle along with repair of the associated anomalies. PMID- 26581186 TI - FK506 regulates pigmentation by maturing the melanosome and facilitating their transfer to keratinocytes. AB - Despite the clinical ability of topical tacrolimus (FK506) to effectively promote repigmentation in vitiligo, the underlying mechanism through which FK506 regulates melanogenesis was previously unclear. We found that FK506 treatment increased the melanin contents (especially that of eumelanin) in both melanocytes and melanoma cells. This treatment did not affect the transcription levels of tyrosinase, suggesting that FK506 increases melanin synthesis by regulating cellular levels of tyrosinase. Interestingly, FK506 promoted melanosome maturation by increasing melanosomal pH (a marker of melanosome maturation), thereby enhancing the stability of melanosome-localized tyrosinase. In addition, FK506 enhanced UVB-mediated melanosome secretion, the uptake of melanosomes by HaCaT cells, and the transfer of melanosomes to keratinocytes co-cultured with melanocytes. Together, these findings suggest that FK506 contributes to melanin synthesis by regulating the maturation of melanosomes and their transfer to keratinocytes. This offers a novel regulatory mechanism through which FK506 and UVB can have a combined effect on melanogenesis. PMID- 26581187 TI - Accuracy of Hysteroscopic Endomyometrial Biopsy in Diagnosis of Adenomyosis. AB - OBJECTIVES: To investigate the diagnostic accuracy of endomyometrial biopsy obtained via office hysteroscopy for the diagnosis of adenomyosis. STUDY DESIGN: Cross-sectional study. SETTING: Cairo University Teaching Hospital, Cairo, Egypt. PATIENTS: A total of 404 premenopausal women with symptoms clinically suggestive of having adenomyosis. INTERVENTIONS: All patients were subjected to 2 dimensional transvaginal sonography (TVS) in-office hysteroscopy examination with endomyometrial biopsy. Patients who subsequently underwent hysterectomy were included in the final analysis. MAIN MEASUREMENTS AND RESULTS: Accuracy of diagnostic modalities was represented using the terms sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy. A total of 292 patients were eligible for final analysis. Of these, 162 (55.47%) were diagnosed with adenomyosis based on hysterectomy specimens. TVS had a high sensitivity (83.95%) and a moderate specificity (60%). In contrast, endomyometrial biopsy was more specific (78.46%) than sensitive (54.32%). Hysteroscopic appearance of the endometrial cavity had low sensitivity (40.74%) and specificity (44.62%). Adding endomyometrial biopsy to TVS improved specificity (89.23%). CONCLUSION: Endomyometrial biopsy obtained via office hysteroscopy can diagnose adenomyosis with a high specificity and is recommended after TVS. PMID- 26581188 TI - Risk of fetal loss associated with invasive testing following combined first trimester screening for Down syndrome: a national cohort of 147,987 singleton pregnancies. AB - OBJECTIVE: To assess prospectively the risk of fetal loss associated with chorionic villus sampling (CVS) and amniocentesis (AC) following combined first trimester screening (cFTS) for Down syndrome. METHODS: This was a nationwide population-based study (Danish Fetal Medicine Database, 2008-2010) including 147,987 women with singleton pregnancy who underwent cFTS. Propensity score stratification was used to assess the risk of fetal loss with and without invasive testing. Analyses were performed between 3 and 21 days after cFTS for CVS and between 28 and 42 days after cFTS for AC. Results are reported as average risk differences with 95% CIs. RESULTS: The risks of miscarriage and stillbirth were not higher in women exposed to CVS or AC compared with unexposed women, independent of the analysis time-point. The average effect of CVS on risk of miscarriage was -0.08% (95% CI, -0.64; 0.47) at 3 days and -0.21% (95% CI, -0.58; 0.15) at 21 days after cFTS, while the effect on risk of stillbirth was -0.18% (95% CI, -0.50; 0.13) at 3 days and -0.27% (95% CI, -0.58; 0.04) at 21 days after cFTS. Regarding the effect of AC on risk of miscarriage, the analysis at 28 days after cFTS showed an average effect of 0.56% (95% CI, -0.21; 1.33), while the effect on risk of stillbirth was 0.09% (95% CI, -0.39; 0.58) at 42 days after cFTS. CONCLUSION: Neither CVS nor AC was associated with increased risk of miscarriage or stillbirth. These findings indicate that the procedure-related risk of CVS and AC is very low. PMID- 26581189 TI - A Motion Simulator Ride Associated With Headache and Subdural Hematoma: First Case Report. AB - We report the first case report of symptomatic bilateral subdural hematomas (SDH) associated with riding a centrifugal motion simulator ride. A previously healthy 55-year-old male developed new onset daily headaches 1 week after going on the ride that were due to symptomatic bilateral SDH requiring operative intervention with a full recovery. There was no history of other trauma or other systemic or intracranial abnormality to account for the development of the SDH. We review the headaches and other clinical features associated with chronic SDH. Twelve cases of roller coaster headaches due to SDH associated with riding roller coasters have been reported. The pathophysiology is reviewed, which we believe is the same mechanism that may be responsible in this case. Although it is possible that this neurovascular injury is truly rare, it is also possible that this injury is underreported as patients and physicians may not make the association or physicians have not reported additional cases. The risk of this injury likely increases with age, as the size of the subdural space increases, and may support the maxim that "roller coasters and simulators are for kids." PMID- 26581190 TI - The Witch Weed Is Able To Detect a Wide Range of Chemicals from Plants through Its Sensitive and Specific Receptors: The Strigolactone Story Updated. AB - Striga is a very noxious weed because of the molecular versatility of its protein receptors to strigolactone and its derivatives. Striga in fact parasitizes host plants and this triggers its seeds production. At molecular level, this is attained by strigolactone detection by a set of receptors with broad specificity and high sensitivity. PMID- 26581191 TI - Comparison of registered and published outcomes in randomized controlled trials: a systematic review. AB - BACKGROUND: Clinical trial registries can improve the validity of trial results by facilitating comparisons between prospectively planned and reported outcomes. Previous reports on the frequency of planned and reported outcome inconsistencies have reported widely discrepant results. It is unknown whether these discrepancies are due to differences between the included trials, or to methodological differences between studies. We aimed to systematically review the prevalence and nature of discrepancies between registered and published outcomes among clinical trials. METHODS: We searched MEDLINE via PubMed, EMBASE, and CINAHL, and checked references of included publications to identify studies that compared trial outcomes as documented in a publicly accessible clinical trials registry with published trial outcomes. Two authors independently selected eligible studies and performed data extraction. We present summary data rather than pooled analyses owing to methodological heterogeneity among the included studies. RESULTS: Twenty-seven studies were eligible for inclusion. The overall risk of bias among included studies was moderate to high. These studies assessed outcome agreement for a median of 65 individual trials (interquartile range [IQR] 25-110). The median proportion of trials with an identified discrepancy between the registered and published primary outcome was 31%; substantial variability in the prevalence of these primary outcome discrepancies was observed among the included studies (range 0% (0/66) to 100% (1/1), IQR 17-45%). We found less variability within the subset of studies that assessed the agreement between prospectively registered outcomes and published outcomes, among which the median observed discrepancy rate was 41% (range 30% (13/43) to 100% (1/1), IQR 33-48%). The nature of observed primary outcome discrepancies also varied substantially between included studies. Among the studies providing detailed descriptions of these outcome discrepancies, a median of 13 % of trials introduced a new, unregistered outcome in the published manuscript (IQR 5-16%). CONCLUSIONS: Discrepancies between registered and published outcomes of clinical trials are common regardless of funding mechanism or the journals in which they are published. Consistent reporting of prospectively defined outcomes and consistent utilization of registry data during the peer review process may improve the validity of clinical trial publications. PMID- 26581193 TI - Contribution of estradiol levels and hormonal contraceptives to sex differences within the fear network during fear conditioning and extinction. AB - BACKGROUND: Findings about sex differences in the field of fear conditioning and fear extinction have been mixed. At the psychophysiological level, sex differences emerge only when taking estradiol levels of women into consideration. This suggests that this hormone may also influence sex differences with regards to activations of brain regions involved in fear conditioning and its extinction. Importantly, the neurobiological correlates associated with the use of hormonal oral contraceptives in women have not been fully contrasted against men and against naturally cycling women with different levels of estradiol. In this study, we begin to fill these scientific gaps. METHODS: We recruited 37 healthy men and 48 healthy women. Of these women, 16 were using oral contraceptives (OC) and 32 were naturally cycling. For these naturally cycling women, a median split was performed on their serum estradiol levels to create a high estradiol (HE) group (n = 16) and a low estradiol (LE) group (n = 16). All participants underwent a 2-day fear conditioning and extinction paradigm in a 3 T MR scanner. Using the 4 groups (men, HE women, LE women, and OC users) and controlling for age and coil type, one-way ANCOVAs were performed to look at significant activations within the nodes of the fear circuit. Using post-hoc analyses, beta weights were extracted in brain regions showing significant effects in order to unveil the differences based on hormonal status (men, HE, LE, OC). RESULTS: Significant main effect of hormonal status group was found across the different phases of the experiment and in different sub-regions of the insular and cingulate cortices, amygdala, hippocampus, and hypothalamus. During conditioning, extinction and recall, most of the observed differences suggested higher activations among HE women relative to men. During the unconditioned response, however, a different pattern was observed with men showing significantly higher brain activations. CONCLUSIONS: Our data further support the important contribution of estradiol levels in the activation of brain regions underlying fear learning and extinction. The results highlight the need to document gonadal hormonal levels, menstrual cycle phase as well as oral contraceptive use in women in order to avoid overlooking sex differences when investigating the neurobiology of emotional regulation. PMID- 26581192 TI - Effects of oxygen on the antigenic landscape of prostate cancer cells. AB - BACKGROUND: Use of allogeneic cancer cells-based immunotherapy for treatment of established prostate cancer (PCa) has only been marginally effective. One reason for failure could stem from the mismatch of antigenic signatures of vaccine cells and cancer in situ. Hence, it is possible that vaccine cells expressed antigens differently than tumor cells in situ. We hypothesized that cells grown in vitro at low oxygen tension (pO2) provide a better antigen match to tumors in situ and could reveal a more relevant antigenic landscape than cells grown in atmospheric pO2. METHODS: We tested this hypothesis by comparing PCa cells propagated at pO2 = 2 kPa and 20 kPa. To identify potential tumor-associated antigens (TAAs), we prepared PCa cell lysates, resolved them by two-dimensional electrophoresis and immunoblotting using spontaneous antibodies from plasma derived from PCa patients and control subjects. Antibody-labeled spots were analyzed by MALDI-TOF mass spectrometry and validated by ELISA. We selected hypoxia-regulated HSP70 and hnRNP L and hypoxia-independent HSP60 and determined the frequency of plasma samples reacting with these molecules. RESULTS: Frequency of HSP60-reactive plasma was low in healthy controls [1.3 % (1/76)], while it was elevated in PCa patients [13.0 % (7/54); p < 0.05]. These data suggest a humoral immune response to HSP60 in PCa. Levels of autoantibodies to HSP70 did not differ from healthy controls [3.7 % (2/54)] in PCa patients [5.3 % (2/38)]. Similarly, hnRNP L autoantibodies did no differ between healthy controls [6.1 % (3/49)] and PCa patients [5.3 % (2/38)]. CONCLUSIONS: Overall our results suggest the value of hypoxia as a modifier of the cellular and antigenic landscape of PCa cells. By modifying the immune reactivity of PCa cells in culture, manipulation of pO2 can be proposed as a new avenue for improving diagnosis, prognosis and immunotherapy for PCa. PMID- 26581194 TI - Peritumoural neutrophils negatively regulate adaptive immunity via the PD-L1/PD-1 signalling pathway in hepatocellular carcinoma. AB - BACKGROUND: PD-L1 expression on neutrophils contributes to the impaired immune response in infectious disease, but the detailed role of PD-L1 expression on neutrophils in HCC remains unclear. METHODS: We investigated the phenotype and morphology of neutrophils infiltrated in tumour tissues from both patients with HCC and hepatoma-bearing mice. RESULTS: We found that neutrophils dominantly infiltrated in the peritumoural region. The neutrophil-to-T cell ratio (NLR) was higher in peritumoural tissue than that in the intratumoural tissue and was negatively correlated with the overall survival of patients with HCC. Infiltrating neutrophils displayed a phenotype of higher frequency of programmed cell death ligand 1 (PD-L1) positive neutrophils. The ratio of PD-L1(+) neutrophils-to-PD-1(+) T cells was higher in peritumoural tissue and better predicted the disease-free survival of patients with HCC. We further confirmed a higher frequency of PD-L1(+) neutrophils and PD-1(+) T cells in hepatoma-bearing mice. Functionally, the PD-L1(+) neutrophils from patients with HCC effectively suppressed the proliferation and activation of T cells, which could be partially reversed by the blockade of PD-L1. CONCLUSIONS: Our results indicate that the tumour microenvironment induces impaired antitumour immunity via the modulation of PD-L1 expression on tumour infiltrating neutrophils. PMID- 26581195 TI - Gene expression analysis at the onset of sex differentiation in turbot (Scophthalmus maximus). AB - BACKGROUND: Controlling sex ratios is essential for the aquaculture industry, especially in those species with sex dimorphism for relevant productive traits, hence the importance of knowing how the sexual phenotype is established in fish. Turbot, a very important fish for the aquaculture industry in Europe, shows one of the largest sexual growth dimorphisms amongst marine cultured species, being all-female stocks a desirable goal for the industry. Although important knowledge has been achieved on the genetic basis of sex determination (SD) in this species, the master SD gene remains unknown and precise information on gene expression at the critical stage of sex differentiation is lacking. In the present work, we examined the expression profiles of 29 relevant genes related to sex differentiation, from 60 up to 135 days post fertilization (dpf), when gonads are differentiating. We also considered the influence of three temperature regimes on sex differentiation. RESULTS: The first sex-related differences in molecular markers could be observed at 90 days post fertilization (dpf) and so we have called that time the onset of sex differentiation. Three genes were the first to show differential expression between males and females and also allowed us to sex turbot accurately at the onset of sex differentiation (90 dpf): cyp19a1a, amh and vasa. The expression of genes related to primordial germ cells (vasa, gsdf, tdrd1) started to increase between 75-90 dpf and vasa and tdrd1 later presented higher expression in females (90-105 dpf). Two genes placed on the SD region of turbot (sox2, fxr1) did not show any expression pattern suggestive of a sex determining function. We also detected changes in the expression levels of several genes (ctnnb1, cyp11a, dmrt2 or sox6) depending on culture temperature. CONCLUSION: Our results enabled us to identify the first sex-associated genetic cues (cyp19a1a, vasa and amh) at the initial stages of gonad development in turbot (90 dpf) and to accurately sex turbot at this age, establishing the correspondence between gene expression profiles and histological sex. Furthermore, we profiled several genes involved in sex differentiation and found specific temperature effects on their expression. PMID- 26581197 TI - Evidence-Based Social Communication Interventions for Children with Autism Spectrum Disorder. AB - Impairments in social communication skills are a core feature of autism spectrum disorder (ASD) and include deficits in social-emotional reciprocity, non-verbal communicative behaviors used for social interaction, and developing, maintaining, and understanding relationships. In order to improve outcomes for children with ASD, much research has been focused on developing effective interventions to treat these social communication deficits. The purpose of this paper is to highlight the evidence-based practices found within the intervention literature that specifically targets social communication impairments and provide an overview of these strategies. Four relevant themes regarding evidence-based social communication interventions are considered and discussed: (a) social communication outcomes and practices relevant to different stages of development, (b) practices that both reduce interfering behaviors and improve social communication skills, PMID- 26581196 TI - Global health leadership training in resource-limited settings: a collaborative approach by academic institutions and local health care programs in Uganda. AB - INTRODUCTION: Due to a limited health workforce, many health care providers in Africa must take on health leadership roles with minimal formal training in leadership. Hence, the need to equip health care providers with practical skills required to lead high-impact health care programs. In Uganda, the Afya Bora Global Health Leadership Fellowship is implemented through the Makerere University College of Health Sciences (MakCHS) and her partner institutions. Lessons learned from the program, presented in this paper, may guide development of in-service training opportunities to enhance leadership skills of health workers in resource-limited settings. METHODS: The Afya Bora Consortium, a consortium of four African and four U.S. academic institutions, offers 1-year global health leadership-training opportunities for nurses and doctors. Applications are received and vetted internationally by members of the consortium institutions in Botswana, Kenya, Tanzania, Uganda, and the USA. Fellows have 3 months of didactic modules and 9 months of mentored field attachment with 80% time dedicated to fellowship activities. Fellows' projects and experiences, documented during weekly mentor-fellow meetings and monthly mentoring team meetings, were compiled and analyzed manually using pre-determined themes to assess the effect of the program on fellows' daily leadership opportunities. RESULTS: Between January 2011 and January 2015, 15 Ugandan fellows (nine doctors and six nurses) participated in the program. Each fellow received 8 weeks of didactic modules held at one of the African partner institutions and three online modules to enhance fellows' foundation in leadership, communication, monitoring and evaluation, health informatics, research methodology, grant writing, implementation science, and responsible conduct of research. In addition, fellows embarked on innovative projects that covered a wide spectrum of global health challenges including critical analysis of policy formulation and review processes, bottlenecks in implementation of national HIV early infant diagnosis and prevention of mother-to-child HIV-transmission programs, and use of routine laboratory data about antibiotic resistance to guide updates of essential drug lists. CONCLUSION: In-service leadership training was feasible, with ensured protected time for fellows to generate evidence-based solutions to challenges within their work environment. With structured mentorship, collaborative activities at academic institutions and local health care programs equipped health care providers with leadership skills. PMID- 26581198 TI - Effectiveness and Cost-effectiveness of School-based Dissemination Strategies of an Internet-based Program for the Prevention and Early Intervention in Eating Disorders: A Randomized Trial. AB - Only little is known about costs and effects (i.e., success) of dissemination strategies, although cost-effective dissemination strategies are crucial for the transfer of interventions into routine care. This study investigates the effects and cost-effectiveness of five school-based dissemination strategies for an Internet-based intervention for the prevention and early intervention of eating disorders. Three-hundred ninety-five schools were randomly assigned to one of five dissemination strategies. Strategies varied with respect to intensity from only sending advertisement materials and asking the school to distribute them among students to organizing presentations and workshops at schools. Effects were defined as the number of page visits, the number of screenings conducted, and the number of registrations to the Internet-based intervention. More expensive strategies proved to be more cost-effective. Cost per page visit ranged from 2.83? (introductory presentation plus workshop) to 20.37? (dissemination by student representatives/peers). Costs per screening ranged from 3.30? (introductory presentation plus workshop) to 75.66? (dissemination by student representatives/peers), and costs per registration ranged from 6.86? (introductory presentation plus workshop) to 431.10? (advertisement materials only). Dissemination of an Internet-based intervention for prevention and early intervention is challenging and expensive. More intense, expensive strategies with personal contact proved to be more cost-effective. The combination of an introductory presentation on eating disorders and a workshop in the high school was most effective and had the best cost-effectiveness ratio. The sole distribution of advertisement materials attracted hardly any participants to the Internet-based program. PMID- 26581201 TI - Complementary and alternative medicine in anesthesia: Are we really going there? PMID- 26581199 TI - A randomized pilot trial testing the safety and immunologic effects of a MAGE-A3 protein plus AS15 immunostimulant administered into muscle or into dermal/subcutaneous sites. AB - INTRODUCTION: Methods to induce T cell responses to protein vaccines have not been optimized. The immunostimulant AS15 has been administered with the recombinant MAGE-A3 protein (recMAGE-A3) i.m. but not i.d. or s.c. This study tests hypotheses that the i.d./s.c. route is safe and will increase CD4(+) and CD8(+) T cell responses to MAGE-A3. PATIENTS AND METHODS: Twenty-five patients with resected stage IIB-IV MAGE-A3(+) melanoma were randomized to immunization with recMAGE-A3 combined with AS15 immunostimulant (MAGE-A3 immunotherapeutic) either i.m. (group A, n = 13) or i.d./s.c. (group B, n = 12). Adverse events were recorded. Ab responses to MAGE-A3 were measured by ELISA. T cell responses to overlapping MAGE-A3 peptides were assessed in PBMC and a sentinel immunized node (SIN) after 1 in vitro stimulation with recMAGE-A3, by IFN-gamma ELISPOT assay and by flow cytometry for multifunctional (TNF-alpha/IFN-gamma) responses. RESULTS: Both routes of immunization were well tolerated without treatment related grade 3 adverse events. All patients had durable Ab responses. For all 25 patients, the T cell response rate by ELISPOT assay was 30 % in SIN (7/23) but only 4 % (1/25) in PBMC. By flow cytometry, multifunctional CD8(+) T cell responses were identified in one patient in each group; multifunctional CD4(+) T cell response rates for groups A and B, respectively, were 31 and 64 % in SIN and 31 and 50 % in PBMC. CONCLUSION: The MAGE-A3 immunotherapeutic was well tolerated after i.d./s.c. administration, with trends to higher CD4(+) T cell response rates than with i.m. administration. This study supports further study of AS15 by i.d./s.c. administration. PMID- 26581202 TI - A Novel Immune Marker Model Predicts Oncological Outcomes of Patients with Colorectal Cancer. AB - BACKGROUND: The purpose of this study was to develop an in situ immune marker model to predict postoperative oncological outcomes in patients with colorectal cancer (CRC). METHODS: Immunohistochemistry for 13 immune cell markers was performed on tumor tissue microarrays from 300 CRC patients who underwent curative resection from January 2000 to January 2006. Genetic algorithm was applied for the construction of an in situ immune marker model. RESULTS: The infiltration of CD3+ cells, CD45RO+ cells, and FOXP3+ cells, but not the infiltration of Tryptase+ cells, in the tumor was significantly associated with better clinical outcome in overall survival (OS) and disease-free survival (DFS) of CRC patients, as assessed by univariate analysis (P < 0.05). Based on the genetic algorithms, a total of 6 markers, including CD3, CD45RO, IL17, CD15, Tryptase, and FOXP3, were selected to construct an immune marker model. Our model was identified to have an independent predictive capability for both OS and DFS in Cox multivariable model (P < 0.001). This was further confirmed by the ROC analysis (area under curve: OS, 0.669; DFS, 0.684). CONCLUSIONS: The in situ immune marker model constructed in this study provides a novel approach to identify CRC patients who were at an increased risk for poor oncological outcomes. PMID- 26581203 TI - Australian Multicenter Study of Isolated Limb Infusion for Melanoma. AB - PURPOSE: Isolated limb infusion (ILI) offers a less invasive alternative to isolated limb perfusion (ILP) for the treatment of locally advanced extremity melanoma. In Australia, ILI has essentially completely replaced ILP. The aim of this study was to collect and evaluate the results of ILI in an Australian multicenter setting. PATIENTS AND METHODS: The results of 316 first ILI procedures, performed between 1992 and 2008 in five Australian institutions, were collectively analyzed, with all five institutions using the same protocol. Melphalan was circulated in the isolated limb for 20-30 min (+/-actinomycin D). Response was determined using the World Health Organization criteria, and limb toxicity was assessed using the Wieberdink scale. RESULTS: The median patient age was 74 years (range 28-100) and 59 % of patients were female. Overall response rate was 75 % (complete response [CR] 33 %; partial response 42 %). Stable disease was seen in 18 % of patients and progressive disease in 7 %. Wieberdink grade III or higher was seen in 30 % of the cases. No toxicity-related amputations occurred, and median survival was 44 months. In patients with a CR, median survival was 80 months (p = 0.014). On multivariate analysis, Breslow thickness, lower-limb ILI, and a procedure performed at the Melanoma Institute Australia remained significant predictors for response, although not for survival. CONCLUSIONS: This Australian multicenter study of ILI is the largest reported to date. ILI is a useful technique that can be safely and effectively performed across tertiary referral centers for the successful management of advanced extremity melanoma. Increased optimization of perioperative factors might allow response rates to be raised further, while maintaining acceptable toxicity. PMID- 26581204 TI - Capsule Commentary on Marshall et al., Effect of Patient Navigation on Breast Cancer Screening Among African American Medicare Beneficiaries: a Randomized Controlled Trial. PMID- 26581205 TI - Efficacy and safety of combination therapy for preventing bone damage in rheumatoid arthritis. AB - The main outcomes of the therapies for rheumatoid arthritis (RA) must be preventing, or at least lessening, the development of structural damage. Biological disease-modifying anti-rheumatic drugs (bDMARDs), targeting tumour necrosis factor-alpha (TNF-alpha) or other key steps (IL-1, IL-6, T cells, B cells) in the pathogenesis of RA, have given clues to be effective and safe as treatments for RA, being capable of improving disease activity, ameliorating functional ability and halting joint damage. A large body of evidence, stemming from randomized clinical trials, observational studies, and registries, has shown that the beneficial effects of the bDMARDs become optimal when combined with synthetic (s)-DMARDs, mainly methotrexate (MTX). Despite combination therapy is advocated by the international guidelines for the management of RA, data from the daily standard of care indicate that almost one third of RA patients are treated with bDMARDs as monotherapy. Many reasons may be taken into account to explain this gap from official recommendations, among which the fact that in real-life settings, the assessment of clinical outcomes is exclusively based on clinical indices, disregarding the evolution of bone damage. Furthermore, some bDMARDs have been launched in the market with the official approval to be used as monotherapy. But even for the latter, there is no conclusive proof that monotherapy regimen is comparable to co-therapy with MTX in preventing articular damage. In conclusion, the most recent published data show that combination therapy with bDMARDs and MTX represents the best therapeutic option for the treatment of RA since it can stop or at least slow the progression of disabling structural damage. PMID- 26581206 TI - Immunohistochemical Expression and Clinical Significance of Suggested Stem Cell Markers in Hepatocellular Carcinoma. AB - BACKGROUND: Increasing evidence has shown that tumor initiation and growth are nourished by a small subpopulation of cancer stem cells (CSCs) within the tumor mass. CSCs are posited to be responsible for tumor maintenance, growth, distant metastasis, and relapse after curative operation. We examined the expression of CSC markers in paraffin-embedded tissue sections of hepatocellular carcinoma (HCC) and correlated the results with clinicopathologic characteristics. METHODS: Immunohistochemical staining for the markers believed to be expressed in the CSCs, including epithelial cell adhesion molecule (EpCAM), keratin 19 (K19), CD133, and CD56, was performed in 82 HCC specimens. RESULTS: EpCAM expression was observed in 56% of the HCCs (46/82) and K19 in 6% (5/82). EpCAM expression in HCC significantly correlated with elevated alpha-fetoprotein level, microvessel invasion of tumor cells, and high histologic grade. In addition, EpCAM expression significantly correlated with K19 expression. The overall survival and relapsefree survival rates in patients with EpCAM-expressing HCC were relatively lower than those in patients with EpCAM-negative HCC. All but two of the 82 HCCs were negative for CD133 and CD56, respectively. CONCLUSIONS: Our results suggest that HCCs expressing EpCAM are associated with unfavorable prognostic factors and have a more aggressive clinical course than those not expressing EpCAM. Further, the expression of either CD133 or CD56 in paraffin-embedded HCC tissues appears to be rare. PMID- 26581207 TI - Soft Tissue Roasi-Dorfman Disease with Features of IgG4-Related Disease in a Patient with a History of Acute Myeloid Leukemia. PMID- 26581208 TI - Review of Medical Advisory Services by the Korean Society of Pathologists from 2003 to 2014. AB - BACKGROUND: Since 2003, the Korean Society of Pathologists (KSP) has been officially providing medical advisory services (MAS). We reviewed the cases submitted to the KSP between 2003 and 2014. METHODS: In total, 1,950 cases were submitted, most by private health insurance companies. The main purposes of the consultations were to clarify the initial diagnoses and to assign a proper disease classification code. We comprehensively reviewed 1,803 consultation cases with detailed information. RESULTS: In spite of some fluctuations, the number of submitted cases has been significantly increasing over the 12 study years. The colon and rectum (40.3%), urinary bladder (14.2%), and stomach (6.9%) were the three most common tissues of origin. The most common diagnoses for each of the three tissues of origin were neuroendocrine tumor (50.7%), non-invasive papillary urothelial carcinoma (70.7%), and adenocarcinoma (36.2%). Regardless of the tissue of origin, neuroendocrine tumor of the digestive system was the most common diagnosis (419 of 1,803). CONCLUSIONS: In the current study, we found that pathologic consultations associated with private health insurance accounted for a large proportion of the MAS. Coding of the biologic behavior of diseases was the main issue of the consultations. In spite of the effort of the KSP to set proper guidelines for coding and classification of tumors, this review revealed that problems still exist and will continue to be an important issue. PMID- 26581209 TI - A Rare Case of Pulmonary Arteriovenous Hemangioma Presenting as a Peribronchial Mass. PMID- 26581210 TI - The status of the species Enterobacter siamensisKhunthongpan et al. 2014. Request for an Opinion. AB - In the course of a taxonomic study describing novel species of the genus Enterobacter it was found that the 16S rRNA gene sequence of the type strain of Enterobacter siamensis, obtained both directly from the authors of the publication on Enterobacter siamensis and from the Korean Collection for Type Cultures (C2361T and KCTC 23282T, respectively), was not congruent with the 16S rRNA gene sequence deposited in the GenBank database under the accession number HQ888848, which was applied for phylogenetic analysis in the species proposal. The remaining deposit in the Japanese type culture collection, NBRC 107138T, showed an identical 16S rRNA gene sequence to the other two cultures and overall, this sequence differed at 35 positions in comparison with the 1429 bp sequence published under the accession number HQ888848.Therefore, the type strain of this species cannot be included in any further scientific comparative study. It is proposed that the Judicial Commission of the International Committee on Systematics of Prokaryotes place the name Enterobacter siamensis on the list of rejected names, if a suitable replacement for the type strain is not found or a neotype strain is not proposed within two years following the publication of this Request for an Opinion. PMID- 26581211 TI - Sociodemographic, clinical and childhood correlates of adult violent victimisation in a large, national survey sample of people with psychotic disorders. AB - PURPOSE: Our aim was to establish the 12-month prevalence of violent victimisation in a large sample of adults with psychotic disorders (N = 1825), compare this to population estimates, and examine correlates of violent victimisation. METHODS: The Australian national psychosis survey used a two-phase design to draw a representative sample of adults aged 18-64 years with psychotic disorders. Interview questions included psychopathology, cognition, sociodemographics, substance use, criminality, and childhood and adult victimisation. Multivariable logistic regression models were used to examine the independent contributions of known risk factors, clinical profile and childhood abuse, on risk of violent victimisation. Differences between men and women were examined. RESULTS: Among adults with psychotic disorders, 12-month prevalence of any victimisation was 38.6% (males 37.4%, females 40.5%), and of violent victimisation was 16.4% (males 15.2%; females 18.3%). Violent victimisation was 4.8 times higher than the population rate of 3.4% (6.5 times higher for women; 3.7 times higher for men). Significant correlates of violent victimisation were established sociodemographic and behavioural risk factors predicting victimisation in the general community: younger age, residence in the most disadvantaged neighbourhoods, homelessness, lifetime alcohol abuse/dependence, and prior criminal offending. Among clinical variables, only mania and self-harm remained significant in the multivariable model. Childhood abuse was independently associated with violent victimisation. CONCLUSIONS: Rates of violent victimisation are high for people with psychotic disorders, especially women, compared to population rates. Greater exposure to sociodemographic and behavioural risks may render them particularly vulnerable to victimisation. Social cognition as a valuable treatment target is discussed. PMID- 26581212 TI - FEN1 participates in repair of the 5'-phosphotyrosyl terminus of DNA single strand breaks. AB - Etoposide is a widely used anticancer drug and a DNA topoisomerase II (Top2) inhibitor. Etoposide produces Top2-attached single-strand breaks (Top2-SSB complex) and double-strand breaks (Top2-DSB complex) that are thought to induce cell death in tumor cells. The Top2-SSB complex is more abundant than the Top2 DSB complex. Human tyrosyl-DNA phosphodiesterase 2 (TDP2) is required for efficient repair of Top2-DSB complexes. However, the identities of the proteins involved in the repair of Top2-SSB complexes are unknown, although yeast genetic data indicate that 5' to 3' structure-specific DNA endonuclease activity is required for alternative repair of Top2 DNA damage. In this study, we purified a flap endonuclease 1 (FEN1) and xeroderma pigmentosum group G protein (XPG) in the 5' to 3' structure-specific DNA endonuclease family and synthesized single-strand break DNA substrates containing a 5'-phoshotyrosyl bond, mimicking the Top2-SSB complex. We found that FEN1 and XPG did not remove the 5'-phoshotyrosyl bond containing DSB substrates but removed the 5'-phoshotyrosyl bond-containing SSB substrates. Under DNA repair conditions, FEN1 efficiently repaired the 5' phoshotyrosyl bond-containing SSB substrates in the presence of DNA ligase and DNA polymerase. Therefore, FEN1 may play an important role in the repair of Top2 SSB complexes in etoposide-treated cells. PMID- 26581213 TI - Synthesis, Characterization and Optoelectronic Properties of Benzodithiophene Based Copolymers for Application in Solar Cells. AB - This paper reports on the synthesis and characterization of novel donor-acceptor (D-A) conjugated polymers containing triisopropylsilylethyny(TIPS)benzo[1,2-b:4,5 b']dithiophene-diketopyrrolopyrrole (P1 and P2) through Stille co-polymerization method. Thermal stability, optical and electrochemical properties of these polymers were determined. Optical band gaps of the polymers as calculated from their film onset absorption edges were found to be 1.46 and 1.44 eV, respectively. Electrochemical studies revealed HOMO and LUMO energy levels to be 5.22, -5.60 eV, and -3.76, -4.16 eV, respectively. The polymers were thermally stable up to 400-440 degrees C. Optoelectronic studies indicated that these materials to be promising candidates in solar cell applications. PMID- 26581214 TI - A photodynamic therapy combined with topical 5-aminolevulinic acid and systemic hematoporphyrin derivative is more efficient but less phototoxic for cancer. AB - PURPOSE: Although photodynamic therapy (PDT) has been shown to be effective in cancer treatment, its side effects, such as a long-lasting skin photosensitivity after the application, still cause patient's inconvenience. In this retrospective cohort study, our objective was to explore a more efficient but less phototoxic PDT for skin cancers. METHODS: The PDT combined with a topical photosensitizer 5 aminolevulinic acid (ALA) and an intravenously injected light-sensitive agent hematoporphyrin derivative (HPD) was used to treat 26 patients with 41 skin cancer lesions in head and face. The findings were then compared with the results of the HPD-PDT alone and the ALA-PDT following CO2 laser ablation on 28 and 41 skin cancer patients, respectively. RESULTS: The complete remission rate for the combined PDT was 100 % in 2 months and 97.6 % in a 6 months to 6 years trial after the treatment compared with those of 92.9 and 95.1 % for the HPD-PDT and the ALA-PDT after a single treatment, respectively. Moreover, while the patient treated with the HPD-PDT needs to avoid strong light exposure for 4-5 weeks, the combined PDT significantly reduced the period to 10-14 days. Also, in the combined PDT, the dose of the HPD, a pro-toxic light-sensitive drug, was much lower than that in the HPD-PDT. CONCLUSIONS: The combined PDT not only shows high cure rate for skin cancers but also decreases the dose of the pro-toxic HPD and significantly shortens the photosensitive period, from which the patients are able to benefit. PMID- 26581215 TI - Decreased MIZ1 Expression in Severe Experimental Acute Pancreatitis: A Rat Study. AB - AIM: We tested our hypothesis that Myc-interacting zinc finger protein 1 (MIZ1), a cell cycle regulator, suppressed inflammation, and therefore, represented a useful prognostic marker in patients with acute necrotizing pancreatitis (ANP) complicated by acute lung injury. METHODS: Sprague-Dawley rats were randomly divided into control and ANP groups at different time points. The MIZ1 protein expression was measured by Western blot and ELISA, and confirmed using immunohistochemistry. The severity of pancreatic and lung injury was evaluated by the injury score and wet/dry weight ratio. The severity of disease was evaluated by serum C-reactive protein (CRP). The MPO activity of lung tissue amylase levels and the degree of inflammation were evaluated by serum tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 expression. The risk due to multiple factors was investigated by relationship analysis. RESULTS: The serum levels of CRP, amylase, TNF-alpha, and IL-6 were gradually increased at 6, 24, and 48 h in ANP when compared with the control rats. The MIZ1 expressions were greatly decreased in ANP rats, especially at 24 h. Statistical analysis showed that there were time dependent differences in ANP rats when compared with control rats (6 vs. 24 or 48 h, P < 0.01). MIZ1 showed close negative correlation with the degree of pancreatic and lung injury, serum amylase, CRP, TNF-alpha, and IL-6 (P < 0.01, respectively). CONCLUSION: The decreasing MIZ1 expression was closely correlated with inflammatory response, and development of ANP. Decreasing MIZ1 levels indicate a risk for ANP. PMID- 26581216 TI - Small Cells, Big Problems. PMID- 26581217 TI - Commissioning's identity crisis. PMID- 26581218 TI - Statistical and radiobiological analysis of the so-called thyroid stunning. AB - BACKGROUND: The origin of the reduction in thyroid uptake after a low activity iodine scan, so-called stunning effect, is still controversial. Two explanations prevail: an individual cell stunning that reduces its capability to store iodine without altering its viability, and/or a significant cell-killing fraction that reduces the number of cells in the tissue still taking up iodine. Our aim is to analyze whether this last assumption could explain the observed reduction. METHODS: The survival fraction after administration of a small radioiodine activity was computed by two independent methods: the application of the statistical theory underlying tissue control probability on recent clinical studies of thyroid remnant (131)I ablation and the use of the radiosensitivities reported in human thyroid cell assays for different radioiodine isotopes. RESULTS: Both methods provided survival fractions in line with the uptake reduction observed after a low (131)I activity scan. The second method also predicts a similar behavior after a low (123)I or (124)I activity scan. CONCLUSIONS: This study shows that the cell-killing fraction is sufficient to explain the uptake reduction effect for (131)I and (123)I after a low activity scan and that even if some still living cells express a stunning effect just after irradiation (as shown in vitro), they will mostly die with time. As the beta/alpha value is very low, this therapy fractionation should not impact the patient outcome in agreement with recent studies. However, in case of huge uptake heterogeneity, pre-therapy scan could specifically kills high-uptake cells and by the way could reduce the cross irradiation to the low-uptake cells during the therapy, resulting in a reduction of the ablation success rate. PMID- 26581219 TI - MRI is unable to illustrate the absorption time of the absorbable TIGR mesh in humans: a case report. AB - A male patient had a bilateral laparoscopic inguinal hernia repair in 2012. The right-sided hernia was treated with a permanent mesh, and the left-sided hernia received an absorbable mesh. The absorbable TIGR mesh has been proved to be completely absorbed and replaced by new connective tissue after 3 years in sheep. The patient was therefore followed for 3 years by annual magnetic resonance imagings (MRIs) to illustrate the absorption time in humans. During follow-up, the thickness of the absorbable mesh slightly decreased, and at the last clinical examination, the patient was without a recurrence. However, MRI failed to illustrate absorption of the TIGR mesh, perhaps since new connective tissue and the mesh material had the same appearance on the images. In conclusion, MRI was unable to confirm an absorption time of 3 years for the TIGR mesh, and further studies are needed to investigate if the mesh also completely absorbs in humans. PMID- 26581220 TI - Transarterial Endoleak Closure After Endovascular Thoracoabdominal Aneurysm Repair: When the "Sandwich" Goes Wrong. AB - PURPOSE: To describe the use of vascular plugs to close a complex type Ib endoleak following the sandwich procedure used in conjunction with endovascular thoracoabdominal aortic aneurysm (TAAA) repair. CASE REPORT: A 59-year-old man with a 6.5-mm TAAA was treated with initial deployment proximally of 2 Zenith TX2 stent-grafts. In preparation for the sandwich technique to preserve flow to the celiac trunk, a 10*100-mm Viabahn covered stent was delivered from a brachial access into the celiac trunk unprotected by the sheath of the introducer. The trigger wire system became snagged on the struts of the distal aortic stent graft; when the wire was pulled, the proximal end of the Viabahn migrated outside the aortic stent-graft, which migrated upward. The main body extension intended for the aortic component of the sandwich technique was deployed close to the distal end of the aneurysm sac, but a large type Ib endoleak formed in the gutter between the Viabahn, aortic extension, and sac wall. The leak perfused the celiac trunk, and the procedure was terminated. Increasing sac size on 3-month imaging prompted closure of the leak with 2 type II Amplatzer vascular plugs aiming to occlude the endoleak outflow into the Viabahn and the endoleak outflow at the site of the gutter. Imaging follow-up at 6 months demonstrated successful exclusion of the TAAA with no residual endoleak and excellent perfusion of the celiac trunk. CONCLUSION: Transarterial treatment of complex endoleaks is feasible when preceded by meticulous imaging and detailed preprocedural planning. PMID- 26581221 TI - Nitroheterocyclic drug resistance mechanisms in Trypanosoma brucei. AB - OBJECTIVES: The objective of this study was to identify the mechanisms of resistance to nifurtimox and fexinidazole in African trypanosomes. METHODS: Bloodstream-form Trypanosoma brucei were selected for resistance to nifurtimox and fexinidazole by stepwise exposure to increasing drug concentrations. Clones were subjected to WGS to identify putative resistance genes. Transgenic parasites modulating expression of genes of interest were generated and drug susceptibility phenotypes determined. RESULTS: Nifurtimox-resistant (NfxR) and fexinidazole resistant (FxR) parasites shared reciprocal cross-resistance suggestive of a common mechanism of action. Previously, a type I nitroreductase (NTR) has been implicated in nitro drug activation. WGS of resistant clones revealed that NfxR parasites had lost >100 kb from one copy of chromosome 7, rendering them hemizygous for NTR as well as over 30 other genes. FxR parasites retained both copies of NTR, but lost >70 kb downstream of one NTR allele, decreasing NTR transcription by half. A single knockout line of NTR displayed 1.6- and 1.9-fold resistance to nifurtimox and fexinidazole, respectively. Since NfxR and FxR parasites are ~6- and 20-fold resistant to nifurtimox and fexinidazole, respectively, additional factors must be involved. Overexpression and knockout studies ruled out a role for a putative oxidoreductase (Tb927.7.7410) and a hypothetical gene (Tb927.1.1050), previously identified in a genome-scale RNAi screen. CONCLUSIONS: NTR was confirmed as a key resistance determinant, either by loss of one gene copy or loss of gene expression. Further work is required to identify which of the many dozens of SNPs identified in the drug-resistant cell lines contribute to the overall resistance phenotype. PMID- 26581222 TI - A panoramic view of chronic liver diseases and natural remedies reported in Traditional Persian Medicine. AB - Regarding limited effectiveness of many hepatic medical approaches, seeking for novel treatment strategies is crucial to improve outcomes. Hence, the current study aims to compile a concise but critical review over reported liver diseases and related medicinal plants from the Persian medicine perspectives. To this end, five main pharmaceutical manuscripts of Persian medicine from 9th-18th A.D. as well as the latest and largest medical textbook of Persian medicine were studied. By searching through databases such as PubMed and ScienceDirect, mechanisms or pharmacological activities of reported medicinal plants in the field of liver diseases were cited and discussed. In all, seventeen different liver diseases, mainly chronic, were cited in Persian medicine. Ninety three medicinal plants with liver tonic, hepatoprotective and related effectiveness belonging to 49 families were derived and authenticated from these studied manuscripts. More than 75% of the herbs showed related hepatoprotectivity and antioxidant activities. However, none of them have been examined clinically. Besides historical clarification, the current investigation compiled an evidence- based study on reported liver herbal remedies from the standpoints of Persian scholars. Conducting attributable clinical trials against the backdrops of proven in vitro and in vivo studies may result in new treatment discoveries for liver diseases. PMID- 26581223 TI - Human Ghrelin: A Gastric Hormone with Cardiovascular Properties. AB - Ghrelin is a growth hormone-releasing peptide, isolated from the stomach. Researches in progress documented that ghrelin participates in the stimulation of the hypothalamus-pituitary-adrenal axis at the hypothalamic level and in the regulation of energy balance. Growth hormone-independent functions have been ascribed to ghrelin. Among others, a large body of literature demonstrated the presence of specific receptors for ghrelin, distributed at the level of cardiomyocytes and endothelial cells. Therefore, a link between ghrelin and cardiovascular system has been hypothesized and, then, demonstrated in both experimental and clinical studies. Ghrelin has largely documented cardiac beneficial effects, including protection from ischemia/reperfusion injury, attenuation of left ventricular remodeling following myocardial infarction, and improvement of left ventricular function. Exercise level in patients with chronic heart failure had also been seen. Ghrelin exerts these effects through several mechanisms, including the inhibition of apoptosis. At the level of blood vessels, ghrelin exerts a significant impact on vascular function. In particular, acutely infused, ghrelin reverses endothelial dysfunction by increasing NO availability and restores the endothelin-1/nitric oxide imbalance in the peripheral microcirculation of patients with metabolic syndrome. Antioxidant/anti inflammatory effects, and-or an ameliorated insulin sensitivity are proposed mechanisms whereby ghrelin exerts its vascular protective actions. At higher doses, ghrelin also decreases blood pressure, by mechanisms that involve the modulation of sympathetic nervous system. This finding highlights the ghrelin system as a promising candidate for cardiovascular drug discovery. PMID- 26581224 TI - Effects of Cardiopulmonary Exercise Rehabilitation on Left Ventricular Mechanical Efficiency and Ventricular-Arterial Coupling in Patients With Systolic Heart Failure. PMID- 26581225 TI - Exercise Strain Echocardiography in Patients With a Hemodynamically Significant Myocardial Bridge Assessed by Physiological Study. AB - BACKGROUND: Although a myocardial bridge (MB) is often regarded as a benign coronary variant, recent studies have associated MB with focal myocardial ischemia. The physiological consequences of MB on ventricular function during stress have not been well established. METHODS AND RESULTS: We enrolled 58 patients with MB of the left anterior descending artery, diagnosed by intravascular ultrasound. Patients underwent invasive physiological evaluation of the MB by diastolic fractional flow reserve during dobutamine challenge and exercise echocardiography. Septal and lateral longitudinal strain (LS) were assessed at rest and immediately after exercise and compared with strain of matched controls. Absolute and relative changes in strain were also calculated. The mean age was 42.5+/-16.0 years. Fifty-five patients had a diastolic fractional flow reserve <=0.76. At rest, there was no significant difference between the 2 groups in septal LS (19.0+/-1.8% for patients with MB versus 19.2+/ 1.5% for control, P=0.53) and lateral LS (20.1+/-2.0% versus 20.0+/-1.6%, P=0.83). With stress, compared with controls, patients with MB had a lower peak septal LS (18.9+/-2.6% versus 21.7+/-1.6%, P<0.001) and lower absolute (-0.1+/ 2.1% versus 2.5+/-1.3%, P<0.001) and relative change (-0.6+/-11.2% versus 13.1+/ 7.8%, P<0.001) in septal LS, whereas there was no significant difference in lateral LS. In multivariate analysis, diastolic fractional flow reserve and length were independent determinants of lower changes in septal LS. CONCLUSIONS: Patients with a hemodynamically significant MB, determined by invasive diastolic fractional flow reserve, have significantly lower change in septal LS on exercise echocardiography, suggesting that septal LS may be useful for noninvasively assessing the hemodynamic significance of an MB. PMID- 26581226 TI - Linking obesogenic dysregulation to prostate cancer progression. AB - The global epidemic of obesity is closely linked to the development of serious co morbidities, including many forms of cancer. Epidemiological evidence consistently shows that obesity is associated with a similar or mildly increased incidence of prostate cancer but, more prominently, an increased risk for aggressive prostate cancer and prostate cancer-specific mortality. Studies in mice demonstrate that obesity induced by high-fat feeding increases prostate cancer progression; however, the mechanisms underpinning this relationship remain incompletely understood. Adipose tissue expansion in obesity leads to local tissue dysfunction and is associated with low-grade inflammation, alterations in endocrine function and changes in lipolysis that result in increased delivery of fatty acids to tissues of the body. The human prostate gland is covered anteriorly by the prominent peri-prostatic adipose tissue and laterally by smaller adipose tissue depots that lie directly adjacent to the prostatic surface. We discuss how the close association between dysfunctional adipose tissue and prostate epithelial cells might result in bi-directional communication to cause increased prostate cancer aggressiveness and progression. However, the literature indicates that several 'mainstream' hypotheses regarding obesity related drivers of prostate cancer progression are not yet supported by a solid evidence base and, in particular, are not supported by experiments using human tissue. Understanding the links between obesity and prostate cancer will have major implications for the health policy for men with prostate cancer and the development of new therapeutic or preventative strategies. PMID- 26581228 TI - Expanding the Clinical and Genetic Spectrum of KRT1, KRT2 and KRT10 Mutations in Keratinopathic Ichthyosis. AB - Twenty-six families with keratinopathic ichthyoses (epidermolytic ichthyosis, superficial epidermolytic ichthyosis or congenital reticular ichthyosiform erythroderma) were studied. Epidermolytic ichthyosis is caused by mutations in the genes KRT1 or KRT10, mutations in the gene KRT2 lead to superficial epidermolytic ichthyosis, and congenital reticular ichthyosiform erythroderma is caused by frameshift mutations in the genes KRT10 or KRT1, which lead to the phenomenon of revertant mosaicism. In this study mutations were found in KRT1, KRT2 and KRT10, including 8 mutations that are novel pathogenic variants. We report here the first case of a patient with congenital reticular ichthyosiform erythroderma carrying a mutation in KRT10 that does not lead to an arginine-rich reading frame. Novel clinical features found in patients with congenital reticular ichthyosiform erythroderma are described, such as mental retardation, spasticity, facial dysmorphisms, symblepharon and malposition of the 4th toe. PMID- 26581227 TI - Bridging progestogens in pregnancy and pregnancy prevention. AB - Steroid hormones have been in use for more than a half a century as contraceptive agents, and only now are researchers elucidating the biochemical mechanisms of action and non-target effects. Progesterone and synthetic progestins, critical for women's health in the US and internationally, appear to have important effects on immune functioning and other diverse systems. Apart from the contraceptive world is a separate field that is devoted to understanding progesterone in other contexts. Based on research following a development timeline parallel to hormonal contraception, progesterone and 17 hydroxyprogesterone caproate are now administered to prevent preterm birth in high-risk pregnant women. Preterm birth researchers are similarly working to determine the precise biochemical actions and immunological effects of progesterone. Progesterone research in both areas could benefit from increased collaboration and bringing these two bodies of literature together. Progesterone, through actions on various hormone receptors, has lifelong importance in different organ systems and researchers have much to learn about this molecule from the combination of existing literatures, and from future studies that build on this combined knowledge base. PMID- 26581229 TI - Deposition pattern and subcellular distribution of disease-associated prion protein in cerebellar organotypic slice cultures infected with scrapie. AB - Organotypic cerebellar slices represent a suitable model for characterizing and manipulating prion replication in complex cell environments. Organotypic slices recapitulate prion pathology and are amenable to drug testing in the absence of a blood-brain-barrier. So far, the cellular and subcellular distribution of disease specific prion protein in organotypic slices is unclear. Here we report the simultaneous detection of disease-specific prion protein and central nervous system markers in wild-type mouse cerebellar slices infected with mouse-adapted prion strain 22L. The disease-specific prion protein distribution profile in slices closely resembles that in vivo, demonstrating granular spot like deposition predominately in the molecular and Purkinje cell layers. Double immunostaining identified abnormal prion protein in the neuropil and associated with neurons, astrocytes and microglia, but absence in Purkinje cells. The established protocol for the simultaneous immunohistochemical detection of disease-specific prion protein and cellular markers enables detailed analysis of prion replication and drug efficacy in an ex vivo model of the central nervous system. PMID- 26581230 TI - Reduced Worries of Hypoglycaemia, High Satisfaction, and Increased Perceived Ease of Use after Experiencing Four Nights of MD-Logic Artificial Pancreas at Home (DREAM4). AB - AIMS: This study assesses the impact of using an AP-system at home on fear of hypoglycaemia. In addition, satisfaction and acceptance of the new technology are evaluated. METHODS: In a multicentre, multinational study of 75 patients using the MD-Logic AP during four consecutive nights in home setting 59 of them (aged 10-54 years, 54% male, HbA1c 7.89 +/- 0.69% [62.72 +/- 7.51 mmol/mol], diabetes duration 11.6 +/- 8.4 yrs) answered standardized questionnaires (HFS, adapted TAM, and AP satisfaction) before and after using the AP. RESULTS: After experiencing the AP in home setting worries of hypoglycaemia were significantly reduced (before 1.04 +/- 0.53 versus after 0.90 +/- 0.63; P = 0.017). Perceived ease of use as a measure of acceptance with the AP significantly increased after personal experience (before 4.64 +/- 0.94 versus after 5.06 +/- 1.09; P = 0.002). The overall satisfaction mean score after using the AP was 3.02 +/- 0.54 (range 0 4), demonstrating a high level of satisfaction with this technology. CONCLUSIONS: The four-night home-based experience of using MD Logic AP was associated with reduced worries of hypoglycaemia, high level of satisfaction, and increased perceived ease of use of the new technology in children, adolescents, and adults. PMID- 26581231 TI - Intrinsic Stepwise Translocation of Stretched ssDNA in Graphene Nanopores. AB - We investigate by means of molecular dynamics simulations stretch-induced stepwise translocation of single-stranded DNA (ssDNA) through graphene nanopores. The intrinsic stepwise DNA motion, found to be largely independent of size and shape of the graphene nanopore, is brought about through alternating conformational changes between spontaneous adhesion of DNA bases to the rim of the graphene nanopore and unbinding due to mechanical force or electric field. The adhesion reduces the DNA bases' vertical conformational fluctuations, facilitating base detection and recognition. A graphene membrane shaped as a quantum point contact permits, by means of transverse electronic conductance measurement, detection of the stepwise translocation of the DNA as predicted through quantum mechanical Green's function-based transport calculations. The measurement scheme described opens a route to enhance the signal-to-noise ratio not only by slowing down DNA translocation to provide sufficient time for base recognition but also by stabilizing single DNA bases and, thereby, reducing thermal noise. PMID- 26581232 TI - Aspheric Solute Ions Modulate Gold Nanoparticle Interactions in an Aqueous Solution: An Optimal Way To Reversibly Concentrate Functionalized Nanoparticles. AB - Nanometer-sized gold particles (AuNPs) are of peculiar interest because their behaviors in an aqueous solution are sensitive to changes in environmental factors including the size and shape of the solute ions. In order to determine these important characteristics, we performed all-atom molecular dynamics simulations on the icosahedral Au144 nanoparticles each coated with a homogeneous set of 60 thiolates (4-mercaptobenzoate, pMBA) in eight aqueous solutions having ions of varying sizes and shapes (Na(+), K(+), tetramethylamonium cation TMA(+), tris-ammonium cation TRS(+), Cl(-), and OH(-)). For each solution, we computed the reversible work (potential of mean of force) to bring two nanoparticles together as a function of their separation distance. We found that the behavior of pMBA protected Au144 nanoparticles can be readily modulated by tuning their aqueous environmental factors (pH and solute ion combinations). We examined the atomistic details on how the sizes and shapes of solute ions quantitatively factor in the definitive characteristics of nanoparticle-environment and nanoparticle-nanoparticle interactions. We predict that tuning the concentrations of nonspherical composite ions such as TRS(+) in an aqueous solution of AuNPs be an effective means to modulate the aggregation propensity desired in biomedical and other applications of small charged nanoparticles. PMID- 26581233 TI - Perspectives of Canadian fitness professionals on exercise and possible anorexia nervosa. AB - BACKGROUND: Many individuals with eating disorders, including anorexia nervosa (AN), engage in overexercise. Little is known about fitness professionals' perceptions of their responsibilities when interacting with clients with possible AN. The purpose of the current study was to examine Alberta fitness professionals' experiences with clients suspected of having AN, and their views on related ethical issues. Specifically, we aimed to examine (1) their experiences with fitness clients suspected of having AN; (2) their opinions about related ethical responsibilities of fitness professionals; and (3) their views on related training and ethical issues. METHODS: We administered a 21-item online survey to 143 Canadian fitness professionals about their experiences and perspectives on encountering individuals with possible AN in exercise classes and at their exercise facilities. RESULTS: Sixty-two percent of respondents had encountered a client they believed had AN. Three-quarters had never received any training on managing clients with AN and felt inadequately prepared for such situations. Although most felt ethically obliged to intervene with such a client, more than two-thirds reported no relevant guidelines in their professional training. CONCLUSIONS: Many fitness professionals are faced with clients with possible AN, have the desire to help, feel ethically obligated to take action, but do not know what course of action to take, if any. Work is needed to clarify ethical issues and related training needs for certification programs for fitness professionals regarding AN. PMID- 26581234 TI - To intervene or not? A man with multidrug-resistant hypertension, endovascular abdominal aneurysm repair, bilateral renal artery stenosis and end-stage renal disease salvaged with renal artery stenting. AB - We report the case of a 69-year-old man with uncontrolled multidrug-resistant secondary hypertension following a 10 year history of endovascular abdominal aortic aneurysm repair, with suprarenal fixation and concurrent angioplasty with stenting of the left renal artery for atherosclerotic renal disease, and progressive chronic kidney disease. Renal scintigraphy revealed complete loss of the right kidney's and severe reduction of the left kidney's perfusion and function. Following recent evidence and consultation with vascular surgeons regarding the technical difficulties of any procedure, escalation of antihypertensive treatment was initially chosen. Careful drug adjustments significantly improved but did not fully control blood pressure (BP); further, the patient experienced an acute ischaemic stroke and renal function deterioration towards end-stage renal disease within a few months. At this point, revascularization of the left renal artery coupled with three haemodialysis sessions to remove contrast media was justified as rescue therapy against permanent renal replacement therapy. Successful intervention achieved an immediate BP reduction, with BP fully controlled, despite a > 70% decrease in antihypertensive treatment, while renal function improved at 6 months from 11.5 to 22 ml/min/1.73 m(2). Renal angioplasty confers undisputed benefits in BP control and nephroprotection, and should be offered without delay to patients with renovascular hypertension and/or ischaemic nephropathy. PMID- 26581236 TI - Angiogenic gene therapy for refractory angina. AB - INTRODUCTION: Stimulation of coronary collateral vessel growth by therapeutic angiogenesis (TA) offers an alternative treatment option for patients with refractory angina. Several TA modalities, including delivery to the heart of angiogenic growth factors (proteins or genes) and cells have been tested in clinical trials in the past two decades, but so far none of them resulted in significant therapeutic efficacy in large scale studies. This review attempts to identify the main obstacles hindering clinical success and recommends measures to overcome them in the future. AREAS COVERED: After stating the medical need and rational for TA, and listing and briefly discussing past and current TA clinical trials, three main areas of obstacles are described: conceptual questions, technical limitations and clinical design uncertainties. Based on scientific and technical advances and lessons learned in past clinical trials, potential solutions to overcome some of these obstacles are proposed. EXPERT OPINION: Several success criteria are identified, which apply to any TA approach of choice. It is emphasized, that each of these criteria needs to be met in future clinical trials to have a chance of therapeutic success. PMID- 26581235 TI - The effects of Chamaecyparis obtusa essential oil on pain-related behavior and expression of pro-inflammatory cytokines in carrageenan-induced arthritis in rats. AB - Chamaecyparis obtusa essential oil (COE) has been widely used to treat allergic diseases and was suggested to exert anti-inflammatory, antioxidant, and antimicrobial effects. This study evaluated the effects of COE on pain-related behavior and pro-inflammatory cytokines in rats with carrageenan (CGN)-induced arthritis. Reduced dynamic weight load on inflamed joint in voluntarily walking rats was used as the behavior test for arthritic pain; 10% COE-treated group was significantly attenuated pain (6-8 h post-CGN injection) compared to VEH (mineral oil)-treated group. In addition, the protein levels of interleukin (IL)-1beta, tumor necrosis factor-alpha, IL-6 (6-8 h), and cyclooxygenase (COX)-2 (8 h) within the synovial membrane, as well as IL-1beta, COX-2 (6-8 h), and IL-6 (5-7 h) within the meniscus, of 10% COE-treated group were significantly reduced. The current results implicate that COE has anti-inflammatory and anti-nociceptive effects on arthritis in rats. PMID- 26581237 TI - Beginning of a novel frontier: T-cell-directed immune manipulation in lymphomas. AB - Checkpoint inhibitors with monoclonal antibodies targeting the CTLA-4 or PD-1 axis have revolutionized treatment in some solid tumors, especially melanoma and lung. The role of the CTLA-4 and PD-1 pathways and their inhibition in lymphoma may be different compared to solid tumors. In heavily pretreated Hodgkin lymphoma, PD-1-directed treatment has led to high remission rates. Several studies are now conducted also including diffuse large B-cell and follicular lymphoma. Besides antibody-based immunotherapy, treatment with chimeric antigen receptor (CAR) T-cells has also come back to the focus of recent studies. Clinical evidence of CAR T-cell treatment in B-cell malignancies is limited to small series, because of the dedicated resources needed. However, impressive response rates have been observed, but toxicities associated with cytokine release can be very severe and fatal. We herein review the background, early clinical evidence, and future perspectives of T-cell-directed immune manipulation for lymphomas including checkpoint inhibitors and CAR T-cell therapies. PMID- 26581238 TI - Key structural and functional differences between early and advanced glycation products. AB - Most of the studies on advanced glycation end products (AGE) have been carried out with uncharacterized mixtures of AGE, so the observed effects cannot be linked to defined structures. Therefore, we analysed the structural differences between glycated human serum albumin (gHSA), a low glycated protein, and AGE human serum albumin (AGE-HSA), a high glycated protein, and we compared their effects on endothelial functionality. Specifically, we characterized glycation and composition on both early and advanced stage glycation products of gHSA and AGE-HSA by using the MALDI-TOF-mass spectrometry assay. Furthermore, we studied the effects of both types of glycation products on reactive oxygen species (ROS) production and in the expression of vascular and intercellular cell adhesion molecules (VCAM-1 and ICAM-1) on human umbilical endothelial cells (HUVEC). We also measured the adhesion of peripheral blood mononuclear cells (PBMC) to HUVEC. Low concentrations of gHSA enhanced long-lasting ROS production in HUVEC, whereas lower concentrations of AGE-HSA caused the anticipation of the induced extracellular ROS production. Both gHSA and AGE-HSA up-regulated the expression of VCAM-1 and ICAM-1 at mRNA levels. Nevertheless, only AGE-HSA increased protein levels and enhanced the adhesion of PBMC to HUVEC monolayers. Functional differences were observed between gHSA and AGE-HSA, causing the latter an anticipation of the pro-oxidant effects in comparison to gHSA. Moreover, although both molecules induced genetic up-regulation of adhesion molecules in HUVEC, only the high glycated protein functionally increased mononuclear cell adhesion to endothelial monolayers. These observations could have important clinical consequences in the development of diabetic vascular complications. PMID- 26581240 TI - Current sampling and analysis techniques in breath research--results of a task force poll. PMID- 26581239 TI - Automated Evaluation of Crithidia luciliae Based Indirect Immunofluorescence Tests: A Novel Application of the EUROPattern-Suite Technology. AB - Systemic lupus erythematosus (SLE) is a severe rheumatic autoimmune disease with various clinical manifestations. Anti-dsDNA antibodies are an important immunological hallmark of SLE and their occurrence represents a major criterion for the diagnosis. Among the commonly applied test systems for determination of anti-dsDNA antibodies, the indirect immunofluorescence test (IIFT) using the flagellated kinetoplastida Crithidia luciliae is considered to be highly disease specific at moderate sensitivity. Since IIFT, however, is claimed to be affected by subjective interpretation and a lack of standardization, there has been an increasing demand for automated pattern interpretation of immunofluorescence reactions in recent years. Corresponding platforms are already available for evaluation of anti-nuclear antibody (ANA) IIFT on HEp-2 cells, the recommended "gold standard" for ANA screening in the diagnosis of various systemic rheumatic autoimmune diseases. For one of these systems, the "EUROPattern-Suite" computer aided immunofluorescence microscopy (CAIFM), automated interpretation of microscopic fluorescence patterns was extended to the Crithidia luciliae based anti-dsDNA IIFT. PMID- 26581241 TI - Brachial Low-Flow-Mediated Constriction is Associated with Delayed Brachial Flow Mediated Dilation. AB - AIM: Flow-mediated vasodilation (FMD) of the brachial artery measures the ability of the artery to dilate after a forearm ischemia lasting for 5 min. During ischemia, and therefore in conditions of low flow, constriction of the brachial artery (L-FMC) has sometimes been reported. The meaning of L-FMC is still unclear. The aims of our study were to establish the prevalence of subjects with L-FMC, to determine whether the magnitude of L-FMC correlates with magnitude of FMD, and to determine whether L-FMC can be used to predict FMD timing. METHODS: A total of 179 outpatients were studied, and the brachial artery diameter was measured every minute during the 5 min forearm ischemia. Subjects who had at least one measurement showing a constriction of > 1% during ischemia were defined as constrictors. FMD was evaluated at 50 s, 2 min, and 3 min after cuff release. On the basis of time, the subjects in whom maximal dilation had occurred were divided into Early, Late, or No dilators. RESULTS: The brachial artery diameter of 70 subjects (39%) constricted during ischemia. Higher the constriction during ischemia, lower was the dilation after ischemia. Constrictors were more likely to have Late (OR 2.6; ICs 95% 1.19-5.81, p=0.02) or No dilation (OR 4.8; ICs 95% 1.90-12-16, p=0.02) compared with no constrictors. CONCLUSIONS: The present study reveals that almost 40% of the subjects had brachial artery L-FMC and a more pronounced constriction during ischemia correlated with a lower dilation after ischemia. Finally, the prevalence of subjects showing L-FMC was significantly higher among subjects with delayed or no vasodilation, suggesting that L-FMC may be a marker of endothelial dysfunction. PMID- 26581242 TI - A First-in-Human Phase I Study of the Oral p38 MAPK Inhibitor, Ralimetinib (LY2228820 Dimesylate), in Patients with Advanced Cancer. AB - PURPOSE: p38 MAPK regulates the production of cytokines in the tumor microenvironment and enables cancer cells to survive despite oncogenic stress, radiotherapy, chemotherapy, and targeted therapies. Ralimetinib (LY2228820 dimesylate) is a selective small-molecule inhibitor of p38 MAPK. This phase I study aimed to evaluate the safety and tolerability of ralimetinib, as a single agent and in combination with tamoxifen, when administered orally to patients with advanced cancer. EXPERIMENTAL DESIGN: The study design consisted of a dose escalation phase performed in a 3+3 design (Part A; n = 54), two dose confirmation phases [Part B at 420 mg (n = 18) and Part C at 300 mg (n = 8)], and a tumor-specific expansion phase in combination with tamoxifen for women with hormone receptor-positive metastatic breast cancer refractory to aromatase inhibitors (Part D; n = 9). Ralimetinib was administered orally every 12 hours on days 1 to 14 of a 28-day cycle. RESULTS: Eighty-nine patients received ralimetinib at 11 dose levels (10, 20, 40, 65, 90, 120, 160, 200, 300, 420, and 560 mg). Plasma exposure of ralimetinib (Cmax and AUC) increased in a dose dependent manner. After a single dose, ralimetinib inhibited p38 MAPK-induced phosphorylation of MAPKAP-K2 in peripheral blood mononuclear cells. The most common adverse events, possibly drug-related, included rash, fatigue, nausea, constipation, pruritus, and vomiting. The recommended phase II dose was 300 mg every 12 hours as monotherapy or in combination with tamoxifen. Although no patients achieved a complete response or partial response,19 patients (21.3%) achieved stable disease with a median duration of 3.7 months, with 9 of these patients on study for >= 6 cycles. CONCLUSIONS: Ralimetinib demonstrated acceptable safety, tolerability, and pharmacokinetics for patients with advanced cancer. PMID- 26581244 TI - Are Doses and Schedules of Small-Molecule Targeted Anticancer Drugs Recommended by Phase I Studies Realistic? AB - Tolerability of molecularly targeted agents (MTA) used in cancer therapeutics is determined in phase I trials. We reviewed the reported incidence of toxicity in phase III trials at doses and schedules recommended by phase I trials to evaluate whether these recommendations are realistic when drugs are used in larger populations of patients. We systematically reviewed a safety profile of small molecule (SM-MTA) and mAb MTA (MA-MTA) approved by the FDA in the last 12 years. There was a significantly increased percentage of grade 3 or 4 adverse events reported with SM-MTA compared with MA-MTA [40% vs. 27%; RR 1.5; 95% confidence interval (CI), 1.10-2.25, P = 0.038] in phase III studies. Importantly, a substantial proportion of patients (45%) treated with SM-MTA required dose modifications due to drug-related toxicity in phase III trials. However, this toxicity was associated to a definitive study drug discontinuation in only 9%. Overall, 25% of SM-MTA declared recommended phase II doses below MTD based on pharmacokinetic-pharmacodynamic data and these trials were associated with a significantly reduced number of dose modifications in registration trials (32% vs. 50%; RR 0.64; 95% CI, 0.43-0.88, P = 0.01). Tolerability is going to come into further focus due to the need for combinations of SM-MTA and other anticancer agents. There was a higher incidence of grade 3-4 toxicity in phase III trials in combinations versus single-agent SM-MTAs (64% vs. 37%; RR 1.73; 95% CI, 1.3-2.3, P = 0.001). These results indicate that phase I studies underestimate toxicity while recommending doses of SM-MTA. Clin Cancer Res; 22(9); 2127-32. (c)2015 AACR. PMID- 26581243 TI - Premedication and Chemotherapy Agents do not Impair Imgatuzumab (GA201)-Mediated Antibody-Dependent Cellular Cytotoxicity and Combination Therapies Enhance Efficacy. AB - PURPOSE: Imgatuzumab (GA201) is a novel anti-EGFR mAb that is glycoengineered for enhanced antibody-dependent cellular cytotoxicity (ADCC). Future treatment schedules for imgatuzumab will likely involve the use of potentially immunosuppressive drugs, such as premedication therapies, to mitigate infusion reactions characteristic of mAb therapy and chemotherapy combination partners. Because of the strong immunologic component of mode of action of imgatuzumab, it is important to understand whether these drugs influence imgatuzumab-mediated ADCC and impact efficacy. EXPERIMENTAL DESIGN: We performed a series of ADCC assays using human peripheral blood mononuclear cells that were first preincubated in physiologically relevant concentrations of commonly used premedication drugs and cancer chemotherapies. The ability of common chemotherapy agents to enhance the efficacy of imgatuzumab in vivo was then examined using orthotopic xenograft models of human cancer. RESULTS: A majority of premedication and chemotherapy drugs investigated had no significant effect on the ADCC activity of imgatuzumab in vitro Furthermore, enhanced in vivo efficacy was seen with imgatuzumab combination regimens compared with single-agent imgatuzumab, single-agent chemotherapy, or cetuximab combinations. CONCLUSIONS: These data indicate that medications currently coadministered with anti-EGFR therapies are unlikely to diminish the ADCC capabilities of imgatuzumab. Further studies using syngeneic models with functional adaptive T-cell responses are now required to fully understand how chemotherapy agents will influence a long-term response to imgatuzumab therapy. Thus, this study and future ones can provide a framework for designing imgatuzumab combination regimens with enhanced efficacy for investigation in phase II trials. Clin Cancer Res; 22(10); 2453-61. (c)2015 AACR. PMID- 26581245 TI - Adrenergic Stimulation of DUSP1 Impairs Chemotherapy Response in Ovarian Cancer. AB - PURPOSE: Chronic adrenergic activation has been shown to associate with adverse clinical outcomes in cancer patients, but the underlying mechanisms are not well understood. The focus of the current study was to determine the functional and biologic effects of adrenergic pathways on response to chemotherapy in the context of ovarian cancer. EXPERIMENTAL DESIGN: Increased DUSP1 production by sympathetic nervous system mediators (e.g., norepinephrine) was analyzed by real time quantitative RT-PCR and by Western blotting. In vitro chemotherapy-induced cell apoptosis was examined by flow cytometry. For in vivo therapy, a well characterized model of chronic stress was used. RESULTS: Catecholamines significantly inhibited paclitaxel- and cisplatin-induced apoptosis in ovarian cancer cells. Genomic analyses of cells treated with norepinephrine identified DUSP1 as a potential mediator. DUSP1 overexpression resulted in reduced paclitaxel-induced apoptosis in ovarian cancer cells compared with control; conversely, DUSP1 gene silencing resulted in increased apoptosis compared with control cells. DUSP1 gene silencing in vivo significantly enhanced response to paclitaxel and increased apoptosis. In vitro analyses indicated that norepinephrine-induced DUSP1 gene expression was mediated through ADRB2 activation of cAMP-PLC-PKC-CREB signaling, which inhibits JNK-mediated phosphorylation of c-Jun and protects ovarian cancer cells from apoptosis. Moreover, analysis of The Cancer Genome Atlas data showed that increased DUSP1 expression was associated with decreased overall (P= 0.049) and progression-free (P= 0.0005) survival. CONCLUSIONS: These findings provide a new understanding of the mechanisms by which adrenergic pathways can impair response to chemotherapy and have implications for cancer management. PMID- 26581246 TI - An Open-Label, Randomized Phase II Trial of Personalized Peptide Vaccination in Patients with Bladder Cancer that Progressed after Platinum-Based Chemotherapy. AB - PURPOSE: The prognosis of platinum-based chemotherapy-resistant metastatic urothelial cancer of the bladder remains poor. Personalized selection of the right peptides for each patient could be a novel approach for a cancer vaccine to boost anticancer immunity. EXPERIMENTAL DESIGN: In this randomized, open-label, phase II study, patients ages >=18 years with progressive bladder cancer after first-line platinum-based chemotherapy were randomly assigned (1:1) to receive personalized peptide vaccination (PPV) plus best supportive care (BSC) or BSC. PPV treatment used a maximum of four peptides chosen from 31 candidate peptides according to human leukocyte antigen types and peptide-reactive IgG titers, for 12 s.c. injections (8 injections, weekly; 4 injections, bi-weekly). The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), immune response, and toxicity. RESULTS: Eighty patients were randomly assigned to receive either PPV plus BSC (n = 39) or BSC (n = 41). No significant improvement in PFS was noted [HR, 0.7; 95% confidence interval (CI), 0.4-1.2, P = 0.17]. For the secondary endpoints, PPV plus BSC significantly prolonged OS compared with BSC (HR, 0.58; 95% CI, 0.34-0.99, P = 0.049), with median OS of 7.9 months (95% CI, 3.5-12.0) in the PPV plus BSC and 4.1 months (95% CI, 2.8-6.9) in the BSC. PPV treatment was well tolerated, without serious adverse drug reactions. CONCLUSIONS: PPV could not prolong PFS, but OS appeared to be improved with low toxicity and immune responses. Further large-scale, randomized trials are needed to confirm these results. PMID- 26581247 TI - Role of P38 MAPK on MMP Activity in Photothrombotic Stroke Mice as Measured using an Ultrafast MMP Activatable Probe. AB - Matrix metalloproteinases (MMPs) exert a dual effect in ischemic stroke and thus represent an ideal target for detection and therapy. However, to date, all clinical trials of MMP inhibitors have failed, and alternative drug candidates and therapeutic targets are urgently required. Nonetheless, further investigations are limited by the lack of non-invasive imaging techniques. Here, we report a novel, fast and ultrasensitive MMP activatable optical imaging probe for the dynamic visualization of MMP activity in photothrombotic stroke mice. This probe provides a significant signal enhancement in as little as 15 min, with the highest signal intensity occurring at 1 h post-injection, and shows high sensitivity in measuring MMP activity alterations, which makes it specifically suitable for the real-time visualization of MMP activity and drug discovery in preclinical research. Moreover, using this probe, we successfully demonstrate that the regulation of the p38 mitogen-activated protein kinase (MAPK) signal pathway is capable of modulating MMP activity after stroke, revealing a novel regulatory mechanism of postischemic brain damage and overcoming the limitations of traditional therapeutic strategies associated with MMP inhibitors by using a non-invasive molecular imaging method. PMID- 26581249 TI - Interventional cardiology: Treating nonischaemic stable CAD lesions--safe to DEFER? PMID- 26581248 TI - Functional role of pyruvate kinase from Lactobacillus bulgaricus in acid tolerance and identification of its transcription factor by bacterial one-hybrid. AB - Lactobacillus delbrueckii subsp. bulgaricus develops acid tolerance response when subjected to acid stress conditions, such as the induction of enzymes associated with carbohydrate metabolism. In this study, pyk gene encoding pyruvate kinase was over-expressed in heterologous host Lactococcus lactis NZ9000, and SDS-PAGE analysis revealed the successful expression of this gene in NZ9000. The survival rate of Pyk-overproducing strain was 45-fold higher than the control under acid stress condition (pH 4.0). In order to determine the transcription factor (TF) which regulates the expression of pyk by bacterial one-hybrid, we constructed a TF library including 65 TFs of L. bulgaricus. Western blotting indicated that TFs in this library could be successfully expressed in host strains. Subsequently, the promoter of pfk-pyk operon in L. bulgaricus was identified by 5'-RACE PCR. The bait plasmid pH3U3-p01 carrying the deletion fragment of pfk-pyk promoter captured catabolite control protein A (CcpA) which could regulate the expression of pyk by binding to a putative catabolite-responsive element (5'-TGTAAGCCCTAACA 3') upstream the -35 region. Real-time qPCR analysis revealed the transcription of pyk was positively regulated by CcpA. This is the first report about identifying the TF of pyk in L. bulgaricus, which will provide new insight into the regulatory network. PMID- 26581250 TI - Hypertension: New study REVEALs no survival benefit of warfarin for IPAH. PMID- 26581253 TI - Defensive drives. PMID- 26581251 TI - Internal-Modified Dithiol DNA-Directed Au Nanoassemblies: Geometrically Controlled Self-Assembly and Quantitative Surface-Enhanced Raman Scattering Properties. AB - In this work, a hierarchical DNA-directed self-assembly strategy to construct structure-controlled Au nanoassemblies (NAs) has been demonstrated by conjugating Au nanoparticles (NPs) with internal-modified dithiol single-strand DNA (ssDNA) (Au-B-A or A-B-Au-B-A). It is found that the dithiol-ssDNA-modified Au NPs and molecule quantity of thiol-modified ssDNA grafted to Au NPs play critical roles in the assembly of geometrically controlled Au NAs. Through matching Au-DNA self assembly units, geometrical structures of the Au NAs can be tailored from one dimensional (1D) to quasi-2D and 2D. Au-B-A conjugates readily give 1D and quasi 2D Au NAs while 2D Au NAs can be formed by A-B-Au-B-A building blocks. Surface enhanced Raman scattering (SERS) measurements and 3D finite-difference time domain (3D-FDTD) calculation results indicate that the geometrically controllable Au NAs have regular and linearly "hot spots"-number-depended SERS properties. For a certain number of NPs, the number of "hot spots" and accordingly enhancement factor of Au NAs can be quantitatively evaluated, which open a new avenue for quantitative analysis based on SERS technique. PMID- 26581252 TI - Collective effects of common SNPs in foraging decisions in Caenorhabditis elegans and an integrative method of identification of candidate genes. AB - Optimal foraging decision is a quantitative flexible behavior, which describes the time at which animals choose to abandon a depleting food supply. The total minor allele content (MAC) in an individual has been shown to correlate with quantitative variations in complex traits. We have studied the role of MAC in the decision to leave a food lawn in recombinant inbred advanced intercross lines (RIAILs) of Caenorhabditis elegans. We found a strong link between MAC and the food lawn leaving rates (Spearman r = 0.4, P = 0.005). We identified 28 genes of unknown functions whose expression levels correlated with both MAC and leaving rates. When examined by RNAi experiments, 8 of 10 tested among the 28 affected leaving rates, whereas only 2 of 9 did among genes that were only associated with leaving rates but not MAC (8/10 vs 2/9, P < 0.05). The results establish a link between MAC and the foraging behavior and identify 8 genes that may play a role in linking MAC with the quantitative nature of the trait. The method of correlations with both MAC and traits may find broad applications in high efficiency identification of target genes for other complex traits in model organisms and humans. PMID- 26581254 TI - Research for all. PMID- 26581255 TI - Dope rules. PMID- 26581256 TI - Time to cry out for academic freedom. PMID- 26581268 TI - Long-sought biological compass discovered. PMID- 26581269 TI - Freefall space cubes are test for gravitational wave spotter. PMID- 26581271 TI - Wayward satellites repurposed to test general relativity. PMID- 26581270 TI - Racial bias continues to haunt NIH grants. PMID- 26581273 TI - The exoplanet files. PMID- 26581274 TI - The quantum source of space-time. PMID- 26581275 TI - Sustainability: Transfer project cannot meet China's water needs. PMID- 26581276 TI - History: Einstein was no lone genius. PMID- 26581277 TI - Mathematics: Logic and Lewis Carroll. PMID- 26581279 TI - Cannabis: monitor policy changes. PMID- 26581280 TI - Peat fires: emissions likely to worsen. PMID- 26581281 TI - Cannabis: debated schizophrenia link. PMID- 26581282 TI - Energy: Time for Russia to tap renewables. PMID- 26581283 TI - Peat fires: consumers to help beat them out. PMID- 26581284 TI - Richard Heck (1931-2015). PMID- 26581285 TI - Imaging techniques: Extra dimension for bone analysis. PMID- 26581286 TI - Astrophysics: Growing planet brought to light. PMID- 26581287 TI - Rehabilitation: Boost for movement. PMID- 26581288 TI - Ecology: Ecosystem responses to climate extremes. PMID- 26581290 TI - Accreting protoplanets in the LkCa 15 transition disk. AB - Exoplanet detections have revolutionized astronomy, offering new insights into solar system architecture and planet demographics. While nearly 1,900 exoplanets have now been discovered and confirmed, none are still in the process of formation. Transition disks, protoplanetary disks with inner clearings best explained by the influence of accreting planets, are natural laboratories for the study of planet formation. Some transition disks show evidence for the presence of young planets in the form of disk asymmetries or infrared sources detected within their clearings, as in the case of LkCa 15 (refs 8, 9). Attempts to observe directly signatures of accretion onto protoplanets have hitherto proven unsuccessful. Here we report adaptive optics observations of LkCa 15 that probe within the disk clearing. With accurate source positions over multiple epochs spanning 2009-2015, we infer the presence of multiple companions on Keplerian orbits. We directly detect Halpha emission from the innermost companion, LkCa 15 b, evincing hot (about 10,000 kelvin) gas falling deep into the potential well of an accreting protoplanet. PMID- 26581291 TI - Nanostructure surveys of macroscopic specimens by small-angle scattering tensor tomography. AB - The mechanical properties of many materials are based on the macroscopic arrangement and orientation of their nanostructure. This nanostructure can be ordered over a range of length scales. In biology, the principle of hierarchical ordering is often used to maximize functionality, such as strength and robustness of the material, while minimizing weight and energy cost. Methods for nanoscale imaging provide direct visual access to the ultrastructure (nanoscale structure that is too small to be imaged using light microscopy), but the field of view is limited and does not easily allow a full correlative study of changes in the ultrastructure over a macroscopic sample. Other methods of probing ultrastructure ordering, such as small-angle scattering of X-rays or neutrons, can be applied to macroscopic samples; however, these scattering methods remain constrained to two dimensional specimens or to isotropically oriented ultrastructures. These constraints limit the use of these methods for studying nanostructures with more complex orientation patterns, which are abundant in nature and materials science. Here, we introduce an imaging method that combines small-angle scattering with tensor tomography to probe nanoscale structures in three-dimensional macroscopic samples in a non-destructive way. We demonstrate the method by measuring the main orientation and the degree of orientation of nanoscale mineralized collagen fibrils in a human trabecula bone sample with a spatial resolution of 25 micrometres. Symmetries within the sample, such as the cylindrical symmetry commonly observed for mineralized collagen fibrils in bone, allow for tractable sampling requirements and numerical efficiency. Small-angle scattering tensor tomography is applicable to both biological and materials science specimens, and may be useful for understanding and characterizing smart or bio-inspired materials. Moreover, because the method is non-destructive, it is appropriate for in situ measurements and allows, for example, the role of ultrastructure in the mechanical response of a biological tissue or manufactured material to be studied. PMID- 26581292 TI - Six-dimensional real and reciprocal space small-angle X-ray scattering tomography. AB - When used in combination with raster scanning, small-angle X-ray scattering (SAXS) has proven to be a valuable imaging technique of the nanoscale, for example of bone, teeth and brain matter. Although two-dimensional projection imaging has been used to characterize various materials successfully, its three dimensional extension, SAXS computed tomography, poses substantial challenges, which have yet to be overcome. Previous work using SAXS computed tomography was unable to preserve oriented SAXS signals during reconstruction. Here we present a solution to this problem and obtain a complete SAXS computed tomography, which preserves oriented scattering information. By introducing virtual tomography axes, we take advantage of the two-dimensional SAXS information recorded on an area detector and use it to reconstruct the full three-dimensional scattering distribution in reciprocal space for each voxel of the three-dimensional object in real space. The presented method could be of interest for a combined six dimensional real and reciprocal space characterization of mesoscopic materials with hierarchically structured features with length scales ranging from a few nanometres to a few millimetres--for example, biomaterials such as bone or teeth, or functional materials such as fuel-cell or battery components. PMID- 26581293 TI - North Pacific deglacial hypoxic events linked to abrupt ocean warming. AB - Marine sediments from the North Pacific document two episodes of expansion and strengthening of the subsurface oxygen minimum zone (OMZ) accompanied by seafloor hypoxia during the last deglacial transition. The mechanisms driving this hypoxia remain under debate. We present a new high-resolution alkenone palaeotemperature reconstruction from the Gulf of Alaska that reveals two abrupt warming events of 4-5 degrees Celsius at the onset of the Bolling and Holocene intervals that coincide with sudden shifts to hypoxia at intermediate depths. The presence of diatomaceous laminations and hypoxia-tolerant benthic foraminiferal species, peaks in redox-sensitive trace metals, and enhanced (15)N/(14)N ratio of organic matter, collectively suggest association with high export production. A decrease in (18)O/(16)O values of benthic foraminifera accompanying the most severe deoxygenation event indicates subsurface warming of up to about 2 degrees Celsius. We infer that abrupt warming triggered expansion of the North Pacific OMZ through reduced oxygen solubility and increased marine productivity via physiological effects; following initiation of hypoxia, remobilization of iron from hypoxic sediments could have provided a positive feedback on ocean deoxygenation through increased nutrient utilization and carbon export. Such a biogeochemical amplification process implies high sensitivity of OMZ expansion to warming. PMID- 26581295 TI - El Nino-Southern Oscillation, local weather and occurrences of dengue virus serotypes. AB - Severe dengue fever is usually associated with secondary infection by a dengue virus (DENV) serotype (1 to 4) that is different to the serotype of the primary infection. Dengue outbreaks only occur following importations of DENV in Cairns, Australia. However, the majority of imported cases do not result in autochthonous transmission in Cairns. Although DENV transmission is strongly associated with the El Nino-Southern Oscillation (ENSO) climate cycle and local weather conditions, the frequency and potential risk factors of infections with the different DENV serotypes, including whether or not they differ, is unknown. This study used a classification tree model to identify the hierarchical interactions between Southern Oscillation Index (SOI), local weather factors, the presence of imported serotypes and the occurrence of the four autochthonous DENV serotypes from January 2000-December 2009 in Cairns. We found that the 12-week moving average of SOI and the 2-week moving average of maximum temperature were the most important factors influencing the variation in the weekly occurrence of the four DENV serotypes, the likelihoods of the occurrence of the four DENV serotypes may be unequal under the same environmental conditions, and occurrence may be influenced by changes in global and local environmental conditions in Cairns. PMID- 26581296 TI - Origami rules for the construction of localized eigenstates of the Hubbard model in decorated lattices. AB - We present a method of construction of exact localized many-body eigenstates of the Hubbard model in decorated lattices, both for U = 0 and U -> infinity. These states are localized in what concerns both hole and particle movement. The starting point of the method is the construction of a plaquette or a set of plaquettes with a higher symmetry than that of the whole lattice. Using a simple set of rules, the tight-binding localized state in such a plaquette can be divided, folded and unfolded to new plaquette geometries. This set of rules is also valid for the construction of a localized state for one hole in the U -> infinity limit of the same plaquette, assuming a spin configuration which is a uniform linear combination of all possible permutations of the set of spins in the plaquette. PMID- 26581297 TI - Long-Term Follow-Up of Renal Function in Living Kidney Donors in a Single Center. AB - BACKGROUND: Living-related donor kidney transplantation has become an important way to overcome the shortage of renal source. However, ethical and social factors lead to concern about the safety of live kidney donation. This study aimed to provide more evidence about the safety of living kidney transplantations. MATERIAL AND METHODS: 148 living kidney transplantations were performed between 2000 and 2011. Living kidney donors underwent comprehensive pre- and post operation inspections, including blood test, serum creatinine, blood urea, glomerular filtration rate and urine protein, and were regularly followed up after the operation. RESULTS: All 148 operations were performed successfully, and none of the living related donors died, including 52 male and 96 female donors, with mean age of 49.8 years; 120 donors underwent retroperitoneal laparoscopic nephrectomy, while the others underwent open nephrectomy. The mean follow-up was 59.6 months. The hemoglobin (HGB) decreased and had significant differences on day 1 and week 1 compared with pre-operation HGB levels. Blood urea increased significantly compared with pre-operation blood urea levels. Serum creatinine increased but did not exceed the normal range. Glomerular filtration rate (GFR) increased after the operation. No urine protein was detected in any donors. CONCLUSIONS: Our study suggests that renal function in living related kidney donors is not damaged after uninephrectomy. PMID- 26581298 TI - CLIPPERS with diffuse white matter and longitudinally extensive spinal cord involvement. PMID- 26581299 TI - Neuroradiologic patterns and novel imaging findings in Aicardi-Goutieres syndrome. AB - OBJECTIVE: To perform an updated characterization of the neuroradiologic features of Aicardi-Goutieres syndrome (AGS). METHODS: The neuroradiologic data of 121 subjects with AGS were collected. The CT and MRI data were analyzed with a systematic approach. Moreover, we evaluated if an association exists between the neuroradiologic findings, clinical features, and genotype. RESULTS: Brain calcifications were present in 110 subjects (90.9%). Severe calcification was associated with TREX1 mutations and early age at onset. Cerebral atrophy was documented in 111 subjects (91.8%). Leukoencephalopathy was present in 120 children (99.2%), with 3 main patterns: frontotemporal, diffuse, and periventricular. White matter rarefaction was found in 54 subjects (50.0%), strongly associated with mutations in TREX1 and an early age at onset. Other novel radiologic features were identified: deep white matter cysts, associated with TREX1 mutations, and delayed myelination, associated with RNASEH2B mutations and early age at onset. CONCLUSIONS: We demonstrate that the AGS neuroradiologic phenotype is expanding by adding new patterns and findings to the classic criteria. The heterogeneity of neuroradiologic patterns is partly explained by the timing of the disease onset and reflects the complexity of the pathogenic mechanisms. PMID- 26581301 TI - Patient-Reported Impact of Symptoms in Myotonic Dystrophy Type 2 (PRISM-2). AB - OBJECTIVE: To determine the frequency and relative importance of the most life affecting symptoms in myotonic dystrophy type 2 (DM2) and to identify the factors that have the strongest association with these symptoms. METHODS: We conducted a cross-sectional study of adult patients with DM2 from a National Registry of DM2 Patients to assess the prevalence and relative importance of 310 symptoms and 21 symptomatic themes. Participant responses were compared by age categories, sex, educational attainment, employment status, and duration of symptoms. RESULTS: The symptomatic themes with the highest prevalence in DM2 were the inability to do activities (94.4%), limitations with mobility or walking (89.2%), hip, thigh, or knee weakness (89.2%), fatigue (89.2%), and myotonia (82.6%). Participants identified the inability to do activities and fatigue as the symptomatic themes that have the greatest overall effect on their lives. Unemployment, a longer duration of symptoms, and less education were associated with a higher average prevalence of all symptomatic themes (p < 0.01). Unemployment, a longer duration of symptoms, sex, and increased age were associated with a higher average effect of all symptomatic themes among patients with DM2 (p < 0.01). CONCLUSIONS: The lives of patients with DM2 are affected by a variety of symptoms. These symptoms have different levels of significance and prevalence in this population and vary across DM2 subgroups in different demographic categories. PMID- 26581300 TI - Loss of TBK1 is a frequent cause of frontotemporal dementia in a Belgian cohort. AB - OBJECTIVE: To assess the genetic contribution of TBK1, a gene implicated in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and FTD-ALS, in Belgian FTD and ALS patient cohorts containing a significant part of genetically unresolved patients. METHODS: We sequenced TBK1 in a hospital-based cohort of 482 unrelated patients with FTD and FTD-ALS and 147 patients with ALS and an extended Belgian FTD-ALS family DR158. We followed up mutation carriers by segregation studies, transcript and protein expression analysis, and immunohistochemistry. RESULTS: We identified 11 patients carrying a loss-of function (LOF) mutation resulting in an overall mutation frequency of 1.7% (11/629), 1.1% in patients with FTD (5/460), 3.4% in patients with ALS (5/147), and 4.5% in patients with FTD-ALS (1/22). We found 1 LOF mutation, p.Glu643del, in 6 unrelated patients segregating with disease in family DR158. Of 2 mutation carriers, brain and spinal cord was characterized by TDP-43-positive pathology. The LOF mutations including the p.Glu643del mutation led to loss of transcript or protein in blood and brain. CONCLUSIONS: TBK1 LOF mutations are the third most frequent cause of clinical FTD in the Belgian clinically based patient cohort, after C9orf72 and GRN, and the second most common cause of clinical ALS after C9orf72. These findings reinforce that FTD and ALS belong to the same disease continuum. PMID- 26581303 TI - Neuroimaging in Aicardi-Goutieres syndrome: Biomarkers for a progressive encephalopathy. PMID- 26581302 TI - A new titinopathy: Childhood-juvenile onset Emery-Dreifuss-like phenotype without cardiomyopathy. AB - OBJECTIVE: To identify the genetic defects present in 3 families with muscular dystrophy, contractures, and calpain 3 deficiency. METHODS: We performed targeted exome sequencing on one patient presenting a deficiency in calpain 3 on Western blot but for which mutations in the gene had been excluded. The identification of a homozygous truncating mutation in the M-line part of titin prompted us to sequence this region in 2 additional patients presenting similar clinical and biochemical characteristics. RESULTS: The 3 patients shared similar features: coexistence of limb-girdle weakness and early-onset diffuse joint contractures without cardiomyopathy. The biopsies showed rimmed vacuoles, a dystrophic pattern, and secondary reduction in calpain 3. We identified a novel homozygous mutation in the exon Mex3 of the TTN gene in the first patient. At protein level, this mutation introduces a stop codon at the level of Mex3. Interestingly, we identified truncating mutations in both alleles in the same region of the TTN gene in patients from 2 additional families. Molecular protein analyses confirm loss of the C-ter part of titin. CONCLUSIONS: Our study broadens the phenotype of titinopathies with the report of a new clinical entity with prominent contractures and no cardiac abnormality and where the recessive mutations lead to truncation of the M-line titin and secondary calpain 3 deficiency. PMID- 26581304 TI - Pregnancy outcomes in aquaporin-4-positive neuromyelitis optica spectrum disorder. AB - OBJECTIVE: To investigate the association between neuromyelitis optica spectrum disorder (NMOSD) and pregnancy outcome. METHODS: An international cohort of women with aquaporin-4 antibody-positive NMOSD and >=1 pregnancy was studied retrospectively. Multivariate logistic regression was used to investigate whether pregnancy after NMOSD onset was associated with an increased risk of miscarriage (cohort of 40 women) or preeclampsia (cohort of 57 women). RESULTS: Miscarriage rate was higher in pregnancies after NMOSD onset (42.9% [95% confidence interval 17.7%-71.1%] vs. 7.04% [2.33%-15.7%]). Pregnancies conceived after, or up to 3 years before, NMOSD onset had an increased odds ratio of miscarriage (7.28 [1.03 51.6] and 11.6 [1.05-128], respectively), independent of maternal age or history of miscarriage. Pregnancies after, or up to 1 year before, NMOSD onset ending in miscarriage were associated with increased disease activity from 9 months before conception to the end of pregnancy, compared to viable pregnancies (mean annualized relapse rate 0.707 vs. 0.100). The preeclampsia rate (11.5% [6.27% 18.9%]) was significantly higher than reported in population studies. The odds of preeclampsia were greater in women with multiple other autoimmune disorders or miscarriage in the most recent previous pregnancy, but NMOSD onset was not a risk factor. CONCLUSIONS: Pregnancy after NMOSD onset is an independent risk factor for miscarriage, and pregnancies conceived at times of high disease activity may be at increased risk of miscarriage. Women who develop NMOSD and have multiple other autoimmune disorders have greater odds of preeclampsia, independent of NMOSD onset timing. PMID- 26581306 TI - Splanchnic Vein Thrombosis: Etiology, Diagnosis, and Treatment. PMID- 26581307 TI - Rearrangement of {alpha-P2W15} to {PW6} moieties during the assembly of transition-metal-linked polyoxometalate clusters. AB - We report the formation of two polyoxotungstates of the general formula [M6(PW6O26)(alpha-P2W15O56)2(H2O)2](23-) (M = Co(II) or Mn(II)), which contain {PW6} fragments generated from the [P2W15O56](12-) precursor, which demonstrates for the first time the transformation of a Dawson lacunae into a Keggin lacunary building block. Solution analysis of the clusters has been conducted via electrospray ionisation mass spectrometry. PMID- 26581305 TI - Dopamine, reward learning, and active inference. AB - Temporal difference learning models propose phasic dopamine signaling encodes reward prediction errors that drive learning. This is supported by studies where optogenetic stimulation of dopamine neurons can stand in lieu of actual reward. Nevertheless, a large body of data also shows that dopamine is not necessary for learning, and that dopamine depletion primarily affects task performance. We offer a resolution to this paradox based on an hypothesis that dopamine encodes the precision of beliefs about alternative actions, and thus controls the outcome sensitivity of behavior. We extend an active inference scheme for solving Markov decision processes to include learning, and show that simulated dopamine dynamics strongly resemble those actually observed during instrumental conditioning. Furthermore, simulated dopamine depletion impairs performance but spares learning, while simulated excitation of dopamine neurons drives reward learning, through aberrant inference about outcome states. Our formal approach provides a novel and parsimonious reconciliation of apparently divergent experimental findings. PMID- 26581308 TI - Quality control of the blood pressure phenotype in the Gaoyou population study. AB - The Korotkoff approach is the only blood pressure (BP) measurement technique that allows contemporary data to be compared with decades of research. We randomly recruited 4483 people (53.3% women; mean age 52.1 years) from Gaoyou County, Jiangsu Province, China. Nine observers recorded the participantsTM BP three times consecutively following Chinese Society of Hypertension guidelines. We assessed the BP phenotype based on five criteria: completeness of readings, percentage of identical BP readings, odd BP readings, end-digit preference and trends in BP from the first to the third reading. The proportion of participants with identical readings were 2.0% and 3.1% for systolic (SBP) and diastolic blood pressure (DBP), respectively. Among 26,898 BP values, 0.3% ended in an odd number. Among observers, the prevalence of identical readings varied from 0% to 5.3% for SBP and from 0% to 6.8% for DBP. Compared with the expected frequency of 20%, those ending in 0 had a lower frequency (17.2%; p < 0.001), whereas those ending in 8 had a higher frequency (22.4%; p < 0.001). From the first to the third measurement, SBP and DBP decreased (p < 0.001) by 0.87 and 0.55 mmHg, respectively. In conclusion, the procedures set up in the Gaoyou study produced a high-quality BP phenotype. PMID- 26581309 TI - The impact of silica encapsulated cobalt zinc ferrite nanoparticles on DNA, lipids and proteins of rat bone marrow mesenchymal stem cells. AB - Nanomaterials are currently the subject of intense research due to their wide variety of potential applications in the biomedical, optical and electronic fields. We prepared and tested cobalt zinc ferrite nanoparticles (Co0.5Zn0.5Fe2O4+gamma [CZF-NPs]) encapsulated by amorphous silica in order to find a safe contrast agent and magnetic label for tracking transplanted cells within an organism using magnetic resonance imaging (MRI). Rat mesenchymal stem cells (rMSCs) were labeled for 48 h with a low, medium or high dose of CZF-NPs (0.05; 0.11 or 0.55 mM); silica NPs (Si-NPs; 0.11 mM) served as a positive control. The internalization of NPs into cells was verified by transmission electron microscopy. Biological effects were analyzed at the end of exposure and after an additional 72 h of cell growth without NPs. Compared to untreated cells, Annexin V/Propidium Iodide labeling revealed no significant cytotoxicity for any group of treated cells and only a high dose of CZF-NPs slowed down cell proliferation and induced DNA damage, manifested as a significant increase of DNA strand breaks and oxidized DNA bases. This was accompanied by high concentrations of 15-F2t-isoprostane and carbonyl groups, demonstrating oxidative injury to lipids and proteins, respectively. No harmful effects were detected in cells exposed to the low dose of CZF-NPs. Nevertheless, the labeled cells still exhibited an adequate relaxation rate for MRI in repeated experiments and ICP-MS confirmed sufficient magnetic label concentrations inside the cells. The results suggest that the silica-coated CZF-NPs, when applied at a non-toxic dose, represent a promising contrast agent for cell labeling. PMID- 26581311 TI - Recombinant Xeno-Free Vitronectin Supports Self-Renewal and Pluripotency in Protein-Induced Pluripotent Stem Cells. AB - Patient safety is a major concern in the application of induced pluripotent stem cells (iPSCs) in cell-based therapy. Efforts are being made to reprogram, maintain, and differentiate iPSCs in defined conditions to provide a safe source of stem cells for regenerative medicine. Recently, human fibroblasts were successfully reprogrammed into pluripotent stem cells using four recombinant proteins (OCT4, c-Myc, KLF4, and SOX2) fused with a cell-penetrating peptide (9R). These protein-induced pluripotent stem cells (piPSCs) are maintained and propagated on a feeder layer of mouse embryonic fibroblasts. Use of animal derived products in maintenance and differentiation of iPSCs poses risks of zoonotic disease transmission and immune rejection when transplanted into humans. To avoid potential incorporation of xenogenic products, we cultured piPSCs on recombinant human matrix proteins. We then tested whether recombinant human matrix proteins can support self-renewal and pluripotency of piPSCs. After long term culture on recombinant human vitronectin in xeno-free conditions, piPSCs retained the expression of pluripotent markers. The pluripotency of these cells was further evaluated by differentiating toward ectoderm, mesoderm, and endoderm lineages in vitro. In conclusion, recombinant human vitronectin can support the long-term culture and maintain the stemness of piPSCs in defined nonxenogenic conditions. PMID- 26581310 TI - Eukaryotic translation initiation factor 5A2 (eIF5A2) regulates chemoresistance in colorectal cancer through epithelial mesenchymal transition. AB - BACKGROUND: Chemoresistance is a major obstacle to successful chemotherapy for colorectal cancer. Eukaryotic translation initiation factor 5A2 (eIF5A2), one of the two isoforms in the eIF5A family, has been reported to be a new oncogene in many types of human cancer. In the present study, we aimed to investigate whether eIF5A2 was involved in the chemoresistance to doxorubicin in colorectal cancer. METHODS: Cell viability was measured by CCK-8 assay with or without doxorubicin treatment. Protein expression was detected by western blot. Tumor cells were transfected with eIF5A2 siRNA or plasmid encoding eIF5A2 to down- or up regulate the expression of eIF5A2. RESULTS: We found that eIF5A2-negtive colon cancer cells (HCT116 and HT29) were more sensitive to doxorubicin compare with the eIF5A2-positive cells (LOVO and SW480). Downregulation of eIF5A2 in LOVO and SW480 cells enhanced the chemosensitivity to doxorubicin. On the contrary, overexpression of eIF5A2 reduced doxorubicin sensitivity in colon cancer cells. In addition, eIF5A2 knockdown increased the protein level of E-cadherin and reduced vimentin expression in LOVO and SW480 cells. Meanwhile, upregulation of eIF5A2 potentiated epithelial mesenchymal transition (EMT) in colon cancer cells. Moreover, blockade of EMT with Twist siRNA abolished eIF5A2-regulated chemoresistance in colon cancer cells. CONCLUSION: Our present study demonstrated that eIF5A2 promoted the chemoresistance to doxorubicin via regulation of EMT in colon cancer cells. Therefore, eIF5A2 inhibition may be a new potential strategy for the reversal of drug resistance in colorectal cancer therapy. PMID- 26581312 TI - Safety evaluation of MP29-02 (a novel intranasal formulation of azelastine hydrochloride and fluticasone propionate) for allergic rhinitis. AB - INTRODUCTION: As a chronic disease, allergic rhinitis (AR) requires regular use of allergy medications for the effective management of symptoms. It is therefore imperative that AR treatments not only provide adequate symptom control but are also well tolerated. AREAS COVERED: MP29-02 (Dymista, Meda, Solna, Sweden) is the first new class of AR medication (WHO ATC R01AD58) since the introduction of intranasal corticosteroids (INS) almost 50 years ago. It is a novel intranasal formulation of azelastine hydrochloride and fluticasone propionate delivered in a single spray. Here we review all the safety information relevant to MP29-02, from the initial phase I bioavailability and disposition data, to the phase III 14-day and 52-week data and finally to phase IV safety data collected during MP29-02 use in routine clinical practice. EXPERT OPINION: MP29-02 is the first real therapeutic advance in AR since the introduction of INS and has the potential to change the way this disease is managed, simplifying AR treatment regimens to a single puff in each nostril twice a day. Patients will benefit from superior symptom relief MP29-02 compared to INS with the added assurance that the safety of MP29-02 has been confirmed in the short term and long term as well as in real life. PMID- 26581313 TI - Neuropsychological Effects of Mercury Exposure Among Dentists in Monastir City. AB - AIMS: The aim of this study is to assess the neuropsychological manifestations of mercury exposure in dentists. METHODS: A cross-sectional study was carried out including 64 dentists matched to a control group according to age and gender. This study protocol included a neurological evaluation, a questionnaire assessing the study groups' general characteristics and personal factors that may affect mercury urinary excretion in both groups. EUROQUEST questionnaire and Hospital Anxiety and Depression scale (HADS) were used to evaluate the neuropsychological symptoms reported during the last 12 months. In both groups, mercury impregnation was assessed by monitoring urinary mercury. RESULTS: In the exposed group, scores of neurological symptoms, memory disturbances and anxiety were found to be significantly higher than those in controls (p < 0.01). Mean scores of HAD Depression's scale were higher in the exposed group than in controls. Most of the neurotoxic manifestations were correlated to the levels of urinary mercury excretion in the exposed group. Mean levels of urinary mercury were significantly higher in the dentists group than in controls, with respective values of 21.1 +/- 19.6 ug/g of creatinine and 0.05 +/- 0.9 ug/g of creatinine. In nine dentists having urinary mercury levels higher than 35 ug/g of creatinine, neurological examination showed a bilateral and symmetric intentional tremor in both upper limbs. In the exposed group, the neuropsychological manifestations and levels of urinary mercury were found to be significantly correlated. CONCLUSION: Increased levels of urinary mercury observed in dentists suggest that exposure to mercury vapour emissions adversely affects dental professionals, therefore prevention measures should be strengthened, with a special medical supervision program of dentists exposed to mercury vapours should be implemented. We have also outlined some relevant patents in this article. PMID- 26581314 TI - Pharmacokinetics and Systemic Activity of a New Patent of an Inhaled Corticosteroid/Long-Acting beta2-Agonist Combination for Use in Asthma Therapy: Fluticasone Furoate/Vilanterol Trifenatate. AB - The present paper reviews pharmacokinetics and systemic activity of a new patent of fluticasone fumarate/vilanterol trifenatate and summarises the efficacy data in children, adolescents and adults with asthma. Bioavailability of oral deposition of fluticasone furoate is approximately 1%, of oral and pulmonary deposition 15%. Fluticasone furoate 400, 600 and 800 ug have been associated with reductions in 24h urine cortisol excretion in adults, whereas several studies on fluticasone furoate/ vilanterol trifenatate 100/25 ug and 200/25 ug once daily found no suppressive effects. Bronchodilation was detected in adults with asthma from 5 minutes after vilanterol trifenatate was inhaled and up to 24 hours after. Five large clinical trials which were sponsored by the manufacturer GlaxoSmithKline provided evidence that dry powder fluticasone furoate/vilanterol trifenatate 100/25 ug and 200/25 ug once daily are efficacious in asthma in patients >= 12 years of age. It remains to be proven, however, that once daily dosing may improve asthma control as compared to twice daily dosing. Efficacy and the systemic activity potential for hypothalamic-pituitary-adrenal and growth suppression of fluticasone furoate have not been established in children. The potential for systemic activity of fluticasone furoate in children may be assessed by knemometry. PMID- 26581315 TI - Recent Patents of Complementary and Alternative Medicine for Allergic Rhinitis. AB - Allergic rhinitis (AR) is a common respiratory disease affecting both adults and children worldwide. Affected patients may experience nasal congestion/stuffiness, rhinorrhea (anterior and/or posterior), nasal/ nasopharyngeal itching and sneezing. Allergen avoidance is the principal step in the management. Nasal saline irrigation to remove allergen (s) in the nose is a useful adjunctive therapy in the management of moderate to severe AR. Symptomatic relief and improved quality of life may be achieved in the majority of patients with appropriate pharmacotherapy. Mild-to-moderate cases are usually managed with either an oral second generation antihistamine or an intranasal corticosteroid. More severe cases may require treatment with an intranasal corticosteroid in combination with various oral medications. Patients who require medications for more than 6 months per year or have intolerable side effects from pharmacotherapy can be considered for immunotherapy. A wide range of complementary and alternative medicines (CAM) have also been proposed. This overview evaluates the evidence of use of CAM for AR. Some methods including acupuncture and herbal medicine have supportive evidence, but the efficacy of other CAM is controversial. Conversely, possible side effects of different modalities are often inadequately documented. The herbal formulae include Butterbur, Nigella sativa, Shi-Bi-Lin, Polyherbal formula, Grapeseed extract, Rosmarinic acid, Spirulina, Biminne, and Bhu-zhong-yi-qi-tong. Further research is needed to assess the efficacy and safety before they are employed in treating AR. This review article also discusses recent CAM patents for use in AR, which are exclusively traditional Chinese medicine (TCM) concoctions primarily for oral consumption but two as topical spray. Only 8 pertinent patents, all TCM compositions for treating AR and registered in 2014, were obtained. Description about their efficacy is impressive but objective outcome evaluation tools are lacking. PMID- 26581316 TI - Characterization of Electrograms from Multipolar Diagnostic Catheters during Atrial Fibrillation. AB - Atrial fibrillation (AF) is the most common arrhythmia in USA with more than 2.3 million people affected annually. Catheter ablation procedure is a method for treatment of AF, which involves 3D electroanatomic mapping of the patient's left atrium (LA) by maneuvering a conventional multipolar diagnostic catheter (MPDC) along the LA endocardial surface after which pulmonary vein (PV) isolation is performed, thus eliminating the AF triggers originating from the PVs. However, it remains unclear how to effectively utilize the information provided by the MPDC to locate the AF-sustaining sites, known as sustained rotor-like activities (RotAs). In this study, we use computer modeling to investigate the variations in the characteristics of the MPDC electrograms, namely, total conduction delay (TCD) and average cycle length (CL), as the MPDC moves towards a RotA source. Subsequently, a study with a human subject was performed in order to verify the predictions of the simulation study. The conclusions from this study may be used to iteratively direct an MPDC towards RotA sources thus allowing the RotAs to be localized for customized and improved AF ablation. PMID- 26581317 TI - Method for making a single-step etch mask for 3D monolithic nanostructures. AB - Current nanostructure fabrication by etching is usually limited to planar structures as they are defined by a planar mask. The realization of three dimensional (3D) nanostructures by etching requires technologies beyond planar masks. We present a method for fabricating a 3D mask that allows one to etch three-dimensional monolithic nanostructures using only CMOS-compatible processes. The mask is written in a hard-mask layer that is deposited on two adjacent inclined surfaces of a Si wafer. By projecting in a single step two different 2D patterns within one 3D mask on the two inclined surfaces, the mutual alignment between the patterns is ensured. Thereby after the mask pattern is defined, the etching of deep pores in two oblique directions yields a three-dimensional structure in Si. As a proof of concept we demonstrate 3D mask fabrication for three-dimensional diamond-like photonic band gap crystals in silicon. The fabricated crystals reveal a broad stop gap in optical reflectivity measurements. We propose how 3D nanostructures with five different Bravais lattices can be realized, namely cubic, tetragonal, orthorhombic, monoclinic and hexagonal, and demonstrate a mask for a 3D hexagonal crystal. We also demonstrate the mask for a diamond-structure crystal with a 3D array of cavities. In general, the 2D patterns on the different surfaces can be completely independently structured and still be in perfect mutual alignment. Indeed, we observe an alignment accuracy of better than 3.0 nm between the 2D mask patterns on the inclined surfaces, which permits one to etch well-defined monolithic 3D nanostructures. PMID- 26581318 TI - Adult systemic anaplastic large-cell lymphoma: recommendations for diagnosis and management. AB - Systemic anaplastic large-cell lymphomas (sALCLs) comprise a heterogeneous group of relatively rare T-cell non-Hodgkin lymphomas (NHLs) characterized by CD30 expression and other unifying pathologic features. Anaplastic lymphoma kinase (ALK) fusions are present in about 50% of cases. Pathological diagnosis can be challenging, particularly in ALK-negative cases. Though ALK-positive and ALK negative sALCLs are similar morphologically and immunophenotypically, they are separate entities with different genetics, clinical behavior, and outcomes. Evidence-based data evaluating treatment regimens are limited as randomized controlled trials are lacking and most prospective studies are too small to draw definitive conclusions. However, recent advances in molecular biology are bringing forth much-needed knowledge in this field, and are likely to guide further targeted therapeutic development. PMID- 26581319 TI - Can old-world and new-world monkeys judge spatial above/below relations to be the same or different? Some of them, but not all of them. AB - Chimpanzees (Pan troglodytes) with the aid of token training can achieve analogical reasoning, or the ability to understand relations-between-relations (e.g., Premack, 1976; Thompson, Oden, & Boysen, 1997). However, extraordinarily few numbers of old- and new-world monkeys have demonstrated this ability in variants of relational matching to sample tasks. Moreover, the rarity of replications leaves open the question of whether the results are normative for other captive colonies of the same species. In experiment one we attempted to replicate whether old world rhesus monkeys (Macaca mulatta) might demonstrate the same level of proficiency on a spatial above/below relational matching task as reported for old world baboons (Papio papio). None of the rhesus monkeys attained above chance performances over 10,000 training trials. In experiment two we attempted to replicate results demonstrating that new-world capuchin monkeys (Cebus apella) match above/below relations. The capuchin monkeys performed above chance only in the absence of 'Clever Hans' controls for cuing of the correct choice by the experimenters. These failures to replicate previously reported results demonstrate that some, but definitely not all monkeys can judge the equivalence of abstract 'relations between relations' and warrant further investigations into the behavioral and cognitive characteristics that underlie these similarities and differences within population and between individuals of different primate species. PMID- 26581320 TI - Different behaviour-body length correlations in two populations of juvenile three spined stickleback (Gasterosteus aculeatus). AB - Behavioural variation among individuals has received a lot of attention by behavioural ecologists in the past few years. Its causes and consequences are becoming vast areas of research. The origin and maintenance of individual variation in behaviour within and among populations is affected by many facets of the biotic and abiotic environment. Here, two populations of lab-reared juvenile three-spined sticklebacks (Gasterosteus aculeatus) are tested for three behaviours (boldness, exploration, and sociability). Given the identical rearing conditions, the only difference between these populations is the parental habitat. In both populations, correlations between behaviour and body length are found. Interestingly, these differ between the populations. In one population body length was negatively correlated with exploratory behaviour, while in the other one body length correlated negatively with sociability. Considering the identical environment these juvenile fish were exposed to, these findings suggest a potential (epi)genetic foundation for these correlations and shows that, in three-spined sticklebacks, the proximate basis for correlations between body length and behaviour appears quite malleable. PMID- 26581321 TI - Clark's nutcrackers (Nucifraga columbiana) are sensitive to distance, but not lighting when caching in the presence of a conspecific. AB - We examined the caching behavior of the Clark's nutcracker (Nucifraga columbiana), a relatively asocial corvid bird, during social and non-social conditions with conspecifics. Past work by Dally et al., (2004, 2005a) has found that the related but more social scrub jay (Aphelocoma californica) caches food in locations that are far away or that are more dimly illuminated when in the presence of an observer. Here, we used procedures comparable to those of Dally's group to examine if the less social nutcracker is also sensitive to these same factors when caching in the presence of a conspecific. We found that nutcrackers cached nuts farther away, but showed no preference for caching in a dimly compared to a brightly illuminated area when in the presence of a conspecific observer. When comparing the measures of cache protection used in the past work with scrub jays the results are consistent with the social organization of these birds; that is, the less social nutcracker engaged in fewer cache protection behaviors than the more social scrub jays, However, we explore other possible explanations for our findings given the wider body of literature on corvid cache protection suggesting that nutcrackers and scrub jays may be more comparable. PMID- 26581322 TI - Implementation of a pediatric surgical quality improvement (QI)-driven M&M conference. AB - BACKGROUND/PURPOSE: The M&M conference at Nationwide Children's Hospital (NCH) categorized failures as technical error or patient disease, but failure modes were never captured, action items rarely assigned, and follow-up rarely completed. In 2013 a QI-driven M&M conference was developed, supporting implementation of directed actions to improve quality of care. METHODS: A classification was developed to enhance analysis of complications. Each complication was analyzed for identification of failure modes with subcategorization of root cause, a level of preventability assigned, and action items designated. Failure determinations from 11/2013-10/2014 were reviewed to evaluate the distribution of failure modes and action items. RESULTS: Two-hundred thirty-seven patients with complications were reviewed. One-hundred thirty patients had complications attributed to patient disease with no individual or system failure identified, whereas 107 patients had identifiable failures. Eighty five patients had one failure identified, and 22 patients had multiple failures identified. Of the 142 failures identified in 107 patients, 112 (78.9%) were individual failures, and 30 (21.1%) were system failures. One-hundred forty-seven action items were implemented including education initiatives, establishing criteria for interdisciplinary consultation, resolving equipment inadequacies, removing high risk medications from formulary, restructuring physician handoffs, and individual practitioner counseling/training. CONCLUSIONS: Development of a QI driven M&M conference allowed us to categorize complications beyond surgical or patient disease categories, ensuring added focus on system solutions and a reliable accountability structure to ensure implementation of assigned interventions intended to address failures. This may lead to improvement in the processes of patient care. PMID- 26581323 TI - Delineation of Platelet Activation Pathway of Scutellarein Revealed Its Intracellular Target as Protein Kinase C. AB - Erigeron breviscapus has been widely used in traditional Chinese medicine (TCM) and its total flavonoid component is commonly used to treat ischemic stroke, coronary heart disease, diabetes and hypertension. Scutellarin is the major ingredient of E. breviscapus and scutellarein is one of the main bioactive metabolites of scutellarin in vivo, but the latter's pharmacological activities have not been fully characterized. Provided evidence that could inhibit platelet aggregation, the effect of scutellarein on rat washed platelets and its underlying mechanisms were evaluated in our research. Scutellarein inhibited platelet adhesion and aggregation induced by multiple G protein coupled receptor agonists such as thrombin, U46619 and ADP, in a concentration-dependent manner. Furthermore, the mild effect of scutellarein on intracellular Ca(2+) mobilization and cyclic AMP (cAMP) level was observed. On the other hand, the role of scutellarein as potential protein kinase C (PKC) inhibitor was confirmed by PKC activity analysis and molecular docking. The phorbol myristate acetate-induced platelets aggregation assay with or without ADP implied that the scutellarein takes PKC(s) as its primary target(s), and acts on it in a reversible way. Finally, scutellarein as a promising agent exhibited a high inhibition effect on ADP-induced platelet aggregation among its analogues. This study clarifies the PKC-related signaling pathway involved in antiplatelet action of scutellarein, and may be beneficial for the treatment of cardiovascular diseases. PMID- 26581324 TI - Cleavage and polyadenylation factor, Rna14 is an essential protein required for the maintenance of genomic integrity in fission yeast Schizosaccharomyces pombe. AB - Faithful segregation of chromosomes is essential for the maintenance of genome integrity. In a genetic screen to identify genes related to checkpoint function, we have characterized the role of rna14, an essential gene in the maintenance of chromosome dynamics. We demonstrate that Rna14 localizes in the nucleus and in the absence of functional Rna14, the cells exhibit chromosomal segregation defects. The mutant allele of rna14 exhibits genetic interaction with key kinetochore components and spindle checkpoint proteins. Inactivation of rna14 leads to accumulation of Bub1-GFP foci, a protein required for spindle checkpoint activation that could be due to the defects in the attachment of mitotic spindle to the chromosome. Consistently, the double mutant of rna14-11 and bub1 knockout exhibits high degree of chromosome mis-segregation. At restrictive condition, the rna14-11 mutant cells exhibit defects in cell cycle progression with high level of septation. The orthologs of Rna14 in Saccharomyces cerevisiae (sc Rna14) and human (CstF3) contain similar domain architecture and are required for 3'-end processing of pre-mRNA. We have also demonstrated that the fission yeast Rna14 is required to prevent transcriptional read-through. These findings reveal the importance of transcription termination in the maintenance of genomic stability through the regulation of kinetochore function. PMID- 26581325 TI - Re: Sun-Kui Ke et al. TRiPping over vasotonus regulation in the lung. PMID- 26581326 TI - CMV promoter mutants with a reduced propensity to productivity loss in CHO cells. AB - The major immediate-early promoter and enhancer of the human cytomegalovirus (hCMV-MIE) is one of the most potent DNA elements driving recombinant gene expression in mammalian cells. Therefore, it is widely employed not only in research but also in large-scale industrial applications, e.g. for the production of therapeutic antibodies in Chinese hamster ovary cells (CHO). As we have reported previously, multi-site methylation of hCMV-MIE is linked to productivity loss in permanently transfected CHO cells lines. In particular, the cytosine located 179 bp upstream of the transcription start site (C-179) is frequently methylated. Therefore, our objective was to study whether mutation of C-179 and other cytosines within hCMV-MIE might lessen the instability of transgene expression. We discovered that the single mutation of C-179 to G can significantly stabilise the production of recombinant protein under control of hCMV-MIE in permanently transfected CHO cells. PMID- 26581327 TI - Single and Multiple Ascending-dose Studies of Oral Delafloxacin: Effects of Food, Sex, and Age. AB - PURPOSE: The objective of this report is describe the results of 2 studies that examined the pharmacokinetic parameters, safety profile, and tolerability of single and multiple ascending doses of oral delafloxacin and the effects of food, sex, and age on oral delafloxacin pharmacokinetic parameters, safety profile, and tolerability. METHODS: The first study contained 3 parts and used unformulated delafloxacin in a capsule. Part 1 was a randomized, double-blind, placebo controlled, single (50, 100, 200, 400, 800, 1200, and 1600 mg) ascending-dose study of oral delafloxacin in healthy men. Part 2 was a single-dose crossover study in which 20 men received 250 mg delafloxacin with or without food. Part 2 also included a parallel group, double-blind, placebo-controlled study in 16 women and 16 elderly men and women who were randomized (3:1) to receive 250 mg delafloxacin or placebo. Part 3 was a randomized, double-blind, placebo controlled, multiple (100, 200, 400, 800, 1200 mg once daily for 5 days) ascending-dose study of oral delafloxacin in healthy men. The second study was a single-dose, randomized, 3-period crossover study in which participants received 900 mg delafloxacin (2 * 450-mg tablets) under fasted conditions, with a high-fat meal, or fasted with a high-fat meal 2 hours after dosing. Serial blood samples were collected, and plasma pharmacokinetic parameters of delafloxacin were determined. FINDINGS: Delafloxacin Cmax and AUC0-infinity increased with increasing oral dose over the dose range of 50 to 1600 mg. The increases in delafloxacin AUC0-infinity were dose proportional at doses of >=200 mg. Steady state was reached by day 3 of dosing with minimal accumulation of delafloxacin. The Cmax of delafloxacin was decreased slightly in the presence of food. No sex difference in delafloxacin pharmacokinetic parameters was observed. In the elderly men and women, mean delafloxacin Cmax and AUC0-infinity were 35% higher than observed for young adults, which could be partially explained by a decrease in the creatinine clearance in the elderly men and women. Delafloxacin was well tolerated at the tested doses, with gastrointestinal adverse effects observed more commonly at doses >=1200 mg. IMPLICATIONS: Delafloxacin exhibits linear pharmacokinetic parameters that reached steady state after 3 days of daily oral dosing with minimal accumulation. Delafloxacin was well tolerated throughout both studies, with gastrointestinal effects observed at the higher doses (>=1200 mg). PMID- 26581328 TI - Chemokine profiles of human visceral adipocytes from cryopreserved preadipocytes: Neutrophil activation and induction of nuclear factor-kappa B repressing factor. AB - AIMS: In obesity, infiltration of adipose tissue by proinflammatory immune cells causes chronic low-grade inflammation. We investigated the chemokine profiles of human visceral adipocytes by the reverse transcription polymerase chain reaction and the effect of human neutrophil elastase (HNE) on monocyte chemoattractant protein-1 (MCP-1) mRNA and protein levels. MAIN METHODS: Human adipocytes were obtained from cryopreserved omental preadipocytes of subjects with a body mass index (BMI) <30kg/m(2) or >30kg/m(2) and were cultured to assess chemokine production. KEY FINDINGS: Chemokine responses associated with obesity-related inflammation were well preserved in cultured human adipocytes derived from cryopreserved preadipocytes. Visceral adipocytes from subjects with a BMI >30kg/m(2) expressed mRNA for MCP-1, regulated on activation, normal T cell expressed and secreted (RANTES), epithelial cell-derived neutrophil-activating peptide-78 (ENA-78), interleukin-8 (IL-8), lymphotactin-beta, and fractalkine. Although visceral adipocytes from subjects with a BMI <30kg/m(2) also expressed MCP-1, RANTES, ENA-78, and IL-8 mRNA, neither lymphotactin-beta nor fraktalkine mRNA was detected. Interestingly, expression of MCP-1 mRNA was decreased significantly after exposure to HNE (85*10(3)MUM/L), suggesting the induction of nuclear factor-kappa B repressing factor. SIGNIFICANCE: Adipocytes from subjects with a BMI >30kg/m(2) or <30kg/m(2) have different chemokine profiles. Only adipocytes from subjects with a BMI >30kg/m(2) express lymphotactin-beta and fractalkine mRNA. Differential chemokine profiles of visceral adipocytes contribute to infiltration of adipose tissue by adaptive immune cells. Neutrophil activation is involved in induction of nuclear factor-kappa B repressing factor, resulting in regulation of immune cell trafficking. PMID- 26581330 TI - Intermediate trophoblast--A distinctive, unique and often unrecognized population of trophoblastic cells. AB - The trophoblast forms an outer layer of the blastocyst in the developing placenta and fetal membrane chorion. It is composed of different types of cells. Two main cell types are cytotrophoblasts and syncytiotrophoblasts. The third type of trophoblastic cells, often "forgotten" in most of histological and embryological textbooks, is morphologically and functionally between the first and second one, therefore, it is called the intermediate trophoblast. There is no mention of it in the internationally accepted Terminologia Embryologica. This term is not universally used by pathologists as some of them prefer the name extravillous trophoblast. This review provides an overview of morphology, localization, function and immunohistochemistry of different types of intermediate trophoblast cells. An indisputable reason for categorizing these cells as a distinct group is the fact that they are a source of various forms of gestational trophoblastic disease. PMID- 26581329 TI - Ggamma recruitment systems specifically select PPI and affinity-enhanced candidate proteins that interact with membrane protein targets. AB - Protein-protein interactions (PPIs) are crucial for the vast majority of biological processes. We previously constructed a Ggamma recruitment system to screen PPI candidate proteins and desirable affinity-altered (affinity-enhanced and affinity-attenuated) protein variants. The methods utilized a target protein fused to a mutated G-protein gamma subunit (Ggammacyto) lacking the ability to localize to the inner leaflet of the plasma membrane. However, the previous systems were adapted to use only soluble cytosolic proteins as targets. Recently, membrane proteins have been found to form the principal nodes of signaling involved in diseases and have attracted a great deal of interest as primary drug targets. Here, we describe new protocols for the Ggamma recruitment systems that are specifically designed to use membrane proteins as targets to overcome previous limitations. These systems represent an attractive approach to exploring novel interacting candidates and affinity-altered protein variants and their interactions with proteins on the inner side of the plasma membrane, with high specificity and selectivity. PMID- 26581331 TI - Biomechanical and biochemical properties of the thoracic aorta in warmblood horses, Friesian horses, and Friesians with aortic rupture. AB - BACKGROUND: Thoracic aortic rupture and aortopulmonary fistulation are rare conditions in horses. It mainly affects Friesian horses. Intrinsic differences in biomechanical properties of the aortic wall might predispose this breed. The biomechanical and biochemical properties of the thoracic aorta were characterized in warmblood horses, unaffected Friesian horses and Friesians with aortic rupture in an attempt to unravel the underlying pathogenesis of aortic rupture in Friesian horses. Samples of the thoracic aorta at the ligamentum arteriosum (LA), mid thoracic aorta (T1) and distal thoracic aorta (T2) were obtained from Friesian horses with aortic rupture (A), nonaffected Friesian (NA) and warmblood horses (WB). The biomechanical properties of these samples were determined using uniaxial tensile and rupture assays. The percentages of collagen and elastin (mg/mg dry weight) were quantified. RESULTS: Data revealed no significant biomechanical nor biochemical differences among the different groups of horses. The distal thoracic aorta displayed an increased stiffness associated with a higher collagen percentage in this area and a higher load-bearing capacity compared to the more proximal segments. CONCLUSIONS: Our findings match reported findings in other animal species. Study results did not provide evidence that the predisposition of the Friesian horse breed for aortic rupture can be attributed to altered biomechanical properties of the aortic wall. PMID- 26581332 TI - Neurological outcomes in children dead on hospital arrival. AB - INTRODUCTION: Obtaining favorable neurological outcomes is extremely difficult in children transported to a hospital without a prehospital return of spontaneous circulation (ROSC) after out-of-hospital cardiac arrest (OHCA). However, the crucial prehospital factors affecting outcomes in this cohort remain unclear. We aimed to determine the prehospital factors for survival with favorable neurological outcomes (Cerebral Performance Category 1 or 2 (CPC 1-2)) in children without a prehospital ROSC after OHCA. METHODS: Of 9093 OHCA children, 7332 children (age <18 years) without a prehospital ROSC after attempting resuscitation were eligible for enrollment. Data were obtained from a prospectively recorded Japanese national Utstein-style database from 2008 to 2012. The primary endpoint was 1-month CPC 1-2 after OHCA. RESULTS: The 1-month survival and 1-month CPC 1-2 rates were 6.92 % (n = 508) and 0.99 % (n = 73), respectively. The proportions of the following prehospital variables were significantly higher in the 1-month CPC 1-2 cohort than in the 1-month CPC 3-5 cohort: age (median, 3 years (interquartile range (IQR), 0-14) versus 1 year (IQR, 0-11), p <0.05), bystander-witnessed arrest (52/73 (71.2 %) versus 1830/7259 (25.2 %), p <0.001), initial ventricular fibrillation (VF)/pulseless ventricular tachycardia (VT) rhythm (28/73 (38.3 %) versus 241/7259 (3.3 %), p <0.001), presumed cardiac causes (42/73 (57.5 %) versus 2385/7259 (32.8 %), p <0.001), and actual shock delivery (25/73 (34.2 %) versus 314/7259 (4.3 %), p <0.0001). Multivariate logistic regression analysis indicated that 2 prehospital factors were associated with 1-month CPC 1-2: initial non-asystole rhythm (VF/pulseless VT: adjusted odds ratio ( aOR), 16.0; 95 % confidence interval (CI), 8.05-32.0; pulseless electrical activity (PEA): aOR, 5.19; 95 % CI, 2.77 9.82) and bystander-witnessed arrest (aOR, 3.22; 95 % CI, 1.84-5.79). The rate of 1-month CPC 1-2 in witnessed-arrest children with an initial VF/pulseless VT was significantly higher than that in those with other initial cardiac rhythms (15.6 % versus 2.3 % for PEA and 1.2 % for asystole, p for trend <0.001). CONCLUSIONS: The crucial prehospital factors for 1-month survival with favorable neurological outcomes after OHCA were initial non-asystole rhythm and bystander-witnessed arrest in children transported to hospitals without a prehospital ROSC. PMID- 26581333 TI - The risk of intra-cranial haemorrhage in those presenting late to the ED following a head injury: a systematic review. AB - BACKGROUND: Head injury represents an extremely common presentation to emergency departments (ED), but not all patients present immediately after injury. There is evidence that clinical deterioration following head injury will usually occur within 24 h. It is unclear whether this means that head injury patients that present in a delayed manner, especially after 24 h, have a lower prevalence of significant traumatic injuries including intra-cranial haemorrhages. METHODS: A systematic review protocol was designed with the aim of systematically identifying and evaluating studies in delayed ED presentation head injury populations in order to establish whether the prevalence of significant intra cranial injury was affected by delay in presentation. Two independent researchers assessed retrieved studies for inclusion against pre-determined inclusion criteria. Studies had to be conducted in ED head injury populations presenting in a delayed manner, and report a measure of prevalence of traumatic CT abnormality as an outcome. RESULTS: Three studies were eligible for inclusion. They were all of poor methodological quality, and heterogeneity prevented meta-analysis. The reported prevalence of traumatic intra-cranial injury on CT was between 2.2 and 6.3%. This is generally lower than reported in the literature for non-delayed presentation head injury populations. CONCLUSIONS: Available evidence suggests that head injury patients who present in a delayed fashion to the ED may have lower rates of intra-cranial injury compared to non-delayed head injury patients. However, the evidence is sparse and it is of too low quality to guide clinical practice. Further research is required to help the clinical risk assessment of this group. TRIAL REGISTRATION: PROSPERO: CRD42015016135. PMID- 26581335 TI - Age at smoking initiation and self-rated health among second grade high school boys and girls in Scania, Sweden, a cross-sectional study. AB - BACKGROUND: Smoking is usually initiated early in life and most adult regular smokers have started smoking before 18 years of age. A younger age at smoking initiation is associated with risk taking behaviours and worse health outcomes regarding psychological and somatic conditions, suggested to be caused by exposure during critical developmental periods. The present study aims to investigate self-rated health among second grade high school boys and girls related to age at smoking initiation (<14 years of age and >= 14 years of age) among current and former smokers, compared to never smokers. METHODS: Data was derived from the Scania public health survey among children and adolescents in 2012. The study was cross-sectional with retrospective information about first time cigarette smoking experiences among 3245 boys and 3434 girls in second grade of high school. Self-rated health was assessed with the question "How do you rate your general health". Associations of age at smoking initiation, current smoking status and poor self-rated health were investigated with logistic regression models. RESULTS: Crude odds ratios of poor self-rated health were increased for all smoking groups compared to never smokers. Former smoking boys and currently smoking girls with early smoking initiation had the highest odds ratios of poor self-rated health, with odds ratios (OR) 2.4 (95 % confidence interval (CI): 1.5 3.7) and OR 2.9 (95 % CI: 2.3-3.6), respectively. After adjustments for sociodemographic factors, health-related behaviours, psychosocial factors, weight and functional disabilities, the results were attenuated, but remained statistically significant regarding former and current smoking boys with early smoking initiation, OR 2.0 (95 % CI: 1.1-3.7) and OR 1.7 (95 % CI: 1.1-2.4) and for current smoking girls with early and later smoking initiation, OR 2.1 (95 % CI: 1.5-2.8) and OR 1.5 (95 % CI: 1.1-2.0). CONCLUSION: Boys and girls in second grade of high school with early smoking initiation reported poorer self-rated health than later initiators and never smokers. Poorer self-rated health persisted also after smoking cessation among early initiating boys. Further studies are needed to understand the adverse health effects associated with timing of smoking initiation. PMID- 26581334 TI - Transcriptome profiling of a spirodiclofen susceptible and resistant strain of the European red mite Panonychus ulmi using strand-specific RNA-seq. AB - BACKGROUND: The European red mite, Panonychus ulmi, is among the most important mite pests in fruit orchards, where it is controlled primarily by acaricide application. However, the species rapidly develops pesticide resistance, and the elucidation of resistance mechanisms for P. ulmi has not kept pace with insects or with the closely related spider mite Tetranychus urticae. The main reason for this lack of knowledge has been the absence of genomic resources needed to investigate the molecular biology of resistance mechanisms. RESULTS: Here, we provide a comprehensive strand-specific RNA-seq based transcriptome resource for P. ulmi derived from strains susceptible and resistant to the widely used acaricide spirodiclofen. From a de novo assembly of the P. ulmi transcriptome, we manually annotated detoxification enzyme families, target-sites of commonly used acaricides, and horizontally transferred genes implicated in plant-mite interactions and pesticide resistance. In a comparative analysis that incorporated sequences available for Panonychus citri, T. urticae, and insects, we identified radiations for detoxification gene families following the divergence of Panonychus and Tetranychus genera. Finally, we used the replicated RNA-seq data from the spirodiclofen susceptible and resistant strains to describe gene expression changes associated with resistance. A cytochrome P450 monooxygenase, as well as multiple carboxylcholinesterases, were differentially expressed between the susceptible and resistant strains, and provide a molecular entry point for understanding resistance to spirodiclofen, widely used to control P. ulmi populations. CONCLUSIONS: The new genomic resources and data that we present in this study for P. ulmi will substantially facilitate molecular studies of underlying mechanisms involved in acaricide resistance. PMID- 26581336 TI - The effect of constitutive over-expression of insulin-like growth factor 1 on the cognitive function in aged mice. AB - The neurotrophic factor insulin-like growth factor (IGF)-1 promotes neurogenesis in the mammalian brain and provides protection against brain injury. However, studies regarding the effects of IGF-1 on cognitive function in aged mice remain limited. We investigated the effects of overexpression of IGF-1 specifically in neural stem cells of the hippocampal dentate gyrus on the recognitive function in 18-month-old transgenic mice. Immunohistocytochemistry and Nissl staining revealed the increased population of BrdU-positive cells as well as the upregulated expression of Nestin and neuronal nuclei (NeuN), respective markers for neural progenitors and neurons, in the hippocampus of the aged IGF-1 transgenic mice versus the wild-type, suggesting that IGF-1 overexpression promotes neurogenesis. In addition, the IGF-1 receptor (IGF-1R), the phosphorylation of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and extracellular signal-regulated kinase (ERK) were enhanced in the transgenic mice than in the wild-type. Transgenic mice also showed superior performance in the Morris water maze and step-down memory tests to their wild-type counterparts. Moreover, the learning and memory abilities of transgenic mice were significantly undermined with the blockage of CaMKII and ERK signaling pathway. Accordingly, our findings indicated that IGF-1 may mitigate the aged-associated cognitive decline via promoting neurogenesis in the hippocampus and activating CaMKII and ERK signaling by binding with IGF-1R. PMID- 26581337 TI - Using hiPSCs to model neuropsychiatric copy number variations (CNVs) has potential to reveal underlying disease mechanisms. AB - Schizophrenia is a neuropsychological disorder with a strong heritable component; genetic risk for schizophrenia is conferred by both common variants of relatively small effect and rare variants with high penetrance. Genetically engineered mouse models can recapitulate rare variants, displaying some behavioral defects associated with schizophrenia; however, these mouse models cannot recapitulate the full genetic architecture underlying the disorder. Patient-derived human induced pluripotent stem cells (hiPSCs) present an alternative approach for studying rare variants, in the context of all other risk alleles. Genome editing technologies, such as CRISPR-Cas9, enable the generation of isogenic hiPSC lines with which to examine the functional contribution of single variants within any genetic background. Studies of these rare variants using hiPSCs have the potential to identify commonly disrupted pathways in schizophrenia and allow for the identification of new therapeutic targets. This article is part of a Special Issue entitled SI:StemsCellsinPsychiatry. PMID- 26581339 TI - Infantile hypertrophic pyloric stenosis at a tertiary care hospital in Tanzania: a surgical experience with 102 patients over a 5-year period. AB - BACKGROUND: Infantile hypertrophic pyloric stenosis (IHPS) is the most common cause of gastric outlet obstruction in infants. There is paucity of published data regarding this condition in our setting. This study describes the clinical presentation, mode of treatment and outcome of treatment of this disease and identifies factors responsible for poor outcome of these patients. METHODS: This was a descriptive retrospective study of infants with HPS admitted to Bugando Medical Centre and subsequently underwent surgery between February 2009 and January 2014. RESULTS: A total of 102 patients (M:F = 4.7:1) were studied. The median age at presentation was 5 weeks. The median duration of illness was 4 weeks. Fifty-four (52.9 %) patients occur in first-born children. Associated anomalies were reported in 7 (6.9 %) patients. Non-bilious vomiting was the most frequent symptom and it was described in all (100 %) patients. A palpable mass was found in 23.5 % of infants. The diagnosis of IHPS was made clinically in 86 (84.3 %) and by ultrasound in 16 (15.7 %) patients. The treatment was Ramstedt's pyloromyotomy in all cases. There were 6 (5.9 %) intra-operative mucosal perforations which were repaired successively. Postoperative complication was 11.8 %. The median length of hospital stay was 12 days and it was significantly associated with prolonged pre-operative hospitalization (p = 0.001). The mortality rate was 4.9 %. Age below 2 weeks, late presentation (>=14 days), severe dehydration on admission, hypokalaemia on admission and surgical site infection were the main predictors of mortality (p < 0.001). CONCLUSION: This study has shown that IHPS is a common condition in our setting. Age <2 weeks, delayed presentation, prolonged preoperative hospital stay, surgical site infection and high proportion of dehydration and electrolyte disturbance were the main predictors of poor outcome. A high index of suspicion is needed in infants with non-bilious vomiting to avoid delay in diagnosis. PMID- 26581340 TI - Effect of exercise on fluoride metabolism in adult humans: a pilot study. AB - An understanding of all aspects of fluoride metabolism is critical to identify its biological effects and avoid fluoride toxicity in humans. Fluoride metabolism and subsequently its body retention may be affected by physiological responses to acute exercise. This pilot study investigated the effect of exercise on plasma fluoride concentration, urinary fluoride excretion and fluoride renal clearance following no exercise and three exercise intensity conditions in nine healthy adults after taking a 1-mg Fluoride tablet. After no, light, moderate and vigorous exercise, respectively, the mean (SD) baseline-adjusted i) plasma fluoride concentration was 9.6(6.3), 11.4(6.3), 15.6(7.7) and 14.9(10.0) ng/ml; ii) rate of urinary fluoride excretion over 0-8 h was 46(15), 44(22), 34(17) and 36(17) MUg/h; and iii) rate of fluoride renal clearance was 26.5(9.0), 27.2(30.4), 13.1(20.4) and 18.3(34.9) ml/min. The observed trend of a rise in plasma fluoride concentration and decline in rate of fluoride renal clearance with increasing exercise intensity needs to be investigated in a larger trial. This study, which provides the first data on the effect of exercise with different intensities on fluoride metabolism in humans, informs sample size planning for any subsequent definitive trial, by providing a robust estimate of the variability of the effect. PMID- 26581338 TI - Experimental detection of short regulatory motifs in eukaryotic proteins: tips for good practice as well as for bad. AB - It has become clear in outline though not yet in detail how cellular regulatory and signalling systems are constructed. The essential machines are protein complexes that effect regulatory decisions by undergoing internal changes of state. Subcomponents of these cellular complexes are assembled into molecular switches. Many of these switches employ one or more short peptide motifs as toggles that can move between one or more sites within the switch system, the simplest being on-off switches. Paradoxically, these motif modules (termed short linear motifs or SLiMs) are both hugely abundant but difficult to research. So despite the many successes in identifying short regulatory protein motifs, it is thought that only the "tip of the iceberg" has been exposed. Experimental and bioinformatic motif discovery remain challenging and error prone. The advice presented in this article is aimed at helping researchers to uncover genuine protein motifs, whilst avoiding the pitfalls that lead to reports of false discovery. PMID- 26581341 TI - A New Na(+)-Dependent RNA-Cleaving DNAzyme with over 1000-fold Rate Acceleration by Ethanol. AB - Enzymes working in organic solvents are important for analytical chemistry, catalysis, and mechanistic studies. Although a few protein enzymes are highly active in organic solvents, little is known regarding nucleic acid-based enzymes. Herein, we report the first RNA-cleaving DNAzyme, named EtNa, that works optimally in concentrated organic solvents containing only monovalent Na(+). The EtNa DNAzyme has a rate of 2.0 h(-1) in 54% ethanol (with 120 mM NaCl and no divalent metal ions), and a Kd of 21 mm Na(+). It retains activity even in 72% ethanol as well as in DMSO. With 4 mm Na(+), the rate in 54% ethanol is >1000 fold higher than that in water. We also demonstrated the use of EtNa to measuring the ethanol content in alcoholic drinks. In total, this DNAzyme has three unique features: divalent metal independent activity, Na(+) selectivity among monovalent metals, and acceleration by organic solvents. PMID- 26581342 TI - The contributions of adjusted ambient ultraviolet B radiation at place of residence and other determinants to serum 25-hydroxyvitamin D concentrations. AB - BACKGROUND: Solar ultraviolet B (UVB) radiation is the major source of vitamin D (vitD) for humans. OBJECTIVES: To describe ambient UVB radiation at wavelengths that induce vitD synthesis (vitD-UVB) in Scotland, and to examine the relationship to serum 25-hydroxyvitamin D (25OHD). METHODS: We estimated the average vitD-UVB dose for each day of the year and for each postcode area in Scotland, using the Tropospheric Emission Monitoring Internet Service database. Cumulative and weighted vitD-UVB (CW-vitD-UVB) exposure at place of residence was calculated for each participant. Plasma 25OHD was assayed in 1964 healthy participants. RESULTS: Significant seasonal and geographical variation in vitD UVB was observed. Ambient vitD-UVB exposure at place of residence was significantly associated with plasma 25OHD (P < 0.01). An average increase in 25OHD of 1 ng mL(-1) was observed for every 1000 mJ cm(-2) higher CW-vitD-UVB dose or for every 2.5 MUg of daily supplement taken. Adequate 25OHD concentration (> 16 ng mL(-1)) was observed in the majority when CW-vitD-UVB dose was > 6000 mJ cm(-2), a level of ambient radiation achieved only in summer months in Scotland. When predicting vitD deficiency, dramatic improvement in the area under the curve was observed (from 0.55 to 0.70) after CW-vitD-UVB dose was added to the model, in addition to a range of other covariates. CONCLUSIONS: Ambient vitD-UVB can be a useful predictor of vitD status. Geotemporally mapped measurements of vitD-UVB can be used as a proxy for vitD status or as a covariate in epidemiological research, particularly if 25OHD is unavailable. PMID- 26581343 TI - Anti-DNA antibodies--quintessential biomarkers of SLE. AB - Antibodies that recognize and bind to DNA (anti-DNA antibodies) are serological hallmarks of systemic lupus erythematosus (SLE) and key markers for diagnosis and disease activity. In addition to common use in the clinic, anti-DNA antibody testing now also determines eligibility for clinical trials, raising important questions about the nature of the antibody-antigen interaction. At present, no 'gold standard' for serological assessment exists, and anti-DNA antibody binding can be measured with a variety of assay formats, which differ in the nature of the DNA substrates and in the conditions for binding and detection of antibodies. A mechanism called monogamous bivalency--in which high avidity results from simultaneous interaction of IgG Fab sites with a single polynucleotide chain- determines anti-DNA antibody binding; this mechanism might affect antibody detection in different assay formats. Although anti-DNA antibodies can promote pathogenesis by depositing in the kidney or driving cytokine production, they are not all alike, pathologically, and anti-DNA antibody expression does not necessarily correlate with active disease. Levels of anti-DNA antibodies in patients with SLE can vary over time, distinguishing anti-DNA antibodies from other pathogenic antinuclear antibodies. Elucidation of the binding specificities and the pathogenic roles of anti-DNA antibodies in SLE should enable improvements in the design of informative assays for both clinical and research purposes. PMID- 26581345 TI - Pesticides in Drinking Water - The Brazilian Monitoring Program. AB - Brazil is the world largest pesticide consumer; therefore, it is important to monitor the levels of these chemicals in the water used by population. The Ministry of Health coordinates the National Drinking Water Quality Surveillance Program (Vigiagua) with the objective to monitor water quality. Water quality data are introduced in the program by state and municipal health secretariats using a database called Sisagua (Information System of Water Quality Monitoring). Brazilian drinking water norm (Ordinance 2914/2011 from Ministry of Health) includes 27 pesticide active ingredients that need to be monitored every 6 months. This number represents <10% of current active ingredients approved for use in the country. In this work, we analyzed data compiled in Sisagua database in a qualitative and quantitative way. From 2007 to 2010, approximately 169,000 pesticide analytical results were prepared and evaluated, although approximately 980,000 would be expected if all municipalities registered their analyses. This shows that only 9-17% of municipalities registered their data in Sisagua. In this dataset, we observed non-compliance with the minimum sampling number required by the norm, lack of information about detection and quantification limits, insufficient standardization in expression of results, and several inconsistencies, leading to low credibility of pesticide data provided by the system. Therefore, it is not possible to evaluate exposure of total Brazilian population to pesticides via drinking water using the current national database system Sisagua. Lessons learned from this study could provide insights into the monitoring and reporting of pesticide residues in drinking water worldwide. PMID- 26581346 TI - Low-Grade Persistent Hyperparathyroidism After Pediatric Renal Transplant. AB - OBJECTIVES: Hyperparathyroidism, a frequent complication of chronic kidney disease, persists after renal transplant. Our aims were to examine the status of parathyroid hormone levels and to determine the clinical and biochemical risk factors of persistent hyperparathyroidism after transplant. MATERIALS AND METHODS: Our study included 44 pediatric renal transplant recipients with stable graft function. Median follow-up after transplant was 17.5 months (range, 12-126 mo). Patients did not receive routine vitamin D or calcium supplements after transplant, and none had undergone previous parathyroidectomy. Bone mineral densitometry of the lumbar spine was measured. RESULTS: Fifteen patients (34%) had parathyroid hormone levels greater than 70 pg/mL (normal range, 10-70 pg/mL). Duration of dialysis before transplant was longer in patients with persistent hyperparathyroidism. Mean serum bicarbonate levels were significantly lower in patients with persistent hyperparathyroidism than in patients without persistent hyperparathyroidism after transplant. A significant negative correlation was noted between parathyroid hormone level and serum bicarbonate level. Another significant negative correlation was shown between parathyroid hormone level and z score. CONCLUSIONS: We found that persistent hyperparathyroidism is related to longer dialysis duration, lower serum bicarbonate level, and lower z score. Pretransplant dialysis duration is an important predictor of persistent hyperparathyroidism. Early identification of factors that contribute to persistent hyperparathyroidism after transplant could lead to treatment strategies to minimize or prevent its detrimental effects on bone health and growth in pediatric transplant recipients. PMID- 26581344 TI - What is damaging the kidney in lupus nephritis? AB - Despite marked improvements in the survival of patients with severe lupus nephritis over the past 50 years, the rate of complete clinical remission after immune suppression therapy is <50% and renal impairment still occurs in 40% of affected patients. An appreciation of the factors that lead to the development of chronic kidney disease following acute or subacute renal injury in patients with systemic lupus erythematosus is beginning to emerge. Processes that contribute to end-stage renal injury include continuing inflammation, activation of intrinsic renal cells, cell stress and hypoxia, metabolic abnormalities, aberrant tissue repair and tissue fibrosis. A deeper understanding of these processes is leading to the development of novel or adjunctive therapies that could protect the kidney from the secondary non-immune consequences of acute injury. Approaches based on a molecular-proteomic-lipidomic classification of disease should yield new information about the functional basis of disease heterogeneity so that the most effective and least toxic treatment regimens can be formulated for individual patients. PMID- 26581348 TI - Early Passage Dependence of Mesenchymal Stem Cell Mechanics Influences Cellular Invasion and Migration. AB - The cellular structures and mechanical properties of human mesenchymal stem cells (hMSCs) vary significantly during culture and with differentiation. Previously, studies to measure mechanics have provided divergent results using different quantitative parameters and mechanical models of deformation. Here, we examine hMSCs prepared for clinical use and subject them to mechanical testing conducive to the relevant deformability associated with clinical injection procedures. Micropipette aspiration of hMSCs shows deformation as a viscoelastic fluid, with little variation from cell to cell within a population. After two passages, hMSCs deform as viscoelastic solids. Further, for clinical applicability during stem cell migration in vivo, we investigated the ability of hMSCs to invade into micropillar arrays of increasing confinement from 12 to 8 MUm spacing between adjacent micropillars. We find that hMSC samples with reduced deformability and cells that are more solid-like with passage are more easily able to enter the micropillar arrays. Increased cell fluidity is an advantage for injection procedures and optimization of cell selection based on mechanical properties may enhance efficacy of injected hMSC populations. However, the ability to invade and migrate within tight interstitial spaces appears to be increased with a more solidified cytoskeleton, likely from increased force generation and contractility. Thus, there may be a balance between optimal injection survival and in situ tissue invasion. PMID- 26581347 TI - Quantitative Ultrasound for Nondestructive Characterization of Engineered Tissues and Biomaterials. AB - Non-invasive, non-destructive technologies for imaging and quantitatively monitoring the development of artificial tissues are critical for the advancement of tissue engineering. Current standard techniques for evaluating engineered tissues, including histology, biochemical assays and mechanical testing, are destructive approaches. Ultrasound is emerging as a valuable tool for imaging and quantitatively monitoring the properties of engineered tissues and biomaterials longitudinally during fabrication and post-implantation. Ultrasound techniques are rapid, non-invasive, non-destructive and can be easily integrated into sterile environments necessary for tissue engineering. Furthermore, high frequency quantitative ultrasound techniques can enable volumetric characterization of the structural, biological, and mechanical properties of engineered tissues during fabrication and post-implantation. This review provides an overview of ultrasound imaging, quantitative ultrasound techniques, and elastography, with representative examples of applications of these ultrasound based techniques to the field of tissue engineering. PMID- 26581349 TI - Safety assessment of lepidopteran insect-protected transgenic rice with cry2A* gene. AB - Numerous genetically modified (GM) crops expressing proteins for insect resistance have been commercialized following extensive testing demonstrating that the foods obtained from them are as safe as that obtained from their corresponding non-GM varieties. In this paper, we report the outcome of safety studies conducted on a newly developed insect-resistant GM rice expressing the cry2A* gene by a subchronic oral toxicity study on rats. GM rice and non-GM rice were incorporated into the diet at levels of 30, 50, and 70% (w/w), No treatment related adverse or toxic effects were observed based on an examination of the daily clinical signs, body weight, food consumption, hematology, serum biochemistry, and organ weight or based on gross and histopathological examination. These results demonstrate that the GM rice with cry2A* gene is as safe for food as conventional non-GM rice. PMID- 26581350 TI - Children, Adolescents, and the Media: Ten Mistakes We've Made and How to Fix Them. PMID- 26581351 TI - Fifteen-Year-Old Female With Delayed Progression of Puberty and Visual Disturbances. PMID- 26581352 TI - Identification, Prevention, and Management of Childhood Overweight and Obesity in a Pediatric Primary Care Center. AB - Background In the United States, overweight/obesity among youth has reached epidemic proportions. The purpose of this project was to (1) examine primary care provider adherence to American Academy of Pediatrics guidelines; (2) compare adherence based on patients' weight classification, age, race, and gender; and (3) identify areas for improvement in health care delivery. Methods A retrospective chart audit and feedback quality improvement project was conducted with a stratified random sample of 175 charts of 6- to 19-year-olds seen for well child visits. Frequencies of provider adherence were reported. chi(2) Analyses of weight classification, age, race, or gender influence on adherence was calculated. Results After discussion with the primary care providers, 5 areas were identified as priorities for change (diagnosis based on BMI, parental history of obesity, sleep assessment, endocrine assessment, and attendance of patients at the follow-up visit). Conclusion Cost-efficient, feasible strategies to improve provider adherence to recommendations for identification, prevention and management of childhood overweight and obesity were identified. PMID- 26581353 TI - The Loneliness of a Long-Distance Academic. PMID- 26581354 TI - Portomesenteric Venous Thrombosis in Previously Healthy Adolescents Presenting With Subacute Abdominal Pain. PMID- 26581355 TI - Pediatric Hereditary Angioedema: Onset, Diagnostic Delay, and Disease Severity. AB - Hereditary angioedema (HAE) typically presents in childhood. Large gaps remain in our understanding of the natural history of HAE during childhood. We examined age of onset, delay in diagnosis, androgen exposure, and their influence on ultimate disease severity in a large cohort of patients with HAE. Median age of first swelling was 11 years with a median age at diagnosis of 19 years. Earlier onset of symptoms correlated with longer delays in diagnosis (P < .001) and predicted a more severe disease course, including increased number of attacks per year (P = .0009) and hospital admissions (P = .009). Earlier age of onset also significantly correlated with increased perceived HAE severity (P = .0002), negative overall life impact (P < .0001), and use of anabolic androgen. Our observations highlight the importance of early HAE diagnosis and suggest the necessity of a disease management plan once the diagnosis has been made. PMID- 26581356 TI - Abdominal Pain, Fatigue, and Constipation in a Teenager Female: Is It Worth Further Investigations? PMID- 26581357 TI - Depression, Anxiety, and Severity of Obesity in Adolescents: Is Emotional Eating the Link? AB - The purposes of this study were to characterize the impact of depression and anxiety on the severity of obesity among youth seeking weight management treatment and to determine the extent to which emotional eating mediates the relationship between depression and/or anxiety and degree of obesity. This cross sectional, retrospective chart review of 102 adolescent patients from a weight management clinic analyzed demographics, body mass index, depression (Patient Health Questionnaire-9), and anxiety (Generalized Anxiety Disorder Scale-7) screens and the Child Eating Behavior Questionnaire, Emotional Over-Eating subscale. After adjusting for demographics and emotional eating, the odds of having severe obesity versus obesity were 3.5 times higher for patients with depression compared with those without (odds ratio [OR] = 3.5; 95% CI = 1.1, 11.3; P = .038) and nearly 5 times higher for those with anxiety (OR = 4.9; CI = 1.2, 20.9; P = .030). Emotional eating, however, was not a mediator between depression/anxiety and degree of adiposity. PMID- 26581358 TI - Lactobacillus acidophilus Mixture in Treatment of Children Hospitalized With Acute Diarrhea. AB - Despite unproven effectiveness, Lactobacillus acidophilus is a widely used probiotic in the treatment of pediatric diarrhea. In this report, we evaluated the association between length of stay (LOS) for 290 young children hospitalized with acute diarrhea and adjuvant therapy with a probiotic mixture containing 80% L acidophilus that was included in treatment for 22.4% of them. Overall, no association between LOS and use of L acidophilus was recorded after controlling for age, length of diarrhea symptoms, duration of intravenous fluids, and prior exposure to antibiotic. However, LOS was directly associated with use of L acidophilus in children with negative stool studies, and no such association was recorded in children with positive stool for rotavirus or other infections. We concluded that adjuvant therapy with L acidophilus mixture is not beneficial for young children hospitalized with acute diarrhea. PMID- 26581359 TI - Psychosocial Dimensions and Functioning in Youth With Postural Orthostatic Tachycardia Syndrome. PMID- 26581360 TI - Screening Tool Predicts Future Underimmunization Among a Pediatric Practice in Tennessee. AB - The Parent Attitudes about Childhood Vaccines (PACV) survey for identifying vaccine-hesitant parents was recently validated in Washington State but did not include all recommended childhood vaccines. The current study compares vaccination rates for all recommended childhood vaccines and PACV scores at one pediatric practice in Tennessee. Children were enrolled at the 2-week well visit, and vaccination rates were assessed at 19 months of age. Outcomes at 19 months of age included mean percentage of days underimmunized and up-to-date status (yes/no) compared with PACV scores. The impact of provider on immunization status was assessed. Complete vaccination data were available for 158 children of 183 enrolled (86%). Higher PACV scores were associated with more days underimmunized (P < .001) and being overdue for vaccine doses at 19 months of age (P < .001). No difference was seen between providers and up-to-date status. Our study supports the predictive validity of the PACV for underimmunization. PMID- 26581361 TI - Implementation of Web-Based Autism Screening in an Urban Clinic. AB - Screening toddlers for autism spectrum disorder (ASD) with the Modified Checklist for Autism in Toddlers, Revised (M-CHAT-R) has been shown to lower age of diagnosis by 2 years. In order to streamline ASD screening, research is exploring the use of web-based screening during well-child checkups. The current study examined implementation of the web-based M-CHAT-R in an urban pediatric clinic in Atlanta, Georgia. Toddlers (N = 2557; 87% African American) were screened during well-child visits (Mage = 22.43 months, SD = 3.65). Using the web-based version resulted in a 58.5% increase in the number of cases screened per month. A similar proportion of toddlers in each modality screened positive (P = .43), but significantly fewer children were missing "Follow-up" in the web-based administration (P < .001). These results suggest that it is feasible to implement web-based screening in underserved populations. Future research is necessary to understand factors that facilitate successful implementation of web-based ASD screening. PMID- 26581362 TI - Clostridium difficile Colonization in Asymptomatic Infants 1 to 12 Months Old, Admitted to a Community Hospital. PMID- 26581363 TI - The anatomy and isometry of a quasi-anatomical reconstruction of the medial patellofemoral ligament. AB - PURPOSE: To describe the anatomy of the medial patellofemoral ligament (MPFL) and its relationship to the Adductor Magnus (AM) tendon as well as the behaviour exhibited in length changes during knee flexion. METHODS: Ten cadaveric knees were dissected. The length from the superior and inferior patellar origin of the MPFL to its femoral insertion was measured at different degrees of knee flexion (0 degrees , 30 degrees , 60 degrees , 90 degrees and 120 degrees ). The same measures were made from both patellar origins of the MPFL up to the femoral insertion of the AM. The distance between the insertion of the AM and the Hunter canal was also measured. RESULTS: In general, isometry up to 90 degrees was seen in all measures of the MPFL and those of the AM. The most isometric behaviour was seen in 2 measures: the length of the AM femoral insertion up to the inferior origin of the MPFL on the patella and the length of the femoral insertion of the MPFL up to the inferior origin of the MPFL on the patella. Similar behaviour was seen regardless of the anatomical or quasi-anatomical femoral point of attachment (n.s.). The distance from the AM tendon to the Hunter canal had a mean value of 78.6 mm (SD 9.4 mm). CONCLUSION: The behaviour exhibited during the changes in the length of the anatomical femoral footprint of the MPFL and the AM is similar. Neurovascular structures were not seen at risk. This is relevant in the daily clinical practice since the AM tendon might be a suitable point of insertion for MPFL reconstruction. PMID- 26581364 TI - Balancing UKA: overstuffing leads to high medial collateral ligament strains. AB - PURPOSE: Balancing unicondylar knee arthroplasty (UKA) is challenging. If not performed properly, it may lead to implant loosening or progression of osteoarthritis in the preserved compartment. This study was aimed to document the biomechanical effects of improper balancing. We hypothesised that overstuffing would lead to more valgus, higher strain in the medial collateral ligament (sMCL), and higher lateral contact force. METHODS: Six fresh-frozen cadaver specimens were mounted in a kinematic rig. Three motion patterns were applied with the native knee and following medial UKA (passive motion, open-chain extension, and squatting), while infrared cameras recorded the trajectories of markers attached to femur and tibia. Three inlay thicknesses were tested (8, 9, 10 mm). RESULTS: Overstuffed knees were in more valgus and showed less tibial rotation and higher strains in the sMCL (p < 0.05). Lateral contact forces were higher in some specimens and lower in others. Stiffening of the medial compartment by UKA, even well balanced, already leads to a knee more in valgus with a more stressed sMCL. Overstuffing increases these effects. Knees with a tight sMCL may even see lower lateral contact force. Biomechanics were closest to the native knee with understuffing. CONCLUSION: The first two hypotheses were confirmed, but not the latter. This underlines the importance of optimal balancing. Overstuffing should certainly be avoided. Although kinematics is only slightly affected, contact forces and ligament strains are considerably changed and this might be of more clinical importance. It is advisable to use thinner inlays, if stability is not compromised. PMID- 26581365 TI - The effect of intraoperative fluoroscopy on the accuracy of femoral tunnel placement in single-bundle anatomic ACL reconstruction. AB - PURPOSE: The purpose of the current study was to investigate the potential effect of intraoperative fluoroscopy on the accuracy of femoral tunnel placement in anatomic ACL reconstruction, using an ideal anatomic point as reference and evaluating postoperative tunnel placement based on 3D CT. METHODS: An experienced ACL surgeon, using the anatomic approach for femoral tunnel placement, relying on intraarticular landmarks and remnants of the torn ACL-and novel to the fluoroscopic assist-was introduced to its use. A prospective series of patients was included where group 1 (without fluoroscopy) and group 2 (with fluoroscopy) both had postoperative CT scans so that femoral tunnel position could be evaluated and compared to an ideal tunnel centre based on anatomic studies by using the Bernard and Hertel grid. RESULTS: Group 2, where fluoroscopy was used, had a mean femoral tunnel that was closer to the ideal anatomic centre than group 1. In the Bernard and Hertel grid, the distance in the high-low axis (y-axis) was found significantly closer (P = 0.001), whilst the deep-shallow axis (x-axis) and a total absolute distance were not significantly closer to the ideal described anatomic centre. CONCLUSIONS: Intraoperative fluoroscopy was found effective as an aid for placing the femoral tunnel in a more accurate position, as compared to a desired anatomic centre. Although the concept of the "one-size-fits-all" approach for tunnel placement is debatable, the avoidance of grossly misplaced tunnels is the benefit of using fluoroscopy during ACL reconstruction. The authors hold that fluoroscopy is readily available, safe and easy to use and therefore a good aid in the anatomic approach for graft tunnel placement, for example, in a learning situation, in revision cases and when performing low volumes of such surgery. LEVEL OF EVIDENCE: III. PMID- 26581366 TI - Femur bowing could be a risk factor for implant flexion in conventional total knee arthroplasty and notching in navigated total knee arthroplasty. AB - PURPOSE: This study aimed to investigate the relationship between preoperative femoral axes and femoral implant position and to determine how femoral sagittal axes, including femoral anterior bowing, influence the femoral component position in total knee arthroplasty (TKA). METHODS: The relationship between femoral axes (femoral anterior bowing, mechanical axis and the anterior cortical line, intramedullary axis) and implant position was compared in 50 conventional and 50 navigated TKAs. Outliers with more than a 3 degrees margin of error in placement of the femoral component compared with the mechanical axis in the sagittal plane were calculated. RESULTS: The femoral component flexion angle was 3.1 degrees in the conventional group and 1.6 degrees in the navigation group (p < 0.001). Anterior femoral bowing correlated positively with the angle between the mechanical axis and implant (r = 0.360, p = 0.010) in the conventional group and negatively with the angle between the anterior cortical line and flange of the femoral component (r = -0.355, p = 0.010) in navigated TKAs. Incidence of outliers was 48 % (24 patients) in the conventional group compared with 10 % (five patients) in the navigated group (p = 0.008). CONCLUSIONS: Femoral anterior bowing was an influential factor for implant position and could be a risk factor for both femoral implant flexion in conventional TKAs and notching in navigated TKAs. The results of this study should be considered by surgeons when assessing the risk factors for femoral geometry before performing TKAs, as these results may help them to avoid an overly flexed or extended position of the femoral component, which would affect clinical long-term survival. LEVEL OF EVIDENCE: Retrospective comparative study, Level III. PMID- 26581368 TI - Natural History of Asymptomatic Papillary Thyroid Microcarcinoma: Time-Dependent Changes in Calcification and Vascularity During Active Surveillance. AB - BACKGROUND: Prospective trials of non-surgical observation have shown progression rates of only 5-10% in patients with asymptomatic papillary microcarcinoma (PMC). This study investigated time-dependent changes in calcification patterns and tumor vascularity on ultrasonography (US) to clarify the natural course of PMC. METHODS: We examined calcification patterns and tumor vascularity for 480 lesions in 384 patients. Calcification patterns were classified as: (A) none; (B) micro; (C) macro; or (D) rim. Tumor vascularity was classified as rich or poor via color Doppler US. RESULTS: After a mean of 6.8 years of observation, 29 lesions (6.0%) had increased in size. Mean age for initial calcification pattern was 52.1 years for A (n = 135), 54.2 years for B (n = 235), 56.3 years for C (n = 96), and 60.1 years for D (n = 14), and the incidence rates of tumor enlargement were 9.6, 5.5, 3.2, and 0%, respectively. The cumulative rate of upgrade in calcification pattern was 51.8% at 10 years. Lesions with initially rich vascularity (n = 70) had significantly higher rate of tumor enlargement than those with poor vascularity (n = 410); however, the majority of tumor (61.4%) with initially rich vascularity had decreased their blood supply during the follow-up. Multivariate analysis showed that strong calcification (C or D) and poor vascularity at last examination correlated significantly with non-progressive disease. CONCLUSIONS: PMCs in older patients showed significantly stronger calcification patterns and poorer vascularity. Both consolidation of calcification and loss of vascularity occurred in a time-dependent manner during observation and were significant indicators for non-progressive disease. PMID- 26581369 TI - Open Repair of Primary Versus Recurrent Male Unilateral Inguinal Hernias: Perioperative Complications and 1-Year Follow-up. AB - INTRODUCTION: The recommendation in the European Hernia Society Guidelines for the treatment of recurrent inguinal hernias is to modify the technique in relation to the previous technique, and use a new plane of dissection for mesh implantation. However, the registry data show that even following previous open suture and mesh repair to treat a primary inguinal hernia, open suture and mesh repair can be used once again for a recurrent hernia. It is therefore important to know what the outcome of open repair of recurrent inguinal hernias is compared with open repair of primary inguinal hernias, while taking the previous operation into account. PATIENTS AND METHODS: In the Herniamed Registry, a total of 17,594 patients with an open primary or recurrent unilateral inguinal hernia repair in men with a 1-year follow-up were prospectively documented between September 1, 2009 and August 31, 2013. Of these patients, 15,274 (86.8 %) had an open primary and 2320 (13.2 %) open recurrent repair. In the unadjusted and multivariable analyses, the dependent variables were intra- and postoperative complications, reoperations, recurrences, pain at rest, pain on exertion, and pain requiring treatment. RESULTS: Open recurrent repair compared with the open primary operation is a significant influence factor for higher intraoperative (p = 0.01) and postoperative (p = 0.05) complication rates, recurrence rate (p < 0.001), and pain rates (p < 0.001). With regard to repair of recurrent inguinal hernia, previous open mesh repair was associated with the least favorable outcome, and with the highest odds ratio, for all outcome criteria. Open recurrent repair following previous endoscopic operation presented the least risk for postoperative complications, complication-related reoperations, and re recurrences. The pain rates identified on follow-up after open recurrent repair were lower following previous open suture operation compared with following open and endoscopic mesh repair. A significantly less favorable perioperative and 1 year follow-up outcome must be expected for open repair of recurrent inguinal hernia in comparison with open primary inguinal hernia repair. After open recurrent repair, the most favorable perioperative complication and recurrence rates were identified following previous endoscopic repair, and the lowest pain rates following previous open suture repair. Open recurrent repair following previous open mesh operation was associated with the highest risks for perioperative complications, re-recurrences, and pain. PMID- 26581371 TI - Syphacia obvelata (Nematode, Oxyuridae) infecting laboratory mice Mus musculus (Rodentia, Muridae): phylogeny and host-parasite relationship. AB - Syphacia obvelata is a pinworm nematode parasite infecting man and laboratory animals in high abundance. This parasitological study was carried out during the period of March 2014-February 2015 to investigate the helminth parasites infecting the laboratory mice Mus musculus in the Animal House at Cairo University, Egypt. The prevalence of S. obvelata in M. musculus was 75.0 %. The extent of infection with S. obvelata is analyzed according to the sex of the host mice. It was shown that the prevalence of male infection was greater than female worms. Morphological characterization revealed that the present Oxyurid species possesses a rounded cephalic end with less developed lips, esophagus divided into cylindrical corpus, and globular bulb supported internally with valvular apparatus; three mamelons are located at the ventral surface with a single chitinized spicule and a gubernaculum provided with an accessory hook in males, and ovijector apparatus opens ventrally by the vulva surrounded by protruded lips in female worms. Body of the male was 0.623-1.130 (0.830 +/- 0.11) mm long and 0.092-0.130 (0.110 +/- 0.01) mm wide; the esophagus was 0.164-0.280 (0.210 +/- 0.01) mm long; the nerve ring and excretory pore are located at 0.035-0.132 (0.073 +/- 0.01) and 0.087-0.191 (0.145 +/- 0.01) mm from the anterior end, respectively, while the female measured 2.930-4.650 (3.540 +/- 0.1) mm long and 0.120-0.232 (0.156 +/- 0.001) mm wide; the esophagus was 0.213-0.410 (0.342 +/- 0.01) mm long; the nerve ring, excretory pore, and vulval opening are located at 0.026-0.157 (0.121 +/- 0.01), 0.134-0.243 (0.195 +/- 0.01), and 0.323-0.632 (0.546 +/- 0.11) mm from the anterior end, respectively; eggs measured 0.120 0.139 (0.129 +/- 0.001) mm long and 0.030-0.052 (0.045 +/- 0.001) mm wide. It compared morphometrically with other Syphacia species described previously and showed little differences in measurements. Molecular characterization based on small subunit ribosomal DNA (rDNA) was done to confirm the obtained morphological and morphometric results. A preliminary genetic comparison between SSU rDNA of the present parasite and other species of Oxyuridae places it as a putative sister taxon to other S. obvelata. PMID- 26581372 TI - Review on the identification and role of Toxoplasma gondii antigenic epitopes. AB - Toxoplasma gondii is an obligate intracellular protozoan parasite with a broad range of hosts, and it causes severe toxoplasmasis in both humans and animals. It is well known that the progression and severity of a disease depend on the immunological status of the host. Immunological studies on antigens indicate that antigens do not exert their functions through the entire protein molecule, but instead, specific epitopes are responsible for the immune response. Protein antigens not only contain epitope structures used by B, T, cytotoxic T lymphocyte (CTL), and NK cells to mediate immunological responses but can also contain structures that are unfavorable for protective immunity. Therefore, the study of antigenic epitopes from T. gondii has not only enhanced our understanding of the structure and function of antigens, the reactions between antigens and antibodies, and many other aspects of immunology but it also plays a significant role in the development of new diagnostic reagents and vaccines. In this review, we summarized the immune mechanisms induced by antigen epitopes and the latest advances in identifying T. gondii antigen epitopes. Particular attention was paid to the potential clinical usefulness of epitopes in this context. Through a critical analysis of the current state of knowledge, we elucidated the latest data concerning the biological effects of epitopes and the immune results aimed at the development of future epitope-based applications, such as vaccines and diagnostic reagents. PMID- 26581374 TI - Detection of canine vector-borne diseases in eastern Poland by ELISA and PCR. AB - The aim of the study was to establish the prevalence of Ehrlichia canis, Anaplasma phagocytophilum and Borrelia burgdorferi in dogs in eastern Poland and to determine the factors associated with exposure (seroposity) or infection (PCR). Anti-A. phagocytophilum, anti-B. burgdorferi and anti-E. canis antibodies were determined in 400 dogs, using the SNAP 4Dx (r) test (IDEXX Laboratories). In addition, PCRs were performed for the detection of E. canis, A. phagocytophilum and B. burgdorferi DNA. In reference to the risk factor analysis, a regression logistic model was determined for each aetiological agent. The overall seroprevalence was highest for B. burgdorferi (11.0 %), followed by A. phagocytophilum (8.0 %) and E. canis (1.5 %). Eleven healthy dogs were found to be infected with A. phagocytophilum, as determined by PCR, while the remainder were seronegative. For B. burgdorferi, the DNA of the spirochetes was detected in the blood of 20 dogs, while the presence of anti-B. burgdorferi IgG was detected in the sera of ten of these. For E. canis, none of the dogs tested positive by PCR. Tick control was included as a protective factor for A. phagocytophilum and B. burgdorferi, while the origin (rural) was included as a risk factor for B. burgdorferi and A. phagocytophilum infection. In addition, breed (pure) was a risk factor for B. burgdorferi infection, and sex (female) was a risk factor for E. canis. PMID- 26581373 TI - Acanthamoeba genotypes T3 and T4 as causative agents of amoebic keratitis in Mexico. AB - Free-living amoebae (FLA) are widely distributed worldwide. Some genera included in this group act as opportunistic pathogens causing fatal encephalitis and Acanthamoeba keratitis (AK), a sight-threatening infection of the cornea associated with the use of soft contact lenses that could even end in blindness if an early diagnosis and treatment are not achieved. Furthermore, the numbers of AK cases keep rising worldwide mainly due to an increase of contact lens wearers and lack of hygiene in the maintenance of lenses and their cases. In Mexico, no cases of AK have been described so far although the isolation of other pathogenic FLA such as Naegleria fowleri and Balamuthia mandrillaris from both clinical and environmental sources has been reported. The present study reports two cases of Acanthamoeba keratitis diagnosed in two patients admitted to the Hospital "Luis Sanchez Bulnes" for Blindness Prevention in Mexico City, Mexico. Corneal scrapes and contact lenses were checked for the presence of Acanthamoeba strains in both patients. Strains were axenized after initial isolation to classify at the genotype level. After sequencing the diagnostic fragment 3 (DF3) region located on the 18S ribosomal DNA (rDNA) gene of Acanthamoeba, genotype T3 and genotype T4 were identified in clinical case 1 and 2, respectively. To our knowledge, these are the first reported cases of AK in Mexico in the literature and the first description of Acanthamoeba genotypes T3 and T4 as causative agents of amoebic infection. PMID- 26581375 TI - Alterations of Bio-elements, Oxidative, and Inflammatory Status in the Zinc Deficiency Model in Rats. AB - Our previous study showed that dietary zinc restriction induces depression-like behavior with concomitant up-regulation of the N-methyl-D-aspartate receptor (NMDAR). Because metal ions, oxidative stress, and inflammation are involved in depression/NMDAR function, in the present study, bio-elements (zinc, copper, iron, magnesium, and calcium), oxidative (thiobarbituric acid-reactive substances; protein carbonyl content), and inflammatory (IL-1alpha, IL-1beta) factors were measured in serum, hippocampus (Hp), and prefrontal cortex (PFC) of male Sprague-Dawley rats subjected to a zinc-adequate (ZnA) (50 mg Zn/kg) or a zinc-deficient (ZnD) (3 mg Zn/kg) diet for 4 or 6 weeks. Both periods of dietary zinc restriction reduced serum zinc and increased serum iron levels. At 4 weeks, lowered zinc level in the PFC and Hp as well as lowered iron level in the PFC of the ZnD rats was observed. At 6 weeks, however, iron level was increased in the PFC of these rats. Although at 6 weeks zinc level in the PFC did not differ between the ZnA and ZnD rats, extracellular zinc concentration after 100 mM KCl stimulation was reduced in the PFC of the ZnD rats and was accompanied by increased extracellular iron and glutamate levels (as measured by the in vivo microdialysis). The examined oxidative and inflammatory parameters were generally enhanced in the tissue of the ZnD animals. The obtained data suggest dynamic redistribution of bio-elements and enhancement of oxidative/inflammatory parameters after dietary zinc restriction, which may have a link with depression like behavior/NMDAR function/neurodegeneration. PMID- 26581376 TI - Additive Neuroprotective Effects of the Multifunctional Iron Chelator M30 with Enriched Diet in a Mouse Model of Amyotrophic Lateral Sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is the most common degenerative disease of the motoneuron system, involving various abnormalities, such as mitochondrial dysfunction, oxidative stress, transitional metal accumulation, neuroinflammation, glutamate excitotoxicity, apoptosis, decreased supply of trophic factors, cytoskeletal abnormalities, and extracellular superoxide dismutase (SOD)-1 toxicity. These multiple disease etiologies implicated in ALS gave rise to the perception that future therapeutic approaches for the disease should be aimed at targeting multiple pathological pathways. In line with this view, we have evaluated in the current study the therapeutic effects of low doses of the novel multifunctional monoamine oxidase (MAO) inhibitor/iron-chelating compound, M30 in combination with high Calorie Energy supplemented Diet (CED) in the SOD1-G93A transgenic mouse model of ALS. Our results demonstrated that the combined administration of M30 with CED produced additive neuroprotective effects on motor performance and increased survival of SOD1-G93A mice. We also found that both M30 and M30/CED regimens caused a significant inhibition of MAO-A and -B activities and decreased the turnover of dopamine in the brain of SOD1-G93A mice. In addition, M30/CED combined treatment resulted in a significant increase in mRNA expression levels of various mitochondrial biogenesis and metabolism regulators, such as peroxisome proliferator-activated receptor-gamma (PPARgamma) co activator 1 alpha (PGC-1alpha), PPARgamma, uncoupling protein 1, and insulin receptor in the gastrocnemius muscle of SOD1-G93A mice. These results suggest that a combination of drug/agents with different, but complementary mechanisms may be beneficial in the treatment of ALS. PMID- 26581378 TI - Dogs (Canis familiaris) adjust their social behaviour to the differential role of inanimate interactive agents. AB - Dogs are able to flexibly adjust their social behaviour to situation-specific characteristics of their human partner's behaviour in problem situations. However, dogs do not necessarily detect the specific role played by the human in a particular situation: they may form expectations about their partners' behaviour based on previous experiences with them. Utilising inanimate objects (UMO-unidentified moving object) as interacting agents offers new possibilities for investigating social behaviour, because in this way we can remove or control the influence of previous experience with the partner. The aim of the present study was to investigate whether dogs are able to recognise the different roles of two UMOs and are able to adjust their communicative behaviour towards them. In the learning phase of the experiment, dogs were presented with a two-way food retrieval problem in which two UMOs, which differed in their physical appearance and abilities, helped the dog obtain a piece of food in their own particular manner. After a short experience with both UMOs, dogs in the test phase faced one of the problems in the presence of both inanimate agents. Overall, dogs displayed similar levels of gazing behaviour towards the UMOs, but in the first test they looked, approached and touched the relevant partner first. This rapid adjustment of social behaviour towards UMOs suggests that dogs may generalise their experiences with humans to unfamiliar agents and are able to select the appropriate partner when facing a problem situation. PMID- 26581377 TI - The vocal repertoire of the domesticated zebra finch: a data-driven approach to decipher the information-bearing acoustic features of communication signals. AB - Although a universal code for the acoustic features of animal vocal communication calls may not exist, the thorough analysis of the distinctive acoustical features of vocalization categories is important not only to decipher the acoustical code for a specific species but also to understand the evolution of communication signals and the mechanisms used to produce and understand them. Here, we recorded more than 8000 examples of almost all the vocalizations of the domesticated zebra finch, Taeniopygia guttata: vocalizations produced to establish contact, to form and maintain pair bonds, to sound an alarm, to communicate distress or to advertise hunger or aggressive intents. We characterized each vocalization type using complete representations that avoided any a priori assumptions on the acoustic code, as well as classical bioacoustics measures that could provide more intuitive interpretations. We then used these acoustical features to rigorously determine the potential information-bearing acoustical features for each vocalization type using both a novel regularized classifier and an unsupervised clustering algorithm. Vocalization categories are discriminated by the shape of their frequency spectrum and by their pitch saliency (noisy to tonal vocalizations) but not particularly by their fundamental frequency. Notably, the spectral shape of zebra finch vocalizations contains peaks or formants that vary systematically across categories and that would be generated by active control of both the vocal organ (source) and the upper vocal tract (filter). PMID- 26581379 TI - Sex Education and Intellectual Disability: Practices and Insight from Pediatric Genetic Counselors. AB - Intellectual disability (ID) with or without other anomalies is a common referral for genetic counseling. Sessions may include discussions of reproductive implications and other issues related to sex education. Patients with ID regularly meet barriers when trying to obtain sex education due to the misperceptions of others as being either asexual or that such education would promote inappropriate sexual behavior. In this pilot study, we surveyed genetic counselors to explore their experiences with being asked to provide sex education counseling and their comfort in doing so for patients with ID ages 9-17. Results were analyzed from 38 respondents. Caregivers and patients most frequently requested information on puberty, sex abuse prevention, and reproductive health. Genetic counselors were most comfortable when they could provide sex education counseling within the context of a particular condition or constellation of features. They were least comfortable when they lacked familiarity with the patient, caregiver, or the family's culture. The most frequently cited barriers that prevented genetic counselors from providing sex education counseling were lack of time, lack of training, the patient's ID being too profound, and a belief that genetic counselors should not be responsible for providing sex education counseling. While many respondents reported that providing sex education counseling is not considered within the scope of a genetic counselor's practice, they also noted that patients' families initiate discussions for which counselors should be prepared. Respondents indicated that resource guides specifically designed for use by genetic counselors would be beneficial to their practice. Genetic counselors have the opportunity to embrace the role of advocate and broach the issue of sexual health with caregivers and patients by directing them toward educational resources, if not providing sex education directly to effectively serve the needs of patients and caregivers. PMID- 26581380 TI - Performance of Nymph and Adult of Piezodorus guildinii (Westwood) (Hemiptera: Pentatomidae) Feeding on Cultivated Legumes. AB - Performance of nymphs and adults of Piezodorus guildinii (Westwood) feeding on different cultivated legumes was studied under controlled laboratory conditions (25 +/- 1 degrees C, 80 +/- 10% RH, 14 h of photophase) on soybean immature pod (SIP; R5.5-R6), birdsfoot trefoil immature pod (BTIP), alfalfa immature pod (AIP), and red clover flower with immature seeds (RCF). Food had significant effects on the life history of P. guildinii. The major differences in nymph survivorship were observed at second and third instars, with similar survivorship on SIP and AIP as hosts and higher than that recorded on BTIP and RCF. Total nymph mortality was much greater on BTIP (87.6%) than on SIP (32.6%) and AIP (54.2%); all nymphs died on RCF. Food did not affect nymph development time (about 20 days). Adult longevity was highest and lowest on AIP and RCF (62 and 32 days), respectively. Percentage of ovipositing females was highest (~ 80%) on SIP and AIP, and intermediate on BTIP (52.2%); no females reproduced on RCF. Fecundity on SIP and AIP was similar (~ 9 egg masses/female; and ~ 141 eggs/female) and twice as higher than on BTIP (4.1 egg masses/female; and 60.2 eggs/female). Egg fertility (58%) did not vary with food sources. Adults fed on SIP and AIP gained weight during 43 days, remained unaltered on BTIP, and decreased on RCF. Data obtained indicated that SIP and AIP are suitable food sources, and emphasize the importance of alfalfa as a host plant of P. guildinii in Uruguay. PMID- 26581381 TI - Metabolomic fingerprint of severe obesity is dynamically affected by bariatric surgery in a procedure-dependent manner. AB - BACKGROUND: Obesity is associated with multiple diseases. Bariatric surgery is the most effective therapy for severe obesity that can reduce body weight and obesity-associated morbidity. The metabolic alterations associated with obesity and respective changes after bariatric surgery are incompletely understood. OBJECTIVE: We comprehensively assessed metabolic alterations associated with severe obesity and distinct bariatric procedures. DESIGN: In our longitudinal observational study, we applied a (1)H-nuclear magnetic resonance-based global, untargeted metabolomics strategy on human serum samples that were collected before and repeatedly <=1 y after distinct bariatric procedures [i.e., a sleeve gastrectomy, proximal Roux-en Y gastric bypass (RYGB), and distal RYGB]. For comparison, we also analyzed serum samples from normal-weight and less-obese subjects who were matched for 1-y postoperative body mass index (BMI) values of the surgical groups. RESULTS: We identified a metabolomic fingerprint in obese subjects that was clearly discriminated from that of normal-weight subjects. Furthermore, we showed that bariatric surgery (sleeve gastrectomy and proximal and distal RYGB) dynamically affected this fingerprint in a procedure-dependent manner, thereby establishing new fingerprints that could be discriminated from those of BMI-matched and normal-weight control subjects. Metabolites that largely contributed to the metabolomic fingerprints of severe obesity were aromatic and branched-chain amino acids (elevated), metabolites related to energy metabolism (pyruvate and citrate; elevated), and metabolites suggested to be derived from gut microbiota (formate, methanol, and isopropanol; all elevated). CONCLUSION: Our data indicate that bariatric surgery, irrespective of the specific kind of procedure used, reverses most of the metabolic alterations associated with obesity and suggest profound changes in gut microbiome-host interactions after the surgery. This trial was registered at clinicaltrials.gov as NCT02480322. PMID- 26581382 TI - Trigemino-hypoglossal somatic reflex in the pharmacological studies of nociception in orofacial area. AB - Disorders involving the orofacial area represent a major medical and social problem. They are a consequence of central nociceptive processes associated with stimulation of the trigeminal nerve nucleus. A rat model of trigeminal pain, utilizing tongue jerks evoked by electrical tooth pulp stimulation during perfusion of the cerebral ventricles with various neuropeptide solutions, can be used in the pharmacological studies of nociception in orofacial area. The investigated neuropeptides diffuse through the cerebroventricular lining producing an analgesic effect either directly, through the trigemino-hypoglossal reflex arc neurons or indirectly through the periaqueductal central gray, raphe nuclei or locus coeruleus neurons. The aim of this review is to present the effect of pharmacological activity of various neuropeptides affecting the transmission of the sensory information from the orofacial area on the example of trigemino-hypoglossal reflex in rats. PMID- 26581383 TI - Pathogenic mutations and sequence variants within mitofusin 2 gene in Polish patients with different hereditary motor-sensory neuropathies. AB - At the time of its first description in 2004, MFN2 was considered the most frequently mutated gene in hereditary motor and sensory neuropathy type 2 (HMSN 2). However recent studies have shown that the frequency of MFN2 gene mutations in HMSN II patients is surprisingly low. To date, no systematic studies devoted to HMSN IIa in Poland have been carried out. In this study, we searched for MFN2 gene mutations in Polish patients representing the population of nearly 40 million. We decided to include a wide spectrum of clinical phenotypes in the study, proving able to detect, in a group of 67 affected patients: 1) 3 pathogenic mutations; 2) 3 sequence variants of unknown pathogenic status; 3) 9 rare MFN2 gene sequence variants; 4) 6 common polymorphisms. The frequency of MFN2 gene mutations in the whole group of patients is 4.5%. Due to the high frequency of MFN2 gene sequence variants within single patients we could not definitely exclude the cumulative effect of these contributing to the HMSN II phenotype. The MFN2 gene should therefore be considered in Polish HMSN II patients, though it is still not possible to determine its position in HMSN II molecular diagnostics. PMID- 26581384 TI - The influence of mild stressors on neurons containing interleukin-1beta in the central (CeA) and medial (MeA) amygdala in the ageing process of rats. AB - Proinflammatory cytokine - interleukin 1beta (IL-1beta) plays an important role in stress reactions in the structures of limbic system. The impact of stress on IL-1beta may depend on the ontogenetic age. The study examined the influence of acute and chronic exposure to forced swim (FS) or high-light open-field (HL-OF) stressors on neurons containing IL-1beta. Double immunofluorescence staining was used to reveal the density of IL-1beta/NeuN (NeuN - a neuronal nuclear marker) - immunoreactive (ir) cells in the amygdaloid central (CeA) and medial (MeA) nuclei, which are closely involved in the regulation of emotional stressors and hypothalamic-pituitary-adrenal axis (HPA) activation. Adult (P90; P - postnatal day), middle-aged (P360), and aged (P720) male Wistar Han rats were used in these experiments. We observed an age-dependent increase in the basal density of IL 1beta/NeuN-ir cells in CeA and MeA in P90 vs. P360 and P360 vs. P720 rats. Neither acute nor chronic FS caused significant changes in the density of IL 1beta-ir neurons in any of the investigated nuclei in P90, P360, and P720 rats as compared with the non-stressed groups. However, chronic but not acute HL-OF caused a marked increase in the density of IL-1beta/NeuN-ir cells in the CeA and MeA of P360 rats and in MeA of the P720 animals. Moreover, chronic HL-OF led to an increase in the density of IL-1beta-ir neurons in relation to acute HL-OF in the CeA and MeA of both P360 and P720 rats. Our results may indicate the involvement of IL-1beta neurons in the development of ageing processes in CeA and MeA. Furthermore, our results point out that chronic HL-OF is an aggravating factor that induces an increase in the density of IL-1beta/NeuN-ir cells in the MeA and/or CeA of middle-aged and aged rats. The increase is possibly due to insufficient control of the HPA axis associated with involutional ageing processes and seems to be a common denominator of the ageing process and stress. PMID- 26581385 TI - Effect of extending grating length and width on human visually evoked potentials. AB - Visually evoked potentials (VEPs) were elicited by Gabor gratings with different lengths and widths at three spatial frequencies (SFs): low, 1.45 c/deg, medium, 2.9 c/deg and high, 5.8 c/deg and at a contrast 3 times above the detection threshold at each SF. An increase of grating length enhanced N1 amplitude at occipital and parietal positions stronger than the increase of grating width at aspect ratios (length : width) above 4:1. The stronger effect of stimulus length than width was reflected also in the amplitude of the later P1 component at central and parietal positions. The larger effect of stimulus length than width on the VEP amplitude was SF specific: it was stronger at 5.8 c/deg, smaller at 2.9 c/deg and vanished at 1.45 c/deg. The results obtained suggest anisotropy in the physiological mechanisms that underlie grating perception and involve bottom- up processes initiated in the occipital cortex. PMID- 26581386 TI - Chronic morphine treatment enhances sciatic nerve stimulation-induced immediate early gene expression in the rat dorsal horn. AB - Synaptic plasticity is a property of neurons that can be induced by conditioning electrical stimulation (CS) of afferent fibers in the spinal cord. This is a widely studied property of spinal cord and hippocampal neurons. CS has been shown to trigger enhanced expression of immediate early gene proteins (IEGPs), with peak increases observed 2 hour post stimulation. Chronic morphine treatment has been shown to promoteinduce opioid-induced hyperalgesia, and also to increase CS induced central sensitization in the dorsal horn. As IEGP expression may contribute to development of chronic pain states, we aimed to determine whether chronic morphine treatment affects the expression of IEGPs following sciatic nerve CS. Changes in expression of the IEGPs Arc, c-Fos or Zif268 were determined in cells of the lumbar dorsal horn of the spinal cord. Chronic Morphine pretreatment over 7 days led to a significant increase in the number of IEGP positive cells observed at both 2 h and 6 h after CS. The same pattern of immunoreactivity was obtained for all IEGPs, with peak increases occurring at 2 h post CS. In contrast, morphine treatment alone in sham operated animals had no effect on IEGP expression. We conclude that chronic morphine treatment enhances stimulus-induced expression of IEGPs in the lumbar dorsal horn. These data support the notion that morphine alters gene expression responses linked to nociceptive stimulation and plasticity. PMID- 26581387 TI - Biochemical and cognitive impairments observed in animal models of schizophrenia induced by prenatal stress paradigm or methylazoxymethanol acetate administration. AB - The aim of the study was to find whether spatial memory impairment and disruption in locomotor activity were found in prenatally stressed rats (PSG) or prenatally methylazoxymethanol acetate-treated rats (MAMG). In addition to this, we examined basal plasma corticosterone level as well as brain-derived neurothropic factor (BDNF) in the PSG and MAMG rats. The effect of prenatal stress (stress paradigm between 14 and 21 day of gestation) and methylazoxymethanol acetate (MAM) administration (17 day of gestation) to the female Wistar rats were studied on the male offspring in the Morris Water Maze (spatial memory) and locomotor activity test. Through Morris Water Maze rats were injected with saline 4 times (on 1, 7, 14 and 21 day of testing) while in locomotor activity test saline was injected only once. Corticosterone level was measured using ELISA Kit while BDNF levels were assessed using ELISA Chemikine TM BDNF kit. Results indicate that both PSG and MAMG rats deteriorate spatial memory as well as increase locomotor activity compared to the control group. Biochemical studies indicate that basal plasma corticosterone level increased in both PSG and MAMG rats compared to the control group. Analyses of the BDNF level, on the other hand, have shown decrease of the neurothropin level in both hippocampus and prefrontal cortex (PFC) in both PSG and MAMG groups of rats. As shown by the obtained results, both the prenatal stress model and prenatal MAM administration model generate a number of behavioural (e.g. spatial memory disorders, increased locomotor activity) and biochemical (e.g. increased corticosterone and decreased BDNF levels) changes in the examined offspring, Thus, these models can be successfully used in the efficacy analysis of the pharmacotherapy applied. PMID- 26581388 TI - Decreased frontal, striatal and cerebellar activation in adults with ADHD during an adaptive delay discounting task. AB - An important characteristic of childhood attention-deficit/hyperactivity disorder (ADHD) is a bias towards small immediate versus larger delayed rewards, but it is not known if this symptom is also a feature of adult ADHD. A delay-discounting task was administered to participants with adult ADHD and a comparison group in conjunction with functional magnetic resonance imaging. Participants responded to a series of questions that required judgments between small sums of money available immediately and larger sums obtained after a temporal delay. Question parameters were adjusted by an adaptive algorithm designed to converge on each participant's discounting indifference point, an individual set point at which there is equal valuation of both choices. In all participants, robust task activation was observed in regions previously identified in functional imaging studies of delay discounting. However, adults with ADHD showed less task activation in a number of regions including the dorsolateral prefrontal cortex, superior frontal gyrus, anterior cingulate, caudate nucleus and declive of the cerebellum. Additionally, the degree to which a participant discounted delayed rewards was inversely related to task activation in the cerebellum. The results suggest that the bias towards immediate rewards in childhood ADHD may not persist behaviorally, but instead present in adulthood as alterations in frontostriatal and frontocerebellar networks. PMID- 26581389 TI - Acute hyperglycemia abolishes cardioprotection by remote ischemic perconditioning. AB - BACKGROUND: Remote ischemic perconditioning (RIPerC) has a promising therapeutic insight to improve the prognosis of acute myocardial infarction. Chronic comorbidities such as diabetes are known to interfere with conditioning interventions by modulating cardioprotective signaling pathways, such as e.g., mTOR pathway and autophagy. However, the effect of acute hyperglycemia on RIPerC has not been studied so far. Therefore, here we investigated the effect of acute hyperglycemia on cardioprotection by RIPerC. METHODS: Wistar rats were divided into normoglycemic (NG) and acute hyperglycemic (AHG) groups. Acute hyperglycemia was induced by glucose infusion to maintain a serum glucose concentration of 15 20 mM throughout the experimental protocol. NG rats received mannitol infusion of an equal osmolarity. Both groups were subdivided into an ischemic (Isch) and a RIPerC group. Each group underwent reversible occlusion of the left anterior descending coronary artery (LAD) for 40 min in the presence or absence of acute hyperglycemia. After the 10-min LAD occlusion, RIPerC was induced by 3 cycles of 5-min unilateral femoral artery and vein occlusion and 5-min reperfusion. After 120 min of reperfusion, infarct size was measured by triphenyltetrazolium chloride staining. To study underlying signaling mechanisms, hearts were harvested for immunoblotting after 35 min in both the NG and AHG groups. RESULTS: Infarct size was significantly reduced by RIPerC in NG, but not in the AHG group (NG + Isch: 46.27 +/- 5.31 % vs. NG + RIPerC: 24.65 +/- 7.45 %, p < 0.05; AHG + Isch: 54.19 +/- 4.07 % vs. 52.76 +/- 3.80 %). Acute hyperglycemia per se did not influence infarct size, but significantly increased the incidence and duration of arrhythmias. Acute hyperglycemia activated mechanistic target of rapamycine (mTOR) pathway, as it significantly increased the phosphorylation of mTOR and S6 proteins and the phosphorylation of AKT. In spite of a decreased LC3II/LC3I ratio, other markers of autophagy, such as ATG7, ULK1 phopsphorylation, Beclin 1 and SQSTM1/p62, were not modulated by acute hyperglycemia. Furthermore, acute hyperglycemia significantly elevated nitrative stress in the heart (0.87 +/- 0.01 vs. 0.50 +/- 0.04 ug 3-nitrotyrosine/mg protein, p < 0.05). CONCLUSIONS: This is the first demonstration that acute hypreglycemia deteriorates cardioprotection by RIPerC. The mechanism of this phenomenon may involve an acute hyperglycemia induced increase in nitrative stress and activation of the mTOR pathway. PMID- 26581391 TI - Welding Molecular Crystals. AB - Both for fundamental and applied sciences, the design of complex molecular systems in the crystalline phase with strict control of order and periodicity at both microscopic and macroscopic levels is of prime importance for development of new solid-state materials and devices. The design and fabrication of complex crystalline systems as networks of crystals displaying task-specific properties is a step toward smart materials. Here we report on isostructural and almost isometric molecular crystals of different colors, their use for fabrication of core-shell crystals, and their welding by 3D epitaxial growth into networks of crystals as single-crystalline entities. Welding of crystals by self-assembly processes into macroscopic networks of crystals is a powerful strategy for the design of hierarchically organized periodic complex architectures composed of different subdomains displaying targeted characteristics. Crystal welding may be regarded as a first step toward the design of new hierarchically organized complex crystalline systems. PMID- 26581390 TI - Upregulation of EGFR signaling is correlated with tumor stroma remodeling and tumor recurrence in FGFR1-driven breast cancer. AB - INTRODUCTION: Despite advances in early detection and adjuvant targeted therapies, breast cancer is still the second most common cause of cancer mortality among women. Tumor recurrence is one of the major contributors to breast cancer mortality. However, the mechanisms underlying this process are not completely understood. In this study, we investigated the mechanisms of tumor dormancy and recurrence in a preclinical mouse model of breast cancer. METHODS: To elucidate the mechanisms driving tumor recurrence, we employed a transplantable Wnt1/inducible fibroblast growth factor receptor (FGFR) 1 mouse mammary tumor model and utilized an FGFR specific inhibitor, BGJ398, to study the recurrence after treatment. Histological staining was performed to analyze the residual tumor cells and tumor stroma. Reverse phase protein array was performed to compare primary and recurrent tumors to investigate the molecular mechanisms leading to tumor recurrence. RESULTS: Treatment with BGJ398 resulted in rapid tumor regression, leaving a nonpalpable mass of dormant tumor cells organized into a luminal and basal epithelial layer similar to the normal mammary gland, but surrounded by dense stroma with markedly reduced levels of myeloid-derived tumor suppressor cells (MDSCs) and decreased tumor vasculature. Following cessation of treatment the tumors recurred over a period of 1 to 4 months. The recurrent tumors displayed dense stroma with increased collagen, tenascin-C expression, and MDSC infiltration. Activation of the epidermal growth factor receptor (EGFR) pathway was observed in recurrent tumors, and inhibition of EGFR with lapatinib in combination with BGJ398 resulted in a significant delay in tumor recurrence accompanied by reduced stroma, yet there was no difference observed in initial tumor regression between the groups treated with BGJ398 alone or in combination with lapatinib. CONCLUSION: These studies have revealed a correlation between tumor recurrence and changes of stromal microenvironment accompanied by altered EGFR signaling. PMID- 26581392 TI - Anti-IgE monoclonal antibody therapy for the treatment of chronic rhinosinusitis: a systematic review. AB - BACKGROUND: Several options are available for the treatment of chronic rhinosinusitis (CRS), but disease control remains elusive for many patients. Recently, literature has emerged describing anti-IgE monoclonal antibody as a potential therapy for CRS. However, its effectiveness and safety are not well known. The purpose of this systematic review was to assess the effectiveness and safety of anti-IgE therapy and to identify evidence gaps that will guide future research for the management of CRS. METHODS: Methodology was registered with PROSPERO (No. CRD42014007600). A comprehensive search was performed of standard bibliographic databases, Google Scholar, and clinical trials registries. Only randomized controlled trials assessing anti-IgE therapy in adult patients for the treatment of CRS were included. Two independent reviewers extracted data using a pre-defined extraction form and performed quality assessment using the Cochrane risk of bias tool and the GRADE framework. RESULTS: Two studies met our inclusion criteria. When comparing anti-IgE therapy to placebo, there was a significant difference in Lund-McKay score (p = 0.04) while no difference was seen for percent opacification on computed tomography (CT). At 16 weeks, treatment led to a decrease in clinical polyp score. No significant difference was seen with regard to quality of life (Total Nasal Symptom Severity (TNSS), p < 0.21; Sinonasal Outcome Test 20 (SNOT-20), p < 0.60), and no serious complications were reported in either trial. Based on the quality assessment, studies were deemed to be of moderate risk of bias and a low overall quality of evidence. CONCLUSIONS: There is currently insufficient evidence to determine the effectiveness of anti IgE monoclonal antibody therapy for the treatment of CRS. PMID- 26581394 TI - Spontaneous Remission in a Case of Giant Cell Myocarditis with Preserved Left Ventricular Ejection Fraction. AB - BACKGROUND: Giant cell myocarditis (GCM) is rapidly progressive fulminant myocarditis causing death or requiring cardiac transplantation despite various immunosuppression therapies. CASE REPORT: A 28-year-old woman with progressive shortness of breath and palpitation following an upper respiratory infection was referred to our institution. On admission, transthoracic echocardiography (TTE) revealed a preserved left ventricular ejection fraction (LVEF) with mildly impaired LV diastolic function despite extensive ECG abnormalities, a mildly elevated troponin I concentration, and moderately elevated N-terminal pro-brain natriuretic peptide (NT-pro-BNP) concentration. The diagnosis of GCM was made by endomyocardial biopsy (EMB), which revealed extensive fibrosis and inflammatory infiltration with multinucleated giant cells, as well as scattered eosinophils and lymphocytes in the absence of granuloma formation. However, the patient's symptoms began to improve without any specific therapy within 2 weeks, followed by the normalization of the ECG abnormalities, TTE-determined diastolic function, and troponin I and NT-pro-BNP concentrations. In sub-acute phase, 18F fluorodeoxyglucose positron emission tomography showed no evidence of inflammation, and repeat EMB showed a significant decrease in the inflammatory infiltration and fibrosis, including absence of giant cells. Given the favorable clinical course, the patient was discharged without medications. At the 6-month follow-up, the patient had no LV functional impairment, cardiovascular events, or arrhythmia. CONCLUSIONS: We encountered a rare case of atypical GCM in which clinical and histologic remission was achieved without immunosuppression therapy. There seems to be a population of GCM patients who improve without immunosuppression therapy. In monitoring GCM patients, clinicians should be aware of the possibility of spontaneous remission. PMID- 26581395 TI - Successful bilateral pudendal neuromodulation to treat male detrusor areflexia following severe pubic symphysis fracture, a case report. AB - BACKGROUND: A Drum Dock Manager in an auto manufacturing company suffers a pelvic fracture, severing the bulbar urethra and completely fracturing the right side of his pelvis. He is unable to void without catheterization but has a complete sensation to void. Can neuromodulation help him achieve spontaneous voiding? CASE PRESENTATION: We reviewed the electronic medical record of Mr. M.E. from Detroit Medical Center following his 2012 forklift accident and subsequent orthopedic surgeries. He successfully underwent bilateral sacral neuromodulation, with a resulting max flow of 16.8 mls/sec and post-void residual urine of 50-100 mls. Unfortunately, he later presented with bilateral pocket and sacral lead infection, and both systems had to be removed. Six weeks later, M.E. had bilateral pudendal neurostimulation placement to avoid the previously infected areas. Max flow improved to 14.5 mls/sec and 0-50 mls residual urine. However, urodynamics proved that his Pdet at max flow was in excess of 120 cm of H20 pressure while he had been on finesteride and tamsulosin for the preceding five years for the management of his documented benign prostate hyperplasia symptoms. He underwent Green light laser transurethral resection of the prostate and had max flow improvement to 22.5 mls/second with zero residual urine with multiple straight catheterization confirmations. CONCLUSION: Sacral neuromodulation may successfully correct traumatic urinary retention in male patients. Additionally, pudendal neuromodulation can be successfully utilized as a salvage method for an infected sacral neuromodulation impulse generator (IPG) and tined lead with a return to proper voiding. PMID- 26581393 TI - Genomics and transcriptomics of Xanthomonas campestris species challenge the concept of core type III effectome. AB - BACKGROUND: The bacterial species Xanthomonas campestris infects a wide range of Brassicaceae. Specific pathovars of this species cause black rot (pv. campestris), bacterial blight of stock (pv. incanae) or bacterial leaf spot (pv. raphani). RESULTS: In this study, we extended the genomic coverage of the species by sequencing and annotating the genomes of strains from pathovar incanae (CFBP 1606R and CFBP 2527R), pathovar raphani (CFBP 5828R) and a pathovar formerly named barbareae (CFBP 5825R). While comparative analyses identified a large core ORFeome at the species level, the core type III effectome was limited to only three putative type III effectors (XopP, XopF1 and XopAL1). In Xanthomonas, these effector proteins are injected inside the plant cells by the type III secretion system and contribute collectively to virulence. A deep and strand-specific RNA sequencing strategy was adopted in order to experimentally refine genome annotation for strain CFBP 5828R. This approach also allowed the experimental definition of novel ORFs and non-coding RNA transcripts. Using a constitutively active allele of hrpG, a master regulator of the type III secretion system, a HrpG-dependent regulon of 141 genes co-regulated with the type III secretion system was identified. Importantly, all these genes but seven are positively regulated by HrpG and 56 of those encode components of the Hrp type III secretion system and putative effector proteins. CONCLUSIONS: This dataset is an important resource to mine for novel type III effector proteins as well as for bacterial genes which could contribute to pathogenicity of X. campestris. PMID- 26581396 TI - Myocardial tissue characterization in Chagas' heart disease by cardiovascular magnetic resonance. AB - BACKGROUND: Chagas' heart disease is an important public health problem in South America. Several aspects of the pathogenesis are not fully understood, especially in its subclinical phases. On pathology Chagas' heart disease is characterized by chronic myocardial inflammation and extensive myocardial fibrosis. The latter has also been demonstrated by late gadolinium enhancement (LGE) by cardiovascular magnetic resonance (CMR). In three clinical phases of this disease, we sought to investigate the presence of LGE, myocardial increase in signal intensity in T2 weighted images (T2W) and in T1-weighted myocardial early gadolinium enhancement (MEGE), previously described CMR surrogates for myocardial fibrosis, myocardial edema and hyperemia, respectively. METHODS: Fifty-four patients were analyzed. Sixteen patients with the indeterminate phase (IND), seventeen patients with the cardiac phase with no left ventricular systolic dysfunction (CPND), and twenty one patients with the cardiac phase with left ventricular systolic dysfunction (CPD). All patients underwent 1.5 T CMR scan including LGE, T2W and MEGE image sequences to evaluate myocardial abnormalities. RESULTS: Late gadolinium enhancement was present in 72.2 % of all patients, in 12.5 % of IND, 94.1 % of the CPND and 100 % of the CPD patients (p < 0.0001). Myocardial increase in signal intensity in T2-weighted images (T2W) was present in 77.8 % of all patients, in 31.3 % of the IND, 94.1 % of the CPND and 100 % of the CPD patients (p < 0.0001). T1-weighted myocardial early gadolinium enhancement (MEGE) was present in 73.8 % of all patients, in 25.0 % of the IND, 92.3 % of the CPND and 94.1 % of the CPD (p < 0.0001). A good correlation between LGE and T2W was observed (r = 0.72, and p < 0.001). CONCLUSIONS: Increase in T2-weighted (T2W) myocardial signal intensity and T1-weighted myocardial early gadolinium enhancement (MEGE) can be detected by CMR in patients throughout all phases of Chagas' heart disease, including its subclinical presentation (IND). Moreover, those findings were parallel to myocardial fibrosis (LGE) in extent and location and also correlated with the degree of Chagas' heart disease clinical severity. These findings contribute to further the knowledge on pathophysiology of Chagas' heart disease, and might have therapeutic and prognostic usefulness in the future. PMID- 26581397 TI - Extensive Melanotic Neuroectodermal Tumor of Infancy. AB - The melanotic neuroectodermal tumor of infancy (MNTI) is a rare childhood neoplasm with an alarming but classical clinical presentation. We present the case of a 2-month-old male infant treated with surgery for an aggressive MNTI on the alveolar process of the maxilla. Radiographic examination showed a diffuse osteolytic radiolucent lesion in the right maxilla, and displacement and dysmorphic changes in the developing primary tooth buds. The patient remained well without evidence of recurrence for 6 months after surgery. We discussed clinicopathological features, management alternatives, and outcome. PMID- 26581398 TI - Uterine artery embolization combined with curettage vs. methotrexate plus curettage for cesarean scar pregnancy. AB - PURPOSE: To compare the efficacy and safety of uterine artery embolization (UAE) combined with curettage and methotrexate (MTX) plus curettage in the treatment of cesarean scar pregnancy (CSP). METHODS: From January 2005 to December 2013, we treated 38 CSP patients with UAE combined with curettage, and another 26 patients with CSP were treated with methotrexate (MTX) plus curettage. The resulting data were analyzed statistically. RESULTS: The median volume of blood loss was 17.5 ml in the UAE combined with curettage (UAE-C) group vs. 335 ml in the MTX plus curettage (MTX-C) group (p < 0.001). The time from the procedure till beta-human chorionic gonadotropin (beta-hCG) concentration returned to normal was 25.13 +/- 3.74 days in the UAE-C group vs. 56.15 +/- 15.99 days in the MTX-C group (p < 0.001). The duration of hospitalization was 7.44 +/- 1.92 vs. 19.38 +/- 8.75 days, respectively (p < 0.001). The percentage of side effects in the UAE-C group was significantly lower than in the MTX-C group. CONCLUSIONS: UAE combined with curettage appears to be superior to MTX plus curettage for treatment of CSP with high serum beta-hCG level, though prospective trials are needed. PMID- 26581399 TI - Anti-tumoral effect of arsenic compound, sodium metaarsenite (KML001), in non Hodgkin's lymphoma: an in vitro and in vivo study. AB - Arsenic compounds have been used in traditional medicine for several centuries. KML001 (sodium metaarsenite; NaAsO2) is an orally bio-available arsenic compound with potential anti-cancer activity. However, the effect of KML001 has not been studied in lymphoid neoplasms. The aim of this study is to evaluate the anti proliferative effect of KML001 in non-Hodgkin's lymphoma and to compare its efficacy with As2O3. KML001 inhibited cellular proliferation in all tested lymphoma cell lines as well as JurkatR cells (adriamycin-resistant Jurkat cells) in a dose-dependent manner, while As2O3 was not effective. Cell cycle regulatory protein studies have suggested that KML001 induces G1 arrest via p27-induced inhibition of the kinase activities of CDK2, 4, and 6. Treatment of KML001 induced apoptosis in Jurkat and JurkatR cells. The apoptotic process was associated with down-regulation of Bcl-2 (antiapoptotic molecule), up-regulation of Bax (proapoptotic molecule), and inhibition of caspase-3, -8, and -9. In addition, cell signaling including the STAT, PI3K/Akt, MAPK, and NF-kappaB signal pathways were inhibited in KML001-treated Jurkat and JurkatR cells. Furthermore, targeting the telomere by KML001 was observed in the Jurkat and JurkatR cells. The In vivo anti-tumoral activity of KML001 was confirmed in a xenograft murine model. Interestingly, partial responses were seen in two lymphoma patients treated with 10 mg/day (follicular lymphoma for 16 weeks and mantle cell lymphoma for 24 weeks) without severe toxicities. These findings suggest that KML001 may be a candidate agent for the treatment of de novo, refractory, and relapsed non Hodgkin's lymphoma patients. PMID- 26581400 TI - A phase II trial of ganetespib, a heat shock protein 90 Hsp90) inhibitor, in patients with docetaxel-pretreated metastatic castrate-resistant prostate cancer (CRPC)-a prostate cancer clinical trials consortium (PCCTC) study. AB - INTRODUCTION: Heat shock protein 90 (Hsp90) has been studied as a therapeutic target in many cancers. In preclinical trials, the Hsp90 ATPase inhibitor ganetespib demonstrated potent inhibition of solid tumor growth, with superior potency than prior Hsp90 inhibitors. Given the promising preclinical outcome and favorable pharmacologic properties of ganetespib, we conducted a phase II trial of single-agent ganetespib in patients with metastatic, castrate-resistant prostate cancer (mCRPC). The primary objective of the study was to determine the 6-month progression-free survival (PFS) rate. METHODS: Patients with mCRPC who had been previously treated with docetaxel were enrolled after meeting eligibility criteria. All patients received ganetespib at 200 mg/m(2) on days 1, 8, and 15 of every 28 days (one cycle). Subjects who tolerated therapy were continued on ganetespib until disease progression. Considering that Hsp90 acetylation may confer insensitivity to Hsp90 inhibitors and maspin inhibits protein deacetylation, maspin-associated molecular markers were evaluated. RESULTS: Eighteen patients were recruited into the trial; most were Caucasian, had performance status 1, had received prior docetaxel, and were heavily pretreated. Of the 17 patients who were treated, none attained 6-month PFS. Only 2 patients achieved PFS > 4 months. The median PFS was 1.9 months. As per the study design, the trial was terminated after the interim analysis. The most frequent types of Grade 3 toxicity were dehydration, diarrhea, and fatigue. Molecular markers provided little additional insight regarding drug activity. CONCLUSIONS: Ganetespib demonstrated minimal clinical activity in men with mCRPC. The true 6-month PFS rate was, at most, 0.20. Possible reasons for this include selection of a heavily pretreated patient population and lack of agent potency in patients with mCRPC. PMID- 26581402 TI - Trapping the Tiger: Efficacy of the Novel BG-Sentinel 2 With Several Attractants and Carbon Dioxide for Collecting Aedes albopictus (Diptera: Culicidae) in Southern France. AB - Targeted trapping of mosquito disease vectors plays an important role in the surveillance and control of mosquito-borne diseases. The Asian tiger mosquito, Aedes albopictus (Skuse), is an invasive species, which is spreading throughout the world, and is a potential vector of 24 arboviruses, particularly efficient in the transmission of chikungunya, dengue, and zika viruses. Using a 4 * 4 Latin square design, we assessed the efficacy of the new BG-Sentinel 2 mosquito trap using the attractants BG-lure and (R)-1-octen-3-ol cartridge, alone or in combination, and with and without carbon dioxide, for the field collection of Ae. albopictus mosquitoes.We found a synergistic effect of attractant and carbon dioxide that significantly increased twofold to fivefold the capture rate of Ae. albopictus. In combination with carbon dioxide, BG-lure cartridge is more effective than (R)-1-octen-3-ol in attracting females, while a combination of both attractants and carbon dioxide is the most effective for capturing males. In the absence of carbon dioxide, BG-lure cartridge alone did not increase the capture of males or females when compared with an unbaited trap. However, the synergistic effect of carbon dioxide and BG-lure makes this the most efficient combination in attracting Ae. albopictus. PMID- 26581401 TI - Phase I trial of FOLFIRI in combination with sorafenib and bevacizumab in patients with advanced gastrointestinal malignancies. AB - BACKGROUND: A previous phase II trial in patients with chemorefractory metastatic colorectal cancer demonstrated a 63 % disease control rate with a combination of bevacizumab and sorafenib. This phase I trial sought to determine the maximum tolerable dose (MTD) of bevacizumab and sorafenib combined with standard cytotoxic therapy for advanced gastrointestinal (GI) cancers. METHODS: A standard 3 + 3 trial design utilized 3 escalating sorafenib dose levels: (1) 200 mg daily, days 3-7, 10-14; (2) 200 mg twice daily, days 3-6, 10-13; and (3) 200 mg twice daily, days 3-7, 10-14 combined with standard dose FOLFIRI (5-fluouracil, leucovorin, and irinotecan) and bevacizumab (5 mg/kg), repeated every 14 days. RESULTS: Fifteen patients were evaluable for safety and response assessment. There were no dose limiting toxicities (DLTs) at dose level 1 or 2. At dose level 3, two patients experienced DLTs (asymptomatic grade 3 hypophosphatemia, grade 3 dehydration and diarrhea). The MTD was determined to be dose level 2: sorafenib 200 mg twice daily, days 3-6, 10-13 combined with FOLFIRI and bevacizumab at standard doses. Four patients had a partial response and 8 had stable disease as best response (disease control rate of 80 %). Three patients with CRC had disease control >12 months. CONCLUSIONS: The MTD of this regimen is sorafenib 200 mg twice daily, days 3-6, 10-13 combined with standard doses of FOLFIRI and bevacizumab. Dual antiangiogenic treatment combined with cytotoxic therapy may provide prolonged disease stabilization for select patients with advanced GI malignancies. PMID- 26581403 TI - Pacing and sensing optimization of permanent His-bundle pacing in cardiac resynchronization therapy/implantable cardioverter defibrillators patients: value of integrated bipolar configuration. AB - AIMS: The clinical implementation of His-bundle pacing (HBP) has been limited by concern over higher capture thresholds (CTs) and lower R-wave amplitudes (RWAs), when compared with right ventricular (RV) pacing. The aim of this study was to assess the optimal pacing configuration for HBP lead when incorporated with cardiac resynchronization therapy/implantable cardioverter defibrillators (CRT D/ICD) by testing of an integrated bipolar configuration. METHODS AND RESULTS: HBP was achieved in 25 CRT-D and 13 ICD patients at implantation. Their RWA, CT@0.5 ms and impedance with His-bundle (HB) tip-RV coil, and HB unipolar and bipolar (tip-ring) configurations were measured acutely. Capture threshold in CRT D patients was that needed to 'correct' complete left bundle block. Among all 16 CRT-D patients with permanent HBP, their RWA, CT@0.5 ms, and pacing impedance with HBP tip-RV coil and HBP tip-ring were measured at 1 month and 3 months follow-up. Higher RWA and lower CT were achieved with HB tip-RV coil configuration than either of the other two configurations at implantation (n = 38, P < 0.05, respectively). At 1 and 3 months follow-up for patients receiving permanent HBP, RWA and CT with HB tip-RV coil configuration remained stable and better than those with HB tip-ring configuration (n = 16, P < 0.05, respectively). Furthermore, HB lead pulse energy delivered with HB tip-RV coil configuration was also less than with HB tip-ring at 3 months (n = 16, P = 0.017). CONCLUSION: Incorporation of HBP into a CRT-D/ICD system is feasible, and pacing thresholds/sensing can be optimized using a novel integrated bipolar configuration with the RV lead. PMID- 26581404 TI - Association between job strain, mental health and empathy among intensive care nurses. AB - BACKGROUND: Nursing shortage is a worldwide issue. It could influence factors such as job strain, nurses' mental health and nurse empathy towards patients. AIM: The aim of the study is to explore the associations between job strain, psychological distress, psychological well-being and empathy in intensive care units (ICUs). DESIGN: A cross-sectional descriptive correlational design. METHODS: Data were collected using questionnaires and an observation tool completed by three observers during a standardized clinical simulation (SCS). A total of 26 nurses practicing in three ICUs participated in the study, which took place over 3 days in December 2011. RESULTS: One dimension of job strain, psychological demand, was associated with two subscales of mental health (psychological distress positively and psychological well-being negatively). Positive correlations were demonstrated between psychological distress and nurse empathy as perceived by both the observers and the actor who played the role of patient. CONCLUSION: Some associations have been confirmed between job strain, psychological distress, psychological well-being and empathy in the ICU while others needs further investigation. RELEVANCE TO CLINICAL PRACTICE: It is important to reduce psychological demand among intensive care nurses in order to prevent psychological distress. The exploration of the connection between empathy and psychological distress should be advanced. This study suggests that SCSs provide an innovative approach that is useful for research. PMID- 26581406 TI - Nearly 10% in US have had problem with drug use, survey finds. PMID- 26581405 TI - ASPM regulates symmetric stem cell division by tuning Cyclin E ubiquitination. AB - We generate a mouse model for the human microcephaly syndrome by mutating the ASPM locus, and demonstrate a premature exhaustion of the neuronal progenitor pool due to dysfunctional self-renewal processes. Earlier studies have linked ASPM mutant progenitor excessive cell cycle exit to a mitotic orientation defect. Here, we demonstrate a mitotic orientation-independent effect of ASPM on cell cycle duration. We pinpoint the cell fate-determining factor to the length of time spent in early G1 before traversing the restriction point. Characterization of the molecular mechanism reveals an interaction between ASPM and the Cdk2/Cyclin E complex, regulating the Cyclin activity by modulating its ubiquitination, phosphorylation and localization into the nucleus, before the cell is fated to transverse the restriction point. Thus, we reveal a novel function of ASPM in mediating the tightly coordinated Ubiquitin- Cyclin E- Retinoblastoma- E2F bistable-signalling pathway controlling restriction point progression and stem cell maintenance. PMID- 26581407 TI - Morphology and Performance of Polymer Solar Cell Characterized by DPD Simulation and Graph Theory. AB - The morphology of active layers in the bulk heterojunction (BHJ) solar cells is critical to the performance of organic photovoltaics (OPV). Currently, there is limited information for the morphology from transmission electron microscopy (TEM) techniques. Meanwhile, there are limited approaches to predict the morphology /efficiency of OPV. Here we use Dissipative Particle Dynamics (DPD) to determine 3D morphology of BHJ solar cells and show DPD to be an efficient approach to predict the 3D morphology. Based on the 3D morphology, we estimate the performance indicator of BHJ solar cells by using graph theory. Specifically, we study poly (3-hexylthiophene)/[6, 6]-phenyl-C61butyric acid methyl ester (P3HT/PCBM) BHJ solar cells. We find that, when the volume fraction of PCBM is in the region 0.4 ~ 0.5, P3HT/PCBM will show bi-continuous morphology and optimum performance, consistent with experimental results. Further, the optimum temperature (413 K) for the morphology and performance of P3HT/PCBM is in accord with annealing results. We find that solvent additive plays a critical role in the desolvation process of P3HT/PCBM BHJ solar cell. Our approach provides a direct method to predict dynamic 3D morphology and performance indicator for BHJ solar cells. PMID- 26581408 TI - ERAIZDA: a model for holistic annotation of animal infectious and zoonotic diseases. AB - There is an urgent need for a unified resource that integrates trans-disciplinary annotations of emerging and reemerging animal infectious and zoonotic diseases. Such data integration will provide wonderful opportunity for epidemiologists, researchers and health policy makers to make data-driven decisions designed to improve animal health. Integrating emerging and reemerging animal infectious and zoonotic disease data from a large variety of sources into a unified open-access resource provides more plausible arguments to achieve better understanding of infectious and zoonotic diseases. We have developed a model for interlinking annotations of these diseases. These diseases are of particular interest because of the threats they pose to animal health, human health and global health security. We demonstrated the application of this model using brucellosis, an infectious and zoonotic disease. Preliminary annotations were deposited into VetBioBase database (http://vetbiobase.igbb.msstate.edu). This database is associated with user-friendly tools to facilitate searching, retrieving and downloading of disease-related information. Database URL: http://vetbiobase.igbb.msstate.edu. PMID- 26581409 TI - Application of density gradient for the isolation of the fecal microbial stool component and the potential use thereof. AB - The idea of considering the gut microbiota as a virtual human organ has led to the concept of fecal microbiota transplantation (FMT), which has recently been extremely successful in the treatment of cases of recurrent Clostridium difficile infection. Administration of safe, viable, and representative fecal microbiota is crucial for FMT. To our knowledge, suitable techniques and systematic conditions for separating the fecal microbiota from stool samples have not been thoroughly investigated. In this work we show the potential to separate stool microorganisms from the rest of fecal material using a procedure with a Nycodenz(r) density gradient, yielding 10(10) viable bacteria per two grams of feces. This procedure did not affect the original microbiota composition in terms of viability, distribution and proportions, as assessed by a phylogenetic metagenomic approach. Obtaining the fecal microbiota by concentration and separation of the microorganisms from the rest of the stool components would allow the standardization of its recovery and its long-term preservation. FMT or similar microbiota restoration therapies could be used for the treatment of several disorders, or even for aesthetic purposes, so the method described in our work may contribute to the setting of the basis for the development of safe and standardized products. PMID- 26581410 TI - Widespread detection and characterization of porcine parainfluenza virus 1 in pigs in the USA. AB - Porcine parainfluenza virus 1 (PPIV1) was first identified in 2013 in slaughterhouse pigs in Hong Kong, China. Here, two near-complete genomes were assembled from swine exhibiting acute respiratory disease that were 90.0-95.3% identical to Chinese PPIV1. Analysis of the HN gene from ten additional PPIV1 positive samples found 85.0-95.5% identity, suggesting genetic diversity between strains. Molecular analysis identified 17 out of 279 (6.1%) positive samples from pigs with respiratory disease. Eleven nursery pigs from a naturally infected herd were asymptomatic; however, nasal swabs from six pigs and the lungs of a single pig were quantitative reverse transcriptase (qRT)-PCR positive. Histopathology identified PPIV1 RNA in the nasal respiratory epithelium and trachea. Two serological assays demonstrated seroconversion of infected pigs and further analysis of 59 swine serum samples found 52.5% and 66.1% seropositivity, respectively. Taken together, the results confirm the widespread presence of PPIV1 in the US swine herd. PMID- 26581411 TI - Short-Term, Low-Dose Use of Tolvaptan as a Bridge Therapy to Expedite Liver Transplant for Severe Hyponatremic, Cirrhotic Patients With High Model for End Stage Liver Disease Scores. AB - For patients on liver transplant waiting lists, hyponatremia is associated with increased mortality before transplant and complications during the early posttransplant period. Conventional therapies, such as fluid restriction or hypertonic saline infusion, are of limited value. We describe 2 patients with high Model for End-Stage Liver Disease scores (> 30) who were referred to our unit for expedited liver transplant. While on waiting lists, these patients developed severe hyponatremia (< 125 mEq/L) that was refractory to conventional therapies. Low-dose, short-term tolvaptan therapy (15 mg/d for 5 d) was then administered, as a bridge therapy to transplant, resulting in prompt restoration of serum sodium levels without any major clinical event. One patient died a few days later as no suitable grafts were available. The other received a liver transplant, and the outcome was uneventful. In conclusion, our report demonstrates that a short-term, low-dose tolvaptan-based strategy promptly resolves hyponatremia in patients who are on expedited waiting lists for liver transplant, allowing surgery with improved sodium levels and possibly limiting peritransplant complications. PMID- 26581413 TI - Analyzing synergistic and non-synergistic interactions in signalling pathways using Boolean Nested Effect Models. AB - MOTIVATION: Understanding the structure and interplay of cellular signalling pathways is one of the great challenges in molecular biology. Boolean Networks can infer signalling networks from observations of protein activation. In situations where it is difficult to assess protein activation directly, Nested Effect Models are an alternative. They derive the network structure indirectly from downstream effects of pathway perturbations. To date, Nested Effect Models cannot resolve signalling details like the formation of signalling complexes or the activation of proteins by multiple alternative input signals. Here we introduce Boolean Nested Effect Models (B-NEM). B-NEMs combine the use of downstream effects with the higher resolution of signalling pathway structures in Boolean Networks. RESULTS: We show that B-NEMs accurately reconstruct signal flows in simulated data. Using B-NEM we then resolve BCR signalling via PI3K and TAK1 kinases in BL2 lymphoma cell lines. AVAILABILITY AND IMPLEMENTATION: R code is available at https://github.com/MartinFXP/B-NEM (github). The BCR signalling dataset is available at the GEO database (http://www.ncbi.nlm.nih.gov/geo/) through accession number GSE68761. CONTACT: martin-franz-xaver.pirkl@ukr.de, Rainer.Spang@ukr.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26581412 TI - An indeterminate mucin-producing cystic neoplasm containing an undifferentiated carcinoma with osteoclast-like giant cells: a case report of a rare association of pancreatic tumors. AB - BACKGROUND: Only few case reports of mucinous cystic pancreatic neoplasm containing an undifferentiated carcinoma with osteoclast-like giant cells have been described in the literature. In the majority of cases this unusual association of tumors seems related to a favorable outcome. We present the second case of an indeterminate mucin-producting cystic neoplasm containing an area of carcinoma with osteoclast-like giant cells. The specific features of the two histotypes and the rapid course of the disease make our clinical case remarkable. CASE PRESENTATION: A 68 year old female came to our attention for a pancreatic macrocystic mass detected with ultrasonography. Her past medical history was silent. The patient reported upper abdominal discomfort for two months; nausea, vomiting or weight loss were not reported. Physical examination revealed a palpable mass in the epigastrium; scleral icterus was absent. Cross-sectional imaging showed a complex mass of the neck and body of the pancreas, characterized by multiple large cystic spaces separated by thick septa and an area of solid tissue located in the caudal portion of the lesion. The patient underwent total pancreatectomy with splenectomy. Pathological examination revealed a mucinous cystic neoplasm with a component of an undifferentiated carcinoma with osteoclast like giant cells. Because of the absence of ovarian-type stroma, the lesion was classified as an indeterminate mucin-producing cystic neoplasm of the pancreas. The immunohistochemical studies evidenced no reactivity of osteclast-like giant cells to epithelial markers but showed a positive reactivity to histiocytic markers. Numerous pleomorphic giant cells with an immunohistochemical sarcomatoid profile were present in the undifferentiated carcinoma with osteoclast-like giant cells. A rapid tumor progression was observed: liver metastases were detected after 4 months. The patient received adjuvant chemotherapy (Gemcitabine) but expired 10 months after surgery. CONCLUSION: Our case confirms that the presence of a solid area in a cystic pancreatic tumor at cross-sectional imaging should raise a suspicion of malignant transformation. The lack of ovarian-type stroma in a pancreatic mucinous cystic neoplasm and the presence of pleomorphic giant cells in an undifferentiated carcinoma with osteoclast-like giant cells could be a marker of a poor prognosis. PMID- 26581414 TI - The optimal number of initial prostate biopsy cores in daily practice: a prospective study using the Nara Urological Research and Treatment Group nomogram. AB - BACKGROUND: To elucidate the optimal number of prostate biopsy cores using a nomogram allocating 6-12 biopsy cores, the number generally used in daily practice, based on age and prostate volume (PV). METHODS: We enrolled 936 patients who received an initial prostate biopsy from April 2006 to January 2009. A number of 6-12 biopsy cores was allocated based on age and PV Nara Urological Research and Treatment Group (NURTG) nomogram. To elucidate the predictive parameters of cancer detection in patients with a prostate specific antigen (PSA) value in the gray zone, univariate and multivariate logistic regression analysis were carried out. RESULTS: The total cancer detection rate and the cancer detection rate in the PSA gray zone (4.1-10.0 ng/mL) were 48.0 and 37.6 %, respectively. The cancer detection rates in the gray zone stratified by patient age of <=59, 60-64, 65-69, 70-74, 75-79, and >=80 years were 28.4, 35.0, 26.9, 37.9, 45.7, and 54.8 %, respectively. The significant predictive parameters of cancer detection in the gray zone were age, volume biopsy ratio (VBR: PV divided by number of biopsy cores), PSA density (PSAD), digital rectal examination findings, and transrectal ultrasound findings in univariate analyses. Finally, age, VBR, and PSAD were independent parameters to predict cancer detection in the gray zone. The adverse event profile was acceptable. CONCLUSIONS: Our present study revealed that the cancer detection rate using the NURTG nomogram allocating 6-12 biopsy cores, the number generally used in daily practice, based on age and PV, could provide similar efficacy as previous studies involving more biopsy cores. In older patients the number of biopsy cores could be reduced. PMID- 26581415 TI - Dissolved inorganic carbon uptake in Thiomicrospira crunogena XCL-2 is Deltap- and ATP-sensitive and enhances RubisCO-mediated carbon fixation. AB - The gammaproteobacterium Thiomicrospira crunogena XCL-2 is an aerobic sulfur oxidizing hydrothermal vent chemolithoautotroph that has a CO2 concentrating mechanism (CCM), which generates intracellular dissolved inorganic carbon (DIC) concentrations much higher than extracellular, thereby providing substrate for carbon fixation at sufficient rate. This CCM presumably requires at least one active DIC transporter to generate the elevated intracellular concentrations of DIC measured in this organism. In this study, the half-saturation constant (K CO2) for purified carboxysomal RubisCO was measured (276 +/- 18 uM) which was much greater than the K CO2 of whole cells (1.03 uM), highlighting the degree to which the CCM facilitates CO2 fixation under low CO2 conditions. To clarify the bioenergetics powering active DIC uptake, cells were incubated in the presence of inhibitors targeting ATP synthesis (DCCD) or proton potential (CCCP). Incubations with each of these inhibitors resulted in diminished intracellular ATP, DIC, and fixed carbon, despite an absence of an inhibitory effect on proton potential in the DCCD-incubated cells. Electron transport complexes NADH dehydrogenase and the bc 1 complex were found to be insensitive to DCCD, suggesting that ATP synthase was the primary target of DCCD. Given the correlation of DIC uptake to the intracellular ATP concentration, the ABC transporter genes were targeted by qRT PCR, but were not upregulated under low-DIC conditions. As the T. crunogena genome does not include orthologs of any genes encoding known DIC uptake systems, these data suggest that a novel, yet to be identified, ATP- and proton potential dependent DIC transporter is active in this bacterium. This transporter serves to facilitate growth by T. crunogena and other Thiomicrospiras in the many habitats where they are found. PMID- 26581416 TI - Isolation of an exopolysaccharide-producing heavy metal-resistant Halomonas sp. MG. AB - An exopolysaccharide (EPS)-producing heavy metal-resistant Gram-negative bacterium was isolated from ore-contaminated soil. The selected strain was identified by 16S rDNA sequencing and designated as Halomonas sp. MG. Phylogenetic analysis of the gene sequence showed its close similarity with Halomonas sp. Field emission scanning electron microscopy analysis revealed that the EPS had a porous structure with small pores. X-ray diffractograms showed the non-crystalline nature of the EPS. Further, FTIR spectroscopic analysis revealed the presence of carboxyl, hydroxyl and amide groups corresponding to a typical EPS. PMID- 26581418 TI - Prostatic Artery Embolization (PAE) for Symptomatic Benign Prostatic Hyperplasia (BPH): Part 1, Pathological Background and Clinical Implications. AB - Pathological features of benign prostatic hyperplasia (BPH) dictate various responses to prostatic artery embolization (PAE). Typically, BPH originates in the transition zone and periurethral region, where should be considered the primary target area in PAE procedures. Given that histological heterogeneity of components in hyperplasia nodules, epithelial or stromal, identifying the more responsive nodules to PAE will have clinical implications. Since some lower urinary tract symptoms (LUTS) in patients with BPH are usually related to bladder outlet obstruction-induced changes in bladder function rather than to outflow obstruction directly, proper selection of candidate patients prior to PAE is of great clinical importance. BPH is a typical chronic progressive condition, suggesting PAE could aim not only to relieve LUTS but also to delay or prevent the clinical progression. Awareness of the pathological background of BPH is essential for interventional radiologists to improve clinical outcomes and develop new treatment strategies in clinical practice of PAE. PMID- 26581417 TI - U-shaped association between telomere length and esophageal squamous cell carcinoma risk: a case-control study in Chinese population. AB - Telomeres play a critical role in biological ageing by maintaining chromosomal integrity and preventing chromosome ends fusion. Epidemiological studies have suggested that inter-individual differences of telomere length could affect predisposition to multiple cancers, but evidence regarding esophageal squamous cell carcinoma (ESCC) was still uncertain. Several telomere length-related single nucleotide polymorphisms (TLSNPs) in Caucasians have been reported in genome-wide association studies. However, the effects of telomere length and TL-SNPs on ESCC development are unclear. Therefore, we conducted a case-control study (1045 ESCC cases and 1433 controls) to evaluate the associations between telomere length, TL SNPs, and ESCC risk in Chinese population. As a result, ESCC cases showed overall shorter relative telomere length (RTL) (median: 1.34) than controls (median: 1.50, P < 0.001). More interestingly, an evident nonlinear U-shaped association was observed between RTL and ESCC risk (P < 0.001), with odds ratios (95% confidence interval) equal to 2.40 (1.84-3.14), 1.36 (1.03-1.79), 1.01 (0.76 1.35), and 1.37 (1.03-1.82) for individuals in the 1st (the shortest), 2nd, 3rd, and 5th (the longest) quintile, respectively, compared with those in the 4th quintile as reference group. No significant associations were observed between the eight reported TL-SNPs and ESCC susceptibility. These findings suggest that either short or extremely long telomeres may be risk factors for ESCC in the Chinese population. PMID- 26581419 TI - Massive turnover rates of fine root detrital carbon in tropical Australian mangroves. AB - Dead fine roots are the major component of organic carbon (C) stored in mangrove forests. We measured the mass and decomposition of fine root detritus in three mangrove forests along an intertidal gradient in tropical Australia to provide the first integrated estimates of the rate of turnover of fine root detritus. The grand mean dry masses of dead fine roots in the forests decreased in the order mid-intertidal Rhizophora (mean 28.4 kg m(-2)), low-intertidal Rhizophora (16.3 kg m(-2)) and high-intertidal Ceriops (mean 8.9 kg m(-2)), and were some of the highest on record. The first-order decay coefficients (day(-1)) for dead fine roots in the low Rhizophora, mid Rhizophora and high Ceriops forest sites were 0.0014, 0.0017 and 0.0007, respectively, and were the lowest on record. The estimated mean fluxes of C via decomposition of dead fine roots were very high in all forests, decreasing in the order mid Rhizophora (18.8 g C m(-2) day(-1)), low Rhizophora (8.4 g C m(-2) day(-1)) and high Ceriops (2.5 g C m(-2) day(-1)). There were relatively low levels of uncertainty in these estimates when all sources of error were considered. The fluxes of C for the two Rhizophora sites integrate all losses from saprophytic decay and leaching of dissolved C and were 50-200 % higher than the estimated total annual loss of C derived by summing rates of bacterial metabolism and export via groundwater and surface waters in these forests. The significant difference reflects both the very high dead root masses and the incorporation of the impact of fungi in our estimates. PMID- 26581420 TI - A naturally heterogeneous landscape can effectively slow down the dispersal of aquatic microcrustaceans. AB - Several studies have suggested that aquatic microcrustaceans are relatively efficient dispersers in a variety of landscapes, whereas others have indicated dispersal limitation at large spatial scales or under specific circumstances. Based on a survey of a set of recently created ponds in an area of approximately 18 * 25 km, we found multiple indications of dispersal limitation affecting the community assembly of microcrustacean communities. Spatial patterns in the community composition were better explained by the geomorphological structure of the landscape than by mere geographic distances. This suggests that ridges separating the network of valleys act as dispersal barriers, and as such may channel the dispersal routes of the studied taxa and, likely, also of their animal vectors. Dispersal limitation was further supported by a strong positive relationship between species richness and the abundance of neighboring water bodies, suggesting that isolation affects colonization rates. Finally, the apparent dispersal limitation of microcrustaceans is further corroborated by the observation of low colonization rates in newly dug experimental ponds in the study area. PMID- 26581421 TI - Intraspecific differences in plant chemotype determine the structure of arthropod food webs. AB - It is becoming increasingly appreciated that the structure and functioning of ecological food webs are controlled by the nature and level of plant chemicals. It is hypothesized that intraspecific variation in plant chemical resistance, in which individuals of a host-plant population exhibit genetic differences in their chemical contents (called 'plant chemotypes'), may be an important determinant of variation in food web structure and functioning. We evaluated this hypothesis using field assessments and plant chemical assays in the tansy plant Tanacetum vulgare L. (Asteraceae). We examined food webs in which chemotypes of tansy plants are the resource for two specialized aphids, their predators and mutualistic ants. The density of the ant-tended aphid Metopeurum fuscoviride was significantly higher on particular chemotypes (borneol) than others. Clear chemotype preferences between predators were also detected. Aphid specialist seven-spotted ladybird beetles (Coccinella septempunctata) were more often found on camphor plants, while significantly higher numbers of the polyphagous nursery web spider (Pisaura mirabilis) were observed on borneol plants. The analysis of plant chemotype effects on the arthropod community clearly demonstrates a range of possible outcomes between plant-aphid-predator networks. The findings help to offer a deeper insight into how one important factor--plant chemical content- influences which species coexist within a food web on a particular host plant and the nature of their trophic linkages. PMID- 26581422 TI - Reference Gene Selection for qPCR Normalization of Kosteletzkya virginica under Salt Stress. AB - Kosteletzkya virginica (L.) is a newly introduced perennial halophytic plant. Presently, reverse transcription quantitative real-time PCR (qPCR) is regarded as the best choice for analyzing gene expression and its accuracy mainly depends on the reference genes which are used for gene expression normalization. In this study, we employed qPCR to select the most stable reference gene in K. virginica which showed stable expression profiles under our experimental conditions. The candidate reference genes were 18S ribosomal RNA (18SrRNA), beta-actin (ACT), alpha-tubulin (TUA), and elongation factor (EF). We tracked the gene expression profiles of the candidate genes and analyzed their stabilities through BestKeeper, geNorm, and NormFinder software programs. The results of the three programs were identical and 18SrRNA was assessed to be the most stable reference gene in this study. However, TUA was identified to be the most unstable. Our study proved again that the traditional reference genes indeed displayed a certain degree of variations under given experimental conditions. Importantly, our research also provides guidance for selecting most suitable reference genes and lays the foundation for further studies in K. virginica. PMID- 26581423 TI - Detection and characterization of carbapenemase-producing Enterobacteriaceae in wounded Syrian patients admitted to hospitals in northern Israel. AB - Since 2013, four hospitals in northern Israel have been providing care for Syrian nationals, primarily those wounded in the ongoing civil war. We analyzed carbapenemase-producing Enterobacteriaceae (CPE) isolates obtained from these patients. Isolate identification was performed using the VITEK 2 system. Polymerase chain reaction (PCR) was performed for the presence of bla KPC, bla NDM, and bla OXA-48. Susceptibility testing and genotyping were performed on selected isolates. During the study period, 595 Syrian patients were hospitalized, most of them young men. Thirty-two confirmed CPE isolates were grown from cultures taken from 30 patients. All but five isolates were identified as Klebsiella pneumoniae and Escherichia coli. Nineteen isolates produced NDM and 13 produced OXA-48. Among a further 29 isolates tested, multilocus sequence typing (MLST) showed that ST278 and ST38 were the major sequence types among the NDM-producing K. pneumoniae and OXA-48-producing E. coli isolates, respectively. Most were resistant to all three carbapenems in use in Israel and to gentamicin, but susceptible to colistin and fosfomycin. The source for bacterial acquisition could not be determined; however, some patients admitted to different medical centers were found to carry the same sequence type. CPE containing bla NDM and bla OXA-48 were prevalent among Syrian wounded hospitalized patients in northern Israel. The finding of the same sequence type among patients at different medical centers implies a common, prehospital source for these patients. These findings have implications for public health throughout the region. PMID- 26581424 TI - Syphilis hospitalisations in Portugal over the last decade. AB - Although several studies have reported an increase of syphilis incidence over the last decade in Western Europe, information concerning syphilis epidemiology in Portugal remains scarce. Therefore, we sought to characterise acquired syphilis associated hospitalisations in Portugal according to demographic and clinical data. We used a database containing all hospitalisations that occurred in mainland Portugal public hospitals with discharges between 2000 and 2014. We analysed all hospitalisations associated with ICD-9-CM codes 091-097.x (corresponding to acquired syphilis diagnosis) concerning inpatients' gender, age and comorbidities. The median length of stay and in-hospital mortality rates were also studied. Between 2000 and 2014, there were a total of 8974 syphilis-related hospitalisations in mainland Portugal. The rate of acquired syphilis hospitalisations per 100,000 inhabitants increased by 33 % during the studied period. Syphilis hospitalisation rates increased by 70 % in males and 139 % among patients aged over 55 years. On the other hand, they declined by 10 % in females and 20 % among patients younger than 55 years old. The percentage of syphilis episodes presenting cardiovascular and neuropsychiatric comorbidities increased, while the percentage of syphilis episodes presenting HIV co-infection decreased by 69 %. A fatal outcome was reported in 5 % of episodes; 4.6 % of them had acquired syphilis as the main reason for hospitalisation. This study illustrates that, despite being a preventable infection, syphilis remains a public health problem. The analysis of hospitalisation and administrative data helps to understand syphilis epidemiology and provides a supplement to traditional case notifications. PMID- 26581425 TI - Development and evaluation of double locus sequence typing for molecular epidemiological investigations of Clostridium difficile. AB - Despite the development of novel typing methods based on whole genome sequencing, most laboratories still rely on classical molecular methods for outbreak investigation or surveillance. Reference methods for Clostridium difficile include ribotyping and pulsed-field gel electrophoresis, which are band-comparing methods often difficult to establish and which require reference strain collections. Here, we present the double locus sequence typing (DLST) scheme as a tool to analyse C. difficile isolates. Using a collection of clinical C. difficile isolates recovered during a 1-year period, we evaluated the performance of DLST and compared the results to multilocus sequence typing (MLST), a sequence based method that has been used to study the structure of bacterial populations and highlight major clones. DLST had a higher discriminatory power compared to MLST (Simpson's index of diversity of 0.979 versus 0.965) and successfully identified all isolates of the study (100 % typeability). Previous studies showed that the discriminatory power of ribotyping was comparable to that of MLST; thus, DLST might be more discriminatory than ribotyping. DLST is easy to establish and provides several advantages, including absence of DNA extraction [polymerase chain reaction (PCR) is performed on colonies], no specific instrumentation, low cost and unambiguous definition of types. Moreover, the implementation of a DLST typing scheme on an Internet database, such as that previously done for Staphylococcus aureus and Pseudomonas aeruginosa ( http://www.dlst.org ), will allow users to easily obtain the DLST type by submitting directly sequencing files and will avoid problems associated with multiple databases. PMID- 26581426 TI - Acute hepatitis B virus infection or acute exacerbation of chronic hepatitis B infection: the differential serological diagnosis. AB - Acute exacerbations of chronic hepatitis B are common, and may even be the first presentation of hepatitis B virus (HBV) infection. Sometimes, patients involved in these scenarios may have mistaken diagnosis of acute hepatitis B. The reason for the confusion is that the two forms of infection manifestation resemble remarkably in clinical, biochemical, and serological features, such as apparent rapid onset of severe disease, advanced grades of encephalopathy, high aminotransferases and prolonged international normalized ratios (INRs), as well as positivity for HBsAg and for IgM anti-HBc antibodies and DNA detection. Therefore, these two entities cannot be distinguished easily without historical information of HBV-associated chronic infection or recent HBV exposure, information that is often inaccurate. Considering the different prognoses, treatment strategies, and the epidemiological impact in the public health context, the correct diagnosis is extremely important. Despite the lack of effective and reliable tests to differentiate between acute infection and acute exacerbation of chronic HBV infection, the expression and kinetic evaluation of viral markers present in the circulation of individuals infected, the observation of physical-chemical properties of specific antibodies, and the combination of these findings represent some strategies in serology that could assist in differentiating between the two entities, or at least in the guidance for the correct diagnosis. PMID- 26581427 TI - The CDKN2A/p16(INK) (4a) 5'UTR sequence and translational regulation: impact of novel variants predisposing to melanoma. AB - Many variants of uncertain functional significance in cancer susceptibility genes lie in regulatory regions, and clarifying their association with disease risk poses significant challenges. We studied 17 germline variants (nine of which were novel) in the CDKN2A 5'UTR with independent approaches, which included mono and bicistronic reporter assays, Western blot of endogenous protein, and allelic representation after polysomal profiling to investigate their impact on CDKN2A mRNA translation regulation. Two of the novel variants (c.-27del23, c.-93 91delAGG) were classified as causal mutations (score >=3), along with the c. 21C>T, c.-34G>T, and c.-56G>T, which had already been studied by a subset of assays. The novel c.-42T>A as well as the previously described c.-67G>C were classified as potential mutations (score 1 or 2). The remaining variants (c. 14C>T, c.-20A>G, c.-25C>T+c.-180G>A, c.-30G>A, c.-40C>T, c.-45G>A, c.-59C>G, c. 87T>A, c.-252A>T) were classified as neutral (score 0). In conclusion, we found evidence that nearly half of the variants found in this region had a negative impact on CDKN2A mRNA translation, supporting the hypothesis that 5'UTR can act as a cellular Internal Ribosome Entry Site (IRES) to modulate p16(INK) (4a) translation. PMID- 26581428 TI - ADAMTS13 and anti-ADAMTS13 autoantibodies in thrombotic thrombocytopenic purpura current perspectives and new treatment strategies. AB - A deficiency in ADAMTS13 (A Disintegrin And Metalloprotease with ThromboSpondin type-1 repeats, member 13) is associated with thrombotic thrombocytopenic purpura (TTP). Congenital TTP is caused by a defect in the ADAMTS13 gene resulting in decreased or absent enzyme activity; acquired TTP results from autoantibodies that either inhibit the activity or increase the clearance of ADAMTS13. Despite major progress in recent years in our understanding of the disease, many aspects around the pathophysiology of TTP are still unclear. Newer studies expanded the TTP field from ADAMTS13 and inhibitory antibodies to immune complexes, cloned autoantibodies, and a possible involvement of other proteases. Additionally, several new treatment strategies supplementing plasma-exchange and infusion are under investigation for a better and more specific treatment of TTP patients. In this review, we discuss the recent insights in TTP pathophysiology and describe upcoming therapeutic opportunities. PMID- 26581429 TI - The Opposing Roles of IVS2+691 CC Genotype and AC/AG Diplotype of 118A>G and IVS2+691G>C of OPRM1 Polymorphisms in Cold Pain Tolerance Among Opioid-Dependent Malay Males on Methadone Therapy. AB - INTRODUCTION: We recently reported that a majority of opioid-dependent Malay males on methadone therapy are cold pain sensitive. It is postulated that common OPRM1 polymorphisms may be responsible. This study investigated the association between 118A>G (dbSNP rs1799971) and IVS2+691G>C (dbSNP rs2075572) variants on cold pain responses among opioid-dependent Malay males on methadone maintenance therapy. METHODS: Cold pain responses including pain threshold, pain tolerance, and pain intensity were measured using the cold pressor test. DNA was extracted from the venous blood before polymerase chain reaction genotyping. Repeated measures analysis of variance was used to compare the cold pain responses and OPRM1 polymorphisms (118A>G and IVS2+691G>C) using models including genotype dominant and recessive models, allelic additive models, and analysis of haplotypes and diplotypes. RESULTS: A total of 148 participants were recruited. With the recessive model, those with IVS2+691 homozygous CC genotype had a shorter cold pain tolerance time than those without CC genotype (i.e., GG/GC genotype; 29.81 vs. 43.08 s, respectively, P = 0.048). On the other hand, with diplotype analysis, participants with combined homozygous 118 AA genotype and heterozygous IVS2+691 GC genotype (i.e., AC/AG diplotype) had a longer cold pain tolerance time than those without this diplotype (49.34 vs. 31.48 s, respectively, P = 0.043). Cold pain threshold was not associated with any of the 118A>G and IVS2+691G>C variations despite being analyzed using various models (all P > 0.05). CONCLUSION: The IVS2+691 CC genotype and AC/AG diplotype of 118A>G and IVS2+691G>C seem to have opposing roles in pain tolerance among opioid dependent Malay males on methadone therapy. Haplotypes of OPRM1 may be associated with altered binding affinity. PMID- 26581430 TI - User Experience Evaluation of a Smoking Cessation App in People With Serious Mental Illness. AB - INTRODUCTION: Smoking rates among people with serious mental illness are 3 to 4 times higher than the general population, yet currently there are no smoking cessation apps specifically designed to address this need. We report the results of a User Experience (UX) evaluation of a National Cancer Institute smoking cessation app, QuitPal, and provide user centered design data that can be used to tailor smoking cessation apps for this population. METHODS: Two hundred forty hours of field experience with QuitPal, 10 hours of recorded interviews and task performances, usage logs and a self-reported usability scale, informed the results of our study. Participants were five individuals recruited from a community mental health clinic with a reported serious mental illness history. Performance, self-reports, usage logs and interview data were triangulated to identify critical usability errors and UX themes emerging from this population. RESULTS: Data suggests QuitPal has below average levels of usability, elevated time on task performances and required considerable amounts of guidance. UX themes provided critical information to tailor smoking cessation apps for this population, such as the importance of breaking down "cessation" into smaller steps and use of a reward system. CONCLUSIONS: This is the first study to examine the UX of a smoking cessation app among people with serious mental illness. Data from this study will inform future research efforts to expand the effectiveness and reach of smoking cessation apps for this highly nicotine dependent yet under served population. IMPLICATIONS: Data from this study will inform future research efforts to expand the effectiveness and reach of smoking cessation apps for people with serious mental illness, a highly nicotine dependent yet under-served population. PMID- 26581432 TI - Spinal cord involvement in posterior reversible encephalopathy syndrome (PRES). PMID- 26581431 TI - Surface modification of zinc oxide nanoparticles with amorphous silica alters their fate in the circulation. AB - Nanoparticle (NP) pharmacokinetics and biological effects are influenced by many factors, especially surface physicochemical properties. We assessed the effects of an amorphous silica coating on the fate of zinc after intravenous (IV) injection of neutron activated uncoated (65)ZnO or silica-coated (65)ZnO NPs in male Wistar Han rats. Groups of IV-injected rats were sequentially euthanized, and 18 tissues were collected and analyzed for (65)Zn radioactivity. The protein coronas on each ZnO NP after incubation in rat plasma were analyzed by SDS-PAGE gel electrophoresis and mass spectrometry of selected gel bands. Plasma clearance for both NPs was biphasic with rapid initial and slower terminal clearance rates. Half-lives of plasma clearance of silica-coated (65)ZnO were shorter (initial - <1 min; terminal - 2.5 min) than uncoated (65)ZnO (initial - 1.9 min; terminal - 38 min). Interestingly, the silica-coated (65)ZnO group had higher (65)Zn associated with red blood cells and higher initial uptake in the liver. The (65)Zn concentrations in all the other tissues were significantly lower in the silica-coated than uncoated groups. We also found that the protein corona formed on silica-coated ZnO NPs had higher amounts of plasma proteins, particularly albumin, transferrin, A1 inhibitor 3, alpha-2-hs-glycoprotein, apoprotein E and alpha-1 antitrypsin. Surface modification with amorphous silica alters the protein corona, agglomerate size, and zeta potential of ZnO NPs, which in turn influences ZnO biokinetic behavior in the circulation. This emphasizes the critical role of the protein corona in the biokinetics, toxicology and nanomedical applications of NPs. PMID- 26581433 TI - When diagnostics meets translational research: detection of hemoglobin fractions in cellular lysates from in vitro erythroid cultures by Capillarys 2 Flex Piercing analyzer (Sebia). AB - Detection of hemoglobin (Hb) variants represents an important issue for diagnosis and adequate treatment of hemoglobinopathies. The Capillarys 2 Flex Piercing analyzer (Capillarys) by Sebia is routinely used in our clinical laboratories to detect Hb variants in peripheral blood (PB). This automated method separates Hb fractions by capillary electrophoresis, giving a spectrophotometric measure of their relative proportion. The scientific research in the field of hemoglobinopathies needs robust procedures to evaluate the efficacy of experimental therapies, as gene therapy. We investigated for the first time the feasibility to use Capillarys on cellular lysates from in vitro erythroid cultures. Because total Hb concentration in erythroid lysates is up to 20-fold lower than in hemolysates from PB, we analyzed diluted blood samples, thanks to the manual mode included in the Capillarys setting. We compared analytical precision, accuracy, sensitivity, and specificity of this procedure to the automatic method, routinely used in diagnostics. For instance, adult Hb intra- and interassay precision were estimated as coefficient of variation 0.2% and 0.3%, respectively. The manual mode is less robust for detection of fractions <3% and the lower level of sensitivity is 2 g/L of total Hb. Specificity of manual and automatic settings was equivalent. We confirmed the performance of the method by analyzing erythroid lysates from thalassemic patients' cultures. Our study demonstrated that the Capillarys 2 Flex Piercing manual method is comparable to the automatic one. The analysis is very robust at low Hb concentrations, as in erythroid cultures from patients affected by hemoglobinopathies, representing a useful tool also in translational research. PMID- 26581434 TI - Risks of miscarriage and inadvertent exposure to artemisinin derivatives in the first trimester of pregnancy: a prospective cohort study in western Kenya. AB - BACKGROUND: The artemisinin anti-malarials are widely deployed as artemisinin based combination therapy (ACT). However, they are not recommended for uncomplicated malaria during the first trimester because safety data from humans are scarce. METHODS: This was a prospective cohort study of women of child bearing age carried out in 2011-2013, evaluating the relationship between inadvertent ACT exposure during first trimester and miscarriage. Community-based surveillance was used to identify 1134 early pregnancies. Cox proportional hazard models with left truncation were used. RESULTS: The risk of miscarriage among pregnancies exposed to ACT (confirmed + unconfirmed) in the first trimester, or during the embryo-sensitive period (>=6 to <13 weeks gestation) was higher than among pregnancies unexposed to anti-malarials in the first trimester: hazard ratio (HR) = 1.70, 95 % CI (1.08-2.68) and HR = 1.61 (0.96-2.70). For confirmed ACT-exposures (primary analysis) the corresponding values were: HR = 1.24 (0.56 2.74) and HR = 0.73 (0.19-2.82) relative to unexposed women, and HR = 0.99 (0.12 8.33) and HR = 0.32 (0.03-3.61) relative to quinine exposure, but the numbers of quinine exposures were very small. CONCLUSION: ACT exposure in early pregnancy was more common than quinine exposure. Confirmed inadvertent artemisinin exposure during the potential embryo-sensitive period was not associated with increased risk of miscarriage. Confirmatory studies are needed to rule out a smaller than three-fold increase in risk. PMID- 26581435 TI - Mammographic density defined by higher than conventional brightness threshold better predicts breast cancer risk for full-field digital mammograms. AB - INTRODUCTION: When measured using the computer-assisted method CUMULUS, mammographic density adjusted for age and body mass index predicts breast cancer risk. We asked if new mammographic density measures defined by higher brightness thresholds gave better risk predictions. METHODS: The Korean Breast Cancer Study included 213 women diagnosed with invasive breast cancer and 630 controls matched for age at full-field digital mammogram and menopausal status. Mammographic density was measured using CUMULUS at the conventional threshold (Cumulus), and in effect at two increasingly higher thresholds, which we call Altocumulus and Cirrocumulus, respectively. All measures were Box-Cox transformed and adjusted for age, body mass index, menopausal status and machine. We used conditional logistic regression to estimate the change in Odds PER standard deviation of transformed and Adjusted density measures (OPERA). The area under the receiver operating characteristic curve (AUC) was estimated. RESULTS: Corresponding Altocumulus and Cirrocumulus density measures were correlated with Cumulus measures (r approximately 0.8 and 0.6, respectively). Altocumulus and Cirrocumulus measures were on average 25% and 80% less, respectively, than the Cumulus measure. For dense area, the OPERA was 1.18 (95% confidence interval: 1.01-1.39, P = 0.03) for Cumulus; 1.36 (1.15-1.62, P < 0.001) for Altocumulus; and 1.23 (1.04-1.45, P = 0.01) for Cirrocumulus. After fitting the Altocumulus measure, the Cumulus measure was no longer associated with risk. After fitting the Cumulus measure, the Altocumulus measure was still associated with risk (P = 0.001). The AUCs for dense area was 0.59 for the Altocumulus measure, greater than 0.55 and 0.57 for the Cumulus and Cirrocumulus measures, respectively (P = 0.001). Similar results were found for percentage dense area measures. CONCLUSIONS: Altocumulus measures perform better than Cumulus measures in predicting breast cancer risk, and Cumulus measures are confounded by Altocumulus measures. The mammographically bright regions might be more aetiologically important for breast cancer, with implications for biological, molecular, genetic and epidemiological research and clinical translation. PMID- 26581436 TI - Prevalence of Taenia solium cysticercosis in pigs entering the food chain in western Kenya. AB - Three hundred forty-three pigs slaughtered and marketed in western Kenya were subjected to lingual examination and HP10 Ag-ELISA for the serological detection of Taenia solium antigen. When estimates were adjusted for the sensitivity and specificity of the diagnostic assays, prevalence of T. solium cysticercosis estimated by lingual exam and HP10 Ag-ELISA was between 34.4% (95% confidence interval (CI) 19.4-49.4%) and 37.6% (95% CI 29.3-45.9%), respectively. All pigs, however, were reported to have passed routine meat inspection. Since T. solium poses a serious threat to public health, these results, if confirmed, indicate that the introduction of control strategies may be appropriate to ensure the safety of pork production in this region. PMID- 26581438 TI - Description of a taxonomically undefined Sclerotiniaceae strain from withered rotten-grapes. AB - A necrotrophic member of the Sclerotiniaceae family (herewith named strain C10) isolated from withered rotten-grapes, is described. Interestingly, the fungus has no defined taxonomic position since it has been impossible to attribute it to an existing genus. Phylogenetic analysis of partial sequences of glyceraldehyde 3 phosphate dehydrogenase (G3PDH), heat shock protein 60 (HSP60) and DNA-directed RNA polymerase II subunit (RPB2), revealed that strain C10 is distantly related to Amphobotrys and Botrytis. This evidence clearly distinguishes this new Sclerotiniaceae member from other taxa of the family. Moreover, its morphological characteristics did not match those of Amphobotrys and Botrytis. Infectivity assays demonstrated that strain C10 could be a potential postharvest pathogen of withered grapes. This study revealed the taxonomic importance of this strain suggesting the existence of a possible new genus, a theory that requires further investigation. PMID- 26581439 TI - Incorporation of FcRn-mediated disposition model to describe the population pharmacokinetics of therapeutic monoclonal IgG antibody in clinical patients. AB - PURPOSE: The two-compartment linear model used to describe the population pharmacokinetics (PK) of many therapeutic monoclonal antibodies (TMAbs) offered little biological insight to antibody disposition in humans. The purpose of this study is to develop a semi-mechanistic FcRn-mediated IgG disposition model to describe the population PK of TMAbs in clinical patients. METHODS: A standard two compartment linear PK model from a previously published population PK model of pertuzumab was used to simulate intensive PK data of 100 subjects for model development. Two different semi-mechanistic FcRn-mediated IgG disposition models were developed and First Order Conditional Estimation (FOCE) with the interaction method in NONMEM was used to obtain the final model estimates. The performances of these models were then compared with the two-compartment linear PK model used to simulate the data for model development. RESULTS: A semi-mechanistic FcRn mediated IgG disposition model consisting of a peripheral tissue compartment and FcRn-containing endosomes in the central compartment best describes the simulated pertuzumab population PK data. This developed semi-mechanistic population PK model had the same number of model parameters, produced very similar concentration-time profiles but provided additional biological insight to the FcRn-mediated IgG disposition in human subjects compared with the standard linear two-compartment linear PK model. CONCLUSION: This first reported semi-mechanistic model may serve as an important model framework for developing future population PK models of TMAbs in clinical patients. PMID- 26581437 TI - A systematic review on the microscopic agglutination test seroepidemiology of bovine leptospirosis in Latin America. AB - The diagnosis of leptospirosis commonly relies on serology, which has three issues that are referred: the sampling, the antigen panel, and the cutoff point. We propose a systematic review of the bovine leptospirosis in Latin America, in order to provide a better understanding of the evolution of the research and of the seroepidemiology of bovine leptospirosis in that region. Internet databases were consulted over the year of 2014. Inclusion criteria for analysis included serosurvey using microscopic agglutination test (MAT), a relevant number of animals, the presence in the antigen panel of at least one representant of serogroup Sejroe, and a cutoff point of >=100. A total of 242 articles that referred to cattle, leptospir*, and one region of Latin America was found. Only 105 articles regarding to serosurveys using MAT were found in several countries, and 61 (58.1 %) met all the inclusion criteria. In conclusion, this systematic review demonstrated a high prevalence of the infection (75.0 % at herd level and 44.2 % at animal level), with predominance of strains of serogroup Sejroe (80.3 %). It was evident that there is the necessity of more studies in several countries, as well as the need for greater standardization in studies, especially with regard to the adopted cutoff point at serological tests. PMID- 26581440 TI - antaRNA--Multi-objective inverse folding of pseudoknot RNA using ant-colony optimization. AB - BACKGROUND: Many functional RNA molecules fold into pseudoknot structures, which are often essential for the formation of an RNA's 3D structure. Currently the design of RNA molecules, which fold into a specific structure (known as RNA inverse folding) within biotechnological applications, is lacking the feature of incorporating pseudoknot structures into the design. Hairpin-(H)- and kissing hairpin-(K)-type pseudoknots cover a wide range of biologically functional pseudoknots and can be represented on a secondary structure level. RESULTS: The RNA inverse folding program antaRNA, which takes secondary structure, target GC content and sequence constraints as input, is extended to provide solutions for such H- and K-type pseudoknotted secondary structure constraint. We demonstrate the easy and flexible interchangeability of modules within the antaRNA framework by incorporating pKiss as structure prediction tool capable of predicting the mentioned pseudoknot types. The performance of the approach is demonstrated on a subset of the Pseudobase ++ dataset. CONCLUSIONS: This new service is available via a standalone version and is also part of the Freiburg RNA Tools webservice. Furthermore, antaRNA is available in Galaxy and is part of the RNA-workbench Docker image. PMID- 26581441 TI - In Memoriam--Robert E. Ryan, Sr., MD. PMID- 26581442 TI - Capsaicin 8% patch versus oral pregabalin in patients with peripheral neuropathic pain. AB - BACKGROUND: Clinical trials have not yet compared the efficacy of capsaicin 8% patch with current standard therapy in peripheral neuropathic pain (PNP). OBJECTIVES: Head-to-head efficacy and safety trial comparing the capsaicin patch with pregabalin in PNP. METHODS: Open-label, randomized, multicentre, non inferiority trial. Patients with PNP, aged 18-80 years, were randomly assigned to either the capsaicin 8% patch (n = 282) or an optimised dose of oral pregabalin (n = 277), and assessed for a >=30% mean decrease in Numeric Pain Rating Scale (NPRS) score from baseline to Week 8. Secondary endpoints included optimal therapeutic effect (OTE), time-to-onset of pain relief and treatment satisfaction. RESULTS: The capsaicin 8% patch was non-inferior to pregabalin in achievement of a >=30% mean decrease in NPRS score from baseline to Week 8 (55.7% vs. 54.5%, respectively; Odds ratio: 1.03 [95% CI: 0.72, 1.50]). The proportion of patients achieving OTE at Week 8 was 52.1% for the capsaicin 8% patch versus 44.8% for pregabalin (difference: 7.3%; 95% CI: -0.9%, 15.6%). The median time-to onset of pain relief was significantly shorter for capsaicin 8% patch versus pregabalin (7.5 vs. 36.0 days; Hazard ratio: 1.68 [95% CI: 1.35, 2.08]; p < 0.0001). Treatment satisfaction was also significantly greater with the capsaicin 8% patch versus pregabalin. TEAEs were mild-to-moderate in severity, and resulted in treatment discontinuation only with pregabalin (n = 24). Systemic adverse drug reactions ranged from 0 to 1.1% with capsaicin 8% patch and 2.5 to 18.4% with pregabalin. CONCLUSIONS: The capsaicin 8% patch provided non-inferior pain relief to an optimized dose of pregabalin in PNP, with a faster onset of action, fewer systemic side effects and greater treatment satisfaction. PMID- 26581443 TI - A new frontonasal dysplasia syndrome associated with deletion of the SIX2 gene. AB - The frontonasal dysplasias are a group of craniofacial phenotypes characterized by hypertelorism, nasal clefting, frontal bossing, and abnormal hairline. These conditions are caused by recessive mutations in members of the aristaless gene family, resulting in abnormal cranial neural crest migration and differentiation. We report a family with a dominantly inherited craniofacial phenotype comprised of frontal bossing with high hairline, ptosis, hypertelorism, broad nasal tip, large anterior fontanelle, cranial base anomalies, and sagittal synostosis. Chromosomal microarray identified a heterozygous 108.3 kilobase deletion of chromosome 2p21 segregating with phenotype and limited to the sine oculis homeobox gene SIX2 and surrounding noncoding DNA. Similar to the human SIX2 deletion phenotype, one mouse model of frontonasal dysplasia, brachyrrhine, exhibits dominant inheritance and impaired cranial base chondrogenesis associated with reduced Six2 expression. We report the first human autosomal dominant frontonasal dysplasia syndrome associated with SIX2 deletion and with phenotypic similarities to murine models of Six2 Loss-of-function. PMID- 26581445 TI - Synthesis and biological evaluation of some dibenzofuran-piperazine derivatives. AB - In the present paper, a novel series of dibenzofuran-piperazine derivatives were synthesized via the treatment of N-(2-methoxy-3-dibenzofuranyl)-2-chloroacetamide with substituted piperazine derivatives. The chemical structures of the compounds were elucidated by (1)H NMR, (13)C NMR, mass spectral data; elemental analysis and HPLC analysis. Each derivative was evaluated for antiplatelet activity and anticholinesterase activity. Compound 2 m with 2-furoyl moiety exhibited high percentage inhibition as much as standard drug aspirin on arachidonic acid (AA) induced platelet aggregation. None of the compounds presented significant inhibitor effect on collagen-induced platelet aggregation. Furthermore, the anticholinesterase activity of the compounds was determined and they did not show promising inhibitor activity compared with standard drug donepezil. PMID- 26581446 TI - Proof of Concept: Magnetic Fixation of Dendron-Functionalized Iron Oxide Nanoparticles Containing Palladium Nanoparticles for Continuous-Flow Suzuki Coupling Reactions. AB - A new concept for the magnetic immobilization of catalytically active material has been developed for continuous-flow Suzuki cross-coupling reactions. The reversible immobilization of the magnetic catalyst material inside a novel capillary microreactor has been achieved by utilizing a newly designed reactor housing with 208 small permanent magnets. As a catalyst material, magnetic Fe3O4 nanoparticles decorated with polyphenylenepyridyl dendrons and loaded with Pd nanoparticles have been employed. Both batch and continuous-flow experiments prove the activity of the catalyst and the applicability of this new microreactor concept. PMID- 26581444 TI - Genome-wide identification and evolutionary analyses of bZIP transcription factors in wheat and its relatives and expression profiles of anther development related TabZIP genes. AB - BACKGROUND: Among the largest and most diverse transcription factor families in plants, basic leucine zipper (bZIP) family participate in regulating various processes, including floral induction and development, stress and hormone signaling, photomorphogenesis, seed maturation and germination, and pathogen defense. Although common wheat (Triticum aestivum L.) is one of the most widely cultivated and consumed food crops in the world, there is no comprehensive analysis of bZIPs in wheat, especially those involved in anther development. Previous studies have demonstrated wheat, T. urartu, Ae. tauschii, barley and Brachypodium are evolutionarily close in Gramineae family, however, the real evolutionary relationship still remains mysterious. RESULTS: In this study, 187 bZIP family genes were comprehensively identified from current wheat genome. 98, 96 and 107 members of bZIP family were also identified from the genomes of T.urartu, Ae.tauschii and barley, respectively. Orthology analyses suggested 69.4 % of TubZIPs were orthologous to 68.8 % of AetbZIPs and wheat had many more in paralogs in the bZIP family than its relatives. It was deduced wheat had a closer phylogenetic relationship with barley and Brachypodium than T.urartu and Ae.tauschii. bZIP proteins in wheat, T.urartu and Ae.tauschii were divided into 14 subgroups based on phylogenetic analyses. Using Affymetrix microarray data, 48 differentially expressed TabZIP genes were identified to be related to anther development from comparison between the male sterility line and the restorer line. Genes with close evolutionary relationship tended to share similar gene structures. 15 of 23 selected TabZIP genes contained LTR elements in their promoter regions. Expression of 21 among these 23 TabZIP genes were obviously responsive to low temperature. These 23 TabZIP genes all exhibited distinct tissue-specific expression pattern. Among them, 11 TabZIP genes were predominantly expressed in anther and most of them showed over-dominance expression mode in the cross combination TY806 * BS366. CONCLUSIONS: The genome wide identification provided an overall insight of bZIP gene family in wheat and its relatives. The evolutionary relationship of wheat and its relatives was proposed based on orthology analyses. Microarray and expression analyses suggested the potential involvement of bZIP genes in anther development and facilitated selection of anther development related gene for further functional characterization. PMID- 26581447 TI - Central dopaminergic neurotransmission plays an important role in thermoregulation and performance during endurance exercise. AB - Dopamine (DA) has been widely investigated for its potential role in determining exercise performance. It was originally thought that DA's ergogenic effect was by mediating psychological responses. Recently, some studies have also suggested that DA may regulate physiological responses, such as thermoregulation. Hyperthermia has been demonstrated as an important limiting factor during endurance exercise. DA is prominent in the thermoregulatory centre, and changes in DA concentration have been shown to affect core temperature regulation during exercise. Some studies have proposed that DA or DA/noradrenaline (NA) reuptake inhibitors can improve exercise performance, despite hyperthermia during exercise in the heat. DA/NA reuptake inhibitors also increase catecholamine release in the thermoregulatory centre. Intracerebroventricularly injected DA has been shown to improve exercise performance through inhibiting hyperthermia-induced fatigue, even at normal ambient temperatures. Further, caffeine has been reported to increase DA release in the thermoregulatory centre and improves endurance exercise performance despite increased core body temperature. Taken together, DA has been shown to have ergogenic effects and increase heat storage and hyperthermia tolerance. The mechanisms underlying these effects seem to involve limiting/overriding the inhibitory signals from the central nervous system that result in cessation of exercise due to hyperthermia. PMID- 26581448 TI - Successful control of juvenile dermatomyositis-associated macrophage activation syndrome and interstitial pneumonia: distinct kinetics of interleukin-6 and -18 levels. AB - BACKGROUND: Macrophage activation syndrome (MAS) is the secondary hemophagocytic lymphohistiocytosis associated with rheumatic diseases. Recently, the different cytokine profiles between systemic juvenile idiopathic arthritis (sJIA) associated MAS (sJIA-MAS) and juvenile systemic lupus erythematosus (JSLE) associated MAS (JSLE-MAS) were reported. However, there is little information about juvenile dermatomyositis (JDM)-associated MAS (JDM-MAS). CASE PRESENTATION: A 4-year-old girl with JDM was hospitalized because of fever, erythema, hepatosplenomegaly, cytopenia, liver dysfunction and coagulopathy. Bone marrow aspiration revealed appreciable numbers of activated and hemophagocytosing macrophages. She was diagnosed as having JDM-MAS complicated with interstitial pneumonia (IP) based on the findings of the elevation of serum Krebs von den Lungen-6 (KL-6) levels and chest computed tomography findings. We analyzed circulating levels of interleukin (IL)-2,4,6,10,18, tumor necrosis factor-alpha and interferon-gamma in the patient. Hypercytokinemia occurred at the diagnosis of MAS and IP, showing with the prominent elevations of IL-6 and IL-18 levels. The cytokine profiles were distinct from those reported in patients with sJIA-MAS or JSLE-MAS. High-dose corticosteroid and cyclosporine therapy led to a drastic improvement of MAS with decreased IL-6 levels. Subsequent cyclophosphamide therapy successfully controlled IP, paralleled with the declining pattern of IL 18 and KL-6 levels. CONCLUSION: This is the first report to describe a successful treatment and the cytokine profile of JDM-MAS and IP. Serum IL-6 and IL-18 levels may be useful for predicting the disease activity of JDM-MAS and IP, respectively. PMID- 26581449 TI - Erratum to: A novel solid state fermentation coupled with gas stripping enhancing the sweet sorghum stalk conversion performance for bioethanol. AB - [This corrects the article DOI: 10.1186/1754-6834-7-53.]. PMID- 26581450 TI - Evaluation of multiple mechanism-based toxicity endpoints in primary cultured human hepatocytes for the identification of drugs with clinical hepatotoxicity: Results from 152 marketed drugs with known liver injury profiles. AB - We report here the results of a collaborative research program to develop a robust and reliable in vitro system to allow an accurate definition of the drug induced liver injury (DILI) potential of new drug entities during drug development. The in vitro hepatotoxic potential of 152 drugs with known DILI profiles were evaluated in primary cultured human hepatocytes with four mechanistically-relevant endpoints: cellular ATP depletion, reactive oxygen species (ROS), glutathione (GSH) depletion, and caspase activation for apoptosis. The drugs, 80 in the testing set and 72 in the validation set, were classified based on serious clinical/regulatory outcomes as defined by reported acute liver failure, black-box warning, and/or withdrawal. The drugs were further sub categorized for dominant types of liver injury. Logistic regression models were performed to calculate the area under the receiver operating characteristics curve (AUROC) and to evaluate the prediction potential of the selected endpoints for serious clinical/regulatory outcomes. The ROS/ATP ratio was found to yield an excellent AUROC in both the testing (0.8989, P < 0.0001) and validation set (0.8545, P < 0.0001), and was found to distinguish drugs associated with severe from non-severe DILI cases (p < 0.0001). The results suggest that evaluation of drugs in primary human hepatocytes using the ROS/ATP ratio endpoint may aid the definition of their potential to cause severe DILI. PMID- 26581451 TI - Synchronous double C-N bond formation via C-H activation for a novel synthetic route to phenazine. AB - A novel synthetic strategy for phenazine formation is reported following self coupling of anilines by Pd-Ag binary nanocluster-catalysed synchronous double C-N bond formation via non-radical mode of ortho-aryl C-H activation. PMID- 26581453 TI - Left ventricular geometry and white matter lesions in ischemic stroke patients. AB - Abnormal left ventricular (LV) geometry is associated with extracardiac organ damage in patients with hypertension. The aim of this study was to determine the relationship between LV geometry and white matter lesions (WMLs) in ischemic stroke patients. We retrospectively analyzed data from 155 patients (median age 62; 49.8% male) with mild ischemic stroke (median National Institutes of Health Stroke Scale score 4) who underwent brain magnetic resonance imaging and echocardiography. Patients were categorized into four groups: normal LV geometry, concentric remodeling, eccentric left ventricular hypertrophy (LVH) and concentric LVH. WMLs were graded using the Fazekas scale on fluid-attenuated inversion recovery images. Extensive WMLs were defined as a Fazekas score > 2. Extensive WMLs were more prevalent in patients with concentric LVH, eccentric LVH and concentric remodeling than in those with normal LV geometry. After adjusting for hypertension, age, diabetes mellitus, hypercholesterolemia, glomerular filtration rate and ischemic heart disease, patients with concentric remodeling [odds ratio (OR) 3.94, 95% confidence interval (CI) 1.26-12.31, p = 0.02] and those with concentric LVH (OR 3.69, 95% CI 1.24-10.95, p = 0.02), but not patients with eccentric LVH (OR 2.44, 95% CI 0.72-8.29, p = 0.15), had higher risk of extensive WMLs than patients with normal LV geometry. PMID- 26581452 TI - Tridax procumbens flavonoids promote osteoblast differentiation and bone formation. AB - BACKGROUND: Tridax procumbens flavonoids (TPFs) are well known for their medicinal properties among local natives. Besides traditionally used for dropsy, anemia, arthritis, gout, asthma, ulcer, piles, and urinary problems, it is also used in treating gastric problems, body pain, and rheumatic pains of joints. TPFs have been reported to increase osteogenic functioning in mesenchymal stem cells. Our previous study showed that TPFs were significantly suppressed the RANKL induced differentiation of osteoclasts and bone resorption. However, the effects of TPFs to promote osteoblasts differentiation and bone formation remain unclear. TPFs were isolated from Tridax procumbens and investigated for their effects on osteoblasts differentiation and bone formation by using primary mouse calvarial osteoblasts. RESULTS: TPFs promoted osteoblast differentiation in a dose dependent manner demonstrated by up-regulation of alkaline phosphatase and osteocalcin. TPFs also upregulated osteoblast differentiation related genes, including osteocalcin, osterix, and Runx2 in primary osteoblasts. TPFs treated primary osteoblast cells showed significant upregulation of bone morphogenetic proteins (BMPs) including Bmp-2, Bmp-4, and Bmp-7. Addition of noggin, a BMP specific-antagonist, inhibited TPFs induced upregulation of the osteocalcin, osterix, and Runx2. CONCLUSION: Our findings point towards the induction of osteoblast differentiation by TPFs and suggested that TPFs could be a potential anabolic agent to treat patients with bone loss-associated diseases such as osteoporosis. PMID- 26581454 TI - Copper Causes Regiospecific Formation of C4 F8 -Containing Six-Membered Rings and their Defluorination/Aromatization to C4 F4 -Containing Rings in Triphenylene/1,4 C4 F8 I2 Reactions. AB - The presence of Cu in reactions of triphenylene (TRPH) and 1,4-C4 F8 I2 at 360 degrees C led to regiospecific substitution of TRPH ortho C(beta) atoms to form C4 F8 -containing rings, completely suppressing substitution on C(alpha) atoms. In addition, Cu caused selective reductive-defluorination/aromatization (RD/A) to form C4 F4 -containing aromatic rings. Without Cu, the reactions of TRPH and 1,4 C4 F8 I2 were not regiospecific and no RD/A was observed. These results, supported by DFT calculations, are the first examples of Cu-promoted 1) regiospecific perfluoroannulation, 2) preparative C-F activation, and 3) RD/A. HPLC-purified products were characterized by X-ray diffraction, low-temperature PES, and (1) H/(19) F NMR. PMID- 26581455 TI - Adaptive Mesh Refinement and Adaptive Time Integration for Electrical Wave Propagation on the Purkinje System. AB - A both space and time adaptive algorithm is presented for simulating electrical wave propagation in the Purkinje system of the heart. The equations governing the distribution of electric potential over the system are solved in time with the method of lines. At each timestep, by an operator splitting technique, the space dependent but linear diffusion part and the nonlinear but space-independent reactions part in the partial differential equations are integrated separately with implicit schemes, which have better stability and allow larger timesteps than explicit ones. The linear diffusion equation on each edge of the system is spatially discretized with the continuous piecewise linear finite element method. The adaptive algorithm can automatically recognize when and where the electrical wave starts to leave or enter the computational domain due to external current/voltage stimulation, self-excitation, or local change of membrane properties. Numerical examples demonstrating efficiency and accuracy of the adaptive algorithm are presented. PMID- 26581456 TI - Surface Texture and Optical Properties of Self-Adhering Composite Materials after Toothbrush Abrasion. AB - This study evaluated the surface texture and optical properties of two self adhering composites and a nanofilled composite before and after toothbrush abrasion. Vertise Flow (Kerr), Fusio Liquid (Pentron Clinical) and Filtek Z350 XT (3M ESPE) composites were divided into 3 groups (n = 6). Disks of 12 mm diameter and 2 mm thick were made. All materials were light-cured with a LED light source for 40 seconds. Analyses of surface roughness, gloss retention and color stability were performed 24 hours after light curing and after 20,000 brushing cycles. Data were analyzed with analysis of variance (ANOVA) and Tukey's test (alpha = 5%). RESULTS: Tukey's test ascertained that toothbrush abrasion resulted in rougher and matte surfaces for all composites tested. Filtek Z350 presented better gloss retention after abrasion. On surface roughness evaluation, there was no statistical difference between Fusio Liquid Dentin and Filtek Z350 resins (p > 0.05). Vertise Flow resin showed better color stability (DeltaE), than the other two materials. CONCLUSION: Nanofilled material presented better gloss retention but it did not produce the best results in aspects related to surface roughness and color stability compared to self-adhering composites. CLINICAL SIGNIFICANCE: A simulation of degradation process by using toothbrush abrasion produced a rougher and matte surface in all composites tested. The surface texture was not only related to filler's amount present in materials, but also with the organic matrix composition of them. The results suggested that the constant development of new materials, seeking for a technical simplification, seems an innovative attraction for dentist's clinical routine, even though larger studies are necessary to promote to everyone a better understanding and improvement of action and effectiveness of this new class of materials. PMID- 26581457 TI - Behaviors and Management of the Dental Problems by the Residents of Madinah, Saudi Arabia. AB - INTRODUCTION: Dental problems are commonly encountered in our lives. Some of the common problems are toothache, bleeding gums and halitosis. OBJECTIVES: How the dental problems were handled, and reasons of not seeking dental treatment by the patients. MATERIALS AND METHODS: This was an observational analytical cross sectional study on adult's age above 14 years from Madinah. RESULTS: A total of 400 adults were included; 208 (52%) were males and 192 (48%) were females. Resident encountered toothache surprisingly only 49% sought dental treatment, while (41%) settled for taking medications. Among bleeding gum patients most of them (45%) went to the dentist, while (41%) settled for using the home care. And dealing with halitosis only (17%) went to the dentist. The most common reasons for not seeking dental treatment were fear and long appointments. And mostly they had fear because of dental drill and dental needle. CONCLUSION: The most common problems for seeking treatment were toothache followed by bleeding gums and the least was halitosis. Number of people who sought treatment was still a low number. The most common reason that stopped patients from going to the dentist was fear and long appointments. There should be increase of dental clinics and patients should be given dental education. PMID- 26581458 TI - Evaluation of the Bond Strength and Fracture Resistance of Different Post Systems. AB - AIM: To compare the bond strength and the fracture resistance of different post systems. MATERIALS AND METHODS: Endodontically treated 60 mandibular incisor and 60 mandibular premolar teeth were used for the bond strength and fracture resistance test respectively. For each test, three groups (n = 20) were formed according to the posts used zirconia posts (ZR post), individually formed glass fiber reinforced composite posts with an (Interpenetrating Polymer Network-IPN post) and cast metal posts. Then groups were randomly assigned into two subgroups according to the post design: 1-parallel sided and 2-tapered (n = 10/group). All posts were luted with a self-adhesive luting agent. For push-out test two 1 mm thick horizontal root sections were obtained and subjected to push-out test. For fracture resistance test, the specimens were loaded vertically at 1 mm/min crosshead speed. The push out test data were analyzed with Kruskal-Wallis and Dunn's test. Analysis of variance (ANOVA) and Tukey significant difference tests were used to compare the fracture resistance. RESULTS: Cast metal posts showed the highest retention (p < 0.05); however, IPN and zirconia posts showed similar results. No significant difference was found between parallel sided or tapered designs of post groups in terms of bond strength (p > 0.05). In terms of fracture resistance, IPN post groups showed lowest fracture resistance (p < 0.05). No significant difference was found between parallel sided or tapered posts in terms of fracture resistance, except zirconia post (p > 0.05). There was no relationship between the bond strength and fracture resistance of the post systems (r = - 0.015, p > 0.700). CONCLUSION: Post type had effect both on the fracture resistance and retention of the posts used. However, post design had effect only on the fracture resistance of the post systems. CLINICAL SIGNIFICANCE: Superficial treatment of the post used can improve the retention of post systems. PMID- 26581459 TI - The Simultaneous Effect of Extended Etching Time and Casein Phosphopeptide Amorphous Calcium Phosphate containing Paste Application on Shear Bond Strength of Etch-and-rinse Adhesive to Caries-affected Dentin. AB - AIM: This study evaluated the simultaneous effect of extended etching time and casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) containing paste application on shear bond strength (SBS) of etch-and-rinse adhesive to caries affected-dentin (CAD). MATERIALS AND METHODS: Fifty human third molars were used; 10 normal in group 1 and 40 caries-affected teeth in groups 2 to 5. In the CAD groups, teeth were randomly assigned into four groups (n = 10). In groups 2 and 4, phosphoric acid etching for 15 and 45 seconds was used and in groups 3 and 5, after 15 or 45 seconds etching respectively, CPP-ACP containing paste (MI paste) was applied for 3 minutes. After rinsing, single bond adhesive system and Z250 composite were used for resin composite build-up in all groups. After storage, SBS test was measured at cross head speed of 0.5 mm/min. Data were analyzed using one/two-way ANOVA and Tukey HSD test (alpha = 0.05). RESULTS: Normal dentin groups showed the highest SBS among different groups. There was a statistically significant difference between different etching times in CAD groups (p < 0.05), but there were no significant differences between SBS of SB adhesive to CAD with or without CPP-ACP pretreated in both etching times. Most of the failure modes were adhesive except in groups 1 and 5 which cohesive failure in composite was also observed. CONCLUSION: The results of our study indicated that extended etching time up to 45 seconds could enhance the SBS of CAD and approach nearly to SBS of normal dentin. Moreover, MI paste pretreatment had not significant effect on SBS of etch-and-rinse adhesive in CAD. CLINICAL SIGNIFICANCE: Simultaneous application of extended etching time and CPP-ACP containing paste may be a suggested method in increasing the SBS of adhesive to CAD. PMID- 26581460 TI - Evaluation of the Surface Roughness and Microleakage of Dental Composites Exposed to Different Beverages. AB - AIM: The purpose of this study was to determine the effect of different solutions cola soft drink (CSD) and coffee on roughness and microleakage of composite resin restorations. MATERIALS AND METHODS: Sixty bovine incisors were prepared and restored using Filtek Z350 XT (3M/ESPE) nanoparticulate resin. The samples were divided into three groups (n = 20): A (control)-Immersion in artificial saliva (14 days); B: Immersion in coffee (14 days), for 15 minutes (3x/day) and C: Immersion in CSD for 14 days (3x/day). Then the samples were analyzed for microleakage (dye penetration) and surface roughness (atomic force microscope). The one-way analysis of variance (ANOVA) was applied to assess the surface roughness and microleakage. The Tukey's test was set at 0.05. RESULTS: Group A (roughness-GAR) presented significantly the lowest average surface roughness. Group C (microleakage-GCM) showed significantly the highest average microleakage. CONCLUSION: It was concluded that CSD and coffee change the surface roughness and increase the microleakage of restorations. CLINICAL SIGNIFICANCE: Nowadays there is a high consumption of artificially sweetened soft drinks, sports drinks, high energy beverages and coffee products by people that cause problems in composite resin restorations. PMID- 26581461 TI - Influence of Image Filters and Variation in Horizontal Angle of Incidence of X ray Beam in Digital Interproximal Radiographs for Diagnosis of Secondary Caries in Esthetic Restorations. AB - BACKGROUND: Secondary or recurrent caries are located around restoration margins or under these lesions, and can lead to tooth loss. The interproximal or bite wing radiograph is the technique of choice to assist diagnosis of secondary caries. OBJECTIVE: To evaluate diagnostic accuracy of secondary caries in pulpal walls artificially created in extracted human premolars, observed in digital bitewing radiographs using variations in horizontal X-ray beam angle of incidence and application of enhancement filters. MATERIALS AND METHODS: The sample consisted of 20 healthy premolars, in which secondary caries lesions were simulated by means of subjecting the pulpal wall of the cavity to wear with spherical carbide drill half, fitted to a high speed handpiece, under constant cooling, focused perpendicular to the tooth surface. The orifices were filled with wax and all teeth were restored with composite resin Filtek Z350 XT((r)). Later teeth were radiographed with a digital sensor complementary metal-oxide semiconductor (CMOS) varying the horizontal angle at intervals of 2 degrees , covering a range of -10 to +10 degrees . RESULTS: The results showed that in the diagnosis of secondary caries, there was no statistically significant difference between the 2 pseudocolor filters, and negative and direct digital radiography. The pseudocolor filter no. 1 showed statistically significant differences, except at a horizontal angle of 0 degrees , thus indicating lower efficiency in the diagnosis of secondary caries. CONCLUSION: Secondary caries with esthetic pulp wall restoration can be diagnosed irrespective of variation in the horizontal angle of incidence of the X-ray beam. The use of different radiographic enhancement filters did not result in improved diagnosis of secondary caries. PMID- 26581462 TI - Smokeless Tobacco-associated Lesions: A Mobile Health Approach. AB - AIM: Globally, India accounts for the highest number of oral cancer cases. The survival rates are about 30% lower than those in developing countries. The main reason for these dismal figures is the late presentation of patients. In order to downstage oral cancer in such a scenario, screening and diagnosis at an early stage is warranted. A pragmatic approach is needed for an oral cancer screening program, hence a mobile health (mHealth) approach was used. In this approach, health workers were empowered with mobile phones with decision-based algorithm. Risk stratification of tobacco habit enables us to identify lesions associated with particular habits. MATERIALS AND METHODS: A specific cohort of factory employees who predominantly had pure tobacco chewing habit was chosen to examine the effect of pure tobacco on oral mucosa. One thousand three hundred and fifty seven subjects were screened in two phases. In the first phase, habits and oral lesions were identified and photographed. The photographs were remotely diagnosed by an oral medicine specialist and those subjects requiring biopsy were recalled for phase II. Cytology and biopsy were performed in phase II. RESULTS: The predominant habit was smokeless tobacco (SLT), in 582 subjects. The most commonly encountered lesion was tobacco pouch keratosis seen in 397 subjects. Biopsy was performed for 71 subjects, most cases showed hyperkeratosis and mild dysplasia. One subject had moderate dysplasia. CONCLUSION: There was minimal alteration of tissues in our study subjects, which can be considered as low-risk. Use of mHealth empowered frontline healthcare workers to identify subjects with lesions and enabled remote diagnosis by specialist in resource-constrained settings. CLINICAL SIGNIFICANCE: Use of mHealth enabled us have an electronic record of subject details. This data shall be used for a planned follow-up of the same cohort after 3 years. PMID- 26581463 TI - An Analysis of the Stress induced in the Periodontal Ligament during Extrusion and Rotation Movements- Part II: A Comparison of Linear vs Nonlinear FEM Study. AB - BACKGROUND: Optimal orthodontic forces are those which stimulate tooth movement with minimal biological trauma to the tooth, periodontal ligament (PDL) during and alveolar bone. Among various types of tooth movements, extrusion and rotational movements are seen to be associated with the least amount of root resorption and have not been studied in detail. The mechanical behavior of the PDL is known to be nonlinear elastic and thus a nonlinear simulation of the PDL provides precision to the calculated stress values. Therefore in this study, the stress patterns in the PDL were evaluated with extrusion and rotational movements using the nonlinear finite element method (FEM). MATERIALS AND METHODS: A three dimensional (3D) FEM model of the maxillary incisors was generated using SOLIDWORKS modelling software. Stresses in the PDL were evaluated with extrusive and rotational movements by a 3D FEM using ANSYS software with nonlinear material properties. RESULTS: It was observed that with the application of extrusive load, the tensile stresses were seen at the apex whereas the compressive stress was distributed at the cervical margin. With the application of rotational movements, maximum compressive stress was distributed at the apex and cervical third whereas the tensile stress was distributed on cervical third of the PDL on the lingual surface. CONCLUSION: For rotational and extrusion movements, stress values over the periodontal ligament was within the range of optimal stress value as proposed by Lee, with a given force system by Proffit as optimum forces for orthodontic tooth movement using nonlinear properties. During rotation there are stresses concentrated at the apex, hence due to the concentration of the compressive forces at the apex a clinician must avoid placing heavy stresses during tooth movement. PMID- 26581464 TI - Fibrinogen Demonstration in Oral Lichen Planus: An Immunofluorescence Study on Archival Tissues. AB - BACKGROUND: Lichen planus is a premalignant condition with minimal diagnostic aids. This study is an attempt to use paraffin embedded sections of lichen planus with immunofluorescein stain and to evaluate the immunofluorescent sections to establish pattern of fibrinogen deposition. MATERIALS AND METHODS: Thirty-five paraffin embedded sections of old and new cases of oral lichen planus (study group) and five normal oral mucosa (control group) were chosen. Two sections of each (H & E) case were taken, one was stained with hematoxylin and eosin and another with fluorescein isothiocynate conjugate (FITC) polyclonal rabbit antibody against fibrinogen. Fluorescent findings were examined with a fluorescent microscope. RESULTS: A high statistical significant correlation was found in respect to fluorescence positivity, intensity of fluorescence and distribution of fluorescence each with p < 0.0001 and fluorescence at blood vessel walls (p = 0.0003). CONCLUSION: This study suggested that paraffin embedded sections can be successfully used in direct immunofluorescence staining in routine set up where only formalin fixed tissues are received. CLINICAL SIGNIFICANCE: Paraffin embedded sections can be successfully used in direct immunofluorescence staining when only formalin fixed tissues are received. PMID- 26581465 TI - Utilization of Dental Services in Public Health Center: Dental Attendance, Awareness and Felt Needs. AB - BACKGROUND: In rural India, dental diseases occur due to many factors, which includes inadequate or improper use of fluoride and a lack of knowledge regarding oral health and oral hygiene, which prevent proper screening and dental care of oral diseases. The objective of the study was to evaluate the dental attendance, awareness and utilization of dental services in public health center. MATERIALS AND METHODS: A cross-sectional study was conducted among 251 study subjects who were visiting dental outpatient department (OPD) of public health centre (PHC), Guda Bishnoi, and Jodhpur using a pretested proforma from month of July 2014 to October 2014. A pretested questionnaire was used to collect the data regarding socioeconomic status and demographic factors affecting the utilization of dental services. Pearson's Chi-square test and step-wise logistic regression were applied for the analysis. RESULTS: Statistically significant results were found in relation to age, educational status, socioeconomic status and gender with dental attendance, dental awareness and felt needs. p-value <0.05 was kept as statistically significant. CONCLUSION: The services provided in public health center should be based on the felt need of the population to increase attendance as well as utilization of dental services, thereby increasing the oral health status of the population. PMID- 26581466 TI - Nickel-Titanium Single-file System in Endodontics. AB - AIM: This work describes clinical cases treated with a innovative single-use and single-file nickel-titanium (NiTi) system used in continuous rotation. BACKGROUND: Nickel-titanium files are commonly used for root canal treatment but they tend to break because of bending stresses and torsional stresses. Today new instruments used only for one treatment have been introduced. They help the clinician to make the root canal shaping easier and safer because they do not require sterilization and after use have to be discarded. A new sterile instrument is used for each treatment in order to reduce the possibility of fracture inside the canal. The new One Shape NiTi single-file instrument belongs to this group. CASE DESCRIPTION: One Shape is used for complete shaping of root canal after an adequate preflaring. Its protocol is simple and some clinical cases are presented. It is helpful for easy cases and reliable for difficult canals. CONCLUSION: After 2 years of clinical practice, One Shape seems to be helpful for the treatment of most of the root canals, with low risk of separation. After each treatment, the instrument is discarded and not sterilized in autoclave or re-used. CLINICAL SIGNIFICANCE: This single-use file simplifies the endodontic therapy, because only one instrument is required for canal shaping of many cases. The respect of clinical protocol guarantees predictable good results. PMID- 26581467 TI - Primary Diffuse Large B-cell Lymphoma involving the Mandible. AB - Lymphomas of the oral cavity are rare and typically present as intraosseous lesions that are most commonly diffuse large B-cell type. Diffuse large B-cell lymphoma (DLBCL) is an aggressive B-cell lymphoma histologically characterized by diffuse proliferation of large neoplastic B-lymphoid cells with a nuclear size equal to or exceeding normal histiocytic nuclei. A case of DLBCL of the mandible in an 18 years old male patient is presented. This report discusses this rare malignancy, including clinical presentation, histopathologic features, immunologic profile, treatment and prognosis. Though lymphoma of mandible is rare, it must be considered in differential diagnosis of swellings arising in the region. PMID- 26581468 TI - Recent Developments in Oral Epithelial Dysplasia Grading: A Critical Appraisal. AB - The final goal of a histopathological examination is to access the course of the presenting lesion. Histopathology is considered the gold standard in segregating benign and malignant entities, but its use in grading oral epithelial dysplasia (OED) has been a constant debate. Interobserver agreement in most studies on OED has averaged between poor to fair. Application of molecular predictive model could solve the disagreement at the histopathological level. But, in order to conduct genetic analysis, it is vital to categorize the entities based on the current diagnostic gold standard, which in turn is histopathological grading. Thus, improvising the standard of histopathological grading would aid in formulating a much reliable molecular predictive model.(1). PMID- 26581469 TI - Morbidity pattern by age, sex and breed in insured cats in Japan (2008-2013). AB - OBJECTIVES: The aim of the study was to describe the morbidity pattern of different diagnostic categories in insured cats in Japan by age, sex and breed. METHODS: The annual incidence rates of having at least one insurance claim were calculated overall and stratified by diagnosis, age, sex and breed using data from insured cats in the period April 2008 to March 2013. RESULTS: The overall annual incidence rate of having at least one insurance claim was 4632 (95% confidence interval 4608-4656) cats per 10,000 cat-years at risk. The highest annual incidence rate was obtained for digestive system disorders, followed by urinary tract disorders and dermatological disorders. The incidence rates varied between breeds for most diagnostic categories: for cardiovascular system disorders, Scottish Fold, American Shorthair, Persian, Maine Coon, Norwegian Forest Cat, Ragdoll and Bengal had a higher annual incidence rate than crossbreeds. CONCLUSIONS AND RELEVANCE: This study provides comparative and quantitative estimates of morbidity pattern in insured Japanese cats. These estimates can be utilised by veterinary practitioners, breeders and owners in diagnostic decision-making, breeding and when selecting a new pet, respectively. PMID- 26581470 TI - Intraoperative end-tidal concentration of isoflurane in cats undergoing ovariectomy that received tramadol, buprenorphine or a combination of both. AB - Objectives The aim of the study was to evaluate the end-tidal concentration of isoflurane required to maintain heart and respiratory rate within +/- 20% of basal measurement in cats undergoing ovariectomy that received buprenorphine, tramadol or a combination of both. Methods Thirty cats, divided into three groups, were enrolled in a simple operator-blinded, randomised study. Cats received acepromazine (0.03 mg/kg) and one of the following treatments: buprenorphine (0.02 mg/kg), tramadol (2 mg/kg) or a combination of both. Anaesthesia was induced with propofol and maintained with isoflurane titrated in order to maintain heart and respiratory rate within the target values recorded before premedication. Results Groups were similar for age, weight, dose of propofol administered, sedation and recovery scores. Cats receiving tramadol with buprenorphine were extubated earlier after isoflurane discontinuation. No statistical differences were detected in end-tidal fraction of isoflurane between buprenorphine alone or with tramadol. In cats that received tramadol or buprenorphine alone, ovarian pedicle traction caused a statistical increase in end-tidal isoflurane concentration compared with that measured during incision and suture of the skin. In cats that received the combination of tramadol plus buprenorphine no differences among surgical time points were observed. Conclusions and relevance Tramadol added to buprenorphine did not provide any advantage in decreasing the end-tidal fraction of isoflurane compared with buprenorphine alone, although it is speculated there may be an infra-additive interaction between tramadol and buprenorphine in cats. PMID- 26581471 TI - Glial response in the central nervous system of cats with feline infectious peritonitis. AB - OBJECTIVES: The aim of the study was to evaluate central nervous system (CNS) lesions in non-effusive and effusive cases of feline infectious peritonitis (FIP) regarding aspects related to astrocytic and microglial reactions. METHODS: Five necropsied cats that were naturally infected with FIP virus, confirmed by reverse transcriptase polymerase chain reaction and immunohistochemistry, with different intensities of CNS lesions, were studied. Brain and cerebellum were evaluated by light microscopy and immunohistochemistry for glial fibrillary acidic protein (GFAP) and vimentin to assess astrocytic morphology, and lectin histochemistry for Ricinus communis agglutinin-I (RCA-I) to detect microglia was performed to evaluate the glial response in the CNS of cats with FIP. RESULTS: An important astrocytic response in many areas of the CNS of all cats, including the periventricular areas of lateral ventricles and fourth ventricle, the molecular layer of the cerebellum and cerebral cortex, was visualized. This astrocytic reactivity was associated with areas of granulomatous or pyogranulomatous vasculitis/perivasculitis in most cases, and it was characterized by multifocal to coalescing astrocytosis and astrogliosis with an increase in the expression of intermediate filaments, such as GFAP. However, astrocytes exhibited strong vimentin expression in neuroparenchyma with severe inflammatory and necrotic changes, but GFAP expression was mild or absent in these cases. A microglial response was present only in severe lesions, and RCA-I expression was detected primarily in gitter cells and resting microglia. CONCLUSIONS AND RELEVANCE: The present study indicates a strong astrocytic response, including the presence of many less differentiated vimentin-positive astrocytes and gitter cells positive for RCA-1 in severe lesions in the CNS of cats with FIP. PMID- 26581472 TI - Spontaneous renal allograft rupture complicated by urinary leakage: case report and review of the literature. AB - BACKGROUND: For more than forty years, graftectomy has been the standard treatment of spontaneous renal transplant rupture. However, recent evidences suggest that graft salvage strategies can be safely pursued, even in difficult cases. CASE PRESENTATION: We report on a thirty-nine-year-old woman who received a deceased donor kidney transplant and experienced spontaneous allograft rupture due to acute rejection. The rupture was further complicated by urinary leakage. The kidney and the ureter were successfully repaired. Eight years after transplantation, graft function is still excellent. CONCLUSION: Due to the lack of transplantable organs and the long time usually spent on the waiting list, graftectomy should be only considered in case of refractory haemodynamic instability or compromised graft viability. PMID- 26581473 TI - A Bayesian Semiparametric Model for Radiation Dose-Response Estimation. AB - In evaluating the risk of exposure to health hazards, characterizing the dose response relationship and estimating acceptable exposure levels are the primary goals. In analyses of health risks associated with exposure to ionizing radiation, while there is a clear agreement that moderate to high radiation doses cause harmful effects in humans, little has been known about the possible biological effects at low doses, for example, below 0.1 Gy, which is the dose range relevant to most radiation exposures of concern today. A conventional approach to radiation dose-response estimation based on simple parametric forms, such as the linear nonthreshold model, can be misleading in evaluating the risk and, in particular, its uncertainty at low doses. As an alternative approach, we consider a Bayesian semiparametric model that has a connected piece-wise-linear dose-response function with prior distributions having an autoregressive structure among the random slope coefficients defined over closely spaced dose categories. With a simulation study and application to analysis of cancer incidence data among Japanese atomic bomb survivors, we show that this approach can produce smooth and flexible dose-response estimation while reasonably handling the risk uncertainty at low doses and elsewhere. With relatively few assumptions and modeling options to be made by the analyst, the method can be particularly useful in assessing risks associated with low-dose radiation exposures. PMID- 26581474 TI - Toxicokinetics of Ag in the terrestrial isopod Porcellionides pruinosus exposed to Ag NPs and AgNO3 via soil and food. AB - Silver nanoparticles (Ag NPs) have been used in numerous consumer products and may enter the soil through the land application of biosolids. However, little is known about the relationship between Ag NP exposure and their bioavailability for soil organisms. This study aims at comparing the uptake and elimination kinetics of Ag upon exposures to different Ag forms (NPs and ionic Ag (as AgNO3)) in the isopod Porcellionides pruinosus. Isopods were exposed to contaminated Lufa 2.2 soil or alder leaves as food. Uptake and elimination rate constants for soil exposure did not significantly differ between Ag NPs and ionic Ag at 30 and 60 mg Ag/kg. For dietary exposure, the uptake rate constant was up to 5 times higher for Ag NPs than for AgNO3, but this was related to feeding activity and exposure concentrations, while no difference in the elimination rate constants was found. When comparing both routes, dietary exposure resulted in lower Ag uptake rate constants but elimination rate constants did not differ. A fast Ag uptake was observed from both routes and most of the Ag taken up seemed not to be eliminated. Synchrotron X-ray fluorescence showed Ag in the S-cells of the hepatopancreas, thus supporting the observations from the kinetic experiment (i.e. low elimination). In addition, our results show that isopods have an extremely high Ag accumulation capacity, suggesting the presence of an efficient Ag storage compartment. PMID- 26581475 TI - Cardiac comorbidity in head and neck cancer patients and its influence on cancer treatment selection and mortality: a prospective cohort study. AB - Comorbidity assessment and a profound cardiac examination were implemented into pre-treatment diagnostics to analyze their influence on head and neck squamous cell carcinoma (HNSCC) therapy selection and short-term mortality. Comorbidity was measured prospectively in 49 HNSCC patients using standard indices between 2012 and 2013. Cardiac examinations included electrocardiogram, echocardiography, and bicycle ergometry. Most patients had stage IV tumors (61 %), smoked (61 %), and showed alcohol abuse (57 %); 38 patients (78 %) received a multimodal therapy; 65 % had an adult comorbidity evaluation 27 index >=2, 59 % a Charlson comorbidity index (CCI) >=4, and 12 % a revised cardiac risk index (RCRI) >=2. Additional cardiac examinations revealed moderate to severe cardiovascular pathologies in 32 % of the patients and led to recommendations for additional therapy in 4 patients (8 %) necessary only after cancer treatment. RCRI was associated with CCI and cardiac examinations (p = 0.009, p = 0.030). Chemotherapy, stroke history, and RCRI >=2 were risk factors for early mortality within first 2 years after cancer therapy (p = 0.037; p = 0.012; p = 0.015). Although one-third of a strongly smoking and drinking patient cohort had relevant cardiac morbidity, extended unselected cardiac diagnostics had only low impact on HNSCC therapy selection. The risk of early mortality after HNSCC cancer treatment seems to be sufficiently reflected by the RCRI. PMID- 26581476 TI - Hemodynamic Performance of a New Punched Stent Strut: A Numerical Study. AB - Local flow disturbance by arterial stent struts has been shown to play an important role in stent thrombosis. To reduce the local flow disturbance near a stent strut, we proposed a new concept of stent design with small holes in the stent struts. The present study evaluated the new design numerically by comparing it with the traditional stent in terms of local hemodynamic parameters such as flow velocity, flow recirculation area, time-averaged wall shear stress (TAWSS), oscillating shear index (OSI), and relative residence time (RRT). The results demonstrated that when compared with the traditional strut, the new design could significantly enhance flow velocity and reduce the flow recirculation zone in the vicinity of the strut. Moreover, the new design would significantly elevate TAWSS and remarkably reduce OSI and RRT along the host arterial wall. In conclusion, the new design of stent struts with punched holes is advantageous over the traditional one in the aspect of improving local hemodynamics, which may reduce thrombosis formation and promote re-endothelialization after stenting. PMID- 26581477 TI - Timing of Antiviral Therapy in Candidates for Liver Transplant for Hepatitis C and Hepatocellular Carcinoma. AB - OBJECTIVES: Hepatitis C virus infection is the most common underlying reason for hepatocellular carcinoma and indication for liver transplant. The increased availability of non-interferon-based therapy has expanded the number of treatment eligible patients. MATERIALS AND METHODS: We used a decision analysis model to compare 2 strategies of treating hepatitis C virus. Included patients were followed for 1 year after liver transplant. The probabilities and costs were obtained from a literature review, an expert panel, and our institution's experience. Sensitivity analyses were performed on all variables. RESULTS: Our model demonstrated that it would be less costly to treat patients after liver transplant than to treat patients while they wait for transplant. When we compared baseline values, the cost difference between the 2 strategies was $25,011 per patient and $41,535 per sustained viral response. Overall survival was 60.1% for both strategies. Our model was robust across most of the variables tested in the sensitivity analysis. CONCLUSIONS: Our results indicated that there is no substantial pharmacoeconomic or survival advantage of treating hepatitis C virus in patients with compensated cirrhosis and hepatocellular carcinoma before liver transplant versus after transplant. PMID- 26581478 TI - Virus evolution during chronic hepatitis B virus infection as revealed by ultradeep sequencing data. AB - Despite chronic hepatitis B virus (HBV) infection (CHB) being a leading cause of liver cirrhosis and cancer, HBV evolution during CHB is not fully understood. Recent studies have indicated that virus diversity progressively increases along the course of CHB and that some virus mutations correlate with severe liver conditions such as chronic hepatitis, cirrhosis and hepatocellular carcinoma. Using ultradeep sequencing (UDS) data from an intrafamilial case, we detected such mutations at low frequencies among three immunotolerant patients and at high frequencies in an inactive carrier. Furthermore, our analyses indicated that the HBV population from the seroconverter patient underwent many genetic changes in response to virus clearance. Together, these data indicate a potential use of UDS for developing non-invasive biomarkers for monitoring disease changes over time or in response to specific therapies. In addition, our analyses revealed that virus clearance seemed not to require the virus effective population size to decline. A detailed genetic analysis of the viral lineages arising during and after the clearance suggested that mutations at or close to critical elements of the core promoter (enhancer II, epsilon encapsidation signal, TA2, TA3 and direct repeat 1-hormone response element) might be responsible for a sustained replication. This hypothesis requires the decline in virus load to be explained by constant clearance of virus-producing hepatocytes, consistent with the sustained progress towards serious liver conditions experienced by many CHB patients. PMID- 26581479 TI - Lateral forces on circularly polarizable particles near a surface. AB - Optical forces allow manipulation of small particles and control of nanophotonic structures with light beams. While some techniques rely on structured light to move particles using field intensity gradients, acting locally, other optical forces can 'push' particles on a wide area of illumination but only in the direction of light propagation. Here we show that spin-orbit coupling, when the spin of the incident circularly polarized light is converted into lateral electromagnetic momentum, leads to a lateral optical force acting on particles placed above a substrate, associated with a recoil mechanical force. This counterintuitive force acts in a direction in which the illumination has neither a field gradient nor propagation. The force direction is switchable with the polarization of uniform, plane wave illumination, and its magnitude is comparable to other optical forces. PMID- 26581481 TI - Direct observation of polyelectrolyte brushes under wet and dry conditions by atmospheric scanning electron microscopy. AB - Polyelectrolyte brushes are polyelectrolyte polymers with one end fixed to a substrate. In this study, direct nano-scale visualization of polyelectrolyte brushes was carried out under 'aqueous conditions' by atmospheric scanning electron microscopy. The thickness of the polyelectrolyte brush layer was measured under both dry and aqueous conditions, experimentally confirming the swollen state of the brushes. These experimental findings qualitatively agreed with the results from previous neutron reflectivity experiments using similar polyelectrolyte brushes. Such direct visualization of polymer brushes in real space opens up a new route for better understanding their surface properties, such as friction, adhesion and wettability. PMID- 26581480 TI - Development of a novel cell based androgen screening model. AB - The androgen receptor (AR) mediates the majority of androgen effects on target cells. The DNA cis-regulatory elements that respond to AR share sequence similarity with cis-regulatory elements for glucocorticoid, mineralocorticoid and progesterone receptors (GR, MR and PR, respectively). As a result, many of the current AR screening models are complicated by inaccurate activation of reporters by one of these receptor pathways. Identification of more selective androgen testing systems would be beneficial for clinical, pharmacological and toxicologic screening of AR activators. The present study describes the development of a selective androgen-responsive reporter cell line that expresses AR but does not express GR, MR and PR. CV1 cells were stably transduced to express human AR and an androgen-responsive gaussia luciferase gene. Clonal populations of AR expressing cells were isolated. Quantitative RT-PCR (qPCR) and western analysis confirmed stable integration of AR in the most responsive clonal line which was named 'CV1-ARluc'. Stimulation of CV1AR-luc with androgenic ligands (testosterone and 5alpha-dihydrotestosterone) for 18h caused an increase in luciferase activity in a dose-dependent manner. Other steroid hormones including aldosterone, cortisol, and progesterone did not stimulate luciferase response. The CV1-ARluc also increased luciferase activity when treated with human serum extracts. In conclusion, the CV1-ARluc cells provide a novel model system for screening of new AR agonists and antagonists and can determine the androgenic activity of human serum samples. PMID- 26581483 TI - Blood transfusion: summary of NICE guidance. PMID- 26581482 TI - Focused molecular analysis of small cell lung cancer: feasibility in routine clinical practice. AB - BACKGROUND: There is an urgent need to identify molecular signatures in small cell lung cancer (SCLC) that may select patients who are likely to respond to molecularly targeted therapies. In this study, we investigate the feasibility of undertaking focused molecular analyses on routine diagnostic biopsies in patients with SCLC. METHODS: A series of histopathologically confirmed formalin-fixed, paraffin-embedded SCLC specimens were analysed for epidermal growth factor receptors (EGFR), KRAS, NRAS and BRAF mutations, ALK gene rearrangements and MET amplification. EGFR and KRAS mutation testing was evaluated using real time polymerase chain reaction (RT-PCR cobas((r))), BRAF and NRAS mutations using multiplex PCR and capillary electrophoresis-single strand conformation analysis, and ALK and MET aberrations with fluorescent in situ hybridization. All genetic aberrations detected were validated independently. RESULTS: A total of 105 patients diagnosed with SCLC between July 1990 and September 2006 were included. 60 (57 %) patients had suitable tumour tissue for molecular testing. 25 patients were successfully evaluated for all six pre-defined molecular aberrations. Eleven patients failed all molecular analysis. No mutations in EGFR, KRAS and NRAS were detected, and no ALK gene rearrangements or MET gene amplifications were identified. A V600E substitution in BRAF was detected in a Caucasian male smoker diagnosed with SCLC with squamoid and glandular features. CONCLUSION: The paucity of patients with sufficient tumour tissue, quality of DNA extracted and low frequency of aberrations detected indicate that alternative molecular characterisation approaches are necessary, such as the use of circulating plasma DNA in patients with SCLC. PMID- 26581484 TI - Laparoscopic Undo of Fundoplication with Roux-en-Y Gastric Bypass in a Morbidly Obese Patient with Prior Nissen's Fundoplication: A Video Report. AB - BACKGROUND: Roux-en-Y gastric bypass (RYGB) may be a better option for morbidly obese patients with gastroesophageal reflux (GERD) for long-term reflux control. It is recommended after fundoplication if a patient is morbidly obese with GERD with failed fundoplication or if bariatric surgery is planned with a prior successful fundoplication (Kim et al., Am Surg 80(7):696-703, 2014; Kambiz Zainabadi, Surg Endosc. 22(12):2737-40, 2008). Complete takedown of the wrap to avoid stapling over the fundoplication creating an obstructed, septated pouch is needed (Kambiz Zainabadi, Surg Endosc. 22(12):2737-40, 2008). The aim of this video was to demonstrate the technical aspect of dissection and undo of Nissen's fundoplication followed by performance of a RYGB in a morbidly obese patient with GERD with prior successful Nissen's fundoplication opting for bariatric surgery after a year. METHODS: We present a case of a 50-year-old woman with a BMI of 36.14 with previous laparoscopic Nissen's fundoplication for severe GERD (controlled after surgery) and a prior laparoscopic intraperitoneal onlay mesh repair who presented for bariatric surgery 1 year after fundoplication. She was successfully treated by laparoscopic undo of the fundoplication with RYGB. RESULTS: In this multimedia high-definition video, we present step-by-step the laparoscopic undo of a Nissen's fundoplication followed by RYGB. The procedure included lysis of all adhesions between the liver and the stomach, dissection of the diaphragmatic crura, complete takedown of the wrap, repair of the hiatal hernia, creation of a gastric pouch, creation of an antecolic Roux limb, gastrojejunal anastomosis, and jejuno-jejunal anastomosis. CONCLUSION: Laparoscopic RYGB after fundoplication in morbidly obese patients with GERD is a technically difficult but feasible option. PMID- 26581485 TI - Adult onset Still's disease associated with malignancy-Cause or coincidence? AB - OBJECTIVE: To analyze all patients with adult onset Still's disease (AOSD) and malignancy described in the literature and to discuss their relation to each other. METHOD: Demographic, clinical, and laboratory characteristics of one index patient with AOSD seen in our institution who subsequently developed a malignant disease were compared with all other cases of AOSD and malignancy identified by a PubMed literature research. Furthermore, characteristics of AOSD patients with malignancy were compared to those without malignancy. RESULTS: We found 46 articles in English, French, Japanese, Korean, and Spanish language reporting 47 cases in addition to our own case. In 36 patients, the diagnosis of AOSD could be confirmed by retrospectively applying classification criteria according to Yamaguchi, Fautrel, and Crispin. The median time between diagnosis of AOSD and subsequent detection of a malignant disease was 9 months, 50% had a hematological disorder and 50% a solid tumor. In 33%, the symptoms of AOSD resolved after successful therapy of the neoplastic disease. Red flags for paraneoplastic AOSD were onset of symptoms at higher age, atypical features of rash, highly elevated lactate dehydrogenase, atypical cells in the differential blood count, and high concentrations of the soluble interleukin-2 receptor. CONCLUSION: A disease resembling AOSD can precede the clinical appearance of a hematologic malignancy or a solid tumor. Thorough diagnostic work-up of AOSD to rule out malignancy and awareness to conspicuous signs for malignancy-associated AOSD are therefore essential in the clinical work-up of such patients. PMID- 26581486 TI - Clinical assessment of effusion in knee osteoarthritis-A systematic review. AB - OBJECTIVE: The aim of this systematic review was to determine the validity and inter- and intra-observer reliability of the assessment of knee joint effusion in osteoarthritis (OA) of the knee. METHODS: MEDLINE, Web of Knowledge, CINAHL, EMBASE, and AMED were searched from their inception to February 2015. Articles were included according to a priori defined criteria: samples containing participants with knee OA; prospective evaluation of clinical tests and assessments of knee effusion that included reliability, sensitivity, and specificity of these tests. RESULTS: A total of 10 publications were reviewed. Eight of these considered reliability and four on validity of clinical assessments against ultrasound effusion. It was not possible to undertake a meta analysis of reliability or validity because of differences in study designs and the clinical tests. Intra-observer kappa agreement for visible swelling ranged from 0.37 (suprapatellar) to 1.0 (prepatellar); for bulge sign 0.47 and balloon sign 0.37. Inter-observer kappa agreement for visible swelling ranged from -0.02 (prepatellar) to 0.65 (infrapatellar), the balloon sign -0.11 to 0.82, patellar tap -0.02 to 0.75 and bulge sign kappa -0.04 to 0.14 or reliability coefficient 0.97. Reliability and diagnostic accuracy tended to be better in experienced observers. Very few data looked at performance of individual clinical tests with sensitivity ranging 18.2-85.7% and specificity 35.3-93.3%, both higher with larger effusions. CONCLUSION: The majority of unstandardized clinical tests to assess joint effusion in knee OA had relatively low intra- and inter-observer reliability. There is some evidence experience improved reliability and diagnostic accuracy of tests. Currently there is insufficient evidence to recommend any particular test in clinical practice. PMID- 26581487 TI - A de novo whole gene deletion of XIAP detected by exome sequencing analysis in very early onset inflammatory bowel disease: a case report. AB - BACKGROUND: Children with very early-onset inflammatory bowel disease (VEO-IBD), those diagnosed at less than 5 years of age, are a unique population. A subset of these patients present with a distinct phenotype and more severe disease than older children and adults. Host genetics is thought to play a more prominent role in this young population, and monogenic defects in genes related to primary immunodeficiencies are responsible for the disease in a small subset of patients with VEO-IBD. CASE PRESENTATION: We report a child who presented at 3 weeks of life with very early-onset inflammatory bowel disease (VEO-IBD). He had a complicated disease course and remained unresponsive to medical and surgical therapy. The refractory nature of his disease, together with his young age of presentation, prompted utilization of whole exome sequencing (WES) to detect an underlying monogenic primary immunodeficiency and potentially target therapy to the identified defect. Copy number variation analysis (CNV) was performed using the eXome-Hidden Markov Model. Whole exome sequencing revealed 1,380 nonsense and missense variants in the patient. Plausible candidate variants were not detected following analysis of filtered variants, therefore, we performed CNV analysis of the WES data, which led us to identify a de novo whole gene deletion in XIAP. CONCLUSION: This is the first reported whole gene deletion in XIAP, the causal gene responsible for XLP2 (X-linked lymphoproliferative Disease 2). XLP2 is a syndrome resulting in VEO-IBD and can increase susceptibility to hemophagocytic lymphohistocytosis (HLH). This identification allowed the patient to be referred for bone marrow transplantation, potentially curative for his disease and critical to prevent the catastrophic sequela of HLH. This illustrates the unique etiology of VEO-IBD, and the subsequent effects on therapeutic options. This cohort requires careful and thorough evaluation for monogenic defects and primary immunodeficiencies. PMID- 26581488 TI - Marchantin M Induces Apoptosis of Prostate Cancer Cells Through Endoplasmic Reticulum Stress. AB - BACKGROUND Apoptosis is mediated by the endoplasmic reticulum (ER) stress pathway, mitochondrial pathway, and death receptor. Data herein suggested an inhibitory effect of marchantin M on tumor formation in nude mice as well as the impact on CHOP and GRP78 expression. MATERIAL AND METHODS The role of marchantin M on proliferation and apoptosis of DU145 cells were measured by MTT and flow cytometry, respectively. Western blot was applied to detect the expression of GRP78 and CHOP. The mice received abdominal injection at 1 time/2 d and 2 ml/time. Tumor volume was measured every 6 days. The mice were euthanatized 30 days after marchantin injection and tumor weight was measured. Cell apoptosis was determined by TUNEL. The expressions of CHOP and GRP78 were detected by immunohistochemistry. RESULTS Tumor size and weight in marchantin groups were significantly lower than in the control group (A, B) (P<0.05), and the inhibitory rate presented a dose-dependent increase. Compared with controls, the levels of CHOP and GRP78 expression elevated obviously following the treatment with marchantin (P<0.05). It showed statistically significant difference among groups C, D, E, with different levels of apoptosis indexes incremented in groups of marchantin H, M, L, compared with groups A and B (P<0.05). CONCLUSIONS Overall, this study shows that marchantin M circumvents the growth of prostate cancer PC-3 tumor and up-regulates expressions of CHOP and GRP78. Our data also indicate that marchantin M limits the proliferation and favors apoptosis of DU145 cells in a time- and dose-dependent manner. PMID- 26581489 TI - Jasmonate signaling in plant stress responses and development - active and inactive compounds. AB - Jasmonates (JAs) are lipid-derived signals mediating plant responses to biotic and abiotic stresses and in plant development. Following the elucidation of each step in their biosynthesis and the important components of perception and signaling, several activators, repressors and co-repressors have been identified which contribute to fine-tuning the regulation of JA-induced gene expression. Many of the metabolic reactions in which JA participates, such as conjugation with amino acids, glucosylation, hydroxylation, carboxylation, sulfation and methylation, lead to numerous compounds with different biological activities. These metabolites may be highly active, partially active in specific processes or inactive. Hydroxylation, carboxylation and sulfation inactivate JA signaling. The precursor of JA biosynthesis, 12-oxo-phytodienoic acid (OPDA), has been identified as a JA-independent signaling compound. An increasing number of OPDA specific processes is being identified. To conclude, the numerous JA compounds and their different modes of action allow plants to respond specifically and flexibly to alterations in the environment. PMID- 26581490 TI - Cost-effective production of biotechnologically important hydrolytic enzymes by Sporotrichum thermophile. AB - Economical production of xylanase and three cellulases, endo-beta-1,4-glucanase (CMCase), exo-beta-1,4-glucanase (FPase), beta-glucosidase (BGL) was studied in submerged fermentation using cane molasses medium. A statistical optimization approach involving Plackett-Burman design and response surface methodology (RSM) resulted in the production of 72,410, 36,420, 32,420 and 5180 U/l of xylanase, CMCase, FPase and beta-glucosidase, respectively. Optimization resulted in more than fourfold improvements in production of xylanolytic and cellulolytic enzymes. Scale up of enzymes production in shake flasks of varied volumes was sustainable, suggesting a good scope for large scale enzyme production. Addition of microparticles engineered fungal morphology and enhanced enzymes production. Xylanase of S. thermophile is a neutral xylanase displaying its optimal activity at 60 degrees C while all the cellulases are optimally active at pH 5.0 and 60 degrees C. The efficacy of enzyme cocktail in waste tea cup paper and rice straw hydrolysis showed that maximum sugar yield of 578.12 and 421.79 mg/g substrate for waste tea cup and rice straw, respectively, were achieved after 24 h. Therefore, concomitant production of cellulolytic and xylanolytic enzymes will be beneficial for the saccharification of lignocellulosics in generating both monomeric and oligomeric sugars for biofuels and other biotechnological applications. PMID- 26581491 TI - Serial examinations of right coronary artery directly injured by radiofrequency catheter ablation with optical coherence tomography and intravascular ultrasound. AB - A 42-year-old man was referred for ablation. The origin of VT was localized close to the right coronary ostium. During ablation, the catheter tip inadvertently fell into a RCA ostium. The patient developed chest discomfort and ST-segment elevation in the inferior leads was observed. Coronary angiography confirmed severe narrowing of the ostial RCA. Stenting was deferred after satisfactory dilatation by a balloon. The patient discharged with eventless clinical course afterward. Follow-up coronary angiographic, FD-OCT, IVUS, and iMap examinations were performed at 3, 6, and 15 months after index procedure. The lesion showed progressive positive remodeling associated with intimal proliferation, medial thickening, and lumen narrowing up to 6 months. The patient underwent stenting at 15 months after the index procedure. The lesion required high-pressure post dilatation to obtain optimal stent expansion. PMID- 26581492 TI - Popliteal artery aneurysm treated with implantation of a covered stent graft (fluency((r))) reinforced with a nitinol stent (S.M.A.R.T. ((r))). AB - A 60-year-old man was admitted for right knee pain provoked by an enlarging popliteal artery aneurysm (PAA) after endovascular therapy for thromboembolism in the right popliteal artery. The PAA was treated with implantation of a covered stent graft (Fluency((r))); however, acute thromboembolism occurred 6 months after the intervention. Therefore, we implanted a nitinol stent (S.M.A.R.T.((r))) in the proximal part of the covered stent where the major hinge point existed in addition to a stent fracture. No vascular event occurred during 4.5 years of follow-up. PMID- 26581493 TI - Controllable Synthesis of Tetraethylenepentamine Modified Graphene Foam (TEPA-GF) for the Removal of Lead ions. AB - 3D graphene foam for water purification has become pervasive recently, not only because it has high specific surface area for adsorption capacity, but also it is easily separated from solution after adsorption. However, it is still challenging because it is hard to improve the adsorption capacity as well as maintain the high mechanical strength. To overcome the challenge, Tetraethylenepentamine modified Graphene Foam (TEPA-GF) was synthesized via a one-step hydrothermal method by using GO and TEPA as raw materials. TEPA acted as both cross-linker to combine GO sheets together and reductant of GO during hydrothermal process. Results indicated that the resultant hydrogel's formation was highly dependent on the mass ratio of TEPA to GO, they cross-linked into a stable hydrogel with perfect cylindrical only when MTEPA: MGO >= 1. What's more, the highest mechanical strength of GF happened at the mass ratio of MTEPA: MGO = 3, which was up to 0.58 kPa. It was worth noting that TEPA-GF demonstrated high adsorption capacity for lead ions, which reached as high as 304.9 mg g(-1), much higher than that of other absorbents. Furthermore, TEPA-GF was easily separated from water after adsorption of Pb(2+), making it a great potential material for water purification. PMID- 26581494 TI - Biting Cousins-Disseminated Neonatal Herpes Simplex Virus Infection from a Human Bite. PMID- 26581495 TI - Organ Transplant Tolerance for Children; in Sight for Some. PMID- 26581496 TI - Intrapulmonary Castleman's Disease Pretending to Be a Lung Cancer-Work Up of an Intrapulmonary Tumour. AB - A 24 year old male presented with a history of recurrent bronchopulmonal infections. Chest computed tomography was performed, revealing a right central mass. In the following bronchoscopy and ultrasound guided needle aspiration of the tumour no specific diagnosis could be obtained. Due to the central location of the tumour thoracotomy and middle lobe resection was performed. Histopathological analysis revealed an intrapulmonary, subpleural located Morbus Castleman of the hyaline-vascular type.Castleman's disease is a very rare disorder of the lymphatic tissue that is differentiated into two clinical subtypes. The localized type presents histologically almost always as the hyaline vascular form. Findings have been reported in mediastinal lymph nodes, the abdomen and peripheral lymphnodes. Intrapulmonary development is very rare and only 9 cases have previously been described in literature.On the other hand the multicentric type accounts for approximately 10%-15% of cases and histologically usually presents as the plasma cell variant. It is accompanied by fatigue and general weakness and often requires systemic steroid or chemotherapy.The localized type develops less clinical symptoms and is curable by complete surgical resection. PMID- 26581497 TI - Cystic Adventitial Disease of the Common Femoral Artery. Case Report and Review of the Literature. AB - PURPOSE: Cystic adventitial artery disease is an uncommon non-atherosclerotic peripheral vessel disease. Furthermore cystic adventitial disease of the common femoral artery is an extremely rare entity. We report the case of a 54 year-old man complaining of intermittent claudication who was referred to our vascular service. METHODS AND RESULTS: Doppler ultrasound and multidetector-row computed tomography (CT) with 3-dimensional volume rendering revealed severe stenosis with cystic an adventitial cyst in the common femoral artery. Intra-operative Doppler ultrasound showed the cyst to be multilocular type. Reversed great saphenous vein interposition was successfully placed. CONCLUSION: Removal of cyst together with artery and interposition using reversed great saphenous vein is the optimal treatment procedure to prevent recurrence. PMID- 26581498 TI - Application of streptavidin mass spectrometric immunoassay tips for immunoaffinity based antibody phage display panning. AB - Antibody phage display panning involves the enrichment of antibodies against specific targets by affinity. In recent years, several new methods for panning have been introduced to accommodate the growing application of antibody phage display. The present work is concerned with the application of streptavidin mass spectrometry immunoassay (MSIATM) Disposable Automation Research Tips (D.A.R.T's(r)) for antibody phage display. The system was initially designed to isolate antigens by affinity selection for mass spectrometry analysis. The streptavidin MSIATM D.A.R.T's(r) system allows for easy attachment of biotinylated target antigens on the solid surface for presentation to the phage library. As proof-of-concept, a domain antibody library was passed through the tips attached with the Hemolysin E antigen. After binding and washing, the bound phages were eluted via standard acid dissociation and the phages were rescued for subsequent panning rounds. Polyclonal enrichment was observed for three rounds of panning with five monoclonal domain antibodies identified. The proposed method allows for a convenient, rapid and semi-automated alternative to conventional antibody panning strategies. PMID- 26581499 TI - Purinergic signalling in brain ischemia. AB - Ischemia is a multifactorial pathology characterized by different events evolving in the time. After ischemia a primary damage due to the early massive increase of extracellular glutamate is followed by activation of resident immune cells, i.e microglia, and production or activation of inflammation mediators. Protracted neuroinflammation is now recognized as the predominant mechanism of secondary brain injury progression. Extracellular concentrations of ATP and adenosine in the brain increase dramatically during ischemia in concentrations able to stimulate their respective specific P2 and P1 receptors. Both ATP P2 and adenosine P1 receptor subtypes exert important roles in ischemia. Although adenosine exerts a clear neuroprotective effect through A1 receptors during ischemia, the use of selective A1 agonists is hampered by undesirable peripheral effects. Evidence up to now in literature indicate that A2A receptor antagonists provide protection centrally by reducing excitotoxicity, while agonists at A2A (and possibly also A2B) and A3 receptors provide protection by controlling massive infiltration and neuroinflammation in the hours and days after brain ischemia. Among P2X receptors most evidence indicate that P2X7 receptor contribute to the damage induced by the ischemic insult due to intracellular Ca(2+) loading in central cells and facilitation of glutamate release. Antagonism of P2X7 receptors might represent a new treatment to attenuate brain damage and to promote proliferation and maturation of brain immature resident cells that can promote tissue repair following cerebral ischemia. Among P2Y receptors, antagonists of P2Y12 receptors are of value because of their antiplatelet activity and possibly because of additional anti-inflammatory effects. Moreover strategies that modify adenosine or ATP concentrations at injury sites might be of value to limit damage after ischemia. This article is part of the Special Issue entitled 'Purines in Neurodegeneration and Neuroregeneration'. PMID- 26581501 TI - Cherry-picked ligands at histamine receptor subtypes. AB - Histamine, a biogenic amine, is considered as a principle mediator of multiple physiological effects through binding to its H1, H2, H3, and H4 receptors (H1 H4Rs). Currently, the HRs have gained attention as important targets for the treatment of several diseases and disorders ranging from allergy to Alzheimer's disease and immune deficiency. Accordingly, medicinal chemistry studies exploring histamine-like molecules and their physicochemical properties by binding and interacting with the four HRs has led to the development of a diversity of agonists and antagonists that display selectivity for each HR subtype. An overview on H1-R4Rs and developed ligands representing some key steps in development is provided here combined with a short description of structure activity relationships for each class. Main chemical diversities, pharmacophores, and pharmacological profiles of most innovative H1-H4R agonists and antagonists are highlighted. Therefore, this overview should support the rational choice for the optimal ligand selection based on affinity, selectivity and efficacy data in biochemical and pharmacological studies. This article is part of the Special Issue entitled 'Histamine Receptors'. PMID- 26581500 TI - Functional modulation of G-protein coupled receptors during Parkinson disease like neurodegeneration. AB - G-protein coupled dopamine and metabotropic glutamate receptors (mGlu) can modulate neurotransmission during Parkinson's disease (PD)-like neurodegeneration. PET imaging studies in a unilateral dopamine denervation model (6-OHDA) showed a significant inverse correlation of presynaptic mGlu4 and postsynaptic mGlu5 expression in the striatum and rapidly declining mGlu4 and enhanced mGlu5 expression in the hippocampus during progressive degeneration over time. Immunohistochemical studies verified the decreased mGlu4 expression in the hippocampus on the lesion side but did not show difference in mGlu5 expression between lesion and control side. Pharmacological MRI studies showed enhanced hemodynamic response in several brain areas on the lesion side compared to the control side after challenge with mGlu4 positive allosteric modulator or mGlu5 negative allosteric modulator. However, mGlu4 response was biphasic having short enhancement followed by negative response on both sides of brain. Studies in mGlu4 expressing cells demonstrated that glutamate induces cooperative increase in binding of mGlu4 ligands - especially at high glutamate levels consistent with in vivo concentration. This suggests that mGlu allosteric modulators as drug candidates will be highly sensitive to changes in glutamate concentration and hence metabolic state. These experiments demonstrate the importance of the longitudinal imaging studies to investigate temporal changes in receptor functions to obtain individual response for experimental drugs. PMID- 26581502 TI - Arabidopsis non-specific phospholipase C1: characterization and its involvement in response to heat stress. AB - The Arabidopsis non-specific phospholipase C (NPC) protein family is encoded by the genes NPC1 - NPC6. It has been shown that NPC4 and NPC5 possess phospholipase C activity; NPC3 has lysophosphatidic acid phosphatase activity. NPC3, 4 and 5 play roles in the responses to hormones and abiotic stresses. NPC1, 2 and 6 has not been studied functionally yet. We found that Arabidopsis NPC1 expressed in Escherichia coli possesses phospholipase C activity in vitro. This protein was able to hydrolyse phosphatidylcholine to diacylglycerol. NPC1-green fluorescent protein was localized to secretory pathway compartments in Arabidopsis roots. In the knock out T-DNA insertion line NPC1 (npc1) basal thermotolerance was impaired compared with wild-type (WT); npc1 exhibited significant decreases in survival rate and chlorophyll content at the seventh day after heat stress (HS). Conversely, plants overexpressing NPC1 (NPC1-OE) were more resistant to HS compared with WT. These findings suggest that NPC1 is involved in the plant response to heat. PMID- 26581503 TI - Systems genetics of intravenous cocaine self-administration in the BXD recombinant inbred mouse panel. AB - RATIONALE: Cocaine addiction is a major public health problem with a substantial genetic basis for which the biological mechanisms remain largely unknown. Systems genetics is a powerful method for discovering novel mechanisms underlying complex traits, and intravenous drug self-administration (IVSA) is the gold standard for assessing volitional drug use in preclinical studies. We have integrated these approaches to identify novel genes and networks underlying cocaine use in mice. METHODS: Mice from 39 BXD strains acquired cocaine IVSA (0.56 mg/kg/infusion). Mice from 29 BXD strains completed a full dose-response curve (0.032-1.8 mg/kg/infusion). We identified independent genetic correlations between cocaine IVSA and measures of environmental exploration and cocaine sensitization. We identified genome-wide significant quantitative trait loci (QTL) on chromosomes 7 and 11 associated with shifts in the dose-response curve and on chromosome 16 associated with sessions to acquire cocaine IVSA. Using publicly available gene expression data from the nucleus accumbens, midbrain, and prefrontal cortex of drug-naive mice, we identified Aplp1 and Cyfip2 as positional candidates underlying the behavioral QTL on chromosomes 7 and 11, respectively. A genome wide significant trans-eQTL linking Fam53b (a GWAS candidate for human cocaine dependence) on chromosome 7 to the cocaine IVSA behavioral QTL on chromosome 11 was identified in the midbrain; Fam53b and Cyfip2 were co-expressed genome-wide significantly in the midbrain. This finding indicates that cocaine IVSA studies using mice can identify genes involved in human cocaine use. CONCLUSIONS: These data provide novel candidate genes underlying cocaine IVSA in mice and suggest mechanisms driving human cocaine use. PMID- 26581504 TI - Does impulsivity change rate dependently following stimulant administration? A translational selective review and re-analysis. AB - RATIONALE: Rate dependence refers to an orderly relationship between a baseline measure of behavior and the change in that behavior following an intervention. The most frequently observed rate-dependent effect is an inverse relationship between the baseline rate of behavior and response rates following an intervention. A previous report of rate dependence in delay discounting suggests that the discounting of delayed reinforcers, and perhaps, other impulsivity measures, may change rate dependently following acute and chronic administration of potentially therapeutic medications in both preclinical and clinical studies. OBJECTIVE: The aim of the current paper was to review the effects of stimulants on delay discounting and other impulsivity tasks. METHODS: All studies identified from the literature were required to include (1) an objective measure of impulsivity; (2) administration of amphetamine, methylphenidate, or modafinil; (3) presentation of a pre- and postdrug administration impulsivity measure; and (4) the report of individual drug effects or results in groups split by baseline or vehicle impulsivity. Twenty-five research reports were then reanalyzed for evidence consistent with rate dependence. RESULTS: Of the total possible instances, 67 % produced results consistent with rate dependence. Specifically, 72, 45, and 80 % of the data sets were consistent with rate dependence following amphetamine, methylphenidate, and modafinil administration, respectively. CONCLUSIONS: These results suggest that rate dependence is a more robust phenomenon than reported in the literature. Impulsivity studies should consider this quantitative signature as a process to determine the effects of variables and as a potential prognostic tool to evaluate the effectiveness of future interventions. PMID- 26581506 TI - Non-organic visual loss in children: prospective and retrospective analysis of associated psychosocial problems and stress factors. AB - PURPOSE: To report on the prevalence of non-organic visual loss (NOVL) and its associated psychopathology and psychosocial stress factors on children presenting with visual problems without an obvious cause at a routine ophthalmological examination. METHODS: One hundred and seventy children presented at our paediatric ophthalmology department between 2007 and 2014 with visual loss. Routine examination showed no obvious underlying cause. Pattern-onset visual evoked potentials (pVEPs) were performed to obtain an objective visual assessment. Selected patients underwent more investigations, and follow-up was organized in every child to differentiate organic visual loss (OVL) from NOVL. In the NOVL group, we retrospectively analysed the medical file data and prospectively the questionnaires completed by patients and their parents. RESULTS: Eighty-five children (50%) were diagnosed with OVL, the other 50% of children were diagnosed with NOVL. In the latter, girls predominated and the mean age was 11.0 years. The most common presenting symptom was binocular reduced visual acuity. pVEPs were normal in all patients. We categorized associated comorbidity in the NOVL group in three subgroups: malingering, psychosocial stressors and child psychiatric disorders. CONCLUSION: Non-organic visual loss in children is a common diagnosis in clinical practice. The diagnosis is made by recognition of characteristic features and by exclusion of organic disease. pVEP is a useful tool to obtain an objective visual acuity and to differentiate functional from organic vision loss. The prognosis in NOVL is good with a spontaneous recovery in the majority of patients. Ophthalmologists should be aware of possible underlying psychosocial and psychiatric disorders; referral can be necessary. PMID- 26581507 TI - Gene expression profiles predict the possible regulatory role of OPN-mediated signaling pathways in rat liver regeneration. AB - Osteopontin (OPN; gene Spp1), as a pro-inflammatory cytokine, has a range of activities relevant to the occurrence and progression of hepatitis, liver fibrosis or liver tumors. However, little is known about the role of OPN in liver regeneration (LR). To reveal the expression profiles of OPN and its receptors and the possible regulatory role of OPN in rat LR, Rat Genome 230 2.0 was used to detect expression profiles of OPN-mediated signaling pathway-associated genes after partial hepatectomy (PH), and the results showed that 81 genes were significantly changed at mRNA level, and among which, 65 genes were up-regulated. Then, k-means clustering was employed to classify above 81 genes into 5 clusters based on gene expression similarity, and EASE analysis further indicated that the above genes were mainly associated with stress response, inflammatory response, cell activation, proliferation, adhesion and migration. Thereafter, IPA software and Western blot were used to analyze potential effects of every branch of OPN signaling pathways during LR, and the results suggested that the genes expression changes of OPN signaling pathways may account for enhanced cell proliferation, survival, adhesion and migration, augmented inflammation response and attenuated apoptosis during LR. PMID- 26581508 TI - Knockdown of HNRNPA1 inhibits lung adenocarcinoma cell proliferation through cell cycle arrest at G0/G1 phase. AB - Heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1), a member of heterogeneous nuclear ribonucleoprotein family in actively growing mammalian cells, is involved in a variety of RNA-related processes. HNRNPA1 can enhance the degradation of inhibitory subunit of nuclear factor kappa B alpha (IkappaBalpha) and lengthen the telomeres. Recently, it is reported that HNRNPA1 is aberrantly expressed in varied tumors. In this study we found HNRNPA1 protein overexpressed in lung cancer tissues. To explore the exact role of HNRNPA1 in lung cancers, we carried out a loss of function analysis of HNRNPA1 in A549 lung cancer cells by RNA interference (RNAi). The results demonstrated that knockdown of HNRNPA1 inhibited cell viability and colony formation of lung cancer cells and arrested cell cycle in G0/G1 phase. Our study suggested that HNRNPA1 might play an important role in lung adenocarcinoma cells and provided a foundation for further study into the potential of HNRNPA1 for lung cancer therapy. PMID- 26581505 TI - Selective participation of c-Jun with Fra-2/c-Fos promotes aggressive tumor phenotypes and poor prognosis in tongue cancer. AB - Tongue squamous cell carcinoma (TSCC) is most aggressive head and neck cancer often associated with HR-HPV infection. The role of AP-1 which is an essential regulator of HPV oncogene expression and tumorigenesis is not reported in tongue cancer. One hundred tongue tissue biopsies comprising precancer, cancer and adjacent controls including two tongue cancer cell lines were employed to study the role of HPV infection and AP-1 family proteins. An exclusive prevalence (28%) of HR-HPV type 16 was observed mainly in well differentiated tongue carcinomas (78.5%). A higher expression and DNA binding activity of AP-1 was observed in tongue tumors and cancer cell lines with c-Fos and Fra-2 as the major binding partners forming the functional AP-1 complex but c-Jun participated only in HPV negative and poorly differentiated carcinoma. Knocking down of Fra-2 responsible for aggressive tongue tumorigenesis led to significant reduction in c-Fos, c-Jun, MMP-9 and HPVE6/E7 expression but Fra-1 and p53 were upregulated. The binding and expression of c-Fos/Fra-2 increased as a function of severity of tongue lesions, yet selective participation of c-Jun appears to promote poor differentiation and aggressive tumorigenesis only in HPV negative cases while HPV infection leads to well differentiation and better prognosis preferably in nonsmokers. PMID- 26581509 TI - Lesions in the wingless gene of the Apollo butterfly (Parnassius apollo, Lepidoptera: Papilionidae) individuals with deformed or reduced wings, coming from the isolated population in Pieniny (Poland). AB - Parnassius apollo (Lepidoptera: Papilionidae) is a butterfly species which was common in Europe in 19th century, but now it is considered as near threatened. Various programs devoted to protect and save P. apollo have been established, between others the one in Pieniny National Park (Poland). An isolated population of this butterfly has been restored there from a small group of 20-30 individuals in early 1990s. However, deformations or reductions of wings occur in this population in a relatively large number of insects, and the cause of this phenomenon is not known. In this report, the occurrence of lesions in the wingless (wg) gene is demonstrated in most of tested butterflies with deformed or reduced wings, but not in normal insects. Although the analyses indicated that wg lesion(s) cannot be the sole cause of the deformed or reduced wings in the population of P. apollo from Pieniny, the discovery that this genetic defect occurs in most of malformed individuals, can be considered as an important step in understanding this phenomenon. PMID- 26581511 TI - Switchable Surface Wettability by Using Boronic Ester Chemistry. AB - Here, we report for the first time the use of a boronic ester as an efficient tool for reversible surface post-functionalization. The boronic ester bond allows surfaces to be reversibly switched from hydrophilic to hydrophobic. Based on the well-known boronic acid/glycol affinity, this strategy offers the opportunity to play with surface hydrophobic properties by adding various boronic acids onto substrates bearing glycol groups. The post-functionalization can then be reversed to regenerate the starting glycol surface. This pathway allows for the preparation of various switchable surfaces for a large range of applications in biosensors, liquid transportation, and separation membranes. PMID- 26581510 TI - Responses of the Hybrid between Sphagneticola trilobata and Sphagneticola calendulacea to Low Temperature and Weak Light Characteristic in South China. AB - Hybridization between exotic and native species is of great interest to evolutionary biologists and ecologists because it usually shows a quick evolution of species and invasiveness. It has been reported that such hybridization frequently increases the adaptation and aggressiveness of the new hybrids. A hybrid between invasive Sphagneticola trilobata and its native congener S. calendulacea was recently found in subtropical China. S. calendulacea has a significantly higher tolerance to low temperature and weak light stress than S. trilobata, and its range includes both tropical and temperate regions. This study examined how the tolerance of the new hybrid to low temperature and weak light conditions (LTWL), expanded its geographical range. All changes of phenotype, gas exchange parameters, chlorophyll fluorescence parameters, contents of malonaldehyde (MDA) and activity of superoxide dismutase (SOD) and peroxidase (POD) indicated that hybridization slightly catalyzed the tolerance of the hybrid to LTWL condition and the responses of the hybrid were more similar with their invasive parent. The results demonstrate that the current hybrid populations may not expand their geographical distribution ranges in a short period, but the distribution of the backcrossed generations is still uncertain. The threat of the hybrid to its native parent in subtropical region should be concerned. PMID- 26581512 TI - Erratum to "Cyclohexane-1,2-dicarboxylic acid diisononyl ester and metabolite effects on rat epididymal stromal vascular fraction differentiation of adipose tissue" [Environ. Res. 140 (2015) 145-156]. PMID- 26581513 TI - Privateer: software for the conformational validation of carbohydrate structures. PMID- 26581514 TI - Protein-RNA interaction restricts telomerase from running through the stop sign. PMID- 26581515 TI - Ribosomal 60S-subunit production: the final scene. PMID- 26581516 TI - Unraveling the ends. PMID- 26581517 TI - A DNA-hairpin model for repeat-addition processivity in telomere synthesis. AB - We propose a DNA-hairpin model for the processivity of telomeric-repeat addition. Concomitantly with template-RNA translocation after each repeat synthesis, the complementary DNA repeat, for example, AGGGTT, loops out in a noncanonical base paired hairpin, thus freeing the RNA template for the next round of repeat synthesis. The DNA hairpin is temporarily stabilized by telomerase and the incoming dGTP but becomes realigned for processive telomere synthesis. PMID- 26581518 TI - Control of telomerase action at human telomeres. AB - Recent progress has greatly increased the understanding of telomere-bound shelterin proteins and the telomerase holoenzyme, predominantly as separate complexes. Pioneering studies have begun to investigate the requirements for shelterin-telomerase interaction. From this vantage point, focusing on human cells, we review and discuss models for how telomerase and shelterin subunits coordinate to achieve balanced telomere-length homeostasis. PMID- 26581519 TI - TERRA and the state of the telomere. AB - Long noncoding telomeric repeat-containing RNA (TERRA) has been implicated in telomere maintenance in a telomerase-dependent and a telomerase-independent manner during replicative senescence and cancer. TERRA's proposed activities are diverse, thus making it difficult to pinpoint the critical roles that TERRA may have. We propose that TERRA orchestrates different activities at chromosome ends in a manner that depends on the state of the telomere. PMID- 26581520 TI - Complex interactions between the DNA-damage response and mammalian telomeres. AB - Natural chromosome ends resemble double-stranded DNA breaks, but they do not activate a damage response in healthy cells. Telomeres therefore have evolved to solve the 'end-protection problem' by inhibiting multiple DNA damage-response pathways. During the past decade, the view of telomeres has progressed from simple caps that hide chromosome ends to complex machineries that have an active role in organizing the genome. Here we focus on mammalian telomeres and summarize and interpret recent discoveries in detail, focusing on how repair pathways are inhibited, how resection and replication are controlled and how these mechanisms govern cell fate during senescence, crisis and transformation. PMID- 26581523 TI - Corrigendum: Structure and multistate function of the transmembrane electron transporter CcdA. PMID- 26581522 TI - Molecular mechanisms of activity and derepression of alternative lengthening of telomeres. AB - Alternative lengthening of telomeres (ALT) involves homology-directed telomere synthesis. This multistep process is facilitated by loss of the ATRX or DAXX chromatin-remodeling factors and by abnormalities of the telomere nucleoprotein architecture, including altered DNA sequence and decreased TRF2 saturation. Induction of telomere-specific DNA damage triggers homology-directed searches, and NuRD-ZNF827 protein-protein interactions provide a platform for the telomeric recruitment of homologous recombination (HR) proteins. Telomere lengthening proceeds by strand exchange and template-driven DNA synthesis, which culminates in dissolution of HR intermediates. PMID- 26581524 TI - Erratum: Plasmepsin V shows its carnivorous side. PMID- 26581521 TI - Molecular basis of telomere dysfunction in human genetic diseases. AB - Mutations in genes encoding proteins required for telomere structure, replication, repair and length maintenance are associated with several debilitating human genetic disorders. These complex telomere biology disorders (TBDs) give rise to critically short telomeres that affect the homeostasis of multiple organs. Furthermore, genome instability is often a hallmark of telomere syndromes, which are associated with increased cancer risk. Here, we summarize the molecular causes and cellular consequences of disease-causing mutations associated with telomere dysfunction. PMID- 26581525 TI - Crystallization pathways of liquid-bcc transition for a model iron by fast quenching. AB - We report simulations on the local structural evolution in the liquid-bcc transition of a model iron. Fourteen main Voronoi polyhedra are chosen as the representatives of short-range orders (SROs) and their transformations during crystallization are also investigated. Thus, the crystallization pathways for the main SROs are drawn. Our results also show that the transformations between two SROs in the crystallization pathways can be classified into two categories, first the enlargement of coordination number, second the transformation of local symmetry from five-fold to four-fold. The former reduces the potential energy while the latter increases it. It is found that the potential energy cannot decease monotonously whatever crystallization pathway is chosen to transform the icosahedral SRO to bcc SRO. Therefore, the latter transformation might provide the energy barrier of crystallization. We propose two transformation styles among SROs. All the transformations in the crystallization pathways can be achieved according to the styles. Moreover, the two transformation styles indicates that the bcc structure is more similar to liquid than other crystals. That might be the reason why the first phase nucleated during a rapid cooling process should be bcc crystal. PMID- 26581526 TI - Pantoea pleuroti sp. nov., Isolated from the Fruiting Bodies of Pleurotus eryngii. AB - Four Gram-negative-staining, facultatively anaerobic bacterial isolates were obtained from the fruiting bodies of the edible mushroom Pleurotus eryngii showing symptoms of bacterial blight disease in Beijing, China. Nearly complete 16S rRNA gene sequencing placed these isolates in the genus Pantoea. Multilocus sequence analysis based on the partial sequences of atpD, gyrB, infB and rpoB revealed Pantoea agglomerans as their closest phylogenetic relatives. DNA-DNA hybridization and phenotypic tests confirmed the classification of the new isolates as a novel species. The name Pantoea pleuroti sp. nov. [type strain KCTC 42084(T) = CGMCC 1.12894(T) = JZB 2120015(T)] is proposed. PMID- 26581527 TI - [Regulation of continuing medical education]. PMID- 26581528 TI - [Risk factors for nosocomial infection in a level III Neonatal Intensive Care Unit]. AB - INTRODUCTION: Nosocomial infections are a major and a frequent problem in neonatal intensive care units and increase morbidity, mortality, and costs. The objective of this study was to identify the risk factors associated with nosocomial infections in a neonatal intensive care unit. METHODS: Nested case control study. Records from patients were registered: gestational age, sex, birth weight, central venous catheter and other devices, congenital malformations, surgeries, mechanical ventilation, steroid use, H2 blockers, length of stay in neonatal intensive care unit, type of infection, and etiological agent. RESULTS: We studied 188 cases with nosocomial infections and 192 controls without nosocomial infections. The most frequent infection was sepsis (34.8%) and coagulase negative Staphylococcus was the principal etiological agent (37.2%). The risk factors associated with nosocomial infection were central venous catheter (OR: 7.3; 95% CI: 2.3-22.8), duration of neonatal intensive care unit stay>14 days (OR: 3.4; 95% CI: 1.7-6.7), H2 blockers (OR: 2.3; 95% CI: 1.2-4.2), number of surgeries>=2 (OR: 3; 95% CI: 1.1-7.9) and mechanical ventilation>7 days (OR: 2.1; 95% CI: 1.1-4.2). CONCLUSIONS: Some risk factors associated to nosocomial infections in this study are similar to those found previously, with the exception of the number of surgeries that was not reported in previous studies. PMID- 26581529 TI - [Effectiveness of trabeculectomy trabeculotomy in the reduction of intraocular pressure in patients with primary congenital glaucoma]. AB - OBJECTIVE: To evaluate the effectiveness of trabeculectomy trabeculotomy in the reduction of intraocular pressure in patients with primary congenital glaucoma. MATERIAL AND METHODS: A pre-experimental before and after study was conducted with several measurements after; patients with intraocular pressure>=21 mmHg were included, of both sexes, and children under six years, which had the trabeculotomy trabeculectomy. Success was defined as the reduction of intraocular pressure<21 mmHg within three months after the procedure. For the descriptive analysis, medians with ranges and quartiles 25 and 75 were used. For the inferential analysis, we conducted a visual graphic and analysis of variance for repeated measures of Friedman. A value of p<0.05 was considered as significant. The software used was SPSSv15. RESULTS: 16 eyes were included with intraocular pressure 27.75 mmHg (23-40), vertical and horizontal corneal diameter of 14 mm (12-16), who had undergone trabeculectomy with mitomycin C trabeculectomy; at three months after surgery the intraocular pressure was 12.5 mmHg (8.5-23) (p<0.001) and no changes were observed in the corneal diameters. An eye with a flat anterior chamber was observed as an adverse effect. Thirteen eyes required topical hypotensors to achieve the target intraocular pressure. CONCLUSIONS: The treatment with trabeculectomy trabeculotomy in primary congenital glaucoma is effective in the reduction of the intraocular pressure. PMID- 26581530 TI - [Factors associated with advanced thyroid cancer in pediatric patients in a high specialty medical unit in Northeast Mexico]. AB - INTRODUCTION: Thyroid cancer represents 2% of all childhood malignances. Its incidence rises 1.1% per year. In comparison with adults, childhood thyroid cancer is detected in a more advanced stage, but with a survival rate above 95%. The objective of this study was to evaluate whether there are factors associated with advanced stages of thyroid cancer in pediatric patients. RESULTS: Nineteen patients were included, 13 (68.4%) were female and six male, all between 7-15 years, with a median of 11 years. Fifteen in advanced and four in early stage. The median age of patients in advanced stage at time of diagnosis was 10.6 years (7-15) and 13.2 (12-14) were in early stage (p=0.075). There was a delay of nine months to get a diagnosis in advanced stage, and 7.2 in early stage (p=0.931). Three of the patients with advanced stage and two with early stage were from Nuevo Leon (Mexico) and the rest were foreign (p=0.567). In the group with advanced stage, two had thyroid cancer familiar history, and none in the early stage group (p=0.452). Nine patients in advanced stage and three in early stage presented thyroid nodule as the first sign of illness. Six patients in advanced stage and one in early stage presented goiter (p=0.590). None of the studied patients had radiation history. Six patients in advanced stage and one in early stage suffered from Hashimoto's Thyroiditis (p=0.590). Eleven in advanced stage and one in early stage had papillary histologic variety. Four in advanced stage and three in early stage had papillary histologic variety with a follicular patter (p=0.083). Eight patients presented lung metastasis at time of diagnosis (p=0.061). CONCLUSIONS: There are no factors associated with advanced stage thyroid cancer in pediatric populations. Although half of studied patients presented lung metastasis, treatment response and survival is satisfactory. PMID- 26581531 TI - [Bone mineral density and its association with body composition and metabolic biomarkers of insulin-glucose axis, bone and adipose tissue in women]. AB - INTRODUCTION: There are few studies integrating the common causes of osteoporosis and obesity (disorders of body composition). A first step is to investigate correlations between their biological phenotypes to determine their common integrative physiology. OBJECTIVE: To correlate the variation of bone mineral density with phenotypes of body composition and biomarkers of bone physiology, insulin-glucose axis, and adipose tissue. METHODS: Cross-sectional study of 75 women (aged 18-45 years). MEASUREMENTS: Body mass index, waist, fat mass, lean mass (dual-energy X-ray absorptiometry), glucose, insulin, osteocalcin, leptin, tumor necrosis factor alpha. STATISTICAL ANALYSIS: multivariate general linear model, SPSS v.22, p<0.05. RESULTS: Age: 32.08+/-7.33. Bone mineral content multivariate general linear model 1 with two phenotypes excluded (glucose, insulin): osteocalcin (beta=-0.228, p=0.011), lean mass (beta=0.606, p=0.001) and fat mass (beta=1.237, p=0.001) in 62.0%. The bone mineral density multivariate general linear model 2 with three phenotypes excluded (body mass index, glucose, tumor necrosis factor alpha): insulin (beta=0.250, p=0.024), osteocalcin (beta= 0.362, p=0.001), lean mass (beta=0.512, p=0.001) and fat mass (beta=0.701, p=0.001) in 46.3%. CONCLUSIONS: Results show that body composition with an increased lean mass is beneficial to bone. This study reaffirms the importance of performing regular exercise to prevent muscle loss. PMID- 26581532 TI - [Evaluation of strategies aimed at reducing the level of noise in different areas of neonatal care in a tertiary hospital]. AB - OBJECTIVE: To determine the noise levels of different areas responsible for newborn care, develop intervention strategies to decrease the noise, and evaluate its effectiveness. METHODS: Prospective, observational and longitudinal study carried out using a sonometer, measuring sound levels for three weeks in the neonatal intensive care unit (NICU), neonatal intermediate care unit (UCIREN), delivery (TOCO QX) and nursery (CUNERO) units. We implemented an intervention program and subsequent measurements were performed under the same initial conditions. RESULTS: When comparing the decibel levels in different areas during the three weeks, pre- and post-intervention, we found at the neonatal intensive care unit 59.9+/-4.8 vs. 56.4+/-4.7 dB (p<0.001), neonatal intermediate care unit 55.3+/-3.9 vs. 51.3+/-4.4 dB (p<0.001), delivery unit 57.3+/-4.6 vs. 57.3+/-5.5 dB (NS), and nursery unit 57.6+/-5.8 vs. 53.9+/-5.8 dB (p<0.001). CONCLUSIONS: There was a significant reduction in noise levels of 3.5 dB at the NICU, 4 dB at UCIREN and 3.7 dB at TOCO QX, so the intervention program was effective in these areas; however, the decibel levels registered continue above those recommended by international standards. PMID- 26581533 TI - [Risk factors associated with bacterial growth in derivative systems from cerebrospinal liquid in pediatric patients]. AB - OBJECTIVE: To determine risk factors associated with bacterial growth in systems derived from cerebrospinal fluid in pediatric patients. METHODS: Case and controls study from January to December 2012, in patients aged <16 years who were carriers of hydrocephalus and who required placement or replacement of derivative system. Cases were considered as children with cultures with bacterial growth and controls with negative bacterial growth. Inferential statistics with Chi-squared and Mann-Whitney U tests. Association of risk with odds ratio. RESULTS: We reviewed 746 registries, cases n=99 (13%) and controls n=647 (87%). Masculine gender 58 (57%) vs. feminine gender 297 (46%) (p=0.530). Age of cases: median, five months and controls, one year (p=0.02). Median weight, 7 vs. 10 kg (p=0.634). Surgical interventions: median n=2 (range, 1-8) vs. n=1 (range, 1-7). Infection rate, 13.2%. Main etiology ductal stenosis, n=29 (29%) vs. n=50 (23%) (p=0.530). Non-communicating, n=50 (51%) vs. 396 (61%) (p=0.456). Predominant microorganisms: enterobacteria, pseudomonas, and enterococcus. Non-use of iodized dressing OR=2.6 (range, 1.8-4.3), use of connector OR=6.8 (range, 1.9-24.0), System replacement OR=2.0 (range, 1.3-3.1), assistant without surgical facemask OR=9.7 (range, 2.3-42.0). CONCLUSIONS: Being a breastfeeding infant, of low weight, non-application of iodized dressing, use of connector, previous derivation, and lack of adherence to aseptic technique were all factors associated with ependymitis. PMID- 26581535 TI - [Phototransduction mediated by melanopsin in intrinsically photosensitive retinal ganglion cells]. AB - Melanopsin is the most recent photopigment described. As all the other opsins, it attaches in the retina as chromophore. Its amino acid sequence resembles more invertebrate opsins than those of vertebrates. The signal transduction pathway of opsins in vertebrates is based on the coupling to the G protein transducin, triggering a signaling cascade that results in the hyperpolarization of the plasma membrane. On the contrary, the photoreceptors of invertebrates activate the Gq protein pathway, which leads to depolarizing responses. Phototransduction mediated by melanopsin leads to the depolarization of those cells where it is expressed, the intrinsically photosensitive retinal ganglion cells; the cellular messengers and the ion channel type(s) responsible for the cells' response is still unclear. Studies to elucidate the signaling cascade of melanopsin in heterologous expression systems, in retina and isolated/cultured intrinsically photosensitive retinal ganglion cells, have provided evidence for the involvement of protein Gq and phospholipase C together with the likely participation of an ion channel member of the transient receptor potential-canonical family, a transduction pathway similar to invertebrate photopigments, particularly Drosophila melanogaster. The intrinsically photosensitive retinal ganglion cells are the sole source of retinal inferences to the suprachiasmatic nucleus; thus, clarifying completely the melanopsin signaling pathway will impact the chronobiology field, including the clinical aspects. PMID- 26581534 TI - [Susceptibility of induced sickle in samples of heterozygous hemoglobin S patients (sickle cell trait) suffering diabetes mellitus type 2]. AB - Hemoglobin S is an abnormal protein that induces morphological changes in erythrocyte in low-oxygen conditions. In Mexico, it is reported that up to 13.7% of the population with mutation in one allele are considered asymptomatic (sickle cell trait). The sickle cell trait and diabetes mellitus are conditions that occur together in more than one million patients worldwide. Both diseases possibly produce microvascular changes in retinopathy and acute chest syndrome. The aim of this study was to evaluate the induction of sickle cells in samples of diabetic patients with sickle cell trait to identify altered red cell parameters. We obtained samples of diabetic patients to determine hemoglobin A1c and S; furthermore, red blood cell biometrics data were analyzed. We found that older men with diabetes were susceptible to generate sickle cells and this correlated with reduced red blood cell count and an increase in media cell volume. In samples of women diabetes, there were no differences. We conclude that samples from patients with sickle cell trait and diabetes can cause sickle cells with high frequency in men, with lower red blood cells count and increased mean corpuscular volume as susceptibility parameters. PMID- 26581536 TI - [News in severe clinical adverse drug reactions: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)]. AB - Stevens-Johnson syndrome and toxic epidermal necrolysis are life-threatening conditions associated with significant morbidity and mortality. They are considered to be part of a spectrum of cutaneous drug reactions, differing only by their extent of skin detachment due to keratinocyte apoptosis. Drugs are assumed as the main cause of Stevens-Johnson syndrome and toxic epidermal necrolysis in most cases. The pathophysiology is incompletely understood; however, current pathogenic models involve Fas ligand, granulysin, and cytokines. Diagnosis relies mainly on clinical signs together with the histological analysis, and treatment requires early cessation of the causative drug and supportive care. Of these conditions, herein we will review the advances in clinical, pathogenesis, and management. PMID- 26581537 TI - [Considerations on family dynamics and the malnutrition syndrome in Mexican children]. AB - Since the early 1990s we noted that family dysfunction was more common in children with severe primary malnutrition than in children admitted to the hospital without malnutrition. Defects on feeding habits during the first year of life, especially early weaning and inadequate complementary feeding were more common in dysfunctional families. We also observed that chronic malnutrition in preschool children, and overweight and obesity in schoolchildren were more common in children from dysfunctional families. Once the association between dysfunctional family dynamics and obesity in schoolchildren was demonstrated, it was observed that low education of fathers and mothers increased twofold the possibility of family dysfunction: OR: 2.06; 95% CI: 1.37-3.10 and OR: 2.47; 95% CI: 1.57-3.89, respectively. In addition, the low-income and the lower purchasing power of foods were associated to family dysfunction (p<0.05). A remaining task is to explore how to assess family dysfunction in composite, extended, single parent families where there exist other persons vulnerable to the different entities of malnutrition syndrome and indeed depend on adults for their care, food and nutrition. PMID- 26581538 TI - [Apixaban as therapeutic option in nephropathy patients with heparin-induced thrombocytopenia (HIT)]. AB - Heparin-induced thrombocytopenia (HIT) is a prothrombotic condition caused by antibodies against the heparin-PF4 complex. This disorder is even more problematic in patients undergoing hemodialysis since they are repeatedly exposed to heparin. The diagnostic and therapeutic approach is particularly challenging in this population. We report the case of a woman with chronic kidney disease and a high pretest probability for heparin-induced thrombocytopenia who was acutely treated with apixaban, an oral selective factor Xa inhibitor. PMID- 26581539 TI - [Left ventricular rupture of mitral valve prosthesis implantation treated using an intra-aortic balloon pump counterpulsation]. AB - Left ventricular rupture is an infrequent but potentially fatal complication of mitral valve replacement. In spite of the fact that several methods of repair have previously been described, the mortality rate remains nearly 85%. The use of the intra-aortic balloon pump counterpulsation may increase the possibilities of success in the repair of this dreaded complication. We present here three cases of left ventricular rupture associated to mitral valve prosthesis implantation successfully treated with the aid of intra-aortic balloon pump counterpulsation. PMID- 26581540 TI - [A brief history of the natural causes of human disease]. AB - In the study of the causes of disease that have arisen during the development of humankind, one can distinguish three major perspectives: the natural, the supernatural, and the artificial. In this paper we distinguish the rational natural causes of disease from the irrational natural causes. Within the natural and rational causal approaches of disease, we can highlight the Egyptian theory of putrid intestinal materials called "wechdu", the humoral theory, the atomistic theory, the contagious theory, the cellular theory, the molecular (genetic) theory, and the ecogenetic theory. Regarding the irrational, esoteric, and mystic causal approaches to disease, we highlight the astrological, the alchemical, the iatrochemical, the iatromechanical, and others (irritability, solidism, brownism, and mesmerism). PMID- 26581541 TI - [The professor and the seamstress: an episode in the life of Jacob Henle]. AB - Jacob Henle was a great German anatomist and one of the most important histologists of all times. One of the most commonly used eponymous terms in renal histology is the loop of Henle, but many other anatomical and pathological findings are associated with his name. During his stay in Zurich he fell in love with Elise Egolff who worked as a maid and seamstress in the house of one of his friends. No one could ever imagine how the wide social chasm that separated the servant-girl and the professor could be bridged. Henle arranged for his sister Marie to educate Elise and give her social polish. In a short time Elise was transformed into a lady of the world. A year and a half later Jacob and Elise were married. This episode inspired the novelist Auerbach to write the novel "The Professor's Wife", and the play "Pygmalion" by George B Shaw. PMID- 26581542 TI - [Diagnostic algorithm for von Willebrand Disease (vWD) in a Mexican population]. PMID- 26581543 TI - Colophony as a marker for fragrance allergy in the general European population. PMID- 26581544 TI - Temporal Bone Pneumatization and Pulsatile Tinnitus Caused by Sigmoid Sinus Diverticulum and/or Dehiscence. AB - BACKGROUND: Although air cells within temporal bone may play an important role in the transmission of pulsatile tinnitus (PT) noise, it has not been studied systematically. PURPOSE: To evaluate the difference in temporal bone pneumatization between PT patients with sigmoid sinus diverticulum and/or dehiscence (SSDD) and healthy people. MATERIAL AND METHODS: A total of 199 unilateral persistent PT patients with SSDD and 302 control subjects underwent dual-phase contrast-enhanced CT (DP-CECT), to assess the grade of temporal bone pneumatization in each ear. RESULTS: In the bilateral temporal bone of 302 controls, 16 ears were grade I, 53 were grade II, 141 were grade III, and 394 were grade IV. Among the affected ears of 199 PT cases, 1 ear was grade I, 18 were grade II, 53 were grade III, and 127 were grade IV. There was no significant difference in the pneumatization grade between the affected PT ear and either ear in the healthy subjects (p > 0.05). CONCLUSION: Although air cells within the temporal bone are an important factor in the occurrence of PT, its severity does not differ significantly from the pneumatization of healthy people. PMID- 26581545 TI - Planned change or emergent change implementation approach and nurses' professional clinical autonomy. AB - BACKGROUND: Nurses' clinical autonomy is considered important for patients' outcome and influenced by the implementation approach of innovations. Emergent change approach with participation in the implementation process is thought to increase clinical autonomy. Planned change approach without this participation is thought not to increase clinical autonomy. Evidence of these effects on clinical autonomy is however limited. AIMS AND OBJECTIVES: To examine the changes in clinical autonomy and in personal norms and values for a planned change and emergent change implementation of an innovation, e.g. intensive insulin therapy. DESIGN: Prospective comparative study with two geographically separated nurses' teams on one intensive care unit (ICU), randomly assigned to the experimental conditions. METHODS: Data were collected from March 2008 to January 2009. Pre existing differences in perception of team and innovation characteristics were excluded using instruments based on the innovation contingency model. The Nursing Activity Scale was used to measure clinical autonomy. The Personal Values and Norms instrument was used to assess orientation towards nursing activities and the Team Learning Processes instrument to assess learning as a team. RESULTS: Pre implementation the measurements did not differ. Post-implementation, clinical autonomy was increased in the emergent change team and decreased in the planned change team. The Personal Values and Norms instrument showed in the emergent change team a decreased hierarchic score and increased developmental and rational scores. In the planned change team the hierarchical and group scores were increased. Learning as a team did not differ between the teams. CONCLUSIONS: In both teams there was a change in clinical autonomy and orientation towards nursing activities, in line with the experimental conditions. Emergent change implementation resulted in more clinical autonomy than planned change implementation. RELEVANCE TO CLINICAL PRACTICE: If an innovation requires the nurses to make their own clinical decisions, an emergent change implementation should help to establish this clinical autonomy. PMID- 26581547 TI - Phase II trial of dacomitinib in patients with HER2-positive gastric cancer. AB - BACKGROUND: Dacomitinib, an irreversible panHER inhibitor, shows significant preclinical antitumor activity in human epidermal growth factor receptor 2 (HER2) positive gastric cancer (GC). The aim of this study was to evaluate the clinical activity of dacomitinib and discover potential biomarkers in HER2-positive GC patients. METHODS: We enrolled previously treated advanced HER2-positive GC [HER2 FISH (+) or HER2 IHC 3+] patients. The patients received dacomitinib 45 mg once daily. RESULTS: A total of 27 patients were enrolled. The number of prior chemotherapy regimens was 1 in 7 patients (26 %), 2 in 9 patients (33 %), and more than 2 in 11 patients (41 %). Seven patients had received prior anti-HER2 therapy. The 4-month progression-free survival (PFS) rate was 22.2 % and median PFS was 2.1 months (95 % CI, 2.3-3.4) There were 2 partial response (PRs) and 9 stable disease (SDs), resulting in 7.4 % (95 % CI, 0-17.5 %) of response rate (RR) and 40.7 % (95 % CI, 21.9-59.6 %) of disease control rate (DCR). Eleven patients (41 %) showed some degree of tumor shrinkage. Overall survival was 7.1 months (95 % CI, 4.4-9.8). The most common toxicities were skin rash, diarrhea, and fatigue, most of which were grade 1 or 2. The Ctrough of dacomitinib was lower in gastrectomy patients than nongastrectomy patients. Higher serum levels of HER2 extracellular domain (ECD) and lower levels of soluble E-cadherin (sECAD) correlated with higher dacomitinib activity. CONCLUSIONS: Dacomitinib functions as a single agent in HER2-positive GC patients with a tolerable safety profile. HER2 ECD and sECAD have the potential to be biomarkers for patient selection in a panHER inhibition strategy for HER2-positive GC. (ClinicalTrials.gov: NCT01152853). PMID- 26581549 TI - Corrigendum. PMID- 26581546 TI - The clinical impact of recent advances in LC-MS for cancer biomarker discovery and verification. AB - Mass spectrometry (MS) -based proteomics has become an indispensable tool with broad applications in systems biology and biomedical research. With recent advances in liquid chromatography (LC) and MS instrumentation, LC-MS is making increasingly significant contributions to clinical applications, especially in the area of cancer biomarker discovery and verification. To overcome challenges associated with analyses of clinical samples (for example, a wide dynamic range of protein concentrations in bodily fluids and the need to perform high throughput and accurate quantification of candidate biomarker proteins), significant efforts have been devoted to improve the overall performance of LC-MS based clinical proteomics platforms. Reviewed here are the recent advances in LC MS and its applications in cancer biomarker discovery and quantification, along with the potentials, limitations and future perspectives. PMID- 26581548 TI - Mass-spectrometry-based quantitation of Her2 in gastroesophageal tumor tissue: comparison to IHC and FISH. AB - BACKGROUND: Trastuzumab has shown a survival benefit in cases of Her2-positive gastroesophageal cancer (GEC). Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) currently determine eligibility for trastuzumab-based therapy. However, these low-throughput assays often produce discordant or equivocal results. METHODS: We developed a targeted proteomic assay based on selected reaction monitoring mass spectrometry (SRM-MS) and quantified levels (amol/MUg) of Her2-SRM protein in cell lines (n = 27) and GEC tissues (n = 139). We compared Her2-SRM protein expression with IHC/FISH, seeking to determine optimal SRM protein expression cutoffs in order to identify HER2 gene amplification. RESULTS: After demonstrating assay development, precision, and stability, Her2-SRM protein measurement was observed to be highly concordant with the HER2/CEP17 ratio, particularly in a multivariate regression model adjusted for SRM expression of the covariates Met, Egfr, Her3, and HER2 heterogeneity, as well as their interactions (cell lines r (2) = 0.9842; FFPE r (2) = 0.7643). In GEC tissues, Her2-SRM protein was detected at any level in 71.2 % of cases. ROC curves demonstrated that Her2-SRM protein levels have a high specificity (100 %) at an upper-level cutoff of >750 amol/ug and sensitivity of 75 % at a lower-level cutoff of <450 amol/MUg for identifying HER2 FISH-amplified tumors. An "equivocal zone" of 450-750 amol/ug of Her2-SRM protein was analogous to IHC2+ but represented fewer cases (9-16 % of cases versus 36-41 %). CONCLUSIONS: Compared to IHC, targeted SRM-Her2 proteomics provided more objective and quantitative Her2 expression with excellent HER2/CEP17 FISH correlation and fewer equivocal cases. Along with its multiplex capability for other relevant oncoproteins, these results demonstrate a refined HER2 protein expression assay for clinical application. PMID- 26581550 TI - Dendritic cells and macrophages neurally hard-wired in the lymph node. AB - The neural hard-wired pathways in which the lymphoid organs are innervated by the nervous system is of special interest with respect to suggested afferent and sensory systems informing the central nervous system about the status of the immune system. Until today efferent also like afferent innervation seem to be unspecific, targeting many types of cells by affecting many cells at the same time. We for the first time show that antigen presenting cells (APC) are abundantly innervated in the T-cell enriched area, the subsinoidal layer and the cortical extrafollicular zone of lymph nodes in rats by a mesh of filamentous neurofilament positive structures originating from single nerve fibers and covering each single APC similar to a glass fishing float, so that we termed them "wired" APC (wAPC). These wAPC also found in humans seem to be restricted to the cell body, not to follow membranous extensions, they may be dynamic and receptive as MAP2 is expressed and axonal growth cones can be detected and they probably lack vesicular activity through missing synaptophysin expression. The specific innervation targeting single cells which show a distribution divided in several areas in one lymph node suggests a form of topographically organized afferent sensory system. PMID- 26581552 TI - Erratum. PMID- 26581551 TI - The Diversity of Biosimilar Design and Development: Implications for Policies and Stakeholders. AB - Biosimilars are required to be similar or highly similar in structure to their biologic reference product but are neither expected nor required to contain identical active substances. For example, glycosylated biosimilars approved to date demonstrate quantitative and qualitative structural differences from their reference product and exemplify the latitude of variations permitted for biosimilars. Although differences between a candidate biosimilar and its reference product will be evaluated for differential clinical effects during biosimilarity assessment, it is unlikely that potential differences between any two indirectly related biosimilars will be formally evaluated. Furthermore, biosimilar pathways permit variations in pharmaceutical attributes, clinical development approaches, and regulatory outcomes, resulting in further diversity of attributes among approved biosimilars. Because biosimilars may vary across the ranges of structural and functional acceptance criteria, they should not be treated like multisource, generic drugs. PMID- 26581553 TI - Opinions on the Legitimacy of Brain Death Among Sunni and Shi'a Scholars. AB - The concept of brain death poses a great challenge to clinicians who may be required to bridge the interface of culture, religion, law, and medicine. This review discusses and applies Islamic jurisprudence to the question of whether brain death is accepted as true death under Islamic law. Among the five sources of Islamic law, the Qur'an and Sunnah do not directly address brain death. Scholarly consensus (Ijma') does not exist, and Qiya does not apply. When applying Ijtihad, the identified collection of non-binding fatwa offer conflicting results. Debate continues as to the validity of brain-death criteria within Islamic circles. PMID- 26581554 TI - Automated Perimetry and Visual Dysfunction in Blast-Related Traumatic Brain Injury. AB - PURPOSE: To evaluate feasibility and results of automated perimetry in veterans with combat blast neurotrauma. DESIGN: Prospective, longitudinal, observational case series. PARTICIPANTS: Sixty-one patients in a Veterans Affairs Polytrauma Center diagnosed with traumatic brain injury (TBI) from combat blast exposure. METHODS: Study participants underwent automated perimetry at baseline (median interval, 2 months after injury) (Humphrey Field Analyzer, Carl Zeiss Meditec, Dublin, CA, Swedish Interactive Threshold Algorithm 30-2 Standard or Fast), and 36 of them were followed up (median interval, 10 months after baseline). Presence of significant mean deviation and pattern standard deviation was determined for testing with reliability indices <=20% for fixation loss, 15% for false positives, and 33% for false-negatives. Test-retest stability of global visual field indices was assessed for tests with these cutoffs or with elevated fixation loss. Associations between global visual field defects and predictors were examined. MAIN OUTCOME MEASURES: Global visual field indices (mean deviation and pattern standard deviation). RESULTS: Among 61 study participants (109 study eyes) with baseline testing, a field that met reliability cutoffs was obtained for 48 participants (79%) and 78 eyes (72%). Fixation loss was found in 29% of eyes in initial testing. Nine study participants (15%) demonstrated hemianopia or quadrantanopia, and an additional 36% had an abnormal global visual field index. Global indices were relatively stable at follow-up testing for tests meeting fixation-loss cutoffs and tests that did not. Visual scotomas due to post chiasmal lesions were associated with moderate to severe TBI or penetrating head injury, but other visual field deficits were prevalent across the range of mild to severe TBI. Ocular injury to the retina or choroid, poorer visual acuity, and pupillary defect were associated with visual field defects. Participants with depressed visual field sensitivity reported lower visual quality of life. CONCLUSIONS: Reliable automated perimetry can be accomplished in most patients with TBI from combat blast exposure and reveals high rates of visual field deficits, indicating that blast forces may significantly affect the eye and visual pathways. PMID- 26581555 TI - Subepidermal Calcified Nodule in the Periocular Region: A Report of 6 Cases. PMID- 26581556 TI - Primary Open-Angle Glaucoma Preferred Practice Pattern((r)) Guidelines. AB - PRIMARY OPEN-ANGLE GLAUCOMA PREFERRED PRACTICE PATTERN(r) GUIDELINES: Evidence based update of the Primary Open-Angle Glaucoma Preferred Practice Pattern(r) (PPP) guidelines, describing the diagnosis and management of patients with primary open-angle glaucoma with an algorithm for patient management and detailed recommendations for evaluation and treatment options. PMID- 26581557 TI - Primary Angle Closure Preferred Practice Pattern((r)) Guidelines. AB - PRIMARY ANGLE CLOSURE PREFERRED PRACTICE PATTERN(r) GUIDELINES: Evidence-based update of the Primary Angle Closure Preferred Practice Pattern(r) (PPP) guidelines, describing the diagnosis and management of patients with primary angle closure with detailed recommendations for evaluation and treatment options. PMID- 26581558 TI - Comprehensive Adult Medical Eye Evaluation Preferred Practice Pattern((r)) Guidelines. AB - COMPREHENSIVE ADULT MEDICAL EYE EVALUATION(r) PREFERRED PRACTICE PATTERN(r) GUIDELINES: Evidence-based update of the Comprehensive Adult Medical Eye Evaluation Preferred Practice Pattern(r) (PPP) guidelines, discussing the rationale and components of an ophthalmic evaluation for adult patients with and without risk factors. PMID- 26581559 TI - Retinal Vein Occlusions Preferred Practice Pattern((r)) Guidelines. AB - RETINAL VEIN OCCLUSIONS PREFERRED PRACTICE PATTERN(r) GUIDELINES: New evidence based Retinal Vein Occlusions Preferred Practice Pattern(r) (PPP) guidelines, discussing the prognosis and risk factors of retinal vein occlusions and the treatment options. PMID- 26581560 TI - Primary Open-Angle Glaucoma Suspect Preferred Practice Pattern((r)) Guidelines. AB - PRIMARY OPEN-ANGLE GLAUCOMA SUSPECT PREFERRED PRACTICE PATTERN(r) GUIDELINES: Evidence-based update of the Primary Open-Angle Suspect Glaucoma Preferred Practice Pattern(r) (PPP) guidelines, describing the diagnosis and management of patients with primary open-angle glaucoma suspect with detailed recommendations for evaluation and treatment options. PMID- 26581561 TI - Identification of putative substrates for cynomolgus monkey cytochrome P450 2C8 by substrate depletion assays with 22 human P450 substrates and inhibitors. AB - Cynomolgus monkeys are widely used in drug developmental stages as non-human primate models. Previous studies used 89 compounds to investigate species differences associated with cytochrome P450 (P450 or CYP) function that reported monkey specific CYP2C76 cleared 19 chemicals, and homologous CYP2C9 and CYP2C19 metabolized 17 and 30 human CYP2C9 and/or CYP2C19 substrates/inhibitors, respectively. In the present study, 22 compounds selected from viewpoints of global drug interaction guidances and guidelines were further evaluated to seek potential substrates for monkey CYP2C8, which is highly homologous to human CYP2C8 (92%). Amodiaquine, montelukast, quercetin and rosiglitazone, known as substrates or competitive inhibitors of human CYP2C8, were metabolically depleted by recombinant monkey CYP2C8 at relatively high rates. Taken together with our reported findings of the slow eliminations of amodiaquine and montelukast by monkey CYP2C9, CYP2C19 and CYP2C76, the present results suggest that these at least four chemicals may be good marker substrates for monkey CYP2C8. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26581562 TI - Application of geographically-weighted regression analysis to assess risk factors for malaria hotspots in Keur Soce health and demographic surveillance site. AB - BACKGROUND: In Senegal, considerable efforts have been made to reduce malaria morbidity and mortality during the last decade. This resulted in a marked decrease of malaria cases. With the decline of malaria cases, transmission has become sparse in most Senegalese health districts. This study investigated malaria hotspots in Keur Soce sites by using geographically-weighted regression. Because of the occurrence of hotspots, spatial modelling of malaria cases could have a considerable effect in disease surveillance. METHODS: This study explored and analysed the spatial relationships between malaria occurrence and socio economic and environmental factors in small communities in Keur Soce, Senegal, using 6 months passive surveillance. Geographically-weighted regression was used to explore the spatial variability of relationships between malaria incidence or persistence and the selected socio-economic, and human predictors. A model comparison of between ordinary least square and geographically-weighted regression was also explored. Vector dataset (spatial) of the study area by village levels and statistical data (non-spatial) on malaria confirmed cases, socio-economic status (bed net use), population data (size of the household) and environmental factors (temperature, rain fall) were used in this exploratory analysis. ArcMap 10.2 and Stata 11 were used to perform malaria hotspots analysis. RESULTS: From Jun to December, a total of 408 confirmed malaria cases were notified. The explanatory variables-household size, housing materials, sleeping rooms, sheep and distance to breeding site returned significant t values of -0.25, 2.3, 4.39, 1.25 and 2.36, respectively. The OLS global model revealed that it explained about 70 % (adjusted R(2) = 0.70) of the variation in malaria occurrence with AIC = 756.23. The geographically-weighted regression of malaria hotspots resulted in coefficient intercept ranging from 1.89 to 6.22 with a median of 3.5. Large positive values are distributed mainly in the southeast of the district where hotspots are more accurate while low values are mainly found in the centre and in the north. CONCLUSION: Geographically-weighted regression and OLS showed important risks factors of malaria hotspots in Keur Soce. The outputs of such models can be a useful tool to understand occurrence of malaria hotspots in Senegal. An understanding of geographical variation and determination of the core areas of the disease may provide an explanation regarding possible proximal and distal contributors to malaria elimination in Senegal. PMID- 26581563 TI - Asthma is a risk factor for new onset chronic migraine: Results from the American migraine prevalence and prevention study. AB - OBJECTIVES: To test the hypothesis that in persons with episodic migraine (EM), asthma is a risk factor for the onset of chronic migraine (CM). BACKGROUND: Migraine and asthma are comorbid chronic disorders with episodic attacks thought to involve inflammatory and neurological mechanisms. Herein, we assess the influence of asthma on the clinical course of EM. METHODS: To be eligible for this observational cohort study, AMPP Study participants had to meet criteria for EM in 2008, complete the validated six-item asthma questionnaire from the European Community Respiratory Health Survey (ECRHS) in 2008, and provide follow up data in 2009. Using the ECRHS, we defined asthma as a binary variable (present or absent) based on an empirical cut score and developed a Respiratory Symptom Severity Score (RSSS) based on the number of positive responses (no severity = 0 positive responses, low severity = 1-2 positive responses, moderate severity = 3 4 positive responses, high severity = 5-6 positive responses). Chronic migraine was the primary outcome measure and was defined as those with >=15 headache days per month on the 2009 AMPP Study survey. We used logistic regression in separate models to assess the influence of asthma as a binary variable (Model 1) and RSSS score categories (Model 2 using no respiratory symptoms as the reference) on CM onset after adjusting for sociodemographic factors, headache day frequency, migraine preventive medication use, and medication overuse. RESULTS: The eligible sample for this study included 4446 individuals with EM in 2008 of whom 17% had asthma. This group had a mean age of 50.4 and was 80.8% female. In 2009, new onset CM developed in 2.9% (131/4446) of the 2008 EM cohort, including 5.4% (40/746) of the asthma subgroup and 2.5% (91/3700) of the non-asthma subgroup. In comparison to those without asthma, the adjusted odds for individuals with asthma and EM in 2008 to develop CM in 2009 were greater than two (adjusted odds ratio [aOR] 2.1; 95% CI: 1.4-3.1). Using the RSSS, the aOR for CM onset increased with the number of asthma symptoms, but only those in the high RSSS category showed a statistically significant increase in the odds of chronic migraine onset in comparison with the no RSSS reference group (aOR 3.3; 95% CI 1.7-6.2). CONCLUSIONS: Asthma is associated with an increased risk of new onset CM 1 year later among individuals with EM, with the highest risk being among those with the greatest number of respiratory symptoms. The exact mechanisms underlying this association are unknown, but could suggest mast cell degranulation, autonomic dysfunction, or shared genetic or environmental factors. PMID- 26581564 TI - Using genomics to combat infectious diseases on a global scale. AB - A report on the seventh annual Infectious Disease Genomics Conference, held in Hinxton, Cambridge, UK, 14-16 October 2015. PMID- 26581565 TI - A simple, rapid, and efficient method for isolating detrusor for the culture of bladder smooth muscle cells. AB - PURPOSE: To establish a simple and rapid method to remove serosa and mucosa from detrusor for the culture of bladder smooth muscle cells (SMCs). METHODS: Fourteen New Zealand rabbits were randomly allocated to two groups. In the first group, pure bladder detrusor was directly obtained from bladder wall using novel method characterized by subserous injection of normal saline. In the second group, full thickness bladder wall sample was cut down, and then, mucosa and serosa were trimmed off detrusor ex vivo. Twelve detrusor samples from two groups were manually minced and enzymatically digested, respectively, to form dissociated cells whose livability was detected by trypan blue exclusion. Proliferative ability of primary culture cells was detected by CCK-8 kit, and purity of second passage SMCs was detected by flow cytometric analyses. Another two detrusor samples from two groups were used for histological examination. RESULTS: Subserous injection of normal saline combined with blunt dissection can remove mucosa and serosa from detrusor layer easily and quickly. Statistical analysis revealed the first group possessed higher cell livability, shorter primary culture cell doubling time, and higher purity of SMCs than the second group (P < 0.05). Histological examination confirmed no serosa and mucosa existed on the surface of detrusor obtained by novel method, while serosa or mucosa residual can be found on the surface of detrusor obtained by traditional method. CONCLUSION: Pure detrusor can be acquired from bladder wall conveniently using novel method. This novel method brought about significantly higher purity and cell livability as compared to traditional method. PMID- 26581566 TI - The impact of slow graft function on graft outcome is comparable to delayed graft function in deceased donor kidney transplantation. AB - PURPOSE: Slow graft function (SGF) can influence overall prognosis in patients receiving deceased donor kidney transplantation (DKT). However, the impact of SGF on renal function remains uncertain. We investigated retrospectively renal function in cases with SGF compared with early graft function (EGF) and delayed graft function (DGF). METHODS: Renal function after transplantation was analyzed in 199 patients who underwent DKT. Patients were classified into 130 (65.3 %) cases with EGF, 27 (13.6 %) cases with SGF, 6 (3.0 %) cases with DGF and one dialysis (DGF1), and 36 (18.1 %) cases with DGF and two or more dialyses (DGF2). RESULTS: The 1-year estimated glomerular filtration rate (eGFR) in the SGF group was lower than that in the EGF group (P = 0.027), but the rate of eGFR decline did not differ between the groups. The risk factors for renal function were evaluated using the area under the eGFR curve over 3 years (AUCeGFR). Donor age was negatively, and recipient age and the number of HLA matches were positively correlated with the AUCeGFR (all P < 0.05). A multivariate analysis revealed that the AUCeGFR was lower in cases of younger recipient age, older donor age, and acute rejection (all P < 0.05). The AUCeGFR was significantly lower in the SGF and DGF2 groups compared with the EGF group (P = 0.031 and 0.006, respectively). CONCLUSIONS: SGF may be an independent risk factor for poor renal function after DKT. Moreover, it was comparable to DGF. Efforts should be dedicated to minimizing the development of SGF and DGF. PMID- 26581567 TI - Self-Reported Sexual Behavioral Interests and Polymorphisms in the Dopamine Receptor D4 (DRD4) Exon III VNTR in Heterosexual Young Adults. AB - Polymorphisms in the dopamine D4 receptor (DRD4) have previously been shown to associate with a variety of human behavioral phenotypes, including ADHD pathology, alcohol and tobacco craving, financial risk-taking in males, and broader personality traits such as novelty seeking. Recent research has linked the presence of a 7-repeat (7R) allele in a 48-bp variable number of tandem repeats (VNTR) along exon III of DRD4 to age at first sexual intercourse, sexual desire, arousal and function, and infidelity and promiscuity. We hypothesized that carriers of longer DRD4 alleles may report interest in a wider variety of sexual behaviors and experiences than noncarriers. Participants completed a 37 item questionnaire measuring sexual interests as well as Cloninger's Temperament and Character Inventory, and were genotyped for the 48-bp VNTR on exon III of DRD4. Based on our final genotyped sample of female (n = 139) and male (n = 115) participants, we found that 7R carriers reported interest in a wider variety of sexual behaviors (r = 0.16) within a young adult heterosexual sample of European descent. To our knowledge, this is the first reported association between DRD4 exon III VNTR genotype and interest in a variety of sexual behaviors. We discuss these findings within the context of DRD4 research and broader trends in human evolutionary history. PMID- 26581568 TI - Sexual Contact in Childhood, Revictimization, and Lifetime Sexual and Psychological Outcomes. AB - Using data from the 2010 to 2011 wave of the National Social Life, Health, and Aging Project-a nationally representative probability sample of older U.S. adults this study queried distinctive linkages of mild and of severe childhood sexual contact with lifetime sexual and psychological outcomes among women and men aged 60-99 years (N = 3283). In addition, we examined stratification of these associations by sexual revictimization (forced sex and/or harassment). Among women, sequelae of childhood contact seemed consistently negative for the mild rather than severe variant-but only in the co-presence of revictimization-a pattern that may have remained obscured in previous analysis of event effects. Men's results suggested lifelong eroticizing but not psychological effects of this early experience-with the co-presence of revictimization potentially enhancing rather than lowering their mental health. Overall, findings appeared to reflect gendered patterns of risk-with mild childhood contact potentially channeling women but not men into revictimization and finally to elevated sexuality and poor mental health in late life. Early sexual experiences should thus be conceptualized not as singular events, but as part of a lifelong career with regularities and rhythms that may influence their pathogenic potential. PMID- 26581569 TI - Mucinous cystic tumor with CK20 and CDX2 expression of the thymus: Is this a benign counterpart of adenocarcinoma of the thymus, enteric type? AB - Primary thymic adenocarcinoma is extremely rare. Moreover, thymic pure epithelial benign neoplasms are extremely rare. We encountered a cystic tumor almost purely composed of goblet cell-like mucus-producing cells of the thymus. A mass lesion of the mediastinum was detected in a 54-year-old man. The gross specimen presented a unilocular cystic lesion containing abundant mucin, measuring 8 * 5.5 * 4.5 cm. Microscopic examination revealed a cystic tumor consisting of bland mucus-producing cells resembling goblet cells and forming tiny daughter cysts within the dense fibrous capsule. No destructive growth or infiltration into surrounding thymic tissue was observed. Papillary growth was found in a small focus. Immunohistochemically, tumor cells were positive for cytokeratin 20 and caudal type homobox 2, which are representative markers of enteric differentiation. The patient has been well without any recurrence for approximately ten years after the operation. Thus, the tumor should be regarded as a mucinous cystic tumor in the thymus. Very recently, thymic adenocarcinoma with enteric differentiation was proposed as a novel subtype of thymic carcinoma. This case could be regarded as a benign counterpart of adenocarcinoma of the thymus, enteric type. A further follow-up study is required to confirm the exact biological behavior of this tumor. PMID- 26581570 TI - A homozygous HOXD13 missense mutation causes a severe form of synpolydactyly with metacarpal to carpal transformation. AB - Synpolydactyly (SPD) is a rare congenital limb disorder characterized by syndactyly between the third and fourth fingers and an additional digit in the syndactylous web. In most cases SPD is caused by heterozygous mutations in HOXD13 resulting in the expansion of a N-terminal polyalanine tract. If homozygous, the mutation results in severe shortening of all metacarpals and phalanges with a morphological transformation of metacarpals to carpals. Here, we describe a novel homozygous missense mutation in a family with unaffected consanguineous parents and severe brachydactyly and metacarpal-to-carpal transformation in the affected child. We performed whole exome sequencing on the index patient, followed by Sanger sequencing of parents and patient to investigate cosegregation. The DNA binding ability of the mutant protein was tested with electrophoretic mobility shift assays. We demonstrate that the c.938C>G (p.313T>R) mutation in the DNA binding domain of HOXD13 prevents binding to DNA in vitro. Our results show to our knowledge for the first time that a missense mutation in HOXD13 underlies severe brachydactyly with metacarpal-to-carpal transformation. The mutation is non-penetrant in heterozygous carriers. In conjunction with the literature we propose the possibility that the metacarpal-to-carpal transformation results from a homozygous loss of functional HOXD13 protein in humans in combination with an accumulation of non-functional HOXD13 that might be able to interact with other transcription factors in the developing limb. PMID- 26581571 TI - Conundrum of IP6. AB - Here are comments on the recent paper on the determination of inositol hexaphosphate (IP6) in human plasma and on its efficacy. PMID- 26581572 TI - Import of proteins into peroxisomes: piggybacking to a new home away from home. AB - Peroxisomes are capable of importing folded and oligomeric proteins. However, it is a matter of dispute whether oligomer import by peroxisomes is the exception or the rule. Here, I argue for a clear distinction between homo-oligomeric proteins that are essentially peroxisomal, and dually localized hetero-oligomers that access the peroxisome by piggyback import, localizing there in limited number, whereas the majority remain in the cytosol. Homo-oligomeric proteins comprise the majority of all peroxisomal matrix proteins. There is evidence that binding by Pex5 in the cytosol can regulate their oligomerization state before import. The hetero-oligomer group is made up of superoxide dismutase and lactate dehydrogenase. These proteins have evolved mechanisms that render import inefficient and retain the majority of proteins in the cytosol. PMID- 26581573 TI - There is no 'Conundrum' of InsP6. AB - Indirect assays have claimed to quantify phytate (InsP6) levels in human biofluids, but these have been based on the initial assumption that InsP6 is there, an assumption that our more direct assays disprove. We have shown that InsP6 does not and cannot (because of the presence of an active InsP6 phosphatase in serum) exist in mammalian serum or urine. Therefore, any physiological effects of dietary InsP6 can only be due either to its actions in the gut as a polyvalent cation chelator, or to inositol generated by its dephosphorylation by gut microflora. PMID- 26581575 TI - MethylRAD: a simple and scalable method for genome-wide DNA methylation profiling using methylation-dependent restriction enzymes. AB - Characterization of dynamic DNA methylomes in diverse phylogenetic groups has attracted growing interest for a better understanding of the evolution of DNA methylation as well as its function and biological significance in eukaryotes. Sequencing-based methods are promising in fulfilling this task. However, none of the currently available methods offers the 'perfect solution', and they have limitations that prevent their application in the less studied phylogenetic groups. The recently discovered Mrr-like enzymes are appealing for new method development, owing to their ability to collect 32-bp methylated DNA fragments from the whole genome for high-throughput sequencing. Here, we have developed a simple and scalable DNA methylation profiling method (called MethylRAD) using Mrr like enzymes. MethylRAD allows for de novo (reference-free) methylation analysis, extremely low DNA input (e.g. 1 ng) and adjustment of tag density, all of which are still unattainable for most widely used methylation profiling methods such as RRBS and MeDIP. We performed extensive analyses to validate the power and accuracy of our method in both model (plant Arabidopsis thaliana) and non-model (scallop Patinopecten yessoensis) species. We further demonstrated its great utility in identification of a gene (LPCAT1) that is potentially crucial for carotenoid accumulation in scallop adductor muscle. MethylRAD has several advantages over existing tools and fills a void in the current epigenomic toolkit by providing a universal tool that can be used for diverse research applications, e.g. from model to non-model species, from ordinary to precious samples and from small to large genomes, but at an affordable cost. PMID- 26581574 TI - Regulation of lamin properties and functions: does phosphorylation do it all? AB - The main functions of lamins are their mechanical and structural roles as major building blocks of the karyoskeleton. They are also involved in chromatin structure regulation, gene expression, intracellular signalling pathway modulation and development. All essential lamin functions seem to depend on their capacity for assembly or disassembly after the receipt of specific signals, and after specific, selective and precisely regulated interactions through their various domains. Reversible phosphorylation of lamins is crucial for their functions, so it is important to understand how lamin polymerization and interactions are modulated, and which sequences may undergo such modifications. This review combines experimental data with results of our in silico analyses focused on lamin phosphorylation in model organisms to show the presence of evolutionarily conserved sequences and to indicate specific in vivo phosphorylations that affect particular functions. PMID- 26581576 TI - The RZZ complex requires the N-terminus of KNL1 to mediate optimal Mad1 kinetochore localization in human cells. AB - The spindle assembly checkpoint is a surveillance mechanism that blocks anaphase onset until all chromosomes are properly attached to microtubules of the mitotic spindle. Checkpoint activity requires kinetochore localization of Mad1/Mad2 to inhibit activation of the anaphase promoting complex/cyclosome in the presence of unattached kinetochores. In budding yeast and Caenorhabditis elegans, Bub1, recruited to kinetochores through KNL1, recruits Mad1/Mad2 by direct linkage with Mad1. However, in human cells it is not yet established which kinetochore protein(s) function as the Mad1/Mad2 receptor. Both Bub1 and the RZZ complex have been implicated in Mad1/Mad2 kinetochore recruitment; however, their specific roles remain unclear. Here, we investigate the contributions of Bub1, RZZ and KNL1 to Mad1/Mad2 kinetochore recruitment. We find that the RZZ complex localizes to the N-terminus of KNL1, downstream of Bub1, to mediate robust Mad1/Mad2 kinetochore localization. Our data also point to the existence of a KNL1-, Bub1 independent mechanism for RZZ and Mad1/Mad2 kinetochore recruitment. Based on our results, we propose that in humans, the primary mediator for Mad1/Mad2 kinetochore localization is the RZZ complex. PMID- 26581578 TI - Ultrasound-guided synovial biopsy. AB - Ultrasound-guided needle biopsy of synovium is an increasingly performed procedure with a high diagnostic yield. In this review, we discuss the normal synovium, as well as the indications, technique, tissue handling and clinical applications of ultrasound-guided synovial biopsy. PMID- 26581577 TI - Proposal of supervised data analysis strategy of plasma miRNAs from hybridisation array data with an application to assess hemolysis-related deregulation. AB - BACKGROUND: Plasma miRNAs have the potential as cancer biomarkers but no consolidated guidelines for data mining in this field are available. The purpose of the study was to apply a supervised data analysis strategy in a context where prior knowledge is available, i.e., that of hemolysis-related miRNAs deregulation, so as to compare our results with existing evidence. RESULTS: We developed a structured strategy with innovative applications of existing bioinformatics methods for supervised analyses including: 1) the combination of two statistical (t- and Anderson-Darling) test results to detect miRNAs with significant fold change or general distributional differences in class comparison, which could reveal hidden differential biological processes worth to be considered for building predictive tools; 2) a bootstrap selection procedure together with machine learning techniques in class prediction to guarantee the transferability of results and explore the interconnections among the selected miRNAs, which is important for highlighting their inherent biological dependences. The strategy was applied to develop a classifier for discriminating between hemolyzed and not hemolyzed plasma samples, defined according to a recently published hemolysis score. We identified five miRNAs with increased expression in hemolyzed plasma samples (miR-486-5p, miR-92a, miR-451, miR-16, miR 22). CONCLUSIONS: We identified four miRNAs previously reported in the literature as hemolysis related together with a new one (miR-22).which needs further investigations. Our findings confirm the validity of the proposed strategy and, in parallel, the hemolysis score capability to be used as pre-analytic hemolysis detector. R codes for implementing the approaches are provided. PMID- 26581579 TI - Genome analysis of Daldinia eschscholtzii strains UM 1400 and UM 1020, wood decaying fungi isolated from human hosts. AB - BACKGROUND: Daldinia eschscholtzii is a wood-inhabiting fungus that causes wood decay under certain conditions. It has a broad host range and produces a large repertoire of potentially bioactive compounds. However, there is no extensive genome analysis on this fungal species. RESULTS: Two fungal isolates (UM 1400 and UM 1020) from human specimens were identified as Daldinia eschscholtzii by morphological features and ITS-based phylogenetic analysis. Both genomes were similar in size with 10,822 predicted genes in UM 1400 (35.8 Mb) and 11,120 predicted genes in UM 1020 (35.5 Mb). A total of 751 gene families were shared among both UM isolates, including gene families associated with fungus-host interactions. In the CAZyme comparative analysis, both genomes were found to contain arrays of CAZyme related to plant cell wall degradation. Genes encoding secreted peptidases were found in the genomes, which encode for the peptidases involved in the degradation of structural proteins in plant cell wall. In addition, arrays of secondary metabolite backbone genes were identified in both genomes, indicating of their potential to produce bioactive secondary metabolites. Both genomes also contained an abundance of gene encoding signaling components, with three proposed MAPK cascades involved in cell wall integrity, osmoregulation, and mating/filamentation. Besides genomic evidence for degrading capability, both isolates also harbored an array of genes encoding stress response proteins that are potentially significant for adaptation to living in the hostile environments. CONCLUSIONS: Our genomic studies provide further information for the biological understanding of the D. eschscholtzii and suggest that these wood-decaying fungi are also equipped for adaptation to adverse environments in the human host. PMID- 26581580 TI - Vulvar and vaginal atrophy in four European countries: evidence from the European REVIVE Survey. AB - OBJECTIVES: The aim of the European REVIVE survey was to achieve a better understanding of vulvovaginal atrophy (VVA), a chronic and progressive condition after menopause. We investigated perceptions, experiences and needs in terms of sexual and vaginal health in a sample of European postmenopausal women. METHODS: An online internet based survey was conducted in Italy, Germany, Spain and the UK with a total surveyed sample of 3768 postmenopausal women (age: 45-75 years). RESULTS: The most common VVA symptom was vaginal dryness (70%). VVA has a significant impact on the ability to be intimate (62%), to enjoy sexual intercourse (72%) and to feel sexual spontaneity (66%). Postmenopausal women with VVA are sexually active (51%), but their sexual drive is reduced. Health-care professionals (HCPs) have discussed VVA with postmenopausal women (62%), but they initiated the conversation only in 10% of the cases. The most common treatments for VVA are over-the-counter, non-hormonal, local vaginal products. Thirty-two per cent of postmenopausal women were naive to any kind of treatment, whereas discussion with the HCP was relevant to be on current treatment (60% of postmenopausal women that discussed VVA with a HCP vs. 23% who did not). The top reasons for poor compliance with vaginal treatments were: not bothersome enough symptoms (18%); vaginal changes not therapeutically reversed (18%); relief from VVA symptoms (17%). Approximately 45% were satisfied with treatment. The most frequent disliked aspects of treatment were the route of administration or the messiness. The fear of hormones was common in postmenopausal women using vaginal prescription products. CONCLUSIONS: The European REVIVE survey confirmed that VVA symptoms are frequent in postmenopausal women and demonstrates a significant impact on quality of life and sexual life. However, the condition is still under diagnosed and under-treated, with a high rate of dissatisfaction for actual available treatments in the four European countries surveyed. The discussion of symptoms with HCPs seems the most critical factor for diagnosis and treatment of VVA. PMID- 26581582 TI - Effect of COD/TP ratio on biological nutrient removal in A2O and SBR processes coupled with microfiltration and effluent reuse potential. AB - Two bench-scale hybrid processes, anaerobic/anoxic/oxic (A(2)O) reactor and sequencing batch reactor (SBR), each followed by the microfiltration (MF) system, were simultaneously operated to compare their performances on the removal of organics and phosphorus from both synthetic and real wastewater to further explore the potential for effluent reuse. The effects of different influent chemical oxygen demand (COD) to total phosphorus (TP) ratios (27, 50, 80, and 200) were investigated. For both processes, when the influent COD/TP ratio was 200, the effluent quality was satisfactory for some reuse potential. The MF membrane system showed an evident further removal of COD (20-89%) and color (18 60%), especially the removal of suspended solids (SS) and turbidity with the final effluent SS <1 mg/L and turbidity <0.1 NTU. When real wastewater was tested, the effluent quality was adequate and met the standard goals for regional reuse purposes. PMID- 26581581 TI - Endogenous IFN-beta signaling exerts anti-inflammatory actions in experimentally induced focal cerebral ischemia. AB - BACKGROUND: Interferon (IFN)-beta exerts anti-inflammatory effects, coupled to remarkable neurological improvements in multiple sclerosis, a neuroinflammatory condition of the central nervous system. Analogously, it has been hypothesized that IFN-beta, by limiting inflammation, decreases neuronal death and promotes functional recovery after stroke. However, the core actions of endogenous IFN beta signaling in stroke are unclear. METHODS: To address this question, we used two clinically relevant models of focal cerebral ischemia, transient and permanent middle cerebral artery occlusion, and two genetically modified mouse lines, lacking either IFN-beta or its receptor, the IFN-alpha/beta receptor. Subsets of inflammatory and immune cells isolated from the brain, blood, and spleen were studied using flow cytometry. Sensorimotor deficits were assessed by a modified composite neuroscore, the rotating pole and grip strength tests, and cerebral infarct volumes were given by lack of neuronal nuclei immunoreactivity. RESULTS: Here, we report alterations in local and systemic inflammation in IFN beta knockout (IFN-betaKO) mice over 8 days after induction of focal cerebral ischemia. Notably, IFN-betaKO mice showed a higher number of infiltrating leukocytes in the brain 2 days after stroke. Concomitantly, in the blood of IFN betaKO mice, we found a higher percentage of total B cells but a similar percentage of mature and activated B cells, collectively indicating a higher proliferation rate. The additional differential regulation of circulating cytokines and splenic immune cell populations in wild-type and IFN-betaKO mice further supports an important immunoregulatory function of IFN-beta in stroke. Moreover, we observed a significant weight loss 2-3 days and a reduction in grip strength 2 days after stroke in the IFN-betaKO group, while endogenous IFN-beta signaling did not affect the infarct volume. CONCLUSIONS: We conclude that endogenous IFN-beta signaling attenuates local inflammation, regulates peripheral immune cells, and, thereby, may contribute positively to stroke outcome. PMID- 26581583 TI - Pyrimidine-2-carboxylic Acid as an Electron-Accepting and Anchoring Group for Dye Sensitized Solar Cells. AB - We report a new dye (INPA) adopting pyrimidine-2-carboxylic acid as an electron accepting and anchoring group to be used in dye-sensitized solar cells. IR spectral analysis indicates that the anchoring group may form two coordination bonds with TiO2 and so facilitate the interaction between the anchoring group and TiO2. The INPA-based cell exhibits an overall conversion efficiency of 5.45%, which is considerably higher than that obtained with cyanoacrylic acid commonly used as the electron acceptor. PMID- 26581584 TI - Patients with normocalcemic primary hyperparathyroidism may have similar metabolic profile as hypercalcemic patients. AB - Primary hyperparathyroidism is well known to be associated with cardiovascular morbidity and mortality. However, it is unclear whether normocalcemic primary hyperparathyroidism (NC-PHPT) and hypercalcemic primary hyperparathyroidism (HC PHPT) share the same risk factors. We aimed to determine prevalence of metabolic syndrome in NC-PHPT and compare metabolic syndrome parameters and insulin resistance in NC-PHPT subjects with those in HC-PHPT and control subjects. After excluding patients with secondary hyperparathyroidism, the study enrolled 25 patients with NC-PHPT, 24 patients with HC-PHPT and 30 age-gender matched controls. All participants were evaluated using the International Diabetes Federation (IDF)-2006 metabolic syndrome criteria. Compared with HC-PHPT patients, NC-PHPT patients had similar prevalence of metabolic syndrome, glucose intolerance, and previous history of hypertension/anti-hypertensive medications, but compared with controls, NC-PHPT patients had significantly higher prevalence of glucose intolerance and previous history of hypertension/anti-hypertensive medications. Not serum calcium but PTH concentration was found to be significantly higher in those with glucose intolerance. Serum fasting triglyceride concentration and waist circumference were found to be positively correlated only with serum PTH concentration. In conclusion, patients with NC PHPT may be prone to similar metabolic disturbances linked to higher cardiovascular risk like patients with HC-PHPT. Although NC-PHPT is thought to occur early in the development of the classical disease, it should be monitored regularly because of its metabolic consequences. PMID- 26581585 TI - Highly Oxygenated Sesquiterpene Lactones from Cousinia aitchisonii and their Cytotoxic Properties: Rhaserolide Induces Apoptosis in Human T Lymphocyte (Jurkat) Cells via the Activation of c-Jun n-terminal Kinase Phosphorylation. AB - Infrared-guided chromatographic fractionation of sesquiterpene lactones from the extracts of Cousinia aitchisonii and Cousinia concolor led to the isolation of five pure compounds. A new sesquiterpene lactone, namely, aitchisonolide, and two known sesquiterpene lactones (desoxyjanerin and rhaserolide) were isolated from C. aitchisonii and two known lignans (arctiin and arctigenin) from C. concolor. The structures of these compounds were elucidated by one-dimensional and two dimensional nuclear magnetic resonance techniques, as well as high-resolution mass spectrometry. The purified and characterized compounds were subjected to cytotoxicity assay. The sesquiterpene lactones desoxyjanerin and rhaserolide showed significant cytotoxic activities against five different cancer cell lines and the normal human embryonic kidney cell line. Rhaserolide was chosen to evaluate the possible mechanism of action. Western blot analysis revealed that rhaserolide could induce apoptosis in Jurkat cells via the activation of c-Jun n terminal kinase phosphorylation. PMID- 26581586 TI - Pharmacotherapeutic options for treating adverse effects of Cisplatin chemotherapy. AB - INTRODUCTION: Cisplatin is widely used in the treatment of several tumors such as lung, ovarian and testicular cancer with different degrees of effectiveness, and its use is burdened by some side effects. AREAS COVERED: This review includes the most important cisplatin side effects such as neurotoxicity, nephrotoxicity, ototoxicity, nausea and vomiting. They can affect patient's quality of life and lead to treatment interruptions with effectiveness reduction. EXPERT OPINION: Specific mechanisms of cisplatin-induced DNA damage and production of reactive oxygen species are the main ones responsible of toxicity. Several clinical approaches have been developed to reduce or prevent these effects with very promising results. The greatest potential for clinical practice is for amifostine, vitamin E, silymarin and NK-1 receptor antagonists. PMID- 26581587 TI - New insight into ectopic thyroid glands between the neck and maxillofacial region from a 42-case study. AB - BACKGROUND: Ectopic thyroid is a rare disease. In the present study at the 9th People's Hospital in Shanghai, China, 42 patients' ectopic thyroid glands between the neck and maxillofacial region were subjected to a retrospective and transverse study based on data from 1978 to 2012 to explore the natural characteristics of ectopic thyroid. METHODS: The patients' clinical data were collected. In addition, scintigraphy (Tc-99 m, Iodine-131), CT scan, histology and pathology were performed. The protein expression of thyroid transcription factor-1 (TTF-1), thyroglobulin (TG), calcitonin (CT), Ki-67 and parathyroid hormone (PTH) were analyzed from paraffin wax-stored specimens of ectopic thyroid tissue compared with those of orthotopic thyroid tissue. RESULTS: There were 42 total ectopic thyroid patients, approximately 1.24 patients per year on average at our hospital. These patients were aged from 6 to 85 years old, and there were 35 females (83.3 %), seven males (16.7 %). In total, 27 of the patients had lingual thyroid (64 %); seven, sublingual thyroid (17 %); five, dual areas occupied by ectopic thyroid (12 %) and three, other types (7 %). The following conditions were also presented: nodular goiter (13 %), adenoma (8.7 %) and Hashimoto's thyroiditis (4.3 %), no malignancy and no accompanying ectopic parathyroid. TTF-1 expression was significantly higher in ectopic samples than that in orthotopic samples (P = 0.007), but CT and Ki-67 levels displayed no difference. PTH was negative in ectopic tissue. CONCLUSION: Ectopic thyroid is a rare disease and females were more prone to the disease. The most frequent location was lingual thyroid. Nodular goiter, adenoma and Hashimoto's thyroiditis was observed as orthotopic thyroid without accompanying ectopic parathyroid. TTF 1 was highly expressed in ectopic tissue, which may be related to abnormal embryogenesis leading to the thyroid gland being in an abnormal position. The expression of calcitonin (CT) and Ki-67 was not increased, and there were no malignant cells in any sample, which could indicate that it is not easy for ectopic thyroids to become malignant between the neck and maxillofacial region. PMID- 26581588 TI - Functional brain regeneration in the acoel worm Symsagittifera roscoffensis. AB - The ability of some animals to regrow their head and brain after decapitation provides a striking example of the regenerative capacity within the animal kingdom. The acoel worm Symsagittifera roscoffensis can regrow its head, brain and sensory head organs within only a few weeks after decapitation. How rapidly and to what degree it also reacquires its functionality to control behavior however remains unknown. We provide here a neuroanatomical map of the brain neuropils of the adult S. roscoffensis and show that after decapitation a normal neuroanatomical organization of the brain is restored in the majority of animals. By testing different behaviors we further show that functionality of both sensory perception and the underlying brain architecture are restored within weeks after decapitation. Interestingly not all behaviors are restored at the same speed and to the same extent. While we find that phototaxis recovered rapidly, geotaxis is not restored within 7 weeks. Our findings show that regeneration of the head, sensory organs and brain result in the restoration of directed navigation behavior, suggesting a tight coordination in the regeneration of certain sensory organs with that of their underlying neural circuits. Thus, at least in S. roscoffensis, the regenerative capacity of different sensory modalities follows distinct paths. PMID- 26581589 TI - Novel myristoylation of the sperm-specific hexokinase 1 isoform regulates its atypical localization. AB - The hexokinase 1 variant in mammalian spermatozoa (HK1S) has a unique N-terminus and this isoform atypically localizes to the plasma membrane. However, the mechanism of this process currently remains ambiguous. In this report, we show that fatty acylation underlies the specific sorting of HK1S. Employing chimeric reporter constructs, we first established that compartmentalization of HK1S does not function exclusively in sperm cells and that this feature is swappable to somatic HEK293 cells. Although the N-terminus lacks the classical consensus signature for myristoylation and the sequence-based predictions fail to predict myristoylation of HK1S, complementary experimental approaches confirmed that HK1S is myristoylated. Using live-cell confocal microscopy, we show that the mutation of a single amino acid, the myristoyl recipient Gly(2), impedes the prominent feature of plasma membrane association and relocates the enzyme to the cytosol but not the nucleus. Additionally, substitutions of the putatively palmitoylated Cys(5) is also reflected in a similar loss of compartmentalization of the protein. Taken together, our findings conclusively demonstrate that the N terminal 'MGQICQ' motif in the unique GCS domain of HK1S acquires hydrophobicity by dual lipidic modifications, N-myristoylation and palmitoylation, to serve the requirements for membranous associations and thus its compartmentalization. PMID- 26581590 TI - Dynamic microtubule organization and mitochondrial transport are regulated by distinct Kinesin-1 pathways. AB - The microtubule (MT) plus-end motor kinesin heavy chain (Khc) is well known for its role in long distance cargo transport. Recent evidence showed that Khc is also required for the organization of the cellular MT network by mediating MT sliding. We found that mutations in Khc and the gene of its adaptor protein, kinesin light chain (Klc) resulted in identical bristle morphology defects, with the upper part of the bristle being thinner and flatter than normal and failing to taper towards the bristle tip. We demonstrate that bristle mitochondria transport requires Khc but not Klc as a competing force to dynein heavy chain (Dhc). Surprisingly, we demonstrate for the first time that Dhc is the primary motor for both anterograde and retrograde fast mitochondria transport. We found that the upper part of Khc and Klc mutant bristles lacked stable MTs. When following dynamic MT polymerization via the use of GFP-tagged end-binding protein 1 (EB1), it was noted that at Khc and Klc mutant bristle tips, dynamic MTs significantly deviated from the bristle parallel growth axis, relative to wild type bristles. We also observed that GFP-EB1 failed to concentrate as a focus at the tip of Khc and Klc mutant bristles. We propose that the failure of bristle tapering is due to defects in directing dynamic MTs at the growing tip. Thus, we reveal a new function for Khc and Klc in directing dynamic MTs during polarized cell growth. Moreover, we also demonstrate a novel mode of coordination in mitochondrial transport between Khc and Dhc. PMID- 26581591 TI - The expression of the T-box selector gene midline in the leg imaginal disc is controlled by both transcriptional regulation and cell lineage. AB - The Drosophila Tbx20 homologs midline and H15 act as selector genes for ventral fate in Drosophila legs. midline and H15 expression defines the ventral domain of the leg and the two genes are necessary and sufficient for the development of ventral fate. Ventral-specific expression of midline and H15 is activated by Wingless (Wg) and repressed by Decapentaplegic (Dpp). Here we identify VLE, a 5 kb enhancer that drives ventral specific expression in the leg disc that is very similar to midline expression. Subdivision of VLE identifies two regions that mediate both activation and repression and third region that only mediates repression. Loss- and gain-of-function genetic mosaic analysis shows that the activating and repressing regions respond to Wg and Dpp signaling respectively. All three repression regions depend on the activity of Mothers-against decapentaplegic, a Drosophila r-Smad that mediates Dpp signaling, and respond to ectopic expression of the Dpp target genes optomoter-blind and Dorsocross 3. However, only one repression region is responsive to loss of schnurri, a co repressor required for direct repression by Dpp-signaling. Thus, Dpp signaling restricts midline expression through both direct repression and through the activation of downstream repressors. We also find that midline and H15 expression are both subject to cross-repression and feedback inhibition. Finally, a lineage analysis indicates that ventral midline-expressing cells and dorsal omb expressing cells do not mix during development. Together this data indicates that the ventral-specific expression of midline results from both transcriptional regulation and from a lack of cell-mixing between dorsal and ventral cells. PMID- 26581592 TI - Gamma-glutamyl transferase and prognosis in patients with coronary artery disease. AB - BACKGROUND: The association between gamma-glutamyl transferase (GGT) activity and outcome of patients with coronary artery disease (CAD) remains poorly investigated. METHODS: The study included 5501 patients with CAD treated with percutaneous coronary intervention and GGT measurements available. The primary outcome was 3-year mortality. RESULTS: GGT activity tertiles were: 1st tertile (GGT<28.10U/L; n=1866), 2nd tertile (GGT>=28.10U/L to49.50U/L; n=1804) and 3rd tertile (GG>49.50U/L; n=1831). There were 110 deaths in the 1st, 111 deaths in the 2nd and 216 deaths in the 3rd GGT tertile (mortality estimates, 7.1%, 7.2% and 13.9%; P<0.001). GGT was independently associated with the increased risk of 3-year all-cause (adjusted hazard ratio [HR]=1.30, 95% confidence interval [CI] 1.18 to 1.44, P<0.001), cardiac (HR=1.21 [1.06-1.39], P=0.005) and non-cardiac (HR=1.42 [1.23-1.63], P<0.001) mortality (all risk estimates calculated per standard deviation increase in the log GGT activity). GGT improved prediction of all-cause (P<0.001) and non-cardiac mortality (P<0.001) but not cardiac mortality (P=0.155). CONCLUSIONS: In patients with CAD, elevated GGT activity is associated with increased risk of 3-year all-cause, cardiac and non-cardiac mortality. GGT provided incremental prognostic information on top of cardiovascular and metabolic risk factors for prediction of all-cause and non-cardiac mortality but not cardiac mortality. PMID- 26581593 TI - Activation of ERK1/2 Ameliorates Liver Steatosis in Leptin Receptor-Deficient (db/db) Mice via Stimulating ATG7-Dependent Autophagy. AB - Although numerous functions of extracellular signal-regulated kinase 1/2 (ERK1/2) are identified, a direct effect of ERK1/2 on liver steatosis has not been reported. Here, we show that ERK1/2 activity is compromised in livers of leptin receptor-deficient (db/db) mice. Adenovirus-mediated activation of mitogen activated protein kinase kinase 1 (MEK1), the upstream regulator of ERK1/2, significantly ameliorated liver steatosis in db/db mice, increased expression of genes related to fatty acid beta-oxidation and triglyceride (TG) export and increased serum beta-hydroxybutyrate (3-HB) levels. Opposite effects were observed in adenovirus-mediated ERK1/2 knockdown C57/B6J wild-type mice. Furthermore, autophagy and autophagy-related protein 7 (ATG7) expression were decreased or increased by ERK1/2 knockdown or activation, respectively, in primary hepatocytes and liver. Blockade of autophagy by the autophagy inhibitor chloroquine or adenovirus-mediated ATG7 knockdown reversed the ameliorated liver steatosis in recombinant adenoviruses construct expressing rat constitutively active MEK1 Ad-CA MEK1 db/db mice, decreased expression of genes related to fatty acid beta-oxidation and TG export, and decreased serum 3-HB levels. Finally, ERK1/2 regulated ATG7 expression in a p38-dependent pathway. Taken together, these results identify a novel beneficial role for ERK1/2 in liver steatosis via promoting ATG7-dependent autophagy, which provides new insights into the mechanisms underlying liver steatosis and important hints for targeting ERK1/2 in treating liver steatosis. PMID- 26581594 TI - Insulitis and beta-Cell Mass in the Natural History of Type 1 Diabetes. AB - Descriptions of insulitis in human islets throughout the natural history of type 1 diabetes are limited. We determined insulitis frequency (the percent of islets displaying insulitis to total islets), infiltrating leukocyte subtypes, and beta cell and alpha-cell mass in pancreata recovered from organ donors with type 1 diabetes (n = 80), as well as from donors without diabetes, both with islet autoantibodies (AAb(+), n = 18) and without islet autoantibodies (AAb(-), n = 61). Insulitis was observed in four of four donors (100%) with type 1 diabetes duration of <=1 year and two AAb(+) donors (2 of 18 donors, 11%). Insulitis frequency showed a significant but limited inverse correlation with diabetes duration (r = -0.58, P = 0.01) but not with age at disease onset. Residual beta cells were observed in all type 1 diabetes donors with insulitis, while beta-cell area and mass were significantly higher in type 1 diabetes donors with insulitis compared with those without insulitis. Insulitis affected 33% of insulin(+) islets compared with 2% of insulin(-) islets in donors with type 1 diabetes. A significant correlation was observed between insulitis frequency and CD45(+), CD3(+), CD4(+), CD8(+), and CD20(+) cell numbers within the insulitis (r = 0.53 0.73, P = 0.004-0.04), but not CD68(+) or CD11c(+) cells. The presence of beta cells as well as insulitis several years after diagnosis in children and young adults suggests that the chronicity of islet autoimmunity extends well into the postdiagnosis period. This information should aid considerations of therapeutic strategies seeking type 1 diabetes prevention and reversal. PMID- 26581595 TI - Antiaging Glycopeptide Protects Human Islets Against Tacrolimus-Related Injury and Facilitates Engraftment in Mice. AB - Clinical islet transplantation has become an established treatment modality for selected patients with type 1 diabetes. However, a large proportion of transplanted islets is lost through multiple factors, including immunosuppressant related toxicity, often requiring more than one donor to achieve insulin independence. On the basis of the cytoprotective capabilities of antifreeze proteins (AFPs), we hypothesized that supplementation of islets with synthetic AFP analog antiaging glycopeptide (AAGP) would enhance posttransplant engraftment and function and protect against tacrolimus (Tac) toxicity. In vitro and in vivo islet Tac exposure elicited significant but reversible reduction in insulin secretion in both mouse and human islets. Supplementation with AAGP resulted in improvement of islet survival (Tac(+) vs. Tac+AAGP, 31.5% vs. 67.6%, P < 0.01) coupled with better insulin secretion (area under the curve: Tac(+) vs. Tac+AAGP, 7.3 vs. 129.2 mmol/L/60 min, P < 0.001). The addition of AAGP reduced oxidative stress, enhanced insulin exocytosis, improved apoptosis, and improved engraftment in mice by decreasing expression of interleukin (IL)-1beta, IL-6, keratinocyte chemokine, and tumor necrosis factor-alpha. Finally, transplant efficacy was superior in the Tac+AAGP group and was similar to islets not exposed to Tac, despite receiving continuous treatment for a limited time. Thus, supplementation with AAGP during culture improves islet potency and attenuates long-term Tac induced graft dysfunction. PMID- 26581596 TI - Metabolism Regulates Exposure of Pancreatic Islets to Circulating Molecules In Vivo. AB - Pancreatic beta-cells modulate insulin secretion through rapid sensing of blood glucose and integration of gut-derived signals. Increased insulin demand during pregnancy and obesity alters islet function and mass and leads to gestational diabetes mellitus and type 2 diabetes in predisposed individuals. However, it is unclear how blood-borne factors dynamically access the islets of Langerhans. Thus, understanding the changes in circulating molecule distribution that accompany compensatory beta-cell expansion may be key to developing novel antidiabetic therapies. Here, using two-photon microscopy in vivo in mice, we demonstrate that islets are almost instantly exposed to peaks of circulating molecules, which rapidly pervade the tissue before clearance. In addition, both gestation and short-term high-fat-diet feeding decrease molecule extravasation and uptake rates in vivo in islets, independently of beta-cell expansion or islet blood flow velocity. Together, these data support a role for islet vascular permeability in shaping beta-cell adaptive responses to metabolic demand by modulating the access and sensing of circulating molecules. PMID- 26581597 TI - Experiments on Analysing Voice Production: Excised (Human, Animal) and In Vivo (Animal) Approaches. AB - : Experiments on human and on animal excised specimens as well as in vivo animal preparations are so far the most realistic approaches to simulate the in vivo process of human phonation. These experiments do not have the disadvantage of limited space within the neck and enable studies of the actual organ necessary for phonation, i.e., the larynx. The studies additionally allow the analysis of flow, vocal fold dynamics, and resulting acoustics in relation to well-defined laryngeal alterations. PURPOSE OF REVIEW: This paper provides an overview of the applications and usefulness of excised (human/animal) specimen and in vivo animal experiments in voice research. These experiments have enabled visualization and analysis of dehydration effects, vocal fold scarring, bifurcation and chaotic vibrations, three-dimensional vibrations, aerodynamic effects, and mucosal wave propagation along the medial surface. Quantitative data will be shown to give an overview of measured laryngeal parameter values. As yet, a full understanding of all existing interactions in voice production has not been achieved, and thus, where possible, we try to indicate areas needing further study. RECENT FINDINGS: A further motivation behind this review is to highlight recent findings and technologies related to the study of vocal fold dynamics and its applications. For example, studies of interactions between vocal tract airflow and generation of acoustics have recently shown that airflow superior to the glottis is governed by not only vocal fold dynamics but also by subglottal and supraglottal structures. In addition, promising new methods to investigate kinematics and dynamics have been reported recently, including dynamic optical coherence tomography, X-ray stroboscopy and three-dimensional reconstruction with laser projection systems. Finally, we touch on the relevance of vocal fold dynamics to clinical laryngology and to clinically-oriented research. PMID- 26581598 TI - Endogenous hepatic glucocorticoid receptor signaling coordinates sex-biased inflammatory gene expression. AB - An individual's sex affects gene expression and many inflammatory diseases present in a sex-biased manner. Glucocorticoid receptors (GRs) are regulators of inflammatory genes, but their role in sex-specific responses is unclear. Our goal was to evaluate whether GR differentially regulates inflammatory gene expression in male and female mouse liver. Twenty-five percent of the 251 genes assayed by nanostring analysis were influenced by sex. Of these baseline sexually dimorphic inflammatory genes, 82% was expressed higher in female liver. Pathway analyses defined pattern-recognition receptors as the most sexually dimorphic pathway. We next exposed male and female mice to the proinflammatory stimulus LPS. Female mice had 177 genes regulated by treatment with LPS, whereas males had 149, with only 66% of LPS-regulated genes common between the sexes. To determine the contribution of GR to sexually dimorphic inflammatory genes we performed nanostring analysis on liver-specific GR knockout (LGRKO) mice in the presence or absence of LPS. Comparing LGRKO to GR(flox/flox) revealed that 36 genes required GR for sexually dimorphic expression, whereas 24 genes became sexually dimorphic in LGRKO. Fifteen percent of LPS-regulated genes in GR(flox/flox) were not regulated in male and female LGRKO mice treated with LPS. Thus, GR action is influenced by sex to regulate inflammatory gene expression. PMID- 26581599 TI - De novo generation of adipocytes from circulating progenitor cells in mouse and human adipose tissue. AB - White adipocytes in adults are typically derived from tissue resident mesenchymal progenitors. The recent identification of de novo production of adipocytes from bone marrow progenitor-derived cells in mice challenges this paradigm and indicates an alternative lineage specification that adipocytes exist. We hypothesized that alternative lineage specification of white adipocytes is also present in human adipose tissue. Bone marrow from transgenic mice in which luciferase expression is governed by the adipocyte-restricted adiponectin gene promoter was adoptively transferred to wild-type recipient mice. Light emission was quantitated in recipients by in vivo imaging and direct enzyme assay. Adipocytes were also obtained from human recipients of hematopoietic stem cell transplantation. DNA was isolated, and microsatellite polymorphisms were exploited to quantify donor/recipient chimerism. Luciferase emission was detected from major fat depots of transplanted mice. No light emission was observed from intestines, liver, or lungs. Up to 35% of adipocytes in humans were generated from donor marrow cells in the absence of cell fusion. Nontransplanted mice and stromal-vascular fraction samples were used as negative and positive controls for the mouse and human experiments, respectively. This study provides evidence for a nontissue resident origin of an adipocyte subpopulation in both mice and humans. PMID- 26581600 TI - IL-17A promotes susceptibility during experimental visceral leishmaniasis caused by Leishmania donovani. AB - Leishmania donovani is an intracellular parasite that infects professional phagocytes and causes visceral leishmaniasis (VL). The immune response during VL has been extensively studied in the context of T-helper (Th)1 and Th2 responses. Immunity against this parasite is dependent on IFN-gamma production and subsequent macrophage activation, and the Th2 response promotes granuloma formation. The cytokine IL-17A is associated with neutrophilic inflammation. Depletion of neutrophils during experimental VL results in enhanced parasitic loads. Furthermore, although patients resistant to VL showed enhanced levels of IL-17A in circulation, little is known about the role of IL-17A during VL infection. Here, we used IL-17A-deficient mice and IL-17A reporter mice to address the role of IL-17A during VL. IL-17A(-/-) mice were highly resistant to VL infection, showing decreased parasites in the liver and spleen. This unexpected phenotype was associated with enhanced IFN-gamma production by T cells and decreased accumulation of neutrophils and monocytes, resulting in reduced number of granulomas. We also found gammadelta T and Th17 cells as the main IL 17A(+) cells during VL infection. Our data reveal an unexpected role of IL-17A rendering susceptibility against L. donovani by regulating the IFN-gamma response and promoting detrimental inflammation. PMID- 26581601 TI - Functional characterization of retromer in GLUT4 storage vesicle formation and adipocyte differentiation. AB - Insulin-stimulated translocation of glucose transporter 4 (GLUT4) storage vesicles (GSVs), the specialized intracellular compartments within mature adipocytes, to the plasma membrane (PM) is a fundamental cellular process for maintaining glucose homeostasis. Using 2 independent adipocyte cell line models, human primary Simpson-Golabi-Behmel syndrome and mouse 3T3-L1 fibroblast cell lines, we demonstrate that the endosome-associated protein-sorting complex retromer colocalizes with GLUT4 on the GSVs by confocal microscopy in mature adipocytes. By use of both confocal microscopy and differential ultracentrifugation techniques, retromer is redistributed to the PM of mature adipocytes upon insulin stimulation. Furthermore, stable knockdown of the retromer subunit-vacuolar protein-sorting 35, or the retromer-associated protein sorting nexin 27, by lentivirus-delivered small hairpin RNA impaired the adipogenesis process when compared to nonsilence control. The knockdown of retromer decreased peroxisome proliferator activated receptor gamma expression during differentiation, generating adipocytes with decreased levels of GSVs, lipid droplet accumulation, and insulin-stimulated glucose uptake. In conclusion, our study demonstrates a role for retromer in the GSV formation and adipogenesis. PMID- 26581602 TI - Frequency of Cardiovascular Events and Effect on Survival in Liver Transplant Recipients for Cirrhosis Due to Alcoholic or Nonalcoholic Steatohepatitis. AB - OBJECTIVES: Frequency of liver transplants because of nonalcoholic steatohepatitis is increasing. Data are conflicting on nonalcoholic steatohepatitis as a risk factor for cardiovascular events after transplant. MATERIALS AND METHODS: We reviewed medical records of liver transplant recipients (between years 2005 and 2010) for alcoholic cirrhosis or nonalcoholic steatohepatitis for cardiovascular events (arrhythmia, congestive heart failure, coronary disease, pulmonary hypertension, or stroke) and patient survival within 3 years. RESULTS: Compared with the 65 transplant recipients for alcoholic cirrhosis, the 78 transplant recipients for nonalcoholic steatohepatitis were significantly (P < .0001 for all) more likely to be female (46% vs 8%), have a larger mean body mass index (34 +/- 7 vs 29 +/- 5), more likely to have diabetes (58% vs 26%), less likely to be hepatitis C virus-positive (3% vs 29%), and less likely to smoke (29% vs 69%). Eleven patients with nonalcoholic steatohepatitis and 9 patients with nonalcoholic steatohepatitis had cardiovascular events; however, these groups were not significantly different 1 year (7.7% vs 6.1%; P = .45) or 3 years (14.1% vs 13.8%; P = .9) after liver transplant. The odds of having a cardiovascular event were about 9-fold greater for patients with concomitant hepatitis C virus and 3-fold greater for men. Eighteen patients died, with patients with cardiovascular events having greater than 4-fold increased mortality (mean 4.1-fold; range, 1.2-fold to 13.9-fold). CONCLUSIONS: Cardiovascular events occurred with similar frequency in transplant recipients for nonalcoholic steatohepatitis or alcoholic cirrhosis. Patient survival was affected in both groups, but male patients with concomitant hepatitis C virus infection remained at higher risk for a cardiovascular event after liver transplant. Development of a cardiac evaluation protocol for liver transplant recipients could help monitor these patients. PMID- 26581603 TI - TLR2/MyD88/NF-kappaB signalling pathway regulates IL-8 production in porcine alveolar macrophages infected with porcine circovirus 2. AB - Porcine circovirus 2 (PCV2) is the primary cause of post-weaning multisystemic wasting syndrome, in which it stimulates a strong IL-8 response that is associated with chronic inflammation as well as lesions in the lymphoid organs. However, the mechanism underlying PCV2-induced IL-8 production is still unclear. In the present study, we demonstrated that increased IL-8 expression during PCV2 infection depends on Toll-like receptor (TLR2), but not TLR4 or TLR9 signalling pathways in porcine alveolar macrophages. Moreover, we found that impairment of the MyD88/NF-kappaB signalling pathway by MyD88 knockdown or NF-kappaB inhibitors markedly decreased PCV2-induced IL-8 secretion. These results suggest that PCV2 induces IL-8 secretion via the TLR2/MyD88/NF-kappaB signalling pathway. Therefore, it is important to elucidate the molecular mechanisms of the PCV2 induced inflammatory response. PMID- 26581604 TI - The role of arthroscopy in carpal instability. AB - Carpal instability is predominantly caused by trauma and presents as a painful wrist with signs and symptoms of weakness, clicking, clunking and a sense of giving way. Wrist arthroscopy is widely regarded as the 'gold standard' in diagnosing and understanding carpal instability. This article is based on an extensive literature search to evaluate the evidence behind the use of wrist arthroscopy in the assessment and management of these patients. There is convincing evidence supporting the role of arthroscopy in diagnosis and assessment of factors involved in the development of carpal instability, but weak evidence for the effectiveness of arthroscopic techniques in the actual treatment of this condition. The article reviews mechanisms behind, and the role for arthroscopy in the management of scapholunate, lunotriquetral, midcarpal and radiocarpal instability. It also presents how the author incorporates the 'evidence-base' into an 'experience-based' clinical practice. PMID- 26581605 TI - Paradigm of plant invasion: multifaceted review on sustainable management. AB - A cascade of reviews and growing body of literature exists on forest invasion ecology, its mechanism or causes; however, no review addressed the sustainable management of invasive plants of forest in totality. Henceforth, the present paper aims to provide a critical review on the management of invasive species particularly in the context of forest plants. Plant invasion in forest is now increasingly being recognized as a global problem, and various continents are adversely affected, although to a differential scale. Quest for the ecological mechanism lying behind the success of invasive species over native species of forest has drawn the attention of researches worldwide particularly in the context of diversity-stability relationship. Transport, colonization, establishment, and landscape spread may be different steps in success of invasive plants in forest, and each and every step is checked through several ecological attributes. Further, several ecological attribute and hypothesis (enemy release, novel weapon, empty niche, evolution of increased competitive ability, etc.) were proposed pertaining to success of invasive plant species in forest ecosystems. However, a single theory will not be able to account for invasion success among all environments as it may vary spatially and temporally. Therefore, in order to formulate a sustainable management plan for invasive plants of forest, it is necessary to develop a synoptic view of the dynamic processes involved in the invasion process. Moreover, invasive species of forest can act synergistically with other elements of global change, including land-use change, climate change, increased concentrations of atmospheric carbon dioxide, and nitrogen deposition. Henceforth, a unified framework for biological invasions that reconciles and integrates the key features of the most commonly used invasion frameworks into a single conceptual model that can be applied to all human-mediated invasions. PMID- 26581606 TI - Potential impacts of seasonal variation on atrazine and metolachlor persistence in andisol soil. AB - To estimate the potential effect of seasonal variation on the fate of herbicides in andisol soil, atrazine and metolachlor residues were investigated through the summer and winter seasons during 2013 and 2014 under field condition. The computed half-lives of atrazine and metolachlor in soil changed significantly through the two seasons of the trial. The half-lives were shorter in summer season with 16.0 and 23.5 days for atrazine and metolachlor, respectively. In contrast, the half-lives were longer during the winter season with 32.7 and 51.8 days for atrazine and metolachlor, respectively. The analysis of soil water balance suggested that more pesticide was lost in deeper soil layers through infiltration in summer than in winter. In addition, during the summer season, metolachlor was more likely to leach into deeper soil layer than atrazine possibly due to high water solubility of metolachlor. PMID- 26581607 TI - Effectiveness of a physical barrier for contaminant control in an unconfined coastal plain aquifer: the case study of the former industrial site of Bagnoli (Naples, southern Italy). AB - A vertical engineered barrier (VEB) coupled with a water treatment plant was surveyed in the framework of a vast remedial action at the brownfield site of the former ILVA of Bagnoli steel making facility located in western Naples, Italy. The VEB was put in place to minimize contaminant migration from the brownfield site toward the sea at the shorelines sites of Bagnoli and Coroglio. The efficiency of the VEB was monitored through 12 piezometers, 8 at the Bagnoli shoreline and 4 at the Coroglio shoreline. Concentrations of inorganic and organic pollutants were examined in upstream and downstream groundwater relative to the VEB. The mean levels of Al, As, Fe, and Mn largely exceeded the legal limits, 10-15-fold, whereas that of Hg was up to 3-fold the rules. The VEB decreased the outlet concentrations only at certain specific location of the barrier, four times for Al, 6-fold for Hg, and by 20% for Mn with means largely exceeding the rules. At the other sites, the downstream water showed marked increases of the pollutants up to 3-fold. Outstanding levels of the hydrocarbons > 12 were detected in the inlet water with means of some hundred times the limits at both sites. Likewise most of screened inorganic pollutants, the downstream water showed marked increases of the hydrocarbons up to ~113%. The treatment plant was very effective, with removal efficiencies >80% for As, Al, Fe, and Mn. The study evidenced the need to put alternative groundwater remedial actions. PMID- 26581608 TI - Zinc, copper, cadmium, and lead concentrations in water, sediment, and Anadara senilis in a tropical estuary. AB - Spatial and seasonal contaminations of zinc, copper, cadmium, and lead were assessed simultaneously in water, sediment, and in the bivalve Arca senilis from the Milliardaires Bay (Cote d'Ivoire) between February and October 2008. The metal load in sediments doubled from the dry season to the rainy season. On the contrary, metal concentrations in waters decreased significantly from the dry season to the rainy season. Zn and Pb concentrations in A. senilis showed similar seasonal variation with sediments. On the other hand, A. senilis regulated Cu concentrations by eliminating about twelve times the concentration accumulated during the dry season. Apparent Zn, Cu, Cd, and Pb concentration gradients were observed, but no significant differences between stations for sediment, water, and A. senilis. Concentrations in sediment increased from stations close to Abidjan Harbor towards farther stations, while concentrations in A. senilis showed a reverse gradient. The distribution gradient of A. senilis indicates pollution from local sources, but a transplant experiment is needed to better understand the observed spatial trend. Zn and Cu concentrations may pose little risk to human health and the environment, but they are the highest on the regional scale. On the contrary, Cd and Pb concentrations in A. senilis exceeded the maximum allowable limits set by the European Commission. Complementary studies including chemical speciation should be considered to provide a more accurate assessment of the risk of heavy metals to the environment. PMID- 26581609 TI - Natural biosorbents (garlic stem and horse chesnut shell) for removal of chromium(VI) from aqueous solutions. AB - The biosorption of Cr(VI) by the garlic stem (GS)-Allium sativum L. and horse chesnut shell (HCS)-Aesculus hippocastanum plant residues in a batch type reactor was studied in detail for the purpose of wastewater treatment. The influence of initial Cr(VI) concentration, time, and pH was investigated to optimize Cr(VI) removal from aqueous solutions and equilibrium isotherms and kinetic data. This influence was evaluated. The adsorption capacity of the GS and the HCS for Cr(VI) was determined with the Langmuir and Freundlich isotherm models, and the data was fitted to the Langmuir. The adsorption capacity of the GS and the HCS was found to be 103.09 and 142.85 mg/g of adsorbent from a solution containing 3000 ppm of Cr(VI), respectively. The GS's capacity was considerably lower than that of the HCS in its natural form. Gibbs free energy was spontaneous for all interactions, and the adsorption process exhibited exothermic enthalpy values. The HCS was shown to be a promising biosorbent for Cr(VI) removal from aqueous solutions. PMID- 26581610 TI - Increased trend in extracorporeal membrane oxygenation use by adults in the United States since 2007. AB - BACKGROUND: Extracorporeal membrane oxygenation (ECMO) has been increasingly studied as a life support modality, but it is unclear if its use has changed over time. Recent publication shows no significant trend in use of ECMO over time; however, this report does not include more recent data. We performed trend analysis to determine if and when the use of ECMO changed in the past decade. RESULTS: We identified hospitalizations (2000-2011) in the Nationwide Inpatient Sample during which ECMO was recorded. We used a segmented linear regression model to determine trend and to identify a temporal change point when rate of ECMO use increased. ECMO use gradually grew until 2007, at which time there was a dramatic increase in the rate (p = 0.0003). There was no difference in mortality after 2007 (p = 0.3374), but there was longer length of stay (p = 0.0001) and smaller percentage of women (p = 0.005). CONCLUSIONS: There has been a marked increase in ECMO use since 2007. As ECMO use becomes more common, further study regarding indications, cost-effectiveness, and outcomes is warranted to guide optimal use. PMID- 26581611 TI - Chemokine Expression Profiles of Human Hepatoma Cell Lines Mediated by Hepatitis B Virus X Protein. AB - The hepatitis B virus X protein (HBx), which is encoded by hepatitis B virus (HBV), plays crucial roles in the tumorigenesis of HBV associated hepatocellular carcinoma (HCC). Recent studies suggest that the HBx is involved in regulation of host immune cytokines and chemokines in HBV-associated HCC patients. However, effects of the HBx on autocrine chemokine expression profiles of hepatoma cells, which were shown in modulation of tumor-immune cell interactions, have not been investigated comprehensively. In the present study, human hepatoma cell lines SMMC-7721 and HepG2 were transfected with HBx-expressing plasmid. Human chemokine antibody array 1 (RayBio(r)), which simultaneously detects 38 chemokine factors, was used to determine chemokine expression profiles. Real-time polymerase chain reaction (real-time PCR) was used to further confirm the differential expression of chemokines. Chemokine antibody array revealed that all 38 chomekines were found to be expressed by SMMC-7721 and HepG2 cell lines. Interleukin-8 (IL-8) was obviously up-regulated, and epithelial neutrophil-activating protein 78 (ENA78), eosinophil chemotactic protein-1 (Eotaxin-1), monocyte chemotactic protein-1 (MCP 1), MCP-2, MCP-3 and macrophage inflammatory protein-3beta (MIP-3beta) were significantly declined in both cell lines following transfection of HBx expressing plasmid. Other chemokines showed little or no significant changes. HBx induced differential chemokine expression levels were validated by real-time PCR. Hierarchical cluster analysis identified a distinction of chomekine expression profiles between HBX-expressing hepatoma cell lines and controls. Our findings provide new evidence that HBx is able to selectively regulate chomekines in hepatoma cells that may be involved in the regulation of tumor-immune cell interactions. PMID- 26581612 TI - Introducing Cytology-Based Theranostics in Oral Squamous Cell Carcinoma: A Pilot Program. AB - We aimed to evaluate the feasibility and reliability of brush cytology in the biomarker expression profiling of oral squamous cell carcinomas within the concept of theranostics, and to correlate this biomarker profile with patient measurable outcomes. Markers representative of prognostic gene expression changes in oral squamous cell carcinoma was selected. These markers were also selected to involve pathways for which commercially available or investigational agents exist for clinical application. A set of 7 markers were analysed by immunocytochemistry on the archival primary tumour material of 99 oral squamous cell carcinoma patients. We confirmed the feasibility of the technique for the expression profiling of oral squamous cell carcinomas. Furthermore, our results affirm the prognostic significance of the epidermal growth factor receptor (EGFR) family and the angiogenic pathway in oral squamous cell carcinoma, confirming their interest for targeted therapy. Brush cytology appears feasible and applicable for the expression profiling of oral squamous cell carcinoma within the concept of theranostics, according to sample availability. PMID- 26581614 TI - Erratum to: PDK1-mTOR signaling pathway inhibitors reduce cell proliferation in MK2206 resistant neuroblastoma cells. AB - [This corrects the article DOI: 10.1186/s12935-015-0239-4.]. PMID- 26581613 TI - Increased Expression of Phosphatidylinositol 3-Kinase p110alpha and Gene Amplification of PIK3CA in Nasopharyngeal Carcinoma. AB - Molecular alterations in PIK3CA oncogene that encodes the p110alpha catalytic subunit of phosphatidylinositol 3-kinase (PI3K p110alpha) are commonly found in human cancers. In this study, we examined the expression of PI3K p110alpha and PIK3CA gene amplification in 74 nasopharyngeal carcinoma (NPC) cases. Immunohistochemical staining demonstrated overexpression of PI3K p110alpha protein in 44.6% (33/74) of NPCs and 4.8% (2/42) of the adjacent normal nasopharyngeal mucosa. Copy number of PIK3CA gene was successfully analyzed in 51 of the total NPC cases and 19 non-malignant nasopharynx tissues by quantitative real-time PCR. Using mean + 2(standard deviation) of copy numbers in the non malignant nasopharynx tissues as a cutoff value, PIK3CA copy number gain was found in 10 of 51 (19.6%) NPC cases. High PI3K p110alpha expression level was correlated with increased PIK3CA copy number (Spearman's rho =0.324, P = 0.02). PI3K p110alpha expression and PIK3CA copy number did not associate with Akt phosphorylation, and patient and tumor variables. This study suggests that PI3K p110alpha overexpression, which is attributed, at least in part, to PIK3CA gene amplification, may contribute to NPC pathogenesis. However, these molecular aberrations may not be responsible for activation of Akt signaling in NPC. PMID- 26581615 TI - Double vision. PMID- 26581617 TI - Association Between Necropsy Evidence of Disseminated Intravascular Coagulation and Hemostatic Variables Before Death in Horses With Colic. AB - BACKGROUND: Disseminated intravascular coagulation (DIC) is frequent in horses with severe gastrointestinal disorders. Postmortem studies have found fibrin microthrombi in tissues of these horses, but studies relating these histopathological findings with antemortem hemostatic data are lacking. HYPOTHESIS: Antemortem classification of coagulopathy is related to the presence and severity of fibrin deposits observed postmortem in horses with severe gastrointestinal disorders. ANIMALS: Antemortem hemostatic profile data and postmortem tissue samples (kidney, lung, liver) from 48 horses with colic. METHODS: Tissue samples were stained with phosphotungstic acid hematoxylin and immunohistochemical methods for histological examination. A fibrin score (grades 0-4) was assigned for each technique, tissue and horse, as well as the presence or absence of DIC at postmortem examination. D-dimer concentration, prothrombin time (PT), activated partial thromboplastin time (aPTT), and antithrombin (AT) activity, as well as the clinicopathological evidence of coagulopathy, were determined from plasma samples collected 0-24 hours before death or euthanasia. Histologic and clinicopathologic data from the same horses were compared retrospectively. RESULTS: No association was found between antemortem classification of coagulopathy and postmortem diagnosis of DIC based on tissue fibrin deposition. None of the hemostatic parameters was significantly different between horses with or without postmortem diagnosis of DIC. There was no association between horses with fibrin in tissues or different cut-offs for D dimer concentration and postmortem evidence of DIC. CONCLUSIONS AND CLINICAL IMPORTANCE: Abnormalities of the routine clotting profile, including D-dimer concentration, were not useful in predicting histologic evidence of DIC at necropsy in horses with severe gastrointestinal disorders. PMID- 26581616 TI - Identification of gait domains and key gait variables following hip fracture. AB - BACKGROUND: Restoration of gait is an important goal of rehabilitation after hip fracture. Numerous spatial and temporal gait variables have been reported in the literature, but beyond gait speed, there is little agreement on which gait variables should be reported and which are redundant in describing gait recovery following hip fracture. The aims of this study were to identify distinct domains of gait and key variables representing these domains, and to explore how known predictors of poor outcome after hip fracture were associated with these key variables. METHODS: Spatial and temporal gait variables were collected four months following hip fracture in 249 participants using an electronic walkway (GAITRite(r)). From the initial set of 31 gait variables, 16 were selected following a systematic procedure. An explorative factor analysis with oblique (oblimin) rotation was performed, using principal component analysis for extraction of factors. Unique domains of gait and the variable best representing these domains were identified. Multiple regression analyses including six predictors; age, gender, fracture type, pain, global cognitive function and grip strength were performed for each of the identified key gait variables. RESULTS: Mean age of participants was 82.6 (SD = 6.0) years, 75 % were women, and mean gait speed was 0.6 (SD = 0.2) m/sec. The factor analysis revealed four distinct gait domains, and the key variables that best represented these domains were double support time, walk ratio, variability of step velocity, and single support asymmetry. Cognitive decline, low grip strength, extra capsular fracture and male gender, but not pain or age, were significant predictors of impaired gait. CONCLUSIONS: This work proposes four key variables to represent gait of older people after hip fracture. These core variables were associated with known predictors of poor outcome after hip fracture and should warrant further assessment to confirm their importance as outcome variables in addition to gait speed. PMID- 26581618 TI - Remote FLS testing in the real world: ready for "prime time". AB - INTRODUCTION: Maintaining the existing FLS test centers requires considerable investment in human and financial resources. It can also be particularly challenging for those outside of North America to become certified due to the limited number of international test centers. Preliminary work suggests that it is possible to reliably score the FLS manual skills component remotely using low cost videoconferencing technology. Significant work remains to ensure that testing procedures adhere to standards defined by SAGES for this approach to be considered equivalent to standard on-site testing. OBJECTIVE: To validate the integrity and validity of the FLS manual skills examination administered remotely in a real-world environment according to FLS testing protocols and to evaluate participants' experience with the setting. METHODS: Individuals with various levels of training from the University of Toronto completed a pre- and a post test questionnaire. Participants presented to one of the two FLS testing rooms available for the study, each connected via Skype to a separate room with a FLS proctor who administered and scored the test remotely (RP). An on-site proctor (OP) was present in the room as a control. An invigilator was also present in the testing room to follow directions from the RP and ensure the integrity of test materials. RESULTS: Twenty-one participants were recruited, and 20 completed the test. There was no significant difference between scores by RP and OP. Interrater reliability between the RP and OP was excellent. One critical error was missed by the RP, but this would not have affected the test outcome. Participants reported being highly satisfied. CONCLUSION: We demonstrate that proctors located remotely can administer the FLS skills test in a secure and reliable fashion, with excellent interrater reliability compared to an on-site proctor. Remote proctoring of the FLS examination could become a strategy to increase certification rates while containing costs. PMID- 26581619 TI - Robotic surgery simulation validity and usability comparative analysis. AB - BACKGROUND: The introduction of simulation into minimally invasive robotic surgery is relatively recent and has seen rapid advancement; therefore, a need exists to develop training curriculums and identify systems that will be most effective at training surgical skills. Several simulators have been introduced to support these aims-the daVinci skills simulator, Mimic dV-Trainer, Surgical Simulated Systems' RoSS, and Simbionix Robotix Mentor. While multiple studies have been conducted to demonstrate the validity of these systems, studies comparing the perceived value of these devices as tools for education and skills are lacking. METHODS: Subjects who qualified as medical students or physicians (n = 105) were assigned a specific order to use each of the three simulators. After completing a demographic questionnaire, participants performed one exercise on the three simulators and completed a second questionnaire regarding their experience with the device. After using all systems, they completed a final questionnaire, which detailed their comparative preferences. The subject's performance metrics were also collected from each simulator. RESULTS: The data confirmed the face, content, and construct validity for the dV-trainer and skills simulator. Similar validities could not be confirmed for the RoSS. >80 % of the time, participants chose the skills simulator in terms of physical comfort, ergonomics, and overall choice. However, only 55 % thought the skills simulator was worth the cost of the equipment. The dV-Trainer had the highest cost preference scores with 71 % of respondents feeling it was worth the investment. CONCLUSIONS: Usability can affect the consistency and commitment of users of robotic surgical simulators. In a previous study, these simulators were objectively reviewed and compared in terms of their system capabilities. Collectively, this work will offer end-users and potential buyers a comparison of the perceived value and preferences of robotic simulators. PMID- 26581620 TI - The Persistence of the Pamphlet: On the Continued Relevance of the Health Information Pamphlet in the Digital Age. AB - Since the early 2000s, web and digital health information and education has progressed in both volume and innovation (Dutta-Bergman 2006; Mano, Computers in Human Behavior 39 404 412, 2014). A growing number of leading Canadian health institutions (e.g., hospitals, community health centers, and health ministries) are migrating much of their vital public health information and education, once restricted to pamphlets and other physically distributed materials, to online platforms. Examples of these platforms are websites and web pages, eLearning modules, eBooks, streamed classrooms, audiobooks, and online health videos. The steady migration of health information to online platforms is raising important questions for fields of patient education, such as cancer education. These questions include, but are not limited to (a) are pamphlets still a useful modality for patient information and education when so much is available on the Internet? (b) If so, what should be the relationship between print-based and online health information and education, and when should one modality take precedence over the other? This article responds to these questions within the Canadian health care context. PMID- 26581621 TI - Determination of DNA adducts by combining acid-catalyzed hydrolysis and chromatographic analysis of the carcinogen-modified nucleobases. AB - The commonly used method of analyzing carcinogen-induced DNA adducts involves the hydrolysis of carcinogen-modified DNA samples by using a mixture of enzymes, followed by (32)P-postlabeling or liquid chromatography (LC)-based analyses of carcinogen-modified mononucleotides/nucleosides. In the present study, we report the development and application of a new approach to DNA adduct analysis by combining the H(+)/heat-catalyzed release of carcinogen-modified nucleobases and the use of LC-based methods to analyze DNA adducts. Results showed that heating the carcinogen-modified DNA samples at 70 degrees C for an extended period of 4 to 6 h in the presence of 0.05% HCl can efficiently induce DNA depurination, releasing the intact carcinogen-modified nucleobases for LC analyses. After optimizing the hydrolysis conditions, DNA samples with C8- and N (2) -modified 2' deoxyguanosine, as well as N (6) -modified 2'-deoxyadenosine, were synthesized by reacting DNA with 1-nitropyrene, acetaldehyde, and aristolochic acids, respectively. These samples were then hydrolyzed, and the released nucleobase adducts were analyzed using LC-based analytical methods. Analysis results demonstrated a dose-dependent release of target DNA adducts from carcinogen modified DNA samples, indicating that the developed H(+)/heat-catalyzed hydrolysis method was quantitative. Comparative studies with enzymatic digestion method on carcinogen-modified DNA samples revealed that the two hydrolysis methods did not yield systematically different results. PMID- 26581622 TI - Tetranitratoethane. AB - Tetranitratoethane (C2H2N4O12), which has an oxygen content of 70.1% was synthesized by nitration of monomeric glyoxal using N2O5 and purified by sublimation. Single crystals could be grown from CH2Cl2/pentane and were used to determine the structure by X-ray diffraction. Several energetic parameters and values were also established. PMID- 26581623 TI - Prognostic Factors for Survival in Pulmonary Hypertension Due to Left Heart Disease. AB - BACKGROUND: The epidemiological data of pulmonary hypertension (PH) due to left heart disease (LHD) are limited. This study investigated hemodynamic and clinical factors associated with mortality in patients with PH due to LHD. METHODS AND RESULTS: We conducted a retrospective review in 243 patients with PH due to LHD, defined as mean pulmonary arterial pressure >=25 mmHg and pulmonary wedge pressure >15 mmHg at rest in right heart catheterization. Kaplan-Meier and Cox proportional hazard regression analyses were performed. Seventy-five patients died during an average follow-up of 52 months (range, 20-73 months). On multivariate analysis, only diastolic pulmonary vascular pressure gradient (DPG) >=7 mmHg among hemodynamic measurements was a predictor of mortality. Elevated N terminal pro-brain natriuretic peptide (NT-pro BNP), more severe New York Heart Association (NYHA) class, anemia, and renal dysfunction were more strongly associated with mortality. Mean right atrial pressure (RAP) and currently available markers of pulmonary vascular remodeling including transpulmonary pressure gradient (TPG) and pulmonary vascular resistance (PVR) had no effect on survival. CONCLUSIONS: DPG is weakly associated with mortality in PH due to LHD. Clinical factors such as NT-pro BNP, NYHA class, anemia and renal dysfunction are superior predictors. The prognostic ability of hemodynamic factors such as mean RAP, TPG, PVR and DPG is limited. PMID- 26581624 TI - Efficacy and Myocardial Injury With Subcutaneous Implantable Cardioverter Defibrillators - Computer Simulation of Defibrillation Shock Conduction. AB - BACKGROUND: Subcutaneous implantable cardiac defibrillator (S-ICD) systems have a lower invasiveness than traditional ICD systems, and expand the indications of ICD implantations. The S-ICD standard defibrillation shock output energy, however, is approximately 4 times that of the traditional ICD system. This raises concern about the efficacy of the defibrillation and myocardial injury. In this study, we investigated the defibrillation efficacy and myocardial injury with S ICD systems based on computer simulations. METHODS AND RESULTS: First, computer simulations were performed based on the S-ICD system configurations proposed in a previous study. Furthermore, simulations were performed by placing the lead at the left or right parasternal margin and the pulse generator in the superior and inferior positions (0-10 cm) of the recommended site. The simulated defibrillation threshold (DFT) for the 4 S-ICD system configurations were 30.1, 41.6, 40.6, and 32.8 J, which were generally similar to the corresponding clinical results of 33.5, 40.4, 40.1, and 34.3 J. CONCLUSIONS: The simulated DFT were generally similar to their clinical counterparts. In the simulation, the S ICD system had a higher DFT but relatively less severe myocardial injury compared with the traditional ICD system. Further, the lead at the right parasternal margin may correspond to a lower DFT and cause less myocardial injury. PMID- 26581625 TI - Redistribution of Kv1 and Kv7 enhances neuronal excitability during structural axon initial segment plasticity. AB - Structural plasticity of the axon initial segment (AIS), the trigger zone of neurons, is a powerful means for regulating neuronal activity. Here, we show that AIS plasticity is not limited to structural changes; it also occurs as changes in ion-channel expression, which substantially augments the efficacy of regulation. In the avian cochlear nucleus, depriving afferent inputs by removing cochlea elongated the AIS, and simultaneously switched the dominant Kv channels at the AIS from Kv1.1 to Kv7.2. Due to the slow activation kinetics of Kv7.2, the redistribution of the Kv channels reduced the shunting conductance at the elongated AIS during the initiation of action potentials and effectively enhanced the excitability of the deprived neurons. The results indicate that the functional plasticity of the AIS works cooperatively with the structural plasticity and compensates for the loss of afferent inputs to maintain the homeostasis of auditory circuits after hearing loss by cochlea removal. PMID- 26581626 TI - Whole exome sequencing for handedness in a large and highly consanguineous family. AB - Pinpointing genes involved in non-right-handedness has the potential to clarify developmental contributions to human brain lateralization. Major-gene models have been considered for human handedness which allow for phenocopy and reduced penetrance, i.e. an imperfect correspondence between genotype and phenotype. However, a recent genome-wide association scan did not detect any common polymorphisms with substantial genetic effects. Previous linkage studies in families have also not yielded significant findings. Genetic heterogeneity and/or polygenicity are therefore indicated, but it remains possible that relatively rare, or even unique, major-genetic effects may be detectable in certain extended families with many non-right-handed members. Here we applied whole exome sequencing to 17 members from a single, large consanguineous family from Pakistan. Multipoint linkage analysis across all autosomes did not yield clear candidate genomic regions for involvement in the trait and single-point analysis of exomic variation did not yield clear candidate mutations/genes. Any genetic contribution to handedness in this unusual family is therefore likely to have a complex etiology, as at the population level. PMID- 26581627 TI - Facial identity and facial expression are initially integrated at visual perceptual stages of face processing. AB - It is frequently assumed that facial identity and facial expression are analysed in functionally and anatomically distinct streams within the core visual face processing system. To investigate whether expression and identity interact during the visual processing of faces, we employed a sequential matching procedure where participants compared either the identity or the expression of two successively presented faces, and ignored the other irrelevant dimension. Repetitions versus changes of facial identity and expression were varied independently across trials, and event-related potentials (ERPs) were recorded during task performance. Irrelevant facial identity and irrelevant expression both interfered with performance in the expression and identity matching tasks. These symmetrical interference effects show that neither identity nor expression can be selectively ignored during face matching, and suggest that they are not processed independently. N250r components to identity repetitions that reflect identity matching mechanisms in face-selective visual cortex were delayed and attenuated when there was an expression change, demonstrating that facial expression interferes with visual identity matching. These findings provide new evidence for interactions between facial identity and expression within the core visual processing system, and question the hypothesis that these two attributes are processed independently. PMID- 26581628 TI - Environmental pH adaption and morphological transitions in Candida albicans. AB - The human fungal pathogen Candida albicans encounters a wide range of pH stresses during its commensal and pathogenic lifestyles. It has been well studied that environmental pH regulates the yeast-filamentous growth transition in this fungus. White-opaque switching is another type of phenotypic transitions in C. albicans. White and opaque cells are two morphologically and functionally distinct cell types, which differ in many aspects including global gene expression profiles, virulence, mating competency, and susceptibility to antifungals. The switch between white and opaque cell types is heritable and epigenetically regulated. In a recently study, Sun et al. (Eukaryot Cell 14:1127 1134, 2015) reported that pH plays a critical role in the regulation of the white opaque phenotypic switch and sexual mating in C. albicans via both the conserved Rim101-mediated pH sensing and cAMP signaling pathways. The effect of pH on the two biological processes may represent a balancing act between host environmental adaptation and sexual reproduction in this pathogenic fungus. PMID- 26581629 TI - Affected chromosome homeostasis and genomic instability of clonal yeast cultures. AB - Yeast cells originating from one single colony are considered genotypically and phenotypically identical. However, taking into account the cellular heterogeneity, it seems also important to monitor cell-to-cell variations within a clone population. In the present study, a comprehensive yeast karyotype screening was conducted using single chromosome comet assay. Chromosome-dependent and mutation-dependent changes in DNA (DNA with breaks or with abnormal replication intermediates) were studied using both single-gene deletion haploid mutants (bub1, bub2, mad1, tel1, rad1 and tor1) and diploid cells lacking one active gene of interest, namely BUB1/bub1, BUB2/bub2, MAD1/mad1, TEL1/tel1, RAD1/rad1 and TOR1/tor1 involved in the control of cell cycle progression, DNA repair and the regulation of longevity. Increased chromosome fragility and replication stress-mediated chromosome abnormalities were correlated with elevated incidence of genomic instability, namely aneuploid events-disomies, monosomies and to a lesser extent trisomies as judged by in situ comparative genomic hybridization (CGH). The tor1 longevity mutant with relatively balanced chromosome homeostasis was found the most genomically stable among analyzed mutants. During clonal yeast culture, spontaneously formed abnormal chromosome structures may stimulate changes in the ploidy state and, in turn, promote genomic heterogeneity. These alterations may be more accented in selected mutated genetic backgrounds, namely in yeast cells deficient in proper cell cycle regulation and DNA repair. PMID- 26581630 TI - What might retrotransposons teach us about aging? AB - Retrotransposons are activated as organisms age, based on work from several model systems. Since these mobile DNA elements can promote genome instability, this has raised the possibility that they can contribute to loss of cellular function with age. Many questions remain to be addressed about the relationship between retrotransposons and aging, so it is unclear if changes in their activity will be found to contribute to aging or to be a consequence of aging. A few broad perspectives are presented regarding how continued work on these elements could provide important insights into the aging process, regardless of whether their mobility is ultimately found to significantly contribute to reduced lifespan and healthspan. PMID- 26581631 TI - The complete mitochondrial genome of Koerneria sudhausi (Diplogasteromorpha: Nematoda) supports monophyly of Diplogasteromorpha within Rhabditomorpha. AB - Testing hypotheses of monophyly for different nematode groups in the context of broad representation of nematode diversity is central to understanding the patterns and processes of nematode evolution. Herein sequence information from mitochondrial genomes is used to test the monophyly of diplogasterids, which includes an important nematode model organism. The complete mitochondrial genome sequence of Koerneria sudhausi, a representative of Diplogasteromorpha, was determined and used for phylogenetic analyses along with 60 other nematode species. The mtDNA of K. sudhausi is comprised of 16,005 bp that includes 36 genes (12 protein-coding genes, 2 ribosomal RNA genes and 22 transfer RNA genes) encoded in the same direction. Phylogenetic trees inferred from amino acid and nucleotide sequence data for the 12 protein-coding genes strongly supported the sister relationship of K. sudhausi with Pristionchus pacificus, supporting Diplogasteromorpha. The gene order of K. sudhausi is identical to that most commonly found in members of the Rhabditomorpha + Ascaridomorpha + Diplogasteromorpha clade, with an exception of some tRNA translocations. Both the gene order pattern and sequence-based phylogenetic analyses support a close relationship between the diplogasterid species and Rhabditomorpha. The nesting of the two diplogasteromorph species within Rhabditomorpha is consistent with most molecular phylogenies for the group, but inconsistent with certain morphology based hypotheses that asserted phylogenetic affinity between diplogasteromorphs and tylenchomorphs. Phylogenetic analysis of mitochondrial genome sequences strongly supports monophyly of the diplogasteromorpha. PMID- 26581632 TI - Observed contrast changes in snow cover phenology in northern middle and high latitudes from 2001-2014. AB - Quantifying and attributing the phenological changes in snow cover are essential for meteorological, hydrological, ecological, and societal implications. However, snow cover phenology changes have not been well documented. Evidence from multiple satellite and reanalysis data from 2001 to 2014 points out that the snow end date (De) advanced by 5.11 (+/-2.20) days in northern high latitudes (52-75 degrees N) and was delayed by 3.28 (+/-2.59) days in northern mid-latitudes (32 52 degrees N) at the 90% confidence level. Dominated by changes in De, snow duration days (Dd) was shorter in duration by 5.57 (+/-2.55) days in high latitudes and longer by 9.74 (+/-2.58) days in mid-latitudes. Changes in De during the spring season were consistent with the spatiotemporal pattern of land surface albedo change. Decreased land surface temperature combined with increased precipitation in mid-latitudes and significantly increased land surface temperature in high latitudes, impacted by recent Pacific surface cooling, Arctic amplification and strengthening westerlies, result in contrasting changes in the Northern Hemisphere snow cover phenology. Changes in the snow cover phenology led to contrasting anomalies of snow radiative forcing, which is dominated by De and accounts for 51% of the total shortwave flux anomalies at the top of the atmosphere. PMID- 26581633 TI - Interaction effects of enniatin B, deoxinivalenol and alternariol in Caco-2 cells. AB - Enniatin B (ENN B), deoxinivalenol (DON) and alternariol (AOH) are secondary metabolites of filamentous fungi. These mycotoxins are contaminants of vegetables and cereals. They are cytotoxic and their effects are enhanced by their mixtures. The objectives of this study were to compare the cytotoxicity of ENN B, DON and AOH alone or in combination in human adenocarcinoma (Caco-2) cells and to evaluate the type of interactions of mycotoxin mixtures by the isobologram analysis. Cells were treated with concentrations ranging from 1.85 to 90MUM (AOH) and from 0.312 to 10MUM (for ENN B and DON), individually and in combination of two and three mycotoxins (from 1.85 to 30MUM for AOH and from 0.312 to 5MUM for ENN B and DON). The relation ratios between the mixtures DON+ENN B was 1:1; AOH+DON and ENN B+AOH was 1:6, and for the tertiary combination DON, ENN B and AOH 1:1:6. The IC50 value of ENN B and DON were 3.87 and 5.54MUM, respectively. No IC50 values were obtained for the AOH at any time tested in Caco-2 cells. With the isobologram the type of interaction between mycotoxin was evaluated. Synergistic, antagonistic and addictive effect was observed for the combination studied depending on the concentration affected. Mycotoxins combinations reduce cellular viability in the following increasing order: (DON+ENN B)>(ENN B+AOH)>(DON+AOH)>(DON+AOH+ENN B). PMID- 26581634 TI - miRNA-200c mediates mono-butyl phthalate-disrupted steroidogenesis by targeting vimentin in Leydig tumor cells and murine adrenocortical tumor cells. AB - The reproductive toxicity of plasticizer di-n-butyl phthalate (DBP) and its active metabolite monobutyl phthalate (MBP) has been demonstrated in rodents. The objective of this study was to explore roles of vimentin and miRNA-200c in steroidogenesis interfered by MBP. Mouse Leydig tumor cells (MLTC-1) and murine adrenocortical tumor cells (Y1) were employed and exposed to various levels of MBP (10(-7), 10(-6), 10(-5) and 10(-4)M). Steroid hormone production was increased significantly when MLTC-1 and Y1 cells were exposed to MBP at 10(-7)M. Additionally, vimentin and steroidogenic acute regulatory protein (StAR) expressions were upregulated at the same dose. It was found that MBP increased the steroidogenesis by facilitating the cholesterol transfer process by vimentin. In contrast, miRNA-200c expression was depressed at doses of MBP (10(-7)M) in both cells. Moreover, vimentin expression and progesterone production were increased in both MLTC-1 and Y1 cells after miRNA-200c expression was artificially inhibited. These results strongly suggested that MBP raised steroid hormone synthesis via upregulated vimentin by miRNA-200c. PMID- 26581635 TI - Inflammatory and fibrotic processes are involved in the cardiotoxic effect of sunitinib: Protective role of L-carnitine. AB - Sunitinib (Su) is currently approved for treatment of several malignances. However, along with the benefits of disease stabilization, cardiovascular toxicities have also been increasingly recognized. The aim of this study was to analyze which mechanisms are involved in the cardiotoxicity caused by Su, as well as to explore the potential cardioprotective effects of l-carnitine (LC). To this end, four groups of Wistar rats were used: (1) control; (2) rats treated with 400mg LC/kg/day; (3) rats treated with 25mg Su/kg/day; and (4) rats treated with LC+Su simultaneously. In addition, cultured rat cardiomyocytes were treated with an inhibitor of nuclear factor kappa B (NF-kappaB), in order to examine the role of this transcription factor in this process. An elevation in the myocardial expression of pro-inflammatory cytokines, together with an increase in the mRNA expression of NF-kappaB, was observed in Su-treated rats. These results were accompanied by an increase in the expression of pro-fibrotic factors, nitrotyrosine and NOX 2 subunit of NADPH oxidase; and by a decrease in that of collagen degradation factor. Higher blood pressure and heart rate levels were also found in Su-treated rats. All these alterations were inhibited by co administration of LC. Furthermore, cardiotoxic effects of Su were blocked by NF kappaB inhibition. Our results suggest that: (i) inflammatory and fibrotic processes are involved in the cardiac toxicity observed following treatment with Su; (ii) these processes might be mediated by the transcription factor NF-kappaB; (iii) LC exerts a protective effect against arterial hypertension, cardiac inflammation and fibrosis, which are all observed after Su treatment. PMID- 26581636 TI - Real life thromboprophylaxis in orthopedic surgery in Italy. Results of the GIOTTO study. AB - INTRODUCTION: Data from a prospective, multicentre observational study (Studio GIOTTO) were analyzed to determine, in clinical practice, the pattern of VTE prophylaxis and adherence to international guidelines recommendations in major orthopedic surgery (MOS) - including total hip arthroplasty (THA), total knee arthroplasty (TKA) and hip fracture surgery (HFS) - and knee arthroscopic surgery (KAS). METHODS: In 2010, the first consecutive 30 patients hospitalized in Italian centers for MOS and the first 15 for KAS were enrolled and treated according to the usual practice. RESULTS: 2010 patients were admitted for MOS (577 TKA, 787 THA and 646 HFS) and 993 for KAS; mean +/- SD age was 71.7 +/- 8 and 43.0 +/- 15 years, and female prevalence was 65.6% and 31.1% in MOS and KAS, respectively. Most (66.7%; 95% CI: 65-69%) patients admitted for MOS received a combined VTE prophylaxis, consisting of both pharmacological and physical tools, and 33.2% (95% CI: 31-35%) only pharmacological. For KAS figures were 23.7 (95% CI: 21-26%) and 75.3% (95% CI: 72-77%). Most MOS (91%; 95% CI: 89-92%) and KAS (95% CI: 98-100%) patients receiving pharmacological thromboprophylaxis were treated with low molecular weight heparin (LMWH), for (median) 40 days in TKR, 39 days in THR, 44 in HFS, and 16 in KAS. Patients receiving <35 days of LMWH prophylaxis among those undergoing THR and HFS were 8.9% and 5.9%, respectively. CONCLUSION: Although most patients undergoing orthopedic surgery received VTE prophylaxis, a gap between clinical practice and international guideline recommendations was observed. The reduced adherence to guideline recommendations is relevant for certain choices like type and duration of VTE, and physicians' behavior may reflect the changing approach of guidelines in their different editions. PMID- 26581637 TI - Free thiol groups in von Willebrand factor (VWF) are required for its full function under physiological flow conditions. AB - INTRODUCTION: von Willebrand factor (VWF) is rich in cysteine; next to important structural disulfide bonds, free thiol groups are present. Free thiols on the surface of plasmatic VWF have been shown to play a role in VWF self-association and in platelet binding under pathologically high levels of shear stress. The present study explores the role of VWF free thiol groups under physiological levels of shear stress and in interactions with collagen and platelet-GPIbalpha receptor. MATERIALS AND METHODS: Free and accessible thiol groups were blocked with N-ethylmaleimide (NEM) and the derivatized molecule was evaluated in functional assays. Reduced cysteine residues were identified using biotin-linked maleimide (MPB) followed by analysis of multimer and domain incorporation and by analysis of derivatized tryptic peptides by mass spectrometry. RESULTS: Blockade of free thiol groups significantly reduced VWF-mediated platelet recruitment to collagen under physiological flow conditions. This resulted from inhibition of VWF binding to both collagen and the platelet GPIb receptor. Evaluation of derivatization sites revealed a high level of derivatization in the cysteine-rich N- and C-termini of VWF. 19 MPB-derivatized peptides, 13 of which are described here for the first time, were identified by mass spectrometry. CONCLUSIONS: This study shows a significant contribution of free thiol groups in VWF to the mediation of platelet adhesion under physiological shear stress conditions. The free thiol groups are shown to be involved in VWF binding to both collagen III and platelet GP1b receptor. PMID- 26581639 TI - Multiple domains in the C-terminus of NMDA receptor GluN2B subunit contribute to neuronal death following in vitro ischemia. AB - Global cerebral ischemia induces selective degeneration of specific subsets of neurons throughout the brain, particularly in the hippocampus and cortex. One of the major hallmarks of cerebral ischemia is excitotoxicity, characterized by overactivation of glutamate receptors leading to intracellular Ca(2+) overload and ultimately neuronal demise. N-methyl-d-aspartate receptors (NMDARs) are considered to be largely responsible for excitotoxic injury due to their high Ca(2+) permeability. In the hippocampus and cortex, these receptors are most prominently composed of combinations of two GluN1 subunits and two GluN2A and/or GluN2B subunits. Due to the controversy regarding the differential role of GluN2A and GluN2B subunits in excitotoxic cell death, we investigated the role of GluN2B in the activation of pro-death signaling following an in vitro model of global ischemia, oxygen and glucose deprivation (OGD). For this purpose, we used GluN2B( /-) mouse cortical cultures and observed that OGD-induced damage was reduced in these neurons, and partially prevented in wild-type rat neurons by a selective GluN2B antagonist. Notably, we found a crucial role of the C-terminal domain of the GluN2B subunit in triggering excitotoxic signaling. Indeed, expression of YFP GluN2B C-terminus mutants for the binding sites to post-synaptic density protein 95 (PSD95), Ca(2+)-calmodulin kinase IIalpha (CaMKIIalpha) or clathrin adaptor protein 2 (AP2) failed to mediate neuronal death in OGD conditions. We focused on the GluN2B-CaMKIIalpha interaction and found a determinant role of this interaction in OGD-induced death. Inhibition or knock-down of CaMKIIalpha exerted a neuroprotective effect against OGD-induced death, whereas overexpression of this kinase had a detrimental effect. Importantly, in comparison with neurons overexpressing wild-type CaMKIIalpha, neurons overexpressing a mutant form of the kinase (CaMKII-I205K), unable to interact with GluN2B, were partially protected against OGD-induced damage. Taken together, our results identify crucial determinants in the C-terminal domain of GluN2B subunits in promoting neuronal death in ischemic conditions. These mechanisms underlie the divergent roles of the GluN2A- and GluN2B-NMDARs in determining neuronal fate in cerebral ischemia. PMID- 26581640 TI - Surface N-glycoproteome patterns reveal key proteins of neuronal differentiation. AB - Pluripotent stem cell-derived committed neural precursors are an important source of cells to treat neurodegenerative diseases including spinal cord injury. There remains an urgency to identify markers for monitoring of neural progenitor specificity, estimation of neural fate and follow-up correlation with therapeutic effect in preclinical studies using animal disease models. Cell surface capture technology was used to uncover the cell surface exposed N-glycoproteome of neural precursor cells upon neuronal differentiation as well as post-mitotic mature hNT neurons. The data presented depict an extensive study of surfaceome during neuronal differentiation, confirming glycosylation at a particular predicted site of many of the identified proteins. Quantitative changes detected in cell surface protein levels reveal a set of proteins that highlight the complexity of the neuronal differentiation process. Several of these proteins including the cell adhesion molecules ICAM1, CHL1, and astrotactin1 as well as LAMP1 were validated by SRM. Combination of immunofluorescence staining of ICAM1 and flow cytometry indicated a possible direction for future scrutiny of such proteins as targets for enrichment of the neuronal subpopulation from mixed cultures after differentiation of neural precursor cells. These surface proteins hold an important key for development of safe strategies in cell-replacement therapies of neuronal disorders. BIOLOGICAL SIGNIFICANCE: Neural stem and/or precursor cells have a great potential for cell-replacement therapies of neuronal diseases. Availability of well characterised and expandable neural cell lineage specific populations is critical for addressing such a challenge. In our study we identified and relatively quantified several hundred surface N-glycoproteins in the course of neuronal differentiation. We further confirmed the abundant changes for several cell adhesion proteins by SRM and outlined a strategy for utilisation of such N-glycoproteins in antibody based cell sorting. The comprehensive dataset presented here demonstrates the molecular background of neuronal differentiation highly useful for development of new plasma membrane markers to identify and select neuronal subpopulation from mixed neural cell cultures. PMID- 26581638 TI - The carbonic anhydrase inhibitor methazolamide prevents amyloid beta-induced mitochondrial dysfunction and caspase activation protecting neuronal and glial cells in vitro and in the mouse brain. AB - Mitochondrial dysfunction has been recognized as an early event in Alzheimer's disease (AD) pathology, preceding and inducing neurodegeneration and memory loss. The presence of cytochrome c (CytC) released from the mitochondria into the cytoplasm is often detected after acute or chronic neurodegenerative insults, including AD. The carbonic anhydrase inhibitor (CAI) methazolamide (MTZ) was identified among a library of drugs as an inhibitor of CytC release and proved to be neuroprotective in Huntington's disease and stroke models. Here, using neuronal and glial cell cultures, in addition to an acute model of amyloid beta (Abeta) toxicity, which replicates by intra-hippocampal injection the consequences of interstitial and cellular accumulation of Abeta, we analyzed the effects of MTZ on neuronal and glial degeneration induced by the Alzheimer's amyloid. MTZ prevented DNA fragmentation, CytC release and activation of caspase 9 and caspase 3 induced by Abeta in neuronal and glial cells in culture through the inhibition of mitochondrial hydrogen peroxide production. Moreover, intraperitoneal administration of MTZ prevented neurodegeneration induced by intra-hippocampal Abeta injection in the mouse brain and was effective at reducing caspase 3 activation in neurons and microglia in the area surrounding the injection site. Our results, delineating the molecular mechanism of action of MTZ against Abeta-mediated mitochondrial dysfunction and caspase activation, and demonstrating its efficiency in a model of acute amyloid-mediated toxicity, provide the first combined in vitro and in vivo evidence supporting the potential of a new therapy employing FDA-approved CAIs in AD. PMID- 26581641 TI - Comparative proteomic analysis of latex from Hevea brasiliensis treated with Ethrel and methyl jasmonate using iTRAQ-coupled two-dimensional LC-MS/MS. AB - Ethrel (ET) is an effective and widely used latex yield stimulant of Hevea brasiliensis (Para rubber tree), and jasmonate (JA) is a key inducer of laticifer differentiation in this plant. To examine variations in the latex proteome caused by these phytohormones, ET and methyl jasmonate (MeJA) were applied to Reyan 7-33 97 rubber tree clones, and comparative proteomic analyses were conducted. On the basis of a transcriptome shotgun assembly (TSA) sequence database and an iTRAQ coupled two-dimensional LC-MS/MS approach, 1499 latex proteins belonging to 1078 clusters were identified. With a 1.5-fold cut-off value to determine up- and down regulated proteins, a total of 101 latex proteins were determined to be regulated by ET and/or MeJA via pairwise comparisons among the three exposure durations (0 h, 6 h, and 48 h). Proteins associated with latex regeneration, including phosphoenolpyruvate carboxylase and acetyl-CoA C-acetyltransferase, and those associated with latex flow, such as chitinase and a sieve element occlusion protein, were affected by the application of ET. Chitinase and polyphenol oxidase were also found to be regulated by MeJA. The findings of this study may provide new insight into the roles of phytohormones in latex yield and the causative mechanisms of laticifer differentiation in rubber trees. SIGNIFICANCE: On the basis of a transcriptome shotgun assembly (TSA) sequence database and an iTRAQ coupled two-dimensional LC-MS/MS approach, the most comprehensive proteome of the latex was profiled, and the ethylene-/jasmonate-responsive proteins were identified in the latex of H. brasiliensis. The findings of this study may provide new insight into the role of phytohormones in latex yield and the causative mechanisms of laticifer differentiation in rubber trees. PMID- 26581642 TI - Discovery of potential colorectal cancer serum biomarkers through quantitative proteomics on the colonic tissue interstitial fluids from the AOM-DSS mouse model. AB - Quantitative proteomic analysis was performed using iTRAQ to discover colorectal cancer (CRC)-related proteins in tissue interstitial fluids (TIFs). A typical inflammation-related CRC mouse model was generated using azoxymethane-dextran sodium sulfate (AOM-DSS), and TIFs were collected from these mice in four stages during CRC development. Using stringent criteria, a total of 144 proteins displayed changes in their abundances during tumor growth, including 45 that consecutively increased, 17 that consecutively decreased and 82 that changed irregularly. Of these 144 proteins, 24 of the consecutively changed proteins were measured using MRM in individual TIF samples, and 18 were verified. Twelve proteins verified to be consecutively increased in TIFs were examined using MRM to evaluate changes in their abundance in individual mouse serum samples. The abundances of leucine-rich alpha-2-glycoprotein 1 (LRG1), tubulin beta-5 chain (TUBB5) and immunoglobulin J chain (IGJ) were significantly higher in CRC mice than in control mice. Using clinical samples and MRM, we further verified that LRG1 and TUBB5 are potential CRC serum biomarkers. These data demonstrate that coupling dynamic TIF proteomics with targeted serum proteomics in an animal model is a promising avenue for pursuing the discovery of tumor serum biomarkers. BIOLOGICAL SIGNIFICANCE: Colorectal cancer (CRC) is one of the most dangerous diseases worldwide. However, few of CRC biomarkers possess satisfied specificity and sensitivity in clinical practices. Exploration of more CRC biomarkers, especially in serum, is an urgent and also a time-consuming campaign in the CRC study. Our study demonstrates that quantitatively evaluating the phase-dependent proteins in colonic tissue interstitial fluids from AOM-DSS mice is a feasible and effective way for exploration of the CRC-related proteins and the potential serum biomarkers. We identified two proteins, LRG1 and TUBB5, which may be practicable in human clinical samples as CRC serum biomarkers. To sum up, this study provides a novel angle to explore the critical factors in tumorigenesis and a new pipeline for potential serum biomarker discovery and verification. PMID- 26581643 TI - Differential proteomic and genomic profiling of mouse striatal cell model of Huntington's disease and control; probable implications to the disease biology. AB - Huntington's disease (HD) is an autosomal dominant disorder of central nervous system caused by expansion of CAG repeats in exon1 of the huntingtin gene (Htt). Among various dysfunctions originated from the mutation in Htt gene, transcriptional deregulation has been considered to be one of the most important abnormalities. Large numbers of investigations identified altered expressions of genes in brains of HD patients and many models of HD. In this study we employed 2D SDS-PAGE/MALDI-MS coupled with 2D-DIGE and real-time PCR experiments of an array of genes focused to HD pathway to determine altered protein and gene expressions in STHdh(Q111)/Hdh(Q111) cells, a cell model of HD and compared with STHdh(Q7)/Hdh(Q7) cells, its wild type counterpart. We annotated 76 proteins from these cells and observed differential expressions of 31 proteins (by 2D-DIGE) involved in processes like unfolded protein binding, negative regulation of neuron apoptosis, response to superoxides etc. Our PCR array experiments identified altered expressions of 47 genes. Altogether significant alteration of 77 genes/proteins could be identified in this HD cell line with potential relevance to HD biology. BIOLOGICAL SIGNIFICANCE: In this study we intended to find out differential proteomic and genomic profiles in HD condition. We used the STHdh cells, a cellular model for HD and control. These are mouse striatal neuronal cell lines harboring 7 and 111 knock-in CAG repeats in their two alleles. The 111Q containing cell line (STHdh(Q111)/Hdh(Q111)) mimics diseased condition, whereas the 7Q containing ones (STHdh(Q7)/Hdh(Q7)), serves as the proper control cell line. Proteomic experiments were performed earlier to obtain differential expressions of proteins in R6/2 mice models, Hdh(Q) knock-in mice and in plasma and CSF from HD patients. However, no earlier report on proteomic alterations in these two HD cell lines and control was available in literature. It was, therefore, an important objective to find out differential expressions of proteins in these two cell lines. In this study, we annotated 76 proteins from STHdh(Q7)/Hdh(Q7) and STHdh(Q111)/Hdh(Q111) cells using 2D-gel/mass spectrometry. Next, by performing 2D-DIGE, we observed differential expressions of 31 proteins (16 upregulated and 15 downregulated) between these two cell lines. We also performed customized qRT-PCR array focused to HD pathway and found differential expressions of 47 genes (8 gene expressions increased and 39 genes were decreased significantly). A total of 77 genes/proteins (Htt downregulated in both the studies) were found to be significantly altered from both the experimental paradigms. We validated the differential expressions of Vim, Hypk, Ran, Dstn, Hspa5 and Sod2 either by qRT-PCR or Western blot analysis or both. Out of these 77, similar trends in alteration of 19 out of 31 and 38 out of 47 proteins/genes were reported in earlier studies. Thus our study confirmed earlier observations on differential gene/protein expressions in HD and are really useful. Additionally, we observed differential expression of some novel genes/proteins. One of this was Hypk, a Htt-interacting chaperone protein with the ability to solubilize mHtt aggregated structures in cell lines. We propose that downregulation of Hypk in STHdh(Q111)/Hdh(Q111) has a causal effect towards HD pathogenesis. Thus the novel findings from our study need further research and might be helpful to understand the molecular mechanism behind HD pathogenesis. PMID- 26581644 TI - Who is who matters-The effects of pseudoreplication in stable isotope analyses. AB - Stable isotope analysis in free-ranging primates is a promising new avenue in reconstructing feeding niches and temporal dietary variation. Particularly, the large sample sizes obtained from non-invasively collected hair and fecal samples from nests of great apes offer great potential. However, analyzing repeated observations of the same individuals without controlling for potential differences among them means to "pseudoreplicate" and can lead to a greatly inflated probability of erroneous significance. We here test the effects of pseudoreplication in stable isotope data of great ape hair by means of simulations. We show that pseudoreplication can severely affect the probability of erroneous significance as well as non-significance. We suggest several strategies to avoid pseudoreplication in primate isotope ecology. First, if applicable, information on individual identity should be included in statistical analyses. Second, if samples derive from unhabituated animals, sampling at far apart locations or territories should avoid resampling of the same animal. In great apes, sampling of independent nests within nest groups can ensure that each sample derives from a different individual. Third, we encourage the combination of genetic surveys with sampling for isotope analyses to ensure the (genetic) identification of individuals. Am. J. Primatol. 78:1017-1030, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26581645 TI - The barrier to the methyl rotation in Cis-2-butene and its isomerization energy to Trans-2-butene, revisited. AB - We respond to the two questions posed by Weinhold, Schleyer, and McKee (WSM) in their study of cis-2-butene (Weinhold et al., J Comput Chem 2014, 35, 1499), in which they solicit explanations for the relative conformational energies of this molecule in terms of the Quantum Theory of Atoms in Molecules (QTAIM). WSM requested answers to the questions: (1) why is cis-2-butene less stable than trans-2-butene despite the presence of a hydrogen-hydrogen (H?H) bond path in the former but not in the latter if the H?H bond path is stabilizing? (2) Why is the potential well of the conformational global minimum of cis-2-butene only 0.8 kcal/mol deep when the H?H bonding is stabilizing by 5 kcal/mol? Both questions raised by WSM are answered by considering the changes in the energies of all atoms as a function of the rotation of one of the two methyl groups from the minimum-energy structure, which exhibits the H?H bond path, to the transition state, which is devoid of this bond path. It is found that the stability gained by the H?H bonding interaction is cancelled by the destabilization of one of the ethylenic carbon atoms which, alone, destabilizes the system by as much as 5 kcal/mol in the global minimum conformation. Further, it is found that the 1.1 kcal/mol stability of trans-2-butene with respect to the cis-isomer is driven by the considerable destabilization of the ethylenic carbons by 11 kcal/mol, while the changes in the atomic energies of the other corresponding atoms in the two isomers account for the observed different stabilities. The error introduced into QTAIM atomic energies by neglecting the virials of the forces on the nuclei for partially optimized structures is discussed. PMID- 26581646 TI - AZOOR - A 10-year follow-up. PMID- 26581647 TI - Colic in infants. AB - INTRODUCTION: Colic in infants leads one in six families (17%) with children to consult a health professional. One systematic review of 15 community-based studies found a wide variation in prevalence, which depended on study design and method of recording. METHODS AND OUTCOMES: We conducted a systematic overview, aiming to answer the following clinical question: What are the effects of treatments for colic in infants? We searched: Medline, Embase, The Cochrane Library, and other important databases up to February 2014 (Clinical Evidence overviews are updated periodically; please check our website for the most up-to date version of this overview). RESULTS: At this update, searching of electronic databases retrieved 47 studies. After deduplication and removal of conference abstracts, 22 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 10 studies and the further review of 12 full publications. Of the 12 full articles evaluated, three systematic reviews and four RCTs were added at this update. We performed a GRADE evaluation for six PICO combinations. CONCLUSIONS: In this systematic overview, we categorise the efficacy for seven interventions based on information relating to the effectiveness and safety of casein hydrolysate milk, cranial osteopathy, Lactobacillus reuteri (probiotic), low-lactose milk, soya-based infant feeds, spinal manipulation, and whey hydrolysate milk. PMID- 26581648 TI - Development of Polar Order in the Liquid Crystal Phases of a 4-Cyanoresorcinol Based Bent-Core Mesogen with Fluorinated Azobenzene Wings. AB - A bent-core mesogen consisting of a 4-cyanoresorcinol unit as the central core and laterally fluorinated azobenzene wings forms four different smectic LC phase structures in the sequence SmA-SmCs -SmCs PAR -M, all involving polar SmCs PS domains with growing coherence length of tilt and polar order on decreasing temperature. The SmA phase is a cluster-type de Vries phase with randomized tilt and polar direction; in the paraelectric SmCs phase the tilt becomes uniform, although polar order is still short-range. Increasing polar correlation leads to a new tilted and randomized polar smectic phase with antipolar correlation between the domains (SmCs PAR ) which then transforms into a viscous polar mesophase M. As another interesting feature, spontaneous symmetry breaking by formation of a conglomerate of chiral domains is observed in the non-polar paraelectric SmCs phase. PMID- 26581649 TI - The biochemistry of blister fluid from pediatric burn injuries: proteomics and metabolomics aspects. AB - Burn injury is a prevalent and traumatic event for pediatric patients. At present, the diagnosis of burn injury severity is subjective and lacks a clinically relevant quantitative measure. This is due in part to a lack of knowledge surrounding the biochemistry of burn injuries and that of blister fluid. A more complete understanding of the blister fluid biochemistry may open new avenues for diagnostic and prognostic development. Burn insult induces a highly complex network of signaling processes and numerous changes within various biochemical systems, which can ultimately be examined using proteome and metabolome measurements. This review reports on the current understanding of burn wound biochemistry and outlines a technical approach for 'omics' profiling of blister fluid from burn wounds of differing severity. PMID- 26581650 TI - U-shaped relationship between current and pitch in helicene molecules. AB - The helicene is constructed by twisted benzene or other aromatic rings, exhibiting a helical structure. Using first-principles calculations, we investigate the electronic transport of helicenes under stretching or compressing. Interestingly, a U-shaped curve of the current against d (the pitch of a helicene) is observed. Further analysis shows that, it is the result of the nonmonotonic change of HOMO-LUMO gap with d. The change of overlap between orbitals induced by conformational deformation is found to be the underlying mechanism. Moreover, the U-curve phenomenon is an intrinsic feature of the helicene molecules, being robust to the electrode materials or doping. This U curve behavior is expected to be extended to helical graphene or other related structures, showing great application potential. PMID- 26581651 TI - Falls in critical care: a local review to identify incidence and risk. AB - BACKGROUND: Patient falls are the most common adverse event in hospitals, resulting in devastating physical, psychological and financial consequences. Therefore the emphasis on falls assessment and prevention is a key priority. Within hospitals those reported at greatest risk of falls are older patients with little known about the factors within critical care. At a local level, a practice development project was identified to review risk factors contributing to falls in critical care. AIMS: To identify the incidence of falls within adult critical care and the risk factors most likely to contribute to a fall. METHODS: Reported falls incidents were reviewed retrospectively using a local incident reporting system, over a 2-year period from four critical care units. FINDINGS: Forty-two incidents were reviewed indicating a low rate of injury and low rate of occurrence (0.99 falls/1000 bed days). The median age of fallers was 58 years and the most common risk factor for falls was confusion or agitation, followed by patients attempting to mobilize against advice. DISCUSSION: Critically ill patients were less likely to fall and were more likely to be younger than patients falling on an acute care ward. Neuroscience/trauma critically ill patients were more likely to fall than general critically ill patients; this was expected to be because of the increased presence of confusion or agitation in this group. The local system used to report falls produced difficulties in identifying risk factors in a consistent way. Although limitations exist, this review has enabled the development of more suitable local critical care falls risk factor assessment and interventions to minimize the risk of falling. CONCLUSIONS: Fall rates, related injuries and circumstances of falls vary considerably among acute care and critical care specialities. Future work should concentrate on better falls reporting systems and further research should include validating risk factors for critical care falls. PMID- 26581652 TI - High carbohydrate intake from starchy foods is positively associated with metabolic disorders: a Cohort Study from a Chinese population. AB - Starchy foods are the main sources of carbohydrates; however, there is limited information on their metabolic impact. Therefore, we assessed the association between carbohydrates from starchy foods (Carb-S) intakes and the metabolic disorders of metabolic syndrome (MetS) and hyperlipidemia. In this study, 4,154 participants from Northern China were followed up for 4.2 years. Carb-S included rice, refined wheat, tubers, and their products. Multivariable regression models were used to calculate risk ratios (RRs) for MetS and hyperlipidemia from Carb-S, total carbohydrates, and carbohydrates from other food sources (Carb-O). Receiver operating characteristic analysis was used to determine a Carb-S cut-off value. High total carbohydrate intake was associated with increased risks of MetS (RR: 2.24, 95% CI: 1.00-5.03) and hyperlipidemia (RR: 3.05, 95% CI: 1.25-7.45), compared with the first quartile. High Carb-S intake (fourth quartile) was significantly associated with MetS (RR: 1.48, 95% CI: 1.01-2.69) and hyperlipidemia (RR: 1.73, 95% CI: 1.05-3.35). No associations with Carb-O were observed. Visceral adiposity, triglyceride levels, and high-density lipoprotein cholesterol significantly contributed to the metabolic disorders. The Carb-S cut off value was 220 g. Both high total carbohydrate and Carb-S intakes were associated with hyperlipidemia and MetS; Carb-S appears to contribute more to these disorders. PMID- 26581653 TI - Increased Expression of Serglycin in Specific Carcinomas and Aggressive Cancer Cell Lines. AB - In the present pilot study, we examined the presence of serglycin in lung, breast, prostate, and colon cancer and evaluated its expression in cell lines and tissues. We found that serglycin was expressed and constitutively secreted in culture medium in high levels in more aggressive cancer cells. It is worth noticing that aggressive cancer cells that harbor KRAS or EGFR mutations secreted serglycin constitutively in elevated levels. Furthermore, we detected the transcription of an alternative splice variant of serglycin lacking exon 2 in specific cell lines. In a limited number of tissue samples analyzed, serglycin was detected in normal epithelium but was also expressed in higher levels in advanced grade tumors as shown by immunohistochemistry. Serglycin staining was diffuse, granular, and mainly cytoplasmic. In some cancer cells serglycin also exhibited membrane and/or nuclear immunolocalization. Interestingly, the stromal cells of the reactive tumor stroma were positive for serglycin, suggesting an enhanced biosynthesis for this proteoglycan in activated tumor microenvironment. Our study investigated for first time the distribution of serglycin in normal epithelial and cancerous lesions in most common cancer types. The elevated levels of serglycin in aggressive cancer and stromal cells may suggest a key role for serglycin in disease progression. PMID- 26581655 TI - CT-detected traumatic small artery extremity injuries: surgery, embolize, or watch? A 10-year experience. AB - Advances in computed tomography (CT) angiography have increased the sensitivity and specificity of detecting small branch arterial injuries in the extremities of trauma patients. However, it is unclear whether these patients should undergo surgery, angioembolization, or conservative watchful waiting. We hypothesized that uncomplicated small arterial branch injuries can be managed successfully with watchful waiting. A 10-year retrospective review of extremity CT angiograms with search findings of arterial "active extravasation" or "pseudoaneurysm" was performed at a level 1 county trauma center. Subgroup analysis was performed on those with isolated extremity injury and those with concurrent injuries. A total of 31 patients had CT-detected active extravasation (84 %) or pseudoaneurysm (16 %), 71 % of which were isolated vascular injuries. Of the patients evaluated, 71 % (n = 22) were managed with watchful waiting, 19 % (n = 6) with angioembolization, and 10 % (n = 3) with surgery. Watchful waiting complications included progression to alternative treatment (n = 1) and blood transfusions (n = 2). Complications of surgery included the inability to find active bleeding (n = 1) and postoperative psychosis (n = 1). Complications of angioembolization were limited to a postprocedure blood transfusion (n = 1). Patients with isolated vascular injuries had an average length of stay of 2.9 days, with management averages of the following: 2.7 days with watchful waiting (n = 16), 3.3 days with angioembolization (n = 3), and 3.7 days with surgery (n = 3). CT angiography has greatly increased the reported incidence of traumatic arterial injury in the extremity. We propose that small branch arterial injuries in the extremities can be managed successfully with watchful waiting and do not often require immediate embolization. PMID- 26581657 TI - Hybridization promotes speciation in Coenonympha butterflies. AB - Hybridization has become a central element in theories of animal evolution during the last decade. New methods in population genomics and statistical model testing now allow the disentangling of the complexity that hybridization brings into key evolutionary processes such as local adaptation, colonization of new environments, species diversification and extinction. We evaluated the consequences of hybridization in a complex of three alpine butterflies in the genus Coenonympha, by combining morphological, genetic and ecological analyses. A series of approximate Bayesian computation procedures based on a large SNP data set strongly suggest that the Darwin's Heath (Coenonympha darwiniana) originated through hybridization between the Pearly Heath (Coenonympha arcania) and the Alpine Heath (Coenonympha gardetta) with different parental contributions. As a result of hybridization, the Darwin's Heath presents an intermediate morphology between the parental species, while its climatic niche seems more similar to the Alpine Heath. Our results also reveal a substantial genetic and morphologic differentiation between the two geographically disjoint Darwin's Heath lineages leading us to propose the splitting of this taxon into two different species. PMID- 26581656 TI - Reference gene selection for normalization of RT-qPCR gene expression data from Actinidia deliciosa leaves infected with Pseudomonas syringae pv. actinidiae. AB - Normalization of data, by choosing the appropriate reference genes (RGs), is fundamental for obtaining reliable results in reverse transcription-quantitative PCR (RT-qPCR). In this study, we assessed Actinidia deliciosa leaves inoculated with two doses of Pseudomonas syringae pv. actinidiae during a period of 13 days for the expression profile of nine candidate RGs. Their expression stability was calculated using four algorithms: geNorm, NormFinder, BestKeeper and the deltaCt method. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and protein phosphatase 2A (PP2A) were the most stable genes, while beta-tubulin and 7s-globulin were the less stable. Expression analysis of three target genes, chosen for RGs validation, encoding the reactive oxygen species scavenging enzymes ascorbate peroxidase (APX), superoxide dismutase (SOD) and catalase (CAT) indicated that a combination of stable RGs, such as GAPDH and PP2A, can lead to an accurate quantification of the expression levels of such target genes. The APX level varied during the experiment time course and according to the inoculum doses, whereas both SOD and CAT resulted down-regulated during the first four days, and up-regulated afterwards, irrespective of inoculum dose. These results can be useful for better elucidating the molecular interaction in the A. deliciosa/P. s. pv. actinidiae pathosystem and for RGs selection in bacteria-plant pathosystems. PMID- 26581658 TI - Multidimensional esthetic evaluation of patients with a cleft lip and palate wearing a maxillary partial removable dental prosthesis: A 5-year retrospective study. AB - STATEMENT OF PROBLEM: No published quantitative or qualitative studies are available of the 2-dimensional (2D) and 3D esthetic evaluation of patients with a cleft lip and palate (CLP) wearing a maxillary partial removable dental prosthesis (MPRDP). PURPOSE: The purpose of this retrospective clinical study was to qualitatively and quantitatively evaluate the facial esthetic improvements of patients with CLP wearing an MPRDP for 5 years by using 2D cephalometric and 3D photogrammetry methods. MATERIAL AND METHODS: Six patients, 2 men and 4 women, with CLP deformity were recruited and treated with an MPRDP by the same dentist over 5 years. Results of the clinical examination were recorded before and after wearing the MPRDP. Sella-nasion-A (SNA) point, the U1-SN, 0-meridian to SN, nasolabial angle, and maxillary incisor exposure were measured by 2D cephalometric analysis before and after wearing the MPRDP. 3D photographs were captured by 3dMD software. Geomagic Spark Studio software was also used to measure the patients' improved upper lip projection after the MPRDP was worn. The paired sample t test was used to compare the participants (alpha=.05). RESULTS: U1-SN (P<.05) and 0-meridian to SN (P<.01) had significant deviation statistically. After patients underwent clinical examination, SNA and nasiolabial angles were found to have improved, although no statistical significance was observed. CONCLUSIONS: A maxillary partial removable dental prosthesis (MPRDP) can advance the upper lip forward, restoring the subnasal and upper lip projection. Patients' nasiolabial angles with MPRDPs were decreased, which led to a more harmonious facial contour. PMID- 26581659 TI - Sealing maxillary titanium obturators with removable flexible caps. AB - Maxillary obturator prostheses with hollow metal obturators can be made of titanium to reduce weight. To prevent perforation of the hollow obturator during modifications, the obturator is slightly undersized and covered with a replaceable cap. This cap is made of a soft copolymer to facilitate uncomplicated modifications in the resection area and to improve function. PMID- 26581654 TI - In vivo small animal micro-CT using nanoparticle contrast agents. AB - Computed tomography (CT) is one of the most valuable modalities for in vivo imaging because it is fast, high-resolution, cost-effective, and non-invasive. Moreover, CT is heavily used not only in the clinic (for both diagnostics and treatment planning) but also in preclinical research as micro-CT. Although CT is inherently effective for lung and bone imaging, soft tissue imaging requires the use of contrast agents. For small animal micro-CT, nanoparticle contrast agents are used in order to avoid rapid renal clearance. A variety of nanoparticles have been used for micro-CT imaging, but the majority of research has focused on the use of iodine-containing nanoparticles and gold nanoparticles. Both nanoparticle types can act as highly effective blood pool contrast agents or can be targeted using a wide variety of targeting mechanisms. CT imaging can be further enhanced by adding spectral capabilities to separate multiple co-injected nanoparticles in vivo. Spectral CT, using both energy-integrating and energy-resolving detectors, has been used with multiple contrast agents to enable functional and molecular imaging. This review focuses on new developments for in vivo small animal micro CT using novel nanoparticle probes applied in preclinical research. PMID- 26581660 TI - Oral squamous cell carcinoma misdiagnosed as a denture-related traumatic ulcer: A clinical report. AB - A 65-year-old woman presented with an ulcerated lesion in the alveolar ridge mucosa, which appeared after new dentures had been inserted. Despite many treatment attempts, the lesion did not recede, even with the interruption of denture wearing. A biopsy was performed, and histopathologic examination revealed an ulcerated, invasive, poorly differentiated oral squamous cell carcinoma. The time from the patient's first contact with the prosthodontist because of the lesion until the appropriate diagnosis was established was approximately 6 months. This clinical report documents a significant delay in the oral squamous cell carcinoma diagnosis and treatment because of a clinical misdiagnosis of a traumatic ulcer resulting from complete dentures. Prosthodontists should be aware of the importance of early diagnosis of oral cancer among elderly prosthesis wearers. PMID- 26581661 TI - Effect of surface treatments on the properties and morphological change of dental zirconia. AB - STATEMENT OF PROBLEM: Creating a rough surface for bonding with airborne-particle abrasion with alumina may damage the surface of zirconia. Other treatment methods for creating a bonding surface without causing damage require investigation. PURPOSE: The purpose of this in vitro study was to find ways of treating the zirconia surface without causing flaws, debris, pits, microcracks, or tetragonal to monoclinic phase transformation. MATERIAL AND METHODS: Yttria-stabilized tetragonal zirconia polycrystal (Y-TZP) ceramic surfaces were treated with gas plasma, argon-ion bombardment, 150-MUm abrasive zirconia particles, and abrasive 150-MUm alumina particles; untreated surfaces were used as the control group. X ray diffraction (XRD) and confocal Raman spectroscopy were used to study the phase transformation. The roughness of specimens was measured with a confocal 3D laser scanning microscope. Modification of surface topography was analyzed with field emission scanning electron microscopy (FESEM), and the flexural strength was measured with a universal testing machine. Statistical analyses were performed with 1-way ANOVA, followed by comparison of means with the Tukey honest significant difference test. The standard deviation was calculated with descriptive statistics. RESULTS: The sintered Y-TZP ceramic used in this study showed 2 phases, tetragonal and cubic. Specimens abraded with 150-MUm alumina particles showed a higher monoclinic volume fraction (VmXRD=8.68%) and roughness (Ra=0.91MUm) than specimens abraded with 150-MUm zirconia particles (VmXRD=1.22%, Ra=0.08MUm). One-way ANOVA indicated a significance difference in roughness among groups (P<.01). No phase transformation was observed in specimens treated with argon-ion bombardment or plasma. According to the Raman results, the volume fraction of the monoclinic phase for the specimens treated with airborne-particle abrasion depended on the distance from the ceramic surfaces and decreased with the increase in this distance. A slightly higher flexural strength was observed for untreated specimens (1009 MPa), followed by specimens treated with gas plasma (1000 MPa) and those airborne-particle abraded with 150-MUm zirconia particles (967 MPa). The flexural strength of other specimens was lower (940 MPa for specimens abraded with 150-MUm alumina particles and 916 MPa for specimens subjected to argon-ion bombardment). One-way ANOVA analysis indicated no significant difference in flexural strengths among all groups (P>.2). FESEM measurements showed that airborne-particle abrading Y-TZP surfaces with 150-MUm alumina particles caused more damage to this area than the other methods. CONCLUSIONS: Y-TZP ceramic surfaces treated with zirconia particles, argon-ion bombardment, and gas plasma were damaged less in comparison with surfaces abraded with alumina particles. PMID- 26581662 TI - Managing a fractured implant: A clinical report. AB - Implant fixture fracture is one of the reasons for late implant failure, with incidence rates ranging from 0.2% to 7.5%. Material defects, occlusal overload, prosthetic design, and nonpassive prosthesis fit have been identified as causative factors for implant fixture fractures. A custom-made prosthetic post was made to connect the remaining implant fixture and the implant-retained crown, as the fractured implant fixture exhibited no signs of infection and the fixture had adequate remaining length. In addition, complete removal of the implant could have resulted in significant bone loss at the site. PMID- 26581664 TI - Mapping and identification of cassava mosaic geminivirus DNA-A and DNA-B genome sequences for efficient siRNA expression and RNAi based virus resistance by transient agro-infiltration studies. AB - Geminiviruses are among the most serious pathogens of many economically important crop plants and RNA interference (RNAi) is an important strategy for their control. Although any fragment of a viral genome can be used to generate a double stranded (ds) RNA trigger, the precursor for generation of siRNAs, the exact sequence and size requirements for efficient gene silencing and virus resistance have so far not been investigated. Previous efforts to control geminiviruses by gene silencing mostly targeted AC1, the gene encoding replication-associated protein. In this study we made RNAi constructs for all the genes of both the genomic components (DNA-A and DNA-B) of African cassava mosaic virus (ACMV-CM), one of the most devastating geminiviruses causing cassava mosaic disease (CMD) in Africa. Using transient agro-infiltration studies, RNAi constructs were evaluated for their ability to trigger gene silencing against the invading virus and protection against it. The results show that the selection of the DNA target sequence is an important determinant for the amount of siRNA produced and the extent of resistance. The ACMV genes AC1, AC2, AC4 from DNA-A and BC1 from DNA-B were effective targets for RNAi-mediated resistance and their siRNA expression was higher compared to other RNAi constructs. The RNAi construct targeting AC2, the suppressor of gene silencing of ACMV-CM gave highest level of resistance in the transient studies. This is the first report of targeting DNA-B to confer resistance to a bipartite geminivirus infection. PMID- 26581663 TI - Undernourishment in utero Primes Hepatic Steatosis in Adult Mice Offspring on an Obesogenic Diet; Involvement of Endoplasmic Reticulum Stress. AB - In order to investigate the possible involvement of endoplasmic reticulum (ER) stress in the developmental origins of hepatic steatosis associated with undernourishment in utero, we herein employed a fetal undernourishment mouse model by maternal caloric restriction in three cohorts; cohort 1) assessment of hepatic steatosis and the ER stress response at 9 weeks of age (wks) before a high fat diet (HFD), cohort 2) assessment of hepatic steatosis and the ER stress response on a HFD at 17 wks, cohort 3) assessment of hepatic steatosis and the ER stress response at 22 wks on a HFD after the alleviation of ER stress with a chemical chaperone, tauroursodeoxycholic acid (TUDCA), from 17 wks to 22 wks. Undernourishment in utero significantly deteriorated hepatic steatosis and led to the significant integration of the ER stress response on a HFD at 17 wks. The alleviation of ER stress by the TUDCA treatment significantly improved the parameters of hepatic steatosis in pups with undernourishment in utero, but not in those with normal nourishment in utero at 22 wks. These results suggest the pivotal involvement of the integration of ER stress in the developmental origins of hepatic steatosis in association with undernourishment in utero. PMID- 26581665 TI - Comparison of Illumina de novo assembled and Sanger sequenced viral genomes: A case study for RNA viruses recovered from the plant pathogenic fungus Sclerotinia sclerotiorum. AB - The advent of 'next generation sequencing' (NGS) technologies has led to the discovery of many novel mycoviruses, the majority of which are sufficiently different from previously sequenced viruses that there is no appropriate reference sequence on which to base the sequence assembly. Although many new genome sequences are generated by NGS, confirmation of the sequence by Sanger sequencing is still essential for formal classification by the International Committee for the Taxonomy of Viruses (ICTV), although this is currently under review. To empirically test the validity of de novo assembled mycovirus genomes from dsRNA extracts, we compared the results from Illumina sequencing with those from random cloning plus targeted PCR coupled with Sanger sequencing for viruses from five Sclerotinia sclerotiorum isolates. Through Sanger sequencing we detected nine viral genomes while through Illumina sequencing we detected the same nine viruses plus one additional virus from the same samples. Critically, the Illumina derived sequences share >99.3 % identity to those obtained by cloning and Sanger sequencing. Although, there is scope for errors in de novo assembled viral genomes, our results demonstrate that by maximising the proportion of viral sequence in the data and using sufficiently rigorous quality controls, it is possible to generate de novo genome sequences of comparable accuracy from Illumina sequencing to those obtained by Sanger sequencing. PMID- 26581666 TI - Can antioxidant-rich blackcurrant juice drink consumption improve photoprotection against ultraviolet radiation? PMID- 26581667 TI - Characterization of Gastric Mucosa Biopsies Reveals Alterations in Huntington's Disease. AB - Weight loss is an important complication of Huntington's disease (HD), however the mechanism for weight loss in HD is not entirely understood. Mutant huntingtin is expressed in the gastrointestinal (GI) tract and, in HD mice, mutant huntingtin inclusions are found within the enteric nervous system along the GI tract. A reduction of neuropeptides, decreased mucosal thickness and villus length, as well as gut motility impairment, have also been shown in HD mice. We therefore set out to study gastric mucosa of patients with HD, looking for abnormalities of mucosal cells using immunohistochemistry. In order to investigate possible histological differences related to gastric acid production, we evaluated the cell density of acid producing parietal cells, as well as gastrin producing cells (the endocrine cell controlling parietal cell function). In addition, we looked at chief cells and somatostatin-containing cells. In gastric mucosa from HD subjects, compared to control subject biopsies, a reduced expression of gastrin (a marker of G cells) was found. This is in line with previous HD mouse studies showing reduction of GI tract neuropeptides. PMID- 26581669 TI - Introductory paragraph. PMID- 26581668 TI - Gun violence prevention: Ripe for the entire medical community. PMID- 26581670 TI - Rehabilitation - a new approach. Part two: the underlying theories. AB - This editorial considers how healthcare systems should approach the problems associated with ongoing, persistent symptoms and limitations on a person's ability to undertake activities. It starts from the premise, established in the first editorial, that the current reliance on the biomedical model of health and illness is no longer 'fit for purpose', and is one major cause of current difficulties within the health service. Among other problems, it may lead to the marginalisation of rehabilitation services, especially when resources are limited. This editorial describes and then highlights the implications of the holistic, biopsychosocial model of illness. It also outlines the rehabilitation process, demonstrating its similarity to the process used by medical services, with the primary difference being the centre of attention: disease for medical service, disability for rehabilitation services. The model of rehabilitation emphasises: the importance of being patient-centred and goal-directed in rehabilitation; the need for liaison by the team and learning by the patient; and that the patient needs to be encouraged and enabled to practice wanted activities. PMID- 26581671 TI - Patterns and predictors of failure following tri-modality therapy for locally advanced esophageal cancer. AB - BACKGROUND: Although tri-modality therapy is an acceptable standard of care in patients with locally advanced esophageal cancer, data regarding patterns of failure is lacking. We report bi-institutional patterns of failure experience treating patients using tri-modality therapy. MATERIALS AND METHODS: We retrospectively reviewed patients who underwent chemoradiation followed by esophagectomy between 2006 and 2011 at two NCI-designated cancer centers. First failure sites were categorized as local, regional nodal, or distant. Statistical analysis was performed using Fisher's exact test, non-parametric Wilcoxon rank sum test, and multiple logistic regression. Kaplan-Meier curves were generated for relapse-free survival (RFS) and overall survival. RESULTS: A total of 132 patients met the inclusion criteria with a median age of 62 (range 36-80) and median follow-up of 28 months (range 4-128). There were a total of six (4.5%) local, 13 (10%) regional nodal, and 32 (23.5%) distant failures. Local failure was correlated with fewer lymph nodes (LN) assessed (p = 0.01) and close/positive margins (p < 0.01). Regional nodal failure was correlated with fewer LN assessed (p < 0.01) and larger pretreatment tumor size (p = 0.04). Patients with <=13 LN evaluated had an inferior locoregional RFS versus patients with >13 LN evaluated (p = 0.003). Distant recurrence was correlated with higher pathologic nodal stage (p < 0.001), ulceration (p = 0.017), perineural invasion (p = 0.029), residual disease (p = 0.004), and higher post-treatment PET SUV max (p = 0.049). Patients with a pathologic complete response (OR 0.19, 95% CI 0.05-0.68) were less likely to experience distant recurrence. CONCLUSION: Tumor and treatment factors may predict for failure in patients undergoing tri-modality therapy for locally advanced esophageal cancer. Further data is needed to identify patterns of failure in these patients. PMID- 26581673 TI - The long-term effects of methamphetamine exposure during pre-adolescence on depressive-like behaviour in a genetic animal model of depression. AB - Methamphetamine (METH) is a psychostimulant and drug of abuse, commonly used early in life, including in childhood and adolescence. Adverse effects include psychosis, anxiety and mood disorders, as well as increased risk of developing a mental disorder later in life. The current study investigated the long-term effects of chronic METH exposure during pre-adolescence in stress-sensitive Flinders Sensitive Line (FSL) rats (genetic model of depression) and control Flinders Resistant Line (FRL) rats. METH or vehicle control was administered twice daily from post-natal day 19 (PostND19) to PostND34, followed by behavioural testing at either PostND35 (early effects) or long-lasting after withdrawal at PostND60 (early adulthood). Animals were evaluated for depressive like behaviour, locomotor activity, social interaction and object recognition memory. METH reduced depressive-like behaviour in both FSL and FRL rats at PostND35, but enhanced this behaviour at PostND60. METH also reduced locomotor activity on PostND35 in both FSL and FRL rats, but without effect at PostND60. Furthermore, METH significantly lowered social interaction behaviour (staying together) in both FRL and FSL rats at PostND35 and PostND60, whereas self grooming time was significantly reduced only at PostND35. METH treatment enhanced exploration of the familiar vs. novel object in the novel object recognition test (nORT) in FSL and FRL rats on PostND35 and PostND60, indicative of reduced cognitive performance. Thus, early-life METH exposure induce social and cognitive deficits. Lastly, early-life exposure to METH may result in acute antidepressant like effects immediately after chronic exposure, whereas long-term effects after withdrawal are depressogenic. Data also supports a role for genetic predisposition as with FSL rats. PMID- 26581672 TI - Disease-Modifying Drugs in Parkinson's Disease. AB - Despite an increased understanding of the pathogenesis of Parkinson's disease (PD), and a number of drugs designed to ameliorate symptoms, finding an effective neuroprotective therapy remains elusive. For decades now, several promising agents targeting different pathways have been explored as potential treatments that could help slow disease progression, but these have met with limited success. There are hurdles to overcome, particularly given that there is no exact animal model of PD and also no reliable biomarkers for PD. Without biomarkers, it is not possible to demonstrate, in the context of a clinical trial, that an intervention prevents neuronal degeneration. However, given the compelling scientific rationale of several compounds, an unrelenting pursuit continues. There have been hundreds of human studies looking at neuroprotection in PD. This article will briefly summarize several of the neuroprotective treatments that have been evaluated in large clinical trials, and will also outline some of the newer therapies that are currently being explored. PMID- 26581674 TI - Sex differences and the role of PPAR alpha in experimental stroke. AB - Males and females respond differently to stroke. Moreover, females often experience worse long-term stroke outcomes. Fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARalpha) agonist has been shown to improve stroke outcome and resolve neuroinflammation in male mice. The present study compares the effect of pretreatment with fenofibrate versus vehicle control in male and female mice during experimental stroke. Mice were treated with low dose fenofibrate 30 min before and once a day for three additional days after stroke onset. We observed a reduction in infarct volume in male mice 96 h post stroke with low-dose fenofibrate pretreatment that was due to increase of an M2 macrophage phenotype in the brain and an increase in regulatory cells in the periphery. These outcomes were not replicated in females, likely due to the lower PPARalpha expression in cells and tissues in females vs males. We conclude that PPARalpha agonist treatment prior to stroke is neuroprotective in males but not females. These findings indicate PPARalpha as a probable mechanism of sex difference in stroke outcome and support the need for representation of females in stroke therapy research. PMID- 26581677 TI - The clinical geneticist and the evaluation of failure to thrive versus failure to feed. AB - Common clinical genetic referrals for the pediatric patient include a single major or multiple minor anomalies, dysmorphic features, especially when accompanied by developmental delay or intellectual disability, and failure to thrive (FTT). This review provides pediatric definitions of FTT and the genetic differential for FTT, which includes chromosomal disorders, microdeletion/duplication syndromes, uniparental disomy/methylation disorder, disorders of DNA repair, teratogens, metabolic syndromes, and skeletal dysplasias. Three clinical genetics cases highlight challenges in deciphering the cause of FTT. The review concludes with a ten-step approach that might improve diagnostic ability in differentiating FTT cases (those with genetic or other metabolic causes) from "failure to feed," in other words FTT as the direct result of neglect and/or child abuse. PMID- 26581675 TI - On the effect of minocycline on the depressive-like behavior of mice repeatedly exposed to malathion: interaction between nitric oxide and cholinergic system. AB - This study was performed to investigate the antidepressant-like effect of minocycline in mice exposed to organophosphate pesticide malathion and possible involvement of nitric oxide/cGMP pathway in this paradigm. Mice were administered specific doses of malathion once daily for 7 consecutive days. After induction of depression, different doses of minocycline were daily injected alone or combined with non-specific NOS inhibitor, L-NAME, specific inducible NOS inhibitor, AG, NO precursor, L-arginine, and PDE5I, sildenafil. After locomotion assessment in open field test, immobility times were recorded in the FST and TST. Moreover, hippocampal nitrite concentrations and acetylcholinesterase activity were measured. The results showed that repeated exposure to malathion induces depressive-like behavior at dose of 250 mg/kg. Minocycline (160 mg/kg) significantly reduced immobility times in FST and TST (P < 0.001). Combination of sub-effective doses of minocycline (80 mg/kg) with either L-NAME (3 mg/kg) or AG (25 mg/kg) significantly exerted a robust antidepressant-like effect in FST and TST (P < 0.001). Furthermore, minocycline at the same dose which has antidepressant-like effect, significantly reduced hippocampal nitrite concentration. The investigation indicates the essential role for NO/cGMP pathway in malathion-induced depressive-like behavior and antidepressant-like effect of minocycline. Moreover, the interaction between nitrergic and cholinergic systems are suggested to be involved in malathion-induced depression. PMID- 26581676 TI - Unconventional T-cell recognition of an arthritogenic epitope of proteoglycan aggrecan released from degrading cartilage. AB - It has been proposed that peptide epitopes bind to MHC class II molecules to form distinct structural conformers of the same MHC II-peptide complex termed type A and type B, and that the two conformers of the same peptide-MHC II complex are recognized by distinct CD4 T cells, termed type A and type B T cells. Both types recognize short synthetic peptides but only type A recognize endosomally processed intact antigen. Type B T cells that recognize self peptides from exogenously degraded proteins have been shown to escape negative selection during thymic development and so have the potential to contribute to the pathogenesis of autoimmunity. We generated and characterized mouse CD4 T cells specific for an arthritogenic epitope of the candidate joint autoantigen proteoglycan aggrecan. Cloned T-cell hybridomas specific for a synthetic peptide containing the aggrecan epitope showed two distinct response patterns based on whether they could recognize processed intact aggrecan. Fine mapping demonstrated that both types of T-cell recognized the same core epitope. The results are consistent with the generation of aggrecan-specific type A and type B T cells. Type B T cells were activated by supernatants released from degrading cartilage, indicating the presence of antigenic extracellular peptides or fragments of aggrecan. Type B T cells could play a role in the pathogenesis of proteoglycan-induced arthritis in mice, a model for rheumatoid arthritis, by recognizing extracellular peptides or protein fragments of joint autoantigens released by inflamed cartilage. PMID- 26581678 TI - Insecticide resistance profile of Anopheles gambiae from a phase II field station in Cove, southern Benin: implications for the evaluation of novel vector control products. AB - BACKGROUND: Novel indoor residual spraying (IRS) and long-lasting insecticidal net (LLIN) products aimed at improving the control of pyrethroid-resistant malaria vectors have to be evaluated in Phase II semi-field experimental studies against highly pyrethroid-resistant mosquitoes. To better understand their performance it is necessary to fully characterize the species composition, resistance status and resistance mechanisms of the vector populations in the experimental hut sites. METHODS: Bioassays were performed to assess phenotypic insecticide resistance in the malaria vector population at a newly constructed experimental hut site in Cove, a rice growing area in southern Benin, being used for WHOPES Phase II evaluation of newly developed LLIN and IRS products. The efficacy of standard WHOPES-approved pyrethroid LLIN and IRS products was also assessed in the experimental huts. Diagnostic genotyping techniques and microarray studies were performed to investigate the genetic basis of pyrethroid resistance in the Cove Anopheles gambiae population. RESULTS: The vector population at the Cove experimental hut site consisted of a mixture of Anopheles coluzzii and An. gambiae s.s. with the latter occurring at lower frequencies (23 %) and only in samples collected in the dry season. There was a high prevalence of resistance to pyrethroids and DDT (>90 % bioassay survival) with pyrethroid resistance intensity reaching 200-fold compared to the laboratory susceptible An. gambiae Kisumu strain. Standard WHOPES-approved pyrethroid IRS and LLIN products were ineffective in the experimental huts against this vector population (8-29 % mortality). The L1014F allele frequency was 89 %. CYP6P3, a cytochrome P450 validated as an efficient metabolizer of pyrethroids, was over-expressed. CONCLUSION: Characterizing pyrethroid resistance at Phase II field sites is crucial to the accurate interpretation of the performance of novel vector control products. The strong levels of pyrethroid resistance at the Cove experimental hut station make it a suitable site for Phase II experimental hut evaluations of novel vector control products, which aim for improved efficacy against pyrethroid resistant malaria vectors to WHOPES standards. The resistance genes identified can be used as markers for further studies investigating the resistance management potential of novel mixture LLIN and IRS products tested at the site. PMID- 26581680 TI - A Vitamin B-6 Antagonist from Flaxseed Perturbs Amino Acid Metabolism in Moderately Vitamin B-6-Deficient Male Rats. AB - BACKGROUND: Pyridoxal 5'-phosphate (PLP) plays a crucial role as a cofactor in amino acid metabolism. There is a prevalence of moderate vitamin B-6 deficiency in the population that may be exacerbated through the ingestion of 1-amino d proline (1ADP), a vitamin B-6 antagonist found in flaxseed. OBJECTIVE: Given prior evidence of the impact of synthetic 1ADP on indexes of pyridoxine metabolism, the current study was designed to investigate the effects of 1ADP derived from flaxseed on amino acid metabolism in moderately vitamin B-6 deficient rats. METHODS: Male weanling rats (n = 8/treatment) consumed a semipurified diet containing either 7 mg pyridoxine hydrochloride/kg diet [optimum vitamin B-6 (OB)] or 0.7 mg pyridoxine hydrochloride/kg diet [moderately vitamin B-6 deficient (MB)], each with 0 or 10 mg vitamin B-6 antagonist/kg diet, in either a synthetic form (1ADP) or as a flaxseed extract (FE), for 5 wk. At the end of the experiment, plasma vitamin B-6 and amino acid concentrations and the activities of hepatic PLP-dependent enzymes were analyzed. RESULTS: Compared with the MB control group, plasma PLP concentrations were 26% and 69% lower, respectively, in the MB+FE and MB+1ADP rats (P <= 0.001). In the MB+FE group, the plasma cystathionine concentration was 100% greater and the plasma alpha aminobutyric acid and glutamic acid concentrations were 59% and 30% lower, respectively, than in the MB control group. Both synthetic 1ADP and FE significantly (P < 0.001) inhibited the in vitro hepatic activities of 2 PLP dependent enzymes, cystathionine beta-synthase (up to 44%) and cystathionine gamma-lyase (up to 60%), irrespective of vitamin B-6 concentrations. Because of vitamin B-6 antagonist exposure, observed perturbations in plasma biomarkers and hepatic enzyme activities were not evident or of lesser magnitude in rats consuming adequate vitamin B-6. CONCLUSION: The current data from a rat model provide evidence that a vitamin B-6 antagonist now prevalent in the human food supply may pose challenges to individuals of moderate vitamin B-6 status. PMID- 26581681 TI - Walnuts Consumed by Healthy Adults Provide Less Available Energy than Predicted by the Atwater Factors. AB - BACKGROUND: Previous studies have shown that the metabolizable energy (ME) content (energy available to the body) of certain nuts is less than predicted by the Atwater factors. However, very few nuts have been investigated to date, and no information is available regarding the ME of walnuts. OBJECTIVE: A study was conducted to determine the ME of walnuts when consumed as part of a typical American diet. METHODS: Healthy adults (n = 18; mean age = 53.1 y; body mass index = 28.8 kg/m(2)) participated in a randomized crossover study with 2 treatment periods (3 wk each). The study was a fully controlled dietary feeding intervention in which the same base diet was consumed during each treatment period; the base diet was unsupplemented during one feeding period and supplemented with 42 g walnuts/d during the other feeding period. Base diet foods were reduced in equal proportions during the walnut period to achieve isocaloric food intake during the 2 periods. After a 9 d diet acclimation period, subjects collected all urine and feces for ~1 wk (as marked by a Brilliant Blue fecal collection marker) for analysis of energy content. Administered diets, walnuts, and fecal and urine samples were subjected to bomb calorimetry, and the resulting data were used to calculate the ME of the walnuts. RESULTS: One 28-g serving of walnuts contained 146 kcal (5.22 kcal/g), 39 kcal/serving less than the calculated value of 185 kcal/serving (6.61 kcal/g). The ME of the walnuts was 21% less than that predicted by the Atwater factors (P < 0.0001). CONCLUSION: Consistent with other tree nuts, Atwater factors overestimate the metabolizable energy value of walnuts. These results could help explain the observations that consumers of nuts do not gain excessive weight and could improve the accuracy of food labeling. This trial was registered at clinicaltrials.gov as NCT01832909. PMID- 26581679 TI - Serum Antioxidants Are Associated with Serum Reproductive Hormones and Ovulation among Healthy Women. AB - BACKGROUND: Evidence is growing that the equilibrium between reactive oxygen species and antioxidants plays a vital role in women's reproductive health. OBJECTIVE: The objective of this study was to evaluate variations in serum antioxidant concentrations across the menstrual cycle and associations between antioxidants and reproductive hormones and anovulation among healthy women. METHODS: The BioCycle Study, a prospective cohort, followed 259 women aged 18-44 y for up to 2 menstrual cycles. Serum fat-soluble vitamin and micronutrient (alpha-tocopherol, gamma-tocopherol, retinol, lutein, lycopene, and beta carotene), ascorbic acid, and reproductive hormone concentrations were measured 5 8 times/cycle. We used weighted linear mixed models to assess associations between antioxidants and hormone concentrations, after adjustment for age, race, body mass index, parity, sleep, pain medication use, total energy intake, concurrent hormones, serum cholesterol, F2-isoprostanes, and other antioxidants. Generalized linear models were used to identify associations with anovulation. RESULTS: Serum antioxidant concentrations varied across the menstrual cycle. Retinol and alpha-tocopherol were associated with higher estradiol [RR: 1.00 pg/mL (95% CI: 0.67, 1.34 pg/mL); RR: 0.02 pg/mL (95% CI: 0.003, 0.03 pg/mL), respectively] and testosterone [RR: 0.61 ng/dL (95% CI: 0.44, 0.78 ng/dL); RR: 0.01 ng/dL (95% CI: 0.001, 0.01 ng/dL), respectively]. Ascorbic acid was associated with higher progesterone (RR: 0.15 ng/mL; 95% CI: 0.05, 0.25 ng/mL) and with lower follicle-stimulating hormone (RR: -0.06 mIU/mL; 95% CI: -0.09, 0.03 mIU/mL). The ratio of alpha- to gamma-tocopherol was associated with an increased risk of anovulation (RR: 1.03; 95% CI: 1.01, 1.06). CONCLUSIONS: These findings shed new light on the intricate associations between serum antioxidants and endogenous hormones in healthy premenopausal women and support the hypothesis that concentrations of serum vitamins affect steroidogenesis even after adjustment for oxidative stress. PMID- 26581682 TI - Cocoa Flavanol Supplementation Influences Skin Conditions of Photo-Aged Women: A 24-Week Double-Blind, Randomized, Controlled Trial. AB - BACKGROUND: The consumption of dietary antioxidants is considered to be a good strategy against photo-aging. However, the results of previous clinical trials that investigated the effects of oral consumption of high-flavanol cocoa products on skin photo-aging have been contradictory. OBJECTIVE: The aim of this study was to investigate whether high-flavanol cocoa supplementation would improve the moderately photo-aged facial skin of female participants, by assessing skin wrinkles and elasticity. METHODS: We performed a 24-wk, randomized, double-blind, placebo-controlled study to evaluate the effects of oral supplementation of cocoa flavanols on cutaneous photo-aging. All participants were moderately photo-aged Korean women with visible facial wrinkles (age range: 43-86 y). Participants were randomly assigned to receive a placebo beverage or cocoa beverage that contained 320 mg total cocoa flavanols/d. We measured wrinkles, skin elasticity, and hydration at baseline and at 12 and 24 wk. The primary endpoint was the mean percentage change in the average roughness value (Rz) at 24 wk. RESULTS: At 24 wk, the mean percentage change in Rz (primary endpoint) was significantly lower in the cocoa group than in the placebo group (-8.7 percentage points; 95% CI: 16.1, -1.3 percentage points; P = 0.023). The mean percentage changes in gross elasticity, as determined by a cutometer, also differed between the groups at 12 wk (9.1 percentage points; 95% CI: 1.5, 16.7 percentage points; P = 0.020) and 24 wk (8.6 percentage points; 95% CI: 1.0, 16.2 percentage points; P = 0.027). However, there were no significant differences in skin hydration and barrier integrity between the 2 groups. CONCLUSIONS: In moderately photo-aged women, regular cocoa flavanol consumption had positive effects on facial wrinkles and elasticity. Cocoa flavanol supplementation may contribute to the prevention of the progression of photo-aging. This trial was registered at clinicaltrials.gov as NCT02060097. PMID- 26581684 TI - Dietary Patterns Are Associated with Predicted Cardiovascular Disease Risk in an Urban Mexican Adult Population. AB - BACKGROUND: Dietary patterns may predict cardiovascular disease (CVD) risk more accurately than does consumption of specific nutrients or foods. OBJECTIVE: We evaluated the association between Mexican adults' dietary patterns and development of a >10% risk of 10-y CVD (using the Framingham risk score) over 7 y of follow-up. METHODS: This prospective cohort study included 1196 men and women aged 20-80 y with a 10-y predicted risk <10% and without a CVD diagnosis at baseline in 2004-2007. Data on sociodemographic, lifestyle, and medical history factors were collected with a self-administered questionnaire. Dietary intake was evaluated by using a semiquantitative food-frequency questionnaire. The relations between dietary patterns and predicted CVD were analyzed by using pooled logistic regression models. RESULTS: With the use of factor analysis, we identified 3 major dietary patterns in participants' dietary data. The "prudent" pattern was characterized by high positive loadings for the consumption of fresh fruit, vegetables, and whole grains. The "meat/fish" pattern showed positive loadings for the consumption of red meat, processed meat, eggs, fats, fish, and poultry. Finally, the "refined foods" pattern featured positive loadings for corn tortillas, refined grains, soft drinks, and alcohol. After adjustment for potential confounders, compared with participants in the lowest quintile of the prudent pattern, those in the highest quintile had a lower RR of 10-y CVD (RR: 0.40; 95% CI: 0.20, 0.79; P-trend = 0.006). In contrast, participants in the highest quintile of the refined-foods pattern had a greater risk of elevated 10-y CVD (RR: 2.98; 95% CI: 1.46, 6.10; P-trend = 0.020) than did those in the lowest quintile. Finally, the meat/fish dietary pattern was not significantly associated with 10-y CVD. CONCLUSION: Our data suggest that the prudent pattern is associated with a reduced risk of 10-y CVD, whereas the refined-foods pattern may increase 10-y CVD in Mexican adults. PMID- 26581683 TI - Green Tea Extract and Catechol-O-Methyltransferase Genotype Modify Fasting Serum Insulin and Plasma Adiponectin Concentrations in a Randomized Controlled Trial of Overweight and Obese Postmenopausal Women. AB - BACKGROUND: Green tea consumption has been associated with favorable changes in body weight and obesity-related hormones, although it is not known whether these changes result from green tea polyphenols or caffeine. OBJECTIVE: We examined the impact of decaffeinated green tea extract (GTE) containing 843 mg of (-) epigallocatechin-3-gallate on anthropometric variables, obesity-associated hormones, and glucose homeostasis. METHODS: The Minnesota Green Tea Trial was a 12-mo randomized, double-blind, placebo-controlled clinical trial of 937 healthy postmenopausal women assigned to either decaffeinated GTE (1315 mg total catechins/d) or a placebo, stratified by catechol-O-methyltransferase (COMT) genotype. This study was conducted in a subset of 237 overweight and obese participants [body mass index (BMI) >=25 kg/m(2)]. RESULTS: No changes in energy intake, body weight, BMI, or waist circumference (WC) were observed over 12 mo in women taking GTE (n = 117) or placebo (n = 120). No differences were seen in circulating leptin, ghrelin, adiponectin, or glucose concentrations at month 12. Participants randomly assigned to GTE with baseline insulin >=10 MUIU/mL (n = 23) had a decrease in fasting serum insulin from baseline to month 12 (-1.43 +/- 0.59 MUIU/mL), whereas those randomly assigned to placebo with baseline insulin >=10 MUIU/mL (n = 19) had an increase in insulin over 12 mo (0.55 +/- 0.64 MUIU/mL, P < 0.01). Participants with the homozygous high-activity (G/G) form of COMT had significantly lower adiponectin (5.97 +/- 0.50 compared with 7.58 +/- 0.53 MUg/mL, P = 0.03) and greater insulin concentrations (7.63 +/- 0.53 compared with 6.18 +/- 0.36 MUIU/mL, P = 0.02) at month 12 compared with those with the low activity (A/A) genotype, regardless of treatment group. CONCLUSIONS: Decaffeinated GTE was not associated with reductions in body weight, BMI, or WC and did not alter energy intake or mean hormone concentrations in healthy postmenopausal women over 12 mo. GTE decreased fasting insulin concentrations in those with elevated baseline fasting concentrations. The high-activity form of the COMT enzyme may be associated with elevations in insulin and a reduction in adiponectin concentrations over time. This trial was registered at http://www.clinicaltrials.gov as NCT00917735. PMID- 26581685 TI - Protein Supplementation at Breakfast and Lunch for 24 Weeks beyond Habitual Intakes Increases Whole-Body Lean Tissue Mass in Healthy Older Adults. AB - BACKGROUND: Key areas of research on the preservation of lean tissue mass (LTM) during aging are determinations of the protein requirement and optimal protein intake at meals. OBJECTIVE: The aim of this study was to determine the effect of protein supplementation at breakfast and lunch for 24 wk beyond habitual intakes on whole-body LTM in healthy adults aged 50-70 y. METHODS: In a single-blinded, randomized, controlled design, 60 healthy older men and women (aged 61 +/- 5 y) with a body mass index (in kg/m(2)) of 25.8 +/- 3.6 consumed either 0.165 g/kg body mass of a milk-based protein matrix (PRO) or an isoenergetic, nonnitrogenous maltodextrin control (CON) at breakfast and midday meals, the lower protein containing meals of the day, for 24 wk. Dual-energy X-ray absorptiometry was used to measure the change in LTM. RESULTS: After the intervention, protein intake in the PRO group increased from 0.23 +/- 0.1 to 0.40 +/- 0.1 g/kg for breakfast and from 0.31 +/- 0.2 to 0.47 +/- 2 g/kg for the midday meal. In response, LTM increased by 0.45 (95% CI: 0.06, 0.83) kg in the PRO group compared with a decrease of 0.16 (95% CI: -0.49, 0.17) kg in the CON group (P = 0.006). Appendicular LTM accounted for the majority of the difference in LTM, increasing by 0.27 (95% CI: 0.05, 0.48) kg in the PRO group compared with no change in the CON group (P = 0.002). CONCLUSIONS: Protein supplementation at breakfast and lunch for 24 wk in healthy older adults resulted in a positive (+0.6 kg) difference in LTM compared with an isoenergetic, nonnitrogenous maltodextrin control. These observations suggest that an optimized and balanced distribution of meal protein intakes could be beneficial in the preservation of lean tissue mass in the elderly. This trial was registered at clinicaltrials.gov as NCT02529124. PMID- 26581686 TI - High levels of physical activity are associated with poorer asthma control in young females but not in males. AB - BACKGROUND AND OBJECTIVE: Earlier studies on the levels of physical activity in asthma patients compared with controls have yielded varying results. We have previously reported that high versus moderate levels of physical activity were associated with higher prevalence of wheezing, especially in females. Here we studied the levels of physical activity in young patients with asthma and healthy subjects and their effect on asthma control. METHODS: Four hundred eight physician-diagnosed patients with asthma and 118 controls (10-34 years) answered questions concerning frequency and/or duration of physical activity and undertook the Asthma Control Test (ACT), spirometry, methacholine challenges and exhaled nitric oxide measurements. RESULTS: Asthma patients were more frequently physically active (P = 0.01) and for longer durations (P = 0.002) than controls. Highly versus moderately physically active patients with asthma had a higher prevalence of not well-controlled asthma (ACT < 20) when physical activity was assessed by frequency (40.6% vs 24.1%, P = 0.001) or duration (39.0% vs 21.7%, P < 0.001). This was only seen in females who had reduced ACT items (P < 0.05). Frequently versus moderately active females had an odds ratio of 4.81 (2.43, 9.51) to have ACT < 20, while no such effect was found in males (OR 1.18 (0.61, 2.30)) and this interaction was statistically significantly associated with gender (P = 0.003). No differences in fraction of exhaled nitric oxide or methacholine reactivity were found between moderately and highly physically active females with asthma. CONCLUSION: Young asthma patients were more active than controls. High levels of physical activity were associated with poor asthma control as judged by the ACT in females, but not in males, and this appears unrelated to airway inflammation or responsiveness. PMID- 26581688 TI - The clinical and therapeutic uses of MDM2 and PSMA and their potential interaction in aggressive cancers. AB - Prostate-specific membrane antigen (PSMA) overexpression is observed in the neovasculature of solid tumors, but not in the vasculature of normal tissues. Increased PSMA expression is positively associated with tumor stage and grade, although its function in cancer remains unclear. Mouse double minute 2 (MDM2) is a negative regulator of the p53 tumor suppressor and is reported to regulate VEGF expression and angiogenesis. Both proteins have been considered as biomarkers and therapeutic targets for advanced solid tumors. Our work and a recent microarray based gene profiling study suggest there could be signaling interplay between MDM2 and PSMA. We herein review the mechanisms underlining the outgrowth of tumors associated with PSMA and MDM2, their potential interaction and how this may be applied to anticancer therapeutics. PMID- 26581687 TI - An evaluation of the DEXLIFE 'self-selected' lifestyle intervention aimed at improving insulin sensitivity in people at risk of developing type 2 diabetes: study protocol for a randomised controlled trial. AB - BACKGROUND: With the global escalation of type 2 diabetes and evidence consistently showing that its onset can be prevented or delayed by changing lifestyle behaviours, there is an urgent need to translate practical, affordable and acceptable interventions from the research setting into the real world. One such approach to lifestyle interventions might be the introduction of a programme in which the individual is provided with choice and facilitated to 'self-select' an exercise programme. Previous research has shown that this is likely to be less resource intensive, an essential requirement for success outside the controlled research environment, while at the same time promoting positive responses relating to adherence, competence and self-efficacy, essential attributes for long-term success. Through a two-group parallel-randomised controlled trial, this study aims to assess the clinical and psychological impact of the DEXLIFE 'self selected' lifestyle modification programme in adults at risk of developing type 2 diabetes. METHODS/DESIGN: A total of 360 subjects at risk of developing type 2 diabetes are randomly assigned in a 1:3 ratio to a control (n = 90) or intervention arm (n = 270). Randomization is stratified by age, sex and body mass index. The control arm receives general information on lifestyle and diabetes risk. The intervention group participate in a 12 week 'self-selected' supervised exercise training programme accompanied with dietary advice to improve food choices. Participants are given access to Dublin City University Sport (an on campus gym) and asked to perform four exercise classes per week. Dublin City University Sport offers over 50 classes per week, many of which are medically supervised. If weight loss is indicated, reduction in total calorie intake by 600 kcal/day is advised. Common to all food plans is <10% saturated fat intake, as well as a dietary fibre intake of >15 g/1000 kcal. Insulin sensitivity is the primary outcome measure. Secondary outcome measures include glucose function, fitness, body composition, anthropometrics, heart rate variability, lipid profiles, blood pressure, physical activity levels, dietary intake and quality of life. DISCUSSION: "Self-selected" lifestyle intervention has not previously been evaluated in type 2 diabetes prevention and if shown to be successful could be implemented in practice immediately. TRIAL REGISTRATION: Current Controlled Trials: ISRCTN66987085. PMID- 26581689 TI - Evaluation of distribution and sources of sewage molecular marker (LABs) in selected rivers and estuaries of Peninsular Malaysia. AB - This is the first extensive report on linear alkylbenzenes (LABs) as sewage molecular markers in surface sediments collected from the Perlis, Kedah, Merbok, Prai, and Perak Rivers and Estuaries in the west of Peninsular Malaysia. Sediment samples were extracted, fractionated, and analyzed using gas chromatography mass spectrometry (GC-MS). The concentrations of total LABs ranged from 68 to 154 (Perlis River), 103 to 314 (Kedah River), 242 to 1062 (Merbok River), 1985 to 2910 (Prai River), and 217 to 329 ng g(-1) (Perak River) dry weight (dw). The highest levels of LABs were found at PI3 (Prai Estuary) due to the rapid industrialization and population growth in this region, while the lowest concentrations of LABs were found at PS1 (upstream of Perlis River). The LABs ratio of internal to external isomers (I/E) in this study ranged from 0.56 at KH1 (upstream of Kedah River) to 1.35 at MK3 (Merbok Estuary) indicating that the rivers receive raw sewage and primary treatment effluents in the study area. In general, the results of this paper highlighted the necessity of continuation of water treatment system improvement in Malaysia. PMID- 26581690 TI - Influence of tea saponin on enhancing accessibility of pyrene and cadmium phytoremediated with Lolium multiflorum in co-contaminated soils. AB - Tea saponin (TS), a kind of biodegradable surfactant, was chosen to improve the accessible solubilization of pyrene and cadmium (Cd) in co-contaminated soils cultivated Lolium multiflorum. TS obviously improved the accessibility of pyrene and Cd for L. multiflorum to accelerate the process of accumulation and elimination of the pollutants. The chemical forms of Cd was transformed from Fe Mn oxides and associated to carbonates fractions into exchangeable fractions by adding TS in single Cd and pyrene-Cd contaminated soils. Moreover, the chemical forms of pyrene were transformed from associated fraction into bioaccessible fraction by adding TS in pyrene and pyrene-Cd contaminated soils. In pyrene-Cd contaminated soil, the exchangeable fraction of Cd was hindered in the existence of pyrene, and bioaccessible fraction of pyrene was promoted by the cadmium. Besides, in the process of the pyrene degradation and Cd accumulation, the effect could be improved by the elongation of roots with adding TS, and the microorganism activity was stimulated by TS to accelerate the removal of pollutions. Therefore, Planting L. multiflorum combined with adding TS would be an effective method on the phytoremediation of organics and heavy metals co contaminated soils. PMID- 26581691 TI - Effects of garlic and diallyl trisulfide on the growth, photosynthesis, and alkaline phosphatase activity of the toxic cyanobacterium Microcystis aeruginosa. AB - To identify a botanical algicide and elucidate the response of cyanobacteria to the extract from higher plants, the effects of garlic and garlic-derived diallyl trisulfide on Microcystis aeruginosa were studied. Effects were evaluated by changes in cell density, chlorophyll a, maximum effective quantum yield (Fv/Fm), effective quantum yield (YII), non-photochemical quenching (NPQ), and rapid light curves of M. aeruginosa. In addition, alkaline phosphatase activity (APA) was measured when M. aeruginosa was incubated with diallyl trisulfide. Results indicated that the inhibition by garlic and diallyl trisulfide was significant. The 120-h 50 % effective concentrations of garlic and diallyl trisulfide (EC50) were 0.75 g L(-1) and 2.84 mg L(-1), respectively. Moreover, the inhibitory rate increased with increasing concentration and the growth of M. aeruginosa was inhibited by 90.0 % at the highest concentrations. We also show that the response of M. aeruginosa to stress could involve both impairment of the photosynthetic center PSII and alteration of APA. For example, at high garlic concentration (2.0 g L(-1)), Fv/Fm significantly decreased from 0.501 to 0.084 (p < 0.05) after 120 h of exposure. Furthermore, the total APA was significantly decreased by exposure to a high diallyl trisulfide concentration after 24 h exposure. As new algal inhibitors, there are several advantages for their utilization, such as being common, cheap, non-toxic, and with high efficiency. It would be meaningful to further research on garlic as an environmentally friendly algicide. PMID- 26581693 TI - Glyphosate and AMPA adsorption in soils: laboratory experiments and pedotransfer rules. AB - Adsorption of the herbicide glyphosate and its main metabolite AMPA (aminomethylphosphonic acid) was investigated on 17 different agricultural soils. Batch equilibration adsorption data are shown by Freundlich adsorption isotherms. Glyphosate adsorption is clearly affected by equilibration concentrations, but the nonlinear AMPA adsorption isotherms indicate saturation of the adsorption sites with increasing equilibrium concentrations. pHCaCl2 (i.e. experimental pH) is the major parameter governing glyphosate and AMPA adsorption in soils. However, considering pHCaCl2 values, available phosphate amount, and amorphous iron and aluminium oxide contents by using a nonlinear multiple regression equation, obtains the most accurate and powerful pedotransfer rule for predicting the adsorption constants for these two molecules. As amorphous iron and aluminium oxide contents in soil are not systematically determined, we also propose a pedotransfer rule with two variables-pHCaCl2 values and available phosphate amount-that remains acceptable for both molecules. Moreover, the use of the commonly measured pHwater or pHKCl values gives less accurate results compared to pHCaCl2 measurements. To our knowledge, this study is the first AMPA adsorption characterization for a significant number of temperate climate soils. PMID- 26581692 TI - Mobility and eco-risk of trace metals in soils at the Hailuogou Glacier foreland in eastern Tibetan Plateau. AB - The concentrations and fractions of cadmium (Cd), copper (Cu), lead (Pb), and zinc (Zn) in soils collected from Hailuogou Glacier foreland in eastern Tibetan Plateau were analyzed to decipher their mobility, and their eco-risk was assessed combined with multiple environmental indices. The concentrations of Cd were more than ten times higher than its local background in the O horizon and nearly three times higher in the A horizon. The concentrations of Pb and Zn were relatively high in the O horizon, whereas that of Cu increased with soil depth. The main fractions of metals in the surface horizons were reducible and acid-soluble for Cd, oxidizable and residual for Cu, reducible and oxidizable for Pb, and reducible and residual for Zn. The metal mobility generally followed the order of Cd > Pb > Zn > Cu in the O horizon and Cd > Pb > Cu > Zn in the A horizon. Sorption and complexation by soil organic matters imparted an important effect on the mobilization and transformation of Cd, Pb, and Zn in the soils. The oxidizable Cu fraction in the soils showed significant correlation with organic matters, and soil pH mainly modulated the acid-soluble and reducible Cu fractions. The concentrations and other environmental indices including contamination factor, enrichment factor, geoaccumulation index, and risk assessment index revealed that Cd reached high contamination and very high eco risk, Pb had medium contamination but low eco-risk, Zn showed low contamination and low eco-risk, and Cu was not contaminated in the soils. The data indicated that Cd was the priority to concern in the soils of Hailuogou Glacier catchment. PMID- 26581694 TI - Romantic Relationship Satisfaction Moderates the Etiology of Adult Personality. AB - The heritability of major normative domains of personality is well-established, with approximately half the proportion of variance attributed to genetic differences. In the current study, we examine the possibility of gene * environment interaction (G*E) for adult personality using the environmental context of intimate romantic relationship functioning. Personality and relationship satisfaction are significantly correlated phenotypically, but to date no research has examined how the genetic and environmental components of variance for personality differ as a function of romantic relationship satisfaction. Given the importance of personality for myriad outcomes from work productivity to psychopathology, it is vital to identify variables present in adulthood that may affect the etiology of personality. In the current study, quantitative models of G*E were used to determine whether the genetic and environmental influences on personality differ as a function of relationship satisfaction. We drew from a sample of now-adult twins followed longitudinally from adolescence through age 29. All participants completed the Multidimensional Personality Questionnaire (MPQ) and an abbreviated version of the Dyadic Adjustment Scale. Biometric moderation was found for eight of the eleven MPQ scales examined: well-being, social potency, negative emotionality, alienation, aggression, constraint, traditionalism, and absorption. The pattern of findings differed, suggesting that the ways in which relationship quality moderates the etiology of personality may depend on the personality trait. PMID- 26581696 TI - Online education: should we take it seriously? PMID- 26581695 TI - Separating Family-Level and Direct Exposure Effects of Smoking During Pregnancy on Offspring Externalizing Symptoms: Bridging the Behavior Genetic and Behavior Teratologic Divide. AB - Maternal smoking during pregnancy (MSDP) has been robustly associated with externalizing problems and their developmental precursors in offspring in studies using behavioral teratologic designs (Wakschlag et al., Am J Public Health 92(6):966-974, 2002; Espy et al., Dev Psychol 47(1):153-169, 2011). In contrast, the use of behavior genetic approaches has shown that the effects commonly attributed to MSDP can be explained by family-level variables (D'Onofrio et al., Dev Psychopathol 20(01):139-164, 2008). Reconciling these conflicting findings requires integration of these study designs. We utilize longitudinal data on a preschool proband and his/her sibling from the Midwest Infant Development Study Preschool (MIDS-P) to test for teratologic and family level effects of MSDP. We find considerable variation in prenatal smoking patterns both within and across pregnancies within families, indicating that binary smoking measures are not sufficiently capturing exposure. Structural equation models indicate that both conduct disorder and oppositional defiant disorder symptoms showed unique effects of MSDP over and above family level effects. Blending high quality exposure measurement with a within-family design suggests that it is premature to foreclose the possibility of a teratologic effect of MSDP on externalizing problems. Implications and recommendations for future studies are discussed. PMID- 26581697 TI - Simultaneous presentation of pancreatic cancer in a genetically unrelated couple. AB - Patients with pancreatic cancer tend to have a poor prognosis despite aggressive treatment, and their 5-year overall survival rate remains dismal. Several risk factors could potentially trigger the development of pancreatic cancer but many of them identified so far have been only weakly linked. Occurrence of pancreatic cancer in a husband and wife around the same time in the same household even when exposed to similar environmental factors is rare. Although familial pancreatic cancer is a known entity, pancreatic cancer in genetically unrelated married couples has not been studied. Here we present such a scenario involving one couple. In this case report, we discuss the chronological events leading to pancreatic cancer in a genetically unrelated married couple and the risk factors that may have led to cancer, in addition to exploring the possible links. PMID- 26581698 TI - Acute myeloid leucaemia presenting as a rapidly progressive polyradiculoneuropathy. AB - Neurological involvement at onset in acute myeloid leucaemia (AML) is rare, with only a few isolated case reports. We present the case of a 46-year-old man with rapidly progressive polyradiculoneuropathy as the presenting feature of AML. The proposed mechanism for this is postulated to be direct intraneural infiltration, although a paraneoplastic, autoimmune-related phenomenon could be possible. Despite chemotherapeutic intervention, the patient died 1 month after initial presentation. Although rare, neurological manifestations of AML do occur and it is important to include haematological malignancies in the differential diagnosis in patients presenting with neurological symptoms. PMID- 26581699 TI - Pneumopericardium, pneumomediastinum, pneumoretroperitoneum and surgical emphysema secondary to a duodenal perforation post-endoscopic retrograde cholangiopancreatography. PMID- 26581700 TI - Cleidocranial dysplasia syndrome (CCD) with an unusual finding in a young patient. AB - Cleidocranial dysplasia (CCD), an autosomal dominant disorder with a prevalence of 1 in 1,000,000 individuals, presents with a wide range of variability. Dentists are often the first to encounter patients with CCD, some of whom do not show typical manifestations. Since it has similar features to other pathologies, CCD is misdiagnosed as other conditions. A 10-year-old boy suffering from CCD was misdiagnosed as having rickets and was referred for non-eruption of a few permanent teeth along with an unaesthetic facial appearance. Clinically and radiologically, a diagnosis of CCD was made. Currently, management of this patient's orofacial manifestations is underway. PMID- 26581701 TI - Radium-223 dichloride therapy in breast cancer with osseous metastases. AB - Osseous metastases occur frequently in patients with breast cancer. Few options exist for bone targeted therapy for hormone refractory patients with breast cancer with progressive bone metastases. We present a case of breast cancer with osseous metastases but no visceral metastases. The patient had been treated with surgery, chemotherapy, radiation and hormonal therapy, but still had extensive symptomatic osseous metastases. She received radium-223 dichloride, a therapeutic radiopharmaceutical Food and Drug Administration (FDA) approved for castration resistant prostate cancer with bone metastases. She tolerated the therapy well with no significant adverse effects. She had an excellent response with significant pain relief obviating need for regular analgaesics. Her tumour markers also dropped significantly. Osseous metastases assessed with F-18 fluorodeoxy glucose (FDG) positron emission tomography/CT (PET/CT) and F-18 sodium fluoride (NaF) bone PET/CT) scans at baseline, after two and six cycles, also showed interval improvement in the lesions. Radium-223 dichloride could potentially be a safe and useful therapeutic option in this setting. PMID- 26581702 TI - Conservative treatment in a patient with diabetic osteomyelitis: antibiotic treatment is sufficient for complete bone regeneration in selected cases. AB - Diabetic foot ulcers are commonly complicated by bone involvement and osteomyelitis. Diagnosing diabetic osteomyelitis can be problematic. However, positive findings at clinical examination and X-ray may set the diagnosis. Recent guidelines suggest that selected cases of diabetic osteomyelitis can be treated conservatively with antibiotics. We report on the successful treatment of a 52 year-old man with diabetes with osteomyelitis in the distal phalanx of a toe. On X-ray, the affected phalanx appeared completely eroded. However, regeneration of the bone tissue was observed following outpatient treatment with antibiotics. We therefore encourage doctors to provide conservative treatment for selected cases of diabetic osteomyelitis. PMID- 26581703 TI - Presentation of cauda equina syndrome during labour. AB - Lumbar disc herniations are rare in pregnancy, with an incidence of 1:10,000. Less than 2% of these herniations result in cauda equina syndrome (CES). Diagnosing CES in pregnant patients can be difficult because changes in bladder and bowel habits are common in normal pregnancies. We present the case of a 29 year-old woman, with a history of lumbar radiculopathy, who presented at 39 weeks gestation with severe lower back and bilateral lower limb radiculopathy. Symptoms of CES began to develop only after the onset of labour. Diagnostic MRI was obtained following delivery and the patient was treated by microdiscectomy. Following surgery, bladder and bowel function began to normalise and at 3 months follow-up, she had made a full recovery. To the best of our knowledge, CES has never been reported to present during labour. This case highlights the diagnostic dilemma and need for a high index of suspicion. PMID- 26581704 TI - Head injury patient with bilateral vocal cord paralysis: a mistake and a lesson learnt. AB - Bilateral recurrent nerve palsy along with head injury is a rare clinical possibility and can be potentially fatal if not properly diagnosed. We report a case of a head injury patient with intact Glasgow Coma Scale requiring immediate re-intubation and tracheostomy after extubation failure as a result of stridor and severe dyspnoea with paradoxical respiratory pattern, possibly because of undiagnosed significant surgical history. PMID- 26581705 TI - Differential diagnosis of double site intussusception in childhood: a 15-year-old girl presenting with bowel obstruction. AB - Abdominal pain in a teenage girl is common; however, thorough history and examination can often distinguish a more rare or sinister diagnosis. We present a case of a 15-year-old girl presenting with abdominal pain, who was subsequently diagnosed with double intussusception secondary to her previously unrecognised Peutz-Jeghers syndrome (PJS). PMID- 26581706 TI - Type B aortic dissection in a chronic haemodialysis patient. PMID- 26581707 TI - Ibuprofen removal in horizontal subsurface flow constructed wetlands: treatment performance and fungal community dynamics. AB - The treatment performance of ibuprofen (IBP)-enriched wastewater by horizontal subsurface flow constructed wetlands planted with cattail (Typha angustifolia) and unplanted control mesocosms was investigated. Removal efficiencies of IBP were significantly (p < .05) enhanced in the planted mesocosms (78.5%) compared to those in the unplanted beds (57.9%). An 18S rRNA gene high-throughput pyrosequencing approach was used to investigate the effects of IBP on the structure of the fungal community in these wetland systems. The overall diversity of the fungal community was reduced under the IBP exposure. Taxonomic analysis revealed that 62.2% of the fungal sequences were affiliated with Basidiomycota, followed by Ascomycota (37.4%) at the phylum level. Uncultured fungus (48.2%), Chaetomium sp. (14.2%), Aspergillus sp. (12.4%), Trichoderma sp. (5.7%), Cladosporium sp. (5.4%), and Emericellopsis sp. (5.2%) were identified as dominant genera. At the genus level, a distinct profile of the fungal community in the IBP-enriched mesocosms was observed as compared to the control beds, and as well specific fungal genera were enhanced in the planted beds, regardless of IBP enrichment. However, despite these differences, the composition of the fungal community (as measured by Bray-Curtis similarity) was mostly unaffected by the significant IBP enrichment. On the other hand, a consistent similarity pattern of fungal community structure in the planted mesocosms suggests that the presence of higher macrophytes in the wetland systems may well help shape the fungal community structure. PMID- 26581708 TI - Optimizing and benchmarking de novo transcriptome sequencing: from library preparation to assembly evaluation. AB - BACKGROUND: RNA-seq enables gene expression profiling in selected spatiotemporal windows and yields massive sequence information with relatively low cost and time investment, even for non-model species. However, there remains a large room for optimizing its workflow, in order to take full advantage of continuously developing sequencing capacity. METHOD: Transcriptome sequencing for three embryonic stages of Madagascar ground gecko (Paroedura picta) was performed with the Illumina platform. The output reads were assembled de novo for reconstructing transcript sequences. In order to evaluate the completeness of transcriptome assemblies, we prepared a reference gene set consisting of vertebrate one-to-one orthologs. RESULT: To take advantage of increased read length of >150 nt, we demonstrated shortened RNA fragmentation time, which resulted in a dramatic shift of insert size distribution. To evaluate products of multiple de novo assembly runs incorporating reads with different RNA sources, read lengths, and insert sizes, we introduce a new reference gene set, core vertebrate genes (CVG), consisting of 233 genes that are shared as one-to-one orthologs by all vertebrate genomes examined (29 species)., The completeness assessment performed by the computational pipelines CEGMA and BUSCO referring to CVG, demonstrated higher accuracy and resolution than with the gene set previously established for this purpose. As a result of the assessment with CVG, we have derived the most comprehensive transcript sequence set of the Madagascar ground gecko by means of assembling individual libraries followed by clustering the assembled sequences based on their overall similarities. CONCLUSION: Our results provide several insights into optimizing de novo RNA-seq workflow, including the coordination between library insert size and read length, which manifested in improved connectivity of assemblies. The approach and assembly assessment with CVG demonstrated here would be applicable to transcriptome analysis of other species as well as whole genome analyses. PMID- 26581710 TI - TSH receptor antibody titers measured with a third-generation assay did not reflect the activity of Graves' ophthalmopathy in untreated Japanese Graves' disease patients. AB - TSH receptor antibody (TRAb) titer has been reported to be correlated with Graves' ophthalmopathy (GO). However, the correlation between GO activity and TRAb titer assessed with a third-generation assay has not been reported. We enrolled 238 untreated Graves' disease patients who came to the outpatient clinic of Ito Hospital and 28 patients who were euthyroid. All of the patients were assessed for GO by an ophthalmologist within 3 months of their initial visit to Ito Hospital. Clinical activity score (CAS), short inversion time inversion recovery (STIR), and sum of the maximum external orbital muscle areas (SEOMA) on a frontal sectional magnetic resonance imaging (MRI). The TRAb titer was significantly higher in patients with inactive ophthalmopathy (the inactive-GO group) than in patients with active ophthalmopathy (the active-GO group) (17.7 +/ 13.5 IU/L vs. 13.0 +/- 13.1 IU/L, p=0.0082). The SEOMA values were not correlated with TRAb titer. The prevalence of active-GO was higher in euthyroid patients than in hyperthyroid patients although the difference was not significant. In conclusion, TRAb titer measured with a third-generation assay dose not correlate with GO activity based on MRI findings in untreated Graves' disease patients, and the prevalence of active-GO is higher in euthyroid patients with lower TRAb titers than in hyperthyroid patients. PMID- 26581711 TI - Great expectations: what patients with unexplained syncope desire. PMID- 26581712 TI - Growth and metabolism of Beauveria bassiana spores and mycelia. AB - BACKGROUND: Fungi are ubiquitous in nature and have evolved over time to colonize a wide range of ecosystems including pest control. To date, most research has focused on the hypocrealean genera Beauveria bassiana, which is a typical filamentous fungus with a high potential for insect control. The morphology and components of fungi are important during the spores germination and outgrow to mycelia. However, to the best of our knowledge, there is no report on the morphology and components of B. bassiana spores and mycelia. In the work, the growth and metabolism of Beauveria bassiana spores and mycelia were studied. High performance liquid chromatography-mass spectrometry (HPLC-MS) was employed to study the metabolism of B. bassiana spores and mycelia. Principal component analysis (PCA) based on HPLC-MS was conducted to study the different components of the spores and mycelia of the fungus. Metabolic network was established based on HPLC-MS and KEGG database. RESULTS: Through Gompertz model based on macroscopic and microscopic techniques, spore elongation length was found to increase exponentially until approximately 23.1 h after cultivation, and then growth became linear. In the metabolic network, the decrease of glyoxylate, pyruvate, fumarate, alanine, succinate, oxaloacetate, dihydrothymine, ribulose, acetylcarnitine, fructose-1, 6-bisphosphate, mycosporin glutamicol, and the increase of betaine, carnitine, ergothioneine, sphingosine, dimethyl guanosine, glycerophospholipids, and in spores indicated that the change of the metabolin can keep spores in inactive conditions, protect spores against harmful effects and survive longer. CONCLUSIONS: Analysis of the metabolic pathway in which these components participate can reveal the metabolic difference between spores and mycelia, which provide the tools for understand and control the process of of spores germination and outgrow to mycelia. PMID- 26581713 TI - Improving the management of gastrointestinal bleeding in patients with cirrhosis. AB - Gastrointestinal bleeding remains a major cause of mortality in patients with cirrhosis. The most common source of bleeding is from gastroesophageal varices but non-variceal bleeding from peptic ulcer disease also carries a significant risk in patients with liver disease. The prognosis is related to the severity of the underlying liver disease, and deaths often occur due to liver failure, infection or renal failure. Optimal management should therefore not only achieve haemostasis but address these complications as well. The management of gastrointestinal bleeding in patients with cirrhosis includes a range of medical, endoscopic and radiological interventions. This article updates the recent developments in this area and highlights topics where further research is still required. PMID- 26581715 TI - Glutaminases in slowly proliferating gastroenteropancreatic neuroendocrine neoplasms/tumors (GEP-NETs): Selective overexpression of mRNA coding for the KGA isoform. AB - Glutamine (Gln) is a crucial metabolite in cancer cells of different origin, and the expression and activity of different isoforms of the Gln-degrading enzyme, glutaminase (GA), have variable implications for tumor growth and metabolism. Human glutaminases are encoded by two genes: the GLS gene encodes the kidney-type glutaminases, KGA and GAC, while the GLS2 gene encodes the liver-type glutaminases, GAB and LGA. Recent studies suggest that the GAC isoform and thus high GAC/KGA ratio, are characteristic of highly proliferating tumors, while GLS2 proteins have an inhibitory effect on tumor growth. Here we analyzed the expression levels of distinct GA transcripts in 7 gastroenteropancreatic neuroendocrine tumors (GEP-NETs) with low proliferation index and 7 non neoplastic tissues. GEP-NETs overexpressed KGA, while GAC, which was the most abundant isoform, was not different from control. The expression of the GLS2 gene showed tendency towards elevation in GEP-NETs compared to control. Collectively, the expression pattern of GA isoforms conforms to the low proliferative capacity of GEP-NETs encompassed in this study. PMID- 26581714 TI - Silencing of Abcc8 or inhibition of newly upregulated Sur1-Trpm4 reduce inflammation and disease progression in experimental autoimmune encephalomyelitis. AB - BACKGROUND: In experimental autoimmune encephalomyelitis (EAE), deletion of transient receptor potential melastatin 4 (Trpm4) and administration of glibenclamide were found to ameliorate disease progression, prompting speculation that glibenclamide acts by directly inhibiting Trpm4. We hypothesized that in EAE, Trpm4 upregulation is accompanied by upregulation of sulfonylurea receptor 1 (Sur1) to form Sur1-Trpm4 channels, which are highly sensitive to glibenclamide, and that Sur1-Trpm4 channels are required for EAE progression. METHODS: EAE was induced in wild-type (WT) and Abcc8-/- mice using myelin oligodendrocyte glycoprotein 35-55 (MOG35-55). Lumbar spinal cords were examined by immunohistochemistry, immuno-Forster resonance energy transfer (immunoFRET), and co-immunoprecipitation for Sur1-Trpm4. WT/EAE mice were administered with the Sur1 inhibitor, glibenclamide, beginning on post-induction day 10. Mice were evaluated for clinical function, inflammatory cells and cytokines, axonal preservation, and white matter damage. RESULTS: Sur1-Trpm4 channels were upregulated in EAE, predominantly in astrocytes. The clinical course and severity of EAE were significantly ameliorated in glibenclamide-treated WT/EAE and in Abcc8-/-/EAE mice. At 30 days, the lumbar spinal cords of glibenclamide-treated WT/EAE and Abcc8-/-/EAE mice showed significantly fewer invading immune cells, including leukocytes (CD45), T cells (CD3), B cells (CD20) and macrophages/microglia (CD11b), and fewer cells expressing pro-inflammatory cytokines (TNF-alpha, IFN-gamma, IL-17). In both glibenclamide-treated WT/EAE and Abcc8-/-/EAE mice, the reduced inflammatory burden correlated with better preservation of myelin, better preservation of axons, and more numerous mature and precursor oligodendrocytes. CONCLUSIONS: Sur-Trpm4 channels are newly upregulated in EAE and may represent a novel target for disease-modifying therapy in multiple sclerosis. PMID- 26581716 TI - Stable Expression and Characterization of an Optimized Mannose Receptor. AB - The mannose receptor (MR) is a macrophage surface receptor that recognizes pathogen associated molecular patterns (PAMPs) from a diverse array of bacterial, fungal and viral pathogens. Functional studies of the MR are hampered by the scarcity of human cell lines that express the receptor. Current model systems available for the study of MR biology often demonstrate low levels of expression and do not retain many of the classical MR properties. Although several laboratories have reported transient and stable expression of MR from plasmids, preliminary data from our laboratory suggests that these plasmids produce a protein that lacks critical domains and is often not stable over time. In this current report we describe the generation and characterization of a novel human codon-optimized system for transient and stable MR expression. Rare codons and sequences that contribute to mRNA instability were modified to produce mRNA that is qualitatively and quantitatively improved. Confocal imaging of the transient and stably expressed optimized receptor demonstrates a distribution consistent with previous reports. To demonstrate the functional characteristics of the optimized receptor, we further show that the introduction of codon-optimized MR plasmid can confer MR-associated phagocytosis of S. aureus to non-phagocytic HeLa cells. We show that three molecules participate in the engagement and internalization of S. aureus. MR was found to colocalize with Toll-like receptor 2 (TLR2) and Rab5 following exposure to pHrodo-stained S. aureus, suggesting cooperation among the three molecules to engage and internalize the bacterial particle. This study describes a transfection capable, optimized MR receptor with functional characteristics similar to the wild type receptor and further demonstrates a new system for the continued study of MR biology and function. PMID- 26581717 TI - Periodontal CD14 mRNA expression is downregulated in patients with chronic periodontitis and type 2 diabetes. AB - BACKGROUND: Patients with type 2 diabetes mellitus (T2DM) have increased severity of periodontitis. Toll-like receptor (TLR)4, its co-receptors CD14 and MD-2, and adaptor MyD88 play pivotal roles in lipopolysaccharide (LPS)-triggered tissue inflammation and periodontitis. This study investigated the effects of T2DM and periodontitis on TLR4, CD14, MD-2 and MyD88 mRNA expression in surgically removed periodontal tissues. METHODS: Periodontal tissue specimens were collected from 14 patients without periodontitis and T2DM (Group 1), 15 patients with periodontitis alone (Group 2), and 7 patients with both periodontitis and T2DM (Group 3). The mRNA of TLR4, CD14, MD-2 and MyD88 was quantified using real-time PCR and compared between the groups. RESULTS: Statistical analysis showed that periodontal expression of CD14 mRNA was significantly reduced across Groups 1, 2 and 3 (p = 0.02) whereas the mRNA expression of TLR4, MD-2 and MyD88 was not significantly different among the groups. Furthermore, when patients in Groups 1 and 2 were combined (n = 22), the CD14 mRNA expression was significantly lower than that in patients of Group 1 (p = 0.04). CONCLUSIONS: CD14 mRNA expression was downregulated across patients with neither periodontitis nor T2DM, patients with periodontitis alone and patients with both diseases, suggesting that CD14 mRNA expression is associated with a favorable host response or subjected to a negative feedback regulation. PMID- 26581718 TI - Anatomical effects of dexamethasone intravitreal implant in diabetic macular oedema: a pooled analysis of 3-year phase III trials. AB - BACKGROUND/AIM: To assess long-term effects of dexamethasone intravitreal implant (DEX implant) monotherapy on retinal morphology in diabetic macular oedema (DME). METHODS: Two multicentre, masked, phase III studies with identical protocols randomised patients with DME, best-corrected visual acuity of 34-68 Early Treatment Diabetic Retinopathy Study letters and central subfield retinal thickness (CSRT) >=300 um to DEX implant 0.7, 0.35 mg or sham procedure. Patients were followed up for 3 years (39 months if treated at month 36), with retreatment allowed at >=6-month intervals. Patients needing other macular oedema (ME) therapy exited the study. Changes from baseline in CSRT, macular volume and ME grade, area of retinal thickening, macular leakage, macular capillary loss and diabetic retinopathy severity were assessed. RESULTS: After 3 years, more eyes treated with DEX implant 0.7 and 0.35 mg than sham showed improvement (although small) in ME grade (p<0.05 vs sham). DEX implant 0.7 mg delayed time to onset of two-step progression in diabetic retinopathy severity by ~12 months. DEX implant 0.7 and 0.35 mg produced small, non-sustained reductions in macular leakage but had no significant effect on macular capillary loss. CONCLUSIONS: DEX implant 0.7 or 0.35 mg, administered at >=6-month intervals over 3 years, produced sustained retinal structural improvement in DME. TRIAL REGISTRATION NUMBER: NCT00168337 and NCT00168389. PMID- 26581720 TI - Memos to the President From a "Council of Psychological Science Advisers". PMID- 26581719 TI - Identification of minimal eukaryotic introns through GeneBase, a user-friendly tool for parsing the NCBI Gene databank. AB - We have developed GeneBase, a full parser of the National Center for Biotechnology Information (NCBI) Gene database, which generates a fully structured local database with an intuitive user-friendly graphic interface for personal computers. Features of all the annotated eukaryotic genes are accessible through three main software tables, including for each entry details such as the gene summary, the gene exon/intron structure and the specific Gene Ontology attributions. The structuring of the data, the creation of additional calculation fields and the integration with nucleotide sequences allow users to make many types of comparisons and calculations that are useful for data retrieval and analysis. We provide an original example analysis of the existing introns across all the available species, through which the classic biological problem of the 'minimal intron' may find a solution using available data. Based on all currently available data, we can define the shortest known eukaryotic GT-AG intron length, setting the physical limit at the 30 base pair intron belonging to the human MST1L gene. This 'model intron' will shed light on the minimal requirement elements of recognition used for conventional splicing functioning. Remarkably, this size is indeed consistent with the sum of the splicing consensus sequence lengths. PMID- 26581721 TI - Hale and Hearty Policies: How Psychological Science Can Create and Maintain Healthy Habits. AB - Strategies are needed to ensure that the U.S. Government meets its goals for improving the health of the nation (e.g., Healthy People 2020). To date, progress toward these goals has been undermined by a set of discernible challenges: People lack sufficient motivation, they frequently fail to translate healthy intentions into action, their efforts are undermined by the persistence of prior unhealthy habits, and they have considerable difficulty maintaining new healthy patterns of behavior. Guided by advances in psychological science, we provide innovative, evidence-based policies that address each of these challenges and, if implemented, will enhance people's ability to create and maintain healthy behavioral practices. PMID- 26581723 TI - How to Improve the Health of American Adolescents. AB - The major threats to the health of American teenagers are behavioral-risky and reckless things adolescents do that threaten their well-being and that of others. The primary approach to preventing adolescent risk taking has been classroom based health education. Yet, most systematic research indicates that even the best programs are successful mainly at changing adolescents' knowledge but not in altering their behavior. Research on adolescent brain development has revolutionized our understanding of this stage of life, but our approach to deterring adolescent risk taking remains grounded in old, antiquated, and erroneous views of the period. Classroom-based health education is an uphill battle against evolution and endocrinology, and it is not a fight we are likely to win. Instead of trying to change teenagers into something they are not, we should try to reduce the risks they are exposed to. We should spend less money and effort trying to influence how adolescents think, and focus more on limiting opportunities for their inherently immature judgment to hurt themselves or others. Although there is evidence that some programs aimed at strengthening adolescents' self-regulation may also deter risky behavior, our public health policies should emphasize changing the context in which adolescents live, rather than solely attempting to change adolescents themselves. PMID- 26581722 TI - Promoting Public Health in the Context of the "Obesity Epidemic": False Starts and Promising New Directions. AB - In the battle to combat obesity rates in the United States, several misconceptions have dominated policy initiatives. We address those misconceptions, including the notion that restrictive diets lead to long-term weight loss, that stigmatizing obesity is an effective strategy for promoting weight reduction, and that weight and physical health should be considered synonymous with one another. In offering correctives to each of these points, we draw on psychological science to suggest new policies that could be enacted at both the local and national levels. Instead of policies that rely solely on individual willpower, which is susceptible to failure, we recommend those that make use of environmental changes to reduce the amount of willpower necessary to achieve healthy behavior. Ultimately, the most effective policies will promote health rather than any arbitrary level of weight. PMID- 26581724 TI - Outsourcing Memory in Response to an Aging Population. AB - With baby boomers entering old age and longevity increasing, policymakers have focused on the physical, social, and health needs of older persons. We urge policymakers to consider cognitive aging as well, particularly normal, age related memory decline. Psychological scientists attribute memory decline mainly to cognitive overload stemming from age-related reductions in sensory capacities, speed of cognitive processing, and the ability to filter out irrelevant information. Even in the absence of decline, however, memory is imperfect and forgetting can be especially consequential for older adults. For example, forgetting to take prescription medicines is an age-related problem largely because older adults tend to ingest many more prescription drugs. We propose that policymakers focus on increasing environmental support for memory that can reduce the burden on cognitive resources and thus improve recall. In providing environmental support, policymakers need to pay careful attention to potential age-related changes in physical and cognitive capacity, as well as behavior. PMID- 26581725 TI - Leveraging Mindsets to Promote Academic Achievement: Policy Recommendations. AB - The United States must improve its students' educational achievement. Race, gender, and social class gaps persist, and, overall, U.S. students rank poorly among peers globally. Scientific research shows that students' psychology-their "academic mindsets"-have a critical role in educational achievement. Yet policymakers have not taken full advantage of cost-effective and well-validated mindset interventions. In this article, we present two key academic mindsets. The first, a growth mindset, refers to the belief that intelligence can be developed over time. The second, a belonging mindset, refers to the belief that people like you belong in your school or in a given academic field. Extensive research shows that fostering these mindsets can improve students' motivation; raise grades; and reduce racial, gender, and social class gaps. Of course, mindsets are not a panacea, but with proper implementation they can be an excellent point of entry. We show how policy at all levels (federal, state, and local) can leverage mindsets to lift the nation's educational outcomes. PMID- 26581726 TI - Jump-Starting Early Childhood Education at Home: Early Learning, Parent Motivation, and Public Policy. AB - By the time children begin formal schooling, their experiences at home have already contributed to large variations in their math and language development, and once school begins, academic achievement continues to depend strongly on influences outside of school. It is thus essential that educational reform strategies involve primary caregivers. Specifically, programs and policies should promote and support aspects of caregiver-child interaction that have been empirically demonstrated to boost early learning and should seek to impede "motivational sinkholes" that threaten to undermine caregivers' desires to engage their children effectively. This article draws on cognitive and behavioral science to detail simple, low-cost, and effective tools caregivers can employ to prepare their children for educational success and then describes conditions that can protect and facilitate caregivers' motivation to use those tools. Policy recommendations throughout focus on using existing infrastructure to more deeply engage caregivers in effective early childhood education at home. PMID- 26581727 TI - Prioritizing Sleep Health: Public Health Policy Recommendations. AB - The schedules that Americans live by are not consistent with healthy sleep patterns. In addition, poor access to educational and treatment aids for sleep leaves people engaging in behavior that is harmful to sleep and forgoing treatment for sleep disorders. This has created a sleep crisis that is a public health issue with broad implications for cognitive outcomes, mental health, physical health, work performance, and safety. New public policies should be formulated to address these issues. We draw from the scientific literature to recommend the following: establishing national standards for middle and high school start times that are later in the day, stronger regulation of work hours and schedules, eliminating daylight saving time, educating the public regarding the impact of electronic media on sleep, and improving access to ambulatory in home diagnostic testing for sleep disorders. PMID- 26581728 TI - Three Principles to REVISE People's Unethical Behavior. AB - Dishonesty and unethical behavior are widespread in the public and private sectors and cause immense annual losses. For instance, estimates of U.S. annual losses indicate $1 trillion paid in bribes, $270 billion lost due to unreported income, and $42 billion lost in retail due to shoplifting and employee theft. In this article, we draw on insights from the growing fields of moral psychology and behavioral ethics to present a three-principle framework we call REVISE. This framework classifies forces that affect dishonesty into three main categories and then redirects those forces to encourage moral behavior. The first principle, reminding, emphasizes the effectiveness of subtle cues that increase the salience of morality and decrease people's ability to justify dishonesty. The second principle, visibility, aims to restrict anonymity, prompt peer monitoring, and elicit responsible norms. The third principle, self-engagement, increases people's motivation to maintain a positive self-perception as a moral person and helps bridge the gap between moral values and actual behavior. The REVISE framework can guide the design of policy interventions to defeat dishonesty. PMID- 26581729 TI - Maximizing the Gains and Minimizing the Pains of Diversity: A Policy Perspective. AB - Empirical evidence reveals that diversity-heterogeneity in race, culture, gender, etc.-has material benefits for organizations, communities, and nations. However, because diversity can also incite detrimental forms of conflict and resentment, its benefits are not always realized. Drawing on research from multiple disciplines, this article offers recommendations for how best to harness the benefits of diversity. First, we highlight how two forms of diversity-the diversity present in groups, communities, and nations, and the diversity acquired by individuals through their personal experiences (e.g., living abroad)-enable effective decision making, innovation, and economic growth by promoting deeper information processing and complex thinking. Second, we identify methods to remove barriers that limit the amount of diversity and opportunity in organizations. Third, we describe practices, including inclusive multiculturalism and perspective taking, that can help manage diversity without engendering resistance. Finally, we propose a number of policies that can maximize the gains and minimize the pains of diversity. PMID- 26581730 TI - Leveraging Psychological Insights to Encourage the Responsible Use of Consumer Debt. AB - U.S. consumers currently hold $880 billion in revolving debt, with a mean household credit card balance of approximately $6,000. Although economic factors play a role in this societal issue, it is clear that psychological forces also affect consumers' decisions to take on and maintain unmanageable debt balances. We examine three psychological barriers to the responsible use of credit and debt. We discuss the tendency for consumers to (a) make erroneous predictions about future spending habits, (b) rely too heavily on values presented on billing statements, and (c) categorize debt and saving into separate mental accounts. To overcome these obstacles, we urge policymakers to implement methods that facilitate better budgeting of future expenses, modify existing credit card statement disclosures, and allow consumers to easily apply government transfers (such as tax credits) to debt repayment. In doing so, we highlight minimal and inexpensive ways to remedy the debt problem. PMID- 26581731 TI - Improving Intelligence Analysis With Decision Science. AB - Intelligence analysis plays a vital role in policy decision making. Key functions of intelligence analysis include accurately forecasting significant events, appropriately characterizing the uncertainties inherent in such forecasts, and effectively communicating those probabilistic forecasts to stakeholders. We review decision research on probabilistic forecasting and uncertainty communication, drawing attention to findings that could be used to reform intelligence processes and contribute to more effective intelligence oversight. We recommend that the intelligence community (IC) regularly and quantitatively monitor its forecasting accuracy to better understand how well it is achieving its functions. We also recommend that the IC use decision science to improve these functions (namely, forecasting and communication of intelligence estimates made under conditions of uncertainty). In the case of forecasting, decision research offers suggestions for improvement that involve interventions on data (e.g., transforming forecasts to debias them) and behavior (e.g., via selection, training, and effective team structuring). In the case of uncertainty communication, the literature suggests that current intelligence procedures, which emphasize the use of verbal probabilities, are ineffective. The IC should, therefore, leverage research that points to ways in which verbal probability use may be improved as well as exploring the use of numerical probabilities wherever feasible. PMID- 26581732 TI - Improving Public Engagement With Climate Change: Five "Best Practice" Insights From Psychological Science. AB - Despite being one of the most important societal challenges of the 21st century, public engagement with climate change currently remains low in the United States. Mounting evidence from across the behavioral sciences has found that most people regard climate change as a nonurgent and psychologically distant risk-spatially, temporally, and socially-which has led to deferred public decision making about mitigation and adaptation responses. In this article, we advance five simple but important "best practice" insights from psychological science that can help governments improve public policymaking about climate change. Particularly, instead of a future, distant, global, nonpersonal, and analytical risk that is often framed as an overt loss for society, we argue that policymakers should (a) emphasize climate change as a present, local, and personal risk; (b) facilitate more affective and experiential engagement; (c) leverage relevant social group norms; (d) frame policy solutions in terms of what can be gained from immediate action; and (e) appeal to intrinsically valued long-term environmental goals and outcomes. With practical examples we illustrate how these key psychological principles can be applied to support societal engagement and climate change policymaking. PMID- 26581733 TI - On Interesting Policymakers. PMID- 26581734 TI - The Rise of Psychology in Policy: The UK's de facto Council of Psychological Science Advisers. PMID- 26581735 TI - Does Oxytocin Increase Trust in Humans? A Critical Review of Research. AB - Behavioral neuroscientists have shown that the neuropeptide oxytocin (OT) plays a key role in social attachment and affiliation in nonhuman mammals. Inspired by this initial research, many social scientists proceeded to examine the associations of OT with trust in humans over the past decade. To conduct this work, they have (a) examined the effects of exogenous OT increase caused by intranasal administration on trusting behavior, (b) correlated individual difference measures of OT plasma levels with measures of trust, and (c) searched for genetic polymorphisms of the OT receptor gene that might be associated with trust. We discuss the different methods used by OT behavioral researchers and review evidence that links OT to trust in humans. Unfortunately, the simplest promising finding associating intranasal OT with higher trust has not replicated well. Moreover, the plasma OT evidence is flawed by how OT is measured in peripheral bodily fluids. Finally, in recent large-sample studies, researchers failed to find consistent associations of specific OT-related genetic polymorphisms and trust. We conclude that the cumulative evidence does not provide robust convergent evidence that human trust is reliably associated with OT (or caused by it). We end with constructive ideas for improving the robustness and rigor of OT research. PMID- 26581736 TI - Causal Conceptions in Social Explanation and Moral Evaluation: A Historical Tour. AB - Understanding the causes of human behavior is essential for advancing one's interests and for coordinating social relations. The scientific study of how people arrive at such understandings or explanations has unfolded in four distinguishable epochs in psychology, each characterized by a different metaphor that researchers have used to represent how people think as they attribute causality and blame to other individuals. The first epoch was guided by an "intuitive scientist" metaphor, which emphasized whether observers perceived behavior to be caused by the unique tendencies of the actor or by common reactions to the requirements of the situation. This metaphor was displaced in the second epoch by an "intuitive lawyer" depiction that focused on the need to hold people responsible for their misdeeds. The third epoch was dominated by theories of counterfactual thinking, which conveyed a "person as reconstructor" approach that emphasized the antecedents and consequences of imagining alternatives to events, especially harmful ones. With the current upsurge in moral psychology, the fourth epoch emphasizes the moral-evaluative aspect of causal judgment, reflected in a "person as moralist" metaphor. By tracing the progression from the person-environment distinction in early attribution theories to present concerns with moral judgment, our goal is to clarify how causal constructs have been used, how they relate to one another, and what unique attributional problems each addresses. PMID- 26581737 TI - Child Development in the Face of Rural-to-Urban Migration in China: A Meta Analytic Review. AB - In the last 30 years, China has undergone one of the largest rural-to-urban migrations in human history, with many children left behind because of parental migration. We present a meta-analytic review of empirical studies on Chinese children's rural-to-urban migration and on rural children left behind because of parental migration. We examine how these events relate to children's emotional, social, and academic developmental outcomes. We include publications in English and in Chinese to uncover and quantify a part of the research literature that has been inaccessible to most Western scholars in the field of child and family studies. Overall, both migrant children and children left behind by migrant parents in China show significantly less favorable functioning across domains than other Chinese children. It appears that, similar to processes found in other parts of the world, the experience of economic and acculturation stress as well as disrupted parent-child relations constitute a risk for nonoptimal child functioning in the Chinese context. Further, we found evidence for publication bias against studies showing less favorable development for migrant children and children left behind. We discuss the results in terms of challenges to Chinese society and to future empirical research on Chinese family life. PMID- 26581739 TI - It's Not "All in Your Head": Understanding Religion From an Embodied Cognition Perspective. AB - Theorists and researchers in the psychology of religion have often focused on the mind as the locus of religion. In this article, we suggest an embodied cognition perspective as a new dimension in studies of religion as a complement to previous research and theorizing. In contrast to the Cartesian view of the mind operating distinctly from the body, an embodied cognition framework posits religion as being grounded in an integrated and dynamic sensorimotor complex (which includes the brain). We review relevant but disparate literature in cognitive and social psychology to demonstrate that embodied cognition shapes the way that people represent the divine and other spiritual beings, guides people's moral intuitions, and facilitates bonding within religious groups. Moreover, commitments to a religious worldview are sometimes manifested in the body. We suggest several promising future directions in the study of religion from an embodied cognition perspective. PMID- 26581738 TI - Seven Fears and the Science of How Mobile Technologies May Be Influencing Adolescents in the Digital Age. AB - Close to 90% of U.S. adolescents now own or have access to a mobile phone, and they are using them frequently. Adolescents send and receive an average of over 60 text messages per day from their devices, and over 90% of adolescents now access the Internet from a mobile device at least occasionally. Many adults are asking how this constant connectivity is influencing adolescents' development. In this article, we examine seven commonly voiced fears about the influence of mobile technologies on adolescents' safety (e.g., cyberbullying and online solicitation), social development (e.g., peer relationships, parent-child relationships, and identity development), cognitive performance, and sleep. Three sets of findings emerge. First, with some notable exceptions (e.g., sleep disruption and new tools for bullying), most online behaviors and threats to well being are mirrored in the offline world, such that offline factors predict negative online experiences and effects. Second, the effects of mobile technologies are not uniform, in that benefits appear to be conferred for some adolescents (e.g., skill building among shy adolescents), whereas risk is exacerbated among others (e.g., worsening existing mental health problems). Third, experimental and quasi-experimental studies that go beyond a reliance on self-reported information are required to understand how, for whom, and under what conditions adolescents' interactions with mobile technologies influence their still developing social relationships, brains, and bodies. PMID- 26581740 TI - Awareness Is Not a Necessary Characteristic of a Perceptual Effect: Commentary on Firestone (2013). AB - Golf holes look larger to golfers who are playing better than others, and hills look steeper to people who are fatigued from a long run-or so claims the action specific account of perception. According to this account, spatial perception of slant, distance, and size is influenced by the perceiver's ability to perform actions such as walking, throwing, or grasping. This claim is based on empirical findings that observers report hills as steeper, distances as farther, and objects as smaller when they are less capable of acting on the objects. Recently, Firestone (2013) challenged the claim that these reports reflect genuine differences in perception. One argument he levied against a perceptual interpretation is that people are not aware of these perceptual differences related to action, and they should be. Here, I argue that awareness is not a necessary condition for an effect to be perceptual, as evidenced by a lack of awareness in the case of a classic visual illusion. However, to make a strong claim for genuine effects in perception, the action-specific account must specify a perceptual mechanism, and it has yet to do so. PMID- 26581741 TI - Family Matters in Bereavement: Toward an Integrative Intra-Interpersonal Coping Model. AB - The death of a loved one can be heartbreaking for those left behind, and indeed, bereavement is associated not only with adverse health effects but also a higher risk of dying oneself. Not surprisingly, its consequences have been the subject of much psychological enquiry, with a major interest in shedding light on how one adapts, who is most at risk, and why. Often the focus is on the bereaved individual, yet people do not typically grieve in isolation; most do so with family members who have likewise experienced the loss. Family dynamics affect personal grief and vice versa. What is more, family concerns, such as reduced finances, legal consequences, and changed family relationships, have to be dealt with. While the latter stressful aspects have been investigated, there is still a huge gap between the individual and family approaches. To move them closer together, we propose a family-level extension of our Dual Process Model, showing how the whole may actually be more-and more accurate-than the sum of the two parts. PMID- 26581742 TI - Toward a Psychology of Surrogate Decision Making. AB - In everyday life, many of the decisions that we make are made on behalf of other people. A growing body of research suggests that we often, but not always, make different decisions on behalf of other people than the other person would choose. This is problematic in the practical case of legally designated surrogate decision makers, who may not meet the substituted judgment standard. Here, we review evidence from studies of surrogate decision making and examine the extent to which surrogate decision making accurately predicts the recipient's wishes, or if it is an incomplete or distorted application of the surrogate's own decision making processes. We find no existing domain-general model of surrogate decision making. We propose a framework by which surrogate decision making can be assessed and a novel domain-general theory as a unifying explanatory concept for surrogate decisions. PMID- 26581743 TI - A Short (Personal) Future History of Revolution 2.0. AB - Crisis of replicability is one term that psychological scientists use for the current introspective phase we are in-I argue instead that we are going through a revolution analogous to a political revolution. Revolution 2.0 is an uprising focused on how we should be doing science now (i.e., in a 2.0 world). The precipitating events of the revolution have already been well-documented: failures to replicate, questionable research practices, fraud, etc. And the fact that none of these events is new to our field has also been well-documented. I suggest four interconnected reasons as to why this time is different: changing technology, changing demographics of researchers, limited resources, and misaligned incentives. I then describe two reasons why the revolution is more likely to catch on this time: technology (as part of the solution) and the fact that these concerns cut across social and life sciences-that is, we are not alone. Neither side in the revolution has behaved well, and each has characterized the other in extreme terms (although, of course, each has had a few extreme actors). Some suggested reforms are already taking hold (e.g., journals asking for more transparency in methods and analysis decisions; journals publishing replications) but the feared tyrannical requirements have, of course, not taken root (e.g., few journals require open data; there is no ban on exploratory analyses). Still, we have not yet made needed advances in the ways in which we accumulate, connect, and extract conclusions from our aggregated research. However, we are now ready to move forward by adopting incremental changes and by acknowledging the multiplicity of goals within psychological science. PMID- 26581744 TI - Evidence for deleterious hepatitis C virus quasispecies mutation loads that differentiate the response patterns in IFN-based antiviral therapy. AB - Viral quasispecies (QS) have long been considered to affect the efficiency of hepatitis C virus (HCV) antiviral therapy, but a correlation between QS diversity and treatment outcomes has not been established conclusively. We previously measured HCV QS diversity by genome-wide quantification of high-resolution mutation load in HCV genotype 1a patients achieving a sustained virological response (1a/SVR) or a null response (1a/null). The current study extended this work into HCV 1a patients experiencing relapse (1a/relapse, n = 19) and genotype 2b patients with SVR (2b/SVR, n = 10). The mean mutation load per patient in 2b/SVR and 1a/relapse was similar, respectively, to 1a/SVR (517.6 +/- 174.3 vs 524 +/- 278.8 mutations, P = 0.95) and 1a/null (829.2 +/- 282.8 vs 805.6 +/- 270.7 mutations, P = 0.78). Notably, a deleterious mutation load, as indicated by the percentage of non-synonymous mutations, was highest in 2b/SVR (33.2 +/- 8.5%) as compared with 1a/SVR (23.6 +/- 7.8%, P = 0.002), 1a/null (18.2 +/- 5.1%, P = 1.9 * 10(-7)) or 1a/relapse (17.8 +/- 5.3%, P = 1.8) * 10(-6). In the 1a/relapse group, continuous virus evolution was observed with excessive accumulation of a deleterious load (17.8 +/- 5.3% vs 35.4 +/- 12.9%, P = 3.5 * 10(-6)), supporting the functionality of Muller's ratchet in a treatment-induced population bottleneck. Taken together, the magnitude of HCV mutation load, particularly the deleterious mutation load, provides an evolutionary explanation for the emergence of multiple response patterns as well as an overall high SVR rate in HCV genotype 2 patients. Augmentation of Muller's ratchet represents a potential strategy to reduce or even eliminate viral relapse in HCV antiviral therapy. PMID- 26581745 TI - Ghrelin, adipokines, metabolic factors in relation with weight status in school children and results of a 1-year lifestyle intervention program. AB - BACKGROUND: Overweight in Guadeloupe is a public health matter affecting children and adults. In the present study we evaluated the metabolic profile, including serum ghrelin, leptin and adiponectin levels, in normal weight, overweight and obese school children and we analyzed the potential changes in anthropometric and metabolic risk factors after a 1-year lifestyle intervention program. METHODS: Parameters were assessed at baseline and at 1 year. Three groups (G) were defined according the International Obesity Task Force reference values, G1: normal weight / G2: overweight / G3: obese. The lifestyle intervention included dietary counseling, regular physical activity and family support. RESULTS: A total of 120 children (G1: n = 44, G2: n = 39, G3: n = 37), aged 11- 15 years and 59 % girls were enrolled. Obese children showed significant lower HDL-C, adiponectin and ghrelin concentrations, higher triglycerides, fasting blood glucose, insulin and leptin levels and also higher frequencies of abdominal obesity (G1: 2.3 %, G2: 28.2 %, G3: 73 %) and insulin resistance (GI: 39 %, G2: 72 %, G3: 89 %) than the other groups. In the overall sample, the linear regressions exploring the associations of ghrelin, adiponectin and leptin with age, gender, BMI z-score, HOMA-IR and tanner stage as independent variables showed strong associations of leptin levels with weight status and insulin resistance at baseline. The models accounted for 58 % of variability in leptin levels compared with 26 and 15 % for adiponectin and ghrelin levels respectively. In 83 children who completed the program, significant decreases in BMI z-score in overweight and obese children were noted. Leptin levels decreased significantly only in the obese group whereas adiponectin concentrations increased significantly in the three groups, In obese children, a significant correlation was found between changes in BMI Z-score, and changes in leptin levels (r = 0.39; P = 0.049) but not with changes in adiponectin levels. CONCLUSIONS: Abdominal obesity and insulin resistance were highly prevalent in obese children highlighting their risk of metabolic complications in adulthood. A 1-year long lifestyle intervention was associated with improvement in BMI z-score and metabolic parameters. PMID- 26581746 TI - The adverse outcome pathway (AOP) for chemical binding to tubulin in oocytes leading to aneuploid offspring. AB - The Organisation for Economic Co-operation and Development (OECD) has launched the Adverse Outcome Pathway (AOP) Programme to advance knowledge of pathways of toxicity and improve the use of mechanistic information in risk assessment. An AOP links a molecular initiating event (MIE) to an adverse outcome (AO) through intermediate key events (KE). Here, we present the scientific evidence in support of an AOP whereby chemicals that bind to tubulin cause microtubule depolymerization resulting in spindle disorganization followed by altered chromosome alignment and segregation and the generation of aneuploidy in female germ cells, ultimately leading to aneuploidy in the offspring. Aneuploidy, an abnormal number of chromosomes that is not an exact multiple of the haploid number, is a well-known cause of human disease and represents a major cause of infertility, pregnancy failure, and serious genetic disorders in the offspring. Among chemicals that induce aneuploidy in female germ cells, a large majority impairs microtubule dynamics and spindle function. Colchicine, a prototypical chemical that binds to tubulin and causes microtubule depolymerization, is used here to illustrate the AOP. This AOP is specific to female germ cells exposed during the periovulation period. Although the majority of the data come from rodent studies, the available evidence suggests that the MIE and KEs are conserved across species and would occur in human oocytes. The development of AOPs related to mutagenicity in germ cells is expected to aid the identification of potential hazards to germ cell genomic integrity and support regulatory efforts to protect population health. PMID- 26581747 TI - Vessel noise pollution as a human threat to fish: assessment of the stress response in gilthead sea bream (Sparus aurata, Linnaeus 1758). AB - This study examined the effects of boat noise pollution on the stress indices of gilthead sea bream (Sparus aurata, Linnaeus 1758). To assess the stress response in these fish, biometric values and plasma parameters such as ACTH, cortisol, glucose, lactate, haematocrit, Hsp70, total protein, cholesterol, triglycerides and osmolarity were analysed. After acclimatization of the animals, the experiment was carried out in a tank fitted with underwater speakers where the fish were exposed to sound treatments (in duplicate) consisting of: 10 days of no sound (control treatment; the animals were only exposed to the experimental tank's background noise) and 10 days of noise derived from original recordings of motor boats, including recreational boats, hydrofoil, fishing boat and ferry boat (vessel noise treatment). The exposure to noise produced significant variations in almost all the plasma parameters assessed, but no differences were observed in weights and fork lengths. A PERMANOVA analysis highlighted significantly increased values (p < 0.05) of ACTH, cortisol, glucose, lactate, haematocrit, Hsp70, cholesterol, triglycerides and osmolarity in the fish exposed to vessel noise for 10 days. This study clearly highlights that anthropogenic noise negatively affects fish, and they are valuable targets for detailed investigations into the effects of this global pollutant. Finally, these experimental studies could represent part of the science that is able to improve the quality of the policies related to management plans for maritime spaces (Marine Strategy Framework Directive 56/2008 CE) that are aimed at stemming this pollutant phenomenon. PMID- 26581748 TI - Recurrent bacteremia after injection of N-butyl-2-cyanoacrylate for treatment of bleeding gastric varices: a case report and review of the literature. AB - BACKGROUND: Bleeding from gastric varices has high mortality rate, and obliteration using N-butyl-2-cyanoacrylate is the treatment of choice. Recurrent bacteremia is rarely reported following the procedure. We aimed to report a case of recurrent bacteremia after N-butyl-2-cyanoacrylate treatment and to review published cases. CASE PRESENTATION AND REVIEW: In May 2014, a 43-year-old Brazilian male presented with lower gastrointestinal bleeding. Endoscopy showed active bleeding from gastric varix. Injection of N-butyl-2-cyanoacrylate was performed and the patient was discharged. Over the next 4 months he presented with three episodes of bacteremia with severe sepsis and no identifiable focus of infection. Oral prophylaxis was initiated in September 2014 and he has remained free of bacteremia. Six other cases of recurrent bacteremia following sclerosis with N-butyl-2-cyanoacrylate were reported in the literature. All patients had portal hypertension and bleeding from gastric varices. Average age of patients was 55.7 years and the median time from endoscopic procedure to the first episode of bacteremia was 105 days (range 14-365). The mean number of episodes of bacteremia per patient was 2.5. CONCLUSION: Recurrent bacteremia associated with endoscopic treatment with N-2-butyl-cyanoacrylate is rare, but should be suspected in patients in which investigation shows no other focus of infection. Secondary prophylaxis should be considered after the first episode. PMID- 26581751 TI - Family Conflict and Resilience in Parenting Self-Efficacy Among High-Risk Mothers. AB - Mothers with a history of institutional care in adolescence are often involved in high-conflict partner relationships, which may undermine relationships with children and confidence in oneself as a parent. Not all mothers think of themselves as bad parents under these circumstances. We turned to psychological resources as an explanation, focusing on mothers' trait self-control. The negative association between family conflict and parenting self-efficacy was tested for moderation by self-control among 104 mothers with a history of institutionalization for behavioral problems and delinquency during adolescence. We found a negative association between current family conflict and parenting self-efficacy among mothers with low self-control, and no significant association among mothers with high self-control. This study draws attention to the needs of high-risk mothers in their parenting role and demonstrates that self-control is a potential resource for mothers to balance the load presented by conflict in their families. The findings suggest new avenues for intervention. PMID- 26581749 TI - Overview of Data Concerning the Safe Use of Antihyperglycemic Medications in Type 2 Diabetes Mellitus and Chronic Kidney Disease. AB - INTRODUCTION: It can be a challenge to manage glycemic control in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD), due to both patient and medication issues. Although most antihyperglycemic medications can be used in mild kidney disease, many medications are either not advised or require dose adjustments in more advanced CKD. This review summarizes product label information, pharmacokinetic and clinical studies, and clinical guidelines relevant to use of antihyperglycemic medications in CKD. METHODS: Product labels and guidelines from North America and Europe, as well as pharmacokinetic and clinical studies of diabetes medication use in CKD were identified through Medline and PubMed searches, up to February 2015. Available data are summarized and correlations between treatment recommendations and available research are discussed, as are glycemic targets for patients with CKD. RESULTS: Newer medications have significantly more data available than older medications regarding use in CKD, although larger clinical studies are still lacking for some drugs. As CKD advances, dose adjustment is needed for many medications [numerous dipeptidyl peptidase-4 inhibitors, some insulins, sodium glucose co-transporter 2 (SGLT2) inhibitors], although not for others (thiazolidinediones, meglitinides). Some medications are not recommended for use in more advanced CKD (metformin, SGLT2 inhibitors, some glucagon-like protein-1 receptor agonists) for safety or efficacy reasons. There is not always good alignment between label recommendations, pharmacokinetic or clinical studies, and guideline recommendations for use of these drugs in CKD. In particular, controversy remains about the use of metformin in moderate CKD and appropriate use of liraglutide and sulfonylureas in advanced CKD. CONCLUSION: Considerable variability exists with respect to recommendations and clinical data for the many antihyperglycemic drugs used in patients with T2DM and CKD. FUNDING: Eli Lilly and Company. PMID- 26581750 TI - Intravenous Esomeprazole for Prevention of Peptic Ulcer Rebleeding: A Randomized Trial in Chinese Patients. AB - INTRODUCTION: High-dose intravenous esomeprazole is the only approved pharmacological treatment for the prevention of peptic ulcer rebleeding (currently approved in over 100 countries worldwide), but has not yet been approved in China. This study aimed to evaluate a high-dose esomeprazole intravenous regimen vs. an active control (cimetidine) for the prevention of rebleeding in Chinese patients with a high risk of peptic ulcer rebleeding who had undergone primary endoscopic hemostatic treatment. METHODS: This was a parallel-group study conducted at 20 centers in China. The study comprised a randomized, double-blind, intravenous treatment phase of 72 h in which 215 patients received either high-dose esomeprazole (80 mg + 8 mg/h) or cimetidine (200 mg + 60 mg/h), followed by an open-label oral treatment phase in which all patients received esomeprazole 40 mg tablets once daily for 27 days. The primary outcome was the rate of clinically significant rebleeding within the first 72 h after initial endoscopic hemostatic therapy. Secondary outcomes included the rates of clinically significant rebleeding within 7 and 30 days; proportions of patients who had endoscopic retreatment and other surgery due to rebleeding; and number of blood units transfused. RESULTS: The rate of clinically significant rebleeding within 72 h was low overall (3.3%) and numerically lower in patients treated with esomeprazole compared with cimetidine (0.9% vs. 5.6%). Overall, the results of the secondary outcomes also showed a numerical trend towards superiority of esomeprazole over cimetidine. All treatments were well tolerated. CONCLUSION: In this phase 3, multicenter, randomized trial conducted in China, esomeprazole showed a numerical trend towards superior clinical benefit over cimetidine in the prevention of rebleeding in patients who had successfully undergone initial hemostatic therapy of a bleeding peptic ulcer, with a similar safety and tolerability profile. These findings suggest that esomeprazole may be an alternative treatment option to cimetidine for this indication in China. FUNDING: AstraZeneca. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01757275. PMID- 26581752 TI - Dodenuclear [Mn(III)(8)Ln(III)(4)] clusters with 2-(hydroxymethyl)pyridine: syntheses, structures, and magnetic properties. AB - A new family of isostructural Mn/Ln dodenuclear clusters: [Mn8Ln4(O)8(hmp)4(O2CPh)12(NO3)4(PhCO2H)(C2H5OH)] [Ln = La (1), Pr (2), Nd (3), Gd (4), Dy(5), hmpH = 2-(hydroxymethyl)pyridine] have been synthesized by the reaction of Mn(NO3)2 and Ln(NO3)3.6H2O with hmpH and benzoic acid as co-ligands. Compounds 1-5 possess a spindle-shaped core of [MnLn(MU4-O)4(MU3-O)4(MU3-OR)2(MU2 OR)8](10+), which is composed of six face-sharing defected cubane units and two square-pyramidal units. The compounds represent the highest nuclearity Mn/Ln clusters with the use of hmpH to date. That the ferromagnetic interactions dominated within complexes 1-4 were suggested by solid-state dc magnetic susceptibility analyses. Compound 4 displays a magnetic-caloric effect (MCE) with 13.94 J kg(-1) K(-1) as the entropy change at 6 K for DeltaH = 8 T. Compounds 1 and 5 exhibit an out-of-phase chi''M peak maximum above 2.0 K. Fitting of the ac susceptibility data to an Arrhenius law gives an energy barrier Ueff = 6.88/7.44 K for compounds 1 and 5 respectively. PMID- 26581754 TI - Optimal Medical Therapy vs. Percutaneous Coronary Intervention for Patients With Coronary Chronic Total Occlusion - A Propensity-Matched Analysis. AB - BACKGROUND: Limited data are available on the long-term clinical outcomes of coronary chronic total occlusion (CTO) patients who receive optimal medical therapy (OMT) compared with percutaneous coronary intervention (PCI). METHODS AND RESULTS: Between March 2003 and February 2012, 2,024 patients with CTO were enrolled in a single-center registry. Among this patient group, we excluded CTO patients who underwent coronary artery bypass grafting and classified patients into the OMT group (n=664) or PCI group (n=883) according to initial treatment strategy. Propensity-score matching was also performed. The primary outcome was cardiac death. The median follow-up duration was 45.8 (interquartile range: 22.8 71.1) months. In the PCI group, 699 patients (79.2%) underwent successful revascularization. In the propensity-score matched population (533 pairs), there was no significant difference in the rate of cardiac death between the OMT and PCI groups (hazard ratio, 1.57; 95% confidence interval, 0.91-2.72, P=0.11). In the subgroup analysis, there were no significant interactions between the PCI strategy and cardiac death among several subgroups except that regarding collateral flow grades 0-2 vs. those with grade 3 (P=0.01). CONCLUSIONS: As an initial treatment strategy, PCI did not reduce cardiac death compared with OMT for the treatment of CTO in the drug-eluting stent era. PMID- 26581753 TI - The association between fine particulate matter exposure during pregnancy and preterm birth: a meta-analysis. AB - BACKGROUND: Although several previous studies have assessed the association of fine particulate matter (PM2.5) exposure during pregnancy with preterm birth, the results have been inconsistent and remain controversial. This meta-analysis aims to quantitatively summarize the association between maternal PM2.5 exposure and preterm birth and to further explore the sources of heterogeneity in findings on this association. METHODS: We searched for all studies published before December 2014 on the association between PM2.5 exposure during pregnancy and preterm birth in the MEDLINE, PUBMED and Embase databases as well as the China Biological Medicine and Wanfang databases. A pooled OR for preterm birth in association with each 10 MUg/m(3) increase in PM2.5 exposure was calculated by a random-effects model (for studies with significant heterogeneity) or a fixed-effects model (for studies without significant heterogeneity). RESULTS: A total of 18 studies were included in this analysis. The pooled OR for PM2.5 exposure (per 10 MUg/m(3) increment) during the entire pregnancy on preterm birth was 1.13 (95% CI = 1.03 1.24) in 13 studies with a significant heterogeneity (Q = 80.51, p < 0.001). The pooled ORs of PM2.5 exposure in the first, second and third trimester were 1.08 (95% CI = 0.92-1.26), 1.09 (95% CI = 0.82-1.44) and 1.08 (95% CI = 0.99-1.17), respectively. The corresponding meta-estimates of PM2.5 effects in studies assessing PM2.5 exposure at individual, semi-individual and regional level were 1.11 (95% CI = 0.89-1.37), 1.14 (95% CI = 0.97-1.35) and 1.07 (95% CI = 0.94 1.23). In addition, significant meta-estimates of PM2.5 exposures were found in retrospective studies (OR = 1.10, 95% CI = 1.01-1.21), prospective studies (OR = 1.42, 95% CI = 1.08-1.85), and studies conducted in the USA (OR = 1.16, 95 % CI = 1.05-1.29). CONCLUSIONS: Maternal PM2.5 exposure during pregnancy may increase the risk of preterm birth,but significant heterogeneity was found between studies. Exposure assessment methods, study designs and study settings might be important sources of heterogeneity, and should be taken into account in future meta-analyses. PMID- 26581755 TI - Clinical Outcomes of Drug-Eluting Stents vs. Bare-Metal Stents in Acute Myocardial Infarction Patients Under Dialysis - A Nationwide Cohort Study. AB - BACKGROUND: Data on the cardiovascular (CV) outcomes of drug-eluting stents (DES) vs. bare-metal stents (BMS) in patients with acute myocardial infarction (AMI) under dialysis are limited. METHODS AND RESULTS: We analyzed the data from 42,592 AMI patients in the Taiwan National Health Insurance Research Database between 1 January 2007 and 31 December 2011. A total of 984 AMI patients under dialysis were selected as the study cohort. We evaluated the clinical outcomes by comparing 492 subjects who had DES to 492 matched subjects who had BMS. The primary composite outcomes, which included recurrent MI, coronary revascularization and CV death, were significantly lower in the DES group than in the BMS group (41.7% vs. 47.6%, hazard ratio (HR), 0.77; 95% confidence interval (CI), 0.63-0.92, P=0.005) after mean 1.2 years. The patients who received DES had a lower risk of recurrent MI (HR, 0.63; 95% CI, 0.45-0.90), CV death (HR, 0.74; 95% CI, 0.56-0.98) and all-cause mortality (HR, 0.74; 95% CI, 0.61-0.89) than those who used BMS, but a similar risk of major bleeding (HR, 0.99; 95% CI, 0.69 1.42, P=0.952) and ischemic stroke (HR, 1.15; 95% CI, 0.66-2.01, P=0.631). CONCLUSIONS: Among AMI patients on dialysis undergoing percutaneous coronary interventions, DES implantation significantly reduced the risk of recurrent MI, CV death and all-cause mortality compared with BMS implantation. PMID- 26581757 TI - Combating climate change. PMID- 26581756 TI - Ameliorative Effect of Zinc Oxide Nanoparticles on Antioxidants and Sperm Characteristics in Streptozotocin-Induced Diabetic Rat Testes. AB - The present study investigated the impact of zinc oxide nanoparticles (ZnONPs) on the oxidative status and sperm characteristics in diabetic rat testicular tissue. Forty male albino rats were used in this study; 10 of them served as a control and 30 rats were injected with a single dose (100 mg/kg) of streptozotocin intraperitoneally. They were subdivided into diabetic, diabetic + ZnONPs (10 mg/kg B.W.), and diabetic and cotreated with ZnONPs + insulin groups. The sperm count and motility were assessed. The activity and mRNA expression of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GRD), and Glutathion-S-Transferase (GST) were determined in the testicular tissue. Malondialdehyde (MDA) and reduced glutathione (GSH) levels were estimated in the testicular tissue. Sperm count and motility increased in ZnONPs treated diabetic rats. A significant increase in the activity and mRNA expression of SOD, CAT, GPx, GRD, and GST was shown in ZnONPs treated diabetic rats. MDA significantly decreased, while GSH increased in testicular tissue of ZnONPs treated diabetic rats. It was concluded that ZnONPs either alone or in combination with insulin have the ability to increase the sperm count and motility and protect the testicular tissue against the oxidative stress induced by diabetes in rats. PMID- 26581758 TI - Daily ambient temperature and renal colic incidence in Guangzhou, China: a time series analysis. AB - Few previous studies have examined the association between temperature and renal colic in developing regions, especially in China, the largest developing country in the world. We collected daily emergency ambulance dispatches (EADs) for renal colic from Guangzhou Emergency Center from 1 January 2008 to 31 December 2012. We used a distributed-lag nonlinear model in addition to the over-dispersed generalized additive model to investigate the association between daily ambient temperature and renal colic incidence after controlling for seasonality, humidity, public holidays, and day of the week. We identified 3158 EADs for renal colic during the study period. This exposure-response curve was almost flat when the temperature was low and moderate and elevated when the temperature increased over 21 degrees C. For heat-related effects, the significant risk occurred on the concurrent day and diminished until lag day 7. The cumulative relative risk of hot temperatures (90th percentile) and extremely hot temperatures (99th percentile) over lag days 0-7 was 1.92 (95 % confidence interval, 1.21, 3.05) and 2.45 (95 % confidence interval, 1.50, 3.99) compared with the reference temperature of 21 degrees C. This time-series analysis in Guangzhou, China, suggested a nonlinear and lagged association between high outdoor temperatures and daily EADs for renal colic. Our findings might have important public health significance to prevent renal colic. PMID- 26581759 TI - Histone H1-mediated epigenetic regulation controls germline stem cell self renewal by modulating H4K16 acetylation. AB - Epigenetics plays critical roles in controlling stem cell self-renewal and differentiation. Histone H1 is one of the most critical chromatin regulators, but its role in adult stem cell regulation remains unclear. Here we report that H1 is intrinsically required in the regulation of germline stem cells (GSCs) in the Drosophila ovary. The loss of H1 from GSCs causes their premature differentiation through activation of the key GSC differentiation factor bam. Interestingly, the acetylated H4 lysine 16 (H4K16ac) is selectively augmented in the H1-depleted GSCs. Furthermore, overexpression of mof reduces H1 association on chromatin. In contrast, the knocking down of mof significantly rescues the GSC loss phenotype. Taken together, these results suggest that H1 functions intrinsically to promote GSC self-renewal by antagonizing MOF function. Since H1 and H4K16 acetylation are highly conserved from fly to human, the findings from this study might be applicable to stem cells in other systems. PMID- 26581760 TI - Gender differences in statin prescription rates, adequacy of dosing, and association of statin therapy with outcome after heart failure hospitalization: a retrospective analysis in a community setting. AB - PURPOSE: The existence of gender differences in the management of statin therapy among patients with chronic heart failure (HF) is still poorly investigated. We aimed at exploring the effect of gender on statin prescription rates and adequacy of dosing and on the association between statin therapy and all-cause 1-year mortality, after HF hospitalization in a community setting. METHODS: Statin prescription rates, adequacy of dosing (estimated as a PDD/DDD ratio >0.80), and 1-year mortality were retrospectively assessed in 2088 consecutive patients discharged from 5 local community hospitals with a definite diagnosis of HF after a mean length of stay of 7.6 days. The effect of gender was explored using multivariable logistic and Cox analyses adjusting to confounders. RESULTS: Women showed a lower statin prescription rate (25.7 vs 35.3%, P < 0.0001) and a lower prevalence of adequate statin dose (32.6 vs 42.3%, P < 0.0001) than men. Female gender was independently associated with a 24% lower probability of statin prescription and a 48% higher probability of inadequate statin dose. Statin prescription and adequacy of dosing were associated with 35 and 44% decreases in the risk of 1-year mortality, respectively, irrespective of gender. A nested case/control analysis confirmed that adequate statin dose was associated with 48% lower 1-year mortality, again without interaction with gender. CONCLUSIONS: In patients with chronic HF, female gender is independently associated with lower statin prescription rates and higher probability of inadequate dose. Statin therapy in these subjects is associated with improved 1-year survival in both men and women. This prognostic benefit is not affected by gender. PMID- 26581761 TI - A longitudinal comparison of drug use among 10-year-old children and 15-year-old adolescents from the German GINIplus and LISAplus birth cohorts. AB - PURPOSE: The purpose of this study was to compare longitudinal data on drug utilization between 10-year-old children and 15-year-old adolescents and to analyse the association of drug use at the age of 15 years with drug use at the age of 10 years. METHODS: Based on the German GINIplus (German infant study on the Influence of Nutrition Intervention plus environmental and genetic influences on allergy development) and LISAplus (Influence of lifestyle factors on the immune system and allergies in East and West Germany plus the influence of traffic emissions and genetics) birth cohorts, data on drug utilization (past 4 weeks) were collected using a self-administered questionnaire for 3642 children (10-year follow-up) and 4677 adolescents (15-year follow-up). The drugs were classified by therapeutic categories (conventional drugs, homeopathic drugs, etc.) and by codes according to the anatomical therapeutic chemical (ATC) classification system. Associations of adolescents' drug use with gender, study area, maternal education, parental income, presence of chronic conditions, and prior drug use at the age of 10 years were analysed using a logistic regression model. RESULTS: The 4-week prevalence rates of overall drug use were similar for adolescents (41.1%) and children (42.3%). However, adolescents used noticeably more anti-inflammatory drugs, analgesics, and systemic antihistamines. Exactly 3194 children/adolescents participated in both follow-ups. Adolescents' use of anti-inflammatory drugs was predicted (OR = 3.37) by use of anti-inflammatory drugs as a child. In summary, the strongest predictor of adolescents' use of specific therapeutic categories or ATC groups was the previous use of the same therapeutic drug category or ATC group as a 10-year-old child. CONCLUSIONS: Despite similar prevalence rates of overall drug utilization among both age groups, there is a noticeable difference concerning the use of drugs from specific ATC groups. Drug use as a child may partly determine what they use as an adolescent. PMID- 26581762 TI - Evaluation of the effect of tooth and dental restoration material on electron dose distribution and production of photon contamination in electron beam radiotherapy. AB - The aim of this study is to evaluate the effect of tooth and dental restoration materials on electron dose distribution and photon contamination production in electron beams of a medical linac. This evaluation was performed on 8, 12 and 14 MeV electron beams of a Siemens Primus linac. MCNPX Monte Carlo code was utilized and a 10 * 10 cm(2) applicator was simulated in the cases of tooth and combinations of tooth and Ceramco C3 ceramic veneer, tooth and Eclipse alloy and tooth and amalgam restoration materials in a soft tissue phantom. The relative electron and photon contamination doses were calculated for these materials. The presence of tooth and dental restoration material changed the electron dose distribution and photon contamination in phantom, depending on the type of the restoration material and electron beam's energy. The maximum relative electron dose was 1.07 in the presence of tooth including amalgam for 14 MeV electron beam. When 100.00 cGy was prescribed for the reference point, the maximum absolute electron dose was 105.10 cGy in the presence of amalgam for 12 MeV electron beam and the maximum absolute photon contamination dose was 376.67 MUGy for tooth in 14 MeV electron beam. The change in electron dose distribution should be considered in treatment planning, when teeth are irradiated in electron beam radiotherapy. If treatment planning can be performed in such a way that the teeth are excluded from primary irradiation, the potential errors in dose delivery to the tumour and normal tissues can be avoided. PMID- 26581763 TI - Use of electronic portal imaging devices for electron treatment verification. AB - This study aims to help broaden the use of electronic portal imaging devices (EPIDs) for pre-treatment patient positioning verification, from photon-beam radiotherapy to photon- and electron-beam radiotherapy, by proposing and testing a method for acquiring clinically-useful EPID images of patient anatomy using electron beams, with a view to enabling and encouraging further research in this area. EPID images used in this study were acquired using all available beams from a linac configured to deliver electron beams with nominal energies of 6, 9, 12, 16 and 20 MeV, as well as photon beams with nominal energies of 6 and 10 MV. A widely-available heterogeneous, approximately-humanoid, thorax phantom was used, to provide an indication of the contrast and noise produced when imaging different types of tissue with comparatively realistic thicknesses. The acquired images were automatically calibrated, corrected for the effects of variations in the sensitivity of individual photodiodes, using a flood field image. For electron beam imaging, flood field EPID calibration images were acquired with and without the placement of blocks of water-equivalent plastic (with thicknesses approximately equal to the practical range of electrons in the plastic) placed upstream of the EPID, to filter out the primary electron beam, leaving only the bremsstrahlung photon signal. While the electron beam images acquired using a standard (unfiltered) flood field calibration were observed to be noisy and difficult to interpret, the electron beam images acquired using the filtered flood field calibration showed tissues and bony anatomy with levels of contrast and noise that were similar to the contrast and noise levels seen in the clinically acceptable photon beam EPID images. The best electron beam imaging results (highest contrast, signal-to-noise and contrast-to-noise ratios) were achieved when the images were acquired using the higher energy electron beams (16 and 20 MeV) when the EPID was calibrated using an intermediate (12 MeV) electron beam energy. These results demonstrate the feasibility of acquiring clinically useful EPID images of patient anatomy using electron beams and suggest important avenues for future investigation, thus enabling and encouraging further research in this area. There is manifest potential for the EPID imaging method proposed in this work to lead to the clinical use of electron beam imaging for geometric verification of electron treatments in the future. PMID- 26581764 TI - Hand movements classification for myoelectric control system using adaptive resonance theory. AB - This research proposes an exploratory study of a simple, accurate, and computationally efficient movement classification technique for prosthetic hand application. Surface myoelectric signals were acquired from the four muscles, namely, flexor carpi ulnaris, extensor carpi radialis, biceps brachii, and triceps brachii, of four normal-limb subjects. The signals were segmented, and the features were extracted with a new combined time-domain feature extraction method. Fuzzy C-means clustering method and scatter plot were used to evaluate the performance of the proposed multi-feature versus Hudgins' multi-feature. The movements were classified with a hybrid Adaptive Resonance Theory-based neural network. Comparative results indicate that the proposed hybrid classifier not only has good classification accuracy (89.09%) but also a significantly improved computation time. PMID- 26581765 TI - The transcriptome of muscle and liver is responding differently to a combined trenbolone acetate and estradiol implant in cattle. AB - We investigated the transcriptomic signature of some anabolic steroids in cattle. Our main objective was to evaluate the effect of a combined trenbolone acetate (TBA, 200mg) and estradiol-17beta (E2, 40 mg) implant (Revalor-XS(r), REV) on the transcriptome of muscle (target tissue for anabolic steroids) and liver (main biotransformation site). Transcriptomic profiling was performed on 60 samples (30 per tissue) representing 2 groups of animals: REV (sustained release implant for 71 days, n=15), and a control group (CTR, n=15). The analyses (REV vs. CTR) evidenced the differential expression of 431 (down-regulated) and 503 transcripts (268 up-regulated and 235 down-regulated) in muscle and liver tissues, respectively. Functional annotation showed the enrichment of several ion transport systems (cation, metal ion and potassium ion transport) in muscle, while revealing the enrichment of carbohydrate, protein and glycoprotein metabolism and biosynthesis mechanisms in the liver. Both tissues had 20 genes commonly expressed in-between. Seven randomly-selected genes showed positive correlation with their corresponding microarray data upon a qPCR cross-validation step. In muscle, but not the liver, Principal Component Analysis (PCA) on the microarray data resulted in the separation of treated animals from the untreated ones (first 2 components=97.87%.). Overall, the identification of different genes, pathways and biological processes has illustrated the distinctive transcriptomic profile of muscle and liver in response to anabolic steroids. Moreover, it is becoming more clear that anabolic steroids are working through a complex interaction of numerous pathways and processes incorporating different tissues. PMID- 26581766 TI - A Novel, Poly(Ethyl Ethylene Ether) Inhibitor to Trypsin from Marine Cyanobacteria, Lyngbya confervoides. AB - A novel, poly(ethyl ethylene ether) inhibitor to trypsin was purified from marine cyanobacteria, Lyngbya confervoides from the coastal areas of Thalassery, North Kerala. The kinetics and the thermodynamic parameters of its interactions with the enzyme were also studied. It was demonstrated that the substrate binding, catalytic triad of the enzyme could be blocked by the inhibitor, as expressed by molecular simulation studies. The study also showed that the cyanobacterial group could prove to be a potential source of novel enzyme inhibitors for various applications. PMID- 26581767 TI - Highly Bactericidal Polyurethane Effective Against Both Normal and Drug-Resistant Bacteria: Potential Use as an Air Filter Coating. AB - The battle against the prevalence of hospital-acquired infections has underscored the importance of identifying and maintaining the cleanliness of possible infection transmission sources in the patient's environment. One of the most crucial lines of defense for mitigating the spread of pathogens in a healthcare facility is the removal of microorganisms from the environment by air filtration systems. After removing the pathogenic microorganisms, the filters used in these systems can serve as reservoirs for the pathogens and pose a risk for secondary infection. This threat, combined with the ever-growing prevalence of drug resistant bacterial strains, substantiates the need for an effective bactericidal air filter. To this end, a broad-spectrum bactericidal polyurethane incorporating immobilized quaternary ammonium groups was developed for use as an air filter coating. In this study, the bactericidal activity of the polymer coating on high efficiency particulate air (HEPA) filter samples was quantified against eight bacterial strains commonly responsible for nosocomial infection-including drug resistant strains, and confirmed when applied as a filter coating in conditions mimicking those of its intended application. The coated HEPA filter samples exhibited high bactericidal activity against all eight strains, and the polyurethane was concluded to be an effective coating in rendering HEPA filters bactericidal. PMID- 26581768 TI - The acceptability of care provided by dental auxiliaries: A systematic review. AB - BACKGROUND: Dental auxiliaries undertaking a limited range of intraoral clinical procedures normally performed by dentists could increase access to care and control costs, yet their acceptability to patients has been questioned. The aim of this study was to assess data on the social acceptability and patient satisfaction of dental auxiliaries performing intraoral clinical procedures. METHODS: The authors searched 14 electronic databases and 2 trial registries for studies of any design (from inception to November 2013). They searched gray literature databases (from inception to July 2014), reference lists of included studies, and high-yield journals (from January 2000 to December 2014). Risk of bias was assessed, and data were extracted. RESULTS: The authors identified 29 studies: 25 considered experiential and 4 on social acceptability. Twenty-three were cross-sectional, 2 were qualitative, 1 was mixed-methods, and 3 had unclear methods. The authors found that patients reported high acceptability of care, comparable or better than that from dentists. Social acceptability varied, with care for children being less acceptable. One-fifth of people were unwilling to receive any treatment from a dental auxiliary. All studies were at high risk of bias, and quality of the evidence was low. CONCLUSIONS: Experiential acceptability of dental auxiliaries by patients appeared high in this study, but their social acceptability varied. PRACTICAL IMPLICATIONS: Given the age of the studies, their settings, and their quality, generalizability to dental practices is limited. Additional high-quality, methodologically rigorous studies are needed. PMID- 26581769 TI - Do glass ionomer cements prevent caries lesions in margins of restorations in primary teeth?: A systematic review and meta-analysis. AB - BACKGROUND: Fluoride released from glass ionomer cements (GICs) is capable of preventing caries lesions. However, the preventive effect in margins of occlusal and occlusoproximal restorations have not been proved. The aim of this study was to evaluate the ability of GIC to prevent caries lesions in margins of occlusal and occlusoproximal restorations in primary teeth compared with that of other restorative materials. TYPES OF STUDIES REVIEWED: The authors conducted a literature search in PubMed and MEDLINE to verify the clinical trials available on the outcome of caries lesions. The inclusion criteria were that the subject related to the scope of this systematic review, the study had a follow-up, and the study was not performed in specific groups. The authors performed all meta analyses by considering the secondary caries rates for the restorations in clinical trials. RESULTS: The search strategy identified 450 potentially relevant studies, and the authors included 8 of them in the review. The main reasons for exclusion were that the studies were not related to the scope of this review or were not longitudinal trials. The secondary caries rate of the occlusal restorations was not different among the restorative materials (odds ratio, 1.2; 95% confidence interval, 0.5-3.1). For occlusoproximal analysis, GIC was associated significantly with better ability to prevent caries lesions (odds ratio, 1.7; 95% confidence interval, 1.2-2.5). CONCLUSIONS AND PRACTICAL IMPLICATIONS: Because new caries lesions in the margins of restorations are the main reason for failure and replacement of restorations in primary teeth, it is important to know whether there is a benefit in using GICs in both occlusal and occlusoproximal cavities. PMID- 26581770 TI - The Specification and Maturation of Nociceptive Neurons from Human Embryonic Stem Cells. AB - Nociceptive neurons play an essential role in pain sensation by transmitting painful stimuli to the central nervous system. However, investigations of nociceptive neuron biology have been hampered by the lack of accessibility of human nociceptive neurons. Here, we describe a system for efficiently guiding human embryonic stem cells into nociceptive neurons by first inducing these cells to the neural lineage. Subsequent addition of retinoic acid and BMP4 at specific time points and concentrations yielded a high population of neural crest progenitor cells (AP2alpha(+), P75(+)), which further differentiated into nociceptive neurons (TRKA(+), Nav1.7(+), P2X3(+)). The overexpression of Neurogenin 1 (Neurog1) promoted the neurons to express genes related to sensory neurons (Peripherin, TrkA) and to further mature into TRPV1(+) nociceptive neurons. Importantly, the overexpression of Neurog1 increased the response of these neurons to capsaicin stimulation, a hallmark of mature functional nociceptive neurons. Taken together, this study reveals the important role that Neurog1 plays in generating functional human nociceptive neurons. PMID- 26581771 TI - Comparative studies on the properties of glycyrrhetinic acid-loaded PLGA microparticles prepared by emulsion and template methods. AB - The O/W emulsion method has been widely used for the production of poly (lactide co-glycolide) (PLGA) microparticles. Recently, a template method has been used to make homogeneous microparticles with predefined size and shape, and shown to be useful in encapsulating different types of active compounds. However, differences between the template method and emulsion method have not been examined. In the current study, PLGA microparticles were prepared by the two methods using glycyrrhetinic acid (GA) as a model drug. The properties of obtained microparticles were characterized and compared on drug distribution, in vitro release, and degradation. An encapsulation efficiency of over 70% and a mean particle size of about 40MUm were found for both methods. DSC thermograms and XRPD diffractograms indicated that GA was highly dispersed or in the amorphous state in the matrix of microparticles. The emulsion method produced microparticles of a broad size distribution with a core-shell type structure and many drug-rich domains inside each microparticle. Its drug release and matrix degradation was slow before Day 50 and then accelerated. In contrast, the template method formed microparticles with narrow size distribution and drug distribution without apparent drug-rich domains. The template microparticles with a loading efficiency of 85% exhibited a zero-order release profile for 3 months after the initial burst release of 26.7%, and a steady surface erosion process as well. The same microparticles made by two different methods showed two distinguished drug release profiles. The two different methods can be supplementary with each other in optimization of drug formulation for achieving predetermined drug release patterns. PMID- 26581772 TI - Encapsulation of volatiles by homogenized partially-cross linked alginates. AB - Cross-linked calcium alginate gels are too viscous to be efficaciously incorporated into spray dried formulations. Thus, viscosity reduction is essential to ensure the processability of calcium alginate gels to be sprayed. Viscosity reduction by high pressure homogenization can open new formulation possibilities. Presently, testing of microcapsule integrity is also limited because either single particle tests neglect collective particle behaviours in bulk or bulk testing methods are often associated with single compressions which may not fully characterize individual particle strengths. The aim of this study was sub-divided into three objectives. First objective was to evaluate the impact of high pressure homogenization on gel viscosity. Second objective was to explore the use of the homogenized gels with modified starch for microencapsulation by spray drying. The final objective was to develop a stamping system as microcapsule strength tester that can assess microcapsules in bulk and evaluate the impact of multiple compressions. Collectively, this study would lead towards developing a pressure-activated patch of microcapsules with encapsulated volatiles and the method to assess the patch efficacy. The alginate gels largely experienced an exponential decay in viscosity when homogenized. Furthermore, the homogenized gels were successfully incorporated in spray drying formulations for microencapsulation. The custom-designed microcapsule strength tester was successfully used and shown to possess the required sensitivity to discern batches of microcapsules containing volatiles to have different release profiles. Addition of homogenized gels strengthened the microcapsules only at high wall to core ratios with low mass-load alginate gels. High mass-load gels weaken the microcapsules, exhibiting a higher release at low stamping pressures and wrinkling on the microcapsules surface. PMID- 26581773 TI - Molecular interaction between glimepiride and Soluplus(r)-PEG 4000 hybrid based solid dispersions: Characterisation and anti-diabetic studies. AB - The objective of this study was to evaluate a novel blend of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol 6000 grafted copolymer (Soluplus(r)) and polyethylene glycol (PEG) 4000 for solubility enhancement, physicochemical stability and anti-diabetic efficacy of the produced solid dispersions containing glimepiride, a biopharmaceutics classification system (BCS) class II sulphonylurea. Different batches of glimepiride solid dispersions (SD) were prepared by the solvent evaporation method using the individual polymers and blends of the polymers at different ratios. The Soluplus(r)-PEG 4000 (sol-PEG) hybrid polymer based glimepiride solid dispersions were characterized by differential scanning calorimetry (DSC), fourier transform infrared (FTIR) spectroscopy, micromeritics and dissolution studies. In vivo anti-diabetic activity was determined by measuring the changes in blood glucose concentrations in albino rats. The solid dispersions showed good flow properties and excellent practical yield. Drug content and release from the different formulations increased when Soluplus(r) was used as the main matrix polymer. The kinetics of drug release from all the solid dispersions followed first order. Solid state characterization confirmed the formation of amorphous glimepiride solid dispersions in the Sol-PEG hybrid polymer and no strong drug-polymer interaction was observed. The blood glucose reduction in albino rats by the Sol-PEG-Glim SDs was significantly (p<0.05) higher and more sustained when compared with the plain drug sample and commercially available product. Optimized SD batches (SP1 and SP3) showed a reduction in blood glucose level from 100% to 9.81% and 8.97%, respectively, at Tmax of 3h. The Sol-PEG-Glim SD was found to be stable over a period of 6 months (at 40 degrees C, 70% RH) with no significant changes in the drug content. Thus, the Sol-PEG polymeric hybrids represent a promising tool for enhanced delivery of glimepiride. PMID- 26581774 TI - Polyethylene glycols in oral and parenteral formulations--A critical review. AB - Polyethylene glycols (PEGs) are frequently employed as vehicles in oral and parenteral dosage forms. PEGs have low toxicity, are miscible with aqueous fluids in all proportions, and dissolve many poorly aqueous soluble compounds. Compounds with poor aqueous solubility and resulting poor bioavailability and considerable individual variability in the absorption were shown to provide exceptionally high bioavailability and reduced inter-subject variability in plasma concentrations when dosed as solutions or suspensions in PEGs. The advantages offered by PEGs, however, are not without potential challenges that must also be considered and which are the focus of this review. First, PEGs often may have high solubilizing power for some poorly aqueous soluble compounds, the high affinity of these vehicles for water can potentially lead to precipitation of the dissolved compounds when the formulations encounter an aqueous environment in vitro or in vivo, resulting in reduced bioavailability of the compounds. Second, PEGs, due to the presence of hydroxyl groups in their structures, are reactive with compounds dissolved within, resulting in the formation of degradation products. Third, PEGs, due to the presence of recurring ether groups in their polymer chains, are also inherently susceptible to autooxidative reactions, resulting in the formation of highly reactive products, which degrade several compounds formulated with PEGs. The objective is to review the applications and limitations of PEGs in pharmaceutical dosage forms and discuss solutions to mitigate challenges that may potentially arise from their use. PMID- 26581775 TI - Correlation between short-term blood pressure variability and left-ventricular mass index: a meta-analysis. AB - Long-term blood pressure variability (BPV) has been associated with cardiovascular events but the prognostic significance of short-term BPV remains uncertain, including its influence on the presence of target-organ damage, specifically left-ventricular hypertrophy. A meta-analysis exploring the correlation between short-term BPV and left-ventricular mass index was performed. Studies were identified by systematic searches in Pubmed and EMBASE. Any summary measure of short-term BPV obtained from ambulatory blood pressure monitoring was included. Twelve studies were included. Average real variability (ARV), s.d., weighted s.d. and coefficient of variation across 24 h/day/night periods were identified as measures of variability. Meta-analysis showed the pooled subgroup correlation coefficients of LVMI with 24 h systolic blood pressure (SBP) s.d., day SBP s.d., weighted s.d. SBP and 24 h ARV SBP were 0.22 (95% confidence interval (CI): 0.12-0.31), 0.19 (95% CI: 0.15-0.25), 0.23 (95% CI: 0.13-0.33), 0.37 (95% CI: 0.01-0.65), respectively. This meta-analysis suggests there is a weak positive correlation, between BPV and LVMI. PMID- 26581776 TI - Effect of selective vagal nerve stimulation on blood pressure, heart rate and respiratory rate in rats under metoprolol medication. AB - Selective vagal nerve stimulation (sVNS) has been shown to reduce blood pressure without major side effects in rats. This technology might be the key to non medical antihypertensive treatment in patients with therapy-resistant hypertension. beta-blockers are the first-line therapy of hypertension and have in general a bradycardic effect. As VNS itself can also promote bradycardia, it was the aim of this study to investigate the influence of the beta1-selective blocker Metoprolol on the effect of sVNS especially with respect to the heart rate. In 10 male Wistar rats, a polyimide multichannel-cuff electrode was placed around the vagal nerve bundle to selectively stimulate the aortic depressor nerve fibers. The stimulation parameters were adapted to the thresholds of individual animals and were in the following ranges: frequency 30-50 Hz, amplitude 0.3-1.8 mA and pulse width 0.3-1.3 ms. Blood pressure responses were detected with a microtip transducer in the carotid artery, and electrocardiography was recorded with s.c. chest electrodes. After IV administration of Metoprolol (2 mg kg(-1) body weight), the animals' mean arterial blood pressure (MAP) and heart rate (HR) decreased significantly. Although the selective electrical stimulation of the baroreceptive fibers reduced MAP and HR, both effects were significantly alleviated by Metoprolol. As a side effect, the rate of stimulation-induced apnea significantly increased after Metoprolol administration. sVNS can lower the MAP under Metoprolol without causing severe bradycardia. PMID- 26581777 TI - Higher efficiency soluble prokaryotic expression, purification, and structural analysis of antimicrobial peptide G13. AB - G13 is a 19-residue cationic antimicrobial peptide derived from granulysin. In order to achieve high-level expression of G13 in Escherichia coli cells, and to reduce downstream processing costs, we introduced an Asp-Pro acid labile bond between the His-Patch thioredoxin and G13 and constructed the recombinant plasmid pThiohisA-DP-G13. The plasmid was transformed into E. coli BL21 (DE3). After induction with isopropyl-beta-d-thiogalactopyranoside for 5 h, the fusion protein accumulated up to 200 mg/L in soluble form. The fusion protein was released by a high pressure homogenizer, cleaved using 13% acetic acid at 50 degrees C hydrolysis for 72 h. The recombinant G13 (r-G13) was then successively purified by fractional precipitation with ammonium sulfate and trichloroacetic acid, followed by one-step cation exchange chromatography. The purified r-G13 displayed a single band (about 2.2 kDa) as analyzed by Tris-Tricine buffered SDS-PAGE, and its precise molecular weight was confirmed using tandem mass spectrometry. Analysis of r-G13 by circular dichroism (CD) indicated that r-G13 contained predominantly beta-sheet and random coil. Agar plate diffusion assay revealed that the r-G13 exhibited antibacterial activity against both Bacillus subtilis and E. coli. PMID- 26581778 TI - Simple method for purification of enterotoxigenic Escherichia coli fimbriae. AB - Enterotoxigenic Escherichia coli (ETEC) are endemic pathogens in the developing world. They frequently cause illness in travelers, and are among the most prevalent causes of diarrheal disease in children. Pathogenic ETEC strains employ fimbriae as adhesion factors to bind the luminal surface of the intestinal epithelium and establish infection. Accordingly, there is marked interest in immunoprophylactic strategies targeting fimbriae to protect against ETEC infections. Multiple strategies have been reported for purification of ETEC fimbriae, however none is ideal. Purification has typically involved the use of highly virulent wild-type strains. We report here a simple and improved method to purify ETEC fimbriae, which was applied to obtain two different Class 5 fimbriae types of clinical relevance (CFA/I and CS4) expressed recombinantly in E. coli production strains. Following removal from cells by shearing, fimbriae proteins were purified by orthogonal purification steps employing ultracentrifugation, precipitation, and ion-exchange membrane chromatography. Purified fimbriae demonstrated the anticipated size and morphology by electron microscopy analysis, contained negligible levels of residual host cell proteins, nucleic acid, and endotoxin, and were recognized by convalescent human anti-sera. PMID- 26581779 TI - Soluble expression and purification of the recombinant bioactive peptide precursor BPP-1 in Escherichia coli using a cELP-SUMO dual fusion system. AB - A bioactive peptide precursor (BPP-1, 14.3 kDa/115AA), a newly designed polypeptide that may exert a potential antihypertensive effect in vivo, is composed of many different ACE inhibitory peptides and antioxidant peptides tandemly linked according to the restriction sites of gastrointestinal proteases. In this report, we present a novel method to obtain soluble BPP-1 in Escherichia coli using cationic elastin-like polypeptide and SUMO (cELP-SUMO) tags. The cELP SUMO-tagged fusion protein was expressed in soluble form at 20 degrees C for 20 h. After purification based on the inverse transition cycling (ITC) method, the purified cELP-SUMO-CFPP fusion protein was subsequently cleaved by a SUMO protease to release the mature BPP-1. After a subsequent simple salt precipitation process, approximately 167.2 mg of recombinant BPP-1 was obtained from 1 l of bacterial culture with at least 92% purity. The molecular mass (Mr) of the recombinant BPP-1 was confirmed by MALDI-TOF MS to equal 14,347. The purified BPP-1 was subjected to simulated gastrointestinal digestion, and the resulting hydrolysates exhibited notable ACE inhibitory and antioxidant activities in vitro. This report provides the first description of the soluble production of a bioactive peptide multimer with potential ACE inhibitory and antioxidant activities in E. coli using a cELP-SUMO tag. PMID- 26581780 TI - Perceptions and Expectations of Host Country Preceptors of Short-Term Learners at Four Clinical Sites in Sub-Saharan Africa. AB - OBJECTIVE: The demand for global health electives among medical students and residents has grown substantially, yet perspectives of international hosts are not well documented. This study aimed to assess how host country supervising clinical preceptors perceive learners on short-term global health electives of up to 6 weeks. METHODS: This study used a cross-sectional survey design and assessed international clinical preceptors' perceptions of short-term learners' (STLs) professional behaviors, medical knowledge, competency in systems-based care, as well as the benefits and burdens of hosting STLs. Surveys were sent to all clinical preceptors (n = 47) at 4 clinical sites in sub-Saharan Africa in 2015. RESULTS: Thirty-two preceptors (68%) responded to the survey. Most respondents (97%) were satisfied in their role hosting STLs and reported that STLs enhanced patient care and the professional image of the clinical site. Nearly half of respondents (45%) reported decreased self-perceived efficiency in clinical care tasks. Qualitative data identified concerns related to STLs' professionalism and teamwork. Respondents also identified knowledge gaps in understanding differences in health systems and epidemiology in host country settings. Respondents preferred that rotations last at least 4 weeks and that STLs complete predeparture training. CONCLUSIONS: STLs were largely positively regarded by international host clinical preceptors. To improve mutuality of benefits, sending institutions should ensure learners understand host country expectations of professionalism and that learners are well prepared for medical, ethical, and cultural challenges through participation in predeparture curricula that prepare them clinically and emotionally for these international experiences. Rotations of at least 4 weeks may enhance benefits to learners and hosts. PMID- 26581781 TI - Structural and electrical properties of catalyst-free Si-doped InAs nanowires formed on Si(111). AB - We report structural and electrical properties of catalyst-free Si-doped InAs nanowires (NWs) formed on Si(111) substrates. The average diameter of Si-doped InAs NWs was almost similar to that of undoped NWs with a slight increase in height. In the previous works, the shape and size of InAs NWs formed on metallic catalysts or patterned structures were significantly changed by introducing dopants. Even though the external shape and size of the Si-doped NWs in this work were not changed, crystal structures inside the NWs were significantly changed. For the undoped InAs NWs, both zincblende (ZB) and wurzite (WZ) structures were observed in transmission-electron microscope images, where the portion of WZ structure was estimated to be more than 30%. However, only ZB was observed with an increase in stacking fault (SF) for the Si-doped NWs. The undoped and Si-doped InAs NWs were used as channels of four-point electrical measurements with Al/Ni electrodes to investigate electrical properties. The resistivity calculated from the current-voltage curve of a Si-doped InAs NW showed 1.32 * 10(-3) Omegacm, which was dramatically decreased from 10.14 * 10(-3) Omegacm for the undoped InAs NW. A relatively low resistivity of catalyst-free Si-doped InAs NWs was achieved without significant change in structural dimensions. PMID- 26581782 TI - Validation of fibromyalgia survey questionnaire and polysymptomatic distress scale in a Persian population. AB - The aim of this study was to assess validity of the fibromyalgia survey questionnaire (FSQ) and polysymptomatic distress scale (PSD) in an Iranian population. We also sought to classify the severity levels of fibromyalgia (FM) symptoms according to the PSD scale. Participants were divided into FM and non-FM chronic pain disorder groups according to expert physician diagnosis. Patients in both groups answered to Persian-translated version of FSQ, fibromyalgia impact questionnaire (FIQ) and Short-Form-12 (SF-12). Both 1990 ACR criteria and FSDC were assessed in participates of two groups. Internal consistency and construct validity were evaluated. There was good internal consistency measured by Cronbach's alpha (0.814 for FSQ). FSQ and its subscales correlated significantly with FIQ scores and SF-12 subscales, indicating acceptable construct validity. The concordance rates of FSQ with 1990 ACR criteria and expert diagnosis were 61.2 and 75.7, respectively (convergence validity). The mean score of PSD and its components in FM group were significantly more than in control groups (discriminative validity). Using lower PSD score cutoff (>=8.5) for the diagnosis of fibromyalgia appeared to be the most effective approach in our population. ROC analysis of the PSD scores revealed 8.5-11.5, 11.5-15 and more than 15, respectively, as a mild, moderate and severe FM. Persian version of FSQ was a valid instrument for application in survey research among Iranian patients with chronic pain disorders. The current study revealed that PSD could be used as a valid tool for assessment of symptoms intensity regardless of fibromyalgia diagnosis. PMID- 26581783 TI - Laser cellulite treatment and laser-assisted lipoplasty of the thighs and buttocks: Combined modalities for single stage contouring of the lower body. AB - BACKGROUND AND OBJECTIVES: Cellulite and lipodystrophy are often found together, especially in areas of the buttocks and thighs, causing skin surface irregularities. Each of these conditions is currently treated independently as two separate surgical procedures. In our practice, we developed a novel combined approach for the simultaneous treatment of cellulite and lipodystrophy, as a single stage procedure in the same anatomic area. For the treatment of cellulite, we used the Nd:YAG laser at a wavelength of 1,440-nm, along with an innovative 1,000-micron directional side-firing fiber optic laser system. For the treatment of lipodystrophy, the Nd:YAG laser with a 1,440 nm wavelength, along with a fiber optic laser system was used. The objective of this study is to determine the efficacy and safety of a combined approach for the simultaneous treatment of cellulite and lipodystrophy. STUDY DESIGN, PATIENTS AND METHODS: In 2012, 16 subjects with noticeable cellulite, Grade II and Grade III, accompanied by mild to-moderate lipodystrophy of the lower body received single treatments of the Nd:YAG laser at a wavelength of 1,440-nm along with the 1,000-micron side-firing fiber optic laser system for simultaneous treatments of both cellulite and lipodystrophy. Patients were assessed at baseline and 3-6 months post-treatment by a modified Nurnberger-Muller scale utilized to quantify the cellulite severity. Additionally, patient satisfaction and a global aesthetic improvement scale were used to measure the improvement in lipodystrophy. RESULTS: Blinded reviewers identified the correct baseline photographs 97% of the time when presented with a set of photographs. The median modified Nurnberger-Muller scale score at baseline was 4.75 +/- 1.2 and the average improvement was 2.0 +/- 1.2. Global aesthetic improvement scores ranged from 1 to 3 with an average of 1.58 indicating a much-improved overall appearance. Satisfaction was high for both physicians and patients with scores corresponding to extremely satisfied/satisfied. CONCLUSION: Precise, effective delivery of laser energy to the dermal-adipose tissue, as well as the deep adipose lipodystrophy is feasible as a safe modality for the simultaneous treatment of cellulite and lipodystrophy in the buttocks and thighs, as a single stage procedure. PMID- 26581784 TI - Anterior lens epithelial cells attachment to the basal lamina. AB - PURPOSE: To study the structure of the anterior lens epithelial cells (aLECs) and the contacts of the aLECs with the basal lamina (BL) in order to understand their role in the lens epithelium's function. METHODS: The aLCs (BL and associated aLECs) were obtained from routine uneventful cataract surgery, prepared for and studied by scanning electron microscopy (SEM), transmission electron microscopy (TEM) and confocal microscopy. RESULTS: SEM shows that the basal surface of the aLECs (~10-15 MUm) is with aLECs foldings (~1-3 MUm) and extensions (~0.5-3 MUm) attached to the BL. Confocal microscopy images of the basal sections of the aLECs after membrane staining also suggest that the basal part of aLECs has foldings (~1-3 MUm). TEM shows in the aLECs basal parts, towards BL, the structures that look like entanglement (~1-4 MUm). In cases where there is a swelling of the cytoplasm and offset of the aLECs from the BL, individual extensions (~0.5-2 MUm) that extend to the BL are visible by TEM. CONCLUSIONS: We provide detail evidence about the structural organization of the aLECs, in particular about their basal side which is in contact with the BL. This is supported by the complementary use of three techniques, SEM, TEM and confocal microscopy, each of them showing the same morphological features, the extensions and the entanglements of the aLECs cytoplasmic membrane at the border with the BL. The basal surface of the aLECs is increased. It suggests the functional importance of the contact between aLECs and BL. PMID- 26581785 TI - Effectiveness of simulation with team-based learning in newborn nursing care. AB - This study determines the effect of simulation with team-based learning (TBL) on newborn nursing care. This randomized controlled trial included 74 nursing students from one university located in Seoul, South Korea. Participants were categorized into two groups according to educational modality: one group involved both simulation and TBL, and the other involved simulation alone. Learning attitudes, academic achievement, and simulation performance were examined to assess effectiveness. The mean difference in learning attitudes between the two groups was non-significant. Low academic achievement differed significantly between the two groups (t = 3.445, P = 0.002). There was no significant difference in mean scores for simulation performance between the two groups. In this study, simulation with TBL was effective in improving learning outcomes. In current nursing education, various learning methods are employed within complex nursing situations and require flexibility and problem-solving approaches. PMID- 26581786 TI - Introduction to the JINS Special Issue: Physical Activity and Brain Plasticity. PMID- 26581787 TI - Long-Term Effects of Resistance Exercise Training on Cognition and Brain Volume in Older Women: Results from a Randomized Controlled Trial. AB - Aerobic exercise training has been shown to attenuate cognitive decline and reduce brain atrophy with advancing age. The extent to which resistance exercise training improves cognition and prevents brain atrophy is less known, and few studies include long-term follow-up cognitive and neuroimaging assessments. We report data from a randomized controlled trial of 155 older women, who engaged in 52 weeks of resistance training (either once- or twice-weekly) or balance-and toning (twice-weekly). Executive functioning and memory were assessed at baseline, 1-year follow-up (i.e., immediately post-intervention), and 2-year follow-up. A subset underwent structural magnetic resonance imaging scans at those time points. At 2-year follow-up, both frequencies of resistance training promoted executive function compared to balance-and-toning (standardized difference [d]=.31-.48). Additionally, twice-weekly resistance training promoted memory (d=.45), reduced cortical white matter atrophy (d=.45), and increased peak muscle power (d=.27) at 2-year follow-up relative to balance-and-toning. These effects were independent of one another. These findings suggest resistance training may have a long-term impact on cognition and white matter volume in older women. PMID- 26581788 TI - Improved Cardiorespiratory Fitness Is Associated with Increased Cortical Thickness in Mild Cognitive Impairment. AB - Cortical atrophy is a biomarker of Alzheimer's disease (AD) that correlates with clinical symptoms. This study examined changes in cortical thickness from before to after an exercise intervention in mild cognitive impairment (MCI) and healthy elders. Thirty physically inactive older adults (14 MCI, 16 healthy controls) underwent MRI before and after participating in a 12-week moderate intensity walking intervention. Participants were between the ages of 61 and 88. Change in cardiorespiratory fitness was assessed using residualized scores of the peak rate of oxygen consumption (VO2peak) from pre- to post-intervention. Structural magnetic resonance images were processed using FreeSurfer v5.1.0. VO2peak increased an average of 8.49%, which was comparable between MCI and healthy elders. Overall, cortical thickness was stable except for a significant decrease in the right fusiform gyrus in both groups. However, improvement in cardiorespiratory fitness due to the intervention (VO2peak) was positively correlated with cortical thickness change in the bilateral insula, precentral gyri, precuneus, posterior cingulate, and inferior and superior frontal cortices. Moreover, MCI participants exhibited stronger positive correlations compared to healthy elders in the left insula and superior temporal gyrus. A 12-week moderate intensity walking intervention led to significantly improved fitness in both MCI and healthy elders. Improved VO2peak was associated with widespread increased cortical thickness, which was similar between MCI and healthy elders. Thus, regular exercise may be an especially beneficial intervention to counteract cortical atrophy in all risk groups, and may provide protection against future cognitive decline in both healthy elders and MCI. PMID- 26581789 TI - Aerobic and Cognitive Exercise (ACE) Pilot Study for Older Adults: Executive Function Improves with Cognitive Challenge While Exergaming. AB - Dementia cases are increasing worldwide; thus, investigators seek to identify interventions that might prevent or ameliorate cognitive decline in later life. Extensive research confirms the benefits of physical exercise for brain health, yet only a fraction of older adults exercise regularly. Interactive mental and physical exercise, as in aerobic exergaming, not only motivates, but has also been found to yield cognitive benefit above and beyond traditional exercise. This pilot study sought to investigate whether greater cognitive challenge while exergaming would yield differential outcomes in executive function and generalize to everyday functioning. Sixty-four community based older adults (mean age=82) were randomly assigned to pedal a stationary bike, while interactively engaging on-screen with: (1) a low cognitive demand task (bike tour), or (2) a high cognitive demand task (video game). Executive function (indices from Trails, Stroop and Digit Span) was assessed before and after a single-bout and 3-month exercise intervention. Significant group * time interactions were found after a single-bout (Color Trails) and after 3 months of exergaming (Stroop; among 20 adherents). Those in the high cognitive demand group performed better than those in the low cognitive dose condition. Everyday function improved across both exercise conditions. Pilot data indicate that for older adults, cognitive benefit while exergaming increased concomitantly with higher doses of interactive mental challenge. PMID- 26581790 TI - Physical Activity Is Positively Associated with Episodic Memory in Aging. AB - Aging is associated with performance reductions in executive function and episodic memory, although there is substantial individual variability in cognition among older adults. One factor that may be positively associated with cognition in aging is physical activity. To date, few studies have objectively assessed physical activity in young and older adults, and examined whether physical activity is differentially associated with cognition in aging. Young (n=29, age 18-31 years) and older adults (n=31, ages 55-82 years) completed standardized neuropsychological testing to assess executive function and episodic memory capacities. An experimental face-name relational memory task was administered to augment assessment of episodic memory. Physical activity (total step count and step rate) was objectively assessed using an accelerometer, and hierarchical regressions were used to evaluate relationships between cognition and physical activity. Older adults performed more poorly on tasks of executive function and episodic memory. Physical activity was positively associated with a composite measure of visual episodic memory and face-name memory accuracy in older adults. Physical activity associations with cognition were independent of sedentary behavior, which was negatively correlated with memory performance. Physical activity was not associated with cognitive performance in younger adults. Physical activity is positively associated with episodic memory performance in aging. The relationship appears to be strongest for face-name relational memory and visual episodic memory, likely attributable to the fact that these tasks make strong demands on the hippocampus. The results suggest that physical activity relates to cognition in older, but not younger adults. PMID- 26581791 TI - Acute Exercise Improves Prefrontal Cortex but not Hippocampal Function in Healthy Adults. AB - The effects of acute aerobic exercise on cognitive functions in humans have been the subject of much investigation; however, these studies are limited by several factors, including a lack of randomized controlled designs, focus on only a single cognitive function, and testing during or shortly after exercise. Using a randomized controlled design, the present study asked how a single bout of aerobic exercise affects a range of frontal- and medial temporal lobe-dependent cognitive functions and how long these effects last. We randomly assigned 85 subjects to either a vigorous intensity acute aerobic exercise group or a video watching control group. All subjects completed a battery of cognitive tasks both before and 30, 60, 90, or 120 min after the intervention. This battery included the Hopkins Verbal Learning Test-Revised, the Modified Benton Visual Retention Test, the Stroop Color and Word Test, the Symbol Digit Modalities Test, the Digit Span Test, the Trail Making Test, and the Controlled Oral Word Association Test. Based on these measures, composite scores were formed to independently assess prefrontal cortex- and hippocampal-dependent cognition. A three-way mixed Analysis of Variance was used to determine whether differences existed between groups in the change in cognitive function from pre- to post-intervention testing. Acute exercise improved prefrontal cortex- but not hippocampal-dependent functioning, with no differences found between delay groups. Vigorous acute aerobic exercise has beneficial effects on prefrontal cortex-dependent cognition and these effects can last for up to 2 hr after exercise. PMID- 26581792 TI - Age Moderates the Association of Aerobic Exercise with Initial Learning of an Online Task Requiring Cognitive Control. AB - The aim of this study was to examine whether people differed in change in performance across the first five blocks of an online flanker task and whether those trajectories of change were associated with self-reported aerobic or resistance exercise frequency according to age. A total of 8752 men and women aged 13-89 completed a lifestyle survey and five 45-s games (each game was a block of ~46 trials) of an online flanker task. Accuracy of the congruent and incongruent flanker stimuli was analyzed using latent class and growth curve modeling adjusting for time between blocks, whether the blocks occurred on the same or different days, education, smoking, sleep, caffeinated coffee and tea use, and Lumosity training status ("free play" or part of a "daily brain workout"). Aerobic and resistance exercise were unrelated to first block accuracies. For the more cognitively demanding incongruent flanker stimuli, aerobic activity was positively related to the linear increase in accuracy [B=0.577%, 95% confidence interval (CI), 0.112 to 1.25 per day above the weekly mean of 2.8 days] and inversely related to the quadratic deceleration of accuracy gains (B=-0.619% CI, -1.117 to -0.121 per day). An interaction of aerobic activity with age indicated that active participants younger than age 45 had a larger linear increase and a smaller quadratic deceleration compared to other participants. Age moderates the association between self-reported aerobic, but not self-reported resistance, exercise and changes in cognitive control that occur with practice during incongruent presentations across five blocks of a 45-s online, flanker task. PMID- 26581793 TI - Association between Lifetime Physical Activity and Cognitive Functioning in Middle-Aged and Older Community Dwelling Adults: Results from the Brain in Motion Study. AB - To determine if total lifetime physical activity (PA) is associated with better cognitive functioning with aging and if cerebrovascular function mediates this association. A sample of 226 (52.2% female) community dwelling middle-aged and older adults (66.5 +/- 6.4 years) in the Brain in Motion Study, completed the Lifetime Total Physical Activity Questionnaire and underwent neuropsychological and cerebrovascular blood flow testing. Multiple robust linear regressions were used to model the associations between lifetime PA and global cognition after adjusting for age, sex, North American Adult Reading Test results (i.e., an estimate of premorbid intellectual ability), maximal aerobic capacity, body mass index and interactions between age, sex, and lifetime PA. Mediation analysis assessed the effect of cerebrovascular measures on the association between lifetime PA and global cognition. Post hoc analyses assessed past year PA and current fitness levels relation to global cognition and cerebrovascular measures. Better global cognitive performance was associated with higher lifetime PA (p=.045), recreational PA (p=.021), and vigorous intensity PA (p=.004), PA between the ages of 0 and 20 years (p=.036), and between the ages of 21 and 35 years (p.5), but partially mediated the relation between current fitness and global cognition. This study revealed significant associations between higher levels of PA (i.e., total lifetime, recreational, vigorous PA, and past year) and better cognitive function in later life. Current fitness levels relation to cognitive function may be partially mediated through current cerebrovascular function. PMID- 26581794 TI - Influence of Physical Activity on Human Sensory Long-Term Potentiation. AB - A growing body of literature has explored the influence of physical activity on brain structure and function. While the mechanisms of this relationship remain largely speculative, recent research suggests that one of the effects of physical exercise is an increase in synaptic long-term potentiation (LTP). This has not yet been explored directly in humans due to the difficulty of measuring LTP non invasively. However, we have previously established that LTP-like changes in visual-evoked potentials (VEPs) can be measured in humans. Here, we investigated whether physical fitness status affects the degree of visual sensory LTP. Using a self-report measure of physical activity, participants were split into two groups: a high-activity group, and a low-activity group. LTP was measured and compared between the two groups using the previously established electroencephalography-LTP paradigm, which assesses the degree to which the N1b component of the VEP elicited by a sine grating is potentiated (enhanced) following a rapid "tetanic" presentation of that grating. Both groups demonstrated increased negativity in the amplitude of the N1b component of the VEP immediately after presentation of the visual "tetanus," indicating potentiation. However, after a 30-min rest period, the N1b for the high-activity group remained potentiated while the N1b for the low-activity group returned to baseline. This study presents the first evidence for the impact of self-reported levels of physical activity on LTP in humans, and sheds light on potential neurological mechanisms underlying the relationship between physical fitness and cognition. PMID- 26581795 TI - Cardiorespiratory Fitness Attenuates the Influence of Amyloid on Cognition. AB - The aim of this study was to examine cross-sectionally whether higher cardiorespiratory fitness (CRF) might favorably modify amyloid-beta (Abeta) related decrements in cognition in a cohort of late-middle-aged adults at risk for Alzheimer's disease (AD). Sixty-nine enrollees in the Wisconsin Registry for Alzheimer's Prevention participated in this study. They completed a comprehensive neuropsychological exam, underwent 11C Pittsburgh Compound B (PiB)-PET imaging, and performed a graded treadmill exercise test to volitional exhaustion. Peak oxygen consumption (VO2peak) during the exercise test was used as the index of CRF. Forty-five participants also underwent lumbar puncture for collection of cerebrospinal fluid (CSF) samples, from which Abeta42 was immunoassayed. Covariate-adjusted regression analyses were used to test whether the association between Abeta and cognition was modified by CRF. There were significant VO2peak*PiB-PET interactions for Immediate Memory (p=.041) and Verbal Learning & Memory (p=.025). There were also significant VO2peak*CSF Abeta42 interactions for Immediate Memory (p<.001) and Verbal Learning & Memory (p<.001). Specifically, in the context of high Abeta burden, that is, increased PiB-PET binding or reduced CSF Abeta42, individuals with higher CRF exhibited significantly better cognition compared with individuals with lower CRF. In a late-middle-aged, at-risk cohort, higher CRF is associated with a diminution of Abeta-related effects on cognition. These findings suggest that exercise might play an important role in the prevention of AD. PMID- 26581797 TI - Physical Activity as Protective Factor against Dementia: A Prospective Population Based Study (NEDICES). AB - The aim of this study was to analyze whether physical activity (PA) is a protective factor for the incidence of dementia after 3 years of follow-up. The Neurological Disorders in Central Spain (NEDICES) is a prospective population based survey of older adults (age 65 years and older) that comprised 5278 census based participants at baseline (1994-1995). A broad questionnaire was used to assess participants' sociodemographic characteristics, health status, and lifestyle. Subsequently, a modified version of Rosow-Breslau questionnaire was applied to classify individuals' baseline PA into groups (i.e., sedentary, light, moderate, and high). Cox regression models adjusted for several covariates (age, sex, education, previous stroke, alcohol consumption, hypertension, health related variables) were carried out to estimate the association between the PA groups and risk of dementia at the 3-year follow-up (1997-1998). A total of 134 incident dementia cases were identified among 3105 individuals (56.6% female; mean age=73.15 +/- 6.26) after 3 years. Hazard ratios (HRs) of the light, moderate, and high PA groups (vs. sedentary group) were 0.40 (95% confidence interval {CI} [0.26, 0.62]; p<.001), 0.32 (95% CI [0.20, 0.54]; p<.001) and 0.23 (95% CI [0.13, 0.40]; p<.001), respectively. Even after controlling for covariates and the exclusion of doubtful dementia cases, HRs remained significant. However, a supplementary analysis showed that the dose-effect hypothesis did not reach statistical significance. PA is a protective factor of incident dementia in this population-based cohort. PMID- 26581796 TI - Daily Physical Activity Is Associated with Subcortical Brain Volume and Cognition in Heart Failure. AB - Cognitive impairment in heart failure (HF) is believed to in part stem from structural brain alterations, including shrinkage of subcortical regions. Fortunately, neurocognitive dysfunction in HF can be mitigated by physical activity (PA), though mechanisms for this phenomenon are unclear. PA is protective against age-related cognitive decline that may involve improved structural integrity to brain regions sensitive to aging (e.g., subcortical structures). Yet, no study has examined the benefits of PA on the brain in HF and we sought to do so and clarify related cognitive implications. Fifty older adults with HF completed a neuropsychological battery and wore an accelerometer for 7 days. All participants underwent brain MRI. This study targeted subcortical brain volume given subcortical alterations are often observed in HF and the sensitivity of PA to subcortical structures in other patient populations. Participants averaged 4348.49 (SD=2092.08) steps per day and greater daily steps predicted better attention/executive function, episodic memory, and language abilities, p's<.05. Medical and demographically adjusted regression analyses revealed higher daily steps per day predicted greater subcortical volume, with specific effects for the thalamus and ventral diencephalon, p's<.05. Greater subcortical volume was associated with better attention/executive function, p<.05. Higher daily PA was associated with increased subcortical brain volume and better cognition in older adults with HF. Longitudinal work is needed to clarify whether daily PA can attenuate brain atrophy in HF to reduce accelerated cognitive decline in this population. PMID- 26581798 TI - Prefrontal and Hippocampal Brain Volume Deficits: Role of Low Physical Activity on Brain Plasticity in First-Episode Schizophrenia Patients. AB - Our objective in the present study was to conduct the first empirical study of the effects of regular physical activity habits and their relationship with brain volume and cortical thickness in patients in the early phase of schizophrenia. Relationships between larger brain volumes and higher physical activity levels have been reported in samples of healthy and aging populations, but have never been explored in first-episode schizophrenia patients. METHOD: We collected MRI structural scans in 14 first-episode schizophrenia patients with either self reported low or high physical activity levels. We found a reduction in total gray matter volume, prefrontal cortex (PFC), and hippocampal gray matter volumes in the low physical activity group compared to the high activity group. Cortical thickness in the dorsolateral and orbitofrontal PFC were also significantly reduced in the low physical activity group compared to the high activity group. In the combined sample, greater overall physical activity levels showed a non significant tendency with better performance on tests of verbal memory and social cognition. Together these pilot study findings suggest that greater amounts of physical activity may have a positive influence on brain health and cognition in first-episode schizophrenia patients and support the implementation of physical exercise interventions in this patient population to improve brain plasticity and cognitive functioning. PMID- 26581802 TI - Lumacaftor alone and combined with ivacaftor: preclinical and clinical trial experience of F508del CFTR correction. AB - Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator protein (CFTR), leading to significant morbidity and mortality. CFTR is a chloride and bicarbonate channel at the epithelial cell membrane. The most common CFTR mutation is F508del, resulting in minimal CFTR at the plasma membrane. Current disease management is supportive, whereas an ultimate goal is to develop therapies to restore CFTR activity. We summarize experience with lumacaftor, a small molecule that increases F508del-CFTR levels at the plasma membrane. Lumacaftor in combination with ivacaftor, a modulator of CFTR gating defects, improves clinical outcome measures in patients homozygous for the F508del mutation. Lumacaftor represents a significant advancement in the treatment of biochemical abnormalities in CF. Further development of CFTR modulators will improve upon current therapies, although it remains unclear whether this approach will provide therapies for all CFTR mutations. PMID- 26581799 TI - Physical Activity Affects Brain Integrity in HIV+ Individuals. AB - Prior research has suggested benefits of aerobic physical activity (PA) on cognition and brain volumes in HIV uninfected (HIV-) individuals, however, few studies have explored the relationships between PA and brain integrity (cognition and structural brain volumes) in HIV-infected (HIV+) individuals. Seventy HIV+ individuals underwent neuropsychological testing, structural neuroimaging, laboratory tests, and completed a PA questionnaire, recalling participation in walking, running, and jogging activities over the last year. A PA engagement score of weekly metabolic equivalent (MET) hr of activity was calculated using a compendium of PAs. HIV+ individuals were classified as physically active (any energy expended above resting expenditure, n=22) or sedentary (n=48). Comparisons of neuropsychological performance, grouped by executive and motor domains, and brain volumes were completed between groups. Physically active and sedentary HIV+ individuals had similar demographic and laboratory values, but the active group had higher education (14.0 vs. 12.6 years, p=.034). Physically active HIV+ individuals performed better on executive (p=.040, unadjusted; p=.043, adjusted) but not motor function (p=.17). In addition, among the physically active group the amount of physical activity (METs) positively correlated with executive (Pearson's r=0.45, p=0.035) but not motor (r=0.21; p=.35) performance. In adjusted analyses the physically active HIV+ individuals had larger putamen volumes (p=.019). A positive relationship exists between PA and brain integrity in HIV+ individuals. Results from the present study emphasize the importance to conduct longitudinal interventional investigation to determine if PA improves brain integrity in HIV+ individuals. PMID- 26581803 TI - Effects of Collective Histone State Dynamics on Epigenetic Landscape and Kinetics of Cell Reprogramming. AB - Cell reprogramming is a process of transitions from differentiated to pluripotent cell states via transient intermediate states. Within the epigenetic landscape framework, such a process is regarded as a sequence of transitions among basins on the landscape; therefore, theoretical construction of a model landscape which exhibits experimentally consistent dynamics can provide clues to understanding epigenetic mechanism of reprogramming. We propose a minimal gene-network model of the landscape, in which each gene is regulated by an integrated mechanism of transcription-factor binding/unbinding and the collective chemical modification of histones. We show that the slow collective variation of many histones around each gene locus alters topology of the landscape and significantly affects transition dynamics between basins. Differentiation and reprogramming follow different transition pathways on the calculated landscape, which should be verified experimentally via single-cell pursuit of the reprogramming process. Effects of modulation in collective histone state kinetics on transition dynamics and pathway are examined in search for an efficient protocol of reprogramming. PMID- 26581804 TI - First-time rhesus monkey mothers, and mothers of sons, preferentially engage in face-to-face interactions with their infants. AB - Face-to-face interactions between mothers and infants occur in both human and non human primates, but there is large variability in the occurrence of these behaviors and the reason for this variability remains largely unexplored. Other types of maternal investment have been shown to be dependent on infant sex (e.g. milk production and maternal responsiveness) and maternal experience (e.g. symmetrical communication). Thus, we sought to determine whether variability in face-to-face interactions, that is, mutual gazing (MG), which are hypothesized to be important for later socio-cognitive development, could be explained by these variables. We studied 28 semi-free ranging rhesus monkey (Macaca mulatta) mother infant dyads (6 primiparous; 12 male infants) born and reared at the Laboratory of Comparative Ethology field station at the NIH Animal Center in Poolesville, MD, across the first 90 postnatal days. Infant sex (i.e. male) was a significant predictor of maternal grooming (beta +/- SE = 0.359 +/- 0.164, Z = 2.19, P = 0.029) whereas both parity (i.e. first time mothers) and infant sex (i.e. male) significantly predicted MG (parity: beta +/- SE = -0.735 +/- 0.223, Z = -3.30, P < 0.001; infant sex: beta +/- SE = 0.436 +/- 0.201, Z = 2.17, P = 0.029). Separation from the mother (outside of arm's reach) was not influenced by parity or infant sex. Together with existing literature, these findings point toward differential maternal investment for sons versus daughters. Mothers may be investing differentially in sons, behaviorally, to ensure their future social competence and thus later reproductive success. Collectively, our findings add to the literature that is beginning to identify early life experiences that may lead to sex differences in neurological and behavioral development. PMID- 26581805 TI - Successful treatment of traumatic scars with combined nonablative fractional laser and pinpoint technique of standard CO2 laser. AB - To evaluate the use of a pinpoint irradiation technique followed by nonablative fractional technique in treatment of traumatic scars. Thirteen patients with traumatic sacrs were treated with pinpoint technique of CO2 laser using traditional headpiece activating laser at a frequency (50 Hz) to deliver pulsed mode with power of 1 W using the focusing technique followed by 3-5 passes of the nonablative 1540 nm fractional Er:glass laser. An independent physician evaluator assessed the treatment outcomes using Vancouver scar scale (VSS) and 5-point grading scale (grade 0, no improvement; grade 1, 1-25%; grade 2, 26-50%; grade 3, 51-75%; grade 4, 76-100% improvement). After the final treatment, average percentage changes of VSS were 41.5%. Improvement was evident in terms of vascularity, pigmentation, and height, while insignificant in terms of Pliability. Based on physician's global assessment, mean grade of 2.5 was achieved. Patient's subjective satisfaction scores paralleled the physician's objective evaluation. Pinpoint irradiation technique by CO2 laser followed by nonablative fractional laser is a safe and effective modality in treatment of scars. PMID- 26581807 TI - Successful Pregnancy Outcome after Laparoscopic Cerclage in a Patient with Cervicovaginal Fistula. AB - Obstetric fistula usually originates from obstructed labor or, less often, from invasive maneuvers on the genital tract or the pregnant uterus. Overall, it is a rare finding in the obstetric practice of high income countries. In this report we describe the case of a successful term pregnancy in a patient with a history of recurrent late miscarriage due to a large cervical fistula of traumatic origin, connecting the uterine cavity and the posterior vaginal fornix. A combined approach of laparoscopic cerclage and transvaginal fistula repair effectively restored cervical competence and created the conditions for a viable birth in a subsequent pregnancy. This unusual cause of cervical incompetence may be included in the indications which benefit from an abdominal cerclage carried out as a minimally invasive procedure in the nonpregnant state. PMID- 26581806 TI - Beneficial impact of Gpnmb and its significance as a biomarker in nonalcoholic steatohepatitis. AB - Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. Gpnmb is classified as a type 1 membrane protein and its soluble form is secreted by ADAM10-mediated cleavage. Gpnmb mRNA was found in the Kupffer cells and white adipose tissues (WATs) and its upregulation in obesity was recently found. Here, we generated aP2 promoter-driven Gpnmb transgenic (Tg) mice and the overexpression of Gpnmb ameliorated the fat accumulation and fibrosis of the liver in diet-induced obesity model. Soluble form of Gpnmb in sera was elevated in Gpnmb Tg mice and Gpnmb concentrated in hepatic macrophages and stellate cells interacted with calnexin, which resulted in the reduction of oxidative stress. In the patients with non-alcoholic steatohepatitis, serum soluble GPNMB concentrations were higher compared with the patients with simple steatosis. The GPNMB is a promising biomarker and therapeutic target for the development and progression of NAFLD in obesity. PMID- 26581808 TI - Intravenous Thrombolysis is Effective in Young Adults: Results from the Baden Wuerttemberg Stroke Registry. AB - BACKGROUND: The efficacy of intravenous thrombolysis (IVT) is sufficiently proven in ischemic stroke patients of middle and older age by means of randomized controlled trials and large observational studies. However, data in young stroke patients <=50 years are still scarce. In this study, we aimed to evaluate the effectiveness and safety of IVT in young adults aged 18-50 years. Data from a consecutive and prospective stroke registry was analyzed that covers a federal state with 10.8 million inhabitants in southwest Germany. METHODS: Our analysis comprises 51,735 ischemic stroke patients aged 18-80 years and hospitalized from January 2008 to December 2012. Of these, 4,140 (8%) were aged 18-50 years and 7,529 (15%) underwent IVT. Data on 8,439 patients (16% of the study population) were missing for National Institutes of Health stroke severity score at admission and/or modified Rankin Scale (mRS) at discharge and were excluded from outcome analysis. In sensitivity analysis, patients with incomplete data were also examined. Binary logistic regression models were used adjusted for patient, hospital, and procedural parameters and stratified by age group (18-50 and 51-80 years, subgroup analyses 18-30, 31-40, and 41-50 years) to assess the relationship between IVT and mRS at discharge. RESULTS: IVT appears equally effective in young adults 18-50 years (adjusted odds ratio 1.40, 95% confidence interval 1.12-1.75; p = 0.003), compared to patients 51-80 years of age (1.33, 1.23-1.43; p < 0.001). Age-stratified analyses suggest an inverse relation of age and effectiveness, which appears to be highest in very young patients 18-30 years of age (2.78, 1.10-7.05; p = 0.03). DISCUSSION: Ischemic stroke etiology, vascular dynamics, and recovery in young patients differ from those of middle and older age. The evidence from routine hospital care in Germany indicates that IVT in young stroke patients appears to be at least equally effective as in the elderly. PMID- 26581809 TI - Combined Mapping of Multiple clUsteriNg ALgorithms (COMMUNAL): A Robust Method for Selection of Cluster Number, K. AB - In order to discover new subsets (clusters) of a data set, researchers often use algorithms that perform unsupervised clustering, namely, the algorithmic separation of a dataset into some number of distinct clusters. Deciding whether a particular separation (or number of clusters, K) is correct is a sort of 'dark art', with multiple techniques available for assessing the validity of unsupervised clustering algorithms. Here, we present a new technique for unsupervised clustering that uses multiple clustering algorithms, multiple validity metrics, and progressively bigger subsets of the data to produce an intuitive 3D map of cluster stability that can help determine the optimal number of clusters in a data set, a technique we call COmbined Mapping of Multiple clUsteriNg ALgorithms (COMMUNAL). COMMUNAL locally optimizes algorithms and validity measures for the data being used. We show its application to simulated data with a known K, and then apply this technique to several well-known cancer gene expression datasets, showing that COMMUNAL provides new insights into clustering behavior and stability in all tested cases. COMMUNAL is shown to be a useful tool for determining K in complex biological datasets, and is freely available as a package for R. PMID- 26581811 TI - Arsenic speciation and diffusion flux in Danshuei Estuary sediments, Northern Taiwan. AB - Sedimentary As, Fe and Mn species in core sediments from the Danshuei Estuary, an anoxic estuary, were studied using a five-sequential extraction method followed by chemical analyses of these elements. The sediment texture, redox potential and dissolved concentrations of these elements in pore water were also determined. Dissolved As diffusion flux was also calculated. Higher concentrations of sedimentary As were found at the middle and lower estuary stations. The sedimentary As species in the samples were dominated by three fractions: amorphous and poorly-crystalline; and well crystallized hydrous oxides of Fe and Al; and residual phases, accounting for 90% of the total As pool. The geochemical behavior of sedimentary As in the Danshuei Estuary is strongly influenced by the redox potential and Fe oxides. The dissolved As concentrations in pore water correlated inversely with the redox potential. The sediment served as a source of dissolved As and the diffusion flux ranged from 0.047-0.35 MUg cm(-2) y(-1). PMID- 26581810 TI - X-linked Alport syndrome associated with a synonymous p.Gly292Gly mutation alters the splicing donor site of the type IV collagen alpha chain 5 gene. AB - BACKGROUND: X-linked Alport syndrome (XLAS) is a progressive hereditary nephropathy caused by mutations in the type IV collagen alpha chain 5 gene (COL4A5). Although many COL4A5 mutations have previously been identified, pathogenic synonymous mutations have not yet been described. METHODS: A family with XLAS underwent mutational analyses of COL4A5 by PCR and direct sequencing, as well as transcript analysis of potential splice site mutations. In silico analysis was also conducted to predict the disruption of splicing factor binding sites. Immunohistochemistry (IHC) of kidney biopsies was used to detect alpha2 and alpha5 chain expression. RESULTS: We identified a hemizygous point mutation, c.876A>T, in exon 15 of COL4A5 in the proband and his brother, which is predicted to result in a synonymous amino acid change, p.(Gly292Gly). Transcript analysis showed that this mutation potentially altered splicing because it disrupted the splicing factor binding site. The kidney biopsy of the proband showed lamellation of the glomerular basement membrane (GBM), while IHC revealed negative alpha5(IV) staining in the GBM and Bowman's capsule, which is typical of XLAS. CONCLUSIONS: This is the first report of a synonymous COL4A5 substitution being responsible for XLAS. Our findings suggest that transcript analysis should be conducted for the future correct assessment of silent mutations. PMID- 26581812 TI - Synthetic ultraviolet light filtering chemical contamination of coastal waters of Virgin Islands national park, St. John, U.S. Virgin Islands. AB - Contamination of surface waters by synthetic ultraviolet light (UV) filtering chemicals is a concern for the Virgin Islands National Park (VINP). Discrete water samples were collected from VINP bays to determine UV filter chemical presence in the coastal waters. Spatial distribution and the potential for partitioning between subsurface waters and the sea surface microlayer (SML) were also examined. The UV filter chemicals 4-methylbenzylidene camphor, benzophenone 3, octinoxate, homosalate, and octocrylene were detected at concentrations up to 6073 ng/L (benzophenone-3). Concentrations for benzophenone-3 and homosalate declined exponentially (r(2)=0.86 to 0.98) with distance from the beach. Limited data indicate that some UV filter chemicals may partition to the SML relative to the subsurface waters. Contamination of VINP coastal waters by UV filter chemicals may be a significant issue, but an improved understanding of the temporal and spatial variability of their concentrations would be necessary to better understand the risk they present. PMID- 26581813 TI - Organic polar pollutants in surface waters of inland seas. AB - Available data about contamination by polar substances are mostly reported for rivers and near-shore waters and only limited studies exists about their occurrence in marine waters. We present concentrations and distribution of several polar pesticides and UV-filters in surface waters of three inland seas, the Baltic, Black and Mediterranean Sea. Many of the investigated compounds were below detection limits, however, those found in off-shore waters raise a concern about their persistence and possible adverse effect on the ecosystem. Despite a longstanding EU-wide ban we were able to detect atrazine in the Mediterranean and the Baltic Sea. Concentrations in the Black Sea were substantially higher. Runoff from agricultural and urban areas was the main transport route to marine ecosystems for investigated compounds, though irgarol in Mediterranean waters was attributed to intense maritime traffic. 2-Phenylbenzimidazole-5-sulfonic acid was the only UV-filter detected in marine waters, while benzophenone-4 was observed in the estuaries. Occurrence of UV-filters was seasonal. PMID- 26581814 TI - Antifouling assessments on biogenic nanoparticles: A field study from polluted offshore platform. AB - Turbinaria ornata mediated silver nanoparticles (TOAg-NPs) were evaluated for antibacterial activity against 15 biofilm forming bacterial isolates. A field study in natural seawater for 60 days showed antifouling activity of TOAg-NPs on stainless steel coupons (SS-304) coated with Apcomin zinc chrome (AZC) primer. Though TOAg-NPs showed broad spectrum of antibacterial activity, the maximum zone of inhibition was with Escherichiacoli (71.9%) and a minimum with Micrococcus sp. (40%) due to the EPS secretion from Gram-positive bacteria. Compared to control coupons (18.9 [ * 10(3)], 67.0 [* 10(3)], 13.5 [ * 10(4)] and 24.7 [ * 10(4)]CFU/cm(2)), experimental biocide coupons (71.0 [ * 10(2)], 32.0 [ * 10(3)], 82.0 [ * 10(3)] and 11.3 [ * 10(4)]CFU/cm(2)) displayed lesser bacterial population density. Toxicity studies revealed 100% mortality for Balanus amphitrite larvae at 250 MUg ml(-1) concentration within 24h, while 56.6% recorded for Artemia marina at the same concentration indicating less toxicity to non target species. It proved that AZC+TOAg-NPs prevent biofouling by its Ag-NS affinity and antimicrobial effectivity. PMID- 26581815 TI - Simulation of scenarios of oil droplet formation from the Deepwater Horizon blowout. AB - Knowledge of the droplet size distribution (DSD) from the Deepwater Horizon (DWH) blowout is an important step in predicting the fate and transport of the released oil. Due to the absence of measurements of the DSD from the DWH incident, we considered herein hypothetical scenarios of releases that explore the realistic parameter space using a thoroughly calibrated DSD model, VDROP-J, and we attempted to provide bounds on the range of droplet sizes from the DWH blowout within 200 m of the wellhead. The scenarios include conditions without and with the presence of dispersants, different dispersant treatment efficiencies, live oil and dead oil properties, and varying oil flow rate, gas flow rate, and orifice diameter. The results, especially for dispersant-treated oil, are very different from recent modeling studies in the literature. PMID- 26581816 TI - Enrichment and isolation of crude oil degrading bacteria from some mussels collected from the Persian Gulf. AB - To date, little is known about existing relationships between mussels and bacteria in hydrocarbon-contaminated marine environments. The aim of this study is to find crude oil degrading bacteria in some mussels at the Persian Gulf. Twenty eight crude oil degrading bacteria were isolated from three mussels species collected from oil contaminated area at Persian Gulf. According to high growth and degradation of crude oil four strains were selected between 28 isolated strains for more study. Determination the nucleotide sequence of the gene encoding for 16S rRNA show that these isolated strains belong to: Shewanella algae isolate BHA1, Micrococcus luteus isolate BHA7, Pseudoalteromonas sp. isolate BHA8 and Shewanella haliotis isolate BHA35. The residual crude oil in culture medium was analysis by Gas Chromatography (GC). The results confirmed that these strains can degrade: 47.24%, 66.08%, 27.13% and 69.17% of crude oil respectively. These strains had high emulsification activity and biosurfactant production. Also, the effects of some factors on crude oil degradation by isolated strains were studied. The results show that the optimum concentration of crude oil was 2.5% and the best degradation take place at 12% of salinity. This research is the first reports on characterization of crude oil degrading bacteria from mussels at Persian Gulf and by using of these bacteria in the field the effect of oil pollution can be reduce on this marine environment. PMID- 26581817 TI - Three decades of sea water abstraction by Kapar power plant (Malaysia): What impacts on tropical zooplankton community? AB - Zooplankton samples collected before (1985-86) and after (2013-14) the establishment of Kapar power station (KPS) were examined to test the hypothesis that increased sea surface temperature (SST) and other water quality changes have altered the zooplankton community structure. Elevated SST and reduced pH were detected between before and after impact pairs, with the greatest impact at the station closest to KPS. Present PAHs and heavy metal concentrations are unlikely causal factors. Water parameter changes did not affect diversity but community structure of the zooplankton. Tolerant small crustaceans, salps and larvaceans likely benefited from elevated temperature, reduced pH and shift to a more significant microbial loop exacerbated by eutrophication, while large crustaceans were more vulnerable to such changes. It is predicted that any further rise in SST will remove more large-bodied crustacean zooplankton, the preferred food for fish larvae and other meroplankton, with grave consequences to fishery production. PMID- 26581818 TI - Assessment of trace metal contamination level and toxicity in sediments from coastal regions of West Bengal, eastern part of India. AB - The work investigated concentration of trace metals in surface sediments (0-10 cm; < 63 MUm grain size) from 15 sampling sites of diverse environmental stresses covering Hugli River Estuary (HRE) and Sundarban Mangrove Wetland (SMW), eastern coastal part of India. The trace metal concentrations in sediments exhibited an overall decreasing trend as follows: Cr (21.2-60.9)>Cu (11.60-102.47)>Ni (19.10 52.60)>Pb (7.09-183.88)>As (4.41-11.46)>Cd (0.02-4.4)>Ag (0.02-0.87). Both the geo-accumulation index (Igeo) and contamination factor (CF) values revealed significant pollution by Ag, Cd and Pb at Nurpur of HRE. Potential Ecological Risk Index (RI) (61.21 +/- 112.40) showed wide range of variations from low (19.76) to serious (463.20) ecological risk. A positive significant correlation was found between metals and organic carbon in sediments. The ecological risk associated with the trace metals in sediment was considered on the consensus based Sediment Quality Guidelines (SQGs). The work suggests that the trace metals present in sediments posed adverse effects on the sediment-dwelling organisms. PMID- 26581822 TI - Correction for Chatterjee et al., RsmC of Erwinia carotovora subsp. carotovora Negatively Controls Motility, Extracellular Protein Production, and Virulence by Binding FlhD and Modulating Transcriptional Activity of the Master Regulator, FlhDC. PMID- 26581823 TI - Retraction for Hantke et al., Escherichia coli Exports Cyclic AMP via TolC. PMID- 26581819 TI - Comparative effectiveness of intervention components for producing long-term abstinence from smoking: a factorial screening experiment. AB - AIMS: To identify promising intervention components that help smokers attain and maintain abstinence during a quit attempt. DESIGN: A 2 * 2 * 2 * 2 * 2 randomized factorial experiment. SETTING: Eleven primary care clinics in Wisconsin, USA. PARTICIPANTS: A total of 544 smokers (59% women, 86% white) recruited during primary care visits and motivated to quit. INTERVENTIONS: Five intervention components designed to help smokers attain and maintain abstinence: (1) extended medication (26 versus 8 weeks of nicotine patch + nicotine gum); (2) maintenance (phone) counseling versus none; (3) medication adherence counseling versus none; (4) automated (medication) adherence calls versus none; and (5) electronic medication monitoring with feedback and counseling versus electronic medication monitoring alone. MEASUREMENTS: The primary outcome was 7-day self-reported point prevalence abstinence 1 year after the target quit day. FINDINGS: Only extended medication produced a main effect. Twenty-six versus 8 weeks of medication improved point-prevalence abstinence rates (43 versus 34% at 6 months; 34 versus 27% at 1 year; P = 0.01 for both). There were four interaction effects at 1 year, showing that an intervention component's effectiveness depended upon the components with which it was combined. CONCLUSIONS: Twenty-six weeks of nicotine patch + nicotine gum (versus 8 weeks) and maintenance counseling provided by phone are promising intervention components for the cessation and maintenance phases of smoking treatment. PMID- 26581826 TI - Clinical and dermoscopic characteristics of extramammary Paget disease: a study of 35 cases. PMID- 26581825 TI - New HDAC6-mediated deacetylation sites of tubulin in the mouse brain identified by quantitative mass spectrometry. AB - The post-translational modifications (PTMs) occurring on microtubules have been implicated in the regulation of microtubule properties and functions. Acetylated K40 of alpha-tubulin, a hallmark of long-lived stable microtubules, is known to be negatively controlled by histone deacetylase 6 (HDAC6). However, the vital roles of HDAC6 in microtubule-related processes such as cell motility and cell division cannot be fully explained by the only known target site on tubulin. Here, we attempt to comprehensively map lysine acetylation sites on tubulin purified from mouse brain tissues. Furthermore, mass spectrometry-based quantitative comparison of acetylated peptides from wild-type vs HDAC6 knockout mice allowed us to identify six new deacetylation sites possibly mediated by HDAC6. Thus, adding new sites to the repertoire of HDAC6-mediated tubulin deacetylation events would further our understanding of the multi-faceted roles of HDAC6 in regulating microtubule stability and cellular functions. PMID- 26581827 TI - The associations of vegetable consumption with food mavenism, personal values, food knowledge and demographic factors. AB - BACKGROUND: Poor dietary choices, in particular low consumption of fruits and vegetables are associated with the prevalence of diet related diseases. Ways to increase consumption are urgently required. This paper examines the associations of demographic, psychographic and food knowledge variables with reported vegetable consumption. METHODS: An online questionnaire was administered in late 2012 to a national sample 2146 Australians who were selected to represent the Australian population in terms of age, sex, education and location of residence. It was divided into sections which assessed food knowledge, food involvement, food mavenism, personal values and personality factors, demographic characteristics and reported consumption of 13 vegetables and the total number of servings of vegetables per day. Principal components analyses of the individual vegetable consumption ratings derived three forms of vegetable consumption scores. These and total serving per day were used as dependent variables in a structural equation model to identify pathways between them and their likely antecedents. MAJOR FINDINGS: Three types of vegetable consumption were formed:Salad vegetables (onion, tomato and lettuce);Dinner vegetables (carrot, peas and beans); and'Green' vegetables (cabbage, spinach broccoli and cauliflower). Food mavenism, food knowledge, food involvement and equality universalist values mediated the relationships between demographics and conscientiousness and the vegetable consumption variables. CONCLUSIONS: The three types of vegetable consumption and total servings per day were associated with different antecedent pathways. The mediating roles of food mavenism, food knowledge, food involvement and equality-universalist values may present opportunities for health promotion and the horticultural industry to increase population vegetable intake. Further research is required to test these associations via experimental and longitudinal studies and qualitative investigation of the meaning and place of the three forms of vegetable consumption in people's daily lives is recommended. PMID- 26581828 TI - Visualization of the medial forebrain bundle using diffusion tensor imaging. AB - Diffusion tensor imaging is a technique that enables physicians the portrayal of white matter tracts in vivo. We used this technique in order to depict the medial forebrain bundle (MFB) in 15 consecutive patients between 2012 and 2015. Men and women of all ages were included. There were six women and nine men. The mean age was 58.6 years (39-77). Nine patients were candidates for an eventual deep brain stimulation. Eight of them suffered from Parkinson's disease and one had multiple sclerosis. The remaining six patients suffered from different lesions which were situated in the frontal lobe. These were 2 metastasis, 2 meningiomas, 1 cerebral bleeding, and 1 glioblastoma. We used a 3DT1-sequence for the navigation. Furthermore T2- and DTI- sequences were performed. The FOV was 200 * 200 mm(2), slice thickness 2 mm, and an acquisition matrix of 96 * 96 yielding nearly isotropic voxels of 2 * 2 * 2 mm. 3-Tesla-MRI was carried out strictly axial using 32 gradient directions and one b0-image. We used Echo-Planar-Imaging (EPI) and ASSET parallel imaging with an acceleration factor of 2. b-value was 800 s/mm(2). The maximal angle was 50 degrees . Additional scanning time was < 9 min. We were able to visualize the MFB in 12 of our patients bilaterally and in the remaining three patients we depicted the MFB on one side. It was the contralateral side of the lesion. These were 2 meningiomas and one metastasis. Portrayal of the MFB is possible for everyday routine for neurosurgical interventions. As part of the reward circuitry it might be of substantial importance for neurosurgeons during deep brain stimulation in patients with psychiatric disorders. Surgery in this part of the brain should always take the preservation of this white matter tract into account. PMID- 26581829 TI - Metabolic alterations in adolescents with obstructive sleep apnea. AB - IMPORTANCE: Obesity is one of the leading health concerns in developed and in developing countries. The risk of obstructive sleep apnea (OSA) is greatly increased by obesity. Obesity is known to be associated with the Metabolic Syndrome and cardiovascular disease in adults. This same association in children is not well defined. Understanding the relationship of obesity, OSA, and metabolic alterations in children would improve understanding of the risks of cardiovascular disease into adulthood. OBJECTIVE: To evaluate the association of OSA and metabolic outcomes, including lipid variables and insulin resistance, in obese adolescents. METHODS: Retrospective, case-control series at a tertiary care children's hospital. Obese adolescents aged 12-18 years who underwent overnight polysomnography (PSG) and routine laboratory testing for lipid levels, fasting glucose, and insulin from January 1, 2006 to December 31, 2012. RESULTS: A total of 42 patients with a mean age of 14.1+/-1.9 years were analyzed. Nineteen (45.2%) were male. The mean body mass index (BMI) z score was 2.23+/-0.86, and all patients were obese (BMI z score >95th percentile). Triglyceride, fasting blood glucose, insulin, and homeostasis model assessment-insulin resistance (HOMA IR) levels were significantly higher in patients with OSA when compared to those with No-OSA (p<0.01). There was incremental worsening of insulin and HOMA-IR with greater severity of OSA. The apnea-hypopnea index (AHI) was positively and significantly correlated with blood glucose and HOMA-IR (p=0.01and p<0.001, respectively). Multiple linear regression analysis showed that the AHI was a predictor of blood glucose (p=0.04) and HOMA-IR (p=0.01) independent of age, gender, total sleep time and BMI z score. Logistic regression analysis showed that elevated levels of blood glucose predicted severe OSA (p=0.02) independent of gender and BMI z score. Elevation in HOMA-IR predicted severe OSA (p=0.004). CONCLUSION: OSA severity is associated with increased fasting insulin, blood glucose and HOMA-IR even after controlling for the age, and BMI z score in adolescents. PMID- 26581830 TI - Better cognitive control of emotional information is associated with reduced pro inflammatory cytokine reactivity to emotional stress. AB - Stress is strongly associated with several mental and physical health problems that involve inflammation, including asthma, cardiovascular disease, certain types of cancer, and depression. It has been hypothesized that better cognitive control of emotional information may lead to reduced inflammatory reactivity to stress and thus better health, but to date no studies have examined whether differences in cognitive control predict pro-inflammatory cytokine responses to stress. To address this issue, we conducted a laboratory-based experimental study in which we randomly assigned healthy young-adult females to either an acute emotional stress (emotionally evocative video) or no-stress (control video) condition. Salivary levels of the key pro-inflammatory cytokines IL-1beta, IL-6, and IL-8 were measured before and after the experimental manipulation, and following the last cytokine sample, we assessed participants' cognitive control of emotional information using an emotional Stroop task. We also assessed participants' cortisol levels before and after the manipulation to verify that documented effects were specific to cytokines and not simply due to increased nonwater salivary output. As hypothesized, the emotional stressor triggered significant increases in IL-1beta, IL-6, and IL-8. Moreover, even in fully adjusted models, better cognitive control following the emotional (but not control) video predicted less pronounced cytokine responses to that stressor. In contrast, no effects were observed for cortisol. These data thus indicate that better cognitive control specifically following an emotional stressor is uniquely associated with less pronounced pro-inflammatory cytokine reactivity to such stress. These findings may therefore help explain why superior cognitive control portends better health over the lifespan. PMID- 26581831 TI - Bovine trypanosomosis and Glossina distribution in selected areas of southern part of Rift Valley, Ethiopia. AB - Cross-sectional study was conducted in 9 selected districts of the southern part the Rift Valley, Ethiopia to estimate the dry period prevalence of bovine trypanosomosis as well as assessment of Glossina species. From a total of 1838 cattle examined for trypanosomosis by buffy coat technique 133 (7.2%) were found infected by trypanosome species. From the total positive animals 66.9 and 33.1% of them accounted to Trypanosoma congolense and Trypanosoma vivax, respectively. Significantly higher prevalence (19.4%., P<0.05) was recorded at Arba-Mnch district. Black colored cattle were the most highly affected (chi(2)=79.35, P<0.05) animals. The overall average PCV value for parasitaemic and aparasitaemic animals was 22.2 (95% CI=21.6-22.7) and 27% (95% CI=26.8-27.2), respectively. The fly caught per trap per day was 1.4 for Glossina species and 2.8 for other biting flies. Two species of Glossina identified namely Glossina pallidipes and Glossina fuscipes. PMID- 26581832 TI - Stretching the Spines of Gymnasts: A Review. AB - Gymnastics is noted for involving highly specialized strength, power, agility and flexibility. Flexibility is perhaps the single greatest discriminator of gymnastics from other sports. The extreme ranges of motion achieved by gymnasts require long periods of training, often occupying more than a decade. Gymnasts also start training at an early age (particularly female gymnasts), and the effect of gymnastics training on these young athletes is poorly understood. One of the concerns of many gymnastics professionals is the training of the spine in hyperextension-the ubiquitous 'arch' seen in many gymnastics positions and movements. Training in spine hyperextension usually begins in early childhood through performance of a skill known as a back-bend. Does practising a back-bend and other hyperextension exercises harm young gymnasts? Current information on spine stretching among gymnasts indicates that, within reason, spine stretching does not appear to be an unusual threat to gymnasts' health. However, the paucity of information demands that further study be undertaken. PMID- 26581833 TI - Can Water Temperature and Immersion Time Influence the Effect of Cold Water Immersion on Muscle Soreness? A Systematic Review and Meta-Analysis. AB - BACKGROUND: Cold water immersion (CWI) is a technique commonly used in post exercise recovery. However, the procedures involved in the technique may vary, particularly in terms of water temperature and immersion time, and the most effective approach remains unclear. OBJECTIVES: The objective of this systematic review was to determine the efficacy of CWI in muscle soreness management compared with passive recovery. We also aimed to identify which water temperature and immersion time provides the best results. METHODS: The MEDLINE, EMBASE, SPORTDiscus, PEDro [Physiotherapy Evidence Database], and CENTRAL (Cochrane Central Register of Controlled Trials) databases were searched up to January 2015. Only randomized controlled trials that compared CWI to passive recovery were included in this review. Data were pooled in a meta-analysis and described as weighted mean differences (MDs) with 95% confidence intervals (CIs). RESULTS: Nine studies were included for review and meta-analysis. The results of the meta analysis revealed that CWI has a more positive effect than passive recovery in terms of immediate (MD = 0.290, 95% CI 0.037, 0.543; p = 0.025) and delayed effects (MD = 0.315, 95% CI 0.048, 0.581; p = 0.021). Water temperature of between 10 and 15 degrees C demonstrated the best results for immediate (MD = 0.273, 95% CI 0.107, 0.440; p = 0.001) and delayed effects (MD = 0.317, 95% CI 0.102, 0.532; p = 0.004). In terms of immersion time, immersion of between 10 and 15 min had the best results for immediate (MD = 0.227, 95% 0.139, 0.314; p < 0.001) and delayed effects (MD = 0.317, 95% 0.102, 0.532, p = 0.004). CONCLUSIONS: The available evidence suggests that CWI can be slightly better than passive recovery in the management of muscle soreness. The results also demonstrated the presence of a dose-response relationship, indicating that CWI with a water temperature of between 11 and 15 degrees C and an immersion time of 11-15 min can provide the best results. PMID- 26581834 TI - Hypothermia During Cardiopulmonary Bypass Increases Need for Inotropic Support but Does Not Impact Inflammation in Children Undergoing Surgical Ventricular Septal Defect Closure. AB - Minimizing the systemic inflammatory response caused by cardiopulmonary bypass is a major concern. It has been suggested that the perfusion temperature affects the inflammatory response. The aim of this prospective study was to compare the effects of moderate hypothermia (32 degrees C) and normothermia (36 degrees C) during cardiopulmonary bypass on markers of the inflammatory response and clinical outcomes (time on ventilator) after surgical closure of ventricular septal defects. During surgical closure of ventricular septal defects under cardiopulmonary bypass, 20 children (median age 4.9 months, range 2.3-38 months; median weight 7.2 kg, range 5.2-11.7 kg) were randomized to a perfusion temperature of either 32 degrees C (Group 1, n = 10) or 36 degrees C (Group 2, n = 10). The clinical data and blood samples were collected before cardiopulmonary bypass, directly after aortic cross-clamp release, and 4 and 24 h after weaning from cardiopulmonary bypass. Time on ventilation as primary outcome did not differ between the two groups. Other clinical outcome parameters like fluid balance or length of stay in the intensive care were also similar in the two groups. Compared with Group 2, Group 1 needed significantly higher and longer inotropic support (P < 0.001). In Group 1, two infants had junctional ectopic tachycardia, and another had a pulmonary hypertensive crisis. Perfusion temperature did not influence cytokine release, organ injury, or coagulation. Cardiopulmonary bypass temperature does not influence time on ventilation or inflammatory marker release. However, in the present study, with a small patient cohort, patients operated under hypothermic bypass needed higher and longer inotropic support. The use of hypothermic cardiopulmonary bypass in infants and children should be approached with care. PMID- 26581835 TI - Expression of the invertebrate sea urchin P16 protein into mammalian MC3T3 osteoblasts transforms and reprograms them into "osteocyte-like" cells. AB - P16 is an acidic phosphoprotein important in both sea urchin embryonic spicule development and transient mineralization during embryogenesis, syncytium formation, and mineralization in mature urchin tooth. Anti-P16 has been used to localize P16 to the syncytial membranes and the calcite mineral. Specific amino acid sequence motifs in P16 are similar to sequences in DSPP, a protein common to all vertebrate teeth, and crucial for their mineralization. Here, we examine the effect of P16 on vertebrate fibroblastic NIH3T3 cells and osteoblastic MC3T3 cells. Transfection of NIH3T3 cells with P16 cDNA resulted in profound changes in the morphology of the cells. In culture, the transfected cells sent out long processes that contacted processes from neighboring cells forming networks or syncytia. There was a similar change in morphology in cultured osteoblastic MC3T3 cells. In addition, the MC3T3 developed numerous dendrites as found in osteocytes. Importantly, there was also a change in the expression of the osteoblast and osteocyte specific genes. MC3T3 cells transfected with P16 showed an 18-fold increase in expression of the osteocyte specific Dentin matrix protein (DMP1) gene, accompanied by decreased expression of osteoblast specific genes: Bone sialoprotein (BSP), osteocalcin (OCN), and beta-catenin decreased by 70%, 64%, and 68 %, respectively. Thus, invertebrate urchin P16 with no previously known analog in vertebrates was able to induce changes in both cell morphology and gene expression, converting vertebrate-derived osteoblast-like precursor cells to an "osteocyte-like" phenotype, an important process in bone biology. The mechanisms involved are presently under study. PMID- 26581836 TI - Comparison of clinical periodontal status among habitual smokeless-tobacco users and cigarette smokers. AB - AIM: Investigating the comparative effect of cigarette smoking and smokeless tobacco use on periodontal health. BACKGROUND: There is a dearth of studies comparing the effects of smoking and smokeless tobacco on periodontal health. Smokeless tobacco is emerging as a major public health hazard, but is often neglected as a risk factor by many clinicians. MATERIALS AND METHODS: A cross sectional study of 286 subjects was conducted. The participants were divided into mutually exclusive groups (i.e. any subject who had the habit of both smoking as well as smokeless tobacco usage was excluded from the study), as follows: a smoking group (SG; n=121); a smokeless-tobacco group (ST; n=81); and a non tobacco-consuming group (NT; n=84). Data were obtained using a questionnaire and by clinical examination. The Periodontal Disease Index (PDI) and Oral Hygiene Index-Simplified (OHI-S) were used to clinically evaluate the periodontal and dental health status of the subjects. Multivariate analysis was performed to identify statistical correlations. RESULTS: The Plaque Index was higher in the ST group than in the SG group and was statistically significantly higher in the ST group than in the NT group. Probing depth and gingival inflammation (components of the PDI) were also higher in the ST group than in the SG and NT groups, but this was not statistically significant. CONCLUSIONS: Within the limits of the study, and for this study population, the impact on the periodontium as a result of smokeless tobacco use appeared to be comparable with that of smoking tobacco. The results of this study affirm the need to consider smokeless tobacco as a possible contributory factor to periodontal disease, in addition to smoking, and to counsel patients accordingly. Further randomised clinical trials are necessary to validate the long-term impact of smokeless tobacco on periodontal disease. PMID- 26581837 TI - Safety of IV amikacin in the treatment of pulmonary non-tuberculous mycobacterial disease. AB - BACKGROUND AND OBJECTIVE: Pulmonary non-tuberculous mycobacterial (NTM) disease has a high mortality rate and often requires treatment with intravenous amikacin. We report on safety data in patients treated with intravenous amikacin for pulmonary. METHODS: A retrospective observational study (2002-2012) was performed including 45 patients that met American Thoracic Society criteria for pulmonary NTM disease and were treated with intravenous amikacin at three hospitals in Brisbane, Australia. The aim was to define the rates of common adverse effects, the patient and regimen factors associated with these adverse effects and describe the rates of treatment success and associated factors. RESULTS: Forty five patients (34 women; median age 63 years) were treated for Mycobacterium intracellulare (25), Mycobacterium abscessus (13), Mycobacterium avium (6) and Mycobacterium fortuitum (1) using multi-drug therapy that included IV amikacin. Transient ototoxicity was seen in eight (18%) but long-term ototoxicity was seen in only three (7%). There were no cases of nephrotoxicity and no long-term vestibulotoxicity. Sustained culture conversion at 6 months was only found in 17 (38%), however, the majority (34 patients, 76%) had a clinical response to treatment determined by an improvement in symptoms. CONCLUSION: Carefully selected and closely monitored patients with pulmonary NTM can be treated using IV amikacin safely with low rates of toxicity. No pretreatment patient or regimen factors were predictive of toxicity or treatment success in this small cohort. Lower treatment success rates were found than previous trials suggest there is a difficult balance in this patient group between treatment success and toxicities. PMID- 26581838 TI - Does Employment Promote Recovery? Meanings from Work Experience in People Diagnosed with Serious Mental Illness. AB - Employment has been highlighted as a determinant of health and as an essential milestone in the recovery process of people with serious mental illness. Different types of programs and public services have been designed to improve the employability of this population. However, there has not been much interest in the meanings attributed to these experiences and the negative aspects of work experience. In this research, we explored the meanings that participants attributed to their work experience and the impact of work on their recovery process. Research participants lived in Andalusia (Spain), a region in southern Europe with a high unemployment rate. Two versions of a semi-structured interview were designed: one for people who were working, and one for unemployed people. Participants' narratives were categorized according to grounded theory and the analyses were validated in group sessions. Apart from several positive effects for recovery, the analysis of the narratives about work experience outlined certain obstacles to recovery. For example, participants mentioned personal conflicts and stress, job insecurity and meaningless jobs. While valid, the idea that employment is beneficial for recovery must be qualified by the personal meanings attributed to these experiences, and the specific cultural and economic factors of each context. PMID- 26581839 TI - Theory of Mind and social relationships in older adults: the role of social motivation. AB - OBJECTIVES: Previous research has shown that individual differences in Theory of Mind (ToM) are crucial for people's social relationships. However, very few studies have investigated this issue in ageing. The present study was designed to fill this gap and examine the associations between ToM and social relationships in elderly adults. In doing so, this study considered people's relationships with their relatives and friends, and examined the possible moderating role of social motivation. METHOD: The study involved 53 healthy older adults (age: M = 67.91; SD = 6.93; range: 60--85 years). All participants were tested collectively during a 2-hr session and completed a demographic questionnaire as well as a battery of tests assessing verbal ability (vocabulary and word fluency), ToM and social relationships. They also answered a social motivation question. RESULTS: Results showed that individual differences in older people's ToM were overall significantly associated with those in relationships with friends, but not relatives. In addition, the Hayes moderating procedure showed that individual differences in ToM were related to those in friendships only for those people who had a high or medium level of social motivation. CONCLUSION: These findings underline the importance of motivation in guiding the use of ToM in everyday social interactions. PMID- 26581840 TI - Child bed net use before, during, and after a bed net distribution campaign in Bo, Sierra Leone. AB - BACKGROUND: This analysis examined how the proportion of children less than 5 years-old who slept under a bed net the previous night changed during and after a national long-lasting insecticidal net (LLIN) distribution campaign in Sierra Leone in November-December 2010. METHODS: A citywide cross-sectional study in 2010-2011 interviewed the caregivers of more than 3000 under-five children from across urban Bo, Sierra Leone. Chi squared tests were used to assess change in use rates over time, and multivariate regression models were used to examine the factors associated with bed net use. RESULTS: Reported rates of last-night bed net use changed from 38.7 % (504/1304) in the months before the LLIN campaign to 21.8 % (78/357) during the week of the campaign to 75.3 % (1045/1387) in the months after the national campaign. The bed net use rate significantly increased (p < 0.01) from before the campaign to after the universal LLIN distribution campaign in all demographic, socioeconomic, and health behaviour groups, even though reported use during the campaign dropped significantly. CONCLUSION: Future malaria prevention efforts will need to promote consistent use of LLINs and address any remaining disparities in insecticide-treated bed net (ITN) use. PMID- 26581841 TI - Hemolytic anemia and irreversible kidney and brain injuries after accidental intravenous injection of albendazole suspension in an infant. PMID- 26581844 TI - Optimizing the Electron-Withdrawing Character on Benzenesulfonyl Moiety Attached to a Glyco-Conjugate to Impart Sensitive and Selective Sensing of Cyanide in HEPES Buffer and on Cellulose Paper and Silica Gel Strips. AB - Dansyl-derivatized, triazole-linked, glucopyranosyl conjugates, (5F)LOH, (2F)LOH, (1F)LOH, and (0F)LOH were synthesized and characterized. While the (5F)LOH acts as a molecular probe for CN(-), (2F)LOH, (1F)LOH, and (0F)LOH acts as control molecules. The reactivity of CN(-) toward (5F)LOH has been elicited through the changes observed in NMR, ESI MS, emission, and absorption spectroscopy. The conjugate (5F)LOH releases a fluorescent product upon reaction by CN(-) in aqueous acetonitrile medium by exhibiting an ~125-fold fluorescence enhancement even in the presence of other anions. Fluorescence switch-on behavior has been clearly demonstrated on the basis of the nucleophilic substitution reaction of CN(-) on (5F)LOH. A minimum detection limit of (2.3 +/- 0.3) * 10(-7) M (6 +/- 1 ppb) was shown by (5F)LOH for CN(-) in solution. All the other anions studied showed no change in the fluorescence emission. The utility of (5F)LOH has been demonstrated by showing its reactivity toward CN(-) on a thin layer of silica gel as well as on Whatman No. 1 cellulose filter paper strips. The role of glucose moiety and the penta-fluorobenzenesulfonyl reactive center present in (5F)LOH in the selectivity of CN(-) over other anions has been demonstrated by fluorescence, absorption and thermodynamics study. Similar studies carried out with the control molecules showed no selectivity for CN(-). The mechanistic aspects of the reactivity of CN(-) toward (5F)LOH were supported by DFT computational study. PMID- 26581843 TI - Enhancement of energy production by black ginger extract containing polymethoxy flavonoids in myocytes through improving glucose, lactic acid and lipid metabolism. AB - Enhancement of muscular energy production is thought to improve locomotive functions and prevent metabolic syndromes including diabetes and lipidemia. Black ginger (Kaempferia parviflora) has been cultivated for traditional medicine in Thailand. Recent studies have shown that black ginger extract (KPE) activated brown adipocytes and lipolysis in white adipose tissue, which may cure obesity related dysfunction of lipid metabolism. However, the effect of KPE on glucose and lipid utilization in muscle cells has not been examined yet. Hence, we evaluated the effect of KPE and its constituents on energy metabolism in pre differentiated (p) and differentiated (d) C2C12 myoblasts. KPE (0.1-10 MUg/ml) was added to pC2C12 cells in the differentiation process for a week or used to treat dC2C12 cells for 24 h. After culturing, parameters of glucose and lipid metabolism and mitochondrial biogenesis were assessed. In terms of the results, KPE enhanced the uptake of 2-deoxyglucose and lactic acid as well as the mRNA expression of glucose transporter (GLUT) 4 and monocarboxylate transporter (MCT) 1 in both types of cells. The expression of peroxisome proliferator-activated receptor gamma coactivator (PGC)-1alpha was enhanced in pC2C12 cells. In addition, KPE enhanced the production of ATP and mitochondrial biogenesis. Polymethoxy flavonoids in KPE including 5-hydroxy-7-methoxyflavone, 5-hydroxy 3,7,4'-trimethoxyflavone and 5,7-dimethoxyflavone enhanced the expression of GLUT4 and PGC-1alpha. Moreover, KPE and 5,7-dimethoxyflavone enhanced the phosphorylation of 5'AMP-activated protein kinase (AMPK). In conclusion, KPE and its polymethoxy flavonoids were found to enhance energy metabolism in myocytes. KPE may improve the dysfunction of muscle metabolism that leads to metabolic syndrome and locomotive dysfunction. PMID- 26581842 TI - Effect of ATorvastatin On Chronic subdural Hematoma (ATOCH): a study protocol for a randomized controlled trial. AB - BACKGROUND: Chronic subdural hematoma (CSDH) is a common disease that is more prevalent in older people. Surgical intervention is a safe treatment of choice. However, the recurrence rate is relatively high and the outcome is not always satisfactory among surgically treated patients. It is believed that aberrant angiogenesis and intracapsular inflammation contribute to the development of CSDH. Atorvastatin is reported to promote angiogenesis and suppress inflammation. We have recently shown that atorvastatin is effective to non-surgically reduce and eliminate CSDH with minimal side effects. Here, we report a clinical research trial protocol that is designed to evaluate the therapeutic effects of atorvastatin on CSDH. METHODS/DESIGN: We have designed a multi-center, randomized, placebo-controlled, double blind clinical trial for evaluating the efficacy of oral atorvastatin in reducing CSDH. We have so far recruited 96 patients with CT-confirmed or MRI-confirmed CSDHs from 16 medical centers in China. These patients were originally recruited for the Oriental Neurosurgical Evidence-based Study Team (ONET) study. After informed consent is provided, patients are randomized to receive either atorvastatin (oral 20 mg/night for 8 weeks) or placebo (dextrin for 8 weeks); and followed for 16 weeks after the treatment. The primary outcome is the change in hematoma volume at the end of 8 week treatment. Secondary outcomes include: changes in 1) the hematoma volume at the 4(th), 12(th), and 24(th) weeks; 2) Markwalder's Grading Scale and Glasgow Coma Scale (MGS-GCS); 3) Glasgow Outcome Score (GOS) and 4) Activities of Daily Life-the Barthel Index scale (ADL-BI). Safety will be assessed during the study by monitoring adverse events, laboratory tests, electrocardiography (ECG), measurements of vital signs (temperature, pulse, and blood pressure) and body weight. DISCUSSION: Results of this trial will provide critical information regarding whether atorvastatin is an effective and safe alternative to surgical treatment of CSDH. TRIAL REGISTRATION: ClinicalTrials.gov Identifier--NCT02024373 The date of trial registration: 7 August 2013. PMID- 26581845 TI - Power generation and gaseous emissions performance of an internal combustion engine fed with blends of soybean and beef tallow biodiesel. AB - This study aimed to compare the performance of an internal combustion engine fed with blends of biodiesel produced from soybean and diesel, and blends of biodiesel produced from beef tallow and diesel. Performance was evaluated in terms of power generated at low loading conditions (0.5, 1.0 and 1.5 kW) and emission of organic and inorganic pollutants. In order to analyse inorganic gases (CO, SO2 and NOx), an automatic analyser was used and the organic emissions (benzene, toluene, ethylbenzene and xylene - BTEX) were carried out using a gas chromatograph. The results indicate that the introduction of the two biodiesels in the fuel caused a reduction in CO, SO2 and BTEX emissions. In addition, the reduction was proportional to the increase in loading regime. Beef tallow biodiesels presented better results regarding emission than soybean biodiesels. The use of pure biodiesels also presented a net reduction in pollutant gas emissions without hindering the engine generator performance. PMID- 26581846 TI - Cutoff value of thyroid uptake of (99m)Tc-pertechnetate to discriminate between Graves' disease and painless thyroiditis: a single center retrospective study. AB - Thyroid uptake of (99m)Tc-pertechnetate is a useful way to determine the cause of thyrotoxicosis. In daily clinical practice, (99m)Tc-pertechnetate uptake is used to discriminate between Graves' disease and painless thyroiditis when clinical information is not enough to make the distinction. However, since the optimal cutoff value of (99m)Tc-pertechnetate uptake has not yet been elucidated, our aim was to determine this value. We recruited patients with thyrotoxicosis in whom (99m)Tc-pertechnetate uptake was measured in clinical settings between 2009 and 2013. Three experienced endocrinologists (who were blinded to the value of (99m)Tc-pertechnetate uptake and initial treatment) diagnosed the cause of thyrotoxicosis based on thyrotropin, free triiodothyronine, free thyroxine, and thyrotropin receptor antibody levels, and by ultrasound findings and using images of thyroid uptake of (99m)Tc-pertechnetate without the actual values. Ninety-four patients diagnosed as having Graves' disease or painless thyroiditis were finally included. According to the diagnosis, the optimal cutoff value of (99m)Tc pertechnetate uptake was determined by receiver operating characteristics analysis. A cutoff value of 1.0% provided optimal sensitivity and specificity of 96.6% and 97.1%, respectively. Then, its validity was confirmed in 78 patients with confirmed Graves' disease or painless thyroiditis diagnosed at another institute. Applying this cutoff value to the patients with thyrotoxicosis revealed positive and negative predictive values for Graves' disease of 100% and 88.9%, respectively. In conclusion, a cutoff value for (99m)Tc-pertechnetate uptake of 1.0% was useful to discriminate between Graves' disease and painless thyroiditis. PMID- 26581847 TI - Biochemical and Behavioral Evaluation of Human MAPT Mutations in Transgenic Drosophila melanogaster. AB - Mutations in the human microtubule-associated protein tau (hMAPT) gene including R406W and V337M result in autosomal dominant neurodegenerative disorder. These mutations lead to hyperphosphorylation and aggregation of Tau protein which is a known genetic factor underlying development of Alzheimer's disease (AD). In the present study, transgenic Drosophila models of AD expressing wild-type and mutant forms of hMAPT exhibit a progressive neurodegeneration which was manifested in the form of early death and impairment of cognitive ability. Moreover, they were also found to have significantly decreased activity of neurotransmitter enzymes accompanied by decreased cellular endogenous antioxidant profile. The extent of neurodegeneration, memory impairment, and biochemical profiles was different in the tau transgenic strains which indicate multiple molecular and cellular responses underlie each particular form of hMAPT. PMID- 26581848 TI - Obesity, More than a 'Cosmetic' Problem. Current Knowledge and Future Prospects of Human Obesity Genetics. AB - Obesity has been designated as a global epidemic by WHO as its prevalence has increased at an alarming rate in the last few decades worldwide. It is a risk factor for diabetes, hypertension, cardiovascular problems, etc. The contribution of genes to the development of obesity was confirmed in late twentieth century. The concept of monogenic obesity came with the identification of leptin, and mutations in its gene, followed by the discovery of more single gene mutations. However, the recent explosion of obesity could not be explained on the basis of these rare mutations and it was after the first genome-wide association study in 2007 that made possible the identification of different effect size variants in many candidate and non-candidate genes acting in a quantitative way to add to body weight. These studies laid down the basis for polygenic cause of common forms of obesity. The role of epigenetic regulation in the modulation of energy regulation pathway was another important explanation put forward in the latter half of the past decade. Taking into account the quantitative contribution of different variants has given the concept of obesity risk scoring in order to score individuals into different risk groups so as to decide for treatment options. PMID- 26581851 TI - Farewell. PMID- 26581852 TI - Lassoing a chimera: the semantics of allergic fungal airway disease. PMID- 26581853 TI - Analysis of IgE binding patterns to house dust mite allergens in scabies-endemic communities: insights for both diseases. PMID- 26581855 TI - Anaphylaxis and cardiovascular disease: therapeutic dilemmas. PMID- 26581857 TI - Endoscopic management of mucosal lesions in the gastrointestinal tract. AB - With the increasing role of endoscopy in patient evaluation, more mucosal lesions, including gastric, duodenal and colonic polyps, are encountered during routine examinations. It is imperative for gastroenterologists to become familiar with the endoscopic management of these various gastrointestinal lesions. In this article, various resection techniques will be discussed, including hot/cold forceps polypectomy, hot/cold snare polypectomy, endoscopic mucosal resection, and endoscopic submucosal dissection. The article will also discuss the evidence regarding the efficacy and safety of these techniques and the future direction of endoscopic management of mucosal lesions in the gastrointestinal tract. PMID- 26581858 TI - Investigating inter-chromosomal regulatory relationships through a comprehensive meta-analysis of matched copy number and transcriptomics data sets. AB - BACKGROUND: Gene regulatory relationships can be inferred using matched array comparative genomics and transcriptomics data sets from cancer samples. The way in which copy numbers of genes in cancer samples are often greatly disrupted works like a natural gene amplification/deletion experiment. There are now a large number of such data sets publicly available making a meta-analysis of the data possible. RESULTS: We infer inter-chromosomal acting gene regulatory relationships from a meta-analysis of 31 publicly available matched array comparative genomics and transcriptomics data sets in humans. We obtained statistically significant predictions of target genes for 1430 potential regulatory genes. The regulatory relationships being inferred are either direct relationships, of a transcription factor on its target, or indirect ones, through pathways containing intermediate steps. We analyse the predictions in terms of cocitations, both publications which cite a regulator with any of its inferred targets and cocitations of any genes in a target list. CONCLUSIONS: The most striking observation from the results is the greater number of inter-chromosomal regulatory relationships involving repression compared to those involving activation. The complete results of the meta-analysis are presented in the database METAMATCHED. We anticipate that the predictions contained in the database will be useful in informing experiments and in helping to construct networks of regulatory relationships. PMID- 26581859 TI - The steroid receptor RNA activator protein (SRAP) controls cancer cell migration/motility. AB - The steroid receptor RNA activator gene (SRA1) produces both a functional RNA (SRA) and a protein (SRAP), whose exact physiological roles remain unknown. To identify cellular processes regulated by SRAP we compared the transcriptome of Hela and MDA-MB-231 cancer cells upon depletion of the SRA/SRAP transcripts or overexpression of the SRAP protein. RNA-seq and Ontology analyses pinpointed cellular movement as potentially regulated by SRAP. Using live cell imaging, we found that SRA/SRAP depletion and SRAP overexpression lead respectively to a decrease and increase in cancer cell motility. Our results highlight for the first time a link existing between SRA1 gene expression and cell motility. PMID- 26581860 TI - Ventral midbrain dopaminergic neurons: From neurogenesis to neurodegeneration. PMID- 26581861 TI - Novel transcripts reveal a complex structure of the human TRKA gene and imply the presence of multiple protein isoforms. AB - BACKGROUND: Tropomyosin-related kinase A (TRKA) is a nerve growth factor (NGF) receptor that belongs to the tyrosine kinase receptor family. It is critical for the correct development of many types of neurons including pain-mediating sensory neurons and also controls proliferation, differentiation and survival of many neuronal and non-neuronal cells. TRKA (also known as NTRK1) gene is a target of alternative splicing which can result in several different protein isoforms. Presently, three human isoforms (TRKAI, TRKAII and TRKAIII) and two rat isoforms (TRKA L0 and TRKA L1) have been described. RESULTS: We show here that human TRKA gene is overlapped by two genes and spans 67 kb--almost three times the size that has been previously described. Numerous transcription initiation sites from eight different 5' exons and a sophisticated splicing pattern among exons encoding the extracellular part of TRKA receptor indicate that there might be a large variety of alternative protein isoforms. TrkA genes in rat and mouse appear to be considerably shorter, are not overlapped by other genes and display more straightforward splicing patterns. We describe the expression profile of alternatively spliced TRKA transcripts in different tissues of human, rat and mouse, as well as analyze putative endogenous TRKA protein isoforms in human SH SY5Y and rat PC12 cells. We also characterize a selection of novel putative protein isoforms by portraying their phosphorylation, glycosylation and intracellular localization patterns. Our findings show that an isoform comprising mainly of TRKA kinase domain is capable of entering the nucleus. CONCLUSIONS: Results obtained in this study refer to the existence of a multitude of TRKA mRNA and protein isoforms, with some putative proteins possessing very distinct properties. PMID- 26581862 TI - Clinical Features, Genetics and Potential Therapeutic Approaches for Birt-Hogg Dube Syndrome. AB - INTRODUCTION: Birt-Hogg-Dube (BHD) syndrome is an autosomal dominant disorder that predisposes to fibrofolliculomas, pulmonary cysts, spontaneous pneumothorax and renal neoplasia. BHD is characterized by germline mutations in tumor suppressor FLCN. Inactivation of the remaining FLCN allele in kidney cells drives tumorigenesis. Novel FLCN-interacting proteins, FNIP1 and FNIP2, were identified. Studies with FLCN-deficient in vitro and in vivo models support a role for FLCN in modulating AKT-mTOR signaling. Emerging evidence suggests that FLCN may interact in a number of pathways/processes. Identification of FLCN's major functional roles will provide the basis for developing targeted therapies for BHD patients. AREAS COVERED: This review covers BHD diagnostic criteria, clinical manifestations and genetics, as well as molecular consequences of FLCN inactivation. Recommended surveillance practices, patient management, and potential therapeutic options are discussed. EXPERT OPINION: In the decade since FLCN was identified as causative for BHD, we have gained a greater understanding of the clinical spectrum and genetics of this cancer syndrome. Recent studies have identified interactions between FLCN and a variety of signaling pathways and cellular processes, notably AKT-mTOR. Currently, surgical intervention is the only available therapy for BHD-associated renal tumors. Effective therapies will need to target primary pathways/processes deregulated in FLCN-deficient renal tumors and fibrofolliculomas. PMID- 26581863 TI - Conditioning of Roots with Hypoxia Increases Aluminum and Acid Stress Tolerance by Mitigating Activation of K+ Efflux Channels by ROS in Barley: Insights into Cross-Tolerance Mechanisms. AB - Aluminum (Al) is prevalent in soils, but Al toxicity is manifested only under acid conditions. It causes severe damages to the root system. Short-term waterlogging stress can occur simultaneously with Al toxicity in areas with high rainfall or an inappropriate irrigation pattern. Barley (Hordeum vulgare L.) is one of the most Al-sensitive small-grained cereals. In this work, we have investigated effects of short-term treatments with hypoxia and phenolic acid (two major constraints in waterlogged soils) on root sensitivity to low-pH and Al stresses. We showed that hypoxia-primed roots maintained higher cell viability when exposed to low-pH/Al stress, in both elongation and mature root zones, and possessed superior ability to retain K(+) in response to low-pH/Al stresses. These priming effects were not related to higher H(+)-ATPase activity and better membrane potential maintenance, and could not be explained by the increased expression levels of HvHAK1, which mediates high-affinity K(+) uptake in roots. Instead, hypoxia-conditioned roots were significantly less sensitive to H2O2 treatment, indicated by the 10-fold reduction in the magnitude of K(+) efflux changes. This suggested that roots pre-treated with hypoxia desensitized reactive oxygen species (ROS)-inducible K(+) efflux channels in root epidermis, most probably via enhanced antioxidative capacity. A possible role for Ca(2+) in stress-induced ROS signaling pathways is also discussed. Overall, our results report, for the first time, the phenomenon of cross-protection between hypoxia and low-pH/Al stresses, and causally link it to the cell's ability to maintain cytosolic K(+) homeostasis. PMID- 26581864 TI - Prediction suppression in monkey inferotemporal cortex depends on the conditional probability between images. AB - When monkeys view two images in fixed sequence repeatedly over days and weeks, neurons in area TE of the inferotemporal cortex come to exhibit prediction suppression. The trailing image elicits only a weak response when presented following the leading image that preceded it during training. Induction of prediction suppression might depend either on the contiguity of the images, as determined by their co-occurrence and captured in the measure of joint probability P(A,B), or on their contingency, as determined by their correlation and as captured in the measures of conditional probability P(A|B) and P(B|A). To distinguish between these possibilities, we measured prediction suppression after imposing training regimens that held P(A,B) constant but varied P(A|B) and P(B|A). We found that reducing either P(A|B) or P(B|A) during training attenuated prediction suppression as measured during subsequent testing. We conclude that prediction suppression depends on contingency, as embodied in the predictive relations between the images, and not just on contiguity, as embodied in their co occurrence. PMID- 26581865 TI - Properties of VIP+ synapses in the suprachiasmatic nucleus highlight their role in circadian rhythm. AB - Circadian rhythms coordinate cyclical behavioral and physiological changes in most organisms. In humans, this biological clock is located within the suprachiasmatic nucleus (SCN) of the hypothalamus and consists of a heterogeneous neuron population characterized by their enriched expression of various neuropeptides. As highlighted here, Fan et al. (J Neurosci 35: 1905-1029, 2015) developed an elegant experimental system to investigate the synaptic properties of vasoactive intestinal peptide (VIP)-expressing neurons between day and night, and further delineate their broader architecture and function within the SCN. PMID- 26581866 TI - Acrolein-mediated conduction loss is partially restored by K+ channel blockers. AB - Acrolein-mediated myelin damage is thought to be a critical mechanism leading to conduction failure following neurotrauma and neurodegenerative diseases. The exposure and activation of juxtaparanodal voltage-gated K(+) channels due to myelin damage leads to conduction block, and K(+) channel blockers have long been studied as a means for restoring axonal conduction in spinal cord injury (SCI) and multiple sclerosis (MS). In this study, we have found that 100 MUM K(+) channel blockers 4-aminopyridine-3-methanol (4-AP-3-MeOH), and to a lesser degree 4-aminopyridine (4-AP), can significantly restore compound action potential (CAP) conduction in spinal cord tissue following acrolein-mediated myelin damage using a well-established ex vivo SCI model. In addition, 4-AP-3-MeOH can effectively restore CAP conduction in acrolein-damaged axons with a range of concentrations from 0.1 to 100 MUM. We have also shown that while both compounds at 100 MUM showed no preference of small- and large-caliber axons when restoring CAP conduction, 4-AP-3-MeOH, unlike 4-AP, is able to augment CAP amplitude while causing little change in axonal responsiveness measured in refractory periods and response to repetitive stimuli. In a prior study, we show that 4-AP-3-MeOH was able to functionally rescue mechanically injured axons. In this investigation, we conclude that 4-AP-3-MeOH is an effective K(+) channel blocker in restoring axonal conduction following both primary (physical) and secondary (chemical) insults. These findings also suggest that 4-AP-3-MeOH is a viable alternative of 4-AP for treating myelin damage and improving function following central nervous system trauma and neurodegenerative diseases. PMID- 26581867 TI - Enhanced crosslimb transfer of force-field learning for dynamics that are identical in extrinsic and joint-based coordinates for both limbs. AB - Humans are able to adapt their motor commands to make accurate movements in novel sensorimotor environments, such as when wielding tools that alter limb dynamics. However, it is unclear to what extent sensorimotor representations, obtained through experience with one limb, are available to the opposite, untrained limb and in which form they are available. Here, we compared crosslimb transfer of force-field compensation after participants adapted to a velocity-dependent curl field, oriented either in the sagittal or the transverse plane. Due to the mirror symmetry of the limbs, the force field had identical effects for both limbs in joint and extrinsic coordinates in the sagittal plane but conflicting joint-based effects in the transverse plane. The degree of force-field compensation exhibited by the opposite arm in probe trials immediately after initial learning was significantly greater after sagittal (26 +/- 5%) than transverse plane adaptation (9 +/- 4%; P < 0.001), irrespective of whether participants learned initially with the left or the right arm or via abrupt or gradual exposure to the force field. Thus transfer was impaired when the orientation of imposed dynamics conflicted in intrinsic coordinates for the two limbs. The data reveal that neural representations of novel dynamics are only partially available to the opposite limb, since transfer is incomplete even when force-field perturbation is spatially compatible for the two limbs, according to both intrinsic and extrinsic coordinates. PMID- 26581868 TI - Peripheral vs. central determinants of vibrotactile adaptation. AB - Long-lasting mechanical vibrations applied to the skin induce a reversible decrease in the perception of vibration at the stimulated skin site. This phenomenon of vibrotactile adaptation has been studied extensively, yet there is still no clear consensus on the mechanisms leading to vibrotactile adaptation. In particular, the respective contributions of 1) changes affecting mechanical skin impedance, 2) peripheral processes, and 3) central processes are largely unknown. Here we used direct electrical stimulation of nerve fibers to bypass mechanical transduction processes and thereby explore the possible contribution of central vs. peripheral processes to vibrotactile adaptation. Three experiments were conducted. In the first, adaptation was induced with mechanical vibration of the fingertip (51- or 251-Hz vibration delivered for 8 min, at 40* detection threshold). In the second, we attempted to induce adaptation with transcutaneous electrical stimulation of the median nerve (51- or 251-Hz constant-current pulses delivered for 8 min, at 1.5* detection threshold). Vibrotactile detection thresholds were measured before and after adaptation. Mechanical stimulation induced a clear increase of vibrotactile detection thresholds. In contrast, thresholds were unaffected by electrical stimulation. In the third experiment, we assessed the effect of mechanical adaptation on the detection thresholds to transcutaneous electrical nerve stimuli, measured before and after adaptation. Electrical detection thresholds were unaffected by the mechanical adaptation. Taken together, our results suggest that vibrotactile adaptation is predominantly the consequence of peripheral mechanoreceptor processes and/or changes in biomechanical properties of the skin. PMID- 26581871 TI - A three-leg model producing tetrapod and tripod coordination patterns of ipsilateral legs in the stick insect. AB - Insect locomotion requires the precise coordination of the movement of all six legs. Detailed investigations have revealed that the movement of the legs is controlled by local dedicated neuronal networks, which interact to produce walking of the animal. The stick insect is well suited to experimental investigations aimed at understanding the mechanisms of insect locomotion. Beside the experimental approach, models have also been constructed to elucidate those mechanisms. Here, we describe a model that replicates both the tetrapod and tripod coordination pattern of three ipsilateral legs. The model is based on an earlier insect leg model, which includes the three main leg joints, three antagonistic muscle pairs, and their local neuronal control networks. These networks are coupled via angular signals to establish intraleg coordination of the three neuromuscular systems during locomotion. In the present three-leg model, we coupled three such leg models, representing front, middle, and hind leg, in this way. The coupling was between the levator-depressor local control networks of the three legs. The model could successfully simulate tetrapod and tripod coordination patterns, as well as the transition between them. The simulations showed that for the interleg coordination during tripod, the position signals of the levator-depressor neuromuscular systems sent between the legs were sufficient, while in tetrapod, additional information on the angular velocities in the same system was necessary, and together with the position information also sufficient. We therefore suggest that, during stepping, the connections between the levator-depressor neuromuscular systems of the different legs are of primary importance. PMID- 26581869 TI - Feeling form: the neural basis of haptic shape perception. AB - The tactile perception of the shape of objects critically guides our ability to interact with them. In this review, we describe how shape information is processed as it ascends the somatosensory neuraxis of primates. At the somatosensory periphery, spatial form is represented in the spatial patterns of activation evoked across populations of mechanoreceptive afferents. In the cerebral cortex, neurons respond selectively to particular spatial features, like orientation and curvature. While feature selectivity of neurons in the earlier processing stages can be understood in terms of linear receptive field models, higher order somatosensory neurons exhibit nonlinear response properties that result in tuning for more complex geometrical features. In fact, tactile shape processing bears remarkable analogies to its visual counterpart and the two may rely on shared neural circuitry. Furthermore, one of the unique aspects of primate somatosensation is that it contains a deformable sensory sheet. Because the relative positions of cutaneous mechanoreceptors depend on the conformation of the hand, the haptic perception of three-dimensional objects requires the integration of cutaneous and proprioceptive signals, an integration that is observed throughout somatosensory cortex. PMID- 26581870 TI - Cat's medullary reticulospinal and subnucleus reticularis dorsalis noxious neurons form a coupled neural circuit through collaterals of descending axons. AB - Animals and human beings sense and react to real/potential dangerous stimuli. However, the supraspinal mechanisms relating noxious sensing and nocifensive behavior are mostly unknown. The collateralization and spatial organization of interrelated neurons are important determinants of coordinated network function. Here we electrophysiologically studied medial medullary reticulospinal neurons (mMRF-RSNs) antidromically identified from the cervical cord of anesthetized cats and found that 1) more than 40% (79/183) of the sampled mMRF-RSNs emitted bifurcating axons running within the dorsolateral (DLF) and ventromedial (VMF) ipsilateral fascicles; 2) more than 50% (78/151) of the tested mMRF-RSNs with axons running in the VMF collateralized to the subnucleus reticularis dorsalis (SRD) that also sent ipsilateral descending fibers bifurcating within the DLF and the VMF. This percentage of mMRF collateralization to the SRD increased to more than 81% (53/65) when considering the subpopulation of mMRF-RSNs responsive to noxiously heating the skin; 3) reciprocal monosynaptic excitatory relationships were electrophysiologically demonstrated between noxious sensitive mMRF-RSNs and SRD cells; and 4) injection of the anterograde tracer Phaseolus vulgaris leucoagglutinin evidenced mMRF to SRD and SRD to mMRF projections contacting the soma and proximal dendrites. The data demonstrated a SRD-mMRF network interconnected mainly through collaterals of descending axons running within the VMF, with the subset of noxious sensitive cells forming a reverberating circuit probably amplifying mutual outputs simultaneously regulating motor activity and spinal noxious afferent input. The results provide evidence that noxious stimulation positively engages a reticular SRD-mMRF-SRD network involved in pain sensory-to-motor transformation and modulation. PMID- 26581872 TI - The rostral ventromedial medulla control of cutaneous vasomotion of paws and tail in the rat: implication for pain studies. AB - Thermal neutrality in rodents is achieved by large cyclic variations of the sympathetic drive of the vasomotion of the tail and paws, the most widely used target organs in current acute or chronic animal models of pain. Given the pivotal functional role of rostral ventromedial medulla (RVM) in nociception and rostral medullary raphe (rMR) in thermoregulation, two largely overlapping brain regions, we aimed at circumscribing the brainstem regions that are the source of premotor afferents to sympathetic preganglionic neurons that control the vasomotor tone of the tail and hind paws. A thermometric infrared camera recorded indirectly the vasomotor tone of the tail and hind paws. During the control period, the rat was maintained in vasoconstriction by preserving a stable, homogeneous, and constant surrounding temperature, slightly below the core temperature. The functional blockade of the RVM/rMR by the GABAA receptor agonist muscimol (0.5 nmol, 50 nl) elicited an extensive increase of the temperature of the paws and tail, associated with a slight decrease of blood pressure and heart rate. Both the increased heat loss through vasodilatation and the decrease heart induced heat production elicited a remarkable reduction of the central temperature. The effective zones were circumscribed to the parts of the RVM/rMR facing the facial nucleus. They match very exactly the brain regions often described as specifically devoted to the control of nociception. Our data support and urge on the highest cautiousness regarding the interpretation of results aimed at studying the effects of any pharmacological manipulations of RVM/rMR with the usual tests of pain. PMID- 26581873 TI - Mechanical sensibility of nociceptive and non-nociceptive fast-conducting afferents is modulated by skin temperature. AB - The ability to distinguish mechanical from thermal input is a critical component of peripheral somatosensory function. Polymodal C fibers respond to both stimuli. However, mechanosensitive, modality-specific fast-conducting tactile and nociceptor afferents theoretically carry information only about mechanical forces independent of the thermal environment. We hypothesize that the thermal environment can nonetheless modulate mechanical force sensibility in fibers that do not respond directly to change in temperature. To study this, fast-conducting mechanosensitive peripheral sensory fibers in male Sprague-Dawley rats were accessed at the soma in the dorsal root ganglia from T11 or L4/L5. Neuronal identification was performed using receptive field characteristics and passive and active electrical properties. Neurons responded to mechanical stimuli but failed to generate action potentials in response to changes in temperature alone, except for the tactile mechanical and cold sensitive neurons. Heat and cold ramps were utilized to determine temperature-induced modulation of response to mechanical stimuli. Mechanically evoked electrical activity in non-nociceptive, low-threshold mechanoreceptors (tactile afferents) decreased in response to changes in temperature while mechanically induced activity was increased in nociceptive, fast-conducting, high-threshold mechanoreceptors in response to the same changes in temperature. These data suggest that mechanical activation does not occur in isolation but rather that temperature changes appear to alter mechanical afferent activity and input to the central nervous system in a dynamic fashion. Further studies to understand the psychophysiological implications of thermal modulation of fast-conducting mechanical input to the spinal cord will provide greater insight into the implications of these findings. PMID- 26581875 TI - Oculomotor selection underlies feature retention in visual working memory. AB - Oculomotor selection, spatial task relevance, and visual working memory (WM) are described as three processes highly intertwined and sustained by similar cortical structures. However, because task-relevant locations always constitute potential saccade targets, no study so far has been able to distinguish between oculomotor selection and spatial task relevance. We designed an experiment that allowed us to dissociate in humans the contribution of task relevance, oculomotor selection, and oculomotor execution to the retention of feature representations in WM. We report that task relevance and oculomotor selection lead to dissociable effects on feature WM maintenance. In a first task, in which an object's location was encoded as a saccade target, its feature representations were successfully maintained in WM, whereas they declined at nonsaccade target locations. Likewise, we observed a similar WM benefit at the target of saccades that were prepared but never executed. In a second task, when an object's location was marked as task relevant but constituted a nonsaccade target (a location to avoid), feature representations maintained at that location did not benefit. Combined, our results demonstrate that oculomotor selection is consistently associated with WM, whereas task relevance is not. This provides evidence for an overlapping circuitry serving saccade target selection and feature-based WM that can be dissociated from processes encoding task-relevant locations. PMID- 26581874 TI - Classifying neuronal subclasses of the cerebellum through constellation pharmacology. AB - A pressing need in neurobiology is the comprehensive identification and characterization of neuronal subclasses within the mammalian nervous system. To this end, we used constellation pharmacology as a method to interrogate the neuronal and glial subclasses of the mouse cerebellum individually and simultaneously. We then evaluated the data obtained from constellation pharmacology experiments by cluster analysis to classify cells into neuronal and glial subclasses, based on their functional expression of glutamate, acetylcholine, and GABA receptors, among other ion channels. Conantokin peptides were used to identify N-methyl-d-aspartate (NMDA) receptor subtypes, which revealed that neurons of the young mouse cerebellum expressed NR2A and NR2B NMDA receptor subunits. Additional pharmacological tools disclosed differential expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazloepropionic, nicotinic acetylcholine, and muscarinic acetylcholine receptors in different neuronal and glial subclasses. Certain cell subclasses correlated with known attributes of granule cells, and we combined constellation pharmacology with genetically labeled neurons to identify and characterize Purkinje cells. This study illustrates the utility of applying constellation pharmacology to classify neuronal and glial subclasses in specific anatomical regions of the brain. PMID- 26581876 TI - Three-dimensional analysis of enamel surface alteration resulting from orthodontic clean-up -comparison of three different tools. AB - BACKGROUND: The present study aimed at 3D analysis of adhesive remnants and enamel loss following the debonding of orthodontic molar tubes and orthodontic clean-up to assess the effectiveness and safety of One-Step Finisher and Polisher and Adhesive Residue Remover in comparison to tungsten carbide bur. MATERIALS AND METHODS: Thirty human molars were bonded with chemical-cure orthodontic adhesive (Unite, 3M, USA), stored 24 h in 0.9 % saline solution, debonded and cleaned using three methods (Three groups of ten): tungsten carbide bur (Dentaurum, Pforzheim, Germany), one-step finisher and polisher (One gloss, Shofu Dental, Kyoto, Japan) and Adhesive Residue Remover (Dentaurum, Pforzheim, Germany). Direct 3D scanning in blue-light technology to the nearest 2 MUm was performed before etching and after adhesive removal. Adhesive remnant height and volume as well as enamel loss depth and volume were calculated. An index of effectiveness and safety was proposed and calculated for every tool; adhesive remnant volume and duplicated enamel lost volume were divided by a sum of multiplicands. Comparisons using parametric ANOVA or nonparametric ANOVA rank Kruskal-Wallis tests were used to compare between tools for adhesive remnant height and volume, enamel loss depth and volume as well as for the proposed index. RESULTS: No statistically significant differences in the volume (p = 0.35) or mean height (p = 0.24) of adhesive remnants were found (ANOVA rank Kruskal-Wallis test) between the groups of teeth cleaned using different tools. Mean volume of enamel loss was 2.159 mm(3) for tungsten carbide bur, 1.366 mm(3) for Shofu One Gloss and 0.659 mm(3) for Adhesive Residue Remover - (F = 2.816, p = 0.0078). A comparison of the proposed new index between tools revealed highly statistically significant differences (p = 0.0081), supporting the best value for Adhesive Residue Remover and the worst - for tungsten carbide bur. CONCLUSIONS: The evaluated tools were all characterized by similar effectiveness. The most destructive tool with regards to enamel was the tungsten carbide bur, and the least was Adhesive Residue Removal. PMID- 26581877 TI - Transient delay of radiation-induced apoptosis by phorbol acetate. AB - The mechanisms of interference of a model tumour promoter 12-O-tetra decanoylphorbol-13-acetate (TPA) with radiation-induced apoptosis in human peripheral lymphocytes have been investigated. The cells were treated with TPA under various conditions and thereafter exposed to a single lethal dose of gamma radiation. Morphological and biochemical changes characteristic of apoptosis were followed up to 72 h of post-irradiation time. Acute exposure to low concentration of TPA resulted in delay in the onset of radiation-induced apoptosis (determined as morphological changes and rate of mitochondrial demise) by 24-48 h as compared to the irradiated, sham TPA-treated cells. The time course of this delay correlated well with confinement of the p53 protein to the cytoplasm and increase in bcl-2 levels at the nuclear periphery of irradiated cells. Our results indicate that confinement of p53 in the cytoplasm is one of the potential mechanisms by which TPA interferes with the process of radiation-induced apoptosis in human lymphocytes. PMID- 26581878 TI - Dysregulation of DNA methylation induced by past arsenic treatment causes persistent genomic instability in mammalian cells. AB - The mechanisms by which arsenic-induced genomic instability is initiated and maintained are poorly understood. To investigate potential epigenetic mechanisms, in this study we evaluated global DNA methylation levels in V79 cells and human HaCaT keratinocytes at several time points during expanded growth of cell cultures following removal of arsenite exposures. We have found altered genomic methylation patterns that persisted up to 40 cell generations in HaCaT cells after the treatments were withdrawn. Moreover, mRNA expression levels were evaluated by RT-PCR for DNMT1, DNMT3A, DNMT3B, HMLH1, and HMSH2 genes, demonstrating that the down regulation of DNMT3A and DNMT3B genes, but not DNMT1, occurred in an arsenic dose-dependent manner, and persisted for many cell generations following removal of the arsenite, offering a plausible mechanism of persistently genotoxic arsenic action. Analyses of promoter methylation status of the DNA mismatch repair genes HMLH1 and HMSH2 show that HMSH2, but not HMLH1, was epigenetically regulated by promoter hypermethylation changes following arsenic treatment. The results reported here demonstrate that arsenic exposure promptly induces genome-wide global DNA hypomethylation, and some specific gene promoter methylation changes, that persist for many cell generations following withdrawal of arsenite, supporting the hypothesis that the cells undergo epigenetic reprogramming at both the gene and genome level that is durable over many cell generations in the absence of further arsenic treatment. These DNA methylation changes, in concert with other known epigenome alterations, are likely contributing to long-lasting arsenic-induced genomic instability that manifests in several ways, including aberrant chromosomal effects. PMID- 26581879 TI - Options for the Development of Noninvasive Glucose Monitoring: Is Nanotechnology an Option to Break the Boundaries? AB - Nowadays nanotechnology has many applications in products used in various areas of daily life; however, this technology has also an option in modern medicine and pharmacy. Therefore, this technology is also an attractive option for the field of diagnosis and treatment of diabetes. Many people with diabetes measure their blood glucose levels regularly to determine the insulin dose. Ideally glucose values would be measured noninvasively (NI). However, none of all the NI approaches studied in the past decades enabled reliable NI measurements under all daily life conditions. Particularly an unfavorable signal-to-noise ratio turned out to be problematic. Based on the known physical possibilities for NI glucose monitoring the focus of this review is on nanotechnology approaches. Functional prototypes exist for some of these that showed promising results under defined laboratory conditions, indicating a good sensitivity and selectivity for glucose. On the second hand is to optimize the technological process of manufacturing. In view of the rapid progress in micro- and nanoelectronics hopefully NI glucose monitoring systems can be developed in the near future. PMID- 26581880 TI - Improving Accuracy of Grading and Referral of Diabetic Macular Edema Using Location and Extent of Hard Exudates in Retinal Photography. AB - BACKGROUND: Hard exudates (HE) are used as a surrogate marker for sight threatening diabetic macular edema (DME) in most telemedicine-based screening programs in the world. This study investigates whether proximity of HE to the center of the macula, and extent of HE are associated with greater clinically significant macular edema (CSME) severity. A novel method for associating optical coherence tomography (OCT) scans with CSME was developed. METHODS: Eligible subjects were recruited from a DRS program in a community clinic in Oakland, California. Ocular fundus of each subject was imaged using 3-field 45-degree digital retinal photography and scanned using central 7-line spectral domain OCT. Two certified graders separated subjects into 2 groups, those with and without HE within 500 microns from the center of the macula. A modified DME severity scale, developed from Early Treatment Diabetic Retinopathy Study data and adapted to OCT thickness measurements, was used to stratify CSME into severe and nonsevere levels for all subjects. RESULTS: The probabilities of severe CSME in groups 1 and 2 were 14.4% (95% CI: 8.2%-23.8%) and 9% (95% CI: 2.4%-25.5%), respectively (P = .556). In post hoc analysis, increase in the number of sectors affected by HE within the central zone of the macula was associated with the increase in the probability of being diagnosed with severe CSME. CONCLUSION: We have proposed OCT based classification of DME into severe and nonsevere CSME. Based on this limited analysis, severity of CSME is related more to extent of HE rather than proximity to the center of the macula. PMID- 26581881 TI - Metabolic Control With the Bio-inspired Artificial Pancreas in Adults With Type 1 Diabetes: A 24-Hour Randomized Controlled Crossover Study. AB - BACKGROUND: The Bio-inspired Artificial Pancreas (BiAP) is a closed-loop insulin delivery system based on a mathematical model of beta-cell physiology and implemented in a microchip within a low-powered handheld device. We aimed to evaluate the safety and efficacy of the BiAP over 24 hours, followed by a substudy assessing the safety of the algorithm without and with partial meal announcement. Changes in lactate and 3-hydroxybutyrate concentrations were investigated for the first time during closed-loop. METHODS: This is a prospective randomized controlled open-label crossover study. Participants were randomly assigned to attend either a 24-hour closed-loop visit connected to the BiAP system or a 24-hour open-loop visit (standard insulin pump therapy). The primary outcome was percentage time spent in target range (3.9-10 mmol/l) measured by sensor glucose. Secondary outcomes included percentage time in hypoglycemia (<3.9 mmol/l) and hyperglycemia (>10 mmol/l). Participants were invited to attend for an additional visit to assess the BiAP without and with partial meal announcements. RESULTS: A total of 12 adults with type 1 diabetes completed the study (58% female, mean [SD] age 45 [10] years, BMI 25 [4] kg/m(2), duration of diabetes 22 [12] years and HbA1c 7.4 [0.7]% [58 (8) mmol/mol]). The median (IQR) percentage time in target did not differ between closed-loop and open-loop (71% vs 66.9%, P = .9). Closed-loop reduced time spent in hypoglycemia from 17.9% to 3.0% (P < .01), but increased time was spent in hyperglycemia (10% vs 28.9%, P = .01). The percentage time in target was higher when all meals were announced during closed-loop compared to no or partial meal announcement (65.7% [53.6-80.5] vs 45.5% [38.2-68.3], P = .12). CONCLUSIONS: The BiAP is safe and achieved equivalent time in target as measured by sensor glucose, with improvement in hypoglycemia, when compared to standard pump therapy. PMID- 26581882 TI - Comparison of Gait Features Between Feet With Callus or Corns and Normal Feet Using Motion Sensors in People With Diabetes and People Without Diabetes. PMID- 26581883 TI - Role of the Porphyromonas gingivalis iron-binding protein PG1777 in oxidative stress resistance. AB - Whole genome sequencing of the response of Porphyromonas gingivalis W83 to hydrogen peroxide revealed an upregulation of several uncharacterized, novel genes. Under conditions of prolonged oxidative stress in P. gingivalis, increased expression of a unique transcriptional unit carrying the grpE, dnaJ and three other hypothetical genes (PG1777, PG1778 and PG1779) was observed. The transcriptional start site of this operon appears to be located 91 bp upstream of the translational start, with a potential -10 region at -3 nt and a -35 region at -39 nt. Isogenic P. gingivalis mutants FLL273 (PG1777 : : ermF-ermAM) and FLL293 (PG1779 : : ermF-ermAM) showed increased sensitivity to and decreased survival after treatment with hydrogen peroxide. P. gingivalis FLL273 showed a fivefold increase in the formation of spontaneous mutants when compared with the parent strain after exposure to hydrogen peroxide. The recombinant PG1777 protein displayed iron-binding properties when incubated with FeSO4 and Fe(NH4)2(SO4).6H2O. The rPG1777 protein protected DNA from degradation when exposed to hydrogen peroxide in the presence of iron. Taken together, the data suggest that the grpE-dnaJ-PG1777-PG1778-PG1779 transcriptional unit may play an important role in oxidative stress resistance in P. gingivalis via its ability to protect against DNA damage. PMID- 26581884 TI - Antiplatelet effect of ticagrelor compared to tirofiban in non-ST-segment elevation ACS patients undergoing PCI. The result of the TE-CLOT trial. AB - Addition of a potent P2Y12 inhibitor to aspirin is the standard therapy for non ST-segment elevation acute coronary syndrome (NSTE-ACS) patients undergoing percutaneous coronary intervention (PCI). Glycoprotein IIb/IIIa inhibitor, together with antiplatelet therapy, may be considered as part of initial therapy in NSTE-ACS patients with high-risk features. This study investigated the antiplatelet effect of ticagrelor loading dose (LD) versus tirofiban bolus injection with a post-bolus infusion on top of aspirin among NSTE-ACS patients planned to PCI. NSTE-ACS patients were randomised to receive either ticagrelor (n = 47) or tirofiban (n = 48). Platelet reactivity was assessed by light transmittance aggregometry at 0, 2, 8, and 24 hours (h) after treatment initiation. Primary endpoint was inhibition of platelet aggregation (IPA, 20 uM ADP, final extent) at 2 h after LD therapy, with a non-inferiority margin of 10%. The prevalence of high on-treatment platelet reactivity (HPR) was also compared at 0, 2, 8, and 24 h. The mean difference in IPA between ticagrelor and tirofiban was -9.9% (95% confidence interval: -25.7% to 5.9%) at 2 h, -1.6% (-8.0% to 4.8%) at 8 h, and -3.3% (-18.4% to 12.0%) at 24 h. The prevalence of HPR did not differ between the two groups at any time point (all p values >= 0.059), which was almost abolished by 8 h post-LD (< 5%). In conclusion, the antiplatelet effect during the early phase (~2 h) after ticagrelor LD appeared to be relatively strong, but it did not reach that of tirofiban in NSTE-ACS patients. PMID- 26581885 TI - Characterizing Spatial Dynamics of Bifurcation to Alternans in Isolated Whole Rabbit Hearts Based on Alternate Pacing. AB - Sudden cardiac death instigated by ventricular fibrillation (VF) is the largest cause of natural death in the USA. Alternans, a beat-to-beat alternation in the action potential duration, has been implicated as being proarrhythmic. The onset of alternans is mediated via a bifurcation, which may occur through either a smooth or a border-collision mechanism. The objective of this study was to characterize the mechanism of bifurcation to alternans based on experiments in isolated whole rabbit hearts. High resolution optical mapping was performed and the electrical activity was recorded from the left ventricle (LV) epicardial surface of the heart. Each heart was paced using an "alternate pacing protocol," where the basic cycle length (BCL) was alternatively perturbed by +/-delta. Local onset of alternans in the heart, BCL(start), was measured in the absence of perturbations (delta = 0) and was defined as the BCL at which 10% of LV exhibited alternans. The influences of perturbation size were investigated at two BCLs: one prior to BCL(start) (BCL(prior) = BCL(start) + 20 ms) and one preceding BCL(prior) (BCL(far) = BCL(start) + 40 ms). Our results demonstrate significant spatial correlation of the region exhibiting alternans with smooth bifurcation characteristics, indicating that transition to alternans in isolated rabbit hearts occurs predominantly through smooth bifurcation. PMID- 26581886 TI - Alzheimer's disease cerebrospinal fluid biomarkers are not influenced by gravity drip or aspiration extraction methodology. AB - INTRODUCTION: Cerebrospinal fluid (CSF) biomarkers, although of established utility in the diagnostic evaluation of Alzheimer's disease (AD), are known to be sensitive to variation based on pre-analytical sample processing. We assessed whether gravity droplet collection versus syringe aspiration was another factor influencing CSF biomarker analyte concentrations and reproducibility. METHODS: Standardized lumbar puncture using small calibre atraumatic spinal needles and CSF collection using gravity fed collection followed by syringe aspirated extraction was performed in a sample of elderly individuals participating in a large long-term observational research trial. Analyte assay concentrations were compared. RESULTS: For the 44 total paired samples of gravity collection and aspiration, reproducibility was high for biomarker CSF analyte assay concentrations (concordance correlation [95%CI]: beta-amyloid1-42 (Abeta42) 0.83 [0.71 - 0.90]), t-tau 0.99 [0.98 - 0.99], and phosphorylated tau (p-tau) 0.82 [95 % CI 0.71 - 0.89]) and Bonferroni corrected paired sample t-tests showed no significant differences (group means (SD): Abeta42 366.5 (86.8) vs 354.3 (82.6), p = 0.10; t-tau 83.9 (46.6) vs 84.7 (47.4) p = 0.49; p-tau 43.5 (22.8) vs 40.0 (17.7), p = 0.05). The mean duration of collection was 10.9 minutes for gravity collection and <1 minute for aspiration. CONCLUSIONS: Our results demonstrate that aspiration of CSF is comparable to gravity droplet collection for AD biomarker analyses but could considerably accelerate throughput and improve the procedural tolerability for assessment of CSF biomarkers. PMID- 26581887 TI - A case of IgG4-related mesenteritis. AB - IgG4-related disease is a newly recognized fibroinflammatory condition characterized by tumefaction consisting of fibrosis with dense infiltration of IgG4-positive plasma cells; affecting various organs. A case of IgG4-related sclerosing mesenteritis is reported. A 64-year-old man was admitted to our hospital with a suspected tumor of the small intestine. Abdominal computed tomography demonstrated a 6-cm soft tissue mass in the right lower mesentery compressing the jejunum, which also showed accumulation of fluorodeoxyglucose uptake on fluorine-18 fluorodeoxyglucose positron emission tomography. With a preoperative diagnosis of suspected malignant lymphoma with lymphadenopathy in the mesentery, partial small bowel resection was performed. Macroscopically, a hard mass, including several swollen lymph nodes, was detected in the mesentery. Microscopically, marked fibrosis showing partially storiform pattern, obstructive phlebitis, follicular hyperplasia, and abundant infiltration of IgG4-positive plasma cells were detected. IgG4-related mesenteritis was diagnosed histopathologically, but the serum IgG4 level was 81 mg/dl postoperatively. Five months after the surgery, an 11-cm soft tissue mass involving the left ureter appeared. Histological examination of a biopsy specimen from the retroperitoneal mass showed fibrosis with inflammatory infiltration. Although IgG4-related retroperitoneal fibrosis could not be confirmed histologically, the tumor responded well to steroid therapy. PMID- 26581888 TI - Control of Giardiasis by Interleukin-17 in Humans and Mice--Are the Questions All Answered? AB - For years, studies of the immune response to Giardia lamblia infection focused on the production of IgA by infected hosts and antigenic variation by the parasite to escape destruction by this IgA. A new study by Hanevik and colleagues (C. S. Saghaug, S. Sornes, D. Peirasmaki, S. Svard, N. Langeland, and K. Hanevik, Clin Vaccine Immunol 23:11-18, 2016, http://dx.doi.org/10.1128/CVI.00419-15) highlights the emerging role of interleukin-17 (IL-17) in immunity to this parasite. Along with recent studies of Giardia infections of animals, this work shows that IL-17 appears to be essential for the control of these infections and to be a key factor linking cellular and humoral immune responses. PMID- 26581889 TI - Characterization of Mucosal Immune Responses to Enterotoxigenic Escherichia coli Vaccine Antigens in a Human Challenge Model: Response Profiles after Primary Infection and Homologous Rechallenge with Strain H10407. AB - Enterotoxigenic Escherichia coli (ETEC) bacteria are the most common bacterial cause of diarrhea in children in resource-poor settings as well as in travelers. Although there are several approaches to develop an effective vaccine for ETEC, no licensed vaccines are currently available. A significant challenge to successful vaccine development is our poor understanding of the immune responses that correlate best with protection against ETEC illness. In this study, ETEC specific mucosal immune responses were characterized and compared in subjects challenged with ETEC strain H10407 and in subjects rechallenged with the homologous organism. IgA responses to lipopolysaccharide (LPS), heat-labile toxin B subunit (LTB), and colonization factor antigen I (CFA/I) in antibody in lymphocyte supernatant (ALS), feces, lavage fluid, and saliva samples were evaluated. In all assay comparisons, ALS was the most sensitive indicator of a local immune response, but serum IgA was also a useful indirect marker of immune response to oral antigens. Volunteers challenged and then rechallenged with strain H10407 were protected from illness following rechallenge. Comparing mucosal antibody responses after primary and homologous rechallenge, protection against disease was reflected in reduced antibody responses to key ETEC antigens and in reduced fecal shedding of the H10407 challenge strain. Subjects challenged with strain H10407 mounted stronger antibody responses to LPS and LTB than subjects in the rechallenge group, while responses to CFA/I in the rechallenge group were higher than in the challenge group. We anticipate that this study will help provide an immunological benchmark for the evaluation of ETEC vaccines and immunization regimens in the future. PMID- 26581890 TI - Lymphocyte Perturbations in Malawian Children with Severe and Uncomplicated Malaria. AB - Lymphocytes are implicated in immunity and pathogenesis of severe malaria. Since lymphocyte subsets vary with age, assessment of their contribution to different etiologies can be difficult. We immunophenotyped peripheral blood from Malawian children presenting with cerebral malaria, severe malarial anemia, and uncomplicated malaria (n = 113) and healthy aparasitemic children (n = 42) in Blantyre, Malawi, and investigated lymphocyte subset counts, activation, and memory status. Children with cerebral malaria were older than those with severe malarial anemia. We found panlymphopenia in children presenting with cerebral malaria (median lymphocyte count, 2,100/MUl) and uncomplicated malaria (3,700/MUl), which was corrected in convalescence and was absent in severe malarial anemia (5,950/MUl). Median percentages of activated CD69(+) NK (73%) and gammadelta T (60%) cells were higher in cerebral malaria than in other malaria types. Median ratios of memory to naive CD4(+) lymphocytes were higher in cerebral malaria than in uncomplicated malaria and low in severe malarial anemia. The polarized lymphocyte subset profiles of different forms of severe malaria are independent of age. In conclusion, among Malawian children cerebral malaria is characterized by lymphocyte activation and increased memory cells, consistent with immune priming. In contrast, there are reduced memory cells and less activation in severe malaria anemia. Further studies are required to understand whether these immunological profiles indicate predisposition of some children to one or another form of severe malaria. PMID- 26581891 TI - The combination of four molecular markers improves thyroid cancer cytologic diagnosis and patient management. AB - BACKGROUND: Papillary thyroid cancer is the most common endocrine malignancy. The most sensitive and specific diagnostic tool for thyroid nodule diagnosis is fine needle aspiration (FNA) biopsy with cytological evaluation. Nevertheless, FNA biopsy is not always decisive leading to "indeterminate" or "suspicious" diagnoses in 10%-30% of cases. BRAF V600E detection is currently used as molecular test to improve the diagnosis of thyroid nodules, yet it lacks sensitivity. The aim of the present study was to identify novel molecular markers/computational models to improve the discrimination between benign and malignant thyroid lesions. METHODS: We collected 118 pre-operative thyroid FNA samples. All 118 FNA samples were characterized for the presence of the BRAF V600E mutation (exon15) by pyrosequencing and further assessed for mRNA expression of four genes (KIT, TC1, miR-222, miR-146b) by quantitative polymerase chain reaction. Computational models (Bayesian Neural Network Classifier, discriminant analysis) were built, and their ability to discriminate benign and malignant tumors were tested. Receiver operating characteristic (ROC) analysis was performed and principal component analysis was used for visualization purposes. RESULTS: In total, 36/70 malignant samples carried the V600E mutation, while all 48 benign samples were wild type for BRAF exon15. The Bayesian neural network (BNN) and discriminant analysis, including the mRNA expression of the four genes (KIT, TC1, miR-222, miR-146b) showed a very strong predictive value (94.12% and 92.16%, respectively) in discriminating malignant from benign patients. The discriminant analysis showed a correct classification of 100% of the samples in the malignant group, and 95% by BNN. KIT and miR-146b showed the highest diagnostic accuracy of the ROC curve, with area under the curve values of 0.973 for KIT and 0.931 for miR-146b. CONCLUSIONS: The four genes model proposed in this study proved to be highly discriminative of the malignant status compared with BRAF assessment alone. Its implementation in clinical practice can help in identifying malignant/benign nodules that would otherwise remain suspicious. PMID- 26581892 TI - Did Neoliberalizing West African Forests Produce a New Niche for Ebola? AB - A recent study introduced a vaccine that controls Ebola Makona, the Zaire ebolavirus variant that has infected 28,000 people in West Africa. We propose that even such successful advances are insufficient for many emergent diseases. We review work hypothesizing that Makona, phenotypically similar to much smaller outbreaks, emerged out of shifts in land use brought about by neoliberal economics. The epidemiological consequences demand a new science that explicitly addresses the foundational processes underlying multispecies health, including the deep-time histories, cultural infrastructure, and global economic geographies driving disease emergence. The approach, for instance, reverses the standard public health practice of segregating emergency responses and the structural context from which outbreaks originate. In Ebola's case, regional neoliberalism may affix the stochastic "friction" of ecological relationships imposed by the forest across populations, which, when above a threshold, keeps the virus from lining up transmission above replacement. Export-led logging, mining, and intensive agriculture may depress such functional noise, permitting novel spillovers larger forces of infection. Mature outbreaks, meanwhile, can continue to circulate even in the face of efficient vaccines. More research on these integral explanations is required, but the narrow albeit welcome success of the vaccine may be used to limit support of such a program. PMID- 26581894 TI - Analysing nature's experiment: Fisher's inductive theorem of natural selection. AB - The paper by Ewens and Lessard (2015) adds to the progress that has been made in exploring the discrete-generation analytical version of Fisher's Fundamental Theorem of Natural Selection introduced by Ewens (1989). Fisher's continuous-time theorem differs from the version described by Ewens and Lessard by using a different concept of fitness. Ewens and Lessard use the conventional 'viability' concept whereas for Fisher the fitness of a genotype was its relative rate of increase or decrease in the population. The sole purpose of the present paper is to emphasize the alternative inductive nature of Fisher's theorem, as presented by him in 1930, by placing it in the context of his contemporary development of the analysis of variance in agricultural experiments. It is not a general discussion of the theorem itself. PMID- 26581893 TI - TRPC6 specifically interacts with APP to inhibit its cleavage by gamma-secretase and reduce Abeta production. AB - Generation of beta-amyloid (Abeta) peptide in Alzheimer's disease involves cleavage of amyloid precursor protein (APP) by gamma-secretase, a protease known to cleave several substrates, including Notch. Finding specific modulators for gamma-secretase could be a potential avenue to treat the disease. Here, we report that transient receptor potential canonical (TRPC) 6 specifically interacts with APP leading to inhibition of its cleavage by gamma-secretase and reduction in Abeta production. TRPC6 interacts with APP (C99), but not with Notch, and prevents C99 interaction with presenilin 1 (PS1). A fusion peptide derived from TRPC6 also reduces Abeta levels without effect on Notch cleavage. Crossing APP/PS1 mice with TRPC6 transgenic mice leads to a marked reduction in both plaque load and Abeta levels, and improvement in structural and behavioural impairment. Thus, TRPC6 specifically modulates gamma-secretase cleavage of APP and preventing APP (C99) interaction with PS1 via TRPC6 could be a novel strategy to reduce Abeta formation. PMID- 26581896 TI - A Look Beyond the Biosimilarity of the Molecules. PMID- 26581895 TI - The Ulcerative Colitis Endoscopic Index of Severity More Accurately Reflects Clinical Outcomes and Long-term Prognosis than the Mayo Endoscopic Score. AB - BACKGROUND AND AIMS: The Ulcerative Colitis Endoscopic Index of Severity (UCEIS) and the Mayo endoscopic score (Mayo ES) are used to evaluate ulcerative colitis (UC) severity. This study compared UCEIS and the Mayo ES for evaluating UC severity and outcomes in patients undergoing remission induction during routine clinical practice with the aim of predicting medium- to long-term prognosis. METHODS: Forty-one UC patients who received colonoscopy before and after tacrolimus remission induction therapy were included. An index of clinical activity and endoscopic findings scored by both the UCEIS and the Mayo ES were determined. Changes in UCEIS and Mayo ES before and after induction therapy were compared. RESULTS: The mean UCEIS improved from 6.2+/-0.9 to 3.4+/-2.1 (p < 0.001). Based on the UCEIS, a significant reduction was reached in both the response and the remission groups. In contrast, the Mayo ES did not reflect a significant change in the response group. The discrepancy appeared to be due to ulcers becoming smaller and shallower during the early stages of mucosal healing; the Mayo ES seems to miss these early changes. In other words, whereas the UCEIS indicates improvements when ulcers shrink, the Mayo ES does not distinguish deep ulcers from shallow ulcers and is 3 (severe UC) for both deep and shallow ulcers. Additionally, better UCEIS strata after induction therapy were associated with lower incidences of colectomy (p = 0.0001) or relapse (p = 0.0008). CONCLUSIONS: The UCEIS accurately reflects clinical outcomes and predicts the medium- to long term prognosis in UC patients undergoing induction therapy. These findings should support decision-making in clinical practice settings. PMID- 26581897 TI - NHS services will be cut without more funds, finance directors predict. PMID- 26581898 TI - Chemotherapy-induced gut toxicity and pain: involvement of TLRs. AB - PURPOSE: Chemotherapy-induced gut toxicity is associated with significant pain, and pain influences gut function. Toll-like receptors (TLRs) that regulate gut homeostasis are activated by tissue damage and microbes, and their altered expression following chemotherapy may change cellular responses. This study examined the interaction between chemotherapy-induced gut toxicity and pain and related these to gut TLR and glial fibrillary acidic protein (GFAP) expression. METHODS: Female tumor bearing Dark Agouti rats received irinotecan (175 mg/kg, n = 34) or vehicle (n = 5) and were assessed over 120 h for gut toxicity (diarrhea, weight loss), pain (facial), and GFAP, TLR2, 4, 5, and 9 gut expression. RESULTS: Irinotecan caused diarrhea (72 % of animals grade >= 1), weight loss (11.1 +/- 6.6 %, P < 0.0001), and pain (5 (0-5), P < 0.0001) all peaking at 72 h. Higher pain scores were observed in rats with diarrhea versus those without: median (range) of 2.0 (0-5) versus 0 (0-5), P = 0.01. Irinotecan also caused a decrease in TLR4 and 5, and an increase in GFAP expression in jejuna crypt at 96 and 120 h (all P < 0.05); with lower TLR4 expression associated with lower pain (P = 0.012). CONCLUSIONS: The association between gut toxicity and pain suggests these toxicities are linked, possibly via TLR-mediated inflammatory pathways. Further, as TLR4 and 5 expression was absent during recovery in the jejuna and GFAP expression was increased in the jejuna, this implies expression of these may be critical in the healing phase following chemotherapy. Detailed studies of gut TLRs and GFAP are now warranted. PMID- 26581899 TI - Cardiorespiratory fitness and physical activity in children with cancer. AB - PURPOSE: This study assessed cardiorespiratory fitness (CRF), physical activity (PA), and sedentary behavior (SB), as well as factors associated with these outcomes in children during or shortly after cancer treatment. METHODS: Cross sectionally, CRF data, obtained by the cardiopulmonary exercise test, and PA and SB data, obtained by an accelerometer, were assessed in children with cancer (8 18 years old). Linear regression models were used to determine associations between CRF, PA, or SB and patient characteristics. RESULTS: Among 60 children with cancer, mean age 12.6 years, 35 boys, 28 % were during cancer treatment. CRF, reported as the z score of VO2peak, showed that 32 children had a VO2peak z score which was -2 below the predicted value. CRF was significantly associated with PA and SB: each additional activity count per minute resulted in 0.05 ml/kg/min VO2peak increase and each additional minute sedentary reduced VO2peak by 0.06 ml/kg/min. Multiple linear regression models of PA and SB showed that decreased activity was significantly associated with higher age, being fatigued, being during childhood cancer treatment (p < 0.001), or having a higher percentage of fat mass. The multiple linear regression model showed that lower CRF was significantly associated with increased fatigue, being during cancer treatment, having a higher percentage of fat mass, and lower belief of own athletic competence (p < 0.001). CONCLUSION: This study revealed that children during or shortly after cancer treatment have low CRF scores. The most inactive children had a higher fat mass, were fatigued, older, and during childhood cancer treatment. Unexpectedly, treatment-related factors showed no significant association with activity behavior. PMID- 26581900 TI - A qualitative exploration of fear of cancer recurrence (FCR) amongst Australian and Canadian breast cancer survivors. AB - PURPOSE: Few studies have explored coping strategies used by cancer survivors to deal with fear of cancer recurrence (FCR), and little research has been conducted on the specific content of recurrence fears. This study aims to qualitatively explore the strategies used by younger breast cancer survivors to cope with FCR and whether women with low, medium and high levels of FCR employ different coping strategies. An additional aim was to understand the specific content of worst recurrence fears. METHOD: Twenty Australian and 10 Canadian women aged <= 45 years diagnosed with stages 0-II disease at least 1 year prior completed telephone interviews. The transcripts of audio-taped interviews were analysed using the qualitative methodology of transcendental realism. RESULTS: Women with higher FCR described using distraction and avoidance and fewer coping skills. The fear of death was a common worst fear at all levels of FCR. However, participants with higher FCR described more elaborate fears of death often involving themes of pain and suffering. Cross-cultural differences were not observed. CONCLUSIONS: Women with higher FCR report using fewer and more avoidance-based coping techniques. Whilst many participants feared death, those with higher FCR reported more elaborate death fears. Women with high levels of FCR may benefit from learning a greater repertoire of coping skills. Understanding the specific content of FCR can help refine existing psychological treatment protocols for FCR. Implications for FCR treatment are discussed. PMID- 26581901 TI - Mutations in MECOM, Encoding Oncoprotein EVI1, Cause Radioulnar Synostosis with Amegakaryocytic Thrombocytopenia. AB - Radioulnar synostosis with amegakaryocytic thrombocytopenia (RUSAT) is an inherited bone marrow failure syndrome, characterized by thrombocytopenia and congenital fusion of the radius and ulna. A heterozygous HOXA11 mutation has been identified in two unrelated families as a cause of RUSAT. However, HOXA11 mutations are absent in a number of individuals with RUSAT, which suggests that other genetic loci contribute to RUSAT. In the current study, we performed whole exome sequencing in an individual with RUSAT and her healthy parents and identified a de novo missense mutation in MECOM, encoding EVI1, in the individual with RUSAT. Subsequent analysis of MECOM in two other individuals with RUSAT revealed two additional missense mutations. These three mutations were clustered within the 8(th) zinc finger motif of the C-terminal zinc finger domain of EVI1. Chromatin immunoprecipitation and qPCR assays of the regions harboring the ETS like motif that is known as an EVI1 binding site showed a reduction in immunoprecipitated DNA for two EVI1 mutants compared with wild-type EVI1. Furthermore, reporter assays showed that MECOM mutations led to alterations in both AP-1- and TGF-beta-mediated transcriptional responses. These functional assays suggest that transcriptional dysregulation by mutant EVI1 could be associated with the development of RUSAT. We report missense mutations in MECOM resulting in a Mendelian disorder that provide compelling evidence for the critical role of EVI1 in normal hematopoiesis and in the development of forelimbs and fingers in humans. PMID- 26581903 TI - Disruptive SCYL1 Mutations Underlie a Syndrome Characterized by Recurrent Episodes of Liver Failure, Peripheral Neuropathy, Cerebellar Atrophy, and Ataxia. AB - Hereditary ataxias comprise a group of genetically heterogeneous disorders characterized by clinically variable cerebellar dysfunction and accompanied by involvement of other organ systems. The molecular underpinnings for many of these diseases are widely unknown. Previously, we discovered the disruption of Scyl1 as the molecular basis of the mouse mutant mdf, which is affected by neurogenic muscular atrophy, progressive gait ataxia with tremor, cerebellar vermis atrophy, and optic-nerve thinning. Here, we report on three human individuals, from two unrelated families, who presented with recurrent episodes of acute liver failure in early infancy and are affected by cerebellar vermis atrophy, ataxia, and peripheral neuropathy. By whole-exome sequencing, compound-heterozygous mutations within SCYL1 were identified in all affected individuals. We further show that in SCYL1-deficient human fibroblasts, the Golgi apparatus is massively enlarged, which is in line with the concept that SCYL1 regulates Golgi integrity. Thus, our findings define SCYL1 mutations as the genetic cause of a human hepatocerebellar neuropathy syndrome. PMID- 26581902 TI - Leveraging Distant Relatedness to Quantify Human Mutation and Gene-Conversion Rates. AB - The rate at which human genomes mutate is a central biological parameter that has many implications for our ability to understand demographic and evolutionary phenomena. We present a method for inferring mutation and gene-conversion rates by using the number of sequence differences observed in identical-by-descent (IBD) segments together with a reconstructed model of recent population-size history. This approach is robust to, and can quantify, the presence of substantial genotyping error, as validated in coalescent simulations. We applied the method to 498 trio-phased sequenced Dutch individuals and inferred a point mutation rate of 1.66 * 10(-8) per base per generation and a rate of 1.26 * 10( 9) for <20 bp indels. By quantifying how estimates varied as a function of allele frequency, we inferred the probability that a site is involved in non-crossover gene conversion as 5.99 * 10(-6). We found that recombination does not have observable mutagenic effects after gene conversion is accounted for and that local gene-conversion rates reflect recombination rates. We detected a strong enrichment of recent deleterious variation among mismatching variants found within IBD regions and observed summary statistics of local sharing of IBD segments to closely match previously proposed metrics of background selection; however, we found no significant effects of selection on our mutation-rate estimates. We detected no evidence of strong variation of mutation rates in a number of genomic annotations obtained from several recent studies. Our analysis suggests that a mutation-rate estimate higher than that reported by recent pedigree-based studies should be adopted in the context of DNA-based demographic reconstruction. PMID- 26581905 TI - Growing magma chambers control the distribution of small-scale flood basalts. AB - Small-scale continental flood basalts are a global phenomenon characterized by regular spatio-temporal distributions. However, no genetic mechanism has been proposed to explain the visible but overlooked distribution patterns of these continental basaltic volcanism. Here we present a case study from eastern China, combining major and trace element analyses with Ar-Ar and K-Ar dating to show that the spatio-temporal distribution of small-scale flood basalts is controlled by the growth of long-lived magma chambers. Evolved basalts (SiO2 > 47.5 wt.%) from Xinchang-Shengzhou, a small-scale Cenozoic flood basalt field in Zhejiang province, eastern China, show a northward younging trend over the period 9.4-3.0 Ma. With northward migration, the magmas evolved only slightly ((Na2O + K2O)/MgO = 0.40-0.66; TiO2/MgO = 0.23-0.35) during about 6 Myr (9.4-3.3 Ma). When the flood basalts reached the northern end of the province, the magmas evolved rapidly (3.3-3.0 Ma) through a broad range of compositions ((Na2O + K2O)/MgO = 0.60-1.28; TiO2/MgO = 0.30-0.57). The distribution and two-stage compositional evolution of the migrating flood basalts record continuous magma replenishment that buffered against magmatic evolution and induced magma chamber growth. Our results demonstrate that the magma replenishment-magma chamber growth model explains the spatio-temporal distribution of small-scale flood basalts. PMID- 26581904 TI - Physical Effects of Buckwheat Extract on Biological Membrane In Vitro and Its Protective Properties. AB - Buckwheat is a valuable source of many biologically active compounds and nutrients. It has properties that reduce blood cholesterol levels, and so reduces the risk of atherosclerosis, seals the capillaries, and lowers blood pressure. The aim of the study was to determine quantitative and qualitative characteristics of polyphenols contained in extracts from buckwheat husks and stalks, the biological activity of the extracts, and biophysical effects of their interaction with the erythrocyte membrane, treated as a model of the cell. An analysis of the extract's composition has shown that buckwheat husk and stalk extracts are a rich source of polyphenolic compounds, the stalk extracts showing more compounds than the husk extract. The study allowed to determine the location which incorporated polyphenols occupy in the erythrocyte membrane and changes in the membrane properties caused by them. It was found that the extracts do not induce hemolysis of red blood cells, causing an increase in osmotic resistance of erythrocytes. They affect mainly the hydrophilic region by changing the degree of order of the polar heads of lipids, but do little to change the fluidity of the membrane and its hydration. The results showed also that polyphenolic substances included in the extracts well protect the membranes of red blood cells against oxidation and exhibit anti-inflammatory effect. PMID- 26581906 TI - Pluripotency transcription factors in lung cancer-a review. AB - Lung cancer is the leading cause of cancer-related mortality worldwide. Diagnosis of lung cancer in an early stage is still a challenge due to the asymptomatic course of early stages of the disease and the lack of a standard screening program for the population. Nowadays, learning about the mechanisms that lead to cancerogenesis in the lung is crucial for the development of new diagnostic and therapeutic strategies. Recently, many studies have proved that cancer stem cells (CSCs) are responsible for the initiation, progression, metastasis, recurrence, and even resistance of chemo- and radiotherapeutic treatment in patients with lung cancer. The expression of pluripotency transcription factors is responsible for stemness properties. In this review, we summarize the current knowledge on the role of CSCs and pluripotency transcription factors in lung carcinogenesis. PMID- 26581907 TI - miR-93 promotes TGF-beta-induced epithelial-to-mesenchymal transition through downregulation of NEDD4L in lung cancer cells. AB - The level of microRNA-93 (miR-93) in tumors has been recently reported to be negatively correlated with survival of lung cancer patients. Considering that the most devastating aspect of lung cancer is metastasis, which can be promoted by transforming growth factor-beta (TGF-beta)-induced epithelial-to-mesenchymal transition (EMT), we sought to determine whether miR-93 is involved in this process. Here, we report that a previously unidentified target of miR-93, neural precursor cell expressed developmentally downregulated gene 4-like (NEDD4L), is able to mediate TGF-beta-mediated EMT in lung cancer cells. miR-93 binds directly to the 3'-UTR of the NEDD4L messenger RNA (mRNA), leading to a downregulation of NEDD4L expression at the protein level. We next demonstrated that the downregulation of NEDD4L enhanced, while overexpression of NEDD4L reduced TGF beta signaling, reflected by increased phosphorylation of SMAD2 in the lung cancer cell line after TGF-beta treatment. Furthermore, overexpression of miR-93 in lung cancer cells promoted TGF-beta-induced EMT through downregulation of NEDD4L. The analysis of publicly available gene expression array datasets indicates that low NEDD4L expression correlates with poor outcomes among patients with lung cancer, further supporting the oncogenic role of miR-93 in lung tumorigenesis and metastasis. PMID- 26581908 TI - Anti-cancer effect of metformin by suppressing signaling pathway of HER2 and HER3 in tamoxifen-resistant breast cancer cells. AB - Development of new therapeutic strategies is becoming increasingly important to overcome tamoxifen resistance. Recently, much interest has been focused on anti tumor effects of metformin commonly used to treat type II diabetes. Increased protein expression and signaling of epidermal growth factor receptor (EGFR) family is a possible mechanism involved in tamoxifen resistance. Since HER2/HER3 heterodimers are able to induce strong downstream signaling and activate various biological responses such as cellular proliferation and growth, we investigated the anti-cancer effect of metformin by inhibition of signaling pathway via downregulation of HER2 and HER3 using tamoxifen-resistant MCF-7 (TR MCF-7) cells. Compared to MCF-7 cells, TR MCF-7 cells showed increased expression of EGFR, HER2, and HER3, and metformin inhibited the expression of these proteins in a dose- and time-dependent manner. Metformin inhibited activation of HER2 (Tyr1248)/HER3 (Tyr1289)/Akt (Ser473) as well as cell proliferation and colony formation by estrogenic promotion in MCF-7 and TR MCF-7 cells. Known as a HER3 ligand, heregulin (HRG)-beta1-induced phosphorylation of HER2, HER3 and Akt, and protein interaction of HER2/HER3 and colony formation were inhibited by metformin in both cells. Consistent with the results in the two cell lines, we identified that metformin inhibited HER2/HER3/Akt signaling axis activated by HRG-beta1 using the HER2 and HER3-overexpressing breast cancer cell line SK-BR-3. Lastly, lapatinib-induced HER3 upregulation was significantly inhibited by treatment of metformin in HER3 siRNA-transfected TR MCF-7 cells. These data suggest that metformin might overcome tamoxifen resistance through the inhibition of expression and signaling of receptor tyrosine kinase HER2 and HER3. PMID- 26581909 TI - MicroRNA-15a-5p suppresses cancer proliferation and division in human hepatocellular carcinoma by targeting BDNF. AB - We examined the expression pattern and functional roles of microRNA 15a-5p (miR 15a-5p) in human hepatocellular carcinoma (HCC). Possible miR-15a-5p aberrant expression in HCC cell lines or clinical HCC specimens was examined by quantitative real-time PCR (qRT-PCR). In HCC HepG2 and SNU-182 cells, miR-15a-5p was ectopically overexpressed by lentiviral transduction. Its effect on HCC proliferation, cancer division, and in vivo tumor growth were examined by 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, cell cycle assay, and tumorigenicity assay, respectively. The targeting of miR-15a-5p on its downstream gene, brain-derived neurotrophic factor (BDNF), was examined by dual luciferase assay, qRT-PCR, and Western blot, respectively. BDNF was then overexpressed in HepG2 and SNU-182 cells to evaluate its selective effect on miR 15a-5p in HCC modulation. MiR-15a-5p is aberrantly downregulated in in vitro HCC cell lines and in vivo HCC clinical specimens. Ectopic overexpression of miR-15a 5p suppressed cancer proliferation, induced cell cycle arrest in HepG2 or SNU-182 cells in vitro, and inhibited HCC tumor growth in vivo. MiR-15a-5p selectively and negatively regulated BDNF at both gene and protein levels in HCC cells. Forced overexpression of BDNF effectively reversed the tumor suppressive functions of miR-15a-5p on HCC proliferation and cell division in vitro. Our study demonstrated that miR-15a-5p is a tumor suppressor in HCC and its regulation is through BDNF in HCC. PMID- 26581910 TI - MicroRNA-143 replenishment re-sensitizes colorectal cancer cells harboring mutant, but not wild-type, KRAS to paclitaxel treatment. AB - Colorectal cancer (CRC) global incidence is one of the highest among cancers. The KRAS gene has been shown as a robust biomarker for poor prognosis and drug resistance. MicroRNA-143 (miR-143) and let-7 are families of tumor suppressor microRNAs that are often downregulated in CRC, especially with coexistent KRAS mutations. In order to evaluate if miR-143 and/or let-7b replenishment would re sensitize CRC cells to paclitaxel treatment, we investigated in effect of miR-143 and let-7b replenishments on sensitivity to paclitaxel treatment in KRAS mutant LoVo and wild-type SW48 CRC cell lines. Our results showed that miR-143, but not let-7b, increased sensitization of KRAS mutant tumor cells to paclitaxel. Furthermore, transfection of miR-143, but not let-7b, mimic negatively regulated the expression of mutant but not wild-type KRAS. Combination of miR-143 mimic and paclitaxel induced the onset of apoptosis, and reverted in vitro metastatic properties (migration and invasion) in KRAS mutant tumor cells. MiR-143 thus can be used as a chemosensitizer for the treatment of KRAS mutant tumors and warrants further investigations in in vitro and pre-clinical in vivo models. PMID- 26581911 TI - Influence of aging and growth hormone on different members of the NFkB family and IkB expression in the heart from a murine model of senescence-accelerated aging. AB - Inflammation is related to several pathological processes. The aim of this study was to investigate the protein expression of the different subunits of the nuclear factor Kappa b (NFkBp65, p50, p105, p52, p100) and the protein expressions of IkB beta and alpha in the hearts from a murine model of accelerated aging (SAM model) by Western blot. In addition, the translocation of some isoforms of NFkB from cytosol to nuclei (NFkBp65, p50, p52) and ATP level content was studied. In addition we investigated the effect of the chronic administration of growth hormone (GH) on these age-related parameters. SAMP8 and SAMR1 mice of 2 and 10 months of age were used (n = 30). Animals were divided into five experimental groups: 2 old untreated (SAMP8/SAMR1), 2 young control (SAMP8/SAMR1) and one GH treated-old groups (SAMP8). Age-related changes were found in the studied parameters. We were able to see decreases of ATP level contents and the translocation of the nuclear factor kappa B p50, p52 and p65 from cytosol to nuclei in old SAMP8 mice together with a decrease of IKB proteins. However p100 and p105 did not show differences with aging. No significant changes were recorded in SAMR1 animals. GH treatment showed beneficial effects in old SAMP8 mice inducing an increase in ATP levels and inhibiting the translocation of some NFkB subunits such as p52. Our results supported the relation of NFkB activation with enhanced apoptosis and pro inflammatory status in old SAMP8 mice and suggested a selective beneficial effect of the GH treatment, which was able to partially reduce the incidence of some deleterious changes in the heart of those mice. PMID- 26581912 TI - Brain activation-based sexual orientation in female-to-male transsexuals. AB - This study was performed to identify the sexual orientation in association with brain activation pattern in response to visual erotic stimuli in female-to-male (FtM) transsexuals by using functional magnetic resonance imaging (fMRI). Eleven FtM transsexuals who have had sex-reassignment surgery to alter their natal bodies with the gender-identity disorder were participated. Brain activation for sexual orientation was induced by visual stimuli with female and male erotic nude pictures compared with emotionally-neutral pictures. During viewing the erotic female pictures, the brain areas dominantly activated consist of the superior frontal gyrus, supplementary motor area, anterior/median cingulate gyri and hypothalamus, whereas during viewing male pictures, the brain areas with predominant activities were the middle frontal gyrus, precentral gyrus, middle temporal gyrus, fusiform gyrus, angular gyrus, precuneus, superior/middle occipital gyri, cerebellar cortex and vermis. These findings demonstrate that the brain activation patterns induced by viewing male or female erotic pictures show some correlation to the sexual orientation opposite to the genetic sex in FtM transsexuals. This study would be helpful to understand the neural mechanism associated with visual sexual arousal in patients with gender disorder. PMID- 26581913 TI - Effects of low sleep quality on sexual function, in women with fibromyalgia. AB - Sexual dysfunction is a common experience in women with fibromyalgia. However, the physiopathology of this association is unclear. We aimed to evaluate whether sleep disturbance has an influence on sexual function in women with fibromyalgia. Fifty-four sexually active premenopausal women with fibromyalgia were enrolled in the study. The following questionnaires were used: the Female Sexual Function Index (FSFI), the Pittsburgh Sleep Quality Index (PSQI), the Fibromyalgia Impact Questionnaire (FIQ) and the Beck Depression Inventory (BDI). Appropriate statistical analyses were used by using SPSS 18. The mean FSFI score was 25.344 +/- 6.52 and showed no correlation with age, body mass index, BDI or duration of fibromyalgia. However, a positive correlation between sexual dysfunction and low sleep quality was found (r=0.43; P=0.001). In addition, the median FSFI score was 29.2 (27.2-32.4) in patients with higher sleep quality (PSQI?5), whereas it was 21.4 (18.9-25.3) in patients with lower sleep quality (PSQI>5) (P<0.001). There was a positive correlation between sexual dysfunction and symptoms of fibromyalgia as indicated by a higher FIQ score (r=0.37; P=0.006). Sexual dysfunction in female patients with fibromyalgia may be due to low sleep quality. Treatment of the sleep disorder may improve female sexual function. PMID- 26581916 TI - Season of birth shapes neonatal immune function. AB - BACKGROUND: Birth season has been reported to be a risk factor for several immune mediated diseases. We hypothesized that this association is mediated by differential changes in neonatal immune phenotype and function with birth season. OBJECTIVE: We sought to investigate the influence of season of birth on cord blood immune cell subsets and inflammatory mediators in neonatal airways. METHODS: Cord blood was phenotyped for 26 different immune cell subsets, and at 1 month of age, 20 cytokines and chemokines were quantified in airway mucosal lining fluid. Multivariate partial least squares discriminant analyses were applied to determine whether certain immune profiles dominate by birth season, and correlations between individual cord blood immune cells and early airway immune mediators were defined. RESULTS: We found a birth season-related fluctuation in neonatal immune cell subsets and in early-life airway mucosal immune function. The seasonal airway immune pattern was associated with the number of activated and regulatory T cells in cord blood whereas it was independent of concomitant presence of pathogenic airway microbes. Specifically, summer newborns presented with the lowest levels of all cell types and mediators; fall newborns displayed high levels of activated T cells and mucosal IL-12p70, TNF-alpha, IL-13, IL-10, and IL-2; and winter newborns had the highest levels of innate immune cells, IL-5, type 17-related immune mediators, and activated T cells. CONCLUSION: Birth season fluctuations seem to affect neonatal immune development and result in differential potentiation of cord blood immune cells and early airway mucosal immune function. PMID- 26581915 TI - A randomized, double-blind, placebo-controlled study of omalizumab combined with oral immunotherapy for the treatment of cow's milk allergy. AB - BACKGROUND: Although studies of oral immunotherapy (OIT) for food allergy have shown promise, treatment is frequently complicated by adverse reactions and, even when successful, has limited long-term efficacy because benefits usually diminish when treatment is discontinued. OBJECTIVE: We sought to examine whether the addition of omalizumab to milk OIT reduces treatment-related reactions, improves outcomes, or both. METHODS: This was a double-blind, placebo-controlled trial with subjects randomized to omalizumab or placebo. Open-label milk OIT was initiated after 4 months of omalizumab/placebo with escalation to maintenance over 22 to 40 weeks, followed by daily maintenance dosing through month 28. At month 28, omalizumab was discontinued, and subjects passing an oral food challenge (OFC) continued OIT for 8 weeks, after which OIT was discontinued with rechallenge at month 32 to assess sustained unresponsiveness (SU). RESULTS: Fifty seven subjects (7-32 years) were randomized, with no significant baseline differences in age, milk-specific IgE levels, skin test results, or OFC results. At month 28, 24 (88.9%) omalizumab-treated subjects and 20 (71.4%) placebo treated subjects passed the 10-g "desensitization" OFC (P = .18). At month 32, SU was demonstrated in 48.1% in the omalizumab group and 35.7% in the placebo group (P = .42). Adverse reactions were markedly reduced during OIT escalation in omalizumab-treated subjects for percentages of doses per subject provoking symptoms (2.1% vs 16.1%, P = .0005), dose-related reactions requiring treatment (0.0% vs 3.8%, P = .0008), and doses required to achieve maintenance (198 vs 225, P = .008). CONCLUSIONS: In this first randomized, double-blind, placebo controlled trial of omalizumab in combination with food OIT, we found significant improvements in measurements of safety but not in outcomes of efficacy (desensitization and SU). PMID- 26581914 TI - Nonreceptor tyrosine kinases ITK and BTK negatively regulate mast cell proinflammatory responses to lipopolysaccharide. AB - BACKGROUND: Mast cells are indispensable for LPS-induced septic hypothermia, in which TNF-alpha plays an essential role to initiate septic responses. ITK and BTK regulate mast cell responses to allergens, but their roles in mast cell responses in LPS-induced sepsis are unclear. OBJECTIVE: We sought to investigate the roles of ITK and BTK in mast cell responses during LPS-induced septic inflammation. METHODS: Mice (genetically modified or bone marrow-derived mast cell reconstituted Sash) were given LPS to induce septic hypothermia in the presence or absence of indicated inhibitors. Flow cytometry was used to determine LPS induced cell influx and TNF-alpha production in peritoneal cells. Microarray was used for genomewide gene expression analysis on bone marrow-derived mast cells. Quantitative PCR and multiplex were used to determine transcribed and secreted proinflammatory cytokines. Microscopy and Western blotting were used to determine activation of signal transduction pathways. RESULTS: The absence of ITK and BTK leads to exacerbation of LPS-induced septic hypothermia and neutrophil influx. Itk(-/-)Btk(-/-) mast cells exhibit hyperactive preformed and LPS-induced TNF alpha production, and lead to more severe LPS-induced septic hypothermia when reconstituted into mast cell-deficient Sash mice. LPS-induced nuclear factor kappa B, Akt, and p38 activation is enhanced in Itk(-/-)Btk(-/-) mast cells, and blockage of phosphatidylinositol-4,5-bisphosphate 3-kinase, Akt, or p38 downstream mitogen-activated protein kinase interacting serine/threonine kinase 1 activation significantly suppresses TNF-alpha hyperproduction and attenuates septic hypothermia. CONCLUSIONS: ITK and BTK regulate thermal homeostasis during septic response through mast cell function in mice. They share regulatory function downstream of Toll-like receptor 4/LPS in mast cells, through regulating the activation of canonical nuclear factor kappa B, phosphatidylinositol-4,5 bisphosphate 3-kinase/Akt, and p38 signaling pathways. PMID- 26581918 TI - The Association Between Serum Selenium Levels with Rheumatoid Arthritis. AB - There are conflicting reports on the correlation between serum selenium (Se) levels with rheumatoid arthritis (RA). Through a meta-analysis approach, the aim of the present study is to clarify the relationship between serum Se levels with RA. We searched literatures that met our predefined criteria in PubMed, ScienceDirect, and OVID published as of September 2015. Ten eligible articles with 14 case-control studies involving 716 subjects were identified. Overall, pooled analysis indicated that subjects with RA had lower serum levels of Se than the healthy controls (standardized mean difference (SMD) = -1.347, 95 % confidence interval (CI) = [-1.872, -0.823], p < 0.001). Further subgroup analysis indicated that subjects with RA had lower serum Se levels than healthy controls in Europe (SMD = -1.063, 95 % CI = [-1.571, -0.556], p < 0.001) and Asia (SMD = -3.254, 95 % CI = [-4.687, -1.821], p < 0.001) but not in USA (SMD = 0.322, 95 % CI = [-0.657, 0.012], p = 0.059). The serum Se levels were lower in RA than healthy controls measured by graphite furnace atom absorption spectrometry (GFAAS) (SMD = -1.026, 95 % CI = [-1.522, -0.530], p < 0.001), electrothermal absorption spectrometry (EAS) (SMD = -1.197, 95 % CI = [-2.373, 0.020], p < 0.05), flame atomic absorption spectrophotometry (FAAS) (SMD = 0.681, 95 % CI = [-1.049, -0.313], p < 0.001), and inductively coupled plasma mass spectrophotometer (ICP-MS) (SMD = -11.707, 95 % CI = [-15.189, -8.224], p < 0.001) but not by neutron activation analysis (NAA) (SMD = -0.674, 95 % CI = [ 1.350, 0.003], p = 0.051). In conclusion, this meta-analysis supports a significant association between low serum Se concentration with RA. However, this finding needs further confirmation by a trans-regional multicenter study to obtain better understanding of causal relationship between serum Se with RA of different human races or regions. PMID- 26581917 TI - Sensitization phenotypes based on protein groups and associations to allergic diseases in children. PMID- 26581919 TI - Innate and adaptive immune responses in migrating spring-run adult chinook salmon, Oncorhynchus tshawytscha. AB - Adult Chinook salmon (Oncorhynchus tshawytscha) migrate from salt water to freshwater streams to spawn. Immune responses in migrating adult salmon are thought to diminish in the run up to spawning, though the exact mechanisms for diminished immune responses remain unknown. Here we examine both adaptive and innate immune responses as well as pathogen burdens in migrating adult Chinook salmon in the Upper Willamette River basin. Messenger RNA transcripts encoding antibody heavy chain molecules slightly diminish as a function of time, but are still present even after fish have successfully spawned. In contrast, the innate anti-bacterial effector proteins present in fish plasma rapidly decrease as spawning approaches. Fish also were examined for the presence and severity of eight different pathogens in different organs. While pathogen burden tended to increase during the migration, no specific pathogen signature was associated with diminished immune responses. Transcript levels of the immunosuppressive cytokines IL-10 and TGF beta were measured and did not change during the migration. These results suggest that loss of immune functions in adult migrating salmon are not due to pathogen infection or cytokine-mediated immune suppression, but is rather part of the life history of Chinook salmon likely induced by diminished energy reserves or hormonal changes which accompany spawning. PMID- 26581921 TI - Idarucizumab approved for reversal of anticoagulant effects of dabigatran. PMID- 26581920 TI - Bringing Health and Fitness Data Together for Connected Health Care: Mobile Apps as Enablers of Interoperability. AB - BACKGROUND: A transformation is underway regarding how we deal with our health. Mobile devices make it possible to have continuous access to personal health information. Wearable devices, such as Fitbit and Apple's smartwatch, can collect data continuously and provide insights into our health and fitness. However, lack of interoperability and the presence of data silos prevent users and health professionals from getting an integrated view of health and fitness data. To provide better health outcomes, a complete picture is needed which combines informal health and fitness data collected by the user together with official health records collected by health professionals. Mobile apps are well positioned to play an important role in the aggregation since they can tap into these official and informal health and data silos. OBJECTIVE: The objective of this paper is to demonstrate that a mobile app can be used to aggregate health and fitness data and can enable interoperability. It discusses various technical interoperability challenges encountered while integrating data into one place. METHODS: For 8 years, we have worked with third-party partners, including wearable device manufacturers, electronic health record providers, and app developers, to connect an Android app to their (wearable) devices, back-end servers, and systems. RESULTS: The result of this research is a health and fitness app called myFitnessCompanion, which enables users to aggregate their data in one place. Over 6000 users use the app worldwide to aggregate their health and fitness data. It demonstrates that mobile apps can be used to enable interoperability. Challenges encountered in the research process included the different wireless protocols and standards used to communicate with wireless devices, the diversity of security and authorization protocols used to be able to exchange data with servers, and lack of standards usage, such as Health Level Seven, for medical information exchange. CONCLUSIONS: By limiting the negative effects of health data silos, mobile apps can offer a better holistic view of health and fitness data. Data can then be analyzed to offer better and more personalized advice and care. PMID- 26581922 TI - Pharmacists can improve COPD care. PMID- 26581923 TI - FDA approves patiromer for nonemergent hyperkalemia. PMID- 26581924 TI - Summaries of Safety Labeling Changes Approved By FDA--Boxed Warnings Highlights July--September 2015. PMID- 26581925 TI - Pharmacy leader Toby Clark dies at 71. PMID- 26581926 TI - Organization promoting optimal medication use. PMID- 26581927 TI - Communication between the pharmacy and the emergency department to facilitate alteplase delivery for patients with stroke. PMID- 26581928 TI - Use of an electronic clinical scoring system to prioritize patients' medication monitoring needs. PMID- 26581929 TI - Empathy and the new practitioner. PMID- 26581930 TI - Celebrating 50 ASHP Midyear Clinical Meetings. PMID- 26581931 TI - Executive leadership: Critical to developing clinical pharmacy programs and services. PMID- 26581932 TI - Probable fenofibrate-induced acute generalized exanthematous pustulosis. AB - PURPOSE: The case of a patient who experienced a severe adverse reaction requiring emergency treatment after a single dose of fenofibrate is described. SUMMARY: A 58-year-old woman with type 1 diabetes was hospitalized for treatment of an extensive blistering rash on the buttocks and trunk accompanied by fever, hypotension, tachycardia, neutrophilia, impaired renal function, and liver enzyme abnormalities. She reported that two days previously she had developed fever and vomiting four hours after taking her first dose of fenofibrate (145 mg). The patient required vasopressor support and was initially treated with broad spectrum antibiotics for 3 days and a course of immune globulin. On hospital day 4, histopathology returned results consistent with acute generalized exanthematous pustulosis (AGEP), and the patient was subsequently treated with topical steroids. Gradual resolution of AGEP was noted at the time of her discharge from the hospital on day 7 and at one-week follow-up. Analysis of the case using the adverse drug reaction probability scale of Naranjo et al. yielded a score of 5, indicating a probable association between fenofibrate use and AGEP development. AGEP is a predominantly drug-induced condition but is not typically associated with fenofibrate use. Cutaneous eruptions in AGEP are often accompanied by systemic symptoms (e.g., fever, leukocytosis), and the disorder can also be associated with impaired creatinine clearance and elevated aminotransaminase levels. CONCLUSION: A woman with type 1 diabetes developed AGEP after taking a single dose of fenofibrate. Her cutaneous symptoms began to resolve within days of discontinuation of fenofibrate use. PMID- 26581933 TI - Comparison and alignment of an academic medical center's strategic goals with ASHP initiatives. AB - PURPOSE: An academic medical center's strategic goals were compared and aligned with the 2015 ASHP Health-System Pharmacy Initiative and the Pharmacy Practice Model Initiative (PPMI). METHODS: The department's pharmacy practice model steering committee identified potential solutions to narrow prioritized gaps using a modified nominal group technique and a multivoting dot technique. RESULTS: Five priority solutions were identified and assigned to work groups to develop business plans, which included admission medication history and reconciliation for high-risk patients and those with complex medication regimens, pharmacist provision of discharge counseling to high-risk patients and those with complex medication regimens, improved measurement and reporting of the impact of PPMI programs on patient outcomes, implementation of a departmentwide formalized peer review and evaluation process, and the greeting of every patient at some time during his or her visit by a pharmacy team member. Stakeholders evaluated the business plans based on feasibility, financial return on investment, and anticipated safety enhancements. The solution that received the highest priority ranking and was subsequently implemented was "improved measurement and reporting of the impact of PPMI programs on patient outcomes." CONCLUSION: A defined process was followed for identifying gaps among current practices at an academic medical center and the 2015 ASHP Health-System Pharmacy Initiative and the PPMI. A key priority to better document the impact of pharmacists on patient care was identified for our department by using a nominal group technique brainstorming process and a multivoting dot technique and creating standardized business plans for five potential priority projects. PMID- 26581935 TI - Evolution of ambulatory care pharmacy practice in the past 50 years. PMID- 26581936 TI - Emergency medicine pharmacy: Still a new clinical frontier. PMID- 26581934 TI - Development of an opioid reduction protocol in an emergency department. AB - PURPOSE: Results of a study of an opioid-sparing protocol for acute pain management in the emergency department (ED) are reported. METHODS: The ED of a large hospital conducted a project, the "Opioid-Free Shift," to test a multimodal pharmacologic approach to analgesic therapy as an alternative to routine use of opioids. During a specified eight-hour period, all adults arriving at the ED with a complaint of pain were treated according to an opioid-sparing protocol based on principles of channel enzyme receptor-targeted analgesia (CERTA). Pain severity was assessed at baseline and at 30 and 60 minutes after analgesia administration using a validated rating scale. RESULTS: Seventeen patients were treated in the ED for acute or chronic pain during the study period. The median pain score on the 11-point rating scale was 8 (range, 4-10) at baseline, declining to 6 (range, 0-10) at 30 minutes and to 5 (range, 1-10) at 60 minutes. At 30 minutes, 7 patients (41%) had a pain score reduction of >= 30% and 3 (18%) had a reduction of >= 50%. Six of the 15 patients (40%) reassessed at 60 minutes had a pain score reduction of >= 30%; 4 patients (27%) had a reduction of >= 50%. More than 80% of patients were satisfied with the pain relief provided through the CERTA-based protocol, and no adverse drug reactions were reported. CONCLUSION: The 17 patients treated for acute or chronic pain during the opioid-free shift were managed mainly with i.v. ketorolac and oral ibuprofen, with only 1 patient requiring rescue opioid therapy. PMID- 26581937 TI - Advances in oncology pharmacy practice. PMID- 26581938 TI - History and future of critical care pharmacy practice. PMID- 26581939 TI - The Ninth-Floor Pharmacy Project at the University of California, San Francisco: A seminal development in clinical pharmacy. PMID- 26581940 TI - Summaries of Safety Labeling Changes Approved By FDA-Boxed Warnings Highlights July-September 2015. PMID- 26581941 TI - Top thinkers talk innovations and aging. PMID- 26581942 TI - Size Dependent Plasmonic Effect on BiVO4 Photoanodes for Solar Water Splitting. AB - Plasmonic nanostructures show great promise in enhancing the solar water splitting efficiency due to their ability to confine light to extremely small volumes inside semiconductors. While size plays a critical role in the plasmonic performance of Au nanoparticles (AuNPs), its influence on plasmon-assisted water splitting is still not fully understood. This holds especially true for low band gap semiconductors, for which interband excitations occur in wavelength regions that overlap with plasmonic resonances. Here, BiVO4 films are modified with AuNPs of diameters varying from 10 to 80 nm to study the size dependence of the plasmonic effect. Plasmon resonance energy transfer (PRET) is found to be the dominant effect in enhancing the water splitting efficiency of BiVO4. "Hot electron" injection effect is weak in the case of BiVO4/AuNP. This is attributed to the interband excitation of BiVO4, which is unfavourable for the hot electrons accumulation in BiVO4 conduction band. The resonant scattering effect also contributes to the enhanced water splitting efficiency for the larger diameter AuNPs. It is also for the first time found that higher PRET effect can be achieved at larger off-normal irradiation angle. PMID- 26581944 TI - Development of a Type I gluten-free sourdough. AB - The aim of this study was the setting up of a gluten-free sourdough from selected lactobacilli and yeasts isolated from a traditional wheat-based Type I sourdough. A gluten-free matrix was inoculated with Lactobacillus sanfranciscensis and Candida humilis, fermented to pH 4.0, and constantly propagated for ten times. A stable association between micro-organisms was observed from the second refreshment with mean values of 9.08 +/- 0.25 log CFU g(-1) for lactobacilli and 7.81 +/- 0.07 log CFU g(-1) for yeasts. In order to have a good workability of the dough, a 230 BU consistency was considered. Rheofermentographic indices remained constant over the ten refreshments, showing an average value of 23.2 mm dough height in about 7.5 h. The CO2 production and retention volumes reached average values of 1430 and 1238 ml respectively. The microbiological and technological data obtained highlighted that a GF sourdough was effectively developed. SIGNIFICANCE AND IMPACT OF THE STUDY: Type I sourdough has a long tradition as a leavening agent of baked goods as its use results in an improved texture, flavour, taste and extended shelf-life of the final products. In this study a Type I gluten-free sourdough was obtained. After few refreshments in controlled conditions, the sourdough presented a stable association between Lactobacillus sanfranciscensis and Candida humilis, constant fermentation times and technological properties (in terms of dough consistency, dough maximum height, CO2 production and retention). The results showed that the gluten-free sourdough developed in this study can improve the overall quality of gluten-free baked products. PMID- 26581945 TI - Neural Discriminability of Object Features Predicts Perceptual Organization. AB - How does the neural representation of simple visual features affect perceptual operations, such as perceptual grouping? If the strength of feature representations in the brain is indicative of how the perceptual system partitions information into visual elements, then identifying the underlying neural representation may determine why things look the way they do. During functional MRI, participants viewed objects that varied along three feature dimensions: shape, color, and orientation. Afterward, participants performed an independent perceptual-grouping task outside the scanner to measure the strength of feature grouping. In lateral occipital cortex, neural feature discriminability, characterized using functional MRI multivariate pattern classification, positively predicted feature grouping strength: The more distinct the neural representations of a particular feature, the stronger the grouping was for that feature outside the scanner. Thus, variation in neural feature representation can be quantified to predict perceptual organization. PMID- 26581946 TI - Virtues, Vices, and Political Influence in the U.S. Senate. AB - What qualities make a political leader more influential or less influential? Philosophers, political scientists, and psychologists have puzzled over this question, positing two opposing routes to political power--one driven by human virtues, such as courage and wisdom, and the other driven by vices, such as Machiavellianism and psychopathy. By coding nonverbal behaviors displayed in political speeches, we assessed the virtues and vices of 151 U.S. senators. We found that virtuous senators became more influential after they assumed leadership roles, whereas senators who displayed behaviors consistent with vices- particularly psychopathy--became no more influential or even less influential after they assumed leadership roles. Our results inform a long-standing debate about the role of morality and ethics in leadership and have important implications for electing effective government officials. Citizens would be wise to consider a candidate's virtue in casting their votes, which might increase the likelihood that elected officials will have genuine concern for their constituents and simultaneously promote cooperation and progress in government. PMID- 26581947 TI - What Comes After /f/? Prediction in Speech Derives From Data-Explanatory Processes. AB - Acoustic cues are short-lived and highly variable, which makes speech perception a difficult problem. However, most listeners solve this problem effortlessly. In the present experiment, we demonstrated that part of the solution lies in predicting upcoming speech sounds and that predictions are modulated by high level expectations about the current sound. Participants heard isolated fricatives (e.g., "s," "sh") and predicted the upcoming vowel. Accuracy was above chance, which suggests that fine-grained detail in the signal can be used for prediction. A second group performed the same task but also saw a still face and a letter corresponding to the fricative. This group performed markedly better, which suggests that high-level knowledge modulates prediction by helping listeners form expectations about what the fricative should have sounded like. This suggests a form of data explanation operating in speech perception: Listeners account for variance due to their knowledge of the talker and current phoneme, and they use what is left over to make more accurate predictions about the next sound. PMID- 26581948 TI - Working with difference: Thematic concepts of Japanese nurses working in New Zealand. AB - The purpose of this study was to compare the differences experienced by Japanese nurses working in New Zealand from an organizational and personal perspective, using a qualitative approach. Interview data was analyzed using a thematic method to abstract increasing levels of themes until one main theme explained the data: finding a voice. This core theme demonstrated that Japanese nurses had to learn to accommodate difference while learning to speak up. Moreover, this needed to occur through a number of cultural filters. The principal conclusion was that migrant nurses face multiple personal and organizational challenges when working in a new environment. Finding a voice is the method in which nurses learn to communicate and work within new healthcare settings. Nurses use a number of filters to manage the transition. The host country needs to recognize these differences and accommodate them through orientation modules. PMID- 26581949 TI - Metabolic changes in transgenic maize mature seeds over-expressing the Aspergillus niger phyA2. AB - KEY MESSAGE: Non-targeted metabolomics analysis revealed only intended metabolic changes in transgenic maize over-expressing the Aspergillus niger phyA2. Genetically modified (GM) crops account for a large proportion of modern agriculture worldwide, raising increasingly the public concerns of safety. Generally, according to substantial equivalence principle, if a GM crop is demonstrated to be equivalently safe to its conventional species, it is supposed to be safe. In this study, taking the advantage of an established non-target metabolomic profiling platform based on the combination of UPLC-MS/MS with GC-MS, we compared the mature seed metabolic changes in transgenic maize over-expressing the Aspergillus niger phyA2 with its non-transgenic counterpart and other 14 conventional maize lines. In total, levels of nine out of identified 210 metabolites were significantly changed in transgenic maize as compared with its non-transgenic counterpart, and the number of significantly altered metabolites was reduced to only four when the natural variations were taken into consideration. Notably, those four metabolites were all associated with targeted engineering pathway. Our results indicated that although both intended and non intended metabolic changes occurred in the mature seeds of this GM maize event, only intended metabolic pathway was found to be out of the range of the natural metabolic variation in the metabolome of the transgenic maize. Therefore, only when natural metabolic variation was taken into account, could non-targeted metabolomics provide reliable objective compositional substantial equivalence analysis on GM crops. PMID- 26581950 TI - Glutathione homeostasis and Cd tolerance in the Arabidopsis sultr1;1-sultr1;2 double mutant with limiting sulfate supply. AB - KEY MESSAGE: Cadmium sensitivity in sultr1;1 - sultr1;2 double mutant with limiting sulfate supply is attributed to the decreased glutathione content that affected oxidative defense but not phytochelatins' synthesis. In plants, glutathione (GSH) homeostasis plays pivotal role in cadmium (Cd) detoxification. GSH is synthesized by sulfur (S) assimilation pathway. Many studies have tried to investigate the role of GSH homeostasis on Cd tolerance using mutants; however, most of them have focused on the last few steps of S assimilation. Until now, mutant evidence that explored the relationship between GSH homeostasis on Cd tolerance and S absorption is rare. To further reveal the role of GSH homeostasis on Cd stress, the wild-type and a sultr1;1-sultr1;2 double mutant which had a defect in two distinct high-affinity sulfate transporters were used in this study. Growth parameters, biochemical or zymological indexes and S assimilation related genes' expression were compared between the mutant and wild-type Arabidopsis plants. It was found that the mutations of SULTR1;1 and SULTR1;2 did not affect Cd accumulation. Compared to the wild-type, the double mutant was more sensitive to Cd under limited sulfate supply and suffered from stronger oxidative damage. More importantly, under the same condition, lower capacity of S assimilation resulted in decreased GSH content in mutant. Faced to the limited GSH accumulation, mutant seedlings consumed a large majority of GSH in pool for the synthesis of phytochelatins rather than participating in the antioxidative defense. Therefore, homeostasis of GSH, imbalance between antioxidative defense and severe oxidative damage led to hypersensitivity of double mutant to Cd under limited sulfate supply. PMID- 26581951 TI - Enhancement of naphthalene tolerance in transgenic Arabidopsis plants overexpressing the ferredoxin-like protein (ADI1) from rice. AB - KEY MESSAGE: The ADI1 Arabidopsis plants enhanced tolerance and degradation efficiency to naphthalene and had great potential for phytoremediation of naphthalene in the plant material before composting or harvesting and removal. Naphthalene is a global environmental concern, because this substance is assumed to contribute considerably to human cancer risk. Cleaning up naphthalene contamination in the environment is crucial. Phytoremediation is an efficient technology to clean up contaminants. However, no gene that can efficiently degrade exogenous recalcitrant naphthalene in plants has yet been discovered. Ferredoxin (Fd) is a key player of biological electron transfer reaction in the PAH degradation process. The biochemical pathway for bacterial degradation of naphthalene has been well investigated. In this study, a rice gene, ADI1, which codes for a putative photosynthetic-type Fd, has been transformed into Arabidopsis thaliana. The transgenic Arabidopsis plants enhanced tolerance and degradation efficiency of naphthalene. Compared with wild-type plants, transgenic plants assimilated naphthalene from the culture media faster and removed more of this substance. When taken together, our findings suggest that breeding plants with overexpressed ADI1 gene is an effective strategy to degrade naphthalene in the environment. PMID- 26581952 TI - An aquaporin gene from halophyte Sesuvium portulacastrum, SpAQP1, increases salt tolerance in transgenic tobacco. AB - KEY MESSAGE: SpAQP1 was strongly induced by salt in an ABA-independent way, promoted seed germination and root growth in transgenic tobaccos and increased salt tolerance by increasing the activities of antioxidative enzymes. Aquaporin (AQP) plays crucial roles in the responses of plant to abiotic stresses such as drought, salt and cold. Compared to glycophytes, halophytes often have excellent salt and drought tolerances. To uncover the molecular mechanism of halophyte Sesuvium portulacastrum tolerance to salt, in this study, an AQP gene, SpAQP1, from S. portulacastrum was isolated and characterized. The amino acid sequence of SpAQP1 shared high homology with that of plant plasma membrane intrinsic proteins (PIPs) and contained the distinct molecular features of PIPs. In the phylogenic tree, SpAQP1 was evidently classified as the PIP2 subfamily. SpAQP1 is expressed in roots, stems and leaves, and was significantly induced by NaCl treatment and inhibited by abscisic acid (ABA) treatment. When heterologously expressed in yeast and tobacco, SpAQP1 enhanced the salt tolerance of yeast strains and tobacco plants and promoted seed germination and root growth under salt stress in transgenic plants. The activity of antioxidative enzymes including superoxide dismutase, peroxidase and catalase was increased in transgenic plants overexpressing SpAQP1. Taken together, our studies suggested that SpAQP1 functioned in the responses of S. portulacastrum to salt stress and could increase salt tolerance by enhancing the antioxidative activity of plants. PMID- 26581953 TI - Didehydro-Cortistatin A: a new player in HIV-therapy? AB - Antiretroviral therapy can effectively suppress HIV-1 infection but is ineffective against integrated proviruses. A latent viral reservoir composed of latently infected CD4(+)T cells persists under suppressive therapy, and infected individuals must remain indefinitely on antiretroviral therapy to prevent viral reactivation and propagation. Despite therapy, some degree of low-level ongoing replication is detected and transient viral reactivation may replenish the latent reservoir. An analog of the natural compound, Cortistatin A, blocks HIV-1 transcription by specifically targeting the viral transactivator, Tat. Treatment of latently infected cells with this Tat inhibitor promotes a state of deep latency from which HIV reactivation capacity is greatly diminished. Here we discuss the use of Tat inhibitors to limit the latent reservoir to achieve a functional cure. PMID- 26581954 TI - Influence of age on rat bone-marrow mesenchymal stem cells potential. AB - Mesenchymal stem cells promising role in cell-based therapies and tissue engineering appears to be limited due to a decline of their regenerative potential with increasing donor age. Six age groups from bone marrow mesenchymal stem cells of Wistar rats were studied (newborn, infant, young, pre-pubertal, pubertal and adult). Quantitative proteomic assay was performance by iTRAQ using an 8-plex iTRAQ labeling and the proteins differentially expressed were grouped in pluripotency, proliferative and metabolism processes. Proliferation makers, CD117 and Ki67 were measure by flow cytometry assay. Real time polymerase chain reaction analysis of pluripotency markers Rex1, Oct4, Sox2 and Nanog were done. Biological differentiation was realized using specific mediums for 14 days to induce osteogenesis, adipogenesis or chondrogenesis and immunostain analysis of differentiated cell resulting were done. Enzimoimmunoassay analysis of several enzymes as L-lactate dehydrogenase and glucose-6-phosphate isomerase were also done to validate iTRAQ data. Taking together these results indicate for the first time that mesenchymal stem cells have significant differences in their proliferative, pluripotency and metabolism profiles and those differences are age depending. PMID- 26581956 TI - ABO incompatibility and bone marrow transplantation in children with thalassemia major. PMID- 26581955 TI - The correlation between alopecia and temperament in rhesus macaques (Macaca mulatta) at four primate facilities. AB - Alopecia is a ubiquitous, multifaceted problem at facilities caring for captive rhesus macaques. There is a wide range of potential etiologies for the hair loss, including compromised immune function, dermatological pathologies, and environmental factors. However, few studies have examined whether various temperamental traits affect vulnerability to develop alopecia. We examined the correlation between alopecia and temperament in 101 (51M) indoor-housed rhesus macaques at four national primate centers. We utilized a cage side version of the Human Intruder test (HIT) to assess response to four conditions: no human present (Alone), human intruder standing next to the cage without making eye contact (Profile), intruder making direct eye contact (Stare) and intruder with back turned (Back). Behavior from all videos was quantified at one facility. We used generalized linear modeling to examine the relationship between behavior on the HIT and alopecia, controlling for facility, age, and sex. There was a significant negative correlation between alopecia and various behaviors associated with an inhibited or anxious temperament, including self-directed behavior (beta = -0.15, P < 0.001) and freeze in the Profile period (beta = -0.0092, P < 0.001), and defensive behaviors (beta = -0.0094, P < 0.001) and time spent in the back of the cage in the Stare period (beta = -0.0023, P = 0.015). Individuals with an inhibited or anxious temperament had less alopecia than others. Further, there were facility differences with respect to several variables on the HIT, including defensive behavior in Stare and freeze in Profile. These results suggest that temperament can influence the development of alopecia in rhesus macaques. Our results also highlight the degree to which facility differences can affect outcomes on standardized behavioral tests. Am. J. Primatol. 79:e22504, 2017. (c) 2015 Wiley Periodicals, Inc. PMID- 26581957 TI - Parallel Optimization of 3D Cardiac Electrophysiological Model Using GPU. AB - Large-scale 3D virtual heart model simulations are highly demanding in computational resources. This imposes a big challenge to the traditional computation resources based on CPU environment, which already cannot meet the requirement of the whole computation demands or are not easily available due to expensive costs. GPU as a parallel computing environment therefore provides an alternative to solve the large-scale computational problems of whole heart modeling. In this study, using a 3D sheep atrial model as a test bed, we developed a GPU-based simulation algorithm to simulate the conduction of electrical excitation waves in the 3D atria. In the GPU algorithm, a multicellular tissue model was split into two components: one is the single cell model (ordinary differential equation) and the other is the diffusion term of the monodomain model (partial differential equation). Such a decoupling enabled realization of the GPU parallel algorithm. Furthermore, several optimization strategies were proposed based on the features of the virtual heart model, which enabled a 200-fold speedup as compared to a CPU implementation. In conclusion, an optimized GPU algorithm has been developed that provides an economic and powerful platform for 3D whole heart simulations. PMID- 26581958 TI - Prenatal exposure to recreational drugs affects global motion perception in preschool children. AB - Prenatal exposure to recreational drugs impairs motor and cognitive development; however it is currently unknown whether visual brain areas are affected. To address this question, we investigated the effect of prenatal drug exposure on global motion perception, a behavioural measure of processing within the dorsal extrastriate visual cortex that is thought to be particularly vulnerable to abnormal neurodevelopment. Global motion perception was measured in one hundred and forty-five 4.5-year-old children who had been exposed to different combinations of methamphetamine, alcohol, nicotine and marijuana prior to birth and 25 unexposed children. Self-reported drug use by the mothers was verified by meconium analysis. We found that global motion perception was impaired by prenatal exposure to alcohol and improved significantly by exposure to marijuana. Exposure to both drugs prenatally had no effect. Other visual functions such as habitual visual acuity and stereoacuity were not affected by drug exposure. Prenatal exposure to methamphetamine did not influence visual function. Our results demonstrate that prenatal drug exposure can influence a behavioural measure of visual development, but that the effects are dependent on the specific drugs used during pregnancy. PMID- 26581961 TI - Epilepsy treatment: precision medicine at a crossroads. PMID- 26581960 TI - Olfactomedin 4 deficiency promotes prostate neoplastic progression and is associated with upregulation of the hedgehog-signaling pathway. AB - Loss of olfactomedin 4 (OLFM4) gene expression is associated with the progression of human prostate cancer, but its role and the molecular mechanisms involved in this process have not been completely understood. In this study, we found that Olfm4-knockout mice developed prostatic intraepithelial neoplasia and prostatic adenocarcinoma. Importantly, we found that the hedgehog-signaling pathway was significantly upregulated in the Olfm4-knockout mouse model. We also found that restoration of OLFM4 in human prostate-cancer cells that lack OLFM4 expression significantly downregulated hedgehog signaling-pathway component expression. Furthermore, we demonstrated that the OLFM4 protein interacts with sonic hedgehog protein, as well as significantly inhibits GLI-reporter activity. Bioinformatic and immunohistochemistry analyses revealed that decreased OLFM4 and increased SHH expression was significantly associated with advanced human prostate cancer. Thus, olfactomedin 4 appears to play a critical role in regulating progression of prostate cancer, and has potential as a new biomarker for prostate cancer. PMID- 26581959 TI - Altered Amygdala Connectivity in Individuals with Chronic Traumatic Brain Injury and Comorbid Depressive Symptoms. AB - Depression is one of the most common psychiatric conditions in individuals with chronic traumatic brain injury (TBI). Though depression has detrimental effects in TBI and network dysfunction is a "hallmark" of TBI and depression, there have not been any prior investigations of connectivity-based neuroimaging biomarkers for comorbid depression in TBI. We utilized resting-state functional magnetic resonance imaging to identify altered amygdala connectivity in individuals with chronic TBI (8 years post-injury on average) exhibiting comorbid depressive symptoms (N = 31), relative to chronic TBI individuals having minimal depressive symptoms (N = 23). Connectivity analysis of these participant sub-groups revealed that the TBI-plus-depressive symptoms group showed relative increases in amygdala connectivity primarily in the regions that are part of the salience, somatomotor, dorsal attention, and visual networks (p voxel < 0.01, p cluster < 0.025). Relative increases in amygdala connectivity in the TBI-plus-depressive symptoms group were also observed within areas of the limbic-cortical mood-regulating circuit (the left dorsomedial and right dorsolateral prefrontal cortices and thalamus) and the brainstem. Further analysis revealed that spatially dissociable patterns of correlation between amygdala connectivity and symptom severity according to subtypes (Cognitive and Affective) of depressive symptoms (p voxel < 0.01, p cluster < 0.025). Taken together, these results suggest that amygdala connectivity may be a potentially effective neuroimaging biomarker for comorbid depressive symptoms in chronic TBI. PMID- 26581962 TI - The end of regulatory monotherapy trials? PMID- 26581964 TI - Gastrostomy in amyotrophic lateral sclerosis: effects of non-invasive ventilation. PMID- 26581965 TI - Gastrostomy in amyotrophic lateral sclerosis: effects of non-invasive ventilation. PMID- 26581966 TI - Gastrostomy in amyotrophic lateral sclerosis: effects of non-invasive ventilation - Authors' reply. PMID- 26581967 TI - Brainwaves from Bhutan. PMID- 26581968 TI - Beth Stevens. PMID- 26581969 TI - Paralysis with muscle atrophy. PMID- 26581970 TI - Cranial functional (psychogenic) movement disorders. AB - Functional (psychogenic) neurological symptoms are frequently encountered in neurological practice. Cranial movement disorders--affecting the eyes, face, jaw, tongue, or palate--are an under-recognised feature of patients with functional symptoms. They can present in isolation or in the context of other functional symptoms; in particular, for functional eye movements, positive clinical signs such as convergence spasms can be triggered by the clinical examination. Although the specialty of functional neurological disorders has expanded, appreciation of cranial functional movement disorders is still insufficient. Identification of the positive features of cranial functional movement disorders such as convergence and unilateral platysmal spasm might lend diagnostic weight to a suspected functional neurological disorder. Understanding of the differential diagnosis, which is broad and includes many organic causes (eg, stroke), is essential to make an early and accurate diagnosis to prevent complications and initiate appropriate management. Increased understanding of these disorders is also crucial to drive clinical trials and studies of individually tailored therapies. PMID- 26581971 TI - The effects of socioeconomic status on stroke risk and outcomes. AB - The latest evidence on socioeconomic status and stroke shows that stroke not only disproportionately affects low-income and middle-income countries, but also socioeconomically deprived populations within high-income countries. These disparities are reflected not only in risk of stroke but also in short-term and long-term outcomes after stroke. Increased average levels of conventional risk factors (eg, hypertension, hyperlipidaemia, excessive alcohol intake, smoking, obesity, and sedentary lifestyle) in populations with low socioeconomic status account for about half of these effects. In many countries, evidence shows that people with lower socioeconomic status are less likely to receive good-quality acute hospital and rehabilitation care than people with higher socioeconomic status. For clinical practice, better implementation of well established treatments, effective management of risk factors, and equity of access to high quality acute stroke care and rehabilitation will probably reduce inequality substantially. Overcoming barriers and adapting evidence-based interventions to different countries and health-care settings remains a research priority. PMID- 26581972 TI - Is a separate monotherapy indication warranted for antiepileptic drugs? AB - Antiepileptic drugs (AEDs) are the only neurotherapeutics for which regulatory approval is consistently separated into monotherapy or adjunctive-therapy indications. Because head-to-head comparisons of AEDs (used in the European Union to approve drugs for monotherapy) have not shown substantial differences in efficacy between drugs, FDA approval for use of an AED as monotherapy has typically been based on trials with novel designs that have been criticised for reasons of ethics and clinical relevance. Many new-generation AEDs have not been approved for monotherapy, causing drug labelling and real-world use to be increasingly inconsistent, with negative consequences for patients. The regulatory requirement for separate monotherapy and adjunctive-therapy indications in epilepsy is unnecessarily restrictive. We recommend that regulatory agencies approve AEDs for the treatment of specific seizure types or epilepsy syndromes, irrespective of concomitant drug use. PMID- 26581973 TI - Profession at the crossroads: A dialog concerning the preparation of nursing scholars and leaders. AB - The purpose of a practice discipline's terminal degree is to develop wise scholars to guide the profession in anticipating and meeting the health-related needs of those served via philosophical, conceptual/theoretical, and empirical inquiry on behalf of professional practice. Each of these dimensions is important for the discipline's ability to meet its obligations to society. However, contemporary circumstances have created a context within which the maturation of the profession may be threatened by an imbalance among the three dimensions of PhD education. Specifically, we discuss the possibility of a tilt toward the empirical at the expense of the other two. Yet, the philosophical and conceptual/theoretical dimensions are those that have permitted core disciplinary knowledge to be developed. We aim to create a dialog about current challenges and the responsibilities of the discipline's scholars for stewardship of the discipline and offer some strategies to ensure balance among the three equally important dimensions. PMID- 26581975 TI - Effective Temperature and Universal Conductivity Scaling in Organic Semiconductors. AB - We investigate the scalability of the temperature- and electric field-dependence of the conductivity of disordered organic semiconductors to 'universal' curves by two different but commonly employed methods; by so-called universal scaling and by using the effective temperature concept. Experimentally both scaling methods were found to be equally applicable to the out-of-plane charge transport in PEDOT: PSS thin films of various compositions. Both methods are shown to be equivalent in terms of functional dependence and to have identical limiting behavior. The experimentally observed scaling behavior can be reproduced by a numerical nearest-neighbor hopping model, accounting for the Coulomb interaction, the high charge carrier concentration and the energetic disorder. The underlying physics can be captured in a simple empirical model, describing the effective temperature of the charge carrier distribution as the outcome of a heat balance between Joule heating and (effective) temperature-dependent energy loss to the lattice. PMID- 26581974 TI - Enhancing the effectiveness of smoking treatment research: conceptual bases and progress. AB - BACKGROUND AND AIMS: A chronic care strategy could potentially enhance the reach and effectiveness of smoking treatment by providing effective interventions for all smokers, including those who are initially unwilling to quit. This paper describes the conceptual bases of a National Cancer Institute-funded research program designed to develop an optimized, comprehensive, chronic care smoking treatment. METHODS: This research is grounded in three methodological approaches: (1) the Phase-Based Model, which guides the selection of intervention components to be experimentally evaluated for the different phases of smoking treatment (motivation, preparation, cessation, and maintenance); (2) the Multiphase Optimization Strategy (MOST), which guides the screening of intervention components via efficient experimental designs and, ultimately, the assembly of promising components into an optimized treatment package; and (3) pragmatic research methods, such as electronic health record recruitment, that facilitate the efficient translation of research findings into clinical practice. Using this foundation and working in primary care clinics, we conducted three factorial experiments (reported in three accompanying papers) to screen 15 motivation, preparation, cessation and maintenance phase intervention components for possible inclusion in a chronic care smoking treatment program. RESULTS: This research identified intervention components with relatively strong evidence of effectiveness at particular phases of smoking treatment and it demonstrated the efficiency of the MOST approach in terms both of the number of intervention components tested and of the richness of the information yielded. CONCLUSIONS: A new, synthesized research approach efficiently evaluates multiple intervention components to identify promising components for every phase of smoking treatment. Many intervention components interact with one another, supporting the use of factorial experiments in smoking treatment development. PMID- 26581976 TI - Preventing Cleavage of the Respiratory Syncytial Virus Attachment Protein in Vero Cells Rescues the Infectivity of Progeny Virus for Primary Human Airway Cultures. AB - All live attenuated respiratory syncytial virus (RSV) vaccines that have advanced to clinical trials have been produced in Vero cells. The attachment (G) glycoprotein in virions produced in these cells is smaller than that produced in other immortalized cells due to cleavage. These virions are 5-fold less infectious for primary well-differentiated human airway epithelial (HAE) cell cultures. Because HAE cells are isolated directly from human airways, Vero cell grown vaccine virus would very likely be similarly inefficient at initiating infection of the nasal epithelium following vaccination, and therefore, a larger inoculum would be required for effective vaccination. We hypothesized that Vero cell-derived virus containing an intact G protein would be more infectious for HAE cell cultures. Using protease inhibitors with increasing specificity, we identified cathepsin L to be the protease responsible for cleavage. Our evidence suggests that cleavage occurs in the late endosome or lysosome during endocytic recycling. Cathepsin L activity was 100-fold greater in Vero cells than in HeLa cells. In addition, cathepsin L was able to cleave the G protein in Vero cell grown virions but not in HeLa cell-grown virions, suggesting a difference in G protein posttranslational modification in the two cell lines. We identified by mutagenesis amino acids important for cleavage, and these amino acids included a likely cathepsin L cleavage site. Virus containing a modified, noncleavable G protein produced in Vero cells was 5-fold more infectious for HAE cells in culture, confirming our hypothesis and indicating the value of including such a mutation in future live attenuated RSV vaccines. IMPORTANCE: Worldwide, RSV is the second leading infectious cause of infant death, but no vaccine is available. Experimental live attenuated RSV vaccines are grown in Vero cells, but during production the virion attachment (G) glycoprotein is cleaved. Virions containing a cleaved G protein are less infectious for primary airway epithelial cells, the natural RSV target. In the study described here we identified the protease responsible, located the cleavage site, and demonstrated that cleavage likely occurs during endocytic recycling. Moreover, we showed that the infectivity of Vero cell-derived virus for primary airway epithelial cells is increased 5-fold if the virus contains a mutation in the G protein that prevents cleavage. The blocking of cleavage should improve RSV vaccine yield, consequently reducing production costs. Posttranslational cleavage of the fusion glycoprotein of many viruses plays an essential role in activation; however, cleavage of the RSV G protein is a novel example of a detrimental effect of cleavage on virus infectivity. PMID- 26581977 TI - Synonymous Deoptimization of Foot-and-Mouth Disease Virus Causes Attenuation In Vivo while Inducing a Strong Neutralizing Antibody Response. AB - Codon bias deoptimization has been previously used to successfully attenuate human pathogens, including poliovirus, respiratory syncytial virus, and influenza virus. We have applied a similar technology to deoptimize the capsid-coding region (P1) of foot-and-mouth disease virus (FMDV). Despite the introduction of 489 nucleotide changes (19%), synonymous deoptimization of the P1 region rendered a viable FMDV progeny. The resulting strain was stable and reached cell culture titers similar to those obtained for wild-type (WT) virus, but at reduced specific infectivity. Studies in mice showed that 100% of animals inoculated with the FMDV A12 P1 deoptimized mutant (A12-P1 deopt) survived, even when the animals were infected at doses 100 times higher than the dose required to cause death by WT virus. All mice inoculated with the A12-P1 deopt mutant developed a strong antibody response and were protected against subsequent lethal challenge with WT virus at 21 days postinoculation. Remarkably, the vaccine safety margin was at least 1,000-fold higher for A12-P1 deopt than for WT virus. Similar patterns of attenuation were observed in swine, in which animals inoculated with A12-P1 deopt virus did not develop clinical disease until doses reached 1,000 to 10,000 times the dose required to cause severe disease in 2 days with WT A12. Consistently, high levels of antibody titers were induced, even at the lowest dose tested. These results highlight the potential use of synonymous codon pair deoptimization as a strategy to safely attenuate FMDV and further develop live attenuated vaccine candidates to control such a feared livestock disease. IMPORTANCE: Foot and-mouth disease (FMD) is one of the most feared viral diseases that can affect livestock. Although this disease appeared to be contained in developed nations by the end of the last century, recent outbreaks in Europe, Japan, Taiwan, South Korea, etc., have demonstrated that infection can spread rapidly, causing devastating economic and social consequences. The Global Foot-and-Mouth Disease Research Alliance (GFRA), an international organization launched in 2003, has set as part of their five main goals the development of next-generation control measures and strategies, including improved vaccines and biotherapeutics. Our work demonstrates that newly developed codon pair bias deoptimization technologies can be applied to FMD virus to obtain attenuated strains with potential for further development as novel live attenuated vaccine candidates that may rapidly control disease without reverting to virulence. PMID- 26581978 TI - Epstein-Barr Virus MicroRNA miR-BART20-5p Suppresses Lytic Induction by Inhibiting BAD-Mediated caspase-3-Dependent Apoptosis. AB - Epstein-Barr virus (EBV) is a human gammaherpesvirus associated with a variety of tumor types. EBV can establish latency or undergo lytic replication in host cells. In general, EBV remains latent in tumors and expresses a limited repertoire of latent proteins to avoid host immune surveillance. When the lytic cycle is triggered by some as-yet-unknown form of stimulation, lytic gene expression and progeny virus production commence. Thus far, the exact mechanism of EBV latency maintenance and the in vivo triggering signal for lytic induction have yet to be elucidated. Previously, we have shown that the EBV microRNA miR BART20-5p directly targets the immediate early genes BRLF1 and BZLF1 as well as Bcl-2-associated death promoter (BAD) in EBV-associated gastric carcinoma. In this study, we found that both mRNA and protein levels of BRLF1 and BZLF1 were suppressed in cells following BAD knockdown and increased after BAD overexpression. Progeny virus production was also downregulated by specific knockdown of BAD. Our results demonstrated that caspase-3-dependent apoptosis is a prerequisite for BAD-mediated EBV lytic cycle induction. Therefore, our data suggest that miR-BART20-5p plays an important role in latency maintenance and tumor persistence of EBV-associated gastric carcinoma by inhibiting BAD-mediated caspase-3-dependent apoptosis, which would trigger immediate early gene expression. IMPORTANCE: EBV has an ability to remain latent in host cells, including EBV-associated tumor cells hiding from immune surveillance. However, the exact molecular mechanisms of EBV latency maintenance remain poorly understood. Here, we demonstrated that miR-BART20-5p inhibited the expression of EBV immediate early genes indirectly, by suppressing BAD-induced caspase-3 dependent apoptosis, in addition to directly, as we previously reported. Our study suggests that EBV-associated tumor cells might endure apoptotic stress to some extent and remain latent with the aid of miR-BART20-5p. Blocking the expression or function of BART20-5p may expedite EBV-associated tumor cell death via immune attack and apoptosis. PMID- 26581979 TI - A Haploid Genetic Screen Identifies Heparan Sulfate Proteoglycans Supporting Rift Valley Fever Virus Infection. AB - Rift Valley fever virus (RVFV) causes recurrent insect-borne epizootics throughout the African continent, and infection of humans can lead to a lethal hemorrhagic fever syndrome. Deep mutagenesis of haploid human cells was used to identify host factors required for RVFV infection. This screen identified a suite of enzymes involved in glycosaminoglycan (GAG) biogenesis and transport, including several components of the cis-oligomeric Golgi (COG) complex, one of the central components of Golgi complex trafficking. In addition, disruption of PTAR1 led to RVFV resistance as well as reduced heparan sulfate surface levels, consistent with recent observations that PTAR1-deficient cells exhibit altered Golgi complex morphology and glycosylation defects. A variety of biochemical and genetic approaches were utilized to show that both pathogenic and attenuated RVFV strains require GAGs for efficient infection on some, but not all, cell types, with the block to infection being at the level of virion attachment. Examination of other members of the Bunyaviridae family for GAG-dependent infection suggested that the interaction with GAGs is not universal among bunyaviruses, indicating that these viruses, as well as RVFV on certain cell types, employ additional unidentified virion attachment factors and/or receptors. IMPORTANCE: Rift Valley fever virus (RVFV) is an emerging pathogen that can cause severe disease in humans and animals. Epizootics among livestock populations lead to high mortality rates and can be economically devastating. Human epidemics of Rift Valley fever, often initiated by contact with infected animals, are characterized by a febrile disease that sometimes leads to encephalitis or hemorrhagic fever. The global burden of the pathogen is increasing because it has recently disseminated beyond Africa, which is of particular concern because the virus can be transmitted by widely distributed mosquito species. There are no FDA-licensed vaccines or antiviral agents with activity against RVFV, and details of its life cycle and interaction with host cells are not well characterized. We used the power of genetic screening in human cells and found that RVFV utilizes glycosaminoglycans to attach to host cells. This furthers our understanding of the virus and informs the development of antiviral therapeutics. PMID- 26581980 TI - Mechanism of Cell Culture Adaptation of an Enteric Calicivirus, the Porcine Sapovirus Cowden Strain. AB - The porcine sapovirus (SaV) (PoSaV) Cowden strain is one of only a few culturable enteric caliciviruses. Compared to the wild-type (WT) PoSaV Cowden strain, tissue culture-adapted (TC) PoSaV has two conserved amino acid substitutions in the RNA dependent RNA polymerase (RdRp) and six in the capsid protein (VP1). By using the reverse-genetics system, we identified that 4 amino acid substitutions in VP1 (residues 178, 289, 324, and 328), but not the substitutions in the RdRp region, were critical for the cell culture adaptation of the PoSaV Cowden strain. The other two substitutions in VP1 (residues 291 and 295) reduced virus replication in vitro. Three-dimensional (3D) structural analysis of VP1 showed that residue 178 was located near the dimer-dimer interface, which may affect VP1 assembly and oligomerization; residues 289, 291, 324, and 328 were located at protruding subdomain 2 (P2) of VP1, which may influence virus binding to cellular receptors; and residue 295 was located at the interface of two monomeric VP1 proteins, which may influence VP1 dimerization. Although reversion of the mutation at residue 291 or 295 from that of the TC strain to that of the WT reduced virus replication in vitro, it enhanced virus replication in vivo, and the revertants induced higher level serum and mucosal antibody responses than those induced by the TC PoSaV Cowden strain. Our findings reveal the molecular basis for PoSaV adaptation to cell culture. These findings may provide new, critical information for the cell culture adaptation of other PoSaV strains and human SaVs or noroviruses. IMPORTANCE: The tissue culture-adapted porcine sapovirus Cowden strain is one of only a few culturable enteric caliciviruses. We discovered that 4 amino acid substitutions in VP1 (residues 178, 289, 324, and 328) were critical for its adaptation to LLC-PK cells. Two substitutions in VP1 (residues 291 and 295) reduced virus replication in vitro but enhanced virus replication and induced higher-level serum and mucosal antibody responses in gnotobiotic pigs than those induced by the tissue culture-adapted strain. Structural modeling analysis of VP1 suggested that residue 178 may affect VP1 assembly and oligomerization; residues 289, 291, 324, and 328 may influence virus binding to cellular receptors; and residue 295 may influence VP1 dimerization. Our findings will provide new information for the cell culture adaptation of other sapoviruses and possibly noroviruses. PMID- 26581981 TI - Human Immunodeficiency Virus Type 1 Monoclonal Antibodies Suppress Acute Simian Human Immunodeficiency Virus Viremia and Limit Seeding of Cell-Associated Viral Reservoirs. AB - Combination antiretroviral therapy (cART) administered shortly after human immunodeficiency virus type 1 (HIV-1) infection can suppress viremia and limit seeding of the viral reservoir, but lifelong treatment is required for the majority of patients. Highly potent broadly neutralizing HIV-1 monoclonal antibodies (MAbs) can reduce plasma viremia when administered during chronic HIV 1 infection, but the therapeutic potential of these antibodies during acute infection is unknown. We tested the ability of HIV-1 envelope glycoprotein specific broadly neutralizing MAbs to suppress acute simian-human immunodeficiency virus (SHIV) replication in rhesus macaques. Four groups of macaques were infected with SHIV-SF162P3 and received (i) the CD4-binding-site MAb VRC01; (ii) a combination of a more potent clonal relative of VRC01 (VRC07 523) and a V3 glycan-dependent MAb (PGT121); (iii) daily cART, all on day 10, just prior to expected peak plasma viremia; or (iv) no treatment. Daily cART was initiated 11 days after MAb administration and was continued for 13 weeks in all treated animals. Over a period of 11 days after a single administration, MAb treatment significantly reduced peak viremia, accelerated the decay slope, and reduced total viral replication compared to untreated controls. Proviral DNA in lymph node CD4 T cells was also diminished after treatment with the dual MAb. These data demonstrate the virological effect of potent MAbs and support future clinical trials that investigate HIV-1-neutralizing MAbs as adjunctive therapy with cART during acute HIV-1 infection. IMPORTANCE: Treatment of chronic HIV-1 infection with potent broadly neutralizing HIV-1 MAbs has been shown to significantly reduce plasma viremia. However, the antiviral effect of MAb treatment during acute HIV-1 infection is unknown. Here, we demonstrate that MAbs targeting the HIV-1 envelope glycoprotein both suppress acute SHIV plasma viremia and limit CD4 T cell-associated viral DNA. These findings provide support for clinical trials of MAbs as adjunctive therapy with antiretroviral therapy during acute HIV-1 infection. PMID- 26581982 TI - Machupo Virus Expressing GPC of the Candid#1 Vaccine Strain of Junin Virus Is Highly Attenuated and Immunogenic. AB - Machupo virus (MACV) is the causative agent of Bolivian hemorrhagic fever. Our previous study demonstrated that a MACV strain with a single amino acid substitution (F438I) in the transmembrane domain of glycoprotein is attenuated but genetically unstable in mice. MACV is closely related to Junin virus (JUNV), the causative agent of Argentine hemorrhagic fever. Others and our group have identified the glycoprotein to be the major viral factor determining JUNV attenuation. In this study, we tested the compatibility of the glycoprotein of the Candid#1 live-attenuated vaccine strain of JUNV in MACV replication and its ability to attenuate MACV in vivo. Recombinant MACV with the Candid#1 glycoprotein (rMACV/Cd#1-GPC) exhibited growth properties similar to those of Candid#1 and was genetically stable in vitro. In a mouse model of lethal infection, rMACV/Cd#1-GPC was fully attenuated, more immunogenic than Candid#1, and fully protective against MACV infection. Therefore, the MACV strain expressing the glycoprotein of Candid#1 is safe, genetically stable, and highly protective against MACV infection in a mouse model. IMPORTANCE: Currently, there are no FDA-approved vaccines and/or treatments for Bolivian hemorrhagic fever, which is a fatal human disease caused by MACV. The development of antiviral strategies to combat viral hemorrhagic fevers, including Bolivian hemorrhagic fever, is one of the top priorities of the Implementation Plan of the U.S. Department of Health and Human Services Public Health Emergency Medical Countermeasures Enterprise. Here, we demonstrate for the first time that MACV expressing glycoprotein of Candid#1 is a safe, genetically stable, highly immunogenic, and protective vaccine candidate against Bolivian hemorrhagic fever. PMID- 26581983 TI - Host MicroRNA miR-197 Plays a Negative Regulatory Role in the Enterovirus 71 Infectious Cycle by Targeting the RAN Protein. AB - Enterovirus 71 (EV71), a member of Picornaviridae, is associated with severe central nervous system complications. In this study, we identified a cellular microRNA (miRNA), miR-197, whose expression was downregulated by viral infection in a time-dependent manner. In miR-197 mimic-transfected cells, EV71 replication was inhibited, whereas the internal ribosome entry site (IRES) activity was decreased in EV71 strains with or without predicted miR-197 target sites, indicating that miR-197 targets host proteins to modulate viral replication. We thus used a quantitative proteomics approach, aided by the TargetScan algorithm, to identify putative target genes of miR-197. Among them, RAN was selected and validated as a genuine target in a 3' untranslated region (UTR) reporter assay. Reduced production of RAN by RNA interference markedly reduced the synthesis of EV71-encoded viral proteins and virus titers. Furthermore, reintroduction of nondegradable RAN into these knockdown cells rescued viral protein synthesis. miR 197 levels were modulated by EV71 to maintain RAN mRNA translatability at late times postinfection since we demonstrated that cap-independent translation exerted by its intrinsic IRES activity was occurring at times when translation attenuation was induced by EV71. EV71-induced downregulation of miR-197 expression increased the expression of RAN, which supported the nuclear transport of the essential viral proteins 3D/3CD and host protein hnRNP K for viral replication. Our data suggest that downregulation of cellular miRNAs may constitute a newly identified mechanism that sustains the expression of host proteins to facilitate viral replication. IMPORTANCE: Enterovirus 71 (EV71) is a picornavirus with a positive-sense single-stranded RNA that globally inhibits the cellular translational system, mainly by cleaving cellular eukaryotic translation initiation factor 4G (eIF4G) and poly(A)-binding protein (PABP), which inhibits the association of the ribosome with the host capped mRNA. We used a microRNA (miRNA) microarray chip to identify the host miRNA 197 (miR-197) that was downregulated by EV71. We also used quantitative mass spectrometry and a target site prediction tool to identify the miR-197 target genes. During viral infection, the expression of the target protein RAN was upregulated considerably, and there was a parallel downregulation of miR-197. The nuclear transport of viral 3D/3CD protein and of the host proteins involved in viral replication proceeded in an RAN-dependent manner. We have identified a new mechanism in picornavirus through which EV71-induced cellular miRNA downregulation can regulate host protein levels to facilitate viral replication. PMID- 26581984 TI - Dysregulation of Toll-Like Receptor 7 Compromises Innate and Adaptive T Cell Responses and Host Resistance to an Attenuated West Nile Virus Infection in Old Mice. AB - The elderly are known to have enhanced susceptibility to infections and an impaired capacity to respond to vaccination. West Nile virus (WNV), a mosquito borne flavivirus, has induced severe neurological symptoms, mostly in the elderly population. No vaccines are available for human use. Recent work showed that an attenuated WNV, a nonstructural (NS) 4B-P38G mutant, induced no lethality but strong immune responses in young (6- to 10-week-old) mice. While studying protective efficacy, we found unexpectedly that old (21- to 22-month) mice were susceptible to WNV NS4B-P38G mutant infection but were protected from subsequent lethal wild-type WNV challenge. Compared to responses in young mice, the NS4B P38G mutant triggered higher inflammatory cytokine and interleukin-10 (IL-10) production, a delayed gammadelta T cell expansion, and lower antibody and WNV specific T cell responses in old mice. Toll-like receptor 7 (TLR7) is expressed on multiple types of cells. Impaired TLR7 signaling in old mice led to dendritic cell (DC) antigen-presenting function compromise and a reduced gammadelta T cell and regulatory T cell (Treg) expansion during NS4B-P38G mutant infection. R848, a TLR7 agonist, decreased host vulnerability in NS4B-P38G-infected old mice by enhancing gammadelta T cell and Treg expansion and the antigen-presenting capacity of DCs, thereby promoting T cell responses. In summary, our results suggest that dysregulation of TLR7 partially contributes to impaired innate and adaptive T cell responses and an enhanced vulnerability in old mice during WNV NS4B-P38G mutant infection. R848 increases the safety and efficacy during immunization of old mice with the WNV NS4B-P38G mutant. IMPORTANCE: The elderly are known to have enhanced susceptibility to infections and an impaired capacity to respond to vaccination. West Nile virus (WNV), an emerging mosquito-borne flavivirus, has induced severe neurological symptoms more frequently in the elderly population. No vaccines are available for human use. Here, we used an aged mouse model to investigate the protective efficacy of an attenuated WNV, the nonstructural 4B-P38G mutant, which was previously shown to induce no lethality but strong immune responses in young adult mice. Studies that contribute to a mechanistic understanding of immune defects in the elderly will allow the development of strategies to improve responses to infectious diseases and to increase vaccine efficacy and safety in aging individuals. PMID- 26581985 TI - Identification of Viral and Host Proteins That Interact with Murine Gammaherpesvirus 68 Latency-Associated Nuclear Antigen during Lytic Replication: a Role for Hsc70 in Viral Replication. AB - Latency-associated nuclear antigen (LANA) is a conserved, multifunctional protein encoded by members of the rhadinovirus subfamily of gammaherpesviruses, including Kaposi sarcoma-associated herpesvirus (KSHV) and murine gammaherpesvirus 68 (MHV68). We previously demonstrated that MHV68 LANA (mLANA) is required for efficient lytic replication. However, mechanisms by which mLANA facilitates viral replication, including interactions with cellular and viral proteins, are not known. Thus, we performed a mass spectrometry-based interaction screen that defined an mLANA protein-protein interaction network for lytic viral replication consisting of 15 viral proteins and 191 cellular proteins, including 19 interactions previously reported in KSHV LANA interaction studies. We also employed a stable-isotope labeling technique to illuminate high-priority mLANA interacting host proteins. Among the top prioritized mLANA-binding proteins was a cellular chaperone, heat shock cognate protein 70 (Hsc70). We independently validated the mLANA-Hsc70 interaction through coimmunoprecipitation and in vitro glutathione S-transferase (GST) pulldown assays. Immunofluorescence and cellular fractionation analyses comparing wild-type (WT) to mLANA-null MHV68 infections demonstrated mLANA-dependent recruitment of Hsc70 to nuclei of productively infected cells. Pharmacologic inhibition and small hairpin RNA (shRNA)-mediated knockdown of Hsc70 impaired MHV68 lytic replication, which functionally correlated with impaired viral protein expression, reduced viral DNA replication, and failure to form viral replication complexes. Replication of mLANA-null MHV68 was less affected than that of WT virus by Hsc70 inhibition, which strongly suggests that Hsc70 function in MHV68 lytic replication is at least partially mediated by its interaction with mLANA. Together these experiments identify proteins engaged by mLANA during the MHV68 lytic replication cycle and define a previously unknown role for Hsc70 in facilitating MHV68 lytic replication. IMPORTANCE: Latency-associated nuclear antigen (LANA) is a conserved gamma-2 herpesvirus protein important for latency maintenance and pathogenesis. For MHV68, this includes regulating lytic replication and reactivation. While previous studies of KSHV LANA defined interactions with host cell proteins that impact latency, interactions that facilitate productive viral replication are not known. Thus, we performed a differential proteomics analysis to identify and prioritize cellular and viral proteins that interact with the MHV68 LANA homolog during lytic infection. Among the proteins identified was heat shock cognate protein 70 (Hsc70), which we determined is recruited to host cell nuclei in an mLANA-dependent process. Moreover, Hsc70 facilitates MHV68 protein expression and DNA replication, thus contributing to efficient MHV68 lytic replication. These experiments expand the known LANA-binding proteins to include MHV68 lytic replication and demonstrate a previously unappreciated role for Hsc70 in regulating viral replication. PMID- 26581986 TI - Enhanced Immune Responses to HIV-1 Envelope Elicited by a Vaccine Regimen Consisting of Priming with Newcastle Disease Virus Expressing HIV gp160 and Boosting with gp120 and SOSIP gp140 Proteins. AB - Newcastle disease virus (NDV) expressing HIV-1 BaL gp160 was evaluated either alone or with monomeric BaL gp120 and BaL SOSIP gp140 protein in a prime-boost combination in guinea pigs to enhance envelope (Env)-specific humoral and mucosal immune responses. We showed that a regimen consisting of an NDV prime followed by a protein boost elicited stronger serum and mucosal Th-1-biased IgG responses and neutralizing antibody responses than NDV-only immunizations. Additionally, these responses were higher after the gp120 than after the SOSIP gp140 protein boost. PMID- 26581988 TI - Generation of an Avian-Mammalian Rotavirus Reassortant by Using a Helper Virus Dependent Reverse Genetics System. AB - The genetic diversity of rotavirus A (RVA) strains is facilitated in part by genetic reassortment. Although this process of genome segment exchange has been reported frequently among mammalian RVAs, it remained unknown if mammalian RVAs also could package genome segments from avian RVA strains. We generated a simian RVA strain SA11 reassortant containing the VP4 gene of chicken RVA strain 02V0002G3. To achieve this, we transfected BSR5/T7 cells with a T7 polymerase driven VP4-encoding plasmid, infected the cells with a temperature-sensitive SA11 VP4 mutant, and selected the recombinant virus by increasing the temperature. The reassortant virus could be stably passaged and exhibited cytopathic effects in MA 104 cells, but it replicated less efficiently than both parental viruses. Our results show that avian and mammalian rotaviruses can exchange genome segments, resulting in replication-competent reassortants with new genomic and antigenic features. IMPORTANCE: This study shows that rotaviruses of mammals can package genome segments from rotaviruses of birds. The genetic diversity of rotaviruses could be broadened by this process, which might be important for their antigenic variability. The reverse genetics system applied in the study could be useful for targeted generation and subsequent characterization of distinct rotavirus reassortant strains. PMID- 26581987 TI - The Structure of Human Parechovirus 1 Reveals an Association of the RNA Genome with the Capsid. AB - Parechoviruses are human pathogens that cause diseases ranging from gastrointestinal disorders to encephalitis. Unlike those of most picornaviruses, parechovirus capsids are composed of only three subunits: VP0, VP1, and VP3. Here, we present the structure of a human parechovirus 1 (HPeV-1) virion determined to a resolution of 3.1 A. We found that interactions among pentamers in the HPeV-1 capsid are mediated by the N termini of VP0s, which correspond to the capsid protein VP4 and the N-terminal part of the capsid protein VP2 of other picornaviruses. In order to facilitate delivery of the virus genome into the cytoplasm, the N termini of VP0s have to be released from contacts between pentamers and exposed at the particle surface, resulting in capsid disruption. A hydrophobic pocket, which can be targeted by capsid-binding antiviral compounds in many other picornaviruses, is not present in HPeV-1. However, we found that interactions between the HPeV-1 single-stranded RNA genome and subunits VP1 and VP3 in the virion impose a partial icosahedral ordering on the genome. The residues involved in RNA binding are conserved among all parechoviruses, suggesting a putative role of the genome in virion stability or assembly. Therefore, putative small molecules that could disrupt HPeV RNA-capsid protein interactions could be developed into antiviral inhibitors. IMPORTANCE: Human parechoviruses (HPeVs) are pathogens that cause diseases ranging from respiratory and gastrointestinal disorders to encephalitis. Recently, there have been outbreaks of HPeV infections in Western Europe and North America. We present the first atomic structure of parechovirus HPeV-1 determined by X-ray crystallography. The structure explains why HPeVs cannot be targeted by antiviral compounds that are effective against other picornaviruses. Furthermore, we found that the interactions of the HPeV-1 genome with the capsid resulted in a partial icosahedral ordering of the genome. The residues involved in RNA binding are conserved among all parechoviruses, suggesting an evolutionarily fixed role of the genome in virion assembly. Therefore, putative small molecules disrupting HPeV RNA-capsid protein interactions could be developed into antiviral inhibitors. PMID- 26581989 TI - Origin of Rebound Plasma HIV Includes Cells with Identical Proviruses That Are Transcriptionally Active before Stopping of Antiretroviral Therapy. AB - Understanding the origin of HIV variants during viral rebound may provide insight into the composition of the HIV reservoir and has implications for the design of curative interventions. HIV single-genome sequences were obtained from 10 AIDS Clinical Trials Group participants who underwent analytic antiretroviral therapy (ART) interruption (ATI). Rebounding variants were compared with those in pre-ART plasma in all 10 participants and with on-ART peripheral blood mononuclear cell (PBMC)-associated DNA and RNA (CA-RNA) in 7/10 participants. The highest viral diversities were found in the DNA and CA-RNA populations. In 3 of 7 participants, we detected multiple, identical DNA and CA-RNA sequences during suppression on ART that exactly matched plasma HIV sequences. Hypermutated DNA and CA-RNA were detected in four participants, contributing to diversities in these compartments that were higher than in the pre-ART and post-ATI plasma. Shifts in the viral rebound populations could be detected in some participants over the 2- to 3-month observation period. These findings suggest that a source of initial rebound viremia could be populations of infected cells that clonally expanded prior to and/or during ART, some of which were already expressing HIV RNA before treatment was interrupted. These clonally expanding populations of HIV-infected cells may represent an important target for strategies aimed at achieving reservoir reduction and sustained virologic remission. IMPORTANCE: Antiretroviral therapy alone cannot eradicate the HIV reservoir, and viral rebound is generally rapid after treatment interruption. It has been suggested that clonal expansion of HIV infected cells is an important mechanism of HIV reservoir persistence, but the contribution of these clonally proliferating cells to the rebounding virus is unknown. We report a study of AIDS Clinical Trials Group participants who underwent treatment interruption and compared rebounding plasma virus with that found within cells prior to treatment interruption. We found several incidences in which plasma HIV variants exactly matched that of multiple proviral DNA copies from infected blood cells sampled before treatment interruption. In addition, we found that these cells were not dormant but were generating unspliced RNA transcripts before treatment was interrupted. Identification of the HIV reservoir and determining its mechanisms for persistence may aid in the development of strategies toward a cure for HIV. (This study was presented in part at the Conference on Retroviruses and Opportunistic Infections, Seattle, WA, February 23 to 26 2015.). PMID- 26581990 TI - Knockdown of Autophagy Inhibits Infectious Hepatitis C Virus Release by the Exosomal Pathway. AB - Hepatitis C virus (HCV) is a major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma in humans. We showed previously that HCV induces autophagy for viral persistence by preventing the innate immune response. Knockdown of autophagy reduces extracellular HCV release, although the precise mechanism remains unknown. In this study, we observed that knockdown of autophagy genes enhances intracellular HCV RNA and accumulates infectious virus particles in cells. Since HCV release is linked with the exosomal pathway, we examined whether autophagy proteins associate with exosomes in HCV-infected cells. We observed an association between HCV and the exosomal marker CD63 in autophagy knockdown cells. Subsequently, we observed that levels of extracellular infectious HCV were significantly lower in exosomes released from autophagy knockdown cells. To understand the mechanism for reduced extracellular infectious HCV in the exosome, we observed that an interferon (IFN)-stimulated BST-2 gene is upregulated in autophagy knockdown cells and associated with the exosome marker CD63, which may inhibit HCV assembly or release. Taken together, our results suggest a novel mechanism involving autophagy and exosome-mediated HCV release from infected hepatocytes. IMPORTANCE: Autophagy plays an important role in HCV pathogenesis. Autophagy suppresses the innate immune response and promotes survival of virus-infected hepatocytes. The present study examined the role of autophagy in secretion of infectious HCV from hepatocytes. Autophagy promoted HCV trafficking from late endosomes to lysosomes, thus providing a link with the exosome. Inhibition of HCV-induced autophagy could be used as a strategy to block exosome-mediated virus transmission. PMID- 26581991 TI - RNA Replication and Membrane Modification Require the Same Functions of Alphavirus Nonstructural Proteins. AB - The alphaviruses induce membrane invaginations known as spherules as their RNA replication sites. Here, we show that inactivation of any function (polymerase, helicase, protease, or membrane association) essential for RNA synthesis also prevents the generation of spherule structures in a Semliki Forest virus trans replication system. Mutants capable of negative-strand synthesis, including those defective in RNA capping, gave rise to spherules. Recruitment of RNA to membranes in the absence of spherule formation was not detected. PMID- 26581992 TI - Pseudorabies Virus US3 Protein Kinase Protects Infected Cells from NK Cell Mediated Lysis via Increased Binding of the Inhibitory NK Cell Receptor CD300a. AB - Several reports have indicated that natural killer (NK) cells are of particular importance in the innate response against herpesvirus infections. As a consequence, herpesviruses have developed diverse mechanisms for evading NK cells, although few such mechanisms have been identified for the largest herpesvirus subfamily, the alphaherpesviruses. The antiviral activity of NK cells is regulated by a complex array of interactions between activating/inhibitory receptors on the NK cell surface and the corresponding ligands on the surfaces of virus-infected cells. Here we report that the US3 protein kinase of the alphaherpesvirus pseudorabies virus (PRV) displays previously uncharacterized immune evasion properties: it triggers the binding of the inhibitory NK cell receptor CD300a to the surface of the infected cell, thereby providing increased CD300a-mediated protection of infected cells against NK cell-mediated lysis. US3 mediated CD300a binding was found to depend on aminophospholipid ligands of CD300a and on group I p21-activated kinases. These data identify a novel alphaherpesvirus strategy for evading NK cells and demonstrate, for the first time, a role for CD300a in regulating NK cell activity upon contact with virus infected target cells. IMPORTANCE: Herpesviruses have developed fascinating mechanisms to evade elimination by key elements of the host immune system, contributing to their ability to cause lifelong infections with recurrent reactivation events. Natural killer (NK) cells are central in the innate antiviral response. Here we report that the US3 protein kinase of the alphaherpesvirus pseudorabies virus displays a previously uncharacterized capacity for evasion of NK cells. Expression of US3 protects infected cells from NK cell-mediated lysis via increased binding of the inhibitory NK cell receptor CD300a. We show that this US3-mediated increase in CD300a binding depends on aminophospholipids and on cellular p21-activated kinases (PAKs). The identification of this novel NK cell evasion strategy may contribute to the design of improved herpesvirus vaccines and may also have significance for other PAK- and CD300a-modulating viruses and cancer cells. PMID- 26581993 TI - Oral Norovirus Infection Is Blocked in Mice Lacking Peyer's Patches and Mature M Cells. AB - A critical early step in murine norovirus (MNV) pathogenesis is crossing the intestinal epithelial barrier to reach the target cells for replication, i.e., macrophages, dendritic cells, and B cells. Our previous work showed that MNV replication decreases in the intestines of mice conditionally depleted of microfold (M) cells. To define the importance of Peyer's patch (PP) M cells during MNV pathogenesis, we used a model of BALB/c mice deficient in recombination-activating gene 2 (Rag2) and the common gamma chain (gammac) (Rag gammac(-/-)), which lack gut-associated lymphoid tissues (GALT), such as Peyer's patches, and mature GP2(+) M cells. Rag-gammac(-/-) mice were infected intraperitoneally or perorally with MNV-1 or CR3 for 24 or 72 h. Although the intestinal laminae propriae of Rag-gammac(-/-) mice have a higher frequency of certain MNV target cells (dendritic cells and macrophages) than those of wild type mice and lack others (B cells), Rag-gammac(-/-) and wild-type BALB/c mice showed relatively similar viral loads in the intestine following infection by the intraperitoneal route, which provides direct access to target cells. However, Rag gammac(-/-) mice were not productively infected with MNV by the oral route, in which virions must cross the intestinal epithelial barrier. These data are consistent with a model whereby PP M cells are the primary route by which MNV crosses the intestinal epithelia of BALB/c mice. IMPORTANCE: Noroviruses (NoVs) are prevalent pathogens that infect their hosts via the intestine. Identifying key factors during the initial stages of virus infection in the host may provide novel points of intervention. Microfold (M) cells, antigen-sampling cells in the intestine, were previously shown to provide a gateway for murine NoV (MNV) into the host, but the relative importance of this uptake pathway remained unknown. Here we show that the absence of gut-associated lymphoid tissues (GALT), such as Peyer's patches, which contain high numbers of mature M cells, renders BALB/c mice refractory to oral infection with MNV. These findings are consistent with the model that M cells represent the primary route by which MNV crosses the intestinal epithelial barrier and infects underlying immune cells during a productive infection. PMID- 26581994 TI - Engineering Enhanced Vaccine Cell Lines To Eradicate Vaccine-Preventable Diseases: the Polio End Game. AB - Vaccine manufacturing costs prevent a significant portion of the world's population from accessing protection from vaccine-preventable diseases. To enhance vaccine production at reduced costs, a genome-wide RNA interference (RNAi) screen was performed to identify gene knockdown events that enhanced poliovirus replication. Primary screen hits were validated in a Vero vaccine manufacturing cell line using attenuated and wild-type poliovirus strains. Multiple single and dual gene silencing events increased poliovirus titers >20 fold and >50-fold, respectively. Host gene knockdown events did not affect virus antigenicity, and clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9-mediated knockout of the top candidates dramatically improved viral vaccine strain production. Interestingly, silencing of several genes that enhanced poliovirus replication also enhanced replication of enterovirus 71, a clinically relevant virus to which vaccines are being targeted. The discovery that host gene modulation can markedly increase virus vaccine production dramatically alters mammalian cell-based vaccine manufacturing possibilities and should facilitate polio eradication using the inactivated poliovirus vaccine. IMPORTANCE: Using a genome-wide RNAi screen, a collection of host virus resistance genes was identified that, upon silencing, increased poliovirus and enterovirus 71 production by from 10-fold to >50-fold in a Vero vaccine manufacturing cell line. This report provides novel insights into enterovirus host interactions and describes an approach to developing the next generation of vaccine manufacturing through engineered vaccine cell lines. The results show that specific gene silencing and knockout events can enhance viral titers of both attenuated (Sabin strain) and wild-type polioviruses, a finding that should greatly facilitate global implementation of inactivated polio vaccine as well as further reduce costs for live-attenuated oral polio vaccines. This work describes a platform-enabling technology applicable to most vaccine-preventable diseases. PMID- 26581995 TI - C-5-Modified Tetrahydropyrano-Tetrahydofuran-Derived Protease Inhibitors (PIs) Exert Potent Inhibition of the Replication of HIV-1 Variants Highly Resistant to Various PIs, including Darunavir. AB - We identified three nonpeptidic HIV-1 protease inhibitors (PIs), GRL-015, -085, and -097, containing tetrahydropyrano-tetrahydrofuran (Tp-THF) with a C-5 hydroxyl. The three compounds were potent against a wild-type laboratory HIV-1 strain (HIV-1(WT)), with 50% effective concentrations (EC50s) of 3.0 to 49 nM, and exhibited minimal cytotoxicity, with 50% cytotoxic concentrations (CC50) for GRL-015, -085, and -097 of 80, >100, and >100 MUM, respectively. All the three compounds potently inhibited the replication of highly PI-resistant HIV-1 variants selected with each of the currently available PIs and recombinant clinical HIV-1 isolates obtained from patients harboring multidrug-resistant HIV 1 variants (HIVMDR). Importantly, darunavir (DRV) was >1,000 times less active against a highly DRV-resistant HIV-1 variant (HIV-1DRV(R) P51); the three compounds remained active against HIV-1DRV(R) P51 with only a 6.8- to 68-fold reduction. Moreover, the emergence of HIV-1 variants resistant to the three compounds was considerably delayed compared to the case of DRV. In particular, HIV-1 variants resistant to GRL-085 and -097 did not emerge even when two different highly DRV-resistant HIV-1 variants were used as a starting population. In the structural analyses, Tp-THF of GRL-015, -085, and -097 showed strong hydrogen bond interactions with the backbone atoms of active-site amino acid residues (Asp29 and Asp30) of HIV-1 protease. A strong hydrogen bonding formation between the hydroxyl moiety of Tp-THF and a carbonyl oxygen atom of Gly48 was newly identified. The present findings indicate that the three compounds warrant further study as possible therapeutic agents for treating individuals harboring wild-type HIV and/or HIVMDR. IMPORTANCE: Darunavir (DRV) inhibits the replication of most existing multidrug-resistant HIV-1 strains and has a high genetic barrier. However, the emergence of highly DRV-resistant HIV-1 strains (HIVDRV(R) ) has recently been observed in vivo and in vitro. Here, we identified three novel HIV-1 protease inhibitors (PIs) containing a tetrahydropyrano tetrahydrofuran (Tp-THF) moiety with a C-5 hydroxyl (GRL-015, -085, and -097) which potently suppress the replication of HIVDRV(R) . Moreover, the emergence of HIV-1 strains resistant to the three compounds was considerably delayed compared to the case of DRV. The C-5 hydroxyl formed a strong hydrogen bonding interaction with the carbonyl oxygen atom of Gly48 of protease as examined in the structural analyses. Interestingly, a compound with Tp-THF lacking the hydroxyl moiety substantially decreased activity against HIVDRV(R) . The three novel compounds should be further developed as potential drugs for treating individuals harboring wild-type and multi-PI-resistant HIV variants as well as HIVDRV(R) . PMID- 26581997 TI - Expression of Alternatively Spliced Human T-Cell Leukemia Virus Type 1 mRNAs Is Influenced by Mitosis and by a Novel cis-Acting Regulatory Sequence. AB - Human T-cell leukemia virus type 1 (HTLV-1) expression depends on the concerted action of Tax, which drives transcription of the viral genome, and Rex, which favors expression of incompletely spliced mRNAs and determines a 2-phase temporal pattern of viral expression. In the present study, we investigated the Rex dependence of the complete set of alternatively spliced HTLV-1 mRNAs. Analyses of cells transfected with Rex-wild-type and Rex-knockout HTLV-1 molecular clones using splice site-specific quantitative reverse transcription (qRT)-PCR revealed that mRNAs encoding the p30Tof, p13, and p12/8 proteins were Rex dependent, while the p21rex mRNA was Rex independent. These findings provide a rational explanation for the intermediate-late temporal pattern of expression of the p30tof, p13, and p12/8 mRNAs described in previous studies. All the Rex-dependent mRNAs contained a 75-nucleotide intronic region that increased the nuclear retention and degradation of a reporter mRNA in the absence of other viral sequences. Selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE) analysis revealed that this sequence formed a stable hairpin structure. Cell cycle synchronization experiments indicated that mitosis partially bypasses the requirement for Rex to export Rex-dependent HTLV-1 transcripts. These findings indicate a link between the cycling properties of the host cell and the temporal pattern of viral expression/latency that might influence the ability of the virus to spread and evade the immune system. IMPORTANCE: HTLV-1 is a complex retrovirus that causes two distinct pathologies termed adult T-cell leukemia/lymphoma and tropical spastic paraparesis/HTLV-1-associated myelopathy in about 5% of infected individuals. Expression of the virus depends on the concerted action of Tax, which drives transcription of the viral genome, and Rex, which favors expression of incompletely spliced mRNAs and determines a 2-phase temporal pattern of virus expression. The findings reported in this study revealed a novel cis-acting regulatory element and indicated that mitosis partially bypasses the requirement for Rex to export Rex-dependent HTLV-1 transcripts. Our results add a layer of complexity to the mechanisms controlling the expression of alternatively spliced HTLV-1 mRNAs and suggest a link between the cycling properties of the host cell and the temporal pattern of viral expression/latency that might influence the ability of the virus to spread and evade the immune system. PMID- 26581998 TI - A Single Amino Acid Change in the Marburg Virus Matrix Protein VP40 Provides a Replicative Advantage in a Species-Specific Manner. AB - Marburg virus (MARV) induces severe hemorrhagic fever in humans and nonhuman primates but only transient nonlethal disease in rodents. However, sequential passages of MARV in rodents boosts infection leading to lethal disease. Guinea pig-adapted MARV contains one mutation in the viral matrix protein VP40 at position 184 (VP40D184N). The contribution of the D184N mutation to the efficacy of replication in a new host is unknown. In the present study, we demonstrated that recombinant MARV containing the D184N mutation in VP40 [rMARVVP40(D184N)] grew to higher titers than wild-type recombinant MARV (rMARVWT) in guinea pig cells. Moreover, rMARVVP40(D184N) displayed higher infectivity in guinea pig cells. Comparative analysis of VP40 functions indicated that neither the interferon (IFN)-antagonistic function nor the membrane binding capabilities of VP40 were affected by the D184N mutation. However, the production of VP40-induced virus-like particles (VLPs) and the recruitment of other viral proteins to the budding site was improved by the D184N mutation in guinea pig cells, which resulted in the higher infectivity of VP40D184N-induced infectious VLPs (iVLPs) compared to that of VP40-induced iVLPs. In addition, the function of VP40 in suppressing viral RNA synthesis was influenced by the D184N mutation specifically in guinea pig cells, thus allowing greater rates of transcription and replication. Our results showed that the improved viral fitness of rMARVVP40(D184N) in guinea pig cells was due to the better viral assembly function of VP40D184N and its lower inhibitory effect on viral transcription and replication rather than modulation of the VP40-mediated suppression of IFN signaling. IMPORTANCE: The increased virulence achieved by virus passaging in a new host was accompanied by mutations in the viral genome. Analyzing how these mutations affect the functions of viral proteins and the ability of the virus to grow within new host cells helps in the understanding of the molecular mechanisms increasing virulence. Using a reverse genetics approach, we demonstrated that a single mutation in MARV VP40 detected in a guinea pig-adapted MARV provided a replicative advantage of rMARVVP40(D184N) in guinea pig cells. Our studies show that this replicative advantage of rMARV VP40D184N was based on the improved functions of VP40 in iVLP assembly and in the regulation of transcription and replication rather than on the ability of VP40 to combat the host innate immunity. PMID- 26581996 TI - Genetics, Receptor Binding, Replication, and Mammalian Transmission of H4 Avian Influenza Viruses Isolated from Live Poultry Markets in China. AB - H4 avian influenza virus (AIV) is one of the most prevalent influenza virus subtypes in the world. However, whether H4 AIVs pose a threat to public health remains largely unclear. Here, we analyzed the phylogenetic relationships, receptor binding properties, replication, and transmissibility in mammals of H4 AIVs isolated from live poultry markets in China between 2009 and 2012. Genomic sequence analysis of 36 representative H4 viruses revealed 32 different genotypes, indicating that these viruses are undergoing complex and frequent reassortment events. All 32 viruses tested could replicate in the respiratory organs of infected mice without prior adaptation. Receptor binding analysis demonstrated that the H4 AIVs bound to alpha-2,6-linked glycans, although they retained the binding preference for alpha-2,3-linked glycans. When we tested the direct-contact transmission of 10 H4 viruses in guinea pigs, we found that three viruses did not transmit to any of the contact animals, one virus transmitted to one of three contact animals, and six viruses transmitted to all three contact animals. When we further tested the respiratory droplet transmissibility of four of the viruses that transmitted efficiently via direct contact, we found that three of them could transmit to one or two of the five exposed animals. Our study demonstrates that the current circulating H4 AIVs can infect, replicate in, and transmit to mammalian hosts, thereby posing a potential threat to human health. These findings emphasize the continual need for enhanced surveillance of H4 AIVs. IMPORTANCE: Numerous surveillance studies have documented the wide distribution of H4 AIVs throughout the world, yet the biological properties of H4 viruses have not been well studied. In this study, we found that multiple genotypes of H4 viruses are cocirculating in the live poultry markets of China and that H4 viruses can replicate in mice, possess human-type receptor binding specificity, and transmit between guinea pigs via direct contact. Strikingly, some H4 strains also can transmit via respiratory droplet, albeit with limited efficiency. These results clearly show the potential threat posed by H4 viruses to public health. PMID- 26581999 TI - Ancestral Mutations Acquired in Refrex-1, a Restriction Factor against Feline Retroviruses, during its Cooption and Domestication. AB - Endogenous retroviruses (ERVs) are remnants of ancestral retroviral infections of germ cells. Retroviral endogenization is an adaptation process for the host genome, and ERVs are gradually attenuated or inactivated by mutation. However, some ERVs that have been "domesticated" by their hosts eventually gain physiological functions, such as placentation or viral resistance. We previously reported the discovery of Refrex-1, a soluble antiretroviral factor in domestic cats that specifically inhibits infection by feline leukemia virus subgroup D (FeLV-D), a chimeric virus of FeLV, and a feline ERV, ERV-DC. Refrex-1 is a truncated envelope protein (Env) encoded by both ERV-DC7 and ERV-DC16 proviral loci. Here, we reconstituted ancestral and functional Env from ERV-DC7 and ERV DC16 envelope genes (env) by inducing reverse mutations. Unexpectedly, ERV-DC7 and ERV-DC16 full-length Env (ERV-DC7 fl and ERV-DC16 fl), reconstructed by removing stop codons, did not produce infectious viral particles. ERV-DC7 fl and ERV-DC16 fl were highly expressed in cells but were not cleaved into surface subunits (SU) and transmembrane subunits, nor were they incorporated into virions. G407R/N427I-A429T and Y431D substitutions within the SU C-terminal domain of ERV-DC7 fl and ERV-DC16 fl, respectively, caused these dysfunctions. The residues glycine 407 and tyrosine 431 are relatively conserved among infectious gammaretroviruses, and their substitution causes the same dysfunctions as the tested retroviruses. Our results reveal that specific mutations within the SU C-terminal domain suppressed Env cleavage and incorporation into virions and indicate that these mutations contributed to the domestication of Refrex-1 through multistep events that occurred in the postintegration period. IMPORTANCE: Domestic cats are colonized with various exogenous retroviruses (exRVs), such as feline leukemia virus (FeLV), and their genomes contain numerous ERVs, some of which are replication-competent proviruses. The feline hosts, exRVs, and ERVs have complicated genetic interactions and provide an interesting field model for triangular relationships: recombination between FeLV and ERV-DC, which is a feline ERV, generated FeLV-D, a chimeric virus, and FeLV-D is restricted by Refrex-1, an antiretroviral factor corresponding to truncated Env of ERV-DC7 and ERV-DC16. Here, we reconstructed ancestral, functional Env from ERV-DC7 and ERV DC16 env by inducing reverse mutations to elucidate how Refrex-1 was generated from its ancestor. Our results reveal that they were repeatedly inactivated by mutations preventing Env maturation. Our results provide insights into how ERVs were "domesticated" by their hosts and identify the mutations that mediated these evolutions. Notably, experiments that restore inactivated ERVs might uncover previously unrecognized features or properties of retroviruses. PMID- 26582001 TI - Personal history of psoriasis and risk of incident cancer among women: a population-based cohort study. PMID- 26582000 TI - Three-Dimensional Structural Characterization of HIV-1 Tethered to Human Cells. AB - Tetherin (BST2, CD317, or HM1.24) is a host cellular restriction factor that prevents the release of enveloped viruses by mechanically linking virions to the plasma membrane. The precise arrangement of tetherin molecules at the plasma membrane site of HIV-1 assembly, budding, and restriction is not well understood. To gain insight into the biophysical mechanism underlying tetherin-mediated restriction of HIV-1, we utilized cryo-electron tomography (cryo-ET) to directly visualize HIV-1 virus-like particles (VLPs) and virions tethered to human cells in three dimensions (3D). Rod-like densities that we refer to as tethers were seen connecting HIV-1 virions to each other and to the plasma membrane. Native immunogold labeling showed tetherin molecules located on HIV-1 VLPs and virions in positions similar to those of the densities observed by cryo-ET. The location of the tethers with respect to the ordered immature Gag lattice or mature conical core was random. However, tethers were not uniformly distributed on the viral membrane but rather formed clusters at sites of contact with the cell or other virions. Chains of tethered HIV-1 virions often were arranged in a linear fashion, primarily as single chains and, to a lesser degree, as branched chains. Distance measurements support the extended tetherin model, in which the coiled coil ectodomains are oriented perpendicular with respect to the viral and plasma membranes. IMPORTANCE: Tetherin is a cellular factor that restricts HIV-1 release by directly cross-linking the virus to the host cell plasma membrane. We used cryo-electron tomography to visualize HIV-1 tethered to human cells in 3D. We determined that tetherin-restricted HIV-1 virions were physically connected to each other or to the plasma membrane by filamentous tethers that resembled rods ~15 nm in length, which is consistent with the extended tetherin model. In addition, we found the position of the tethers to be arbitrary relative to the ordered immature Gag lattice or the mature conical cores. However, when present as multiple copies, the tethers clustered at the interface between virions. Tethered HIV-1 virions were arranged in a linear fashion, with the majority as single chains. This study advances our understanding of tetherin-mediated HIV-1 restriction by defining the spatial arrangement and orientation of tetherin molecules at sites of HIV-1 restriction. PMID- 26582002 TI - The influence of NK cell-mediated ADCC: Structure and expression of the CD16 molecule differ among FcgammaRIIIa-V158F genotypes in healthy Japanese subjects. AB - NK cells express the CD16 (FcgammaRIIIa) receptor, which mediates antibody dependent cellular cytotoxicity (ADCC), on their cell surface. Therefore, ADCC activity may be influenced by qualitative or quantitative changes in the CD16 molecule on NK cells. Responses to NK cell-mediated ADCC have been shown to depend on single nucleotide polymorphisms (SNPs) at FcgammaRIIIa amino acid position 158. However, a consensus has not yet been reached regarding differences in the structure and expression levels of the CD16 molecule among FcgammaRIIIa V158F genotypes, which have not yet been adequately investigated in healthy Japanese individuals. We herein examined the influence of the FcgammaRIIIa polymorphism on ADCC, binding affinity of CD16 to the Fc region, FCGR3A gene expression, and cell-surface CD16 expression in healthy Japanese subjects. FcgammaRIIIa-V158F genotyping was performed for 101 subjects. The results obtained showed that all parameters analyzed increased in the order of V/V>V/F>F/F and were significantly higher in V/V subjects than in F/F subjects. Moreover, a positive correlation was observed between ADCC activity and binding affinity, FCGR3A transcript levels, and surface CD16 expression levels. These results suggest that the structure and expression of the CD16 molecule differs among FcgammaRIIIa-V158F genotypes, and the FcgammaRIIIa-V158F polymorphism may be represent a haplotype with other SNPs in regulatory regions in Japanese subjects. PMID- 26582003 TI - Early post-transplant neopterin associated with one year survival and bacteremia in liver transplant recipients. AB - Bacterial infections are the most common complications, and the major cause of mortality after liver transplantation (Tx). Neopterin, a marker of immune activation, is produced in monocyte/macrophages in response to inflammation. The aim of our study was to investigate whether early post-operation serum levels of neopterin were associated with post-transplant bacteremia and mortality in liver transplant recipients. We studied 162 of 262 liver Tx patients between January 2008 and February 2011 of whom pre- and early post-Tx sera samples were available. Pre- and early post-operative risk factors of infection and mortality were evaluated in 45 bacteremic patients and 117 non-bacteremic patients. During one-year follow-up, 28 of 262 patients died because of graft failure, septicemia and other diseases. Post-Tx serum neopterin on day 10 (p<0.001) were significantly higher in bacteriemic patients than in patients without bacteremia. Logistic regression analyses showed that day 10 post-Tx neopterin serum level ?40 nmol/l has a predictive value (OR=6.86: p<0.001) for bacteremia and mortality (OR=3.47: p=0.021). Our results suggest that early post-Tx neopterin serum levels are very sensitive predictive markers of one-year post-Tx bacteremia and mortality in liver Tx recipients. PMID- 26582004 TI - Association of CTLA4 exon-1 polymorphism with the tumor necrosis factor-alpha in the risk of systemic lupus erythematosus among South Indians. AB - Cytotoxic T lymphocyte associated-antigen (CTLA4) is a potential negative regulatory molecule of T-cells and associated with several autoimmune diseases. Several reports from different ethnic groups showed that the polymorphisms of the CTLA4 gene have been associated with autoimmune diseases including SLE. Therefore, we aimed to investigate the +49 A/G polymorphism in South Indian SLE patients and its association with disease aetiology and serological markers. A total of 534 samples were genotyped for the +49 A/G polymorphism in exon 1 of the CTLA-4 gene through PCR-RFLP method. We found significant association of genotype and allele frequencies with +49 A/G polymorphism in SLE patients. The frequency of the +49 A/G polymorphism rs231775 'GG' genotype was significantly higher in patients with SLE (12.32%) than those in healthy control subjects (4.6%) (OR: 1.797; 95% CI 1.264-2.554; p=0.001). The frequency of mutant allele 'G' also found to be significantly higher in cases (36.01%) than controls (24.92%) (OR: 1.695, 95% CI: 1.298-2.214, p<0.001). We observed significant increase in serum TNF-alpha, interferon-alpha, IL-10 and IL-12 in SLE cases compared to controls. We also found a significant association of serum TNF-alpha, interferon-alpha, IL 10 and IL-12 with SLE phenotypes. In addition there was a significant increase in serum TNF-alpha level in "GG" genotype SLE subjects suggesting that it might play a major role in the advancement of SLE disease. PMID- 26582005 TI - HLA imputation in an admixed population: An assessment of the 1000 Genomes data as a training set. AB - Methods to impute HLA alleles based on dense single nucleotide polymorphism (SNP) data provide a valuable resource to association studies and evolutionary investigation of the MHC region. The availability of appropriate training sets is critical to the accuracy of HLA imputation, and the inclusion of samples with various ancestries is an important pre-requisite in studies of admixed populations. We assess the accuracy of HLA imputation using 1000 Genomes Project data as a training set, applying it to a highly admixed Brazilian population, the Quilombos from the state of Sao Paulo. To assess accuracy, we compared imputed and experimentally determined genotypes for 146 samples at 4 HLA classical loci. We found imputation accuracies of 82.9%, 81.8%, 94.8% and 86.6% for HLA-A, -B, -C and -DRB1 respectively (two-field resolution). Accuracies were improved when we included a subset of Quilombo individuals in the training set. We conclude that the 1000 Genomes data is a valuable resource for construction of training sets due to the diversity of ancestries and the potential for a large overlap of SNPs with the target population. We also show that tailoring training sets to features of the target population substantially enhances imputation accuracy. PMID- 26582006 TI - The epitranscriptome in modulating spatiotemporal RNA translation in neuronal post-synaptic function. AB - The application of next-generation-sequencing based methods has recently allowed the sequence-specific occurrence of RNA modifications to be investigated in transcriptome-wide settings. This has led to the emergence of a new field of molecular genetics research termed "epitranscriptomics." Investigations have shown that these modifications can exert control over protein synthesis via various mechanisms, and particularly when occurring on messenger RNAs, can be dynamically regulated. Here, we propose that RNA modifications may be a critical regulator over the spatiotemporal control of protein-synthesis in neurons, which is supported by our finding that the RNA methylase NSun2 colocalizes with the translational-repressor FMRP at neuronal dendrites. We also observe that NSun2 commonly methylates mRNAs which encode components of the postsynaptic proteome, and further find that NSun2 and FMRP likely share a common subset of mRNA targets which include those that are known to be translated at dendrites in an activity dependent manner. We consider potential roles for RNA modifications in space- time- and activity-dependent regulation of protein synthesis in neuronal physiology, with a particular focus on synaptic plasticity modulation. PMID- 26582007 TI - Optical properties of orthodontic aligners--spectrophotometry analysis of three types before and after aging. AB - BACKGROUND: The aim was to assess and compare absorbance and transmittance values of three types of clear orthodontic aligners before and after two cycles of in vitro aging. METHODS: Nine samples of orthodontic aligners from three different manufacturers (Invisalign, Align Technology, Santa Clara, CA, USA; All-In, Micerium, Avegno, GE, Italy; F22 Aligner, Sweden & Martina, Due Carrare, PD, Italy) were selected, and each sample was subjected to spectrophotometry analysis of both its transmittance and absorbance a total of 27 times. Samples were subsequently aged in vitro at a constant temperature in artificial saliva supplemented with food colouring for two cycles of 14 days each. The spectrophotometry protocol was then repeated, and the resulting data were analysed and compared by means of ANOVA (p < 0.05). RESULTS: All types of aligners tested yielded lower transmittance and higher absorbance values after aging, but the difference was not significant in any case. That being said, the F22 aligners were found to be most transparent, both before and after aging, followed by Invisalign and All-In, and these differences were statistically significant. CONCLUSIONS: Commercial aligners possess significantly different optical, and therefore aesthetic, properties, both as delivered and following aging. PMID- 26582008 TI - Relationship between health behaviour and body mass index in the Serbian adult population: data from National Health Survey 2013. AB - OBJECTIVES: To determine relationship between health behaviour and body mass index (BMI) in a Serbian adult population. METHODS: Study population included adults aged 20 and more years. A stratified, two-stage national representative random sampling approach was used for the selection of the survey sample. RESULTS: Regarding BMI, out of the 12,461 subjects of both sexes, 2.4 % were underweight, 36.5 % overweight and 22.4 % obese. Multivariate logistic regression analysis showed that both in men and women, risk factors for obesity were former smoking, irregular eating breakfast and low physical activity level, while in women only risk of obesity was associated with alcohol consumption. In both sexes, risk factors for overweight were former smoking and low physical activity level, and in women additionally those were alcohol consumption, irregular eating breakfast, always adding salt to meals and consumption of 2-4 portions of fruit daily. Smoking and irregular eating of breakfast in men were risk factors for underweight. CONCLUSIONS: Physical activity, alcohol consumption, smoking, irregular breakfast consumption, adding salt to meals, frequency of vegetable and fruit consumption were related to BMI in adult Serbian population. PMID- 26582009 TI - Preferred flavors and reasons for e-cigarette use and discontinued use among never, current, and former smokers. AB - OBJECTIVES: To compare e-cigarette flavors preferred and reasons for use and discontinued use across never, current, and former e-cigarette users and cigarette smokers. METHODS: We recruited 1567 participants aged 18-34 years through Facebook ads targeting tobacco users and nonusers in August 2014 to complete an online survey. We assessed tobacco use, preferred flavors, and reasons for e-cigarette use and discontinued use. RESULTS: Our sample was 49 % male, 87 % White; 56 % current cigarette smokers; and 53 % e-cigarette users. Current e-cigarette users used an average of 20.9 days in the past 30 (SD = 11.7) and 55.2 puffs/day (SD = 37.3). Compared to never and current smokers, former smokers used e-cigarettes more frequently (p's <0.001). Among users and nonusers, the most preferred was fruit flavors, and the most commonly reported reason for e cigarette use was "they might be less harmful than cigarettes". The most endorsed reason for discontinued e-cigarette use was "using other tobacco products instead". Never, current, and former smokers had distinct reasons for e-cigarette use and discontinued use and differed in flavor preferences. CONCLUSIONS: Regulating marketing and flavors may impact e-cigarette uptake by young adults. PMID- 26582010 TI - Parviterribacter kavangonensis gen. nov., sp. nov. and Parviterribacter multiflagellatus sp. nov., novel members of Parviterribacteraceae fam. nov. within the order Solirubrobacterales, and emended descriptions of the classes Thermoleophilia and Rubrobacteria and their orders and families. AB - Two Gram-type-positive, non-spore-forming bacteria, strains D16/0/H6T and A22/0/F9_1T, were isolated from Namibian semiarid savannah soils. 16S rRNA gene sequence analysis revealed 96.6 % identity between the two strains and placed them within the order Solirubrobacterales of the class Thermoleophilia. The closest phylogenetic relatives with validly published names were several strains of the genus Solirubrobacter and the species Conexibacter arvalis, with pairwise sequence similarities of <= 94.0 %. Cells of strain D16/0/H6T were ovoid to rod shaped, whereas strain A22/0/F9_1T formed regular rods. Cells of both strains were motile and divided by binary fission. Colonies were pink and white to pale yellowish/brownish, respectively. Strains D16/0/H6T and A22/0/F9_1T were aerobic, chemoheterotrophic mesophiles with broad temperature (13-43 and 17-43 degrees C, respectively) and pH (pH 4.5-8.5 and 5.0-9.5) ranges for growth. Complex proteinaceous substrates and glucose were the preferred carbon and energy sources. Strain A22/0/F9_1T also grew on various carboxylic acids. For both strains, the peptidoglycan diamino acid was meso-2,6-diaminopimelic acid. The major quinone was MK-8. As a minor compound, MK-7 occurred in strain D16/0/H6T; strain A22/0F9_1T also contained MK-7, MK-7(H2) and MK-8(H2). Major fatty acids of strain D16/0/H6T were 10-methyl C17 : 0, iso-C16 : 0 and C18 : 1omega9c. Strain A22/0F9_1T contained C18 : 1omega9c, C17 : 1omega8c, C17 : 1omega6c and iso-C16 : 0 as major components. The DNA G+C contents of strains D16/0/H6T and A22/0/F9_1T were 72.8 and 74.0 mol%, respectively. Based on these characteristics, the two isolates are assigned to novel species of the new genus Parviterribacter gen. nov., the type species Parviterribacter kavangonensis sp. nov. (type strain D16/0/H6T = DSM 25205T = LMG 26950T) and a second species Parviterribacter multiflagellatus sp. nov. (type strain A22/0/F9_1T = DSM 25204T = LMG 26949T). As the novel genus and species cannot be clearly assigned to an established family within the order Solirubrobacterales, the novel family Parviterribacteraceae fam. nov. is proposed. Emended descriptions of the classes Thermoleophilia and Rubrobacteria and their orders and families are also provided. PMID- 26582013 TI - An overview of chronic myeloid leukemia and its animal models. AB - Chronic myeloid leukemia (CML) is a form of leukemia characterized by the presence of clonal bone marrow stem cells with the proliferation of mature granulocytes (neutrophils, eosinophils, and basophils) and their precursors. CML is a type of myeloproliferative disease associated with a characteristic chromosomal translocation called the Philadelphia (Ph) chromosome or t (9;22) translocation (BCR-ABL). CML is now usually treated with targeted drugs called tyrosine kinase inhibitors (TKIs). The mechanism and natural history of CML is still unclear. Here, we summarize the present CML animal disease models and compare them with each other. Meanwhile, we propose that it is a very wise choice to establish zebrafish (Danio rerio) CML model mimics clinical CML. This model could be used to learn more about the mechanism of CML, and to aid in the development of new drugs to treat CML. PMID- 26582012 TI - Risks associated with dispersive nocturnal flights of sylvatic Triatominae to artificial lights in a model house in the northeastern plains of Colombia. AB - BACKGROUND: Control initiatives and continuous surveillance of vector-borne transmission have proved to be effective measures for diminishing the incidence of Chagas disease in endemic countries. However, the active dispersal of infected sylvatic adult triatomines by flight represents one of the main obstacles to eliminating domestic transmission. METHODS: In order to determine the risk that active dispersal of sylvatic adult triatomines represents in Colombian northeastern plains, we quantified the distribution and abundance of triatomines in palm trees (primarily Attalea butyracea) using live bait traps. Directional light traps were used to estimate the frequency of sylvatic triatomine dispersal and their possible origin. Finally, the effect of environmental parameters and artificial light sources on the take-off of sylvatic Rhodnius prolixus was evaluated in field experiments. RESULTS: R. prolixus was found in 90 % of the palm trees that densely aggregated toward the northern portion of the study area. R. prolixus, and three other sylvatic triatomine species were found to actively disperse and were attracted to the directional light traps (Triatoma maculata, Panstrongylus geniculatus and Psammolestes arthuri). Temperature, relative humidity, wind speed and night luminosity did not affect the active dispersal of the triatomines which is higher the first two hours after sunset. Artificial lights from houses at 60 and 110 m played a key role in the directionality of the R. prolixus take-offs. Trypanosoma cruzi was isolated from R. prolixus, T. maculata and P. geniculatus and was genotyped as T. cruzi I, III and IV. CONCLUSIONS: Our results highlight the potential risk in Colombian northeastern plains of actively dispersing sylvatic triatomines and their role in the domestic introduction of Discrete Typing Units of T. cruzi associated to sylvatic foci of Chagas disease transmission. PMID- 26582014 TI - Pathways related to PMA-differentiated THP1 human monocytic leukemia cells revealed by RNA-Seq. AB - Previous analyses have reported that the human monocytic cell line THP1 can be differentiated into cells with macrophage-like characteristics by phorbol 12 myristate 13-acetate (PMA). However, little is known about the mechanism responsible for regulating this differentiation process. Here, we performed high throughput RNA-Seq analysis to investigate the genes differently expressed in THP1 cells treated with and without PMA and examined those that may be responsible for the PMA-induced differentiation of monocytes into macrophages. We found 3,000 genes to be differentially expressed after PMA treatment. Gene ontology analysis revealed that genes related to cellular processes and regulation of biological processes were significantly enriched. KEGG analysis also demonstrated that the differentially expressed genes (DEGs) were significantly enriched in the PI3K/AKT signaling pathway and phagosome pathway. Importantly, we reveal an important role of the PI3K/AKT pathway in PMA-induced THP1 cell differentiation. The identified DEGs and pathways may facilitate further study of the detailed molecular mechanisms of THP1 differentiation. Thus, our results provide numerous potential therapeutic targets for modulation of the differentiation of this disease. PMID- 26582015 TI - Selective oxidation of UDP-glucose to UDP-glucuronic acid using permeabilized Schizosaccharomyces pombe expressing human UDP-glucose 6-dehydrogenase. AB - OBJECTIVES: To use permeabilized cells of the fission yeast, Schizosaccharomyces pombe, that expresses human UDP-glucose 6-dehydrogenase (UGDH, EC 1.1.1.22), for the production of UDP-glucuronic acid from UDP-glucose. RESULTS: In cell extracts no activity was detected. Therefore, cells were permeabilized with 0.3 % (v/v) Triton X-100. After washing away all low molecular weight metabolites, the permeabilized cells were directly used as whole cell biocatalyst. Substrates were 5 mM UDP-glucose and 10 mM NAD(+). Divalent cations were not added to the reaction medium as they promoted UDP-glucose hydrolysis. With this reaction system 5 mM UDP-glucose were converted into 5 mM UDP-glucuronic acid within 3 h. CONCLUSIONS: Recombinant permeabilized cells of S. pombe can be used to synthesize UDP-glucuronic acid with 100 % yield and selectivity. PMID- 26582016 TI - Evolution of the additive genetic variance-covariance matrix under continuous directional selection on a complex behavioural phenotype. AB - Given the pace at which human-induced environmental changes occur, a pressing challenge is to determine the speed with which selection can drive evolutionary change. A key determinant of adaptive response to multivariate phenotypic selection is the additive genetic variance-covariance matrix ( G: ). Yet knowledge of G: in a population experiencing new or altered selection is not sufficient to predict selection response because G: itself evolves in ways that are poorly understood. We experimentally evaluated changes in G: when closely related behavioural traits experience continuous directional selection. We applied the genetic covariance tensor approach to a large dataset (n = 17 328 individuals) from a replicated, 31-generation artificial selection experiment that bred mice for voluntary wheel running on days 5 and 6 of a 6-day test. Selection on this subset of G: induced proportional changes across the matrix for all 6 days of running behaviour within the first four generations. The changes in G: induced by selection resulted in a fourfold slower-than-predicted rate of response to selection. Thus, selection exacerbated constraints within G: and limited future adaptive response, a phenomenon that could have profound consequences for populations facing rapid environmental change. PMID- 26582017 TI - Coral reef fish populations can persist without immigration. AB - Determining the conditions under which populations may persist requires accurate estimates of demographic parameters, including immigration, local reproductive success, and mortality rates. In marine populations, empirical estimates of these parameters are rare, due at least in part to the pelagic dispersal stage common to most marine organisms. Here, we evaluate population persistence and turnover for a population of orange clownfish, Amphiprion percula, at Kimbe Island in Papua New Guinea. All fish in the population were sampled and genotyped on five occasions at 2-year intervals spanning eight years. The genetic data enabled estimates of reproductive success retained in the same population (reproductive success to self-recruitment), reproductive success exported to other subpopulations (reproductive success to local connectivity), and immigration and mortality rates of sub-adults and adults. Approximately 50% of the recruits were assigned to parents from the Kimbe Island population and this was stable through the sampling period. Stability in the proportion of local and immigrant settlers is likely due to: low annual mortality rates and stable egg production rates, and the short larval stages and sensory capacities of reef fish larvae. Biannual mortality rates ranged from 0.09 to 0.55 and varied significantly spatially. We used these data to parametrize a model that estimated the probability of the Kimbe Island population persisting in the absence of immigration. The Kimbe Island population was found to persist without significant immigration. Model results suggest the island population persists because the largest of the subpopulations are maintained due to having low mortality and high self recruitment rates. Our results enable managers to appropriately target and scale actions to maximize persistence likelihood as disturbance frequencies increase. PMID- 26582018 TI - Metabolic programming mediated by an essential fatty acid alters body composition and survival skills of a marine fish. AB - Metabolic programming occurs when variations in nutrition during a specific developmental window result in long-term metabolic effects. It has been studied almost exclusively in humans and other mammals but never in an ecological context. Here, we report metabolic programming and its functional consequences in a marine fish, red drum. We demonstrate that maternal provisioning of eggs with an essential fatty acid, docosahexaenoic acid (DHA), varies with DHA content of the maternal diet. When offspring are reared on a DHA-replete diet, whole-body DHA content of offspring depends upon the amount of DHA that was in the egg. We further demonstrate that whole-body DHA content is correlated with traits related to offspring fitness (escape responses, routine swimming, growth, and survival). DHA content of red drum eggs produced in nature is in the range where the effects of metabolic programming are most pronounced. Our findings indicate that during a brief developmental window, DHA plays a role in establishing the metabolic capacity for its own uptake or storage, with protracted and possibly permanent effects on ecologically important survival skills of individuals and important implications for dynamics of populations and food webs. PMID- 26582019 TI - The parasite's long arm: a tapeworm parasite induces behavioural changes in uninfected group members of its social host. AB - Parasites can induce alterations in host phenotypes in order to enhance their own survival and transmission. Parasites of social insects might not only benefit from altering their individual hosts, but also from inducing changes in uninfected group members. Temnothorax nylanderi ant workers infected with the tapeworm Anomotaenia brevis are known to be chemically distinct from nest-mates and do not contribute to colony fitness, but are tolerated in their colonies and well cared for. Here, we investigated how tapeworm- infected workers affect colony aggression by manipulating their presence in ant colonies and analysing whether their absence or presence resulted in behavioural alterations in their nest-mates. We report a parasite-induced shift in colony aggression, shown by lower aggression of uninfected nest-mates from parasitized colonies towards conspecifics, potentially explaining the tolerance towards infected ants. We also demonstrate that tapeworm-infected workers showed a reduced flight response and higher survival, while their presence caused a decrease in survival of uninfected nest-mates. This anomalous behaviour of infected ants, coupled with their increased survival, could facilitate the parasites' transmission to its definitive hosts, woodpeckers. We conclude that parasites exploiting individuals that are part of a society not only induce phenotypic changes within their individual hosts, but in uninfected group members as well. PMID- 26582020 TI - Annual coral bleaching and the long-term recovery capacity of coral. AB - Mass bleaching events are predicted to occur annually later this century. Nevertheless, it remains unknown whether corals will be able to recover between annual bleaching events. Using a combined tank and field experiment, we simulated annual bleaching by exposing three Caribbean coral species (Porites divaricata, Porites astreoides and Orbicella faveolata) to elevated temperatures for 2.5 weeks in 2 consecutive years. The impact of annual bleaching stress on chlorophyll a, energy reserves, calcification, and tissue C and N isotopes was assessed immediately after the second bleaching and after both short- and long term recovery on the reef (1.5 and 11 months, respectively). While P. divaricata and O. faveolata were able to recover from repeat bleaching within 1 year, P. astreoides experienced cumulative damage that prevented full recovery within this time frame, suggesting that repeat bleaching had diminished its recovery capacity. Specifically, P. astreoides was not able to recover protein and carbohydrate concentrations. As energy reserves promote bleaching resistance, failure to recover from annual bleaching within 1 year will likely result in the future demise of heat-sensitive coral species. PMID- 26582022 TI - First- and second-order sociality determine survival and reproduction in cooperative cichlids. AB - Cooperative breeders serve as a model to study the evolution of cooperation, where costs and benefits of helping are typically scrutinized at the level of group membership. However, cooperation is often observed in multi-level social organizations involving interactions among individuals at various levels. Here, we argue that a full understanding of the adaptive value of cooperation and the evolution of complex social organization requires identifying the effect of different levels of social organization on direct and indirect fitness components. Our long-term field data show that in the cooperatively breeding, colonial cichlid fish Neolamprologus pulcher, both large group size and high colony density significantly raised group persistence. Neither group size nor density affected survival at the individual level, but they had interactive effects on reproductive output; large group size raised productivity when local population density was low, whereas in contrast, small groups were more productive at high densities. Fitness estimates of individually marked fish revealed indirect fitness benefits associated with staying in large groups. Inclusive fitness, however, was not significantly affected by group size, because the direct fitness component was not increased in larger groups. Together, our findings highlight that the reproductive output of groups may be affected in opposite directions by different levels of sociality, and that complex forms of sociality and costly cooperation may evolve in the absence of large indirect fitness benefits and the influence of kin selection. PMID- 26582021 TI - Spectral shifts of mammalian ultraviolet-sensitive pigments (short wavelength sensitive opsin 1) are associated with eye length and photic niche evolution. AB - Retinal opsin photopigments initiate mammalian vision when stimulated by light. Most mammals possess a short wavelength-sensitive opsin 1 (SWS1) pigment that is primarily sensitive to either ultraviolet or violet light, leading to variation in colour perception across species. Despite knowledge of both ultraviolet- and violet-sensitive SWS1 classes in mammals for 25 years, the adaptive significance of this variation has not been subjected to hypothesis testing, resulting in minimal understanding of the basis for mammalian SWS1 spectral tuning evolution. Here, we gathered data on SWS1 for 403 mammal species, including novel SWS1 sequences for 97 species. Ancestral sequence reconstructions suggest that the most recent common ancestor of Theria possessed an ultraviolet SWS1 pigment, and that violet-sensitive pigments evolved at least 12 times in mammalian history. We also observed that ultraviolet pigments, previously considered to be a rarity, are common in mammals. We then used phylogenetic comparative methods to test the hypotheses that the evolution of violet-sensitive SWS1 is associated with increased light exposure, extended longevity and longer eye length. We discovered that diurnal mammals and species with longer eyes are more likely to have violet sensitive pigments and less likely to possess UV-sensitive pigments. We hypothesize that (i) as mammals evolved larger body sizes, they evolved longer eyes, which limited transmittance of ultraviolet light to the retina due to an increase in Rayleigh scattering, and (ii) as mammals began to invade diurnal temporal niches, they evolved lenses with low UV transmittance to reduce chromatic aberration and/or photo-oxidative damage. PMID- 26582023 TI - The oxidative costs of reproduction are group-size dependent in a wild cooperative breeder. AB - Life-history theory assumes that reproduction entails a cost, and research on cooperatively breeding societies suggests that the cooperative sharing of workloads can reduce this cost. However, the physiological mechanisms that underpin both the costs of reproduction and the benefits of cooperation remain poorly understood. It has been hypothesized that reproductive costs may arise in part from oxidative stress, as reproductive investment may elevate exposure to reactive oxygen species, compromising survival and future reproduction and accelerating senescence. However, experimental evidence of oxidative costs of reproduction in the wild remains scarce. Here, we use a clutch-removal experiment to investigate the oxidative costs of reproduction in a wild cooperatively breeding bird, the white-browed sparrow weaver, Plocepasser mahali. Our results reveal costs of reproduction that are dependent on group size: relative to individuals in groups whose eggs were experimentally removed, individuals in groups that raised offspring experienced an associated cost (elevated oxidative damage and reduced body mass), but only if they were in small groups containing fewer or no helpers. Furthermore, during nestling provisioning, individuals that provisioned at higher rates showed greater within-individual declines in body mass and antioxidant protection. Our results provide rare experimental evidence that reproduction can negatively impact both oxidative status and body mass in the wild, and suggest that these costs can be mitigated in cooperative societies by the presence of additional helpers. These findings have implications for our understanding of the energetic and oxidative costs of reproduction, and the benefits of cooperation in animal societies. PMID- 26582024 TI - Downregulation of the evolutionary capacitor Hsp90 is mediated by social cues. AB - The relationship between robustness and evolvability is a long-standing question in evolution. Heat shock protein 90 (HSP90), a molecular chaperone, has been identified as a potential capacitor for evolution, since it allows for the accumulation and release of cryptic genetic variation, and also for the regulation of novel genetic variation through transposon activity. However, to date, it is unknown whether Hsp90 expression is regulated upon demand (i.e. when the release of cryptic genetic variation is most needed). Here, we show that Hsp90 has reduced transcription under conditions where the mobilization of genetic variation could be advantageous. We designed a situation that indicates a stressful environment but avoids the direct effects of stress, by placing untreated (focal) red flour beetles, Tribolium castaneum, into groups together with wounded conspecifics, and found a consistent reduction in expression of two Hsp90 genes (Hsp83 and Hsp90) in focal beetles. We moreover observed a social transfer of immunity in this non-eusocial insect: there was increased activity of the phenoloxidase enzyme and downregulation of the immune regulator, imd. Our study poses the exciting question of whether evolvability might be regulated through the use of information derived from the social environment. PMID- 26582025 TI - The agonistic adrenal: melatonin elicits female aggression via regulation of adrenal androgens. AB - Classic findings have demonstrated an important role for sex steroids as regulators of aggression, but this relationship is lacking within some environmental contexts. In mammals and birds, the adrenal androgen dehydroepiandrosterone (DHEA), a non-gonadal precursor of biologically active steroids, has been linked to aggression. Although females, like males, use aggression when competing for limited resources, the mechanisms underlying female aggression remain understudied. Here, we propose a previously undescribed endocrine mechanism regulating female aggression via direct action of the pineal hormone melatonin on adrenal androgens. We examined this in a solitary hamster species, Phodopus sungorus, in which both sexes are highly territorial across the seasons, and display increased aggression concomitant with decreased serum levels of sex steroids in short 'winter-like' days. Short- but not long-day females had increased adrenal DHEA responsiveness co-occurring with morphological changes in the adrenal gland. Further, serum DHEA and total adrenal DHEA content were elevated in short days. Lastly, melatonin increased DHEA and aggression and stimulated DHEA release from cultured adrenals. Collectively, these findings demonstrate that DHEA is a key peripheral regulator of aggression and that melatonin coordinates a 'seasonal switch' from gonadal to adrenal regulation of aggression by direct action on the adrenal glands. PMID- 26582026 TI - Reconciling laboratory and field assessments of neonicotinoid toxicity to honeybees. AB - European governments have banned the use of three common neonicotinoid pesticides due to insufficiently identified risks to bees. This policy decision is controversial given the absence of clear consistency between toxicity assessments of those substances in the laboratory and in the field. Although laboratory trials report deleterious effects in honeybees at trace levels, field surveys reveal no decrease in the performance of honeybee colonies in the vicinity of treated fields. Here we provide the missing link, showing that individual honeybees near thiamethoxam-treated fields do indeed disappear at a faster rate, but the impact of this is buffered by the colonies' demographic regulation response. Although we could ascertain the exposure pathway of thiamethoxam residues from treated flowers to honeybee dietary nectar, we uncovered an unexpected pervasive co-occurrence of similar concentrations of imidacloprid, another neonicotinoid normally restricted to non-entomophilous crops in the study country. Thus, its origin and transfer pathways through the succession of annual crops need be elucidated to conveniently appraise the risks of combined neonicotinoid exposures. This study reconciles the conflicting laboratory and field toxicity assessments of neonicotinoids on honeybees and further highlights the difficulty in actually detecting non-intentional effects on the field through conventional risk assessment methods. PMID- 26582027 TI - Sperm number trumps sperm size in mammalian ejaculate evolution. AB - Postcopulatory sexual selection is widely accepted to underlie the extraordinary diversification of sperm morphology. However, why does it favour longer sperm in some taxa but shorter in others? Two recent hypotheses addressing this discrepancy offered contradictory explanations. Under the sperm dilution hypothesis, selection via sperm density in the female reproductive tract favours more but smaller sperm in large, but the reverse in small, species. Conversely, the metabolic constraint hypothesis maintains that ejaculates respond positively to selection in small endothermic animals with high metabolic rates, whereas low metabolic rates constrain their evolution in large species. Here, we resolve this debate by capitalizing on the substantial variation in mammalian body size and reproductive physiology. Evolutionary responses shifted from sperm length to number with increasing mammalian body size, thus supporting the sperm dilution hypothesis. Our findings demonstrate that body-size-mediated trade-offs between sperm size and number can explain the extreme diversification in sperm phenotypes. PMID- 26582028 TI - Health trajectories reveal the dynamic contributions of host genetic resistance and tolerance to infection outcome. AB - Resistance and tolerance are two alternative strategies hosts can adopt to survive infections. Both strategies may be genetically controlled. To date, the relative contribution of resistance and tolerance to infection outcome is poorly understood. Here, we use a bioluminescent Listeria monocytogenes (Lm) infection challenge model to study the genetic determination and dynamic contributions of host resistance and tolerance to listeriosis in four genetically diverse mouse strains. Using conventional statistical analyses, we detect significant genetic variation in both resistance and tolerance, but cannot capture the time-dependent relative importance of either host strategy. We overcome these limitations through the development of novel statistical tools to analyse individual infection trajectories portraying simultaneous changes in infection severity and health. Based on these tools, early expression of resistance followed by expression of tolerance emerge as important hallmarks for surviving Lm infections. Our trajectory analysis further reveals that survivors and non survivors follow distinct infection paths (which are also genetically determined) and provides new survival thresholds as objective endpoints in infection experiments. Future studies may use trajectories as novel traits for mapping and identifying genes that control infection dynamics and outcome. A Matlab script for user-friendly trajectory analysis is provided. PMID- 26582029 TI - Macroevolutionary assembly of ant/plant symbioses: Pseudomyrmex ants and their ant-housing plants in the Neotropics. AB - Symbioses include some of the clearest cases of coevolution, but their origin, loss or reassembly with different partners can rarely be inferred. Here we use ant/plant symbioses involving three plant clades to investigate the evolution of symbioses. We generated phylogenies for the big-eyed arboreal ants (Pseudomyrmecinae), including 72% of their 286 species, as well as for five of their plant host groups, in each case sampling more than 61% of the species. We show that the ant-housing Vachellia (Mimosoideae) clade and its ants co diversified for the past 5 Ma, with some species additionally colonized by younger plant-nesting ant species, some parasitic. An apparent co-radiation of ants and Tachigali (Caesalpinioideae) was followed by waves of colonization by the same ant clade, and subsequent occupation by a younger ant group. Wide crown and stem age differences between the ant-housing genus Triplaris (Polygonaceae) and its obligate ant inhabitants, and stochastic trait mapping, indicate that its domatium evolved earlier than the ants now occupying it, suggesting previous symbioses that dissolved. Parasitic ant species evolved from generalists, not from mutualists, and are younger than the mutualistic systems they parasitize. Our study illuminates the macroevolutionary assembly of ant/plant symbioses, which has been highly dynamic, even in very specialized systems. PMID- 26582030 TI - Molecular diversity and distribution of marine fungi across 130 European environmental samples. AB - Environmental DNA and culture-based analyses have suggested that fungi are present in low diversity and in low abundance in many marine environments, especially in the upper water column. Here, we use a dual approach involving high throughput diversity tag sequencing from both DNA and RNA templates and fluorescent cell counts to evaluate the diversity and relative abundance of fungi across marine samples taken from six European near-shore sites. We removed very rare fungal operational taxonomic units (OTUs) selecting only OTUs recovered from multiple samples for a detailed analysis. This approach identified a set of 71 fungal 'OTU clusters' that account for 66% of all the sequences assigned to the Fungi. Phylogenetic analyses demonstrated that this diversity includes a significant number of chytrid-like lineages that had not been previously described, indicating that the marine environment encompasses a number of zoosporic fungi that are new to taxonomic inventories. Using the sequence datasets, we identified cases where fungal OTUs were sampled across multiple geographical sites and between different sampling depths. This was especially clear in one relatively abundant and diverse phylogroup tentatively named Novel Chytrid-Like-Clade 1 (NCLC1). For comparison, a subset of the water column samples was also investigated using fluorescent microscopy to examine the abundance of eukaryotes with chitin cell walls. Comparisons of relative abundance of RNA-derived fungal tag sequences and chitin cell-wall counts demonstrate that fungi constitute a low fraction of the eukaryotic community in these water column samples. Taken together, these results demonstrate the phylogenetic position and environmental distribution of 71 lineages, improving our understanding of the diversity and abundance of fungi in marine environments. PMID- 26582031 TI - Social benefits of non-kin food sharing by female vampire bats. AB - Regurgitations of blood among vampire bats appear to benefit both direct and indirect fitness. To maximize inclusive fitness, reciprocal food sharing should occur among close kin. Why then do females with kin roost-mates help non-kin? We tested the hypothesis that helping non-kin increases a bat's success at obtaining future donations by expanding its network of potential donors. On six occasions, we individually fasted 14 adult females and measured donations from 28 possible donors. Each female was fasted before, during and after a treatment period, when we prevented donations from past donors (including 10 close relatives) by simultaneously fasting or removing them. This experiment was designed to detect partner switching and yielded three main results. First, females received less food when we prevented donations from a past donor versus a control bat. Donors within a group are therefore not interchangeable. Second, the treatment increased the variance in donors' contributions to food received by subjects, suggesting the possibility of alternative responses to a partner's inability to reciprocate. Finally, bats that fed more non-kin in previous years had more donors and received more food during the treatment. These results indicate that a bat can expand its network of possible donors by helping non-kin. PMID- 26582032 TI - Identification and annotation of conserved promoters and macrophage-expressed genes in the pig genome. AB - BACKGROUND: The FANTOM5 consortium used Cap Analysis of Gene Expression (CAGE) tag sequencing to produce a comprehensive atlas of promoters and enhancers within the human and mouse genomes. We reasoned that the mapping of these regulatory elements to the pig genome could provide useful annotation and evidence to support assignment of orthology. RESULTS: For human transcription start sites (TSS) associated with annotated human-mouse orthologs, 17% mapped to the pig genome but not to the mouse, 10% mapped only to the mouse, and 55% mapped to both pig and mouse. Around 17% did not map to either species. The mapping percentages were lower where there was not clear orthology relationship, but in every case, mapping to pig was greater than to mouse, and the degree of homology was also greater. Combined mapping of mouse and human CAGE-defined promoters identified at least one putative conserved TSS for >16,000 protein-coding genes. About 54% of the predicted locations of regulatory elements in the pig genome were supported by CAGE and/or RNA-Seq analysis from pig macrophages. CONCLUSIONS: Comparative mapping of promoters and enhancers from humans and mice can provide useful preliminary annotation of other animal genomes. The data also confirm extensive gain and loss of regulatory elements between species, and the likelihood that pigs provide a better model than mice for human gene regulation and function. PMID- 26582033 TI - The repair of full-thickness articular cartilage defect using intra-articular administration of N-acetyl-D-glucosamine in the rabbit knee: randomized controlled trial. AB - BACKGROUND: Although various alterative models of therapy are used for cartilage repair, no definite conclusion has been reached. Glucosamine (GlcN) is widely used as a nutritional supplement. However, the clinical- evidence-based outcome of GlcN administration remains controversial. N-acetyl-D-glucosamine (GlcNAc), a derivative of GlcN, shows chondroprotective activity and mediates the activation of articular chondrocytes. Therefore, we investigated the effect of intra articular administration of GlcNAc in rabbits' knee joints with experimental full thickness articular cartilage (FTAC) defects. METHODS: Twelve male adult New Zealand white rabbits, providing 24 knees, were used in this study. FTAC defects were created in the high-weight-bearing area of the medial femoral condyles of bilateral knees. All rabbits were randomly allocated to analysis at postsurgical week 4 or postsurgical week 12. In the week 4 group, rabbits' knees (six per group) were intra-articularly injected with normal saline or with GlcNAc twice per week for 3 weeks, beginning 1 week postoperatively. In the week 12 group, the rabbits' knees (six in each group) were intra-articularly injected with normal saline or with GlcNAc twice per week for 4 weeks, beginning 1 week postoperatively. Rabbits were sacrificed at 4 or 12 weeks after surgery for macroscopic, histological and radiological examinations of the knee joints. RESULTS: All rabbits had no systemic or local adverse effects. The saline and GlcNAc groups showed visible differences in healing of the FTAC defect at the end of testing. At week 4, the GlcNAc group had a higher level of collagen type II (COL II) and showed up-regulated production of transforming growth factor (TGF) beta2 and TGF-beta3, suggesting the involvement of endogenous growth factors. At week 12, the GlcNAc group displayed formation of hyaline-like cartilage regeneration with mature chondrocytes (SOX9+), robust glycosaminoglycan (GAG) content, and positive COL II content in both the adjacent cartilage and reparative sites. However, the saline group demonstrated mainly fibrocartilage scar tissue, indicating COL I expression. Furthermore, the GlcNAc group had significantly higher bone volume per tissue volume and higher trabecular thickness than the saline group. CONCLUSIONS: Intra-articular GlcNAc may promote the repair of experimental FTAC defects in the rabbit knee joint model. PMID- 26582034 TI - Transcriptional regulatory networks controlling woolliness in peach in response to preharvest gibberellin application and cold storage. AB - BACKGROUND: Postharvest fruit conservation relies on low temperatures and manipulations of hormone metabolism to maintain sensory properties. Peaches are susceptible to chilling injuries, such as 'woolliness' that is caused by juice loss leading to a 'wooly' fruit texture. Application of gibberellic acid at the initial stages of pit hardening impairs woolliness incidence, however the mechanisms controlling the response remain unknown. We have employed genome wide transcriptional profiling to investigate the effects of gibberellic acid application and cold storage on harvested peaches. RESULTS: Approximately half of the investigated genes exhibited significant differential expression in response to the treatments. Cellular and developmental process gene ontologies were overrepresented among the differentially regulated genes, whereas sequences in cell death and immune response categories were underrepresented. Gene set enrichment demonstrated a predominant role of cold storage in repressing the transcription of genes associated to cell wall metabolism. In contrast, genes involved in hormone responses exhibited a more complex transcriptional response, indicating an extensive network of crosstalk between hormone signaling and low temperatures. Time course transcriptional analyses demonstrate the large contribution of gene expression regulation on the biochemical changes leading to woolliness in peach. CONCLUSION: Overall, our results provide insights on the mechanisms controlling the complex phenotypes associated to postharvest textural changes in peach and suggest that hormone mediated reprogramming previous to pit hardening affects the onset of chilling injuries. PMID- 26582035 TI - Minding the gap: access to palliative care and the homeless. AB - BACKGROUND: With an ever increasing number of individuals living with chronic and terminal illnesses, palliative care as an emerging field is poised for unprecedented expansion. Today's rising recognition of its key role in patients' illnesses has led to increased interest in access to palliative care. It is known that homelessness as a social determinant of health has been associated with decreased access to health resources in spite of poorer health outcomes and some would argue, higher need. This article aims to discuss the current state of affairs with regards to accessing palliative care for the homeless in Canada. DISCUSSION: Recent review of the literature reveals differential access to palliative care services and outcomes with differing socio-economic status (SES). Notably, individuals of lower SES and in particular, those who are homeless have poorer health outcomes in addition to poor access to quality palliative care. Current palliative care services are ill equipped to care for this vulnerable population and most programs are built upon an infrastructure that is prohibitive for the homeless to access its services. A preliminary review of existing Canadian programs in place to address this gap in access identified a paucity of sporadic palliative care programs across the country with a focus on homeless and vulnerably-housed individuals. It is apparent that there is no unified national strategy to address this gap in access. The changing landscape of the Canadian population calls for an expansion of palliative care as a field and as many have put it, as a right. The right to access quality palliative and end of life care should not be confined to particular population groups. This article calls for the development of a unified national strategy to address this glaring gap in our healthcare provision and advocates for attention to and adoption of policy and processes that would support the homeless populations' right to quality palliative care. PMID- 26582036 TI - The drug-drug interaction of sorafenib mediated by P-glycoprotein and CYP3A4. AB - 1. The aim of this study was to investigate the potential drug-drug interaction of sorafenib mediated by P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4). 2. In this research, a sensitive and reliable LC-MS/MS method was developed and applied for the determination of sorafenib in rat plasma. The pharmacokinetic profiles of orally administered sorafenib from rats with and without verapamil pretreatment were investigated. 3. The results indicated that when the rats were pretreated with verapamil, the Cmax of sorafenib increased from 55.73 ng/ml to 87.72 ng/ml (57.40%), and the AUC(0-t) increased by approximately 58.2% when sorafenib was co-administered with verapamil. Additionally, the effects of verapamil on the absorption of sorafenib were investigated using the Caco-2 cell transwell model, and the effects of verapamil on the metabolic stability of sorafenib were also studied using rat liver microsomes incubation systems. A markedly higher transport of sorafenib across the Caco-2 cells was observed in the basolateral-to-apical direction and was abrogated in the presence of the P-gp inhibitor, verapamil. The results indicated that P-gp was involved in the transport of sorafenib, and verapamil could increase its absorption in the Caco-2 cell model, and the metabolic stability of sorafenib was prolonged by the pretreatment with verapamil. 4. In conclusion, the drug-drug interaction of sorafenib might happen when sorafenib was co-administered with P-gp or CYP3A4 inhibitors. PMID- 26582037 TI - Dietary conjugated linoleic acids increase intramuscular fat deposition and decrease subcutaneous fat deposition in Yellow Breed * Simmental cattle. AB - This study was conducted to estimate the effect of dietary conjugated linoleic acids (CLA) on intramuscular and subcutaneous fat deposition in Yellow Breed * Simmental cattle. The experiment was conducted for 60 days. The results showed that the average backfat thickness, (testicles + kidney + pelvic) fat percentage and subcutaneous fat percentage in dietary CLA were significantly lower than in the control group, while intramuscular the fat percentage was significantly higher. Compared to the control group, the Longissimus muscle enzyme activities of lipoprotein lipase (LPL), fatty acid synthase (FAS) and acetyl-coenzyme A carboxylase (ACC) in dietary CLA and the subcutaneous fat enzyme activities of LPL, hormone-sensitive lipase (HSL) and carnitine palmitoyltransferase-1 (CPT-1) were significantly increased. Similarly, compared to the control group, the Longissimus muscle sterol regulatory element binding protein 1 (SREBP-1), FAS, stearoyl-coenzyme A desaturase (SCD), ACC, peroxisome proliferator-activated receptor gamma (PPARgamma), heart fatty-acid binding protein (H-FABP) and LPL gene expression in dietary CLA were significant increased, as were the subcutaneous fat of PPARgamma, H-FABP, LPL, CPT-1 and HSL in dietary CLA. These results indicated that dietary CLA increases IMF deposition mainly by the up regulation of lipogenic gene expression, while decreasing subcutaneous fat deposition mainly by the up-regulation of lipolytic gene expression. PMID- 26582038 TI - Paradoxical Effect of Nonphysiological Shear Stress on Platelets and von Willebrand Factor. AB - Blood can become hypercoagulable by shear-induced platelet activation and generation of microparticles. It has been reported that nonphysiological shear stress (NPSS) could induce shedding of platelet receptor glycoprotein (GP) Ibalpha, which may result in an opposite effect to hemostasis. The aim of this study was to investigate the influence of the NPSS on platelets and von Willebrand factor (vWF). Human blood was exposed to two levels of NPSS (25 Pa, 125 Pa) with an exposure time of 0.5 s, generated by using a novel blood-shearing device. Platelet activation (P-selectin expression, GPIIb/IIIa activation and generation of microparticles) and shedding of three platelet receptors (GPIbalpha, GPVI, GPIIb/IIIa) in sheared blood were quantified using flow cytometry. Aggregation capacity of sheared blood induced by ristocetin and collagen was evaluated using an aggregometer. Shear-induced vWF damage was characterized with Western blotting. Consistent with the published data, the NPSS caused significantly more platelets to become activated with increasing NPSS level. Meanwhile, the NPSS induced the shedding of platelet receptors. The loss of the platelet receptors increased with increasing NPSS level. The aggregation capacity of sheared blood induced by ristocetin and collagen decreased. There was a loss of high molecular weight multimers (HMWMs) of vWF in sheared blood. These results suggest that the NPSS induced a paradoxical effect. More activated platelets increase the risk of thrombosis, while the reduction in platelet receptors and the loss of HMWM-vWF increased the propensity of bleeding. The finding might provide a new perspective to understand thrombosis and acquired bleeding disorder in patients supported with blood contacting medical devices. PMID- 26582039 TI - Chronic hepatitis B infection presenting with chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS): a case report. AB - INTRODUCTION: Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids is a brainstem disorder characterized by perivascular pathologic reaction with lymphocyte infiltration and leading to diplopia, facial palsy, dysarthria, and gait ataxia. It was thought to be an autoimmune disorder without distinct pathogenesis. Chronic hepatitis B virus infection has been proposed in correlation with autoimmune diseases, including central nervous system demyelinating disease. Patients with chronic hepatitis B infection may develop the syndrome of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids. CASE PRESENTATION: A 34 year-old Taiwanese man who had been a hepatitis B virus carrier for a decade presented to our emergency room. He had influenza symptoms and progressive symptoms of left hemifacial numbness, double vision, and an unsteady gait of 2 days' duration. Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids was diagnosed, with increased hepatitis B viral load at the same time. He had no past history of similar neurologic deficits, and his liver function tests had been within normal limits before this episode. After corticosteroid and entecavir treatments, his neurological deficits and neuroimaging anomalies improved and his serum hepatitis B virus DNA viral load normalized. CONCLUSIONS: Hepatitis B virus infection may induce central nervous system autoimmune reactions, including chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids. In such cases, concomitant administration of corticosteroids and antiviral agent was helpful. We suggest further investigations in patients with regulatory T cell dysfunction, which may assist in clarifying a loss of immune tolerance in patients with such disorders. PMID- 26582040 TI - The prognostic value of regadenoson SPECT myocardial perfusion imaging in patients with end-stage renal disease. AB - BACKGROUND: The prognostic value of regadenoson SPECT myocardial perfusion imaging (MPI) has not been specifically studied in patients with end-stage renal disease (ESRD). METHODS AND RESULTS: We prospectively followed ESRD patients enrolled in the ASSUAGE and ASSUAGE-CKD trials in which they received regadenoson stress 99mTc-tetrofosmin SPECT-MPI. Images were semiquantitatively analyzed by an investigator blinded to clinical and outcome data. Patients were followed for cardiac death, myocardial infarction (MI), and coronary revascularization (CR). Revascularizations occurring >90 days post-MPI were considered "late" events. Survival analysis was performed using Cox regression models, adjusting for age, gender, diabetes, dyslipidemia, smoking, and known coronary artery disease. We analyzed 303 patients (mean age 54 years; 64% men), who were followed for 35 +/- 10 months. Adjusting for clinical covariates, abnormal regadenoson-stress MPI (SSS >= 4) was associated with increased risk of the composite of cardiac death or MI (23.9% vs 14.4%; HR 1.88; CI 1.04-3.41; P = .037) and the composite of cardiac death, MI, or late CR (27.3% vs 16.7%; HR 1.80; CI 1.03-3.14; P = .039). Adjusting for clinical covariates, regadenoson-induced myocardial ischemia (SDS >= 2) was associated with increased rate of the composite endpoint of cardiac death, MI, or CR (33.3% vs 16.9%; HR 1.97; CI 1.19-3.27; P = .008). CONCLUSION: Regadenoson-stress SPECT-MPI provides a significant prognostic value in patients with ESRD. ESRD patients with normal SPECT-MPI have relatively high adverse event rates. PMID- 26582041 TI - 'They hear "Africa" and they think that there can't be any good services'- perceived context in cross-national learning: a qualitative study of the barriers to Reverse Innovation. AB - BACKGROUND: Country-of-origin of a product can negatively influence its rating, particularly if the product is from a low-income country. It follows that how non traditional sources of innovation, such as low-income countries, are perceived is likely to be an important part of a diffusion process, particularly given the strong social and cognitive boundaries associated with the healthcare professions. METHODS: Between September and December 2014, we conducted eleven in depth face-to-face or telephone interviews with key informants from innovation, health and social policy circles, experts in international comparative policy research and leaders in Reverse Innovation in the United States. Interviews were open-ended with guiding probes into the barriers and enablers to Reverse Innovation in the US context, specifically also to understand whether, in their experience translating or attempting to translate innovations from low-income contexts into the US, the source of the innovation matters in the adopter context. Interviews were recorded, transcribed and analyzed thematically using the process of constant comparison. RESULTS: Our findings show that innovations from low-income countries tend to be discounted early on because of prior assumptions about the potential for these contexts to offer solutions to healthcare problems in the US. Judgments are made about the similarity of low income contexts with the US, even though this is based oftentimes on flimsy perceptions only. Mixing levels of analysis, local and national, leads to country level stereotyping and missed opportunities to learn from low-income countries. CONCLUSIONS: Our research highlights that prior expectations, invoked by the Low income country cue, are interfering with a transparent and objective learning process. There may be merit in adopting some techniques from the cognitive psychology and marketing literatures to understand better the relative importance of source in healthcare research and innovation diffusion. Counter-stereotyping techniques and decision-making tools may be useful to help decision-makers evaluate the generalizability of research findings objectively and transparently. We suggest that those interested in Reverse Innovation should reflect carefully on the value of disclosing the source of the innovation that is being proposed, if doing so is likely to invoke negative stereotypes. PMID- 26582042 TI - Imaging in Diabetic Retinopathy: A Review of Current and Future Techniques. AB - BACKGROUND: Diabetic eye disease is the most common cause of blindness worldwide in the population under 65 years of age. The prevalence of sight-threatening diabetic eye disease continues to rise rapidly, resulting in an increasing burden on health systems worldwide. This highlights the need to develop new tools to help in the screening, diagnosis and management of diabetic eye disease. PURPOSE: This review aims to provide a brief overview of the current standard in care for diabetic eye disease, before providing an up to date overview of newer imaging modalities, with potential application in the management of diabetic eye care. METHODS: A literature search for the terms "enhanced depth imaging OCT", "swept source OCT", "retinal oximetry", "OCT angiography", "fundus autofluorescence" with the term "diabetes" was performed using the pubmed and google scholar databases. Only articles published within the last two years were selected for use in this article. DISCUSSION: There has been a rapid increase in the available imaging techniques used to manage diabetic eye disease. To date there has been variable use of these next generation imaging techniques. A greater understanding of how phenotypic findings link to the risk of sight loss is required before there is more widespread adoption by mainstream diabetic eye services. PMID- 26582043 TI - Sex-specific age association with primary DNA transfer. AB - Practicing forensic scientists who are called to provide expert witness testimony are often asked to explain both the presence and the absence of DNA on objects that have been handled by perpetrators with bare hands. Unwashed hands, depending on what they have come in contact with previously, may become the vehicle of both primary and secondary transfer of DNA. In this study, we investigated the propensity of primary and secondary transfer of DNA from unwashed bare hands of 128 individuals onto plastic tubes. Our experiments, carried out in triplicate, have shown that DNA was not detected on all the touched tubes, secondary transfer of DNA, through unwashed hands, was small, and in the majority of cases primary DNA transfer could be distinguished from secondary DNA transfer. A statistically significant association was demonstrated between percent DNA profile deposited on plastic tubes, through unwashed hands, and the age of male individuals. PMID- 26582044 TI - Nicotine and Toxicant Exposure among U.S. Smokeless Tobacco Users: Results from 1999 to 2012 National Health and Nutrition Examination Survey Data. AB - BACKGROUND: It has been suggested that smokeless tobacco users have high nicotine and toxicant exposure, but studies with nationally representative data have been limited. METHODS: We analyzed biomarkers of tobacco exposure for 23,684 adult participants from the National Health and Nutrition Examination Survey from 1999 to 2012. The biomarkers analyzed were serum cotinine, urinary 4 (methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), blood lead, blood cadmium, blood mercury, urinary arsenic, and urinary N-acetyl-S-(2-cyanoethyl)-L-cysteine. We calculated geometric mean concentrations for each biomarker by tobacco use category and geometric mean ratios adjusting for demographic factors. RESULTS: Exclusive smokeless tobacco users had higher geometric mean concentrations of serum cotinine [178.9 ng/mL, 95% confidence interval (CI), 145.5-220.0] and NNAL (583.0 pg/mg creatinine, 95% CI, 445.2-763.5) than exclusive cigarette smokers (130.6 ng/mL, 95% CI, 122.3-139.6 and 217.6 pg/mg creatinine, 95% CI, 193.0 245.2, respectively). Smokeless tobacco users also had higher concentrations of blood lead compared with nontobacco users (adjusted geometric mean ratio = 1.30, 95% CI, 1.21-1.38). Based on limited sample sizes, NNAL concentrations for smokeless tobacco users appear to have declined from 2007 to 2008 (geometric mean = 1013.7 pg/mg creatinine, 95% CI, 738.9-1390.8) to 2011 to 2012 (geometric mean = 325.7 pg/mg creatinine, 95% CI, 159.6-664.9). CONCLUSIONS: Exclusive smokeless tobacco users have higher observed levels of exposure to nicotine and carcinogenic tobacco-specific nitrosamines, as measured by cotinine and NNAL biomarker concentrations, than exclusive cigarette smokers. These patterns in NNAL levels for smokeless tobacco users may be changing over time. IMPACT: High exposure to harmful constituents among smokeless tobacco users is a continuing health issue. PMID- 26582045 TI - Improving the Care of Dual Eligible Patients in Rural Federally Qualified Health Centers: The Impact of Care Coordinators and Clinical Pharmacists. AB - BACKGROUND: Dual eligible persons are those covered by both Medicare and Medicaid. There were 9.6 million dual eligible persons in the United States and 82 000 in West Virginia in 2010. Dual eligibles are poorer, sicker, and more burdened with serious mental health conditions than Medicare or Medicaid patients as a whole. Their health care costs are significantly higher and they are more likely to receive fragmented ineffective care. PURPOSE: To improve the care experience and health care outcomes of dual eligible patients by the expanded use of care coordinators and clinical pharmacists. METHODS: During 2012, 3 rural federally qualified community health centers in West Virginia identified 200 dual eligible patients each. Those with hospitalizations received more frequent care coordinator contacts. Those on more than 15 chronic medications had drug utilization reviews with recommendations to primary care providers. Baseline measures included demographics, chronic diseases, total medications and Beers list medications, hospitalization, and emergency room (ER) use in the previous year. Postintervention measures included hospitalization, ER use, total medications, and Beers list medications. RESULTS: Out of 556 identified patients, 502 were contacted and enrolled. Sixty-five percent were female. The median age was 69 years, with a range of 29 to 93 years. Nineteen percent (19%) of patients were on 15 or more medications, 56% on psychotropic medication, and 33% on chronic opiates. One site showed reductions of 34% in hospitalizations and 25% in ER visits during the intervention year. For all sites combined, there was a 5.5% reduction in total medications and a 14.8% reduction in Beers list medications. CONCLUSIONS: A modest investment in care coordination and clinical pharmacy review can produce significant reductions in hospitalization and harmful polypharmacy for community dwelling dual eligible patients. PMID- 26582046 TI - Dimethyl Sulfoxide Induced Destabilization and Disassembly of Various Structural Variants of Insulin Fibrils Monitored by Vibrational Circular Dichroism. AB - Dimethyl sulfoxide (DMSO) induced destabilization of insulin fibrils has been previously studied by Fourier transform infrared spectroscopy and interpreted in terms of secondary structural changes. The variation of this process for fibrils with different types of higher-order morphological structures remained unclear. Here, we utilize vibrational circular dichroism (VCD), which has been reported to provide a useful biophysical probe of the supramolecular chirality of amyloid fibrils, to characterize changes in the macroscopic chirality following DMSO induced disassembly for two types of insulin fibrils formed under different conditions, at different reduced pH values with and without added salt and agitation. We confirm that very high concentrations of DMSO can disaggregate both types of insulin fibrils, which initially maintained a beta-sheet conformation and eventually changed their secondary structure to a disordered form. The two types responded to varying concentrations of DMSO, and disaggregation followed different mechanisms. Interconversion of specific insulin fibril morphological types also occurred during the destabilization process as monitored by VCD. With transmission electron microscopy, we were able to correlate the changes in VCD sign patterns to alteration of morphology of the insulin fibrils. PMID- 26582047 TI - Effect of intraoperative application of ketamine on postoperative depressed mood in patients undergoing elective orthopedic surgery. AB - PURPOSE: A depressed mood frequently occurs in perioperative patients, negatively impacting patient recovery. Recent studies suggested that ketamine has a rapid, obvious, and persistent antidepressant effect. The purpose of this study was to investigate the impact of intraoperative application of ketamine on postoperative depressive mood in patients undergoing elective orthopedic surgery. METHODS: This was a randomized, double-blind, controlled study. A total of 120 patients (ASA grade I-II) undergoing elective orthopedic surgery were divided randomly into a ketamine group (group K) and a control group (group C). In the K group, 0.5 mg/kg (0.05 ml/kg) ketamine was given at induction of anesthesia, followed by 0.25 mg/kg/h (0.025 ml/kg/h) continuous infusion for 30 min. In the C group, 0.05 ml/kg 0.9 % saline was used at induction of anesthesia, followed by 0.025 ml/kg/h continuous infusion of saline for 30 min. PHQ-9 score was recorded preoperatively (1 day before surgery) and postoperatively (on day 1 and day 5 following surgery). Blood at these time points was drawn for serum brain-derived neurotrophic factor (BDNF) level analysis. Intraoperative blood loss, surgery time, postoperative visual analog scale pain scores and perioperative complications were also recorded. RESULTS: There were no differences in age, sex, surgery time, blood loss, and preoperative PHQ-9 scores between the two groups (P > 0.05). There were no differences in PHQ-9 scores preoperatively and postoperatively for the C group (P > 0.05); however, the PHQ-9 postoperative scores were lower than the preoperative PHQ-9 scores in the K group (P < 0.01). Postoperative PHQ-9 scores of K group were lower than those of C group (P < 0.05). There were no differences in serum BDNF levels in C group pre- to postoperatively (P > 0.05). Compared with the preoperative BDNF levels of K group, postoperative BDNF levels in K group increased significantly (P < 0.01). An inverse correlation between PHQ-9 score and serum BDNF level was shown. CONCLUSION: Intraoperative application of ketamine was associated with improved scores for depressed mood and increased serum BDNF levels in patients undergoing elective orthopedic surgery. PMID- 26582048 TI - Lipid-rich bovine serum albumin improves the viability and hatching ability of porcine blastocysts produced in vitro. AB - The effects of lipid-rich bovine serum albumin (LR-BSA) on the development of porcine blastocysts produced in vitro were examined. Addition of 0.5 to 5 mg/ml LR-BSA to porcine blastocyst medium (PBM) from Day 5 (Day 0 = in vitro fertilization) significantly increased the hatching rates of blastocysts on Day 7 and the total cell numbers in Day-7 blastocysts. When Day-5 blastocysts were cultured with PBM alone, PBM containing LR-BSA, recombinant human serum albumin or fatty acid-free BSA, addition of LR-BSA significantly enhanced hatching rates and the cell number in blastocysts that survived compared with other treatments. The diameter, ATP content and numbers of both inner cell mass and total cells in Day-6 and Day-7 blastocysts cultured with PBM containing LR-BSA were significantly higher than in blastocysts cultured with PBM alone, whereas LR-BSA had no effect on mitochondrial membrane potential. The mRNA levels of enzymes involved in fatty acid metabolism and beta-oxidation (ACSL1, ACSL3, CPT1, CPT2 and KAT) in Day-7 blastocysts were significantly upregulated by the addition of LR-BSA. The results indicated that LR-BSA enhanced hatching ability and quality of porcine blastocysts produced in vitro, as determined by ATP content, blastocyst diameter and expression levels of the specific genes, suggesting that the stimulatory effects of LR-BSA arise from lipids bound to albumin. PMID- 26582050 TI - Coexistence of Two Congeneric Praying Mantids: A 7-Year Field Study of Reproductive Success and Failure. AB - Two species of Asian praying mantids, Tenodera angustipennis (Saussure) and Tenodera aridifolia sinensis (Saussure), which have become common to old fields in the northeastern United States, share a common resource base that raises the question of how they can coexist in the same habitat. We studied the reproductive output measured by numbers of oothecae of naturally established populations of these two species in an old field during 7 yr (2009-2015) of secondary succession. During the initial herbaceous vegetation-dominated stage, T. angustipennis oothecae were more abundant than those of its congener, but numbers steadily declined, until it had nearly disappeared by 2014. In contrast, numbers of T. a. sinensis oothecae increased from 2007 until 2014, and then sharply declined in 2015. The steady increase in abundance of this species throughout most of the successional development during the study may be owing to greater diversity of plant species used for oviposition. We believe that the most likely reasons for the continuous decline in T. angustipennis were a combination of intraguild predation by the larger T. a. sinensis, and egg parasitism by the wasp Podagrion mantis, which is not able to parasitize oothecae of T. a. sinensis. The later decline in T. a. sinensis may reflect the fact that the site had become dominated by trees, and neither of these species is typically found in forest habitats. PMID- 26582049 TI - Does the Ribosome Challenge our Understanding of the RNA World? AB - In a recent article published in these pages, Bowman and colleagues propose that the ribosome represents a challenge to the RNA world model, a long-standing framework to explain the origin of DNA and genetically encoded proteins from a hypothetical RNA-based system. Specifically, they outline a scenario for the emergence and subsequent coevolution of the peptidyl transferase centre (PTC) of the ribosome with non-templated peptide products of this RNA through chemical evolution. They also propose that the PTC would have predated the emergence of enzymatic RNA replication, and that this in turn indicates that the RNA world never existed. We and others have previously incorporated non-templated peptide production as an early stage in the evolution of protein synthesis, which we would count as a chemical process, in agreement with Bowman and colleagues' model. However, their model raises an important question: to what extent could early protein synthesis and its products have evolved in the absence of Darwinian processes? We argue that evolution of the early ribosome requires Darwinian evolution, and that, while chemical evolution could give rise to peptidyl transferase activity, it is insufficient for subsequent improvement of a proto PTC, or for ongoing coevolution of the proto-PTC with its early non-templated peptide products. We conclude that it is difficult to preclude the involvement of replicative processes, themselves subject to Darwinian evolution, from the evolution of the PTC. Finally, Bowman et al. call into question current models for the RNA to protein transition. We show that the difficulty that Bowman et al. have with this scenario is down to a misreading of our previous work. PMID- 26582051 TI - Israeli agents raid Hebron hospital and kill visiting relative of wanted man. PMID- 26582052 TI - IDegLira Versus Alternative Intensification Strategies in Patients with Type 2 Diabetes Inadequately Controlled on Basal Insulin Therapy. AB - INTRODUCTION: IDegLira is a once-daily combination of insulin degludec (IDeg) and liraglutide. Trials directly comparing IDegLira with alternative strategies for intensifying basal insulin are ongoing. While awaiting results, this analysis compared indirectly how different strategies affected glycated hemoglobin (HbA1c) and other outcomes. METHODS: A pooled analysis of five completed Novo Nordisk randomized clinical trials in patients with type 2 diabetes inadequately controlled on basal insulin was used to compare indirectly IDegLira (N = 199) with: addition of liraglutide to basal insulin (N = 225) [glucagon-like peptide-1 receptor agonist (GLP-1RA) add-on strategy]; basal-bolus (BB) insulin [insulin glargine (IGlar) + insulin aspart] (N = 56); or up-titration of IGlar (N = 329). A supplementary analysis was performed with the BB arm including patients who received IGlar or IDeg as basal insulin in the relevant trial (N = 210). All trials had comparable inclusion/exclusion criteria and baseline characteristics. Individual patient-level data were analyzed using multivariable statistical models with potential baseline heterogeneity accounted for using explanatory variables. RESULTS: At end of study, differences between IDegLira and BB or up titrated IGlar, respectively, were as follows: reduction in HbA1c -0.30%, 95% confidence interval (-0.58; -0.01) and -0.65% (-0.83; -0.47); change in body weight -6.89 kg (-7.92; -5.86) and -4.04 kg (-4.69; -3.40) all in favor of IDegLira. Confirmed hypoglycemia rate was 122.8 (90.7; 166.1), 1060.8 (680.2; 1654.4), and 286.1 (231.1; 354.1) events/100 patient-years for IDegLira, BB, and up-titrated IGlar, respectively. Odds ratios for achieving HbA1c <7.0%, <7.0% without hypoglycemia, and <7.0% without hypoglycemia and no weight gain were greater with IDegLira versus up-titrated IGlar. The supplementary analysis yielded similar results to the main analysis. Results with IDegLira were similar to those for the 'GLP-1RA add-on' arm. CONCLUSION: These results suggest that IDegLira may be more effective, with lower hypoglycemia rates and less weight gain, than up-titrated basal insulin or BB in patients uncontrolled on basal insulin. PMID- 26582053 TI - Frank-ter Haar syndrome--additional findings? AB - Frank-ter Haar syndrome is a genetic disease that is transmitted by autosomal recessive pattern with characteristic features such as megalocornea or glaucoma, a prominent coccyx, heart defects, developmental delays, brachycephaly, a wide anterior fontanel, finger flexion deformities, full cheeks and micrognathia. Dentomaxillofacial features of this syndrome are not well documented in the literature. We present of a 21-year-old male with Frank-ter Haar syndrome and some features that may be linked with this syndrome not reported before in the literature. PMID- 26582054 TI - Cardioprotective effects of lysyl oxidase inhibition against volume overload induced extracellular matrix remodeling. AB - A hallmark of heart failure (HF) is adverse extracellular matrix (ECM) remodeling, which is regulated by the collagen cross-linking enzyme, lysyl oxidase (LOX). In this study, we evaluate the efficacy of LOX inhibition to prevent adverse left ventricular (LV) remodeling and dysfunction using an experimental model of HF. Sprague-Dawley rats were subjected to surgically induced volume overload (VO) by creation of aortocaval fistula (ACF). A LOX inhibitor, beta-aminopropionitrile (BAPN; 100 mg/kg/day), was administered to rats with ACF or sham surgery at eight weeks postsurgery. Echocardiography was used to assess progressive alterations in cardiac ventricular structure and function. Left ventricular (LV) catheterization was used to assess alterations in contractility, stiffness, LV pressure and volume, and other indices of cardiac function. The LV ECM alterations were assessed by: (a) histological staining of collagen, (b) protein expression of collagen types I and III, (c) hydroxyproline assay, and (d) cross-linking assay. LOX inhibition attenuated VO-induced increases in cardiac stress, and attenuated increases in interstitial myocardial collagen, total collagen, and protein levels of collagens I and III. Both echocardiography and catheterization measurements indicated improved cardiac function post-VO in BAPN treated rats vs. untreated. Inhibition of LOX attenuated VO-induced decreases in LV stiffness and cardiac function. Overall, our data indicate that LOX inhibition was cardioprotective in the volume overloaded heart. PMID- 26582055 TI - Beneficial effects of mycophenolate mofetil on cardiotoxicity induced by tacrolimus in wistar rats. AB - The immunosuppressive drug tacrolimus (TAC) is used clinically to reduce the rejection rate in transplant patients. TAC has contributed to an increased prevalence of cardiovascular disease in patients receiving solid organ transplantation. Mycophenolate mofetil (MMF), a potent inhibitor of de novo purine synthesis, is known to prevent ongoing rejection in combination with TAC. In the present study, we investigated the antioxidant and antigenotoxic effect of MMF on TAC-induced cardiotoxicity in rats. Oral administration of TAC at 2.4, 24, and 60 mg/kg b.w. corresponding, respectively, to 1, 10, and 25% of LD50 for 24 h caused cardiac toxicity in a dose-dependant manner. TAC increased significantly DNA damage level in hearts of treated rats. Furthermore, it increased malondialdehyde (MDA) and protein carbonyl (PC) levels and decreased catalase (CAT) and superoxide dismutase (SOD) activities. The oral administration of MMF at 50 mg/kg b.w. simultaneously with TAC at 60 mg/kg b.w. proved a significant cardiac protection by decreasing DNA damage, MDA, and PC levels, and by increasing the antioxidant activities of CAT and SOD. Thus, our study showed, for the first time, the protective effect of MMF against cardiac toxicity induced by TAC. This protective effect was mediated via an antioxidant process. PMID- 26582056 TI - p21 induction plays a dual role in anti-cancer activity of ursolic acid. AB - Previous studies have shown that induction of G1 arrest and apoptosis by ursolic acid is associated with up-regulation of cyclin-dependent kinase inhibitor (CDKI) protein p21 in multiple types of cancer cells. However, the functional role of p21 induction in G1 cell cycle arrest and apoptosis, and the mechanisms of p21 induction by ursolic acid have not been critically addressed. In the current study, we demonstrated that p21 played a mediator role in G1 cell cycle arrest by ursolic acid, whereas p21-mediated up-regulation of Mcl-1 compromised apoptotic effect of ursolic acid. These results suggest that p21 induction plays a dual role in the anti-cancer activity of ursolic acid in terms of cell cycle and apoptosis regulation. p21 induction by ursolic acid was attributed to p53 transcriptional activation. Moreover, we found that ursolic acid was able to inhibit murine double minute-2 protein (MDM2) and T-LAK cell-originated protein kinase (TOPK), the two negative regulator of p53, which in turn contributed to ursolic acid-induced p53 activation. Our findings provided novel insights into understanding of the mechanisms involved in cell cycle arrest and apoptosis induction in response to ursolic acid exposure. PMID- 26582058 TI - Treatment of Psoriasis with Mesenchymal Stem Cells. PMID- 26582057 TI - Prostate specific G protein coupled receptor is associated with prostate cancer prognosis and affects cancer cell proliferation and invasion. AB - BACKGROUND: There is limited information about the clinical and biological significance of prostate specific G protein coupled receptor (PSGR) in prostate cancer (PCa) initiation and progression. Here, we evaluated the expression of PSGR protein, studied its diagnostic and prognostic value in PCa, and also explored its role in cancer cell growth and invasion. METHODS: The expression of PSGR in paired adjacent normal prostate, high grade prostatic intraepithelial neoplasia (PIN), and PCa were determined by immunohistochemistry on tissue microarrays constructed from 150 radical prostatectomy specimens. The effects of PSGR on PCa cell growth and invasion were investigated using human PCa cell lines. RESULTS: Membranous and cytoplasmic PSGR staining was observed at luminal epithelial cells of prostate. PSGR protein expression was significantly higher in PIN compared to normal prostate. Interestingly, the expression of PSGR decreased as PIN progressed to PCa. Low PSGR expression in PCa was associated with high Gleason score, and poor overall survival. Activated PSGR increased cancer cell invasive ability, but retarded cell growth. PSGR did not affect mTOR activity, but suppressed P70 S6 kinase activity. CONCLUSIONS: PSGR may participate in PCa progression through affecting cell proliferation and invasion. High expression of PSGR in PIN may implicate its role in early neoplastic transformation of PCa. Low expression of PSGR in PCa may serve as a potential indicator for poor prognosis. PMID- 26582059 TI - Beta-human Chorionic Gonadotropin-producing Renal Cell Carcinoma. PMID- 26582060 TI - AdVanceXP male sling: 2-year results of a multicentre study. AB - PURPOSE: For the treatment of persistent post-prostatectomy incontinence (PPI), several surgical treatment options including male slings are available. In 2010, the second generation of the retrourethral male sling Advance, AdVanceXP, was introduced. Aim of the study was to examine in a prospective multicentre study the outcome of AdVanceXP in the treatment of PPI. METHODS: Ninety-four patients were treated with AdVanceXP. Patients with nocturnal incontinence, previous incontinence surgery, with coaptive zone <1 cm and irradiated patients were excluded. Measurements included: daily pad usage, 24-h pad weight test, post operative pain in the visual analogue scale, International Quality of Life questionnaire, International Consultation on Incontinence Questionnaire short form, IEEF5 and Patient Global Impression of Improvement. Adverse events were recorded. All patients with no pads and 0-5 g in the 24-h pad test were defined as cured and those with a reduction in urine loss >50 % as improved. RESULTS: Preoperatively, the median 24-h pad weight test was 274 g and daily pad usage was 3. At 1-year follow-up, 66.3 % of patients could be classified as cured and 25.3 % as improved. After 2 years, 73.1 % could be classified as cured and 19.6 % as improved. Urine loss decreased (p < 0.001), and quality of life improved significantly (p < 0.001). Mean PGI was 1.5 after 1 year and 1.4 after 2 years. Majority of complications were minor. No intraoperative complications and five serious post-operative events occurred (grade IIIB complications). No explantation was necessary. CONCLUSIONS: AdVanceXP, when correctly indicated, shows good effectiveness and low complication rates after up to 2 years. PMID- 26582062 TI - Breast Cancer Chemoprevention: A Network Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND: Several agents have been advocated for breast cancer primary prevention. However, few of them appear effective, the associated severe adverse effects limiting their uptake. METHODS: We performed a comprehensive search for randomized controlled trials (RCTs) reporting on the ability of chemoprevention agents (CPAs) to reduce the incidence of primary breast carcinoma. Using network meta-analysis, we ranked CPAs based simultaneously on efficacy and acceptability (an inverse measure of toxicity). All statistical tests were two-sided. RESULTS: We found 48 eligible RCTs, enrolling 271 161 women randomly assigned to receive either placebo or one of 21 CPAs. Aromatase inhibitors (anastrozole and exemestane, considered a single CPA class because of the lack of between-study heterogeneity; relative risk [RR] = 0.468, 95% confidence interval [CI] = 0.346 to 0.634), arzoxifene (RR = 0.415, 95% CI = 0.253 to 0.682), lasofoxifene (RR = 0.208, 95% CI = 0.079 to 0.544), raloxifene (RR = 0.572, 95% CI = 0.372 to 0.881), tamoxifen (RR = 0.708, 95% CI = 0.595 to 0.842), and tibolone (RR = 0.317, 95% CI = 0.127 to 0.792) were statistically significantly associated with a therapeutic effect, which was restricted to estrogen receptor-positive tumors of postmenopausal women (except for tamoxifen, which is active also during premenopause). Network meta-analysis ranking showed that the new selective estrogen receptor modulators (SERMs) arzoxifene, lasofoxifene, and raloxifene have the best benefit-risk ratio. Aromatase inhibitors and tamoxifen ranked second and third, respectively. CONCLUSIONS: These results provide physicians and health care regulatory agencies with RCT-based evidence on efficacy and acceptability of currently available breast cancer CPAs; at the same time, we pinpoint how much work still remains to be done before pharmacological primary prevention becomes a routine option to reduce the burden of this disease. PMID- 26582063 TI - Doing More for More: Unintended Consequences of Financial Incentives for Oncology Specialty Care. AB - BACKGROUND: Specialty care remains a significant contributor to health care spending but largely unaddressed in novel payment models aimed at promoting value based delivery. Bladder cancer, chiefly managed by subspecialists, is among the most costly. In 2005, Centers for Medicare and Medicaid Services (CMS) dramatically increased physician payment for office-based interventions for bladder cancer to shift care from higher cost facilities, but the impact is unknown. This study evaluated the effect of financial incentives on patterns of fee-for-service (FFS) bladder cancer care. METHODS: Data from a 5% sample of Medicare beneficiaries from 2001-2013 were evaluated using interrupted time series analysis with segmented regression. Primary outcomes were the effects of CMS fee modifications on utilization and site of service for procedures associated with the diagnosis and treatment of bladder cancer. Rates of related bladder cancer procedures that were not affected by the fee change were concurrent controls. Finally, the effect of payment changes on both diagnostic yield and need for redundant procedures were studied. All statistical tests were two-sided. RESULTS: Utilization of clinic-based procedures increased by 644% (95% confidence interval [CI] = 584% to 704%) after the fee change, but without reciprocal decline in facility-based procedures. Procedures unaffected by the fee incentive remained unchanged throughout the study period. Diagnostic yield decreased by 17.0% (95% CI = 12.7% to 21.3%), and use of redundant office-based procedures increased by 76.0% (95% CI = 59% to 93%). CONCLUSIONS: Financial incentives in bladder cancer care have unintended and costly consequences in the current FFS environment. The observed price sensitivity is likely to remain a major issue in novel payment models failing to incorporate procedure-based specialty physicians. PMID- 26582064 TI - Cancer surgeons and health system innovation: incentivizing change. PMID- 26582065 TI - Characterization of the products attained from a thermal treatment of a mix of zinc-carbon and alkaline batteries. AB - This study applies a thermal separation process (TSP) to recover Fe, Mn, and Zn from hazardous spent zinc-carbon and alkaline batteries. In the TSP, the batteries were heated together with a reducing additive and the metals in batteries, according to their boiling points and densities, were found to move into three major output materials: slag, ingot (mainly Fe and Mn), and particulate (particularly Zn). The slag well encapsulated the heavy metals of interest and can be recycled for road pavement or building materials. The ingot had high levels of Fe (522,000 mg/kg) and Mn (253,000 mg/kg) and can serve as an additive for stainless steel-making processes. The particulate phase had a Zn level of 694,000 mg/kg which is high enough to be directly sold for refinement. Overall, the TSP effectively recovered valuable metals from the hazardous batteries. PMID- 26582066 TI - Preoperative staging in childhood craniopharyngioma: standardization as a first step towards improved outcome. PMID- 26582061 TI - Comparison of Prediction Models for Lynch Syndrome Among Individuals With Colorectal Cancer. AB - BACKGROUND: Recent guidelines recommend the Lynch Syndrome prediction models MMRPredict, MMRPro, and PREMM1,2,6 for the identification of MMR gene mutation carriers. We compared the predictive performance and clinical usefulness of these prediction models to identify mutation carriers. METHODS: Pedigree data from CRC patients in 11 North American, European, and Australian cohorts (6 clinic- and 5 population-based sites) were used to calculate predicted probabilities of pathogenic MLH1, MSH2, or MSH6 gene mutations by each model and gene-specific predictions by MMRPro and PREMM1,2,6. We examined discrimination with area under the receiver operating characteristic curve (AUC), calibration with observed to expected (O/E) ratio, and clinical usefulness using decision curve analysis to select patients for further evaluation. All statistical tests were two-sided. RESULTS: Mutations were detected in 539 of 2304 (23%) individuals from the clinic based cohorts (237 MLH1, 251 MSH2, 51 MSH6) and 150 of 3451 (4.4%) individuals from the population-based cohorts (47 MLH1, 71 MSH2, 32 MSH6). Discrimination was similar for clinic- and population-based cohorts: AUCs of 0.76 vs 0.77 for MMRPredict, 0.82 vs 0.85 for MMRPro, and 0.85 vs 0.88 for PREMM1,2,6. For clinic- and population-based cohorts, O/E deviated from 1 for MMRPredict (0.38 and 0.31, respectively) and MMRPro (0.62 and 0.36) but were more satisfactory for PREMM1,2,6 (1.0 and 0.70). MMRPro or PREMM1,2,6 predictions were clinically useful at thresholds of 5% or greater and in particular at greater than 15%. CONCLUSIONS: MMRPro and PREMM1,2,6 can well be used to select CRC patients from genetics clinics or population-based settings for tumor and/or germline testing at a 5% or higher risk. If no MMR deficiency is detected and risk exceeds 15%, we suggest considering additional genetic etiologies for the cause of cancer in the family. PMID- 26582067 TI - Associations between two single-nucleotide polymorphisms (rs1801278 and rs2943641) of insulin receptor substrate 1 gene and type 2 diabetes susceptibility: a meta-analysis. AB - The objective of the study is to assess the association between rs1801278 and rs2943641 of insulin receptor substrate 1 gene (IRS1) and the susceptibility to type 2 diabetes. A literature search strategy was conducted to identify all references lists of relevant studies. The fixed or random effect model was used to calculate the pooled ORs on the basis of heterogeneity. Further analyses were performed to explore the sources of heterogeneity by sensitivity analysis, meta regression analysis, and subgroup analysis. There was significant association between rs1801278 and type 2 diabetes risk in recessive model (AA vs. GA + GG, p = 0.043) and codominant model (AA vs. GG, p = 0.007). Subgroup analysis showed that the association between rs1801278 and type 2 diabetes risk was significant in dominant model (GA + AA vs. GG, p = 0.044), codominant model (GA vs. GG, p = 0.039), codominant model (AA vs. GG, p = 0.044), overdominant model (GG + AA vs. GA, p = 0.037) in Asian and codominant model (AA vs. GG, p = 0.039) in Caucasian of rs1801278. The association between rs2943641 and type 2 diabetes risk was significant in codominant model (CT vs. CC, p = 0.023) in Caucasian. This meta analysis suggests that rs1801278 may play a role in type 2 diabetes risk, especially in Asian. It also indicates that rs2943641 may be associated with type 2 diabetes risk in Caucasian. Further larger studies should be performed to warrant confirmation. PMID- 26582069 TI - The (de)politicisation of nuclear power: The Finnish discussion after Fukushima. AB - When the Fukushima accident occurred in March 2011, Finland was at the height of a nuclear renaissance, with the Government's decision-in-principle in 2010 to allow construction of two new nuclear reactors. This article examines the nuclear power debate in Finland after Fukushima. We deploy the concepts of (de)politicisation and hyperpoliticisation in the analysis of articles in the country's main newspaper. Our analysis indicates that Finnish nuclear exceptionalism manifested in the safety-related depoliticising and the nation's prosperity-related hyperpoliticisation arguments of the pro-nuclear camp. The anti-nuclear camp used politicisation strategies, such as economic arguments, to show the unprofitability of nuclear power. The Fukushima accident had a clear effect on Finnish nuclear policy: the government programme of 2011 excluded the nuclear new build. However, in 2014 the majority of Parliament again supported nuclear power. Hence, the period after Fukushima until 2014 could be described as continued but undermined loyalty to nuclear power. PMID- 26582068 TI - Predominance of a single clone of the most widely distributed bamboo species Phyllostachys edulis in East Asia. AB - Phyllostachys edulis, one of the most dominant bamboo species with the leptomorph rhizome system, has been asexually expanding its range into adjacent natural forest sites by shooting new culms. The resulting ecological problems include simplification of stand structure and decline in the species diversity of local flora. In this study, the genetic diversity of P. edulis for the entire distribution range from Japan to China was analyzed using 16 microsatellite markers. Among these, 12 loci were fixed by a single allele, whereas only two alleles were detected for each of the remaining 4 loci; all adult samples shared the same genotype at all loci including the four heterozygous loci. These observations indicate that all current samples from Japan and China comprise an identical clone. The clone is distributed over more than 2,800 km with an estimated biomass of approximately 6.6 * 10(11) kg, which is exceptionally large. Among seedlings from flowering events in 2005 and 2006, 20 different genets were generated by recombination through selfing of a single flowering genet. Predominance of a single clone in the wild and a diverse composition of genets among seedlings suggest that the intermittent flowering of P. edulis in the wild has produced a variety of clones through recombination. However, the resulting seedlings cannot compete with other tree species or adult P. edulis, and almost all adult P. edulis growing in Japan and China likely propagated through vegetative reproduction of a single clone by human transplantation, and subsequently expanded into adjacent forest sites by shooting young sprouts. The relatively small size of the flowering area and rapid culm reproduction has led to the stability of P. edulis communities. However, the low genetic diversity is an important consideration for the long-term management of this prevailing bamboo species. PMID- 26582070 TI - Spiderman and science: How students' perceptions of scientists are shaped by popular media. AB - This study addresses the influence of popular media on how young children perceive science and the work of scientists. Using an adapted version of the Draw A-Scientist Test, 15 classes of fourth graders (9-10 years old) at three different schools in Singapore were sampled ( n = 266). The students' drawings as well as their identification of three sources from which they obtained inspiration for their drawings were analyzed. Our results showed a strong relationship between students' drawings of scientists and their reported sources of inspiration. The results suggest that popular media play a large role in shaping how young children view scientists. PMID- 26582071 TI - Novel avenues in immunotherapies for colorectal cancer. AB - Since it is known that the immune system affects tumor growth, it has been studied if immunotherapy can be developed to combat cancer. While some successes have been claimed, the increasing knowledge on tumor-immune interactions has, however, also shown the limitations of this approach. Tumors may show selective outgrowth of cells escaped from immune control. Escape variants arise spontaneously due to the genetically instable nature of tumor cells. This is one of the most obvious limitations of cancer immunotherapy. However, new therapies are becoming available, designed to respond to tumor-immune escape. PMID- 26582073 TI - Stachyose increases absorption and hepatoprotective effect of tea polyphenols in high fructose-fed mice. AB - SCOPE: The consumption of tea polyphenols (TP) and stachyose contributes to preventive effects on hepatic injury. This study examined the effects of stachyose on absorption and hepatoprotective effects of TP in mice. METHODS AND RESULTS: GC-MS measurement showed that stachyose significantly increased serum total phenolic, ECG and EGCG contents in mice. The mice fed with high fructose (HF)-diet for 56 days exhibited oxidative stress observed by an increase in hepatic MDA levels and decreases in GSH-Px and SOD activities. Serum TC, TG, LDL C and CRP levels, and ALT and AST activities were increased, while HDL-C concentrations were decreased following HF diet. Co-supplementation of stachyose and TP more effectively improved all parameters mentioned above when compared to administration of stachyose or TP alone. Histological observations of hepatic tissues also confirmed the beneficial effects of co-administration of stachyose and TP. CONCLUSION: Our results suggest that stachyose enhances absorption and hepatoprotective effects of TP, and combined ingestion of stachyose and TP is a novel strategy for alleviating HF diet-induced hepatic injury. PMID- 26582072 TI - Analysis of Mitochondrial Proteins in the Surviving Myocardium after Ischemia Identifies Mitochondrial Pyruvate Carrier Expression as Possible Mediator of Tissue Viability. AB - The endogenous mechanisms contributing to tissue survival following myocardial infarction are not fully understood. We investigated the alterations in the mitochondrial proteome after ischemia-reperfusion (I/R) and its possible implications on cell survival. Mitochondrial proteomic analysis of cardiac tissue from an in vivo porcine I/R model found that surviving tissue in the peri-infarct border zone showed increased expression of several proteins. Notably, these included subunits of the mitochondrial pyruvate carrier (MPC), namely MPC1 and MPC2. Western blot, immunohistochemistry, and mRNA analysis corroborated the elevated expression of MPC in the surviving tissue. Furthermore, MPC1 and MPC2 protein levels were found to be markedly elevated in the myocardium of ischemic cardiomyopathy patients. These findings led to the hypothesis that increased MPC expression is cardioprotective due to enhancement of mitochondrial pyruvate uptake in the energy-starved heart following I/R. To test this, isolated mouse hearts perfused with a modified Krebs buffer (containing glucose, pyruvate, and octanoate as metabolic substrates) were subjected to I/R with or without the MPC transport inhibitor UK5099. UK5099 increased myocardial infarction and attenuated post-ischemic recovery of left ventricular end-diastolic pressure. However, aerobically perfused control hearts that were exposed to UK5099 did not modulate contractile function, although pyruvate uptake was blocked as evidenced by increased cytosolic lactate and pyruvate levels. Our findings indicate that increased expression of MPC leads to enhanced uptake and utilization of pyruvate during I/R. We propose this as a putative endogenous mechanism that promotes myocardial survival to limit infarct size. PMID- 26582074 TI - Joint Associations of Dual Sensory Impairment and No-Activity Involvement With 1 Year Mortality in Nursing Homes: Results From the SHELTER Study. AB - BACKGROUND: Concurrent vision and hearing impairment, known as dual sensory impairment (DSI), is associated with increased mortality. We aimed to examine individual and joint associations of DSI and involvement in activities with mortality in a large European nursing home study. METHODS: In total, 2,851 nursing home residents in 59 facilities in eight countries were followed for 1 year in the Services and Health for Elderly in Long TERm Care study. Vision and hearing impairment and average time of involvement in activities were assessed by trained research staff using the interRAI Long Term Care Facilities. Association between DSI and 1-year all-cause mortality was examined using Cox proportional hazards models adjusted for age, sex, facility, diagnoses of coronary heart disease and diabetes mellitus, self-rated health, end-stage disease, and functional and cognitive status. The modifying effect of involvement in activities on the association was investigated by the additive hazard model. RESULTS: DSI, defined as moderate to severe impairment in both senses, was independently associated with a 35% increased risk of 1-year mortality compared with non-DSI. Residents with DSI who were involved in activities did not have higher mortality, while residents with DSI who were not involved in activities had 51% higher mortality than non-DSI residents who were involved in activities, equivalent to approximately 209 additional deaths per 1,000 person-years (p = .012) due to the interaction between DSI and no involvement in activities. CONCLUSIONS: DSI is associated with increased mortality at nursing homes when combined with no involvement in activities. PMID- 26582076 TI - Prevalence of dentinal hypersensitivity and study of associated factors: a cross sectional study based on the general dental population of Davangere, Karnataka, India. AB - BACKGROUND: Dentin hypersensitivity (DH) is a common clinical finding with a wide variation in prevalence and aetiological factors. The aim of this cross-sectional study was to determine the prevalence and examine some associated aetiological factors of DH in a study of an Indian population residing in and around Davangere district of Karnataka. MATERIAL AND METHODS: A total of 404 patients (3,859 teeth) were examined for the presence of DH by means of a questionnaire and intraoral tests (air and tactile stimuli). Plaque, gingival recession, abrasion/erosion, labioversion and toothbrushing habits were noted. RESULTS: A total of 795 teeth, in 404 patients, were diagnosed as having DH, giving an overall prevalence figure for DH of 20.6%. The chi-square test and the Z-test values for proportions were used to evaluate statistical correlations. The 36-45 years' age group was the cohort with the highest number of subjects with DH, and female subjects had greater predilection for DH compared with male subjects. Incisors were the tooth type most affected. DH was significantly correlated with gingival recession, labioversion and abrasion/erosion (P<0.05). Both gingival recession and abrasion/erosion were significantly correlated with brushing once daily in a horizontal direction and use of a toothbrush with medium-hardness bristles (P<0.05). CONCLUSION: The prevalence of DH in the Indian population is 20.6%, with a higher predilection for DH in the age cohort 36-45 years and in female subjects. DH is a multifactorial entity with several aetiological factors, making its diagnosis and treatment a challenge for the clinician. PMID- 26582075 TI - What is a Clinically Meaningful Improvement in Leg-Extensor Power for Mobility limited Older Adults? AB - BACKGROUND: Muscle power is a key predictor of physical function in older adults; however, clinically meaningful improvements in leg-extensor muscle power have yet to be identified. The purpose of this study is to establish the minimal clinically important improvement (MCII) and substantial improvement (SI) for leg extensor power and muscle contraction velocity in mobility-limited older adults. METHODS: Data were extracted from three randomized trials of leg-extensor muscle power training interventions (3- to 6-month duration). Measurements of leg extensor power and velocity were obtained using dynamic bilateral leg press at 40% and 70% of the one-repetition maximum. Anchor-based MCIIs were calculated using selected items extracted from the Late Life Function and Disability Instrument. Standard error of measurement and effect size methods were used to calculate the distribution-based MCII. RESULTS: Data from 164 participants (mean age: 76.6 +/- 5.6 years; Short Physical Performance Battery score: 7.8 +/- 1.3) were used in this analysis. The respective MCII and SI estimates for 40% leg extensor power were 18.3 (9%) and 30.5 (15%) W, and 23.1 (10%) and 41.6 (18%) W for 70% leg-extensor power. The respective MCII and SI estimates for 40% average velocity were 0.03(7%) and 0.08(18%) m/s, and 0.02(6%) and 0.05(15%) m/s for 70% average velocity. CONCLUSIONS: This is the first study to establish a clinically meaningful improvement of leg-extensor power (9%-10%) and velocity (6%-7%) in mobility-limited older adults. These findings should be used to aid in the design and interpretation of clinical trials and interventions that target improvements in muscle power in this high-risk population. PMID- 26582077 TI - The incidence and treatment of bleeding episodes in non-severe haemophilia A patients with inhibitors. AB - The development of an inhibitory antibody in non-severe haemophilia A patients may aggravate the bleeding phenotype considerably. Effective treatment of bleeding episodes may be challenging, with ensuing severe complications. At present, evidence is scarce for optimal treatment of bleeding episodes in this patient group. The aim of this study was to describe the incidence and the treatment of bleeding episodes in inhibitor patients in a population-based unselected cohort of non-severe haemophilia A patients with clinically relevant inhibitors. Data were available for 100 of the 107 non-severe haemophilia A patients (factor VIII (FVIII) baseline, 2-40 IU/dl) from 29 centres in Europe and one centre in Australia who had developed a clinically relevant inhibitor between 1980 and 2011. The majority (89 %) of the patients were treated during the inhibitor period for bleeding episodes or a surgical intervention: 66 % needed treatment for bleeding episodes, at a median annual bleeding rate (ABR) of 1.1 (interquartile range (IQR) 0.1-2.5) and a median total of 2 (IQR 1-6) bleeding episodes. Compared to the median ABR before inhibitor development of 0.095 bleeds per year (IQR 0.02-0.42), the increase in ABR is more than a 10-fold. More than 90 % of the bleeding episodes were treated with only one type of product, most frequently (51 %) FVIII concentrates. This study provides the incidence of bleeding episodes and treatment choices in non-severe haemophilia A patients with inhibitors. The 10-fold increase to a median ABR of 1.1 episodes per year emphasizes the impact of inhibitor development for non-severe haemophilia A patients. PMID- 26582078 TI - Mutations in Biosynthetic Enzymes for the Protein Linker Region of Chondroitin/Dermatan/Heparan Sulfate Cause Skeletal and Skin Dysplasias. AB - Glycosaminoglycans, including chondroitin, dermatan, and heparan sulfate, have various roles in a wide range of biological events such as cell signaling, cell proliferation, tissue morphogenesis, and interactions with various growth factors. Their polysaccharides covalently attach to the serine residues on specific core proteins through the common linker region tetrasaccharide, -xylose galactose-galactose-glucuronic acid, which is produced through the stepwise addition of respective monosaccharides by four distinct glycosyltransferases. Mutations in the human genes encoding the glycosyltransferases responsible for the biosynthesis of the linker region tetrasaccharide cause a number of genetic disorders, called glycosaminoglycan linkeropathies, including Desbuquois dysplasia type 2, spondyloepimetaphyseal dysplasia, Ehlers-Danlos syndrome, and Larsen syndrome. This review focused on recent studies on genetic diseases caused by defects in the biosynthesis of the common linker region tetrasaccharide. PMID- 26582079 TI - Application of NIR and MIR spectroscopy for rapid determination of antioxidant activity of Radix Scutellariae from different geographical regions. AB - INTRODUCTION: The beneficial health effects of traditional Chinese medicines are often attributed to their potent antioxidant activities, usually established in vitro. However, these wet chemical methods for determining antioxidant activities are time-consuming, laborious, and expensive. OBJECTIVES: This study was conducted to establish a rapid determination of antioxidant activity of Radix Scutellariae using near-infrared (NIR) and mid-infrared (MIR) spectroscopy. MATERIAL AND METHODS: Antioxidant capabilities were evaluated using 2,2-diphenyl 1-picrylhydrazyl hydrazyl (DPPH) and oxygen radical absorbance capacity (ORAC) assays. The total flavonoid contents (TFCs) of Radix Scutellariae were measured by the aluminium chloride colorimetric method. The same sample was then scanned using NIR and MIR spectroscopy. Chemometrics analysis using partial least-squares (PLS) regression was performed to establish the models for predicting the antioxidant activities of Radix Scutellariae. RESULTS: A better predictive performance was achieved using PLS models based on NIR data. The determination coefficient (R(2)) and the residual predictive deviation (RPD) for the validation set were 0.9298 and 2.84 for DPPH, and 0.9436 and 2.66 for TFCs, respectively. MIR-PLS algorithms gave a slightly lower reliability (R(2) = 0.9090 and 0.9374, RPD = 2.01 and 2.42, for DPPH and TFC, respectively). Very comparable results for ORAC were obtained with the two methods. CONCLUSION: The developed spectroscopic method can be successfully applied in high-throughput screening of the antioxidant capability of Radix Scutellariae samples. It can also be a viable and advantageous alternative to laborious chemical procedures. PMID- 26582081 TI - Percutaneous endoscopic gastrostomy for nutritional support in dementia patients. AB - BACKGROUND: A link between aging, dementia and malnutrition is established and leads to poor prognosis. Endoscopic gastrostomy (PEG) is used without clear benefit on survival, nutritional status or quality of life. AIMS: This work aims to assess the effectiveness of PEG-feeding for nutritional support in patients with dementia. METHODS: We conducted an observational, longitudinal and retrospective study using records from patients with moderate-severe dementia that underwent PEG. Age, gender, dementia subtype and mortality were considered. Body mass index (BMI), serum albumin, transferrin and total cholesterol were recorded at the time of the PEG procedure (T0) and repeated after 3 months (T3). The evolution of those parameters was analysed and compared to survival. RESULTS: We obtained data from 46 patients (16 men/30 women) between 50 and 94 years (M = 79 years). Most had Alzheimer's. Mean survival was 21 months. Mortality rate at 3 months was 15 %. At T0, 30 patients were undernourished according to BMI and 29, 31 and 16 patients displayed low albumin, transferrin and total cholesterol, respectively. Albumin (p < 0.01) and transferrin levels (p < 0.05) were significantly increased from T0 to T3. High albumin (r = 0.2), transferrin (r = 0.3) and cholesterol (r = 0.1) at T0 were positively correlated with longer survival. CONCLUSIONS: Low albumin, transferrin and cholesterol were predictors of a poor survival. PEG improves low albumin and transferrin, serum markers of malnutrition and poor outcome. PEG should be considered on an individual basis in patients with moderate-severe dementia when risk of malnutrition and aspiration is present. PMID- 26582080 TI - Hyperglycemia is a risk factor for high-grade envenomations after European viper bites (Vipera spp.) in children. AB - CONTEXT: Hyperglycemia has been described in severe scorpion envenomation, we wanted to analyze if it was applicable to viper bites in children. AIM: To describe clinical, biological, and therapeutic characteristics of 83 children bitten by European viper (Vipera spp.) and to confirm that hyperglycemia is a risk factor for high-grade envenomation. MATERIAL AND METHODS: A retrospective study was conducted between 2001 and 2014 in the pediatric emergency department of a tertiary level children's hospital. Collected data were: age and sex of children; day and time of admission; day, time and circumstances of the accident; snake identification; bite location; envenomation severity; presence of fang marks; prehospital care; laboratory abnormalities, use of specific immunotherapy, associated treatments; length of stay; hospital course. RESULTS: Eighty-three children were included (62 boys, 21 girls). The mean age was 7.4 +/- 3.9 years. Bites were most often located on the lower extremities (66%). The classification of envenomation was: 83% low grade (absent or minor envenomation) and 17% high grade (moderate to severe envenomation). All high-grade envenomations received specific immunotherapy (Viperfav(TM), (Aventis Pasteur, MSD, Lyon, France). Being bitten on an upper extremity (odds ratio [OR] 51.1 95% class interval [CI] [6.1 424], p < 0.0001), during the afternoon (OR 13.4 95% CI [1.7-107.9], p = 0.015), feeling violent pain (OR 4.2 95% CI [1.1-16.5], p = 0.023), and high initial plasma glucose level (6.5 +/- 1.7 mmol/L versus 5.0 +/- 0.9 mmol/L, p = 0.027) were associated with a significant risk of high-grade envenomation. CONCLUSION: We have confirmed a potential link between initial hyperglycemia and the risk of progression to high-grade envenomation as well as its association with other published predictive factors. PMID- 26582082 TI - Analysis of Benign Prostatic Hyperplasia Patients' Perspective Through a Third Party-administered Survey. AB - OBJECTIVE: To assess patient-reported functional and quality-of-life (QoL) outcomes associated with various surgical treatments for benign prostate hyperplasia (BPH). MATERIALS AND METHODS: An independent third-party survey was sent to all patients who underwent any surgical treatment for BPH at our institution from January 2007 through January 2013. Overall satisfaction and urinary and sexual outcomes were evaluated using Sexual Health Inventory for Men (SHIM), International Prostate Symptoms Score (IPSS) for urinary function, and International Continence Society-Short Form (ICSmaleSF) questionnaires. RESULTS: Four hundred and seventy-nine respondents (response rate, 55.6%) had undergone holmium laser enucleation of the prostate (HoLEP; n = 214), transurethral resection of the prostate (n = 210), holmium laser ablation of the prostate (n = 21), photoselective vaporization (n = 18), transurethral incision of the prostate (n = 9), and open simple prostatectomy (n = 7). Postoperatively, Sexual Health Inventory for Men scores were not different. However, total IPSS varied significantly among surgical techniques (P < .001). Mean (standard deviation) IPSS was lowest for open simple prostatectomy (4.0 [2.6]), followed by HoLEP (5.8 [5.4]). For individual domains, significant differences were in intermittency (P < .001), weak stream (P = .003), straining (P < .001), and QoL (P = .001). In all these domains, HoLEP had the lowest scores. Regarding International Continence Society-Short Form, we observed a significant difference favoring transurethral resection of the prostate in incontinence (P < .001) and favoring HoLEP in voiding (P = .02) and QoL domains (P = .03). Most patients were satisfied with their surgical intervention, independent of the procedure type. Regret was least in patients who underwent HoLEP (P = .02). CONCLUSION: Patients generally expressed satisfaction with various interventions for BPH. However, those who underwent HoLEP had the best outcomes. PMID- 26582083 TI - Stable Lithium Argon compounds under high pressure. AB - High pressure can fundamentally alter the bonding patterns of chemical elements. Its effects include stimulating elements thought to be "inactive" to form unexpectedly stable compounds with unusual chemical and physical properties. Here, using an unbiased structure search method based on CALYPSO methodology and density functional total energy calculations, the phase stabilities and crystal structures of Li-Ar compounds are systematically investigated at high pressure up to 300 GPa. Two unexpected LimArn compounds (LiAr and Li3Ar) are predicted to be stable above 112 GPa and 119 GPa, respectively. A detailed analysis of the electronic structure of LiAr and Li3Ar shows that Ar in these compounds attracts electrons and thus behaves as an oxidizing agent. This is markedly different from the hitherto established chemical reactivity of Ar. Moreover, we predict that the P4/mmm phase of Li3Ar has a superconducting transition temperature of 17.6 K at 120 GPa. PMID- 26582084 TI - Aberrant NEAT1 expression is associated with clinical outcome in high grade glioma patients. AB - Long noncoding RNA (lncRNA) NEAT1 has been reported to play critical roles in various human tumor entities and related to the survival of patients with malignancies. However, little is known about the role of lncRNA NEAT1 in glioma patients. The aim of this study was to investigate the expression of NEAT1 in human glioma and its correlation with clinicopathological features and prognosis in human glioma; we analyzed the relationship of lncRNA NEAT1 expression with clinicopathological characteristics and prognosis in glioma patients. In our results, the relative level of NEAT1 expression was higher in cancer tissues compared with adjacent noncancerous tissues (p < 0.001). High NEAT1 expression was observed to be closely correlated with larger tumor size (p = 0.023), higher WHO grade (p = 0.005), and recurrence (p = 0.011). Kaplan-Meier curves showed that patients with high NEAT1 expression showed unfavorable overall survival (OS) than the low NEAT1 expression group (p = 0.002). Multivariate analysis results revealed that NEAT1 overexpression was an independent prognostic factor for OS in addition to postoperative chemoradiotherapy and WHO grade. Moreover, high NEAT1 expression in patients with stage III~IV disease and postoperative chemoradiotherapy conferred unfavorable OS (stage III~IV p = 0.002, postoperative chemoradiotherapy p = 0.000). This study supports NEAT1 as a potential prognostic predictor with its high expression in cancer tissues and its association with carcinogenesis and progression in glioma. PMID- 26582085 TI - Novosphingobium colocasiae sp. nov., isolated from a taro field. AB - A novel bacterial strain, designated Teta-03T, was isolated from a taro field in Taiwan and characterized using a polyphasic taxonomic approach. Cells of strain Teta-03T were aerobic, Gram-stain-negative, rod-shaped and non-motile and formed bright yellow colonies. Growth occurred at 10-37 degrees C (optimum, 20 degrees C), with 0-1.0 % (w/v) NaCl (optimum, 0 %) and at pH 3.0-9.0 (optimum, pH 7.0 8.0). The major fatty acids (>10 %) of strain Teta-03T were C18 : 1omega7c, summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c) and C16 : 0. The polar lipid profile consisted of phosphatidylglycerol, phosphatidylethanolamine, phosphatidylmonomethylethanolamine, phosphatidyldimethylethanolamine, sphingoglycolipid, phosphatidylcholine, an uncharacterized glycolipid and an uncharacterized aminolipid. The major polyamine was spermidine. The major isoprenoid quinone was Q-10. The DNA G+C content was 65.0 mol%. On the basis of 16S rRNA gene sequence analysis, strain Teta-03T was shown to belong to the genus Novosphingobium and showed highest similarity to Novosphingobium barchaimii LL02T (96.8 %). Phenotypic characteristics of the novel strain also differed from those of the closest related species of the genus Novosphingobium. On the basis of the genotypic, chemotaxonomic and phenotypic data, strain Teta-03T represents a novel species of the genus Novosphingobium, for which the name Novosphingobium colocasiae sp. nov. is proposed. The type strain is Teta-03T ( = LMG 27385T = KCTC 32255T). PMID- 26582086 TI - Microsatellite Typing of Aspergillus flavus Strains in a Tunisian Onco-hematology Unit. AB - Aspergillus flavus is the most common species associated with invasive aspergillosis in Tunisia. The molecular epidemiology of the species is poorly documented. We used five highly discriminative microsatellite markers for the genotyping of clinical and hospital environmental A. flavus strains to assess whether IA could be hospital-acquired in the onco-hematology unit of the Farhat Hached teaching hospital of Sousse, Tunisia. The genotyping of 18 clinical isolates, collected from sputa of 17 acute leukemia patients, and 81 isolates, collected in these patients' hospital environment and food, identified 57 isolates that were grouped in 10 clones, each of them including 2-17 isolates. The remaining 42 isolates showed a unique genotype. Two main transmission scenarios were observed: (1) the same clone was isolated from different patients; (2) the same clone was isolated from a patient, its hospital environment and/or food. These findings strongly suggest the occurrence of hospital-acquired A. flavus infection/colonization in the investigated onco-hematology unit. PMID- 26582087 TI - Heterozygous Mutations in BMP6 Pro-peptide Lead to Inappropriate Hepcidin Synthesis and Moderate Iron Overload in Humans. AB - BACKGROUND & AIMS: Hereditary hemochromatosis is a heterogeneous group of genetic disorders characterized by parenchymal iron overload. It is caused by defective expression of liver hepcidin, the main regulator of iron homeostasis. Iron stimulates the gene encoding hepcidin (HAMP) via the bone morphogenetic protein (BMP)6 signaling to SMAD. Although several genetic factors have been found to cause late-onset hemochromatosis, many patients have unexplained signs of iron overload. We investigated BMP6 function in these individuals. METHODS: We sequenced the BMP6 gene in 70 consecutive patients with a moderate increase in serum ferritin and liver iron levels who did not carry genetic variants associated with hemochromatosis. We searched for BMP6 mutations in relatives of 5 probands and in 200 healthy individuals (controls), as well as in 2 other independent cohorts of hyperferritinemia patients. We measured serum levels of hepcidin by liquid chromatography-tandem mass spectrometry and analyzed BMP6 in liver biopsy specimens from patients by immunohistochemistry. The functions of mutant and normal BMP6 were assessed in transfected cells using immunofluorescence, real-time quantitative polymerase chain reaction, and immunoblot analyses. RESULTS: We identified 3 heterozygous missense mutations in BMP6 (p.Pro95Ser, p.Leu96Pro, and p.Gln113Glu) in 6 unrelated patients with unexplained iron overload (9% of our cohort). These mutations were detected in less than 1% of controls. p.Leu96Pro also was found in 2 patients from the additional cohorts. Family studies indicated dominant transmission. Serum levels of hepcidin were inappropriately low in patients. A low level of BMP6, compared with controls, was found in a biopsy specimen from 1 patient. In cell lines, the mutated residues in the BMP6 propeptide resulted in defective secretion of BMP6; reduced signaling via SMAD1, SMAD5, and SMAD8; and loss of hepcidin production. CONCLUSIONS: We identified 3 heterozygous missense mutations in BMP6 in patients with unexplained iron overload. These mutations lead to loss of signaling to SMAD proteins and reduced hepcidin production. These mutations might increase susceptibility to mild-to-moderate late-onset iron overload. PMID- 26582090 TI - Asynchronous update based networked predictive control system using a novel proactive compensation strategy. AB - Networked predictive control system (NPCS) has been proposed to address random delays and data dropouts in networked control systems (NCSs). A remaining challenge of this approach is that the controller has uncertain information about the actual control inputs, which leads to the predicted control input errors. The main contribution of this paper is to develop an explicit mechanism running in the distributed network nodes asynchronously, which enables the controller node to keep informed of the states of the actuator node without a priori knowledge about the network. Based on this mechanism, a novel proactive compensation strategy is proposed to develop asynchronous update based networked predictive control system (AUBNPCS). The stability criterion of AUBNPCS is derived analytically. A simulation experiment based on Truetime demonstrates the effectiveness of the scheme. PMID- 26582089 TI - Topological robustness analysis of protein interaction networks reveals key targets for overcoming chemotherapy resistance in glioma. AB - Biological networks display high robustness against random failures but are vulnerable to targeted attacks on central nodes. Thus, network topology analysis represents a powerful tool for investigating network susceptibility against targeted node removal. Here, we built protein interaction networks associated with chemoresistance to temozolomide, an alkylating agent used in glioma therapy, and analyzed their modular structure and robustness against intentional attack. These networks showed functional modules related to DNA repair, immunity, apoptosis, cell stress, proliferation and migration. Subsequently, network vulnerability was assessed by means of centrality-based attacks based on the removal of node fractions in descending orders of degree, betweenness, or the product of degree and betweenness. This analysis revealed that removing nodes with high degree and high betweenness was more effective in altering networks' robustness parameters, suggesting that their corresponding proteins may be particularly relevant to target temozolomide resistance. In silico data was used for validation and confirmed that central nodes are more relevant for altering proliferation rates in temozolomide-resistant glioma cell lines and for predicting survival in glioma patients. Altogether, these results demonstrate how the analysis of network vulnerability to topological attack facilitates target prioritization for overcoming cancer chemoresistance. PMID- 26582088 TI - TLR4 Signaling via NANOG Cooperates With STAT3 to Activate Twist1 and Promote Formation of Tumor-Initiating Stem-Like Cells in Livers of Mice. AB - BACKGROUND & AIMS: Obesity and alcohol consumption contribute to steatohepatitis, which increases the risk for hepatitis C virus (HCV)-associated hepatocellular carcinomas (HCCs). Mouse hepatocytes that express HCV-NS5A in liver up-regulate the expression of Toll-like receptor 4 (TLR4), and develop liver tumors containing tumor-initiating stem-like cells (TICs) that express NANOG. We investigated whether the TLR4 signals to NANOG to promote the development of TICs and tumorigenesis in mice placed on a Western diet high in cholesterol and saturated fat (HCFD). METHODS: We expressed HCV-NS5A from a transgene (NS5A Tg) in Tlr4-/- (C57Bl6/10ScN), and wild-type control mice. Mice were fed a HCFD for 12 months. TICs were identified and isolated based on being CD133+, CD49f+, and CD45-. We obtained 142 paraffin-embedded sections of different stage HCCs and adjacent nontumor areas from the same patients, and performed gene expression, immunofluorescence, and immunohistochemical analyses. RESULTS: A higher proportion of NS5A Tg mice developed liver tumors (39%) than mice that did not express HCV NS5A after the HCFD (6%); only 9% of Tlr4-/- NS5A Tg mice fed HCFD developed liver tumors. Livers from NS5A Tg mice fed the HCFD had increased levels of TLR4, NANOG, phosphorylated signal transducer and activator of transcription (pSTAT3), and TWIST1 proteins, and increases in Tlr4, Nanog, Stat3, and Twist1 messenger RNAs. In TICs from NS5A Tg mice, NANOG and pSTAT3 directly interact to activate expression of Twist1. Levels of TLR4, NANOG, pSTAT3, and TWIST were increased in HCC compared with nontumor tissues from patients. CONCLUSIONS: HCFD and HCV-NS5A together stimulated TLR4-NANOG and the leptin receptor (OB-R)-pSTAT3 signaling pathways, resulting in liver tumorigenesis through an exaggerated mesenchymal phenotype with prominent Twist1-expressing TICs. PMID- 26582092 TI - Characteristics of the HIV/AIDS Epidemic in Women Aged 15-49 Years from 2005 to 2012 in China. AB - OBJECTIVE: To describe the characteristics of the HIV/AIDS epidemic in women aged 15-49 years in China. METHODS: HIV/AIDS cases from 2005 to 2012 that fulfilled the inclusion and exclusion criteria were identified on the Chinese HIV/AIDS case reporting system. Descriptive and spatial analyses were performed. RESULTS: A total of 103,559 female HIV/AIDS cases were included in our study. Based on the descriptive analysis, between 2005 and 2012, the proportion of heterosexually acquired HIV infection among women (15-49 years) increased rapidly from 35.8% to 87.4%. Approximately 60% of these cases were infected through non-marital heterosexual contact. Among older women (40-49 years), a slightly increasing trend was identified. The spatial analysis detected 'hot spots' in the Xinjiang, Yunnan, Sichuan, Guangxi, and Chongqing provinces. The epidemic trends in these areas were predominately driven by heterosexual transmission. CONCLUSION: Non marital heterosexual contact is a very important factor in the HIV/AIDS epidemic in women aged 15-49 years, and the HIV infection rate in older women is increasing. Several epidemic hot spots were detected in northwestern and southwestern China. Efficient interventions are needed to control the spread of HIV/AIDS among women living in these areas. PMID- 26582091 TI - HIV-1 gp120Bal down-Regulates Phosphorylated NMDA Receptor Subunit 1 in Cortical Neurons via Activation of Glutamate and Chemokine Receptors. AB - HIV-1 envelope glycoprotein gp120 (gp120) is a major virulence protein implicated in the pathogenesis of HIV-associated neurocognitive disorders (HAND). Although gp120 has been suggested to cause synaptic and neuronal injuries by disrupting NMDA receptor (NMDAR) function, the underlying mechanism is unclear. Here, we show that gp120Bal down-regulates the phosphorylation of the NMDAR subunit1 NR1 (at Ser896 and Ser897), which is essential for NMDAR function. This effect of gp120Bal is blocked by specific antagonists of both NMDA and AMPA receptors, indicating a critical role of synaptic activation. Furthermore, AMD3100 and maraviroc, antagonists of CCR5 and CXCR4 chemokine receptors, respectively, inhibit the effect of gp120Bal on NR1, suggesting that CXCR4 and CCR5 activation are involved. These findings may provide mechanistic insights into the synaptopathogenesis caused by HIV-1 infection. PMID- 26582093 TI - Indoor Allergen Levels and Household Distributions in Nine Cities Across China. AB - OBJECTIVE: Chinese allergic subjects have high levels of sensitization to house dust mite (HDM) and other indoor allergens. This study quantifies common indoor allergen levels in Chinese households. METHODS: Dust samples were collected from nine cities. Major allergens Der p 1 and Der f 1 from Dermatophagoides pteronyssinus and D. farinae, and specific antigens of Blomia tropicalis, Tyrophagus putrescentiae, Acarus siro, and cockroach species Blattella germanica and Periplaneta americana were measured by ELISA. RESULTS: HDM allergens were found in dust samples from bedding in 95% of the Chinese households. The median levels varied from <0.006 to 9.2 ug/g of dust, depending on the city. The percentages of households having HDM allergen levels associated with the risk of developing allergy sensitization and asthma were 65% and 25%, respectively. Specific antigens of the storage mite and cockroach were only found in samples from the southern and tropical regions of China. Levels of mite allergens were generally higher in samples from bedding compared to samples from the living room, even for storage mites, whereas levels of cockroach antigens were higher in the living room samples. CONCLUSION: HDM allergens are present in bedding dust samples from most Chinese households. Cities in southern and central China have relatively high levels of HDM major allergens compared to cities in northern and western China. Antigens of storage mites and cockroaches are not as common as HDM allergens. PMID- 26582094 TI - Antitumor Activities and Apoptosis-regulated Mechanisms of Fermented Wheat Germ Extract in the Transplantation Tumor Model of Human HT-29 Cells in Nude Mice. AB - OBJECTIVE: A subcutaneous transplantation tumor model of human HT-29 cells in nude mice was established to evaluate anticarcinogenic activities, and the apoptosis-regulated mechanism effect of aqueous extract of fermented wheat germ with Lactobacillus plantarum dy-1 (LFWGE). METHODS: The HT-29 cells were transplanted via subcutaneous injection of 1*107 cells into the right flank of each nude mouse. Then, nude mice were treated for 30 d with LFWGE (high-dose 2 g/kg/d; low-dose 1 g/kg/d) and for 7 d with 5-fluorouracil (5-FU, 25 mg/kg/d) by gavage and intraperitoneal injection, respectively. An inhibition of tumor growth was observed. RESULTS: Tumor volume and weights decreased significantly in both groups of nude mice treated with LFWGE. In addition, the cell apoptosis rate of the LFWGE group (2 g/kg/d, 60.1%+/-4.4%; 1 g/kg/d, 58.6%+/-6.9%) was significantly higher than that of the control group (11.5%+/-1.6%) and 5-FU group (32.1%+/-3.5%) as measured by the TUNEL assay. Moreover, the real-time fluorescent quantitative PCR and Western blot method further confirmed these enhancing apoptosis and growth inhibition effects. The involvement of LFWGE in inducing apoptosis was confirmed by the expression of Bax, Bcl-2, Caspase-3, and CyclinD1. CONCLUSION: The results showed that LFWGE could induce subcutaneous transplantation tumor apoptosis in nude mice and could be as a natural nutrient supplements or chemopreventive agent in the treatment of human colon cancer. PMID- 26582095 TI - Early Biomarkers in 1H Nuclear Magnetic Resonance Spectroscopy of Striatal Pathological Mechanisms after Acute Carbon Monoxide Poisoning in Rats. AB - OBJECTIVE: In vivo Proton Magnetic Resonance Spectroscopy (1H-MRS) can be used to evaluate the levels of specific neurochemical biomarkers of pathological mechanisms in the brain. METHODS: We conducted T2-Weighted Magnetic Resonance Imaging (MRI) and 1H-MRS with a 3.0-Tesla animal MRI system to investigate the early microstructural and metabolic profiles in vivo in the striatum of rats following carbon monoxide (CO) poisoning. RESULTS: Compared to baseline, we found significant cortical surface deformation, cerebral edema changes, which were indicated by the unclear gray/white matter border, and lateral ventricular volume changes in the brain. A significant reduction in the metabolite to total creatine (Cr) ratios of N-acetylaspartate (NAA) was observed as early as 1 h after the last CO administration, while the lactate (Lac) levels increased marginally. Both the Lac/Cr and NAA/Cr ratios leveled off at 6 h and showed no subsequent significant changes. In addition, compared to the control, the choline (Cho)/Cr ratio was slightly reduced in the early stages and significantly increased after 6 h. In addition, a pathological examination revealed mild cerebral edema on cessation of the insult and more severe cerebral injury after additional CO poisoning. CONCLUSION: The present study demonstrated that 1H-MRS of the brain identified early metabolic changes after CO poisoning. Notably, the relationship between the increased Cho/Cr ratio in the striatum and delayed neuropsychologic sequelae requires further research. PMID- 26582096 TI - Application of UPLC-MS/MS Method for Analyzing B-vitamins in Human Milk. AB - OBJECTIVE: To determine ten B-vitamins in human milk by ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). METHODS: The pretreated human milk samples were adequately separated and quantified within 11 min by UPLC-MS/MS with an Acquity UPLC HSS T3 column (2.1*100 mm, 1.8 um). The mobile phase was a gradient of 2.5 mmol/L ammonium formate aqueous solution and acetonitrile at a flow rate of 0.35 mL/min. Stable isotope internal standards were used in the analysis, to correct for the method variability, including matrix and ionization effects. The homogenized human milk samples were deproteinzed using methanol, unknown contaminants were extracted with diethyl ether and hydrophobic phase was discarded. The analytes were monitored via ESI+ionization and detected in multiple reaction monitoring (MRM) with three acquisition functions. RESULTS: Calibration curves ranged from 0.5-160 ng/mL (thiamin, riboflavin, biotin, nicotinic acid, pyridoxine, pyridoxamine, pyridoxal), and 2.5-800 ng/mL (pantothenic acid, FAD and nicotinamide) (R2=0.990 0.999). The relative recovery ranged from 80.1% to 120.2%; accuracy was determined to be 98.3% to 108.0%. Intra-day and inter-day variation were 3.4% 19.9% and 5.9%-18.1%, respectively. The limit of quantification (LOQ) for all vitamins was between 0.25 and 3 ug/L. CONCLUSION: This method was successfully applied for simultaneous analysis of ten B-vitamins in human milk. PMID- 26582097 TI - Overview of Molecular Typing Tools for The Characterization of Salmonella enterica in Malaysia. PMID- 26582098 TI - Drinking Behavior and Associated Factors among Middle School Students in Shanghai, China. AB - The purpose of our study was to assess drinking status in middle school students and to understand the associated factors. The adjusted drinking rates were 50.9%, 39.8%, and 15.1% for lifetime, past-year, and current drinking, respectively. Multivariable logistic regression revealed the following variables positively related to drinking during the past year: family income, maternal educational level, family members who drink, parents who support drinking, best friends who drink, friends who encourage drinking, frequently attending friends' parties, smoking, and actuation trend (P<0.05). The main risk factors were friends (OR=6.77, 95% CI: 6.17, 7.43) and smoking (OR=4.70, 95% CI: 3.44, 6.43). These results contribute to obtaining the potential associated factors and aid in targeted intervention into the drinking behavior of middle school students. PMID- 26582099 TI - Maternal Genistein Intake Can Reduce Body Weight in Male Offspring. AB - The study objectives were to investigate the relationship between early exposure to genistein and obesity in young adulthood and to evaluate changes in reproductive health during puberty and adulthood following in utero exposure to genistein. Thirty-two female rats were randomized into four groups; low dose 400 mg genistein/kg diet group (LG), mid-dose 1200 mg genistein/kg diet group (MG), high dose 3600 mg genistein/kg diet group (HG), and control group without genistein diet (CON). Rats were fed genistein at the beginning of pregnancy along with a high-fat diet. Pups were sacrificed at week 4 and week 8 after birth. High performance liquid chromatography (HPLC) results showed a correlation between maternal genistein intake and genistein concentration in pups' plasma. Compared to CON, body weight reduced significantly in male HG group at week 8. No statistical differences were found in plasma estradiol (E2), testosterone (T), interleukin (IL)-6, and C-reactive protein (CRP) levels with early genistein exposure. Furthermore, uterine histopathology showed notable changes in groups HG and MG compared with CON at week 4 and week 8. In conclusion, maternal genistein supplement could reduce body weight in male pups and alter uterine histopathology in female pups. PMID- 26582100 TI - Valproic Acid Enhances the Anti-tumor Effect of (-)-gossypol to Burkitt Lymphoma Namalwa Cells. AB - Burkitt lymphoma is a highly aggressive B-cell neoplasm. New therapeutic methods are needed to overcome the adverse effect of intensive chemotherapy regimens. Valproic acid and (-)-gossypol are two kinds of chemical compounds used as new anti-tumor drugs in recent years. To investigate the anti-tumor effect of valproic acid and (-)-gossypol, Burkitt lymphoma Namalwa cells were cultured and treated with valproic acid and (-)-gossypol at different concentrations. The proliferation of Namalwa cells was dramatically suppressed after the combination treatment with 2 mmol/L valproic acid and 5 MUmol/L (-)-gossypol. The combined treatment also enhanced intrinsic apoptosis by down-regulating anti-apoptotic protein Mcl-1. Moreover, the autophagy flux significantly increased in Namalwa cells after combined treatment. However, the enhanced autophagy showed little effect on cell survival with present regimen. The results confirmed that combination of valproic acid and (-)-gossypol had synergistic anti-tumor effect to Burkitt lymphoma Namalwa cells. The related mechanisms might include the down regulation of anti-apoptotic protein Mcl-1 and avianized pro-survival role of autophagy. PMID- 26582101 TI - Enhancement of the Chemiluminescence Response of Enzymatic Reactions by Plasmonic Surfaces for Biosensing Applications. AB - We report the enhancement of chemiluminescence response of horseradish peroxidase (HRP) in bioassays by plasmonic surfaces, which are comprised of (i) silver island films (SIFs) and (ii) metal thin films (silver, gold, copper, and nickel, 1 nm thick) deposited onto glass slides. A model bioassay, based on the interactions of avidin-modified HRP with a monolayer of biotinylated poly(ethylene-glycol)-amine, was employed to evaluate the ability of plasmonic surfaces to enhance chemiluminescence response of HRP. Chemiluminescence response of HRP in model bioassays were increased up to ~3.7-fold as compared to the control samples (i.e. glass slides without plasmonic nanoparticles), where the largest enhancement of the chemiluminescence response was observed on SIFs with high loading. These findings allowed us to demonstrate the use of SIFs (high loading) for the detection of a biologically relevant target protein (glial fibrillary acidic protein or GFAP), where the chemiluminescence response of the standard bioassay for GFAP was enhanced up to ~50% as compared to bioassay on glass slides. PMID- 26582102 TI - Genome wide association and genomic prediction for growth traits in juvenile farmed Atlantic salmon using a high density SNP array. AB - BACKGROUND: The genetic architecture of complex traits in farmed animal populations is of interest from a scientific and practical perspective. The use of genetic markers to predict the genetic merit (breeding values) of individuals is commonplace in modern farm animal breeding schemes. Recently, high density SNP arrays have become available for Atlantic salmon, which facilitates genomic prediction and association studies using genome-wide markers and economically important traits. The aims of this study were (i) to use a high density SNP array to investigate the genetic architecture of weight and length in juvenile Atlantic salmon; (ii) to assess the utility of genomic prediction for these traits, including testing different marker densities; (iii) to identify potential candidate genes underpinning variation in early growth. RESULTS: A pedigreed population of farmed Atlantic salmon (n = 622) were measured for weight and length traits at one year of age, and genotyped for 111,908 segregating SNP markers using a high density SNP array. The heritability of both traits was estimated using pedigree and genomic relationship matrices, and was comparable at around 0.5 and 0.6 respectively. The results of the GWA analysis pointed to a polygenic genetic architecture, with no SNPs surpassing the genome-wide significance threshold, and one SNP associated with length at the chromosome-wide level. SNPs surpassing an arbitrary threshold of significance (P < 0.005, ~ top 0.5 % of markers) were aligned to an Atlantic salmon reference transcriptome, identifying 109 SNPs in transcribed regions that were annotated by alignment to human, mouse and zebrafish protein databases. Prediction of breeding values was more accurate when applying genomic (GBLUP) than pedigree (PBLUP) relationship matrices (accuracy ~ 0.7 and 0.58 respectively) and 5,000 SNPs were sufficient for obtaining this accuracy increase over PBLUP in this specific population. CONCLUSIONS: The high density SNP array can effectively capture the additive genetic variation in complex traits. However, the traits of weight and length both appear to be very polygenic with only one SNP surpassing the chromosome-wide threshold. Genomic prediction using the array is effective, leading to an improvement in accuracy compared to pedigree methods, and this improvement can be achieved with only a small subset of the markers in this population. The results have practical relevance for genomic selection in salmon and may also provide insight into variation in the identified genes underpinning body growth and development in salmonid species. PMID- 26582105 TI - Synthesis of (+/-)-Lasubine II Using N-Methoxyamines. AB - The synthesis of (+/-)-lasubine II has been achieved through a three-component allylation capitalizing on the unique properties of N-methoxyamines. This reaction enabled the installation of all the carbon atoms of lasubine II in a single operation. The N-methoxy group was efficiently used for the subsequent nitrone formation. A single-step cyclization of isoxazolidines or N-methoxyamines to form functionalized piperidine rings was also developed. PMID- 26582104 TI - A Comprehensive Review on Cyclodextrin-Based Carriers for Delivery of Chemotherapeutic Cytotoxic Anticancer Drugs. AB - Most of the cytotoxic chemotherapeutic agents have poor aqueous solubility. These molecules are associated with poor physicochemical and biopharmaceutical properties, which makes the formulation difficult. An important approach in this regard is the use of combination of cyclodextrin and nanotechnology in delivery system. This paper provides an overview of limitations associated with anticancer drugs, their complexation with cyclodextrins, loading/encapsulating the complexed drugs into carriers, and various approaches used for the delivery. The present review article aims to assess the utility of cyclodextrin-based carriers like liposomes, niosomes, nanoparticles, micelles, millirods, and siRNA for delivery of antineoplastic agents. These systems based on cyclodextrin complexation and nanotechnology will camouflage the undesirable properties of drug and lead to synergistic or additive effect. Cyclodextrin-based nanotechnology seems to provide better therapeutic effect and sustain long life of healthy and recovered cells. Still, considerable study on delivery system and administration routes of cyclodextrin-based carriers is necessary with respect to their pharmacokinetics and toxicology to substantiate their safety and efficiency. In future, it would be possible to resolve the conventional and current issues associated with the development and commercialization of antineoplastic agents. PMID- 26582103 TI - Eye Care Quality and Accessibility Improvement in the Community (EQUALITY) for adults at risk for glaucoma: study rationale and design. AB - BACKGROUND: Primary open angle glaucoma is a chronic, progressive eye disease that is the leading cause of blindness among African Americans. Glaucoma progresses more rapidly and appears about 10 years earlier in African Americans as compared to whites. African Americans are also less likely to receive comprehensive eye care when glaucoma could be detected before irreversible blindness. Screening and follow-up protocols for managing glaucoma recommended by eye-care professional organizations are often not followed by primary eye-care providers, both ophthalmologists and optometrists. There is a pressing need to improve both the accessibility and quality of glaucoma care for African Americans. Telemedicine may be an effective solution for improving management and diagnosis of glaucoma because it depends on ocular imaging and tests that can be electronically transmitted to remote reading centers where tertiary care specialists can examine the results. We describe the Eye Care Quality and Accessibility Improvement in the Community project (EQUALITY), set to evaluate a teleglaucoma program deployed in retail-based primary eye care practices serving communities with a large percentage of African Americans. METHODS/DESIGN: We conducted an observational, 1-year prospective study based in two Walmart Vision Centers in Alabama staffed by primary care optometrists. EQUALITY focuses on new or existing adult patients who are at-risk for glaucoma or already diagnosed with glaucoma. Patients receive dilated comprehensive examinations and diagnostic testing for glaucoma, followed by the optometrist's diagnosis and a preliminary management plan. Results are transmitted to a glaucoma reading center where ophthalmologists who completed fellowship training in glaucoma review results and provide feedback to the optometrist, who manages the care of the patient. Patients also receive eye health education about glaucoma and comprehensive eye care. Research questions include diagnostic and management agreement between providers, the impact of eye health education on patients' knowledge and adherence to follow-up and medication, patient satisfaction, program cost effectiveness, and EQUALITY's impact on Walmart pharmacy prescription rates. DISCUSSION: As eye-care delivery systems in the US strive to improve quality while reducing costs, telemedicine programs including teleglaucoma initiatives such as EQUALITY could contribute toward reaching this goal, particularly among underserved populations at-risk for chronic blinding diseases. PMID- 26582106 TI - The crucial role of PpMYB10.1 in anthocyanin accumulation in peach and relationships between its allelic type and skin color phenotype. AB - BACKGROUND: Red coloration of fruit skin is one of the most important traits in peach (Prunus persica), and it is mainly due to the accumulation of anthocyanins. Three MYB10 genes, PpMYB10.1, PpMYB10.2, and PpMYB10.3, have been reported as important regulators of red coloration and anthocyanin biosynthesis in peach fruit. In this study, contribution of PpMYB10.1/2/3 to anthocyanin accumulation in the fruit skin was investigated in the Japanese peach cultivars, white-skinned 'Mochizuki' and red-skinned 'Akatsuki'. We then investigated the relationships between allelic type of PpMYB10.1 and skin color phenotype in 23 Japanese peach cultivars for future establishment of DNA-marker. RESULTS: During the fruit development of 'Mochizuki' and 'Akatsuki', anthocyanin accumulation was observed only in the skin of red 'Akatsuki' fruit in the late ripening stages concomitant with high mRNA levels of the last step gene leading to anthocyanin accumulation, UDP-glucose:flavonoid-3-O-glucosyltransferase (UFGT). This was also correlated with the expression level of PpMYB10.1. Unlike PpMYB10.1, expression levels of PpMYB10.2/3 were low in the skin of both 'Mochizuki' and 'Akatsuki' throughout fruit development. Moreover, only PpMYB10.1 revealed expression levels associated with total anthocyanin accumulation in the leaves and flowers of 'Mochizuki' and 'Akatsuki'. Introduction of PpMYB10.1 into tobacco increased the expression of tobacco UFGT, resulting in higher anthocyanin accumulation and deeper red transgenic tobacco flowers; however, overexpression of PpMYB10.2/3 did not alter anthocyanin content and color of transgenic tobacco flowers when compared with wild-type flowers. Dual-luciferase assay showed that the co-infiltration of PpMYB10.1 with PpbHLH3 significantly increased the activity of PpUFGT promoter. We also found close relationships of two PpMYB10.1 allelic types, MYB10.1 1/MYB10.1-2, with the intensity of red skin coloration. CONCLUSION: We showed that PpMYB10.1 is a major regulator of anthocyanin accumulation in red-skinned peach and that it activates PpUFGT transcription. PpMYB10.2/3 may be involved in functions other than anthocyanin accumulation in peach. The peach cultivars having two MYB10.1-2 types resulted in the white skin color. By contrast, those with two MYB10.1-1 or MYB10.1-1/MYB10.1-2 types showed respective red or pale red skin color. These findings contribute to clarifying the molecular mechanisms of anthocyanin accumulation and generating gene-based markers linked to skin color phenotypes. PMID- 26582107 TI - Cep55 regulates spindle organization and cell cycle progression in meiotic oocyte. AB - Cep55 is a relatively novel member of the centrosomal protein family. Here, we show that Cep55 is expressed in mouse oocytes from the germinal vesicle (GV) to metaphase II (MII) stages. Immuostaining and confocal microscopy as well as time lapse live imaging after injection of mRNA encoding fusion protein of Cep55 and GFP identified that Cep55 was localized to the meiotic spindle, especially to the spindle poles at metaphase, while it was concentrated at the midbody in telophase in meiotic oocytes. Knockdown of Cep55 by specific siRNA injection caused the dissociation of gamma-tubulin from the spindle poles, resulting in severely defective spindles and misaligned chromosomes, leading to metaphase I arrest and failure of first polar body (PB1) extrusion. Correspondingly, cyclin B accumulation and spindle assembly checkpoint (SAC) activation were observed in Cep55 knockdown oocytes. Our results suggest that Cep55 may act as an MTOC associated protein regulating spindle organization, and thus cell cycle progression during mouse oocyte meiotic maturation. PMID- 26582108 TI - [Effects of Family Support Programs for Caregivers of People with Dementia - Caregiving Burden, Depression, and Stress: Systematic Review and Meta-analysis]. AB - PURPOSE: The objective of this systematic review was to assess the effects of family support programs on caregiving burden, depression, and stress in family caregivers of people with dementia. METHODS: A literature search was conducted of electronic databases to identify randomized controlled studies with family support programs done between 2000 and 2014. Studies published in English and/or Korean were included for the analysis with search strategies adapted from the Cochrane Dementia and Cognitive Improvement Group. Studies were rated for quality assessment by two independent reviewers using the appraisal checklist developed by Cochrane Reviews and Dissemination. Of 8,334 articles identified in the literature search, full texts of 76 articles that met the inclusion criteria were reviewed and 38 were found to include relevant outcomes. RESULTS: Results from selected studies were pooled in statistical meta-analysis using Review Manager Software and heterogeneity between combined studies was assessed using the Chi square test. Meta-analysis showed that the effect sizes of family caregiver support programs were small to medium for categories of caregiving burden (Hedge's g=-0.17, 95% CI=-0.30~-0.04), depression (Hedge's g=-0.30, 95% CI=-0.40~ 0.20), and stress (Hedge's g=-0.39, 95% CI=-0.52~-0.25). CONCLUSION: The review results indicate that a support programs can assist family caregivers in reducing their psycho-emotional distress. PMID- 26582109 TI - [A Review on the Use of Effect Size in Nursing Research]. AB - PURPOSE: The purpose of this study was to introduce the main concepts of statistical testing and effect size and to provide researchers in nursing science with guidance on how to calculate the effect size for the statistical analysis methods mainly used in nursing. METHODS: For t-test, analysis of variance, correlation analysis, regression analysis which are used frequently in nursing research, the generally accepted definitions of the effect size were explained. RESULTS: Some formulae for calculating the effect size are described with several examples in nursing research. Furthermore, the authors present the required minimum sample size for each example utilizing G*Power 3 software that is the most widely used program for calculating sample size. CONCLUSION: It is noted that statistical significance testing and effect size measurement serve different purposes, and the reliance on only one side may be misleading. Some practical guidelines are recommended for combining statistical significance testing and effect size measure in order to make more balanced decisions in quantitative analyses. PMID- 26582110 TI - [Development of a Measurement Instrument for Parenting Behavior of Primary Caregivers in Early Childhood]. AB - PURPOSE: The purpose of this study was to develop an instrument to measure the parenting behavior of primary caregivers of children in early childhood. METHODS: An instrument was developed according to Devellis's instrument development process. The participants in this study who completed the main survey were 370 mothers and grandmothers. The survey was conducted from June 1 to July 30, 2014, and collected data were analyzed using item analysis, half-split reliability and Cronbach's alpha coefficient, exploratory and confirmatory factor analysis, convergent validity. RESULTS: The factor structure of the instrument showed the cumulative variance as 55.7% in the factor analysis. As a result of a confirmatory factor analysis, a four-factor structure was found to be appropriate, and the construct validity and convergent validity of the instrument were thereby confirmed. The finalized parenting behavior instrument consisted of 26 items and four independent factors: affectionate, laissez-faire, educational and impulsive. A five-point Likert scale was employed, and a higher score in a particular factor showed that most of the behaviors belonged to the factor. CONCLUSION: The instrument developed in this study was found to be reliable and valid, and can be used to develop parent-child relationship building. PMID- 26582111 TI - [Disturbance in ADL from Chemotherapy-induced Peripheral Neuropathy and Quality of Life in Cancer Patients: The Mediating Effect of Psychological Distress]. AB - PURPOSE: The purpose of this study was to examine the mediation of psychological distress in the relationship between disturbance in ADL from chemotherapy induced peripheral neuropathy and quality of life in order to provide a basis for planning nursing interventions to improve the quality of life in cancer patients. METHODS: A purposive sample of 130 patients treated with chemotherapy were recruited in the cross-sectional survey design. Data were collected using self report questionnaires. The instruments were the Chemotherapy Induced Peripheral Neuropathy Assessment Tool (CIPNAT), Hospital Anxiety Depression Scale (HADS), and Functional Assessment of Cancer Therapy-General (FACT-G). RESULTS: The mean score for disturbance in ADL from chemotherapy induced peripheral neuropathy was 3.30. Overall quality of life was 2.48. The mean score was 1.04 for psychological distress. The prevalence was 35.4% for anxiety and 47.7% for depression. There were significant correlations among the three variables, disturbance in ADL from chemotherapy induced peripheral neuropathy, psychosocial distress, and quality of life. Psychosocial distress had a complete mediating effect (beta=-.74, p<.001) in the relationship between disturbance in ADL from chemotherapy induced peripheral neuropathy and quality of life (Sobel test: Z=-6.11, p<.001). CONCLUSION: Based on the findings of this study, nursing intervention programs focusing on disturbance of ADL management, and decrease of psychological distress are highly recommended to improve quality of life in cancer patients. PMID- 26582112 TI - [Leadership Experience of Clinical Nurses: Applying Focus Group Interviews]. AB - PURPOSE: The purpose of this study was to understand and describe the leadership experience of clinical nurses. METHODS: During 2014, data were collected using focus group interviews. Three focus group interviews were held with a total of 20 clinical nurses participating. All interviews were recorded as they were spoken and transcribed and data were analyzed using qualitative content analysis. RESULTS: Fifteen categories emerged from the five main themes. 1) Thoughts on the leadership category: to lead others, to cope with problem situations adequately and to serve as a shield against difficulties. 2) Situations requiring leadership: situation that requires correct judgement, coping and situations that need coordination and cooperation. 3-1) Leadership behaviors: other-oriented approach and self-oriented approach. 3-2) Leadership behavior consequences: relevant compensation and unfair termination. 4-1) Facilitators of leadership: confidence and passion for nursing and external support and resources. 4-2) Barriers to leadership: non-supportive organization culture and deficiency in own leadership competencies. 5) Strategies of leadership development: strengthen leadership through self-development and organizational leadership development. CONCLUSION: In conclusion, the results indicate that it is necessary to enhance clinical nurses' leadership role in healthcare. Enhancement can be achieved through leadership programs focused on enlarging leadership experience, constant self-development, leadership training, and development of leadership competencies suited to the nursing environment. PMID- 26582113 TI - [Development of a Cultural Competence Scale for Nursing Students]. AB - PURPOSE: This methodological study was conducted to develop and test a cultural competence scale for nursing students. METHODS: Based on the five constructs of cultural competency identified in the conceptual analysis of Suh, 76 items for the tool were derived initially. These items were reduced to 58 items after content validity tests (two times) by 6 multicultural experts. Data collected from 526 nursing students were utilized to test the validity and reliability of the preliminary tool. Item analysis, factor analysis, Pearson correlation coefficients, and Cronbach's alpha were used for the analysis. RESULTS: Twenty seven items were selected for the final scale, and categorized into 5 factors explaining 62.1% of the total variance. Cronbach's alpha was .91 and the reliability of the subscales ranged from .76 to .91. Criterion validity between the developed tool and empathy (r=.26, p<.001) was significant. CONCLUSION: The results show that this scale can provide scientific and empirical data when evaluating the effectiveness of school curriculums or multicultural empowerment programs regarding cultural competence of nursing students. PMID- 26582114 TI - [Factors Influencing Changes in Quality of Life in Patients undergoing Hematopoietic Stem Cell Transplantation: A Longitudinal and Multilevel Analysis]. AB - PURPOSE: This study was a prospective longitudinal study to identify changes in quality of life in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). It was based on Roy's adaptation model. METHODS: The questionnaires were administered before HSCT, 30 and 100 days after HSCT. Of the 48 potentially eligible patients, 44 (91.7%) participated in the study and 40 (90.9%) completed the questionnaires at 100 days after HSCT. Multilevel analysis was applied to analyze changes in quality of life. RESULTS: Overall, quality of life showed a decreasing tendency from pre-HSCT to 100 days after HSCT. The adaptation level of participants was compensatory. Type of conditioning was the significant factor influencing quality of life before HSCT (beta00=79.92, p<.001; beta01=-12.64, p<.001) and the change rate of quality of life (beta10=-1.66, p=.020; beta11=2.88, p=.014). Symptom severity (beta20=-1.81, p=.004), depression (beta30=-0.58, p=.001), social dependency (beta40=-0.35, p=.165), and loneliness (beta50=-0.23, p=.065) had a negative effect on changes in quality of life. Symptom severity and depression were statistically significant factors influencing changes in quality of life. CONCLUSION: According to the results of this study, the development of nursing intervention is needed to improve quality of life in patients undergoing allogeneic hematopoietic stem cell transplantation in the early immune reconstruction period. The interventions should include programs to enhance coping capacity and programs to help control symptom severity and depression. Also these interventions need to be started from the beginning of HSCT and a multidisciplinary approach would be helpful. PMID- 26582115 TI - [Effects of a Patient Educational Video Program on Bowel Preparation Prior to Colonoscopy]. AB - PURPOSE: The purpose of this study was to evaluate the effects of an educational video program on bowel preparation for a colonoscopy. METHODS: The study used a non-equivalent control group and non-synchronized design as a quasi-experimental research involving 101 participants undergoing bowel preparation for a colonoscopy (experimental group 51, control group 50 subjects) at W. university hospital, from Aug. 7 to Oct. 31, 2013. The control group received verbal education with an explanatory note while the experimental group received education using a video program. To measure knowledge of diet restrictions and compliance with ingesting bowel preparation solutions, a questionnaire, based on The Korean Society of Gastrointestinal Endoscopy's Guide (2003), developed by Sam Sook You, was used after revisions and supplementation was done. To measure bowel cleanness, the 'Aronchick Bowel Preparation Scale' was adopted. Data were analyzed using the SPSS WIN 12.0 program. RESULTS: A higher proportion of the experimental group showed a positive change in knowledge level on diet restrictions (U=1011.50, p=.035) and ingestion of bowel preparation solutions (U=980.50, p=.019), a higher level of compliance with diet restrictions (U=638.50, p<.001), ingesting bowel preparation solutions (U=668.00, p<.001) and the level of bowel cleanness (chi2=17.00, p<.001) than the control group. CONCLUSION: The results of this study indicate that a video educational program for patients having a colonoscopy can improve knowledge, level of compliance with diet restrictions, ingestion of bowel preparation solutions, and bowel cleanness. Therefore video educational program should be used with this patient group. PMID- 26582116 TI - [Effects of Electric Stimulation and Biofeedback for Pelvic Floor Muscle Exercise in Women with Vaginal Rejuvenation Women]. AB - PURPOSE: The purpose of this study was to investigate the effects of pelvic floor muscle exercise using electric stimulation and biofeedback on maximum pressure of vaginal contraction, vaginal contraction duration and sexual function in women who have had vaginal rejuvenation. METHODS: The research design was a non equivalent control group non-synchronized design study. Participants in this study were women who had vaginal rejuvenation at C obstetrics and gynecology hospital. The 15 participants in the experimental group were given pelvic floor muscle exercise using electric stimulation and biofeedback and the 15 participants in the control group received self pelvic floor muscle exercise. RESULTS: For maximum pressure of vaginal contraction, the experimental group showed a statistically significant increase compared to than the control group (t=5.96, p<.001). For vaginal contraction duration, the experimental group also showed a statistically significant increase compared to the control group (t=3.23, p=.003). For women's sexual function, the experimental group showed a significant increase when compared to the control group in total sexual function scores (t=3.41, p=.002). CONCLUSION: The results indicate that pelvic floor muscle exercise with electric stimulation and biofeedback after vaginal rejuvenation is effective in strengthening vaginal contraction pressure, vaginal contraction and that it also positively functions to increase women's sexual function. PMID- 26582117 TI - [Non-linear System Dynamics Simulation Modeling of Adolescent Obesity: Using Korea Youth Risk Behavior Web-based Survey]. AB - PURPOSE: The purpose of this study was to develop a system dynamics model for adolescent obesity in Korea that could be used for obesity policy analysis. METHODS: On the basis of the casual loop diagram, a model was developed by converting to stock and flow diagram. The Vensim DSS 5.0 program was used in the model development. We simulated method of moments to the calibration of this model with data from The Korea Youth Risk Behavior Web-based Survey 2005 to 2013. We ran the scenario simulation. RESULTS: This model can be used to understand the current adolescent obesity rate, predict the future obesity rate, and be utilized as a tool for controlling the risk factors. The results of the model simulation match well with the data. It was identified that a proper model, able to predict obesity probability, was established. CONCLUSION: These results of stock and flow diagram modeling in adolescent obesity can be helpful in development of obesity by policy planners and other stakeholders to better anticipate the multiple effects of interventions in both the short and the long term. In the future we suggest the development of an expanded model based on this adolescent obesity model. PMID- 26582118 TI - [Impact of Bowel Function, Anxiety and Depression on Quality of Life in Patients with Sphincter-preserving Resection for Rectal Cancer]. AB - PURPOSE: This study was a descriptive survey research to identify the impact of bowel function, anxiety and depression on quality of life in patients with rectal cancer who had a sphincter-preserving resection. METHODS: Participants were 100 patients who had rectal cancer surgery at W hospital in Korea. Bowel function, anxiety & depression, and quality of life were measured using the BFI (Bowel Function Instrument), HADS (Hospital Anxiety-Depression Scale) and the FACT-C (Functional Assessment of Cancer Therapy-Colorectal). RESULTS: The mean scores were 39.81+/-5.16 for bowel function, 6.15+/-3.25 for anxiety, 7.24+/-3.13 for depression, and 72.50+/-13.27 for quality of life. There were significant negative correlations between quality of life and anxiety (r=-.59, p<.001) and between quality of life and depression (r=-.53, p<.001). But the correlation between quality of life and bowel function was significantly positive (r=.22, p=.025). The influence of the independent variables on the total quality of life was examined using multiple regression analysis. Anxiety (beta=-.38, p=.002), bowel function (beta=-.25, p=.028) and occupation (beta=.16, p=.048) were identified as factors affecting quality of life. The explanation power of this regression model was 44% and it was statistically significant (F=16.53, p<.001). CONCLUSION: The results of this study indicate that in order to improve the bowel function of patients after sphincter-preserving resection for rectal cancer, effective nursing interventions should be developed. As psychological problem such as anxiety and depression can relate to quality of life for these patients, nurses should work on improving the situation by providing continuous emotional nursing. PMID- 26582119 TI - [Current Status of Home Visit Programs: Activities and Barriers of Home Care Nursing Services]. AB - PURPOSE: The purpose of this study was to examine the current status of home care nursing services provided by community health nurses and to identify barriers to the services. METHODS: A cross-sectional survey was conducted with three types of community health care nurses. Participants were 257 nurses, 46 of whom were hospital based home care nurses, 176 were community based visiting nurses, and 35 were long term care insurance based visiting nurses. A structured questionnaire on 7 domains of home care nursing services with a 4-point Likert scale was used to measure activities and barriers to care. Data were analyzed using SPSS WIN 21.0 program. RESULTS: Hospital based home care nurses showed a high level of service performance activity in the domain of clinical laboratory tests, medications and injections, therapeutic nursing, and education. Community based visiting nurses had a high level of service performance in the reference domain. Long term care insurance based visiting nurses showed a high level of performance in the service domains of fundamental nursing and counseling. CONCLUSION: The results show that although health care service provided by the three types of community health nurse overlapped, the focus of the service is differentiated. Therefore, these results suggest that existing home care services will need to be utilized efficiently in the development of a new nursing care service for patients living in the community after hospital discharge. PMID- 26582120 TI - [Effect of Adolescents' Abuse Experience on Suicidal Ideation: Focused on Moderated Mediation Effect of Self-esteem on Depression and Anxiety]. AB - PURPOSE: The purpose of this study was to examine the moderating mediation effect of self-esteem on the relations among adolescents' abuse experiences, depression and anxiety, and suicidal ideation. METHODS: The participants were selected using secondary data from a population in the 2012 Korea Welfare Panel Survey (KOWEPS). Data were analyzed using SPSS 15.0 and SPSS Macro, and bootstrapping and hierarchical regression analysis were performed to analyze multilevel models. RESULTS: First, analysis of the mediating effect of the adolescents' abuse showed that there was significant mediating influence between suicidal ideation and depression and anxiety. Second, hierarchical regression analysis showed that self esteem had significant mediation effect on depression and anxiety in adolescents' suicidal ideation. Third, SPSS Macro showed that self-esteem also significantly moderated the mediating effect of adolescents' abuse experiences on suicidal ideation through depression and anxiety. CONCLUSION: The study results suggest that in future research on adolescent's abuse experience, the risk of suicide in depression and anxiety scores should be selected through evaluation of each individual's self-esteem scale. Coping strategies with immediate early intervention should be suggested. PMID- 26582121 TI - [Operating Room Nurses' Experiences of Securing for Patient Safety]. AB - PURPOSE: This study was done to evaluate the experience of securing patient safety in hospital operating rooms. METHODS: Experiential data were collected from 15 operating room nurses through in-depth interviews. The main question was "Could you describe your experience with patient safety in the operating room?". Qualitative data from the field and transcribed notes were analyzed using Strauss and Corbin's grounded theory methodology. RESULTS: The core category of experience with patient safety in the operating room was 'trying to maintain principles of patient safety during high-risk surgical procedures'. The participants used two interactional strategies: 'attempt continuous improvement', 'immersion in operation with sharing issues of patient safety'. CONCLUSION: The results indicate that the important factors for ensuring the safety of patients in the operating room are manpower, education, and a system for patient safety. Successful and safe surgery requires communication, teamwork and recognition of the importance of patient safety by the surgical team. PMID- 26582122 TI - [The Experience of Fluid Management in Hemodialysis Patients]. AB - PURPOSE: The purpose of this study was to explore the experience of fluid management in hemodialysis patients by describing how they manage fluid intake and what affects fluid management. METHODS: Purposive sampling yielded 11 patients who have received hemodialysis for one year or longer in one general hospital. Data were collected through in-depth interviews and analysed using Giorgi's phenomenological method. Data collection and analysis were performed concurrently. RESULTS: The findings regarding how hemodialysis patients manage fluid intake were classified into four constituents: 'recognizing the need for fluid control', 'observing the status of fluid accumulation', 'controlling fluid intake and output', 'getting used to fluid management'. The factors that affect fluid management of hemodialysis patients were revealed as 'willpower', 'change in the mindset', 'support system', and 'emotional state'. CONCLUSION: The study results show that hemodialysis patients manage fluid intake through food and exercise as well as interpersonal relationships. These findings suggest that strategies in the development of nursing interventions for hemodialysis patients should be directed at assisting them in familiarization with fluid management based on an understanding of their sociocultural contexts. PMID- 26582123 TI - Combining Spinach-tagged RNA and gene localization to image gene expression in live yeast. AB - Although many factors required for the formation of export-competent mRNPs have been described, an integrative view of the spatiotemporal coordinated cascade leading mRNPs from their site of transcription to their site of nuclear exit, at a single cell level, is still partially missing due to technological limitations. Here we report that the RNA Spinach aptamer is a powerful tool for mRNA imaging in live S. cerevisiae with high spatial-temporal resolution and no perturbation of the mRNA biogenesis properties. Dedicated image processing workflows are developed to allow detection of very low abundance of transcripts, accurate quantitative dynamic studies, as well as to provide a localization precision close to 100 nm at consistent time scales. Combining these approaches has provided a state-of-the-art analysis of the osmotic shock response in live yeast by localizing induced transcription factors, target gene loci and corresponding transcripts. PMID- 26582125 TI - Anonymous nuclear markers reveal taxonomic incongruence and long-term disjunction in a cactus species complex with continental-island distribution in South America. AB - The Pilosocereus aurisetus complex consists of eight cactus species with a fragmented distribution associated to xeric enclaves within the Cerrado biome in eastern South America. The phylogeny of these species is incompletely resolved, and this instability complicates evolutionary analyses. Previous analyses based on both plastid and microsatellite markers suggested that this complex contained species with inherent phylogeographic structure, which was attributed to recent diversification and recurring range shifts. However, limitations of the molecular markers used in these analyses prevented some questions from being properly addressed. In order to better understand the relationship among these species and make a preliminary assessment of the genetic structure within them, we developed anonymous nuclear loci from pyrosequencing data of 40 individuals from four species in the P. aurisetus complex. The data obtained from these loci were used to identify genetic clusters within species, and to investigate the phylogenetic relationship among these inferred clusters using a species tree methodology. Coupled with a palaeodistributional modelling, our results reveal a deep phylogenetic and climatic disjunction between two geographic lineages. Our results highlight the importance of sampling more regions from the genome to gain better insights on the evolution of species with an intricate evolutionary history. The methodology used here provides a feasible approach to develop numerous genealogical molecular markers throughout the genome for non-model species. These data provide a more robust hypothesis for the relationship among the lineages of the P. aurisetus complex. PMID- 26582124 TI - CpG island erosion, polycomb occupancy and sequence motif enrichment at bivalent promoters in mammalian embryonic stem cells. AB - In embryonic stem (ES) cells, developmental regulators have a characteristic bivalent chromatin signature marked by simultaneous presence of both activation (H3K4me3) and repression (H3K27me3) signals and are thought to be in a 'poised' state for subsequent activation or silencing during differentiation. We collected eleven pairs (H3K4me3 and H3K27me3) of ChIP sequencing datasets in human ES cells and eight pairs in murine ES cells, and predicted high-confidence (HC) bivalent promoters. Over 85% of H3K27me3 marked promoters were bivalent in human and mouse ES cells. We found that (i) HC bivalent promoters were enriched for developmental factors and were highly likely to be differentially expressed upon transcription factor perturbation; (ii) murine HC bivalent promoters were occupied by both polycomb repressive component classes (PRC1 and PRC2) and grouped into four distinct clusters with different biological functions; (iii) HC bivalent and active promoters were CpG rich while H3K27me3-only promoters lacked CpG islands. Binding enrichment of distinct sets of regulators distinguished bivalent from active promoters. Moreover, a 'TCCCC' sequence motif was specifically enriched in bivalent promoters. Finally, this analysis will serve as a resource for future studies to further understand transcriptional regulation during embryonic development. PMID- 26582126 TI - Caring in an atmosphere of uncertainty: perspectives and experiences of caregivers of peoples undergoing haemodialysis in Iran. AB - BACKGROUND: Chronic renal failure is one of the major causes of mortality and disability worldwide. Although dialysis treatment is considered as a life-saving treatment for these patients, their caregivers face various problems making the atmosphere of caring uncertain. AIMS: This study is aimed to explore and describe the experiences and perspectives of family caregivers of the patients undergoing haemodialysis. METHODS: In this study, 20 haemodialysis family caregivers were selected by purposeful sampling. Data gathering techniques in this research were in-depth and unstructured interview and field observation. The researchers used an inductive thematic analysis approach to analysing the interviews' data. FINDINGS: Three main themes emerged from the data indicating the patients' care are conducted in a state of uncertainty including constant struggle to learn, effort and adherence to the divine thread, and in disease's captivity. CONCLUSIONS: Caring in an uncertain atmosphere leads to decreased efficiency and quality of family caregivers' care. To promote and improve the efficiency of care, healthcare planners should pay attention to the challenges and perspectives of caregivers of the patients undergoing haemodialysis. PMID- 26582127 TI - Copper(II) complexes with naringenin and hesperetin: cytotoxic activity against A 549 human lung adenocarcinoma cells and investigation on the mode of action. AB - Copper(II) complexes [Cu(H2O)2 (L1)(phen)](ClO4) (1) and [Cu(H2O)(L2)(phen)](ClO4) (2) (HL1 = naringenin; HL2 = hesperetin) were obtained, in which an anionic flavonoid ligand is attached to the metal center along with 1,10-phenanthroline (phen) as co-ligand. Complexes (1) and (2) were assayed for their cytotoxic activity against A549 lung carcinoma and against normal lung fibroblasts (LL-24) and human umbilical vein endothelial cells (HUVEC). We found IC50 = 16.42 uM (1) and IC50 = 5.82 uM (2) against A549 tumor cells. Complexes (1) and (2) exhibited slight specificity, being more cytotoxic against malignant than against non-malignant cells. 1 and 2 induced apoptosis on A549 cells in a mitochondria-independent pathway, and showed antioxidant activity. The antioxidant effect of the complexes could possibly improve their apoptotic action, most likely by a PI3K-independent reduction of autophagy. Complexes (1) and (2) interact in vitro with calf thymus DNA by an intercalative binding mode. EPR data indicated that 1 and 2 interact with human serum albumin (HSA) forming mixed ligand species. PMID- 26582128 TI - Single-Dose Anti-CD138 Radioimmunotherapy: Bismuth-213 is More Efficient than Lutetium-177 for Treatment of Multiple Myeloma in a Preclinical Model. AB - OBJECTIVES: Radioimmunotherapy (RIT) has emerged as a potential treatment option for multiple myeloma (MM). In humans, a dosimetry study recently showed the relevance of RIT using an antibody targeting the CD138 antigen. The therapeutic efficacy of RIT using an anti-CD138 antibody coupled to (213)Bi, an alpha emitter, was also demonstrated in a preclinical MM model. Since then, RIT with beta-emitters has shown efficacy in treating hematologic cancer. In this paper, we investigate the therapeutic efficacy of RIT in the 5T33 murine MM model using a new anti-CD138 monoclonal antibody labeled either with (213)Bi for alpha-RIT or (177)Lu for beta-RIT. METHODS: A new monoclonal anti-CD138 antibody, 9E7.4, was generated by immunizing a rat with a murine CD138-derived peptide. Antibody specificity was validated by flow cytometry, biodistribution, and alpha-RIT studies. Then, a beta-RIT dose-escalation assay with the (177)Lu-radiolabeled 9E7.4 mAb was performed in KalwRij C57/BL6 mice 10 days after i.v. engraftment with 5T33 MM cells. Animal survival and toxicological parameters were assessed to define the optimal activity. RESULTS: alpha-RIT performed with 3.7 MBq of (213)Bi labeled 9E7.4 anti-CD138 mAb increased median survival to 80 days compared to 37 days for the untreated control and effected cure in 45% of animals. beta-RIT performed with 18.5 MBq of (177)Lu-labeled 9E7.4 mAb was well tolerated and significantly increased mouse survival (54 vs. 37 days in the control group); however, no mice were cured with this treatment. CONCLUSION: This study revealed the advantages of alpha-RIT in the treatment of MM in a preclinical model where beta-RIT shows almost no efficacy. PMID- 26582130 TI - Advantage of MALDI-TOF-MS over biochemical-based phenotyping for microbial identification illustrated on industrial applications. AB - Fast microbial identification is becoming increasingly necessary in industry to improve microbial control and reduce biocide consumption. We compared the performances of two systems based on MALDI-TOF MS (VITEK MS and BIOTYPER) and two based on biochemical testing (BIOLOG, VITEK 2 Compact) with genetic methods for the identification of environmental bacteria. At genus level both MALDI-TOF MS based systems showed the lowest number of false (4%) and approx. 60% correct identifications. In contrast, the biochemical-based systems assigned 25% of the genera incorrectly. The differences were even more apparent at the species level. The BIOTYPER was most conservative, where assigning a species led to the lowest percentage of species identifications (54%) but also to the least wrong assignments (4%). The other three systems showed higher levels of false assignments: 8.7, 40 and 46% respectively. The genus identification performance on four industrial products of the BIOTYPER could be increased up to 94.3% (average 88% of 167 isolates) by evolving the database in a product specific manner. Comparison of the bacterial population in the example of paints, and raw materials used therein, at different production steps demonstrated unequivocally that the contamination of the final paint product originated not from the main raw material. SIGNIFICANCE AND IMPACT OF THE STUDY: MALDI-TOF-MS has revolutionized speed and precision of microbial identification for clinical isolates outperforming conventional methods. In contrast, few performance studies have been published so far focusing on suitability for particularly industrial applications, geomicrobiology and environmental analytics. This study evaluates the performance of this proteomic phenotyping on such industrial isolates in comparison with biochemical-based phenotyping and genotyping. Further the study exemplifies the power of MALDI-TOF-MS to trace cost-efficiently the dominating cultivable bacterial species throughout an industrial paint production process. Vital information can be retrieved to identify the most crucial contaminating source for the final product. PMID- 26582129 TI - Ixodes scapularis and Ixodes ricinus tick cell lines respond to infection with tick-borne encephalitis virus: transcriptomic and proteomic analysis. AB - BACKGROUND: Ixodid ticks are important vectors of a wide variety of viral, bacterial and protozoan pathogens of medical and veterinary importance. Although several studies have elucidated tick responses to bacteria, little is known about the tick response to viruses. To gain insight into the response of tick cells to flavivirus infection, the transcriptomes and proteomes of two Ixodes spp cell lines infected with the flavivirus tick-borne encephalitis virus (TBEV) were analysed. METHODS: RNA and proteins were isolated from the Ixodes scapularis derived cell line IDE8 and the Ixodes ricinus-derived cell line IRE/CTVM19, mock infected or infected with TBEV, on day 2 post-infection (p.i.) when virus production was increasing, and on day 6 p.i. when virus production was decreasing. RNA-Seq and mass spectrometric technologies were used to identify changes in abundance of, respectively, transcripts and proteins. Functional analyses were conducted on selected transcripts using RNA interference (RNAi) for gene knockdown in tick cells infected with the closely-related but less pathogenic flavivirus Langat virus (LGTV). RESULTS: Differential expression analysis using DESeq resulted in totals of 43 and 83 statistically significantly differentially-expressed transcripts in IDE8 and IRE/CTVM19 cells, respectively. Mass spectrometry detected 76 and 129 statistically significantly differentially represented proteins in IDE8 and IRE/CTVM19 cells, respectively. Differentially expressed transcripts and differentially-represented proteins included some that may be involved in innate immune and cell stress responses. Knockdown of the heat shock proteins HSP90, HSP70 and gp96, the complement-associated protein Factor H and the protease trypsin resulted in increased LGTV replication and production in at least one tick cell line, indicating a possible antiviral role for these proteins. Knockdown of RNAi-associated proteins Argonaute and Dicer, which were included as positive controls, also resulted in increased LGTV replication and production in both cell lines, confirming their role in the antiviral RNAi pathway. CONCLUSIONS: This systems biology approach identified several molecules that may be involved in the tick cell innate immune response against flaviviruses and highlighted that ticks, in common with other invertebrate species, have other antiviral responses in addition to RNAi. PMID- 26582131 TI - Defining Hsp70 Subnetworks in Dengue Virus Replication Reveals Key Vulnerability in Flavivirus Infection. AB - Viral protein homeostasis depends entirely on the machinery of the infected cell. Accordingly, viruses can illuminate the interplay between cellular proteostasis components and their distinct substrates. Here, we define how the Hsp70 chaperone network mediates the dengue virus life cycle. Cytosolic Hsp70 isoforms are required at distinct steps of the viral cycle, including entry, RNA replication, and virion biogenesis. Hsp70 function at each step is specified by nine distinct DNAJ cofactors. Of these, DnaJB11 relocalizes to virus-induced replication complexes to promote RNA synthesis, while DnaJB6 associates with capsid protein and facilitates virion biogenesis. Importantly, an allosteric Hsp70 inhibitor, JG40, potently blocks infection of different dengue serotypes in human primary blood cells without eliciting viral resistance or exerting toxicity to the host cells. JG40 also blocks replication of other medically-important flaviviruses including yellow fever, West Nile and Japanese encephalitis viruses. Thus, targeting host Hsp70 subnetworks provides a path for broad-spectrum antivirals. PMID- 26582132 TI - Sequence-Intrinsic Mechanisms that Target AID Mutational Outcomes on Antibody Genes. AB - In activated B lymphocytes, AID initiates antibody variable (V) exon somatic hypermutation (SHM) for affinity maturation in germinal centers (GCs) and IgH switch (S) region DNA breaks (DSBs) for class-switch recombination (CSR). To resolve long-standing questions, we have developed an in vivo assay to study AID targeting of passenger sequences replacing a V exon. First, we find AID targets SHM hotspots within V exon and S region passengers at similar frequencies and that the normal SHM process frequently generates deletions, indicating that SHM and CSR employ the same mechanism. Second, AID mutates targets in diverse non-Ig passengers in GC B cells at levels similar to those of V exons, definitively establishing the V exon location as "privileged" for SHM. Finally, Peyer's patch GC B cells generate a reservoir of V exons that are highly mutated before selection for affinity maturation. We discuss the implications of these findings for harnessing antibody diversification mechanisms. PMID- 26582134 TI - Changes in postural control in patients with Parkinson's disease: a posturographic study. AB - OBJECTIVES: Postural instability is one of the most disabling features in Parkinson's disease (PD), and often leads to falls that reduce mobility and functional capacity. The objectives of this study were to analyse the limit of stability (LOS) and influence of the manipulation of visual, somatosensorial and visual-vestibular information on postural control in patients with PD and healthy subjects. DESIGN: Cross-sectional. SETTING: Movement Disorders Unit, university setting. PARTICIPANTS: Eighty-two subjects aged between 37 and 83 years: 41 with Parkinson's disease in the 'on' state and 41 healthy subjects with no neurological disorders. Both groups were matched in terms of sex and age. MAIN OUTCOME MEASURES: Unified Parkinson's Disease Rating Scale (UPDRS)-motor score, modified Hoehn and Yahr staging, Dynamic Gait Index (DGI) and posturography with integrated virtual reality. The parameters analysed by posturography were LOS area, area of body centre of pressure excursion and balance functional reserve in the standing position in 10 conditions (open and closed eyes, unstable surface with eyes closed, saccadic and optokinetic stimuli, and visual-vestibular interaction). RESULTS: The mean UPDRS motor score and DGI score were 27 [standard deviation (SD) 14] and 21 (SD 3), respectively. Thirteen participants scored between 0 and 19 points, indicating major risk of falls. Posturographic assessment showed that patients with PD had significantly lower LOS area and balance functional reserve values, and greater body sway area in all posturographic conditions compared with healthy subjects. CONCLUSIONS: Patients with PD have reduced LOS area and greater postural sway compared with healthy subjects. The deterioration in postural control was significantly associated with major risk of falls. PMID- 26582135 TI - The influence of social and symbolic cues on observers' gaze behaviour. AB - Research has shown that social and symbolic cues presented in isolation and at fixation have strong effects on observers, but it is unclear how cues compare when they are presented away from fixation and embedded in natural scenes. We here compare the effects of two types of social cue (gaze and pointing gestures) and one type of symbolic cue (arrow signs) on eye movements of observers under two viewing conditions (free viewing vs. a memory task). The results suggest that social cues are looked at more quickly, for longer and more frequently than the symbolic arrow cues. An analysis of saccades initiated from the cue suggests that the pointing cue leads to stronger cueing than the gaze and the arrow cue. While the task had only a weak influence on gaze orienting to the cues, stronger cue following was found for free viewing compared to the memory task. PMID- 26582133 TI - Jagged 1 Rescues the Duchenne Muscular Dystrophy Phenotype. AB - Duchenne muscular dystrophy (DMD), caused by mutations at the dystrophin gene, is the most common form of muscular dystrophy. There is no cure for DMD and current therapeutic approaches to restore dystrophin expression are only partially effective. The absence of dystrophin in muscle results in dysregulation of signaling pathways, which could be targets for disease therapy and drug discovery. Previously, we identified two exceptional Golden Retriever muscular dystrophy (GRMD) dogs that are mildly affected, have functional muscle, and normal lifespan despite the complete absence of dystrophin. Now, our data on linkage, whole-genome sequencing, and transcriptome analyses of these dogs compared to severely affected GRMD and control animals reveals that increased expression of Jagged1 gene, a known regulator of the Notch signaling pathway, is a hallmark of the mild phenotype. Functional analyses demonstrate that Jagged1 overexpression ameliorates the dystrophic phenotype, suggesting that Jagged1 may represent a target for DMD therapy in a dystrophin-independent manner. PAPERCLIP. PMID- 26582136 TI - Ionic liquids and their bases: Striking differences in the dynamic heterogeneity near the glass transition. AB - Ionic liquids (ILs) constitute an active field of research due to their important applications. A challenge for these investigations is to explore properties of ILs near the glass transition temperature Tg, which still require our better understanding. To shed a new light on the issues, we measured ILs and their base counterparts using the temperature modulated calorimetry. We performed a comparative analysis of the dynamic heterogeneity at Tg for bases and their salts with a simple monoatomic anion (Cl(-)). Each pair of ionic and non-ionic liquids is characterized by nearly the same chemical structure but their intermolecular interactions are completely different. We found that the size of the dynamic heterogeneity of ILs near Tg is considerably smaller than that established for their dipolar counterparts. Further results obtained for several other ILs near Tg additionally strengthen the conclusion about the relatively small size of the dynamic heterogeneity of molecular systems dominated by electrostatic interactions. Our finding opens up new perspectives on designing different material properties depending on intermolecular interaction types. PMID- 26582137 TI - Food advertising, children's food choices and obesity: interplay of cognitive defences and product evaluation: an experimental study. AB - OBJECTIVES: To investigate the role of product evaluations, nutritional and persuasion knowledge on children's food choices conducted because of limited evidence about the role of product evaluations on consumer choices in conjunction with cognitive defences. DESIGN: A randomised controlled 2 * 2 factorial experiment with an exposure to a food and a control (toy) advertisement conducted in a non-laboratory setting at an annual event traditionally visited by families. SUBJECTS: Children aged 7-13 years with biometric/weight data representative of the general Australian population. MEASUREMENTS: Height and weight (converted into body mass index z-scores) measured in addition to children's nutritional and persuasion knowledge, product evaluations, age and gender. RESULTS: The factors that undermine children's cognitive defences relate to taste, social appeal of foods and low nutritional and persuasion knowledge. An interplay between the above-mentioned factors was also observed, identifying four groups among young consumers, alluding to a complex and at times impulsive nature of children's decisions: (1) knowledgeable children with less positive product evaluations choosing a healthy snack; (2) knowledgeable but hedonism-oriented children seeking peer conformity choosing an advertised product; (3) knowledgeable children who chose a snack belonging to the same product category; and (4) less knowledgeable children with positive product evaluations and low nutritional knowledge choosing snacks from the advertised product category. Obese children were more likely to belong to a cluster of less knowledgeable and hedonism oriented children. CONCLUSIONS: The problem of consumption of less healthy foods is complex and multiple factors need to be considered by health practitioners, social marketers and parents to address the issue of childhood obesity. Nutritional knowledge alone is not sufficient to ensure children make healthier food choices and emphasis should also be placed on persuasion knowledge education, targeting of peer norms, self-efficacy and stricter regulation of advertising aimed at children. PMID- 26582139 TI - Current status and future prospects of using advanced computer-based methods to study bacterial colonial morphology. AB - Despite the advancement of recent molecular technologies, culturing is still considered the gold standard for microbial sample analysis. Here we review three different bacterial colony-based screening modalities that provide significant information beyond the simple shape and color of the colony. The plate imaging technique provides numeration and quantitative spectral reflectance information for each colony, while Raman spectroscopic analysis of bacteria colonies relates the Raman-shifted peaks to specific chemical bonding. Finally, the elastic-light scatter technique provides a volumetric interaction of the whole colony through laser-bacteria interactions, instantly capturing the morphological traits of the colony and allowing quantitative classifications. PMID- 26582138 TI - Using the Consolidated Framework for Implementation Research to Identify Barriers and Facilitators for the Implementation of an Internet-Based Patient-Provider Communication Service in Five Settings: A Qualitative Study. AB - BACKGROUND: Although there is growing evidence of the positive effects of Internet-based patient-provider communication (IPPC) services for both patients and health care providers, their implementation into clinical practice continues to be a challenge. OBJECTIVE: The 3 aims of this study were to (1) identify and compare barriers and facilitators influencing the implementation of an IPPC service in 5 hospital units using the Consolidated Framework for Implementation Research (CFIR), (2) assess the ability of the different constructs of CFIR to distinguish between high and low implementation success, and (3) compare our findings with those from other studies that used the CFIR to discriminate between high and low implementation success. METHODS: This study was based on individual interviews with 10 nurses, 6 physicians, and 1 nutritionist who had used the IPPC to answer messages from patients. RESULTS: Of the 36 CFIR constructs, 28 were addressed in the interviews, of which 12 distinguished between high and low implementation units. Most of the distinguishing constructs were related to the inner setting domain of CFIR, indicating that institutional factors were particularly important for successful implementation. Health care providers' beliefs in the intervention as useful for themselves and their patients as well as the implementation process itself were also important. A comparison of constructs across ours and 2 other studies that also used the CFIR to discriminate between high and low implementation success showed that 24 CFIR constructs distinguished between high and low implementation units in at least 1 study; 11 constructs distinguished in 2 studies. However, only 2 constructs (patient need and resources and available resources) distinguished consistently between high and low implementation units in all 3 studies. CONCLUSIONS: The CFIR is a helpful framework for illuminating barriers and facilitators influencing IPPC implementation. However, CFIR's strength of being broad and comprehensive also limits its usefulness as an implementation framework because it does not discriminate between the relative importance of its many constructs for implementation success. This is the first study to identify which CFIR constructs are the most promising to distinguish between high and low implementation success across settings and interventions. Findings from this study can contribute to the refinement of CFIR toward a more succinct and parsimonious framework for planning and evaluation of the implementation of clinical interventions. CLINICALTRIAL: Clinicaltrials.gov NCT00971139; http://clinicaltrial.gov/ct2/show/NCT00971139 (Archived by WebCite at http://www.webcitation.org/6cWeqN1uY). PMID- 26582140 TI - Comparative effectiveness of motivation phase intervention components for use with smokers unwilling to quit: a factorial screening experiment. AB - AIMS: To screen promising intervention components designed to reduce smoking and promote abstinence in smokers initially unwilling to quit. DESIGN: A balanced, four-factor, randomized factorial experiment. SETTING: Eleven primary care clinics in southern Wisconsin, USA. PARTICIPANTS: A total of 517 adult smokers (63.4% women, 91.1% white) recruited during primary care visits who were willing to reduce their smoking but not quit. INTERVENTIONS: Four factors contrasted intervention components designed to reduce smoking and promote abstinence: (1) nicotine patch versus none; (2) nicotine gum versus none; (3) motivational interviewing (MI) versus none; and (4) behavioral reduction counseling (BR) versus none. Participants could request cessation treatment at any point during the study. MEASUREMENTS: The primary outcome was percentage change in cigarettes smoked per day at 26 weeks post-study enrollment; the secondary outcomes were percentage change at 12 weeks and point-prevalence abstinence at 12 and 26 weeks post-study enrollment. FINDINGS: There were few main effects, but a significant four-way interaction at 26 weeks post-study enrollment (P = 0.01, beta = 0.12) revealed relatively large smoking reductions by two component combinations: nicotine gum combined with BR and BR combined with MI. Further, BR improved 12 week abstinence rates (P = 0.04), and nicotine gum, when used without MI, increased 26-week abstinence after a subsequent aided quit attempt (P = 0.01). CONCLUSIONS: Motivation-phase nicotine gum and behavioral reduction counseling are promising intervention components for smokers who are initially unwilling to quit. PMID- 26582142 TI - Dual transcriptome sequencing reveals resistance of TLR4 ligand-activated bone marrow-derived macrophages to inflammation mediated by the BET inhibitor JQ1. AB - Persistent macrophage activation is associated with the expression of various pro inflammatory genes, cytokines and chemokines, which may initiate or amplify inflammatory disorders. A novel synthetic BET inhibitor, JQ1, was proven to exert immunosuppressive activities in macrophages. However, a genome-wide search for JQ1 molecular targets has not been undertaken. The present study aimed at evaluating the anti-inflammatory function and underlying genes that are targeted by JQ1 in LPS-stimulated primary bone marrow-derived macrophages (BMDMs) using global transcriptomic RNA sequencing and quantitative real-time PCR. Among the annotated genes, transcriptional sequencing of BMDMs that were treated with JQ1 revealed a selective effect on LPS-induced gene expression in which the induction of cytokines/chemokines, interferon-stimulated genes, and prominent (transcription factors) TFs was suppressed. Additionally, we found that JQ1 reduced the expression of previously unidentified genes that are important in inflammation. Importantly, these inflammatory genes were not affected by JQ1 treatment alone. Furthermore, we confirmed that JQ1 reduced cytokines/chemokines in the supernatants of LPS treated BMDMs. Moreover, the biological pathways and gene ontology of the differentially expressed genes were determined in the JQ1 treatment of BMDMs. These unprecedented results suggest that the BET inhibitor JQ1 is a candidate for the prevention or therapeutic treatment of inflammatory disorders. PMID- 26582141 TI - Differential contributions of ApoE4 and female sex to BACE1 activity and expression mediate Abeta deposition and learning and memory in mouse models of Alzheimer's disease. AB - Alzheimer's disease (AD), the most common form of dementia, disproportionately affects women in both prevalence and severity. This increased vulnerability to AD in women is strongly associated with age-related ovarian hormone loss and apolipoprotein E 4 allele (ApoE4), the most important genetic risk factor for sporadic AD. Up to date, the mechanism involved in the interaction between ApoE4 and sex/gender in AD is still unclear. This study evaluated the sex-dependent ApoE4 effects on learning and memory, Abeta deposition and potential mechanisms, using mice bearing both sporadic (ApoE4) and familial (APPSwe, PS1M146V, tauP301L; 3xTg) AD risk factors and compared with sex- and age-matched 3xTg or nonTg mice. Compared to nonTg mice, transgenic mice of both sexes showed spatial learning and memory deficits in the radial arm water maze and novel arm discrimination tests at 20 months of age. However, at 10 months, only ApoE4/3xTg mice showed significant learning and memory impairment. Moreover, molecular studies of hippocampal tissue revealed significantly higher protein levels of Abeta species, beta-site APP cleavage enzyme (BACE1) and Sp1, a transcription factor of BACE1, in female ApoE4/3xTg when compared with female nonTg, female 3xTg, and male ApoE4/3xTg mice. Significantly increased BACE1 enzymatic activities were observed in both male and female mice carrying ApoE4; however, only the females showed significant higher BACE1 expressions. Together, these data suggest that ApoE4 allele is associated with increased BACE1 enzymatic activity, while female sex plays an important role in increasing BACE1 expression. The combination of both provides a molecular basis for high Abeta pathology and the resultant hippocampus-dependent learning and memory deficits in female ApoE4 carriers. PMID- 26582143 TI - Distribution of Lipids in the Grain of Wheat (cv. Hereward) Determined by Lipidomic Analysis of Milling and Pearling Fractions. AB - Lipidomic analyses of milling and pearling fractions from wheat grain were carried out to determine differences in composition that could relate to the spatial distribution of lipids in the grain. Free fatty acids and triacylglycerols were major components in all fractions, but the relative contents of polar lipids varied, particularly those of lysophosphatidylcholine and digalactosyldiglyceride, which were enriched in flour fractions. By contrast, minor phospholipids were enriched in bran and offal fractions. The most abundant fatty acids in the analyzed acyl lipids were C16:0 and C18:2 and their combinations, including C36:4 and C34:2. Phospholipids and galactolipids have been reported to have beneficial properties for breadmaking, whereas free fatty acids and triacylglycerols are considered detrimental. The subtle differences in the compositions of fractions determined in the present study could therefore underpin the production of flour fractions with optimized compositions for different end uses. PMID- 26582144 TI - Anti-hyperglycaemic effects of herbal porridge made of Scoparia dulcis leaf extract in diabetics - a randomized crossover clinical trial. AB - BACKGROUND: Leaf extracts of Scoparia dulcis, is used as a herbal remedy by diabetics worldwide. Fresh Scoparia dulcis porridge elicited a low glycaemic index (GI) and anti-hyperglycaemic effects when fed to diabetic Wistar rats. Commercially produced Scoparia dulcis porridge (SDC) elicited medium GI. Present study was aimed at studying the anti-diabetic effects of consumption of commercially produced S. dulcis porridge. METHOD: A randomized crossover clinical trial with type 2 diabetic patients (n = 35) on medication, with mild and moderate diabetes [fasting blood glucose (FBG) 126-300 mg/dL, age 35-70 years] was conducted. Within the first three months (study period 1) group 1 was the test and group 2 was the control. Following a wash-out period, the two groups were crossed over (study period 2: group 1 - control; group 2 - test). Test group consumed commercially produced SDC for 3 days/week for three months and the control group any other food. At the onset and end of each study period glucose measurements [Fasting Blood Glucose (FBG), HbA1c], lipid measurements (total cholesterol, HDL-C, LDL-C, triglycerides, cholesterol ratios), toxicity parameters (liver enzymes, creatinine, CRP, eGFR) were analyzed by enzyme assay kit methods using a KONELAB 20XT auto analyzer. Significances between groups were analyzed by one way ANOVA (normal distribution) and Mann Whitney test (if the values were not normally distributed). Within group comparisons were carried out by Bonferroni post hoc test. RESULTS: During the crossover clinical trial HbA1c of group 1 decreased from 7.9 +/- 0.5 to 6.5 +/- 0.3 (p = 0.003) while HbA1c of group 2 decreased from 7.0 +/- 0.3to 6.7 +/- 0.3 while in the test group. Therefore, both test groups (1 and 2) elicited a decrease in HbA1c compared to respective control groups. Both test groups elicited a non significant decrease in FBG following the intervention (group 1 - from 174 +/- 14 to 160 +/- 10 mg/dL; group 2 - from 183 +/- 13 to 160 +/- 7 mg/dL). No significant differences (p >0.05) in insulin, cholesterol measurements (total cholesterol, LDL-C, HDL-C, triglycerides and cholesterol ratios) and atherogenic index between or within groups were observed. All other measurements (AST, ALT, ALP, creatinine, CRP, eGFR) were normal and not significantly different between or within groups. CONCLUSION: Porridge made with SDC leaf extract decreased FBG and HbA1c (p >0.05) of type 2 diabetic patients. The porridge had no effect on cholesterol measurements and no toxicity was observed at the dose tested. Therefore, the SDC porridge can be recommended as a suitable meal for diabetic patients. PMID- 26582146 TI - High-Fidelity Simulation of Primary Blast: Direct Effects on the Head. AB - The role of primary blast in blast-induced traumatic brain injury (bTBI) is controversial in part due to the technical difficulties of generating free-field blast conditions in the laboratory. The use of traditional shock tubes often results in artifacts, particularly of dynamic pressure, whereas the forces affecting the head are dependent on where the animal is placed relative to the tube, whether the exposure is whole-body or head-only, and on how the head is actually exposed to the insult (restrained or not). An advanced blast simulator (ABS) has been developed that enables high-fidelity simulation of free-field blastwaves, including sharply defined static and dynamic overpressure rise times, underpressures, and secondary shockwaves. Rats were exposed in head-only fashion to single-pulse blastwaves of 15 to 30 psi static overpressure. Head restraints were configured so as to eliminate concussive and minimize whiplash forces exerted on the head, as shown by kinematic analysis. No overt signs of trauma were present in the animals post-exposure. However, significant changes in brain 2',3'-cyclic nucleotide 3'-phosphohydrolase (CNPase) and neurofilament heavy chain levels were evident by 7 days. In contrast to most studies of primary blast induced TBI (PbTBI), no elevation of glial fibrillary acidic protein (GFAP) levels was noted when head movement was minimized. The ABS described in this article enables the generation of shockwaves highly representative of free-field blast. The use of this technology, in concert with head-only exposure, minimized head movement, and the kinematic analysis of the forces exerted on the head provide convincing evidence that primary blast directly causes changes in brain function and that GFAP may not be an appropriate biomarker of PbTBI. PMID- 26582147 TI - Increased Expression of Aldehyde Dehydrogenase 2 Reduces Renal Cell Apoptosis During Ischemia/Reperfusion Injury After Hypothermic Machine Perfusion. AB - Hypothermic machine perfusion (MP) can reduce graft's injury after kidney transplantation; however, the mechanism has not been elucidated. In the past decade, many studies showed that aldehyde dehydrogenase 2 (ALDH2) is a protease which can inhibit cell apoptosis. Therefore, this study aims to explore whether ALDH2 takes part in reducing organ damage after MP. Eighteen healthy male New Zealand rabbits (12 weeks old, weight 3.0 +/- 0.3 kg) were randomly divided into three groups: normal group, MP group, and cold storage (CS) group (n = 6). The left kidney of rabbits underwent warm ischemia for 35 min through clamping the left renal pedicle and then reperfusion for 1 h. Left kidneys were preserved by MP or CS (4 degrees C for 4 h) in vivo followed by the right nephrectomy and 24-h reperfusion, and then the specimens and blood were collected. Finally, concentration of urine creatinine (Cr), blood urea nitrogen (BUN), and 4-HNE were tested. Renal apoptosis was detected by TUNEL staining, and the expression of ALDH2, cleaved-caspase 3, bcl-2/ bax, MAPK in renal tissue was detected by immunohistochemistry or Western blot; 24 h after surgery, the concentration of Cr in MP group was 355 +/- 71MUmol/L, in CS group was 511 +/- 44 MUmol/L (P < 0.05), while the BUN was 15.02 +/- 2.34 mmol/L in MP group, 22.64 +/- 3.58 mmol/L in CS group (P < 0.05). The rate of apoptosis and expression of cleaved caspase-3, p P38, p-ERK, and p-JNK in MP group was significantly lower than that in CS group (P < 0.05), while expression of ALDH2 and bcl-2/bax in MP group was significantly higher than that in CS group (P < 0.05); expression of cleaved caspase-3 in both MP and CS group significantly increased as compared with that in normal group (P < 0.05). In conclusion, increased expression of ALDH2 can reduce the renal cell apoptosis through inhibiting MAPK pathway during ischemia/reperfusion injury (IRI) after hypothermic MP. PMID- 26582148 TI - Mobile health technology for adolescent transplant recipients: What's h'app'ening in adherence promotion? PMID- 26582150 TI - Effects of blend of canola oil and palm oil on nutrient intake and digestibility, growth performance, rumen fermentation and fatty acids in goats. AB - The study examined the effects of blend of 80% canola oil and 20% palm oil (BCPO) on nutrient intake and digestibility, growth performance, rumen fermentation and fatty acids (FA) in goats. Twenty-four Boer bucks were randomly assigned to diets containing 0, 4 and 8% BCPO on a dry matter basis, fed for 100 days and slaughtered. Diet did not affect feed efficiency, growth performance, intake and digestibility of all nutrients except ether extract. Intakes and digestibilities of ether extract, unsaturated fatty acids (FA) and total FA were higher (P < 0.05) while digestibility of C18:0 was lower (P < 0.05) in oil-fed goats than the control goats. Total volatile FA, acetate, butyrate, acetate/propionate ratio and methane decreased (P < 0.05) with increasing BCPO but propionate, NH3 -N and rumen pH did not differ between diets. Ruminal concentration of C18:0, n-3 FA and total FA increased (P < 0.05) while C12:0, C14:0, C15:0 and n-6 FA decreased with increasing BCPO. Analysis of the FA composition of Triceps brachii muscle showed that concentrations of C16:0, C14:0 and C18:2n-6 were lower (P < 0.05) while C18:1n-9, C18:3n-3 and C20:5n-3 were higher in oil-fed goats compared with control goats. Dietary BCPO altered muscle lipids without having detrimental effects on nutrient intake and digestibility and growth performance in goats. PMID- 26582151 TI - Lipophilisation of Caffeic Acid through Esterification with Propanol Using Water tolerable Acidic Ionic Liquid as Catalyst. AB - Propyl caffeate was synthesized to produce lipophilic antioxidant, which used caffeic acid and propanol as starting materials, acidic ionic liquid as catalyst. The highest yield of propyl caffeate (98.7+/-0.8%) have been achieved under the optimum as follows: 1-butylsulfonic-3-methylimidazolium tosylate showed the best catalytic performance, molar ratio of caffeic acid to propanol was 1:20, reaction temperature was 90 degrees C and the amount of acidic ionic liquid was 40%. The relationship between temperature and the forward rate constant gave the activation energy of 33.6 kJ mol(-1), which indicated that acidic ionic liquid possesses high catalytic activity in the synthesis of PC. And the activity of acidic ionic liquid was not inhibited by the water produced during the esterification process. More importantly, this reaction system can even proceed smoothly when initial water content was 5%. PMID- 26582149 TI - Design, Synthesis, and Investigation of Novel Nitric Oxide (NO)-Releasing Prodrugs as Drug Candidates for the Treatment of Ischemic Disorders: Insights into NO-Releasing Prodrug Biotransformation and Hemoglobin-NO Biochemistry. AB - We have developed novel nitric oxide (NO)-releasing prodrugs of efaproxiral (RSR13) for their potential therapeutic applications in a variety of diseases with underlying ischemia. RSR13 is an allosteric effector of hemoglobin (Hb) that decreases the protein's affinity for oxygen, thereby increasing tissue oxygenation. NO, because of its vasodilatory property, in the form of ester prodrugs has been found to be useful in managing several cardiovascular diseases by increasing blood flow and oxygenation in ischemic tissues. We synthesized three NO-donor ester derivatives of RSR13 (DD-1, DD-2, and DD-3) by attaching the NO-releasing moieties nitrooxyethyl, nitrooxypropyl, and 1-(pyrrolidin-1 yl)diazen-1-ium-1,2-diolate, respectively, to the carboxylate of RSR13. In vitro studies demonstrated that the compounds released NO in a time-dependent manner upon being incubated with l-cysteine (1.8-9.3%) or human serum (2.3-52.5%) and also reduced the affinity of Hb for oxygen in whole blood (DeltaP50 of 4.9-21.7 mmHg vs DeltaP50 of 25.4-32.1 mmHg for RSR13). Crystallographic studies showed RSR13, the hydrolysis product of the reaction between DD-1 and deoxygenated Hb, bound to the central water cavity of Hb. Also, the hydrolysis product, NO, was observed exclusively bound to the two alpha hemes, the first such HbNO structure to be reported, capturing the previously proposed physiological bis-ligated nitrosylHb species. Finally, nitrate was observed bound to betaHis97. Ultraperformance liquid chromatography-mass spectrometry analysis of the compounds incubated with matrices used for the various studies demonstrated the presence of the predicted reaction products. Our findings, beyond the potential therapeutic application, provide valuable insights into the biotransformation of NO-releasing prodrugs and their mechanism of action and into hemoglobin-NO biochemistry at the molecular level. PMID- 26582152 TI - Essential Oil of Amomum maximum Roxb. and Its Bioactivities against Two Stored Product Insects. AB - Amomum maximum Roxb. is a perennial herb distributed in South China and Southeast Asia. The objective of this work was to analyze the chemical constituents and assess insecticidal and repellent activities of the essential oil from Amomum maximum fruits against Tribolium castaneum (Herbst) and Liposcelis bostrychophila (Badonnel). The essential oil was obtained by hydrodistillation and analyzed by gas chromatography-flame ionization detector and gas chromatography-mass spectrometry. The main components of the essential oil were identified to be beta pinene (23.39%), beta-caryophyllene (16.43%), alpha-pinene (7.55%), sylvestrene (6.61%) and c-cadinene (4.19%). It was found that the essential oil of A. maximum fruits possessed contact and fumigant toxicities against T. castaneum adults (LD50 = 29.57 MUg/adult and LC(50) = 23.09 mg/L air, respectively) and showed contact toxicity against L. bostrychophila (LD(50) = 67.46 MUg/cm(2)). Repellency of the crude oil was also evaluated. After 2 h treatment, the essential oil possessed 100% repellency at 78.63 nL/cm(2) against T. castaneum and 84% repellency at 63.17 nL/cm(2) against L. bostrychophila. The results indicated that the essential oil of A. maximum fruits had the potential to be developed as a natural insecticide and repellent for control of T. castaneum and L. bostrychophila. PMID- 26582153 TI - Feasibility of Continuous Frying System to Improve the Quality Indices of Palm Olein for the Production of Extruded Product. AB - Comparative frying studies on the processing of extruded product were conducted under intermittent and continuous frying conditions using two separate frying systems, i.e batch and pilot scale continuous fryers, respectively. Thermal resistance of palm olein were assessed for a total of 5 days of frying operation at 155 degrees C - the unconventional frying temperature gave the product moisture content of 3% after intermittent and continuous frying for 2.5 min and 2 min, respectively. The formation of free fatty acid in palm olein in the case of intermittent frying was more than 2-fold higher compared to its counterpart (0.66%). Smoke point inversely evolved with oil acidity: the value dropped progressively from 215 to 177 degrees C and from 219 to 188 degrees C when extruded product was intermittently and continuously fried, respectively. In the light of induction period, repeated frying exhibited a gradual decrease in the value after 5 days of frying (12.2 h). Interestingly, continuous frying gave somewhat similar induction period, as demonstrated by fresh palm olein, across frying time. Frying at lower temperature, to some extent, provides opportunity for palm olein to retain 74% of its initial vitamin E during continuous frying. This benefit, however, is somehow denied when extruded product was processed under intermittent frying conditions--only 27% of vitamin E was remained at the end of frying session. Regardless of frying protocols, transient in polar compounds was minimal and hence comparable. The colour in the case of continuous frying appeared to be darker due to higher degree of oil utilisation for frying. The data obtained will provide useful information for food processors on how palm olein behaves when frying is undertaken under different frying protocols. PMID- 26582145 TI - Critical needs in drug discovery for cessation of alcohol and nicotine polysubstance abuse. AB - Polysubstance abuse of alcohol and nicotine has been overlooked in our understanding of the neurobiology of addiction and especially in the development of novel therapeutics for its treatment. Estimates show that as many as 92% of people with alcohol use disorders also smoke tobacco. The health risks associated with both excessive alcohol consumption and tobacco smoking create an urgent biomedical need for the discovery of effective cessation treatments, as opposed to current approaches that attempt to independently treat each abused agent. The lack of treatment approaches for alcohol and nicotine abuse/dependence mirrors a similar lack of research in the neurobiology of polysubstance abuse. This review discusses three critical needs in medications development for alcohol and nicotine co-abuse: (1) the need for a better understanding of the clinical condition (i.e. alcohol and nicotine polysubstance abuse), (2) the need to better understand how these drugs interact in order to identify new targets for therapeutic development and (3) the need for animal models that better mimic this human condition. Current and emerging treatments available for the cessation of each drug and their mechanisms of action are discussed within this context followed by what is known about the pharmacological interactions of alcohol and nicotine. Much has been and will continue to be gained from studying comorbid alcohol and nicotine exposure. PMID- 26582154 TI - A Novel Methodology for the Synthesis of Acyloxy Castor Polyol Esters: Low Pour Point Lubricant Base Stocks. AB - Castor oil, a non-edible oil containing hydroxyl fatty acid, ricinoleic acid (89.3 %) was chemically modified employing a two step procedure. The first step involved acylation (C(2)-C(6) alkanoic anhydrides) of -OH functionality employing a green catalyst, Kieselguhr-G and solvent free medium. The catalyst after reaction was filtered and reused several times without loss in activity. The second step is esterification of acylated castor fatty acids with branched mono alcohol, 2-ethylhexanol and polyols namely neopentyl glycol (NPG), trimethylolpropane (TMP) and pentaerythritol (PE) to obtain 16 novel base stocks. The base stocks when evaluated for different lubricant properties have shown very low pour points (-30 to -45 degrees C) and broad viscosity ranges 20.27 cSt to 370.73 cSt, higher viscosity indices (144-171), good thermal and oxidative stabilities, and high weld load capacities suitable for multi-range industrial applications such as hydraulic fluids, metal working fluids, gear oil, forging and aviation applications. The study revealed that acylated branched mono- and polyol esters rich in monounsaturation is desirable for developing low pour point base stocks. PMID- 26582155 TI - Anthocyanin-rich Phytochemicals from Aronia Fruits Inhibit Visceral Fat Accumulation and Hyperglycemia in High-fat Diet-induced Dietary Obese Rats. AB - Aronia fruits (chokeberry: Aronia melanocarpa E.) containing phenolic phytochemicals, such as cyanidin 3-glycosides and chlorogenic acid, have attracted considerable attention because of their potential human health benefits in humans including antioxidant activities and ability to improved vision. In the present study, the effects of anthocyanin-rich phytochemicals from aronia fruits (aronia phytochemicals) on visceral fat accumulation and fasting hyperglycemia were examined in rats fed a high-fat diet (Experiment 1). Total visceral fat mass was significantly lower in rats fed aronia phytochemicals than that in both the control group and bilberry phytochemicals-supplemented rats (p < 0.05). Moreover, perirenal and epididymal adipose tissue mass in rats fed aronia phytochemicals was significantly lower than that in both the control and bilberry phytochemicals group. Additionally, the mesenteric adipose tissue mass in aronia phytochemicals fed rats was significantly low (p < 0.05). Furthermore, the fasting blood glucose levels significantly decreased in rats fed aronia phytochemicals for 4 weeks compared to that in the control rats (p < 0.05). Therefore, we investigated the effects of phytochemicals on postprandial hyperlipidemia after corn oil loading in rats, pancreatic lipase activity in vitro, and the plasma glycemic response after sucrose loading in order to elucidate the preventive factor of aronia phytochemical on visceral fat accumulation. In the oral corn oil tolerance tests (Experiment 2), aronia phytochemicals significantly inhibited the increases in plasma triglyceride levels, with a half-maximal inhibitory concentration (IC(50)) of 1.50 mg/mL. However, the inhibitory activity was similar to that of bilberry and tea catechins. In the sucrose tolerance tests (Experiment 3), aronia phytochemicals also significantly inhibited the increases in blood glucose levels that were observed in the control animals (p < 0.05). These results suggest that anthocyanin-rich phytochemicals in aronia fruits suppress visceral fat accumulation and hyperglycemia by inhibiting pancreatic lipase activity and/or intestinal lipid absorption. PMID- 26582156 TI - A Comparative Study of the Effects upon LPS Induced Macrophage RAW264.7 Inflammation in vitro of the Lipids of Hippocampus trimaculatus Leach. AB - The present study attempts to investigate the anti-inflammatory potential of the isolated lipid extracts of three-spot seahorse which is rare marine bony fish. Petroleum ether (PE) extract was obtained from systematic solvent extraction after reflux extraction with 95% ethanol. FrIV was collected after silica gel column chromatography, and neutral lipids (NL), glycolipids (GL), phospholipids (PL) were separated from FrIV. Basic compositions were detected and analyzed via thin layer chromatography (TLC) and Fourier transform infrared spectroscopy (FTIR). Anti-inflammatory activities of total lipids (TL), isolated NL, GL, and PL were detected by secretion of pro-inflammatory cytokines induced by lipopolysaccharide (LPS) in murine monocyte macrophage RAW264.7 cells in vitro. The results revealed that lipids of seahorse showed a positive correlation with the in vitro suppression of the release of nitric oxide (NO), interleukin (IL)-6, IL-1beta and tumor necrosis factor (TNF)-alpha potently in a dose dependent manner, and showed cell compatibility. Among the fractions, GL (50 MUg/mL) showed the highest capacity to attenuate the generation of pro-inflammatory cytokines which was comparable to that of the positive drug dexamethasone (DX) (20 MUg/mL). Collectively, our findings indicated that the lipids from seahorse may be effective in the management of inflammation. PMID- 26582157 TI - Effects of Aster scaber Seed Oil Containing trans-Delta3 Fatty Acids on Lipid Profiles of Hamsters and Rats. AB - The effects of Aster scaber seed oil (ASO) on lipid profiles were studied in rats and hamsters. ASO contained considerable amounts of Delta3t-16:1 (11.4%), Delta3t, 9c-18:2 (4.6%), and Delta3t, 9c, 12c-18:3 (11.3%). Young rats and hamsters were fed diets containing ASO, soybean oil (SBO), or olive oil (OLO) as fat sources for 4 weeks in separate experiments with or without cholesterol. In the rat study, there were no significant differences in the concentrations of serum total cholesterol, high-density lipoprotein (HDL)-cholesterol, and triacylglycerol among the groups. The serum but not liver malondialdehyde (MDA) level was significantly lower in the ASO-fed group than it was in the other groups. The biochemical and growth parameters revealed no significant biological damages in the ASO-fed animals. In the hamster study, dietary cholesterol dependent effects were evident in the serum lipids profiles, whereas the fat induced effect was only observed in the ratio of serum low-density lipoprotein (LDL)-/HDL-cholesterol. Furthermore, fat- and cholesterol-induced effects were evident in the ratio of serum LDL-/HDL-cholesterol. Significant interactions between dietary fat and cholesterol were observed as evident from the concentration of serum cholesterol and triacylglycerol, as well as the activity of serum cholesterol ester transfer protein. These results suggest that dietary ASO containing trans-Delta3 fatty acids appeared to improve the serum LDL-/HDL cholesterol ratio more than the SBO did, especially when hamsters were simultaneously fed cholesterol-supplemented diet. PMID- 26582158 TI - Long-term survival following multidisciplinary treatment of metastatic sarcomatoid renal cell carcinoma: a case report. AB - INTRODUCTION: We report the case of a 62-year-old woman diagnosed with sarcomatoid renal cell carcinoma. CASE PRESENTATION: A 62-year-old Asian woman presented with macroscopic hematuria. A histological and immunohistochemical study of a tumor biopsy specimen led to a suspected diagnosis of sarcomatoid renal cell carcinoma. She underwent surgical tumor resection that included her left kidney. A histological and immunohistochemical study of the resected tumor confirmed the diagnosis of sarcomatoid renal cell carcinoma. The pathological stage was pT3bpN2, and multiple lung metastases were detected (pT3bpN2cM1; stage IV). Our patient was classified as "poor risk" according to the Memorial Sloan Kettering Cancer Center risk criteria. Interferon-alpha was administered as adjuvant therapy, and her lung metastases remained stable. However, a computed tomography scan and bone scintigraphy 2 years later revealed multiple bone metastases. External beam radiotherapy was performed for the bone metastases. Despite continuing interferon-alpha during radiotherapy, multiple skull and liver metastases appeared. Oral administration of the tyrosine kinase inhibitor axitinib was initiated as a second-line therapy, and our patient achieved a stable state for 11 months. As the liver metastases progressed and meningeal dissemination newly appeared, oral administration of the mammalian target of rapamycin inhibitor everolimus was initiated as a third-line therapy. Our patient remains alive 71 months after diagnosis and has maintained a comparatively good quality of life. CONCLUSION: A literature review revealed that metastatic sarcomatoid renal cell carcinoma has very poor prognosis, with a survival of <1 year despite systemic therapy. Our patient in this present case achieved long term survival, a rare incidence worthy of report. PMID- 26582159 TI - Rethinking health care commercialization: evidence from Malaysia. AB - BACKGROUND: Against the backdrop of systemic inefficiency in the public health care system and the theoretical claims that markets result in performance and efficiency improvement, developing countries' governments have been rapidly commercializing health care delivery. This paper seeks to determine whether commercialization through an expansion in private hospitals has led to performance improvements in public hospitals. METHODS: Inpatient utilization records of all public hospitals in Peninsular Malaysia over the period 2006-2010 were used in this study. These records were obtained from the Ministry of Health. The study relied on utilization ratios, bed occupancy rates (BOR), bed turnover rates (BTR) and average length of stay (ALOS). The data were analyzed using SPSS 22 Statistical Software and the Pabon Lasso technique. RESULTS: Over 60 % of public hospitals in Malaysia are inefficient and perform sub-optimally. Average BOR among the public hospitals was 56 % in 2006 and 61 % in 2010. There was excessive BTR of 65 and 73 times within the period. Overall, the ALOS was low, falling from 3.4 days in 2006 to 3.1 days in 2010. CONCLUSIONS: This study demonstrates that commercialization has not led to performance improvements in the public health care sector in Malaysia. The evidence suggests that efforts to improve performance will require a focus directly on public hospitals. PMID- 26582160 TI - Structural dissociation of optic disc margin components with optic disc tilting: a spectral domain optical coherence tomography study. AB - PURPOSE: To investigate the dissociation of the Bruch's membrane opening (BMO) from the scleral canal opening (SO) of the optic disc. METHODS: In this prospective, cross-sectional, observational study, 101 eyes from 101 patients or suspected subjects of primary open angle glaucoma were included. Enhanced depth imaging spectral domain optical coherence tomography images along the long axis of the optic disc were used to visualize better the deep structures around the optic disc on both the temporal and nasal sides. The distances between the BMO and SO were measured at the temporal and nasal sides of the optic disc, and their correlations with age, axial length, intraocular pressure, disc size, disc ovality index, disc torsion degree, and visual field mean deviation were investigated. RESULTS: The temporal and nasal distances of BMO from SO correlated significantly with each other (R = 0.632, P < 0.0001). By multiple linear regression analysis, significant correlations were found for disc ovality index (temporal: beta = -0.691, P < 0.0001; nasal: beta = -0.420, P < 0.0001) and axial length (temporal: beta = 0.224, P = 0.002; nasal: beta = 0.310, P = 0.001). The other factors did not show any significant correlation. CONCLUSION: Locations of the SO at not only the temporal, but also the nasal side of the optic disc are nasally shifted from the BMO with optic disc tilting and axial length elongation in glaucomatous eyes, and are significantly correlated to each other. The nasal shift of the deep structures of the optic disc should be considered especially when assessing myopic eyes with optic disc tilt. PMID- 26582161 TI - Influence of optic disc leakage on objective optic nerve head assessment in patients with uveitis. AB - PURPOSE: Secondary glaucoma is a common complication in patients with uveitis. Heidelberg Retina Tomography (HRT) and retinal nerve fiber layer (RNFL) thickness on optical coherence tomography (OCT) are widely used for examining optic nerve head changes. We evaluated these parameters in patients with uveitis and secondary glaucoma and with inflammatory papillary leakage on fluorescein angiography. METHODS: Prospective single-center analysis of patients with uveitis, evaluating the impact of optic disc leakage on objective optic disc imaging parameters. RESULTS: Overall, 96 eyes of 59 patients were included. Papillary leakage was found in 42 eyes (43.8 %), and secondary glaucoma was found in 41 eyes (42.7 %). Glaucoma and papillary leakage were present in 12 (29 %) eyes with leakage and in 29 (54 %) eyes without leakage (p = 0.023). Neuroretinal rim area (p = 0.004), rim volume on HRT (p = 0.004), and RNFL thickness on OCT (p = 0.0008) were significantly increased in eyes with papillary leakage, while RNFL on HRT was unchanged (p = 0.255). When only eyes with normal IOP were examined, all objective parameters on OCT and HRT were significantly increased, whereas in eyes with secondary glaucoma, there was only a trend in the same direction, which did not reach significance. A comparison of eyes with secondary glaucoma and optic disc leakage to normal eyes with no glaucoma or leakage revealed no difference in any of the parameters. CONCLUSIONS: The objective parameters of optic nerve head imaging tools are significantly influenced by papillary leakage. In patients with secondary glaucoma and papillary leakage, these techniques are unable to detect and monitor glaucomatous damage. PMID- 26582162 TI - Responding to a rebuttal letter concerning the BERVOLT study. PMID- 26582163 TI - Recurrence of macular edema in eyes with branch retinal vein occlusion changes the diameter of unaffected retinal vessels. PMID- 26582164 TI - Restless Legs Syndrome After Single Low Dose Quetiapine Administration. AB - Restless legs syndrome is an underdiagnosed sensori-motor disorder and psychotropic drugs are one of the main secondary causes of the illness. The most common psychotropic agents that cause restless legs syndrome are antidepressants; however, antipsychotics have also been reported to induce restless legs syndrome. The prevalence, vulnerability factors and the underlying mechanism of antipsychotic-induced restless legs syndrome are unclear. A possible explanation is that dopaminergic blockade is the main precipitator of the syndrome. Quetiapine-induced restless legs syndrome is another point of interest because of its low binding to D2 receptors. We herein report the case of a restless legs syndrome that emerged after a single low dose quetiapine administration. PMID- 26582165 TI - Changes in multifidus and abdominal muscle size in response to microgravity: possible implications for low back pain research. AB - PURPOSE: In microgravity, muscle atrophy occurs in the intrinsic muscles of the spine, with changes also observed in the abdominal muscles. Exercises are undertaken on the International Space Station and on Earth following space flight to remediate these effects. Similar effects have been seen on Earth in prolonged bed rest studies and in people with low back pain (LBP). The aim of this case report was to examine the effects of microgravity, exercise in microgravity and post-flight rehabilitation on the size of the multifidus and antero-lateral abdominal muscles. METHODS: Ultrasound imaging was used to assess size of the multifidus, transversus abdominis and internal oblique muscles at four time points: pre-flight and after daily rehabilitation on day one (R + 1), day 8 (R + 8) and day 14 (R + 14) after return to Earth (following 6 months in microgravity). RESULTS: Exercises in microgravity maintained multifidus size at L2-L4, however, after spaceflight, size of the multifidus muscle at L5 was reduced, size of the internal oblique muscle was increased and size of transversus abdominis was reduced. Rehabilitation post-space flight resulted in hypertrophy of the multifidus muscle to pre-mission size at the L5 vertebral level and restoration of antero-lateral abdominal muscle size. CONCLUSIONS: Exercise in space can prevent loss of spinal intrinsic muscle size. For the multifidus muscles, effectiveness varied at different levels of the spine. Post mission rehabilitation targeting specific motor control restored muscle balance between the antero-lateral abdominal and multifidus muscles, similar to results from intervention trials for people with LBP. A limitation of the current investigation is that only one astronaut was studied, however, the microgravity model could be valuable as predictable effects on trunk muscles can be induced and interventions evaluated. Level of Evidence Case series. PMID- 26582166 TI - Virtually bloodless posterior midline exposure of the lumbar spine using the "para-midline" fatty plane. AB - PURPOSE: The authors have developed a "para-midline" approach to the posterior lumbar spine using a virtually avascular surgical plane not previously described in the literature. It was their purpose to document consistent MRI presence of this plane and to prospectively evaluate its clinical use in terms of blood loss. METHODS: Fifty consecutive patients undergoing primary lumbar surgery on 1-3 levels were prospectively enrolled from September 2014 to May 2015. The para midline approach was used in all cases. The deep lumbar fascia is longitudinally incised on either side of the spinous processes instead of directly in the midline, which reveals the para-midline fatty plane. Blood loss during the approach and overall blood loss were recorded for all patients. MRIs from each patient were reviewed by an experienced neuroradiologist to determine the presence of the para-midline fatty plane. RESULTS: There was no recorded blood loss during the approach for all procedures. The average overall blood loss was 60 cc (20-200 cc). No patient required a transfusion intraoperatively or postoperatively. The fatty para-midline plane was noted on preoperative MRI at all operated levels in all patients. The average width of this plane was 6.5 mm (2-17 mm). CONCLUSIONS: The para-midline approach for lumbar surgery is associated with less blood loss than traditional, subperiosteal exposure techniques. The fatty interval through which this approach is made is universally present and identifiable on MRI. The authors offer this approach as a means of decreasing the risks associated with blood loss and transfusion with posterior lumbar surgery. PMID- 26582167 TI - Presentation and outcome of patients treated non-operatively or operatively for Copenhagen Disease: a 30-year experience. AB - PURPOSE: Our purpose was to analyse the presentation, management and clinical outcome of patients treated operatively and non-operatively for Copenhagen Disease (CD). METHODS: We performed a retrospective analysis of 10 patients (n = 10) with CD, with a mean follow-up time of 14.7 years. Seven patients underwent non-operative treatment and three patients were treated operatively. Clinical presentation and radiological findings were analysed. Health-related quality of life (HRQOL) outcome measures utilized included Oswestry Disability Index (ODI), Short Form 12 Health Survey (SF-12) and visual analogue scale (VAS). RESULTS: Patients tended to present with back pain. No significant difference was detected in functional scores at time of diagnosis and when compared to last follow-up. ODI improved from 20.0 to 18.4 (p = 0.839), PCS component of SF-12 from 44.5 to 45.9 (p = 0.719), MCS component of SF-12 from 45.7 to 46.9 (p = 0.840) and VAS score remained at 2.8 (p = 1.000). There was no significant difference in functional scores when comparing operative and non-operative treatment groups. CONCLUSION: CD is likely to remain stable with time or slightly improve after treatment according to functional outcomes tests. Progression of the kyphosis can be halted at different degrees with operative and non-operative treatments although it does not correlate with changes in symptomatology. PMID- 26582168 TI - Measuring severe maternal morbidity: validation of potential measures. AB - BACKGROUND: Both maternal mortality rate and severe maternal morbidity rate have risen significantly in the United Sates. Recently, the Centers for Disease Control and Prevention introduced International Classification of Diseases, 9th revision, criteria for defining severe maternal morbidity with the use of administrative data sources; however, those criteria have not been validated with the use of chart reviews. OBJECTIVE: The primary aim of the current study was to validate the Centers for Disease Control and Prevention International Classification of Diseases, 9th revision, criteria for the identification of severe maternal morbidity. This analysis initially required the development of a reproducible set of clinical conditions that were judged to be consistent with severe maternal morbidity to be used as the clinical gold standard for validation. Alternative criteria for severe maternal morbidity were also examined. STUDY DESIGN: The 67,468 deliveries that occurred during a 12-month period from 16 participating California hospitals were screened initially for severe maternal morbidity with the presence of any of 4 criteria: (1) Centers for Disease Control and Prevention International Classification of Diseases, 9th revision, diagnosis and procedure codes; (2) prolonged postpartum length of stay (>3 standard deviations beyond the mean length of stay for the California population); (3) any maternal intensive care unit admissions (with the use of hospital billing sources); and (4) the administration of any blood product (with the use of transfusion service data). Complete medical records for all screen positive cases were examined to determine whether they satisfied the criteria for the clinical gold standard (determined by 4 rounds of a modified Delphi technique). Descriptive and statistical analyses that included area under the receiver operating characteristic curve and C-statistic were performed. RESULTS: The Centers for Disease Control and Prevention International Classification of Diseases, 9th revision, criteria had a reasonably high sensitivity of 0.77 and a positive predictive value of 0.44 with a C-statistic of 0.87. The most important source of false-positive cases were mothers whose only criterion was 1-2 units of blood products. The Centers for Disease Control and Prevention International Classification of Diseases, 9th revision, criteria screen rate ranged from 0.51 2.45% among hospitals. True positive severe maternal morbidity ranged from 0.05 1.13%. When hospitals were grouped by their neonatal intensive care unit level of care, severe maternal morbidity rates were statistically lower at facilities with lower level neonatal intensive care units (P < .0001). CONCLUSION: The Centers for Disease Control and Prevention International Classification of Diseases, 9th revision, criteria can serve as a reasonable administrative metric for measuring severe maternal morbidity at population levels. Caution should be used with the use of these criteria for individual hospitals, because case-mix effects appear to be strong. PMID- 26582169 TI - Applying to subspecialty fellowship: clarifying the confusion and conflicts! AB - Of graduating obstetrics and gynecology residents, 40% apply for fellowship training and this percentage is likely to increase. The fellowship interview process creates a substantial financial burden on candidates as well as significant challenges in scheduling the multiple interviews for residents, residency programs, and fellowship programs. Coverage with relatively short lead time is needed for some resident rotations, multiple residents may request time off during overlapping time periods, and applicants may not be able to interview based on conflicting interview dates or the inability to find coverage from other residents for their clinical responsibilities. To address these issues, we propose that each subspecialty fellowship within obstetrics and gynecology be allocated a specified and limited time period to schedule their interviews with minimal overlap between subspecialties. Furthermore, programs in close geographic areas should attempt to coordinate their interview dates. This will allow residents to plan their residency rotation schedules far in advance to minimize the impact on rotations that are less amenable to time away from their associated clinical duties, and decrease the numbers of residents needing time off for interviews during any one time period. In addition, a series of formal discussions should take place between subspecialties related to these issues as well as within subspecialties to facilitate coordination. PMID- 26582170 TI - International Collaboration in Endourology: Multicenter Evaluation of Prestenting for Ureterorenoscopy. AB - INTRODUCTION: Semirigid and flexible ureterorenoscopy (URS) procedures are safe and efficient treatment options for urolithiasis of all localizations. Sometimes, a Double-J stent is placed in preparation of definitive treatment. The aim of our study was to evaluate the influence of prestenting on the outcome of URS. PATIENTS AND METHODS: We retrospectively analyzed 565 patients of our prospective, multicenter multinational database who underwent URS for renal or ureteral stones from June 2011 to December 2013. Demographic and stone-related data, surgery time, stone clearance, and complications were evaluated. Statistical analysis was performed comparing the prestented and nonstented groups. RESULTS: Demographic data, stone size, and localization were comparable in both groups. Three hundred twenty-three patients were prestented and 242 nonstented. Overall, prestenting had significant influence on the stone-free rate (SFR) (86% prestented vs 74% not prestented, p = 0.0003) and complication rate (6.5% vs 14.5%, p = 0.003), but not on surgery time (55 +/- 36 minutes vs 61 +/- 35 minutes, p = 0.071). Subgrouped, this was also true for renal stones (83% vs 60%, p = 0.0001, odds ratio [OR] 3.15; confidence interval, CI [1.77, 5.62]/8.7% vs 19.4%, p = 0.02, 0.39 [CI 0.19, 0.83]). For ureteral stones, there was no significant influence on SFR (94% vs 90%, p = 0.4, OR 1.63 [CI 0.63, 4.22]), but significantly more complications (3.1% vs 10.7%, p = 0.02, OR 0.27 [CI 0.08, 0.86]) in the nonstented group. CONCLUSION: Prestenting positively affects safety and efficacy of URS. This is more pronounced in the treatment of kidney stones compared with ureteral stones. Although the SFR for ureteral stones is comparable without prestenting, the complication rate is higher. PMID- 26582171 TI - Infertility Education: Experiences and Preferences of Childhood Cancer Survivors. AB - The majority of children diagnosed with cancer will become long-term survivors; however, many will suffer late effects of treatment, including infertility. Educating patients about potential risk for infertility is important, yet little is known regarding when patients would like to hear this information. The purpose of this study was to assess young adult survivors' previous experience in receiving education about their risk for infertility and determine their preferences for infertility education at various time points during and after treatment. Only 36% of survivors report receiving education about risk for infertility at diagnosis, 39% at end of therapy, and 72% in long-term follow up/survivor clinic visits. Survivors consistently identified their oncologist as a preferred educator at each time point. Although almost all participants identified wanting education at diagnosis, this time point alone may not be sufficient. End of therapy and survivorship may be times this message should be repeated and adapted for the survivor's needs and developmental stage: conversations about the impact of cancer treatment on future fertility should be ongoing. PMID- 26582172 TI - Potassium citrate decreases urine calcium excretion in patients with hypocitraturic calcium oxalate nephrolithiasis. AB - Two previous studies (<10 patients each) have demonstrated that alkali therapy may reduce urine calcium excretion in patients with calcium oxalate nephrolithiasis. The hypothesized mechanisms are (1) a decrease in bone turnover due to systemic alkalinization by the medications; (2) binding of calcium by citrate in the gastrointestinal tract; (3) direct effects on TRPV5 activity in the distal tubule. We performed a retrospective review of patients on potassium citrate therapy to evaluate the effects of this medication on urinary calcium excretion. A retrospective review was performed of a metabolic stone database at a tertiary care academic hospital. Patients were identified with a history of calcium oxalate nephrolithiasis and hypocitraturia who were on potassium citrate therapy for a minimum of 3 months. 24-h urine composition was assessed prior to the initiation of potassium citrate therapy and after 3 months of therapy. Patients received 30-60 mEq potassium citrate by mouth daily. Inclusion criterion was a change in urine potassium of 20 mEq/day or greater, which suggests compliance with potassium citrate therapy. Paired t test was used to compare therapeutic effect. Twenty-two patients were evaluated. Mean age was 58.8 years (SD 14.0), mean BMI was 29.6 kg/m(2) (SD 5.9), and gender prevalence was 36.4% female:63.6% male. Mean pre-treatment 24-h urine values were as follows: citrate 280.0 mg/day, potassium 58.7 mEq/day, calcium 216.0 mg/day, pH 5.87. Potassium citrate therapy was associated with statistically significant changes in each of these parameters-citrate increased to 548.4 mg/day (p < 0.0001), potassium increased to 94.1 mEq/day (p < 0.0001), calcium decreased to 156.5 mg/day (p = 0.04), pH increased to 6.47 (p = 0.001). Urine sodium excretion was not different pre- and post-therapy (175 mEq/day pre-therapy versus 201 mEq/day post-therapy, p = NS). Urinary calcium excretion decreased by a mean of 60 mg/day on potassium citrate therapy-a nearly 30 % decrease in urine calcium excretion. These data lend support to the hypothesis that alkali therapy reduces urine calcium excretion. PMID- 26582173 TI - Optimization of electrochemical reaction for nitrogen removal from biological secondary-treated milking centre wastewater. AB - In order to remove the residual nitrogen from the secondary-treated milking centre wastewater, the electrochemical reaction including NH4-N oxidation and NOx N reduction has been known as a relatively simple technique. Through the present study, the electrochemical reactor using the Ti-coated IrO2 anode and stainless steel cathode was optimized for practical use on farm. The key operational parameters [electrode area (EA) (cm(2)/L), current density (CD) (A/cm(2)), electrolyte concentration (EC) (mg/L as NaCl), and reaction time (RT) (min)] were selected and their effects were evaluated using response surface methodology for the responses of nitrogen and colour removal efficiencies, and power consumption. The experimental design was followed for the central composite design as a fractional factorial design. As a result of the analysis of variance, the p values of the second-order polynomial models for three responses were significantly fit to the empirical values. The nitrogen removal was significantly influenced by CD, EC, and RT (p < .05), whereas colour removal was significantly governed by EA, CD, RT, the interaction of EA and EC (p < .05). For higher efficiency of nitrogen removal over 90%, the combination of [EA, 20 cm(2)/L; CD, 0.044 A/cm(2); EC, 3.87 g/L as NaCl; RT, 240 min] was revealed as an optimal operational condition. The investigation on cathodic reduction of NOx-N may be required with respect to nitrite and nitrate separately as a future work. PMID- 26582174 TI - THE IMPACT OF X-RAY UNIT TYPE USED FOR ENDOSCOPIC RETROGRADE CHOLANGIOPANCREATOGRAPHY PROCEDURES ON PATIENT DOSES. AB - To investigate whether the X-ray unit type used for interventional endoscopic retrograde cholangiopancreatography (ERCP) procedures may affect patient radiation doses. A total of 471 ERCP procedures performed in 4 hospitals with 4 types of X-ray units were studied. Kerma-area product (KAP), fluoroscopy time (T) and total number of radiographs acquired (F) were recorded. KAP, T and F values exhibited a great variation, ranging from 0.1 to 130.2 Gy cm2 (mean 16 Gy cm2), 0.13 to 33.7 min (mean 5.4 min) and 0 to 26 radiographs (mean 3.5), respectively. The respective mean values for the four types of X-ray units that were investigated were as follows: KAP: 17.4, 12.5, 5.6 and 36.3 Gy cm2, T: 4.7, 5.2, 3.8 and 11.5 min and F: 1.7, 7.4, 1.9 and 4.6 radiographs. The type of the X-ray unit seems to significantly affect patient radiation dose, with the C-arm delivering the lowest and the angiography unit the highest patient doses. PMID- 26582175 TI - THE EFFECT OF RADIATION SHIELDS ON OPERATOR EXPOSURE DURING CONGENITAL CARDIAC CATHETERISATION. AB - Cardiac catheterisation personnel are exposed to occupational radiation and its health risks. Little data exist regarding the efficacy of radiation-protective equipment from congenital catheterisation laboratories (CLs). The authors retrospectively reviewed data in which CL operators wore a radiation dosemeter during catheterizations on patients of >20 kg. A leaded under-table skirt was present in all cases. Three additional radiation-protective devices were utilised at operator discretion: a top extension to the under-table skirt, a ceiling mounted shield and a disposable patient drape. Case details, operator position, fluoroscopy time, incident air KERMA in the patient plane (K, mGy) and dose-area product (DAP, uGy.m2) were recorded. A total of 136 catheterizations over 8 months were included. Median operator dose (OpD) was 12 uSv (range 0-930) and indexed to K and DAP to correct for patient factors and case times. Indexed OpD decreased significantly with each additional shield used (14.8 vs. 1.3 nSv uGy-1 m-2 and 124 vs. 14 nSv mGy-1 with one and four shields, respectively, p < 0.001). This trend was not significant with operator at head-of-bed. Combinations that included the ceiling shield had the lowest indexed OpD. The patient drape did not further reduce OpD when all other shields were used (1.3 vs. 2.2 nSv uGy-1 m-2, p = 0.5; 14 vs. 17 nSv mGy-1, p = 0.4) and was associated with higher patient exposure indexed to weight and fluoroscopy time (4.5 vs. 3.1 uGy m2 kg-min-1, p = 0.009; and 0.51 vs. 0.38 mGy kg-min-1, p = 0.01). Supplemental radiation barriers can decrease operator-absorbed radiation. A ceiling-mounted shield may provide greatest benefit. The authors do not recommend routine use of disposable patient drapes. PMID- 26582177 TI - Natural trans fat, dairy fat, partially hydrogenated oils, and cardiometabolic health: the Ludwigshafen Risk and Cardiovascular Health Study. PMID- 26582176 TI - Chronic Treatment with the AMPK Agonist AICAR Prevents Skeletal Muscle Pathology but Fails to Improve Clinical Outcome in a Mouse Model of Severe Spinal Muscular Atrophy. AB - Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder characterized by spinal and brainstem motor neuron (MN) loss and skeletal muscle paralysis. Currently, there is no effective treatment other than supportive care to ameliorate the quality of life of patients with SMA. Some studies have reported that physical exercise, by improving muscle strength and motor function, is potentially beneficial in SMA. The adenosine monophosphate-activated protein kinase agonist 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) has been reported to be an exercise mimetic agent that is able to regulate muscle metabolism and increase endurance both at rest and during exercise. Chronic AICAR administration has been shown to ameliorate the dystrophic muscle phenotype and motor behavior in the mdx mouse, a model of Duchenne muscular dystrophy. Here, we investigated whether chronic AICAR treatment was able to elicit beneficial effects on motor abilities and neuromuscular histopathology in a mouse model of severe SMA (the SMNDelta7 mouse). We report that AICAR improved skeletal muscle atrophy and structural changes found in neuromuscular junctions of SMNDelta7 animals. However, although AICAR prevented the loss of glutamatergic excitatory synapses on MNs, this compound was not able to mitigate MN loss or the microglial and astroglial reaction occurring in the spinal cord of diseased mice. Moreover, no improvement in survival or motor performance was seen in SMNDelta7 animals treated with AICAR. The beneficial effects of AICAR in SMA found in our study are SMN-independent, as no changes in the expression of this protein were seen in the spinal cord and skeletal muscle of diseased animals treated with this compound. PMID- 26582178 TI - The performance of NLST screening criteria in Asian lung cancer patients. AB - BACKGROUND: Screening high-risk individuals with low dose CT decreased lung cancer mortality in the National Lung Screening Trial (NLST), but the validity of directly extrapolating these results to an Asian population is unclear. Using statistical models on Surveillance, Epidemiology and End Result (SEER) data, 27% of lung cancer patients in the United States were estimated to meet the screening criteria. This study aims to evaluate the performance of the NLST criteria in Asian lung cancer patients and to examine the characteristics of those who did not meet the criteria. METHODS: We conducted a retrospective study of Asian lung cancer patients treated at Maimonides Cancer Center between 1/2008 and 6/2013. Data on demographics, smoking history, cancer stage, histology, and EGFR/ALK mutation status were collected and analyzed. RESULTS: Of 116 eligible patients, 75 patients (65%) were smokers which included 26 light smokers (22%). Thirty-two patients (27.8%) met the NLST criteria. Extending the age limit to 79 would cover 8% more patients while removing the lower age limit would only cover 2% more. None of the female patients met the criteria as they were all never or light smokers. Two-thirds of male patients younger than age 55 were never or light smokers. The EGFR mutation rate was 67% in female and 28% in male patients. CONCLUSION: The percentage of Asian patients meeting the NLST criteria is similar to that estimated for the United States population, suggesting that extension of the criteria to an Asian population is valid. One-third of the patients were non smokers and an additional one-fourth were light smokers, comprised mostly of female and young male patients. Further strategies for screening these individuals based on non-tobacco factors are urgently needed. PMID- 26582179 TI - New strategies for the early detection of pancreatic cancer. AB - Pancreatic cancer (PC) remains a deadly disease and early detection through screening is likely to be our best hope to improve survival. Considering the low incidence of PC, population-based screening is not feasible, but is advisable for high-risk patients. Screening individuals at high risk for developing PC leads to the detection of premalignant lesions. High-grade pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasm are the targets for early detection of PC. Endoscopic ultrasound (EUS) and magnetic resonance imaging are considered the most accurate techniques for pancreatic imaging; in particular EUS has emerged as a promising imaging test given its potential for tissue sampling to obtain diagnosis and to provide material for molecular profiling of PC. At the moment, screening should be performed within research protocols at experienced centers with a specific clinical and research interest, where a multidisciplinary team of specialists is available. PMID- 26582180 TI - Outcome After Salvage Arthrodesis for Failed Total Ankle Replacement. AB - BACKGROUND: In cases with total ankle replacement (TAR) failure, a decision between revision TAR and salvage arthrodesis (SA) must be made. In a previous study, we analyzed revision TAR and found low functional outcome and satisfaction. The aims of the current study were to analyze SA concerning failure rate and patient-related outcome measures (PROMs). METHODS: Until September 2014, a total of 1110 primary TARs were recorded in the Swedish Ankle Registry. Of the 188 failures, 118 were revised with SA (and 70 with revision TAR). Patient- and implant-specific data for SA cases were analyzed as well as arthrodesis techniques. Failure of SA was defined as repeat arthrodesis or amputation. Generic and region-specific PROMs of 68 patients alive with a solid unilateral SA performed more than 1 year before were analyzed. RESULTS: The first-attempt solid arthrodesis rate of SA was 90%. Overall, 25 of 53 (47%) patients were very satisfied or satisfied. Mean Self-reported Foot and Ankle Score (SEFAS) was 22 (95% confidence interval 20-24), Euro Qol-5 Dimensions 0.57 (0.49-0.65), Euro Qol Visual Analogue Scale 59 (53-64), Short Form-36 physical 34 (31-37) and mental 50 (46-54). The scores and satisfaction were similar to those after revision TAR but the reoperation rate was significantly lower in SA (P < .05). CONCLUSION: Salvage arthrodesis after failed TAR had a solid arthrodesis rate of 90% at first attempt, but similar to revision TAR, less than 50% of the patients were satisfied and the functional scores were low. Until studies show true benefit of revision TAR over SA, we favor SA for failed TAR. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 26582181 TI - Representations of Self and Parents, and Relationship Themes, in Adolescents with Post Traumatic Stress Disorder (PTSD). AB - Negative perceptions of self and others have lately become one of the criteria for Posttraumatic Stress Disorder (PTSD) among adults and adolescents. Drawing from theories of mental representations in psychopathology, this study examined self-reported negative cognitions, self and parental representations, and relationship themes among adolescents with and without PTSD. Thirty one adolescents with PTSD (11 boys, mean age = 14.06, SD = 2.24) were matched with 29 adolescents who had no psychiatric diagnosis (11 boys, mean age = 14.96, SD = 1.78). Adolescents completed self-report measures, wrote a description of self, mother and father, and were interviewed about positive and negative relationship episodes with mother, father, and peers. Adolescents with PTSD reported more self criticism and performance evaluation than did controls. Their self-representation exhibited a lower sense of agency, which was related to structural variables (i.e., less integrative description). Although parental representations of adolescents with PTSD were not generally less benevolent or more punitive than those of controls, their relationship themes revealed a higher proportion of the wish to be distant from others. Adolescents with PTSD exhibited more passive responses and perceived more dominant or controlling responses from their parents. Findings point out to a serious impairment in representations of self and relationship patterns in adolescent PTSD. PMID- 26582182 TI - Early Callous-Unemotional Behavior, Theory-of-Mind, and a Fearful/Inhibited Temperament Predict Externalizing Problems in Middle and Late Childhood. AB - Childhood externalizing problems are more likely to be severe and persistent when combined with high levels of callous-unemotional (CU) behavior. A handful of recent studies have shown that CU behavior can also be reliably measured in the early preschool years, which may help to identify young children who are less likely to desist from early externalizing behaviors. The current study extends previous literature by examining the role of CU behavior in very early childhood in the prediction of externalizing problems in both middle and late childhood, and tests whether other relevant child characteristics, including Theory-of-Mind (ToM) and fearful/inhibited temperament moderate these pathways. Multi-method data, including parent reports of child CU behavior and fearful/inhibited temperament, observations of ToM, and teacher-reported externalizing problems were drawn from a prospective, longitudinal study of children assessed at ages 3, 6, and 10 (N = 241; 48 % female). Results demonstrated that high levels of CU behavior predicted externalizing problems at ages 6 and 10 over and above the effect of earlier externalizing problems at age 3, but that these main effects were qualified by two interactions. High CU behavior was related to higher levels of externalizing problems specifically for children with low ToM and a low fearful/inhibited temperament. The results show that a multitude of child characteristics likely interact across development to increase or buffer risk for child externalizing problems. These findings can inform the development of targeted early prevention and intervention for children with high CU behavior. PMID- 26582183 TI - How do field of view and resolution affect the information content of panoramic scenes for visual navigation? A computational investigation. AB - The visual systems of animals have to provide information to guide behaviour and the informational requirements of an animal's behavioural repertoire are often reflected in its sensory system. For insects, this is often evident in the optical array of the compound eye. One behaviour that insects share with many animals is the use of learnt visual information for navigation. As ants are expert visual navigators it may be that their vision is optimised for navigation. Here we take a computational approach in asking how the details of the optical array influence the informational content of scenes used in simple view matching strategies for orientation. We find that robust orientation is best achieved with low-resolution visual information and a large field of view, similar to the optical properties seen for many ant species. A lower resolution allows for a trade-off between specificity and generalisation for stored views. Additionally, our simulations show that orientation performance increases if different portions of the visual field are considered as discrete visual sensors, each giving an independent directional estimate. This suggests that ants might benefit by processing information from their two eyes independently. PMID- 26582184 TI - Christian Jessen: perfectly all right as I am. PMID- 26582185 TI - Calcium supplementation modulates gut microbiota in a prebiotic manner in dietary obese mice. AB - SCOPE: Dietary calcium has been inversely associated with body fat and energy balance. The main scope of this study has been to assess the potential contribution of gut microbiota on energy regulation mediated by calcium. METHODS AND RESULTS: Gut microbiota in C57BL/6J mice receiving calcium supplementation under a high-fat (HF) diet were analysed by PCR and their relationships with host metabolic parameters were determined. Calcium conferred a prebiotic-like effect on gut microbiota, and animals presented lower plasmatic endotoxin levels, increased expression of angiopoietin-like 4 in intestine and lower hepatic lipid content, although increased expression of stress markers in adipose tissue and of inflammation in liver was also found. To determine whether slimming effects could be transferred to obese mice, a faecal microbial transplant (FMT) was carried out, showing that host bacteria grown under a HF diet could not be superseded by those from calcium-fed animals. Therefore, FMT was not able to transfer the beneficial effects of calcium. CONCLUSION: In conclusion, calcium modulated gut microbiota in a prebiotic manner, establishing a host cross-talk and promoting a healthier metabolic profile. However, lack of effectiveness of FMT suggests the need of further appropriate dietary factors in addition to the bacteria per se. PMID- 26582186 TI - Patulin is a cultivar-dependent aggressiveness factor favouring the colonization of apples by Penicillium expansum. AB - The blue mould decay of apples is caused by Penicillium expansum and is associated with contamination by patulin, a worldwide regulated mycotoxin. Recently, a cluster of 15 genes (patA-patO) involved in patulin biosynthesis was identified in P. expansum. blast analysis revealed that patL encodes a Cys6 zinc finger regulatory factor. The deletion of patL caused a drastic decrease in the expression of all pat genes, leading to an absence of patulin production. Pathogenicity studies performed on 13 apple varieties indicated that the PeDeltapatL strain could still infect apples, but the intensity of symptoms was weaker compared with the wild-type strain. A lower growth rate was observed in the PeDeltapatL strain when this strain was grown on nine of the 13 apple varieties tested. In the complemented PeDeltapatL:patL strain, the ability to grow normally in apple and the production of patulin were restored. Our results clearly demonstrate that patulin is not indispensable in the initiation of the disease, but acts as a cultivar-dependent aggressiveness factor for P. expansum. This conclusion was strengthened by the fact that the addition of patulin to apple infected by the PeDeltapatL mutant restored the normal fungal colonization in apple. PMID- 26582187 TI - Cerebral and Peripheral Metabolism to Predict Successful Reperfusion After Cardiac Arrest in Rats: A Microdialysis Study. AB - BACKGROUND: In clinical practice, monitoring of the efficacy of resuscitation can be challenging. The prediction of cerebral and overall outcome in particular is an unmet medical need. Microdialysis is a minimally invasive technique for the continuous determination of metabolic parameters in vivo. Using this technique, we set out to establish a model allowing for concomitant determination of cerebral and peripheral metabolism in a cardiac arrest setting in rodents. METHODS: Microdialysis settings were optimized in vitro and then used in male Sprague-Dawley rats. Probes were implanted into the CA1 region of the right hippocampus and the right femoral vein. With a time interval of 8 min, glucose, lactate, pyruvate, and glutamate levels were determined during baseline conditions, untreated ventricular fibrillation cardiac arrest, cardiopulmonary resuscitation (CPR), reperfusion, and death. RESULTS: In 16 rodents, restoration of spontaneous circulation was achieved in seven animals. Characteristic metabolic changes were evident during cardiac arrest and reperfusion with both probes. Ischemic patterns in peripheral compartments were delayed and more variable compared to the changes in cerebral metabolism highlighting the importance of cerebral metabolic monitoring. Microdialysis allowed distinguishing between survivors and non-survivors 8 min after termination of CPR. Cerebral glutamate showed a trend toward higher levels in non-survivors during CPR. CONCLUSIONS: We established a new rodent model for research in hypoxic ischemic encephalopathy. This setting allows to investigate the impact of resuscitation methods on cerebral and peripheral metabolism simultaneously. The present model may be used to evaluate different resuscitation strategies in order to optimize brain survival in future studies. PMID- 26582188 TI - Analysis of human dentition from Early Bronze Age: 4000-year-old puzzle. AB - This paper presents the first ever paleodontological investigation of human remains from an archeological site in Central Europe dating from the Early Bronze Age and attributed to the Strzyzow Culture. It corroborates the knowledge gained from archeological, anthropological and genetical investigations. Our study aimed to assess dental status, dental morphology and dental pathologies as well as tooth wear and enamel hypoplasia based on visual inspection and stereomicroscopic investigation. The research was supported by CBCT imaging to obtain digital images and 3D reconstructions as well as 2D radiographs essential for dental age estimation. All of the 191 teeth discovered showed morphological similarity, with adult teeth showing similar color, shape and size. A maxillary molar presenting with a unique root morphology and a mandibular molar with a rare occlusal surface were found. Both permanent and deciduous dentition presented significant tooth wear. A few specimens displayed signs of dental caries, periapical pathology and antemortem tooth loss. Three individuals exhibited linear enamel hypoplasia. CBCT provided high-quality 2D images useful for dental age estimation by non destructive methods. Estimated dental age correlated with the age estimated by other anthropological methods. In one case, this was crucial because of insufficient material for anthropological analysis. The presented studies have proved that besides the skeleton, teeth can be used as a fundamental tool in assessing the overall health and living conditions of paleopopulations. It would seem that there is potential for considerable development to be made in the research and investigation of paleodontological material using CBCT. PMID- 26582189 TI - [Measurement of canine and feline pancreatic lipase immunoreactivity - analytical comparison of new commercial assays with established assays]. AB - OBJECTIVE: Commercial assays for the measurement of canine and feline pancreatic lipase immunoreactivity (Spec cPL(r) and Spec fPL(r)) have been available for a few years. The aim of this study was to compare new commercial assays that have not previously been validated in the literature to the established assays. MATERIAL AND METHODS: Leftover serum samples from diagnostic submissions to the GI-lab of the Texas A&M University were collected based on certain parameters (e.g., good quality sample, hemolytic, lipemic, or icteric sample) and were assigned random sample ID numbers. The samples were evaluated by Spec cPL(r) or Spec fPL(r) and sent on dry ice to the Kleintierklinik am Hochberg (Germany). From here one aliquot of each sample was blindly submitted to the diagnostic laboratory Laboklin (Germany) for measurement of cPL and fPL by their newly released assay and also to the GI-Lab (Texas) for repeated analysis to exclude any effect of shipping. RESULTS: There was no significant difference between serum cPL or fPL concentrations before or after shipping at the GI-Lab (Texas) (Wilcoxon paired sample signed rank tests p = 0.581 and 0.712, respectively). Significant differences were found between serum cPL or fPL concentrations of the newly released assays and the established assays (p < 0.0004 and p = 0.025, respectively). The newly released and the established assays showed some association (Spearman r: 0.775 and 0.739, respectively), however, there was a strong bias between the new assays and the established assays. The strength of agreement between the new and established canine and feline assays was poor (concordance coefficient 0.539 and 0.465, respectively). Also, the clinical interpretation for serum cPL and fPL results did not agree for many of the samples. CONCLUSION AND CLINICAL RELEVANCE: In conclusion, the newly released assays for the measurement of cPL and fPL show significant bias and poor concordance and provide different clinical interpretations when compared with validated assays. Thus, further research is needed before these newly released assays can be recommended for clinical use. PMID- 26582190 TI - Perioperative Evaluation of Patient Outcomes after Severe Acid Corrosive Injury. AB - We reviewed 64 patients with perforation or full-thickness injury of the alimentary tract after acid ingestion. Based on our classification of laparotomy findings, there were class I (n = 15); class II (n = 13); class III (n = 16); and class IV (n = 20). Study parameters were preoperative laboratory data, gastric perforation, associated visceral injury, and extension of the injury. End points of the study were the patients' mortality and length of hospital stay. All these patients underwent esophagogastrectomy with (n = 16) or without (n = 24) concomitant resection, esophagogastroduodenojejunectomy with (n = 4) or without (n = 13) concomitant resection, and laparotomy only (n = 7). Concomitant resections were performed on the spleen (n = 10), colon (n = 2), pancreas (n = 1), gall bladder (n = 1), skipped areas of jejunum (n = 4), and the first portion of the duodenum (n = 4). The study demonstrates five preoperative risk factors, female gender, shock status, shock index, pH value, and base deficit, and four intraoperative risk factors, gastric perforation, associated visceral injury, injury beyond the pylorus, and continuous involvement of the jejunum over a length of 50 cm. The overall mortality rate was 45.3%, which increased significantly with advancing class of corrosive injury. PMID- 26582191 TI - Direct-to-consumer genetic testing for predicting sports performance and talent identification: Consensus statement. AB - The general consensus among sport and exercise genetics researchers is that genetic tests have no role to play in talent identification or the individualised prescription of training to maximise performance. Despite the lack of evidence, recent years have witnessed the rise of an emerging market of direct-to-consumer marketing (DTC) tests that claim to be able to identify children's athletic talents. Targeted consumers include mainly coaches and parents. There is concern among the scientific community that the current level of knowledge is being misrepresented for commercial purposes. There remains a lack of universally accepted guidelines and legislation for DTC testing in relation to all forms of genetic testing and not just for talent identification. There is concern over the lack of clarity of information over which specific genes or variants are being tested and the almost universal lack of appropriate genetic counselling for the interpretation of the genetic data to consumers. Furthermore independent studies have identified issues relating to quality control by DTC laboratories with different results being reported from samples from the same individual. Consequently, in the current state of knowledge, no child or young athlete should be exposed to DTC genetic testing to define or alter training or for talent identification aimed at selecting gifted children or adolescents. Large scale collaborative projects, may help to develop a stronger scientific foundation on these issues in the future. PMID- 26582192 TI - Risk factors associated with lower extremity stress fractures in runners: a systematic review with meta-analysis. AB - BACKGROUND: Stress fractures are common overuse injuries with up to 95% occurring in the lower extremities. Among runners, stress fractures account for 15-20% of all musculoskeletal injuries. PURPOSE: We systematically reviewed and critiqued the evidence regarding risk factors associated with increased risk of lower extremity stress fractures in runners. STUDY DESIGN: Systematic review. METHODS: A systematic, computerised literature search of Medline, Embase, PubMed, SPORTDiscus, and CINAHL databases (from database inception through 9 January 2014) using keywords related to risk factors and stress fractures. This systematic review with meta-analysis utilised the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for the search and reporting phases of the study. Inverse variance meta-analyses, using a random effects model were used to summarise ORs. RESULTS: 8 articles met the inclusion criteria; 7 were considered low risk. 4 articles qualified for meta-analysis. Results of the meta-analysis identified previous history of stress fracture and female sex as the primary risk factors for future stress fracture with a pooled OR of 4.99 (95% CI 2.91 to 8.56; p<0.001; I(2)=0%) and 2.31 (95% CI 1.24 to 4.29; p<0.01; I(2)=0%), respectively. CONCLUSIONS: Currently, only previous history of stress fracture and female sex are risk factors for lower extremity stress fractures strongly supported by the data. PMID- 26582193 TI - Genoprotective and neuroprotective effects of Daphne gnidium leaf methanol extract, tested on male mice. AB - Methanol extract of Daphne gnidium leaves was assessed for its antigenotoxic and neuroprotective effects through antioxidant and antibutyrylcholinesterase activities. Antigenotoxic activity was evaluated against methyl methanesulfonate injected intraperitoneally to mice, using the comet assay. The protective effect of D. gnidium reached 99.12%, at the lowest tested dose (44 mg/kg b.w.) in kidney cells, and 92.16% at the dose of 88 mg/kg b.w. in blood cells. The extract was dissolved in water and administrated to mice by intraperitoneal injection. Antioxidant activity was tested against DPPH radicals. It reached a maximum of 74.52% with an IC50 value of 45 ug/ml. Anticholinesterase activity was determined against butyrylcholinesterase, an enzyme linked to Alzheimer disease. The extract exhibited antibutyrylcholinestrase effect with an inhibition percentage of 35.82% at the lowest tested dose (44 mg/kg b.w.). PMID- 26582194 TI - Effects of one's sex and sex hormones on sympathetic responses to chemoreflex activation. AB - NEW FINDINGS: What is the topic of this review? This review summarizes sex dependent differences in the sympathetic responses to chemoreflex activation, with a focus on the role of circulating sex hormones on the sympathetic outcomes. What advances does it highlight? The importance of circulating sex hormones for the regulation of sympathetic nerve activity in humans has only recently begun to be elucidated, and few studies have examined this effect during chemoreflex regulation. We review recent studies indicating that changes in circulating sex hormones are associated with alterations to chemoreflex-driven increases in sympathetic activity and highlight those areas which require further study. Sex dependent differences in baseline sympathetic nerve activity are established, but little information exists on the influence of sex on sympathetic activation during chemoreflex stimulation. In this article, we review the evidence for the effect of sex on chemoreflex-driven increases in sympathetic nerve activity. We also review recent studies which indicate that changes in circulating sex hormones, as initiated by the menstrual cycle and hormonal contraceptive use, elicit notable changes in the muscle sympathetic activation during chemoreflex stimulation. PMID- 26582195 TI - "Codeine Is My Helper": Misuse of and Dependence on Codeine-Containing Medicines in South Africa. AB - Misuse of codeine-containing medicines is an emerging global public health concern. The majority of research has been conducted in developed countries (European Members States, Australia, the United States). This study aimed to gain an understanding of unique individual and collective experiences of trajectories of codeine misuse and dependence in South Africa. In-depth interviews were conducted with a purposive sample of adult codeine misusers and dependents ( n = 25). Narratives were analyzed using the empirical phenomenological psychological five-step method. Nine themes with 63 categories emerged, with two additional high levels of abstraction. Findings are illustrated: participant profile and product preferences, motives for use, transitioning to misuse and dependence, pharmacy purchasing and alternative sourcing routes, effects and withdrawal experiences, help-seeking and treatment experiences, and strategies for prevention. The study underscores the need for continued support for enhanced patient awareness of risk of habit forming use and related health consequences and professional pharmacovigilance. PMID- 26582197 TI - FcgammaRIIIa-Syk Co-signal Modulates CD4+ T-cell Response and Up-regulates Toll like Receptor (TLR) Expression. AB - CD4(+) T-cells in systemic lupus erythematosus (SLE) patients show altered T-cell receptor signaling, which utilizes Fc-receptor gamma-chain FcRgamma-Syk. A role for FcgammaRIIIa activation from immune complex (IC) ligation and sublytic terminal complement complex (C5b-9) in CD4(+) T-cell responses is not investigated. In this study, we show that the ICs present in SLE patients by ligating to FcgammaRIIIa on CD4(+) T-cells phosphorylate Syk and provide a co stimulatory signal to CD4(+) T-cells in the absence of CD28 signal. This led to the development of pathogenic IL-17A(+) and IFN-gamma(high) CD4(+) T-cells in vitro. Cytokines IL-1beta, IL-6, TGF-beta1, and IL-23 were the only requirement for the development of both populations. SLE patients CD4(+) T-cells that expressed CD25, CD69, and CD98 bound to ICs showed pSyk and produced IFN-gamma and IL-17A. This FcgammaRIIIa-mediated co-signal differentially up-regulated the expression of IFN pathway genes compared with CD28 co-signal. FcgammaRIIIa-pSyk up-regulated several toll-like receptor genes as well as the HMGB1 and MyD88 gene transcripts. ICs co-localized with these toll-like receptor pathway proteins. These results suggest a role for the FcgammaRIIIa-pSyk signal in modulating adaptive immune responses. PMID- 26582198 TI - Two Na+ Sites Control Conformational Change in a Neurotransmitter Transporter Homolog. AB - In LeuT, a prokaryotic homolog of neurotransmitter transporters, Na(+) stabilizes outward-open conformational states. We examined how each of the two LeuT Na(+) binding sites contributes to Na(+)-dependent closure of the cytoplasmic pathway using biochemical and biophysical assays of conformation. Mutating either of two residues that contribute to the Na2 site completely prevented cytoplasmic closure in response to Na(+), suggesting that Na2 is essential for this conformational change, whereas Na1 mutants retained Na(+) responsiveness. However, mutation of Na1 residues also influenced the Na(+)-dependent conformational change in ways that varied depending on the position mutated. Computational analyses suggest those mutants influence the ability of Na1 binding to hydrate the substrate pathway and perturb an interaction network leading to the extracellular gate. Overall, the results demonstrate that occupation of Na2 stabilizes outward-facing conformations presumably through a direct interaction between Na(+) and transmembrane helices 1 and 8, whereas Na(+) binding at Na1 influences conformational change through a network of intermediary interactions. The results also provide evidence that N-terminal release and helix motions represent distinct steps in cytoplasmic pathway opening. PMID- 26582199 TI - S-Adenosyl-l-methionine Modulates CO and NO* Binding to the Human H2S-generating Enzyme Cystathionine beta-Synthase. AB - Cystathionine beta-synthase (CBS) is a key enzyme in human (patho)physiology with a central role in hydrogen sulfide metabolism. The enzyme is composed of a pyridoxal 5'-phosphate-binding catalytic domain, flanked by the following two domains: a heme-binding N-terminal domain and a regulatory C-terminal domain binding S-adenosyl-l-methionine (AdoMet). CO or NO(*) binding at the ferrous heme negatively modulates the enzyme activity. Conversely, AdoMet binding stimulates CBS activity. Here, we provide experimental evidence for a functional communication between the two domains. We report that AdoMet binding significantly enhances CBS inhibition by CO. Consistently, we observed increased affinity (~5-fold) and faster association (~10-fold) of CO to the ferrous heme at physiological AdoMet concentrations. NO(*) binding to reduced CBS was also enhanced by AdoMet, although to a lesser extent (~2-fold higher affinity) as compared with CO. Importantly, CO and NO(*) binding was unchanged by AdoMet in a truncated form of CBS lacking the C-terminal regulatory domain. These unprecedented observations demonstrate that CBS activation by AdoMet puzzlingly sensitizes the enzyme toward inhibition by exogenous ligands, like CO and NO(*). This further supports the notion that CBS regulation is a complex process, involving the concerted action of multiple physiologically relevant effectors. PMID- 26582200 TI - Lifeguard Inhibits Fas Ligand-mediated Endoplasmic Reticulum-Calcium Release Mandatory for Apoptosis in Type II Apoptotic Cells. AB - Death receptors are members of the tumor necrosis factor receptor superfamily involved in the extrinsic apoptotic pathway. Lifeguard (LFG) is a death receptor antagonist mainly expressed in the nervous system that specifically blocks Fas ligand (FasL)-induced apoptosis. To investigate its mechanism of action, we studied its subcellular localization and its interaction with members of the Bcl 2 family proteins. We performed an analysis of LFG subcellular localization in murine cortical neurons and found that LFG localizes mainly to the ER and Golgi. We confirmed these results with subcellular fractionation experiments. Moreover, we show by co-immunoprecipitation experiments that LFG interacts with Bcl-XL and Bcl-2, but not with Bax or Bak, and this interaction likely occurs in the endoplasmic reticulum. We further investigated the relationship between LFG and Bcl-XL in the inhibition of apoptosis and found that LFG protects only type II apoptotic cells from FasL-induced death in a Bcl-XL dependent manner. The observation that LFG itself is not located in mitochondria raises the question as to whether LFG in the ER participates in FasL-induced death. Indeed, we investigated the degree of calcium mobilization after FasL stimulation and found that LFG inhibits calcium release from the ER, a process that correlates with LFG blockage of cytochrome c release to the cytosol and caspase activation. On the basis of our observations, we propose that there is a required step in the induction of type II apoptotic cell death that involves calcium mobilization from the ER and that this step is modulated by LFG. PMID- 26582201 TI - beta-Arrestin 2 Promotes Hepatocyte Apoptosis by Inhibiting Akt Protein. AB - Recent studies reveal that multifunctional protein beta-arrestin 2 (Arrb2) modulates cell apoptosis. Survival and various aspects of liver injury were investigated in WT and Arrb2 KO mice after bile duct ligation (BDL). We found that deficiency of Arrb2 enhances survival and attenuates hepatic injury and fibrosis. Following BDL, Arrb2-deficient mice as compared with WT controls displayed a significant reduction of hepatocyte apoptosis as demonstrated by the TUNEL assay. Following BDL, the levels of phospho-Akt and phospho-glycogen synthase kinase 3beta (GSK3beta) in the livers were significantly increased in Arrb2 KO compared with WT mice, although p-p38 increased in WT but not in Arrb2 deficient mice. Inhibition of GSK3beta following BDL decreases hepatic apoptosis and decreased p-p38 in WT mice but not in Arrb2 KO mice. Activation of Fas receptor with Jo2 reduces phospho-Akt and increases apoptosis in WT cells and WT mice but not in Arrb2-deficient cells and Arrb2-deficient mice. Consistent with direct interaction of Arrb2 with and regulating Akt phosphorylation, the expression of a full-length or N terminus but not the C terminus of Arrb2 reduces Akt phosphorylation and coimmunoprecipates with Akt. These results reveal that the protective effect of deficiency of Arrb2 is due to loss of negative regulation of Akt due to BDL and decreased downstream GSK3beta and p38 MAPK signaling pathways. PMID- 26582202 TI - The Activation Mechanism of Glycoprotein Hormone Receptors with Implications in the Cause and Therapy of Endocrine Diseases. AB - Glycoprotein hormones (GPHs) are the main regulators of the pituitary-thyroid and pituitary-gonadal axes. Selective interaction between GPHs and their cognate G protein-coupled receptors ensure specificity in GPH signaling. The mechanisms of how these hormones activate glycoprotein hormone receptors (GPHRs) or how mutations and autoantibodies can alter receptor function were unclear. Based on the hypothesis that GPHRs contain an internal agonist, we systematically screened peptide libraries derived from the ectodomain for agonistic activity on the receptors. We show that a peptide (p10) derived from a conserved sequence in the C-terminal part of the extracellular N terminus can activate all GPHRs in vitro and in GPHR-expressing tissues. Inactivating mutations in this conserved region or in p10 can inhibit activation of the thyroid-stimulating hormone receptor by autoantibodies. Our data suggest an activation mechanism where, upon extracellular ligand binding, this intramolecular agonist isomerizes and induces structural changes in the 7-transmembrane helix domain, triggering G protein activation. This mechanism can explain the pathophysiology of activating autoantibodies and several mutations causing endocrine dysfunctions such as Graves disease and hypo- and hyperthyroidism. Our findings highlight an evolutionarily conserved activation mechanism of GPHRs and will further promote the development of specific ligands useful to treat Graves disease and other dysfunctions of GPHRs. PMID- 26582203 TI - A Single Glycan at the 99-Loop of Human Kallikrein-related Peptidase 2 Regulates Activation and Enzymatic Activity. AB - Human kallikrein-related peptidase 2 (KLK2) is a key serine protease in semen liquefaction and prostate cancer together with KLK3/prostate-specific antigen. In order to decipher the function of its potential N-glycosylation site, we produced pro-KLK2 in Leishmania tarentolae cells and compared it with its non-glycosylated counterpart from Escherichia coli expression. Mass spectrometry revealed that Asn 95 carries a core glycan, consisting of two GlcNAc and three hexoses. Autocatalytic activation was retarded in glyco-pro-KLK2, whereas the activated glyco-form exhibited an increased proteolytic resistance. The specificity patterns obtained by the PICS (proteomic identification of protease cleavage sites) method are similar for both KLK2 variants, with a major preference for P1 Arg. However, glycosylation changes the enzymatic activity of KLK2 in a drastically substrate-dependent manner. Although glyco-KLK2 has a considerably lower catalytic efficiency than glycan-free KLK2 toward peptidic substrates with P2-Phe, the situation was reverted toward protein substrates, such as glyco-pro KLK2 itself. These findings can be rationalized by the glycan-carrying 99-loop that prefers to cover the active site like a lid. By contrast, the non glycosylated 99-loop seems to favor a wide open conformation, which mostly increases the apparent affinity for the substrates (i.e. by a reduction of Km). Also, the cleavage pattern and kinetics in autolytic inactivation of both KLK2 variants can be explained by a shift of the target sites due to the presence of the glycan. These striking effects of glycosylation pave the way to a deeper understanding of kallikrein-related peptidase biology and pathology. PMID- 26582204 TI - The A-kinase Anchoring Protein GSKIP Regulates GSK3beta Activity and Controls Palatal Shelf Fusion in Mice. AB - A-kinase anchoring proteins (AKAPs) represent a family of structurally diverse proteins, all of which bind PKA. A member of this family is glycogen synthase kinase 3beta (GSK3beta) interaction protein (GSKIP). GSKIP interacts with PKA and also directly interacts with GSK3beta. The physiological function of the GSKIP protein in vivo is unknown. We developed and characterized a conditional knock out mouse model and found that GSKIP deficiency caused lethality at birth. Embryos obtained through Caesarean section at embryonic day 18.5 were cyanotic, suffered from respiratory distress, and failed to initiate breathing properly. Additionally, all GSKIP-deficient embryos showed an incomplete closure of the palatal shelves accompanied by a delay in ossification along the fusion area of secondary palatal bones. On the molecular level, GSKIP deficiency resulted in decreased phosphorylation of GSK3beta at Ser-9 starting early in development (embryonic day 10.5), leading to enhanced GSK3beta activity. At embryonic day 18.5, GSK3beta activity decreased to levels close to that of wild type. Our findings reveal a novel, crucial role for GSKIP in the coordination of GSK3beta signaling in palatal shelf fusion. PMID- 26582205 TI - Cooperative Interactions of Oligosaccharide and Peptide Moieties of a Glycopeptide Derived from IgE with Galectin-9. AB - We previously showed that galectin-9 suppresses degranulation of mast cells through protein-glycan interaction with IgE. To elucidate the mechanism of the interaction in detail, we focused on identification and structural analysis of IgE glycans responsible for the galectin-9-induced suppression using mouse monoclonal IgE (TIB-141). TIB-141 in combination with the antigen induced degranulation of RBL-2H3 cells, which was almost completely inhibited by human and mouse galectin-9. Sequential digestion of TIB-141 with lysyl endopeptidase and trypsin resulted in the identification of a glycopeptide (H-Lys13-Try3; 48 amino acid residues) with a single N-linked oligosaccharide near the N terminus capable of neutralizing the effect of galectin-9 and another glycopeptide with two N-linked oligosaccharides (H-Lys13-Try1; 16 amino acid residues) having lower activity. Enzymatic elimination of the oligosaccharide chain from H-Lys13-Try3 and H-Lys13-Try1 completely abolished the activity. Removal of the C-terminal 38 amino acid residues of H-Lys13-Try3 with glutamyl endopeptidase, however, also resulted in loss of the activity. We determined the structures of N-linked oligosaccharides of H-Lys13-Try1. The galectin-9-binding fraction of pyridylaminated oligosaccharides contained asialo- and monosialylated bi/tri antennary complex type oligosaccharides with a core fucose residue. The structures of the oligosaccharides were consistent with the sugar-binding specificity of galectin-9, whereas the nonbinding fraction contained monosialylated and disialylated biantennary complex type oligosaccharides with a core fucose residue. Although the oligosaccharides linked to H-Lys13-Try3 could not be fully characterized, these results indicate the possibility that cooperative binding of oligosaccharide and neighboring polypeptide structures of TIB-141 to galectin-9 affects the overall affinity and specificity of the IgE lectin interaction. PMID- 26582206 TI - Nutrient Loads Flowing into Coastal Waters from the Main Rivers of China (2006 2012). AB - Based on monthly monitoring data of unfiltered water, the nutrient discharges of the eight main rivers flowing into the coastal waters of China were calculated from 2006 to 2012. In 2012, the total load of NH3-N (calculated in nitrogen), total nitrogen (TN, calculated in nitrogen) and total phosphorus (TP, calculated in phosphorus) was 5.1 * 10(5), 3.1 * 10(6) and 2.8 * 10(5) tons, respectively, while in 2006, the nutrient load was 7.4 * 10(5), 2.2 * 10(6) and 1.6 * 10(5) tons, respectively. The nutrient loading from the eight major rivers into the coastal waters peaked in summer and autumn, probably due to the large water discharge in the wet season. The Yangtze River was the largest riverine nutrient source for the coastal waters, contributing 48% of the NH3-N discharges, 66% of the TN discharges and 84% of the TP discharges of the eight major rivers in 2012. The East China Sea received the majority of the nutrient discharges, i.e. 50% of NH3-N (2.7 * 10(5) tons), 70% of TN (2.2 * 10(6) tons) and 87% of TP (2.5 * 10(5) tons) in 2012. The riverine discharge of TN into the Yellow Sea and Bohai Sea was lower than that from the direct atmospheric deposition, while for the East China Sea, the riverine TN input was larger. PMID- 26582207 TI - Evaluation of physical activity interventions in children via the reach, efficacy/effectiveness, adoption, implementation, and maintenance (RE-AIM) framework: A systematic review of randomized and non-randomized trials. AB - CONTEXT: Existing reviews of physical activity (PA) interventions designed to increase PA behavior exclusively in children (ages 5 to 11years) focus primarily on the efficacy (e.g., internal validity) of the interventions without addressing the applicability of the results in terms of generalizability and translatability (e.g., external validity). OBJECTIVE: This review used the RE-AIM (Reach, Efficacy/Effectiveness, Adoption, Implementation, Maintenance) framework to measure the degree to which randomized and non-randomized PA interventions in children report on internal and external validity factors. METHODS AND RESULTS: A systematic search for controlled interventions conducted within the past 12years identified 78 studies that met the inclusion criteria. Based on the RE-AIM criteria, most of the studies focused on elements of internal validity (e.g., sample size, intervention location and efficacy/effectiveness) with minimal reporting of external validity indicators (e.g., representativeness of participants, start-up costs, protocol fidelity and sustainability). CONCLUSIONS: Results of this RE-AIM review emphasize the need for future PA interventions in children to report on real-world challenges and limitations, and to highlight considerations for translating evidence-based results into health promotion practice. PMID- 26582208 TI - Prostate cancer screening in Switzerland: 20-year trends and socioeconomic disparities. AB - BACKGROUND: Despite important controversy in its efficacy, prostate cancer (PCa) screening has become widespread. Important socioeconomic screening disparities have been reported. However, trends in PCa screening and social disparities have not been investigated in Switzerland, a high risk country for PCa. We used data from five waves (from 1992-2012) of the population-based Swiss Health Interview Survey to evaluate trends in PCa screening and its association with socioeconomic indicators. METHODS: We used multivariable Poisson regression to estimate prevalence ratios (PR) and 95% Confidence Intervals (CI) adjusting for demographics, health status, and use of healthcare. RESULTS: The study included 12,034 men aged >=50 years (mean age: 63.9). Between 1992 and 2012, ever use of PCa screening increased from 55.3% to 70.0% and its use within the last two years from 32.6% to 42.4% (p-value <0.05). Income, education, and occupational class were independently associated with PCa screening. PCa screening within the last two years was greater in men with the highest (>$6,000/month) vs. lowest income (<=$2,000) (46.5% vs. 38.7% in 2012, PR for overall period =1.29, 95%CI: 1.13 1.48). These socioeconomic disparities did not significantly change over time. CONCLUSIONS: This study shows that about half of Swiss men had performed at least one PCa screening. Men belonging to high socioeconomic status are clearly more frequently screened than those less favored. Given the uncertainty of the usefulness of PCa screening, men, including those with high socioeconomic status, should be clearly informed about benefits and harms of PCa screening, in particular, the adverse effect of over-diagnosis and of associated over treatment. PMID- 26582209 TI - Neighborhood and family perceived environments associated with children's physical activity and body mass index. AB - BACKGROUND: A growing body of research has been examining neighborhood environment related to children's physical activity and obesity. However, there is still not enough evidence from Latin America. OBJECTIVE: To investigate the association of neighborhood and family perceived environments, use of and distance to public open spaces with leisure-time physical activity (LTPA) and body mass index (BMI) in Argentinean school-aged children. METHODS: School-based, cross-sectional study with 1777 children (9 to 11years) and their parents, in Cordoba city during 2011. Children were asked about LTPA and family perceived environment. Parents were asked about neighborhood perceived environment, children's use of public open spaces and distance. Weight and height were measured for BMI. We modeled children's LTPA and BMI z-score with structural equation models with latent variables for built, social and safety neighborhood environments. RESULTS: Parents' perceived neighborhood environment was not related with children's LTPA and BMI. Children's perceived autonomy and family environment were positively associated with LTPA. Use of unstructured open spaces and, indirectly, the distance to these, was associated with LTPA among girls. Greater distance to parks reduced their use by children. CONCLUSIONS: Policies to increase children's LTPA should include access to better public open spaces, increasing options for activity. A family approach should be incorporated, reinforcing its role for healthy development. PMID- 26582210 TI - Prevalence and correlates of local health department activities to address mental health in the United States. AB - Mental health has been recognized as a public health priority for nearly a century. Little is known, however, about what local health departments (LHDs) do to address the mental health needs of the populations they serve. Using data from the 2013 National Profile of Local Health Departments - a nationally representative survey of LHDs in the United States (N=505) - we characterized LHDs' engagement in eight mental health activities, factors associated with engagement, and estimated the proportion of the U.S. population residing in jurisdictions where these activities were performed. We used Handler's framework of the measurement of public health systems to select variables and examined associations between LHD characteristics and engagement in mental health activities using bivariate analyses and multilevel, multivariate logistic regression. Assessing gaps in access to mental healthcare services (39.3%) and implementing strategies to improve access to mental healthcare services (32.8%) were the most common mental health activities performed. LHDs that provided mental healthcare services were significantly more likely to perform population based mental illness prevention activities (adjusted odds ratio: 7.1; 95% CI: 5.1, 10.0) and engage in policy/advocacy activities to address mental health (AOR: 3.9; 95% CI: 2.7, 5.6). Our study suggests that many LHDs are engaged in activities to address mental health, ranging from healthcare services to population-based interventions, and that LHDs that provide healthcare services are more likely than others to perform mental health activities. These findings have implications as LHDs reconsider their roles in the era of the Patient Protection and Affordable Care Act and LHD accreditation. PMID- 26582211 TI - Absolute and relative densities of fast-food versus other restaurants in relation to weight status: Does restaurant mix matter? AB - BACKGROUND: Given the continuing epidemic of obesity, policymakers are increasingly looking for levers within the local retail food environment as a means of promoting healthy weights. PURPOSE: To examine the independent and joint associations of absolute and relative densities of restaurants near home with weight status in a large, urban, population-based sample of adults. METHODS: We studied 10,199 adults living in one of four cities in southern Ontario, Canada, who participated in the Canadian Community Health Survey (cycles 2005, 2007/08, 2009/10). Multivariate models assessed the association of weight status (obesity and body mass index) with absolute densities (numbers) of fast-food, full-service and other restaurants, and the relative density (proportion) of fast-food restaurants (FFR) relative to all restaurants within ~10-minute walk of residential areas. RESULTS: Higher numbers of restaurants of any type were inversely related to excess weight, even in models adjusting for a range of individual covariates and area deprivation. However, these associations were no longer significant after accounting for higher walkability of areas with high volumes of restaurants. In contrast, there was a direct relationship between the proportion of FFR relative to all restaurants and excess weight, particularly in areas with high volumes of FFR (e.g., odds ratio for obesity=2.55 in areas with 5+ FFR, 95% confidence interval: 1.55-4.17, across the interquartile range). CONCLUSIONS: Policies aiming to promote healthy weights that target the volume of certain retail food outlets in residential settings may be more effective if they also consider the relative share of outlets serving more and less healthful foods. PMID- 26582212 TI - Respiratory allergies in childhood: Recent advances and future challenges. AB - The burden of allergic airway diseases still represents a major health problem in childhood. Despite many different options are currently available for the diagnostic work-up and management, the overall disease control in terms of impact on quality of life, morbidity and mortality, is not yet satisfactory. The extreme variability of individual risk factors and severity determinants may account for it. On the other side, the knowledge of the multifaceted allergy background could pave the way to primary prevention, early intervention and disease course modification. In fact, most of current research is focusing on the identification of biological and clinical predictive markers of allergy and asthma onset. This review aims at summarizing the latest achievements concerning the complex inter relation between genetic predisposition and environmental factors, and their impact on prevention strategies and early identification of at risk subjects. An update on the diagnostic and monitoring tools as well as an insight into the newest treatments options is also provided. PMID- 26582213 TI - The Combined Effects of Daily Stressors and Major Life Events on Daily Subjective Ages. AB - Objectives: Stressors may be a contributing factor in determining how old an individual feels, looks, or would like to be. Currently, little research has been devoted to understanding the relationship between stressors and subjective age in older adults. We focus on the combined impact of major life-event stressors and daily stressors on multiple indicators of subjective age: felt age, ideal age, and look age. Furthermore, we examine the process by which daily stressors relate to subjective ages by testing whether positive affect, control, and negative affect mediate this relationship. Method: Using a daily-diary design, the current study measured older adults' (60-96 years old) stressors, subjective ages, personal control, and affect. Results: Felt, ideal, and look ages each demonstrated a unique pattern of interactions between daily stressors and major life-event stressors. Furthermore, our findings suggest that on the daily level, the relationship between stressors and felt age is mediated by negative affect but not by control and positive affect. Discussion: Findings indicate the need to consider the broader contextual picture of stressors, as well as their differential impact on multiple indicators of subjective age. PMID- 26582214 TI - Successful resection of large esophageal leiomyoma by a combined thoracoscopic endoscopic submucosal tunneling method. PMID- 26582215 TI - Intestinal organoids for assessing nutrient transport, sensing and incretin secretion. AB - Intestinal nutrient transport and sensing are of emerging interest in research on obesity and diabetes and as drug targets. Appropriate in vitro models are lacking that allow both, studies on transport processes as well as sensing and subsequent incretin hormone secretion including intracellular signaling. We here demonstrate that murine small-intestinal organoids are the first in vitro model system enabling concurrent investigations of nutrient and drug transport, sensing and incretin hormone secretion as well as fluorescent live-cell imaging of intracellular signaling processes. By generating organoid cultures from wild type mice and animals lacking different nutrient transporters, we show that organoids preserve the main phenotypic features and functional characteristics of the intestine. This turns them into the best in vitro model currently available and opens new avenues for basic as well as medical research. PMID- 26582217 TI - Retrograde femoral nailing of periprosthetic fractures around total knee replacements. AB - INTRODUCTION: The incidence of primary total knee replacement (TKR) is increasing with a resultant rise in those patients sustaining distal femoral periprosthetic fractures around TKRs. The management of these fractures pose a significant challenge. The compatibility of retrograde femoral intramedullary (IM) nails with femoral TKR components needs to be considered preoperatively when this complex pathology is addressed. The aim of this study was to update the literature and assess the compatibility of the most commonly used primary TKR prostheses and retrograde femoral IM nails using a Sawbone anatomical model. METHODS AND MATERIALS: Eight of the most commonly used primary TKR prostheses and four of the most commonly used retrograde femoral IM nails were identified. The femoral components of the TKRs were implanted onto left sided femoral Sawbones using the manufacturer's guides and cutting blocks and positioned appropriately. The retrograde IM nails were inserted using the conventional entry point and a nail was deemed compatible if this was possible through the femoral prosthesis. Details of whether a posterior entry point was required to allow insertion, whether the femoral nail was scratched by the femoral TKR prosthesis on insertion and whether excess force was required to insert the retrograde femoral IM nail were recorded. RESULTS: The Biomet AGC Cruciate Retaining (CR) and Posterior Stabilised (PS) TKR were the only prostheses that were compatible with all the nails used. The other TKR prostheses were not compatible because of the force required to gain entry, scratching of the retrograde femoral IM nail or because a posterior entry point was required to gain entry through the intercondylar notch. CONCLUSION: The majority of standard sized retrograde femoral nails are technically feasible for insertion through most femoral TKR components but this study has found that they are not compatible due to excessive force required for insertion, damage to the nail during insertion or the risk of anterior cortex perforation. Further studies are required to update the compatibility table and cadaveric studies would confirm the findings and allow further mechanical testing. PMID- 26582216 TI - The role of tonsillectomy in IgA nephropathy. AB - The IgA nephropathy (IgAN) is a very common glomerulonephritis and can result in end-stage renal disease. From a clinical point of view, IgAN is characterised by repeated events of macrohaematuria associated with infections of the upper airways. In IgAN, the IgA released by the tonsillar lymphatic tissue into blood circulation are defective in glycosylation. These aberrant IgA can reach the glomeruli and deposit into mesangium causing an inflammation with cellular proliferation. The treatment is not yet well defined: steroids and immunosuppressive drugs are suggested in cases with a progressive disease. Tonsillectomy was proposed to reduce the infective events of upper airways and the lymphatic tissue producing undergalactosylated IgA. The experiences in literature coming from Asia report positive effects of tonsillectomy on IgAN. In patients with tonsillectomy, the renal signs improved (less haematuria and proteinuria) and the renal outcome was better (slower progression of renal damage). These were uncontrolled studies and tonsillectomy was associated with steroid and immunosuppressive treatment, so it is not possible to tell the real effect of tonsillectomy. In contrast, the European studies reported that the tonsillectomy was not associated with a better outcome of IgAN. A critical review of the subject reveals that most of the papers with positive results were uncontrolled retrospective experiences, while in a randomised controlled trial paper the advantages of tonsillectomy disappeared. In conclusion, this review, in agreement with the international guidelines, concludes that tonsillectomy does not play any role in the progression of IgAN. PMID- 26582218 TI - Fate of the syndesmotic screw--Search for a prudent solution. AB - INTRODUCTION: Ankle fractures are common injuries. Since the recognition of the importance of syndesmotic injury in ankle fractures, much of the scientific work has been focused on concomitant syndesmotic injury. Despite the invention of novel devices for restoration and maintenance of the congruent syndesmosis following syndesmotic injury, the metallic syndesmotic screw is still considered to be the "gold standard". The aim of this study was to compare the clinical results in patients who retained the syndesmosis screw with those in whom the screw was removed following open reduction and internal fixation of the malleolar fracture associated with syndesmosis disruption. MATERIALS AND METHODS: This was a retrospective study of 82 patients. Minimum follow-up was 12 months. Clinical evaluation included American Orthopaedic Foot and Ankle Society (AOFAS) score and Visual Analogue Scale (VAS) for patient general satisfaction. The condition of the screw (removed, intact or broken), presence of radiolucency around the syndesmotic screw and the tibiofibular clear space were recorded using final follow-up radiographs. RESULTS: Three cortices were engaged in 66 patients (80%) and quadricortical fixation was performed in the remaining 16 patients (20%). The number of engaged cortices did not correlate with the clinical outcome and screw fracture. A single syndesmotic screw was used in 71 patients (86%. The mean AOFAS score in the group with intact screw (I) was 83; the scores in the group with broken screw (B) and removed screw (R) were 92.5 and 85.5, respectively. There was a statistically significant difference between the three groups: this was due to the difference between groups I and B; the difference between groups I and R and groups B and R were not statistically significant. There were no statistically significant differences in VAS results. CONCLUSION: There were no statistically significant differences in clinical outcome between the group with the screw retained and the group in which the screw was removed; however, the group with broken screws had the best clinical outcome based on AOFAS score. Widening of the syndesmosis after screw removal was not evident. We do not recommend routine syndesmosis screw removal. PMID- 26582219 TI - Pattern of emergency room mortality among road traffic crash victims. AB - Road traffic injuries are a major cause of death in the emergency room. The goal of this study was to highlight the demographic pattern of road traffic-related deaths in the accident and emergency room of a regional trauma centre. This was a 5-year retrospective study in which road traffic-related cases of emergency room mortality between June 2009 and June 2014 were reviewed. A total of 33 road traffic crash-related deaths occurred during this period with a male-to-female ratio of 2.3:1. Most of these patients were pedestrians with severe injuries involving two or more Abbreviated Injury Scale (AIS) coded regions. The mean time between injury and presentation in the first trauma facility was 112.1 (+/ 55.4)min, and between presentation in the emergency room and death was 410 (+/ 645)min. Mangled lower extremity, bilateral long bone lower limb fractures, pelvic injuries, blunt injuries to the chest and abdomen, and cranial fossae fractures were the common injury pattern. Median ISS and NISS in these patients were 22 (interquartile range [IQR]=11) and 25 (IQR=17), respectively. Severe injuries, delayed presentation, multiple referrals and delayed resuscitative measures contribute to road traffic crash-related mortality. PMID- 26582220 TI - [Effect of TRAF6 Downregulation on Malignant Biological Behavior of?Lung Cancer Cell Lines]. AB - BACKGROUND AND OBJECTIVE: It has been proven that tumor necrosis factor receptor associated factor 6 (TRAF6) was a commonly amplified oncogene in lung cancer. However, the precise role of TRAF6 protein in lung cancer has not been extensively investigated. This study analyzed the effects of TRAF6 on the proliferation, apoptosis, cell cycle, migration, and invasion capability of lung cancer cell lines, as well as the potential molecular mechanisms involved. METHODS: To address the expression of TRAF6 in lung cancer cells, four lung cancer cell lines (A549, H1650, SPC-A-1 and Calu-3) were assayed to determine the expression of TRAF6 protein by Western blot and TRAF6 mRNA via qRT-PCR. Moreover, siRNA targeting TRAF6 was introduced into SPC-A-1 and Calu-3 cells. Nuclear factor-?B (NF-?B) DNA-binding activity, apoptosis rates, cell proliferation, cell cycle, migration, and invasion were determined by electrophoretic mobility shift assay, flow cytometry, MTS assay, flow cytometry, scratch test, and transwell chamber assay, respectively. Western blot analysis was also performed to evaluate the expression of the following proteins through K63-ubiquitination: P65, CD24 and CXCR4. Whole-genome sequencing analysis was conducted using a second generation sequencer in SPC-A-1 cells. RESULTS: TRAF6 was highly up-expressed in SPC-A-1 and Calu-3 cell lines than the other two cells, which also showed K63 ubiquitinization in TRAF6. However, constitutive activation of NF-?B was observed only in SPC-A-1 lung cancer cells. Downregulation of TRAF6 suppressed the NF kappaB activation, cell migration, and invasion but promoted the cell apoptosis of SPC-A-1 cells. Markedly decreased expression of CD24 and CXCR4 was observed in SPC-A-1 cells transfected by TRAF6 siRNA. Nevertheless, TRAF6 downregulation did not affect the proliferation and cell cycle of SPC-A-1 cells. Additionally, TRAF6 regulation did not affect the proliferation, apoptosis, cell cycle, migration, and invasion of Calu-3 cells. No mutations and no changes in gene copy numbers of TRAF6 were found by whole-exome sequencing of SPC-A-1 cells. CONCLUSIONS: TRAF6 may be involved in cell migration, invasion, and apoptosis of SPC-A-1 cells, possibly through regulating the NF-?B-CD24/CXCR4 pathway.?. PMID- 26582221 TI - [The Supernatant Obtained from Cultured Anip973 Cells Enhances the Biological Activities of HUVEC]. AB - BACKGROUND AND OBJECTIVE: Unlike normal tissue-derived microvascular endothelial cells, tumor microvessel endothelial cells are highly reactive to growth factors and exhibit more adhesion molecules. Thus, vascular tumors are highly permeable and grow vigorously; this occurrence results in rapid growth and metastasis cancer cells. Therefore, understanding the characteristics of endothelial cells in the tumor microenvironment guides anti-angiogenic therapy. To this end, we explore the effect of the supernatant obtained from cultured Anip973 cells (high metastatic human lung adenocarcinoma cells) on the biological behavior and on the cell surface markers of the human umbilical vein endothelial cell (HUVEC). METHODS: The HUVEC that was cultured in a medium (RPMI-1640 + 10% fetal bovine serum) containing various concentrations of Anip973 supernatants was categorized into experimental groups. The HUVEC cultured in a medium without Anip973 supernatants served as the control group. Proliferation was determined with CCK 8; blood vessel formation was investigated with three-dimensional culture techniques in vitro; and HUVEC migration was observed via transwell assay. At the same time, the expressions of CD105, CD31, and the apoptotic marker of Annexin V were detected through flow cytometry for analyzing the relationship between the expression of cell surface markers and biological behavior. RESULTS: Following incubation with the supernatant obtained from cultured Anip973 cells, HUVEC proliferated more than the control group did, and the proliferation rate was maximized when incubated in a supernatant concentration of 250 MUL/mL for 24 h (P=0.002). In addition, the experimental groups exhibited varying degrees of migration and forms of vascular lumen sample structure, especially at supernatant concentrations of 125 uL/mL (P<0.001) and 250 uL/mL (P=0.002), respectively. CD105 expression was optimized at 250 MUL/mL (P=0.028), and CD31 expression also increased with an increase in concentration. However, the percentage of apoptotic cells decreased. Correlation analysis results showed that cell proliferation, migration, and CD105 expression were significantly and positively correlated with one another. By contrast, no significant correlation was detected between CD31 expression and biological behavior. CONCLUSIONS: Anip973 supernatants can promote HUVEC proliferation and migration, as well as angiogenesis. In addition, cell surface markers can change concurrently and relatively. To a certain extent, changes in CD105 expression can be attributed to shifts in its biological behavior.?. PMID- 26582222 TI - [Investigational Study of Mesenchymal Stem Cells on Lung Cancer Cell Proliferation and Invasion]. AB - BACKGROUND AND OBJECTIVE: Mesenchymal stem cells (MSC) are adult stem cells derived from mesoderm. Evidence has shown that MSC could migrate towards tumor tissue and differentiate into tumor associated fibroblast in tumor microenvironment, which influences tumor growth and metastasis. However, the reports of MSC in non-small cell lung cancer (NSCLC) are few and controversial. The aim of this study is to explore the chemotaxis of MSC towards NSCLC and to test the effects of MSC on the proliferation and invasion ability of NSCLC. METHODS: Transwell assay was used to test MSC and NSCLC migration and invasion, and Thymidine incorporation assay was adopted to measure NSCLC cells proliferation. The expression of interleukin-6 (IL-6), insulinlike growth factor (IGF-1), vascular endothelial growth factor (VEGF) and dickkopf-related protein 1 (DKK1) of MSCs were determined by real time PCR. A549 lung cancer xenograft animal tumor model was set up to evaluate the MSC effect in vivo. RESULTS: Lung cancer cells could attract MSC tropism. MSC conditioned medium favored lung cancer cell proliferation and lung cancer cells stimulated the expression of IL 6, IGF-1, VEGF and DKK1 on MSCs. In vivo animal study showed that the tumor with MSC injection grew much faster compared to control group. CONCLUSIONS: MSCs could migrate towards NSCLC cells and favor tumor growth. In turn, NSCLC cells could stimulate the overexpression of cytokines on MSCs which are essential for the tumor growth. PMID- 26582223 TI - [Computed Tomography Guided Hook-wire Precise Localization and Minimally Invasive Resection of Pulmonary Nodules]. AB - BACKGROUND AND OBJECTIVE: Localization of pulmonary ground glass nodule is the technical difficulty of minimally invasive operation resection. The aim of this study is to evaluate the value of computed tomography (CT)-guided Hook-wire precise localization in resection of pulmonary nodules by video-assisted thoracoscopic surgery (VATS) as well as to discuss the necessity and feasibility of surgical resection of GGOs through a minimally invasive approach. METHODS: CT guided Hook-wire precise localization and wedge resection was done on 25 cases with 26 pulmonary nodules by VATS from May 2013 to June 2015. The efficacy of localization was evaluated in terms of procedure time, VATS success rate, and associated complications of localization. RESULTS: All the 26 pulmonary nodules (6 solid nodules and 20 GGOs ) of 25 patients (10 males and 15 females) were preoperatively detected and localized with Hook-wire under CT guidance. Nodule diameters ranged from 5 mm-20 mm (mean: 8 mm). The distance of lung lesions from the nearest pleural surfaces ranged within 5 mm-30 mm (mean: 14 mm). All resections of lesions guided by the Hook-wire were successfully performed by VATS (success rate: 100%). The mean procedure time for the CT-guided Hook-wire localization was 10 min (range: 5 min-10 min). The mean procedure time for VATS wedge resection was 20 min (range: 15 min-40 min). The mean hospital time was 4 d (range: 3 d-6 d). The major complication of CT-guided Hook-wire localization was mild pneumothorax in 4 patients, but no one needed chest tube drainage. Wedge resection was performed successfully in all cases. The dislocation of Hook-wire was found in only one patient during the operation, but the lesion was still successfully resected under VATS. Results of pathological examination of 16 mGGOs revealed 8 primary lung cancers and 8 nonspecific chronic inflammations. Results of pathological examination of 4 pGGOs revealed 1 primary lung cancers, 1 atypical adenomatous hyperplasia (AAH), and 2 nonspecific chronic inflammations. CONCLUSIONS: The preoperative CT-guided Hook-wire localization for pulmonary nodules particularly for GGOs is an effective and safe technique to assist VATS resection of the nodules. It can increase the ratio of lung wedge resection with little complications and may be better used in clinical diagnosis and treatment of small pulmonary nodules with VATS. Lung mGGOs carry a high risk of malignancy. Aggressive surgical resection of these mGGOs is necessary and feasible. PMID- 26582224 TI - [Detection and Analysis of EGFR and KRAS Mutation with Lung Adenocarcinoma]. AB - BACKGROUND AND OBJECTIVE: Mutations in epidermal growth factor receptor (EGFR) and KRAS are important markers in non-small cell lung cancer, which are closely related to the clinical therapeutic effect. To analysis the EGFR and KRAS gene mutation rate and its relationship with clinical features in patients with lung adenocarcinoma. METHODS: 395 patients with treatment naive lung adenocarcinoma, tumor tissue samples were available for testing. Tumor sample EGFR and KRAS mutation status were detected using mutant enriched liquidchip. RESULTS: 395 cases of lung adenocarcinoma, EGFR mutations were detected in 192 cases (48.9%), KRAS mutations were detected in 29 cases (7.8%), and the presence of EGFR and KRAS mutation were detected in 1 case (0.3%). EGFR mutations were found to occur significantly more often in female than in male patients (62.0% vs 37.1%, P<0.001) and in never smokers than in smokers (61.9% vs 30.3%, P<0.001), no significant differences were observed in age, stage and different biopsy type. KRAS mutations were not found to have statistical significance (P>0.05) in each clinical factors, only occurred in the wild type EGFR gene in patients (13.5%, 27/200) was significantly higher than that of patients with EGFR mutation (1.0%, 2/192), the difference was statistically significant (P<0.001). CONCLUSIONS: In lung adenocarcinomas, EGFR mutation was higher in female and non-smoking patients, KRAS mutation only in patients with wild-type EGFR gene was higher. Before using TKI targeted therapy, EGFR and KRAS mutations should be detected.? PMID- 26582225 TI - [Value of Detection of CAIX in the Pleural Effusion and Its Sediment in the Diagnosis of Lung Cancer]. AB - BACKGROUND AND OBJECTIVE: Carbonic anhydrase IX (CAIX) is widely expressed in a variety of malignant tumors, including-lung cancer. Our previous study has shown that the serum level of soluble form of carbonic anhydrase IX (s-CAIX) was significantly higher in patients with lung cancer than that in the healthy group. The aim of this study is to detect the s-CAIX level in the pleural effusion and its sediment, and to evaluate the significance of CAIX detection in the diagnosis of lung cancer. METHODS: The s-CAIX level in pleural effusion of 29 lung cancer patients and 27 patients with tuberculosis was detected by ELISA. The expression of CAIX in the pleural effusion sediment of 21 lung cancer patients with malignant pleural effusion and 6 patients with benign pleural effusion was examined by immunohistochemistry. With pathological diagnosis as the gold standard, receiver operating characteristic (ROC) curve of pleural effusion s CAIX was established for the diagnosis of lung cancer with malignant pleural effusion. RESULTS: The s-CAIX level in the malignant pleural effusion was significantly higher than that in the tuberculosis group (P<0.05). The AUC of pleural effusion s-CAIX level was 0.761. At a threshold level of 109.135 pg/mL, sensitivity and specificity were 92.3% and 58.3%, respectively. The CAIX expression in all samples of the benign pleural effusion sediment was negative. The positive rate of CAIX expression in malignant pleural effusion sediment was 66.67%. CONCLUSIONS: Detection of CAIX in the pleural effusion and its sediment exhibits high sensitivity and specificity, and is helpful in diagnosis of lung cancer with malignant pleural effusion. PMID- 26582226 TI - [Anterior or Posterior Approach with Video-assisted Thoracoscopic Surgery for Superior Sulcus Tumors]. AB - BACKGROUND AND OBJECTIVE: The surgical resection for pancoast tumors remains challenging. There are only few reports explaining the use of VATS in the treatment of Pancoast tumors. The aim of this study is to assess whether the use of video-assisted thoracoscopic surgery (VATS) for the surgical treatment of Pancoast tumors was feasible and safe. METHODS: Between Janunary 2010 and June 2013, ten patients who were diagnosed as Pancoast tumors were recruited. Six patients were accepted for surgical treatment either through an anterior (n=3) or a posterior approach (n=3) combined with VATS. The observation index of this study included: Operation safety and mortality; The integrity of the tumor resection; General data of operation and postoperative complications; Tumor recurrence and metastasis at twelve months after operation. RESULTS: There were no perioperative deaths. The average time of operation time was 242 min. The radical en bloc resection of the involved chest wall were done in each patients. The average amount of blood loss was 308 mL and the average time of hospital stay was 14 d. Only one patient had postoperative pneumonia and recovered after use of antibiotics. There was none of severe postoperative complications. No patient developed a local recurrence or distant metastasis within twelve months. CONCLUSIONS: The use of VATS has practical value in the management of Pancoast tumors. It is useful to make an accurate extent of the resection of chest-wall and provides a better exposure. Anterior or posterior approach with VATS surgery can facilitate the safety management of Pancoast tumors. PMID- 26582227 TI - [Advances of Pulmonary Adenocarcinoma with Micropapillary Pattern]. AB - Lung adenocarcinoma with micropapillary pattern (MPP) is a kind of rare high invasive malignant tumor, which has been noticed because of high mortality. In 2011, the new pathological classification of lung adenocarcinoma classify it as an independent pathological type, researches on the individual treatment of the disease had been gradually expanded. Recent studies have demonstrated that lung adenocarcinoma with MPP has obvious heterogeneities in metastasis mechanism, clinical pathology, imageology, therapeusis and prognosis. In this paper, we discuss the progress of metastasis mechanism and clinical relevance in lung adenocarcinoma with MPP. PMID- 26582228 TI - [Clinical Research Progress of Anti PD-1/PD-L1 Monoclonal Antibody in the Treatment of Lung Cancer]. AB - Recently, the immune checkpoint inhibitors which target programmed death-1 (PD 1)/PD-1 ligand (PD-L1) have made a breakthrough in the treatment of advanced non small cell lung cancer. Researches on immune checkpoint inhibitors have been rapidly implemented in various types of lung cancer, such as small cell lung cancer and locally advanced non-small cell lung cancer. These inhibitors have been applied in combination with other treatment strategies, including chemotherapy, targeting therapy and radiotherapy. However, there are still many problems to be solved, such as searching for ideal biomarkers, exploring different combination treatment models, and identifying the potential mechanisms of primary or secondary drug resistance. Along with these problems to be successfully solved, the immune checkpoint inhibitors will have broader applications in lung cancer therapy. PMID- 26582229 TI - [Advances in Research of Osteopontion and Its Receptor CD44v in Tumor Invasion and Metastasis]. AB - Osteopontin (OPN) is a multifunctional, extracellular matrix-associated, secretory, glyco-protein. It can be used as an adhesion protein involved in tumor cell adhesion,migration; but also as a cytokine, promoting tumor angiogenesis, evading immune surveillance and inhibiting cellular apoptosis. CD44v glycoprotein, is one of the cell surface adhesion molecule that mediates cell matrix and cell-cell interactions. Extensive research has suggested the important role of OPN in regulating signaling pathways that contribute to tumor progression and metastasis, and the serum level is associated with the prognosis of various malignancies. Therefore, clarifying OPN in the molecular mechanisms of tumor progression and its signaling pathway contributes to seeking a novel anti-cancer therapy. PMID- 26582230 TI - Combined Double Sleeve Lobectomy and Superior Vena Cava Resection for Non-small Cell Lung Cancer with Persistent Left Superior Vena Cava. AB - A 65-year-old man with right central type of lung squamous carcinoma was admitted to our department. Bronchoscopy displayed complete obstruction of right upper lobe bronchus and infiltration of the bronchus intermedius with tumor. Chest contrast computed tomography revealed the tumor invaded right pulmonary artery, superior vena cava, and the persistant left superior vena cava flowed into the coronary sinus. The tumor was successfully removed by means of bronchial and pulmonary artery sleeve resection of the right upper and middle lobes combined with resection and reconstruction of superior vena cava (SVC) utilizing ringed polytetrafluoroethylene graft. To the best of our knowledge, this was the first report of complete resection of locally advanced lung cancer involving superior vena cava, right pulmonary artery trunk and main bronchus with persistant left superior vena cava. PMID- 26582231 TI - Marivivens donghaensis gen. nov., sp. nov., isolated from seawater. AB - A Gram-stain-negative, non-flagellated, aerobic and coccoid, ovoid or rod-shaped bacterium, designated AM-4T, was isolated from seawater collected from the East Sea, South Korea and subjected to a taxonomic study using a polyphasic approach. The novel strain grew optimally at 30-35 degrees C, at pH 7.0-8.0 and in the presence of 1.0-3.0 % (w/v) NaCl. Phylogenetic trees based on 16S rRNA gene sequences showed that strain AM-4T forms a distinct evolutionary lineage independent of other taxa of the family Rhodobacteraceae. Strain AM-4T exhibited 16S rRNA gene sequence similarities of 95.1-95.5 % to the type strains of Aestuariihabitans beolgyonensis, Donghicola eburneus and Pseudooctadecabacter jejudonensis, and of less than 94.9 % to the type strains of other taxa. Strain AM-4T contained Q-10 as the predominant ubiquinone and C18 : 1omega7c and C16 : 0 as the major fatty acids. The major polar lipids detected in strain AM-4T were phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, one unidentified lipid, one unidentified aminolipid and one unidentified glycolipid. The fatty acid and polar lipid profiles of strain AM-4T were distinguished from those of the phylogenetically related taxa. The DNA G+C content of strain AM-4T was 57.2 mol%. On the basis of the phylogenetic, chemotaxonomic and other phenotypic properties, strain AM-4T represents a novel species of a new genus in the family Rhodobacteraceae, for which the name Marivivens donghaensis gen. nov., sp. nov., is proposed. The type strain of the type species is AM-4T ( = KCTC 42776T = CECT 8947T). PMID- 26582232 TI - Post-operative shoulder imbalance in adolescent idiopathic scoliosis: a study of clinical photographs. AB - STUDY DESIGN: Retrospective observational study. OBJECTIVE: To assess what features determine post-operative shoulder asymmetry in Adolescent Idiopathic Scoliosis (AIS). SUMMARY OF BACKGROUND DATA: Shoulder balance is one of the major determinants of the cosmetic outcomes of AIS surgery. Yet, other than level of the shoulders we are not clear what parameters are to be measured to assess torso symmetry. This study looks at the various features that might affect the appearance of the shoulder region. METHODS: The records of 157 operated cases of AIS were retrospectively reviewed. Eight patients with documented post-operative shoulder asymmetry and were dissatisfied with their cosmetic outcomes were selected for the study. Their clinical photographs alone were studied. Three regions- the base of the neck, the shoulder and upper arm region- were analysed separately. Four measures each for the neck and shoulder and two for the arms were documented. No statistical tools were employed since the numbers were quite small but consensus was obtained between two Consultant Orthopaedic surgeons regarding the cosmetic impact of each parameter. RESULTS: The neck and the shoulder appeared independent determinants of cosmesis of the proximal trunk. The base of neck symmetry seemed to be dependent on four features viz. centralization of the neck, neck tilt, trapezius angle and base of neck angle. The appearance of the shoulder itself depended on its level, axillary fold level, scapular level and the scapular prominence. The upper arm parameters appeared less critical in determining the cosmetic impact. CONCLUSIONS: Proximal trunk symmetry in AIS depends on the symmetry of the base of the neck and shoulder regions. The level of the shoulders, axillary folds along with the base of neck angle, Trapezius angle appear to be key determinants of symmetry. PMID- 26582233 TI - Retinoic Acid Prevents Disruption of Blood-Spinal Cord Barrier by Inducing Autophagic Flux After Spinal Cord Injury. AB - Spinal cord injury (SCI) induces the disruption of the blood-spinal cord barrier (BSCB), which leads to infiltration of blood cells, inflammatory responses and neuronal cell death, with subsequent development of spinal cord secondary damage. Recent reports pointed to an important role of retinoic acid (RA), the active metabolite of the vitamin A, in the induction of the blood-brain barrier (BBB) during human and mouse development, however, it is unknown whether RA plays a role in maintaining BSCB integrity under the pathological conditions such as SCI. In this study, we investigated the BSCB protective role of RA both in vivo and in vitro and demonstrated that autophagy are involved in the BSCB protective effect of RA. Our data show that RA attenuated BSCB permeability and also attenuated the loss of tight junction molecules such as P120, beta-catenin, Occludin and Claudin5 after injury in vivo as well as in brain microvascular endothelial cells. In addition, RA administration improved functional recovery of the rat model of trauma. We also found that RA could significantly increase the expression of LC3-II and decrease the expression of p62 both in vivo and in vitro. Furthermore, combining RA with the autophagy inhibitor chloroquine (CQ) partially abolished its protective effect on the BSCB and exacerbated the loss of tight junctions. Together, our studies indicate that RA improved functional recovery in part by the prevention of BSCB disruption via the activation of autophagic flux after SCI. PMID- 26582236 TI - Evidence-Based Medicine as a Tool for Undergraduate Probability and Statistics Education. AB - Most students have difficulty reasoning about chance events, and misconceptions regarding probability can persist or even strengthen following traditional instruction. Many biostatistics classes sidestep this problem by prioritizing exploratory data analysis over probability. However, probability itself, in addition to statistics, is essential both to the biology curriculum and to informed decision making in daily life. One area in which probability is particularly important is medicine. Given the preponderance of pre health students, in addition to more general interest in medicine, we capitalized on students' intrinsic motivation in this area to teach both probability and statistics. We use the randomized controlled trial as the centerpiece of the course, because it exemplifies the most salient features of the scientific method, and the application of critical thinking to medicine. The other two pillars of the course are biomedical applications of Bayes' theorem and science and society content. Backward design from these three overarching aims was used to select appropriate probability and statistics content, with a focus on eliciting and countering previously documented misconceptions in their medical context. Pretest/posttest assessments using the Quantitative Reasoning Quotient and Attitudes Toward Statistics instruments are positive, bucking several negative trends previously reported in statistics education. PMID- 26582234 TI - Regulating Factors in Acid-Sensing Ion Channel 1a Function. AB - In recent years, research of acid sensing ion channels (ASICs) has increased tremendously, especially studies focusing on ASIC1a, which plays a critical role in many important physiologic and pathological functions. This review will discuss factors regulating ASIC1a expression and activity in various conditions and will provide a theoretical basis for clinical development and application of ASIC1a modifiers. PMID- 26582237 TI - Beyond the Biology: A Systematic Investigation of Noncontent Instructor Talk in an Introductory Biology Course. AB - Instructors create classroom environments that have the potential to impact learning by affecting student motivation, resistance, and self-efficacy. However, despite the critical importance of the learning environment in increasing conceptual understanding, little research has investigated what instructors say and do to create learning environments in college biology classrooms. We systematically investigated the language used by instructors that does not directly relate to course content and defined the construct of Instructor Talk. Transcripts were generated from a semester-long, cotaught introductory biology course (n = 270 students). Transcripts were analyzed using a grounded theory approach to identify emergent categories of Instructor Talk. The five emergent categories from analysis of more than 600 quotes were, in order of prevalence, 1) Building the Instructor/Student Relationship, 2) Establishing Classroom Culture, 3) Explaining Pedagogical Choices, 4) Sharing Personal Experiences, and 5) Unmasking Science. Instances of Instructor Talk were present in every class session analyzed and ranged from six to 68 quotes per session. The Instructor Talk framework is a novel research variable that could yield insights into instructor effectiveness, origins of student resistance, and methods for overcoming stereotype threat. Additionally, it holds promise in professional development settings to assist instructors in reflecting on the learning environments they create. PMID- 26582238 TI - Career Development among American Biomedical Postdocs. AB - Recent biomedical workforce policy efforts have centered on enhancing career preparation for trainees, and increasing diversity in the research workforce. Postdoctoral scientists, or postdocs, are among those most directly impacted by such initiatives, yet their career development remains understudied. This study reports results from a 2012 national survey of 1002 American biomedical postdocs. On average, postdocs reported increased knowledge about career options but lower clarity about their career goals relative to PhD entry. The majority of postdocs were offered structured career development at their postdoctoral institutions, but less than one-third received this from their graduate departments. Postdocs from all social backgrounds reported significant declines in interest in faculty careers at research-intensive universities and increased interest in nonresearch careers; however, there were differences in the magnitude and period of training during which these changes occurred across gender and race/ethnicity. Group differences in interest in faculty careers were explained by career interest differences formed during graduate school but not by differences in research productivity, research self-efficacy, or advisor relationships. These findings point to the need for enhanced career development earlier in the training process, and interventions sensitive to distinctive patterns of interest development across social identity groups. PMID- 26582239 TI - Genes related to mitochondrial functions are differentially expressed in phosphine-resistant and -susceptible Tribolium castaneum. AB - BACKGROUND: Phosphine is a valuable fumigant to control pest populations in stored grains and grain products. However, recent studies indicate a substantial increase in phosphine resistance in stored product pests worldwide. RESULTS: To understand the molecular bases of phosphine resistance in insects, we used RNA Seq to compare gene expression in phosphine-resistant and susceptible laboratory populations of the red flour beetle, Tribolium castaneum. Each population was evaluated as either phosphine-exposed or no phosphine (untreated controls) in triplicate biological replicates (12 samples total). Pairwise analysis indicated there were eight genes differentially expressed between susceptible and resistant insects not exposed to phosphine (i.e., basal expression) or those exposed to phopshine (>8-fold expression and 90 % C.I.). However, 214 genes were differentially expressed among all four treatment groups at a statistically significant level (ANOVA, p < 0.05). Increased expression of 44 cytochrome P450 genes was found in resistant vs. susceptible insects, and phosphine exposure resulted in additional increases of 21 of these genes, five of which were significant among all treatment groups (p < 0.05). Expression of two genes encoding anti-diruetic peptide was 2- to 8-fold reduced in phosphine-resistant insects, and when exposed to phosphine, expression was further reduced 36- to 500 fold compared to susceptible. Phosphine-resistant insects also displayed differential expression of cuticle, carbohydrate, protease, transporter, and many mitochondrial genes, among others. Gene ontology terms associated with mitochondrial functions (oxidation biological processes, monooxygenase and catalytic molecular functions, and iron, heme, and tetrapyyrole binding) were enriched in the significantly differentially expressed dataset. Sequence polymorphism was found in transcripts encoding a known phosphine resistance gene, dihydrolipoamide dehydrogenase, in both susceptible and resistant insects. Phosphine-resistant adults also were resistant to knockdown by the pyrethroid deltamethrin, likely due to the increased cytochrome P450 expression. CONCLUSIONS: Overall, genes associated with the mitochondria were differentially expressed in resistant insects, and these differences may contribute to a reduction in overall metabolism and energy production and/or compensation in resistant insects. These data provide the first gene expression data on the response of phosphine-resistant and -susceptible insects to phosphine exposure, and demonstrate that RNA-Seq is a valuable tool to examine differences in insects that respond differentially to environmental stimuli. PMID- 26582240 TI - LAP TGF-Beta Subset of CD4(+)CD25(+)CD127(-) Treg Cells is Increased and Overexpresses LAP TGF-Beta in Lung Adenocarcinoma Patients. AB - Lung cancer is the leading cause of cancer death worldwide. Adenocarcinoma, the most commonly diagnosed histologic type of lung cancer, is associated with smoking. Cigarette smoke promotes inflammation on the airways, which might be mediated by Th17 cells. This inflammatory environment may contribute to tumor development. In contrast, some reports indicate that tumors may induce immunosuppressive Treg cells to dampen immune reactivity, supporting tumor growth and progression. Thus, we aimed to analyze whether chronic inflammation or immunosuppression predominates at the systemic level in lung adenocarcinoma patients, and several cytokines and Th17 and Treg cells were studied. Higher proportions of IL-17-producing CD4(+) T-cells were found in smoking control subjects and in lung adenocarcinoma patients compared to nonsmoking control subjects. In addition, lung adenocarcinoma patients increased both plasma concentrations of IL-2, IL-4, IL-6, and IL-10, and proportions of Latency Associated Peptide (LAP) TGF-beta subset of CD4(+)CD25(+)CD127(-) Treg cells, which overexpressed LAP TGF-beta. This knowledge may lead to the development of immunotherapies that could inhibit the suppressor activity mediated by the LAP TGF-beta subset of CD4(+)CD25(+)CD127(-) Treg cells to promote reactivity of immune cells against lung adenocarcinoma cells. PMID- 26582241 TI - Progress in the development of protein biomarkers of oesophageal and gastric cancers. AB - Upper gastrointestinal cancers originating in the oesophagus and stomach often present late and have a very poor prognosis. Treatment options include surgery for localised disease but, increasingly, neoadjuvant chemotherapy and radiotherapy are being employed to improve outcome. There is often a variable response to neoadjuvant treatment between individual patients and side effects are relatively common. There is an urgent need for novel biomarkers of upper gastrointestinal cancer, not only to improve screening and early diagnosis of the oesophageal and gastric cancers when treatment options are potentially more effective, but also to accurately guide therapy in more advanced disease. The development of predictive biomarkers will also help to more effectively identify those patients that will benefit from targeted therapies. Although many promising results have been derived from these studies there remains a lack of validated clinically applicable biomarkers available for translation into routine clinical use. This review will provide an overview of the recent proteomic research on upper gastrointestinal cancer protein biomarker identification and validation. The challenges faced in the development of validated, clinically acceptable and accurate protein biomarkers will also be discussed, along with possible areas of future progress. PMID- 26582242 TI - Effect of Lymph Node Count on Pathological Stage III Rectal Cancer with Preoperative Radiotherapy. AB - Lymph node (LN) status after surgery for rectal cancer is affected by preoperative radiotherapy. The purpose of this study was to perform a population based evaluation of the impact of pathologic LN status after neoadjuvant radiotherapy on survival. A total of 1,650 patients receiving neoadjuvant chemotherapy in Surveillance, Epidemiology, and End Results Program (SEER) registered ypIII stage rectal cancer was analyzed. We identified the optimal cutoff for retrieved LNs as 10 (chi2 = 14.006, P < 0.001), which was validated as an independent prognosis factors in a Cox regression model. Further analysis showed that the LN count was only a prognosis factor with the number from 8 to 16(except for 13).After the number 16, the 5-year survival rate decreased gradually. Collectively, our results confirmed that the number of LNs in yp III stage rectal patients was a prognosis factor only with the numbers from 8 to 16(except for 13). Using the total mesorectal excision technique with an adequate pathologic examination, a large number of LNs retrieved (>=17) might indicate worse tumor response grade and poorer survival. PMID- 26582243 TI - Enhancing Breast Cancer Recurrence Algorithms Through Selective Use of Medical Record Data. AB - BACKGROUND: The utility of data-based algorithms in research has been questioned because of errors in identification of cancer recurrences. We adapted previously published breast cancer recurrence algorithms, selectively using medical record (MR) data to improve classification. METHODS: We evaluated second breast cancer event (SBCE) and recurrence-specific algorithms previously published by Chubak and colleagues in 1535 women from the Life After Cancer Epidemiology (LACE) and 225 women from the Women's Health Initiative cohorts and compared classification statistics to published values. We also sought to improve classification with minimal MR examination. We selected pairs of algorithms-one with high sensitivity/high positive predictive value (PPV) and another with high specificity/high PPV-using MR information to resolve discrepancies between algorithms, properly classifying events based on review; we called this "triangulation." Finally, in LACE, we compared associations between breast cancer survival risk factors and recurrence using MR data, single Chubak algorithms, and triangulation. RESULTS: The SBCE algorithms performed well in identifying SBCE and recurrences. Recurrence-specific algorithms performed more poorly than published except for the high-specificity/high-PPV algorithm, which performed well. The triangulation method (sensitivity = 81.3%, specificity = 99.7%, PPV = 98.1%, NPV = 96.5%) improved recurrence classification over two single algorithms (sensitivity = 57.1%, specificity = 95.5%, PPV = 71.3%, NPV = 91.9%; and sensitivity = 74.6%, specificity = 97.3%, PPV = 84.7%, NPV = 95.1%), with 10.6% MR review. Triangulation performed well in survival risk factor analyses vs analyses using MR-identified recurrences. CONCLUSIONS: Use of multiple recurrence algorithms in administrative data, in combination with selective examination of MR data, may improve recurrence data quality and reduce research costs. PMID- 26582244 TI - Maintenance Therapy With Immunomodulatory Drugs in Multiple Myeloma: A Meta Analysis and Systematic Review. AB - BACKGROUND: Immunomodulatory drugs (IMiDs) and proteasome inhibitors have dramatically changed management of multiple myeloma (MM). While MM remains incurable, consolidation and maintenance therapy aimed at improving duration of response can potentially improve survival outcomes. A majority of randomized controlled trials (RCTs) have demonstrated benefit of IMiD-based maintenance therapy in delaying disease progression; however, whether this therapy can lead to improved survival remains controversial. METHODS: PubMed and abstract databases of major hematology and/or oncology meetings were searched for RCTs that studied maintenance therapy with IMiDs in MM. A meta-analysis was conducted to systematically evaluate the impact of IMiD-based maintenance therapy on survival outcomes and serious adverse events associated with the therapy. All statistical tests were two-sided. RESULTS: Eighteen phase 3 RCTs enrolling 7730 patients were included. IMiD-based maintenance therapy statistically significantly prolonged progression-free survival (PFS; hazard ratio (HR) = 0.62, 95% confidence interval (CI) = 0.57 to 0.67, P < .001) but failed to improve overall survival (OS; HR = 0.93, 95% CI = 0.85 to 1.01, P = .082). Stratified analyses demonstrated that both thalidomide and lenalidomide provided PFS but not OS benefit in transplantation as well as nontransplantation settings. IMiD-based maintenance therapy in MM led to a higher risk of grade 3-4 thromboembolism (risk ratio = 2.52, 95% CI = 1.41 to 4.52, P = .002). Thalidomide maintenance therapy increased the risk of peripheral neuropathy; lenalidomide maintenance therapy increased the risks of myelosuppression and second primary hematological malignancies. CONCLUSIONS: Thalidomide- or lenalidomide-based maintenance therapy improves PFS but not OS in MM and increases risks of grade 3-4 adverse events, including thromboembolism, peripheral neuropathy, neutropenia, and infection. PMID- 26582245 TI - Recognizing the Limitations of Cancer Overdiagnosis Studies: A First Step Towards Overcoming Them. AB - Numerous studies have attempted to quantify the number of breast cancers that would never have been diagnosed in the absence of screening. Unfortunately, results are highly variable across studies and there is considerable disagreement about both the frequency of overdiagnosis and the validity of different methodologic approaches. In this Commentary, we review limitations of the two major approaches used in existing studies. Studies that use excess incidence as a proxy for overdiagnosis require a valid estimate of incidence in the absence of screening and sufficient follow-up to ensure the excess excludes relevant (ie, nonoverdiagnosed) cancers detected early. The requirement of sufficient follow-up applies to both population studies and clinical trials, but only certain clinical trial designs have the potential to yield unbiased results. Studies that model disease natural history to infer overdiagnosis must, in addition, examine whether their models produce valid estimates in the presence of nonprogressive cases. In this setting, limited follow-up could lead to a lack of identifiability of the parameters needed to accurately infer overdiagnosis. In a polarized research community, the excess incidence and modeling approaches are generally viewed as competitors, but we argue that they are complementary, with models being more complex but having greater potential to inform about disease natural history and the outcomes of candidate screening policies. Rather than arguing why one approach should be preferred to another, investigators should focus on developing studies that generate reliable estimates of overdiagnosis. Recognizing that both approaches have limitations, which existing studies rarely overcome, is a first step towards reconciling methodologic perspectives and achieving consensus about the real magnitude of the overdiagnosis problem. PMID- 26582246 TI - The apoB100/apoAI ratio is independently associated with the severity of coronary heart disease: a cross sectional study in patients undergoing coronary angiography. AB - BACKGROUND: Lipoprotein ratios have been shown to be associated with the occurrence of coronary heart disease (CHD), but little is known about their relationships with the severity of CHD. METHODS: A total of 792 angiographically defined CHD patients were enrolled following their admission. Patients were stratified into three groups based on the tertile of the Gensini scores (<=33(rd) percentile, 33(rd) to 66(th) percentile and >=66(th) percentile) or the number of stenotic coronary branches (single-branch stenosis, double-branch stenosis and multi-branch stenosis). Demographic and biochemical data were collected and lipoprotein ratios were calculated. Logistic regression and path analysis were employed to examine the relationships between the lipoprotein ratios and the severity of CHD. RESULTS: The ratios of low-density lipoprotein cholesterol (LDL C)/high-density lipoprotein cholesterol (HDL-C) and apolipoprotein B100 (apoB100)/apolipoprotein AI (apoAI) increased with the tertile of the Gensini scores (P < 0.05 for both). The ratios of triglyceride (TG)/HDL-C, total cholesterol (TC)/HDL-C, LDL-C/HDL-C and apoB100/apoAI increased with the number of stenotic coronary branches (P < 0.05 for all). The univariate logistic regression showed that the ratios of TC/HDL-C, LDL-C/HDL-C and apoB100/apoAI were positively associated with both the tertile of the Gensini scores and the number of stenotic vessels (P < 0.05 for all), and the ratio of TG/HDL-C was positively associated with the number of stenotic vessels (P < 0.05). In multivariate logistic analysis, only the ratio of apoB100/apoAI was independently and positively associated with the tertile of the Gensini scores (OR = 2.93, 95% CI = 1.17-7.34, P = 0.022) and the number of stenotic vessels (OR = 3.14, 95 % CI = 1.01-6.47, P = 0.048) after adjusting for the possible confounding variables. The apoB100/apoAI ratio was also shown to be a direct mediator between the risk factors including age, BMI, HDL-C, LDL-C, apoB100 and apoAI and the severity of CHD by path analysis. CONCLUSION: Our data indicate that the apoB100/apoAI ratio could be a useful predictor for evaluating the severity of coronary stenosis in CHD patients. PMID- 26582247 TI - Racial disparities and socioeconomic status in the incidence of colorectal cancer in Arizona. AB - BACKGROUND: The prevalence of racial and socioeconomic disparities in the development of colorectal cancer (CRC) is well known; however, statewide variability exits across the United States. The aim of our study was to determine the overall incidence, socioeconomic and racial disparities in the development of CRC in the state of Arizona. METHODS: We performed a 16-year (1995 to 2011) retrospective review of the Arizona Cancer Registry including all patients with CRC. Patient demographics, stage of CRC disease, and patient outcomes were recorded. The outcome measures were incidence of CRC and the difference in racial and economic characteristics among patients. Logistic regression analysis was performed to identify factors associated with the incidence of CRC. RESULTS: A total of 40,314 patients with CRC were included of which 16% (n = 6,450) were stage IV. The overall incidence of CRC decreased 17% over the study period. The highest incidence rates were seen in White non-Hispanic and African American populations. Right-sided tumors were more common in White non-Hispanic and African Americans whereas American Indians had higher incidence of rectal tumors and Asian/Pacific Islanders more commonly had left-sided tumors. African Americans had the highest occurrence (42.8%) of more advanced disease (stage III and stage IV). A negative correlation existed between socioeconomic status and the incidence of CRC. CONCLUSIONS: Overall CRC incidence decreased in Arizona by 17%, with greatest decrease rate among, White non-Hispanic and African American populations. Educated patients with higher economic earnings experienced a lower decrease in the incidence of CRC. PMID- 26582248 TI - Topology-generating interfacial pattern formation during liquid metal dealloying. AB - Liquid metal dealloying has emerged as a novel technique to produce topologically complex nanoporous and nanocomposite structures with ultra-high interfacial area and other unique properties relevant for diverse material applications. This process is empirically known to require the selective dissolution of one element of a multicomponent solid alloy into a liquid metal to obtain desirable structures. However, how structures form is not known. Here we demonstrate, using mesoscale phase-field modelling and experiments, that nano/microstructural pattern formation during dealloying results from the interplay of (i) interfacial spinodal decomposition, forming compositional domain structures enriched in the immiscible element, and (ii) diffusion-coupled growth of the enriched solid phase and the liquid phase into the alloy. We highlight how those two basic mechanisms interact to yield a rich variety of topologically disconnected and connected structures. Moreover, we deduce scaling laws governing microstructural length scales and dealloying kinetics. PMID- 26582250 TI - Towards the emerging crosstalk: ERBB family and steroid hormones. AB - Growth factors acting through receptor tyrosine kinases (RTKs) of ERBB family, along with steroid hormones (SH) acting through nuclear receptors (NRs), are critical signalling mediators of cellular processes. Deregulations of ERBB and steroid hormone receptors are responsible for several diseases, including cancer, thus demonstrating the central role played by both systems. This review will summarize and shed light on an emerging crosstalk between these two important receptor families. How this mutual crosstalk is attained, such as through extensive genomic and non-genomic interactions, will be addressed. In light of recent studies, we will describe how steroid hormones are able to fine-tune ERBB feedback loops, thus impacting on cellular output and providing a new key for understanding the complexity of biological processes in physiological or pathological conditions. In our understanding, the interactions between steroid hormones and RTKs deserve further attention. A system biology approach and advanced technologies for the analysis of RTK-SH crosstalk could lead to major advancements in molecular medicine, providing the basis for new routes of pharmacological intervention in several diseases, including cancer. PMID- 26582251 TI - A piece of the pi(e): The diverse roles of animal piRNAs and their PIWI partners. AB - Small non-coding RNAs are indispensable to many biological processes. A class of endogenous small RNAs, termed PIWI-interacting RNAs (piRNAs) because of their association with PIWI proteins, has known roles in safeguarding the genome against inordinate transposon mobilization, embryonic development, and stem cell regulation, among others. This review discusses the biogenesis of animal piRNAs and their diverse functions together with their PIWI protein partners, both in the germline and in somatic cells, and highlights the evolutionarily conserved aspects of these molecular players in animal biology. PMID- 26582249 TI - Intravenous multipotent adult progenitor cell treatment decreases inflammation leading to functional recovery following spinal cord injury. AB - Following spinal cord injury (SCI), immune-mediated secondary processes exacerbate the extent of permanent neurological deficits. We investigated the capacity of adult bone marrow-derived stem cells, which exhibit immunomodulatory properties, to alter inflammation and promote recovery following SCI. In vitro, we show that human multipotent adult progenitor cells (MAPCs) have the ability to modulate macrophage activation, and prior exposure to MAPC secreted factors can reduce macrophage-mediated axonal dieback of dystrophic axons. Using a contusion model of SCI, we found that intravenous delivery of MAPCs one day, but not immediately, after SCI significantly improves urinary and locomotor recovery, which was associated with marked spinal cord tissue sparing. Intravenous MAPCs altered the immune response in the spinal cord and periphery, however biodistribution studies revealed that no MAPCs were found in the cord and instead preferentially homed to the spleen. Our results demonstrate that MAPCs exert their primary effects in the periphery and provide strong support for the use of these cells in acute human contusive SCI. PMID- 26582252 TI - Women's help-seeking behaviour during a first acute myocardial infarction. AB - Studies indicate that the time from onset of symptoms to medical treatment has decreased in acute myocardial infarction (AMI). However, there are still variations indicating that women wait longer than men before making the decision to seek medical care. Multidimensional factors hindering and facilitating the decision have been identified in previous studies, though few have fully explored how social context affects women's expectations, interpretations and actions and so influences the decision-making process. The aim of this study was therefore to identify how women's experiences interacted and influenced the decision to seek medical care at their first AMI. Seventeen women, aged 38-75 years, were interviewed, at home or in the hospital, between June 2011 and May 2012. Grounded theory was used as a method, and data collection and analysis were carried out simultaneously. The results showed that before deciding to seek medical care, these women went through three defined but interrelated processes that together hindered their normal activities and made them act according to existential needs. The women's experiences of the progression of the disease, in terms of both symptoms and time, were very different, so they sought medical care at different times, sometimes life-threateningly late and sometimes before developing an AMI. Three mechanisms had to coincide if the women were to receive medical care. First, the women had to acknowledge their symptoms as something more than common bodily changes. Second, the healthcare system had to be accessible when the women made their decision to seek care. Third, the women must have come into contact with healthcare providers when the heart muscle had taken enough damage to measure. PMID- 26582253 TI - [A rare cause of acute respiratory failure]. AB - This article describes a case report on a rare cause of acute respiratory failure. The patient suffered from a rapidly progressing respiratory insufficiency due to intoxication with a neurotoxin (botulism). A rapid diagnosis proved to be very difficult due to the rarity of the disease itself and the difficulties encountered in the clinical examination caused by early initiation of intubation, artificial ventilation and analgosedation. PMID- 26582254 TI - [High-flow oxygen therapy in hypoxic respiratory failure : Possible alternative to noninvasive ventilation]. PMID- 26582255 TI - Prevalence and risk factors of premature coronary artery disease in patients undergoing coronary angiography in Kurdistan, Iraq. AB - BACKGROUND: Premature coronary artery disease (PCAD) seems to increase, particularly in developing countries. Given the lack of such studies in the country, this study examines the prevalence, associated cardiovascular risk factors, and coronary angiographic profile of the disease in Iraq. METHODS: Data was collected from a total of 445 adult patients undergoing coronary angiography at Duhok Heart Center, Kurdistan in a period between March and September 2014. Patients were divided into PCAD (male <45 years and female < 55 years) and mature coronary artery disease (MCAD). RESULTS: The prevalence of the angiographically documented PCAD was 31 %. The PCAD had higher rates of hyperlipidemia (p = 0.04), positive family history of coronary artery disease (p = 0.002), type A lesions (p = 0.02), single vessel disease (p = 0.01) and medical treatment (p = 0.01) than the MCAD. Logistic regression model indicated that male sex (OR 3.38, C.I 1.96 7.22), smoking (OR 2.08, C.I 1.05-4.12), hypertension (OR 1.58, C.I 1.25-2.03), hyperlipidemia (OR 1.89, C.I 1.17-2.42) and positive family history of coronary artery disease (OR 2.62, C.I 1.38-9.54) were associated with the PCAD. Sensitivity analysis showed highest specificity (94.2 %) and positive predictive value (96.5 %) in patients with coronary stenosis >70 % compared to lesser obstruction. CONCLUSIONS: Premature coronary artery disease is alarming in the country. Cardiovascular risk factors are clustered among them. But the angiographic profile and therapeutic options of PCAD are close to those reported from previous studies. PMID- 26582256 TI - Hexavalent chromium affects sperm motility by influencing protein tyrosine phosphorylation in the midpiece of boar spermatozoa. AB - Hexavalent chromium reportedly induces reproductive toxicity and further inhibits male fertility in mammals. In this study, we investigated the molecular mechanism by which hexavalent chromium affects motility signaling in boar spermatozoa in vitro. The results indicated that Cr(VI) decreased sperm motility, protein phosphorylation, mitochondrial membrane potential (DeltaPsim) and metabolic enzyme activity starting at 4MUmol/mL following incubation for 1.5h. Notably, all parameters were potently inhibited by 10MUmol/mL Cr, while supplementation with the dibutyryl-cAMP (dbcAMP) and the 3-isobutyl-1-methylxanthine (IBMX) prevented the inhibition of protein phosphorylation. Interestingly, high concentrations of Cr (>10MUmol/mL) increased the tyrosine phosphorylation of some high-molecular weight proteins in the principle piece but decreased that in the middle piece associated with an extreme reduction of sperm motility. These results suggest that chromium affects boar sperm motility by impairing tyrosine phosphorylation in the midpiece of sperm by blocking the cAMP/PKA pathway in boar sperm in vitro. PMID- 26582257 TI - Quaternary ammonium disinfectants cause subfertility in mice by targeting both male and female reproductive processes. AB - Alkyl dimethyl benzyl ammonium chloride (ADBAC) and didecyl dimethyl ammonium chloride (DDAC) are common ingredients in household bathroom and kitchen cleaning sprays. ADBAC+DDAC cause reproductive toxicity in mice. The aim of the present study was to investigate gender-specific reproductive effects from ADBAC+DDAC. Female reproduction was assessed through ovulation, oocyte implantation, and estrus cycling. Male reproductive function was assessed by sperm concentration, motility, and viability. Numbers of corpora lutea were not different after 2 weeks, but decreased after 8 weeks of ADBAC+DDAC exposure. Dams exposed for 5 weeks to ADBAC+DDAC spent significantly less time in estrus. ADBAC+DDAC exposed males exhibited declines in both sperm concentration and motility, but not sperm viability. Subfertility in mice from ADBAC+DDAC exposure is, therefore, mediated through reproductive disturbances in both females and males. While the effect of ADBAC+DDAC exposure on human health is unclear, widespread exposure necessitates further consideration of their potential reproductive toxicity. PMID- 26582258 TI - Structural characterization of highly glucosylated crocins and regulation of their biosynthesis during flower development in Crocus. AB - Crocin biosynthesis in Crocus has been proposed to proceed through a zeaxanthin cleavage pathway catalyzed by carotenoid cleavage dioxygenase 2 (CCD2), and followed by glucosylation reactions catalyzed by CsGT2 (UGT74AD1). In Crocus ancyrensis flowers, crocins with eight (crocin-1), seven (crocin-2), and six glucose (crocin-3) moieties accumulated both in stigma and tepals. We have characterized the structure of these highly glucosylated crocins and follow up their accumulation by high-resolution liquid chromatography coupled with diode array detector along the development of both tissues, and coupled to the isolation and analysis of the expression of eighteen genes (PSY-I, PSY-II, PDS-(I V), ISO-ZDS, ZDS, CtrISO, LYC-I and II, BCH, CaCCD2, UGT74AD2-5) related with the apocarotenoid metabolism in C. ancyrensis tepals and stigmas. Structure elucidation of crocin-1 and crocin-2 was done by the combined use of 1D and 2D [(1)H, (1)H] (gCOSY and TOCSY and ROESY) and [(1)H-(13)C] NMR experiments, revealing that for crocin-1 was all-trans-crocetin O-[beta-D- Glucopyranosyl)-(1 >4)-(beta-D-glucopyranosyl)-(1->2)]-O-[beta-D-glucopyranosyl-(1->6)]-beta-D glucopyranosyl diester, while crocin-2 showed an identical structure except for the absence of one glucose residue in one end of the molecule. Crocins accumulation was not synchronically regulated in stigma and tepals, although in both cases crocins accumulation parallels tissue development, decreasing at anthesis. The expression of the carotenogenic genes PSY, ZDS-V, BCH, and LCY-II was correlated with crocins accumulation. In addition, CaCCD2 and only one of the four glucosyltransferase encoding genes, UGT74AD2, were highly expressed, and the expression was correlated with high levels of crocins accumulation in stigma and tepals. PMID- 26582259 TI - Reverse genetic screen for loss-of-function mutations uncovers a frameshifting deletion in the melanophilin gene accountable for a distinctive coat color in Belgian Blue cattle. AB - In the course of a reverse genetic screen in the Belgian Blue cattle breed, we uncovered a 10-bp deletion (c.87_96del) in the first coding exon of the melanophilin gene (MLPH), which introduces a premature stop codon (p.Glu32Aspfs*1) in the same exon, truncating 94% of the protein. Recessive damaging mutations in the MLPH gene are well known to cause skin, hair, coat or plumage color dilution phenotypes in numerous species, including human, mice, dog, cat, mink, rabbit, chicken and quail. Large-scale array genotyping undertaken to identify p.Glu32Aspfs*1 homozygous mutant animals revealed a mutation frequency of 5% in the breed and allowed for the identification of 10 homozygous mutants. As expression of a colored coat requires at least one wild type allele at the co-dominant Roan locus encoded by the KIT ligand gene (KITLG), homozygous mutants for p.Ala227Asp corresponding with the missense mutation were excluded. The six remaining colored calves displayed a distinctive dilution phenotype as anticipated. This new coat color was named 'cool gray'. It is the first damaging mutation in the MLPH gene described in cattle and extends the already long list of species with diluted color due to recessive mutations in MLPH and broadens the color palette of gray in this breed. PMID- 26582260 TI - Towards Using Microstate-Neurofeedback for the Treatment of Psychotic Symptoms in Schizophrenia. A Feasibility Study in Healthy Participants. AB - Spontaneous EEG signal can be parsed into sub-second periods of stable functional states (microstates) that assumingly correspond to brief large scale synchronization events. In schizophrenia, a specific class of microstate (class "D") has been found to be shorter than in healthy controls and to be correlated with positive symptoms. To explore potential new treatment options in schizophrenia, we tested in healthy controls if neurofeedback training to self regulate microstate D presence is feasible and what learning patterns are observed. Twenty subjects underwent EEG-neurofeedback training to up-regulate microstate D presence. The protocol included 20 training sessions, consisting of baseline trials (resting state), regulation trials with auditory feedback contingent on microstate D presence, and a transfer trial. Response to neurofeedback was assessed with mixed effects modelling. All participants increased the percentage of time spent producing microstate D in at least one of the three conditions (p < 0.05). Significant between-subjects across-sessions results showed an increase of 0.42 % of time spent producing microstate D in baseline (reflecting a sustained change in the resting state), 1.93 % of increase during regulation and 1.83 % during transfer. Within-session analysis (performed in baseline and regulation trials only) showed a significant 1.65 % increase in baseline and 0.53 % increase in regulation. These values are in a range that is expected to have an impact upon psychotic experiences. Additionally, we found a negative correlation between alpha power and microstate D contribution during neurofeedback training. Given that microstate D has been related to attentional processes, this result provides further evidence that the training was to some degree specific for the attentional network. We conclude that microstate neurofeedback training proved feasible in healthy subjects. The implementation of the same protocol in schizophrenia patients may promote skills useful to reduce positive symptoms by means of EEG-neurofeedback. PMID- 26582261 TI - Theory of Mind in Children With Specific Language Impairment: A Systematic Review and Meta-Analysis. AB - The relation between language and theory of mind (ToM) has been debated for more than two decades. In a similar vein, ToM has been examined in children with specific language impairment (SLI), albeit with inconsistent results. This meta analysis of 17 studies with 745 children between the ages of 4 and 12 found that children with SLI had substantially lower ToM performance compared to age-matched typically developing children (d = .98). This effect size was not moderated by age and gender. By revealing that children with SLI have ToM impairments, this finding emphasizes the need for further investigation into the developmental interface between language and ToM as well as the extended consequences of atypical language development. PMID- 26582262 TI - Phenalenone derivatives and the unusual tricyclic sesterterpene acid from the marine fungus Lophiostoma bipolare BCC25910. AB - Ten compounds including nine phenalenone derivatives (five bipolarides and four bipolarols) and a sesterterpene acid (bipolarenic acid), were isolated from a marine isolated of the fungus Lophiostoma bipolare (BCC25910), along with the known compounds, (-)-scleroderolide, (-)-sclerodin, and oxasetin. Chemical structures were elucidated based on NMR spectroscopic data and HRESIMS analysis. In addition, the absolute configurations of the phenalenones were resolved using specific rotations and chemical means, while the relative configuration of bipolarenic acid was confirmed by X-ray crystallographic analysis. The compounds were evaluated for biological activity against the Plasmodium falciparum K-1 strain, Candida albicans, and Bacillus cereus, and for cytotoxicity against both cancerous and non-cancerous cells. PMID- 26582264 TI - High-throughput sequencing insights into T-cell receptor repertoire diversity in aging. AB - Decline in T-cell generation leading to T-cell receptor repertoire contraction is a cornerstone of immune system aging, and consequent disorders. High-throughput sequencing enables in-depth immune repertoire characterization, but blood samples are too small to capture its total diversity. New computational models could enable accurate estimation of this diversity. PMID- 26582263 TI - An Efficient Site-Specific Method for Irreversible Covalent Labeling of Proteins with a Fluorophore. AB - Fluorophore labeling of proteins while preserving native functions is essential for bulk Forster resonance energy transfer (FRET) interaction and single molecule imaging analysis. Here we describe a versatile, efficient, specific, irreversible, gentle and low-cost method for labeling proteins with fluorophores that appears substantially more robust than a similar but chemically distinct procedure. The method employs the controlled enzymatic conversion of a central Cys to a reactive formylglycine (fGly) aldehyde within a six amino acid Formylglycine Generating Enzyme (FGE) recognition sequence in vitro. The fluorophore is then irreversibly linked to the fGly residue using a Hydrazinyl Iso-Pictet-Spengler (HIPS) ligation reaction. We demonstrate the robust large scale fluorophore labeling and purification of E.coli (Ec) mismatch repair (MMR) components. Fluorophore labeling did not alter the native functions of these MMR proteins in vitro or in singulo. Because the FGE recognition sequence is easily portable, FGE-HIPS fluorophore-labeling may be easily extended to other proteins. PMID- 26582265 TI - Clinical, biochemical and mutation profile in Indian patients with Sandhoff disease. AB - Sandhoff disease (SD) is an autosomal recessive neurodegenerative lysosomal storage disorder caused by mutations in HEXB gene. Molecular pathology is unknown in Indian patients with SD. The present study is aimed to determine mutations spectrum and molecular pathology leading to SD in 22 unrelated patients confirmed by the deficiency of beta-hexosaminidase-A and total-hexosaminidase in leukocytes. To date, nearly 86 mutations of HEXB have been described, including five large deletions. Over all we have identified 13 mutations in 19 patients, eight of which were novel, including two missense mutations [c.611G>A (p.G204E), c. 634A>T (p.H212Y)], two nonsense mutations [c.333G>A (p.W111X), c.298C>T (p.R100X)], one splice site mutation c.1082+5 G>T, two small in-frame deletions [c.534_541delAGTTTATC (p.V179RfsX10), c.1563_1573delTATGGATGACG (p.M522LfsX2)] and one insertion c.1553_1554insAAGA (p.D518EfsX8). We have also identified previously known, five sequence variations leading to amino acid changes [c.926G>A (p.C309Y), c.1597C>T (p.R533C)], one nonsense mutation c.850 C>T (p.R284X), one splice site mutation c.1417+1 G-A and one insertion c.1591_1592insC (p.R531TfsX22). Mutation was not identified in three patients. We observed from this study that mutation c.850C>T (p.R284X) was identified in 4/19 (21%) patients which is likely to be the most common mutation in the country. This is the first study providing insight into the molecular basis of SD in India. PMID- 26582266 TI - Whole-exome sequencing and neurite outgrowth analysis in autism spectrum disorder. AB - Autism spectrum disorder (ASD) is a complex group of clinically heterogeneous neurodevelopmental disorders with unclear etiology and pathogenesis. Genetic studies have identified numerous candidate genetic variants, including de novo mutated ASD-associated genes; however, the function of these de novo mutated genes remains unclear despite extensive bioinformatics resources. Accordingly, it is not easy to assign priorities to numerous candidate ASD-associated genes for further biological analysis. Here we developed a convenient system for identifying an experimental evidence-based annotation of candidate ASD-associated genes. We performed trio-based whole-exome sequencing in 30 sporadic cases of ASD and identified 37 genes with de novo single-nucleotide variations (SNVs). Among them, 5 of those 37 genes, POGZ, PLEKHA4, PCNX, PRKD2 and HERC1, have been previously reported as genes with de novo SNVs in ASD; and consultation with in silico databases showed that only HERC1 might be involved in neural function. To examine whether the identified gene products are involved in neural functions, we performed small hairpin RNA-based assays using neuroblastoma cell lines to assess neurite development. Knockdown of 8 out of the 14 examined genes significantly decreased neurite development (P<0.05, one-way analysis of variance), which was significantly higher than the number expected from gene ontology databases (P=0.010, Fisher's exact test). Our screening system may be valuable for identifying the neural functions of candidate ASD-associated genes for further analysis and a substantial portion of these genes with de novo SNVs might have roles in neuronal systems, although further detailed analysis might eliminate false positive genes from identified candidate ASD genes. PMID- 26582267 TI - Birth weight modifies the association between central nervous system gene variation and adult body mass index. AB - Genome wide association studies have identified ~100 loci associated with body mass index (BMI). Persons with low birth weight have an increased risk of metabolic disorders. We postulate that normal mechanisms of body weight regulation are disrupted in subjects with low birth weight. The present analyses included 2215 African American women from the Black Women's Health Study, and were based on genotype data on 20 BMI-associated loci and self-reported data on birth weight, weight at age 18 and adult weight. We used general linear models to assess the association of individual single-nucleotide polymorphisms (SNPs) with BMI at age 18 and later in adulthood within strata of birth weight (above and below the median, 3200 g). Three SNPs (rs1320330 near TMEM18, rs261967 near PCSK1 and rs17817964 in FTO), and a genetic score combining these three variants, showed significant interactions with birth weight in relation to BMI. Among women with birth weight <3200 g, there was an inverse association between genetic score and BMI; beta-coefficient=-0.045 (95% confidence intervals (CI) -0.104, 0.013) for BMI at age 18, and -0.055 (95% CI -0.112, 0.002) for adult BMI. Among women with birth weight ?3200 g, genetic score was positively associated with BMI: beta coefficient=0.110 (95% CI 0.051, 0.169) for BMI at age 18 (P for interaction=0.0002), and 0.112 (95% CI 0.054, 0.170) for adult BMI (P for interaction<0.0001). Because TMEM18, PCSK1 and FTO are highly expressed in the central nervous system (CNS), our results suggest that low-birth weight may disrupt mechanisms of CNS body weight regulation. PMID- 26582268 TI - Real-Time and Retrospective Health-Analytics-as-a-Service: A Novel Framework. AB - BACKGROUND: Analytics-as-a-service (AaaS) is one of the latest provisions emerging from the cloud services family. Utilizing this paradigm of computing in health informatics will benefit patients, care providers, and governments significantly. This work is a novel approach to realize health analytics as services in critical care units in particular. OBJECTIVE: To design, implement, evaluate, and deploy an extendable big-data compatible framework for health analytics-as-a-service that offers both real-time and retrospective analysis. METHODS: We present a novel framework that can realize health data analytics-as-a service. The framework is flexible and configurable for different scenarios by utilizing the latest technologies and best practices for data acquisition, transformation, storage, analytics, knowledge extraction, and visualization. We have instantiated the proposed method, through the Artemis project, that is, a customization of the framework for live monitoring and retrospective research on premature babies and ill term infants in neonatal intensive care units (NICUs). RESULTS: We demonstrated the proposed framework in this paper for monitoring NICUs and refer to it as the Artemis-In-Cloud (Artemis-IC) project. A pilot of Artemis has been deployed in the SickKids hospital NICU. By infusing the output of this pilot set up to an analytical model, we predict important performance measures for the final deployment of Artemis-IC. This process can be carried out for other hospitals following the same steps with minimal effort. SickKids' NICU has 36 beds and can classify the patients generally into 5 different types including surgical and premature babies. The arrival rate is estimated as 4.5 patients per day, and the average length of stay was calculated as 16 days. Mean number of medical monitoring algorithms per patient is 9, which renders 311 live algorithms for the whole NICU running on the framework. The memory and computation power required for Artemis-IC to handle the SickKids NICU will be 32 GB and 16 CPU cores, respectively. The required amount of storage was estimated as 8.6 TB per year. There will always be 34.9 patients in SickKids NICU on average. Currently, 46% of patients cannot get admitted to SickKids NICU due to lack of resources. By increasing the capacity to 90 beds, all patients can be accommodated. For such a provisioning, Artemis-IC will need 16 TB of storage per year, 55 GB of memory, and 28 CPU cores. CONCLUSIONS: Our contributions in this work relate to a cloud architecture for the analysis of physiological data for clinical decisions support for tertiary care use. We demonstrate how to size the equipment needed in the cloud for that architecture based on a very realistic assessment of the patient characteristics and the associated clinical decision support algorithms that would be required to run for those patients. We show the principle of how this could be performed and furthermore that it can be replicated for any critical care setting within a tertiary institution. PMID- 26582270 TI - Suppression and reversal of motion perception around the time of the saccade. AB - We make fast, "saccadic" eye movements to capture finely resolved foveal snapshots of the world but these saccades cause motion artefacts. The artefacts go unnoticed, perhaps because the brain suppresses them through subcortical oculomotor signals feeding back into visual cortex. Opposing views, however, claim that passive mechanisms suffice: saccadic shearing forces might render the retina insensitive to the artefacts or post-saccadic snapshots might mask them before they enter consciousness. Crucially, only active suppression could explain perceptual changes that precede saccades but existing evidence for presaccadic misperception are ill-suited for addressing this issue: Previous studies have found misperceptions of space for objects briefly flashed before saccades, but perhaps only because observers confused the timing of flashes and saccades before they could be tested ("postdiction"), and presaccadic motion perception might have appeared to decline because motion stimuli persisted past eye movement onset. Here we addressed these concerns using briefly flashed two-frame animations (50 ms) to probe people's motion sensitivity during and around saccades. We found that sensitivity declined before saccade onset, even when the probe appeared entirely outside the saccade, and this sensitivity decline was present for motion in every direction relative to saccade, ruling out problems with postdiction. Intriguingly, brief periods during the saccade produced negative sensitivity as if motion was reversed, arguably due to postsaccadic enhancement. These data suggest that motion perception is minimized during saccades through active suppression, complementing neurophysiological findings of colliculo-pulvinar projections that suppress the cortical middle temporal area around the time of the saccade. PMID- 26582269 TI - Identifying effective intervention components for smoking cessation: a factorial screening experiment. AB - AIMS: To identify promising intervention components intended to help smokers to attain and maintain abstinence in their quit smoking attempts. DESIGN: A fully crossed, six-factor randomized fractional factorial experiment. SETTING: Eleven primary care clinics in southern Wisconsin, USA. PARTICIPANTS: A total of 637 adult smokers (55% women, 88% white) motivated to quit smoking who visited primary care clinics. INTERVENTIONS: Six intervention components designed to prepare smokers to quit, and achieve and maintain abstinence (i.e. for the preparation, cessation and maintenance phases of smoking treatment): (1) preparation nicotine patch versus none; (2) preparation nicotine gum versus none; (3) preparation counseling versus none; (4) intensive cessation in-person counseling versus minimal; (5) intensive cessation telephone counseling versus minimal; and (6) 16 versus 8 weeks of combination nicotine replacement therapy (nicotine patch + nicotine gum). MEASUREMENTS: Seven-day self-reported point prevalence abstinence at 16 weeks. FINDINGS: Preparation counseling significantly improved week 16 abstinence rates (P = .04), while both forms of preparation nicotine replacement therapy interacted synergistically with intensive cessation in-person counseling (P < 0.05). Conversely, intensive cessation phone counseling and intensive cessation in-person counseling interacted antagonistically (P < 0.05)-these components produced higher abstinence rates by themselves than in combination. CONCLUSIONS: Preparation counseling and the combination of intensive cessation in-person counseling with preparation nicotine gum or patch are promising intervention components for smoking and should be evaluated as an integrated treatment package. PMID- 26582271 TI - The preferential accumulation of heavy metals in different tissues following frequent respiratory exposure to PM2.5 in rats. AB - This study aimed to explore the pattern of accumulation of some of main heavy metals in blood and various organs of rats after exposed to the atmospheric fine particulate matter (PM2.5). Rats were randomly divided into control and three treatment groups (tracheal perfusion with 10 mg/kg, 20 mg/kg and 40 mg/kg of PM2.5 suspension liquid, respectively). Whole blood and the lung, liver, kidney, and cerebral cortex were harvested after rats were treated and sacrificed. The used heavy metals were detected using inductively coupled plasma-mass spectrometry (ICP-MS) instrument. As results, Lead was increased in the liver, lung and cerebral cortex and the level of manganese was significantly elevated in the liver and cerebral cortex in PM2.5 treated rats. Besides, arsenic was prominently enriched both in cerebral cortex and in blood, and so did the aluminum in the cerebral cortex and the copper in the liver. However, cadmium, chromium and nickel have shown no difference between the control group and the three PM2.5 treated groups. Following the exposure of PM2.5, different heavy metals are preferentially accumulated in different body tissues. PMID- 26582272 TI - A systematic review on the role of environmental toxicants in stem cells aging. AB - Stem cells are an important target for environmental toxicants. As they are the main source for replenishing of organs in the body, any changes in their normal function could affect the regenerative potential of organs, leading to the appearance of age-related disease and acceleration of the aging process. Environmental toxicants could exert their adverse effect on stem cell function via multiple cellular and molecular mechanisms, resulting in changes in the stem cell differentiation fate and cell transformation, and reduced self-renewal capacity, as well as induction of stress-induced cellular senescence. The present review focuses on the effect of environmental toxicants on stem cell function associated with the aging process. We categorized environmental toxicants according to their preferred molecular mechanism of action on stem cells, including changes in genomic, epigenomic, and proteomic levels and enhancing oxidative stress. Pesticides, tobacco smoke, radiation and heavy metals are well studied toxicants that cause stem cell dysfunction via induction of oxidative stress. Transgenerational epigenetic changes are the most important effects of a variety of toxicants on germ cells and embryos that are heritable and could affect health in the next several generations. A better understanding of the underlying mechanisms of toxicant-induced stem cell aging will help us to develop therapeutic intervention strategies against environmental aging. Meanwhile, more efforts are required to find the direct in vivo relationship between adverse effect of environmental toxicants and stem cell aging, leading to organismal aging. PMID- 26582273 TI - Family history assessment for colorectal cancer (CRC) risk analysis - comparison of diagram- and questionnaire-based web interfaces. AB - BACKGROUND: Colorectal cancer (CRC) has a high incidence, especially in New Zealand. The reasons for this are unknown. While most cancers develop sporadically, a positive family history, determined by the number and age at diagnosis of affected first and second degree relatives with CRC is one of the major factors, which may increase an individual's lifetime risk. Before a patient can be enrolled in a surveillance program a detailed assessment and documentation of the family history is important but time consuming and often inaccurate. The documentation is usually paper-based. Our aim was therefore to develop and validate the usability and efficacy of a web-based family history assessment tool for CRC suitable for the general population. The tool was also to calculate the risk and make a recommendation for surveillance. METHODS: Two versions of an electronic assessment tool, diagram-based and questionnaire-based, were developed with the risk analysis and recommendations for surveillance based on the New Zealand Guidelines Group recommendations. Accuracy of our tool was tested prior to the study by comparing risk calculations based on family history by experienced gastroenterologists with the electronic assessment. The general public, visiting a local science fair were asked to use and comment on the usability of the two interfaces. RESULTS: Ninety people assessed and commented on the two interfaces. Both interfaces were effective in assessing the risk to develop CRC through their familial history for CRC. However, the questionnaire based interface performed with significantly better satisfaction (p = 0.001) than the diagram-based interface. There was no difference in efficacy though. CONCLUSION: We conclude that a web-based questionnaire tool can assist in the accurate documentation and analysis of the family history relevant to determine the individual risk of CRC based on local guidelines. The calculator is now implemented and assessable through the web-page of a local charity for colorectal cancer awareness and integral part of the local general practitioners' e-referral system for colonic imaging. PMID- 26582274 TI - Avoiding degradation of chemotherapy drugs: is graphene the answer? PMID- 26582275 TI - What potential is there for the use of ZrO2 nanostructures for image-guided thermotherapy? PMID- 26582276 TI - Highlights from the latest articles in nanomedicine: light-activated therapeutics. PMID- 26582278 TI - The European project NanoAthero to fight cardiovascular diseases using nanotechnologies. AB - Cardiovascular diseases are the main causes of death in the world. Nanosystems with contrast agents or drugs appear as promising tools for early detection and treatments. NanoAthero, a large-scale 5-year project funded by the European Union FP7 gathers 16 partners from ten different countries to demonstrate the benefit of the use of nanoparticle technologies. Through the design and characterization of nanosystems, preclinical and clinical validations, toxicology, industrial development and production in good manufacturing practice forms, several studies are underway for plaque and stroke both for imaging and treatment. A clinical study was already completed using a good manufacturing practice liposomal formulation in patients with carotid atheroma. NanoAthero is a unique opportunity to open new strategies for the management of cardiovascular diseases. PMID- 26582279 TI - Polyamidoamine nanoparticles as nanocarriers for the drug delivery to malaria parasite stages in the mosquito vector. AB - Malaria is arguably one of the main medical concerns worldwide because of the numbers of people affected, the severity of the disease and the complexity of the life cycle of its causative agent, the protist Plasmodium spp. With the advent of nanoscience, renewed hopes have appeared of finally obtaining the long sought after magic bullet against malaria in the form of a nanovector for the targeted delivery of antimalarial compounds exclusively to Plasmodium-infected cells, thus increasing drug efficacy and minimizing the induction of resistance to newly developed therapeutic agents. Polyamidoamine-derived nanovectors combine into a single chemical structure drug encapsulating capacity, antimalarial activity, low unspecific toxicity, specific targeting to Plasmodium, optimal in vivo activity and affordable synthesis cost. After having shown their efficacy in targeting drugs to intraerythrocytic parasites, now polyamidoamines face the challenge of spearheading a new generation of nanocarriers aiming at the malaria parasite stages in the mosquito vector. PMID- 26582280 TI - The Effect of Diode Laser With Different Parameters on Root Fracture During Irrigation Procedure. AB - The aim of this study is to compare the effect of a single diode laser application and agitation of EDTA with diode laser with different parameters at different time intervals on root fracture. Ninety mandibular incisors were instrumented except the negative control group. The specimens were divided randomly into 10 groups according to final irrigation procedure: (G1) non instrumented; (G2) distilled water; (G3) 15% EDTA; (G4) ultrasonically agitated EDTA; (G5) single 1.5W/100 Hz Diode laser; (G6) single 3W/100 Hz Diode laser; (G7) 1.5W/100 Hz Diode laser agitation of EDTA for 20 s; (G8) 1.5W/100 Hz Diode laser agitation of EDTA for 40 s; (G9) 3W/100 Hz Diode laser agitation of EDTA for 20 s; and (G10) 3W/100 Hz Diode laser agitation of EDTA for 40 s. The specimens were filled, mounted in acrylic resin, and compression strength test was performed on each specimen. Statistical analysis was carried out using one way ANOVA and Tukey's post hoc tests (P = 0.05). The statistical analysis revealed that there were statistically significant differences among the groups (P < 0.05). Laser-agitated irrigation with a 3W/100 Hz Diode laser for both 20 s and 40 s decreased the fracture resistance of teeth. PMID- 26582281 TI - N-Linked Glycans of Chloroviruses Sharing a Core Architecture without Precedent. AB - N-glycosylation is a fundamental modification of proteins and exists in the three domains of life and in some viruses, including the chloroviruses, for which a new type of core N-glycan is herein described. This N-glycan core structure, common to all chloroviruses, is a pentasaccharide with a beta-glucose linked to an asparagine residue which is not located in the typical sequon N-X-T/S. The glucose is linked to a terminal xylose unit and a hyperbranched fucose, which is in turn substituted with a terminal galactose and a second xylose residue. The third position of the fucose unit is always linked to a rhamnose, which is a semiconserved element because its absolute configuration is virus-dependent. Additional decorations occur on this core N-glycan and represent a molecular signature for each chlorovirus. PMID- 26582282 TI - Prophylaxis vs. on-demand treatment with Nuwiq((r)) (Human-cl rhFVIII) in adults with severe haemophilia A. AB - INTRODUCTION: Haemophilia A is treated with FVIII, either prophylactically or on demand. Prophylaxis is the gold standard in children and evidence is accumulating in adults. AIMS/METHODS: The aim of this analysis was to compare prophylaxis vs. on-demand treatment with Nuwiq((r)) (Human-cl rhFVIII), a new-generation rFVIII expressed in a human cell line, in previously treated patients (PTPs) with severe haemophilia A. Data were analysed from two similarly designed, multinational, prospective, open-label studies with similar inclusion and exclusion criteria and comparable patient demographics. Human-cl rhFVIII was administered either prophylactically in a study of 32 adults or on-demand in a study of 22 patients (20 adults and two adolescents). RESULTS: Patients treated prophylactically experienced 36 bleeds compared with 997 bleeds in patients treated on-demand (mean observation periods: 180 and 335 days respectively). Based on a negative binomial regression model, annualized bleeding rate (ABR) during prophylaxis was 2.30 (95% CI: 1.54, 3.44) compared with 57.74 (95% CI: 43.36, 76.91) during on demand treatment, which equates to a 96% lower ABR during prophylaxis. 'Excellent' or 'good' efficacy in the treatment of bleeds was achieved with Human cl rhFVIII in 100% of 28 evaluated bleeds during the prophylaxis study and 94.5% of 985 evaluated bleeds during the on-demand study. No inhibitors, treatment related serious adverse events or severe adverse events were recorded during prophylaxis or or-demand treatment. CONCLUSIONS: Prophylaxis with Human-cl rhFVIII reduces recurrent bleeding in adult PTPs with severe haemophilia A and adds further supportive evidence for the benefits of prophylaxis in adults. PMID- 26582283 TI - Evaluation and characterization of new alpha-L-rhamnosidase-producing yeast strains. AB - A total of thirty yeast strains were isolated from a whey beverage and screened for alpha-L-rhamnosidase enzyme production. Of these, only four isolates were capable of producing the alpha-L-rhamnosidase enzyme by hydrolyzing naringin. Scanning electron microscopy images showed that the morphology of the yeast isolate (isolate No. 84) producing the greatest enzyme, changed from oval to filamentous in the presence of naringin. On the basis of morphological and molecular characterization (ITS sequencing), these four isolates were identified as Clavispora lusitaniae-84, Clavispora lusitaniae-B82, Candida sp.-86 and Candida hyderabadensis-S82). Fermentation parameters and the biochemical characterization of the alpha-L-rhamnosidase-producing yeast isolates were studied based on carbon substrate utilization profiles using BIOLOG phenotype microarray plates. Intra-species genetic diversity among the isolates was evaluated by whole genome analysis with repetitive DNA sequences (ERIC, REP and BOX) based DNA fingerprinting. On the basis of these results, it was found that these isolates of yeast producing L-rhamnosidase have a great potential application for beverage quality enhancement, and can build a strong foundation of alpha-L-rhamnosidase-producing yeast strains in the debittering of citrus juice. PMID- 26582284 TI - Fibrinolytic enzyme production by newly isolated Bacillus cereus SRM-001 with enhanced in-vitro blood clot lysis potential. AB - The discovery of plasmin-like microbial fibrinolytic enzymes having high specificity and negligible side effects is crucial for thrombolytic therapy. Herein, we report one such extra-cellular fibrinolytic enzyme producing Bacillus cereus SRM-001 isolated from the blood-laden soil of a chicken dump yard. The potency of the enzyme was established with fibrin plate assay and in-vitro blood clot lysis assay. The shake-flask operating parameters and media composition were optimized for maximizing the productivity of the enzyme. The operating parameters, pH 7, 37 degrees C, 1% inoculum volume and 24 h inoculum age, were found to be the optimum. The levels of media components, corn flour (0.3% w/v), soyabean powder (1.9% w/v) and MnSO4 (11.5 mM) were optimized by statistical analysis using Box-Behnken design derived RSM. This resulted in an almost 1.8 fold increase in fibrinolytic enzyme productivity. The 3D response surface plots showed soyabean powder and MnSO4 to be the key ingredients for enhancing the enzyme productivity, whereas corn flour had a marginal effect. The in-vitro blood clot lysis assay conducted at near physiological pH 7 at 37 degrees C showed the enzyme to be a potential therapeutic thrombolytic agent. PMID- 26582285 TI - Bioremediation potential of glyphosate-degrading Pseudomonas spp. strains isolated from contaminated soil. AB - Bacterial strains capable of utilizing glyphosate as the sole carbon source were isolated from contaminated soil by the enrichment culture method and identified based on partial 16S rRNA gene sequence analysis. Pseudomonas spp. strains GA07, GA09 and GC04 demonstrated the best degradation capabilities towards glyphosate and were used for the laboratory experiments of glyphosate bioremediation. Inoculating glyphosate-treated soil samples with these three strains resulted in a 2-3 times higher rate of glyphosate removal than that in non-inoculated soil. The degradation kinetics was found to follow a first-order model with regression values greater than 0.96. Cell numbers of the introduced bacteria decreased from 4.4 * 10(6) CFU/g to 3.4-6.7 * 10(5) CFU/g dry soil within 18 days of inoculation. Due to the intense degradation of glyphosate, the total dehydrogenase activity of the soil microbial community increased by 21.2-25.6%. Analysis of glyphosate degradation products in cell-free extracts showed that glyphosate breakdown in strain GA09 was catalyzed both by C-P lyase and glyphosate oxidoreductase. Strains GA07 and GC04 degraded glyphosate only via glyphosate oxidoreductase, but no further metabolite was detected. These results highlight the potential of the isolated bacteria to be used in the bioremediation of GP-contaminated soils. PMID- 26582286 TI - Community analysis of picocyanobacteria in an oligotrophic lake by cloning 16S rRNA gene and 16S rRNA gene amplicon sequencing. AB - In this study, the picocyanobacterial species composition of Lake Miyagase was examined by analyzing the 16S rRNA gene in a clone library and by amplicon sequencing using a benchtop next-generation sequencer. Five separate samples were analyzed from different days over a ten-month period. In the picocyanobacterial lineage, 9 and 12 OTUs were identified from a clone library and by amplicon sequencing, respectively. Both analyses suggested that a picocyanobacterium related to Synechococcus sp. MW6B4 was dominant in Lake Miyagase. Our findings suggest that 16S rRNA gene amplicon sequencing enables detailed evaluation of picocyanobacteria composition. One OTU identified was found to be a novel cluster that does not group with any of the known freshwater picocyanobacteria. PMID- 26582287 TI - Study on in vivo effects of bacterial histidine kinase inhibitor, Waldiomycin, in Bacillus subtilis and Staphylococcus aureus. AB - Two-component signal transduction systems (TCSs) represent one of the primary means by which bacteria sense and respond to changes in their environment, both intra- and extracellular. The highly conserved WalK (histidine kinase)/WalR (response regulator) TCS is essential for cell wall metabolism of low G+C Gram positive bacteria and acts as a master regulatory system in controlling and coordinating cell wall metabolism with cell division. Waldiomycin, a WalK inhibitor, has been discovered by screening metabolites from actinomycetes and belongs to the family of angucycline antibiotics. In the present study, we have shown that waldiomycin inhibited autophosphorylation of WalK histidine kinases in vitro from Bacillus subtilis, Staphylococcus aureus, Enterococcus faecalis, and Streptococcus mutans at half-maximal inhibitory concentrations of 10.2, 8.8, 9.2, and 25.8 MUM, respectively. Quantitative RT-PCR studies of WalR regulon genes have suggested that waldiomycin repressed the WalK/WalR system in B. subtilis and S. aureus cells. Morphology of waldiomycin-treated S. aureus cells displayed increased aggregation instead of proper cellular dissemination. Furthermore, autolysis profiles of S. aureus cells revealed that waldiomycin-treated cells were highly resistant to Triton X-100- and lysostaphin-induced lysis. These phenotypes are consistent with those of cells starved for the WalK/WalR system, indicating that waldiomycin inhibited the autophosphorylation activity of WalK in cells. We have also confirmed that waldiomycin inhibits WalK autophosphorylation in vivo by actually observing the phosphorylated WalK ratio in cells using Phos tag SDS-PAGE. The results of our current study strongly suggest that waldiomycin targets WalK histidine kinases and inhibits the WalR regulon genes expression, thereby affecting both cell wall metabolism and cell division. PMID- 26582288 TI - Biodegradation of engine oil by fungi from mangrove habitat. AB - The pollution of land and water by petroleum compounds is a matter of growing concern necessitating the development of methodologies, including microbial biodegradation, to minimize the impending impacts. It has been extensively reported that fungi from polluted habitats have the potential to degrade pollutants, including petroleum compounds. The Red Sea is used extensively for the transport of oil and is substantially polluted, due to leaks, spills, and occasional accidents. Tidal water, floating debris, and soil sediment were collected from mangrove stands on three polluted sites along the Red Sea coast of Saudi Arabia and forty-five fungal isolates belonging to 13 genera were recovered from these samples. The isolates were identified on the basis of a sequence analysis of the 18S rRNA gene fragment. Nine of these isolates were found to be able to grow in association with engine oil, as the sole carbon source, under in vitro conditions. These selected isolates and their consortium accumulated greater biomass, liberated more CO2, and produced higher levels of extracellular enzymes, during cultivation with engine oil as compared with the controls. These observations were authenticated by gas chromatography-mass spectrophotometry (GC MS) analysis, which indicated that many high mass compounds present in the oil before treatment either disappeared or showed diminished levels. PMID- 26582289 TI - Effect of soil salinity and nutrient levels on the community structure of the root-associated bacteria of the facultative halophyte, Tamarix ramosissima, in southwestern United States. AB - Tamarix ramosissima is a tree species that is highly resistant to salt and drought. The Tamarix species survives in a broad range of environmental salt levels, and invades major river systems in southwestern United States. It may affect root-associated bacteria (RB) by increasing soil salts and nutrients. The effects of RB on host plants may vary even under saline conditions, and the relationship may be important for T. ramosissima. However, to the best of our knowledge, there have been no reports relating to T. ramosissima RB and its association with salinity and nutrient levels. In this study, we have examined this association and the effect of arbuscular mycorrhizal colonization of T. ramosissima on RB because a previous study has reported that colonization of arbuscular mycorrhizal fungi affected the rhizobacterial community (Marschner et al., 2001). T. ramosissima roots were collected from five locations with varying soil salinity and nutrient levels. RB community structures were examined by terminal restriction fragment (T-RF) length polymorphism, cloning, and sequencing analyses. The results suggest that RB richness, or the diversity of T. ramosissima, have significant negative relationships with electrical conductivity (EC), sodium concentration (Na), and the colonization of arbuscular mycorrhizal fungi, but have a significant positive relationship with phosphorus in the soil. However, at each T-RF level, positive correlations between the emergence of some T-RFs and EC or Na were observed. These results indicate that high salinity decreased the total number of RB species, but some saline-tolerant RB species multiplied with increasing salinity levels. The ordination scores of nonmetric multidimensional scale analysis of RB community composition show significant relationships with water content, calcium concentration, available phosphorus, and total nitrogen. These results indicate that the RB diversity and community composition of T. ramosissima are affected by soil salinity and nutrient levels. Sequence analysis detected one Bacteroidetes and eight Proteobacteria species. Most 16S rRNA gene sequences had high similarities with the bacteria isolated from saline conditions, indicating that at least a portion of the RB species observed in T. ramosissima was halotolerant. PMID- 26582290 TI - Protozoal ciliate promotes bacterial autoinducer-2 accumulation in mixed culture with Escherichia coli. AB - We have previously demonstrated conjugation of Escherichia coli into vacuoles of the protozoal ciliate (Tetrahymena thermophila). This indicated a possible role of ciliates in evoking bacterial quorum sensing, directly connecting bacterial survival via accumulation in the ciliate vacuoles. We therefore assessed if ciliates promoted bacterial autoinducer (AI)-2 accumulation with vacuole formation, which controls quorum sensing. E. coli AI-2 accumulation was significantly enhanced in the supernatants of a mixed culture of ciliates and bacteria, likely depending on ciliate density rather than bacterial concentration. As expected, AI-2 production was significantly correlated with vacuole formation. The experiment with E. coli luxS mutants showed that ciliates failed to enhance bacterial AI-2 accumulation, denying a nonspecific phenomenon. Fluorescence microscopy revealed accumulation of fragmented bacteria in ciliate vacuoles, and, more importantly, expulsion of the vacuoles containing disrupted bacteria into the culture supernatant. There was no increase in the expression of luxS (encoding AI-2) or ydgG (a transporter for controlling bacterial export of AI-2). We conclude that ciliates promote bacterial AI-2 accumulation in a mixed culture, via accumulation of disrupted bacteria in ciliate vacuoles followed by expulsion of the vacuoles, independently of luxS or ydgG gene induction. This is believed to be the first demonstration of a relationship between E. coli AI-2 dynamics and ciliates. In the natural environment, ciliate biotopes may provide a survival advantage to bacteria inhabiting such biotopes, via evoking quorum sensing. PMID- 26582292 TI - J. Gen. Appl. Microbiol., 61, 132-138 (2015) doi 10.2323/jgam.61.132. PMID- 26582291 TI - Construction of a URA5.3 deletion strain of the unicellular red alga Cyanidioschyzon merolae: A backgroundless host strain for transformation experiments. PMID- 26582293 TI - Splenogonadal fusion-limb deformity syndrome: a rare but important cause of undescended testis. AB - BACKGROUND: Splenogonadal fusion is a rare congenital anomaly which is characterized by fusion formation between the spleen and gonad. METHODS: We report a case of a 14-month boy with spleongonadal fusion-limb deformity syndrome focusing on the importance of awareness of this syndrome. RESULTS: The patient was admitted to our clinic because of a left undescended testis, and preoperative diagnosis was not made. During the operation, "spleen-like" tissue attached to the gonad induced splenogonadal fusion, which was confirmed by laparoscopy. The patient also had a short right femur, hip dysplasia and a syndromic face. CONCLUSION: Splenogonadal fusion anomaly should be considered in the evaluation of undescended testis, especially in patients with facial and limb deformities. PMID- 26582294 TI - Prematurity and the burden of influenza and respiratory syncytial virus disease. AB - BACKGROUND: Respiratory morbidity of former preterm infants and especially those with bronchopulmonary dysplasia (BPD) is high during infancy and early childhood. DATA SOURCES: We performed a review based on a literature search including EMBASE, MEDLINE, and CINAHL databases to identify all relevant papers published in the English and German literature on influenza and respiratory syncytial virus infection associated with preterm infant, prematurity, and BPD between 1980 and 2014. RESULTS: Recurrent respiratory symptoms remain common at preschool age, school age and even into young adulthood. Acute viral respiratory tract infections due to different pathogens cause significant morbidity and necessitate rehospitalizations during the first years of life. Influenza virus infection plays a minor role compared to respiratory syncytial virus (RSV) associated respiratory tract infection during infancy and early childhood. Nevertheless, particular morbidity to both viruses is high. CONCLUSIONS: The particular burden of both viral diseases in preterm infants is dominated by RSV and its associated rehospitalizations during the first two years of life. Prophylactic measures include vaccination against influenza virus of family members and caregivers and active immunization starting at the age of 6 months, and monthly injections of palivizumab during the cold season to avoid severe RSV disease and its sequelae. PMID- 26582295 TI - Immune neutropenias of infancy and childhood. AB - BACKGROUND: Anti-neutrophil antibodies are a well-recognized cause of neutropenia, producing a potential increase in risk of infection: in the majority of patients antibodies react against antigens located on the IgG Fc receptor type 3b (FcRIIIb), but other target antigens have been identified. DATA SOURCES: In this review the most important papers of auto and alloimmune neutropenias of infancy and childhood were analyzed. PubMed, Google Scholar and Thompson ISI Web of Knowledge were searched for identifying relevant papers. RESULTS: Primary autoimmune neutropenia of infancy is mostly a benign condition with self-limited course, whereas isolated alloimmune neonatal neutropenia or secondary autoimmune neutropenia may be occasionally complicated by severe infections. CONCLUSION: Granulocyte colony stimulating factor is an effective therapy for patients affected by all types of autoimmune and alloimmune neutropenia, even though most of them do not need any therapy. PMID- 26582296 TI - Determinants of moderate to vigorous physical activity and obesity in children: a structural equation modeling analysis. AB - BACKGROUND: The determinants of physical activity (PA) and body fatness in Chinese adolescents are rarely examined. This study aimed to investigate the effect of attitude toward PA, screen time, parents' socioeconomic status (SES), and exercise habit on PA and body fatness among Chinese children by using structural equation modeling (SEM) analysis. METHODS: Data obtained from the second Community Fitness Survey in Hong Kong were utilized, in which students from one secondary school of each of the 18 districts of Hong Kong were recruited. A total of 2517 questionnaires with physical fitness items were successfully distributed to students aged 13-19 years in these districts. Families' SES, parents' exercise habit, children's intention to participate in PA, amount of moderate to vigorous PA (MVPA), screen time, children's attitude toward PA, and children's body fat percentage were measured and analyzed with SEM. The structural equation model was composed of a measurement model and a structural model. The model was tested with Mplus 6. The Chi-square test, root mean square error of approximation, comparative fit index, and Tucker-Lewis index were calculated to evaluate model fit. The model was then modified based on the model fit indices. RESULTS: Children's intention to participate in PA was a strong predictor of their engagement in MVPA. Parents' exercise habit had both direct and indirect (via attitude) effects on their children's intention to participate in PA. Screen time was not a predictor of body composition. Children's intention to participate in PA directly affected their body composition. Children's attitude toward PA, parents' exercise habit, and SES had significant effects on the children's intention to participate in PA. Furthermore, obesity had a negative effect on the children's attitude toward PA. CONCLUSION: To promote MVPA and prevent obesity in Chinese children of Hong Kong, it is important to design intervention that enhances children's intention and attitude in PA, as well as parent's exercise habits. Tailormade programs that take SES into consideration are also essential. Further studies are necessary to extend the results and test the model in other metropolitan areas in China. PMID- 26582297 TI - Liposomal bupivacaine versus continuous infusion bupivacaine via an elastomeric pump for the treatment of postoperative pain. AB - PURPOSE: The duration of analgesia and comparative efficacy of liposomal bupivacaine and an elastomeric bupivacaine pump in a diverse surgical population were determined. METHODS: A retrospective cohort study was conducted to evaluate patient outcomes following liposomal bupivacaine and elastomeric bupivacaine pump use from January through June 2013. The primary objective of the study was to evaluate 24-hour postoperative opioid use (in morphine equivalents). RESULTS: Sixty-seven liposomal bupivacaine and 262 elastomeric bupivacaine pump patients were included. Significant between-group differences were seen in American Society of Anesthesiologists physical status, patient-controlled analgesia use, postoperative nonopioid use, and surgical procedure. On univariate analysis, liposomal bupivacaine-in comparison with elastomeric bupivacaine pump -was associated with reduced median (interquartile range, IQR) 24-hour postoperative opioid use (33.0 mg morphine equivalents [IQR, 19.0-80.4 mg morphine equivalents] versus 70.4 mg morphine equivalents [IQR, 37.1-115.4 mg morphine equivalents], p < 0.001) and median 72-hour postoperative opioid use (61.3 mg morphine equivalents [IQR, 28.7-142.8 mg morphine equivalents] versus 115.9 mg morphine equivalents [IQR, 69.9-175.4 mg morphine equivalents], p < 0.001). However, after adjustment for potential confounders with linear regression analysis, study medication was not associated with a decrease in 24-hour (beta coefficient for elastomeric bupivacaine pump: 10.26; 95% confidence interval [CI]: -8.42 to 28.95; p = 0.281) or 72-hour postoperative opioid use (beta coefficient for elastomeric bupivacaine pump: 2.23; 95% CI: -29.88 to 34.34; p = 0.891). CONCLUSION: No difference was found between patients who received liposomal bupivacaine compared with elastomeric continuous infusion bupivacaine from a traditional pump in 24- or 72-hour postoperative opioid utilization after adjustment for baseline differences. PMID- 26582298 TI - Hospital delirium treatment: Continuation of antipsychotic therapy from the intensive care unit to discharge. AB - PURPOSE: The rate of continuation of antipsychotics for the management of delirium during hospital transitions of care in a tertiary care medical center was investigated. METHODS: A retrospective chart review was conducted for adult patients admitted to the medical intensive care unit (MICU) between June 1, 2011, and May 31, 2012, who were initiated on antipsychotic therapy at least 24 hours before transfer out of the MICU. The primary outcome evaluated was the percentage of patients initiated on an antipsychotic in the MICU who were continued on therapy after transfer to a medical ward. Secondary outcomes included the appropriateness of continuing antipsychotic therapy during transitions of care and the percentage of patients continued on an antipsychotic after hospital discharge. RESULTS: Of the 87 patients who met the study inclusion criteria, 23 (26%) were continued on antipsychotic therapy after their transfer from the MICU to the medical ward. Of the 23 patients continued on antipsychotic therapy, 9 (39%) were discharged from the hospital with an antipsychotic. Fourteen of the 23 patients were eligible for assessment of inappropriate antipsychotic continuation upon transfer from the MICU. Of these 14 patients, 9 (64%) were inappropriately continued on an antipsychotic. Patients continued on antipsychotic therapy at hospital discharge were more likely to be discharged to a facility (rehabilitation, skilled nursing facility, or healthcare institution) (p = 0.049).Future areas for study should include (1) prospective analysis to understand the clinical decision-making of providers when treating delirium, (2) evaluation of the long-term impact of continuing antipsychotic therapy for delirium, and (3) ways to improve communication of medication regimens during transitions of care. Plans to reduce antipsychotic continuation could involve reassessing patients on the medical wards, improving documentation of the indication for use in the medical record, or developing protocols to taper off antipsychotics before patients are discharged from the hospital. CONCLUSION: The continuation of antipsychotics for the management of delirium during transitions of care was a common practice at a tertiary care medical center. Patients receiving antipsychotics for treatment of delirium in the MICU were inappropriately continued on these agents when transferred from the MICU to the medical floor or discharged from the hospital. PMID- 26582299 TI - Establishing a community pharmacy residency at an independent pharmacy: Time allocation and valuation. AB - PURPOSE: The value of a first-year community pharmacy residency program (CPRP) at an independent pharmacy was estimated based on time allocation for resident responsibilities. METHODS: Predefined time allocation categories for the pharmacy resident were used to consistently classify and document time completing residency activities. Benefit-to-cost ratio was determined by tabulating total costs and total benefits of the residency program. A retrospective-prospective comparison of overall change in revenue, operating expense, and prescription volume was performed between the preresident time period (July 2012 to June 2013) and the postresident time period (July 2013 to June 2014). This comparison accounted for resident activities that did not directly generate revenue. RESULTS: Time allocations for the resident out of 2,221 total hours logged were dispensing (40%), clinical setup (16%), research (8%), professional meetings (7%), clinical activities (5%), resident education (5%), site precepting (4%), residency meetings (4%), didactic teaching (3%), miscellaneous (3%), marketing (2%), training (2%), and public health promotion (1%). Total costs were $77,422, and total benefits were $118,410. The benefit-to-cost ratio was 1.53. The postresident time interval had $172,451 more revenue and $6,622 more in operating expenses than the preresident time interval, and prescription volume decreased by 2,000 prescriptions compared to the previous year. CONCLUSION: The benefit-to cost analysis indicated a $1.53 return for every $1.00 invested into a CPRP. An increase in revenue and operating expenses for the pharmacy was observed after implementation of the CPRP compared to the previous year. PMID- 26582300 TI - Improvements in a program to convert i.v. to oral medications at an academic medical center. AB - PURPOSE: Results of a study to implement targeted interventions to increase the number of documented i.v.-to-oral conversions and to increase cost savings from these documented conversions are reported. METHODS: A before-and-after analysis of i.v.-to-oral conversions at an academic medical center following the addition of targeted interventions to an existing pharmacist-initiated conversion program was conducted. Targeted interventions included staff training on i.v.-to-oral conversions, implementation of a new documentation system, and feedback to the staff. Major outcomes studied included the total number of i.v.-to-oral conversions documented per month and the cost savings generated by these conversions. RESULTS: The mean +/- S.D. number of i.v.-to-oral conversions documented per month significantly increased after the implementation of targeted interventions (25 +/- 9 before and 57 +/- 6 after implementation, p < 0.0001). There was a nonsignificant increase in cost savings generated per month after implementation of the interventions. The most commonly converted medication was pantoprazole. Conversions of levetiracetam generated the highest cost savings. CONCLUSION: Addition of several targeted interventions to an existing pharmacist initiated i.v.-to-oral conversion program led to a significant increase in the total number of documented conversions. PMID- 26582301 TI - Prolonged oral antibiotic suppression in osteomyelitis and associated outcomes in a Veterans population. AB - OBJECTIVE: Prolonged oral antimicrobial suppression has been suggested as an alternative treatment for patients with prosthetic joint infections who are unable or unwilling to undergo surgical intervention; however, little data exists for utilizing this approach in patients with chronic osteomyelitis and no artificial hardware. METHODS: We retrospectively reviewed the medical records of all patients over a 5-year time frame who were treated with chronic oral antibiotic suppression for osteomyelitis and who had no artificial hardware. Clinical outcomes, risk factors for treatment failure, and adverse drug reactions were evaluated. RESULTS: A total of 20 patients were included for evaluation, of which 12 (60%) were able to achieve successful suppression of disease for a mean duration of 778 +/- 408 days after discontinuation. Diabetic patients were found to be at higher risk for treatment failure (p = 0.0281). We also identified a high rate of adverse events (25%) attributable to suppressive medications. Despite elevated inflammatory markers contributing to the decision to initiate antibiotic suppression in the majority of patients, few were able to achieve normal values throughout suppressive therapy. CONCLUSION: Further randomized, controlled studies are needed to determine the utility of antibiotic suppression. However, prolonged oral antibiotic suppression may be a reasonable last-line treatment alternative for chronic osteomyelitis, even in the absence of artificial hardware, for patients who are unwilling or unable to undergo optimal surgical intervention. PMID- 26582302 TI - Adherence to evidence-based treatment guidelines for bipolar depression in an inpatient setting. AB - OBJECTIVE: The purpose of this study is to determine whether patients with a discharge diagnosis of bipolar depression were prescribed medications that are in accordance with evidence-based treatment guidelines and are FDA-approved for bipolar depression. METHODS: A retrospective study was conducted to assess prescribing of evidence-based therapies for patients discharged between November 2007 and August 2010 with a diagnosis code of BPD at the time of discharge. The primary objective of the study was to determine if evidence-based medications were prescribed at the time of discharge. Secondary objectives included analysis of other medications used, concomitant disease states and drug therapy, rate of readmission, and rate of therapeutic drug monitoring. RESULTS: Of 294 patients, 170 (58%) were prescribed evidence-based medications upon discharge. The most commonly used medication was quetiapine. The most commonly prescribed off-label medications were atypical antipsychotics. For patients on antipsychotics, rates of appropriate monitoring were variable. Seventy percent of patients receiving lithium had a therapeutic concentration prior to discharge. Differences in rates of readmission between groups were not significant. CONCLUSIONS: Rates of prescribing evidence-based medications at discharge for patients with BPD were low. Additionally, evidence-based monitoring for specific medications was variable. Future studies reviewing treatment course and illness severity may provide more information about appropriate medication use in patients with BPD. PMID- 26582303 TI - Retrospective chart review comparing morphine and methadone in neonates treated for neonatal abstinence syndrome. AB - OBJECTIVE: The primary objective was to determine whether oral morphine sulfate contributed to decreased length of stay, both in the hospital and neonatal intensive care unit (NICU), when compared to oral methadone for the treatment of neonatal abstinence syndrome (NAS). Secondary objectives included evaluation of NAS scores, opioid requirements, use of adjuvant therapy, and total cost of hospital stay. METHODS: An equal number of neonates who received oral morphine sulfate and oral methadone as treatment for NAS were identified. Inclusion criteria included in utero exposure to opioids as determined by maternal history, toxicology reports during pregnancy or at the time of delivery, or infant urine toxicology reports and symptoms of NAS requiring pharmacological treatment. Exclusion criteria included neonates transferred to or from another facility during treatment, neonates discharged on NAS treatment, and neonates diagnosed with iatrogenic NAS due to postnatal exposure to opioids. RESULTS: Twenty six neonates met inclusion criteria. Statistically significant decreases in length of hospital and NICU stay, length of treatment, maximum opioid requirements, and total cost were found when neonates treated for NAS with oral morphine sulfate were compared to those treated with oral methadone. No statistically significant differences in average maximum NAS score or use of adjuvant therapy were found between the two groups. CONCLUSION: Oral morphine sulfate reduced length of NICU and hospital stay, length of treatment, and total cost of treatment for neonates treated for NAS. PMID- 26582304 TI - A careful balancing act. AB - New practitioners are challenged with transitioning from student and resident roles into those roles of an independent practitioner. Specific challenges include project undertaking and management; establishing an understanding of expected timeframes; incorporating efficiencies in daily workflow; establishing and enforcing personal limitations and asking for assistance. The new practitioner will achieve fulfillment in both his/her professional and personal life by incorporating techniques described to overcome those challenges associated with the demands of residency programs. PMID- 26582305 TI - Unfractionated heparin anticoagulation using estimated blood volume based dosing versus weight-based dosing in a Veteran population. AB - OBJECTIVE: The purpose of this study is to compare estimated blood volume (EBV) versus weight-based (WB) dosing of unfractionated heparin in terms of safety and ability to achieve therapeutic antifactor-Xa (AF-Xa) levels. METHODS: This was a retrospective, cohort study including 32 male veterans who received UFH. Primary outcome measures included time until therapeutic anticoagulation, number of adjustments needed to achieve therapeutic anticoagulation, median AF-Xa levels and the percentage of patients who were therapeutic after the first and second levels. Safety was determined as the incidence of major and minor bleeding. RESULTS: EBV dosing may be associated with a decrease in the average time to therapeutic range (20.4 +/- 16.7 hours with EBV vs. 26.8 +/- 26 hours with WB; p = 0.404) and an increase in the percentage of patients achieving therapeutic anticoagulation after the first AF-Xa level (50% with EBV vs. 35.7% with WB; p = 0.611) although these results were not statistically significant. WB dosing required fewer adjustments (2.7 +/- 2.9 with WB vs. 4 +/- 2.6 with EBV; p = 0.192) with more patients within the therapeutic range after the second AF-Xa level (42.9% with WB vs. 33.3% with EBV; p = 0.897). There was one major and three minor bleeds in the WB dosing group versus one minor bleed for the EBV dosing cohort (p = 0.438 and p = 0.323, respectively). CONCLUSION: EBV dosing achieved quick therapeutic anticoagulation with less bleeding compared to WB dosing in a veteran population. Due to the study's limitations, larger, randomized, comparative trials are needed to confirm our findings. PMID- 26582306 TI - Evaluation of the treatment of diabetic ketoacidosis in the medical intensive care unit. AB - OBJECTIVE: To determine if treatment of DKA in a sample of adult medical intensive care unit (MICU) patients was consistent with the 2006 ADA Hyperglycemic Crises in Adult Patients with Diabetes Clinical Guidelines. METHODS: Medical records were reviewed for all adult patients admitted to a MICU with a diagnosis of DKA between July 1, 2007 and June 30, 2010. The primary composite endpoint assessed fluid resuscitation (total mL/kg) at 24 hours, insulin bolus dose, and continuous insulin infusion (units/kg or units/kg/hour) to determine whether the 2006 ADA clinical guidelines for Hyperglycemic Crises in Adult Patients with Diabetes were followed. Secondary outcome measures were DKA resolution, ICU length of stay, frequency of rebound DKA within 48 hours, frequency of hypoglycemia, and time to transition to subcutaneous insulin. RESULTS: A total of 60 patients met inclusion criteria. For patients treated in compliance with the clinical guidelines compared to those that were not, total volume IV fluid infused during the first 24 hours (4.88 +/- 0.77 mL/kg/hour and 2.74 +/- 1.08 mL/kg/hour), mean dose of the insulin bolus (0.13 +/- 0.04 units/kg and 0.06 +/- 0.06 units/kg) and initial rate of the insulin infusions (0.11 +/- 0.02 units/kg/hour and 0.08 +/- 0.03 units/kg/hour) were significantly different (p <0.001). Treatment of 12 patients (20%) followed the 2006 ADA clinical guidelines, and mean time to resolution of DKA and MICU length of stay trended toward a shorter duration in these patients. CONCLUSION: Compliance with the 2006 ADA Hyperglycemic Crises in Adult Patients with Diabetes clinical guidelines was low for treatment of DKA in a sample of adult patients admitted to a MICU. Institutional guidelines for the management of diabetic ketoacidosis should be investigated as a strategy to improve compliance with national guidelines. PMID- 26582307 TI - Comparison of metoprolol succinate versus carvedilol in time to cardiovascular admission in a Veterans Affairs healthcare system: An observational study. AB - OBJECTIVE: To determine if metoprolol succinate or carvedilol is more effective in delaying the time to first cardiovascular disease hospital admission in systolic heart failure patients. As a secondary objective, to determine the most effective dose of each agent in delaying first cardiovascular disease hospital admission, including but not limited to heart failure exacerbation, myocardial infarction, ischemic heart disease, cardiac arrhythmias, or death. METHODS: This study was a retrospective chart review of 272 veterans at the VA Boston Healthcare System newly started on metoprolol succinate (n = 157) or carvedilol (n = 115) between January 2000 and December 2008. After an 8-week study medication titration period, subjects were subcategorized into low-, medium-, and high-dose ranging groups and followed until the first cardiovascular disease hospitalization, death, or 365 days. The main outcome measure was time to first cardiovascular hospitalization or death. RESULTS: The mean age (69.9 years vs. 67.9 years) and ejection fraction (26% vs. 25%) were comparable between study arms at baseline. Mean time to first cardiovascular disease hospitalization was significantly different (p = 0.001) between study groups with 330.6 days with in metoprolol succinate group vs. 282.6 days in the carvedilol groups. High-dose carvedilol significantly delayed time to first hospitalization in comparison to medium or low carvedilol doses (p = 0.015, p = 0.005). Low- and high-dose metoprolol succinate were not significantly different (p = 0.509) in time to first event, and both dosing groups fared better compared to medium dose metoprolol succinate (p = 0.046). CONCLUSION: In this veteran patient population in need of additional heart failure treatments, metoprolol succinate use resulted in a delayed time to first cardiovascular disease hospitalization or death compared to carvedilol. Both low and high doses of metoprolol succinate showed a significant delay of time to first cardiovascular hospitalization compared to medium doses of metoprolol succinate. Higher doses of carvedilol showed a significant delay of time to cardiovascular hospitalization than lower carvedilol doses. PMID- 26582308 TI - Protective effect of anti-SUAM antibodies on Streptococcus uberis mastitis. AB - In the present study, the effect of anti-recombinant Streptococcus uberis adhesion molecule (SUAM) antibodies against S. uberis intramammary infections (IMI) was evaluated using a passive protection model. Mammary quarters of healthy cows were infused with S. uberis UT888 opsonized with affinity purified anti rSUAM antibodies or hyperimmune sera. Non-opsonized S. uberis UT888 were used as a control. Mammary quarters infused with opsonized S. uberis showed mild-to undetectable clinical symptoms of mastitis, lower milk bacterial counts, and less infected mammary quarters as compared to mammary quarters infused with non opsonized S. uberis. These findings suggest that anti-rSUAM antibodies interfered with infection of mammary gland by S. uberis which might be through preventing adherence to and internalization into mammary gland cells, thus facilitating clearance of S. uberis, reducing colonization, and causing less IMI. PMID- 26582309 TI - Decreased functional connectivity between ventral tegmental area and nucleus accumbens in Internet gaming disorder: evidence from resting state functional magnetic resonance imaging. AB - BACKGROUND: Internet gaming disorder (IGD) has become an increasing mental health problem worldwide. Decreased resting-state functional connectivity (rsFC) between the ventral tegmental area (VTA) and the nucleus accumbens (NAcc) has been found in substance use and is thought to play an important role in the development of substance addiction. However, rsFC between the VTA and NAcc in a non-substance addiction, such as IGD, has not been assessed previously. The current study aimed to investigate: (1) if individuals with IGD exhibit alterations in VTA-NAcc functional connectivity; and (2) whether VTA-NAcc functional connectivity is associated with subjective Internet craving. METHODS: Thirty-five male participants with IGD and 24 healthy control (HC) individuals participated in resting-state functional magnetic resonance imaging. Regions of interest (left NAcc, right NAcc and VTA) were selected based on the literature and were defined by placing spheres centered on Talairach Daemon coordinates. RESULTS: In comparison with HCs, individuals with IGD had significantly decreased rsFC between the VTA and right NAcc. Resting-state functional connectivity strength between the VTA and right NAcc was negatively correlated with self-reported subjective craving for the Internet. CONCLUSIONS: These results suggest possible neural functional similarities between individuals with IGD and individuals with substance addictions. PMID- 26582310 TI - Does a 20-week aerobic exercise training programme increase our capabilities to buffer real-life stressors? A randomized, controlled trial using ambulatory assessment. AB - PURPOSE: The cross-stressor adaptation hypothesis suggests that regular exercise leads to adaptations in the stress response systems that induce decreased physiological responses to psychological stressors. Even though an exercise intervention to buffer the detrimental effects of psychological stressors on health might be of utmost importance, empirical evidence is mixed. This may be explained by the use of cross-sectional designs and non-personally relevant stressors. Using a randomized controlled trial, we hypothesized that a 20-week aerobic exercise training does reduce physiological stress responses to psychological real-life stressors in sedentary students. METHODS: Sixty-one students were randomized to either a control group or an exercise training group. The academic examination period (end of the semester) served as a real-life stressor. We used ambulatory assessment methods to assess physiological stress reactivity of the autonomic nervous system (heart rate variability: LF/HF, RMSSD), physical activity and perceived stress during 2 days of everyday life and multilevel models for data analyses. Aerobic capacity (VO2max) was assessed pre- and post-intervention via cardiopulmonary exercise testing to analyze the effectiveness of the intervention. RESULTS: During real-life stressors, the exercise training group showed significantly reduced LF/HF (beta = -0.15, t = 2.59, p = .01) and increased RMSSD (beta = 0.15, t = 2.34, p = .02) compared to the control group. CONCLUSIONS: Using a randomized controlled trial and a real life stressor, we could show that exercise appears to be a useful preventive strategy to buffer the effects of stress on the autonomic nervous system, which might result into detrimental health outcomes. PMID- 26582312 TI - Effects of Implantable Collamer Lens V4c Placement on Iridocorneal Angle Measurements by Fourier-Domain Optical Coherence Tomography. AB - PURPOSE: To assess by Fourier-domain optical coherence tomography (FDOCT) changes produced in iridocorneal angle measurements in patients undergoing Visian Implantable Collamer Lens (ICL) V4c (STAAR Surgical AG) placement. DESIGN: Prospective interventional case series. METHODS: In 50 eyes of 25 myopic subjects consecutively scheduled for ICL implant, FDOCT (RTVue; Optovue Inc) iridocorneal angle measurements were made before and 1 and 3 months after surgery. Trabecular iris angle (TIA) and angle opening distance 500 MUm anterior to the scleral spur (AOD500) were compared among the quadrants nasal, temporal, and inferior, and correlations with ocular variables including lens vault were examined. RESULTS: Preoperative TIA was 48.7 +/- 8.7, 48.2 +/- 8.7, and 48.7 +/- 9.3 degrees for the nasal, temporal, and inferior quadrants, with no differences (P = 1.000). Following ICL implant, corresponding values fell to 31.2 +/- 11.5, 30.0 +/- 10.7, and 29.7 +/- 8.1 degrees at 1 month postsurgery, indicating angle narrowing of 34%-42%, and to 30.6 +/- 12.3, 30.1 +/- 11.9, and 29.8 +/- 12.3 degrees, respectively, at 3 months postsurgery. Angle measurements failed to vary between 1 month and 3 months postsurgery (P = .481). In 8 eyes, iridotrabecular contact attributable to surgery was observed. One month after surgery, vault measurements correlated with TIA (R = -.309; P = .048). Six variables were identified as predictors of TIA at 1 month postsurgery (R(2) = .907). CONCLUSIONS: Although considerable angle narrowing was detected 1 month after ICL V4c implant, this narrowing remained stable at 3 months postsurgery. Factors predictive of TIA could serve to identify suitable candidates for ICL placement. PMID- 26582311 TI - Inverted Internal Limiting Membrane Insertion for Macular Hole-Associated Retinal Detachment in High Myopia. AB - PURPOSE: To investigate the surgical outcomes of inverted internal limiting membrane (ILM) insertion in macular hole (MH)-associated retinal detachment (RD) in high myopia. DESIGN: Retrospective, interventional, consecutive case series. METHODS: This study was conducted at 2 medical centers. Consecutive cases of highly myopic eyes with MH-associated RD were included. Forty eyes were divided into 2 groups: Group 1 (20 eyes) received vitrectomy, ILM peeling within the arcade area, and air-fluid exchange, and Group 2 (20 eyes) received vitrectomy, inverted ILM inserted into the macular hole, and air-fluid exchange. Optical coherence tomography was used to observe the closure of the macular hole. Corrected visual acuity (VA) was also recorded. Two-sample t test and Mann Whitney U test were used for statistical analysis to compare differences between the 2 groups. RESULTS: MH was closed in 35% of the eyes in Group 1 and in all eyes in Group 2 (P < .001). Significant improvement in VA in logarithm of minimal angle of resolution (logMAR) was achieved in both groups. There was no difference in the initial, final, or improvement of logMAR VA in the 2 groups. CONCLUSION: Inverted ILM insertion into a macular hole effectively helps close the macular hole in MH-associated RD in high myopia. This may prevent the possible re detachment from the MH. A prospective study with a larger number of cases and longer follow-up may help validate our findings. PMID- 26582313 TI - Toward a synthesis of genotypic typing and phenotypic inference in the genomics era. PMID- 26582314 TI - Enhanced transport of Si-coated nanoscale zero-valent iron particles in porous media. AB - Laboratory column experiments were conducted to evaluate the effect of previously described silica coating method on the transport of nanoscale zero-valent iron (nZVI) in porous media. The silica coating method showed the potential to prevent the agglomeration of nZVI. Transport experiments were conducted using laboratory scale sand-packed columns at conditions that were very similar of natural groundwater. Transport properties of non-coated and silica-coated nZVI are investigated in columns of 40 cm length, which were filled with porous media. A suspension was injected in three different Fe particle concentrations (100, 500, and 1000 mg/L) at flow 5 mL/min. Experimental results were compared using nanoparticle attachment efficiency and travel distances which were calculated by classical particle filtration theory. It was found that non-coated particles were essentially immobile in porous media. In contrast, silica-coated particles showed significant transport distances at the tested conditions. Results of this study suggest that silica can increase nZVI mobility in the subsurface. PMID- 26582316 TI - The Immune System and the Brain: Crosstalk with a Broad Impact From Host Defense to Cognition. PMID- 26582315 TI - Ultrasound-guided ilioinguinal/iliohypogastric block did not reduce emergence delirium after ambulatory pediatric inguinal hernia repair: a prospective randomized double-blind study. AB - PURPOSE: Emergence delirium (ED) is a common postoperative complication of ambulatory pediatric surgery done under general anesthesia with sevoflurane. However, perioperative analgesic techniques have been shown to reduce sevoflurane induced ED. The primary objective of this investigation was to examine whether an ultrasound-guided ilioinguinal/iliohypogastric (II/IH) nerve block for ambulatory pediatric inguinal hernia repair could reduce the incidence of sevoflurane induced ED. METHODS: The subjects of this prospective randomized double-blind study were 40 boys ranging in age from 1 to 6 years, who were scheduled to undergo ambulatory inguinal hernia repair. The patients were randomized to either receive or not to receive an ultrasound-guided II/IH nerve block (Group B and Group NB, respectively). General anesthesia was maintained with sevoflurane and nitrous oxide. The primary outcome assessed was ED, evaluated using the Pediatric Anesthesia Emergence Delirium (PAED) scale 30 min after emergence from general anesthesia. The secondary outcomes assessed were postoperative pain, evaluated using the Behavioral Observational Pain Scale (BOPS), and the amount of intra operative sevoflurane given. RESULTS: The median PAED scale scores did not differ between Groups B and NB at 30 min (P = 0.41). BOPS scores also did not differ significantly between the groups, but the mean amount of intraoperative sevoflurane given was significantly lower in Group B than in Group NB (P < 0.01). CONCLUSIONS: Ultrasound-guided II/IH nerve block for ambulatory pediatric inguinal hernia repair did not reduce ED, but it did decrease the amount of intra operative sevoflurane needed. CLINICAL TRIAL REGISTRATION: UMIN000008586. PMID- 26582317 TI - Prevalence of Vitamin D deficiency in Pakistan and implications for the future. AB - BACKGROUND AND AIMS: vitamin D deficiency (25-hydroxyvitamin D) affects over one billion people worldwide. Vitamin D deficiency results in progression of osteoporosis as well as other conditions. Previous studies have shown high rates of vitamin D deficiency in Pakistan despite appreciable levels of sunshine. However, none have assessed vitamin D deficiency across all age groups, genders, incomes, and locations to guide future strategies. METHODS: Questionnaire and blood sampling among 4830 randomly selected citizens. RESULTS: High levels of deficiency among all age groups, genders, income levels, and locations. Amongst the selected citizens, 53.5% had vitamin D deficiency, 31.2% had insufficient vitamin D, and only 15.3% normal vitamin D. CONCLUSION: High rates of vitamin D deficiency in Pakistan despite high levels of sunshine and previous Food Acts asking for food fortification with vitamin D. Public health strategies are needed to address high deficiency rates, including food fortification, i.e. nurture, alongside increasing exposure to sunlight, i.e. nature. This will involve all key stakeholder groups. PMID- 26582319 TI - Measuring the Sensitivity and Construct Validity of 6 Utility Instruments in 7 Disease Areas. AB - BACKGROUND: Health services that affect quality of life (QoL) are increasingly evaluated using cost utility analyses (CUA). These commonly employ one of a small number of multiattribute utility instruments (MAUI) to assess the effects of the health service on utility. However, the MAUI differ significantly, and the choice of instrument may alter the outcome of an evaluation. AIMS: The present article has 2 objectives: 1) to compare the results of 3 measures of the sensitivity of 6 MAUI and the results of 6 tests of construct validity in 7 disease areas and 2) to rank the MAUI by each of the test results in each disease area and by an overall composite index constructed from the tests. METHODS: Patients and the general public were administered a battery of instruments, which included the 6 MAUI, disease-specific QoL instruments (DSI), and 6 other comparator instruments. In each disease area, instrument sensitivity was measured 3 ways: by the unadjusted mean difference in utility between public and patient groups, by the value of the effect size, and by the correlation between MAUI and DSI scores. Content and convergent validity were tested by comparison of MAUI utilities and scores from the 6 comparator instruments. These included 2 measures of health state preferences, measures of subjective well-being and capabilities, and generic measures of physical and mental QoL derived from the SF-36. RESULTS: The apparent sensitivity of instruments varied significantly with the measurement method and by disease area. Validation test results varied with the comparator instruments. Notwithstanding this variability, the 15D, AQoL-8D, and the SF-6D generally achieved better test results than the QWB and EQ-5D-5L. PMID- 26582318 TI - Analysis of cbbL, nifH, and pufLM in Soils from the Sor Rondane Mountains, Antarctica, Reveals a Large Diversity of Autotrophic and Phototrophic Bacteria. AB - Cyanobacteria are generally thought to be responsible for primary production and nitrogen fixation in the microbial communities that dominate Antarctic ecosystems. Recent studies of bacterial communities in terrestrial Antarctica, however, have shown that Cyanobacteria are sometimes only scarcely present, suggesting that other bacteria presumably take over their role as primary producers and diazotrophs. The diversity of key genes in these processes was studied in surface samples from the Sor Rondane Mountains, Dronning Maud Land, using clone libraries of the large subunit of ribulose-1,5-biphosphate carboxylase/oxygenase (RuBisCO) genes (cbbL, cbbM) and dinitrogenase-reductase (nifH) genes. We recovered a large diversity of non-cyanobacterial cbbL type IC in addition to cyanobacterial type IB, suggesting that non-cyanobacterial autotrophs may contribute to primary production. The nifH diversity recovered was predominantly related to Cyanobacteria, particularly members of the Nostocales. We also investigated the occurrence of proteorhodopsin and anoxygenic phototrophy as mechanisms for non-Cyanobacteria to exploit solar energy. While proteorhodopsin genes were not detected, a large diversity of genes coding for the light and medium subunits of the type 2 phototrophic reaction center (pufLM) was observed, suggesting for the first time, that the aerobic photoheterotrophic lifestyle may be important in oligotrophic high-altitude ice-free terrestrial Antarctic habitats. PMID- 26582320 TI - Growth-suppressive effect of suberoylanilide hydroxamic acid (SAHA) on human oral cancer cells. AB - PURPOSE: The histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) has been reported to exhibit anticancer activities in various cancer cell types, but as yet there are few reports on the anticancer effects of SAHA in oral squamous cell carcinoma (OSCC)-derived cells and xenograft models. METHODS: The anti-proliferative and apoptotic activities of SAHA were assessed in human HSC-3 and HSC-4 (OSCC)-derived cell lines and JB6 normal mouse skin-derived epidermal cells using histone acetylation, soft agar colony formation, trypan blue exclusion, 4'-6-diamidino-2-phenylindole (DAPI) staining, Live/Dead viability/cytotoxicity and Western blot analyses. RESULTS: We found that SAHA treatment resulted in hyperacetylation of histones H2A and H3 and a concomitant decrease in the viability of HSC-3 and HSC-4 cells. SAHA also significantly inhibited the neoplastic transformation of JB6 cells treated with TPA, whereas the viability of these cells was not affected by this treatment. Additionally, we found that SAHA suppressed the anchorage-independent growth (colony forming capacity in soft agar) of HSC-3 and HSC-4 cells. DAPI staining, Live/Dead and Western blot analyses revealed that SAHA can induce caspase-dependent apoptosis in HSC-3 and HSC-4 cells. We also found that SAHA treatment led to inhibition of ERK phosphorylation, and that two MEK inhibitors potentiated SAHA-mediated apoptosis. Okadaic acid treatment inhibited SAHA-mediated apoptosis in both the HSC-3 and HSC-4 cell lines, wheras SAHA induced a profound in vivo inhibition of tumor growth in HSC-3 xenografts. CONCLUSIONS: Our results indicate that the ERK signaling pathway may constitute a critical denominator of SAHA-induced apoptosis in OSCC-derived cells and that SAHA may have therapeutic potential for OSCC. PMID- 26582321 TI - Flavonoids as dopaminergic neuromodulators. AB - SCOPE: The present study aimed to characterize and evaluate flavonoids effects on organic cation uptake in neuronal cells. METHODS AND RESULTS: Uptake experiments were conducted using radiolabeled methyl-4-phenylpyridinuim ([(3) H]-MPP(+) ), in human neuronal dopaminergic cells, SH-SY5Y. Catechin did not alter [(3) H]-MPP(+) uptake, however its metabolite 4'-methyl-catechin decreased it by almost 50%. Epicatechin and its methylated metabolites also decreased [(3) H]-MPP(+) uptake. Interestingly, the quercetin flavonol and its metabolite conjugated with glucuronic acid, as well as the flavanones naringenin and hesperitin, increased [(3) H]-MPP(+) uptake. CONCLUSION: These results showed that different classes of flavonoids, as well as its metabolites, differently influence neuronal organic cation uptake. Several xeno- and endobiotics, including neurotransmitters, are organic cations. Specific food recommendations may be beneficial in pathological conditions where levels of neurotransmitters, as dopamine, are either increased or decreased. PMID- 26582322 TI - Contrast does not lie, but can we see the true? AB - The ability to estimate true length in the coronary artery by simple visual inspection appears to be as inaccurate as estimates of coronary stenosis. Recognizing this physician-related factor may play a roll in correct choice of stent length and thereby effect procedural outcome is the first step in improving results. Further work is needed on how adjunctive equipment with reference markers such as wires or balloons may improve on the estimate of length is needed. PMID- 26582323 TI - AVERTing contrast nephropathy--delivering less to get more? AB - Delivered contrast volume is the major modifiable risk factor for contrast nephropathy. The AVERT system can divert 31-40% of contrast for peripheral angiography. The upcoming results of the AVERT clinical trial will demonstrate whether the AVERT system reduces contrast nephropathy. PMID- 26582324 TI - One step forward or eight needles back: A retro(grade) approach to femoral hemostasis for TAVR. AB - Percutaneous approach rather than surgical cutdown is the procedure of choice for TAVR patients to minimize morbidity and procedure time. ProGlide has been shown to have noninferior outcomes versus surgical cutdown with shorter procedure time and less pain; noninferiority was not demonstrated by single Prostar XL in a randomized trial of "preclosure" for endovascular aortic aneurysm repair. The current study did not include a ProGlide arm. As the size of Transcatheter Aortic Valve Replacement devices continues to decrease, the need for large bulky 4 needle devices like the Prostar XL is likely to become obsolete. PMID- 26582325 TI - Poor mobility independently predicts mortality in TAVI: Are we closer to a universal definition for frailty? AB - Frailty assessment aids appropriate patient selection for transcatheter aortic valve implantation (TAVI). An uncumbersome and easy to use evaluation tool is needed to facilitate wider uptake among TAVI teams. Mobility assessment by the euroSCORE definition can be utilized as a one-point measure and may be indicative of short- and long-term outcomes post TAVI. Frailty is an evolving concept and further data are warranted, with validation across regions to determine a gold standard. PMID- 26582326 TI - Mitral valve-in-valve with the Lotus mechanically expanding platform. AB - Disadvantages of existing balloon expandable or self-expanding transcatheter platforms for mitral valve-in-valve include the potential for malposition during deployment and for LV outflow tract obstruction Controlled mechanical valve expansion, the option to reposition, and stable hemodynamics throughout the procedure make the LOTUS valve an attractive option for mitral valve-in-valve Correct sizing remains a critical aspect of all trancatheter valve implant procedures, including valve-in-valve implants. PMID- 26582328 TI - Unusual paraneoplastic neurological syndrome secondary to a well differentiated pancreatic neuroendocrine tumor: a case report and review of the literature. AB - BACKGROUND: Paraneoplastic neurological syndrome (PNS) is a heterogeneous group of disorders affecting any part of the nervous system, in a patient affected by cancer. PNS is estimated to occur in 0.01 to 8% of cancer patients, with higher incidence in those with small cell lung cancer, gynecological tumours or hematological disease. Paraneoplastic cerebellar degeneration (PCD) is the most common PNS, but it has never been reported in patients with pancreatic well differentiated neuroendocrine tumours. CASE PRESENTATION: A 61-year-old man presented with an unusual PNS and absence of circulating neural auto-antibodies. Subsequently, contrast-enhanced computed tomography revealed a large pancreatic mass, together with multiple liver metastases, histologically diagnosed as a well differentiated neuroendocrine tumor. Initial treatment with long-acting somatostatin analogue (octreotide LAR) and prednisone achieved a biochemical response (reduction of chromogranin A level) and a radiological disease control, but patient experienced only a brief improvement of neurological symptoms. Seven months after the onset of the symptoms, he died from neurological impairment. CONCLUSIONS: PNS can be associated with metastatic non-functioning well differentiated pancreatic neuroendocrine tumors. These tumors may be unresponsive to treatment with somatostatin analogues and an early neurological treatment should be considered for the optimal management of these uncommon cases. PMID- 26582329 TI - Computational models of atrial cellular electrophysiology and calcium handling, and their role in atrial fibrillation. AB - The complexity of the heart makes an intuitive understanding of the relative contribution of ion channels, transporters and signalling pathways to cardiac electrophysiology challenging. Computational modelling of cardiac cellular electrophysiology has proven useful to integrate experimental findings, extrapolate results obtained in expression systems or animal models to other systems, test quantitatively ideas based on experimental data and provide novel hypotheses that are experimentally testable. While the bulk of computational modelling has traditionally been directed towards ventricular bioelectricity, increasing recognition of the clinical importance of atrial arrhythmias, particularly atrial fibrillation, has led to widespread efforts to apply computational approaches to understanding atrial electrical function. The increasing availability of detailed, atrial-specific experimental data has stimulated the development of novel computational models of atrial-cellular electrophysiology and Ca(2+) handling. To date, more than 300 studies have employed mathematical simulations to enhance our understanding of atrial electrophysiology, arrhythmogenesis and therapeutic responses. Future modelling studies are likely to move beyond current whole-cell models by incorporating new data on subcellular architecture, macromolecular protein complexes, and localized ion-channel regulation by signalling pathways. At the same time, more integrative multicellular models that take into account regional electrophysiological and Ca(2+) handling properties, mechano-electrical feedback and/or autonomic regulation will be needed to investigate the mechanisms governing atrial arrhythmias. A combined experimental and computational approach is expected to provide the more comprehensive understanding of atrial arrhythmogenesis that is required to develop improved diagnostic and therapeutic options. Here, we review this rapidly expanding area, with a particular focus on Ca(2+) handling, and provide ideas about potential future directions. PMID- 26582330 TI - Clustering of monozygotic twinning in IVF. AB - PURPOSE: The aim of this analysis was to study whether monozygotic twinning (MZT) events occur in clusters after IVF and, if so, to explore possible explanations for this clustering. METHODS: This is a retrospective cohort study carried out in a single, large university-affiliated reproductive medicine practice. Medical records of all patients who had undergone fresh IVF cycles, resulting in a viable clinical pregnancy, from Jan 2002 to Dec 2013 were reviewed. The incidence of MZT in 6-month intervals and the association with independent risk factors such as maternal age, extended embryo culture, PGD/intracytoplasmic sperm injection (ICSI)/assisted hatching performed were analyzed. RESULTS: Over the 12-year study period, 25,502 fresh IVF cycles were performed, resulting in 8598 clinical pregnancies. Ninety-five cycles (1.1 %) resulted in MZ twins. The percentage of MZT was >2 standard deviations (SD) higher than the overall percentage of MZT in 4 of the 24 6-month intervals. PGD, extended embryo culture (>=4 days), and more recent cycles (2005 or later) were independent risk factors for MZT. The use of multivariable logistic regression modeling to control for risk factors for MZT did not correct for this clustering effect, with both high-risk interval (clustering) and extended embryo culture remaining significant. CONCLUSION: This study supports our hypothesis that MZT occurs in clusters and that this clustering effect could not be explained by demographics and cycle characteristics alone. Although we are unable to explain the clustering phenomenon, this study is important as it highlights high-risk intervals for MZT and opens the door to performing a more detailed investigation, to identify the mechanisms responsible for the spikes of MZT incidence. PMID- 26582331 TI - [Computed tomography with computer-assisted detection of pulmonary nodules in dogs and cats]. AB - OBJECTIVE: The aim of this study was to assess the potential benefit of computer assisted detection (CAD) of pulmonary nodules in veterinary medicine. Therefore, the CAD rate was compared to the detection rates of two individual examiners in terms of its sensitivity and false-positive findings. MATERIALS AND METHODS: We included 51 dogs and 16 cats with pulmonary nodules previously diagnosed by computed tomography. First, the number of nodules >= 3 mm was recorded for each patient by two independent examiners. Subsequently, each examiner used the CAD software for automated nodule detection. With the knowledge of the CAD results, a final consensus decision on the number of nodules was achieved. The software used was a commercially available CAD program. RESULTS: The sensitivity of examiner 1 was 89.2%, while that of examiner 2 reached 87.4%. CAD had a sensitivity of 69.4%. With CAD, the sensitivity of examiner 1 increased to 94.7% and that of examiner 2 to 90.8%. CONCLUSION AND CLINICAL RELEVANCE: The CAD-system, which we used in our study, had a moderate sensitivity of 69.4%. Despite its severe limitations, with a high level of false-positive and false-negative results, CAD increased the examiners' sensitivity. Therefore, its supportive role in diagnostics appears to be evident. PMID- 26582332 TI - The 28th International Symposium on Paediatric Surgical Research. PMID- 26582334 TI - Enhanced oral bioavailability of lurasidone by self-nanoemulsifying drug delivery system in fasted state. AB - OBJECTIVE: The purpose of this work was to develop a new formulation to enhance the bioavailability and reduce the food effect of lurasidone using self nanoemulsifying drug delivery systems (SNEDDSs). METHODS: The formulation of lurasidone-SNEDDS was selected by the solubility and pseudo-ternary phase diagram studies. The prepared lurasidone-SNEDDS formulations were characterized for self emulsification time, effect of pH and robustness to dilution, droplet size analysis, zeta potential and in vitro drug release. Lurasidone-SNEDDSs were administered to beagle dogs in fed and fasted state and their pharmacokinetics were compared to commercial available tablet as a control. RESULTS: The result showed lurasidone-SNEDDS was successfully prepared using Capmul MCM, Tween 80 and glycerol as oil phase, surfactant and co-surfactant, respectively. In vitro drug release studies indicated that the lurasidone-SNEDDS showed improved drug release profiles and the release behavior was not affected by the medium pH with total drug release of over 90% within 5 min. Pharmacokinetic study showed that the AUC(0-infinity) and Cmax for lurasidone-SNEDDS are similar in the fasted and fed state, indicating essentially there is no food effect on the drug absorption. CONCLUSION: It was concluded that enhanced bioavailability and no food effect of lurasidone had been achieved by using SNEDDS. PMID- 26582335 TI - Natural product derived insecticides: discovery and development of spinetoram. AB - This review highlights the importance of natural product research and industrial microbiology for product development in the agricultural industry, based on examples from Dow AgroSciences. It provides an overview of the discovery and development of spinetoram, a semisynthetic insecticide derived by a combination of a genetic block in a specific O-methylation of the rhamnose moiety of spinosad coupled with neural network-based QSAR and synthetic chemistry. It also emphasizes the key role that new technologies and multidisciplinary approaches play in the development of current spinetoram production strains. PMID- 26582336 TI - Mean arterial pressure at 12, 22, 32 and 36 weeks' gestation in screening for pre eclampsia. AB - OBJECTIVE: To examine the distribution of mean arterial pressure (MAP) at 12, 22, 32 and 36 weeks' gestation in singleton pregnancies which develop pre-eclampsia (PE) and examine the performance of this biomarker in screening for PE. METHODS: MAP was measured in 77 343 cases at 11-13 weeks, in 31 120 cases at 19-24 weeks, in 29 802 at 30-34 weeks and 5543 at 35-37 weeks. Bayes' theorem was used to combine the a-priori risk from maternal characteristics and medical history with MAP. The performance of screening for PE requiring delivery < 32, at 32 + 0 to 36 + 6 and >= 37 weeks' gestation was estimated. RESULTS: In pregnancies that developed PE, MAP was increased and the separation in multiples of the median (MoM) values from normal was greater with an earlier, compared to later, gestational age at which delivery for PE became necessary. Additionally, the slope of the regression lines of MAP MoM with gestational age at delivery in pregnancies that developed PE increased with advancing gestational age at screening. The detection rate (DR), at a false-positive rate of 10%, for PE delivering < 32 weeks was 66% and 72% with screening at 12 and 22 weeks, respectively. The DR for PE delivering at 32 + 0 to 36 + 6 weeks was 54%, 56% and 81% with screening at 12, 22 and 32 weeks. The DR for PE delivering >= 37 weeks was 45%, 43%, 49% and 59% with screening at 12, 22, 32 and 36 weeks, respectively. CONCLUSIONS: The performance of combined screening with maternal factors and MAP is superior in screening for early, compared to late, PE and, to a certain extent, improves with advancing gestational age at screening. Copyright (c) 2015 ISUOG. Published by John Wiley & Sons Ltd. PMID- 26582333 TI - The Effects of Lipid Membranes, Crowding and Osmolytes on the Aggregation, and Fibrillation Propensity of Human IAPP. AB - Type 2 diabetes mellitus (T2DM) is an age-related and metabolic disease. Its development is hallmarked, among others, by the dysfunction and degeneration of beta-cells of the pancreatic islets of Langerhans. The major pathological characteristic thereby is the formation of extracellular amyloid deposits consisting of the islet amyloid polypeptide (IAPP). The process of human IAPP (hIAPP) self-association, and the intermediate structures formed as well as the interaction of hIAPP with membrane systems seem to be, at least to a major extent, responsible for the cytotoxicity. Here we present a summary and comparison of the amyloidogenic propensities of hIAPP in bulk solution and in the presence of various neutral and charged lipid bilayer systems as well as biological membranes. We also discuss the cellular effects of macromolecular crowding and osmolytes on the aggregation pathway of hIAPP. Understanding the influence of different cellular factors on hIAPP aggregation will provide more insight into the onset of T2DM and help to develop novel therapeutic strategies. PMID- 26582337 TI - Effects of X-radiation on lung cancer cells: the interplay between oxidative stress and P53 levels. AB - Lung cancer (LC) ranks as the most prevalent and deadliest cause of cancer death worldwide. Treatment options include surgery, chemotherapy and/or radiotherapy, depending on LC staging, without specific highlight. The aim was to evaluate the effects of X-radiation in three LC cell lines. H69, A549 and H1299 cell lines were cultured and irradiated with 0.5-60 Gy of X-radiation. Cell survival was evaluated by clonogenic assay. Cell death and the role of reactive oxygen species, mitochondrial membrane potential, BAX, BCL-2 and cell cycle were analyzed by flow cytometry. Total and phosphorylated P53 were assessed by western blotting. Ionizing radiation decreases cell proliferation and viability in a dose , time- and cell line-dependent manner, inducing cell death preferentially by apoptosis with cell cycle arrest. These results may be related to differences in P53 expression and oxidative stress response. The results obtained indicate that sensibility and/or resistance to radiation may be dependent on molecular LC characteristics which could influence response to radiotherapy and treatment success. PMID- 26582338 TI - Ligand-driven conformational changes of MurD visualized by paramagnetic NMR. AB - Proteins, especially multi-domain proteins, often undergo drastic conformational changes upon binding to ligands or by post-translational modifications, which is a key step to regulate their function. However, the detailed mechanisms of such dynamic regulation of the functional processes are poorly understood because of the lack of an efficient tool. We here demonstrate detailed characterization of conformational changes of MurD, a 47 kDa protein enzyme consisting of three domains, by the use of solution NMR equipped with paramagnetic lanthanide probe. Quantitative analysis of pseudocontact shifts has identified a novel conformational state of MurD, named semi-closed conformation, which is found to be the key to understand how MurD regulates the binding of the ligands. The modulation of the affinity coupled with conformational changes accentuates the importance of conformational state to be evaluated in drug design. PMID- 26582339 TI - Magnetic chitosan-graphene oxide composite for anti-microbial and dye removal applications. AB - Magnetic chitosan-graphene oxide (MCGO) nanocomposite was prepared as a multi functional nanomaterial for the applications of antibacterial and dye removal. The nanocomposite was characterized by scanning electronic microscope (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD) and Fourier transform infrared spectrometer (FTIR). The antibacterial performance for MCGO against Escherichia coli was varied depending on the concentration of MCGO. SEM images of E. coli cells demonstrated that the antimicrobial performance of MCGO nanocomposite was possibly due to the damage of cell membrane. This work also explored MCGO's adsorption performance for methyl orange (MO). The experimental parameters including adsorbent mass, pH value, contact time and concentration of MO on the adsorption capacity were investigated. The maximum adsorption capacity of MCGO for MO was 398.08 mg/g. This study showed that the MCGO offered enormous potential applications for water treatment. PMID- 26582340 TI - Thermochemical properties of cellulose acetate blends with acetosolv and sawdust lignin: A comparative study. AB - Sawdust (SD) and cotton-lignin blends (CLB) were acetylated and the effect of lignin type and content on thermoplastic properties of the acetate produced was studied. The lignin in samples did not significantly affect the degree of acetylation. An increase in acetyl groups of 1-3% was observed in acetylated SD (ASD) unlike acetylated CLB (ACLB). Thermogravimetric analysis showed two thermal degradation zones; one at 190-200 degrees C and the other at 330-370 degrees C. The early degradation in ASD corresponds to galactoglucomannans while that in ACLB corresponds to the low-molecular-weight lignin. The second degradation is due to decomposition of cellulose acetate and high-molecular-weight lignin. DSC analysis showed homogeneous behaviour in ASD with only one glass transition temperature (Tg) at 170-180 degrees C, unlike ACLB that showed two Tgs at 170-180 degrees C. Sawdust acetylation, taking advantage of its residual lignin, showed higher reactivity and miscibility as compared to the same material produced by adding previously extracted lignin on cotton. PMID- 26582341 TI - Impact of germination on the structures and in vitro digestibility of starch from waxy brown rice. AB - The in vitro digestibility as well as the molecular and crystalline structures of waxy rice starches isolated from brown rice, germinated brown rice (GBR), ultrasonicated GBR, and heat-moisture treated GBR were investigated. The germinated brown rice starch (GBRS) had a lower average molecular weight and a higher proportion of DP 6-12 in amylopectin than brown rice starch (BRS). The relative crystallinity, intensity ratio of the band at 1,047 cm(-1) and 1,022 cm( 1), gelatinization temperature and pasting temperature of waxy rice starch were reduced by germination. However, the ultrasonication and heat-moisture treatment of GBRS increased the relative crystallinity and gelatinization temperature. The digestibility of starch from brown waxy rice was increased by germination. The rapidly digestible starch (RDS), slowly digestible starch (SDS) and resistant starch (RS) contents were 50.5%, 42.4%, and 7.1% in BRS, and 69.0%, 27.9% and 3.1% in GBRS, respectively. The ultrasonication and heat-moisture treatment of GBRS reduced RDS content and increased RS content in raw and gelatinized starches. The decrease in starch digestibility of cooked GBR was more pronounced after heat-moisture treatment than after ultrasonication. PMID- 26582342 TI - Exopolysaccharide produced by Enterobacter sp. YG4 reduces uranium induced nephrotoxicity. AB - Uranium nephrotoxicity is a health concern with very few treatment options. Bacterial exopolysaccharides (EPS) possess multiple biological activities and appear as prospective candidates for treating uranium nephrotoxicity. This study focuses on the ability of an EPS produced by a bacterial strain Enterobacter sp. YG4 to reduce uranium nephrotoxicity in vivo. This bacterium was isolated from the gut contents of a slug Laevicaulis alte (Ferussac). Based on the aniline blue staining reaction and infrared spectral analysis, the EPS was identified as beta glucan and its molecular weight was 11.99*10(6)Da. The EPS showed hydroxyl radical scavenging ability and total antioxidant capacity in vitro. To assess the protection provided by the EPS against uranium nephrotoxicity, a single dose of 2mg/kg uranyl nitrate was injected intraperitoneally to albino Wistar rats. As intervention, the EPS was administered orally (100mg/kg/day) for 4 consecutive days. The rats were sacrificed on the fifth day and analyses were conducted. Increased serum creatinine and urea nitrogen levels and histopathological alterations in kidneys were observed in uranyl nitrate treated animals. All these alterations were reduced with the administration of Enterobacter sp. YG4 EPS, emphasizing a novel approach in treating uranium nephrotoxicity. PMID- 26582343 TI - Porphyric neuropathies in an acute intermittent porphyria family. AB - The objective of this study was to investigate two patients with porphyric neuropathy in a family with acute intermittent porphyria. Molecular analysis of the porphobilinogen deaminase (PBGD) gene was performed. We analyzed the clinical course of peripheral neuropathy and serial changes in nerve conduction studies (NCS) of the two patients. We also examined the pathological findings of sural nerve biopsy in one patient. Molecular analysis of the PBGD gene revealed a missense mutation (Arg26His) in exon 2 for two patients and their family members. Distal polyneuropathy was noted in the patients with chronic porphyric neuropathy. In the follow-up NCS, recovery was relatively poor in the lower limb in one patient with severe polyneuropathy, and NCS evidence of deterioration was found following frequent hormone-related porphyric attacks in another patient. The sural nerve biopsy showed marked loss of myelinated and unmyelinated fibers in one patient with chronic porphyric neuropathy. In contrast to radial and fibular motor nerves in acute porphyric neuropathy, the sural nerve is vulnerable to involvement in chronic porphyric neuropathy following repeated porphyric attack as seen in the NCS. PMID- 26582344 TI - Insulin-like growth factor I (IGF-I) in Chinese alligator, Alligator sinensis: Molecular characterization, tissue distribution and mRNA expression changes during the active and hibernating periods. AB - The Chinese alligator Alligator sinensis is an endangered species endemic to China, up to date, little is known about the regulation of its growth and development. Insulin-like growth factor I (IGF-I) plays a vital role in regulating vertebrate growth and development. In this study, the full-length cDNA of IGF-I in Chinese alligator (caIGF-I) was obtained for the first time, it contains 890-bp nucleotides encoding a 153-amino acid precursor, the mature caIGF I consists of 70 amino acids by cleaving the signal peptide and C-terminal extension (E domain). The caIGF-I contains all the features of IGF-I peptide with B, C, A, and D domains and the six conservative cysteine residues involved in the stable tertiary structure. Multiple alignment analysis showed that the amino acid sequence of caIGF-I shares high identity with American alligator Alligator mississippiensis (100%) and birds (95-97%). Phylogenetic tree analysis of the IGF I amino acid sequences indicated that alligators cluster into the bird branch. Real-time quantitative PCR technique showed that caIGF-I is widely expressed in all the examined tissues with the highest expression level in liver, higher in pancreas and oviduct while lower in heart, spleen, lung, kidney, stomach, intestines, ovary and muscles. During hibernation, the caIGF-I expression level decreased significantly in liver, pancreas, oviduct and kidney, while did not significantly change in heart, spleen, lung, stomach, small intestine, ovary and muscles. The mRNA expression changes during the two periods implicate that caIGF I might play an important role in the regulation of feeding and growth in the Chinese alligator. PMID- 26582345 TI - Is emergency and salvage coronary artery bypass grafting justified? The Nordic Emergency/Salvage coronary artery bypass grafting study. AB - OBJECTIVES: According to the EuroSCORE-II criteria, patients undergoing emergency coronary artery bypass grafting (CABG) are operated on before the beginning of the next working day after decision to operate while salvage CABG patients require cardiopulmonary resuscitation en route to the operating theatre. The objective of this multicentre study was to investigate the efficacy of emergency and salvage CABG. METHODS: A retrospective analysis of all patients that underwent emergency or salvage CAGB at four North-European university hospitals from 2006 to 2014. RESULTS: A total of 614 patients; 580 emergency and 34 salvage CABG patients (mean age 67 +/- 10 years, 56% males) were included. All patients had an acute coronary syndrome: 234 (38%) had an ST segment elevation myocardial infarction (STEMI) and 289 (47%) had a non-STEMI. Haemodynamic instability requiring inotropic drugs and/or intra-aortic balloon pump preoperatively occurred in 87 (14%) and 82 (13%) of the patients, respectively. Three hundred and thirty-one patient (54%) were transferred to the operating room immediately after angiography and 205 (33%) had a failure of an attempted percutaneous coronary intervention. Cardiopulmonary resuscitation within 1 h before the operation was performed in 49 patients (8%), and 9 patients (1%) received cardiac massage during sternotomy. Hospital mortality for emergency and salvage operations was 13 and 41%, respectively. Early complications included reoperation for bleeding (15%), postoperative stroke (6%) and de novo dialysis for acute kidney injury (6%). Overall 5-year survival rate was 79% for emergency operations and 46% for salvage operations. Only one out of 9 patients receiving cardiac massage during sternotomy survived. CONCLUSIONS: Early mortality in patients undergoing emergent and salvage CABG is substantial, especially in salvage patients. Long-term survival is acceptable in both emergent and salvage patients. Life-saving emergency and salvage CABG is justified in most patients but salvage patients have dismal prognosis if cardiac massage is needed during sternotomy. PMID- 26582346 TI - Sleep apnoea is a risk factor for acute kidney injury after coronary artery bypass grafting. AB - OBJECTIVES: Acute kidney injury (AKI) is a common complication in patients who undergo coronary artery bypass grafting (CABG). Sleep apnoea is associated with sympathetic activation, inflammatory reaction and plaque burden. The possible status of sleep apnoea as a risk factor for AKI after CABG has not been studied. METHODS: We recruited 169 patients for an overnight sleep study using a Food and Drug Administration-approved portable device before they underwent elective CABG. AKI after CABG was defined as a relative increase of greater than 25% or an absolute increase of greater than 0.5 mg/dl in the serum creatinine level from baseline within 5 days after CABG. A generalized structural equation model (gSEM) was then applied to ascertain whether sleep apnoea, defined as an Apnoea Hypopnoea index (AHI) of 15 or higher, was associated with AKI after CABG after adjusting for the effects of confounding variables. RESULTS: Of the 150 patients (88.8%) who completed the study, the incidence of AKI after CABG was 22.7%. The mean AHI was higher in the AKI group (27.4 +/- 19.8) than that in the non-AKI group (18.3 +/- 16.5; P < 0.01). The prevalence of sleep apnoea was higher in the AKI group (64.7%) than that in the non-AKI group (45.7%; P = 0.05). The patients in the AKI group were older (P < 0.01) and shorter (P = 0.03) and had higher systolic blood pressures (P = 0.01), greater waist circumferences (P = 0.04) and larger left atrial diameters (P < 0.01) than those in the non-AKI group. The patients in the AKI group had higher serum haemoglobin levels (P = 0.04) and lower glucose levels (P < 0.01) than those in the non-AKI group. A gSEM based on binomial distributions showed that sleep apnoea was an independent predictor of AKI after CABG (adjusted odds ratio, 2.89; confidence interval, 1.09-7.09; P = 0.03) after adjustment for the effects of haemoglobin, glucose levels, the left atrial diameter and systolic blood pressure. CONCLUSIONS: Sleep apnoea is prevalent and is associated with AKI after CABG. The data presented here provide the first insights into the potential of treating sleep apnoea to attenuate the risk of AKI after CABG. PMID- 26582348 TI - Effect of hyperemesis gravidarum on gestational diabetes mellitus screening. AB - OBJECTIVE: To clarify the effect of starvation due to hyperemesis gravidarum on the screening of gestational diabetes mellitus (GDM). METHODS: A retrospective study was undertaken of pregnant women who delivered at Tsukuba University Hospital, Japan, between October 1, 2010, and September 30, 2013. GDM screening was performed in the first trimester using the random blood glucose test with a cutoff value of 5.2mmol/L and in the second trimester using a 50-g glucose challenge test with a cutoff value of 7.8mmol/L. If the screening was positive, a 75-g oral glucose tolerance test was performed for a definite diagnosis. RESULTS: Among 2112 eligible women, 33 (1.6%) required hospitalization for hyperemesis; the remaining 2079 women formed the control group. In the first trimester, the positive GDM screening rate was significantly higher in the hyperemesis group than in the control group (13 [39.4%] vs 115 [5.5%]; P<0.001). Additionally, the positive predictive value was significantly lower in the hyperemesis group (23.1% vs 73.9%; P<0.001). In the second trimester, no significant differences were observed between groups. CONCLUSION: Hyperemesis gravidarum affects the positive GDM screening rate in the first trimester. PMID- 26582347 TI - Slit2N Inhibits Transmission of HIV-1 from Dendritic Cells to T-cells by Modulating Novel Cytoskeletal Elements. AB - Dendritic cells are among the first cells to encounter sexually acquired human immunodeficiency virus (HIV-1), in the mucosa, and they can transmit HIV-1 to CD4(+) T-cells via an infectious synapse. Recent studies reveal that actin-rich membrane extensions establish direct contact between cells at this synapse and facilitate virus transmission. Genesis of these contacts involves signaling through c-Src and Cdc42, which modulate actin polymerization and filopodia formation via the Arp2/3 complex and Diaphanous 2 (Diaph2). We found that Slit2N, a ligand for the Roundabout (Robo) receptors, blocked HIV-1-induced signaling through Arp2/3 and Diaph2, decreased filopodial extensions on dendritic cells, and inhibited cell-to-cell transmission of HIV-1 in a Robo1-dependent manner. Employing proteomic analysis, we identified Flightless-1 as a novel, Robo1 interacting protein. Treatment with shRNAs reduced levels of Flightless-1 and demonstrated its role in efficient cell-to-cell transfer of HIV-1. These results suggest a novel strategy to limit viral infection in the host by targeting the Slit/Robo pathway with modulation of cytoskeletal elements previously unrecognized in HIV-1 transmission. PMID- 26582349 TI - Can the Use of Neuromuscular Electrical Stimulation Be Improved to Optimize Quadriceps Strengthening? AB - CONTEXT: Neuromuscular electrical stimulation (NMES) is a common modality used to retrain muscles and improve muscular strength after injury or surgery, particularly for the quadriceps muscle. There are parameter adjustments that can be made to maximize the effectiveness of NMES. While NMES is often used in clinical practice, there are some limitations that clinicians should be aware of, including patient discomfort, muscle fatigue, and muscle damage. EVIDENCE ACQUISITION: PubMed was searched through August 2014 and all articles cross referenced. STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 3. RESULTS: Clinicians can optimize torque production and decrease discomfort by altering parameter selection (pulse duration, pulse frequency, duty cycle, and amplitude). Pulse duration of 400 to 600 MUs and a pulse frequency of 30 to 50 Hz appear to be the most effective parameters to optimize torque output while minimizing discomfort, muscle fatigue, or muscle damage. Optimal electrode placement, conditioning programs, and stimulus pattern modulation during long-term NMES use may improve results. CONCLUSION: Torque production can be enhanced while decreasing patient discomfort and minimizing fatigue. PMID- 26582350 TI - Gene worlds. AB - Drawing from a critical sociology of knowledge perspective, we situate the production of genetic information within relevant political, financial, and professional contexts. We consider as well the broad range of social conditions that render genetic knowledge salient in clinical settings and for population health. This sociological analysis of genetic knowledge highlights how genetic knowledge flourishes and shapes social environments and how in turn environments select for particular forms of genetic knowledge. We examine the role of the laboratory, regulatory state, and social movements in the production of genetic knowledge and the clinic, family, and population health as critical sites where genetic knowledge becomes actionable. PMID- 26582351 TI - From sick role to narrative subject: An analytic memoir. AB - Questions of illness experience and identity are discussed, based on the analysis of a story told by the breast-cancer activist Audre Lorde. Displacing Parsons' conceptualization of illness as a sick role, I understand the ill person as a narrative subject, defined by discursive possibilities. Three discourses of illness are proposed: the medical institutional discourse, the discourse of illness experience, and the pink-ribbon discourse. Each has its preferred narratives. These discourses overlap and mutually affect each other. Problems with the Foucauldian conceptualization of the subject are considered, and a dialogical imagination of relations of governmentality is proposed. PMID- 26582352 TI - Primary care referral to multidisciplinary high risk foot services - too few, too late. AB - BACKGROUND: To determine if patients with no contact with a multi-disciplinary team High Risk Foot Service (MDT-HRFS) had an increased rate of hospital admission for diabetes foot infection compared to patients with contact. Secondary aims were to report on clinical outcomes. METHODS: A retrospective study was conducted at a major tertiary referral hospital in metropolitan Sydney over 12 months. An ICD-10 search of the electronic medical record system and paper medical charts identified patients with diabetes mellitus (type 1 or type 2) and a primary admission for diabetes foot infection (DFI). Patients were categorised as having contact or no contact with an MDT-HRFS. RESULTS: One hundred ninety-six hospital admissions (156 patients) were identified with DFI over a 12-month period. Patients with no contact with a MDT-HRFS represented three quarters of admissions (no contact = 116, 74.7 % vs. contact = 40, 25.6 %, p = 0.0001) and presented with more severe infection (no contact = 39 vs. contact = 12). The odds of lower extremity amputation increased five-fold when both no contact and severe infection occurred in combination (no contact with severe infection and amputation = 34, 82.9 % vs. contact with severe infection and amputation = 7, 17.1 %, OR 4.9, 95 % CI 1.1-21.4, p = 0.037). Using estimates of both the contact and no contact population of people with diabetes and high-risk feet and assuming the risk of amputation was the same, than the number of expected amputations in the no contact group should have been 55, however the observed number was 77, 22 more than expected (p = 0.0001). CONCLUSIONS: Patients with no contact with a MDT-HRFS represented the majority of admissions for DFIs to a tertiary referral hospital. This group on population estimates appears to be at high risk of amputation of the lower extremity and therefore early referral of this high-risk group might lower this risk. PMID- 26582354 TI - Lifestyle, reproductive factors and food intake in Greenlandic pregnant women: the ACCEPT - sub-study. AB - BACKGROUND: In the past decades, Greenland has changed from a hunter society to a more western lifestyle, causing less intake of traditional food, such as marine mammals, fish and seabirds. These changes in the living conditions and food habits might impact the maternal health in Greenland. OBJECTIVES: To describe lifestyle, reproductive factors and food intake in Greenlandic pregnant women, and to assess possible age and geographical differences. DESIGN: Cross-sectional study of 189 Greenlandic pregnant women. Inclusion criteria were >=18 years and lived >50% of their life in Greenland. Data were collected in 2010-2011, and information was obtained from lifestyle and food frequency questionnaires. Two age groups for comparison were given for the pregnant women (<27 years vs. >=27 years) with regard to the median age. Region groups for comparison were West, Disko Bay, South, North and East. RESULTS: Population characteristics showed that 43.3% had pre-pregnancy body mass index (BMI) >25.0 kg/m(2), 46.3% were current smokers in the beginning of their pregnancy and few participants consumed alcohol during pregnancy. Women <27 years were more in doubt regarding planned breastfeeding period and consumed more dried fish and fast food. A trend for higher alcohol intake during pregnancy was found for women >=27 years. The regional differences showed that women living >50% in North, South and West had a higher alcohol intake during pregnancy. Women in North had the fewest breastfeeding plans. Women in Disko Bay had the lowest intake of terrestrial species. No significant geographical differences were found for intake of marine mammals or seabirds. CONCLUSIONS: The present study found relatively high BMI level and high smoking frequency in Greenlandic pregnant women. Age and region differences were found for alcohol consumption, breastfeeding plans and food intake profile. Further research is needed to implement relevant maternal health intervention programs in Greenland. PMID- 26582355 TI - Does Computer-Assisted Femur First THR Improve Musculoskeletal Loading Conditions? AB - We have developed a novel, computer-assisted operation method for minimal invasive total hip replacement (THR) following the concept of "femur first/combined anteversion," which incorporates various aspects of performing a functional optimization of the prosthetic stem and cup position (CAS FF). The purpose of this study is to assess whether the hip joint reaction forces and patient's gait parameters are being improved by CAS FF in relation to conventional THR (CON). We enrolled 60 patients (28 CAS FF/32 CON) and invited them for gait analysis at three time points (preoperatively, postop six months, and postop 12 months). Data retrieved from gait analysis was processed using patient-specific musculoskeletal models. The target parameters were hip reaction force magnitude (hrf), symmetries, and orientation with respect to the cup. Hrf in the CAS FF group were closer to a young healthy normal. Phase-shift symmetry showed an increase in the CAS FF group. Hrf orientation in the CAS FF group was closer to optimum, though no edge or rim-loading occurred in the CON group as well. The CAS FF group showed an improved hrf orientation in an early stage and a trend to an improved long-term outcome. PMID- 26582356 TI - Inmirania thermothiophila gen. nov., sp. nov., a thermophilic, facultatively autotrophic, sulfur-oxidizing gammaproteobacterium isolated from a shallow-sea hydrothermal vent. AB - A novel thermophilic, facultatively autotrophic bacterium, strain S2479T, was isolated from a thermal spring located in a tidal zone of a geothermally heated beach (Kuril Islands, Russia). Cells of strain S2479T were rod-shaped and motile with a Gram-negative cell-wall type. The temperature range for growth was 35-68 degrees C (optimum 65 degrees C), and the pH range for growth was pH 5.5-8.8 (optimum pH 6.5). Growth of strain S2479T was observed in the presence of NaCl concentrations ranging from 0.5 to 3.5 % (w/v) (optimum 1.5-2.0 %). The strain oxidized sulfur and thiosulfate as sole energy sources for autotrophic growth under anaerobic conditions with nitrate as electron acceptor. Strain S2479T was also capable of heterotrophic growth by reduction of nitrate with oxidation of low-chain fatty acids and a limited number of other carboxylic acids or with complex proteinaceous compounds. Nitrate was reduced to N2. Sulfur compounds were oxidized to sulfate. Strain S2479T did not grow aerobically during incubation at atmospheric concentration of oxygen but was able to grow microaerobically (1 % of oxygen in gas phase). Phylogenetic analysis based on 16S rRNA gene sequences indicated that the strain was a member of the family Ectothiorhodospiraceae, order Chromatiales, class Gammaproteobacteria. On the basis of phylogenetic and phenotypic properties, strain S2479T represents a novel species of a new genus, for which the name Inmirania thermothiophila gen. nov., sp. nov. is proposed. The type strain of the type species is S2479T ( = DSM 100275T = VKM B-2962T). PMID- 26582357 TI - Controlled Release from Zein Matrices: Interplay of Drug Hydrophobicity and pH. AB - PURPOSE: In earlier studies, the corn protein zein is found to be suitable as a sustained release agent, yet the range of drugs for which zein has been studied remains small. Here, zein is used as a sole excipient for drugs differing in hydrophobicity and isoelectric point: indomethacin, paracetamol and ranitidine. METHODS: Caplets were prepared by hot-melt extrusion (HME) and injection moulding (IM). Each of the three model drugs were tested on two drug loadings in various dissolution media. The physical state of the drug, microstructure and hydration behaviour were investigated to build up understanding for the release behaviour from a zein based matrix for drug delivery. RESULTS: Drug crystallinity of the caplets increases with drug hydrophobicity. For ranitidine and indomethacin, swelling rates, swelling capacity and release rates were pH dependent as a consequence of the presence of charged groups on the drug molecules. Both hydration rates and release rates could be approached by existing models. CONCLUSION: The drug state and pH dependant electrostatic interactions are hypothesised to influence release kinetics. Both factors can potentially be used to influence release kinetics release, thereby broadening the horizon for zein as a tuneable release agent. PMID- 26582359 TI - The Inverse Method for a Childhood Infectious Disease Model with Its Application to Pre-vaccination and Post-vaccination Measles Data. AB - In this paper, we improve the classic SEIR model by separating the juvenile group and the adult group to better describe the dynamics of childhood infectious diseases. We perform stability analysis to study the asymptotic dynamics of the new model, and perform sensitivity analysis to uncover the relative importance of the parameters on infection. The transmission rate is a key parameter in controlling the spread of an infectious disease as it directly determines the disease incidence. However, it is essentially impossible to measure the transmission rate for certain infectious diseases. We introduce an inverse method for our new model, which can extract the time-dependent transmission rate from either prevalence data or incidence data in existing open databases. Pre- and post-vaccination measles data sets from Liverpool and London are applied to estimate the time-varying transmission rate. From the Fourier transform of the transmission rate of Liverpool and London, we observe two spectral peaks with frequencies 1/year and 3/year. These dominant frequencies are robust with respect to different initial values. The dominant 1/year frequency is consistent with common belief that measles is driven by seasonal factors such as environmental changes and immune system changes and the 3/year frequency indicates the superiority of school contacts in driving measles transmission over other seasonal factors. Our results show that in coastal cities, the main modulator of the transmission of measles virus, paramyxovirus, is school seasons. On the other hand, in landlocked cities, both weather and school seasons have almost the same influence on paramyxovirus transmission. PMID- 26582358 TI - Mathematical Model of Cardiovascular and Metabolic Responses to Umbilical Cord Occlusions in Fetal Sheep. AB - Fetal acidemia during labor is associated with an increased risk of brain injury and lasting neurological deficits. This is in part due to the repetitive occlusions of the umbilical cord (UCO) induced by uterine contractions. Whereas fetal heart rate (FHR) monitoring is widely used clinically, it fails to detect fetal acidemia. Hence, new approaches are needed for early detection of fetal acidemia during labor. We built a mathematical model of the UCO effects on FHR, mean arterial blood pressure (MABP), oxygenation and metabolism. Mimicking fetal experiments, our in silico model reproduces salient features of experimentally observed fetal cardiovascular and metabolic behavior including FHR overshoot, gradual MABP decrease and mixed metabolic and respiratory acidemia during UCO. Combined with statistical analysis, our model provides valuable insight into the labor-like fetal distress and guidance for refining FHR monitoring algorithms to improve detection of fetal acidemia and cardiovascular decompensation. PMID- 26582360 TI - A Mixed-Culture Biofilm Model with Cross-Diffusion. AB - We propose a deterministic continuum model for mixed-culture biofilms. A crucial aspect is that movement of one species is affected by the presence of the other. This leads to a degenerate cross-diffusion system that generalizes an earlier single-species biofilm model. Two derivations of this new model are given. One, like cellular automata biofilm models, starts from a discrete in space lattice differential equation where the spatial interaction is described by microscopic rules. The other one starts from the same continuous mass balances that are the basis of other deterministic biofilm models, but it gives up a simplifying assumption of these models that has recently been criticized as being too restrictive in terms of ecological structure. We show that both model derivations lead to the same PDE model, if corresponding closure assumptions are introduced. To investigate the role of cross-diffusion, we conduct numerical simulations of three biofilm systems: competition, allelopathy and a mixed system formed by an aerobic and an anaerobic species. In all cases, we find that accounting for cross diffusion affects local distribution of biomass, but it does not affect overall lumped quantities such as the total amount of biomass in the system. PMID- 26582361 TI - Persistence in a Two-Dimensional Moving-Habitat Model. AB - Environmental changes are forcing many species to track suitable conditions or face extinction. In this study, we use a two-dimensional integrodifference equation to analyze whether a population can track a habitat that is moving due to climate change. We model habitat as a simple rectangle. Our model quickly leads to an eigenvalue problem that determines whether the population persists or declines. After surveying techniques to solve the eigenvalue problem, we highlight three findings that impact conservation efforts such as reserve design and species risk assessment. First, while other models focus on habitat length (parallel to the direction of habitat movement), we show that ignoring habitat width (perpendicular to habitat movement) can lead to overestimates of persistence. Dispersal barriers and hostile landscapes that constrain habitat width greatly decrease the population's ability to track its habitat. Second, for some long-distance dispersal kernels, increasing habitat length improves persistence without limit; for other kernels, increasing length is of limited help and has diminishing returns. Third, it is not always best to orient the long side of the habitat in the direction of climate change. Evidence suggests that the kurtosis of the dispersal kernel determines whether it is best to have a long, wide, or square habitat. In particular, populations with platykurtic dispersal benefit more from a wide habitat, while those with leptokurtic dispersal benefit more from a long habitat. We apply our model to the Rocky Mountain Apollo butterfly (Parnassius smintheus). PMID- 26582362 TI - Role of Interlayer Coupling on the Evolution of Band Edges in Few-Layer Phosphorene. AB - Using first-principles calculations, we have investigated the evolution of band edges in few-layer phosphorene as a function of the number of P layers. Our results predict that monolayer phosphorene is an indirect band gap semiconductor and its valence band edge is extremely sensitive to strain. Its band gap could undergo an indirect-to-direct transition under a lattice expansion as small as 1% along the zigzag direction. A semiempirical interlayer coupling model is proposed, which can reproduce the evolution of valence band edges obtained by first-principles calculations well. We conclude that the interlayer coupling plays a dominant role in the evolution of the band edges via decreasing both band gap and carrier effective masses with the increase of phosphorene thickness. Scrutiny of the orbital-decomposed band structure provides a better understanding of the upward shift of the valence band maximum, surpassing that of the conduction band minimum. PMID- 26582363 TI - Complete depletion of primordial germ cells in an All-female fish leads to Sex biased gene expression alteration and sterile All-male occurrence. AB - BACKGROUND: Gynogenesis is one of unisexual reproduction modes in vertebrates, and produces all-female individuals with identical genetic background. In sexual reproduction vertebrates, the roles of primordial germ cells on sexual dimorphism and gonadal differentiation have been largely studied, and two distinct functional models have been proposed. However, the role of primordial germ cells remains unknown in unisexual animals, and it is also unclear whether the functional models in sexual reproduction animals are common in unisexual animals. RESULTS: To solve these puzzles, we attempt to utilize the gynogenetic superiority of polyploid Carassius gibelio to create a complete germ cell depleted gonad model by a similar morpholino-mediated knockdown approach used in other examined sexual reproduction fishes. Through the germ cell-depleted gonad model, we have performed comprehensive and comparative transcriptome analysis, and revealed a complete alteration of sex-biased gene expression. Moreover, the expression alteration leads to up-regulation of testis-biased genes and down regulation of ovary-biased genes, and results in the occurrence of sterile all males with testis-like gonads and secondary sex characteristics in the germ cell depleted gynogenetic Carassius gibelio. CONCLUSIONS: Our current results have demonstrated that unisexual gynogenetic embryos remain keeping male sex determination information in the genome, and the complete depletion of primordial germ cells in the all-female fish leads to sex-biased gene expression alteration and sterile all-male occurrence. PMID- 26582365 TI - Arrays of coupled chemical oscillators. AB - Oscillating chemical reactions result from complex periodic changes in the concentration of the reactants. In spatially ordered ensembles of candle flame oscillators the fluctuations in the ratio of oxygen atoms with respect to that of carbon, hydrogen and nitrogen produces an oscillation in the visible part of the flame related to the energy released per unit mass of oxygen. Thus, the products of the reaction vary in concentration as a function of time, giving rise to an oscillation in the amount of soot and radiative emission. Synchronisation of interacting dynamical sub-systems occurs as arrays of flames that act as master and slave oscillators, with groups of candles numbering greater than two, creating a synchronised motion in three-dimensions. In a ring of candles the visible parts of each flame move together, up and down and back and forth, in a manner that appears like a "worship". Here this effect is shown for rings of flames which collectively empower a central flame to pulse to greater heights. In contrast, situations where the central flames are suppressed are also found. The phenomena leads to in-phase synchronised states emerging between periods of anti phase synchronisation for arrays with different columnar sizes of candle and positioning. PMID- 26582364 TI - Loss of Either Rac1 or Rac3 GTPase Differentially Affects the Behavior of Mutant Mice and the Development of Functional GABAergic Networks. AB - Rac GTPases regulate the development of cortical/hippocampal GABAergic interneurons by affecting the early development and migration of GABAergic precursors. We have addressed the function of Rac1 and Rac3 proteins during the late maturation of hippocampal interneurons. We observed specific phenotypic differences between conditional Rac1 and full Rac3 knockout mice. Rac1 deletion caused greater generalized hyperactivity and cognitive impairment compared with Rac3 deletion. This phenotype matched with a more evident functional impairment of the inhibitory circuits in Rac1 mutants, showing higher excitability and reduced spontaneous inhibitory currents in the CA hippocampal pyramidal neurons. Morphological analysis confirmed a differential modification of the inhibitory circuits: deletion of either Rac caused a similar reduction of parvalbumin positive inhibitory terminals in the pyramidal layer. Intriguingly, cannabinoid receptor-1-positive terminals were strongly increased only in the CA1 of Rac1 depleted mice. This increase may underlie the stronger electrophysiological defects in this mutant. Accordingly, incubation with an antagonist for cannabinoid receptors partially rescued the reduction of spontaneous inhibitory currents in the pyramidal cells of Rac1 mutants. Our results show that Rac1 and Rac3 have independent roles in the formation of GABAergic circuits, as highlighted by the differential effects of their deletion on the late maturation of specific populations of interneurons. PMID- 26582366 TI - SUMOylation of TARBP2 regulates miRNA/siRNA efficiency. AB - Small RNA-induced gene silencing is essential for post-transcriptional regulation of gene expression; however, it remains unclear how miRNA/siRNA efficiency is regulated. Here we show that TARBP2 is SUMOylated at K52, which can be enhanced by its phosphorylation. This modification can stabilize TARBP2 via repressing its K(48)-linked ubiquitination. We find that TARBP2 SUMOylation does not influence the overall production of mature miRNAs, but it regulates miRNA/siRNA efficiency. SUMOylated TARBP2 recruits Ago2 to constitute the RNA-induced silencing complex (RISC)-loading complex (RLC), and simultaneously promotes more pre-miRNAs to load into the RLC. Consequently, Ago2 is stabilized and miRNAs/siRNAs bound by TARBP2/Dicer is effectively transferred to Ago2. Thus, these processes lead to the formation of the effective RISC for RNA interference (RNAi). Collectively, our data suggest that SUMOylation of TARBP2 is required for regulating miRNA/siRNA efficiency, which is a general mechanism of miRNA/siRNA regulation. PMID- 26582367 TI - Anti-inflammatory activity of low molecular weight polysialic acid on human macrophages. AB - Oligosialic and polysialic acid (oligoSia and polySia) of the glycocalyx of neural and immune cells are linear chains, in which the sialic acid monomers are alpha2.8-glycosidically linked. Sialic acid-binding immunoglobulin-like lectin-11 (SIGLEC-11) is a primate-lineage specific receptor of human tissue macrophages and microglia that binds to alpha2.8-linked oligoSia. Here, we show that soluble low molecular weight polySia with an average degree of polymerization 20 (avDP20) interacts with SIGLEC-11 and acts anti-inflammatory on human THP1 macrophages involving the SIGLEC-11 receptor. Soluble polySia avDP20 inhibited the lipopolysaccharide (LPS)-induced gene transcription and protein expression of tumor necrosis factor-alpha (Tumor Necrosis Factor Superfamily Member 2, TNFSF2). In addition, polySia avDP20 neutralized the LPS-triggered increase in macrophage phagocytosis, but did not affect basal phagocytosis or endocytosis. Moreover, polySia avDP20 prevented the oxidative burst of human macrophages triggered by neural debris or fibrillary amyloid-beta1-42. In a human macrophage-neuron co culture system, polySia avDP20 also reduced loss of neurites triggered by fibrillary amyloid-beta1-42. Thus, treatment with polySia avDP20 might be a new anti-inflammatory therapeutic strategy that also prevents the oxidative burst of macrophages. PMID- 26582368 TI - The E3 ubiquitin-ligase SEVEN IN ABSENTIA like 7 mono-ubiquitinates glyceraldehyde-3-phosphate dehydrogenase 1 isoform in vitro and is required for its nuclear localization in Arabidopsis thaliana. AB - The E3 ubiquitin-protein ligases are associated to various processes such as cell cycle control and diverse developmental pathways. Arabidopsis thaliana SEVEN IN ABSENTIA like 7, which has ubiquitin ligase activity, is located in the nucleus and cytosol and is expressed at several stages in almost all plant tissues suggesting an important role in plant functions. However, the mechanism underlying the regulation of this protein is unknown. Since we found that the SEVEN IN ABSENTIA like 7 gene expression is altered in plants with impaired mitochondria, and in plants deficient in the glycolytic enzyme glyceraldehyde-3 phosphate dehydrogenase 1, we decided to study the possible interactions between both proteins as potential partners in plant signaling functions. We found that SEVEN IN ABSENTIA like 7 is able to interact in vitro with glyceraldehyde-3 phosphate dehydrogenase and that the Lys231 residue of the last is essential for this function. Following the interaction, a concomitant increase in the glyceraldehyde-3-phosphate dehydrogenase catalytic activity was observed. However, when SEVEN IN ABSENTIA like 7 was supplemented with E1 and E2 proteins to form a complete E1-E2-E3 modifier complex, we observed the mono-ubiquitination of glyceraldehyde-3-phosphate dehydrogenase 1 at the Lys76 residue and a dramatic decrease of its catalytic activity. Moreover, we found that localization of glyceraldehyde-3-phosphate dehydrogenase 1 in the nucleus is dependent on the expression SEVEN IN ABSENTIA like 7. These observations suggest that the association of both proteins might result in different biological consequences in plants either through affecting the glycolytic flux or via cytoplasm-nucleus relocation. PMID- 26582369 TI - Mechanism of sphingosine-1-phosphate induced cardioprotection against I/R injury in diabetic rat heart: Possible involvement of glycogen synthase kinase 3beta and mitochondrial permeability transition pore. AB - There is growing evidence that diabetes mellitus causes attenuation of the bioactive metabolite of membrane sphingolipids, sphingosine-1-phosphate, and this may be a key mechanism in the decreased cardioprotective effect of ischaemic preconditioning (IPC) in the diabetic heart. Thus, this study has been designed to investigate the role and pharmacological potential of sphingosine-1-phosphate in diabetic rat heart. Diabetes was produced in Wistar rats by administration of a low dose of streptozotocin (STZ) (35 mg/kg, i.p., once) and feeding a high fat diet (HFD) for 6 weeks. Isolated rat heart was subjected to 30 min ischaemia followed by 120 min of reperfusion (I/R). The heart was subjected to pre ischaemic treatment (before ischaemia for 20 min) and pharmacological preconditioning with the S1P agonist FTY720 (0.6 MUmol/L) with and without atractyloside (an mPTP opener; in the last episode of reperfusion before I/R). Myocardial infarction was assessed in terms of increase in lactate dehydrogenase (LDH), creatinine kinase-MB (CK-MB), myeloperoxidase (MPO) level and infarct size (triphenyltetrazolium chloride staining). Immunohistochemistry analysis was done for assessment of tumour necrosis factor (TNF)-alpha and glycogen synthase kinase (GSK)-3beta level in cardiac tissue. Pre-ischaemic treatment and pharmacological preconditioning with FTY720 significantly decreased I/R-induced myocardial infarction, TNF-alpha, GSK-3beta level and release of LDH and CK-MB as compared to control group. The cardioprotective effect of S1P agonist was significantly attenuated by atractyloside. It may be concluded that S1P agonist FTY720 prevents the diabetic heart from ischaemic reperfusion injury, possibly through inhibition of GSK-3beta and regulation of opening of mitochondrial permeability transition pore. PMID- 26582371 TI - Pre-treatment of rats with ad-hepcidin prevents iron-induced oxidative stress in the brain. AB - Our recent investigation showed that hepcidin can reduce iron in the brain of iron-overloaded rat by down-regulating iron-transport proteins. It has also been demonstrated that iron is a major generator of reactive oxygen species. We therefore hypothesized that hepcidin could prevent iron accumulation and thus reduce iron-mediated oxidative stress in iron-overloaded rats. To test this hypothesis, we investigated the effects of pre-treatment of rats with recombinant hepcidin-adenovirus (ad-hepcidin) on the contents of iron, dichlorofluorescein and 8-isoprostane in the brain. Hepcidin expression was detected by real-time PCR and immunofluorescence analysis. Iron contents were measured using Perl's staining as well as graphite furnace atomic absorption spectrophotometry. Dichlorofluorescein and 8-isoprostane were determined using a fluorescence spectrophotometer and an ELISA kit, respectively. We found that hepcidin contents in the cortex, hippocampus, striatum and substantia nigra of rats treated with ad hepcidin are 3.50, 2.98, 2.93 and 4.07 fold of those of the control rats respectively. Also, we demonstrated that the increased iron as well as dichlorofluorescein and 8-isoprostane levels in all four brain regions, induced by injection of iron dextran, could be effectively prevented by pre-treatment of the rats with ad-hepcidin. We concluded that pre-treatment with ad-hepcidin could increase hepcidin expression and prevent the increase in iron and reduce reactive oxygen species in the brain of iron-overloaded rats. PMID- 26582370 TI - Chitosan functionalisation of gold nanoparticles encourages particle uptake and induces cytotoxicity and pro-inflammatory conditions in phagocytic cells, as well as enhancing particle interactions with serum components. AB - BACKGROUND: Gold nanoparticles (AuNPs) are a popular choice for use in medical and biomedical research applications. With suitable functionalisation AuNPs can be applied in drug delivery systems, or can aid in disease diagnosis. One such functionalisation is with chitosan, which enables efficient interaction and permeation of cellular membranes, providing an effective adjuvant. As both AuNPs and chitosan have been shown to have low toxicity and high biocompatibility their proposed use in nanomedicine, either individually or combined, is expanding. However, further toxicological and immunological assessments of AuNP-chitosan conjugates are still needed. Therefore, we have evaluated how AuNP functionalisation with chitosan can affect uptake, cytotoxicity, and immunological responses within mononuclear cells, and influence the interaction of AuNPs with biomolecules within a complex biofluid. The AuNPs used were negatively charged through citrate-coating, or presented either low or high positive charge through chitosan-functionalisation. Uptake by THP-1 cells was assessed via transmission electron microscopy and electron energy loss spectroscopy, pro-inflammatory responses by ELISA and qRT-PCR, and cell death and viability via lactate dehydrogenase release and mitochondrial activity, respectively. Interactions of AuNPs with protein components of a frequently used in vitro cell culture medium supplement, foetal calf serum, were investigated using mass spectrometry. RESULTS: Although cells internalised all AuNPs, uptake rates and specific routes of intracellular trafficking were dependent upon chitosan-functionalisation. Accordingly, an enhanced immune response was found to be chitosan-functionalisation-dependent, in the form of CCL2, IL-1beta, TNF-alpha and IL-6 secretion, and expression of IL-1beta and NLRP3 mRNA. A corresponding increase in cytotoxicity was found in response to chitosan-coated AuNPs. Furthermore, chitosan-functionalisation was shown to induce an increase in unique proteins associating with these highly charged AuNPs. CONCLUSIONS: It can be concluded that functionalisation of AuNPs with the perceived non-toxic biocompatible molecule chitosan at a high density can elicit functionalisation dependent intracellular trafficking mechanisms and provoke strong pro inflammatory conditions, and that a high affinity of these NP-conjugates for biomolecules may be implicit in these cellular responses. PMID- 26582372 TI - Flavonolignan 2,3-dehydroderivatives: Preparation, antiradical and cytoprotective activity. AB - The protective constituents of silymarin, an extract from Silybum marianum fruits, have been extensively studied in terms of their antioxidant and hepatoprotective activities. Here, we explore the electron-donor properties of the major silymarin flavonolignans. Silybin (SB), silychristin (SCH), silydianin (SD) and their respective 2,3-dehydroderivatives (DHSB, DHSCH and DHSD) were oxidized electrochemically and their antiradical/antioxidant properties were investigated. Namely, Folin-Ciocalteau reduction, DPPH and ABTS(+) radical scavenging, inhibition of microsomal lipid peroxidation and cytoprotective effects against tert-butyl hydroperoxide-induced damage to a human hepatocellular carcinoma HepG2 cell line were evaluated. Due to the presence of the highly reactive C3-OH group and the C-2,3 double bond (ring C) allowing electron delocalization across the whole structure in the 2,3-dehydroderivatives, these compounds are much more easily oxidized than the corresponding flavonolignans SB, SCH and SD. This finding was unequivocally confirmed not only by experimental approaches, but also by density functional theory (DFT) calculations. The hierarchy in terms of ability to undergo electrochemical oxidation (DHSCH~DHSD>DHSB>>SCH/SD>SB) was consistent with their antiradical activities, mainly DPPH scavenging, as well as in vitro cytoprotection of HepG2 cells. The results are discussed in the context of the antioxidant vs. prooxidant activities of flavonolignans and molecular interactions in complex biological systems. PMID- 26582373 TI - Peroxiredoxin 5 prevents amyloid-beta oligomer-induced neuronal cell death by inhibiting ERK-Drp1-mediated mitochondrial fragmentation. AB - Alzheimer's disease (AD), a neurodegenerative disorder, is caused by amyloid-beta oligomers (AbetaOs). AbetaOs induce cell death by triggering oxidative stress and mitochondrial dysfunction. A recent study showed that AbetaO-induced oxidative stress is associated with extracellular signal-regulated kinase (ERK)-dynamin related protein 1 (Drp1)-mediated mitochondrial fission. Reactive oxygen species (ROS) are regulated by antioxidant enzymes, especially peroxiredoxins (Prxs) that scavenge H2O2. These enzymes inhibit neuronal cell death induced by various neurotoxic reagents. However, it is unclear whether Prx5, which is specifically expressed in neuronal cells, protects these cells from AbetaO-induced damage. In this study, we found that Prx5 expression was upregulated by AbetaO-induced oxidative stress and that Prx5 decreased ERK-Drp1-mediated mitochondrial fragmentation and apoptosis of HT-22 neuronal cells. Prx5 expression was affected by AbetaO, and amelioration of oxidative stress by N-acetyl-L-cysteine decreased AbetaO-induced Prx5 expression. Prx5 overexpression reduced ROS as well as RNS and apoptotic cell death but Prx5 knockdown did not. In addition, Prx5 overexpression ameliorated ERK-Drp1-mediated mitochondrial fragmentation but Prx5 knockdown did not. These results indicated that inducible Prx5 expression by AbetaO plays a key role in inhibiting both ERK-Drp1-induced mitochondrial fragmentation and neuronal cell death by regulating oxidative stress. Thus, Prx5 may be a new therapeutic agent for treating AD. PMID- 26582374 TI - Hodgkin lymphoma in children and adolescents: improving the therapeutic index. AB - Hodgkin lymphoma (HL) is a highly curable form of childhood cancer, with estimated 5 year survival rates exceeding 98%. However, the establishment of a "standard of care" approach to its management is complicated by the recognition that long-term overall survival declines in part from delayed effects of therapy and that there continue to be subgroups of patients at risk for relapse for which prognostic criteria cannot adequately define. This challenge has resulted in the development of various strategies aimed at identifying the optimal balance between maintaining overall survival and avoidance of long-term morbidity of therapy, often representing strategies quite different from those used for adults with HL. More precise risk stratification and methods for assessing the chemosensitivity of HL through imaging studies and biomarkers are in evolution. Recent advances in the understanding of the biology of HL have led to the introduction of targeted therapies in both the frontline and relapsed settings. However, significant barriers exist in the development of new combination therapies, necessitating collaborative studies across pediatric HL research consortia and in conjunction with adult groups for the adolescent and young adult (AYA) population with HL. PMID- 26582375 TI - Complement in hemolytic anemia. AB - Complement is increasingly being recognized as an important driver of human disease, including many hemolytic anemias. Paroxysmal nocturnal hemoglobinuria (PNH) cells are susceptible to hemolysis because of a loss of the complement regulatory proteins CD59 and CD55. Patients with atypical hemolytic uremic syndrome (aHUS) develop a thrombotic microangiopathy (TMA) that in most cases is attributable to mutations that lead to activation of the alternative pathway of complement. For optimal therapy, it is critical, but often difficult, to distinguish aHUS from other TMAs, such as thrombotic thrombocytopenic purpura; however, novel bioassays are being developed. In cold agglutinin disease (CAD), immunoglobulin M autoantibodies fix complement on the surface of red cells, resulting in extravascular hemolysis by the reticuloendothelial system. Drugs that inhibit complement activation are increasingly being used to treat these diseases. This article discusses the pathophysiology, diagnosis, and therapy for PNH, aHUS, and CAD. PMID- 26582376 TI - Primary acute myeloid leukemia cells with overexpression of EVI-1 are sensitive to all-trans retinoic acid. AB - Enhanced expression of ecotropic viral integration site 1 (EVI-1) occurs in ~10% of acute myeloid leukemia (AML) patients and is associated with a very poor disease outcome. Patients with EVI-1-positive AML have poor initial responses to chemotherapy and high relapse rates, indicating an urgent need for alternative treatment strategies improving clinical outcome for these patients. Because treatment of acute promyelocytic patients with all-trans retinoic acid (ATRA) has improved the survival of these patients substantially, we investigated whether ATRA might also be effective for the subgroup of AML patients with EVI-1 overexpression. Here, we show that a substantial part of the EVI-1-positive AML cases respond to ATRA by induction of differentiation and decreased clonogenic capacity of myeloid blasts. Most importantly, we demonstrate that in vivo treatment of primary EVI-1-positive AML with ATRA leads to a significant reduction in leukemic engraftment. Altogether, our results show that a considerable part of the EVI-1-positive primary AML cases are sensitive to ATRA, suggesting that combining ATRA with the currently used conventional chemotherapy might be a promising treatment strategy decreasing relapse rates and enhancing complete remissions in this poor prognostic subgroup of AML patients. PMID- 26582377 TI - [GeSRU residents training curriculum 2015: Weiterbildung, Karriere und Netzwerke, Wissenschaft, Multimedia]. PMID- 26582378 TI - [Age 70 and older a criterion for inclusion - not exclusion]. AB - BACKGROUND: Although older people are frequently prescribed more drugs than younger people, they are rarely included in clinical trials. Elderly patients often suffer from multimorbidity and are prescribed many drugs simultaneously. With age, physiological changes occur that can affect the pharmacokinetics and pharmacodynamics of the drugs used, e.g., changes in the duration of action. There are several problematic implications to this, particularly relating to tolerability and possible negative effects for patients. OBJECTIVES: Not only are guidelines for the treatment of elderly patients lacking, but also basic information about efficacy, tolerability, and interactions of drugs that are commonly prescribed to the elderly often missing. Physicians sometimes have no choice but to estimate the correct dosages for the elderly. METHODS: Evaluations of secondary data and clinical trials, discussion, and analysis of basic research work on the basis of expert analysis. RESULTS: There are very few clinical trials that include people over the age of 70. On the one hand, elderly people receive more drug prescriptions due to multimorbidity, compared with younger people, while on the other hand the risk of adverse drug reaction increases for precisely these individuals. CONCLUSIONS: In order to improve treatment safety in older people in terms of duration and dosage, randomized control trials (RCT) are essential to provide evidence of the benefits of a drug to patients. For this reason, the call for clinical trials after as well as before authorization, on patients treated with these drugs-and that especially means elderly patients-is long overdue. PMID- 26582379 TI - [Changes in ageing towards a dynamic elderly society]. AB - BACKGROUND: Longer healthy life expectancy and the ageing of new generations result in rapid changes of life-styles and behaviors of the elderly. OBJECTIVES: How far are trends to active ageing countervailing factors to processes of demographic ageing? MATERIALS AND METHODS: Official statistics and survey data are analyzed. RESULTS: Increased individualism particularly among healthy retired men and women result in more active attitudes to ageing processes. At least in affluent regions significant cohort changes in ageing are also observed among men and women aged 80 and older. These changes affect future medical treatments of elderly patients. PMID- 26582380 TI - [Sexuality in the elderly: The role of the physicians in maintaining sexual health of older men]. AB - BACKGROUND: Sexuality in the elderly is still a social taboo. A commitment by medical practices to address the topic of sexuality in later life is essential, given that the sexual health is part of the quality of life. OBJECTIVES: Identification of barriers and discourse of effects in the physician's behavior when dealing with the sexuality of older people. MATERIALS AND METHODS: Review and discussion of interdisciplinary literature and social discourse. Compilation of expert opinions. RESULTS: Although the introduction of phosphodiesterase 5 inhibitors led to a removal of taboos concerning erectile dysfunction, the sexuality of older men became narrowed to physiological aspects. The elderly still complain that consultations concerning their sexuality receives too little attention in medical practice. Problems are boundaries of shame and disregard of the sexuality of elderly. CONCLUSIONS: Sexuality in old age will have to become more prominent in medical practices, due to demographic changes and changing self images of the elderly. The social role of physicians enables straightforward discussions about sexuality. Taking a sexual history and choosing an active approach proved to be practicable to discuss sexual problems with older people. PMID- 26582382 TI - [Inguinal lymphadenectomy in penile cancer: Study for prevention of wound complications after inguinal lymphadenectomy in patients with penile cancer by epidermal vacuum therapy (PraVAC, EUDAMED: CIV-12-07-008204; DRKS-ID: DRKS00005257)]. PMID- 26582381 TI - [Neuroendocrine prostate cancer]. AB - BACKGROUND: Neuroendocrine carcinoma of the prostate (NEPC) is a rare, androgen independent variant of prostate cancer with increasing incidence of over the past few years. It commonly progresses rapidly and is associated with a poor prognosis. Based on a different tumor biology compared to adenocarcinomas of the prostate, standard therapeutic approaches for prostate cancer are ineffective. To date, no specific treatment for NEPC exists. OBJECTIVES: The purpose of this work is to provide an overview of current histopathologic characteristics, histomorphologic classifications, and current as well as future treatment options for NEPC. MATERIALS AND METHODS: The literature was reviewed and clinical trials focusing on the above mentioned objectives are discussed. RESULTS: Current histomorphologic classifications aim to differentiate between NEPC including its variants and neuroendocrine transdifferentiated adenocarcinoma of the prostate. Regarding conventional chemotherapy, platinum-based schemes are still widely used. Antiangiogenetic drugs represent potential alternatives and are currently under clinical investigation. CONCLUSIONS: Histomorphological subtypes distinguish themselves in terms of aggressiveness, prognosis, and preferred therapeutic approaches. Treatment of NEPC differs fundamentally compared to adenocarcinoma of the prostate. There is only limited data available for the treatment of NEPC. PMID- 26582383 TI - Does Caring for a Spouse With Dementia Accelerate Cognitive Decline? Findings From the Health and Retirement Study. AB - Purpose of the Study: The purpose of this study is to expand our recent work, which showed that spousal dementia caregivers compared to spousal nondementia caregivers experience an accelerated rate of frailty over time, by exploring cognitive health outcomes between dementia and nondementia caregivers. Design and Methods: Using 8 biannual waves of the Health and Retirement Study data and performance on the modified Telephone Interview for Cognitive Status, we examined changes in cognitive health among surviving spousal caregivers (N = 1,255) of individuals with dementia (n = 192) and without dementia (n = 1,063), 2 waves prior and 2 waves following the death of the care recipient. Results: Controlling for baseline health and contextual factors (e.g., frailty status, age, education), results revealed that dementia caregivers had significantly greater cognitive decline (p < .01) compared to nondementia caregivers. Relative to 2 waves prior to the death of their spouse, dementia caregivers declined by 1.77 points relative to nondementia caregivers (0.87 points) at the time their spouses' deaths were reported and 1.89 relative to the 1.18 points at the wave following these deaths, respectively. Implications: The findings from this study show that spousal caregivers of persons with dementia experience accelerated cognitive decline themselves compared to nondementia caregivers. These results, along with our previous study findings, suggest that this vulnerable group could benefit from early cognitive screening and psychosocial interventions designed to help dementia caregivers better maintain their cognitive and physical health during and following their intensive caregiving responsibilities. PMID- 26582384 TI - The Trajectory of Tolerance for Wandering-related Boundary Transgression: An Exploration of Care Staff and Family Perceptions. AB - Purpose of the Study: This study aimed to explore the experience of living with and caring for a person with dementia who wanders and transgresses boundaries into out-of-bounds and potentially hazardous areas (wandering-related boundary transgression [BT]), from the perspective of family members and care staff. Design and Methods: This descriptive qualitative study utilized four focus groups with care staff (n = 28), one with family members (n = 4), and individual interviews (n = 8) with family members. Content analysis generated key concepts that formed the basis of the development of a theoretical understanding of the experience. Results and Implications: Care staff and families described wandering related BT as a common dementia-related behavior in residential aged care (RAC). Drawing on the generated concepts, a complex theoretical trajectory of tolerance for BT was developed. At one end of the trajectory, BT was perceived as being beyond the control of the individual and when unwitnessed by others, having little or no impact. Tolerance for BT shifted when the BT was witnessed by others, and potentially unsafe consequences for the person who wanders or their coresidents were experienced. Under the latter circumstances, BT was perceived as a troubling behavior that needed more effective management. Underpinning the complexity of this behavior was a constantly shifting perception of how hazardous this behavior might be, a factor that appeared to contribute to the challenges faced by families and care staff. PMID- 26582385 TI - Service-Related Exposures and Physical Health Trajectories Among Aging Veteran Men. AB - PURPOSE OF THE STUDY: We examined the association of military service-related exposures (SREs) with physical health trajectories to establish whether combat and other hazards have lasting connections to health in later life. We also examined potential confounders and mechanisms to further understand the associations. DESIGN AND METHODS: We used the 2013 HRS Veterans Mail Survey linked to the longitudinal Health and Retirement Study (HRS) to examine military service experiences and health over a decade (2000-2010) among veteran men. We employed latent class analysis to disaggregate trajectories of health in later life. RESULTS: Most veteran men experienced good health over the decade. Although we found a connection between combat and later health, it was driven primarily by hazardous or traumatic exposures. Service-related disability, current health behaviors, and mental health were not likely explanations for these associations. IMPLICATIONS: The measurement of service experiences is primary in understanding health implications of military service and projecting the health service needs of aging veterans. SREs are varied and complex and have differential connections to health. These connections remain unexplained by current behaviors and mental health, suggesting the need to examine earlier life course pathways and mechanisms. PMID- 26582386 TI - The feasibility and acceptability of using the Mother-Generated Index (MGI) as a Patient Reported Outcome Measure in a randomised controlled trial of maternity care. AB - BACKGROUND: Using patient-reported outcome measures (PROMs) to assess Quality of Life (QoL) is well established, but commonly-used PROM item-sets do not necessarily capture what all respondents consider important. Measuring complex constructs is particularly difficult in randomised controlled trials (RCTs). The Mother-Generated Index (MGI) is a validated antenatal and postnatal QoL instrument in which the variables and scores are completely respondent-driven. This paper reports on the feasibility and acceptability of the MGI in an RCT, and compares the resulting variables and QoL scores with more commonly used instruments. METHODS: The single-page MGI was included at the end of a ten page questionnaire pack and posted to the RCT participants at baseline (28-32 weeks' gestation) and follow-up (six weeks postnatal). Feasibility and acceptability were assessed by ease of administration, data entry and completion rates. Variables cited by women were analysed thematically. MGI QoL scores were compared with outcomes from the EQ-5D-3 L; Edinburgh Postnatal Depression Scale; Satisfaction With Life Scale; and State Trait Anxiety Inventory. RESULTS: Six hundred and seventy eight pregnant women returned the pack at baseline; 668 completed the MGI (98.5%); 383/400 returns at follow up included a completed MGI (95.7%). Quantitative data were scanned into SPSS using a standard data scanning system, and were largely error-free; qualitative data were entered manually. The variables recorded by participants on the MGI forms incorporated many of those in the comparison instruments, and other outcomes commonly used in intrapartum trials, but they also revealed a wider range of issues affecting their quality of life. These included financial and work-related worries; moving house; and concerns over family illness and pets. The MGI scores demonstrated low-to moderate correlation with other tools (all r values p < .01). CONCLUSIONS: Without face-to-face explanation and at the end of a long questionnaire, the MGI was feasible to use, and acceptable to RCT participants. It allowed individual participants to include issues that were important to them, but which are not well captured by existing tools. The MGI unites the explanatory power of qualitative research with the comparative power of quantitative designs, is inexpensive to administer, and requires minimal linguistic and conceptual translation. TRIAL REGISTRATION: ISRCTN27575146 (date assigned 23 March 2011). PMID- 26582387 TI - Identification and characterization of miRNAs in the ovaries of a highly prolific sheep breed. AB - Until recently, there have been few studies concerning miRNAs or miRNA-mediated biological processes in sheep (Ovis aries). In the present study, we used a deep sequencing approach to examine ovarian miRNAs and the mRNA transcriptomes in two ewes of a highly prolific breed, Finnsheep. We identified 113 known sheep miRNAs, 131 miRNAs conserved in other mammals and 60 novel miRNAs, the expression levels of which accounted for 78.22%, 21.73% and 0.05% of the total respectively. Furthermore, the 10 most abundantly expressed miRNAs in the two libraries were characterized in detail, and the putative target genes of these miRNAs were annotated using GO annotation and KEGG pathway enrichment analyses. Among the target genes, intracellular transducers (SMAD1, SMAD4, SMAD5 and SMAD9) and bone morphogenetic protein (BMP) receptors (BMPR1B and BMPR2) were involved in the transforming growth factor beta (TGFbeta) signaling pathway in the reproductive axis, and the most significant GO terms were intracellular part (GO:0044424), binding (GO:0005488) and biological_process (GO:0008150) for cellular component, molecular function and biological process respectively. Thus, these results expanded the sheep miRNA database and provided additional information on the prolificacy trait regulated through specific miRNAs in sheep and other mammals. PMID- 26582388 TI - [Construction of a tool to measure perceptions about the use of the World Health Organization Safe Surgery Checklist Program]. AB - BACKGROUND: The World Health Organization (WHO) has recommended greater attention to patient safety, particularly regarding preventable adverse events. The Safe Surgery Saves Lives (CSSV) program was released recommending the application of a surgical checklist for items on the safety of procedures. The checklist implementation reduced the hospital mortality rate in the first 30 days. In Brazil, we found no studies of anesthesiologists' adherence to the practice of the checklist. OBJECTIVE: The main objective was to develop a tool to measure the attitude of anesthesiologists and residents regarding the use of checklist in the perioperative period. METHOD: This was a cross-sectional study performed during the 59(th) CBA in BH/MG, whose participants were enrolled physicians who responded to the questionnaire with quantitative epidemiological approach. RESULTS: From the sample of 459 participants who answered the questionnaire, 55% were male, 44.2% under 10 years of practice, and 15.5% with over 30 years of medical school completion. Seven items with 78% reliability coefficient were selected. There was a statistically significant difference between the groups of anesthesiologists who reported using the instrument in less or more than 70% of patients, indicating that the attitude questionnaire discriminates between these two groups of professionals. CONCLUSIONS: The seven items questionnaire showed adequate internal consistency and a well-defined factor structure, and can be used as a tool to measure the anesthesiologists' perceptions about the checklist usefulness and applicability. PMID- 26582389 TI - Arl13b and the exocyst interact synergistically in ciliogenesis. AB - Arl13b belongs to the ADP-ribosylation factor family within the Ras superfamily of regulatory GTPases. Mutations in Arl13b cause Joubert syndrome, which is characterized by congenital cerebellar ataxia, hypotonia, oculomotor apraxia, and mental retardation. Arl13b is highly enriched in cilia and is required for ciliogenesis in multiple organs. Nevertheless, the precise role of Arl13b remains elusive. Here we report that the exocyst subunits Sec8, Exo70, and Sec5 bind preferentially to the GTP-bound form of Arl13b, consistent with the exocyst being an effector of Arl13b. Moreover, we show that Arl13b binds directly to Sec8 and Sec5. In zebrafish, depletion of arl13b or the exocyst subunit sec10 causes phenotypes characteristic of defective cilia, such as curly tail up, edema, and abnormal pronephric kidney development. We explored this further and found a synergistic genetic interaction between arl13b and sec10 morphants in cilia dependent phenotypes. Through conditional deletion of Arl13b or Sec10 in mice, we found kidney cysts and decreased ciliogenesis in cells surrounding the cysts. Moreover, we observed a decrease in Arl13b expression in the kidneys from Sec10 conditional knockout mice. Taken together, our results indicate that Arl13b and the exocyst function together in the same pathway leading to functional cilia. PMID- 26582390 TI - mTOR controls lysosome tubulation and antigen presentation in macrophages and dendritic cells. AB - Macrophages and dendritic cells exposed to lipopolysaccharide (LPS) convert their lysosomes from small, punctate organelles into a network of tubules. Tubular lysosomes have been implicated in phagosome maturation, retention of fluid phase, and antigen presentation. There is a growing appreciation that lysosomes act as sensors of stress and the metabolic state of the cell through the kinase mTOR. Here we show that LPS stimulates mTOR and that mTOR is required for LPS-induced lysosome tubulation and secretion of major histocompatibility complex II in macrophages and dendritic cells. Specifically, we show that the canonical phosphatidylinositol 3-kinase-Akt-mTOR signaling pathway regulates LPS-induced lysosome tubulation independently of IRAK1/4 and TBK. Of note, we find that LPS treatment augmented the levels of membrane-associated Arl8b, a lysosomal GTPase required for tubulation that promotes kinesin-dependent lysosome movement to the cell periphery, in an mTOR-dependent manner. This suggests that mTOR may interface with the Arl8b-kinesin machinery. To further support this notion, we show that mTOR antagonists can block outward movement of lysosomes in cells treated with acetate but have no effect in retrograde movement upon acetate removal. Overall our work provides tantalizing evidence that mTOR plays a role in controlling lysosome morphology and trafficking by modulating microtubule-based motor activity in leukocytes. PMID- 26582391 TI - TORC1 and TORC2 work together to regulate ribosomal protein S6 phosphorylation in Saccharomyces cerevisiae. AB - Nutrient-sensitive phosphorylation of the S6 protein of the 40S subunit of the eukaryote ribosome is highly conserved. However, despite four decades of research, the functional consequences of this modification remain unknown. Revisiting this enigma in Saccharomyces cerevisiae, we found that the regulation of Rps6 phosphorylation on Ser-232 and Ser-233 is mediated by both TOR complex 1 (TORC1) and TORC2. TORC1 regulates phosphorylation of both sites via the poorly characterized AGC-family kinase Ypk3 and the PP1 phosphatase Glc7, whereas TORC2 regulates phosphorylation of only the N-terminal phosphosite via Ypk1. Cells expressing a nonphosphorylatable variant of Rps6 display a reduced growth rate and a 40S biogenesis defect, but these phenotypes are not observed in cells in which Rps6 kinase activity is compromised. Furthermore, using polysome profiling and ribosome profiling, we failed to uncover a role of Rps6 phosphorylation in either global translation or translation of individual mRNAs. Taking the results together, this work depicts the signaling cascades orchestrating Rps6 phosphorylation in budding yeast, challenges the notion that Rps6 phosphorylation plays a role in translation, and demonstrates that observations made with Rps6 knock-ins must be interpreted cautiously. PMID- 26582392 TI - Developmentally regulated GTP-binding protein 2 coordinates Rab5 activity and transferrin recycling. AB - The small GTPase Rab5 regulates the early endocytic pathway of transferrin (Tfn), and Rab5 deactivation is required for Tfn recycling. Rab5 deactivation is achieved by RabGAP5, a GTPase-activating protein, on the endosomes. Here we report that recruitment of RabGAP5 is insufficient to deactivate Rab5 and that developmentally regulated GTP-binding protein 2 (DRG2) is required for Rab5 deactivation and Tfn recycling. DRG2 was associated with phosphatidylinositol 3 phosphate-containing endosomes. It colocalized and interacted with EEA1 and Rab5 on endosomes in a phosphatidylinositol 3-kinase-dependent manner. DRG2 depletion did not affect Tfn uptake and recruitment of RabGAP5 and Rac1 to Rab5 endosomes. However, it resulted in impairment of interaction between Rab5 and RabGAP5, Rab5 deactivation on endosomes, and Tfn recycling. Ectopic expression of shRNA resistant DRG2 rescued Tfn recycling in DRG2-depleted cells. Our results demonstrate that DRG2 is an endosomal protein and a key regulator of Rab5 deactivation and Tfn recycling. PMID- 26582394 TI - The Effect of Induction Chemotherapy Using Docetaxel, Cisplatin, and Fluorouracil on Survival in Locally Advanced Head and Neck Squamous Cell Carcinoma: A Meta Analysis. AB - PURPOSE: The purpose of this study was to compare the survival of patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) undergoing concurrent chemoradiotherapy (CRT) alone with that of patients undergoing induction chemotherapy (IC) using docetaxel, cisplatin, and 5-fluorouracil (TPF) followed by CRT. MATERIALS AND METHODS: A search of the PubMed, EMBASE, and Cochrane Library databases was performed in April 2015 and abstracts from the American Society of Clinical Oncology meetings (2008-2014) were reviewed. Summaries of the results were pooled using a fixed-effect model, and the risk of bias was evaluated using the Cochrane tool. RESULTS: A total of six relevant trials comprising 1,280 patients were identified. There was no statistically significant overall survival (OS) advantage for TPF prior to CRT (TPF/CRT) over CRT alone (hazard ratio [HR] 0.92; 95% confidence interval [CI], 0.79 to 1.09; p=0.339). Progression-free survival (PFS) was significantly longer in the TPF/CRT arms (HR, 0.82; 95% CI, 0.70 to 0.95; p=0.009). Patients with non-oropharyngeal LA-HNSCC obtained the greatest OS and PFS benefits from TPF (HR, 0.68; 95% CI, 0.47 to 0.99; p=0.043 and HR, 0.67; 95% CI, 0.48 to 0.94; p=0.022, respectively). The complete response rate was significantly increased (risk ratio [RR], 1.34; 95% CI, 1.14 to 1.56; p < 0.001), and the distant metastasis rate tended to decrease (RR, 0.65; 95% CI, 0.40 to 1.04; p=0.071) in the TPF/CRT arms. CONCLUSION: IC with TPF followed by CRT is not superior to CRT alone for OS. However, PFS and the complete response rate were significantly improved in the TPF/CRT arms. TPF/CRT for patients with nonoropharyngeal LA-HNSCC provided clear survival advantages. PMID- 26582393 TI - Genetic counselling difficulties and ethical implications of incidental findings from array-CGH: a 7-year national survey. AB - Microarray-based comparative genomic hybridization (aCGH) is commonly used in diagnosing patients with intellectual disability (ID) with or without congenital malformation. Because aCGH interrogates with the whole genome, there is a risk of being confronted with incidental findings (IF). In order to anticipate the ethical issues of IF with the generalization of new genome-wide analysis technologies, we questioned French clinicians and cytogeneticists about the situations they have faced regarding IF from aCGH. Sixty-five IF were reported. Forty corresponded to autosomal dominant diseases with incomplete penetrance, 7 to autosomal dominant diseases with complete penetrance, 14 to X-linked diseases, and 4 were heterozygotes for autosomal recessive diseases with a high prevalence of heterozygotes in the population. Therapeutic/preventive measures or genetic counselling could be argued for all cases except four. These four IF were intentionally not returned to the patients. Clinicians reported difficulties in returning the results in 29% of the cases, mainly when the question of IF had not been anticipated. Indeed, at the time of the investigation, only 48% of the clinicians used consents mentioning the risk of IF. With the emergence of new technologies, there is a need to report such national experiences; they show the importance of pre-test information on IF. PMID- 26582395 TI - Isotype-Specific Inhibition of Histone Deacetylases: Identification of Optimal Targets for Radiosensitization. AB - PURPOSE: Histone deacetylase (HDAC) inhibitors radiosensitize tumor cells. To elucidate mechanisms underlying radiosensitization by HDAC inhibition, understanding of differential contributions of HDAC isotypes is needed. The aim of this study was to investigate involvement of known HDAC isotypes in modulation of cellular radiosensitivity. MATERIALS AND METHODS: Because pharmacologic HDAC inhibitors lack isotype-specificity, RNA interference against 11 HDAC isotypes was used to inhibit HDAC in an isotype-specific manner. Radiation cell survival was evaluated using a clonogenic assay in SQ20B cells transfected with small interfering RNA specifically targeting HDAC isotypes. Immunocytochemistry was performed for detection of gammaH2AX foci. Protein expression was measured using Western blotting. RESULTS: Among 11 HDAC isotypes tested, specific inhibition of 7 isotypes (HDAC1, HDAC3, HDAC4, HDAC6, HDAC7, HDAC10, and HDAC11) enhanced radiation lethality in SQ20B cells. Radiosensitization by inhibition of these HDAC isotypes was accompanied by delay of DNA double strand break repair. Radiosensitivity of SQ20B cells was not altered by selective inhibition of the remaining four isotypes (HDAC2, HDAC5, HDAC8, and HDAC9). Inhibition of HDAC isotypes resulted in downregulation of various proteins involved in pro-survival and DNA damage repair pathways. CONCLUSION: Isotype-specificity exists in HDAC inhibition-induced radiosensitization. Different HDAC isotypes are differentially involved in modulation of cellular radiosensitivity. PMID- 26582396 TI - Effect of Helicobacter pylori Eradication on Long-Term Survival after Distal Gastrectomy for Gastric Cancer. AB - PURPOSE: Negative Helicobacter pylori status has been identified as a poor prognostic factor for survival in gastric cancer (GC) patients who underwent surgery. The aim of this study was to examine the effect of H. pylori eradication on long-term outcomes after distal gastrectomy for GC. MATERIALS AND METHODS: We analyzed the survival of 169 distal GC patients enrolled in a prospective randomized trial evaluating histologic changes of gastric mucosa after H. pylori eradication in the remnant stomach. The outcomes measured were overall survival (OS) and GC recurrence rates. RESULTS: The median follow-up duration was 9.4 years. In the modified intention-to-treat analysis including patients who underwent H. pylori treatment (n=87) or placebo (n=82), 5-year OS rates were 98.9% in the treatment group and 91.5% in the placebo group, and Kaplan-Meier analysis showed no significant difference in OS (p=0.957) between groups. In multivariate analysis, no difference in overall mortality was observed between groups (adjusted hazard ratio [aHR] for H. pylori treatment, 0.75; p=0.495) or H. pylori-eradicated status (aHR for positive H. pylori status, 1.16; p=0.715), while old age, male sex, and advanced stage >= IIIa were independent risk factors. Six patients in the treatment group (6.9%) and seven patients in the placebo group (8.5%) had GC recurrences, and GC recurrence rates were not different according to H. pylori treatment (5-year GC recurrence rates, 4.6% in the treatment group vs. 8.5% in the placebo group; p=0.652). CONCLUSION: H. pylori eradication for GC patients who underwent distal gastrectomy did not compromise long-term survival after surgery. PMID- 26582397 TI - Prospective Study on the Incidence of Postoperative Venous Thromboembolism in Korean Patients with Colorectal Cancer. AB - PURPOSE: Pharmacologic thromboprophylaxis is routinely recommended for Western cancer patients undergoing major surgery for prevention of venous thromboembolism (VTE). However, it is uncertainwhetherroutine administration of pharmacologic thromboprophylaxis is necessary in all Asian surgical cancer patients. This prospective study was conducted to examine the incidence of and risk factors for postoperative VTE in Korean colorectal cancer (CRC) patients undergoing major abdominal surgery. MATERIALS AND METHODS: This study comprised two cohorts, and none of patients received perioperative pharmacologic thromboprophylaxis. In cohort A (n=400), patients were routinely screened for VTE using lower-extremity Doppler ultrasonography (DUS) on postoperative days 5-14. In cohort B (n=148), routine DUS was not performed, and imaging was only performed when there were symptoms or signs that were suspicious for VTE. The primary endpoint was the VTE incidence at 4 weeks postoperatively in cohort A. RESULTS: The postoperative incidence of VTE was 3.0% (n=12) in cohort A. Among the 12 patients, eight had distal calf vein thromboses and one had symptomatic thrombosis. Age >= 70 years (odds ratio [OR], 5.61), >= 2 comorbidities (OR, 13.42), and white blood cell counts of > 10,000/MUL (OR, 17.43) were independent risk factors for postoperative VTE (p < 0.05). In cohort B, there was one case of VTE (0.7%). CONCLUSION: The postoperative incidence of VTE, which included asymptomatic cases, was 3.0% in Korean CRC patients who did not receive pharmacologic thromboprophylaxis. Perioperative pharmacologic thromboprophylaxis should be administered to Asian CRC patients on a risk-stratified basis. PMID- 26582398 TI - Increased expression of circulating miRNA-93 in women with polycystic ovary syndrome may represent a novel, non-invasive biomarker for diagnosis. AB - MicroRNAs (miRNA) are a novel class of small noncoding single-stranded RNA molecules that regulate gene expression. There is increasing evidence of their importance in polycystic ovary syndrome (PCOS). The objective was to determine if miRNA-93 and miRNA-223 are differentially expressed in the circulation of women with PCOS compared to age matched women. A case-control study comparing women with PCOS (n = 25) to age and weight matched controls (n = 24) without PCOS was performed. MiRNA-93 and miRNA-223 were determined by total RNA reverse transcription. Both miRNA-93 and miRNA-223 were significantly increased relative to the control group (p < 0.01, p = 0.029 respectively). In both groups there was no correlation of either miRNA-93 or miRNA-223 with insulin, HOMA-IR, HOMA-beta or testosterone levels. The area under the receiver operator characteristic curve for miR-223 and miR-93 was 0.66 and 0.72 respectively, suggesting miR-93 is a more efficient biomarker than miR-223 for diagnosis of PCOS. The combination of the two miRNAs together, tested using multiple logistic regression analysis, did not improve the diagnostic potential. In conclusion, circulating miRNA-93 and miRNA-223 were higher in women with PCOS compared to age and weight matched controls independent of insulin resistance and testosterone levels, and miR-93 may represent a novel diagnostic biomarker for PCOS. PMID- 26582399 TI - Prenatal factors and infant feeding in relation to risk of benign breast disease in young women. AB - Benign breast disease (BBD) is a well-established risk factor for breast cancer, but little work has considered a girl's early life and her risk for BBD in adulthood. We investigated factors, from pre-conception through infant feeding practices, in relation to subsequent BBD risk in young women. The Growing Up Today Study (GUTS) includes 9032 females, born 1980-1987, who completed questionnaires annually from 1996 through 2001, then 2003, 2005, 2007, 2010, and 2013. In 1996, their mothers provided each participant's birth weight and length, gestational age, biological father's height, and infant feeding factors (e.g., breast-fed, type of formula). In 1999, their mothers reported maternal pre pregnancy weight and weight gain during index pregnancy. Beginning in 2005, daughters (18 years+) reported whether they had ever been diagnosed with biopsy confirmed BBD (n = 142 cases, through 2013). Logistic regression estimated associations between early life factors and biopsy-confirmed BBD. Girls whose mother's BMI prior to pregnancy was 20-25 kg/m(2) were at lower risk of BBD as young women (OR = 0.66, p = 0.04, vs. maternal pre-pregnancy BMI < 20). Girls whose mothers gained 20 + pounds (vs. <20 pounds) during pregnancy were at lower risk (among full-term singleton births: OR = 0.48, p = 0.007, if mother gained 20 35 pounds). However, neither birth weight nor BMI at birth were associated with subsequent BBD risk. We found no evidence that infant feeding practices were linked to BBD. A healthy maternal BMI before pregnancy and sufficient weight gain during pregnancy may produce daughters at lower risk for BBD as young women. Further examination of these findings is needed. PMID- 26582400 TI - Short day transcriptomic programming during induction of dormancy in grapevine. AB - Bud dormancy in grapevine is an adaptive strategy for the survival of drought, high and low temperatures and freeze dehydration stress that limit the range of cultivar adaptation. Therefore, development of a comprehensive understanding of the biological mechanisms involved in bud dormancy is needed to promote advances in selection and breeding, and to develop improved cultural practices for existing grape cultivars. The seasonally indeterminate grapevine, which continuously develops compound axillary buds during the growing season, provides an excellent system for dissecting dormancy, because the grapevine does not transition through terminal bud development prior to dormancy. This study used gene expression patterns and targeted metabolite analysis of two grapevine genotypes that are short photoperiod responsive (Vitis riparia) and non responsive (V. hybrid, Seyval) for dormancy development to determine differences between bud maturation and dormancy commitment. Grapevine gene expression and metabolites were monitored at seven time points under long (LD, 15 h) and short (SD, 13 h) day treatments. The use of age-matched buds and a small (2 h) photoperiod difference minimized developmental differences and allowed us to separate general photoperiod from dormancy specific gene responses. Gene expression profiles indicated three distinct phases (perception, induction and dormancy) in SD-induced dormancy development in V. riparia. Different genes from the NAC DOMAIN CONTAINING PROTEIN 19 and WRKY families of transcription factors were differentially expressed in each phase of dormancy. Metabolite and transcriptome analyses indicated ABA, trehalose, raffinose and resveratrol compounds have a potential role in dormancy commitment. Finally, a comparison between V. riparia compound axillary bud dormancy and dormancy responses in other species emphasized the relationship between dormancy and the expression of RESVERATROL SYNTHASE and genes associated with C3HC4-TYPE RING FINGER and NAC DOMAIN CONTAINING PROTEIN 19 transcription factors. PMID- 26582401 TI - Targeting Endogenous Repair Pathways after AKI. AB - AKI remains a highly prevalent disease associated with poor short- and long-term outcomes and high costs. Although significant advances in our understanding of repair after AKI have been made over the last 5 years, this knowledge has not yet been translated into new AKI therapies. A consensus conference held by the Acute Dialysis Quality Initiative was convened in April of 2014 and reviewed new evidence on successful kidney repair to identify the most promising pathways that could be translated into new treatments. In this paper, we provide a summary of current knowledge regarding successful kidney repair and offer a framework for conceptualizing the therapeutic targeting that may facilitate this process. We outline gaps in knowledge and suggest a research agenda to more efficiently bring new discoveries regarding repair after AKI to the clinic. PMID- 26582402 TI - International Comparisons to Assess Effects of Payment and Regulatory Changes in the United States on Anemia Practice in Patients on Hemodialysis: The Dialysis Outcomes and Practice Patterns Study. AB - For years, erythropoiesis-stimulating agent (ESA) use among patients on dialysis was much higher in the United States than in Europe or Japan. Sweeping changes to dialysis reimbursement and regulatory policies for ESA in the United States in 2011 were expected to reduce ESA use and hemoglobin levels. We used the Dialysis Outcomes and Practice Patterns Study (DOPPS) data from 7129 patients in 223 in center hemodialysis facilities (average per month) to estimate and compare time trends in ESA dose and hemoglobin levels among patients on hemodialysis in the United States, Germany, Italy, Spain, the United Kingdom, and Japan. From 2010 to 2013, substantial declines in ESA use and hemoglobin levels occurred in the United States but not in other DOPPS countries. Between August of 2010 and April of 2013, mean weekly ESA dose in the United States decreased 40.4% for black patients and 38.0% for nonblack patients; mean hemoglobin decreased from 11.5 g/dl in black patients and 11.4 g/dl in nonblack patients to 10.6 g/dl in both groups. In 2010 and 2013, adjusted weekly ESA doses per kilogram were 41% and 11% lower, respectively, in patients in Europe and 60% and 18% lower, respectively, in patients in Japan than in nonblack patients in the United States. Adjusted hemoglobin levels in 2010 and 2013 were 0.07 g/dl lower and 0.56 g/dl higher, respectively, in patients in Europe and 0.93 and 0.01 g/dl lower, respectively, in patients in Japan than in nonblack patients in the United States. In conclusion, ESA dosing reductions in the United States likely reflect efforts in response to changes in reimbursement policy and regulatory guidance. PMID- 26582403 TI - Systematic review of interventions to reduce illicit drug use in female drug dependent street sex workers. AB - OBJECTIVES: Most female street-based sex workers (SSWs) are drug users and this group experience particularly poor outcomes in achieving and maintaining abstinence. In 2010 the UK adopted a recovery-orientated Drug Strategy. This strategy did not specifically highlight the complex drug treatment needs of SSWs. Therefore we sought to synthesise and critically appraise existing evidence of interventions to reduce illicit drug use in this group, in order to guide service change toward better provision for the drug treatment needs of SSWs. METHODS: A systematic review of evidence on the effectiveness of interventions to reduce illicit drug use in female SSWs. Following the PRISMA guidelines, a structured search strategy was used. Searches included databases, organisational and government websites to identify published and grey literature, as well as contacting experts in the field, and hand-searching reference lists and journals. RESULTS: Six studies, one experimental and five observational, were identified which met review inclusion criteria. Intervention approaches evaluated included substitute prescribing, educational sessions and motivational interviewing. All studies reported a positive intervention effect but the five observational studies were all subject to a relatively high risk of bias. By contrast, the experimental study provided little or no evidence of positive effect (OR for reduction of illicit drug in intervention compared to controls 1.17 95%CI 0.84 1.66 at 3 months and 1.14 (95% CI 0.8 to 1.61) at 6 months follow-up). All six studies described challenges and solutions to study recruitment, retention and follow-up, which were influenced by issues affecting SSWs' health and social stability. CONCLUSIONS: There is currently no strong evidence for effectiveness of interventions to reduce illicit drug use in female SSWs with problematic drug use. Thus, the development and robust evaluation of effective interventions should be a priority if recovery-orientated goals are to become more achievable for this group. PMID- 26582404 TI - Effectiveness and safety of 1 vs 4 h blood pressure profile with clinical and laboratory assessment for the exclusion of gestational hypertension and pre eclampsia: a retrospective study in a university affiliated maternity hospital. AB - OBJECTIVE: We asked whether 60 compared with 240 min observation is sufficiently informative and safe for pregnancy day assessment (PDAC) of suspected pre eclampsia (PE). DESIGN: A retrospective study of 209 pregnant women (475 PDAC assessments, 6 months) with routinely collected blood pressure (BP), symptom and laboratory information. We proposed a 60 min screening algorithm comprising: absence of symptoms, normal laboratory parameters and <=1high-BP reading (systolic blood pressure, SBP 140 mm Hg or higher or diastolic blood pressure, DBP 90 mm Hg or higher). We also evaluated two less inclusive screening algorithms. We determined short-term outcomes (within 4 h): severe hypertension, proteinuric hypertension and pregnancy-induced hypertension, as well as long-term outcome: PE-related diagnoses up to the early puerperium. We assessed performance of alternate screening algorithms performance using 2*2 tables. RESULTS: 1 in 3 women met all screen negative criteria at 1 h. Their risk of hypertension requiring treatment in the next 3 h was 1.8% and of failing to diagnose proteinuric hypertensive PE at 4 h was 5.1%. If BP triggers were 5 mm Hg lower, 1 in 6 women would be screen-negative of whom 1.1% subsequently develops treatment requiring hypertension and 4.5% demonstrate short-term proteinuric hypertension. We present sensitivity, specificity, negative and positive likelihood ratios for alternate screening algorithms. CONCLUSIONS: We endorse further research into the safest screening test where women are considered for discharge after 60 min. Safety, patient and staff satisfaction should be assessed prospectively. Any screening test should be used in conjunction with good clinical care to minimise maternal and perinatal hazards of PE. PMID- 26582405 TI - Protocol for extended antibiotic therapy after laparoscopic cholecystectomy for acute calculous cholecystitis (Cholecystectomy Antibiotic Randomised Trial, CHART). AB - INTRODUCTION: Acute calculous cholecystitis represents one of the most common complications of cholelithiasis. While laparoscopic cholecystectomy is the standard treatment in mild and moderate forms, the need for antibiotic therapy after surgery remains undefined. The aim of the randomised controlled Cholecystectomy Antibiotic Randomised Trial (CHART) is therefore to assess if there are benefits in the use of postoperative antibiotics in patients with mild or moderate acute cholecystitis in whom a laparoscopic cholecystectomy is performed. METHODS AND ANALYSIS: A single-centre, double-blind, randomised trial. After screening for eligibility and informed consent, 300 patients admitted for acute calculus cholecystitis will be randomised into two groups of treatment, either receiving amoxicillin/clavulanic acid or placebo for 5 consecutive days. Postoperative evaluation will take place during the first 30 days. Postoperative infectious complications are the primary end point. Secondary end points are length of hospital stay, readmissions, need of reintervention (percutaneous or surgical reinterventions) and overall mortality. The results of this trial will provide strong evidence to either support or abandon the use of antibiotics after surgery, impacting directly in the incidence of adverse events associated with the use of antibiotics, the emergence of bacterial resistance and treatment costs. ETHICS AND DISSEMINATION: This study and informed consent sheets have been approved by the Research Projects Evaluating Committee (CEPI) of Hospital Italiano de Buenos Aires (protocol N degrees 2111). RESULTS: The results of the trial will be reported in a peer-reviewed publication. TRIAL REGISTRATION NUMBER: NCT02057679. PMID- 26582406 TI - Acupuncture for postoperative pain following total knee arthroplasty: a systematic review protocol. AB - INTRODUCTION: Total knee arthroplasty (TKA) is a common surgical method in orthopaedics; however, pain management after TKA remains a significant challenge. This review provides a comprehensive evaluation of the effects of acupuncture for postoperative pain after TKA. METHODS AND ANALYSIS: The following 10 databases will be searched until August 2015: MEDLINE, EMBASE, CENTRAL, AMED, CINAHL, three Chinese databases (the China National Knowledge Infrastructure Database, the Chongqing VIP Chinese Science and Technology Periodical Database, and Wanfang Database) and five Korean databases (the Korean Medical Database, the Korean Studies Information Service System, the National Discovery for Science Leaders, the Database Periodical Information Academic, and the Oriental Medicine Advanced Searching Integrated System). All eligible randomised controlled trials related to the use of acupuncture for postoperative pain after TKA will be included. Assessment of risk of bias will be performed with the Cochrane risk-of-bias method. Mean differences or standardised mean differences will be calculated with 95% CIs for continuous data; the risk ratio will be used with 95% CIs for dichotomous data. DISSEMINATION: This systematic review will be presented in a peer-reviewed journal. The result of this review will also be disseminated at a relevant conference presentation. TRIAL REGISTRATION NUMBER: PROSPERO 2015: CRD42015020924. PMID- 26582407 TI - Fluoroquinolones and collagen associated severe adverse events: a longitudinal cohort study. AB - OBJECTIVES: Fluoroquinolone-associated tendon ruptures are a recognised complication, but other severe collagen-associated adverse events may also be possible. Our objectives were to confirm the association of fluoroquinolones and tendon rupture, to clarify the potential association of fluoroquinolones and retinal detachment, and to test for a potentially lethal association between fluoroquinolones and aortic aneurysms. SETTING: Population-based longitudinal cohort study in Ontario, Canada. PARTICIPANTS: Older adults turning 65 years between April 1 1997 and March 31 2012 were followed until primary outcome, death, or end of follow-up (March 31 2014). Fluoroquinolone prescriptions were measured as a time-varying covariate, with patients considered at risk during and for 30 days following a treatment course. PRIMARY OUTCOME MEASURES: Severe collagen-associated adverse events defined as tendon ruptures, retinal detachments and aortic aneurysms diagnosed in hospital and emergency departments. RESULTS: Among the 1,744,360 eligible patients, 657,950 (38%) received at least one fluoroquinolone during follow-up, amounting to 22,380,515 days of treatment. The patients experienced 37,338 (2.1%) tendon ruptures, 3246 (0.2%) retinal detachments, and 18,391 (1.1%) aortic aneurysms. Severe collagen-associated adverse events were more common during fluoroquinolone treatment than control periods, including tendon ruptures (0.82 vs 0.26/100-person years, p<0.001), retinal detachments (0.03 vs 0.02/100-person-years, p=0.003) and aortic aneurysms (0.35 vs 0.13/100-person-years, p<0.001). Current fluoroquinolones were associated with an increased hazard of tendon rupture (HR 3.13, 95% CI 2.98 to 3.28; adjusted HR 2.40, 95% CI 2.24 to 2.57) and an increased hazard of aortic aneurysms (HR 2.72, 95% CI 2.53 to 2.93; adjusted HR2.24, 95% CI 2.02 to 2.49) that were substantially greater in magnitude than the association of these outcomes with amoxicillin. The hazard of retinal detachment was marginal (HR 1.28, 95% CI 0.99 to 1.65; adjusted HR 1.47, 95% CI 1.08 to 2.00) and not greater in magnitude than that observed with amoxicillin. CONCLUSIONS: Fluoroquinolones are associated with subsequent tendon ruptures and may also contribute to aortic aneurysms. PMID- 26582409 TI - Cannabis potency: the need for global monitoring. PMID- 26582408 TI - Western Australian Public Opinions of a Minimum Pricing Policy for Alcohol: Study Protocol. AB - BACKGROUND: Excessive alcohol consumption has significant adverse economic, social, and health outcomes. Recent estimates suggest that the annual economic costs of alcohol in Australia are up to AUD $36 billion. Policies influencing price have been demonstrated to be very effective in reducing alcohol consumption and alcohol-related harms. Interest in minimum pricing has gained traction in recent years. However, there has been little research investigating the level of support for the public interest case of minimum pricing in Australia. OBJECTIVE: This article describes protocol for a study exploring Western Australian (WA) public knowledge, understanding, and reaction to a proposed minimum price policy per standard drink. METHODS: The study will employ a qualitative methodological design. Participants will be recruited from a wide variety of backgrounds, including ethnic minorities, blue and white collar workers, unemployed, students, and elderly/retired populations to participate in focus groups. Focus group participants will be asked about their knowledge of, and initial reactions to, the proposed policy and encouraged to discuss how such a proposal may affect their own alcohol use and alcohol consumption at the population level. Participants will also be asked to discuss potential avenues for increasing acceptability of the policy. The focus groups will adopt a semi-structured, open ended approach guided by a question schedule. The schedule will be based on feedback from pilot samples, previous research, and a steering group comprising experts in alcohol policy and pricing. RESULTS: The study is expected to take approximately 14 months to complete. CONCLUSIONS: The findings will be of considerable interest and relevance to government officials, policy makers, researchers, advocacy groups, alcohol retail and licensed establishments and organizations, city and town planners, police, and other stakeholder organizations. PMID- 26582410 TI - Common variants in the Na(+)-coupled bicarbonate transporter genes and salt sensitivity of blood pressure: the GenSalt study. AB - The current study comprehensively examined the association between common variants in the Na(+)-coupled bicarbonate transporter (NCBT) genes and blood pressure (BP) responses to dietary sodium intervention. A 7-day low-sodium followed by a 7-day high-sodium dietary intervention was conducted among 1906 Han participants from rural areas of northern China. Nine BP measurements were obtained at baseline and each intervention using a random-zero sphygmomanometer. A mixed-effect model was used to assess the additive associations of 76 common variants in five NCBT genes, including SLC4A4, SLC4A5, SLC4A7, SLC4A8 and SLC4A10, with salt sensitivity phenotypes. The Bonferroni method was used to adjust for multiple testing. SLC4A4 marker rs4254735 was significantly associated with diastolic BP (DBP) response to low-sodium intervention (P=5.05 * 10(-4)), with mean (95% confidence interval (CI)) response of -2.91 (-3.21, -2.61) and 0.40 (-1.84, 1.05) mmHg for genotype AA and AG, respectively. In addition, BP responses to high-sodium intervention significantly increased with the number of minor C alleles of SLC4A4 marker rs10022637. Mean systolic BP responses among those with genotypes TT, CT and CC were 4.62 (4.29, 4.99), 5.94 (5.31, 6.58) and 6.00 (3.57, 8.43) mmHg (P=1.14 * 10(-4)); mean DBP responses were 1.72 (1.41, 2.03), 3.22 (2.52, 3.92) and 3.94 (1.88, 5.99) mmHg (P=2.26 * 10(-5)) and mean arterial pressure responses were 2.69 (2.40, 2.97), 4.13 (3.57, 4.70) and 4.61 (2.51, 6.71) mmHg (P=2.07 * 10(-6)), respectively. In brief, the present study indicated that common variants in the SLC4A4 gene might contribute to the variation of BP responses to dietary sodium intake in Han Chinese population. PMID- 26582411 TI - From malignant hypertension to hypertension-MOD: a modern definition for an old but still dangerous emergency. AB - The prevalence of malignant hypertension has clearly fallen with the advent of anti-hypertensive medication but has remained stable over the past 30-40 years in spite of progress in diagnosis and management of hypertension. A diagnosis of malignant hypertension is usually based on the association of severely elevated blood pressure with a Keith and Wagener stage III or IV retinopathy. We believe that this definition can be reconsidered for several reasons. Although simple and pragmatic, this definition corresponds to a time when there were few techniques for assessment of hypertensive target organ involvement, and does not take into account involvement of kidney, brain and heart; whereas the overall prognosis largely depends on how much they are affected. On the contrary, the acute blood pressure level and especially diastolic should not be a hard diagnostic criterion as it does not itself constitute the prognosis of the condition. We propose to consider that malignant hypertension with retinopathy is only one of a number of possible presentation(s) of acute hypertension with multi organ damage (hypertension multi organ damage (MOD)) and that the recognition of these hypertensive emergencies, when retinopathy is lacking, be based on acute elevation of BP associated with impairment of at least three different target organs. The objective of a new and expanded definition is to facilitate recognition of these true emergencies. The condition is more common than usually perceived and would have a much worse prognosis than the usual forms of hypertension. Early recognition and management of hypertension-MOD are fundamental to any improvement in prognosis. PMID- 26582412 TI - Fur-type transcriptional repressors and metal homeostasis in the cyanobacterium Synechococcus sp. PCC 7002. AB - Metal homeostasis is a crucial cellular function for nearly all organisms. Some heavy metals (e.g., Fe, Zn, Co, Mo) are essential because they serve as cofactors for enzymes or metalloproteins, and chlorophototrophs such as cyanobacteria have an especially high demand for iron. At excessive levels, however, metals become toxic to cyanobacteria. Therefore, a tight control mechanism is essential for metal homeostasis. Metal homeostasis in microorganisms comprises two elements: metal acquisition from the environment and detoxification or excretion of excess metal ions. Different families of metal-sensing regulators exist in cyanobacteria and each addresses a more or less specific set of target genes. In this study the regulons of three Fur-type and two ArsR-SmtB-type regulators were investigated in a comparative approach in the cyanobacterium Synechococcus sp. PCC 7002. One Fur type regulator controls genes for iron acquisition (Fur); one controls genes for zinc acquisition (Zur); and the third controls two genes involved in oxidative stress (Per). Compared to other well-investigated cyanobacterial strains, however, the set of target genes for each regulator is relatively small. Target genes for the two ArsR-SmtB transcriptional repressors (SmtB (SYNPCC7002_A2564) and SYNPCC7002_A0590) are involved in zinc homeostasis in addition to Zur. Their target genes, however, are less specific for zinc and point to roles in a broader heavy metal detoxification response. PMID- 26582413 TI - Immunogenomics: a foundation for intelligent immune design. AB - The complexity of the immune system is now being interrogated using methodologies that generate extensive multi-dimensional data. Effective collection, integration and interpretation of these data remain difficult, but overcoming these important challenges will provide new insights into immune function and opportunities for the rational design of new immune interventions. PMID- 26582415 TI - Cigarette smoke-induced reduction in binding of the salivary translocator protein is not mediated by free radicals. AB - Oral cancer is the most common malignancy of the head and neck and its main inducer is exposure to cigarette smoke (CS) in the presence of saliva. It is commonly accepted that CS contributes to the pathogenesis of oral cancer via reactive free radicals and volatile aldehydes. The 18 kDa translocator protein (TSPO) is an intracellular receptor involved in proliferation and apoptosis, and has been linked to various types of cancer. The presence of TSPO in human saliva has been linked to oral cancer, and its binding affinity to its ligand is reduced following exposure to CS. In the present study we wished to further investigate the mechanism behind the CS-induced reduction of TSPO binding by exploring the possible mediatory role of reactive oxygen species (ROS) and volatile aldehydes in this process. We first analyzed TSPO binding in control saliva and in saliva exposed to CS in the presence and absence of various antioxidants. These experiments found that TSPO binding ability was not reversed by any of the antioxidants added, suggesting that CS exerts its effect on TSPO via mechanisms that do not involve volatile aldehydes and free radicals tested. Next, we analyzed TSPO binding in saliva following addition of exogenous ROS in the form of H2O2. These experiments found that TSPO binding was enhanced due to the treatment, once again showing that the CS-induced TSPO binding reduction is not mediated by this common form of ROS. However, the previously reported CS-induced reduction in salivary TSPO binding together with the role of TSPO in cells and its link to cancer strongly suggest that TSPO has a critical role in the pathogenesis of CS-induced oral cancer. The importance of further elucidating the mechanisms behind it should be emphasized. PMID- 26582414 TI - Body mass index and risk of lung cancer: Systematic review and dose-response meta analysis. AB - Questions remain about the significance of the dose-response relationship between body mass index (BMI) and lung cancer (LC) risk. Pertinent studies were identified through a search in EMBASE and PUBMED from July 2014 until March 2015. The summary relative risk (SRR) and confidence interval (CI) were estimated. The dose-response relationship was assessed using a restricted cubic spline. The overall meta-analysis showed evidence of a nonlinear association between BMI and LC risk (Pnonlinearity < 0.001). The SRR were 0.98 (95%CI: 0.95-1.01) for 25 kg/m(2), 0.91 (95%CI: 0.85-0.98) for 30 kg/m(2) and 0.81 (95% CI: 0.72-0.91) for 35 kg/m(2), with mild between-study heterogeneity (I(2) = 5%). The results of the stratified analysis by gender were comparable to those of the overall meta analysis. When stratified by smoking status, linear dose-response associations were observed for current smokers, ex-smokers and non-smokers (Pnonlinearity > 0.05), whereas the effects were attenuated when restricting analysis to non smokers, and at the point of 30 kg/m(2), the SRR was 0.96 (95%CI: 0.86-1.07) for males and 0.95 (95%CI: 0.89-1.02) for females. This meta-analysis provides quantitative evidence that increasing BMI is a protective factor against LC. Keeping normal-to-moderate BMI should be prescribed as an evidence-based lifestyle tip for LC prevention in smokers. PMID- 26582416 TI - Alteration of cathepsin D trafficking induced by hypoxia and extracellular acidification in MCF-7 breast cancer cells. AB - The microenvironment that surrounds tumor cells is characterized by hypoxic conditions and extracellular acidity. These hostile conditions induce crucial changes in cell behavior and can promote the secretion of many soluble factors such as growth factors, cytokines and enzymes. The lysosomal aspartyl endopeptidase cathepsin D (CD) is a marker of poor prognosis in breast cancer and is associated with a metastatic risk. In this study, the transport of CD was investigated in a model of breast cancer cells line (MCF-7) cultivated under hypoxia and acidification of media. CD secretion was assessed using Western blot analysis and protease activity was measured in conditioned culture media. We demonstrate that cultured MCF-7 cells secrete an active 52 kDa pCD precursor and report that under hypoxia there was an increased amount of pCD secreted. More surprisingly, extracellular acidification (pH 6 and 5.6) induced the secretion of the fully-mature and active (34 kDa + 14 kDa) double chain CD. Our findings reflect the fact that chemical anomalies influence the secretion path of CD in a breast cancer cell model, resulting in altered trafficking of the mature form. This important result may provide new arguments in favor of the role of extracellular CD in the degradation of the matrix proteins that constitute the breast tumor microenvironment. PMID- 26582417 TI - Glucosylceramidases and malignancies in mammals. AB - Sphingolipids represent a major class of lipids that are essential constituents of eukaryotic cells. They are predominantly located in plasma membrane microdomains, and play an important structural role in regulating membrane fluidity. They are also bioactive effectors involved in diverse key cellular functions such as apoptosis and proliferation. The implication of some sphingolipids in cancer is well established whereas that of some others is still a matter of intense investigation. Glucosylceramide is the backbone of more than 300 structurally different glycosphingolipids including gangliosides and sulfatides, and is essential for mammalian development. Therefore, glucosylceramidases (also named GBA1, GBA2 and GBA3 beta-glucosidases), the enzymes that hydrolyse beta-glucosylceramide, play important functions. GBA1 is a lysosomal hydrolase whose deficiency causes Gaucher disease, the most prevalent inherited lysosomal storage disorder. GBA2 is a ubiquitous non-lysosomal glucosylceramidase whose mutations have been associated with some forms of hereditary spastic paraplegia. GBA3 is a cytosolic beta-glucosidase, mostly present in the kidney, liver, spleen, intestine and lymphocytes of mammals, the function of which is still unclear. Whereas glucosylceramide synthase is implicated in multidrug resistance, the role of glucosylceramide breakdown in cancer is not yet fully appreciated. Defective GBA1 enzyme activity in humans, i.e., Gaucher disease, is associated with an increased risk of multiple myeloma and other malignancies. Putative molecular links between Gaucher disease and cancer, which might implicate the malignant cell and/or its microenvironment, are reviewed. The functions of GBA2 and GBA3 in cancer progression are also discussed. PMID- 26582418 TI - How to model temporal changes in comorbidity for cancer patients using prospective cohort data. AB - BACKGROUND: The presence of comorbid conditions is strongly related to survival and also affects treatment choices in cancer patients. This comorbidity is often quantified by the Charlson Comorbidity Index (CCI) using specific weights (1, 2, 3, or 6) for different comorbidities. It has been shown that the CCI increases at different times and with different sizes, so that traditional time to event analysis is not adequate to assess these temporal changes. Here, we present a method to model temporal changes in CCI in cancer patients using data from PCBaSe Sweden, a nation-wide population-based prospective cohort of men diagnosed with prostate cancer. Our proposed model is based on the assumption that a change in comorbidity, as quantified by the CCI, is an irreversible one-way process, i.e., CCI accumulates over time and cannot decrease. METHODS: CCI was calculated based on 17 disease categories, which were defined using ICD-codes for discharge diagnoses in the National Patient Register. A state transition model in discrete time steps (i.e., four weeks) was applied to capture all changes in CCI. The transition probabilities were estimated from three modelling steps: 1) Logistic regression model for vital status, 2) Logistic regression model to define any changes in CCI, and 3) Poisson regression model to determine the size of CCI change, with an additional logistic regression model for CCI changes >= 6. The four models combined yielded parameter estimates to calculate changes in CCI with their confidence intervals. RESULTS: These methods were applied to men with low risk prostate cancer who received active surveillance (AS), radical prostatectomy (RP), or curative radiotherapy (RT) as primary treatment. There were large differences in CCI changes according to treatment. CONCLUSIONS: Our method to model temporal changes in CCI efficiently captures changes in comorbidity over time with a small number of regression analyses to perform - which would be impossible with tradition time to event analyses. However, our approach involves a simulation step that is not yet included in standard statistical software packages. In our prostate cancer example we showed that there are large differences in development of comorbidities among men receiving different treatments for prostate cancer. PMID- 26582419 TI - pH-Dependent Equilibrium between 5-Guanidinohydantoin and Iminoallantoin Affects Nucleotide Insertion Opposite the DNA Lesion. AB - Four-electron oxidation of 2'-deoxyguanosine (dG) yields 5-guanidinohydantoin (dGh) as a product. Previously, we hypothesized that dGh could isomerize to iminoallantoin (dIa) via a mechanism similar to the isomerization of allantoin. The isomerization reaction was monitored by HPLC and found to be pH dependent with a transition pH = 10.1 in which dGh was favored at low pH and dIa was favored at high pH. The structures for these isomers were confirmed by UV-vis, MS, and (1)H and (13)C NMR. Additionally, the UV-vis and NMR experimental results are supported by density functional theory calculations. A mechanism is proposed to support the pH dependency of the isomerization reaction. Next, we noted the hydantoin ring of dGh mimics thymine, while the iminohydantoin ring of dIa mimics cytosine; consequently, a dGh/dIa site was synthesized in a DNA template strand, and standing start primer extension studies were conducted with Klenow fragment exo(-). The dATP/dGTP insertion ratio opposite the dGh/dIa site as a function of pH was evaluated from pH 6.5-9.0. At pH 6.5, only dATP was inserted, but as the pH increased to 9.0, the amount of dGTP insertion steadily increased. This observation supports dGh to dIa isomerization in DNA with a transition pH of ~8.2. PMID- 26582420 TI - Brain laterality, depression and anxiety disorders: New findings for emotional and verbal dichotic listening in individuals at risk for depression. AB - Studies using dichotic listening tests and electroencephalographic (EEG) measures of hemispheric asymmetry have reported evidence of abnormal brain laterality in patients having depressive disorders. We present new findings from a multigenerational study of risk for depression, in which perceptual asymmetry was measured in dichotic listening tests of emotional and verbal processing. Biological offspring and grandchildren of probands with a major depressive disorder (MDD) who were at high risk and those of nondepressed controls who were at low risk were tested on dichotic emotional recognition and consonant-vowel syllable tests. In the emotion test, individuals with a lifetime diagnosis of MDD had a smaller right hemisphere advantage than those without a MDD, but there was no difference between high- and low-risk groups or between those with or without an anxiety disorder. In the syllable test, a smaller left hemisphere advantage was found in individuals with an anxiety disorder compared to those without an anxiety disorder, but there was no difference between high- and low-risk groups or between those with or without a MDD. This double dissociation indicates that lifetime diagnosis of MDD and anxiety disorders have a differential impact on lateralized hemispheric processing of emotional and verbal information. PMID- 26582421 TI - Continuous Metabolic Monitoring in Infant Cardiac Surgery: Toward an Individualized Cardiopulmonary Bypass Strategy. AB - Cardiopulmonary bypass (CPB) in infants is associated with morbidity due to systemic inflammatory response syndrome (SIRS). Strategies to mitigate SIRS include management of perfusion temperature, hemodilution, circuit miniaturization, and biocompatibility. Traditionally, perfusion parameters have been based on body weight. However, intraoperative monitoring of systemic and cerebral metabolic parameters suggest that often, nominal CPB flows may be overestimated. The aim of the study was to assess the safety and efficacy of continuous metabolic monitoring to manage CPB in infants during open-heart repair. Between December 2013 and October 2014, 31 consecutive neonates, infants, and young children undergoing surgery using normothermic CPB were enrolled. There were 18 male and 13 female infants, aged 1.4 +/- 1.7 years, with a mean body weight of 7.8 +/- 3.8 kg and body surface area of 0.39 m(2) . The study was divided into two phases: (i) safety assessment; the first 20 patients were managed according to conventional CPB flows (150 mL/min/kg), except for a 20-min test during which CPB was adjusted to the minimum flow to maintain MVO2>70% and rSO2>45% (group A); (ii) efficacy assessment; the following 11 patients were exclusively managed adjusting flows to maintain MVO2>70% and rSO2>45% for the entire duration of CPB (group B). Hemodynamic, metabolic, and clinical variables were compared within and between patient groups. Demographic variables were comparable in the two groups. In group A, the 20-min test allowed reduction of CPB flows greater than 10%, with no impact on pH, blood gas exchange, and lactate. In group B, metabolic monitoring resulted in no significant variation of endpoint parameters, when compared with group A patients (standard CPB), except for a 10% reduction of nominal flows. There was no mortality and no neurologic morbidity in either group. Morbidity was comparable in the two groups, including: inotropic and/or mechanical circulatory support (8 vs. 1, group A vs. B, P = 0.07), reexploration for bleeding (1 vs. none, P = not significant [NS]), renal failure requiring dialysis (none vs. 1, P = NS), prolonged ventilation (9 vs. 4, P = NS), and sepsis (2 vs. 1, P = NS). The present study shows that normothermic CPB in neonates, infants, and young children can be safely managed exclusively by systemic and cerebral metabolic monitoring. This strategy allows reduction of at least 10% of predicted CPB flows under normothermia and may lay the ground for further tailoring of CPB parameters to individual patient needs. PMID- 26582422 TI - Appearance Investment, Quality of Life, and Metabolic Control Among Women with Type 1 Diabetes. AB - BACKGROUND: Concomitants of Type 1 diabetes management include weight gain and dietary restraint. Body image concerns, particularly among women, are therefore common. PURPOSE: The study evaluated associations between the appearance investment component of body image, age, quality of life and self-reported metabolic control were examined, along with the practice of insulin restriction as a weight control strategy. METHOD: A questionnaire comprising demographic and diabetes-related information, the Appearance Schemas Inventory, and Diabetes Quality of Life Brief Clinical Inventory was completed by Australian women diagnosed with type 1 diabetes (N = 177). RESULTS: Self-evaluative salience was higher among younger participants, those with a lower quality of life, and those with better metabolic control of their diabetes, with the relationships between metabolic control and all of age, quality of life, and self-evaluative salience noted to be non-linear. Among participants who reported restricting insulin for weight control, self-evaluative salience was particularly relevant. Motivational salience was not related to other study variables. CONCLUSION: Clinically, the provision of information regarding appearance changes that might arise in order to mitigate later body image difficulties is a potentially beneficial adjunct to standard diabetes management protocols that may lead to more successful disease adjustment. PMID- 26582423 TI - Interleukin-10 production at the early stage of infection with foot-and-mouth disease virus related to the likelihood of persistent infection in cattle. AB - The factors leading to persistent infection of foot-and-mouth disease (FMD) virus in ruminants are not well defined. This paper provides evidence of the presence of interleukin-10 (IL-10) early in the course of infection (1-4 days) as a factor in the development of persistence of FMD virus in cattle. Results showed that serum IL-10 in carrier cattle infected with FMD virus type O (n = 4) was detected and peaked at 1 or 2 days post infection and rapidly declined thereafter. In contract, serum IL-10 levels in non-carrier cattle (n = 21) were very low or undetectable during the same period. PMID- 26582424 TI - Effect of prostate-specific membrane antigen positron emission tomography on the decision-making of radiation oncologists. AB - BACKGROUND: Positron emission tomography (PET) imaging is routinely used in many cancer types, although is not yet a standard modality for prostate carcinoma. Prostate-specific membrane antigen (PSMA) PET is a promising new modality for staging prostate cancer, with recent studies showing potential advantages over traditional computed tomography (CT), magnetic resonance imaging (MRI) and nuclear medicine bone scan imaging. However, the impact of PSMA PET on the decision-making of radiation oncologists and outcomes after radiotherapy is yet to be determined. Our aim was to determine the impact of PSMA PET on a radiation oncologist's clinical practice. FINDINGS: Patients in a radiation oncology clinic who underwent PSMA PET were prospectively recorded in an electronic oncology record. Patient demographics, outcomes of imaging, and impact on decision-making were evaluated. Fifty-four patients underwent PSMA PET between January and May 2015. The major reasons for undergoing PET included staging before definitive (14.8%) or post-prostatectomy (33.3%) radiotherapy, and investigation of PSA failures following definitive (16.7%) or post-prostatectomy (33.3%) radiotherapy. In 46.3% of patients PSMA was positive after negative traditional imaging, in 9.3% PSMA was positive after equivocal imaging, and in 13.0% PSMA was negative after equivocal imaging. PSMA PET changed radiotherapy management in 46.3% of cases, and hormone therapy in 33.3% of patients, with an overall change in decision-making in 53.7% of patients. CONCLUSIONS: PSMA PET has the potential to significantly alter the decision-making of radiation oncologists, and may become a valuable imaging tool in the future. PMID- 26582425 TI - A Free-Radical-Promoted Stereospecific Decarboxylative Silylation of alpha,beta Unsaturated Acids with Silanes. AB - A stereospecific decarboxylative silylation of acrylic and propiolic acids with silanes was developed. This reaction represents the first example of decarboxylative C-Si bond formation and provides an efficient and convenient approach to various synthetically useful alkenyl and alkynyl organosilicon compounds through the reaction of alpha,beta-unsaturated acids with silanes. Spin trapping and EPR experiments support a radical addition/elimination process. PMID- 26582427 TI - Convergent elevation trends in canopy chemical traits of tropical forests. AB - The functional biogeography of tropical forests is expressed in foliar chemicals that are key physiologically based predictors of plant adaptation to changing environmental conditions including climate. However, understanding the degree to which environmental filters sort the canopy chemical characteristics of forest canopies remains a challenge. Here, we report on the elevation and soil-type dependence of forest canopy chemistry among 75 compositionally and environmentally distinct forests in nine regions, with a total of 7819 individual trees representing 3246 species collected, identified and assayed for foliar traits. We assessed whether there are consistent relationships between canopy chemical traits and both elevation and soil type, and evaluated the general role of phylogeny in mediating patterns of canopy traits within and across communities. Chemical trait variation and partitioning suggested a general model based on four interconnected findings. First, geographic variation at the soil Order level, expressing broad changes in fertility, underpins major shifts in foliar phosphorus (P) and calcium (Ca). Second, elevation-dependent shifts in average community leaf dry mass per area (LMA), chlorophyll, and carbon allocation (including nonstructural carbohydrates) are most strongly correlated with changes in foliar Ca. Third, chemical diversity within communities is driven by differences between species rather than by plasticity within species. Finally, elevation- and soil-dependent changes in N, LMA and leaf carbon allocation are mediated by canopy compositional turnover, whereas foliar P and Ca are driven more by changes in site conditions than by phylogeny. Our findings have broad implications for understanding the global ecology of humid tropical forests, and their functional responses to changing climate. PMID- 26582426 TI - Anoctamin 1 (Ano1) is required for glucose-induced membrane potential oscillations and insulin secretion by murine beta-cells. AB - Anions such as Cl(-) and HCO3 (-) are well known to play an important role in glucose-stimulated insulin secretion (GSIS). In this study, we demonstrate that glucose-induced Cl(-) efflux from beta-cells is mediated by the Ca(2+)-activated Cl(-) channel anoctamin 1 (Ano1). Ano1 expression in rat beta-cells is demonstrated by reverse transcriptase-polymerase chain reaction, western blotting, and immunohistochemistry. Typical Ano1 currents are observed in whole cell and inside-out patches in the presence of intracellular Ca(++): at 1 MUM, the Cl(-) current is outwardly rectifying, and at 2 MUM, it becomes almost linear. The relative permeabilities of monovalent anions are NO3 (-) (1.83 +/- 0.10) > Br(-) (1.42 +/- 0.07) > Cl(-) (1.0). A linear single-channel current voltage relationship shows a conductance of 8.37 pS. These currents are nearly abolished by blocking Ano1 antibodies or by the inhibitors 2-(5-ethyl-4-hydroxy-6 methylpyrimidin-2-ylthio)-N-(4-(4-methoxyphenyl)thiazol-2-yl)acetamide (T-AO1) and tannic acid (TA). These inhibitors induce a strong decrease of 16.7-mM glucose-stimulated action potential rate (at least 87 % on dispersed cells) and a partial membrane repolarization with T-AO1. They abolish or strongly inhibit the GSIS increment at 8.3 mM and at 16.7 mM glucose. Blocking Ano1 antibodies also abolish the 16.7-mM GSIS increment. Combined treatment with bumetanide and acetazolamide in low Cl(-) and HCO3 (-) media provokes a 65 % reduction in action potential (AP) amplitude and a 15-mV AP peak repolarization. Although the mechanism triggering Ano1 opening remains to be established, the present data demonstrate that Ano1 is required to sustain glucose-stimulated membrane potential oscillations and insulin secretion. PMID- 26582428 TI - Retinal involvement in amyotrophic lateral sclerosis: a study with optical coherence tomography and diffusion tensor imaging. AB - Although motor neuron degeneration is the predominant feature in ALS, recent data point to a more widespread pathology also comprising non-motor symptoms. Retinal thinning has been reported in a variety of neurodegenerative conditions. Yet, studies of retinal involvement in ALS are sparse and results are heterogeneous. We studied retinal alterations in ALS using a systematic approach combining Optical Coherence Tomography (OCT), Diffusion Tensor Imaging (DTI) and clinical phenotyping. We hypothesized that selective changes of specific retinal layers may be a reflection of overall neurodegeneration as measured by DTI. Spectral domain OCT images were analyzed to calculate the average thickness of retinal layers in 71 ALS patients and 20 controls. In 30 patients, the region of interest (ROI) based fractional anisotrophy (FA) was measured in the corticospinal tract (CST), as this region is preferentially affected by motor neuron degeneration. Clinical data were collected for correlation analysis. Patients showed a significant thinning of the inner nuclear layer (INL; p = 0.04) and the retinal nerve fibre layer (RNFL; p = 0.004) compared to controls. We saw significant correlations between retinal thickness and FA values of the CST in patients (p = 0.005). No significant correlation between clinical parameters and retinal involvement was observed. Our study provides evidence for a retinal involvement in ALS. Interestingly, ALS patients show a reduction in FA of the CST, which is correlated to retinal thinning. We conclude that retinal involvement is in fact associated to overall neurodegeneration and may be regarded as a potential technical biomarker in ALS. PMID- 26582429 TI - Characterization of oil-palm trunk residue degradation enzymes derived from the isolated fungus, Penicillium rolfsii c3-2(1) IBRL. AB - This study characterizes crude enzymes derived from Penicillium rolfsii c3-2(1) IBRL, a mesophilic fungus isolated from the local soil of Malaysia. Prior to enzyme activity evaluation, P. rolfsii c3-2(1) IBRL was inoculated into a broth medium containing oil-palm trunk residues for the preparation of crude enzymes. Oil-palm trunk residues were optimally hydrolysed at pH5.0 and 50 degrees C. P. rolfsii c3-2(1) IBRL-derived crude enzymes displayed higher thermal stability compared with the commercial enzymes, Celluclast 1.5 L and Acellerase 1500. Moreover, the hydrolysing activities of the P. rolfsii c3-2(1) IBRL-derived crude enzymes (xylan, arabinan, and laminarin) were superior compared to that of Celluclast 1.5 L and Acellerase 1500, and exhibit 2- to 3-fold and 3- to 4-fold higher oil-palm trunk residues-hydrolysing specific activity, respectively. This higher hydrolysis efficiency may be attributed to the weak 'lignin-binding' ability of the P. rolfsii c3-2(1) IBRL-derived enzymes compared to the commercial enzymes. PMID- 26582430 TI - Attenuation of quorum sensing-mediated virulence of Acinetobacter baumannii by Glycyrrhiza glabra flavonoids. AB - AIM: To develop an alternative quorum quenching therapy against multidrug resistant Acinetobacter baumannii. METHODS & RESULTS: Activity-guided partially purified fraction (F1) from Glycyrrhiza glabra significantly (p < 0.05) reduced quorum sensing regulated virulence factors of A. baumannii viz. motility, biofilm formation and production of antioxidant enzymes. Mechanistically, F1 downregulated the expression of autoinducer synthase gene, abaI, and consequently reduced (92%) the production of 3-OH-C12-HSL as determined by ESI-MS. Q-TOF and Q TRAP analyses suggested the presence of flavonoids viz. licoricone, glycyrin and glyzarin as the active ingredients. CONCLUSION: This is the first report on quorum quenching activity of G. glabra linked to its flavonoids that downregulated the expression of abaI and attenuated quorum sensing regulated virulence of A. baumannii. PMID- 26582431 TI - Ceritinib for the treatment of patients with anaplastic lymphoma kinase (ALK) positive metastatic non-small cell lung cancer. AB - Non-small cell lung cancer (NSCLC) represents the paradigm of personalized treatment of human cancer. Several oncogenic druggable alterations have been so far identified, with anaplastic lymphoma kinase (ALK) gene rearrangements representing one of the newest and most appealing. Crizotinib is now recognized as the standard of care in ALK-positive NSCLC due to the positive results of recently published trials. Unfortunately, resistance inevitably occurs within the first year of treatment. Overcoming resistance is the major challenge in clinical oncology, and novel potent ALK inhibitors are currently under evaluation, including ceritinib. Ceritinib is an oral, potent, second-generation ALK inhibitor demonstrating activity in patients who develop resistance to crizotinib. Recent data also suggested efficacy in ALK-inhibitor-naive population, thus supporting investigation of the drug in front-line setting. PMID- 26582432 TI - Integrated pathway-based and network-based analysis of GC-MS rice metabolomics data under diazinon stress to infer affected biological pathways. AB - Diazinon insecticide is widely applied in rice (Oryza sativa L.) fields in Iran. However, concerns are now being raised about its potential adverse impacts on rice. In this study, a time-course metabolic change in rice plants was investigated after diazinon treatment using gas chromatography-mass spectrometry (GC-MS) and subsequently three different methods, MetaboAnalyst, MetaboNetwork, and analysis of reporter reactions, as a potential multivariate method were used to find the underlying changes in metabolism with stronger evidence in order to link differentially expressed metabolites to biological pathways. Results clearly showed the similarity of acetylcholinesterase (AChE) of rice plants to that of animals in terms of its inhibitability by diazinon and emphasized that subsequent accumulation of AChE mainly affects the metabolism of osmolites and tricarboxylic acid intermediates subsequent accumulation of ACh mainly affects the metabolism of osmolites and TCA intermediates. PMID- 26582433 TI - Multichannel quartz crystal microbalance array: Fabrication, evaluation, application in biomarker detection. AB - A multichannel quartz crystal microbalance array (MQCM) with three pairs of gold electrodes was fabricated for detection of two biomarkers: acetone and nitric oxide (NO). The gold electrodes were deposited symmetrically on an AT-cut 10 MHz circular quartz plate using photolithography, sputtering, and lift-off technologies. The effect of gold layer thickness on MQCM performance was investigated and the optimized thickness was 101 nm. The simulation values of the electric parameters C0, Cq, Lq, and Rq in the Butterworth-Van Dike equivalent circuit for the MQCM device were 97 pF, 1.3 pF, 1.05 mH, and 9.8 Omega, respectively. Simulation values were in the theoretical range, which indicated that the fabricated MQCM device had good resonance performance. Two types of nanocomposites, titanium dioxide-multiwalled carbon nanotubes and cobalt (II)phthalocyanine-silica, were synthesized as sensing materials. The sensing mechanism is based on coordination adsorption of target molecules onto the sensing material, resulting in a resonant frequency shift of modified QCM sensor. A linear range from 4.33 to 129.75 ppmv for acetone was obtained and one from 5.75 to 103.45 ppbv for NO. PMID- 26582434 TI - Primary Pulmonary Angiosarcoma Presenting with Hemoptysis and Ground-Glass Opacity: A Case Report and Literature Review. AB - Angiosarcoma originates from the vascular endothelium and accounts for only 1-2% of all sarcomatous malignancies. The skin is one of the most common primary sites. However, primary pulmonary angiosarcoma is rare, and only 31 cases of primary pulmonary angiosarcoma have been reported. A 79-year-old Japanese female developed bloody sputum, and chest X-ray and chest computed tomography (CT) showed consolidation with ground-glass opacity (GGO) on the right middle and lower lung fields. The bronchoscopic findings demonstrated bleeding from the right B(4) and B(5), and bronchial arterial embolization was subsequently performed. However, the CT findings demonstrated new pulmonary nodules with GGO in the left lung, and she presented with hemosputum and a progression of anemia. Right hemothorax also occurred, and surgical lung resection was performed to control the bleeding. The pathological analysis of the resected lung revealed the focal growth of atypical alveolar epithelioid-like cells that were positive for CD31 and negative for epithelial membrane antigen, and these atypical cells were replacing the endothelium of the pulmonary artery. Based on these findings, the patient was diagnosed with pulmonary angiosarcoma, which might originate from the endothelium of the pulmonary artery. No abnormal findings were observed except for the pulmonary involvement on systemic CT scanning. However, the patient passed away due to respiratory failure with compression of the brainstem caused by brain metastasis three months after the first visit. Early surgical resection is the important treatment for patients with angiosarcoma. In addition, we review the literature reporting the patients with primary pulmonary angiosarcoma. PMID- 26582435 TI - Preparation of molecularly imprinted polymeric fibers using a single bifunctional monomer for the solid-phase microextraction of parabens from environmental solid samples. AB - In this study, molecularly imprinted polymer fibers for solid-phase microextraction have been prepared with a single bifunctional monomer, N,O bismethacryloyl ethanolamine using the so-called "one monomer molecularly imprinted polymers" method, replacing the conventional combination of functional monomer and cross-linker to form high fidelity binding sites. For comparison, imprinted fibers were prepared following the conventional approach based on ethylene glycol dimethacrylate as cross-linker and methacrylic acid as monomer. The recognition performance of the new fibers was evaluated in the solid-phase microextraction of parabens, and from this study it was concluded that they provided superior performance over conventionally formulated fibers. Ultimately, real-world environmental testing on spiked solid samples was successful by the molecularly imprinted solid-phase microextraction of samples, and the relative recoveries obtained at enrichment levels of 10 ng/g of parabens were within 78 109% for soil and 83-109% for sediments with a relative standard deviation <15% (n = 3). PMID- 26582437 TI - Sudden onset of severe anterior knee pain and knee locking during sleep. PMID- 26582436 TI - Sex Disparity in Blood Pressure Levels Among Nigerian Health Workers. AB - Sex disparity in hypertension prevalence is well established in developed nations; however, there is paucity of data on the distribution of hypertension prevalence between the sexes in developing countries. Therefore, the authors examined sex differences in hypertension prevalence and cardiovascular risk factors in a sample of 352 healthy hospital workers in Nigeria. The mean ages of the men and women were 37.2+/-7.9 and 44.7+/-9.1 years, respectively. Thirty-five percent of participants were hypertensive, with 54% on treatment and 70% with controlled blood pressure. Men had a higher prevalence of hypertension (38.4% vs 33.0%) and prehypertension (37.6% vs 29.7%). Women had significantly higher odds of developing hypertension and of being on treatment. Mean blood pressure and fasting plasma glucose values were higher in men, while women were more often older, obese, and dyslipidemic and had a lower mean estimated glomerular filtration rate (P<.0001). These findings indicate sex disparity in blood pressure among hospital employees. Sex-focused management of hypertension is therefore advocated for hospital employees. PMID- 26582438 TI - Relapses in dogs with steroid-responsive meningitis-arteritis. AB - OBJECTIVES: To describe relapse rates in steroid-responsive meningitis-arteritis and to describe clinical and laboratory parameters in dogs with and without relapses. METHODS: Seventy-four dogs with steroid-responsive meningitis-arteritis were retrospectively identified and assigned to one of three groups: (1) without relapse; (2) at least one relapse and (3) unknown relapse status. The following parameters are reported for the first two groups: sex, age, breed, body weight, nucleated cell count, total protein concentration and percentage of neutrophils on initial cerebrospinal fluid analysis, immunoglobulin A in serum and initial cerebrospinal fluid analysis, nucleated cell count on cerebrospinal fluid analysis at 3-month re-evaluation, C-reactive protein in serum and initial cerebrospinal fluid analysis and at 3-month re-evaluation. RESULTS: Relapses occurred in 32 . 4% of dogs (one relapse: 62 . 5%; two relapses: 25 . 0%; three relapses: 8 . 3%; four relapses: 4 . 2%), 55 . 4% were relapse-free and in 12 . 2% the relapse status was unknown. C-reactive protein in serum and cerebrospinal fluid on 3-month re-evaluation was normal in 80% and 75% of dogs with relapses, respectively. In dogs without relapse, C-reactive protein in serum and cerebrospinal fluid on 3-month re-evaluation was normal in 100% and 90% of dogs, respectively. CLINICAL SIGNIFICANCE: Relapses are frequent but no reliable predictive indicator has emerged in this study. Nevertheless, elevated C-reactive protein in serum warrants continuing therapy; normal C-reactive protein in serum does not exclude future relapse. PMID- 26582439 TI - Anisotropic perception of slant from texture gradient: Size contrast hypothesis. AB - When we see an optical pattern that has a gradient of the size and/or density of its texture elements, we often perceive a surface that is slanted in depth. Our inquiry was to ask whether the effect of a texture gradient depends on the direction of the gradient (ground, ceiling, and sidewall patterns) or on the position of the observer's head (upward, forward, or downward). In Experiments 1 and 2, a total of 63 observers judged the apparent slant of polka-dot, grid, or flagstone patterns; regardless of head position, the ground patterns were judged to be closer to the frontal plane than were the other patterns. This means that there is a visual anisotropy in head-centric slant perception. To explain this result, we assumed accumulated positional effects of size contrast-that is, a tendency to perceive the size of the upper part of visual space to be larger than the size of the lower part. This hypothesis was examined in two subsequent experiments by reducing the size contrast among the texture elements. When 23 observers viewed regularly arranged same-sized-dot patterns with gradients of the interdot interval and with linear perspective of the dotted lines, anisotropic effects were still detected. When 22 observers viewed dynamic random-dot patterns with gradients of velocity, the anisotropic effects mentioned above were removed in many cases, and the ceiling patterns were sometimes judged to be less slanted than the other patterns. These results partially support the size contrast hypothesis and were compared with the predictions from other hypotheses. PMID- 26582440 TI - Long-term Sequelae of Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis. AB - Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse drug reactions characterized by different extents of epidermal necrosis and mucosal breakdown. A limited number of studies have reported the long-term patterns of SJS and TEN complications in patient populations over long follow-up periods. The aim of this retrospective study was to collect data on long-term sequelae in patients admitted for SJS, SJS/TEN overlap, or TEN between 1998 and 2012. Among all 102 patients eligible for analysis, the 2 most common sequelae were cutaneous and ocular problems, both with incidences of 44.1%. Visceral organ involvement was observed in 2 patients with irreversible deterioration of chronic kidney disease and in one patient with interstitial lung disease. Autoimmune disease was present in 6 patients: Sjogren's syndrome or Sjogren-like syndrome in 5 patients and concomitant systemic lupus erythematosus and Hashimoto thyroiditis in one patient. PMID- 26582442 TI - Cytokine-Stimulating (In Vitro) Effect on Human Monocytes of Conjugates of Soluble Curdlan and Albumin Microbeads. AB - Four kinds of conjugates (BSA-M-SC-Ra, BSA-M-SC-Re, AP-M-SC-Ra, and AP-M-SC-Re) composed of soluble fragments of [beta](1 +/- 3)-D-glucan (SC) and bovine serum albumin (BSA) or amine-modifled polystyrene (AP) microbeads were prepared: the contents of SC on the microbeads were found to be 13.6, 8.0, 3.6, and 2.6 MUg per 1 X 10(8) microbeads, respectively. Unconjugated BSA and AP microbeads and SC did not show cytokine-stimulating activity. BSA-M-SC-Re, BSA-M-SC-Ra, and AP-M-SC-Re showed strong cytokine-stimulating activity in vitro, indicating that conjugates composed of inactive fragments of polysaccharides and microbeads are able to induce cytokine release from mononuclear phagocytes. Conjugates with the SC linked to BSA microbeads by the reducing terminal (BSA-M-SC-Re) showed a stronger effect than conjugates in which SC was linked with BSA microbeads at random positions (BSA-M-SC-Ra). PMID- 26582443 TI - Antamanide Prevents Bradykinin-lnduced Filamin Translocation by Inhibiting Extracellular Calcium Influx. AB - Bradykinin-induced paracellular gap formation in cultured endothelial cells (ECs) is preceded by cytoskeletal rearrangement. Actin binding proteins, such as nonmuscle filamin, perform a pivotal role in modulating actin organization. In response to bradykinin treatment, EC filamin translocates from the cell periphery to the cytosol within 1 min and the dynamics of filamin translocation parallel intracellular Ca(2+) increases. Intracellular Ca(2+) increases are essential for bradykinin-induced filamin translocation. In this study, we examine the role of extracellular Ca(2+) influx in mediating bradykinin-induced filamin translocation. Several K(+) channel blockers, including antamanide, tetraethylam monium chloride (TEA), and charybdotoxin (CTX), are evaluated. All of these agents inhibit extracellular Ca(2+) influx with minimal or partial inhibition of intracellular Ca(2+) release. Bradykinin-induced filamin translocation is prevented by pretreatment with these K(+) channel blockers. Moreover, incubation of ECs in high-K(+) saline inhibits bradykinin-induced extracellular Ca(2+) influx as well as filamin translocation. To examine the efficacy of antamanide as an anti-inflammatory drug that affects filamin translocation, bradykinin-induced paracellular gap formation is quantified and compared in the presence or absence of antamanide pretreatment. Antamanide does not completely block bradykinin induced gap formation; however, a significant attenuation is observed. This suggests that extracellular Ca(2+) influx is required for bradykinin-induced filamin translocation, which in part regulates microvascular EC barrier function, and that antamanide may be a useful anti-inflammatory agent. PMID- 26582444 TI - Anthracycline Efficacy in vitro: Cytotoxicity of Liposomal/Nonliposomal Daunorubicin and Doxorubicin for Multiple Tumor Cell Types. AB - Anthracyclines, including daunorubicin (DnR) and doxorubicin (DoX), have shown clinical chemotherapeutic utility, albeit in association with cumulative dose associated cardiotoxicities. Despite structural similarity, however, DnR and DoX treatments have been directed toward leukemias and solid tumor types, respectively. Due to a paucity of in vitro data regarding differential use of DnR or DoX, we assessed the cytotoxicity of these compounds against solid and hematological tumor cell types. In addition, we examined liposomal formulations of DnR (L-DnR) and DoX (PEG-DoX), which, in contrast to DnR or DoX, demonstrate antineoplastic activity with reduced cardiotoxicity in vivo. Accordingly, cytotoxicity testing (with [methyl/-(3)H]thymidine incorporation) of DnR, DoX, L DnR, and PEG-DoX on a range of different human tumor cell lines (e.g., breast, lung, ovarian, prostate, melanoma, lymphoma, and leukemia tumor cell types) was performed. Our data indicate comparable activity for DnR, DoX, or L-DnR in all tumor cell types examined [e.g., SK-BR-3 (breast adenocarcinoma) cells: IC50 values = 5.9, 9.1, and 4.7 ng/mL for DnR, DoX, and L-DnR respectively]. In addition, several solid tumor cell types were more responsive to DnR than DoX [e.g., DU-145 (prostate carcinoma) cells: IC50 values = 10.4 and 41.2 ng/mL for DnR and DoX, respectively; p >. 001]. Interestingly, PEG-DoX was substantively less effective for all tumor cells (IC50 values were about 100-10,000 times greater for PEG-DoX than for DnR, DoX, or L-DnR; p >. 001, all cases). Reduced PEG-DoX activity in vitro may be related to polyethylene glycol (PEG) moieties present on the liposomal exterior of PEG-DoX, which are not present on L-DnR. Nonetheless, taken together, these data suggest that DnR and DoX demonstrate comparable efficacy in vitro and that specific liposomal encapsulation (L-DnR) does not mitigate DnR efficacy in vitro. PMID- 26582445 TI - Tumor Gene Targeting Using Microspheres: Cell Culture and in vivo Studies. AB - In a previous study, Dass et al. (Pharm. Sci. 2:401-405, 1996), it was shown that 1 mg of two types of ion-exchange microspheres was capable of binding and releasing plasmids in a continuous-flow system to the order of 10(11) copies in phosphate-buffered saline at 37 degrees C. However, the functionality of the plasmids was not evaluated. In this study, one of the plasmids, pCMV-CAT, was bound to both microspheres and the functionality of the biomol-ecule was examined in cell culture and in vivo transfection studies. Rat tumor cells incubated with the hydroxyapatite (HA) plasmids were transfected 5.4-fold better than when incubated with free plasmids and 56.0-fold better than polystyrene divinylbenzene (PDB) microspheres. Cells incubated with PDB microspheres were transfected 10.4 fold less than cells incubated with free plasmids. However, HA microspheres were highly cytotoxic to the cells whereas PDB spheres had no effect on cell numbers compared with control cells. Based on expression levels of delivered plasmids in the in vivo study, delivery on microspheres to kidneys was 2.7-fold better than plasmids delivered free. Microspherical delivery of plasmids to tumors was 1.6 fold better than free delivery. However, these results were not significantly different (p >. 05). The tumor/normal tissue ratio of gene expression was 4.5:1 for free delivery and 2.6-fold when delivered on microspheres. Although the difference between deliveries in the two tissues was significant (p > 0.005) for free delivery, it was not so for micro-spherical delivery. Expression of the CAT gene was not noted in either liver or spleen of any of the animals. This present study has proved that ion-exchange microspheres have no detrimental effect on released plasmid DNA expression. In an in vivo setting, resistance to enzymatic degradation of plasmids that are bound to microspheres and subsequent release of plasmids once embolization has occurred in the tumor vascular bed effected better transfection than delivery of free plasmids. PMID- 26582441 TI - On the Environmental Factors Affecting the Structural and Cytotoxic Properties of IAPP Peptides. AB - Pancreatic islets in type 2 diabetes mellitus (T2DM) patients are characterized by reduced beta-cells mass and diffuse extracellular amyloidosis. Amyloid deposition involves the islet amyloid polypeptide (IAPP), a neuropancreatic hormone cosecreted with insulin by beta-cells. IAPP is physiologically involved in glucose homeostasis, but it may turn toxic to beta-cells owing to its tendency to misfold giving rise to oligomers and fibrils. The process by which the unfolded IAPP starts to self-assemble and the overall factors promoting this conversion are poorly understood. Other open questions are related to the nature of the IAPP toxic species and how exactly beta-cells die. Over the last decades, there has been growing consensus about the notion that early molecular assemblies, notably small hIAPP oligomers, are the culprit of beta-cells decline. Numerous environmental factors might affect the conformational, aggregation, and cytotoxic properties of IAPP. Herein we review recent progress in the field, focusing on the influences that membranes, pH, and metal ions may have on the conformational conversion and cytotoxicity of full-length IAPP as well as peptide fragments thereof. Current theories proposed for the mechanisms of toxicity will be also summarized together with an outline of the underlying molecular links between IAPP and amyloid beta (Abeta) misfolding. PMID- 26582446 TI - Comparative Assessment of Intestinal Transport of Hydrophilic Drugs Between Small Intestine and Large Intestine. AB - Intestinal passive transport of several hydrophilic drugs (and probe compounds) was examined in the large intestine (colon), in comparison with that in the small intestine, in an effort to obtain basic information for developing rational colonic drug delivery strategies. The drugs tested were polyethylene glycol (PEG 900), L-glucose, D-xylose, 5-fluorouracil (5-FU) and urea. In everted intestinal sacs, the uptake of every drug was larger in the small intestine than in the large intestine, although by various extents. The uptake of urea was larger than those of D-xylose and L-glucose in both the small intestine and large intestine and associated with a larger large intestine (LI)/small intestine (SI) uptake ratio. Assuming that passive transport via the paracellular route (or aqueous pore) is predominant for them, the large intestine may have smaller paracellular (or aqueous) pores, restricting the transport of those monosaccharides compared with smaller molecules such as urea by a larger extent in the large intestine than in the small intestine. The passive transport of 5-FU was significantly larger than those of the monosaccharides in both the small intestine and large intestine and associated with a larger LI/SI uptake ratio, even though 5-FU has a molecular weight close to that of the monosaccharides. 5-FU may be transported predominantly by transcellular diffusion, because its oil-to-water partition coefficient is about 200 times larger than those of the monosaccharides. Although transport mechanisms, including transport pathways, are yet to be fully clarified, drugs with physicochemical properties similar to those of 5-FU or urea may be more feasible for colonic drug delivery than those with physicochemical properties similar to those of monosaccharides. PMID- 26582447 TI - Indomethacin-Dipalmitoylphosphatidylcholine Interaction. A Calorimetric Study of Drug Release from Poly(Lactide-co-glycolide) Microspheres into Multilamellar Vesicles. AB - A comparative study of indomethacin controlled release from poly(lactide-co glycolide) (50:50, molecular weight 3000) (PLGA) microspheres loaded with two different amounts of drug (10.9 +/- 1%, and 34.1 +/- 1% w/w) and pure free indomethacin, considering the effects exerted by the drug on the thermotropic behavior of dipalmitoylphosphatidylcholine multilamellar vesicles, was carried out by differential scanning calorimetry (DSC). The release was monitored by comparing the effect exerted by the free indomethacin on lipid thermotropic behavior with that of the drug released by the microspheres and relating these effects to a lipid aqueous dispersion containing the molar ratio of drug able to cause it. By DSC measurements, the pure free indomethacin was found to be able to have a fluidifying effect on the model membrane, causing a shift toward lower values of the transitional temperature (Tm), characteristic of phospholipid liposomes, without variations in the enthalpic changes (DeltaH). This shift was found to be modulated by the drug molar fraction with respect to the lipid concentration in the aqueous dispersion. Successively, calorimetric measurements were performed on suspensions of blank liposomes added to weighed amounts of unloaded and indometha-cin-loaded microspheres as well as free powdered indomethacin, and the Tm shifts of the lipid bilayer caused by the drug released from the polymeric system, as well as by the free drug, were compared with that caused by free drug increasing molar fractions dispersed directly on the membrane, employed as a calibration curve to obtain the fraction of drug released. This drug release model could be employed to determine the different kinetics involved in the drug transfer from the microspheres to a membrane. This in vitro study suggests that the kinetic process involved in drug release is influenced by the amount of drug loaded in the microspheres. This calorimetric study shows that the PLGA microspheres are a good delivery system able to sustain drug release. Moreover, the DSC technique applied to the drug interaction with biomembranes constitutes a good tool for determining the drug release representing an innovative alternative in vitro model. PMID- 26582448 TI - Studies of in vivo Gene Transfer by Electropulsation at the Low Skin Resistance Points (LSRPs). AB - Electropulsation has been proved to be a powerful technique for DNA transfection in vitro. This study was undertaken to assess the feasibility and evaluate the potential of applying this approach for facilitating gene transfer in vivo. The pCMVbeta plasmid, containing the Escherichia coli lacZ open reading frame under the cytomegalovirus early promoter, was complexed with poly-L-lysine (PLL) and injected directly into the livers of Wistar rats; electropulsation was then applied either at the low skin resistance points (LSRPs) of the skin, the non LSRP, or directly at the liver by either a portable electrostimulator or an electropulsation unit. The locations of the LSRPs were detected by the unijunction transistor (UJT) relaxation oscillator. Seventy-two hours after gene transfer, the animals were sacrificed and the livers were excised, followed by examination of the transgene expression. The results obtained from X-gal staining, in situ hybridization, and Western blot analysis indicated that lacZ gene was expressed in the livers. Variations of the electropulsation parameters, including site of electropulsation, wave type, amplitude of the pulses, repetition rate, duty cycle, and duration of electropulsation treatment, do not reveal any statistically significant effects of differences of these variables on the transgene expression. Comparison of the results obtained from direct injection of PLL/pCMVbeta (1:1) followed by electropulsation at the LSRPs with that of direct PLL/pCMVbeta (1:1) injection, however, suggests that gene transfer by electropulsation achieved a higher transfection efficiency in vivo (p >. 05). PMID- 26582449 TI - Effective Electroporation Therapy of Human Pancreatic Tumors Implanted in Nude Mice. AB - Electroporation therapy (EPT), also known as electrochemo-therapy (ECT), of a poorly differentiated human pancreatic carcinoma (Panc-3) implanted subcutaneously in nude mice significantly enhanced the cytotoxicity of bleomycin to tumor cells. A single treatment of intratumoral injection of bleomycin followed by 6 * 99 MUs square wave electrical pulses of 1370 V resulted in complete tumor regression in 68% and partial regression (>80%) in 20% of the treated mice on day 28 following treatment. No palpable tumor was observed in 64% of the mice even 120 days after treatment. Histological studies of tissue samples taken from tumor sites 120 days after treatment in the D+E+ group showed complete absence of tumor cells. PMID- 26582450 TI - Carboplatin-Loaded PLGA Microspheres for Intracerebral Implantation: In Vivo Characterization. AB - Carboplatin is a potent anticancer agent that has shown efficacy in clinical trials against malignant glioma, one of the most deadly cancers in humans. However, a high systemic dose is required to achieve an effective concentration in the brain because of the presence of the blood-brain barrier (BBB). Such a high dose can cause many side effects. Local delivery of antitumor agents to the brain using injectable and biodegradable microspheres is a new strategy for the treatment of malignant glioma. This method is able to bypass the BBB and allows maximal local exposure and minimal systemic exposure to avoid the severe side effects of carboplatin. Delivering sustained-release microspheres directly to the tumor site could also control local tumor recurrence and improve survival. In the present studies, carboplatin-loaded microspheres were delivered intracerebrally in rats. No signs of systemic or neurologic toxicity associated with the microspheres implanted in the rat brain were observed. The in vivo release of carboplatin followed apparently zero-order release kinetics up to 30 days. The surface characteristics of the microspheres retrieved from the rat brains changed with the progress of polymer biodegradation. Implantation of the microspheres evoked a transient and localized inflammatory reaction that was well tolerated by the animals. PMID- 26582451 TI - Patent Briefing. PMID- 26582452 TI - Literature Alerts. PMID- 26582454 TI - Pharmacokinetics and safety of cyclophosphamide and docetaxel in a hemodialysis patient with early stage breast cancer: a case report. AB - BACKGROUND: Standardized chemotherapy used in cancer patients with severe kidney insufficiency is ineffective. Although there are some pharmacokinetic studies on cyclophosphamide in kidney insufficiency patients, to the best of our knowledge, the pharmacokinetics and safety of combination of cyclophosphamide and docetaxel as postoperative chemotherapy in a patient with early stage breast cancer undergoing hemodialysis is unclear thus far. CASE PRESENTATION: The patient received regular TC regimen (cyclophosphamide 600 mg/m2, docetaxel 75 mg/m2). She underwent hemodialysis 48 h after chemotherapy. Blood samples at multiple time points were collected for determination of plasma levels of cyclophosphamide and docetaxel. Pharmacokinetic analyses indicated that compared with the reference data, the in vivo half-life (66.96 h) and drug exposure (150%) of cyclophosphamide significantly increased; however, pharmacokinetic parameters of docetaxel was unaffected. Patient developed grade I thrombocytopenia and grade III leukopenia without any other severe adverse reactions. In total, four cycles of treatment were completed. After the chemotherapy, the patient received tamoxifen as endocrine therapy for one and a half years. No recurrence was reported. CONCLUSION: These results suggest that the standard TC regimen is mostly safe and could be used as postoperative adjuvant chemotherapy for hemodialysis patients with early stage breast cancer. PMID- 26582455 TI - Maternal serum placental growth factor at 12, 22, 32 and 36 weeks' gestation in screening for pre-eclampsia. AB - OBJECTIVE: To examine the distribution of maternal serum placental growth factor (PlGF) at 12, 22, 32 and 36 weeks' gestation in singleton pregnancies which develop pre-eclampsia (PE) and examine the performance of this biomarker in screening for PE. METHODS: Serum PlGF was measured in 40 212 cases at 11-13 weeks, in 10 282 cases at 19-24 weeks, in 10 400 at 30-34 weeks and 4043 at 35-37 weeks. Bayes' theorem was used to combine the a-priori risk from maternal characteristics and medical history with serum PlGF. The performance of screening for PE requiring delivery < 32, at 32 + 0 to 36 + 6 and >= 37 weeks' gestation was estimated. RESULTS: In pregnancies that developed PE, serum PlGF was decreased and the separation in multiples of the median (MoM) values from normal was greater with earlier, compared to later, gestational age at which delivery for PE became necessary. Additionally, the slope of the regression lines of PlGF MoM with gestational age at delivery in pregnancies that developed PE increased with advancing gestational age at screening. The detection rates (DRs), at a false-positive rate (FPR) of 10%, for PE delivering < 32 weeks were 79% and 97% with screening at 12 and 22 weeks, respectively. The DRs for PE delivering at 32 + 0 to 36 + 6 weeks were 57%, 65% and 90% with screening at 12, 22 and 32 weeks. The DRs for PE delivering >= 37 weeks were 40%, 37%, 54% and 64% with screening at 12, 22, 32 and 36 weeks, respectively. CONCLUSIONS: The performance of combined screening with maternal factors, medical history and PlGF is superior in screening for early, compared to late, PE and improves with advancing gestational age at screening. Copyright (c) 2015 ISUOG. Published by John Wiley & Sons Ltd. PMID- 26582456 TI - Single-molecule FRET studies on alpha-synuclein oligomerization of Parkinson's disease genetically related mutants. AB - Oligomers of alpha-synuclein are toxic to cells and have been proposed to play a key role in the etiopathogenesis of Parkinson's disease. As certain missense mutations in the gene encoding for alpha-synuclein induce early-onset forms of the disease, it has been suggested that these variants might have an inherent tendency to produce high concentrations of oligomers during aggregation, although a direct experimental evidence for this is still missing. We used single-molecule Forster Resonance Energy Transfer to visualize directly the protein self-assembly process by wild-type alpha-synuclein and A53T, A30P and E46K mutants and to compare the structural properties of the ensemble of oligomers generated. We found that the kinetics of oligomer formation correlates with the natural tendency of each variant to acquire beta-sheet structure. Moreover, A53T and A30P showed significant differences in the averaged FRET efficiency of one of the two types of oligomers formed compared to the wild-type oligomers, indicating possible structural variety among the ensemble of species generated. Importantly, we found similar concentrations of oligomers during the lag-phase of the aggregation of wild-type and mutated alpha-synuclein, suggesting that the properties of the ensemble of oligomers generated during self-assembly might be more relevant than their absolute concentration for triggering neurodegeneration. PMID- 26582457 TI - Prenatal carbon monoxide impairs migration of interneurons into the cerebral cortex. AB - Prenatal exposure to carbon monoxide (CO) disrupts brain development, however little is known about effects on neocortical maturation. We exposed pregnant mice to CO from embryonic day 7 (E7) until birth. To study the effect of CO on neuronal migration into the neocortex we injected BrdU during corticogenesis and observed misplaced BrdU+ cells. The majority of cells not in their proper layer colocalized with GAD65/67, suggesting impairment of interneuron migration; interneuron subtypes were also affected. We subsequently followed interneuron migration from E15 organotypic cultures of mouse neocortex exposed to CO; the leading process length of migrating neurons diminished. To examine an underlying mechanism, we assessed the effects of CO on the cellular cascade mediating the cytoskeletal protein vasodilator-stimulated phosphoprotein (VASP). CO exposure resulted in decreased cGMP and in a downstream target, phosphorylated VASP. Organotypic cultures grown in the presence of the phosphodiesterase inhibitor IBMX resulted in a recovery of the leading processes. These data support the idea that CO acts as a signaling molecule and impairs function and neuronal migration by acting through the CO/NO-cGMP pathway. In addition, treated mice demonstrated functional impairment in behavioral tests. PMID- 26582458 TI - The effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the development and function of the blood-brain barrier. AB - Prenatal exposure to environmental chemicals such as dioxins is known to have adverse effects on the developing central nervous system (CNS) in mammals. Because the fetal blood-brain barrier (BBB) is immature, dioxins are thought to exert their toxic effects on the CNS by crossing the BBB and acting on neural cells directly. However, little is known whether dioxins alter the BBB. In this study, to investigate the effects of dioxins on BBB function, we exposed an in vitro BBB system comprising rat endothelial cells, astrocytes, and pericytes to the toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) either before or after BBB formation. We assessed BBB permeability and the function of tight junctions by measuring transendothelial electric resistance (TEER) values following exposure. Subsequently, total RNA and proteins were obtained from the cells for analysis. TEER values following TCDD exposure before but not after BBB formation were lower than those of the control group. We also observed that the expression of the tight junction proteins ZO-1 and claudin-5 was suppressed following TCDD exposure. To examine the cause of this reduction in protein levels, we performed a real-time quantitative polymerase chain reaction assay and observed low expression of the glial cell line-derived neurotrophic factor (GDNF) mRNA in the exposed groups. Moreover, to rescue the effects of TCDD, we applied extrinsic GDNF with TCDD. The several disruptions caused by TCDD were rescued by the GDNF addition. Our findings suggest that exposure to TCDD during BBB formation disrupts and impairs BBB function in part by the suppression of GDNF action, which may contribute to the adverse effects of TCDD on the fetal CNS. PMID- 26582459 TI - S6 kinase phosphorylated at T229 is involved in tau and actin pathologies in Alzheimer's disease. AB - The 70-kDa ribosomal protein S6 kinase (S6K), a serine/threonine kinase that modulates the phosphorylation of the 40S ribosomal protein S6, regulates cell cycle progression and is known as a tau kinase in Alzheimer's disease (AD). In AD brains, neurofibrillary tangles (NFTs) have been shown to be positively stained with antibodies against S6K proteins phosphorylated at T389 (pT389-S6K) or T421/S424 (pT421/S424-S6K) by the mammalian target of rapamycin and mitogen activated protein kinase pathways, respectively. However, there is little information available about S6K proteins directly phosphorylated at T229 (pT229 S6K) by the PI3K-PDK1 pathway. In the present study, we investigated the distribution of pT229-S6K in post mortem human brain tissues from elderly (control) and patients with AD using immnunoblotting and immunohistochemistry. pT229-S6K immunoreactivity was localized to small granular structures in neurons and endothelial cells in control and AD brains. In AD brains, intense pT229-S6K immunoreactivity was detected in 16.3% of AT8-positive NFTs, neuropil threads, and dystrophic neurites in the hippocampus and other vulnerable brain areas. In addition, Hirano bodies were also positive for pT229-S6K but were negative for pT389-S6K or pT421/S424-S6K. The present results indicate that S6K phosphorylation via the PI3K-PD1 pathway is involved in tau pathology in NFTs and abnormal neurites as well as actin pathology in Hirano bodies. PMID- 26582461 TI - [Structural lag and room for possibilities in old age exemplified by central transitions. Initial results of a novel discipline trialogue between diaconal studies, psychology and theology]. AB - BACKGROUND: Although the need for interdisciplinary research is generally accepted in gerontology, such interdisciplinary communication is often limited to various combinations of psychological, sociological and biomedical scientific approaches. We argue that gerontology requires a continuous examination of novel disciplinary constellations to obtain a better understanding of aging in its complexity and to further develop this scientific field in its entirety. OBJECTIVE: The present study introduced and tested for the first time an innovative disciplinary trialogue, i.e. the combination of psychology, theology and diaconal studies. In particular, it is assumed that this combination can contribute to a more profound interpretation of the prominent concept of structural lag which is underresearched in gerontology. MATERIAL AND METHODS: The analysis of structural lag with another overarching concept, "room for possibilities", can provide a synergy-rich interpretation category for a range of challenges connected with old age. In this respect, three major transitions were selected to shed light on these concepts and examined by means of three focus group interviews: transition to retirement, need for long-term care in the private home context and transition to nursing home life. The data were evaluated using qualitative content analysis. RESULTS: The interdisciplinary-oriented evaluation of the interviews and the qualitative data analysis revealed the relevance of different perceptions of time in all three transitions. In addition, different dynamics in terms of the interplay of gains and losses as well as participation were found to be important for a better understanding of the three transitions. In particular, the subjective interpretation of the time remaining for living and the predetermined or self-selected time structuring of the daily routine were important factors for the perception of one's own potential. The results also underline a range of unused room for possibilities and the existence of structural lag for each transition. CONCLUSION: By the cooperation of the participating disciplines aspects of aging and their interdependence became visible. At the same time this pilot-like disciplinary trialogue revealed the challenges in combining interdisciplinary perspectives by the combination of empirical and hermeneutical methods. PMID- 26582462 TI - [Do nursing homes with higher quality ratings provide a better quality of care? : Empirical study based on administrative data]. AB - BACKGROUND: In 2009 a new system for the objective evaluation of nursing homes was introduced in Germany. The so-called nursing transparency agreement (Pflege Transparenzvereinbarungen) was introduced to provide a reliable tool for an objective comparison of inpatient (PTVS) and outpatient (PTVA) care; however, the new regulations have been the subject of a broad discussion regarding reliability, efficiency and objectivity. AIMS: To overcome the lack of objective health outcomes, this study used administrative data from Germany's largest health insurance fund, the Techniker Krankenkasse, in order to analyze the association between the quality ratings and objective quality measures on an individual level. This is the first study that provides empirical evidence on this topic using administrative data. MATERIAL AND METHODS: The administrative dataset contained information on several individual characteristics as well as data on injuries, poisoning and other extrinsic effects on care-dependent individuals over the age of 64 years who were living in a nursing home in 2009. Based on these data an objective measure was constructed to test whether higher quality ratings of nursing homes led to a better quality of care of the respective patients using non-linear regression models. RESULTS: The results of the estimated models showed no significant evidence of such a relationship, neither considering the probability nor the number of injuries, poisoning and other extrinsic effects. Significant effects were only observed for gender and specific diseases. CONCLUSION: The results of this study support the argument that the current rating procedure for nursing homes has to be refined. Using quality indicators in combination with the administrative data could possibly contribute to such an enhancement. PMID- 26582463 TI - Role of smooth muscle Nox4-based NADPH oxidase in neointimal hyperplasia. AB - Elevated levels of reactive oxygen species (ROS) in the vascular wall play a key role in the development of neointimal hyperplasia. Nox4-based NADPH oxidase is a major ROS generating enzyme in the vasculature, but its roles in neointimal hyperplasia remain unclear. OBJECTIVE: Our purpose was to investigate the role of smooth muscle cell (SMC) Nox4 in neointimal hyperplasia. APPROACH AND RESULTS: Mice overexpressing a human Nox4 mutant form, carrying a P437H dominant negative mutation (Nox4DN) and driven by SM22alpha promoter, to achieve specific expression in SMC, were generated in a FVB/N genetic background. After wire injury-induced endothelial denudation, Nox4DN had significantly decreased neointima formation compared with non-transgenic littermate controls (NTg). ROS production, serum-induced proliferation and migration, were significantly decreased in aortic SMCs isolated from Nox4DN compared with NTg. Both mRNA and protein levels of thrombospondin 1 (TSP1) were significantly downregulated in Nox4DN SMCs. Downregulation of TSP1 by siRNA decreased cell proliferation and migration in SMCs. Similar to Nox4DN, downregulation of Nox4 by siRNA significantly decreased TSP1 expression level, cell proliferation and migration in SMCs. CONCLUSIONS: Downregulation of smooth muscle Nox4 inhibits neointimal hyperplasia by suppressing TSP1, which in part can account for inhibition of SMC proliferation and migration. PMID- 26582465 TI - The role of secreted protein acidic and rich in cysteine (SPARC) in cardiac repair and fibrosis: Does expression of SPARC by macrophages influence outcomes? AB - Secreted protein acidic and rich in cysteine (SPARC) is a matricellular, collagen binding protein. Matricellular proteins are described as extracellular matrix associated proteins that do not serve classical structural roles in the matrix such as those ascribed to laminins and collagens. The family of matricellular proteins modulates cell:extracellular matrix interactions and is actively expressed during tissue remodeling. Functional activities attributed to SPARC in cultured cells include regulation of cell adhesion, cytoskeletal rearrangement, proliferation, and matrix assembly. The primary phenotype characteristic of SPARC null mice is a deficit in amounts of fibrillar collagen and fibril morphology. Strikingly, SPARC-null mice demonstrate a blunted fibrotic response in a number of different tissue settings. The role of monocyte/macrophages as an important component of tissue fibrosis is becoming increasingly appreciated. Expression of SPARC by bone marrow derived inflammatory cells raises the interesting proposition that SPARC produced by infiltrating leukocytes might contribute to the course of inflammation and tissue fibrosis in the heart. This review will summarize results from studies defining the function of SPARC in myocardial repair and fibrosis and results from other non-cardiac tissues that shed light onto possible consequences of SPARC expression by monocyte/macrophages in the setting of heart disease. PMID- 26582464 TI - Lost in translation: miRNAs and mRNAs in ischemic preconditioning and ischemia/reperfusion injury. AB - Ischemic stress involves nutrient deprivation, hypoxia, acidosis, and altered levels of various ions and metabolites. Reperfusion, which abruptly alters these parameters, is a second stress to already stressed cells. Ischemic preconditioning, in which brief ischemia alternates with reperfusion to elicit a protective response to ischemia/reperfusion (I/R) injury, revealed the existence of a highly conserved, cell-autonomous, and nearly ubiquitous program. While we often assume that evolutionary selection is irrelevant with respect to myocardial infarctions-which generally occur long after reproduction-the program of ischemia tolerance may date back much further, to hibernating squirrels, turtles, and estivating frogs and snails (extremophiles), which must survive by entering a hypometabolic state. This relationship is further strengthened by the presence of similar signaling pathways and regulatory mechanisms such as mRNA localization and miRNA regulation. These parallels may offer new insights into the myocardial response to I/R injury. This review will explore some of the recent advances in our understanding of autophagy and mitochondrial turnover in the setting of I/R injury, and related findings drawn from research on hibernating extremophiles. PMID- 26582466 TI - Tripchlorolide Attenuates beta-amyloid Generation via Suppressing PPARgamma Regulated BACE1 Activity in N2a/APP695 Cells. AB - Due to its apparent rate-limiting function, BACE1 (beta-secretase) appears to be a prime target for prevention of amyloid-beta (Abeta) generation in brains with Alzheimer's disease (AD). The activity of BACE1 is regulated by peroxisome proliferator-activated receptor-gamma (PPARgamma), a transcription factor binding site of the BACE1 promoter, indicating that PPARgamma may be a potential target for AD treatment. Several studies have demonstrated that PPARgamma activation is involved in the immunostimulation of amyloid-beta precursor protein processing by nonsteroidal anti-inflammatory drugs (NSAIDs). The present study found that tripchlorolide (T4), with a similar chemical structure to that of NSAIDs, decreased the levels of Abeta secreted in N2a-APP695 cells. T4 treatment reduced the mRNA and protein levels of BACE1 and the protein level of sAPPbeta, a cleaved N-terminal fragment of APP by BACE1. The treatment also translocated PPARgamma from cytoplasm to nuclear. Intriguingly, T4, like pioglitazone (a PPARgamma agonist), suppressed the BACE1 activity in N2a-APP695 cells, which was attenuated by GW9662 (a PPARgamma antagonist). These results indicate that T4 may be a PPARgamma agonist to enhance the binding of nuclear PPARgamma to the BACE1 promoter, which may in turn inhibit the transcription and translation of BACE1, suppress the activity of BACE1, and ultimately attenuate the generation of Abeta. Due to its capability to alter Abeta generation and to protect central neural system against the neurotoxicity of Abeta, T4 may serve as a promising agent in modulating Abeta-related pathology in Alzheimer's disease. PMID- 26582467 TI - Loss of Heterozygosity of 9p Is Associated with Poorer Survival in Patients with Gliomas. AB - The prognostic factors associated with the survival of glioma patients have not been well established. Loss of heterozygosity (LOH) of 9p was known to be a typical molecular signature of gliomas, but it was still unclear whether LOH of 9p was associated with poorer survival in patients with gliomas. We searched PubMed and Embase databases from the earliest records to May 2015 to identify studies that met the inclusion criteria. Either a fixed- or a random-effects model was used to calculate the pooled hazard ratio (HR) according to the between study heterogeneity. Thirteen eligible studies involving 1465 cases of gliomas were included in the meta-analysis. There was little between-study heterogeneity (I 2 = 15 %), and the fixed-effects model was used to calculate the pooled HR. Meta-analysis of total 13 studies showed that LOH of 9p was significantly associated with poorer prognosis of glioma patients (HR = 1.39, 95%CI 1.17-1.64, P = 0.0002). Meta-analysis of eight studies reporting adjusted estimates showed that LOH of 9p was independently associated with poorer prognosis of glioma patients (HR = 1.40, 95%CI 1.14-1.72, P = 0.001). Subgroup analysis by types of gliomas showed that LOH of 9p was significantly associated with poorer prognosis in patients with glioblastoma (HR = 1.34, 95%CI 1.01-1.78, P = 0.04). There was no obvious risk of publication bias shown in the funnel plot. LOH of 9p is significantly associated with poorer prognosis of glioma patients, which is a useful biomarker in predicting patients' survival. PMID- 26582469 TI - Long-term follow-up of a patient with 5q31.3 microdeletion syndrome and the smallest de novo 5q31.2q31.3 deletion involving PURA. AB - BACKGROUND: Purine-rich element binding protein A (PURA, MIM 600473), is considered the crucial phenocritical gene for an emerging 5q31.3 microdeletion syndrome. To date, at least seven affected individuals with overlapping 5q31.2q31.3 deletions, varying in size from 2.6 to 5 Mb, have been reported sharing neurologic features such as severe developmental delay, neonatal hypotonia, early feeding difficulties, respiratory distress and EEG abnormalities. The recent finding that de novo PURA point mutations are indeed sufficient to cause the severe neurological symptoms also observed in patients with 5q31.2q31.3 deletion further reinforces the gene's causative role in 5q31.3 microdeletion syndrome. CASE PRESENTATION: The present patient, aged 26 years, is the oldest reported individual and carries the smallest de novo 5q31.2q31.3 microdeletion encompassing PURA (360 kb). Her clinical history summarizes the mainly neurodevelopmental phenotype described in children with 5q31.3 microdeletion syndrome. In addition, our patient exhibited a remarkable deterioration of clinical symptoms, starting at the beginning of adolescence, pubertal delay and primary amenorrhea. While epileptic seizures were successfully treated during her life, feeding problems showed a poor outcome, her respiratory problems increased and eventually became severe enough to cause her death. CONCLUSION: The clinical and molecular findings reported here provide further evidence that 5q31.3 microdeletion syndrome is a clinically discernible PURA related disorder and describe the previously unreported natural evolution of the disease in a 26 years old patient. PMID- 26582468 TI - The Role of Extracellular Vesicles: An Epigenetic View of the Cancer Microenvironment. AB - Exosomes, microvesicles, and other extracellular vesicles are released by many cell types, including cancer cells and cancer-related immune cells. Extracellular vesicles can directly or indirectly facilitate the transfer of bioinformation to recipient cells or to the extracellular environment. In cancer, exosomes have been implicated in tumor initiation, proliferation, and metastasis. Extracellular vesicles can transmit proteins and nucleic acids that participate in DNA methylation, histone modification, and posttranscriptional regulation of RNA. Factors transmitted by extracellular vesicles reflect the donor cell status, and extracellular vesicles derived from tumor cells may be also responsible for altering expression of tumor promoting and tumor suppressing genes in recipient cells. Thus, circulating extracellular vesicles may act as biomarkers of cancer, and detection of these biomarkers may be applied to diagnosis or assessment of prognosis in patients with cancer. PMID- 26582470 TI - Interventions to prevent and manage overweight or obesity in preschool children: A systematic review. AB - OBJECTIVES: The preschool period is a pivotal time for lifestyle interventions to begin the establishment of long-term physical activity and healthy eating habits. This systematic review sought to (a) examine the effects of prevention and management interventions on overweight/obesity among children aged 2-5 years, and (b) explore factors that may influence intervention effects. DESIGN: A systematic review of randomized controlled studies was conducted. DATA SOURCES: Six databases, including PubMed, CINAHL, EMBASE, PsycINFO, ERIC, and Cochrane library, were searched for relevant studies. REVIEW METHODS: Data were extracted and checked by two reviewers. Each study was appraised based on 4 quality indicators adapted from the Cochrane Handbook for Systematic Reviews of Interventions. A narrative summary technique was used to describe the review findings. RESULTS: Thirty-seven articles describing 32 randomized controlled trials and 29 unique interventions were retained. Eight of 23 prevention and 4 of 6 management interventions resulted in significant weight loss, with 3 prevention and 5 management interventions showing sustained effects over 6 to 24 months. Of the 12 efficacious interventions, 10 included physical activity and nutrition components, 9 actively involved parents, and only 4 were theory-based. Interactive education was the most common strategy used for parents in prevention interventions, compared to behavioral therapy techniques in management interventions. For children, interactive education and hands-on experiences involving physical activity and healthy eating were equally used. CONCLUSIONS: Management interventions showed greater effects in weight loss compared to prevention interventions. Future prevention interventions in preschool children should target both parents and children, and focus on physical activity and nutrition through interactive education and hands-on experiences, although intervention effects were less than optimal. Management interventions should focus on parents as the "agents of change" for physical activity and nutrition while integrating behavioral therapy techniques and interactive education. PMID- 26582471 TI - Indium-free, highly transparent, flexible Cu2O/Cu/Cu2O mesh electrodes for flexible touch screen panels. AB - We report on an indium-free and cost-effective Cu2O/Cu/Cu2O multilayer mesh electrode grown by room temperature roll-to-roll sputtering as a viable alternative to ITO electrodes for the cost-effective production of large-area flexible touch screen panels (TSPs). By using a low resistivity metallic Cu interlayer and a patterned mesh structure, we obtained Cu2O/Cu/Cu2O multilayer mesh electrodes with a low sheet resistance of 15.1 Ohm/square and high optical transmittance of 89% as well as good mechanical flexibility. Outer/inner bending test results showed that the Cu2O/Cu/Cu2O mesh electrode had a mechanical flexibility superior to that of conventional ITO films. Using the diamond patterned Cu2O/Cu/Cu2O multilayer mesh electrodes, we successfully demonstrated TSPS of the flexible film-film type and rigid glass-film-film type TSPs. The TSPs with Cu2O/Cu/Cu2O mesh electrode were used to perform zoom in/out functions and multi-touch writing, indicating that these electrodes are promising cost efficient transparent electrodes to substitute for conventional ITO electrodes in large-area flexible TSPs. PMID- 26582472 TI - Phosphorylation of rat kidney Na-K pump at Ser938 is required for rapid angiotensin II-dependent stimulation of activity and trafficking in proximal tubule cells. AB - How angiotensin (ANG) II acutely stimulates the Na-K pump in proximal tubules is only partially understood, limiting insight into how ANG II increases blood pressure. First, we tested whether ANG II increases the number of pumps in plasma membranes of native rat proximal tubules under conditions of rapid activation. We found that exposure to 100 pM ANG II for 2 min, which was previously shown to increase affinity of the Na-K pump for Na and stimulate activity threefold, increased the amount of the Na-K pump in plasma membranes of native tubules by 33%. Second, we tested whether previously observed increases in phosphorylation of the Na-K pump at Ser(938) were part of the stimulatory mechanism. These experiments were carried out in opossum kidney cells, cultured proximal tubules stably coexpressing the ANG type 1 (AT1) receptor, and either wild-type or a S938A mutant of rat kidney Na-K pump under conditions found by others to stimulate activity. We found that 10 min of incubation in 10 pM ANG II stimulated activity of wild-type pumps from 2.3 to 3.5 nmol K . mg protein(-1) . min(-1) and increased the amount of the pump in the plasma membrane by 80% but had no effect on cells expressing the S938A mutant. We conclude that acute stimulation of Na-K pump activity in native rat proximal tubules includes increased trafficking to the plasma membrane and that phosphorylation at Ser(938) is part of the mechanism by which ANG II directly stimulates activity and trafficking of the rat kidney Na K pump in opossum kidney cells. PMID- 26582473 TI - Divergent signaling via SUMO modification: potential for CFTR modulation. AB - The cystic fibrosis transmembrane conductance regulator (CFTR) is generally responsible for the cAMP/PKA regulated anion conductance at the apical membranes of secretory epithelial cells. Mutations in CFTR underlie cystic fibrosis (CF), in which the most common variant, F508del, causes protein misfolding and its proteasome-mediated degradation. A new pathway that contributes to mutant CFTR degradation is mediated by the small heat shock protein, Hsp27, which cooperates with Ubc9, the E2 enzyme for SUMOylation, to selectively conjugate mutant CFTR with SUMO-2/3. This SUMO paralog can form polychains, which are recognized by the ubiquitin E3 enzyme, RNF4, leading to CFTR ubiquitylation and recognition by the proteasome. We found also that F508del CFTR could be modified by SUMO-1, a paralog that does not support SUMO polychain formation. The use of different SUMO paralogs to modify and target a single substrate for divergent purposes is not uncommon. In this short review we discuss the possibility that conjugation with SUMO-1 could protect mutant CFTR from disposal by RNF4 and similar ubiquitin ligases. We hypothesize that such a pathway could contribute to therapeutic efforts to stabilize immature mutant CFTR and thereby enhance the action of therapeutics that correct CFTR trafficking to the apical membranes. PMID- 26582475 TI - Ultrafast photoreaction dynamics of a light-driven sodium-ion-pumping retinal protein from Krokinobacter eikastus revealed by femtosecond time-resolved absorption spectroscopy. AB - We report the first femtosecond time-resolved absorption study on ultrafast photoreaction dynamics of a recently discovered retinal protein, KR2, which functions as a light-driven sodium-ion pump. The obtained data show that the excited-state absorption around 460 nm and the stimulated emission around 720 nm decay concomitantly with a time constant of 180 fs. This demonstrates that the deactivation of the S1 state of KR2, which involves isomerization of the retinal chromophore, takes place three times faster than that of bacteriorhodopsin. In accordance with this rapid electronic relaxation, the photoproduct band assignable to the J intermediate grows up at ~620 nm, indicating that the J intermediate is directly formed with the S1 -> S0 internal conversion. The photoproduct band subsequently exhibits a ~30 nm blue shift with a 500 fs time constant, corresponding to the conversion to the K intermediate. On the basis of the femtosecond absorption data obtained, we discuss the mechanism for the rapid photoreaction of KR2 and its relevance to the unique function of the sodium-ion pump. PMID- 26582474 TI - The cytoplasmic domain is essential for transport function of the integral membrane transport protein SLC4A11. AB - Large cytoplasmic domains (CD) are a common feature among integral membrane proteins. In virtually all cases, these CD have a function (e.g., binding cytoskeleton or regulatory factors) separate from that of the membrane domain (MD). Strong associations between CD and MD are rare. Here we studied SLC4A11, a membrane transport protein of corneal endothelial cells, the mutations of which cause genetic corneal blindness. SLC4A11 has a 41-kDa CD and a 57-kDa integral MD. One disease-causing mutation in the CD, R125H, manifests a catalytic defect, suggesting a role of the CD in transport function. Expressed in HEK-293 cells without the CD, MD-SLC4A11 is retained in the endoplasmic reticulum, indicating a folding defect. Replacement of CD-SLC4A11 with green fluorescent protein did not rescue MD-SLC4A11, suggesting some specific role of CD-SLC4A11. Homology modeling revealed that the structure of CD-SLC4A11 is similar to that of the Cl(-)/HCO3(-) exchange protein AE1 (SLC4A1) CD. Fusion to CD-AE1 partially rescued MD-SLC4A11 to the cell surface, suggesting that the structure of CD-AE1 is similar to that of CD-SLC4A11. The CD-AE1-MD-SLC4a11 chimera, however, had no functional activity. We conclude that CD-SLC4A11 has an indispensable role in the transport function of SLC4A11. CD-SLC4A11 forms insoluble precipitates when expressed in bacteria, suggesting that the domain cannot fold properly when expressed alone. Consistent with a strong association between CD-SLC4A11 and MD-SLC4A11, these domains specifically associate when coexpressed in HEK-293 cells. We conclude that SLC4A11 is a rare integral membrane protein in which the CD has strong associations with the integral MD, which contributes to membrane transport function. PMID- 26582476 TI - Translation symmetry breakdown in low-dimensional lattices of pentagonal rings. AB - The mechanism of translation symmetry breakdown in newly proposed low-dimensional carbon pentagon-constituted nanostructures (e.g., pentagraphene) with multiple sp(2)/sp(3) sublattices was studied by GGA DFT, DFTB, and model potential approaches. It was found that finite nanoclusters suffer strong uniform unit cell bending followed by breaking of crystalline lattice linear translation invariance caused by structural mechanical stress. It was shown that 2D sp(2)/sp(3) nanostructures are correlated transition states between two symmetrically equivalent bent structures. At DFT level of theory the distortion energy of the flakes (7.5 * 10(-2) eV/atom) is much higher the energy of dynamical stabilization of graphene. Strong mechanical stress prevents stabilization of the nanoclusters on any type of supports by either van der Waals or covalent bonding and should lead to formation of pentatubes, nanorings, or nanofoams rather than infinite nanoribbons or nanosheets. Formation of two-layered pentagraphene structures leads to compensation of the stress and stabilization of flat finite pentaflakes. PMID- 26582477 TI - Ultrabroadband, More than One Order Absorption Enhancement in Graphene with Plasmonic Light Trapping. AB - This paper presents an comprehensive study of light trapping and absorption enhancement in graphene through metallic plasmonic structures and shows a strategy to realize both ultrabroadband and strong absorption enhancement. Three different plasmonic absorber designs are investigated by numerical simulations. The excitation of localized plasmons in the metallic structures significantly enhances the interactions between graphene and light at the resonances. By employing a splitted cross design for plasmonic resonant antennas and integrating two types of sub-antennas with different sizes, more than 30% of optical absorption in monolayer graphene is realized in a ultrabroad spectral range from 780 to 1760 nm. This enhancement functionality can be translated to any wavelength band from ultraviolet to terahertz ranges by modifying the geometric design of the plasmonic structure and can be applied for other two dimensional materials and their heterogeneous structures. It may significantly improve the efficiency of optical devices such as broadband photodetectors and solar cells based on graphene and other two-dimensional materials. PMID- 26582478 TI - The role of extracellular and intracellular proteolytic systems in aneurysms of the ascending aorta. AB - Aneurysms of the ascending aorta are an outstanding challenge to clinicians as they may persist asymptomatic until they present with dissection or rupture. Intensive research is performed to reveal the molecular mechanisms causing aneurysm formation. Calpains are ubiquitous non-lysosomal cysteine proteases which are classically activated by calcium signaling. The two major forms of the calpain-family are calpain-I and calpain-II. Calpastatin specifically inhibits the proteolytic activity of calpain-I and -II. Recently it has been demonstrated in aneurysm tissues from ascending aortas obtained from Marfan syndrome patients that calpain-II expression is increased and calpastatin expression is decreased. Thus, we were interested in the probable role of calpains in aneurysms of ascending aorta in non-Marfan patients. Therefore, ascending aortic samples of dilated and non-dilated aortas were analyzed according to their calpain-I, -II and calpastatin content as well as the expression levels of MMPs and elastin as well as the infiltration of inflammatory cells. We have found significant differences in calpain-I and calpastatin protein expression and serum levels in patients with aneurysm of the ascending aorta. Furthermore, MMP-1 and MMP-3 expression levels correlate with calpain-I protein levels. Due to our findings we conclude that calpain-1 seems to be related to fibrotic alteration in aortic aneurysm tissue in our experimental group. The change in calpain-1 modulates the structure of aortic tissue causing alteration in elastin structure, thus enabling macrophage infiltration and elevation of MMP levels. Circulating levels of calpain-1 may be used as a prognostic marker in the future if further correlation analyses are done. PMID- 26582479 TI - Phyllonema aviceniicola gen. nov., sp. nov. and Foliisarcina bertiogensis gen. nov., sp. nov., epiphyllic cyanobacteria associated with Avicennia schaueriana leaves. AB - Cyanobacteria dwelling on the salt-excreting leaves of the mangrove tree Avicennia schaueriana were isolated and characterized by ecological, morphological and genetic approaches. Leaves were collected in a mangrove with a history of oil contamination on the coastline of Sao Paulo state, Brazil, and isolation was achieved by smearing leaves on the surface of solid media or by submerging leaves in liquid media. Twenty-nine isolated strains were shown to belong to five cyanobacterial orders (thirteen to Synechococcales, seven to Nostocales, seven to Pleurocapsales, one to Chroococcales, and one to Oscillatoriales) according to morphological and 16S rRNA gene sequence evaluations. More detailed investigations pointed six Rivulariacean and four Xenococcacean strains as novel taxa. These strains were classified as Phyllonema gen. nov. (type species Phyllonema aviceniicola sp. nov. with type strain CENA341T) and Foliisarcina gen. nov. (type species Foliisarcina bertiogensis sp. nov. with type strain CENA333T), according to the International Code of Nomenclature for Algae, Fungi, and Plants. This investigation shows some of the unique cyanobacteria inhabiting the phyllosphere of Avicennia schaueriana can be retrieved by culturing techniques, improving current taxonomy and providing new insights into the evolution, ecology, and biogeography of this phylum. PMID- 26582480 TI - Supervision of professionals: Interdependency between embodied experiences and professional knowledge. AB - Social work counsellors, exposed to hardships of clients' lives, might, over time, experience strain as bodily reactions of muscle tension and pain. Within the framework of improving professional practice, the aim was to explore meanings attached to moving and breathing by studying the influence of supervision, encompassing experiences and reflections on bodily exercises, and reflection on challenging professional experiences. Action research of interdisciplinary supervision for seven counsellors, based on observations, field notes, reflection notes, and a focus group interview, was carried out. Data were analysed across participants within sessions and over time to compare meaning variations. The counsellors' change of experiences were identified as phases: What is in it for me, not knowing what to perceive, attention as basis for knowing how to move, experiencing and creating connections, and knowing oneself better. Adjusted to change of experiences, supervisors encouraged counsellors to give attention to, become aware of, and relieve and explore muscle tension and breathing restrictions to contexts of meaning. Supervision based on movement opened access to personal learning. Supervision as approaches of movements and reflections contributed to increased self-knowledge in professional social work practices. Based on ability to perceive and relieve muscle tension and flow of breathing, the approach might be a potential for professionals to handle challenging situations. The findings, related to the lived body, encompass appearances of new meanings and new uses to experiences of muscular tension and flow of breathing. PMID- 26582481 TI - Lupus erythematosus-lichen planus overlap syndrome in an HIV-infected individual. AB - Lupus erythematosus-lichen planus (LE-LP) overlap syndrome is an uncommon disorder with clinical, histological and/or immunopathological features of both diseases. We report a case of LE-LP overlap syndrome in a patient with HIV infection. To the best of our knowledge, LE-LP overlap syndrome with HIV infection has never been reported in literature. PMID- 26582482 TI - Medicine information leaflets for non-steroidal anti-inflammatory drugs in Thailand. AB - BACKGROUND: The importance of promoting the use of patient-oriented medicines leaflets is recognized in many countries. Leaflets should include basic information plus specific warnings, and be provided with all medicines, but there is little attempt at enforcement of these requirements in Thailand. OBJECTIVE: To determine content and availability of Thai information leaflets for nonsteroidal anti-inflammatory drugs (NSAIDs). METHODS: Leaflets for all NSAIDs available for purchase from 34 pharmacies in a large city were evaluated against a checklist and number of leaflets assessed against number of medicine packs available in each pharmacy. RESULTS: Of the 76 leaflets for ten different NSAIDs, 67 (88 %) were for locally manufactured products. Only 22 % of 76 leaflets were sufficient in number for distribution with medicines, while only 4 % had patient-oriented leaflets. No leaflet covered all topics in the checklist. Less than half included safety information, such as contraindications (46 %), precautions (47 %), and adverse drug reactions (34 %). Locally-produced leaflets provided less information than those for originator products and no leaflet included all the warnings required by Thai regulations. CONCLUSION: This study illustrates the variable availability and quality of NSAID information leaflets. The lack of accessible essential information about medicines in Thailand requires urgent attention to enable patients to minimise adverse reactions. PMID- 26582483 TI - Medication reviews in primary care in Sweden: importance of clinical pharmacists' recommendations on drug-related problems. AB - BACKGROUND: One way of preventing and solving drug-related problems in frail elderly is to perform team-based medication reviews. OBJECTIVE: To evaluate the quality of the clinical pharmacy service to primary care using structured medication reviews, focusing on the clinical significance of the recommendations made by clinical pharmacists. SETTING: A random sample of 150 patients (out of 1541) who received structured team based medication reviews. The patients lived at a geriatric nursing home or were >=65 years and lived in ordinary housing with medication-related community help. METHOD: Based on information on symptoms, kidney function, blood pressure, diagnoses and the medication list, a pharmacist identified possible drug-related problems and supplied recommendations for the general practitioner to act on. Two independent physicians retrospectively ranked the clinical significance of the recommendations according to Hatoum, with rankings ranging between 1 (adverse significance) and 6 (extremely significant). Main outcome measure The clinical significance of the recommendations. Results In total 349 drug-related problems were identified, leading to recommendations. The vast majority of the recommendations (96 %) were judged to have significance 3 or higher and more than the half were judged to have significance 4 or higher. CONCLUSION: The high proportion of clinically significant recommendations provided by pharmacists when performing team-based medication reviews suggest that these clinical pharmacy services have potential to increase prescribing quality. As such, the medication reviews have the potential for contributing to a better and safer drug therapy for elderly patients. PMID- 26582484 TI - Maternal thyroid disease in the Danish National Birth Cohort: prevalence and risk factors. AB - OBJECTIVE: Thyroid disorders are common in women of reproductive age, but the exact burden of disease before, during and after a pregnancy is not clear. We describe the prevalence of thyroid disease in women enrolled in the Danish National Birth Cohort (DNBC) and investigate some of its risk factors. DESIGN: Population-based study within the DNBC, which included 101,032 pregnancies (1997 2003). METHODS: We studied women enrolled in the DNBC who gave birth to a live born child. Information on maternal thyroid disease (hyperthyroidism, hypothyroidism, benign goiter/nodules, thyroid cancer, and other) before, during and up to 5 years after the woman's first pregnancy in the cohort was obtained from self-report (telephone interview in median gestational week 17) and from nationwide registers on hospital diagnosis of thyroid disease/thyroid surgery (from 1977) and prescriptions of thyroid drugs (from 1995). RESULTS: Of the 77,445 women studied, 3018 (3.9%) were identified with an onset of thyroid disease before (2.0%), during (0.1%) or in the 5-year period after the pregnancy (1.8%). During the pregnancy, 153 (0.2%) women received antithyroid drugs and 365 (0.5%) received thyroid hormone for hypothyroidism (83 after previous hyperthyroidism, 42 after previous surgery for benign goiter/nodules or thyroid cancer). Significant risk factors for maternal thyroid disease were age, parity, origin, iodine intake, smoking, alcohol, and BMI. CONCLUSIONS: Around 4% of Danish pregnant women had either a history of thyroid disease or thyroid disease during pregnancy or were diagnosed with thyroid disease for the first-time in the years following a pregnancy. The spectrum of thyroid disease was influenced by demographic and environmental factors. PMID- 26582485 TI - Carrier-mediated ferromagnetism in the magnetic topological insulator Cr-doped (Sb,Bi)2Te3. AB - Magnetically doped topological insulators, possessing an energy gap created at the Dirac point through time-reversal-symmetry breaking, are predicted to exhibit exotic phenomena including the quantized anomalous Hall effect and a dissipationless transport, which facilitate the development of low-power consumption devices using electron spins. Although several candidates of magnetically doped topological insulators were demonstrated to show long-range magnetic order, the realization of the quantized anomalous Hall effect is so far restricted to the Cr-doped (Sb,Bi)2Te3 system at extremely low temperature; however, the microscopic origin of its ferromagnetism is poorly understood. Here we present an element-resolved study for Cr-doped (Sb,Bi)2Te3 using X-ray magnetic circular dichroism to unambiguously show that the long-range magnetic order is mediated by the p-hole carriers of the host lattice, and the interaction between the Sb(Te) p and Cr d states is crucial. Our results are important for material engineering in realizing the quantized anomalous Hall effect at higher temperatures. PMID- 26582487 TI - Multidetector computed tomography (MDCT) findings of abdominal aortic aneurysm eroding lumbar vertebra. PMID- 26582486 TI - Adipose tissue macrophages induce PPARgamma-high FOXP3(+) regulatory T cells. AB - Numerous regulatory T cells (Tregs) are present in adipose tissues compared with other lymphoid or non-lymphoid tissues. Adipose Tregs regulate inflammatory state and insulin sensitivity. However, the mechanism that maintains Tregs in adipose tissue remains unclear. Here, we revealed the contribution of adipose tissue macrophages (ATMs) to the induction and proliferation of adipose Tregs. ATMs isolated from mice under steady state conditions induced Tregs with high expression of PPARgamma compared with splenic dendritic cells in vitro. Furthermore, ATMs from obese mice prompted the differentiation of PPARgamma low Tregs. Adoptive transfer of ATMs induced differentiation and proliferation of Tregs, whereas depletion of ATMs by clodronate-liposome resulted in reduction of adipose Tregs, in vivo. Deficiency of anti-inflammatory adipocytokine, Adipoq, resulted in small proportions of ATMs and adipose Tregs without alteration of other immune cells in vivo. Therefore, these data suggest that the abundance of Tregs in adipose tissue could be partly attributed to the ability of ATMs to induce PPARgamma-expressing Tregs. PMID- 26582488 TI - Effects of hemostatic polysaccharide agent on epidural fibrosis formation after lumbar laminectomy in rats. AB - BACKGROUND CONTEXT: Epidural fibrosis is a common adverse outcome of spinal surgery that can compress the dural sac and nerve root. Local hemostatic agents have many indications in numerous types of spinal surgery. As these agents may behave as foreign bodies, inducing inflammation and delaying regeneration, they could enhance the risk of epidural fibrosis. PURPOSE: We evaluated the effects of hemostatic polysaccharide on epidural fibrosis development in laminectomized rats. STUDY DESIGN: This is a randomized controlled trial. OUTCOME MEASURES: One month after surgery, tissues were histopathologically examined. Spinal tissue surrounding the laminectomy site was cut with a microtome and stained with hematoxylin and eosin and Masson trichrome. Slides were evaluated by a pathologist in a blinded fashion. The extent of epidural fibrosis, fibroblast cell density, cartilage, and bone regeneration was evaluated. METHODS: Rats were randomly assigned to receive sham surgery, laminectomy, or laminectomy with hemostatic polysaccharide (seven rats per group). Sham surgery that consisted of a skin incision was performed without laminectomy. Laminectomy was performed at the L1 and L2 vertebrae. In the experimental group, the polysaccharide hemostatic material, HaemoCer was placed in the laminectomy area. RESULTS: The proportion of rats with epidural fibrosis in laminectomized mice (both with and without hemostatic material) was higher than in sham-operated rats (p<.01). There was no difference in fibrosis between the two groups of laminectomized rats (p>.05). CONCLUSIONS: Our study indicates that hemostatic polysaccharide does not enhance epidural fibrosis following laminectomy in rodents, suggesting that absorbable polysaccharides may be appropriate for use in hemostasis during spinal surgery. PMID- 26582489 TI - An initial biomechanical investigation of fusionless anterior tether constructs for controlled scoliosis correction. AB - BACKGROUND CONTEXT: Conservative treatment for adolescent idiopathic scoliosis is often unsuccessful and requires surgical intervention. Theoretically, anterior fusionless surgery can achieve correction as the patient grows to skeletal maturity. PURPOSE: The objective of the present study was to determine differences in range of motion (ROM) between multiple anterior tether constructs and tensioning techniques. Coronal plane Cobb angles were evaluated. STUDY DESIGN/SETTING: This is a cadaveric biomechanical study. METHODS: Cadaveric spines underwent biomechanical testing to investigate two factors relevant to anterior tether reconstruction: (1) effect of fixation at the T4, superior, and T12, inferior, levels (S-I), as opposed to fixation at all T4-T12 continuous levels (Cont.); and (2) tensioning of the tether sequentially (SEQ T) or only at terminal points (T). Reconstructions were conducted at Cont., and ROM and coronal plane Cobb angles were measured. Rigid rods (R) were used as control for the tether. Funding for the present study was provided by Globus Medical, Inc., and three of five authors are employees of Globus Medical, Inc. RESULTS: Normalized lateral bending ROM for intact was 100(+/-33)%. The S-I R construct reduced motion to 39(+/-8)%. Tethering at terminal points resulted in ROM for S-I T and S I No T of 61(+/-21)% and 70(+/-17)%, respectively. Screws placed at every level resulted in motion of 28(+/-9)% for the Cont. R construct, and a stepwise increase in motion to 44(+/-15)%, 47(+/-18)%, and 71(+/-19)%, respectively, for Cont. SEQ T, Cont. T, and Cont. No T. These relative trends were the same in all loading modes. Average change in overall coronal plane Cobb angle from intact was 4.6(+/-3.2) degrees and 9.9(+/-5.5) degrees for Cont. T and Cont. SEQ T constructs, respectively. CONCLUSIONS: Tensioned tether constructs allowed greater ROM than rigid constructs, and no significant difference in ROM was noted between tensioning techniques. Sequential tensioning can produce greater correction with no biomechanical advantage. PMID- 26582490 TI - Ruptured posterior spinal artery aneurysm: intraoperative and histologic findings with appreciable thrombosis. AB - BACKGROUND CONTEXT: Little is known on the natural course of ruptured spinal artery aneurysm, and a treatment strategy remains to be elucidated. PURPOSE: This case report aims to describe a rare case of a posterior spinal artery aneurysm that showed progressive thrombosis following subarachnoid hemorrhage. STUDY DESIGN: This is a case report and literature review. METHODS: A 54-year-old man presented with subarachnoid hemorrhage due to posterior spinal artery aneurysm at the T10 level. The patient underwent surgery 19 days after onset. RESULTS: Most of the aneurysm appeared unenhanced on intraoperative indocyanine green video angiography, and total resection was performed. Histologic examination confirmed spontaneous thrombosis of the lesion. A review of the literature identified 19 cases of ruptured posterior spinal artery aneurysm. Thrombosed aneurysm and thrombosed parent artery were observed in 7 (44%) of the 16 cases treated with surgical or endovascular interventions. In the three cases treated conservatively, fatal rebleeding in the acute stage was noted in one case, whereas the lesion disappeared spontaneously in the chronic stage without rebleeding in two cases. CONCLUSIONS: Ruptured spinal artery aneurysms are prone to spontaneous thrombosis. The healing process of the lesion was well documented in the present case. Repeated angiographic follow-up offers a feasible alternative in the management of this fairly rare aneurysm. PMID- 26582491 TI - Malignant peripheral nerve sheath tumor presented with back pain and lump. PMID- 26582492 TI - Mode of detection: an independent prognostic factor for women with breast cancer. AB - OBJECTIVES: To investigate breast cancer survival and risk of breast cancer death by detection mode (screen-detected, interval, and detected outside the screening programme), adjusting for prognostic and predictive tumour characteristics. METHODS: Information about detection mode, prognostic (age, tumour size, histologic grade, lymph node status) and predictive factors (molecular subtypes based on immunohistochemical analyses of hormone receptor status (estrogen and progesterone) and Her2 status) were available for 8344 women in Norway aged 50-69 at diagnosis of breast cancer, 2005-2011. A total of 255 breast cancer deaths were registered by the end of 2011. Kaplan-Meier method was used to estimate six years breast cancer specific survival and Cox proportional hazard model to estimate hazard ratio (HR) for breast cancer death by detection mode, adjusting for prognostic and predictive factors. RESULTS: Women with screen-detected cancer had favourable prognostic and predictive tumour characteristics compared with interval cancers and those detected outside the screening programme. The favourable characteristics were present for screen-detected cancers, also within the subtypes. Adjusted HR of dying from breast cancer was two times higher for women with symptomatic breast cancer (interval or outside the screening), using screen-detected tumours as the reference. CONCLUSIONS: Detection mode is an independent prognostic factor for women diagnosed with breast cancer. Information on detection mode might be relevant for patient management to avoid overtreatment. PMID- 26582493 TI - Response to Hersch et al. PMID- 26582494 TI - The importance of enabling informed decision making for women considering breast cancer screening. PMID- 26582495 TI - A genomic approach to understand interactions between Streptococcus pneumoniae and its bacteriophages. AB - BACKGROUND: Bacteriophage replication depends on bacterial proteins and inactivation of genes coding for such host factors should interfere with phage infection. To gain further insights into the interactions between S. pneumoniae and its pneumophages, we characterized S. pneumoniae mutants selected for resistance to the virulent phages SOCP or Dp-1. RESULTS: S. pneumoniae R6-SOCP(R) and R6-DP1(R) were highly resistant to the phage used for their selection and no cross-resistance between the two phages was detected. Adsorption of SOCP to R6 SOCP(R) was partly reduced whereas no difference in Dp-1 adsorption was noted on R6-DP1(R). The replication of SOCP was completely inhibited in R6-SOCP(R) while Dp-1 was severely impaired in R6-DP1(R). Genome sequencing identified 8 and 2 genes mutated in R6-SOCP(R) and R6-DP1(R), respectively. Resistance reconstruction in phage-sensitive S. pneumoniae confirmed that mutations in a GntR-type regulator, in a glycerophosphoryl phosphodiesterase and in a Mur ligase were responsible for resistance to SOCP. The three mutations were additive to increase resistance to SOCP. In contrast, resistance to Dp-1 in R6-DP1(R) resulted from mutations in a unique gene coding for a type IV restriction endonuclease. CONCLUSION: The characterization of mutations conferring resistance to pneumophages highlighted that diverse host genes are involved in the replication of phages from different families. PMID- 26582496 TI - Cadmium induced inhibition of autophagy is associated with microtubule disruption and mitochondrial dysfunction in primary rat cerebral cortical neurons. AB - Recent studies have reported that mitochondria serve as direct targets for cadmium- (Cd-) induced neuronal toxicity, which can be attenuated by autophagy. The molecular mechanisms' underlying Cd-induced mitochondrial dysfunction and autophagy in neurons are not known. In this study, we studied the upstream signaling pathways induced by Cd-mediated mitochondrial metabolism alterations using primary rat neuron as a model. We found that Cd induced the destruction of microtubules (MTs), and resulted in tau hyper-phosphorylation and decreased acetylated tubulin levels, which were related to a decrease in mitochondrial membrane potential (MMP) and adenosine triphosphate (ATP) levels. As a result of taxol disruption, alterations in macroautophagy, like altered cellular distribution of the autophagy-related protein light chain 3 beta (LC3B) and the expression of Atg5 were found compared with Cd group. We found for the first time that MT disruption induced by Cd reduced the levels of autophagy, leading to mitochondrial dysfunction. These observations suggest new therapeutic strategies aimed to activate or ameliorate pro-survival macroautophagy. PMID- 26582497 TI - An overview of butanol-induced developmental neurotoxicity and the potential mechanisms related to these observed effects. AB - The purpose of this article is to briefly review the published literature on the developmental neurotoxic effects, including potential mechanisms, of four butanols: n-butanol, sec-butanol, tert-butanol, isobutanol, and identify data gaps and research needs for evaluation of human health risks in this area. Exposure potential to these four butanols is considerable given the high production volume (>1 billion lb) of n- and tert-butanol and moderate production volumes (100-500 million lb) of sec- and isobutanol. With the impetus to derive cleaner gasoline blends, butanols are being considered for use as fuel oxygenates. Notable signs of neurotoxicity and developmental neurotoxicity have been observed in some studies where laboratory animals (rodents) were gestationally exposed to n- or tert-butanol. Mechanistic data relevant to the observed developmental neurotoxicity endpoints were also reviewed to hypothesize potential mechanisms associated with the developmental neurotoxicity outcome. Data from the related and highly characterized alcohol, ethanol, were included to examine consistencies between this compound and the four butanols. It is widely known that alcohols, including butanols, interact with several ion channels and modulate the function of these targets following both acute and chronic exposures. In addition, n- and sec-butanol have been demonstrated to inhibit fetal rat brain astroglial cell proliferation. Further, rat pups exposed to n butanol in utero were also reported to have significant increases in brain levels of dopamine and serotonin, but decreases in serotonin levels were noted with gestational exposure to tert-butanol. tert-Butanol was reported to inhibit muscarinic receptor-stimulated phosphoinositide metabolism which has been hypothesized to be a possible target for the neurotoxic effects of ethanol during brain development. The mechanistic data for the butanols support developmental neurotoxicity that has been observed in some of the rodent studies. However, careful studies evaluating the neurobehavior of developing pups in sensitive strains, as well as characterizing the plausible mechanisms involved, need to be conducted in order to further elucidate the neurodevelopmental effects of butanols for risk evaluation. PMID- 26582499 TI - SNP genotypes of olfactory receptor genes associated with olfactory ability in German Shepherd dogs. AB - To find out the relationship between SNP genotypes of canine olfactory receptor genes and olfactory ability, 28 males and 20 females from German Shepherd dogs in police service were scored by odor detection tests and analyzed using the Beckman GenomeLab SNPstream. The representative 22 SNP loci from the exonic regions of 12 olfactory receptor genes were investigated, and three kinds of odor (human, ice drug and trinitrotoluene) were detected. The results showed that the SNP genotypes at the OR10H1-like:c.632C>T, OR10H1-like:c.770A>T, OR2K2-like:c.518G>A, OR4C11-like:c.511T>G and OR4C11-like:c.692G>A loci had a statistically significant effect on the scenting abilities (P < 0.001). The kind of odor influenced the performances of the dogs (P < 0.001). In addition, there were interactions between genotype and the kind of odor at the following loci: OR10H1 like:c.632C>T, OR10H1-like:c.770A>T, OR4C11-like:c.511T>G and OR4C11 like:c.692G>A (P < 0.001). The dogs with genotype CC at the OR10H1-like:c.632C>T, genotype AA at the OR10H1-like:c.770A>T, genotype TT at the OR4C11-like:c.511T>G and genotype GG at the OR4C11-like:c.692G>A loci did better at detecting the ice drug. We concluded that there was linkage between certain SNP genotypes and the olfactory ability of dogs and that SNP genotypes might be useful in determining dogs' scenting potential. PMID- 26582498 TI - Developmental Profile, Morphology, and Synaptic Connectivity of Cajal-Retzius Cells in the Postnatal Mouse Hippocampus. AB - Cajal-Retzius (CR) cells are early generated neurons, involved in the assembly of developing neocortical and hippocampal circuits. However, their roles in networks of the postnatal brain remain poorly understood. In order to get insights into these latter functions, we have studied their morphological and synaptic properties in the postnatal hippocampus of the CXCR4-EGFP mouse, where CR cells are easily identifiable. Our data indicate that CR cells are nonuniformly distributed along different subfields of the hippocampal formation, and that their postnatal decline is regulated in a region-specific manner. In fact, CR cells persist in distinct areas of fully mature animals. Subclasses of CR cells project and target either local (molecular layers) or distant regions [subicular complex and entorhinal cortex (EC)] of the hippocampal formation, but have similar firing patterns. Lastly, CR cells are biased toward targeting dendritic shafts compared with spines, and produce large-amplitude glutamatergic unitary postsynaptic potentials on gamma-aminobutyric acid (GABA) containing interneurons. Taken together, our results suggest that CR cells are involved in a novel excitatory loop of the postnatal hippocampal formation, which potentially contributes to shaping the flow of information between the hippocampus, parahippocampal regions and entorhinal cortex, and to the low seizure threshold of these brain areas. PMID- 26582500 TI - Rapid restoration of bone mass after surgical management of hyperthyroidism: A prospective case control study in Southern India. AB - CONTEXT: The rate and the extent of bone remineralization at cancellous versus cortical sites after treatment of hyperthyroidism is unclear. Few studies have examined the effect of operative management of hyperthyroidism on recovery of bone mass. OBJECTIVE: To evaluate prospectively the bone mineral density (BMD), bone mineral content (BMC), and bone areal size at the spine, hip, and forearm before and after total thyroidectomy. DESIGN AND SETTING: A prospective case control observational study from August 2011 to July 2014 in a single center. PARTICIPANTS: This study evaluated 40 overt hyperthyroid patients and 31 age matched euthyroid controls who were operative candidates. MAIN OUTCOME MEASURES: Bone indices were measured at baseline and 6-month postoperatively using dual energy x-ray absorptiometry. Serum levels of alkaline phosphatase and 25-hydroxy vitamin D3 (25OHD) were assessed. RESULTS: Baseline BMD of hyperthyroid subjects at the spine, hip, and forearm were less than euthyroid controls (P = .001) with concomitant increases in serum alkaline phosphatase (mean +/- SD, 143 +/- 72 vs 72 +/- 23 IU/L control; P < .001). The 25OHD level was 24.3 +/- 10.6 and 26.1 +/- 14.6 ng/mL in patients and controls, respectively. Among hyperthyroid patients, posttreatment BMD expressed as g/cm(2) were 0.97 +/- 0.12 (vs pretreatment 0.91 +/- 0.14; P = .001) at the spine, 0.87 +/- 0.12 (vs pretreatment 0.80 +/- 0.13; P = .001) at the hip, and 0.67 +/- 0.09 (vs pretreatment 0.64 +/- 0.11; P = .191) at the forearm. The percent change in BMD was greatest at spine (8.3%) followed by the hip (7.6%) and forearm (3.0%). CONCLUSION: Operative management with total thyroidectomy improved the bone loss associated with hyperthyroidism as early as 6 months postoperatively at the hip and spine despite concomitant vitamin D deficiency. Delayed recovery of bone indices at the forearm, a cortical bone, requires further long-term evaluation. PMID- 26582501 TI - Synthetic high-density lipoprotein nanoparticles: A novel therapeutic strategy for adrenocortical carcinomas. AB - BACKGROUND: Chemotherapeutic strategies for adrenocortical carcinoma (ACC) carry substantial toxicities. Cholesterol is critical for ACC cell growth and steroidogenesis, and ACC cells overexpress scavenger receptor BI, which uptakes cholesterol from circulating high-density lipoprotein (HDL) cholesterol. We hypothesize that cholesterol-free synthetic-HDL nanoparticles (sHDL) will deplete cholesterol and synergize with chemotherapeutics to achieve enhanced anticancer effects at lesser (less toxic) drug levels. METHODS: The antiproliferative efficacy of ACC cells for the combinations of sHDL with chemotherapeutics was tested by Cell-Titer Glo. Cortisol levels were measured from the culture media. Effects on steroidogenesis was measured by real-time polymerase chain reaction (RT-PCR). Induction of apoptosis was evaluated by flow cytometry. RESULTS: Combination Index (CI) for sHDL and either etoposide (E), cisplatin (P), or mitotane (M) demonstrated synergy (CI < 1) for antiproliferation. Alone or in combination with the chemotherapy drugs, sHDL was able to decrease cortisol production by 70-90% compared with P alone or controls (P < .01). RT-PCR indicated inhibition of steroidogenic enzymes for sHDL (P < .01 vs no sHDL). Combination therapy with sHDL increased apoptosis by 30-50% compared with drug or sHDL alone (P < .03), confirmed by a decrease in the mitochondrial potential. CONCLUSION: sHDL can act synergistically and lessen the amount of M/E/P needed for anticancer efficacy in ACC in part owing to cholesterol starvation. This novel treatment strategy warrants further investigation translationally. PMID- 26582503 TI - Discussion. PMID- 26582502 TI - Liver steatosis assessed by preoperative MRI: An independent risk factor for severe complications after major hepatic resection. AB - BACKGROUND: Steatosis assessed by histology is commonly considered to be a significant risk factor for liver surgery. MRI is considered as the new gold standard for noninvasive liver fat quantification. The purpose was to assess whether liver steatosis determined by preoperative MRI is an independent risk factor of complications after major liver resection. METHODS: All patients who underwent liver MRI before major liver resection in our institution between January 2001 and December 2011 were included in this retrospective study. The liver fat fraction (LFF) was assessed on in- and opposed-phase T1-weighted dual echo gradient echo MRI and steatosis was defined as a MRI LFF of >= 5%. The association between steatosis and postoperative complications (Clavien-Dindo classification, ascites > 500 mL at day 5, 50-50 criteria, fistula/collection, blood liver test alterations, pulmonary complications, nonpulmonary complications, >1 complication, duration of stay in the intensive care unit, duration of hospital stay, and death) was assessed by multivariate analysis using the appropriate model. RESULTS: A MRI LFF of >= 5% was associated with severe postoperative complications (Clavien-Dindo score >= IIIa; P = .04), more pulmonary complications (P = .02), and longer duration of hospital stay (P = .02) on the multivariate model adjusted for confounding factors. The postoperative aminotransferase levels were higher in patients with a MRI LFF of >= 5%, than in other patients (P = .0008). CONCLUSION: Liver steatosis assessed by routine preoperative MRI is shown to be an independent risk factor of severe postoperative complications after major liver resection. PMID- 26582504 TI - Metabolic profiles of placenta in preeclampsia using HR-MAS MRS metabolomics. AB - INTRODUCTION: Preeclampsia is a heterogeneous gestational disease characterized by maternal hypertension and proteinuria, affecting 2-7% of pregnancies. The disorder is initiated by insufficient placental development, but studies characterizing the placental disease components are lacking. METHODS: Our aim was to phenotype the preeclamptic placenta using high-resolution magic angle spinning nuclear magnetic resonance spectroscopy (HR-MAS MRS). Placental samples collected after delivery from women with preeclampsia (n = 19) and normotensive pregnancies (n = 15) were analyzed for metabolic biomarkers including amino acids, osmolytes, and components of the energy and phospholipid metabolism. The metabolic biomarkers were correlated to clinical characteristics and inflammatory biomarkers in the maternal sera. RESULTS: Principal component analysis showed inherent differences in placental metabolic profiles between preeclamptic and normotensive pregnancies. Significant differences in metabolic profiles were found between placentas from severe and non-severe preeclampsia, but not between preeclamptic pregnancies with fetal growth restricted versus normal weight neonates. The placental metabolites correlated with the placental stress marker sFlt-1 and triglycerides in maternal serum, suggesting variation in placental stress signaling between different placental phenotypes. DISCUSSION: HR-MAS MRS is a sensitive method for defining the placental disease component of preeclampsia, identifying several altered metabolic pathways. Placental HR-MAS MRS analysis may improve insight into processes affected in the preeclamptic placenta, and represents a novel long-required tool for a sensitive placental phenotyping of this heterogeneous disease. PMID- 26582505 TI - Correlation of long-chain fatty acid oxidation with oxidative stress and inflammation in pre-eclampsia-like mouse models. AB - INTRODUCTION: Pre-eclampsia has been further recognized as a syndrome during pregnancy. Recent studies have found that long-chain fatty acid oxidation (FAO) disorders may be associated with some of pre-eclampsia. However, the mechanism remains unclear. In this study, we investigated the role of FAO and its relationship with oxidative stress and inflammatory signaling pathways in the pathogenesis of pre-eclampsia. METHODS: PE-like groups included ApoC3 transgenic mice with abnormal fatty acid metabolism, classical PE-like models with injection of Nomega-nitro-l-arginine-methyl ester (L-NA) or lipopolysaccharide (LPS), and antiphospholipid syndrome (APS) mouse model with beta2GPI injection. The control group included wild-type mice with normal saline injection. Serum FFA was compared and placental and hepatic LCHAD, p47phox and NF-kappaB mRNA and protein were detected using real-time quantitative PCR and western blot. RESULTS: FFA levels were significantly increased and were positively correlated with P47phox and NF-kappaB mRNA and protein expression in liver of all groups (p < 0.05), except LPS group (p < 0.05) as compared to control. LCHAD mRNA and protein expression in the liver and placenta was significantly increased in ApoC3+NS, ApoC3+L-NA, and beta2GPI group, whereas decreased in L-NA group (p < 0.05) as compared to the control group. P47phox mRNA, NF-kappaB mRNA, and protein expression in the liver of all groups, except in LPS and in the placenta of beta2GPI and L-NA groups, significantly increased (p < 0.05). DISCUSSION: FAO disorders were involved in the pathogenesis of pre-eclampsia through oxidative stress and inflammatory endothelial cell injury. PMID- 26582506 TI - Laparoscopic resection of a huge mature cystic teratoma of the right adrenal gland through retroperitoneal approach: a case report and literature review. AB - BACKGROUND: At present, the primary mature cystic teratoma in the adrenal gland is extremely rare in adults, according to the literature. In addition, a completely retroperitoneoscopic resection of mature cystic teratomas has been reported only in two cases. CASE PRESENTATION: We report a case of a large mature cystic teratoma with a regular margin in the right adrenal gland. Three months before surgery, abdominal enhanced computer tomography revealed a 5.7 * 4.9 * 4.3 cm lipoid tumour of mixed density with calcification in the tumorous centre, clinically diagnosed as adrenal myelolipoma or adenoma. Retroperitoneoscopic adrenalectomy was successfully performed; however, the tumour had increased in size to approximately 6.0 * 7.0 * 11 cm. The pathological report suggested the final diagnosis of mature cystic teratoma. The patient had an uneventful course after the surgery and was free of recurrence or metastasis within 8 months of follow-up. CONCLUSIONS: Retroperitoneoscopic adrenalectomy for large adrenal masses is safe and feasible. To the best of our knowledge, this is the first report where of a large mature cystic teratoma of the right adrenal gland has been completely resected using retroperitoneoscopic approach. PMID- 26582507 TI - Practice and nap schedules modulate children's motor learning. AB - Night- or day-time sleep enhances motor skill acquisition. However, prominent issues remained about the circadian (time-of-day) and homeostatic (time since last sleep) effects of sleep on developmental motor learning. Therefore, we examined the effects of nap schedules and nap-test-intervals (NTIs) on the learning of finger tapping sequences on computer keyboards. Children aged 6-7, 8 9, and 10-11 years explicitly acquired the short and long tapping orders that share the same movement strings (4-2-3-1-4, 4-2-3-1-4-2-3-1-4). Following a constant 8- or 10-hr post-learning period in one of the four NTIs (2, 4, 5, 7 hr), children in the morning napping groups, the afternoon napping groups, or the waking group performed the original long sequence in retention test (4-2-3-1-4-2 3-1-4) and the mirrored-order sequence in transfer test (1-3-2-4-1-3-2-4-1). Age and treatment differences in the movement time (MT, ms) and sequence accuracy (SA, %) were compared during skill learning and in retrieval tests. Results suggest that practice or nap affects MT and SA in a greater extent for the younger learners than for the older learners. The circadian effects might not change nap-based skill learning. Importantly, the longer NTIs resulted in superior retention performance than the shorter ones, suggesting that children require a relatively longer post-nap period to form motor memory. Finally, nap based motor learning was more marked in skill retention than in skill transfer. Brain development may play an important role in motor learning. Our discussion centers on memory consolidation and its relevance for skill acquisition from early to late childhood. PMID- 26582508 TI - Detailed mapping of a resistance locus against Fusarium wilt in cultivated eggplant (Solanum melongena). AB - KEY MESSAGE: This is the first report on genetic mapping of a resistance locus against Fusarium wilt caused by the plant pathogen Fusarium oxysporum f. sp. melongenae in cultivated eggplant. ABSTRACT: Fusarium wilt, caused by the plant pathogen Fusarium oxysporum f. sp. melongenae, is a major soil-borne disease threatening stable production in eggplant (Solanum melongena). Although three eggplant germplasms, LS1934, LS174, and LS2436, are known to be highly resistant to the pathogen, their resistance loci have not been mapped. In this study, we performed quantitative trait locus analyses in F2:3 populations and detected a resistance locus, FM1, at the end of chromosome 2, with two alleles, Fm1(L) and Fm1(E), in the F2 populations LWF2 [LS1934 * WCGR112-8 (susceptible)] and EWF2 [EPL-1 (derived from LS174) * WCGR112-8], respectively. The percentage of phenotypic variance explained by Fm1(L) derived from LS1934 was 75.0% [Logarithm of the odds (LOD) = 29.3], and that explained by Fm1(E) derived from EPL-1 was 92.2% (LOD = 65.8). Using backcrossed inbred lines, we mapped FM1 between two simple sequence repeat markers located ~4.881 cM apart from each other. Comparing the location of the above locus to those of previously reported ones, the resistance locus Rfo-sa1 from an eggplant ally (Solanum aethiopicum gr. Gilo) was mapped very close to FM1, whereas another resistance locus, from LS2436, was mapped to the middle of chromosome 4. This is the first report of mapping of a Fusarium resistance locus in cultivated eggplant. The availability of resistance linked markers will enable the application of marker-assisted selection to overcome problems posed by self-incompatibility and introduction of negative traits because of linkage drag, and will lead to clear understanding of genetic mechanism of Fusarium resistance. PMID- 26582509 TI - Reparametrization-based estimation of genetic parameters in multi-trait animal model using Integrated Nested Laplace Approximation. AB - KEY MESSAGE: A novel reparametrization-based INLA approach as a fast alternative to MCMC for the Bayesian estimation of genetic parameters in multivariate animal model is presented. ABSTRACT: Multi-trait genetic parameter estimation is a relevant topic in animal and plant breeding programs because multi-trait analysis can take into account the genetic correlation between different traits and that significantly improves the accuracy of the genetic parameter estimates. Generally, multi-trait analysis is computationally demanding and requires initial estimates of genetic and residual correlations among the traits, while those are difficult to obtain. In this study, we illustrate how to reparametrize covariance matrices of a multivariate animal model/animal models using modified Cholesky decompositions. This reparametrization-based approach is used in the Integrated Nested Laplace Approximation (INLA) methodology to estimate genetic parameters of multivariate animal model. Immediate benefits are: (1) to avoid difficulties of finding good starting values for analysis which can be a problem, for example in Restricted Maximum Likelihood (REML); (2) Bayesian estimation of (co)variance components using INLA is faster to execute than using Markov Chain Monte Carlo (MCMC) especially when realized relationship matrices are dense. The slight drawback is that priors for covariance matrices are assigned for elements of the Cholesky factor but not directly to the covariance matrix elements as in MCMC. Additionally, we illustrate the concordance of the INLA results with the traditional methods like MCMC and REML approaches. We also present results obtained from simulated data sets with replicates and field data in rice. PMID- 26582511 TI - Direct and Convenient Mass Spectrometry Sampling with Ambient Flame Ionization. AB - Recent innovations in ambient ionization technology for the direct analysis of various samples in their native environment facilitate the development and applications of mass spectrometry in natural science. Presented here is a novel, convenient and flame-based ambient ionization method for mass spectrometric analysis of organic compounds, termed as the ambient flame ionization (AFI) ion source. The key features of AFI ion source were no requirement of (high) voltages, laser beams and spray gases, but just using small size of n-butane flame (height approximately 1 cm, about 500 (o)C) to accomplish the rapid desorption and ionization for direct analysis of gaseous-, liquid- and solid phase organic compounds, as well as real-world samples. This method has high sensitivity with a limit of detection of 1 picogram for propyphenazone, which allows consuming trace amount of samples. Compared to previous ionization methods, this ion source device is extremely simple, maintain-free, low-cost, user-friendly so that even an ordinary lighter (with n-butane as fuel) can achieve efficient ionization. A new orientation to mass spectrometry ion source exploitation might emerge from such a convenient, easy and inexpensive AFI ion source. PMID- 26582510 TI - Genotype by watering regime interaction in cultivated tomato: lessons from linkage mapping and gene expression. AB - KEY MESSAGE: In tomato, genotype by watering interaction resulted from genotype re-ranking more than scale changes. Interactive QTLs according to watering regime were detected. Differentially expressed genes were identified in some intervals. ABSTRACT: As a result of climate change, drought will increasingly limit crop production in the future. Studying genotype by watering regime interactions is necessary to improve plant adaptation to low water availability. In cultivated tomato (Solanum lycopersicum L.), extensively grown in dry areas, well-mastered water deficits can stimulate metabolite production, increasing plant defenses and concentration of compounds involved in fruit quality, at the same time. However, few tomato Quantitative Trait Loci (QTLs) and genes involved in response to drought are identified or only in wild species. In this study, we phenotyped a population of 119 recombinant inbred lines derived from a cross between a cherry tomato and a large fruit tomato, grown in greenhouse under two watering regimes, in two locations. A large genetic variability was measured for 19 plant and fruit traits, under the two watering treatments. Highly significant genotype by watering regime interactions were detected and resulted from re-ranking more than scale changes. The population was genotyped for 679 SNP markers to develop a genetic map. In total, 56 QTLs were identified among which 11 were interactive between watering regimes. These later mainly exhibited antagonist effects according to watering treatment. Variation in gene expression in leaves of parental accessions revealed 2259 differentially expressed genes, among which candidate genes presenting sequence polymorphisms were identified under two main interactive QTLs. Our results provide knowledge about the genetic control of genotype by watering regime interactions in cultivated tomato and the possible use of deficit irrigation to improve tomato quality. PMID- 26582512 TI - Civic Stratification and the Exclusion of Undocumented Immigrants from Cross border Health Care. AB - This paper proposes a theoretical framework and an empirical example of the relationship between the civic stratification of immigrants in the United States, and their access to healthcare. We use the 2007 Pew Hispanic Center/Robert Wood Johnson Foundation Hispanic Healthcare Survey, a nationally representative survey of U.S. Latinos (N = 2,783 foreign-born respondents) and find that immigrants who are not citizens or legal permanent residents are significantly more likely to be excluded from care in both the United States and across borders. Legal-status differences in cross-border care utilization persisted after controlling for health status, insurance coverage, and other potential demographic and socioeconomic predictors of care. Exclusion from care on both sides of the border was associated with reduced rates of receiving timely preventive services. Civic stratification, and political determinants broadly speaking, should be considered alongside social determinants of population health and health care. PMID- 26582513 TI - Adolescent Survival Expectations: Variations by Race, Ethnicity, and Nativity. AB - Adolescent survival expectations are linked to a range of problem behaviors, poor health, and later socioeconomic disadvantage, yet scholars have not examined how survival expectations are differentially patterned by race, ethnicity, and/or nativity. This is a critical omission given that many risk factors for low survival expectations are themselves stratified by race and ethnicity. Using the National Longitudinal Study of Adolescent to Adult Health, we modeled racial, ethnic, and immigrant group differences in trajectories of adolescent survival expectations and assess whether these differences are accounted for by family, neighborhood, and/or other risk factors (e.g., health care access, substance use, exposure to violence). Findings indicated that most racial, ethnic, and immigrant groups were more pessimistic about their survival than were non-Hispanic whites, with the exception of Cuban youth, who were the most optimistic. Foreign-born Mexican youth had the lowest survival expectations, contrary to expectations from the "healthy-immigrant" hypothesis. PMID- 26582514 TI - Moroccan medical students' perceptions of their educational environment. AB - This study aimed to assess students' perceptions of their educational environment in the Faculty of Medicine and Pharmacy of Rabat, Morocco, using the Dundee Ready Educational Environment Measure (DREEM). A cross-sectional survey was conducted in the Faculty of Medicine and Pharmacy of Rabat, Morocco, in which medical students' perceptions of their educational environment were assessed using the DREEM criteria during the 2013-2014 academic years. The DREEM inventory encompasses 50 items divided into five subdomains: perceptions of learning, perceptions of teaching, academic self-perceptions, perceptions of atmosphere, and social self-perceptions. The DREEM has a maximum score of 200, which would correspond to a perfect educational environment. The mean scores (+/-standard deviation) of students' responses were compared according to their year of study and gender. The responses of 189 postgraduate medical students were included. The mean total DREEM score was 90.8 (45.4%). The mean total scores for five subdomains were 21.2/48 (44.2%), 21.8/44 (49.6%), 13.1/32 (40.9%), 19.0/48 (39.6%), and 15.6/28 (55.7%) respectively. Female students reported higher perceptions of teaching scores than males (P=0.002), and students in their fifth year of study reported significantly higher social self-perceptions scores than those in their fourth year (P=0.03). In this study of the oldest faculty of medicine in Morocco, students perceived the educational environment as having many problems. PMID- 26582517 TI - Return to the days of von Magnus. PMID- 26582519 TI - Austerity, precariousness, and the health status of Greek labour market participants: A view from inside. PMID- 26582521 TI - [Transgenic crops]. PMID- 26582520 TI - Web-Based Intervention for Nutritional Management in Cystic Fibrosis: Development, Usability, and Pilot Trial. AB - OBJECTIVES: Usability and pilot testing of a web intervention (BeInCharge.org [BIC]) of behavior plus nutrition intervention for children with cystic fibrosis (CF) ages 4-9 years. METHODS: Think Aloud methodology was used with five mothers to assess usability and refine the intervention. A pilot trial was then conducted with 10 mothers of children with CF ages 4-9 years randomized to the web-based BIC or a Standard Care Control (STC). Change in weight gain for each group was compared in a pre-to-post design. RESULTS: Mothers rated the usability and clarity of BIC highly. The pilot trial showed children of mothers who received BIC had a significant change in weight pre-to-post-treatment (0.67 kg, p = .04). Change for the STC was not significant (0.41 kg, p = .10). CONCLUSIONS: A web based behavior plus nutrition intervention appears promising in increasing weight gain in children with CF. PMID- 26582522 TI - [Recent advances in transmissible tumors]. AB - Transmissible tumors are a class of tumor that can be transmitted between individuals through living cells. So far, four types of transmissible tumors including canine transmissible venereal tumor (CTVT),Tasmanian devil facial tumor disease (DFTD), soft-shell clams leukemia (SSCL), and hamsters reticulum cell sarcoma (HRCS)have been discovered and identified. In the last decades, these transmissible tumors have been proved to be transmitted through living cells by cytological, histological and genetic studies. CTVT, the oldest mammalian somatic cell line, and DFTD originated from Schwann cell have been reported to avoid immunological recognition by down-regulating MHC expression, while a high copy number of Steamer retrotransposon is commonly exist in SSCL. In recent years, the whole-genome sequencing of CTVT and DFTD have been completed which facilitates studies on the mechanisms of tumorigenesis, transmission and evolution of transmissible tumors at the whole-genome level. In this review, we summarize the recent advances in transmissible tumors and discuss the research focus in next decade. PMID- 26582523 TI - [The role of long non-coding RNAs in hematologic malignancies]. AB - With the rapid development of molecular biology technology, researchers have got much deeper understanding of the role of long non-coding RNA (lncRNA). It is not only indispensable for biological processes, but also plays an important role in human diseases especially in tumor. Previous studies have shown that a variety of lncRNAs are closely associated with hematologic malignancies. These lncRNAs are involved in diseases through diverse functions including affecting the expression of tumor suppressor gene p15, regulating p53 protein function, and interacting with miRNAs. In this review, we summarize the hematological tumor-associated lncRNAs and focus on p15, p53 and miRNA-related lncRNAs as well as the role of their interaction in hematological malignancies, which may provide a comprehensive understanding of the role of hematological tumor-associated lncRNAs and some insights for research, diagnosis and treatment of hematologic malignancies. PMID- 26582524 TI - [Progress in the molecular genetic mechanism of gonadoblastoma]. AB - Gonadoblastoma (GB), a rare in situ germ cell tumor derived from sex cord and germ cells, is closely associated with gonadal dysgenesis. About 80% of GB individuals exhibit 46, XY female phenotype while the others are 45, XY and 46, XX with disorders of sex development. Moreover, 35% of GB can eventually develop into malignant tumors, such as seminoma and dysgerminoma tumors. The molecular genetic mechanism of GB remains to be fully uncovered due to phenotypic and genetic heterogeneity. Increasing studies show that the formation of GB is closely related to genes regulating sexual differentiation and determination (e.g., SRY, WT1, SOX9, Foxl2, TSPY, etc), and is affected by the interaction of genetic and epigenetic regulation. Here we describe the clinical and pathological features, diagnosis and treatment of GB, and also summarize the molecular genetic and epigenetic mechanisms underlying the gonadal abnormalities that lead to GB. We analyze and construct the common gene regulatory networks related to the development of GB, and describe some obstacles and deficiencies in current studies to provide innovative perspectives on further studying the pathological and molecular mechanisms of GB. PMID- 26582525 TI - [Effect of autophagy on liver regeneration]. AB - Autophagy is a lysosome-mediated degradation pathway, which plays an important role in hepatic physiological and pathological processes, in eukaryotic cells. The liver has a remarkable regenerative capacity. After acute or chronic injury, the residual hepatic cells can be activated to enter the cell-cycle for proliferation, in order to compensate for lost liver tissue and recover liver function. In this review, we summarize the relationship between liver regeneration (LR) after various types of injury and autophagy. For example, autophagy is activated to accelerate LR after physically, alcohol and food borne induced liver injury, while the role of autophagy in animal models of LR after chemical injury remains controversial. Autophagy can also be used to promote the replication of virus particles by some hepatotropic viruses (e.g., HBV, HCV) and inhibit LR after viral infection. Studies on mechanisms of autophagy and LR will contribute to clarify the regenerative process and provide new methods for the treatment of liver disease. PMID- 26582526 TI - [sgRNA design for the CRISPR/Cas9 system and evaluation of its off-target effects]. AB - The third generation of CRISPR/Cas9-mediated genome editing technology has been successfully applied to genome modification of various species including animals, plants and microorganisms. How to improve the efficiency of CRISPR/Cas9 genome editing and reduce its off-target effects has been extensively explored in this field. Using sgRNA (Small guide RNA) with high efficiency and specificity is one of the critical factors for successful genome editing. Several software have been developed for sgRNA design and/or off-target evaluation, which have advantages and disadvantages respectively. In this review, we summarize characters of 16 kinds online and standalone software for sgRNA design and/or off-target evaluation and conduct a comparative analysis of these different kinds of software through developing 38 evaluation indexes. We also summarize 11 experimental approaches for testing genome editing efficiency and off-target effects as well as how to screen highly efficient and specific sgRNA. PMID- 26582515 TI - Innate Immune Signaling Activated by MDR Bacteria in the Airway. AB - Health care-associated bacterial pneumonias due to multiple-drug resistant (MDR) pathogens are an important public health problem and are major causes of morbidity and mortality worldwide. In addition to antimicrobial resistance, these organisms have adapted to the milieu of the human airway and have acquired resistance to the innate immune clearance mechanisms that normally prevent pneumonia. Given the limited efficacy of antibiotics, bacterial clearance from the airway requires an effective immune response. Understanding how specific airway pathogens initiate and regulate innate immune signaling, and whether this response is excessive, leading to host-induced pathology may guide future immunomodulatory therapy. We will focus on three of the most important causes of health care-associated pneumonia, Staphylococcus aureus, Pseudomonas aeruginosa, and Klebsiella pneumoniae, and review the mechanisms through which an inappropriate or damaging innate immune response is stimulated, as well as describe how airway pathogens cause persistent infection by evading immune activation. PMID- 26582527 TI - [Association study of telomere length with idiopathic male infertility]. AB - Telomeres are evolutionary conserved, multifunctional DNA-protein complexes located at the ends of eukaryotic chromosomes. Telomeres maintain chromosome stability and genome integrity and also play an important role in meiosis which aid in synapsis, homologous recombination, and segregation. Sperm telomere has been reported to play an important role in fertilization and embryo development. Nowadays, the association between telomere and reproduction is one of the major areas of interest, however whether sperm telomere associated with male infertility is not clear. In this study, in order to find out the association between Chinese idiopathic infertility and sperm telomere length, we analyzed the difference of sperm telomere length between idiopathic infertile men and normal fertile men, as well as the correlations between sperm telomere length and human semen characteristics. We analyzed 126 Chinese idiopathic infertile men and 138 normal fertile men for sperm telomere length by using quantitative PCR. We found that the relative sperm mean telomere length of infertile men was significantly shorter than that of fertile men (2.894 +/- 0.115 vs. 4.016 +/- 0.603, P=5.097 x 10-5). Both sperm count and semen progressive motility are related with telomere length. Our results suggest that sperm telomere length is associated with idiopathic male infertility of China and we proposed the possibility that shorter telomeres in sperm chromosome will reduce spermatogenesis and sperm functions, which finally affected the fertility of male. PMID- 26582528 TI - [A quick and efficient method to generate hemophilia B mouse models by the CRISPR/Cas system]. AB - Hemophilia B, or the Christmas disease, is a common human disease caused by coagulation factor IX (FIX) deficiency. It is an X-linked recessive hereditary disease. Here we obtained FIX-knockout mouse strains with phenotype of hemophilia B with the CRISPR/Cas system efficiently. We chose the 8th exon as the target locus, and co-injected codon-optimized Cas9 mRNA with sgRNA of FIX into C57BL/6 mice zygotes. We obtained 60 mice in total and genotyped them by high resolution melting (HRM) and sequencing. The results showed the mutation rate was 85.0% in total, and 79.5% and 95.2% in males and females, respectively. No off-targets were detected in the similar locus by HRM. We future measured the FIX activity of each mice. The FIX: C of mutant mice were significantly below the normal level and reduced to 6.82% of wild-type mice. The activity assay demonstrated that all the mutant mice were lack of FIX. In summary, we have generated hemophilia B model mice with extreme efficiency, using the RNA-guided Cas9 nuclease gene editing system. PMID- 26582516 TI - Male Reproductive Disorders and Fertility Trends: Influences of Environment and Genetic Susceptibility. AB - It is predicted that Japan and European Union will soon experience appreciable decreases in their populations due to persistently low total fertility rates (TFR) below replacement level (2.1 child per woman). In the United States, where TFR has also declined, there are ethnic differences. Caucasians have rates below replacement, while TFRs among African-Americans and Hispanics are higher. We review possible links between TFR and trends in a range of male reproductive problems, including testicular cancer, disorders of sex development, cryptorchidism, hypospadias, low testosterone levels, poor semen quality, childlessness, changed sex ratio, and increasing demand for assisted reproductive techniques. We present evidence that several adult male reproductive problems arise in utero and are signs of testicular dysgenesis syndrome (TDS). Although TDS might result from genetic mutations, recent evidence suggests that it most often is related to environmental exposures of the fetal testis. However, environmental factors can also affect the adult endocrine system. Based on our review of genetic and environmental factors, we conclude that environmental exposures arising from modern lifestyle, rather than genetics, are the most important factors in the observed trends. These environmental factors might act either directly or via epigenetic mechanisms. In the latter case, the effects of exposures might have an impact for several generations post-exposure. In conclusion, there is an urgent need to prioritize research in reproductive physiology and pathophysiology, particularly in highly industrialized countries facing decreasing populations. We highlight a number of topics that need attention by researchers in human physiology, pathophysiology, environmental health sciences, and demography. PMID- 26582529 TI - [Genetic basis of immune response of lymphocyte-like cells in the mucosal immune system of Lampetra japonica]. AB - In recent years, the antigen recognition mechanism based on variable lymphocyte receptors (VLRs) was found in agnathan lamprey. To illuminate the genetic basis of immune response of lymphocyte-like cells in the mucosal immune system of lamprey and explore the evolutionary relationship of adaptive immune responses between the jawless and jawed vertebrates, we constructed cDNA libraries of lamprey (Lampetra japonica) gills before and after stimulation, and then performed high-throughput transcriptome sequencing and analysis. Through functional annotation of 88 525 assembled unigenes, 21 704 and 9769 unigenes were annotated in Gene Ontology (GO) and Kyto Encyclopedia of Genes and Genomes (KEGG) databases, respectively. Among 999 unigenes involved in multiple pathways of immune system, 184 unigenes were highly homologous to 51 TCR (T cell receptor) and BCR (B cell receptor) signalling molecules in higher vertebrates, indicating that molecules involved in adaptive immune signalling pathways in higher vertebrates also exist in lampreys. In addition, identification of five VLRA, seven VLRB and four VLRC molecules suggest that at least three types of lymphocyte subsets are distributed in lamprey gill mucosal immune tissues. The results of real-time fluorescence quantitative PCR showed that the expression levels of Lck, Fyn and Zap70 were up-regulated after immune stimulation while those of Syk, Btk and Blnk were not changed significantly, indicating the activation of TCR-like signal transduction pathway after antigen stimulation in lamprey gill tissues. Our studies preliminaryly proved that two parallel adaptive immune systems in jawless and jawed vertebrates have common genetic basis, and also provided valuable clues to the exploration of signalling processes of VLRA+, VLRB+, and VLRC+ lymphocyte-like cells in response to antigens. PMID- 26582530 TI - [Identification of C(2)M interacting proteins by yeast two-hybrid screening]. AB - The synaptonemal complex (SC) is a huge structure which assembles between the homologous chromosomes during meiotic prophase I. Drosophila germ cell-specific nucleoprotein C(2)M clustering at chromosomes can induce SC formation. To further study the molecular function and mechanism of C(2)M in meiosis, we constructed a bait vector for C(2)M and used the yeast two-hybrid system to identify C(2)M interacting proteins. Forty interacting proteins were obtained, including many DNA and histone binding proteins, ATP synthases and transcription factors. Gene silencing assays in Drosophila showed that two genes, wech and Psf1, may delay the disappearance of SC. These results indicate that Wech and Psf1 may form a complex with C(2)M to participate in the formation or stabilization of the SC complex. PMID- 26582532 TI - Tyrosine Kinases in Cancer. PMID- 26582531 TI - [Efficient genome editing in human pluripotent stem cells through CRISPR/Cas9]. AB - The RNA-guided CRISPR (clustered regularly interspaced short palindromic repeat) associated Cas9 nuclease has offered a new platform for genome editing with high efficiency. Here, we report the use of CRISPR/Cas9 technology to target a specific genomic region in human pluripotent stem cells. We show that CRISPR/Cas9 can be used to disrupt a gene by introducing frameshift mutations to gene coding region; to knock in specific sequences (e.g. FLAG tag DNA sequence) to targeted genomic locus via homology directed repair; to induce large genomic deletion through dual-guide multiplex. Our results demonstrate the versatile application of CRISPR/Cas9 in stem cell genome editing, which can be widely utilized for functional studies of genes or genome loci in human pluripotent stem cells. PMID- 26582533 TI - Correlation between band gap, dielectric constant, Young's modulus and melting temperature of GaN nanocrystals and their size and shape dependences. AB - With structural miniaturization down to the nanoscale, the detectable parameters of materials no longer remain constant but become tunable. For GaN nanocrystals example, the band gap increases while the dielectric constant, Young's modulus and melting temperature decrease with decreasing the solid size. Herein, we developed the models to describe the size and shape dependences of these seemingly uncorrelated parameters for GaN nanocrystals, based on our established thermodynamic model for cohesive energy of metallic nanocrystals. Consistency between our theoretical predictions and the corresponding experimental or simulated results confirms the accuracy of the developed models and indicates the essentiality of cohesive energy in describing the effects of size and shape on the physicochemical properties of different low-dimensional systems. PMID- 26582534 TI - Cerebellar asymmetry, cortical asymmetry and handedness: Two independent networks. AB - In 46 right-handers and 46 left-handers, we used functional magnetic resonance imaging to record activity in the frontal lobes while they generated words, the temporal lobe while they made synonym judgments, and the parietal lobe while they watched videos of manual actions. In each case we also recorded activity in the cerebellum. Laterality indices showed a significant left-hemispheric bias in each cortical lobe and a right-hemispheric bias in the cerebellum for the 2 language tasks, but not during action observation. Cerebellar asymmetry also correlated negatively with frontal and temporal asymmetry, reflecting contralateral connections, but not with parietal asymmetry. A factor analysis of the inter correlations among laterality indices revealed 2 factors, implying independent lateralized networks, with cerebellar asymmetry strongly linked to a language network in frontal and temporal cortices, and handedness strongly linked to an action-observation network in the parietal lobe. PMID- 26582535 TI - Optimization of the Biosynthesis Conditions of Daptomycin by the Biostatistical Methodology. AB - Response surface methodology (RSM) was employed to optimize medium components including oxygen vector of n-dodecane of a mutant strain GC-63 of Streptomyces roseosporus NRRL 11379. The two-level Plackett-Burman design (PB factorial design) with fourteen variables including oxygen vector was used to screen the most significant factors affecting antibiotic production. Then, the RSM based on center composite design was used to identify the optimum levels of the significant variables to generate optimal response. Glucose, soybean meal, asparagine and n-dodecane were screened to significantly influence the daptomycin production. The medium composition optimized with response surface methodology was (g/L): glucose, 9.46; soluble starch, 25; dextrin, 12.5; yeast extract, 12.5; soybean meal, 21.34; peptone, 25; casein, 5; asparagine, 2.68; K2SO4, 6; (NH4)2Fe(SO4)2, 2; MgSO4, 1; CaCO3, 5; MnCl2, 0.5; n-dodecane, 7.47 % (v/v). The maximum daptomycin concentration reached 979.36 mg/L which was nearly 2.2-fold higher compared to that in the basal medium, with predicted optimal concentrations in a 7.5-L fermentor. PMID- 26582536 TI - A predictive coding account of MMN reduction in schizophrenia. AB - The mismatch negativity (MMN) is thought to be an index of the automatic activation of a specialized network for active prediction and deviance detection in the auditory cortex. It is consistently reduced in schizophrenic patients and has received a lot of interest as a clinical and translational tool. The main neuronal hypothesis regarding the mechanisms leading to a reduced MMN in schizophrenic patients is a dysfunction of NMDA receptors (NMDA-R). However, this hypothesis has never been implemented in a neuronal model. In this paper, we examine the consequences of NMDA-R dysfunction in a neuronal model of MMN based on predictive coding principle. I also investigate how predictive processes may interact with synaptic adaptation in MMN generations and examine the consequences of this interaction for the use of MMN paradigms in schizophrenia research. PMID- 26582537 TI - Hook tool manufacture in New Caledonian crows: behavioural variation and the influence of raw materials. AB - BACKGROUND: New Caledonian crows use a range of foraging tools, and are the only non-human species known to craft hooks. Based on a small number of observations, their manufacture of hooked stick tools has previously been described as a complex, multi-stage process. Tool behaviour is shaped by genetic predispositions, individual and social learning, and/or ecological influences, but disentangling the relative contributions of these factors remains a major research challenge. The properties of raw materials are an obvious, but largely overlooked, source of variation in tool-manufacture behaviour. We conducted experiments with wild-caught New Caledonian crows, to assess variation in their hooked stick tool making, and to investigate how raw-material properties affect the manufacture process. RESULTS: In Experiment 1, we showed that New Caledonian crows' manufacture of hooked stick tools can be much more variable than previously thought (85 tools by 18 subjects), and can involve two newly discovered behaviours: 'pulling' for detaching stems and bending of the tool shaft. Crows' tool manufactures varied significantly: in the number of different action types employed; in the time spent processing the hook and bending the tool shaft; and in the structure of processing sequences. In Experiment 2, we examined the interaction of crows with raw materials of different properties, using a novel paradigm that enabled us to determine subjects' rank-ordered preferences (42 tools by 7 subjects). Plant properties influenced: the order in which crows selected stems; whether a hooked tool was manufactured; the time required to release a basic tool; and, possibly, the release technique, the number of behavioural actions, and aspects of processing behaviour. Results from Experiment 2 suggested that at least part of the natural behavioural variation observed in Experiment 1 is due to the effect of raw-material properties. CONCLUSIONS: Our discovery of novel manufacture behaviours indicates a plausible scenario for the evolutionary origins, and gradual refinement, of New Caledonian crows' hooked stick tool making. Furthermore, our experimental demonstration of a link between raw-material properties and aspects of tool manufacture provides an alternative hypothesis for explaining regional differences in tool behaviours observed in New Caledonian crows, and some primate species. PMID- 26582538 TI - Human embryonic and induced pluripotent stem cells in clinical trials. AB - BACKGROUND: Human embryonic and induced pluripotent stem cells (hESC and hiPSC) have tremendous potential for clinical implementation. In spite of all hurdles and controversy, clinical trials in treatment of spinal cord injury, macular degeneration of retina, type 1 diabetes and heart failure are already ongoing. SOURCES OF DATA: ClinicalTrials.gov database, International Clinical Trials Registry Platform, PubMed and press releases and websites of companies and institutions working on hESC- and iPSC-based cellular therapy. AREAS OF AGREEMENT: The initial results from multiple clinical trials demonstrate that hESC-based therapies are safe and promising. AREAS OF CONTROVERSY: Are iPSC cells safe in the clinical application? Is there a room for both hESC and iPSC in the future clinical applications? GROWING POINTS: Increasing number of new clinical trials. AREAS TIMELY FOR DEVELOPING RESEARCH: Development of hESC- and/or iPSC based cellular therapy for other diseases. PMID- 26582539 TI - The development of urban community health centres for strengthening primary care in China: a systematic literature review. AB - INTRODUCTION: This review outlines the development of China's primary care system, with implications for improving equitable health care. SOURCES OF DATA: Government documents, official statistics, and recent literature identified through systematic searches performed on NCBI PubMed. AREAS OF AGREEMENT: Community health centres (CHCs) are being developed as the major primary care provider in urban China, with laudable achievements. The road towards a strong primary care-led system is promising but challenging. AREAS OF CONTROVERSY: The effectiveness in improving equitable care through the expansion of primary care workforce and redesign of the social medical insurance system warrants further exploration. GROWING POINTS: Healthcare disparities exist in the health system wherein universal health coverage and gatekeepers have not yet been established. AREAS TIMELY FOR DEVELOPING RESEARCH: Future prospective studies should aim to provide solutions for strengthening the leading role of CHCs in providing equitable care in response to population ageing and multimorbidity challenges. PMID- 26582540 TI - Health, equity and the north of England: a case study on a new approach. AB - INTRODUCTION OR BACKGROUND: In 2013, responsibility for public health returned to local government from the National Health Service (NHS) in England. This article describes, as a case study, a new fresh approach to tackling health inequalities, which built on a desire by local councils in the north of England to rethink approaches and collaborate on new ideas to improving health and reducing health inequalities. SOURCES OF DATA: The collaboration was supported by an independently commissioned inquiry that assessed the evidence and proposed new policy options. This article describes the context to the collaboration, called Health Equity North, findings from the independent inquiry and emerging impact. Four areas for action were recommended: linking poverty with economic prosperity, devolution and public sector reform, investment in early years and renewed impetus for the health sector. AREAS OF AGREEMENT: That health service action alone had been limited without addressing the wider determinants of health such as employment, education and housing. AREAS OF CONTROVERSY: The so-called north south divide appears to be widening, and renewed efforts are needed locally and nationally to tackle these wider determinants of health. GROWING POINTS: This collaborative approach spanning a large geography supported by local and national leaderships, enabled new work locally and influenced policy nationally, such as devolution of power and resources to local areas. AREAS TIMELY FOR DEVELOPING RESEARCH: Research is needed on the economic returns of investing in the social determinants of health. The examples of local action indicate the need for research on 'asset-based approaches' to improving community health, presented so to empower local lay decision makers such as councillor rather than for technical experts. PMID- 26582542 TI - Hemodynamic Response to Hemodialysis With Ultrafiltration Rate Profiles Either Gradually Decreasing or Gradually Increasing. AB - Hemodialysis (HD) is usually performed with the gradually decreasing ultrafiltration rate (UFR) profile (dUFR). The aim of the present study was to compare the hemodynamic response to HD with the dUFR to that of HD with the gradually increasing UFR profile (iUFR). The study population included 10 patients (three women, mean age: 28 +/- 8 years) undergoing maintenance HD who had reached dry weight without taking antihypertensive medications. Each patient received (in random order) one HD session with the dUFR and another with the iUFR (both with 3 h total UFR = 2200 mL). Hemodynamic response was evaluated with a brachial blood pressure (BP) monitor, echocardiogram and Portapres to measure digital BP, heart rate, cardiac output, stroke volume, and peripheral resistance. Mean values were compared at each HD hour during the first 3 h of a 4-h HD session. The HD characteristics, including Kt/V, were similar for both UFR profiles. Relative blood volume decreased more gradually and linearly with the iUFR. Hemodynamic variables were not significantly different between the two profiles, but brachial BP was more stable with the iUFR. Digital diastolic BP increased with both profiles. Peripheral resistance increased with both profiles, and tended to increase more with the iUFR. Echocardiographic variables changed similarly during the HD session with both profiles. In conclusion, these two UFR profiles are similar in most hemodynamic variables. The statistical equivalence of both profiles suggests that either could be prescribed based on the clinical characteristics of the patient. PMID- 26582541 TI - RNA-Seq and microarray analysis of the Xenopus inner ear transcriptome discloses orthologous OMIM((r)) genes for hereditary disorders of hearing and balance. AB - BACKGROUND: Auditory and vestibular disorders are prevalent sensory disabilities caused by genetic and environmental (noise, trauma, chemicals) factors that often damage mechanosensory hair cells of the inner ear. Development of treatments for inner ear disorders of hearing and balance relies on the use of animal models such as fish, amphibians, reptiles, birds, and non-human mammals. Here, we aimed to augment the utility of the genus Xenopus for uncovering genetic mechanisms essential for the maintenance of inner ear structure and function. RESULTS: Using Affymetrix GeneChip((r)) X. laevis Genome 2.0 Arrays and Illumina-Solexa sequencing methods, we determined that the transcriptional profile of the Xenopus laevis inner ear comprises hundreds of genes that are orthologous to OMIM((r)) genes implicated in deafness and vestibular disorders in humans. Analysis of genes that mapped to both technologies demonstrated that, with our methods, a combination of microarray and RNA-Seq detected expression of more genes than either platform alone. CONCLUSIONS: As part of this study we identified candidate scaffold regions of the Xenopus tropicalis genome that can be used to investigate hearing and balance using genetic and informatics procedures that are available through the National Xenopus Resource (NXR), and the open access data repository, Xenbase. The results and approaches presented here expand the viability of Xenopus as an animal model for inner ear research. PMID- 26582543 TI - Characterization of sintering dust collected in the various fields of the electrostatic precipitator. AB - Sinter plant off-gas is usually de-dusted by electrostatic precipitators. Compliance with the dust emission limits is often difficult because of the high specific resistivity of the emitted dust. Mechanical properties of the dust are also relevant for the electrostatic precipitator design. Dust samples from the four consecutive electrostatic precipitator fields were characterized in this study. Most measured parameters showed a considerable variation in the various dust samples. The particle size of the dust as well as its bulk density continuously decreased from the first field to the fourth field. The flowability of the dusts was generally bad and decreased from the first to the last field. In contrast, the wall friction angles with structural steel were quite constant at approximately 30 degrees . The Fe content was lower in the dust from the last two fields while the concentration of K, Na, Cl(-) and [Formula: see text] was significantly higher. At the same time the particle density was lower. The maximum specific dust resistivity for the first field and second field dust was approximately 3 * 10(11) Omega cm and no signs for the occurrence of back corona were detected. For the dusts from the last two fields the maximum value was approximately 2 * 10(12) Omega cm. Back corona was observed in the temperature range from 120 degrees C to 210 degrees C. In this area the dust resistivity values were higher than 4 * 10(11) Omega cm. PMID- 26582544 TI - Haemodynamic analysis of femoral artery bifurcation models under different physiological flow waveforms. AB - Thrombus in a femoral artery may form under stagnant flow conditions which vary depending on the local arterial waveform. Four different physiological flow waveforms - poor (blunt) monophasic, sharp monophasic, biphasic and triphasic - can exist in the femoral artery as a result of different levels of peripheral arterial disease progression. This study aims to examine the effect of different physiological waveforms on femoral artery haemodynamics. In this regard, a fluid structure interaction analysis was carried out in idealised models of bifurcated common femoral artery. The results showed that recirculation zones occur in almost all flow waveforms; however, the sites at where these vortices are initiated, the size and structure of vortices are highly dependent on the type of flow waveform being used. It was shown that the reverse diastolic flow in biphasic and triphasic waveforms leads to the occurrence of a retrograde flow which aids in 'washout' of the disturbed flow regions. This may limit the likelihood of thrombus formation, indicating the antithrombotic role of retrograde flow in femoral arteries. Furthermore, our data revealed that the flow particles experience considerably higher residence time under blunt and sharp monophasic waveforms than under biphasic and triphasic waveforms. This confirms that the risk of atherothrombotic plaque initiation and development in femoral arteries is higher under blunt and sharp monophasic waveforms than under biphasic and triphasic flow waveforms. PMID- 26582545 TI - Single-Crystalline Ultrathin Nickel Nanosheets Array from In Situ Topotactic Reduction for Active and Stable Electrocatalysis. AB - Simultaneously synthesizing and structuring atomically thick or ultrathin 2D non precious metal nanocrystal may offer a new class of materials to replace the state-of-art noble-metal electrocatalysts; however, the synthetic strategy is the bottleneck which should be urgently solved. Here we report the synthesis of an ultrathin nickel nanosheet array (Ni-NSA) through in situ topotactic reduction from Ni(OH)2 array precursors. The Ni nanosheets showed a single-crystalline lamellar structure with only ten atomic layers in thickness and an exposed (111) facet. Combined with a superaerophobic (low bubble adhesive) arrayed structure the Ni-NSAs exhibited a dramatic enhancement on both activity and stability towards the hydrazine-oxidation reaction (HzOR) relative to platinum. Furthermore, the partial oxidization of Ni-NSAs in ambient atmosphere resulted in effective water-splitting electrocatalysts for the hydrogen-evolution reaction (HER). PMID- 26582547 TI - From richer to poorer: successful invasion by freshwater fishes depends on species richness of donor and recipient basins. AB - Evidence for the theory of biotic resistance is equivocal, with experiments often finding a negative relationship between invasion success and native species richness, and large-scale comparative studies finding a positive relationship. Biotic resistance derives from local species interactions, yet global and regional studies often analyze data at coarse spatial grains. In addition, differences in competitive environments across regions may confound tests of biotic resistance based solely on native species richness of the invaded community. Using global and regional data sets for fishes in river and stream reaches, we ask two questions: (1) does a negative relationship exist between native and non-native species richness and (2) do non-native species originate from higher diversity systems. A negative relationship between native and non native species richness in local assemblages was found at the global scale, while regional patterns revealed the opposite trend. At both spatial scales, however, nearly all non-native species originated from river basins with higher native species richness than the basin of the invaded community. Together, these findings imply that coevolved ecological interactions in species-rich systems inhibit establishment of generalist non-native species from less diverse communities. Consideration of both the ecological and evolutionary aspects of community assembly is critical to understanding invasion patterns. Distinct evolutionary histories in different regions strongly influence invasion of intact communities that are relatively unimpacted by human actions, and may explain the conflicting relationship between native and non-native species richness found at different spatial scales. PMID- 26582546 TI - Comparative immune responses against Psoroptes ovis in two cattle breeds with different susceptibility to mange. AB - The sheep scab mite, Psoroptes ovis, is a major problem in the beef cattle industry, especially in Belgian Blue (BB) cattle. This breed is naturally more predisposed to psoroptic mange but reasons for this high susceptibility remain unknown. Different immune responses could be a potential cause; thus in this study, the cutaneous immune response and in vitro cellular immune response after antigen re-stimulation were examined in naturally infested BB. Cytokine production in the skin and in circulating re-stimulated peripheral blood mononuclear cells (PBMC) demonstrated a mixed pro-inflammatory Th2/Th17 profile, with transcription of IL-4, IL-13, IL-6 and IL-17. Strong IL-17 up-regulation in the skin of BB was associated with an influx of eosinophils and other immune cells, potentially leading towards more severe symptoms. Virtually no changes in cutaneous IFN-gamma transcription were detected, while there was substantial IFN gamma up-regulation in re-stimulated PBMC from infested and uninfested animals, potentially indicating a role of this pro-inflammatory cytokine in the innate immune response. In Holstein-Friesian (HF) cattle, generally more resistant to P. ovis infection, a largely similar immunologic response was observed. Differences between HF and BB were the lack of cutaneous IL-17 response in infested HF and low transcription levels of IFN-gamma and high IL-10 transcription in re stimulated PBMC from both infested and uninfested animals. Further research is needed to identify potential cell sources and biological functions for these cytokines and to fully unravel the basis of this different breed susceptibility to P. ovis. PMID- 26582548 TI - Understanding the Solution and Solid-State Structures of Pd and Pt PSiP Pincer Supported Hydrides. AB - The PSiP pincer-supported complex ((Cy)PSiP)PdH [(Cy)PSiP = Si(Me)(2-PCy2-C6H4)2] has been implicated as a crucial intermediate in carboxylation of both allenes and boranes. At this stage, however, there is uncertainty regarding the exact structure of ((Cy)PSiP)PdH, especially in solution. Previously, both a Pd(II) structure with a terminal Pd hydride and a Pd(0) structure featuring an eta(2) silane have been proposed. In this contribution, a range of techniques were used to establish that ((Cy)PSiP)PdH and the related Pt species, ((Cy)PSiP)PtH, are true M(II) hydrides in both the solid state and solution. The single-crystal X ray structures of ((Cy)PSiP)MH (M = Pd and Pt) and the related species ((iPr)PSiP)PdH [(iPr)PSiP = Si(Me)(2-P(i)Pr2-C6H4)2] are in agreement with the presence of a terminal metal hydride, and the exact geometry of ((Cy)PSiP)PtH was confirmed using neutron diffraction. The (1)H and (29)Si{(1)H}NMR chemical shifts of ((Cy)PSiP)MH (M = Pd and Pt) are consistent with a structure containing a terminal hydride, especially when compared to the chemical shifts of related pincer-supported complexes. In fact, in this work, two general trends relating to the (1)H NMR chemical shifts of group 10 pincer-supported terminal hydrides were elucidated: (i) the hydride shift moves downfield from Ni to Pd to Pt and (ii) the hydride shift moves downfield with more trans-influencing pincer central donors. DFT calculations indicate that structures containing a M(II) hydride are lower in energy than the corresponding eta(2)-silane isomers. Furthermore, the calculated NMR chemical shifts of the M(II) hydrides using a relativistic four component methodology incorporating all significant scalar and spin-orbit corrections are consistent with those observed experimentally. Finally, in situ X ray absorption spectroscopy (XAS) was used to provide further support that ((Cy)PSiP)MH exist as M(II) hydrides in solution. PMID- 26582549 TI - Shoe heel abrasion and its possible biomechanical cause: a transversal study with infantry recruits. AB - BACKGROUND: Excessive shoe heel abrasion is of concern to patients and shoe manufacturers, but little scientific information is available about this feature and its possible causes. The purpose of this study was to relate this phenomenon with biomechanical factors that could predispose to shoe heel abrasion. METHODS: Ninety-seven recruits (median age 25) were enrolled in this study. Shoe abrasion was assessed manually with a metric plastic tape on the posterior part of the heel that comes in contact with the ground. The number of sprains, foot alignment, and calf muscle shortening (Silfverskiold test) was also assessed in order to relate it with shoe heel abrasion. After using our exclusion criteria, 86 recruits and 172 were considered for this study. RESULTS: The most common abrasion site was the lateral portion of the heel surface (50 %). Forty-four percent of the participants had neutral hind-foot alignment and 39 % had valgus alignment. Twenty-six (30 %) patients have had previous ankle or foot sprains. Neutral foot was related with less calf muscle shortening. On the other hand, valgus hind-foot alignment was more associated with Achilles shortening (p < 0.05). Patients with neutral alignment were associated with more uniform shoe heel abrasion and varus feet were associated with more central and lateral abrasion (p < 0.05). The pattern of shoe heel abrasion was not statistically related with calf muscle shortening nor with number of sprains. CONCLUSION: This study was able to correlate shoe heel abrasion with biomechanical causes (neutral alignment-uniform abrasion/varus alignment-central and lateral abrasion). More effort has to be done to continue evaluating outsole abrasion with its possible biomechanical cause in order to predict and treat possible associated injuries. PMID- 26582550 TI - Isotopic Scintigraphy Coupled With Computed Tomography for the Investigation of Intrathecal Baclofen Device Malfunction. AB - OBJECTIVE: To assess the potential use of indium-111 diethylenetriamine pentaacetic acid ((111)In-DTPA) scintigraphy coupled with computed tomography (CT) for the investigation of intrathecal baclofen (ITB) device malfunction. DESIGN: Retrospective study of a case series of patients. SETTING: Neurosurgical and physical and rehabilitation medicine departments. PARTICIPANTS: Patients (N=7) with reduced ITB effectiveness in whom prior conventional radiographs were inconclusive. INTERVENTION: Nine (111)In-DTPA scintigraphic studies and 8 CT scans. Planar acquisitions were followed by tomoscintigraphy combined with CT. MAIN OUTCOME MEASURE: Progression of the radiotracer in the pump, catheters, and in the subarachnoid space. RESULTS: In 7 cases, scintigraphy coupled with CT showed leakage behind the pump, lack of activity outside the pump reservoir, abrupt interruption of activity in the catheter, or abnormal distribution of the radiotracer, thus demonstrating that the drug did not reach its target. Surgical revision confirmed these findings in 5 cases. In 1 case, combined imagery ruled out device dysfunction. In the remaining case, only planar acquisitions were performed, showing correct diffusion of the radiotracer. CONCLUSIONS: The combination of scintigraphy and CT provides simultaneous functional and anatomic imagery of the device. The slow infusion of the radioisotope mimics the diffusion of baclofen, and this could be a useful method to explore intrathecal device malfunction. Further studies are required to compare scintigraphy coupled with CT, to radiopaque injection followed by fluoroscopy or CT. PMID- 26582551 TI - The Type III Secretion System (T3SS) is a Determinant for Rice-Endophyte Colonization by Non-Photosynthetic Bradyrhizobium. AB - Plant associations by bradyrhizobia have been detected not only in leguminous plants, but also in non-leguminous species including rice. Bradyrhizobium sp. SUTN9-2 was isolated from Aeschynomene americana L., which is a leguminous weed found in the rice fields of Thailand. This strain promoted the highest total rice (Oryza sativa L. cultivar Pathum Thani 1) dry weight among the endophytic bradyrhizobial strains tested, and was, thus, employed for the further characterization of rice-Bradyrhizobium interactions. Some known bacterial genes involved in bacteria-plant interactions were selected. The expression of the type III secretion component (rhcJ), type IV secretion component (virD4), and pectinesterase (peces) genes of the bacterium were up-regulated when the rice root exudate was added to the culture. When SUTN9-2 was inoculated into rice seedlings, the peces, rhcJ, virD4, and exopolysaccharide production (fliP) genes were strongly expressed in the bacterium 6-24 h after the inoculation. The gene for glutathione-S-transferase (gst) was slightly expressed 12 h after the inoculation. In order to determine whether type III secretion system (T3SS) is involved in bradyrhizobial infections in rice plants, wild-type SUTN9-2 and T3SS mutant strains were inoculated into the original host plant (A. americana) and a rice plant (cultivar Pathum Thani 1). The ability of T3SS mutants to invade rice tissues was weaker than that of the wild-type strain; however, their phenotypes in A. americana were not changed by T3SS mutations. These results suggest that T3SS is one of the important determinants modulating rice infection; however, type IV secretion system and peces may also be responsible for the early steps of rice infection. PMID- 26582552 TI - Sulphated Polysaccharide Isolated from the Seaweed Gracilaria caudata Exerts an Antidiarrhoeal Effect in Rodents. AB - Diarrhoea is a significant health problem for children in developing countries that causes more than 1 million deaths annually. This study aimed to evaluate the antidiarrhoeal effect of sulphated polysaccharide (PLS) from the alga Gracilaria caudata in rodents. For the evaluation, acute diarrhoea was induced in Wistar rats (150-200 g) by administration of castor oil (10 mg/kg). Then, different parameters, including enteropooling and gastrointestinal transit and its pharmacological modulation by opioid and cholinergic pathways, were assessed using activated charcoal in Swiss Mice (25-30 g). Secretory diarrhoea was examined using cholera toxin (CT) (1 mg/loop)-treated, isolated intestinal loops from Swiss mice (25-30 g), which were also used to examine fluid secretion, loss of chloride ions into the intestinal lumen and absorption. In addition, a GM1 dependent ELISA was used to evaluate the interaction between PLS, CT and the GM1 receptor. Pre-treatment with PLS (10, 30 and 90 mg/kg) reduced faecal mass, diarrhoeal faeces and enteropooling. However, 90 mg/kg more effectively reduced these symptoms; therefore, it was used as the standard dose in subsequent experiments. Gastrointestinal transit was also reduced by PLS treatment via a cholinergic mechanism. Regarding the diarrhoea caused by CT, PLS reduced all study parameters, and the ELISA showed that PLS can interact with both the GM1 receptor and CT. These results show that PLS from G. caudata effectively improved the parameters observed in acute and secretory diarrhoea, which affects millions of people, and may lead to the development of a new alternative therapy for this disease. PMID- 26582553 TI - Phosphate toxicity: a stealth biochemical stress factor? PMID- 26582555 TI - Arterial Stiffness: Good Predictor for Hypertensive Patients. PMID- 26582554 TI - Enhanced growth of influenza A virus by coinfection with human parainfluenza virus type 2. AB - It has been reported that dual or multiple viruses can coinfect epithelial cells of the respiratory tract. However, little has been reported on in vitro interactions of coinfected viruses. To explore how coinfection of different viruses affects their biological property, we examined growth of influenza A virus (IAV) and human parainfluenza virus type 2 (hPIV2) during coinfection of Vero cells. We found that IAV growth was enhanced by coinfection with hPIV2. The enhanced growth of IAV was not reproduced by coinfection with an hPIV2 mutant with reduced cell fusion activity, or by ectopic expression of the V protein of hPIV2. In contrast, induction of cell fusion by ectopic expression of the hPIV2 HN and F proteins augments IAV growth. hPIV2 coinfection supported IAV growth in cells originated from the respiratory epithelium. The enhancement correlated closely with cell fusion ability of hPIV2 in those cells. These results indicate that cell fusion induced by hPIV2 infection is beneficial to IAV replication and that enhanced viral replication by coinfection with different viruses can modify their pathological consequences. PMID- 26582556 TI - Magnesium Deficiency and Proton-Pump Inhibitor Use: A Clinical Review. AB - The association of proton-pump inhibitor (PPI) use and hypomagnesemia has garnered much attention over the last 5 years. A large body of observational data has linked chronic PPI use with hypomagnesemia, presumably due to decreased intestinal absorption and consequent magnesium deficiency. However, despite the increasing prevalence of this highly popular class of medicine, and despite potential significant risks associated with magnesium depletion, including cardiac arrhythmias and seizures, there are no well-designed studies to delineate the nature of this observed association. Consequently, providers must use best judgment to inform clinical decision making. This review summarizes the current body of evidence linking PPI use with hypomagnesemia, acknowledges the possibility of significant residual confounding in the observational data, explains potential physiologic mechanisms, and offers clinical recommendations. PMID- 26582557 TI - Visual short-term memory deficits in REM sleep behaviour disorder mirror those in Parkinson's disease. AB - Individuals with REM sleep behaviour disorder are at significantly higher risk of developing Parkinson's disease. Here we examined visual short-term memory deficits--long associated with Parkinson's disease--in patients with REM sleep behaviour disorder without Parkinson's disease using a novel task that measures recall precision. Visual short-term memory for sequentially presented coloured bars of different orientation was assessed in 21 patients with polysomnography proven idiopathic REM sleep behaviour disorder, 26 cases with early Parkinson's disease and 26 healthy controls. Three tasks using the same stimuli controlled for attentional filtering ability, sensorimotor and temporal decay factors. Both patients with REM sleep behaviour disorder and Parkinson's disease demonstrated a deficit in visual short-term memory, with recall precision significantly worse than in healthy controls with no deficit observed in any of the control tasks. Importantly, the pattern of memory deficit in both patient groups was specifically explained by an increase in random responses. These results demonstrate that it is possible to detect the signature of memory impairment associated with Parkinson's disease in individuals with REM sleep behaviour disorder, a condition associated with a high risk of developing Parkinson's disease. The pattern of visual short-term memory deficit potentially provides a cognitive marker of 'prodromal' Parkinson's disease that might be useful in tracking disease progression and for disease-modifying intervention trials. PMID- 26582558 TI - Human autoantibodies to amphiphysin induce defective presynaptic vesicle dynamics and composition. AB - Stiff-person syndrome is the prototype of a central nervous system disorder with autoantibodies targeting presynaptic antigens. Patients with paraneoplastic stiff person syndrome may harbour autoantibodies to the BAR (Bin/Amphiphysin/Rvs) domain protein amphiphysin, which target its SH3 domain. These patients have neurophysiological signs of compromised central inhibition and respond to symptomatic treatment with medication enhancing GABAergic transmission. High frequency neurotransmission as observed in tonic GABAergic interneurons relies on fast exocytosis of neurotransmitters based on compensatory endocytosis. As amphiphysin is involved in clathrin-mediated endocytosis, patient autoantibodies are supposed to interfere with this function, leading to disinhibition by reduction of GABAergic neurotransmission. We here investigated the effects of human anti-amphiphysin autoantibodies on structural components of presynaptic boutons ex vivo and in vitro using electron microscopy and super-resolution direct stochastic optical reconstruction microscopy. Ultrastructural analysis of spinal cord presynaptic boutons was performed after in vivo intrathecal passive transfer of affinity-purified human anti-amphiphysin autoantibodies in rats and revealed signs of markedly disabled clathrin-mediated endocytosis. This was unmasked at high synaptic activity and characterized by a reduction of the presynaptic vesicle pool, clathrin coated intermediates, and endosome-like structures. Super-resolution microscopy of inhibitory GABAergic presynaptic boutons in primary neurons revealed that specific human anti-amphiphysin immunoglobulin G induced an increase of the essential vesicular protein synaptobrevin 2 and a reduction of synaptobrevin 7. This constellation suggests depletion of resting pool vesicles and trapping of releasable pool vesicular proteins at the plasma membrane. Similar effects were found in amphiphysin deficient neurons from knockout mice. Application of specific patient antibodies did not show additional effects. Blocking alternative pathways of clathrin independent endocytosis with brefeldin A reversed the autoantibody induced effects on molecular vesicle composition. Endophilin as an interaction partner of amphiphysin showed reduced clustering within presynaptic terminals. Collectively, these results point towards an autoantibody-induced structural disorganization in GABAergic synapses with profound changes in presynaptic vesicle pools, activation of alternative endocytic pathways, and potentially compensatory rearrangement of proteins involved in clathrin-mediated endocytosis. Our findings provide novel insights into synaptic pathomechanisms in a prototypic antibody-mediated central nervous system disease, which may serve as a proof-of-principle example in this evolving group of autoimmune disorders associated with autoantibodies to synaptic antigens. PMID- 26582560 TI - Gonococcal Osteomyelitis Resulting in Permanent Sequelae. PMID- 26582559 TI - Different decision deficits impair response inhibition in progressive supranuclear palsy and Parkinson's disease. AB - Progressive supranuclear palsy and Parkinson's disease have distinct underlying neuropathology, but both diseases affect cognitive function in addition to causing a movement disorder. They impair response inhibition and may lead to impulsivity, which can occur even in the presence of profound akinesia and rigidity. The current study examined the mechanisms of cognitive impairments underlying disinhibition, using horizontal saccadic latencies that obviate the impact of limb slowness on executing response decisions. Nineteen patients with clinically diagnosed progressive supranuclear palsy (Richardson's syndrome), 24 patients with clinically diagnosed Parkinson's disease and 26 healthy control subjects completed a saccadic Go/No-Go task with a head-mounted infrared saccadometer. Participants were cued on each trial to make a pro-saccade to a horizontal target or withhold their responses. Both patient groups had impaired behavioural performance, with more commission errors than controls. Mean saccadic latencies were similar between all three groups. We analysed behavioural responses as a binary decision between Go and No-Go choices. By using Bayesian parameter estimation, we fitted a hierarchical drift-diffusion model to individual participants' single trial data. The model decomposes saccadic latencies into parameters for the decision process: decision boundary, drift rate of accumulation, decision bias, and non-decision time. In a leave-one-out three way classification analysis, the model parameters provided better discrimination between patients and controls than raw behavioural measures. Furthermore, the model revealed disease-specific deficits in the Go/No-Go decision process. Both patient groups had slower drift rate of accumulation, and shorter non-decision time than controls. But patients with progressive supranuclear palsy were strongly biased towards a pro-saccade decision boundary compared to Parkinson's patients and controls. This indicates a prepotency of responding in combination with a reduction in further accumulation of evidence, which provides a parsimonious explanation for the apparently paradoxical combination of disinhibition and severe akinesia. The combination of the well-tolerated oculomotor paradigm and the sensitivity of the model-based analysis provides a valuable approach for interrogating decision-making processes in neurodegenerative disorders. The mechanistic differences underlying participants' poor performance were not observable from classical analysis of behavioural data, but were clearly revealed by modelling. These differences provide a rational basis on which to develop and assess new therapeutic strategies for cognition and behaviour in these disorders. PMID- 26582561 TI - Evolutionary Study of Birds' Sense of Smell Reveals Important Clues for Behavior and Adaptation. PMID- 26582563 TI - Percutaneous delivery of alpha-melanocyte-stimulating hormone for the treatment of imiquimod-induced psoriasis. AB - PURPOSE: alpha-Melanocyte-stimulating hormone (alpha-MSH) is an endogenous peptide hormone with anti-inflammatory responses. We developed topical formulation(s) of alpha-MSH to reduce psoriasis-related inflammation. METHODS: Transcutol (TC) and n-methyl 2-pyrrolidone (NMP) were used to formulate a gel for alpha-MSH. Skin permeation and dermal microdialysis of the solution and optimized gel were performed. The inflammatory response of alpha-MSH gel was investigated in imiquimod-induced psoriasis mouse model. Histology and immunohistochemistry were then performed on treated skin. RESULTS: Solution comprising 50%w/w TC and 10%w/w NMP showed higher (p < 0.05) skin retention (0.27 +/- 0.024 ug of alpha MSH/mg of skin) than solutions containing either 50% w/w TC or 10% w/w NMP at 24 h. Dispersion of alpha-MSH in Carbopol Ultrez 10 produced a uniform dispersion. alpha-MSH gel showed pseudoplastic flow with thixotropic behavior. Dermal microdialysis results suggested that skin permeation of gel after 5 h was 1.9 folds higher than the solution. Further, gel-treated psoriatic-like plaque skin sections showed significant (p < 0.05) decrease in the expression of a melanocortin receptor, in the psoriasis area and severity index score and transepidermal water loss compared to the solution. CONCLUSION: TC, NMP and Carbopol Ultrez 10 form a stable gel with improved skin permeation of alpha-MSH for a reduction in psoriasis-associated inflammation. PMID- 26582564 TI - Maternal serum soluble fms-like tyrosine kinase-1 at 12, 22, 32 and 36 weeks' gestation in screening for pre-eclampsia. AB - OBJECTIVE: To examine the distribution of maternal serum soluble fms-like tyrosine kinase-1 (sFlt-1) at 12, 22, 32 and 36 weeks' gestation in singleton pregnancies that develop pre-eclampsia (PE) and examine the performance of this biomarker in screening for PE. METHODS: Serum sFlt-1 was measured in 7066 cases at 11-13 weeks, 8079 cases at 19-24 weeks, 8472 at 30-34 weeks and 4043 at 35-37 weeks. Bayes' theorem was used to combine the a-priori risk from maternal characteristics and medical history with serum levels of sFlt-1. The performance of screening for PE in women requiring delivery < 32, between 32 + 0 and 36 + 6 and >= 37 weeks' gestation was estimated. RESULTS: In pregnancies that developed PE, serum sFlt-1 was increased and the separation in multiples of the median (MoM) values from normal was greater with earlier, compared to later, gestational age at which delivery for PE became necessary. In pregnancies that developed PE, the slope of the regression lines of sFlt-1 MoM with gestational age at delivery increased with advancing gestational age at screening. Measurement of sFlt-1 at 11-13 weeks did not improve the prediction of PE achieved by maternal factors alone, sFlt-1 at 19-24 weeks improved the prediction of PE delivering < 37 weeks but not for PE delivering >= 37 weeks, sFlt-1 at 30-34 weeks improved the prediction of PE delivering < 37 and PE delivering >= 37 weeks and sFlt-1 at 35 37 weeks improved the prediction of PE delivering >= 37 weeks. The detection rates (DRs), at a false-positive rate (FPR) of 10%, of PE delivering < 32 weeks were 52% and 65% with screening at 12 and 22 weeks, respectively. The DRs for PE delivering between 32 + 0 and 36 + 6 weeks were 44%, 44% and 93% with screening at 12, 22 and 32 weeks. The DR for PE delivering >= 37 weeks were 37%, 37%, 52% and 69% with screening at 12, 22, 32 and 36 weeks, respectively. CONCLUSIONS: The performance of combined screening with maternal factors, medical history and serum sFlt-1 is superior for detection of early, compared to late, PE and improves with advancing gestational age at screening. Copyright (c) 2015 ISUOG. Published by John Wiley & Sons Ltd. PMID- 26582562 TI - Signatures of Evolutionary Adaptation in Quantitative Trait Loci Influencing Trace Element Homeostasis in Liver. AB - Essential trace elements possess vital functions at molecular, cellular, and physiological levels in health and disease, and they are tightly regulated in the human body. In order to assess variability and potential adaptive evolution of trace element homeostasis, we quantified 18 trace elements in 150 liver samples, together with the expression levels of 90 genes and abundances of 40 proteins involved in their homeostasis. Additionally, we genotyped 169 single nucleotide polymorphism (SNPs) in the same sample set. We detected significant associations for 8 protein quantitative trait loci (pQTL), 10 expression quantitative trait loci (eQTLs), and 15 micronutrient quantitative trait loci (nutriQTL). Six of these exceeded the false discovery rate cutoff and were related to essential trace elements: 1) one pQTL for GPX2 (rs10133290); 2) two previously described eQTLs for HFE (rs12346) and SELO (rs4838862) expression; and 3) three nutriQTLs: The pathogenic C282Y mutation at HFE affecting iron (rs1800562), and two SNPs within several clustered metallothionein genes determining selenium concentration (rs1811322 and rs904773). Within the complete set of significant QTLs (which involved 30 SNPs and 20 gene regions), we identified 12 SNPs with extreme patterns of population differentiation (FST values in the top 5% percentile in at least one HapMap population pair) and significant evidence for selective sweeps involving QTLs at GPX1, SELENBP1, GPX3, SLC30A9, and SLC39A8. Overall, this detailed study of various molecular phenotypes illustrates the role of regulatory variants in explaining differences in trace element homeostasis among populations and in the human adaptive response to environmental pressures related to micronutrients. PMID- 26582565 TI - PET/MRI and PET/CT: is there room for both at the top of the food chain? PMID- 26582566 TI - Correlation between theoretical anatomical patterns of lymphatic drainage and lymphoscintigraphy findings during sentinel node detection in head and neck melanomas. AB - PURPOSE: In the diagnosis of head and neck melanoma, lymphatic drainage is complex and highly variable. As regional lymph node metastasis is one of the most important prognostic factors, lymphoscintigraphy can help map individual drainage patterns. The aim of this study was to compare the results of lymphoscintigraphy and sentinel lymph node (SLN) detection with theoretical anatomical patterns of lymphatic drainage based on the location of the primary tumour lesion in patients with head and neck melanoma. We also determined the percentage of discrepancies between our lymphoscintigraphy and the theoretical location of nodal drainage predicted by a large lymphoscintigraphic database, in order to explain recurrence and false-negative SLN biopsies. METHODS: In this retrospective study of 152 patients with head and neck melanoma, the locations of the SLNs on lymphoscintigraphy and detected intraoperatively were compared with the lymphatic drainage predicted by on-line software based on a large melanoma database. RESULTS: All patients showed lymphatic drainage and in all patients at least one SLN was identified by lymphoscintigraphy. Of the 152 patients, 4 had a primary lesion in areas that were not described in the Sydney Melanoma Unit database, so agreement could only be evaluated in 148 patients. Agreement between lymphoscintigraphic findings and the theoretical lymphatic drainage predicted by the software was completely concordant in 119 of the 148 patients (80.4 %, 95 % CI 73.3 - 86 %). However, this concordance was partial (some concordant nodes and others not) in 18 patients (12.2 %, 95 % CI 7.8 - 18.4 %). Discordance was complete in 11 patients (7.4 %, 95 % CI 4.2 - 12.8 %). CONCLUSION: In melanoma of the head and neck there is a high correlation between lymphatic drainage found by lymphoscintigraphy and the predicted drainage pattern and basins provided by a large reference database. Due to unpredictable drainage, preoperative lymphoscintigraphy is essential to accurately detect the SLNs in head and neck melanoma. PMID- 26582568 TI - Significant contribution of stacking faults to the strain hardening behavior of Cu-15%Al alloy with different grain sizes. AB - It is commonly accepted that twinning can induce an increase of strain-hardening rate during the tensile process of face-centered cubic (FCC) metals and alloys with low stacking fault energy (SFE). In this study, we explored the grain size effect on the strain-hardening behavior of a Cu-15 at.%Al alloy with low SFE. Instead of twinning, we detected a significant contribution of stacking faults (SFs) irrespective of the grain size even in the initial stage of tensile process. In contrast, twinning was more sensitive to the grain size, and the onset of deformation twins might be postponed to a higher strain with increasing the grain size. In the Cu-15 at.%Al alloy with a mean grain size of 47 MUm, there was a stage where the strain-hardening rate increases with strain, and this was mainly induced by the SFs instead of twinning. Thus in parallel with the TWIP effect, we proposed that SFs also contribute significantly to the plasticity of FCC alloys with low SFE. PMID- 26582567 TI - New perspectives in gaze sensitivity research. AB - Attending to where others are looking is thought to be of great adaptive benefit for animals when avoiding predators and interacting with group members. Many animals have been reported to respond to the gaze of others, by co-orienting their gaze with group members (gaze following) and/or responding fearfully to the gaze of predators or competitors (i.e., gaze aversion). Much of the literature has focused on the cognitive underpinnings of gaze sensitivity, namely whether animals have an understanding of the attention and visual perspectives in others. Yet there remain several unanswered questions regarding how animals learn to follow or avoid gaze and how experience may influence their behavioral responses. Many studies on the ontogeny of gaze sensitivity have shed light on how and when gaze abilities emerge and change across development, indicating the necessity to explore gaze sensitivity when animals are exposed to additional information from their environment as adults. Gaze aversion may be dependent upon experience and proximity to different predator types, other cues of predation risk, and the salience of gaze cues. Gaze following in the context of information transfer within social groups may also be dependent upon experience with group-members; therefore we propose novel means to explore the degree to which animals respond to gaze in a flexible manner, namely by inhibiting or enhancing gaze following responses. We hope this review will stimulate gaze sensitivity research to expand beyond the narrow scope of investigating underlying cognitive mechanisms, and to explore how gaze cues may function to communicate information other than attention. PMID- 26582569 TI - Noninvasive dissection of mouse sleep using a piezoelectric motion sensor. AB - BACKGROUND: Changes in autonomic control cause regular breathing during NREM sleep to fluctuate during REM. Piezoelectric cage-floor sensors have been used to successfully discriminate sleep and wake states in mice based on signal features related to respiration and other movements. This study presents a classifier for noninvasively classifying REM and NREM using a piezoelectric sensor. NEW METHOD: Vigilance state was scored manually in 4-s epochs for 24-h EEG/EMG recordings in 20 mice. An unsupervised classifier clustered piezoelectric signal features quantifying movement and respiration into three states: one active; and two inactive with regular and irregular breathing, respectively. These states were hypothesized to correspond to Wake, NREM, and REM, respectively. States predicted by the classifier were compared against manual EEG/EMG scores to test this hypothesis. RESULTS: Using only piezoelectric signal features, an unsupervised classifier distinguished Wake with high (89% sensitivity, 96% specificity) and REM with moderate (73% sensitivity, 75% specificity) accuracy, but NREM with poor sensitivity (51%) and high specificity (96%). The classifier sometimes confused light NREM sleep - characterized by irregular breathing and moderate delta EEG power - with REM. A supervised classifier improved sensitivities to 90, 81, and 67% and all specificities to over 90% for Wake, NREM, and REM, respectively. COMPARISON WITH EXISTING METHODS: Unlike most actigraphic techniques, which only differentiate sleep from wake, the proposed piezoelectric method further dissects sleep based on breathing regularity into states strongly correlated with REM and NREM. CONCLUSIONS: This approach could facilitate large-sample screening for genes influencing different sleep traits, besides drug studies or other manipulations. PMID- 26582570 TI - Interrelationships between BMI, skinfold thicknesses, percent body fat, and cardiovascular disease risk factors among U.S. children and adolescents. AB - BACKGROUND: Although the estimation of body fatness by Slaughter skinfold thickness equations (PBF(Slaughter)) has been widely used, the accuracy of this method is uncertain. We have previously examined the interrelationships among the body mass index (BMI), PBF(Slaughter), percent body fat from dual energy X-ray absorptiometry (PBF(DXA)) and CVD risk factor levels among children who were examined in the Bogalusa Heart Study and in the Pediatric Rosetta Body Composition Project. The current analyses examine these associations among 7599 8 to 19-year-olds who participated in the (U.S.) National Health and Nutrition Examination Survey from 1999 to 2004. METHODS: We analyzed (1) the agreement between (1) estimates of percent body fat calculated from the Slaughter skinfold thickness equations and from DXA, and (2) the relation of lipid, lipoprotein, and blood pressure levels to BMI, PBF(Slaughter) and PBF(DXA). RESULTS: PBF(Slaughter) was highly correlated (r ~ 0.85) with PBF(DXA). However, among children with a relatively low skinfold thicknesses sum (triceps + subscapular), PBF(Slaughter) underestimated PBF(DXA) by 8 to 9 percentage points. In contrast, PBF(Slaughter) overestimated PBF(DXA) by 10 points among boys with a skinfold thickness sum >= 50 mm. After adjustment for sex and age, lipid levels were related similarly to the body mass index, PBF(DXA) and PBF(Slaughter). There were, however, small differences in associations with blood pressure levels: systolic blood pressure was more strongly associated with body mass index, but diastolic blood pressure was more strongly associated with percent body fat. CONCLUSIONS: The Slaughter equations yield biased estimates of body fatness. In general, lipid and blood pressure levels are related similarly to levels of BMI (following adjustment for sex and age), PBF(Slaughter,) and PBF(DXA). PMID- 26582571 TI - Modelling repeated competition records in genetic evaluations of Danish sport horses. AB - Genetic evaluations of sport performance typically consider competition records of ranking points in each competition, accumulated lifetime points or annual earnings. Repeated observations have the advantage of allowing for adjustment of effects associated with each competition such as rider experience, judge and competing horses, but also demands more computer capacity than single-trait records, which could prohibit multiple-trait evaluations. The aim of the study was to compare CPU times, estimated breeding values (EBVs), reliabilities and model prediction abilities when modelling repeated competition ranking points (run A), mean ranking points (runs B and C), mean ranking points precorrected for effects associated with each competition (run D) and accumulated lifetime points (run E) for Danish Warmblood horses. CPU times for run A were 632-776 times (show jumping) and 59-96 times (dressage) as high as for runs B-E. EBVs of run D were perfectly correlated (1.00) with those of run A. Reliabilities were highest in runs E and A. Best model prediction ability and least bias were found in run C (dressage) and run E (show jumping), but the best choice in each discipline was not preferable for the other. Run D was the second best in both disciplines (D), and is expected to increase in performance over time as omission of a relatively large amount of historic data becomes less important. PMID- 26582572 TI - Safety and efficacy of second-generation versus first-generation cryoballoons for treatment of atrial fibrillation: a meta-analysis of current evidence. AB - BACKGROUND: The newer second-generation cryoballoons (CB-2 or Arc-Adv-CB) have been shown to achieve significantly lower temperature and faster pulmonary vein isolation (PVI) time in comparison with first-generation cryoballoons (CB-1 or Arc-CB). To test the premise that second-generation cryoballoons can improve clinical outcomes in comparison to first-generation cryoballoons in terms of safety and efficacy, we pooled data for systemic review and meta-analyses from all available literature comparing their clinical performance. METHODS: The Cochrane Library, PubMed, Google Scholar, and studies presented at various meetings were searched for any published literature comparing safety and efficacy of the second-generation cryoballoons (Arctic Front Advance cryoballoons) with first-generation cryoballoons (Arctic Front Cryoballoons). A total of ten published studies, with 2310 patients, were included in this meta-analysis with 957 patients in second-generation cryoballoon group and 1237 patients in first generation cryoballoon group. RESULTS: The pooled analysis showed significant superiority of second-generation cryoballoons in terms of less procedure time, less fluoroscopic time, and fewer incidences of arrhythmia recurrences compared to first-generation cryoballoons at the cost of higher incidence of persistent and transient phrenic nerve palsy. The differences in the rate of pericardial effusion and incidence of access site complications were not statistically significant. CONCLUSIONS: Second-generation cryoballoons are associated with a shorter procedure time and fluoroscopy time, along with lower arrhythmia recurrence rates, reflecting higher procedure efficacy when compared to first generation cryoballoons. However, they are also associated with a higher incidence of transient and persistent phrenic nerve palsies with a non significant difference in rates of access site complications and pericardial effusion. PMID- 26582574 TI - Novel Features of DAG-Activated PKC Isozymes Reveal a Conserved 3-D Architecture. AB - Diacylglycerol (DAG) activates the eight conventional and novel isozymes of protein kinase C (PKC) by binding to their C1 domains. The crystal structure of PKCbetaII in a partially activated conformation showed how the C1B domain regulates activity by clamping a helix in the C-terminal AGC extension of the kinase domain. Here we show that the global three-dimensional shape of the conventional and novel PKCs is conserved despite differences in the order of the domains in their primary sequences. The membrane translocation phenotypes of mutants in the C1B clamp are consistent across all DAG-activated PKCs, demonstrating conservation of this regulatory interface. We now identify a novel interface that sequesters the C1A domain in PKCbetaII in a membrane-inaccessible state and we generalize this to all DAG-activated PKCs. In the conventional PKCs, we identify a novel element of their C2 domains that additionally contributes to the stability of the inactive conformation. We demonstrate that the interdomain linkers play important roles in permitting and stabilizing this state. We propose a multi-step activation mechanism in which the sequential and cooperative binding of the regulatory domains to the membrane is coupled to allosteric activation of the kinase domain by DAG and that acquisition of full catalytic activity requires DAG binding to the C1B domain. In light of the conservation of shape and intramolecular architecture, we propose that this mechanism is common to all DAG activated PKCs. PMID- 26582573 TI - Upregulation of microRNA-96 and its oncogenic functions by targeting CDKN1A in bladder cancer. AB - BACKGROUND: Genome-wide miRNA expression profile has identified microRNA (miR)-96 as one of upregulated miRNAs in clinical bladder cancer (BC) tissues compared to normal bladder tissues. The aim of this study was to confirm the expression pattern of miR-96 in BC tissues and to investigate its involvement in carcinogenesis. METHODS: Quantitative real-time PCR was performed to detect the expression levels of miR-96 in 60 BC and 40 normal control tissues. Bioinformatics prediction combined with luciferase reporter assay were used to verify whether the cyclin-dependent kinase inhibitor CDKN1A was a potential target gene of miR-96. Cell counting kit-8 and apoptosis assays were further performed to evaluate the effects of miR-96-CDKN1A axis on cell proliferation and apoptosis of BC cell lines. RESULTS: We validated that miR-96 was significantly increased in both human BC tissues and cell lines. According to the data of miRTarBase, CDKN1A might be a candidate target gene of miR-96. In addition, luciferase reporter and Western blot assays respectively demonstrated that miR-96 could bind to the putative seed region in CDKN1A mRNA 3'UTR, and significantly reduce the expression level of CDKN1A protein. Moreover, we found that the inhibition of miR-96 expression remarkably decreased cell proliferation and promoted cell apoptosis of BC cell lines, which was consistent with the findings observed following the introduction of CDKN1A cDNA without 3'UTR restored miR-96. CONCLUSIONS: Our data reveal that miR-96 may function as an onco-miRNA in BC. Upregulation of miR-96 may contribute to aggressive malignancy partly through suppressing CDKN1A protein expression in BC cells. PMID- 26582575 TI - Total Hip Arthroplasty Using the S-ROM-A Prosthesis for Anatomically Difficult Asian Patients. AB - BACKGROUND: The S-ROM-A prosthesis has been designed for the Asian proximal femur with a small deformed shape and narrow canal. In this study, the clinical and radiological results using the S-ROM-A prosthesis for Japanese patients with severe deformity due to dysplasia and excessive posterior pelvic tilt were examined. METHODS: 94 hips were followed up for a mean of 55 months, with a mean age at surgery of 61 years. The primary diagnoses were 94 coxarthritis cases, including 51 dysplasia and 37 primary OA, 1 avascular necrosis, 2 traumatic arthritis, and 3 Perthes disease. Thirty-one hips had been treated with osteotomy of the hip joints. Preoperative intramedullary canal shapes were stovepipe in 23 hips, normal in 51 hips, and champagne-flute in 5 hips. The maximum pelvic inclination angle was 56 degrees . RESULTS: The mean JOA score improved from 46 points preoperatively to 80 points at final follow-up. On radiological evaluation of the fixation of the implants according to the Engh classification, 92 (97%) hips were classified as "bone ingrown fixation." CONCLUSION: In primary THA, using the S-ROM-A prosthesis for Asian patients with proximal femoral deformity, even after osteotomy and with posterior pelvic tilt, provided good short- to midterm results. PMID- 26582576 TI - Identification and quantification of 56 targeted phenols in wines, spirits, and vinegars by online solid-phase extraction - ultrahigh-performance liquid chromatography - quadrupole-orbitrap mass spectrometry. AB - Phenolic compounds seriously affect the sensory and nutritional qualities of food products, both through the positive contribution of wood transfer in barrel-aged products and as off-flavours. A new targeted analytical approach combining on line solid-phase extraction (SPE) clean-up to reduce matrix interference and rapid chromatographic detection performed with ultrahigh-performance liquid chromatography coupled with quadrupole/high-resolution mass spectrometry (Q Orbitrap), was developed for the quantification of 56 simple phenols. Considering the advantages of using on-line SPE and a resolving power of 140,000, the proposed method was applied to define phenolic content in red (N=8) and white (8) wines, spirits (8), common (8) and balsamic (8) vinegars. The final method was linear from the limits of quantification (0.0001-0.001MUgmL(-1)) up to 10MUgmL( 1) with R(2) of at least 0.99. Recovery, used to define method accuracy, ranged from 80 to 120% for 89% of compounds. The method was suitable for analytical requirements in the tested matrices being able to analyse 46 phenols in red wines, 41 phenols in white wines and in spirits, 42 phenols in common vinegars and 44 phenols in balsamic vinegars. PMID- 26582577 TI - Proteome analysis of male accessory gland secretions in oriental fruit flies reveals juvenile hormone-binding protein, suggesting impact on female reproduction. AB - In insects, the accessory gland proteins (Acps) secreted by male accessory glands (MAGs) account for the majority of seminal fluids proteins. Mixed with sperm, they are transferred to the female at mating and so impact reproduction. In this project, we identified 2,927 proteins in the MAG secretions of the oriental fruit fly Bactrocera dorsalis, an important agricultural pest worldwide, using LC-MS analysis, and all sequences containing open reading frames were analyzed using signalP. In total, 90 Acps were identified. About one third (26) of these 90 Acps had a specific functional description, while the other two thirds (64) had no functional description including dozens of new classes of proteins. Hence, several of these novel Acps were abundant in the MAG secretions, and we confirmed their MAG-specific expression by qPCR. Finally and interestingly, one of these novel proteins was functionally predicted as juvenile hormone-binding protein, suggesting the impact of Acps with reproductive events in the female. Our results will aid in the development of an experimental method to identify Acps in insects, and in turn this information with new Acps in B. dorsalis will pave the way of further exploration their function in reproduction and potential development as new insecticide targets. PMID- 26582578 TI - Increased dietary levels of alpha-linoleic acid inhibit mammary tumor growth and metastasis. AB - OBJECTIVE: The aim of this study was to determine whether alpha-linolenic acid (ALA omega-3 fatty acid) enriched diet affects growth parameters when applied to a syngeneic model of mammary carcinoma. MATERIALS AND METHODS: BALB/c mice were divided and fed with: 1) a chia oil diet, rich in ALA or 2) a corn oil diet, rich in linoleic acid (LA omega-6 fatty acid). Mice were subcutaneously inoculated with a tumor cell line LM3, derived from a murine mammary adenocarcinoma. RESULTS: After 35 days, tumor incidence, weight, volume and metastasis number were lower in the ALA-fed mice, while tumor latency time was higher, and the release of pro-tumor metabolites derived from omega-6 fatty acids decreased in the tumor. Compared to the control group, a lower number of mitosis, a higher number of apoptotic bodies and higher T-lymphocyte infiltration were consistently observed in the ALA group. An ALA-rich diet decreased the estrogen receptor (ER) alpha expression, a recognized breast cancer promotor while showing an opposite effect on ERbeta in tumor lysates. CONCLUSION: These data support the anticancer effect of an ALA-enriched diet, which might be used as a dietary strategy in breast cancer prevention. PMID- 26582579 TI - Efficacy and safety of a natural mineral water rich in magnesium and sulphate for bowel function: a double-blind, randomized, placebo-controlled study. AB - PURPOSE: The present placebo-controlled, double-blind, randomized trial aimed to investigate whether a natural mineral water rich in magnesium sulphate and sodium sulphate (Donat Mg) may help to improve bowel function. METHODS: A total of 106 otherwise healthy subjects with functional constipation were randomly assigned to consume 300 or 500 mL of a natural mineral water as compared to placebo water, over a course of 6 weeks. The 300-mL arms were terminated due to the results of a planned interim analysis. Subjects documented the complete spontaneous bowel movements, spontaneous and overall bowel movements/week, stool consistency, gastrointestinal symptoms and general well-being in a diary. Change in the number of complete spontaneous bowel movements was defined as the primary outcome. RESULTS: For the 75 subjects in the 500-mL arms, the change in the number of complete spontaneous bowel movements per week tended to be higher in the active group when compared to placebo after 6 weeks (T2 = 1.8; p value = 0.036; one sided). The mean number of spontaneous bowel movements significantly increased over the course of the study, with significant differences between study arms considering the whole study time (F test = 4.743; p time * group = 0.010, 2 sided). Stool consistency of spontaneous bowel movements (p < 0.001) and the subjectively perceived symptoms concerning constipation (p = 0.005) improved significantly with the natural mineral water as compared to placebo. CONCLUSIONS: The daily consumption of a natural mineral water rich in magnesium sulphate and sodium sulphate improved bowel movement frequency and stool consistency in subjects with functional constipation. Moreover, the subjects' health-related quality of life improved. CLINICAL TRIAL REGISTRATION: EudraCT No 2012-005130-11. PMID- 26582580 TI - Muscle-specific deletion of signal transducer and activator of transcription 5 augments lipid accumulation in skeletal muscle and liver of mice in response to high-fat diet. AB - PURPOSE: Growth hormone (GH) controls liver metabolism through the transcription factor signal transducer and activator of transcription 5 (STAT5). However, it remains to be fully understood to what extent other GH/STAT5 target tissues contribute to lipid and glucose metabolism. This question was now addressed in muscle-specific STAT5 knockout (STAT5 MKO) mice model. METHODS: Changes in lipid and glucose metabolism were investigated at physiological and molecular levels in muscle and liver tissues of STAT5 MKO mice under normal diet or high-fat diet (HFD) conditions. RESULTS: STAT5 MKO mice exhibited an increased intramyocellular lipid (IMCL) accumulation in the quadriceps in HFD group. Decreased lipolytic hormone-sensitive lipase transcript levels may contribute to the increased IMCL accumulation in STAT5 MKO mice. STAT5 MKO induced hepatic lipid accumulation without deregulated STAT5 signaling. The upregulation of lipoprotein lipase and Cd36 mRNA levels, an increased trend of very low-density lipoprotein receptor mRNA levels, and elevated circulating concentrations of free fatty acid, triglyceride, and total cholesterol support the increase in hepatic lipid accumulation. CONCLUSIONS: STAT5 MKO in conjunction with a HFD deregulated both lipid and glucose metabolism in skeletal muscle, and this deregulation induced hepatic fat accumulation via increased circulating glucose, FFA, and TG concentrations. Our study emphasizes that muscle-specific STAT5 signaling is important for balancing lipid and glucose metabolism in peripheral tissues, including muscle and liver and that the deregulation of local STAT5 signaling augments HFD-induced lipid accumulation in both muscle and liver. PMID- 26582582 TI - Canadian connective tissue conference London, Ontario: an editorial. PMID- 26582581 TI - Finding a Place for Systems-Based, Collaborative Research in Emerging Disease Research in Asia. AB - The need to adequately predict, prevent and respond to infectious diseases emerging unexpectedly from human-animal-environmental systems has driven interest in multisectoral, socio-economic, systems-based, collaborative (MSC) research approaches such as EcoHealth and One Health. Our goals were to document how MSC research has been used to address EIDs in Asia, and to explore how MSC approaches align with current priorities for EID research in Asia. We gathered priorities for EID research from the peer-reviewed and grey literature, documented organizational descriptions of MCS research approaches, and analysed a series of EID MSC projects. We found that priority areas for EID research in Asia included (1) understanding host-pathogen-environment interactions; (2) improving tools and technologies; (3) changing people's behaviour; and (4) evaluating the effectiveness of interventions. We found that the unifying characteristics of MSC research were that it was action-oriented and sought to inspire change under real world conditions at the complex interface of human and natural systems. We suggest that MSC research can be considered a type of 'pragmatic research' and might be most useful in describing change in complex human-animal-environmental systems, accelerating research-to-action, and evaluating effectiveness of interventions in 'real world' settings. PMID- 26582583 TI - Subcellular localization of EGFR in esophageal carcinoma cell lines. AB - BACKGROUND: The EGF receptor is a therapeutic target in cancer cells, whereby mutations of EGFR and/or signalling members act as predictive markers. EGFR however also exhibits dynamic changes of subcellular localization, leading to STAT5 complex formation, nuclear translocation and induction of Aurora-A expression in squamous cancer cells. We previously described high EGFR and Aurora A expression in esophageal cancer cells. Here, we investigated subcellular localization of EGFR and STAT5 in esophageal cancer cells. RESULTS: Quantitative immunofluorescence analyses of four esophageal cancer cell lines reflecting esophageal squamous cell carcinomas (ESCC) and esophageal adenocarcinomas (EAC) revealed that the subcellular localization of EGFR was shifted from a membranous to cytoplasmic localization upon EGF-stimulation in OE21 (ESCC) cells. Thereby, EGFR in part co-localized with E-Cadherin. In parallel, phosphorylated STAT5 Tyr694 appeared to increase in the nucleus and to decrease at the cell membrane. In three additional cell lines, EGFR was only marginally (Kyse-410/ESCC; OE19/EAC) and weakly (OE33, EAC) detectable at the cell membrane. Partial co localization of EGFR and E-Cadherin occurred in OE33 cells. Post EGF-stimulation, EGFR was detected in the cytoplasm, resembling endosomal compartments. Furthermore, OE19 and OE33 exhibited nuclear STAT5-Tyr694 phosphorylation upon EGF-stimulation. None of the four cell lines showed nuclear EGFR expression and localization. CONCLUSION: In contrast to other (squamous) cancer cells, activation of EGFR in esophageal squamous cancer cells does not result in nuclear translocation of EGFR. Still, the subcellular localization of EGFR may influence STAT5-associated signaling pathways in esophageal cancer cells and hence possibly also the responses to ErbB, respective EGFR-targeted therapies. PMID- 26582584 TI - Bioactive Glass for Large Bone Repair. AB - There has been an ongoing quest for new biomedical materials for the repair and regeneration of large segmental bone defects caused by disease or trauma. Autologous bone graft (ABG) remains the gold standard for bone repair despite their limited supply and donor-site morbidity. The current tissue engineering approach with synthetically derived bone grafts requires a bioactive ceramic or polymeric scaffold loaded with growth factors for osteoinduction and angiogenesis, and bone marrow stromal cells (BMSCs) for osteogenic properties. Unfortunately, this approach has serious drawbacks: the low mechanical strength of scaffolds, the high cost of growth factors, and a lack of optimal strategies for growth-factor delivery. Here, it is shown that, for the first time, a synthetic material alone can repair large bone defects as efficiently as the gold standard ABG. Through the use of strong and resorbable bioactive glass scaffolds, complete bone healing, and defect bridging can be achieved in a rabbit femur segmental defect model without growth factors or BMSCs. New bone and blood vessel formation, in both inner and peripheral scaffolds, demonstrates the excellent osteoinductive and osteogenic properties of these scaffolds similar as ABG. PMID- 26582585 TI - Galectin-3 level and the severity of cardiac diastolic dysfunction using cellular and animal models and clinical indices. AB - Heart failure with preserved ejection fraction (HFPEF) is characterized by myocardial interstitial fibrosis. A total of 146 patients with HFPEF, were recruited. HFPEF severity was determined using Doppler imaging (E/Em) and also cardiac magnetic resonance imaging (CMRI). Canine modeling of HFPEF was induced by aortic banding. Hemodynamic and echocardiographic data were obtained before and after pressure loading and myocardial Galectin-3 was determined. Mechanical stretch of cultured cardiomyocytes served as the cellular model of HFPEF. Patients with severe HFPEF had significantly higher plasma Galectin-3 levels. Significant correlation between plasma Galectin-3 and E/Em in advanced HFPEF patients was noted. After 2 weeks of pressure overload in canine models, the protein expression of Galectin-3 from LV myocardial tissue was significantly increased (p < 0.01) compared with controls. Galectin-3 expression paralleled the severity of LV diastolic dysfunction by evaluation of CMRI (r = -0.58, p = 0.003) and tissue fibrosis (r = 0.59, p = 0.002). After adjusting for confounders for diastolic dysfunction, Galectin-3 levels were still associated with diastolic parameters both in humans (p < 0.001) and canine model (p = 0.041). Mechanical stretch increased Galectin-3 secretion in cultured cardiomyocytes. Both plasma and myocardial Galectin-3 levels correlated with severity of cardiac diastolic dysfunction. PMID- 26582587 TI - Asymmetric Amyloid Deposition in the Brain Following Unilateral Electroconvulsive Therapy. PMID- 26582586 TI - Recommendations for standards of monitoring during anaesthesia and recovery 2015: Association of Anaesthetists of Great Britain and Ireland. AB - This guideline updates and replaces the 4th edition of the AAGBI Standards of Monitoring published in 2007. The aim of this document is to provide guidance on the minimum standards for physiological monitoring of any patient undergoing anaesthesia or sedation under the care of an anaesthetist. The recommendations are primarily aimed at anaesthetists practising in the United Kingdom and Ireland. Minimum standards for monitoring patients during anaesthesia and in the recovery phase are included. There is also guidance on monitoring patients undergoing sedation and also during transfer of anaesthetised or sedated patients. There are new sections discussing the role of monitoring depth of anaesthesia, neuromuscular blockade and cardiac output. The indications for end tidal carbon dioxide monitoring have been updated. PMID- 26582588 TI - Treatment-Resistant Schizophrenia in a Patient With 17q12 Duplication. PMID- 26582589 TI - A deuterostome origin of the Spemann organiser suggested by Nodal and ADMPs functions in Echinoderms. PMID- 26582590 TI - Cnuibacter physcomitrellae gen. nov., sp. nov., a novel member of the family Microbacteriaceae isolated from the moss of Physcomitrella patens. AB - A Gram-stain-positive, strictly aerobic and rod-shaped bacterium, designated strain XAT, was isolated from the moss, Physcomitrella patens, and characterized by using a polyphasic taxonomic approach. The novel strain was non-spore-forming, non-motile, catalase-positive and oxidase-negative. Its optimal temperature for growth occurred at 28-30 degrees C and the optimum pH for growth was 7.0-7.5. The major fatty acids comprised anteiso-C15 : 0, iso-C16 : 0, omega-cyclohexyl C17 : 0 and anteiso-C17 : 0. The polar lipids contained diphosphatidylglycerol, phosphatidylglycerol, seven unidentified glycolipids, one unidentified phospholipid and one unidentified lipid. The major menaquinone was MK-11, followed by MK-10 and MK-12. The peptidoglycan type was B2gamma and contained the amino acids 2,4-diaminobutyric acid, alanine, glycine, 3-hydroxy-glutamic acid and small amounts of glutamic acid. The genomic DNA G+C content of strain XAT was 68.2 mol%. Strain XAT exhibited highest 16S rRNA gene sequence similarity with Leifsonia lichenia 2SbT (96.3 %) and Humibacter antri D7-27T (96.2 %). However, phylogenetic analyses showed that strain XAT did not cluster with any species of the genera Leifsonia, Humibacter or other genera of the family Microbacteriaceae and the phylum Actinobacteria. Based on 16S rRNA gene sequence analyses, and the phenotypic and chemotaxonomic data, strain XAT is considered to represent a novel species of a novel genus, for which the name Cnuibacter physcomitrellae gen. nov., sp. nov. is proposed. The type strain is XAT ( = CGMCC 1.15041T = DSM 29843T). PMID- 26582591 TI - The accumulation mechanism of the hypoxia imaging probe "FMISO" by imaging mass spectrometry: possible involvement of low-molecular metabolites. AB - (18)F-fluoromisonidazole (FMISO) has been widely used as a hypoxia imaging probe for diagnostic positron emission tomography (PET). FMISO is believed to accumulate in hypoxic cells via covalent binding with macromolecules after reduction of its nitro group. However, its detailed accumulation mechanism remains unknown. Therefore, we investigated the chemical forms of FMISO and their distributions in tumours using imaging mass spectrometry (IMS), which visualises spatial distribution of chemical compositions based on molecular masses in tissue sections. Our radiochemical analysis revealed that most of the radioactivity in tumours existed as low-molecular-weight compounds with unknown chemical formulas, unlike observations made with conventional views, suggesting that the radioactivity distribution primarily reflected that of these unknown substances. The IMS analysis indicated that FMISO and its reductive metabolites were nonspecifically distributed in the tumour in patterns not corresponding to the radioactivity distribution. Our IMS search found an unknown low-molecular-weight metabolite whose distribution pattern corresponded to that of both the radioactivity and the hypoxia marker pimonidazole. This metabolite was identified as the glutathione conjugate of amino-FMISO. We showed that the glutathione conjugate of amino-FMISO is involved in FMISO accumulation in hypoxic tumour tissues, in addition to the conventional mechanism of FMISO covalent binding to macromolecules. PMID- 26582592 TI - Genetic testing and genetic counseling in patients with sudden death risk due to heritable arrhythmias. AB - Sudden cardiac death due to heritable ventricular arrhythmias is an important cause of mortality, especially in young healthy individuals. The identification of the genetic basis of Mendelian diseases associated with arrhythmia has allowed the integration of this information into the diagnosis and clinical management of patients and at-risk family members. The rapid expansion of genetic testing options and the increasing complexity involved in the interpretation of results creates unique opportunities and challenges. There is a need for competency to incorporate genetics into clinical management and to provide appropriate family based risk assessment and information. In addition, disease-specific genetic knowledge is required to order and correctly interpret and apply genetic testing results. Importantly, genetic diagnosis has a critical role in the risk stratification and clinical management of family members. This review summarizes the approach to genetic counseling and genetic testing for inherited arrhythmias and highlights specific genetic principles that apply to long QT syndrome, short QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia. PMID- 26582593 TI - Remembering James Alan Bassham (1922-2012). AB - James Alan Bassham, known to many as Al, was born on November 26, 1922, in Sacramento, California (CA), USA. He died on November 19, 2012, in El Cerrito, CA. To celebrate his life at his 3rd death anniversary, we present here a brief biography, comments on his discoveries, but most importantly, remembrances from family and friends; we remember this wonderful and modest person who had played a major pivotal role in the discoveries that led to what he would like to call the P(hotosynthetic) C(arbon) R(eduction) cycle, known to many as the Calvin Cycle, the Calvin-Benson Cycle, or the Calvin-Benson-Bassham Cycle. Based on a personal request by Bassham himself to one of us (Govindjee), we refrain from including his name in the cycle-in recognition of his many students and associates he would have liked to honor. PMID- 26582594 TI - Hospital staff corridor conversations: work in passing. AB - AIMS: First, to document the prevalence of corridor occupations and conversations among the staff of a hospital clinic, and their main features. Second, to examine the activities accomplished through corridor conversations and their interactional organization. BACKGROUND: Despite extensive research on mobility in hospital work, we still know fairly little about the prevalence and features of hospital staff corridor conversations and how they are organized. DESIGN: We conducted a study combining descriptive statistical analysis and multimodal conversation analysis of video recordings of staff corridor practices in a hospital outpatient clinic in Switzerland. METHODS: In 2012, we collected 59 hours of video recordings in a corridor of a hospital clinic. We coded and statistically analysed the footage that showed the clinic staff exclusively. We also performed qualitative multimodal conversation analysis on a selection of the recorded staff conversations. RESULTS: Corridor occupations by the clinic staff are frequent and brief and rarely involve stops. Talk events (which include self talk, face-to-face conversations and telephone conversations) during occupations are also brief and mobile, overwhelmingly focus on professional topics and are particularly frequent when two or more staff members occupy the corridor. The conversations present several interactional configurations and comprise an array of activities consequential to the provision of care and work organization. CONCLUSION: These practices are related to the fluid work organization of a spatially distributed team in a fast-paced, multitasking environment and should be taken into consideration in any undertaking aimed at improving hospital units' functioning. PMID- 26582595 TI - Critical EPICOT items were absent in Cochrane human immunodeficiency virus systematic reviews: a bibliometric analysis. AB - OBJECTIVES: To summarize the current gaps in human immunodeficiency virus (HIV) research evidence, describe the adequacy of reporting "implications for research," and map the number of studies that inform reviews with the prevalence of HIV for each country. STUDY DESIGN AND SETTING: A bibliometric analyses of HIV reviews in the Cochrane Database of Systematic Reviews with content analysis of the "implications for research" section. RESULTS: We analyzed 103 high-quality reviews published as of March 2014. They included a median of five studies (min 0 and max 44). Almost all the reviews recommended more trials (89.3%). Limitations in trial design, duration, setting, sample size, and choice of participants were also noted. Reporting of EPICOT+ items was as follows: evidence (35.9%), population (57.3%), intervention (71.8%), comparison (20.4%), outcomes (57.3%), time stamp (34.0%), and disease burden (13.6%). The primary studies were conducted in 67 countries. Six of the top 10 countries in which primary studies were conducted had a high HIV prevalence. CONCLUSION: Knowledge gaps were identified for research in younger participants, over longer periods, using more pragmatic interventions, conducted in resource-limited settings and incorporating economic evaluations. Implications for research are not always reported according to the EPICOT+ format. Not all countries with a high prevalence of HIV are contributing sufficiently to HIV research. PMID- 26582596 TI - A Novel Immunocompetent Mouse Model of Pancreatic Cancer with Robust Stroma: a Valuable Tool for Preclinical Evaluation of New Therapies. AB - A valid preclinical tumor model should recapitulate the tumor microenvironment. Immune and stromal components are absent in immunodeficient models of pancreatic cancer. While these components are present in genetically engineered models such as Kras(G12D); Trp53(R172H); Pdx-1Cre (KPC), immense variability in development of invasive disease makes them unsuitable for evaluation of novel therapies. We have generated a novel mouse model of pancreatic cancer by implanting tumor fragments from KPC mice into the pancreas of wild type mice. Three-millimeter tumor pieces from KPC mice were implanted into the pancreas of C57BL/6J mice. Four to eight weeks later, tumors were harvested, and stromal and immune components were evaluated. The efficacy of Minnelide, a novel compound which has been shown to be effective against pancreatic cancer in a number of preclinical murine models, was evaluated. In our model, consistent tumor growth and metastases were observed. Tumors demonstrated intense desmoplasia and leukocytic infiltration which was comparable to that in the genetically engineered KPC model and significantly more than that observed in KPC tumor-derived cell line implantation model. Minnelide treatment resulted in a significant decrease in the tumor weight and volume. This novel model demonstrates a consistent growth rate and tumor-associated mortality and recapitulates the tumor microenvironment. This convenient model is a valuable tool to evaluate novel therapies. PMID- 26582597 TI - When Should We Propose Liver Transplant After Resection of Hepatocellular Carcinoma? A Comparison of Salvage and De Principe Strategies. AB - INTRODUCTION: The aim of this study was to compare survival outcomes in patients enlisted for liver transplantation following liver resection for hepatocellular carcinoma before or at recurrence. METHODS: All patients enlisted for liver transplantation following liver resection for hepatocellular carcinoma from 1996 to 2013 were included and compared according to their status at the time of enlistment: before (de principe) or at (salvage) recurrence. Primary end-point was survival since resection. RESULTS: One hundred and twenty-one patients were enlisted for liver transplantation following liver resection for hepatocellular carcinoma. Ten patients enlisted for cirrhosis decompensation were excluded from the analysis. Sixty-three patients were enlisted de principe, and 48 for a salvage transplantation. Eleven patients dropped-out. According to per-protocol analysis, the mean diameter of the largest tumor was the only different pathological characteristic of initial resection between groups (31.6 mm in the de principe group versus 48.3 in the salvage, p = 0.017). The 5-year overall survival rate was significantly increased in the de principe group compared to salvage (84.6 versus 74.8%, p = 0.017). In a multivariate analysis, the salvage strategy was the only independent prognostic factor for death (p = 0.040; OR = 2.5 [1.1-5.8]). CONCLUSION: De principe enlistment for liver transplantation following liver resection for hepatocellular carcinoma is associated with greater survival. PMID- 26582598 TI - Impact of a National Bariatric Surgery Center of Excellence Program on Medicare Expenditures. AB - INTRODUCTION: In 2006, the Centers for Medicare and Medicaid Services (CMS) issued a national coverage decision restricting bariatric surgery to designated centers of excellence (COE). Although prior studies show mixed results on complications and reoperations, no prior studies evaluated whether this policy reduced spending for bariatric surgery. We sought to determine whether the coverage restriction to COE-designated hospitals was associated with lower payments from CMS. METHODS: We utilized national Medicare claims data to examine 30-day episode payments for patients who underwent bariatric surgery from 2003 to 2010 (n = 72,117 patients). We performed an interrupted time series analysis, adjusting for patient factors, preexisting temporal trends, and changes in procedure type, to determine whether the 2006 coverage decision was associated with lower Medicare payments above and beyond any existing secular trends. For these analyses, we included payments for the index hospitalization, readmissions, physician services, and post-discharge ancillary care. RESULTS: After accounting for patient factors, preexisting temporal trends, and changes in procedure type, there were no statistically significant improvements in episode payments after (US$14,720) vs before (US$14,283) the coverage decision (+US$437, 95% CI, -US$10 to +US$883). In a direct assessment of payments for COE-designated hospitals (US$14,481) vs. non-COE-designated hospitals (US$14,756), no significant differences in episode payments were found (-US$275, 95% CI, -US$696 to +US$145). CONCLUSIONS: We found no significant reductions in 30-day episode payments after vs before restricting coverage to COE-designated hospitals. Center of excellence status is not a proxy for savings to the healthcare system. PMID- 26582599 TI - Predicting the development of liver cirrhosis by simple modelling in patients with chronic hepatitis C. AB - BACKGROUND: Data are scarce on the natural history of chronic hepatitis C (CHC) in patients with mild hepatitis C who did not respond to anti-viral therapy. AIM: To predict the risk of progression to cirrhosis, identifying patients with the more urgent need for therapy with effective anti-virals. METHODS: A cohort of 1289 noncirrhotic CHC patients treated with interferon-based therapy between 1990 and 2004 in two referral hospitals were followed up for a median of 12 years. RESULTS: Overall, SVR was achieved in 46.6% of patients. Data from a randomly split sample (n = 832) was used to estimate a model to predict outcomes. Among nonresponders (n = 444), cirrhosis developed in 123 (28%) patients. In this group, the 3, 5 and 10-year cumulative probabilities of cirrhosis were 4%, 7% and 22%, respectively, compared to <1% in the SVR-group (P < 0.05). Baseline factors independently associated with progression to cirrhosis in nonresponders were: fibrosis >=F2, age >40 years, AST >100 IU/L, GGT >40 IU/L. Three logistic regression models that combined these simple variables were highly accurate in predicting the individual risk of developing cirrhosis with areas under the receiving operating characteristic curves (AUC) at 5, 7 and 10 years of ~0.80. The reproducibility of the models in the validation cohort (n = 457, nonresponders = 244), was consistently high. CONCLUSIONS: Modelling based on simple laboratory and clinical data can accurately identify the individual risk of progression to cirrhosis in nonresponder patients with chronic hepatitis C, becoming a very helpful tool to prioritise the start of oral anti-viral therapy in clinical practice. PMID- 26582600 TI - Subarray coherence based postfilter for eigenspace based minimum variance beamformer in ultrasound plane-wave imaging. AB - This paper introduces a new beamformer, which combines the eigenspace based minimum variance (ESBMV) beamformer with a subarray coherence based postfilter (SCBP), for improving the quality of ultrasound plane-wave imaging. The ESBMV beamformer has been validated in improving the imaging contrast, but the difficulty in dividing the signal subspace limits the usage of it in the low signal-to-noise ratio (SNR) scenarios. Coherence factor (CF) based methods could optimize the output of a distortionless beamformer to reduce sidelobes, but the influence by the subarray decorrelation technique on the postfilter design has not attracted enough concern before. Accordingly, an ESBMV-SCBP beamformer was proposed in this paper, which used the coherence of the subarray signal to compute an SCBP to optimize the ESBMV results. Simulated and experimental data were used to evaluate the performance of the proposed method. The results showed that the ESBMV-SCBP method achieved an improved imaging quality compared with the ESBMV beamformer. In the simulation study, the contrast ratio (CR) for an anechoic cyst was improved by 9.88 dB and the contrast-to-noise ratio (CNR) was improved by 0.97 over the ESBMV. In the experimental study, the CR improvements for two anechoic cysts were 7.32 dB and 9.45 dB, while the CNRs were improved by 1.27 and 0.66, respectively. The ESBMV-SCBP also showed advantages over the ESBMV Wiener beamformer in preserving a less grainy speckle, which is closer to that of distortionless beamformers and benefits the imaging contrast. With a relatively small extra computational load, the proposed method has potential to enhance the quality of the ultrasound plane-wave imaging. PMID- 26582601 TI - Systematic Review of Self-Report Family Assessment Measures. AB - A systematic review of self-report family assessment measures was conducted with reference to their psychometric properties, clinical utility and theoretical underpinnings. Eight instruments were reviewed: The McMaster Family Assessment Device (FAD); Circumplex Model Family Adaptability and Cohesion Evaluation Scales (FACES); Beavers Systems Model Self-Report Family Inventory (SFI); Family Assessment Measure III (FAM III); Family Environment Scale (FES); Family Relations Scale (FRS); and Systemic Therapy Inventory of Change (STIC); and the Systemic Clinical Outcome Routine Evaluation (SCORE). Results indicated that five family assessment measures are suitable for clinical use (FAD, FACES-IV, SFI, FAM III, SCORE), two are not (FES, FRS), and one is a new system currently under going validation (STIC). PMID- 26582602 TI - DNA methylation mediated silencing of microRNA-145 is a potential prognostic marker in patients with lung adenocarcinoma. AB - The molecular mechanism of down-regulated microRNA-145 (miR-145) expression in lung adenocarcinoma (LAC) remains largely unknown. We hypothesized that aberrant hyper-methylation of the CpG sites silenced the expression of miR-145 in LAC. In consideration of its pivotal role in LAC development and progression, we also evaluated the clinical utility of miR-145 as a prognostic marker. We assessed the DNA methylation status of the miR-145 promoter region in 20 pairs of LAC and the matched non-tumor specimens. We subsequently applied our own LAC tissue microarray containing 92 pairs of tumor and non-tumor tissues with long time follow-up records to evaluate whether miR-145 is a potential prognostic marker in LAC. The Sequenom EpiTYPER MassArray analysis showed that miR-145 was down regulated in human LAC tissues accompanied by increased DNA methylation of its upstream region, which was further validated by the data from TCGA database. Significance was observed between miR-145 expression and clinic-pathologic parameters. Univariate and multivariate analysis revealed that miR-145 expression level was an independent risk factor for both OS and DFS in LAC patients. Taken together, DNA hyper-methylation in the miR-145 promoter region reduced its expression in LAC and miR-145 expression level might serve as a novel prognostic biomarker. PMID- 26582603 TI - Hyaluronan oligomers sensitize chronic myeloid leukemia cell lines to the effect of Imatinib. AB - Chronic myeloid leukemia is a myeloproliferative syndrome characterized by the presence of the Philadelphia chromosome (Ph), generated by a reciprocal translocation occurring between chromosomes 9 and 22 [t(9;22)(q34;q11)]. As a consequence, a fusion gene (bcr-abl) encoding a constitutively active kinase is generated. The first-line treatment consists on BCR-ABL inhibitors such as Imatinib, Nilotinib and Dasatinib. Nevertheless, such treatment may lead to the selection of resistant cells. Therefore, finding molecules that enhance the anti proliferative effect of first-line drugs is of value. Hyaluronan oligomers (oHA) are known to be able to sensitize several tumor cells to chemotherapy. We have previously demonstrated that oHA can revert Vincristine resistance in mouse lymphoma and human leukemia cell lines. However, little is known about the role of oHA in hematological malignancies. The aim of this work was to determine whether oHA are able to modulate the anti-proliferative effect of Imatinib in chronic myeloid leukemia (CML) cell lines. The effect on apoptosis and senescence as well as the involvement of signaling pathways were also evaluated. For this purpose, the human CML cell lines K562 and Kv562 (resistant) were used. We demonstrated that oHA sensitized both cell lines to the anti-proliferative effect of Imatinib increasing apoptosis and senescence. Moreover, this effect would be accomplished through the down-regulation of the PI3K signaling pathway. These findings highlight the potential of oHA when used as a co-adjuvant therapy for chronic myeloid leukemia. PMID- 26582604 TI - Mechanisms of the sialidase and trans-sialidase activities of bacterial sialyltransferases from glycosyltransferase family 80. AB - Many important biological functions are mediated by complex glycan structures containing the nine-carbon sugar sialic acid (Sia) at terminal, non-reducing positions. Sia are introduced onto glycan structures by enzymes known as sialyltransferases (STs). Bacterial STs from the glycosyltransferase family GT80 are a group of well-studied enzymes used for the synthesis of sialylated glycan structures. While highly efficient at sialyl transfer, these enzymes also demonstrate sialidase and trans-sialidase activities for which there is some debate surrounding the corresponding enzymatic mechanisms. Here we propose a mechanism for STs from the glycosyltransferase family GT80 in which sialidase and trans-sialidase activities occur through reverse sialylation of CMP. The resulting CMP-Sia is then enzymatically hydrolyzed or used as a donor in subsequent ST reactions resulting in sialidase and trans-sialidase activities, respectively. We provide evidence for this mechanism by demonstrating that CMP is required for sialidase and trans-sialidase activities and that its removal with phosphatase ablates activity. We also confirm the formation of CMP-Sia using a coupled enzyme assay. A clear understanding of the sialidase and trans-sialidase mechanisms for this class of enzymes allows for more effective use of these enzymes in the synthesis of glycoconjugates. PMID- 26582605 TI - Structure and gene cluster of the O-antigen of Escherichia coli O165 containing 5 N-acetyl-7-N-[(R)-3-hydroxybutanoyl]pseudaminic acid. AB - Upon mild acid degradation of the lipopolysaccharide of Escherichia coli O165, the O-polysaccharide chain was cleaved at the glycosidic linkage of 5-N-acetyl-7 N-[(R)-3-hydroxybutanoyl]pseudaminic acid (Pse5Hb7Ac). Analysis of the resulting linear tetrasaccharide and alkali-treated lipopolysaccharide by (1)H/(13)C 1D and 2D nuclear magnetic resonance spectroscopy enabled elucidation of the following structure of the O-polysaccharide: ->8)-alpha-Psep5Hb7Ac-(2 -> 6)-beta-d-Galp-(1 > 4)-beta-d-Glsp-(1 -> 3)-alpha-d-GlspNAc-(1->. The beta-d-Galp-(1 -> 4)-beta-d Glsp-(1 -> 3)-d-GlspNAc structural element is also present in the O polysaccharide of E. coli O82. The content of the O-antigen gene cluster of E. coli O165 was found to be consistent with the O-polysaccharide structure established. Functions of proteins encoded in the gene cluster, including enzymes involved in the Pse5Hb7Ac biosynthesis and glycosyltransferases, were putatively assigned by comparison with sequences in available databases. PMID- 26582606 TI - Comprehensive analysis of flagellin glycosylation in Campylobacter jejuni NCTC 11168 reveals incorporation of legionaminic acid and its importance for host colonization. AB - Campylobacter jejuni is the leading cause of bacterial gastroenteritis. It relies on several virulence factors for host colonization, including glycosylated flagella. C. jejuni NCTC 11168 modifies its flagellins with pseudaminic acid derivatives. It is also presumed to modify these proteins with legionaminic acid, although no glycopeptide evidence was available at the onset of this study. The enzyme encoded by cj1319 can be used to make legionaminic acid in vitro, but the pathway for legionaminic acid synthesis partially inferred by knockout mutagenesis in Campylobacter coli VC167 excludes Cj1319. To address this contradiction, we examined the presence of legionaminic acid in flagellin glycopeptides of wild-type (WT) C. jejuni NCTC 11168 and of a cj1319 knockout mutant. We used high-energy collision-induced dissociation to obtain amino acid sequences while also visualizing signature sugar oxonium ions. Data analysis was performed with PEAKS software, and spectra were manually inspected for glycopeptide determination and verification. We showed that legionaminic acid is present on the flagellins of C. jejuni NCTC 11168 and that flagellin glycosylation is highly heterogeneous, with up to six different sugars singly present at a given site. We found that the cj1319 mutant produces more legionaminic acid than WT, thus excluding the requirement for Cj1319 for legionaminic acid synthesis. We also showed that this mutant has enhanced chicken colonization compared with WT, which may in part be attributed to the high content of legionaminic acid on its flagella. PMID- 26582607 TI - Design of an alpha-L-transfucosidase for the synthesis of fucosylated HMOs. AB - Human milk oligosaccharides (HMOs) are recognized as benefiting breast-fed infants in multiple ways. As a result, there is growing interest in the synthesis of HMOs mimicking their natural diversity. Most HMOs are fucosylated oligosaccharides. alpha-l-Fucosidases catalyze the hydrolysis of alpha-l-fucose from the non-reducing end of a glucan. They fall into the glycoside hydrolase GH29 and GH95 families. The GH29 family fucosidases display a classic retaining mechanism and are good candidates for transfucosidase activity. We recently demonstrated that the alpha-l-fucosidase from Thermotoga maritima (TmalphaFuc) from the GH29 family can be evolved into an efficient transfucosidase by directed evolution ( Osanjo et al. 2007). In this work, we developed semi-rational approaches to design an alpha-l-transfucosidase starting with the alpha-l fucosidase from commensal bacteria Bifidobacterium longum subsp. infantis (BiAfcB, Blon_2336). Efficient fucosylation was obtained with enzyme mutants (L321P-BiAfcB and F34I/L321P-BiAfcB) enabling in vitro synthesis of lactodifucotetraose, lacto-N-fucopentaose II, lacto-N-fucopentaose III and lacto N-difucohexaose I. The enzymes also generated more complex HMOs like fucosylated para-lacto-N-neohexaose (F-p-LNnH) and mono- or difucosylated lacto-N-neohexaose (F-LNnH-I, F-LNnH-II and DF-LNnH). It is worth noting that mutation at these two positions did not result in a strong decrease in the overall activity of the enzyme, which makes these variants interesting candidates for large-scale transfucosylation reactions. For the first time, this work provides an efficient enzymatic method to synthesize the majority of fucosylated HMOs. PMID- 26582608 TI - Schistosoma mansoni alpha1,3-fucosyltransferase-F generates the Lewis X antigen. AB - Genetic evidence suggests that the Schistosoma mansoni genome contains six genes that encode alpha1,3-fucosyltransferases (smFuTs). To date, the activities and specificities of these putative fucosyltransferases are unknown. As Schistosoma express a variety of fucosylated glycans, including the Lewis X antigen Galbeta1 4(Fucalpha1-3)GlcNAcbeta-R, it is likely that this family of genes encode enzymes that are partly responsible for the generation of those structures. Here, we report the molecular cloning of fucosyltransferase-F (smFuT-F) from S. mansoni, as a soluble, green fluorescent protein fusion protein and its acceptor specificity. The gene smFuT-F was expressed in HEK freestyle cells, purified by affinity chromatography, and analyzed toward a broad panel of glycan acceptors. The enzyme product of smFuT-F effectively utilizes a type II chain acceptor Galbeta1-4GlcNAc-R, but notably not the LDN sequence GalNAcbeta1-4GlcNAc-R, to generate Lewis X type-glycans, and smFuT-F transcripts are present in all intramammalian life stages. PMID- 26582610 TI - Sweating the small stuff: Glycoproteins in human sweat and their unexplored potential for microbial adhesion. AB - There is increasing evidence that secretory fluids such as tears, saliva and milk play an important role in protecting the human body from infection via a washing mechanism involving glycan-mediated adhesion of potential pathogens to secretory glycoproteins. Interaction of sweat with bacteria is well established as the cause of sweat-associated malodor. However, the role of sweat glycoproteins in microbial attachment has received little, if any, research interest in the past. In this review, we demonstrate how recent published studies involving high throughput proteomic analysis have inadvertently, and fortuitously, exposed an abundance of glycoproteins in sweat, many of which have also been identified in other secretory fluids. We bring together research demonstrating microbial adhesion to these secretory glycoproteins in tears, saliva and milk and suggest a similar role of the sweat glycoproteins in mediating microbial attachment to sweat and/or skin. The contribution of glycan-mediated microbial adhesion to sweat glycoproteins, and the associated impact on sweat derived malodor and pathogenic skin infections are unchartered new research areas that we are beginning to explore. PMID- 26582609 TI - The dependence of chemokine-glycosaminoglycan interactions on chemokine oligomerization. AB - Both chemokine oligomerization and binding to glycosaminoglycans (GAGs) are required for their function in cell recruitment. Interactions with GAGs facilitate the formation of chemokine gradients, which provide directional cues for migrating cells. In contrast, chemokine oligomerization is thought to contribute to the affinity of GAG interactions by providing a more extensive binding surface than single subunits alone. However, the importance of chemokine oligomerization to GAG binding has not been extensively quantified. Additionally, the ability of chemokines to form different oligomers has been suggested to impart specificity to GAG interactions, but most studies have been limited to heparin. In this study, several differentially oligomerizing chemokines (CCL2, CCL3, CCL5, CCL7, CXCL4, CXCL8, CXCL11 and CXCL12) and select oligomerization deficient mutants were systematically characterized by surface plasmon resonance to determine their relative affinities for heparin, heparan sulfate (HS) and chondroitin sulfate-A (CS-A). Wild-type chemokines demonstrated a hierarchy of binding affinities for heparin and HS that was markedly dependent on oligomerization. These results were corroborated by their relative propensity to accumulate on cells and the critical role of oligomerization in cell presentation. CS-A was found to exhibit greater chemokine selectivity than heparin or HS, as it only bound a subset of chemokines; moreover, binding to CS-A was ablated with oligomerization-deficient mutants. Overall, this study definitively demonstrates the importance of oligomerization for chemokine-GAG interactions, and demonstrates diversity in the affinity and specificity of different chemokines for GAGs. These data support the idea that GAG interactions provide a mechanism for fine-tuning chemokine function. PMID- 26582611 TI - Effect of Head Position on Intraocular Pressure During Lumbar Spine Fusion: A Randomized, Prospective Study. AB - BACKGROUND: Ischemic optic neuropathy resulting in visual loss is a rare but devastating complication of spine surgery. Elevated intraocular pressure (IOP) results in decreased perfusion and possibly ischemic optic neuropathy. We performed a randomized, prospective trial to evaluate the effect of head positioning on IOP during lumbar spine fusion. METHODS: The study included fifty two patients treated at one institution. Inclusion criteria were a lumbar spine fusion and an age of eighteen to eighty years. Exclusion criteria were a diagnosis of tumor, infection, or traumatic injury or a history of eye disease, ocular surgery, cervical spine surgery, chronic neck pain, or cervical stenosis. The control group underwent the surgery with the head in neutral and the face parallel to the level operating room table whereas, in the experimental group, the neck was extended so that the face had a 10 degrees angle of inclination in relation to the table. IOP measurements were recorded along with the corresponding blood pressure and PCO2 values at the same time points. The primary outcome measure was the change in intraocular pressure (DeltaIOP, defined as the maximum IOP minus the initial IOP). RESULTS: Analysis of covariance (ANCOVA) was used for categorical risk factors, and regression analysis was used for continuous risk factors. The mean DeltaIOP, corrected for duration of surgery, was significantly (p = 0.0074) lower in the group treated with the head elevated than it was in the group treated with the head in neutral (difference between the two groups, 4.53 mm Hg [95% confidence interval, 1.29 to 7.79 mm Hg]). No patient sustained visual loss or any cervical-spine-related complications. CONCLUSIONS: Head elevation for adult lumbar spine fusion performed with the patient prone resulted in significantly lower IOP measurements than those seen when the operation was done with the patient's head in neutral. As lower IOP correlates with increased optic nerve perfusion, this intervention could mitigate the risk of perioperative blindness after spine surgery done with the patient prone. PMID- 26582612 TI - Prevalence, Timing, Causes, and Outcomes of Hyponatremia in Hospitalized Orthopaedic Surgery Patients. AB - BACKGROUND: Hyponatremia is common among orthopaedic patients and is associated with adverse clinical outcomes. We examined the prevalence, timing, causes, and outcomes of hyponatremia in adult hospitalized orthopaedic surgery patients. METHODS: We evaluated the medical records of 1067 consecutive orthopaedic surgery patients admitted to a tertiary academic institution. The medical records were reviewed to investigate hyponatremia (serum sodium <135 mEq/L) that (1) had been present on hospital admission or (2) had developed postoperatively. The primary outcomes were the prevalence and timing of, and risk factors for, presentation with or development of hyponatremia. Secondary outcomes were hospital length of stay, total hospital cost, and discharge disposition. Multivariable logistic regression models were used to assess the variables associated with hyponatremia and the effects of hyponatremia on clinical outcomes. RESULTS: Of the 1067 patients, seventy-one (7%) had preoperative hyponatremia and 319 (30%) developed hyponatremia postoperatively. Of the latter, 298 (93%) developed hyponatremia within forty-eight hours postoperatively. Compared with patients with normonatremia, those who presented with hyponatremia, on the average, were older (67.2 versus 60.5 years, p < 0.001), had longer hospital stays (4.6 versus 3.3 days, p < 0.001), incurred higher hospital costs ($19,200 versus $17,000, p = 0.006), and were more likely to be discharged to an extended-care facility (odds ratio [OR] = 2.87, p < 0.001). Developing hyponatremia postoperatively resulted, on average, in a longer hospital stay (3.7 versus 3.3 days, p = 0.002) and greater hospital cost ($18,800 versus $17,000, p < 0.001). Age (OR = 1.13 per decade, p = 0.012), spine surgery (OR = 2.76 versus knee, p < 0.001), hip surgery (OR = 1.76 versus knee, p < 0.001), and the amount of lactated Ringer solution used (OR = 1.16, p = 0.002) increased the risk of developing hyponatremia. CONCLUSIONS: Hyponatremia in orthopaedic patients is associated with longer, costlier hospitalizations. The factors that significantly increased the risk of developing postoperative hyponatremia were an older age, spine fusion, hip arthroplasty, and the amount of lactated Ringer solution used. PMID- 26582613 TI - Clinical Outcome and Glenoid Morphology After Arthroscopic Repair of Chronic Osseous Bankart Lesions: A Five to Eight-Year Follow-up Study. AB - BACKGROUND: Arthroscopic osseous Bankart repair for shoulders with chronic recurrent anterior instability has been reported as an effective procedure with promising short-term outcomes. However, to date, we know of no report describing longer-term outcomes and glenoid morphologic change. The purpose of the present study was to report intermediate to long-term outcomes and glenoid morphologic change after arthroscopic osseous Bankart repair in patients with substantial glenoid bone loss. METHODS: A consecutive series of eighty-five patients with traumatic anterior glenohumeral instability associated with a chronic osseous Bankart lesion underwent arthroscopic repair from January 2005 through December 2006. Forty-six patients with bone loss of >15% of the inferior glenoid diameter relative to the assumed inferior circle regardless of the fragment size were selected as candidates for this study. Thirty-eight patients (83%), including thirty-four male and four female patients, with a mean age of 23.4 years (range, fifteen to thirty-six years) at the time of surgery, were available for final follow-up at a mean of 6.2 years (range, 5.0 to 8.1 years) after surgery. RESULTS: One patient had a redislocation during a traffic accident five months after surgery before obtaining an osseous union. The mean Rowe score and the mean Western Ontario Shoulder Instability Index improved significantly from 30.7 points preoperatively to 95.4 points postoperatively and from 26.5% to 81.5%, respectively. Although the mean preoperative fragment size was measured as only 4.7%, the mean glenoid bone loss improved from 20.4% preoperatively to -1.1% postoperatively. CONCLUSIONS: Arthroscopic osseous Bankart repair is an effective primary treatment for shoulders with substantial glenoid bone loss as it provides successful outcomes without recurrence of instability once osseous union is obtained. Glenoid morphology can be normalized during the intermediate to long term postoperative period, even in shoulders with a smaller fragment. PMID- 26582614 TI - Local Injection of Aminoglycosides for Prophylaxis Against Infection in Open Fractures. AB - BACKGROUND: The purpose of this study was to determine the efficacy of local wound cavity injections of aqueous aminoglycosides (gentamicin and tobramycin), in conjunction with systemic antibiotics, to lower the prevalence of infection in patients with open fractures. METHODS: Three hundred and fifty-one open fractures were identified by Current Procedural Terminology codes 11011 and 11012. Data on patient demographic characteristics, injury characteristics, infection, and fracture union were obtained from the electronic medical records. Patients in the control group (183 fractures) received systemic antibiotics only. Patients in the intervention group (168 fractures) received, in addition to systemic antibiotics, a locally administered aminoglycoside (2 mg/mL) at the time of the index surgical procedure. At the discretion of the attending surgeon, some wounds also received postoperative irrigations of aqueous aminoglycoside (n = 34). For wounds that could not be closed and wounds that received postoperative irrigations, negative pressure dressings were used. RESULTS: The deep and superficial infection rate in the control group was 19.7% (thirty-six of 183 fractures), but it was significantly lower (p = 0.010) in the intervention group at 9.5% (sixteen of 168 fractures). When comparing only the deep infections, the infection rate in the control group was 14.2% (twenty-six of 183 fractures) compared with 6.0% (ten of 168 fractures) in the intervention group (p = 0.011). After multivariate analysis to adjust for possible confounding factors, the administration of local antibiotics was found to be an independent predictor of lower infection rates in both deep and superficial infections (odds ratio, 2.6 [95% confidence interval, 1.2 to 5.6]; p = 0.015) and deep infections only (odds ratio, 3.0 [95% confidence interval, 1.1 to 8.5]; p = 0.034). The use of local antibiotics did not have an impact on nonunion rate (p = 0.881), with a type-I error rate of alpha = 0.05 and 0.8 power. CONCLUSIONS: This study suggests that local aqueous aminoglycoside administration as an adjunct to systemic antibiotics may be effective in lowering infection rates in open fractures; further research with higher-level research designs are needed. PMID- 26582615 TI - Systemic Administration of Sclerostin Antibody Enhances Bone Morphogenetic Protein-Induced Femoral Defect Repair in a Rat Model. AB - BACKGROUND: Recombinant human bone morphogenetic protein (rhBMP)-2 is a potent osteoinductive agent; however, its clinical use has been reduced because of safety and efficacy concerns. In preclinical studies involving a critical-sized defect in a rat model, sclerostin antibody (Scl-Ab) treatment increased bone formation within the defect but did not result in reliable healing. The purpose of the current study was to evaluate bone repair of a critical-sized femoral defect in a rat model with use of local implantation of rhBMP-2 combined with systemic administration of Scl-Ab. METHODS: A critical-sized femoral defect was created in rats randomized into three treatment groups: local rhBMP-2 and systemic Scl-Ab (Scl + BMP), local rhBMP-2 alone, and collagen sponge alone (operative control). The Scl + BMP group received local rhBMP-2 (10 MUg) on a collagen sponge placed within the defect intraoperatively and then twice weekly injections of Scl-Ab (25 mg/kg) administered postoperatively. The femora were evaluated at twelve weeks with use of radiography, microcomputed tomography (microCT), histomorphometric analysis, and biomechanical testing. RESULTS: At twelve weeks, all Scl + BMP and rhBMP-2 only samples were healed. No femora healed in the operative control group. Histomorphometric analysis demonstrated more bone in the Scl + BMP samples than in the samples treated with rhBMP-2 alone (p = 0.029) and the control samples (p = 0.003). MicroCT revealed that the Scl + BMP group had a 90% greater bone volume within the defect region compared with the rhBMP-2 group and a 350% greater bone volume compared with the operative control group (p < 0.001). Biomechanical testing showed that the group treated with Scl + BMP had greater torsional strength and rigidity compared with the rhBMP-2 group (p < 0.001 and p = 0.047) and the intact femoral control group (p < 0.001). Torque to failure was lower in the rhBMP-2 group compared with the intact femoral control group (p < 0.002). Mean energy to failure was higher in the Scl + BMP samples compared with the rhBMP-2 only samples (p = 0.001). CONCLUSIONS: In a critical-sized femoral defect in a rat model, local rhBMP-2 combined with systemic administration of Scl-Ab resulted in more robust healing that was stronger and more rigid than results for rhBMP-2 alone and intact nonoperative femora. CLINICAL RELEVANCE: Our study demonstrated that combining an osteoinductive agent with a systemically administered antibody that promotes bone formation can enhance bone repair and has potential as a therapeutic regimen in humans. PMID- 26582616 TI - Diagnosis of Occult Scaphoid Fractures: A Cost-Effectiveness Analysis. AB - BACKGROUND: Scaphoid fractures are common but may be missed on initial radiographs. Advanced imaging modalities such as computed tomography (CT) and magnetic resonance imaging (MRI) have improved diagnostic accuracy, but at an increased initial cost. The purpose of this study was to evaluate the cost effectiveness of immediate advanced imaging for suspected occult scaphoid fractures. METHODS: A decision analysis model was created to evaluate three diagnostic strategies for patients with concerning history and examination but negative radiographs: (1) empiric cast immobilization with orthopaedic follow-up and repeat radiography at two weeks post-injury, (2) immediate CT scanning, or (3) immediate MRI. Prevalence of occult scaphoid fracture, sensitivity and specificity of CT and MRI, and risks and outcomes of a missed fracture were derived from published clinical trials. Costs of imaging, lost worker productivity, and surgical costs of nonunion surgery were estimated on the basis of the literature. RESULTS: Advanced imaging was dominant over empiric cast immobilization; advanced imaging had lower costs and its health outcomes were projected to be better than those of empiric cast immobilization. MRI was slightly more cost-effective than CT on the basis of the mean published diagnostic performance, but was highly sensitive to test performance characteristics. Advanced imaging would have to increase in cost to more than $2000 or decrease in sensitivity to <25% for CT or <32% for MRI for empiric cast immobilization to be cost-effective. CONCLUSIONS: Given its relatively low cost and high diagnostic accuracy, advanced imaging for suspected scaphoid fractures in the setting of negative radiographs represents a cost-effective strategy for reducing both costs and morbidity. The decision to use CT compared with MRI is a function of individual institutional costs and local test performance characteristics. PMID- 26582617 TI - Improved Magnetic Resonance Imaging Utilization for Children with Musculoskeletal Infection. AB - BACKGROUND: Magnetic resonance imaging (MRI) with sedation is an important resource used to evaluate children with musculoskeletal infection. This study assesses the impact of multidisciplinary guidelines and continuous process improvement on MRI utilization at a tertiary pediatric medical center. METHODS: A multidisciplinary team developed a guideline for MRI with sedation, and it was implemented at our institution. Scan duration, anatomic regions imaged, sequences performed, timing of surgical intervention, length of hospital stay, and readmissions for these children were compared with these measures among a cohort of similar children who had been treated prior to guideline implementation. Comparative data were gathered for the subsequent cohort to determine any impact of the continued process improvement program on MRI utilization. Statistical comparison was performed to determine significant differences between groups. RESULTS: Children evaluated prior to the guideline implementation had 9.0 MRI sequences per scan, an MRI scan duration of 111.6 minutes, and a hospital stay of 7.5 days. In comparison, children in the initial MRI guideline cohort had 7.5 sequences per scan, a scan duration of 76.1 minutes, and a hospital stay of 5.4 days. Children in the subsequent guideline cohort had 6.5 sequences per scan, a scan duration of 56.3 minutes, and a hospital stay of 5.0 days. The rate of immediate surgical procedure under continued anesthesia was 16.7% prior to the guideline, 50.5% among children in the initial guideline cohort, and 64% among children in the subsequent guideline cohort. Differences between cohorts were significant (p < 0.0001). In aggregate, 264 hours of MRI scan time and 809 hospital bed-days were conserved for more than thirty months. CONCLUSIONS: This initiative promoted improvement in diagnostic efficiency, therapeutic consistency, and patient safety for children with musculoskeletal infection. CLINICAL RELEVANCE: The findings of this study illustrate the beneficial impact of interdisciplinary coordination of care on clinical outcomes for children with musculoskeletal infection. Tangible improvements occurred for both length of stay and resource utilization. PMID- 26582618 TI - Gait Analysis and Functional Outcome After Calcaneal Fracture. AB - BACKGROUND: Calcaneal fractures are associated with substantial morbidity and socioeconomic impact, frequently leading to limited functional outcome and high economic costs. The Oxford foot model (OFM) has been reported as a valid addition to the biomechanical examination of the foot. The aim of our study was to analyze the gait of patients after operative repair of a calcaneal fracture in relation to functional outcome and radiographic findings. METHODS: Thirteen patients with a calcaneal fracture underwent gait analysis with OFM at a minimum of six months after open surgery. Intersegmental range of motion was measured during gait. Results were compared with those of healthy subjects and those of patients who had undergone subtalar arthrodesis. Patient-reported questionnaires and radiographic images were also evaluated. RESULTS: The range of motion between the hindfoot and the tibia in the push-off phase in the transverse plane was significantly correlated with the clinical outcome as reported by patients based on the Foot and Ankle Disability Index (FADI) (r(2) = 0.51; p < 0.001) and the Short Form (SF)-36 physical component summary score (r(2) = 0.52; p < 0.001). We found a significant correlation between the step-off in the subtalar joint as measured on postoperative computed tomography (CT) and range of motion (r(2) = 0.74; p = 0.004). The step-off was also correlated with the patient-reported outcome questionnaire FADI (r(2) = -0.76; p = 0.003) and the SF-36 physical component summary score (r(2) = -0.78; p = 0.002). CONCLUSIONS: This study demonstrated that the subtalar joint range of motion of patients after a calcaneal fracture was related both to the quality of the reduction of the subtalar joint as evaluated on postoperative CT scans and patient-reported functional outcome. PMID- 26582619 TI - X-Stop Resulted in a Higher Reoperation Rate Than Minimally Invasive Decompression, But Both Decreased Symptoms of Neurogenic Intermittent Claudication in Patients with Lumbar Spinal Stenosis. PMID- 26582620 TI - Surgical and Nonsurgical Treatment Produced Similar Outcomes for Proximal Humeral Fractures. PMID- 26582621 TI - Patient-Specific Cutting Guides Were Not Better Than Conventional Instrumentation for Total Knee Arthroplasty. PMID- 26582622 TI - What's New in Orthopaedic Rehabilitation. PMID- 26582623 TI - The Evidence Base for the Prognosis and Treatment of Adolescent Idiopathic Scoliosis: The 2015 Orthopaedic Research and Education Foundation Clinical Research Award. PMID- 26582624 TI - Tibial Growth Disturbance Following Distal Femoral Resection and Expandable Endoprosthetic Reconstruction. AB - BACKGROUND: In growing children, an expandable endoprosthesis is commonly used after distal femoral resection to compensate for loss of the distal femoral physis. Our hypothesis was that such prostheses can affect proximal tibial growth, which would contribute to an overall leg-length discrepancy and cause angular deformity. METHODS: Twenty-three skeletally immature patients underwent the placement of a distal femoral expandable endoprosthesis between 1994 and 2012. Tibial length, femoral length, and mechanical axis were measured radiographically to determine the growth rate. RESULTS: No patient had radiographic evidence of injury to the proximal tibial physis at the time of surgery other than insertion of the tibial stem. Fifteen (65%) of the patients experienced less proximal tibial growth in the operative compared with the contralateral limb. In ten (43%) of the patients, the discrepancy progressively worsened, whereas in five (22%) of the patients, the discrepancy stabilized. Seven patients did not develop tibial length discrepancy, and one patient had overgrowth of the tibia. For the ten patients with progressive shortening, the proximal tibial physis grew an average of 4.0 mm less per year in the operative limb. Five (22%) of the patients had >= 20 mm of tibial length discrepancy at last follow-up. Three of these patients underwent contralateral tibial epiphysiodesis. Three patients required corrective surgery for angular deformity. CONCLUSIONS: The tibial growth plate may not resume normal growth after implantation of a distal femoral prosthesis. Physeal bar resection, prosthesis revision, and contralateral tibial epiphysiodesis may be needed to address tibial growth abnormalities. PMID- 26582625 TI - The Relationship of Obesity to Increasing Health-Care Burden in the Setting of Orthopaedic Polytrauma. AB - BACKGROUND: With the rise of obesity in the American population, there has been a proportionate increase of obesity in the trauma population. The purpose of this study was to use a computed tomography-based measurement of adiposity to determine if obesity is associated with an increased burden to the health-care system in patients with orthopaedic polytrauma. METHODS: A prospective comprehensive trauma database at a level-I trauma center was utilized to identify 301 patients with polytrauma who had orthopaedic injuries and intensive care unit admission from 2006 to 2011. Routine thoracoabdominal computed tomographic scans allowed for measurement of the truncal adiposity volume. The truncal three dimensional reconstruction body mass index was calculated from the computed tomography-based volumes based on a previously validated algorithm. A truncal three-dimensional reconstruction body mass index of <30 kg/m(2) denoted non-obese patients and >= 30 kg/m(2) denoted obese patients. The need for orthopaedic surgical procedure, in-hospital mortality, length of stay, hospital charges, and discharge disposition were compared between the two groups. RESULTS: Of the 301 patients, 21.6% were classified as obese (truncal three-dimensional reconstruction body mass index of >= 30 kg/m(2)). Higher truncal three dimensional reconstruction body mass index was associated with longer hospital length of stay (p = 0.02), more days spent in the intensive care unit (p = 0.03), more frequent discharge to a long-term care facility (p < 0.0002), higher rate of orthopaedic surgical intervention (p < 0.01), and increased total hospital charges (p < 0.001). CONCLUSIONS: Computed tomographic scans, routinely obtained at the time of admission, can be utilized to calculate truncal adiposity and to investigate the impact of obesity on patients with polytrauma. Obese patients were found to have higher total hospital charges, longer hospital stays, discharge to a continuing-care facility, and a higher rate of orthopaedic surgical intervention. PMID- 26582626 TI - Saline Soliloquy: Shaking Up Our Thoughts on Perioperative Hyponatremia: Commentary on an article by E. Hennrikus, MD, et al.: "Prevalence, Timing, Causes, and Outcomes of Hyponatremia in Hospitalized Orthopaedic Surgery Patients". PMID- 26582627 TI - Exploring an Anabolic Approach to Address Nonunion After Bone Fracture: Commentary on an article by Brian A. Tinsley, MD, et al.: "Systemic Administration of Sclerostin Antibody Enhances Bone Morphogenetic Protein-Induced Femoral Defect Repair in a Rat Model". PMID- 26582628 TI - Pre-clinical versus clinical medical students' attitudes towards the poor in the United States. AB - This study assessed the poverty-related attitudes of pre-clinical medical students (first and second years) versus clinical medical students (third and fourth years). First through fourth year medical students voluntarily completed the Attitude Towards Poverty scale. First and second year students were classified together in the preclinical group and third and fourth year students together in the clinical group. A total of 297 students participated (67% response rate). Statistically significant differences were noted between pre clinical and clinical students for scores on the subscales personal deficiency (P<0.001), stigma (P=0.023), and for total scores (P=0.016). Scores across these subscales and for total scores were all higher in the clinical group. The only subscale which did not show statistical significance between pre-clinical and clinical students was the structural perspective. Medical students in their clinical training have a less favorable attitude towards the poor than their preclinical counterparts. PMID- 26582629 TI - Developing a situational judgment test blueprint for assessing the non-cognitive skills of applicants to the University of Utah School of Medicine, the United States. AB - PURPOSE: The situational judgment test (SJT) shows promise for assessing the non cognitive skills of medical school applicants, but has only been used in Europe. Since the admissions processes and education levels of applicants to medical school are different in the United States and in Europe, it is necessary to obtain validity evidence of the SJT based on a sample of United States applicants. METHODS: Ninety SJT items were developed and Kane's validity framework was used to create a test blueprint. A total of 489 applicants selected for assessment/interview day at the University of Utah School of Medicine during the 2014-2015 admissions cycle completed one of five SJTs, which assessed professionalism, coping with pressure, communication, patient focus, and teamwork. Item difficulty, each item's discrimination index, internal consistency, and the categorization of items by two experts were used to create the test blueprint. RESULTS: The majority of item scores were within an acceptable range of difficulty, as measured by the difficulty index (0.50-0.85) and had fair to good discrimination. However, internal consistency was low for each domain, and 63% of items appeared to assess multiple domains. The concordance of categorization between the two educational experts ranged from 24% to 76% across the five domains. CONCLUSION: The results of this study will help medical school admissions departments determine how to begin constructing a SJT. Further testing with a more representative sample is needed to determine if the SJT is a useful assessment tool for measuring the non-cognitive skills of medical school applicants. PMID- 26582630 TI - Visible Facebook profiles and e-professionalism in undergraduate medical students in India. AB - PURPOSE: This study aimed to assess medical students' presence on Facebook and the extent of their visible activity, with particular reference to online professionalism. METHODS: This was a cross-sectional study including all medical students enrolled in the University College of Medical Sciences, University of Delhi, India during the period of the study, which was conducted from 2011 to 2012. After approval by the Institutional Ethical Committee, the full names of all students were obtained from our institution. After creating a fictitious profile, Facebook was searched for students' profiles, and those found were examined for visible content and unprofessional behaviour. RESULTS: Of 611 students, 477 (78.1%) had detectable Facebook profiles. Out of 477 profiles, date of birth, address, email, phone number, religion, and political views were rarely shared; sexual orientation and relationship status were displayed on approximately one third of the profiles; and an identifiable profile picture (80.3%), field of study (51.6%), and institution (86.2%) were commonly shared . The visible content included friend lists (88.7%), photo albums (36.1%), and associations with diverse groups and pages (97.1%). Five profiles (1.05%) displayed unprofessional content, including one profile photograph depicting alcohol consumption, one association with groups relating to excessive alcohol consumption, two profiles containing sexually explicit language, and one association with a sexist page. CONCLUSION: Most of our students use Facebook's privacy settings to hide some content from others. Unprofessional content was rarely visible from a stranger's profile. However, even when hidden from strangers, unprofessional behaviour is still unprofessional behaviour. As Facebook is an integral part of life, it is important for medical educators and students to understand the implications and importance of e-professionalism. Professionalism curricula should address e-professionalism. PMID- 26582631 TI - The role of prehealth student volunteers at a student-run free clinic in New York, United States. AB - PURPOSE: The medical student-run Einstein Community Health Outreach Clinic provides free healthcare to the uninsured adult population of New York, the United States. During the summer, prehealth student volunteers are recruited to assist with clinic operations. METHODS: We designed a survey study to identify the baseline characteristics of the volunteers between June and August of 2013 and 2014 in order to evaluate the influence of working in a medical student-run free clinic on their education, impressions, and career goals. RESULTS: A total of 38 volunteers (response rate, 83%) participated in the study. The volunteers were demographically diverse and interested in primary care specialties and community service. CONCLUSION: After the Einstein Community Health Outreach program, the volunteers showed an improved understanding of the healthcare process and issues relevant to uninsured patients. They also developed favorable attitudes towards primary care medicine and an increased level of interest in pursuing careers in primary care. PMID- 26582632 TI - Emergency medicine and internal medicine trainees' smartphone use in clinical settings in the United States. AB - PURPOSE: Smartphone technology offers a multitude of applications (apps) that provide a wide range of functions for healthcare professionals. Medical trainees are early adopters of this technology, but how they use smartphones in clinical care remains unclear. Our objective was to further characterize smartphone use by medical trainees at two United States academic institutions, as well as their prior training in the clinical use of smartphones. METHODS: In 2014, we surveyed 347 internal medicine and emergency medicine resident physicians at the University of Utah and Brigham and Women's Hospital about their smartphone use and prior training experiences. Scores (0%-100%) were calculated to assess the frequency of their use of general features (email, text) and patient-specific apps, and the results were compared according to resident level and program using the Mann-Whitney U-test. RESULTS: A total of 184 residents responded (response rate, 53.0%). The average score for using general features, 14.4/20 (72.2%) was significantly higher than the average score for using patient-specific features and apps, 14.1/44 (33.0%, P<0.001). The average scores for the use of general features, were significantly higher for year 3-4 residents, 15.0/20 (75.1%) than year 1-2 residents, 14.1/20 (70.5%, P=0.035), and for internal medicine residents, 14.9/20 (74.6%) in comparison to emergency medicine residents, 12.9/20 (64.3%, P= 0.001). The average score reflecting the use of patient-specific apps was significantly higher for year 3-4 residents, 16.1/44 (36.5%) than for year 1 2 residents, 13.7/44 (31.1%; P=0.044). Only 21.7% of respondents had received prior training in clinical smartphone use. CONCLUSION: Residents used smartphones for general features more frequently than for patient-specific features, but patient-specific use increased with training. Few residents have received prior training in the clinical use of smartphones. PMID- 26582633 TI - Acute Inflammatory Response to Low-, Moderate-, and High-Load Resistance Exercise in Women With Breast Cancer-Related Lymphedema. AB - Background Resistance exercise is emerging as a potential adjunct therapy to aid in the management of breast cancer-related lymphedema (BCRL). However, the mechanisms underlying the relationships between the acute and long-term benefits of resistance exercise on BCRL are not well understood. Purpose To examine the acute inflammatory response to upper-body resistance exercise in women with BCRL and to compare these effects between resistance exercises involving low, moderate, and high loads. The impact on lymphedema status and associated symptoms was also compared. Methods A total of 21 women, 62 +/- 10 years old, with BCRL participated in the study. Participants completed low-load (15-20 repetition maximum [RM]), moderate-load (10-12 RM), and high-load (6-8 RM) exercise sessions consisting of 3 sets of 6 upper-body resistance exercises. Sessions were completed in a randomized order separated by a 7- to 10-day wash-out period. Venous blood samples were obtained to assess markers of exercise-induced muscle damage and inflammation. Lymphedema status was assessed using bioimpedance spectroscopy and arm circumferences, and associated symptoms were assessed using Visual Analogue Scales for pain, heaviness, and tightness. Measurements were conducted before and 24 hours after the exercise sessions. Results No significant changes in creatine kinase, C-reactive protein, interleukin-6, and tumor necrosis factor-alpha were observed following the 3 resistance exercise sessions. There were no significant changes in arm swelling or symptom severity scores across the 3 resistance exercise conditions. Conclusions The magnitude of acute exercise induced inflammation following upper-body resistance exercise in women with BCRL does not vary between resistance exercise loads. PMID- 26582634 TI - Next-generation sequencing reveals differentially amplified tandem repeats as a major genome component of Northern Europe's oldest Camellia japonica. AB - Northern Europe's oldest and largest Camellia japonica growing at the Pillnitz Castle (Germany) for over 200 years is of botanical and cultural importance and is a reference for C. japonica molecular scale analysis. In order to provide a fundament for genome analysis of the genus Camellia, we characterize the C. japonica tandem repeat fraction, constituting 12.5 % of the Pillnitz camellia's genome. A genomic library of the Pillnitz C. japonica was produced and Illumina sequenced to generate 36 Gb of paired-end reads. We performed graph-based read clustering implemented in the RepeatExplorer pipeline to estimate the C. japonica repeat fraction of 73 %. This enabled us to identify and characterize the most prominent satellite DNAs, Camellia japonica satellite 1-4 (CajaSat1-CajaSat4), and the 5S ribosomal DNA (rDNA) by bioinformatics, fluorescent in situ and Southern hybridization. Within the Camellia genus, satellite spreading, array expansion and formation of higher-order structures highlight different modes of repeat evolution. The CajaSat satellites localize at prominent chromosomal sites, including (peri)centromeres and subtelomeres of all chromosomes, thus serving as chromosomal landmarks for their identification. This work provides an insight into the C. japonica chromosome organization and significantly expands the Camellia genomic knowledge, also with respect to the tea plant Camellia sinensis. PMID- 26582636 TI - Role of the kidney in the pathogenesis of hypertension: time for a neo-Guytonian paradigm or a paradigm shift? AB - The "Guytonian paradigm" places the direct effect of arterial pressure, on renal excretion of salt and water, at the center of long-term control of blood pressure, and thus the pathogenesis of hypertension. It originated in the sixties and remains influential within the field of hypertension research. However, the concept of one central long-term feedback loop, through which arterial pressure is maintained by its influence on renal function, has been questioned. Furthermore, some concepts in the paradigm are undermined by experimental observations. For example, volume retention and increased cardiac output induced by high salt intake do not necessarily lead to increased arterial pressure. Indeed, in multiple models of salt-sensitive hypertension the major abnormality appears to be failure of the vasodilator response to increased cardiac output, seen in salt-resistant animals, rather than an increase in cardiac output itself. There is also evidence that renal control of extracellular fluid volume is driven chiefly by volume-dependent neurohumoral control mechanisms rather than through direct or indirect effects of changes in arterial pressure, compatible with the concept that renal sodium excretion is controlled by parallel actions of different feedback systems, including hormones, reflexes, and renal arterial pressure. Moreover, we still do not fully understand the sequence of events underlying the phenomenon of "whole body autoregulation." Thus the events by which volume retention may develop to hypertension characterized by increased peripheral resistance remain enigmatic. Finally, by definition, animal models of hypertension are not "essential hypertension;" progress in our understanding of essential hypertension depends on new results on system functions in patients. PMID- 26582635 TI - The interplay between centrosomes and the Hippo tumor suppressor pathway. AB - Centrosome amplification is a common feature of both solid and hematological human malignancies. Extra centrosomes are not merely innocent bystanders in cancer cells, but rather promote tumor progression by disrupting normal cellular architecture and generating chromosome instability. Consequently, centrosome amplification correlates with advanced tumor grade and overall poor clinical prognosis. By contrast, extra centrosomes are adversely tolerated in non transformed cells and hinder cell proliferation. This suggests that in addition to acquiring extra centrosomes, cancer cells must also adapt to overcome the deleterious consequences associated with them. Here, we review evidence that implicates core components of the Hippo tumor suppressor pathway as having key roles in both the direct and indirect regulation of centrosome number. Intriguingly, functional inactivation of the Hippo pathway, which is common across broad spectrum of human cancers, likely represents one key adaptation that enables cancer cells to tolerate extra centrosomes. PMID- 26582637 TI - Cohort of estrogen-induced microRNAs regulate adrenomedullin expression. AB - Estrogen regulates the expression of many genes and has been correlated with differences in cardiac contraction; however, the underlying mechanisms remain poorly defined. Adrenomedullin (Adm = gene; AM = protein) is a multifunctional peptide with inotropic actions. Previous studies have demonstrated that estrogen enhances the expression of Adm, suggesting a relationship between AM and estrogen in cardiac contraction during physiological and pathological states. In this study, female mice in a mouse model of genetic Adm overexpression, abbreviated as Adm(hi/hi), were found to express 60 times more Adm in the heart than wild-type littermates, compared with the three-fold elevation of Adm previously reported in Adm(hi/hi) male hearts. Thus, this study sought to further investigate any functional consequences of increased cardiac Adm expression and begin exploring the mechanisms that regulate Adm expression in an estrogen-dependent fashion. This study revealed that heart function is enhanced in Adm(hi/hi) females, which along with Adm expression levels, was reversed following ovariectomization. Since the Adm(hi/hi) line was generated by the displacement of the 3' untranslated region (UTR), the native 3'UTR was examined for estrogen-induced microRNAs target sites to potentially explain the aberrant overexpression observed in Adm(hi/hi) female hearts. Using a bioinformatic approach, it was determined that the mouse Adm 3'UTR contains many target sites for previously characterized estrogen induced microRNAs. This study also determined that the novel microRNA, miR-879, is another estrogen-induced microRNA that interacts with the 3'UTR of Adm to destabilize the mRNA. Together, these studies revealed that estrogen-induced microRNAs are important for balancing cardiac Adm expression in females. PMID- 26582639 TI - Acclimation and acute temperature effects on population differences in oxidative phosphorylation. AB - Temperature changes affect metabolism on acute, acclamatory, and evolutionary time scales. To better understand temperature's affect on metabolism at these different time scales, we quantified cardiac oxidative phosphorylation (OxPhos) in three Fundulus taxa acclimated to 12 and 28 degrees C and measured at three acute temperatures (12, 20, and 28 degrees C). The Fundulus taxa (northern Maine and southern Georgia F. heteroclitus, and a sister taxa, F. grandis) were used to identify evolved changes in OxPhos. Cardiac OxPhos metabolism was quantified by measuring six traits: state 3 (ADP and substrate-dependent mitochondrial respiration); E state (uncoupled mitochondrial activity); complex I, II, and IV activities; and LEAK ratio. Acute temperature affected all OxPhos traits. Acclimation only significantly affected state 3 and LEAK ratio. Populations were significantly different for state 3. In addition to direct effects, there were significant interactions between acclimation and population for complex I and between population and acute temperature for state 3. Further analyses suggest that acclimation alters the acute temperature response for state 3, E state, and complexes I and II: at the low acclimation temperature, the acute response was dampened at low assay temperatures, and at the high acclimation temperature, the acute response was dampened at high assay temperatures. Closer examination of the data also suggests that differences in state 3 respiration and complex I activity between populations were greatest between fish acclimated to low temperatures when assayed at high temperatures, suggesting that differences between the populations become more apparent at the edges of their thermal range. PMID- 26582638 TI - Hemodynamic and neural responses to renal denervation of the nerve to the clipped kidney by cryoablation in two-kidney, one-clip hypertensive rats. AB - Renal artery stenosis is increasing in prevalence. Angioplasty plus stenting has not proven to be better than medical management. There has been a reluctance to use available denervation methodologies in this condition. We studied conscious, chronically instrumented, two-kidney, one-clip (2K-1C) Goldblatt rats, a model of renovascular hypertension, to test the hypothesis that renal denervation by cryoablation (cryo-DNX) of the renal nerve to the clipped kidney decreases mean arterial pressure (MAP), plasma and tissue ANG II, and contralateral renal sympathetic nerve activity (RSNA). Five-week-old male Sprague-Dawley rats underwent sham (ShC) or right renal artery clipping (2K-1C), placement of telemetry transmitters, and pair-feeding with a 0.4% NaCl diet. After 6 wk, rats were randomly assigned to cryo-DNX or sham cryotreatment (sham DNX) of the renal nerve to the clipped kidney. MAP was elevated in 2K-1C and decreased significantly in both ShC cryo-DNX and 2K-1C cryo-DNX. Tissue norepinephrine was ~85% lower in cryo-DNX kidneys. Plasma ANG II was higher in 2K-1C sham DNX but not in 2K-1C cryo-DNX vs ShC. Renal tissue ANG II in the clipped kidney decreased after cryo-DNX. Baseline integrated RSNA of the unclipped kidney was threefold higher in 2K-1C versus ShC and decreased in 2K-1C cryo-DNX to values similar to ShC. Maximum reflex response of RSNA to baroreceptor unloading in 2K-1C was lower after cryo-DNX. Thus, denervation by cryoablation of the renal nerve to the clipped kidney decreases not only MAP but also plasma and renal tissue ANG II levels and RSNA to the contralateral kidney in conscious, freely moving 2K-1C rats. PMID- 26582640 TI - Treadmill walking in water induces greater respiratory muscle fatigue than treadmill walking on land in healthy young men. AB - The purpose of the present study was to investigate the effect of walking in water on respiratory muscle fatigue compared with that of walking on land at the same exercise intensity. Ten healthy males participated in 40-min treadmill walking trials on land and in water at an intensity of 60% of peak oxygen consumption. Respiratory function and respiratory muscle strength were evaluated before and after walking trials. Inspiratory muscle strength and forced expiratory volume in 1 s were significantly decreased immediately after walking in water, and expiratory muscle strength was significantly decreased immediately and 5 min after walking in water compared with the baseline. The decreases of inspiratory and expiratory muscle strength were significantly greater compared with that after walking on land. In conclusion, greater inspiratory and expiratory muscle fatigue was induced by walking in water than by walking on land at the same exercise intensity in healthy young men. PMID- 26582641 TI - Interscalene brachial plexus blockade does not guarantee complete C8-T1 root block. PMID- 26582642 TI - Quarter of patients think it's fine to use friend or family member's antibiotics, survey finds. PMID- 26582643 TI - BTK inhibition results in impaired CXCR4 chemokine receptor surface expression, signaling and function in chronic lymphocytic leukemia. AB - Bruton's tyrosine kinase (BTK) is involved in the regulation of B-cell growth, migration and adhesion. The importance of BTK in cell trafficking is emphasized by the clonal contraction proceeded by lymphocytosis typical for the enzyme inhibitor, ibrutinib, in B-cell malignancies, including chronic lymphocytic leukemia (CLL). Here, we investigated BTK regulation of leukemic B-cell trafficking in a mouse model of aggressive TCL1 CLL-like disease. Inhibiting BTK by ibrutinib reduced surface membrane (sm) levels of CXCR4 but not CXCR5, CD49d and other adhesion/homing receptors. Decreased smCXCR4 levels resulted from blocking receptor signal transduction, which in turn aborted cycling from and to the membrane. This resulted in rapid re-distribution of CLL cells from spleens and lymph nodes into the circulation. CLL cells with impaired smCXCR4 from BTK inhibition failed to home to spleens. These functional changes mainly resulted from inhibition of CXCR4 phosphorylation at Ser339, mediated directly by blocking BTK enzymatic activity and indirectly by affecting the function of downstream targets PLCgamma2 and PKCMU, and eventually synthesis of PIM-1 and BTK itself. Our data identify CXCR4 as a key regulator in BTK-mediated CLL-cell retention and have elucidated a complex set of not previously described mechanisms responsible for these effects. PMID- 26582645 TI - Pretreatment d-2-hydroxyglutarate serum levels negatively impact on outcome in IDH1-mutated acute myeloid leukemia. AB - Mutations in isocitrate dehydrogenases (IDHs) 1 and 2 frequently occur in acute myeloid leukemia (AML) and result in the production of the oncometabolite d-2 hydroxyglutarate (D2HG). D2HG has been shown to promote leukemogenesis even in the absence of mutated IDH, but the prognostic significance of pretreatment serum D2HG levels in patients with IDH-mutated AML is unclear. We measured D2HG serum levels in 84 patients with IDH-mutated AML treated in the prospective, randomized multicenter AML2003 trial of the German Study Alliance Leukemia. Multivariate Cox regression showed D2HG levels to negatively impact on event-free survival (EFS) as a continuous variable in the entire IDH(mut) cohort (P=0.04), with no effect on overall survival (OS). In a subgroup analysis, the negative impact of D2HG on EFS was found to be restricted to patients with mutations in IDH1 (P=0.003), adjusted for age, leukocyte count, serum lactate dehydrogenase and European LeukemiaNet risk score. We thus conclude that pretreatment D2HG serum levels may yield prognostic information in patients with IDH1-mutated, but not in IDH2 mutated AML, possibly due to different subcellular localizations of IDH1 and IDH2. PMID- 26582644 TI - Cooperation of BRAF(F595L) and mutant HRAS in histiocytic sarcoma provides new insights into oncogenic BRAF signaling. AB - Activating BRAF mutations, in particular V600E/K, drive many cancers and are considered mutually exclusive with mutant RAS, whereas inactivating BRAF mutations in the D(594)F(595)G(596) motif cooperate with RAS via paradoxical MEK/ERK activation. Due to the increasing use of comprehensive tumor genomic profiling, many non-V600 BRAF mutations are being detected whose functional consequences and therapeutic actionability are often unknown. We investigated an atypical BRAF mutation, F595L, which was identified along with mutant HRAS in histiocytic sarcoma and also occurs in epithelial cancers, melanoma and neuroblastoma, and determined its interaction with mutant RAS. Unlike other DFG motif mutants, BRAF(F595L) is a gain-of-function variant with intermediate activity that does not act paradoxically, but nevertheless cooperates with mutant RAS to promote oncogenic signaling, which is efficiently blocked by pan-RAF and MEK inhibitors. Mutation data from patients and cell lines show that BRAF(F595L), as well as other intermediate-activity BRAF mutations, frequently coincide with mutant RAS in various cancers. These data define a distinct class of activating BRAF mutations, extend the spectrum of patients with systemic histiocytoses and other malignancies who are candidates for therapeutic blockade of the RAF-MEK-ERK pathway and underscore the value of comprehensive genomic testing for uncovering the vulnerabilities of individual tumors. PMID- 26582646 TI - Molecular prognostic factors in acute myeloid leukemia receiving first-line therapy with azacitidine. PMID- 26582647 TI - Extreme mutational selectivity of axitinib limits its potential use as a targeted therapeutic for BCR-ABL1-positive leukemia. PMID- 26582649 TI - Association of social support, functional status, and psychological variables with changes in health-related quality of life outcomes in patients with colorectal cancer. AB - BACKGROUND: The aim of this study was to explore the association of social support received, and functional and psychological status of colorectal cancer patients before surgery with changes in health-related quality of life (HRQoL) outcomes measured by EORTC QLQ-C30 at 1-year post-intervention. METHODS: Consecutive patients that were because of undergo therapeutic surgery for the first time for colon or rectum cancer in nine hospitals in Spain were eligible for the study. Patients completed questionnaires before surgery and 12 months afterwards: one HRQoL instrument, the EORTC QLQ-C30; a social network and social support questionnaire, the Duke-UNC Functional Social Support Questionnaire; the Hospital Anxiety and Depression Scale, to assess anxiety and depression; and the Barthel Index, to assess functional status; as well as questions about sociodemographic information. General linear models were built to explore the association of social support, functional status, and psychological variables with changes in HRQoL 12 months after intervention. RESULTS: A total of 972 patients with colorectal cancer took part in the study. Patients' functional status, social support, and anxiety and depression were associated with changes in at least one HRQoL domain. The higher functional status, and the higher social support, the more they improved in HRQoL domains. Regarding anxiety and depression, the more anxiety and depression patients have at baseline, less they improve in HRQoL domains. CONCLUSIONS: Patients with colorectal cancer who have more social support and no psychological distress may have better results in HRQoL domains at 1 year after surgery. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26582648 TI - Evidence that a lipolytic enzyme--hematopoietic-specific phospholipase C-beta2- promotes mobilization of hematopoietic stem cells by decreasing their lipid raft mediated bone marrow retention and increasing the promobilizing effects of granulocytes. AB - Hematopoietic stem/progenitor cells (HSPCs) reside in the bone marrow (BM) microenvironment and are retained there by the interaction of membrane lipid raft associated receptors, such as the alpha-chemokine receptor CXCR4 and the alpha4beta1-integrin (VLA-4, very late antigen 4 receptor) receptor, with their respective specific ligands, stromal-derived factor 1 and vascular cell adhesion molecule 1, expressed in BM stem cell niches. The integrity of the lipid rafts containing these receptors is maintained by the glycolipid glycosylphosphatidylinositol anchor (GPI-A). It has been reported that a cleavage fragment of the fifth component of the activated complement cascade, C5a, has an important role in mobilizing HSPCs into the peripheral blood (PB) by (i) inducing degranulation of BM-residing granulocytes and (ii) promoting their egress from the BM into the PB so that they permeabilize the endothelial barrier for subsequent egress of HSPCs. We report here that hematopoietic cell-specific phospholipase C-beta2 (PLC-beta2) has a crucial role in pharmacological mobilization of HSPCs. On the one hand, when released during degranulation of granulocytes, it digests GPI-A, thereby disrupting membrane lipid rafts and impairing retention of HSPCs in BM niches. On the other hand, it is an intracellular enzyme required for degranulation of granulocytes and their egress from BM. In support of this dual role, we demonstrate that PLC-beta2-knockout mice are poor mobilizers and provide, for the first time, evidence for the involvement of this lipolytic enzyme in the mobilization of HSPCs. PMID- 26582650 TI - Skin-to-skin contact with an umbilical venous catheter: prospective evaluation in a level 3 unit. AB - The aim was to assess the incidence of complications related to skin-to-skin contact (SSC) in newborns with an umbilical venous catheter (UVC). We carried out a prospective follow-up study of all UVCs in a level 3 unit where SSC is systematic. A total of 333 babies were included (mean gestational age of 31.3 weeks (24-41), mean birth weight of 1618 g (454-4900). Two hundred sixty-three babies (78.9 %) had SSC, at a mean postnatal age of 24 h (3-144 h). Two babies presented with a significant umbilical bleeding, all in the first 3 h, before SSC. In 17 cases of UVC leaking, this necessitated an unwanted withdrawal of the UVC; of these, 14 UVCs (82 %) were in sub-hepatic position. In five cases of UVC displacement, babies had no SSC. The overall incidence (3 % [95 % CI = 1.4-5.4]) and incidence density (6.2/1000 UVC-day [95 % CI = 3-11.4]) of catheter associated infections are similar to those identified by the French multicenter network NEOCAT in 2012 (5 % [95 % CI = 4.1-5.9] and 11.3/1000 UVC-day [95 % CI = 9.3-13.2]). CONCLUSION: In this prospective, non-randomized study in a level unit, routine practice of SSC with a UVC does not seem to influence the incidence of mechanical and infectious complications. What is known? * SSC is beneficial for pretem infants. * Fear of mechanical problems and/or infections with a UVC is an obstacle to early use of SSC. What is New: * In this study, SSC for preterm infants with a UVC is associated with low risks of mechanical complications, and does not seem to be associated with any higher risk of catheter-related infections. PMID- 26582651 TI - Tooth Germ-Like Construct Transplantation for Whole-Tooth Regeneration: An In Vivo Study in the Miniature Pig. AB - The purpose of this study was to demonstrate the feasibility of whole-tooth regeneration using a tooth germ-like construct. Dental pulp from upper incisors, canines, premolars, and molars were extracted from sexually mature miniature pigs. Pulp tissues were cultured and expanded in vitro to obtain dental pulp stem cells (DPSCs), and cells were differentiated into odontoblasts and osteoblasts. Epithelial cells were isolated from gingival epithelium. The epithelial cells, odontoblasts, and osteoblasts were seeded onto the surface, upper, and lower layers, respectively, of a bioactive scaffold. The lower first and second molar tooth germs were removed bilaterally and the layered cell/scaffold constructs were transplanted to the mandibular alveolar socket of a pig. At 13.5 months postimplantation, seven of eight pigs developed two teeth with crown, root, and pulp structures. Enamel-like tissues, dentin, cementum, odontoblasts, and periodontal tissues were found upon histological inspection. The regenerated tooth expressed dentin matrix protein-1 and osteopontin. All pigs had regenerated molar teeth regardless of the original tooth used to procure the DPSCs. Pigs that had tooth germs removed or who received empty scaffolds did not develop teeth. Although periodontal ligaments were generated, ankylosis was found in some animals. This study revealed that implantation of a tooth germ-like structure generated a complete tooth with a high success rate. The implant location may influence the morphology of the regenerated tooth. PMID- 26582652 TI - Robust Photocatalytic H2O2 Production by Octahedral Cd3(C3N3S3)2 Coordination Polymer under Visible Light. AB - Herein, we reported a octahedral Cd3(C3N3S3)2 coordination polymer as a new noble metal-free photocatalyst for robust photocatalytic H2O2 production from methanol/water solution. The coordination polymer can give an unprecedented H2O2 yield of ca. 110.0 mmol * L(-1) * g(-1) at pH = 2.8 under visible light illumination. The characterization results clearly revealed that the photocatalytic H2O2 production proceeds by a pathway of two-electron reduction of O2 on the catalyst surface. This work showed the potential perspective of Mx(C3N3S3)y (M = transitional metals) coordination polymers as a series of new materials for solar energy storage and conversion. PMID- 26582653 TI - Limited value of cabergoline in Cushing's disease: a prospective study of a 6 week treatment in 20 patients. AB - CONTEXT AND OBJECTIVE: The role of cabergoline in Cushing's disease (CD) remains controversial. The experience is limited to case reports and few open studies that report the effects determined after >=1 month of treatment. In prolactinomas and dopamine-responsive GH-secreting tumours, effects of cabergoline are seen within days or weeks. Here, we searched for short-term effects of cabergoline in CD. DESIGN: Twenty patients (19 naive and one recurrent) were included in a prospective study. Cabergoline was administered in increasing doses of 0.5-5 mg/week over 6 weeks. METHODS: Urinary free cortisol (UFC) 24 h, morning cortisol and ACTH, and salivary cortisol at 0800, 1600 and 2300 h were determined once weekly throughout. Diurnal curves (six samples) of serum cortisol were measured at start and end. RESULTS: At study end, the median cabergoline dose was 5 mg, range 2.5-5 mg/week. The prolactin levels, markers of compliance, were suppressed in all patients. During the treatment, hypercortisolism varied, gradual and dose dependent reductions were not seen. Five patients had a >50% decrease of UFC, three had a >50% rise of UFC. Salivary cortisol at 2300 h showed a congruent >50% change with UFC in two of the five cases with decreased UFC, and in one of the three cases with increased UFC. One patient with decreases in both UFC and 2300 h salivary cortisol also had a reduction in diurnal serum cortisol during the course of the study. CONCLUSIONS: Cabergoline seems to be of little value in the management of CD. Only one patient had a response-like pattern. Given the known variability of disease activity in CD, this might represent a chance finding. PMID- 26582654 TI - T-type calcium channels cause bursts of spikes in motor but not sensory thalamic neurons during mimicry of natural patterns of synaptic input. AB - Although neurons within intact nervous systems can be classified as 'sensory' or 'motor,' it is not known whether there is any general distinction between sensory and motor neurons at the cellular or molecular levels. Here, we extend and test a theory according to which activation of certain subtypes of voltage-gated ion channel (VGC) generate patterns of spikes in neurons of motor systems, whereas VGC are proposed to counteract patterns in sensory neurons. We previously reported experimental evidence for the theory from visual thalamus, where we found that T-type calcium channels (TtCCs) did not cause bursts of spikes but instead served the function of 'predictive homeostasis' to maximize the causal and informational link between retinogeniculate excitation and spike output. Here, we have recorded neurons in brain slices from eight sensory and motor regions of rat thalamus while mimicking key features of natural excitatory and inhibitory post-synaptic potentials. As predicted by theory, TtCC did cause bursts of spikes in motor thalamus. TtCC-mediated responses in motor thalamus were activated at more hyperpolarized potentials and caused larger depolarizations with more spikes than in visual and auditory thalamus. Somatosensory thalamus is known to be more closely connected to motor regions relative to auditory and visual thalamus, and likewise the strength of its TtCC responses was intermediate between these regions and motor thalamus. We also observed lower input resistance, as well as limited evidence of stronger hyperpolarization-induced ('H-type') depolarization, in nuclei closer to motor output. These findings support our theory of a specific difference between sensory and motor neurons at the cellular level. PMID- 26582655 TI - Circulating tumor DNA identified by targeted sequencing in advanced-stage non small cell lung cancer patients. AB - Non-small cell lung cancers (NSCLC) have unique mutation patterns, and some of these mutations may be used to predict prognosis or guide patient treatment. Mutation profiling before and during treatment often requires repeated tumor biopsies, which is not always possible. Recently, cell-free, circulating tumor DNA (ctDNA) isolated from blood plasma has been shown to contain genetic mutations representative of those found in the primary tumor tissue DNA (tDNA), and these samples can readily be obtained using non-invasive techniques. However, there are still no standardized methods to identify mutations in ctDNA. In the current study, we used a targeted sequencing approach with a semi-conductor based next-generation sequencing (NGS) platform to identify gene mutations in matched tDNA and ctDNA samples from 42 advanced-stage NSCLC patients from China. We identified driver mutations in matched tDNA and ctDNA in EGFR, KRAS, PIK3CA, and TP53, with an overall concordance of 76%. In conclusion, targeted sequencing of plasma ctDNA may be a feasible option for clinical monitoring of NSCLC in the near future. PMID- 26582656 TI - Non-coding RNA as mediators in microenvironment-breast cancer cell communication. AB - The tumor microenvironment has a critical role in the survival and decision of the cancer cells. These include support by enhanced angiogenesis, and metastasis or adaptation of dormancy. This article discusses methods by which the microenvironment sustains the tumor. This process is important as it will identify avenues of drug targets. Non-coding RNAs (ncRNAs) are evolving as key mediators in the interaction between the cancer cells and the microenvironment. Thus, the question is how to develop methods to effectively block the effects of the ncRNA and/or to introduce them to prevent metastasis, dormancy or to reverse dormancy. We focused on the advantages of using mesenchymal stem cells (MSCs) for RNA delivery. MSCs can be available as "off-the-shelf" cells. Thus far, MSCs are shown to be safe when transplanted across allogeneic barriers. We discussed the various methods by which MSCs can interact with cancer cells to deliver ncRNA or antagomirs. We also include the advances and possible confounds of using these methods. Overall, this review article provides a potential method by which MSCs can be used for effective delivery of nucleic acid to treat cancer. PMID- 26582659 TI - Re: Risk Stratification for Bladder Recurrence of Upper Urinary Tract Urothelial Carcinoma after Radical Nephroureterectomy. PMID- 26582657 TI - Dietary tocopherols inhibit PhIP-induced prostate carcinogenesis in CYP1A humanized mice. AB - Tocopherols, the major forms of vitamin E, exist as alpha-tocopherol (alpha-T), beta-T, gamma-T and delta-T. The cancer preventive activity of vitamin E is suggested by epidemiological studies, but recent large-scale cancer prevention trials with high dose of alpha-T yielded disappointing results. Our hypothesis that other forms of tocopherols have higher cancer preventive activities than alpha-T was tested, herein, in a novel prostate carcinogenesis model induced by 2 amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP), a dietary carcinogen, in the CYP1A-humanized (hCYP1A) mice. Treatment of hCYP1A mice with PhIP (200 mg/kg b.w., i.g.) induced high percentages of mouse prostatic intraepithelial neoplasia (mPIN), mainly in the dorsolateral glands. Supplementation with a gamma-T-rich mixture of tocopherols (gamma-TmT, 0.3% in diet) significantly inhibited the development of mPIN lesions and reduced PhIP-induced elevation of 8-oxo deoxyguanosine, COX-2, nitrotyrosine, Ki-67 and p-AKT, and the loss of PTEN and Nrf2. Further studies with purified delta-T, gamma-T or alpha-T (0.2% in diet) showed that delta-T was more effective than gamma-T or alpha-T in preventing mPIN formations and p-AKT elevation. These results indicate that gamma-TmT and delta-T could be effective preventive agents of prostate cancer. PMID- 26582658 TI - Parainfluenza virus infections in hematopoietic cell transplant recipients and hematologic malignancy patients: A systematic review. AB - Parainfluenza viral infections are increasingly recognized as common causes of morbidity and mortality in cancer patients, particularly in hematopoietic cell transplant (HCT) recipients and hematologic malignancy (HM) patients because of their immunocompromised status and susceptibility to lower respiratory tract infections. Advances in diagnostic methods, including polymerase chain reaction, have led to increased identification and awareness of these infections. Lack of consensus on clinically significant endpoints and the small number of patients affected in each cancer institution every year make it difficult to assess the efficacy of new or available antiviral drugs. In this systematic review, we summarized data from all published studies on parainfluenza virus infections in HM patients and HCT recipients, focusing on incidence, risk factors, long-term outcomes, mortality, prevention, and management with available or new investigational agents. Vaccines against these viruses are lacking; thus, infection control measures remain the mainstay for preventing nosocomial spread. A multi-institutional collaborative effort is recommended to standardize and validate clinical endpoints for PIV infections, which will be essential for determining efficacy of future vaccine and antiviral therapies. PMID- 26582660 TI - Re: SUCCINCT: An Open-Label, Single-Arm, Non-Randomised, Phase 2 Trial of Gemcitabine and Cisplatin Chemotherapy in Combination with Sunitinib as First Line Treatment for Patients with Advanced Urothelial Carcinoma. PMID- 26582661 TI - Re: Incompletely Characterized Incidental Renal Masses: Emerging Data Support Conservative Management. PMID- 26582662 TI - Re: Comparing Open Radical Cystectomy and Robot-Assisted Laparoscopic Radical Cystectomy: A Randomized Clinical Trial. PMID- 26582663 TI - Re: Impact of Surgeon Volume on the Morbidity and Costs of Radical Cystectomy in the USA: A Contemporary Population-Based Analysis. PMID- 26582664 TI - Re: Health-Related Quality of Life after Radical Cystectomy and Neobladder Reconstruction in Women: Impact of Voiding and Continence Status. PMID- 26582665 TI - Re: Adverse Pathology and Undetectable Ultrasensitive Prostate-Specific Antigen after Radical Prostatectomy: Is Adjuvant Radiation Warranted? PMID- 26582666 TI - Re: Predicting High-Grade Cancer at Ten-Core Prostate Biopsy Using Four Kallikrein Markers Measured in Blood in the ProtecT Study. PMID- 26582667 TI - Re: Obesity and Hypogonadism Are Associated with an Increased Risk of Predominant Gleason 4 Pattern on Radical Prostatectomy Specimen. PMID- 26582668 TI - Re: Craniocaudal Retroperitoneal Node Length as a Risk Factor for Relapse from Clinical Stage I Testicular Germ Cell Tumor. PMID- 26582669 TI - Re: Is Fosfomycin a Potential Treatment Alternative for Multidrug-Resistant Gram Negative Prostatitis? PMID- 26582670 TI - Re: Development and Validation of a Nomogram Predicting Recurrence Risk in Women with Symptomatic Urinary Tract Infection. PMID- 26582671 TI - Re: The Microbiome of the Urinary Tract--A Role Beyond Infection. PMID- 26582672 TI - Re: Antimicrobial Resistance in Urinary Pathogens among Swedish Nursing Home Residents Remains Low: A Cross-Sectional Study Comparing Antimicrobial Resistance from 2003 to 2012. PMID- 26582673 TI - Re: Intermittent Self Catheterisation with Hydrophilic, Gel Reservoir, and Non Coated Catheters: A Systematic Review and Cost Effectiveness Analysis. PMID- 26582674 TI - Re: Risk of Associated Conditions in Relatives of Subjects with Interstitial Cystitis. PMID- 26582675 TI - Re: Shorter Waitlist Times and Improved Graft Survivals are Observed in Patients Who Accept Hepatitis C Virus+ Renal Allografts. PMID- 26582676 TI - Re: Hypercalciuria may Persist after Successful Parathyroid Surgery and it is Associated with Parathyroid Hyperplasia. PMID- 26582677 TI - Re: Does Stepwise Voltage Ramping Protect the Kidney from Injury during Extracorporeal Shockwave Lithotripsy? Results of a Prospective Randomized Trial. PMID- 26582678 TI - Re: Nomogram to Predict Uric Acid Kidney Stones Based on Patient's Age, BMI and 24-Hour Urine Profiles: A Multicentre Validation. PMID- 26582679 TI - Re: Laparoscopic Omentoplasty to Support Anastomotic Urethroplasty in Complex and Redo Pelvic Fracture Urethral Defects. PMID- 26582680 TI - Re: The Cost of Surveillance after Urethroplasty. PMID- 26582681 TI - Re: Trends, Utilization, and Immediate Perioperative Complications of Urethroplasty in the United States: Data from the National Inpatient Sample 2000 2010. PMID- 26582682 TI - Re: Robotic Management of Genitourinary Injuries from Obstetric and Gynaecological Operations: A Multi-Institutional Report of Outcomes. PMID- 26582683 TI - Re: Expectations of Stress Urinary Incontinence Surgery in Patients with Mixed Urinary Incontinence. PMID- 26582684 TI - Re: Mixed Incontinence: What Takes Precedence in Its Management? PMID- 26582685 TI - Re: Committee Opinion No. 603: Evaluation of Uncomplicated Stress Urinary Incontinence in Women before Surgical Treatment. PMID- 26582686 TI - Re: Individually Tailored Ultrasound-Assisted Prompted Voiding for Institutionalized Older Adults with Urinary Incontinence. PMID- 26582687 TI - Re: How Often Should Shelf/Gellhorn Pessaries be Changed? A Survey of IUGA Urogynaecologists. PMID- 26582688 TI - Re: Long-Term Follow-up after Colpocleisis: Regret, Bowel, and Bladder Function. PMID- 26582689 TI - Re: Holmium Laser Enucleation (HoLEP) and Photoselective Vaporisation of the Prostate (PVP) for Patients with Benign Prostatic Hyperplasia (BPH) and Chronic Urinary Retention. PMID- 26582690 TI - Re: Comparison of the Efficacy of Isosorbide Mononitrate and Doxazosin in the Treatment of Lower Urinary Tract Symptoms and Benign Prostatic Hyperplasia: A Randomized Clinical Trial. PMID- 26582691 TI - Re: Treatment of Benign Prostatic Hyperplasia by Occlusion of the Impaired Urogenital Venous System--First Experience. PMID- 26582692 TI - Re: Randomized Controlled Trial on the Efficacy of Bladder Training before Removing the Indwelling Urinary Catheter in Patients with Acute Urinary Retention Associated with Benign Prostatic Hyperplasia. PMID- 26582693 TI - Re: Sex Offenders Seeking Treatment for Sexual Dysfunction--Ethics, Medicine, and the Law. PMID- 26582694 TI - Re: Increased Risk of Dementia in Patients with Erectile Dysfunction: A Population-Based, Propensity Score-Matched, Longitudinal Follow-up Study. PMID- 26582695 TI - Re: Impact of Urinary Incontinence on Sexual Functioning in Community-Dwelling Older Women. PMID- 26582697 TI - Re: Medicated Sex in Britain: Evidence from the Third National Survey of Sexual Attitudes and Lifestyles. PMID- 26582698 TI - Re: Use of Phosphodiesterase Type 5 Inhibitors for Erectile Dysfunction and Risk of Malignant Melanoma. PMID- 26582699 TI - Re: Relationship between Physical Occupational Exposures and Health on Semen Quality: Data from the Longitudinal Investigation of Fertility and the Environment (LIFE) Study. PMID- 26582700 TI - Re: Exposure to Bisphenol-A and Reproductive Hormones among Male Adults. PMID- 26582701 TI - Re: Impairment of Male Reproductive Function after Sleep Deprivation. PMID- 26582702 TI - Re: Infertility Etiologies Are Genetically and Clinically Linked with Other Diseases in Single Meta-Diseases. PMID- 26582703 TI - Re: Optimizing Human Semen Cryopreservation by Reducing Test Vial Volume and Repetitive Test Vial Sampling. PMID- 26582704 TI - Re: Spinal Ultrasound in Patients with Anorectal Malformations: Is This the End of an Era? PMID- 26582705 TI - Re: The "Rescue Operation" for Patients with Cloacal Exstrophy and its Variants. PMID- 26582706 TI - Re: Modified Penile Disassembly Technique for Boys with Epispadias and Those Undergoing Complete Primary Repair of Exstrophy: Long-Term Outcomes. PMID- 26582707 TI - Re: Sexual Function and Health-Related Quality of Life in Women with Classic Bladder Exstrophy. PMID- 26582708 TI - Re: Prospective Evaluation of Urinary Metabolic Indices in Severely Obese Adolescents after Weight Loss Surgery. PMID- 26582709 TI - Re: Brain Feminization Requires Active Repression of Masculinization via DNA Methylation. PMID- 26582710 TI - Re: A Feedback Regulation between miR-145 and DNA Methyltransferase 3b in Prostate Cancer Cell and Their Responses to Irradiation. PMID- 26582711 TI - Re: Bone Marrow-Derived Cells Contribute to Regeneration of Injured Prostate Epithelium and Stroma. PMID- 26582712 TI - DNA Repair. AB - DNA is constantly damaged by various endogenous and exogenous events. Repair systems constantly scan the genome for DNA lesions and replace damaged and mismatched bases, which finally enables the complex DNA double strand to store genetic information. This year's Nobel Prize in Chemistry was awarded to pioneers in this field, T. Lindahl, P. Modrich, and A. Sancar. PMID- 26582713 TI - Identification of an "Exceptional Responder" Cell Line to MEK1 Inhibition: Clinical Implications for MEK-Targeted Therapy. AB - The identification of somatic genetic alterations that confer sensitivity to pharmacologic inhibitors has led to new cancer therapies. To identify mutations that confer an exceptional dependency, shRNA-based loss-of-function data were analyzed from a dataset of numerous cell lines to reveal genes that are essential in a small subset of cancer cell lines. Once these cell lines were determined, detailed genomic characterization from these cell lines was utilized to ascertain the genomic aberrations that led to this extreme dependency. This method, in a large subset of lung cancer cell lines, yielded a single lung adenocarcinoma cell line, NCI-H1437, which is sensitive to RNA interference of MAP2K1 expression. Notably, NCI-H1437 is the only lung cancer cell line included in the dataset with a known activating mutation in MAP2K1 (Q56P). Subsequent validation using shRNA and CRISPR-Cas9 confirmed MAP2K1 dependency. In vitro and in vivo inhibitor studies established that NCI-H1437 cells are sensitive to MEK1 inhibitors, including the FDA-approved drug trametinib. Like NCI-H1437 cells, the MAP2K1 mutant cell lines SNU-C1 (colon) and OCUM-1 (gastric) showed decreased viability after MAP2K1 depletion via Cas9-mediated gene editing. Similarly, these cell lines were particularly sensitive to trametinib treatment compared with control cell lines. On the basis of these data, cancers that harbor driver mutations in MAP2K1 could benefit from treatment with MEK1 inhibitors. Furthermore, this functional data mining approach provides a general method to experimentally test genomic features that confer dependence in tumors. IMPLICATIONS: Cancers with an activated RAS/MAPK pathway driven by oncogenic MAP2K1 mutations may be particularly sensitive to MEK1 inhibitor treatments. PMID- 26582714 TI - Irisin relaxes mouse mesenteric arteries through endothelium-dependent and endothelium-independent mechanisms. AB - Irisin, a newly discovered myokine, has been shown to produce modest weight loss and improve glucose intolerance in mice. The purpose of this study was to investigate the effects of irisin on vascular activity and the mechanisms involved. Experiments were performed on mouse mesenteric arteries. We demonstrated that irisin induced relaxation in mesenteric arteries with or without endothelium in a concentration-dependent manner. It was further demonstrated that the irisin-induced vasorelaxation effects on endothelium-intact mesenteric arteries were reduced by pretreatment with Nomega-nitro-L-arginine methyl ester (L-NAME) or 1H-[1, 2, 4] oxadizolo [4, 3-a] quinoxalin-1-one (ODQ). However, pretreatment with indomethacin (INDO), a nonselective cyclooxygenase inhibitor did not modulate irisin-induced relaxation. In addition, the contraction due to extracellular Ca(2+) influx and intracellular Ca(2+) release was also inhibited by irisin. In summary, these results suggested that the endothelium-dependent relaxation of irisin is mediated by the nitric oxide (NO) guanosine 3', 5'-cyclic phosphate (cGMP)-dependent pathway but not the prostaglandin I2 (PGI2)-cyclic adenosine monophosphate (cAMP)-dependent mechanism. Endothelium-independent relaxation may be depend on inhibiting Ca(2+) influx through blocking VDCCs and intracellular Ca(2+) release through both IP3R and RyR channels. PMID- 26582715 TI - Radiation-induced salivary hypofunction may become a thing of the past. PMID- 26582716 TI - An efficient empirical Bayes method for genomewide association studies. AB - Linear mixed model (LMM) is one of the most popular methods for genomewide association studies (GWAS). Numerous forms of LMM have been developed; however, there are two major issues in GWAS that have not been fully addressed before. The two issues are (i) the genomic background noise and (ii) low statistical power after Bonferroni correction. We proposed an empirical Bayes (EB) method by assigning each marker effect a normal prior distribution, resulting in shrinkage estimates of marker effects. We found that such a shrinkage approach can selectively shrink marker effects and reduce the noise level to zero for majority of non-associated markers. In the meantime, the EB method allows us to use an 'effective number of tests' to perform Bonferroni correction for multiple tests. Simulation studies for both human and pig data showed that EB method can significantly increase statistical power compared with the widely used exact GWAS methods, such as GEMMA and FaST-LMM-Select. Real data analyses in human breast cancer identified improved detection signals for markers previously known to be associated with breast cancer. We therefore believe that EB method is a valuable tool for identifying the genetic basis of complex traits. PMID- 26582717 TI - Use of Mycophenolate Mofetil in Patients with Severe Localized Scleroderma Resistant or Intolerant to Methotrexate. AB - To assess the efficacy and safety of mycophenolate mofetil (MMF) in patients with localized scleroderma (LoS) resistant or intolerant to previous treatment with methotrexate (MTX). A case series of patients with LoS treated with MMF. Outcome was assessed through clinical examination. Adverse events were documented. Seven patients with LoS were treated with MMF. Median age at MMF initiation was 15 years (range 7-74 years). Three patients received MMF due to MTX ineffectiveness and 4 due to MTX intolerance. Disease remission was achieved in 4 patients and maintained in one patient. One patient showed a favourable response, but had to discontinue treatment due to elevated liver enzymes. The remaining patient experienced disease progression. MMF was shown to improve the clinical condition of patients with refractory LoS and may be a relatively safe alternative in patients who are intolerant to MTX. PMID- 26582718 TI - The "long tail" of the protein tumbling correlation function: observation by (1)H NMR relaxometry in a wide frequency and concentration range. AB - Inter-protein interactions in solution affect the auto-correlation function of Brownian tumbling not only in terms of a simple increase of the correlation time, they also lead to the appearance of a weak slow component ("long tail") of the correlation function due to a slowly changing local anisotropy of the microenvironment. The conventional protocol of correlation time estimation from the relaxation rate ratio R1/R2 assumes a single-component tumbling correlation function, and thus can provide incorrect results as soon as the "long tail" is of relevance. This effect, however, has been underestimated in many instances. In this work we present a detailed systematic study of the tumbling correlation function of two proteins, lysozyme and bovine serum albumin, at different concentrations and temperatures using proton field-cycling relaxometry combined with R1rho and R2 measurements. Unlike high-field NMR relaxation methods, these techniques enable a detailed study of dynamics on a time scale longer than the normal protein tumbling correlation time and, thus, a reliable estimate of the parameters of the "long tail". In this work we analyze the concentration dependence of the intensity and correlation time of the slow component and perform simulations of high-field (15)N NMR relaxation data demonstrating the importance of taking the "long tail" in the analysis into account. PMID- 26582719 TI - Maternal serum alpha-fetoprotein at 12, 22 and 32 weeks' gestation in screening for pre-eclampsia. AB - OBJECTIVE: To examine the distribution of maternal serum alpha-fetoprotein (AFP) at 12, 22 and 32 weeks' gestation in singleton pregnancies which develop pre eclampsia (PE) and examine the performance of this biomarker in screening for PE. METHODS: Serum AFP was measured in 17 071 cases at 11-13 weeks, in 8583 cases at 19-24 weeks and 8609 cases at 30-34 weeks' gestation. Bayes' theorem was used to combine the a-priori risk from maternal characteristics and medical history with AFP. The performance of screening for PE requiring delivery < 32, at 32 + 0 to 36 + 6, < 37 and >= 37 weeks' gestation was estimated. RESULTS: In pregnancies that developed PE, serum AFP multiples of the median (MoM) was increased at 11-13 and 19-24 weeks' gestation, but not at 30-34 weeks, and the values were inversely related to gestational age at delivery. Combined screening with maternal factors and serum AFP improved the prediction provided by maternal factors alone for PE delivering < 37 weeks, but not for PE delivering >= 37 weeks. The performance of screening for preterm PE was better at 19-24 weeks than at 11-13 weeks and the detection rate (DR) for a given false-positive rate (FPR) was higher for PE delivering < 32 weeks than for PE delivering at 32 + 0 to 36 + 6 weeks. The DRs, at 10% FPR, of combined screening at 11-13 weeks for PE delivering < 32 and at 32 + 0 to 36 + 6 weeks were 54% and 45%, respectively, and these improved to 72% and 53% with screening at 19-24 weeks. CONCLUSIONS: Measurement of serum AFP at 11-13 and 19-24 weeks' gestation improves the prediction of preterm PE provided by maternal factors alone. Copyright (c) 2015 ISUOG. Published by John Wiley & Sons Ltd. PMID- 26582721 TI - IL-17A production by neutrophils. PMID- 26582720 TI - Consensus Recommendations on Initiating Prescription Therapies for Opioid-Induced Constipation. AB - OBJECTIVE: Aims of this consensus panel were to determine (1) an optimal symptom based method for assessing opioid-induced constipation in clinical practice and (2) a threshold of symptom severity to prompt consideration of prescription therapy. METHODS: A multidisciplinary panel of 10 experts with extensive knowledge/experience with opioid-associated adverse events convened to discuss the literature on assessment methods used for opioid-induced constipation and reach consensus on each objective using the nominal group technique. RESULTS: Five validated assessment tools were evaluated: the Patient Assessment of Constipation-Symptoms (PAC-SYM), Patient Assessment of Constipation-Quality of Life (PAC-QOL), Stool Symptom Screener (SSS), Bowel Function Index (BFI), and Bowel Function Diary (BF-Diary). The 3-item BFI and 4-item SSS, both clinician administered, are the shortest tools. In published trials, the BFI and 12-item PAC-SYM are most commonly used. The 11-item BF-Diary is highly relevant in opioid induced constipation and was developed and validated in accordance with US Food and Drug Administration guidelines. However, the panel believes that the complex scoring for this tool and the SSS, PAC-SYM, and 28-item PAC-QOL may be unfeasible for clinical practice. The BFI is psychometrically validated and responsive to changes in symptom severity; scores range from 0 to 100, with higher scores indicating greater severity and scores >28.8 points indicating constipation. CONCLUSIONS: The BFI is a simple assessment tool with a validated threshold of clinically significant constipation. Prescription treatments for opioid-induced constipation should be considered for patients who have a BFI score of >=30 points and an inadequate response to first-line interventions. PMID- 26582722 TI - House dust mite-specific IgA2 is associated with protection against eczema in allergic patients. AB - Upon inhalation, house dust mite (HDM) allergens are deposited at the nasal and oral mucosa, where IgA is produced abundantly. IgA subclasses have been linked to protection against respiratory allergy previously. It is currently not known whether and how the human IgA subclasses IgA1 and IgA2 contribute to the clinical status of house dust mite-allergic patients. Saliva and serum samples were collected, and HDM-specific, IgE, IgG4, IgA1 and IgA2 levels were determined. HDM specific levels of IgA in serum were similar to levels measured in nonallergic controls, but HDM-specific levels of IgA2 in saliva were decreased in allergic subjects. HDM-allergic patients who suffered from rhinitis and eczema showed a significant decrease in IgA2-levels compared to patients who suffered from rhinitis only. Taken together, our findings indicate that HDM-specific IgA2, but not IgA1, levels in serum and saliva are reduced in HDM-allergic patients suffering from eczema. PMID- 26582723 TI - Media coverage and hospital notifications: Correlation analysis and optimal media impact duration to manage a pandemic. AB - News reporting has the potential to modify a community's knowledge of emerging infectious diseases and affect peoples' attitudes and behavior. Here we developed a quantitative approach to evaluate the effects of media on such behavior. Statistically significant correlations between the number of new hospital notifications, during the 2009 A/H1N1 influenza epidemic in the Shaanxi province of China, and the number of daily news items added to eight major websites were found from Pearson correlation and cross-correlation analyses. We also proposed a novel model to examine the implication for transmission dynamics of these correlations. The model incorporated the media impact function into the intensity of infection, and enhanced the traditional epidemic SEIR model with the addition of media dynamics. We used a nonlinear least squares estimation to identify the best-fit parameter values in the model from the observed data. We also carried out the uncertainty and sensitivity analyses to determine key parameters during early phase of the disease outbreak for the final outcome of the outbreak with media impact. The findings confirm the importance of responses by individuals to the media reports, with behavior changes having important consequence for the emerging infectious disease control. Therefore, for mitigating emerging infectious diseases, media reports should be focused on how to guide people's behavioral changes, which are critical for limiting the spread of disease. PMID- 26582724 TI - Smallness of the number of incompatibility loci can facilitate parapatric speciation. AB - We studied the time to speciation by geographic isolation for a species living on two islands connected by infrequent migration. Assumptions were that incompatibility was controlled by a finite number of quantitative loci, and individuals differing in loci of more than some threshold fraction do not mix genetically with each other. We also assumed sexual haploid species, each population being nearly monomorphic, and free recombination between loci for within-population processes. The genetic distance (defined as the fraction of loci differing between populations) followed stochastic processes, which were analyzed by means of stochastic differential equations, diffusion equations, and individual-based simulations. The distance increases by the accumulation of novel mutations but decreases by migration and hybridization. It may converge to a quasi-equilibrium around which it fluctuates thereafter. If the threshold fraction of speciation is controlled, the smallness of the number of incompatibility loci enhanced the magnitude of fluctuation around the quasi equilibrium and shortened the time to speciation considerably. Novel species were created by mutation accumulation and repeated infrequent migration, and the rate of species creation was the fastest for an intermediate rate of migration. A smaller number of loci increased the optimal migration rate and the species creation rate. PMID- 26582725 TI - Profiling of the Early Nitrogen Stress Response in the Diatom Phaeodactylum tricornutum Reveals a Novel Family of RING-Domain Transcription Factors. AB - Diatoms often inhabit highly variable habitats where they are confronted with a wide variety of stresses, frequently including starvation of nutrients such as nitrogen. In this study, the transcriptome of the model diatom Phaeodactylum tricornutum was profiled during the onset of nitrogen starvation by RNA sequencing, and overrepresented motifs were determined in promoters of genes that were early and strongly up-regulated during the nitrogen stress response. One of these motifs could be bound by a nitrogen starvation-inducible RING-domain protein termed RING-GAF-Gln-containing protein (RGQ1), which was shown to act as a transcription factor and belongs to a previously uncharacterized family that is conserved in heterokont algae. PMID- 26582726 TI - Genome-Wide Analysis of Alternative Splicing during Development and Drought Stress in Maize. AB - Alternative splicing plays a crucial role in plant development as well as stress responses. Although alternative splicing has been studied during development and in response to stress, the interplay between these two factors remains an open question. To assess the effects of drought stress on developmentally regulated splicing in maize (Zea mays), 94 RNA-seq libraries from ear, tassel, and leaf of the B73 public inbred line were constructed at four developmental stages under both well-watered and drought conditions. This analysis was supplemented with a publicly available series of 53 libraries from developing seed, embryo, and endosperm. More than 48,000 novel isoforms, often with stage- or condition specific expression, were uncovered, suggesting that developmentally regulated alternative splicing occurs in thousands of genes. Drought induced large developmental splicing changes in leaf and ear but relatively few in tassel. Most developmental stage-specific splicing changes affected by drought were tissue dependent, whereas stage-independent changes frequently overlapped between leaf and ear. A linear relationship was found between gene expression changes in splicing factors and alternative spicing of other genes during development. Collectively, these results demonstrate that alternative splicing is strongly associated with tissue type, developmental stage, and stress condition. PMID- 26582727 TI - Rj4, a Gene Controlling Nodulation Specificity in Soybeans, Encodes a Thaumatin Like Protein But Not the One Previously Reported. AB - Rj4 is a dominant gene in soybeans (Glycine max) that restricts nodulation by many strains of Bradyrhizobium elkanii. The soybean-B. elkanii symbiosis has a low nitrogen-fixation efficiency, but B. elkanii strains are highly competitive for nodulation; thus, cultivars harboring an Rj4 allele are considered favorable. Cloning the Rj4 gene is the first step in understanding the molecular basis of Rj4-mediated nodulation restriction and facilitates the development of molecular tools for genetic improvement of nitrogen fixation in soybeans. We finely mapped the Rj4 locus within a small genomic region on soybean chromosome 1, and validated one of the candidate genes as Rj4 using both complementation tests and CRISPR/Cas9-based gene knockout experiments. We demonstrated that Rj4 encodes a thaumatin-like protein, for which a corresponding allele is not present in the surveyed rj4 genotypes, including the reference genome Williams 82. Our conclusion disagrees with the previous report that Rj4 is the Glyma.01G165800 gene (previously annotated as Glyma01g37060). Instead, we provide convincing evidence that Rj4 is Glyma.01g165800-D, a duplicated and unique version of Glyma.01g165800, that has evolved the ability to control symbiotic specificity. PMID- 26582728 TI - Continuous access to medication and health outcomes in uninsured adults with type 2 diabetes. AB - BACKGROUND AND PURPOSE: Achievement of recommended targets for HbA1c, low-density lipoproteins (LDLs), and blood pressure (BP) improves outcomes in adults with diabetes. To meet targets, access to an affordable and consistent supply of medication is necessary, which can be challenging for the medically underserved. The Social Determinants of Health (SDOH) framework guided variable selection in this study, which explored the relationship between continuous access to medication and HbA1c, LDL, and BP in adults with type 2 diabetes who are uninsured and of low socioeconomic status. METHODS: This study was conducted using archived medical record data and a convenience sample of adults (n = 65) who received health care on a mobile health van and medications from a pharmaceutical procurement program. Pre-post data were analyzed using dependent t tests. CONCLUSIONS: Continuous access to medication was related to improved HbA1c (p = .003), LDL (p = .004), and systolic BP (p = .025). Access to a consistent source of medications for chronic disease is related to improved health outcomes. PRACTICE IMPLICATIONS: Knowledge was gained about the effect of improved access, nontraditional healthcare delivery systems, and improved outcomes related to collaboration among community partners. Interventions aimed at the wider SDOH may reduce disparities of the medically underserved. PMID- 26582729 TI - Molecular Interplay between microRNA-34a and Sirtuin1 in Hyperglycemia-Mediated Impaired Angiogenesis in Endothelial Cells: Effects of Metformin. AB - Impaired angiogenesis is a prominent risk factor that contributes to the development of diabetes-associated cardiovascular disease. MicroRNAs (miRNAs), small noncoding RNAs, are implicated as important regulators of vascular function, including endothelial cell differentiation, proliferation, and angiogenesis. In silico analysis and in vitro studies indicate that silent information regulator 1 (SIRT1) is a potential target for endothelial cell specific miRNAs. In this study, we investigated the molecular crosstalk between miR-34a, the protein product of SIRT1 (sirtuin1), and the antidiabetic drug, metformin, in hyperglycemia-mediated impaired angiogenesis in mouse microvascular endothelial cells (MMECs). MMECs were cultured, transfected with either a miR-34a inhibitor or mimic in normal glucose (11 mM) or high glucose (HG, 40 mM) in the presence or absence of metformin. The expression of miR-34a, sirtuin1, and their signaling targets was evaluated. miR-34a expression is upregulated in a hyperglycemic milieu and parallels changes in the expression of sirtuin1, post translational modification of endothelial nitric oxide synthase (phospho/acetylation), as well as an impairment in angiogenesis. The presence of metformin, or the inhibition of miR-34a using an anti-miR-34a inhibitor, increases the expression of sirtuin1 and attenuates the impairment in angiogenesis in HG-exposed MMECs. In contrast, overexpression of a miR-34a mimic prevents metformin-mediated protection. These data indicate that miR-34a, via the regulation of sirtuin1 expression, has an anti-angiogenic action in MMECs, which can be modulated by metformin. In summary, miR-34a represents both a target whereby metformin mediates its vasculoprotective actions and also a potential therapeutic target for the prevention/treatment of diabetic vascular disease. PMID- 26582730 TI - Evidence for Classical Cholinergic Toxicity Associated with Selective Activation of M1 Muscarinic Receptors. AB - The muscarinic acetylcholine receptor subtype 1 (M1) receptors play an important role in cognition and memory, and are considered to be attractive targets for the development of novel medications to treat cognitive impairments seen in schizophrenia and Alzheimer's disease. Indeed, the M1 agonist xanomeline has been shown to produce beneficial cognitive effects in both Alzheimer's disease and schizophrenia patients. Unfortunately, the therapeutic utility of xanomeline was limited by cholinergic side effects (sweating, salivation, gastrointestinal distress), which are believed to result from nonselective activation of other muscarinic receptor subtypes such as M2 and M3. Therefore, drug discovery efforts targeting the M1 receptor have focused on the discovery of compounds with improved selectivity profiles. Recently, allosteric M1 receptor ligands have been described, which exhibit excellent selectivity for M1 over other muscarinic receptor subtypes. In the current study, the following three compounds with mixed agonist/positive allosteric modulator activities that are highly functionally selective for the M1 receptor were tested in rats, dogs, and cynomologous monkeys: (3-((1S,2S)-2-hydrocyclohexyl)-6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3 yl)methyl)benzo[h]quinazolin-4(3H)-one; 1-((4-cyano-4-(pyridin-2-yl)piperidin-1 yl)methyl)-4-oxo-4H-quinolizine-3-carboxylic acid; and (R)-ethyl 3-(2 methylbenzamido)-[1,4'-bipiperidine]-1'-carboxylate). Despite their selectivity for the M1 receptor, all three compounds elicited cholinergic side effects such as salivation, diarrhea, and emesis. These effects could not be explained by activity at other muscarinic receptor subtypes, or by activity at other receptors tested. Together, these results suggest that activation of M1 receptors alone is sufficient to produce unwanted cholinergic side effects such as those seen with xanomeline. This has important implications for the development of M1 receptor targeted therapeutics since it suggests that dose-limiting cholinergic side effects still reside in M1 receptor selective activators. PMID- 26582731 TI - Novel Probes Establish Mas-Related G Protein-Coupled Receptor X1 Variants as Receptors with Loss or Gain of Function. AB - The Mas-related G protein-coupled receptor X1 (MrgprX1) is a human seven transmembrane-domain protein with a putative role in nociception and pruritus. This receptor is expressed in dorsal root ganglion neurons and is activated by a variety of endogenous peptides, including bovine adrenal medulla peptide (BAM) and gamma2-melanocyte-stimulating hormone (gamma2-MSH). In the present work, we study how naturally occurring missense mutations alter the activity of MrgprX1. To characterize selected receptor variants, we initially used the endogenous peptide ligand BAM8-22. In addition, we generated and characterized a panel of novel recombinant and synthetic peptide ligands. Our studies identified a mutation in the second intracellular loop of MrgprX1, R131S, that causes a decrease in both ligand-mediated and constitutive signaling. Another mutation in this region, H133R, results in a gain of function phenotype reflected by an increase in ligand-mediated signaling. Using epitope-tagged variants, we determined that the alterations in basal and ligand-mediated signaling were not explained by changes in receptor expression levels. Our results demonstrate that naturally occurring mutations can alter the pharmacology of MrgprX1. This study provides a theoretical basis for exploring whether MrgprX1 variability underlies differences in somatosensation within human populations. PMID- 26582732 TI - Enteric Dysfunctions in Experimental Parkinson's Disease: Alterations of Excitatory Cholinergic Neurotransmission Regulating Colonic Motility in Rats. AB - Parkinson's disease is frequently associated with gastrointestinal symptoms, mostly represented by constipation and defecatory dysfunctions. This study examined the impact of central dopaminergic denervation, induced by injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle, on distal colonic excitatory cholinergic neuromotor activity in rats. Animals were euthanized 4 and 8 weeks after 6-OHDA injection. In vivo colonic transit was evaluated by radiologic assay. Electrically induced and carbachol-induced cholinergic contractions were recorded in vitro from longitudinal and circular muscle colonic preparations, whereas acetylcholine levels were assayed in the incubation media. Choline acetyltransferase (ChAT), HuC/D (pan-neuronal marker), muscarinic M2 and M3 receptors were assessed by immunohistochemistry or western blot assay. As compared with control rats, at week 4, 6-OHDA-treated animals displayed the following changes: decreased in vivo colonic transit rate, impaired electrically evoked neurogenic cholinergic contractions, enhanced carbachol-induced contractions, decreased basal and electrically stimulated acetylcholine release from colonic tissues, decreased ChAT immunopositivity in the neuromuscular layer, unchanged density of HuC/D immunoreactive myenteric neurons, and increased expression of colonic muscarinic M2 and M3 receptors. The majority of such alterations were also detected at week 8 post 6-OHDA injection. These findings indicate that central nigrostriatal dopaminergic denervation is associated with an impaired excitatory neurotransmission characterized by a loss of myenteric neuronal ChAT positivity and decrease in acetylcholine release, resulting in a dysregulated smooth muscle motor activity, which likely contributes to the concomitant decrease in colonic transit rate. PMID- 26582733 TI - [Genetic polymorphism of cytochrome P450 2E1 and the risk of nasopharyngeal carcinoma]. AB - Cytochrome P450 2E1 (CYP2E1) is a detoxifying enzyme that belongs to the phase I metabolism of xenobiotics. This enzyme is encoded by a highly polymorphic gene whose common polymorphism corresponds to the substitution of cytosine (C) and thymine (T) at position -1019 (rs2031920). This polymorphism has been identified in several cancers including nasopharyngeal cancer (NPC). The study involved 124 patients with nasopharyngeal carcinoma, compared with 166 healthy controls. The presence or absence of the polymorphism is determined by PCR-RFLP. The frequency comparison between the two groups is determined by the chi(2) test. The analysis of our results showed a significant difference between the two groups regarding the mutant genotype (C2/C2) (5% vs. 0.5%, P=0.04) and has a risk factor for NPC in Tunisia (OR=8.39; CI 95% [0.99-388.1]). Also, the C2 allele was significantly associated with the group of patients than the control group (6% vs. 2%, P=0.016) and increased three times the risk of NPC in Tunisia (OR=2.99, CI 95% [1.12 8.79]). Our results confirm the results reported in other populations and emphasize the importance of the involvement of this gene in the development of detoxification of the NPC, which seems more and more strongly associated with environmental factors. PMID- 26582734 TI - [PI3K-AKT-mTOR pathway: Description, therapeutic development, resistance, predictive/prognostic biomarkers and therapeutic applications for cancer]. AB - Among many cancer cells signaling pathways, PI3K-AKT-mTOR plays a major role in growth, proliferation and cellular survival. This is a complex pathway activated either by an extracellular way (receptors with tyrosine kinase activity) or by an intracellular way with transformed or overexpressed proteins involved in the signal transduction. To date, there are many applications of mTOR inhibitors in oncology with an expanding development rapidly. However, resistances appear to mTOR inhibitors which lead to 2nd generation mTOR inhibitors development. A better knowledge of predictive and prognostic biomarkers will allow to specify the group of patients who may benefit from these treatments and help to the choice. PMID- 26582735 TI - Development and Validation of a Four-Item Migraine Screening Algorithm Among a Nonclinical Sample: The Migraine-4. AB - OBJECTIVES: The present study sought to develop and validate a screening algorithm from the ICHD-3 beta diagnostic criteria for migraine utilizing a nonclinical sample. The goal was to determine the most sensitive and specific symptoms for differentiating migraine from other headache disorders and to validate the derived symptom algorithm as a screening measure. BACKGROUND: Despite its prevalence and impact, migraine remains under-recognized and under treated. The U.S. Headache Consortium recommended development and dissemination of validated screening measures as a means to improve diagnosis. METHODS: Participants were 1829 young adults (71.5% female; 74.4% white; mean age = 19.09 years [SD = 2.05]) who reported headache via computerized diagnostic interview. From this group, 158 were found to have ICHD episodic or chronic migraine and were randomly split into experimental and holdout validation samples. Within the experimental sample, receiver operating characteristic (ROC) curve data were obtained for each candidate symptom (item); backward stepwise logistic regression analysis was performed among the items with the most predictive likelihood ratios to determine the optimal model for differentiating migraine from non-migrainous headache. The retained four-symptom algorithm was then validated among the holdout sample, in which various cutoff points were compared to gold standard diagnosis via ROC curve estimations to determine the optimal operating point (OOP) of the algorithm as a screening measure. RESULTS: Attack duration of 4-72 hours (100% [95% CI = 95-100%]), severity >= 5 (91% [82-97%]), photophobia (90% [80-96%]), and phonophobia (90% [80-96%]) showed the highest sensitivity, while vomiting (98% [96-99%]), duration of 4-72 hours (92% [90-94%]), nausea (89% [86 91%]), and headache-related disability (88% [85-91%]) showed the highest specificity. The optimal retained model (Migraine-4) included: duration of 4-72 hours, nausea, photophobia, and phonophobia. Among the holdout validation sample, the OOP was positive endorsement of three out of four symptoms, which had a sensitivity of 94% (95% CI = 87-98%), a specificity of 92% (90-94%), and an area under the curve of 93% (90-96%; +LR = 12.37, -LR = 0.06, PPV = 67%, NPV = 99%). CONCLUSIONS: The optimal model shares some similarities with previous models but performed better than prior screeners at differentiating migraine from other headache presentations. The Migraine-4 has utility in identifying migraine among nonclinical and young adult samples. Further research with this measure is warranted to determine its utility with treatment-seeking patients and validity in direct comparison to established screening instruments. PMID- 26582736 TI - Chitosan polyplex mediated delivery of miRNA-124 reduces activation of microglial cells in vitro and in rat models of spinal cord injury. AB - Traumatic injury to the central nervous system (CNS) is further complicated by an increase in secondary neuronal damage imposed by activated microglia/macrophages. MicroRNA-124 (miR-124) is responsible for mouse monocyte quiescence and reduction of their inflammatory cytokine production. We describe the formulation and ex vivo transfection of chitosan/miR-124 polyplex particles into rat microglia and the resulting reduction of reactive oxygen species (ROS) and TNF-alpha and lower expression of MHC-II. Upon microinjection into uninjured rat spinal cords, particles formed with Cy3-labeled control sequence RNA, were specifically internalized by OX42 positive macrophages and microglia cells. Alternatively particles injected in the peritoneum were transported by macrophages to the site of spinal cord injury 72 h post injection. Microinjections of chitosan/miR-124 particles significantly reduced the number of ED-1 positive macrophages in the injured spinal cord. Taken together, these data present a potential treatment technique to reduce inflammation for a multitude of CNS neurodegenerative conditions. FROM THE CLINICAL EDITOR: The treatment of spinal cord injury remains an unresolved problem. Secondary damage is often the result of inflammation caused by activated microglia and/or macrophages. In this article, the authors developed their formulation of chitosan/miR-124 polyplex particles and investigated their use in the suppression of neuronal inflammation. This exciting data may provide a new horizon for patients who suffer from spinal cord injury. PMID- 26582737 TI - Review article: the natural history of paediatric-onset ulcerative colitis in population-based studies. AB - BACKGROUND: A better knowledge of the natural history of disabling chronic diseases is essential to improve patient management, evaluate the impact of treatment strategies and provide predictors for disabling disease and comprehensive information for patients. AIM: To summarise our current knowledge issued from population-based studies of the natural history of ulcerative colitis (UC) in children. METHODS: We searched MEDLINE (source PubMed) and international conference abstracts, and included all population-based studies that evaluated long-term outcome of paediatric-onset (<17 years at diagnosis) UC. RESULTS: A total of 26 population-based studies were considered in this review from the total of 61 articles or abstracts screened. Most patients presented disease extension and about two-thirds of patients had pancolitis at the end of follow up. One-half of patients experienced extra-intestinal manifestations and primary sclerosing cholangitis was observed in 5-10% of patients. Overall, patients did not appear to have any significant growth retardation or delayed puberty. About two-thirds of patients required corticosteroid therapy and up to 25% were steroid dependent. An increased use of thiopurines was observed and the most recent data indicate that up to one-half of patients were exposed to thiopurines and 10-30% were exposed to anti-tumour necrosis factor. One-half of patients required hospitalisations and 20% of patients required colectomy after a follow-up of 10 years. CONCLUSIONS: Paediatric-onset UC is characterised by a high rate of disease extension. About 20% of patients had been operated at 10-year follow-up. New population-based studies are needed to evaluate the impact of new treatment strategies comprising immunosuppressants and biologics. PMID- 26582738 TI - Systematic review of case reports on the abscopal effect. AB - Radiation therapy is a highly effective local treatment for cancer. However, sporadic events of tumor regression in unirradiated fields, known as abscopal effect, have been observed for decades. This abscopal effect has more recently been postulated to be a result of antitumor immune response induced by radiation therapy. With the advent of modern immunotherapy, the potential for immune activation by radiation therapy defines a novel role for radiation therapy in systemic disease. In this context, we have searched documented cases abscopal effect of radiation therapy in literature. A total of 46 reported cases have been identified from 1969 to 2014 with median radiation dose of 31 Gy, median follow up of 17.5 months, and median documented time to notice the abscopal effect was 2 months. This review systematically summarizes all clinical case reports of abscopal effect to gain insight into this uncommon but important phenomenon. PMID- 26582739 TI - OX2 orexin/hypocretin receptor signal transduction in recombinant Chinese hamster ovary cells. AB - There are two subtypes of orexin receptors, OX1 and OX2. Signalling pathways have been mapped in much higher detail for OX1 receptors than OX2 receptors. Almost all the detailed studies have been performed in Chinese hamster ovary cells, and we thus chose the same cell background for the studies on human OX2 receptors to allow comparison to human OX1 receptors. Adenylyl cyclase, phospholipase A2, C and D and diacylglycerol lipase activities were assessed by precursor radiolabelling and chromatographic separation (ion exchange, affinity or thin layer), calcium by a fluorescent method, and receptor binding with [(125)I] orexin-A. Upon activation with orexin-A, OX2 receptors stimulated phospholipase A2, C and D, diacylglycerol lipase and calcium elevation, and both inhibited and stimulated adenylyl cyclase; i.e., the responses to OX2 activation by orexin-A were principally like those of OX1, in contrast to some previous suggestions. The responses occurred mostly in the same concentration range as those for OX1 activation and via the same signal cascades. However, some responses were weaker, suggesting a partially differential coupling to some cascades. In summary, OX2 receptor signalling is principally similar to OX1 receptor signalling suggesting also a physiologically similar coupling, though this needs to be verified in physiological contexts. Some (relatively weak) differences between the receptors may be investigated in further studies. PMID- 26582740 TI - Amino acid-dependent NPRL2 interaction with Raptor determines mTOR Complex 1 activation. AB - We assign a new function to a tumor suppressor NPRL2 that activates the mTOR complex 1 (mTORC1) activity. The positive regulation of mTORC1 activity by NPRL2 is mediated through NPRL2 interaction with Raptor. While NPRL2 interacts with Rag GTPases, RagD in particular, to interfere with mTORC1 activity in amino acid scarcity, NPRL2 interacts with Raptor in amino acid sufficiency to activate mTORC1. A reciprocal relationship exists between NPRL2 binding to Rag GTPases and Raptor. NPRL2 majorly locates in the lysosomal membranes and has a higher binding affinity to the dominant negative mutant heterodimer of RagA(GDP)/RagD(GTP) that inactivates mTORC1. However, the binding affinity of NPRL2 with Raptor is much less pronounced in cells expressing the dominant negative mutant heterodimer of RagA(GDP)/RagD(GTP) than in cells expressing the dominant positive mutant heterodimer, RagA(GTP)/RagD(GDP). The positive effect of NPRL2 on TORC1 pathway was also evidenced in Drosophila animal model. Here, we propose a 'seesaw' model in which the interactive behavior of NPRL2 with Raptor determines mTORC1 activation by amino acid signaling in animal cells. PMID- 26582741 TI - Orthodontic correction of overjet/overbite ('parrot mouth') in 73 foals (1999 2013). AB - REASONS FOR PERFORMING STUDY: There are limited reports on the efficacy of functional orthodontic correction of overjet or overbite in foals. OBJECTIVES: To report the outcome of using orthodontic tension bands in combination with an inclined plane biteplate in the treatment of overjet, with or without concurrent overbite, rates of correction of these 2 malocclusions and associated complications. And to examine factors associated with outcomes. STUDY DESIGN: Retrospective case series. METHODS: Clinical records for 73 foals treated at a single clinic, by the same surgeon were analysed. Overall change and rates of change in overjet and overbite were calculated. Associations between potential explanatory variables including age, severity of initial malocclusion and surgeon experience were examined using linear regression. RESULTS: Records for 73 foals (43 colts, 30 fillies) were evaluated. The median number of implant placements per animal was 2 (range 1-4). Of 61 cases with complete records, reduction in overjet and overbite dimensions were achieved in 95% and 90% of foals, respectively, with mean reductions in malocclusions of 9.9 and 8.4 mm, respectively. Complete reduction in overjet was achieved in 25% (15/61) and reduction of malocclusion dimensions to <=5 mm (i.e. functionally corrected) was achieved in 51% (31/61). Increasing animal age was significantly associated with decreased total reduction in overjet and decreased rate of reduction in overbite. Increased original severity of overbite was significantly associated with increased rate of its correction. Short-term complications included intraoperative haemorrhage, transient facial nerve neuropraxia and irritation of the mare's udder by the brace. Longer-term complications included cheek teeth diastema formation and incisor discoloration and maleruption. CONCLUSIONS: Using this technique, correction or improvement of these malocclusions is rapid, with minimal complications. Often more than one implant is required. Animal age at the start of treatment is associated with rate and amount of correction achievable, so initiating treatment at an early age is recommended. PMID- 26582743 TI - Lymphocyte subsets contribute to the degree of lobulitis and ductitis in sclerosing lymphocytic lobulitis of the breast. AB - AIMS: Sclerosing lymphocytic lobulitis (SLL) of the breast is characterised by lymphocytic lobulitis, ductitis, vasculitis and dense keloidal fibrosis with epithelioid fibroblasts. However, the subsets of the infiltrating lymphocytes and their contribution to disease progression have not been fully explored. METHODS: CD20, CD3, CD4, CD8 and regulatory T (Treg) lymphocytes were evaluated in the epithelial and vascular areas in SLL. The relationship between the lymphocyte subset in different regions and the degree of inflammation was analysed. RESULTS: Lymphocytic infiltration was mainly located in peri-lobular, peri-ductal and peri vascular areas. No significant differences between CD20 and CD3 lymphocytes were found in peri-epithelial areas. However, there were more intra-ductal/lobular epithelial CD3 than CD20 lymphocytes (p<0.001). For T lymphocyte subsets, more CD4 than CD8 lymphocytes were found in the peri-lobular/vascular regions (p<=0.026); but an opposite trend was seen in the intra-ductal/lobular regions (p<0.001). In the peri-lobular/vascular regions, generally, different lymphocyte subsets correlated with each other. Interestingly, in the peri-ductal region, only CD4 lymphocytes showed significant correlations with all other subsets (p<=0.020). Regarding their relationship with the degree of inflammation, significant positive correlations were observed for all subsets in peri vascular/lobular regions (p<=0.045). Only regulatory T cells, but not the others, at the peri-ductal region showed significant correlation with the degree of inflammation at all three regions (p<=0.014). CONCLUSIONS: In addition to B lymphocyte subsets, T lymphocyte subsets could be involved differently in SLL. CD4 lymphocytes may have a pivotal role in recruiting other subsets to the inflamed site, and triggered the cascade of inflammatory changes resulting in fibrosis. PMID- 26582744 TI - Fifteen years of sector-wide approach (SWAp) in Bangladesh health sector: an assessment of progress. AB - The Ministry of Health and Family Welfare (MOHFW) of the Government of Bangladesh embarked on a sector-wide approach (SWAp) modality for the health, nutrition and population (HNP) sector in 1998. This programmatic shift initiated a different set of planning disciplines and practices along with institutional changes in the MOHFW. Over the years, the SWAp modality has evolved in Bangladesh as the MOHFW has learnt from its implementation and refined the program design. This article explores the progress made, both in terms of achievement of health outcomes and systems strengthening results, since the implementation of the SWAp for Bangladesh's health sector. Secondary analyses of survey data from 1993 to 2011 as well as a literature review of published and grey literature on health SWAp in Bangladesh was conducted for this assessment. Results of the assessment indicate that the MOHFW made substantial progress in health outcomes and health systems strengthening. SWAps facilitated the alignment of funding and technical support around national priorities, and improved the government's role in program design as well as in implementation and development partner coordination. Notable systemic improvements have taken place in the country systems with regards to monitoring and evaluation, procurement and service provision, which have improved functionality of health facilities to provide essential care. Implementation of the SWAp has, therefore, contributed to an accelerated improvement in key health outcomes in Bangladesh over the last 15 years. The health SWAp in Bangladesh offers an example of a successful adaptation of such an approach in a complex administrative structure. Based on the lessons learned from SWAp implementation in Bangladesh, the MOHFW needs to play a stronger stewardship and regulatory role to reap the full benefits of a SWAp in its subsequent programming. PMID- 26582745 TI - MALDI-TOF Utility in a Region With Low Antibacterial Resistance Rates. PMID- 26582746 TI - HIV Postexposure Prophylaxis Starter Packs Were Not Designed to Help or Hinder Adherence. PMID- 26582747 TI - Reply to Zimmer. PMID- 26582748 TI - Clinical and Healthcare Burden of Multiple Recurrences of Clostridium difficile Infection. AB - BACKGROUND: Clostridium difficile infection (CDI) is associated with a high risk of recurrence (rCDI). Few studies have focused on multiple recurrences. To evaluate the potential of novel treatments targeting recurrence, we assessed the burden and severity of rCDI. METHODS: This was a retrospective cohort of adults diagnosed with CDI in a hospital in Sherbrooke, Canada (1998-2013). An rCDI episode was defined by the reappearance of diarrhea leading to a treatment, with or without a positive toxin assay, within 14-60 days after the previous episode. RESULTS: We included 1527 patients. The probability of developing a first rCDI was 25% (354/1418); a second, 38% (128/334); a third, 29% (35/121); and a fourth or more, 27% (9/33). Two or more rCDIs were observed in 9% (128/1389) of patients. The risk of a first recurrence fluctuated over time, but there was no such variation for second or further recurrences. The proportion of severe cases decreased (47% for initial episodes, 31% for first recurrences, 25% for second, 17% for third), as did the risk of complicated CDI (5.8% to 2.8%). The severity and risk of complications of first recurrences decreased over time, while oral vancomycin was used more systemically. A hospital admission was needed for 34% (148/434) of recurrences. CONCLUSIONS: This study documented the clinical and healthcare burden of rCDI: 34% of patients with rCDI needed admission, 28% developed severe CDI, and 4% developed a complication. Secular changes in the severity of recurrences could reflect variations in the predominant strain, or better management. PMID- 26582749 TI - Effects of Interaction Between Ventricular Assist Device Assistance and Autoregulated Mock Circulation Including Frank-Starling Mechanism and Baroreflex. AB - A mock heart circulation loop (MHCL) is a hydraulic model simulating the human circulatory system. It allows in vitro investigations of the interaction between cardiac assist devices and the human circulatory system. In this study, a preload sensitive MHCL, the MHCLAUTO , was developed to investigate the interaction between the left ventricle and left ventricular assist devices (LVADs). The Frank Starling mechanism was modeled by regulating the stroke volume (SV) based on the measured mean diastolic left atrial pressure (MLAPdiast ). The baroreflex autoregulation mechanism was implemented to maintain a constant mean aortic pressure (MAP) by varying ventricular contractility (Emax ), heart rate (HR), afterload/systemic vascular resistance (SVR) and unstressed venous volume (UVV). The DP3 blood pump (Medos Medizintechnik GmbH) was used to simulate the LVAD. Characteristic parameters were measured in pathological conditions both with and without LVAD to assess the hemodynamic effect of LVAD on the MHCLAUTO . The results obtained from the MHCLAUTO show a high correlation to literature data. The study demonstrates the possibility of using the MHCLAUTO as a research tool to better understand the physiological interactions between cardiac implants and human circulation. PMID- 26582750 TI - The frequency of spontaneous seizures in rats correlates with alterations in sensorimotor gating, spatial working memory, and parvalbumin expression throughout limbic regions. AB - Cognitive deficits and psychotic symptoms are highly prevalent in patients with temporal lobe epilepsy (TLE). Imaging studies in humans have suggested that these comorbidities are associated with atrophy in temporal lobe structures and other limbic regions. It remains to be clarified whether TLE comorbidities are due to the frequency of spontaneous seizures or to limbic structural damage per se. Here, we used the pilocarpine model of chronic spontaneous seizures to evaluate the possible association of seizure frequency with sensorimotor gating, spatial working memory, and neuropathology throughout limbic regions. For TLE modeling, we induced a 2-h status epilepticus by the systemic administration of lithium pilocarpine. Once spontaneous seizures were established, we tested the locomotor activity (open field), spatial working memory (eight-arm radial maze), and sensorimotor gating (prepulse inhibition of acoustic startle). After behavioral testing, the brains were sectioned for hematoxylin-eosin staining (cell density) and parvalbumin immunohistochemistry (GABAergic neuropil) in the prefrontal cortex, nucleus accumbens, thalamus, amygdala, hippocampus, and entorhinal cortex. The animal groups analyzed included chronic epileptic rats, their controls, and rats that received lithium-pilocarpine but eventually failed to express status epilepticus or spontaneous seizures. Epileptic rats showed deficits in sensorimotor gating that negatively correlated with the radial maze performance, and impairments in both behavioral tests correlated with seizure frequency. In addition to neuronal loss at several sites, we found increased parvalbumin immunostaining in the prefrontal cortex (infralimbic area), thalamus (midline and reticular nuclei), amygdala, Ammon's horn, dentate gyrus, and entorhinal cortex. These tissue changes correlated with seizure frequency and impairments in sensorimotor gating. Our work indicates that chronic seizures might impact the inhibitory-excitatory balance in the temporal lobe and its interconnected limbic regions, which could increase the likelihood of cognitive deficits and interictal psychiatric disorders. PMID- 26582751 TI - Early use of azithromycin may reduce severity of wheezing, study finds. PMID- 26582752 TI - Hierarchical Self-Assembly of Supramolecular Muscle-Like Fibers. AB - An acid-base switchable [c2]daisy chain rotaxane terminated with two 2,6 diacetylamino pyridine units has been self-assembled with a bis(uracil) linker. The complementary hydrogen-bond recognition patterns, together with lateral van der Waals aggregations, result in the hierarchical formation of unidimensional supramolecular polymers associated in bundles of muscle-like fibers. Microscopic and scattering techniques reveal that the mesoscopic structure of these bundles depends on the extended or contracted states that the rotaxanes show within individual polymer chains. The observed local dynamics span over several length scales because of a combination of supramolecular and mechanical bonds. This work illustrates the possibility to modify the hierarchical mesoscopic structuring of large polymeric systems by the integrated actuation of individual molecular machines. PMID- 26582753 TI - Isolation and characterization of dental epithelial cells derived from amelogenesis imperfecta rat. AB - OBJECTIVE: Disruption of the third zinc finger domain of specificity protein 6 (SP6) presents an enamel-specific defect in a rat model of amelogenesis imperfecta (AMI rats). To understand the molecular basis of amelogenesis imperfecta caused by the Sp6 mutation, we established and characterized AMI derived rat dental epithelial (ARE) cells. MATERIALS AND METHODS: ARE cell clones were isolated from the mandibular incisors of AMI rats, and amelogenesis-related gene expression was analyzed by reverse transcription polymerase chain reaction (RT-PCR). Localization of wild-type SP6 (SP6WT) and mutant-type SP6 (SP6AMI) was analyzed by immunocytochemistry. SP6 transcriptional activity was monitored by rho-associated protein kinase 1 (Rock1) promoter activity with its specific binding to the promoter region in dental (G5 and ARE) and non-dental (COS-7) epithelial cells. RESULTS: Isolated ARE cells were varied in morphology and gene expression. Both SP6WT and SP6AMI were mainly detected in nuclei. The promoter analysis revealed that SP6WT and SP6AMI enhanced Rock1 promoter activity in G5 cells but that enhancement by SP6AMI was weaker, whereas no enhancement was observed in the ARE and COS-7 cells, even though SP6WT and SP6AMI bound to the promoter in all instances. CONCLUSION: ARE cell clones can provide a useful in vitro model to study the mechanism of SP6-mediated amelogenesis imperfecta. PMID- 26582754 TI - Protein localisation by electron microscopy reveals the architecture of the yeast spliceosomal B complex. AB - The spliceosome assembles on a pre-mRNA intron by binding of five snRNPs and numerous proteins, leading to the formation of the pre-catalytic B complex. While the general morphology of the B complex is known, the spatial arrangement of proteins and snRNP subunits within it remain to be elucidated. To shed light on the architecture of the yeast B complex, we immuno-labelled selected proteins and located them by negative-stain electron microscopy. The B complex exhibited a triangular shape with main body, head and neck domains. We located the U5 snRNP components Brr2 at the top and Prp8 and Snu114 in the centre of the main body. We found several U2 SF3a (Prp9 and Prp11) and SF3b (Hsh155 and Cus1) proteins in the head domain and two U4/U6 snRNP proteins (Prp3 and Lsm4) in the neck domain that connects the main body with the head. Thus, we could assign distinct domains of the B complex to the respective snRNPs and provide the first detailed picture of the subunit architecture and protein arrangements of the B complex. PMID- 26582755 TI - Pharmacological induction of skin pigmentation unveils the neuroendocrine circuit regulated by light. AB - Light-regulated skin colour change is an important physiological process in invertebrates and lower vertebrates, and includes daily circadian variation and camouflage (i.e. background adaptation). The photoactivation of melanopsin expressing retinal ganglion cells (mRGCs) in the eye initiates an uncharacterized neuroendocrine circuit that regulates melanin dispersion/aggregation through the secretion of alpha-melanocyte-stimulating hormone (alpha-MSH). We developed experimental models of normal or enucleated Xenopus embryos, as well as in situ cultures of skin of isolated dorsal head and tails, to analyse pharmacological induction of skin pigmentation and alpha-MSH synthesis. Both processes are triggered by a melanopsin inhibitor, AA92593, as well as chloride channel modulators. The AA9253 effect is eye-dependent, while functional data in vivo point to GABAA receptors expressed on pituitary melanotrope cells as the chloride channel blocker target. Based on the pharmacological data, we suggest a neuroendocrine circuit linking mRGCs with alpha-MSH secretion, which is used normally during background adaptation. PMID- 26582756 TI - Uterine artery pulsatility index at 12, 22, 32 and 36 weeks' gestation in screening for pre-eclampsia. AB - OBJECTIVE: To examine the distribution of uterine artery pulsatility index (UtA PI) at 12, 22, 32 and 36 weeks' gestation in singleton pregnancies which develop pre-eclampsia (PE) and examine the performance of this biomarker in screening for PE. METHODS: UtA-PI was measured in 92 712 singleton pregnancies at 11-13 weeks, in 67 605 cases at 19-24 weeks, in 31 741 at 30-34 weeks and in 5523 at 35-37 weeks. Bayes' theorem was used to combine the a-priori risk from maternal characteristics and medical history with UtA-PI. The performance of screening for PE requiring delivery < 32, at 32 + 0 to 36 + 6, < 37 and >= 37 weeks' gestation was estimated. The results of combined screening were compared to those of screening by UtA-PI and by maternal factors alone. RESULTS: In pregnancies that developed PE, UtA-PI was increased and the separation in multiples of the median (MoM) values from normal was greater with earlier, compared to later, gestational age at which delivery for PE became necessary. Additionally, the slope of regression lines of UtA-PI MoM with gestational age at delivery in pregnancies that developed PE increased with increasing gestational age at screening. The detection rate (DR), at a 10% false-positive rate (FPR), for PE delivering < 32 weeks was 71% and 88% with combined screening at 11-13 and 19-24 weeks, respectively, and the DR for PE delivering at 32 + 0 to 36 + 6 weeks was 52%, 63% and 71% with screening at 11-13, 19-24 and 30-34 weeks, respectively. However, the DR of PE delivering >= 37 weeks was only about 40%, irrespective of the gestational age at screening. The performance of screening by the approach utilizing Bayes' theorem was superior to that of using a percentile cut-off of UtA-PI for gestational age. CONCLUSIONS: The performance of combined screening with maternal factors and UtA-PI is superior for detection of early, compared to late, PE and, to a certain extent, improves with advancing gestational age at screening. Copyright (c) 2015 ISUOG. Published by John Wiley & Sons Ltd. PMID- 26582757 TI - Can improved quality of care explain the success of orthogeriatric units? A population-based cohort study. AB - BACKGROUND: admission to orthogeriatric units improves clinical outcomes for patients with hip fracture; however, little is known about the underlying mechanisms. OBJECTIVE: to compare quality of in-hospital care, 30-day mortality, time to surgery (TTS) and length of hospital stay (LOS) among patients with hip fracture admitted to orthogeriatric and ordinary orthopaedic units, respectively. DESIGN: population-based cohort study. MEASURES: using prospectively collected data from the Danish Multidisciplinary Hip Fracture Registry, we identified 11,461 patients aged >=65 years admitted with a hip fracture between 1 March 2010 and 30 November 2011. The patients were divided into two groups: (i) those treated at an orthogeriatric unit, where the geriatrician is an integrated part of the multidisciplinary team, and (ii) those treated at an ordinary orthopaedic unit, where geriatric or medical consultant service are available on request. Outcome measures were the quality of care as reflected by six process performance measures, 30-day mortality, the TTS and the LOS. Data were analysed using log binomial, linear and logistic regression controlling for potential confounders. RESULTS: admittance to orthogeriatric units was associated with a higher chance for fulfilling five out of six process performance measures. Patients who were admitted to an orthogeriatric unit experienced a lower 30-day mortality (adjusted odds ratio (aOR) 0.69; 95% CI 0.54-0.88), whereas the LOS (adjusted relative time (aRT) of 1.18; 95% CI 0.92-1.52) and the TTS (aRT 1.06; 95% CI 0.89-1.26) were similar. CONCLUSIONS: admittance to an orthogeriatric unit was associated with improved quality of care and lower 30-day mortality among patients with hip fracture. PMID- 26582759 TI - Together we have fun: native-place networks and sexual risk behaviours among Chinese male rural-urban migrants. AB - Some scholars argue that the maintenance of social networks contributes to the lower prevalence of deviant behaviours and fewer adverse health effects among migrants. But others suggest that if migrants are embedded in homogeneous networks, such networks may enable the formation of a deviant subculture that promotes risk taking. Facing this dilemma, the present study investigates how native-place networks influence sexual risk behaviours (SRBs), specifically the pursuit of commercial sex and condomless sex with sex workers, for male rural urban migrants. Using a multi-stage sample of 1,591 male rural-urban migrants from two major migrant-influx cities within China, we assessed migrants' general friend network ties and native place networks (townsmen in migrants' local networks) and tested their associations with SRBs. Multiple logistic regression analyses indicate that native-place network ties are associated with paying for sex (OR = 1.33, p < 0.001) and condomless sex with sex workers (OR = 1.33, p < 0.001), while general friendship network ties reduce such risks (OR = 0.74, p < 0.001; OR = 0.84, p < 0.01) even after controlling for demographic background, housing conditions, length of stay, health beliefs and behaviours, and spousal companionship. Our findings suggest that native-place networks among Chinese male rural-urban migrants are associated with SRBs because homogenous networks may serve as a platform for the emergence of a deviant subculture that promotes risk behaviours. A Virtual Abstract of this paper is available at: https://www.youtube.com/watch?v=3Wg20I6j8XQ. PMID- 26582758 TI - Observational cohort study: deprivation and access to anti-dementia drugs in the UK. AB - BACKGROUND: UK National Dementia Strategies prioritise fair access to dementia treatments for the whole population. We investigated for the first time inequalities in NHS national dementia prescribing and how they have varied between UK countries and over time. METHOD: we investigated the association between Townsend deprivation score and anti-dementia drug prescribing in 77,045 dementia patients from UK primary care records from 2002 to 2013. RESULTS: we included 77,045 patients with recorded dementia diagnosis or anti-dementia drug prescription. Least deprived patients were 25% more likely to be initiated on anti-dementia drugs than the most deprived (adjusted incidence rate ratio 1.25, 95% confidence interval 1.19-1.31). This was driven by data from English practices where prescribing rates were consistently lower in more deprived patients compared with Scotland, Northern Ireland and Wales, where prescribing was not related to deprivation quintile. Compared with English practices, anti dementia medication was prescribed more often in Northern Irish (1.81, 1.41-2.34) and less in Welsh practices (0.68, 0.55-0.82), with a trend towards more prescribing in Scottish practices (1.14, 0.98-1.32). Drug initiation rates were also higher in younger people and men. CONCLUSION: four years after the English National Dementia Strategy, there is no evidence that the Strategy's key objective of reducing treatment inequalities is being achieved. Higher overall anti-dementia drug prescribing in Scottish and Northern Irish practices, and differing clinical guidelines in Scotland from other UK countries might explain greater equality in prescribing in these countries. Strategies to offer treatment to more deprived people with dementia in England are needed. PMID- 26582760 TI - Serotonergic regulation of distention-induced ATP release from the urothelium. AB - Serotonin [5-hydroxytryptamine (5-HT)] is involved in both motor and sensory functions in hollow organs, especially in the gastrointestinal tract. However, the involvement of 5-HT in visceral sensation of the urinary bladder remains unknown. Because distention-induced ATP release from the urothelium plays an essential role in visceral sensation of the urinary bladder, we investigated the regulation of urothelial ATP release by the 5-HT signaling system. RT-PCR and immunohistochemical analyses of the urothelium revealed specific expression of 5 HT1D and 5-HT4 receptors. The addition of 5-HT did not affect urothelial ATP release without bladder distention, but it significantly reduced distention induced ATP release by physiological pressure during urine storage (5 cmH2O). The inhibitory effect of 5-HT on distention-elicited ATP release was blocked by preincubation with the 5-HT1B/1D antagonist GR-127935 but not by the 5-HT4 antagonist SB-204070. mRNA encoding tryptophan hydroxylase 1 was detected in the urinary bladder by nested RT-PCR amplification, and l-tryptophan or the selective serotonin reuptake inhibitor citalopram also inhibited ATP release, indicating that 5-HT is endogenously synthesized and released in the urinary bladder. The addition of GR-127935 significantly enhanced the distention-elicited ATP release 40 min after distention, whereas SB-204070 reduced the amount of ATP release 20 min after distention. These data suggest that 5-HT4 facilitates the distention induced ATP release at an earlier stage, whereas 5-HT1D inhibits ATP release at a later stage. The net inhibitory effect of 5-HT indicates that the action of 5-HT on the urothelium is mediated predominantly by 5-HT1D. PMID- 26582761 TI - The role of calbindin-D28k on renal calcium and magnesium handling during treatment with loop and thiazide diuretics. AB - Calbindin-D28k (CBD-28k) is a calcium binding protein located in the distal convoluted tubule (DCT) and plays an important role in active calcium transport in the kidney. Loop and thiazide diuretics affect renal Ca and Mg handling: both cause Mg wasting, but have opposite effects on Ca excretion as loop diuretics increase, but thiazides decrease, Ca excretion. To understand the role of CBD-28k in renal Ca and Mg handling in response to diuretics treatment, we investigated renal Ca and Mg excretion and gene expression of DCT Ca and Mg transport molecules in wild-type (WT) and CBD-28k knockout (KO) mice. Mice were treated with chlorothiazide (CTZ; 50 mg . kg(-1) . day(-1)) or furosemide (FSM; 30 mg . kg(-1) . day(-1)) for 3 days. To avoid volume depletion, salt was supplemented in the drinking water. Urine Ca excretion was reduced in WT, but not in KO mice, by CTZ. FSM induced similar hypercalciuria in both groups. DCT Ca transport molecules, including transient receptor potential vanilloid 5 (TRPV5), TRPV6, and CBD-9k, were upregulated by CTZ and FSM in WT, but not in KO mice. Urine Mg excretion was increased and transient receptor potential subfamily M, member 6 (TRPM6) was upregulated by both CTZ and FSM in WT and KO mice. In conclusion, CBD 28k plays an important role in gene expression of DCT Ca, but not Mg, transport molecules, which may be related to its being a Ca, but not a Mg, intracellular sensor. The lack of upregulation of DCT Ca transport molecules by thiazides in the KO mice indicates that the DCT Ca transport system is critical for Ca conservation by thiazides. PMID- 26582762 TI - Reducing alphaENaC expression in the kidney connecting tubule induces pseudohypoaldosteronism type 1 symptoms during K+ loading. AB - Genetic inactivation of the epithelial Na(+) channel alpha-subunit (alphaENaC) in the renal collecting duct (CD) does not interfere with Na(+) and K(+) homeostasis in mice. However, inactivation in the CD and a part of the connecting tubule (CNT) induces autosomal recessive pseudohypoaldosteronism type 1 (PHA-1) symptoms in subjects already on a standard diet. In the present study, we further examined the importance of alphaENaC in the CNT. Knockout mice with alphaENaC deleted primarily in a part of the CNT (CNT-KO) were generated using Scnn1a(lox/lox) mice and Atp6v1b1::Cre mice. With a standard diet, plasma Na(+) concentration ([Na(+)]) and [K(+)], and urine Na(+) and K(+) output were unaffected. Seven days of Na(+) restriction (0.01% Na(+)) led to a higher urine Na(+) output only on days 3-5, and after 7 days plasma [Na(+)] and [K(+)] were unaffected. In contrast, the CNT-KO mice were highly susceptible to a 2-day 5% K(+) diet and showed lower food intake and relative body weight, lower plasma [Na(+)], higher fractional excretion (FE) of Na(+), higher plasma [K(+)], and lower FE of K(+). The higher FE of Na(+) coincided with lower abundance and phosphorylation of the Na(+)-Cl(-) cotransporter. In conclusion, reducing ENaC expression in the CNT induces clear PHA-1 symptoms during high dietary K(+) loading. PMID- 26582763 TI - Distribution, species composition and relative abundances of sandflies in North Waziristan Agency, Pakistan. AB - This study was conducted to investigate the diversity of sandflies (Psychodidae: Phlebotominae) and the incidence of leishmaniasis in three villages of North Waziristan Agency, Pakistan. Sandflies were sampled monthly during 2012, at dusk and dawn, in selected indoor habitats including both bedrooms and animal sheds using a knock-down spray catch method. A total of 3687 sandflies were collected, including 1444 individuals in Drezanda, 1193 in Damdil and 1050 in Dattakhel. This study revealed 14 species of two genera, Phlebotomus (Phlebotomus sergenti, Phlebotomus papatasi, Phlebotomus caucasicus, Phlebotomus kazeruni, Phlebotomus alexandri and Phlebotomus salehi) and Sergentomyia (Sergentomyia dentate, Sergentomyia baghdadis, Sergentomyia babu, Sergentomyia theodori, Sergentomyia sumbarica, Sergentomyia dreyfussitur kestanica, Sergentomyia hogsoni pawlowskyi and Sergentomyia fallax afghanica) (both: Diptera: Psychodidae). Phlebotomus sergenti was the most abundant species (42.1%), followed by S. dentata (17.7%) and S. baghdadis (17.4%). The number of males collected represented about twice that of female flies, and the maximum number was collected in July, followed by August. The determination of the species composition of sandfly populations, seasonal variations, relative abundances and estimations of infection in the vector population may provide information about the dynamics of leishmaniasis transmission that is useful in planning vector control activities. PMID- 26582764 TI - A comparison of arthroscopy to ultrasonography for identification of pathology of the equine stifle. AB - REASONS FOR PERFORMING STUDY: To evaluate and compare the diagnostic capability of arthroscopy and ultrasonography for the detection of pathological change in equine stifle joints. Although descriptions of the arthroscopic and ultrasonographic boundaries of the normal femorotibial joint exist, there are few examples in the literature comparing the pathological changes observed with each imaging modality. OBJECTIVES: To evaluate and compare arthroscopic and ultrasonographic examinations for characterising pathological change in the stifle joint. To describe how the results of arthroscopic and ultrasonographic examinations may differ in characterising the severity of lesions and to evaluate which lesions are best assessed with each modality. STUDY DESIGN: Retrospective review of ultrasonographic and arthroscopic examinations. METHODS: The structures of the stifle joint were evaluated and graded for pathological change by scoring arthroscopic and ultrasonographic examinations. The presence and severity of the lesions were then compared between each modality. RESULTS: Medial meniscal lesions were detected more often with ultrasonography than with arthroscopy. Conversely, arthroscopy was better for detection of cranial medial meniscotibial ligament (CrMMTL) tearing. Articular cartilage defects were best detected with arthroscopy and periarticular osteophytes of the medial femoral condyle with ultrasonography. Four cases had defects within one of the patellar ligaments, all of which were only characterised with ultrasonography. CONCLUSIONS: Ultrasonography and arthroscopy should be combined to best evaluate pathology of the stifle, since each modality has its own limitations depending on the location and type of lesion. PMID- 26582765 TI - Severe Congenital Obstruction of the Left Main Coronary Artery Coexisting With Supravalvular Aortic Stenosis in Williams Syndrome: A Dangerous Association. AB - Congenital obstruction of the left main coronary artery is a complicating feature of supravalvular aortic stenosis. We describe an eight-month-old female patient with Williams syndrome, supravalvular aortic stenosis, and branch pulmonary artery stenosis, with concomitant anomaly of severe obstruction of the left coronary artery orifice. PMID- 26582767 TI - Sixty seconds on...maternal deaths. PMID- 26582766 TI - Genetic Susceptibility to Lipid Levels and Lipid Change Over Time and Risk of Incident Hyperlipidemia in Chinese Populations. AB - BACKGROUND: Multiple genetic loci associated with lipid levels have been identified predominantly in Europeans, and the issue of to what extent these genetic loci can predict blood lipid levels increases over time and the incidence of future hyperlipidemia remains largely unknown. METHODS AND RESULTS: We conducted a meta-analysis of genome-wide association studies of lipid levels in 8344 subjects followed by replication studies including 14 739 additional individuals. We replicated 17 previously reported loci. We also newly identified 3 Chinese-specific variants in previous regions (HLA-C, LIPG, and LDLR) with genome-wide significance. Almost all the variants contributed to lipid levels change and incident hyperlipidemia >8.1-year follow-up among 6428 individuals of a prospective cohort study. The strongest associations for lipid levels change were detected at LPL, TRIB1, APOA1-C3-A4-A5, LIPC, CETP, and LDLR (P range from 4.84*10(-4) to 4.62*10(-18)), whereas LPL, TRIB1, ABCA1, APOA1-C3-A4-A5, CETP, and APOE displayed significant strongest associations for incident hyperlipidemia (P range from 1.20*10(-3) to 4.67*10(-16)). The 4 lipids genetic risk scores were independently associated with linear increases in their corresponding lipid levels and risk of incident hyperlipidemia. A C-statistics analysis showed significant improvement in the prediction of incident hyperlipidemia on top of traditional risk factors including the baseline lipid levels. CONCLUSIONS: These findings identified some evidence for allelic heterogeneity in Chinese when compared with Europeans in relation to lipid associations. The individual variants and those cumulative effects were independent risk factors for lipids increase and incident hyperlipidemia. PMID- 26582769 TI - Turtles in Their Natural Habitats. PMID- 26582770 TI - Mucinous Variant of Follicular Carcinoma of the Thyroid Gland: Case Report and Review of the Literature. AB - The rare reports of mucinous variant of follicular carcinoma of the thyroid gland have not provided enough evidence to support the recognition of these tumors as a distinct clinicopathologic entity or to understand their etiopathogenesis. We report the fourth case of mucinous variant of follicular carcinoma displaying a minimally invasive tumor with diffuse expression of thyroglobulin, TTF-1, CD56, PAX-8, cytokeratins 7 and 19, in the absence of monoclonal carcinoembryonic antigen (CEA), cytokeratin 20, chromogranin, HBME-1, P63 expression, and BRAF gene mutation, in a 51-year-old woman who is alive without signs of disease 13 months after total thyroidectomy, bilateral neck dissection, and radioactive iodine. Herein, fine-needle aspiration cytology disclosed "worrisome" cytologic features consisting of large epithelial cells arranged in clusters or singularly, with high nucleocytoplasmic ratio, nuclear grooves and evident nucleoli which were shared by those of mucin-producing papillary thyroid carcinoma. Therefore, knowledge of the cytological and histopathological spectrum of this lesion is important to avoid misdiagnosis. The morphologic clues leading to the correct diagnosis of mucinous variant of follicular neoplasm have been correlated with the data of the literature, and the differential diagnosis is briefly discussed. PMID- 26582768 TI - Abo1, a conserved bromodomain AAA-ATPase, maintains global nucleosome occupancy and organisation. AB - Maintenance of the correct level and organisation of nucleosomes is crucial for genome function. Here, we uncover a role for a conserved bromodomain AAA-ATPase, Abo1, in the maintenance of nucleosome architecture in fission yeast. Cells lacking abo1(+) experience both a reduction and mis-positioning of nucleosomes at transcribed sequences in addition to increased intragenic transcription, phenotypes that are hallmarks of defective chromatin re-establishment behind RNA polymerase II. Abo1 is recruited to gene sequences and associates with histone H3 and the histone chaperone FACT. Furthermore, the distribution of Abo1 on chromatin is disturbed by impaired FACT function. The role of Abo1 extends to some promoters and also to silent heterochromatin. Abo1 is recruited to pericentromeric heterochromatin independently of the HP1 ortholog, Swi6, where it enforces proper nucleosome occupancy. Consequently, loss of Abo1 alleviates silencing and causes elevated chromosome mis-segregation. We suggest that Abo1 provides a histone chaperone function that maintains nucleosome architecture genome-wide. PMID- 26582771 TI - Postirradiation Leiomyosarcoma of Rectum Presenting as a Polyp: Case Report and Review of the Literature. AB - Radiation-induced leiomyosarcomas of the gastrointestinal tract are rare. Very few cases have been documented to date. The histological similarity to gastrointestinal stromal tumor has raised doubts if many of the cases originally reported to be leiomyosarcoma before the widespread use of CD117 were indeed gastrointestinal stromal tumors. We present a case of post-irradiation leiomyosarcoma presenting as a rectal polyp and review the literature. PMID- 26582772 TI - Renal Angiomyolipoma With Sarcoid Granulomas: Report of a Unique Case. AB - Angiomyolipoma is a mesenchymal neoplasm characterized by the coexpression of melanocytic and smooth muscle markers. Sarcoidosis is a multisystem disorder of unknown etiology, which presents with characteristic nonnecrotizing granulomas and rarely involves the kidney. The coexistence of renal sarcoidosis with renal neoplasms is exceedingly rare and was reported only with renal cell carcinoma. Renal sarcoidosis associated with a nonepithelial renal neoplasm, such as an angiomyolipoma has never been reported. We present the first reported case of sarcoid granulomas in a renal angiomyolipoma, including morphologic and immunohistochemical features. PMID- 26582773 TI - Emojis for the Surgical Pathologist. PMID- 26582774 TI - Innate Immune Factors in Mothers' Breast Milk and Their Lack of Association With Rotavirus Vaccine Immunogenicity in Nicaraguan Infants. AB - To better understand underlying causes of lower rotavirus vaccine effectiveness in low-middle income countries (LMICs), we measured innate antiviral factors in Nicaraguan mothers' milk and immune response to the first dose of the pentavalent rotavirus vaccine in corresponding infants. No relationship was found between concentrations of innate factors and rotavirus vaccine response. PMID- 26582776 TI - David Oliver: a fairy tale mandate for the NHS. PMID- 26582775 TI - Identification of the (Pro)renin Receptor as a Novel Regulator of Low-Density Lipoprotein Metabolism. AB - RATIONALE: The (pro)renin receptor ([P]RR) interacts with (pro)renin at concentrations that are >1000* higher than observed under (patho)physiological conditions. Recent studies have identified renin-angiotensin system-independent functions for (P)RR related to its association with the vacuolar H(+)-ATPase. OBJECTIVE: To uncover renin-angiotensin system-independent functions of the (P)RR. METHODS AND RESULTS: We used a proteomics-based approach to purify and identify (P)RR-interacting proteins. This resulted in identification of sortilin 1 (SORT1) as a high-confidence (P)RR-interacting protein, a finding which was confirmed by coimmunoprecipitation of endogenous (P)RR and SORT1. Functionally, silencing (P)RR expression in hepatocytes decreased SORT1 and low-density lipoprotein (LDL) receptor protein abundance and, as a consequence, resulted in severely attenuated cellular LDL uptake. In contrast to LDL, endocytosis of epidermal growth factor or transferrin remained unaffected by silencing of the (P)RR. Importantly, reduction of LDL receptor and SORT1 protein abundance occurred in the absence of changes in their corresponding transcript level. Consistent with a post-transcriptional event, degradation of the LDL receptor induced by (P)RR silencing could be reversed by lysosomotropic agents, such as bafilomycin A1. CONCLUSIONS: Our study identifies a renin-angiotensin system independent function for the (P)RR in the regulation of LDL metabolism by controlling the levels of SORT1 and LDL receptor. PMID- 26582778 TI - The Authors Reply. PMID- 26582777 TI - Association of Aging-Related Endophenotypes With Mortality in 2 Cohort Studies: the Long Life Family Study and the Health, Aging and Body Composition Study. AB - One method by which to identify fundamental biological processes that may contribute to age-related disease and disability, instead of disease-specific processes, is to construct endophenotypes comprising linear combinations of physiological measures. Applying factor analyses methods to phenotypic data (2006 2009) on 28 traits representing 5 domains (cognitive, cardiovascular, metabolic, physical, and pulmonary) from 4,472 US and Danish individuals in 574 pedigrees from the Long Life Family Study (United States and Denmark), we constructed endophenotypes and assessed their relationship with mortality. The most dominant endophenotype primarily reflected the physical activity and pulmonary domains, was heritable, was significantly associated with mortality, and attenuated the association of age with mortality by 24.1%. Using data (1997-1998) on 1,794 Health, Aging and Body Composition Study participants from Memphis, Tennessee, and Pittsburgh, Pennsylvania, we obtained strikingly similar endophenotypes and relationships to mortality. We also reproduced the endophenotype constructs, especially the dominant physical activity and pulmonary endophenotype, within demographic subpopulations of these 2 cohorts. Thus, this endophenotype construct may represent an underlying phenotype related to aging. Additional genetic studies of this endophenotype may help identify genetic variants or networks that contribute to the aging process. PMID- 26582779 TI - Re: Parental Age at Birth and Risk of Hematological Malignancies in Older Adults. PMID- 26582780 TI - Five minutes with...the president of the Royal College of Psychiatrists. PMID- 26582781 TI - Trends in Modifiable Risk Factors Are Associated With Declining Incidence of Hospitalized and Nonhospitalized Acute Coronary Heart Disease in a Population. AB - BACKGROUND: Few studies have used individual person data to study whether contemporary trends in the incidence of coronary heart disease are associated with changes in modifiable coronary risk factors. METHODS AND RESULTS: We identified 29 582 healthy men and women >=25 years of age who participated in 3 population surveys conducted between 1994 and 2008 in Tromso, Norway. Age- and sex-adjusted incidence rates were calculated for coronary heart disease overall, out-of-hospital sudden death, and hospitalized ST-segment-elevation and non-ST segment-elevation myocardial infarction. We measured coronary risk factors at each survey and estimated the relationship between changes in risk factors and changes in incidence trends. A total of 1845 participants had an incident acute coronary heart disease event during 375 064 person-years of follow-up from 1994 to 2010. The age- and sex-adjusted incidence of total coronary heart disease decreased by 3% (95% confidence interval, 2.0-4.0; P<0.001) each year. This decline was driven by decreases in out-of-hospital sudden death and hospitalized ST-segment-elevation myocardial infarction. Changes in coronary risk factors accounted for 66% (95% confidence interval, 48-97; P<0.001) of the decline in total coronary heart disease. Favorable changes in cholesterol contributed 32% to the decline, whereas blood pressure, smoking, and physical activity each contributed 14%, 13%, and 9%, respectively. CONCLUSIONS: We observed a substantial decline in the incidence of coronary heart disease that was driven by reductions in out-of-hospital sudden death and hospitalized ST-segment-elevation myocardial infarction. Changes in modifiable coronary risk factors accounted for 66% of the decline in coronary heart disease events. PMID- 26582782 TI - Falling Coronary Heart Disease Rates: A Better Explanation? PMID- 26582783 TI - Mental imagery and bipolar disorders: Introducing scope for psychological treatment development? PMID- 26582784 TI - Relationships among depression during pregnancy, social support and health locus of control among Iranian pregnant women. AB - BACKGROUND: Prenatal depression is a significant predictor of postpartum depression and is detrimental to fetal development. AIM: To examine whether depression during pregnancy is associated with social support and health locus of control (HLC). METHOD: Data were collected from a sample of 208 Iranian pregnant women using a demographic questionnaire, the Edinburgh Postnatal Depression Scale, the multidimensional HLC Scale and the social support appraisals. RESULTS: Depression was experienced by 37% of participants. Overall, women reported higher level of family support (6.88 +/- 1.15) than other supports (6.87 +/- 1.29). Protective supports from other resources (6.87 +/- 1.29) were higher than those from friends (5.94 +/- 1.5). Internal, powerful others and chance beliefs had the highest mean scores. Social support and chance HLC significantly influenced the proposed mediator (depressive mood) in the linear regression model. Bivariate analysis showed significant associations between social support (friend, family and others) and depressive mood. Internal HLC had a significant association with social support and powerful others HLC. However, Pearson correlation coefficient was not significant between depressive mood and all dimensions of HLC. CONCLUSION: Clinicians could assess social support and chance HLC to identify and treat women at risk of prenatal depression. By providing support during pregnancy, depression levels in women and its effects on the fetus may be decreased, which could prevent postpartum depression. PMID- 26582785 TI - The prevalence and predictors of self-stigma of individuals with mental health illness in two Chinese cities. AB - BACKGROUND: Although self-stigma is found to have adverse effects on the lives of persons with mental illness, little is known on the self-stigma of these individuals in Chinese societies. OBJECTIVE: This research study explores the prevalence rate and predicting factors of self-stigma of consumers in two Chinese cities, Hong Kong and Guangzhou. METHODS: A cross-sectional research design is adopted which involves a random sample of 266 consumers from Hong Kong and a convenient sample of 208 consumers from Guangzhou. These individuals have been assessed in terms of their self-stigma, recovery, self-esteem and quality of life by using standardized assessment scales. RESULTS: In all, 38.3% of the Hong Kong participants and 49.5% of the Guangzhou participants report to have self-stigma. Also, self-stigma is found to be negatively related to self-esteem and quality of life. A logistic regression analysis shows that hope and well-being are predicting factors of self-stigma. CONCLUSION: Self-stigma is found to be higher in Guangzhou, probably due to the influence of traditional cultural values. Also, as hope and well-being are found to be predicting factors of self-stigma, suitable recovery-orientated interventions that facilitate hope and well-being should be developed so as to reduce self-stigma of consumers in Chinese societies. PMID- 26582786 TI - US physician group calls for ban on direct to consumer drug advertising. PMID- 26582788 TI - Regulation of Reprogramming and Cellular Plasticity through Histone Exchange and Histone Variant Incorporation. AB - Early embryonic cells are totipotent and can generate a complete organism including embryonic and extraembryonic tissues. After division, cells lose their potency as they move toward a pluripotent state characterized by decreased cellular plasticity. During this transition, drastic changes in transcriptional programs occur in parallel with global chromatin reorganization. The epigenetic mechanisms governing the changes in chromatin signatures during the transitions of cellular plasticity states are starting to be understood. Among these mechanisms, recent studies highlight the importance of histone variant incorporation and/or eviction from chromatin in the regulation of the chromatin state that is linked to cellular potential. In this review, we discuss the role of histone variants during in vivo and in vitro reprogramming events. These results sustain the hypothesis that histone variants and histone exchange are key actors in the establishment of cellular plasticity programs. PMID- 26582787 TI - Mechanisms Underlying the Selection and Function of Macrophage-Specific Enhancers. AB - Macrophages populate every tissue of the body and play vital roles in homeostasis, pathogen elimination, and tissue healing. These cells possess the ability to adapt to a multitude of abruptly changing and complex environments. Furthermore, different populations of resident tissue macrophages each show their own defining gene signatures. The enhancer repertoire of these cells underlies both the cellular identity of a given subset of resident macrophage population and their ability to dynamically alter, in an efficient manner, their gene expression programs in response to internal and external signals. Notably, transcription is pervasive at active enhancers and enhancer RNAs, or eRNAs, are tightly correlated to regulated transcription of protein-coding genes. Furthermore, selection and establishment of enhancers is a dynamic and plastic process in which activation of intracellular signaling pathways by factors present in a macrophage's environment play a determining role. Here, we review recent studies providing insights into the distinct mechanisms that contribute to the selection and function of enhancers in macrophages and the relevance of studying these mechanisms to gain a better understanding of complex human diseases. PMID- 26582789 TI - Transcriptional Enhancers: Bridging the Genome and Phenome. AB - Enhancers play a major role in animal development by modulating spatiotemporal expression of genes. They interact with sequence-specific transcriptional regulators in response to internal and external cues to bring about transcriptional changes, thus serving as the critical link between an organism's genome and its phenotypic traits. Deciphering the biology of enhancers is a key to understanding the genetic basis of common human diseases. Although a large number of candidate enhancers have been annotated through genome-wide analyses of chromatin accessibility, transcription factor binding, and histone modification in diverse cell types, efforts to characterize their biological roles in human diseases have only begun. Recent experiments have suggested a role for the three dimensional chromatin architecture in regulation of gene expression by enhancers. PMID- 26582790 TI - Biological Networks Governing the Acquisition, Maintenance, and Dissolution of Pluripotency: Insights from Functional Genomics Approaches. AB - The repertoire of transcripts encoded by the genome contributes to the diversity of cellular states. Functional genomics aims to comprehensively uncover the roles of these transcripts to reconstruct biological networks and transform this information into useful knowledge. High-throughput functional screening has served as a powerful genetic discovery tool by enabling massively parallel implementation of biological assays. In recent years, high-throughput screening has unearthed crucial players in the regulation of different aspects of pluripotency, which is a unique property that enables a cell to differentiate into multiple cell types of the three major lineages. Pluripotency thus represents an interesting biological paradigm for studying the acquisition, maintenance, and dissolution of cellular states. In this review, we highlight the major findings of high-throughput studies to dissect these three aspects of pluripotency for the mouse and human systems. Collectively, they provide new insights into cell fate maintenance and transition. In addition, we also discuss the opportunities and challenges awaiting high-throughput screening in the future. PMID- 26582791 TI - Silent pericentromeric repeats speak out. PMID- 26582792 TI - The dorsal anterior cingulate cortex is selective for pain: Results from large scale reverse inference. AB - Dorsal anterior cingulate cortex (dACC) activation is commonly observed in studies of pain, executive control, conflict monitoring, and salience processing, making it difficult to interpret the dACC's specific psychological function. Using Neurosynth, an automated brainmapping database [of over 10,000 functional MRI (fMRI) studies], we performed quantitative reverse inference analyses to explore the best general psychological account of the dACC function P(Psi process|dACC activity). Results clearly indicated that the best psychological description of dACC function was related to pain processing--not executive, conflict, or salience processing. We conclude by considering that physical pain may be an instance of a broader class of survival-relevant goals monitored by the dACC, in contrast to more arbitrary temporary goals, which may be monitored by the supplementary motor area. PMID- 26582793 TI - QnAs with Jeannie T. Lee. PMID- 26582794 TI - Cracking the brain's genetic code. PMID- 26582795 TI - MicroRNA-3151 inactivates TP53 in BRAF-mutated human malignancies. AB - The B-Raf proto-oncogene serine/threonine kinase (BRAF) gene is the most frequently mutated gene in malignant melanoma (MM) and papillary thyroid cancer (PTC) and is causally involved in malignant cell transformation. Mutated BRAF is associated with an aggressive disease phenotype, thus making it a top candidate for targeted treatment strategies in MM and PTC. We show that BRAF mutations in both MM and PTC drive increased expression of oncomiR-3151, which is coactivated by the SP1/NF-kappaB complex. Knockdown of microRNA-3151 (miR-3151) with short hairpin RNAs reduces cell proliferation and increases apoptosis of MM and PTC cells. Using a targeted RNA sequencing approach, we mechanistically determined that miR-3151 directly targets TP53 and other members of the TP53 pathway. Reducing miR-3151's abundance increases TP53's mRNA and protein expression and favors its nuclear localization. Consequently, knockdown of miR-3151 also leads to caspase-3-dependent apoptosis. Simultaneous inhibition of aberrantly activated BRAF and knockdown of miR-3151 potentiates the effects of sole BRAF inhibition with the BRAF inhibitor vemurafenib and may provide a novel targeted therapeutic approach in BRAF-mutated MM and PTC patients. In conclusion, we identify miR-3151 as a previously unidentified player in MM and PTC pathogenesis, which is driven by BRAF-dependent and BRAF-independent mechanisms. Characterization of TP53 as a downstream effector of miR-3151 provides evidence for a causal link between BRAF mutations and TP53 inactivation. PMID- 26582796 TI - Human hepatitis A virus is united with a host of relations. PMID- 26582797 TI - Fine tuning of a DNA fork by the RecQ helicase. PMID- 26582798 TI - Articular Cartilage Degenerates After Subtotal/Total Lateral Meniscectomy but Radiographic Arthrosis Progression Is Reduced After Meniscal Transplantation. AB - BACKGROUND: Little is known about the degree of articular cartilage degeneration after subtotal/total lateral meniscectomy in patients who later undergo isolated lateral meniscal allograft transplantation (LMAT). It has not yet been studied whether arthritic changes as shown on radiographs were lower during the posttransplantation period than during the meniscus-deficient period. HYPOTHESIS: Articular cartilage will significantly degenerate during the meniscus-deficient period, but the progression in radiographic arthrosis is reduced after LMAT. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: This study retrospectively reviewed 49 patients who underwent subtotal/total lateral meniscectomy before isolated LMAT performed over 1 year later by the same surgeon. International Cartilage Repair Society (ICRS) grades of the femorotibial joint at the time of subtotal/total meniscectomy and at LMAT were compared. Radiographic evaluation was performed at the time of initial meniscectomy, LMAT, and the latest follow-up in 38 patients (after 11 patients whose radiographs showed incomplete ossification at the time of meniscectomy were excluded). Arthrosis, based on Kellgren-Lawrence (K-L) grades, was determined on standing anteroposterior views. Joint space width (JSW) was measured on weightbearing flexion posteroanterior views. RESULTS: Over a mean meniscus-deficient period of 4.5 years (range, 1-13 years), articular cartilage significantly degenerated on the femoral and tibial sides (P < .001). Grade >=3 degeneration on the lateral tibial plateau was observed in 13 patients (27%) at the time of initial meniscectomy; this incidence doubled to 28 patients (57%) by the time of LMAT. The K-L grades worsened (P < .001) and JSWs narrowed significantly (-0.65 +/- 1.09 mm; P = .001) during the mean meniscus-deficient period of 3.1 years. At radiographic assessment, however, the K-L grades (P = .097) and JSWs (4.06 +/- 1.19 vs 3.92 +/- 1.21 mm; mean difference, -0.14 +/- 0.68 mm; P = .213) did not significantly change during the mean posttransplantation period of 3.8 years. The changes in ICRS grade and JSW during the meniscus-deficient period were not associated with age, body mass index, mechanical axis deviation, or Tegner activity level (P > .05 for all relationships). CONCLUSION: Patients who underwent isolated LMAT showed substantial articular cartilage degeneration at the time of initial subtotal/total lateral meniscectomy, and this degeneration progressed thereafter. Further progression of radiographic arthrosis was delayed after LMAT. PMID- 26582800 TI - Adult ADHD Symptoms and Satisfaction With Life: Does Age and Sex Matter? AB - OBJECTIVE: To investigate adult ADHD symptoms and satisfaction with life, with a focus on age and sex differences. METHOD: This study is based on parents in the Norwegian Mother and Child Cohort Study (MoBa). The Adult Self-Report Scale (ASRS 6) and Satisfaction With Life Scale (SWLS) scores were analyzed from 33,210 men and 41,983 women from young to middle adulthood. RESULTS: Mean ASRS total score was significantly higher in men, where 5.1% scored above cutoff, compared with 2.9% in women. Factor loadings supported the two ASRS subscales: Inattention (Inatt) and Hyperactivity-Impulsivity (HyImp) in both sexes. A significant decline with age was found on HyImp, whereas Inatt scores were reasonably stable in men and u-curved in women. High ASRS scores were associated with lower SWLS, but poor satisfaction with life was found only in high-scoring women. CONCLUSION: Our findings suggest caution to age and sex when using the ASRS-6. PMID- 26582799 TI - Motivations Associated With Nondisclosure of Self-Reported Concussions in Former Collegiate Athletes. AB - BACKGROUND: Previous studies examining nondisclosure among athletes in various settings have found substantial proportions of athletes with undisclosed concussions. Substantial gaps exist in our understanding of the factors influencing athletes' disclosure of sports-related concussions. PURPOSE: To examine the prevalence of, and factors associated with, nondisclosure of recalled concussions in former collegiate athletes. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: Former collegiate athletes (N = 797) completed an online questionnaire. Respondents recalled self-identified sports-related concussions (SISRCs) that they sustained while playing sports in high school, college, or professionally, and whether they disclosed these SISRCs to others. Respondents also recalled motivations for nondisclosure. The prevalence of nondisclosure was calculated among those who recalled SISRCs. Multivariate binomial regression estimated adjusted prevalence ratios (PRs) with 95% CIs, controlling for sex, level of contact in sports, and year the athletes began playing collegiate sports. RESULTS: A total of 214 respondents (26.9%) reported sustaining at least 1 SISRC. Of these, 71 (33.2%) reported not disclosing at least 1 SISRC. Former football athletes were most likely to report nondisclosure (68.3% of those recalling SISRCs); female athletes who participated in low/noncontact sports were the least likely to report nondisclosure (11.1% of those recalling SISRC). The prevalence of nondisclosure was higher among men than women in the univariate analysis (PR, 2.88; 95% CI, 1.62-5.14), multivariate analysis (PR, 2.11; 95% CI, 1.13-3.96), and multivariate analysis excluding former football athletes (PR, 2.11; 95% CI, 1.12-3.94). The most commonly reported motivations were as follows: did not want to leave the game/practice (78.9%), did not want to let the team down (71.8%), did not know it was a concussion (70.4%), and did not think it was serious enough (70.4%). CONCLUSION: Consistent with previous studies, a substantial proportion of former athletes recalled SISRCs that were not disclosed. Male athletes were less likely to disclose all of their SISRCs than female athletes. PMID- 26582801 TI - Effects of Cigarette Smoke, Cessation, and Switching to Two Heat-Not-Burn Tobacco Products on Lung Lipid Metabolism in C57BL/6 and Apoe-/- Mice-An Integrative Systems Toxicology Analysis. AB - The impact of cigarette smoke (CS), a major cause of lung diseases, on the composition and metabolism of lung lipids is incompletely understood. Here, we integrated quantitative lipidomics and proteomics to investigate exposure effects on lung lipid metabolism in a C57BL/6 and an Apolipoprotein E-deficient (Apoe(-/ )) mouse study. In these studies, mice were exposed to high concentrations of 3R4F reference CS, aerosol from potential modified risk tobacco products (MRTPs) or filtered air (Sham) for up to 8 months. The 2 assessed MRTPs, the prototypical MRTP for C57BL/6 mice and the Tobacco Heating System 2.2 for Apoe(-/-) mice, utilize "heat-not-burn" technologies and were each matched in nicotine concentrations to the 3R4F CS. After 2 months of CS exposure, some groups were either switched to the MRTP or underwent cessation. In both mouse strains, CS strongly affected several categories of lung lipids and lipid-related proteins. Candidate surfactant lipids, surfactant proteins, and surfactant metabolizing proteins were increased. Inflammatory eicosanoids, their metabolic enzymes, and several ceramide classes were elevated. Overall, CS induced a coordinated lipid response controlled by transcription regulators such as SREBP proteins and supported by other metabolic adaptations. In contrast, most of these changes were absent in the mice exposed to the potential MRTPs, in the cessation group, and the switching group. Our findings demonstrate the complex biological response of the lungs to CS exposure and support the benefits of cessation or switching to a heat-not-burn product using a design such as those employed in this study. PMID- 26582803 TI - Development of an HTRF Assay for the Detection and Characterization of Inhibitors of Catechol-O-Methyltransferase. AB - Catechol-O-methyltransferase (COMT) plays an important role in the deactivation of catecholamine neurotransmitters and hormones. Inhibitors of COMT, such as tolcapone and entacapone, are used clinically in the treatment of Parkinson's disease. Discovery of novel inhibitors has been hampered by a lack of suitable assays for high-throughput screening (HTS). Although assays using esculetin have been developed, these are affected by fluorescence, a common property of catechol type compounds. We have therefore evaluated a new homogenous time-resolved fluorescence (HTRF)-based assay from CisBio (Codolet, France), which measures the production of S-adenosyl-L-homocysteine (SAH). The assay has been run in both HTS and medium-throughput screening (MTS) modes. The assay was established using membranes expressing human membrane-bound COMT and was optimized for protein and time to give an acceptable signal window, good potency for tolcapone, and a high degree of translation between data in fluorescence ratio and data in terms of [SAH] produced. pIC50 values for the hits from the HTS mode were determined in the MTS mode. The assay also proved suitable for kinetic studies such as Km,app determination. PMID- 26582804 TI - Continuous intraperitoneal insulin infusion (CIPII) for type 1 diabetes: Effective therapy but a case of bad timing? PMID- 26582802 TI - Pyruvate Kinase Isoform Switching and Hepatic Metabolic Reprogramming by the Environmental Contaminant 2,3,7,8-Tetrachlorodibenzo-p-Dioxin. AB - The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) elicits dose-dependent hepatotoxicity that includes fat accumulation, inflammation, and fibrosis that may progress to hepatocellular carcinoma. To further investigate these effects, RNA-Seq data were integrated with computationally identified putative dioxin response elements, and complementary targeted metabolomic and aryl hydrocarbon receptor (AhR) ChIP-Seq data from female C57BL/6 mice gavaged with TCDD every 4 days for 28 days. Data integration using CytoKEGG with manual curation identified dose-dependent alterations in central carbon and amino acid metabolism. More specifically, TCDD increased pyruvate kinase isoform M2 (PKM2) gene and protein expression. PKM2 has lower catalytic activity resulting in decreased glycolytic flux and the accumulation of upstream intermediates that were redirected to the pentose phosphate pathway and serine/folate biosynthesis, 2 important NADPH producing pathways stemming from glycolysis. In addition, the GAC:KGA glutaminase (GLS1) protein isoform ratio was increased, consistent with increases in glutaminolysis which serves an anaplerotic role for the TCA cycle and compensates for the reduced glycolytic flux. Collectively, gene expression, protein, and metabolite changes were indicative of increases in NADPH production in support of cytochrome P450 activity and ROS defenses. This AhR-mediated metabolic reprogramming is similar to the Warburg effect and represents a novel advantageous defense mechanism to increase anti-oxidant capacity in normal differentiated hepatocytes. PMID- 26582805 TI - Intraperitoneal versus subcutaneous insulin therapy in the treatment of type 1 diabetes mellitus. AB - BACKGROUND: Continuous intraperitoneal insulin infusion (CIPII), a last-resort type 1 diabetes mellitus (T1DM) treatment, has only been investigated in small or controlled studies. We aimed to investigate glycaemia and quality of life (QoL) with CIPII versus subcutaneous (SC) insulin therapy during usual T1DM care. METHODS: A prospective, observational case-control study. CIPII-treated cases were matched to SC controls. The primary endpoint was a non-inferiority assessment (pre-defined margin of -5.5 mmol/mol) of the baseline adjusted difference in HbA1c between groups during a 26-week follow-up. Secondary outcomes included QoL, clinical and biochemical measurements. RESULTS: In total, 183 patients were analysed (CIPII n = 39 and SC n = 144). The HbA1c difference between treatment groups was -3.0 mmol/mol (95% CI -5.0, -1.0), being lower in the SC group. Patients using SC insulin therapy spent less percentage of time in hyperglycaemia (-9.3% (95% CI -15.8, -2.8)) and more in euglycaemia (6.9% (95% CI 1.2, 12.5) as compared with CIPII-treated patients. Besides a 3.6 U/l (95% CI 1.2, 6.0) lower concentration of alanine aminotransferase with CIPII, no biochemical and clinical differences were present. Most QoL scores were lower at baseline among CIPII-treated patients. However, besides lower health status, there were no differences in the baseline-adjusted general and diabetes-specific QoL and treatment satisfaction. CONCLUSION: Although patients using CIPII had a higher glycaemic profile compared with patients using SC insulin therapy, the HbA1c difference was non-inferior. Overall, health status was lower among CIPII treated patients, although diabetes-specific QoL and treatment satisfaction was similar to subcutaneously treated patients. PMID- 26582806 TI - Modified Bova score for risk stratification and short-term outcome in acute pulmonary embolism. AB - INTRODUCTION: Risk stratification in acute pulmonary embolism (PE) is crucial to identify those patients with a poorer prognosis. We aimed to investigate a modified Bova score for risk stratification in acute PE. MATERIALS AND METHODS: We performed a retrospective analysis of PE patients treated in the internal medicine department. Both haemodynamically stable and unstable PE patients, >= 18 years with measurements of cardiac troponin I (cTnI) and existing echocardiography were included in the analysis. RESULTS: Data from 130 patients were included for this retrospective analysis. Three patients (2.3%) died in hospital; 84 patients had a Bova score of < 4 points and 46 >= 4 points. PE patients with a score >= 4 points were older (71.2 +/- 13.8 vs. 66.3 +/- 15.5 years, p = 0.0733), died more frequently during the in-hospital course (6.5% vs. 0.0%, p = 0.0183), had a more prevalent high-risk PE status (10.9% vs. 1.2%, p = 0.0122), more often had right ventricular dysfunction (100.0% vs. 35.7%, p < 0.000001), presented more frequently with syncope/collapse (21.7% vs. 3.6%, p = 0.00101) and had a higher heart rate (104.6 +/- 23.5 vs. 90.0 +/- 20.6/min, p = 0.000143), shock index (0.91 +/- 0.59 vs. 0.62 +/- 0.18, p = 0.000232), cTnI (0.36 +/- 0.42 vs. 0.03+/- 0.10ng/ml, p < 0.000001) and creatinine (1.32 +/- 0.50 vs. 1.03 +/- 0.27 mg/dl, p = 0.000170). Adjusted multivariate logistic regressions revealed significant associations between the Bova score and in hospital death (OR 4.172, 95% CI 1.125-15.464, p = 0.0326) as well as pneumonia based on PE-related lung infarction (OR 1.207, 95% CI 1.005-1.449, p = 0.0442). ROC analysis for Bova score predicting in-hospital death and pneumonia based on PE-related lung infarction showed area under the curve values of 0.908 and 0.606 with Bova score cut-off values of 3.5 points and 1.5 points, respectively. CONCLUSIONS: The modified Bova score is highly effective to predict poorer outcome in acute PE. PMID- 26582807 TI - The estimated future disease burden of hepatitis C virus in the Netherlands with different treatment paradigms. AB - BACKGROUND & AIMS: Prevalence of hepatitis C virus (HCV) infection in the Netherlands is low (anti-HCV prevalence 0.22%). All-oral treatment with direct acting antivirals (DAAs) is tolerable and effective but expensive. Our analysis projected the future HCV-related disease burden in the Netherlands by applying different treatment scenarios. METHODS: Using a modelling approach, the size of the HCV-viraemic population in the Netherlands in 2014 was estimated using available data and expert consensus. The base scenario (based on the current Dutch situation) and different treatment scenarios (with increased efficacy, treatment uptake, and diagnoses) were modelled and the future HCV disease burden was predicted for each scenario. RESULTS: The estimated number of individuals with viraemic HCV infection in the Netherlands in 2014 was 19,200 (prevalence 0.12%). By 2030, this number is projected to decrease by 4 5% in the base scenario and by 85% if the number of treated patients increases. Furthermore, the number of individuals with hepatocellular carcinoma and liver-related deaths is estimated to decrease by 19% and 27%, respectively, in the base scenario, but may both be further decreased by 68% when focusing on treatment of HCV patients with a fibrosis stage of >= F2. CONCLUSIONS: A substantial reduction in HCV-related disease burden is possible with increases in treatment uptake as the efficacy of current therapies is high. Further reduction of HCV-related disease burden may be achieved through increases in diagnosis and preventative measures. These results might inform the further development of effective disease management strategies in the Netherlands. PMID- 26582808 TI - Epstein-Barr virus mimicking lymphoma--a case report. AB - A 50-year-old male without a relevant medical history came to the emergency department with fever, muscle pain and fatigue without any localising symptoms. Blood and urine cultures remained negative. Laboratory work- up showed elevated liver enzymes and lactate dehydrogenase; Epstein-Barr virus (EBV) serology was negative. Additional imaging showed a splenomegaly and cervical, axillary, mediastinal and hilar lymphadenopathy. Pathological examination of one of the lymph nodes and bone marrow biopsy revealed a peripheral T-cell non-Hodgkin's lymphoma not otherwise specified. Before the start of treatment he was asymptomatic, the laboratory results had normalised and the EBV polymerase chain reaction was strongly positive. Computed tomography scan was repeated and showed complete remission of the lymphadenopathy and normalised spleen volume. Follow-up bone marrow analysis including clonal rearrangement of the T-cell receptor after three months and one year revealed a decreasing clonal T-cell population (41%, 39% and 11% respectively). In conclusion, this was an extreme course of an EBV infection. The clinical relevance of the remaining small monoclonal T-cell population detectable in the bone marrow is unclear. PMID- 26582809 TI - Non-articular Felty's syndrome: An uncommon diagnosis. AB - Felty's syndrome is a triad of rheumatoid arthritis, neutropenia, and splenomegaly. We hereby report an unusual case of non-articular Felty's syndrome and its management along with discussing the importance of appropriately ruling out alternate causes of neutropenia with splenomegaly. PMID- 26582810 TI - Girl with conjunctival nodule. Onchocerciasis. PMID- 26582812 TI - A painful blue foot. Phlegmasia cerulea dolens (PCD). PMID- 26582814 TI - Two siblings with hepatosplenomegaly and pulmonary reticulation. Niemann-Pick disease type B. PMID- 26582816 TI - Gentamicin is frequently underdosed in patients with sepsis in the emergency department. PMID- 26582819 TI - Increase of methanol in exhaled breath quantified by SIFT-MS following aspartame ingestion. AB - Aspartame, methyl-L-alpha-aspartyl-L-phenylalaninate, is used worldwide as a sweetener in foods and drinks and is considered to be safe at an acceptable daily intake (ADI) of 40 mg per kg of body weight. This compound is completely hydrolyzed in the gastrointestinal tract to aspartic acid, phenylalanine and methanol, each being toxic at high levels. The objective of the present study was to quantify the volatile methanol component in the exhaled breath of ten healthy volunteers following the ingestion of a single ADI dose of aspartame. Direct on line measurements of methanol concentration were made in the mouth and nose breath exhalations using selected ion flow tube mass spectrometry, SIFT-MS, several times before aspartame ingestion in order to establish individual pre dose (baseline) levels and then during two hours post-ingestion to track their initial increase and subsequent decrease. The results show that breath methanol concentrations increased in all volunteers by 1082 +/- 205 parts-per-billion by volume (ppbv) from their pre-ingestion values, which ranged from 193 to 436 ppbv to peak values ranging from 981-1622 ppbv, from which they slowly decreased. These observations agree quantitatively with a predicted increase of 1030 ppbv estimated using a one-compartment model of uniform dilution of the methanol generated from a known amount of aspartame throughout the total body water (including blood). In summary, an ADI dose of aspartame leads to a 3-6 fold increase of blood methanol concentration above the individual baseline values. PMID- 26582817 TI - Oriented cell division: new roles in guiding skin wound repair and regeneration. AB - Tissue morphogenesis depends on precise regulation and timely co-ordination of cell division and also on the control of the direction of cell division. Establishment of polarity division axis, correct alignment of the mitotic spindle, segregation of fate determinants equally or unequally between daughter cells, are essential for the realization of oriented cell division. Furthermore, oriented cell division is regulated by intrinsic cues, extrinsic cues and other cues, such as cell geometry and polarity. However, dysregulation of cell division orientation could lead to abnormal tissue development and function. In the present study, we review recent studies on the molecular mechanism of cell division orientation and explain their new roles in skin repair and regeneration. PMID- 26582818 TI - Biochemical and structural characterization of polyphosphate kinase 2 from the intracellular pathogen Francisella tularensis. AB - The metabolism of polyphosphate is important for the virulence of a wide range of pathogenic bacteria and the enzymes of polyphosphate metabolism have been proposed as an anti-bacterial target. In the intracellular pathogen Francisella tularensis, the product of the gene FTT1564 has been identified as a polyphosphate kinase from the polyphosphate kinase 2 (PPK2) family. The isogenic deletion mutant was defective for intracellular growth in macrophages and was attenuated in mice, indicating an important role for polyphosphate in the virulence of Francisella. Herein, we report the biochemical and structural characterization of F. tularensis polyphosphate kinase (FtPPK2) with a view to characterizing the enzyme as a novel target for inhibitors. Using an HPLC-based activity assay, the substrate specificity of FtPPK2 was found to include purine but not pyrimidine nts. The activity was also measured using (31)P-NMR. FtPPK2 has been crystallized and the structure determined to 2.23 A (1 A=0.1 nm) resolution. The structure consists of a six-stranded parallel beta-sheet surrounded by 12 alpha-helices, with a high degree of similarity to other members of the PPK2 family and the thymidylate kinase superfamily. Residues proposed to be important for substrate binding and catalysis have been identified in the structure, including a lid-loop and the conserved Walker A and B motifs. The DeltaFTT1564 strain showed significantly increased sensitivity to a range of antibiotics in a manner independent of the mode of action of the antibiotic. This combination of biochemical, structural and microbiological data provide a sound foundation for future studies targeting the development of PPK2 small molecule inhibitors. PMID- 26582820 TI - Instant effects of changing body positions on compositions of exhaled breath. AB - Concentrations of exhaled volatile organic compounds (VOCs) may depend not only on biochemical or pathologic processes but also on physiological parameters. As breath sampling may be done in different body positions, effects of the sampling position on exhaled VOC concentrations were investigated by means of real-time mass spectrometry. Breaths from 15 healthy volunteers were analyzed in real-time by PTR-ToF-MS-8000 during paced breathing (12/min) in a continuous side-stream mode. We applied two series of body positions (setup 1: sitting, standing, supine, and sitting; setup 2: supine, left lateral, right lateral, prone, and supine). Each position was held for 2 min. Breath VOCs were quantified in inspired and alveolar air by means of a custom-made algorithm. Parallel monitoring of hemodynamics and capnometry was performed noninvasively. In setup 1, when compared to the initial sitting position, normalized mean concentrations of isoprene, furan, and acetonitrile decreased by 24%, 26%, and 9%, respectively, during standing and increased by 63%, 36%, and 10% during lying mirroring time profiles of stroke volume and pET-CO2. In contrast, acetone and H2S concentrations remained almost constant. In setup 2, when compared to the initial supine position, mean alveolar concentrations of isoprene and furan increased significantly up to 29% and 16%, respectively, when position was changed from lying on the right side to the prone position. As cardiac output and stroke volume decreased at that time, the reasons for the observed concentrations changes have to be linked to the ventilation/perfusion ratio or compartmental distribution rather than to perfusion alone. During final postures, all VOC concentrations, hemodynamics, and pET-CO2 returned to baseline. Exhaled blood borne VOC profiles changed due to body postures. Changes depended on cardiac stroke volume, origin, compartmental distribution and physico-chemical properties of the substances. Patients' positions and cardiac output have to be controlled when concentrations of breath VOCs are to be interpreted in terms of biomarkers. PMID- 26582821 TI - Immature myeloid Gr-1+ CD11b+ cells from lipopolysaccharide-immunosuppressed mice acquire inhibitory activity in the bone marrow and migrate to lymph nodes to exert their suppressive function. AB - Secondary infections due to post-sepsis immunosuppression are a major cause of death in patients with sepsis. Repetitive inoculation of increasing doses of lipopolysaccharide (LPS) into mice mimics the immunosuppression associated with sepsis. Myeloid-derived suppressor cells (MDSCs, Gr-1(+) CD11b(+)) are considered a major component of the immunosuppressive network, interfering with T-cell responses in many pathological conditions. We used LPS-immunosuppressed (IS) mice to address whether MDSCs acquired their suppressive ability in the bone marrow (BM) and whether they could migrate to lymph nodes (LNs) to exert their suppressive function. Our results showed that Gr-1(+) CD11b(+) cells of IS mice already had the potential to inhibit T-cell proliferation in the BM. Moreover, soluble factors present in the BM from IS mice were responsible for inducing this inhibitory ability in control BM cells. In addition, migration of Gr-1(+) CD11b(+) to LNs in vivo was maximal when cells obtained from the BM of IS mice were inoculated into an IS context. In this regard, we found chemoattractant activity in cell-free LN extracts (LNEs) from IS mice and an increased expression of the LN-homing chemokine receptor C-C chemokine receptor type 7 (CCR7) in IS BM Gr-1(+) CD11b(+) cells. These results indicate that Gr-1(+) CD11b(+) cells found in BM from IS mice acquire their suppressive activity in the same niche where they are generated, and migrate to LNs to exert their inhibitory role. A better understanding of MDSC generation and/or regulation of factors able to induce their inhibitory function may provide new and more effective tools for the treatment of sepsis-associated immunosuppression. PMID- 26582822 TI - Dietary fatty acids for the treatment of OA, including fish oil. PMID- 26582823 TI - Effects of colchicine on risk of cardiovascular events and mortality among patients with gout: a cohort study using electronic medical records linked with Medicare claims. AB - BACKGROUND: Colchicine may have beneficial effects on cardiovascular (CV) disease, but there are sparse data on its CV effect among patients with gout. We examined the potential association between colchicine and CV risk and all-cause mortality in gout. METHODS: The analyses used data from an electronic medical record (EMR) database linked with Medicare claims (2006-2011). To be eligible for the study cohort, subjects must have had a diagnosis of gout in the EMR and Medicare claims. New users of colchicine were identified and followed up from the first colchicine dispensing date. Non-users had no evidence of colchicine prescriptions during the study period and were matched to users on the start of follow-up, age and gender. Both groups were followed for the primary outcome, a composite of myocardial infarction, stroke or transient ischaemic attack. We calculated HRs in Cox regression, adjusting for potential confounders. RESULTS: We matched 501 users with an equal number of non-users with a median follow-up of 16.5 months. During follow-up, 28 primary CV events were observed among users and 82 among non-users. Incidence rates per 1000 person-years were 35.6 for users and 81.8 for non-users. After full adjustment, colchicine use was associated with a 49% lower risk (HR 0.51, 95% CI 0.30 to 0.88) in the primary CV outcome as well as a 73% reduction in all-cause mortality (HR 0.55, 95% CI 0.35 to 0.85, p=0.007). CONCLUSIONS: Colchicine use was associated with a reduced risk of a CV event among patients with gout. PMID- 26582824 TI - Critical care admission trends and outcomes in individuals with bronchiectasis in the UK. AB - BACKGROUND: There are limited data on admission trends and outcomes of individuals with bronchiectasis admitted to intensive care (ICU). Using national critical care data, we analysed admissions to ICU and estimated outcomes in terms of mortality in individuals with bronchiectasis and chronic obstructive pulmonary disease (COPD) admitted to ICU. METHODS: Using data from the Intensive Care National Audit and Research Centre, admissions from bronchiectasis and COPD from 1 January 2009 to 31 December 2013 were extracted. Crude admission rates for bronchiectasis and COPD were calculated and Poisson regression was used to estimate unadjusted annual admission rate ratios. We investigated changes to length of stay on ICU, ICU mortality and in-hospital mortality during the study period. We also compared mortality rates in people with bronchiectasis and COPD aged 70 or above. RESULTS: We found an annual increase of 8% (95% Confidence Interval [CI] 2-15) in the number of ICU admissions from bronchiectasis, whilst the yearly increase in ICU admissions from COPD was 1% (95% CI 0.3-2). ICU and in hospital mortality was higher in individuals with bronchiectasis compared with those with COPD, especially in people aged 70 years or above. CONCLUSION: Admission to ICU in people with bronchiectasis are uncommon, but are increasing in frequency over time, and carries a substantial mortality rate. This needs to be considered allocating health care resources and planning respiratory services. PMID- 26582825 TI - Point-of-care lactate measurement in resource-poor settings. PMID- 26582826 TI - Congenital brachymetatarsia and Turner syndrome. PMID- 26582827 TI - Unveiling New Aspects of Meningococcal Carriage and Disease Prevention. AB - Recently, two protein-based vaccines have been approved for the prevention of invasive meningococcal disease caused by Neisseria meningitidis serogroup B (MenB). It is therefore important to study carefully if and how these pathogens respond to widespread vaccination. Traditionally, meningococci have been classified on the basis of capsular phenotypes, but variable levels of capsule expression can influence the results, mainly among MenB strains. In this issue, Jones and colleagues (J Clin Microbiol 54:25-34, 2016, http://dx.doi.org/10.1128/JCM.01447-15) compare whole-genome sequencing to traditional phenotypic methods of classifying meningococci. They demonstrate that for MenB in particular, sequencing-based methods are far superior to traditional methods, especially when it comes to characterizing carriage isolates. This has important implications for future surveillance. PMID- 26582828 TI - Development of an Enzyme-Linked Immunosorbent Assay Based on Fusion VP2332-452 Antigen for Detecting Antibodies against Aleutian Mink Disease Virus. AB - For detection of Aleutian mink disease virus (AMDV) antibodies, an enzyme-linked immunosorbent assay (ELISA) was developed using the recombinant VP2332-452 protein as an antigen. Counterimmunoelectrophoresis (CIEP) was used as a reference test to compare the results of the ELISA and Western blotting (WB); the specificity and sensitivity of the VP2332-452 ELISA were 97.9% and 97.3%, respectively, which were higher than those of WB. Therefore, this VP2332-452 ELISA may be a preferable method for detecting antibodies against AMDV. PMID- 26582829 TI - Enhanced Tracking of Nosocomial Transmission of Endemic Sequence Type 22 Methicillin-Resistant Staphylococcus aureus Type IV Isolates among Patients and Environmental Sites by Use of Whole-Genome Sequencing. AB - Whole-genome sequencing (WGS) of 41 patient and environmental sequence type 22 methicillin-resistant Staphylococcus aureus staphylococcal cassette chromosome mec type IV (ST22-MRSA-IV) isolates recovered over 6 weeks in one acute hospital ward in Dublin, Ireland, where ST22-MRSA IV is endemic, revealed 228 pairwise combinations differing by <40 single nucleotide variants corresponding to potential cross-transmission events (CTEs). In contrast, 15 pairwise combinations of isolates representing five CTEs were previously identified by conventional molecular epidemiological typing. WGS enhanced ST22-MRSA-IV tracking and highlighted potential transmission of MRSA via the hospital environment. PMID- 26582830 TI - Usefulness of High-Quality Core Genome Single-Nucleotide Variant Analysis for Subtyping the Highly Clonal and the Most Prevalent Salmonella enterica Serovar Heidelberg Clone in the Context of Outbreak Investigations. AB - Salmonella enterica serovar Heidelberg is the second most frequently occurring serovar in Quebec and the third-most prevalent in Canada. Given that conventional pulsed-field gel electrophoresis (PFGE) subtyping for common Salmonella serovars, such as S. Heidelberg, yields identical subtypes for the majority of isolates recovered, public health laboratories are desperate for new subtyping tools to resolve highly clonal S. Heidelberg strains involved in outbreak events. As PFGE was unable to discriminate isolates from three epidemiologically distinct outbreaks in Quebec, this study was conducted to evaluate whole-genome sequencing (WGS) and phylogenetic analysis as an alternative to conventional subtyping tools. Genomes of 46 isolates from 3 Quebec outbreaks (2012, 2013, and 2014) supported by strong epidemiological evidence were sequenced and analyzed using a high-quality core genome single-nucleotide variant (hqSNV) bioinformatics approach (SNV phylogenomics [SNVphyl] pipeline). Outbreaks were indistinguishable by conventional PFGE subtyping, exhibiting the same PFGE pattern (SHEXAI.0001/SHEBNI.0001). Phylogenetic analysis based on hqSNVs extracted from WGS separated the outbreak isolates into three distinct groups, 100% concordant with the epidemiological data. The minimum and maximum number of hqSNVs between isolates from the same outbreak was 0 and 4, respectively, while >59 hqSNVs were measured between 2 previously indistinguishable outbreaks having the same PFGE and phage type, thus corroborating their distinction as separate unrelated outbreaks. This study demonstrates that despite the previously reported high clonality of this serovar, the WGS-based hqSNV approach is a superior typing method, capable of resolving events that were previously indistinguishable using classic subtyping tools. PMID- 26582832 TI - Evaluation of the BD Max Enteric Parasite Panel for Clinical Diagnostics. AB - We compared the performance of the BD Max enteric parasite panel to routine microscopy and an in-house PCR for the detection of Giardia intestinalis, Entamoeba histolytica, and Cryptosporidium spp. The enteric parasite panel showed good specificity for all targets and good sensitivity for E. histolytica and Cryptosporidium spp. Sensitivity for G. intestinalis with the BD Max enteric parasite panel was equivalent to that with microscopy. PMID- 26582831 TI - Blood Transcriptional Biomarkers for Active Tuberculosis among Patients in the United States: a Case-Control Study with Systematic Cross-Classifier Evaluation. AB - Blood transcriptional signatures are promising for tuberculosis (TB) diagnosis but have not been evaluated among U.S. PATIENTS: To be used clinically, transcriptional classifiers need reproducible accuracy in diverse populations that vary in genetic composition, disease spectrum and severity, and comorbidities. In a prospective case-control study, we identified novel transcriptional classifiers for active TB among U.S. patients and systematically compared their accuracy to classifiers from published studies. Blood samples from HIV-uninfected U.S. adults with active TB, pneumonia, or latent TB infection underwent whole-transcriptome microarray. We used support vector machines to classify disease state based on transcriptional patterns. We externally validated our classifiers using data from sub-Saharan African cohorts and evaluated previously published transcriptional classifiers in our population. Our classifier distinguishing active TB from pneumonia had an area under the concentration-time curve (AUC) of 96.5% (95.4% to 97.6%) among U.S. patients, but the AUC was lower (90.6% [89.6% to 91.7%]) in HIV-uninfected Sub-Saharan Africans. Previously published comparable classifiers had AUC values of 90.0% (87.7% to 92.3%) and 82.9% (80.8% to 85.1%) when tested in U.S. PATIENTS: Our classifier distinguishing active TB from latent TB had AUC values of 95.9% (95.2% to 96.6%) among U.S. patients and 95.3% (94.7% to 96.0%) among Sub-Saharan Africans. Previously published comparable classifiers had AUC values of 98.0% (97.4% to 98.7%) and 94.8% (92.9% to 96.8%) when tested in U.S. PATIENTS: Blood transcriptional classifiers accurately detected active TB among U.S. adults. The accuracy of classifiers for active TB versus that of other diseases decreased when tested in new populations with different disease controls, suggesting additional studies are required to enhance generalizability. Classifiers that distinguish active TB from latent TB are accurate and generalizable across populations and can be explored as screening assays. PMID- 26582833 TI - Comparative Study of a Novel Biochemical Assay, the Rapidec Carba NP Test, for Detecting Carbapenemase-Producing Enterobacteriaceae. AB - The novel biochemical test, the Rapidec Carba NP (RCNP), was evaluated using carbapenemase- and non-carbapenemase-producing Enterobacteriaceae isolates. The RCNP test was compared with the Carba NP test (CNP) and the modified Hodge test. Compared to the CNP test, the RCNP test had identical sensitivity (96%) and lower specificity (93% versus 100%). The medium used to culture the isolates significantly affected test sensitivity and specificity. The RCNP test was quicker and easier to perform than the other tests. PMID- 26582834 TI - Characterization of Samples Identified as Hepatitis C Virus Genotype 1 without Subtype by Abbott RealTime HCV Genotype II Assay Using the New Abbott HCV Genotype Plus RUO Test. AB - Hepatitis C virus (HCV) genotyping continues to be relevant for therapeutic strategies. Some samples are reported as genotype 1 (gt 1) without subtype by the Abbott RealTime HCV Genotype II (GT II) test. To characterize such samples further, the Abbott HCV Genotype Plus RUO (Plus) assay, which targets the core region for gt 1a, gt 1b, and gt 6 detection, was evaluated as a reflex test in reference to NS5B or 5'-untranslated region (UTR)/core region sequencing. Of 3,626 routine samples, results of gt 1 without subtype were received for 171 samples (4.7%), accounting for 11.5% of gt 1 specimens. The Plus assay and sequencing were applied to 98 of those samples. NS5B or 5'-UTR/core region sequencing was successful for 91/98 specimens (92.9%). Plus assay and sequencing results were concordant for 87.9% of specimens (80/91 samples). Sequencing confirmed Plus assay results for 82.6%, 85.7%, 100%, and 89.3% of gt 1a, gt 1b, gt 6, and non-gt 1a/1b/6 results, respectively. Notably, 12 gt 6 samples that had been identified previously as gt 1 without subtype were assigned correctly here; for 25/28 samples reported as "not detected" by the Plus assay, sequencing identified the samples as gt 1 with subtypes other than 1a/1b. The genetic variability of HCV continues to present challenges for the current genotyping platforms regardless of the applied methodology. Samples identified by the GT II assay as gt 1 without subtype can be further resolved and reliably characterized by the new Plus assay. PMID- 26582835 TI - Changes in the Population of Methicillin-Resistant Staphylococcus pseudintermedius and Dissemination of Antimicrobial-Resistant Phenotypes in the Netherlands. AB - Methicillin-resistant Staphylococcus pseudintermedius (MRSP), which is often multidrug resistant (MDR), has recently emerged as a threat to canine health worldwide. Knowledge of the temporal distribution of specific MRSP lineages, their antimicrobial resistance phenotypes, and their association with clinical conditions may help us to understand the emergence and spread of MRSP in dogs. The aim of this study was to determine the yearly proportions of MRSP lineages and their antimicrobial-resistant phenotypes in the Netherlands and to examine possible associations with clinical conditions. MRSP was first isolated from a canine specimen submitted for diagnostics to the Faculty of Veterinary Medicine of Utrecht University in 2004. The annual cumulative incidence of MRSP among S. pseudintermedius increased from 0.9% in 2004 to 7% in 2013. MRSP was significantly associated with pyoderma and, to a lesser extent, with wound infections and otitis externa. Multilocus sequence typing (MLST) of 478 MRSP isolates yielded 39 sequence types (ST) belonging to 4 clonal complexes (CC) and 15 singletons. CC71 was the dominant lineage that emerged since 2004, and CC258, CC45, and several unlinked isolates became more frequent during the following years. All but two strains conferred an MDR phenotype, but strains belonging to CC258 or singletons were less resistant. In conclusion, our study showed that MDR CC71 emerged as the dominant lineage from 2004 and onward and that less-resistant lineages were partly replacing CC71. PMID- 26582836 TI - Multicenter Evaluation of MRSASelect II Chromogenic Agar for Identification of Methicillin-Resistant Staphylococcus aureus from Wound and Nasal Specimens. AB - Hospitals strive to reduce methicillin-resistant Staphylococcus aureus (MRSA) prevalence via active surveillance of inpatient populations. Rapid and inexpensive screening methods are utilized when molecular methods are not operationally feasible. In this multisite clinical trial, the utility of Bio Rad's MRSASelect II was evaluated for MRSA identification from remnant nares and wound swabs. The prevalence of MRSA was 11.1% (n = 1,384) from nares samples and 18.1% (n = 842) from wound samples. MRSASelect II had an overall concordance of 95.4% (confidence interval [CI] = 94.5% to 96.2%) compared to a broth-enriched reference standard. Comparisons between results, stratified by examination times, exhibited a nonsignificant trend toward increased positivity at prolonged incubation times. Cefoxitin screening of colonies directly from MRSASelect II was 96.7% (95.8% to 97.3%) concordant compared to testing of colonies following broth enrichment. A comparison of MRSASelect and MRSASelect II revealed no statistical differences; however, the latter exhibited earlier positivity, greater selectivity, and more intense indicator staining, which resulted in facilitated differentiation of positive results. MRSASelect II agar is a simple, rapid, and robust method to routinely screen patients for MRSA colonization without the need for additional testing. PMID- 26582837 TI - A Simple and Safe Protocol for Preparing Brucella Samples for Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry Analysis. AB - We describe a simple protocol to inactivate the biosafety level 3 (BSL3) pathogens Brucella prior to their analysis by matrix-assisted laser desorption ionization-time of flight mass spectrometry. This method is also effective for several other bacterial pathogens and allows storage, and eventually shipping, of inactivated samples; therefore, it might be routinely applied to unidentified bacteria, for the safety of laboratory workers. PMID- 26582838 TI - Evaluation of an Image Analysis Device (APAS) for Screening Urine Cultures. AB - While advancements have been made in some areas of pathology with diagnostic materials being screened using image analysis technologies, the reporting of cultures from agar plates remains a manual process. We compared the results for 2,163 urine cultures read by a reference panel of microbiologists, by the routine laboratory process, and by an automated plate reading system, APAS (LBT Innovations Ltd., South Australia). APAS detected colonies with a sensitivity of 99.1% and a specificity of 99.3% on blood agar, while on MacConkey agar, the colony detection sensitivity was 99.4% with a specificity of 99.3%. The device's ability to enumerate growth had an accuracy of 89.2%, and the morphological identification of colonies showed a high level of performance for the colony types typical of Escherichia coli and other enteric bacilli. On blood agar, lactose-fermenting colonies were morphologically identified with a sensitivity of 98.9%, while on MacConkey agar they were identified with a sensitivity of 99.2%. In this first clinical evaluation, APAS demonstrated high performance in the detection, enumeration, and colony classification of isolates compared with that for conventional plate-reading methods. The device found all cases reported by the laboratory and detected the most commonly encountered organisms found in urinary tract infections. PMID- 26582839 TI - Comparison of Two Culture Methods for Use in Assessing Microbial Contamination of Duodenoscopes. AB - Recent outbreaks of carbapenem-resistant Enterobacteriaceae infections associated with duodenoscopes used for endoscopic retrograde cholangiopancreatography have highlighted the challenge of cleaning and high-level disinfection of these instruments. The Food and Drug Administration has suggested that duodenoscope surveillance by microbiological culturing, along with strict adherence to reprocessing protocols, may help reduce the risk of duodenoscope-associated infection transmission. We developed and validated an effective, user-friendly duodenoscope sampling and culture protocol and compared its performance to the interim Centers for Disease Control and Prevention-recommended guidelines. Our protocol resulted in a 65% recovery rate for Gram-negative organisms, demonstrating a 2-fold increased recovery rate compared to the CDC method. The implementation of this protocol may increase the feasibility of duodenoscope surveillance for microbiology laboratories and endoscopy departments. PMID- 26582840 TI - Long noncoding RNAs in regulation of human breast cancer. AB - Less than 2% of the human genome DNA is composed of protein-coding genes, although the majority of the human genome is transcribed, indicating the transcripts mostly are noncoding RNAs. Those noncoding RNAs with length between 200 nt and 200 kb are categorized as long noncoding RNA (lncRNA). Around 30 000 lncRNAs have been predicted or identified, although little is known regarding the regulatory function for a vast majority of these sequences. Emerging evidence demonstrated that lncRNAs play crucial roles in regulation of many cancer types, including breast cancer, serving as oncogenes or tumor suppressors. Aberrant and differential expression of lncRNA in breast cancer has been frequently reported. Their regulation of breast cancer is still the beginning to be elucidated. This review collected those experimentally validated lncRNAs in human breast cancer, summarizing their biological function as well as the regulatory mechanism. In addition, the potential of lncRNAs as biomarkers for better diagnosis or therapeutic targets for cancer treatment was discussed. PMID- 26582841 TI - Predictions replaced by facts: a keystone species' behavioural responses to declining arctic sea-ice. AB - Since the first documentation of climate-warming induced declines in arctic sea ice, predictions have been made regarding the expected negative consequences for endemic marine mammals. But, several decades later, little hard evidence exists regarding the responses of these animals to the ongoing environmental changes. Herein, we report the first empirical evidence of a dramatic shift in movement patterns and foraging behaviour of the arctic endemic ringed seal (Pusa hispida), before and after a major collapse in sea-ice in Svalbard, Norway. Among other changes to the ice-regime, this collapse shifted the summer position of the marginal ice zone from over the continental shelf, northward to the deep Arctic Ocean Basin. Following this change, which is thought to be a 'tipping point', subadult ringed seals swam greater distances, showed less area-restricted search behaviour, dived for longer periods, exhibited shorter surface intervals, rested less on sea-ice and did less diving directly beneath the ice during post-moulting foraging excursions. In combination, these behavioural changes suggest increased foraging effort and thus also likely increases in the energetic costs of finding food. Continued declines in sea-ice are likely to result in distributional changes, range reductions and population declines in this keystone arctic species. PMID- 26582842 TI - Molecular cytogenetics of tragelaphine and alcelaphine interspecies hybrids: hybridization, introgression and speciation in some African antelope. AB - Hybridization can occur naturally among diverging lineages as part of the evolutionary process leading to complete reproductive isolation, or it can result from range shifts and habitat alteration through global warming and/or other anthropogenic influences. Here we report a molecular cytogenetic investigation of hybridization between taxonomically distinct species of the Alcelaphini (Alcelaphus buselaphus 2n = 40 * Damaliscus lunatus 2n = 36) and the Tragelaphini (Tragelaphus strepsiceros 2n = 31/32 * Tragelaphus angasii 2n = 55/56). Cross species fluorescence in situ hybridization provides unequivocal evidence of the scale of karyotypic difference distinguishing parental species. The findings suggest that although hybrid meiosis of the former cross would necessitate the formation of a chain of seven, a ring of four and one trivalent, the progeny follow Haldane's rule showing F1 male sterility and female fertility. The tragelaphine F1 hybrid, a male, was similarly sterile and, given the 11 trivalents and chain of five anticipated in its meiosis, not unexpectedly so. We discuss these findings within the context of the broader evolutionary significance of hybridization in African antelope, and reflect on what these hold for our views of antelope species and their conservation. PMID- 26582844 TI - Health promoters should and do take the lead in preventing violence against women. PMID- 26582843 TI - Successful elimination of a lethal wildlife infectious disease in nature. AB - Methods to mitigate the impacts of emerging infectious diseases affecting wildlife are urgently needed to combat loss of biodiversity. However, the successful mitigation of wildlife pathogens in situ has rarely occurred. Indeed, most strategies for combating wildlife diseases remain theoretical, despite the wealth of information available for combating infections in livestock and crops. Here, we report the outcome of a 5-year effort to eliminate infection with Batrachochytrium dendrobatidis affecting an island system with a single amphibian host. Our initial efforts to eliminate infection in the larval reservoir using a direct application of an antifungal were successful ex situ but infection returned to previous levels when tadpoles with cleared infections were returned to their natal sites. We subsequently combined antifungal treatment of tadpoles with environmental chemical disinfection. Infection at four of the five pools where infection had previously been recorded was eradicated, and remained so for 2 years post-application. PMID- 26582845 TI - In vitro and in vivo effects of ulipristal acetate on fertilization and early embryo development in mice. AB - STUDY QUESTION: Does ulipristal acetate (UPA), a selective progesterone receptor modulator used for emergency contraception (EC), interfere with fertilization or early embryo development in vitro and in vivo? SUMMARY ANSWER: At doses similar to those used for EC, UPA does not affect mouse gamete transport, fertilization or embryo development. WHAT IS KNOWN ALREADY: UPA acts as an emergency contraceptive mainly by inhibiting or delaying ovulation. However, there is little information regarding its effects on post-ovulatory events preceding implantation. STUDY DESIGN, SIZE, DURATION: This was an in vitro and in vivo experimental study involving the use of mouse gametes and embryos from at least three animals in each set of experiments. PARTICIPANTS/MATERIALS, SETTING, METHODS: For in vitro fertilization experiments, mouse epididymal spermatozoa capacitated in the presence of different concentrations of UPA (0-1000 ng/ml) were used to inseminate cumulus-intact or cumulus-free eggs in the presence or absence of UPA during gamete co-incubation, and the percentage of fertilized eggs was determined. For in vivo fertilization experiments, superovulated females caged with proven fertile males were injected with UPA (40 mg/kg) or vehicle just before or just after mating and the percentage of fertilized eggs recovered from the ampulla was determined. To investigate the effect of UPA on embryo development, zygotes were recovered from mated females, cultured in the presence of UPA (1000 ng/ml) for 4 days and the progression of embryo development was monitored daily. MAIN RESULTS AND THE ROLE OF CHANCE: In vitro studies revealed that the presence of UPA during capacitation and/or gamete co-incubation does not affect fertilization. Whereas the in vivo administration of UPA at the same time as hCG injection produced a decrease in the number of eggs ovulated compared with controls (vehicle injected animals, P < 0.05), no effects on fertilization were observed when UPA was administered shortly before or after mating. No differences were observed in either the percentage of cleaved embryos or the cleavage speed when UPA was present during in vitro embryo culture. LIMITATIONS, REASONS FOR CAUTION: Considering the ethical and technical limitations inherent to the use of human gametes for fertilization studies, the mouse model was used as an approach for exploring the potential effects of UPA on in vivo sperm transport and fertilization. Nevertheless, the extrapolation of these results to humans requires further investigation. WIDER IMPLICATIONS OF THE FINDINGS: This study presents new evidence on the lack of effect of UPA on gamete interaction and embryo development, providing new insights into the mechanism of action of UPA as an emergency contraceptive method with potential clinical implications. These new findings could contribute to increase the acceptability and proper use of UPA as an emergency contraceptive method. STUDY FUNDING/COMPETING INTERESTS: This study was partially supported by a National Agency of Scientific and Technological Promotion (ANPCyT), Argentina grants PICT 2011-061 to D.J.C. and PICT 2011-2023 to P.S.C. None of the authors has any competing interests to declare. PMID- 26582846 TI - Impact of paraquat regulation on suicide in South Korea. AB - BACKGROUND: Ingestion of pesticides (mainly paraquat) accounted for one-fifth of suicides in South Korea in 2006-10. We investigated the effect on suicide mortality of regulatory action, culminating in a ban on paraquat in South Korea in 2011-12. METHODS: We calculated age-standardized method-specific suicide mortality rates among people aged >=15 in South Korea (1983-2013) using registered death data. Negative binomial regression was used to estimate changes in the rate and number of pesticide suicides in 2013, compared with those expected based on previous trends (2003-11). RESULTS: Pesticide suicide mortality halved from 5.26 to 2.67 per 100 000 population between 2011 and 2013. Compared with the number expected based on previous trends, the regulations were followed by an estimated 847 [95% confidence interval (CI) -1180 to -533] fewer pesticide suicides, a 37% reduction in rates (rate ratio = 0.63, 95% CI 0.55 to 0.73) in 2013. The decline in pesticide suicides after the regulations was seen in all age/sex/geographical groups. The absolute reduction in the number of suicides was greatest among men, the elderly and in rural areas. The reduction in pesticide suicides contributed to 56% of the decline in overall suicides that occurred between 2011 and 2013. There was no impact of the regulations on crop yield. CONCLUSIONS: The regulation of paraquat in South Korea in 2011-12 was associated with a reduction in pesticide suicide. Further legislative interventions to prevent the easy availability of highly lethal suicide methods are recommended for reducing the number of suicides worldwide. PMID- 26582847 TI - Deep neuromuscular block improves the surgical conditions for laryngeal microsurgery. AB - BACKGROUND: Adequate neuromuscular block is required throughout laryngeal microsurgery. We hypothesized that the surgical conditions would improve under a deeper level of rocuronium-induced neuromuscular block. METHODS: Seventy-two patients undergoing laryngeal microsurgery were randomly allocated to either the 'post-tetanic counts 1-2' (PTC1-2) group or the 'train-of-four counts 1-2' (TOFcount1-2) group according to the level of neuromuscular block used. Two different doses of rocuronium (1.2 or 0.5 mg kg(-1)) were used after anaesthetic induction, and two respective targets of neuromuscular block (post-tetanic counts <=2 or train-of-four count of 1 or 2) were used. Surgical conditions were assessed by the surgeon using a five-point rating scale (extremely poor/poor/acceptable/good/optimal), and clinically acceptable surgical conditions were defined as those which were rated acceptable, good, or optimal. The occurrence of vocal cord movement and postoperative adverse events was assessed. RESULTS: The surgical conditions were significantly different between the PTC1-2 and TOFcount1-2 groups (extremely poor/poor/acceptable/good/optimal: 0/2/1/7/26 and 3/10/2/14/7, respectively, P<0.001). The incidence of clinically acceptable surgical conditions was significantly higher in the PTC1-2 group than in the TOFcount1-2 group (94 vs 64%, P=0.003). The percentage of patients who exhibited vocal cord movement was significantly lower in the PTC1-2 group than in the TOFcount1-2 group (3 vs 39%, P<0.001). The incidence of postoperative adverse events was not significantly different except for the less frequent occurrence of mouth dryness in the PTC1-2 group (P=0.035). CONCLUSIONS: Deep neuromuscular block (post-tetanic count of 1-2) surgical conditions in patients undergoing laryngeal microsurgery improves. CLINICAL TRIAL REGISTRATION: NCT01980069. PMID- 26582848 TI - Incidence and risk factors for intensive care unit admission after bariatric surgery: a multicentre population-based cohort study. AB - BACKGROUND: With increasing rates of bariatric surgery and the consequential involvement of increasingly complex patients, uncertainty remains regarding the use of intensive care unit (ICU) services after bariatric surgery. Our objective was to define the incidence, indications, and outcomes of patients requiring ICU admission after bariatric surgery and assess whether unplanned ICU admission could be predicted using preoperative factors. METHODS: All adult bariatric surgery patients between 2007 and 2011 in Western Australia were identified from the Department of Health Data Linkage Unit database and merged with a separate database encompassing all subsequent ICU admissions pertaining to bariatric surgery. The minimal and mean follow-up periods were 12 months and 3.4 yr, respectively. RESULTS: Of the 12 062 patients who underwent bariatric surgery during the study period, 590 patients (4.9%; 650 ICU admissions) were admitted to an ICU after their bariatric surgery. Patients admitted to the ICU were older (48 vs 43 yr, P<0.001), more likely to be male (49.7 vs 20.2%, P<0.001), and more likely to require revisional bariatric surgery (14.4 vs 7.1%, P<0.001). One hundred and seventy-six patients required an emergent unplanned ICU admission, with 51 requiring multiple ICU admissions. Revisional or open surgery, diabetes mellitus, chronic respiratory disease, and obstructive apnoea were the strongest preoperative factors associated with unplanned ICU admission. CONCLUSIONS: Intensive care unit admission after bariatric surgery was uncommon (4.9% of all patients), with 30.9% of all referrals being unplanned. A nomogram and smartphone application based on five important preoperative factors may assist anaesthetists to conduct preoperative planning for high-risk bariatric surgical patients. PMID- 26582849 TI - Postoperative pain assessment in children: a pilot study of the usefulness of the analgesia nociception index. AB - BACKGROUND: The ability to perform objective pain assessment is very important in paediatric patients. The goal of this study was to investigate the relationship between the analgesia nociception index (ANI), which is based on the heart rate variability, and objective measurements of pain intensity in young or cognitively impaired children, after surgical or imaging procedures (control group) under general anaesthesia. METHODS: On arrival in the recovery room and subsequently at 5-10 min intervals, the level of pain was rated using the FLACC pain scale (0 10). The ANI values (0-100; 0 indicating the worst pain) were recorded simultaneously. The area under the receiver operating characteristic curve (AUC) and grey zone approach were used to evaluate the performance of the ANI to detect patients with FLACC >4. Instantaneous ANI values were compared with ANI values averaged over 256 s periods of time. RESULTS: All children in the surgical group (n=32) developed moderate-to-severe pain (FLACC >4). Children in the control group (n=30) exhibited minimal pain. Instantaneous ANI values were lower in children of the surgical group than in the control group [52 (sd16) vs 69 (16), P<0.001]. The AUC for the 256 s ANI recording period [0.94 (95% confidence interval 0.85-0.99)] was significantly higher than for instantaneous ANI (P<0.05). When measured for a period of 256 s, an ANI cut-off value of 56 (grey zone [58-60]) was most predictive of a FLACC >=4. CONCLUSIONS: The ANI may provide an objective measurement of acute postoperative pain, which is correlated with that measured on a FLACC scale in young or cognitively impaired children. PMID- 26582850 TI - Early thromboelastometry variables predict maximum clot firmness in children undergoing cardiac and non-cardiac surgery. AB - BACKGROUND: Early clot amplitudes measured on thromboelastometry (ROTEM(r)) predict maximum clot firmness (MCF) in adults. In this multicentre, retrospective study, we aimed to confirm the suspected relationship between early ROTEM(r) variables and MCF, in children undergoing cardiac or non-cardiac surgery. METHODS: 4762 ROTEM(r) tests (e.g. EXTEM, INTEM, FIBTEM, APTEM, and HEPTEM) performed in children undergoing cardiac or non-cardiac surgery at three University hospitals between January 2011 and June 2014 were reviewed. To assess the correlation between clot amplitudes measured after 5, 10 and 15 min and MCF, each variable was compared with the corresponding MCF by calculating Spearman's correlation coefficient. RESULTS: For the EXTEM(r) test, we observed that amplitude measured after 5 min (A5: r=0.91, P<0.001), 10 min (A10: r=0.95, P<0.001) and 15 min (A15: r=0.96, P<0.001) were strongly correlated to MCF. The same correlations were observed for INTEM(r) test (A5: r=0.93, P<0.001; A10: r=0.97, P<0.001; A15: r=0.97, P<0.001), and FIBTEM(r) test (A5: r=0.93, P<0.001; A10: r=0.94, P<0.001; A15: r=0.96, P<0.001). In addition, the amplitudes measured after five, 10 and 15 min were also strongly correlated with MCF in the APTEM(r) and the HEPTEM(r) tests. Receiver operating characteristics (ROC) analysis confirmed that A5, A10, A15 strongly predicted decreased MCF on all ROTEM(r) tests. CONCLUSIONS: This study confirmed that early values of clot amplitudes measured as soon as five, 10 or 15 min after clotting time could be used to predict maximum clot firmness in all ROTEM(r) tests. PMID- 26582851 TI - Pregabalin reduces postoperative opioid consumption and pain for 1 week after hospital discharge, but does not affect function at 6 weeks or 3 months after total hip arthroplasty. AB - BACKGROUND: This study examined whether a perioperative regimen of pregabalin added to celecoxib improved pain scores and functional outcomes postdischarge up to 3 months after total hip arthroplasty (primary outcome) and acute postoperative pain and adverse effects (secondary outcomes). METHODS: One hundred and eighty-four patients were enrolled in a randomized, double-blind, placebo controlled study. Two hours before receiving a spinal anaesthetic and undergoing surgery, patients received celecoxib 400 mg p.o. and were randomly assigned to receive either pregabalin 150 mg p.o. or placebo p.o. After surgery, patients received pregabalin 75 mg or placebo twice daily in hospital and for 7 days after discharge. Patients also received celecoxib 200 mg every 12 h for 72 h and morphine i.v. patient-controlled analgesia for 24 h. Pain and function were assessed at baseline, 6 weeks, and 3 months after surgery. RESULTS: There was no difference between groups in physical function or incidence and intensity of chronic pain 3 months after total hip arthroplasty. The pregabalin group used less morphine [mean (sd): 39.85 (28.1) mg] than the placebo group [54.01 (31.2) mg] in the first 24 h after surgery (P<0.01). Pain scores were significantly lower in the pregabalin group vs the placebo group on days 1-7 after hospital discharge, and the pregabalin group required less adjunctive opioid medication (Percocet) 1 week after hospital discharge (P<0.05). CONCLUSIONS: Perioperative administration of pregabalin did not improve pain or physical function at 6 weeks or 3 months after total hip arthroplasty. Perioperative administration of pregabalin decreased opioid consumption in hospital and reduced daily pain scores and adjunct opioid consumption for 1 week after discharge. PMID- 26582852 TI - Comparative evaluation of the visibility and block characteristics of a stimulating needle and catheter vs an echogenic needle and catheter for sciatic nerve block with a low-frequency ultrasound probe. AB - BACKGROUND: Clear visibility of the needle and catheter tip is desirable to perform safe and successful ultrasound-guided peripheral nerve blocks. This can be challenging with deeper blocks in obese patients. This study compared the visibility of echogenic and non-echogenic block needles and catheters in proximal sciatic blocks when performed with a low-frequency curved probe. METHODS: Seventy eight patients undergoing total knee joint arthroplasty were randomized to receive an ultrasound-guided continuous sciatic nerve block using either a non echogenic needle and stimulating catheter or an echogenic needle and echogenic non-stimulating catheter. Block needles in both groups were placed using both neurostimulation and ultrasound guidance, after which the catheter was positioned using either neurostimulation alone (Stimulating group) or imaging alone (Echogenic group). Three anaesthetists blinded to group allocation graded video clips recorded during the blocks for nerve, needle and catheter visibility. Performance characteristics and block parameters were also compared. RESULTS: No significant differences between the two groups were observed with regard to needle or catheter visibility (P=0.516). The Stimulating group required more needle redirections (P=0.009), had a longer procedure time [Echogenic median 274 s vs Stimulating 344 s (P=0.016)], and resulted in greater patient discomfort (P=0.012). There were no significant differences between the two groups in terms of block onset or completion time. CONCLUSIONS: Use of echogenic needles and catheters reduced procedure time and patient discomfort compared with a stimulating catheter system. There were no differences in the visibility scores of the two systems. CLINICAL TRIAL REGISTRATION: CTR Protocol ID: R-11-495, Clinical Trials.Gov ID: NCT 01492660. PMID- 26582853 TI - Optimal volume of local anaesthetic for adductor canal block: using the continual reassessment method to estimate ED95. AB - BACKGROUND: Theoretically, the ideal volume of local anaesthetic for adductor canal block (ACB) would ensure sufficient filling of the canal and avoid proximal spread to the femoral triangle. In this dose-finding study, we aimed to investigate the minimal effective volume for an ACB needed to fill the adductor canal distally in at least 95% of patients (ED95). METHODS: We performed a blinded trial, enrolling 40 healthy men. All subjects received an ACB with lidocaine 1%. Volumes were assigned sequentially to the subjects using the continual reassessment method followed by Bayesian analysis to determine the ED95. Distal filling of the adductor canal was assessed by magnetic resonance imaging (primary outcome). Secondary outcomes were the effect of volume on proximal spread to the femoral triangle (also assessed by magnetic resonance imaging), quadriceps muscle weakness (decrease by >=25% from baseline) and sensory block. RESULTS: The ED95 was 20 ml, with an estimated probability of sufficiently filling the canal of 95.1% (95% credibility interval: 0.91-0.98). Proximal spread to the femoral triangle was seen in 0/4 (0%), 7/12 (58%), 4/8 (50%), and 8/16 (50%) subjects with the 5, 10, 15, and 20 ml doses, respectively (P=0.25). Seven subjects had a reduction in muscle strength, but there was no difference between groups (P=0.85). CONCLUSIONS: For an ACB, the dose closest to the ED95 needed to fill the adductor canal distally was 20 ml. There was no significant correlation between volume and proximal spread or muscle strength. CLINICAL TRIAL REGISTRATION: NCT02033356. PMID- 26582854 TI - Neuromuscular blocking effects of cisatracurium and its antagonism with neostigmine in a canine model of autosomal-recessive centronuclear myopathy. AB - BACKGROUND: Centronuclear myopathy (CNM) is a rare congenital condition associated with skeletal muscle weakness. Patients with CNM may have decreased acetylcholine receptor expression and a reduced number of releasable quanta. Such perturbations could affect the time-course of neuromuscular blocking agents (NMBAs) and their antagonism with cholinesterase inhibitors. As a result of the rarity of CNM, prospective data regarding NMBA use in this subpopulation is scarce. We evaluated the neuromuscular blocking effects of cisatracurium and its antagonism with neostigmine in a canine model of CNM. METHODS: Six dogs with congenital autosomal-recessive CNM and six controls received cisatracurium 0.15 mg kg(-1) i.v. under general anaesthesia and intermittent positive pressure ventilation. Neuromuscular function was monitored with acceleromyography.When the second response (T2) to train-of-four (TOF) stimulation returned, neostigmine 0.04 mg kg(-1) (with glycopyrrolate) were administered i.v. The onset time, time to spontaneous return of T2, and the time to reach a TOF ratio >=0.9 after neostigmine administration were recorded. RESULTS: Onset time was no different between groups. Median (interquartile range) time to return of T2 was 27 (24-31) min for control dogs and 26 (22-31) min for CNM dogs (P=0.93).After neostigmine administration, a TOF ratio >=0.9 was reached in 12 (10-15) min and 17 (16-19) min in control and CNM, respectively (P=0.005). CONCLUSIONS: The spontaneous return of T2 was not different between groups. However, neostigmine-facilitated recovery was significantly slower in dogs with CNM. Canine autosomal-recessive CNM does not preclude the use of cisatracurium or its antagonism with neostigmine. PMID- 26582855 TI - Ultrasound standard of peripheral nerve block for shoulder arthroscopy: a single penetration double-injection approach targeting the superior trunk and supraclavicular nerve in the lateral decubitus position. PMID- 26582856 TI - Large increases in both response and state entropy to awake values antagonized with administration of incremental rocuronium. PMID- 26582857 TI - The significant contribution of the partitioning effect in lipid resuscitation for bupivacaine-induced cardiotoxicity: evaluation using centrifuged solution in vivo and in isolated hearts. PMID- 26582858 TI - An alternative anaesthetic technique on nonagenerians undergoing endovascular aortic surgery and long term outcomes. PMID- 26582859 TI - Ultrasound standard for popliteal sciatic block: circular expansion of the paraneural sheath with the needle in-plane from lateral-to-medial in the 'reverse Sim's position'. PMID- 26582860 TI - Social media and anaesthesia journals. PMID- 26582861 TI - Transitioning from routine to on-demand test ordering in intensive care units: a prospective, multicentre, interventional study. PMID- 26582862 TI - Haemodynamic monitoring: the inseparable relation of accuracy and trending. PMID- 26582863 TI - Hazards of perioperative beta-blockers are likely to be dose related. PMID- 26582864 TI - Predictors of early postoperative troponin increase after noncardiac surgery: a pilot study in a real-world population admitted to the recovery room. PMID- 26582868 TI - Variation in Antibiotic Prescribing Across a Pediatric Primary Care Network. AB - BACKGROUND: Outpatient respiratory tract infections are the most common reason for antibiotic prescribing to children. Although prior studies suggest that antibiotic overuse occurs, patient-specific data or data exploring the variability and determinants of variability across practices and practitioners is lacking. METHODS: This study was conducted from a retrospective cohort of encounters to 25 diverse pediatric practices with 222 clinicians, from January 1 to December 31, 2009. Diagnoses, medications, comorbid conditions, antibiotic allergy, and demographic data were obtained from a shared electronic health record and validated by manual review. Practice-specific antibiotic prescription and acute respiratory tract infection diagnosis rates were calculated to assess across-practice differences after adjusting for patient demographics and clustering of encounters within clinicians. RESULTS: A total of 102 102 (28%) of 399 793 acute visits by 208 015 patients resulted in antibiotic prescriptions. After adjusting for patient age, sex, race, and insurance type, and excluding encounters by patients with chronic conditions, antibiotic prescribing by practice ranged from 18% to 36% of acute visits, and the proportion of antibiotic prescriptions that were broad-spectrum ranged from 15% to 58% across practices, despite additional exclusion of patients with antibiotic allergies or prior antibiotic use. Diagnosis of (Dx) and broad-spectrum antibiotic prescribing (Broad) for acute otitis media (Dx: 8%-20%; Broad: 18%-60%), sinusitis (Dx: 0.5% 9%; Broad: 12%-78%), Streptococcal pharyngitis (Dx: 1.8%-6.4%; Broad: 2%-30%), and pneumonia (Dx: 0.4%-2%; Broad: 1%-70%) also varied by practice (P < 0.001 for all comparisons). CONCLUSIONS: Antibiotic prescribing for common pediatric infections varied substantially across practices. This variability could not be explained by patient-specific factors. These data suggest the need for and provide high-impact targets for outpatient antimicrobial stewardship interventions. PMID- 26582869 TI - Quantifying the Burden of Hospital-Acquired Bloodstream Infection in Children in England by Estimating Excess Length of Hospital Stay and Mortality Using a Multistate Analysis of Linked, Routinely Collected Data. AB - BACKGROUND: Hospital-acquired bloodstream infection (HA-BSI) is associated with substantial morbidity, mortality, and healthcare costs in all patient populations. Young children have been shown to have a high rate of healthcare associated infections compared with the adult population. We aimed to quantify the excess mortality and length of stay in pediatric patients from HA-BSI. METHODS: We analyzed data collected retrospectively from a probabilistically linked national database of pediatric (aged 1 month-18 years) in-patients with a microbiologically confirmed HA-BSI in England between January and March 2009. A time-dependent Cox regression model was fit to determine the presence of any effect. Furthermore, a multistate model, adjusted for the time to onset of HA BSI, was used to compare outcomes in patients with HA-BSI to those without HA BSI. We further adjusted for patients' characteristics as recorded in hospital admission data. RESULTS: The dataset comprised 333 605 patients, with 214 cases of HA-BSI. After adjustment for time to HA-BSI and comorbidities, the hazard for discharge (dead or alive) from hospital for patients with HA-BSI was 0.9 times (95% confidence interval [CI], .8-1.1) that of noninfected patients. Excess length of stay associated with all-cause HA-BSI was 1.6 days (95% CI, .2-3.0), although this duration varied by pathogen. Patients with HA-BSI had a 3.6 (95% CI, 1.3-10.4) times higher hazard for in-hospital death than noninfected patients. CONCLUSIONS: Hospital-acquired bloodstream infection increased the length of stay and mortality of pediatric inpatients. The results of this study provide an evidence base to judge the health and economic impact of programs to prevent and control HA-BSI in children. PMID- 26582866 TI - Cyclin D1 Promotes Androgen-Dependent DNA Damage Repair in Prostate Cancer Cells. AB - Therapy resistance and poor outcome in prostate cancer is associated with increased expression of cyclin D1. Androgens promote DNA double-strand break repair to reduce DNA damage, and cyclin D1 was also shown to enhance DNA damage repair (DDR). In this study, we investigated the significance of cyclin D1 in androgen-induced DDR using established prostate cancer cells and prostate tissues from cyclin D1 knockout mice. We demonstrate that endogenous cyclin D1 further diminished the dihydrotestosterone (DHT)-dependent reduction of gammaH2AX foci in vitro. We also show that cyclin D1 was required for the androgen-dependent DNA damage response both in vitro and in vivo. Furthermore, cyclin D1 was required for androgen-enhanced DDR and radioresistance of prostate cancer cells. Moreover, microarray analysis of primary prostate epithelial cells from cyclin D1-deficient and wild-type mice demonstrated that most of the DHT-dependent gene expression changes are also cyclin D1 dependent. Collectively, our findings suggest that the hormone-mediated recruitment of cyclin D1 to sites of DDR may facilitate the resistance of prostate cancer cells to DNA damage therapies and highlight the need to explore other therapeutic approaches in prostate cancer to prevent or overcome drug resistance. PMID- 26582867 TI - Burden of Influenza-Related Hospitalizations and Attributable Mortality in Pediatric Acute Lymphoblastic Leukemia. AB - BACKGROUND: Influenza can be severe in patients with underlying malignancy; however, the rate of influenza hospitalizations and attributable mortality in children with cancer is unknown. METHODS: We performed a retrospective cohort study among 10 698 children with new-onset acute lymphoblastic leukemia (ALL) from 41 US children's hospitals between January 1999 and September 2011. Influenza-related hospitalizations were identified using ICD-9 discharge diagnosis codes, excluding hospitalizations during low-prevalence influenza periods. Follow-up was censored at the earliest of 5 events: end of study period, expected end of chemotherapy, last known hospitalization, hematopoietic stem cell transplant, or death. Data were collected on hospitalization characteristics and resource utilization. Hospitalization rates were calculated using season-adjusted person-time. Crude attributable in-hospital mortality was calculated using baseline mortality for noninfluenza hospitalizations during the same period. Subgroup analysis was performed by time from ALL diagnosis and by age category. RESULTS: The rate of influenza-related hospitalizations was 618.3 per 100 000 person-months. Rates were similar by time from ALL diagnosis and across age categories. Overall attributable in-hospital mortality was 1.0% (95% confidence interval [CI], 0.3%-2.3%) and was highest for children <6 months from diagnosis (1.6%; 95% CI, 0.4%-4.5%) and children <2 years of age (6.7%; 95% CI, 1.3% 22.7%). Total length of stay, days of broad-spectrum antibiotic exposure, and duration of intensive care were significantly greater for influenza-related hospitalizations compared with noninfluenza hospitalizations. CONCLUSIONS: The burden of influenza-related hospitalizations in children with ALL is high and associated with significantly increased resource utilization and attributable mortality. PMID- 26582871 TI - Coprevalence of Epstein-Barr Virus, Cytomegalovirus, and Herpes Simplex Virus Type-1 Antibodies Among United States Children and Factors Associated With Their Acquisition. AB - BACKGROUND: Epstein-Barr virus (EBV), cytomegalovirus (CMV), and herpes simplex virus type-1 (HSV-1) infections are common worldwide, but age-specific prevalence of primary infection varies by race or ethnicity and geographical location. Comparing demographic groups could identify factors influencing the rate of acquisition, age-specific antibody prevalence is relevant for determining when to administer prophylactic vaccines, and coprevalence suggests similar risk factors. METHODS: Stored sera collected from the cross-sectional National Health and Nutrition Examination Surveys 2003-2004 cycle were tested for EBV, CMV, and HSV-1 antibody. Demographic information was obtained through self-reported questionnaires. Statistical analysis included logistic regression and multivariate analysis adjusting for the multistage cluster design. RESULTS: Overall, 36% of children had antibody against 2 or more of the viruses. Coprevalence with EBV, CMV, and HSV-1 was higher in females, in non-Hispanic blacks, and Mexican Americans, compared with non-Hispanic whites, and in those without health insurance. Antibody prevalence was associated with (1) lower household income and education and (2) greater crowding. Nearly all children with CMV antibody or HSV-1 antibody had been infected with EBV. CONCLUSIONS: There was a disproportionately high prevalence of EBV, CMV, and HSV-1 antibody among Mexican Americans and non-Hispanic blacks, groups with a lower poverty income ratio, and those with less household education. They might benefit from receiving prophylactic herpes vaccines when fairly young. The presence of EBV, CMV, or HSV 1 antibody increases the odds of having antibody against one of the other viruses and is a ripe area for future research. PMID- 26582870 TI - A Prospective, International Cohort Study of Invasive Mold Infections in Children. AB - BACKGROUND: Invasive mold infections (IMIs) are a leading cause of mortality in immunocompromised children, yet there has never been an international epidemiologic investigation of pediatric IMIs. METHODS: This international, prospective cohort study was performed to characterize the epidemiology, antifungal therapy, and outcomes of pediatric IMIs. Children (<=18 years) with proven or probable IMIs were enrolled between August 2007 and May 2011 at 22 sites. Risk factors, underlying diagnoses, and treatments were recorded. Outcomes were assessed at 12 weeks after diagnosis using European Organization for Research and Treatment of Cancer/Mycoses Study Group response criteria. RESULTS: One hundred thirty-one pediatric patients with IMIs were enrolled; the most common IMI was invasive aspergillosis ([IA] 75%). Children with IA and those with other types of IMIs had similar underlying risk factors, except that children with IMIs caused by non-Aspergillus species were more likely to have received mold-active antifungal agents preceding diagnosis. The most commonly used antifungal classes after diagnosis were triazoles (82%) and polyenes (63%). Combination therapy was used in 53% of patients. Use of combination therapy was associated with an increased risk of adverse events (risk ratio, 1.98; 95% confidence interval, 1.06-3.68; P = .031), although there was no detectable difference in outcome. CONCLUSIONS: Although risk factors for IMIs are similar across specific subtypes, preceding antifungal therapy may be an important modifier. Combination antifungal therapy requires further study to determine its true risks and benefits. PMID- 26582872 TI - Outbreak of KPC-3 Producing Carbapenem-Resistant Klebsiella pneumoniae in a US Pediatric Hospital. AB - BACKGROUND: The increase in carbapenem-resistant Enterobacteriaceae (CRE) infections is a critical public health issue. We recently experienced the largest single-center pediatric outbreak of carbapenem-resistant Klebsiella pneumoniae (CRKP) at our hospital. The objective of this study was to describe the molecular epidemiology of this outbreak before and after infection-prevention interventions. METHODS: All positive cultures and associated clinical conditions were reviewed to determine whether health care-associated infections (HAIs) exist. HAIs were defined using Centers for Disease Control and Prevention guidelines. CRKP isolates were collected and screened for the presence of beta lactamase genes. Strain relatedness of CRKP isolates was determined by field inversion gel electrophoresis (FIGE) and multilocus sequence typing (MLST). Polymerase chain reaction (PCR) amplification and sequencing of blaTEM, blaSHV, and blaKPC genes were performed on representative isolates. RESULTS: During March July 2010, 18 CRKP isolates were recovered from 15 unique patients. Six isolates were considered HAIs; all were central-line-associated bloodstream infections. All isolates testing positive by PCR for blaKPC were found to carry KPC-3 in transposon Tn4401 isotype "b." FIGE revealed 2 prevalent patterns (accounting for 10 and 3 CRKP isolates, respectively) that MLST demonstrated to consist entirely of strains from ST730; the remaining FIGE types corresponded to ST14, ST15, and ST1559 (a single-locus variant of ST730), with these alternate backgrounds appearing later in the outbreak. New CRKP cases decreased after the implementation of infection-control interventions. All isolates were ciprofloxacin sensitive. CONCLUSIONS: Molecular analyses document the introduction of a KPC-3-producing CRKP clone into our hospital setting, though some isolates appear to have other mechanisms of carbapenem resistance. The transition to a polyclonal epidemiology suggests that the initial outbreak was due to nosocomial spread of a single ST730 clone, while latter isolates may have been secondary to the introduction of a blaKPC-3/Tn4401 isotype "b"-containing plasmid into other K pneumoniae strain backgrounds versus new carbapenemase producing bacteria. PMID- 26582874 TI - Systemic Meglumine Antimoniate in Cutaneous Leishmaniasis of Children: Clinical and Laboratory Complications. AB - Children account for 7%-20% of cutaneous leishmaniasis cases in Iran, but there are few safety data to guide pediatric antiparasitic therapy. We evaluated the clinical and laboratory tolerance of the systemic pentavalent antimonial compound meglumine antimoniate, in 70 Iranian children with cutaneous leishmaniasis. Adverse effects were similar to those seen in adults. PMID- 26582873 TI - Safety and Immunogenicity of Human Serum Albumin-Free MMR Vaccine in US Children Aged 12-15 Months. AB - BACKGROUND: M-M-R(TM)II (MMRII; Merck & Co) is currently the only measles-mumps rubella (MMR) vaccine licensed in the United States. Another licensed vaccine would reinforce MMR supply. This study assessed the immunogenicity of a candidate vaccine (Priorix(TM), GlaxoSmithKline Vaccines [MMR-RIT]) when used as a first dose among eligible children in the United States. METHODS: In this exploratory Phase-2, multicenter, observer-blind study, 1220 healthy subjects aged 12-15 months were randomized (3:3:3:3) and received 1 dose of 1 of 3 MMR-RIT lots with differing mumps virus titers (MMR-RIT-1 [4.8 log10]; MMR-RIT-2 [4.1 log10]; MMR RIT-3 [3.7 log10] CCID50) or MMRII co-administered with hepatitis A vaccine (HAV), varicella vaccine (VAR) and 7-valent pneumococcal conjugate vaccine (PCV7). Immune response to measles, mumps, and rubella viruses was evaluated at Day 42 post-vaccination. Incidence of solicited injection site, general, and serious adverse events was assessed. RESULTS: Seroresponse rates for MMR vaccine viral components in MMR-RIT lots were 98.3-99.2% (measles), 89.7-90.7% (mumps), and 97.5-98.8% (rubella), and for MMRII were 99.6%, 91.1%, and 100%, respectively. Immune responses to HAV, VAR, and PCV7 were similar when co administered with any of the 3 MMR-RIT lots or MMRII. There were no apparent differences in solicited or serious adverse events among the 4 groups. CONCLUSIONS: Immune responses were above threshold levels for projected protection against the 3 viruses from MMR-RIT lots with differing mumps virus titers. MMR-RIT had an acceptable safety profile when co-administered with HAV, VAR, and PCV7. CLINICAL TRIALS REGISTRATION: NCT00861744; etrack; 111870. PMID- 26582875 TI - Concurrent Outbreaks of Tuberculosis in a School and the Wider Community in Macau. AB - Between 2009 and 2012, 22 adolescents of age 15-20 from a day school in Macau were diagnosed with tuberculosis. Detection of multiple molecular clusters may suggest the presence of concurrent outbreaks, and could reflect also ongoing transmissions in the community. Careful interpretation of molecular epidemiology data is crucial in contact investigations. PMID- 26582876 TI - Pediatric Fistula Initiative: Reducing Bloodstream Infections in an Outpatient Pediatric Hemodialysis Center. AB - Bloodstream infection is a major contributor to morbidity and mortality in children on hemodialysis (HD). From January 2009 through April 2011, the incidence of access-related bloodstream infections (ARBs) in pediatric patients on HD at our hospital was 3.45/1000 patient days. Almost all of these children were receiving HD via central line catheters, and none were receiving HD via arteriovenous fistulas (AVFs). In an effort to reduce the rate of infection in children receiving HD at our institution, we introduced the Pediatric Fistula Initiative, a program to increase creation and use of AVFs in children. Thirty three children on HD were observed, 9 of whom received AVFs during the study period. The incidence of ARBs decreased to 1.30/1000 patient days (P < .001) during the 24-month intervention period from May 2011 through May 2013. PMID- 26582877 TI - Toward an Improved Scale for Assessing Symptom Severity in Children With Acute Otitis Media. AB - The objective of the present study was to determine whether changes in the previously developed 7-item Acute Otitis Media Severity of Symptoms scale could improve its responsiveness and its longitudinal construct validity. The items "diminished activity" and "diminished appetite" had low or borderline levels of responsiveness and longitudinal construct validity. Dropping these items seems to be potentially advantageous. PMID- 26582878 TI - Pharmacodynamic Characteristics of Nephrotoxicity Associated With Vancomycin Use in Children. AB - BACKGROUND: Limited studies incorporating population-based pharmacokinetic modeling have been conducted to determine pharmacodynamic indices associated with nephrotoxicity during vancomycin exposure in children. METHODS: A retrospective cohort analysis was conducted from September 2003 to December 2011 at 2 hospitals. Nephrotoxicity was defined as an increase in serum creatinine concentration (SCr) by >=0.5 mg/dL, or >=50% increase in baseline SCr, either persisting for >=2 consecutive days. A 1-compartment model with first-order kinetics was used in NONMEM 7.2 to estimate trough concentrations (Cmin) and area under the curve over 24 hours (AUC). Univariate, classification and regression tree (CART), and multivariate analyses were conducted to identify factors contributing to nephrotoxicity. RESULTS: The analyses included 680 pediatric subjects with 1576 vancomycin serum concentrations. Based on univariate analysis, median Cmin (14.2 [interquartile range, IQR, 7.1-25.4] vs 8.4 [IQR, 5.5-12.4] mcg/mL; P = .001) and AUC (544 [IQR, 359-801] vs 378 [IQR, 304-494]; P < .001) were significantly higher in the nephrotoxic group compared with the non nephrotoxic group. Using CART, we discovered that subjects with doses >=60 mg/kg per day and AUC >1063 mg-h/L had a significantly higher occurrence of nephrotoxicity (P = .005). Adjusting for intensive care unit stay and concomitant nephrotoxic drugs, steady-state vancomycin Cmin >=15 mcg/mL (adjusted odds ratio [aOR], 2.5; 95% confidence interval [CI], 1.1-5.8; P = .028) and AUC >=800 mg-h/L (aOR, 3.7; 95% CI, 1.2-11.0; P = .018) were associated with increased risk of nephrotoxicity. CONCLUSIONS: Our study describes the pediatric exposure nephrotoxicity relationships for vancomycin. Vancomycin Cmin >=15 mcg/mL and AUC >=800 mg-h/L in children are independently associated with a > 2.5-fold increased risk of nephrotoxicity and may provide justification for use of alternative antibiotics in selected situations. PMID- 26582880 TI - Inpatient Antimicrobial Stewardship in Pediatrics: A Systematic Review. AB - BACKGROUND: The clinical and economic outcomes associated with pediatric antimicrobial stewardship programs (ASPs) and other supplemental antimicrobial stewardship (AS) interventions have not been well described or reviewed. METHODS: We performed a systematic review using PubMed to identify studies with any of the following terms in the title or abstract: "antimicrobial stewardship," "antimicrobial control," "antibiotic control," or "antibiotic stewardship." Studies were further limited to inpatient studies in the United States that contained the terms: "child," "children," "pediatric*" ("*" includes all terms with the same stem), "paediatric,*" "newborn," "infant," or "neonat,*" in the title or abstract. Clinical and economic outcomes from each relevant study were summarized. RESULTS: Nine original studies reported outcomes related to formal pediatric ASPs. An additional 8 studies focused on specific AS interventions; 3 on management of community-acquired pneumonia, 2 on vancomycin-specific initiatives, and 1 each on clinical support, antibiotic restriction, and antibiotic rotation. Reported outcomes include decreases in antimicrobial utilization (11 studies), prescribing errors (3 studies), and drug costs (3 studies). Five studies assessed the potential adverse effects of AS interventions on patient safety and found none. Data to support an association between pediatric AS interventions and antimicrobial resistance are limited. CONCLUSIONS: A small number of pediatric studies evaluating ASPs or other AS strategies have been published. These studies demonstrate reductions in antimicrobial utilization, cost, and prescribing errors with no apparent negative impact on patient safety. Although the studies are promising, the current evidence base is limited. Additional studies focusing on the appropriateness and outcomes of antimicrobial prescribing practices as well as more formalized economic evaluations are needed. PMID- 26582879 TI - Treatment Failures and Excess Mortality Among HIV-Exposed, Uninfected Children With Pneumonia. AB - BACKGROUND: Human immunodeficiency virus (HIV)-exposed, uninfected (HIV-EU) children are at increased risk of infectious illnesses and mortality compared with children of HIV-negative mothers (HIV-unexposed). However, treatment outcomes for lower respiratory tract infections among HIV-EU children remain poorly defined. METHODS: We conducted a hospital-based, prospective cohort study of N = 238 children aged 1-23 months with pneumonia, defined by the World Health Organization. Children were recruited within 6 hours of presentation to a tertiary hospital in Botswana. The primary outcome--treatment failure at 48 hours -was assessed by an investigator blinded to HIV exposure status. RESULTS: Median age was 6.0 months; 55% were male. One hundred fifty-three (64%) children were HIV-unexposed, 64 (27%) were HIV-EU, and 20 (8%) were HIV-infected; the HIV exposure status of 1 child could not be established. Treatment failure at 48 hours occurred in 79 (33%) children, including in 36 (24%) HIV-unexposed, 30 (47%) HIV-EU, and 12 (60%) HIV-infected children. In multivariable analyses, HIV EU children were more likely to fail treatment at 48 hours (risk ratio [RR]: 1.83, 95% confidence interval [CI]: 1.27-2.64, P = .001) and had higher in hospital mortality (RR: 4.31, 95% CI: 1.44-12.87, P = .01) than HIV-unexposed children. Differences in outcomes by HIV exposure status were observed only among children under 6 months of age. HIV-EU children more frequently received treatment with a third-generation cephalosporin, but this did not reduce the risk of treatment failure in this group. CONCLUSIONS: HIV-EU children with pneumonia have higher rates of treatment failure and in-hospital mortality than HIV unexposed children during the first 6 months of life. Treatment with a third generation cephalosporins did not improve outcomes among HIV-EU children. PMID- 26582881 TI - Variability in Antibiotic Prescribing: An Inconvenient Truth. PMID- 26582882 TI - Concomitant Medical Conditions and Therapies Preclude Accurate Classification of Children With Severe or Severe Complicated Clostridium difficile Infection. AB - Severe and severe complicated Clostridium difficile infections (SCDI/SCCDI) were retrospectively assessed in a pediatric cohort. Underlying medical conditions and concomitant medical therapy preclude accurate classification of children with SCDI/SCCDI, using current CDI severity definitions. Revised CDI definitions in children should focus on more objective, age-appropriate, and CDI-specific markers of severity. PMID- 26582883 TI - Evaluation of a Live-Attenuated Human Parainfluenza Type 1 Vaccine in Adults and Children. AB - We conducted a phase I clinical trial (clinicaltrials.gov identifier, NCT00641017) of the experimental live-attenuated human parainfluenza virus type 1 (HPIV-1) vaccine rHPIV-1/84/del 170/942A sequentially in 3 groups: adults, HPIV-1 seropositive children, and HPIV-1-seronegative children, the target population for vaccination. rHPIV-1/84/del 170/942A was appropriately restricted in replication in adults and HPIV-1-seropositive children but was overattenuated (ie, insufficiently infectious and immunogenic) for HPIV-1-seronegative children. PMID- 26582884 TI - Antimicrobial Susceptibility Patterns Among Extended-Spectrum beta-Lactamase Producing Enterobacteriaceae in a Large Pediatric Hospital in the United Kingdom. AB - Of the 551 extended spectrum beta-lactamase-producing isolates characterized, the MIC90 for Escherichia coli, Klebsiella spp., and Enterobacter spp. were in the susceptible range when tested against meropenem, but were in the resistant range for all other antimicrobials tested excluding E coli and Klebsiella spp. against ertapenem and ciprofloxacin, and for Enterobacter spp. against ciprofloxacin. PMID- 26582885 TI - Single-Dose Universal Hepatitis A Immunization in Argentina: Low Viral Circulation and High Persistence of Protective Antibodies Up to 4 Years. AB - BACKGROUND: Single-dose hepatitis A virus (HAV) vaccination was implemented in all Argentinean children aged 12 months in 2005. Between 2005 and 2011, a dramatic decline was observed in HAV infection rates, fulminant hepatitis, and liver transplantation. This study assessed current viral circulation and estimated protective antibody persistence 4 years after vaccination. METHODS: Prevalence of prevaccination anti-HAV antibodies in 12-month-old children was evaluated as an indirect estimation of viral circulation (Group A). Seroprevalence was also measured in 5-year-old children who received 1 dose of HAV vaccine at 1 year of age (Group B). Blood samples were tested for immunoglobulin (Ig)G anti-HAV antibodies (seroprotection = >=10 mIU/mL). All Group A-positive samples were tested for IgM anti-HAV antibodies to identify recent infections. Logistic regression analysis was done to evaluate associations between demographic and socioeconomic variables and seroprotection. RESULTS: Of 433 children from Group A, 29.5% (95% confidence interval [CI], 25.2-33.8) were positive for IgG anti-HAV antibodies with a geometric mean concentration (GMC) of 6.17 mIU/mL (95% CI, 5.33-7.15 mIU/mL); all IgM anti-HAV were negative. From 1139 in Group B, 93% (95% CI, 91.7-94.6) maintained seroprotection with a GMC of 97.96 mIU/mL (95% CI, 89.21-107.57 mIU/mL). Kindergarten attendance was associated with seroprotection in Group B (odds ratio [OR], 2.0; 95% CI, 1.26-3.3). In contrast, high maternal educational level was associated with a lack of seroprotection in this group (OR, .26; 95% CI, .09-.8). CONCLUSIONS: Single-dose, universal hepatitis A immunization in infants resulted in low HAV circulation and persistent immunologic protection up to 4 years in Argentina. Variables associated with presence or absence of seroprotection in vaccinated children could be related to differences in hygiene habits in settings with residual viral circulation. PMID- 26582888 TI - Use of Surveillance Data to Assess the Impact of Vaccination on Circulating Rotavirus Strains. PMID- 26582886 TI - Diagnosis, Clinical Course, and Treatment of Primary Amoebic Meningoencephalitis in the United States, 1937-2013. AB - BACKGROUND: Primary amoebic meningoencephalitis (PAM) is a rapidly progressing waterborne illness that predominately affects children and is nearly always fatal. PAM is caused by Naegleria fowleri, a free-living amoeba found in bodies of warm freshwater worldwide. METHODS: We reviewed exposure location, clinical signs and symptoms, diagnostic modalities, and treatment from confirmed cases of PAM diagnosed in the United States during 1937-2013. Patients were categorized into the early (ie, flu-like symptoms) or late (ie, central nervous system signs) group on the basis of presenting clinical characteristics. Here, we describe characteristics of the survivors and decedents. RESULT: The median age of the patients was 12 years (83% aged <=18 years); males (76%) were predominately affected (N = 142). Most infections occurred in southern-tier states; however, 4 recent infections were acquired in northern states: Minnesota (2), Kansas (1), and Indiana (1). Most (72%) of the patients presented with central nervous system involvement. Cerebrospinal fluid analysis resembled bacterial meningitis with high opening pressures, elevated white blood cell counts with predominantly neutrophils (median, 2400 cells/MUL [range, 5-26 000 cells/MUL]), low glucose levels (median, 23 mg/dL [range, 1-92 mg/dL]), and elevated protein levels (median, 365 mg/dL [range, 24-1210 mg/dL]). Amoebas found in the cerebrospinal fluid were diagnostic, but PAM was diagnosed for only 27% of the patients before death. Imaging results were abnormal in approximately three-fourths of the patients but were not diagnostic for amoebic infection. Three patients in the United States survived. CONCLUSIONS: To our knowledge, this is the first comprehensive clinical case series of PAM presented in the United States. PAM is a fatal illness with limited treatment success and is expanding into more northern regions. Clinicians who suspect that they have a patient with PAM should contact the US Centers for Disease Control and Prevention at 770-488-7100 (available 24 hours/day, 7 days/week) to discuss diagnostic testing and treatment options (see cdc.gov/naegleria). PMID- 26582893 TI - Yoga vs Standard Care for Schizophrenia. PMID- 26582887 TI - Pharmacokinetics and 48-Week Safety and Efficacy of Raltegravir for Oral Suspension in Human Immunodeficiency Virus Type-1-Infected Children 4 Weeks to 2 Years of Age. AB - BACKGROUND: IMPAACT P1066 is a Phase I/II open-label multicenter trial to evaluate safety, tolerability, pharmacokinetics (PK), and efficacy of multiple raltegravir (RAL) formulations in human immunodeficiency virus (HIV)-infected youth. METHODS: Dose selection of the oral suspension formulation for each cohort (IV: 6 months to <2 years and V: 4 weeks to <6 months) was based on review of short-term safety (4 weeks) and intensive PK evaluation. Safety data through Weeks 24 and 48 and Grade >=3 or serious adverse events (AEs) were assessed. The primary virologic endpoint was achieving HIV RNA <400 copies/mL or >=1 log10 reduction from baseline at Week 24 (Success). For Cohort IV, optimized background therapy (OBT) could have been initiated with RAL either at study entry or after intensive PK sampling was completed at Day 5-12. An OBT was started when RAL was initiated for Cohort V subjects because they were not permitted to have received direct antiretroviral therapy before enrollment. RESULTS: Total accrual was 27 subjects in these 2 cohorts, including 1 subject who was enrolled but never started study drug (excluded from the analyses). The targeted PK parameters (area under the curve [AUC]0-12hr and C12hr) were achieved for each cohort allowing for dose selection. Through Week 48, there were 10 subjects with Grade 3+ AEs. Two were judged related to study drug. There was 1 discontinuation due to an AE of skin rash, 1 event of immune reconstitution syndrome, and no drug-related deaths. At Week 48, for Cohorts IV and V, 87.5% of subjects achieved virologic success and 45.5% had HIV RNA <50 copies/mL. At Week 48, gains in CD4 cells of 527.6 cells/mm(3) and 7.3% were observed. CONCLUSIONS: A total of 6 mg/kg per dose twice daily of RAL for oral suspension was well tolerated and showed favorable virologic and immunologic responses. PMID- 26582894 TI - Africa's leadership in biomedical research: Shifting the center of gravity. PMID- 26582895 TI - Nanomedicine gets personal. AB - Companion nanoparticle imaging merges with drug delivery technologies toward personalized nanomedicine (Miller et al., this issue). PMID- 26582896 TI - Comment on "Antibodies to influenza nucleoprotein cross-react with human hypocretin receptor 2". AB - Did hypocretin receptor 2 autoantibodies cause narcolepsy with hypocretin deficiency in Pandemrix-vaccinated children, as suggested by Ahmed et al.? Using newly developed mouse models to report and inactivate hypocretin receptor expression, Vassalli et al. now show that hypocretin neurons (whose loss causes narcolepsy) do not express hypocretin autoreceptors, raising questions to the interpretation of Ahmed et al.'s findings. PMID- 26582897 TI - Response to comment on "Antibodies to influenza nucleoprotein cross-react with human hypocretin receptor 2". AB - Vassalli et al.'s study does not involve or provide additional data regarding influenza virus, influenza vaccines, human samples, animal models of narcolepsy, or experiments related to mimicry and cross-reactivity. They present data on the distribution of hypocretin (HCRT) (also known as orexin) receptors in the brain of an engineered mouse developed by them. PMID- 26582898 TI - Predicting therapeutic nanomedicine efficacy using a companion magnetic resonance imaging nanoparticle. AB - Therapeutic nanoparticles (TNPs) have shown heterogeneous responses in human clinical trials, raising questions of whether imaging should be used to identify patients with a higher likelihood of NP accumulation and thus therapeutic response. Despite extensive debate about the enhanced permeability and retention (EPR) effect in tumors, it is increasingly clear that EPR is extremely variable; yet, little experimental data exist to predict the clinical utility of EPR and its influence on TNP efficacy. We hypothesized that a 30-nm magnetic NP (MNP) in clinical use could predict colocalization of TNPs by magnetic resonance imaging (MRI). To this end, we performed single-cell resolution imaging of fluorescently labeled MNPs and TNPs and studied their intratumoral distribution in mice. MNPs circulated in the tumor microvasculature and demonstrated sustained uptake into cells of the tumor microenvironment within minutes. MNPs could predictably demonstrate areas of colocalization for a model TNP, poly(d,l-lactic-co-glycolic acid)-b-polyethylene glycol (PLGA-PEG), within the tumor microenvironment with >85% accuracy and circulating within the microvasculature with >95% accuracy, despite their markedly different sizes and compositions. Computational analysis of NP transport enabled predictive modeling of TNP distribution based on imaging data and identified key parameters governing intratumoral NP accumulation and macrophage uptake. Finally, MRI accurately predicted initial treatment response and drug accumulation in a preclinical efficacy study using a paclitaxel encapsulated NP in tumor-bearing mice. These approaches yield valuable insight into the in vivo kinetics of NP distribution and suggest that clinically relevant imaging modalities and agents can be used to select patients with high EPR for treatment with TNPs. PMID- 26582899 TI - The E3 ubiquitin ligase Idol controls brain LDL receptor expression, ApoE clearance, and Abeta amyloidosis. AB - Apolipoprotein E (ApoE) is an important modifier of Alzheimer's disease (AD) pathogenesis, and its abundance has been linked to the clearance of beta-amyloid (Abeta) in the brain. The pathways that control the clearance of ApoE in the brain are incompletely understood. We report that Idol, an E3 ubiquitin ligase that targets the low-density lipoprotein receptor (LDLR) for degradation, is a critical determinant of brain ApoE metabolism and Abeta plaque biogenesis. Previous work has shown that Idol contributes minimally to the regulation of hepatic LDLR expression in mice. By contrast, we demonstrate that Idol is a primary physiological regulator of LDLR protein in the brain, controlling the clearance of both ApoE-containing high-density lipoprotein (HDL) particles and Abeta. We studied the consequences of loss of Idol expression in a transgenic mouse model of Abeta amyloidosis. Idol deficiency increased brain LDLR, decreased ApoE, decreased soluble and insoluble Abeta, reduced amyloid plaque burden, and ameliorated neuroinflammation. These findings identify Idol as a gatekeeper of LDLR-dependent ApoE and Abeta clearance in the brain and a potential enzyme target for therapeutic intervention in AD. PMID- 26582901 TI - Targeting LGR5+ cells with an antibody-drug conjugate for the treatment of colon cancer. AB - Cancer stem cells (CSCs) are hypothesized to actively maintain tumors similarly to how their normal counterparts replenish differentiated cell types within tissues, making them an attractive therapeutic target for the treatment of cancer. Because most CSC markers also label normal tissue stem cells, it is unclear how to selectively target them without compromising normal tissue homeostasis. We evaluated a strategy that targets the cell surface leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), a well-characterized tissue stem cell and CSC marker, with an antibody conjugated to distinct cytotoxic drugs. One antibody-drug conjugate (ADC) demonstrated potent tumor efficacy and safety in vivo. Furthermore, the ADC decreased tumor size and proliferation, translating to improved survival in a genetically engineered model of intestinal tumorigenesis. These data demonstrate that ADCs can be leveraged to exploit differences between normal and cancer stem cells to successfully target gastrointestinal cancers. PMID- 26582900 TI - AZD9150, a next-generation antisense oligonucleotide inhibitor of STAT3 with early evidence of clinical activity in lymphoma and lung cancer. AB - Next-generation sequencing technologies have greatly expanded our understanding of cancer genetics. Antisense technology is an attractive platform with the potential to translate these advances into improved cancer therapeutics, because antisense oligonucleotide (ASO) inhibitors can be designed on the basis of gene sequence information alone. Recent human clinical data have demonstrated the potent activity of systemically administered ASOs targeted to genes expressed in the liver. We describe the preclinical activity and initial clinical evaluation of a class of ASOs containing constrained ethyl modifications for targeting the gene encoding the transcription factor STAT3, a notoriously difficult protein to inhibit therapeutically. Systemic delivery of the unformulated ASO, AZD9150, decreased STAT3 expression in a broad range of preclinical cancer models and showed antitumor activity in lymphoma and lung cancer models. AZD9150 preclinical activity translated into single-agent antitumor activity in patients with highly treatment-refractory lymphoma and non-small cell lung cancer in a phase 1 dose escalation study. PMID- 26582903 TI - Photo Quiz: False Intestinal Brush Border. Intestinal spirochetosis. PMID- 26582902 TI - Bioengineered vocal fold mucosa for voice restoration. AB - Patients with voice impairment caused by advanced vocal fold (VF) fibrosis or tissue loss have few treatment options. A transplantable, bioengineered VF mucosa would address the individual and societal costs of voice-related communication loss. Such a tissue must be biomechanically capable of aerodynamic-to-acoustic energy transfer and high-frequency vibration and physiologically capable of maintaining a barrier against the airway lumen. We isolated primary human VF fibroblasts and epithelial cells and cocultured them under organotypic conditions. The resulting engineered mucosae showed morphologic features of native tissue, proteome-level evidence of mucosal morphogenesis and emerging extracellular matrix complexity, and rudimentary barrier function in vitro. When grafted into canine larynges ex vivo, the mucosae generated vibratory behavior and acoustic output that were indistinguishable from those of native VF tissue. When grafted into humanized mice in vivo, the mucosae survived and were well tolerated by the human adaptive immune system. This tissue engineering approach has the potential to restore voice function in patients with otherwise untreatable VF mucosal disease. PMID- 26582906 TI - Captures of Wild Ceratitis capitata, Bactrocera dorsalis, and Bactrocera cucurbitae (Diptera: Tephritidae) in Traps with Improved Multilure TMR Dispensers Weathered in California. AB - During 2012-2013, solid Mallet TMR (trimedlure [TML], methyl eugenol [ME], raspberry ketone [RK]) wafers impregnated with DDVP (2, 2-dichlorovinyl dimethyl phosphate) insecticide were weathered during summer (8 wk) and winter (12 wk) in five California citrus-growing counties (Kern, Ventura, Orange, Tulare, and Riverside). In addition, TMR wafers without DDVP and with a Hercon Vaportape II insecticidal strip were compared with TMR dispensers with DDVP at Exeter and Riverside. Weathered treatments were shipped every week (overnight delivery) to Hawaii and frozen for a later bioassay in a 1,335-ha coffee plantation near Numila, Kauai Island, HI, where Mediterranean fruit fly, Ceratitis capitata (Wiedemann), oriental fruit fly, Bactrocera dorsalis Hendel, and melon fly, Bactrocera cucurbitae Coquillett, were all present. We compared trap captures of the three species, C. capitata, B. dorsalis, and B. cucurbitae, for the five different weathering locations. Captures of C. capitata, B. dorsalis, and B. cucurbitae with Mallet TMR dispensers (with DDVP) were not significantly different for the five locations. Captures with the Mallet TMR dispenser without DDVP and Vaportape were similar to those for Mallet TMR with DDVP, although there were some slight location differences. In conclusion, based on these results, the Mallet TMR dispenser could potentially be used in California habitats where large numbers of detection traps are currently deployed. Use of Vaportape with dispensers would not require them to be registered with US Environmental Protection Agency (EPA). Dispensers for use as Male Annihilation Technique (MAT) devices will be tested further in Hawaii. PMID- 26582907 TI - Therapeutic Efficacy of Fresh, Autologous Mesenchymal Stem Cells for Severe Refractory Gingivostomatitis in Cats. AB - Mesenchymal stem cells (MSCs) are a promising therapy for immune-mediated and inflammatory disorders, because of their potent immunomodulatory properties. In this study, we investigated the use of fresh, autologous, adipose-derived MSCs (ASCs) for feline chronic gingivostomatitis (FCGS), a chronic, debilitating, idiopathic, oral mucosal inflammatory disease. Nine cats with refractory FCGS were enrolled in this pilot study. Each cat received 2 intravenous injections of 20 million autologous ASCs, 1 month apart. Oral biopsies were taken before and at 6 months after the first ASC injection. Blood immune cell subsets, serum protein, and cytokine levels were measured at 0, 1, 3, and 6 months after treatment to assess immunomodulatory effects. Seven of the 9 cats completed the study. Five cats responded to treatment by either complete clinical remission (n=3) or substantial clinical improvement (n=2). Two cats were nonresponders. Cats that responded to treatment also exhibited systemic immunomodulation demonstrated by decreased numbers of circulating CD8+ T cells, a normalization of the CD4/CD8 ratio, decreased neutrophil counts, and interferon-gamma and interleukin (IL) 1beta concentration, and a temporary increase in serum IL-6 and tumor necrosis factor-alpha concentration. No clinical recurrence has occurred following complete clinical remission (follow-up of 6-24 months). In this study, cats with <15% cytotoxic CD8 T cells with low expression of CD8 (CD8lo) cells were 100% responsive to ASC therapy, whereas cats with >15% CD8lo cells were nonresponders. The relative absence of CD8lo cells may be a biomarker to predict response to ASC therapy, and may shed light on pathogenesis of FCGS and mechanisms by which ASCs decrease oral inflammation and affect T-cell phenotype. SIGNIFICANCE: This study is the first to demonstrate the safety and efficacy of fresh, autologous, adipose derived stem cell systemic therapy for a naturally occurring, chronic inflammatory disease in cats. The findings demonstrate that this therapy resulted in complete clinical and histological resolution or reduction in clinical disease severity and immune modulation in most cats. This study also identified a potentially useful biomarker that could dictate patient enrollment and shed light on immune modulation mechanism. As a naturally occurring animal model, FCGS also provides a strategic platform for potentially translatable therapy for the treatment of human oral inflammatory disease. PMID- 26582908 TI - Magnetic Resonance Imaging of Iron Oxide-Labeled Human Embryonic Stem Cell Derived Cardiac Progenitors. AB - Given the limited regenerative capacity of the heart, cellular therapy with stem cell-derived cardiac cells could be a potential treatment for patients with heart disease. However, reliable imaging techniques to longitudinally assess engraftment of the transplanted cells are scant. To address this issue, we used ferumoxytol as a labeling agent of human embryonic stem cell-derived cardiac progenitor cells (hESC-CPCs) to facilitate tracking by magnetic resonance imaging (MRI) in a large animal model. Differentiating hESCs were exposed to ferumoxytol at different time points and varying concentrations. We determined that treatment with ferumoxytol at 300 MUg/ml on day 0 of cardiac differentiation offered adequate cell viability and signal intensity for MRI detection without compromising further differentiation into definitive cardiac lineages. Labeled hESC-CPCs were transplanted by open surgical methods into the left ventricular free wall of uninjured pig hearts and imaged both ex vivo and in vivo. Comprehensive T2*-weighted images were obtained immediately after transplantation and 40 days later before termination. The localization and dispersion of labeled cells could be effectively imaged and tracked at days 0 and 40 by MRI. Thus, under the described conditions, ferumoxytol can be used as a long-term, differentiation-neutral cell-labeling agent to track transplanted hESC-CPCs in vivo using MRI. SIGNIFICANCE: The development of a safe and reproducible in vivo imaging technique to track the fate of transplanted human embryonic stem cell derived cardiac progenitor cells (hESC-CPCs) is a necessary step to clinical translation. An iron oxide nanoparticle (ferumoxytol)-based approach was used for cell labeling and subsequent in vivo magnetic resonance imaging monitoring of hESC-CPCs transplanted into uninjured pig hearts. The present results demonstrate the use of ferumoxytol labeling and imaging techniques in tracking the location and dispersion of cell grafts, highlighting its utility in future cardiac stem cell therapy trials. PMID- 26582909 TI - Sphere-Derived Multipotent Progenitor Cells Obtained From Human Oral Mucosa Are Enriched in Neural Crest Cells. AB - : Although isolation of oral mucosal stromal stem cells has been previously reported, complex isolation methods are not suitable for clinical application. The neurosphere culture technique is a convenient method for the isolation of neural stem cells and neural crest stem cells (NCSCs); neurosphere generation is a phenotype of NCSCs. However, the molecular details underlying the isolation and characterization of human oral mucosa stromal cells (OMSCs) by neurosphere culture are not understood. The purpose of the present study was to isolate NCSCs from oral mucosa using the neurosphere technique and to establish effective in vivo bone tissue regeneration methods. Human OMSCs were isolated from excised human oral mucosa; these cells formed spheres in neurosphere culture conditions. Oral mucosa sphere-forming cells (OMSFCs) were characterized by biological analyses of stem cells. Additionally, composites of OMSFCs and multiporous polylactic acid scaffolds were implanted subcutaneously into immunocompromised mice. OMSFCs had the capacity for self-renewal and expressed neural crest-related markers (e.g., nestin, CD44, slug, snail, and MSX1). Furthermore, upregulated expression of neural crest-related genes (EDNRA, Hes1, and Sox9) was observed in OMSFCs, which are thought to contain an enriched population of neural crest derived cells. The expression pattern of alpha2-integrin (CD49b) in OMSFCs also differed from that in OMSCs. Finally, OMSFCs were capable of differentiating into neural crest lineages in vitro and generating ectopic bone tissues even in the subcutaneous region. The results of the present study suggest that OMSFCs are an ideal source of cells for the neural crest lineage and hard tissue regeneration. SIGNIFICANCE: The sphere culture technique is a convenient method for isolating stem cells. However, the isolation and characterization of human oral mucosa stromal cells (OMSCs) using the sphere culture system are not fully understood. The present study describes the isolation of neural crest progenitor cells from oral mucosa using this system. Human OMSCs form spheres that exhibit self-renewal capabilities and multipotency, and are enriched with neural crest-derived cells. These oral mucosa sphere-forming cells can generate ectopic bone tissue in vivo. Therefore, the results of the present study show that the sphere culture system can be applied, without the need for complex isolation techniques, to produce multipotent spheres with the properties of neural crest stem cells. Furthermore, a convenient strategy is demonstrated for the isolation and culture of human OMSCs that could have clinical applications. PMID- 26582910 TI - Thrombus aspiration in non-ST-elevation myocardial infarction - 12-month clinical outcome of the randomised TATORT-NSTEMI trial. AB - BACKGROUND: In the randomised TATORT-NSTEMI trial routine thrombus aspiration in comparison with standard percutaneous coronary intervention (PCI) did not reduce the primary endpoint of microvascular obstruction assessed by cardiac magnetic resonance imaging in patients with non-ST-elevation myocardial infarction (NSTEMI). So far, no data on long-term outcome of head-to-head comparisons between both treatment strategies in NSTEMI patients have been reported. METHODS: The prospective, controlled, multicentre, randomised, open-label TATORT-NSTEMI trial assigned patients with NSTEMI and thrombus-containing lesions to aspiration thrombectomy plus PCI ( n=221) or standard PCI only ( n=219). The primary endpoint of the current analysis was the occurrence of major adverse cardiac events defined as the composite of death, myocardial reinfarction, target vessel revascularisation, and new congestive heart failure at 12-month follow-up. In addition, functional outcome and quality of life were assessed. RESULTS: At one year, major adverse cardiac events occurred in 19 patients in the thrombectomy arm and 29 patients in the standard PCI group (8.7% vs. 13.4%, relative risk 0.63, 95% confidence interval 0.35-1.12, p=0.11). The individual components of the combined endpoint such as death ( p=0.20), myocardial reinfarction ( p=0.73), target vessel revascularisation ( p=0.42), and congestive heart failure ( p=0.18) were similar in both groups. Functional outcome and quality of life did not differ significantly between both groups (Canadian Cardiovascular Society class: p=0.68, New York Heart Association class: p=0.70 and EuroQol5D score: p=0.96). Post-hoc analyses revealed consistent results with regard to the occurrence of major adverse cardiac events across a wide range of subgroups (all p>0.05). CONCLUSIONS: In this first randomised trial on thrombectomy in NSTEMI patients, routine thrombus aspiration before PCI did not improve clinical outcome at 12 month follow-up. PMID- 26582911 TI - The quorum-sensing regulator ComA from Bacillus subtilis activates transcription using topologically distinct DNA motifs. AB - ComA-like transcription factors regulate the quorum response in numerous Gram positive bacteria. ComA proteins belong to the tetrahelical helix-turn-helix superfamily of transcriptional activators, which bind as homodimers to inverted sequence repeats in the DNA. Here, we report that ComA from Bacillus subtilis recognizes a topologically distinct motif, in which the binding elements form a direct repeat. We provide in vitro and in vivo evidence that the canonical and non-canonical site play an important role in facilitating type I and type II promoter activation, respectively, by interacting with different subunits of RNA polymerase. We furthermore show that there is a variety of contexts in which the non-canonical site can occur and identify new direct target genes that are located within the integrative and conjugative element ICEBs1. We therefore suggest that ComA acts as a multifunctional transcriptional activator and provides a striking example for complexity in protein-DNA interactions that evolved in the context of quorum sensing. PMID- 26582912 TI - The structures of the SNM1A and SNM1B/Apollo nuclease domains reveal a potential basis for their distinct DNA processing activities. AB - The human SNM1A and SNM1B/Apollo proteins are members of an extended family of eukaryotic nuclease containing a motif related to the prokaryotic metallo-beta lactamase (MBL) fold. SNM1A is a key exonuclease during replication-dependent and transcription-coupled interstrand crosslink repair, while SNM1B/Apollo is required for maintaining telomeric overhangs. Here, we report the crystal structures of SNM1A and SNM1B at 2.16 A. While both proteins contain a typical MBL-beta-CASP domain, a region of positive charge surrounds the active site of SNM1A, which is absent in SNM1B and explains the greater apparent processivity of SNM1A. The structures of both proteins also reveal a putative, wide DNA-binding groove. Extensive mutagenesis of this groove, coupled with detailed biochemical analysis, identified residues that did not impact on SNM1A catalytic activity, but drastically reduced its processivity. Moreover, we identified a key role for this groove for efficient digestion past DNA interstrand crosslinks, facilitating the key DNA repair reaction catalysed by SNM1A. Together, the architecture and dimensions of this groove, coupled to the surrounding region of high positive charge, explain the remarkable ability of SNM1A to accommodate and efficiently digest highly distorted DNA substrates, such as those containing DNA lesions. PMID- 26582914 TI - GPCRdb: an information system for G protein-coupled receptors. AB - Recent developments in G protein-coupled receptor (GPCR) structural biology and pharmacology have greatly enhanced our knowledge of receptor structure-function relations, and have helped improve the scientific foundation for drug design studies. The GPCR database, GPCRdb, serves a dual role in disseminating and enabling new scientific developments by providing reference data, analysis tools and interactive diagrams. This paper highlights new features in the fifth major GPCRdb release: (i) GPCR crystal structure browsing, superposition and display of ligand interactions; (ii) direct deposition by users of point mutations and their effects on ligand binding; (iii) refined snake and helix box residue diagram looks; and (iii) phylogenetic trees with receptor classification colour schemes. Under the hood, the entire GPCRdb front- and back-ends have been re-coded within one infrastructure, ensuring a smooth browsing experience and development. GPCRdb is available at http://www.gpcrdb.org/ and it's open source code at https://bitbucket.org/gpcr/protwis. PMID- 26582913 TI - Phosphorylation of the chromatin remodeling factor DPF3a induces cardiac hypertrophy through releasing HEY repressors from DNA. AB - DPF3 (BAF45c) is a member of the BAF chromatin remodeling complex. Two isoforms have been described, namely DPF3a and DPF3b. The latter binds to acetylated and methylated lysine residues of histones. Here, we elaborate on the role of DPF3a and describe a novel pathway of cardiac gene transcription leading to pathological cardiac hypertrophy. Upon hypertrophic stimuli, casein kinase 2 phosphorylates DPF3a at serine 348. This initiates the interaction of DPF3a with the transcriptional repressors HEY, followed by the release of HEY from the DNA. Moreover, BRG1 is bound by DPF3a, and is thus recruited to HEY genomic targets upon interaction of the two components. Consequently, the transcription of downstream targets such as NPPA and GATA4 is initiated and pathological cardiac hypertrophy is established. In human, DPF3a is significantly up-regulated in hypertrophic hearts of patients with hypertrophic cardiomyopathy or aortic stenosis. Taken together, we show that activation of DPF3a upon hypertrophic stimuli switches cardiac fetal gene expression from being silenced by HEY to being activated by BRG1. Thus, we present a novel pathway for pathological cardiac hypertrophy, whose inhibition is a long-term therapeutic goal for the treatment of the course of heart failure. PMID- 26582915 TI - piRNA cluster database: a web resource for piRNA producing loci. AB - Piwi proteins and their guiding small RNAs, termed Piwi-interacting (pi-) RNAs, are essential for silencing of transposons in the germline of animals. A substantial fraction of piRNAs originates from genomic loci termed piRNA clusters and sequences encoded in these piRNA clusters determine putative targets for the Piwi/piRNA system. In the past decade, studies of piRNA transcriptomes in different species revealed additional roles for piRNAs beyond transposon silencing, reflecting the astonishing plasticity of the Piwi/piRNA system along different phylogenetic branches. Moreover, piRNA transcriptomes can change drastically during development and vary across different tissues.Since piRNA clusters crucially shape piRNA profiles, analysis of these loci is imperative for a thorough understanding of functional and evolutionary aspects of the piRNA pathway. But despite the ever-growing amount of available piRNA sequence data, we know little about the factors that determine differential regulation of piRNA clusters, nor the evolutionary events that cause their gain or loss.In order to facilitate addressing these subjects, we established a user-friendly piRNA cluster database (http://www.smallrnagroup-mainz.de/piRNAclusterDB.html) that provides comprehensive data on piRNA clusters in multiple species, tissues and developmental stages based on small RNA sequence data deposited at NCBI's Sequence Read Archive (SRA). PMID- 26582916 TI - Site-specific replacement of the thymine methyl group by fluorine in thrombin binding aptamer significantly improves structural stability and anticoagulant activity. AB - Here we report investigations, based on circular dichroism, nuclear magnetic resonance spectroscopy, molecular modelling, differential scanning calorimetry and prothrombin time assay, on analogues of the thrombin binding aptamer (TBA) in which individual thymidines were replaced by 5-fluoro-2'-deoxyuridine residues. The whole of the data clearly indicate that all derivatives are able to fold in a G-quadruplex structure very similar to the 'chair-like' conformation typical of the TBA. However, only ODNs TBA-F4: and TBA-F13: have shown a remarkable improvement both in the melting temperature (DeltaTm ~ +10) and in the anticoagulant activity in comparison with the original TBA. These findings are unusual, particularly considering previously reported studies in which modifications of T4 and T13 residues in TBA sequence have clearly proven to be always detrimental for the structural stability and biological activity of the aptamer. Our results strongly suggest the possibility to enhance TBA properties through tiny straightforward modifications. PMID- 26582917 TI - Mcm10 coordinates the timely assembly and activation of the replication fork helicase. AB - Mcm10 is an essential replication factor that is required for DNA replication in eukaryotes. Two key steps in the initiation of DNA replication are the assembly and activation of Cdc45-Mcm2-7-GINS (CMG) replicative helicase. However, it is not known what coordinates helicase assembly with helicase activation. We show in this manuscript, using purified proteins from budding yeast, that Mcm10 directly interacts with the Mcm2-7 complex and Cdc45. In fact, Mcm10 recruits Cdc45 to Mcm2-7 complex in vitro. To study the role of Mcm10 in more detail in vivo we used an auxin inducible degron in which Mcm10 is degraded upon addition of auxin. We show in this manuscript that Mcm10 is required for the timely recruitment of Cdc45 and GINS recruitment to the Mcm2-7 complex in vivo during early S phase. We also found that Mcm10 stimulates Mcm2 phosphorylation by DDK in vivo and in vitro. These findings indicate that Mcm10 plays a critical role in coupling replicative helicase assembly with helicase activation. Mcm10 is first involved in the recruitment of Cdc45 to the Mcm2-7 complex. After Cdc45-Mcm2-7 complex assembly, Mcm10 promotes origin melting by stimulating DDK phosphorylation of Mcm2, which thereby leads to GINS attachment to Mcm2-7. PMID- 26582918 TI - ClinVar: public archive of interpretations of clinically relevant variants. AB - ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) at the National Center for Biotechnology Information (NCBI) is a freely available archive for interpretations of clinical significance of variants for reported conditions. The database includes germline and somatic variants of any size, type or genomic location. Interpretations are submitted by clinical testing laboratories, research laboratories, locus-specific databases, OMIM(r), GeneReviewsTM, UniProt, expert panels and practice guidelines. In NCBI's Variation submission portal, submitters upload batch submissions or use the Submission Wizard for single submissions. Each submitted interpretation is assigned an accession number prefixed with SCV. ClinVar staff review validation reports with data types such as HGVS (Human Genome Variation Society) expressions; however, clinical significance is reported directly from submitters. Interpretations are aggregated by variant-condition combination and assigned an accession number prefixed with RCV. Clinical significance is calculated for the aggregate record, indicating consensus or conflict in the submitted interpretations. ClinVar uses data standards, such as HGVS nomenclature for variants and MedGen identifiers for conditions. The data are available on the web as variant-specific views; the entire data set can be downloaded via ftp. Programmatic access for ClinVar records is available through NCBI's E-utilities. Future development includes providing a variant-centric XML archive and a web page for details of SCV submissions. PMID- 26582919 TI - EBI metagenomics in 2016--an expanding and evolving resource for the analysis and archiving of metagenomic data. AB - EBI metagenomics (https://www.ebi.ac.uk/metagenomics/) is a freely available hub for the analysis and archiving of metagenomic and metatranscriptomic data. Over the last 2 years, the resource has undergone rapid growth, with an increase of over five-fold in the number of processed samples and consequently represents one of the largest resources of analysed shotgun metagenomes. Here, we report the status of the resource in 2016 and give an overview of new developments. In particular, we describe updates to data content, a complete overhaul of the analysis pipeline, streamlining of data presentation via the website and the development of a new web based tool to compare functional analyses of sequence runs within a study. We also highlight two of the higher profile projects that have been analysed using the resource in the last year: the oceanographic projects Ocean Sampling Day and Tara Oceans. PMID- 26582920 TI - iGNM 2.0: the Gaussian network model database for biomolecular structural dynamics. AB - Gaussian network model (GNM) is a simple yet powerful model for investigating the dynamics of proteins and their complexes. GNM analysis became a broadly used method for assessing the conformational dynamics of biomolecular structures with the development of a user-friendly interface and database, iGNM, in 2005. We present here an updated version, iGNM 2.0 http://gnmdb.csb.pitt.edu/, which covers more than 95% of the structures currently available in the Protein Data Bank (PDB). Advanced search and visualization capabilities, both 2D and 3D, permit users to retrieve information on inter-residue and inter-domain cross correlations, cooperative modes of motion, the location of hinge sites and energy localization spots. The ability of iGNM 2.0 to provide structural dynamics data on the large majority of PDB structures and, in particular, on their biological assemblies makes it a useful resource for establishing the bridge between structure, dynamics and function. PMID- 26582921 TI - Probing the active site tryptophan of Staphylococcus aureus thioredoxin with an analog. AB - Genetically encoded non-canonical amino acids are powerful tools of protein research and engineering; in particular they allow substitution of individual chemical groups or atoms in a protein of interest. One such amino acid is the tryptophan (Trp) analog 3-benzothienyl-l-alanine (Bta) with an imino-to-sulfur substitution in the five-membered ring. Unlike Trp, Bta is not capable of forming a hydrogen bond, but preserves other properties of a Trp residue. Here we present a pyrrolysyl-tRNA synthetase-derived, engineered enzyme BtaRS that enables efficient and site-specific Bta incorporation into proteins of interest in vivo. Furthermore, we report a 2.1 A-resolution crystal structure of a BtaRS*Bta complex to show how BtaRS discriminates Bta from canonical amino acids, including Trp. To show utility in protein mutagenesis, we used BtaRS to introduce Bta to replace the Trp28 residue in the active site of Staphylococcus aureus thioredoxin. This experiment showed that not the hydrogen bond between residues Trp28 and Asp58, but the bulky aromatic side chain of Trp28 is important for active site maintenance. Collectively, our study provides a new and robust tool for checking the function of Trp in proteins. PMID- 26582922 TI - SureChEMBL: a large-scale, chemically annotated patent document database. AB - SureChEMBL is a publicly available large-scale resource containing compounds extracted from the full text, images and attachments of patent documents. The data are extracted from the patent literature according to an automated text and image-mining pipeline on a daily basis. SureChEMBL provides access to a previously unavailable, open and timely set of annotated compound-patent associations, complemented with sophisticated combined structure and keyword based search capabilities against the compound repository and patent document corpus; given the wealth of knowledge hidden in patent documents, analysis of SureChEMBL data has immediate applications in drug discovery, medicinal chemistry and other commercial areas of chemical science. Currently, the database contains 17 million compounds extracted from 14 million patent documents. Access is available through a dedicated web-based interface and data downloads at: https://www.surechembl.org/. PMID- 26582924 TI - enviPath--The environmental contaminant biotransformation pathway resource. AB - The University of Minnesota Biocatalysis/Biodegradation Database and Pathway Prediction System (UM-BBD/PPS) has been a unique resource covering microbial biotransformation pathways of primarily xenobiotic chemicals for over 15 years. This paper introduces the successor system, enviPath (The Environmental Contaminant Biotransformation Pathway Resource), which is a complete redesign and reimplementation of UM-BBD/PPS. enviPath uses the database from the UM-BBD/PPS as a basis, extends the use of this database, and allows users to include their own data to support multiple use cases. Relative reasoning is supported for the refinement of predictions and to allow its extensions in terms of previously published, but not implemented machine learning models. User access is simplified by providing a REST API that simplifies the inclusion of enviPath into existing workflows. An RDF database is used to enable simple integration with other databases. enviPath is publicly available at https://envipath.org with free and open access to its core data. PMID- 26582923 TI - Improved knockdown from artificial microRNAs in an enhanced miR-155 backbone: a designer's guide to potent multi-target RNAi. AB - Artificial microRNA (amiRNA) sequences embedded in natural microRNA (miRNA) backbones have proven to be useful tools for RNA interference (RNAi). amiRNAs have reduced off-target and toxic effects compared to other RNAi-based methods such as short-hairpin RNAs (shRNA). amiRNAs are often less effective for knockdown, however, compared to their shRNA counterparts. We screened a large empirically-designed amiRNA set in the synthetic inhibitory BIC/miR-155 RNA (SIBR) scaffold and show common structural and sequence-specific features associated with effective amiRNAs. We then introduced exogenous motifs into the basal stem region which increase amiRNA biogenesis and knockdown potency. We call this modified backbone the enhanced SIBR (eSIBR) scaffold. Using chained amiRNAs for multi-gene knockdown, we show that concatenation of miRNAs targeting different genes is itself sufficient for increased knockdown efficacy. Further, we show that eSIBR outperforms wild-type SIBR (wtSIBR) when amiRNAs are chained. Finally, we use a lentiviral expression system in cultured neurons, where we again find that eSIBR amiRNAs are more potent for multi-target knockdown of endogenous genes. eSIBR will be a valuable tool for RNAi approaches, especially for studies where knockdown of multiple targets is desired. PMID- 26582925 TI - Start2Fold: a database of hydrogen/deuterium exchange data on protein folding and stability. AB - Proteins fulfil a wide range of tasks in cells; understanding how they fold into complex three-dimensional (3D) structures and how these structures remain stable while retaining sufficient dynamics for functionality is essential for the interpretation of overall protein behaviour. Since the 1950's, solvent exchange based methods have been the most powerful experimental means to obtain information on the folding and stability of proteins. Considerable expertise and care were required to obtain the resulting datasets, which, despite their importance and intrinsic value, have never been collected, curated and classified. Start2Fold is an openly accessible database (http://start2fold.eu) of carefully curated hydrogen/deuterium exchange (HDX) data extracted from the literature that is open for new submissions from the community. The database entries contain (i) information on the proteins investigated and the underlying experimental procedures and (ii) the classification of the residues based on their exchange protection levels, also allowing for the instant visualization of the relevant residue groups on the 3D structures of the corresponding proteins. By providing a clear hierarchical framework for the easy sharing, comparison and (re-)interpretation of HDX data, Start2Fold intends to promote a better understanding of how the protein sequence encodes folding and structure as well as the development of new computational methods predicting protein folding and stability. PMID- 26582926 TI - eggNOG 4.5: a hierarchical orthology framework with improved functional annotations for eukaryotic, prokaryotic and viral sequences. AB - eggNOG is a public resource that provides Orthologous Groups (OGs) of proteins at different taxonomic levels, each with integrated and summarized functional annotations. Developments since the latest public release include changes to the algorithm for creating OGs across taxonomic levels, making nested groups hierarchically consistent. This allows for a better propagation of functional terms across nested OGs and led to the novel annotation of 95 890 previously uncharacterized OGs, increasing overall annotation coverage from 67% to 72%. The functional annotations of OGs have been expanded to also provide Gene Ontology terms, KEGG pathways and SMART/Pfam domains for each group. Moreover, eggNOG now provides pairwise orthology relationships within OGs based on analysis of phylogenetic trees. We have also incorporated a framework for quickly mapping novel sequences to OGs based on precomputed HMM profiles. Finally, eggNOG version 4.5 incorporates a novel data set spanning 2605 viral OGs, covering 5228 proteins from 352 viral proteomes. All data are accessible for bulk downloading, as a web service, and through a completely redesigned web interface. The new access points provide faster searches and a number of new browsing and visualization capabilities, facilitating the needs of both experts and less experienced users. eggNOG v4.5 is available at http://eggnog.embl.de. PMID- 26582927 TI - Comprehensive evaluation of fusion transcript detection algorithms and a meta caller to combine top performing methods in paired-end RNA-seq data. AB - BACKGROUND: Fusion transcripts are formed by either fusion genes (DNA level) or trans-splicing events (RNA level). They have been recognized as a promising tool for diagnosing, subtyping and treating cancers. RNA-seq has become a precise and efficient standard for genome-wide screening of such aberration events. Many fusion transcript detection algorithms have been developed for paired-end RNA-seq data but their performance has not been comprehensively evaluated to guide practitioners. In this paper, we evaluated 15 popular algorithms by their precision and recall trade-off, accuracy of supporting reads and computational cost. We further combine top-performing methods for improved ensemble detection. RESULTS: Fifteen fusion transcript detection tools were compared using three synthetic data sets under different coverage, read length, insert size and background noise, and three real data sets with selected experimental validations. No single method dominantly performed the best but SOAPfuse generally performed well, followed by FusionCatcher and JAFFA. We further demonstrated the potential of a meta-caller algorithm by combining top performing methods to re-prioritize candidate fusion transcripts with high confidence that can be followed by experimental validation. CONCLUSION: Our result provides insightful recommendations when applying individual tool or combining top performers to identify fusion transcript candidates. PMID- 26582928 TI - WeGET: predicting new genes for molecular systems by weighted co-expression. AB - We have developed the Weighted Gene Expression Tool and database (WeGET, http://weget.cmbi.umcn.nl) for the prediction of new genes of a molecular system by correlated gene expression. WeGET utilizes a compendium of 465 human and 560 murine gene expression datasets that have been collected from multiple tissues under a wide range of experimental conditions. It exploits this abundance of expression data by assigning a high weight to datasets in which the known genes of a molecular system are harmoniously up- and down-regulated. WeGET ranks new candidate genes by calculating their weighted co-expression with that system. A weighted rank is calculated for human genes and their mouse orthologs. Then, an integrated gene rank and p-value is computed using a rank-order statistic. We applied our method to predict novel genes that have a high degree of co expression with Gene Ontology terms and pathways from KEGG and Reactome. For each query set we provide a list of predicted novel genes, computed weights for transcription datasets used and cell and tissue types that contributed to the final predictions. The performance for each query set is assessed by 10-fold cross-validation. Finally, users can use the WeGET to predict novel genes that co express with a custom query set. PMID- 26582929 TI - Impact of anti-glomerular basement membrane antibodies and glomerular neutrophil activation on glomerulonephritis in experimental myeloperoxidase-antineutrophil cytoplasmic antibody vasculitis. AB - BACKGROUND: Antineutrophil cytoplasmic antibody (ANCA) and neutrophil interactions play important roles in ANCA-associated vasculitis (AAV) pathogenesis. However, mechanisms underlying the pathogenesis of crescent formation in ANCA-associated vasculitis have not been completely elucidated. To ascertain the involvement of these interactions in necrotizing crescentic glomerulonephritis (NCGN), we used an AAV rat model and investigated the effects of the anti-myeloperoxidase (MPO) antibody (Ab) titer, tumor necrosis factor alpha (TNF-alpha), granulocyte colony-stimulating factor (G-CSF) and subnephritogenic anti-glomerular basement membrane (GBM) Abs, as proinflammatory stimuli. METHODS: NCGN was induced in Wistar Kyoto rats by human MPO (hMPO) immunization. Renal function, pathology, and glomerular cytokine and chemokine expression were evaluated in hMPO-immunized rats with/without several co treatments (TNF-alpha, G-CSF or subnephritogenic anti-GBM Abs). Rat neutrophils activation by IgG purified from rat serum in each group was examined in vitro. RESULTS: The hMPO-immunized rats had significantly higher level of anti-hMPO Ab production. The induced anti-hMPO Abs cross-reacted with TNF-alpha- or G-CSF primed rat neutrophils secreting TNF-alpha and interleukin-1beta in vitro. The reactivity of anti-MPO Abs against rat MPO, crescent formation with neutrophil extracellular traps and glomerular-activated neutrophil infiltration in the rat model were significantly enhanced by subnephritogenic anti-GBM Ab but not by TNF alpha or G-CSF administration. The model rats injected with the subnephritogenic anti-GBM Abs showed increased urinary albumin excretion and serum TNF-alpha, chemokine (C-X-C) ligand 1 (CXCL1) and CXCL2 levels. TNF-alpha, CXCL1, CXCL2 and CXCL8 increased in the glomeruli with significant amounts of crescent formation. In addition, in vitro activated neutrophils decreased CXC chemokine receptor 1 (CXCR1) and CXCR2 expressions. CONCLUSIONS: The coexistence of subnephritogenic anti-GBM Abs leads to the inflammatory environment in glomeruli that is amplified by the interaction of ANCA and neutrophils. Development of NCGN in MPO-AAV may be necessary for not only the accumulation of neutrophils in glomeruli, but also the aberrant neutrophil activation on glomerulonephritis. PMID- 26582931 TI - There was more to osmolyte selection than just osmotic balance. PMID- 26582930 TI - Homeobox C9 suppresses Beclin1-mediated autophagy in glioblastoma by directly inhibiting the transcription of death-associated protein kinase 1. AB - BACKGROUND: The transcription factor homeobox C9 (HOXC9) plays a crucial role in developmental regulatory systems, where it determines the specific positional identities of cells along the anteroposterior axis. The expression of HOXC9 has been found to be dysregulated in some cancers such as lung cancer, breast cancer, and neuroblastoma. Here, we report for the first time that HOXC9 is a novel autophagy regulator and reveal its oncogenic role in cell survival and its usefulness as a prognostic marker in glioblastoma patients. METHODS: Kaplan-Meier analysis was performed to evaluate the possible prognostic value of HOXC9 in glioblastoma. Growth curve assays, subcutaneous, and orthotopic implantations were used to analyze cell viability and tumor formation, respectively. Luciferase and chromatin immunoprecipitation assays were employed to explore the mechanisms involved in the association between HOXC9 and its downstream effector, death associated protein kinase 1 (DAPK1). RESULTS: High expression of HOXC9 was found to be an indicator of a poor prognosis in glioblastoma. HOXC9 knockdown resulted in a significant reduction of cell viability, migration, invasion, and tumorigenicity and a marked increase in autophagy. During the autophagy process, HOXC9 inhibited DAPK1 transcription by directly binding to its promoter. The downregulation of HOXC9 releases its transcriptional inhibition of DAPK1, resulting in the activation of the DAPK1-Beclin1 pathway, which induces autophagy in glioblastoma cells. CONCLUSIONS: Collectively, our data indicate that HOXC9 is an oncogene in glioblastoma. We have revealed its role in the control of autophagy, and we suggest that HOXC9 is a novel and promising therapeutic target. PMID- 26582932 TI - The response of anosteocytic bone to controlled loading. AB - The bones of the skeleton of most advanced teleost fish do not contain osteocytes. Considering the pivotal role assigned to osteocytes in the process of modeling and remodeling (the adaptation of external and internal bone structure and morphology to external loads and the repair of areas with micro-damage accumulation, respectively) it is unclear how, and even whether, their skeleton can undergo modeling and remodeling. Here, we report on the results of a study of controlled loading of the anosteocytic opercula of tilapia (Oreochromis aureus). Using a variety of microscopy techniques we show that the bone of the anosteocytic tilapia actively adapts to applied loads, despite the complete absence of osteocytes. We show that in the directly loaded area, the response involves a combination of bone resorption and bone deposition; we interpret these results and the structure of the resultant bone tissue to mean that both modeling and remodeling are taking place in response to load. We further show that adjacent to the loaded area, new bone is deposited in an organized, layered manner, typical of a modeling process. The material stiffness of the newly deposited bone is higher than that of the bone which was present prior to loading. The absence of osteocytes requires another candidate cell for mechanosensing and coordinating the modeling process, with osteoblasts seeming the most likely candidates. PMID- 26582933 TI - Flea fitness is reduced by high fractional concentrations of CO2 that simulate levels found in their hosts' burrows. AB - Nidicolous ectoparasites such as fleas and gamasid mites that feed on small and medium-sized mammals spend much of their time in their hosts' burrows, which provide an environment for living, and often feeding, to their pre-imaginal and/or adult stages. Thus, these ectoparasites should be adapted to environmental conditions in burrows, including high fractional concentrations of CO2 (F(CO2)). We examined how a high F(CO2) (0.04) affected survival and reproductive success of a hematophagous ectoparasite of burrowing rodents using fleas Xenopsylla ramesis and Sundevall's jirds Meriones crassus. In the first experiment, fleas fed on hosts housed in high-CO2 (F(CO2) =0.04) or atmospheric-CO2 (F(CO2) ~0.0004) air, and were allowed to breed. In a second experiment, fleas were maintained in high CO2 or CO2-free air with no hosts to determine how CO2 levels affect survival and activity levels. We found that at high F(CO2) fleas laid fewer eggs, reducing reproductive success. In addition, at high F(CO2), activity levels and survival of fleas were reduced. Our results indicate that fleas do not perform well in the F(CO2) used in this experiment. Previous research indicated that the type and intensity of the effects of CO2 concentration on the fitness of an insect depend on the F(CO2) used, so we advise caution when generalizing inferences drawn to insects exposed to other F(CO2). If, however, F(CO2) found in natural mammal burrows brings about reduced fitness in fleas in general, then burrowing hosts may benefit from reduced parasite infestation if burrow air F(CO2) is high. PMID- 26582934 TI - Avian thermoregulation in the heat: resting metabolism, evaporative cooling and heat tolerance in Sonoran Desert doves and quail. AB - Birds in subtropical deserts face significant thermoregulatory challenges because environmental temperatures regularly exceed avian body temperature. To understand the differing susceptibility of desert birds to increasing temperatures, we examined thermoregulatory performance and estimated heat tolerance limits (HTLs) for three Sonoran Desert nesting bird species - Gambel's quail, mourning doves and white-winged doves. Using flow-through respirometry we measured daytime resting metabolism, evaporative water loss and real-time body temperature at air temperatures (T(air)) from 30 degrees C to 66 degrees C. We found marked increases in resting metabolism at the upper critical temperature (T(uc)), which was significantly lower in the quail (T(air)=41.1 degrees C) than in both dove species (T(air)=45.9-46.5 degrees C). Gambel's quail maintained low resting metabolic rates and low rates of evaporative water loss at their T(uc) (0.71 W and 1.20 g H2O h(-1), respectively), but were more sensitive to increasing air temperature, reaching their HTL at T(air) of 52 degrees C. Mourning doves and white-winged doves maintained low resting metabolic rates (0.66 and 0.94 W), but higher rates of evaporative water loss (1.91 and 2.99 g H2O h(-1)) at their T(uc) and reached their HTL at T(air) of 58-60 degrees C. Mass-specific evaporative water loss in white-winged doves (147 g) and mourning doves (104 g) was 45% and 30% greater, respectively, than the rate observed in Gambel's quail (161 g) at Tair of 48 degrees C. Higher rates of evaporation and higher T(uc) made the doves exceptionally heat tolerant, allowing them to maintain body temperatures at least 14 degrees C below air temperatures as high as 60 degrees C (140 degrees F). PMID- 26582938 TI - Single-pass split-bolus CT protocol in polytrauma: reproducibility and diagnostic efficacy. PMID- 26582935 TI - Tight coordination of aerial flight maneuvers and sonar call production in insectivorous bats. AB - Echolocating bats face the challenge of coordinating flight kinematics with the production of echolocation signals used to guide navigation. Previous studies of bat flight have focused on kinematics of fruit and nectar-feeding bats, often in wind tunnels with limited maneuvering, and without analysis of echolocation behavior. In this study, we engaged insectivorous big brown bats in a task requiring simultaneous turning and climbing flight, and used synchronized high speed motion-tracking cameras and audio recordings to quantify the animals' coordination of wing kinematics and echolocation. Bats varied flight speed, turn rate, climb rate and wingbeat rate as they navigated around obstacles, and they adapted their sonar signals in patterning, duration and frequency in relation to the timing of flight maneuvers. We found that bats timed the emission of sonar calls with the upstroke phase of the wingbeat cycle in straight flight, and that this relationship changed when bats turned to navigate obstacles. We also characterized the unsteadiness of climbing and turning flight, as well as the relationship between speed and kinematic parameters. Adaptations in the bats' echolocation call frequency suggest changes in beam width and sonar field of view in relation to obstacles and flight behavior. By characterizing flight and sonar behaviors in an insectivorous bat species, we find evidence of exquisitely tight coordination of sensory and motor systems for obstacle navigation and insect capture. PMID- 26582939 TI - Response to "Single-pass split-bolus CT protocol in polytrauma: reproducibility and diagnostic efficacy". PMID- 26582944 TI - Predictors of Prolonged In-Hospital Stay After Primary Percutaneous Coronary Intervention for ST-Elevation Myocardial Infarction. AB - Health care costs increase with prolonged in-hospital stays. Many factors influence the length of stay for patients with ST-elevation myocardial infarction (STEMI). In this study, we aimed to determine the differences between long-stay and early discharged patients with STEMI. For this retrospective study, a total of 2486 consecutive patients with STEMI (mean age: 56.2 +/- 11.7 years, 16.5% female) who had undergone primary percutaneous coronary intervention (pPCI) were enrolled. Patients were divided into 2 groups based on mean in-hospital stay: <6 days and >=6 days. Anterior STEMI (odds ratio [OR]: 1.61, 95% confidence interval [CI]: 1.02-2.54; P = 0.03), angiographic failure (OR: 2.89, 95% CI: 1.19-7.01; P = .01), and peripheral vascular complications (PVCs; OR: 4.18, 95% CI: 1.16 15.03; P = .02) were found to be independent predictors of >=6-day in-hospital stay. The incidence of long-term total mortality and composite end point for death, reinfarction, and target vessel revascularization were significantly higher in >=6-day in-hospital stay patients. Anterior STEMI, angiographic failure, and PVCs were found to be independently associated with prolonged in hospital stay for patients with STEMI following pPCI. PMID- 26582945 TI - Migration of CD8+ T Cells into the Central Nervous System Gives Rise to Highly Potent Anti-HIV CD4dimCD8bright T Cells in a Wnt Signaling-Dependent Manner. AB - The role of CD8(+) T cells in HIV control in the brain and the consequences of such control are unclear. Approximately 3% of peripheral CD8(+) T cells dimly express CD4 on their surface. This population is known as CD4(dim)CD8(bright) T cells. We evaluated the role of CD4(dim)CD8(bright) and CD8 single positive T cells in HIV-infected brain using NOD/SCID/IL-2rcgamma(-/-) mice reconstituted with human PBMCs (NSG-huPBMC). All three T cell populations (CD4 single positive, CD8 single positive, and CD4(dim)CD8(bright)) were found in NSG-huPBMC mouse brain within 2 wk of infection. Wnts secreted from astrocytes induced CD4(dim)CD8(bright) T cells by 2-fold in vitro. Injection of highly purified CD8 single positive T cells into mouse brain induced CD4(dim)CD8(bright) T cells by 10-fold, which were proliferative and exhibited a terminally differentiated effector memory phenotype. Brain CD4(dim)CD8(bright) T cells from HIV-infected mice exhibited anti-HIV-specific responses, as demonstrated by induction of CD107ab post exposure to HIV peptide-loaded targets. Further, higher frequency of CD4(dim)CD8(bright) T cells (R = -0.62; p <= 0.001), but not CD8 single positive T cells (R = -0.24; p <= 0.27), negatively correlated with HIV gag mRNA transcripts in HIV-infected NSG-huPBMC brain. Together, these studies indicate that single positive CD8(+) T cells entering the CNS during HIV infection can give rise to CD4(dim)CD8(bright) T cells, likely through a Wnt signaling dependent manner, and that these cells are associated with potent anti-HIV control in the CNS. Thus, CD4(dim)CD8(bright) T cells are capable of HIV control in the CNS and may offer protection against HIV-associated neurocognitive disorders. PMID- 26582946 TI - Group 2 Innate Lymphoid Cells Express Functional NKp30 Receptor Inducing Type 2 Cytokine Production. AB - Group 2 innate lymphoid cells (ILC2) are important in effector functions for eliciting allergic inflammation, parasite defense, epithelial repair, and lipid homeostasis. ILC2 lack rearranged Ag-specific receptors, and although many soluble factors such as cytokines and lipid mediators can influence ILC2, direct interaction of these cells with the microenvironment and other cells has been less explored. Natural cytotoxicity receptors are expressed by subsets of group 1 ILC and group 3 ILC and thought to be important for their effector function, but they have not been shown to be expressed by ILC2. Therefore, we sought to investigate the expression and functional properties of the natural cytotoxicity receptor NKp30 on human ILC2. A subset of ex vivo and cultured ILC2 express NKp30 that upon interaction with its cognate activatory ligand B7-H6 induces rapid production of type 2 cytokines. This interaction can be blocked by NKp30 blocking Ab and an inhibitory ligand, galectin-3. Higher expression of B7-H6 was observed in lesional skin biopsies of patients with atopic dermatitis, and incubation of keratinocytes with proinflammatory and type 2 cytokines upregulated B7-H6, leading to increased ILC2 cytokine production. NKp30-B7-H6 interaction is a novel cell contact mechanism that mediates activation of ILC2 and identifies a potential target for the development of novel therapeutics for atopic dermatitis and other atopic diseases. PMID- 26582947 TI - gammadelta T Cells Shape Preimmune Peripheral B Cell Populations. AB - We previously reported that selective ablation of certain gammadelta T cell subsets, rather than removal of all gammadelta T cells, strongly affects serum Ab levels in nonimmunized mice. This type of manipulation also changed T cells, including residual gammadelta T cells, revealing some interdependence of gammadelta T cell populations. For example, in mice lacking Vgamma4(+) and Vgamma6(+) gammadelta T cells (B6.TCR-Vgamma4(-/-)/6(-/-)), we observed expanded Vgamma1(+) cells, which changed in composition and activation and produced more IL-4 upon stimulation in vitro, increased IL-4 production by alphabeta T cells as well as spontaneous germinal center formation in the spleen, and elevated serum Ig and autoantibodies. We therefore examined B cell populations in this and other gammadelta-deficient mouse strains. Whereas immature bone marrow B cells remained largely unchanged, peripheral B cells underwent several changes. Specifically, transitional and mature B cells in the spleen of B6.TCR-Vgamma4(-/-)/6(-/-) mice and other peripheral B cell populations were diminished, most of all splenic marginal zone (MZ) B cells. However, relative frequencies and absolute numbers of Ab-producing cells, as well as serum levels of Abs, IL-4, and BAFF, were increased. Cell transfers confirmed that these changes are directly dependent on the altered gammadelta T cells in this strain and on their enhanced potential of producing IL-4. Further evidence suggests the possibility of direct interactions between gammadelta T cells and B cells in the splenic MZ. Taken together, these data demonstrate the capability of gammadelta T cells of modulating size and productivity of preimmune peripheral B cell populations. PMID- 26582948 TI - Zinc and Manganese Chelation by Neutrophil S100A8/A9 (Calprotectin) Limits Extracellular Aspergillus fumigatus Hyphal Growth and Corneal Infection. AB - Calprotectin, a heterodimer of S100A8 and S100A9, is an abundant neutrophil protein that possesses antimicrobial activity primarily because of its ability to chelate zinc and manganese. In the current study, we showed that neutrophils from calprotectin-deficient S100A9(-/-) mice have an impaired ability to inhibit Aspergillus fumigatus hyphal growth in vitro and in infected corneas in a murine model of fungal keratitis; however, the ability to inhibit hyphal growth was restored in S100A9(-/-) mice by injecting recombinant calprotectin. Furthermore, using recombinant calprotectin with mutations in either the Zn and Mn binding sites or the Mn binding site alone, we show that both zinc and manganese binding are necessary for calprotectin's antihyphal activity. In contrast to hyphae, we found no role for neutrophil calprotectin in uptake or killing of intracellular A. fumigatus conidia either in vitro or in a murine model of pulmonary aspergillosis. We also found that an A. fumigatus ?zafA mutant, which demonstrates deficient zinc transport, exhibits impaired growth in infected corneas and following incubation with neutrophils or calprotectin in vitro as compared with wild-type. Collectively, these studies demonstrate a novel stage specific susceptibility of A. fumigatus to zinc and manganese chelation by neutrophil-derived calprotectin. PMID- 26582949 TI - Caspase-12, but Not Caspase-11, Inhibits Obesity and Insulin Resistance. AB - Inflammation is well established to significantly impact metabolic diseases. The inflammatory protease caspase-1 has been implicated in metabolic dysfunction; however, a potential role for the related inflammatory caspases is currently unknown. In this study, we investigated a role for caspase-11 and caspase-12 in obesity and insulin resistance. Loss of caspase-12 in two independently generated mouse strains predisposed mice to develop obesity, metabolic inflammation, and insulin resistance, whereas loss of caspase-11 had no effect. The use of bone marrow chimeras determined that deletion of caspase-12 in the radio-resistant compartment was responsible for this metabolic phenotype. The Nlrp3 inflammasome pathway mediated the metabolic syndrome of caspase-12-deficient mice as ablation of Nlrp3 reversed Casp12(-/-) mice obesity phenotype. Although the majority of people lack a functional caspase-12 because of a T(125) single nucleotide polymorphism that introduces a premature stop codon, a fraction of African descendents express full-length caspase-12. Expression of caspase-12 was linked to decreased systemic and adipose tissue inflammation in a cohort of African American obese children. However, analysis of the Dallas Heart Study African American cohort indicated that the coding T(125)C single nucleotide polymorphism was not associated with metabolic parameters in humans, suggesting that host specific differences mediate the expressivity of metabolic disease. PMID- 26582950 TI - The Mitochondrial Phosphatase PGAM5 Is Dispensable for Necroptosis but Promotes Inflammasome Activation in Macrophages. AB - The cytokine IL-1beta is intimately linked to many pathological inflammatory conditions. Mature IL-1beta secretion requires cleavage by the inflammasome. Recent evidence indicates that many cell death signal adaptors have regulatory roles in inflammasome activity. These include the apoptosis inducers FADD and caspase 8, and the necroptosis kinases receptor interacting protein kinase 1 (RIPK1) and RIPK3. PGAM5 is a mitochondrial phosphatase that has been reported to function downstream of RIPK3 to promote necroptosis and IL-1beta secretion. To interrogate the biological function of PGAM5, we generated Pgam5(-/-) mice. We found that Pgam5(-/-) mice were smaller compared with wild type littermates, and male Pgam5(-/-) mice were born at sub-Mendelian ratio. Despite these growth and survival defects, Pgam5(-/-) cells responded normally to multiple inducers of apoptosis and necroptosis. Rather, we found that PGAM5 is critical for IL-1beta secretion in response to NLRP3 and AIM2 inflammasome agonists. Moreover, vesicular stomatosis virus-induced IL-1beta secretion was impaired in Pgam5(-/-) bone marrow-derived macrophages, but not in Ripk3(-/-) bone marrow-derived dendritic cells, indicating that PGAM5 functions independent of RIPK3 to promote inflammasome activation. Mechanistically, PGAM5 promotes ASC polymerization, maintenance of mitochondrial integrity, and optimal reactive oxygen species production in response to inflammasome signals. Hence PGAM5 is a novel regulator of inflammasome and caspase 1 activity that functions independently of RIPK3. PMID- 26582952 TI - Abdominal migraine. AB - BACKGROUND: Abdominal migraine (AM) is a syndrome usually recognised in childhood. The syndrome is characterised by episodic attacks of severe abdominal pain and vasomotor symptoms, nausea and vomiting. It is a poorly understood disorder largely due to a limited recognition of this condition by the medical community. However, the publication of AM diagnostic guidelines by the International Headache Society a decade ago and the recognition of AM in the Rome Classification of functional gastrointestinal disorders have helped to legitimise this disorder and facilitate research. OVERVIEW: AM is relatively common, affecting up to 4% of the paediatric population. Whilst AM is not believed to continue into adulthood for the majority of children, it has the propensity to develop into probable migraine and recurrent abdominal pain in adulthood. The pathophysiology of this condition remains unclear and as a result treatment for this condition is suboptimal with avoidance of triggers and prophylactic treatment currently recommended when an episode begins. CONCLUSION: The recognition of AM by the IHS and the Rome Foundation should help facilitate future research into the pathophysiology of this debilitating condition and as a result better treatments for AM should emerge. Randomised controlled trials should be a priority. PMID- 26582951 TI - Helios Controls a Limited Subset of Regulatory T Cell Functions. AB - A subpopulation (60-70%) of Foxp3(+) regulatory T cells (Tregs) in both mouse and man expresses the transcription factor Helios, but its role in Treg function is still unknown. We generated Treg-specific Helios-deficient mice to examine the function of Helios in Tregs. We show that the selective deletion of Helios in Tregs leads to slow, progressive systemic immune activation, hypergammaglobulinemia, and enhanced germinal center formation in the absence of organ-specific autoimmunity. Helios-deficient Treg suppressor function was normal in vitro, as well as in an in vivo inflammatory bowel disease model. However, Helios-deficient Tregs failed to control the expansion of pathogenic T cells derived from scurfy mice, failed to mediate T follicular regulatory cell function, and failed to control both T follicular helper cell and Th1 effector cell responses. In competitive settings, Helios-deficient Tregs, particularly effector Tregs, were at a disadvantage, indicating that Helios regulates effector Treg fitness. Thus, we demonstrate that Helios controls certain aspects of Treg suppressive function, differentiation, and survival. PMID- 26582953 TI - Humanized Mice--A Neoteric Animal Disease Model for Ebola Virus? PMID- 26582954 TI - Differential Expression of the Eicosanoid Pathway in Patients With Localized or Mucosal Cutaneous Leishmaniasis. AB - Unfettered inflammation is thought to play critical role in the development of different clinical forms of tegumentary leishmaniasis. Eicosanoids are potent mediators of inflammation and tightly associated with modulation of immune responses. In this cross-sectional exploratory study, we addressed whether targets from the eicosanoid biosynthetic pathway, assessed by multiplexed expression assays in lesion biopsy and plasma specimens, could highlight a distinct biosignature in patients with mucocutaneous leishmaniasis (MCL) or localized cutaneous leishmaniasis (LCL). Differences in immunopathogenesis between MCL and LCL may result from an imbalance between prostaglandins and leukotrienes, which may serve as targets for future host-directed therapies. PMID- 26582956 TI - Digging Deeper Into Hepatitis C Virus Outbreaks. PMID- 26582955 TI - Accurate Genetic Detection of Hepatitis C Virus Transmissions in Outbreak Settings. AB - Hepatitis C is a major public health problem in the United States and worldwide. Outbreaks of hepatitis C virus (HCV) infections are associated with unsafe injection practices, drug diversion, and other exposures to blood and are difficult to detect and investigate. Here, we developed and validated a simple approach for molecular detection of HCV transmissions in outbreak settings. We obtained sequences from the HCV hypervariable region 1 (HVR1), using end-point limiting-dilution (EPLD) technique, from 127 cases involved in 32 epidemiologically defined HCV outbreaks and 193 individuals with unrelated HCV strains. We compared several types of genetic distances and calculated a threshold, using minimal Hamming distances, that identifies transmission clusters in all tested outbreaks with 100% accuracy. The approach was also validated on sequences obtained using next-generation sequencing from HCV strains recovered from 239 individuals, and findings showed the same accuracy as that for EPLD. On average, the nucleotide diversity of the intrahost population was 6.2 times greater in the source case than in any incident case, allowing the correct detection of transmission direction in 8 outbreaks for which source cases were known. A simple and accurate distance-based approach developed here for detecting HCV transmissions streamlines molecular investigation of outbreaks, thus improving the public health capacity for rapid and effective control of hepatitis C. PMID- 26582958 TI - Monitoring of Prognostic Laboratory Markers in Ebola Virus Disease. PMID- 26582957 TI - Evolutionarily Successful Asian 1 Dengue Virus 2 Lineages Contain One Substitution in Envelope That Increases Sensitivity to Polyclonal Antibody Neutralization. AB - The 4 dengue virus serotypes (DENV-1-4) cause the most prevalent mosquito-borne viral disease of humans worldwide. DENV-2 Asian 1 (A1) genotype viruses replaced the Asian-American (AA) genotype in Vietnam and Cambodia, after which A1 viruses containing Q or M at envelope (E) residue 160 became more prevalent than those with residue 160K in both countries (2008-2011). We investigated whether these substitutions conferred a fitness advantage by measuring neutralizing antibody titer against reporter virus particles (RVPs) representing AA, A1-160K, A1-160Q, and A1-160M, using patient sera from Vietnam and a well-characterized Nicaraguan cohort. Surprisingly, we found that A1-160Q and A1-160M RVPs were better neutralized by heterologous antisera than A1-160K. Despite this, Vietnamese patients infected with A1-160Q or A1-160M viruses had higher viremia levels than those infected with A1-160K. We thus found that independent lineages in Vietnam and Cambodia acquired a substitution in E that significantly increased polyclonal neutralization but nonetheless were successful in disseminating and infecting human hosts. PMID- 26582959 TI - Peginterferon Is Superior to Nucleos(t)ide Analogues for Prevention of Hepatocellular Carcinoma in Chronic Hepatitis B. AB - BACKGROUND: Clinical factors associated with hepatocellular carcinoma (HCC) have been extensively studied in antiviral treatment-naive patients with chronic hepatitis B virus (HBV) infection but not in treatment-experienced patients. Owing to the wide availability of antiviral agents that effectively suppress HBV replication, we investigated HCC risk factors in treatment-experienced patients. METHODS: In a cohort of 330 patients who underwent pretherapeutic liver biopsy, we analyzed the HCC incidence in relationship to clinical parameters. Ultra-deep sequencing of the viral genome was performed on 11 entecavir-treated and pegylated interferon (peginterferon)-treated patients. RESULTS: Initial univariate/multivariate explorations indicated that cirrhosis and antiviral treatment were independently associated with HCC occurrence. The peginterferon experienced patients had a lower HCC incidence than the nucleos(t)ide analogue treated patients (P = .011). The peginterferon and entecavir monotherapy groups also differed in HCC incidence (P = .018). Results of analysis of baseline matched subgroups concurred with cohort analysis (P = .009 for comparison of peginterferon-experienced vs nucleotide analogue-treated patients; P = .022 for comparison of peginterferon- vs entecavir-treated patients). Viral loads of entecavir-treated patients were constantly suppressed to levels lower than those of peginterferon-treated patients (P < .001). Oncogenic surface antigen truncation mutations were detected in entecavir-treated patients with HCC but not in peginterferon-treated patients (P = .015). CONCLUSIONS: Treatment by peginterferon was associated with a lower HCC incidence than nucleos(t)ide analogue treatment in chronic HBV infection. PMID- 26582960 TI - Shiga Toxin 2a-Induced Endothelial Injury in Hemolytic Uremic Syndrome: A Metabolomic Analysis. AB - BACKGROUND: Endothelial dysfunction plays a pivotal role in the pathogenesis of postenteropathic hemolytic uremic syndrome (HUS), most commonly caused by Shiga toxin (Stx)-producing strains of Escherichia coli. METHODS: To identify new treatment targets, we performed a metabolomic high-throughput screening to analyze the effect of Stx2a, the major Stx type associated with HUS, on human renal glomerular endothelial cells (HRGEC) and umbilical vein endothelial cells (HUVEC). Cells were treated either with sensitizing tumor necrosis factor alpha (TNF-alpha) or Stx2a, a sequence of both or remained untreated. RESULTS: We identified 341 metabolites by combined liquid chromatography/tandem mass spectrometry and gas chromatography/mass spectrometry. Both cell lines exhibited distinct metabolic reaction profiles but shared elevated levels of free fatty acids. Stx2a predominantly altered the nicotinamide adenine dinucleotide (NAD) cofactor pathway and the inflammation-modulating eicosanoid pathway, which are associated with lipid metabolism. In HRGEC, Stx2a strongly diminished NAD derivatives, leading to depletion of the energy substrate acetyl coenzyme A and the antioxidant glutathione. HUVEC responded to TNF-alpha and Stx2a by increasing production of the counteracting eicosanoids prostaglandin I2, E1, E2, and A2, while in HRGEC only more prostaglandin I2 was detected. CONCLUSIONS: We conclude that disruption of energy metabolism and depletion of glutathione contributes to Stx-induced injury of the renal endothelium and that the inflammatory response to Stx is highly cell-type specific. PMID- 26582962 TI - Glycosylphosphatidylinositol (GPI) Anchors: Biochemistry and Cell Biology: Introduction to a Thematic Review Series. PMID- 26582961 TI - Humanized Mouse Model of Ebola Virus Disease Mimics the Immune Responses in Human Disease. AB - Animal models recapitulating human Ebola virus disease (EVD) are critical for insights into virus pathogenesis. Ebola virus (EBOV) isolates derived directly from human specimens do not, without adaptation, cause disease in immunocompetent adult rodents. Here, we describe EVD in mice engrafted with human immune cells (hu-BLT). hu-BLT mice developed EVD following wild-type EBOV infection. Infection with high-dose EBOV resulted in rapid, lethal EVD with high viral loads, alterations in key human antiviral immune cytokines and chemokines, and severe histopathologic findings similar to those shown in the limited human postmortem data available. A dose- and donor-dependent clinical course was observed in hu BLT mice infected with lower doses of either Mayinga (1976) or Makona (2014) isolates derived from human EBOV cases. Engraftment of the human cellular immune system appeared to be essential for the observed virulence, as nonengrafted mice did not support productive EBOV replication or develop lethal disease. hu-BLT mice offer a unique model for investigating the human immune response in EVD and an alternative animal model for EVD pathogenesis studies and therapeutic screening. PMID- 26582963 TI - Religiosity and Spiritual Engagement in Two American Indian Populations. AB - Social scientific investigation into the religiospiritual characteristics of American Indians rarely includes analysis of quantitative data. After reviewing information from ethnographic and autobiographical sources, we present analyses of data from a large, population-based sample of two tribes (n = 3,084). We examine salience of belief in three traditions: aboriginal, Christian, and Native American Church. We then investigate patterns in sociodemographic subgroups, determining the significant correlates of salience with other variables controlled. Finally, we examine frequency with which respondents assign high salience to only one tradition (exclusivity) or multiple traditions (nonexclusivity), again investigating subgroup variations. This first detailed, statistical portrait of American Indian religious and spiritual lives links work on tribal ethnic identity to theoretical work on America's "religious marketplace." Results may also inform social/behavioral interventions that incorporate religiospiritual elements. PMID- 26582964 TI - Religio-Spiritual Participation in Two American Indian Populations. AB - Following a previous investigation of religio-spiritual beliefs in American Indians, this article examined prevalence and correlates of religio-spiritual participation in two tribes in the Southwest and Northern Plains (N = 3,084). Analysis suggested a "religious profile" characterized by strong participation across three traditions: aboriginal, Christian, and Native American Church. However, sociodemographic variables that have reliably predicted participation in the general American population, notably gender and age, frequently failed to achieve significance in multivariate analyses for each tradition. Religio spiritual participation was strongly and significantly related to belief salience for all traditions. Findings suggest that correlates of religious participation may be unique among American Indians, consistent with their distinctive religious profile. Results promise to inform researchers' efforts to understand and theorize about religio-spiritual behavior. They also provide tribal communities with practical information that might assist them in harnessing social networks to confront collective challenges through community-based participatory research collaborations. PMID- 26582967 TI - Reasoning with Vectors: A Continuous Model for Fast Robust Inference. AB - This paper describes the use of continuous vector space models for reasoning with a formal knowledge base. The practical significance of these models is that they support fast, approximate but robust inference and hypothesis generation, which is complementary to the slow, exact, but sometimes brittle behavior of more traditional deduction engines such as theorem provers. The paper explains the way logical connectives can be used in semantic vector models, and summarizes the development of Predication-based Semantic Indexing, which involves the use of Vector Symbolic Architectures to represent the concepts and relationships from a knowledge base of subject-predicate-object triples. Experiments show that the use of continuous models for formal reasoning is not only possible, but already demonstrably effective for some recognized informatics tasks, and showing promise in other traditional problem areas. Examples described in this paper include: predicting new uses for existing drugs in biomedical informatics; removing unwanted meanings from search results in information retrieval and concept navigation; type-inference from attributes; comparing words based on their orthography; and representing tabular data, including modelling numerical values. The algorithms and techniques described in this paper are all publicly released and freely available in the Semantic Vectors open-source software package. PMID- 26582966 TI - The Effects of Viral Load Burden on Pregnancy Loss among HIV-Infected Women in the United States. AB - BACKGROUND: To evaluate the effects of HIV viral load, measured cross-sectionally and cumulatively, on the risk of miscarriage or stillbirth (pregnancy loss) among HIV-infected women enrolled in the Women's Interagency HIV Study between 1994 and 2013. METHODS: We assessed three exposures: most recent viral load measure before the pregnancy ended, log10 copy-years viremia from initiation of antiretroviral therapy (ART) to conception, and log10 copy-years viremia in the two years before conception. RESULTS: The risk of pregnancy loss for those with log10 viral load >4.00 before pregnancy ended was 1.59 (95% confidence interval (CI): 0.99, 2.56) times as high as the risk for women whose log10 viral load was <=1.60. There was not a meaningful impact of log10 copy-years viremia since ART or log10 copy-years viremia in the two years before conception on pregnancy loss (adjusted risk ratios (aRRs): 0.80 (95% CI: 0.69, 0.92) and 1.00 (95% CI: 0.90, 1.11), resp.). CONCLUSIONS: Cumulative viral load burden does not appear to be an informative measure for pregnancy loss risk, but the extent of HIV replication during pregnancy, as represented by plasma HIV RNA viral load, predicted loss versus live birth in this ethnically diverse cohort of HIV-infected US women. PMID- 26582965 TI - Intestinal Permeability in Inflammatory Bowel Disease: Pathogenesis, Clinical Evaluation, and Therapy of Leaky Gut. AB - The pathogenesis of inflammatory bowel disease (IBD) is multifactorial with data suggesting the role of a disturbed interaction between the gut and the intestinal microbiota. A defective mucosal barrier may result in increased intestinal permeability which promotes the exposition to luminal content and triggers an immunological response that promotes intestinal inflammation. IBD patients display several defects in the many specialized components of mucosal barrier, from the mucus layer composition to the adhesion molecules that regulate paracellular permeability. These alterations may represent a primary dysfunction in Crohn's disease, but they may also perpetuate chronic mucosal inflammation in ulcerative colitis. In clinical practice, several studies have documented that changes in intestinal permeability can predict IBD course. Functional tests, such as the sugar absorption tests or the novel imaging technique using confocal laser endomicroscopy, allow an in vivo assessment of gut barrier integrity. Antitumor necrosis factor-alpha (TNF-alpha) therapy reduces mucosal inflammation and restores intestinal permeability in IBD patients. Butyrate, zinc, and some probiotics also ameliorate mucosal barrier dysfunction but their use is still limited and further studies are needed before considering permeability manipulation as a therapeutic target in IBD. PMID- 26582968 TI - The association between substance use disorders and early and combined use of alcohol and marijuana in two American Indian populations. AB - OBJECTIVE: To study the relationships between early and combined use of alcohol and marijuana with diagnoses of alcohol and marijuana use disorders in two American Indian (AI) populations. METHOD: Data were drawn from a psychiatric epidemiologic study of 3084 AIs living on or near two reservations. We analysed data for adults aged 18-54 years at the time of interview (n = 2739). Logistic regression models were estimated to examine associations between early and combined use of alcohol and marijuana with lifetime diagnoses of abuse and dependence. RESULTS: Overall, younger AIs (18-29 years old) were more likely than older AIs (40-54 years old) to initiate substance use early and initiate use with marijuana, with or without alcohol. Persons who initiated alcohol use before age 14 were more than twice as likely as those who initiated use at older ages to meet criteria for alcohol or marijuana use disorders (p < 0.01). The odds of abuse or dependence were two to five times higher among persons who reported combined use of alcohol and marijuana (p < 0.01) than among those who reported use of either substance. CONCLUSIONS: These findings document the need to address both early and combined use of alcohol and marijuana in prevention and treatment programmes. PMID- 26582969 TI - Nurses respond to patients' psychosocial needs by dealing, ducking, diverting and deferring: an observational study of a hospice ward. AB - BACKGROUND: Psychosocial support is considered a central component of nursing care but it remains unclear as to exactly how this is implemented in practice. The aim of this study was to provide a descriptive exploration of how psychosocial needs (PNs) of patients in a hospice ward are expressed and met, in order to develop an understanding of the provision of psychosocial support in practice. METHODS: An embedded mixed-methods study was conducted in one hospice ward. Data collection included observations of patients' expressions of PNs and nurses' responses to those expressed PNs, shift hand-overs and multi-disciplinary meetings. Interviews about the observed care were conducted with the patients and nurses and nursing documentation pertaining to psychosocial care was collated. Descriptive statistical techniques were applied to quantitative data in order to explore and support the qualitative observational, interview and documentary data. RESULTS: During the 8-month period of observation, 227 encounters within 38 episodes of care were observed among 38 nurses and 47 patients. Within these encounters, 330 PNs were expressed. Nurses were observed immediately responding to expressed PNs in one of four ways: dealing (44.2 %), deferring (14.8 %), diverting (10.3 %) and ducking (30.7 %). However, it is rare that one type of PN was clearly expressed on its own: many were expressed at the same time and usually while the patient was interacting with the nurse for another reason, thus making the provision of psychosocial support challenging. The nurses' response patterns varied little according to type of need. CONCLUSIONS: The provision of psychosocial support is very complex and PNs are not always easily recognised. This study has allowed an exploration of the actual PNs of patients in a hospice setting, the way in which they were expressed, and how nurses responded to them. The nurses faced the challenge of responding to PNs whilst carrying out the other duties of their shift, and the fact that nurses can provide psychosocial support as an inherent component of practice was verified. The data included in this paper, and the discussions around the observed care, provides nurses everywhere with an example against which to compare their own practice. PMID- 26582970 TI - Estimating distributions of health state severity for the global burden of disease study. AB - BACKGROUND: Many major causes of disability in the Global Burden of Disease (GBD) study present with a range of severity, and for most causes finding population distributions of severity can be difficult due to issues of sparse data, inconsistent measurement, and need to account for comorbidities. We developed an indirect approach to obtain severity distributions empirically from survey data. METHODS: Individual-level data were used from three large population surveys from the US and Australia that included self-reported prevalence of major diseases and injuries as well as generic health status assessments using the 12-Item Short Form Health Survey (SF-12). We developed a mapping function from SF-12 scores to GBD disability weights. Mapped scores for each individual respondent were regressed against the reported diseases and injuries using a mixed-effects model with a logit-transformed response variable. The regression outputs were used to predict comorbidity-corrected health-state weights for the group of individuals with each condition. The distribution of these comorbidity-corrected weights were used to estimate the fraction of individuals with each condition falling into different GBD severity categories, including asymptomatic (implying disability weight of zero). RESULTS: After correcting for comorbid conditions, all causes analyzed had some proportion of the population in the asymptomatic category. For less severe conditions, such as alopecia areata, we estimated that 44.1 % [95 % CI: 38.7 %-49.4 %] were asymptomatic while 28.3 % [26.8 %-29.6 %] of anxiety disorders had asymptomatic cases. For 152 conditions, full distributions of severity were estimated. For anxiety disorders for example, we estimated the mean population proportions in the mild, moderate, and severe states to be 40.9 %, 18.5 %, and 12.3 % respectively. Thirty-seven of the analyzed conditions were used in the GBD 2013 estimates and are reported here. CONCLUSION: There is large heterogeneity in the disabling severity of conditions among individuals. The GBD 2013 approach allows explicit accounting for this heterogeneity in GBD estimates. Existing survey data that have collected health status together with information on the presence of a series of comorbid conditions can be used to fill critical gaps in the information on condition severity while correcting for effects of comorbidity. Our ability to make these estimates may be limited by lack of geographic variation in the data and by the current methodology for disability weights, which implies that severity must be binned rather than expressed in as a full distribution. Future country-specific data collection efforts will be needed to advance this research. PMID- 26582971 TI - ANTIOXIDANT CAPACITY OF WYOMING BIG SAGEBRUSH (ARTEMISIA TRIDENTATA SSP. WYOMINGENSIS) VARIES SPATIALLY AND IS NOT RELATED TO THE PRESENCE OF A SAGEBRUSH DIETARY SPECIALIST. AB - Sagebrush (Artemisia spp.) in North America is an abundant native plant species that is ecologically and evolutionarily adapted to have a diverse array of biologically active chemicals. Several of these chemicals, specifically polyphenols, have antioxidant activity that may act as biomarkers of biotic or abiotic stress. This study investigated the spatial variation of antioxidant capacity, as well as the relationship between a mammalian herbivore and antioxidant capacity in Wyoming big sagebrush (Artemisia tridentata wyomingensis). We quantified and compared total polyphenols and antioxidant capacity of leaf extracts from sagebrush plants from different spatial scales and at different levels of browsing by a specialist mammalian herbivore, the pygmy rabbit (Brachylagus idahoensis). We found that antioxidant capacity of sagebrush extracts was positively correlated with total polyphenol content. Antioxidant capacity varied spatially within and among plants. Antioxidant capacity in sagebrush was not related to either browsing intensity or duration of association with rabbits. We propose that the patterns of antioxidant capacity observed in sagebrush may be a result of spatial variation in abiotic stress experienced by sagebrush. Antioxidants could therefore provide a biomarker of environmental stress for sagebrush that could aid in management and conservation of this plant in the threatened sagebrush steppe. PMID- 26582972 TI - The effect of 6 days of alpha glycerylphosphorylcholine on isometric strength. AB - BACKGROUND: Ergogenic aides are widely used by fitness enthusiasts and athletes to increase performance. Alpha glycerylphosphorylcholine (A-GPC) has demonstrated some initial promise in changing explosive performance. The purpose of the present investigation was to determine if 6 days of supplementation with A-GPC would augment isometric force production compared to a placebo. METHODS: Thirteen college-aged males (Means +/- SD; Age: 21.9 +/- 2.2 years, Height: 180.3 +/- 7.7 cm, Weight: 87.6 +/- 15.6 kg; VO2 max: 40.08 +/- 7.23 ml O2*Kg(-1)*min(-1), Body Fat: 17.5 +/- 4.6%) gave written informed consent to participate in the study. The study was a double blind, placebo controlled, cross-over design. The participants reported to the lab for an initial visit where they were familiarized with the isometric mid thigh pull in a custom squat cage on a force platform and upper body isometric test against a high frequency load cell, and baseline measurements were taken for both. The participant then consumed either 600 mg per day of A-GPC or placebo and at the end of 6 days performed isometric mid thigh pulls and an upper body isometric test. A one-week washout period was used before the participants' baseline was re-measured and crossed over to the other treatment. RESULTS: The A-GPC treatment resulted in significantly greater isometric mid thigh pull peak force change from baseline (t = 1.76, p = 0.044) compared with placebo (A-GPC: 98.8. +/- 236.9 N vs Placebo: -39.0 +/- 170.9 N). For the upper body test the A-GPC treatment trended towards greater change from baseline force production (A-GPC: 50.9 +/- 67.2 N Placebo: -14.9 +/- 114.9 N) but failed to obtain statistical significance (t = 1.16, p = 0.127). CONCLUSIONS: A GPC is effective at increasing lower body force production after 6 days of supplementation. Sport performance coaches can consider adding A-GPC to the diet of speed and power athletes to enhance muscle performance. PMID- 26582973 TI - Synaptic activity and Alzheimer's disease: a critical update. AB - Synapses have been known for many years to be the crucial target of pathology in different forms of dementia, in particular Alzheimer's disease (AD). Synapses and their appropriate activation or inhibition are fundamental for the proper brain function. Alterations in synaptic/neuronal activity and brain metabolism are considered among the earliest symptoms linked to the progression of AD, and lead to a central question in AD research: what is the role played by synaptic activity in AD pathogenesis? Intriguingly, in the last decade, important studies demonstrated that the state of activation of synapses affects the homeostasis of beta-amyloid (Abeta) and tau, both of which aggregate and accumulate during AD, and are involved in neuronal dysfunction. In this review we aim to summarize the up-to-date data linking synaptic/neuronal activity with Abeta and tau; moreover, we also intend to provide a critical overview on brain activity alterations in AD, and their role in the disease's pathophysiology. PMID- 26582974 TI - Effectiveness of music therapy as an aid to neurorestoration of children with severe neurological disorders. AB - This study was a two-armed parallel group design aimed at testing real world effectiveness of a music therapy (MT) intervention for children with severe neurological disorders. The control group received only the standard neurorestoration program and the experimental group received an additional MT "Auditory Attention plus Communication protocol" just before the usual occupational and speech therapy. Multivariate Item Response Theory (MIRT) identified a neuropsychological status-latent variable manifested in all children and which exhibited highly significant changes only in the experimental group. Changes in brain plasticity also occurred in the experimental group, as evidenced using a Mismatch Event Related paradigm which revealed significant post intervention positive responses in the latency range between 308 and 400 ms in frontal regions. LORETA EEG source analysis identified prefrontal and midcingulate regions as differentially activated by the MT in the experimental group. Taken together, our results showing improved attention and communication as well as changes in brain plasticity in children with severe neurological impairments, confirm the importance of MT for the rehabilitation of patients across a wide range of dysfunctions. PMID- 26582975 TI - Post-training activation of Rac1 in the basolateral amygdala is required for the formation of both short-term and long-term auditory fear memory. AB - Rac1, a member of the Rho family of small GTPases, is crucial for morphological changes of the mature neuronal synapse including spine formation and activity dependent spine enlargement, while its role in the formation of associated memories, such as conditioned fear memory, is not clear. Here, we report that selective deletion of Rac1 in excitatory neurons, but not in parvalbumin inhibitory neurons, impaired short- and long-term memories (STM and LTM) of fear conditioning. Conditional knockout of Rac1 before associative fear training in the basolateral amygdala (BLA), a key area for fear memory acquisition and storage, impaired fear memory. The expression of dominant-negative mutant of Rac1, or infusion of Rac1 inhibitor NSC23766 into BLA blocked both STM and LTM of fear conditioning. Furthermore, selective inhibition of Rac1 activation in BLA immediately following fear conditioning impaired STM and LTM, demonstrating that fear conditioning-induced Rac1 activation in BLA plays a critical role in the formation of both STM and LTM of conditioned fear. PMID- 26582977 TI - Decoding brain state transitions in the pedunculopontine nucleus: cooperative phasic and tonic mechanisms. AB - Cholinergic neurons of the pedunculopontine nucleus (PPN) are most active during the waking state. Their activation is deemed to cause a switch in the global brain activity from sleep to wakefulness, while their sustained discharge may contribute to upholding the waking state and enhancing arousal. Similarly, non cholinergic PPN neurons are responsive to brain state transitions and their activation may influence some of the same targets of cholinergic neurons, suggesting that they operate in coordination. Yet, it is not clear how the discharge of distinct classes of PPN neurons organize during brain states. Here, we monitored the in vivo network activity of PPN neurons in the anesthetized rat across two distinct levels of cortical dynamics and their transitions. We identified a highly structured configuration in PPN network activity during slow wave activity that was replaced by decorrelated activity during the activated state (AS). During the transition, neurons were predominantly excited (phasically or tonically), but some were inhibited. Identified cholinergic neurons displayed phasic and short latency responses to sensory stimulation, whereas the majority of non-cholinergic showed tonic responses and remained at high discharge rates beyond the state transition. In vitro recordings demonstrate that cholinergic neurons exhibit fast adaptation that prevents them from discharging at high rates over prolonged time periods. Our data shows that PPN neurons have distinct but complementary roles during brain state transitions, where cholinergic neurons provide a fast and transient response to sensory events that drive state transitions, whereas non-cholinergic neurons maintain an elevated firing rate during global activation. PMID- 26582978 TI - Exploring functions for the non-lemniscal auditory thalamus. AB - The functions of the medial geniculate body (MGB) in normal hearing still remain somewhat enigmatic, in part due to the relatively unexplored properties of the non-lemniscal MGB nuclei. Indeed, the canonical view of the thalamus as a simple relay for transmitting ascending information to the cortex belies a role in higher-order forebrain processes. However, recent anatomical and physiological findings now suggest important information and affective processing roles for the non-primary auditory thalamic nuclei. The non-lemniscal nuclei send and receive feedforward and feedback projections among a wide constellation of midbrain, cortical, and limbic-related sites, which support potential conduits for auditory information flow to higher auditory cortical areas, mediators for transitioning among arousal states, and synchronizers of activity across expansive cortical territories. Considered here is a perspective on the putative and unresolved functional roles of the non-lemniscal nuclei of the MGB. PMID- 26582980 TI - Optogenetic silencing of locus coeruleus activity in mice impairs cognitive flexibility in an attentional set-shifting task. AB - The locus coeruleus (LC) is the sole source of noradrenergic projections to the cortex and essential for attention-dependent cognitive processes. In this study we used unilateral optogenetic silencing of the LC in an attentional set-shifting task (ASST) to evaluate the influence of the LC on prefrontal cortex-dependent functions in mice. We expressed the halorhodopsin eNpHR 3.0 to reversibly silence LC activity during task performance, and found that silencing selectively impaired learning of those parts of the ASST that most strongly rely on cognitive flexibility. In particular, extra-dimensional set-shifting (EDS) and reversal learning was impaired, suggesting an involvement of the medial prefrontal cortex (mPFC) and the orbitofrontal cortex. In contrast, those parts of the task that are less dependent on cognitive flexibility, i.e., compound discrimination (CD) and the intra-dimensional shifts (IDS) were not affected. Furthermore, attentional set formation was unaffected by LC silencing. Our results therefore suggest a modulatory influence of the LC on cognitive flexibility, mediated by different frontal networks. PMID- 26582979 TI - Basal ganglia-thalamus and the "crowning enigma". AB - When Hubel (1982) referred to layer 1 of primary visual cortex as "... a 'crowning mystery' to keep area-17 physiologists busy for years to come ..." he could have been talking about any cortical area. In the 80's and 90's there were no methods to examine this neuropile on the surface of the cortex: a tangled web of axons and dendrites from a variety of different places with unknown specificities and doubtful connections to the cortical output neurons some hundreds of microns below. Recently, three changes have made the crowning enigma less of an impossible mission: the clear presence of neurons in layer 1 (L1), the active conduction of voltage along apical dendrites and optogenetic methods that might allow us to look at one source of input at a time. For all of those reasons alone, it seems it is time to take seriously the function of L1. The functional properties of this layer will need to wait for more experiments but already L1 cells are GAD67 positive, i.e., inhibitory! They could reverse the sign of the thalamic glutamate (GLU) input for the entire cortex. It is at least possible that in the near future normal activity of individual sources of L1 could be detected using genetic tools. We are at the outset of important times in the exploration of thalamic functions and perhaps the solution to the crowning enigma is within sight. Our review looks forward to that solution from the solid basis of the anatomy of the basal ganglia output to motor thalamus. We will focus on L1, its afferents, intrinsic neurons and its influence on responses of pyramidal neurons in layers 2/3 and 5. Since L1 is present in the whole cortex we will provide a general overview considering evidence mainly from the somatosensory (S1) cortex before focusing on motor cortex. PMID- 26582976 TI - Extracellular proteolysis in structural and functional plasticity of mossy fiber synapses in hippocampus. AB - Brain is continuously altered in response to experience and environmental changes. One of the underlying mechanisms is synaptic plasticity, which is manifested by modification of synapse structure and function. It is becoming clear that regulated extracellular proteolysis plays a pivotal role in the structural and functional remodeling of synapses during brain development, learning and memory formation. Clearly, plasticity mechanisms may substantially differ between projections. Mossy fiber synapses onto CA3 pyramidal cells display several unique functional features, including pronounced short-term facilitation, a presynaptically expressed long-term potentiation (LTP) that is independent of NMDAR activation, and NMDA-dependent metaplasticity. Moreover, structural plasticity at mossy fiber synapses ranges from the reorganization of projection topology after hippocampus-dependent learning, through intrinsically different dynamic properties of synaptic boutons to pre- and postsynaptic structural changes accompanying LTP induction. Although concomitant functional and structural plasticity in this pathway strongly suggests a role of extracellular proteolysis, its impact only starts to be investigated in this projection. In the present report, we review the role of extracellular proteolysis in various aspects of synaptic plasticity in hippocampal mossy fiber synapses. A growing body of evidence demonstrates that among perisynaptic proteases, tissue plasminogen activator (tPA)/plasmin system, beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) and metalloproteinases play a crucial role in shaping plastic changes in this projection. We discuss recent advances and emerging hypotheses on the roles of proteases in mechanisms underlying mossy fiber target specific synaptic plasticity and memory formation. PMID- 26582982 TI - How previous experience shapes perception in different sensory modalities. AB - What has transpired immediately before has a strong influence on how sensory stimuli are processed and perceived. In particular, temporal context can have contrastive effects, repelling perception away from the interpretation of the context stimulus, and attractive effects (TCEs), whereby perception repeats upon successive presentations of the same stimulus. For decades, scientists have documented contrastive and attractive temporal context effects mostly with simple visual stimuli. But both types of effects also occur in other modalities, e.g., audition and touch, and for stimuli of varying complexity, raising the possibility that context effects reflect general computational principles of sensory systems. Neuroimaging shows that contrastive and attractive context effects arise from neural processes in different areas of the cerebral cortex, suggesting two separate operations with distinct functional roles. Bayesian models can provide a functional account of both context effects, whereby prior experience adjusts sensory systems to optimize perception of future stimuli. PMID- 26582981 TI - Ongoing behavioral state information signaled in the lateral habenula guides choice flexibility in freely moving rats. AB - The lateral habenula (LHb) plays a role in a wide variety of behaviors ranging from maternal care, to sleep, to various forms of cognition. One prominent theory with ample supporting evidence is that the LHb serves to relay basal ganglia and limbic signals about negative outcomes to midbrain monoaminergic systems. This makes it likely that the LHb is critically involved in behavioral flexibility as all of these systems have been shown to contribute when flexible behavior is required. Behavioral flexibility is commonly examined across species and is impaired in various neuropsychiatric conditions including autism, depression, addiction, and schizophrenia; conditions in which the LHb is thought to play a role. Therefore, a thorough examination of the role of the LHb in behavioral flexibility serves multiple functions including understanding possible connections with neuropsychiatric illnesses and additional insight into its role in cognition in general. Here, we assess the LHb's role in behavioral flexibility through comparisons of the roles its afferent and efferent pathways are known to play. Additionally, we provide new evidence supporting the LHb contributions to behavioral flexibility through organization of specific goal directed actions under cognitively demanding conditions. Specifically, in the first experiment, a majority of neurons recorded from the LHb were found to correlate with velocity on a spatial navigation task and did not change significantly when reward outcomes were manipulated. Additionally, measurements of local field potential (LFP) in the theta band revealed significant changes in power relative to velocity and reward location. In a second set of experiments, inactivation of the LHb with the gamma-aminobutyric acid (GABA) agonists baclofen and muscimol led to an impairment in a spatial/response based repeated probabilistic reversal learning task. Control experiments revealed that this impairment was likely due to the demands of repeated switching behaviors as rats were unimpaired on initial discrimination acquisition or retention of probabilistic learning. Taken together, these novel findings compliment other work discussed supporting a role for the LHb in action selection when cognitive or emotional demands are increased. Finally, we discuss future mechanisms by which a superior understanding of the LHb can be obtained through additional examination of behavioral flexibility tasks. PMID- 26582985 TI - Corticospinal excitability modulation in resting digit muscles during cyclical movement of the digits of the ipsilateral limb. AB - We investigated how corticospinal excitability of the resting digit muscles was modulated by the digit movement in the ipsilateral limb. Subjects performed cyclical extension-flexion movements of either the right toes or fingers. To determine whether corticospinal excitability of the resting digit muscles was modulated on the basis of movement direction or action coupling between ipsilateral digits, the right forearm was maintained in either the pronated or supinated position. During the movement, the motor evoked potential (MEP) elicited by transcranial magnetic stimulation (TMS) was measured from either the resting right finger extensor and flexor, or toe extensor and flexor. For both finger and toe muscles, independent of forearm position, MEP amplitude of the flexor was greater during ipsilateral digit flexion as compared to extension, and MEP amplitude of the extensor was greater during ipsilateral digit extension as compared to flexion. An exception was that MEP amplitude of the toe flexor with the supinated forearm did not differ between during finger extension and flexion. These findings suggest that digit movement modulates corticospinal excitability of the digits of the ipsilateral limb such that the same action is preferred. Our results provide evidence for a better understanding of neural interactions between ipsilateral limbs, and may thus contribute to neurorehabilitation after a stroke or incomplete spinal cord injury. PMID- 26582983 TI - Functional Connectivity Disruption in Neonates with Prenatal Marijuana Exposure. AB - Prenatal marijuana exposure (PME) is linked to neurobehavioral and cognitive impairments; however, findings in childhood and adolescence are inconsistent. Type-1 cannabinoid receptors (CB1R) modulate fetal neurodevelopment, mediating PME effects on growth of functional circuitry sub-serving behaviors critical for academic and social success. The purpose of this study was to investigate the effects of prenatal marijuana on development of early brain functional circuitry prior to prolonged postnatal environmental influences. We measured resting state functional connectivity during unsedated sleep in infants at 2-6 weeks (+MJ: 20 with PME in combination with nicotine, alcohol, opiates, and/or selective serotonin reuptake inhibitors; -MJ: 23 exposed to the same other drugs without marijuana, CTR: 20 drug-free controls). Connectivity of subcortical seed regions with high fetal CB1R expression was examined. Marijuana-specific differences were observed in insula and three striatal connections: anterior insula-cerebellum, right caudate-cerebellum, right caudate-right fusiform gyrus/inferior occipital, left caudate-cerebellum. +MJ neonates had hypo-connectivity in all clusters compared with -MJ and CTR groups. Altered striatal connectivity to areas involved in visual spatial and motor learning, attention, and in fine-tuning of motor outputs involved in movement and language production may contribute to neurobehavioral deficits reported in this at-risk group. Disrupted anterior insula connectivity may contribute to altered integration of interoceptive signals with salience estimates, motivation, decision-making, and later drug use. Compared with CTRs, both +MJ and -MJ groups demonstrated hyper-connectivity of left amygdala seed with orbital frontal cortex and hypo-connectivity of posterior thalamus seed with hippocampus, suggesting vulnerability to multiple drugs in these circuits. PMID- 26582984 TI - A hypothesis on improving foreign accents by optimizing variability in vocal learning brain circuits. AB - Rapid vocal motor learning is observed when acquiring a language in early childhood, or learning to speak another language later in life. Accurate pronunciation is one of the hardest things for late learners to master and they are almost always left with a non-native accent. Here, I propose a novel hypothesis that this accent could be improved by optimizing variability in vocal learning brain circuits during learning. Much of the neurobiology of human vocal motor learning has been inferred from studies on songbirds. Jarvis (2004) proposed the hypothesis that as in songbirds there are two pathways in humans: one for learning speech (the striatal vocal learning pathway), and one for production of previously learnt speech (the motor pathway). Learning new motor sequences necessary for accurate non-native pronunciation is challenging and I argue that in late learners of a foreign language the vocal learning pathway becomes inactive prematurely. The motor pathway is engaged once again and learners maintain their original native motor patterns for producing speech, resulting in speaking with a foreign accent. Further, I argue that variability in neural activity within vocal motor circuitry generates vocal variability that supports accurate non-native pronunciation. Recent theoretical and experimental work on motor learning suggests that variability in the motor movement is necessary for the development of expertise. I propose that there is little trial by-trial variability when using the motor pathway. When using the vocal learning pathway variability gradually increases, reflecting an exploratory phase in which learners try out different ways of pronouncing words, before decreasing and stabilizing once the "best" performance has been identified. The hypothesis proposed here could be tested using behavioral interventions that optimize variability and engage the vocal learning pathway for longer, with the prediction that this would allow learners to develop new motor patterns that result in more native-like pronunciation. PMID- 26582987 TI - Aesthetic perception of visual textures: a holistic exploration using texture analysis, psychological experiment, and perception modeling. AB - Modeling human aesthetic perception of visual textures is important and valuable in numerous industrial domains, such as product design, architectural design, and decoration. Based on results from a semantic differential rating experiment, we modeled the relationship between low-level basic texture features and aesthetic properties involved in human aesthetic texture perception. First, we compute basic texture features from textural images using four classical methods. These features are neutral, objective, and independent of the socio-cultural context of the visual textures. Then, we conduct a semantic differential rating experiment to collect from evaluators their aesthetic perceptions of selected textural stimuli. In semantic differential rating experiment, eights pairs of aesthetic properties are chosen, which are strongly related to the socio-cultural context of the selected textures and to human emotions. They are easily understood and connected to everyday life. We propose a hierarchical feed-forward layer model of aesthetic texture perception and assign 8 pairs of aesthetic properties to different layers. Finally, we describe the generation of multiple linear and non linear regression models for aesthetic prediction by taking dimensionality reduced texture features and aesthetic properties of visual textures as dependent and independent variables, respectively. Our experimental results indicate that the relationships between each layer and its neighbors in the hierarchical feed forward layer model of aesthetic texture perception can be fitted well by linear functions, and the models thus generated can successfully bridge the gap between computational texture features and aesthetic texture properties. PMID- 26582986 TI - Categorical discrimination of human body parts by magnetoencephalography. AB - Humans recognize body parts in categories. Previous studies have shown that responses in the fusiform body area (FBA) and extrastriate body area (EBA) are evoked by the perception of the human body, when presented either as whole or as isolated parts. These responses occur approximately 190 ms after body images are visualized. The extent to which body-sensitive responses show specificity for different body part categories remains to be largely clarified. We used a decoding method to quantify neural responses associated with the perception of different categories of body parts. Nine subjects underwent measurements of their brain activities by magnetoencephalography (MEG) while viewing 14 images of feet, hands, mouths, and objects. We decoded categories of the presented images from the MEG signals using a support vector machine (SVM) and calculated their accuracy by 10-fold cross-validation. For each subject, a response that appeared to be a body-sensitive response was observed and the MEG signals corresponding to the three types of body categories were classified based on the signals in the occipitotemporal cortex. The accuracy in decoding body-part categories (with a peak at approximately 48%) was above chance (33.3%) and significantly higher than that for random categories. According to the time course and location, the responses are suggested to be body-sensitive and to include information regarding the body-part category. Finally, this non-invasive method can decode category information of a visual object with high temporal and spatial resolution and this result may have a significant impact in the field of brain-machine interface research. PMID- 26582988 TI - Neurostereology protocol for unbiased quantification of neuronal injury and neurodegeneration. AB - Neuronal injury and neurodegeneration are the hallmark pathologies in a variety of neurological conditions such as epilepsy, stroke, traumatic brain injury, Parkinson's disease and Alzheimer's disease. Quantification of absolute neuron and interneuron counts in various brain regions is essential to understand the impact of neurological insults or neurodegenerative disease progression in animal models. However, conventional qualitative scoring-based protocols are superficial and less reliable for use in studies of neuroprotection evaluations. Here, we describe an optimized stereology protocol for quantification of neuronal injury and neurodegeneration by unbiased counting of neurons and interneurons. Every 20th section in each series of 20 sections was processed for NeuN(+) total neuron and parvalbumin(+) interneuron immunostaining. The sections that contain the hippocampus were then delineated into five reliably predefined subregions. Each region was separately analyzed with a microscope driven by the stereology software. Regional tissue volume was determined by using the Cavalieri estimator, as well as cell density and cell number were determined by using the optical disector and optical fractionator. This protocol yielded an estimate of 1.5 million total neurons and 0.05 million PV(+) interneurons within the rat hippocampus. The protocol has greater predictive power for absolute counts as it is based on 3D features rather than 2D images. The total neuron counts were consistent with literature values from sophisticated systems, which are more expensive than our stereology system. This unbiased stereology protocol allows for sensitive, medium-throughput counting of total neurons in any brain region, and thus provides a quantitative tool for studies of neuronal injury and neurodegeneration in a variety of acute brain injury and chronic neurological models. PMID- 26582989 TI - HDL and glucose metabolism: current evidence and therapeutic potential. AB - High-density lipoprotein (HDL) and its principal apolipoprotein A-I (ApoA-I) have now been convincingly shown to influence glucose metabolism through multiple mechanisms. The key clinically relevant observations are that both acute HDL elevation via short-term reconstituted HDL (rHDL) infusion and chronically raising HDL via a cholesteryl ester transfer protein (CETP) inhibitor reduce blood glucose in individuals with type 2 diabetes mellitus (T2DM). HDL may mediate effects on glucose metabolism through actions in multiple organs (e.g., pancreas, skeletal muscle, heart, adipose, liver, brain) by three distinct mechanisms: (i) Insulin secretion from pancreatic beta cells, (ii) Insulin independent glucose uptake, (iii) Insulin sensitivity. The molecular mechanisms appear to involve both direct HDL signaling actions as well as effects secondary to lipid removal from cells. The implications of glucoregulatory mechanisms linked to HDL extend from glycemic control to potential anti-ischemic actions via increased tissue glucose uptake and utilization. Such effects not only have implications for the prevention and management of diabetes, but also for ischemic vascular diseases including angina pectoris, intermittent claudication, cerebral ischemia and even some forms of dementia. This review will discuss the growing evidence for a role of HDL in glucose metabolism and outline related potential for HDL therapies. PMID- 26582990 TI - Peroxisome proliferator-activated receptor alpha, PPARalpha, directly regulates transcription of cytochrome P450 CYP2C8. AB - The cytochrome P450, CYP2C8, metabolizes more than 60 clinically used drugs as well as endogenous substances including retinoic acid and arachidonic acid. However, predictive factors for interindividual variability in the efficacy and toxicity of CYP2C8 drug substrates are essentially lacking. Recently we demonstrated that peroxisome proliferator-activated receptor alpha (PPARalpha), a nuclear receptor primarily involved in control of lipid and energy homeostasis directly regulates the transcription of CYP3A4. Here we investigated the potential regulation of CYP2C8 by PPARalpha. Two linked intronic SNPs in PPARalpha (rs4253728, rs4823613) previously associated with hepatic CYP3A4 status showed significant association with CYP2C8 protein level in human liver samples (N = 150). Furthermore, siRNA-mediated knock-down of PPARalpha in HepaRG human hepatocyte cells resulted in up to ~60 and ~50% downregulation of CYP2C8 mRNA and activity, while treatment with the PPARalpha agonist WY14,643 lead to an induction by >150 and >100%, respectively. Using chromatin immunoprecipitation scanning assay we identified a specific upstream gene region that is occupied in vivo by PPARalpha. Electromobility shift assay demonstrated direct binding of PPARalpha to a DR-1 motif located at positions -2762/-2775 bp upstream of the CYP2C8 transcription start site. We further validated the functional activity of this element using luciferase reporter gene assays in HuH7 cells. Moreover, based on our previous studies we demonstrated that WNT/beta-catenin acts as a functional inhibitor of PPARalpha-mediated inducibility of CYP2C8 expression. In conclusion, our data suggest direct involvement of PPARalpha in both constitutive and inducible regulation of CYP2C8 expression in human liver, which is further modulated by WNT/beta-catenin pathway. PPARA gene polymorphism could have a modest influence on CYP2C8 phenotype. PMID- 26582991 TI - No-dependent signaling pathways in unloaded skeletal muscle. AB - The main focus of the current review is the nitric oxide (NO)-mediated signaling mechanism in unloaded skeletal. Review of the published data describing muscles during physical activity and inactivity demonstrates that NO is an essential trigger of signaling processes, which leads to structural and metabolic changes of the muscle fibers. The experiments with modulation of NO-synthase (NOS) activity during muscle unloading demonstrate the ability of an activated enzyme to stabilize degradation processes and prevent development of muscle atrophy. Various forms of muscle mechanical activity, i.e., plantar afferent stimulation, resistive exercise and passive chronic stretch increase the content of neural NOS (nNOS) and thus may facilitate an increase in NO production. Recent studies demonstrate that NO-synthase participates in the regulation of protein and energy metabolism in skeletal muscle by fine-tuning and stabilizing complex signaling systems which regulate protein synthesis and degradation in the fibers of inactive muscle. PMID- 26582992 TI - Protective effects of intermittent hypoxia on brain and memory in a mouse model of apnea of prematurity. AB - Apnea of prematurity (AOP) is considered a risk factor for neurodevelopmental disorders in children based on epidemiological studies. This idea is supported by studies in newborn rodents in which exposure to intermittent hypoxia (IH) as a model of AOP significantly impairs development. However, the severe IH used in these studies may not fully reflect the broad spectrum of AOP severity. Considering that hypoxia appears neuroprotective under various conditions, we hypothesized that moderate IH would protect the neonatal mouse brain against behavioral stressors and brain damage. On P6, each pup in each litter was randomly assigned to one of three groups: a group exposed to IH while separated from the mother (IH group), a control group exposed to normoxia while separated from the mother (AIR group), and a group of untreated unmanipulated pups left continuously with their mother until weaning (UNT group). Exposure to moderate IH (8% O2) consisted of 20 hypoxic events/hour, 6 h per day from postnatal day 6 (P6) to P10. The stress generated by maternal separation in newborn rodents is known to impair brain development, and we expected this effect to be smaller in the IH group compared to the AIR group. In a separate experiment, we combined maternal separation with excitotoxic brain lesions mimicking those seen in preterm infants. We analyzed memory, angiogenesis, neurogenesis and brain lesion size. In non-lesioned mice, IH stimulated hippocampal angiogenesis and neurogenesis and improved short-term memory indices. In brain-lesioned mice, IH decreased lesion size and prevented memory impairments. Contrary to common perception, IH mimicking moderate apnea may offer neuroprotection, at least in part, against brain lesions and cognitive dysfunctions related to prematurity. AOP may therefore have beneficial effects in some preterm infants. These results support the need for stratification based on AOP severity in clinical trials of treatments for AOP, to determine whether in patients with moderate AOP, these treatments are beneficial or deleterious. PMID- 26582993 TI - Negative response of photosynthesis to natural and projected high seawater temperatures estimated by pulse amplitude modulation fluorometry in a temperate coral. AB - Balanophyllia europaea is a shallow water solitary zooxanthellate coral, endemic to the Mediterranean Sea. Extensive field studies across a latitudinal temperature gradient highlight detrimental effects of rising temperatures on its growth, demography, and skeletal characteristics, suggesting that depression of photosynthesis at high temperatures might cause these negative effects. Here we test this hypothesis by analyzing, by means of pulse amplitude modulation fluorometry, the photosynthetic efficiency of B. europaea specimens exposed in aquaria to the annual range of temperatures experienced in the field (13, 18, and 28 degrees C), and two extreme temperatures expected for 2100 as a consequence of global warming (29 and 32 degrees C). The indicators of photosynthetic performance analyzed (maximum and effective quantum yield) showed that maximum efficiency was reached at 20.0-21.6 degrees C, slightly higher than the annual mean temperature in the field (18 degrees C). Photosynthetic efficiency decreased from 20.0 to 13 degrees C and even more strongly from 21.6 to 32 degrees C. An unusual form of bleaching was observed, with a maximum zooxanthellae density at 18 degrees C that strongly decreased from 18 to 32 degrees C. Chlorophyll a concentration per zooxanthellae cell showed an opposite trend as it was minimal at 18 degrees C and increased from 18 to 32 degrees C. Since the areal chlorophyll concentration is the product of the zooxanthellae density and its cellular content, these trends resulted in a homogeneous chlorophyll concentration per coral surface across temperature treatments. This confirms that B. europaea photosynthesis is progressively depressed at temperatures >21.6 degrees C, supporting previous hypotheses raised by the studies on growth and demography of this species. This study also confirms the threats posed to this species by the ongoing seawater warming. PMID- 26582994 TI - Negative and positive externalities in intergroup conflict: exposure to the opportunity to help the outgroup reduces the inclination to harm it. AB - Outgroup hate, in the context of intergroup conflict, can be expressed by harming the outgroup, but also by denying it help. Previous work established that this distinction-whether the externality on the outgroup is negative or positive-has an important effect on the likelihood of outgroup hate emerging as a motivation for individual participation in intergroup conflict. The current work uses a within-subject design to examine the behavior of the same individuals in intergroup conflict with negative and positive externalities on the outgroup. Each participant made two choices, one for each type of externality, and the order was counter balanced. The main results are that (1) behavior is fairly consistent across negative and positive externalities, i.e., the tendency to display outgroup hate by harming the outgroup is correlated with the tendency to display outgroup hate by avoiding to help the outgroup; (2) People are reluctant to harm the outgroup after being exposed to the opportunity to help it; (3) Groupness-the degree to which people care about their group and its well-being-is related to outgroup hate only when participants encounter the opportunity to harm the outgroup first (before they encounter the opportunity to help it). In this setting the relationship between groupness and outgroup hate spilled over to the subsequent interaction, where it was possible to help the outgroup. When the opportunity to help the outgroup was encountered first, groupness was not related to outgroup hate. PMID- 26582995 TI - An evaluation of neurocognitive models of theory of mind. AB - We review nine current neurocognitive theories of how theory of mind (ToM) is implemented in the brain and evaluate them based on the results from a recent meta-analysis by Schurz et al. (2014), where we identified six types of tasks that are the most frequently used in imaging research on ToM. From theories about cognitive processes being associated with certain brain areas, we deduce predictions about which areas should be engaged by the different types of ToM tasks. We then compare these predictions with the observed activations in the meta-analysis, and identify a number of unexplained findings in current theories. These can be used to revise and improve future neurocognitive accounts of ToM. PMID- 26582996 TI - Capturing socially motivated linguistic change: how the use of gender-fair language affects support for social initiatives in Austria and Poland. AB - Gender-fair language consists of the symmetric linguistic treatment of women and men instead of using masculine forms as generics. In this study, we examine how the use of gender-fair language affects readers' support for social initiatives in Poland and Austria. While gender-fair language is relatively novel in Poland, it is well established in Austria. This difference may lead to different perceptions of gender-fair usage in these speech communities. Two studies conducted in Poland investigate whether the evaluation of social initiatives (Study 1: quotas for women on election lists; Study 2: support for women students or students from countries troubled by war) is affected by how female proponents (lawyers, psychologists, sociologists, and academics) are referred to, with masculine forms (traditional) or with feminine forms (modern, gender-fair). Study 3 replicates Study 2 in Austria. Our results indicate that in Poland, gender-fair language has negative connotations and therefore, detrimental effects particularly when used in gender-related contexts. Conversely, in Austria, where gender-fair language has been implemented and used for some time, there are no such negative effects. This pattern of results may inform the discussion about formal policies regulating the use of gender-fair language. PMID- 26582997 TI - Language may indeed influence thought. AB - We discuss four interconnected issues that we believe have hindered investigations into how language may affect thinking. These have had a tendency to reappear in the debate concerning linguistic relativity over the past decades, despite numerous empirical findings. The first is the claim that it is impossible to disentangle language from thought, making the question concerning "influence" pointless. The second is the argument that it is impossible to disentangle language from culture in general, and from social interaction in particular, so it is impossible to attribute any differences in the thought patterns of the members of different cultures to language per se. The third issue is the objection that methodological and empirical problems defeat all but the most trivial version of the thesis of linguistic influence: that language gives new factual information. The fourth is the assumption that since language can potentially influence thought from "not at all" to "completely," the possible forms of linguistic influence can be placed on a cline, and competing theories can be seen as debating the actual position on this cline. We analyze these claims and show that the first three do not constitute in-principle objections against the validity of the project of investigating linguistic influence on thought, and that the last one is not the best way to frame the empirical challenges at hand. While we do not argue for any specific theory or mechanism for linguistic influence on thought, our discussion and the reviewed literature show that such influence is clearly possible, and hence in need of further investigations. PMID- 26582998 TI - Ghost-in-the-Machine reveals human social signals for human-robot interaction. AB - We used a new method called "Ghost-in-the-Machine" (GiM) to investigate social interactions with a robotic bartender taking orders for drinks and serving them. Using the GiM paradigm allowed us to identify how human participants recognize the intentions of customers on the basis of the output of the robotic recognizers. Specifically, we measured which recognizer modalities (e.g., speech, the distance to the bar) were relevant at different stages of the interaction. This provided insights into human social behavior necessary for the development of socially competent robots. When initiating the drink-order interaction, the most important recognizers were those based on computer vision. When drink orders were being placed, however, the most important information source was the speech recognition. Interestingly, the participants used only a subset of the available information, focussing only on a few relevant recognizers while ignoring others. This reduced the risk of acting on erroneous sensor data and enabled them to complete service interactions more swiftly than a robot using all available sensor data. We also investigated socially appropriate response strategies. In their responses, the participants preferred to use the same modality as the customer's requests, e.g., they tended to respond verbally to verbal requests. Also, they added redundancy to their responses, for instance by using echo questions. We argue that incorporating the social strategies discovered with the GiM paradigm in multimodal grammars of human-robot interactions improves the robustness and the ease-of-use of these interactions, and therefore provides a smoother user experience. PMID- 26582999 TI - From biomechanics to sport psychology: the current oscillatory approach. PMID- 26583000 TI - Socio-motivational moderators-two sides of the same coin? Testing the potential buffering role of socio-motivational relationships on achievement drive and test anxiety among German and Canadian secondary school students. AB - The current cross-national study investigates the potential buffering role of socio-motivational relationships for the association of achievement drive (AD) and test anxiety (TX) in secondary school students from Canada and Germany. One thousand and eighty-eight students (54% girls, M age = 13.71, SD = 0.53, age span 12-15 years) from the state of Brandenburg and 389 students from Quebec (55.9% girls, M age = 13.43, SD = 0.82, age span 12-16 years) were asked about their socio-motivational relationships with their teachers and peers, their drive for achievement, and TX. Multigroup latent moderated structural equations were conducted to test for the moderator role of socio-motivational relationships that would buffer feelings of TX related to the drive for achievement. The analyses revealed the two-sided role socio-motivational relationships can have for students with different levels of AD; intensifying or mitigating feelings of TX. Thereby, the results of this study extend the buffering hypothesis by Cohen and Wills (1985). Cross-national differences between Canada and Germany were found concerning the studied moderators on the association of AD and TX: While for German students teacher-student relationships acted as moderator, for Canadian students student-student relationships and teachers acting as positive motivators displayed a moderator role. PMID- 26583001 TI - Revisiting the empirical case against perceptual modularity. AB - Some theorists hold that the human perceptual system has a component that receives input only from units lower in the perceptual hierarchy. This thesis, that we shall here refer to as the encapsulation thesis, has been at the center of a continuing debate for the past few decades. Those who deny the encapsulation thesis often rely on the large body of psychological findings that allegedly suggest that perception is influenced by factors such as the beliefs, desires, goals, and the expectations of the perceiver. Proponents of the encapsulation thesis, however, often argue that, when correctly interpreted, these psychological findings are compatible with the thesis. In our view, the debate over the significance and the correct interpretation of these psychological findings has reached an impasse. We hold that this impasse is due to the methodological limitations over psychophysical experiments, and it is very unlikely that such experiments, on their own, could yield results that would settle the debate. After defending this claim, we argue that integrating data from cognitive neuroscience resolves the debate in favor of those who deny the encapsulation thesis. PMID- 26583002 TI - Quantifying the Ebbinghaus figure effect: target size, context size, and target context distance determine the presence and direction of the illusion. AB - Over the last 20 years, visual illusions, like the Ebbinghaus figure, have become widespread to investigate functional segregation of the visual system. This segregation reveals itself, so it is claimed, in the insensitivity of movement to optical illusions. This claim, however, faces contradictory results (and interpretations) in the literature. These contradictions may be due to methodological weaknesses in, and differences across studies, some of which may hide a lack of perceptual illusion effects. Indeed, despite the long history of research with the Ebbinghaus figure, standardized configurations to predict the illusion effect are missing. Here, we present a complete geometrical description of the Ebbinghaus figure with three target sizes compatible with Fitts' task. Each trial consisted of a stimulus and an isolated probe. The probe was controlled by the participant's response through a staircase procedure. The participant was asked whether the probe or target appeared bigger. The factors target size, context size, target-context distance, and a control condition resulted in a 3 * 3 * 3+3 factorial design. The results indicate that the illusion magnitude, the perceptual distinctiveness, and the response time depend on the context size, distance, and especially, target size. In 33% of the factor combinations there was no illusion effect. The illusion magnitude ranged from zero to (exceptionally) 10% of the target size. The small (or absent) illusion effects on perception and its possible influence on motor tasks might have been overlooked or misinterpreted in previous studies. Our results provide a basis for the application of the Ebbinghaus figure in psychophysical and motor control studies. PMID- 26583004 TI - A trait profile of top and middle managers. PMID- 26583003 TI - Processing of masked and unmasked emotional faces under different attentional conditions: an electrophysiological investigation. AB - In order to investigate the interactions between non-spatial selective attention, awareness and emotion processing, we carried out an ERP study using a backward masking paradigm, in which angry, fearful, happy, and neutral facial expressions were presented, while participants attempted to detect the presence of one or the other category of facial expressions in the different experimental blocks. ERP results showed that negative emotions enhanced an early N170 response over temporal-occipital leads in both masked and unmasked conditions, independently of selective attention. A later effect arising at the P2 was linked to awareness. Finally, selective attention was found to affect the N2 and N3 components over occipito-parietal leads. Our findings reveal that (i) the initial processing of facial expressions arises prior to attention and awareness; (ii) attention and awareness give rise to temporally distinct periods of activation independently of the type of emotion with only a partial degree of overlap; and (iii) selective attention appears to be influenced by the emotional nature of the stimuli, which in turn impinges on unconscious processing at a very early stage. This study confirms previous reports that negative facial expressions can be processed rapidly, in absence of visual awareness and independently of selective attention. On the other hand, attention and awareness may operate in a synergistic way, depending on task demand. PMID- 26583005 TI - Language or motor: reviewing categorical etiologies of speech sound disorders. PMID- 26583006 TI - Whole genome investigation of a divergent clade of the pathogen Streptococcus suis. AB - Streptococcus suis is a major porcine and zoonotic pathogen responsible for significant economic losses in the pig industry and an increasing number of human cases. Multiple isolates of S. suis show marked genomic diversity. Here, we report the analysis of whole genome sequences of nine pig isolates that caused disease typical of S. suis and had phenotypic characteristics of S. suis, but their genomes were divergent from those of many other S. suis isolates. Comparison of protein sequences predicted from divergent genomes with those from normal S. suis reduced the size of core genome from 793 to only 397 genes. Divergence was clear if phylogenetic analysis was performed on reduced core genes and MLST alleles. Phylogenies based on certain other genes (16S rRNA, sodA, recN, and cpn60) did not show divergence for all isolates, suggesting recombination between some divergent isolates with normal S. suis for these genes. Indeed, there is evidence of recent recombination between the divergent and normal S. suis genomes for 249 of 397 core genes. In addition, phylogenetic analysis based on the 16S rRNA gene and 132 genes that were conserved between the divergent isolates and representatives of the broader Streptococcus genus showed that divergent isolates were more closely related to S. suis. Six out of nine divergent isolates possessed a S. suis-like capsule region with variation in capsular gene sequences but the remaining three did not have a discrete capsule locus. The majority (40/70), of virulence-associated genes in normal S. suis were present in the divergent genomes. Overall, the divergent isolates extend the current diversity of S. suis species but the phenotypic similarities and the large amount of gene exchange with normal S. suis gives insufficient evidence to assign these isolates to a new species or subspecies. Further, sampling and whole genome analysis of more isolates is warranted to understand the diversity of the species. PMID- 26583007 TI - Identification and significance of Weissella species infections. AB - Weissella spp. are non-spore forming, catalase-negative, gram-positive coccobacilli. They are often misidentified by traditional and commercial phenotypic identification methods as Lactobacillus spp. or Lactobacillus-like organisms. Weissella spp. were previously grouped along with Lactobacillus spp., Leuconostoc spp., and Pediococcus spp. Utilization of more sensitive methods like DNA sequencing or Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF MS) has facilitated identification of Weissella as a unique genus. Nineteen species have been identified to date. W. confusa, W. cibaria, and W. viridescens are the only species isolated from humans. The true prevalence of Weissella spp. continues to be probably underestimated. Weissella spp. strains have been isolated from a wide range of habitats including raw milk, feces, fermented cereals, and vegetables. Weisella is believed to be a rare cause of usually nonfatal infections in humans, and is often considered a contaminant. However, in recent years, Weissella spp. have been implicated in bacteremia, abscesses, prosthetic joint infections, and infective endocarditis. Alterations of the gut flora from surgery or chemotherapy are believed to facilitate translocation of Weissella spp. due to disruption of the mucosal barrier, predisposing the host to infection with this organism. Implications of the isolation of Weissella spp. from blood must be interpreted in context of underlying risk factors. Weissella spp. are inherently resistant to vancomycin. Therefore, early consideraton of the pathogenic role of this bacteria and choice of alternate therapy is important to assure better outcomes. PMID- 26583008 TI - Comparative metagenomics reveals impact of contaminants on groundwater microbiomes. AB - To understand patterns of geochemical cycling in pristine versus contaminated groundwater ecosystems, pristine shallow groundwater (FW301) and contaminated groundwater (FW106) samples from the Oak Ridge Integrated Field Research Center (OR-IFRC) were sequenced and compared to each other to determine phylogenetic and metabolic difference between the communities. Proteobacteria (e.g., Burkholderia, Pseudomonas) are the most abundant lineages in the pristine community, though a significant proportion ( >55%) of the community is composed of poorly characterized low abundance (individually <1%) lineages. The phylogenetic diversity of the pristine community contributed to a broader diversity of metabolic networks than the contaminated community. In addition, the pristine community encodes redundant and mostly complete geochemical cycles distributed over multiple lineages and appears capable of a wide range of metabolic activities. In contrast, many geochemical cycles in the contaminated community appear truncated or minimized due to decreased biodiversity and dominance by Rhodanobacter populations capable of surviving the combination of stresses at the site. These results indicate that the pristine site contains more robust and encodes more functional redundancy than the stressed community, which contributes to more efficient nutrient cycling and adaptability than the stressed community. PMID- 26583009 TI - Survival of free-living Acholeplasma in aerated pig manure slurry revealed by (13)C-labeled bacterial biomass probing. AB - Many studies have been performed on microbial community succession and/or predominant taxa during the composting process; however, the ecophysiological roles of microorganisms are not well understood because microbial community structures are highly diverse and dynamic. Bacteria are the most important contributors to the organic-waste decomposition process, while decayed bacterial cells can serve as readily digested substrates for other microbial populations. In this study, we investigated the active bacterial species responsible for the assimilation of dead bacterial cells and their components in aerated pig manure slurry by using (13)C-labeled bacterial biomass probing. After 3 days of forced aeration, (13)C-labeled and unlabeled dead Escherichia coli cell suspensions were added to the slurry. The suspensions contained (13)C-labeled and unlabeled bacterial cell components, possibly including the cell wall and membrane, as well as intracellular materials. RNA extracted from each slurry sample 2 h after addition of E. coli suspension was density-resolved by isopycnic centrifugation and analyzed by terminal restriction fragment length polymorphism, followed by cloning and sequencing of bacterial 16S rRNA genes. In the heavy isotopically labeled RNA fraction, the predominant (13)C-assimilating population was identified as belonging to the genus Acholeplasma, which was not detected in control heavy RNA. Acholeplasma spp. have limited biosynthetic capabilities and possess a wide variety of transporters, resulting in their metabolic dependence on external carbon and energy sources. The prevalence of Acholeplasma spp. was further confirmed in aerated pig manure slurry from four different pig farms by pyrosequencing of 16S rRNA genes; their relative abundance was ~4.4%. Free-living Acholeplasma spp. had a competitive advantage for utilizing dead bacterial cells and their components more rapidly relative to other microbial populations, thus allowing the survival and prevalence of Acholeplasma spp. in pig manure slurry. PMID- 26583010 TI - Systemic colonization of clover (Trifolium repens) by Clostridium botulinum strain 2301. AB - In recent years, cases of botulism in cattle and other farm animals and also in farmers increased dramatically. It was proposed, that these cases could be affiliated with the spreading of compost or other organic manures contaminated with Clostridium botulinum spores on farm land. Thus, soils and fodder plants and finally farm animals could be contaminated. Therefore, the colonization behavior and interaction of the botulinum neurotoxin (BoNT D) producing C. botulinum strain 2301 and the non-toxin producing Clostridium sporogenes strain 1739 were investigated on clover (Trifolium repens) in a field experiment as well as in phytochamber experiments applying axenic and additionally soil based systems under controlled conditions. Plants were harvested and divided into root and shoot parts for further DNA isolation and polymerase chain reaction (PCR) assays; subsamples were fixed for fluorescence in situ hybridization analysis in combination with confocal laser scanning microscopy. In addition, we observed significant differences in the growth behavior of clover plants when inoculated with clostridial spores, indicating a plant growth promoting effect. Inoculated plants showed an increased growth index (shoot size, wet and dry weight) and an enlarged root system induced by the systemic colonization of clover by C. botulinum strain 2301. To target C. botulinum and C. sporogenes, 16S rDNA directed primers were used and to specifically detect C. botulinum, BoNT D toxin genes targeted primers, using a multiplex PCR approach, were applied. Our results demonstrate an effective colonization of roots and shoots of clover by C. botulinum strain 2301 and C. sporogenes strain 1739. Detailed analysis of colonization behavior showed that C. botulinum can occur as individual cells, in cell clusters and in microcolonies within the rhizosphere, lateral roots and within the roots tissue of clover. PMID- 26583011 TI - The role of biofilms as environmental reservoirs of antibiotic resistance. AB - Antibiotic resistance has become a significant and growing threat to public and environmental health. To face this problem both at local and global scales, a better understanding of the sources and mechanisms that contribute to the emergence and spread of antibiotic resistance is required. Recent studies demonstrate that aquatic ecosystems are reservoirs of resistant bacteria and antibiotic resistance genes as well as potential conduits for their transmission to human pathogens. Despite the wealth of information about antibiotic pollution and its effect on the aquatic microbial resistome, the contribution of environmental biofilms to the acquisition and spread of antibiotic resistance has not been fully explored in aquatic systems. Biofilms are structured multicellular communities embedded in a self-produced extracellular matrix that acts as a barrier to antibiotic diffusion. High population densities and proximity of cells in biofilms also increases the chances for genetic exchange among bacterial species converting biofilms in hot spots of antibiotic resistance. This review focuses on the potential effect of antibiotic pollution on biofilm microbial communities, with special emphasis on ecological and evolutionary processes underlying acquired resistance to these compounds. PMID- 26583012 TI - Exposure to pairs of Aeromonas strains enhances virulence in the Caenorhabditis elegans infection model. AB - Aeromonad virulence remains poorly understood, and is difficult to predict from strain characteristics. In addition, infections are often polymicrobial (i.e., are mixed infections), and 5-10% of such infections include two distinct aeromonads, which has an unknown impact on virulence. In this work, we studied the virulence of aeromonads recovered from human mixed infections. We tested them individually and in association with other strains with the aim of improving our understanding of aeromonosis. Twelve strains that were recovered in pairs from six mixed infections were tested in a virulence model of the worm Caenorhabditis elegans. Nine isolates were weak worm killers (median time to death, TD50, >=7 days) when administered alone. Two pairs showed enhanced virulence, as indicated by a significantly shortened TD50 after co-infection vs. infection with a single strain. Enhanced virulence was also observed for five of the 14 additional experimental pairs, and each of these pairs included one strain from a natural synergistic pair. These experiments indicated that synergistic effects were frequent and were limited to pairs that were composed of strains belonging to different species. The genome content of virulence-associated genes failed to explain virulence synergy, although some virulence-associated genes that were present in some strains were absent from their companion strain (e.g., T3SS). The synergy observed in virulence when two Aeromonas isolates were co-infected stresses the idea that consideration should be given to the fact that infection does not depend only on single strain virulence but is instead the result of a more complex interaction between the microbes involved, the host and the environment. These results are of interest for other diseases in which mixed infections are likely and in particular for water-borne diseases (e.g., legionellosis, vibriosis), in which pathogens may display enhanced virulence in the presence of the right partner. This study contributes to the current shift in infectiology paradigms from a premise that assumes a monomicrobial origin for infection to one more in line with the current pathobiome era. PMID- 26583013 TI - A cell-free enzymatic activity assay for the evaluation of HIV-1 drug resistance to protease inhibitors. AB - Due to their high frequency of genomic mutations, human retroviruses often develop resistance to antiretroviral drugs. The emergence of drug-resistant human immunodeficiency virus type 1 (HIV-1) is a significant obstacle to the effective long-term treatment of HIV infection. The development of a rapid and versatile drug-susceptibility assay would enable acquisition of phenotypic information and facilitate determination of the appropriate choice of antiretroviral agents. In this study, we developed a novel in vitro method, termed the Cell-free drug susceptibility assay (CFDSA), for monitoring phenotypic information regarding the drug resistance of HIV-1 protease (PR). The CFDSA utilizes a wheat germ cell-free protein production system to synthesize enzymatically active HIV-1 PRs directly from PCR products amplified from HIV-1 molecular clones or clinical isolates in a rapid one-step procedure. Enzymatic activity of PRs can be readily measured by AlphaScreen (Amplified Luminescent Proximity Homogeneous Assay Screen) in the presence or absence of clinically used protease inhibitors (PIs). CFDSA measurement of drug resistance was based on the fold resistance to the half maximal inhibitory concentration (IC50) of various PIs. The CFDSA could serve as a non-infectious, rapid, accessible, and reliable alternative to infectious cell based phenotypic assays for evaluation of PI-resistant HIV-1. PMID- 26583014 TI - Self-healing of early age cracks in cement-based materials by mineralization of carbonic anhydrase microorganism. AB - This research investigated the self-healing potential of early age cracks in cement-based materials incorporating the bacteria which can produce carbonic anhydrase. Cement-based materials specimens were pre-cracked at the age of 7, 14, 28, 60 days to study the repair ability influenced by cracking time, the width of cracks were between 0.1 and 1.0 mm to study the healing rate influenced by width of cracks. The experimental results indicated that the bacteria showed excellent repairing ability to small cracks formed at early age of 7 days, cracks below 0.4 mm was almost completely closed. The repair effect reduced with the increasing of cracking age. Cracks width influenced self-healing effectiveness significantly. The transportation of CO2and Ca(2+) controlled the self-healing process. The computer simulation analyses revealed the self-healing process and mechanism of microbiologically precipitation induced by bacteria and the depth of precipitated CaCO3 could be predicted base on valid Ca(2+). PMID- 26583015 TI - Self-protected nitrate reducing culture for intrinsic repair of concrete cracks. AB - Attentive monitoring and regular repair of concrete cracks are necessary to avoid further durability problems. As an alternative to current maintenance methods, intrinsic repair systems which enable self-healing of cracks have been investigated. Exploiting microbial induced CaCO3 precipitation (MICP) using (protected) axenic cultures is one of the proposed methods. Yet, only a few of the suggested healing agents were economically feasible for in situ application. This study presents a [Formula: see text] reducing self-protected enrichment culture as a self-healing additive for concrete. Concrete admixtures Ca(NO3)2 and Ca(HCOO)2 were used as nutrients. The enrichment culture, grown as granules (0.5 2 mm) consisting of 70% biomass and 30% inorganic salts were added into mortar without any additional protection. Upon 28 days curing, mortar specimens were subjected to direct tensile load and multiple cracks (0.1-0.6 mm) were achieved. Cracked specimens were immersed in water for 28 days and effective crack closure up to 0.5 mm crack width was achieved through calcite precipitation. Microbial activity during crack healing was monitored through weekly NOx analysis which revealed that 92 +/- 2% of the available [Formula: see text] was consumed. Another set of specimens were cracked after 6 months curing, thus the effect of curing time on healing efficiency was investigated, and mineral formation at the inner crack surfaces was observed, resulting in 70% less capillary water absorption compared to healed control specimens. In conclusion, enriched mixed denitrifying cultures structured in self-protecting granules are very promising strategies to enhance microbial self-healing. PMID- 26583017 TI - Mycotoxins are a component of Fusarium graminearum stress-response system. PMID- 26583018 TI - Stable transformation and expression of GhEXPA8 fiber expansin gene to improve fiber length and micronaire value in cotton. AB - Cotton fiber is multigenic trait controlled by number of genes. Previous studies suggest that one of these genes may be responsible for switching cotton fiber growth on and off to influence the fiber quality produced from a cotton seed. In the present study, the Gossypium hirsutum GhEXPA8 fiber expansin gene was introduced into local cotton variety NIAB 846 by using an Agrobacterium-mediated gene transformation. The neomycin phosphotransferase (NPTII) gene was used as a selection marker for screening of putative transgenic cotton plants. Integration and expression of the fiber expansin gene in cotton plants was confirmed with molecular techniques including Southern blot analyses, real-time PCR. Cellulose assay was used for measurement of cellulose contents of transgenic cotton fiber. The data collected from 3 years of field performance of the transgenic cotton plants expressing GhEXPA8 showed that significant improvement has been made in fiber lengths and micronaire values as compared to control G. hirsutum variety NIAB 846 cotton plants. Statistical techniques were also used for analysis of fiber and agronomic characteristics. The results of this study support improvement of cotton fiber through genetic modification. PMID- 26583016 TI - Heroin inhibits HIV-restriction miRNAs and enhances HIV infection of macrophages. AB - Although opioids have been extensively studied for their impact on the immune system, limited information is available about the specific actions of opioids on intracellular antiviral innate immunity against HIV infection. Thus, we investigated whether heroin, one of the most abused drugs, inhibits the expression of intracellular HIV restriction microRNA (miRNA) and facilitates HIV replication in macrophages. Heroin treatment of macrophages enhanced HIV replication, which was associated with the downregulation of several HIV restriction miRNAs. These heroin-mediated actions on the miRNAs and HIV could be antagonized by naltrexone, an opioid receptor antagonist. Furthermore, the in vitro negative impact of heroin on HIV-associated miRNAs was confirmed by the in vivo observation that heroin addicts had significantly lower levels of macrophage derived HIV restriction miRNAs than those in the control subjects. These in vitro and in vivo findings indicate that heroin use compromises intracellular anti-HIV innate immunity, providing a favorable microenvironment for HIV survival in the target cells. PMID- 26583019 TI - Transcriptome analysis reveals regulatory networks underlying differential susceptibility to Botrytis cinerea in response to nitrogen availability in Solanum lycopersicum. AB - Nitrogen (N) is one of the main limiting nutrients for plant growth and crop yield. It is well documented that changes in nitrate availability, the main N source found in agricultural soils, influences a myriad of developmental programs and processes including the plant defense response. Indeed, many agronomical reports indicate that the plant N nutritional status influences their ability to respond effectively when challenged by different pathogens. However, the molecular mechanisms involved in N-modulation of plant susceptibility to pathogens are poorly characterized. In this work, we show that Solanum lycopersicum defense response to the necrotrophic fungus Botrytis cinerea is affected by plant N availability, with higher susceptibility in nitrate-limiting conditions. Global gene expression responses of tomato against B. cinerea under contrasting nitrate conditions reveals that plant primary metabolism is affected by the fungal infection regardless of N regimes. This result suggests that differential susceptibility to pathogen attack under contrasting N conditions is not only explained by a metabolic alteration. We used a systems biology approach to identify the transcriptional regulatory network implicated in plant response to the fungus infection under contrasting nitrate conditions. Interestingly, hub genes in this network are known key transcription factors involved in ethylene and jasmonic acid signaling. This result positions these hormones as key integrators of nitrate and defense against B. cinerea in tomato plants. Our results provide insights into potential crosstalk mechanisms between necrotrophic defense response and N status in plants. PMID- 26583020 TI - Sunflower centromeres consist of a centromere-specific LINE and a chromosome specific tandem repeat. AB - The kinetochore is a protein complex including kinetochore-specific proteins that plays a role in chromatid segregation during mitosis and meiosis. The complex associates with centromeric DNA sequences that are usually species-specific. In plant species, tandem repeats including satellite DNA sequences and retrotransposons have been reported as centromeric DNA sequences. In this study on sunflowers, a cDNA-encoding centromere-specific histone H3 (CENH3) was isolated from a cDNA pool from a seedling, and an antibody was raised against a peptide synthesized from the deduced cDNA. The antibody specifically recognized the sunflower CENH3 (HaCENH3) and showed centromeric signals by immunostaining and immunohistochemical staining analysis. The antibody was also applied in chromatin immunoprecipitation (ChIP)-Seq to isolate centromeric DNA sequences and two different types of repetitive DNA sequences were identified. One was a long interspersed nuclear element (LINE)-like sequence, which showed centromere specific signals on almost all chromosomes in sunflowers. This is the first report of a centromeric LINE sequence, suggesting possible centromere targeting ability. Another type of identified repetitive DNA was a tandem repeat sequence with a 187-bp unit that was found only on a pair of chromosomes. The HaCENH3 content of the tandem repeats was estimated to be much higher than that of the LINE, which implies centromere evolution from LINE-based centromeres to more stable tandem-repeat-based centromeres. In addition, the epigenetic status of the sunflower centromeres was investigated by immunohistochemical staining and ChIP, and it was found that centromeres were heterochromatic. PMID- 26583021 TI - Exogenous spermidine alleviates oxidative damage and reduce yield loss in rice submerged at tillering stage. AB - To figure out whether spermidine (Spd) can alleviate oxidative damage on rice (Oryza sativa L.) caused by submergence stress, Ningjing 3 was used in this study. The results showed that, spraying Spd on rice leaves at a concentration of 0.5 mM promoted the growth recovery of rice after drainage, such as green leaves, tillers, and aboveground dry mass. According to physiological analysis, Spd accelerate restored chlorophylls damage by submergence, and decreased the rate of [Formula: see text] generation and H2O2 content, inhibited submergence-induced lipid peroxidation. Spd also helped to maintain antioxidant enzyme activities after drainage, such as superoxide dismutase, peroxidase, and GR, which ultimately improved the recovery ability of submerged rice. With the effect of Spd, the rice yields increased by 12.1, 17.9, 13.5, and 18.0%, of which submerged for 1, 3, 5, 7 days, respectively. It is supposed that exogenous Spd really has an alleviate effect on submergence damage and reduce yield loss of rice. PMID- 26583022 TI - Diversified glucosinolate metabolism: biosynthesis of hydrogen cyanide and of the hydroxynitrile glucoside alliarinoside in relation to sinigrin metabolism in Alliaria petiolata. AB - Alliaria petiolata (garlic mustard, Brassicaceae) contains the glucosinolate sinigrin as well as alliarinoside, a gamma-hydroxynitrile glucoside structurally related to cyanogenic glucosides. Sinigrin may defend this plant against a broad range of enemies, while alliarinoside confers resistance to specialized (glucosinolate-adapted) herbivores. Hydroxynitrile glucosides and glucosinolates are two classes of specialized metabolites, which generally do not occur in the same plant species. Administration of [UL-(14)C]-methionine to excised leaves of A. petiolata showed that both alliarinoside and sinigrin were biosynthesized from methionine. The biosynthesis of alliarinoside was shown not to bifurcate from sinigrin biosynthesis at the oxime level in contrast to the general scheme for hydroxynitrile glucoside biosynthesis. Instead, the aglucon of alliarinoside was formed from metabolism of sinigrin in experiments with crude extracts, suggesting a possible biosynthetic pathway in intact cells. Hence, the alliarinoside pathway may represent a route to hydroxynitrile glucoside biosynthesis resulting from convergent evolution. Metabolite profiling by LC-MS showed no evidence of the presence of cyanogenic glucosides in A. petiolata. However, we detected hydrogen cyanide (HCN) release from sinigrin and added thiocyanate ion and benzyl thiocyanate in A. petiolata indicating an enzymatic pathway from glucosinolates via allyl thiocyanate and indole glucosinolate derived thiocyanate ion to HCN. Alliarinoside biosynthesis and HCN release from glucosinolate-derived metabolites expand the range of glucosinolate-related defenses and can be viewed as a third line of defense, with glucosinolates and thiocyanate forming protein being the first and second lines, respectively. PMID- 26583024 TI - Five willow varieties cultivated across diverse field environments reveal stem density variation associated with high tension wood abundance. AB - Sustainable and inexpensive production of biomass is necessary to make biofuel production feasible, but represents a challenge. Five short rotation coppice willow cultivars, selected for high biomass yield, were cultivated on sites at four diverse regions of Quebec in contrasting environments. Wood composition and anatomical traits were characterized. Tree height and stem diameter were measured to evaluate growth performance of the cultivars according to the diverse pedoclimatic conditions. Each cultivar showed very specific responses to its environment. While no significant variation in lignin content was observed between sites, there was variation between cultivars. Surprisingly, the pattern of substantial genotype variability in stem density was maintained across all sites. However, wood anatomy did differ between sites in a cultivar (producing high and low density wood), suggesting a probable response to an abiotic stress. Furthermore, twice as many cellulose-rich G-fibers, comprising over 50% of secondary xylem, were also found in the high density wood, a finding with potential to bring higher value to the lignocellulosic bioethanol industry. PMID- 26583023 TI - Hypothesis: NDL proteins function in stress responses by regulating microtubule organization. AB - N-MYC DOWNREGULATED-LIKE proteins (NDL), members of the alpha/beta hydrolase superfamily were recently rediscovered as interactors of G-protein signaling in Arabidopsis thaliana. Although the precise molecular function of NDL proteins is still elusive, in animals these proteins play protective role in hypoxia and expression is induced by hypoxia and nickel, indicating role in stress. Homology of NDL1 with animal counterpart N-MYC DOWNREGULATED GENE (NDRG) suggests similar functions in animals and plants. It is well established that stress responses leads to the microtubule depolymerization and reorganization which is crucial for stress tolerance. NDRG is a microtubule-associated protein which mediates the microtubule organization in animals by causing acetylation and increases the stability of alpha-tubulin. As NDL1 is highly homologous to NDRG, involvement of NDL1 in the microtubule organization during plant stress can also be expected. Discovery of interaction of NDL with protein kinesin light chain- related 1, enodomembrane family protein 70, syntaxin-23, tubulin alpha-2 chain, as a part of G protein interactome initiative encourages us to postulate microtubule stabilizing functions for NDL family in plants. Our search for NDL interactors in G protein interactome also predicts the role of NDL proteins in abiotic stress tolerance management. Based on published report in animals and predicted interacting partners for NDL in G protein interactome lead us to hypothesize involvement of NDL in the microtubule organization during abiotic stress management in plants. PMID- 26583026 TI - Proteomics: a promising tool for research on sex-related differences in dioecious plants. PMID- 26583025 TI - Versatile roles of brassinosteroid in plants in the context of its homoeostasis, signaling and crosstalks. AB - Brassinosteroids (BRs) are a class of steroidal plant hormones that play diverse roles in plant growth and developmental processes. Recently, the easy availability of biological resources, and development of new molecular tools and approaches have provided the required impetus for deeper understanding of the processes involved in BRs biosynthesis, transport, signaling and degradation pathways. From recent studies it is also evident that BRs interact with other phytohormones such as auxin, cytokinin, ethylene, gibberellin, jasmonic acid, abscisic acid, salicylic acid and polyamine in regulating wide range of physiological and developmental processes in plants. The inputs from these studies are now being linked to the versatile roles of BRs. The present review highlights the conceptual development with regard to BR homeostasis, signaling and its crosstalk with other phytohormones. This information will assist in developing predictive models to modulate various useful traits in plants and address current challenges in agriculture. PMID- 26583027 TI - Genome-specific differential gene expressions in resynthesized Brassica allotetraploids from pair-wise crosses of three cultivated diploids revealed by RNA-seq. AB - Polyploidy is popular for the speciation of angiosperms but the initial stage of allopolyploidization resulting from interspecific hybridization and genome duplication is associated with different extents of changes in genome structure and gene expressions. Herein, the transcriptomes detected by RNA-seq in resynthesized Brassica allotetraploids (Brassica juncea, AABB; B. napus, AACC; B. carinata, BBCC) from the pair-wise crosses of the same three diploids (B. rapa, AA; B. nigra, BB; B. oleracea, CC) were compared to reveal the patterns of gene expressions from progenitor genomes and the effects of different types of genome combinations and cytoplasm, upon the genome merger and duplication. From transcriptomic analyses for leaves and silique walls, extensive expression alterations were revealed in these resynthesized allotetraploids relative to their diploid progenitors, as well as during the transition from vegetative to reproductive development, for differential and transgressive gene expressions were variable in numbers and functions. Genes involved in glucosinolates and DNA methylation were transgressively up-regulated among most samples, suggesting that gene expression regulation was immediately established after allopolyploidization. The expression of ribosomal protein genes was also tissue specific and showed a similar expression hierarchy of rRNA genes. The balance between the co-up and co-down regulation was observed between reciprocal B. napus with different types of the cytoplasm. Our results suggested that gene expression changes occurred after initial genome merger and such profound alterations might enhance the growth vigor and adaptability of Brassica allotetraploids. PMID- 26583028 TI - The Arabidopsis a zinc finger domain protein ARS1 is essential for seed germination and ROS homeostasis in response to ABA and oxidative stress. AB - The phytohormone abscisic acid (ABA) induces accumulation of reactive oxygen species (ROS), which can disrupt seed dormancy and plant development. Here, we report the isolation and characterization of an Arabidopsis thaliana mutant called ars1 (aba and ros sensitive 1) that showed hypersensitivity to ABA during seed germination and to methyl viologen (MV) at the seedling stage. ARS1 encodes a nuclear protein with one zinc finger domain, two nuclear localization signal (NLS) domains, and one nuclear export signal (NES). The ars1 mutants showed reduced expression of a gene for superoxide dismutase (CSD3) and enhanced accumulation of ROS after ABA treatment. Transient expression of ARS1 in Arabidopsis protoplasts strongly suppressed ABA-mediated ROS production. Interestingly, nuclear-localized ARS1 translocated to the cytoplasm in response to treatment with ABA, H2O2, or MV. Taken together, these results suggest that ARS1 modulates seed germination and ROS homeostasis in response to ABA and oxidative stress in plants. PMID- 26583029 TI - Transcriptome sequencing of purple petal spot region in tree peony reveals differentially expressed anthocyanin structural genes. AB - The pigmented cells in defined region of a petal constitute the petal spots. Petal spots attract pollinators and are found in many angiosperm families. Several cultivars of tree peony contain a single red or purple spot at the base of petal that makes the flower more attractive for the ornamental market. So far, the understanding of the molecular mechanism of spot formation is inadequate. In this study, we sequenced the transcriptome of the purple spot and the white non spot of tree peony flower. We assembled and annotated 67,892 unigenes. Comparative analyses of the two transcriptomes showed 1,573 differentially expressed genes, among which 933 were up-regulated, and 640 were down-regulated in the purple spot. Subsequently, we examined four anthocyanin structural genes, including PsCHS, PsF3'H, PsDFR, and PsANS, which expressed at a significantly higher level in the purple spot than in the white non-spot. We further validated the digital expression data using quantitative real-time PCR. Our result uncovered transcriptome variance between the spot and non-spot of tree peony flower, and revealed that the co-expression of four anthocyanin structural genes was responsible for spot pigment in tree peony. The data will further help to unravel the genetic mechanism of peony flower spot formation. PMID- 26583030 TI - Integrative analysis and expression profiling of secondary cell wall genes in C4 biofuel model Setaria italica reveals targets for lignocellulose bioengineering. AB - Several underutilized grasses have excellent potential for use as bioenergy feedstock due to their lignocellulosic biomass. Genomic tools have enabled identification of lignocellulose biosynthesis genes in several sequenced plants. However, the non-availability of whole genome sequence of bioenergy grasses hinders the study on bioenergy genomics and their genomics-assisted crop improvement. Foxtail millet (Setaria italica L.; Si) is a model crop for studying systems biology of bioenergy grasses. In the present study, a systematic approach has been used for identification of gene families involved in cellulose (CesA/Csl), callose (Gsl) and monolignol biosynthesis (PAL, C4H, 4CL, HCT, C3H, CCoAOMT, F5H, COMT, CCR, CAD) and construction of physical map of foxtail millet. Sequence alignment and phylogenetic analysis of identified proteins showed that monolignol biosynthesis proteins were highly diverse, whereas CesA/Csl and Gsl proteins were homologous to rice and Arabidopsis. Comparative mapping of foxtail millet lignocellulose biosynthesis genes with other C4 panicoid genomes revealed maximum homology with switchgrass, followed by sorghum and maize. Expression profiling of candidate lignocellulose genes in response to different abiotic stresses and hormone treatments showed their differential expression pattern, with significant higher expression of SiGsl12, SiPAL2, SiHCT1, SiF5H2, and SiCAD6 genes. Further, due to the evolutionary conservation of grass genomes, the insights gained from the present study could be extrapolated for identifying genes involved in lignocellulose biosynthesis in other biofuel species for further characterization. PMID- 26583031 TI - The effector repertoire of Fusarium oxysporum determines the tomato xylem proteome composition following infection. AB - Plant pathogens secrete small proteins, of which some are effectors that promote infection. During colonization of the tomato xylem vessels the fungus Fusarium oxysporum f.sp. lycopersici (Fol) secretes small proteins that are referred to as SIX (Secreted In Xylem) proteins. Of these, Six1 (Avr3), Six3 (Avr2), Six5, and Six6 are required for full virulence, denoting them as effectors. To investigate their activities in the plant, the xylem sap proteome of plants inoculated with Fol wild-type or either AVR2, AVR3, SIX2, SIX5, or SIX6 knockout strains was analyzed with nano-Liquid Chromatography-Mass Spectrometry (nLC-MSMS). Compared to mock-inoculated sap 12 additional plant proteins appeared while 45 proteins were no longer detectable in the xylem sap of Fol-infected plants. Of the 285 proteins found in both uninfected and infected plants the abundance of 258 proteins changed significantly following infection. The xylem sap proteome of plants infected with four Fol effector knockout strains differed significantly from plants infected with wild-type Fol, while that of the SIX2-knockout inoculated plants remained unchanged. Besides an altered abundance of a core set of 24 differentially accumulated proteins (DAPs), each of the four effector knockout strains affected specifically the abundance of a subset of DAPs. Hence, Fol effectors have both unique and shared effects on the composition of the tomato xylem sap proteome. PMID- 26583032 TI - Classifying aging as a disease in the context of ICD-11. AB - Aging is a complex continuous multifactorial process leading to loss of function and crystalizing into the many age-related diseases. Here, we explore the arguments for classifying aging as a disease in the context of the upcoming World Health Organization's 11th International Statistical Classification of Diseases and Related Health Problems (ICD-11), expected to be finalized in 2018. We hypothesize that classifying aging as a disease with a "non-garbage" set of codes will result in new approaches and business models for addressing aging as a treatable condition, which will lead to both economic and healthcare benefits for all stakeholders. Actionable classification of aging as a disease may lead to more efficient allocation of resources by enabling funding bodies and other stakeholders to use quality-adjusted life years (QALYs) and healthy-years equivalent (HYE) as metrics when evaluating both research and clinical programs. We propose forming a Task Force to interface the WHO in order to develop a multidisciplinary framework for classifying aging as a disease with multiple disease codes facilitating for therapeutic interventions and preventative strategies. PMID- 26583033 TI - A new conceptual framework for investigating complex genetic disease. AB - Some common diseases are known to have an inherited component, however, their population- and familial-incidence patterns do not conform to any known monogenic Mendelian pattern of inheritance and instead they are currently much better explained if an underlying polygenic architecture is posited. Studies that have attempted to identify the causative genetic factors have been designed on this polygenic framework, but so far the yield has been largely unsatisfactory. Based on accumulating recent observations concerning the roles of somatic mosaicism in disease, in this article a second framework which posits a single gene-two hit model which can be modulated by a mutator/anti-mutator genetic background is suggested. I discuss whether such a model can be considered a viable alternative based on current knowledge, its advantages over the current polygenic framework, and describe practical routes via which the new framework can be investigated. PMID- 26583034 TI - Feed-Forward Neural Network Soft-Sensor Modeling of Flotation Process Based on Particle Swarm Optimization and Gravitational Search Algorithm. AB - For predicting the key technology indicators (concentrate grade and tailings recovery rate) of flotation process, a feed-forward neural network (FNN) based soft-sensor model optimized by the hybrid algorithm combining particle swarm optimization (PSO) algorithm and gravitational search algorithm (GSA) is proposed. Although GSA has better optimization capability, it has slow convergence velocity and is easy to fall into local optimum. So in this paper, the velocity vector and position vector of GSA are adjusted by PSO algorithm in order to improve its convergence speed and prediction accuracy. Finally, the proposed hybrid algorithm is adopted to optimize the parameters of FNN soft sensor model. Simulation results show that the model has better generalization and prediction accuracy for the concentrate grade and tailings recovery rate to meet the online soft-sensor requirements of the real-time control in the flotation process. PMID- 26583035 TI - FXR expression is associated with dysregulated glucose and lipid levels in the offspring kidney induced by maternal obesity. AB - BACKGROUND: Maternal obesity is associated with dysregulation of glucose and lipid metabolism with consequent exposure of the fetus to an abnormal metabolic milieu. It is recognized that maternal obesity predisposes offspring to chronic kidney disease (CKD). We aimed to determine whether the nuclear Farnesoid X receptor (FXR), known to play a role in maintaining homeostasis of glucose and lipid metabolism, is involved in renal injury in offspring of obese mothers. METHODS: Maternal obesity was established in a rat model by feeding dams with high-fat diet prior to and during pregnancy and lactation. The offspring's kidneys were examined at postnatal Day 1and Day 20. Human kidney 2 (HK2) cells were exposed to high glucose with or without the FXR agonist GW4064 or when FXR mRNA was silenced. RESULTS: Glucose intolerance in the offspring of obese mothers was evident at weaning, with associated downregulation of renal FXR expression and upregulation of monocyte chemoattractant protein-1 (MCP-1) and transforming growth factor-beta1 (TGF-beta1). HK2 cells exposed to high glucose had reduced FXR expression and increased MCP-1, TGF-beta1, fibronectin and collagen IV expression, which was reversed in the presence of GW4064. FXR-silenced HK2 cells had amplified pro-inflammatory and pro-fibrotic markers under high glucose conditions. CONCLUSIONS: Maternal obesity influences renal expression of pro inflammatory and fibrotic factors that predispose the offspring to CKD. This was associated with the downregulation of the renal FXR expression suggesting a potential protective role for FXR. PMID- 26583036 TI - Comparative study of the modulation of fructose/sucrose-induced hepatic steatosis by mixed lipid formulations varying in unsaturated fatty acid content. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in developed countries. NAFLD encompasses a spectrum of diseases, ranging from hepatic steatosis to non-alcoholic steatohepatitis (NASH), cirrhosis, and liver failure. The etiology of NAFLD remains unclear but is thought to relate to increased fatty acid flux within the liver that results in toxic fatty acid metabolite production. One source of increased fatty acid flux is fructose/sucrose-induced hepatic lipogenesis. Current treatment for NAFLD encompasses dietary modifications. However, little scientific evidence exists on which to base many dietary recommendations, especially the intake of different types of carbohydrates and fats. We hypothesized that lipid mixtures of unsaturated fatty acids would inhibit lipogenesis and subsequent hepatic steatosis induced by high carbohydrate diets. The aim of this study was to examine the effects of different complex mixtures of fatty acids upon the development of fructose/sucrose-induced hepatic steatosis. METHODS: C57BL/6 mice were randomized to normocaloric chow-based diets that varied in the type of carbohydrate (starch, sucrose, fructose). Animals in each carbohydrate group were further randomized to diets that varied in lipid type (no additional lipid, soybean oil, fish oil, olive/soybean oil, macadamia nut oil). These oils were chosen based upon their content of omega-6 polyunsaturated fatty acids, omega-3 polyunsaturated fatty acids, omega-9 monounsaturated fatty acids, or omega-7 monounsaturated fatty acids. Fatty acid flux in the liver was determine by assessing hepatic lipid content (steatosis). We also assessed fatty acid levels in the plasma and liver of the animals, hepatic lipogenesis activity, hepatic stearoyl-CoA-1 desaturase activity, and hepatic elongase activity. RESULTS: Animals consumed similar amounts of the diets and maintained normal body weights throughout the study. Both sucrose and fructose induced hepatic lipogenesis and steatosis, with fructose being more potent. All mixed lipids similarly inhibited steatosis, limiting lipid content to levels found in the control (starch) animals. Lipogenesis and stearoyl-CoA-1 desaturase activity were increased in the sucrose and fructose groups. Levels of these enzymatic processes remained at baseline in all of the lipid groups. CONCLUSION: This is the first study to compare various complex lipid mixtures, based upon dietary oils with different types of long-chain fatty acids, upon development of sucrose/fructose-induced steatosis. Both carbohydrate source and lipid content appear important for the modulation of steatosis. Moderate intake of complex lipids with high unsaturated to saturated fatty acid ratios inhibited both lipogenesis and steatosis. PMID- 26583037 TI - High fat plus high cholesterol diet lead to hepatic steatosis in zebrafish larvae: a novel model for screening anti-hepatic steatosis drugs. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD), characterized as excessive lipid accumulation within hepatocytes, is growing in prevalence. The exploitation of effective drugs for NAFLD has been proven challenging. Herein, we aimed to establish a dietary model of hepatic steatosis using transparent zebrafish larvae in which high-throughput chemical screens could be conducted. METHODS: Zebrafish larvae fed with high fat (HF) diet and high fat plus high cholesterol (HFC) diet were compared to the control. We analyzed intrahepatic lipid accumulation, biological indexes and various pathways including lipid metabolism, ER stress and inflammation. In addition, the effects of ezetimibe and simvastatin on HFC diet induced steatosis were evaluated. RESULTS: Zebrafish larvae fed with HF and HFC diets developed steatosis for 7 and 10 days. The incidence and degree of steatosis were more severe in HFC diet-fed larvae compared with the control and HF diet-fed larvae, suggesting that adding cholesterol to the HF diet promotes the hepatic lipid accumulation. These data were confirmed by the pathological observation. Biological indexes, free cholesterol (FC), total cholesterol (TC) and triacylglycerol (TG) were elevated in the liver of HFC diet-fed larvae compared with the control and HF diet-fed larvae. Additionally, the expression levels of endoplasmic reticulum (ER) stress and lipolytic molecules (atf6, hspa5, hsp90b1, pparab, cpt1a and acox3) were significantly up-regulated in the liver of HF and HFC diets-fed larvae compared to the control, whereas the expression of lipogenic molecules (acaca, fasn, srebf2, hmgcs1 and hmgcra) were decreased in the liver of HF and HFC diets-fed larvae compared to the control. To validate the reliability of the HFC model and utility value for screening potential anti steaotsis drugs, HFC-fed larvae were treated with two accepted lipid-lowing drugs (ezetimibe and simvastatin). The results showed that these drugs significantly ameliorated HFC-induced steatosis. CONCLUSION: Our results demonstrate that the zebrafish larvae steatosis model established and validated in this study could be used for in vivo steatosis studies and drug screening. PMID- 26583038 TI - Influence of obesity on vertebral fracture prevalence and vitamin D status in postmenopausal women. AB - BACKGROUND: It is well established that weight is an important determinant of bone health. Whereas obesity is associated with increased mortality and morbidity from diabetes and cardiovascular diseases, high body weight is widely believed to be associated to hypovitaminosis D and protective against the development of osteoporosis and fracture risk. The objective of the study was to evaluate the effect of BMI on vitamin D status and on densitometric vertebral fractures (VFs) in a large series of asymptomatic women aged over 50 who had a VFA examination during their bone mineral density (BMD) testing. METHODS: We enrolled 429 postmenopausal women (mean age, weight and BMI of 59.5 +/- 8.3 (50 to 83) years, 75.8 +/- 13.3 (35 to 165) kgs and 29.9 +/- 5.2 (14.6 to 50.8) kg/m(2), respectively. Lateral VFA images and scans of the lumbar spine and proximal femur were obtained using a Lunar Prodigy densitometer. VFs were defined using the Genant semiquantitative (SQ) approach. Clinical risk factors of osteoporosis were collected and 25-hydroxivitamin D was measured using electrochimiluminescence (Roche). RESULTS: Prevalence of osteoporosis and hypovitaminosis D (<20 ng/ml) was 21.0 % and 78.1 % respectively. VFs grade 2/3were identified in 76 (17.7 %). Comparison between women according to their BMI showed that obese women had a higher BMD and less proportion of women with osteoporosis and VFs grade 2/3 than lean and overweight women. The prevalence of VFs globally increased with age and as BMI and BMD declined. Stepwise regression analysis showed that the presence of osteoporosis was independently related to BMI and history of fractures while the presence of grade 2/3 VFs was independently related to age, hypovitaminosis D and years of menopause. CONCLUSION: Obese women had a higher BMD and lower prevalence of VFs. VFs were significantly related to age, hypovitaminosis D and years since menopause. However, among obese women, prevalence of VFs was increased in osteoporotic women. PMID- 26583039 TI - Neurotoxic syndrome induced by clomipramine plus risperidone in a patient with autistic spectrum disorder: serotonin or neuroleptic malignant syndrome? AB - To the best of our knowledge, there are no case studies of serotonin syndrome (SS) in patients with autism spectrum disorder. We report the case of a 33-year old male who presented SS under the combined use of clomipramine and risperidone. More specifically, within 2 days after clomipramine (10 mg/BID-two times a day) was added to risperidone (4 mg/OD-once a day), mirtazapine 45 mg/OD and alprazolam (0,5 mg/TID-three times a day) he began to present mental, neurological and autonomic symptoms. All his psychopathological manifestations and laboratory findings normalized after the above-mentioned drugs' discontinuation, and the administration of supportive medical care and lorazepam 2,5 mg/TID. The diagnosis of serotonin syndrome was challenging due to the relatively low dose of clomipramine, an increase of risperidone which had taken place before clomipramine administration and clinical symptoms which could be attributed to both serotonin and neuroleptic malignant syndrome. PMID- 26583040 TI - Sex differences in plasma clozapine and norclozapine concentrations in clinical practice and in relation to body mass index and plasma glucose concentrations: a retrospective survey. AB - BACKGROUND: Clozapine is widely prescribed and, although effective, can cause weight gain and dysglycemia. The dysmetabolic effects of clozapine are thought to be more prevalent in women with this gender on average attaining 17 % higher plasma clozapine concentrations than men. METHODS: We investigated the relationship between dose, body mass index (BMI), plasma glucose concentration, and plasma clozapine and N-desmethylclozapine (norclozapine) concentrations in 100 individuals with a severe enduring mental illness. RESULTS: Mean (10th/90th percentile) plasma clozapine concentrations were higher for women [0.49 (0.27 0.79) mg/L] compared with men [0.44 (0.26-0.70) mg/L] (F = 2.2; p = 0.035). There was no significant gender difference in the prescribed clozapine dose. BMI was significantly higher in women [mean (95 % CI) = 34.5 (26.0-45.3)] for females compared with 32.5 (25.2-41.0) for males. Overall, BMI increased by 0.7 kg/m(2) over a mean follow-up period of 210 days. A lower proportion, 41 % of women had a fasting blood glucose <=6.0 mmol/L (<6.0 mmol/L is defined by the International Diabetes Federation as normal glucose handling), compared with 88 % of men (chi (2) = 18.6, p < 0.0001). CONCLUSIONS: We have shown that mean BMI and blood glucose concentrations are higher in women prescribed clozapine than in men. Women also tended to attain higher plasma clozapine concentrations than men. The higher BMI and blood glucose in women may relate to higher tissue exposure to clozapine, as a consequence of sex differences in drug metabolism. PMID- 26583041 TI - Strengthening the human rights framework to protect breastfeeding: a focus on CEDAW. AB - BACKGROUND: There have been recent calls for increased recognition of breastfeeding as a human right. The United Nations Convention on the Elimination of All Forms of Discrimination against Women, 1979 (CEDAW) is the core human rights treaty on women. CEDAW's approach to breastfeeding is considered from an historical perspective. A comparison is drawn with breastfeeding protection previously outlined in the International Labour Organization's Maternity Protection Convention, 1919 (ILO C3), and its 1952 revision (ILO C103), and subsequently, in the United Nations Convention on the Rights of the Child, 1989 (CRC). DISCUSSION: Despite breastfeeding's sex-specific significance to an international human rights treaty on women and CEDAW's emphasis on facilitating women's employment, CEDAW is, in reality, a relatively weak instrument for breastfeeding protection. In both its text and subsequent interpretations explicit recognition of breastfeeding is minimal or nonexistent. Explanations for this are proposed and contextualised in relation to various political, social and economic forces, especially those influencing notions of gender equality. During the mid to late 1970s -when CEDAW was formulated - breastfeeding posed a strategic challenge for key feminist goals, particularly those of equal employment opportunity, gender neutral childrearing policy and reproductive rights. Protective legislation aimed at working women had been rejected as outdated and oppressive. Moreover, the right of women to breastfeed was generally assumed, with choice over infant feeding practices often perceived as the right NOT to breastfeed. There was also little awareness or analysis of the various structural obstacles to breastfeeding's practice, such as lack of workplace support, that undermine 'choice'. Subsequent interpretations of CEDAW show that despite significant advances in scientific and epidemiological knowledge about breastfeeding's importance for short-term and long-term maternal health, breastfeeding continues to be inadequately addressed in international human rights law on women. A comparison is made with CRC and its subsequent elaborations. Increasing recognition of the need to protect, promote and support breastfeeding within the framework of CRC but not that of CEDAW suggests that breastfeeding is regarded primarily as a children's rights issue but only minimally as a women's rights issue. SUMMARY: The human rights framework requires strengthening in every direction to protect, promote and support breastfeeding. Discussion is needed regarding whether a separate strengthening of the international human rights framework on women is required with regard to breastfeeding. PMID- 26583042 TI - "Rolled-upness": phenotyping leaf rolling in cereals using computer vision and functional data analysis approaches. AB - BACKGROUND: The flag leaf of a wheat (Triticum aestivum L.) plant rolls up into a cylinder in response to drought conditions and then unrolls when leaf water relations improve. This is a desirable trait for extending leaf area duration and improving grain size particularly under drought. But how do we quantify this phenotype so that different varieties of wheat or different treatments can be compared objectively since this phenotype can easily be confounded with inter genotypic differences in root-water uptake and/or transpiration at the leaf level if using traditional methods? RESULTS: We present a new method to objectively test a range of lines/varieties/treatments for their propensity of leaves to roll. We have designed a repeatable protocol and defined an objective measure of leaf curvature called "rolled-upness" which minimises confounding factors in the assessment of leaf rolling in grass species. We induced leaf rolling by immersing leaf strips in an osmoticum of known osmotic pressure. Using micro-photographs of individual leaf cross-sections at equilibrium in the osmoticum, two approaches were used to quantify leaf rolling. The first was to use some properties of the convex hull of the leaf cross-section. The second was to use cubic smoothing splines to approximate the transverse leaf shape mathematically and then use a statistic derived from the splines for comparison. Both approaches resulted in objective measurements that could differentiate clearly between breeding lines and varieties contrasting genetically in their propensity for leaf rolling under water stress. The spline approach distinguished between upward and downward curvature and allowed detailed properties of the rolling to be examined, such as the position on the strip where maximum curvature occurs. CONCLUSIONS: A method applying smoothing splines to skeletonised images of transverse wheat leaf sections enabled objective measurements of inter-genotypic variation for hydronastic leaf rolling in wheat. Mean-curvature of the leaf cross-section was the measure selected to discriminate between genotypes, as it was straightforward to calculate and easily construed. The method has broad applicability and provides an avenue to genetically dissect the trait in cereals. PMID- 26583043 TI - Synthesis and dynamics studies of barbituric acid derivatives as urease inhibitors. AB - BACKGROUND: Discovery of potent inhibitors of urease (jack bean) enzyme is the first step in the development of drugs against diseases caused by ureolytic enzyme. RESULTS: Thirty-two derivatives of barbituric acid as zwitterionic adducts of diethyl ammonium salts were synthesized. All synthesized compounds (4a z and 5a-s) were screened for their in vitro inhibition potential against urease enzyme (jack bean urease). The compounds 4i (IC50 = 17.6 +/- 0.23 uM) and 5l (IC50 = 17.2 +/- 0.44 uM) were found to be the most active members of the series, and showed several fold more urease inhibition activity than the standard compound thiourea (IC50 = 21.2 +/- 1.3 uM). Whereas, compounds 4a-b, 4d-e, 4g-h, 4j-4r, 4x, 4z, 5b, 5e, 5k, 5n-5q having IC50 values in the range of 22.7 +/- 0.20 uM-43.8 +/- 0.33 uM, were also found as potent urease inhibitors. Furthermore, Molecular Dynamics simulation and molecular docking studies were carried out to analyze the binding mode of barbituric acid derivatives using MOE. During MD simulation enol form is found to be more stable over its keto form due to their coordination with catalytic Nickel ion of Urease. Additionally, structural activity relationship using automated docking method was applied where the compounds with high biological activity are deeply buried within the binding pocket of urease. As multiple hydrophilic crucial interactions with Ala169, KCX219, Asp362 and Ala366 stabilize the compound within the binding site, thus contributing greater activity. CONCLUSIONS: This research study is useful for the discovery of economically, efficient viable new drug against infectious diseases.Graphical abstract:STD. Thiourea (IC50 = 21.2 +/- 1.3 uM). PMID- 26583044 TI - Controlling microbial contamination during hydrolysis of AFEX-pretreated corn stover and switchgrass: effects on hydrolysate composition, microbial response and fermentation. AB - BACKGROUND: Microbial conversion of lignocellulosic feedstocks into biofuels remains an attractive means to produce sustainable energy. It is essential to produce lignocellulosic hydrolysates in a consistent manner in order to study microbial performance in different feedstock hydrolysates. Because of the potential to introduce microbial contamination from the untreated biomass or at various points during the process, it can be difficult to control sterility during hydrolysate production. In this study, we compared hydrolysates produced from AFEX-pretreated corn stover and switchgrass using two different methods to control contamination: either by autoclaving the pretreated feedstocks prior to enzymatic hydrolysis, or by introducing antibiotics during the hydrolysis of non autoclaved feedstocks. We then performed extensive chemical analysis, chemical genomics, and comparative fermentations to evaluate any differences between these two different methods used for producing corn stover and switchgrass hydrolysates. RESULTS: Autoclaving the pretreated feedstocks could eliminate the contamination for a variety of feedstocks, whereas the antibiotic gentamicin was unable to control contamination consistently during hydrolysis. Compared to the addition of gentamicin, autoclaving of biomass before hydrolysis had a minimal effect on mineral concentrations, and showed no significant effect on the two major sugars (glucose and xylose) found in these hydrolysates. However, autoclaving elevated the concentration of some furanic and phenolic compounds. Chemical genomics analyses using Saccharomyces cerevisiae strains indicated a high correlation between the AFEX-pretreated hydrolysates produced using these two methods within the same feedstock, indicating minimal differences between the autoclaving and antibiotic methods. Comparative fermentations with S. cerevisiae and Zymomonas mobilis also showed that autoclaving the AFEX-pretreated feedstocks had no significant effects on microbial performance in these hydrolysates. CONCLUSIONS: Our results showed that autoclaving the pretreated feedstocks offered advantages over the addition of antibiotics for hydrolysate production. The autoclaving method produced a more consistent quality of hydrolysate, and also showed negligible effects on microbial performance. Although the levels of some of the lignocellulose degradation inhibitors were elevated by autoclaving the feedstocks prior to enzymatic hydrolysis, no significant effects on cell growth, sugar utilization, or ethanol production were seen during bacterial or yeast fermentations in hydrolysates produced using the two different methods. PMID- 26583045 TI - Thromboxane promotes smooth muscle phenotype commitment but not remodeling of hypoxic neonatal pulmonary artery. AB - BACKGROUND: Persistent pulmonary hypertension of the newborn (PPHN) is characterized by vasoconstriction and pulmonary vascular remodeling. Remodeling is believed to be a response to physical or chemical stimuli including pro mitotic inflammatory mediators such as thromboxane. Our objective was to examine the effects of hypoxia and thromboxane signaling ex vivo and in vitro on phenotype commitment, cell cycle entry, and proliferation of PPHN and control neonatal pulmonary artery (PA) myocytes in tissue culture. METHODS: To examine concurrent effects of hypoxia and thromboxane on myocyte growth, serum-fed first passage newborn porcine PA myocytes were randomized into normoxic (21 % O2) or hypoxic (10 % O2) culture for 3 days, with daily addition of thromboxane mimetic U46619 (10(-9) to 10(-5) M) or diluent. Cell survival was detected by MTT assay. To determine the effect of chronic thromboxane exposure (versus whole serum) on activation of arterial remodeling, PPHN was induced in newborn piglets by a 3-day hypoxic exposure (FiO2 0.10); controls were 3 day-old normoxic and day 0 piglets. Third-generation PA were segmented and cultured for 3 days in physiologic buffer, Ham's F-12 media (in the presence or absence of 10 % fetal calf serum), or media with 10(-6) M U46619. DNA synthesis was measured by (3)H-thymidine uptake, protein synthesis by (3)H-leucine uptake, and proliferation by immunostaining for Ki67. Cell cycle entry was studied by laser scanning cytometry of nuclei in arterial tunica media after propidium iodide staining. Phenotype commitment was determined by immunostaining tunica media for myosin heavy chain and desmin, quantified by laser scanning cytometry. RESULTS: Contractile and synthetic myocyte subpopulations had differing responses to thromboxane challenge. U46619 decreased proliferation of synthetic and contractile myocytes. PPHN arteries exhibited decreased protein synthesis under all culture conditions. Serum supplemented PA treated with U46619 had decreased G1/G0 phase myocytes and an increase in S and G2/M. When serum-deprived, PPHN PA incubated with U46619 showed arrested cell cycle entry (increased G0/G1, decreased S and G2/M) and increased abundance of contractile phenotype markers. CONCLUSIONS: We conclude that thromboxane does not initiate phenotypic dedifferentiation and proliferative activation in PPHN PA. Exposure to thromboxane triggers cell cycle exit and myocyte commitment to contractile phenotype. PMID- 26583046 TI - Target enhanced 2D similarity search by using explicit biological activity annotations and profiles. AB - BACKGROUND: The enriched biological activity information of compounds in large and freely-accessible chemical databases like the PubChem Bioassay Database has become a powerful research resource for the scientific research community. Currently, 2D fingerprint based conventional similarity search (CSS) is the most common widely used approach for database screening, but it does not typically incorporate the relative importance of fingerprint bits to biological activity. RESULTS: In this study, a large-scale similarity search investigation has been carried out on 208 well-defined compound activity classes extracted from PubChem Bioassay Database. An analysis was performed to compare the search performance of three types of 2D similarity search approaches: 2D fingerprint based conventional similarity search approach (CSS), iterative similarity search approach with multiple active compounds as references (ISS), and fingerprint based iterative similarity search with classification (ISC), which can be regarded as the combination of iterative similarity search with active references and a reversed iterative similarity search with inactive references. Compared to the search results returned by CSS, ISS improves recall but not precision. Although ISC causes the false rejection of active hits, it improves the precision with statistical significance, and outperforms both ISS and CSS. In a second part of this study, we introduce the profile concept into the three types of searches. We find that the profile based non-iterative search can significantly improve the search performance by increasing the recall rate. We also find that profile based ISS (PBISS) and profile based ISC (PBISC) significantly decreases ISS search time without sacrificing search performance. CONCLUSIONS: On the basis of our large scale investigation directed against a wide spectrum of pharmaceutical targets, we conclude that ISC and ISS searches perform better than 2D fingerprint similarity searching and that profile based versions of these algorithms do nearly as well in less time. We also suggest that the profile version of the iterative similarity searches are both better performing and potentially quicker than the standard algorithm. PMID- 26583047 TI - Progesterone ameliorates diabetic nephropathy in streptozotocin-induced diabetic Rats. AB - BACKGROUND: Previous studies reported that 17beta-estradiol may influence the progression of diabetic renal disease in females. The present study was intended to provide an insight into the specific effects of progesterone, the other female sex hormone, in the diabetic renal complications. METHODS: Adult female wistar rats were divided into four groups (n = 6/group): intact control (non-diabetic, ND), intact diabetic (D), ovariectomized diabetic (D-OVX) and ovariectomized diabetic which were treated with progesterone (D-OVX + P; 10 mg/kg, s.c, every second day) for 10 weeks. Diabetes was induced by a single dose injection of 55 mg/kg streptozotocin. Expressions of transforming growth factor-beta (TGF-beta), fibronectin, vascular endothelial growth factor-A (VEGF-A), angiotensin II type 1 receptor (ATR1) and podocyte markers (nephrin and podocin) were assessed by immunohistochemistry and real-time PCR. RESULTS: The treatment of D-OVX rats with progesterone attenuated diabetic-associated increases in the urinary albumin to creatinine ratio, glomerulosclerosi and the expression of profibrotic and angiogenic factors (TGF-beta, Fibronectin and VEGF-A). Furthermore, progesterone supplementation prevented diabetes-induced downregulation of nephrin and podocin while the overexpression of ATR1 in the diabetic rats was inhibited by the progesterone supplementation. CONCLUSION: These results provided evidence, for the first time, that the replacement of progesterone can ameliorate the renal damage in the experimental models of diabetic nephropathy through improving the renal function; the inhibition of renal fibrosis and abnormal angiogenesis; along with the amelioration of podocyte injury. Additionally, the blocking of renin angiotensin system through the down-regulation of ATR1 expression may also account for the reno-protective effect of progesterone. PMID- 26583048 TI - Effects of high glucose on human umbilical vein endothelial cell permeability and myosin light chain phosphorylation. AB - BACKGROUND: Diabetes mellitus is one of the most important risk factors for atherosclerosis. However, the mechanisms underlying high-glucose-induced atherosclerosis remain unclear. This study was designed to observe the effects of high-glucose stimulation on the permeability of cultured human umbilical vein endothelial cells (HUVECs), and to explore the effects of RhoA-Rho-associated protein kinase (ROCK) signal transduction pathway activation and myosin light chain (MLC) phosphorylation. METHODS: HUVECs were cultured in conventional M199 medium to produce endothelial cell monolayers, and stimulated with high-glucose M199 medium. The transmembrane transport of dextran and THP-1 cells and levels of MLC phosphorylation were measured. The effects of blocking the RhoA-ROCK pathway using dnRhoA or the ROCK inhibitor Y27632 on dextran and THP-1 transport and MLC phosphorylation were observed. RESULTS: Transendothelial migration of dextran and THP-1 cells were significantly increased by stimulation of HUVEC monolayers with high glucose (P < 0.05). This effect was attenuated by treatment with dnRhoA or Y27632. CONCLUSION: High-glucose stimulation upregulated MLC phosphorylation and increased endothelial permeability by activating the RhoA-ROCK signaling pathway in HUVECs in vitro. PMID- 26583049 TI - Metabolic abnormalities in patients with prolactinoma: response to treatment with cabergoline. AB - BACKGROUND: Hyperprolactinemia has been associated with changes in body composition and metabolic abnormalities. Normalization of prolactin (PRL) with dopamine agonists has been found to reverse these abnormalities. This study was designed to assess the anthropometric and metabolic alterations associated with prolactinoma and response of these abnormalities to cabergoline treatment. METHODS: In a non-randomised matched prospective design, 19 consecutive patients with prolactinoma (median PRL 118.6 (105.3) MUg/L) and 20 controls were studied. The controls were age, gender and body mass index (BMI) matched. Anthropometric data and metabolic variables were studied at baseline, 3 and 6 months after cabergoline treatment. RESULTS: Patients with prolactinoma had increased level of fasting plasma glucose (P < .001), LDL-cholesterol (P = .001) and triglycerides (TG) (P = .009) as compared to age, gender and BMI matched healthy controls. There was a significant decrease of body weight at 3 months (P = .029), with a further decline at 6 months (P < .001) of cabergoline therapy. In addition, there was a significant decrement of BMI (P < .001), waist circumference (P = .003), waist-hip ratio (P = .03) and total body fat (P = .003) at 6 months of cabergoline treatment. A significant decline in plasma glucose (P < .001), total cholesterol (P = .009), LDL-cholesterol (P < .001) and TG (P < .001) was seen after 6 months of cabergoline treatment. CONCLUSIONS: Patients with prolactinoma have adverse metabolic profile compared with matched controls. Normalization of PRL with cabergoline corrects all the metabolic abnormalities. PMID- 26583050 TI - Amination of omega-Functionalized Aliphatic Primary Alcohols by a Biocatalytic Oxidation-Transamination Cascade. AB - Amination of non-activated aliphatic fatty alcohols to the corresponding primary amines was achieved through a five-enzyme cascade reaction by coupling a long chain alcohol oxidase from Aspergillus fumigatus (LCAO_Af) with a omega transaminase from Chromobacterium violaceum (omega-TA_Cv). The alcohol was oxidized at the expense of molecular oxygen to yield the corresponding aldehyde, which was subsequently aminated by the PLP-dependent omega-TA to yield the final primary amine product. The overall cascade was optimized with respect to pH, O2 pressure, substrate concentration, decomposition of H2O2 (derived from alcohol oxidation), NADH regeneration, and biocatalyst ratio. The substrate scope of this concept was investigated under optimized conditions by using terminally functionalized C4-C11 fatty primary alcohols bearing halogen, alkyne, amino, hydroxy, thiol, and nitrile groups. PMID- 26583051 TI - Identification of Active and Spectator Sn Sites in Sn-beta Following Solid-State Stannation, and Consequences for Lewis Acid Catalysis. AB - Lewis acidic zeolites are rapidly emerging liquid-phase Lewis acid catalysts. Nevertheless, their inefficient synthesis procedure currently prohibits greater utilization and exploitation of these promising materials. Herein, we demonstrate that SnIV-containing zeolite beta can readily be prepared both selectively and extremely rapidly by solid-state incorporation (SSI) method. Through a combination of spectroscopic (XRD, UV/Vis, X-ray absorption, magic-angle spinning NMR, and diffuse reflectance infrared Fourier transform spectroscopy) studies, we unambiguously demonstrate that site-isolated, isomorphously substituted SnIV sites dominate the Sn population up to a loading of 5 wt % Sn. These sites are identical to those found in conventionally prepared Sn-beta, and result in our SSI material exhibiting identical levels of intrinsic activity (that is, turnover frequency) despite the threefold increase in Sn loading, and the extremely rapid and benign nature of our preparation methodology. We also identify the presence of spectator sites, in the form of SnIV oligomers, at higher levels of Sn loading. The consequences of this mixed population with regards to catalysis (Meerwein-Pondorf-Verley reaction and glucose isomerization) are also identified. PMID- 26583052 TI - Incorporating Virtual Reactions into a Logic-based Ligand-based Virtual Screening Method to Discover New Leads. AB - The use of virtual screening has become increasingly central to the drug development pipeline, with ligand-based virtual screening used to screen databases of compounds to predict their bioactivity against a target. These databases can only represent a small fraction of chemical space, and this paper describes a method of exploring synthetic space by applying virtual reactions to promising compounds within a database, and generating focussed libraries of predicted derivatives. A ligand-based virtual screening tool Investigational Novel Drug Discovery by Example (INDDEx) is used as the basis for a system of virtual reactions. The use of virtual reactions is estimated to open up a potential space of 1.21*1012 potential molecules. A de novo design algorithm known as Partial Logical-Rule Reactant Selection (PLoRRS) is introduced and incorporated into the INDDEx methodology. PLoRRS uses logical rules from the INDDEx model to select reactants for the de novo generation of potentially active products. The PLoRRS method is found to increase significantly the likelihood of retrieving molecules similar to known actives with a p-value of 0.016. Case studies demonstrate that the virtual reactions produce molecules highly similar to known actives, including known blockbuster drugs. PMID- 26583053 TI - Epigenetic alterations following early postnatal stress: a review on novel aetiological mechanisms of common psychiatric disorders. AB - Stressor exposure during early life has the potential to increase an individual's susceptibility to a number of neuropsychiatric conditions such as mood and anxiety disorders and schizophrenia in adulthood. This occurs in part due to the dysfunctional stress axis that persists following early adversity impairing stress responsivity across life. The mechanisms underlying the prolonged nature of this vulnerability remain to be established. Alterations in the epigenetic signature of genes involved in stress responsivity may represent one of the neurobiological mechanisms. The overall aim of this review is to provide current evidence demonstrating changes in the epigenetic signature of candidate gene(s) in response to early environmental adversity. More specifically, this review analyses the epigenetic signatures of postnatal adversity such as childhood abuse or maltreatment and later-life psychopathology in human and animal models of early life stress. The results of this review shows that focus to date has been on genes involved in the regulation of hypothalamic-pituitary-adrenal (HPA) axis and its correlation to subsequent neurobiology, for example, the role of glucocorticoid receptor gene. However, epigenetic changes in other candidate genes such as brain-derived neurotrophic factor (BDNF) and serotonin transporter are also implicated in early life stress (ELS) and susceptibility to adult psychiatric disorders. DNA methylation is the predominantly studied epigenetic mark followed by histone modifications specifically acetylation and methylation. Further, these epigenetic changes are cell/tissue-specific in regulating expression of genes, providing potential biomarkers for understanding the trajectory of early stress-induced susceptibility to adult psychiatric disorders. PMID- 26583055 TI - Copper Uptake in Mammary Epithelial Cells Activates Cyclins and Triggers Antioxidant Response. AB - The toxicologic effects of copper (Cu) on tumor cells have been studied during the past decades, and it is suggested that Cu ion may trigger antiproliferative effects in vitro. However, in normal cells the toxicologic effects of high exposures of free Cu are not well understood. In this work, Cu uptake, the expression of genes associated with cell cycle regulation, and the levels of ROS production and related oxidative processes were evaluated in Cu-treated mammary epithelial MCF10A nontumoral cells. We have shown that the Cu additive is associated with the activation of cyclin D1 and cyclin B1, as well as cyclin dependent kinase 2 (CDK2). These nontumor cells respond to Cu-induced changes in the oxidative balance by increase of the levels of reduced intracellular glutathione (GSH), decrease of reactive oxygen species (ROS) generation, and accumulation during progression of the cell cycle, thus preventing the cell abnormal proliferation or death. Taken together, our findings revealed an effect that contributes to prevent a possible damage of normal cells exposed to chemotherapeutic effects of drugs containing the Cu ion. PMID- 26583054 TI - Imprinting disorders: a group of congenital disorders with overlapping patterns of molecular changes affecting imprinted loci. AB - Congenital imprinting disorders (IDs) are characterised by molecular changes affecting imprinted chromosomal regions and genes, i.e. genes that are expressed in a parent-of-origin specific manner. Recent years have seen a great expansion in the range of alterations in regulation, dosage or DNA sequence shown to disturb imprinted gene expression, and the correspondingly broad range of resultant clinical syndromes. At the same time, however, it has become clear that this diversity of IDs has common underlying principles, not only in shared molecular mechanisms, but also in interrelated clinical impacts upon growth, development and metabolism. Thus, detailed and systematic analysis of IDs can not only identify unifying principles of molecular epigenetics in health and disease, but also support personalisation of diagnosis and management for individual patients and families. PMID- 26583056 TI - Sulforaphane Protects against Cardiovascular Disease via Nrf2 Activation. AB - Cardiovascular disease (CVD) causes an unparalleled proportion of the global burden of disease and will remain the main cause of mortality for the near future. Oxidative stress plays a major role in the pathophysiology of cardiac disorders. Several studies have highlighted the cardinal role played by the overproduction of reactive oxygen or nitrogen species in the pathogenesis of ischemic myocardial damage and consequent cardiac dysfunction. Isothiocyanates (ITC) are sulfur-containing compounds that are broadly distributed among cruciferous vegetables. Sulforaphane (SFN) is an ITC shown to possess anticancer activities by both in vivo and epidemiological studies. Recent data have indicated that the beneficial effects of SFN in CVD are due to its antioxidant and anti-inflammatory properties. SFN activates NF-E2-related factor 2 (Nrf2), a basic leucine zipper transcription factor that serves as a defense mechanism against oxidative stress and electrophilic toxicants by inducing more than a hundred cytoprotective proteins, including antioxidants and phase II detoxifying enzymes. This review will summarize the evidence from clinical studies and animal experiments relating to the potential mechanisms by which SFN modulates Nrf2 activation and protects against CVD. PMID- 26583057 TI - Glucose Oxidase Induces Cellular Senescence in Immortal Renal Cells through ILK by Downregulating Klotho Gene Expression. AB - Cellular senescence can be prematurely induced by oxidative stress involved in aging. In this work, we were searching for novel intermediaries in oxidative stress-induced senescence, focusing our interest on integrin-linked kinase (ILK), a scaffold protein at cell-extracellular matrix (ECM) adhesion sites, and on the Klotho gene. Cultured renal cells were treated with glucose oxidase (GOx) for long time periods. GOx induced senescence, increasing senescence associated beta galactosidase activity and the expression of p16. In parallel, GOx increased ILK protein expression and activity. Ectopic overexpression of ILK in cells increased p16 expression, even in the absence of GOx, whereas downregulation of ILK inhibited the increase in p16 due to oxidative stress. Additionally, GOx reduced Klotho gene expression and cells overexpressing Klotho protein did not undergo senescence after GOx addition. We demonstrated a direct link between ILK and Klotho since silencing ILK expression in cells and mice increases Klotho expression and reduces p53 and p16 expression in renal cortex. In conclusion, oxidative stress induces cellular senescence in kidney cells by increasing ILK protein expression and activity, which in turn reduces Klotho expression. We hereby present ILK as a novel downregulator of Klotho gene expression. PMID- 26583058 TI - Mitochondrial Retrograde Signaling: Triggers, Pathways, and Outcomes. AB - Mitochondria are essential organelles for eukaryotic homeostasis. Although these organelles possess their own DNA, the vast majority (>99%) of mitochondrial proteins are encoded in the nucleus. This situation makes systems that allow the communication between mitochondria and the nucleus a requirement not only to coordinate mitochondrial protein synthesis during biogenesis but also to communicate eventual mitochondrial malfunctions, triggering compensatory responses in the nucleus. Mitochondria-to-nucleus retrograde signaling has been described in various organisms, albeit with differences in effector pathways, molecules, and outcomes, as discussed in this review. PMID- 26583059 TI - PRMT1 and PRMT4 Regulate Oxidative Stress-Induced Retinal Pigment Epithelial Cell Damage in SIRT1-Dependent and SIRT1-Independent Manners. AB - Oxidative stress-induced retinal pigment epithelial (RPE) cell damage is involved in the progression of diabetic retinopathy. Arginine methylation catalyzed by protein arginine methyltransferases (PRMTs) has emerged as an important histone modification involved in diverse diseases. Sirtuin (SIRT1) is a protein deacetylase implicated in the onset of metabolic diseases. Therefore, we examined the roles of type I PRMTs and their relationship with SIRT1 in human RPE cells under H2O2-induced oxidative stress. H2O2 treatment increased PRMT1 and PRMT4 expression but decreased SIRT1 expression. Similar to H2O2 treatment, PRMT1 or PRMT4 overexpression increased RPE cell damage. Moreover, the H2O2-induced RPE cell damage was attenuated by PRMT1 or PRMT4 knockdown and SIRT1 overexpression. In this study, we revealed that SIRT1 expression was regulated by PRMT1 but not by PRMT4. Finally, we found that PRMT1 and PRMT4 expression is increased in the RPE layer of streptozotocin-treated rats. Taken together, we demonstrated that oxidative stress induces apoptosis both via PRMT1 in a SIRT1-dependent manner and via PRMT4 in a SIRT1-independent manner. The inhibition of the expression of type I PRMTs, especially PRMT1 and PRMT4, and increased SIRT1 could be therapeutic approaches for diabetic retinopathy. PMID- 26583060 TI - hCLOCK Causes Rho-Kinase-Mediated Endothelial Dysfunction and NF-kappaB-Mediated Inflammatory Responses. AB - BACKGROUND: The human Circadian Locomotor Output Cycle protein Kaput (CLOCK) gene was originally discovered as a regulator of essential human daily rhythms. This seemingly innocuous gene was then found to be associated with a multitude of human malignancies, via several biochemical pathways. We aimed to further investigate the role of hCLOCK in the hypoxia-oxidative stress response system at the biochemical level. METHODS: Expression levels of Rho GTPases were measured in normoxic and hypoxic states. The effect of hCLOCK on the hypoxic response was evaluated with the use of a retroviral shRNA vector system, a Rho inhibitor, and a ROS scavenger by analyzing expression levels of hCLOCK, Rho GTPases, and NF kappaB pathway effectors. Finally, in vitro ROS production and tube formation in HUVECs were assessed. RESULTS: Hypoxia induces ROS production via hCLOCK. hCLOCK activates the RhoA and NF-kappaB signaling pathways. Conversely, inhibition of hCLOCK deactivates these pathways. Furthermore, inhibition of RhoA or decreased levels of ROS attenuate these pathways, but inhibition of RhoA does not lead to decreased levels of ROS. Overall findings show that hypoxia increases the expression of hCLOCK, which leads to ROS production, which then activates the RhoA and NF-kappaB pathways. CONCLUSION: Our findings suggest that hypoxic states induce vascular oxidative damage and inflammation via hCLOCK-mediated production of ROS, with subsequent activation of the RhoA and NF-kappaB pathways. PMID- 26583061 TI - Effects of Exercise Intensity on Postexercise Endothelial Function and Oxidative Stress. AB - PURPOSE: To measure endothelial function and oxidative stress immediately, 90 minutes, and three hours after exercise of varying intensities. METHODS: Sixteen apparently healthy men completed three exercise bouts of treadmill running for 30 minutes at 55% VO(2max) (mild); 20 minutes at 75% VO(2max) (moderate); or 5 minutes at 100% VO(2max) (maximal) in random order. Brachial artery flow-mediated dilation (FMD) was assessed with venous blood samples drawn for measurement of endothelin-1 (ET-1), lipid hydroperoxides (LOOHs), and lipid soluble antioxidants. RESULTS: LOOH increased immediately following moderate exercise (P < 0.05). ET-1 was higher immediately after exercise and 3 hours after exercise in the mild trial compared to maximal one (P < 0.05). Transient decreases were detected for DeltaFMD/Shear(AUC) from baseline following maximal exercise, but it normalised at 3 hours after exercise (P < 0.05). Shear rate was higher immediately after exercise in the maximal trial compared to mild exercise (P < 0.05). No changes in baseline diameter, peak diameter, absolute change in diameter, or FMD were observed following any of the exercise trials (P > 0.05). CONCLUSIONS: Acute exercise at different intensities elicits varied effects on oxidative stress, shear rate, and ET-1 that do not appear to mediate changes in endothelial function measured by FMD. PMID- 26583062 TI - Nrf2 Signaling and the Slowed Aging Phenotype: Evidence from Long-Lived Models. AB - Studying long-lived animals provides novel insight into shared characteristics of aging and represents a unique model to elucidate approaches to prevent chronic disease. Oxidant stress underlies many chronic diseases and resistance to stress is a potential mechanism governing slowed aging. The transcription factor nuclear factor (erythroid-derived 2)-like 2 is the "master regulator" of cellular antioxidant defenses. Nrf2 is upregulated by some longevity promoting interventions and may play a role in regulating species longevity. However, Nrf2 expression and activity in long-lived models have not been well described. Here, we review evidence for altered Nrf2 signaling in a variety of slowed aging models that accomplish lifespan extension via pharmacological, nutritional, evolutionary, genetic, and presumably epigenetic means. PMID- 26583063 TI - Increased Susceptibility of Gracilinanus microtarsus Liver Mitochondria to Ca2+ Induced Permeability Transition Is Associated with a More Oxidized State of NAD(P). AB - In addition to be the cell's powerhouse, mitochondria also contain a cell death machinery that includes highly regulated processes such as the membrane permeability transition pore (PTP) and reactive oxygen species (ROS) production. In this context, the results presented here provide evidence that liver mitochondria isolated from Gracilinanus microtarsus, a small and short life span (one year) marsupial, when compared to mice, are much more susceptible to PTP opening in association with a poor NADPH dependent antioxidant capacity. Liver mitochondria isolated from the marsupial are well coupled and take up Ca(2+) but exhibited a much lower Ca(2+) retention capacity than mouse mitochondria. Although the known PTP inhibitors cyclosporin A, ADP, and ATP significantly increased the marsupial mitochondria capacity to retain Ca(2+), their effects were much larger in mice than in marsupial mitochondria. Both fluorescence and HPLC analysis of mitochondrial nicotinamide nucleotides showed that both content and state of reduction (mainly of NADPH) were lower in the marsupial mitochondria than in mice mitochondria despite the similarity in the activity of the glutathione peroxidase/reductase system. Overall, these data suggest that PTP opening is an important event in processes of Ca(2+) signalling to cell death mediated by mitochondrial redox imbalance in G. microtarsus. PMID- 26583064 TI - Key Roles of Glutamine Pathways in Reprogramming the Cancer Metabolism. AB - Glutamine (GLN) is commonly known as an important metabolite used for the growth of cancer cells but the effects of its intake in cancer patients are still not clear. However, GLN is the main substrate for DNA and fatty acid synthesis. On the other hand, it reduces the oxidative stress by glutathione synthesis stimulation, stops the process of cancer cachexia, and nourishes the immunological system and the intestine epithelium, as well. The current paper deals with possible positive effects of GLN supplementation and conditions that should be fulfilled to obtain these effects. The analysis of GLN metabolism suggests that the separation of GLN and carbohydrates in the diet can minimize simultaneous supply of ATP (from glucose) and NADPH2 (from glutamine) to cancer cells. It should support to a larger extent the organism to fight against the cancer rather than the cancer cells. GLN cannot be considered the effective source of ATP for cancers with the impaired oxidative phosphorylation and pyruvate dehydrogenase inhibition. GLN intake restores decreased levels of glutathione in the case of chemotherapy and radiotherapy; thus, it facilitates regeneration processes of the intestine epithelium and immunological system. PMID- 26583065 TI - Biomolecular Modulation of Neurodegenerative Events during Ageing. AB - The objective is to assess the modulation of retinal and optic nerve degenerative events induced by the combination of alpha-lipoic acid (ALA) and superoxide dismutase (SOD) in an animal model of ageing. For this study, 24 male Wistar Harlan strain rats were left to age for up to 24 months. One group of rats was subjected to a diet supplemented with ALA and SOD for 8 weeks, while another group was used as a positive control and not subjected to any dietary treatment. To assess the cytoprotective effects of the antioxidants, a morphological analysis was carried out on sections of retina and optic nerve head, stained with haematoxylin-eosin, followed by an analysis of the modifications to nuclear DNA detected by the TUNEL technique. The lipid peroxidation assay was used to assess the damage induced by oxidative stress at cell membrane level. The molecules involved in apoptosis mediated by oxidative stress, such as caspase-3 and inducible nitric oxide synthase, were also assayed by immunolocalization and western blot. ALA and SOD are able to counteract senile neurodegenerative deterioration to the retina and optic nerve. Indeed, the combination of these antioxidant molecules can reduce oxidative stress levels and thus prevent both nuclear degradation and subsequent cell death. PMID- 26583066 TI - The Effects of Age and Latent Cytomegalovirus Infection on NK-Cell Phenotype and Exercise Responsiveness in Man. AB - The redeployment of NK-cells in response to an acute bout of exercise is thought to be an integral component of the "fight-or-flight" response, preparing the body for potential injury or infection. We showed previously that CMV seropositivity impairs the redeployment of NK-cells with exercise in the young. In the current study, we examined the effect of aging on the redeployment of NK-cells with exercise in the context of CMV. We show here that CMV blunts the exercise-induced redeployment of NK-cells in both younger (23-39 yrs) and older (50-64 yrs) subjects with older CMV(neg) subjects showing the largest postexercise mobilization and 1 h postexercise egress of NK-cells. The blunted exercise response in CMV(pos) individuals was associated with a decreased relative redeployment of the CD158a+ and CD57+ NK-cell subsets in younger and older individuals. In addition, we show that aging is associated with a CMV-independent increase in the proportion of NK-cells expressing the terminal differentiation marker CD57, while CMV is associated with an age-dependent decrease in the proportion of NK-cells expressing the inhibitory receptors KLRG1 (in the younger group) and CD158a (in the older group). Collectively, these data suggest that CMV may decrease NK-cell mediated immunosurveillance after exercise in both younger and older individuals. PMID- 26583067 TI - A neuroligin-3 mutation implicated in autism causes abnormal aggression and increases repetitive behavior in mice. AB - BACKGROUND: Aggression is common in patients with autism spectrum disorders (ASD) along with the core symptoms of impairments in social communication and repetitive behavior. Risperidone, an atypical antipsychotic, is widely used to treat aggression in ASD. In order to understand the neurobiological underpinnings of these challenging behaviors, a thorough characterisation of behavioral endophenotypes in animal models is required. METHODS: We investigated aggression in mice containing the ASD-associated R451C (arginine to cysteine residue 451 substitution) mutation in neuroligin-3 (NL3). Furthermore, we sought to verify social interaction impairments and assess olfaction, anxiety, and repetitive and restrictive behavior in NL3(R451C) mutant mice. RESULTS: We show a pronounced elevation in aggressive behavior in NL3(R451C) mutant mice. Treatment with risperidone reduced this aggression to wild-type (WT) levels. Juvenile and adult social interactions were also investigated, and subtle differences in initiation of interaction were seen in juvenile NL3(R451C) mice. No genotype differences in olfactory discrimination or anxiety were observed indicating that aggression was not dependent on altered olfaction, stress response, or social preference. We also describe repetitive behavior in NL3(R451C) mice as assessed by a clinically relevant object exploration task. CONCLUSIONS: The presence of aberrant aggression and other behavioral phenotypes in NL3(R451C) mice consistent with clinical traits strengthen face validity of this model of ASD. Furthermore, we demonstrate predictive validity in this model through the reversal of the aggressive phenotype with risperidone. This is the first demonstration that risperidone can ameliorate aggression in an animal model of ASD and will inform mechanistic and therapeutic research into the neurobiology underlying abnormal behaviors in ASD. PMID- 26583069 TI - Usability study of a simplified electroencephalograph as a health-care system. AB - A healthy lifestyle is becoming increasingly important worldwide, and various health monitoring devices that support this trend are currently being developed. Devices measuring blood pressure, weight, temperature, and pulse have been mainstream. In contrast, electroencephalography has been only useful in medical practice and brain research. For an electroencephalograph to be used in health care, it must be small and user-friendly. The conventional electroencephalograph uses more than twelve electrodes attached to a user's head with paste and hence is very precise. In contrast, the simplified electroencephalograph has inferior precision, but it is cheap, lightweight, paste-free, and requires only a short setup time. In this study, we verified the usefulness of the simplified electroencephalograph in investigating the mental condition of persons. We present interesting results associated with the setting position of the electrodes, the behavior of brain waves during work, and the appearance of individual differences. Consequently, we predict that this simplified device will be widely used for health diagnosis. PMID- 26583068 TI - The hidden burden of adult allergic rhinitis: UK healthcare resource utilisation survey. AB - BACKGROUND: The affliction of allergic rhinitis (AR) has been trivialised in the past. Recent initiatives by the European Academy of Allergy & Clinical Immunology and by the EU parliament seek to rectify that situation. The aim of this study was to provide a comprehensive picture of the burden and unmet need of AR patients. METHODS: This was a cross-sectional, online, questionnaire-based study (June-July 2011) including symptomatic seasonal AR (SAR) patients (>=18 years) from a panel. SAR episode pattern, severity, medication/co-medication usage, residual symptoms on treatment, number of healthcare visits, absenteeism and presenteeism were collected. RESULTS: One thousand patients were recruited (mild: n = 254; moderate/severe: n = 746). Patients with moderate/severe disease had significantly more symptomatic episodes/year (8.0 vs 6.0/year; p = 0.025) with longer episode-duration (12.5 vs 9.8 days; p = 0.0041) and more commonly used >=2 AR therapies (70.5 vs 56.1 %; OR 1.87; p = 0.0001), looking for better and faster nasal and ocular symptom relief. The reported symptom burden was high irrespective of treatment, and significantly (p < 0.0001) higher in the moderate/severe group. Patients with moderate/severe AR were more likely to visit their GP (1.61 vs 1.19 times/year; OR: 1.49; p = 0.0061); due to dissatisfaction with therapy in 35.4 % of cases. Patients reported SAR-related absenteeism from work on 4.1 days/year (total cost to UK: L1.25 billion/year) and noted presenteeism for a mean of 37.7 days/year (vs 21.0 days/year; OR 1.71; p = 0.0048). Asthma co-morbid patients reported the need to increase their reliever- (1 in 2 patients) and controller-medication (1 in 5 patients) if they did not take their rhinitis medication. CONCLUSIONS: This study differentiated between patients with mild and moderate/severe AR, demonstrating a burden of poorly controlled symptoms and high co-medication use. The deficiency in obtaining symptom control with what are currently considered firstline treatments suggests the need for a novel therapeutic approach. PMID- 26583070 TI - Establishing a Canadian national clinical trials network for kidney disease: proceedings of a planning workshop. AB - Knowledge generation through randomized controlled trials (RCTs) is critical to advance the medical evidence base, inform decision-making, and improve care and outcomes. Unfortunately, nephrology has typically lagged behind other medical specialties in this regard. The establishment of formal clinical trial networks can facilitate the successful conduct of RCTs and has significantly increased the number of RCTs performed worldwide in other medical specialties. No such formal network of nephrology trialists exists in Canada. On April 24, 2014, the Canadian Kidney Knowledge Translation and Generation Network (CANN-NET) Clinical Trials Committee held a stakeholder engagement meeting to address this gap and improve the nephrology clinical trial landscape in Canada. The meeting was held in Vancouver in association with the 2014 Canadian Society of Nephrology Annual General Meeting and was co-sponsored by the Kidney Foundation of Canada and CANN NET. Attendees included nephrologists from university- and non-university affiliated nephrology practices, administrators, and representatives from the Kidney Foundation of Canada. Through structured presentations and facilitated group discussions, the group explored the extent to which nephrology trials are currently happening in Canada, barriers to leading or participating in larger investigator-initiated trials, and strategies to improve clinical trial output in nephrology in Canada. The themes and action items arising from this meeting are discussed. PMID- 26583071 TI - Plasticity in PYD assembly revealed by cryo-EM structure of the PYD filament of AIM2. AB - Absent in melanoma 2 (AIM2) is an essential cytosolic double-stranded DNA receptor that assembles with the adaptor, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and caspase-1 to form the AIM2 inflammasome, which leads to proteolytic maturation of cytokines and pyroptotic cell death. AIM2 contains an N-terminal Pyrin domain (PYD) that interacts with ASC through PYD/PYD interactions and nucleates ASCPYD filament formation. To elucidate the molecular basis of AIM2-induced ASCPYD polymerization, we generated AIM2PYD filaments fused to green fluorescent protein (GFP) and determined its cryo-electron microscopic (cryo-EM) structure. The map showed distinct definition of helices, allowing fitting of the crystal structure. Surprisingly, the GFP AIM2PYD filament is a 1-start helix with helical parameters distinct from those of the 3-start ASCPYD filament. However, despite the apparent symmetry difference, helical net and detailed interface analyses reveal minimal changes in subunit packing. GFP-AIM2PYD nucleated ASCPYD filament formation in comparable efficiency as untagged AIM2PYD, suggesting assembly plasticity in both AIM2PYD and ASCPYD. The DNA-binding domain of AIM2 is able to form AIM2/DNA filaments, within which the AIM2PYD is brought into proximity to template ASCPYD filament assembly. Because ASC is able to interact with many PYD-containing receptors for the formation of inflammasomes, the observed structural plasticity may be critically important for this versatility in the PYD/PYD interactions. PMID- 26583072 TI - Nutrition and Reproductive Health: Sperm versus Erythrocyte Lipidomic Profile and omega-3 Intake. AB - Fatty acid analyses of sperm and erythrocyte cell membrane phospholipids in idiopathic infertile patients evidenced that erythrocyte contents of EPA, DHA, omega-6-omega-3 ratio and arachidonic acid provide a mathematical correspondence for the prediction of EPA level in sperm cells. The erythrocyte lipidomic profile of patients was significantly altered, with signatures of typical Western pattern dietary habits and no fish intake. A supplementation with nutritional levels of EPA and DHA and antioxidants was then performed for 3 months, with the follow-up of both erythrocyte and sperm cell membranes composition as well as conventional sperm parameters. Some significant changes were found in the lipidomic membrane profile of erythrocyte but not in sperm cells, which correspondently did not show significant parameter ameliorations. This is the first report indicating that membrane lipids of different tissues do not equally metabolize the fatty acid elements upon supplementation. Molecular diagnostic tools are necessary to understand the cell metabolic turnover and monitor the success of nutraceuticals for personalized treatments. PMID- 26583074 TI - A Spiral in the Heart: Mitral Valve Endocarditis with Unusual Vegetation Shape Potentially Affecting Effectiveness of Antibiotic Therapy. AB - We report an unusual case of infective endocarditis (IE) in an 88-year-old woman, occurring on a prolapsing mitral valve and characterized by an atypical vegetation shape resembling a spiral-like appearance. After the patient refused surgical correction, persistent IE despite prolonged antibiotic therapy was observed, resulting in an ischemic stroke probably secondary to septic embolus. The importance of vegetation shape in the management of patients with IE was classically related to the increased risk of embolization associated with pedunculated, irregular, and multilobed masses. We hypothesize that the unusual spiral-like vegetation shape in our patient may have favored IE persistence by two mechanisms, namely, a decrease of the exposed vegetation surface with creation of an internal core where the penetration of antimicrobial agents was obstacled and the creation of blood turbulence within the vegetation preventing a prolonged contact with circulating antibiotics. These considerations suggest that vegetation shape might be considered of importance in patients with IE not only because of its classical association with embolization risk, but also because of its potential effect on the efficacy of antibiotic therapy. PMID- 26583073 TI - Diet and Skin Cancer: The Potential Role of Dietary Antioxidants in Nonmelanoma Skin Cancer Prevention. AB - Nonmelanoma skin cancer (NMSC) is the most common cancer among Americans. Ultraviolet (UV) radiation exposure is the major risk factor for the development of NMSC. Dietary AOs may prevent free radical-mediated DNA damage and tumorigenesis secondary to UV radiation. Numerous laboratory studies have found that certain dietary AOs show significant promise in skin cancer prevention. These results have been substantiated by animal studies. In human studies, researchers have evaluated both oral AO supplements and dietary intake of AOs via whole foods. In this review, we provide an overview of the role of AOs in preventing tumorigenesis and outline four targeted dietary AOs. We review the results of research evaluating oral AOs supplements as compared to dietary AOs intake via whole foods. While these specific supplements have not shown efficacy, intake of AOs via consumption of whole foods has shown some promise. Lessons learned from the field of hypertension research may provide important guidance in future study design. Further research on the role of dietary AOs in the prevention of NMSC is warranted and should focus on intake via whole food consumption. PMID- 26583075 TI - Primary Adrenal Failure due to Antiphospholipid Syndrome. AB - Background. Antiphospholipid syndrome (APS) characterized by thrombosis and abortus may rarely cause primary adrenal failure. Case Presentations. A 34-year old male presented with hypotension, hypoglycemia, hyperpigmentation on his skin and oral mucosa, scars on both legs, and loss of consciousness. In laboratory examinations, hyponatremia (135 mmol/L), hyperpotassemia (6 mmol/L), and thrombocytopenia (83 K/uL) were determined. Cortisol (1.91 ug/dL) and adrenocorticotropic (550 pg/mL) hormone levels were also evaluated. The patient was hospitalized with a diagnosis of acute adrenal crisis due to primary adrenal insufficiency. A Doppler ultrasound revealed venous thrombosis. The patient was diagnosed with antiphospholipid syndrome after the detection of venous thrombosis, thrombocytopenia, elevated aPTT, and anticardiolipin antibody levels. Anticoagulation treatment was started for antiphospholipid syndrome. The patient is now following up with hydrocortisone, fludrocortisone, and warfarin sodium. Conclusion. Antiphospholipid syndrome is a rare reason for adrenal failure. Antiphospholipid syndrome should be suspected if patients have morbidity secondary to venous-arterial thrombosis. PMID- 26583077 TI - Waddlia chondrophila induces systemic infection, organ pathology, and elicits Th1 associated humoral immunity in a murine model of genital infection. AB - Waddlia chondrophila is a known bovine abortigenic Chlamydia-related bacterium that has been associated with adverse pregnancy outcomes in human. However, there is a lack of knowledge regarding how W. chondrophila infection spreads, its ability to elicit an immune response and induce pathology. A murine model of genital infection was developed to investigate the pathogenicity and immune response associated with a W. chondrophila infection. Genital inoculation of the bacterial agent resulted in a dose-dependent infection that spread to lumbar lymph nodes and successively to spleen and liver. Bacterial-induced pathology peaked on day 14, characterized by leukocyte infiltration (uterine horn, liver, and spleen), necrosis (liver) and extramedullary hematopoiesis (spleen). Immunohistochemistry demonstrated the presence of a large number of W. chondrophila in the spleen on day 14. Robust IgG titers were detected by day 14 and remained high until day 52. IgG isotypes consisted of high IgG2a, moderate IgG3 and no detectable IgG1, indicating a Th1-associated immune response. This study provides the first evidence that W. chondrophila genital infection is capable of inducing a systemic infection that spreads to major organs, induces uterus, spleen, and liver pathology and elicits a Th1-skewed humoral response. This new animal model will help our understanding of the mechanisms related to intracellular bacteria-induced miscarriages, the most frequent complication of pregnancy that affects one in four women. PMID- 26583076 TI - Microenvironmental Targets in Sarcoma. AB - Sarcomas are rare malignant tumors affecting all age groups. They are typically classified according to their resemblance to corresponding normal tissue. Their heterogeneous features, for example, in terms of disease-driving genetic aberrations and body location, complicate both disease classification and development of novel treatment regimens. Many years of failure of improved patient outcome in clinical trials has led to the conclusion that novel targeted therapies are likely needed in combination with current multimodality regimens. Sarcomas have not, in contrast to the common carcinomas, been the subject of larger systematic studies on how tumor behavior relates to characteristics of the tumor microenvironment. There is consequently an urgent need for identifying suitable molecular targets, not only in tumor cells but also in the tumor microenvironment. This review discusses preclinical and clinical data about potential molecular targets in sarcomas. Studies on targeted therapies involving the tumor microenvironment are prioritized. A greater understanding of the biological context is expected to facilitate more successful design of future clinical trials in sarcoma. PMID- 26583078 TI - Transforming growth factor-beta: an important mediator in Helicobacter pylori associated pathogenesis. AB - Helicobacter pylori (H.pylori) is a Gram-negative, microaerophilic, helical bacillus that specifically colonizes the gastric mucosa. The interaction of virulence factors, host genetic factors, and environmental factors contributes to the pathogenesis of H. pylori-associated conditions, such as atrophic gastritis and intestinal metaplasia. Infection with H. pylori has recently been recognized as the strongest risk factor for gastric cancer. As a pleiotropic cytokine, transforming growth factor (TGF)-beta regulates various biological processes, including cell cycle, proliferation, apoptosis, and metastasis. Recent studies have shed new light on the involvement of TGF-beta signaling in the pathogenesis of H. pylori infection. This review focuses on the potential etiological roles of TGF-beta in H. pylori-mediated gastric pathogenesis. PMID- 26583079 TI - Comprehensive identification of virulence factors required for respiratory melioidosis using Tn-seq mutagenesis. AB - Respiratory melioidosis is a disease presentation of the biodefense pathogen, Burkholderia pseudomallei, which is frequently associated with a lethal septicemic spread of the bacteria. We have recently developed an improved respiratory melioidosis model to study the pathogenesis of Burkholderia pseudomallei in the lung (intubation-mediated intratracheal [IMIT] inoculation), which more closely models descriptions of human melioidosis, including prominent septicemic spread from the lung and reduced involvement of the upper respiratory tract. We previously demonstrated that the Type 3 Secretion System cluster 3 (T3SS3) is a critical virulence determinant for B. pseudomallei when delivered directly into the lung. We decided to comprehensively identify all virulence determinants required for respiratory melioidosis using the Tn-seq phenotypic screen, as well as to investigate which virulence determinants are required for dissemination to the liver and spleen. While previous studies have used Tn-seq to identify essential genes for in vitro cultured B. pseudomallei, this represents the first study to use Tn-seq to identify genes required for in vivo fitness. Consistent with our previous findings, we identified T3SS3 as the largest genetic cluster required for fitness in the lung. Furthermore, we identified capsular polysaccharide and Type 6 Secretion System cluster 5 (T6SS5) as the two additional major genetic clusters facilitating respiratory melioidosis. Importantly, Tn-seq did not identify additional, novel large genetic systems supporting respiratory melioidosis, although these studies identified additional small gene clusters that may also play crucial roles in lung fitness. Interestingly, other previously identified virulence determinants do not appear to be required for lung fitness, such as lipopolysaccharide. The role of T3SS3, capsule, and T6SS5 in lung fitness was validated by competition studies, but only T3SS3 was found to be important for respiratory melioidosis when delivered as a single strain challenge, suggesting that competition studies may provide a higher resolution analysis of fitness factors in the lung. The use of Tn-seq phenotypic screening also provided key insights into the selective pressure encountered in the liver. PMID- 26583080 TI - Sugar tags and tumorigenesis. PMID- 26583082 TI - Corrigendum: Warm Ambient Temperature Decreases Food Intake in a Simulated Office Setting: A Pilot Randomized Controlled Trial. AB - [This corrects the article on p. 20 in vol. 2, PMID: 26322311.]. PMID- 26583081 TI - microRNAs: An Emerging Paradigm in Lung Cancer Chemoresistance. AB - Lung cancer is considered the most deadly of all cancers, with limited therapeutic options. Although advanced drugs have been tried in clinic, the therapeutic success has largely been hampered due to rapid development of drug resistance mechanisms. Recently, microRNAs (miRNAs), a class of small non-coding RNAs, have occupied center stage in cancer biology. miRNAs negatively regulate gene expression either by promoting degradation or by interfering with translation of messenger RNA targets. Several lines of evidence have confirmed the crucial role of miRNAs in carcinogenesis, and, importantly, in the acquisition of resistance to chemotherapeutics. Modulation of miRNA expression levels has been proven to increase the efficacy of genotoxic drugs in various preclinical cancer studies. Therefore, comprehensive understanding of the role(s) of these key players in drug resistance may provide novel opportunities to design effective combinatorial therapeutic strategies for cancer treatment. In this review, we highlight recent findings on miRNAs acting as oncomiRs and tumor suppressor genes in lung cancer. Moreover, we discuss the involvement of miRNAs in different mechanisms of drug resistance in this deadly disease. PMID- 26583083 TI - Effects of Exercise on Spinal Deformities and Quality of Life in Patients with Adolescent Idiopathic Scoliosis. AB - OBJECTIVES: This systematic review was conducted to examine the effects of exercise on spinal deformities and quality of life in patients with adolescent idiopathic scoliosis (AIS). DATA SOURCES: Electronic databases, including PubMed, CINAHL, Embase, Scopus, Cochrane Register of Controlled Trials, PEDro, and Web of Science, were searched for research articles published from the earliest available dates up to May 31, 2015, using the key words "exercise," "postural correction," "posture," "postural curve," "Cobb's angle," "quality of life," and "spinal deformities," combined with the Medical Subject Heading "scoliosis." STUDY SELECTION: This systematic review was restricted to randomized and nonrandomized controlled trials on AIS published in English language. The quality of selected studies was assessed by the PEDro scale, the Cochrane Collaboration's tool, and the Grading of Recommendations Assessment, Development, and Evaluation System (GRADE). DATA EXTRACTION: Descriptive data were collected from each study. The outcome measures of interest were Cobb angle, trunk rotation, thoracic kyphosis, lumbar kyphosis, vertebral rotation, and quality of life. DATA SYNTHESIS: A total of 30 studies were assessed for eligibility. Six of the 9 selected studies reached high methodological quality on the PEDro scale. Meta analysis revealed moderate-quality evidence that exercise interventions reduce the Cobb angle, angle of trunk rotation, thoracic kyphosis, and lumbar lordosis and low-quality evidence that exercise interventions reduce average lateral deviation. Meta-analysis revealed moderate-quality evidence that exercise interventions improve the quality of life. CONCLUSIONS: A supervised exercise program was superior to controls in reducing spinal deformities and improving the quality of life in patients with AIS. PMID- 26583085 TI - In Vivo Targeted Magnetic Resonance Imaging of Endogenous Neural Stem Cells in the Adult Rodent Brain. AB - Neural stem cells in the adult mammalian brain have a significant level of neurogenesis plasticity. In vivo monitoring of adult endogenous NSCs would be of great benefit to the understanding of the neurogenesis plasticity under normal and pathological conditions. Here we show the feasibility of in vivo targeted MR imaging of endogenous NSCs in adult mouse brain by intraventricular delivery of monoclonal anti-CD15 antibody conjugated superparamagnetic iron oxide nanoparticles. After intraventricular administration of these nanoparticles, the subpopulation of NSCs in the anterior subventricular zone and the beginning of the rostral migratory stream could be in situ labeled and were in vivo visualized with 7.0-T MR imaging during a period from 1 day to 7 days after the injection. Histology confirmed that the injected targeted nanoparticles were specifically bound to CD15 positive cells and their surrounding extracellular matrix. Our results suggest that in vivo targeted MR imaging of endogenous neural stem cells in adult rodent brain could be achieved by using anti-CD15-SPIONs as the molecular probe; and this targeting imaging strategy has the advantage of a rapid in vivo monitoring of the subpopulation of endogenous NSCs in adult brains. PMID- 26583084 TI - Role of Exosomal Noncoding RNAs in Lung Carcinogenesis. AB - Lung cancer is the major cause of cancer death worldwide. Novel, recently discovered classes of noncoding RNAs (ncRNAs) have diverse functional and regulatory activities and increasing evidence suggests crucial roles for deregulated ncRNAs in the onset and progression of cancer, including lung cancer. Exosomes are small extracellular membrane vesicles of endocytic origin that are released by many cells and are found in most body fluids. Tumor-derived exosomes mediate tumorigenesis by facilitating tumor growth and metastasis. MicroRNAs (miRNAs) are a subclass of ncRNAs that are present in exosomes. miRNAs are taken up by neighboring or distant cells and modulate various functions of recipient cells. Here, we review exosome-derived ncRNAs with a focus on miRNAs and their role in lung cancer biology. PMID- 26583086 TI - The Impact of a Vestibular-Stimulating Exercise Regime on Postural Stability in People with Visual Impairment. AB - The aim of the study was to assess the impact of a vestibular-stimulating exercise regime on postural stability in individuals with visual impairment. The study group consisted of 70 people, including 28 persons (15 female and 13 male) with visual impairment and 42 (21 female and 21 male) without visual impairment. Each individual in the group with visual impairment was medically qualified for a 3-month training program. The research methodology included medical examination, anthropometric tests, and stabilometry tests on a Biodex Balance System SD (BBS). The tests were conducted twice: once before the start of training and again after 3 months of rehabilitation. The group with visual impairment showed significantly worse postural stability results than the control group for most of the stability parameters evaluated (OSI, APSI, and MLSI). Differences were noted between the groups with and without visual impairment for dynamic tests in women and for static tests in men. After training, the two groups showed roughly similar results for the stabilometry test with eyes closed. We conclude that exercises stimulating the vestibular system with head and body movements should be recommended for individuals with visual impairments to achieve better balance retention. PMID- 26583087 TI - Vitamin A Impairs the Reprogramming of Tregs into IL-17-Producing Cells during Intestinal Inflammation. AB - Maintaining the identity of Foxp3(+) regulatory T cells (Tregs) is critical for controlling immune responses in the gut, where an imbalance between Tregs and T effector cells has been linked to inflammatory bowel disease. Accumulating evidence suggests that Tregs can convert into Th17 cells and acquire an inflammatory phenotype. In this study, we used an adoptive transfer model of Ag specific T cells to study the contribution of different factors to the reprogramming of in vitro-generated Treg cells (iTreg) into IL-17-producing cells in a mouse model of gut inflammation in vivo. Our results show that intestinal inflammation induces the reprogramming of iTreg cells into IL-17-producing cells and that vitamin A restrains reprogramming in the gut. We also demonstrate that the presence of IL-2 during the in vitro generation of iTreg cells confers resistance to Th17 conversion but that IL-2 and retinoic acid (RA) cooperate to maintain Foxp3 expression following stimulation under Th17-polarizing conditions. Additionally, although IL-2 and RA differentially regulate the expression of different Treg cell suppressive markers, Treg cells generated under different polarizing conditions present similar suppressive capacity. PMID- 26583090 TI - The Association between Cerebral White Matter Lesions and Plasma Omega-3 to Omega 6 Polyunsaturated Fatty Acids Ratio to Cognitive Impairment Development. AB - OBJECTIVE: Cerebral white matter hyperintensity (WMH) with magnetic resonance imaging (MRI) has a potential for predicting cognitive impairment. Serum polyunsaturated fatty acid (PUFA) levels are important for evaluating the extent of atherosclerosis. We investigated whether abnormal PUFA levels affected WMH grading and cognitive function in patients without significant cognitive impairment. METHODS: Atherosclerotic risk factors, the internal carotid artery (ICA) plaque, and serum ratios of eicosapentaenoic to arachidonic acids (EPA/AA) and docosahexaenoic to arachidonic acids (DHA/AA) were assessed in 286 patients. The relationship among these risk factors, WMH, and cognitive function was evaluated using WMH grading and the Mini-Mental State Examination (MMSE). RESULTS: The development of WMH was associated with aging, hypertension, ICA plaques, and a low serum EPA/AA ratio (<0.38, obtained as the median value) but was not related to dyslipidemia, diabetes, smoking, and a low serum DHA/AA ratio (<0.84, obtained as the median value). In addition, the MMSE score deteriorated slightly with the progression of WMH (29.7 +/- 1.0 compared to 28.4 +/- 2.1, P < 0.0001). CONCLUSIONS: The progression of WMH was associated with a low serum EPA/AA ratio and accompanied minimal deterioration in cognitive function. Sufficient omega-3 PUFA intake may be effective in preventing the development of cognitive impairment. PMID- 26583088 TI - Recent Advances on Pathophysiology, Diagnostic and Therapeutic Insights in Cardiac Dysfunction Induced by Antineoplastic Drugs. AB - Along with the improvement of survival after cancer, cardiotoxicity due to antineoplastic treatments has emerged as a clinically relevant problem. Potential cardiovascular toxicities due to anticancer agents include QT prolongation and arrhythmias, myocardial ischemia and infarction, hypertension and/or thromboembolism, left ventricular (LV) dysfunction, and heart failure (HF). The latter is variable in severity, may be reversible or irreversible, and can occur soon after or as a delayed consequence of anticancer treatments. In the last decade recent advances have emerged in clinical and pathophysiological aspects of LV dysfunction induced by the most widely used anticancer drugs. In particular, early, sensitive markers of cardiac dysfunction that can predict this form of cardiomyopathy before ejection fraction (EF) is reduced are becoming increasingly important, along with novel therapeutic and cardioprotective strategies, in the attempt of protecting cardiooncologic patients from the development of congestive heart failure. PMID- 26583091 TI - PI3K/AKT/mTOR/p70S6K Pathway Is Involved in Abeta25-35-Induced Autophagy. AB - Disruption or deregulation of the autophagy system has been implicated in neurodegenerative disorders such as Alzheimer's disease (AD). Abeta plays an important role in this autophagic system. In many cases, autophagy is regulated by the phosphatidylinositol 3-phosphate kinase/AKT/mammalian target of rapamycin/p70 ribosomal protein S6 kinase (PI3K/AKT/mTOR/p70S6K) signaling pathway. However, whether this signaling pathway is involved in Abeta-induced autophagy in neuronal cells is not known. Here, we studied whether Abeta25-35 induces autophagy in HT22 cells and C57 mice and investigated whether PI3K is involved in the autophagy induction. We found that Abeta25-35 inhibited HT22 cell viability in a dose- and time-dependent manner. Abeta25-35 induced autophagosome formation, the conversion of microtubule-associated protein light chain 3 (LC3), and the suppression of the mTOR pathway both in vitro and in vivo. Furthermore, Abeta25-35 impaired the learning abilities of C57 mice. Our study suggests that Abeta25-35 induces autophagy and the PI3K/AKT/mTOR/p70S6K pathway is involved in the process, which improves our understanding of the pathogenesis of AD and provides an additional model for AD research. PMID- 26583089 TI - Extracellular Membrane Vesicles as Vehicles for Brain Cell-to-Cell Interactions in Physiological as well as Pathological Conditions. AB - Extracellular vesicles are involved in a great variety of physiological events occurring in the nervous system, such as cross talk among neurons and glial cells in synapse development and function, integrated neuronal plasticity, neuronal glial metabolic exchanges, and synthesis and dynamic renewal of myelin. Many of these EV-mediated processes depend on the exchange of proteins, mRNAs, and noncoding RNAs, including miRNAs, which occurs among glial and neuronal cells. In addition, production and exchange of EVs can be modified under pathological conditions, such as brain cancer and neurodegeneration. Like other cancer cells, brain tumours can use EVs to secrete factors, which allow escaping from immune surveillance, and to transfer molecules into the surrounding cells, thus transforming their phenotype. Moreover, EVs can function as a way to discard material dangerous to cancer cells, such as differentiation-inducing proteins, and even drugs. Intriguingly, EVs seem to be also involved in spreading through the brain of aggregated proteins, such as prions and aggregated tau protein. Finally, EVs can carry useful biomarkers for the early diagnosis of diseases. Herein we summarize possible roles of EVs in brain physiological functions and discuss their involvement in the horizontal spreading, from cell to cell, of both cancer and neurodegenerative pathologies. PMID- 26583092 TI - An In Vivo Study of Low-Dose Intra-Articular Tranexamic Acid Application with Prolonged Clamping Drain Method in Total Knee Replacement: Clinical Efficacy and Safety. AB - BACKGROUND: Recently, combined intra-articular tranexamic acid (IA-TXA) injection with clamping drain method showed efficacy for blood loss and transfusion reduction in total knee replacement (TKR). However, until now, none of previous studies revealed the effect of this technique on pharmacokinetics, coagulation, and fibrinolysis. MATERIALS AND METHODS: An experimental study was conducted, during 2011-2012, in 30 patients undergoing unilateral TKR. Patients received IA TXA application and then were allocated into six groups regarding clamping drain duration (2-, 4-, 6-, 8-, 10-, and 12-hours). Blood and drainage fluid were collected to measure tranexamic acid (TXA) level and related coagulation and fibrinolytic markers. Postoperative complication was followed for one year. RESULTS: There was no significant difference of serum TXA level at 2 hour and 24 hour among groups (p < 0.05). Serum TXA level at time of clamp release was significantly different among groups with the highest level at 2 hour (p < 0.0001). There was no significant difference of TXA level in drainage fluid, postoperative blood loss, blood transfusion, and postoperative complications (p < 0.05). CONCLUSIONS: Low-dose IA-TXA application in TKR with prolonged clamping drain method is a safe and effective blood conservative technique with only minimal systemic absorption and without significant increase in systemic absorption over time. PMID- 26583094 TI - Basis for the Induction of Tissue-Level Phase-2 Reentry as a Repolarization Disorder in the Brugada Syndrome. AB - AIMS: Human action potentials in the Brugada syndrome have been characterized by delayed or even complete loss of dome formation, especially in the right ventricular epicardial layers. Such a repolarization pattern is believed to trigger phase-2 reentry (P2R); however, little is known about the conditions necessary for its initiation. This study aims to determine the specific mechanisms that facilitate P2R induction in Brugada-affected cardiac tissue in humans. METHODS: Ionic models for Brugada syndrome in human epicardial cells were developed and used to study the induction of P2R in cables, sheets, and a three dimensional model of the right ventricular free wall. RESULTS: In one-dimensional cables, P2R can be induced by adjoining lost-dome and delayed-dome regions, as mediated by tissue excitability and transmembrane voltage profiles, and reduced coupling facilitates its induction. In two and three dimensions, sustained reentry can arise when three regions (delayed-dome, lost-dome, and normal epicardium) are present. CONCLUSIONS: Not only does P2R induction by Brugada syndrome require regions of action potential with delayed-dome and lost-dome, but in order to generate a sustained reentry from a triggered waveback multiple factors are necessary, including heterogeneity in action potential distribution, tissue coupling, direction of stimulation, the shape of the late plateau, the duration of lost-dome action potentials, and recovery of tissue excitability, which is predominantly modulated by tissue coupling. PMID- 26583095 TI - Design and Evaluation of a Fully Implantable Control Unit for Blood Pumps. AB - As the number of donor hearts is limited while more and more patients suffer from end stage biventricular heart failure, Total Artificial Hearts become a promising alternative to conventional treatment. While pneumatic devices sufficiently supply the patients with blood flow, the patient's quality of life is limited by the percutaneous pressure lines and the size of the external control unit. This paper describes the development of the control unit of the ReinHeart, a fully implantable Total Artificial Heart. General requirements for any implantable control unit are defined from a technical and medical point of view: necessity of a Transcutaneous Energy Transmission, autonomous operation, safety, geometry, and efficiency. Based on the requirements, a prototype is designed; it incorporates a LiFePo4 battery pack with charger, a rectifier for transcutaneous energy transmission, the motor's driver electronics, and a microcontroller which monitors and controls all functions. In validation tests, the control unit demonstrated a stable operation on TET and battery supply and a safe switching from one supply to the other. The overall mean efficiency is 14% on TET and 22% on battery supply. The control unit is suitable for chronic animal trials of the ReinHeart. PMID- 26583093 TI - T Helper Subsets, Peripheral Plasticity, and the Acute Phase Protein, alpha1 Antitrypsin. AB - The traditional model of T helper differentiation describes the naive T cell as choosing one of several subsets upon stimulation and an added reciprocal inhibition aimed at maintaining the chosen subset. However, to date, evidence is mounting to support the presence of subset plasticity. This is, presumably, aimed at fine-tuning adaptive immune responses according to local signals. Reprograming of cell phenotype is made possible by changes in activation of master transcription factors, employing epigenetic modifications that preserve a flexible mode, permitting a shift between activation and silencing of genes. The acute phase response represents an example of peripheral changes that are critical in modulating T cell responses. alpha1-antitrypsin (AAT) belongs to the acute phase responses and has recently surfaced as a tolerogenic agent in the context of adaptive immune responses. Nonetheless, AAT does not inhibit T cell responses, nor does it shutdown inflammation per se; rather, it appears that AAT targets non-T cell immunocytes towards changing the cytokine environment of T cells, thus promoting a regulatory T cell profile. The present review focuses on this intriguing two-way communication between innate and adaptive entities, a crosstalk that holds important implications on potential therapies for a multitude of immune disorders. PMID- 26583096 TI - Biological Behaviour and Enhanced Anticorrosive Performance of the Nitrided Superelastic Ti-23Nb-0.7Ta-2Zr-0.5N Alloy. AB - The influence of gas nitriding surface treatment on the superelastic Ti-23Nb 0.7Ta-2Zr-0.5N alloy was evaluated. A thorough characterization of bare and nitrided Ti-based alloy and pure Ti was performed in terms of surface film composition and morphology, electrochemical behaviour, and short term osteoblast response. XPS analysis showed that the nitriding treatment strongly influenced the composition (nitrides and oxynitrides) and surface properties both of the substrate and of the bulk alloy. SEM images revealed that the nitrided surface appears as a similar dotted pattern caused by the formation of N-rich domains coexisting with less nitrided domains, while before treatment only topographical features could be observed. All the electrochemical results confirmed the high chemical stability of the nitride and oxynitride coating and the superiority of the applied treatment. The values of the corrosion parameters ascertained the excellent corrosion resistance of the coated alloy in the real functional conditions from the human body. Cell culture experiments with MG63 osteoblasts demonstrated that the studied biomaterials do not elicit any toxic effects and support cell adhesion and enhanced cell proliferation. Altogether, these data indicate that the nitrided Ti-23Nb-0.7Ta-2Zr-0.5N alloy is the most suitable substrate for application in bone implantology. PMID- 26583097 TI - Does Metal Transfer Differ on Retrieved Ceramic and CoCr Femoral Heads? AB - Metal transfer has been observed on retrieved THA femoral heads for both CoCr and ceramic bearing materials. In vitro wear testing has shown increased wear to polyethylene acetabular liners with the presence of metal transfer. This study sought to investigate the extent of metal transfer on the bearing surface of CoCr and ceramic femoral heads and identify prevalent morphologies. Three bearing couple cohorts: M-PE (n = 50), C-PE (n = 35), and C-C (n = 15), were derived from two previously matched collections (n = 50/group) of CoCr and ceramic femoral heads. From the three cohorts, 75% of the femoral heads showed visual evidence of metal transfer. These femoral heads were analyzed using direct measurement, digital photogrammetry, and white light interferometry. Surface area coverage and curved median surface area were similar among the three cohorts. The most prevalent metal transfer patterns observed were random stripes (n = 21/75), longitudinal stripes (n = 17/75), and random patches (n = 13/75). Metal transfer arc length was shorter in the M-PE cohort. Understanding the morphology of metal transfer may be useful for more realistic recreation of metal transfer in in vitro pin-on-disk and joint simulators studies. PMID- 26583098 TI - The Relevance of the High Frequency Audiometry in Tinnitus Patients with Normal Hearing in Conventional Pure-Tone Audiometry. AB - OBJECTIVE: The majority of tinnitus patients suffer from hearing loss. But a subgroup of tinnitus patients show normal hearing thresholds in the conventional pure-tone audiometry (125 Hz-8 kHz). Here we explored whether the results of the high frequency audiometry (>8 kHz) provide relevant additional information in tinnitus patients with normal conventional audiometry by comparing those with normal and pathological high frequency audiometry with respect to their demographic and clinical characteristics. SUBJECTS AND METHODS: From the database of the Tinnitus Clinic at Regensburg we identified 75 patients with normal hearing thresholds in the conventional pure-tone audiometry. We contrasted these patients with normal and pathological high-frequency audiogram and compared them with respect to gender, age, tinnitus severity, pitch, laterality and duration, comorbid symptoms and triggers for tinnitus onset. RESULTS: Patients with pathological high frequency audiometry were significantly older and had higher scores on the tinnitus questionnaires in comparison to patients with normal high frequency audiometry. Furthermore, there was an association of high frequency audiometry with the laterality of tinnitus. CONCLUSION: In tinnitus patients with normal pure-tone audiometry the high frequency audiometry provides useful additional information. The association between tinnitus laterality and asymmetry of the high frequency audiometry suggests a potential causal role for the high frequency hearing loss in tinnitus etiopathogenesis. PMID- 26583099 TI - Th17 Cell Plasticity and Functions in Cancer Immunity. AB - Th17 cells represent a particular subset of T helper lymphocytes characterized by high production of IL-17 and other inflammatory cytokines. Th17 cells participate in antimicrobial immunity at mucosal and epithelial barriers and particularly fight against extracellular bacteria and fungi. While a role for Th17 cells in promoting inflammation and autoimmune disorders has been extensively and elegantly demonstrated, it is still controversial whether and how Th17 cells influence tumor immunity. Although Th17 cells specifically accumulate in many different types of tumors compared to healthy tissues, the outcome might however differ from a tumor type to another. Th17 cells were consequently associated with both good and bad prognoses. The high plasticity of those cells toward cells exhibiting either anti-inflammatory or in contrast pathogenic functions might contribute to Th17 versatile functions in the tumor context. On one hand, Th17 cells promote tumor growth by inducing angiogenesis (via IL-17) and by exerting themselves immunosuppressive functions. On the other hand, Th17 cells drive antitumor immune responses by recruiting immune cells into tumors, activating effector CD8(+) T cells, or even directly by converting toward Th1 phenotype and producing IFN-gamma. In this review, we are discussing the impact of the tumor microenvironment on Th17 cell plasticity and function and its implications in cancer immunity. PMID- 26583100 TI - T Helper Lymphocyte Subsets and Plasticity in Autoimmunity and Cancer: An Overview. AB - In response to cytokine signalling and other factors, CD4-positive T lymphocytes differentiate into distinct populations that are characterized by the production of certain cytokines and are controlled by different master transcription factors. The spectrum of such populations, which was initially limited to Th1 and Th2 subsets, is currently broadened to include Th17 and Treg subsets, as well as a number of less studied subtypes, such as Tfh, Th9, and Th22. Although these subsets appear to be relatively stable, certain plasticity exists that allows for transition between the subsets and formation of hybrid transition forms. This provides the immune system flexibility needed for adequate response to pathogens but, at the same time, can play a role in the pathogenic processes in cases of deregulation. In this review, we will discuss the properties of T lymphocyte subsets and their plasticity, as well as its implications for cancer and autoimmune diseases. PMID- 26583101 TI - Mobile Phone-Based Joint Angle Measurement for Functional Assessment and Rehabilitation of Proprioception. AB - Assessment of joint functional and proprioceptive abilities is essential for balance, posture, and motor control rehabilitation. Joint functional ability refers to the capacity of movement of the joint. It may be evaluated thereby measuring the joint range of motion (ROM). Proprioception can be defined as the perception of the position and of the movement of various body parts in space. Its role is essential in sensorimotor control for movement acuity, joint stability, coordination, and balance. Its clinical evaluation is commonly based on the assessment of the joint position sense (JPS). Both ROM and JPS measurements require estimating angles through goniometer, scoliometer, laser pointer, and bubble or digital inclinometer. With the arrival of Smartphones, these costly clinical tools tend to be replaced. Beyond evaluation, maintaining and/or improving joint functional and proprioceptive abilities by training with physical therapy is important for long-term management. This review aims to report Smartphone applications used for measuring and improving functional and proprioceptive abilities. It identifies that Smartphone applications are reliable for clinical measurements and are mainly used to assess ROM and JPS. However, there is lack of studies on Smartphone applications which can be used in an autonomous way to provide physical therapy exercises at home. PMID- 26583102 TI - Identification and Biological Characterization of Leishmania (Viannia) guyanensis Isolated from a Patient with Tegumentary Leishmaniasis in Goias, a Nonendemic Area for This Species in Brazil. AB - The aim of this study was to characterize clinical field isolates of Leishmania spp. obtained from patients with American Tegumentary Leishmaniasis (ATL) who live in Goias state, Brazil. The presumed areas of infection were in Goias, Tocantins, and Para states. Three isolates of parasites were identified as L. (Viannia) braziliensis and one as L. (V.) guyanensis. The in vitro growth profiles were found to be similar for all parasites. Nevertheless, in C57BL/6 mice, L. (V.) guyanensis infection was better controlled than L. (V.) braziliensis. Yet in C57BL/6 mice deficient in interferon gamma, L. (V.) guyanensis lesions developed faster than those caused by L. (V.) braziliensis isolates. In BALB/c mice, the development of lesions was similar for isolates from both species; however, on the 11th week of infection, amastigotes could not be observed in macrophages from L. (V.) guyanensis-infected mice. Thus, L. (V.) guyanensis can be circulating in Goias, a state where autochthonous cases of this species had not yet been reported. Considering the difficulties to differentiate L. (V.) guyanensis from L. (V.) braziliensis at the molecular, morphological, and clinical (human and murine models) levels, the presence of L. (V.) guyanensis infections is possibly underestimated in several regions of Brazil. PMID- 26583103 TI - Iodine-Supported Hip Implants: Short Term Clinical Results. AB - We developed a new povidone iodine coating technology for titanium hip implants and performed a clinical trial to assess its usefulness in suppressing postoperative infection. Results indicate that iodine-supported titanium has favorable antibacterial activity, biocompatibility, and no cytotoxicity. Thirty joints in 28 patients were treated using iodine-supported implants. Fourteen joints were revision total hip arthroplasty (THA) after periprosthetic infection, 13 were primary THA for immunosuppressive conditions or pyogenic arthritis, and 3 were conversions from hemiarthroplasty to THA for immunosuppressive conditions. Two examinations were conducted sequentially until final follow-up: white blood cell (WBC) and C-reactive protein (CRP) were measured pre- and postoperatively and thyroid hormone levels in the blood were examined. The mean follow-up period was 33 months (14-78). There were no signs of infection in any patient at the last follow-up. WBC and CRP levels returned to normal within several weeks. No abnormalities of thyroid gland function were detected. Loosening of the implants did not occur in any patient. Excellent bone ingrowth and ongrowth were found around prostheses. No cytotoxicity or adverse effects were detected. These results suggest that iodine-supported THA implants can be highly effective in preventing and treating postoperative infections. PMID- 26583104 TI - Mobility and Balance and Their Correlation with Physiological Factors in Elderly with Different Foot Postures. AB - This study determines (1) the correlation between mobility and balance performances with physiological factors and (2) the relationship between foot postures with anthropometric characteristics and lower limb characteristics among elderly with neutral, pronated, and supinated foot. A cross-sectional observational study was conducted in community-dwelling elderly (age: 69.86 +/- 5.62 years). Participants were grouped into neutral (n = 16), pronated (n = 14), and supinated (n = 14) foot based on the foot posture index classification. Anthropometric data (height, weight, and BMI), lower limb strength (5-STS) and endurance (30 s chair rise test), mobility (TUG), and balance (FSST) were determined. Data were analyzed using Spearman's correlation coefficient. Body weight was negatively and moderately correlated (r(s) = -0.552, P < 0.05) with mobility in supinated foot; moderate-to-high positive linear rank correlation was found between lower limb strength and mobility (r(s) = 0.551 to 0.804, P < 0.05) for pronated and neutral foot. Lower limb endurance was negatively and linearly correlated with mobility in pronated (r(s) = -0.699) and neutral (r(s) = -0.573) foot. No correlation was observed in balance performance with physiological factors in any of the foot postures. We can conclude that muscle function may be the most important feature to make movement possible in older persons regardless of the type of foot postures. PMID- 26583105 TI - Organotypic Cultures of Intervertebral Disc Cells: Responses to Growth Factors and Signaling Pathways Involved. AB - Intervertebral disc (IVD) degeneration is strongly associated with low back pain, a major cause of disability worldwide. An in-depth understanding of IVD cell physiology is required for the design of novel regenerative therapies. Accordingly, aim of this work was the study of IVD cell responses to mitogenic growth factors in a three-dimensional (3D) organotypic milieu, comprising characteristic molecules of IVD's extracellular matrix. In particular, annulus fibrosus (AF) cells were cultured inside collagen type-I gels, while nucleus pulposus (NP) cells in chondroitin sulfate A (CSA) supplemented collagen gels, and the effects of Platelet-Derived Growth Factor (PDGF), basic Fibroblast Growth Factor (bFGF), and Insulin-Like Growth Factor-I (IGF-I) were assessed. All three growth factors stimulated DNA synthesis in both AF and NP 3D cell cultures, with potencies similar to those observed previously in monolayers. CSA supplementation inhibited basal DNA synthesis rates, without affecting the response to growth factors. ERK and Akt were found to be phosphorylated following growth factor stimulation. Blockade of these two signaling pathways using pharmacologic inhibitors significantly, though not completely, inhibited growth factor-induced DNA synthesis. The proposed culture systems may prove useful for further in vitro studies aiming at future interventions for IVD regeneration. PMID- 26583106 TI - Effects of Surface Modification and Bulk Geometry on the Biotribological Behavior of Cross-Linked Polyethylene: Wear Testing and Finite Element Analysis. AB - The wear and creep deformation resistances of polymeric orthopedic bearing materials are both important for extending their longevity. In this study, we evaluated the wear and creep deformation resistances, including backside damage, of different polyethylene (PE) materials, namely, conventional PE, cross-linked PE (CLPE), and poly(2-methacryloyloxyethyl phosphorylcholine)- (PMPC-) grafted CLPE, through wear tests and finite element analysis. The gravimetric and volumetric degrees of wear of disks (3 or 6 mm in thickness) of these materials against a cobalt-chromium-molybdenum alloy pin were examined using a multidirectional pin-on-disk tester. Cross-linking and PMPC grafting decreased the gravimetric wear of the PE disks significantly. The volumetric wear at the bearing surface and the volumetric penetration in the backside of the 3-mm thick PE disk were higher than those of the 6-mm thick PE disk, regardless of the bearing material. The geometrical changes induced in the PE disks consisted of creep, because the calculated internal von Mises stress at the bearing side of all disks and that at the backside of the 3-mm thick disks exceeded their actual yield strengths. A highly hydrated bearing surface layer, formed by PMPC grafting, and a cross-linking-strengthened substrate of adequate thickness are essential for increasing the wear and creep deformation resistances. PMID- 26583107 TI - Cognitive Interventions in Older Persons: Do They Change the Functioning of the Brain? AB - BACKGROUND: Cognitive interventions for older persons that may diminish the burden of cognitive problems and could delay conversion to dementia are of great importance. The underlying mechanisms of such interventions might be psychological compensation and neuronal plasticity. This review provides an overview of the literature concerning the evidence that cognitive interventions cause brain activation changes, even in damaged neural systems. METHOD: A systematic search of the literature was conducted in several international databases, Medline, Embase, Cinahl, Cochrane, and Psychinfo. The methodological quality was assessed according to the guidelines of the Dutch Institute for Health Care Improvement (CBO). RESULTS: Nineteen relevant articles were included with varied methodological quality. All studies were conducted in diverse populations from healthy elderly to patients with dementia and show changes in brain activation after intervention. CONCLUSIONS: The results thus far show that cognitive interventions cause changes in brain activation patterns. The exact interpretation of these neurobiological changes remains unclear. More study is needed to understand the extent to which cognitive interventions are effective to delay conversion to dementia. Future studies should more explicitly try to relate clinically significant improvement to changes in brain activation. Long-term follow-up data are necessary to evaluate the stability of the effects. PMID- 26583108 TI - Quantitative Evaluation of Tissue Surface Adaption of CAD-Designed and 3D Printed Wax Pattern of Maxillary Complete Denture. AB - OBJECTIVE: To quantitatively evaluate the tissue surface adaption of a maxillary complete denture wax pattern produced by CAD and 3DP. METHODS: A standard edentulous maxilla plaster cast model was used, for which a wax pattern of complete denture was designed using CAD software developed in our previous study and printed using a 3D wax printer, while another wax pattern was manufactured by the traditional manual method. The cast model and the two wax patterns were scanned in the 3D scanner as "DataModel," "DataWaxRP," and "DataWaxManual." After setting each wax pattern on the plaster cast, the whole model was scanned for registration. After registration, the deviations of tissue surface between "DataModel" and "DataWaxRP" and between "DataModel" and "DataWaxManual" were measured. The data was analyzed by paired t-test. RESULTS: For both wax patterns produced by the CAD&RP method and the manual method, scanning data of tissue surface and cast surface showed a good fit in the majority. No statistically significant (P > 0.05) difference was observed between the CAD&RP method and the manual method. CONCLUSIONS: Wax pattern of maxillary complete denture produced by the CAD&3DP method is comparable with traditional manual method in the adaption to the edentulous cast model. PMID- 26583109 TI - Psychophysiological Associations between Chronic Tinnitus and Sleep: A Cross Validation of Tinnitus and Insomnia Questionnaires. AB - BACKGROUND: The aim of the present study was to assess the prevalence of insomnia in chronic tinnitus and the association of tinnitus distress and sleep disturbance. METHODS: We retrospectively analysed data of 182 patients with chronic tinnitus who completed the Tinnitus Questionnaire (TQ) and the Regensburg Insomnia Scale (RIS). Descriptive comparisons with the validation sample of the RIS including exclusively patients with primary/psychophysiological insomnia, correlation analyses of the RIS with TQ scales, and principal component analyses (PCA) in the tinnitus sample were performed. TQ total score was corrected for the TQ sleep items. RESULTS: Prevalence of insomnia was high in tinnitus patients (76%) and tinnitus distress correlated with sleep disturbance (r = 0.558). TQ sleep subscore correlated with the RIS sum score (r = 0.690). PCA with all TQ and RIS items showed one sleep factor consisting of all RIS and the TQ sleep items. PCA with only TQ sleep and RIS items showed sleep- and tinnitus-specific factors. The sleep factors (only RIS items) were sleep depth and fearful focusing. The TQ sleep items represented tinnitus-related sleep problems. DISCUSSION: Chronic tinnitus and primary insomnia are highly related and might share similar psychological and neurophysiological mechanisms leading to impaired sleep quality. PMID- 26583110 TI - Recovery of Posture Stability at Different Foot Placements in Patients Who Underwent Minimally Invasive Total Hip Arthroplasty: A One-Year Follow-Up Study. AB - To understand the progression of recovery in postural stability and physical functioning after patients received the minimally invasive total hip arthroplasty (MTHA), we monitor the pain level, functional capacity, and postural stability before and after operation within one year. In total of 23 subjects in our study, we found out that MTHA was effective in relieving pain in first 2 weeks and restoring the hip joint integrity, but the postural stability was influenced especially in tandem stand in both anterior-posterior and medial-lateral directions. The recovery of postural stability and functional capacity in one year duration fluctuated and no consistent improvement tendency was found. We suggested clinicians designing postsurgery rehabilitation program for consistent and progressive long-term recovery of postural stability and fall prevention to optimize surgical results and prevent undesired postoperative consequences. PMID- 26583111 TI - Lost Polarization of Aquaporin4 and Dystroglycan in the Core Lesion after Traumatic Brain Injury Suggests Functional Divergence in Evolution. AB - OBJECTIVE: To understand how aquaporin4 (AQP4) and dystroglycan (DG) polarized distribution change and their roles in brain edema formation after traumatic brain injury (TBI). METHODS: Brain water content, Evans blue detection, real-time PCR, western blot, and immunofluorescence were used. RESULTS: At an early stage of TBI, AQP4 and DG maintained vessel-like pattern in perivascular endfeet; M1, M23, and M1/M23 were increased in the core lesion. At a later stage of TBI, DG expression was lost in perivascular area, accompanied with similar but delayed change of AQP4 expression; expression of M1, M23, and DG and the ratio of M1/M2 were increased. CONCLUSION: At an early stage, AQP4 and DG maintained the polarized distribution. Upregulated M1 and M23 could retard the cytotoxic edema formation. At a later stage AQP4 and DG polarized expression were lost from perivascular endfeet and induced the worst cytotoxic brain edema. The alteration of DG expression could regulate that of AQP4 expression after TBI. PMID- 26583112 TI - Simulating Cardiac Electrophysiology Using Unstructured All-Hexahedra Spectral Elements. AB - We discuss the application of the spectral element method to the monodomain and bidomain equations describing propagation of cardiac action potential. Models of cardiac electrophysiology consist of a system of partial differential equations coupled with a system of ordinary differential equations representing cell membrane dynamics. The solution of these equations requires solving multiple length scales due to the ratio of advection to diffusion that varies among the different equations. High order approximation of spectral elements provides greater flexibility in resolving multiple length scales. Furthermore, spectral elements are extremely efficient to model propagation phenomena on complex shapes using fewer degrees of freedom than its finite element equivalent (for the same level of accuracy). We illustrate a fully unstructured all-hexahedra approach implementation of the method and we apply it to the solution of full 3D monodomain and bidomain test cases. We discuss some key elements of the proposed approach on some selected benchmarks and on an anatomically based whole heart human computational model. PMID- 26583113 TI - Titanium-Nitride Coating of Orthopaedic Implants: A Review of the Literature. AB - Surfaces of medical implants can be enhanced with the favorable properties of titanium-nitride (TiN). In a review of English medical literature, the effects of TiN-coating on orthopaedic implant material in preclinical studies were identified and the influence of these effects on the clinical outcome of TiN coated orthopaedic implants was explored. The TiN-coating has a positive effect on the biocompatibility and tribological properties of implant surfaces; however, there are several reports of third body wear due to delamination, increased ultrahigh molecular weight polyethylene wear, and cohesive failure of the TiN coating. This might be due to the coating process. The TiN-coating process should be optimized and standardized for titanium alloy articulating surfaces. The clinical benefit of TiN-coating of CoCrMo knee implant surfaces should be further investigated. PMID- 26583114 TI - The Relevance of Interoception in Chronic Tinnitus: Analyzing Interoceptive Sensibility and Accuracy. AB - In order to better understand tinnitus and distress associated with tinnitus, psychological variables such as emotional and cognitive processing are a central element in theoretical models of this debilitating condition. Interoception, that is, the perception of internal processes, may be such a psychological factor relevant to tinnitus. Against this background, 20 participants suffering from chronic tinnitus and 20 matched healthy controls were tested with questionnaires, assessing interoceptive sensibility, and participated in two tasks, assessing interoceptive accuracy: the Schandry task, a heartbeat estimation assignment, and a skin conductance fluctuations perception task assessing the participants' ability to perceive phasic increases in sympathetic activation were used. To test stress reactivity, a construct tightly connected to tinnitus onset, we also included a stress induction. No differences between the groups were found for interoceptive accuracy and sensibility. However, the tinnitus group tended to overestimate the occurrence of phasic activation. Loudness of the tinnitus was associated with reduced interoceptive performance under stress. Our results indicate that interoceptive sensibility and accuracy do not play a significant role in tinnitus. However, tinnitus might be associated with a tendency to overestimate physical changes. PMID- 26583115 TI - T Lymphocyte Dynamics in Inflammatory Bowel Diseases: Role of the Microbiome. AB - Humans have coevolved with a complex community of bacterial species also referred to as the microbiome, which reciprocally provides critical contributions to human metabolism and immune system development. Gut microbiome composition differs significantly between individuals depending on host genetics, diet, and environmental factors. A dysregulation of the symbiotic nature of the intestinal host-microbial relationship and an aberrant and persistent immune response are the fundamental processes involved in inflammatory bowel diseases (IBD). Considering the essential role of T cells in IBD and the contributing role of the microbiome in shaping the immune response during the pathogenesis of IBD, this review focuses on the complex relationship, interplay, and communication between the gut microbiome and T cells, including their differentiation into different subsets of effector or regulatory cells. PMID- 26583117 TI - An Overview of the Mechanical Integrity of Dental Implants. AB - With the growing use of dental implants, the incidence of implants' failures grows. Late treatment complications, after reaching full osseointegration and functionality, include mechanical failures, such as fracture of the implant and its components. Those complications are deemed severe in dentistry, albeit being usually considered as rare, and therefore seldom addressed in the clinical literature. The introduction of dental implants into clinical practice fostered a wealth of research on their biological aspects. By contrast, mechanical strength and reliability issues were seldom investigated in the open literature, so that most of the information to date remains essentially with the manufacturers. Over the years, implants have gone through major changes regarding the material, the design, and the surface characteristics aimed at improving osseointegration. Did those changes improve the implants' mechanical performance? This review article surveys the state-of-the-art literature about implants' mechanical reliability, identifying the known causes for fracture, while outlining the current knowledge gaps. Recent results on various aspects of the mechanical integrity and failure of implants are presented and discussed next. The paper ends by a general discussion and suggestions for future research, outlining the importance of mechanical considerations for the improvement of their future performance. PMID- 26583116 TI - Functional and Phenotypic Plasticity of CD4(+) T Cell Subsets. AB - The remarkable plasticity of CD4(+) T cells allows individuals to respond to environmental stimuli in a context-dependent manner. A balance of CD4(+) T cell subsets is critical to mount responses against pathogen challenges to prevent inappropriate activation, to maintain tolerance, and to participate in antitumor immune responses. Specification of subsets is a process beginning in intrathymic development and continuing within the circulation. It is highly flexible to adapt to differences in nutrient availability and the tissue microenvironment. CD4(+) T cell subsets have significant cross talk, with the ability to "dedifferentiate" given appropriate environmental signals. This ability is dependent on the metabolic status of the cell, with mTOR acting as the rheostat. Autoimmune and antitumor immune responses are regulated by the balance between regulatory T cells and Th17 cells. When a homeostatic balance of subsets is not maintained, immunopathology can result. CD4(+) T cells carry complex roles within tumor microenvironments, with context-dependent immune responses influenced by oncogenic drivers and the presence of inflammation. Here, we examine the signals involved in CD4(+) T cell specification towards each subset, interconnectedness of cytokine networks, impact of mTOR signaling, and cellular metabolism in lineage specification and provide a supplement describing techniques to study these processes. PMID- 26583118 TI - Neural Processing of Emotional Prosody across the Adult Lifespan. AB - Emotion recognition deficits emerge with the increasing age, in particular, a decline in the identification of sadness. However, little is known about the age related changes of emotion processing in sensory, affective, and executive brain areas. This functional magnetic resonance imaging (fMRI) study investigated neural correlates of auditory processing of prosody across adult lifespan. Unattended detection of emotional prosody changes was assessed in 21 young (age range: 18-35 years), 19 middle-aged (age range: 36-55 years), and 15 older (age range: 56-75 years) adults. Pseudowords uttered with neutral prosody were standards in an oddball paradigm with angry, sad, happy, and gender deviants (total 20% deviants). Changes in emotional prosody and voice gender elicited bilateral superior temporal gyri (STG) responses reflecting automatic encoding of prosody. At the right STG, responses to sad deviants decreased linearly with age, whereas happy events exhibited a nonlinear relationship. In contrast to behavioral data, no age by sex interaction emerged on the neural networks. The aging decline of emotion processing of prosodic cues emerges already at an early automatic stage of information processing at the level of the auditory cortex. However, top-down modulation may lead to an additional perceptional bias, for example, towards positive stimuli, and may depend on context factors such as the listener's sex. PMID- 26583120 TI - Image-Based Structural Modeling of the Cardiac Purkinje Network. AB - The Purkinje network is a specialized conduction system within the heart that ensures the proper activation of the ventricles to produce effective contraction. Its role during ventricular arrhythmias is less clear, but some experimental studies have suggested that the Purkinje network may significantly affect the genesis and maintenance of ventricular arrhythmias. Despite its importance, few structural models of the Purkinje network have been developed, primarily because current physical limitations prevent examination of the intact Purkinje network. In previous modeling efforts Purkinje-like structures have been developed through either automated or hand-drawn procedures, but these networks have been created according to general principles rather than based on real networks. To allow for greater realism in Purkinje structural models, we present a method for creating three-dimensional Purkinje networks based directly on imaging data. Our approach uses Purkinje network structures extracted from photographs of dissected ventricles and projects these flat networks onto realistic endocardial surfaces. Using this method, we create models for the combined ventricle-Purkinje system that can fully activate the ventricles through a stimulus delivered to the Purkinje network and can produce simulated activation sequences that match experimental observations. The combined models have the potential to help elucidate Purkinje network contributions during ventricular arrhythmias. PMID- 26583119 TI - Screening and Identification of ssDNA Aptamer for Human GP73. AB - As one tumor marker of HCC, Golgi Protein 73 (GP73) is given more promise in the early diagnosis of HCC, and aptamers have been developed to compete with antibodies as biorecognition probes in different detection system. In this study, we utilized GP73 to screen specific ssDNA aptamers by SELEX technique. First, GP73 proteins were expressed and purified by prokaryotic expression system and Nickle ion affinity chromatography, respectively. At the same time, the immunogenicity of purified GP73 was confirmed by Western blotting. The enriched ssDNA library with high binding capacity for GP73 was obtained after ten rounds of SELEX. Then, thirty ssDNA aptamers were sequenced, in which two ssDNA aptamers with identical DNA sequence were confirmed, based on the alignment results, and designated as A10-2. Furthermore, the specific antibody could block the binding of A10-2 to GP73, and the specific binding of A10-2 to GP73 was also supported by the observation that several tumor cell lines exhibited variable expression level of GP73. Significantly, the identified aptamer A10-2 could distinguish normal and cancerous liver tissues. So, our results indicate that the aptamer A10-2 might be developed into one molecular probe to detect HCC from normal liver specimens. PMID- 26583121 TI - Effects of Unilateral Cochlear Implantation on Balance Control and Sensory Organization in Adult Patients with Profound Hearing Loss. AB - Many studies were interested in the consequence of vestibular dysfunction related to cochlear implantation on balance control. This pilot study aimed to assess the effects of unilateral cochlear implantation on the modalities of balance control and sensorimotor strategies. Posturographic and vestibular evaluations were performed in 10 patients (55 +/- 20 years) with profound hearing loss who were candidates to undergo unilateral multichannel cochlear implantation. The evaluation was carried out shortly before and one year after surgery. Posturographic tests were also performed in 10 age-matched healthy participants (63 +/- 16 years). Vestibular compensation was observed within one year. In addition, postural performances of the patients increased within one year after cochlear implantation, especially in the more complex situations, in which sensory information is either unavailable or conflicting. Before surgery, postural performances were higher in the control group compared to the patients' group. One year after cochlear implantation, postural control was close to normalize. The improvement of postural performance could be explained by a mechanism of vestibular compensation. In addition, the recovery of auditory information which is the consequence of cochlear implantation could lead to an extended exploration of the environment possibly favoring the development of new balance strategies. PMID- 26583122 TI - Loss of flfl Triggers JNK-Dependent Cell Death in Drosophila. AB - falafel (flfl) encodes a Drosophila homolog of human SMEK whose in vivo functions remain elusive. In this study, we performed gain-of-function and loss-of-function analysis in Drosophila and identified flfl as a negative regulator of JNK pathway mediated cell death. While ectopic expression of flfl suppresses TNF-triggered JNK-dependent cell death, loss of flfl promotes JNK activation and cell death in the developing eye and wing. These data report for the first time an essential physiological function of flfl in maintaining tissue homeostasis and organ development. As the JNK signaling pathway has been evolutionary conserved from fly to human, a similar role of PP4R3 in JNK-mediated physiological process is speculated. PMID- 26583123 TI - The Effect of Risk Factors on the Levels of Chemical Elements in the Tibial Plateau of Patients with Osteoarthritis following Knee Surgery. AB - The aim of this study was to evaluate the aforementioned chemical elements in tibial plateau samples obtained during knee arthroplasty. The gender-specific analysis of chemical element levels in the bone samples revealed that there were statistically significant differences in the concentration of Pb and Se/Pb ratio. The contents of elements in the tibial plateau in the patients with osteoarthritis (OA) can be arranged in the following descending order: F(-) > K > Zn > Fe > Sr > Pb > Mn > Se > Cd > THg. We observed statistical significant effects of environmental factors including smoking, seafood diet, and geographical distribution on the levels of the elements in tibial bone. Significant positive correlation coefficients were found for the relationships K Cd, Zn-Sr, Zn-F(-), THg-Pb, Pb-Cd, Se-Se/Pb, Se-Se/Cd, Se/Pb-Se/Cd, Pb-Cd/Ca, Cd Cd/Ca, and F(-)-F(-)/Ca.1000. Significant negative correlations were found for the relationships THg-Se/Pb, Pb-Se/Pb, Cd-Se/Pb, K-Se/Cd, Pb-Se/Cd, Cd-Se/Cd, THg Se/THg, Pb-Se/THg, Se-Pb/Cd, Zn-Cd/Ca, and Se/Cd-Cd/Ca. The results reported here may provide a basis for establishing reference values for the tibial plateau in patients with OA who had undergone knee replacement surgery. The concentrations of elements in the bone with OA were determined by age, presence of implants, smoking, fish and seafood diet, and sport activity. PMID- 26583124 TI - Revisiting the Posttherapeutic Cure Criterion in Chagas Disease: Time for New Methods, More Questions, Doubts, and Polemics or Time to Change Old Concepts? AB - One of the most relevant issues beyond the effectiveness of etiological treatment of Chagas disease is the lack of consensual/feasible tools to identify and certify the definitive parasitological cure. Several methods of distinct natures (parasitological, serological, and molecular) have been continuously proposed and novel perspectives are currently under investigation. Although the simultaneous use of distinct tests may offer better contributions and advances, it also leads to controversies of interpretation, with lack of mutual consent of cure criterion amongst researchers and physicians. In fact, when distinct host compartments (blood/tissues) are evaluated and explored, novel questions may arise due to the nature and sensitivity limit of each test. This short analytical review intends to present a chronological and critical overview and discuss the state-of-the-art distinct devices available for posttherapeutic cure assessment in Chagas disease, their contributions, meanings, and interpretation, aiming to point out the major gaps and propose novel insight for future perspectives of posttherapeutic management of Chagas disease patients. PMID- 26583125 TI - Correlation between Trunk Posture and Neck Reposition Sense among Subjects with Forward Head Neck Postures. AB - OBJECTIVE: To assess the correlation of abnormal trunk postures and reposition sense of subjects with forward head neck posture (FHP). METHODS: In all, postures of 41 subjects were evaluated and the FHP and trunk posture including shoulder, scapular level, pelvic side, and anterior tilting degrees were analyzed. We used the head repositioning accuracy (HRA) test to evaluate neck position senses of neck flexion, neck extension, neck right and left side flexion, and neck right and left rotation and calculated the root mean square error in trials for each subject. Spearman's rank correlation coefficients and regression analysis were used to assess the degree of correlation between the trunk posture and HRA value, and a significance level of alpha = 0.05 was considered. RESULTS: There were significant correlations between the HRA value of right side neck flexion and pelvic side tilt angle (p < 0.05). If pelvic side tilting angle increases by 1 degree, right side neck flexion increased by 0.76 degrees (p = 0.026). However, there were no significant correlations between other neck motions and trunk postures. CONCLUSION: Verifying pelvic postures should be prioritized when movement is limited due to the vitiation of the proprioceptive sense of neck caused by FHP. PMID- 26583126 TI - High LIN28A Expressing Ovarian Cancer Cells Secrete Exosomes That Induce Invasion and Migration in HEK293 Cells. AB - Epithelial ovarian cancer is the most aggressive and deadly form of ovarian cancer and is the most lethal gynecological malignancy worldwide; therefore, efforts to elucidate the molecular factors that lead to epithelial ovarian cancer are essential to better understand this disease. Recent studies reveal that tumor cells release cell-secreted vesicles called exosomes and these exosomes can transfer RNAs and miRNAs to distant sites, leading to cell transformation and tumor development. The RNA-binding protein LIN28 is a known marker of stem cells and when expressed in cancer, it is associated with poor tumor outcome. We hypothesized that high LIN28 expressing ovarian cancer cells secrete exosomes that can be taken up by nontumor cells and cause changes in gene expression and cell behavior associated with tumor development. IGROV1 cells were found to contain high LIN28A and secrete exosomes that were taken up by HEK293 cells. Moreover, exposure to these IGROV1 secreted exosomes led to significant increases in genes involved in Epithelial-to-Mesenchymal Transition (EMT), induced HEK293 cell invasion and migration. These changes were not observed with exosomes secreted by OV420 cells, which contain no detectable amounts of LIN28A or LIN28B. No evidence was found of LIN28A transfer from IGROV1 exosomes to HEK293 cells. PMID- 26583127 TI - Simulation of Ectopic Pacemakers in the Heart: Multiple Ectopic Beats Generated by Reentry inside Fibrotic Regions. AB - The inclusion of nonconducting media, mimicking cardiac fibrosis, in two models of cardiac tissue produces the formation of ectopic beats. The fraction of nonconducting media in comparison with the fraction of healthy myocytes and the topological distribution of cells determines the probability of ectopic beat generation. First, a detailed subcellular microscopic model that accounts for the microstructure of the cardiac tissue is constructed and employed for the numerical simulation of action potential propagation. Next, an equivalent discrete model is implemented, which permits a faster integration of the equations. This discrete model is a simplified version of the microscopic model that maintains the distribution of connections between cells. Both models produce similar results when describing action potential propagation in homogeneous tissue; however, they slightly differ in the generation of ectopic beats in heterogeneous tissue. Nevertheless, both models present the generation of reentry inside fibrotic tissues. This kind of reentry restricted to microfibrosis regions can result in the formation of ectopic pacemakers, that is, regions that will generate a series of ectopic stimulus at a fast pacing rate. In turn, such activity has been related to trigger fibrillation in the atria and in the ventricles in clinical and animal studies. PMID- 26583128 TI - Long-Term Outcomes of Cervical Laminoplasty in the Elderly. AB - Incidences of cervical laminoplasty in the elderly are increasing; the influence of other age-related complications and neurological status must be considered for justifying surgery. This study identified the aforementioned influence on long term outcomes of cervical laminoplasty in patients aged >=75 years. Thirty-seven of 38 consecutive patients aged >=75 years who underwent cervical laminoplasty were retrospectively evaluated. Minimum 5-year follow-up was acceptable if patients were complication-free. Follow-up was terminated when neurological evaluation was not possible, owing to death or other serious complications affecting activities of daily living (ADL). Postoperative neurological changes and newly developed severe complications were investigated. Postoperatively, one patient died of acute pneumonia, one remained nonambulatory owing to cerebral infarction, and 35 were ambulatory and were discharged. At a mean follow-up of 78 months, three patients died and nine developed serious complications severely affecting ADL. Of the 25 remaining patients, 23 remained ambulatory at mean follow-up of 105 months. Cox proportional hazard analysis revealed that postoperative motor upper and lower extremities JOA scores of <=2 and <=1, respectively, were risk factors for mortality or other severe complications. Postoperative neurological status can be maintained in the elderly if they remain complication-free. Poorer neurological status significantly affected their ADL and mortality. PMID- 26583129 TI - Relationships of Balance, Gait Performance, and Functional Outcome in Chronic Stroke Patients: A Comparison of Left and Right Lesions. AB - INTRODUCTION: This study compared the balance by center of pressure (COP) and its relationship with gait parameters and functional independence in left (LH) and right (RH) chronic stroke patients. METHODS: In this cross-sectional study, twenty-one hemiparetic stroke patients were assessed for Functional Independence Measure (FIM), balance with a force platform, and gait in the Motion Analysis Laboratory. RESULTS: The amplitudes of the COP in the anteroposterior and mediolateral directions were similar in both groups. The anteroposterior direction was greater than the mediolateral direction. Only the temporal parameters showed any statistically significant differences. The LH showed a significant correlation between stride length, step length, and gait velocity with COP velocity sway for the healthy and paretic lower limbs. In both groups, the area of COP was significantly correlated with stride length. Motor FIM was significantly correlated with the COP in the LH group. CONCLUSION: There was no difference in the performance of balance, gait, and functional independence between groups. The correlation of the COP sway area with stride length in both groups can serve as a guideline in the rehabilitation of these patients where training the static balance may reflect the improvement of the stride length. PMID- 26583130 TI - Importation and Transmission of Parasitic and Other Infectious Diseases Associated with International Adoptees and Refugees Immigrating into the United States of America. AB - Each year, hundreds of millions of people travel across international borders or even oceans, and up to 230 million may remain for long periods. Among these, 3-5 million settle permanently in their new homes, with about 1 million migrating permanently to the United States of America. This may result in transport of parasites and other pathogens, which might become established, infecting individuals in the new location. Beyond concern of disease spread, the health of migrants is of concern since the rigors, circumstances, and living conditions surrounding migrations may increase the vulnerability of migrants to infections. International adoptees and refugees are a small subset of these migrants but are of special significance inasmuch as adoptees may be more vulnerable to infection due to their immature immune status, and refugees may be more vulnerable due to substandard living conditions. Both originate from diverse regions, but often from environments of low hygiene and health care standards. This review examines recent examples of infections reported from adoptees and refugees entering the USA through 2010, highlighting the most common origin countries and the diseases most frequently involved, including Chagas disease, Balamuthia amebic meningoencephalitis, giardiasis, microsporidiosis, hepatitis, measles, pertussis, tuberculosis, malaria, intestinal helminths, and syphilis. PMID- 26583131 TI - Self-Trained Supervised Segmentation of Subcortical Brain Structures Using Multispectral Magnetic Resonance Images. AB - The aim of this paper is investigate the feasibility of automatically training supervised methods, such as k-nearest neighbor (kNN) and principal component discriminant analysis (PCDA), and to segment the four subcortical brain structures: caudate, thalamus, pallidum, and putamen. The adoption of supervised classification methods so far has been limited by the need to define a representative training dataset, operation that usually requires the intervention of an operator. In this work the selection of the training data was performed on the subject to be segmented in a fully automated manner by registering probabilistic atlases. Evaluation of automatically trained kNN and PCDA classifiers that combine voxel intensities and spatial coordinates was performed on 20 real datasets selected from two publicly available sources of multispectral magnetic resonance studies. The results demonstrate that atlas-guided training is an effective way to automatically define a representative and reliable training dataset, thus giving supervised methods the chance to successfully segment magnetic resonance brain images without the need for user interaction. PMID- 26583132 TI - Hyaluronan's Role in Fibrosis: A Pathogenic Factor or a Passive Player? AB - Fibrosis is a debilitating condition that can lead to impairment of the affected organ's function. Excessive deposition of extracellular matrix (ECM) molecules is characteristic of most fibrotic tissues. Fibroblasts activated by cytokines or growth factors differentiate into myofibroblasts that drive fibrosis by depositing ECM molecules, such as collagen, fibronectin, and connective tissue growth factor. Transforming growth factor-beta (TGF-beta) is one of the major profibrotic cytokines which promotes fibrosis by signaling abnormal ECM regulation. Hyaluronan (HA) is a major ECM glycosaminoglycan that is regulated by TGF-beta and whose role in fibrosis is emerging. Aside from its role as a hydrating, space filling polymer, HA regulates different cellular functions and is known to have a role in wound healing and inflammation. Importantly, HA deposition is increased in multiple fibrotic diseases. In this review we highlight studies that link HA to fibrosis and discuss what is known about the role of HA, its receptors, and its anabolic and catabolic enzymes in different fibrotic diseases. PMID- 26583133 TI - Tinnitus and Headache. AB - BACKGROUND: Tinnitus and headache are frequent disorders. Here, we aimed to investigate whether the occurrence of headache among tinnitus patients is purely coincidental or whether tinnitus and headache are pathophysiologically linked. We investigated a large sample of patients with tinnitus and headache to estimate prevalence rates of different headache forms, to determine the relationship between tinnitus laterality and headache laterality, and to explore the relationship between tinnitus and headache over time. METHOD: Patients who presented at a tertiary referral center because of tinnitus and reported comorbid headache were asked to complete validated questionnaires to determine the prevalence of migraine and tension-type headache and to assess tinnitus severity. In addition, several questions about the relationship between headache and tinnitus were asked. RESULTS: Datasets of 193 patients with tinnitus and headache were analysed. 44.6% suffered from migraine, 13% from tension-type headache, and 5.7% from both. Headache laterality was significantly related to tinnitus laterality and in the majority of patients fluctuations in symptom severity of tinnitus and headache were interrelated. CONCLUSION: These findings suggest a significant relationship between tinnitus and headache laterality and symptom interaction over time and argue against a purely coincidental cooccurrence of tinnitus and headache. Both disorders may be linked by common pathophysiological mechanisms. PMID- 26583134 TI - Effects of Nogo-A Silencing on TNF-alpha and IL-6 Secretion and TH Downregulation in Lipopolysaccharide-Stimulated PC12 Cells. AB - Parkinson's disease (PD) is a common degenerative disease that lacks efficient treatment. Myelin-associated neurite outgrowth inhibitor A (Nogo-A) is relevant with inhibition of nerve regeneration and may play vital role in pathogenesis of PD. The study aimed to establish the shRNA expression plasmids of Nogo-A gene and explore the regulatory effects of Nogo-A silencing on the expression of inflammation factor tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL 6) as well as tyrosine hydroxylase (TH) in lipopolysaccharide- (LPS-) stimulated rat PC12 cells. The results showed that both mRNA and protein levels of Nogo-A in pGenesil-nogoA-shRNA group were downregulated. The viabilities of PC12 cells decreased with increase of LPS concentrations. LPS significantly increased the supernatant TNF-alpha and IL-6 concentrations and reduced TH protein expression in PC12 cells, while silencing Nogo-A could block these effects. These results suggested that LPS can activate PC12 cells to secrete inflammatory cytokines and lower the TH expression, which can be regulated by Nogo-A gene silencing. Nogo-A silencing might provide new ideas for PD treatment in the future. PMID- 26583136 TI - Species Composition and Diversity of Malaria Vector Breeding Habitats in Trincomalee District of Sri Lanka. AB - INTRODUCTION: Mosquito larval ecology is important in determining larval densities and species assemblage. This in turn influences malaria transmission in an area. Therefore, understanding larval habitat ecology is important in designing malaria control programs. METHOD: Larval surveys were conducted in 20 localities under five sentinel sites (Padavisiripura, Gomarankadawala, Thoppur, Mollipothana, and Ichchallampaththu) in Trincomalee District, Eastern Province of Sri Lanka, between June 2010 and July 2013. The relationship between seven abiotic variables (temperature, pH, conductivity, Total Dissolved Solid (TDS), turbidity, Dissolved Oxygen (DO), and salinity) was measured. RESULTS: A total of 21,347 anophelines were recorded representing 15 species. Anopheles subpictus 24.72% (5,278/21,347) was the predominant species, followed by 24.67% (5,267/21,347) of An. nigerrimus and 14.56% (3,109/21,347) of An. peditaeniatus. A total of 9,430 breeding habitats under twenty-one categories were identified. An. culcicifacies was noted to be highest from built wells (20.5%) with high salinity (1102.3 +/- 81.8 mg/L), followed by waste water collections (20.2%) having low DO levels (2.85 +/- 0.03 mg/L) and high TDS (1,654 +/- 140 mg/L). CONCLUSION: This study opens an avenue to explore new breeding habitats of malaria vectors in the country and reemphasizes the requirement of conducting entomological surveillance to detect potential transmission of malaria in Sri Lanka under the current malaria elimination programme. PMID- 26583137 TI - Dental Implants Fatigue as a Possible Failure of Implantologic Treatment: The Importance of Randomness in Fatigue Behaviour. AB - OBJECTIVE: To show how random variables concern fatigue behaviour by a probabilistic finite element method. METHODS: Uncertainties on material properties due to the existence of defects that cause material elastic constant are not the same in the whole dental implant the dimensions of the structural element and load history have a decisive influence on the fatigue process and therefore on the life of a dental implant. In order to measure these uncertainties, we used a method based on Markoff chains, Bogdanoff and Kozin cumulative damage model, and probabilistic finite elements method. RESULTS: The results have been obtained by conventional and probabilistic methods. Mathematical models obtained the same result regarding fatigue life; however, the probabilistic model obtained a greater mean life but with more information because of the cumulative probability function. CONCLUSIONS: The present paper introduces an improved procedure to study fatigue behaviour in order to know statistics of the fatigue life (mean and variance) and its probability of failure (fatigue life versus probability of failure). PMID- 26583135 TI - Role of Extracellular Vesicles in Hematological Malignancies. AB - In recent years the role of tumor microenvironment in the progression of hematological malignancies has been widely recognized. Recent studies have focused on how cancer cells communicate within the microenvironment. Among several factors (cytokines, growth factors, and ECM molecules), a key role has been attributed to extracellular vesicles (EV), released from different cell types. EV (microvesicles and exosomes) may affect stroma remodeling, host cell functions, and tumor angiogenesis by inducing gene expression modulation in target cells, thus promoting cancer progression and metastasis. Microvesicles and exosomes can be recovered from the blood and other body fluids of cancer patients and contain and deliver genetic and proteomic contents that reflect the cell of origin, thus constituting a source of new predictive biomarkers involved in cancer development and serving as possible targets for therapies. Moreover, due to their specific cell-tropism and bioavailability, EV can be considered natural vehicles suitable for drug delivery. Here we will discuss the recent advances in the field of EV as actors in hematological cancer progression, pointing out the role of these vesicles in the tumor-host interplay and in their use as biomarkers for hematological malignancies. PMID- 26583138 TI - Clinical End-Points Associated with Mycobacterium tuberculosis and Lung Cancer: Implications into Host-Pathogen Interaction and Coevolution. AB - There is a recent emerging theory that suggests a cross-link between pathogens and cancer. In this context, we examined the association between the Mycobacterium tuberculosis (MTB) with its L-forms (MTB-L) and lung cancer. In the present study, we have optimized and applied a highly sensitive assay to detect the presence of MTB and MTB-L in 187 lung cancer samples and 39 samples of other cancer origins. By carefully controlling confounding factors, we have found that 62% of the lung cancer samples are MTB-L positive, while only 5.1% of the other cancer samples are MTB-L positive. Through generalized linear models and random forest models, we have further identified a set of clinical end-points that are strongly associated with MTB-L presence. Our finding provides the basis for future studies to investigate the underlying mechanism linking MTB-L infection to lung cancer development. PMID- 26583139 TI - The Role of Ankle Proprioception for Balance Control in relation to Sports Performance and Injury. AB - Balance control improvement is one of the most important goals in sports and exercise. Better balance is strongly positively associated with enhanced athletic performance and negatively associated with lower limb sports injuries. Proprioception plays an essential role in balance control, and ankle proprioception is arguably the most important. This paper reviews ankle proprioception and explores synergies with balance control, specifically in a sporting context. Central processing of ankle proprioceptive information, along with other sensory information, enables integration for balance control. When assessing ankle proprioception, the most generalizable findings arise from methods that are ecologically valid, allow proprioceptive signals to be integrated with general vision in the central nervous system, and reflect the signal-in-noise nature of central processing. Ankle proprioceptive intervention concepts driven by such a central processing theory are further proposed and discussed for the improvement of balance control in sport. PMID- 26583140 TI - Durable Mechanical Circulatory Support versus Organ Transplantation: Past, Present, and Future. AB - For more than 30 years, heart transplantation has been a successful therapy for patients with terminal heart failure. Mechanical circulatory support (MCS) was developed as a therapy for end-stage heart failure at a time when cardiac transplantation was not yet a useful treatment modality. With the more successful outcomes of cardiac transplantation in the 1980s, MCS was applied as a bridge to transplantation. Because of donor scarcity and limited long-term survival, heart transplantation has had a trivial impact on the epidemiology of heart failure. Surgical implementation of MCS, both for short- and long-term treatment, affords physicians an opportunity for dramatic expansion of a meaningful therapy for these otherwise mortally ill patients. This review explores the evolution of mechanical circulatory support and its potential for providing long-term therapy, which may address the limitations of cardiac transplantation. PMID- 26583141 TI - A 2D Electromechanical Model of Human Atrial Tissue Using the Discrete Element Method. AB - Cardiac tissue is a syncytium of coupled cells with pronounced intrinsic discrete nature. Previous models of cardiac electromechanics often ignore such discrete properties and treat cardiac tissue as a continuous medium, which has fundamental limitations. In the present study, we introduce a 2D electromechanical model for human atrial tissue based on the discrete element method (DEM). In the model, single-cell dynamics are governed by strongly coupling the electrophysiological model of Courtemanche et al. to the myofilament model of Rice et al. with two-way feedbacks. Each cell is treated as a viscoelastic body, which is physically represented by a clump of nine particles. Cell aggregations are arranged so that the anisotropic nature of cardiac tissue due to fibre orientations can be modelled. Each cell is electrically coupled to neighbouring cells, allowing excitation waves to propagate through the tissue. Cell-to-cell mechanical interactions are modelled using a linear contact bond model in DEM. By coupling cardiac electrophysiology with mechanics via the intracellular Ca(2+) concentration, the DEM model successfully simulates the conduction of cardiac electrical waves and the tissue's corresponding mechanical contractions. The developed DEM model is numerically stable and provides a powerful method for studying the electromechanical coupling problem in the heart. PMID- 26583142 TI - Crossover versus Stabilometric Platform for the Treatment of Balance Dysfunction in Parkinson's Disease: A Randomized Study. AB - Balance dysfunctions are a major challenge in the treatment of Parkinson's disease (PD). Previous studies have shown that rehabilitation can play a role in their treatment. In this study, we have compared the efficacy of two different devices for balance training: stabilometric platform and crossover. We have enrolled 60 PD patients randomly assigned to two groups. The first one (stabilometric group) performed a 4-week cycle of balance training, using the stabilometric platform, whereas the second one (crossover group) performed a 4 week cycle of balance training, using the crossover. The outcome measures used were Unified Parkinson's Disease Rating Scale (UPDRS) part II, Berg Balance Scale (BBS), Timed Up and Go (TUG), and Six Minutes Walking Test (6MWT). Results showed that TUG, BBS, and UPDRS II improved in both groups. There was not difference in the efficacy of the two balance treatments. Patients in both groups improved also the meters walked in the 6MWT at the end of rehabilitation, but the improvement was better for patients performing crossover training. Our results show that the crossover and the stabilometric platform have the same effect on balance dysfunction of Parkinsonian patients, while crossover gets better results on the walking capacity. PMID- 26583143 TI - Calreticulin Binds to Fas Ligand and Inhibits Neuronal Cell Apoptosis Induced by Ischemia-Reperfusion Injury. AB - BACKGROUND: Calreticulin (CRT) can bind to Fas ligand (FasL) and inhibit Fas/FasL mediated apoptosis of Jurkat T cells. However, its effect on neuronal cell apoptosis has not been investigated. PURPOSE: We aimed to evaluate the neuroprotective effect of CRT following ischemia-reperfusion injury (IRI). METHODS: Mice underwent middle cerebral artery occlusion (MCAO) and SH-SY5Y cells subjected to oxygen glucose deprivation (OGD) were used as models for IRI. The CRT protein level was detected by Western blotting, and mRNA expression of CRT, caspase-3, and caspase-8 was measured by real-time PCR. Immunofluorescence was used to assess the localization of CRT and FasL. The interaction of CRT with FasL was verified by coimmunoprecipitation. SH-SY5Y cell viability was determined by MTT assay, and cell apoptosis was assessed by flow cytometry. The measurement of caspase-8 and caspase-3 activity was carried out using caspase activity assay kits. RESULTS: After IRI, CRT was upregulated on the neuron surface and bound to FasL, leading to increased viability of OGD-exposed SH-SY5Y cells and decreased activity of caspase-8 and caspase-3. CONCLUSIONS: This study for the first time revealed that increased CRT inhibited Fas/FasL-mediated neuronal cell apoptosis during the early stage of ischemic stroke, suggesting it to be a potential protector activated soon after IRI. PMID- 26583144 TI - Effects of Sevoflurane and Propofol on Organ Blood Flow in Left Ventricular Assist Devices in Pigs. AB - The aim of this study was to assess the effect of sevoflurane and propofol on organ blood flow in a porcine model with a left ventricular assist device (LVAD). Ten healthy minipigs were divided into 2 groups (5 per group) according to the anesthetic received (sevoflurane or propofol). A Biomedicus centrifugal pump was implanted. Organ blood flow (measured using colored microspheres), markers of tissue injury, and hemodynamic parameters were assessed at baseline (pump off) and after 30 minutes of partial support. Blood flow was significantly higher in the brain (both frontal lobes), heart (both ventricles), and liver after 30 minutes in the sevoflurane group, although no significant differences were recorded for the lung, kidney, or ileum. Serum levels of alanine aminotransferase and total bilirubin were significantly higher after 30 minutes in the propofol group, although no significant differences were detected between the groups for other parameters of liver function, kidney function, or lactic acid levels. The hemodynamic parameters were similar in both groups. We demonstrated that, compared with propofol, sevoflurane increases blood flow in the brain, liver, and heart after implantation of an LVAD under conditions of partial support. PMID- 26583145 TI - Effect of Workplace- versus Home-Based Physical Exercise on Muscle Response to Sudden Trunk Perturbation among Healthcare Workers: A Cluster Randomized Controlled Trial. AB - OBJECTIVES: The present study investigates the effect of workplace- versus home based physical exercise on muscle reflex response to sudden trunk perturbation among healthcare workers. METHODS: Two hundred female healthcare workers (age: 42 [SD 11], BMI: 24 [SD 4], and pain intensity: 3.1 [SD 2.2] on a scale of 0-10) from 18 departments at three hospitals were randomized at the cluster level to 10 weeks of (1) workplace physical exercise (WORK) performed in groups during working hours for 5 * 10 minutes per week and up to 5 group-based coaching sessions on motivation for regular physical exercise, or (2) home-based physical exercise (HOME) performed during leisure time for 5 * 10 minutes per week. Mechanical and neuromuscular (EMG) response to randomly assigned unloading and loading trunk perturbations and questions of fear avoidance were assessed at baseline and 10-week follow-up. RESULTS: No group by time interaction for the mechanical trunk response and EMG latency time was seen following the ten weeks (P = 0.17-0.75). However, both groups demonstrated within-group changes (P < 0.05) in stopping time during the loading and unloading perturbation and in stopping distance during the loading perturbation. Furthermore, EMG preactivation of the erector spinae and fear avoidance were reduced more following WORK than HOME (95% CI -2.7--0.7 (P < 0.05) and -0.14 (-0.30 to 0.02) (P = 0.09)), respectively. WORK and HOME performed 2.2 (SD: 1.1) and 1.0 (SD: 1.2) training sessions per week, respectively. CONCLUSIONS: Although training adherence was higher following WORK compared to HOME this additional training volume did not lead to significant between-group differences in the responses to sudden trunk perturbations. However, WORK led to reduced fear avoidance and reduced muscle preactivity prior to the perturbation onset, compared with HOME. This trial is registered with Clinicaltrials.gov (NCT01921764). PMID- 26583146 TI - Effectiveness and Limitations of Unsupervised Home-Based Balance Rehabilitation with Nintendo Wii in People with Multiple Sclerosis. AB - Balance training represents a critical part of the rehabilitation process of individuals living with multiple sclerosis (MS) since impaired postural control is a distinctive symptom of the disease. In recent years, the use of the Nintendo Wii system has become widespread among rehabilitation specialists for this purpose, but few studies have verified the effectiveness of such an approach using quantitative measures of balance. In this study, we analyzed the postural sway features of a cohort of twenty-seven individuals with MS before and after 5 weeks of unsupervised home-based balance training with the Wii system. Center of pressure (COP) time-series were recorded using a pressure platform and processed to calculate sway area, COP path length, displacements, and velocities in mediolateral (ML) and anteroposterior (AP) directions. Although the results show a significant reduction in sway area, COP displacements, and velocity, such improvements are essentially restricted to the ML direction, as the Wii platform appears to properly stimulate the postural control system in the frontal plane but not in the sagittal one. Available Wii games, although somewhat beneficial, appear not fully suitable for rehabilitation in MS owing to scarce flexibility and adaptability to MS needs and thus specific software should be developed. PMID- 26583147 TI - Hexosamine-Induced TGF-beta Signaling and Osteogenic Differentiation of Dental Pulp Stem Cells Are Dependent on N-Acetylglucosaminyltransferase V. AB - Glycans of cell surface glycoproteins are involved in the regulation of cell migration, growth, and differentiation. N-acetyl-glucosaminyltransferase V (GnT V) transfers N-acetyl-d-glucosamine to form beta1,6-branched N-glycans, thus playing a crucial role in the biosynthesis of glycoproteins. This study reveals the distinct expression of GnT-V in STRO-1 and CD-146 double-positive dental pulp stem cells (DPSCs). Furthermore, we investigated three types of hexosamines and their N-acetyl derivatives for possible effects on the osteogenic differentiation potential of DPSCs. Our results showed that exogenous d-glucosamine (GlcN), N acetyl-d-glucosamine (GlcNAc), d-mannosamine (ManN), and acetyl-d-mannosamine (ManNAc) promoted DPSCs' early osteogenic differentiation in the absence of osteogenic supplements, but d-galactosamine (GalN) or N-acetyl-galactosamine (GalNAc) did not. Effects include the increased level of TGF-beta receptor type I, activation of TGF-beta signaling, and increased mRNA expression of osteogenic differentiation marker genes. The hexosamine-treated DPSCs showed an increased mineralized matrix deposition in the presence of osteogenic supplements. Moreover, the level of TGF-beta receptor type I and early osteogenic differentiation were abolished in the DPSCs transfected with siRNA for GnT-V knockdown. These results suggest that GnT-V plays a critical role in the hexosamine-induced activation of TGF-beta signaling and subsequent osteogenic differentiation of DPSCs. PMID- 26583149 TI - Occult Infection in Aseptic Joint Loosening and the Diagnostic Role of Implant Sonication. AB - Our aim was to determine the incidence of occult infection and to examine the role of ultrasound sonication of the implants in cases of presumed aseptic loosening in a prospective trial. Joint swabs, aspirates, and deep tissue samples were obtained from around the prosthesis for routine microbiology. Each prosthesis was sonicated and the sonicate examined with Gram staining and extended cultures. There were 106 joints in the study of which 54 were revised for aseptic loosening and 52 were assigned to the control revision group. There were 9 positive cultures with 8/54 positive cultures in the aseptic loosening group and 1/52 in the control revision group (p = 0.017, associated OR 47.7). We found concordant results between sonication fluid culture and conventional samples in 5/9 cultures. Preoperative inflammatory markers were not prognostic for infection. Coagulase-negative Staphylococcus was the most commonly cultured organism (7/9). Previously unrecognised infection was present in 15% of patients undergoing revision for aseptic loosening. Ultrasound sonication of the removed prosthesis was less sensitive than conventional sampling techniques. We recommend routine intraoperative sampling for patients having revision for aseptic loosening, but we do not support the routine use of ultrasound sonication for its detection. PMID- 26583150 TI - Transcriptional Changes Associated with Long-Term Left Ventricle Volume Overload in Rats: Impact on Enzymes Related to Myocardial Energy Metabolism. AB - Patients with left ventricle (LV) volume overload (VO) remain in a compensated state for many years although severe dilation is present. The myocardial capacity to fulfill its energetic demand may delay decompensation. We performed a gene expression profile, a model of chronic VO in rat LV with severe aortic valve regurgitation (AR) for 9 months, and focused on the study of genes associated with myocardial energetics. Methods. LV gene expression profile was performed in rats after 9 months of AR and compared to sham-operated controls. LV glucose and fatty acid (FA) uptake was also evaluated in vivo by positron emission tomography in 8-week AR rats treated or not with fenofibrate, an activator of FA oxidation (FAO). Results. Many LV genes associated with mitochondrial function and metabolism were downregulated in AR rats. FA beta-oxidation capacity was significantly impaired as early as two weeks after AR. Treatment with fenofibrate, a PPARalpha agonist, normalized both FA and glucose uptake while reducing LV dilation caused by AR. Conclusion. Myocardial energy substrate preference is affected early in the evolution of LV-VO cardiomyopathy. Maintaining a relatively normal FA utilization in the myocardium could translate into less glucose uptake and possibly lesser LV remodeling. PMID- 26583151 TI - Evaluation of Myoelectric Activity of Paraspinal Muscles in Adolescents with Idiopathic Scoliosis during Habitual Standing and Sitting. AB - There is a number of research work in the literature that have applied sEMG biofeedback as an instrument for muscle rehabilitation. Therefore, sEMG is a good tool for this research work and is used to record the myoelectric activity in the paraspinal muscles of those with AIS during habitual standing and sitting. After the sEMG evaluation, the root-mean-square (RMS) sEMG values of the paraspinal muscles in the habitual postures reflect the spinal curvature situation of the PUMC Type Ia and IIc subjects. Both groups have a stronger average RMS sEMG value on the convex side of the affected muscle regions. Correction to posture as instructed by the physiotherapist has helped the subjects to achieve a more balanced RMS sEMG ratio in the trapezius and latissimus dorsi regions; the erector spinae in the thoracic region and/or erector spinae in the lumbar region. It is, therefore, considered that with regular practice of the suggested positions, those with AIS can use motor learning to achieve a more balanced posture. Consequently, the findings can be used in less intrusive early orthotic intervention and provision of care to those with AIS. PMID- 26583148 TI - Novel Therapeutic Strategies for Reducing Right Heart Failure Associated Mortality in Fibrotic Lung Diseases. AB - Fibrotic lung diseases carry a significant mortality burden worldwide. A large proportion of these deaths are due to right heart failure and pulmonary hypertension. Underlying contributory factors which appear to play a role in the mechanism of progression of right heart dysfunction include chronic hypoxia, defective calcium handling, hyperaldosteronism, pulmonary vascular alterations, cyclic strain of pressure and volume changes, elevation of circulating TGF-beta, and elevated systemic NO levels. Specific therapies targeting pulmonary hypertension include calcium channel blockers, endothelin (ET-1) receptor antagonists, prostacyclin analogs, phosphodiesterase type 5 (PDE5) inhibitors, and rho-kinase (ROCK) inhibitors. Newer antifibrotic and anti-inflammatory agents may exert beneficial effects on heart failure in idiopathic pulmonary fibrosis. Furthermore, right ventricle-targeted therapies, aimed at mitigating the effects of functional right ventricular failure, include beta-adrenoceptor (beta-AR) blockers, angiotensin-converting enzyme (ACE) inhibitors, antioxidants, modulators of metabolism, and 5-hydroxytryptamine-2B (5-HT2B) receptor antagonists. Newer nonpharmacologic modalities for right ventricular support are increasingly being implemented. Early, effective, and individualized therapy may prevent overt right heart failure in fibrotic lung disease leading to improved outcomes and quality of life. PMID- 26583152 TI - Efficacy and Safety of Repeated Courses of rTMS Treatment in Patients with Chronic Subjective Tinnitus. AB - BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has shown promising effects in the treatment of chronic subjective tinnitus. However, little is known about maintenance treatment in order to achieve long-lasting improvements. OBJECTIVE: This study addresses the questions whether the repeated application of rTMS treatment can contribute to the maintenance or enhancement of treatment effects and if so in which cases repetitive treatment courses are beneficial. METHODS: 55 patients with chronic tinnitus were treated with two rTMS treatment courses with ten treatment sessions each. The mean intertreatment interval was 20.65 +/- 18.56 months. Tinnitus severity was assessed before and after each treatment course. RESULTS: Both treatments were well tolerated and caused significant improvement of tinnitus severity. The main predictor for the outcome of the second treatment was the development of tinnitus distress in the phase between both treatment courses: the more patients worsened in this interval, the more they improved during the second treatment course. CONCLUSION: Repeated application of rTMS seems to be useful in tinnitus management and should preferentially be offered to patients who experience a worsening of their tinnitus during the intertreatment interval, irrespective of their response to the first treatment course. PMID- 26583153 TI - Peer Support and Psychosocial Pain Management Strategies for Children with Systemic Lupus Erythematosus. AB - This paper reviews information on Systemic Lupus Erythematosus (SLE) in children. Children with this chronic illness often experience pain related to their condition. They also can experience social isolation. This paper reviews psychosocial information on peer support and cognitive behavioral pain management strategies. The information presented in this paper provides new insights for health professionals assisting children and families in coping with psychological facets of this disease. Research focusing on ways by which peers and friends can support the child's use of psychological pain management strategies will provide new information for the literature. PMID- 26583154 TI - RNA 1 and RNA 2 Genomic Segments of Chronic Bee Paralysis Virus Are Infectious and Induce Chronic Bee Paralysis Disease. AB - Chronic bee paralysis virus (CBPV) causes an infectious and contagious disease of adult honeybees. Its segmented genome is composed of two major positive single stranded RNAs, RNA 1 (3,674 nt) and RNA 2 (2,305 nt). Three minor RNAs (about 1,000 nt each) have been described earlier but they were not detected by sequencing of CBPV genome. In this study, the results of in vivo inoculation of the two purified CBPV major RNAs are presented and demonstrate that RNA 1 and RNA 2 are infectious. Honeybees inoculated with 10(9) RNA copies per bee developed paralysis symptoms within 6 days after inoculation. The number of CBPV RNA copies increased significantly throughout the infection. Moreover, the negative strand of CBPV RNA was detected by RT-PCR, and CBPV particles were visualized by electronic microscopy in inoculated honeybees. Taken together, these results show that CBPV RNA 1 and CBPV RNA 2 segments can induce virus replication and produce CBPV virus particles. Therefore, the three minor RNAs described in early studies are not essential for virus replication. These data are crucial for the development of a reverse genetic system for CBPV. PMID- 26583155 TI - Prolactin and Dehydroepiandrosterone Levels in Women with Systemic Lupus Erythematosus: The Role of the Extrapituitary Prolactin Promoter Polymorphism at 1149G/T. AB - Systemic lupus erythematosus (SLE) has shown an association with high levels of prolactin, low levels of dehydroepiandrosterone (DHEA), and induction of inflammatory cytokines in the serum of patients with the disease. This preliminary study examined the relevance of a -1149G/T functional single nucleotide polymorphism (SNP) (rs1341239) in the promoter of the extrapituitary prolactin gene in a cohort of African American and European American women with lupus. Examination of this SNP revealed that the -1149TT genotype was correlated with higher levels of prolactin in serum and prolactin gene expression (p = 0.0001) in peripheral blood mononuclear cells (PBMCs). Lower levels of DHEA in serum were demonstrated in lupus patients (p = 0.001); those with the -1149TT genotype had the lowest levels of DHEA. Furthermore, a small subset of women who were on DHEA therapy and had a TT genotype showed a significant decrease in prolactin gene expression and lower disease activity scores (SLEDAI). Lupus patients, particularly African Americans, had significantly higher levels of IL-6 (p = 0.0001) and TNF-alpha (p = 0.042). This study suggests that the -1149TT genotype may be a risk factor for lupus and may predict who could possibly benefit from DHEA therapy; therefore, these results should be validated in a larger cohort with all ethnic groups. PMID- 26583157 TI - High Avidity dsDNA Autoantibodies in Brazilian Women with Systemic Lupus Erythematosus: Correlation with Active Disease and Renal Dysfunction. AB - We investigated in Brazilian women with SLE the prevalence and levels of high avidity (HA) dsDNA antibodies and tested their correlation with lupus activity and biomarkers of renal disease. We also compared these correlations to those observed with total dsDNA antibodies and antibodies against nucleosome (ANuA). Autoantibodies were detected by ELISA, while C3 and C4 levels were determined by nephelometry. Urine protein/creatinine ratio was determined, and lupus activity was measured by SLEDAI-2K. The prevalence of total and HA dsDNA antibodies was similar to but lower than that verified for ANuA. The levels of the three types of antibodies were correlated, but the correlation was more significant between HA dsDNA antibodies and ANuA. High avidity dsDNA antibodies correlated positively with ESR and SLEDAI and inversely with C3 and C4. Similar correlations were observed for ANuA levels, whereas total dsDNA antibodies only correlated with SLEDAI and C3. The levels of HA dsDNA antibodies were higher in patients with proteinuria, but their levels of total dsDNA antibodies and ANuA were unaltered. High avidity dsDNA antibodies can be found in high prevalence in Brazilian women with SLE and are important biomarkers of active disease and kidney dysfunction. PMID- 26583156 TI - Pros and Cons of Antigen-Presenting Cell Targeted Tumor Vaccines. AB - In therapeutic antitumor vaccination, dendritic cells play the leading role since they decide if, how, when, and where a potent antitumor immune response will take place. Since the disentanglement of the complexity and merit of different antigen presenting cell subtypes, antitumor immunotherapeutic research started to investigate the potential benefit of targeting these subtypes in situ. This review will discuss which antigen-presenting cell subtypes are at play and how they have been targeted and finally question the true meaning of targeting antitumor-based vaccines. PMID- 26583159 TI - Relationship of serum uric acid, serum creatinine and serum cystatin C with maternal and fetal outcomes in rural Indian pregnant women. AB - BACKGROUND: Hypertensive disorders are the most common in pregnancy. Several studies showed a positive correlation between elevated maternal serum uric acid (UA), serum creatinine and adverse maternal and fetal outcomes, but only a few studies are available on serum cystatin C and maternal and fetal outcomes. The present study was undertaken to study the association of serum UA, creatinine and cystatin C with maternal and fetal outcomes. METHODS: Out of 116 pregnant women 69 women had no hypertension and 47 had hypertension with or without proteinuria. Serum UA, creatinine and cystatin C was measured by modified Uricase method, modified kinetic Jaffe's reaction and particle-enhanced immunonephelometric assay respectively. Multivariate logistic regression was performed to determine the independent effects of serum UA, creatinine and cystatin C on maternal and fetal outcomes using stata 13.1. RESULTS: The adjusted odds ratio (OR) was 3.73 (95% CI: 1.18-11.75; P=0.024) for UA; 15.79 (95% CI: 3.04-81.94; P=0.001) for creatinine and 2.03 (95% CI: 0.70-5.87; P=0.192) for cystatin C in hypertensive disorders of pregnancy. All the three renal parameters were not significantly associated with birth weight, gestational age of delivery and mode of delivery after adjusting for the confounding factors. CONCLUSIONS: Serum creatinine and uric acid are independent risk factors for hypertensive disorders of pregnancy. High serum uric acid is associated with low birth weight and delivery by caesarian section whereas high serum creatinine with preterm delivery only before adjustment for confounding factors and not after adjustment. Serum cystatin C was not significantly associated with the maternal and fetal outcomes. PMID- 26583164 TI - Biomarker detection technologies and future directions. AB - Biomarkers play a vital role in disease detection and treatment follow-up. It is important to note that diseases in the early stage are typically treated with the greatest probability of success. However, due to various technical difficulties in current technologies for the detection of biomarkers, the potential of biomarkers is not explored completely. Therefore, the developments of technologies, which can enable the accurate detection of prostate cancer at an early stage with simple, experimental protocols are highly inevitable. This critical review evaluates the current methods and technologies used in the detection of biomarkers. The aim of this article is to provide a comprehensive review covering the advantages and disadvantages of the biomarker detection methods. Future directions for the development of technologies to achieve highly selective and sensitive detection of biomarkers for point-of-care applications are also commented on. PMID- 26583165 TI - Analysis of cobalt phosphide (CoP) nanorods designed for non-enzyme glucose detection. AB - The nanorods of cobalt phosphide have been prepared and evaluated as an electrocatalyst for non-enzyme glucose detection. The nanorods were used to modify the surface of an electrode and detect glucose without the help of an enzyme for the first time. The crystal structure and composition of cobalt phosphide were identified by XRD and XPS, respectively, and the morphology of the as-prepared samples was observed by FESEM and TEM. The electrochemical measurement results indicate that the CoP-based sensor exhibits excellent catalytic activity and a far lower detection potential compared to bare GCE. Specifically, the electrocatalytic mechanism of CoP in the detection of glucose was proposed based on a series of physical characterization methods, electrochemical measurements, and theoretical calculations. PMID- 26583158 TI - Viral Interference and Persistence in Mosquito-Borne Flaviviruses. AB - Mosquito-borne flaviviruses are important pathogens for humans, and the detection of two or more flaviviruses cocirculating in the same geographic area has often been reported. However, the epidemiological impact remains to be determined. Mosquito-borne flaviviruses are primarily transmitted through Aedes and Culex mosquitoes; these viruses establish a life-long or persistent infection without apparent pathological effects. This establishment requires a balance between virus replication and the antiviral host response. Viral interference is a phenomenon whereby one virus inhibits the replication of other viruses, and this condition is frequently associated with persistent infections. Viral interference and persistent infection are determined by several factors, such as defective interfering particles, competition for cellular factors required for translation/replication, and the host antiviral response. The interaction between two flaviviruses typically results in viral interference, indicating that these viruses share common features during the replicative cycle in the vector. The potential mechanisms involved in these processes are reviewed here. PMID- 26583198 TI - Structure, Energies, and Vibrational Frequencies of Solvated Li(+) in Ionic Liquids: Role of Cation Type. AB - This study examines the structure of five ionic liquids all of them containing bis[(trifluoromethyl)sulfonyl]imide (TFSI) as the anion with five different cations: Dimethylammonium, N-propylammonium, N-methyl-1-propylpiperidinium, N methyl-3-methylpyridinium, and N-methylpyrrolidinium. This study is based on quantum chemical calculations of structure, energetics, and vibrational spectroscopy associated with solutions of Li(+) in the five ionic liquids examined. We have shown that the Li-TFSI ion-pair stabilization is 2.5-4 fold larger than those of the ion pairs of five cations with TFSI. A large number of different species containing LikTFSInCtm (Ct represent one of five cations studied, k, n, m = 0-2) were examined in detail. The results suggest that Li (TFSI)2 is a highly stable species and may be responsible for the transport of Li ions in these ionic liquids. The vibrational analysis suggests that the high stability of the Li-TFSI ion pair is mainly due to Coulomb interaction between the Li ion and two oxygen atoms bound to the two sulfur atoms in the TFSI anion. This O-Li-O bond exhibits stretching and bending modes that may allow monitoring of these ion pairs. PMID- 26583199 TI - Reply to Perez and Ball. PMID- 26583200 TI - Quantum Yield of Single Surface Plasmons Generated by a Quantum Dot Coupled with a Silver Nanowire. AB - The interactions between surface plasmons (SPs) in metal nanostructures and excitons in quantum emitters (QEs) lead to many interesting phenomena and potential applications that are strongly dependent on the quantum yield of SPs. The difficulty in distinguishing all the possible exciton recombination channels hinders the experimental determination of SP quantum yield. Here, we experimentally measured for the first time the quantum yield of single SPs generated by the exciton-plasmon coupling in a system composed of a single quantum dot and a silver nanowire (NW). By utilizing the SP guiding property of the NW, the decay rates of all the exciton recombination channels, i.e., direct free space radiation channel, SP generation channel, and nonradiative damping channel, are quantitatively obtained. It is determined that the optimum emitter NW coupling distance for the largest SP quantum yield is about 10 nm, resulting from the different distance-dependent decay rates of the three channels. These results are important for manipulating the coupling between plasmonic nanostructures and QEs and developing on-chip quantum plasmonic devices for potential nanophotonic and quantum information applications. PMID- 26583201 TI - Pinpointing RNA-Protein Cross-Links with Site-Specific Stable Isotope-Labeled Oligonucleotides. AB - High affinity RNA-protein interactions are critical to cellular function, but directly identifying the determinants of binding within these complexes is often difficult. Here, we introduce a stable isotope mass labeling technique to assign specific interacting nucleotides in an oligonucleotide-protein complex by photo cross-linking. The method relies on generating site-specific oxygen-18-labeled phosphodiester linkages in oligonucleotides, such that covalent peptide oligonucleotide cross-link sites arising from ultraviolet irradiation can be assigned to specific sequence positions in both RNA and protein simultaneously by mass spectrometry. Using Lin28A and a let-7 pre-element RNA, we demonstrate that mass labeling permits unambiguous identification of the cross-linked sequence positions in the RNA-protein complex. PMID- 26583202 TI - Time savings of weekly versus three-times-per-week administration of erythropoiesis stimulating agents in United States dialysis patients. AB - OBJECTIVE: Previous research suggests that erythropoiesis stimulating agent (ESA) administration in dialysis is a time-consuming task and switching to less frequently dosed ESAs may offer operational efficiencies. Our objective was to describe and measure the time spent on tasks in the ESA administration process in US dialysis centers, and to estimate potential efficiency gains of using weekly (QW) administration vs three-times-per-week (TIW) administration. METHODS: We conducted a time and motion study of staff time required to prepare, administer and document ESA doses. Dialysis centers using intravenous administration of TIW epoetin alfa (EPO) or QW darbepoetin alfa (DPO) were selected in pairs (one EPO, one DPO) from the same organization to help control for differences in ESA protocols and staffing patterns across organizations. ESA-related tasks were timed by trained observers. Time savings of TIW vs QW administration were estimated. Staff were interviewed about alternate activities that could be accomplished if time were saved in the ESA process. RESULTS: A total of 200 administrations were observed (81 DPO, 119 EPO). A mean of 2.26 (95% CI: 2.1-2.5) minutes per dose were required for ESA administration. ESA process time per administration did not vary significantly between EPO and DPO (p = 0.83). Estimated potential monthly staff time savings for an average facility of 70 patients totaled 23 hours, due to fewer ESA administrations using QW DPO. Patient education and fulfillment of care plans were identified as opportunities for improved care processes that could be implemented if staff time was freed up from the ESA process. LIMITATIONS: Results should not be generalized to other countries, ESAs and/or dosing frequencies. CONCLUSIONS: Switching from TIW EPO to QW DPO can result in time savings due to fewer administrations and provide opportunities to redirect nurse time towards activities aimed at improving patient care. PMID- 26583203 TI - Correlates of Trichomonas vaginalis Among Middle Age and Older Adults Who Use Drugs. AB - BACKGROUND: Recent studies have reported high rates of Trichomonas vaginalis among middle age and older adults. Though trichomoniasis risk factors in this age cohort remain largely unknown, illicit drug use has been associated with increased incidence of sexually transmitted infections (STIs). The number of mid older adults using illicit drugs has increased significantly in recent years suggesting the need to understand the relationship between drug use and STIs in this age cohort. OBJECTIVES: This study examined the relationship between drug use, sexual-risk behaviors, and biologically confirmed T. vaginalis in a sample of mid-older and younger adults who reported recent drug use. METHODS: The cross sectional design examined the relationship between past 6-month drug use, sexual risk-behaviors, and PCR-confirmed T. vaginalis in 264 adults age 18-64 who were recruited from Baltimore, Maryland. These relationships were also explored in the age-stratified sample among those 18-44 years ("younger") and individuals 45+ years ("mid-older"). RESULTS: Trichomoniasis prevalence did not differ significantly between younger (18.8%) and mid-older (19.1%) adults. Mid-older adults that tested positive for T. vaginalis were more likely to have used marijuana and crack in the past 6 months. Among younger adults, there were no associations between trichomoniasis and past 6-month drug use and sexual-risk behavior. CONCLUSIONS/IMPORTANCE: Age- and drug-related immune decline is hypothesized to contribute to increase susceptibility to T. vaginalis in mid older adults. Broad screening for trichomoniasis, particularly among older adults who are often not regarded as at risk for STIs, is needed to control this often asymptomatic infection. PMID- 26583205 TI - Optical Signature of Formation of Protein Corona in the Firefly Luciferase-CdSe Quantum Dot Complex. AB - Theoretical investigation of protein corona is challenging because of the size of the protein-dot complex. In this work, we have addressed this computational bottleneck by combining pseudopotential + explicitly correlated Hartree-Fock QM calculations with molecular mechanics, molecular dynamics, and Monte Carlo techniques. The optical gap of a 5 nm CdSe quantum dot (Cd1159Se1183) was computed by sequential addition of luciferase (Lu), and a red shift of 8 nm in the lambdamax of protein corona (CdSe-Lu7) was observed. PMID- 26583206 TI - Quantifying Computational Effort Required for Stochastic Averages. AB - We propose a measure that quantifies the effort needed to compute a given stochastic average, considered in the context of molecular modeling. This "difficulty index" is defined in terms of CPU time, observed uncertainty, and a characteristic scale for the quantity being computed. This metric provides a focus for optimization and comparison of methods and, if applied broadly, could aid understanding of the impact of models, algorithms, implementations, and platforms on performance of molecular modeling techniques. PMID- 26583204 TI - Zoonotic Leprosy in the Southeastern United States. AB - Nine-banded armadillos (Dasypus novemcinctus) are naturally infected with Mycobacterium leprae and have been implicated in zoonotic transmission of leprosy. Early studies found this disease mainly in Texas and Louisiana, but armadillos in the southeastern United States appeared to be free of infection. We screened 645 armadillos from 8 locations in the southeastern United States not known to harbor enzootic leprosy for M. leprae DNA and antibodies. We found M. leprae-infected armadillos at each location, and 106 (16.4%) animals had serologic/PCR evidence of infection. Using single-nucleotide polymorphism variable number tandem repeat genotyping/genome sequencing, we detected M. leprae genotype 3I-2-v1 among 35 armadillos. Seven armadillos harbored a newly identified genotype (3I-2-v15). In comparison, 52 human patients from the same region were infected with 31 M. leprae types. However, 42.3% (22/52) of patients were infected with 1 of the 2 M. leprae genotype strains associated with armadillos. The geographic range and complexity of zoonotic leprosy is expanding. PMID- 26583207 TI - Assignment of Electronic Bands in the Photoelectron Spectrum of the VO2(-) Anion. AB - Assignments of electronic bands in the high resolution photoelectron spectrum of the VO2- anion obtained via slow electron velocity-map imaging are discussed in light of a recent theoretical paper that questioned them and proposed an alternate assignment. PMID- 26583208 TI - Diabatic Population Matrix Formalism for Performing Molecular Mechanics Style Simulations with Multiple Electronic States. AB - An accurate description of nonbonded interactions is important in investigating dynamics of molecular systems. In many situations, fixed point charge models are successfully applied to explaining various chemical phenomena. However, these models with conventional formulations will not be appropriate in elucidating the detailed dynamics during nonadiabatic events. This is mainly because the chemical properties of any molecule, especially its electronic populations, significantly change with respect to molecular distortions in the vicinity of the surface crossing. To overcome this issue in molecular simulations yet within the framework of the fixed point charge model, we define a diabatic electronic population matrix and substitute it for the conventional adiabatic partial charges. We show that this matrix can be readily utilized toward attaining more reliable descriptions of Coulombic interactions, in combination with the interpolation formalism for obtaining the intramolecular interaction potential. We demonstrate how the mixed formalism with the diabatic charges and the interpolation can be applied to molecular simulations by conducting adiabatic and nonadiabatic molecular dynamics trajectory calculations of the green fluorescent protein chromophore anion in aqueous environment. PMID- 26583209 TI - Infinite Boundary Terms of Ewald Sums and Pairwise Interactions for Electrostatics in Bulk and at Interfaces. AB - We present a unified derivation of the Ewald sum for electrostatics in a three dimensional infinite system that is periodic in one, two, or three dimensions. The derivation leads to the Ewald3D sum being expressed as a sum of a real space contribution and a reciprocal space contribution, as in previous work. However, the k -> 0 term in the reciprocal space contribution is analyzed further and found to give an additional contribution that is not part of previous reciprocal space contributions. The transparent derivation provides a unified view of the existing conducting infinite boundary term, the vacuum spherical infinite boundary term and the vacuum planar infinite boundary term for the Ewald3D sum. The derivation further explains that the infinite boundary term is conditional for the Ewald3D sum because it depends on the asymptotic behavior that the system approaches the infinite in 3D but it becomes a definite term for the Ewald2D or Ewald1D sum irrespective of the asymptotic behavior in the reduced dimensions. Moreover, the unified derivation yields two formulas for the Ewald sum in one dimensional periodicity, and we rigorously prove that the two formulas are equivalent. These formulas might be useful for simulations of organic crystals with wirelike shapes or liquids confined in uniform cylinders. More importantly, the Ewald3D, Ewald2D, and Ewald1D sums are further written as sums of well defined pairwise potentials overcoming the difficulty in splitting the total Coulomb potential energy into contributions from each individual group of charges. The pairwise interactions with their clear physical meaning of the explicit presence of the periodic images thus can be used to consistently perform analysis based on the trajectories from computer simulations of bulk or interfaces. PMID- 26583210 TI - The Theory of Ultra-Coarse-Graining. 2. Numerical Implementation. AB - The increasing interest in the modeling of complex macromolecular systems in recent years has spurred the development of numerous coarse-graining (CG) techniques. However, many of the CG models are constructed assuming that all details beneath the resolution of CG degrees of freedom are fast and average out, which sets limits on the resolution of feasible coarse-grainings and on the range of applications of the CG models. Ultra-coarse-graining (UCG) makes it possible to construct models at any desired resolution while accounting for discrete conformational or chemical changes within the CG sites that can modulate the interactions between them. Here, we discuss the UCG methodology and its numerical implementation. We pay particular attention to the numerical mechanism for including state transitions between different conformations within CG sites because this has not been discussed previously. Using a simple example of 1,2 dichloroethane, we demonstrate the ability of the UCG model to reproduce the multiconfigurational behavior of this molecular liquid, even when each molecule is modeled with only one CG site. The methodology can also be applied to other molecular liquids and macromolecular systems with time scale separation between conformational transitions and other intramolecular motions and rotations. PMID- 26583211 TI - Multiple-Replica Strategies for Free-Energy Calculations in NAMD: Multiple-Walker Adaptive Biasing Force and Walker Selection Rules. AB - From the most powerful supercomputers to multicore desktops and laptops, parallel computing architectures have been in the mainstream for some time. However, numerical schemes for calculating free energies in molecular systems that directly leverage this hardware paradigm, usually taking the form of multiple replica strategies, are just now on the cusp of becoming standard practice. Here, we present a modification of the popular molecular dynamics program NAMD that is envisioned to facilitate the use of powerful multiple-replica strategies to improve ergodic sampling for a specific class of free-energy methods known as adaptive biasing force. We describe the software implementation in a so-called multiple-walker context, alongside the interface that makes the proposed approach accessible to the end users. We further evaluate the performance of the adaptive biasing force multiple-walker strategy for a model system, namely, the reversible folding of a short peptide, and show, in particular, in regions of the transition coordinate where convergence of the free-energy calculation is encumbered by hidden barriers, that the multiple-walker strategy can yield far more reliable results in appreciably less real time on parallel architectures, relative to standard, single-replica calculations. PMID- 26583212 TI - Spin Density Distribution in Open-Shell Transition Metal Systems: A Comparative Post-Hartree-Fock, Density Functional Theory, and Quantum Monte Carlo Study of the CuCl2 Molecule. AB - We present a comparative study of the spatial distribution of the spin density of the ground state of CuCl2 using Density Functional Theory (DFT), quantum Monte Carlo (QMC), and post-Hartree-Fock wave function theory (WFT). A number of studies have shown that an accurate description of the electronic structure of the lowest-lying states of this molecule is particularly challenging due to the interplay between the strong dynamical correlation effects in the 3d shell and the delocalization of the 3d hole over the chlorine atoms. More generally, this problem is representative of the difficulties encountered when studying open shell metal-containing molecular systems. Here, it is shown that qualitatively different results for the spin density distribution are obtained from the various quantum-mechanical approaches. At the DFT level, the spin density distribution is found to be very dependent on the functional employed. At the QMC level, Fixed Node Diffusion Monte Carlo (FN-DMC) results are strongly dependent on the nodal structure of the trial wave function. Regarding wave function methods, most approaches not including a very high amount of dynamic correlation effects lead to a much too high localization of the spin density on the copper atom, in sharp contrast with DFT. To shed some light on these conflicting results Full CI-type (FCI) calculations using the 6-31G basis set and based on a selection process of the most important determinants, the so-called CIPSI approach (Configuration Interaction with Perturbative Selection done Iteratively) are performed. Quite remarkably, it is found that for this 63-electron molecule and a full CI space including about 10(18) determinants, the FCI limit can almost be reached. Putting all results together, a natural and coherent picture for the spin distribution is proposed. PMID- 26583213 TI - Analytic Gradient for Density Functional Theory Based on the Fragment Molecular Orbital Method. AB - The equations for the response terms for the fragment molecular orbital (FMO) method interfaced with the density functional theory (DFT) gradient are derived and implemented. Compared to the previous FMO-DFT gradient, which lacks response terms, the FMO-DFT analytic gradient has improved accuracy for a variety of functionals, when compared to numerical gradients. The FMO-DFT gradient agrees with the fully ab initio DFT gradient in which no fragmentation is performed, while reducing the nonlinear scaling associated with standard DFT. Solving for the response terms requires the solution of the coupled perturbed Kohn-Sham (CPKS) equations, where the CPKS equations are solved through a decoupled Z vector procedure called the self-consistent Z-vector method. FMO-DFT is a nonvariational method and the FMO-DFT gradient is unique compared to standard DFT gradients in that the FMO-DFT gradient requires terms from both DFT and time dependent density functional theory (TDDFT) theories. PMID- 26583214 TI - Efficient Implementation of Local Excitation Approximation for Treating Excited States of Molecules in Condensed Phase. AB - An efficient implementation of the local excitation approximation (LEA) of time dependent density functional theory (TDDFT) or time-dependent Hartree-Fock, (TDHF) (or configuration interaction singles, CIS) method has been developed in this work. The LEA-TDDFT, -TDHF, and -CIS methods have been applied to investigate the solvatochromic shift of the n -> pi* vertical excitation energy of acetone in aqueous solution. The main idea of the LEA scheme is that only local electron excitations within a certain active region (called as chromophore) are treated to obtain the excitation energies for locally excited electronic states. We have proposed an efficient localization procedure to obtain regional localized molecular orbitals (RLMOs) localized on the chromophore subunit. To ensure the accuracy of the TDDFT, TDHF, and CIS schemes for the studied system, we choose one acetone and six nearest-neighboring waters as the active region for each acetone-water cluster. For acetone in aqueous solution, the LEA-TDDFT calculations on 600 acetone-water configurations (generated from molecular dynamics simulation) suggest that the blueshift in the n -> pi* vertical electronic excitation energy is 1621 +/- 52 cm(-1), which is in good agreement with the available experimental blue shift of 1500-1700 cm(-1). PMID- 26583215 TI - Binding and Diffusion of Lithium in Graphite: Quantum Monte Carlo Benchmarks and Validation of van der Waals Density Functional Methods. AB - Highly accurate diffusion quantum Monte Carlo (QMC) studies of the adsorption and diffusion of atomic lithium in AA-stacked graphite are compared with van der Waals-including density functional theory (DFT) calculations. Predicted QMC lattice constants for pure AA graphite agree with experiment. Pure AA-stacked graphite is shown to challenge many van der Waals methods even when they are accurate for conventional AB graphite. Highest overall DFT accuracy, considering pure AA-stacked graphite as well as lithium binding and diffusion, is obtained by the self-consistent van der Waals functional vdW-DF2, although errors in binding energies remain. Empirical approaches based on point charges such as DFT-D are inaccurate unless the local charge transfer is assessed. The results demonstrate that the lithium-carbon system requires a simultaneous highly accurate description of both charge transfer and van der Waals interactions, favoring self consistent approaches. PMID- 26583216 TI - Variational, Self-Consistent Implementation of the Perdew-Zunger Self-Interaction Correction with Complex Optimal Orbitals. AB - A variational, self-consistent implementation of the Perdew-Zunger self interaction correction (PZ-SIC), based on a unified Hamiltonian and complex optimal orbitals, is presented for finite systems and atom-centered basis sets. A simplifying approximation allowing the use of real canonical orbitals is proposed. The algorithm is based on two-step self-consistent field iterations, where the updates of the canonical orbitals and the optimal orbitals are done separately. Calculations of the energy of atoms ranging from H to Ar are presented, using various generalized gradient functionals (PBE, APBE, PBEsol) and a meta-generalized gradient functional (TPSS). While the energy of atoms is poorly described by PBEsol, which is a functional optimized to reproduce properties of solids, the PZ-SIC brings the calculations into good agreement with the best ab initio estimates. The importance of using complex optimal orbitals becomes particularly clear in calculations using the TPSS functional, where the original functional gives good results while the application of PZ-SIC with real orbitals gives highly inaccurate results. With complex optimal orbitals, PZ-SIC slightly improves the accuracy of the TPSS functional. The charge localization problem that plagues Kohn-Sham DFT functionals, including hybrid functionals, is illustrated by calculations on the CH3 + F(-) complex, where even PBEsol with PZ SIC is found to give estimates of both energy and charge with accuracy comparable to that of coupled cluster calculations. PMID- 26583217 TI - Molecular Binding in Post-Kohn-Sham Orbital-Free DFT. AB - Molecular binding in post-Kohn-Sham orbital-free DFT is investigated, using noninteracting kinetic energy functionals that satisfy the uniform electron gas condition and which are inhomogeneous under density scaling. A parameter is introduced that quantifies binding, and a series of functionals are determined from fits to near-exact effective homogeneities and/or Kohn-Sham noninteracting kinetic energies. These are then used to investigate the relationship between binding and the accuracy of the effective homogeneity and noninteracting kinetic energy at the equilibrium geometry. For a series of 11 molecules, the binding broadly improves as the effective homogeneity improves, although the extent to which it improves is dependent on the accuracy of the noninteracting kinetic energy; optimal binding appears to require both to be accurate simultaneously. The use of a Thomas-Fermi-von Weizsacker form, augmented with a second gradient correction, goes some way toward achieving this, exhibiting molecular binding on average. The findings are discussed in terms of the noninteracting kinetic potential and the Hellmann-Feynman theorem. The extent to which the functionals can reproduce the system-dependence of the near-exact effective homogeneity is quantified, and potential energy curves are presented for selected molecules. The study provides impetus for including density scaling homogeneity considerations in the design of noninteracting kinetic energy functionals. PMID- 26583218 TI - Accurate Excited State Geometries within Reduced Subspace TDDFT/TDA. AB - A method for the calculation of TDDFT/TDA excited state geometries within a reduced subspace of Kohn-Sham orbitals has been implemented and tested. Accurate geometries are found for all of the fluorophore-like molecules tested, with at most all valence occupied orbitals and half of the virtual orbitals included but for some molecules even fewer orbitals. Efficiency gains of between 15 and 30% are found for essentially the same level of accuracy as a standard TDDFT/TDA excited state geometry optimization calculation. PMID- 26583219 TI - Nucleic Acid Quadruplexes Based on 8-Halo-9-deazaxanthines: Energetics and Noncovalent Interactions in Quadruplex Stems. AB - Structural and energetic features of artificial DNA quadruplexes consisting of base tetrads and their stacks with Na(+)/K(+) ion(s) inside the central pore and incorporating halogenated derivatives of xanthine, 8-fluoro-9-deazaxanthine (FdaX), 8-chloro-9-deazaxanthine (CldaX), 8-bromo-9-deazaxanthine (BrdaX), or 8 iodo-9-deazaxanthine (IdaX), have been investigated by modern state-of-the-art computational tools. The DNA (or RNA) quadruplex models based on 8-halo-9 deazaxanthines are predicted to be more stable relative to those with unmodified xanthine due to the increased stabilizing contributions coming from all three main types of weak interactions (H-bonding, stacking, and ion coordination). Methods for analyzing the electron density are used to understand the nature of forces determining the stability of the system and to gain a predictive potential. Quadruplex systems incorporating polarizable halogen atoms (chlorine, bromine, or iodine) benefit significantly from the stabilizing stacking between the individual tetrads due to an increased dispersion contribution as compared to xanthine and guanine, natural references used. Ion coordination induces a significant rearrangement of electron density in the quadruplex stem as visualized by electron deformation density (EDD) and analyzed by ETS-NOCV and Voronoi charges. Na(+) induces larger electron polarization from the quadruplex toward the ion, whereas K(+) has a higher propensity to electron sharing (identified by QTAIM delocalization index). We expect that our results will contribute to the development of novel strategies to further modify and analyze the natural G-quadruplex core. PMID- 26583220 TI - Ab Initio Implementation of the Frenkel-Davydov Exciton Model: A Naturally Parallelizable Approach to Computing Collective Excitations in Crystals and Aggregates. AB - A fragment-based method for computing vertical excitation energies of molecular clusters is introduced based on an ab initio implementation of a Frenkel-Davydov exciton model consisting of singly excited monomer basis states. Our strategy is to construct and diagonalize the exact Hartree-Fock Hamiltonian in such a basis. Matrix elements between nonorthogonal determinants are computed via the corresponding orbital transformation and the resulting generalized eigenvalue problem is solved to determine collective excitation energies and wave functions. The basis may be expanded to include higher-lying fragment excited states in order to account for interfragment polarization effects. Absolute errors of ?0.1 eV (relative to supersystem methods) are achievable for systems such as water clusters and crystalline arrays of organic chromophores such as pentacene and napthalenediimide. Preliminary tests for a nine-chromophore subunit of an organic nanotube suggest that it is possible to target the optically bright state, even when it is a high-lying excitation, by using carefully selected basis states. The highly parallel nature of this method provides a foundation for further developments to treat collective excitations in large molecular assemblies. PMID- 26583221 TI - Expanding the Scope of Density Derived Electrostatic and Chemical Charge Partitioning to Thousands of Atoms. AB - The density derived electrostatic and chemical (DDEC/c3) method is implemented into the onetep program to compute net atomic charges (NACs), as well as higher order atomic multipole moments, of molecules, dense solids, nanoclusters, liquids, and biomolecules using linear-scaling density functional theory (DFT) in a distributed memory parallel computing environment. For a >1000 atom model of the oxygenated myoglobin protein, the DDEC/c3 net charge of the adsorbed oxygen molecule is approximately -1e (in agreement with the Weiss model) using a dynamical mean field theory treatment of the iron atom, but much smaller in magnitude when using the generalized gradient approximation. For GaAs semiconducting nanorods, the system dipole moment using the DDEC/c3 NACs is about 5% higher in magnitude than the dipole computed directly from the quantum mechanical electron density distribution, and the DDEC/c3 NACs reproduce the electrostatic potential to within approximately 0.1 V on the nanorod's solvent accessible surface. As examples of conducting materials, we study (i) a 55-atom Pt cluster with an adsorbed CO molecule and (ii) the dense solids Mo2C and Pd3V. Our results for solid Mo2C and Pd3V confirm the necessity of a constraint enforcing exponentially decaying electron density in the tails of buried atoms. PMID- 26583222 TI - Computation of the Density Matrix in Electronic Structure Theory in Parallel on Multiple Graphics Processing Units. AB - The algorithm developed in Cawkwell, M. J. et al. J. Chem. Theory Comput. 2012 , 8 , 4094 for the computation of the density matrix in electronic structure theory on a graphics processing unit (GPU) using the second-order spectral projection (SP2) method [ Niklasson, A. M. N. Phys. Rev. B 2002 , 66 , 155115 ] has been efficiently parallelized over multiple GPUs on a single compute node. The parallel implementation provides significant speed-ups with respect to the single GPU version with no loss of accuracy. The performance and accuracy of the parallel GPU-based algorithm is compared with the performance of the SP2 algorithm and traditional matrix diagonalization methods on a multicore central processing unit (CPU). PMID- 26583223 TI - Local Hybrid QM/QM Calculations of Reaction Pathways in Metallobiosites. AB - The accurate calculation of activation barriers is fundamental for the modeling of reaction pathways. However, the computational cost of describing electronic correlation at metal sites can be a deterrent. A possible solution to this problem is the use of hybrid QM/QM approaches, which combine different levels of theory in a single calculation. In this way, the metal and its direct vicinity can be treated, for example, with a coupled cluster method, with the remaining system at the MP2 level. We present calculations on two selected molybdenum complexes modeling the active sites of sulfite oxidase and dimethyl sulfoxide reductase. Use is made of the LMOMO scheme, a hybrid QM/QM model that enables the partition of the system directly at the orbital level, thus avoiding the use of model systems. The results show that even when the high-level calculations are restricted to the orbitals directly located at the metal atom, most of the electronic correlation effects are captured. PMID- 26583224 TI - Distributed Multipoles from a Robust Basis-Space Implementation of the Iterated Stockholder Atoms Procedure. AB - The recently developed iterated stockholder atoms (ISA) approach of Lillestolen and Wheatley (Chem. Commun. 2008, 5909) offers a powerful method for defining atoms in a molecule. However, the real-space algorithm is known to converge very slowly, if at all. Here, we present a robust, basis-space algorithm of the ISA method and demonstrate its applicability on a variety of systems. We show that this algorithm exhibits rapid convergence (taking around 10-80 iterations) with the number of iterations needed being unrelated to the system size or basis set used. Further, we show that the multipole moments calculated using this basis space ISA method are as good as, or better than, those obtained from Stone's distributed multipole analysis (J. Chem. Theory Comput. 2005, 1, 1128), exhibiting better convergence properties and resulting in better behaved penetration energies. This can have significant consequences in the development of intermolecular interaction models. PMID- 26583225 TI - Stable and Efficient Linear Scaling First-Principles Molecular Dynamics for 10000+ Atoms. AB - The recent progress of linear-scaling or O(N) methods in density functional theory (DFT) is remarkable. Given this, we might expect that first-principles molecular dynamics (FPMD) simulations based on DFT could treat more realistic and complex systems using the O(N) technique. However, very few examples of O(N) FPMD simulations exist to date, and information on the accuracy and reliability of the simulations is very limited. In this paper, we show that efficient and robust O(N) FPMD simulations are now possible by the combination of the extended Lagrangian Born-Oppenheimer molecular dynamics method, which was recently proposed by Niklasson ( Phys. Rev. Lett. 2008 , 100 , 123004 ), and the density matrix method as an O(N) technique. Using our linear-scaling DFT code Conquest, we investigate the reliable calculation conditions for accurate O(N) FPMD and demonstrate that we are now able to do practical, reliable self-consistent FPMD simulations of a very large system containing 32768 atoms. PMID- 26583226 TI - Getting down to the Fundamentals of Hydrogen Bonding: Anharmonic Vibrational Frequencies of (HF)2 and (H2O)2 from Ab Initio Electronic Structure Computations. AB - This work presents a systematic investigation into the basis set convergence of harmonic vibrational frequencies of (H2O)2 and (HF)2 computed with second-order Moller-Plesset perturbation theory (MP2) and the coupled-cluster singles and doubles method with perturbative connected triples, CCSD(T), while employing correlation-consistent basis sets as large as aug-cc-pV6Z. The harmonic vibrational frequencies presented here are expected to lie within a few cm(-1) of the complete basis set (CBS) limit. For these important hydrogen-bonding prototype systems, a basis set of at least quadruple-zeta quality augmented with diffuse functions is required to obtain harmonic vibrational frequencies within 10 cm(-1) of the CBS limit. In addition, second-order vibrational perturbation theory (VPT2) anharmonic corrections yield CCSD(T) vibrational frequencies in excellent agreement with experimental spectra, differing by no more than a few cm(-1) for the intramonomer fundamental vibrations. D0 values predicted by CCSD(T) VPT2 computations with a quadruple-zeta basis set reproduce the experimental values of (HF)2 and (H2O)2 to within 2 and 21 cm(-1), respectively. PMID- 26583227 TI - Halogen Bonding from Dispersion-Corrected Density-Functional Theory: The Role of Delocalization Error. AB - Halogen bonds are formed when a Lewis base interacts with a halogen atom in a different molecule, which acts as an electron acceptor. Due to its charge transfer component, halogen bonding is difficult to model using many common density-functional approximations because they spuriously overstabilize halogen bonded dimers. It has been suggested that dispersion-corrected density functionals are inadequate to describe halogen bonding. In this work, we show that the exchange-hole dipole moment (XDM) dispersion correction coupled with functionals that minimize delocalization error (for instance, BH&HLYP, but also other half-and-half functionals) accurately model halogen-bonded interactions, with average errors similar to other noncovalent dimers with less charge-transfer effects. The performance of XDM is evaluated for three previously proposed benchmarks (XB18 and XB51 by Kozuch and Martin, and the set proposed by Bauza et al.) spanning a range of binding energies up to ~50 kcal/mol. The good performance of BH&HLYP-XDM is comparable to M06-2X, and extends to the "extreme" cases in the Bauza set. This set contains anionic electron donors where charge transfer occurs even at infinite separation, as well as other charge transfer dimers belonging to the pnictogen and chalcogen bonding classes. We also show that functional delocalization error results in an overly delocalized electron density and exact-exchange hole. We propose intermolecular Bader delocalization indices as an indicator of both the donor-acceptor character of an intermolecular interaction and the delocalization error coming from the underlying functional. PMID- 26583228 TI - Ab Initio QM/MM Study Shows a Highly Dissociated SN2 Hydrolysis Mechanism for the cGMP-Specific Phosphodiesterase-5. AB - Phosphodiesterases (PDEs) are the sole enzymes hydrolyzing the important second messengers cGMP and cAMP and have been identified as therapeutic targets for several diseases. The most successful examples are PDE5 inhibitors (i.e., sildenafil and tadalafil), which have been approved for the treatment of male erectile dysfunction and pulmonary hypertension. However, the side effects mostly due to nonselective inhibition toward other PDE isoforms, set back the clinical usage of PDE5 inhibitors. Until now, the exact catalytic mechanism of the substrate cGMP by PDE5 is still unclear. Herein, the first computational study on the catalytic hydrolysis mechanism of cGMP for PDE5 (catalytic domain) is performed by employing the state-of-the-art ab initio quantum mechanics/molecular mechanics (QM/MM) molecular dynamics (MD) simulations. Our simulations show a SN2 type reaction procedure via a highly dissociated transition state with a reaction barrier of 8.88 kcal/mol, which is quite different from the previously suggested hydrolysis mechanism of cAMP for PDE4. Furthermore, the subsequent ligand exchange and the release of the product GMP have also been investigated by binding energy analysis and MD simulations. It is deduced that ligand exchange would be the rate-determining step of the whole reaction, which is consistent with many previous experimental results. The obtained mechanistic insights should be valuable for not only the rational design of more specific inhibitors toward PDE5 but also understanding the general hydrolysis mechanism of cGMP-specific PDEs. PMID- 26583229 TI - Catalytic Mechanism of Retroviral Integrase for the Strand Transfer Reaction Explored by QM/MM Calculations. AB - Integrase (IN) is one of the three fundamental enzymes for the HIV life cycle. It irreversibly inserts the viral DNA into the host DNA, infecting the host cells. Although there are 37 compounds currently used in the HIV-1 antiretroviral therapy, only three have IN as a target. Lack of structural and mechanistic information on IN greatly contributes to such a small number. Prototype Foamy Virus (PFV) IN has an enzymatic activity remarkably similar to HIV IN and is considered a model system to study the catalytic mechanism of HIV IN. Recently, the crystal structure of the PFV intasome became available, which allowed us to perform accurate high-level quantum mechanics/molecular mechanics (QM/MM) calculations to determine the strand transfer reaction mechanism followed by IN. We describe here, for the first time with atomic detail, the integration of a viral genome into the DNA of a host cell. We found that the strand transfer reaction mechanism has three distinct steps: deprotonation and activation of the nucleophile; SN2 transesterification involving a pentacoordinated transition state; and protonation of the leaving group. The chemical steps have a limiting potential activation energy of 14.8 kcal/mol at the MPWB1K/6-311++G(2d,2p) level of theory, which is consistent with the upper limit established experimentally (25.1 kcal/mol) associated with the product release. This work improves the mechanistic knowledge on the IN chemistry and provides accurate structures of all the intermediates and transition states, which can be used as templates for the discovery of new IN inhibitors. PMID- 26583230 TI - Benchmarks for Characterization of Minima, Transition States, and Pathways in Atomic, Molecular, and Condensed Matter Systems. AB - A set of benchmark systems is defined to compare different computational approaches for characterizing local minima, transition states, and pathways in atomic, molecular, and condensed matter systems. Comparisons between several commonly used methods are presented. The strengths and weaknesses are discussed, as well as implementation details that are important for achieving good performance. All of the benchmarks and methods are provided in an online database to make the implementation details available and the results reproducible. While this paper provides a snapshot of the benchmark results, the online framework is structured to be dynamic and incorporate new methods and codes as they are developed. PMID- 26583231 TI - Treatment of Ionic Strength in Biomolecular Simulations of Charged Lipid Bilayers. AB - Biological membranes are complex systems that have recently attracted a significant scientific interest. Due to the presence of many different anionic lipids, these membranes are usually negatively charged and sensitive to pH. The protonation states of lipids and the ion distribution close to the bilayer are two of the main challenges in biomolecular simulations of these systems. These two problems have been circumvented by using ionized (deprotonated) anionic lipids and enough counterions to preserve the electroneutrality. In this work, we propose a method based on the Poisson-Boltzmann equation to estimate the counterion and co-ion concentration close to a lipid bilayer that avoids the need for neutrality at this microscopic level. The estimated number of ions was tested in molecular dynamics simulations of a 25% DMPA/DMPC lipid bilayer at different ionization levels. Our results show that the system neutralization represents an overestimation of the number of counterions. Consequently, the resulting lipid bilayer becomes too ordered and practically insensitive to ionization. On the other hand, our proposed approach is able to correctly model the ionization dependent isothermal phase transition of the bilayer observed experimentally. Furthermore, our approach is not too computationally expensive and can easily be used to model diverse charged biomolecular systems in molecular dynamics simulations. PMID- 26583232 TI - Systematic Improvement of Potential-Derived Atomic Multipoles and Redundancy of the Electrostatic Parameter Space. AB - We assess the accuracy of force field (FF) electrostatics at several levels of approximation from the standard model using fixed partial charges to conformational specific multipole fits including up to quadrupole moments. Potential-derived point charges and multipoles are calculated using least-squares methods for a total of ~1000 different conformations of the 20 natural amino acids. Opposed to standard charge fitting schemes the procedure presented in the current work employs fitting points placed on a single isodensity surface, since the electrostatic potential (ESP) on such a surface determines the ESP at all points outside this surface. We find that the effect of multipoles beyond partial atomic charges is of the same magnitude as the effect due to neglecting conformational dependency (i.e., polarizability), suggesting that the two effects should be included at the same level in FF development. The redundancy at both the partial charge and multipole levels of approximation is quantified. We present an algorithm which stepwise reduces or increases the dimensionality of the charge or multipole parameter space and provides an upper limit of the ESP error that can be obtained at a given truncation level. Thereby, we can identify a reduced set of multipole moments corresponding to ~40% of the total number of multipoles. This subset of parameters provides a significant improvement in the representation of the ESP compared to the simple point charge model and close to the accuracy obtained using the complete multipole parameter space. The selection of the ~40% most important multipole sites is highly transferable among different conformations, and we find that quadrupoles are of high importance for atoms involved in pi-bonding, since the anisotropic electric field generated in such regions requires a large degree of flexibility. PMID- 26583233 TI - AMBER-DYES: Characterization of Charge Fluctuations and Force Field Parameterization of Fluorescent Dyes for Molecular Dynamics Simulations. AB - Recent advances in single molecule fluorescence experiments and theory allow a direct comparison and improved interpretation of experiment and simulation. To this end, force fields for a larger number of dyes are required which are compatible with and can be integrated into existing biomolecular force fields. Here, we developed, characterized, and implemented AMBER-DYES, a modular fluorescent label force field, for a set of 22 fluorescent dyes and their linkers from the Alexa, Atto, and Cy families, which are in common use for single molecule spectroscopy experiments. The force field is compatible with the AMBER protein force fields and the GROMACS molecular dynamics simulation program. The high electronic polarizability of the delocalized pi-electron orbitals, as found in many fluorescent dyes, poses a particular challenge to point charge based force fields such as AMBER. To quantify the charge fluctuations due to the electronic polarizability, we simulated the 22 dyes in explicit solvent and sampled the charge fluctuations using QM/MM simulations at the B3LYP/6 31G*//TIP3P level of theory. The analysis of the simulations enabled us to derive ensemble fitted RESP charges from the solvated charge distributions of multiple trajectories. We observed broad, single peaked charge distributions for the conjugated ring atoms with well-defined mean values. The charge fitting procedure was validated against published charges of the dyelike amino acid tryptophan, which showed good agreement with existing tryptophan parameters from the AMBER, CHARMM, and OPLS force field families. A principal component analysis of the charge fluctuations revealed that a small number of collective coordinates suffices to describe most of the in-plane dye polarizability. The AMBER-DYES force field allows the rapid preparation of all atom molecular dynamics simulations of fluorescent systems for state of the art multi microsecond trajectories. PMID- 26583234 TI - Efficient Handling of Gaussian Charge Distributions: An Application to Polarizable Molecular Models. AB - We present a mesh-based Ewald summation method that is suitable for the calculation of the electrostatic interaction between Gaussian charge distributions, instead of point charges. As an application, we implemented the method in the Gromacs simulation package and tested it with a polarizable water model, showing that the interaction between Gaussian charge distributions can be computed with a small (10%) additional computational cost with respect to the point charge case. In addition, since the performance of polarizable models is strongly influenced by the number of iterations required for the self-consistent field solution, we tested also the Always Stable Predictor-Corrector (ASPC) method of Kolafa (Kolafa, J. J. Comp. Chem. 2003, 25, 335) as an alternative to the steepest descent (SD) based algorithm with predictor implemented in the Gromacs, and found that it speeds up the integration of the equations of motion by a factor of 1.6-2.0, depending on the target model. PMID- 26583235 TI - Mode Robustness in Raman Optical Activity. AB - By reformulating Raman and ROA invariants we provide ground for the definition of robust modes in ROA spectroscopy. Introduction of two parameters defining robustness helps characterization and assignment of ROA bands. Application and use of robustness parameters to [n]helicenes and oxirane/thiirane derivatives are presented. PMID- 26583236 TI - Solvent Effects on Excited-State Structures: A Quantum Monte Carlo and Density Functional Study. AB - We present the first application of quantum Monte Carlo (QMC) in its variational flavor combined with the polarizable continuum model (PCM) to perform excited state geometry optimization in solution. Our implementation of the PCM model is based on a reaction field that includes both volume and surface polarization charges and is determined self-consistently with the molecular wave function during the QMC optimization of the solute geometry. For acrolein, acetone, methylenecyclopropene, and the propenoic acid anion, we compute the optimal exited-state geometries in water and compare our results with the structures obtained with second-order perturbation theory (CASPT2) and other correlated methods, and with time-dependent density functional theory (TDDFT). We find that QMC predicts a structural response to solvation in good agreement with CASPT2 with the only exception of the pi -> pi* state of acrolein where the robustness of the QMC geometry must be contrasted to the sensitivity of the perturbation result to the details of the calculation. As regards TDDFT, we show that all investigated functionals systematically overestimate the geometrical changes from the gas phase to solution, sometimes giving bond variations opposite in trend to QMC. PMID- 26583237 TI - Describing Excited State Relaxation and Localization in TiO2 Nanoparticles Using TD-DFT. AB - We have investigated the description of excited state relaxation in naked and hydrated TiO2 nanoparticles using Time-Dependent Density Functional Theory (TD DFT) with three common hybrid exchange-correlation (XC) potentials: B3LYP, CAM B3LYP and BHLYP. Use of TD-CAM-B3LYP and TD-BHLYP yields qualitatively similar results for all structures, which are also consistent with predictions of coupled cluster theory for small particles. TD-B3LYP, in contrast, is found to make rather different predictions; including apparent conical intersections for certain particles that are not observed with TD-CAM-B3LYP nor with TD-BHLYP. In line with our previous observations for vertical excitations, the issue with TD B3LYP appears to be the inherent tendency of TD-B3LYP, and other XC potentials with no or a low percentage of Hartree-Fock like exchange, to spuriously stabilize the energy of charge-transfer (CT) states. Even in the case of hydrated particles, for which vertical excitations are generally well described with all XC potentials, the use of TD-B3LYP appears to result in CT problems during excited state relaxation for certain particles. We hypothesize that the spurious stabilization of CT states by TD-B3LYP even may drive the excited state optimizations to different excited state geometries from those obtained using TD CAM-B3LYP or TD-BHLYP. Finally, focusing on the TD-CAM-B3LYP and TD-BHLYP results, excited state relaxation in small naked and hydrated TiO2 nanoparticles is predicted to be associated with a large Stokes' shift. PMID- 26583238 TI - Assessment of Franck-Condon Methods for Computing Vibrationally Broadened UV-vis Absorption Spectra of Flavin Derivatives: Riboflavin, Roseoflavin, and 5 Thioflavin. AB - We address the performance of the vertical and adiabatic Franck-Condon (VFC/AFC) approaches combined with time-independent or time-dependent (TI/TD) formalisms in simulating the one-photon absorption spectra of three flavin compounds with distinct structural features. Calculations were done in the gas phase and in two solvents (water, benzene) for which experimental reference measurements are available. We utilized the independent mode displaced harmonic oscillator model without or with frequency alteration (IMDHO/IMDHO-FA) and also accounted for Duschinsky mixing effects. In the initial validation on the first excited singlet state of riboflavin, the range-separated functionals, CAM-B3LYP and omegaB97xD, showed the best performance, but B3LYP also gave a good compromise between peak positions and spectral topology. Large basis sets were not mandatory to obtain high-quality spectra for the selected systems. The presence of a symmetry plane facilitated the computation of vibrationally broadened spectra, since different FC variants yield similar results and the harmonic approximation holds rather well. Compared with the AFC approach, the VFC approach performed equally well or even better for all three flavins while offering several advantages, such as avoiding error-prone geometry optimization procedures on excited-state surfaces. We also explored the advantages of curvilinear displacements and of a Duschinsky treatment for the AFC spectra in cases when a rotatable group is present on the chromophore. Taken together, our findings indicate that the combination of the VFC approach with the TD formalism and the IMDHO-FA model offers the best overall performance. PMID- 26583239 TI - Equation-of-Motion Coupled-Cluster Theory for Excitation Energies of Closed-Shell Systems with Spin-Orbit Coupling. AB - Excitation energies of closed-shell systems based on the equation-of-motion (EOM) coupled-cluster theory at the singles and doubles (CCSD) level with spin-orbit coupling (SOC) included in the post-Hartree-Fock treatment are implemented in the present work. SOC can be included in both the CC and EOM steps (EOM-SOC-CCSD) or only in the EOM part (SOC-EOM-CCSD). The latter approach is an economical way to account for SOC effects, but excitation energies with this approach are not size intensive. When the unlinked term in the latter approach is neglected (cSOC-EOM CCSD), size-intensive excitation energies can be obtained. Time-reversal symmetry and spatial symmetry are exploited to reduce the computational effort. Imposing time-reversal symmetry results in a real matrix representation for the similarity transformed Hamiltonian, which facilitates the requirement of time-reversal symmetry for new trial vectors in Davidson's algorithm. Results on some closed shell atoms and molecules containing heavy elements show that EOM-SOC-CCSD can provide excitation energies and spin-orbit splittings with reasonable accuracy. On the other hand, the SOC-EOM-CCSD approach is able to afford accurate estimates of SOC effects for valence electrons of systems containing elements up to the fifth row, while cSOC-EOM-CCSD is less accurate for spin-orbit splittings of transitions involving p1/2 spinors, even for Kr. PMID- 26583240 TI - Computational Protocol for Modeling Thermochromic Molecular Crystals: Salicylidene Aniline As a Case Study. AB - A computational protocol that combines periodic and QM/QM' calculations has been applied to investigate the structural (geometrical and electronic) and photophysical absorption properties of the salicylidene aniline (SA) thermochromic molecular crystal. The protocol consists of three different steps, namely (i) the description of the molecular crystal using a periodic approach taking into account dispersion interactions, (ii) the identification of reliable finite models (clusters), and (iii) the calculation of vertical transition energies including environmental effects through the use of an electronic embedding model (QM/QM' ONIOM approach). The encouraging results obtained in this work for the beta polymorph of SA, both in terms of accuracy and computational cost, open the way to the simulation and the prediction of the photophysical behavior of other molecular crystals, especially those much less well characterized experimentally. PMID- 26583241 TI - Computational Chemistry Meets Experiments for Explaining the Behavior of Bibenzyl: A Thermochemical and Spectroscopic (Infrared, Raman, and NMR) Investigation. AB - The structure, conformational behavior, and spectroscopic parameters of bibenzyl have been investigated by a computational protocol including proper treatment of anharmonic and hindered rotor contributions. Conventional hybrid functionals overstabilize the anti conformer while low-order post-Hartree-Fock (MP2) approaches strongly favor the gauche conformer. However, inclusion of semiempirical dispersion effects in density functionals or coupled cluster post Hartree-Fock models agree in forecasting the simultaneous presence of both conformers in the gas phase with a slightly larger stability (0.7 kcal.mol(-1)) of the gauche conformer. Addition of thermal and entropic effects finally leads to very close Gibbs free energies for both conformers and, thus, to a slight preference for the gauche form due to statistical factors (2 vs 1). The situation remains essentially the same in solution. On these grounds, perturbative vibrational computations including both electrical and mechanical anharmonicities lead to IR and Raman spectra in remarkable agreement with experiment. Full assignment of the IR spectra explains the presence of peaks from gauche or anti conformers. Comparison between computed and experimental Raman spectra confirms that both conformers are present in liquid phase, whereas the anti conformer seems to be preponderant in the solid state. Also computed NMR parameters are in good agreement with experiment. PMID- 26583242 TI - Actinoid(III) Hydration-First Principle Gibbs Energies of Hydration Using High Level Correlation Methods. AB - The Gibbs energies of hydration of actinoid(III) ions are evaluated for density functional optimized geometries of [An(H2O)h](3+) complexes (h = 8, 9) at the coupled cluster singles, doubles, and perturbative triples level by means of the incremental scheme. Scalar-relativistic 5f-in-core pseudopotentials for actinoids and basis sets of polarized triple-zeta quality were applied. The calculated Gibbs energies for the octa- and nona-aquo complexes agree within 1% with the experimental values which are available only for uranium and plutonium. Compared to the hydrate complexes of the lanthanoid(III) ions those of the actinoid(III) series are slightly less stable. PMID- 26583243 TI - Order Parameters and Algorithmic Approaches for Detection and Demarcation of Interfaces in Hydrate-Fluid and Ice-Fluid Systems. AB - Some aspects of the use of order parameter fields in molecular dynamics simulations to delimit solid phases containing water, namely ice and hydrate, in both hydrophilic and hydrophobic fluids are examined; this includes the influences of rectangular meshes and of filtering on the quality of these parameters. Three order parameters are studied: the mass density, rho; an angular tetrahedrality measure, Sg (Chau and Hardwick, Mol. Phys. 1998, 93, 511); and the water-dimer dihedral angle, F4 (Rodger et al. Fluid Phase Equilib. 1996, 116, 326). The parameters are studied to find their ability to distinguish between bulk phases, their consistency in different environments, their noise susceptibility, and their ability to demarcate the interface region. Spatial sampling and filtering are covered in detail, and some temporal features are illustrated by using autocorrelation maps. The parameters are employed to determine the position of interfaces as functions of time and, with the capillary wave fluctuation method (Hoyt et al. Phys. Rev. Lett. 2001, 86, 5530; Math. Comput. Simul. 2010, 80, 1382), to estimate solid-fluid interfacial stiffnesses, with partial success for the hydrophilic/hydrophobic-type interfaces. PMID- 26583244 TI - Surface Adsorption in Nonpolarizable Atomic Models. AB - Many ionic solutions exhibit species-dependent properties, including surface tension and the salting-out of proteins. These effects may be loosely quantified in terms of the Hofmeister series, first identified in the context of protein solubility. Here, our interest is to develop atomistic models capable of capturing Hofmeister effects rigorously. Importantly, we aim to capture this dependence in computationally cheap "hard" ionic models, which do not exhibit dynamic polarization. To do this, we have performed an investigation detailing the effects of the water model on these properties. Though incredibly important, the role of water models in simulation of ionic solutions and biological systems is essentially unexplored. We quantify this via the ion-dependent surface attraction of the halide series (Cl, Br, I) and, in so doing, determine the relative importance of various hypothesized contributions to ionic surface free energies. Importantly, we demonstrate surface adsorption can result in hard ionic models combined with a thermodynamically accurate representation of the water molecule (TIP4Q). The effect observed in simulations of iodide is commensurate with previous calculations of the surface potential of mean force in rigid molecular dynamics and polarizable density-functional models. Our calculations are direct simulation evidence of the subtle but sensitive role of water thermodynamics in atomistic simulations. PMID- 26583245 TI - Benchmarking the AK13 Exchange Functional: Ionization Potentials and Electron Affinities. AB - We perform benchmark calculations for the ionization potential and electronic affinity of atoms and small molecules using several semilocal exchange correlation functionals of density-functional theory with improved asymptotic behavior. We are particularly interested in a new generalized-gradient approximation for exchange [Armiento and Kummel, Phys. Rev. Lett. 2013, 111, 036402] that provides an energy functional whose functional derivative yields a potential with better decay behavior. We find that it yields energies that are worse than traditional energy functionals and potentials that are less accurate than functionals that model directly the exchange-correlation potential. However, we find that this functional offers a excellent balance between the quality of the energy and of the potential and is therefore a good compromise for applications that require at the same time reasonable energies and good potentials. PMID- 26583246 TI - Two-Photon Absorption of Metal-Assisted Chromophores. AB - Aiming to understand the effect of a metal surface on nonlinear optical properties and the combined effects of surface and solvent environments on such properties, we present a multiscale response theory study, integrated with dynamics of the two-photon absorption of 4-nitro-4'-amino-trans-stilbene physisorbed on noble metal surfaces, considering two such surfaces, Ag(111) and Au(111), and two solvents, cyclohexane and water, as cases for demonstration. A few conclusions of general character could be drawn: While the geometrical change of the chromophore induced by the environment was found to notably alter (diminish) the two-photon absorption cross section in the polar medium, the effects of the metal surface and solvent on the electronic structure of the chromophore surpasses the geometrical effects and leads to a considerably enhanced two-photon absorption cross section in the polar solvent. This enhancement of two-photon absorption arises essentially from the metal charge image induced enlargement of the difference between the dipole moment of the excited state and the ground state. The orientation-dependence of the two-photon absorption is found to connect with the lateral rotation of the chromophore, where the two-photon absorption reaches its maximum when the polarization of the incident light coincides with the long-axis of the chromophore. Our results demonstrate a distinct enhancement of the two-photon absorption by a metal surface and a polar medium and envisage the employment of metal-chromophore composite materials for future development of nonlinear optical materials with desirable properties. PMID- 26583247 TI - Modeling the Partial Atomic Charges in Inorganometallic Molecules and Solids and Charge Redistribution in Lithium-Ion Cathodes. AB - Partial atomic charges are widely used for the description of charge distributions of molecules and solids. These charges are useful to indicate the extent of charge transfer and charge flow during chemical reactions in batteries, fuel cells, and catalysts and to characterize charge distributions in capacitors, liquid-phase electrolytes, and solids and at electrochemical interfaces. However, partial atomic charges given by various charge models differ significantly, especially for systems containing metal atoms. In the present study, we have compared various charge models on both molecular systems and extended systems, including Hirshfeld, CM5, MK, ChElPG, Mulliken, MBS, NPA, DDEC, LoProp, and Bader charges. Their merits and drawbacks are compared. The CM5 charge model is found to perform well on the molecular systems, with a mean unsigned percentage deviation of only 9% for the dipole moments. We therefore formulated it for extended systems and applied it to study charge flow during the delithiation process in lithium-containing oxides used as cathodes. Our calculations show that the charges given by the CM5 charge model are reasonable and that during the delithiation process, the charge flow can occur not only on the transition metal but also on the anions. The oxygen atoms can lose a significant density of electrons, especially for deeply delithiated materials. We also discuss other methods in current use to analyze the charge transfer and charge flow in batteries, in particular the use of formal charge, spin density, and orbital occupancy. We conclude that CM5 charges provide useful information in describing charge distributions in various materials and are very promising for the study of charge transfer and charge flows in both molecules and solids. PMID- 26583248 TI - Generation of Well-Relaxed All-Atom Models of Large Molecular Weight Polymer Melts: A Hybrid Particle-Continuum Approach Based on Particle-Field Molecular Dynamics Simulations. AB - A procedure based on Molecular Dynamics (MD) simulations employing soft potentials derived from self-consistent field (SCF) theory (named MD-SCF) able to generate well-relaxed all-atom structures of polymer melts is proposed. All-atom structures having structural correlations indistinguishable from ones obtained by long MD relaxations have been obtained for poly(methyl methacrylate) (PMMA) and poly(ethylene oxide) (PEO) melts. The proposed procedure leads to computational costs mainly related on system size rather than to the chain length. Several advantages of the proposed procedure over current coarse-graining/reverse mapping strategies are apparent. No parametrization is needed to generate relaxed structures of different polymers at different scales or resolutions. There is no need for special algorithms or back-mapping schemes to change the resolution of the models. This characteristic makes the procedure general and its extension to other polymer architectures straightforward. A similar procedure can be easily extended to the generation of all-atom structures of block copolymer melts and polymer nanocomposites. PMID- 26583249 TI - Assessment of a Cost-Effective Approach to the Calculation of Kinetic and Thermodynamic Properties of Methyl Methacrylate Homopolymerization: A Comprehensive Theoretical Study. AB - In this work, we carried out a comprehensive density functional theory (DFT) study on the basis of a trimer-to-tetramer radical reaction model to assess a cost-effective approach to perform the calculation of kinetic and thermodynamic properties of methyl methacrylate (MMA) free-radical homopolymerization. By comparing results from several different functionals (PBE, M06-2X, wB97XD, KMLYP, and MPW1B95), in conjunction with a series of basis sets (6-31G(d,p), 6 31+G(d,p), 6-31G(2df,p), 6-311G(d,p), 6-311+G(d,p), 6-311+G(2df,p), 6 311+G(2df,2p)), we show that calculations using M06-2X/6-311+G(2df,p)//B3LYP/6 31G(2df,p) provide an activation energy of 5.25 kcal mol(-1) for the homopropagation step, which is within 1 kcal mol(-1) of the experimental value. However, this method predicts a heat of polymerization of 17.37 kcal mol(-1) that is larger than the experimental value by 3.5 kcal mol(-1). MPW1B95/6-311+G(2df,p) on the B3LYP/6-31G(2df,p) geometries produces a heat of polymerization value within 1 kcal mol(-1) of experimental data, yet overestimates the activation energy by 3 kcal mol(-1). In addition, we evaluated the performance of ONIOM MO:MO calculations on the geometry optimization of species comprising our MMA polymerization model and found that ONIOM(B3LYP/6-31G(2df,p):B3LYP/6-31G(d)) is capable of producing geometries in very good agreement with the full B3LYP/6 31G(2df,p) calculations. Subsequent calculations of energies using M06-2X/6 311+G(2df,p) based on the ONIOM geometries provided an activation energy value comparable to that based on the full B3LYP/6-31G(2df,p) geometries. PMID- 26583250 TI - Mechanisms of Differential Allosteric Modulation in Homologous Proteins: Insights from the Analysis of Internal Dynamics and Energetics of PDZ Domains. AB - Allostery is a general phenomenon in proteins whereby a perturbation at one site reverberates into a functional change at another one, through modulation of its conformational dynamics. Herein, we address the problem of how the molecular signal encoded by a ligand is differentially transmitted through the structures of two homologous PDZ proteins: PDZ2, which responds to binding with structural and dynamical changes in regions distal from the ligand site, and PDZ3, which is characterized by less-intense dynamical variations. We use novel methods of analysis of MD simulations in the unbound and bound states to investigate the determinants of the differential allosteric behavior of the two proteins. The analysis of the correlations between the redistribution of stabilization energy and local fluctuation patterns highlights the nucleus of residues responsible for the stabilization of the 3D fold, the stability core, as the substructure that defines the difference in the allosteric response: in PDZ2, it undergoes a consistent dynamic and energetic reorganization, whereas in PDZ3, it remains largely unperturbed. Specifically, we observe for PDZ2 a significant anticorrelation between the motions of distal loops and residues of the stability core and differences in the correlation patterns between the bound and unbound states. Such variation is not observed in PDZ3, indicating that its energetics and internal dynamics are less affected by the presence/absence of the ligand. Finally, we propose a model with a direct link between the modulation of the structural, energetic and dynamic properties of a protein, and its allosteric response to a perturbation. PMID- 26583251 TI - Accelerating All-Atom MD Simulations of Lipids Using a Modified Virtual-Sites Technique. AB - We present two new implementations of the virtual sites technique which completely suppresses the degrees of freedom of the hydrogen atoms in a lipid bilayer allowing for an increased time step of 5 fs in all-atom simulations of the CHARMM36 force field. One of our approaches uses the derivation of the virtual sites used in GROMACS while the other uses a new definition of the virtual sites of the CH2 groups. Our methods is tested on a DPPC (no unsaturated chain), a POPC (one unsaturated chain), and a DOPC (two unsaturated chains) lipid bilayers. We calculate various physical properties of the membrane of our simulations with and without virtual sites and explain the differences and similarity observed. The best agreements are obtained for the GROMACS original virtual sites on the DOPC bilayer where we get an area per lipid of 67.3 +/- 0.3 A(2) without virtual sites and 67.6 +/- 0.3 A(2) with virtual sites. In conclusion the virtual-sites technique on lipid membranes is a powerful simulation tool, but it should be used with care. The procedure can be applied to other force fields and lipids in a straightforward manner. PMID- 26583252 TI - Reparameterized United Atom Model for Molecular Dynamics Simulations of Gel and Fluid Phosphatidylcholine Bilayers. AB - A new united atom parametrization of diacyl lipids like dipalmitoylphosphatidylcholine (DPPC) and the dimyristoylphosphatidylcholine (DMPC) has been constructed based on ab initio calculations to obtain fractional charges and the dihedral potential of the hydrocarbon chains, while the Lennard Jones parameters of the acyl chains were fitted to reproduce the properties of liquid hydrocarbons. The results have been validated against published experimental X-ray and neutron scattering data for fluid and gel phase DPPC. The derived charges of the lipid phosphatidylcholine (PC) headgroup are shown to yield dipole components in the range suggested by experiments. The aim has been to construct a new force field that retains and improves the good agreement for the fluid phase and at the same time produces a gel phase at low temperatures, with properties coherent with experimental findings. The gel phase of diacyl-PC lipids forms a regular triangular lattice in the hydrocarbon region. The global bilayer tilt obtains an azimuthal value of 31 degrees and is aligned between lattice vectors in the bilayer plane. We also show that the model yields a correct heat of melting as well as decent heat capacities in the fluid and gel phase of DPPC. PMID- 26583253 TI - Surprisal Metrics for Quantifying Perturbed Conformational Dynamics in Markov State Models. AB - Markov state models (MSMs), which model conformational dynamics as a network of transitions between metastable states, have been increasingly used to model the thermodynamics and kinetics of biomolecules. In considering perturbations to molecular dynamics induced by sequence mutations, chemical modifications, or changes in external conditions, it is important to assess how transition rates change, independent of changes in metastable state definitions. Here, we present a surprisal metric to quantify the difference in metastable state transitions for two closely related MSMs, taking into account the statistical uncertainty in observed transition counts. We show that the surprisal is a relative entropy metric closely related to the Jensen-Shannon divergence between two MSMs, which can be used to identify conformational states most affected by perturbations. As examples, we apply the surprisal metric to a two-dimensional lattice model of a protein hairpin with mutations to hydrophobic residues, all-atom simulations of the Fs peptide alpha-helix with a salt-bridge mutation, and a comparison of protein G beta-hairpin with its trpzip4 variant. Moreover, we show that surprisal based adaptive sampling is an efficient strategy to reduce the statistical uncertainty in the Jensen-Shannon divergence, which could be a useful strategy for molecular simulation-based ab initio design. PMID- 26583255 TI - Correction to An Explicit Consideration of Desolvation is Critical to Binding Free Energy Calculations of Charged Molecules at Ionic Surfaces. PMID- 26583254 TI - cluster: Searching for Unique Low Energy Minima of Structures Using a Novel Implementation of a Genetic Algorithm. AB - A new flexible implementation of a genetic algorithm for locating unique low energy minima of isomers of clusters is described and tested. The strategy employed can be applied to molecular or atomic clusters and has a flexible input structure so that a system with several different elements can be built up from a set of individual atoms or from fragments made up of groups of atoms. This cluster program is tested on several systems, and the results are compared to computational and experimental data from previous studies. The quality of the algorithm for locating reliably the most competitive low energy structures of an assembly of atoms is examined for strongly bound Si-Li clusters, and ZnF2 clusters, and the more weakly interacting water trimers. The use of the nuclear repulsion energy as a duplication criterion, an increasing population size, and avoiding mutation steps without loss of efficacy are distinguishing features of the program. For the Si-Li clusters, a few new low energy minima are identified in the testing of the algorithm, and our results for the metal fluorides and water show very good agreement with the literature. PMID- 26583257 TI - Exploring Dynamics and Cage-Guest Interactions in Clathrate Hydrates Using Solid State NMR. AB - Interactions between guest molecules and the water cages in clathrates are dominated by isotropic van der Waals forces at low temperatures because the cage structures satisfy the hydrogen bonding propensity of the water. However, above 200 K the water molecules become more labile and may interact strongly with the guests through hydrogen bonding. In this work we compare the dynamics of tetrahydrofuran (THF) and cyclopentane (CP) guests in the hydrate cages above 200 K. Since THF can form hydrogen bonds while CP cannot, the dynamics provide insight into host-guest hydrogen bonding. We use magic angle spinning (MAS) solid state NMR to measure proton spin-lattice relaxation times (T1) of the guests as a function of temperature and find that the activation barrier to the motion of THF molecules is 4.7 kcal/mol (19.7 kJ/mol) at temperatures above 200 K. This is almost 5 times higher than the barrier at lower temperatures. In contrast, the barrier to guest motion in CP hydrate is found to be about 0.67 kcal/mol (2.8 kJ/mol), which agrees well with data at lower temperatures. These results demonstrate that hydrogen bonding interactions between the THF guest and the clathrate cage are significant above 200 K due to the host lattice mobility. PMID- 26583256 TI - Biofilms as "Connectors" for Oral and Systems Medicine: A New Opportunity for Biomarkers, Molecular Targets, and Bacterial Eradication. AB - Oral health and systems medicine are intimately related but have remained, sadly, as isolated knowledge communities for decades. Are there veritable connector knowledge domains that can usefully link them together on the critical path to biomarker research and "one health"? In this context, it is noteworthy that bacteria form surface-attached communities on most biological surfaces, including the oral cavity. Biofilm-forming bacteria contribute to periodontal diseases and recent evidences point to roles of these bacteria in systemic diseases as well, with cardiovascular diseases, obesity, and cancer as notable examples. Interestingly, the combined mass of microorganisms such as bacteria are so large that when we combine all plants and animals on earth, the total biomass of bacteria is still bigger. They literally do colonize everywhere, not only soil and water but our skin, digestive tract, and even oral cavity are colonized by bacteria. Hence efforts to delineate biofilm formation mechanisms of oral bacteria and microorganisms and the development of small molecules to inhibit biofilm formation in the oral cavity is very timely for both diagnostics and therapeutics. Research on biofilms can benefit both oral and systems medicine. Here, we examine, review, and synthesize new knowledge on the current understanding of oral biofilm formation, the small molecule targets that can inhibit biofilm formation in the mouth. We suggest new directions for both oral and systems medicine, using various omics technologies such as SILAC and RNAseq, that could yield deeper insights, biomarkers, and molecular targets to design small molecules that selectively aim at eradication of pathogenic oral bacteria. Ultimately, devising new ways to control and eradicate bacteria in biofilms will open up novel diagnostic and therapeutic avenues for oral and systemic diseases alike. PMID- 26583258 TI - Prolene Suture Web-Shoelace-Like Pattern: An Alternative to Avoid the Use of Mesh in the Repair of a Large Hiatus Hernia. AB - INTRODUCTION: The purpose of this report is to describe a tension-free repair we have used successfully in 12 patients with large hiatal defects. It is based on the creation of a web-shoelace pattern of polypropylene (Prolene(r); Ethicon, Somerville, NJ) suture of the crura that functions as a barrier, with the advantages of being stronger and more economical than a mesh without the potential complications that may follow mesh repair or suture repair of a large hiatus hernia without mesh. Despite a success rate of 85%-95% reported in large series with a mid- and long-term follow-up evaluation, significant complications have been associated with hiatus hernia repair. Some of these complications include a slipped Nissen repair with intrathoracic wrap migration and hiatal hernia recurrence, resulting from inadequate closure of the crura, fundoplication disruption, or dehiscence of the hiatoplasty. MATERIALS AND METHODS: From June 2013 to June 2014, we have used this technique on 12 patients (6 women and 6 men). Only patients with a large hiatus hernia of >4 cm were enrolled in this study. All patients underwent laparoscopic Nissen fundoplication and hiatoplasty using our technique. They were all severely symptomatic with dysphagia, retrosternal pain, gastroesophageal reflux disease, and respiratory symptoms at night. RESULTS: Of the 12 patients who underwent this type of repair, all of them have reported good to excellent functional and symptomatic outcomes with minimal morbidity, no deaths, and no recurrence. CONCLUSIONS: It is our belief that when a correct repair of the hiatus is not achieved with three stitches, adding more sutures will not lead to a tension-free repair, and this hiatoplasty will have an increased risk of dehiscence. It is for this reason that we recommend using our technique instead of using simple nonabsorbable sutures or a prosthetic mesh. PMID- 26583259 TI - Preorganized Peptide Scaffolds as Mimics of Phosphorylated Proteins Binding Sites with a High Affinity for Uranyl. AB - Cyclic peptides with two phosphoserines and two glutamic acids were developed to mimic high-affinity binding sites for uranyl found in proteins such as osteopontin, which is believed to be a privileged target of this ion in vivo. These peptides adopt a beta-sheet structure that allows the coordination of the latter amino acid side chains in the equatorial plane of the dioxo uranyl cation. Complementary spectroscopic and analytical methods revealed that these cyclic peptides are efficient uranyl chelating peptides with a large contribution from the phosphorylated residues. The conditional affinity constants were measured by following fluorescence tryptophan quenching and are larger than 10(10) at physiological pH. These compounds are therefore promising models for understanding uranyl chelation by proteins, which is relevant to this actinide ion toxicity. PMID- 26583260 TI - Vectorborne Transmission of Leishmania infantum from Hounds, United States. AB - Leishmaniasis is a zoonotic disease caused by predominantly vectorborne Leishmania spp. In the United States, canine visceral leishmaniasis is common among hounds, and L. infantum vertical transmission among hounds has been confirmed. We found that L. infantum from hounds remains infective in sandflies, underscoring the risk for human exposure by vectorborne transmission. PMID- 26583261 TI - Prediction of 4H-SiC betavoltaic microbattery characteristics based on practical Ni-63 sources. AB - We have investigated the performance of 4H-SiC betavoltaic microbatteries under exposure to the practical Ni-63 sources using the Monte Carlo method and Synopsys(r) Medici device simulator. A typical planar p-n junction betavoltaic device with the Ni-63 source of 20% purity on top is modeled in the simulation. The p-n junction structure includes a p+ layer, a p- layer, an n+ layer, and an n layer. In order to obtain an accurate and valid predication, our simulations consider several practical factors, including isotope impurities, self absorption, and full beta energy spectra. By simulating the effects of both the p n junction configuration and the isotope source thickness on the battery output performance, we have achieved the optimal design of the device and maximum energy conversion efficiency. Our simulation results show that the energy conversion efficiency increases as the doping concentration and thickness of the p- layer increase, whereas it is independent of the total depth of the p-n junction. Furthermore, the energy conversion efficiency decreases as the thickness of the practical Ni-63 source increases, because of self-absorption in the isotope source. Therefore, we propose that a p-n junction betavoltaic cell with a thicker and heavily doped p- layer under exposure to a practical Ni-63 source with an appreciable thickness could produce the optimal energy conversion efficiency. PMID- 26583262 TI - Alpha spectrometry applications with mass separated samples. AB - (241)Am has been deposited using a novel technique that employs a commercial inductively coupled plasma mass spectrometer. This work presents results of high resolution alpha spectrometry on the (241)Am samples using a small area passivated implanted planar silicon detector. We have also investigated the mass based separation capability by developing a (238)Pu sample, present as a minor constituent in a (244)Pu standard, and performed subsequent radiometric counting. With this new sample development method, the (241)Am samples achieved the intrinsic energy resolution of the detector used for these measurements. There was no detectable trace of any other isotopes contained in the (238)Pu implant demonstrating the mass-based separation (or enhancement) attainable with this technique. PMID- 26583263 TI - 1,9-seco-Bicyclic Polyprenylated Acylphloroglucinols from Hypericum uralum. AB - Hyperuralones C-H (1-6), six new 1,9-seco-bicyclic polyprenylated acylphloroglucinols (1,9-seco-BPAPs) derived from the normal polyprenylated acylphloroglucinols with a bicyclo[3.3.1]nonane-2,4,9-trione core, together with six known analogues, were isolated from the aerial parts of Hypericum uralum. The structures of 1-6 were elucidated on the basis of the interpretation of NMR and MS spectroscopic data. The structure of attenuatumione B, a known compound isolated from H. attenuatum, was revised to that of a 1,9-seco-BPAP by NMR spectroscopic analysis and previous biomimetic synthesis methods. The inhibitory activities of these isolates on acetylcholinesterase were tested, and compounds 1 and 2 exhibited moderate activities with IC50 values of 9.6 and 7.1 MUM, respectively. PMID- 26583266 TI - Hepatocellular Carcinoma Screening and Surveillance: Practice Guidelines and Real Life Practice. AB - Hepatocellular carcinoma (HCC) is the seventh most common malignancy worldwide. HCC meets all the criteria established by the World Health Organization for performing surveillance on those at-risk for developing cancer. Although there are consensus guidelines in the United States, Europe, and Asia for HCC surveillance, it is unclear if these guidelines are regularly implemented in routine practice to optimize real-life clinical outcomes. We reviewed the current literature on the adherence to current HCC practice guidelines by the American Association for the Study of Liver Diseases (2009), the European Association for the Study of the Liver (2012), and the Asia Pacific Association for the Study of the Liver (2010) for screening/surveillance and outcomes of optimal versus poor adherence. We performed PubMed search for relevant articles regarding HCC surveillance and screening worldwide. Currently, HCC screening is underutilized to a large extent. In most studies, the adherence to HCC screening and surveillance is suboptimal. Various patient, provider, and health care system factors may have all contributed to such nonadherence. Strategies to improve HCC screening and surveillance are urgently needed for early HCC detection and improved survival of HCC patients. Further research is needed to elucidate the various medical and/or cultural knowledge, belief, and practice patterns that can lead to barriers to HCC screening and surveillance at both patient and provider levels. These data will help focus and target advocacy and educational efforts to improve HCC surveillance at all levels: patients, providers, and health care system/government. PMID- 26583267 TI - Race/Ethnicity-specific Disparities in Hepatocellular Carcinoma Stage at Diagnosis and its Impact on Receipt of Curative Therapies. AB - GOALS: To evaluate race/ethnicity-specific disparities in hepatocellular carcinoma (HCC) stage at diagnosis and how this impacts receiving curative therapies. BACKGROUND: HCC is a leading cause of morbidity and mortality worldwide. The highest incidence of HCC is seen among ethnic minorities in the United States. STUDY: Using the 2003-2011 Surveillance, Epidemiology, and End Results database and United Network of Organ Sharing, population-based registries for cancer and liver transplantation (LT) in the United States, race/ethnicity specific cancer stage at diagnosis and treatment received among adults with HCC were evaluated. RESULTS: Compared with non-Hispanic whites, blacks had significantly more advanced HCC at diagnosis [odds ratio (OR), 1.20; 95% confidence interval (CI), 1.10-1.30; P<0.001], whereas Asians were less likely to have advanced disease (OR, 0.87; CI, 0.80-0.94; P<0.001). Among patients with HCC meeting Milan criteria, Hispanics (OR, 0.64; 95% CI, 0.57-0.71; P<0.001) and blacks (OR, 0.67; 95% CI, 0.59-0.76; P<0.001) were significantly less likely to receive curative therapy (resection or LT), whereas Asians were more likely to receive curative therapy (OR, 1.22; 95% CI, 1.10-1.35; P<0.001) compared with non Hispanic whites. However, Asians (OR, 0.49; 95% CI, 0.42-0.58; P<0.001) and Hispanics (OR, 0.51; 95% CI, 0.44-0.60; P<0.001) were less likely to receive LT. CONCLUSIONS: Among US adults with HCC, blacks consistently had more advanced stage at diagnosis and lower rates of receiving treatment. After correcting for cancer stage and evaluating the subset of patients eligible for curative therapies, blacks and Hispanics had significantly lower rates of curative HCC treatment. PMID- 26583268 TI - An Apple a Day Keeps the Doctor Away, Provided You Eat the Apple. PMID- 26583264 TI - Reactive Oxygen-Related Diseases: Therapeutic Targets and Emerging Clinical Indications. AB - SIGNIFICANCE: Enhanced levels of reactive oxygen species (ROS) have been associated with different disease states. Most attempts to validate and exploit these associations by chronic antioxidant therapies have provided disappointing results. Hence, the clinical relevance of ROS is still largely unclear. RECENT ADVANCES: We are now beginning to understand the reasons for these failures, which reside in the many important physiological roles of ROS in cell signaling. To exploit ROS therapeutically, it would be essential to define and treat the disease-relevant ROS at the right moment and leave physiological ROS formation intact. This breakthrough seems now within reach. CRITICAL ISSUES: Rather than antioxidants, a new generation of protein targets for classical pharmacological agents includes ROS-forming or toxifying enzymes or proteins that are oxidatively damaged and can be functionally repaired. FUTURE DIRECTIONS: Linking these target proteins in future to specific disease states and providing in each case proof of principle will be essential for translating the oxidative stress concept into the clinic. PMID- 26583269 TI - Fellowship Training in Colonoscopy: On Letting the Colt Out of the Barn. PMID- 26583270 TI - In Response. PMID- 26583271 TI - Corrigendum: De novo Assembly and Characterization of the Testis Transcriptome and Development of EST-SSR Markers in the Cockroach Periplaneta americana. PMID- 26583272 TI - Economic Cost of a Listeria monocytogenes Outbreak in Canada, 2008. AB - Estimates of the economic costs associated with foodborne disease are important to inform public health decision-making. In 2008, 57 cases of listeriosis and 24 deaths in Canada were linked to contaminated delicatessen meat from one meat processing plant. Costs associated with the cases (including medical costs, nonmedical costs, and productivity losses) and those incurred by the implicated plant and federal agencies responding to the outbreak were estimated to be nearly $242 million Canadian dollars (CAD, 2008). Case costs alone were estimated at approximately $2.8 million (CAD, 2008) including loss of life. This demonstrates the considerable economic burden at both the individual and population levels associated with foodborne disease and foodborne outbreaks in particular. Foodborne outbreaks due to severe pathogens, such as Listeria monocytogenes and those that result in product recalls, are typically the most costly from the individual and/or societal perspective. Additional economic estimates of foodborne disease would contribute to our understanding of the burden of foodborne disease in Canada and would support the need for ongoing prevention and control activities. PMID- 26583273 TI - Health Literate Equates to Patient-Centered. PMID- 26583275 TI - Filling the gap. Human cranial remains from Gombore II (Melka Kunture, Ethiopia; ca. 850 ka) and the origin of Homo heidelbergensis. AB - African archaic humans dated to around 1,0 Ma share morphological affinities with Homo ergaster and appear distinct in cranio-dental morphology from those of the Middle Pleistocene that are referred to Homo heidelbergensis. This observation suggests a taxonomic and phylogenetic discontinuity in Africa that ranges across the Matuyama/Brunhes reversal (780 ka). Yet, the fossil record between roughly 900 and 600 ka is notoriously poor. In this context, the Early Stone Age site of Gombore II, in the Melka Kunture formation (Upper Awash, Ethiopia), provides a privileged case-study. In the Acheulean layer of Gombore II, somewhat more recent than 875 +/-10 ka, two large cranial fragments were discovered in 1973 and 1975 respectively: a partial left parietal (Melka Kunture 1) and a right portion of the frontal bone (Melka Kunture 2), which probably belonged to the same cranium. We present here the first detailed description and computer-assisted reconstruction of the morphology of the cranial vault pertaining to these fossil fragments. Our analysis suggest that the human fossil specimen from Gombore II fills a phenetic gap between Homo ergaster and Homo heidelbergensis. This appears in agreement with the chronology of such a partial cranial vault, which therefore represents at present one of the best available candidates (if any) for the origin of Homo heidelbergensis in Africa. PMID- 26583276 TI - Observing videos of a baby crying or smiling induces similar, but not identical, electroencephalographic responses in biological and adoptive mothers. AB - It is well-known that adoptive mothers respond to cues from their babies in similar ways to biological mothers, and that cortical processing is critical for adequate motive-emotional maternal responses. This study used electroencephalographic activity (EEG) to characterize prefrontal, parietal and temporal functioning in biological mothers (BM), adoptive mothers (AM), and non mothers (NM), while viewing videos of a baby smiling or crying. The BM presented higher absolute power (AP) in the delta and theta bands (associated with pleasant, positive emotional experiences) in the frontal and parietal areas under all conditions. In response to the smiling video, both types of mothers presented a lower AP in alpha1 in the three cortices (indicative of increased attention) and, mainly in temporal areas, a higher AP in the fast frequencies (beta and gamma, reflecting increased alertness to sensory stimuli and cognitive processing). This EEG pattern in the BM and AM could reflect the greater attention and, probably, the positive mood caused by the smiling video, showing that both are sensitive to these pleasant stimuli. When viewing the video of a baby crying, the AM had higher AP in the fast frequencies (temporal and parietal areas), indicating that they were more reactive to this unpleasant video, while the NM presented only a lower AP in alpha1 in all cortices, a finding that could be associated with the general activation induced by these unpleasant stimuli as a consequence of their lack of maternal experience. These findings should help improve our understanding of the neural mechanisms involved in the processing of sensorial stimuli that establish affective-emotional links during motherhood. PMID- 26583277 TI - Emerging Rabbit Hemorrhagic Disease Virus 2 (RHDVb), Australia. PMID- 26583279 TI - Minocycline Inhibits Inflammation and Squamous Metaplasia of Conjunctival Tissue Culture in Airlift Conditions. AB - PURPOSE: Inflammation and squamous metaplasia is a common pathological process that occurs in many ocular surface diseases such as dry eye, Stevens-Johnson syndrome, mucous membrane pemphigoid, and chemical/thermal burns. At present, there is no ideal medicinal treatment for this abnormality. We report herein on an ex vivo conjunctival inflammation and squamous metaplasia model by culturing human conjunctival tissues at an air-liquid interface for up to 8 days to study the effects of minocycline on inflammation and squamous metaplasia. METHODS: The levels of inflammatory mediators including interleukin-1beta, tumor necrosis factor-alpha, and metalloproteinase-9 in the cultured human conjunctival tissues were determined by enzyme-linked immuno-sorbent assay and real-time polymerase chain reaction. The total and phosphorylated nuclear factor-kappaB were detected by western blot. Differentiation markers K10, MUC5AC, and Pax6 and proliferation markers Ki67, p63, and K14 were determined by immunofluorescence or immunohistochemical staining. RESULTS: The results indicated that minocycline inhibited inflammation, decreased the expression of interleukin-1beta, tumor necrosis factor-alpha, and metalloproteinase -9, and squamous metaplasia features such as hyperproliferation and abnormal epidermal differentiation of conjunctival epithelium. CONCLUSIONS: These findings highlight the possibility that minocycline could be used to treat dry eye and other ocular surface diseases exhibiting epithelial cell inflammation and squamous metaplasia. PMID- 26583278 TI - Rapid and long-lasting reduction of crowding through training. AB - Crowding is the failure to identify an object in the peripheral visual field in the presence of nearby objects. Recent studies have shown that crowding can be alleviated after several days of training, but the processes underlying this improvement are still unclear. Here we tested whether a few hundred trials within a short period of training can alleviate crowding, whether the learning is location specific, and whether the improvement reflects facilitation by target enhancement or flankers suppression. Observers were asked to identify the orientation of a letter in the periphery surrounded by two flanker letters. Observers were tested before (pretest) and after (posttest) training (600 trials). In Experiment 1 we tested whether learning is location specific or can transfer to a different location; the training and test occurred at the same or different hemifields. In a control experiment, we ruled out alternative explanations for the learning effect in Experiment 1. In Experiment 2, we assessed different components of feature selection by training with either the same flanker polarity as the pre/posttest but opposite polarity group (flanker polarity group) or the same target polarity as the pre/posttest but opposite flanker polarity (target polarity group). Following training, overall performance increased in all four conditions, but only the same-location group (Experiment 1) and the same flanker polarity (Experiment 2) showed a significant reduction in crowding as assessed by the distance at which the flankers no longer interfere with target identification, that is, the critical spacing. These results show that training can rapidly reduce crowding and that improvement primarily reflects learning to ignore the irrelevant flankers. Remarkably, in the two conditions in which training significantly reduced crowding, the benefit of short training persisted for up to a year. PMID- 26583280 TI - Quantification and Patterns of Endothelial Cell Loss Due to Eye Bank Preparation and Injector Method in Descemet Membrane Endothelial Keratoplasty Tissues. AB - PURPOSE: To evaluate endothelial cell damage after eye bank preparation and passage through 1 of 2 different injectors for Descemet membrane endothelial keratoplasty grafts. METHODS: Eighteen Descemet membrane endothelial keratoplasty grafts were prepared by Lions VisionGift with the standard partial prepeel technique and placement of an S-stamp for orientation. The grafts were randomly assigned to injection with either a glass-modified Jones tube injector (Gunther Weiss Scientific Glass) or a closed-system intraocular lens injector (Viscoject 2.2; Medicel). After injection, the grafts were stained with the vital fluorescent dye Calcein AM and digitally imaged. The percentage of cell loss was calculated by measuring the area of nonfluorescent pixels and dividing it by the total graft area pixels. RESULTS: Grafts injected using the modified Jones tube injector had an overall cell loss of 27% +/- 5% [95% confidence interval, 21% 35%]. Grafts injected using the closed-system intraocular lens injector had a cell loss of 32% +/- 8% (95% confidence interval, 21%-45%). This difference was not statistically significant (P = 0.3). Several damage patterns including damage due to S-stamp placement were observed, but they did not correlate with injector type. CONCLUSIONS: In this in vitro study, there was no difference in the cell loss associated with the injector method. Grafts in both groups sustained significant cell loss and displayed evidence of graft preparation and S-stamp placement. Improvement in graft preparation and injection methods may improve cell retention. PMID- 26583281 TI - Deep Anterior Lamellar Keratoplasty Versus Penetrating Keratoplasty: A Meta Analysis of Randomized Controlled Trials. AB - PURPOSE: To evaluate the efficacy and safety of deep anterior lamellar keratoplasty (DALK) compared with penetrating keratoplasty (PK) for patients who had corneal stromal pathologies without endothelial abnormalities. METHODS: We performed a meta-analysis using databases including PUBMED, EMBASE, and ClinicalTrials.gov to find relevant randomized controlled trials. Efficacy parameters were the postoperative best-corrected visual acuity, uncorrected visual acuity, and refractive error. Safety parameters were postoperative endothelial cell loss and graft rejection. RESULTS: Five randomized controlled trials were selected for this meta-analysis, including 409 eyes (217 eyes in the DALK group and 192 eyes in the PK group). Postoperative logarithm of the minimum angle of resolution BCVA and UCVA were significantly better for PK than that for DALK [weighted mean difference (WMD) = 0.04, 95% confidence interval (CI), 0.01 0.07, P = 0.005 and WMD = 0.12, 95% CI, 0.05-0.18, P = 0.0007, respectively], whereas, the proportion of patients whose postoperative best-corrected visual acuity >= 20/40 did not differ statistically [risk ratio (RR) = 0.97, 95% CI, 0.89-1.07, P = 0.57]. There were no significant differences in terms of refractive error either by spherical equivalent or astigmatism (P = 0.11 and P = 0.25, respectively). The endothelial cell loss percentage in the PK group was significantly higher compared with the DALK group (WMD = -8.75, 95% CI, -15.25 to -2.25, P = 0.008). The DALK group was associated with a significantly lower frequency of graft rejection and endothelial rejection than the PK group (RR = 0.48, 95% CI, 0.28-0.82, P = 0.007 and RR = 0.07, 95% CI, 0.01-0.35, P = 0.001, respectively). CONCLUSIONS: DALK is an alternative surgical procedure for corneal stromal pathologies without endothelial abnormalities, with lower efficacy but better safety. PMID- 26583282 TI - Synthesis of KCa2Nb3O10 Crystals with Varying Grain Sizes and Their Nanosheet Monolayer Films As Seed Layers for PiezoMEMS Applications. AB - The layered perovskite-type niobate KCa2Nb3O10 and its derivatives show advantages in several fields, such as templated film growth and (photo)catalysis. Conventional synthesis routes generally yield crystal size smaller than 2 MUm. We report a flux synthesis method to obtain KCa2Nb3O10 crystals with significantly larger sizes. By using different flux materials (K2SO4 and K2MoO4), crystals with average sizes of 8 and 20 MUm, respectively, were obtained. The KCa2Nb3O10 crystals from K2SO4 and K2MoO4 assisted synthesis were protonated and exfoliated into monolayer nanosheets, and the optimal exfoliation conditions were determined. Using pulsed laser deposition, highly (001)-oriented piezoelectric stacks (SrRuO3/PbZr0.52Ti0.48O3/SrRuO3, SRO/PZT/SRO) were deposited onto Langmuir Blodgett films of Ca2Nb3O10(-) (CNO) nanosheets with varying lateral nanosheet sizes on Si substrates. The resulting PZT thin films showed high crystallinity irrespective of nanosheet size. The small sized nanosheets yielded a high longitudinal piezoelectric coefficient d33 of 100 pm/V, while the larger sized sheets had a d33 of 72 pm/V. An enhanced transverse piezoelectric coefficient d31 of -107 pm/V, an important input parameter for the actuation of active structures in microelectromechanical systems (MEMS) devices, was obtained for PZT films grown on CNO nanosheets with large lateral size, while the corresponding value on small sized sheets was -96 pm/V. PMID- 26583283 TI - Anxiety and depression in cystic fibrosis. AB - Cystic fibrosis (CF) is the most common genetic disorders in the Caucasian population, with estimated between 70,000 and 100,000 patients worldwide. Even if improved diagnostics and clinical management have led to an increased life expectancy, CF still remains a disease that significantly impacts patients' life in terms of symptoms, daily functioning, psychological morbidity and health related quality of life. Available data suggest that symptoms of anxiety and depression, such as in other chronic conditions, are common features in CF patients and in their caregivers, with a significant impact on disease outcomes. In this review we analyze and discuss the findings of The International Depression and Anxiety Epidemiological Study (TIDES), recently published on Thorax. This study was aimed to determine the prevalence of symptoms of depression and anxiety in a large population of adolescents and adults with CF and in parents of children with CF, across eight European countries and the USA. The TIDES provides useful insights about the psychological/psychiatric comorbidities in CF and its conclusions are absolutely shareable. Nevertheless some doubts remain on the methods and the tools. Further investigation and understanding of anxiety and depression in CF (in terms of prevalence, association with clinical, psychological and sociocultural factors) is necessary and evidence is crescent that a global and multidisciplinary approach is wanted. PMID- 26583284 TI - Asymmetric dimethylarginine (ADMA): will be or will not be a new revolutionary biomarker of bronchial asthma. AB - Carraro et al. measured asymmetric dimethylarginine (ADMA) in the exhaled breath condensate (EBC) obtained from children with asthma and from healthy subjects. The authors demonstrated higher levels of ADMA in EBC of asthmatics compared to controls. ADMA levels in EBC did not correlate with serum levels, lung function parameters, and fractional exhaled nitric oxide. ADMA levels in EBC did not significantly differ between asthmatic patients regularly treated with inhaled steroids and those who were steroid naive. Further studies are necessary in order to evaluate the role of this biomarker in the characterization of phenotypes of severe bronchial asthma. PMID- 26583285 TI - Choose the best route: ultrasound-guided transbronchial and transesophageal needle aspiration with echobronchoscope in the diagnosis of mediastinal and pulmonary lesions. AB - Nodal mediastinal staging is a crucial part of the diagnostic workup of patients with nonsmall- cell lung cancer (NSCLC) for planning optimal treatment. Transesophageal endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) and real-time endobronchial ultrasounds transbronchial needle aspiration (EBUS-TBNA) are accurate, minimally invasive and safe diagnostic techniques for mediastinal staging. Because of the different accessibility to the mediastinum, they are considered complementary and their combination increases the diagnostic yield as compared with the either alone. Recent studies have shown that endosonography represents the best initial test for invasive mediastinal evaluation in NSCLC. Endoscopic ultrasound (with bronchoscope)-guided fine needle aspiration (EUS-B FNA) is a recently introduced procedure consisting of a transesophageal needle aspiration using an ultrasound bronchoscope. It allows to perform both transbronchial and transesophageal needle sampling with the same instrument, in the same session and by one operator only, thus maximizing time and costs savings. In a recent study Oki et al. randomized 110 patients with hilar/mediastinal adenopathies or lung abnormalities adjoining both the esophagus and the bronchi, to undergo EBUSTBNA or EUS-FNA performed by pulmonologists with an echobronchoscope. The Authors demonstrated that both procedures provide a high diagnostic yield, without any difference in the number of adverse events and a good comparable tolerance. Nevertheless, the transesophageal approach guaranteed a significantly lower dose of anesthetics and sedatives, a shorter procedural time, fewer oxygen desaturations, a significantly lower cough score and a higher operator satisfaction. In this review our aim was to discuss the findings by Oki et al. in the context of medical literature, highlighting the importance of the EUS-B needle aspiration technique in diagnosing mediastinal and lung lesions, when EBUS-TBNA is deemed less suitable. Finally, we pointed out the importance of interventional pulmonologists being trained to perform mediastinal sampling by the esophageal route, to choose the best solution in every technical and clinical occurence. PMID- 26583286 TI - Toxicity assessment and geochemical model of chromium leaching from AOD slag. AB - AOD (Argon Oxygen Decarburization) slag is a by-product of the stainless steel refining process. The leaching toxicity of chromium from AOD slag cannot be ignored in the recycling process of the AOD slag. To assess the leaching toxicity of the AOD slag, batch leaching tests have been performed. PHREEQC simulations combined with FactSage were carried out based on the detailed mineralogical analysis and petrophysical data. Moreover, Pourbaix diagram of the Cr-H2O system was protracted by HSC 5.0 software to explore the chromium speciation in leachates. It was found that AOD slag leachate is an alkaline and reductive solution. The Pourbaix diagram of the Cr-H2O system indicated that trivalent chromium, such as Cr(OH)4(-), is the major chromium species in the experimental Eh-pH region considered. However, toxic hexavalent chromium was released with maximum concentrations of 30 ug L(-1) and 18 ug L(-1) at L/S 10 and 100, respectively, during the earlier leaching stage. It concluded that the AOD slag possessed a certain leaching toxicity. After 10 d of leaching, trivalent chromium was the dominant species in the leachates, which corresponded to the results of PHREEQC simulation. Leaching toxicity of AOD slag is based on the chromium speciation and its transformation. Great attention should be focused on such factors as aging, crystal form of chromium-enriched minerals, and electrochemical characteristics of the leachates. PMID- 26583287 TI - Periphytic biofilm: A buffer for phosphorus precipitation and release between sediments and water. AB - The influence of periphytic biofilm on phosphorus (P) content and species between water and sediment interfaces was evaluated in a simulated experiment. Results showed that the concentration of all P species (TP, TDP, DIP, PP, and DOP) in overlying water decreased to significantly low levels (<0.05 mg L(-1)) in the presence of periphytic biofilms, while the TP increased (>1.8 mg L(-1)) in the control (without periphytic biofilm). Periphytic biofilm increased the water pH (maximal value at about 10) favoring co-precipitation between P and metal salt. The presence of periphytic biofilm also slowed the loss of P fractions such as Fe/Al-P and Ca-P from sediment. In addition, the P content of periphytic biofilms, mainly in forms of Fe/Al-P and Ca-P, increased by 100% after 60 d. These results suggested that periphytic biofilm was capable of entrapping P from water, attenuating P release, and storing P as a sink, thereby forming a buffer for P release and precipitation. This study not only offers some valuable insights into the role of periphytic biofilms or similar microbial aggregates in P biogeochemical processes in water-sediment interfaces, but also contributes to the management of water eutrophication from internal P loadings. PMID- 26583288 TI - Fate of Fe and Cd upon microbial reduction of Cd-loaded polyferric flocs by Shewanella oneidensis MR-1. AB - Polyferric sulphate has been widely used for emergent control on incidental release of heavy metals such as Cd to surface water, causing precipitation of Cd loaded polyferric flocs to the sediment. To date, little is known about whether the dissolution of the flocs in the presence of dissimilatory iron reducing bacteria (DIRB) can occur and how the dissolution influences the fate of Fe and Cd in the sediment. Here, we demonstrated that Shewanella oneidensis MR-1, as representative DIRB, has the ability to reduce the flocs, resulting in the release of Fe(2+) and Cd(2+) to the solution. Batch experiment results showed that the concentrations of Fe(2+) and Cd(2+)reached the maximum values at 48 h and then decreased over the remaining incubation time. The characterizations on the solid phase by the scanning electron microscopy coupled with energy dispersive spectrometer, X-ray diffraction, and X-ray photoelectron spectroscopy technologies revealed the formation of iron minerals such as goethite and magnetite as a consequence of microbial Fe(III) reduction. The newly formed iron minerals played a significant role in re-immobilizing Cd by sorption. These results imply that microbial reduction of polyferric flocs is an important contributor to the transport and transformation of metals in the sediment-water interface. PMID- 26583289 TI - Factors influencing atmospheric concentrations of polybrominated diphenyl ethers in Japan. AB - We used polybrominated diphenyl ether (PBDE) data in air at 38 sites across Japan (2009-2012), which were measured by the Japan Ministry of Environment (JMOE), to elucidate the time trend and seasonality of atmospheric PBDEs. In order to address few (7% for BDE-47) to many (63% for BDE-153 and 183) non-detect data, Tobit model, also called a censored regression model was used. The model revealed that the concentrations of PBDE congeners were influenced by a combination of year, temperature, rainfall rate, and population density. Greater declines were observed for BDE-47, -99, -153 and -183 (-21, -25, -17, -23%/year, p < 0.05) than for BDE-209 (-6%/year, p = 0.065). These trends were consistent with the estimated trends of penta-, octa- and deca-BDE contained in in-use products based on domestic demand for PBDEs in Japan and product lifespan. Seasonal patterns were opposite for light congeners (BDE-47 and -99), which increased with temperature, and heavy congeners (BDE-183, and -209), which decreased with temperature. Temperature-dependent emission (evaporation) for light congeners and temperature-independent emission (abrasion) for heavy congeners, coupled with seasonality of atmospheric boundary layer height, might explain these seasonal patterns. Human population density showed a positive correlation with all PBDE congener concentrations, whereas PBDEs showed negative correlation with rainfall rate. PMID- 26583290 TI - A novel sequential process for remediating rare-earth wastewater. AB - A novel and economic sequential process consisting of precipitation, adsorption, and oxidation was developed to remediate actual rare-earth (RE) wastewater containing various toxic pollutants, including radioactive species. In the precipitation step, porous air stones (PAS) containing waste oyster shell (WOS), PASWOS, was prepared and used to precipitate most heavy metals with >97% removal efficiencies. The SEM-EDS analysis revealed that PAS plays a key role in preventing the surface coating of precipitants on the surface of WOS and in releasing the dissolved species of WOS successively. For the adsorption step, a polyurethane (PU) impregnated by coal mine drainage sludge (CMDS), PUCMDS, was synthesized and applied to deplete fluoride (F), arsenic (As), uranium (U), and thorium (Th) that remained after precipitation. The continuous-mode sequential process using PAS(WOS), PU(CMDS), and ozone (O3) had 99.9-100% removal efficiencies of heavy metals, 99.3-99.9% of F and As, 95.8-99.4% of U and Th, and 92.4% of COD(Cr) for 100 days. The sequential process can treat RE wastewater economically and effectively without stirred-tank reactors, pH controller, continuous injection of chemicals, and significant sludge generation, as well as the quality of the outlet met the EPA recommended limits. PMID- 26583291 TI - Leaching behaviour of hexabromocyclododecane from treated curtains. AB - A series of laboratory experiments were conducted, whereby two HBCDD treated polyester curtain samples were contacted with deionised Milli-Q water as leaching fluid and HBCDD determined in the resulting leachate. As well as single batch (no replenishment of leaching fluid), serial batch (draining of leachate and replenishment with fresh leaching fluid at various time intervals) experiments were conducted. In single batch experiments at 20 degrees C, SigmaHBCDD concentrations increased only slightly with increasing contact time (6 h, 24 h, and 48 h). This is supported by serial batch tests at 20 degrees C in which leaching fluid was replaced after 6 h, 24 h, 48 h, 72 h, 96 h, and 168 h. Data from these experiments show that while concentrations of HBCDD in leachate after 24 h cumulative contact time exceed those at 6 h; concentrations in samples collected at subsequent contact times remained steady at ~50% of those in the 24 h sample. Consistent with this, leaching is shown to be second order, whereby a period of initially intense dissolution of more labile HBCDD is followed by a slower stage corresponding to external diffusion of the soluble residue within the textile. In experiments conducted at 20 degrees C, alpha-HBCDD is preferentially leached compared to beta- and gamma-HBCDD. However, at higher temperatures, the relatively more hydrophobic diastereomers are proportionally more readily leached, i.e. raising the temperature from 20 degrees C to 80 degrees C increased concentrations of gamma-HBCDD in the leachate by a factor of 28-33 while corresponding alpha-HBCDD concentrations only increased by a factor of 4.3-4.8. PMID- 26583292 TI - Perfluoroalkylated substances (PFASs) in home and commercially produced chicken eggs from the Netherlands and Greece. AB - Dietary intake is a major route of human exposure to perfluoroalkylated substances (PFASs). However, the available information on PFAS levels in food, including chicken eggs, is limited. In the present study, home produced and commercially produced eggs (organic, battery and free range eggs) were collected from the Netherlands (n = 95) and Greece (n = 76). The egg yolks were analysed for 11 PFASs by liquid chromatography-tandem mass spectrometry using isotope dilution. PFAS levels in yolk were higher in home produced eggs from the Netherlands (median 3.1, range < LOQ - 31.2 ng g(-1)) and Greece (median 1.1, range < LOQ - 15.0 ng g(-1)) compared to the eggs collected from supermarkets. In these eggs, all PFAS levels were below the LOQ of 0.5 ng g(-1), except for a small amount of perfluorooctane sulfonate (PFOS) in 1 sample in each country (1.1 ng g(-1) and 0.9 ng g(-1) for the Netherlands and Greece respectively). PFOS was the predominant PFAS, making up on average 85% of ?PFASs. The highest PFOS concentration was detected in a Dutch home produced egg sample (24.8 ng g(-1)). The contamination pattern was similar in both countries with the long-chain PFASs (C >= 8) being most frequently detected, while short-chain PFASs were rarely found. The most likely cause of the contamination of home produced eggs is ingestion of soil through pecking. Although regular consumption of home produced eggs will lead to an increased PFOS exposure, it is not expected that it will lead to exceedance of the tolerable daily intake established by EFSA. PMID- 26583293 TI - Arsenic and fluoride removal from groundwater by electrocoagulation using a continuous filter-press reactor. AB - We investigated simultaneous arsenic and fluoride removal from ground water by electrocoagulation (EC) using aluminum as the sacrificial anode in a continuous filter-press reactor. The groundwater was collected at a depth of 320 m in the Bajio region in Guanajuato Mexico (arsenic 43 ug L(-1), fluoride 2.5 mg L(-1), sulfate 89.6 mg L(-1), phosphate 1.8 mg L(-1), hydrated silica 112.4 mg L(-1), hardness 9.8 mg L(-1), alkalinity 31.3 mg L(-1), pH 7.6 and conductivity 993 uS cm(-1)). EC was performed after arsenite was oxidized to arsenate by addition of 1 mg L(-1) hypochlorite. The EC tests revealed that at current densities of 4, 5 and 6 mA cm(-2) and flow velocities of 0.91 and 1.82 cm s(-1), arsenate was abated and residual fluoride concentration satisfies the WHO standard (CF < 1.5 mg L(-1)). Spectrometric analyses performed on aluminum flocs indicated that these are mainly composed of aluminum-silicates of calcium and magnesium. Arsenate removal by EC involves adsorption on aluminum flocs, while fluoride replaces a hydroxyl group from aluminum aggregates. The best EC was obtained at 4 mA cm(-2) and 1.82 cm s(-1) with electrolytic energy consumption of 0.34 KWh m( 3). PMID- 26583294 TI - Uptake dynamics of inorganic mercury and methylmercury by the earthworm Pheretima guillemi. AB - Mercury uptake dynamics in the earthworm Pheretima guillemi, including the dissolved uptake rate constant (ku) from pore-water and assimilation efficiencies (AEs) from mercury-contaminated soil, was quantified in this study. Dissolved uptake rate constants were 0.087 and 0.553 L g(-1) d(-1) for inorganic mercury (IHg) and methylmercury (MeHg), respectively. Assimilation efficiency of IHg in field-contaminated soil was 7.2%, lower than 15.4% of spiked soil. In contrast, MeHg exhibited comparable AEs for both field-contaminated and spiked soil (82.4 87.2%). Within the framework of biodynamic model, we further modelled the exposure pathways (dissolved exposure vs soil ingestion) to source the accumulated mercury in Pheretima guillemi. The model showed that the relative importance of soil ingestion to mercury bioaccumulation depended largely on mercury partitioning coefficients (K(d)), and was also influenced by soil ingestion rate of earthworms. In the examined field-contaminated soil, almost (>99%) accumulated IHg and MeHg was predicted to derive from soil ingestion. Therefore, soil ingestion should be carefully considered when assessing mercury exposure risk to earthworms. PMID- 26583295 TI - Modelling the impact of room temperature on concentrations of polychlorinated biphenyls (PCBs) in indoor air. AB - Buildings contaminated with polychlorinated biphenyls (PCBs) are a health concern for the building occupants. Inhalation exposure is linked to indoor air concentrations of PCBs, which are known to be affected by indoor temperatures. In this study, a highly PCB contaminated room was heated to six temperature levels between 20 and 30 C, i.e. within the normal fluctuation of indoor temperatures, while the air exchange rate was constant. The steady-state air concentrations of seven PCBs were determined at each temperature level. A model based on Clausius Clapeyron equation, ln(P) = -DeltaH/RT + a(0), where changes in steady-state air concentrations in relation to temperature, was tested. The model was valid for PCB-28, PCB-52 and PCB-101; the four other congeners were sporadic or non detected. For each congener, the model described a large proportion (R(2)>94%) of the variation in indoor air PCB levels. The results showed that one measured concentration of PCB at a known steady-state temperature can be used to predict the steady-state concentrations at other temperatures under circumstances where e.g. direct sunlight does not influence temperatures and the air exchange rate is constant. The model was also tested on field data from a PCB remediation case in an apartment in another contaminated building complex where PCB concentrations and temperature were measured simultaneously and regularly throughout one year. The model fitted relatively well with the regression of measured PCB air concentrations, ln(P) vs. 1/T, at varying temperature between 16.3 and 28.2 degrees C, even though the measurements were carried out under uncontrolled environmental condition. PMID- 26583296 TI - Seasonal and spatial distributions of atmospheric polychlorinated naphthalenes in Shanghai, China. AB - Air samples were collected in Shanghai during summer and winter 2013, and the gas and particulate concentrations of polychlorinated naphthalenes (PCNs) were measured. All 75 congeners were quantified and the corresponding toxic equivalents (TEQs) were calculated. PCN concentrations were higher in summer than winter, at 8.22-102 pg/m(3) (average of 61.3 pg/m(3)) in summer and 16.5-61.1 pg/m(3) (average of 37.7 pg/m(3)) in winter. Their seasonal TEQ values were in contrast, at 1.35-7.31 fg/m(3) (average of 3.84 fg/m(3)) in summer and 4.08-23.3 fg/m(3) (average of 8.80 fg/m(3)) in winter, because of the seasonal change in congener profiles. Tri-CNs were the predominant homologs in both the summer and winter samples. However, the major congeners in summer were PCNs containing less chlorine, but these decreased over winter. Air mass back trajectories suggested that wind direction over various sites was similar in the summer and winter seasons, yet there were clear seasonal variations in atmospheric PCN concentrations. Ratios of several characteristic congeners were calculated and the results indicated that the ratios varied only to a limited extent with PCN emissions profile from industrial thermal sources, but varied strongly with profiles of technical PCN and PCN contaminants in polychlorinated biphenyl mixtures. The results of principal component analysis suggest that local industrial thermal emissions (thermal processes containing waste incineration and secondary metal smelting processes) still play a considerable role in influencing the atmospheric PCNs in Shanghai. PMID- 26583298 TI - Predicting terrestrial gamma dose rate based on geological and soil information: case study of Perak state, Malaysia. AB - An extensive terrestrial gamma radiation dose (TGRD) rate survey has been conducted in Perak State, Peninsular Malaysia. The survey has been carried out taking into account geological and soil information, involving 2930 in situ surveys. Based on geological and soil information collected during TGRD rate measurements, TGRD rates have been predicted in Perak State using a statistical regression analysis which would be helpful to focus surveys in areas that are difficult to access. An equation was formulated according to a linear relationship between TGRD rates, geological contexts and soil types. The comparison of in situ measurements and predicted TGRD dose rates was tabulated and showed good agreement with the linear regression equation. The TGRD rates in the study area ranged from 38 nGy h(-1) to 1039 nGy h(-1) with a mean value of 224 +/- 138 nGy h(-1). This value is higher than the world average as reported in UNSCEAR 2000. The TGRD rates contribute an average dose rate of 1.37 mSv per year. An isodose map for the study area was developed using a Kriging method based on predicted and in situ TGRD rate values. PMID- 26583297 TI - Correlation between DNAPL distribution area and dissolved concentration in surfactant enhanced aquifer remediation effluent: A two-dimensional flow cell study. AB - During the process of surfactant enhanced aquifer remediation (SEAR), free phase dense non-aqueous phase liquid (DNAPL) may be mobilized and spread. The understanding of the impact of DNAPL spreading on the SEAR remediation is not sufficient with its positive effect infrequently mentioned. To evaluate the correlation between DNAPL spreading and remediation efficiency, a two-dimensional sandbox apparatus was used to simulate the migration and dissolution process of 1,2-DCA (1,2-dichloroethane) DNAPL in SEAR. Distribution area of DNAPL in the sandbox was determined by digital image analysis and correlated with effluent DNAPL concentration. The results showed that the effluent DNAPL concentration has significant positive linear correlation with the DNAPL distribution area, indicating the mobilization of DNAPL could improve remediation efficiency by enlarging total NAPL-water interfacial area for mass transfer. Meanwhile, the vertical migration of 1,2-DCA was limited within the boundary of aquifer in all experiments, implying that by manipulating injection parameters in SEAR, optimal remediation efficiency can be reached while the risk of DNAPL vertical migration is minimized. This study provides a convenient visible and quantitative method for the optimization of parameters for SEAR project, and an approach of rapid predicting the extent of DNAPL contaminant distribution based on the dissolved DNAPL concentration in the extraction well. PMID- 26583299 TI - Device-associated pneumonia of very low birth weight infants in Polish Neonatal Intensive Care Units. AB - PURPOSE: Late-Onset Pneumonia (LO-PNEU) is still the most important complication associated with the hospitalization of infants with very low birth weight (<1501g). The purpose of this paper is to summarize the results of an ongoing surveillance program defining LO-PNEU as associated or not associated with respiratory support in the NICU and distribution of causative pathogens from the Polish Neonatology Surveillance Network (PNSN). MATERIALS AND METHODS: Surveillance of infections was conducted in the years 2009-2011 at six Polish NICUs. RESULTS: The incidence was 3.1/1000 NICU patient days (pds). The mean gestational age and birth weight among infants with LO-PNEU were significantly lower. The VAP incidence was of 18.2/1000 NICU pds for mechanically ventilated (MV) infants, while the rates for those receiving only CPAP were as low as 7.7/1000 NICU pds. MV significantly increased the risk of PNEU, but MV or CPAP for <10 days did not increase the risk of LO-PNEU. Significantly associated with LO-PNEU was the use of central or peripheral venous catheters and total parenteral nutrition for longer periods. Microorganisms isolated in cases of LO PNEU were Gram-positive cocci (53.5%) and Gram-negative rods, with predominating E. coli. Non fermentative bacilli were significantly more frequent in cases of VAP than in other cases. CONCLUSIONS: Observed incidence rates associated with VAP and CPAP-PNEU, were higher than in other national surveillance systems and expressing the feasibility of lowering the risk of LO-PNEU and increasing patient safety. The incidence of pneumonia was found to be lower when using CPAP as compared to using MV. PMID- 26583300 TI - Exploring the role of donepezil in dementia with Lewy bodies. AB - Dementia with Lewy bodies (DLB) is considered the second most common form of dementia in the elderly. The cognitive fluctuations, hallucinations and extrapyramidal symptoms and signs suggest simultaneous neurodegeneration in multiple neuronal pathways including both dopaminergic and cholinergic transmission. In the past few years, several small studies have demonstrated the benefit of acetylcholinesterase inhibitors (AChEIs) on the cognitive and behavioral symptoms of DLB. These drugs, by reversibly blocking the hydrolytic activity of AChE, increase the availability of synaptic acetylcholine. Neuropathological and neuroimaging studies demonstrated that cholinergic neurotransmission is more defective in DLB than in Alzheimer's disease (AD). Despite the relevance of AChEIs to DLB, there are no FDA-approved drugs for its management. The aim of this review is to summarize the literature on the application of donepezil in DLB. Although the results are inconclusive, when one compares and contrasts them to the results of the AD-donepezil trials, the effect size appears larger. Placebo-controlled, randomized, well-powered studies of adequate length are needed to avoid underutilization of a potentially efficacious drug. PMID- 26583301 TI - Targeted biological therapies reach the heart: the case of serelaxin for heart failure. AB - Acute heart failure (AHF) is one of the most important causes of mortality, morbidity and rising healthcare costs. Despite this, there has been minimal advancement in the management of AHF and the treatment continues to focus on symptomatic improvement using vasodilators, diuretics and inotropes, none of which have shown any mortality benefits. Though originally thought of as a reproductive hormone, relaxin is now recognized as a potent vasodilator that modulates systemic and renal vascular tone, resulting in pre- and after-load reduction and a decrease in cardiac workload. A single intravenous infusion of relaxin over 48 hours has been shown to provide significant dyspnea relief among AHF patients, with an ongoing study to evaluate its potential for mortality benefit. This article provides an insight into the pharmacology of this novel therapy for AHF with an eye towards future clinical applications. PMID- 26583302 TI - Tavaborole topical solution, 5% for the treatment of toenail onychomycosis. AB - Tavaborole topical solution, 5% (tavaborole) is a novel, boron-based, antifungal pharmaceutical agent indicated for treatment of toenail onychomycosis due to the dermatophytes Trichophyton rubrum or Trichophyton mentagrophytes. In preclinical studies, tavaborole effectively penetrated through full-thickness, non-diseased cadaver fingernails, including those with up to four layers of nail polish. Limited systemic absorption was observed following topical application of tavaborole. In phase III clinical trials involving patients with distal subungual onychomycosis affecting 20-60% of a target great toenail, significantly more patients treated with tavaborole versus vehicle achieved completely clear nail with negative mycology following daily application for 48 weeks. Treatment emergent adverse events reported by at least 1% of patients treated with tavaborole and at a greater frequency versus vehicle included ingrown toenail, exfoliation, erythema and dermatitis. Treatment discontinuations were uncommon. Results from preclinical studies and phase III clinical trials establish tavaborole as a safe and efficacious treatment for toenail onychomycosis. PMID- 26583303 TI - European Pharmaceutical Pricing and Reimbursement--SMi's 21st Annual Meeting (October 5-6, 2015--London, UK). AB - Translating perceived market value for pharmaceutical products into a willingness to pay remains the key factor in ensuring market access and return on investment. How price is managed in the context of new market entrants or new approval settings can create complex challenges, and further complexity is added through diverse global reimbursement structures and the myriad of stakeholders involved at every step of value identification. SMi's 21st Annual Meeting on European Pricing and Reimbursement presented a program focused on the measures being taken by European healthcare systems as they seek to facilitate access to the latest treatments while delivering value for payers and patients. Supporting patient access to life-changing medicines is a challenge, and funders are responding in many different ways; however, while the pharma industry continues to focus its efforts on high cost drugs that treat diseases of the few, the disconnect will be not be resolved. The speakers and delegates at the annual meeting believe success is possible by focusing on value for patients, driven by provider experience, scale and learning. Instead of simply lowering costs, companies, providers and payers can more adequately contribute to the goals of funders as well as the treatment needs of patients. PMID- 26583304 TI - COPD: Novel therapeutics and management strategies--SMi's 7th Annual Conference (October 19-20, 2015--London, UK). AB - In 2004 the WHO estimated that 64 million people worldwide suffered from chronic obstructive pulmonary disease (COPD), with 3 million dying from related complications in 2005. Although many patients go undiagnosed, the number of people with the disease continues to increase, and by 2030 it is thought it will be the third most common cause of death in the world. With no cure for COPD, treatment of symptoms increased the European health bill by USD 10 million last year and the market is thought to increase to approximately USD 37.7 million by 2030. These staggering numbers were presented by Frank Thielman (Novartis Pharma) as he opened SMi's Seventh Annual COPD Conference in London, U.K. The meeting gathered experts and scientific pioneers in the respiratory area to discuss developments in known and new therapies, devices and diagnosis, including biomarker models to gain greater disease understanding. This report covers highlights from the 2-day meeting. PMID- 26583305 TI - SMi'S 4th Annual Orphan Drugs and Rare Diseases Conference (October 19-20, 2015- London, UK). AB - The story of rare diseases is a story of people. Often very young, and usually with little hope of treatment, it is often a desperately sad and tragic story, but increasingly a story of hope. Statistics are inescapable when discussing the subject: small numbers of patients in huge populations, the massively disproportionate contribution to pediatric mortality, and the necessarily high prices for rare drugs. Almost every speaker at the SMi's Fourth Orphan Drugs and Rare Diseases conference provided figures that illustrated just how different this area is to the macro-world of the blockbuster drug. PMID- 26583306 TI - Efficient synthetic methods for the installation of boron-nitrogen bonds in conjugated organic molecules. AB - Polycyclic aromatic hydrocarbons in which one or more CC units have been replaced by isoelectronic BN units have attracted interest as potentially improved organic materials in various devices. This promise has been hampered by a lack of access to gram quantities of these materials. However, the exploitation of keystone reactions such as ring closing metathesis, borylative cyclization of amino styrenes and electrophilic borylation has lead to strategies for access to workable amounts of material. These strategies can be augmented by judicious postfunctionalization reactions to diversify the library of materials available. This Frontier article highlights some of the recent successes and shows that the long promised applications of BN-doped PAHs are beginning to be explored in a meaningful way. PMID- 26583307 TI - COMPARISON OF MANUAL AND SEMIAUTOMATED FUNDUS AUTOFLUORESCENCE ANALYSIS OF MACULAR ATROPHY IN STARGARDT DISEASE PHENOTYPE. AB - PURPOSE: To evaluate manual and semiautomated grading techniques for assessing decreased fundus autofluorescence (DAF) in patients with Stargardt disease phenotype. METHODS: Certified reading center graders performed manual and semiautomated (region finder-based) grading of confocal scanning laser ophthalmoscopy (cSLO) fundus autofluorescence (FAF) images for 41 eyes of 22 patients. Lesion types were defined based on the black level and sharpness of the border: definite decreased autofluorescence (DDAF), well, and poorly demarcated questionably decreased autofluorescence (WDQDAF, PDQDAF). Agreement in grading between the two methods and inter- and intra-grader agreement was assessed by kappa coefficients (kappa) and intraclass correlation coefficients (ICC). RESULTS: The mean +/- standard deviation (SD) area was 3.07 +/- 3.02 mm for DDAF (n = 31), 1.53 +/- 1.52 mm for WDQDAF (n = 9), and 6.94 +/- 10.06 mm for PDQDAF (n = 17). The mean +/- SD absolute difference in area between manual and semiautomated grading was 0.26 +/- 0.28 mm for DDAF, 0.20 +/- 0.26 mm for WDQDAF, and 4.05 +/- 8.32 mm for PDQDAF. The ICC (95% confidence interval) for method comparison was 0.992 (0.984-0.996) for DDAF, 0.976 (0.922-0.993) for WDQDAF, and 0.648 (0.306-0.842) for PDQDAF. Inter- and intra-grader agreement in manual and semiautomated quantitative grading was better for DDAF (0.981-0.996) and WDQDAF (0.995-0.999) than for PDQDAF (0.715-0.993). CONCLUSION: Manual and semiautomated grading methods showed similar levels of reproducibility for assessing areas of decreased autofluorescence in patients with Stargardt disease phenotype. Excellent agreement and reproducibility were observed for well demarcated lesions. PMID- 26583308 TI - CHOROIDAL THICKNESS IN INFANTS WITH RETINOPATHY OF PREMATURITY. AB - PURPOSE: To evaluate choroidal thickness in premature infants and its relationship with stage of retinopathy of prematurity (ROP) using spectral domain optical coherence tomography (SD-OCT). METHODS: Spectral domain optical coherence tomography imaging for measuring subfoveal choroidal thickness was performed for 80 premature infants. Subfoveal choroidal thickness was defined as the distance from the hyperreflective line of the outermost retinal pigment epithelium (RPE) to the innermost hyperreflective line of the choroidoscleral junction. Each measurement was performed at the central fovea (CF) and 0.75 mm to 1.5 mm nasal (N1 and N2) and temporal (T1 and T2) to the fovea. Subfoveal choroidal thickness and grading of cystoid macular edema (CME) were analyzed statistically. RESULTS: Choroidal thickness of CF was found to be significantly greater than nasal (N1 and N2) and temporal (T1 and T2) choroidal thickness (P < 0.05). There was no significant relationship between stage of ROP and nasal (N1 and N2) choroidal thickness (P = 0.057, P = 0.282, respectively). However, CF and temporal (T1 and T2) choroidal thickness was found to be significantly lower at a higher stage of ROP (P = 0.005, P = 0.01 and P = 0.001). No significant relationship was found between subfoveal choroidal thickness and the grades of cystoid macular edema (P > 0.05). The choroidal thickness of CF was found to be correlated with birth weight (r = 0.267, P = 0.017) but not birth week (r = 0.140, P = 0.217). Maximum stage of ROP was found to be negatively correlated with choroidal thickness, at N1, T1, and T2 (r < -0.250, P < 0.02). CONCLUSION: The subfoveal choroid in premature infants can be effectively evaluated using a portable SD-OCT device. Choroidal thickness gets thinner with the severity of ROP and the decrease is more prominent at the central and temporal location. Cystoid macular edema is not correlated with choroidal thickness in premature infants. PMID- 26583309 TI - RANIBIZUMAB FOR DIABETIC MACULAR EDEMA REFRACTORY TO MULTIPLE PRIOR TREATMENTS. AB - PURPOSE: Diabetic macular edema can be refractory to multiple treatment modalities. Although there have been anecdotal reports of ranibizumab showing efficacy when other modalities provided limited benefit, little has been published on treatment for refractory diabetic macular edema. This study sought to investigate this observation further. METHODS: Retrospective chart review. RESULTS: Thirty-three eyes of 22 patients with refractory diabetic macular edema were treated with 0.3 mg intravitreal ranibizumab. This group of eyes received an average of 5.1 prior treatments (macular laser, intravitreal bevacizumab, triamcinolone acetonide, or dexamethasone implant). The mean best corrected visual acuity before the initial ranibizumab injection was 20/110 and the mean central subfield thickness was 384 MUm. After 7 visits over an average of 48 weeks, during which an average of 6 ranibizumab injections were administered, the mean visual acuity improved to 20/90 and the mean central subfield thickness improved to 335 MUm. Both central subfield thickness and best corrected visual acuity improved with number of days of follow-up in a statistically significant fashion (P < 0.01). Similarly, both central subfield thickness and visual acuity improved with number of ranibizumab injections in a linear fashion, but this was not statistically significant. CONCLUSION: Ranibizumab can improve diabetic macular edema refractory to prior treatments of laser photocoagulation, intravitreal triamcinolone acetonide, and bevacizumab. PMID- 26583310 TI - CORRELATION OF VISUAL ACUITY WITH FIBROTIC SCAR LOCATION IN TREATED NEOVASCULAR AGE-RELATED MACULAR DEGENERATION EYES. AB - PURPOSE: To determine whether the optical coherence tomography location of a subfoveal fibrovascular scar is correlated with visual outcome in eyes successfully treated with antivascular endothelial growth factor agents for neovascular age-related macular degeneration. METHODS: Fifty-six eyes from 56 patients with a subfoveal disciform scar after antivascular endothelial growth factor treatment were included. The initial and final visual acuity, fluorescein angiography, and spectral domain optical coherence tomography scar characteristics were retrospectively reviewed. RESULTS: Thirty-five of 56 eyes (62.5%) were classified as having entirely subretinal pigment epithelial (sub RPE) scars, and 21 eyes (37.5%) had subretinal component scars. Mean initial visual acuity was similar between sub-RPE and subretinal scars (20/100 vs. 20/125, P = 0.517); mean final visual acuity was better in the sub-RPE scar group (20/60 vs. 20/200, P = 0.001). Eyes with sub-RPE scar had better preservation of the external limiting membrane, ellipsoid layer, and retinal thickness (P < 0.001, P = 0.017, P = 0.004, respectively) than subretinal component scar eyes. There was no difference between the groups in scar thickness or scar area (P = 0.707, P = 0.186, respectively). CONCLUSION: Sub-RPE location of subfoveal scarring in eyes treated for neovascular age-related macular degeneration is associated with better preservation of outer retinal structures and better vision, when compared with a subretinal scar. PMID- 26583311 TI - OPTIC NERVE INFILTRATION BY RETINOBLASTOMA: Predictive Clinical Features and Outcome. AB - PURPOSE: To identify the clinical features predictive of any optic nerve infiltration and postlaminar optic nerve infiltration by retinoblastoma on histopathology and to report the outcome (metastasis and death) in these patients. METHODS: Retrospective study. RESULTS: Of the 403 patients who underwent primary enucleation for retinoblastoma, 196 patients had optic nerve tumor infiltration (Group 1) and 207 patients had no evidence of optic nerve tumor infiltration (Group 2). Group 1 included patients with prelaminar (n = 47; 24%), laminar (n = 74; 38%), and postlaminar tumor infiltration with or without involving optic nerve transection (n = 74; 38%). Comparing Group 1 and Group 2, the patients in Group 1 had prolonged duration of symptoms (>6 months) (16% vs. 8%; P = 0.02) and were associated with no vision at presentation (23% vs. 10%; P = 0.01), higher rates of secondary glaucoma (42% vs. 12%; P < 0.0001), iris neovascularization (39% vs. 23%; P < 0.001), and larger tumors (mean tumor thickness, 12.8 mm vs. 12 mm; P = 0.0001). There was a higher prevalence of metastasis in Group 1 than in Group 2 (4% vs. 0%; P = 0.006). On multivariate analysis, clinical features predictive of any optic nerve tumor infiltration secondary glaucoma (hazard ratio = 5.38; P < 0.001) and those predictive of postlaminar optic nerve tumor infiltration included iris neovascularization (hazard ratio = 2.66; P = 0.001) and secondary glaucoma (hazard ratio = 3.13; P < 0.001). CONCLUSION: In this study, clinical features predictive of any optic nerve tumor infiltration included secondary glaucoma and those predictive of postlaminar optic nerve tumor infiltration included iris neovascularization and secondary glaucoma. Despite adjuvant treatment in those with postlaminar optic nerve tumor infiltration, metastasis occurred in 8% of patients. PMID- 26583312 TI - WIDEFIELD FLUORESCEIN ANGIOGRAPHY IN PATIENTS WITHOUT PERIPHERAL DISEASE: A Study of Normal Peripheral Findings. AB - PURPOSE: Widefield photography and angiography provide access up to 200-degrees of the retinal periphery. The range of normal peripheral findings has not been characterized, yet is relevant to studies addressing putative peripheral retinal vascular pathology. METHODS: This study was an observational retrospective cohort study. Adult patients with epiretinal membrane or choroidal nevi who underwent imaging with Optos 200 MA/200Tx were included. Dye transit times, peripheral arteriovenous shunting, presence of vessels crossing the horizontal raphe, right angle vessels, terminal networks, absence of capillary detail, ground glass hyperfluorescence, peripheral drusen, and microaneurysms were evaluated. RESULTS: Fifty-eight eyes of 31 patients met inclusion criteria. Mean peripheral arterial filling time was 8.65 +/- 2.54 seconds (range 3-15 seconds). One or more peripheral anomalies were noted in all patients (P < 0.01). The prevalences of findings were: arteriovenous shunting (0.00%), vessels crossing the horizontal raphe (44.83%), right angle vessels (70.69%), terminal networks (77.59%), absence of capillary detail (98.28%), ground glass hyperfluorescence (87.93%), drusen (34.48%), and microaneurysms (41.38%). CONCLUSION: There was a high prevalence of peripheral vascular anatomic variations in eyes expected to have normal peripheral retinal vasculature. These findings may provide a reference for future studies addressing putative pathologic peripheral angiographic findings. PMID- 26583313 TI - Parainfluenza Virus 5 as Possible Cause of Severe Respiratory Disease in Calves, China. PMID- 26583315 TI - Probing of chain conformations in conjugated polymer nanoparticles by electron spin resonance spectroscopy. AB - In the case of conjugated polymer chains usually considered as rigid or stiff, it is an open question how the individual chains adopt their conformation inside nanoparticles. Here, the conformation of such a rigid conjugated polymer chain is elucidated for the first time. For this purpose, electron paramagnetic resonance spectroscopy as a method allowing for a direct observation is established. PMID- 26583314 TI - Microwave gallium-68 radiochemistry for kinetically stable bis(thiosemicarbazone) complexes: structural investigations and cellular uptake under hypoxia. AB - We report the microwave synthesis of several bis(thiosemicarbazones) and the rapid gallium-68 incorporation to give the corresponding metal complexes. These proved kinetically stable under 'cold' and 'hot' biological assays and were investigated using laser scanning confocal microscopy, flow cytometry and radioactive cell retention studies under normoxia and hypoxia. (68)Ga complex retention was found to be 34% higher in hypoxic cells than in normoxic cells over 30 min, further increasing to 53% at 120 min. Our data suggests that this class of gallium complexes show hypoxia selectivity suitable for imaging in living cells and in vivo tests by microPET in nude athymic mice showed that they are excreted within 1 h of their administration. PMID- 26583317 TI - Approaching the Kinetic Inertness of Macrocyclic Gadolinium(III)-Based MRI Contrast Agents with Highly Rigid Open-Chain Derivatives. AB - A highly rigid open-chain octadentate ligand (H4 cddadpa) containing a diaminocylohexane unit to replace the ethylenediamine bridge of 6,6'-[(ethane-1,2 diylbis{(carboxymethyl)azanediyl})bis(methylene)]dipicolinic acid (H4 octapa) was synthesized. This structural modification improves the thermodynamic stability of the Gd(3+) complex slightly (log KGdL =20.68 vs. 20.23 for [Gd(octapa)](-) ) while other MRI-relevant parameters remain unaffected (one coordinated water molecule; relaxivity r1 =5.73 mm(-1) s(-1) at 20 MHz and 295 K). Kinetic inertness is improved by the rigidifying effect of the diaminocylohexane unit in the ligand skeleton (half-life of dissociation for physiological conditions is 6 orders of magnitude higher for [Gd(cddadpa)](-) (t1/2 =1.49*10(5) h) than for [Gd(octapa)](-) . The kinetic inertness of this novel chelate is superior by 2-3 orders of magnitude compared to non-macrocyclic MRI contrast agents approved for clinical use. PMID- 26583316 TI - Deep clinical and neuropathological phenotyping of Pick disease. AB - OBJECTIVE: To characterize sequential patterns of regional neuropathology and clinical symptoms in a well-characterized cohort of 21 patients with autopsy confirmed Pick disease. METHODS: Detailed neuropathological examination using 70MUm and traditional 6MUm sections was performed using thioflavin-S staining and immunohistochemistry for phosphorylated tau, 3R and 4R tau isoforms, ubiquitin, and C-terminally truncated tau. Patterns of regional tau deposition were correlated with clinical data. In a subset of cases (n = 5), converging evidence was obtained using antemortem neuroimaging measures of gray and white matter integrity. RESULTS: Four sequential patterns of pathological tau deposition were identified starting in frontotemporal limbic/paralimbic and neocortical regions (phase I). Sequential involvement was seen in subcortical structures, including basal ganglia, locus coeruleus, and raphe nuclei (phase II), followed by primary motor cortex and precerebellar nuclei (phase III) and finally visual cortex in the most severe (phase IV) cases. Behavioral variant frontotemporal dementia was the predominant clinical phenotype (18 of 21), but all patients eventually developed a social comportment disorder. Pathological tau phases reflected the evolution of clinical symptoms and degeneration on serial antemortem neuroimaging, directly correlated with disease duration and inversely correlated with brain weight at autopsy. The majority of neuronal and glial tau inclusions were 3R tau-positive and 4R tau-negative in sporadic cases. There was a relative abundance of mature tau pathology markers in frontotemporal limbic/paralimbic regions compared to neocortical regions. INTERPRETATION: Pick disease tau neuropathology may originate in limbic/paralimbic cortices. The patterns of tau pathology observed here provide novel insights into the natural history and biology of tau-mediated neurodegeneration. PMID- 26583318 TI - Role of necroptosis in the pathogenesis of solid organ injury. AB - Necroptosis is a type of regulated cell death dependent on the activity of receptor-interacting serine/threonine-protein (RIP) kinases. However, unlike apoptosis, it is caspase independent. Increasing evidence has implicated necroptosis in the pathogenesis of disease, including ischemic injury, neurodegeneration, viral infection and many others. Key players of the necroptosis signalling pathway are now widely recognized as therapeutic targets. Necrostatins may be developed as potent inhibitors of necroptosis, targeting the activity of RIPK1. Necrostatin-1, the first generation of necrostatins, has been shown to confer potent protective effects in different animal models. This review will summarize novel insights into the involvement of necroptosis in specific injury of different organs, and the therapeutic platform that it provides for treatment. PMID- 26583320 TI - HSP70 protects human neuroblastoma cells from apoptosis and oxidative stress induced by amyloid peptide isoAsp7-Abeta(1-42). PMID- 26583319 TI - Palmitate induces ER calcium depletion and apoptosis in mouse podocytes subsequent to mitochondrial oxidative stress. AB - Pathologic alterations in podocytes lead to failure of an essential component of the glomerular filtration barrier and proteinuria in chronic kidney diseases. Elevated levels of saturated free fatty acid (FFA) are harmful to various tissues, implemented in the progression of diabetes and its complications such as proteinuria in diabetic nephropathy. Here, we investigated the molecular mechanism of palmitate cytotoxicity in cultured mouse podocytes. Incubation with palmitate dose-dependently increased cytosolic and mitochondrial reactive oxygen species, depolarized the mitochondrial membrane potential, impaired ATP synthesis and elicited apoptotic cell death. Palmitate not only evoked mitochondrial fragmentation but also caused marked dilation of the endoplasmic reticulum (ER). Consistently, palmitate upregulated ER stress proteins, oligomerized stromal interaction molecule 1 (STIM1) in the subplasmalemmal ER membrane, abolished the cyclopiazonic acid-induced cytosolic Ca(2+) increase due to depletion of luminal ER Ca(2+). Palmitate-induced ER Ca(2+) depletion and cytotoxicity were blocked by a selective inhibitor of the fatty-acid transporter FAT/CD36. Loss of the ER Ca(2+) pool induced by palmitate was reverted by the phospholipase C (PLC) inhibitor edelfosine. Palmitate-dependent activation of PLC was further demonstrated by following cytosolic translocation of the pleckstrin homology domain of PLC in palmitate-treated podocytes. An inhibitor of diacylglycerol (DAG) kinase, which elevates cytosolic DAG, strongly promoted ER Ca(2+) depletion by low-dose palmitate. GF109203X, a PKC inhibitor, partially prevented palmitate induced ER Ca(2+) loss. Remarkably, the mitochondrial antioxidant mitoTEMPO inhibited palmitate-induced PLC activation, ER Ca(2+) depletion and cytotoxicity. Palmitate elicited cytoskeletal changes in podocytes and increased albumin permeability, which was also blocked by mitoTEMPO. These data suggest that oxidative stress caused by saturated FFA leads to mitochondrial dysfunction and ER Ca(2+) depletion through FAT/CD36 and PLC signaling, possibly contributing to podocyte injury. PMID- 26583321 TI - Hepatitis B virus stimulates G6PD expression through HBx-mediated Nrf2 activation. AB - Metabolic reprogramming is a hallmark of physiological changes in cancer. Cancer cells primarily apply glycolysis for cell metabolism, which enables the cells to use glycolytic intermediates for macromolecular biosynthesis in order to meet the needs of cell proliferation. Here, we show that glucose-6-phosphate dehydrogenase (G6PD), the first and rate-limiting enzyme of the pentose phosphate pathway, is highly expressed in chronic hepatitis B virus (HBV)-infected human liver and HBV associated liver cancer, together with an elevated activity of the transcription factor Nrf2. In hepatocytes, HBV stimulates by its X protein (HBx) the expression of G6PD in an Nrf2 activation-dependent pathway. HBx associates with the UBA and PB1 domains of the adaptor protein p62 and augments the interaction between p62 and the Nrf2 repressor Keap1 to form HBx-p62-Keap1 complex in the cytoplasm. The aggregation of HBx-p62-Keap1 complexes hijacks Keap1 from Nrf2 leading to the activation of Nrf2 and consequently G6PD transcription. Our data suggest that HBV upregulates G6PD expression by HBx-mediated activation of Nrf2. This implies a potential effect of HBV on the reprogramming of the glucose metabolism in hepatocytes, which may be of importance in the development of HBV-associated hepatocarcinoma. PMID- 26583322 TI - Discrete roles of canonical and non-canonical Wnt signaling in hematopoiesis and lymphopoiesis. AB - The mechanisms that regulate proliferation, fate decisions and differentiation of hematopoietic stem cells (HSC) and thymic stem cells are highly complex. Several signaling pathways including Wnt signaling have important roles during these processes. Both canonical and non-canonical Wnt signaling are important in normal and malignant hematopoiesis and lymphoid development, yet their precise roles are controversial. In a side-by-side comparison, we investigated the roles of the canonical and non-canonical Wnt pathway in hematopoiesis and thymopoiesis. As complete loss-of-function models for non-canonical Wnt signaling are not yet available and highly complex for canonical Wnt signaling, we decided to use a gain-of-function approach. To this end, Wnt3a and Wn5a, two well-known prototypical canonical and non-canonical Wnt ligands were produced in hematopoiesis supporting stromal assays. High levels of Wnt3a signaling blocked T cell development at early stages, whereas intermediate levels accelerated T-cell development. In contrast, Wnt5a signaling prompted apoptosis in developing thymocytes, without affecting differentiation at a particular stage. To explore the role of Wnt3a and Wnt5a in vivo, we transduced HSCs isolated from fetal liver, transduced with Wnt3a and Wnt5a vectors, and performed reconstitution assays in irradiated C57Bl/6 mice. Wnt3a overexpression led to increased lymphopoiesis, whereas Wnt5a augments myelopoiesis in the bone marrow (BM) and spleen. Thus, the canonical and non-canonical Wnt signaling have discrete roles in hematopoiesis and thymopoiesis, and understanding their right dose of action is crucial for prospective translational applications. PMID- 26583323 TI - Prospects of adjuvant RANKL inhibition in breast cancer? PMID- 26583324 TI - Novel beta-carbolines inhibit Wnt/beta-catenin signaling. PMID- 26583325 TI - Smad4 represses the generation of memory-precursor effector T cells but is required for the differentiation of central memory T cells. AB - The transcriptional regulation underlying the differentiation of CD8(+) effector and memory T cells remains elusive. Here, we show that 18-month-old mice lacking the transcription factor Smad4 (homolog 4 of mothers against decapentaplegic, Drosophila), a key intracellular signaling effector for the TGF-beta superfamily, in T cells exhibited lower percentages of CD44(hi)CD8(+) T cells. To explore the role of Smad4 in the activation/memory of CD8(+) T cells, 6- to 8-week-old mice with or without Smad4 in T cells were challenged with Listeria monocytogenes. Smad4 deficiency did not affect antigen-specific CD8(+) T-cell expansion but led to partially impaired cytotoxic function. Less short-lived effector T cells but more memory-precursor effector T cells were generated in the absence of Smad4. Despite that, Smad4 deficiency led to reduced memory CD8(+) T-cell responses. Further exploration revealed that the generation of central memory T cells was impaired in the absence of Smad4 and the cells showed survival issue. In mechanism, Smad4 deficiency led to aberrant transcriptional programs in antigen specific CD8(+) T cells. These findings demonstrated an essential role of Smad4 in the control of effector and memory CD8(+) T-cell responses to infection. PMID- 26583326 TI - Blue light-induced retinal lesions, intraretinal vascular leakage and edema formation in the all-cone mouse retina. AB - Little is known about the mechanisms underlying macular degenerations, mainly for the scarcity of adequate experimental models to investigate cone cell death. Recently, we generated R91W;Nrl(-/-) double-mutant mice, which display a well ordered all-cone retina with normal retinal vasculature and a strong photopic function that generates useful vision. Here we exposed R91W;Nrl(-/-) and wild type (wt) mice to toxic levels of blue light and analyzed their retinas at different time points post illumination (up to 10 days). While exposure of wt mice resulted in massive pyknosis in a focal region of the outer nuclear layer (ONL), the exposure of R91W;Nrl(-/-) mice led to additional cell death detected within the inner nuclear layer. Microglia/macrophage infiltration at the site of injury was more pronounced in the all-cone retina of R91W;Nrl(-/-) than in wt mice. Similarly, vascular leakage was abundant in the inner and outer retina in R91W;Nrl(-/-) mice, whereas it was mild and restricted to the subretinal space in wt mice. This was accompanied by retinal swelling and the appearance of cystoid spaces in both inner and ONLs of R91W;Nrl(-/-) mice indicating edema in affected areas. In addition, basal expression levels of tight junction protein-1 encoding ZO1 were lower in R91W;Nrl(-/-) than in wt retinas. Collectively, our data suggest that exposure of R91W;Nrl(-/-) mice to blue light not only induces cone cell death but also disrupts the inner blood-retinal barrier. Macular edema in humans is a result of diffuse capillary leakage and microaneurysms in the macular region. Blue light exposure of the R91W;Nrl(-/-) mouse could therefore be used to study molecular events preceding edema formation in a cone-rich environment, and thus potentially help to develop treatment strategies for edema-based complications in macular degenerations. PMID- 26583328 TI - Understanding drug-cytokine synergistic toxicity. PMID- 26583327 TI - Membrane-bound and soluble Fas ligands have opposite functions in photoreceptor cell death following separation from the retinal pigment epithelium. AB - Fas ligand (FasL) triggers apoptosis of Fas-positive cells, and previous reports described FasL-induced cell death of Fas-positive photoreceptors following a retinal detachment. However, as FasL exists in membrane-bound (mFasL) and soluble (sFasL) forms, and is expressed on resident microglia and infiltrating monocyte/macrophages, the current study examined the relative contribution of mFasL and sFasL to photoreceptor cell death after induction of experimental retinal detachment in wild-type, knockout (FasL-/-), and mFasL-only knock-in (DeltaCS) mice. Retinal detachment in FasL-/- mice resulted in a significant reduction of photoreceptor cell death. In contrast, DeltaCS mice displayed significantly more apoptotic photoreceptor cell death. Photoreceptor loss in DeltaCS mice was inhibited by a subretinal injection of recombinant sFasL. Thus, Fas/FasL-triggered cell death accounts for a significant amount of photoreceptor cell loss following the retinal detachment. The function of FasL was dependent upon the form of FasL expressed: mFasL triggered photoreceptor cell death, whereas sFasL protected the retina, indicating that enzyme-mediated cleavage of FasL determines, in part, the extent of vision loss following the retinal detachment. Moreover, it also indicates that treatment with sFasL could significantly reduce photoreceptor cell loss in patients with retinal detachment. PMID- 26583329 TI - Platelet-derived CXCL12 regulates monocyte function, survival, differentiation into macrophages and foam cells through differential involvement of CXCR4-CXCR7. AB - Platelets store and release CXCL12 (SDF-1), which governs differentiation of hematopoietic progenitors into either endothelial or macrophage-foam cells. CXCL12 ligates CXCR4 and CXCR7 and regulates monocyte/macrophage functions. This study deciphers the relative contribution of CXCR4-CXCR7 in mediating the effects of platelet-derived CXCL12 on monocyte function, survival, and differentiation. CXCL12 and macrophage migration inhibitory factor (MIF) that ligate CXCR4-CXCR7 induced a dynamic bidirectional trafficking of the receptors, causing CXCR4 internalization and CXCR7 externalization during chemotaxis, thereby influencing relative receptor availability, unlike MCP-1. In vivo we found enhanced accumulation of platelets and platelet-macrophage co-aggregates in peritoneal fluid following induction of peritonitis in mice. The relative surface expression of CXCL12, CXCR4, and CXCR7 among infiltrated monocytes was also enhanced as compared with peripheral blood. Platelet-derived CXCL12 from collagen-adherent platelets and recombinant CXCL12 induced monocyte chemotaxis specifically through CXCR4 engagement. Adhesion of monocytes to immobilized CXCL12 and CXCL12-enriched activated platelet surface under static and dynamic arterial flow conditions were mediated primarily through CXCR7 and were counter-regulated by neutralizing platelet-derived CXCL12. Monocytes and culture-derived-M1-M2 macrophages phagocytosed platelets, with the phagocytic potential of culture-derived-M1 macrophages higher than M2 involving CXCR4-CXCR7 participation. CXCR7 was the primary receptor in promoting monocyte survival as exerted by platelet-derived CXCL12 against BH3-mimetic induced apoptosis (phosphatidylserine exposure, caspase-3 activation, loss of mitochondrial transmembrane potential). In co culture experiments with platelets, monocytes predominantly differentiated into CD163(+) macrophages, which was attenuated upon CXCL12 neutralization and CXCR4/CXCR7 blocking antibodies. Moreover, OxLDL uptake by platelets induced platelet apoptosis, like other platelet agonists TRAP and collagen-related peptide (CRP). CXCL12 facilitated phagocytosis of apoptotic platelets by monocytes and M1-M2 macrophages, also promoted their differentiation into foam cells via CXCR4 and CXCR7. Thus, platelet-derived CXCL12 could regulate monocyte macrophage functions through differential engagement of CXCR4 and CXCR7, indicating an important role in inflammation at site of platelet accumulation. PMID- 26583331 TI - Adherence pattern to study drugs in clinical trials by patients with cystic fibrosis. AB - BACKGROUND: Clinical trials are all based on the assumption that patients are adherent to the study protocol. Many reports indicate that general adherence of patients with CF to their daily routine therapies is poor. However, no data exists on adherence to study drug regimens. METHODS: All clinical trials carried out at the Hadassah CF Center from 2008 to 2013 were reviewed. Actual adherence as determined by counted drugs was analyzed according to drug administration mode, study lengths and number of study visits. A subset of patients answered a two-part questionnaire covering study specific and general treatment specific issues. RESULTS: Eight studies including 118 patients, with patient numbers varying between 4 and 32 per trial were analyzed. For 7/8 studies mean adherence was between 78% to 100%. Comparison with administration mode showed that adherence decreased substantially if the drugs were not provided as "ready to be used" (63%). Study length influenced adherence, the longer the study the poorer the adherence (82% trial beginning, 44% post 36 months [two combined studies with identical drug]). A substantial decrease was noted over Holiday periods and during the summer vacation months. No correlation was found between number of study visits and adherence to study drug. CONCLUSION: Adherence to study drug is generally higher than that for regular treatment. Study length, mode of administration, and timing according to Holidays and vacations adversely affect adherence. PMID- 26583332 TI - Focus on shared governance: Evaluation of a professional practice model. PMID- 26583330 TI - SOX4 contributes to the progression of cervical cancer and the resistance to the chemotherapeutic drug through ABCG2. AB - SOX4, a member of the SOX (sex-determining region Y-related HMG box) transcription factor family, has been reported to be abnormally expressed in a wide variety of cancers, and to exert a pleiotropic function. However, its function in progression of cervical cancer (CC) remains unknown. In this study, we found that SOX4 was highly expressed in CC cells and tissues, and overexpression of SOX4 in CC CaSki cells enhanced tumor clone formation and cell proliferation, and accelerated cell cycle progress. Meanwhile, downregulation of SOX4 by shRNA in CaSki cells inhibited cell proliferation, and slowed cell cycle progress, indicating that SOX4 contributes to the development of CC. In addition, SOX4 overexpression by gene transfer reduced the sensitivity of CaSki cells in response to the chemotherapeutic drug cisplatin, and SOX4 downregulation by RNA interference increased the sensitivity of CaSki cells in response to cisplatin. Moreover, SOX4 overexpression upregulated multiple drug resistant gene ABCG2, and SOX4 downregulation inhibited ABCG2 expression. Taken together, these results suggested that SOX4 functions to modulate cancer proliferation by regulation of cell cycle, and inhibit cancer cell sensitivity to therapeutic drug via upregulation of ABCG2. Thus, SOX4 may be a target for CC chemotherapy. PMID- 26583333 TI - Establishing a primary nursing model of care. PMID- 26583334 TI - Understanding health information exchange. PMID- 26583335 TI - Classroom assessment techniques. PMID- 26583337 TI - Rising above risk: Eliminating infant falls. PMID- 26583338 TI - The sepsis core measures initiative. PMID- 26583339 TI - Does mindfulness-based stress reduction training improve nurse satisfaction? PMID- 26583340 TI - Nurse leader competencies: A toolkit for success. PMID- 26583341 TI - Identifying substance use disorder in nursing. PMID- 26583342 TI - Leadership Q&A. PMID- 26583343 TI - How does electronic cigarette access affect adolescent smoking? AB - Understanding electronic cigarettes' effect on tobacco smoking is a central economic and policy issue. This paper examines the causal impact of e-cigarette access on conventional cigarette use by adolescents. Regression analyses consider how state bans on e-cigarette sales to minors influence smoking rates among 12 to 17 year olds. Such bans yield a statistically significant 0.9 percentage point increase in recent smoking in this age group, relative to states without such bans. Results are robust to multiple specifications as well as several falsification and placebo checks. This effect is both consistent with e-cigarette access reducing smoking among minors, and large: banning electronic cigarette sales to minors counteracts 70 percent of the downward pre-trend in teen cigarette smoking for a given two-year period. PMID- 26583344 TI - ACR Appropriateness Criteria(r) Diffuse Large B-Cell Lymphoma. AB - The management of diffuse large B-cell lymphoma depends on the initial diagnosis including molecular and immunophenotypic characteristics, Ann Arbor staging, and International Prognostic Index (IPI score). Treatment approaches with different chemotherapy regimens used is discussed in detail. The role of radiation as a consolidation is discussed including: (1) the prerituximab randomized trials that challenged the role of radiation, (2) recent prospective studies (UNFOLDER/RICOVER-60), and (3) retrospective studies; the last 2 showed a potential benefit of radiation both for early and advanced stage. The document also discusses the role of positron emission tomography/computed tomography for predicting outcome and potentially guiding therapy. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. PMID- 26583346 TI - Evaluation of radiofrequency ablation using the 1-Fr wire electrode in the porcine pancreas, liver, gallbladder, spleen, kidney, stomach, and lymph nodes: A pilot study. AB - OBJECTIVES: The frequency of detecting asymptomatic incidental lesions of the pancreas is increasing. A substantial number of these lesions are either malignant or premalignant, thus mandating pancreatic resection. A less invasive treatment option may be feasible for selected patients. Endoscopic ultrasound guided radiofrequency ablation (RFA) may be offered as a treatment option for these patients. The objective of this study was to evaluate the performance characteristics of monopolar RFA using a 1-Fr wire electrode in the porcine pancreas, liver, gallbladder, spleen, kidney, stomach, and lymph nodes. METHODS: Six Yorkshire pigs were used for this study. The internal organs were accessed after a midline laparotomy. Manual monopolar RFAs were performed over a 90-second period using a wide range of power settings (3, 4, 5, 10, 15, and 25 W). The pancreas was exposed at all power settings; the other organs were exposed at power settings of 3, 4, 5, and 10 W. The maximum diameter of coagulative necrosis was measured. RESULTS: In all study animals, RFA was performed in the target organs without difficulty. Only the pancreas showed definite coagulative necrosis. The maximum diameter of coagulative necrosis (8.0+/-1.7 mm) was achieved at 5 W. No definite coagulative necrosis was noted in the other organs. CONCLUSIONS: Monopolar RFA using a 1-Fr wire electrode resulted in coagulative necrosis in the porcine pancreas. RFA in higher power settings resulted in relatively homogeneous necrosis. At a given power setting, the RFA effect is likely to be differ according to electrical properties of the target tissue. This article is protected by copyright. All rights reserved. PMID- 26583347 TI - Effect of family structure and TPH2 G-703T on the stability of dysregulation profile throughout adolescence. AB - BACKGROUND: Two different polymorphisms (TPH2 G-703T and 5-HTTLPR) involved in the serotonergic pathway have been reported to play a role, both alone and in interaction with the environment, in early and adult emotion regulation. As most of these studies are cross-sectional, we know little about the impact of these polymorphisms over time, particularly during adolescence. METHODS: Because we were interested in the effects of these polymorphisms and environment (i.e., family structure) at different time-points on the emotional dysregulation profile, we performed a path analysis model in a general adolescent population sample of a five-year follow-up study. RESULTS: We found a high stability of Dysregulation Profile problems independently from the examined allelic variants. We also found that early family structure directly influences the levels of dysregulation problems in early adolescence, both alone and in interaction with TPH2, suggesting the presence of a gene-environment interaction effect. Furthermore, we found that in adolescents homozygous for the TPH2 G allele, the effect of the early family structure remains active during late adolescence, albeit mediated by earlier emotional problems. LIMITATIONS: The high attrition rate, the use of only one source on behavioral problems of adolescents, and the focus on a single polymorphism in the investigated genes could limit the generalizability of the present results. CONCLUSIONS: These results suggest that early family structure could play a significant role in the development and maintenance of emotional and behavioral problems not only in early adolescence but also in late-adolescence, although this effect was mediated and moderated by behavioral and genetic variables. PMID- 26583348 TI - The impact of intimate partner relationships on suicidal thoughts and behaviours: A systematic review. AB - BACKGROUND: A systematic review was conducted to identify the impact of intimate partner relationships on suicidality. The aim of the review was to identify factors within intimate partner relationships that influence suicidal ideation, attempts and completion. METHOD: Fifty-one articles were identified through Scopus, PubMed and PsycINFO databases. Due to the high heterogeneity of the included studies, a narrative data synthesis was conducted. RESULTS: The research drew attention to specific contingents of the population, for example examining suicide risk in individuals under the age of 35 or lesbian, gay, bisexual and transgender (LGBT) individuals who are experiencing relationship discord, and in males who have recently separated. LIMITATIONS: Interpretation of these findings is constrained by methodological limitations prevalent in much of the literature. Limitations of the existing literature and corresponding directions for future research are discussed. CONCLUSIONS: Relationship separation and poor quality relationships are likely to be important risk factors for suicidal thoughts and behaviours and are frequent triggers for a suicide attempt. This review highlights intimate partner relationships as a significant component in a suicide risk assessment, regardless of the clinical setting. Consequently, clinicians should be aware that individuals reporting relationship problems are likely to be at increased risk of suicidal thoughts and behaviours. PMID- 26583349 TI - Prevalence and correlates of bipolar disorders in patients with eating disorders. AB - BACKGROUND: To investigate the prevalence and correlates of bipolar disorders in patients with eating disorders (EDs), and to examine differences in effects between major depressive disorder and bipolar disorder on these patients. METHODS: Sequential attendees were invited to participate in a two-phase survey for EDs at the general psychiatric outpatient clinics. Patients diagnosed with EDs (n=288) and controls of comparable age, sex, and educational level (n=81) were invited to receive structured interviews for psychiatric co-morbidities, suicide risks, and functional level. All participants also completed several self administered questionnaires assessing general and eating-related pathology and impulsivity. Characteristics were compared between the control, ED-only, ED with major depressive disorder, and ED with bipolar disorder groups. RESULTS: Patients with all ED subtypes had significantly higher rates of major depressive disorder (range, 41.3-66.7%) and bipolar disorder (range, 16.7-49.3%) than controls did. Compared to patients with only EDs, patients with comorbid bipolar disorder and those with comorbid major depressive disorder had significantly increased suicidality and functional impairments. Moreover, the group with comorbid bipolar disorder had increased risks of weight dysregulation, more impulsive behaviors, and higher rates of psychiatric comorbidities. LIMITATIONS: Participants were selected in a tertiary center of a non-Western country and the sample size of individuals with bipolar disorder in some ED subtypes was small. CONCLUSION: Bipolar disorders were common in patients with EDs. Careful differentiation between bipolar disorder and major depressive disorder in patients with EDs may help predict associated psychopathology and provide accurate treatment. PMID- 26583350 TI - Screening for cognitive dysfunction in unipolar depression: Validation and evaluation of objective and subjective tools. AB - BACKGROUND: Persistent cognitive dysfunction in unipolar depression (UD) contributes to socio-occupational impairment, but there are no feasible methods to screen for and monitor cognitive dysfunction in this patient group. The present study investigated the validity of two new instruments to screen for cognitive dysfunction in UD, and their associations with socio-occupational capacity. METHOD: Participants (n=53) with UD in partial or full remission and healthy control persons (n=103) were assessed with two new screening instruments, the Danish translations of the Screen for Cognitive Impairment in Psychiatry (SCIP-D) and Cognitive Complaints in Bipolar Disorder Rating Assessment (COBRA) and with established neuropsychological and self-assessment measures. Depression symptoms and socio-occupational function were rated with the Hamilton Depression Rating Scale and Functional Assessment Short Test respectively. RESULTS: The SCIP D and COBRA were valid for detection of objective and subjective cognitive impairment, respectively. The three parallel SCIP-D forms were equivalent. A combined SCIP-D-COBRA measure showed high sensitivity and good specificity for objective cognitive impairment (91% and 70%, respectively). There was no correlation between subjective and objective measures of cognition. Subjective cognitive difficulties correlated more with socio-occupational impairment (r=0.7, p<0.01) than did objective cognitive difficulties, for which there was a weak correlation with the executive skills domain only (r =-0.3, p=0.05). LIMITATIONS: A modest sample size. CONCLUSIONS: The SCIP-D and COBRA are valid measures of objective and subjective cognitive impairment, respectively, and should ideally be implemented together in the screening for cognitive dysfunction in UD. PMID- 26583351 TI - Latino suicidal adolescent psychosocial service utilization: The role of mood fluctuations and inattention. AB - BACKGROUND: Little is known about the specific factors related to whether or not Latino adolescents with suicide ideation (SI) will seek services. Utilizing Andersen's Behavior Model of Health Services Use (2008) the goal of this study is to identify the factors related to utilization of mental health services by Latino adolescents with SI to inform and improve suicide prevention efforts. METHOD: Data from Wave 1 of the National Longitudinal Study of Adolescent Health was examined. Predispositional (gender, age), enabling/disabling (income, lack of insurance, difficulty obtaining medical care), and need (depressed mood, suicide attempt, perceived health, impulsivity, mood fluctuations, difficulties with attention, etc.) variables were examined via logistic regression as potential correlates of mental health service utilization. RESULTS: Twenty-eight percent of the Latino adolescents with suicidal ideation (SI) in our sample received mental health services. Need factors such as daily mood fluctuations within the past 12 months (OR=4.78) and frequent difficulty focusing attention within the past week (OR=4.96), but not impulsivity, were associated with an increased likelihood of receiving mental health services. No additional associations were observed. LIMITATIONS: The current study is based on cross-sectional data. Therefore, statements about causality cannot be made. CONCLUSIONS: These findings suggest that emotion regulation (e.g., daily mood fluctuations) and neurocognitive factors (e.g., difficulty with focusing attention) may be important factors to consider in the clinical assessment of Latino adolescents with SI. PMID- 26583352 TI - Maternal attachment insecurity is a potent predictor of depressive symptoms in the early postnatal period. PMID- 26583353 TI - Study of light emission and collection in a transparent dielectric cantilever based near-field optical probe. AB - We report the design of a new type of scanning near-field optical microscopy probes combining the advantages of both tapered optical fibres type and cantilever type commercial scanning near-field optical microscopy probes. The material is an organomineral synthesized by the sol-gel method. This material matches mechanical and optical performances for such a scanning near-field optical microscopy probe fabrication. Numerical calculations were carried out using finite element method in order to study the optical transmission of the probe in emission and collection modes. The influence of the probe geometry on the intensity distribution in the vicinity of the aperture and in the extremity of the cantilever is studied in details. PMID- 26583355 TI - Predictions interact with missing sensory evidence in semantic processing areas. AB - Human brain function draws on predictive mechanisms that exploit higher-level context during lower-level perception. These mechanisms are particularly relevant for situations in which sensory information is compromised or incomplete, as for example in natural speech where speech segments may be omitted due to sluggish articulation. Here, we investigate which brain areas support the processing of incomplete words that were predictable from semantic context, compared with incomplete words that were unpredictable. During functional magnetic resonance imaging (fMRI), participants heard sentences that orthogonally varied in predictability (semantically predictable vs. unpredictable) and completeness (complete vs. incomplete, i.e. missing their final consonant cluster). The effects of predictability and completeness interacted in heteromodal semantic processing areas, including left angular gyrus and left precuneus, where activity did not differ between complete and incomplete words when they were predictable. The same regions showed stronger activity for incomplete than for complete words when they were unpredictable. The interaction pattern suggests that for highly predictable words, the speech signal does not need to be complete for neural processing in semantic processing areas. Hum Brain Mapp 37:704-716, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26583356 TI - Laparoscopic-assisted endoscopic full-thickness resection of a colonic lesion - a video vignette. PMID- 26583359 TI - Update on Advances in Musculoskeletal Magnetic Resonance Imaging. PMID- 26583358 TI - Colorimetric aptasensing of ochratoxin A using Au@Fe3O4 nanoparticles as signal indicator and magnetic separator. AB - Gold nanoparticles (Au NPs) doped Fe3O4 (Au@Fe3O4) NPs have been synthesized by a facile one-step solvothermal method. The peroxidase-like activity of Au@Fe3O4 NPs was effectively enhanced due to the synergistic effect between the Fe3O4 NPs and Au NPs. On this basis, an efficient colorimetric aptasensor has been developed using the intrinsic dual functionality of the Au@Fe3O4 NPs as signal indicator and magnetic separator. Initially, the amino-modified aptamer specific for a typical mycotoxin, ochratoxin A (OTA), was surface confined on the amino terminated glass beads surafce using glutaraldehyde as a linker. Subsequently, the amino-modified capture DNA (cDNA) was labeled with the amino-functionalized Au@Fe3O4 NPs and the aptasensor was thus fabricated through the hybridization reaction between cDNA and the aptamers. While upon OTA addition, aptamers preferred to form the OTA-aptamer complex and the Au@Fe3O4 NPs linked on the cDNA were released into the bulk solution. Through a simple magnetic separation, the collected Au@Fe3O4 NPs can produce a blue colored solution in the presence of 3,3',5,5'-tetramethylbenzidine and H2O2. When the reaction was terminated by addition of H(+) ions, the blue product could be changed into a yellow one with higher absorption intensity. This colorimetric aptasensor can detect as low as 30 pgmL(-1) OTA with high specificity. To the best of our knowledge, the present colorimetric aptasensor is the first attempt to use the peroxidase-like activity of nanomaterial for OTA detection, which may provide an acttractive path toward routine quality control of food safety. PMID- 26583357 TI - Neurocognitive and Patient-Reported Outcomes in Adult Survivors of Childhood Osteosarcoma. AB - IMPORTANCE: This study provides the first objective data documenting neurocognitive impairment in long-term survivors of childhood osteosarcoma. OBJECTIVE: To examine neurocognitive, neurobehavioral, emotional, and quality-of life outcomes in long-term survivors of childhood osteosarcoma. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional cohort study at an academic research hospital, with prospective treatment and chronic health predictors. Outcome data were collected from June 2008 to August 2014. Data analysis was completed in April 2015. Survivors of osteosarcoma recruited from the St Jude Lifetime Cohort Study were compared with community controls. MAIN OUTCOMES AND MEASURES: Neurocognitive function, neurobehavioral symptoms, emotional distress, and quality of life. Outcomes were examined in relation to pharmacokinetic indices of methotrexate exposure and current chronic health conditions, which were assessed through medical examination and coded according to Common Terminology Criteria for Adverse Events, Version 4.03. RESULTS: Eighty survivors of osteosarcoma (mean [SD] age, 38.9 [7.6] years; time since diagnosis, 24.7 [6.6] years; 42% female) were compared with 39 community controls (age, 39.0 [11.7] years; 56% female). Survivors demonstrated lower mean scores in reading skills (-0.21 [95% CI, -0.32 to -0.10] vs 0.05 [95% CI, -0.13 to 0.23]; P = .01), attention (-0.78 [95% CI, 1.32 to -0.24] vs 0.24 [95% CI, -0.07 to 0.55]; P = .002), memory (-0.24 [95% CI, -0.48 to 0] vs 0.27 [95% CI, -0.08 to 0.62]; P = .01), and processing speed ( 0.15 [95% CI, -0.35 to 0.05] vs 0.74 [95% CI, 0.44 to 1.03]; P < .001). Results of pharmacokinetic analysis showed that high-dose methotrexate maximum plasma concentration (estimate = 0; P = .48), median clearance (estimate = -0.11; P = .76), and median/cumulative exposure (estimate = 0; P = .45) were not associated with neurocognitive outcomes. Any grade 3 or 4 Common Terminology Criteria for Adverse Events cardiac, pulmonary, or endocrine condition was associated with poorer memory (t = 2.93; P = .006) and slower processing speed (t = 3.03; P = .002). Survivor-reported poor general health was associated with decreased sustained attention (estimate = 0.24; P = .05) and processing speed (estimate = 0.34; P = .005). CONCLUSIONS AND RELEVANCE: Long-term survivors of osteosarcoma are at risk for neurocognitive impairment, which is related to current chronic health conditions and not to original treatment with high-dose methotrexate. Prospective longitudinal studies are needed to identify onset and progression of impairment to inform optimal interventions. PMID- 26583360 TI - Understanding 3D TSE Sequences: Advantages, Disadvantages, and Application in MSK Imaging. AB - Three-dimensional (3D) turbo-spin echo (TSE) sequences have outgrown the stage of mere sequence optimization and by now are clinically applicable. Image blurring and acquisition times have been reduced, and contrast for T1-, T2-, and moderately T2-weighted (or intermediate-weighted) fat-suppressed variants has been optimized. Data on sound-to-noise ratio efficiency and contrast are available for moderately T2-weighted fat-saturated sequence protocols. The 3-T MRI scanners help to better exploit isotropic spatial resolution and multiplanar reformatting. Imaging times range from 5 to 10 minutes, and they are shorter than the cumulative acquisition times of three separate orthogonal two-dimensional (2D) sequences. Recent suggestions go beyond secondary reformations by using online 3D rendering for image evaluation. Comparative clinical studies indicate that the diagnostic performance of 3D TSE for imaging of internal derangements of joints is at least comparable with conventional 2D TSE with potential advantages of 3D TSE for small highly curved structures. But such studies, especially those with direct arthroscopic correlation, are still sparse. Whether 3D TSE will succeed in entering clinical routine imaging on a broader scale will depend on further published clinical evidence, on further reduction of imaging time, and on improvement of its integration into daily practice. PMID- 26583361 TI - Advances in Metal Artifact Reduction Techniques for Periprosthetic Soft Tissue Imaging. AB - Artifact from metallic orthopedic prosthesis is caused by inhomogeneity in the B0 magnetic field, particularly in the frequency encoding direction. This results in signal voids, signal pileup, and geometric distortion. Advances in reducing this artifact allow us to assess the complications of joint replacement and improve imaging of nearby tissues such as within the pelvis. Selection of titanium implants and lower field strength MR units provide optimal conditions for artifact reduction. Conventional sequences can be optimized by using inversion recovery sequences, large matrices, high receiver bandwidths, and thin slices. Optimizing these parameters comes with a penalty in terms of signal-to-noise ratio or increased acquisition times. Successful artifact reduction depends on the strength of the frequency encoding gradients. Newer dedicated artifact reduction sequences include view-angle-tilting and a selection of multispectral techniques including multiacquisition variable-resonance image combination (MAVRIC) and slice encoding for metal artifact correction (SEMAC). Many of these are being used in combination. The multispectral sequences acquire three dimensional data at very narrow frequencies and use of phase encoding for spatial localization. Planar images can then be reconstructed with very little susceptibility artifact. PMID- 26583362 TI - Fat Suppression with Dixon Techniques in Musculoskeletal Magnetic Resonance Imaging: A Pictorial Review. AB - Dixon techniques are part of the methods used to suppress the signal of fat in MRI. They present many advantages compared with other fat suppression techniques including (1) the robustness of fat signal suppression, (2) the possibility to combine these techniques with all types of sequences (gradient echo, spin echo) and different weightings (T1-, T2-, proton density-, intermediate-weighted sequences), and (3) the availability of images both with and without fat suppression from one single acquisition. These advantages have opened many applications in musculoskeletal imaging. We first review the technical aspects of Dixon techniques including their advantages and disadvantages. We then illustrate their applications for the imaging of different body parts, as well as for tumors, neuromuscular disorders, and the imaging of metallic hardware. PMID- 26583363 TI - The Increasing Spectrum of Indications of Whole-Body MRI Beyond Oncology: Imaging Answers to Clinical Needs. AB - Whole-body coverage using MRI was developed almost 2 decades ago. The first applications focused on the investigation of the skeleton to detect neoplastic disease, mainly metastases from solid cancers, and involvement by multiple myeloma and lymphoma. But the extensive coverage of the whole musculoskeletal system, combined with the exquisite sensitivity of MRI to tissue alteration in relation to different pathologic conditions, mainly inflammation, has led to the identification of a growing number of indications outside oncology. Seronegative rheumatisms, systemic sclerosis, inflammatory diseases involving muscles or fascias, and multifocal osseous, vascular, or neurologic diseases represent currently validated or emerging indications of whole-body MRI (WB-MRI). We first illustrate the most valuable indications of WB-MRI in seronegative rheumatisms that include providing significant diagnostic information in patients with negative or ambiguous MRI of the sacroiliac joints and the lumbar spine, assessing disease activity in advanced (ankylosed) central disease, and evaluating the peripherally dominant forms of spondyloarthropathy. Then we review the increasing indications of WB-MRI in other rheumatologic and nonneoplastic disorders, underline the clinical needs, and illustrate the role of WB-MRI in the positive diagnosis and evaluation of disease burden, therapeutic decisions, and treatment monitoring. PMID- 26583364 TI - MRI of the Musculoskeletal System: Advanced Applications using High and Ultrahigh Field MRI. AB - In vivo MRI has revolutionized the diagnosis and treatment of musculoskeletal disorders over the past 3 decades. Traditionally performed at 1.5 T, MRI at higher field strengths offers several advantages over lower field strengths including increased signal-to-noise ratio, higher spatial resolution, improved spectral resolution for spectroscopy, improved sensitivity for X-nucleus imaging, and decreased image acquisition times. However, the physics of imaging at higher field strengths also presents technical challenges. These include B0 and B1+ field inhomogeneity, design and construction of dedicated radiofrequency (RF) coils for use at high field, increased chemical shift and susceptibility artifacts, increased RF energy deposition (specific absorption rate), increased metal artifacts, and changes in relaxation times compared with the lower field scanners. These challenges were overcome in optimizing high-field (HF) (3 T) MRI over a decade ago. HF MRI systems have since gained universal acceptance for clinical musculoskeletal imaging and have also been widely utilized for the study of musculoskeletal anatomy and physiology. Recently there has been an increasing interest in exploring musculoskeletal applications of ultrahigh field (UHF) (7 T) systems. However, technical challenges similar to those encountered when moving from 1.5 T to 3 T have to be overcome to optimize 7 T musculoskeletal imaging. In this narrative review, we discuss the many potential opportunities and technical challenges presented by the HF and UHF MRI systems. We highlight recent developments in in vivo imaging of musculoskeletal tissues that benefit most from HF imaging including cartilage, skeletal muscle, and bone. PMID- 26583365 TI - Qualitative and Quantitative Ultrashort Echo Time Imaging of Musculoskeletal Tissues. AB - Ultrashort echo time (UTE) sequences represent a group of clinically compatible techniques that are capable of using echo times < 1 ms. With these techniques, direct imaging of short T2/T2* tissues or tissue components can now be performed. Continuing modifications to the UTE techniques have allowed for faster and more robust sequences now comparable with conventional clinical sequences. UTE also allows for morphological imaging and quantitative evaluation in a manner not previously possible with conventional imaging sequences utilizing much longer echo times. Numerous potential clinical applications have emerged that are discussed in this review article. PMID- 26583366 TI - Tractography: Possible Applications in Musculoskeletal Radiology. AB - Tractography (or fiber tracking) consists of three-dimensional modeling of the preferential movement of water molecules in the form of fiber tracks from the tensor field information. This technique allows a new approach for the microarchitectural analysis of anisotropic structures such as nerves, white matter, and muscles. Many disorders have been studied including cervical myelopathy, carpal tunnel syndrome, nerve root compression, and nerve tumors. Muscles have been less evaluated. Tractography is still a research technique, and its validation and widespread routine clinical use will require a good deal of work toward a harmonization of the MRI protocols and data postprocessing methods. PMID- 26583368 TI - Vladimir Jevtic, 1944-2015. PMID- 26583367 TI - Recommendations of the ESSR Arthritis Subcommittee for the Use of Magnetic Resonance Imaging in Musculoskeletal Rheumatic Diseases. AB - This article presents the recommendations of the European Society of Musculoskeletal Radiology Arthritis Subcommittee regarding the standards of the use of MRI in the diagnosis of musculoskeletal rheumatic diseases. The recommendations discuss (1) the role of MRI in current classification criteria of musculoskeletal rheumatic diseases (including early diagnosis of inflammation, disease follow-up, and identification of disease complications); (2) the impact of MRI on the diagnosis of axial and peripheral spondyloarthritis, rheumatoid arthritis, and juvenile spondyloarthritis; (3) MRI protocols for the axial and peripheral joints; (4) MRI interpretation and reporting for axial and peripheral joints; and finally, (5) methods for assessing MR images including quantitative, semiquantitative, and dynamic contrast-enhanced MRI studies. PMID- 26583369 TI - Plasma fasting cholesterol profiles and age at onset in Parkinson's disease. PMID- 26583370 TI - Multimerized HIV-gp41-derived peptides as fusion inhibitors and vaccines. AB - To date, several antigens based on the amino-terminal leucine/isoleucine heptad repeat (NHR) region of an HIV-1 envelope protein gp41 and fusion inhibitors based on the carboxy-terminal leucine/isoleucine heptad repeat (CHR) region of gp41 have been reported. We have developed a synthetic antigen targeting the membrane fusion mechanism of HIV-1. This uses a template designed with C3-symmetric linkers and mimics the trimeric form of the NHR-derived peptide N36. The antiserum obtained by immunization of the N36 trimeric antigen binds preferentially to the N36 trimer and blocks HIV-1 infection effectively, compared with the antiserum obtained by immunization of the N36 monomer. Using another template designed with different C3-symmetric linkers, we have also developed a synthetic peptide mimicking the trimeric form of the CHR-derived peptide C34, with ~100 times the inhibitory activity against the HIV-1 fusion mechanism than that of the monomer C34 peptide. A dimeric derivative of C34 has potent inhibitory activity at almost the same levels as this C34 trimer mimic, suggesting that presence of a dimeric form of C34 is structurally critical for fusion inhibitors. As examples of rising mid-size drugs, this review describes an effective strategy for the design of HIV vaccines and fusion inhibitors based on a relationship with the native structure of proteins involved in HIV fusion mechanisms. (c) 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 622-628, 2016. PMID- 26583371 TI - Replication Capacity of Avian Influenza A(H9N2) Virus in Pet Birds and Mammals, Bangladesh. AB - Avian influenza A(H9N2) is an agricultural and public health threat. We characterized an H9N2 virus from a pet market in Bangladesh and demonstrated replication in samples from pet birds, swine tissues, human airway and ocular cells, and ferrets. Results implicated pet birds in the potential dissemination and zoonotic transmission of this virus. PMID- 26583372 TI - A Novel Treatment for Proliferative Diabetic Retinopathy: Anti-Vascular Endothelial Growth Factor Therapy. PMID- 26583373 TI - A dual thermal and photo-switchable shrinking-swelling supramolecular peptide dendron gel. AB - A supramolecular dendron gel was fabricated through the co-assembly of an L glutamic acid terminated amphiphilic dendron and a positively charged azobenzene derivative, which showed a dual thermal and photo-switched reversible volume phase transition or shrinking/swelling. PMID- 26583374 TI - MPA-capped CdTe quantum dots exposure causes neurotoxic effects in nematode Caenorhabditis elegans by affecting the transporters and receptors of glutamate, serotonin and dopamine at the genetic level, or by increasing ROS, or both. AB - As quantum dots (QDs) are widely used in biomedical applications, the number of studies focusing on their biological properties is increasing. While several studies have attempted to evaluate the toxicity of QDs towards neural cells, the in vivo toxic effects on the nervous system and the molecular mechanisms are unclear. The aim of the present study was to investigate the neurotoxic effects and the underlying mechanisms of water-soluble cadmium telluride (CdTe) QDs capped with 3-mercaptopropionic acid (MPA) in Caenorhabditis elegans (C. elegans). Our results showed that exposure to MPA-capped CdTe QDs induced behavioral defects, including alterations to body bending, head thrashing, pharyngeal pumping and defecation intervals, as well as impaired learning and memory behavior plasticity, based on chemotaxis or thermotaxis, in a dose-, time- and size-dependent manner. Further investigations suggested that MPA-capped CdTe QDs exposure inhibited the transporters and receptors of glutamate, serotonin and dopamine in C. elegans at the genetic level within 24 h, while opposite results were observed after 72 h. Additionally, excessive reactive oxygen species (ROS) generation was observed in the CdTe QD-treated worms, which confirmed the common nanotoxicity mechanism of oxidative stress damage, and might overcome the increased gene expression of neurotransmitter transporters and receptors in C. elegans induced by long-term QD exposure, resulting in more severe behavioral impairments. PMID- 26583375 TI - Disseminated Infection Caused by Francisella philomiragia, France, 2014. PMID- 26583376 TI - Chromosomal Abnormalities in Embryonic and Somatic Stem Cells. AB - The potential use of stem cells (SCs) for tissue engineering, regenerative medicine, disease modeling, toxicological studies, drug delivery, and as in vitro model for the study of basic developmental processes implies large-scale in vitro culture. Here, after a brief description of the main techniques used for karyotype analysis, we will give a detailed overview of the chromosome abnormalities described in pluripotent (embryonic and induced pluripotent SCs) and somatic SCs, and the possible causes of their origin during culture. PMID- 26583377 TI - Unleashing Cancer Cells on Surfaces Exposing Motogenic IGDQ Peptides. AB - Thiolated peptides bearing the Ile-Gly-Asp (IGD) motif, a highly conserved sequence of fibronectin, are used for the preparation of anisotropic self assembled monolayers (SAM gradients) to study the whole-population migratory behavior of metastatic breast cancer cells (MDA-MB-231 cells). Ile-Gly-Asp-Gln (IGDQ)-exposing SAMs sustain the adhesion of MDA-MB-231 cells by triggering focal adhesion kinase phosphorylation, similarly to the analogous Gly-Arg-Gly-Asp (GRGD)-terminating surfaces. However, the biological responses of different cell lines interfaced with the SAM gradients show that only those exposing the IGDQ sequence induce significant migration of MDA-MB-231 cells. In particular, the observed migratory behavior suggests the presence of cell subpopulations associated with a "stationary" or a "migratory" phenotype, the latter determining a considerable cell migration at the sub-cm length scale. These findings are of great importance as they suggest for the first time an active role of biological surfaces exposing the IGD motif in the multicomponent orchestration of cellular signaling involved in the metastatic progression. PMID- 26583378 TI - SAAS-CNV: A Joint Segmentation Approach on Aggregated and Allele Specific Signals for the Identification of Somatic Copy Number Alterations with Next-Generation Sequencing Data. AB - Cancer genomes exhibit profound somatic copy number alterations (SCNAs). Studying tumor SCNAs using massively parallel sequencing provides unprecedented resolution and meanwhile gives rise to new challenges in data analysis, complicated by tumor aneuploidy and heterogeneity as well as normal cell contamination. While the majority of read depth based methods utilize total sequencing depth alone for SCNA inference, the allele specific signals are undervalued. We proposed a joint segmentation and inference approach using both signals to meet some of the challenges. Our method consists of four major steps: 1) extracting read depth supporting reference and alternative alleles at each SNP/Indel locus and comparing the total read depth and alternative allele proportion between tumor and matched normal sample; 2) performing joint segmentation on the two signal dimensions; 3) correcting the copy number baseline from which the SCNA state is determined; 4) calling SCNA state for each segment based on both signal dimensions. The method is applicable to whole exome/genome sequencing (WES/WGS) as well as SNP array data in a tumor-control study. We applied the method to a dataset containing no SCNAs to test the specificity, created by pairing sequencing replicates of a single HapMap sample as normal/tumor pairs, as well as a large-scale WGS dataset consisting of 88 liver tumors along with adjacent normal tissues. Compared with representative methods, our method demonstrated improved accuracy, scalability to large cancer studies, capability in handling both sequencing and SNP array data, and the potential to improve the estimation of tumor ploidy and purity. PMID- 26583379 TI - The Effect of Intrauterine Lidocaine and Rectal Indomethacin on Pain during Office Vaginoscopic Hysteroscopy: Randomized Double-Blind Controlled Study. AB - BACKGROUNDS/AIMS: The aim of this study was to investigate the effect of rectal and intrauterine anesthesia during vaginoscopic hysteroscopy. METHODS: This was a randomized, double-blind, placebo-controlled study. Patients were randomized to rectal indomethacin, intrauterine lidocaine and placebo groups. Patients with conditions that could cause or contribute to pelvic pain were excluded. Pain was evaluated with Visual Analog Scale, when the cervical canal was passed, while within the cavity and at 10 min after procedure. The Analog Pain Scale scores of the 3 groups were compared with the Kruskal-Wallis 1-way analysis of variance test. A value of p < 0.05 was accepted as statistically significant. RESULTS: The study included a total of 206 patients. No difference was seen between the groups in respect of indication, age, gravid and duration of procedure. While the anesthesia was determined as superior to the placebo in reducing pain at all 3 stages (p < 0.05), intrauterine lidocaine was determined to be more effective than rectal indomethacin in reducing pain within the cavity and 10 min after the procedure (p < 0.05). CONCLUSION: Rectal or intrauterine anesthesia applied with the vaginoscopic technique is useful in hysteroscopy. However, intrauterine anesthesia is more effective in reducing pain. PMID- 26583381 TI - From Sin to Crime: Laws on Infanticide in the Middle Ages. AB - This is the second of three papers investigating the legislative history concerning infanticide. It compares the efforts of various states to protect the newborn infant between 534 and 1532 CE. When the Roman Empire collapsed in the 5th century, the jurisdiction of infanticide was relegated to the church, which regarded carnal delicts a sin rather than a crime. The punishment - public penance of the mother for 7-15 years - was milder than that which the murder of an adult would incur. The Council of Florence decreed in 1439 that the souls of children who died without having been baptized descend to hell. This turned infanticide from a penitential sin to the most heinous of all crimes. The states passed laws that abominated infanticide even more than the murder of older humans and punished women with ever more cruel forms of execution. Towards the men, however, who usually abandoned the women they had impregnated, the laws were lenient. Churches and society continued to vilify illegitimate birth, thus enhancing rather than preventing infanticide. The Habsburg-German legislation of 1532 ordained to torture any woman who had concealed pregnancy and birth and claimed the infant was stillborn. Legislation developed similarly in other countries, albeit at a different speed. French (1556) and British (1623) legislation reversed the burden of proof and demanded the death penalty for concealing pregnancy and birth when a dead infant was found. PMID- 26583380 TI - Arthropod Vectors and Disease Transmission: Translational Aspects. PMID- 26583382 TI - Infection Risk for Persons Exposed to Highly Pathogenic Avian Influenza A H5 Virus-Infected Birds, United States, December 2014-March 2015. AB - Newly emerged highly pathogenic avian influenza (HPAI) A H5 viruses have caused outbreaks among birds in the United States. These viruses differ genetically from HPAI H5 viruses that previously caused human illness, most notably in Asia and Africa. To assess the risk for animal-to-human HPAI H5 virus transmission in the United States, we determined the number of persons with self-reported exposure to infected birds, the number with an acute respiratory infection (ARI) during a 10 day postexposure period, and the number with ARI who tested positive for influenza by real-time reverse transcription PCR or serologic testing for each outbreak during December 15, 2014-March 31, 2015. During 60 outbreaks in 13 states, a total of 164 persons were exposed to infected birds. ARI developed in 5 of these persons within 10 days of exposure. H5 influenza virus infection was not identified in any persons with ARI, suggesting a low risk for animal-to-human HPAI H5 virus transmission. PMID- 26583384 TI - Complementarity between Quantum and Classical Mechanics in Chemical Modeling. The H + HeH+ -> H2 + + He Reaction: A Rigourous Test for Reaction Dynamics Methods. AB - In this work we present a dynamical study of the H + HeH+ -> H2+ + He reaction in a collision energy range from 0.1 meV to 10 eV, suitable to be used in applicative models. The paper extends and complements a recent work [ Phys. Chem. Chem. Phys. 2014, 16, 11662] devoted to the characterization of the reactivity from the ultracold regime up to the three-body dissociation breakup. In particular, the accuracy of the quasi-classical trajectory method below the three body dissociation threshold has been assessed by a detailed comparison with previous calculations performed with different reaction dynamics methods, whereas the reliability of the results in the high energy range has been checked by a direct comparison with the available experimental data. Integral cross sections for several HeH+ roto-vibrational states have been analyzed and used to understand the extent of quantum effects in the reaction dynamics. By using the quasi-classical trajectory method and quantum mechanical close coupling data, respectively, in the high and low collision energy ranges, we obtain highly accurate thermal rate costants until 15 000 K including all (178) the roto vibrational bound and quasi-bound states of HeH+. The role of the collision induced dissociation is also discussed and explicitly calculated for the ground roto-vibrational state of HeH+. PMID- 26583383 TI - Water as Source of Francisella tularensis Infection in Humans, Turkey. AB - Francisella tularensis DNA extractions and isolates from the environment and humans were genetically characterized to elucidate environmental sources that cause human tularemia in Turkey. Extensive genetic diversity consistent with genotypes from human outbreaks was identified in environmental samples and confirmed water as a source of human tularemia in Turkey. PMID- 26583385 TI - Reversibly Switching Bilayer Permeability and Release Modules of Photochromic Polymersomes Stabilized by Cooperative Noncovalent Interactions. AB - We report on the fabrication of photochromic polymersomes exhibiting photoswitchable and reversible bilayer permeability from newly designed poly(ethylene oxide)-b-PSPA (PEO-b-PSPA) diblock copolymers, where SPA is spiropyran (SP)-based monomer containing a unique carbamate linkage. Upon self assembling into polymersomes, SP moieties within vesicle bilayers undergo reversible phototriggered isomerization between hydrophobic spiropyran (SP, lambda2 > 450 nm irradiation) and zwitterionic merocyanine (MC, lambda1 < 420 nm irradiation) states. For both SP and MC polymersomes, their microstructures are stabilized by multiple cooperative noncovalent interactions including hydrophobic, hydrogen bonding, pi-pi stacking, and paired electrostatic (zwitterionic) interactions, with the latter two types being exclusive for MC polymersomes. Control experiments using analogous block copolymers of hydrophobic SP monomer with a carbonate linkage (SPO) and conventional spiropyran methacrylate monomer (SPMA) containing a single ester functionality were then conducted, revealing that carbamate-incurred hydrogen bonding interactions in PEO b-PSPA are crucial for polymersome stabilization in the zwitterionic MC state. Moreover, reversible phototriggered SP-to-MC polymersome transition is accompanied by membrane polarity and permeability switching from being nonimpermeable to selectively permeable toward noncharged, charged, and zwitterionic small molecule species below critical molar masses. Intriguingly, UV actuated MC polymersomes possess two types of release modules: (1) sustained release upon short UV irradiation duration by taking advantage of the unexpectedly slow spontaneous MC-to-SP transition kinetics (t1/2 > 20 h) under dark conditions; (2) on-demand and switchable release under alternated UV-vis light irradiation. We further demonstrate photoswitchable spatiotemporal release of 4',6-diamidino-2-phenylindole (DAPI, cell nuclei-staining dye) within living HeLa cells. PMID- 26583386 TI - Band-Filling Correction Method for Accurate Adsorption Energy Calculations: A Cu/ZnO Case Study. AB - We present a simple method, the "band-filling correction", to calculate accurate adsorption energies (Eads) in the low coverage limit from finite-size supercell slab calculations using DFT. We show that it is necessary to use such a correction if charge transfer takes place between the adsorbate and the substrate, resulting in the substrate bands either filling up or becoming depleted. With this correction scheme, we calculate Eads of an isolated Cu atom adsorbed on the ZnO(1010) surface. Without the correction, the calculated Eads is highly coverage-dependent, even for surface supercells that would typically be considered very large (in the range from 1 nm * 1 nm to 2.5 nm * 2.5 nm). The correction scheme works very well for semilocal functionals, where the corrected Eads is converged within 0.01 eV for all coverages. The correction scheme also works well for hybrid functionals if a large supercell is used and the exact exchange interaction is screened. PMID- 26583387 TI - Accurate Open-Shell Noncovalent Interaction Energies from the Orbital-Optimized Moller-Plesset Perturbation Theory: Achieving CCSD Quality at the MP2 Level by Orbital Optimization. AB - The accurate description of noncovalent interactions is one of the most challenging problems in modern computational chemistry, especially those for open shell systems. In this study, an investigation of open-shell noncovalent interactions with the orbital-optimized MP2 and MP3 (OMP2 and OMP3) is presented. For the considered test set of 23 complexes, mean absolute errors in noncovalent interaction energies (with respect to CCSD(T) at complete basis set limits) are 0.68 (MP2), 0.37 (OMP2), 0.59 (MP3), 0.23 (OMP3), and 0.38 (CCSD) kcal mol(-1) . Hence, with a greatly reduced computational cost, one may achieve CCSD quality at the MP2 level by orbital optimization [scaling formally as O(N(6)) for CCSD compared to O(N(5)) for OMP2, where N is the number of basis functions]. Further, one may obtain a considerably better performance than CCSD using the OMP3 method, which has also a lower cost than CCSD. PMID- 26583388 TI - Optimization of Umbrella Sampling Replica Exchange Molecular Dynamics by Replica Positioning. AB - The positioning of sampling windows in an umbrella sampling simulation has an effect on the rate of convergence and computational efficiency. When such simulation is coupled with a Hamiltonian replica exchange setup, we show that such positioning can be optimized for maximal convergence of the results. We present a method for estimating the exchange acceptance ratio (EAR) between two arbitrary positions on a reaction coordinate in umbrella sampling replica exchange (USRE) molecular dynamics (MD). We designed a scoring function to optimize the position of the set of replicas (windows). By maximizing the scoring function, we make EAR the same for all neighbor replica pairs, increasing the efficiency of the method. We tested our algorithm by sampling a torsion for butane in implicit solvent and by studying a salt bridge in explicit solvent. We found that the optimized set of replicas recovers the correct free energy profile much faster than for equally spaced umbrellas. PMID- 26583390 TI - Three-Dimensional RISM Integral Equation Theory for Polarizable Solute Models. AB - Modeling solute polarizability is a key ingredient for improving the description of solvation phenomena. In recent years, polarizable molecular mechanics force fields have emerged that circumvent the limitations of classical fixed charge force fields by the ability to adapt their electrostatic potential distribution to a polarizing environment. Solvation phenomena are characterized by the solute's excess chemical potential, which can be computed by expensive fully atomistic free energy simulations. The alternative is to employ an implicit solvent model, which poses a challenge to the formulation of the solute-solvent interaction term within a polarizable framework. Here, we adapt the three dimensional reference interaction site model (3D RISM) integral equation theory as a solvent model, which analytically yields the chemical potential, to the polarizable AMOEBA force field using an embedding cluster (EC-RISM) strategy. The methodology is analogous to our earlier approach to the coupling of a quantum chemical solute description with a classical 3D RISM solvent. We describe the conceptual physical and algorithmic basis as well as the performance for several benchmark cases as a proof of principle. The results consistently show reasonable agreement between AMOEBA and quantum-chemical free energies in solution in general and allow for separate assessment of energetic and solvation-related contributions. We find that, depending on the parametrization, AMOEBA reproduces the chemical potential in better agreement with reference quantum-chemical calculations than the intramolecular energies, which suggests possible routes toward systematic improvement of polarizable force fields. PMID- 26583389 TI - Using Multistate Reweighting to Rapidly and Efficiently Explore Molecular Simulation Parameters Space for Nonbonded Interactions. AB - Multistate reweighting methods such as the multistate Bennett acceptance ratio (MBAR) can predict free energies and expectation values of thermodynamic observables at poorly sampled or unsampled thermodynamic states using simulations performed at only a few sampled states combined with single point energy reevaluations of these samples at the unsampled states. In this study, we demonstrate the power of this general reweighting formalism by exploring the effect of simulation parameters controlling Coulomb and Lennard-Jones cutoffs on free energy calculations and other observables. Using multistate reweighting, we can quickly identify, with very high sensitivity, the computationally least expensive nonbonded parameters required to obtain a specified accuracy in observables compared to the answer obtained using an expensive "gold standard" set of parameters. We specifically examine free energy estimates of three molecular transformations in a benchmark molecular set as well as the enthalpy of vaporization of TIP3P. The results demonstrates the power of this multistate reweighting approach for measuring changes in free energy differences or other estimators with respect to simulation or model parameters with very high precision and/or very low computational effort. The results also help to identify which simulation parameters affect free energy calculations and provide guidance to determine which simulation parameters are both appropriate and computationally efficient in general. PMID- 26583391 TI - Bending Vibration-Governed Solvation Dynamics of an Excess Electron in Liquid Acetonitrile Revealed by Ab Initio Molecular Dynamics Simulation. AB - We report an ab initio molecular dynamics simulation study of the solvation and dynamics of an excess electron in liquid acetonitrile (ACN). Four families of states are observed: a diffusely solvated state and three ACN core-localized states with monomer core, quasi-dimer (pi*-Rydberg mode) core, and dual core/dimer core (a coupled dual-core). These core localized states cannot be simply described as the corresponding anions because only a part of the excess electron resides in the core molecule(s). The quasi-dimer core state actually is a mixture that features cooperative excess electron capture by the pi* and Rydberg orbitals of two ACNs. Well-defined dimer anion and solvated electron cavity were not observed in the 5-10 ps simulations, which may be attributed to slow dynamics of the formation of the dimer anion and difficulty of the formation of a cavity in such a fluxional medium. All of the above observed states have near-IR absorptions and thus can be regarded as the solvated electron states but with different structures, which can interpret the experimentally observed IR band. These states undergo continuous conversions via a combination of long lasting breathing oscillation and core switching, characterized by highly cooperative oscillations of the electron cloud volume and vertical detachment energy. The quasi-dimer core and diffusely solvated states dominate the time evolution, with the monomer core and dual-core/dimer core states occurring occasionally during the breathing and core switching processes, respectively. All these oscillations and core switchings are governed by a combination of the electron-impacted bending vibration of the core ACN molecule(s) and thermal fluctuations. PMID- 26583392 TI - Performance of Density Functionals for Activation Energies of Zr-Mediated Reactions. AB - Coupled cluster CCSD(T) calculations with core-valence correlation and complete basis set (CBS) limit extrapolation are used to benchmark the performance of commonly used density functionals in computing energy barriers for Zr-mediated reactions involving zirconocene species. These reactions include (a) insertions of the Zr-H bond of Cp2Zr(H)Cl into C?C, C=C, and C?O bonds and (b) C-H activations by Zr?N bond in Cp2Zr?NH. The best performing functionals are M06-L, M06, and M06-2X in the M06 series, all having mean unsigned deviations (MUD) less than 2 kcal/mol. The worst performing functional is OLYP, with a distinctly large MUD of more than 10 kcal/mol. Considering also the trends in barrier heights and the systematic barrier height deviation, our best recommended functional is M06 2X. In this work, DFT empirical dispersion correction (DFT-D3) is found to improve the performance of barrier height values for most functionals (especially of OLYP and B3LYP). With DFT empirical dispersion correction, we also recommend M06-2X for reaction barrier calculations of Zr-mediated reactions. PMID- 26583393 TI - Locally Refined Multigrid Solution of the All-Electron Kohn-Sham Equation. AB - We present a fully numerical multigrid approach for solving the all-electron Kohn Sham equation in molecules. The equation is represented on a hierarchy of Cartesian grids, from coarse ones that span the entire molecule to very fine ones that describe only a small volume around each atom. This approach is adaptable to any type of geometry. We demonstrate it for a variety of small molecules and obtain high accuracy agreement with results obtained previously for diatomic molecules using a prolate-spheroidal grid. We provide a detailed presentation of the numerical methodology and discuss possible extensions of this approach. PMID- 26583394 TI - Excitation Energies with Cost-Reduced Variant of the Active-Space EOMCCSDT Method: The EOMCCSDt-3 Approach. AB - In this paper, we discuss the performance of several simplified variants of equation-of-motion coupled cluster method (EOMCC) with iterative inclusion of singles, doubles, and active-space triples (EOMCCSDt). In particular, we explore simplified EOMCCSDt approaches that enable one to generate the triply excited amplitudes in an on-the-fly manner. The original EOMCCSDt formulation has already demonstrated great success in encapsulating the most important excited-state correlation effects due to triples. In analogy to the original EOMCCSDT-3 formulation, the proposed approach can bypass the typical bottlenecks associated with the need for storing triply excited amplitudes. In this paper, we illustrate the performance of several approximate EOMCCSDt methods, named EOMCCSDt-3 and EOMCCSDt-3, on typical benchmark systems including C2, N2, ozone, ethene, and E butadiene molecules. These new methods yield excitation energies close to the EOMCCSDt ones. The extrapolation of excitation energies for basis sets ranging from cc-pVDZ to cc-pV6Z for N2 and C2 shows very good convergence to the experimental results for states dominated by single excitations. The performance of the EOMCCSDt-3x approach is also compared with the results obtained with popular CCSDR(3) and CC3 approaches. PMID- 26583395 TI - W3X: A Cost-Effective Post-CCSD(T) Composite Procedure. AB - We have formulated the W3X procedure by incorporating cost-effective post-CCSD(T) components (up to the CCSDT(Q) level) into the W1X-1 protocol, the latter representing a recently reported economical yet accurate approximation to CCSD(T)/CBS. For medium-sized systems, W3X is moderately more computationally demanding than W1X-1, but it is significantly less costly than the W3.2lite and (especially) W3.2 procedures. Because of the use of the cost-effective W1X-1 method as the underlying CCSD(T) component, W3X is also less expensive than the W2.2 protocol, which does not incorporate post-CCSD(T) excitations. We find that, for single-reference systems (the G2/97 set and most of the W4-11 set), W3X is comparable in accuracy to the underlying W1X-1 protocol, as might have been expected. For the more challenging cases of the multireference systems within the W4-11 set, the dissociation of F2 and the automerization of cyclobutadiene, W3X provides improved performance compared with the CCSD(T)-based procedures (W1X-1 and W2.2). Highly multireference chromium oxides CrO, CrO2, and CrO3 are still somewhat challenging for W3X (and even for the higher-level W3.2lite and W3.2 procedures), but the inclusion of the economical post-CCSD(T) terms in W3X already leads to a significant improvement over W1X-1. Thus, W3X provides a cost effective means for treating systems with significant (but perhaps not excessive) multireference character that are otherwise not well-described by CCSD(T)-based methods. PMID- 26583396 TI - Atomic Charges and the Electrostatic Potential Are Ill-Defined in Degenerate Ground States. AB - A system in a spatially degenerate ground state responds in a qualitatively different way to positive and negative point charges. This means that the molecular electrostatic potential is ill-defined for degenerate ground states due to the ill-defined nature of the electron density. It also means that it is impossible, in practice, to define fixed atomic charges for molecular mechanics simulations of molecules with (quasi-)degenerate ground states. Atomic polarizability-based models and electronegativity-equalization-type models for molecular polarization also fail to capture this effect. We demonstrate the ambiguity in the electrostatic potential using several molecules of different degree of degeneracy, quasi-degeneracy, and symmetry. PMID- 26583397 TI - All-Metal Aromaticity: Revisiting the Ring Current Model among Transition Metal Clusters. AB - We present new insight into the nature of aromaticity in metal clusters. We give computational arguments in favor of using the ring-current model over local indices, such as nucleus independent chemical shifts, for the determination of the magnetic aromaticity. Two approaches for estimating magnetically induced ring currents are employed for this purpose, one based on the quantum theory of atoms in molecules (QTAIM) and the other where magnetically induced current densities (MICD) are explicitly calculated. We show that the two-zone aromaticity/antiaromaticity of a number of 3d metallic clusters (Sc3(-), Cu3(+), and Cu4(2-)) can be explained using the QTAIM-based magnetizabilities. The reliability of the calculated atomic and bond magnetizabilities of the metallic clusters are verified by comparison with MICD computed at the multiconfiguration self-consistent field (MCSCF) and density functional levels of theory. Integrated MCSCF current strength susceptibilities as well as a visual analysis of the calculated current densities confirm the interpretations based on the QTAIM magnetizabilities. In view of the new findings, we suggest a simple explanation based on classical electromagnetic theory to explain the anomalous magnetic shielding in different transition metal clusters. Our results suggest that the nature of magnetic aromaticity/antiaromaticity in transition-metal clusters should be assessed more carefully based on global indices. PMID- 26583398 TI - Static and Field-Oriented Properties of Bowl-Shaped Polynuclear Aromatic Hydrocarbon Fragments. AB - First principles techniques are used to investigate the structure, linear polarizability, and field-oriented property trends of the series of bowl shaped polynuclear aromatic hydrocarbon fragments, C20H10, C30H10, C40H10, and C50H10. Such structures represent a sequence of minimalistic, capped bucky tube units based on the corannulene molecule, with interesting technological promise imparted by their curvature. Specific issues associated with how the intrinsic dipole and static linear polarizability influences the orientation of these structures in the presence of an external electric field are addressed and shown to correlate well with a simple analytical model. At moderate electric fields, the induced dipoles become comparable and even larger than the intrinsic dipoles due to the large in-plane polarizabilities in these systems. This generates a nontrivial and field dependent orientation of the molecule that can be exploited, for example, to induce switching behavior within molecular nanojunctions. PMID- 26583399 TI - In Search of Organic Compounds Presenting a Double Exchange Phenomenon. AB - The objective of this paper is to design a consistent series of organic molecules that may present a double exchange mechanism and study their low energy spectrum using spin unrestricted Density Functional Theory. For this purpose, organic tetra-methylene methane units having an S = 1 spin ground state and diamagnetic organic bridges are taken as building blocks for constructing molecules having two or more magnetic units. When biunit systems are ionized, the ground state of the resulting molecular ions may be either a quartet, if the spectrum is ruled by a double exchange mechanism, or a doublet, if it obeys the logic of a monoelectronic picture. A strategy based on the physical analysis of the leading interactions is followed in order to energetically favor a high-spin ground state. It is shown that the most promising compounds involve bridges that have both a large gap between the highest occupied and the lowest unoccupied molecular orbitals and small coefficients on the atoms to which the magnetic units are connected. While the followed strategy enables one to conceive organic compounds exhibiting a double exchange phenomenon, it is shown that the electronic mechanism ruling the spectrum of such organic double exchange compounds is different from that of their inorganic homologues. A new method to reconstruct the spectrum of low energy from various spin unrestricted DFT solutions is proposed and applied. Finally monodimensional and bidimensional periodic lattices based on the most promising organic architecture are suggested. PMID- 26583400 TI - Complementarity of QTAIM and ELF Partitions: Deeper Understanding of the Anomeric Effect. AB - In this work, fragments with chemical significance are defined inside QTAIM basins through the use of the ELF partition. In an ideal situation, core and monosynaptic ELF basins for an atom A (CA and VA, respectively) should belong exclusively to its atomic basin (CA, VA ? OmegaA), while disynaptic ones ought to be divided between the atoms of the corresponding bond (for an A-B bond, VA-B ? OmegaA ? OmegaB). Several examples here analyzed verify this situation (within 0.01 au). This combined partitioning is also applied to the analysis of the conformational preference in diverse anomeric compounds. Results lead to an alternative interpretation, independent of hyperconjugative effects. PMID- 26583401 TI - Frozen-Orbital and Downfolding Calculations with Auxiliary-Field Quantum Monte Carlo. AB - We describe the implementation of the frozen-orbital and downfolding approximations in the auxiliary-field quantum Monte Carlo (AFQMC) method. These approaches can provide significant computational savings, compared to fully correlating all of the electrons. While the many-body wave function is never explicit in AFQMC, its random walkers are Slater determinants, whose orbitals may be expressed in terms of any one-particle orbital basis. It is therefore straightforward to partition the full N-particle Hilbert space into active and inactive parts to implement the frozen-orbital method. In the frozen-core approximation, for example, the core electrons can be eliminated in the correlated part of the calculations, greatly increasing the computational efficiency, especially for heavy atoms. Scalar relativistic effects are easily included using the Douglas-Kroll-Hess theory. Using this method, we obtain a way to effectively eliminate the error due to single-projector, norm-conserving pseudopotentials in AFQMC. We also illustrate a generalization of the frozen orbital approach that downfolds high-energy basis states to a physically relevant low-energy sector, which allows a systematic approach to produce realistic model Hamiltonians to further increase efficiency for extended systems. PMID- 26583402 TI - Intrinsic Atomic Orbitals: An Unbiased Bridge between Quantum Theory and Chemical Concepts. AB - Modern quantum chemistry can make quantitative predictions on an immense array of chemical systems. However, the interpretation of those predictions is often complicated by the complex wave function expansions used. Here we show that an exceptionally simple algebraic construction allows for defining atomic core and valence orbitals, polarized by the molecular environment, which can exactly represent self-consistent field wave functions. This construction provides an unbiased and direct connection between quantum chemistry and empirical chemical concepts, and can be used, for example, to calculate the nature of bonding in molecules, in chemical terms, from first principles. In particular, we find consistency with electronegativities (chi), C 1s core-level shifts, resonance substituent parameters (sigmaR), Lewis structures, and oxidation states of transition-metal complexes. PMID- 26583403 TI - Many-Body Convergence of the Electrostatic Properties of Water. AB - The many-body convergence of the dipole moment and the dipole-dipole polarizability of water is investigated. It is found that, for systems of low symmetry like the water clusters examined here, simple measures such as dipole magnitudes and average polarizabilities may lead to an incomplete interpretation of the underlying physics. Alternative metrics are introduced that allow for an unambiguous characterization of both properties. The convergence of the many-body decomposition of the total dipole and the polarizability is studied for (H2O)N, with N = 4-6 being minimum energy water clusters and N = 14 being clusters that were extracted from condensed phase simulations. For these clusters, it is demonstrated that both the total dipole and polarizability are almost entirely pairwise additive, with three-body terms contributing less than 4% and all higher order terms being essentially negligible. PMID- 26583404 TI - Accurate Surface Chemistry beyond the Generalized Gradient Approximation: Illustrations for Graphene Adatoms. AB - Simulations of surface chemistry often use density functional theory with generalized gradient approximations (GGAs) for the exchange-correlation functional. GGAs have well-known limitations for gas-phase chemistry, including underestimated reaction barriers, and are largely superseded by meta-GGAs and hybrids. Our simulations of O and Li adatoms on graphene add to a growing body of evidence that GGAs have similar limitations on surfaces and that meta-GGAs and screened hybrids are computationally feasible for such systems. Meta-GGAs and screened hybrids systematically improve accuracy, just as they do for gas-phase chemistry, motivating their continued exploration in surface chemistry. PMID- 26583405 TI - Range-Separated DFT Functionals are Necessary to Model Thio-Michael Additions. AB - The textbook mechanism for the addition of a thiol to an olefin is the Michael type addition, which involves a nucleophilic attack of a thiolate anion on an alkene to form a carbanion intermediate. Previous computational models of these reactions have proposed alternative mechanisms, as no minimum corresponding to the carbanion intermediate was present on the potential energy surface. We show that many popular pure and hybrid DFT functionals, such as PBE and B3LYP, erroneously predict that the carbanion is not an intermediate, favoring a noncovalent charge-transfer complex stabilized spuriously by delocalization error. Range-separated DFT functionals correct this problem and predict stable carbanion structures and energies. In particular, calculations using the omegaB97X-D functional are in close agreement with CCSD(T) data for the structures and energies of a series of thio-carbanions. Range-separated functionals will make it possible to model the reaction mechanisms of Michael type additions that occur in biochemistry, such as the covalent modification of a cysteine side chain by drugs containing an electrophilic double bond. PMID- 26583406 TI - Method for Visualizing and Quantifying the Nonvalence Character of Excess Electrons. PMID- 26583407 TI - Evolutionary Algorithm in the Optimization of a Coarse-Grained Force Field. AB - Simulations using residue-scale coarse-grained models of biomolecules are less computationally demanding than simulations employing full-atomistic force fields. However, the coarse-grained models are often difficult and tedious to parametrize for certain applications. Therefore, a systematic and objective method to help develop or adapt the coarse-grained models is needed. We present an automatic method that implements an evolutionary algorithm to find a set of optimal force field parameters for a one-bead coarse-grained model. In addition to an optimized force field, parameter correlations and significance of the potential energy terms can be determined. The method is applied to two classes of problems: the dynamics of an RNA helix and the RNA structure prediction. PMID- 26583408 TI - Molecular Dynamics Simulations of Graphene Oxide Frameworks. AB - We use quantum mechanical calculations to develop a full set of force field parameters in order to perform molecular dynamics simulations to understand and optimize the molecular storage properties inside graphene oxide frameworks (GOFs). A set of boron-related parameters for commonly used empirical force fields is determined to describe the nonbonded and bonded interactions between linear boronic acid linkers and graphene sheets of GOF materials. The transferability of the parameters is discussed and their validity is quantified by comparing quantum mechanical and molecular mechanical structural and vibrational properties. The application of the model to the dynamics of water inside the GOFs reveals significant variations in structural flexibility depending on the linker density, which is shown to be usable as a tuning parameter for desired diffusion properties. PMID- 26583409 TI - Extensions of the Time-Dependent Density Functional Based Tight-Binding Approach. AB - The time-dependent density functional based tight-binding (TD-DFTB) approach is generalized to account for fractional occupations. In addition, an on-site correction leads to marked qualitative and quantitative improvements over the original method. Especially, the known failure of TD-DFTB for the description of sigma -> pi* and n -> pi* excitations is overcome. Benchmark calculations on a large set of organic molecules also indicate a better description of triplet states. The accuracy of the revised TD-DFTB method is found to be similar to first principles TD-DFT calculations at a highly reduced computational cost. As a side issue, we also discuss the generalization of the TD-DFTB method to spin polarized systems. In contrast to an earlier study, we obtain a formalism that is fully consistent with the use of local exchange-correlation functionals in the ground state DFTB method. PMID- 26583410 TI - Geometries and Vertical Excitation Energies in Retinal Analogues Resolved at the CASPT2 Level of Theory: Critical Assessment of the Performance of CASSCF, CC2, and DFT Methods. AB - A systematic investigation of structural properties and vertical excitation energies of a series of structurally modified 11-cis-retinal chromophores in vacuo was performed by means of multiconfigurational second-order perturbation theory (CASPT2). CASPT2-based geometries agree reasonably well with Moller Plesset second-order perturbation theory (MP2), local second-order approximate coupled cluster singles and doubles (LCC2), and density functional theory (DFT) geometries, while the complete active space self-consistent field (CASSCF) method exaggerates dramatically the bond length pattern in the polyene chain. The quality of the resulting vertical excitation energies obtained by employing CASSCF, second-order approximate coupled cluster singles and doubles (CC2), LCC2, and time-dependent density functional theory (TD-DFT) approaches is assessed with respect to the CASPT2 data. We show that the commonly used CASSCF/CASPT2 approach works reasonably well in the case of vertical excitation energies of planar structures, but lack of dynamic correlation leads to large errors in energetics for strongly strained structures. For example, the highly twisted conformers of 9,10-dimethyl and 9,10,13-trimethyl species are found as global minima at the CASSCF level, whereas they turn almost planar at the CASPT2, MP2, LCC2, and DFT levels of theory. The CC2 method has shown a remarkable performance, manifested by a maximum deviation of 0.05 eV from the reference CASPT2 results, whereas the local version of CC2 seems to fail to describe the charge-transfer character of the S0 -> S1 transitions correctly. We believe that our CASPT2 benchmark set will provide a reference that can be utilized for validation and development studies on 11-cis-retinal protonated Schiff base chromophore analogues. PMID- 26583411 TI - Toward Reliable Prediction of the Energy Ladder in Multichromophoric Systems: A Benchmark Study on the FMO Light-Harvesting Complex. AB - We present an evaluation of the performance of various single-reference QM methods for the prediction of the relative site energies and transition moments of the Q bands in the bacteriochlorophyll a (BChl a) pigments of the Fenna Matthew-Olson (FMO) complex. We examine the relative merits of ZINDO, CIS, TD-DFT (with the functionals PBE, BLYP, PBE0, B3LYP, and CAM-B3LYP) and RI-CC2 in reproducing the variations across the pigments that occur as a consequence of geometrical and electrostatic effects of the FMO complex by comparison to DFT BHLYP/MRCI. We find that these pigments are near-multiconfigurational in nature and, thus, constitute critical cases for the RI-CC2 method. The commonly used ZINDO method is fairly reliable for the site energies of the isolated pigments; however, it overestimates the coupling to the environment, thereby leading to variations across the embedded pigments that are too drastic. The overall best performance is provided by the investigated TD-DFT methods, where PBE0 is found to be slightly superior to the other functionals tested. PMID- 26583412 TI - Near and Above Ionization Electronic Excitations with Non-Hermitian Real-Time Time-Dependent Density Functional Theory. AB - We present a real-time time-dependent density functional theory (RT-TDDFT) prescription for capturing near and post-ionization excitations based on non Hermitian von Neumann density matrix propagation with atom-centered basis sets, tuned range-separated DFT, and a phenomenological imaginary molecular orbital based absorbing potential to mimic coupling to the continuum. The computed extreme ultraviolet absorption spectra for acetylene (C2H2), water (H2O), and Freon 12 (CF2Cl2) agree well with electron energy loss spectroscopy (EELS) data over the range of 0-50 eV. The absorbing potential removes spurious high-energy finite basis artifacts, yielding correct bound-to-bound transitions, metastable (autoionizing) resonance states, and consistent overall absorption shapes. PMID- 26583413 TI - Harmonic Models in Cartesian and Internal Coordinates to Simulate the Absorption Spectra of Carotenoids at Finite Temperatures. AB - When large structural displacements take place between the ground state (GS) and excited state (ES) minima of polyatomic molecules, the choice of a proper set of coordinates can be crucial for a reliable simulation of the vibrationally resolved absorption spectrum. In this work, we study two carotenoids that undergo structural displacements from GS to ES minima of different magnitude, from small displacements for violaxanthin to rather large ones for beta-carotene isomers. Their finite-temperature (77 and 300 K) spectra are simulated at the harmonic level, including Duschinsky effect, by time-dependent (TD) and time-independent (TI) approaches, using (TD)DFT computed potential energy surfaces (PES). We adopted two approaches to construct the harmonic PES, the Adiabatic (AH) and Vertical Hessian (VH) models and, for AH, two reference coordinate frames: Cartesian and valence internal coordinates. Our results show that when large displacements take place, Cartesian coordinates dramatically fail to describe curvilinear displacements and to account for the Duschinsky matrix, preventing a realistic simulation of the spectra within the AH model, where the GS and ES PESs are quadratically expanded around their own equilibrium geometry. In contrast, internal coordinates largely amend such deficiencies and deliver reasonable spectral widths. As expected, both coordinate frames give similar results when small displacements occur. The good agreement between VH and experimental line shapes indicates that VH model, in which GS and ES normal modes are both evaluated at the GS equilibrium geometry, is a good alternative to deal with systems exhibiting large displacements. The use of this model can be, however, problematic when imaginary frequencies arise. The extent of the nonorthogonality of the Dushinsky matrix in internal coordinates and its correlation with the magnitude of the displacement of the GS and ES geometries is analyzed in detail. PMID- 26583414 TI - The PYXAID Program for Non-Adiabatic Molecular Dynamics in Condensed Matter Systems. AB - This work introduces the PYXAID program, developed for non-adiabatic molecular dynamics simulations in condensed matter systems. By applying the classical path approximation to the fewest switches surface hopping approach, we have developed an efficient computational tool that can be applied to study photoinduced dynamics at the ab initio level in systems composed of hundreds of atoms and involving thousands of electronic states. The technique is used to study in detail the ultrafast relaxation of hot electrons in crystalline pentacene. The simulated relaxation occurs on a 500 fs time scale, in excellent agreement with experiment, and is driven by molecular lattice vibrations in the 200-250 cm(-1) frequency range. The PYXAID program is organized as a Python extension module and can be easily combined with other Python-driven modules, enhancing user friendliness and flexibility of the software. The source code and additional information are available on the Web at the address http://gdriv.es/pyxaid . The program is released under the GNU General Public License. PMID- 26583415 TI - Photoisomerization of Stilbene: The Detailed XMCQDPT2 Treatment. AB - We report the detailed XMCQDPT2/cc-pVTZ study of trans-cis photoisomerization in one of the core systems of both experimental and computational photochemistry-the stilbene molecule. For the first time, the potential energy surface (PES) of the S1 state has been directly optimized and scanned using a multistate multiconfiguration second-order perturbation theory. We characterize the trans stilbene, pyramidalized (phantom), and DHP-cis-stilbene geometric domains of the S1 state and describe their stationary points including the transition states between them, as well as S1/S0 intersections. Also reported are the minima and the activation barriers in the ground state. Our calculations correctly predict the kinetic isotope effect due to H/D exchange at ethylenic hydrogens, the dynamic behavior of excited cis-stilbene, and trans-cis branching ratio after relaxation to S0 through a rather unsymmetric conical intersection. In general, the XMCQDPT2 results confirm the qualitative adequacy of the TDDFT (especially SF TDDFT) picture of the excited stilbene but also reveal quantitative discrepancies that deserve further exploration. PMID- 26583416 TI - Longest-Wavelength Electronic Excitations of Linear Cyanines: The Role of Electron Delocalization and of Approximations in Time-Dependent Density Functional Theory. AB - The lowest-energy/longest-wavelength electronic singlet excitation energies of linear cyanine dyes are examined, using time-dependent density functional theory (TDDFT) and selected wave function methods in comparison with literature data. Variations of the bond-length alternation obtained with different optimized structures produce small differences of the excitation energy in the limit of an infinite chain. Hybrid functionals with range-separated exchange are optimally 'tuned', which is shown to minimize the delocalization error (DE) in the cyanine pi systems. Much unlike the case of charge-transfer excitations, small DEs are not strongly correlated with better performance. A representative cyanine is analyzed in detail. Compared with accurate benchmark data, TDDFT with 'pure' local functionals gives too high singlet excitation energies for all systems, but DFT-based DeltaSCF calculations with a local functional severely underestimates the energies. TDDFT strongly overestimates the difference between singlet and triplet excitation energies. An analysis points to systematically much too small magnitudes of integrals from the DFT components of the exchange-correlation response kernel as the likely culprit. The findings support previous suggestions that the differential correlation energy between the ground and excited state is not correctly produced by TDDFT with most functionals. PMID- 26583417 TI - Explicit Solvation Shell Model and Continuum Solvation Models for Solvation Energy and pKa Determination of Amino Acids. PMID- 26583418 TI - Quantum Chemical Free Energies: Structure Optimization and Vibrational Frequencies in Normal Modes. AB - A computational protocol is presented that uses normal mode coordinates for structure optimization and for obtaining harmonic frequencies by numerical differentiation. It reduces numerical accuracy problems encountered when density functional theory with plane wave basis sets is applied to systems with flat potential energy surfaces. The approach is applied to calculate Gibbs free energies for adsorption of methane, ethane, and propane on the Bronsted acidic sites of zeolite H-CHA. The values obtained (273.15 K, 0.1 MPa,), -0.25, -5.95, and -16.76 kJ/mol, respectively, follow the trend of the experimental values, which is not the case for results obtained with the standard approach (Cartesian optimization, frequencies from Cartesian distortions). Anharmonicity effects have been approximately taken into account by solving one-dimensional Schrodinger equations along each normal mode. This leads to a systematic increase of the Gibbs free energy of adsorption of 4.5, 5.0, and 3.1 kJ/mol for methane, ethane, and propane, respectively, making adsorption at a given pressure and temperature less likely. This is due to an increase of low vibrational frequencies associated with hindered translations and rotations of the adsorbed molecules and the floppy modes of the zeolite framework. PMID- 26583419 TI - Critical Evaluation of Implicit Solvent Models for Predicting Aqueous Oxidation Potentials of Neutral Organic Compounds. AB - Quantum chemical implicit solvent models are used widely to estimate aqueous redox potentials. We compared the accuracy of several popular implicit solvent models (SM8, SMD, C-PCM, IEF-PCM, and COSMO-RS) for the prediction of aqueous single electron oxidation potentials of a diverse test set of neutral organic compounds for which accurate experimental oxidation potential and gas-phase ionization energy data are available. Using a thermodynamic cycle, we decomposed the free energy of oxidation into contributions arising from the gas-phase adiabatic ionization energy, the solvation free energy of the closed-shell neutral species, and the solvation free energy of the radical cation species. For aqueous oxidation potentials, implicit solvent models exhibited mean unsigned errors (MUEs) ranging from 0.27 to 0.50 V, depending on the model. The principal source of error was attributed to the computed solvation free energy of the oxidized radical cation. Based on these results, a recommended implicit solvation approach is the SMD model for the solvation free energy combined with CBS-QB3 for the gas-phase ionization energy. With this approach, the MUE in computed oxidation potentials was 0.27 V, and the MUE in solvation free energy of the charged open-shell species was 0.32 eV. This baseline assessment provides a compiled benchmark test set of vetted experimental data that may be used to judge newly developed solvation models for their ability to produce improved predictions for aqueous oxidation potentials and related properties. PMID- 26583420 TI - An Explicit Consideration of Desolvation is Critical to Binding Free Energy Calculations of Charged Molecules at Ionic Surfaces. AB - Identifying factors that control the strength and specificity of interactions between peptides and nanoparticles is essential for understanding the potential beneficial and deleterious effects of nanoparticles on biological systems. Computer simulations are valuable in this context, although the reliability of such calculations depends on the force field and sampling algorithm, as well as how the binding constant and binding free energy are defined; the latter must be carefully defined with a clear connection to microscopic models based on statistical mechanics. Using the example of formate binding to the rutile titanium dioxide (TiO2) (110) surface, we demonstrate that a reliable description of the binding process requires an explicit consideration of changes in the solvation state of the binding site. Specifically, we carry out metadynamics simulations in which the solvent coordination number of the binding site, s, is introduced as a collective variable in addition to the vertical distance of the adsorbate to the surface (z). The resulting two-dimensional potential of mean force (2D-PMF) clearly shows that explicitly including the local desolvation of the binding site on the TiO2 surface strongly impacts the convergence and result of the binding free energy calculations. Projecting the 2D-PMF into a one dimensional PMF along either z or s leads to large errors in the free energy barriers. Results from metadynamics simulations are quantitatively supported by independent alchemical free energy simulations, in which the solvation state of the binding site is also carefully considered by explicitly introducing water molecules to the binding site as the adsorbate is decoupled from the system. On the other hand, preliminary committor analysis for the approximate transition state ensemble constructed based on the 2D-PMF suggests that to properly describe the binding/unbinding kinetics, variables beyond s and z, such as those describing the hydrogen bonding pattern of the adsorbate and surface water, need to be included. We expect that the insights and computational methodologies established in this work will be generally applicable to the analysis of binding interactions between highly charged adsorbates and ionic surfaces in solution, such as those implicated in peptide/nanoparticle binding and biomineralization processes. PMID- 26583421 TI - Characterization of the Methane-Graphene Hydrophobic Interaction in Aqueous Solution from Ab Initio Simulations. AB - In this article, the interaction between a methane molecule and a graphene plane in liquid water has been characterized employing DFT-based free energy Molecular Dynamics calculations. This system represents a good model to understand the generic interaction between a small hydrophobic solute (methane molecule) and an extense hydrophobic surface (graphene plane). The structural and dynamical properties of graphene and methane hydration water are analyzed and found to be closely related to the main features of the potential of mean force. The results could be used in coarse-grained models to take into account the effect of the hydrophobic interaction in realistic systems relevant to experiment. PMID- 26583422 TI - Molecular Force Field Development for Aqueous Electrolytes: 1. Incorporating Appropriate Experimental Data and the Inadequacy of Simple Electrolyte Force Fields Based on Lennard-Jones and Point Charge Interactions with Lorentz Berthelot Rules. AB - It is known that none of the available simple molecular interaction models of aqueous electrolytes based on SPC/E water and their associated force fields are able to reproduce the concentration dependence of important thermodynamic properties of even the simplest electrolyte, NaCl, at ambient conditions over the entire experimentally accessible concentration range [ Moucka , F. ; Nezbeda , I. ; Smith , W. R. J. Chem. Phys. 2013 , 138 , 154102 ]. This paper explores the possibility of improving their performance by incorporating concentration dependent experimental data for the total ionic chemical potential and the density into the fitting procedure, in addition to experimental values of solubility and solid chemical potential. We describe a general parameter estimation methodology for a studied class of models that incorporates the aforementioned experimental data. When the entire concentration range is considered, although the resulting force field is a slight improvement over others currently available in the literature, overall quantitative agreement with the experimental data over this range remains unsatisfactory. This indicates an inherent limitation of such simple molecular interaction models and strongly suggests that more complex mathematical forms of such models are required to quantitatively predict the properties of aqueous electrolyte solutions when the entire concentration range is of interest. Our parameter estimation methodology is also applicable to such cases. PMID- 26583423 TI - Simulation of Adsorption Processes at Metallic Interfaces: An Image Charge Augmented QM/MM Approach. AB - A novel method for including polarization effects within hybrid quantum mechanics/molecular mechanics (QM/MM) simulations of adsorbate-metal systems is presented. The interactions between adsorbate (QM) and metallic substrate (MM) are described at the MM level of theory. Induction effects are additionally accounted for by applying the image charge formulation. The charge distribution induced within the metallic substrate is modeled by a set of Gaussian charges (image charges) centered at the metal atoms. The image charges and the electrostatic response of the QM potential are determined self-consistently by imposing the constant-potential condition within the metal. The implementation is embedded in a highly efficient Gaussian and plane wave framework and is naturally suited for periodic systems. Even though the electronic properties of the metallic substrate are not taken into account explicitly, the augmented QM/MM scheme can reproduce characteristic polarization effects of the adsorbate. The method is assessed through the investigation of structural and electronic properties of benzene, nitrobenzene, thymine, and guanine on Au(111). The study of small water clusters adsorbed on Pt(111) is also reported in order to demonstrate that the approach provides a sizable correction of the MM-based interactions between adsorbate and substrate. Large-scale molecular dynamics (MD) simulations of a water film in contact with a Pt(111) surface show that the method is suitable for simulations of liquid/metal interfaces at reduced computational cost. PMID- 26583424 TI - Predicting the Thermodynamics and Kinetics of Helix Formation in a Cyclic Peptide Model. AB - The peptide Ac-(cyclo-2,6)-R[KAAAD]-NH2 (cyc-RKAAAD) is a short cyclic peptide known to adopt a remarkably stable single turn alpha-helix in water. Due to its simplicity and the availability of thermodynamic and kinetic experimental data, cyc-RKAAAD poses as an ideal model for evaluating the aptness of current molecular dynamics (MD) simulation methodologies to accurately sample conformations that reproduce experimentally observed properties. In this work, we extensively sample the conformational space of cyc-RKAAAD using microsecond timescale MD simulations. We characterize the peptide conformational preferences in terms of secondary structure propensities and, using Cartesian-coordinate principal component analysis (cPCA), construct its free energy landscape, thus obtaining a detailed weighted discrimination between the helical and nonhelical subensembles. The cPCA state discrimination, together with a Markov model built from it, allowed us to estimate the free energy of unfolding (-0.57 kJ/mol) and the relaxation time (~0.435 MUs) at 298.15 K, which are in excellent agreement with the experimentally reported values (-0.22 kJ/mol and 0.42 MUs, Serrano, A. L.; Tucker, M. J.; Gai, F. J. Phys. Chem. B, 2011, 115, 7472-7478.). Additionally, we present simulations conducted using two enhanced sampling methods: replica-exchange molecular dynamics (REMD) and bias-exchange metadynamics (BE-MetaD). We compare the free energy landscape obtained by these two methods with the results from MD simulations and discuss the sampling and computational gains achieved. Overall, the results obtained attest to the suitability of modern simulation methods to explore the conformational behavior of peptide systems with a high level of realism. PMID- 26583425 TI - Role of Prion Disease-Linked Mutations in the Intrinsically Disordered N-Terminal Domain of the Prion Protein. AB - Prion diseases are fatal neurodegenerative disorders in mammals and other animal species. In humans, about 15% of these maladies are caused by pathogenic mutations (PMs) in the gene encoding for the prion protein (PrP(C)). Seven PMs are located in the naturally unfolded PrP(C) N-terminal domain, which constitutes about half of the protein. Intriguingly and in sharp contrast to other PMs clustered in the folded domain, N-terminal PMs barely affect the conversion to the pathogenic (scrapie, or PrP(Sc)) isoform of PrP(C). Here, we hypothesize that the neurotoxicity of these PMs arises from changes in structural determinants of the N-terminal domain, affecting the protein binding with its cellular partners and/or the cotranslational translocation during the PrP(C) biosynthesis. We test this idea by predicting the conformational ensemble of the wild-type (WT) and mutated mouse PrP(C) N-terminal domain, whose sequence is almost identical to that of the human one and for which the largest number of in vivo data is available. The conformational properties of the WT are consistent with those inferred experimentally. Importantly, the PMs turn out to affect in a subtle manner the intramolecular contacts in the putative N-terminal domain binding sites for Cu(2+) ions, sulphated glycosaminoglycans, and other known PrP(C) cellular partners. The PMs also alter the local structural features of the transmembrane domain and adjacent stop transfer effector, which act together to regulate the protein topology. These results corroborate the hypothesis that N terminal PMs affect the PrP(C) binding to functional interactors and/or the translocation. PMID- 26583426 TI - Multiscale Simulation of Liquid Water Using a Four-to-One Mapping for Coarse Graining. AB - We present a multiresolution simulation scheme for the solvent environment where four atomistic water molecules are mapped onto one coarse-grained bead. Soft restraining potentials are used to allow a resolution exchange of four water molecules into a single coarse-grained site. We first study the effect of adding restraining potentials in liquid water using full all-atom simulations. The usage of very soft restraining potentials to bundle four nearest neighbor water molecules does not disrupt the hydrogen bonding patterns in the liquid water. The structural properties of the first solvation shell around hydrophobic, hydrophilic, and ionic solutes are well preserved when soft restraining potentials are added. By modeling a bundle of four water molecules as a single molecule, a smooth transition and free exchange between coarse-grained and all atom resolution is possible by using the adaptive resolution scheme (AdResS). PMID- 26583427 TI - On the Reliability of Pure and Hybrid DFT Methods for the Evaluation of Halogen, Chalcogen, and Pnicogen Bonds Involving Anionic and Neutral Electron Donors. AB - In this article, we report a comprehensive theoretical study of halogen, chalcogen, and pnicogen bonding interactions using a large set of pure and hybrid functionals and some ab initio methods. We have observed that the pure and some hybrid functionals largely overestimate the interaction energies when the donor atom is anionic (Cl(-) or Br(-)), especially in the halogen bonding complexes. To evaluate the reliability of the different DFT (BP86, BP86-D3, BLYP, BLYP-D3, B3LYP, B97-D, B97-D3, PBE0, HSE06, APFD, and M06-2X) and ab initio (MP2, RI-MP2, and HF) methods, we have compared the binding energies and equilibrium distances to those obtained using the CCSD(T)/aug-cc-pVTZ level of theory, as reference. The addition of the latest available correction for dispersion (D3) to pure functionals is not recommended for the calculation of halogen, chalcogen, and pnicogen complexes with anions, since it further contributes to the overestimation of the binding energies. In addition, in chalcogen bonding interactions, we have studied how the hybridization of the chalcogen atom influences the interaction energies. PMID- 26583429 TI - Polarity and Nonpolarity of Ionic Liquids Viewed from the Rotational Dynamics of Carbon Monoxide. AB - The rotational dynamics of carbon monoxide (CO) in a molten salt, ionic liquids (ILs), and alkanes were investigated by (17)O NMR T1 measurements using labeled C(17)O. The molten salt and the studied ILs have the bis(trifluoromethanesulfonyl)imide anion ([NTf2](-)) in common. In hexane near room temperature, the rotational relaxation times are close to the values predicted from the slip boundary condition in the Stokes-Einstein-Debye (SED) theory. However, in contradiction to the theoretical prediction, the rotational relaxation times decrease as the value of eta/T increases, where eta and T are the viscosity and absolute temperature, respectively. In other alkanes and ILs used in this study, the rotational relaxation times are much faster than those predicted by SED, and show a unique dependence on the number of alkyl carbons. For the same value of eta/T, the CO rotational relaxation times in ILs composed of short-alkyl-chain-length imidazolium cations (1-ethyl-3-methylimidazolium and 1-butyl-3-methylimidazolium) are close to those for a molten salt (Cs[NTf2]). On the other hand, the rotational relaxation times in ILs composed of long-chain length imidazolium (1-methyl-3-octylimidazolium) and phosphonium (tributylmethylphosphonium and tetraoctylphosphonium) cations are much shorter than the SED predictions. This deviation from theory increases as the alkyl chain length increases. We also found that the rotational relaxation times in dodecane and squalane are similar to those in ILs with a similar number of alkyl carbons. These results are discussed in terms of heterogeneous solvation and in comparison with the translational diffusion of CO in ILs. PMID- 26583428 TI - Gauging and Tuning Cross-Linking Kinetics of Catechol-PEG Adhesives via Catecholamine Functionalization. AB - The curing time of an adhesive material is determined by the polymerization and cross-linking kinetics of the adhesive formulation and needs to be optimized for the particular application. Here, we explore the possibility of tuning the polymerization kinetics and final mechanical properties of tissue-adhesive PEG gels formed by polymerization of end-functionalized star-PEGs with catecholamines with varying substituents. We show strong differences in cross-linking time and cohesiveness of the final gels among the catecholamine-PEG variants. Installation of an electron-withdrawing but pi-electron donating chloro substituent on the catechol ring resulted in faster and more efficient cross-linking, while opposite effects were observed with the strongly electron-withdrawing nitro group. Chain substitution slowed down the kinetics and hindered cross-linking due either to chain breakdown (beta-OH group, in norepinephrine) or intramolecular cyclization (alpha-carboxyl group, in DOPA). Interesting perspectives derive from use of mixtures of catecholamine-PEG precursors offering further opportunities for fine tuning of the curing parameters. These are interesting properties for the application of catecholamine-PEG gels as tissue glues or biomaterials for cell encapsulation. PMID- 26583430 TI - Construction of Plasmonic Core-Satellite Nanostructures on Substrates Based on DNA-Directed Self-Assembly as a Sensitive and Reproducible Biosensor. AB - We report the successful construction of plasmonic core-satellite nanostructured assemblies on two-dimensional substrates, based on a strategy of combining DNA functionalized plasmonic nanoparticles (NPs) with the specific recognition ability toward target to enable satellite NPs to self-assemble around the core immobilized on substrates. A strongly coupled plasmonic resonance band was observed because of the close proximity between core and satellite NPs, which presented significant red-shift and enhanced extinction with respect to the local surface plasmon resonance (LSPR) band of individual core NPs on the substrate. The functionality of this core-satellite nanostructured assembly as a biosensor was further explored, and the changes in extinction intensity and the peak shift of the plasmonic coupling resonance band arising from the probe-target DNA binding event all proved to be useful criteria for target DNA detection. Moreover, high selectivity down to single-base mismatched DNA was achieved using this strongly coupled plasmonic core-satellite nanostructured assembly on a substrate. Such substrate-based detection was advantageous, and its reusability and high cycle stability were demonstrated after five cycles of disassembly and reassembly. Our work demonstrates the biosensing capacity of this DNA functionalized plasmonic nanoassembly model system on two-dimensional substrate, which is also applicable to the detection of numerous DNA-recognized biomolecules. Likewise, the presented construction method can be extended to fabricate other compositional core-satellite nanoassemblies. PMID- 26583431 TI - Controlled Clustering in Binary Charged Colloids by Adsorption of Ionic Surfactants. AB - We report on the controlled clustering of oppositely charged colloidal particles by the adsorption of ionic surfactants, which tunes charge numbers Z of particles. In particular, we studied the heteroclustering of submicron-sized polystyrene (PS) and silica particles, both of which are negatively charged, in the presence of cetylpyridinium chloride (CPC), a cationic surfactant. The surfactant concentration Csurf was selected below the critical micelle concentration. As CPC molecules were adsorbed, Z values of the PS and silica particles decreased, inverting to positive when Csurf exceeded the isoelectric point Ciep. Hydrophobic PS particles exhibited much lower Ciep than hydrophilic silica particles. At Csurf valuess between their Ciep values, the particles were oppositely charged, and clustering was enabled. To explain the clustering behavior, we investigated adsorption isotherms of the CPC and screened-Coulomb type pair potential. Expected applications of the present findings are the control of colloidal associations and construction of various particle types into heterogeneous colloidal clusters. PMID- 26583432 TI - APPL proteins promote TGFbeta-induced nuclear transport of the TGFbeta type I receptor intracellular domain. AB - The multifunctional cytokine transforming growth factor-beta (TGFbeta) is produced by several types of cancers, including prostate cancer, and promote tumour progression in autocrine and paracrine manners. In response to ligand binding, the TGFbeta type I receptor (TbetaRI) activates Smad and non-Smad signalling pathways. The ubiquitin-ligase tumour necrosis factor receptor associated factor 6 (TRAF6) was recently linked to regulate intramembrane proteolytic cleavage of the TbetaRI in cancer cells. Subsequently, the intracellular domain (ICD) of TbetaRI enters in an unknown manner into the nucleus, where it promotes the transcription of pro-invasive genes, such as MMP2 and MMP9. Here we show that the endocytic adaptor molecules APPL1 and APPL2 are required for TGFbeta-induced nuclear translocation of TbetaRI-ICD and for cancer cell invasiveness of human prostate and breast cancer cell lines. Moreover, APPL proteins were found to be expressed at high levels in aggressive prostate cancer tissues, and to be associated with TbetaRI in a TRAF6-dependent manner. Our results suggest that the APPL-TbetaRI complex promotes prostate tumour progression, and may serve as a prognostic marker. PMID- 26583433 TI - Characteristics of Traveler with Middle East Respiratory Syndrome, China, 2015. PMID- 26583434 TI - In Reply to Dr. Anchondo and the Ellyn Satter Institute RE: MA-CORD. PMID- 26583435 TI - Induced sputum deposition improves diagnostic yields of pulmonary alveolar proteinosis: A clinicopathological and methodological study of 17 cases. AB - Pulmonary alveolar proteinosis (PAP) is a rare diffuse lung disease characterized by the accumulation of intra-alveolar lipoprotein-like surfactants. Lung core biopsy and bronchoalveolar lavage (BAL) fluid are currently the two major sources of sampling for diagnosis. In the present study, we assessed the value of induced sputum in diagnosing PAP by transmission electron microscopy and examined the PAP 2-year death rate in Asians. Transmission electron microscopy was performed on the samples from 17 patients with PAP, 13 patients with inflammatory lung diseases, and 13 healthy adults. The PAP patients were followed up for 3-156 months, and inflammatory lung diseases patients or healthy adults for 12-36 months. The ultrastructural features including diagnostic lamellar bodies of induced sputum deposition (ISD) samples were similar to that of the BAL fluid sediment. However, the rates of lamellar bodies were 73.7% in the ISD group, significantly higher than the spontaneous sputum deposition (SSD) group (42.1%, P < .0487) and similar to the BAL sediment (76.2%) and the lung biopsy (54.5%) groups. The overall 2-year death rate of our PAP patients was 17.6% (3/17), not statistically different from the healthy adults and patients with inflammatory diseases (0/13, P = .237 for both). ISD may be the preferred non-invasive sampling method for diagnosing PAP by electronic microscopy because of the higher diagnostic yield than SSD. The diagnostic yields of this noninvasive method were similar to that of lung core biopsy and BAL. PMID- 26583436 TI - Impact of postoperative nausea and vomiting prophylaxis with dexamethasone on the risk of recurrence of endometrial cancer. AB - OBJECTIVE: To assess whether antiemetic doses of dexamethasone are associated with an increased risk of cancer recurrence in women who underwent surgery for endometrial cancer. RESEARCH DESIGN AND METHODS: This is a retrospective study at an academic university medical center. Women who underwent surgery for endometrial cancer from 2003 to 2007 were identified from a prospectively collected endometrial cancer database. Perioperative records were reviewed to determine administration of dexamethasone. Patients were divided into two groups: those who received dexamethasone 4-10 mg for postoperative nausea and vomiting prophylaxis and those who did not receive dexamethasone. We collected information on patient demographics, cancer stage, cancer grade, histology, year of surgery, chemotherapy, radiation therapy, duration of surgery, perioperative blood transfusion, receipt of epidural analgesia, dose of dexamethasone given, follow up time, and co-morbidities. MAIN OUTCOME MEASURES: Primary endpoint was recurrence-free survival. Secondary endpoints included progression-free survival and overall survival. RESULTS: Three hundred and nine patients were included in the analysis. There were no significant differences between dexamethasone exposed (n = 107) and non-exposed patients in recurrence-free survival ([5 year estimate (95% CI)] = 71 (62-82) % vs. 71 (64-78) %, p = 1.0), progression-free survival (57 [47-68] % vs. 60 [53-68] %, p = 0.9), or overall survival (68 [59-79] % vs. 71 [64-79] %, p = 1.0). In univariate analysis, significant predictors of recurrence-free survival were tumor stage (p = 0.02), tumor grade (0.003) and receipt of adjuvant chemotherapy (p < 0.001). In the multivariable model, higher tumor grade (hazard ratio [HR] [95% CI] = 2.3 [1.4-3.9], p = 0.002) and receipt of adjuvant chemotherapy (3.2 [1.8-5.8], p < 0.001), but not dexamethasone (0.9 [0.5-1.5], p = 0.7), were significant predictors of recurrence-free survival. CONCLUSIONS: Dexamethasone administration was not associated with an increased risk of recurrence in women having surgery for endometrial cancer. Limitations of the study include its retrospective single center design and the fact that administration of dexamethasone was not randomized. PMID- 26583438 TI - Editorial: Psychodynamic Psychiatry and Psychoanalysis: Two Different Models. PMID- 26583437 TI - Gold nanoparticles alter parameters of oxidative stress and energy metabolism in organs of adult rats. AB - This study evaluated the parameters of oxidative stress and energy metabolism after the acute and long-term administration of gold nanoparticles (GNPs, 10 and 30 nm in diameter) in different organs of rats. Adult male Wistar rats received a single intraperitoneal injection or repeated injections (once daily for 28 days) of saline solution, GNPs-10 or GNPs-30. Twenty-four hours after the last administration, the animals were killed, and the liver, kidney, and heart were isolated for biochemical analysis. We demonstrated that acute administration of GNPs-30 increased the TBARS levels, and that GNPs-10 increased the carbonyl protein levels. The long-term administration of GNPs-10 increased the TBARS levels, and the carbonyl protein levels were increased by GNPs-30. Acute administration of GNPs-10 and GNPs-30 increased SOD activity. Long-term administration of GNPs-30 increased SOD activity. Acute administration of GNPs-10 decreased the activity of CAT, whereas long-term administration of GNP-10 and GNP 30 altered CAT activity randomly. Our results also demonstrated that acute GNPs 30 administration decreased energy metabolism, especially in the liver and heart. Long-term GNPs-10 administration increased energy metabolism in the liver and decreased energy metabolism in the kidney and heart, whereas long-term GNPs-30 administration increased energy metabolism in the heart. The results of our study are consistent with other studies conducted in our research group and reinforce the fact that GNPs can lead to oxidative damage, which is responsible for DNA damage and alterations in energy metabolism. PMID- 26583439 TI - Understanding Defense Mechanisms. AB - Understanding defense mechanisms is an important part of psychotherapy. In this article, we trace the history of the concept of defense, from its origin with Freud to current views. The issue of defense as an unconscious mechanism is examined. The question of whether defenses are pathological, as well as their relation to pathology, is discussed. The effect of psychotherapy on the use of defenses, and their relation to a therapeutic alliance is explored. A series of empirical research studies that demonstrate the functioning of defense mechanisms and that support the theory is presented. Research also shows that as part of normal development, different defenses emerge at different developmental periods, and that gender differences in defense use occur. PMID- 26583440 TI - Discussion of Understanding Defense Mechanisms. PMID- 26583441 TI - Use of Telepsychiatry in Psychodynamic Psychiatry. AB - This article reviews the organization, infrastructure basics, applications, effectiveness, outreach, and implementation barriers related to telepsychiatry. We highlight the tremendous potential and promise that this technology holds and also discuss the importance that telepsychiatry may play in the field of psychodynamic psychiatry. Given the growing effectiveness evidence base for therapy delivered over the Internet, telepsychiatry holds a large unexplored territory to help psychodynamically minded patients connect with psychodynamically oriented psychiatrists. This economically advantageous medium can be utilized to deliver psychodynamically guided approaches to the patient, alone or in combination with pharmacological and other psychosocial interventions. We hope, this article will help psychodynamically trained psychiatrists to consider bridging the gap with the remotely located, chronically mentally ill population which oftentimes has scarcity of resources. PMID- 26583442 TI - Comparing Psychodynamic Teaching, Supervision, and Psychotherapy Over Videoconferencing Technology with Chinese Students. AB - How do experts compare teaching, supervision, and treatment from a psychodynamic perceptive over the Internet with in-person work? Our methodology was based on the expert opinions of 176 teachers, supervisors, and therapists in the China American Psychoanalytic Alliance (CAPA) who use videoconferencing (VCON) with Chinese students. The results from our online survey indicate: (1), The longer teachers teach, the more effective they rate teaching over VCON; (2), Teaching, supervision, and treatment were all rated in the range of "slightly less effective" than in-person, with supervision rated significantly more effective than teaching and treatment over VCON; (3), When doing psychodynamic treatment over VCON the issues of symptom reduction, exploring mental life, working on transference, relational problems, resistance, privacy issues, countertransference, are all equally rated in the range of "slightly less effective" than in-person treatment; (4), The highest significantly rated indications for treatment over VCON are: "To offer high quality treatment to underserved or remote patients" and "When patient is house-bound or travel would be impractical"; and (5), The highest significantly rated contraindication for treatment over VCON is: "Patient needs close observation due to crisis or decompensation." Overall, this survey suggests that VCON teaching, supervision, and treatment from a psychodynamic perceptive is a worthwhile option when considering its unique contribution to extending services where needed. PMID- 26583443 TI - Davanloo's Technique of Total Removal of Resistance and Optimum Mobilization of the Transference Component of the Resistance. AB - Davanloo's Intensive Short-Term Dynamic Psychotherapy (IS-TDP) is a unique brief dynamic psychotherapy characterized by relentless therapist intervention. While Davanloo has published extensively on his findings, there has been a paucity of publications on his most recent work involving the Montreal Closed Circuit Training Program. The purpose of this article is to highlight Davanloo's current understanding of his technique as well as his newest research findings. This will be done contextually, by highlighting case vignettes from the Montreal Closed Circuit Training Program. A special focus will be placed on the handling of resistance and Davanloo's concept of the "Transference Component of the Resistance" or TCR. This work was presented at Davanloo's 35th Annual Metapsychology Meeting in Montreal in October, 2014. PMID- 26583444 TI - Termination: A Case Study. AB - In this article I posit and examine certain criteria and qualities for ending an analysis. The case study describes the end phase of a four-year psychoanalysis in which the patient's decision to move to another area forced the end of his analysis. We continued to explore and work through his core neurotic conflicts that included issues of competitive rivalry, dominance and submission, control, and anxiety about birth and death. A shift in the transference from me as a negative father to me as a supportive but competitive older brother was also examined in the context of ending treatment as well as other aspects of the transference. In addition, we analyzed the meaning of his ending treatment based on an extra-analytic circumstance. In discussing this phase of treatment, the definition and history of the term "termination" and its connotations are reviewed. Various criteria for completing an analysis are examined, and technical observations about this phase of treatment are investigated. It was found that while a significant shift in the transference occurred in this phase of the patient's analysis, conflicts related to the transference were not "resolved" in the classical sense. Terminating treatment was considered as a practical matter in which the patient's autonomy and sense of choice were respected and analyzed. PMID- 26583447 TI - Laparoscopic Surgery for Transverse Colon Cancer: Short- and Long-Term Outcomes in Comparison with Conventional Open Surgery. AB - BACKGROUND: Published studies on laparoscopic surgery for transverse colon cancer are scarce. More studies are necessary to evaluate the feasibility, safety, and long-term oncologic outcomes of laparoscopic surgery for transverse colon cancer. SUBJECTS AND METHODS: From April 1996 to December 2010, 102 consecutive patients with stage II or III disease who had undergone curative resection for transverse colon cancer were enrolled. Seventy-nine patients underwent laparoscopy-assisted colectomy (LAC), whereas 23 patients underwent conventional open colectomy (OC). Short- and long-term outcomes of the two groups were compared. RESULTS: The OC group had a larger tumor size (7.6 +/- 3.4 cm versus 5.2 +/- 2.3 cm, P = .004) and more retrieved lymph nodes (26.4 +/- 11.6 versus 17.5 +/- 9.4, P = .002), without differences in resection margins. In the LAC group, return to diet was faster (4.5 +/- 1.2 days versus 5.4 +/- 1.8 days, P = .013), and postoperative hospital stay was shorter (12.1 +/- 4.2 days versus 15.9 +/- 4.8 days, P = .000). There were no differences in occurrence of intra- or postoperative complications. There were no statistically significant differences in overall survival rate (OS) or disease-free survival rate (DFS) between the two groups (5-year OS, 90.4% versus 90.5%, P = .670; 5-year DFS, 84.2% versus 90.7%, P = .463). CONCLUSIONS: Laparoscopic surgery for transverse colon cancer has better short-term outcomes compared with open surgery, with acceptable long-term outcomes. As in colorectal cancer of other sites, laparoscopic surgery can be a feasible alternative to conventional surgery for transverse colon cancer. PMID- 26583448 TI - Selected Ion Flow-Drift Tube Mass Spectrometry: Quantification of Volatile Compounds in Air and Breath. AB - A selected ion flow-drift tube mass spectrometric analytical technique, SIFDT-MS, is described that extends the established selected ion flow tube mass spectrometry, SIFT-MS, by the inclusion of a static but variable E-field along the axis of the flow tube reactor in which the analytical ion-molecule chemistry occurs. The ion axial speed is increased in proportion to the reduced field strength E/N (N is the carrier gas number density), and the residence/reaction time, t, which is measured by Hadamard transform multiplexing, is correspondingly reduced. To ensure a proper understanding of the physics and ion chemistry underlying SIFDT-MS, ion diffusive loss to the walls of the flow-drift tube and the mobility of injected H3O(+) ions have been studied as a function of E/N. It is seen that the derived diffusion coefficient and mobility of H3O(+) ions are consistent with those previously reported. The rate coefficient has been determined at elevated E/N for the association reaction of the H3O(+) reagent ions with H2O molecules, which is the first step in the production of H3O(+)(H2O)1,2,3 reagent hydrate ions. The production of hydrated analyte ion was also experimentally investigated. The analytical performance of SIFDT-MS is demonstrated by the quantification of acetone and isoprene in exhaled breath. Finally, the essential features of SIFDT-MS and SIFT-MS are compared, notably pointing out that a much lower speed of the flow-drive pump is required for SIFDT MS, which facilitates the development of smaller cost-effective analytical instruments for real time breath and fluid headspace analyses. PMID- 26583449 TI - Computational modeling of acute myocardial infarction. AB - Myocardial infarction, commonly known as heart attack, is caused by reduced blood supply and damages the heart muscle because of a lack of oxygen. Myocardial infarction initiates a cascade of biochemical and mechanical events. In the early stages, cardiomyocytes death, wall thinning, collagen degradation, and ventricular dilation are the immediate consequences of myocardial infarction. In the later stages, collagenous scar formation in the infarcted zone and hypertrophy of the non-infarcted zone are auto-regulatory mechanisms to partly correct for these events. Here we propose a computational model for the short term adaptation after myocardial infarction using the continuum theory of multiplicative growth. Our model captures the effects of cell death initiating wall thinning, and collagen degradation initiating ventricular dilation. Our simulations agree well with clinical observations in early myocardial infarction. They represent a first step toward simulating the progression of myocardial infarction with the ultimate goal to predict the propensity toward heart failure as a function of infarct intensity, location, and size. PMID- 26583450 TI - Correlates of Skin and Soft Tissue Infections in Injection Drug Users in a Syringe-Exchange Program in Malmo, Sweden. AB - BACKGROUND: Injection drug users (IDUs) are at increased risk of various medical conditions, including bacterial skin and soft tissue infections (SSTIs). SSTIs, which are painful and can lead to life-threatening complications, are common but scarcely studied. OBJECTIVES: To investigate life time, past 12 month and past 30 day prevalence for SSTI related to injection drug use, in IDUs at Malmo syringe exchange program (Malmo SEP). To investigate factors associated with having ever had an SSTI. METHODS: IDUs were recruited from Malmo SEP (N = 80). They participated in a survey with questions about demographics, drug use, and experience of SSTIs. Factors independently associated with self-reported SSTI ever were assessed using logistic regression analysis. RESULTS: The lifetime reported prevalence of SSTI was 58%, past 12 months 30%, and past 30 days 14%. Factors independently associated with SSTI ever were age (adjusted odds ratio [AOR] = 1.09; 95% confidence interval [CI] = 1.01-1.18), female sex (AOR = 6.75; 95% CI = 1.40-32.47), having ever injected prescribed drugs (AOR = 52.15; 95% CI = 5.17-525.67), and having ever injected in the neck (AOR = 8.08; 95% CI = 1.16 56.08). CONCLUSIONS/IMPORTANCE: SSTI is common among IDUs in Malmo. Women and those injecting in the neck or injecting prescribed drugs (crushed tablets/liquids), are more likely to have had an SSTI. PMID- 26583451 TI - Selective IgA deficiency presenting with chest pain. PMID- 26583452 TI - Teething and affecting factors: experiences from Turkey. AB - BACKGROUND: The aim of this study was to investigate the experiences of Turkish mothers in teething period and the factors affecting teething. METHODS: This study was performed by filling in questionnaire forms with a face-to-face interview technique with the mothers of 792 patients presenting to the outpatient clinics of pediatrics of Fatih (Turgut Ozal) University Faculty of Medicine between 1 April and 31 July 2012. RESULTS: This study was conducted in a total of 792 children (mean age: 24.2+/-7.9, range 12-42 months; 430 males). Of the study population, 6.1% had a family history of premature teething, 9.7% had a family history of delayed teething, 98% had been breastfed, 91.9% had used vitamin D, 67.6% had used iron supplements, and 3.9% had fluorine use. The first teething was at 7.8+/-2.5 months and the first teeth to appear was the anterior lower incisor (58.7%). The symptoms the patients had during teething were irritability (64.9%), fever (64.1%), increased mastication (61.6%), increased salivation (58.2%), and diarrhea (45.6%). The rate of admission to a physician with these complaints was 19.6%. The factors affecting the teething time were a family history of premature or delayed teething and birth with natal tooth, and male gender. CONCLUSIONS: In this study we found that nutritional or local factors were not effective on teething time. Teething period was characterized by nonspecific symptoms including irritability, subfebrile fever, increased mastication and salivation, and diarrhea. Linear regression analysis revealed that male gender and a family history of premature teething were the factors responsible from a shortening in teething time. PMID- 26583453 TI - Correlation between criteria of diagnosis of low bone mineral density in adult and pediatric thalassemic patients: a prospective study. AB - BACKGROUND: Finding the correlation between criteria for low bone mineral density (BMD) in adulthood and childhood is a matter of interest. This study aimed to find how many of thalassemic patients with Z-Score <=-2 during childhood, will be found with T-Score <=-2.5 or Z-Score <=-2.0 in adulthood. METHODS: The results of BMDs (one in childhood and one in adulthood) of 30 patients with beta thalassemia major (12 males and 18 females) with mean age of 17.63 y/o in childhood and 20.67 y/o in adulthood were studied, retrospectively. A Norland XR-46 device was used for measuring BMD. RESULTS: Z-Score <=-2 was found in 33% of children and T-Score <=-2.5 and Z-Score <=-2.0 was found in 43 and 66% of adults, respectively. Correlation of pediatric Z-scores was good with adult T-scores and Z-scores (0.699-0.833). Relation of low BMD diagnosis in pediatric and adults was significant, and Kappa showed a moderate to good correlation between criteria for low BMD in childhood and adulthood, both with special significance in femoral region (8.10-14.47 and 0.258-0.703, respectively). Z-score <=-2 significantly increased risk of low BMD in adulthood only when T-Score <=-2.5 was used as low BMD criteria in adulthood (6.2-15.7). More patients dropped to poorer diagnosis group when Z-Score <=-2.0 was used as low BMD criteria in adulthood. CONCLUSIONS: There is a moderate to good agreement of these criteria, at least in femoral region but using T-Score <=-2.5 as low BMD criteria in adulthood caused a better prediction power for Z-Score <=-2 of childhood. PMID- 26583454 TI - Less physically active children are shorter. AB - BACKGROUND: Current concepts of linear growth include genetic, endocrine and nutritional factors. Limited and controversial results exist regarding the effect of physical activity (PA) on linear growth. In 2009, we showed that PA promotes foot length in hypoactive children with Prader-Willi-Syndrome. In the present study we tested the hypothesis that PA related epiphyseal loading has a positive modulating effect on linear growth in healthy school children. METHODS: In 99 healthy schoolchildren, we measured height, foot length and PA by tri-axial accelerometry. PA related epiphyseal loading was expressed as the product between mass (body weight) and acceleration (vector magnitude). Correlation between height, foot length and PA were calculated taking into account co-variables age, sex, parental height, lean and fat mass measured by DEXA. RESULTS: Height SDS (P<0.015, r=0.245) as well as foot length SDS (P<0.001, r=0.363) correlated with PA. Multiple linear regression models showed that muscle mass expressed by lean body mass has higher correlation with PA, height SDS and foot length SDS than fat mass. CONCLUSIONS: This study shows that physically less active children are shorter and have shorter feet. In analogy to the "muscle bone unit", we propose a "muscle epiphyseal unit" which regulates local bone growth as long as epiphyseal plates are still open. PMID- 26583455 TI - Habit reversal training in children and adolescents with chronic tic disorders: an Italian randomized, single-blind pilot study. AB - BACKGROUND: The aim of the present study was to test the possibility to apply habit reversal training (HRT) in Italy and to evaluate the effectiveness of HRT in reducing tic severity compared with the "usual care" (UC) in Italian children and adolescents with Tourette Syndrome. METHODS: We performed a single blind, randomized, pilot study comparing HRT (active treatment) and UC (usual treatment). Out of 69 patients seen during the study period, we were able to enroll 21 patients (11 randomized to HRT e 10 to UC). Assessment included in depth neurological and psychiatric examination, K-SADS-PL, YGTSS, KIDSCREEN, GTS QOL, CGI and C-GAS. All these evaluations but the K-SADS-PL were used for baseline assessment but also one week after the end of treatment (T1) and then 3, 6 and 9 months later (respectively T2, T3, and T4). RESULTS: The sample was largely composed of patients of relevant clinical severity (CGI>=3: 85%). OCD and ADHD were the most frequent comorbidities (30% each). Only minor differences in terms of treatment effectiveness were found, although the HRT group turned out to include patients with more tics and a more compromised general functioning despite randomization. CONCLUSIONS: We had a high number of patients who refused to be randomized (23 out of 69) and a high number of drop outs (27% in the HRT group, 50% in the UC group). There was an improvement in terms of reduced tics and improved global functioning in both groups, without significant changes in terms of Quality of Life. PMID- 26583456 TI - Comparison of neurally-adjusted ventilator assist in infants before and after extubation. AB - BACKGROUND: To compare invasive (iNAVA) and non-invasive (nivNAVA) neurally adjusted ventilatory assist in infants, respect to gas exchange, breathing pattern, respiratory drive, infant-ventilator interaction and synchrony, vital parameters and required sedation. METHODS: Ten consecutive intubated term infants admitted for respiratory failure of different etiology underwent to 2-hour not randomized trials of iNAVA and, after extubation, nivNAVA, the latter with unchanged ventilator settings and with air-leaks compensating software. Arterialized capillary blood was sampled at the end of each trial. We computed: 1) the minimum (EAdimin) and peak (EAdipeak) values of the diaphragm electrical activity; 2) ventilator (RRmec) and own patients' (RRneu) respiratory rates; 3) inspiratory (delayTR-insp) and expiratory trigger delays (delayTR-exp) and the time of synchrony between patient's effort and ventilator assistance (Timesynch/Tineu); 4) the asynchrony index. Vital parameters and required sedation were also recorded. RESULTS: iNAVA and nivNAVA did not differ between in terms of gas exchange (pH (7.35 [7.31-7.41] vs. 7.36 [7.30-7.40], P=0.745), PcCO2 (38.4 [34.8-42.6] vs. 36.9 [33.9-41.6] mmHg, P=0.469) and PcO2/FiO2 (211 [168 323] vs. 214 [189-282], P=0.195), respectively). EAdimin, EAdipeak, RRmec and RRneu were similar before and after extubation. Both modes confirmed an optimal infant-ventilator interaction (i.e. delayTR-insp, delayTR-exp and Timesynch/Tineu), irrespective of the interface, and no patients showed clinical relevant asynchronies. A low requirement of sedation with fentanyl was recorded during both trials, without differences between. CONCLUSIONS: We found iNAVA and nivNAVA to be characterized by similar gas exchange, breathing pattern, respiratory drive, infant-ventilator interaction and synchrony, vital parameters and required sedation. PMID- 26583457 TI - Assessing sexual trauma histories in homeless women. AB - Almost 1 out of every 3 homeless women (32%) in the United States, United Kingdom, and Australia has experienced childhood sexual trauma. We assessed lifetime sexual trauma histories among 29 homeless women from three Southern California community sites: one residential safe house and two safe parking areas. More than half of the women (54%) reported a history of sexual trauma. That rate was higher (86%) among women living at the safe home than among women staying at the safe parking sites (only 42%). All four of the women who had served in the military reported having experienced military sexual trauma. The high percentages of sexual trauma found in homeless women highlight the need for effective interventions for sexual trauma. PMID- 26583458 TI - Staff lens doses in interventional urology. A comparison with interventional radiology, cardiology and vascular surgery values. AB - The purpose of this work is to evaluate radiation doses to the lens of urologists during interventional procedures and to compare them with values measured during interventional radiology, cardiology and vascular surgery. The measurements were carried out in a surgical theatre using a mobile C-arm system and electronic occupational dosimeters (worn over the lead apron). Patient and staff dose measurements were collected in a sample of 34 urology interventions (nephrolithotomies). The same dosimetry system was used in other medical specialties for comparison purposes. Median and 3rd quartile values for urology procedures were: patient doses 30 and 40 Gy cm(2); personal dose equivalent Hp(10) over the apron (MUSv/procedure): 393 and 848 (for urologists); 21 and 39 (for nurses). Median values of over apron dose per procedure for urologists resulted 18.7 times higher than those measured for radiologists and cardiologists working with proper protection (using ceiling suspended screens) in catheterisation laboratories, and 4.2 times higher than the values measured for vascular surgeons at the same hospital. Comparison with passive dosimeters worn near the eyes suggests that dosimeters worn over the apron could be a reasonable conservative estimate for ocular doses for interventional urology. Authors recommend that at least the main surgeon uses protective eyewear during interventional urology procedures. PMID- 26583459 TI - An epidemiological study of neuropathic pain symptoms in Canadian adults. PMID- 26583460 TI - Comparison of transcutaneus electrical nerve stimulation and parasternal block for postoperative pain management after cardiac surgery. PMID- 26583461 TI - Research priorities in the field of post-traumatic pain and disability: Results of a transdisciplinary consensus-generating workshop. PMID- 26583462 TI - Facial expression overrules lumbopelvic kinematics for clinical judgements regarding low back pain intensity. PMID- 26583464 TI - The need for improved management of painful diabetic neuropathy in primary care. PMID- 26583463 TI - Prevention of opioid misuse: A summary with suggestions from a Pain Working Group. PMID- 26583465 TI - Alternative Routes of Zoonotic Vaccinia Virus Transmission, Brazil. PMID- 26583466 TI - Polyphosphazenes for the Stille reaction: a new type of recyclable stannyl reagent. AB - A random phosphazene copolymer {[N = P((CH2)7-Br)Ph]0.5[N = PMePh]0.5}n (2) and a block copolyphosphazene {[N = P((CH2)7-Br)Ph]0.5[N = PMePh]0.5}45-b-[N = P(O2C12H8)]55 (5), having a branch with two randomly distributed units, have been synthesized and used as precursors for the stannyl derivatives {[N = P((CH2)7 SnBu2An)Ph]0.5[N = PMePh]0.5}n (3) and {[N = P((CH2)7-SnBu2An)Ph]0.5[N = PMePh]0.5}45-b-[N = P(O2C12H8)]55 (6, An = p-MeOC6H4). Polymers 3 and 6 were tested as recyclable tin reagents in the Stille cross-coupling reaction with ArI, using various Pd catalysts and different experimental conditions. Polymer 6 can be recycled without a significant release of tin, but its efficiency decreased after three consecutive cycles. This effect was explained by studying the self assembly of the polymer under the same conditions used for the catalytic experiments, which evidenced the progressive coalescence of the polymeric vesicles (polymersomes) leading to stable and bigger core-shell aggregates by the attraction of the [N = P(O2C12H8)] rich membranes, thus decreasing the accessibility of the tin active centers. PMID- 26583467 TI - Quantifying Progressive Anterior Overgrowth in the Thoracic Vertebrae of Adolescent Idiopathic Scoliosis Patients: A Sequential Magnetic Resonance Imaging Study. AB - STUDY DESIGN: Anterior and posterior vertebral body heights were measured from sequential magnetic resonance imaging (MRI) scans of adolescent idiopathic scoliosis (AIS) patients and healthy controls. OBJECTIVE: To measure changes in vertebral body height over time during scoliosis progression to assess how vertebral body height discrepancies change during growth. SUMMARY OF BACKGROUND DATA: Relative anterior overgrowth has been proposed as a potential driver for AIS initiation and progression. This theory proposes that the anterior column grows faster, and the posterior column slower, in AIS patients when compared with healthy controls. There is a disagreement in the literature as to whether the anterior vertebral body heights are proportionally greater than posterior vertebral body heights in AIS patients when compared with healthy controls. To some extent, these discrepancies may be attributed to methodological differences. METHODS: MRI scans of the major curve of 21 AIS patients (mean age 12.5 +/- 1.4 years, mean Cobb 32.2 +/- 12.8 degrees) and between T4 and T12 of 21 healthy adolescents (mean age 12.1 +/- 0.5 years) were captured for this study. Of the 21 AIS patients, 14 had a second scan on average 10.8 +/- 4.7 months after the first. Anterior and posterior vertebral body heights were measured from the true sagittal plane of each vertebra such that anterior overgrowth could be quantified. RESULTS: The difference between anterior and posterior vertebral body height in healthy, nonscoliotic children was significantly greater than in AIS patients with mild to moderate scoliosis. There was; however, no significant relationship between the overall anterior-posterior vertebral body height difference in AIS and either severity of the curve or its progression over time. CONCLUSION: Whilst AIS patients have a proportionally longer anterior column than nonscoliotic controls, the degree of anterior overgrowth was not related to the rate of progression or the severity of the scoliotic curve. LEVEL OF EVIDENCE: 3. PMID- 26583468 TI - The Study of Cobb Angular Velocity in Cervical Spine during Dynamic Extension Flexion. AB - STUDY DESIGN: A kinematic study of cervical spine. OBJECTIVE: The aim of the study was to confirm the interesting manifestation observed in the dynamic images of the cervical spine movement from full-extension to full-flexion. To further explore the fine motion of total process of cervical spine movement with the new concept of Cobb angular velocity (CAV). SUMMARY OF BACKGROUND DATA: Traditionally range of motion (ROM) is used to describe the cervical spine movement from extension to flexion. It is performed with only end position radiographs. However, these radiographs fail to explain how the elaborate movement happens. METHODS: The dynamic images of the cervical spine movement from full-extension to full-flexion of 12 asymptomatic subjects were collected. After transforming these dynamic images to static lateral radiographs, we overlapped C7 cervical vertebrae of each subject and divided the total process of cervical spine movement into five equal partitions. Finally, CAV values from C2/3 to C6/7 were measured and analyzed. RESULTS: A broken line graph was created based on the data of CAV values. A simple motion process was observed in C2/3 and C3/4 segments. The motion processes of C4/5 and C5/6 segments exhibited a more complex track of "N" and "W" than the other segments. The peak CAV values of C4/5 and C5/6 were significantly greater than the other segments. From C2/3 to C6/7, the peak CAV value appeared in sequence. CONCLUSION: The intervertebral movements of cervical spine did not take a uniform motion form when the cervical spine moved from full extension to full-flexion. From C2/3 to C6/7, the peak CAV value appeared in order. The C4/5 and C5/6 segments exhibited more complex kinematic characteristics in sagittal movement. This leads to C4/5 and C5/6 more vulnerable to injury and degeneration. We had a hypothesis that there was a positive correlation between injury/degeneration and complexity of intervertebral movement in the view of CAV. LEVEL OF EVIDENCE: N/A. PMID- 26583469 TI - Relationship Between T1 Slope and Cervical Alignment Following Multilevel Posterior Cervical Fusion Surgery: Impact of T1 Slope Minus Cervical Lordosis. AB - STUDY DESIGN: Retrospective study. OBJECTIVE: To assess the relationship between sagittal alignment of the cervical spine and patient-reported health-related quality-of-life scores following multilevel posterior cervical fusion, and to explore whether an analogous relationship exists in the cervical spine using T1 slope minus C2-C7 lordosis (T1S-CL). SUMMARY OF BACKGROUND DATA: A recent study demonstrated that, similar to the thoracolumbar spine, the severity of disability increases with sagittal malalignment following cervical reconstruction surgery. METHODS: From 2007 to 2013, 38 consecutive patients underwent multilevel posterior cervical fusion for cervical stenosis, myelopathy, and deformities. Radiographic measurements included C0-C2 lordosis, C2-C7 lordosis, C2-C7 sagittal vertical axis (SVA), T1 slope, and T1S-CL. Pearson correlation coefficients were calculated between pairs of radiographic measures and health-related quality-of life. RESULTS: C2-C7 SVA positively correlated with neck disability index (NDI) scores (r = 0.495). C2-C7 lordosis (P = 0.001) and T1S-CL (P = 0.002) changes correlated with NDI score changes after surgery. For significant correlations between C2-C7 SVA and NDI scores, regression models predicted a threshold C2-C7 SVA value of 50 mm, beyond which correlations were most significant. The T1S-CL also correlated positively with C2-C7 SVA and NDI scores (r = 0.871 and r = 0.470, respectively). Results of the regression analysis indicated that a C2-C7 SVA value of 50 mm corresponded to a T1S-CL value of 26.1 degrees . CONCLUSION: This study showed that disability of the neck increased with cervical sagittal malalignment following surgical reconstruction and a greater T1S-CL mismatch was associated with a greater degree of cervical malalignment. Specifically, a mismatch greater than 26.1 degrees corresponded to positive cervical sagittal malalignment, defined as C2-C7 SVA greater than 50 mm. LEVEL OF EVIDENCE: 3. PMID- 26583470 TI - Duplex Ultrasonography-Detected Positional Vertebral Artery Occlusion in Upper Cervical Rheumatoid Arthritis. AB - STUDY DESIGN: Prospective imaging study. OBJECTIVE: To clarify the frequency of positional vertebral artery (VA) occlusion using duplex ultrasonography in patients with rheumatoid arthritis (RA). SUMMARY OF BACKGROUND DATA: Some patients with upper cervical RA develop thromboembolic stroke related to positional and transient VA occlusions; however, whether RA patients have positional VA occlusion without neurological symptoms is unclear. METHODS: Outpatients with RA were enrolled. Clinical data were collected, and radiograph examinations were performed to measure the anterior atlantodental interval (AADI), the posterior atlantodental interval (PADI), and the Ranawat method. Patients underwent duplex ultrasonography during rotation to the contralateral side of the examination side, flexion, and extension of their neck. If positional VA occlusion was detected, CT angiography was conducted in the neutral position and in the same position that showed VA occlusion on duplex ultrasonography. Clinical and radiological data were compared between the VA occlusion (VAO) group and the non-VAO group. Sensitivity-specificity curve analyses were performed to clarify optimal threshold values of AADI, PADI, and the Ranawat method for predicting positional VA occlusion. RESULTS: Of the 132 RA patients, dynamic duplex ultrasonography showed positional VA occlusion in eight (6%) patients. Patients in the VAO group had a greater AADI (median, 7.4 vs. 2.3 mm; P < 0.001), a shorter PADI (median, 13.7 vs. 19.6 mm; P = 0.002), and a lower Ranawat value (median, 13.7 vs. 16.8 mm; P = 0.006) than those in the non-VAO group. Cut-off values of AADI, PADI, and the Ranawat method for predicting positional VA occlusion were 6.5, 14.0, and 15.5 mm, respectively. CONCLUSION: A subset of RA patients developed positional VA occlusion associated with cervical spine involvement. PMID- 26583471 TI - Elevation of Microglial Basic Fibroblast Growth Factor Contributes to Development of Neuropathic Pain after Spinal Nerve Ligation in Rats. AB - STUDY DESIGN: Reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistological analysis of spinal cord and pain behavior analysis in a rat neuropathic pain model were conducted to examine the function of microglial basic fibroblast growth factor (bFGF) in the development of neuropathic pain. OBJECTIVE: To investigate the role of bFGF in spinal microglia during the development of allodynia following spinal nerve ligation in rats. SUMMARY OF BACKGROUND DATA: Evidence suggests that the production of bFGF by spinal cord glial cells is increased in response to peripheral nerve injury. Although an association between bFGF and astrocytes has been widely reported, the relationship between bFGF and microglia, particularly with respect to the development of neuropathic pain, remains poorly understood. METHODS: Spinal nerve ligation rats were used. After surgery, bFGF expression in the spinal cord was investigated using RT-PCR and immunohistochemistry. Neutralizing antibodies to bFGF were injected intrathecally into rats after spinal nerve ligaton. Spinal cords were used for RT-PCR analysis and pain behavior was analyzed using the von Frey test. RESULTS: bFGF mRNA expression was significantly increased in the spinal cord 6 hours after spinal nerve ligation compared with untreated rats. Immunohistochemical analysis revealed that bFGF co-localized with ionized calcium binding adaptor molecule 1, a microglial marker, and myeloperoxidase. Neutralizing antibodies to bFGF attenuated mechanical allodynia and myeloperoxidase mRNA expression. CONCLUSION: bFGF increased in spinal microglia during the development allodynia after spinal nerve ligation. Thus, controlling bFGF release from microglia during the acute stage of peripheral nerve injury may suppress the progression of allodynia. LEVEL OF EVIDENCE: N/A. PMID- 26583472 TI - Glycosaminoglycan Chemical Exchange Saturation Transfer of Lumbar Intervertebral Discs in Healthy Volunteers. AB - STUDY DESIGN: Evaluation of a new quantitative imaging technique in a prospective study design. OBJECTIVE: To assess glycosaminoglycan (GAG) content of lumbar intervertebral discs (IVDs) in healthy volunteers with chemical exchange saturation transfer (CEST). SUMMARY OF BACKGROUND DATA: Biochemical alterations of lumbar discs are present before the appearance of morphological changes. GAG loss plays a central role in these degenerative processes. METHODS: Lumbar intervertebral discs of healthy controls (26 women, 22 men; mean age 31 +/- 8 years; range: 21-49 years) without lumbar back pain were examined at a 3 Tesla magnetic resonance imaging (MRI) scanner in this prospective study. None of the participants were overweight or had previous surgery of the lumbar spine. The MRI protocol included standard morphological, sagittal and transversal T2-weighted (T2w) images to assess Pfirrmann score and to detect disc disorders according to the Combined Task Force classification of five lumbar IVDs (L1 to S1). A prototype glycosaminoglycan chemical exchange saturation transfer (gagCEST) sequence was applied to measure GAG content of the nucleus pulposus (NP) and annulus fibrosus (AF) by identifying the magnetization transfer asymmetry ratio (MTRasym) in a region-of-interest analysis. Morphological and biochemical imaging analysis were statistically tested for quantitative differences between different grades of IVD degeneration and disc disorders. RESULTS: gagCEST values of NP demonstrated a significant negative correlation with morphological Pfirrmann score (r = -0.562; P < 0.0001). The MTRasym values were higher in non degenerative lumbar IVDs (Pfirrmann 1-2) compared with degenerative lumbar discs (Pfirrmann 3-5; 2.92% +/- 1.42% vs. 0.78% +/- 1.38%; P < 0.0001). The MTRasym values of NP were significantly higher in normal appearing discs compared with herniated IVDs (2.83% +/- 1.52% vs. 1.55% +/- 1.61%; P < 0.0001). We found a significant negative correlation between gagCEST values and the graduation of disc herniation (r = -0.372; P < 0.0001). CONCLUSION: Biochemical imaging with gagCEST distinguished morphologically degenerative from non-degenerative lumbar IVDs (in NP and AF) of healthy volunteers at a clinical 3T-MRI system. The depletion of GAG content in degenerative lumbar discs correlated significantly with the morphological disc classification. We could demonstrate that disc disorders, such as protrusion and extrusion, were accompanied by lower GAG content. LEVEL OF EVIDENCE: 2. PMID- 26583473 TI - Downregulation of miR-27b is Involved in Loss of Type II Collagen by Directly Targeting Matrix Metalloproteinase 13 (MMP13) in Human Intervertebral Disc Degeneration. AB - STUDY DESIGN: A microRNA (miRNA) study. OBJECTIVE: The purpose of this study was to identify intervertebral disc degeneration (IDD)-specific miRNAs, followed by functional validation of results. SUMMARY OF BACKGROUND DATA: IDD is the major contributor to back radicular pain, and the molecular mechanisms underlying this disease are not completely understood. Accumulating evidence suggests that miRNAs play an important role in IDD, but the role of specific miRNAs involved in this disease remains elusive. METHODS: An initial screening of nucleus pulposus (NP) tissues, miRNA expression by miRNA microarray, was performed using samples from 10 patients with degenerative disc disease and 10 patients with lumbar fracture (as controls). Subsequently, differential expression was validated using quantitative reverse transcriptase PCR (qRT-PCR). The level of differentially expressed miRNAs in degenerative NP tissues was investigated, and then functional analysis of the miRNAs in regulating collagen II expression was carried out. Western blotting and luciferase reporter assays were also used to detect the target gene. RESULTS: We identified 23 miRNAs that were differentially expressed (16 upregulated and 7 downregulated) in patients compared with controls. After qRT-PCR confirmation, miR-27b was significantly downregulated in degenerative NP tissues when compared with controls. Moreover, its level was correlated with grade of disc degeneration. Overexpression of miR-27b promoted type II collagen expression in NP cells. Bioinformatics target prediction identified matrix metalloproteinase 13 (MMP13) as a putative target of miR-27b. Futhermore, luciferase reporter assays demonstrated that miR-27b directly targets MMP13 and affects the protein expression of MMP13 in NP cells. Expression of MMP13 negatively correlated with miR-27b expression in degenerative NP tissues. CONCLUSION: The downregulation of miR-27b induces type II collagen loss by directly targeting MMP13, leading to the development of IDD. Our study also underscores the potential of miR-27b as a novel therapeutic target in human IDD. LEVEL OF EVIDENCE: 3. PMID- 26583474 TI - Advantages of Direct Insertion of a Straight Probe Without a Guide Tube During Anterior Odontoid Screw Fixation of Odontoid Fractures. AB - STUDY DESIGN: A retrospective cohort study. OBJECTIVE: The aim of this study was to compare the anterior odontoid screw fixation (AOSF) with a guide tube or with a straight probe. SUMMARY OF BACKGROUND DATA: AOSF associates with several complications, including malpositioning, fixation loss, and screw breakage. Screw pull-out from the C2 body is the most common complication. METHODS: All consecutive patients with type II or rostral shallow type III odontoid fractures who underwent AOSFs during the study period were enrolled retrospectively. The guide-tube AOSF method followed the standard published method except C3 body and C2-3 disc annulus rimming was omitted to prevent disc injury; instead, the guide tube was anchored at the anterior inferior C2 vertebra corner. After 2 screw pull outs, the guide-tube cohort was analyzed to identify the cause of instrument failure. Thereafter, the straight-probe method was developed. A guide tube was not used. A small pilot hole was made on the most anterior side of the inferior endplate, followed by insertion of a 2.5 mm straight probe through the C2 body. Non-union and instrument failure rates and screw-direction angles of the guide tube and straight-probe groups were recorded. RESULTS: The guide-tube group (n = 13) had 2 screw pull-outs and 1 non-union. The straight-probe group (n = 8) had no complications and significantly larger screw-direction angles than the guide tube group (60.5 +/- 4.63 vs. 54.8 +/- 3.82 degrees; P = 0.047). CONCLUSION: Straight-probe AOSF yielded larger direction angles without injuring bone and disc. Complications were absent. The procedure was easier than guide-tube AOSF and assured sufficient engagement, even in horizontal fracture orientation cases. LEVEL OF EVIDENCE: 3. PMID- 26583475 TI - Surgical Treatment Assessment of Cervical Laminoplasty Using Quantitative Performance Evaluation in Elderly Patients: A Prospective Comparative Study in 505 Patients With Cervical Spondylotic Myelopathy. AB - STUDY DESIGN: A prospective cohort study. OBJECTIVE: The purpose of this study was to compare surgical outcomes between non-elderly and elderly patients with cervical spondylotic myelopathy (CSM) who underwent laminoplasty. SUMMARY OF BACKGROUND DATA: Since age at the time of surgery influences the surgical outcome, we designed a large-scale cohort study to examine the surgical outcome for CSM from a single operative procedure used exclusively in elderly patients. METHODS: A total of 505 consecutive patients with CSM (311 men; 194 women) were prospectively enrolled. The mean age was 66.6 years (range, 41-91), and the average postoperative follow-up period was 26.5 +/- 12.5 months. Patients were divided into three groups according to age: non-elderly (<65 yr, n = 201), young old (65-74 yr, n = 186), and old-old (>=75 yr, n = 118). Pre- and postoperative neurological status was evaluated using the Japanese Orthopaedic Association scoring system for cervical myelopathy (JOA score) and quantifiable tests-the 10 s grip and release test (10-s G&R test) and the 10-s step test. RESULTS: Mean achieved JOA scores in non-elderly, young-old, and old-old groups were 3.1, 3.2, and 3.0, respectively, with no significant difference among three groups (P = 0.5735). Mean preoperative 10-s G&R test results were 17.3, 14.4, and 13.0, respectively, indicating a significant decrease with increasing age, whereas postoperative results significantly improved in all groups (21.0, 17.9, and 16.3, respectively). Similarly, the 10-s step test significantly decreased with age, with preoperative scores of 14.3, 11.5, and 8.6, respectively, whereas postoperative scores improved to 17.3, 14.9, and 12.5, respectively. The three groups showed no significant difference in the rate of postoperative complications. CONCLUSION: Elderly patients adequately recovered from laminoplasty in terms of achieved JOA score, the 10-s G&R test, and the 10-s step test. Therefore, laminoplasty for CSM is beneficial in elderly patients. LEVEL OF EVIDENCE: 2. PMID- 26583476 TI - The Impact of Small Spinal Curves in Adolescents Who Have Not Presented to Secondary Care: A Population-Based Cohort Study. AB - STUDY DESIGN: A prospective, population-based, birth cohort study. OBJECTIVE: The aim of this study was to identify whether there is any hidden burden of disease associated with smaller spinal curves. SUMMARY OF BACKGROUND DATA: Adolescent idiopathic scoliosis is present in 3% to 5% of the general population. Large curves are associated with increased pain and reduced quality of life. However, no information is available on the impact of smaller curves, many of which do not reach secondary care. METHODS: The Avon Longitudinal Study of Parents and Children (ALSPAC) recruited over 14,000 pregnant women from the Bristol area of South-West England between 1991 and 1992 and has followed up their offspring regularly. At age 15, presence or absence of spinal curvature >=6 degrees in the offspring was identified using the validated dual-energy X-ray absorptiometry Scoliosis Measure on 5299 participants. At age 18, a structured pain questionnaire was administered to 4083 participants. Logistic regression was used to investigate any association between presence of a spinal curve at age 15 and self-reported outcomes at age 18 years. RESULTS: Full data were available for 3184 participants. Two hundred two (6.3%) had a spinal curve >=6 degrees and 125 (3.9%) had a curve >=10 degrees (median curve size of 11 degrees). About 46.3% reported aches and pains that lasted for a day or longer in the previous month. About 16.3% reported back pain. Those with spinal curves were 42% more likely to report back pain than those without (odds ratio 1.42, 95% confidence interval 1.00-2.02, P = 0.047). Those with spinal curves had more days off school and were more likely to avoid activities that caused their pain. CONCLUSION: Our results highlight that small scoliotic curves may be less benign than previously thought. Teenagers with small curves may not present to secondary care, but are nonetheless reporting increased pain, more days off school, and avoidance of activities. These data suggest that we should reconsider current scoliosis screening and treatment practices. LEVEL OF EVIDENCE: 2. PMID- 26583477 TI - Anatomical Origin of Abnormal Somatosensory-Evoked Potential (SEP) in Adolescent Idiopathic Scoliosis With Different Curve Severity and Correlation With Cerebellar Tonsillar Level Determined by MRI. AB - STUDY DESIGN: A prospective cohort study. OBJECTIVE: The aim of this study was to compare the somatosensory-evoked potential (SEP) findings of adolescent idiopathic scoliosis (AIS) subjects of different curve severity with age- and gender-matched controls and to evaluate any correlation between the site of the SEP abnormality with cerebellar tonsillar level measured by magnetic resonance imaging (MRI). SUMMARY OF BACKGROUND DATA: Our previous studies showed that a higher percentage of SEP abnormality and cerebellar tonsillar ectopia was present in AIS patients than in normal controls. However, the relationship between the anatomical site of the neurophysiological abnormality and the severity in AIS patients has not been defined. METHODS: SEP measurement was conducted on 91 Chinese AIS girls with major right thoracic curve of different curve severity (mild, moderate, severe) and 49 matched normal controls. Waveform characteristics (latency and amplitude) were compared among groups. Specific location of SEP abnormality was identified from tibial to cortical levels. Cerebellar tonsillar ectopia was defined by the previously established reference line between basion and opisthion on MRI. RESULTS: Significant prolonged P37 latency was found on the right side between severe AIS patients and normal controls, while increased inter side P37 latency difference was found between severe versus moderate, and severe versus normal controls. Cerebellar tonsillar ectopia was detected in 27.3% of severe group, 5.8% to 6.7% in mild and moderate group, but none in normal controls. Abnormal SEP occurred superior to C5 region in all surgical (severe) patients, of whom 58% had cerebellar tonsillar ectopia. CONCLUSION: AIS patients showed significant prolonged latency and increased latency difference on the side of major curvature. The incidence of SEP abnormality increased with curve severity and occurred above the C5 level. The findings suggested that there was a subgroup of progressive AIS with subclinical neurophysiological dysfunction, associated with underlying neuromorphological abnormalities, which were only detectable by SEP and MRI. LEVEL OF EVIDENCE: 3. PMID- 26583478 TI - Generic Preference-based Measures for Low Back Pain: Which of Them Should Be Used? AB - STUDY DESIGN: Systematic review. OBJECTIVE: This systematic review examines validity and responsiveness of three generic preference-based measures in patients with low back pain (LBP). SUMMARY OF BACKGROUND DATA: LBP is a very common incapacitating disease with a significant impact on health-related quality of life (HRQoL). Health state utility values can be derived from various preference-based HRQoL instruments, and among them the most widely ones are EuroQol 5 dimensions (EQ-5D), Short Form 6 Dimensions (SF-6D), and Health Utilities Index 3 (HUI III). The ability of these instruments to reflect HRQoL has been tested in various contexts, but never for LBP populations. METHODS: A systematic search on electronic literature databases was undertaken to identify studies of patients with LBP where health state utility values were reported. Records were screened using a set of predefined eligibility criteria. Data on validity (correlations and known group methods) and responsiveness (effect sizes, standardized response means, tests of statistical significance) of instruments were extracted using a customized extraction template, and assessed using predefined criteria. RESULTS: There were substantial variations in the 37 included papers identified in relation to study design and outcome measures used. EQ-5D demonstrated good convergent validity, as it was able to distinguish between known groups. EQ-5D was also able to capture changes of health states as results of different interventions. Evidence for SF-6D and HUI III was limited to allow an appropriate evaluation. CONCLUSION: EQ-5D performs well in LBP population and its scores seem to be suitable for economic evaluation of LBP interventions. However, the paucity of information on the other instruments makes it impossible to determine its relative validity and responsiveness compared with them. PMID- 26583479 TI - An "Industrial Revolution" in Health Care: The Data Tell Us the Time Has Come. PMID- 26583481 TI - Within- and Across-Subject Variability of Repeated Measurements of Medial Olivocochlear-Induced Changes in Transient-Evoked Otoacoustic Emissions. AB - OBJECTIVES: Measurement of changes in transient-evoked otoacoustic emissions (TEOAEs) caused by activation of the medial olivocochlear reflex (MOCR) may have clinical applications, but the clinical utility is dependent in part on the amount of variability across repeated measurements. The purpose of this study was to investigate the within- and across-subject variability of these measurements in a research setting as a step toward determining the potential clinical feasibility of TEOAE-based MOCR measurements. DESIGN: In 24 normal-hearing young adults, TEOAEs were elicited with 35 dB SL clicks and the MOCR was activated by 35 dB SL broadband noise presented contralaterally. Across a 5-week span, changes in both TEOAE amplitude and phase evoked by MOCR activation (MOC shifts) were measured at four sessions, each consisting of four independent measurements. Efforts were undertaken to reduce the effect of potential confounds, including slow drifts in TEOAE amplitude across time, activation of the middle-ear muscle reflex, and changes in subjects' attentional states. MOC shifts were analyzed in seven 1/6-octave bands from 1 to 2 kHz. The variability of MOC shifts was analyzed at the frequency band yielding the largest and most stable MOC shift at the first session. Within-subject variability was quantified by the size of the standard deviations across all 16 measurements. Across-subject variability was quantified as the range of MOC shift values across subjects and was also described qualitatively through visual analyses of the data. RESULTS: A large majority of MOC shifts in subjects were statistically significant. Most subjects showed stable MOC shifts across time, as evidenced by small standard deviations and by visual clustering of their data. However, some subjects showed within- and across-session variability that could not be explained by changes in hearing status, middle ear status, or attentional state. Simulations indicated that four baseline measurements were sufficient to predict the expected variability of subsequent measurements. However, the measured variability of subsequent MOC shifts in subjects was often larger than expected (based on the variability present at baseline), indicating the presence of additional variability at subsequent sessions. CONCLUSIONS: Results indicated that a wide range of within- and across-subject variability of MOC shifts was present in a group of young normal-hearing individuals. In some cases, very large changes in MOC shifts (e.g., 1.5 to 2 dB) would need to occur before one could attribute the change to either an intervention or pathology, rather than to measurement variability. It appears that MOC shifts, as analyzed in the present study, may be too variable for clinical use, at least in some individuals. Further study is needed to determine the extent to which changes in MOC shifts can be reliably measured across time for clinical purposes. PMID- 26583480 TI - Qualities of Single Electrode Stimulation as a Function of Rate and Place of Stimulation with a Cochlear Implant. AB - OBJECTIVES: Although it has been shown previously that changes in temporal coding produce changes in pitch in all cochlear regions, research has suggested that temporal coding might be best encoded in relatively apical locations. The authors hypothesized that although temporal coding may provide useable information at any cochlear location, low rates of stimulation might provide better sound quality in apical regions that are more likely to encode temporal information in the normal ear. In the present study, sound qualities of single electrode pulse trains were scaled to provide insight into the combined effects of cochlear location and stimulation rate on sound quality. DESIGN: Ten long-term users of MED-EL cochlear implants with 31-mm electrode arrays (Standard or FLEX) were asked to scale the sound quality of single electrode pulse trains in terms of how "Clean," "Noisy," "High," and "Annoying" they sounded. Pulse trains were presented on most electrodes between 1 and 12 representing the entire range of the long electrode array at stimulation rates of 100, 150, 200, 400, or 1500 pulses per second. RESULTS: Although high rates of stimulation are scaled as having a Clean sound quality across the entire array, only the most apical electrodes (typically 1 through 3) were considered Clean at low rates. Low rates on electrodes 6 through 12 were not rated as Clean, whereas the low-rate quality of electrodes 4 and 5 were typically in between. Scaling of Noisy responses provided an approximately inverse pattern as Clean responses. High responses show the trade-off between rate and place of stimulation on pitch. Because High responses did not correlate with Clean responses, subjects were not rating sound quality based on pitch. CONCLUSIONS: If explicit temporal coding is to be provided in a cochlear implant, it is likely to sound better when provided apically. In addition, the finding that low rates sound clean only at apical places of stimulation is consistent with previous findings that a change in rate of stimulation corresponds to an equivalent change in perceived pitch at apical locations. Collectively, the data strongly suggest that temporal coding with a cochlear implant is optimally provided by electrodes placed well into the second cochlear turn. PMID- 26583482 TI - Human Frequency Following Response: Neural Representation of Envelope and Temporal Fine Structure in Listeners with Normal Hearing and Sensorineural Hearing Loss. AB - OBJECTIVE: Listeners with sensorineural hearing loss (SNHL) typically experience reduced speech perception, which is not completely restored with amplification. This likely occurs because cochlear damage, in addition to elevating audiometric thresholds, alters the neural representation of speech transmitted to higher centers along the auditory neuroaxis. While the deleterious effects of SNHL on speech perception in humans have been well-documented using behavioral paradigms, our understanding of the neural correlates underlying these perceptual deficits remains limited. Using the scalp-recorded frequency following response (FFR), the authors examine the effects of SNHL and aging on subcortical neural representation of acoustic features important for pitch and speech perception, namely the periodicity envelope (F0) and temporal fine structure (TFS; formant structure), as reflected in the phase-locked neural activity generating the FFR. DESIGN: FFRs were obtained from 10 listeners with normal hearing (NH) and 9 listeners with mild-moderate SNHL in response to a steady-state English back vowel /u/ presented at multiple intensity levels. Use of multiple presentation levels facilitated comparisons at equal sound pressure level (SPL) and equal sensation level. In a second follow-up experiment to address the effect of age on envelope and TFS representation, FFRs were obtained from 25 NH and 19 listeners with mild to moderately severe SNHL to the same vowel stimulus presented at 80 dB SPL. Temporal waveforms, Fast Fourier Transform and spectrograms were used to evaluate the magnitude of the phase-locked activity at F0 (periodicity envelope) and F1 (TFS). RESULTS: Neural representation of both envelope (F0) and TFS (F1) at equal SPLs was stronger in NH listeners compared with listeners with SNHL. Also, comparison of neural representation of F0 and F1 across stimulus levels expressed in SPL and sensation level (accounting for audibility) revealed that level-related changes in F0 and F1 magnitude were different for listeners with SNHL compared with listeners with NH. Furthermore, the degradation in subcortical neural representation was observed to persist in listeners with SNHL even when the effects of age were controlled for. CONCLUSIONS: Overall, our results suggest a relatively greater degradation in the neural representation of TFS compared with periodicity envelope in individuals with SNHL. This degraded neural representation of TFS in SNHL, as reflected in the brainstem FFR, may reflect a disruption in the temporal pattern of phase-locked neural activity arising from altered tonotopic maps and/or wider filters causing poor frequency selectivity in these listeners. Finally, while preliminary results indicate that the deleterious effects of SNHL may be greater than age-related degradation in subcortical neural representation, the lack of a balanced age-matched control group in this study does not permit us to completely rule out the effects of age on subcortical neural representation. PMID- 26583483 TI - Durability of Infliximab Is Associated With Disease Extent in Children With Inflammatory Bowel Disease. AB - OBJECTIVES: The aim of the study was to evaluate infliximab (IFX) dosing and treatment durability relative to luminal disease burden in patients with inflammatory bowel disease. METHODS: Records from 98 pediatric patients treated with IFX between 2012 and 2014 were reviewed. Disease extent was classified as "limited," "moderate," or "extensive" based on cumulative assessment of mucosal involvement. Patients started taking standard 5 mg/kg dosing were compared with those initiated taking 10 mg/kg with regard to treatment durability. RESULTS: Overall, 26.4%, 58.3%, and 70% with limited, moderate, or extensive disease, respectively, started taking a standard IFX dose of 5 mg/kg required therapy escalation. Patients with moderate and extensive disease, started taking the 5 mg/kg per dose, showed statistically significant shorter times to escalation than those with limited disease. The percentage of patients remaining on their initial 5 mg/kg per dose at 12 months was 80.1%, 56.9%, and 40.0% for limited, moderate, and extensive disease, respectively. Among patients started taking 10 mg/kg, 100% remained on this dose. All the patients with limited disease who required dose escalation continued on the higher dose at the time of analysis; however, among those with the most extensive disease, 43% failed escalation because of nonresponse or infusion reaction. CONCLUSIONS: Patients with extensive disease started taking 5 mg/kg of IFX were more likely to require dose escalation compared to those with limited or moderate disease. All of the patients with moderate and extensive disease started taking 10 mg/kg of IFX remained on this dose. These results suggest that patients with more extensive disease may benefit from higher initial IFX dosing as it relates to durability of the treatment. PMID- 26583484 TI - Fe-D Up: Ending Iron and Vitamin D Deficiency in Toddlers. PMID- 26583485 TI - Tap dancing birds: the multimodal mutual courtship display of males and females in a socially monogamous songbird. AB - According to classical sexual selection theory, complex multimodal courtship displays have evolved in males through female choice. While it is well-known that socially monogamous songbird males sing to attract females, we report here the first example of a multimodal dance display that is not a uniquely male trait in these birds. In the blue-capped cordon-bleu (Uraeginthus cyanocephalus), a socially monogamous songbird, both sexes perform courtship displays that are characterised by singing and simultaneous visual displays. By recording these displays with a high-speed video camera, we discovered that in addition to bobbing, their visual courtship display includes quite rapid step-dancing, which is assumed to produce vibrations and/or presumably non-vocal sounds. Dance performances did not differ between sexes but varied among individuals. Both male and female cordon-bleus intensified their dance performances when their mate was on the same perch. The multimodal (acoustic, visual, tactile) and multicomponent (vocal and non-vocal sounds) courtship display observed was a combination of several motor behaviours (singing, bobbing, stepping). The fact that both sexes of this socially monogamous songbird perform such a complex courtship display is a novel finding and suggests that the evolution of multimodal courtship display as an intersexual communication should be considered. PMID- 26583486 TI - In situ 2D-extraction of DNA wheels by 3D through-solution transport. AB - Controlled transfer of DNA nanowheels from a hydrophilic to a hydrophobic surface was achieved by complexation of the nanowheels with a cationic lipid (2C12N(+)). 2D surface-assisted extraction, '2D-extraction', enabled structure-persistent transfer of DNA wheels, which could not be achieved by simple drop-casting. PMID- 26583487 TI - Biotechnological promises of Fe-filled CNTs for cell shepherding and magnetic fluid hyperthermia applications. AB - Fe-filled carbon nanotubes (Fe@CNTs) recently emerged as an effective class of hybrid nanoparticles for biotechnological applications, such as magnetic cell sorting and magnetic fluid hyperthermia. Aiming at studying the effects of both the Fe loading and the magnetocrystalline characteristics in these applications, we describe herein the preparation of Fe@CNTs containing different Fe phases that, upon functionalization with the antibody Cetuximab (Ctxb), allow the targeting of cancer cells. Our experimental findings reveal that an optimal Ctxb/Fe weight ratio of 1.2 is needed for efficient magnetic cell shepherding, whereas enhanced MFH-induced mortality (70 vs. 15%) can be reached with hybrids enriched in the coercive Fe(3)C phase. These results suggest that a synergistic effect between the Ab loading and the Fe distribution in each nanotube exists, for which the maximum shepherding and hyperthermia effects are observed when higher densities of Fe@CNTs featuring the more coercive phase are interfaced with the cells. PMID- 26583488 TI - Microwave assisted synthesis of a mono organoimido functionalized Anderson polyoxometalate. AB - The synthesis of an aliphatic organoimido functionalized polyoxometalate has been achieved through a microwave assisted reaction protocol in the absence of any activating reagents. Characterization of the pendant amine containing polyanion [Mo6O18NC(OCH2)3MnMo6O18(OCH2)3CNH2](5-) (1) includes single crystal XRD, NMR, ESI-MS, IR and SAXS. PMID- 26583489 TI - Relationship Between Cerebrospinal Fluid Protein Levels and Electrophysiologic Abnormalities in Guillain-Barre Syndrome. AB - OBJECTIVES: The cerebrospinal fluid (CSF) protein level is known to be elevated in patients with Guillain-Barre syndrome (GBS). This report correlates the degree of CSF protein elevation with the number of electrophysiologic abnormalities on nerve conduction study (NCS). METHODS: We reviewed 38 patients admitted to our institution with a diagnosis of GBS and had both a measured CSF protein level and a NCS within 24 hours of each other. RESULTS: CSF protein level correlates with the number of NCS demyelination criteria, as described by Cornblath, in patients with GBS. CONCLUSIONS: This retrospective study is the first to demonstrate a relationship between the CSF protein level and the electrophysiologic abnormalities that accompany GBS. PMID- 26583490 TI - Histopathologic Findings in 5 Patients With Hypomyopathic Dermatomyositis: The Importance of MHC-1 Expression on Myofibers. AB - Muscle histopathologic findings in hypomyopathic dermatomyositis (HDM) have not been adequately characterized. We sought to determine the results of conventional and immunohistopathology in HDM. Light microscopic and immunohistochemical analysis was performed on muscle from 5 patients with HDM without muscle weakness. Ages ranged from 49 to 56 years. Creatine kinase level was normal. Electromyography showed mild "myopathic" changes in 2. The median duration of skin disease before biopsy was 18 months. Abnormal major histocompatibility (MHC) class I immunoreactivity was noted in myofibers in all specimens even when conventional histopathology was normal (1 patient) or only mildly abnormal (3 patients). One specimen had the characteristic findings of dermatomyositis. Patchy MHC-1 expression on myofibers was a consistent finding in HDM in the absence of other histopathologic abnormalities. The presence of MHC-1 expression could indicate a degree of endoplasmic reticulum stress even in the absence of clinical muscle weakness, muscle enzyme abnormalities, or significant inflammatory infiltrate. PMID- 26583491 TI - Limb-Girdle Muscular Dystrophy Type 2A Resulting From c.C479G and c.G1818A Mutations in the Calpain-3 Gene. AB - Limb-Girdle Muscular Dystrophy type 2A (LGMD2A) is an autosomal recessive disorder characterized by progressive weakness of proximal muscles. Here, we describe a patient with clinical features consistent with LGMD2A who harbors 2 rare changes in the CAPN3 gene sequence of unknown clinical significance. Mechanisms by which these 2 mutations could affect the protein are discussed. The c.C479G mutation seems to affect the proteolytic domain of calpain-3. Whereas the novel mutation c.G1818A seems to affect mRNA translation of the protein region involved in titin binding. We strongly believe that these genomic variants in CAPN3 are indeed deleterious and thus are currently misclassified. Since LGMD2 is considered a disorder of autosomal recessive inheritance, further population studies involving the molecular characterization of symptomatic patients must be performed as well as in vitro studies to ascertain the functional effects of these specific variants. PMID- 26583492 TI - Utility of Paraneoplastic Antibody Testing in the Diagnosis of Motor Neuron Disease. AB - OBJECTIVE: To evaluate the role of paraneoplastic autoantibody testing in the diagnosis of motor neuron disease (MND). BACKGROUND: There have been rare case reports of paraneoplastic MND that have prompted many physicians to test for paraneoplastic autoantibodies in patients with MND. Our study is the first to determine the utility of such testing. METHODS: Retrospective chart review of patients with MND from a tertiary referral center from 2007 to 2014. RESULTS: Of 316 patients with MND reviewed, 44% (n = 138) were evaluated by a Mayo Clinic paraneoplastic autoantibody panel. Of note, 73% of these patients (n = 101) were diagnosed with amyotrophic lateral sclerosis, fulfilling possible, probable, or definite revised El Escorial criteria. Of note, 9% of patients (13/138) of those who had paraneoplastic antibody testing performed were positive for at least 1 paraneoplastic antibody. Three patients had negative testing for malignancy. None had a different disease course than expected. CONCLUSIONS: Testing for paraneoplastic antibodies does not seem to change the diagnosis, management, or outcome in the setting of MND and is therefore of limited value. PMID- 26583493 TI - Expanding Phenotype of VRK1 Mutations in Motor Neuron Disease. AB - OBJECTIVE: In the past decade, hereditary forms of motor neuron disease (spinal muscular atrophy and/or amyotrophic lateral sclerosis) are increasingly identified. As advanced genetic testing is performed, molecular diagnosis can be obtained. Identifying new gene mutations can lead to further understanding of disease. METHODS AND RESULTS: We report a single case of a patient with early onset amyotrophic lateral sclerosis, evaluated at University of Texas Health Houston Science Center from 2011-2014. Initial genetic testing did not reveal an etiology in this patient. Through whole-exome sequencing, a VRK1 mutation was identified. CONCLUSIONS AND RELEVANCE: We identify a possible new cause of hereditary amyotrophic lateral sclerosis, VRK1 mutation. This case report also expands the phenotypic spectrum of this mutation in neurologic diseases. PMID- 26583494 TI - Anticholinesterase Therapy Worsening Head Drop and Limb Weakness Due to a Novel DOK7 Mutation. AB - Dok-7 myasthenia is an autosomal recessive congenital myasthenic syndrome due to DOK7 mutations. Anticholinesterase therapy is ineffective and may worsen the weakness in patients with Dok-7 myasthenia or few other forms of congenital myasthenic syndromes. We describe a 31-year-old man previously diagnosed with seronegative myasthenia gravis. Repetitive stimulation of the right spinal accessory nerve showed 51% decrement. Needle electromyography revealed myopathic changes in clinically affected muscles. Muscle biopsy was normal. The patient was referred to us for worsening weakness after taking pyridostigmine. We searched for DOK7 mutations and identified compound heterozygous mutations of a common c.1124_1127dupTGCC mutation and a novel splice site mutation, c.772+2_+4delinsCCGGGCAGGCGGGCA. Discontinuation of pyridostigmine improved weakness. He further regained strength with oral albuterol therapy and decrement was reduced to 25%. Worsening of symptoms with anticholinesterase therapy in patients with "seronegative myasthenia gravis" should prompt clinicians to consider a possibility of congenital myasthenic syndromes to avoid unnecessary use of immunosuppressive therapy. Patients with Dok-7 myasthenia respond well to oral albuterol treatment. PMID- 26583495 TI - Chronic Inflammatory Demyelinating Polyneuropathy Manifesting as Neuropathy With Liability to Pressure Palsies: A Case Report. AB - INTRODUCTION: Chronic inflammatory demyelinating polyneuropathy (CIDP) is a progressive demyelinating neuropathy, which typically presents with proximal and distal neuropathic symptoms and is typically responsive to immunomodulatory therapies. Many variants have been subsequently described in the literature and have similarly shown to be responsive to immunotherapy. CASE PRESENTATION: We present a case of a 43-year-old Middle Eastern/Arabic man presenting with symptoms of mixed sensorimotor neuropathy most evident at entrapment sites mimicking hereditary neuropathy with liability to pressure palsies. His electrodiagnostic study revealed features of acquired demyelinating neuropathy and a negative genetic workup. Alternative diagnosis of CIDP was considered in the context of symptomatic disease progression, negative genetic workup, and electrodiagnosis leading to initiation of immunotherapy with intravenous immunoglobulins. His neuropathy responded confirming our diagnosis of an inflammatory demyelinating polyneuropathy. CONCLUSIONS: We describe a previously unknown variant of CIDP with phenotypic characteristics of hereditary neuropathy with liability to pressure palsies and its potential for successful treatment with intravenous immunoglobulins. This case illustrates an unusual presentation of CIDP mimicking hereditary neuropathy with liability to pressure palsies. PMID- 26583496 TI - Fascicular Involvement of the Posterior Tibial Nerve as a Result of Perineural Ganglion Cyst at the Posterior Tibial Nerve in the Calf: A Case Report and Review of Literature. AB - We report a 19-year-old woman with a 6-month history of nontraumatic left foot numbness associated with intermittent weakness. Nerve conduction studies and electromyography localized the lesion to the posterior tibial nerve, below the innervation to the soleus and medial gastrocnemius muscles. MRI of the left leg revealed a multiloculated cystic collection near the proximal tibiofibular joint. Surgical excision and pathology confirmed the diagnosis of a ganglion cyst, in an atypical location distal to the popliteal fossa. We believe this is the first reported case of fascicular posterior tibial nerve involvement by a ganglion cyst in the calf. PMID- 26583497 TI - POEMS Syndrome in a Juvenile Initially Diagnosed as Treatment Resistant Chronic Inflammatory Demyelinating Polyneuropathy. AB - POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes) is a disorder that mainly affects adults. We report a pediatric patient, initially considered to have Guillain-Barre syndrome, who continued to have progression of neuropathic disease leading to the diagnosis of chronic inflammatory demyelinating polyneuropathy. Diagnosis of POEMS was established by an abnormal bone marrow biopsy, prompted by laboratory and imaging findings, which became abnormal later in the course of the disease. POEMS syndrome is extremely rare in children, and neuropathic features in this age group have not been previously described. This case illustrates that "Guillain-Barre syndrome like" initial presentation for POEMS, which has not been previously reported. It also emphasizes that in children with progressive acquired neuropathies that are treatment unresponsive, POEMS syndrome should be considered. PMID- 26583498 TI - Fatal Calciphylaxis Presenting as Polymyalgia Rheumatica and Temporal Arteritis. PMID- 26583499 TI - A Case of Spinocerebellar Ataxia With a Reversible Splenium Lesion Due to Malnutrition and Vitamin Deficiency. PMID- 26583500 TI - Frontal Variant Alzheimer Disease or Frontotemporal Lobe Degeneration With Incidental Amyloidosis? PMID- 26583501 TI - Association of mitral annular velocity with myocardial ischemia assessed by single-photon emission computed tomography in patients with suspected coronary artery disease and preserved ejection fraction. AB - BACKGROUND: Left ventricular diastolic dysfunction is a sensitive and early sign of myocardial ischemia. We assessed whether mitral annular velocity reflected the severity of myocardial ischemia evaluated by single-photon emission computed tomography in patients with suspected coronary artery disease (CAD) and preserved ejection fraction. METHODS AND RESULTS: The study population consisted of 125 patients with suspected CAD who underwent both single-photon emission computed tomography and transthoracic echocardiography. There were 68 patients with no ischemia, 42 patients with mild ischemia, and 15 patients with severe ischemia. With increasing severity of myocardial ischemia, septal e' decreased. Compared with patients with no ischemia, septal e' was significantly lower even in patients with mild ischemia (6.6 +/- 1.4 vs. 6.1 +/- 1.4 cm/s, P < 0.05). Septal E/e' (9.9 +/- 2.6 vs. 13.6 +/- 4.0, P < 0.01) and lateral E/e' (7.7 +/- 2.3 vs. 10.3 +/- 3.6, P < 0.01) were significantly higher finally in patients with severe ischemia. Multivariate logistic regression analyses showed that BMI [odds ratio (OR) 1.13, 95% confidence interval (CI) 1.01-1.29; P = 0.03] and septal e' (OR 0.71, 95% CI 0.53-0.94; P = 0.02) were independent predictors of any myocardial ischemia and that diabetes (OR 5.78, 95% CI 1.58-23.0; P = 0.008) and septal E/e' (OR 1.38, 95% CI 1.13-1.76; P = 0.001) were independent predictors of severe myocardial ischemia. CONCLUSION: Our data suggested that decreased e' was useful in detecting mild myocardial ischemia and increased E/e' was useful in detecting severe myocardial ischemia in patients with suspected CAD and preserved ejection fraction. PMID- 26583502 TI - Development and Validation of a Novel Fibrosis Marker in Biliary Atresia during Infancy. AB - OBJECTIVES: Most biliary atresia (BA) patients suffer from liver fibrosis and often require liver transplantation. The aim of this study was to develop and validate a novel fibrosis marker for BA patients aged <1 year-the infant BA liver fibrosis (iBALF) score-subsequent to the previously reported fibrosis marker for BA patients aged >=1 year. METHODS: From three institutions for pediatric surgery, BA patients and their native liver histology examinations performed at the age of <1 year were retrospectively identified and assigned to a development cohort (58 patients and 73 examinations) or validation cohort (92 patients and 117 examinations) according to their institutions. Histological fibrosis stages (F0-F4), blood test results, and clinical information at the time of liver histology examination were reviewed. The iBALF score was determined using multivariate ordered logistic regression analysis and was assessed for its associations with histological fibrosis stages. RESULTS: The iBALF score equation was composed of natural logarithms, including serum total bilirubin level, blood platelet counts, and days of age. The score revealed a strong correlation with fibrosis stage (r=0.80 and 0.73 in the development and validation cohorts, respectively; P<0.001). The areas under the receiver-operating characteristic curves for diagnosing each fibrosis stage were 0.86-0.94 in the development cohort and 0.86-0.90 in the validation cohort (P<0.001), indicating good diagnostic power. In addition, no patient with an iBALF score >6 (equivalent to F4) at the initial surgery survived with their native liver at 1 year of age (n=9). CONCLUSIONS: The iBALF score that was developed was a good noninvasive marker of native liver fibrosis for BA patients aged <1 year. PMID- 26583504 TI - Reverse Watson-Crick G-G base pair in G-quadruplex formation. AB - A stable intermediate dimeric G-rich form as a precursor of tetrameric G quadruplex structures has been detected via MALDI-TOF spectrometry. Molecular dynamics simulation offered detailed insights at the atomic level, assigning reverse Watson-Crick G-G base pairing (not Hoogsteen) in the G-rich dimer. In support of this, cisplatin formed a stable adduct by binding to the dimeric G rich structure, eliminating the possibility of G-G Hoogsteen hydrogen bond formation. PMID- 26583503 TI - Development of Advanced Imaging Criteria for the Endoscopic Identification of Inflammatory Polyps. AB - OBJECTIVES: Inflammatory polyps (IPs) are frequently encountered at colonoscopy in inflammatory bowel disease (IBD) patients and are associated with an increased risk of colon cancer. The aim of this prospective endoscopic image review and analysis was to describe endoscopic features of IPs in IBD patients at surveillance colonoscopy and determine the ability to endoscopically discern IPs from other colon polyps using high-definition white light (WL), narrow band imaging with magnification (NBI), and chromoendoscopy (CE). METHODS: Digital images of IPs using WL, NBI, and CE were reviewed by four attending gastroenterologists using a two-round modified Delphi method. The ability to endoscopically discern IPs from other colon polyps was determined among groups of gastroenterology fellows and attendings. IPs were classified by gross appearance, contour, surface pattern, pit pattern, and appearance of surrounding mucosa in IPs, as well as accuracy of diagnosis. RESULTS: Features characteristic of IPs included a fibrinous cap, surface friability and ulceration, an appendage-like appearance, the halo sign with CE, and a clustering of a multiplicity of IPs. The overall diagnostic accuracy for IP identification was 63% for WL, 42% for NBI, and 64% for CE. High degrees of histologic inflammation significantly improved the accuracy of diagnosis of IP with WL and CE, whereas the use of NBI significantly impaired IP accuracy. CONCLUSIONS: The overall diagnostic accuracy when applying these criteria to clinical images was modest, with incremental benefit with addition of CE to WL. CE showed promise predicting IP histology in actively inflamed tissue. Institutional Review Board approval was obtained. ClinicalTrials.gov Identifier: NCT01557387. PMID- 26583505 TI - Thermoelectricity at the molecular scale: a large Seebeck effect in endohedral metallofullerenes. AB - Single molecule devices provide a unique system to study the thermoelectric energy conversion at an atomistic level and can provide valuable information for the design of organic thermoelectric materials. Here we present a comprehensive study of the thermoelectric transport properties of molecular junctions based on C(82), Gd@C(82), and Ce@C(82). We combine precise scanning tunneling microscope break-junction measurements of the thermopower and conductance with quantitatively accurate self-energy-corrected first-principles transport calculations. We find that all three fullerene derivatives give rise to a negative thermopower (n-conducting). The absolute value, however, is much larger for the Gd@C(82) and Ce@C(82) junctions. The conductance, on the other hand, remains comparable for all three systems. The power factor determined for the Gd@C(82) based junction is so far the highest obtained for a single-molecule device. Although the encapsulated metal atom does not directly contribute to the transport, we show that the observed enhancement of the thermopower for Gd@C(82) and Ce@C(82) is elucidated by the substantial changes in the electronic- and geometrical structure of the fullerene molecule induced by the encapsulated metal atom. PMID- 26583506 TI - Role of the active viscosity and self-propelling speed in channel flows of active polar liquid crystals. AB - We study channel flows of active polar liquid crystals (APLCs) focusing on the role played by the active viscosity (beta) and the self-propelling speed (omega) on the formation and long time evolution of spontaneous flows using a continuum model. First, we study the onset of spontaneous flows by carrying out a linear stability analysis on two special steady states subject to various physical boundary conditions. We identify a single parameter b1, proportional to a linear combination of the active viscosity and the self-propelling speed, and inversely proportional to a Frank elastic constant, the solvent viscosity, and the liquid crystal relaxation time. We show that the active viscosity and the self propelling speed influence the onset of spontaneous flows through b1 in that for any fixed value of the bulk activity parameter zeta, large enough |b1| can suppress the spontaneous flow. We then follow spontaneous flows in long time to further investigate the role of beta and omega on spatial-temporal structures in the nonlinear regime numerically. The numerical study demonstrates a strong correlation between the most unstable eigenfunction obtained from the linear analysis and the terminal steady state or the persistent, traveling wave structure, revealing the genesis of flow and orientational structures in the active matter system. In the nonlinear regime, a nonzero b1 facilitates the formation of traveling waves in the case of boundary anchoring (the Dirichlet boundary condition) so long as the linear stability analysis predicts an onset of spontaneous flows; in the case of the free boundary condition (the Neumann boundary condition), a stable, spatially homogeneous tilted state always emerges in the presence of two active effects. Finally, we note that various fully out-of plane spatio-temporal structures can emerge in long time dynamics depending on the boundary condition as well as the initial state of the polarity vector field. PMID- 26583509 TI - Bringing Light to Dental Trauma and Oral Cavity Cancer. PMID- 26583510 TI - Bringing Light to Dental Trauma and Oral Cavity Cancer-Reply. PMID- 26583511 TI - The Effectiveness of Using Laryngeal Electromyography Guidelines for Injection Augmentation. PMID- 26583512 TI - The Effectiveness of Using Laryngeal Electromyography Guidelines for Injection Augmentation-Reply. PMID- 26583513 TI - Assessment of Blinding in a Tinnitus Treatment Trial. PMID- 26583514 TI - Assessment of Blinding in a Tinnitus Treatment Trial-Reply. PMID- 26583516 TI - Medians and Milestones in Describing the Path to Cancer Cures: Telling "Tails". PMID- 26583517 TI - In vitro fertilisation for unexplained subfertility. AB - BACKGROUND: One-third of subfertile couples have no identifiable cause for their inability to conceive. In vitro fertilisation (IVF) is a widely accepted treatment for this condition; however, this treatment is invasive and expensive and is associated with risks. OBJECTIVES: To evaluate the effectiveness and safety of IVF compared with expectant management, unstimulated intrauterine insemination (IUI) or intrauterine insemination along with ovarian stimulation with gonadotropins (IUI + gonadotropins) or clomiphene (IUI + CC) or letrozole (IUI + letrozole) in improving pregnancy outcomes. SEARCH METHODS: This review has drawn on the search strategy developed by the Cochrane Menstrual Disorders and Subfertility Group. We searched the Cochrane Menstrual Disorders and Subfertility Group Trials Register (searched May 2015), the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, first quarter), MEDLINE (1946 to May 2015), EMBASE (1985 to May 2015), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (May 2015) and reference lists of articles. We searched the following trial registries: clinicaltrials.gov (http://www.clinicaltrials.gov) and the World Health Organization International Trials Registry Platform search portal (http://www.who.int/trialsearch/Default.aspx). We searched the Web of Science (http://wokinfo.com/) as another source of trials and conference abstracts, OpenGrey (http://www.opengrey.eu/) for unpublished literature from Europe and the Latin American Caribbean Health Sciences Literature (LILACS) database (http://regional.bvsalud.org/php/index.php?lang=en). Moreover, we handsearched relevant conference proceedings and contacted study authors to ask about additional publications.Two review authors independently assessed trial eligibility, extracted data and assessed risk of bias. The primary review outcome was cumulative live birth rate. Multiple pregnancy and other adverse effects were secondary outcomes. We combined data to calculate pooled risk ratios (RRs) and 95% confidence intervals (CIs). We assessed statistical heterogeneity by using the I(2) statistic. We assessed the overall quality of evidence for the main comparisons using Grades of Recommendation, Assessment, Development and Evaluation (GRADE) methods. SELECTION CRITERIA: We included randomised controlled trials (RCTs) in which the effectiveness of IVF in couples with unexplained subfertility was compared with that of other treatments, including expectant management, unstimulated IUI and stimulated IUI using gonadotropins or clomiphene or letrozole.Live birth rate (LBR) per woman was the primary outcome. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the eligibility and quality of trials and evaluated the quality of the evidence by using GRADE criteria. MAIN RESULTS: IVF versus expectant management (two RCTs):Live birth rate per woman was higher with IVF than with expectant management (odds ratio (OR) 22.00, 95% confidence interval (CI) 2.56 to 189.37, one RCT, 51 women, very low quality evidence). Multiple pregnancy rates (MPRs), ovarian hyperstimulation syndrome (OHSS) and miscarriage were not reported. IVF versus unstimulated IUI (two RCTs):Live birth rate was higher with IVF than with unstimulated IUI (OR 2.47, 95% CI 1.19 to 5.12, two RCTs, 156 women, I(2) = 60%, low quality evidence). There was no evidence of a difference between the groups in multiple pregnancy rates (OR 1.03, 95% CI 0.04 to 27.29, one RCT, 43 women, very low quality evidence) IVF versus IUI + ovarian stimulation with gonadotropins (three RCTs) or clomiphene (one RCT) or letrozole (no RCTs):Data from these trials could not be pooled because of high statistical heterogeneity (I(2) = 93.3%). Heterogeneity was eliminated when studies were stratified by pretreatment status.In trials comparing IVF versus IUI + gonadotropins among treatment-naive women, there was no conclusive evidence of a difference between the groups in live birth rates (OR 1.27, 95% CI 0.94 to 1.73, four RCTs, 745 women, I(2) = 8.0%, moderate-quality evidence). In women pretreated with IUI + clomiphene, a higher live birth rate was reported among those who underwent IVF than those given IUI + gonadotropins (OR 3.90, 95% CI 2.32 to 6.57, one RCT, 280 women, moderate-quality evidence).There was no conclusive evidence of a difference in live birth rates between IVF and IUI + CC in treatment-naive women (OR 2.51, 95% CI 0.96 to 6.55, one RCT, 103 women, low quality evidence).In treatment-naive women, there was no evidence of a difference in rates of multiple pregnancy between women who underwent IVF and those who received IUI + gonadotropins (OR 0.79, 95% CI 0.45 to 1.39, four RCTs, 745 women, I(2) = 0%, moderate quality evidence). There was no evidence of a difference in MPRs between women who underwent IVF compared with those given IUI + CC (OR 1.02, 95% CI 0.20 to 5.31, one RCT, 103 women, low-quality evidence).There was no evidence of a difference in ovarian hyperstimulation syndrome rate between treatment-naive women who underwent IVF and those given IUI + gonadotropins (OR 1.23, 95% CI 0.36 to 4.14, two RCTs, 221 women, low quality evidence). There was no evidence of a difference in OHSS rates between groups receiving IVF versus those receiving IUI + CC (OR 1.02, 95% CI 0.20 to 5.31, one RCT, 103 women, low-quality evidence).In treatment naive women, there was no evidence of a difference in miscarriage rates between IVF and IUI + CC (OR 1.16, 95% CI 0.44 to 3.02, one RCT, 103 women, low quality evidence), nor between women treated with IVF versus those receiving IUI+ gonadotropins (OR 1.16, 95% CI 0.44 to 3.02, one RCT, 103 women).No studies compared IVF with IUI + letrozole.The quality of the evidence ranged from very low to moderate. The main limitation was serious imprecision resulting from small study numbers and low event rates. AUTHORS' CONCLUSIONS: IVF may be associated with higher live birth rates than expectant management, but there is insufficient evidence to draw firm conclusions. IVF may also be associated with higher live birth rates than unstimulated IUI. In women pretreated with clomiphene + IUI, IVF appears to be associated with higher birth rates than IUI + gonadotropins. However in women who are treatment-naive there is no conclusive evidence of a difference in live birth rates between IVF and IUI + gonadotropins or between IVF and IUI + clomiphene. Adverse events associated with these interventions could not be adequately assessed owing to lack of evidence. PMID- 26583518 TI - Are Retirement Villages Promoting Active Aging? AB - PURPOSE: This study investigated physical activity (PA) facilities of retirement villages (RVs) and neighborhood PA barriers identified by RV residents in Perth, Australia. METHODS: An environmental audit of PA facilities was undertaken on 50 RV with 50+ independent living units, using the Audit of Physical Activity Resources for Seniors. Telephone interviews with 200 RV residents were conducted to identify neighborhood barriers to walking, and to obtain information on utilization of facilities and attendance of PA programs. RESULTS: Larger size RV appeared to provide significantly more PA facilities and programs. Utilization of PA facilities and program attendance were low (~ 50%) and not associated with the RV environment (size, age, and facilities). Neighborhood barriers to walking were unsafe streets and hills. DISCUSSION: RV offers an attractive residential option with facilities that support active aging, but it is important to understand the barriers and enablers to use such facilities and attend programs offered. PMID- 26583520 TI - Comparative Raman spectroscopic study of phase stability and anharmonic effects in AZr2(PO4)3 (A=K, Rb and Cs). AB - AZr2(PO4)3 (A=Na, K, Rb, Cs) are a set of framework structured compounds that exhibit tunable ultralow thermal expansion over the wide temperature range of 293 1273K. We report a systematic Raman spectroscopic investigation on AZr2(PO4)3 (A=K, Rb and Cs) compounds as a function of temperature in the range 80-860K and pressures of up to 32GPa. To get insight into the thermal expansion property, phonon anharmonicity has been investigated by studying the temperature and pressure dependence of Raman peak shifts and line widths and computed bulk modulus. We have compared the phase transition and amorphization pressures of the various members of AZr2(PO4)3 to account for the stability of the ambient rhombohedral phase. We find that unlike most of the anomalous thermal expansion materials, in AZr2(PO4)3 (A=K, Rb and Cs), the phonons that are anharmonic with temperature do not necessarily exhibit anharmonicity with pressure. PMID- 26583519 TI - Lignocellulose degradation mechanisms across the Tree of Life. AB - Organisms use diverse mechanisms involving multiple complementary enzymes, particularly glycoside hydrolases (GHs), to deconstruct lignocellulose. Lytic polysaccharide monooxygenases (LPMOs) produced by bacteria and fungi facilitate deconstruction as does the Fenton chemistry of brown-rot fungi. Lignin depolymerisation is achieved by white-rot fungi and certain bacteria, using peroxidases and laccases. Meta-omics is now revealing the complexity of prokaryotic degradative activity in lignocellulose-rich environments. Protists from termite guts and some oomycetes produce multiple lignocellulolytic enzymes. Lignocellulose-consuming animals secrete some GHs, but most harbour a diverse enzyme-secreting gut microflora in a mutualism that is particularly complex in termites. Shipworms however, house GH-secreting and LPMO-secreting bacteria separate from the site of digestion and the isopod Limnoria relies on endogenous enzymes alone. The omics revolution is identifying many novel enzymes and paradigms for biomass deconstruction, but more emphasis on function is required, particularly for enzyme cocktails, in which LPMOs may play an important role. PMID- 26583521 TI - Tri-color emission and colorimetric recognition of acetate using semicarbazide and thio-semicarbazide derivatives: Experimental and computational studies. AB - Two new fluorescence probes having semicarbazide (DSC) and thio-semicarbazide (DTSC) units have been derived upon reaction with 2-hydroxy-5-methylbenzene-1,3 dialdehyde. Both the probes show excellent selectivity for acetate ion in DMSO medium whereby DTSC generates tricolor emission. The association constants of DSC and DTSC for acetate are 6.6*10(4)M(-1) and 2*10(3)M(-1) respectively with corresponding detection limits, 1.06*10(-7)M and 2.5*10(-6)M. Density functional theoretical (DFT) studies nicely demonstrate the interaction between the DTSC and acetate ion. PMID- 26583522 TI - The increased binding affinity of curcumin with human serum albumin in the presence of rutin and baicalin: A potential for drug delivery system. AB - The impacts of rutin and baicalin on the interaction of curcumin (CU) with human serum albumin (HSA) were investigated by fluorescence and circular dichroism (CD) spectroscopies under imitated physiological conditions. The results showed that the fluorescence quenching of HSA by CU was a simultaneous static and dynamic quenching process, irrespective of the presence or absence of flavonoids. The binding constants between CU and HSA in the absence and presence of rutin and baicalin were 2.268*10(5)M(-1), 3.062*10(5)M(-1), and 3.271*10(5)M(-1), indicating that the binding affinity was increased in the case of two flavonoids. Furthermore, the binding distance determined according to Forster's theory was decreased in the presence of flavonoids. Combined with the fact that flavonoids and CU have the same binding site (site I), it can be concluded that they may simultaneously bind in different regions in site I, and formed a ternary complex of flavonoid-HSA-CU. Meanwhile, the results of fluorescence quenching, CD and three-dimensional fluorescence spectra revealed that flavonoids further strengthened the microenvironmental and conformational changes of HSA induced by CU binding. Therefore, it is possible to develop a novel complex involving CU, flavonoid and HSA for CU delivery. The work may provide some valuable information in terms of improving the poor bioavailabiliy of CU. PMID- 26583523 TI - Systematic study on the TD-DFT calculated electronic circular dichroism spectra of chiral aromatic nitro compounds: A comparison of B3LYP and CAM-B3LYP. AB - B3LYP is one of the most widely used functional for the prediction of electronic circular dichroism spectra, however if the studied molecule contains aromatic nitro group computations may fail to produce reliable results. A test set of molecules of known stereochemistry were synthesized to study this phenomenon in detail. Spectra were computed by B3LYP and CAM-B3LYP functionals with 6 311++G(2d,2p) basis set. It was found that the range separated CAM-B3LYP gives better predictions than B3LYP for all test molecules. Fragment population analysis revealed that the nitro groups form highly localized molecule orbitals but the exact composition depends on the functional. CAM-B3LYP allows sufficient spatial overlap between the nitro group and distant parts of the molecule, which is necessary for the accurate description of excited states especially for charge transfer states. This phenomenon and the synthesized test molecules can be used to benchmark theoretical methods as well as to help the development of new functionals intended for spectroscopical studies. PMID- 26583524 TI - Floor of Mouth Mass. Intraductal papilloma. PMID- 26583525 TI - Pyrethroid and DDT Resistance and Organophosphate Susceptibility among Anopheles spp. Mosquitoes, Western Kenya. AB - We conducted standard insecticide susceptibility testing across western Kenya and found that the Anopheles gambiae mosquito has acquired high resistance to pyrethroids and DDT, patchy resistance to carbamates, but no resistance to organophosphates. Use of non-pyrethroid-based vector control tools may be preferable for malaria prevention in this region. PMID- 26583526 TI - Porous cationic polymers: the impact of counteranions and charges on CO2 capture and conversion. AB - Porous cationic polymers (PCPs) with surface areas up to 755 m(2) g(-1) bearing positively charged viologen units in their backbones and different counteranions have been prepared. We have demonstrated that by simply varying counteranions both gas sorption and catalytic properties of PCPs can be tuned for metal-free capture and conversion of CO2 into value-added products such as cyclic carbonates with excellent yields. PMID- 26583527 TI - Severe Ocular Cowpox in a Human, Finland. PMID- 26583528 TI - Constrained optimization of gradient waveforms for generalized diffusion encoding. AB - Diffusion MRI is a useful probe of tissue microstructure. The conventional diffusion encoding sequence, the single pulsed field gradient, has recently been challenged as more general gradient waveforms have been introduced. Out of these, we focus on q-space trajectory imaging, which generalizes the scalar b-value to a tensor valued entity. To take full advantage of its capabilities, it is imperative to respect the constraints imposed by the hardware, while at the same time maximizing the diffusion encoding strength. We provide a tool that achieves this by solving a constrained optimization problem that accommodates constraints on maximum gradient amplitude, slew rate, coil heating and positioning of radio frequency pulses. The method's efficacy and flexibility is demonstrated both experimentally and by comparison with previous work on optimization of isotropic diffusion sequences. PMID- 26583529 TI - Electron spin echo envelope modulation of molecular motions of deuterium nuclei. AB - Electron Spin Echo Envelope Modulation (ESEEM) spectroscopy is a powerful technique for the study of hyperfine interactions between an unpaired electron and nearby nuclei in solids, and is employed in quantitative structural studies. Here, we describe the use of ESEEM to study the slow motion of deuterium nuclei using their nuclear quadrupole resonance (NQR) line shapes. Two ESEEM techniques were employed: the conventional three-pulse ESEEM experiment, pi/2 - tau - pi/2 - T- pi/2 - tau - echo, and the four-pulse ESEEM, pi/2 - tau - pi/2 - T/2 - pi - T/2 - pi/2 - tau - echo, with the time variable T scanned in both cases. The nitroxide free radical 4-tert-butyliminomethyl-2,2,5,5-tetramethyl(d12)-3 imidazoline-1-oxyl with four deuterated methyl groups was investigated in a glassy ortho-terphenyl matrix over a wide temperature range. It was shown that four-pulse ESEEM allowed measurement of the nearly pure (2)H NQR line shape. Between 90K and 120K, the ESEEM spectra change drastically. At low temperatures, four-pulse ESEEM spectra show a Pake-like pattern, which evolves into a single line at higher temperatures, which is typical for NQR of rotating methyl CD3 groups. Comparison with literature data on NQR allows estimation of the reorientation rate, k. At ~100K, where the spectral changes are most pronounced, k was found to be ~10(5)s(-1). The spectral linewidths for the three-pulse ESEEM were found to decrease similarly with increasing temperature; so the three-pulse technique is also capable to detect motion of this type. The ESEEM approach, along with site-directed spin labeling, may be useful for detection of motional transitions near the spin labels in biological systems, when information on motion is required in a wide temperature range. PMID- 26583530 TI - Nuclear spin-lattice relaxation in nanofluids with paramagnetic impurities. AB - We study the spin-lattice relaxation of the nuclear spins in a liquid or a gas entrapped in nanosized ellipsoidal cavities with paramagnetic impurities. Two cases are considered where the major axes of cavities are in orientational order and isotropically disordered. The evolution equation and analytical expression for spin lattice relaxation time are obtained which give the dependence of the relaxation time on the structural parameters of a nanocavity and the characteristics of a gas or a liquid confined in nanocavities. For the case of orientationally ordered cavities, the relaxation process is exponential. When the nanocavities are isotropically disordered, the time dependence of the magnetization is significantly non-exponential. As shown for this case, the relaxation process is characterized by two time constants. The measurements of the relaxation time, along with the information about the cavity size, allow determining the shape and orientation of the nanocavity and concentration of the paramagnetic impurities. PMID- 26583532 TI - Theoretical Study of the Spin Competition in Small-Sized Al Clusters. AB - Stern-Gerlach (SG) experiments on aluminum clusters indicate that some small sized aggregates exhibit a deflection signal consistent with the existence of magnetic moments. However, in the particular case of Al6 and Al8 clusters, electronic structure investigations show ambiguity on the 0 K ground spin state. In this work extensive computations of the electronic structure have been carried out in order to determine the ground state of these structures. Electron correlation has been introduced at MP2, MP4, and CCSD(T) theory level as well as by DFT computations with different density functionals. DFT-based Born Oppenheimer molecular dynamics results at different simulation temperatures complete this investigation. One of our main conclusions is that singlet spin states are systematically the more stable configuration at 0 K. These Al clusters exhibit almost degenerate electronic structures at singlet and triplet spin states. The geometries are similar, and the paths connecting both structures allow an intersystem crossing through a spin-orbit coupling mechanism, indicating a dynamical interchange of both spin states at finite temperatures. PMID- 26583531 TI - Combined effects of pollutants and salinity on embryo-larval development of the Pacific oyster, Crassostrea gigas. AB - For several years, low larval recruitment has been observed in Arcachon Bay, in southwest France. Exposure to pollutants could partly account for the reduction of early life stages of the Pacific oyster. This study evaluated the effects of copper and S-metolachlor in combination with salinity on the early life stages of Crassostrea gigas. Embryos were exposed to concentrations of copper (1, 10 and 50 MUg L(-1)) or S-metolachlor (10, 100 and 1000 ng L(-1)) and six salinities (18, 21, 24, 27, 30 and 33 u.s.i). Embryotoxicity was measured by considering both the percentage of abnormalities and arrested development in D-shaped larvae. Embryo larval development was only affected at salinities <=24 u.s.i, which have never been observed during C. gigas reproduction period in Arcachon Bay. Both contaminants had an effect at environmental concentrations. Our results suggest that copper and metolachlor toxicity was enhanced with decreasing salinity. PMID- 26583533 TI - Enhanced Raman Scattering on In-Plane Anisotropic Layered Materials. AB - Surface-enhanced Raman scattering (SERS) on two-dimensional (2D) layered materials has provided a unique platform to study the chemical mechanism (CM) of the enhancement due to its natural separation from electromagnetic enhancement. The CM stems from the charge interactions between the substrate and molecules. Despite the extensive studies of the energy alignment between 2D materials and molecules, an understanding of how the electronic properties of the substrate are explicitly involved in the charge interaction is still unclear. Lately, a new group of 2D layered materials with anisotropic structures, including orthorhombic black phosphorus (BP) and triclinic rhenium disulfide (ReS2), has attracted great interest due to their unique anisotropic electrical and optical properties. Herein, we report a unique anisotropic Raman enhancement on few-layered BP and ReS2 using copper phthalocyanine (CuPc) molecules as a Raman probe, which is absent on isotropic graphene and h-BN. According to detailed Raman tensor analysis and density functional theory calculations, anisotropic charge interactions between the 2D materials and molecules are responsible for the angular dependence of the Raman enhancement. Our findings not only provide new insights into the CM process in SERS, but also open up new avenues for the exploration and application of the electronic properties of anisotropic 2D layered materials. PMID- 26583534 TI - High Prevalence of Intermediate Leptospira spp. DNA in Febrile Humans from Urban and Rural Ecuador. AB - Leptospira spp., which comprise 3 clusters (pathogenic, saprophytic, and intermediate) that vary in pathogenicity, infect >1 million persons worldwide each year. The disease burden of the intermediate leptospires is unclear. To increase knowledge of this cluster, we used new molecular approaches to characterize Leptospira spp. in 464 samples from febrile patients in rural, semiurban, and urban communities in Ecuador; in 20 samples from nonfebrile persons in the rural community; and in 206 samples from animals in the semiurban community. We observed a higher percentage of leptospiral DNA-positive samples from febrile persons in rural (64%) versus urban (21%) and semiurban (25%) communities; no leptospires were detected in nonfebrile persons. The percentage of intermediate cluster strains in humans (96%) was higher than that of pathogenic cluster strains (4%); strains in animal samples belonged to intermediate (49%) and pathogenic (51%) clusters. Intermediate cluster strains may be causing a substantial amount of fever in coastal Ecuador. PMID- 26583535 TI - Mimicking the Cell: Bio-Inspired Functions of Supramolecular Assemblies. PMID- 26583537 TI - Association of Human Q Fever with Animal Husbandry, Taiwan, 2004-2012. AB - In Taiwan, Q fever cases in humans began increasing in 2004 and peaked in 2007 but dramatically declined in 2008 and 2011. Cases were significantly correlated with the number of goats. The decline might be associated with the collateral effects of measures to control goat pox in 2008 and 2010. PMID- 26583538 TI - A Natural Helical Crystal Lattice Model for Carbon Nanotubes. AB - We propose a novel helical crystal lattice model for chiral and achiral carbon nanotubes (CNTs) where the unit cell and the helical crystal vector are defined in a unique and systematic manner for arbitrary CNTs. The small unit cell of this helical crystal lattice leads to a natural and convenient description of the electronic structure of chiral CNTs. Also, using this model, the degenerate frontier Bloch wave functions at the Gamma point can be conveniently chosen by their symmetry properties. In particular, the contour of the Bloch wave functions at the Fermi level can be easily predicted for all metallic CNTs. PMID- 26583536 TI - Force Field for Mg(2+), Mn(2+), Zn(2+), and Cd(2+) Ions That Have Balanced Interactions with Nucleic Acids. AB - Divalent metal ions are of fundamental importance to the function and folding of nucleic acids. Divalent metal ion-nucleic acid interactions are complex in nature and include both territorial and site specific binding. Commonly employed nonbonded divalent ion models, however, are often parametrized against bulk ion properties and are subsequently utilized in biomolecular simulations without considering any data related to interactions at specific nucleic acid sites. Previously, we assessed the ability of 17 different nonbonded Mg(2+) ion models to reproduce different properties of Mg(2+) in aqueous solution including radial distribution functions, solvation free energies, water exchange rates, and translational diffusion coefficients. In the present work, we depart from the recently developed 12-6-4 potential models for divalent metal ions developed by Li and Merz and tune the pairwise parameters for Mg(2+), Mn(2+), Zn(2+), and Cd(2+) binding dimethyl phosphate, adenosine, and guanosine in order to reproduce experimental site specific binding free energies derived from potentiometric pH titration data. We further apply these parameters to investigate a metal ion migration previously proposed to occur during the catalytic reaction of the hammerhead ribozyme. The new parameters are shown to be accurate and balanced for nucleic acid binding in comparison with available experimental data and provide an important tool for molecular dynamics and free energy simulations of nucleic acids where these ions may exhibit different binding modes. PMID- 26583539 TI - Are DFT Methods Accurate in Mononuclear Ruthenium-Catalyzed Water Oxidation? An ab Initio Assessment. AB - Mononuclear Ru-based water oxidation catalysts (WOCs) are an important class of WOCs for water splitting. In this work, through high-level coupled cluster calculations (CCSD(T)/CBS), we have examined a variety of density functionals for their performances in the whole catalytic cycle of water oxidation catalyzed by mononuclear Ru-based WOCs. The tested functionals cover a wide range from pure GGA and meta-GGA to hybrids and double hybrids (TPSS, OLYP, BP86, M06-L, B3LYP, PBE0, M06, M06-2X, TPSSh, CAM-B3LYP, wB97X, B2-PLYP, B2GP-PLYP). Depending on different reaction types and species in the catalytic cycle, the performances of different DFTs vary severely, whose trends are summarized in the paper. Our results indicate that using a single approximate functional to accurately model all reactions involved in the whole Ru-based WOC catalytic cycle is still a very challenging task. In the current status, PBE0 and M06 may be recommended for the whole catalytic cycle. Generally, this study provides a guide for selecting an appropriate DFT method in modeling each of the various steps in water oxidation catalyzed by Ru-based WOCs. The sensitivity of DFT and ab initio results upon the degree of basis set completeness found in this work is also worthy of attention in the future theoretical study of mononuclear Ru-based WOCs. PMID- 26583540 TI - The Optical Rotation of Methyloxirane in Aqueous Solution: A Never Ending Story? AB - The long-standing problem of the calculation of the optical rotation (OR) of (R) methyloxirane in aqueous solution at different wavelengths is solved by means of a novel gauge-invariant computational protocol able to take into account at the same time for intramolecular averaging specific and bulk solvent effects, leading for the first time to a quantitative agreement (both sign and absolute value) between computed and experimental OR values at several frequencies. PMID- 26583541 TI - A Site Density Functional Theory for Water: Application to Solvation of Amino Acid Side Chains. AB - We report a site density functional theory (SDFT) based on the conventional atomistic models of water and the universality ansatz of the bridge functional. The excess Helmholtz energy functional is formulated in terms of a quadratic expansion with respect to the local density deviation from that of a uniform system and a universal functional for all higher-order terms approximated by that of a reference hard-sphere system. With the atomistic pair direct correlation functions of the uniform system calculated from MD simulation and an analytical expression for the bridge functional from the modified fundamental measure theory, the SDFT can be used to predict the structure and thermodynamic properties of water under inhomogeneous conditions with a computational cost negligible in comparison to that of brute-force simulations. The numerical performance of the SDFT has been demonstrated with the predictions of the solvation free energies of 15 molecular analogs of amino acid side chains in water represented by SPC/E, SPC, and TIP3P models. For theTIP3P model, a comparison of the theoretical predictions with MD simulation and experimental data shows agreement within 0.64 and 1.09 kcal/mol on average, respectively. PMID- 26583542 TI - The Influence of a Presence of a Heavy Atom on (13)C Shielding Constants in Organomercury Compounds and Halogen Derivatives. AB - (13)C nuclear magnetic resonance shielding constants have been calculated by means of density functional theory (DFT) for several organomercury compounds and halogen derivatives of aliphatic and aromatic compounds. Relativistic effects have been included through the four-component Dirac-Kohn-Sham (DKS) method, two component Zeroth Order Regular Approximation (ZORA) DFT, and DFT with scalar effective core potentials (ECPs). The relative shieldings have been analyzed in terms of the position of carbon atoms with respect to the heavy atom and their hybridization. The results have been compared with the experimental values, some newly measured and some found in the literature. The main aim of the calculations has been to evaluate the magnitude of heavy atom effects on the (13)C shielding constants and to check what are the relative contributions of scalar relativistic effects and spin-orbit coupling. Another object has been to compare the DKS and ZORA results and to check how the approximate method of accounting for the heavy atom-on-light-atom (HALA) relativistic effect by means of scalar effective core potentials on heavy atoms performs in comparison with the more rigorous two- and four-component treatment. PMID- 26583543 TI - Halogen Bonds: Benchmarks and Theoretical Analysis. AB - We carried out an extensive survey of wave function and DFT methods to test their accuracy on geometries and dissociation energies of halogen bonds (XB). For that purpose, we built two benchmark sets (XB18 and XB51). Between the DFT methods, it was found that functionals with high exact exchange or long-range corrections were suitable for these dimers, especially M06-2X, omegaB97XD, and double hybrids. Dispersion corrections tend to be detrimental, in spite of the fact that XB is considered a noncovalent interaction. Wave function techniques require heavy correlated methods (i.e., CCSD(T)) or parametrized ones (SCS-MP2 or SCS(MI)MP2). Heavy basis sets are needed to obtain high accuracy, such as aVQZ or aVTZ+CP, and ideally a CBS extrapolation. Relativistic ECPs are also important, even for the bromine based dimers. In addition, we explored some XB with new theoretical tools, the NCI ("Non-Covalent Interactions") method and the NOFF ("Natural Orbital Fukui Functions"). PMID- 26583544 TI - Relativistic Density Functional Calculations of Hyperfine Coupling with Variational versus Perturbational Treatment of Spin-Orbit Coupling. AB - Different approaches are compared for relativistic density functional theory (DFT) and Hartree-Fock (HF) calculations of electron-nucleus hyperfine coupling (HFC) in molecules with light atoms, in transition metal complexes, and in selected actinide halide complexes with a formal metal 5f(1) configuration. The comparison includes hybrid density functionals with range-separated exchange. Within the variationally stable zeroth-order regular approximation (ZORA) relativistic framework, the HFC is obtained (i) with a linear response (LR) method where spin-orbit (SO) coupling is treated as a linear perturbation, (ii) with a spin-polarized approach closely related to a DFT method for calculating magnetic anisotropy (MA) previously devised by van Wullen et al. where SO coupling is included variationally, (iii) with a quasi-restricted variational SO method previously devised by van Lenthe, van der Avoird, and Wormer (LWA). The MA and LWA approaches for HFC calculations were implemented in the open-source NWChem quantum chemistry package as part of this study. The methodology extends recent implementations for calculations of electronic g-factors (J. Chem. Theor. Comput.2013, 9, 1052). The impact of electron correlation (DFT vs HF) and DFT delocalization errors, the effects of spin-polarization, the importance of treating spin-orbit coupling beyond first-order, and the magnitude of finite nucleus effects, are investigated. Similar to calculations of g-factors, the MA approach in conjunction with hybrid functionals performs reasonably well for theoretical predictions of HFC in a wide range of scenarios. PMID- 26583545 TI - Noniterative Multireference Coupled Cluster Methods on Heterogeneous CPU-GPU Systems. AB - A novel parallel algorithm for noniterative multireference coupled cluster (MRCC) theories, which merges recently introduced reference-level parallelism (RLP) [Bhaskaran-Nair, K.; Brabec, J.; Apra, E.; van Dam, H. J. J.; Pittner, J.; Kowalski, K. J. Chem. Phys.2012, 137, 094112] with the possibility of accelerating numerical calculations using graphics processing units (GPUs) is presented. We discuss the performance of this approach applied to the MRCCSD(T) method (iterative singles and doubles and perturbative triples), where the corrections due to triples are added to the diagonal elements of the MRCCSD effective Hamiltonian matrix. The performance of the combined RLP/GPU algorithm is illustrated on the example of the Brillouin-Wigner (BW) and Mukherjee (Mk) state-specific MRCCSD(T) formulations. PMID- 26583546 TI - Conformational Effects on the Magnetic Properties of an Organic Diradical: A Computational Study. AB - A theoretical study on the singlet triplet energy splitting in a m-phenylene bridged organic diradical has been performed using an original computational protocol developed in our group. The method is based on post Hatree-Fock calculations and has proven to provide accurate results with reasonable computational effort. By virtue of such efficiency, the full PES of both the singlet and triplet states as a function of the two "soft" torsional degrees of freedom at the meta position of the ring has been explored. In agreement with literature findings, we found a pronounced dependence of the sign of the energy gap from the torsional angles. Finally, exploiting the two-dimensional surface, a statistical analysis is carried out at low temperatures and a comparison with available experimental data addressed. PMID- 26583547 TI - Accurate Computation of Cohesive Energies for Small to Medium-Sized Gold Clusters. AB - High-level CCSD(T)-F12-type procedures have been used to assess the performance of a variety of computationally less demanding methods for the calculation of cohesive energies for small to medium-sized gold clusters. For geometry optimization for small gold clusters, the PBE-PBE/cc-pVDZ-PP procedure gives structures that are in close agreement with the benchmark geometries. We have devised a CCSD(T)-F12b-based composite protocol for the accurate calculation of cohesive energies for medium-sized gold clusters. Using these benchmark (nonspin orbit vibrationless) cohesive energies, we find that fairly good agreement is achieved by the PBE-PBE-D3/cc-pVTZ-PP method. In conjunction with PBE-PBE/cc-pVDZ PP zero-point vibrational energies and spin-obit corrections obtained with the PBE-PBE-2c/dhf-TZVP-2c method, we have calculated 0 K cohesive energies for Au2 Au20. Extrapolation of these cohesive energies to bulk yields an estimated value of 383.2 kJ mol(-1), which compares reasonably well with the experimental value of 368 kJ mol(-1). PMID- 26583548 TI - Understanding the Nature of the CH...HC Interactions in Alkanes. AB - To understand the dispersion stabilization of hydrocarbons in solids and of encumbered molecules, wherein CH...HC interactions act as sticky fingers, we developed here a valence bond (VB) model and applied it to analyze the H...H interactions in dimers of H2 and alkanes. The VB analysis revealed two distinct mechanisms of "dispersion." In the dimers of small molecules like H-H...H-H and H3CH...HCH3, the stabilization arises primarily due to the increased importance of the VB structures which possess charge alternation, e.g., C(+)H(-)...H(+)C(-) and C(-)H(+)...H(-)C(+), and hence bring about electrostatic stabilization that holds the dimer. This is consistent with the classical mechanism of oscillating dipoles as the source of dispersion interactions. However, in larger alkanes, this mechanism is insufficient to glue the two molecules together. Here, the "dispersion" interaction comes about through perturbational mixing of VB structures, which reorganize the bonding electrons of the two interacting CH bonds via recoupling of these electrons to H...H, C...C, and C...H "bonds." Finally, an attempt is made to create a bridge from VB to molecular orbital (MO) and local pair natural-orbital coupled electron pair approximation (LPNO-CEPA/1) analyses of the interactions, which bring about CH...HC binding. PMID- 26583549 TI - Extended Energy Divide-and-Conquer Method Based on Charge Conservation. AB - The divide-and-conquer (DC) scheme, the most popular linear-scaling method, is very important in the quantum mechanics computation of large systems. However, when a chemical system is divided into subsystems, its covalent bonds are often broken and then capped by complementary atoms/groups. In this paper, we show that the charge transfer between subsystems and the complementary atoms/groups causes the nonconservation of the total charge of the whole system, and this is the main source of error for the computed total energy. On the basis of this finding, an extension of the many-body expansion method (energy-based divide-and-conquer, EDC) utilizing charge conservation (E-EDC) is proposed. In the E-EDC method, initially the total energies of the whole system at different many-body correction levels are computed according to the EDC scheme. The total charges of the whole system, that is, the sum of the charges of the subsystems without cap atoms/groups at different many-body correction levels, are also computed. Then the total energy is extrapolated to the value at which the net charge of the whole system equals to the real value. Other properties such as atomic forces can also be extrapolated in a similar way. In the test of 24 and 32 glycine oligomers, this scheme reduces the error of the total energy by about 40-70%, but the computational cost is almost the same as that of the EDC scheme. PMID- 26583550 TI - Ligand Binding Pathway Elucidation for Cryptophane Host-Guest Complexes. AB - Modeling binding pathways can provide insight into molecular recognition, including kinetic mechanisms, barriers to binding, and gating effects. This work represents a novel computational approach, Hopping Minima, for the determination of conformational transitions of single molecules as well as binding pathways for molecular complexes. The method begins by thoroughly sampling a set of conformational minima for a molecular system. The natural motions of the system are modeled using the normal modes of the sampled minima. The natural motions are utilized to connect conformational minima and are finally combined to form association/binding pathways in the case of molecular complexes. We provide an implementation and example application of the method using alanine dipeptide and a set of chemical host-guest systems: two cryptophane hosts with two guest cations, trimethylammonium and tetramethylammonium. Our results demonstrate that conformational transitions can be modeled and extended to find binding pathways as well as energetic information relevant to the minimum conformations involved. This approach has advantages over simulation-based methods for studying systems with slow binding processes and can help design molecules with preferred binding kinetics. PMID- 26583551 TI - Polarizable Interaction Model for Liquid, Supercritical, and Aqueous Ammonia. AB - A polarizable model for ammonia is optimized based on the ab initio properties of the NH3 molecule and the NH3-NH3 and NH3-H2O dimers calculated at the MP2 level. For larger (NH3)m, NH3(H2O)n, and H2O(NH3)n clusters (m = 2-7 and n = 1-4), the model yields structural and binding energies in good agreement with ab initio calculations without further adjustments. It also reproduces the structure, density, heat of vaporization, self-diffusion coefficient, heat capacity, and isothermal compressibility of liquid ammonia at the boiling point. The model is further validated by calculating some of these properties at various temperatures and pressures spanning the liquid and supercritical phases of the fluid (up to 700 K and 200 MPa). The excellent transferability of the model suggests that it can be used to investigate properties of fluid ammonia under conditions for which experiments are not easy to perform. For aqueous ammonia solutions, the model yields liquid structures and densities in good agreement with experimental data and allows the nonlinearity in the density-composition plot to be interpreted in terms of structural changes with composition. Finally, the model is used to investigate the solvation structure of ammonia in liquid water and of water in liquid ammonia and to calculate the solvation free energy of NH3 and H2O in aqueous ammonia as a function of solution composition and temperature. The simulation results suggest the presence of a transition around 50% molar NH3/H2O compositions, above which water molecules are preferably solvated by ammonia. PMID- 26583552 TI - Computational Spectroscopy of Large Systems in Solution: The DFTB/PCM and TD DFTB/PCM Approach. AB - The Density Functional Tight Binding (DFTB) and Time Dependent DFTB (TD-DFTB) methods have been coupled with the Polarizable Continuum Model (PCM) of solvation, aiming to study spectroscopic properties for large systems in condensed phases. The calculation of the ground and the excited state energies, together with the analytical gradient and Hessian of the ground state energy, have been implemented in a fully analytical and computationally effective approach. After sketching the theoretical background of both DFTB and PCM, we describe the details of both the formalism and the implementation. We report a number of examples ranging from vibrational to electronic spectroscopy, and we identify the strengths and the limitations of the DFTB/PCM method. We also evaluate DFTB as a component in a hybrid approach, together with a more refined quantum mechanical (QM) method and PCM, for the specific case of anharmonic vibrational spectra. PMID- 26583554 TI - Free Energy Calculations with Reduced Potential Cutoff Radii. AB - The Jarzynski Equality, the Crooks Fluctuation Theorem, and the Maximum Likelihood Estimator use a nonequilibrium approach for the determination of free energy differences due to a change in the state of a system. Here, this approach is used in combination with a novel transformation algorithm to increase computational efficiency in simulations with interacting particles, without losing accuracy. The algorithm is shown to work well for a Lennard-Jones fluid undergoing a change in density over three very different density ranges, and for the systems considered the algorithm demonstrates computational savings of up to approximately 90%. The results obtained directly from the Jarzynski Equality and from the Maximum Likelihood Estimator are also compared. PMID- 26583553 TI - Insights for an Accurate Comparison of Computational Data to Experimental Absorption and Emission Spectra: Beyond the Vertical Transition Approximation. AB - In this work we carefully investigate the relationship between computed data and experimental electronic spectra. To that end, we compare both vertical transition energies, EV, and characteristic frequencies of the spectrum like the maximum, nu(max), and the center of gravity, M(1), taking advantage of an analytical expression of M(1) in terms of the parameters of the initial- and final-state potential energy surfaces. After pointing out that, for an accurate comparison, experimental spectra should be preliminarily mapped from wavelength to frequency domain and transformed to normalized lineshapes, we simulate the absorption and emission spectra of several prototypical chromophores, obtaining lineshapes in very good agreement with experimental data. Our results indicate that the customary comparison of experimental nu(max) and computational EV, without taking into account vibrational effects, is not an adequate measure of the performance of an electronic method. In fact, it introduces systematic errors that, in the investigated systems, are on the order of 0.1-0.3 eV, i.e., values comparable to the expected accuracy of the most accurate computational methods. On the contrary, a comparison of experimental and computed M(1) and/or 0-0 transition frequencies provides more robust results. Some rules of thumbs are proposed to help rationalize which kind of correction one should expect when comparing EV, M(1), and nu(max). PMID- 26583555 TI - Noncovalent Interactions of DNA Bases with Naphthalene and Graphene. AB - The complexes of a DNA base bound to graphitic systems are studied. Considering naphthalene as the simplest graphitic system, DNA base-naphthalene complexes are scrutinized at high levels of ab initio theory including coupled cluster theory with singles, doubles, and perturbative triples excitations [CCSD(T)] at the complete basis set (CBS) limit. The stacked configurations are the most stable, where the CCSD(T)/CBS binding energies of guanine, adenine, thymine, and cytosine are 9.31, 8.48, 8.53, 7.30 kcal/mol, respectively. The energy components are investigated using symmetry-adapted perturbation theory based on density functional theory including the dispersion energy. We compared the CCSD(T)/CBS results with several density functional methods applicable to periodic systems. Considering accuracy and availability, the optB86b nonlocal functional and the Tkatchenko-Scheffler functional are used to study the binding energies of nucleobases on graphene. The predicted values are 18-24 kcal/mol, though many body effects on screening and energy need to be further considered. PMID- 26583556 TI - A Transferable Force Field for Primary, Secondary, and Tertiary Alkanolamines. AB - Due to the importance of alkanolamines as solvents in several industrial processes and the absence of a dedicated transferable force field for them, we have developed an anisotropic united-atom (AUA4) force field for primary, secondary, and tertiary alkanolamines. In addition to correctly reproducing the experimental densities, additional properties for six different molecules have been verified at different temperatures including vaporization enthalpies, vapor pressures, normal boiling points, critical temperatures, and critical densities. A qualitative analysis of the radial distribution function of pure monoethanolamine has also been carried out. Furthermore, the viscosity coefficients were also calculated as a function of temperature and found to be in good agreement with experimental data. Finally, and perhaps most strikingly, the prediction of the excess enthalpies of alkanolamines in aqueous solutions has been found to be in excellent qualitative agreement with experimental data. PMID- 26583557 TI - Automated Fragmentation QM/MM Calculation of Amide Proton Chemical Shifts in Proteins with Explicit Solvent Model. AB - We have performed a density functional theory (DFT) calculation of the amide proton NMR chemical shift in proteins using a recently developed automated fragmentation quantum mechanics/molecular mechanics (AF-QM/MM) approach. Systematic investigation was carried out to examine the influence of explicit solvent molecules, cooperative hydrogen bonding effects, density functionals, size of the basis sets, and the local geometry of proteins on calculated chemical shifts. Our result demonstrates that the predicted amide proton ((1)HN) NMR chemical shift in explicit solvent shows remarkable improvement over that calculated with the implicit solvation model. The cooperative hydrogen bonding effect is also shown to improve the accuracy of (1)HN chemical shifts. Furthermore, we found that the OPBE exchange-correlation functional is the best density functional for the prediction of protein (1)HN chemical shifts among a selective set of DFT methods (namely, B3LYP, B3PW91, M062X, M06L, mPW1PW91, OB98, OPBE), and the locally dense basis set of 6-311++G**/4-31G* is shown to be sufficient for (1)HN chemical shift calculation. By taking ensemble averaging into account, (1)HN chemical shifts calculated by the AF-QM/MM approach can be used to validate the performance of various force fields. Our study underscores that the electronic polarization of protein is of critical importance to stabilizing hydrogen bonding, and the AF-QM/MM method is able to describe the local chemical environment in proteins more accurately than most widely used empirical models. PMID- 26583558 TI - Computer Folding of RNA Tetraloops? Are We There Yet? AB - RNA hairpin loops represent important RNA motifs with indispensable biological functions in RNA folding and tertiary interactions, with the 5'-UNCG-3' and 5' GNRA-3' families being the most abundant. Molecular dynamics simulations represent a powerful method to investigate the structure, folding, and function of these tetraloops (TLs), but previous AMBER force fields were unable to maintain even the native structure of small TL RNAs. Here, we have used Replica Exchange Molecular Dynamics (REMD) with our recent reparameterization of AMBER RNA force field to study the folding of RNA hairpins containing representatives UNCG and GNRA TLs. We find that in each case, we are able to reach conformations within 2 A of the native structure, in contrast to results with earlier force fields. Although we find that the REMD simulation runs of a total of ~19 MUs (starting from both folded and unfolded state) in duration for each TL are still far from obtaining a representative equilibrium distribution at each temperature, we are nonetheless able to map the stable species on the folding energy landscape. The qualitative picture we obtain is consistent with experimental studies of RNA folding in that there are a number of stable on- and off-pathway intermediates en route to the native state. In particular, we have identified a misfolded-bulged state of GNRA TL, which shares many structural features with the X-ray structure of GNRA TL in the complex with restrictocin, namely the bulged out AL4 base. Since this is the same conformation observed in the complex of the TL with restrictocin, we argue that GNRA TL is able to bind restrictocin via a "conformational selection" mechanism, with the RL3 and AL4 bases being exposed to the solvent prior to binding. In addition we have identified a misfolded-anti state of UUCG TL, which is structurally close to the native state except that the GL4 nucleotide is in an anti-conformation instead of the native syn. Our data suggest that the UUCG misfolded-anti state may be a kinetic trap for the UUCG folding. PMID- 26583559 TI - Hybrid Metaheuristic Approach for Nonlocal Optimization of Molecular Systems. AB - Accurate modeling of molecular systems requires a good knowledge of the structure; therefore, conformation searching/optimization is a routine necessity in computational chemistry. Here we present a hybrid metaheuristic optimization (HMO) algorithm, which combines ant colony optimization (ACO) and particle swarm optimization (PSO) for the optimization of molecular systems. The HMO implementation meta-optimizes the parameters of the ACO algorithm on-the-fly by the coupled PSO algorithm. The ACO parameters were optimized on a set of small difluorinated polyenes where the parameters exhibited small variance as the size of the molecule increased. The HMO algorithm was validated by searching for the closed form of around 100 molecular balances. Compared to the gradient-based optimized molecular balance structures, the HMO algorithm was able to find low energy conformations with a 87% success rate. Finally, the computational effort for generating low-energy conformation(s) for the phenylalanyl-glycyl-glycine tripeptide was approximately 60 CPU hours with the ACO algorithm, in comparison to 4 CPU years required for an exhaustive brute-force calculation. PMID- 26583560 TI - Feasibility of optical coherence tomography for the evaluation of Barrett's mucosa buried underneath esophageal squamous epithelium. AB - OBJECTIVES: The evaluation of Barrett's glands buried underneath esophageal squamous epithelium becomes increasingly important to achieve curative treatments. However, clinically available endoscopies have critical limitations in depicting the subsurface structure, resulting in non-curative treatments. Optical coherence tomography (OCT) can acquire a high-resolution cross-sectional image, equivalent to an 'optical biopsy'. We aimed to assess the feasibility of the in vivo use of probe-type OCT imaging to evaluate Barrett's mucosa buried underneath esophageal squamous epithelium METHODS: We conducted a single-center prospective study with 14 consecutive patients with Barrett's adenocarcinoma from 2008 to 2014. The enrolled patients were examined by a probe-type OCT in vivo, followed by en bloc endoscopic submucosal dissection (ESD) with electric marking. Then, the one-to-one correlations between the OCT images of the buried mucosa and their histological assessment were examined. RESULTS: The overall accuracy, sensitivity, specificity, positive predictive value and negative predictive value of the buried mucosa in the OCT imaging were 85.7% (12/14), 77.8% (7/9), 100% (5/5), 100% (7/7) and 71.4% (5/7), respectively. However, OCT could not easily distinguish non-dysplastic glands from dysplastic glands. Additionally, the linear distance from the histological squamo-columnar junction in correct cases tended to be longer than that in incorrect cases (mm, median [range]: 2.0 [0.7 7.5] vs. 0.5 [0.5-0.5]). CONCLUSIONS: We demonstrated, for the first time, that pre-operative OCT imaging might be feasible for detecting the oral side extension of buried Barrett's mucosa to remove the entire area with malignant potential by ESD. This article is protected by copyright. All rights reserved. PMID- 26583561 TI - "Click" Incorporation of Radical/Ionic Sites into a Reactive Block Copolymer: A Facile and On-Demand Domain Functionalization Approach toward Organic Resistive Memory. AB - Reversible addition-fragmentation chain transfer polymerization yields reactive block copolymers bearing the pentafluorophenyl ester (PFPA) group, and subsequent Click amidation using 2,2,6,6-tetramethylpiperidine-N-oxyl- and imidazolium functionalized primary amines produces the corresponding functional block copolymers, leading to installation of statistical radical- and ionic sites into the PFPA segment. The monolayered thin film devices fabricated using the obtained block copolymers exhibit repeatable switching of electric conductivity (on/off ratio > 103 ) under a bias voltage, which reveals that the coexistence of radicals and ions in the same spherical domain of the copolymer layer is a prerequisite for repeatable switching memory. PMID- 26583562 TI - Layer-by-Layer Assembly of a Self-Healing Anticorrosion Coating on Magnesium Alloys. AB - Fabrication of self-healing anticorrosion coatings has attracted attention as it has the ability to extend the service life and prevent the substrate from corrosive attack. However, a coating system with a rapid self-healing ability and an improved corrosion resistance is rarely reported. In this work, we developed a self-healing anticorrosion coating on a magnesium alloy (AZ31). The coating comprises a cerium-based conversion layer, a graphene oxide layer, and a branched poly(ethylene imine) (PEI)/poly(acrylic acid) (PAA) multilayer. We incorporated the graphene oxide as corrosion inhibitors and used the PEI/PAA multilayers to provide the self-healing ability to the coating systems. X-ray diffraction (XRD) and Raman spectroscopy were used to characterize the composition of the multilayers, and scanning electron microscopy (SEM) was used to analyze the surface morphology. The electrochemical impedance spectroscopy (EIS) results illustrate the improved corrosion resistance of the coating. The proposed coating also has a rapid self-healing ability in the presence of water. PMID- 26583563 TI - Quantitative description of collagen fibre network on trabecular bone surfaces based on AFM imaging. AB - The collagen fibre network is an important part of extracellular matrix (ECM) on trabecular bone surface. The geometry features of the network can provide us insights into its physical and physiological properties. However, previous researches have not focused on the geometry and the quantitative description of the collagen fibre network on trabecular bone surface. In this study,we developed a procedure to quantitatively describe the network and verified the validity of the procedure. The experiment proceeds as follow. Atomic force microscopy (AFM) was used to acquire submicron resolution images of the trabecular surface. Then, an image analysing procedure was built to extract important parameters, including, fibre orientation, fibre density, fibre width, fibre crossing numbers, the number of holes formed by fibre s, and the area of holes from AFM images. In order to verify the validity of the parameters extracted by image analysing methods, we adopted two other methods, which are statistical geometry model and computer simulation, to calculate those same parameters and check the consistency of the three methods' results. Statistical tests indicate that there is no significant difference between three groups. We conclude that, (a) the ECM on trabecular surface mainly consists of random collagen fibre network with oriented fibres; (b) our method based on image analysing can be used to characterize quantitative geometry features of the collagen fibre network effectively. This method may provide a basis for quantitative investigating the architecture and function of collagen fibre network. PMID- 26583564 TI - Development of a sufficiently reactive thioalkylester involving the side-chain thiol of cysteine applicable for kinetically controlled ligation. AB - N(alpha) -Trifluoroacetyl-Cys-Leu-NH2 (TfaC-Leu-NH2 ) was incorporated into thioesters through its side-chain thiol group to develop a more reactive peptide thioester than the commonly used peptide-3-mercaptopropionic acid (MPA) thioester. The TfaC-thioester could be readily synthesized by solid-phase peptide synthesis (SPPS) with Boc chemistry using in situ neutralization protocols in sufficient yield without any side reaction associated with the use of TfaC. This thioester proved to display a much higher reactivity in the thiol-free native chemical ligation (NCL) reaction than the MPA-thioester and to be comparable to the thioarylester, such as the 4-mercaptophenylacetic acid (MPAA)-thioester, in terms of the ligation rate. We were able to demonstrate the usefulness of the TfaC-thioester by using it to synthesize neuromedin S via a one-pot sequential NCL approach followed by desulfurization. (c) 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 503-511, 2016. PMID- 26583565 TI - Genes and Environment in Multiple Sclerosis project: A platform to investigate multiple sclerosis risk. AB - The Genes and Environment in Multiple Sclerosis project establishes a platform to investigate the events leading to multiple sclerosis (MS) in at-risk individuals. It has recruited 2,632 first-degree relatives from across the USA. Using an integrated genetic and environmental risk score, we identified subjects with twice the MS risk when compared to the average family member, and we report an initial incidence rate in these subjects that is 30 times greater than that of sporadic MS. We discuss the feasibility of large-scale studies of asymptomatic at risk subjects that leverage modern tools of subject recruitment to execute collaborative projects. PMID- 26583566 TI - A model of acute kidney injury in mice with cirrhosis and infection. AB - BACKGROUND & AIMS: Infectious acute kidney injury (AKI) is a life threatening complication of cirrhosis with limited therapeutic options. The aim of this study was to develop a model of infectious AKI in cirrhotic mice. METHODS: Cirrhosis was established by intragastric administration of carbon tetrachloride (CCl4 ). Systemic haemodynamics was assessed invasively while cardiac function was assessed by echocardiography. AKI was induced using varying doses of lipopolysaccharide (LPS) titrated to produce 50% lethality. Renal function was assessed from serum creatinine and urine output (UOP). Renal injury was evaluated by urinalysis (proteinuria and casts) and renal histology. These mice were compared to: (i) normal mice, (ii) normal mice + LPS, and (iii) mice treated with CCl4 alone. RESULTS: Cirrhosis with increased cardiac output, decreased systemic vascular resistance, activation of renin-angiotensin-aldosterone axis developed after 12 weeks of CCl4 administration. LPS injection produced a dose-dependent increase in mortality (33% at 2 mg/kg vs. 80% at 6 mg/kg) without urine (casts or proteinuria) or histological evidence of tubular injury. 2 mg/kg LPS injection produced a rise in creatinine (0.79 +/- 0.27 mg/dl in CCl4 +LPS compared to 0.45 +/- 0.14 in CCl4 alone, P < 0.05) and a decrease in UOP (0.86 +/- 0.4 ml/16 h in CCl4 + LPS compared to 1.70 +/- 0.7 ml/16 h in CCl4 mice, P < 0.05). UOP remained low in mice that died while it recovered over 48-72 h in those that recovered. Control mice treated with 2 mg/kg LPS did not experience AKI. CONCLUSIONS: Cirrhotic CCl4 treated mice develop functional AKI and mimic most of the features of infectious AKI following LPS injection. PMID- 26583568 TI - Systematic review and meta-analysis of salivary protein concentration in Parkinson's disease. PMID- 26583567 TI - Novel oral transforming growth factor-beta signaling inhibitor EW-7197 eradicates CML-initiating cells. AB - Recent strategies for treating CML patients have focused on investigating new combinations of tyrosine kinase inhibitors (TKIs) as well as identifying novel translational research agents that can eradicate CML leukemia-initiating cells (CML-LICs). However, little is known about the therapeutic benefits such CML-LIC targeting therapies might bring to CML patients. In this study, we investigated the therapeutic potential of EW-7197, an orally bioavailable transforming growth factor-beta signaling inhibitor which has recently been approved as an Investigational New Drug (NIH, USA), to suppress CML-LICs in vivo. Compared to TKI treatment alone, administration of TKI plus EW-7197 to CML-affected mice significantly delayed disease relapse and prolonged survival. Notably, combined treatment with EW-7197 plus TKI was effective in eliminating CML-LICs even if they expressed the TKI-resistant T315I mutant BCR-ABL1 oncogene. Collectively, these results indicate that EW-7197 may be a promising candidate for a new therapeutic that can greatly benefit CML patients by working in combination with TKIs to eradicate CML-LICs. PMID- 26583569 TI - The Equilibrium Spreading Tension of Pulmonary Surfactant. AB - Monomolecular films at an air/water interface coexist at the equilibrium spreading tension (gamma(e)) with the bulk phase from which they form. For individual phospholipids, gamma(e) is single-valued, and separates conditions at which hydrated vesicles adsorb from tensions at which overcompressed monolayers collapse. With pulmonary surfactant, isotherms show that monolayers compressed on the surface of bubbles coexist with the three-dimensional collapsed phase over a range of surface tensions. gamma(e) therefore represents a range rather than a single value of surface tension. Between the upper and lower ends of this range, rates of collapse for spread and adsorbed films decrease substantially. Changes during adsorption across this narrow region of coexistence between the two- and three-dimensional structures at least partially explain how alveolar films of pulmonary surfactant become resistant to collapse. PMID- 26583571 TI - Outcomes of Interorganizational Networks in Canada for Chronic Disease Prevention: Insights From a Concept Mapping Study, 2015. AB - INTRODUCTION: We conducted a mixed methods study from June 2014 to March 2015 to assess the perspectives of stakeholders in networks that adopt a population approach for chronic disease prevention (CDP). The purpose of the study was to identify important and feasible outcome measures for monitoring network performance. METHODS: Participants from CDP networks in Canada completed an online concept mapping exercise, which was followed by interviews with network stakeholders to further understand the findings. RESULTS: Nine concepts were considered important outcomes of CDP networks: enhanced learning, improved use of resources, enhanced or increased relationships, improved collaborative action, network cohesion, improved system outcomes, improved population health outcomes, improved practice and policy planning, and improved intersectoral engagement. Three themes emerged from participant interviews related to measurement of the identified concepts: the methodological difficulties in measuring network outcomes, the dynamic nature of network evolution and function and implications for outcome assessment, and the challenge of measuring multisectoral engagement in CDP networks. CONCLUSION: Results from this study provide initial insights into concepts that can be used to describe the outcomes of networks for CDP and may offer foundations for strengthening network outcome-monitoring strategies and methodologies. PMID- 26583570 TI - Daunorubicin-Loaded DNA Origami Nanostructures Circumvent Drug-Resistance Mechanisms in a Leukemia Model. AB - Many cancers show primary or acquired drug resistance due to the overexpression of efflux pumps. A novel mechanism to circumvent this is to integrate drugs, such as anthracycline antibiotics, with nanoparticle delivery vehicles that can bypass intrinsic tumor drug-resistance mechanisms. DNA nanoparticles serve as an efficient binding platform for intercalating drugs (e.g., anthracyclines doxorubicin and daunorubicin, which are widely used to treat acute leukemias) and enable precise structure design and chemical modifications, for example, for incorporating targeting capabilities. Here, DNA nanostructures are utilized to circumvent daunorubicin drug resistance at clinically relevant doses in a leukemia cell line model. The fabrication of a rod-like DNA origami drug carrier is reported that can be controllably loaded with daunorubicin. It is further directly verified that nanostructure-mediated daunorubicin delivery leads to increased drug entry and retention in cells relative to free daunorubicin at equal concentrations, which yields significantly enhanced drug efficacy. Our results indicate that DNA origami nanostructures can circumvent efflux-pump mediated drug resistance in leukemia cells at clinically relevant drug concentrations and provide a robust DNA nanostructure design that could be implemented in a wide range of cellular applications due to its remarkably fast self-assembly (~5 min) and excellent stability in cell culture conditions. PMID- 26583572 TI - The Impact of Repeat Hospitalizations on Hospitalization Rates for Selected Conditions Among Adults With and Without Diabetes, 12 US States, 2011. AB - INTRODUCTION: Hospitalization data typically cannot be used to estimate the number of individuals hospitalized annually because individuals are not tracked over time and may be hospitalized multiple times annually. We examined the impact of repeat hospitalizations on hospitalization rates for various conditions and on comparison of rates by diabetes status. METHODS: We analyzed hospitalization data for which repeat hospitalizations could be distinguished among adults aged 18 or older from 12 states using the 2011 Agency for Healthcare Research and Quality's State Inpatient Databases. The Behavioral Risk Factor Surveillance System was used to estimate the number of adults with and without diagnosed diabetes in each state (denominator). We calculated percentage increases due to repeat hospitalizations in rates and compared the ratio of diabetes with non-diabetes rates while excluding and including repeat hospitalizations. RESULTS: Regardless of diabetes status, hospitalization rates were considerably higher when repeat hospitalizations within a calendar year were included. The magnitude of the differences varied by condition. Among adults with diabetes, rates ranged from 13.0% higher for stroke to 41.6% higher for heart failure; for adults without diabetes, these rates ranged from 9.5% higher for stroke to 25.2% higher for heart failure. Ratios of diabetes versus non-diabetes rates were similar with and without repeat hospitalizations. CONCLUSION: Hospitalization rates that include repeat hospitalizations overestimate rates in individuals, and this overestimation is especially pronounced for some causes. However, the inclusion of repeat hospitalizations for common diabetes-related causes had little impact on rates by diabetes status. PMID- 26583573 TI - Racial Disparities in Asthma Hospitalizations Following Implementation of the Smoke-Free Air Law, Michigan, 2002-2012. AB - INTRODUCTION: Exposure to secondhand smoke has immediate adverse respiratory and cardiovascular effects. A growing body of literature examining health trends following the implementation of public smoking bans has demonstrated reductions in the rates of myocardial infarction and stroke, but there has been no extensive work examining asthma hospitalizations. The aim of this study was to determine the impact of the Michigan Smoke-Free Air Law (SFA law) on the rate of asthma hospitalizations among adults in Michigan and to determine any differential effects by race or sex. METHODS: Data on adult asthma hospitalizations were obtained from the Michigan Inpatient Database (MIDB). Poisson regression was used to model relative risks for asthma hospitalization following the SFA law with adjustments for sex, race, age, insurance type, and month of year. Race-based and sex-based analyses were performed. RESULTS: In the first year following implementation of the SFA law, adjusted adult asthma hospitalization rates decreased 8% (95% confidence interval [CI], 7%-10%; P < .001). While asthma hospitalization rates for both blacks and whites declined in the 12 months following implementation of the SFA law, blacks were 3% more likely to be hospitalized for asthma than whites (95% CI, 0%-7%; P = .04). The rate of decline in adult asthma hospitalizations did not differ by sex. CONCLUSION: The implementation of the SFA law was associated with a reduction in adult asthma hospitalization rates, with a greater decrease in hospitalization rates for whites compared with blacks. These results demonstrate that the SFA law is protecting the public's health and saving health care costs. PMID- 26583574 TI - Aspirin Use for the Primary Prevention of Myocardial Infarction Among Men in North Carolina, 2013. AB - INTRODUCTION: The US Preventive Services Task Force recommends aspirin use for men aged 45 to 79, when the potential benefit of preventing myocardial infarctions outweighs the potential harm of gastrointestinal hemorrhage. We determined prevalence and predictors of aspirin use for primary prevention of myocardial infarction vis-a-vis risk among men aged 45 to 79 in North Carolina. METHODS: The study used data for men aged 45 to 79 without contraindications to aspirin use or a history of cardiovascular disease from the 2013 North Carolina Behavioral Risk Factor Surveillance System survey. Stratification by risk of myocardial infarction was based on history of diabetes, high cholesterol, high blood pressure, and smoking. Analyses were performed in Stata version 13.0 (StataCorp LP); survey commands were used to account for complex sampling design. RESULTS: Most respondents, 74.2% (95% confidence interval [CI], 71.2%-77.0%), had at least one risk factor for myocardial infarction. Prevalence of aspirin use among respondents with risk factors was 44.8% (95% CI, 41.0-48.5) and was significantly higher than the prevalence among respondents without risk factors (prevalence ratio: 1.44 [95% CI, 1.17-1.78]). No significant linear dose (number of risk factors)-response (taking aspirin) relationship was found (P for trend = .25). Older age predicted (P = .03) aspirin use among respondents with at least one myocardial infarction risk factor. CONCLUSION: Most men aged 45 to 79 in North Carolina have at least one risk factor for myocardial infarction, but less than half use aspirin. Interventions aimed at boosting aspirin use are needed among at-risk men in North Carolina. PMID- 26583575 TI - Relationship of Age for Grade and Pubertal Stage to Early Initiation of Substance Use. AB - INTRODUCTION: Studies suggest students who are substantially older than the average age for their grade engage in risky health behaviors, including substance use. However, most studies do not account for the distinct reasons why students are old for their grade (ie, grade retention vs delayed school entry) or for their pubertal stage. Thus, whether the association between age for grade and substance use is confounded by these factors is unknown. We sought to determine whether age, grade, or pubertal stage were associated with early substance use. METHODS: Cross-sectional Healthy Passages Wave I survey data from 5,147 fifth graders and their caregivers in Alabama, California, and Texas from 2004 through 2006 were analyzed in 2014. Logistic regressions examined whether older age for grade, grade retention, delayed school entry, or pubertal stage were associated with use of any substance, cigarettes, alcohol, or other drugs. RESULTS: Seventeen percent of fifth graders reported trying at least 1 substance. Among boys, advanced pubertal stage was associated with increased odds of cigarette, alcohol, or other drug use, whereas delayed school entry was associated with lower odds of any substance, alcohol, or other drug use. Among girls, advanced pubertal stage was associated only with higher odds of alcohol use, and delayed school entry was not associated with substance use. Neither older age for grade or grade retention was independently associated with substance use after controlling for potential confounders. CONCLUSION: Advanced pubertal stage may be a more important risk factor for substance use than age for grade. Pediatricians should consider initiating substance use screening earlier for patients with advanced pubertal stage. PMID- 26583578 TI - Tetrahydroxystilbene glucoside inhibits TNF-alpha-induced migration of vascular smooth muscle cells via suppression of vimentin. AB - Vascular smooth muscle cell (VSMC) migration triggered by TNF-alpha is an important event that occurs during the development of atherosclerosis. 2,3,5,4' Tetrahydroxystilbene-2-O-beta-d-glucoside (TSG) has been proven to exhibit significant anti-atherosclerotic activity. Herein we investigate the inhibitory effect of TSG on TNF-alpha-induced VSMC migration and explore the underlying mechanisms. TSG pretreatment markedly inhibited TNF-alpha-induced cell migration. The inhibition of vimentin redistribution and expression was involved in the inhibitory effect of TSG on VSMC migration. The suppression of vimentin expression by shRNA in VSMCs significantly inhibited TNF-alpha-induced cell migration. Furthermore, TSG inhibited the TNF-alpha-induced expression of TGFbeta1 and TGFbetaR1, and phosphorylation of TGFbetaR1 and Smad2/3. TSG also suppressed the nuclear translocation of Smad4 induced by TNF-alpha. These results suggest that TSG inhibits VSMC migration induced by TNF-alpha through inhibiting vimentin rearrangement and expression. The interruption of TGFbeta/Smad pathway appears to be responsible for the suppression of TSG on vimentin expression. PMID- 26583576 TI - Metformin for cancer and aging prevention: is it a time to make the long story short? AB - During the last decade, the burst of interest is observed to antidiabetic biguanide metformin as candidate drug for cancer chemoprevention. The analysis of the available data have shown that the efficacy of cancer preventive effect of metformin (MF) and another biguanides, buformin (BF) and phenformin (PF), has been studied in relation to total tumor incidence and to 17 target organs, in 21 various strains of mice, 4 strains of rats and 1 strain of hamsters (inbred, outbred, transgenic, mutant), spontaneous (non- exposed to any carcinogenic agent) or induced by 16 chemical carcinogens of different classes (polycycIic aromatic hydrocarbons, nitroso compounds, estrogen, etc.), direct or indirect (need metabolic transformation into proximal carcinogen), by total body X-rays and gamma- irradiation, viruses, genetic modifications or special high fat diet, using one stage and two-stage protocols of carcinogenesis, 5 routes of the administration of antidiabetic biguanides (oral gavage, intraperitoneal or subcutaneous injections, with drinking water or with diet) in a wide ranks of doses and treatment regimens. In the majority of cases (86%) the treatment with biguanides leads to inhibition of carcinogenesis. In 14% of the cases inhibitory effect of the drugs was not observed. Very important that there was no any case of stimulation of carcinogenesis by antidiabetic biguanides. It was conclude that there is sufficient experimental evidence of anti-carcinogenic effect of antidiabetic biguanides. PMID- 26583579 TI - Women and Aging. PMID- 26583577 TI - A combined upflow anaerobic sludge bed, aerobic, and anoxic fixed-bed reactor system for removing tetramethylammonium hydroxide and nitrogen from light emitting diode wastewater. AB - A laboratory study using a combined upflow anaerobic sludge bed (UASB) and aerobic and anoxic fixed-bed reactor system was undertaken to explore its capability for removing tetramethylammonium hydroxide (TMAH) and nitrogen from light-emitting diode wastewater. When the organic loading rate was maintained at 0.26-0.65 kg TMAH m(-3 )d(-1), the UASB reactor removed 70-100% of TMAH through methanogenesis. When the [Formula: see text] -N loading rate was maintained at 0.73-1.4 kg [Formula: see text]-N m(-3 )d(-1), the aerobic reactor oxidized 31 59% of [Formula: see text]-N to [Formula: see text]-N through nitritation. When the nitrogen loading rate was maintained at 0.42-0.75 kg N m(-3 )d(-1), the anoxic reactor removed 27-63% of nitrogen through anammox. The performance data of the combined reactor system agreed well with the stoichiometric relationships of methanogenesis, nitritation, and anammox. The batch studies showed that a higher initial TMAH concentration of up to 2520 mg L(-1) gave a higher methanogenic activity of up to 16 mL CH4 g(-1) VSS d(-1). An increase in the initial TMAH concentration of up to 500 mg L(-1) gradually decreased the activity of ammonia-oxidizing bacteria; whereas an increase in the initial TMAH concentration of up to 47 mg L(-1) imposed a marked inhibiting effect on the activity of anammox bacteria. PMID- 26583582 TI - Follicle-Stimulating Hormone Induces Postmenopausal Dyslipidemia Through Inhibiting Hepatic Cholesterol Metabolism. AB - CONTEXT: The elevated low-density-lipoprotein cholesterol (LDL-C) in menopausal women is associated with higher risks of cardiovascular diseases. OBJECTIVE: The aim of this study is to investigate the influence and mechanism by which high postmenopausal FSH levels affect lipid profiles. METHODS: The serum FSH and lipid levels were examined in 400 Chinese postmenopausal women. The FSH receptor (FSHR) expression was identified in liver and HepG2 cells by PCR and Western blotting. The effects of FSH on lipid metabolism were confirmed in an ovariectomized mouse model by using GnRH agonist with or without additional FSH to mimic different FSH status. LDL receptor (LDLR), a necessary factor for clearance of LDL-C through endocytosis, was examined by PCR and Western blotting. RESULTS: The postmenopausal women with higher serum FSH (>=78.3 IU/L at baseline) had higher serum total cholesterol and LDL-C levels than those women with FSH levels of 40 78.3 IU/L (P < .01). The improvements of total cholesterol and LDL-C levels were more significant in higher FSH women group after treatment with hormone replacement therapy. It was only in the women whose FSH levels were reduced more than 30% after hormone replacement therapy who showed significant improvement of lipid levels. Ovariectomized mice had high serum FSH and lipids levels and reduced hepatic LDLR expression. In HepG2 cells, FSH inhibited the LDLR in a dose and time-dependent manner, and the FSHR knockdown with specific siRNA reversed the lower LDLR induced by FSH. CONCLUSIONS: FSH may interact with its receptors in hepatocytes and reduce LDLR levels, which subsequently attenuates the endocytosis of LDL-C, resulting in an elevated circulating LDL-C level. PMID- 26583583 TI - Prevalence of Thyroid Dysfunction in Autoimmune and Type 2 Diabetes: The Population-Based HUNT Study in Norway. AB - CONTEXT: Associations between autoimmune diabetes and autoimmune thyroid disease are known but insufficiently characterized. Some evidence suggests that type 2 diabetes may also be associated with hypothyroidism. OBJECTIVE: The objective of the study was to investigate associations of autoimmune and type 2 diabetes with the prevalence of hypo- and hyperthyroidism. DESIGN AND SETTING: This was a cross sectional, population-based study of adults in two surveys of the Nord-Trondelag Health (HUNT) Study. PARTICIPANTS: A total of 34 235 participants of HUNT2 (1995 1997) and 48 809 participants of HUNT3 (2006-2008) participated in the study. MAIN OUTCOME MEASURES: Prevalence of hypo- and hyperthyroidism was estimated, assessed by self-report, serum measurements, and linkage with the Norwegian Prescription Database. RESULTS: In HUNT2, autoimmune diabetes was associated with a higher age-adjusted prevalence of hypothyroidism among both women (prevalence ratio 1.79, 95% confidence interval [CI] 1.30-2.47) and men (prevalence ratio 2.71, 95% CI 1.76-4.19), compared with having no diabetes. For hyperthyroidism, the corresponding cumulative prevalence ratios were 2.12 (95% CI 1.36-3.32) in women and 2.54 (95% CI 1.24-5.18) in men with autoimmune diabetes. The age adjusted excess prevalence of hypothyroidism (~6 percentage points) and the presence of thyroid peroxidase antibodies (8-10 percentage points) associated with autoimmune diabetes was similar in women and men. Type 2 diabetes was not associated with the prevalence of hypothyroidism. In HUNT3, associations were broadly similar to those in HUNT2. CONCLUSIONS: Autoimmune diabetes, but not type 2 diabetes, was strongly and gender neutrally associated with an increased prevalence of hypo- and hyperthyroidism and the presence of thyroid peroxidase antibodies. Increased surveillance for hypothyroidism appears not necessary in patients with type 2 diabetes. PMID- 26583584 TI - Coming Up Short: Risks of Bias in Assessing Psychological Outcomes in Growth Hormone Therapy for Short Stature. AB - CONTEXT: Two often cited assumptions for treating children with GH are that short stature (SS), as an isolated physical characteristic, is associated with psychosocial morbidity and that GH treatment may increase height and improve psychological adjustment. Findings across studies regarding the psychological consequences associated with GH management of children with SS are variable and frequently contradictory. The purpose of this systematic review is to evaluate the degree to which any conclusions about the relative risks or benefits of GH treatment on psychological outcomes can be made based on the published literature. EVIDENCE ACQUISITION: Electronic databases were searched for randomized clinical trials and nonrandomized studies, published between 1958 2014, in which GH was administered for management of children with SS and psychosocial, cognitive, academic, or health-related quality of life outcomes were assessed. Methodological quality of each study was assessed using the Cochrane Collaboration's tool for assessing risk of bias. EVIDENCE SYNTHESIS: Eighty studies were evaluated. No studies were rated as having a low risk of bias, the risk of bias was unclear in seven study outcome areas, and the remaining studies were judged as having a high risk of bias. CONCLUSIONS: The high risk of bias present in the majority of the literature on GH treatment effects on psychological outcomes (in particular, lack of blinding) substantially weakens confidence in their results. This may serve to explain the variability of findings for these outcomes across studies. PMID- 26583585 TI - Accumulation and Changes in Composition of Collagens in Subcutaneous Adipose Tissue After Bariatric Surgery. AB - CONTEXT: Extracellular matrix (ECM) in sc adipose tissue (scAT) undergoes pathological remodeling during obesity. However, its evolution during weight loss remains poorly explored. OBJECTIVE: The objective of the investigation was to study the histological, transcriptomic, and physical characteristics of scAT ECM remodeling during the first year of bariatric surgery (BS)-induced weight loss and their relationships with metabolic and bioclinical improvements. DESIGN, SETTING, PATIENTS, AND INTERVENTIONS: A total of 118 morbidly obese candidates for BS were recruited and followed up during 1 year after BS. MAIN OUTCOME MEASURES: scAT surgical biopsy and needle aspiration as well as scAT stiffness measurement were performed in three subgroups before and after BS. Fourteen nonobese, nondiabetic subjects served as controls. RESULTS: Significantly increased picrosirius-red-stained collagen accumulation in scAT after BS was observed along with fat mass loss, despite metabolic and inflammatory improvements and undetectable changes of scAT stiffness. Collagen accumulation positively associated with M2-macrophages (CD163(+) cells) before BS but negatively afterward. Expression levels of genes encoding ECM components (eg, COL3A1, COL6A1, COL6A2, ELN), cross-linking enzymes (eg, lysyl oxidase [LOX], LOXL4, transglutaminase), metalloproteinases, and their inhibitors were modified 1 year after BS. LOX expression and protein were significantly decreased and associated with decreased fat mass as well as other cross-linking enzymes. Although total collagen I and VI staining decreased 1 year after BS, we found increased degraded collagen I and III in scAT, suggesting increased degradation. CONCLUSIONS: After BS-induced weight loss and related metabolic improvements, scAT displays major collagen remodeling with an increased picrosirius-red staining that relates to increased collagen degradation and importantly decreased cross-linking. These features are in agreement with adequate ECM adaptation during fat mass loss. PMID- 26583587 TI - Breastfeeding Medicine: A Journal for the Future. PMID- 26583586 TI - Maternal and Birth Characteristics Are Determinants of Offspring Thyroid Function. AB - BACKGROUND: Intrauterine adaptation to the outside environment is an important mechanism via which the fetus increases its chance to thrive after birth. Therefore, various maternal-, pregnancy-, and labor-related factors are potential determinants of thyroid function of the offspring. Animal studies suggest that very high maternal thyroid hormone levels during pregnancy can alter the development of the hypothalamic-pituitary-thyroid axis set point of the child. However, to what extent maternal and birth characteristics (including maternal thyroid function, smoking, and birth weight) are associated with thyroid function of the offspring is currently unknown. METHODS: We selected 4273 mother-child pairs from a large population-based prospective cohort with data available on maternal gestational TSH and free T4 (FT4) levels and newborn TSH and FT4 (n = 3339; at birth) or childhood TSH and FT4 (n = 2523; median age, 6 y). We used multivariable (non)linear regression models to study the association of potential determinants (including maternal TSH, FT4, thyroid peroxidase antibodies, iodine excretion, age, body mass index, smoking status, parity, pre-eclampsia, fetal distress, gestational age at birth, birth weight, mode of delivery, and thyroid function-associated single nucleotide polymorphisms) with newborn and childhood TSH and FT4. RESULTS: There was a strong association of maternal TSH and FT4 levels during pregnancy with newborn and childhood TSH and FT4 levels, respectively (for both, P < .0001). Maternal FT4 was also associated with newborn TSH levels (P = .0009). Birth weight, fetal distress, gestational age at birth and maternal parity were all associated with newborn TSH and/or FT4 (P < .0001), but these associations did not persist into childhood. Genetic risk scores for TSH and FT4 were strongly associated with newborn and childhood thyroid function (P <= .0005). The association between maternal and offspring thyroid function did not change after correction for genetic risk scores. CONCLUSIONS: In this study, childhood thyroid function was predominantly determined by maternal TSH or FT4 levels and thyroid-specific single nucleotide polymorphisms. Effects of stress related changes in thyroid function at birth were transient. Other potential factors were not associated with offspring thyroid function. PMID- 26583588 TI - The Mediating Role of Emotion Dysregulation in the Relations Between Childhood Trauma History and Adult Attachment and Borderline Personality Disorder Features: A Study of Italian Nonclinical Participants. AB - In order to evaluate if emotion dysregulation significantly mediates the relationships between childhood abuse and adult attachment and borderline personality disorder features, 354 community Italian adults were administered the Borderline Personality Inventory (Leichsenring, 1999a), the Difficulties in Emotion Regulation Scale (Gratz & Roemer, 2004), the Child Abuse and Trauma Scale (Sanders & Becker-Lausen, 1995), and the Attachment Style Questionnaire (Feeney, Noller, & Hanrahan, 1994). Hierarchical regression analyses showed that both childhood abuse and adult attachment were positively associated with emotion dysregulation and borderline personality features; however, only emotional abuse and the attachment dimension of need for approval were common predictors of both dependent variables. No significant interaction effects were detected in regression analyses. Mediation analyses provided support for partial mediation, revealing a significant mediating role of emotion dysregulation in the relationships between both emotional abuse and need for approval and borderline personality features in this community sample. PMID- 26583589 TI - Sexual Orientation and Borderline Personality Disorder Features in a Community Sample of Adolescents. AB - Empirical literature demonstrates that sexual minorities are at an increased risk of developing psychopathology, including borderline personality disorder (BPD). The specific link between sexual orientation and BPD has received significantly less attention in youth, and it remains unclear what drives this relation. Given that there are higher rates of psychopathology in both sexual minorities and individuals with BPD, the present study aimed to determine if sexual orientation uniquely contributes to borderline personality pathology, controlling for other psychopathology. An ethnically diverse sample of 835 adolescents completed self report measures of borderline features, depression, anxiety, and sexual orientation. Sexual minorities scored higher on borderline features compared to heterosexual adolescents. When controlling for depression and anxiety, sexual orientation remained significantly associated with borderline features. The relation between sexual orientation and BPD cannot fully be explained by other psychopathology. Future research is necessary to understand potential mechanisms underlying this relation. PMID- 26583590 TI - Developmental Antecedents of the Facets of Psychopathy: The Role of Multiple Abuse Experiences. AB - The etiology of psychopathy remains poorly understood, despite the wealth of studies focused on examining this serious and complex personality disorder. The present study explored the contribution of psychological, physical, and sexual abuse in predicting PCL-R facet and total scores. The study was conducted on a sample of 397 adult male sexual offenders, using archival ratings and developmental data gathered with a self-report inventory, the Multidimensional Assessment of Sex and Aggression (the MASA). All types of abuse covaried with the total PCL-R score, but the kinds of abuse were differentially associated with the facet scores. Sexual abuse was positively associated with Interpersonal and Lifestyle facet scores, whereas physical abuse was associated with Lifestyle and Antisocial facets. Psychological abuse covaried with the Affective facet, but the relation was negative. The results of the structural equation model underscored the significance of physical abuse, above and beyond psychological and sexual abuse. PMID- 26583591 TI - Comparison of Two Laparoscopic Techniques for Gastropexy in Children. AB - BACKGROUND: Laparoscopic gastrostomy is a widely used interventional procedure in pediatric surgery. We report comparative data for two endosurgical methods for the fixation of the stomach against the abdominal wall, using the U-stitches technique and the Saf-T-Pexy(r) (Halyard Health Inc., Alpharetta, GA) system. MATERIALS AND METHODS: Within the period from January 2012 to June 2014 we performed 24 operations involving laparoscopic placement of a gastrostomy tube using U-stitches (Group I) and 24 operations using the Saf-T-Pexy system (Group II). The two groups of patients were compared in terms of demographics and intraoperative and postoperative results. RESULTS: No statistical difference (P > .05) was found while comparing the patients' demographics and intra- and postoperative results. The mean duration of the surgical procedure in Group I was 23.75 minutes; in contrast, the mean duration of surgery in Group II was 22.71 minutes (P > .05). The time to first feeding (9.96 hours versus 10.63 hours) and time to full enteral feeding (23.13 hours versus 24.5 hours) were consistent for patients from both groups (P > .05). A similar postoperative duration of stay was recorded for the patients from the comparison groups (7.25 days versus 7.21 days; P > .05). Statistical analysis of the two groups demonstrated a significant difference in the parameters of minor postoperative complications (41.67% versus 8.33%; P < .05). CONCLUSIONS: Use of the Saf-T-Pexy system is a simple and efficient method for gastropexy involving placement of gastrostomy tubes that significantly reduces the number of postoperative complications. PMID- 26583592 TI - Optimized Diagnostic Assays Based on Redox Tagged Bioreceptive Interfaces. AB - Among the numerous label free electronic biomarker assay methodologies now available, impedance based electrochemical capacitance spectroscopy (ECS), based upon mapping the perturbations in interfacial charging of redox elements incorporated into a biologically receptive interface, has recently been shown to be a convenient and highly sensitive mode of transduction and one which, additionally, requires no predoping of analytical solution. We present, herein, a data acquisition and analysis methodology based on frequency resolved immittance function analysis. Ultimately, this enables both a maximization of assay sensitivity and a reduction in assay acquisition time by an order of magnitude. PMID- 26583593 TI - Timing of renal replacement therapy in acute kidney injury. AB - Acute kidney injury (AKI) is a frequent finding in patients with critical illness. In many of these patients renal replacement therapy (RRT) is needed to support organ dysfunction. Although international guidelines on the management of AKI have been developed and are widely accepted, there is still considerable controversy on the optimal timing of RRT. The clinician is in a constant dilemma that level of evidence (on timing of acute RRT) is low and the issue is of high importance. Despite this paucity of high quality prospective data, this review will give the reader an idea on how to approach the difficult question of initiating RRT. Obviously, no general recommendation can be given covering every aspect of intensive care medicine. Therefore, general thoughts are displayed, followed by a focus on specific clinical situations. The role of "novel" biomarkers in the process of deciding when to start is also discussed. PMID- 26583594 TI - Prevention and conservative management of acute kidney injury. AB - The incidence of acute kidney injury (AKI) is increasing steadily. This can be attributed to a growing prevalence of risk factors for AKI, such as aging, diabetes, underlying cardiovascular disease and the escalating application of more complex procedures. Currently, there is no treatment for established AKI, except for renal replacement therapy in case of life-threatening conditions. The focus should thus be shifted towards AKI prevention rather than treatment. Several promising pharmacological and non-pharmacological interventions for prevention of AKI in animal models did not fulfill the expectations when applied in humans. There are multiple reasons why these interventions prove to be disappointing. The pathophysiology of AKI in different settings has not been fully elucidated, the underlying cause of AKI in the clinical setting is often multifactorial, and animal AKI models often do not mimic human AKI very well. Ischemia-reperfusion models are representative for human AKI in the setting of aortic clamping or in case of delayed graft function after kidney transplantation, but are not suited to study AKI in many other conditions such as sepsis. Moreover, several drugs for AKI prevention are associated with deleterious adverse events in humans as they lack selectivity. In this review, an overview of the strategies that can be used in the clinical setting for AKI prevention will be presented. Potential preventive strategies in certain specific clinical conditions will also be reviewed. PMID- 26583595 TI - Urachal cancer: contemporary review of the pathological, surgical, and prognostic aspects of this rare disease. AB - Surgery is the mainstay of treatment for patients with urachal cancer (UraC). Still, one third of patients are un-resectable at presentation. Histology shows adenocarcinomas in the majority of cases with resemblance to enteric tumors. Standard chemotherapeutic regimens for bladder cancer have failed these patients. The role and efficacy of radiotherapy remains unclear due to its use in combination with chemotherapy or in a palliative setting. A lack of background knowledge about this disease leaves practitioners with unanswered questions when recommending (neo)adjuvant or palliative treatment options. Despite the lack of large multicenter series or randomized studies, independent case series have found commonalities with gastric, colorectal or ovarian cancers. Better clinical staging, advanced surgical techniques and a variety of (neo)adjuvant therapy combinations spawn hope for improved survival for these patients. Genetic and immunohistochemical studies are debating a common origin of this disease. Meta analyses of clinical data are showing prognosticators and risk factors. UraC is a rare disease characterized by malignant degeneration of the urachal remnant with the highest incidence in fifty to sixty year old individuals. Unlike bladder cancer, the majority of UraC cases are adenocarcinomas. Its classical location at the bladder dome, advanced stage at presentation and symptoms like hematuria and mucinuria, should make the clinician suspicious. It is important to look for metastases or mucous cysts during clinical staging to determine the possibility of a curative approach. Up to date, surgery including on-bloc resection of the urachal ligament, the bladder dome and the umbilicus is the only proven cure. R0 resection is crucial for recurrence free survival. Adjuvant or palliative therapy can prolong survival in un-resectable or recurrent disease. While curative patients have a survival well above 50% over five years, palliative patients average only two years. Scientific knowledge about UraC is comprised of single center experiences, small collected cohorts or pathology/cancer registry database searches. Many questions like validated staging, (neo)adjuvant treatment options, differences in outcome for different tumor types and the existence of a common genetic origin are still unanswered. Future studies and trials are needed to address these important topics. PMID- 26583596 TI - Experimental determination of the lateral dose response functions of detectors to be applied in the measurement of narrow photon-beam dose profiles. AB - This study aims at the experimental determination of the detector-specific 1D lateral dose response function K(x) and of its associated rotational symmetric counterpart K(r) for a set of high-resolution detectors presently used in narrow beam photon dosimetry. A combination of slit-beam, radiochromic film, and deconvolution techniques served to accomplish this task for four detectors with diameters of their sensitive volumes ranging from 1 to 2.2 mm. The particular aim of the experiment was to examine the existence of significant negative portions of some of these response functions predicted by a recent Monte-Carlo-simulation (Looe et al 2015 Phys. Med. Biol. 60 6585-607). In a 6 MV photon slit beam formed by the Siemens Artiste collimation system and a 0.5 mm wide slit between 10 cm thick lead blocks serving as the tertiary collimator, the true cross-beam dose profile D(x) at 3 cm depth in a large water phantom was measured with radiochromic film EBT3, and the detector-affected cross-beam signal profiles M(x) were recorded with a silicon diode, a synthetic diamond detector, a miniaturized scintillation detector, and a small ionization chamber. For each detector, the deconvolution of the convolution integral M(x) = K(x) * D(x) served to obtain its specific 1D lateral dose response function K(x), and K(r) was calculated from it. Fourier transformations and back transformations were performed using function approximations by weighted sums of Gaussian functions and their analytical transformation. The 1D lateral dose response functions K(x) of the four types of detectors and their associated rotational symmetric counterparts K(r) were obtained. Significant negative curve portions of K(x) and K(r) were observed in the case of the silicon diode and the diamond detector, confirming the Monte-Carlo-based prediction (Looe et al 2015 Phys. Med. Biol. 60 6585-607). They are typical for the perturbation of the secondary electron field by a detector with enhanced electron density compared with the surrounding water. In the cases of the scintillation detector and the small ionization chamber, the negative curve portions of K(x) practically vanish. It is planned to use the measured functions K(x) and K(r) to deconvolve clinical narrow-beam signal profiles and to correct the output factor values obtained with various high resolution detectors. PMID- 26583597 TI - Efficacy of visual-scanning training and prism adaptation for neglect rehabilitation. AB - Unilateral spatial neglect consists of the inability of a patient to respond, orient, and attend to stimuli on the left side of a space following a right hemisphere lesion. Many rehabilitation approaches have been proposed to reduce neglect. The aim of our study was to compare the effect of visual-scanning training (VST) and prismatic adaptation (PA) on patients with neglect following a right-hemisphere lesion. Twenty patients with left neglect were enrolled in the study. Before and after training, a comprehensive neuropsychological assessment of visuospatial abilities, evaluating personal, peripersonal, and extrapersonal neglect, was performed. After assessment, patients were alternately assigned to 1 of 2 groups, VST or PA. Both trainings consisted of 20 sessions, 1 per day, 5 days a week for 4 weeks. The results showed that both treatments improved patient neglect, especially in personal and peripersonal spaces. No difference between pretreatment and posttreatment was found in extrapersonal subscales. This finding could be due to the fact that there were no exercises requiring the use of objects within reach in either training. In conclusion, no difference between the 2 approaches was found, and both are useful rehabilitation techniques that appear to improve neglect. PMID- 26583599 TI - Hunter Island Group Phlebovirus in Ticks, Australia. PMID- 26583598 TI - Continued Substance Use Among People Living With HIV-Hepatitis-C Co-Infection and Receiving Antiretroviral Therapy. AB - BACKGROUND: Co-infection with human immunodeficiency virus (HIV) and Hepatitis-C virus (HCV) poses a significant threat to personal and public health. Substance use among co-infected persons leads to increased morbidity and mortality. The purpose of this study is to examine the continued substance use of people living with HIV-HCV co-infection and receiving antiretroviral therapy (ART). METHODS: Individuals living with HIV infection in Atlanta, GA and currently receiving ART (N = 678) completed audio-computer-assisted self-interviews for demographic, health, and behavior characteristics; unannounced pill counts to assess ART adherence over one month; finger-stick blood specimens collected for HCV antibody testing and urine specimens for drug use screening; and obtained HIV viral load and CD4 cell counts from their medical provider. We performed cross-sectional analyses for behavioral and biological markers of health, health behaviors, and substance use. RESULTS: Among participants, 131 (19%) were HIV-HCV co-infected; 53% were HIV-mono-infected, and 60% of HIV-HCV co-infected participants tested positive for use of at least one non-alcohol drug: tetrahydrocannabinol (THC) and cocaine were most prevalent. HIV-HCV co-infected individuals were older, with no other significant differences. Within the HIV-HCV co-infected participants, drug users (N = 87) did not differ from non-drug users (N = 53) in terms of ART adherence. However, drug users were significantly more likely to have uncontrolled HIV (17%) compared with those who did not test drug positive (4%). CONCLUSIONS: Substance use is prevalent in persons with HIV-HCV co-infection and may interfere with ART. Research with a larger and more representative sample is needed to replicate and confirm these results. PMID- 26583600 TI - Cardiopulmonary Exercise Testing in Patients with Asymptomatic or Equivocal Symptomatic Aortic Stenosis: Feasibility, Reproducibility, Safety and Information Obtained on Exercise Physiology. AB - OBJECTIVE: The aim of this study was to determine the feasibility, reproducibility, safety and information obtained on exercise physiology from cardiopulmonary exercise testing (CPX) in patients with aortic stenosis. METHODS: Patients with an aortic valve area (AVA) <1.3 cm2 who were judged asymptomatic or equivocal symptomatic underwent CPX and an inert gas rebreathing test. Only those where comprehensive evaluation of CPX results indicated haemodynamic compromise from aortic stenosis were referred for valve replacement. RESULTS: The mean patient age was 72 (+/-9) years; an AVA index <0.6 cm2/m2 and equivocal symptomatic status were found in 90 and 70%, respectively. CPX was feasible in 130 of the 131 patients. The coefficients of repeatability by test-retest were 5.4% (pVO2) and 4.6% (peak O2 pulse). A pVO2 <83% of the expected was predicted by a lower stroke volume at exercise, lower peak heart rate and FEV1, and higher VE/VCO2, but not by AVA index. Equivocal symptomatic status and a low gradient but high valvulo-arterial impedance were associated with a lower pVO2, but not with an inability to increase stroke volume. In total, 18 patients were referred for valve replacement. At 1 year, no cardiovascular deaths had occurred. CONCLUSIONS: CPX was feasible and reproducible and provided comprehensive data on exercise physiology. A CPX-guided treatment strategy was safe up to 1 year. PMID- 26583601 TI - Catalytic metallodrugs based on the LaR2C peptide target HCV SLIV IRES RNA. AB - Prior work has demonstrated the potential effectiveness of a new class of metallopeptides as catalytic metallodrugs that target HCV IRES SLIIb RNA (Cu GGHYrFK, 1). Herein new catalytic metallodrugs (GGHKYKETDLLILFKDDYFAKKNEERK, 2; and GGHKYKETDL, 3) are described based on the LaR2C peptide that has been shown to bind to the SLIV HCV IRES domain. In vitro fluorescence assays yielded KD values ~10 MUM for both peptides and reaction of the copper derivatives with SLIV RNA demonstrated initial rates comparable across different assays as well as displaying pseudo-Michaelis-Menten behavior. The sites of reaction and cleavage mechanisms were determined by MALDI-TOF mass spectrometry. The primary site of copper-promoted SLIV cleavage is shown to occur in the vicinity of the 5' G17C18A19C20-3' sequence that corresponds to a known binding site of the RM2 motif of the human La protein and has previously been reported to be important for viral translation. This domain also flanks the internal start codon (AUG). Both copper complexes also showed efficacy in an HCV replicon assay (IC50 = 0.75 MUM for 2-Cu, and 2.17 MUM for 3-Cu) and show potential for treatment of hepatitis C, complementing other marketed drugs by acting on a distinct therapeutic target by a novel mechanism of action. PMID- 26583602 TI - Longitudinal Assessment of Left and Right Myocardial Function in Preterm Infants Using Strain and Strain Rate Imaging. AB - BACKGROUND: There is a paucity of longitudinal data on left ventricular (LV) and right ventricular (RV) function in preterm infants of less than 29 weeks' gestation. OBJECTIVE: The aim of this study was to describe changes in tissue Doppler-derived basal longitudinal strain (BLS) and systolic (SRs), early (SRe) and late (SRa) diastolic strain rates in extremely premature infants from birth to 36 weeks postmenstrual age (PMA). METHODS: Echocardiographic assessments were carried out on days 1, 2, 5-7 and at 36 weeks PMA. We assessed the following associations: correlation with systemic vascular resistance (SVR) on day 1, influence of a patent ductus arteriosus (PDA) during days 5-7, and the effect of chronic lung disease (CLD). RESULTS: In total, 105 infants with a median gestation of 27.1 weeks (IQR 26.0-28.1) and a birthweight of 965 g (IQR 785 1,153) were included. There was an increase in most of the measurements across the four time points. On day 1, there was a weak negative correlation between SVR and LV BLS (r = -0.3, p = 0.01), SVR and septal BLS (r = -0.4, p < 0.001) and SVR and LV SRe (r = -0.4, p = 0.005). On days 5-7, infants with a PDA >1.5 mm had higher LV BLS [-13.0 (2.4) vs. -11.9 (1.9)%, p = 0.03]. At 36 weeks, infants with CLD (n = 28/47) had lower RV BLS [-26.4 (5.0) vs. -30.7 (5.5)%, p = 0.01] and lower RV SRa [4.2 (1.3) vs. 5.3 (1.9) s-1, p = 0.04]. CONCLUSION: Myocardial function undergoes important longitudinal changes in preterm infants. Left heart strain measurements appear to be weakly influenced by changes in preload and afterload. CLD appears to leave a negative impact on RV function. PMID- 26583603 TI - Serum Prolactin and CA-125 Levels as Biomarkers of Peritoneal Endometriosis. PMID- 26583604 TI - Idarucizumab (Praxbind)--an antidote for dabigatran. PMID- 26583605 TI - Bexsero--a second serogroup B meningococcal vaccine. PMID- 26583606 TI - Cobicistat (Tybost) combinations for HIV. PMID- 26583607 TI - Tiotropium/olodaterol (Stiolto Respimat) for COPD. PMID- 26583608 TI - Technivie for HCV genotype 4 infection. PMID- 26583609 TI - Estimating Effects of Arsenic Exposure During Pregnancy on Perinatal Outcomes in a Bangladeshi Cohort. AB - BACKGROUND: The relationship between arsenic and birth weight is not well understood. The objective was to evaluate the causal relationship between prenatal arsenic exposure and birth weight considering the potential mediation effects of gestational age and maternal weight gain during pregnancy using structural equation models. METHODS: A prospectively enrolled cohort of pregnant women was recruited in Bangladesh from 2008 to 2011. Arsenic was measured in personal drinking water at the time of enrollment (gestational age <16 weeks, N = 1,140) and in toenails collected <=1 month postpartum (N = 624) using inductively coupled plasma mass spectrometry. Structural equation models estimated the direct and indirect effects of arsenic on birth weight with gestational age and maternal weight gain considered as mediating variables. RESULTS: Every unit increase in natural log water arsenic was indirectly associated with decreased birth weight (beta = -19.17 g, 95% confidence interval [CI]: -24.64, -13.69) after adjusting for other risk factors. This association was mediated entirely through gestational age (beta = -17.37 g, 95% CI: -22.77, -11.98) and maternal weight gain during pregnancy (beta = -1.80 g, 95% CI: -3.72, 0.13). When exposure was modeled using toenail arsenic concentrations, similar results were observed. Every increase in natural log toenail arsenic was indirectly associated with decreased birth weight (beta = -15.72 g, 95% CI: -24.52, -6.91) which was mediated through gestational age (beta = -13.59 g, 95% CI: -22.10, -5.07) and maternal weight gain during pregnancy (beta = -2.13 g, 95% CI: -5.24, 0.96). CONCLUSION: Arsenic exposure during pregnancy was associated with lower birth weight. The effect of arsenic on birth weight appears to be mediated mainly through decreasing gestational age and to a lesser extent by lower maternal weight gain during pregnancy. PMID- 26583611 TI - Hemophagocytic Lymphohistiocytosis After Initiation of Chemotherapy for Bilateral Adrenal Neuroblastoma. AB - Hemophagocytic lymphohistiocytosis (HLH) is a rare and aggressive syndrome characterized by overactivation of the immune system. Although secondary HLH has been frequently associated with malignancies, this entity is rarely triggered by solid tumors, such as neuroblastomas. Herein, we describe a 14-month-old girl with a late diagnosis of bilateral adrenal neuroblastoma who developed HLH 6 days after the initiation of chemotherapy. On the basis of the large tumoral mass and the time of onset of her symptoms suggestive of HLH, we hypothesize that tumor cell destruction induced by chemotherapy drugs was the trigger to the development of hematophagocytic lymphohistiocytosis syndrome. PMID- 26583610 TI - Amyotrophic Lateral Sclerosis and the Military: A Population-based Study in the Danish Registries. AB - BACKGROUND: Prior studies have suggested that military service may be associated with the development of amyotrophic lateral sclerosis (ALS). We conducted a population-based case-control study in Denmark to assess whether occupation in the Danish military is associated with an increased risk of developing ALS. METHODS: There were 3,650 incident cases of ALS recorded in the Danish National Patient Registry between 1982 and 2009. Each case was matched to 100 age- and sex matched population controls alive and free of ALS on the date of the case diagnosis. Comprehensive occupational history was obtained from the Danish Pension Fund database, which began in 1964. RESULTS: 2.4% (n = 8,922) of controls had a history of employment in the military before the index date. Military employees overall had an elevated rate of ALS (odds ratio [OR] = 1.3; 95% confidence interval [CI]: 1.1, 1.6). A 10-year increase in years employed by the military was associated with an OR of 1.2 (95% CI: 1.0, 1.4), and all quartiles of time employed were elevated. There was little suggestion of a pattern across calendar year of first employment, but there was some evidence that increasing age at first employment was associated with increased ALS rates. Rates were highest in the decade immediately following the end of employment (OR = 1.6; 95% CI: 1.2, 2.2). CONCLUSIONS: In this large population-based case-control study, employment by the military is associated with increased rates of ALS. These findings are consistent with earlier findings that military service or employment may entail exposure to risk factors for ALS. PMID- 26583612 TI - Rapid Infusion of Rituximab in a Heterogenous Pediatric Population: Safety and Feasibility. PMID- 26583613 TI - RAPID Trial Demonstrates Low Positive Predictive Value of Interim FDG-PET in Early-stage Hodgkin Lymphoma After Three Cycles of ABVD. PMID- 26583614 TI - Low Vitamin D Levels Are Associated With an Adverse Clinical Outcome in Febrile Neutropenia. AB - AIM: The aim of the study was to evaluate the levels of vitamin D in patients of aplastic anemia presenting with febrile neutropenia and its association with clinically important parameters. MATERIALS AND METHODS: The 25-hydroxy vitamin D (25(OH)D) levels were measured in 35 patients of aplastic anemia with febrile neutropenia in the age group of 4 to 16 years. About 30 healthy children served as controls. Vitamin D deficiency was defined as 25(OH)D<20 ng/mL, insufficiency 20 to 29 ng/mL, and sufficiency>=30 ng/mL. RESULTS: The median age of patients was 9.3 years. The mean 25(OH)D level was 17.71+/-8.90 ng/mL in patients against 23.67+/-10.80 ng/mL in the control group (P<0.01). About 65.7% of the patients were 25(OH)D deficient (<20 ng/mL). Only 8.6% had sufficient levels. Older (above 10 y) patients, male children, and those from a rural background and a low socioeconomic status had significantly lower 25(OH)D levels as compared with controls. Low 25(OH)D levels were associated with a longer duration (>=7 d) of febrile neutropenia (17.26+/-7.19 vs. 20.01+/-12.12 ng/mL) although the difference was not statistically significant. Two patients who expired had significantly lower 25(OH)D levels (12.85+/-4.12 ng/mL) compared with those who improved (22.86+/-6.47 ng/mL, P<0.05). CONCLUSIONS: A high prevalence of vitamin D deficiency was observed in patients with febrile neutropenia. Low levels were associated with an adverse clinical outcome. PMID- 26583615 TI - Selective Ophthalmic Artery Infusion Chemotherapy for Advanced Intraocular Retinoblastoma: CCHMC Early Experience. AB - Selective ophthalmic artery infusion chemotherapy (SOAIC) is increasingly used to treat retinoblastoma. We report the toxicities and outcome of 19 eyes in 17 patients with retinoblastoma receiving SOAIC treatment between 2008 and 2013. From the 87 treatments, mild local reactions were common. Myelosuppression was more common after triple-agent SOAIC (melphalan, carboplatin, and topotecan) than single-agent melphalan. Ocular salvage was achieved in 11 of 19 eyes and associated with triple-agent therapy. SOAIC is a effective therapy for some retinoblastoma with manageable toxicity; however, systemic toxicity increases with increasing therapeutic intensity of SOAIC. PMID- 26583616 TI - Analysis of Risk Factors for Hyponatremia During or Following Chemotherapy in Children With Cancer: A Hospital-based, Retrospective Cohort Study. AB - Hyponatremia is the most common electrolyte abnormality in hospitalized patients. The objective of this study was to identify risk factors for hyponatremia during chemotherapy in children. A total of 111 consecutive pediatric patients (age, 0 to 18 y) with hematological malignancy (n=87) or solid tumor (n=24) who received chemotherapy in our hospital between 2010 and 2014 were enrolled. The number of chemotherapy cycles reviewed was 472, with a median of 3 (range, 1 to 8) per patient. Hyponatremia was defined as a serum sodium level of <135 mmol/L. Hyponatremia was observed in 80 of 111 (72%) patients, and 138 of 472 (29%) cycles. Neurological sequelae were seen in 2 of 111 (2%) patients, and 2 of 472 (0.4%) cycles. Multivariate logistic regression identified age 10 to 18 years (odds ratio [OR]=3.24, 95% confidence interval [CI], 2.07-5.07), total parenteral nutrition (OR=8.15, 95% CI, 2.17-30.5), first or second chemotherapy cycle (OR=1.74, 95% CI, 1.12-2.70) as independent risk factors for hyponatremia. Clinical conditions of patients and chemotherapeutic agents may have a profound impact on the development of hyponatremia. Patients with these factors should be managed carefully to prevent severe symptoms and sequelae caused by hyponatremia. PMID- 26583618 TI - Aplastic Crisis Secondary to Parvovirus B19 Infection as the First Manifestation of an Undiagnosed Hereditary Spherocytosis: Report of a Pediatric Series of Spanish Patients. PMID- 26583617 TI - Early Cardiac Involvement and Risk Factors for the Development of Arrhythmia in Patients With beta-Thalassemia Major. AB - BACKGROUND: Cardiac iron overload is the most serious complication in thalassemia; even patients treated with intensive chelation suffer at a certain point from cardiomyopathy and arrhythmia. AIM: The aim of the study was to identify indicators of cardiac dysfunction in thalassemia as well as risk factors associated with the development of arrhythmia. PATIENTS AND METHODS: A total of 45 patients with beta-thalassemia major were enrolled in this cross-sectional study. Patients were divided into 2 groups according to the absence (group A) or the presence of arrhythmia (group B). Cardiac parameters in thalassemic groups were evaluated using 24-Holter recording, Stress electrocardiogram, and M-mode echocardiography. Serum ferritin and Cardiac T2* were used to assess the iron status. RESULTS: Group B showed significantly higher values of cardiac T2* and serum ferritin (P<0.05). Group B patients had significantly higher maximum heart rate with significant attacks of bradycardia and ST segment changes. In addition, they achieved a lower percentage of maximum age predicted heart rate and lower values of maximum metabolic equivalents (P<0.05). Significantly higher values of the left atrial diameter, the interventricular septum diameter, and the left ventricle posterior wall diameter (P<0.05) were identified in group B. CONCLUSIONS: The increase in left atrial diameter, interventricular septum diameter, and left-ventricle posterior wall diameter seems to be related to the development of arrhythmia in patients with thalassemia, especially supraventricular arrhythmias. PMID- 26583619 TI - Hemoglobin F Only Syndrome at Birth: A Case of Maternal HbA2' Complicating the Diagnosis of beta-Thalassemia. AB - An asymptomatic infant of Ghanaian descent had hemoglobin F only detected on newborn screening. beta-globin gene sequencing identified the intervening sequence (IVS)-II-849 (A -> G) mutation with no normal beta-globin gene. beta globin/delta-globin gene sequencing showed that both parents were heterozygous for the IVS-II-849 (A -> G) mutation. The mother was heterozygous for the HbA2' delta-globin mutation (delta16 (A13) Gly -> Arg), thus beta-thalassemia trait was unrecognized due to coinheritance of HbA2'. The infant developed anemia, splenomegaly, and began transfusion therapy by the age 6 of months. This is the first report of beta-thalassemia major with homozygous IVS-II-849 (A -> G) mutations. This case highlights the importance of delta-globin gene mutations in prenatal testing. PMID- 26583620 TI - Outcomes of Patients With Relapsed Hepatoblastoma Enrolled on Children's Oncology Group (COG) Phase I and II Studies. AB - Data are limited regarding outcomes of patients treated for relapsed hepatoblastoma. We reviewed enrollment patterns and outcomes of patients with hepatoblastoma on Children's Oncology Group (COG) phase I/II studies. The medical literature was searched for reports of COG phase I/II studies using PUBMED as well as an inventory from the COG publications office searching manuscripts published from 2000 to 2014. Seventy-one patients with relapsed hepatoblastoma were enrolled on 23 separate COG phase I/II studies. Four studies collected alpha fetoprotein (AFP) data, but none utilized AFP decline in assessing response. Most studies enrolled few patients with relapsed hepatoblastoma: 7 studies enrolled 1 patient, and another 7 studies enrolled 2 patients each. Only 9 studies enrolled 3 or more patients with relapsed hepatoblastoma. Four responses were reported. Dedicated strata and/or focus on 1 or 2 studies with compelling biological or clinical rationale for hepatoblastoma may improve accrual (and statistical significance of response data) of patients with relapsed hepatoblastoma. Prospective study of AFP decline versus RECIST response could help determine the optimal method of assessing response to identify potentially beneficial treatments in hepatoblastoma. PMID- 26583621 TI - Rituximab-induced Cytokine Storm in the Absence of Overt Lymphoproliferative Disease. AB - Rituximab is a monoclonal antibody that first demonstrated efficacy in the treatment of lymphoma but has since seen a dramatic growth in its use for other conditions. Cytokine release syndrome (CRS) is a rare but potentially fatal complication of rituximab infusion that has been described in patients with bulky lymphoproliferative disease. Here we report a convincing case of CRS occurring in a patient with no demonstrable lymphoproliferation. This case has implications for our understanding of the pathogenesis of CRS, our attempts to define an at risk population and the design of future monoclonal antibodies. PMID- 26583622 TI - Wilms Tumor in a Child With Bilateral Polycystic Kidneys and PHACE Syndrome: Successful Treatment Outcome Using Partial Nephrectomy and Chemotherapy. AB - Congenital anomalies may be associated with Wilms tumor either as isolated anomalies or as part of a congenital malformation syndrome. Nephroblastoma occurring in association with polycystic kidneys is very rare. The optimal surgical management of nephroblastoma in the setting of polycystic kidneys is not defined because of the rarity of this presentation. PHACE syndrome includes posterior fossa anomalies, hemangioma, arterial lesions, cardiac abnormalities/coarctation of aorta, and eye abnormalities. We report a 17-month old baby with bilateral polycystic kidneys and PHACE syndrome who developed nephroblastoma in the right polycystic kidney which was treated successfully with nephron-sparing partial nephrectomy and chemotherapy. PMID- 26583623 TI - Comparison of Thyroid Nodule Prevalence by Ultrasound in Childhood Cancer Survivors With and Without Thyroid Radiation Exposure. AB - PURPOSE: Children receiving radiotherapy of the head, neck, or chest as treatment of primary malignancies are at increased risk for secondary thyroid malignancy. We hypothesized that current standards (yearly thyroid physical examination) lead to a substantial number of missed thyroid nodules. Our objectives were: (1) use thyroid ultrasound to assess thyroid nodules in childhood cancer survivors; and (2) compare prevalence of thyroid nodules in thyroid radiation-exposed patients as compared with cancer survivors without radiation exposure. METHODS: We recruited 60 patients with thyroid radiation and chemotherapy exposure (median age at cancer diagnosis 10.8 y) and 59 patients with chemotherapy exposure alone (median age at diagnosis 4.3 y) from our long-term survivorship clinics. Each patient had a thyroid physical examination and thyroid ultrasound performed. RESULTS: Thirty-three patients (27.7%) had nodules >0.3 cm of which 2 were palpated (6.1%). We found 22 radiated patients (36.7%) with nodules versus 11 nonradiated patients (18.6%) (P=0.03). Eleven patients were biopsied and 1 diagnosis of secondary papillary thyroid carcinoma was confirmed. CONCLUSION: Our study supports further examination of incorporating thyroid ultrasounds into long term survivorship follow-up guidelines in radiation-exposed patients for the detection of thyroid nodules and secondary malignancies. PMID- 26583624 TI - Multimodality Imaging in Pediatric Osteosarcoma in the Era of Image Gently and Image Wisely Campaign With a Close Look at the CT Scan Radiation Dose. AB - The increasing use of serial multimodality imaging in the management of pediatric osteosarcoma raises concern of over exposure to ionizing radiation in children, especially from repeated computed tomographic (CT) scans. This study reviews the utilization of multimodality imaging in patients with osteosarcoma at our institution and analyzes any potential radiation-related complications. Twenty eight patients were identified. Three patients developed late complications-acute myeloid leukemia, myelodysplastic syndrome, and early menopause. Using the patient's age and body part imaged, CT dose length product and effective dose was estimated with the use of a conversion factor for 19 patients. The effective doses were higher in the 3 patients with late complications than the other patients in the cohort (P=0.018). These results suggest an increased risk for adverse effects with higher CT exposures and effective doses. On the basis of our data and published data, methods to decrease the doses of radiation from medical imaging need to be explored. The number of CT scans may be limited. Implementing the Image Gently concept to decrease radiation exposure can be beneficial in modification of CT acquisition parameters. PMID- 26583625 TI - Wiskott-Aldrich Syndrome: Description of a New Gene Mutation Without Immunodeficiency. PMID- 26583626 TI - Do I Have Hope? Framing End-of-Life Care Discussions. PMID- 26583627 TI - Active Despite Pain: Patient Experiences With Guided Imagery With Relaxation Compared to Planned Rest. AB - Inadequate pain control remains a threat to the quality of life of patients with cancer. Guided imagery with relaxation (GIR) is a mind-body therapy that has shown promise in reducing chronic pain. This article discusses a qualitative, descriptive study for which the objective was to compare the experiences of patients with cancer with reported pain using GIR compared to planned rest.?. PMID- 26583628 TI - Reducing Central Line-Associated Bloodstream Infections ?on Inpatient Oncology Units Using Peer Review. AB - The purpose of this article is to describe a peer-to-peer program and the outcomes of interventions to reduce the incidence of central line-associated bloodstream infections in patients in bone marrow transplantation, medical, and surgical oncology units. The article reviews the process and describes tools used to achieve success in a Magnet(r)-designated academic medical center. PMID- 26583629 TI - Nursing Fatigue: An Evidence-Based Practice Review for Oncology Nurses?. AB - Nursing fatigue is a current and well-researched topic. Many negative outcomes and consequences exist for patients and nurses that have been linked to nursing fatigue. Medical errors are one such consequence, and these errors have become one of the top three preventable deaths in the United States. Oncology nurses are not immune to fatigue, and the consequences of their fatigue can be much more harmful to patients. PMID- 26583630 TI - Risk Prediction Tools in Oncology. AB - Cancer prediction tools are widely available to clinicians, and the data retrieved from these tools can assist with patient counseling sessions on risk, prognosis, treatment, and recurrence. Current tools are able to synthesize data in a concise, unbiased, and evidence-based method, allowing patients to make better-informed decisions about their treatment options. As useful as these tools can be, clinicians must understand their limitations and evaluate the tools for quality and applicability.?. PMID- 26583631 TI - Preventing Safety Hazards Associated With Do-Not-Resuscitate Orders. AB - Do-not-resuscitate orders can promote patients' dignity near the end of life, but they also can carry safety hazards associated with miscommunication and inappropriate withdrawal of certain kinds of care. Oncology nurses have a responsibility to identify these potential hazards and to intervene as necessary.?. PMID- 26583633 TI - Lifestyle Counseling Practices of Oncology Nurses in the United States and Canada. AB - BACKGROUND: Oncology nurses are well poised to provide lifestyle behavior counseling to cancer survivors. However, very little is known about the current lifestyle behavior counseling practices of oncology nurses. OBJECTIVES: The primary purpose of this study was to examine lifestyle behavior counseling practices of oncology nurses. The secondary purpose was to examine differences in lifestyle behavior counseling based on nurses' health behaviors, additional training received, and country of residence. METHODS: Oncology nurses (N = 314) were primarily recruited through emails from oncology nursing email lists. Participants completed an online survey. FINDINGS: Overall, oncology nurses reported providing lifestyle counseling to most cancer survivors when appropriate. The majority of oncology nurses said they were receptive to receiving additional training about lifestyle counseling. Participants who had received additional training and who lived in the United States were more likely to provide counseling to cancer survivors. Concerning their own health behaviors, no meaningful differences were found regarding lifestyle behavior counseling practices, which contrasts with findings from previous research. Strengthening oncology nurses' lifestyle behavior counseling knowledge and skills may offer opportunities to enhance survivors' optimal health and quality of life and to reduce their risk of recurrence. PMID- 26583632 TI - Needs and Lifestyle Challenges of Adolescents and Young Adults With Cancer: Summary of an Institute of Medicine and Livestrong Foundation Workshop. AB - BACKGROUND: Among adolescents and young adults (AYAs) in the United States, cancer is the leading cause of disease-related death. AYA survivors face numerous short- and long-term health and psychosocial issues, as well as increased risk for behavioral and lifestyle challenges, including poor diet, low physical activity (PA), and substance abuse. Many of these behaviors are modifiable, but gaps in care serve as barriers for AYA survivors. OBJECTIVES: The purpose of this article is to (a) raise awareness of AYAs' increased risk for poor diet, low PA, and substance abuse; (b) examine previous interventions addressing these issues; and (c) provide recommendations for future directions. METHODS: This article summarizes a workshop coordinated by the Institute of Medicine and the Livestrong Foundation to address AYA survivors' needs and ways to enhance their quality of care. FINDINGS: Oncology nurses can promote the inclusion of lifestyle behaviors in survivorship care plans of AYA patients and serve as a valuable resource in improving AYA care on a larger scale. In addition, oncology nurse researchers may offer greater understanding of AYA patients' and survivors' needs and best practices by conducting much-needed research with this understudied population. PMID- 26583635 TI - Understanding Immune Checkpoint Inhibitors for Effective Patient Care. AB - BACKGROUND: Immune checkpoint inhibitors represent a paradigm change in the treatment of melanoma and other advanced cancers. These agents manipulate key immune-regulating pathways to restore immune responses against tumors. The success of this approach is demonstrated by ipilimumab (Yervoy(r)) for the treatment of advanced melanoma, with improvement in three-year survival rates of about 20%. Newer checkpoint inhibitors targeting the programmed death-1 (PD-1) pathway have been approved and may have higher response rates and improved tolerability. OBJECTIVES: This article aims to educate nurses and increase their comfort level with these new therapies. METHODS: The mechanism of action of immune checkpoint inhibitors is reviewed, and insight is provided on how nurses can use this knowledge to more effectively care for patients receiving these therapies. FINDINGS: The use of immuno-oncology agents is increasing. Oncology nurses must understand the basic immune mechanism of action responsible for the novel toxicity profile characterized by immune-related adverse events (irAEs) and clinical response patterns. Managing irAEs with immune checkpoint inhibitors is not necessarily more difficult than with conventional agents, but a difference does exist. Nurses and other healthcare providers must consider the underlying cause of toxicity with immune checkpoint inhibitors when making management decisions. PMID- 26583634 TI - Discussing Death, Dying, and End-of-Life Goals of Care: A Communication Skills Training Module for Oncology Nurses. AB - BACKGROUND: Effective communication, particularly at the end of life, is an essential skill for oncology nurses, but few receive formal training in this area. OBJECTIVES: The aim of this article is to adapt an end-of-life care communication skills training (CST) module, originally developed for oncologists, for oncology nurses and to evaluate participants' confidence in using the communication skills learned and their satisfaction with the module. METHODS: The adapted end-of-life care module consisted of a 45-minute didactic, exemplary video and 90 minutes of small group interaction and experiential role play with a simulated patient. Using a five-point Likert-type scale, 247 inpatient oncology nurses completed pre-/post-workshop surveys rating their confidence in discussing death, dying, and end-of-life goals of care with patients, as well as overall satisfaction with the module. FINDINGS: Nurses' confidence in discussing death, dying, and end-of-life goals of care increased significantly after attending the workshop. Nurse participants indicated satisfaction with the module by agreeing or strongly agreeing to all six items assessing satisfaction 90%-98% of the time. Nurses' CST in discussing death, dying, and end-of-life care showed feasibility, acceptability, and potential benefit at improving confidence in having end-of life care discussions. PMID- 26583636 TI - Navigating Treatment of Metastatic Castration- Resistant Prostate Cancer: Nursing Perspectives. AB - BACKGROUND: Treatment of metastatic castration-resistant prostate cancer (mCRPC) has evolved rapidly. In particular, five new treatments that extend survival in mCRPC have been approved since 2010, including the chemotherapy cabazitaxel (Jevtana(r)), hormonal agents abiraterone (Zytiga(r)) and enzalutamide (Xtandi(r)), vaccine sipuleucel-T (Provenge(r)), and radiopharmaceutical radium 223 (Xofigo(r)); all have different indications and toxicity profiles. OBJECTIVES: This review discusses treatment advances in mCRPC, including considerations for side-effect management and treatment sequencing. Studies relating to quality of care in prostate cancer are also discussed. METHODS: Nonsystematic searches were performed on published manuscripts and abstracts from major oncology or urology congresses, focusing on practical characteristics of the previously mentioned new treatments that extend survival in mCRPC, as well as studies relating to quality of care and the role of nurses in prostate cancer management. FINDINGS: To ensure that patients derive optimal clinical benefit, assessing overall health and proactively managing expected side effects are essential. Treatment sequencing in mCRPC is an important consideration, but clinical data in this area are limited. Despite medical advances in mCRPC, studies have identified other aspects of care in which improvement is needed. Nurses can make major contributions to addressing supportive care needs, which has been shown to improve patient care and outcomes in prostate cancer. Although patient navigation programs have improved coordination of care, inconsistent implementation among centers has been identified for prostate cancer. Greater use of outcome measures can help to identify unmet patient needs. PMID- 26583637 TI - Targeted Therapies for Non-Small Cell Lung Cancer: An Update on Epidermal Growth Factor Receptor and Anaplastic Lymphoma Kinase Inhibitors. AB - BACKGROUND: The development of targeted therapies has revolutionized the treatment of advanced non-small cell lung cancer (NSCLC), with new clinical trials and therapies consistently providing new information. This rapidly changing field mandates ongoing education for nursing professionals whose foremost priority is patient care. OBJECTIVES: This review aims to summarize the history and current status of targeted therapies for NSCLC, focusing on two types of drugs that have had the most impact to date. METHODS: The safety profiles of first- and second-generation EGFR and ALK inhibitors are described, and strategies for the management of the most commonly experienced adverse events are summarized. Information is also provided to help identify which patients might be eligible for treatment with EGFR or ALK inhibitors in addition to the implications of targeted therapies. FINDINGS: Therapies designed to target specific molecular features of individual tumor cells are one of the most important developments in treating NSCLC. The safety profiles of targeted therapies differ greatly from chemotherapy and present unique challenges to nurses. Education of nurses and patients on implementation of effective adverse event management and improvement in patient adherence will maximize the benefits of these drugs. PMID- 26583638 TI - Clinical Predictors of Fatigue in Men With Non-Metastatic Prostate Cancer Receiving External Beam Radiation Therapy. AB - BACKGROUND: Fatigue is one of the most distressing symptoms experienced by people with cancer receiving radiation therapy. OBJECTIVES: The goal of this study is to evaluate clinical predictors of worsening fatigue during external beam radiation therapy (EBRT) in men with non-metastatic prostate cancer. METHODS: Thirty-five men with non-metastatic prostate cancer scheduled for EBRT were followed at baseline, midpoint, and completion of EBRT. The Functional Assessment of Cancer Therapy-Fatigue scale was administered. Demographic and clinical data were obtained by chart review. Paired t-tests, correlations, general linear models, and logistic regressions were used to determine associations between fatigue scores and clinical data. FINDINGS: Red blood cells, hemoglobin, and hematocrit levels were highly intercorrelated and, therefore, were grouped as one composite variable termed heme. Heme levels at baseline and androgen-deprivation therapy (ADT) were significantly correlated with worsening of fatigue symptoms from baseline to midpoint and endpoint. ADT alone did not have a significant correlation with fatigue, but it indirectly affected fatigue levels by influencing heme markers as treatment progressed. These findings provide evidence that hematologic markers and the use of ADT assist in predicting radiation therapy-related fatigue and guide symptom management. PMID- 26583639 TI - Nursing Implications of Chemotherapy Agents and Their Associated Side Effects in Patients With Pancreatic Cancer. AB - BACKGROUND: Survival for patients with advanced (locally advanced unresectable and metastatic disease) pancreatic cancer is very poor; however, several advances in treatment have been made during the past several years. Gemcitabine (Gemzar(r))-based regimens, FOLFIRINOX, and nab-paclitaxel (Abraxane(r))-based regimens have demonstrated efficacy in patients with advanced pancreatic cancer. Understanding the unique safety profile of each of these regimens is crucial in helping nurses identify symptoms, develop patient education strategies, and ultimately improve outcomes. OBJECTIVES: This article aims to provide background information on and nursing implications of the treatment of patients with advanced pancreatic cancer by exploring the mechanism of action and efficacy and safety profiles of standard treatment regimens. METHODS: Key trials of standard treatment regimens used in the treatment of advanced pancreatic cancer were examined with respect to efficacy outcomes and the most commonly observed adverse events. Symptom identification and management strategies are discussed from the nursing perspective. FINDINGS: The current standard treatment options for patients with advanced pancreatic cancer have differences in efficacy and safety profiles. Nurses should educate themselves on these differences, particularly on associated adverse events and their management. PMID- 26583640 TI - Application of Proteomics in Acute Graft-Versus-Host Disease Management: An Integrative Review and Nursing Implications. AB - BACKGROUND: After allogeneic hematopoietic stem cell transplantation, one of the major barriers to clinical management of acute graft-versus-host disease (aGVHD) is a lack of reliable and validated noninvasive tests for diagnosis and prognosis. Proteomic studies have indicated a strong correlation between the level of certain body fluid proteins and clinical outcomes after aGVHD. Specific proteins have been identified that could be robust biomarkers for overall prognosis or for differential diagnosis of target organs in aGVHD. OBJECTIVES: The authors aimed to evaluate the literature related to proteomic biomarkers that are indicated in the occurrence, severity, and management of aGVHD. METHODS: PubMed and CINAHL(r) databases were searched for articles published from January 2004 to June 2014. Eight articles matching the inclusion criteria were identified, and the findings of these articles were summarized and their clinical implications noted. FINDINGS: Proteomics appears to be a promising tool to assist oncology nurses and nurse practitioners with patient education, develop personalized plans of care to reduce morbidity, initiate communication regarding end-of-life decisions, and improve overall nursing management of the population of patients with aGVHD. PMID- 26583641 TI - Why Women Are Choosing Bilateral Mastectomy. AB - The rate of women choosing to have a bilateral mastectomy as a treatment for unilateral breast cancer has increased since the 1990s, particularly among younger women. This article describes a qualitative study that was conducted to explore this decision-making process. PMID- 26583642 TI - Evaluation of a Preoperative Clinic for Women With Gynecologic Cancer. AB - Although many patients with gynecologic cancer undergo surgery, time constraints during the preoperative consultation may affect the accuracy of the information exchange, as well as compromise the quality of the patient assessment and care plan. Both put patients at a higher risk for complications during surgery and the postoperative period. This article describes an advanced practice RN-led preoperative assessment and education clinic designed to improve the quality of preoperative preparation and postoperative outcomes of patients with gynecologic cancer. PMID- 26583644 TI - Bill and Jean: A Lifetime Together. PMID- 26583643 TI - Fellowship Program to Develop the Next Generation of Oncology Nurses. AB - An oncology nursing fellowship program for undergraduate nursing students has the potential to help develop a much-needed talent pool for the next generation of oncology nurses. By raising awareness of the value of this program, the Oncology Nursing Society can help foster expansion of this program nationally to help address the growing need for oncology nurses. Improving awareness about this program could lead to the establishment of similar fellowship programs at other cancer hospitals and undergraduate nursing schools. This program provides an opportunity for experienced oncology nurses to serve as preceptors and program managers at leading cancer hospitals, select and mentor program participants, and, ultimately, recruit and develop future mentors for the program. PMID- 26583645 TI - Planning for the Size of the Nursing Staff at an Outpatient Chemotherapy Unit. AB - BACKGROUND: Use of a patient classification system particular to the unit, including size of nursing staff, is required for nurses to have adequate staffing and provide high-quality nursing care in oncology units. OBJECTIVES: The study was conducted to create a planning system for nursing staff size for an outpatient chemotherapy unit at a university hospital. METHODS: The study was conducted with the nurses working in an outpatient chemotherapy unit of a university hospital and patients who received five weeks of treatment. Patients were classified by using the Magnuson Model. Data related to job analysis were collected by two independent observers who made measurements with a stopwatch, in line with safety and quality standards on the chemotherapy units. FINDINGS: A total of 1,795 patients who received care at the outpatient chemotherapy unit were classified using the model. Based on the job analysis, on average, 17.12 nurses per day were needed to care for the patients. PMID- 26583646 TI - Von Hippel-Lindau: Current Evidence in Diagnosis, Treatment, and Nursing Implications. AB - BACKGROUND: Von Hippel-Lindau (VHL) is a rare autosomal dominant hereditary disorder that predisposes individuals to benign and malignant tumors in the brain, eyes, kidneys, pancreas, genital tract, or other body parts. The VHL gene, which is located on the short arm of chromosome 3, prevents cells from dividing too rapidly. Mutations in the VHL gene result in uncontrollable cell growth and tumor formation. OBJECTIVES: The purpose of this article is to summarize the current research literature describing diagnosis, treatment, and nursing implications of VHL. METHODS: Three electronic databases, relevant journals, and relevant websites were searched. FINDINGS: The majority of patients affected with VHL have an affected parent, but a small percentage develop VHL from a new mutation that takes place in a single egg or sperm during conception or from a post-conception mutation. Genetic testing, either through sequence analysis, Southern blot analysis, or quantitative polymerase chain reaction, is considered standard in evaluating patients suspected of having VHL. A diagnosis of VHL can be made by identifying one VHL tumor for a patient who has a confirmed family history of VHL. The presence of at least two tumors is required to make a diagnosis of VHL in a patient without a positive family history. The nursing role includes providing resources on VHL genetic counseling, genetic testing, and palliative care. PMID- 26583647 TI - Use of Videos as Supplemental Education Tools Across the Cancer Trajectory. AB - BACKGROUND: Patients who are dealing with life changes as a result of a cancer diagnosis often search for information about the disease and its treatment. Knowledge gained from this information helps patients with cancer during survivorship and improves their active participation with the healthcare team. To provide patients with the information they need, healthcare providers must offer various methods for the delivery of educational materials. The use of video as a delivery mechanism should be considered as one option for patient content acquisition. OBJECTIVES: This article describes the use of videos as supplemental education tools before, during, or after one-on-one patient teaching interactions. METHODS: A literature review was performed that focused on locating, reviewing, and synthesizing published data from clinical studies related to the use of video in patient education. FINDINGS: Videos deliver material in a way that is flexible and often familiar to patients. For example, delivery can occur via smartphone, electronic health record, computer, DVD, or television, and it does not require reading or a high level of literacy. Healthcare providers in oncology settings should consider establishing a process for instructional video development as part of a multimedia patient education library. PMID- 26583648 TI - Optimizing Care and Compliance for the Treatment of Mycosis Fungoides Cutaneous T Cell Lymphoma With Mechlorethamine Gel. AB - BACKGROUND: Mycosis fungoides is the most common form of cutaneous T-cell lymphoma (MF-CTCL). Quality nursing care is necessary for effective diagnosis and treatment of patients with MF-CTCL. Early-stage MF-CTCL (stages Ia and Ib) is most often managed in both dermatology and multidisciplinary settings. These stages can be effectively controlled by skin-directed therapies such as mechlorethamine gel (Valchlor(r)). Topical mechlorethamine has been used since the 1940s as an alkylating agent; however, compounded formulas have disadvantages that limit patient compliance. In contrast, newly approved mechlorethamine gel has demonstrated an efficacious and well-tolerated profile that has longer stability and is quicker to dry than its compounded counterpart. OBJECTIVES: This article aims to provide recommendations for optimal nursing care of patients who have been diagnosed with stage Ia or Ib MF-CTCL. METHODS: Four real-world patient cases are examined, along with practical considerations for the use of mechlorethamine gel to treat patients with MF-CTCL. FINDINGS: Nurses can promote patient adherence through specific interventions and strategies, such as education about mechlorethamine gel, its mechanism of action, and safety and efficacy, as well as connecting patients with patient assistance programs or other supportive services. PMID- 26583649 TI - Effects of polarity, hydrophobicity, and density of ionic liquids on cellulose solubility. AB - We have synthesised novel ionic liquids (ILs) to show both cellulose dissolution ability and LCST-type phase transition after mixing with water. To realise both polar and hydrophobic properties, tetraalkylphosphonium cations and a series of carboxylate anions were employed to assume hydrophobic and highly polar properties, respectively. Effects of their alkyl chain length on the water compatibility and cellulose solubility of the corresponding ILs were systematically examined. We succeeded in synthesising novel ILs which dissolve cellulose and separable with water at moderate temperature. Through the present study, we have clarified that not only polarity but also density of ILs is an important factor in designing the ILs for cellulose dissolution. PMID- 26583650 TI - Prevention of Malaria Resurgence in Greece through the Association of Mass Drug Administration (MDA) to Immigrants from Malaria-Endemic Regions and Standard Control Measures. AB - Greece was declared malaria-free in 1974 after a long antimalarial fight. In 2011 2012, an outbreak of P. vivax malaria was reported in Evrotas, an agricultural area in Southern Greece, where a large number of immigrants from endemic countries live and work. A total of 46 locally acquired and 38 imported malaria cases were detected. Despite a significant decrease of the number of malaria cases in 2012, a mass drug administration (MDA) program was considered as an additional measure to prevent reestablishment of the disease in the area. During 2013 and 2014, a combination of 3-day chloroquine and 14-day primaquine treatment was administered under direct observation to immigrants living in the epicenter of the 2011 outbreak in Evrotas. Adverse events were managed and recorded on a daily basis. The control measures implemented since 2011 continued during the period of 2013-2014 as a part of a national integrated malaria control program that included active case detection (ACD), vector control measures and community education. The MDA program was started prior to the transmission periods (from May to December). One thousand ninety four (1094) immigrants successfully completed the treatment, corresponding to 87.3% coverage of the target population. A total of 688 adverse events were recorded in 397 (36.2%, 95% C.I.: 33.4-39.1) persons, the vast majority minor, predominantly dizziness and headache for chloroquine (284 events) and abdominal pain (85 events) for primaquine. A single case of primaquine-induced hemolysis was recorded in a person whose initial G6PD test proved incorrect. No malaria cases were recorded in Evrotas, Laconia, in 2013 and 2014, though three locally acquired malaria cases were recorded in other regions of Greece in 2013. Preventive antimalarial MDA to a high-risk population in a low transmission setting appears to have synergized with the usual antimalarial activities to achieve malaria elimination. This study suggests that judicious use of MDA can be a useful addition to the antimalarial armamentarium in areas threatened with the reintroduction of the disease. PMID- 26583652 TI - Spent turmeric reduces fat mass in rats fed a high-fat diet. AB - Indigestible carbohydrates may improve obesity. Spent turmeric contains high levels of dietary fibre and resistant starch (RS), which have fermentation potential in vitro. We hypothesised that indigestible carbohydrates in spent turmeric might prevent obesity development. In the first study, rats were administered 10% turmeric powder (TP) or spent turmeric powder (STP) in a high fat (HF) diet for 28 d. In the second study, rats were fed 10% STP in a HF diet with or without antibiotics for 15 d. In the third study, rats were treated with a STP-containing suspension. In study 1, the TP and STP diet increased the caecal short-chain fatty acid (SCFA) content compared to that of a control diet. The lower energy intake in the TP and STP group was strongly related to the decrease in visceral fat weight. In study 2, after caecal fermentation suppression with antibiotics, STP treatment decreased the visceral fat mass. In study 3, the plasma glucose levels and incremental area under the curve (AUC) after ingestion of a STP-containing suspension were lower than those after ingestion of suspension alone. These findings suggest the reduction of carbohydrate absorption during the gastrointestinal passage after TP and STP treatment. Our data indicate that the reduced obesity development in rats fed a HF diet may be attributed to the low metabolisable energy density of carbohydrates in the spent turmeric, independent of SCFA-mediated factors. PMID- 26583653 TI - Effectiveness of Nalmefene in Binge Eating Disorder: A Case Report. PMID- 26583651 TI - Insect Resistance to Bacillus thuringiensis Toxin Cry2Ab Is Conferred by Mutations in an ABC Transporter Subfamily A Protein. AB - The use of conventional chemical insecticides and bacterial toxins to control lepidopteran pests of global agriculture has imposed significant selection pressure leading to the rapid evolution of insecticide resistance. Transgenic crops (e.g., cotton) expressing the Bt Cry toxins are now used world wide to control these pests, including the highly polyphagous and invasive cotton bollworm Helicoverpa armigera. Since 2004, the Cry2Ab toxin has become widely used for controlling H. armigera, often used in combination with Cry1Ac to delay resistance evolution. Isolation of H. armigera and H. punctigera individuals heterozygous for Cry2Ab resistance in 2002 and 2004, respectively, allowed aspects of Cry2Ab resistance (level, fitness costs, genetic dominance, complementation tests) to be characterised in both species. However, the gene identity and genetic changes conferring this resistance were unknown, as was the detailed Cry2Ab mode of action. No cross-resistance to Cry1Ac was observed in mutant lines. Biphasic linkage analysis of a Cry2Ab-resistant H. armigera family followed by exon-primed intron-crossing (EPIC) marker mapping and candidate gene sequencing identified three independent resistance-associated INDEL mutations in an ATP-Binding Cassette (ABC) transporter gene we named HaABCA2. A deletion mutation was also identified in the H. punctigera homolog from the resistant line. All mutations truncate the ABCA2 protein. Isolation of further Cry2Ab resistance alleles in the same gene from field H. armigera populations indicates unequal resistance allele frequencies and the potential for Bt resistance evolution. Identification of the gene involved in resistance as an ABC transporter of the A subfamily adds to the body of evidence on the crucial role this gene family plays in the mode of action of the Bt Cry toxins. The structural differences between the ABCA2, and that of the C subfamily required for Cry1Ac toxicity, indicate differences in the detailed mode-of-action of the two Bt Cry toxins. PMID- 26583655 TI - Fighting for Academic Surgical Oncology: Where Do We Come From, Where Are We Now, and Where Should We Head? PMID- 26583656 TI - Effects of Art on Surgical Patients: A Systematic Review and Meta-analysis. AB - OBJECTIVES: The aim of the study was to assess the effect of art including ambient features such as music, interior design including visual art, and architectural features on health outcomes in surgical patients. BACKGROUND: Healing environments can have a positive influence on many patients, but data focusing on art in surgical patients remain scarce. METHODS: We conducted a systematic search following the PRISMA guidelines from January 2000 to October 2014 on art in surgical patients. For music interventions, we pooled controlled studies measuring health outcomes (eg, pain, anxiety, blood pressure, and heart rate) in a meta-analysis. For other art forms (ambient and architectural features and interior design), we did a narrative review, also including nonsurgical patients, and looked for examples covering 3 countries. RESULTS: Our search identified 1101 hits with 48 studies focusing on art in surgical patients: 47 studies on musical intervention and 1 on sunlight. The meta-analysis of these studies disclosed significant effects for music on pain after surgery, anxiety, systolic blood pressure, and heart rate, when compared with control groups without music. Effects of music were larger with self-selected music, and lower in surgical interventions performed under general anesthesia. Interior design features such as nature images and more spacious rooms, and architectural features providing more sunlight had positive effects on anxiety and postoperative pain. CONCLUSIONS: Self-selected music for surgical patients is an effective and low-cost intervention to enhance well being and possibly faster recovery. Although potentially very important, the impact of environmental features and spacious architecture with wide access to sunlight remains poorly explored in surgery. Further experimental research is needed to better assess the magnitude of the impact and cost effectiveness. PMID- 26583657 TI - Randomized Multicenter Trial Comparing Glue Fixation, Self-gripping Mesh, and Suture Fixation of Mesh in Lichtenstein Hernia Repair (FinnMesh Study). AB - OBJECTIVE: Three different mesh fixation techniques were compared to find out how to perform a safe and cost-effective open inguinal hernioplasty in day-case setting with the best outcomes with regard to chronic pain. SUMMARY BACKGROUND DATA: Mesh fixation method may influence on the incidence of chronic pain after Lichtenstein hernioplasty. METHODS: Lichtenstein hernioplasty was performed under local anesthesia in 625 patients as day-case surgery in 8 Finnish hospitals. The patients were randomized to receive either a cyanoacrylate glue (Histoacryl, n = 216), self-gripping mesh (Parietex ProGrip, n = 202), or conventional nonabsorbable sutures (Prolene 2-0, n = 207) for mesh fixation. The incidence of wound complications, pain, recurrences, and patients discomfort was recorded on days 1, 7, 30, and 1 year after surgery. The primary endpoint was the sensation of pain measured by pain scores and the need of analgesics after 1 year of surgery. RESULTS: The type and size of inguinal hernias were similar in the 3 study groups. The duration of operation was 34 +/- 13, 32 +/- 9, and 38 +/- 9 minutes in the glue, self-gripping, and suture groups, respectively (P < 0.001). There were no significant differences postoperatively in pain response or need for analgesics between the study groups. Two superficial infections (0.3%), 31 wound seromas (5.0%), and 4 recurrent hernias (0.6%) were recorded during a 1 year follow-up. Some 25 patients (4.2%) needed occasionally analgesics for chronic groin pain. A feeling of a foreign object and quality of life were similar in all study groups. CONCLUSIONS: This randomized trial failed to prove that mesh fixation without sutures causes less inguinodynia than suture fixation in Lichtenstein hernioplasty. Mesh fixation without sutures is feasible without compromising postoperative outcome. PMID- 26583658 TI - Laparoscopic Mesh-augmented Hiatoplasty With Cardiophrenicopexy Versus Laparoscopic Nissen Fundoplication for the Treatment of Gastroesophageal Reflux Disease: A Double-center Randomized Controlled Trial. AB - OBJECTIVE: Laparoscopic mesh-augmented hiatoplasty with cardiophrenicopexy (LMAH C) might represent an alternative treatment of gastroesophageal reflux disease (GERD) and may provide durable reflux control without fundoplication. The expected benefit is the prevention of fundoplication-related side effects. Aim of the present trial was to compare LMAH-C with laparoscopic Nissen fundoplication (LNF) in patients with GERD. METHODS: In a double-center randomized controlled trial (RCT) patients with proven GERD were eligible and assigned by central randomization to either LMAH-C (n = 46) or LNF (n = 44). The indigestion subscore of the Gastrointestinal Symptom Rating Scale questionnaire (GSRS) indicating gas related symptoms as possible side effects of LNF was the primary endpoint. Secondary endpoints comprised pH testing and endoscopy and other symptoms measured by the GSRS, dysphagia, and the Gastrointestinal Quality of Life Index. The follow-up period was 36 months. RESULTS: Indigestion subscore (LMAH-C 2.9 +/- 1.5 vs LNF 3.7 +/- 1.6; P = 0.031) but not dysphagia (2.8 +/- 1.9 vs 2.3 +/- 1.7; P = 0.302) and quality of life (106.9 +/- 25.5 vs 105.8 +/- 24.9; P = 0.838) differed between the groups at 36 months postoperatively. Although the reflux subscore improved in both groups, it was worse in LMAH-C patients (2.5 +/- 1.6 vs 1.6 +/- 1.0; P = 0.004) corresponding to a treatment failure of 77.3% in LMAH-C patients and of 34.1% in LNF patients (P < 0.001). CONCLUSIONS: LNF is more effective in the treatment of GERD than LMAH-C. Procedure-related side effects seem to exist but do not affect the quality of life. Laparoscopic fundoplication therefore remains the standard surgical treatment for GERD. PMID- 26583659 TI - Cosmesis and Body Image in Patients Undergoing Single-port Versus Conventional Laparoscopic Cholecystectomy: A Multicenter Double-blinded Randomized Controlled Trial (SPOCC-trial). AB - OBJECTIVE: To evaluate cosmesis, body image, pain, and quality of life (QoL) after single-port laparoscopic cholecystectomy (SPLC) versus conventional 4-port laparoscopic cholecystectomy (4PLC). BACKGROUND: The impact of SPLC on improving cosmesis, body image, pain, and QoL has not been evaluated in double-blinded randomized controlled trials (RCT). This approach therefore remains controversial. METHODS: Between October 2011 and February 2014, 110 patients from 2 centers were randomly assigned to SPLC (n = 55) or 4PLC (n = 55). Primary endpoints were a validated cosmesis (3-24 points) and body image (5-20 points) score after 3 and 12 months. Secondary endpoints included operative duration, postoperative pain, complications, QoL, and length of hospital stay. Patients, physicians, and nurses were blinded until the seventh postoperative day. RESULTS: Demographics were equally distributed between both groups (mean age: 46 years, SD: 14, 62 females, 34 males). The SPLC-group showed superior mean cosmesis and body image compared with the 4PLC-group at 12-weeks (21 vs 16, P < 0.001 and 5 vs 6, P = 0.013, respectively) and at 1-year (24 vs 16, P < 0.001 and 5 vs 6, P < 0.017, respectively). Operation duration was longer in the SPLC-group (mean 101 vs 90 minutes, p = 0.031). Although postoperative pain was less in the SPLC-group (mean VAS 1 vs 2, p = 0.005), there were no differences in complications, and length of hospital-stay. CONCLUSIONS: This is the first multicenter double blinded RCT reporting superior short- and long-term cosmetic and body image, postoperative pain, and QoL in SPLC compared with 4PLC. Although cost effectiveness is still a subject of ongoing debate, SPLC should be offered to patients undergoing surgery for benign gallbladder disease. PMID- 26583660 TI - Can Laparoscopic Cholecystectomy Prevent Recurrent Idiopathic Acute Pancreatitis?: A Prospective Randomized Multicenter Trial. AB - OBJECTIVE: The aim of the present trial was to ascertain whether laparoscopic cholecystectomy (LCC) can prevent recurrent attacks of idiopathic acute pancreatitis (IAP). SUMMARY: Up to 50% to 75% of IAP may be due to microlithiasis, which is undetectable by conventional imaging methods. METHODS: This randomized, prospective trial included 85 patients (39 in the LCC and 46 in the control group) in 8 hospitals in Finland. We included adult patients (over 18 years) with their first attack of IAP. The diagnosis of IAP was based on the exclusion of common etiological reasons for acute pancreatitis (AP), whereafter the patients were randomized into conservative watchful waiting (controls) or LCC group. The primary end point was the number of patients with recurrent AP during the follow-up. All recurrent attacks of AP after an initial IAP episode were registered. RESULTS: During a median follow-up of 36 (5-58) months, the recurrence of IAP was significantly higher in the control group than in LCC group (14/46 vs. 4/39, P = 0.016), as was also the number of recurrences (23/46 vs. 8/39, P = 0.003). In the subgroup of patients with at least 24 months' follow-up, the recurrence was still higher among controls (14/37 vs. 4/35, P = 0.008). In patients with normal liver function, recurrence was also significantly higher in the control than in the LCC group (13/46 vs. 4/39, P = 0.026). During surgery, 23/39 (59%) of the gallbladders were found to contain biliary stones or sludge. CONCLUSIONS: LCC can effectively prevent the recurrence of IAP when all other possible etiologies of pancreatitis are carefully excluded. A total of 5 patients needed to be treated (NNT-value) to prevent 1 IAP. PMID- 26583661 TI - Long-term Outcome After Laparoscopic Ventral Mesh Rectopexy: An Observational Study of 919 Consecutive Patients. AB - OBJECTIVE: This multicenter study aims to assess long-term functional outcome, early and late (mesh-related) complications, and recurrences after laparoscopic ventral mesh rectopexy (LVR) for rectal prolapse syndromes in a large cohort of consecutive patients. BACKGROUND: Long-term outcome data for prolapse repair are rare. A high incidence of mesh-related problems has been noted after transvaginal approaches using nonresorbable meshes. METHODS: All patients treated with LVR at the Meander Medical Centre, Amersfoort, the Netherlands and the University Hospital Leuven, Belgium between January 1999 and March 2013 were enrolled in this study. All data were retrieved from a prospectively maintained database. Kaplan-Meier estimates were calculated for recurrences and mesh-related problems. RESULTS: 919 consecutive patients (869 women; 50 men) underwent LVR. A 10-year recurrence rate of 8.2% (95% confidence interval, 3.7-12.7) for external rectal prolapse repair was noted. Mesh-related complications were recorded in 18 patients (4.6%), of which mesh erosion to the vagina occurred in 7 patients (1.3%). In 5 of these patients, LVR was combined with a perineotomy. Both rates of fecal incontinence and obstructed defecation decreased significantly (P < 0.0001) after LVR compared to the preoperative incidence (11.1% vs 37.5% for incontinence and 15.6% vs 54.0% for constipation). CONCLUSIONS: LVR is safe and effective for the treatment of different rectal prolapse syndromes. Long-term recurrence rates are in line with classic types of mesh rectopexy and occurrence of mesh-related complications is rare. PMID- 26583662 TI - Long-term Results of Domino Liver Transplantation for Hepatocellular Carcinoma Using the "Double Piggy-back" Technique: A 13-Year Experience. AB - OBJECTIVES: The aim of this study was to evaluate the long-term outcome of liver transplantation (LT) for hepatocellular carcinoma (HCC) with Domino LT (DLT) using the "Double Piggy-back" technique. BACKGROUND DATA: DLT using livers from familial amyloidotic polyneuropathy (FAP) patients is a well-described technique and useful for expanding the donor pool. However, data on long-term results for HCC are limited, particularly regarding the use of the "Double Piggy-back" technique. METHODS: Between 2001 and 2014, a total of 260 patients undergoing LT for HCC were analyzed from a prospective database. Of those, 114 were submitted to DLT. Comparisons between groups were performed using propensity score matching. RESULTS: Median follow-up was 34 months (1-152). Overall and disease free 5-year survival rates for the whole population were 58% and 56%, respectively. There were 177 (68%) patients within Milan Criteria and an additional 26 (10%) within University of California San Francisco (UCSF) criteria. Patients older than 50 years were more likely to receive an FAP liver [odds ratio (OR) 1.94, confidence interval (CI) 1.02-3.69]. DLT patients had more major complications (23.7% vs 13.0%, P = 0.025). Only patients undergoing DLT presented with piggy-back syndrome (7% vs 0%, P = 0.001). After adjusting for potential confounders, DLT and cadaveric LT had a similar 5-year survival rate (59% vs 44%, respectively, P = 0.117). Thirteen patients (11.4%) evidenced FAP disease but not before 6 years after DLT. CONCLUSIONS: DLT for HCC is feasible and achieves equivalent results to cadaveric LT. The benefit of expanding the donor pool must be balanced against higher morbidity and a real risk of disease transmission. PMID- 26583663 TI - Laparoscopic Living Donor Left Lateral Sectionectomy: A New Standard Practice for Donor Hepatectomy. AB - OBJECTIVE: The aim of the study was to compare the short-term donor outcomes of laparoscopic left lateral sectionectomy (LLLS) for adult to child living donor liver transplantation (A-C LDLT) and laparoscopic donor nephrectomy (LDN). BACKGROUND: Although laparoscopy has become the standard approach in kidney donors, its use remains limited and controversial in LLS for A-C LDLT due to the lack of conclusive assessment of procedure-related morbidity. METHODS: From 2001 to 2014, 124 healthy donors undergoing laparoscopic LLLS for A-C LDLT at 5 tertiary referral centers in Europe, North America, and Asia, and 300 healthy donors undergoing LDN at 2 tertiary centers in Europe were retrospectively analyzed. The outcomes of LLLS were compared with those of LDN including the use of the comprehensive complication index (CCI). RESULTS: Although liver donors experienced significantly less overall (16.9% vs 31.7%, P = 0.002) and grade 1 to 2 (12.1% vs 24.7%, P = 0.004) complications than kidney donors, the rates of major complication (>= grade 3) were similar between the 2 groups. In both groups, donors experiencing postoperative complications had similar CCI (19.3 vs 21.9 for liver and kidney donors, respectively, P = 0.29). After propensity score analysis allowing for matching donors on age, sex, and body mass index, the postoperative outcomes remained comparable between the 2 groups. CONCLUSION: Laparoscopic LLS for A-C LDLT yields at least similar short-term donor outcomes as LDN. These results provide the first validation for a laparoscopic donor hepatectomy and suggest that the laparoscopic approach should be considered a new standard practice for retrieval of left lateral section liver grafts as it is for kidney donation. PMID- 26583664 TI - First Comparison of Hypothermic Oxygenated PErfusion Versus Static Cold Storage of Human Donation After Cardiac Death Liver Transplants: An International-matched Case Analysis. AB - BACKGROUND: Exposure of donor liver grafts to prolonged periods of warm ischemia before procurement causes injuries including intrahepatic cholangiopathy, which may lead to graft loss. Due to unavoidable prolonged ischemic time before procurement in donation after cardiac death (DCD) donation in 1 participating center, each liver graft of this center was pretreated with the new machine perfusion "Hypothermic Oxygenated PErfusion" (HOPE) in an attempt to improve graft quality before implantation. METHODS: HOPE-treated DCD livers (n = 25) were matched and compared with normally preserved (static cold preservation) DCD liver grafts (n = 50) from 2 well-established European programs. Criteria for matching included duration of warm ischemia and key confounders summarized in the balance of risk score. In a second step, perfused and unperfused DCD livers were compared with liver grafts from standard brain dead donors (n = 50), also matched to the balance of risk score, serving as baseline controls. RESULTS: HOPE treatment of DCD livers significantly decreased graft injury compared with matched cold-stored DCD livers regarding peak alanine-aminotransferase (1239 vs 2065 U/L, P = 0.02), intrahepatic cholangiopathy (0% vs 22%, P = 0.015), biliary complications (20% vs 46%, P = 0.042), and 1-year graft survival (90% vs 69%, P = 0.035). No graft failure due to intrahepatic cholangiopathy or nonfunction occurred in HOPE treated livers, whereas 18% of unperfused DCD livers needed retransplantation. In addition, HOPE-perfused DCD livers achieved similar results as control donation after brain death livers in all investigated endpoints. CONCLUSIONS: HOPE seems to offer important benefits in preserving higher-risk DCD liver grafts. PMID- 26583665 TI - Failure to Achieve a 2-Stage Hepatectomy for Colorectal Liver Metastases: How to Prevent It? AB - OBJECTIVES: The aim of the study was to identify predictive factors of failure of 2-stage hepatectomy (TSH) for the selection of patients with extensive bilobar colorectal liver metastases (CRLM), who are candidates for TSH. BACKGROUND: The main weakness of TSH is the risk of failure to complete both the sequential procedures. METHODS: Between 2000 and 2012, from a total cohort of 845 patients resected for CRLM, 125 patients (14.8%) with extensive CRLM were planned for TSH. All factors related to the failure of TSH were analyzed, and a predictive model was built utilizing the independent predictive factors of failure. RESULTS: Forty four patients (35.2%) could not proceed to the second stage, and their overall survival (OS) was significantly worse than that of those who completed the TSH (5 year OS: 0% vs 44.2%; P < 0.0001). Multivariate analysis revealed that carcinoembryonic antigen >30 ng/mL [relative risk (RR) 2.73, P = 0.03], tumor size >40 mm (RR 2.89, P = 0.04), chemotherapy cycles >12 (RR 3.46, P = 0.01), and tumor progression during first-line chemotherapy (RR 6.56, P = 0.01) were independent predictive factors of failure. For patients not presenting any factors, the probability of failure was 10.5%, with a 5-year OS rate of 41.9%. The addition of each subsequent factor increased the risk to 43.5%, 72.7%, 88.5%, and 95.5%, and decreased the 5-year OS to 38.8%, 29.2%, 0%, and 0%, respectively, for 1, 2, 3, and 4 factors. CONCLUSIONS: TSH should not be recommended in patients with more than 2 risk factors. Avoidance of these factors significantly reduces the risk of failure and is crucial for long-term survival. PMID- 26583666 TI - Prediction of Mortality After ALPPS Stage-1: An Analysis of 320 Patients From the International ALPPS Registry. AB - OBJECTIVES: The aim of this study was to identify predictors of 90-day mortality after Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS), available after stage-1, either to omit or delay stage-2. BACKGROUND DATA: ALPPS is a two-stage hepatectomy for patients with extensive liver tumors with predicted small liver remnants, which has been criticized for its high mortality rate. Risk factors for mortality are unknown. METHODS: Patients in the International Registry undergoing ALPPS from April 2011 to July 2014 were analyzed. Primary outcome was 90-day mortality. Liver function after stage-1 was assessed using the criteria of the International Study Group for Liver Surgery (ISGLS) after stage-1 among others. A multivariable model was used to identify independent predictors of 90-day mortality. RESULTS: Three hundred twenty patients registered by 55 centers worldwide were evaluated. Overall 90-day mortality was 8.8% (28/320). The predominant cause for 90-day mortality was postoperative liver failure in 75% of patients. Fourteen percent of patients developed liver failure according to ISGLS criteria already after stage-1 ALPPS. Those and patients with a model of end-stage liver disease (MELD) score more than 10 before stage-2 were at significantly higher risk for 90-day mortality after stage-2 with an odds ratio (OR) 3.9 [confidence interval (CI) 1.4-10.9, P = 0.01] and OR 4.9 (CI 1.9-12.7, P = 0.006), respectively. Other factors, such as size of future liver remnant (FLR) before stage-2 and time between stages, were not predictive. CONCLUSIONS: This analysis of the largest cohort of ALPPS patients so far identifies those patients in whom stage-2 ALPPS surgery should be delayed or even denied. These findings may help to make ALPPS safer. PMID- 26583667 TI - Arterial Lactate Concentration at the End of an Elective Hepatectomy Is an Early Predictor of the Postoperative Course and a Potential Surrogate of Intraoperative Events. AB - OBJECTIVES: To test the prognostic impact of arterial lactate concentration at the end-of-surgery (LCT-EOS) on postoperative outcome after elective liver resections and to identify the predictors of an increase in LCT-EOS. BACKGROUND DATA: A recent systematic-review of risk-prediction-models for liver resections has evidenced their poor accuracy and a deficit in the evaluation of intraoperative events. LCT-EOS is a marker of impaired tissue oxygenation. METHODS: This prospectively-designed study was based on a training-cohort of 519 patients and a validation-cohort of 466 patients. For each of the endpoints (high comprehensive complication index (CCI) scores, 90-day-mortality and severe morbidity), prognostic-models were built by logistic-regression using the training-cohort. These models were thereafter tested in the validation-cohort and their performance (discrimination, accuracy, calibration) assessed. Independent predictors of LCT-EOS were also identified. RESULTS: In the training-cohort, LCT EOS cutoff best discriminating high-CCI, 90-day-mortality and severe-morbidity were 3, 3 and 2.8 mmol/L (and the corresponding AUROC 0.86, 0.87 and 0.76). LCT EOS was an independent predictor of endpoints and adding LCT-EOS to the other predictors increased by 16.4%, 34.5% and 17.7% the accuracy of the models for high-CCI, 90-day-mortality and severe-morbidity, respectively. The models had high calibration and accuracy. Diabetes, repeat-hepatectomy, major-hepatectomy, synchronous-major-procedure, inflow-occlusion and blood-transfusion were independent predictors of LCT-EOS >3 mmol/L. CONCLUSIONS: LCT-EOS >3 mmol/L is an early predictor of postoperative-outcome and should be used as a tool to determine patients requiring critical-care and as an endpoint in studies measuring the impact of perioperative interventions. PMID- 26583668 TI - Early and Long-term Oncological Outcomes After Laparoscopic Resection for Colorectal Liver Metastases: A Propensity Score-based Analysis. AB - OBJECTIVE: To compare early and long-term outcomes in patients undergoing resection for colorectal liver metastases (CLM) by either a laparoscopic (LA) or an open (OA) approach. BACKGROUND: The LA is still a matter of debate regarding the surgical management of CLM. METHODS: Data of all patients from 32 French surgical centers who underwent liver resection for CLM from January 2006 to December 2013 were collected. Aiming to obtain 2 well-balanced cohorts for available variables influencing early outcome and survival, the LA group was matched 1:1 with the OA group by using a propensity score (PS)-based method. RESULTS: The unmatched initial cohort consisted of 2620 patients (LA: 176, OA: 2444). In the matched cohort for operative risk factors (LA: 153, OA: 153), the LA group had shorter hospitalization stays [11.1 (+/-9) days vs 13.9 (+/-10) days; P = 0.01] and was associated with lower rates of grade III to V complications [odds ratio (OR): 0.27, 95% confidence interval (CI) 0.14-0.51; P = 0.0002] and inhospital transfusions (OR: 0.33 95% CI 0.18-0.59; P < 0.0001). On a prognostic factors well-balanced population (LA: 73, OA: 73), the LA group and the OA group experienced similar overall (OS) and disease-free (DFS) survival rates [OS rates of 88% and 78% vs 84% and 75% at 3 and 5 years, respectively (P = 0.72) and DFS rates of 40% and 32% vs 52% and 36% at 3 and 5 years, respectively (P = 0.60)]. CONCLUSIONS: In the patients who are suitable for LA, laparoscopy yields better operative outcomes without impairing long-term survival. PMID- 26583669 TI - Prospective Study of Malabsorption and Malnutrition After Esophageal and Gastric Cancer Surgery. AB - OBJECTIVE: To study malabsorption and malnutrition after curative resection of esophageal and gastric cancer. DESIGN: Prospective cohort study. BACKGROUND: Improved cure rates for esophageal and gastric cancer have increased focus on health-related quality of life (HR-QL) in survivorship. Although malnutrition is well described in long-term follow-up, and gastrointestinal symptoms are common, data on gut and pancreatic-related malabsorption are scant. METHODS: Disease-free patients at least 18 months after esophageal or gastric oncologic resections represented the study cohort. A modified Gastrointestinal Symptom Rating Scale questionnaire was completed, and weight, fecal elastase (FE), albumin, vitamins, and micronutrients measured preoperatively and at 1, 6, and 18 to 24 months postoperatively. Small intestinal bacterial overgrowth (SIBO) and changes in body composition were also evaluated postoperatively. RESULTS: At a median follow-up of 23 months, 45 of 66 patients in a consecutive series were disease-free. Mean weight (78 +/- 19 vs 67 +/- 16 kg), body mass index (27 +/- 5 vs 24 +/- 5 kg/m), Vitamin A (1.7 +/- 0.6 vs 1.2 +/- 0.4 umol/L), and Vitamin E (28 +/- 7 vs 20 +/- 7 umol/L) were significantly decreased (P < 0.01) at last follow-up compared with preoperatively. Malabsorption was evident in 73% of patients, of whom 44% had FE < 200 MUg/g and 38% had evidence of SIBO. Total body fat-free mass (175 +/- 96 vs 84 +/- 71, P < 0.001) and skeletal muscle index (44 +/- 8 vs 39 +/- 8, P = 0.007) were significantly decreased at 18 to 24 months. CONCLUSIONS: Malabsorption and malnutrition are prevalent in survivorship of esophageal and stomach cancer. This may be underappreciated, and both gut and pancreatic insufficiency represent modifiable targets in the interdisciplinary approach to recovery of HR-QL. PMID- 26583670 TI - International Multicenter Study on the Impact of Extracapsular Lymph Node Involvement in Primary Surgery Adenocarcinoma of the Esophagus on Overall Survival and Staging Systems. AB - OBJECTIVE: The current pathological lymph node (pN) staging is based on the number of positive lymph nodes but does not take into consideration characteristics of the involved lymph nodes itself. The current study aims to examine the prognostic value of extracapsular lymph node involvement (EC-LNI) and intracapsular lymph node involvement (IC-LNI) for esophageal adenocarcinoma treated by primary surgery. METHODS: From the databases of five European high volume centers, 1639 adenocarcinoma patients with primary R0-resection were withheld after excluding 90-day mortality. Oncologic variables, including number of resected lymph nodes, number of resected positive lymph nodes, and EC-LNI/IC LNI were examined. The Union Internationale contre le Cancer (UICC) 7th edition prognostic staging was used as baseline staging system. Statistical analysis was performed by Cox proportional hazards modeling and verified using the Random Survival Forest technique. RESULTS: EC-LNI showed significantly worse overall 5 year survival compared with IC-LNI overall (13.4% vs 37.2%, P < 0.0001), including in each pN-category [16.4% vs 45.6% in pN1 (P < 0.0001), 16.1% vs 23.8% (P = 0.047) in pN2 (P = 0.065), and 8.7% vs 26.3% in pN3 categories, respectively]. pN1 IC-LNI patients show a 5-year overall survival comparable (P = 0.92) with stage IIB (ie, pT3N0). Reclassifying the UICC prognostic stages according to these findings into an adapted staging model showed a significant (P < 0.0001) increase in homogeneity, discriminatory ability, and monotonicity compared with the original UICC TNM 7th edition prognostic staging. CONCLUSIONS: These data suggest that lymph node capsular status is an important prognostic factor and should be considered for the future edition of the TNM staging system for esophageal cancer. PMID- 26583671 TI - Laparoscopic Gastric Mobilization Reduces Postoperative Mortality After Esophageal Cancer Surgery: A French Nationwide Study. AB - OBJECTIVE: This study was designed to investigate the impact of laparoscopic gastric mobilization (LGM) on 30-day postoperative mortality (POM) after surgery for esophageal cancer (EC). BACKGROUND: Meta-analyses of nonrandomized studies have failed to demonstrate any significant benefit of hybrid minimally invasive esophagectomy on POM, potentially due to small population samples. Moreover, none of the published randomized trials have been designed to answer this question. METHODS: All consecutive patients who underwent EC resection between 2010 and 2012 in France were included in this nationwide study (n = 3009). Data were extracted from the French National Health Service Database with internal and external quality controls. Patients treated with LGM (LGM group, n = 663) were compared with those treated with open approach (open group, n = 2346). Propensity score matching and multivariable analyses were used to compensate for the differences in baseline characteristics. RESULTS: The 30-day POM rate was 5.2%, significantly lower after LGM, compared with open surgery (3.3% vs 5.7%, P = 0.005), as well as in-hospital (5.6% vs 8.1%, P = 0.028), and 90-day POM (6.9% vs 10.0%, P = 0.016). After propensity score matching, 30-day POM rates were 3.3% versus 5.9%, respectively (P = 0.029). By multivariable analysis, age >=60 years, malnutrition and cardiovascular comorbidity were independently associated with higher POM, whereas LGM was associated with a decrease in POM (OR 0.60, 95% CI 0.37-0.98, P = 0.041). CONCLUSIONS: This all-inclusive nationwide study strongly suggests that POM is significantly reduced after LGM for EC. This is high valuable evidence that helps decision making regarding the optimal approach for EC surgery. PMID- 26583672 TI - Gut Hormone Suppression Increases Food Intake After Esophagectomy With Gastric Conduit Reconstruction. AB - OBJECTIVES: To characterize the gut hormone profile and determine the effect of satiety gut hormone blockade on food intake in disease-free postesophagectomy patients. BACKGROUND: Improved oncologic outcomes for esophageal cancer have resulted in increased survivorship and a focus on health-related quality of life. Anorexia and early satiety are common, but putative causative factors, in particular the gut-brain hormonal axis, have not been systematically studied. METHODS: In a double-blind, placebo-controlled, randomized crossover study, disease-free patients at least 1 year postresection and gastric conduit reconstruction received either 1 mL 0.9% saline or 1 mL (100 MUg) octreotide acetate subcutaneously followed by a standardized ad libitum meal on each of two assessments. Fasting and postprandial plasma glucagon-like peptide 1 (GLP-1), peptide YY (PYY), and ghrelin immunoreactivity were measured. Gut hormone responses and calorie intake postsaline versus octreotide were compared between experimental and control groups. RESULTS: Eighteen subjects [esophagectomy (ES), n = 10, 2.4 +/- 0.75 years postresection; and unoperated control subjects, n = 8] were studied. ES demonstrated significant weight loss at 3, 6, 12, and 24 months postoperatively (all P < 0.05). Ghrelin levels were similar (P = 0.58) for both groups, but postprandial GLP-1 and PYY responses were significantly (P < 0.001) greater among ES as compared with controls. After octreotide, ad libitum calorie intake increased among ES (1.5 +/- 0.2 fold-change, P = 0.02) but not controls (1.1 +/- 0.1 fold-change, P = 0.30). CONCLUSIONS: ES demonstrated an exaggerated postprandial satiety gut hormone response that was attenuated by octreotide, thus identifying a potential therapeutic target to modulate in the ES patient with early satiety. PMID- 26583673 TI - Laparoscopic Versus Open Surgery for Gastric Gastrointestinal Stromal Tumors: What Is the Impact on Postoperative Outcome and Oncologic Results? AB - OBJECTIVES: The aim of the study was to compare the postoperative and oncologic outcomes of laparoscopic versus open surgery for gastric gastrointestinal stromal tumors (gGISTs). BACKGROUND: The feasibility of the laparoscopic approach for gGIST resection has been demonstrated; however, its impact on outcomes, particularly its oncologic safety for tumors greater than 5 cm, remains unknown. METHODS: Among 1413 patients treated for a GIST in 61 European centers between 2001 and 2013, patients who underwent primary resection for a gGIST smaller than 20 cm (N = 666), by either laparoscopy (group L, n = 282) or open surgery (group O, n = 384), were compared. Multivariable analyses and propensity score matching were used to compensate for differences in baseline characteristics. RESULTS: In hospital mortality and morbidity rates in groups L and O were 0.4% versus 2.1% (P = 0.086) and 11.3% vs 19.5% (P = 0.004), respectively. Laparoscopic resection was independently protective against in-hospital morbidity (odds ratio 0.54, P = 0.014). The rate of R0 resection was 95.7% in group L and 92.7% in group O (P = 0.103). After 1:1 propensity score matching (n = 224), the groups were comparable according to age, sex, tumor location and size, mitotic index, American Society of Anesthesiology score, and the extent of surgical resection. After adjustment for BMI, overall morbidity (10.3% vs 19.6%; P = 0.005), surgical morbidity (4.9% vs 9.8%; P = 0.048), and medical morbidity (6.2% vs 13.4%; P = 0.01) were significantly lower in group L. Five-year recurrence-free survival was significantly better in group L (91.7% vs 85.2%; P = 0.011). In tumors greater than 5 cm, in-hospital morbidity and 5-year recurrence-free survival were similar between the groups (P = 0.255 and P = 0.423, respectively). CONCLUSIONS: Laparoscopic resection for gGISTs is associated with favorable short-term outcomes without compromising oncologic results. PMID- 26583674 TI - Inhibition of MicroRNA-494 Reduces Carotid Artery Atherosclerotic Lesion Development and Increases Plaque Stability. AB - OBJECTIVES: Unstable atherosclerotic lesions in carotid arteries require surgical endarterectomy to reduce the risk of ischemic stroke. We aimed to identify microRNAs that exert a broad effect on atherosclerotic plaque formation and stability in the carotid artery. BACKGROUND: We made a selection of 164 genes involved in atherosclerosis. Using www.targetscan.org, we determined which microRNAs potentially regulate expression of these genes. We identified multiple microRNAs from the 14q32 microRNA cluster, which is highly involved in vascular remodeling. In human plaques, collected during carotid endarterectomy surgery, we found that 14q32 microRNA (miR-494) was abundantly expressed in unstable lesions. METHODS: We induced atherosclerotic plaque formation in hypercholesterolemic ApoE mice by placing semiconstrictive collars around both carotid arteries. We injected "Gene Silencing Oligonucleotides" against miR-494 (GSO-494) or negative control (GSO-control). Using fluorescently labeled GSOs, we confirmed uptake of GSOs in affected areas of the carotids, but not elsewhere in the vasculature. RESULTS: After injection of GSO-494, we observed significant downregulation of miR-494 expression in the carotid arteries, although miR-494 target genes were upregulated. Further analyses revealed a 65% decrease in plaque size after GSO 494 treatment. Plaque stability was increased in GSO-494-treated mice, determined by an 80% decrease in necrotic core size and a 50% increase in plaque collagen content. Inhibition of miR-494 also resulted in decreased cholesterol levels and decreased very low-density lipoprotein (VLDL) fractions. CONCLUSIONS: Treatment with GSO-494 results in smaller atherosclerotic lesions with increased plaque stability. Inhibition of miR-494 may decrease the risk of surgical complications or even avert endarterectomy surgery in some cases. PMID- 26583675 TI - Restorative Proctocolectomy and Ileal Pouch-anal Anastomosis. AB - OBJECTIVES: To assess mortality after restorative proctocolectomy (RPC) and determine the influencing factors with a specific focus on institutional caseload and surgical approach in France. BACKGROUND: RPC is an uncommonly performed and demanding procedure; case volume may exert a significant influence on outcome. METHODS: Data of all patients who underwent RPC in France between 2009 and 2012, including demographics, diagnosis, procedures, mode of admission, discharge, and hospital type were collected. RESULTS: One thousand one hundred sixty-six RPCs were performed in 237 centers (mean: 1.65 procedure/year/center). Rate of laparoscopic procedures was 47.1% (n = 549). Mortality reached 1.5% (n = 17). Independent factors for mortality were ageless than 45 years (odds ratio, OR = 3.9) and surgery in a center performing less than 3 RPC per year (OR = 3.2). Centers performing less than 3 RPC per year represented 89% of all centers, accounted for 37% (n = 431) of all patients and represented 70.6% of all deaths (n = 12). Underlying pathology exerted a significant effect on mortality; mortality rate after "classical" indications (polyposis and inflammatory bowel disease) was 0.7% (8/1078) and was 16.7% (9/54) for "nonclassical" indications (peritonitis, carcinomatosis, and so on) (P < 0.0001). Nonclassical diagnoses were observed more frequently in centers performing less than 3 RPC per year [40/412 (7.3%) vs 24/720 (3.3%), P = 0.0027]. A laparoscopic approach was associated with a low mortality rate on univariate analysis (0.7% vs 1.2%, P = 0.05), a shorter hospital stay (15.8 +/- 0.6 vs 17.8 +/- 0.55, P = 0.0053) and more frequently performed in experienced centers >=3 RPC/year (50.8% vs 40.7%, P = 0.0009). CONCLUSIONS: Mortality after RPC in centers performing 3 or less RPC per year was significantly higher, and accounted for more than half of all deaths. In France, consolidating all RPCs to higher volume centers may lead to better outcomes. PMID- 26583676 TI - Rectovaginal Fistula: What Is the Optimal Strategy?: An Analysis of 79 Patients Undergoing 286 Procedures. AB - OBJECTIVES: The aim of this study was to assess results of surgery for rectovaginal fistula (RVF) and prognostic factors for success. BACKGROUND DATA: Management of RVF remains challenging and numerous surgical options are available. Few large reports of RVF are available and success prognostic factors remain unknown. METHODS: All patients operated for RVF from 1996 to 2014 were included. RESULTS: Seventy-nine patients presented RVF due to Crohn disease in 34 (43%), postoperative in 25 (32%), obstetrical in 7 (9%), radiation proctitis in 4 (5%), and miscellaneous in 9 (11%). A total of 286 procedures (132 with associated stoma, 46%) were performed including 217 conservative (76%) [seton drainage (n = 59; 21%), vaginal (n = 49, 17%) or rectal advancement flap (n = 46; 16%), diverting stoma only (n = 27; 9%), plug (n = 15; 5%), glue (n = 13; 5%), or others (n = 8, 3%)]; and 69 major procedures (24%) [gracilis muscle interposition (n = 32; 11%), coloanal or colorectal anastomosis (n = 19; 7%) including 11 delayed anastomosis with colonic pull-through, biomesh interposition (n = 9, 3%), and abdominoperineal resection (n = 9; 3%)]. After a mean follow-up of 33 months, overall success rate was 57 of 79 (72%). Per-procedure-based multivariate analysis identified major procedure [odds ratio (OR): 6.4 (2.9-14.2); P < 0.001], diverting stoma [OR: 3.5 (1.4-8.7); P = 0.009], less than 9 months between diagnosis and first surgery [OR: 2.3 (1.1-5.3); P = 0.046], and first surgery in our institution [OR: 3.2 (1.5-6.9); P = 0.003], as independent factors for success. CONCLUSIONS: Our study suggested that aggressive surgical treatment of RVF, including early use of temporary stoma and major procedure in case of failure of previous local treatment, leads to high success rates. PMID- 26583677 TI - Effects of Curative Colorectal Cancer Surgery on Exhaled Volatile Organic Compounds and Potential Implications in Clinical Follow-up. AB - OBJECTIVE: The aim of this study was to determine whether the volatile organic compounds (VOCs) pattern in colorectal cancer (CRC) patients is modified by curative surgery for a potential application in the oncologic follow-up. BACKGROUND: CRC has been proved to induce metabolic derangements detectable by high through-output techniques in exhaled breath showing a specific pattern of VOCs. METHODS: Forty-eight CRC patients and 55 healthy controls (HC) entered the study. Thirty-two patients (M/F: 1.4; mean age 63 years) attended the oncologic follow-up (mean 24 months) and were found disease-free. Breath samples were collected under similar environmental conditions into a Tedlar bags and processed offline by thermal-desorption gas chromatography-mass spectrometry (TD-GC-MS). VOCs were selected by U test to build a Probabilistic Neural Network (PNN) model to set-up a training phase, which was cross-validated using the leave-one out method. RESULTS: A total of 11 VOCs were finally selected for their excellent discriminant performance in identifying disease-free patients in follow-up from CRC patients before surgery, (sensitivity 100%, specificity 97.92%, accuracy 98.75%, and AUC: 1). The same VOCs pattern discriminated follow-up patients from HC, with a sensitivity of 100%, specificity of 90.91%, accuracy of 94.25%, and AUC 0.959. CONCLUSIONS: Exhaled VOCs pattern from CRC patients is modified by cancer removal confirming the tight relationship between tumor metabolism and exhaled VOCs. PNN analysis provides a high discriminatory tool to identify patients disease-free after curative surgery suggesting potential implications in CRC screening and secondary prevention. PMID- 26583678 TI - Laparoscopic Distal Pancreatectomy for Pancreatic Ductal Adenocarcinoma: Time for a Randomized Controlled Trial? Results of an All-inclusive National Observational Study. AB - OBJECTIVES: The aim of this study is to compare at a national level, the early and long-term outcome of distal pancreatectomy (DP) performed by laparoscopy (LapDP) or open surgery (OpenDP) for pancreatic ductal adenocarcinoma (PDAC). BACKGROUND DATA: LapDP is feasible and safe for benign conditions but its use for PDAC is controversial. METHODS: French healthcare databases were screened to identify all patients who had undergone LapDP or OpenDP for PDAC between 2007 and 2012. Endpoints were (i) 90-day mortality, (ii) morbidity, (iii) transfusion rate, (iv) length of hospital stay (LOS), and (v) long-term survival. Logistic regression and adjusted Cox models were used to compare LapDP and OpenDP with regard to these outcomes. Confounders included (i) patients' characteristics; (ii) associated surgical procedures; and (iii) characteristics of the hospital. Performance of the resulting models was determined by the area under the receiver operating characteristic (ROC) curve. RESULTS: Over the 6-year period, there were 2753 operations for PDAC: 2406 OpenDP and 347 LapDP (12.6%). The overall 90-day mortality rate was 5.2%; median LOS was 15 days, and median survival was 38 months. LapDP was not correlated with 90-day mortality but was associated with reduced pleuropulmonary morbidity (odds ratio (OR) 0.73, P = 0.028), blood transfusion (OR 0.44, P = 0.001), and LOS (P = 0.042), and was associated with increased survival (P = 0.0007). CONCLUSIONS: LapDP has not been adopted widely for PDAC. The early and long-term results of LapDP as currently practiced are as good as those of OpenDP. The next step in the evaluation of LapDP should be a randomized controlled trial (RCT), but such a trial is likely to suffer from insufficient recruitment. PMID- 26583679 TI - Main-duct Intraductal Papillary Mucinous Neoplasm: High Cancer Risk in Duct Diameter of 5 to 9 mm. AB - OBJECTIVE: The 2012 international consensus guidelines for the management of intraductal papillary mucinous neoplasms (IPMN) recommend surgical treatment in main-duct IPMN patients with a main pancreatic duct (MPD) diameter of >=10 mm. Aim of the present study was to analyze cancer risk in patients with an MPD diameter of less than 10 mm. METHODS: All consecutive patients (prospective data protocol) with histological proof of IPMN who underwent surgery between January 2004 and December 2013 were included in the study. Clinical characteristics, particularly preoperative imaging with regard to morphology of the MPD, were correlated with final histopathology. RESULTS: Among a total of 605 patients who underwent surgery for IPMN, there were 320 patients with MPD involvement, 238 patients with mixed-type IPMN, and 82 patients with main-duct IPMN alone. The total malignancy rate including high-grade dysplasia and invasive carcinoma in IPMNs with MPD involvement was 68%. When the MPD diameter was 5 to 9 mm, malignancy rate was 59%, whereas in MPD diameter more than 10 mm, it was 73%. No statistical correlations were observed between MPD diameter and clinical and/or IPMN features such as age, cyst location, mural nodules, serum tumor markers, or bilirubin. CONCLUSIONS: Main-duct IPMNs with a MPD between 5 and 9 mm already bear a significant risk of malignancy. Therefore, surgical treatment is clearly indicated in patients with a MPD diameter of >=5 mm and the 2012 guidelines should be discussed and adapted with regard to this topic. PMID- 26583680 TI - Influence of Depression on Recovery After Major Noncardiac Surgery: A Prospective Cohort Study. AB - OBJECTIVES: To determine the influence of patient depression (and anxiety) on postoperative outcome and surgeons' consideration of it. BACKGROUND: Patients' mental state influences the course of nonpsychiatric diseases. Evidence in the surgical setting comes mainly from cardiac-surgery patients and no predictive model of postoperative outcome considers this dimension. METHODS: This prospective multicenter study included patients undergoing liver resections, a model of major abdominal surgery, between September 2013 and September 2014 in 8 centers. The primary outcome was postoperative morbidity or mortality (assessed by the Clavien-Dindo grade and the Comprehensive Complication Index) and the postoperative length of stay (LOS). Depression and anxiety were assessed preoperatively with the Hospital Anxiety and Depression Scale and a validated cutoff. Surgeons were preoperatively asked to predict outcome. Multivariable mixed-effects Cox models were fitted to evaluate the influence of depression on actual and surgeon-anticipated outcome and on the difference between actual and surgeon-anticipated LOS. RESULTS: Hospital Anxiety and Depression Scale identified 142 of 591 patients (24.0%) as depressed and 40.3% as anxious. Neither condition was independently correlated with morbidity or mortality, but depression was an independent risk factor for prolonged LOS (adjusted hazard ratio 0.65, 95% confidence interval 0.50-0.83, P = 0.001). Depression was not correlated with anticipated LOS. Three variables explained the gap between anticipated and actual LOS: depression (P = 0.003), associated surgical procedures in addition to liver resection (P = 0.007), and postoperative morbidity (P < 0.001). CONCLUSIONS: Nearly 1 quarter of patients undergoing major abdominal surgery are depressed preoperatively. This depression is a strong independent predictor of prolonged LOS and partly explains surgeons' failure to predict outcome accurately. PMID- 26583681 TI - Elucidating the general principles of cell adhesion with a coarse-grained simulation model. AB - Cell adhesion plays an indispensable role in coordinating physiological functions in multicellular organisms. During this process, specific types of cell adhesion molecules interact with each other from the opposite sides of neighboring cells. Following this trans-interaction, many cell adhesion molecules further aggregate into clusters through cis interactions. Beyond the molecule level, adhesion can be affected by multiple cellular factors due to the complexity of membrane microenvironments, including its interplay with cell signaling. However, despite tremendous advances in experimental developments, little is understood about the general principles of cell adhesion and its functional impacts. Here a mesoscopic simulation method is developed to tackle this problem. We illustrated that specific spatial patterns of membrane protein clustering are originated from different geometrical arrangements of their binding interfaces, while the size of clusters is closely regulated by molecular flexibility. Different scenarios of cooperation between trans and cis interactions of cell adhesion molecules were further tested. Additionally, impacts of membrane environments on cell adhesion were evaluated, such as the presence of a cytoskeletal meshwork, the membrane tension and the size effect of different membrane proteins on cell surfaces. Finally, by simultaneously simulating adhesion and oligomerization of signaling receptors, we found that the interplay between these two systems can be either positive or negative, closely depending on the spatial and temporal patterns of their molecular interactions. Therefore, our computational model pave the way for understanding the molecular mechanisms of cell adhesion and its biological functions in regulating cell signaling pathways. PMID- 26583682 TI - What works in genomics education: outcomes of an evidenced-based instructional model for community-based physicians. AB - PURPOSE: Education of practicing health professionals is likely to be one factor that will speed appropriate integration of genomics into routine clinical practice. Yet many health professionals, including physicians, find it difficult to keep up with the rapid pace of clinical genomic advances and are often uncomfortable using genomic information in practice. METHODS: Having identified the genomics educational needs of physicians in a Silicon Valley-area community hospital, we developed, implemented, and evaluated an educational course entitled Medicine's Future: Genomics for Practicing Doctors. The course structure and approach were based on best practices in adult learning, including interactivity, case-based learning, skill-focused objectives, and sequential monthly modules. RESULTS: Approximately 20-30 physicians attended each module. They demonstrated significant gains in genomics knowledge and confidence in practice skills that were sustained throughout and following the course. Six months following the course, the majority of participants reported that they had changed their practice to incorporate skills learned during the course. CONCLUSION: We believe the adult-learning principles underlying the development and delivery of Medicine's Future were responsible for participants' outcomes. These principles form a model for the development and delivery of other genomics educational programs for health professionals.Genet Med 18 7, 737-745. PMID- 26583683 TI - A systematic literature review of individuals' perspectives on broad consent and data sharing in the United States. AB - PURPOSE: In 2011, an Advanced Notice of Proposed Rulemaking proposed that de identified human data and specimens be included in biobanks only if patients provide consent. The National Institutes of Health Genomic Data Sharing policy went into effect in 2015, requiring broad consent from almost all research participants. METHODS: We conducted a systematic literature review of attitudes toward biobanking, broad consent, and data sharing. Bibliographic databases included MEDLINE, Web of Science, EthxWeb, and GenETHX. Study screening was conducted using DistillerSR. RESULTS: The final 48 studies included surveys (n = 23), focus groups (n = 8), mixed methods (n = 14), interviews (n = 1), and consent form analyses (n = 2). Study quality was characterized as good (n = 19), fair (n = 27), and poor (n = 2). Although many participants objected, broad consent was often preferred over tiered or study-specific consent, particularly when broad consent was the only option, samples were de-identified, logistics of biobanks were communicated, and privacy was addressed. Willingness for data to be shared was high, but it was lower among individuals from under-represented minorities, individuals with privacy and confidentiality concerns, and when pharmaceutical companies had access to data. CONCLUSIONS: Additional research is needed to understand factors affecting willingness to give broad consent for biobank research and data sharing in order to address concerns to enhance acceptability.Genet Med 18 7, 663-671. PMID- 26583684 TI - Using a gene expression signature when controversy exists regarding the indication for adjuvant systemic treatment reduces the proportion of patients receiving adjuvant chemotherapy: a nationwide study. AB - PURPOSE: The Dutch national guideline advises use of gene-expression signatures, such as the 70-gene signature (70-GS), in case of ambivalence regarding the benefit of adjuvant chemotherapy (CT). In this nationwide study, the impact of 70 GS use on the administration of CT in early breast cancer patients with a dubious indication for CT is assessed. METHODS: Patients within a national guideline directed indication area for 70-GS use who were surgically treated between November 2011 and April 2013 were selected from the Netherlands Cancer Registry database. The effect of 70-GS use on the administration of CT was evaluated in guideline- and age-delineated subgroups addressing potential effect of bias by linear mixed-effect modeling and instrumental variable (IV) analyses. RESULTS: A total of 2,043 patients within the indicated area for 70-GS use were included, of whom 298 received a 70-GS. Without use of the 70-GS, 45% of patients received CT. The 70-GS use was associated with a 9.5% decrease in CT administration (95% confidence interval (CI): -15.7 to -3.3%) in linear mixed-effect model analyses and IV analyses showed similar results (-9.9%; 95% CI: -19.3 to -0.4). CONCLUSION: In patients in whom the Dutch national guidelines suggest the use of a gene-expression profile, 70-GS use is associated with a 10% decrease in the administration of adjuvant CT.Genet Med 18 7, 720-726.Genetics in Medicine (2016); 18 7, 720-726. doi:10.1038/gim.2015.152. PMID- 26583686 TI - Endovascular Treatment of Stroke, Oral Anticoagulant-associated Intracerebral Hemorrhage, and Treatment of Extracranial Dissection. PMID- 26583685 TI - Institutional review board perspectives on obligations to disclose genetic incidental findings to research participants. AB - PURPOSE: Researchers' obligations to disclose genetic incidental findings (GIFs) have been widely debated, but there has been little empirical study of the engagement of institutional review boards (IRBs) with this issue. METHODS: This article presents data from the first extensive (n = 796) national survey of IRB professionals' understanding of, experience with, and beliefs surrounding GIFs. RESULTS: Most respondents had dealt with questions about GIFs (74%), but only a minority (47%) felt prepared to address them. Although a majority believed that there is an obligation to disclose GIFs (78%), there is still not consensus about the supporting ethical principles. Respondents generally did not endorse the idea that researchers' additional time and effort (7%), and lack of resources (29%), were valid reasons for diminishing a putative obligation. Most (96%) supported a right not to know, but this view became less pronounced (63%) when framed in terms of specific case studies. CONCLUSIONS: IRBs are actively engaged with GIFs but have not yet reached consensus. Respondents were uncomfortable with arguments that could be used to limit an obligation to return GIFs. This could indicate that IRBs are providing some of the impetus for the trend toward returning GIFs, although questions remain about the relative contribution of other stakeholders.Genet Med 18 7, 705-711. PMID- 26583687 TI - Geometric reconstruction of biological orthogonal plywoods. AB - In this paper we focus on the structural determination of biological orthogonal plywoods, fiber-like composite analogues of liquid crystalline phases, where the fibrils of the building blocks show sharp 90 degrees orientation jumps between fibers in adjacent domains. We present an original geometric and computational modelling that allows us to determine the fibrillary orientation in biological plywoods from periodic herringbone patterns commonly observed in cross-sections. Although herringbone patterns were long reported, the specific and quantitative relationships between herringbones and the orthogonal plywoods were absent or at best incomplete. Here we provide an efficient and new procedure to perform an inverse problem that connects two specific features of the herringbone patterns (aperture angle and wavelength) with the 3D morphology of the structure, whose accuracy and validity were ascertained through in silico simulations and also with real specimens ("Eremosphaera viridis"). This contribution extends significantly the better known characterization methods of 2D cross sections, such as the arced patterns observed in biological helicoidal plywoods, and with the present proposed methodology it adds another characterization tool for a variety of biological fibrous composites that form cornea-like tissues. PMID- 26583688 TI - One-pot synthesis and control of aqueous soluble and organic soluble carbon dots from a designable waterborne polyurethane emulsion. AB - Carbon dots (CDs) have a wide range of applications and have drawn great interest in the recent decade. The fabrication and control of CDs with different solubilities are still urgent problems for their practical use. In this paper, aqueous soluble and organic soluble CDs (ACDs, OCDs) were produced by one-pot hydrothermal treatment of a designable waterborne polyurethane (WPU) emulsion. The difference in the solubility and fluorescence of these two kinds of CDs was attributed to the various functional groups on the surface, which were derived from the different segment fragments formed by hydrothermal treatment of a block polymer. It was found that the yields of the ACDs and OCDs could be regulated by means of selecting different soft segments in WPU. The more hydrophobic soft segments could result in an increase of the OCDs and a decrease of the ACDs. While the soft segments were hydrophilic or hydrolysable under hydrothermal conditions, only ACDs were obtained. The ACDs had good fluorescence and showed low cytotoxicity for use in multicolour bio-imaging. The OCDs processed good solubility in a wide range of organic solvents and were suitable for preparing fluorescent composite films with polymers. PMID- 26583690 TI - Mechanoelectrochemistry of PPy(DBS) from correlated characterization of electrochemical response and extensional strain. AB - This paper investigates nanostructured morphology-dependent charge storage and coupled mechanical strain of polypyrrole membranes doped with dodecylbenzenesulfonate (PPy(DBS)). Nanoscale features introduced in PPy(DBS) using phospholipid vesicles as soft-templates create a uniform and long-range order to the polymer morphology, and lead to higher specific capacitance. It is widely stated that nanostructured architecture offer reduced mechanical loading at higher charge capacities, but metrics and methods to precisely quantify coupled localized strains do not exist. Towards this goal, we demonstrate the use of scanning electrochemical microscope with shear force imaging hardware (SECM SF) to precisely measure charge storage function and volumetric strain simultaneously, and define two metrics--filling efficiency and chemomechanical coupling coefficient to compare nanostructured morphologies and thicknesses. For thin membranes (smaller charge densities), planar and vesicle-templated membranes have comparable mechanoelectrochemical response. For thick membranes (0.4 to 0.8 C cm(-2)), a 15% increase in charge storage is associated with 50% reduction in extensional strain. These results allow for the formulation of rules to design nanostructured PPy(DBS)-based actuators and energy storage devices. PMID- 26583691 TI - Open-Angle Glaucoma and an Enlarged Superior Orbital Fissure Caused by Trauma. PMID- 26583692 TI - Omega-3 Index of Canadian adults. AB - BACKGROUND: Cardioprotective properties have been associated with two fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The Omega-3 Index indicates the percentage of EPA+DHA in red blood cell fatty acids. Omega-3 Index levels of the Canadian population have not been directly measured. DATA AND METHODS: Data for respondents aged 20 to 79 from cycle 3 (2012/2013) of the Canadian Health Measures Survey were used to calculate means and the prevalence of Omega-3 Index coronary heart disease (CHD) risk cut-offs-high (4% or less), moderate (more than 4% to less than 8%), and low (8% or more)-by sociodemographic and lifestyle characteristics, including fish consumption and use of omega-3 supplements. Associations between the Omega-3 Index and CHD-related factors including biomarkers, risk factors, and previous CHD events, were examined in multivariate regression models. RESULTS: The mean Omega-3 Index level of Canadians aged 20 to 79 was 4.5%. Levels were higher for women, older adults, Asians and other non-white Canadians, omega-3 supplement users, and fish consumers; levels were lower for smokers and people who were obese. Fewer than 3% of adults had levels associated with low CHD risk; 43% had levels associated with high risk. No CHD-related factor was associated with the Omega-3 Index when control variables were taken into account. INTERPRETATION: Omega-3 Index levels among Canadian adults were strongly related to age, race, supplement use, fish consumption, smoking status and obesity. Fewer than 3% of adults had Omega-3 Index levels associated with low risk for CHD. PMID- 26583693 TI - A surveillance tool to assess diets according to Eating Well with Canada's Food Guide. AB - BACKGROUND: A surveillance tool was developed to assess dietary intake collected by surveys in relation to Eating Well with Canada's Food Guide (CFG). The tool classifies foods in the Canadian Nutrient File (CNF) according to how closely they reflect CFG. This paper describes the validation exercise conducted to ensure that CNF foods determined to be "in line with CFG" were appropriately classified. DATA AND METHODS: With statistical modelling, 8,000 simulated diets (500 for each of the 16 Dietary Reference Intake [DRI] age/sex groups) were generated using commonly consumed foods classified as "in line with CFG." Criteria for assessing the energy content and nutrient distributions of the simulated diets were based on factors considered in the development of CFG, including Estimated Energy Requirement (EER) and Dietary Reference Intake (DRI) values. RESULTS: The median energy content of the simulated diets was at or below reference EERs. Most age/sex group distributions had macronutrient profiles that met the assessment criterion of 80% of the distribution within the Acceptable Macronutrient Distribution Range, and almost all age/sex group distributions had a low prevalence (less than 10%) of micronutrient profiles below the Estimated Average Requirements. Overall, the findings indicate that diets consisting of foods that are commonly consumed by Canadians and that are "in line with CFG" have a low probability of energy excess and nutrient inadequacy. INTERPRETATION: The classification of foods in the CNF accurately reflects CFG recommendations and can be used to assess surveillance data. PMID- 26583694 TI - Housing and health among Inuit children. AB - BACKGROUND: Housing conditions have been associated with child health. Inuit children are generally in poorer health than other Canadian children. They are also more likely to live in crowded households, in dwellings that need major repair, and to be exposed to second-hand smoke in the home. DATA AND METHODS: This study uses the 2006 Aboriginal Children's Survey to examine associations between physical and psychosocial housing characteristics and physical and mental health outcomes of Inuit children aged 2 to 5. RESULTS: Physical and psychosocial housing characteristics were associated with selected indicators of Inuit children's health. The presence of a smoker in the home, homeownership, and parental housing satisfaction were associated with specific physical and/or mental health outcomes, even after adjusting for other housing factors and family and child sociodemographic characteristics. INTERPRETATION: Housing conditions were associated with the physical and mental health of young Inuit children, even when sociodemographic factors were taken into account. Homeownership and housing satisfaction appeared to be particularly important for young Inuit children's health. PMID- 26583695 TI - Task-Oriented Exercise to Reduce Activities of Daily Living Disability in Vulnerable Older Adults: A Feasibility Study of the 3-Step Workout for Life. AB - The purpose of this feasibility study was to evaluate the 3-Step Workout for Life program, a 10-week exercise program that included moderate-intensity muscle strength training followed by task-oriented training. Fourteen participants completed the program (mean age = 73 years; SD = 6.83). The Box and Block test (Z = -2.24, p = .03) and the 30-s chair stand test (Z = -2.21, p = .03) indicate improved physical functioning of the upper and lower extremities. More importantly, results of the function component from the Late-Life Function and Disability Instrument (Z = -2.04, p = .04) and motor skills scale from the Assessment of Motor and Process Skills (Z = -2.97, p = .003) indicate subjective and objective improvements on performing activities of daily living. Supplementing moderate-intensity muscle strength exercise with task-oriented training components is feasible. Preliminary data support the effectiveness of 3 Step Workout for Life in reducing late-life disability. PMID- 26583696 TI - Social Impact of Facial Infantile Hemangiomas in Preteen Children. AB - IMPORTANCE: Involuted infantile facial hemangiomas (IHs) may adversely affect the social skills of children. OBJECTIVE: To assess the social impact of involuted facial IHs, with or without prior treatment, in preteen children. DESIGN, SETTING, AND PARTICIPANTS: An observational, cross-sectional study of social anxiety and skills in preteen children with facial IHs diagnosed during infancy. The study took place in an academic institution and a community dermatology practice between January 1, 2013, and July 30, 2014. Records on 236 children with IHs located in a cosmetically sensitive area were identified; of those, 144 potential participants (parents) were reached by telephone and mailed study packets. Thirty completed questionnaires were returned. Data analysis was performed from August 1, 2014, to September 7, 2015. INTERVENTIONS: The questionnaires included the following psychiatric scales: (1) Social Anxiety Scale for Children-Revised (SASC-R), completed by parents and children, including the domains of Fear of Negative Evaluation and Social Avoidance/Distress in New Situations (SAD-New) (higher scores indicate greater social anxiety), and (2) Social Competency Inventory (SCI), completed by parents, including the domains of Prosocial Behavior and Social Initiative (lower scores indicate poorer social competency). MAIN OUTCOMES AND MEASURES: Demographics, clinical details, and survey responses were collected. Analysis was conducted using t tests to compare scores for each survey domain with established normative data and between sex as well as between treatment vs nontreatment groups. RESULTS: Of the 144 potential participants, 30 (21%) responded. The mean age of the preteen subjects was 10.0 years (range, 5.4-12.9 years) with a 2:1 female to male ratio. Twenty-five children (83%) had a single IH, and the remaining 5 participants (17%) had multiple IHs, with at least 1 IH in a cosmetically sensitive area. The periocular region was the most common site of the IH (10 [33%]), followed by the nose (6 [20%]), cheek (5 [17%]), forehead (4 [13%]), lip or perioral region (4 [13%]), and ear (1 [3%]). Eighteen children (60%) had received treatment for their IH. With results reported as mean (SD), the SASC-R test showed that social anxiety of the children was not increased over normative data; however, those who did not receive IH treatment had significantly greater anxiety for new situations compared with those who received treatment (SAD-New: 15.5 [5.1] vs 11.5 [3.8]; P = .02). Results of the SCI scale indicated that the Prosocial Orientation domain score for the children was similar to normative data (3.96 [0.48] vs 3.89 [0.55], P = .50). Social Initiative domain scores were significantly poorer in children who did not receive treatment vs those who received treatment (3.45 [0.43] vs 4.03 [0.55]; P = .006). CONCLUSIONS AND RELEVANCE: Preteen children with involuted, untreated facial IHs have higher Social Anxiety domain scores in new situations and decreased Social Initiative domain scores compared with children who receive treatment for facial IH. Although this study is limited by a small sample size, it raises important considerations for whether early treatment of facial IHs in cosmetically sensitive areas has a beneficial effect on social skills in preteens. PMID- 26583697 TI - Hendra Virus Infection in Dog, Australia, 2013. AB - Hendra virus occasionally causes severe disease in horses and humans. In Australia in 2013, infection was detected in a dog that had been in contact with an infected horse. Abnormalities and viral RNA were found in the dog's kidney, brain, lymph nodes, spleen, and liver. Dogs should be kept away from infected horses. PMID- 26583698 TI - A 3D networked polydiacetylene sensor for enhanced sensitivity. AB - A three order sensitivity enhancement over a 2D system was achieved with a polydiacetylene-immobilized 3D networked sensor matrix. PMID- 26583699 TI - Human Alveolar Echinococcosis, Czech Republic, 2007-2014. PMID- 26583700 TI - Study of Topological Effects Concerning the Lowest A" and the Three A' States for the CO2(+) Ion. AB - A study of the topological effects, viz., the Jahn-Teller (JT) and Renner-Teller (RT) effects, in CO2(+) has been carried out by calculating nonadiabatic coupling terms (NACTs) at the state-averaged CASSCF level using the cc-pVTZ basis set for the lowest three A' states and one A" state along a circular contour. Using the NACTs, the privileged adiabatic-to-diabatic transformation (ADT) angles (gamma12) for 1A' and 2A' states of CO2(+) have been calculated along various circular contours. Employing one of the oxygen atoms as the test particle exposed two conical intersections (ci) located on each side of the CO diatom. The main purpose of this study is to explore the possibility of forming reliable diabatic potential energy surfaces for this system. Success in achieving this goal is guaranteed by the ability to calculate quantized privileged ADT angles along closed contours covering large regions in configuration space (see, e.g., J. Phys. Chem. A 2014 , 118 , 6361 ). The calculations were carried out for two and three JT states. In most cases very nice quantization has been achieved although the calculations were frequently done, as required, for large regions in configuration space (sometimes >=18 A(2)). In one case, for which the quantization was not gratifying, the inclusion of the RT effect modified it considerably. PMID- 26583701 TI - Dynamic Characterization of Crystalline Supramolecular Rotors Assembled through Halogen Bonding. AB - A modular molecular kit for the preparation of crystalline molecular rotors was devised from a set of stators and rotators to gain simple access to a large number of structures with different dynamic performance and physical properties. In this work, we have accomplished this with crystalline molecular rotors self assembled by halogen bonding of diazabicyclo[2.2.2]octane, acting as a rotator, and a set of five fluorine-substituted iodobenzenes that take the role of the stator. Using variable-temperature (1)H T1 spin-lattice relaxation measurements, we have shown that all structures display ultrafast Brownian rotation with activation energies of 2.4-4.9 kcal/mol and pre-exponential factors of the order of (1-9) * 10(12) s(-1). Line shape analysis of quadrupolar echo (2)H NMR measurements in selected examples indicated rotational trajectories consistent with the 3-fold or 6-fold symmetric potential of the rotator. PMID- 26583702 TI - Factors Associated with Severe Leptospirosis, Martinique, 2010-2013. AB - To identify factors associated with disease severity, we examined 102 patients with quantitative PCR-confirmed leptospirosis in Martinique during 2010-2013. Associated factors were hypotension, chest auscultation abnormalities, icterus, oligo/anuria, thrombocytopenia, prothrombin time <68%, high levels of leptospiremia, and infection with L. interrogans serovar Icterohaemorrhagiae/Copenhageni. PMID- 26583704 TI - The quest for biocompatible phthalocyanines for molecular imaging: Photophysics, relaxometry and cytotoxicity studies. AB - Water soluble phthalocyanines bearing either four PEG500 or four choline substituents in the macrocyclic structure, as well as their Zn(II) and Mn(III) complexes were synthesized. The metal-free and Zn(II) complexes present relatively high fluorescence quantum yields (up to 0.30), while the Mn(III) complexes show no fluorescence as a consequence of rapid non-radiative deactivation of the Mn(III) phthalocyanine excited states through low-lying metal based or charge-transfer states. The effect of DMSO on the aggregation of the phthalocyanines was studied. It was not possible to obtain the Mn(II) complexes by reduction of the corresponding Mn(III) complexes due to the presence of electron donating substituents at the periphery of the phthalocyanines. The (1)H NMRD plots of the PEG500 and choline substituted Mn(III)-phthalocyanine complexes are typical of self-aggregated Mn(III) systems with r1 relaxivities of 4.0 and 5.7mM(-1)s(-1) at 20MHz and 25 degrees C. The Mn(III)-phthalocyanine-PEG4 complex shows no significant cytotoxicity to HeLa cell cultures after 2h of incubation up to 2mM concentration. After 24h of cell exposure to the compound, significant toxicity was observed for all the concentrations tested with IC50 of 1.105mM. PMID- 26583703 TI - Effect of Cytochrome P450 Reductase Deficiency on 2-Amino-9H-pyrido[2,3-b]indole Metabolism and DNA Adduct Formation in Liver and Extrahepatic Tissues of Mice. AB - 2-Amino-9H-pyrido[2,3-b]indole (AalphaC), a carcinogen formed during the combustion of tobacco and cooking of meat, undergoes cytochrome P450 (P450) metabolism to form the DNA adduct N-(deoxyguanosin-8-yl)-2-amino-9H-pyrido[2,3 b]indole (dG-C8-AalphaC). We evaluated the roles of P450 expressed in the liver and intestine to bioactivate AalphaC by employing male B6 wild-type (WT) mice, liver-specific P450 reductase (Cpr)-null (LCN) mice, and intestinal epithelium specific Cpr-null (IECN) mice. Pharmacokinetic parameters were determined for AalphaC, 2-amino-9H-pyrido[2,3-b]indol-3-yl sulfate (AalphaC-3-OSO3H), and N(2) (beta-1-glucosidurony1)-2-amino-9H-pyrido[2,3-b]indole (AalphaC-N(2)-Glu) with animals dosed by gavage with AalphaC (13.6 mg/kg). The uptake of AalphaC was rapid with no difference in the plasma half-lives (t1/2) of AalphaC, AalphaC-3 OSO3H, and AalphaC-N(2)-Glu among mouse models. The maximal plasma concentrations (Cmax) and the areas under concentration-time curve (AUC0-24h) of AalphaC and AalphaC-N(2)-Glu were 4-24-fold higher in LCN than in WT mice, but they were not different between WT and IECN mice. These findings are consistent with the ablation of hepatic P450 activity in LCN mice. However, the Cmax and AUC0-24h of AalphaC-3-OSO3H in plasma were not substantially different among the mouse models. Similar pharmacokinetic parameters were obtained with WT and LCN mice treated with a lower AalphaC dose (1.36 mg kg(-1)). dG-C8-AalphaC was detected at similar levels in the livers of all three mouse models at the high AalphaC dose; levels of dG-C8-AalphaC in colon, bladder, and lung were greater in LCN than in WT mice and were the same in colon of IECN and WT mice. At the low AalphaC dose, dG-C8-AalphaC occurred at ~ 40% lower levels in liver of LCN mouse than in WT mouse liver, but adduct levels remained higher in extrahepatic tissues of LCN mice. Therefore, hepatic P450 plays an important role in detoxication of AalphaC, but other hepatic or extrahepatic enzymes contribute to the bioactivation of AalphaC. P450s expressed in the intestine do not appreciably contribute to bioactivation of AalphaC in mice. PMID- 26583706 TI - Chemoselective Synthesis of 1-Substituted 4-Amino-2-(trifluoromethyl)-1H-pyrroles through the Heterocyclization Reaction of 4-Methoxy-5-bromo-1,1,1-trifluoropent-3 en-2-ones with Amines. AB - A concise method to synthesize 1-substituted 4-amino-2-(trifluoromethyl)-1H pyrroles from the heterocyclization reaction of 5-bromo-4-methoxy-1,1,1 trifluoropent-3-en-2-ones with amines is described. This method has the following advantages: it uses a wide range of primary amines, starting materials are easily available, it is simple to perform, the reaction conditions are mild, it is environmentally friendly, and it furnishes yields of up to 98%. PMID- 26583705 TI - Transferrin conjugates of triazacyclononane-based bifunctional NE3TA chelates for PET imaging: Synthesis, Cu-64 radiolabeling, and in vitro and in vivo evaluation. AB - Three different polyaminocarboxylate-based bifunctional NE3TA (7-[2 [carboxymethyl)amino]ethyl]-1,4,7-triazacyclononane-1,4-diacetic acid) chelating agents were synthesized for potential use in copper 64-PET imaging applications. The bifunctional chelates were comparatively evaluated using transferrin (Tf) as a model targeting vector that binds to the transferrin receptor overexpressed in many different cancer cells. The transferrin conjugates of the NE3TA-based bifunctional chelates were evaluated for radiolabeling with (64)Cu. In vitro stability and cellular uptake of (64)Cu-radiolabeled conjugates were evaluated in human serum and prostate (PC-3) cancer cells, respectively. Among the three NE3TA Tf conjugates tested, N-NE3TA-Tf was identified as the best conjugate for radiolabeling with (64)Cu. N-NE3TA-Tf rapidly bound to (64)Cu (>98% radiolabeling efficiency, 1min, RT), and (64)Cu-N-NE3TA-Tf remained stable in human serum for 2days and demonstrated high uptake in PC-3 cancer cells. (64)Cu-N-NE3TA-Tf was shown to have rapid blood clearance and increasing tumor uptake in PC-3 tumor bearing mice over a 24h period. This bifunctional chelate presents highly efficient chelation chemistry with (64)Cu under mild condition that can be applied for radiolabeling of various tumor-specific biomolecules with (64)Cu for potential use in PET imaging applications. PMID- 26583708 TI - Describing Noncovalent Interactions beyond the Common Approximations: How Accurate Is the "Gold Standard," CCSD(T) at the Complete Basis Set Limit? AB - We have quantified the effects of approximations usually made even in accurate CCSD(T)/CBS calculations of noncovalent interactions, often considered as the "gold standard" of computational chemistry. We have investigated the effect of excitation series truncation, frozen core approximation, and relativistic effects in a set of 24 model complexes. The final CCSD(T) results at the complete basis set limit with corrections to these approximations are the most accurate estimate of the true interaction energies in noncovalent complexes available. The average error due to these approximations was found to be about 1.5% of the interaction energy. PMID- 26583707 TI - Influenza A(H6N1) Virus in Dogs, Taiwan. AB - We determined the prevalence of influenza A virus in dogs in Taiwan and isolated A/canine/Taiwan/E01/2014. Molecular analysis indicated that this isolate was closely related to influenza A(H6N1) viruses circulating in Taiwan and harbored the E627K substitution in the polymerase basic 2 protein, which indicated its ability to replicate in mammalian species. PMID- 26583709 TI - Toward a Deeper Understanding of Enzyme Reactions Using the Coupled ELF/NCI Analysis: Application to DNA Repair Enzymes. AB - The combined Electron Localization Funtion (ELF)/ Noncovalent Interaction (NCI) topological analysis (Gillet et al. J. Chem. Theory Comput.2012, 8, 3993) has been extended to enzymatic reaction paths. We applied ELF/NCI to the reactions of DNA polymerase lambda and the epsilon subunit of DNA polymerase III. ELF/NCI is shown to provide insights on the interactions during the evolution of enzymatic reactions including predicting the location of TS from structures located earlier along the reaction coordinate, differential metal coordination, and on barrier differences with two different cations. PMID- 26583710 TI - Modeling the Self-Assembly of Nano Objects: Applications to Supramolecular Organic Monolayers Adsorbed on Metal Surfaces. AB - We present here the implementation of a code developed for the simulation of the self-assembly of nano objects (SANO). The code has the ability to predict the molecular self-assembly of different structural motifs by tuning the molecular building blocks as well as the metallic substrate. It consists in a two dimensional grand canonical Monte Carlo (GCMC) approach developed to perform atomistic simulations of thousands of large organic molecules self-assembling on metal surfaces. By computing adsorption isotherms at room temperature and spanning over the characteristic submicrometric scales, we confront the robustness of the approach with three different well-known systems: ZnPcCl8 on Ag(111), CuPcF16 on Au(111), and PTBC on Ag(111). We retrieve respectively their square, oblique, and hexagonal supramolecular tilling. The code incorporates generalized force fields to describe the molecular interactions, which provides transferability to many organic building blocks and metal surfaces. Ultimately, the method is versatile and can be an interesting multiscale approach if one aims to bridge quantum level calculations to the experimental scales and within a treatment in temperature. PMID- 26583711 TI - Correlation Consistent Gaussian Basis Sets for H, B-Ne with Dirac-Fock AREP Pseudopotentials: Applications in Quantum Monte Carlo Calculations. AB - In this paper, we introduce correlation consistent Gaussian-type orbital basis sets for the H and B-Ne atoms for use with the CASINO Dirac-Fock AREP pseudopotentials. These basis sets are tested in coupled cluster calculations on H2, B2, C2, N2, O2, and F2 as well as in quantum Monte Carlo calculations on the water monomer and dimer and the water-benzene complex, where they are found to give low variances in variational Monte Carlo calculations and to lead to reduced time step errors and improved convergence in diffusion Monte Carlo calculations compared to the use of nonoptimized basis sets. The use of basis sets with a large number of contracted s and p primitives is found to be especially important for the convergence of the energy in the diffusion Monte Carlo calculations. PMID- 26583712 TI - Chemical Interactions and Spin Structure in (O2)4: Implications for the epsilon O2 Phase. AB - The chemical interactions and spin structure of (O2)4 in its ground singlet state are analyzed by means of Quantum Chemical Topology descriptors. The energetic contributions of the Interacting Quantum Atoms approach are used to obtain information about the class of interactions displayed along the dissociation path of (O2)4. The exchange-correlation contribution to the binding energy is non negligible for the O2-O2 interactions at intermolecular distances close to those found for the pressure induced epsilon phase of solid (O2) and this strengthening of the intermolecular bonding is built up from a simultaneous weakening of the intramolecular bond. This result is of interest in connection with the observed softening of the IR vibron frequency in the lower pressure range of the epsilon phase. The spin structure in the real space along the dissociation process is interpreted with the help of the so-called electron number distribution functions. At large distances, the four triplet O2 molecules are arranged in a way consistent with an antiferromagnetic structure, whereas at short distances, a significant spin redistribution is driven by the exchange process and it involves a propensity toward a null magnetic moment per molecule. Such probability behavior can be related with the magnetic evolution of solid oxygen across the delta -> epsilon phase transition. Additional calculations of (O2)4 excited states support the conclusion that the relative stabilization and magnetic features of the ground singlet state are due to the onset of the new intermolecular bonds, and not to an exclusive modification of the electronic character within the O2 molecules. PMID- 26583713 TI - Multiconfigurational Self-Consistent Field Calculations of the Magnetically Induced Current Density Using Gauge-Including Atomic Orbitals. AB - Nondynamical electron correlation based on a genuine multiconfigurational theory is of considerable importance for a balanced ab initio calculation of aromatic and antiaromatic molecules either with open-shell character or quasi-degeneracy in the electronic states. Among the various aromaticity indices, the calculation of magnetically induced ring current densities (MICD) has emerged as a strong contender, providing both a qualitative and a quantitative description of the effect. We report here the first implementation of MICD at the multiconfigurational self-consistent field (MCSCF) level of theory together with example calculations. This extension makes the method applicable to systems that cannot be appropriately handled with earlier implementations based on a single reference starting function. We present the formulation of the MCSCF MICD theory along with applications to a prototypical antiaromatic (cyclobutadiene) and an aromatic (benzyne) system, both systems that require a multiconfigurational description. We compare the MCSCF results to those obtained using Hartree-Fock and Kohn-Sham density functional theory and discuss the effects of static correlation on the aromaticity. PMID- 26583714 TI - A Benchmark Ab Initio and DFT Study of the Structure and Binding of Methane in the sigma-Alkane Complex CpRe(CO)2(CH4). AB - Ab initio molecular orbital theory and density functional theory (DFT) procedures have been used to study the binding of methane in CpRe(CO)2(CH4), the simplest sigma-alkane complex in the experimentally widely studied CpRe(CO)2(alkane) family. We find the optimal Re...C, Re...H and C...H distances to be 2.60, 1.92, and 1.15 A, respectively, on the composite-CCSD(T)/def2-QZVPP (CCSD(T)/def2-TZVP with supplement for the larger def2-QZVPP basis set at the second-order Moller Plesset perturbation theory level) potential energy surface which has been mapped out at this level of theory. The enthalpy of binding at 298 K was determined to be 62.0 kJ mol(-1) at the composite-CCSD(T)/CBS//B3-PW91/aug-cc-pVTZ-PP level. Benchmarks on the various DFT procedures show that some functionals give good geometries but underestimate binding energies, while others yield poor geometries but give closer agreements with the composite-CCSD(T) binding energy. On the other hand, the omegaB97X-D functional gives fair agreements with composite CCSD(T) for both geometry optimization as well as binding energy. Thus, it appears to be a reliable, easily implemented, and cost-effective means for studying Re-alkane complexes. Good binding energies are also obtained with several common functionals when D3 dispersion corrections are applied. Selected dispersion-corrected DFT methods (B3PW91-D3, TPSSh-D3, and B98-D3) were found to be quite accurate for the calculation of binding energies of several other model metal-CH4 complexes containing a range of metal centers (Rh, Pd, W, Ir, Pt). We also note that, for single-point energy calculation of the Re-CH4 binding, the PWP-B95-D3 double-hybrid DFT procedure provides an excellent agreement with the benchmark energy at only a slightly higher computational requirement. PMID- 26583715 TI - Benchmarking Time-Dependent Density Functional Theory for Excited State Geometries of Organic Molecules in Gas-Phase and in Solution. AB - We analyze potentials and limits of the Time-Dependent Density Functional Theory (TD-DFT) approach for the determination of excited-state geometries of organic molecules in gas-phase and in solution. Three very popular DFT exchange correlation functionals, two hybrids (B3LYP and PBE0) and one long-range corrected (CAM-B3LYP), are here investigated, and the results are compared to the correlated RI-CC2 wave function approach. Solvent effects are further analyzed by means of a polarizable continuum model. A total of 15 organic chromophores (including both small molecules and larger push-pull systems) are considered as prototypes of n -> pi* and pi -> pi* singlet excitations. Our analysis allows to point out specific correlations between the accuracy of the various functionals and the type of excitation and/or the type of chemical bonds involved. We find that while the best ground-state geometries are obtained with PBE0 and B3LYP, CAM B3LYP yields the most accurate description of electronic and geometrical characteristics of excited states, both in gas-phase and in solution. PMID- 26583716 TI - Hirshfeld-E Partitioning: AIM Charges with an Improved Trade-off between Robustness and Accurate Electrostatics. AB - For the development of ab initio derived force fields, atomic charges must be computed from electronic structure computations, such that (i) they accurately describe the molecular electrostatic potential (ESP) and (ii) they are transferable to the force-field application of interest. The Iterative Hirshfeld (Hirshfeld-I or HI) scheme meets both requirements for organic molecules. For inorganic oxide clusters, however, Hirshfeld-I becomes ambiguous because electron densities of nonexistent isolated anions are needed as input. Herein, we propose a simple Extended Hirshfeld (Hirshfeld-E or HE) scheme to overcome this limitation. The performance of the new HE scheme is compared to four popular atoms-in-molecules schemes, using two tests involving a set of 248 silica clusters. These tests show that the new HE scheme provides an improved trade-off between the ESP accuracy and the transferability of the charges. The new scheme is a generalization of the Hirshfeld-I scheme, and it is expected that its improvements are to a large extent applicable to molecular systems containing elements from the entire periodic table. PMID- 26583717 TI - Fully Integrated Effective Fragment Molecular Orbital Method. AB - In this work, the effective fragment potential (EFP) method is fully integrated (FI) into the fragment molecular orbital (FMO) method to produce an effective fragment molecular orbital (EFMO) method that is able to account for all of the fundamental types of both bonded and intermolecular interactions, including many body effects, in an accurate and efficient manner. The accuracy of the method is tested and compared to both the standard FMO method as well as to fully ab initio methods. It is shown that the FIEFMO method provides significant reductions in error while at the same time reducing the computational cost associated with standard FMO calculations by up to 96%. PMID- 26583718 TI - Density Scaling of Noninteracting Kinetic Energy Functionals. AB - The influence of imposing an approximate density scaling condition on a noninteracting kinetic energy functional is investigated. A simple generalized gradient approximation (GGA) is presented, which satisfies both the density scaling condition and the usual coordinate scaling condition; the remaining multiplicative constant is determined from an energy criterion. In post-Kohn-Sham calculations, noninteracting kinetic energies of the closed-shell molecules of the G1 set determined using the GGA are a modest improvement over those determined using the corresponding local functional, which does not satisfy the density scaling condition. Potential energy curves of CO, F2, and P2 exhibit binding with the GGA, compared to purely repulsive curves with the local functional. Adjusting the exponent in the GGA form in order to optimize energy accuracy violates the density scaling condition, and two of the diatomics no longer exhibit binding. Results are compared with those from other local/GGA functionals in the literature. PMID- 26583719 TI - Meta-GGA Exchange-Correlation Functional with a Balanced Treatment of Nonlocality. AB - We construct a meta-generalized-gradient approximation which properly balances the nonlocality contributions to the exchange and correlation at the semilocal level. This nonempirical functional shows good accuracy for a broad palette of properties (thermochemistry, structural properties) and systems (molecules, metal clusters, surfaces, and bulk solids). The accuracy for several well-known problems in electronic structure calculations, such as the bending potential of the silver trimer and the dimensional crossover of anionic gold clusters, is also demonstrated. The inclusion of empirical dispersion corrections is finally discussed and analyzed. PMID- 26583720 TI - Directional Noncovalent Interactions: Repulsion and Dispersion. AB - The interaction energies between an argon atom and the dihalogens Br2, BrCl, and BrF have been investigated using frozen core CCSD(T)(fc)/aug-cc-pVQZ calculations as reference values for other levels of theory. The potential-energy hypersurfaces show two types of minima: (1) collinear with the dihalogen bond and (2) in a bridging position. The former represent the most stable minima for these systems, and their binding energies decrease in the order Br > Cl > F. Isotropic atom-atom potentials cannot reproduce this binding pattern. Of the other levels of theory, CCSD(T)(fc)/aug-cc-pVTZ reproduces the reference data very well, as does MP2(fc)/aug-cc-pVDZ, which performs better than MP2 with the larger basis sets (aug-cc-pVQZ and aug-cc-pvTZ). B3LYP-D3 and M06-2X reproduce the binding patterns moderately well despite the former using an isotropic dispersion potential correction. B3LYP-D3(bj) performs even better. The success of the B3LYP D3 methods is because polar flattening of the halogens allows the argon atom to approach more closely in the direction collinear with the bond, so that the sum of dispersion potential and repulsion is still negative at shorter distances than normally possible and the minimum is deeper at the van der Waals distance. Core polarization functions in the basis set and including the core orbitals in the CCSD(T)(full) calculations lead to a uniform decrease of approximately 20% in the magnitudes of the calculated interaction energies. The EXXRPA+@EXX (exact exchange random phase approximation) orbital-dependent density functional also gives interaction energies that correlate well with the highest level of theory but are approximately 10% low. The newly developed EXXRPA+@dRPA functional represents a systematic improvement on EXXRPA+@EXX. PMID- 26583721 TI - Multicenter Bonding in Ditetracyanoethylene Dianion: A Simple Aromatic Picture in Terms of Three-Electron Bonds. AB - The nature of the multicenter, long bond in ditetracyanoethylene dianion complex [TCNE]2(2-) is elucidated using high level ab initio Valence Bond (VB) theory coupled with Quantum Monte Carlo (QMC) methods. This dimer is the prototype of the general family of pancake-bonded dimers with large interplanar separations. Quantitative results obtained with a compact wave function in terms of only six VB structures match the reference CCSD(T) bonding energies. Analysis of the VB wave function shows that the weights of the VB structures are not compatible with a covalent bond between the pi* orbitals of the fragments. On the other hand, these weights are consistent with a simple picture in terms of two resonating bonding schemes, one displaying a pair of interfragment three-electron sigma bonds and the other displaying intrafragment three-electron pi bonds. This simple picture explains at once (1) the long interfragment bond length, which is independent of the countercations but typical of three-electron (3-e) CC sigma bonds, (2) the interfragment orbital overlaps which are very close to the theoretical optimal overlap of 1/6 for a 3-e sigma bond, and (3) the unusual importance of dynamic correlation, which is precisely the main bonding component of 3-e bonds. Moreover, it is shown that the [TCNE]2(2-) system is topologically equivalent to the square C4H4(2-) dianion, a well-established aromatic system. To better understand the role of the cyano substituents, the unsubstituted diethylenic Na(+)2[C2H4]2(2-) complex is studied and shown to be only metastable and topologically equivalent to a rectangular C4H4(2-) dianion, devoid of aromaticity. PMID- 26583722 TI - Modeling Transition Metal Reactions with Range-Separated Functionals. AB - The performance of range-separated functionals for the calculation of reaction profiles of organometallic compounds is considered. Sets of high-level computational results are used as reference data for the most part. The benchmark data include a number of reactions involving small molecules reacting with the Pd atom, PdCl(-), PdCl2, and a Ni atom, the reaction of a model Grubbs catalyst, and the ligand binding in a real Grubbs catalyst. Range-separated functionals are found to improve upon most standard local functionals especially if an optimized range-separation parameter is used. They do not represent an improvement upon the better-performed global hybrid functionals or a local functional that includes a larger number of adjustable parameters. Some unusual results for molecule molecule interaction energies are observed and explained by a detailed analysis of the contributions to the bonding energies. The influence of range separation on the barriers and reaction energies is also investigated. PMID- 26583723 TI - Mechanism of AMPPD Chemiluminescence in a Different Voice. AB - The chemiluminescence phenomenon of 3-(2'-spiroadamantyl)-4-methoxy-4-(3" phosphoryloxy)-phenyl-1,2-dioxetane (AMPPD or m-AMPPD) has been routinely applied in clinical diagnostics. Although the AMPDD chemiluminescence immunoassay is one of the most successful immunoassays, the mechanism of AMPPD chemiluminescence remains largely unknown. The AMPPD chemiluminescence process is composed of three steps: AMPPD is enzymatically triggered to produce 3-(2'-spiroadamantyl)-4 methoxy-4-(3"-hydroxyphenyl)-1,2-dioxetane (m-AMPD); m-AMPD decomposes into the excited-state methyl m-oxybenzoate anion (m-MOB(-)); the excited-state m-MOB(-) relaxes to its ground state and emits light. Obviously, the middle step is critical for the chemiluminescence and has not been well understood because of both experimental and theoretical difficulties. We performed the first theoretical study on the chemiluminescent decomposition mechanism of m-AMPD and its para isomer, p-AMPD, using the complete active space self-consistent field and the second-order multiconfigurational perturbation methods in addition to the density functional method. This investigation revealed that (1) neither the intramolecular chemical initiated electron exchange luminescence (CIEEL) nor the concerted charge transfer (CT) mechanism can describe the decomposition of m- and p-AMPD well. Instead, their decomposition occurs according to our previously proposed mechanism of gradually reversible CT-initiated luminescence. (2) The different stabilities of the m- and p-AMPD chemiexcited states might be the basis for the large difference in their chemiluminescence efficiencies. (3) The relationship between the chemiluminescence efficiency and the position of the electron donor on the aromatic ring, the so-called "odd/even selection rule," does not fully explain the chemiluminescence efficiency of dioxetanes. The odd/even selection rule is only correct for partial dioxetanes, because it does not capture the origin of the relationship between the chemiluminescence and the donor. We revealed that the origin consists of a combination of conjugation, induction, and steric effects. On the basis of this combination of effects, we theoretically designed some 1,2-dioxetanes to guide experimentalists in the synthesis of these excellent chemiluminescent molecules. PMID- 26583724 TI - Toward a Broadly Applicable Force Field for d(6)-Piano Stool Complexes. AB - Three-legged piano stool complexes are prototypical organometallic complexes relevant to a wide range of chemically relevant questions. Force field parametrization of transition-metal complexes is difficult and underdeveloped, and metal-specific force fields and software are required. Here we report our efforts to derive parameters for the conventional CHARMM and the Valbond-CHARMM force fields for d(6)-piano stool complexes. In Valbond-CHARMM, the usual angular term is replaced with hybrid orbital strength functions. These functions describe the energy not only of distorted bond angles around the minimum but also at very large distortions. Structure optimizations led to a good agreement between the calculated force field and the X-ray structures. They were comparable to RMSDs obtained between X-ray and DFT structures. In addition, and contrary to treating the systems with DFT, molecular dynamics simulations on the multiple nanosecond time scale are possible and allow to compute meaningful structural and energetic observables. Explicit solvent simulations of the complexes in methanol and water allow to determine the solvent distribution around the complexes. The parametrization presented here will be a useful starting point for dynamics investigations of catalysts in structurally more demanding environments. PMID- 26583725 TI - Molecular Dynamics Investigation of Alkali Metal Ions in Liquid and Aqueous Ammonia. AB - A polarizable potential model for M(+)-NH3 interactions (M(+) = Li(+), Na(+), K(+), Rb(+), Cs(+)) is optimized based on the ab initio properties of the ion ammonia dimers calculated at the MP2 level of theory. The optimized model reproduces the ab initio binding energies of M(+)(NH3)n (n = 2-4) and M(+)(NH3)n(H2O)m (n, m = 1-3 and n + m <= 4) clusters and gives relative solvation free energies in liquid ammonia in good agreement with experimental data, without further adjustments. It also reproduces binding cooperativity in ion-ammonia and ion-ammonia-water clusters. The model is used in molecular dynamics simulations of isolated ions in liquid ammonia and in aqueous ammonia solutions with various ammonia molar fractions (0.0 <= xNH3 <= 1.0). Simulations in liquid ammonia show coordination numbers of 4.0 for Li(+), 5.3 for Na(+), 6.1 for K(+), 6.7 for Rb(+), and 7.7 for Cs(+), in very good agreement with available experimental results. Simulations of ions in aqueous ammonia show preferential solvation by water in their first solvation shells and preferential solvation by ammonia in their second shells. Potentials of mean force are calculated between each ion and NH3 in liquid water, and between each ion and H2O in liquid ammonia. The results suggest that, in liquid water, Li(+) and Na(+) bind NH3 in their second solvation shells only, while Cs(+) binds NH3 in its first solvation shell only (K(+) and Rb(+) ions show only weak affinity for NH3 in water). In liquid ammonia, the ions bind H2O in their first solvation shells with an affinity following the trend Li(+) > Na(+) > K(+) ~ Rb(+) > Cs(+). PMID- 26583726 TI - State-Specific Embedding Potentials for Excitation-Energy Calculations. AB - Embedding potentials are frequently used to describe the effect of an environment on the electronic structure of molecules in larger systems, including their excited states. If such excitations are accompanied by significant rearrangements in the electron density of the embedded molecule, large differential polarization effects may take place, which in turn can require state-specific embedding potentials for an accurate theoretical description. We outline here how to extend wave function in density functional theory (WF/DFT) methods to compute the excitation energies of a molecule in a responsive environment through the use of state-specific density-based embedding potentials constructed within a modified subsystem DFT approach. We evaluate the general expression of the ground- and excited-state energy difference of the total system both with the use of state independent and state-dependent embedding potentials and propose some practical recipes to construct the approximate excited-state DFT density of the active part used to polarize the environment. We illustrate these concepts with the state independent and state-dependent WF/DFT computation of the excitation energies of p-nitroaniline, acrolein, methylenecyclopropene, and p-nitrophenolate in various solvents. PMID- 26583728 TI - Validating and Analyzing EPR Hyperfine Coupling Constants with Density Functional Theory. PMID- 26583727 TI - Excited-State Geometries of Heteroaromatic Compounds: A Comparative TD-DFT and SAC-CI Study. AB - The structures of low-lying singlet excited states of nine pi-conjugated heteroaromatic compounds have been investigated by the symmetry-adapted cluster configuration interaction (SAC-CI) method and the time-dependent density functional theory (TDDFT) using the PBE0 functional (TD-PBE0).In particular, the geometry relaxation in some pipi* and npi* excited states of furan, pyrrole, pyridine, p-benzoquinone, uracil, adenine, 9,10-anthraquinone, coumarin, and 1,8 naphthalimide as well as the corresponding vertical transitions, including Rydberg excited states, have been analyzed in detail. The basis set and functional dependence of the results was also examined. The SAC-CI and TD-PBE0 calculations showed reasonable agreement in both transition energies and excited state equilibrium structures for these heteroaromatic compounds. PMID- 26583729 TI - Physicochemical Properties of Hazardous Energetic Compounds from Molecular Simulation. AB - A protocol is presented and used for the computation of physicochemical properties of nitroaromatic energetic compounds (ECs) using molecular simulation. Solvation and self-solvation free energies of ECs are computed using an expanded ensemble (EE) molecular dynamics method, with the TraPPE-UA/CHELPG and CGenFF/CHELPG force field models. Thermodynamic pathways relating Gibbs free energies and physicochemical properties are used to predict the room temperature vapor pressures, solubilities (in water and 1-octanol), Henry's law constants, and partition coefficients (octanol-water, air-water, and air-octanol) for liquid, subcooled, and solid ECs from the molecular simulations. These predictions are compared to experimental data where available. It is found that the use of the TraPPE-UA model with CHELPG charges computed here leads to predictions of measured physicochemical properties of comparable accuracy to that of other theoretical and empirical models. However, the advantage of the method used here is that with no experimental data, unlike other methods, a number of physicochemical properties for a compound can be calculated from only its atomic connectivity, charges obtained from density function theory (DFT), and choice of force field using two simulations: its self-solvation free energy and its Gibbs free energy in a solvent. PMID- 26583730 TI - Crown Graphene Nanomeshes: Highly Stable Chelation-Doped Semiconducting Materials. AB - Graphene nanomeshes (GNMs) formed by the creation of pore superlattices in graphene are a possible route to graphene-based electronics due to their semiconducting properties, including the emergence of fractional electronvolt band gaps. The utility of GNMs would be markedly increased if a scheme to stably and controllably dope them was developed. In this work, a chemically motivated approach to GNM doping based on selective pore-perimeter passivation and subsequent ion chelation is proposed. It is shown by first-principles calculations that ion chelation leads to stable doping of the passivated GNMs both n- and p-doping are achieved within a rigid-band picture. Such chelated or "crown" GNM structures are stable, high mobility semiconducting materials possessing intrinsic doping-concentration control; these can serve as building blocks for edge-free graphene nanoelectronics including GNM-based complementary metal oxide semiconductor (CMOS)-type logic switches. PMID- 26583731 TI - Does Dispersion Dominate over H-Bonds in Drug-Surface Interactions? The Case of Silica-Based Materials As Excipients and Drug-Delivery Agents. AB - Amorphous silica is widely employed in pharmaceutical formulations both as a tableting, anticaking agent and as a drug delivery system, whereas MCM-41 mesoporous silica has been recently proposed as an efficient support for the controlled release of drugs. Notwithstanding the relevance of this topic, the atomistic details about the specific interactions between the surfaces of the above materials and drugs and the energetic of adsorption are almost unknown. In this work, we resort to a computational ab initio approach, based on periodic Density Functional Theory (DFT), to study the adsorption behavior of two popular drugs (aspirin and ibuprofen) on two models of an amorphous silica surface characterized by different hydrophilic/hydrophobic properties due to different SiOH surface groups' density. Particular effort was devoted to understand the role of dispersive (vdW) interactions in the adsorption mechanism and their interplay with H-bond interactions. On the hydrophilic silica surface, the H-bond pattern of the Si-OH groups rearranges to comply with the formation of new H-bond interactions triggered by the adsorbed drug. The interaction energy of ibuprofen with the hydrophilic model of the silica surface is computed to be very close to the sublimation energy of the ibuprofen molecular crystal, accounting for the experimental evidence of ibuprofen crystal amorphization induced by the contact with the mesoporous silica material. For both surface models, dispersion interactions play a crucial role in dictating the features of the drug/silica system, and they become dominant for the hydrophobic surface. It was proved that a competition may exist between directional H-bonds and nonspecific dispersion driven interactions, with important structural and energetic consequences for the adsorption. The results of this work emphasize the inadequacy of plain DFT methods to model adsorption processes involving inorganic surfaces and drugs of moderate size, due to the missing term accounting for London dispersion interactions. PMID- 26583732 TI - Understanding the Chemistry of Lead at a Molecular Level: The Pb(II) 6s6p Lone Pair Can Be Bisdirected in Proteins. AB - Pb(2+) complexes can attain several different topologies, depending of the shape of the Pb 6s6p lone pair. In this paper, we study structures with a bisdirected Pb lone pair with quantum mechanics (DFT) and QM/MM calculations. We study small symmetric Pb(2+) models to see what factors are needed to get a bisdirected lone pair. Two important mechanisms have been found: First, the repulsion of the lone pair of Pb(2+) with other lone pairs in the equatorial plane leads to a bisdirected structure. Second, a bisdirected lone pair can also arise due to interactions with double bonds, lone pairs, or hydrogen atoms. Moreover, we have analyzed Pb(2+) sites in proteins and to see if a bisdirected lone pair can exist in an asymmetrical environment. Several instances of bisdirected lone pairs were discovered. PMID- 26583733 TI - Quantum-Chemical Electron Densities of Proteins and of Selected Protein Sites from Subsystem Density Functional Theory. AB - The ability to calculate accurate electron densities of full proteins or of selected sites in proteins is a prerequisite for a fully quantum-mechanical calculation of protein-protein and protein-ligand interaction energies. Quantum chemical subsystem methods capable of treating proteins and other biomolecular systems provide a route to calculate the electron densities of proteins efficiently and further make it possible to focus on specific parts. Here, we evaluate and extend the 3-partition frozen-density embedding (3-FDE) scheme [Jacob, C. R.; Visscher, L. J. Chem. Phys.2008, 128, 155102] for this purpose. In particular, we have extended this scheme to allow for the treatment of disulfide bridges and charged amino acid residues and have introduced the possibility to employ more general partitioning schemes. These extensions are tested both for the prediction of full protein electron densities and for focusing on the electron densities of a selected protein site. Our results demonstrate that 3-FDE is a promising tool for the fully quantum-chemical treatment of proteins. PMID- 26583734 TI - Rhodopsin Absorption from First Principles: Bypassing Common Pitfalls. AB - Bovine rhodopsin is the most extensively studied retinal protein and is considered the prototype of this important class of photosensitive biosystems involved in the process of vision. Many theoretical investigations have attempted to elucidate the role of the protein matrix in modulating the absorption of retinal chromophore in rhodopsin, but, while generally agreeing in predicting the correct location of the absorption maximum, they often reached contradicting conclusions on how the environment tunes the spectrum. To address this controversial issue, we combine here a thorough structural and dynamical characterization of rhodopsin with a careful validation of its excited-state properties via the use of a wide range of state-of-the-art quantum chemical approaches including various flavors of time-dependent density functional theory (TDDFT), different multireference perturbative schemes (CASPT2 and NEVPT2), and quantum Monte Carlo (QMC) methods. Through extensive quantum mechanical/molecular mechanical (QM/MM) molecular dynamics simulations, we obtain a comprehensive structural description of the chromophore-protein system and sample a wide range of thermally accessible configurations. We show that, in order to obtain reliable excitation properties, it is crucial to employ a sufficient number of representative configurations of the system. In fact, the common use of a single, ad hoc structure can easily lead to an incorrect model and an agreement with experimental absorption spectra due to cancelation of errors. Finally, we show that, to properly account for polarization effects on the chromophore and to quench the large blue-shift induced by the counterion on the excitation energies, it is necessary to adopt an enhanced description of the protein environment as given by a large quantum region including as many as 250 atoms. PMID- 26583735 TI - The Theory of Ultra-Coarse-Graining. 1. General Principles. AB - Coarse-grained (CG) models provide a computationally efficient means to study biomolecular and other soft matter processes involving large numbers of atoms correlated over distance scales of many covalent bond lengths and long time scales. Variational methods based on information from simulations of finer grained (e.g., all-atom) models, for example the multiscale coarse-graining (MS CG) and relative entropy minimization methods, provide attractive tools for the systematic development of CG models. However, these methods have important drawbacks when used in the "ultra-coarse-grained" (UCG) regime, e.g., at a resolution level coarser or much coarser than one amino acid residue per effective CG particle in proteins. This is due to the possible existence of multiple metastable states "within" the CG sites for a given UCG model configuration. In this work, systematic variational UCG methods are presented that are specifically designed to CG entire protein domains and subdomains into single effective CG particles. This is accomplished by augmenting existing effective particle CG schemes to allow for discrete state transitions and configuration-dependent resolution. Additionally, certain conclusions of this work connect back to single-state force matching and open up new avenues for method development in that area. These results provide a formal statistical mechanical basis for UCG methods related to force matching and relative entropy CG methods and suggest practical algorithms for constructing optimal approximate UCG models from fine-grained simulation data. PMID- 26583736 TI - Calculating the Bimolecular Rate of Protein-Protein Association with Interacting Crowders. AB - We have recently introduced a method termed Poisson-Boltzmann semianalytical method (PB-SAM) for solving the linearized Poisson-Boltzmann equation for large numbers of arbitrarily shaped dielectric cavities with controlled precision. In this work we extend the applicability of the PB-SAM approach by deriving force and torque expressions that fully account for mutual polarization in both the zero- and first-order derivatives of the surface charges, that can now be embedded into a Brownian dynamics scheme to look at electrostatic-driven mesoscale assembly and kinetics. We demonstrate the capabilities of the PB-SAM approach by simulating the protein concentration effects on the bimolecular rate of association of barnase and barstar, under periodic boundary conditions and evaluated through mean first passage times. We apply PB-SAM to the pseudo-first order reaction rate conditions in which either barnase or barstar are in great excess relative to the other protein (124:1). This can be considered a specific case in which the PB-SAM approach can be applied to crowding conditions in which crowders are not inert but can form interactions with other molecules. PMID- 26583737 TI - A Polarizable Force-Field for Cholesterol and Sphingomyelin. AB - A polarizable force-field, based on the Drude oscillator model, has been developed for cholesterol and the sphingomyelin class of lipids crucial to membrane raft formation, with testing performed on several 100 ns simulations. These have been validated against experimental observables as well as previous, nonpolarizable force-fields. Membrane bilayer properties, such as area-per-lipid and membrane thickness, produce results of comparable quantitative accuracy to those from the nonpolarizable force-field, while the membrane dipole potential is computed to be approximately 260 mV for a pure sphingomyelin bilayer, showing quantitative agreement with experimental results. PMID- 26583738 TI - A Mixed Protein Structure Network and Elastic Network Model Approach to Predict the Structural Communication in Biomolecular Systems: The PDZ2 Domain from Tyrosine Phosphatase 1E As a Case Study. AB - Graph theory is being increasingly used to study the structural communication in biomolecular systems. This requires incorporating information on the system's dynamics, which is time-consuming and not suitable for high-throughput investigations. We propose a mixed Protein Structure Network (PSN) and Elastic Network Model (ENM)-based strategy, i.e., PSN-ENM, for fast investigation of allosterism in biological systems. PSN analysis and ENM-Normal Mode Analysis (ENM NMA) are implemented in the structural analysis software Wordom, freely available at http://wordom.sourceforge.net/ . The method performs a systematic search of the shortest communication pathways that traverse a protein structure. A number of strategies to compare the structure networks of a protein in different functional states and to get a global picture of communication pathways are presented as well. The approach was validated on the PDZ2 domain from tyrosine phosphatase 1E (PTP1E) in its free (APO) and peptide-bound states. PDZ domains are, indeed, the systems whose structural communication and allosteric features are best characterized both in vitro and in silico. The agreement between predictions by the PSN-ENM method and in vitro evidence is remarkable and comparable to or higher than that reached by more time-consuming computational approaches tested on the same biological system. Finally, the PSN-ENM method was able to reproduce the salient communication features of unbound and bound PTP1E inferred from molecular dynamics simulations. High speed makes this method suitable for high throughput investigation of the communication pathways in large sets of biomolecular systems in different functional states. PMID- 26583739 TI - Record Surface State Mobility and Quantum Hall Effect in Topological Insulator Thin Films via Interface Engineering. AB - Material defects remain as the main bottleneck to the progress of topological insulators (TIs). In particular, efforts to achieve thin TI samples with dominant surface transport have always led to increased defects and degraded mobilities, thus making it difficult to probe the quantum regime of the topological surface states. Here, by utilizing a novel buffer layer scheme composed of an In2Se3/(Bi0.5In0.5)2Se3 heterostructure, we introduce a quantum generation of Bi2Se3 films with an order of magnitude enhanced mobilities than before. This scheme has led to the first observation of the quantum Hall effect in Bi2Se3. PMID- 26583740 TI - Impact of biofilm on bacterial transport and deposition in porous media. AB - Laboratory scale experiments were conducted to obtain insights into factors that influence bacterial transport and deposition in porous media. According to colloidal filtration theory, the removal efficiency of a filter medium is characterized by two main factors: collision efficiency and sticking efficiency. In the case of bacterial transport in porous media, bacteria attached to a solid surface can establish a thin layer of biofilm by excreting extracellular polymeric substances which can significantly influence both of these factors in a porous medium, and thus, affect the overall removal efficiency of the filter medium. However, such polymeric interactions in bacterial adhesion are not well understood and a method to calculate polymeric interactions is not yet available. Here, to determine how the migration of bacteria flowing within a porous medium is affected by the presence of surface-associated extracellular polymeric substances previously produced and deposited by the same bacterial species, a commonly used colloidal filtration model was applied to study transport and deposition of Pseudomonas fluorescens in small-scale columns packed with clean and biofilm coated glass beads. Bacterial recoveries were monitored in column effluents and used to quantify biofilm interactions and sticking efficiencies of the biofilm coated packed-beds. The results indicated that, under identical hydraulic conditions, the sticking efficiencies in packed-beds were improved consistently by 36% when covered by biofilm. PMID- 26583741 TI - Evaluation of a numerical simulation model for a system coupling atmospheric gas, surface water and unsaturated or saturated porous medium. AB - Numerical simulations that couple flow in a surface fluid with that in a porous medium are useful for examining problems of pollution that involve interactions among the atmosphere, surface water and groundwater, including, for example, saltwater intrusion along coasts. We previously developed a numerical simulation method for simulating a coupled atmospheric gas, surface water, and groundwater system (called the ASG method) that employs a saturation equation for flow in a porous medium; this equation allows both the void fraction of water in the surface system and water saturation in the porous medium to be solved simultaneously. It remained necessary, however, to evaluate how global pressure, including gas pressure, water pressure, and capillary pressure, should be specified at the boundary between the surface and the porous medium. Therefore, in this study, we derived a new equation for global pressure and integrated it into the ASG method. We then simulated water saturation in a porous medium and the void fraction of water in a surface system by the ASG method and reproduced fairly well the results of two column experiments. Next, we simulated water saturation in a porous medium (sand) with a bank, by using both the ASG method and a modified Picard (MP) method. We found only a slight difference in water saturation between the ASG and MP simulations. This result confirmed that the derived equation for global pressure was valid for a porous medium, and that the global pressure value could thus be used with the saturation equation for porous media. Finally, we used the ASG method to simulate a system coupling atmosphere, surface water, and a porous medium (110m wide and 50m high) with a trapezoidal bank. The ASG method was able to simulate the complex flow of fluids in this system and the interaction between the porous medium and the surface water or the atmosphere. PMID- 26583742 TI - Determination of O2 Mass Transport at the Pt | PFSA Ionomer Interface under Reduced Relative Humidity. AB - Oxygen mass transport resistance through the ionomer component in the cathode catalyst layer is considered to contribute overpotential losses in polymer electrolyte membrane fuel cells. Whereas it is known that water uptake, water transport, and proton conductivity are reduced upon reducing relative humidity, the effect on oxygen mass transport remains unknown. We report a two-electrode approach to determine mass transport coefficients for the oxygen reduction reaction in air at the Pt/perfluorosulfonic acid ionomer membrane interface between 90 and 30% RH at 70 degrees C using a Pt microdisk in a solid state electrochemical cell. Potential-step chronoamperometry was performed at specific mass-transport limiting potentials to allow for the elucidation of the oxygen diffusion coefficient (D(bO2)) and oxygen concentration (c(bO2)). In our efforts, novel approaches in data acquisition, as well as analysis, were examined because of the dynamic nature of the membrane under lowered hydration conditions. Linear regression analysis reveals a decrease in oxygen permeability (D(bO2c(bO2)) by a factor of 1.7 and 3.4 from 90 to 30% RH for Nafion 211 membrane and membranes cast from Nafion DE2020 ionomer solutions, respectively. Additionally, nonlinear curve fitting by way of the Shoup-Szabo equation is employed to analyze the entire current transient during potential step controlled ORR. We also report on the presence of an RH dependence of our previously reported time-dependency measurements for O2 mass transport coefficients. PMID- 26583743 TI - Editorial Comment from Dr Izumi to Clinicopathological features and outcomes in patients with late recurrence of renal cell carcinoma after radical surgery. PMID- 26583744 TI - Electrospinning of Crystallizable Polypeptoid Fibers. AB - A unique fabrication process of low molar mass, crystalline polypeptoid fibers is described. Thermoresponsive fiber mats are prepared by electrospinning a homogeneous blend of semicrystalline poly(N-(n-propyl) glycine) (PPGly; 4.1 kDa) with high molar mass poly(ethylene oxide) (PEO). Annealing of these fibers at ~100 degrees C selectively removes the PEO and produces stable crystalline fiber mats of pure PPGly, which are insoluble in aqueous solution but can be redissolved in methanol or ethanol. The formation of water-stable polypeptoid fiber mats is an important step toward their utilization in biomedical applications such as tissue engineering or wound dressing. PMID- 26583745 TI - Glutamate drug reduces dopamine inhibition of phosphorylation. PMID- 26583746 TI - Reply. PMID- 26583747 TI - An alternative way to perform gastroscopy in large frogs and toads. PMID- 26583748 TI - Validation of the FIB-4 index for evaluation of fibrosis in patients with recurrent hepatitis C after living donor liver transplantation: A single center experience. AB - AIM: The FIB-4 index has been proposed as a simple, non-invasive surrogate marker of liver fibrosis in patients with hepatitis C virus (HCV). However, the utility of FIB-4 in HCV positive patients after living donor liver transplantation (LDLT) has not been assessed. The aim of this study was to evaluate the efficacy of FIB 4 in the detection of significant liver graft fibrosis caused by recurrent HCV infection after LDLT compared with other simple fibrosis markers. METHODS: A total of 259 liver biopsies (LB) with evidence of recurrent HCV were taken from 110 HCV positive LDLT patients who had undergone concomitant splenectomy before administration of antiviral therapy. In LB performed at 3 months or later after LT (n = 202, subject group), FIB-4 was compared between fibrosis stages and the accuracy of FIB-4 in predicting significant fibrosis (METAVIR, F >= 2) was assessed compared with aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio, age-platelet index, and AST to platelet ratio index (APRI). RESULTS: FIB-4 was significantly different between all fibrosis stages (F0 and F1-F4, P = 0.022; F0/1 and F2-F4, P < 0.0005; and F0-F2 and F3F4, P = 0.034) and provided the best area under the receiver-operator curve (AUROC) compared with other markers (FIB-4, 0.711; APRI, 0.693; age-platelet index, 0.663; and AST to ALT ratio, 0.562). The optimal cut-off value to identify significant fibrosis was 2.20 with 65% sensitivity and 69% specificity. CONCLUSION: FIB-4 is a more reliable marker for diagnosing significant liver fibrosis than APRI, age-platelet index, and AST to ALT ratio in LDLT patients with HCV. PMID- 26583749 TI - WFA(+)-M2BP: a novel biomarker with diagnostic and therapeutic implications in liver diseases. PMID- 26583751 TI - CryoEM and computer simulations reveal a novel kinase conformational switch in bacterial chemotaxis signaling. AB - Chemotactic responses in bacteria require large, highly ordered arrays of sensory proteins to mediate the signal transduction that ultimately controls cell motility. A mechanistic understanding of the molecular events underlying signaling, however, has been hampered by the lack of a high-resolution structural description of the extended array. Here, we report a novel reconstitution of the array, involving the receptor signaling domain, histidine kinase CheA, and adaptor protein CheW, as well as a density map of the core-signaling unit at 11.3 A resolution, obtained by cryo-electron tomography and sub-tomogram averaging. Extracting key structural constraints from our density map, we computationally construct and refine an atomic model of the core array structure, exposing novel interfaces between the component proteins. Using all-atom molecular dynamics simulations, we further reveal a distinctive conformational change in CheA. Mutagenesis and chemical cross-linking experiments confirm the importance of the conformational dynamics of CheA for chemotactic function. PMID- 26583750 TI - The ATPases of cohesin interface with regulators to modulate cohesin-mediated DNA tethering. AB - Cohesin tethers together regions of DNA, thereby mediating higher order chromatin organization that is critical for sister chromatid cohesion, DNA repair and transcriptional regulation. Cohesin contains a heterodimeric ATP-binding Cassette (ABC) ATPase comprised of Smc1 and Smc3 ATPase active sites. These ATPases are required for cohesin to bind DNA. Cohesin's DNA binding activity is also promoted by the Eco1 acetyltransferase and inhibited by Wpl1. Recently we showed that after cohesin stably binds DNA, a second step is required for DNA tethering. This second step is also controlled by Eco1 acetylation. Here, we use genetic and biochemical analyses to show that this second DNA tethering step is regulated by cohesin ATPase. Furthermore, our results also suggest that Eco1 promotes cohesion by modulating the ATPase cycle of DNA-bound cohesin in a state that is permissive for DNA tethering and refractory to Wpl1 inhibition. PMID- 26583752 TI - Dynamics and heterogeneity of a fate determinant during transition towards cell differentiation. AB - Yan is an ETS-domain transcription factor responsible for maintaining Drosophila eye cells in a multipotent state. Yan is at the core of a regulatory network that determines the time and place in which cells transit from multipotency to one of several differentiated lineages. Using a fluorescent reporter for Yan expression, we observed a biphasic distribution of Yan in multipotent cells, with a rapid inductive phase and slow decay phase. Transitions to various differentiated states occurred over the course of this dynamic process, suggesting that Yan expression level does not strongly determine cell potential. Consistent with this conclusion, perturbing Yan expression by varying gene dosage had no effect on cell fate transitions. However, we observed that as cells transited to differentiation, Yan expression became highly heterogeneous and this heterogeneity was transient. Signals received via the EGF Receptor were necessary for the transience in Yan noise since genetic loss caused sustained noise. Since these signals are essential for eye cells to differentiate, we suggest that dynamic heterogeneity of Yan is a necessary element of the transition process, and cell states are stabilized through noise reduction. PMID- 26583753 TI - Burst muscle performance predicts the speed, acceleration, and turning performance of Anna's hummingbirds. AB - Despite recent advances in the study of animal flight, the biomechanical determinants of maneuverability are poorly understood. It is thought that maneuverability may be influenced by intrinsic body mass and wing morphology, and by physiological muscle capacity, but this hypothesis has not yet been evaluated because it requires tracking a large number of free flight maneuvers from known individuals. We used an automated tracking system to record flight sequences from 20 Anna's hummingbirds flying solo and in competition in a large chamber. We found that burst muscle capacity predicted most performance metrics. Hummingbirds with higher burst capacity flew with faster velocities, accelerations, and rotations, and they used more demanding complex turns. In contrast, body mass did not predict variation in maneuvering performance, and wing morphology predicted only the use of arcing turns and high centripetal accelerations. Collectively, our results indicate that burst muscle capacity is a key predictor of maneuverability. PMID- 26583754 TI - The Use of Videogames as Complementary Therapeutic Tool for Cognitive Behavioral Therapy in Bulimia Nervosa Patients. AB - Although cognitive behavioral therapy (CBT) has been demonstrated to be the most effective approach for the treatment of bulimia nervosa (BN), there is lack of studies showing whether a combination with a serious video game (SVG) might be useful to enhance patients' emotional regulation capacities and general outcome. The aims of this study were (a) to analyze whether outpatient CBT + SVG, when compared with outpatient CBT - SVG, shows better short-term outcome; (b) to examine whether the CBT + SVG group is more effective in reducing emotional expression and levels of anxiety than CBT - SVG. Thirty-eight patients diagnosed as having BN according to DSM-5 criteria were consecutively assigned to two outpatient group therapy conditions (that lasted for 16 weekly sessions): 20 CBT + SVG versus 18 CBT - SVG. Patients were assessed before and after treatment using not only a food and binging/purging diary and clinical questionnaires in the field of eating disorders but also additional indexes for measuring anger expression and anxiety. Regarding the post-treatment psychometric measures, most of the mean differences (Eating Disorder Inventory-2, Symptom Checklist-Revised, State-Trait Anxiety Index, and partially State-Trait Anger Expression Inventory) achieved moderate to high effect size (d > 0.5), in the sense that CBT + SVG obtained the best results compared with the CBT - SVG group. Regarding therapy outcome (dropout, partial remission, and total remission), CBT + SVG showed better results and a moderate effect size emerged for the comparison of the risk of dropout during the treatment, being higher for CBT - SVG compared with CBT + SVG (44.1 percent versus 20.0 percent, d = 0.54). Although the sample size in our study was low, and consequently results should be considered with caution, we have obtained promising findings suggesting that in the short-term CBT + SVG might be a good option not only for improving emotional dysregulation and approaching the current limitations of CBT - SVG in BN but also for enhancing the therapy adherence of patients. PMID- 26583755 TI - Size effects of potato waste on its treatment by microbial fuel cell. AB - The performance of microbial fuel cell (MFC) in treating potato cubes with different sizes (the edge size of 3, 5 and 7 mm) was investigated. Current density was found lower as the size of potato cubes increased, even if the differences in their removal were less apparent. At the end of MFC operation for 81 days, both total and soluble chemical oxygen demand reached nearly identical values, irrespective of the potato sizes; and citrate and isobutyrate were two major organic acids remaining in the solutions. Bacterial community analysis using polymerase chain reaction, denaturing gradient gel electrophoresis and sequencing indicated that bacterial species on the anode and in the anodic solution were similar and did not change obviously with potato sizes, and that, in similarity with previous studies on potato-processing wastewater treatment, Proteobacteria and Firmicutes were two dominating phyla. Geobacter was found richer on the anode than in the anodic solutions. PMID- 26583756 TI - Influence of Surfactant Bilayers on the Refractive Index Sensitivity and Catalytic Properties of Anisotropic Gold Nanoparticles. AB - Shape-controlled synthesis of gold nanoparticles generally involves the use of surfactants, typically cetyltrimethylammonium (CTAX, X = Cl(-) , Br(-)), to regulate the nucleation growth process and to obtain colloidally stable nanoparticles. The surfactants adsorb on the nanoparticle surface making further functionalization difficult and therefore limit their use in many applications. Herein, the influence of CTAX on nanoparticle sensitivity to local dielectric environment changes is reported. It is shown, both experimentally and theoretically, that the CTAX bilayer significantly reduces the refractive index (RI) sensitivity of anisotropic gold nanoparticles such as nanocubes and concave nanocubes, nanorods, and nanoprisms. The RI sensitivity can be increased by up to 40% by removing the surfactant layer from nanoparticles immobilized on a solid substrate using oxygen plasma treatment. This increase compensates for the otherwise problematic decrease in RI sensitivity caused by the substrate effect. Moreover, the removal of the surfactants both facilitates nanoparticle biofunctionalization and significantly improves their catalytic properties. The strategy presented herein is a simple yet effective universal method for enhancing the RI sensitivity of CTAX-stabilized gold nanoparticles and increasing their potential as transducers in nanoplasmonic sensors, as well as in catalytic and biomedical applications. PMID- 26583757 TI - Screening of a kinase library reveals novel pro-senescence kinases and their common NF-kappaB-dependent transcriptional program. AB - Cellular senescence results in proliferation arrest and acquisition of hallmarks such as the Senescence-Associated Secretory Phenotype (SASP). Senescence is involved in regulating numerous physio-pathological responses, including embryonic development, cancer, and several aging-related diseases. Only a few kinases, centered on the RAS signaling pathway, have been identified as inducing premature senescence. About possible other senescence-regulating kinases and signaling pathways, practically little is known. By screening a library of activated kinases, we identified 33 kinases whose constitutive expression decreases cell proliferation and induces expression of senescence markers; p16 and SASP components. Focusing on some kinases showing the strongest pro senescence effects, we observed that they all induce expression of SASP-component genes through activation of an NF-kappaB-dependent transcriptional program. Furthermore, inhibition of the p53 or Rb pathway failed to prevent the SASP inducing effect of pro-senescence kinases. Inhibition of the NF-kappaB, p53, or Rb pathway proved insufficient to prevent kinase-triggered cell cycle arrest. We have thus identified a repertoire of novel pro-senescence kinases and pathways. These results will open new perspectives in the understanding on the role of cellular senescence in various physio-pathological responses. PMID- 26583758 TI - Winged Metal Needles versus Plastic Winged and Nonwinged Cannulae for Subcutaneous Infusions in Palliative Care: A Quality Improvement Project To Enhance Patient Care and Medical Staff Safety in a Singaporean Hospital. AB - BACKGROUND AND OBJECTIVES: A comparison of metal needles and plastic cannulae (winged and nonwinged) for continuous subcutaneous infusion was done during a quality improvement project to reduce device-induced complications at our hospital. Design, Setting, and Measurements: Data were collected on incidence of site reactions (bruising, swelling, erythema, and blisters); mechanical complications (kinking and dislodgement); device durability; type, and volume of medications; and incidence of needle-stick injuries. All infusion devices used for patients in the Palliative Care Service from February 3 to March 26, 2014 were studied. Devices examined were: winged metal needle (Venofix((r)), 23G, B. Braun Melsungen AG, Melsungen, Germany), winged vialon cannula (BD NexivaTM, 24G, Becton Dickinson Infusion Therapy Systems Inc., Sandy, UT), and nonwinged polyurethane cannula (Introcan Safety((r)), 24G, B. Braun Medical, Mundelein, IL). RESULTS: Thirty devices (10 per type) were used. Incidence of site reactions was 50.0%, 10.0%, and 0.0% for the metal needles, polyurethane cannulae, and vialon cannulae, respectively. Incidence of mechanical complications was 20.0% for the polyurethane cannulae and 0.0% for the metal needles and vialon cannulae. Duration of use was up to 60 hours, 83 hours, and 113 hours for the metal needles, polyurethane cannulae, and vialon cannulae, respectively. Daily volumes infused were up to 28.9 mL, 60.0 mL, and 29.4 mL for the metal needles, polyurethane cannulae, and vialon cannulae, respectively. No needle-stick injuries occurred. CONCLUSIONS: The winged vialon cannula was the most durable, with no site reactions or mechanical complications, tolerating a volume comparable to that of the metal needle. We suggest its utilization for continuous subcutaneous infusions and consideration of future randomized controlled trials with an integrated economic evaluation for further in-depth comparisons of subcutaneous indwelling devices. PMID- 26583759 TI - What is the future of PEGylated therapies? AB - The tremendous potential of biologic drugs is hampered by short half-lives in vivo, resulting in significantly lower potency than activity seen in vitro. These short-acting therapeutic agents require frequent dosing profiles that can reduce applicability to the clinic, particularly for chronic conditions. Therefore, half life extension technologies are entering the clinic to enable improved or new biologic therapies. PEGylation is the first successful technology to improve pharmacokinetic (PK) profiles of therapeutic agents and has been applied in the clinic for over 25 years. Over 10 PEGylated therapeutics have entered the clinic since the early 1990 s, and new PEGylated agents continue to expand clinical pipelines and drug patent life. PEGylation is the most established half-life extension technology in the clinic with proven safety in humans for over two decades. Still, it is one of the most evolving and emerging technologies that will be applied for the next two decades. PMID- 26583760 TI - MR Imaging of Brachial Plexus and Limb-Girdle Muscles in Patients with Amyotrophic Lateral Sclerosis. AB - PURPOSE: To assess brachial plexus magnetic resonance (MR) imaging features and limb-girdle muscle abnormalities as signs of muscle denervation in patients with amyotrophic lateral sclerosis (ALS). MATERIALS AND METHODS: This study was approved by the local ethical committees on human studies, and written informed consent was obtained from all subjects before enrollment. By using an optimized protocol of brachial plexus MR imaging, brachial plexus and limb-girdle muscle abnormalities were evaluated in 23 patients with ALS and clinical and neurophysiologically active involvement of the upper limbs and were compared with MR images in 12 age-matched healthy individuals. Nerve root and limb-girdle muscle abnormalities were visually evaluated by two experienced observers. A region of interest-based analysis was performed to measure nerve root volume and T2 signal intensity. Measures obtained at visual inspection were analyzed by using the Wald chi(2) test. Mean T2 signal intensity and volume values of the regions of interest were compared between groups by using a hierarchical linear model, accounting for the repeated measurement design. RESULTS: The level of interrater agreement was very strong (kappa = 0.77-1). T2 hyperintensity and volume alterations of C5, C6, and C7 nerve roots were observed in patients with ALS (P < .001 to .03). Increased T2 signal intensity of nerve roots was associated with faster disease progression (upper-limb Medical Research Council scale progression rate, r = 0.40; 95% confidence interval: 0.001, 0.73). Limb girdle muscle alterations (ie, T2 signal intensity alteration, edema, atrophy) and fat infiltration also were found, in particular, in the supraspinatus muscle, showing more frequent T2 signal intensity alterations and edema (P = .01) relative to the subscapularis and infraspinatus muscles. CONCLUSION: Increased T2 signal intensity and volume of brachial nerve roots do not exclude a diagnosis of ALS and suggest involvement of the peripheral nervous system in the ALS pathogenetic cascade. MR imaging of the peripheral nervous system and the limb girdle muscle may be useful for monitoring the evolution of ALS and distinguishing patients with ALS from those with inflammatory neuropathy, respectively. PMID- 26583761 TI - Effect of Iterative Reconstruction on the Detection of Systemic Sclerosis-related Interstitial Lung Disease: Clinical Experience in 55 Patients. AB - PURPOSE: To evaluate the effect of iterative reconstruction on the depiction of systemic sclerosis-related interstitial lung disease (ILD) when the radiation dose is reduced by 60%. MATERIALS AND METHODS: This study was based on retrospective interpretation of prospectively acquired data over a 12-month period and approved by the institutional review board. The requirement to obtain informed consent was waived. Fifty-five chest computed tomographic (CT) examinations were performed in 38 women and 17 men (mean age, 55.8 years; range, 23-82 years) by using a dual-source CT unit with (a) both tubes set at similar energy (120 kVp) and (b) the total reference milliampere seconds (ie, 110 mAs) split up in a way that 40% was applied to tube A and 60% to tube B. Two series of images were generated simultaneously from the same dataset: (a) standard-dose images (generated from both tubes) reconstructed with filtered back projection (group 1, the reference standard) and (b) reduced-dose images (generated from tube A; 60% dose reduction) reconstructed with sinogram-affirmed iterative reconstruction (SAFIRE) (group 2). In both groups, the analyzed parameters comprised the image noise and the visualization and conspicuity of CT features of ILD. Two readers independently analyzed images from both groups. Results were compared by using the Wilcoxon test for paired samples; the 95% confidence interval was calculated when appropriate. RESULTS: The mean level of objective noise in group 2 was significantly lower than that in group 1 (22.02 HU vs 26.23 HU, respectively; P < .0001). The CT features of ILD in group 1 were always depicted in group 2, with subjective conspicuity scores (a) improved in group 2 for ground-glass opacity, reticulation, and bronchiectasis and/or bronchiolectasis and (b) identical in both groups for honeycombing. The interobserver agreement for their depiction was excellent in both groups (kappa, 0.84-0.98). CONCLUSION: Despite a 60% dose reduction, images reconstructed with SAFIRE allowed similar detection of systematic sclerosis-related ILD compared with the reference standard. PMID- 26583762 TI - Thank You and Farewell. PMID- 26583763 TI - Urologic-Induced Complications of Prophylactic Ureteral Localization Stent Placement for Colorectal Surgery Cases. AB - PURPOSE: A prophylactic ureteral localization stent (PULSe) placed by urologists aids in intraoperative localization and detection of suspected ureteral injury during complex colorectal surgery (CRS) cases. We evaluated the incidence and management of urologic-induced complications secondary to PULSe placement during CRS cases at a single center. MATERIALS AND METHODS: We performed a retrospective review of all patients who underwent cystoscopy and PULSe placement at the time of CRS over a 12-month period. Bilateral 5 French *70-cm TigerTail(r) (Bard Medical Division, Covington, GA) PULSe devices were placed without assistance of routine fluoroscopy. RESULTS: Ninety-nine patients (mean age, 58.1 years; range, 17-88 years) underwent bilateral PULSe placement, with a male:female ratio of 44:55 and a mean body mass index of 26.8 (17.0-38.6) kg/m(2). Mean pre- and postprocedural creatinine levels were 0.91 and 1.01 mg/dL, respectively. Twenty two of 99 (22%) cases utilized a guidewire to aid in placement of PULSe. Four Clavien grade IIIb complications occurred: mucosal edema, reflex anuria, ureteral perforation, and ureteral obstruction secondary to significant clot burden. Three of the grade IIIb complications were managed endoscopically with double-J stent placement. The ureteral perforation case required percutaneous nephrostomy tube placement. Subgroup analysis of the four grade IIIb complications revealed a mean age of 62.3 years, body mass index of 26.98 kg/m(2), and pre- and postprocedural creatinine levels of 0.95 and 4.83 mg/dL, respectively. Only one of the four grade IIIb complications utilized a guidewire prior to PULSe placement. CONCLUSIONS: The incidence of Clavien grade III urologic-induced complications during PULSe placement is approximately 2% (4/188). Mandatory adoption of fluoroscopy and guidewires may be required to minimize complications of PULSe placement. PMID- 26583764 TI - Dried Blood Spot Technique for the Monitoring of Ambrisentan, Bosentan, Sildenafil, and Tadalafil in Patients with Pulmonary Arterial Hypertension. AB - Endothelin receptor antagonists (ERA) and phosphodiesterase 5 inhibitors (PDE5I) are long-term therapeutics for the treatment of pulmonary arterial hypertension (PAH). Their interindividual pharmacokinetic variability is remarkably large, and despite the seriousness of the disease, nonadherence is occurring. Therefore, methods to monitor sufficient circulating drug levels are essential. The objectives of this study were to develop and validate dried blood spot (DBS) assays for the quantification of ambrisentan, bosentan, sildenafil, tadalafil, and their main metabolites. We also quantified the influence of different hematocrit levels and assessed the correlation of simultaneously taken capillary whole blood (DBS) and venous plasma samples. The aliquot punches were extracted by liquid/liquid extraction followed by liquid chromatography/tandem mass spectrometry (LC/MS/MS) quantification methods. All assays fulfilled the requirements of the FDA and EMA guidelines for assay validation with a lower limit of quantification of 2.5 ng/mL for the ERAs, 5 ng/mL for sildenafil, and 10 ng/mL for tadalafil. All analytes were stable for at least 147 days when stored on DBS filter paper cards at room temperature in the dark. Due to poor distribution into erythrocytes, drug concentrations in DBS were always lower than in plasma, resulting in conversion factors of 1.58 for ambrisentan and sildenafil and 1.52 for bosentan and tadalafil. PMID- 26583765 TI - Racial comparisons in perceptions of maternal and peer attitudes, body dissatisfaction, and eating disorders among African American and White women. AB - Although once thought primarily to affect White women, body dissatisfaction and disordered eating exist among all racial groups. In the current study, the authors determined whether the relationship between participants' perceived maternal/peer attitudes toward appearance and the outcomes of body dissatisfaction and eating pathology varied by race. Self-reported data, including measures of body dissatisfaction, disordered eating behaviors, body mass index (BMI), and perceptions of maternal/peer attitudes, were collected from December 2012 to May 2013 at a large Mid-Atlantic university. BMI (beta = 0.20, p = .01), perceptions of peers' attitudes toward appearance (beta = 0.23, p = .02), and White race (beta = 0.33, p < .001) were independently associated with body dissatisfaction. Additionally, race interacted with perceptions of peers' attitudes toward appearance such that at high perceptions, African American women reported high levels of body dissatisfaction (beta = -0.20, p = .04), but this was not true for White women. Higher perceived peer concern about weight and shape (beta = 0.32, p < .001), increased BMI (beta = 0.30, p < .001), and White race (beta = 0.21, p = .002), also were associated with disordered eating. The results of this study have implications for prevention programs that address disordered eating for racially diverse groups of women. PMID- 26583766 TI - Diabetes Among Asians and Native Hawaiians or other Pacific Islanders--United States, 2011-2014. AB - Asians and Native Hawaiians or other Pacific Islanders (NHPIs) are fast-growing U.S. minority populations at high risk for type 2 diabetes. Although national studies have described diabetes prevalence, incidence, and risk factors among Asians and NHPIs compared with non-Hispanic whites, little is known about state level diabetes prevalence among these two racial groups, or about how they differ from one another with respect to diabetes risk factors. To examine state-level prevalence of self-reported, physician-diagnosed (diagnosed) diabetes and risk factors among Asians and NHPIs aged >=18 years, CDC analyzed data from the 2011 2014 Behavioral Risk Factor Surveillance System (BRFSS). Among five states and Guam with sufficient data about NHPIs for analysis, the age-adjusted diabetes prevalence estimate for NHPIs ranged from 13.4% (New York) to 19.1% (California). Among 32 states, the District of Columbia (DC), and Guam that had sufficient data about Asians for analysis, diabetes prevalence estimates for Asians ranged from 4.9% (Arizona) to 15.3% (New York). In the five states and Guam with sufficient NHPI data, NHPIs had a higher age-adjusted prevalence of diabetes than did Asians, and a higher proportion of NHPIs were overweight or obese and had less than a high school education compared with Asians. Effective interventions and policies might reduce the prevalence of diabetes in these growing, high-risk minority populations. PMID- 26583767 TI - The Effect of Response Bias on the Personality Inventory for DSM-5 (PID-5). AB - Valid self-report assessment of psychopathology relies on accurate and credible responses to test questions. There are some individuals who, in certain assessment contexts, cannot or choose not to answer in a manner typically representative of their traits or symptoms. This is referred to, most broadly, as test response bias. In this investigation, we explore the effect of response bias on the Personality Inventory for DSM-5 (PID-5; Krueger, Derringer, Markon, Watson, & Skodol, 2013 ), a self-report instrument designed to assess the pathological personality traits used to inform diagnosis of the personality disorders in Section III of DSM-5. A set of Minnesota Multiphasic Personality Inventory Restructured Form (MMPI-2-RF; Ben-Porath & Tellegen, 2008 / 2011 ) validity scales, which are used to assess and identify response bias, were employed to identify individuals who engaged in either noncredible overreporting (OR) or underreporting (UR), or who were deemed to be reporting or responding to the items in a "credible" manner-credible responding (CR). A total of 2,022 research participants (1,587 students, 435 psychiatric patients) completed the MMPI-2-RF and PID-5; following protocol screening, these participants were classified into OR, UR, or CR response groups based on MMPI-2-RF validity scale scores. Groups of students and patients in the OR group scored significantly higher on the PID-5 than those students and patients in the CR group, whereas those in the UR group scored significantly lower than those in the CR group. Although future research is needed to explore the effects of response bias on the PID-5, results from this investigation provide initial evidence suggesting that response bias influences scale elevations on this instrument. PMID- 26583769 TI - Clinical Outcomes among Women with Mucinous Adenocarcinoma of the Ovary. AB - BACKGROUND/AIMS: Patterns of metastasis and clinical behavior of mucinous ovarian cancers are poorly understood because of their rarity. METHODS: A retrospective review of records of women identified with pure mucinous invasive ovarian/tubal/peritoneal cancer during 1992-2012 at one institution. Survival differences were compared using Kaplan-Meier methods with log-rank tests. RESULTS: Among 42 women with mucinous adenocarcinomas, the median age was 55 (range 33-83 years). Most cancers were well differentiated (n = 26, 68%) and in stage I/II (n = 31, 74%). One of 27 women with sampled nodes had nodal metastasis; one additional woman had recurrence in a pelvic node. Most had no visible residual tumor after initial surgery, but of 10 women with stage III/IV cancer and documented residual, 8 had >2 cm residual. Except for 1 woman alive with disease at last follow-up, all who had a recurrence died of the disease. Five-year survival was 83% for stage I/II cases but 29% among stage III/IV cases. Stage was a strong predictor of survival (hazard ratio of death among women with stage III/IV cancer 7.73, 95% CI 2.33-25.66, p < 0.001 vs. women with stage I/II cancer). CONCLUSION: Mucinous ovarian cancers have a distinct biology, such that lymphadenectomy for staging is unnecessary and metastatic cancers have poor prognosis. PMID- 26583770 TI - The Parental Bond and Alcohol Use Among Adolescents: The Mediating Role of Drinking Motives. AB - BACKGROUND: Alcohol use and alcohol-related problems represent a significant health concern. Few empirical researches focused on understanding the interrelationships and links between the parental bond, drinking motives, and alcohol use during adolescence. OBJECTIVES: The present study examined the relationships between a supportive parental bond, drinking motives, and alcohol use, with a focus on the role of mediation. METHODS: The sample comprised 298 adolescents, aged from 16 to 20 years. The technique of structural equation modelling (SEM) was used to assess the direct and indirect effects of the parental bond on alcohol use among adolescents through motives for drinking. RESULTS: The relationship between the parental bond and frequency of alcohol use by adolescents was not mediated by any motives for drinking, neither for males nor females. Regarding the relationships between the parental bond and quantity of adolescent alcohol consumption, findings for females showed significant indirect effects of maternal bond on alcohol quantity, when coping, enhancement, and social drinking motives were entered as mediator variables. Rather, paternal bond did not predict drinking quantity, not even indirectly. On the contrary, results for males indicated that the parental bond was neither directly nor indirectly associated with adolescent alcohol use. CONCLUSIONS/IMPORTANCE: Mothers are the relational fulcrum of the family, while fathers seem to maintain a more peripheral position. Gender differences are discussed on the basis of the different cultural and parental socialisation processes that operate for male and female adolescents. PMID- 26583768 TI - Outborns or Inborns: Where Are the Differences? A Comparison Study of Very Preterm Neonatal Intensive Care Unit Infants Cared for in Australia and New Zealand and in Canada. AB - BACKGROUND: Very preterm infants born outside tertiary centers are at higher risks of adverse outcomes than inborn infants. Regionalization of perinatal care has been introduced worldwide to improve outcomes. OBJECTIVE: To compare the risk adjusted outcomes of both inborn and outborn infants cared for in tertiary neonatal intensive care units in Australia and New Zealand and in Canada. METHODS: Deidentified data of infants <32 weeks' gestational age from the 29 Australian and New Zealand Neonatal Network units (ANZNN; n = 9,893) and 26 Canadian Neonatal Network units (CNN; n = 7,133) between 2005 and 2007 were analyzed for predischarge adverse outcomes. RESULTS: ANZNN had lower rates of outborns compared to CNN (13 vs. 19%), particularly of late admissions (>2 days of age; 5.8 vs. 22.2% of outborns) who had high morbidity rates. After adjusting for confounding variables including gestation, ANZNN inborn infants had lower odds of chronic lung disease [CLD; 17.0 vs. 23.3%; adjusted odds ratio (AOR) = 0.70, 95% CI: 0.64-0.77], severe neurological injuries on ultrasound (SNI; 4.1 vs. 6.7%; AOR = 0.62, 95% CI: 0.53-0.73), severe retinopathy (5.6 vs. 7%; AOR = 0.71, 95% CI: 0.59-0.84) and necrotizing enterocolitis (3.5 vs. 5.4%; AOR = 0.67, 95% CI: 0.56-0.79), but no difference in mortality odds. After excluding the late outborn admissions, ANZNN outborns had lower odds of SNI (AOR = 0.43, 95% CI: 0.32-0.58) and CLD (AOR = 0.63, 95% CI: 0.49-0.81) than CNN. CONCLUSIONS: ANZNN inborn and early admitted outborn infants had lower odds of neonatal morbidities than their CNN counterparts. However, compared to ANZNN, the higher CNN rates of outborns and their late admissions are likely related to the differences in regionalization and referral practices, and may explain differences in outcomes. PMID- 26583771 TI - A Bio-inspired Collision Avoidance Model Based on Spatial Information Derived from Motion Detectors Leads to Common Routes. AB - Avoiding collisions is one of the most basic needs of any mobile agent, both biological and technical, when searching around or aiming toward a goal. We propose a model of collision avoidance inspired by behavioral experiments on insects and by properties of optic flow on a spherical eye experienced during translation, and test the interaction of this model with goal-driven behavior. Insects, such as flies and bees, actively separate the rotational and translational optic flow components via behavior, i.e. by employing a saccadic strategy of flight and gaze control. Optic flow experienced during translation, i.e. during intersaccadic phases, contains information on the depth-structure of the environment, but this information is entangled with that on self-motion. Here, we propose a simple model to extract the depth structure from translational optic flow by using local properties of a spherical eye. On this basis, a motion direction of the agent is computed that ensures collision avoidance. Flying insects are thought to measure optic flow by correlation-type elementary motion detectors. Their responses depend, in addition to velocity, on the texture and contrast of objects and, thus, do not measure the velocity of objects veridically. Therefore, we initially used geometrically determined optic flow as input to a collision avoidance algorithm to show that depth information inferred from optic flow is sufficient to account for collision avoidance under closed loop conditions. Then, the collision avoidance algorithm was tested with bio inspired correlation-type elementary motion detectors in its input. Even then, the algorithm led successfully to collision avoidance and, in addition, replicated the characteristics of collision avoidance behavior of insects. Finally, the collision avoidance algorithm was combined with a goal direction and tested in cluttered environments. The simulated agent then showed goal-directed behavior reminiscent of components of the navigation behavior of insects. PMID- 26583772 TI - Markerless tumor tracking using short kilovoltage imaging arcs for lung image guided radiotherapy. AB - The ability to monitor tumor motion without implanted markers is clinically advantageous for lung image-guided radiotherapy (IGRT). Existing markerless tracking methods often suffer from overlapping structures and low visibility of tumors on kV projection images. We introduce the short arc tumor tracking (SATT) method to overcome these issues. The proposed method utilizes multiple kV projection images selected from a nine-degree imaging arc to improve tumor localization, and respiratory-correlated 4D cone-beam CT (CBCT) prior knowledge to minimize the effects of overlapping anatomies. The 3D tumor position is solved as an optimization problem with prior knowledge incorporated via regularization. We retrospectively validated SATT on 11 clinical scans from four patients with central tumors. These patients represent challenging scenarios for markerless tumor tracking due to the inferior adjacent contrast. The 3D trajectories of implanted fiducial markers were used as the ground truth for tracking accuracy evaluation. In all cases, the tumors were successfully tracked at all gantry angles. Compared to standard pre-treatment CBCT guidance alone, trajectory errors were significantly smaller with tracking in all cases, and the improvements were the most prominent in the superior-inferior direction. The mean 3D tracking error ranged from 2.2-9.9 mm, which was 0.4-2.6 mm smaller compared to pre-treatment CBCT. In conclusion, we were able to directly track tumors with inferior visibility on kV projection images using SATT. Tumor localization accuracies are significantly better with tracking compared to the current standard of care of lung IGRT. Future work involves the prospective evaluation and clinical implementation of SATT. PMID- 26583773 TI - Cryosurgery during Imiquimod (Immunocryosurgery) for Periocular Basal Cell Carcinomas: An Efficacious Minimally Invasive Treatment Alternative. AB - BACKGROUND/AIM: Periocular basal cell carcinomas (pBCC) remain a treatment challenge. Our aim was to retrospectively evaluate the feasibility and efficacy of immunocryosurgery for the treatment of pBCC. METHODS: Immunocryosurgery is given in 5-week cycles of daily imiquimod, with cryosurgery on day 14. Patients treated between 1/1/2008 and 31/12/2014 were included in this study. RESULTS: Immunocryosurgery was offered to 19 patients. Of these, 16 (i.e., 6 males and 10 females, average age 74.9 years, median tumor diameter 15 mm, range 5-60 mm), with 1 tumor each, were treated. Six tumors (37.5%) were relapses after surgery and 2 were of metatypical histology. All BCC were high risk for recurrence after treatment; 10 tumors had 2 risk factors for relapse, 5 had 3, and 1 had 4. The follow-up period ranged between 3 and 60 months (average 25.6 months). Of the 16 tumors treated, 14 (all with a diameter <40 mm) cleared with immunocryosurgery (total efficacy 87.5%); 7 out of 16 tumors (44%; all with a diameter <=20 mm) cleared with 1 conventional 5-week immunocryosurgery treatment cycle. Seven additional tumors (including 2 with a diameter >20 mm) required intensified treatment schemes (of up to 10 weeks) for clearance. The 2 tumors that did not clear responded partially and were also the 2 largest ones (diameter 40 and 60 mm). Of the 14 cleared tumors, 2 relapsed during follow-up; 1 cleared with immunocryosurgery. At the last examination during follow-up, 13 out of 16 (81%) patients were in sustained clinical remission. CONCLUSIONS: For most pBCC, immunocryosurgery is a feasible and efficacious alternative to surgical excision. PMID- 26583775 TI - A Falls Wheel in a Large Academic Medical Center: An Intervention to Reduce Patient Falls With Harm. AB - This article presents an evaluation of a multifaceted fall prevention initiative. The main element of this initiative was the creation and implementation of a Falls Wheel--a visual communication tool of a patient's fall injury risk for all care team members placed on every patient door throughout the health system. The Falls Wheel allows for patient categorization along two dimensions simultaneously: risk of fall and risk of injury from a fall. During the yearlong implementation, the rate of falls with harm dropped by almost 50%. A process audit revealed that there was high fidelity to the intervention components, including displaying the wheel correctly 95% of the time, and the Falls Wheel was updated to match the risk level in the electronic health record 70% of the time. The goal of this article was to share the experience of one health system and encourage others to adopt and rigorously test the Falls Wheel. Replication and extension of this program at other hospitals and health systems will enable staff and empower patients to reduce falls with harm and their unintended consequences. PMID- 26583774 TI - Comparative Genomics of Field Isolates of Mycobacterium bovis and M. caprae Provides Evidence for Possible Correlates with Bacterial Viability and Virulence. AB - Mycobacteria of the Mycobacterium tuberculosis complex (MTBC) greatly affect humans and animals worldwide. The life cycle of mycobacteria is complex and the mechanisms resulting in pathogen infection and survival in host cells are not fully understood. Recently, comparative genomics analyses have provided new insights into the evolution and adaptation of the MTBC to survive inside the host. However, most of this information has been obtained using M. tuberculosis but not other members of the MTBC such as M. bovis and M. caprae. In this study, the genome of three M. bovis (MB1, MB3, MB4) and one M. caprae (MB2) field isolates with different lesion score, prevalence and host distribution phenotypes were sequenced. Genome sequence information was used for whole-genome and protein targeted comparative genomics analysis with the aim of finding correlates with phenotypic variation with potential implications for tuberculosis (TB) disease risk assessment and control. At the whole-genome level the results of the first comparative genomics study of field isolates of M. bovis including M. caprae showed that as previously reported for M. tuberculosis, sequential chromosomal nucleotide substitutions were the main driver of the M. bovis genome evolution. The phylogenetic analysis provided a strong support for the M. bovis/M. caprae clade, but supported M. caprae as a separate species. The comparison of the MB1 and MB4 isolates revealed differences in genome sequence, including gene families that are important for bacterial infection and transmission, thus highlighting differences with functional implications between isolates otherwise classified with the same spoligotype. Strategic protein-targeted analysis using the ESX or type VII secretion system, proteins linking stress response with lipid metabolism, host T cell epitopes of mycobacteria, antigens and peptidoglycan assembly protein identified new genetic markers and candidate vaccine antigens that warrant further study to develop tools to evaluate risks for TB disease caused by M. bovis/M.caprae and for TB control in humans and animals. PMID- 26583777 TI - Postsynthetic bromination of UiO-66 analogues: altering linker flexibility and mechanical compliance. AB - A new member of the UiO-66 series of zirconium metal-organic frameworks (MOFs) is reported, and the postsynthetic bromination of its integral alkene moeities in a single-crystal to single-crystal manner is fully characterised. Nanoindentation is used to probe the bromination of unsaturated carbon-carbon bonds, in it and an analogous Zr MOF, which leads to more compliant materials with lower elastic moduli. PMID- 26583776 TI - ABCs of Insect Resistance to Bt. PMID- 26583778 TI - The impact of long-term dietary pattern of fecal donor on in vitro fecal fermentation properties of inulin. AB - Although the composition of the gut microbiota is of interest, the functionality, or metabolic activity, of the gut microbiota is of equal importance: the gut microbiota can produce either harmful metabolites associated with human disease or beneficial metabolites that protect against disease. The purposes of this study were to determine the associations between dietary intake variables and fecal short and branched chain fatty acid (S/BCFA) concentrations; to determine the associations between dietary intake variables and inulin degradation, short and branched chain fatty acid (S/BCFA) production, and ammonia production during in vitro fecal fermentation of a highly fermentable substrate (inulin); and finally to compare results from the fermentation of inulin with those obtained in a previous report using a poorly fermentable substrate (whole wheat; Yang and Rose, Nutr. Res., 2014, 34, 749-759). Stool samples from eighteen individuals that had completed one-year dietary records were used in an in vitro fecal fermentation system with long-chain inulin as substrate. Few dietary intake variables were correlated with fecal S/BCFA concentrations; however, intakes of several plant-based foods, especially whole grain, dry beans, and certain vegetables that provided dietary fiber, plant protein, and B vitamins, were associated with acetate, propionate, butyrate, and total SCFA production during inulin fermentation. In contrast, intake of dairy and processed meats that provided cholesterol and little fiber, were associated with ammonia and BCFA production. Comparing results between inulin and whole wheat fermentations, significant correlations were only found for butyrate and BCFA, suggesting that regardless of the type of carbohydrate provided to the microbiota, long-term diet may have a pronounced effect on the propensity of the gut microbiota toward either beneficial metabolism (butyrate production) or detrimental metabolism (BCFA production). These results may help in the development of new dietary strategies to improve gut microbiota functionality to promote human health. PMID- 26583779 TI - Toxoplasma gondii in Wild Red Squirrels, the Netherlands, 2014. PMID- 26583784 TI - Insulin-coated gold nanoparticles as a new concept for personalized and adjustable glucose regulation. AB - Diabetes mellitus is a chronic metabolic disease, characterized by high blood glucose levels, affecting millions of people around the world. Currently, the main treatment for diabetes requires multiple daily injections of insulin and self-monitoring of blood glucose levels, which markedly affect patients' quality of life. In this study we present a novel strategy for controlled and prolonged glucose regulation, based on the administration of insulin-coated gold nanoparticles (INS-GNPs). We show that both intravenous and subcutaneous injection of INS-GNPs into a mouse model of type 1 diabetes decreases blood glucose levels for periods over 3 times longer than free insulin. We further showed that conjugation of insulin to GNPs prevented its rapid degradation by the insulin-degrading-enzyme, and thus allows controlled and adjustable bio-activity. Moreover, we assessed different sizes and concentrations of INS-GNPs, and found that both parameters have a critical effect in vivo, enabling specific adjustment of blood glucose levels. These findings have the potential to improve patient compliance in diabetes mellitus. PMID- 26583786 TI - Comment on 'Closed reduction of slipped capital femoral epiphysis: high-risk factor for avascular necrosis'. PMID- 26583785 TI - Effects of VKORC1 Genetic Polymorphisms on Warfarin Maintenance Dose Requirement in a Chinese Han Population. AB - BACKGROUND VKORC1 is reported to be capable of treating several diseases with thrombotic risk, such as cardiac valve replacement. Some single-nucleotide polymorphisms (SNPs) in VKORC1 are documented to be associated with clinical differences in warfarin maintenance dose. This study explored the correlations of VKORC1-1639 G/A, 1173 C/T and 497 T/G genetic polymorphisms with warfarin maintenance dose requirement in patients undergoing cardiac valve replacement. MATERIAL AND METHODS A total of 298 patients undergoing cardiac valve replacement were recruited. During follow-up, clinical data were recorded. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was applied to detect VKORC1-1639 G/A, 1173 C/T and 497 T/G polymorphisms, and genotypes were analyzed. RESULTS Correlations between warfarin maintenance dose and baseline characteristics revealed statistical significances of age, gender and operation methods with warfarin maintenance dose (all P<0.05). Warfarin maintenance dose in VKORC1-1639 G/A AG + GG carriers was obviously higher than in AA carriers (P<0.001). As compared with patients with TT genotype in VKORC1 1173 C/T, warfarin maintenance dose was apparently higher in patients with CT genotype (P<0.001). Linear regression analysis revealed that gender, operation method, method for heart valve replacement, as well as VKORC1-1639 G/A and 1173 C/T gene polymorphisms were significantly related to warfarin maintenance dose (all P<0.05). CONCLUSIONS VKORC1 gene polymorphisms are key genetic factors to affect individual differences in warfarin maintenance dose in patients undergoing cardiac valve replacement; meanwhile, gender, operation method and method for heart valve replacement might also be correlate with warfarin maintenance dose. PMID- 26583787 TI - Arginiemia is not a contraindication for botulinum toxin injection. PMID- 26583788 TI - Retinal Nerve Fiber Layer Thickness Alteration in Apneic Children. AB - PURPOSE: We examined retinal nerve fiber layer (RNFL) thickness alterations in children with chronic upper airway obstructions (UAOs) and obstructive sleep apnea syndrome (OSAS). We also investigated whether it was affected by an adenotonsillectomy operation. METHODS: Forty-two children aged 3 to 8 years with chronic UAO resulting from adenotonsillar enlargement and 34 age-matched controls were included in the study. Patients underwent a Brouillette scoring questionnaire to be divided into mild (N = 10), moderate (N = 22), severe (N = 10), and total (N = 42) UAO groups. According to the scoring, the severe UAO group was defined as the severe OSAS group, the moderate group was suspicious for OSAS, and the mild UAO group was defined as the non-OSAS group. The patients' demographic data for age, sex, and body mass index were obtained. Ophthalmologic evaluations were performed with optical coherence tomography. Central corneal thickness, macular thickness, intraocular pressure (IOP), and RNFL thickness were measured. An adenotonsillectomy was performed on all patients, and eye examinations and scoring were repeated after the surgery. RESULTS: Higher IOP levels were obtained between the total UAO group and the control group (p > 0.05). There were significant differences between UAO groups and the control group except for the moderate UAO group. There was no significant difference in RNFL thickness (p > 0.05) between preoperative UAO groups and the control group. However, after surgery, some significant differences emerged in the superior, inferior, and average RNFL thickness (p < 0.05). Also, IOP levels were significantly lower in the mild, moderate, and total UAO groups after the operation (p < 0.05). CONCLUSIONS: Upper airway obstruction and OSAS seem to worsen some RNFL and IOP parameters in children, and eye examinations may be useful in these patients. PMID- 26583789 TI - Non-Contact and Contact Tonometry in Corneal Edema. AB - PURPOSE: To compare the intraocular pressure (IOP) values by Goldmann applanation tonometry (GAT) and Reichert 7 CR noncontact tonometry (R7CR-NCT) in patients with postsurgical corneal edema and to examine the impact of postoperative corneal edema on these values. METHODS: Forty-six patients with grade 4 and 5 cataracts were included in this study. Intraocular pressure was measured using GAT and R7CR-NCT before and 1 day after phacoemulsification. Central corneal thickness (CCT) was determined before and after surgery to quantify postsurgical corneal edema. The R7CR-NCT provided a Goldmann-correlated IOP (IOPg) and corneal compensated IOP (IOPcc). RESULTS: The CCT increased significantly 1 day after surgery (the mean preoperative CCT, 543.5 +/- 25.4 MUm; the mean postoperative CCT, 681.5 +/- 19.8 MUm; p < 0.001), a mean increase of 26.7%. The preoperative R7CR-NCT measurements (the mean IOPcc, 18.8 +/- 5.6 mm Hg; the mean IOPg, 17.8 +/ 4.5 mm Hg) were significantly higher than GAT measurements (the mean GAT-IOP, 16.0 +/- 3.4 mm Hg) (p < 0.001). On postoperative day 1, the R7CR-NCT measurement (the mean IOPcc, 27.0 +/- 9.8 mm Hg; the mean IOPg, 25.1 +/- 8.9 mm Hg) were significantly higher than GAT measurements (the mean GAT-IOP, 18.3 +/- 7.9 mm Hg) (p < 0.001). The difference between postoperative R7CR-NCT and GAT-IOP values were significantly higher than the difference between preoperative R7CR-NCT and GAT-IOP values (p < 0.001 for both IOPcc to GAT-IOP and IOPg to GAT-IOP). The difference between postoperative IOPcc and GAT-IOP was significantly correlated to the change in CCT (r = 0.526, p < 0.001). Similarly, the difference between postoperative IOPg and GAT-IOP was significantly correlated to the change in CCT (r = 0.536, p < 0.001). CONCLUSIONS: The R7CR-NCT IOP values were high in patients with postsurgical intensive corneal edema. Consequently, the difference between R7CR-NCT IOP and GAT-IOP increased in edematous corneas. PMID- 26583790 TI - Comparison of Near Addition Value Prescription Methods for Myopic Children. AB - PURPOSE: To compare personalized near addition values for myopic children that induce a reasonable phoria (Ph) (meeting Sheard's criterion) and induce a null lag of accommodation at near and to evaluate changes in these metrics after lens adaptation. METHODS: Fifty-three myopic children participated in this study. Accommodative response, Ph, and fusional amplitudes (FAs) were measured at 33 cm through multiple addition lenses (0D, +1.00D, +1.50D, +2.00D, +2.50D, +3.00D). The adaptation effect on measured parameters was evaluated after 6 min of near work with each addition. The FA/Ph ratios were calculated for each addition and fitted using a rational function to obtain the optimal addition value satisfying Sheard's criterion (FA/Ph >= 2). Lag of accommodation change in association with addition value was assessed using linear regressions to obtain the addition values inducing a null lag. RESULTS: Lag of accommodation (r = -0.987, p < 0.001) and Ph (r = -0.999, p < 0.001) decreased linearly with addition value. The 6-min adaptation induced a small but significant increase in accommodative lag and an exophoric shift (p < 0.05). Three FA/Ph patterns with respect to addition lenses were observed based on the near Ph: orthophoria/exophoria, low esophoria, and large esophoria. Addition values based on Sheard's criterion (mean +/- SD, +2.16 +/- 0.79D) were significantly lower than those based on null lag (+2.83 +/- 0.44D, t = 19.86, p < 0.001). The FA/Ph ratio was less than 2.0 in 75.5% of subjects with additions determined through null accommodative lag. Additions determined through FA/Ph >= 2 induced a lag of accommodation of 0.38 +/- 0.42D. CONCLUSIONS: Personalized near addition values using Sheard's criterion were lower than those obtained through null lag of accommodation. These values should allow a better binocular balance especially for exophoric children. PMID- 26583791 TI - In Vitro Cholesterol Deposition on Daily Disposable Contact Lens Materials. AB - PURPOSE: The goal of this study was to analyze how various incubation times affect the uptake of cholesterol on silicone hydrogel (SH) and conventional hydrogel (CH) daily disposable (DD) contact lens materials using an in vitro radiochemical detection method. METHODS: Three SH (somofilcon A, delefilcon A, and narafilcon A) and four CH (etafilcon A, nesofilcon A, ocufilcon A, and nelfilcon A) contact lenses were incubated in an artificial tear solution that contained major tear film components and a portion of radioactive C-cholesterol. Lenses (N = 4) were incubated for four incubation times (2, 6, 12, or 16 h) to assess the effects on cholesterol deposition. Subsequent to the incubation, the lenses were extracted using 2:1 chloroform:methanol, and the extracts were analyzed in a beta counter and (in nanograms per lens) extrapolated from standard curves. RESULTS: In general, cholesterol deposited statistically significantly more on SH lenses than CHs (p <= 0.033), with the exception of somofilcon A and nesolfilcon A materials (p = 0.067). Within the SH materials, narafilcon A accumulated the largest quantity of cholesterol (p < 0.05) and somofilcon A the lowest (p < 0.05). The uptake of cholesterol ranged from 22.63 +/- 2.98 ng/lens to 97.94 +/- 4.18 ng/lens for all lens materials. The accumulation of cholesterol was shown to be continuous throughout the 16 h of incubation, without reaching a plateau (p < 0.001). CONCLUSIONS: For the periods that DD lens materials are worn, cholesterol deposits significantly more onto SH contact lenses than CHs. This could have implications for wearers who have higher levels of lipid in their tears that are fitted with SH DD materials. PMID- 26583792 TI - A Proposed Model for Integrated Low-Vision Rehabilitation Services in Canada. AB - PURPOSE: The provision and funding of low-vision rehabilitation (LVR) are very variable across Canada. Quebec is well served by 14 government-funded rehabilitation centers. In most provinces, there are no such multidisciplinary services-optometrists offer LVR from their offices to a greater or lesser degree or undertake assessments in centers run by CNIB (formerly Canadian National Institute for the Blind). No integrated model for LVR exists across Canada. This document proposes such a model, which focuses on the profession of optometry, but may also be applicable to ophthalmology. METHODS: This article describes different models of LV provision, the evidence for their relative effectiveness, the current situation in Canada, including the variability between areas and the need to increase referrals to LVR, and the current international consensus for LV provision. With the projected increase in people with LV, a generally accepted LV model for Canada is required to improve patient care. RESULTS: It has become recognized in the global community that a tiered system may be required to provide for patients who range in their visual rehabilitation needs and geographic locations. The proposed LVR model includes three levels: 1. Screening/recognition of a potential patient with LV followed by appropriate triage. All optometrists should be involved at this level. 2. Management of the patient with minimum visual impairment/disability. This level of LVR can take place in a local optometry office with a minimal of extra equipment or devices. Level 3: Comprehensive LVR for patients with more vision loss and greater disabilities. Level 3 requires collaboration with other professionals, and three mechanisms are proposed by this which may take place. CONCLUSIONS: The proposed model is expected to be useful for future education, policy decisions, and collaboration in Canada, and it may also be of interest for the development of LV services in other countries. PMID- 26583793 TI - Anterior Segment Biometry Changes with Cycloplegia in Myopic Adults. AB - PURPOSE: To determine the effect of cycloplegia on corneal thickness, corneal curvature, anterior chamber depth (ACD), angle-to-angle (ATA) and white-to-white (WTW) distances, and axial length (AL). METHODS: Changes in corneal thickness, corneal curvature, ACD, ATA and WTW distances, and AL with and without cycloplegia were analyzed in 31 eyes of 31 young myopic adults, aged 26.4 +/- 3.0 years. Pentacam was used to measure the corneal thickness, corneal volume, and corneal curvatures. Visante optical coherent tomography (OCT) measured corneal thickness, ATA distance, ACD, and pupil size. The AL and WTW distance were measured using IOLMaster. RESULTS: Cycloplegia induced significant flattening of corneal curvatures (p = 0.019, 0.001, and 0.003 for anterior sagittal, posterior tangential, and posterior sagittal curvatures, respectively). The difference in the posterior corneal curvature was greater in corneas with steeper posterior curvatures. Cycloplegia also induced significant deepening of ACD (0.08 +/- 0.06, p < 0.001) and widening of both WTW (0.42 +/- 0.43, p < 0.001) and ATA (0.08 +/- 0.17, p = 0.015) distances. The cycloplegia-related increase in the ATA distance correlated negatively with AL (r = -0.361, p = 0.046), whereas the cycloplegia related increase in WTW distance correlated weakly with the increase in ACD (r = 0.347, p = 0.056) but not with AL. The AL did not change with cycloplegia. Pentacam measured a slightly thicker cornea than OCT (p = 0.002). Both Pentacam and OCT detected a significant increase in corneal thickness of 4 MUm, which could be attributed to reflex tearing, after cycloplegia. CONCLUSIONS: Cycloplegia resulted in deeper ACD, greater ATA distance, and flatter corneal curvatures. Surgeons should be aware of these cycloplegia-related alterations for more accurate phakic/functional intraocular lens selection and better refraction results. PMID- 26583794 TI - Identification of MFRP Mutations in Chinese Families with High Hyperopia. AB - PURPOSE: Mutations in MFRP have been reported to cause autosomal recessive posterior microphthalmia, nanophthalmos, and an ophthalmic syndrome characterized by posterior microphthalmia, high hyperopia, retinitis pigmentosa, foveoschisis, and optic disc drusen. High hyperopia is a consistent sign of this syndrome. The purpose of this study was to detect MFRP mutations in 46 unrelated Chinese probands with high hyperopia. METHODS: Clinical data and genomic DNA were collected from 46 Chinese probands diagnosed as having high hyperopia. Genomic DNA from 42 probands was initially analyzed by whole exome sequencing. MFRP variants were confirmed by Sanger sequencing. The coding sequence of MFRP for four additional probands was also analyzed by Sanger sequencing. Candidate MFRP variants were further validated in available family members and 192 normal individuals. RESULTS: Potential pathogenic compound heterozygous mutations, including c.287_291del (p.P96Lfs*6), c.1615C>T (p.R539C), c.664C>A (p.P222T), c.1150dup (p.H384Pfs*8), and c.1549C>T (p.R517W), were detected in three of the 46 probands included in this study. The clinical data revealed that all patients in this study had high hyperopia of +13.50D or higher and an eye axial length of 16.78 mm or less. Electroretinography showed normal responses in a patient with missense mutations and reduced rod responses in another patient with missense and truncation mutations in whom optical coherence tomography showed developmental cystoid macular degeneration in both eyes. CONCLUSIONS: The current study expands our knowledge of the mutation spectrum of MFRP and its associated phenotypes. To our knowledge, this is the first report of MFRP mutations in a Chinese cohort. PMID- 26583795 TI - Functional Visual Acuity in Age-Related Macular Degeneration. AB - PURPOSE: We evaluated whether a functional visual acuity (FVA) system can detect subtle changes in central visual acuity that reflect pathological findings associated with age-related macular degeneration (AMD). METHODS: Twenty-eight patients with unilateral AMD and logMAR monocular best corrected VA better than 0 in both eyes, as measured by conventional chart examination, were analyzed between November 2012 and April 2013. After measuring conventional VA, FVA, and contrast VA with best correction, routine eye examinations including spectral domain-optical coherence tomography were performed. Standard Schirmer test was performed, and corneal and lens densities were measured. RESULTS: The FVA score (p < 0.001) and visual maintenance ratio (p < 0.001) measured by the FVA system, contrast VA (p < 0. 01), and conventional VA (p < 0.01) were significantly worse in the AMD-affected eyes than in the fellow eyes. No significant differences were observed in the anterior segment conditions. Forward stepwise regression analysis demonstrated that the length of interdigitation zone disruption, as visualized by optical coherence tomography imaging, correlated with the FVA score (p < 0.01) but not with any other parameters investigated. CONCLUSIONS: The FVA system detects subtle changes in best corrected VA in AMD-affected eyes and reflects interdigitation zone disruption, an anatomical change in the retina recorded by optical coherence tomography. Further studies are required to understand the value of the FVA system in detecting subtle changes in AMD. PMID- 26583796 TI - Epidemiology of Intermittent Exotropia in Preschool Children in China. AB - PURPOSE: To determine the prevalence, subtypes, and associated risk factors for intermittent exotropia (IXT) in preschool children aged 3 to 6 years in eastern China. METHODS: A population-based study including 5831 preschool children aged 3 to 6 years was conducted from 2011 to 2012 in Yuhua District, Nanjing, China, using an age-stratified random sampling procedure. Clinical examinations including ocular alignment, ocular motility, visual acuity, prism cover test, cycloplegia refraction, stereopsis screening, slitlamp examination, and fundus examination were performed by trained ophthalmologists and optometrists. Intermittent exotropia was defined as an acquired intermittent exodeviation of at least 10 prism diopters in an otherwise healthy child following the classification recommended by the National Eye Institute. RESULTS: The overall prevalence of IXT in this population was 3.24% (95% confidence interval, 2.79 to 3.69%), with no age (p = 0.19) and sex (p = 0.89) differences. Among 166 children with IXT, the "basic type" was the most common type of IXT (74.7%), the "divergence excess" was the second (19.9%), whereas the "convergence weakness" was the rarest (5.4%). In multivariate analysis adjusting for age, sex, and other confounders, the presence of IXT was only associated with a history of hypoxia at birth (odds ratio, 4.41; 95% confidence interval, 2.47 to 7.86). CONCLUSIONS: Intermittent exotropia affected approximately 1 in 30 Chinese preschool-aged children in eastern China, indicating a relatively higher burden of this pediatric eye condition in the world's most populous country. The presence of IXT was strongly associated with a history of hypoxia at birth. PMID- 26583797 TI - Atypical Exophytic Retinal Capillary Hemangioma and Diagnostic Modalities. AB - PURPOSE: Retinal capillary hemangioma (RCH) can occur in isolation or may be associated with von Hippel-Lindau disease. The classic RCH is described as a globular reddish lesion with a dilated feeding artery and a tortuous draining vein, indicative of a common endophytic growth pattern. Exophytic patterns are far more rare and, because of its subtle appearance, often missed or misdiagnosed. CASE REPORT: A 24-year-old woman presented with complaints of a mid peripheral superior field defect OS. She had no family history of von Hippel Lindau disease. Best-corrected visual acuity was 20/20 OD, OS. Dilated fundus examination of the left eye revealed a peripheral large inferotemporal retinal lesion with an overlying vascular network. Corresponding feeding and draining vasculature was not clearly noted on dilated fundus examination. Optical coherence tomography, ultrasonography, and fluorescein angiography testing were used to confirm the diagnosis of an exophytic peripheral RCH. Anti-vascular endothelial growth factor injections and cryotherapy were initiated, and the patient was scheduled for radioactive plaque brachytherapy. Genetic testing and proper scans were also recommended. CONCLUSIONS: This case illustrates an atypical exophytic peripheral RCH, rarely reported in the literature. The utilization of a variety of diagnostic modalities was highly effective, aiding in the diagnosis of this condition. PMID- 26583798 TI - Atypical Acute Posterior Multifocal Placoid Pigment Epitheliopathy. AB - PURPOSE: To report a case of acute posterior multifocal placoid pigment epitheliopathy (APMPPE) with atypical features. CASE REPORT: A 30-year-old otherwise healthy woman presented with a 7-day history of visual disturbance in her left eye. The best corrected visual acuity in her left eye was 6/36. Funduscopy revealed multiple cream-colored placoid lesions, serous macular elevation, and papillitis. Fundus fluorescein angiography revealed early hypofluorescence and late hyperfluorescence. Systemic and neurologic assessments were normal. The case shared features with both APMPPE and Harada's disease, making it a diagnostic challenge. However, APMPPE may rarely mimic Harada's disease when it manifests with atypical features, like serous retinal detachment and papillitis. The patient was managed with oral prednisolone with slow tapering. Her visual acuity improved gradually to 6/12. Neither involvement of fellow eye nor recurrence in same eye was noted for a period of 1 year. CONCLUSIONS: Acute posterior multifocal placoid pigment epitheliopathy may rarely manifest with atypical features, including papillitis and serous retinal detachment, perplexing the diagnosis and management. PMID- 26583799 TI - Biometric Changes After Trabeculectomy with Contact and Non-contact Biometry. AB - PURPOSE: To compare biometric changes measured with contact and noncontact methods after mitomycin-C-augmented trabeculectomy. METHODS: In this prospective study, 31 eyes from 31 glaucoma patients scheduled for primary trabeculectomy were enrolled. Biometric parameters including axial length (AL), anterior chamber depth (ACD), and lens thickness (LT) were measured using contact ultrasound biometry (UD-6000 Ultrasonic A/B scanner biometer; Tomey Corporation, Nagoya, Japan) and a noncontact optical biometry device (Lenstar; Haag-Streit AG, Koeniz, Switzerland). Measurements were taken the day before trabeculectomy and then compared with measurements obtained 3 and 6 months after surgery. RESULTS: The AL and ACD were significantly decreased at 3 and 6 months compared with baseline values taken with each biometry method. There was a significant increase in LT measured by the Lenstar device at the 3- and 6-month follow-up. At both the 3- and 6-month follow-up, the mean AL measurement reduction with the Lenstar device was significantly lower than that of the A-scan ultrasound measurements. The mean ACD changes between the two devices were not significantly different. CONCLUSIONS: There is a small but significant decrease in the AL and ACD after trabeculectomy as measured with both the contact and noncontact methods. The amount of AL reduction measured is significantly smaller using the noncontact method, making it the preferable method for intraocular lens power calculation for patients who need cataract surgery combined with or after trabeculectomy. The LT measured by the Lenstar device increased significantly after the operation, which can be an early sign of the progression of cataractous changes after trabeculectomy. PMID- 26583800 TI - Contact Lens Corneal Inflammatory Events in a University Population. AB - PURPOSE: To identify the contact lens-related modifiable and nonmodifiable factors associated with corneal inflammatory events (CIEs) in a university eye care center. METHODS: Contact lens-wearing undergraduate and graduate/professional students (age range, 18 to 36 years) with CIEs and contact lens wearers without complications (non-CIEs) were surveyed about their age, education level, overnight wear, brand of lens, brand of care solution, storage case age, topping-off, and lens replacement. Logistic regression was used to assess the impact of participant characteristics (demographic and behavior) and contact lens factors on the risk of a CIE. RESULTS: There were 160 participants enrolled, with 76 presenting with a CIE. Age was significant in the multivariate model (p < 0.001) as was an interaction between disinfectant and wearing schedule (p = 0.027). When daily wear (DW) and disinfectant were compared, polyquaternium 1/myristamidopropyl dimethylamine (PQ-1/MAPD) was associated with a greater risk of CIE versus peroxide (adjusted odds ratio [aOR], 18.4; 95% confidence interval [95% CI], 1.9-173.9) and versus polyhexamethylene biguanide or polyaminopropyl biguanide (PHMB) (aOR, 15.0; 95% CI, 4.5-50.0). For PHMB users only, extended wear (EW) compared with DW increased CIE risk (aOR, 10.0; 95% CI, 2.0-51.2). There was no difference in risk between EW and DW for PQ-1/MAPD (aOR, 0.8; 95% CI, 0.2, 2.6). CONCLUSIONS: The multivariate analysis suggests that younger age and the use of PQ-1/MAPD, particularly in DW, increase the risk of acquiring a CIE with soft contact lens wear in college-aged students. For PHMB users, EW compared with DW increases the risk of a CIE; but for PQ-1/MAPD users, there is no difference between EW and DW. PMID- 26583801 TI - Impact of Metformin on Exercise-Induced Metabolic Adaptations to Lower Type 2 Diabetes Risk. AB - Combining metformin with exercise has been proposed to improve glucose homeostasis. However, we primarily discuss evidence suggesting that metformin and other pharmacological agents/dietary supplements (e.g., statins, resveratol, or antioxidants) may in fact oppose exercise-induced benefits on insulin sensitivity and cardiometabolic health. We explore the novel hypothesis that attenuation of oxidative stress from exercise by these exogenous compounds blunts metabolic adaptation. PMID- 26583802 TI - Defining the metal binding pathways of human metallothionein 1a: balancing zinc availability and cadmium seclusion. AB - Metallothioneins (MTs) are cysteine-rich, metal-binding proteins that are found throughout Nature. This ubiquity highlights their importance in essential metal regulation, heavy metal detoxification and cellular redox chemistry. Missing from the current description of MT function is the underlying mechanism by which MTs achieve their proposed biological functions. To date, there have been conflicting reports on the mechanism of metal binding and the structures of the metal binding intermediates formed during metalation of apoMTs. The form of the metal-bound intermediates dictates the metal sequestering and metal-donating properties of the protein. Through a detailed analysis of spectral data from electrospray ionization mass spectromeric and circular dichroism methods we report that Zn(ii) and Cd(ii) metalation of the human MT1a takes place through two distinct pathways. The first pathway involves formation of beaded structures with up to five metals bound terminally to the 20 cysteines of the protein via a noncooperative mechanism. The second pathway is dominated by the formation of the four-metal domain cluster structure M4SCYS11via a cooperative mechanism. We report that there are different pathway preferences for Zn(ii) and Cd(ii) metalation of apo-hMT1a. Cd(ii) binding follows the beaded pathway above pH 7.1 but beginning below pH 7.1 the clustered (Cd4Scys11) pathway begins to dominate. In contrast, Zn(ii) binding follows the terminal, "beaded", pathway at all physiologically relevant pH (pH >= 5.2) only following the clustered pathway below pH 5.1. The results presented here allow us to reconcile the conflicting reports concerning the presence of different metalation intermediates of MTs. The conflict regarding cooperative versus noncooperative binding mechanisms is also reconciled with the experimental results described here. These two metal-specific pathways and the presence of radically different intermediate structures provide insight into the multi-functional nature of MT: binding Zn(ii) terminally for donation to metalloenzymes and sequestering toxic Cd(ii) in a cluster structure. PMID- 26583805 TI - Suspensions of carbon nanofibers in organic medium: rheo-electrical properties. AB - The nonaqueous suspensions of carbon nanofibers (CNFs) in 1 M lithium bis(trifluoromethanesulfonaimide) in propylene carbonate electrolyte reveal unique structural evolution and shear-induced transition due to the high aspect ratio. The rheo-electrical behavior elucidates a microstructural transition from entangled-to-aggregated networks above a distinct percolation threshold. Under shear flow, both networks show a three-regime flow curve and an inverted-bell like conductivity curve as a consequence of shear-induced alignment (entangled network) and shear-induced breaking up (aggregated network). The different particle morphology of carbon nanofibers (anisometric) and carbon black (CB; isometric) causes different aggregation mechanisms (aggregate vs. particulate) and then varied microstructure for their suspensions in the same electrolyte. This fact explains the higher rigidity and lower electric conductivity of CNFs than CB suspensions. Interestingly, the suspension of hybrid carbons at the optimum mixing ratio merges the advantages of both carbons to operate efficiently as precursors in the formulation of electrodes for energy storage systems. PMID- 26583803 TI - Neuroblastomas vary widely in their sensitivities to herpes simplex virotherapy unrelated to virus receptors and susceptibility. AB - Although most high-risk neuroblastomas are responsive to chemotherapy, relapse is common and long-term survival is < 40%, underscoring the need for more effective treatments. We evaluated the responsiveness of 12 neuroblastoma cell lines to the Deltagamma134.5 attenuated oncolytic herpes simplex virus (oHSV), Seprehvir (HSV1716), which is currently used in pediatric phase I trials. We found that entry of Seprehvir in neuroblastoma cells is independent of the expression of nectin-1 and the sum of all four known major HSV entry receptors. We observed varying levels of sensitivity and permissivity to Seprehvir, suggesting that the cellular anti-viral response, not virus entry, is the key determinant of efficacy with this virus. In vivo, we found significant anti-tumor efficacy following Seprehvir treatment, which ranged from 6/10 complete responses in the CHP-134 model to a mild prolonged median survival in the SK-N-AS model. Taken together, these data suggest that anti-tumor efficacy cannot be solely predicted based on in vitro response. Whether or not this discordance holds true for other viruses or tumor types is unknown. Our results also suggest that profiling the expression of known viral entry receptors on neuroblastoma cells may not be entirely predictive of their susceptibility to Seprehvir therapy. PMID- 26583806 TI - Experimental studies on the rheology of cubic blue phases. AB - We report detailed experimental studies on the rheology of cubic blue phases. We observe several flow regimes within each blue phase from rheomicroscopy and small angle light scattering experiments. Both the cubic blue phases exhibit solid-like response while the cholesteric phase shows gel-like behavior. The elastic modulus of BP-I is larger than that of BP-II. The shear induced yield transition occurs at a higher strain in BP-II than BP-I. Both the blue phases show stress relaxation through periodic modulation in step-strain experiments. Our results show that the rheological responses of these two phases are significantly different owing to the distinct networks of defect-disclinations. PMID- 26583804 TI - rAAV-mediated overexpression of sox9, TGF-beta and IGF-I in minipig bone marrow aspirates to enhance the chondrogenic processes for cartilage repair. AB - Administration of therapeutic gene sequences coding for chondrogenic and chondroreparative factors in bone marrow aspirates using the clinically adapted recombinant adeno-associated virus (rAAV) vector may provide convenient, single step approaches to improve cartilage repair. Here, we tested the ability of distinct rAAV constructs coding for the potent SOX9, transforming growth factor beta (TGF-beta) and insulin-like growth factor I (IGF-I) candidate factors to modify marrow aspirates from minipigs to offer a preclinical large animal model system adapted for a translational evaluation of cartilage repair upon transplantation in sites of injury. Our results demonstrate that high, prolonged rAAV gene transfer efficiencies were achieved in the aspirates (up to 100% for at least 21 days) allowing to produce elevated amounts of the transcription factor SOX9 that led to increased levels of matrix synthesis and chondrogenic differentiation and of the growth factors TGF-beta and IGF-I that both increased cell proliferation, matrix synthesis and chondrogenic differentiation (although to a lower level than SOX9) compared with control (lacZ) condition. Remarkably, application of the candidate SOX9 vector also led to reduced levels of hypertrophic differentiation in the aspirates, possibly by modulating the beta catenin, Indian hedgehog and PTHrP pathways. The present findings show the benefits of modifying minipig marrow concentrates via rAAV gene transfer as a future means to develop practical strategies to promote cartilage repair in a large animal model. PMID- 26583808 TI - Macrophages, Inflammation, and Lung Cancer. AB - Lung cancer is the leading cause of cancer mortality worldwide, and at only 18%, it has one of the lowest 5-year survival rates of all malignancies. With its highly complex mutational landscape, treatment strategies against lung cancer have proved largely ineffective. However with the recent success of immunotherapy trials in lung cancer, there is renewed enthusiasm in targeting the immune component of tumors. Macrophages make up the majority of the immune infiltrate in tumors and are a key cell type linking inflammation and cancer. Although the mechanisms through which inflammation promotes cancer are not fully understood, two connected hypotheses have emerged: an intrinsic pathway, driven by genetic alterations that lead to neoplasia and inflammation, and an extrinsic pathway, driven by inflammatory conditions that increase cancer risk. Here, we discuss the contribution of macrophages to these pathways and subsequently their roles in established tumors. We highlight studies investigating the association of macrophages with lung cancer prognosis and discuss emerging therapeutic strategies for targeting macrophages in the tumor microenvironment. PMID- 26583809 TI - Enhancement of T(c) in the atomic phase of iodine-doped hydrogen at high pressures. AB - The high-pressure structures and superconductivity of iodine-doped hydrogen have been studied by ab initio calculations. Above 100 GPa, we discover a stable phase with Pnma symmetry in the H2I stoichiometry that consists of a monatomic iodine tube trapping hydrogen molecular units. Interestingly, H2 molecular units dissociate and form a novel atomic phase with R3m symmetry at 246 GPa. Further electron-phonon coupling calculations predict the critical temperature of superconductivity T(c) to be 3.8 K for the Pnma phase and 33 K for the R3m phase at 240 GPa. Significantly, the T(c) of the R3m phase is enhanced approximately 8 times that of the Pnma phase, which is mainly attributed to the reason that H2 molecules are broken exhibiting an atomic character in the R3m phase. PMID- 26583810 TI - AAGBI recommendations for standards of monitoring during anaesthesia and recovery 2015 - a further example of 'aggregation of marginal gains'. PMID- 26583811 TI - Vitrectomy for Proliferative Diabetic Retinopathy: Does Anyone Know the Complication Rate? PMID- 26583815 TI - [40-year old patient with strongly distended abdomen and diarrhea]. PMID- 26583816 TI - [Progress in cardiovascular therapy - surgery or intervention?]. PMID- 26583817 TI - [Indications for surgery for valvular heart disease]. AB - Due to the demographic change, chronic valvular heart disease becomes increasingly important - especially age-related primary diseases of the aortic and mitral valve as well as secondary diseases of the mitral and tricuspid valve caused by other age-related cardiac disorders. Medical treatment is limited to symptom relief by use of diuretics. Specific drugs or drugs with a prognostic benefit are not available. Thus, valve repair or replacement are the key options for treatment of relevant valvular heart disease. While open heart surgery was the only approach for a long time, interventional, catheter-based therapies have evolved in the last decade. This article describes up-to-date recommendations on indications for surgery for the most prevalent valvular heart diseases in adults aortic stenosis, and aortic, mitral and tricuspid regurgitation). PMID- 26583818 TI - [Stable coronary heart disease - when is bypass surgery appropriate?]. AB - Medical treatment is the therapeutic cornerstone in patients with stable coronary artery disease (SCAD). Although an increasing number of these patients is treated with percutaneous interventions (PCI), bypass surgery remains an important therapeutic option. Bypass surgery improves the prognosis of patients with complex coronary anatomy as compared to PCI. Modern surgical techniques lead to a considerable reduction of the invasiveness of the operation. PMID- 26583819 TI - [Established Indications for Invasive Treatment of Thoracic Aortic Aneurysm]. AB - Thoracic aortic aneurysms are associated with high morbidity and mortality due to rupture and dissection. Conservative medical treatment is associated with a 5 year survival rate of 13 %. This rises to 70-79 % in case of surgical treatment. While classical surgical strategies still dominate the care for acute and chronic pathology of the ascending aorta and the proximal arch region, new endovascular concepts are emerging and are likely to evolve as primary treatment strategies for descending aortic pathology in suitable patients. PMID- 26583820 TI - [Fine needle aspiration of peripheral lymph nodes]. AB - Fine needle aspiration of peripheral lymph nodes is a minimal invasive procedure to extract material for cytological analyses. The method is safe, rapidly to apply, less expensive and almost painless for the patient. The puncture of low lying lymph nodes shoud be performed via ultrasound navigation. PMID- 26583821 TI - [Pregabalin as a rare cause of liver disease]. AB - In this report we describe a patient who developed liver failure due to new administration of pregabaline. HISTORY AND ADMISSION FINDINGS: A 76-year old woman was admitted with a sacral fracture after conservative treatment in a trauma surgery ward for further rehabilitative treatment. INVESTIGATIONS: At admittance the patient complaint of lower back pain. Physical examination revealed unsteadiness in walking tests. Laboratory tests revealed mildly elevated infection parameters (CRP 0.67 mg / dl) and alkaline phosphatase (191U / I). TREATMENT AND COURSE: Physical training was initiated. Multimodal therapy for pain was continued with tilidin / naloxon, which had been started at the trauma surgery ward. Due to persistent pain and its radicular nature additional pregabaline treatment was initiated. Ten days thereafter the patient developed nausea without vomiting and subsequently (day 15) jaundice. Blood examination revealed elevated liver enzymes (ALT 246U / I, AST 86U / I, GGT 2068U / I and bilirubine 6 mg / dl). Abdominal sonography and MRCP were normal. After discontinuation of pregabaline treatment nausea disappeared within several days and liver enzymes declined to normal values within several weaks. CONCLUSION: Pregabaline should be taken into account as cause of acute liver failure. PMID- 26583822 TI - [Can water be poisonous?]. AB - HISTORY AND ADMISSION FINDINGS: Two female patients aged over 80 years developed central nervous symptoms after drinking large amounts of water (more than 3 l per day). INVESTIGATIONS: Both had a hypoosmolar hyponatremia that was induced by concomitant treatment with hydrochlorothiazid (HCT) in the one case and in the other case relied on a distal tubular damage due to reflux nephropathy. DIAGNOSIS, TREATMENT AND COURSE: Hyponatremia was corrected after withdrawal of HCT and fluid restriction and central nervous symptoms disappeared rapidly. CONCLUSIONS: Distal tubular urinary dilution can be disturbed by HCT and parenchymal renal disease and can result in symptomatic hyponatremia after drinking large amounts of water. PMID- 26583823 TI - [Update: chronic inflammatory bowel disease]. AB - Crohn's disease and ulcerative colitis are the major entities of inflammatory bowel diseases (IBD). IBD is a clinical diagnosis, which is supported by endoscopic, histologic, radiologic, sonographic and laboratory findings. IBD are not restricted to the GI-tract but are instead systemic diseases that often involve extra-intestinal manifestations. Aim of the rational medical therapy is the induction and maintenance of a steroid-free remission. The medical therapy depends on the severity, activity and extent of disease as well as the disease course of the patient. There is the dire necessity for an individualized therapeutic concept as the natural disease course differs between the patients. PMID- 26583824 TI - [Ethics in the emergency care of geriatric patients - when is enough enough?]. PMID- 26583825 TI - [Recent antibiotic use in German acute care hospitals - from benchmarking to improved prescribing and quality care]. AB - BACKGROUND: In view of increasing rates of bacterial resistance and Clostridium difficile infections efforts to enhance appropriate and intelligent antibiotic prescribing have become important. A prerequisite is the availability of reliable antibiotic use data. So far antibiotic consumption data in this country had only a very limited coverage of acute care hospitals. METHODS: We obtained drug dispensing data from 109 German acute care hospital pharmacies and calculated yearly antibiotic use density values stratified for hospital size and type of service / department. Antibiotic use density was expressed as daily doses per 100 patient days (occupied bed days). For daily dose definition, both hospital adapted doses of antibiotics ("recommended daily dose", RDD) as well as the official WHO-defined daily doses (DDD) were used. RESULTS: The overall antibiotic use density was 43.5 RDD/100 patient days (median) with an interquartile range of 36-48 RDD/100 - corresponding to a median of 64.4 DDD/100 (interquartile range, 53-73 DDD/100). The antibiotic use levels in university hospitals were higher than in non-university hospitals that, in turn, showed similar antibiotic use density values across different hospital size categories. Antibiotic use density values for intensive care units were approximately twice as high as for normal wards but the proportion of antibiotic doses prescribed in intensive care per hospital-wide consumption was only 12 % (non-university hospitals) to 18 % (university hospitals). Extensive antibiotic use was also observed in university hospital hematology-oncology departments. Overall, cephalosporins were used slightly more frequently than penicillins, and fluoroquinolones were the third most frequently prescribed drug class. The proportion of first and second generation cephalosporins, and of third and fourth generation cephalosporins ranged between 5-37 % and between < 1 to 29 % of all dispensed antibiotic doses across the hospitals, respectively. The top five used drugs were cefuroxime, piperacillin-tazobactam, ceftriaxon, metronidazole und ciprofloxacin. CONCLUSIONS: Prescribing of antibiotics on almost every second day of hospitalization was extensive and highly variable, and the frequent use of cephalosporins is noteworthy. It is possible that the development of resistance and the rate of Clostridium difficile infection is associated with the diverse antibiotic use intensity and preferences for prescribing of cephalosporins and fluoroquinolones. Continuous antibiotic use surveillance and evaluation of prescribing patterns in acute care with feedback and benchmarking will help optimizing antibiotic use and better assessing strategies to minimize resistance and Clostridium difficile infection, and eventually improve patient safety. PMID- 26583826 TI - [Risk-adapted anticoagulation in atrial fibrillation in Germany, Austria and Switzerland - an analysis from the PREFER-in-AF study]. AB - BACKGROUND: The management of patients with atrial fibrillation (AF) has substantially improved in recent years, among others due to the introduction of new risk scores for the stratification of patients, as well as the availability of the non-vitamin K oral antagonists (NOAC). The PREFER-in-AF study aimed to document the management of AF patients with particular focus on stroke prevention on the basis of anticoagulants. METHODS AND RESULTS: In Germany, Austria and Switzerland a total of 1771 patients were enrolled between January 2012 and January 2013 (mean age 71.9 +/- 9.2 years; 63 % males).At inclusion, the mean time since AF diagnosis was 4.8 +/- 5.3 years. Paroxysmal AF was present in 30.7 %, persistent in 11 %, long standing persistent in 4.7 % and permanent AF in 53.3 % of the patients. 25.1 % of the Patients were in sinus rhythm. Mean CHA2DS2-VASc Score was 3.7 +/- 1.8 points (0 points in 3.0 %, 1 point in 7.1 %, >= 2 points in 89.9 %).For the prevention of thromboembolic events 68.1 % of patients received vitamin K antagonists (VKA, mainly phenprocoumon), 11.6 % received a NOAC (mainly rivaroxaban or dabigatran), 7.6 % an antiplatelet agent, and 7.7 % a combination of VKA plus an antiplatelet agent. 5.0 % of patients did not receive any anticoagulant. During the 12 months prior to inclusion, interruption of VKA therapy due to an interventions was reported in 29.7 %. In the group of patients with known INR values and available CHA2DS2-VASc score, 75.1 % were adequately controlled (defined as at least 2 of 3 INR values in the range of 2.0 3.0).Bleeding propensity or bleedings in patient history were reported for 5.1 % of the patients, hospitalizations due to major bleeding events in the past 12 months for 1.9 %. Possible risk factors associated with anticoagulation were present in 76.7 %. Mean HAS-BLED score was 2.1 +/- 1.1 points. CONCLUSION: The rates of AF patients who received oral anticoagulation were about 90 % and substantially higher compared to previous observational studies. NAOCs were administered to 11.7 % of patients. PMID- 26583827 TI - A Review of the Accuracy and Utility of Motion Sensors to Measure Physical Activity of Frail, Older Hospitalized Patients. AB - The purpose of this review was to examine the utility and accuracy of commercially available motion sensors to measure step-count and time spent upright in frail older hospitalized patients. A database search (CINAHL and PubMed, 2004-2014) and a further hand search of papers' references yielded 24 validation studies meeting the inclusion criteria. Fifteen motion sensors (eight pedometers, six accelerometers, and one sensor systems) have been tested in older adults. Only three have been tested in hospital patients, two of which detected postures and postural changes accurately, but none estimated step-count accurately. Only one motion sensor remained accurate at speeds typical of frail older hospitalized patients, but it has yet to be tested in this cohort. Time spent upright can be accurately measured in the hospital, but further validation studies are required to determine which, if any, motion sensor can accurately measure step-count. PMID- 26583828 TI - Intracapsular and Extracapsular Tonsillectomy and Adenoidectomy in Pediatric Obstructive Sleep Apnea. AB - IMPORTANCE: Limited information exists regarding clinical outcomes of children undergoing extracapsular tonsillectomy and adenoidectomy (ETA) or intracapsular tonsillectomy and adenoidectomy (ITA) for treatment of obstructive sleep apnea syndrome (OSAS). OBJECTIVES: To quantify polysomnography (PSG) and clinical outcomes of ETA and ITA in children with OSAS and to assess the contribution of comorbid conditions of asthma and obesity. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study using medical records at a tertiary pediatrics inner city hospital. Medical records from 89 children who underwent ETA or ITA between October 1, 2008, and December 31, 2013, were analyzed. The dates of our analysis were January 6, 2014, to April 11, 2014. Inclusion criteria required no evidence of craniofacial or neurological disorders, confirmation of OSAS by PSG within the 2 years before surgery, and a second PSG within the 2 years after surgery. INTERVENTIONS: Each child underwent ETA or ITA after being evaluated by a pediatric otolaryngologist and obtaining written parental informed consent. MAIN OUTCOMES AND MEASURES: Main primary outcomes were derived from PSG. Secondary outcomes included treatment failure, defined as residual OSAS with an obstructive apnea-hypopnea index of at least 5 events per hour. Comparisons were made between and within groups. Logistic regression was used to identify factors associated with treatment failure. RESULTS: Fifty-two children underwent ETA, and 37 children underwent ITA. Children in the ETA group were older (7.5 vs 5.2 years, P = .001) and more obese (60% [31 of 52] vs 30% [11 of 37], P = .004). However, both groups had similar severity of OSAS, with median preoperative obstructive apnea-hypopnea indexes of 17.0 in the ETA group and 24.1 in the ITA group (P = .21), and similar prevalences of asthma (38% [20 of 52] vs 38% [14 of 37]). After surgery, significant improvement was noted on PSG in both groups, with no differences in any clinical outcomes. There was no association between procedure type, age, or body mass index z score and treatment failure. However, in a subset of patients with asthma and obesity, ITA was associated with residual OSAS (odds ratio, 16.5; 95% CI, 1.1-250.2; P = .04). CONCLUSIONS AND RELEVANCE: Both ETA and ITA are effective modalities to treat OSAS, with comparable surgical outcomes on short-term follow-up. However, when comorbid diagnoses of both asthma and obesity exist, OSAS is likely to be refractory to treatment with ITA compared with ETA. PMID- 26583830 TI - Mesoscopic perovskite solar cells with an admixture of nanocrystalline TiO2 and Al2O3: role of interconnectivity of TiO2 in charge collection. AB - Perovskite solar cells with high power conversion efficiency usually employ mesoporous TiO2, however the role of the TiO2 layer has not been clearly resolved. Here we prepared MAPbI3 (MA = CH3NH3) perovskite solar cells with an admixture of nanocrystalline TiO2 and Al2O3 to investigate the role of the mesoporous TiO2 layer. The Al2O3 content was varied from 0% (pure TiO2) to 100% (pure Al2O3) with nominal composition of (1 - x)TiO2 + xAl2O3 (x = 0, 0.25, 0.5, 0.75 and 1). The photocurrent density and fill factor decreased as Al2O3 content increased, whereas the open-circuit voltage was hardly changed. Steady-state photoluminescence (PL) was less quenched as the Al2O3 content increased due to its non-electron-injecting characteristics, where a decrease in PL intensity with increasing TiO2 content was correlated to an increase in photocurrent. Electron injection to TiO2 was also evidenced by time-resolved PL and time-limited photocurrent measurements, where interconnection of TiO2 particles played an important role in charge collection. The slight change in voltage with Al2O3 content was explained by balancing the Fermi position due to a trade-off between charge recombination and the Fermi level. The results observed from the admixture mesoporous layer comprising electron-injecting and electron-non-injecting oxides suggest that electron-injection characteristics play an important role in determining photovoltaic parameters. PMID- 26583829 TI - Kinetics of Serologic Responses to MERS Coronavirus Infection in Humans, South Korea. AB - We investigated the kinetics of serologic responses to Middle East respiratory syndrome coronavirus (MERS-CoV) infection by using virus neutralization and MERS CoV S1 IgG ELISA tests. In most patients, robust antibody responses developed by the third week of illness. Delayed antibody responses with the neutralization test were associated with more severe disease. PMID- 26583831 TI - Use of Capture-Recapture to Estimate Underreporting of Ebola Virus Disease, Montserrado County, Liberia. PMID- 26583832 TI - When biochemistry meets mechanics: a systems view of growth control in plants. AB - The emergence of complex shapes during the development of plants is under the control of genetically determined molecular networks. Such regulatory networks, comprising hormones and transcription factors, regulate the collective behavior of cell growth within a tissue. Because all the cells within a tissue are linked together by the cell wall, their collective growth generates a good amount of mechanical stress. In the last few years a compelling amount of evidence has shown that growth-generated mechanical stress can feed back on plant developmental programs by modifying cell growth. This involves primarily responses from the microtubules and interaction with auxin transport and signaling. Here we discuss the most recent advances in the understanding of mechanical feedbacks in plant development. PMID- 26583833 TI - 7-Hydroxyflavone Revisited. 2. Substitution Effect on Spectral and Acid-Base Properties in the Ground and Excited States. AB - Three derivatives of 7-hydroxy-2-phenyl-4H-chromen-4-one (7-hydroxyflavone), containing chloro, methoxy, and dimethylamino substituents at position 4', were synthesized and investigated from the view of their ground-state and electronically excited-state behavior. Spectral and fluorescent properties in a wide range of pH/H0, thermodynamics of the ground and S1 states, and kinetics of the excited-state deactivation of the compounds were investigated by means of steady-state electronic absorption, steady-state, and time-resolved fluorescent spectroscopies as well as by computational methods. The results are rationalized from the point of view of the substituent effect. In spite of a similar structure and the same acid-base centers, the compounds strongly differ in fluorescence characteristics as well as in the dependence of fluorescent properties on pH/H0 of the media. Various protolytic/tautomeric forms of the compounds investigated absorb light in the 300-500 nm range and fluoresce in the whole visible range of spectra. The electron-releasing substituents at position 4' of 7-hydroxyflavone immensely affect spectral properties as well as the excited-state thermodynamics and kinetics, whereas the electron-withdrawing ones cause minimal effect. PMID- 26583834 TI - Predictors of surgical outcome in ossification of the posterior longitudinal ligament. AB - STUDY DESIGN: A retrospective study. OBJECTIVE: To clarify the predictors of the operation results for ossification of the posterior longitudinal ligament (OPLL). SUMMARY OF BACKGROUND DATA: Detailed analyses of surgical outcomes of OPLL have been rare because most survey aimed to investigate cervical spondylotic myelopathy. METHODS: All patients who underwent cervical operation for OPLL between January 2011 and December 2011 were included in this analysis. We investigated the patients' characteristics and surgical approaches, and compared the radiographical characteristics of OPLL. RESULTS: The mean mJOA score improved from 8.312 +/- 3.021 points preoperatively to 11.24 +/- 3.43 points at 24 months after operation (P<0.001). The average change in mJOA score was significantly greater in patients with a higher Nirik score than in those with lower Nirik scores (P<0.0001). The average change in mJOA score was also significantly different in patients with trauma history (P<0.0001). The average recovery ratio was 42 +/- 26.3% in young patients and 30 +/- 31.6% in the group older than 50 years (P=0.012). The average recovery ratio in patients with acute and chronic symptoms was 48 +/- 22.9% and 26 +/- 33.9%, respectively. There was great difference between the two groups. CONCLUSION: OPLL patients with myelopathy would receive good result after the operation. Age and symptom duration are related to the surgical outcomes. Patients with lower Nirick grade and without trauma history would receive better results before and after the operation. PMID- 26583835 TI - Endoscopic lumbar discectomy under local anesthesia may be an alternative to microdiscectomy: A single centre's experience using the far lateral approach. AB - OBJECTIVES: Since the turn of the century, minimally invasive surgery has become increasingly widespread. Discectomy surgery has evolved from wide open to microscopic and now endoscopic. This study aims to demonstrate that transforaminal endoscopic discectomy is an alternative and safe approach for degenerative disk surgery. PATIENTS AND METHODS: Two year retrospective assessments of patients who underwent transforaminal endoscopic discectomy at a tertiary neurosurgical center in the United Kingdom by a single surgeon. Under strict confidentiality, data was collected from online patient data and PACS systems. Patient feedback was achieved using phone call follow up and clinic appointments. Standard statistical analysis was performed. RESULTS: 201 patients had endoscopic discectomy and the mean age was 41 years. Male:female ratio was 1.3:1.0. Mean time of onset of symptoms was 5.5 months and the most common level was L4/5 (53%). All endoscopic discectomies were performed under local anesthesia. Theater time was on average 110 min. 10 patients were lost to follow up. 95% of patients were discharged within 7h post operatively. Visual acuity score of the pain dropped from an average of 7/10 pre-operatively to 0-1/10 in 95% of patients two weeks post operatively. 87% patients went back to their normal daily activities within two weeks. There were no cases of CSF leak, hematoma formation or wound infection. 1% of patients developed a nerve root injury. 6% of patients had recurrent herniation and require microdiscectomy. CONCLUSION: Endoscopic discectomy can be an alternative approach to microdiscectomy. While it can take more expertise to perform endoscopic discectomy, our data shows that the far lateral endoscopic discectomy using the TESSYS technique has comparable outcomes to microdiscectomy. PMID- 26583836 TI - Sindbis and Middelburg Old World Alphaviruses Associated with Neurologic Disease in Horses, South Africa. AB - Old World alphaviruses were identified in 52 of 623 horses with febrile or neurologic disease in South Africa. Five of 8 Sindbis virus infections were mild; 2 of 3 fatal cases involved co-infections. Of 44 Middelburg virus infections, 28 caused neurologic disease; 12 were fatal. Middelburg virus likely has zoonotic potential. PMID- 26583837 TI - Cyclization of N-Arylacrylamides via Radical Arylsulfenylation of Carbon-Carbon Double Bonds with Sulfonyl Hydrazides. AB - An unprecedented tandem radical sulfenylation/cyclization reaction of N arylacrylamides with sulfonyl hydrazides has been developed in the presence of iodine for the selective synthesis of 3-(sulfenylmethyl)oxindoles and 3-sulfenyl 3,4-dihydroquinolin-2(1H)-ones. Preliminary mechanistic studies showed that sulfonyl hydrazides decomposed completely at an early stage to thiosulfonates and disulfides, both of which underwent tandem radical sulfenylation/cyclization with N-arylacrylamides at a late stage. PMID- 26583838 TI - Haemodynamic characterisation and heart catheterisation complications in children with pulmonary hypertension: Insights from the Global TOPP Registry (tracking outcomes and practice in paediatric pulmonary hypertension). AB - BACKGROUND: The TOPP Registry has been designed to provide epidemiologic, diagnostic, clinical, and outcome data on children with pulmonary hypertension (PH) confirmed by heart catheterisation (HC). This study aims to identify important characteristics of the haemodynamic profile at diagnosis and HC complications of paediatric patients presenting with PH. METHODS AND RESULTS: HC data sets underwent a blinded review for confirmation of PH (defined as mean pulmonary arterial pressure >= 25 mmHg, pulmonary capillary wedge pressure <= 12 mmHg and pulmonary vascular resistance index [PVRI] of >3 WU * m(2)). Of 568 patients enrolled, 472 who fulfilled the inclusion criteria and had sufficient data from HC were analysed. A total of 908 diagnostic and follow-up HCs were performed and complications occurred in 5.9% of all HCs including five (0.6%) deaths. General anaesthesia (GA) was used in 53%, and conscious sedation in 47%. Complications at diagnosis were more likely to occur if GA was used (p=0.04) and with higher functional class (p=0.02). Mean cardiac index (CI) was within normal limits at diagnosis when analysed for the entire group (3.7 L/min/m(2); 95% confidence interval 3.4-4.1), as was right atrial pressure despite a severely increased PVRI (16.6 WU * m(2,) 95% confidence interval 15.6-17.76). However, 24% of the patients had a CI of <2.5L/min/m(2) at diagnosis. A progressive increase in PVRI and decrease in CI was observed with age (p<0.001). CONCLUSION: In TOPP, haemodynamic assessment was remarkable for preserved CI in the majority of patients despite severely elevated PVRI. HC-related complication incidence was 5.9%, and was associated with GA and higher functional class. PMID- 26583840 TI - Brugada phenocopy in percutaneous coronary intervention of the right coronary artery. PMID- 26583839 TI - History of anxiety and/or depression in patients with Takotsubo syndrome: A need for further exploration. PMID- 26583841 TI - Left ventricular volume predicts exercise capacity in hypertrophic cardiomyopathy. PMID- 26583842 TI - Percutaneous transcatheter obliteration of mitral prosthetic paravalvular leaks. PMID- 26583843 TI - Preoperative hepatic dysfunction could predict postoperative mortality and morbidity in patients undergoing cardiac surgery: Utilization of the MELD scoring system. AB - BACKGROUND: According to recent advances in operative techniques, an increasing number of patients with liver dysfunction have been subjected to cardiac surgery. Model of End-Stage Liver Disease (MELD and MELD-XI) scores allow risk stratification of patients undergoing cardiac and non-cardiac surgeries. METHODS: We retrospectively analyzed 1856 consecutive patients (69.3% male, mean 66.8 +/- 12.2 years) undergoing cardiac surgery between 2008 and 2013 at our institution. RESULTS: The mean values of MELD/MELD-XI scores obtained from the total cohort were 9.7 +/- 4.6/11.9 +/- 4.8. Patients with high MELD/MELD-XI scores (>12) were older, more anemic, and had lower left ventricular ejection fraction than those with low scores (all p<0.0001). High scores were associated with longer hospitalization (36.8 +/- 33.0 vs. 23.6 +/- 21.5 days for MELD, 36.7 +/- 34.0 vs. 23.5 +/- 21.0 days for MELD-XI, both p<0.0001) and higher in-hospital all-cause mortality (6.6% vs. 1.0% for MELD, 7.7% vs. 0.7% for MELD-XI). Atrial fibrillation occurred more frequently in the high MELD group, but this difference was not found for MELD-XI. MELD/MELD-XI could predict mortality with a sensitivity of 64.3%/60.0% and specificity of 79.1%/85.3%. Comparison of AUC values among MELD scores, individual MELD components, and Child-Turcotte-Pugh (CTP) classification showed that the predictive strength of MELD scores for mortality was stronger than individual parameters or CTP classification (AUC: 0.7702 for MELD, 0.7655 for MELD-XI, 0.5799 for CTP classification with pairwise p<0.0001 and p=0.0002 vs. MELD and MELD-XI, respectively). CONCLUSIONS: Assessment of liver dysfunction using the MELD scores can be useful for predicting postoperative morbidity and mortality, which may allow additional risk stratification in patients undergoing cardiac surgery. PMID- 26583844 TI - Treatment of drug-eluting stents in-stent restenosis with paclitaxel-coated balloon angioplasty: Insights from the French "real-world" prospective GARO Registry. AB - BACKGROUND: Data about paclitaxel-eluting balloon (PCB) angioplasty to treat drug eluting stents (DES) in-stent restenosis (ISR) were mainly collected in selected patient populations in the setting of randomized trials. The main goal of this prospective registry was to confirm the positive findings of these studies in an unselected population in clinical practice. METHODS: Consecutive patients with DES-ISR treated by PCB angioplasty were recruited in this prospective real-world registry. The primary endpoint was clinically driven target-lesion revascularization (TLR) at 9 months. Secondary endpoints included acute technical success, in-hospital outcomes, 9-month major adverse cardiac events (MACE) a composite of death, myocardial infarction (MI) and TLR and the occurrence of target vessel revascularization. RESULTS: A total of 206 patients (67.7 +/- 10.2 years, 80.6% male, 41.3% diabetics) with 210 lesions were recruited. Unstable coronary artery disease was present in 55.3% of patients. The time from DES implantation to DES-ISR was 3.0 +/- 2.4 years. Quantitative analyses revealed that patterns of treated DES-ISR were focal in 55.7% and diffuse in 44.3%. The reference diameter was 2.76 +/- 0.64 mm. The 9-month follow-up rate was 90.8% (187/206). At 9 months, the TLR rate was 7.0% (13/187) whereas the rates for MACE, MI and cardiac death were 10.7% (20/187), 4.8% (9/187) and 2.1% (4/187) respectively. Results were consistent in patients with paclitaxel and non paclitaxel-eluting stents (PES) ISR. CONCLUSION: This large prospective registry demonstrated acceptable rates of TLR and MACE at 9 months after treatment of DES ISR by PCB angioplasty. PCB angioplasty was equally effective in patients with PES-ISR and non PES-ISR. PMID- 26583845 TI - Short and long-term survival after primary percutaneous coronary intervention in young patients with ST-elevation myocardial infarction. AB - The long-term prognosis of patients with ST-elevation myocardial infarction (STEMI) aged 45 years or younger and differences according to gender have not been well characterized. METHODS: We included 16,685 consecutive STEMI patients from 2003 to 2012 (67,992 patient-years follow-up) from the Eastern Danish Heart Registry and the Swedish Coronary Angiography and Angioplasty Registry who were treated with primary percutaneous coronary intervention (PCI). RESULTS: We identified 1026 (6.2%) patients up to 45 years of age (mean age: 40.7 vs. 66.3 years, P<0.001). Patients in the young group were predominantly men (79.7% vs. 71.9%) and smokers (71.2% vs. 44.2%, P<0.001) but with a lower prevalence of hypertension (17.3% vs. 39.3%), hyperlipidemia (18.0% vs. 23.8%), diabetes (9.0% vs. 12.4%) and previous myocardial infarction (6.9% vs. 12.2%, all P<0.001) compared with older patients. Young patients had a 0.8% annual mortality. During the follow-up period 6.3% of young patients died vs. 28.5% of older patients (P<0.001). Both 30-day-mortality (adjusted hazard ratio [HR]=0.26, 95% confidence interval [CI]: 0.12-0.54, P<0.001) and mortality after 30 days and onwards (HR=0.25, CI: 0.17-0.37, P<0.001) were significantly lower in the young group. There was no difference in short-term (HR=0.78, CI: 0.32-1.90, P=0.59) or long term (HR=0.62, CI: 0.33-1.91, P=0.59) mortality between women and men in the young group (HR=0.79, CI: 0.21-1.80, P=0.39). CONCLUSIONS: STEMI patients, aged 45 years or younger, have an excellent prognosis after treatment with primary PCI. Long-term annual survival is more than 99% in these patients. Young women with STEMI do not have a worse long-term prognosis than young men with STEMI. PMID- 26583846 TI - Pin1 inhibitor Juglone prevents diabetic vascular dysfunction. AB - BACKGROUND: Atherosclerosis is a major cause of mortality in patients with diabetes. However, novel breakthrough therapies have yet to be approved in this setting. Prolyl-isomerase-1 (Pin1) is emerging as a key molecule implicated in vascular oxidative stress and inflammation. In the present study, we investigate whether pharmacological inhibition of Pin1 may protect against diabetes-induced oxidative stress, endothelial dysfunction and vascular inflammation. METHODS AND RESULTS: Experiments were performed in human aortic endothelial cells (HAECs) exposed to normal (5 mmol/L) or high glucose (25 mmol/L) concentrations, in the presence of Pin1 inhibitor Juglone (10 MUM) or vehicle (<1% ethanol). In parallel, streptozotocin-induced diabetic mice were treated with Juglone i.p. every other day for 30 days (1mg/Kg). Organ chamber experiments were performed in aortic rings to assess endothelium-dependent relaxations to acetylcholine (Ach 10(-9) to 10(-6)mol/L). Mitochondrial oxidative stress, organelle integrity as well as NF-kB-dependent inflammatory signatures were determined both in HAECs and aortas from diabetic mice. In HAECs, ambient hyperglycemia increased mitochondrial superoxide anion generation while treatment with Juglone prevented this phenomenon. Pharmacological inhibition of Pin1 also preserved mitochondrial integrity, nitric oxide availability and endothelial expression of adhesion molecules. Interestingly enough, endothelial dysfunction, oxidative stress and NF kB-driven inflammation were significantly attenuated in diabetic mice chronically treated with Juglone as compared to vehicle-treated animals. CONCLUSION: Pharmacological inhibition of Pin1 by Juglone prevents hyperglycemia-induced vascular dysfunction. Taken together, our findings may set the stage for novel therapeutic approaches to prevent vascular complications in patients with diabetes. PMID- 26583848 TI - The Fe(III)(H2O2) Complex as a Highly Efficient Oxidant in Sulfoxidation Reactions: Revival of an Underrated Oxidant in Cytochrome P450. AB - This work demonstrates that the Fe(III)(H2O2) complex, which has been considered as an unlikely oxidant in P450, is actually very efficient in sulfoxidation reactions. Thus, Fe(III)(H2O2) undergoes a low-barrier nucleophilic attack by sulfur on the distal oxygen, resulting in heterolytic O-O cleavage coupled to proton transfer. We further show that Fe(III)(H2O2) is an efficient sulfoxidation catalyst in synthetic iron porphyrin and iron corrolazine compounds. In all cases, Fe(III)(H2O2) performs the oxidation much faster than it converts to Cpd I and will therefore bypass Cpd I in the presence of a thioether. Thus, this paper not only suggests a plausible resolution of a longstanding issue in P450 chemistry regarding the "second oxidant" but also highlights a new mechanistic pathway for sulfoxidation reactions in P450s and their multitude of synthetic analogues. These findings have far-reaching implications for transition metal compounds, where H2O2 is used as the terminal oxidant. PMID- 26583849 TI - Transient Polymorphism in NaCl. AB - We introduce a new collective variable (CV) that can be used to increase the frequency with which nucleation events are observed in biased atomistic simulations. This CV forces the ions to aggregate into clusters but does not force the ions to order themselves in a particular pattern. We perform metadynamics simulations using this CV in order to examine nucleation in a solution of sodium chloride and find that for small cluster sizes the usual bulk rocksalt structure is less stable than a structure that resembles wurtzite. PMID- 26583847 TI - Methicillin-Resistant Staphylococcus aureus Prevalence among Captive Chimpanzees, Texas, USA, 2012(1). AB - Methicillin-resistant Staphylococcus aureus (MRSA) infection in humans and animals is concerning. In 2012, our evaluation of a captive chimpanzee colony in Texas revealed MRSA prevalence of 69%. Animal care staff should be aware of possible zoonotic MRSA transmission resulting from high prevalence among captive chimpanzees. PMID- 26583850 TI - A Charge Moving Algorithm for Molecular Dynamics Simulations of Gas-Phase Proteins. AB - A method for moving charges in a coarse-grained simulation of gas-phase proteins is presented which uses a Monte Carlo approach to move charges between charge sites. The method is used to study the role of charge movement in the dissociation mechanism of protein complexes in order to better understand experimentally observed mass spectra from CID studies. The charge hopping process is analyzed using energy distributions and a pair correlation plot. Hopping rates, charge distributions, and structural parameters (radius of gyration and RMSD) are also calculated. The importance of charge movement for the unfolding of protein complexes is demonstrated. The algorithm is implemented in the GROMACS molecular dynamics software package. In this study, transthyretin (TTR) tetramer is used with the MARTINI force field as a model system, and comparisons to experiments are made. The hopping and unfolding are found to be controlled by the Coulomb repulsion among the charges in the complex. PMID- 26583851 TI - Molecular Insight into Different Denaturing Efficiency of Urea, Guanidinium, and Methanol: A Comparative Simulation Study. AB - We have designed various nanoslit systems, whose opposing surfaces can be either hydrophobic, hydrophilic, or simply a water-vapor interface, for the molecular dynamics simulation of confined water with three different protein denaturants, i.e., urea, guanidinium chloride (GdmCl), and methanol, respectively. Particular attention is placed on the preferential adsorption of the denaturant molecules onto the opposing surfaces and associated resident time in the vicinal layer next to the surfaces, as well as their implication in the denaturing efficiency of different denaturant molecules. Our simulation results show that among the three denaturants, the occupancy of methanol in the vicinal layer is the highest while the residence time of Gdm is the longest. Although the occupancy and the residence time of urea in the vicinal layer is less than those of the other two denaturant molecules, urea entails "all-around" properties for being a highly effective denaturant. The distinct characteristics of three denaturants may suggest a different molecular mechanism for the protein denaturation. This comparative simulation by design allows us to gain additional insights, on the molecular level, into the denaturation effect and related hydrophobic effect. PMID- 26583852 TI - Monte Carlo Simulation Methods for Computing Liquid-Vapor Saturation Properties of Model Systems. AB - We discuss molecular simulation methods for computing the phase coexistence properties of complex molecules. The strategies that we pursue are histogram based approaches in which thermodynamic properties are related to relevant probability distributions. We first outline grand canonical and isothermal isobaric methods for directly locating a saturation point at a given temperature. In the former case, we show how reservoir and growth expanded ensemble techniques can be used to facilitate the creation and insertion of complex molecules within a grand canonical simulation. We next focus on grand canonical and isothermal isobaric temperature expanded ensemble techniques that provide a means to trace saturation lines over a wide range of temperatures. To demonstrate the utility of the strategies introduced here, we present phase coexistence data for a series of molecules, including n-octane, cyclohexane, water, 1-propanol, squalane, and pyrene. Overall, we find the direct grand canonical approach to be the most effective means to directly locate a coexistence point at a given temperature and the isothermal-isobaric temperature expanded ensemble scheme to provide the most effective means to follow a saturation curve to low temperature. PMID- 26583853 TI - Revisitation of Nonorthogonal Spin Adaptation in Coupled Cluster Theory. AB - The benefits of what is alternatively called a nonorthogonally spin-adapted, spin free, or orbital representation of the coupled cluster equations is discussed relative to orthogonally spin-adapted, spin-orbital, and spin-integrated theories. In particular, specific linear combinations of the orbital cluster amplitudes, denoted spin-summed amplitudes, are shown to reduce the number of contractions that must be explicitly performed and to simplify the expressions and their derivation. The computational efficiency of the spin-summed approach is discussed and compared to orthogonally spin-adapted and spin-integrated approaches. The spin-summed approach is shown to have significant computational advantages relative to the other methods for CCSDT and CCSDTQ. PMID- 26583854 TI - Exploration of Various Aspects of UGA-SUMRCC: Size Extensivity, Possible Use of Sufficiency Conditions, and an Extension for Direct Determination of Energy Differences. AB - The Unitary Group Adapted State Universal Multireference Coupled Cluster (UGA SUMRCC) theory, recently developed by us (J. Chem. Phys.2012, 137, 074104), contains exactly the right number of linearly independent cluster operators. This avoids any redundancy of the excitation manifold in a way exactly paralleling the traditional spin-orbital based SUMRCC. The choice of the linearly independent cluster operators inducing the same change of orbital occupancy becomes increasingly cumbersome if we go over to the cases of active CSFs with more than two active quasiparticles. In the present development, we explore several aspects of the UGA-SUMRCC theory: (a) The first is a variant where we have deliberately incorporated redundancy of the cluster amplitudes to simplify the working equations and have shown that it can serve as a very good approximation to the parent UGA-SUMRCC theory for states with more than two valence occupancies. This in turn suggests that it could be a useful avenue to pursue for arbitrary mh-np situation since the working equations assume simpler algebraic structure in such cases. (b) The analyses of the aspects of size extensivity are known to involve greater complexity if they involve various reduced density matrices (RDMs), since the RDMs are not size-extensive quantities. We have presented the proof for UGA SUMRCC starting from equations containing h-p RDMs via a decomposition involving products of size-extensive cumulants and argue that it has relevance for general cases beyond the h-p model spaces. (c) A useful extension of UGA-SUMRCC lies in formulating the theory for direct calculations of energy differences of spectroscopic interest such as excitation energies, ionization potentials, and electron affinities relative to a closed shell ground state, thus providing attractive alternatives to other allied methods such as SAC-CI, CC-LRT, EOM-CC, STEOM-CC, or ADC. This extension, called UGA-based Quasi-Fock MRCC by us, also leads to exact cancellation of common correlation terms between the initial and final states. Taking a cue from the hierarchical development in Fock-space theories but keeping in mind the advantages of a state-universal (equivalently called a valence specific) theory, our formulation proposes a spin-adapted, accurate, and compact scheme for studying such energy differences. Our results demonstrate superior performance of the method as compared to EOM-CC. PMID- 26583855 TI - A Tuned LRC-DFT Design of Ambipolar Diketopyrrolopyrrole-Containing Quinoidal Molecules Interesting for Molecular Electronics. AB - This work presents a Density Functional Theory (DFT) study on the charge transport related properties of two quinoidal diketopyrrolopyrrole (DPP) based systems. System A, recently synthesized, shows high efficiency as n-type organic semiconductor material while system B, not synthesized yet, has a linking benzothiadiazole (BT) unit between DPP moieties and would display an ambipolar character. The use of tuned, long-range corrected (LRC) functionals allows one to predict HOMO, LUMO, and charge transport properties for compound A in concordance with those experimentally observed. The use of BT building blocks allows for a conclusion that compound B is expected to display balanced and efficient charge injection along with high mobilities both for holes and electrons, which points to its potential to obtain high performances as an ambipolar semiconductor. PMID- 26583856 TI - Linearized Coupled Cluster Corrections to Antisymmetrized Product of Strongly Orthogonal Geminals: Role of Dispersive Interactions. AB - A linearized Multireference Coupled Cluster (MR-LCC) theory is formulated based on the Antisymmetrized Product of Strongly Orthogonal Geminals (APSG) reference state. The role of dispersive interbond interactions is discussed. The presented theory has led to qualitatively correct potential curves for the case when both OH bonds dissociate in H2O, a result that cannot be achieved by adding only perturbative corrections to APSG. The potential curve obtained for the He...He problem practically coincides with the full CI (FCI) result, showing the unexpected accuracy of the MR-LCC approach in this case. PMID- 26583857 TI - Electronic Delocalization in Coordination Polymers Based on Bimetallic Carboxylates. AB - Computational methods (DFT at the B3LYP, PBE0 and m06 levels, MO fragments decomposition, and the broken symmetry approach) have been used to evaluate the influence of the bridging ligand (BL) on the extent of electron delocalization in coordination polymers based on diruthenium tetracarboxylates. The efficiency of three different nitrogenated axial ligands, namely pyrazine (pz), phenazine (phz), and tetrazine (tz), to mediate electron coupling between Ru2(II,II) or Ru2(II,III) centers has been estimated through four different parameters: calculated Ru-N distances, HOMO-LUMO gaps, HOMO and LUMO compositions, and magnetic coupling constants J. All these parameters pointed toward a coordination polymer based on Ru2(II,II) centers axially linked by tetrazine being the best candidate for exhibiting electron delocalization through the Ru2-BL framework. Such a compound has been synthesized and characterized; its vis-NIR spectrum exhibited the predicted features, mainly an intense low-energy MLCT band, assigned to the expected Ru2(II,II) -> tz process associated with electron delocalization. PMID- 26583858 TI - Intermolecular Interactions in Crystalline Theobromine as Reflected in Electron Deformation Density and (13)C NMR Chemical Shift Tensors. AB - An understanding of the role of intermolecular interactions in crystal formation is essential to control the generation of diverse crystalline forms which is an important concern for pharmaceutical industry. Very recently, we reported a new approach to interpret the relationships between intermolecular hydrogen bonding, redistribution of electron density in the system, and NMR chemical shifts (Babinsky et al. J. Phys. Chem. A, 2013, 117, 497). Here, we employ this approach to characterize a full set of crystal interactions in a sample of anhydrous theobromine as reflected in (13)C NMR chemical shift tensors (CSTs). The important intermolecular contacts are identified by comparing the DFT-calculated NMR CSTs for an isolated theobromine molecule and for clusters composed of several molecules as selected from the available X-ray diffraction data. Furthermore, electron deformation density (EDD) and shielding deformation density (SDD) in the proximity of the nuclei involved in the proposed interactions are calculated and visualized. In addition to the recently reported observations for hydrogen bonding, we focus here particularly on the stacking interactions. Although the principal relations between the EDD and CST for hydrogen bonding (HB) and stacking interactions are similar, the real-space consequences are rather different. Whereas the C-H...X hydrogen bonding influences predominantly and significantly the in-plane principal component of the (13)C CST perpendicular to the HB path and the C?O...H hydrogen bonding modulates both in-plane components of the carbonyl (13)C CST, the stacking modulates the out-of-plane electron density resulting in weak deshielding (2-8 ppm) of both in-plane principal components of the CST and weak shielding (~ 5 ppm) of the out-of-plane component. The hydrogen-bonding and stacking interactions may add to or subtract from one another to produce total values observed experimentally. On the example of theobromine, we demonstrate the power of this approach to identify and classify the intermolecular forces that govern the packing motifs in crystals and modulate the NMR CSTs. PMID- 26583859 TI - A Non-antisymmetric Tensor Contraction Engine for the Automated Implementation of Spin-Adapted Coupled Cluster Approaches. AB - We present a symbolic manipulation algorithm for the efficient automated implementation of rigorously spin-free coupled cluster (CC) theories based on a unitary group parametrization. Due to the lack of antisymmetry of the unitary group generators under index permutations, all quantities involved in the equations are expressed in terms of non-antisymmetric tensors. Given two tensors, all possible contractions are first generated by applying Wick's theorem. Each term is then put down in the form of a non-antisymmetric Goldstone diagram by assigning its contraction topology. The subsequent simplification of the equations by summing up equivalent terms and their factorization by identifying common intermediates is performed via comparison of these contraction topologies. The definition of the contraction topology is completely general for non antisymmetric Goldstone diagrams, which enables our algorithm to deal with noncommuting excitations in the cluster operator that arises in the unitary group based CC formulation for open-shell systems. The resulting equations are implemented in a new code, in which tensor contractions are performed by successive application of matrix-matrix multiplications. Implementation of the unitary group adapted CC equations for closed-shell systems and for the simplest open-shell case, i.e., doublets, is discussed, and representative calculations are presented in order to assess the efficiency of the generated codes. PMID- 26583860 TI - Electron Correlation in the Condensed Phase from a Resolution of Identity Approach Based on the Gaussian and Plane Waves Scheme. AB - The second-order Moller-Plesset perturbation energy (MP2) and the Random Phase Approximation (RPA) correlation energy are increasingly popular post-Kohn-Sham correlation methods. Here, a novel algorithm based on a hybrid Gaussian and Plane Waves (GPW) approach with the resolution-of-identity (RI) approximation is developed for MP2, scaled opposite-spin MP2 (SOS-MP2), and direct-RPA (dRPA) correlation energies of finite and extended system. The key feature of the method is that the three center electron repulsion integrals (MUnu|P) necessary for the RI approximation are computed by direct integration between the products of Gaussian basis functions MUnu and the electrostatic potential arising from the RI fitting densities P. The electrostatic potential is obtained in a plane waves basis set after solving the Poisson equation in Fourier space. This scheme is highly efficient for condensed phase systems and offers a particularly easy way for parallel implementation. The RI approximation allows to speed up the MP2 energy calculations by a factor 10 to 15 compared to the canonical implementation but still requires O(N(5)) operations. On the other hand, the combination of RI with a Laplace approach in SOS-MP2 and an imaginary frequency integration in dRPA reduces the computational effort to O(N(4)) in both cases. In addition to that, our implementations have low memory requirements and display excellent parallel scalability up to tens of thousands of processes. Furthermore, exploiting graphics processing units (GPU), a further speedup by a factor ~2 is observed compared to the standard only CPU implementations. In this way, RI-MP2, RI-SOS MP2, and RI-dRPA calculations for condensed phase systems containing hundreds of atoms and thousands of basis functions can be performed within minutes employing a few hundred hybrid nodes. In order to validate the presented methods, various molecular crystals have been employed as benchmark systems to assess the performance, while solid LiH has been used to study the convergence with respect to the basis set and system size in the case of RI-MP2 and RI-dRPA. PMID- 26583861 TI - Specific Reaction Path Hamiltonian for Proton Transfer in Water: Reparameterized Semiempirical Models. AB - The semiempirical MNDO-based AM1 and PM3 methods and the orthogonalization corrected OM1, OM2, and OM3 models were reparameterized to improve their description of bulk water and of proton transfer in water. Reference data included the gas-phase geometries and energies of the water molecule, small water clusters, the hydronium ion, and small hydronium ion-water clusters, as well as the gas-phase potential energy surface for proton transfer between the two water molecules in a Zundel ion, all calculated at the MP2/aug-cc-pVTZ level of theory. Combined QM/MM molecular dynamics simulations were carried out for bulk water and for a proton solvated in water using large cluster models. Both the authentic and reparameterized semiempirical models were employed in the simulations. The reparameterization led to significantly better results in all cases. The new set of OM3 parameters gave the best overall results for the structural and dynamic properties of water and the hydrated proton, with a small but finite barrier of 0.1-0.2 kcal/mol in the potential of mean force for proton transfer, in agreement with ab initio path-integral molecular dynamics simulations. The reparameterized OM3 model is expected to be useful for efficient modeling of proton transfer in aqueous solution. PMID- 26583862 TI - Accuracy and Efficiency of Coupled-Cluster Theory Using Density Fitting/Cholesky Decomposition, Frozen Natural Orbitals, and a t1-Transformed Hamiltonian. AB - We present an algorithm for coupled-cluster through perturbative triples [CCSD(T)] based on a t1-dressed Hamiltonian and the use of density fitting (DF) or Cholesky decomposition (CD) approximations for the construction and contraction of all electron repulsion integrals (ERIs). An efficient implementation of this algorithm is then used to explore whether preoptimized density fitting basis sets [specifically, the (aug-)cc-pVXZ-RI series designed for DF-MP2 computations] are suitable for DF-CCSD(T) computations and how they compare to the CD representation of the integrals. The code is also used to systematically explore the accuracy and efficiency of DF/CD combined with frozen natural orbitals (FNOs) to reduce computational costs. The mean absolute errors due to DF/CD in the CCSD(T)/aug-cc-pVDZ interaction energies of 11 van der Waals dimers are only 0.001 kcal mol(-1) for the preoptimized RI basis set and only 0.002 and 0.001 kcal mol(-1) for CD with cutoffs of 10(-4) and 10(-5), respectively. The very similar performance of the aug-cc-pVDZ-RI auxiliary set is a bit surprising considering that the numbers of CD vectors using these thresholds are, on average, 28% and 73% larger than the dimension of the RI set. When FNOs are coupled with DF/CD, the DF/CD error is roughly an order of magnitude less than the FNO truncation error (at a conservative FNO occupation cutoff of 10(-5)). Utilizing t1-dressed three-index integrals, which remove the explicit dependence of the doubles residual equations on the t1-amplitudes, results in a moderate performance acceleration for the CCSD portion of the algorithm. Moreover, the t1-dressing results in a simpler code which will be more amenable to parallelization. Utilizing both CD and FNO techniques, we observe a speedup of four times for the evaluation of the three-body contribution to the interaction energy for the benzene trimer described by an aug-cc-pVDZ basis set; the error incurred by the CD and FNO approximations in the three-body contribution is only 0.002 kcal mol(-1). PMID- 26583863 TI - Computational Studies of Bridging Structures and Isomerism in Substituted Disilynes. AB - The substituted disilyne molecules, Si2Li2 and Si2HX, where X = Li, F, and Cl, have been investigated using the high-level CCSD(T) and CCSD(T)-F12 ab initio methods. The calculations have found or confirmed the existence of several isomeric forms and transition states for each molecule. Optimized geometries, relative energies, and harmonic vibration frequencies are reported. Bridging structures exist in all cases. Comparisons are made with existing literature results for the related Si2H2, C2X2, and C2HX isomerizing systems. Additionally, CCSD(T) and CCSD(T)-F12 calculations were performed for Si2H2, for which experimental spectroscopic data are available. Results calculated with CCSD(T) F12 and the cc-pVTZ-F12 basis set are of comparable quality as those computed with CCSD(T) and the much larger cc-pV(6+d)Z basis set, at much less computational cost. We recommend the CCSD(T)-F12/cc-pVTZ-F12 level of theory as a very attractive alternative to conventional CCSD(T). PMID- 26583864 TI - Explicit Ligand Hydration Shells Improve the Correlation between MM-PB/GBSA Binding Energies and Experimental Activities. AB - Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) and Molecular Mechanics Generalized Born Surface Area (MM-GBSA) methods are widely used for drug design/discovery purposes. However, it is not clear if the correlation between predicted and experimental binding affinities can be improved by explicitly considering selected water molecules in the calculation of binding energies, since different and sometimes diverging opinions are found in the literature. In this work, we evaluated how variably populated hydration shells explicitly considered around the ligands may affect the correlation between MM PB/GBSA computed binding energy and biological activities (IC50 and DeltaGbind, depending on the available experimental data). Four different systems-namely, the DNA-topoisomerase complex, alpha-thrombin, penicillopepsin, and avidin-were considered and ligand hydration shells populated by 10-70 water molecules were systematically evaluated. We found that the consideration of a hydration shell populated by a number of water residues (Nwat) between 30 and 70 provided, in all of the considered examples, a positive effect on correlation between MM-PB/GBSA calculated binding affinities and experimental activities, with a negligible increment of computational cost. PMID- 26583865 TI - Parameters for Molecular Dynamics Simulations of Manganese-Containing Metalloproteins. AB - A set of geometrical parameters has been determined for single manganese metalloproteins for the AMBER force field, and ultimately to other force fields with a similar philosophy. Twelve (12) models from 9 different single-cluster manganese proteins were optimized and parametrized, using a bonded model approach. Mn-ligand bonds, Mn-ligand angles, and Restrained Electrostatic Potential charges for all the 74 residues in the first metal coordination sphere of each Mn metalloprotein were parametrized. The determined parameters were validated with molecular dynamics simulations and several statistics strategies were used to analyze the results. In addition, to validate the parametrized models, frequency and normal mode calculations were performed and comparisons were obtained for the overall structures both with quantum mechanics and molecular mechanics calculations. Linear and polynomial fittings were performed to estimate Mn-ligand bond force constants for generic manganese centers. Furthermore, averages are proposed for the main Mn-ligand angle interactions of typical manganese coordination centers: axial, square and triangular equatorial planes, and tetrahedral positions, for the different combinations of donor atoms from waters and hard ligands. PMID- 26583866 TI - Choosing a Functional for Computing Absorption and Fluorescence Band Shapes with TD-DFT. AB - The band shapes corresponding to both the absorption and emission spectra of a set of 20 representative conjugated molecules, including recently synthesized structures, have been simulated with a Time-Dependent Density Functional Theory model including diffuse atomic orbitals and accounting for bulk solvent effects. Six hybrid functionals, including two range-separated hybrids (B3LYP, PBE0, M06, M06-2X, CAM-B3LYP, and LC-PBE) have been assessed in light of the experimental band shapes obtained for these conjugated compounds. Basis set and integration grid effects have also been evaluated. It turned out that all tested functionals but LC-PBE reproduce the main experimental features for both absorption and fluorescence, though the average errors are significantly larger for the latter phenomena. No single functional stands out as the most accurate for all aspects, but B3LYP yields the smallest mean absolute deviation. On the other hand, M06-2X could be a valuable compromise for excited-states as it reproduces the 0-0 energies and also gives reasonable band shapes. The typical mean absolute deviations between the relative positions of the experimental and theoretical peaks in the vibrationally resolved spectra are ca. 100 cm(-1) for absorption and 250 cm(-1) for emission. In the same time, the relative intensities of the different maxima are reproduced by TD-DFT with a ca. 10-15% accuracy. PMID- 26583867 TI - Self-consistent Formulation of Constricted Variational Density Functional Theory with Orbital Relaxation. Implementation and Applications. AB - We introduce here a new version of the constricted nth order variational density functional method (CV(n)-DFT) in which the occupied excited state orbitals are allowed to relax in response to the change of both the Coulomb and exchange correlation potential in going from the ground state to the excited state. The new scheme is termed the relaxed self-consistent field nth order constricted variational density functional (RSCF-CV(n)-DFT) method. We have applied the RSCF CV(n)-DFT scheme to the nsigma->pi* transitions in which an electron is moved from an occupied lone-pair orbital nsigma to a virtual pi* orbital. A total of 34 transitions involving 16 different compounds were considered using the LDA, B3LYP, and BHLYP functionals. The DFT-based results were compared to the "best estimates" (BE) from high level ab initio calculations. With energy terms included to second order in the variational parameters (CV(2)-DFT), our theory is equivalent to the adiabatic version of time dependent DFT . We find that calculated excitation energies for CV(2)-DFT using LDA and BHLYP differ substantially from BE with root-mean-square-deviations (RMSD) of 0.87 and 0.65 eV, respectively, whereas B3LYP affords an excellent fit with BE at RMSD = 0.33 eV. Resorting next to CV(infinity)-DFT where energy terms to all orders in the variational parameters are included results for all three functionals in too high excitation energies with RMSD = 1.62, 1.14, and 1.48 eV for LDA, B3LYP, and BHLYP, respectively. Allowing next for a relaxation of the orbitals (nsigma,pi*) that participate directly in the transition (SCF-CV(n)-DFT) leads to an improvement with RMSD = 0.49 eV (LDA), 0.50 eV (B3LYP), and 1.12 eV (BHLYP). The best results are obtained with full relaxation of all orbitals (RSCF-CV(n)) where now RMSD = 0.61 eV (LDA), 0.32 eV (B3LYP), and 0.52 eV (BHLYP). We discuss finally the relation between RSCF-CV(n) and Slater's DeltaSCF method and demonstrate that the two schemes affords quite similar results in those cases where the excitation can be described by a single orbital displacement (nsigma >pi*). PMID- 26583868 TI - Hydration Free Energies of Multifunctional Nitroaromatic Compounds. AB - Nitroaromatic compounds (NACs) are used as energetic materials, reagents, and pesticides; however, they are potentially hazardous for the environment and human health. To predict the environmental distribution of these compounds, the vapor pressure, aqueous solubility, and Henry's law constant are important properties, as is the solvation free energy in water from which the latter two can be computed. Here, we have calculated the hydration free energies for a set of nine nitroaromatic compounds containing one, two, and three nitro groups using the expanded ensemble molecular dynamics simulation method with TIP3P water and the GAFF, CGenFF, OPLS-AA, and TraPPE force field parameters and the RESP (gas phase), CHELPG (gas phase), and CM4 (aqueous phase) partial atomic charges calculated here. Also, we have computed hydration free energies using the reported default partial atomic charges of the OPLS-AA force field and using the semiempirical AM1-BCC charges with GAFF parameters. The effect of water model flexibility on the computation of hydration free energy is examined with CGenFF/(CHELPG+SPC-Fw) model. All the force fields studied generally led to less accurate predictions with increasing numbers of nitro groups. The average unsigned errors (AUE) show that 6 of 16 force-field/(charge+water) models used perform approximately equally well in predicting measured hydration free energies: these are CGenFF/(CHELPG+TIP3P), CGenFF/(CM4+TIP3P), OPLS AA/(CHELPG+TIP3P), OPLS-AA/(CM4+TIP3P), TraPPE-UA/(CHELPG+TIP3P), and TraPPE UA/(CM4+TIP3P). When using the default atomic charges, the OPLS-AA force field was the most accurate, though using CHELPG and CM4 charges led to better predictions. Our analyses indicate that not only the charges but also the van der Waals interaction parameters for the nitro-group nitrogen and oxygen atoms in the force fields are partly responsible for the performance variations in predicting solvation free energies. We also compared the force field-based simulation results with the predictions from the SM6 solvation model and Abraham linear solvation energy relationship (LSER) method. With an appropriate choice of theory and basis set both for geometry optimization and computation, which unfortunately is not known a priori, the SM6 model hydration free energy predictions for the NACs are comparable to the simulation results here. The Abraham LSER predictions with descriptors obtained from the Platts method are of reasonable accuracy. A useful addition to this paper is the Supporting Information that contains a compiled and evaluated list of the hydration free energies of the NACs studied here assembled from the literature. PMID- 26583869 TI - Fixed-Point Optimization of Atoms and Density in DFT. AB - I describe an algorithm for simultaneous fixed-point optimization (mixing) of the density and atomic positions in Density Functional Theory calculations which is approximately twice as fast as conventional methods, is robust, and requires minimal to no user intervention or input. The underlying numerical algorithm differs from ones previously proposed in a number of aspects and is an autoadaptive hybrid of standard Broyden methods. To understand how the algorithm works in terms of the underlying quantum mechanics, the concept of algorithmic greed for different Broyden methods is introduced, leading to the conclusion that if a linear model holds that the first Broyden method is optimal, the second if a linear model is a poor approximation. How this relates to the algorithm is discussed in terms of electronic phase transitions during a self-consistent run which results in discontinuous changes in the Jacobian. This leads to the need for a nongreedy algorithm when the charge density crosses phase boundaries, as well as a greedy algorithm within a given phase. An ansatz for selecting the algorithm structure is introduced based upon requiring the extrapolated component of the curvature condition to have projected positive eigenvalues. The general convergence of the fixed-point methods is briefly discussed in terms of the dielectric response and elastic waves using known results for quasi-Newton methods. The analysis indicates that both should show sublinear dependence with system size, depending more upon the number of different chemical environments than upon the number of atoms, consistent with the performance of the algorithm and prior literature. This is followed by details of algorithm ranging from preconditioning to trust region control. A number of results are shown, finishing up with a discussion of some of the many open questions. PMID- 26583870 TI - Spin-Polarized Electron Transport Across Metal-Organic Molecules: A Density Functional Theory Approach. AB - In the field of molecular spintronics, experimental techniques have achieved a stage where it is feasible to explore the interplay between quantum electron transport and magnetism at the single molecule level. An example is a spin polarized STM, which can probe local electrical currents through organic molecules deposited on magnetic surfaces. The atomistic complexity of nanoscale systems calls for a first-principles description of spin-dependent transport phenomena, e.g., based on the nonequilibrium Green's function (NEGF) formalism merged with density functional theory (DFT). However, for the case of molecular junctions with transition metal electrodes, a computation of the underlying Kohn Sham Hamiltonian can be a challenging problem: a simultaneous and accurate description of spin ordered magnetic surfaces together with the electronic structure of a molecule is required. In the present work, we provide a solution for this problem. We present an implementation, within a standard quantum chemistry package, of the NEGF formalism with an efficient approximation for the self-energy, which accounts both for absorbing boundary conditions and for exchange splitting of the energy bands in ferromagnetic electrodes. We demonstrate an ability to simulate a variety of magnetic configurations including nanoscale domain walls, which are realized when a molecule with few spin centers is brought in contact with differently magnetized reservoirs. The magnetoresistance effect arising on the molecular scale is discussed based on examples including Ni atomic-sized contact, electron transport across a prototypical molecular magnet (vanadium-benzene multidecker cluster), and tunneling through Co-phthalocyanine. Furthermore, we verify the stability of magnetically nontrivial solutions against electron correlations within the DFT+U approach. PMID- 26583871 TI - Optimization-Based Design of Metal-Organic Framework Materials. AB - Metal-organic frameworks (MOFs) are a class of porous materials constructed from metal or metal oxide building blocks connected by organic linkers. MOFs are highly tunable structures that can in theory be custom designed to meet the specific pore geometry and chemistry required for a given application such as methane storage or carbon capture. However, due to the sheer number of potential materials, identification of optimal MOF structures is a significant challenge. In this contribution we describe an automated technique for MOF design based on mathematical optimization. Optimization is performed on linkers represented by abstract space-filling shapes, in order to generalize the desirable geometric parameters describing linkers, and optimal shapes are projected to real molecules to illustrate realistic MOFs exhibiting the calculated properties. Six examined topologies of MOF and two distinct geometrical pore properties relevant to guest adsorption phenomena are explored. We demonstrate that the optimal shapes of linkers depend on both the topology and the property of interest and moreover that synthetically challenging linkers are not necessary to achieve the most promising candidate materials. PMID- 26583872 TI - Analysis of Protein Dynamics Simulations by a Stochastic Point Process Approach. AB - MD simulations can now explore the complex dynamics of proteins and their associated solvent in atomic detail on a millisecond time scale. Among the phenomena that thereby become amenable to detailed study are intermittent conformational transitions where the protein accesses transient high-energy states that often play key roles in biology. Here, we present a coherent theoretical framework, based on the stochastic theory of stationary point processes, that allows the essential dynamical characteristics of such processes to be efficiently extracted from the MD trajectory without assuming Poisson statistics. Since the complete information content of a point process is contained in the sequence of residence or interevent times, the experimentally relevant survival correlation function can be computed several orders of magnitude more efficiently than with the conventional approach, involving averaging over initial times. We also present a detailed analysis of the statistical and binning errors, of particular importance when MD results are compared with experiment. As an illustration of the general theoretical framework, we use a 1 ms MD trajectory of the protein BPTI to analyze the exchange kinetics of an internal water molecule and the dynamics of the rare conformational fluctuations that govern the rate of this exchange process. PMID- 26583873 TI - Efficiency of Adaptive Temperature-Based Replica Exchange for Sampling Large Scale Protein Conformational Transitions. AB - Temperature-based replica exchange (RE) is now considered a principal technique for enhanced sampling of protein conformations. It is also recognized that existence of sharp cooperative transitions (such as protein folding/unfolding) can lead to temperature exchange bottlenecks and significantly reduce the sampling efficiency. Here, we revisit two adaptive temperature-based RE protocols, namely, exchange equalization (EE) and current maximization (CM), that were previously examined using atomistic simulations (Lee and Olson, J. Chem. Physics2011, 134, 24111). Both protocols aim to overcome exchange bottlenecks by adaptively adjusting the simulation temperatures, either to achieve uniform exchange rates (in EE) or to maximize temperature diffusion (CM). By designing a realistic yet computationally tractable coarse-grained protein model, one can sample many reversible folding/unfolding transitions using conventional constant temperature molecular dynamics (MD), standard REMD, EE-REMD, and CM-REMD. This allows rigorous evaluation of the sampling efficiency, by directly comparing the rates of folding/unfolding transitions and convergence of various thermodynamic properties of interest. The results demonstrate that both EE and CM can indeed enhance temperature diffusion compared to standard RE, by ~3- and over 10-fold, respectively. Surprisingly, the rates of reversible folding/unfolding transitions are similar in all three RE protocols. The convergence rates of several key thermodynamic properties, including the folding stability and various 1D and 2D free energy surfaces, are also similar. Therefore, the efficiency of RE protocols does not appear to be limited by temperature diffusion, but by the inherent rates of spontaneous large-scale conformational rearrangements. This is particularly true considering that virtually all RE simulations of proteins in practice involve exchange attempt frequencies (~ps(-1)) that are several orders of magnitude faster than the slowest protein motions (~MUs(-1)). Our results also suggest that the efficiency of RE will not likely be improved by other protocols that aim to accelerate exchange or temperature diffusion. Instead, protocols with some types of guided tempering will likely be necessary to drive faster large scale conformational transitions. PMID- 26583874 TI - Achieving Low Overpotential Li-O2 Battery Operations by Li2O2 Decomposition through One-Electron Processes. AB - As a promising high-capacity energy storage technology, Li-O2 batteries face two critical challenges, poor cycle lifetime and low round-trip efficiencies, both of which are connected to the high overpotentials. The problem is particularly acute during recharge, where the reactions typically follow two-electron mechanisms that are inherently slow. Here we present a strategy that can significantly reduce recharge overpotentials. Our approach seeks to promote Li2O2 decomposition by one-electron processes, and the key is to stabilize the important intermediate of superoxide species. With the introduction of a highly polarizing electrolyte, we observe that recharge processes are successfully switched from a two-electron pathway to a single-electron one. While a similar one-electron route has been reported for the discharge processes, it has rarely been described for recharge except for the initial stage due to the poor mobilities of surface bound superoxide ions (O2(-)), a necessary intermediate for the mechanism. Key to our observation is the solvation of O2(-) by an ionic liquid electrolyte (PYR14TFSI). Recharge overpotentials as low as 0.19 V at 100 mA/g(carbon) are measured. PMID- 26583875 TI - AIEE-Active and Electrochromic Bifunctional Polymer and a Device Composed thereof Synchronously Achieve Electrochemical Fluorescence Switching and Electrochromic Switching. AB - A novel alternating polymer, ProDOT-TPE, with aggregation-enhanced fluorescent emission and electrochromic properties based on thiophene and tetraphenylethene derivatives was designed, synthesized, and characterized. The polymer displays weak photoluminescence in tetrahydrofuran, but its corresponding film prepared by spray-coating exhibits yellow-green fluorescent light at 540 nm. The color of the polymer film could be switched from bright yellow to navy blue by applying a relatively low voltage. An electrochromic device (ECD) of the polymer was fabricated that differs from common ECDs because both its color and fluorescent state could be synchronously switched by an applied voltage, making the polymer a unique candidate for electrochemical fluorescence and electrochromic applications. PMID- 26583876 TI - Editorial Comment to Validation of an educational program balancing surgeon training and surgical quality control during robot-assisted radical prostatectomy. PMID- 26583877 TI - Feasibility study of using intravoxel incoherent motion mri to detect parotid gland abnormalities in early-stage Sjogren syndrome patients. AB - PURPOSE: To determine whether intravoxel incoherent motion (IVIM) magnetic resonance imaging (MRI) could detect parotid gland abnormalities in Sjogren's syndrome (SS) patients who were not identified by conventional MRI. MATERIALS AND METHODS: Ten consecutive patients with clinically proven SS who were not identified by conventional MRI were assessed by IVIM MRI with a 3.0T MRI scanner. Quantitative parameters (tissue diffusivity, D; pseudodiffusion coefficient, D*; perfusion fraction, f) derived from IVIM MRI were compared between the SS group and healthy control group (n = 15). A receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value of each significant parameter. RESULTS: Excellent inter- and intrareader agreements were obtained during the measurement of D, f, and D* values (interreader, 0.980, 0.942, and 0.883; intrareader, 0.991, 0.952, and 0.896, respectively). All three parameters of the SS group were significantly higher than those of the healthy group (D, 1.049 +/- 0.056 * 10(-3) mm(2) /s vs. 0.976 +/- 0.116 * 10(-3) mm(2) /s, P = 0.012; D*, 20.410 +/- 1.786 * 10(-3) mm(2) /s vs. 18.764 +/- 2.433 * 10(-3) mm(2) /s, P = 0.013; f, 0.207 +/- 0.003 vs. 0.182 +/- 0.002, P = 0.004). ROC analysis showed that the f value had the best diagnostic performance (AUC, 0.712; Sensitivity, 0.80; Specificity, 0.57; Cutoff value, 0.185) in detecting the parotid gland abnormalities in early SS patients. CONCLUSION: IVIM MRI detected parotid gland abnormalities in early-stage SS patients. J. Magn. Reson. Imaging 2016;43:1455 1461. PMID- 26583878 TI - Is fresh frozen plasma as good as prothrombin complex concentrate for vitamin K antagonist reversal in acute intracerebral hemorrhage? PMID- 26583879 TI - Unexpected toxicity of very low dose MPTP in mice: A clue to the etiology of Parkinson's disease? AB - Although much progress have been made in recent years, the etiology of idiopathic Parkinson's disease remains obscure. The chance discovery that injection of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces a syndrome very similar to parkinsonism introduced the "environmental toxin" hypothesis but no toxin was ever found in any quantity in patients' brains. We have unexpectedly now found, however, that, in mice, very low doses of MPTP induce as much dopaminergic neuronal death as far higher doses. Cellular detoxification mechanisms would appear to be incapacitated at such low doses. This could infer that the barely discernible presence of an unidentified neurotoxin may be responsible for the onset of Parkinson's disease. PMID- 26583880 TI - Macroevolution of leaf defenses and secondary metabolites across the genus Helianthus. AB - Leaf defenses are widely recognized as key adaptations and drivers of plant evolution. Across environmentally diverse habitats, the macroevolution of leaf defenses can be predicted by the univariate trade-off model, which predicts that defenses are functionally redundant and thus trade off, and the resource availability hypothesis, which predicts that defense investment is determined by inherent growth rate and that higher defense will evolve in lower resource environments. Here, we examined the evolution of leaf physical and chemical defenses and secondary metabolites in relation to environmental characteristics and leaf economic strategy across 28 species of Helianthus (the sunflowers). Using a phylogenetic comparative approach, we found few evolutionary trade-offs among defenses and no evidence for defense syndromes. We also found that leaf defenses are strongly related to leaf economic strategy, with higher defense in more resource-conservative species, although there is little support for the evolution of higher defense in low-resource habitats. A wide variety of physical and chemical defenses predict resistance to different insect herbivores, fungal pathogens, and a parasitic plant, suggesting that most sunflower defenses are not redundant in function and that wild Helianthus represents a rich source of variation for the improvement of crop sunflower. PMID- 26583881 TI - miRNA-548p suppresses hepatitis B virus X protein associated hepatocellular carcinoma by downregulating oncoprotein hepatitis B x-interacting protein. AB - AIM: miR-548p is a recently identified and poorly characterized miRNA. However, its role of miR-548p in tumorigenesis and progression remains poorly understood. Here, we aimed to investigate the biofunction of miR-548p in hepatocellular carcinogenesis. METHODS: The expression levels of miR-548p were detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The role of miR-548p in hepatocellular carcinoma (HCC) was determined by colony formation, flow cytometry assay and nude mice xenograft experiments. miR-548p target genes were analyzed by miRNA target predication programs and verified by qRT-PCR, western blotting assay and dual-luciferase reporter assay. RESULTS: miR-548p is repressed by hepatitis B virus X protein (HBx) in HCC tumor tissues and hepatoma cells, and inhibited cell growth by inhibiting cell proliferation and promoting cell apoptosis. miR-548p directly downregulated the expression of hepatitis B x interacting protein (HBXIP) by binding to the 3'-untranslated region of HBXIP mRNA. Further study showed that hepatocyte nuclear factor-4a (HNF4A) promoted the expression of miR-548p and inhibited the transcription of HBXIP. HNF4A is a dominant transcriptional regulator of hepatocyte differentiation and hepatocellular carcinogenesis, and is shown to be repressed by HBx. CONCLUSION: We proposed the model for HBx/HNF4A/miR-548p/HBXIP pathway that controls hepatoma cell growth and tumorigenesis of HCC. miR-548p was identified as a tumor suppressor in HBx-associated hepatocellular carcinogenesis. PMID- 26583882 TI - Sofosbuvir and simeprevir in hepatitis C genotype 1-patients with end-stage renal disease on haemodialysis or GFR <30 ml/min. AB - BACKGROUND & AIMS: Treating chronic hepatitis C (CHC) in patients with end-stage renal disease (ESRD) has suboptimal tolerability and cure rates. Safety and efficacy of sofosbuvir plus simeprevir regimen in CHC-infected patients with ESRD on haemodialysis (HD) or glomerular filtration rate (GFR) <30 ml/min is unknown. We evaluated the safety and efficacy of sofosbuvir and simeprevir in this special patient population. METHODS: All (n = 17) patients in the analysis had ESRD on HD or GFR <30 ml/min. All received sofosbuvir 400 mg daily and simeprevir 150 mg daily, without ribavirin for 12 weeks. Safety and efficacy data were collected; including SVR4 and SVR12 data for all patients after completing therapy. RESULTS: In this 17 patient cohort, eight (47%) were cirrhotic, four (24%) had stage three liver fibrosis and 13 (76%) were genotype 1A. All 17 have completed 12 weeks of therapy. Treatment was overall well tolerated with no treatment discontinuations reported. Four (24%) patients reported mild adverse events (AE). These AEs were insomnia (n = 2), headache (n = 1), nausea (n = 1) and worsening anaemia requiring blood transfusion (n = 1). All 17 patients reached post-treatment week 12 follow-up, and achieved SVR12 or virological cure (100% SVR12). CONCLUSIONS: Daily, full dose of sofosbuvir plus simeprevir for 12 weeks of therapy appears to be well tolerated in patients with ESRD on HD or GFR <30 ml/min. Most common AEs resembled those of healthier CHC patients without significant renal impairment. The cure rates obtained in this cohort treated with sofosbuvir and simeprevir are dramatically superior to any previous treatment regimen studied & published in this special patient population. PMID- 26583883 TI - Baby, Where Did You Get Those Eyes?: IEEE Pulse talks with Mark Sagar about the new face of artificial intelligence. AB - Mark Sagar is changing the way we look at computers by giving them faces?disconcertingly realistic human faces. Sagar first gained widespread recognition for his pioneering work in rendering faces for Hollywood movies, including Avatar and King Kong. With a Ph.D. degree in bioengineering and two Academy Awards under his belt, Sagar now directs a research lab at the University of Auckland, New Zealand, a combinatorial hub where artificial intelligence (AI), neuroscience, computer science, philosophy, and cognitive psychology intersect in creating interactive, intelligent technologies. PMID- 26583884 TI - It's All in the Eyes: The eyes as a window to the body and brain may not be a brand-new idea - but it is a newly revitalized one, thanks to improved technologies. AB - In a blog post in January 2014, Google unveiled one of its latest forays into the health market?a smart contact lens for diabetics. It was sleek and appealingly futuristic, with a minute microchip equipped with tiny glucose sensors, embedded in a soft, biocompatible lens material. Already, the company said, the prototype could measure tear glucose as often as once per second, and it may someday include tiny LED lights to signal warnings to the wearers when their blood sugar rises or falls to dangerous levels. PMID- 26583885 TI - The Portable Eye Examination Kit: Mobile phones can screen for eye disease in low resource settings. AB - In 2010, the World Health Organization estimated that 285 million people exhibit some form of vision impairment. Of these, almost 40 million people are functionally blind [1]. Yet, 80% of blindness could either be treated or avoided at the point of onset. PMID- 26583886 TI - The Present and Future of Low-Cost Diagnostics: A new class of portable, easy-to use products is increasing access to health care around the world, yet challenges remain. AB - Imagine you?re in a rural health clinic in a Kenyan village. A child comes in with a fever. It could be any one of a number of life-threatening infectious diseases. There?s no refrigeration, no access to sophisticated laboratory equipment, and no highly trained personnel. How do you go about diagnosing and treating this child? PMID- 26583887 TI - The Saudi Human Genome Program: An oasis in the desert of Arab medicine is providing clues to genetic disease. AB - Oil wells, endless deserts, stifling heat, masses of pilgrims, and wealthy looking urban areas still dominate the widespread mental image of Saudi Arabia. Currently, this image is being extended to include a recent endeavor that is reserving a global share in the limelight as one of the top ten genomics projects currently underway: the Saudi Human Genome Program (SHGP). With sound funding, dedicated resources, and national determination, the SHGP targets the sequencing of 100,000 human genomes over the next five years to conduct world-class genomics based biomedical research in the Saudi population. Why this project was conceived and thought to be feasible, what is the ultimate target, and how it operates are the questions we answer in this article. PMID- 26583888 TI - Incubating Innovation: A standard model for nurturing new businesses, the incubator gains prominence in the world of biotech. AB - Incubators, accelerators, innovation centers, launch pads. Everyone defines the idea a bit differently, but, generally, these infrastructures refer to a subsidized space where fledgling companies get support?a combination of mentorship, funding, low rent, networking opportunities, and other training?with the goal of propelling early businesses to success. PMID- 26583889 TI - Linking Engineering and Medical Training: A USC program seeks to introduce medical and engineering students to medical device development. AB - Medical students are attracted by the prospect of a meaningful addition to their clinical work. Engineering students are excited by a unique opportunity to learn directly alongside their medical student peers. For both, as well as the scientific community at large, the boutique program at the University of Southern California (USC) linking engineering and medical training at the graduate level is instructive of a new way of approaching engineering education that can potentially provide benefits to both students and society. Students who have grown up in an era of ?mass customization? in the retail and service industries can enjoy that same degree of flexibility also in the realm of education. At the same time, society gains engineers who have developed an increased empathy and awareness of the clinical contexts in which their innovations will be implemented. PMID- 26583891 TI - Aquaculture. AB - John Lucas introduces aquaculture, the cultivation of aquatic organisms and its role in human food production for a sustainable future. PMID- 26583890 TI - Evaluation of a Nurse-Managed Insulin Infusion Protocol. AB - BACKGROUND: The purpose of this study was to evaluate the performance of an insulin infusion protocol targeting a blood glucose (BG) level of 140-180 mg/dL and to characterize protocol adherence. MATERIALS AND METHODS: This was a retrospective observational cohort study including patients for whom the protocol was ordered from January 2012 to May 2013. Performance metrics were assessed in all patients and in patients with an initial BG level of >=200 mg/dL. Protocol adherence was assessed in a random subset of 50 patients without hypoglycemia and in all hypoglycemic patients. RESULTS: In patients with an initial BG level of >=200 mg/dL, the mean time to goal was 7.1 h. The rate of decline of BG level in the first 6 h was 16.4 mg/dL/h. Mean BG level was 167 mg/dL, with 43.9% of BG values within goal and 80.3% between 80 and 199 mg/dL. The rate of hypoglycemic events was 0.14 per 100 h. The mean protocol violation rate was higher in patients with hypoglycemia compared with those without (39.8 vs. 23.5 per 100 h, P = 0.002), and 60.7% of hypoglycemic events were attributable to protocol violations. The protocol violation rate (42.8 vs. 17.6 per 100 h; P < 0.001) and the odds of hypoglycemia (odds ratio = 5.2; 95% confidence interval, 1.6, 16.5) were higher in the cardiac surgery patients compared with other patients. CONCLUSIONS: This protocol provides adequate BG control within the clinically acceptable range of 80-199 mg/dL but not within the narrower range of 140-180 mg/dL, with a low incidence of hypoglycemia. Risk factors for hypoglycemia and barriers to protocol adherence in the cardiac surgery population should be elucidated. PMID- 26583892 TI - Widespread mistaken identity in tropical plant collections. AB - Specimens of plants and animals preserved in museums are the primary source of verifiable data on the geographical and temporal distribution of organisms. Museum datasets are increasingly being uploaded to aggregated regional and global databases (e.g. the Global Biodiversity Information Facility; GBIF) for use in a wide range of analyses. Thus, digitisation of natural history collections is providing unprecedented information to facilitate the study of the natural world on a global scale. The digitisation of this information utilises information provided on specimen labels, and assumes they are correctly identified. Here we evaluate the accuracy of names associated with 4,500 specimens of African gingers from 40 herbaria in 21 countries. Our data show that at least 58% of the specimens had the wrong name prior to a recent taxonomic study. A similar pattern of wrongly named specimens is also shown for Dipterocarps and Ipomoea (morning glory). We also examine the number of available plant specimens worldwide. Our data demonstrate that, while the world's collections have more than doubled since 1970, more than 50% of tropical specimens, on average, are likely to be incorrectly named. This finding has serious implications for the uncritical use of specimen data from natural history collections. PMID- 26583893 TI - Optogenetic stimulation of neuronal repair. AB - Environmental insult, disease or trauma can affect the physical integrity of neuronal circuits, and the inability of many neurons to regenerate injured axons invariably leads to irreversible neural dysfunction. The conserved second messenger cyclic adenosine monophosphate (cAMP) can promote axonal re-growth. Widely used pharmacological or genetic approaches to increase intracellular levels of cAMP are often inadequate for precise neural-circuit reconstruction because their activity cannot be easily timed to specific target cells. These shortcomings have prevented the controlled repair of pre-defined neurons at selected time points in whole specimens. Thus, technologies to guide neuronal repair in time and space would enable studies of neural-circuit recovery with unprecedented resolution. Towards this aim, we have implemented a proof-of principle optogenetic method to promote the selective regeneration of refractory axons in a living vertebrate. PMID- 26583894 TI - Animal Behavior: Electric Eels Amp Up for an Easy Meal. AB - The high voltage discharge generated by electric eels is a powerful predatory weapon. A new study shows that eels exploit basic physics to increase the voltage delivered to prey, inducing muscle fatigue that turns challenging prey items into easy targets. PMID- 26583895 TI - Entomology: A Bee Farming a Fungus. AB - Farming is done not only by humans, but also by some ant, beetle and termite species. With the discovery of a stingless bee farming a fungus that provides benefits to its larvae, bees can be added to this list. PMID- 26583896 TI - Plant Immunity: A Little Help from Fungal Friends. AB - Yew trees are famous for production of the anti-cancer drug Taxol (paclitaxel). A new study sheds light on why endophytic fungi that live inside Yew trees also make the same drug. PMID- 26583897 TI - Social Evolution: Uneasy Lies the Head. AB - Inclusive fitness theory explains why workers in insect societies sometimes kill their queen. As the theory predicts, workers in a wasp species are more likely to act matricidally when more highly related to potential worker offspring. PMID- 26583898 TI - Animal Evolution: Only Rocks Can Set the Clock. AB - Molecular clocks have become the method of choice to date the tree of life. A new study demonstrates that there are limits to their precision, which may only be overcome by improving our knowledge of the fossil record. PMID- 26583899 TI - Systems Neuroscience: Shaping the Reward Prediction Error Signal. AB - A recent study shows that midbrain GABA (inhibitory) neurons code for environmentally predicted rewards. These GABA neurons communicate with dopamine neurons, where the reward prediction is subtracted from delivered reward. Thus, the GABA prediction signal shapes the dopamine reward prediction error signal. PMID- 26583900 TI - Evolution: Big Bawls, Small Balls. AB - Males must carefully allocate the energy they devote to sex. A new study of howler monkeys shows that males who use vocalizations to ward off rivals invest less in producing large numbers of sperm. PMID- 26583901 TI - Neurobiology: What Drives Flies to Sleep? AB - The number of wake-promoting neurons in the Drosophila brain is relatively small, and only some of them have the unique ability to promote robust recovery sleep following wakefulness. PMID- 26583902 TI - Marine Ecology: A Wonderland of Marine Activity in the Arctic Night. AB - Studies carried out on a wide variety of Arctic species during the polar night reveal continued feeding, growth and reproduction, changing our view of this period from one of biological stasis to a time of continued high activity levels. PMID- 26583903 TI - Endocytic Trafficking of Integrins in Cell Migration. AB - Integrins are a family of heterodimeric receptors that bind to components of the extracellular matrix and influence cellular processes as varied as proliferation and migration. These effects are achieved by tight spatiotemporal control over intracellular signalling pathways, including those that mediate cytoskeletal reorganisation. The ability of integrins to bind to ligands is governed by integrin conformation, or activity, and this is widely acknowledged to be an important route to the regulation of integrin function. Over the last 15 years, however, the pathways that regulate endocytosis and recycling of integrins have emerged as major players in controlling integrin action, and studying integrin trafficking has revealed fresh insight into the function of this fascinating class of extracellular matrix receptors, in particular in the context of cell migration and invasion. Here, we review our current understanding of the contribution of integrin trafficking to cell motility. PMID- 26583904 TI - Targeted gene enrichment and high-throughput sequencing for environmental biomonitoring: a case study using freshwater macroinvertebrates. AB - Recent studies have advocated biomonitoring using DNA techniques. In this study, two high-throughput sequencing (HTS)-based methods were evaluated: amplicon metabarcoding of the cytochrome C oxidase subunit I (COI) mitochondrial gene and gene enrichment using MYbaits (targeting nine different genes including COI). The gene-enrichment method does not require PCR amplification and thus avoids biases associated with universal primers. Macroinvertebrate samples were collected from 12 New Zealand rivers. Macroinvertebrates were morphologically identified and enumerated, and their biomass determined. DNA was extracted from all macroinvertebrate samples and HTS undertaken using the illumina miseq platform. Macroinvertebrate communities were characterized from sequence data using either six genes (three of the original nine were not used) or just the COI gene in isolation. The gene-enrichment method (all genes) detected the highest number of taxa and obtained the strongest Spearman rank correlations between the number of sequence reads, abundance and biomass in 67% of the samples. Median detection rates across rare (<1% of the total abundance or biomass), moderately abundant (1 5%) and highly abundant (>5%) taxa were highest using the gene-enrichment method (all genes). Our data indicated primer biases occurred during amplicon metabarcoding with greater than 80% of sequence reads originating from one taxon in several samples. The accuracy and sensitivity of both HTS methods would be improved with more comprehensive reference sequence databases. The data from this study illustrate the challenges of using PCR amplification-based methods for biomonitoring and highlight the potential benefits of using approaches, such as gene enrichment, which circumvent the need for an initial PCR step. PMID- 26583905 TI - Filter media properties of mineral fibres produced by plasma spray. AB - The purpose of this study was to determine the properties of fibrous gas filtration media produced from mineral zeolite. Fibres were generated by direct current plasma spray. The paper characterizes morphology, chemical composition, geometrical structure of elementary fibres, and thermal resistance, as well as the filtration properties of fibre media. The diameter of the produced elementary fibres ranged from 0.17 to 0.90 MUm and the length ranged from 0.025 to 5.1 mm. The release of fibres from the media in the air stream was noticed, but it was minimized by hot-pressing the formed fibre mats. The fibres kept their properties up to the temperature of 956 degrees C, while further increase in temperature resulted in the filter media becoming shrunk and brittle. The filtration efficiency of the prepared filter mats ranged from 95.34% to 99.99% for aerosol particles ranging in a size between 0.03 and 10.0 MUm. Unprocessed fibre media showed the highest filtration efficiency when filtering aerosol particles smaller than 0.1 um. Hot-pressed filters were characterized by the highest quality factor values, ranging from 0.021 to 0.064 Pa(-1) (average value 0.034 Pa(-1)). PMID- 26583906 TI - Reversing cancer stemness. PMID- 26583907 TI - Aggregate Exposure and Cumulative Risk Assessment--Integrating Occupational and Non-occupational Risk Factors. AB - Occupational exposure limits have traditionally focused on preventing morbidity and mortality arising from inhalation exposures to individual chemical stressors in the workplace. While central to occupational risk assessment, occupational exposure limits have limited application as a refined disease prevention tool because they do not account for all of the complexities of the work and non occupational environments and are based on varying health endpoints. To be of greater utility, occupational exposure limits and other risk management tools could integrate broader consideration of risks from multiple exposure pathways and routes (aggregate risk) as well as the combined risk from exposure to both chemical and non-chemical stressors, within and beyond the workplace, including the possibility that such exposures may cause interactions or modify the toxic effects observed (cumulative risk). Although still at a rudimentary stage in many cases, a variety of methods and tools have been developed or are being used in allied risk assessment fields to incorporate such considerations in the risk assessment process. These approaches, which are collectively referred to as cumulative risk assessment, have potential to be adapted or modified for occupational scenarios and provide a tangible path forward for occupational risk assessment. Accounting for complex exposures in the workplace and the broader risks faced by the individual also requires a more complete consideration of the composite effects of occupational and non-occupational risk factors to fully assess and manage worker health problems. Barriers to integrating these different factors remain, but new and ongoing community-based and worker health-related initiatives may provide mechanisms for identifying and integrating risk from aggregate exposures and cumulative risks from all relevant sources, be they occupational or non-occupational. PMID- 26583908 TI - Considerations for Using Genetic and Epigenetic Information in Occupational Health Risk Assessment and Standard Setting. AB - Risk assessment forms the basis for both occupational health decision-making and the development of occupational exposure limits (OELs). Although genetic and epigenetic data have not been widely used in risk assessment and ultimately, standard setting, it is possible to envision such uses. A growing body of literature demonstrates that genetic and epigenetic factors condition biological responses to occupational and environmental hazards or serve as targets of them. This presentation addresses the considerations for using genetic and epigenetic information in risk assessments, provides guidance on using this information within the classic risk assessment paradigm, and describes a framework to organize thinking about such uses. The framework is a 4 * 4 matrix involving the risk assessment functions (hazard identification, dose-response modeling, exposure assessment, and risk characterization) on one axis and inherited and acquired genetic and epigenetic data on the other axis. The cells in the matrix identify how genetic and epigenetic data can be used for each risk assessment function. Generally, genetic and epigenetic data might be used as endpoints in hazard identification, as indicators of exposure, as effect modifiers in exposure assessment and dose-response modeling, as descriptors of mode of action, and to characterize toxicity pathways. Vast amounts of genetic and epigenetic data may be generated by high-throughput technologies. These data can be useful for assessing variability and reducing uncertainty in extrapolations, and they may serve as the foundation upon which identification of biological perturbations would lead to a new paradigm of toxicity pathway-based risk assessments. PMID- 26583910 TI - Empagliflozin and linagliptin combination therapy for treatment of patients with type 2 diabetes mellitus. AB - INTRODUCTION: Many patients with type 2 diabetes mellitus (T2DM) fail to achieve the desired A1c goal because the antidiabetic medications used do not correct the underlying pathophysiologic abnormalities and monotherapy is not sufficiently potent to reduce the A1c to the 6.5 - 7.0% range. Insulin resistance and islet (beta and alpha) cell dysfunction are major pathophysiologic abnormalities in T2DM. We examine combination therapy with linagliptin plus empagliflozin as a therapeutic approach for the treatment of inadequately controlled T2DM patients. AREAS COVERED: A literature search of all human diabetes, metabolism and general medicine journals from year 2000 to the present was conducted. Glucagon like peptide-1 (GLP-1) deficiency/resistance contributes to islet cell dysfunction by impairing insulin secretion and increasing glucagon secretion. DPP-4 inhibitors (DPP4i) improve pancreatic islet function by augmenting glucose-dependent insulin secretion and decreasing elevated plasma glucagon levels. Linagliptin, a DPP-4 inhibitor, reduces HbA1c, is weight neutral, has an excellent safety profile and a low risk of hypoglycemia. The expression of sodium-glucose cotransporter-2 (SGLT2) in the proximal renal tubule is upregulated in T2DM, causing excess reabsorption of filtered glucose. The SGLT2 inhibitor (SGLT2i), empagliflozin, improves HbA1c by causing glucosuria and ameliorating glucotoxicity. It also decreases weight and blood pressure, and has a low risk of hypoglycemia. EXPERT OPINION: The once daily oral combination of linagliptin plus empagliflozin does not increase the risk of hypoglycemia and tolerability and discontinuation rates are similar to those with each as monotherapy. At HbA1c values below 8.5% linagliptin/empagliflozin treatment produces an additive effect, whereas above 8.5%, there is a less than additive reduction with combination therapy compared with the effect of each agent alone. Linagliptin/empagliflozin addition is a logical combination in patients with T2DM, especially those with an HbA1c < 8.5%. PMID- 26583909 TI - Setting Occupational Exposure Limits for Chemical Allergens--Understanding the Challenges. AB - Chemical allergens represent a significant health burden in the workplace. Exposures to such chemicals can cause the onset of a diverse group of adverse health effects triggered by immune-mediated responses. Common responses associated with workplace exposures to low molecular weight (LMW) chemical allergens range from allergic contact dermatitis to life-threatening cases of asthma. Establishing occupational exposure limits (OELs) for chemical allergens presents numerous difficulties for occupational hygiene professionals. Few OELs have been developed for LMW allergens because of the unique biological mechanisms that govern the immune-mediated responses. The purpose of this article is to explore the primary challenges confronting the establishment of OELs for LMW allergens. Specific topics include: (1) understanding the biology of LMW chemical allergies as it applies to setting OELs; (2) selecting the appropriate immune mediated response (i.e., sensitization versus elicitation); (3) characterizing the dose (concentration)-response relationship of immune-mediated responses; (4) determining the impact of temporal exposure patterns (i.e., cumulative versus acute exposures); and (5) understanding the role of individual susceptibility and exposure route. Additional information is presented on the importance of using alternative exposure recommendations and risk management practices, including medical surveillance, to aid in protecting workers from exposures to LMW allergens when OELs cannot be established. PMID- 26583912 TI - Developing Asymmetry at Mammography: Correlation with US and MR Imaging and Histopathologic Findings. AB - PURPOSE: To evaluate ultrasonographic (US) and magnetic resonance (MR) imaging findings, histopathologic etiologies, and outcomes for developing asymmetry at mammography. MATERIALS AND METHODS: In this institutional review board-approved, informed consent-waived, HIPAA-compliant, retrospective review of a mammography database for records from January 1, 2009 to December 31, 2012, 2354 consecutive diagnostic mammograms classified as showing focal asymmetry were identified. After patients with benign results, those considered stable, and those without prior mammograms were excluded, images from 521 studies were reviewed and 202 developing lesions were identified in 201 women. Patient demographics, US and MR imaging findings, and clinical and histopathologic outcomes were obtained from the electronic medical records. Equivocal US correlates of findings with developing asymmetry detected at mammography were excluded from statistical analysis. The Fisher exact test and Student t test analysis were performed and relative risk and 95% confidence intervals (CIs) were determined. RESULTS: Biopsy was performed in 73 (36%) of 201 patients with developing asymmetries, with 42 (58%) benign and 31 (42%) malignant results. Of 128 patients with nonbiopsied lesions, 110 (86%) were stable at 24 months (considered benign), 12 (9.4%) were stable at less than 24 months, and six (4.7%) were lost to follow-up. Diagnostic US was performed in 186 (93%) of 201 patients, 74 (40%) with correlates. US was performed in 30 (97%) of 31 patients with malignant developing asymmetries, 17 (57%) with correlates, and in 140 (92%) of 152 patients with benign lesions, 51 (36%) with correlates (risk ratio, 1.92; 95% CI: 1.001, 3.695; two-tailed P = .064, one-tailed P = .038). MR imaging was performed in 66 (33%) of 201 patients, 26 (39%) with correlates. MR imaging was performed in 10 (32%) of 31 patients with malignant developing asymmetries, all with correlates, and 53 (35%) of 152 patients with benign lesions, 15 (28%) with correlates (P < .0001). CONCLUSION: Developing asymmetries were malignant in 15% (95% CI: 11%, 21.1%) of patients. Presence of a US or MR imaging correlate was predictive of malignancy. PMID- 26583911 TI - Tracking and Therapeutic Value of Human Adipose Tissue-derived Mesenchymal Stem Cell Transplantation in Reducing Venous Neointimal Hyperplasia Associated with Arteriovenous Fistula. AB - PURPOSE: To determine if adventitial transplantation of human adipose tissue derived mesenchymal stem cells (MSCs) to the outflow vein of B6.Cg-Foxn1(nu)/J mice with arteriovenous fistula (AVF) at the time of creation would reduce monocyte chemoattractant protein-1 (Mcp-1) gene expression and venous neointimal hyperplasia. The second aim was to track transplanted zirconium 89 ((89)Zr) labeled MSCs serially with positron emission tomography (PET) for 21 days. MATERIALS AND METHODS: All animal experiments were performed according to protocols approved by the institutional animal care and use committee. Fifty B6.Cg-Foxn1(nu)/J mice were used to accomplish the study aims. Green fluorescent protein was used to stably label 2.5 * 10(5) MSCs, which were injected into the adventitia of the outflow vein at the time of AVF creation in the MSC group. Eleven mice died after AVF placement. Animals were sacrificed on day 7 after AVF placement for real-time polymerase chain reaction (n = 6 for MSC and control groups) and histomorphometric (n = 6 for MSC and control groups) analyses and on day 21 for histomorphometric analysis only (n = 6 for MSC and control groups). In a separate group of experiments (n = 3), animals with transplanted (89)Zr-labeled MSCs were serially imaged with PET for 3 weeks. Multiple comparisons were performed with two-way analysis of variance, followed by the Student t test with post hoc Bonferroni correction. RESULTS: In vessels with transplanted MSCs compared with control vessels, there was a significant decrease in Mcp-1 gene expression (day 7: mean reduction, 62%; P = .029), with a significant increase in the mean lumen vessel area (day 7: mean increase, 176% [P = .013]; day 21: mean increase, 415% [P = .011]). Moreover, this was accompanied by a significant decrease in Ki-67 index (proliferation on day 7: mean reduction, 81% [P = .0003]; proliferation on day 21: mean reduction, 60%, [P = .016]). Prolonged retention of MSCs at the adventitia was evidenced by serial PET images of (89)Zr-labeled cells. CONCLUSION: Adventitial transplantation of MSCs decreases Mcp-1 gene expression, accompanied by a reduction in venous neointimal hyperplasia. PMID- 26583914 TI - The effects of a reformer Pilates program on body composition and morphological characteristics in active women after a detraining period. AB - The aim of this quasi-experimental pilot study was to explore the effects of a reformer Pilates program on the anthropometry, body composition, and somatotype of active adult women after a short non-exercise period. Twenty-eight women (mean age: 40.21 +/- standard deviation of 8.12 years old) with one to three years of reformer Pilates experience participated in the study. The women participated in a reformer Pilates program for 16 weeks (one hour, twice per week) after 4 weeks of detraining (summer holidays) in 2012. The International Society for the Advancement of Kinanthropometry full profile was assessed before and after the intervention program. Significant decreases (p <= 0.05) from pre- to post-program were observed for triceps, iliac crest, supraspinale, abdominal, front thigh and medial calf skinfold thicknesses, six and eight skinfold thickness sums, forearm and ankle girths, waist/hip ratio, endomorphy, and fat mass. Significant increases (p <= .05) were observed for corrected arm, corrected calf girths, and muscle mass. Generally, women showed a mesomorphic endomorph (endomorphy predominant) and mesomorph-endomorph (endomorphy and mesomorphy predominant) in the pre- and posttests, respectively. In conclusion, the practice of reformer Pilates was associated with healthy changes in anthropometric parameters, body composition, and somatotype in Pilates-experienced women after 4 weeks of no physical exercise. PMID- 26583913 TI - Most Common Foodborne Pathogens and Mycotoxins on Fresh Produce: A Review of Recent Outbreaks. AB - Every year millions of people are affected and thousands of them die due to infections and intoxication as a result of foodborne outbreaks, which also cause billions of dollars' worth of damage, public health problems, and agricultural product loss. A considerable portion of these outbreaks is related to fresh produce and caused by foodborne pathogens on fresh produce and mycotoxins. Escherichia coli O104:H4 outbreak, occurred in Germany in 2011, has attracted a great attention on foodborne outbreaks caused by contaminated fresh produce, and especially the vulnerability and gaps in the early warning and notification networks in the surveillance systems in all around the world. In the frame of this paper, we reviewed the most common foodborne pathogens on fresh produce, traceback investigations of the outbreaks caused by these pathogens, and lastly international early warning and notification systems, including PulseNet International and Rapid Alert System for Food and Feed, aiming to detect foodborne outbreaks. PMID- 26583915 TI - Exposure to Elevated Carbon Monoxide Levels at an Indoor Ice Arena--Wisconsin, 2014. AB - On December 13, 2014, the emergency management system in Lake Delton, Wisconsin, was notified when a male hockey player aged 20 years lost consciousness after participation in an indoor hockey tournament that included approximately 50 hockey players and 100 other attendees. Elevated levels of carbon monoxide (CO) (range = 45 ppm-165 ppm) were detected by the fire department inside the arena. The emergency management system encouraged all players and attendees to seek medical evaluation for possible CO poisoning. The Wisconsin Department of Health Services (WDHS) conducted an epidemiologic investigation to determine what caused the exposure and to recommend preventive strategies. Investigators abstracted medical records from area emergency departments (EDs) for patients who sought care for CO exposure during December 13-14, 2014, conducted a follow-up survey of ED patients approximately 2 months after the event, and conducted informant interviews. Ninety-two persons sought ED evaluation for possible CO exposure, all of whom were tested for CO poisoning. Seventy-four (80%) patients had blood carboxyhemoglobin (COHb) levels consistent with CO poisoning; 32 (43%) CO poisoning cases were among hockey players. On December 15, the CO emissions from the propane-fueled ice resurfacer were demonstrated to be 4.8% of total emissions when actively resurfacing and 2.3% when idling, both above the optimal range of 0.5%-1.0%. Incomplete fuel combustion by the ice resurfacer was the most likely source of elevated CO. CO poisonings in ice arenas can be prevented through regular maintenance of ice resurfacers, installation of CO detectors, and provision of adequate ventilation. PMID- 26583916 TI - The Prognostic Nutritional Index Predicts Survival and Identifies Aggressiveness of Gastric Cancer. AB - Nutritional status has been associated with long-term outcomes in cancer patients. The prognostic nutritional index (PNI) is calculated by serum albumin concentration and absolute lymphocyte count, and it may be a surrogate biomarker for nutritional status and possibly predicts overall survival (OS) of gastric cancer. We evaluated the value of the PNI as a predictor for disease-free survival (DFS) in addition to OS in a cohort of 314 gastric cancer patients who underwent curative surgical resection. There were 77 patients in PNI-low group (PNI <= 47.3) and 237 patients in PNI-high group (PNI > 47.3). With a median follow-up of 36.5 mo, 5-yr DFS rates in PNI-low group and PNI-high group were 63.5% and 83.6% and 5-yr OS rates in PNI-low group and PNI-high group were 63.5% and 88.4%, respectively (DFS, P < 0.0001; OS, P < 0.0001). In the multivariate analysis, the only predictors for DFS were PNI, tumor-node-metastasis (TNM) stage, and perineural invasion, whereas the only predictors for OS were PNI, age, TNM stage, and perineural invasion. In addition, the PNI was independent of various inflammatory markers. In conclusion, the PNI is an independent prognostic factor for both DFS and OS, and provides additional prognostic information beyond pathologic parameters. PMID- 26583917 TI - Reference Ranges for Neonatal Basal Ganglia Perfusion as Measured by Fractional Moving Blood Volume. AB - BACKGROUND: Regional changes in cerebral blood flow and perfusion are implicated in the pathogenesis of adverse neurological events that lead to death and severe disability in the newborn infant. The basal ganglia, in particular, are extremely sensitive to acute hypoxia in the perinatal period, but normal perfusion to this area is unknown. OBJECTIVES: To establish a reference range for regional basal ganglia perfusion using fractional moving blood volume (FMBV) as an index. METHODS: Head ultrasounds were performed on neonates from 25 to 41 weeks' gestation. Power Doppler images were obtained from a pre-specified coronal plane. FMBV was calculated offline after selecting the basal ganglia as a region of interest. The average of five calculations was considered to be representative of the regional perfusion for each neonate. The data were analysed, and a neonatal reference range was defined. RESULTS: 124 neonates were included in the study, and all had analysable data. The mean FMBV was 28.8% (+/-9.6) with a reference range defined as 10-48%. The mean FMBV for neonates <32 weeks', 32-35 weeks' and >35 weeks' gestation were 29.4% (+/-7.8), 29.2% (+/-11.0) and 27.4% (+/-9.7), respectively. Analysis of variance showed no significant difference between neonates based on gestation. CONCLUSIONS: We have successfully used the index FMBV to define a reference range for perfusion in the basal ganglia. These data can be used as a reference for subsequent studies that evaluate basal ganglia perfusion in pathological conditions. PMID- 26583918 TI - Addiction and Other Reasons Adolescent Smokers Give to Justify Smoking. AB - BACKGROUND: The primary purpose of this paper is to examine youth addiction and other justifications for adolescent smoking, and how they affect the level of consumption. METHODS: Data from the Spanish 'State Survey on Drug Use among High School Students' aged between 14 and 18 years old were used in this paper. To account for the nature of the cigarette consumption data, several count data models were estimated in order to select the one that best fits adolescent smoking consumption. RESULTS: Most adolescent smokers smoke because it relaxes them, and about a quarter of them recognize that they are addicted. Moreover, the latter group smoke 44% more cigarettes than the rest (IRR = 1.444), revealing the strong addictive nature of tobacco, even at early ages. Moreover, parents' smoking increases the probability of smoking and has an impact on the level of consumption. CONCLUSIONS: The implications of these findings offer insight for parents, researchers, educators, and cessation interventionists, as awareness of self-reported and other predictors held by smoking youth creates a vantage point to facilitate changes in smoking behavior. PMID- 26583919 TI - Simulation of temperature field for temperature-controlled radio frequency ablation using a hyperbolic bioheat equation and temperature-varied voltage calibration: a liver-mimicking phantom study. AB - This study aims at improving the accuracy of temperature simulation for temperature-controlled radio frequency ablation (RFA). We proposed a new voltage calibration method in the simulation and investigated the feasibility of a hyperbolic bioheat equation (HBE) in the RFA simulation with longer durations and higher power. A total of 40 RFA experiments was conducted in a liver-mimicking phantom. Four mathematical models with multipolar electrodes were developed by the finite element method in COMSOL software: HBE with/without voltage calibration, and the Pennes bioheat equation (PBE) with/without voltage calibration. The temperature-varied voltage calibration used in the simulation was calculated from an experimental power output and temperature-dependent resistance of liver tissue. We employed the HBE in simulation by considering the delay time tau of 16 s. First, for simulations by each kind of bioheat equation (PBE or HBE), we compared the differences between the temperature-varied voltage calibration and the fixed-voltage values used in the simulations. Then, the comparisons were conducted between the PBE and the HBE in the simulations with temperature-varied voltage calibration. We verified the simulation results by experimental temperature measurements on nine specific points of the tissue phantom. The results showed that: (1) the proposed voltage-calibration method improved the simulation accuracy of temperature-controlled RFA for both the PBE and the HBE, and (2) for temperature-controlled RFA simulation with the temperature-varied voltage calibration, the HBE method was 0.55 degrees C more accurate than the PBE method. The proposed temperature-varied voltage calibration may be useful in temperature field simulations of temperature-controlled RFA. Besides, the HBE may be used as an alternative in the simulation of long-duration high-power RFA. PMID- 26583920 TI - Flexible MOFs under stress: pressure and temperature. AB - In the recent past an enormous number of Metal-Organic Framework type compounds (MOFs) have been synthesized. The novelty resides in their extremely high surface area and the ability to include additional features to their structure either during synthesis or as additives to the MOF. This versatility allows for MOFs to be designed for specific applications. However, the question arises as to whether a particular MOF can withstand the stress that may be encountered in fulfillment of the designated application. In this study we describe the behavior of two flexible MOFs under pressure and several others under temperature increase. The pressure study includes both experimental and theoretical calculations. In the thermal processes evidence for colossal negative thermal expansion were encountered. PMID- 26583921 TI - In Memoriam: A Tribute to Dr. William E. Paul. PMID- 26583922 TI - "Broadband" Bioinformatics Skills Transfer with the Knowledge Transfer Programme (KTP): Educational Model for Upliftment and Sustainable Development. AB - A shortage of practical skills and relevant expertise is possibly the primary obstacle to social upliftment and sustainable development in Africa. The "omics" fields, especially genomics, are increasingly dependent on the effective interpretation of large and complex sets of data. Despite abundant natural resources and population sizes comparable with many first-world countries from which talent could be drawn, countries in Africa still lag far behind the rest of the world in terms of specialized skills development. Moreover, there are serious concerns about disparities between countries within the continent. The multidisciplinary nature of the bioinformatics field, coupled with rare and depleting expertise, is a critical problem for the advancement of bioinformatics in Africa. We propose a formalized matchmaking system, which is aimed at reversing this trend, by introducing the Knowledge Transfer Programme (KTP). Instead of individual researchers travelling to other labs to learn, researchers with desirable skills are invited to join African research groups for six weeks to six months. Visiting researchers or trainers will pass on their expertise to multiple people simultaneously in their local environments, thus increasing the efficiency of knowledge transference. In return, visiting researchers have the opportunity to develop professional contacts, gain industry work experience, work with novel datasets, and strengthen and support their ongoing research. The KTP develops a network with a centralized hub through which groups and individuals are put into contact with one another and exchanges are facilitated by connecting both parties with potential funding sources. This is part of the PLOS Computational Biology Education collection. PMID- 26583923 TI - Enhancement of carotenoid bioaccessibility from carrots using excipient emulsions: influence of particle size of digestible lipid droplets. AB - The influence of initial lipid droplet size on the ability of excipient emulsions to increase carotenoid bioaccessibility from carrots was investigated using a simulated gastrointestinal tract (GIT). Corn oil-in-water excipient emulsions were fabricated with different surface-weighted mean droplet diameters: d32 = 0.17 MUm (fine), 0.46 MUm (medium), and, 10 MUm (large). Bulk oil containing a similar quantity of lipids as the emulsions was used as a control. The excipient emulsions and control were mixed with pureed carrots, and then passed through a simulated GIT (mouth, stomach, and small intestine), and changes in particle size, charge, microstructure, lipid digestion, and carotenoid bioaccessibility were measured. Carotenoid bioaccessibility significantly increased with decreasing lipid droplet size in the excipient emulsions, which was attributed to the rapid formation of mixed micelles that could solubilize the carotenoids in the intestinal fluids. These results have important implications for designing excipient foods, such as dressings, dips, creams, and sauces, to increase the bioavailability of health-promoting nutraceuticals in foods. PMID- 26583924 TI - Short versus Standard Mifepristone and Misoprostol Regimen for Second- and Third Trimester Termination of Pregnancy for Fetal Anomaly. AB - BACKGROUND: Termination of pregnancy requires a 48-hour 'window' between mifepristone and misoprostol. Shorter durations have been used in first-trimester termination, but there are few data available in later termination for fetal anomaly. MATERIAL AND METHODS: We reviewed all terminations for fetal anomaly at >=13 weeks from May 2013 to May 2014. Cases were managed using a short (<=12 h) or standard (>=36 h) mifepristone-to-misoprostol interval. RESULTS: Two hundred and twenty women underwent a termination of pregnancy for fetal anomaly during the study period, of which 119 were included for analysis. Sixty-six (55%) women were managed according to the short regimen and 53 (45%) women with the standard regimen. The short regimen resulted in a shorter mifepristone-to-delivery interval but was less likely to result in delivery within 12 h of misoprostol. Delivery rates at 24 h were equivocal. There was no difference in blood loss, vaginal delivery rates, complications or bed nights. The short regimen did require more doses of misoprostol. Feticide or previous uterine scar had no effect on outcomes. DISCUSSION: There was no significant difference in clinical outcome for women managed with a short (<=12 h) or a standard (>=36 h) regimen for medical termination of pregnancy for fetal anomaly, suggesting that either regimen could be offered. PMID- 26583925 TI - Simple, Rapid Mycobacterium ulcerans Disease Diagnosis from Clinical Samples by Fluorescence of Mycolactone on Thin Layer Chromatography. AB - INTRODUCTION: Mycobacterium ulcerans infection, known as Buruli ulcer, is a disease of the skin and subcutaneous tissues which is an important but neglected tropical disease with its major impact in rural parts of West and Central Africa where facilities for diagnosis and management are poorly developed. We evaluated fluorescent thin layer chromatography (f-TLC) for detection of mycolactone in the laboratory using samples from patients with Buruli ulcer and patients with similar lesions that gave a negative result on PCR for the IS2404 repeat sequence of M. ulcerans. METHODOLOGY/PRINCIPAL FINDINGS: Mycolactone and DNA extracts from fine needle aspiration (FNA), swabs and biopsy specimen were used to determine the sensitivity and specificity of f-TLC when compared with PCR for the IS2404. For 71 IS2404 PCR positive and 28 PCR negative samples the sensitivity was 73.2% and specificity of 85.7% for f-TLC. The sensitivity was similar for swabs (73%), FNAs (75%) and biopsies (70%). CONCLUSIONS: We have shown that mycolactone can be detected from M. ulcerans infected skin tissue by f-TLC technique. The technique is simple, easy to perform and read with minimal costs. In this study it was undertaken by a member of the group from each endemic country. It is a potentially implementable tool at the district level after evaluation in larger field studies. PMID- 26583927 TI - CTX-M-15-Producing Escherichia coli in Dolphin, Portugal. PMID- 26583926 TI - Epigenetic Control of Salmonella enterica O-Antigen Chain Length: A Tradeoff between Virulence and Bacteriophage Resistance. AB - The Salmonella enterica opvAB operon is a horizontally-acquired locus that undergoes phase variation under Dam methylation control. The OpvA and OpvB proteins form intertwining ribbons in the inner membrane. Synthesis of OpvA and OpvB alters lipopolysaccharide O-antigen chain length and confers resistance to bacteriophages 9NA (Siphoviridae), Det7 (Myoviridae), and P22 (Podoviridae). These phages use the O-antigen as receptor. Because opvAB undergoes phase variation, S. enterica cultures contain subpopulations of opvABOFF and opvABON cells. In the presence of a bacteriophage that uses the O-antigen as receptor, the opvABOFF subpopulation is killed and the opvABON subpopulation is selected. Acquisition of phage resistance by phase variation of O-antigen chain length requires a payoff: opvAB expression reduces Salmonella virulence. However, phase variation permits resuscitation of the opvABOFF subpopulation as soon as phage challenge ceases. Phenotypic heterogeneity generated by opvAB phase variation thus preadapts Salmonella to survive phage challenge with a fitness cost that is transient only. PMID- 26583928 TI - Interest of fusion imaging and modern navigation tools with hybrid rooms in endovascular aortic procedures. AB - Because of the emergence of hybrid operating rooms, cone-beam CT scans (CBCT) allow new intraoperative imaging to be produced. Image fusion (3D preoperative CT scan overlaid onto 2D live fluoroscopy image) is the most popular application and makes it possible to navigate throughout the aorta and its branches without having to make use of an additional injection, and allows a reduction to be achieved in the quantity of contrast medium and irradiation required during complex procedures. Planning-oriented software available in hybrid rooms makes it possible to adjust to the patient and the nature of the procedure, the information that is relevant during the operation. CBCT can also be used as a diagnostic tool at the end of a procedure for the detection of endoleaks and could replace routine CT scans made during the first month following the procedure, indirectly contributing again to a reduction of X-ray and contrast agent doses. PMID- 26583930 TI - Screw versus pin fixation with open reduction of pediatric lateral condyle fractures. AB - Good results have been described for lateral condyle fractures treated by open reduction and fixation using Kirschner wires or screws. We, in our level III retrospective comparison clinical research study, retrospectively reviewed 84 patients (43 K-wire, 41 screw fixation; average age 5.6 years, average follow-up 6.8 months). With K-wires there were three nonunions (average time to union 9.6 weeks). With screws, all fractures healed (average of 7.8 weeks). Screw fixation patients spent fewer days in a cast and had a greater range of motion at the last follow-up. Screw fixation is associated with fewer nonunions and faster time to union, but a secondary procedure for removal is required. PMID- 26583931 TI - Primary nonunion of the distal radius fractures in healthy children. AB - There are no published case series of nonunion of distal radius fractures in healthy children because of the rarity of its occurrence. We searched for all reported cases of this condition in Pubmed, Google scholar, and SCOPUS. We found three series, which included one previously reported by our group. The aim of the present study was to define the predisposing factors leading to nonunion after treatment of distal radius fractures in healthy children. We also aimed to emphasize that nonunion should be included in the list of complications of distal radius fractures in children and be mentioned in the textbook of pediatric trauma. PMID- 26583932 TI - Self-harm, Assault, and Undetermined Intent Injuries Among Pediatric Emergency Department Visits. AB - OBJECTIVES: Although injuries are a known cause of morbidity and mortality among children and adolescents, little is known about the epidemiology of injury related emergency department (ED) visits in the United States by injury intent. The objective of this analysis was to examine ED outcomes, defined as death in the ED, inpatient admission, and visit cost, among ED visits stratified by injury intent (i.e., self-harm, assault, and injury with undetermined intent, as compared with unintentional injuries). METHODS: All injury-related ED visits in the United States for children and adolescents, ages 8 to 17 years, were identified using the 2008 Nationwide Emergency Department Sample. Multivariate survey weighted logistic and linear regression analyses were then used to estimate the likelihood of death on ED visit, inpatient admission, and cost across the 4 injury types. RESULTS: In 2008, with the use of weighted estimates, there were 66,895 self-harm, 176,125 assault, 24,144 undetermined injury, and 4,244,589 unintentional injury ED visits among children 8 to 17 years. Visits due to self-harm, assault and undetermined injuries were more likely to result in death during the ED visit compared with visits due to unintentional injuries. Self-harm and undetermined intent were also associated with greater odds of inpatient admission as well as 90% and 60% higher ED visit costs, respectively. CONCLUSIONS: Data from this nationwide sample of pediatric ED visits highlight the resource burden of self-harm, undetermined intent, and assault injury visits. Pediatric EDs may provide a window of opportunity for better case identification and intervention with children experiencing violence and injury. PMID- 26583933 TI - The Association Between Weight Status and Pediatric Forearm Fractures Resulting From Ground-Level Falls. AB - OBJECTIVE: The purpose of our study was to evaluate the hypothesis that pediatric forearm fractures resulting from ground-level falls are associated with increased weight status (weight for age/sex percentile >= 95th) in comparison with those resulting from major trauma. METHODS: This is a retrospective case-control study nested within a case series of 929 children, ages 0 to 17 years, with self identified residence in Washington, DC, who were treated for isolated forearm fractures in an urban, academic pediatric emergency department between 2003 and 2006. Multivariable logistic regression was performed to test for the association of weight status with mechanism of injury while controlling for sex, age, race/ethnicity, bone fractured, and season. RESULTS: Of 929 forearm fractures, there were 226 (24.3%) with ground-level falls and 54 (5.8%) with major trauma. Compared with children with forearm fractures resulting from major trauma, ground level fall cases were significantly older (10.4 [3.4] vs 7.4 [4.2] years, P < 0.05), had greater adjusted odds of having a weight for age/sex of 95th percentile or higher (odds ratio, 2.7; 95% confidence interval, 1.2-6.5), and had significantly more radius-only fractures (odds ratio, 2.3; 95% confidence interval, 1.2-4.7). These groups did not differ in sex, race/ethnicity, or injury season. CONCLUSIONS: Ground-level falls are a common mechanism of pediatric forearm fracture and are significantly associated with increased weight status and radius-only fractures. These results suggest the need for further investigation into obesity and bone health in pediatric patients with forearm fractures caused by ground-level falls. PMID- 26583934 TI - Emergency Childcare for Hospital Workers During Disasters. AB - OBJECTIVES: The objectives were to determine the impact of emergency childcare (EC) needs on health care workers' ability and likelihood to work during a pandemic versus an earthquake as well as to determine the anticipated need and expected use of an on-site, hospital-provided EC program. METHODS: An online survey was distributed to all employees of an academic, urban pediatric hospital. Two disaster scenarios were presented (pandemic influenza and earthquake). Ability to work based on childcare needs, planned use of proposed hospital provided EC, and demographics of children being brought in were obtained. RESULTS: A total of 685 employees participated (96.6% female, 79.6% white), with a 40% response rate. Those with children (n = 307) reported that childcare needs would affect their work decisions during a pandemic more than an earthquake (61.1% vs 56.0%; t = 3.7; P < 0.001). Only 28.0% (n = 80) of those who would need childcare (n = 257) report an EC plan. The scenario did not impact EC need or planned use; during scheduled versus unscheduled shifts, 40.7% versus 63.0% reported need for EC, and 50.8% versus 63.2% reported anticipated using EC. CONCLUSIONS: Hospital workers have a high anticipated use of hospital-provided EC. Provisions for EC should be an integral part of hospital disaster planning. PMID- 26583935 TI - IBD LIVE Case Series--Case 3: Very Early-Onset Inflammatory Bowel Disease: When Genetic Testing Proves Beneficial. PMID- 26583936 TI - TCM, brain function and drug space. AB - Covering: up to 2015. Traditional Chinese medicine has played a significant role in the mainstream healthcare system in China for thousands of years. Here, we summarize 84 major compounds from 15 selected herbal medicines targeting neurodegenerative diseases. We present a perspective based on the analysis of physicochemical properties of these TCM compounds, and comparison with current drugs and candidates for the treatment of Parkinson's and Alzheimer's disease. The results demonstrate that traditional Chinese medicines contain compounds possessing physicochemical properties that have excellent overlap with developed western medicines. PMID- 26583937 TI - Correction: Acid-catalyzed carboxylic acid esterification and ester hydrolysis mechanism: acylium ion as a sharing active intermediate via a spontaneous trimolecular reaction based on density functional theory calculation and supported by electrospray ionization-mass spectrometry. AB - Correction for 'Acid-catalyzed carboxylic acid esterification and ester hydrolysis mechanism: acylium ion as a sharing active intermediate via a spontaneous trimolecular reaction based on density functional theory calculation and supported by electrospray ionization-mass spectrometry' by Hongchang Shi et al., Phys. Chem. Chem. Phys., 2015, DOI: 10.1039/c5cp02914g. PMID- 26583938 TI - Analysis of changes in maternal circulating angiogenic factors throughout pregnancy for the prediction of preeclampsia. AB - OBJECTIVE: To assess whether changes in maternal angiogenic factors throughout pregnancy predict the development of preeclampsia. STUDY DESIGN: Placental growth factor (PlGF) and soluble fms-like tyrosine kinase 1 receptor (sFlt-1) were measured in 2355 women at 10, 18, 26 and 35 weeks gestation. Receiver operator characteristic analysis was used to calculate test characteristics for changes in analytes between time points. Linear mixed-effects models generated slopes of analytes throughout pregnancy, which in turn were used as predictors in adjusted logistic regression models. RESULT: Changes in analytes yielded positive predictive values of 9 to 19% and negative predictive values of 93 to 97%. Individuals with lowest quartile slopes in PlGF had sixfold greater odds (95% confidence interval (CI): 3.5, 10.2) of preeclampsia compared with individuals in the highest quartile. With respect to sFlt-1, the highest quartile had 5.1 times greater odds (95% CI: 3.1, 8.4) than the lowest quartile. CONCLUSION: Measuring the trend in PlGF and sFlt-1 across pregnancy segregates women at increased risk of preeclampsia. However, changes in these factors throughout pregnancy lack clinically useful predictive power. PMID- 26583940 TI - To evaluate and compare the efficacy of combined sucrose and non-nutritive sucking for analgesia in newborns undergoing minor painful procedure: a randomized controlled trial. AB - OBJECTIVE: The objective of this study was to evaluate and compare the efficacy of combined sucrose and non-nutritive sucking (NNS) for analgesia in newborn infants undergoing heel-stick procedures. STUDY DESIGN: This randomized control trial was conducted in the neonatal intensive care unit of a tertiary care hospital over a period of 1 year. One hundred and eighty full-term neonates with birth weight >2200 g and age >24 h were randomized to one of four interventions administered 2 min before the procedure: 2 ml of 30% sucrose (group I, n=45) or NNS (group II, n=45) or both (group III, n=45) or none (group IV, n=45). Primary outcome was composite score based on Premature Infant Pain Profile (PIPP) score. RESULT: Baseline variables were comparable among the groups. Median (interquartile range) PIPP score was 3 (2 to 4) in group III as compared with 7 (6.5 to 8) in group I, 9 (7 to 11) in group II and 13 (10.5 to 15) in group IV. Group III had significant decrease in the median PIPP score compared with other groups (P=0.000). Median PIPP score also decreased significantly with any intervention as compared with no intervention (P=0.000). CONCLUSION: Sucrose and/or NNS are effective in providing analgesia in full-term neonates undergoing heel-stick procedures, with the combined intervention being more effective compared with any single intervention. PMID- 26583939 TI - Cardiorespiratory events in preterm infants: etiology and monitoring technologies. AB - Every year, an estimated 15 million infants are born prematurely (<37 weeks gestation) with premature birth rates ranging from 5 to 18% across 184 countries. Although there are a multitude of reasons for this high rate of preterm birth, once birth occurs, a major challenge of infant care includes the stabilization of respiration and oxygenation. Clinical care of this vulnerable infant population continues to improve, yet there are major areas that have yet to be resolved including the identification of optimal respiratory support modalities and oxygen saturation targets, and reduction of associated short- and long-term morbidities. As intermittent hypoxemia is a consequence of immature respiratory control and resultant apnea superimposed upon an immature lung, improvements in clinical care must include a thorough knowledge of premature lung development and pathophysiology that is unique to premature birth. In Part 1 of a two-part review, we summarize early lung development and diagnostic methods for cardiorespiratory monitoring. PMID- 26583941 TI - Use of neonatal simulation models to assess competency in bag-mask ventilation. AB - OBJECTIVE: Providing adequate bag-mask ventilation (BMV) is an essential skill for neonatal resuscitation. Often this skill is learned using simulation manikins. Currently, there is no means of measuring the adequacy of ventilation in simulated scenarios. Thus, it is not possible to ascertain proficiency. The first aim of this study was to measure the pressure generated during BMV as performed by providers with different skill levels and measure the impact of different feedback mechanisms. The second aim was to measure the pressure volume characteristics of two neonatal manikins to see how closely they reflect newborn lung mechanics. STUDY DESIGN: In Phase I to achieve the first aim, we evaluated BMV skills in different level providers including residents (n=5), fellows (n=5), neonatal nurse practitioners (n=5) and neonatologists (n=5). Each provider was required to provide BMV for 2-min epochs on the SimNewB (Laerdal), which had been instrumented to measure pressure-volume characteristics. In sequential 2-min epochs, providers were given different feedback including chest-wall movement alone compared to manometer plus chest-wall movement or chest-wall movement plus manometer plus laptop lung volume depiction. In Phase II of the study we measured pressure-volume characteristics in instrumented versions of the SimNewB (Laerdal) and NeoNatalie (Laerdal). RESULTS: In Phase I, all providers are compared with the neonatologists. All measurements of tidal volume (Vt) are below the desired 5 ml kg(-1). The greatest difference in Vt between the neonatologists and other providers occurs when only chest-wall movement is provided. A linear relationship is noted between Vt and PIP for both SimNewB and NeoNatalie. The compliance curves are not 'S-shaped' and are different between the two models (P<0.001). CONCLUSION: Phase I of this study demonstrates that the SimNewB with the feedback of chest-wall movement alone was the best method of distinguishing experienced from inexperienced providers during simulated BMV. Therefore this is likely to be the best method to ascertain proficiency. Phase II of the study shows that the currently available neonatal simulation manikins do not have pressure-volume characteristics that are reflective of newborn lung mechanics, which can result in suboptimal training. PMID- 26583942 TI - Extremely premature birth and the choice of neonatal intensive care versus palliative comfort care: an 18-year single-center experience. AB - OBJECTIVE: Review all live births 22 0/7 through 26 6/7 weeks gestation born 1996 through 2013 at our institution to describe the decision process and immediate outcomes of palliative comfort care (PCC) versus neonatal intensive care (NICU) and whether any significant family complaints or quality assurance concerns arose. STUDY DESIGN: Retrospective chart review, physician and ethicist interview process and database review focused upon our established periviability counseling guidelines that are directive of PCC at 22 weeks gestation and NICU at 26 weeks but supportive of informed family choice of either option at 23, 24 and 25 weeks. RESULT: At 22 weeks--all 54 infants had PCC; at 23 weeks--29/78 (37%) chose NICU care, 6/29 (21%) infants survived; at 24 weeks--79/108 (73%) chose NICU care, 47/79 (59%) survived; at 25 weeks--147/153 (96%) chose NICU care, 115/147 (78%) survived; and at 26 weeks--all infants had NICU care, 176/203 (87%) survived. Over 18 years and 606 births, we identified only three significant concerns from families and/or physicians that required formal review. CONCLUSION: Most pregnant women and families choose NICU care for their extremely premature infant, but if given the option via shared decision making, a significant proportion will choose PCC at gestational ages that some NICUs mandate resuscitation. We support a reasoned dialogue and bioethical framework that recognizes human values to be irreducibly diverse, sometimes conflicting, and ultimately incommensurable--value pluralism. Respectful shared decision making requires thoughtful and compassionate flexibility, nuanced and individualized suggestions for PCC or NICU and the reduction of hierarchical directives from physicians to families. We continue to advocate and rely upon informed family preference between 23 and 25 weeks gestation in our updated 2015 periviability guidelines. PMID- 26583944 TI - Neonatal airway simulators, how good are they? A comparative study of physical and functional fidelity. AB - OBJECTIVE: Proficiency in airway management is critical for neonatal health-care professionals. Simulation is a proven method to improve airway management skills. Skills transfer from simulation to the real life requires simulators with appropriate physical and functional fidelity. STUDY DESIGN: A cohort of neonatal health-care professionals evaluated eight different neonatal airway simulators for physical and functional fidelity. RESULT: Twenty-seven subjects completed 151 simulator evaluations. Significant differences were found between the simulators evaluated (P<0.001). The manikins with the highest fidelity scores were the SimNewB, Newborn Anne and Premature Anne (Laerdal Medical). The task trainers with the highest fidelity scores were the Neonatal Intubation Trainer (Laerdal Medical) and the Newborn Airway Trainer (Syndaver Labs). CONCLUSION: Simulator fidelity is an important aspect of simulation training, but is rarely evaluated. The results of this study can aid in choosing the best simulators for training and research, and provide feedback to the industry to guide future simulator development. PMID- 26583943 TI - Cardiorespiratory events in preterm infants: interventions and consequences. AB - Stabilization of respiration and oxygenation continues to be one of the main challenges in clinical care of the neonate. Despite aggressive respiratory support including mechanical ventilation, continuous positive airway pressure, oxygen and caffeine therapy to reduce apnea and accompanying intermittent hypoxemia, the incidence of intermittent hypoxemia events continues to increase during the first few months of life. Even with improvements in clinical care, standards for oxygen saturation targeting and modes of respiratory support have yet to be identified in this vulnerable infant cohort. In addition, we are only beginning to explore the association between the incidence and pattern of cardiorespiratory events during early postnatal life and both short- and long term morbidity including retinopathy of prematurity, growth, sleep-disordered breathing and neurodevelopmental impairment. Part 1 of this review included a summary of lung development and diagnostic methods of cardiorespiratory monitoring. In Part 2 we focus on clinical interventions and the short- and long term consequences of cardiorespiratory events in preterm infants. PMID- 26583945 TI - Jaundice, phototherapy and DNA damage in full-term neonates. AB - OBJECTIVE: Phototherapy is the standard therapeutic approach for neonatal hyperbilirubinemia. Oxidative effects of phototherapy may have potential harms, including DNA damage. Unconjugated bilirubin (UCB) might also possess antigenotoxic potential. Intensive phototherapy is more efficacious than conventional phototherapy in treating hyperbilirubinemia. This study aimed to assess the impact of hyperbilirubinemia and the two different types of phototherapy on DNA damage in peripheral blood mononuclear cells of neonates. STUDY DESIGN: The study was conducted on term neonates with non-hemolytic hyperbilirubinemia and control healthy neonates. Genotoxicity was assessed using single-cell gel electrophoresis (Comet assay) in peripheral mononuclear cells. Blood samples were obtained at enrollment in all infants and after intensive or conventional phototherapy in jaundiced infants. RESULT: DNA damage did not significantly differ between jaundiced and non-jaundiced neonates (11.4+/-8.7 and 10.9+/-8.3 arbitrary units (AU), respectively, P=0.58). It increased significantly after exposure to phototherapy compared with prephototherapy values (45.6+/-14.7 vs 11.4+/-8.7 AU, respectively, P<0.001). The duration of phototherapy correlated positively with markers of DNA damage (r=0.86, P<0.001); however, the intensity of used light did not significantly impact genotoxicity. CONCLUSION: Hyperbilirubinemia does not influence DNA damage, whereas both conventional and intensive phototherapy are associated with DNA damage in term infants with hyperbilirubinemia. PMID- 26583946 TI - Monitoring the respiratory rate by miniature motion sensors in premature infants: a comparative study. AB - OBJECTIVE: Existing respiratory rate (RR) monitors suffer from inaccuracy. The study assesses the accuracy of a novel modality that monitors lung ventilation with miniature motion sensors. STUDY DESIGN: RR was measured by three methods: impedance technology, motion sensors and visual count, in babies (n=9) that breathed spontaneously or with respiratory support and babies (n=12) that received high-frequency oscillatory ventilation (HFOV). RESULTS: A line close to equality (slope=0.96, r(2)=0.83) was obtained between the motion sensor and the visual count of the RR with narrow 95% limits of agreements (<14.0 b.p.m.). The relationship between the impedance and the visual count showed a lower correlation (r(2)=0.65) and wider 95% limits of agreements (21.4 b.p.m.). The motion sensor- and the ventilator-determined RRs demonstrated a good agreement during HFOV, whereas the impedance failed to measure the RR during HFOV. CONCLUSION: Monitoring RR with motion sensors is more accurate compared with the impedance, in infants, in all ventilation modes. PMID- 26583947 TI - A Facial Nerve Anniversary--Twelve Months of Treatment Time Saved. PMID- 26583949 TI - White light emission from a two-component hybrid gel via an energy transfer process. AB - A two-component light-harvesting organogel containing a naphthalimide-based gelator (1) as a donor and a phosphorescent Ir(III) complex [Ir(bt)2(acac)] (bt = 2-phenylbenzothiazole and acac = acetylacetone) (Ir) as an acceptor was used to produce white-light-emitting organogels. The addition of complex Ir to the gel 1 had a certain effect on the self-assembly behaviour of molecule 1, but did not affect the gelation ability, mechanical strength and structure surface wettability of the gel. The optical properties of the two-component gel 1-Ir could be tuned via high intermolecular energy transfer efficiency between 1 and complex Ir, which was confirmed by geometry optimizations and harmonic vibrational analyses. The white-light-emitting organogel was obtained with the molar ratio of complex Ir in the range of 0.3-1.0. In particular, the gel 1-Ir with the addition of 0.5 equivalent of Ir could emit white-light with the Commission Internationale de L' eclairage (CIE) coordinates of 0.33 and 0.31 under the excitation of 374 nm light. PMID- 26583950 TI - Incidence of Orbital Recurrence After Enucleation or Ophthalmic Artery Chemosurgery for Advanced Intraocular Retinoblastoma. PMID- 26583948 TI - Small Molecule T315 Promotes Casitas B-Lineage Lymphoma-Dependent Degradation of Epidermal Growth Factor Receptor via Y1045 Autophosphorylation. AB - RATIONALE: Despite the fact that tyrosine kinase inhibitors (TKIs) have been found effective in treating patients harboring activating mutations of epidermal growth factor receptor (EGFR), an acquired secondary mutation, T790M, which lowers the affinity to TKIs, can lead to EGFR TKI resistance after this standard treatment. OBJECTIVES: To evaluate the effect of small molecule T315 on EGFR degradation and its therapeutic efficacy in vitro and in vivo. METHODS: Lung adenocarcinoma cells were treated with T315, and cell proliferation and apoptotic proportion were determined by the CellTiter 96 AQueous MTS (3-[4,5 dimethylthiazol-2-yl]-5-[3-carboxymethoxyphenyl]-2-[4-sulfophenyl]-2H tetrazolium, inner salt) assay and flow cytometry. The effects of T315 on EGFR mRNA and protein levels, autophosphorylation, ubiquitination, and degradation were evaluated by real-time polymerase chain reaction and Western blot, respectively. Direct targeting of T315 to EGFR was confirmed by the in vitro kinase assay and mass spectrometry. Finally, the preclinical effect of T315 was validated in the murine xenograft model in combination with a second-generation TKI, afatinib. MEASUREMENTS AND MAIN RESULTS: We identified T315 as a novel, potent small molecule for suppressing cancer cell proliferation in vitro and in vivo. The therapeutic effect was verified after T315 was combined with a second generation TKI, afatinib, compared with a single drug administration. We found a new mechanism of action, in that T315 appears to directly bind EGFR and triggers EGFR-Y1045 autophosphorylation, whereby its degradation is triggered through the ubiquitin-proteasome pathway. CONCLUSIONS: Our evidence suggests that T315 is a novel class of anticancer drug that is able to inhibit the growth of EGFR-TKI resistant lung adenocarcinoma cells by inducing the degradation of EGFR. PMID- 26583951 TI - Multivariate piecewise exponential survival modeling. AB - In this article, we develop a piecewise Poisson regression method to analyze survival data from complex sample surveys involving cluster-correlated, differential selection probabilities, and longitudinal responses, to conveniently draw inference on absolute risks in time intervals that are prespecified by investigators. Extensive simulations evaluate the developed methods with extensions to multiple covariates under various complex sample designs, including stratified sampling, sampling with selection probability proportional to a measure of size (PPS), and a multi-stage cluster sampling. We applied our methods to a study of mortality in men diagnosed with prostate cancer in the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial to investigate whether a biomarker available from biospecimens collected near time of diagnosis stratifies subsequent risk of death. Poisson regression coefficients and absolute risks of mortality (and the corresponding 95% confidence intervals) for prespecified age intervals by biomarker levels are estimated. We conclude with a brief discussion of the motivation, methods, and findings of the study. PMID- 26583952 TI - Confocal laser endomicroscopy: a novel method for prediction of relapse in Crohn's disease. AB - BACKGROUND AND STUDY AIMS: Confocal laser endomicroscopy (CLE) has been shown to predict relapse in ulcerative colitis in remission, but little is currently known about its role in Crohn's disease. The aim of this study was to identify reproducible CLE features in patients with Crohn's disease and to examine whether these are risk factors for relapse. PATIENTS AND METHODS: This was a single center prospective feasibility study of CLE imaging in patients with Crohn's disease. CLE imaging was performed in the terminal ileum and four colorectal sites, and was correlated with histopathology and macroscopic appearance. Clinical relapse, defined as the need for treatment escalation or surgical intervention, was recorded during follow-up. RESULTS: The study included 50 patients: 39 with Crohn's disease (20 in remission), and 11 controls. Ileal fluorescein leakage and microerosions were significantly more frequent in patients with endoscopically active Crohn's disease compared with patients with inactive Crohn's disease and controls (P = 0.005 and (P = 0.006, respectively). The same applied to colorectal fluorescein leakage and vascular alterations ((P = 0.043 and (P = 0.034, respectively). During a 12-month follow-up period, ileal fluorescein leakage and microerosions were significant risk factors for relapse in the subgroup of patients in remission (log rank (P = 0.009 and (P = 0.007, respectively) as well as in the entire group of patients with Crohn's disease (log rank (P = 0.006 and (P = 0.01, respectively). Inter- and intraobserver reproducibility was almost perfect (kappa > 0.80) or substantial (kappa > 0.60) for the majority of CLE parameters. CONCLUSIONS: CLE can identify reproducible microscopic changes in the terminal ileum that are risk factors for relapse in patients with otherwise inactive Crohn's disease. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01738529). PMID- 26583953 TI - The Effects of Slackline Balance Training on Postural Control in Older Adults. AB - The present study investigated whether slackline training enhances postural control in older adults. Twenty-four participants were randomized into an intervention and a control group. The intervention group received 6 weeks of slackline training, two times per week. Pre-post measurement included the time of different standing positions on a balance platform with and without an external disturbance and the acceleration of the balance platform. Results showed significantly improved standing times during one-leg stance without external disturbance and a significantly reduced acceleration of the balance platform for the intervention group after the training period during tandem stance with and without an external disturbance. We conclude that slackline training in older adults has a positive impact on postural control and thus on the reduction of fall risk. PMID- 26583954 TI - Predictors of treatment outcome in an effectiveness trial of cognitive behavioral therapy for children with anxiety disorders. AB - A substantial number of children with anxiety disorders do not improve following cognitive behavioral therapy (CBT). Recent effectiveness studies have found poorer outcome for CBT programs than what is typically found in efficacy studies. The present study examined predictors of treatment outcome among 181 children (aged 8-15 years), with separation anxiety, social phobia, or generalized anxiety disorder, who participated in a randomized, controlled effectiveness trial of a 10-session CBT program in community clinics. Potential predictors included baseline demographic, child, and parent factors. Outcomes were as follows: a) remission from all inclusion anxiety disorders; b) remission from the primary anxiety disorder; and c) child- and parent-rated reduction of anxiety symptoms at post-treatment and at 1-year follow-up. The most consistent findings across outcome measures and informants were that child-rated anxiety symptoms, functional impairment, a primary diagnosis of social phobia or separation anxiety disorder, and parent internalizing symptoms predicted poorer outcome at post treatment. Child-rated anxiety symptoms, lower family social class, lower pretreatment child motivation, and parent internalizing symptoms predicted poorer outcome at 1-year follow-up. These results suggest that anxious children with more severe problems, and children of parents with elevated internalizing symptom levels, may be in need of modified, additional, or alternative interventions to achieve a positive treatment outcome. PMID- 26583955 TI - Use of 18F-Fludeoxyglucose-Positron Emission Tomography/Computed Tomography for Patient Management and Outcome in Oropharyngeal Squamous Cell Carcinoma: A Review. AB - 18F-fludeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) has been performed widely in diagnosis and management of patients with oropharyngeal squamous cell carcinoma (OPSCC). This review summarizes the literature on this tool in the management of these patients. The use of FDG PET/CT helps in accurate staging of primary tumor, nodal involvement, and distant metastasis of patients with OPSCC. Contrast-enhanced FDG-PET/CT combines high resolution CT and functional FDG-PET, providing the optimum imaging information for patient management. Using contrast-enhanced PET/CT leads to a combined anatomic and metabolic approach to radiation therapy planning in OPSCC. Moreover, PET/CT not only is a good modality for therapy assessment but also is a powerful tool in early recurrence detection of OPSCC. Finally, the PET/CT parameters provide survival information in patients with OPSCC; however, further studies are needed to introduce a scoring system to use clinically for prognosis prediction. PMID- 26583956 TI - No Evidence of Gouleako and Herbert Virus Infections in Pigs, Cote d'Ivoire and Ghana. AB - A recent report suggested that 2 novel bunyaviruses discovered in insects in Cote d'Ivoire caused lethal disease in swine in South Korea. We conducted cell culture studies and tested serum from pigs exposed to mosquitoes in Cote d'Ivoire and Ghana and found no evidence for infection in pigs. PMID- 26583957 TI - Malformations Caused by Shuni Virus in Ruminants, Israel, 2014-2015. PMID- 26583958 TI - Transmission of force to the hyoid bone during manual strangulation: Simulation using finite element numerical models. AB - INTRODUCTION: Strangulation is a medicolegal form of mechanical asphyxia, and can be difficult to identify if cutaneous damage to the neck is limited. We began by creating a numerical model of a hyoid bone with adjustable anthropometric parameters and then subjected our model to compression simulating a precision grip on the neck from the front. MATERIALS AND METHODS: We selected six bones from the 77 hyoid bones contained in the database we created during a previous study led by our laboratory, in which we demonstrated the sexual dimorphism of this bone and identified the minimal force required for fracture. The anthropometric characteristics of these six bones (angle, length and width) corresponded to those of the 10th, 50th and 90th percentiles from cluster 1 (male individuals) and cluster 2 (female individuals), respectively. After enhancing, developing and meshing the selected 3D models, we analysed and reproduced simulation conditions that were as close as possible to the in vivo conditions of neck strangulation from the front (area of pressure on the bone, tissue environment, and biological variability of this bone). RESULTS: We modelled the six numerical hyoid bone models using the finite element method. For all models, the simulation of mechanical pressure applied to simulate anterior strangulation resulted in fractures. The forces required to produce these fractures matched the results obtained in the experimental testing of dissected hyoid bones. CONCLUSION: Six finite element numerical models were created, covering the anthropometric morphological variability of the hyoid bone. These six models enabled numerical simulation of the in vivo behaviour of a hyoid bone subjected to one-handed strangulation. PMID- 26583959 TI - The polymorphism of crime scene investigation: An exploratory analysis of the influence of crime and forensic intelligence on decisions made by crime scene examiners. AB - A growing body of scientific literature recurrently indicates that crime and forensic intelligence influence how crime scene investigators make decisions in their practices. This study scrutinises further this intelligence-led crime scene examination view. It analyses results obtained from two questionnaires. Data have been collected from nine chiefs of Intelligence Units (IUs) and 73 Crime Scene Examiners (CSEs) working in forensic science units (FSUs) in the French speaking part of Switzerland (six cantonal police agencies). Four salient elements emerged: (1) the actual existence of communication channels between IUs and FSUs across the police agencies under consideration; (2) most CSEs take into account crime intelligence disseminated; (3) a differentiated, but significant use by CSEs in their daily practice of this kind of intelligence; (4) a probable deep influence of this kind of intelligence on the most concerned CSEs, specially in the selection of the type of material/trace to detect, collect, analyse and exploit. These results contribute to decipher the subtle dialectic articulating crime intelligence and crime scene investigation, and to express further the polymorph role of CSEs, beyond their most recognised input to the justice system. Indeed, they appear to be central, but implicit, stakeholders in intelligence-led style of policing. PMID- 26583960 TI - Postmortem tissue distribution of acetyl fentanyl, fentanyl and their respective nor-metabolites analyzed by ultrahigh performance liquid chromatography with tandem mass spectrometry. AB - In the last two years, an epidemic of fatal narcotic overdose cases has occurred in the Tampa area of Florida. Fourteen of these deaths involved fentanyl and/or the new designer drug, acetyl fentanyl. Victim demographics, case histories, toxicology findings and causes and manners of death, as well as, disposition of fentanyl derivatives and their nor-metabolites in postmortem heart blood, peripheral blood, bile, brain, liver, urine and vitreous humor are presented. In the cases involving only acetyl fentanyl (without fentanyl, n=4), the average peripheral blood acetyl fentanyl concentration was 0.467 mg/L (range 0.31 to 0.60 mg/L) and average acetyl norfentanyl concentration was 0.053 mg/L (range 0.002 to 0.086 mg/L). In the cases involving fentanyl (without acetyl fentanyl, n=7), the average peripheral blood fentanyl concentration was 0.012 mg/L (range 0.004 to 0.027 mg/L) and average norfentanyl blood concentration was 0.001 mg/L (range 0.0002 to 0.003 mg/L). In the cases involving both acetyl fentanyl and fentanyl (n=3), the average peripheral blood acetyl fentanyl concentration was 0.008 mg/L (range 0.006 to 0.012 mg/L), the average peripheral blood acetyl norfentanyl concentration was 0.001 mg/L (range 0.001 to 0.002 mg/L), the average peripheral blood fentanyl concentration was 0.018 mg/L (range 0.015 to 0.021mg/L) and the average peripheral blood norfentanyl concentration was 0.002 mg/L (range 0.001 mg/L to 0.003 mg/L). Based on the toxicology results, it is evident that when fentanyl and/or acetyl fentanyl were present, they contributed to the cause of death. A novel ultrahigh performance liquid chromatography (UPLC) tandem mass spectrometry (MS/MS) method to identify and quantify acetyl fentanyl, acetyl norfentanyl, fentanyl and norfentanyl in postmortem fluids and tissues is also presented. PMID- 26583961 TI - Spillover of Peste des Petits Ruminants Virus from Domestic to Wild Ruminants in the Serengeti Ecosystem, Tanzania. AB - We tested wildlife inhabiting areas near domestic livestock, pastures, and water sources in the Ngorongoro district in the Serengeti ecosystem of northern Tanzania and found 63% seropositivity for peste des petits ruminants virus. Sequencing of the viral genome from sick sheep in the area confirmed lineage II virus circulation. PMID- 26583962 TI - Evaluation of GalaxyDock Based on the Community Structure-Activity Resource 2013 and 2014 Benchmark Studies. AB - We analyze the results of the GalaxyDock protein-ligand docking program in the two recent experiments of Community Structure-Activity Resource (CSAR), CSAR 2013 and 2014. GalaxyDock performs global optimization of a modified AutoDock3 energy function by employing the conformational space annealing method. The energy function of GalaxyDock is quite sensitive to atomic clashes. Such energy functions can be effective for sampling physically correct conformations but may not be effective for scoring when conformations are not fully optimized. In phase 1 of CSAR 2013, we successfully selected all four true binders of digoxigenin along with three false positives. However, the energy values were rather high due to insufficient optimization of the conformations docked to homology models. A posteriori relaxation of the model complex structures by GalaxyRefine improved the docking energy values and differentiated the true binders from the false positives better. In the scoring test of CSAR 2013 phase 2, we selected the best poses for each of the two targets. The results of CSAR 2013 phase 3 suggested that an improved method for generating initial conformations for GalaxyDock is necessary for targets involving bulky ligands. Finally, combining existing binding information with GalaxyDock energy-based optimization may be needed for more accurate binding affinity prediction. PMID- 26583963 TI - NHANES Data Support Link between Handling of Thermal Paper Receipts and Increased Urinary Bisphenol A Excretion. AB - Some thermal paper receipts, commonly referred to as cash register receipts, contain high levels of bisphenol A (BPA). The goal of this study is to investigate whether increased contact with thermal paper receipts is associated with an increase in urinary BPA excretion. Individuals from the NHANES 2003-2004 survey were stratified based on occupation to compare urinary BPA excretion levels. The first major finding demonstrates that individuals with potential occupational exposure to thermal paper receipts are more likely to have detectable levels of urinary BPA compared to individuals with unlikely occupational exposure (p-value <0.001). The second major finding is that females with potential occupational exposure to thermal paper receipts have significantly higher levels of urinary BPA excretion (geometric mean (GM): 5.45 MUg/L, 95% CI: (4.02, 7.39)) compared to females with unlikely occupational exposure (GM: 2.16 MUg/L, 95% CI: (1.73, 2.70)). This association continues to remain statistically significant when controlling for creatinine, race, body mass index (BMI), and age. Notably, there was no statistically significant association between occupation and urinary BPA excretion among males. These results suggest that exposure to BPA from thermal paper should be considered when determining aggregate BPA exposure. PMID- 26583964 TI - Cooperativity and Site-Selectivity of Intramolecular Hydrogen Bonds on the Fluorescence Quenching of Modified GFP Chromophores. AB - This paper provides the first example of experimentally characterized hydrogen bond cooperativity on fluorescence quenching with a modified green fluorescence protein (GFP) chromophore that contains a 6-membered C?N...H-O and a 7-membered C?O...H-O intramolecular H-bonds. Variable-temperature (1)H NMR and electronic absorption and emission spectroscopies were used to elucidate the preference of intra- vs intermolecular H-bonding at different concentrations (1 mM and 10 MUM), and X-ray crystal structures provide clues of possible intermolecular H-bonding modes. In the ground state, the 6-membered H-bond is significant but the 7 membered one is rather weak. However, fluorescence quenching is dominated by the 7-membered H-bond, indicating a strengthening of the H-bond in the excited state. The H-bonding effect is more pronounced in more polar solvents, and no intermediates were observed from femtosecond fluorescence decays. The fluorescence quenching is attributed to the occurrence of diabatic excited-state proton transfer. Cooperativity of the two intramolecular H-bonds on spectral shifts and fluorescence quenching is evidenced by comparing with both the single H-bonded and the non-H-bonded counterparts. The H-bond cooperativity does not belong to the conventional patterns of sigma- and pi-cooperativity but a new type of polarization interactions, which demonstrates the significant interplay of H bonds for multiple H-bonding systems in the electronically excited states. PMID- 26583965 TI - Associations between sensor-based physical activity behaviour features and health related parameters. AB - OBJECTIVES: Wearable actimetry devices are used increasingly in cohort and cross sectional studies to assess physical activity (PA) behaviour objectively. Thus far, the medical relevance of distinct PA groups, as identified by using new methods of sensor data analysis, remains unclear. The objective of this research paper is to evaluate whether such PA groups differ in commonly accepted health risk parameters. METHODS: PA sensor data and corresponding outcome data of the NHANES 2005-06 study were obtained. Data pre-processing included elimination of potential outliers, data splitting and the computation of PA parameters, including a novel regularity measure. PA groups were identified using the x-Means clustering algorithm, and groups were evaluated for differences in CRP, BMI and HDL. RESULTS: Data sets of 7334 NHANES participants were analysed, and four distinct PA groups were identified. Statistically significant group differences were found for CRP and BMI (p<0.001), but not for HDL (p=0.67). CONCLUSIONS: PA groups derived from objective accelerometer mass data differ in exemplary health related outcome parameters. The novel PA regularity measure is of particular interest and may become part of future PA assessments, especially when regarding low-intensity, short-lived PA events. Further research in pattern recognition methods and analytic algorithms for PA data from current multi-sensing devices is necessary. PMID- 26583966 TI - Evidence of muscular adaptations within four weeks of barbell training in women. AB - We investigated the time course of neuromuscular and hypertrophic adaptations associated with only four weeks of barbell squat and deadlift training. Forty seven previously untrained women (mean+/-SD, age=21+/-3years) were randomly assigned to low volume training (n=15), moderate volume training (n=16), and control (n=16) groups. The low and moderate volume training groups performed two and four sets, respectively, of five repetitions per exercise, twice a week. Testing was performed weekly, and included dual X-ray absorptiometry and vastus lateralis and rectus femoris B-mode ultrasonography. Bipolar surface electromyographic (EMG) signals were detected from the vastus lateralis and biceps femoris during isometric maximal voluntary contractions of the leg extensors. Significant increases in lean mass for the combined gynoid and leg regions for the low (+0.68kg) and moderate volume (+0.47kg) groups were demonstrated within three weeks. Small-to-moderate effect sizes were shown for leg lean mass, vastus lateralis thickness and pennation angle, and peak torque, but EMG amplitude was unaffected. These findings demonstrated rapid muscular adaptations in response to only eight sessions of back squat and deadlift training in women despite the absence of changes in agonist-antagonist EMG amplitude. PMID- 26583967 TI - Twist within a somersault. AB - The twisting somersault is a key skill in diving and gymnastics. The components of twist and somersault are defined with respect to anatomical axes, and combinations of multiples of half rotations of twist and somersault define specific twisting somersault skills. To achieve a twisting somersault skill twist must be continuous; otherwise oscillations in twist while somersaulting may be observed. The posture-dependent inertial properties of the athlete and the initial conditions determine if continuous or oscillating twist is observed. The paper derives equations for the amount of somersault required per half twist, or per twist oscillation, without making assumptions about the relative magnitudes of the moments of inertia. From these equations the skills achievable may be determined. The error associated with the common assumption that the medial and transverse principal moments of inertia are equal is explored. It is concluded that the error grows as the number of twists per somersault decreases, when the medial and transverse moments of inertia diverge, and when the longitudinal moment of inertia approaches either the medial or transverse moment of inertia. Inertial property data for an example athlete are used to illustrate the various rotational states that can occur. PMID- 26583968 TI - Novel Waddlia Intracellular Bacterium in Artibeus intermedius Fruit Bats, Mexico. AB - An intracellular bacterium was isolated from fruit bats (Artibeus intermedius) in Cocoyoc, Mexico. The bacterium caused severe lesions in the lungs and spleens of bats and intracytoplasmic vacuoles in cell cultures. Sequence analyses showed it is related to Waddlia spp. (order Chlamydiales). We propose to call this bacterium Waddlia cocoyoc. PMID- 26583969 TI - On Pair Functions for Strong Correlations. AB - The UHF wave function may be written as a spin-contaminated pair wave function of the APSG form, and the overlap of the alpha and beta corresponding orbitals of the UHF solution can be taken as a proxy for the strength of the correlation captured by breaking symmetry. We demonstrate this with calculations on one- and two-dimensional hydrogen clusters and make contact with the well studied Hubbard model. The UHF corresponding orbitals pair in a manner that allows a smooth evolution from doubly occupied orbitals at small distance to one in which wave function breaks symmetry, segregating the alpha and beta electrons onto distinct sublattices at large distances. By performing spin projection on these UHF solutions, we address strong correlations that are difficult to capture at intermediate distances using a single determinant. PMID- 26583970 TI - Rapid Conformational Fluctuations of Disordered HIV-1 Fusion Peptide in Solution. AB - The conformationally flexible fusion peptide (FP) of HIV-1 is indispensible for viral infection of host cells, due to its ability to insert into and tightly couple with phospholipid membranes. There are conflicting reports on the membrane associated structure of FP, and solution structure information is limited, yet such a structure is the target for a novel class of antiretroviral inhibitors. An ensemble of explicit solvent molecular dynamics simulations, initiated from a disordered HIV-1 FP (aggregate time of ~30 MUs), revealed that while the vast majority of conformations predominantly lack secondary structure, both spontaneous formation and rapid interconversion of local secondary structure elements occur, highlighting the structural plasticity of the peptide. Therefore, even at this rapid time scale, FP constitutes a diverse and flexible conformational ensemble in solution. Secondary structure clustering reveals that the most prominent ordered elements are alpha- and 3-10-helical subsets of membrane-bound conformations, while trace populations within 2 A RMSD of all complete membrane-bound conformations are found to pre-exist in the solution ensemble. Since inhibitor bound conformations of FP are only rarely found, FP inhibitors could function by modulating the conformational ensemble and binding to nonfusogenic FP structures. A thermodynamic characterization of the most prominent ordered nonfusogenic structures could facilitate the future design of improved FP inhibitors. PMID- 26583971 TI - Including Torsional Anharmonicity in Canonical and Microcanonical Reaction Path Calculations. AB - We reformulate multistructural variational transition state theory by removing the approximation of calculating torsional anharmonicity only at stationary points. The multistructural method with torsional anharmonicity is applied to calculate the reaction-path free energy of the hydrogen abstraction from the carbon-1 position in isobutanol by OH radical. The torsional potential anharmonicity along the reaction path is taken into account by a coupled torsional potential. The calculations show that it can be critical to include torsional anharmonicity in searching for canonical and microcanonical variational transition states. The harmonic-oscillator approximation fails to yield reasonable free energy curves along the reaction path. PMID- 26583972 TI - Sampling of Transition States for Predicting Diastereoselectivity Using Automated Search Method-Aqueous Lanthanide-Catalyzed Mukaiyama Aldol Reaction. AB - To predict the stereoselectivity of large and flexible reaction systems, structural sampling of many transition states (TSs) is required. We used an automated search method, the artificial force induced reaction (AFIR) method, for TS sampling and found 91 syn- and 73 anti-TSs for the diastereoselective C-C bond formation step of the aqueous lanthanide-catalyzed Mukaiyama aldol reaction. Among them 11 syn- and six anti-TSs are found to contribute significantly to the diastereomeric ratio at room temperature. PMID- 26583973 TI - Effects of Temperature Control Algorithms on Transport Properties and Kinetics in Molecular Dynamics Simulations. AB - Temperature control algorithms in molecular dynamics (MD) simulations are necessary to study isothermal systems. However, these thermostatting algorithms alter the velocities of the particles and thus modify the dynamics of the system with respect to the microcanonical ensemble, which could potentially lead to thermostat-dependent dynamical artifacts. In this study, we investigate how six well-established thermostat algorithms applied with different coupling strengths and to different degrees of freedom affect the dynamics of various molecular systems. We consider dynamic processes occurring on different times scales by measuring translational and rotational self-diffusion as well as the shear viscosity of water, diffusion of a small molecule solvated in water, and diffusion and the dynamic structure factor of a polymer chain in water. All of these properties are significantly dampened by thermostat algorithms which randomize particle velocities, such as the Andersen thermostat and Langevin dynamics, when strong coupling is used. For the solvated small molecule and polymer, these dampening effects are reduced somewhat if the thermostats are applied to the solvent alone, such that the solute's temperature is maintained only through thermal contact with solvent particles. Algorithms which operate by scaling the velocities, such as the Berendsen thermostat, the stochastic velocity rescaling approach of Bussi and co-workers, and the Nose-Hoover thermostat, yield transport properties that are statistically indistinguishable from those of the microcanonical ensemble, provided they are applied globally, i.e. coupled to the system's kinetic energy. When coupled to local kinetic energies, a velocity scaling thermostat can have dampening effects comparable to a velocity randomizing method, as we observe when a massive Nose-Hoover coupling scheme is used to simulate water. Correct dynamical properties, at least those studied in this paper, are obtained with the Berendsen thermostat applied globally, despite the fact that it yields the wrong kinetic energy distribution. PMID- 26583974 TI - Learning Kinetic Distance Metrics for Markov State Models of Protein Conformational Dynamics. AB - Statistical modeling of long timescale dynamics with Markov state models (MSMs) has been shown to be an effective strategy for building quantitative and qualitative insight into protein folding processes. Existing methodologies, however, rely on geometric clustering using distance metrics such as root mean square deviation (RMSD), assuming that geometric similarity provides an adequate basis for the kinetic partitioning of phase space. Here, inspired by advances in the machine learning community, we introduce a new approach for learning a distance metric explicitly constructed to model kinetic similarity. This approach enables the construction of models, especially in the regime of high anisotropy in the diffusion constant, with fewer states than was previously possible. Application of this technique to the analysis of two ultralong molecular dynamics simulations of the FiP35 WW domain identifies discrete near-native relaxation dynamics in the millisecond regime that were not resolved in previous analyses. PMID- 26583975 TI - Constant Pressure Path Integral Gibbs Ensemble Monte Carlo Method. AB - We present the implementation of a real-space constant pressure path integral Gibbs ensemble Monte Carlo (CP-PIGEMC) method for the simulation of one-component fluid consists of distinguishable quantum particles (henceforth referred to as Boltzmannons) in an external potential field at finite temperatures. We apply this simulation method to study the para-H2 adsorption in NaX zeolite at 77 K and pressures up to 100 bar. We present a new set of effective solid-fluid parameters optimized for path integral simulations of hydrogen isotope adsorption and separation in synthetic zeolites. The agreement among CP-PIGEMC, experiment, and the path integral grand canonical Monte Carlo method (PIGCMC) is very good, even at high pressures. CP-PIGEMC is a particularly useful method for simulation of one-component quantum fluid composed of Boltzmannons at finite temperatures, when the chemical potential is difficult to measure or calculate explicitly. PMID- 26583976 TI - Investigating the Effects of Basis Set on Metal-Metal and Metal-Ligand Bond Distances in Stable Transition Metal Carbonyls: Performance of Correlation Consistent Basis Sets with 35 Density Functionals. AB - Density functional theory (DFT) is a widely used method for predicting equilibrium geometries of organometallic compounds involving transition metals, with a wide choice of functional and basis set combinations. A study of the role of basis set size in predicting the structural parameters can be insightful with respect to the effectiveness of using small basis sets to optimize larger molecular systems. For many organometallic systems, the metal-metal and metal carbon distances are the most important structural features. In this study, we compare the equilibrium metal-ligand and metal-metal distances of six transition metal carbonyl compounds predicted by the Hood-Pitzer double-zeta polarization (DZP) basis set, against those predicted employing the standard correlation consistent cc-pVXZ (X = D,T,Q) basis sets, for 35 different DFT methods. The effects of systematically increasing the basis set size on the structural parameters are carefully investigated. The Mn-Mn bond distance in Mn2(CO)10 shows a greater dependence on basis set size compared to the other M-M bonds. However, the DZP predictions for re(Mn-Mn) are closer to experiment than those obtained with the much larger cc-pVQZ basis set. Our results show that, in general, DZP basis sets predict structural parameters with an accuracy comparable to the triple and quadruple-zeta basis sets. This finding is very significant, because the quadruple-zeta basis set for Mn2(CO)10 includes 1308 basis functions, while the equally effective double-zeta set (DZP) includes only 366 basis functions. Overall, the DZP M06-L method predicts structures that are very consistent with experiment. PMID- 26583977 TI - Parametrization of the SCC-DFTB Method for Halogens. AB - Parametrization of the approximative DFT method SCC-DFTB for halogen elements is presented. The new parameter set is intended to describe halogenated organic as well as inorganic molecules, and it is compatible with the established parametrization of SCC-DFTB for carbon, hydrogen, oxygen, and nitrogen. The performance of the parameter set is tested on a representative set of molecules and discussed. PMID- 26583978 TI - Density Functional Theory and Beyond for Band-Gap Screening: Performance for Transition-Metal Oxides and Dichalcogenides. AB - The performance of a wide variety of commonly used density functionals, as well as two screened hybrid functionals (HSE06 and TB-mBJ), on predicting electronic structures of a large class of en vogue materials, such as metal oxides, chalcogenides, and nitrides, is discussed in terms of band gaps, band structures, and projected electronic densities of states. Contrary to GGA, hybrid functionals and GGA+U, both HSE06 and TB-mBJ are able to predict band gaps with an appreciable accuracy of 25% and thus allow the screening of various classes of transition-metal-based compounds, i.e., mixed or doped materials, at modest computational cost. The calculated electronic structures are largely unaffected by the choice of basis functions and software implementation, however, might be subject to the treatment of the core electrons. PMID- 26583979 TI - Orbital Entanglement in Bond-Formation Processes. AB - The accurate calculation of the (differential) correlation energy is central to the quantum chemical description of bond-formation and bond-dissociation processes. In order to estimate the quality of single- and multireference approaches for this purpose, various diagnostic tools have been developed. In this work, we elaborate on our previous observation [J. Phys. Chem. Lett.2012, 3, 3129] that one- and two-orbital-based entanglement measures provide quantitative means for the assessment and classification of electron correlation effects among molecular orbitals. The dissociation behavior of some prototypical diatomic molecules features all types of correlation effects relevant for chemical bonding. We demonstrate that our entanglement analysis is convenient to dissect these electron correlation effects and to provide a conceptual understanding of bond-forming and bond-breaking processes from the point of view of quantum information theory. PMID- 26583980 TI - A Density Functional Theory Based Protocol to Compute the Redox Potential of Transition Metal Complex with the Correction of Pseudo-Counterion: General Theory and Applications. AB - We propose an accurate scheme to evaluate the redox potential of a wide variety of transition metal complexes by adding a charge-dependent correction term for a counterion around the charged complexes, which is based on Generalized Born theory, to the solvation energy. The mean absolute error (MAE) toward experimental redox potentials of charged complexes is considerably reduced from 0.81 V (maximum error 1.22 V) to 0.22 V (maximum error 0.50 V). We found a remarkable exchange-correlation functional dependence on the results rather than the basis set ones. The combination of Wachters+f (for metal) and 6-31++G(d,p) (for other atoms) with the B3LYP functional gives the least MAE 0.15 V for the test complexes. This scheme is applicable to other solvents, and heavier transition metal complexes such as M1(CO)5(pycn) (M1 = Cr, Mo, W), M2(mnt)2 (M2 = Ni, Pd, Pt), and M3(bpy)3 (M3 = Fe, Ru, Os) with the same quality. PMID- 26583981 TI - Third-Order Incremental Dual-Basis Set Zero-Buffer Approach: An Accurate and Efficient Way To Obtain CCSD and CCSD(T) Energies. AB - An efficient way to obtain accurate CCSD and CCSD(T) energies for large systems, i.e., the third-order incremental dual-basis set zero-buffer approach (inc3-db B0), has been developed and tested. This approach combines the powerful incremental scheme with the dual-basis set method, and along with the new proposed K-means clustering (KM) method and zero-buffer (B0) approximation, can obtain very accurate absolute and relative energies efficiently. We tested the approach for 10 systems of different chemical nature, i.e., intermolecular interactions including hydrogen bonding, dispersion interaction, and halogen bonding; an intramolecular rearrangement reaction; aliphatic and conjugated hydrocarbon chains; three compact covalent molecules; and a water cluster. The results show that the errors for relative energies are <1.94 kJ/mol (or 0.46 kcal/mol), for absolute energies of <0.0026 hartree. By parallelization, our approach can be applied to molecules of more than 30 atoms and more than 100 correlated electrons with high-quality basis set such as cc-pVDZ or cc-pVTZ, saving computational cost by a factor of more than 10-20, compared to traditional implementation. The physical reasons of the success of the inc3-db-B0 approach are also analyzed. PMID- 26583982 TI - X-ray Constrained Extremely Localized Molecular Orbitals: Theory and Critical Assessment of the New Technique. AB - Following the X-ray constrained wave function approach proposed by Jayatilaka, we have devised a new technique that allows to extract molecular orbitals strictly localized on small molecular fragments from sets of experimental X-ray structure factors amplitudes. Since the novel strategy enables to obtain electron distributions that have quantum mechanical features and that can be easily interpreted in terms of traditional chemical concepts, the method can be also considered as a new useful tool for the determination and the analysis of charge densities from high-resolution X-ray experiments. In this paper, we describe in detail the theory of the new technique, which, in comparison to our preliminary work, has been improved both treating the effects of isotropic secondary extinctions and introducing a new protocol to halt the fitting procedure against the experimental X-ray scattering data. The performances of the novel strategy have been studied both in function of the basis-sets flexibility and in function of the quality of the considered crystallographic data. The tests performed on four different systems (alpha-glycine, l-cysteine, (aminomethyl)phosphonic acid and N-(trifluoromethyl)formamide) have shown that the achievement of good statistical agreements with the experimental measures mainly depends on the quality of the crystal structures (i.e., geometry positions and thermal parameters) used in the X-ray constrained calculations. Finally, given the reliable transferability of the obtained Extremely Localized Molecular Orbitals (ELMOs), we envisage to exploit the novel approach to construct new ELMOs databases suited to the development of linear-scaling methods for the refinement of macromolecular crystal structures. PMID- 26583983 TI - A Caveat on SCC-DFTB and Noncovalent Interactions Involving Sulfur Atoms. AB - Accurate modeling of noncovalent interactions involving sulfur today is ubiquitous, particularly with regard to the role played by sulfur-containing heterocycles in the field of organic electronics. The density functional tight binding (DFTB) method offers a good compromise between computational efficiency and accuracy, enabling the treatment of thousands of atoms at a fraction of the cost of density functional theory (DFT) evaluations. DFTB is an approximate quantum chemical approach that is based on the DFT total energy expression. Here, we address a critical issue inherent to the DFTB parametrization, which prevents the use of the DFTB framework for simulating noncovalent interactions involving sulfur atoms and precludes its combination with a dispersion correction. (1-5) Dramatic examples of structural patterns relevant to the field of organic electronics illustrate that DFTB delivers erroneous (i.e., qualitatively wrong) results involving spurious binding. PMID- 26583984 TI - Electron-Nuclear Motion in the Cope Rearrangement of Semibullvalene: Ever Synchronous? AB - The effect of nuclear motion on the synchronicity of the pincer motion type electronic rearrangement associated with bond making and bond breaking and vice versa is investigated for the degenerate Cope rearrangement of semibullvalene using a time-independent quantum chemical approach. We find that distinct paths along the potential energy surface corresponding to synchronous nuclear rearrangement involve asynchronous electronic fluxes out of the old and into the new bond while synchronous electronic fluxes entail asynchronous nuclear rearrangement. In order to demonstrate the robustness of the results, various high-level quantum chemical methods including full structure optimizations up to second order multireference perturbation theory using triple-zeta basis sets (RS2/cc-pVTZ), which are subsequently refined at the RS3/cc-pVTZ and MRCI+Dav/cc pVTZ levels of theory, are used for solving the electronic Schrodinger equation. These benchmark results extend previous quantum chemical data for the degenerate Cope rearrangement of semibullvalene and are tested against lower level methods (e.g., density functional theory calculations using the B3LYP and B3PW91 functionals). PMID- 26583985 TI - Reliable Transition State Searches Integrated with the Growing String Method. AB - The growing string method (GSM) is highly useful for locating reaction paths connecting two molecular intermediates. GSM has often been used in a two-step procedure to locate exact transition states (TS), where GSM creates a quality initial structure for a local TS search. This procedure and others like it, however, do not always converge to the desired transition state because the local search is sensitive to the quality of the initial guess. This article describes an integrated technique for simultaneous reaction path and exact transition state search. This is achieved by implementing an eigenvector following optimization algorithm in internal coordinates with Hessian update techniques. After partial convergence of the string, an exact saddle point search begins under the constraint that the maximized eigenmode of the TS node Hessian has significant overlap with the string tangent near the TS. Subsequent optimization maintains connectivity of the string to the TS as well as locks in the TS direction, all but eliminating the possibility that the local search leads to the wrong TS. To verify the robustness of this approach, reaction paths and TSs are found for a benchmark set of more than 100 elementary reactions. PMID- 26583986 TI - Comparison of Molecular and Primitive Solvent Models for Electrical Double Layers in Nanochannels. AB - In a recent article (Lee et al. J. Comput. Theor. Chem., 2012, 8, 2012-2022.), it was shown that an electrolyte solution can be modeled in molecular dynamics (MD) simulations using a uniform dielectric constant in place of a polar solvent to validate Fluid Density Functional Theory (f-DFT) simulations. This technique can be viewed as a coarse-grained approximation of the polar solvent and reduces computational cost by an order of magnitude. However, the consequences of replacing the polar solvent with an effective permittivity are not well characterized, despite its common usage in f-DFT, Monte Carlo simulation, and Poisson-Boltzmann theory. In this paper, we have examined two solvent models of different fidelities with MD simulation of nanochannels. We find that the models produce qualitatively similar ion density profiles, but physical quantities such as electric field, electric potential, and capacitance differ by over an order of magnitude. In all cases, the bulk is explicitly modeled so that surface properties can be evaluated relative to a reference state. Moreover, quantities that define the reference state, such as bulk ion density, bulk solvent density, applied electric field, and temperature, are measurable, so cases with the same thermodynamic state can be compared. Insights into the solvent arrangement, most of which can not be determined from the coarse-grained model, are drawn from the model with an explicitly described polar solvent. PMID- 26583987 TI - Ab Initio Extension of the AMOEBA Polarizable Force Field to Fe(2.). AB - We extend the AMOEBA polarizable molecular mechanics force field to the Fe(2+) cation in its singlet, triplet, and quintet spin states. Required parameters are obtained either directly from first principles calculations or optimized so as to reproduce corresponding interaction energy components in a hexaaquo environment derived from quantum mechanical energy decomposition analyses. We assess the importance of the damping of point-dipole polarization at short distance as well as the influence of charge-transfer for metal-water interactions in hydrated Fe(2+); this analysis informs the selection of model systems employed for parametrization. We validate our final Fe(2+) model through comparison of molecular dynamics (MD) simulations to available experimental data for aqueous ferrous ion in its quintet electronic ground state. PMID- 26583988 TI - PTRAJ and CPPTRAJ: Software for Processing and Analysis of Molecular Dynamics Trajectory Data. AB - We describe PTRAJ and its successor CPPTRAJ, two complementary, portable, and freely available computer programs for the analysis and processing of time series of three-dimensional atomic positions (i.e., coordinate trajectories) and the data therein derived. Common tools include the ability to manipulate the data to convert among trajectory formats, process groups of trajectories generated with ensemble methods (e.g., replica exchange molecular dynamics), image with periodic boundary conditions, create average structures, strip subsets of the system, and perform calculations such as RMS fitting, measuring distances, B-factors, radii of gyration, radial distribution functions, and time correlations, among other actions and analyses. Both the PTRAJ and CPPTRAJ programs and source code are freely available under the GNU General Public License version 3 and are currently distributed within the AmberTools 12 suite of support programs that make up part of the Amber package of computer programs (see http://ambermd.org ). This overview describes the general design, features, and history of these two programs, as well as algorithmic improvements and new features available in CPPTRAJ. PMID- 26583989 TI - CH Stretching Region: Computational Modeling of Vibrational Optical Activity. AB - Most organic compounds provide vibrational spectra within the CH stretching region, yet the signal is difficult to interpret because of multiple difficulties in experiment and modeling. To better understand various factors involved, the ability of several harmonic and anharmonic computational approaches to describe these vibrations was explored for alpha-pinene, fenchone, and camphor as test compounds. Raman, Raman optical activity (ROA), infrared absorption (IR), and vibrational circular dichroism (VCD) spectra were measured and compared to quantum chemical computations. Surprisingly, the harmonic vibrational approach reasonably well reproduced the measured spectral patterns, including the vibrational optical activity (VOA). The CH stretching, however, appeared to be more sensitive to the basis set and solvent variations than lower-frequency vibrations. For a higher accuracy in frequencies and spectral shapes, anharmonic corrections were necessary. Accurate harmonic and anharmonic force fields were obtained with the mPW2PLYP double-hybrid functional. A limited vibrational configuration interaction (LVCI) where the CH stretching motion was decoupled from other vibrations provided the best simulated spectra. A balanced harmonic oscillator basis set had to be used, containing also states indirectly interacting with fundamental vibrations. A simpler second-order perturbational approach (PT2) appeared less useful. The modeling provided unprecedented agreement with experimental vibrational frequencies; spectral shapes were reproduced less faithfully. The possibility of ab initio interpretation of the CH spectral region for relatively large molecules further broadens the application span of vibrational spectroscopy. PMID- 26583990 TI - Robustness of Frequency, Transition Dipole, and Coupling Maps for Water Vibrational Spectroscopy. AB - Infrared spectroscopy of the water OH stretch provides a sensitive probe of the local hydrogen-bonding structure and dynamics of water molecules. Previously, we have utilized a mixed quantum/classical model to calculate vibrational spectroscopic observables for bulk water, ice, the liquid/vapor interface, and small water clusters, as well as water interacting with ions and biological molecules. These studies rely on spectroscopic maps that relate the OH stretching frequency and transition dipole to the local environment around a water molecule. Our spectroscopic maps were parametrized based on water clusters taken from bulk water simulations; in this article, we test the robustness of these maps for water in nonbulk-liquid environments. We find that the frequency, transition dipole, and coupling maps work as well for the water surface, ice Ih, and the water hexamer as they do for liquid water. This suggests that these maps may be generally applied to study the vibrational spectroscopy of water in diverse, potentially heterogeneous environments. PMID- 26583991 TI - On the Metric of Charge Transfer Molecular Excitations: A Simple Chemical Descriptor. AB - A new index is defined with the aim of further exploring the metric of excited electronic states in the framework of the time-dependent density functional theory. This descriptor, called Deltar, is based on the charge centroids of the orbitals involved in the excitations and can be interpreted in term of the hole electron distance. The tests carried out on a set of molecules characterized by a significant number of charge-transfer excitations well illustrate its ability in discriminating between short (Deltar <= 1.5 A) and long-range (Deltar >= 2.0 A) excitations. On the basis of the well-known pitfalls of TD-DFT, its values can be then associated to the functional performances in reproducing different type of transitions and allow for the definition of a "trust radius" for GGA and hybrid functionals. The study of other systems, including some well-known difficult cases for other metric descriptors, gives further evidence of the high discrimination power of the proposed index. The combined use with other density or orbital-based descriptors is finally suggested to have a reliable diagnostic test of TD-DFT transitions. PMID- 26583992 TI - Boranil and Related NBO Dyes: Insights From Theory. AB - The simulations of excited-state properties, that is, the 0-0 energies and vibronic shapes, of a large panel of fluorophores presenting a NBO atomic sequence have been achieved with a Time-Dependent Density Functional Theory (TD DFT) approach. We have combined eight hybrid exchange-correlation functionals (B3LYP, PBE0, M06, BMK, M06-2X, CAM-B3LYP, omegaB97X-D, and omegaB97) to the linear-response (LR) and the state specific (SS) Polarizable Continuum Model (PCM) methods in both their equilibrium (eq) and nonequilibrium (neq) limits. We show that the combination of the SS-PCM scheme to a functional incorporating a low amount of exact exchange can yield unphysical values for molecules presenting large increase of their dipole moments upon excitation. We therefore apply a functional possessing a large exact exchange ratio to simulate the properties of NBO dyes, including large dyads. PMID- 26583993 TI - Thermodynamics of the Electron Revisited and Generalized. AB - The accurate evaluation of redox potentials in various media and the ability of electron transfer in some biological or chemical reactions are subject to the determination of the accurate gas phase thermodynamic data of the electron. These data are also useful to describe with a high accuracy the movement of the electron in a stellar core. However, these data were not available at all temperatures, and the available data were not sufficiently accurate. I addressed this matter using a robust and reliable self-consistent iterative procedure which determines the entropy of a gas phase free electron and, thereafter, allows the calculation of its heat capacity, enthalpy, and free energy. Extremely accurate analytic expressions of the aforementioned thermodynamic parameters were provided at all temperatures. The thermodynamic parameters of the gas phase electron are now known at all temperatures (integer or noninteger) in the standard atmosphere with a high accuracy. Analytic expressions proposed for the thermodynamic parameters are highly advisable where iteratively computed data are unavailable. Note that at room temperature (T = 298.15 K), the values recommended for the thermodynamic parameters of the gas phase electron are S = 22.6432 J mol(-1) K( 1), CP = 17.1062 J mol(-1) K(-1), DeltaH = 3.1351 kJ mol(-1), and DeltaG = 3.6160 kJ mol(-1). PMID- 26583994 TI - First-Principles Elucidation of Atomic Size Effects Using DFT-Chemical Pressure Analysis: Origins of Ca36Sn23's Long-Period Superstructure. AB - The space requirements of atoms are empirically known to play key roles in determining structure and reactivity across compounds ranging from simple molecules to extended solid state phases. Despite the importance of this concept, the effects of atomic size on stability remain difficult to extract from quantum mechanical calculations. Recently, we outlined a quantitative yet visual and intuitive approach to the theoretical analysis of atomic size in periodic structures: the DFT-Chemical Pressure (DFT-CP) analysis. In this Article, we describe the methodological details of this DFT-CP procedure, with a particular emphasis on refinements of the method to make it useful for a wider variety of systems. A central improvement is a new integration scheme with broader applicability than our earlier Voronoi cell method: contact volume space partitioning. In this approach, we make explicit our assumption that the pressure at each voxel is most strongly influenced by its two closest atoms. The unit cell is divided into regions corresponding to individual interatomic contacts, with each region containing all points that share the same two closest atoms. The voxel pressures within each contact region are then averaged, resulting in effective interatomic pressures. The method is illustrated through the verification of the role of Ca-Ca repulsion (deduced earlier from empirical considerations by Corbett and co-workers) in the long-period superstructure of the W5Si3 type exhibited by Ca36Sn23. PMID- 26583995 TI - Delta Self-Consistent Field Method for Natural Anthocyanidin Dyes. AB - We present an application of the Delta self-consistent field (DeltaSCF) method, which we have implemented and tested in the DFT code CONQUEST, on the study of excited states of natural anthocyanidin dyes. We show that DeltaSCF allows relaxation of the atomic structure for systems in excited states by following gradients on the excited Born-Oppenheimer surface. We compare the vertical excitation energies of some anthocyanidins in gas-phase to results from time dependent density functional theory (TDDFT) and experiments. To reproduce a typical dye-sensitized solar cell interface, we adsorb cyanidin on TiO2 anatase (101), focusing on the shift of the lowest excitation energy due to the adsorption. We have found that important modifications occur in the excited state geometry of the adsorbed cyanidin. PMID- 26583996 TI - Tree Growth-Hybrid Genetic Algorithm for Predicting the Structure of Small (TiO2)n, n = 2-13, Nanoclusters. AB - The initial structures for the search for the global minimum of TiO2 nanoclusters were generated by combining a tree growth (TG) algorithm with a hybrid genetic algorithm (HGA). In the TG algorithm, the clusters grow from a small seed to the size of interest stepwise. New atoms are added to the smaller cluster from the previous step, by analogy to new leaves grown by a tree. The addition of the new atoms is controlled by predefined geometry parameters to reduce the computational cost and to provide physically meaningful structures. In each step, the energies for the various generated structures are evaluated, and those with the lowest energies are carried into the next step. The structures that match the formulas of interest are collected as HGA candidates during the various steps. Low energy candidates are fed to the HGA component to search for the global minimum for each formula of interest. The lowest energy structures from the HGA are then optimized by using density functional theory to study the dissociation energies of the clusters and the evolution in the structure as the size of the cluster increases. The optimized geometries of the (TiO2)n nanoclusters for n = 2-13, do not show the character of a TiO2 bulk crystal with a hexacoordinate Ti. The average clustering energy ?DeltaEn? converges slowly to the bulk value for rutile. The TiO2 dissociation energies for (TiO2)n clusters approach the bulk value for rutile more quickly but show larger variations. The (TiO2)12 cluster appears to be quite stable, and the (TiO2)13 cluster is quite unstable on a relative scale. PMID- 26583997 TI - MODYLAS: A Highly Parallelized General-Purpose Molecular Dynamics Simulation Program for Large-Scale Systems with Long-Range Forces Calculated by Fast Multipole Method (FMM) and Highly Scalable Fine-Grained New Parallel Processing Algorithms. AB - Our new molecular dynamics (MD) simulation program, MODYLAS, is a general-purpose program appropriate for very large physical, chemical, and biological systems. It is equipped with most standard MD techniques. Long-range forces are evaluated rigorously by the fast multipole method (FMM) without using the fast Fourier transform (FFT). Several new methods have also been developed for extremely fine grained parallelism of the MD calculation. The virtually buffering-free methods for communications and arithmetic operations, the minimal communication latency algorithm, and the parallel bucket-relay communication algorithm for the upper level multipole moments in the FMM realize excellent scalability. The methods for blockwise arithmetic operations avoid data reload, attaining very small cache miss rates. Benchmark tests for MODYLAS using 65 536 nodes of the K-computer showed that the overall calculation time per MD step including communications is as short as about 5 ms for a 10 million-atom system; that is, 35 ns of simulation time can be computed per day. The program enables investigations of large-scale real systems such as viruses, liposomes, assemblies of proteins and micelles, and polymers. PMID- 26583998 TI - Stability Mechanisms of Laccase Isoforms using a Modified FoldX Protocol Applicable to Widely Different Proteins. AB - A recent computational protocol that accurately predicts and rationalizes protein multisite mutant stabilities has been extended to handle widely different isoforms of laccases. We apply the protocol to four isoenzymes of Trametes versicolor laccase (TvL) with variable lengths (498-503 residues) and thermostability (Topt ~ 45-80 degrees C) and with 67-77% sequence identity. The extended protocol uses (i) statistical averaging, (ii) a molecular-dynamics validated "compromise" homology model to minimize bias that causes proteins close in sequence to a structural template to be too stable due to having the benefits of the better sampled template (typically from a crystal structure), (iii) correction for hysteresis that favors the input template to overdestabilize, and (iv) a preparative protocol to provide robust input sequences of equal length. The computed DeltaDeltaG values are in good agreement with the major trends in experimental stabilities; that is, the approach may be applicable for fast estimates of the relative stabilities of proteins with as little as 70% identity, something that is currently extremely challenging. The computed stability changes associated with variations are Gaussian-distributed, in good agreement with experimental distributions of stability effects from mutation. The residues causing the differential stability of the four isoforms are consistent with a range of compiled laccase wild type data, suggesting that we may have identified general drivers of laccase stability. Several sites near Cu, notably 79, 241, and 245, or near substrate, mainly 265, are identified that contribute to stability function trade-offs, of relevance to the search for new proficient and stable variants of these important industrial enzymes. PMID- 26583999 TI - Efficient Methods for the Quantum Chemical Treatment of Protein Structures: The Effects of London-Dispersion and Basis-Set Incompleteness on Peptide and Water Cluster Geometries. AB - We demonstrate how quantum chemical Hartree-Fock (HF) or density functional theory (DFT) optimizations with small basis sets of peptide and water cluster structures are decisively improved if London-dispersion effects, the basis-set superposition error (BSSE), and other basis-set incompleteness errors are addressed. We concentrate on three empirical corrections to these problems advanced by Grimme and co-workers that lead to computational strategies that are both accurate and efficient. Our analysis encompasses a reoptimized version of Hobza's P26 set of tripeptide structures, a new test set of conformers of cysteine dimers, and isomers of the water hexamer. These systems reflect features commonly found in protein crystal structures. In all cases, we recommend Grimme's DFT-D3 correction for London-dispersion. We recommend usage of large basis sets such as cc-pVTZ whenever possible to reduce any BSSE effects and, if this is not possible, to use Grimme's gCP correction to account for BSSE when small basis sets are used. We demonstrate that S-S and C-S bond lengths are very prone to basis-set incompleteness and that polarization functions should always be used on S atoms. At the double-zeta level, the PW6B95-D3-gCP DFT method combined with the SVP and 6-31G* basis sets yields accurate results. Alternatively, the HF-D3 gCP/SV method is recommended, with inclusion of polarization functions for S atoms only. Minimal basis sets offer an intriguing route to highly efficient calculations, but due to significant basis-set incompleteness effects, calculated bond lengths are seriously overestimated, making applications to large proteins very difficult, but we show that Grimme's newest HF-3c correction overcomes this problem and so makes this computational strategy very attractive. Our results provide a useful guideline for future applications to the optimization, quantum refinement, and dynamics of large proteins. PMID- 26584000 TI - From Atoms to Fullerene: Stochastic Surface Walking Solution for Automated Structure Prediction of Complex Material. AB - It is of general concern whether the automated structure prediction of unknown material without recourse to any knowledge from experiment is ever possible considering the daunting complexity of potential energy surface (PES) of material. Here we demonstrate that the stochastic surface walking (SSW) method can be a general and promising solution to this ultimate goal, which is applied to assemble carbon fullerenes containing up to 100 atoms (including 60, 70, 76, 78, 80, 84, 90, 96, and 100 atoms) from randomly distributed atoms, a long standing challenge in global optimization. Combining the SSW method with a parallel replica exchange algorithm, we can locate the global minima (GM) of these large fullerenes efficiently without being trapped in numerous energy nearly degenerate isomers. Detailed analyses on the SSW trajectories allow us to rationalize how and why the SSW method is able to explore the highly complex PES, which highlights the abilities of SSW method for surmounting the high barrier and the preference of SSW trajectories to the low energy pathways. The work demonstrates that the parallel SSW method is a practical tool for predicting unknown materials. PMID- 26584001 TI - Correction to Constant pH Molecular Dynamics in Explicit Solvent with lambda Dynamics. PMID- 26584002 TI - Total Synthesis of (-)-Lepadiformine A Utilizing Hg(OTf)2-Catalyzed Cycloisomerization Reaction. AB - A cytotoxic marine alkaloid (-)-lepadiformine A (1) possesses a unique structure characterized by the trans-1-azadecalin AB ring system fused with the AC spiro cyclic ring. In this research, we found that a cycloisomerization reaction from amino ynone 2 to a 1-azaspiro[4.5]decane skeleton 3, corresponding to the AC ring system of 1, is promoted by Hg(OTf)(2). Thus, we have accomplished the efficient total synthesis of (-)-lepadiformine A in 28% overall yield by featuring the novel Hg(OTf)(2)-catalyzed cycloisomerization. PMID- 26584003 TI - Exogenous Gene Integration for Microalgal Cell Transformation Using a Nanowire Incorporated Microdevice. AB - Superior green algal cells showing high lipid production and rapid growth rate are considered as an alternative for the next generation green energy resources. To achieve the biomass based energy generation, transformed microalgae with superlative properties should be developed through genetic engineering. Contrary to the normal cells, microalgae have rigid cell walls, so that target gene delivery into cells is challengeable. In this study, we report a ZnO nanowire incorporated microdevice for a high throughput microalgal transformation. The proposed microdevice was equipped with not only a ZnO nanowire in the microchannel for gene delivery into cells but also a pneumatic polydimethylsiloxane (PDMS) microvalve to modulate the cellular attachment and detachment from the nanowire. As a model, hygromycin B resistance gene cassette (Hyg3) was functionalized on the hydrothermally grown ZnO nanowires through a disulfide bond and released into green algal cells, Chlamydomonas reinhardtii, by reductive cleavage. During Hyg3 gene delivery, a monolithic PDMS membrane was bent down, so that algal cells were pushed down toward ZnO nanowires. The supply of vacuum in the pneumatic line made the PDMS membrane bend up, enabling the gene delivered algal cells to be recovered from the outlet of the microchannel. We successfully confirmed Hyg3 gene integrated in microalgae by amplifying the inserted gene through polymerase chain reaction (PCR) and DNA sequencing. The efficiency of the gene delivery to algal cells using the ZnO nanowire incorporated microdevice was 6.52 * 10(4)- and 9.66 * 10(4)-fold higher than that of a traditional glass bead beating and electroporation. PMID- 26584004 TI - Excitotoxicity in ALS: Overstimulation, or overreaction? AB - Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disease that results in motor dysfunction and death, generally from respiratory failure. 90% of ALS cases are sporadic with no known cause. Familial cases have been linked with mutations in several disparate classes of genes, including those involved in DNA/RNA metabolism, protein misfolding, oxidative stress and the cytoskeleton, leading to the proposition that ALS could be a multi-factorial disease. However, alterations in excitability have been reported in all types of ALS cases, and may be a common disease mechanism predisposing neurons to degeneration. Excitotoxicity has long been suspected as a mediator in the disease process, and may arise from changes in synaptic inputs, or alterations in the excitability of the neurons being stimulated. Although the glutamatergic system is widely recognised as a therapeutic avenue with the potential to extend lifespan and delay disease onset, the causes of altered excitability in ALS are currently unclear and warrant further investigation. This article reviews current evidence of alterations to excitatory and inhibitory signalling in the cortex and spinal cord, and in the intrinsic excitability of motor neurons, in ALS. PMID- 26584005 TI - Editorial Comment from Dr Shigemura and Dr Fujisawa to Predictive value of urinary interleukin-6 for symptomatic urinary tract infections in a nursing home population. PMID- 26584006 TI - Simplified Bernoulli's method significantly underestimates pulmonary transvalvular pressure drop. AB - PURPOSE: To determine whether neglecting the flow unsteadiness in simplified Bernoulli's equation significantly affects the pulmonary transvalvular pressure drop estimation. MATERIALS AND METHODS: 3.0T magnetic resonance imaging (MRI) 4D velocity mapping was performed on four healthy volunteers, seven patients with repaired tetralogy of Fallot, and thirteen patients with transposition of the great arteries repaired by arterial switch. Pulmonary transvalvular pressure drop was estimated based on two methods: General Bernoulli's Equation (GBE), ie, the most complete form; and Simplified Bernoulli's Equation (SBE), known as 4V(2) . More than 2300 individual pressure drop measurements were used to compare the simplified and the general Bernoulli's methods. A linear mixed-effects model was employed for statistical analyses, fully accounting for clustering of observations among the methods and systolic phases. RESULTS: The simplified Bernoulli's method systematically underestimated the pressure drop compared to general Bernoulli's method during the entire systolic phase (P < 0.05), including the peak systole, where on average DeltapSBE/DeltapGBE=78%. CONCLUSION: The simplified Bernoulli method underestimated the pressure drop during all systolic phases in all the studied subjects. Therefore, it is necessary to take into account the flow unsteadiness for more accurate estimation of the pressure drop. J. Magn. Reson. Imaging 2016;43:1313-1319. PMID- 26584007 TI - Proteogenomic Study beyond Chromosome 9: New Insight into Expressed Variant Proteome and Transcriptome in Human Lung Adenocarcinoma Tissues. AB - This is a report of a human proteome project (HPP) related to chromosome 9 (Chr 9). To reveal missing proteins and undiscovered features in proteogenomes, both LC-MS/MS analysis and next-generation RNA sequencing (RNA-seq)-based identification and characterization were conducted on five pairs of lung adenocarcinoma tumors and adjacent nontumor tissues. Before our previous Chromosome-Centric Human Proteome Project (C-HPP) special issue, there were 170 remaining missing proteins on Chr 9 (neXtProt 2013.09.26 rel.); 133 remain at present (neXtProt 2015.04.28 rel.). In the proteomics study, we found two missing protein candidates that require follow-up work and one unrevealed protein across all chromosomes. RNA-seq analysis detected RNA expression for four nonsynonymous (NS) single nucleotide polymorphisms (SNPs) (in CDH17, HIST1H1T, SAPCD2, and ZNF695) and three synonymous SNPs (in CDH17, CST1, and HNF1A) in all five tumor tissues but not in any of the adjacent normal tissues. By constructing a cancer patient sample-specific protein database based on individual RNA-seq data and by searching the proteomics data from the same sample, we identified four missense mutations in four genes (LTF, HDLBP, TF, and HBD). Two of these mutations were found in tumor samples but not in paired normal tissues. In summary, our proteogenomic study of human primary lung tumor tissues detected additional and revealed novel missense mutations and synonymous SNP signatures, some of which are specific to lung cancers. Data from mass spectrometry have been deposited in the ProteomeXchange with the identifier PXD002523. PMID- 26584008 TI - Analysis of the distal gut bacterial community by 454-pyrosequencing in captive giraffes (Giraffa camelopardalis). AB - The objective of this study was to characterize the structure of the fecal bacterial community of five giraffes (Giraffa camelopardalis) at Disney's Animal Kingdom, FL. Fecal genomic DNA was extracted and variable regions 1-3 of the 16S rRNA gene was PCR-amplified and then sequenced. The MOTHUR software-program was used for sequence processing, diversity analysis, and classification. A total of 181,689 non-chimeric bacterial sequences were obtained, and average number of sequences per sample was 36,338 -+/- 8,818. Sequences were assigned to 8,284 operational taxonomic units (OTU) with 95% of genetic similarity, which included 2,942 singletons (36%). Number of OTUs per sample was 2,554 +/- 264. Samples were normalized and alpha (intra-sample) diversity indices; Chao1, Inverse Simpson, Shannon, and coverage were estimated as 3,712 +/- 430, 116 -+/- 70, 6.1 +/- 0.4, and 96 +/- 1%, respectively. Thirteen phyla were detected and Firmicutes, Bacteroidetes, and Spirochaetes were the most dominant phyla (more than 2% of total sequences), and constituted 92% of the classified sequences, 66% of total sequences, and 43% of total OTUs. Our computation predicted that three OTUs were likely to be present in at least three of the five samples at greater than 1% dominance rate. These OTUs were Treponema, an unidentified OTU belonging to the order Bacteroidales, and Ruminococcus. This report was the first to characterize the bacterial community of the distal gut in giraffes utilizing fecal samples, and it demonstrated that the distal gut of giraffes is likely a potential reservoir for a number of undocumented species of bacteria. PMID- 26584009 TI - Early prenatal exposure to MPTP does not affect nigrostrial neurons in macaque monkey. AB - The discovery of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a toxin that induces parkinsonism in both human and primate, has prompted the search for environmental toxins potentially responsible for idiopathic Parkinson's disease (PD). The present study reports the ultimate effects of MPTP intoxication of a female macaque monkey, which unraveled to be pregnant after parkinsonism had developed, upon its fetus. Detailed examination of the offpsring nigrostriatal pathway showed that tyrosine hydroxylase immunoreactivity in caudate-putamen nuclei and substantia nigra compacta (SNc) was not different from an age-matched control. Biochemical analysis of the tissue content of dopaminergic markers further suggested modification of metabolism in the MPTP-exposed monkey. These data suggest that early prenatal intoxication does not destroy nigrostriatal neurons, most likely because dopamine neurons had not developed yet when exposed to MPTP. PMID- 26584010 TI - Development of a smart, anti-water polyurethane polymer hair coating for style setting. AB - OBJECTIVE: The goal of this work was to develop a novel polyurethane polymer coating for the surface of the hair that could be used for style setting via the shape memory effect (SME). The features of the films are in accordance with conventional hair styling methods used in the laboratory. METHODS: In this study, a new polyurethane polymer was synthesized; the morphology and mechanical behaviour of the coated hair were systematically investigated using a scanning electron microscope (SEM) and an Instron 5566 (with a temperature oven). The SME of the hair was tested using a 35-g weight and over five washing and drying cycles. RESULTS: The experimental result shows that the polyurethane polymer has effects on the mechanical behaviour of the hair. It indicates that the fixed shape (at 22 degrees C) and recover rate (at 60 degrees C) of different casted thickness films are similar. And the stress of the film becomes larger with increasing film thickness. Furthermore, the shape memory ability could be endowed with the hair styling using this polymer; the hair fibre could recover to the 65% of its original shape after five cycle deformation by 35 g mass under the heat treated condition; it could recover its original setting styling even after 5th water washing and drying. The SEM results indicated that the microsurface of the hair is coated with the polymer membrane; it contributes to the shape memory ability of the coated hair to keep and recover to the original setting styling. The styling hair can return to the original hair because the polyurethane polymer can be washed out by water with suitable strength and shampoo totally which does not leave any flake. CONCLUSION: The polyurethane polymer-based hair setting agent has been developed successfully, and it could be coated evenly on the human hair with good hand feeling and SMEs. The SME is highly related to the quantity of polyurethane polymer solution, and the effect could be improved by increasing the solution quantity. The maximum deformation of the coated hair could be recovered 94% at 75 degrees C, once its shape is changed by an external force. The treated hair can withstand warm water rinsing for at least five cycles, and it can keep 65% of its original setting style after water rinsing. The polyurethane polymer could be totally removed by shampooing the hair and hot towel covering for 5-10 min. This research provides an effective way for the development of new intelligent shaping agents. PMID- 26584011 TI - Protective role of necrostatin-1 in acute myocardial infarction. PMID- 26584012 TI - Noncovalent Interaction of Graphene with Heterocyclic Compounds: Benzene, Imidazole, Tetracene, and Imidazophenazines. AB - Noncovalent functionalization of graphene with organic molecules offers a direct route to multifunctional modification of this nanomaterial, leading to its various possible practical applications. In this work, the structures of hybrids formed by linear heterocyclic compounds such as imidazophenazine (F1) and its derivatives (F2-F4) with graphene and the corresponding interaction energies are studied by using the DFT method. Special attention is paid to the hybrids where the attached molecule is located along the graphene zigzag (GZZ ) and armchair (GAC ) directions. The interaction energies corresponding to the graphene hybrids of the F1-F4 compounds for the two directions are found to be distinct, while tetracene (being a symmetrical molecule) shows a small difference between these binding energies. It is found that the back-side CH3 and CF3 groups have an important influence on the arrangements of F1 derivatives on graphene and on their binding energies. The contribution of the CF3 group to the total binding energy of the F3 molecule with graphene is the largest (3.4 kcal mol(-1) ) (the GZZ direction) while the CH3 group increases this energy of F2 only by 2.0 kcal mol(-1) (the GAC direction). It is shown that replacing the carbons with other atoms or adding a back-side group enables one to vary the polarizability of graphene. PMID- 26584013 TI - Response to clinical assessments of health status as a potential marker to identify patients who are too sick to undergo transplantation. PMID- 26584014 TI - Osteoblast-Specific Overexpression of Human WNT16 Increases Both Cortical and Trabecular Bone Mass and Structure in Mice. AB - Previous genome-wide association studies have identified common variants in genes associated with bone mineral density (BMD) and risk of fracture. Recently, we identified single nucleotide polymorphisms (SNPs) in Wingless-type mouse mammary tumor virus integration site (WNT)16 that were associated with peak BMD in premenopausal women. To further identify the role of Wnt16 in bone mass regulation, we created transgenic (TG) mice overexpressing human WNT16 in osteoblasts. We compared bone phenotypes, serum biochemistry, gene expression, and dynamic bone histomorphometry between TG and wild-type (WT) mice. Compared with WT mice, WNT16-TG mice exhibited significantly higher whole-body areal BMD and bone mineral content (BMC) at 6 and 12 weeks of age in both male and female. Microcomputer tomography analysis of trabecular bone at distal femur revealed 3 fold (male) and 14-fold (female) higher bone volume/tissue volume (BV/TV), and significantly higher trabecular number and trabecular thickness but lower trabecular separation in TG mice compared with WT littermates in both sexes. The cortical bone at femur midshaft also displayed significantly greater bone area/total area and cortical thickness in the TG mice in both sexes. Serum biochemistry analysis showed that male TG mice had higher serum alkaline phosphatase, osteocalcin, osteoprotegerin (OPG), OPG to receptor activator of NF kB ligand (tumor necrosis family ligand superfamily, number 11; RANKL) ratio as compared with WT mice. Also, lower carboxy-terminal collagen cross-link (CTX) to tartrate-resistant acid phosphatase 5, isoform b (TRAPc5b) ratio was observed in TG mice compared with WT littermates in both male and female. Histomorphometry data demonstrated that both male and female TG mice had significantly higher cortical and trabecular mineralizing surface/bone surface and bone formation rate compared with sex-matched WT mice. Gene expression analysis demonstrated higher expression of Alp, OC, Opg, and Opg to Rankl ratio in bone tissue in the TG mice compared with WT littermates. Our data indicate that WNT16 is critical for positive regulation of both cortical and trabecular bone mass and structure and that this molecule might be targeted for therapeutic interventions to treat osteoporosis. PMID- 26584015 TI - Trenbolone Improves Cardiometabolic Risk Factors and Myocardial Tolerance to Ischemia-Reperfusion in Male Rats With Testosterone-Deficient Metabolic Syndrome. AB - The increasing prevalence of obesity adds another dimension to the pathophysiology of testosterone (TEST) deficiency (TD) and potentially impairs the therapeutic efficacy of classical TEST replacement therapy. We investigated the therapeutic effects of selective androgen receptor modulation with trenbolone (TREN) in a model of TD with the metabolic syndrome (MetS). Male Wistar rats (n=50) were fed either a control standard rat chow (CTRL) or a high-fat/high sucrose (HF/HS) diet. After 8 weeks of feeding, rats underwent sham surgery or an orchiectomy (ORX). Alzet miniosmotic pumps containing either vehicle, 2-mg/kg.d TEST or 2-mg/kg.d TREN were implanted in HF/HS+ORX rats. Body composition, fat distribution, lipid profile, and insulin sensitivity were assessed. Infarct size was quantified to assess myocardial damage after in vivo ischaemia reperfusion, before cardiac and prostate histology was performed. The HF/HS+ORX animals had increased sc and visceral adiposity; circulating triglycerides, cholesterol, and insulin; and myocardial damage, with low circulating TEST compared with CTRLs. Both TEST and TREN protected HF/HS+ORX animals against sc fat accumulation, hypercholesterolaemia, and myocardial damage. However, only TREN protected against visceral fat accumulation, hypertriglyceridaemia, and hyperinsulinaemia and reduced myocardial damage relative to CTRLs. TEST caused widespread cardiac fibrosis and prostate hyperplasia, which were less pronounced with TREN. We propose that TEST replacement therapy may have contraindications for males with TD and obesity-related MetS. TREN treatment may be more effective in restoring androgen status and reducing cardiovascular risk in males with TD and MetS. PMID- 26584016 TI - Validation of the Driver Behaviour Questionnaire in a representative sample of drivers in Australia. AB - The Driver Behaviour Questionnaire (DBQ) is a widely used measure of driving behaviours that may increase a driver's risk of crash involvement. However, there are several different versions of the DBQ varying in terms of number of items and factor structure. The aim of the current research was to assess the construct validity of the popular 28-item four-factor DBQ solution in a representative sample of drivers in Australia. A further aim was to test the factorial invariance of the measure across gender, age and also between fleet and non-fleet drivers using multigroup confirmatory factor analyses. Data on a range of attitudes towards road safety were collected using an online survey. A stratified sampling procedure was undertaken to ensure the age, gender and location distributions of participants were representative of the Australian population. A total of 2771 responses were obtained from fully licensed motor vehicle drivers (male: 46%). Confirmatory factor analysis supported the 28-item four-factor DBQ in the Australian sample. The DBQ was also found to be gender-invariant and strong partial measurement invariance was found for drivers aged from 26 to 64, but not for younger (17-25) or older (65-75) drivers. Modifications to the DBQ suggest how the DBQ can be improved for use in these two age groups. PMID- 26584017 TI - Comparison between two forms of granular activated carbon for the removal of pharmaceuticals from different waters. AB - The aim of this study was to evaluate the performance of two forms of basic granular activated carbon (GAC), mineral (pH = 10.5) and vegetal (pH = 9), for the removal of three pharmaceuticals, as sulphamethoxazole (SMX), diclofenac (DCF) and 17beta-estradiol (E2), from two different matrices: fortified distilled (2.4-3.0 mg L(-1) and pH from 5.5 to 6.5) and natural (~1.0 mg L(-1) and pH from 7.1 to 7.2) water in a bench scale. The Rapid Small-Scale Column Test used to assess the ability of mineral and vegetal GAC on removal of such pharmaceuticals led to removal capacities varying from 14.9 to 23.5 mg g(-1) for E2, from 23.7 to 24.2 mg g(-1) for DCF and from 20.5 to 20.6 mg g(-1) for SMX. Removal efficiencies of 71%, 88% and 74% for DCF, SMX and E2, respectively, were obtained at breakthrough point when using mineral GAC, whereas for the vegetal GAC the figures were 76%, 77% and 65%, respectively. The carbon usage rate at the breakthrough point varied from 11.9 to 14.5 L g(-1) for mineral GAC and from 8.8 to 14.8 L g(-1) for vegetal GAC. Mineral CAG also exhibited the best performance when treating fortified natural water, since nearly complete removal was observed for all contaminants in the column operated for 22 h at a carbon usage rate of 2.9 L g(-1). PMID- 26584019 TI - Losing p53 loosens up ER-stress. PMID- 26584018 TI - Preparation of Engineered Salmonella Typhimurium-Driven Hyaluronic-Acid-Based Microbeads with Both Chemotactic and Biological Targeting Towards Breast Cancer Cells for Enhanced Anticancer Therapy. AB - In this study, a new type of targeted bacteriobots is prepared and investigated as a therapeutic strategy against solid tumors. Maleimide-functionalized hyaluronic acid (HA) polymer is synthesized and cross-linked with four-arm thiolated polyethylene glycol (PEG-SH) to form HA microbeads with diameter of 8 MUm through the Michael-type addition. Docetaxel (DTX)-loaded nanoparticles are encapsulated in HA-PEG microbeads and sustained in vitro drug-release pattern of the DTX from the HA-PEG microbeads is observed for up to 96 h. Dual-targeted bacteriobots are prepared using CD 44 receptor-targeted HA microbeads synthesized via microfluidics, followed by the attachment of the flagellar bacterium Salmonella typhimurium, which have been genetically engineered for tumor targeting, onto the surface of the HA microbeads by the specific interaction between streptavidin on the HA beads and biotin on the bacteria. After the attachment of bacteria, the bacteriobots show an average velocity of 0.72 MUm s( 1) and high chemotactic migration velocity of 0.43 MUm s(-1) towards 4T1 cells lysates. CD 44 receptor-specific cellular uptake is verified through flow cytometry analysis and confocal imaging, demonstrating enhanced intracellular uptake in CD 44 receptor positive tumor cells compared to normal cells. Therefore, the present study suggests that these bacteriobots have dual-tumor targeting abilities displaying their potential for targeted anticancer therapy. PMID- 26584020 TI - Preclinical assessment of beta-d-mannuronic acid (M2000) as a non-steroidal anti inflammatory drug. AB - CONTEXT: beta-d-Mannuronic acid (M2000) has shown its therapeutic effects with the greatest tolerability and efficacy in various experimental models such as experimental autoimmune encephalomyelitis (EAE), adjuvant induced arthritis (AIA), nephrotic syndrome, and acute glomerulonephritis. Despite pharmacological effects of beta-D-mannuronic acid, there have been no systematic toxicological studies on its safety so far. OBJECTIVE: The study was designed to determine the acute and subchronic toxicity of beta-D-mannuronic acid, an anti-inflammatory agent, in healthy male NMRI mice and Wistar rats, respectively. MATERIALS AND METHODS: For the acute toxicity study, the animals received orally five different single doses of beta-D-mannuronic acid and were kept under observation for 14 d. In the subchronic study, 24 Wistar male rats were divided into four groups and were treated orally (gavage) once daily with test substance preparation at dose levels of 0, 50, 250, and 1250 mg/kg body weight for at least 63 consecutive days (9 weeks). Mortality, clinical signs, body weight changes, hematological and biochemical parameters, gross findings, organ weights, and histopathological determinations were monitored during the study. RESULTS: The results of acute toxicity indicated that the LD50 of beta-D-mannuronic acid is 4.6 g/kg. We found no mortality and no abnormality in clinical signs, body weight, relative organ weights, or necropsy in any of the animals in the subchronic study. Additionally, the results showed no significant difference in hematological, biochemical, and histopathological parameters in rats. CONCLUSIONS: Our results suggest that beta D-mannuronic acid is relatively safe when administered orally in animals. PMID- 26584021 TI - Impact of a Palliative Care Program on Tracheostomy Utilization in a Community Hospital. AB - BACKGROUND: Tracheostomies are typically provided to wean patients off the ventilator. However, in many circumstances tracheostomies are placed in patients who are at the end of their life with little hope of meaningful recovery. Palliative care teams decrease utilization of aggressive medical interventions in patients who are at the end of life. OBJECTIVE: The study objective was to determine the impact of a palliative care team on tracheostomy utilization in a community hospital setting. METHODS: The study was a four-year retrospective analysis of adult patients undergoing elective tracheostomy two years before and after the establishment of a palliative care program. The study in an ethnically diverse community hospital included patients older than 18 years old, with patients undergoing a tracheostomy due to trauma excluded. Before and after comparisons were made of demographics, in-hospital mortality, length of stay, and discharge status of patients undergoing tracheostomy. RESULTS: Seven hundred ninety patients undergoing tracheostomy were identified (n = 406, n = 384 before and after September 10, 2010, respectively). Patients were ethnically diverse (Caucasian 43%, Asian 23%, African American 11%, Hispanic 7%). The number of hospital admissions slightly increased during these two time periods (n = 58,926; n = 60,662, respectively). There were no statistical differences in age (73 versus 72, p = 0.827); gender (n = 218 [54%] versus n = 217 [57%] male, p = 0.426); or race (n = 187 [46%] versus n = 150 [39%] Caucasian, p = 0.073) in the two time periods. Patients who underwent tracheostomy after a palliative care service was established had less incidence of comorbid disease (Charlson Comorbidity Index score [CCIS]: 2 versus 3, p = 0.025); lower inpatient mortality (n = 107 [28%] versus n = 148 [37%], p = 0.009]); greater discharge to home or rehabilitation (n = 262 [68%] versus n = 249 [62%], p = 0.01); and lower rates of palliative weaning from mechanical ventilation (n = 61[16%] versus n = 113 [28%], p < 0.001). CONCLUSIONS: In an ethnically diverse community hospital, the institution of a palliative care program appears to have improved patient selection for tracheostomy with lower rates of inpatient mortality, improved rates of home discharge, and lower rates of palliative weaning from mechanical ventilation. PMID- 26584022 TI - Salivary hormones and anxiety in winners and losers of an international judo competition. AB - The purpose of this study was to investigate the responses of salivary hormones and salivary secretory immunoglobulin A (SIgA) and anxiety in winners and losers during an international judo competition. Twenty-three trained, male, national level judo athletes provided three saliva samples during a competition day: morning, in anticipation of competition after an overnight fast, mid-competition, and post-competition within 15 min post-fight for determination of salivary cortisol, salivary testosterone, salivary testosterone/cortisol ratio, SIgA absolute concentrations, SIgA secretion rate and saliva flow rate. The competitive state anxiety inventory questionnaire was completed by the athletes (n = 12) after the first saliva collection for determination of somatic anxiety, cognitive anxiety and self-confidence. Winners were considered 1-3 ranking place (n = 12) and losers (n = 11) below third place in each weight category. Winners presented higher anticipatory salivary cortisol concentrations (p = 0.03) and a lower mid-competition salivary testosterone/cortisol ratio (p = 0.003) compared with losers with no differences for salivary testosterone. Winners tended to have higher SIgA secretion rates (p = 0.07) and higher saliva flow rates (p = 0.009) at mid-competition. Higher levels of cognitive anxiety (p = 0.02) were observed in the winners, without differences according to the outcome in somatic anxiety and self-confidence. The results suggest that winners experienced higher levels of physiological arousal and better psychological preparedness in the morning, and as the competition progressed, the winners were able to control their stress response better. PMID- 26584023 TI - Lymphangiosarcoma: Is Stewart-Treves Syndrome a Preventable Condition? AB - BACKGROUND: Stewart-Treves syndrome is a rare complication of breast cancer treatment, representing a lymphangiosarcoma commonly associated with lymphedema and severely impacting patient's outcome. The tumor typically develops in the atrophic, pachydermatous, hyperkeratotic skin of limbs affected by long-standing lymphedema. Clinical data associated with Stewart-Treves syndrome and lymphedema management have rarely been published. METHODS AND RESULTS: In the period between 1980 and 2009, ten patients with Stewart-Treves syndrome were diagnosed and treated at the Foeldiklinik, Hinterzarten, Germany. Nine of the ten patients were female. Five patients had previously suffered from breast cancer (and were treated with mastectomy); two from other malignancies; two patients had primary lymphedema, and one had undergone lower extremity lymphadenectomy. All cancer patients had undergone radiation treatment. In all cases, the sarcoma developed in non-irradiated areas 6-48 years (average 16.3 years) after the onset of lymphedema. None of the patients had received complex decongestive physical therapy (CDT). Two patients had above-elbow amputation, one had shoulder exarticulation, two patients had wide excision and skin grafting, two patients had above-knee amputation procedure, two patients had a below-knee amputation procedure, and one patient had no surgical treatment at all. The time to recurrence after surgery, time to metastasis, patient survival and CDT were recorded. CONCLUSIONS: Patients with lymphedema should be closely examined starting 5 years from the time of lymphedema onset, paying special attention to those with associated malignancies. Only early diagnosis and treatment by radical ablative surgery confers a reasonable prognosis with this rare but aggressive disease. A potential effect of CDT on lymphangiosarcoma has to be studied in a greater patient cohort. PMID- 26584025 TI - 3rd International Clinical Trials Methodology Conference. PMID- 26584024 TI - Crystal Structure of Recoverin with Calcium Ions Bound to Both Functional EF Hands. AB - Recoverin (Rv), a small Ca(2+)-binding protein that inhibits rhodopsin kinase (RK), has four EF hands, two of which are functional (EF2 and EF3). Activation requires Ca(2+) in both EF hands, but crystal structures have never been observed with Ca(2+) ions in both sites; all previous structures have Ca(2+) bound to only EF3. We suspected that this was due to an intermolecular crystal contact between T80 and a surface glutamate (E153) that precluded coordination of a Ca(2+) ion in EF2. We constructed the E153A mutant, determined its X-ray crystal structure to 1.2 A resolution, and showed that two Ca(2+) ions are bound, one in EF3 and one in EF2. Additionally, several other residues are shown to adopt conformations in the 2Ca(2+) structure not seen previously and not seen in a second structure of the E153A mutant containing Na(+) instead of Ca(2+) in the EF2 site. The side chain rearrangements in these residues form a 28 A allosteric cascade along the surface of the protein connecting the Ca(2+)-binding site of EF2 with the active site pocket responsible for binding RK. PMID- 26584026 TI - Progress Toward Poliomyelitis Eradication--Pakistan, January 2014-September 2015. AB - Since Nigeria reported its last case of wild poliovirus type 1 (WPV1) in July 2014, Pakistan and Afghanistan remain the only two countries where WPV transmission has never been interrupted. This report describes actions taken and progress achieved toward polio eradication in Pakistan during January 2014 September 2015 and updates previous reports. A total of 38 WPV1 cases were reported in Pakistan during January-September 2015, compared with 243 during the same period in 2014 (an 84% decline). Among WPV1 cases reported in 2015, 32 (84%) occurred in children aged <36 months, nine (32%) of whom had never received oral poliovirus vaccine (OPV). Twenty-six (68%) of the 38 reported cases occurred in the Federally Administered Tribal Areas (FATA) and Khyber Pakhtunkhwa (KPK) Province. During January-September 2015, WPV1 was detected in 20% (64 of 325) of environmental samples collected, compared with 34% (98 of 294) of samples collected during the same period in 2014. The quality and scope of polio eradication activities improved considerably following the establishment of a national Emergency Operations Center, which coordinated polio eradication partners' activities. All activities are following a National Polio Eradication Emergency Action Plan that includes a rigorous action plan for the polio low transmission season (January-April). The presence of WPV1 in environmental samples in areas where no polio cases are detected highlights the need to improve surveillance for acute flaccid paralysis (AFP). Focused efforts to close remaining immunity gaps by locating, tracking, and vaccinating continually missed children and improving coverage with OPV through the routine vaccination program are needed to stop WPV transmission in Pakistan. PMID- 26584028 TI - Inhibitory effects of small molecular peptides from Spirulina (Arthrospira) platensis on cancer cell growth. AB - In this study, the whole proteins of Spirulina (Arthrospira) platensis were extracted, hydrolysis with three proteases (trypsin, alcalase and papain) was performed, and gel filtration chromatography was employed to separate hydrolysates. Totally, 15 polypeptides were isolated, which showed anti proliferation activities on five cancer cells (HepG-2, MCF-7, SGC-7901, A549 and HT-29), with the IC50 values between <31.25 and 336.57 MUg mL(-1). Moreover, a new peptide YGFVMPRSGLWFR was identified from papain-digested hydrolysates. It also exhibited inhibitory activities on cancer cells, and the best activity was observed on A549 cancer cells (IC50 values 104.05 MUg mL(-1)). In other words, these polypeptides exhibited anti-proliferation activities on cancer cells, and low toxicity or stimulatory activity on normal cells, suggesting that they are promising ingredients in food and pharmaceutical applications. PMID- 26584029 TI - Evidence and Consensus on the Management of Hepatocellular Carcinoma: Update 2015. PMID- 26584027 TI - Metabolic Mechanisms in Obesity and Type 2 Diabetes: Insights from Bariatric/Metabolic Surgery. AB - Obesity and the related diabetes epidemics represent a real concern worldwide. Bariatric/metabolic surgery emerged in last years as a valuable therapeutic option for obesity and related diseases, including type 2 diabetes mellitus (T2DM). The complicated network of mechanisms involved in obesity and T2DM have not completely defined yet. There is still a debate on which would be the first metabolic defect leading to metabolic deterioration: insulin resistance or hyperinsulinemia? Insight into the metabolic effects of bariatric/metabolic surgery has revealed that, beyond weight loss and food restriction, other mechanisms can be activated by the rearrangements of the gastrointestinal tract, such as the incretinic/anti-incretinic system, changes in bile acid composition and flow, and modifications of gut microbiota; all of them possibly involved in the remission of T2DM. The complete elucidation of these mechanisms will lead to a better understanding of the pathogenesis of this disease. Our aim was to review some of the metabolic mechanisms involved in the development of T2DM in obese patients as well as in the remission of this condition in patients submitted to bariatric/metabolic surgery. PMID- 26584030 TI - Evaluation of ART Scores for Repeated Transarterial Chemoembolization in Japanese Patients with Hepatocellular Carcinoma. AB - OBJECTIVE: Transarterial chemoembolization (TACE) is recommended as a first-line therapy for hepatocellular carcinoma (HCC) patients ineligible for curative therapy and without portal invasion. The Assessment for Retreatment with TACE (ART) scoring system was recently proposed for identifying patients who would not show sufficient survival benefit from repeated TACE. We reevaluated the performance of ART in HCC patients treated in Japan, where selective TACE is commonly used. METHODS: Between 2000 and 2013, 988 patients with HCC underwent TACE at Kinki University Hospital, and 627 received >=2 sessions of TACE. Seventy six patients who underwent >=2 TACE sessions within 90 days were investigated for their performance of the ART score in the context of overall survival (OS). RESULTS: Only 12% (76/627) of patients underwent >=2 TACE sessions within 90 days. Of those, 52 patients showed a low ART score (0-1.5), and 24 had a high ART score (>=2.5); the median OS was 20.2 and 37.6 months, respectively (p = 0.8207). CONCLUSION: The ART scoring system did not demonstrate a sufficiently predictive impact on OS among the patients who underwent >=2 TACE sessions within 90 days. Application of the ART score should be carefully considered because differences in TACE procedures and post-TACE treatment can affect the results while evaluating OS. PMID- 26584031 TI - Initial Experience Performing Percutaneous Ultrasound Examination with Real-Time Virtual Sonography with Color Display. AB - PURPOSE: We report the efficacy of percutaneous ultrasound (US) examination using a novel real-time virtual sonography (RVS) method that collates multiple Digital Imaging and Communications in Medicine (DICOM) data sources and displays reference images in color. MATERIALS AND METHODS: A total of 7 patients with 9 hepatocellular carcinomas were evaluated. Using the SYNAPSE VINCENT volume analyzer, DICOM data of the portal vein, hepatic vein, tumor, and hepatic segment were isolated from contrast-enhanced computed tomography DICOM data. Each portion of DICOM data was uploaded into an US scanner (HI VISION Ascendus, Hitachi Aloka Medical Ltd., Tokyo, Japan) and unified on a US platform to create a single reference image. Each uploaded portion of DICOM data was assigned a different color. Further, conventional RVS was performed using this information. RESULTS: The maximal tumoral diameter ranged from 6.4 to 15 mm (mean +/- SD, 11.0 +/- 2.8). DICOM data could be isolated, enabling the display of color RVS in all patients. Color RVS facilitated superior visibility compared with conventional grayscale RVS and facilitated the comprehension of spatial positioning. CONCLUSION: RVS with color display demonstrates utility in increasing operator comprehension of spatial and positional relationships during percutaneous US examination. PMID- 26584032 TI - Percutaneous Radiofrequency Ablation for Intermediate-Stage Hepatocellular Carcinoma. AB - OBJECTIVES: Radiofrequency ablation plays a key role in the treatment of early stage hepatocellular carcinoma. However, it is not recommended for intermediate stage hepatocellular carcinoma. The objective of this study was to clarify the efficacy and safety of radiofrequency ablation for treating intermediate-stage hepatocellular carcinoma. METHODS: We examined the outcome of 65 consecutive patients who were treated with radiofrequency ablation with or without transarterial chemoembolization for intermediate-stage hepatocellular carcinoma. RESULTS: With a median follow-up of 37 months, overall survival rates of 65 cases at 1, 3, 5, and 7 years were 90, 70, 51, and 36%, respectively. Multivariate analysis of clinical parameters revealed that the multicentric occurrence (MC)/intrahepatic metastasis (IM) was the only significant prognostic factor for overall survival (hazard ratio, 4.9; 95% confidence intervals, 2.1-11.4). Tumor size and tumor number were not significant factors for survival. The overall survival rates of patients with MC (n = 33) at 1, 3, 5, and 7 years were 97, 90, 80, and 59%, respectively; those for patients with IM (n = 32) were 86, 55, 14, and 8%, respectively (p < 0.0001). Two cases (4.9%) had complications of hemothorax and diaphragmatic burn; however, no major complications were observed. CONCLUSION: Radiofrequency ablation is safe and effective for the treatment of intermediate-stage hepatocellular carcinoma, especially for patients with MC. PMID- 26584033 TI - Balloon-Occluded Transcatheter Arterial Chemoembolization for Hepatocellular Carcinoma: A Single-Center Experience. AB - OBJECTIVE: To investigate whether balloon-occluded transcatheter arterial chemoembolization (b-TACE) can produce a more dense accumulation of iodized oil in various stages of hepatocellular carcinoma (HCC), from single to uncountable, to overcome inferior local control. MATERIALS AND METHODS: We studied 27 patients with HCC, including single to uncountable multiple lesions, who underwent b-TACE between August 2013 and April 2015. Dynamic CT was performed at baseline and 1-3 months after b-TACE. The treatment effect (TE) after b-TACE was evaluated using the Response Evaluation Criteria in Cancer of the Liver (RECICL) proposed by the Liver Cancer Study Group of Japan. RESULTS: In the countable HCC group, contrast enhanced CT demonstrated RECICL TE4 in 43.8% (14/32), TE3 in 12.5% (4/32), TE2 in 37.5% (12/32), and TE1 in 6.3% (2/32) of patients. For the TACE-naive cohort, the objective response rate was 52.9%. The objective response rate was 60% for the previously TACE-treated cohort. In the uncountable multiple HCC group, the objective response rate was 0% (0/10), with progressive disease in 90% (9/10) of patients. CONCLUSION: Our observations suggested that b-TACE did not reduce the efficacy of retreatment for HCC with an insufficient outcome from conventional TACE, but it could not improve the efficacy of treatment for uncountable multiple HCCs. PMID- 26584034 TI - Hyperenhanced Rim Surrounding Liver Metastatic Tumors in the Postvascular Phase of Sonazoid-Enhanced Ultrasonography: A Histological Indication of the Presence of Kupffer Cells. AB - AIM: A hyperenhanced rim (termed 'HER') in the postvascular phase is detected in some cases of liver metastasis by Sonazoid-enhanced ultrasonography (US). Here, the association of the HER with histological features was investigated to clarify the cause of this characteristic imaging pattern. SUBJECTS AND METHODS: A total of 13 hepatic nodules obtained from 11 patients with metastatic liver cancer who underwent Sonazoid-enhanced US followed by surgical resection were analyzed. The distribution density of CD68-positive cells in the tumor rim and the nontumor area was calculated and compared between the HER-positive and HER-negative groups. The relation between the pathological features of the tumor rim and the rate of necrosis within the tumor was also investigated. RESULTS: In the HER positive group (n = 8), the distribution density of CD68-positive cells was 2.9 +/- 0.9, which was significantly higher than that (1.0 +/- 0.3) in the HER negative group (p < 0.05). Inflammatory cell infiltrates, including CD8-positive lymphocytes, were detected in all the HER-positive cases in the area surrounding the tumor, while fibrosis was observed in all the HER-negative cases. The necrotic area within the tumor was significantly larger in the HER-negative group. CONCLUSION: The HER-positive sign in liver metastases could reflect an increase in Kupffer cells in the tumor rim. The presence of the HER was associated with inflammatory cell infiltrates including CD8-positive lymphocytes surrounding the metastatic liver tumor. PMID- 26584035 TI - Comparison of Daclatasvir and Asunaprevir for Chronic HCV 1b Infection with Telaprevir and Simeprevir plus Peginterferon and Ribavirin, with a Focus on the Prevention of Occurrence and Recurrence of Hepatocellular Carcinoma. AB - OBJECTIVES: The efficacy of the all-oral administration of daclatasvir and asunaprevir for 24 weeks was compared with that of telaprevir for 12 weeks plus pegylated interferon and ribavirin (PEG-IFN/RBV) for 24 weeks, and that of simeprevir for 12 weeks plus PEG-IFN/RBV for 24 weeks, with a focus on the prevention of occurrence and recurrence of hepatocellular carcinoma (HCC). The levels of alanine aminotransferase (ALT) and alpha-fetoprotein (AFP) as suppressive markers of HCC were also measured. METHODS: Patients received daclatasvir and asunaprevir (n = 17), simeprevir plus PEG-IFN/RBV (n = 15) and telaprevir plus PEG-IFN/RBV (n = 25). Sustained virological response (SVR) and the mean change in the level of serum ALT, AFP and platelet (PLT) count were compared among the three groups. RESULTS: No difference in SVR was observed in patients given daclatasvir with asunaprevir (SVR4), telaprevir plus PEG-IFN/RBV or simeprevir plus PEG-IFN/RBV (SVR24). Also, no significant difference was observed in the mean change of serum ALT, AFP or PLT count among the three groups. CONCLUSION: The preventive effect of the IFN-free, all-oral regimen of daclatasvir and asunaprevir was observed with a focus on the occurrence and recurrence of HCC, as was IFN-based treatment with telaprevir or simeprevir plus PEG-IFN/RBV. PMID- 26584036 TI - Validation of a Modified Substaging System (Kinki Criteria) for Patients with Intermediate-Stage Hepatocellular Carcinoma. AB - INTRODUCTION: Barcelona Clinic Liver Cancer (BCLC) stage B, an intermediate stage, includes various conditions of hepatocellular carcinoma (HCC). This heterogeneity of the patients with intermediate-stage HCC makes it difficult to predict their survival rates. In the present study, we examined the validity of the modified Bolondi classification (Kinki criteria) as a subclassification of patients with BCLC stage B HCC. METHODS: Of 906 patients who underwent conventional transarterial chemoembolization at Kinki University Hospital, 753, who met the inclusion criteria, were examined. Of these 753 patients, 425 (56.4%) with BCLC stage B were subclassified using the Kinki criteria to examine the survival rate. RESULTS: According to the Kinki criteria, 158 (37.2%) were subclassified into subclass B1, 236 (55.5%) into B2, and 31 (7.3%) into B3. The comparison of the survival rates showed that the median overall survival was 3.9 years (95% CI, 3.2-4.6) in the BCLC subclass B1 group, 2.5 years (95% CI, 2.2 3.1) in the B2 group, and 1.1 years (95% CI, 0.6-1.5) in the B3 group (p < 0.001). CONCLUSION: When the BCLC stage B patients were subclassified according to the Kinki criteria, survival curves were stratified with significant differences, suggesting that the Kinki criteria were suitable for the subclassification of the intermediate-stage HCC patients. PMID- 26584037 TI - Recent Advances in the Management of Chronic Hepatitis B Including Suppression of Hepatocellular Carcinoma by Entecavir and Interferon. AB - At present, for adults with chronic hepatitis B virus (HBV) infection, two new analogues, entecavir (ETV) and tenofovir, are recommended as the first-line therapy by the EASL (European Association for the Study of the Liver), AASLD (American Association for the Study of Liver Diseases), and APASL (Asian Pacific Association for the Study of the Liver) guidelines. The use of pegylated interferon-alpha (PEG IFN-alpha) is recommended as the first-line therapy instead of standard IFN-alpha according to the above 3 guidelines. In this paper, the aim was to assess: (1) the long-term efficacy and safety as well as the resistance to ETV and tenofovir disoproxil fumarate (TDF); (2) the efficacy of PEG IFN-alpha; (3) the role of combination therapy with IFN plus two analogues, such as lamivudine and ETV; (4) the efficacy and safety of two analogues with cirrhosis, and (5) suppression of hepatocellular carcinoma (HCC) by ETV and IFN treatment. The results are as follows: (1) both ETV and TDF showed long-term efficacy and safety; (2) PEG IFN-alpha resulted in a greater decline in HBV DNA levels and a higher rate of HBeAg seroconversion; (3) combination therapy with IFN plus two analogues did not elevate the rate of sustained responses; (4) both ETV and TDF showed efficacy and safety with cirrhosis (ETV especially displayed efficacy and safety with decompensated cirrhosis), and (5) suppression of HCC was observed by ETV and IFN. PMID- 26584039 TI - Sleep Patterns of Emergency Department Nurses on Workdays and Days Off. AB - BACKGROUND: Shift workers, particularly night workers, are prone to disrupted circadian rhythms and sleep deprivation resulting in fatigue and sleepiness, thereby endangering patient safety. Little is known about the sleep patterns of emergency nurses who work highly variable around-the-clock schedules to meet the demands of fluctuating patient census and acuities throughout the 24-hour period. PURPOSE: The purpose of this pilot study was to determine whether there are shift related sleep pattern differences in emergency department nurses over seven consecutive 24-hour periods that include both workdays and days off. METHODS: A New Jersey mailing list (1514 members) was rented from the Emergency Nurses' Association. Three hundred on this list were systematically sampled and invited by mail to participate. The final sample consisted of 35 emergency nurses. Participants wore actigraphs for 24 hours each day for 7 days and completed sleep diaries upon awakening from their daily main sleep periods. Queries included caffeine and hypnotics usage. The nurses also completed the Standard Shiftwork Index General Biographical Information Section for demographic and scheduling data. Participants received a $50 honorarium upon completion of the protocol. The actigraph data were downloaded into a personal computer using Act Millennium and analyzed with Action W software (Ambulatory Monitoring, Inc., Ardsley, NY, USA). RESULTS: Sleep durations ranged from 6.6 to 8.1 hours on workdays and from 6.2 to 8.1 hours on days off. There were no significant shift- or workday-related differences in sleep patterns. However, trends indicated that, regardless of shift, workday sleep became more disturbed and less efficient toward the end of the week. Daily caffeine usage was reported by 85.9% of the sample. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: Shift working nurses need to obtain adequate and consistent sleep on workdays and days off throughout the work week to reduce fatigue and to provide safe patient care. Understanding the sleep patterns of emergency nurses and their schedules is critical to facilitating the development of shift-specific sleep promotion interventions to enhance sleep and thereby counteract fatigue. PMID- 26584040 TI - The Initial Development of a Checklist for Assessing Thirst in Patients With Advanced Dementia. AB - BACKGROUND: Patients with advanced dementia (PwAD) often have difficulty expressing their needs verbally because of cognitive impairments. PwAD thus often communicate these needs through behaviors and psychological symptoms. Understanding the behavioral characteristics of certain needs is critical for caregivers and clinicians when caring for PwAD. PURPOSE: The purpose of this study was to develop a checklist that may be used to assess the thirst status of PwAD. METHODS: A mixed method design was used. The checklist was developed using qualitative interviews and surveys. The initial items were developed through interviews with 10 professional nurses who were caring for PwAD. Four experts in dementia assessed the content validity of these items. PwAD caregivers from eight facilities were then invited to complete the checklist based on their current PwAD patient care experience. Data obtained in this study were analyzed with regard to content validity, interrater reliability, internal consistency, and exploratory factor analysis. RESULTS: The content validity of the initial 18 items was .96, interrater reliability was -.33 to 1, and internal consistency reliability was .52. Exploratory factor analysis identified seven checklist items, including repetitive movements, squirming, restlessness or anxiety, persistent or unreasonable demands, pacing back and forth, repeating a sentence or question without purpose, and slow reaction. The factor loadings of these seven items accounted for 49.3% of the total variance. The reassessed internal consistency reliability was .66. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: Caregivers may use this checklist as an aid to identify the thirst or fluid needs of PwAD who are unable to communicate their needs effectively. PMID- 26584041 TI - Predictors of Antenatal Psychosocial Stress in Taiwanese Women. AB - BACKGROUND: Antenatal stress has been associated with adverse outcomes in mothers and their children. However, little research has been conducted to identify the factors associated with psychosocial stress in pregnant women. PURPOSE: This study explored the predictors of psychosocial stress during pregnancy. METHODS: A convenience sample of 136 second-trimester and 164 third-trimester pregnant women were recruited from a medical center in southern Taiwan. Data were collected using a demographic form, Pregnancy Stress Rating Scale (PSRS), Edinburgh Prenatal Depression Scale, Pittsburgh Sleep Quality Index, Maternal-Fetal Attachment Scale, and Interpersonal Support Evaluation List. RESULTS: The results of this study found positive correlations between PSRS and both Edinburgh Prenatal Depression Scale (r = .368, p < .01) and Maternal-Fetal Attachment Scale (r = .168, p < .01) and negative correlations between PSRS and both gravidity (r = -.137, p < .05) and Interpersonal Support Evaluation List (r = -.266, p < .01). Higher pregnancy stress was predicted by depression, lower social support, maternal-fetal attachment, and primigravid status, which together explained 20% of the total variance. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: Depression, social support, maternal-fetal attachment, and gravidity are discrete predictive factors of psychosocial stress in pregnant women. These findings add to existing knowledge of the factors associated with prenatal stress. Future research should include depression in a support model of antenatal stress management. PMID- 26584043 TI - Origin of highly active metal-organic framework catalysts: defects? Defects! AB - This article provides a comprehensive review of the nature of catalytic sites in MOFs. In the last decade, a number of striking studies have reported outstanding catalytic activities of MOFs. In all cases, the authors were intrigued as it was unexpected from the ideal structure. We demonstrate here that (surface) defects are at the origin of the catalytic activities for the reported examples. The vacancy of ligands or linkers systematically generates (surface) terminations which can possibly show Lewis and/or Bronsted acido-basic features. The engineering of catalytic sites at the nodes by the creation of defects (on purpose) appears today as a rational approach for the design of active MOFs. Similarly to zeolite post-treatments, post-modifications of MOFs by linker or metal cation exchange appear to be methods of choice. Despite the mild acidity of defective MOFs, we can account for very active MOFs in a number of catalytic applications which show higher performances than zeolites or benchmark catalysts. PMID- 26584044 TI - Is STAPLE algorithm confident to assess segmentation methods in PET imaging? AB - Accurate tumor segmentation in [18F]-fluorodeoxyglucose positron emission tomography is crucial for tumor response assessment and target volume definition in radiation therapy. Evaluation of segmentation methods from clinical data without ground truth is usually based on physicians' manual delineations. In this context, the simultaneous truth and performance level estimation (STAPLE) algorithm could be useful to manage the multi-observers variability. In this paper, we evaluated how this algorithm could accurately estimate the ground truth in PET imaging. Complete evaluation study using different criteria was performed on simulated data. The STAPLE algorithm was applied to manual and automatic segmentation results. A specific configuration of the implementation provided by the Computational Radiology Laboratory was used. Consensus obtained by the STAPLE algorithm from manual delineations appeared to be more accurate than manual delineations themselves (80% of overlap). An improvement of the accuracy was also observed when applying the STAPLE algorithm to automatic segmentations results. The STAPLE algorithm, with the configuration used in this paper, is more appropriate than manual delineations alone or automatic segmentations results alone to estimate the ground truth in PET imaging. Therefore, it might be preferred to assess the accuracy of tumor segmentation methods in PET imaging. PMID- 26584045 TI - Untangling Brain-Wide Dynamics in Consciousness by Cross-Embedding. AB - Brain-wide interactions generating complex neural dynamics are considered crucial for emergent cognitive functions. However, the irreducible nature of nonlinear and high-dimensional dynamical interactions challenges conventional reductionist approaches. We introduce a model-free method, based on embedding theorems in nonlinear state-space reconstruction, that permits a simultaneous characterization of complexity in local dynamics, directed interactions between brain areas, and how the complexity is produced by the interactions. We demonstrate this method in large-scale electrophysiological recordings from awake and anesthetized monkeys. The cross-embedding method captures structured interaction underlying cortex-wide dynamics that may be missed by conventional correlation-based analysis, demonstrating a critical role of time-series analysis in characterizing brain state. The method reveals a consciousness-related hierarchy of cortical areas, where dynamical complexity increases along with cross-area information flow. These findings demonstrate the advantages of the cross-embedding method in deciphering large-scale and heterogeneous neuronal systems, suggesting a crucial contribution by sensory-frontoparietal interactions to the emergence of complex brain dynamics during consciousness. PMID- 26584046 TI - Bidirectional Influence: A Longitudinal Analysis of Size of Drug Network and Depression Among Inner-City Residents in Baltimore, Maryland. AB - BACKGROUND: The prevalence of depression among drug users is high. It has been recognized that drug use behaviors can be influenced and spread through social networks. OBJECTIVES: We investigated the directional relationship between social network factors and depressive symptoms among a sample of inner-city residents in Baltimore, MD. METHODS: We performed a longitudinal study of four-wave data collected from a network-based HIV/STI prevention intervention for women and network members, consisting of both men and women. Our primary outcome and exposure were depression using CESD scale and social network characteristics, respectively. Linear-mixed model with clustering adjustment was used to account for both repeated measurement and network design. RESULTS: Of the 746 participants, those who had high levels of depression tended to be female, less educated, homeless, smokers, and did not have a main partner. In the univariate longitudinal model, larger size of drug network was significantly associated with depression (OR = 1.38, p < .001). This relationship held after controlling for age, gender, homeless in the past 6 months, college education, having a main partner, cigarette smoking, perceived health, and social support network (aOR = 1.19, p = .001). In the univariate mixed model using depression to predict size of drug network, the data suggested that depression was associated with larger size of drug network (coef. = 1.23, p < .001) and the same relation held in multivariate model (adjusted coef. = 1.08, p = .001). CONCLUSIONS: The results suggest that larger size of drug network is a risk factor for depression, and vice versa. Further intervention strategies to reduce depression should address social networks factors. PMID- 26584047 TI - Prenatal Evaluation of the Fetal Conus Medullaris on a Routine Scan. AB - OBJECTIVE: To assess the ability to identify the conus medullaris (CM) and measure the conus-sacrum distance (CS distance) on a routine scan and the relationship with maternal and fetal factors. METHODS: This was a prospective study. The assessment of the CM and the CS distance and the influence of the body mass index (BMI), gestational age (GA) and fetal position were analyzed. The correlation between the femur length (FL) and the GA with the CS distance was evaluated. RESULTS: A total of 696 fetuses were analyzed. The CM could be visualized in 82.3% of the cases, and the CS distance could be analyzed in 81.2% of the cases. The CM assessment was statistically associated with BMI and fetal position but not with GA. The CS distance assessment was statistically associated with BMI and GA but not with fetal position. We determined a significant association between the FL/CS distance and between the GA/CS distance. CONCLUSIONS: Assessment of the CM is possible on most routine scans. The CS distance could be introduced to routine scans for the assessment of prenatal skin covered spinal dysraphism. High BMI, advanced GA and breech presentation could be potential factors limiting the feasibility of evaluating the CM. PMID- 26584048 TI - Identification and Characterization of a New Enterotoxin Produced by Clostridium perfringens Isolated from Food Poisoning Outbreaks. AB - There is a strain of Clostridium perfringens, W5052, which does not produce a known enterotoxin. We herein report that the strain W5052 expressed a homologue of the iota-like toxin components sa and sb of C. spiroforme, named Clostridium perfringens iota-like enterotoxin, CPILE-a and CPILE-b, respectively, based on the results of a genome sequencing analysis and a systematic protein screening. In the nicotinamide glyco-hydrolase (NADase) assay the hydrolysis activity was dose-dependently increased by the concentration of rCPILE-a, as judged by the mass spectrometry analysis. In addition, the actin monomer of the lysates of Vero and L929 cells were radiolabeled in the presence of [32P]NAD and rCPILE-a. These findings indicated that CPILE-a possesses ADP-ribosylation activity. The culture supernatant of W5052 facilitated the rounding and killing of Vero and L929 cells, but the rCPILE-a or a non-proteolyzed rCPILE-b did not. However, a trypsin treated rCPILE-b did. Moreover, a mixture of rCPILE-a and the trypsin-treated rCPILE-b enhanced the cell rounding and killing activities, compared with that induced by the trypsin-treated rCPILE-b alone. The injection of the mixture of rCPILE-a and the trypsin-treated rCPILE-b into an ileum loop of rabbits evoked the swelling of the loop and accumulation of the fluid dose-dependently, suggesting that CPILE possesses enterotoxic activity. The evidence presented in this communication will facilitate the epidemiological, etiological, and toxicological studies of C. perfringens food poisoning, and also stimulate studies on the transfer of the toxins' gene(s) among the Genus Clostridium. PMID- 26584049 TI - The Fanconi Anemia Pathway Protects Genome Integrity from R-loops. AB - Co-transcriptional RNA-DNA hybrids (R loops) cause genome instability. To prevent harmful R loop accumulation, cells have evolved specific eukaryotic factors, one being the BRCA2 double-strand break repair protein. As BRCA2 also protects stalled replication forks and is the FANCD1 member of the Fanconi Anemia (FA) pathway, we investigated the FA role in R loop-dependent genome instability. Using human and murine cells defective in FANCD2 or FANCA and primary bone marrow cells from FANCD2 deficient mice, we show that the FA pathway removes R loops, and that many DNA breaks accumulated in FA cells are R loop-dependent. Importantly, FANCD2 foci in untreated and MMC-treated cells are largely R loop dependent, suggesting that the FA functions at R loop-containing sites. We conclude that co-transcriptional R loops and R loop-mediated DNA damage greatly contribute to genome instability and that one major function of the FA pathway is to protect cells from R loops. PMID- 26584050 TI - Onchocerca lupi Nematode in Cat, Portugal. PMID- 26584051 TI - Surfactant modulated aggregation induced enhancement of emission (AIEE)--a simple demonstration to maximize sensor activity. AB - A new type of easily synthesized rhodamine-based chemosensor L(3), with potential NO2 donor atoms, selectively and rapidly recognizes Hg(2+) ions in the presence of all biologically relevant metal ions and toxic heavy metals. A very low detection limit (78 nM) along with cytoplasmic cell imaging applications with no or negligible cytotoxicity indicate good potential for in vitro/in vivo cell imaging studies. SEM and TEM studies reveal strongly agglomerated aggregations in the presence of 5 mM SDS which turn into isolated core shell microstructures in the presence of 9 mM SDS. The presence of SDS causes an enhanced quantum yield (phi) and stability constant (Kf) compared to those in the absence of SDS. Again, the FI of the [L(3)-Hg](2+) complex in an aqueous SDS (9 mM) medium is unprecedentedly enhanced (~143 fold) compared to that in the absence of SDS. All of these observations clearly manifest in the enhanced rigidity of the [L(3) Hg](2+) species in the micro-heterogeneous environment significantly restricting its dynamic movements. This phenomenon may be ascribed as an aggregation induced emission enhancement (AIEE). The fluorescence anisotropy assumes a maximum at 5 mM SDS due to strong trapping (sandwiching) of the doubly positively charged [L(3)-Hg](2+) complex between two co-facial laminar microstructures of SDS under pre-miceller conditions where there is a strong electrostatic interaction that causes an improved inhibition to dynamic movement of the probe-mercury complex. On increasing the SDS concentration there is a phase transition in the SDS microstructures and micellization starts to prevail at SDS >= 7.0 mM. The doubly positively charged [L(3)-Hg](2+) complex is trapped inside the hydrophobic inner core of the micelle which is apparent from the failure to quench the fluorescence of the complex on adding 10 equivalents of H2EDTA(2-) solution but in the absence of SDS it is quenched effectively. PMID- 26584053 TI - Percutaneous extraction of a fractured and protruding ostial stent fragment using a vascular retrieval forceps device. PMID- 26584054 TI - Respiratory Muscle Activity During Simultaneous Stationary Cycling and Inspiratory Muscle Training. AB - Inspiratory muscle training (IMT) strengthens the muscles of respiration, improves breathing efficiency, and increases fitness. The IMT is generally performed independently of aerobic exercise; however, it is not clear whether there is added benefit of performing the IMT while simultaneously performing aerobic exercise in terms of activating and strengthening inspiratory muscles. The purpose of our study was to determine the effect of IMT on respiratory muscle electromyography (EMG) activity during stationary cycling in the upright and drops postures as compared with that when the IMT was performed alone. Diaphragm and sternocleidomastoid EMG activity was measured under different resting and cycling postures, with and without the use of the IMT at 40% maximal inspiratory pressure (n = 10; mean age 37). Cycling in an upright posture while simultaneously performing the IMT resulted in a significantly greater diaphragm EMG activity than while performing the IMT at rest in upright or drops postures (p <= 0.05). Cycling in drops postures while performing the IMT had a significantly greater diaphragm EMG activity than when performing the IMT at rest in either upright or drops postures (p <= 0.05). Sternocleidomastoid muscle activity increased with both cycling and IMT, although posture had little effect. These results support our hypothesis in that the IMT while cycling increases respiratory EMG activity to a significantly greater extent than when performing the IMT solely at rest, suggesting that the combination of IMT and cycling may provide an additive training effect. PMID- 26584055 TI - Elispot Igra With Purified Protein Derivative Stimulation For Diagnosing Nontuberculous Mycobacterial Cervical Lympadenitis. AB - Childhood cervical lymphadenitis caused by nontuberculous mycobacteria is a diagnostic challenge for the clinician. We present a new promising diagnostic method for childhood nontuberculous mycobacterial lymphadenitis. The modified T SPOT.TB test with purified protein derivative as an additional antigen is noninvasive with estimated sensitivity and specificity of 1.00 and 0.81, respectively. PMID- 26584056 TI - Vaccine Serotypes of Streptococcus pneumoniae with High-level Antibiotic Resistance Isolated More Frequently Seven Years After the Licensure of PCV7 in Beijing. AB - BACKGROUND: Streptococcus pneumoniae 7-valent conjugate vaccine (PCV7) was made available in China in the private sector in September 2008. METHODS: This study investigated the serotype distribution, antibiotic resistance, and molecular characteristics of S. pneumoniae in hospitalized pediatric patients. Pneumococcal isolates were collected from hospitalized children younger than 14 years. Their serotypes were determined using Quellung reactions with antisera; antibiotic resistance against 13 antimicrobials was tested using the E-test method or disc diffusion. The sequence types (STs) were analyzed with multilocus sequence typing. RESULTS: A total of 187 pneumococcal specimens were collected, including 21 invasive and 166 noninvasive isolates. The prevailing serotypes were 19F (31.6%), 19A (19.8%), 23F (11.2%), 6A (9.1%), 14 (9.1%) and 15B (5.9%). The coverage rates of PCV7, PCV10 and PCV13 were 56.2% (105/187), 56.7% (106/187) and 86.1% (161/187), respectively. The overall nonsusceptibility rate against penicillin was 8.0%; however, this rate would have been 91.5% if based on an oral breakpoint. All but one of the isolates were highly resistant to erythromycin. Multidrug resistance was exhibited by 177 (94.7%) isolates. The 5 predominant multilocus sequence typings for all pneumococci were ST271 (24.1%), ST320 (18.2%), ST81 (7.5%), ST876 (7%) and ST3397 (5.3%), which were primarily related to serotypes 19F, 19A, 23F, 14 and 15B, respectively. CC271 was the most frequent antibiotic-resistant complex clone. CONCLUSIONS: The coverage rates of PCVs were high, and the antibiotic resistance rates were of serious concern among hospitalized children. Universal immunization using PCVs would likely prevent episodes of S. pneumoniae diseases and the spread of antibiotic resistance in Beijing. PMID- 26584057 TI - Unilateral Proptosis in an Immunocompetent Child From the Middle East. PMID- 26584058 TI - Mechanism of periodic height variations along self-aligned VLS-grown planar nanostructures. AB - In this study we report in-plane nanotracks produced by molecular-beam-epitaxy (MBE) exhibiting lateral self-assembly and unusual periodic and out-of-phase height variations across their growth axes. The nanotracks are synthesized using bismuth segregation on the GaAsBi epitaxial surface, which results in metallic liquid droplets capable of catalyzing GaAsBi nanotrack growth via the vapor liquid-solid (VLS) mechanism. A detailed examination of the nanotrack morphologies is carried out employing a combination of scanning electron and atomic force microscopy and, based on the findings, a geometric model of nanotrack growth during MBE is developed. Our results indicate diffusion and shadowing effects play significant roles in defining the interesting nanotrack shape. The unique periodicity of our lateral nanotracks originates from a rotating nucleation "hot spot" at the edge of the liquid-solid interface, a feature caused by the relative periodic circling of the non-normal ion beam flux incident on the sample surface, inside the MBE chamber. We point out that such a concept is divergent from current models of crawling mode growth kinetics and conclude that these effects may be utilized in the design and assembly of planar nanostructures with controlled non-monotonous structure. PMID- 26584059 TI - Crystal phase-controlled synthesis, properties and applications of noble metal nanomaterials. AB - The functional properties of noble metal nanomaterials are determined by their size, shape, composition, architecture and crystal structure/phase. In recent years, the crystal phase control of noble metal nanomaterials has emerged as an efficient and versatile strategy to tune their properties. In this tutorial review, we will give an overview of the latest research progress in the crystal phase-controlled synthesis of noble metal nanomaterials. Moreover, the crystal phase-dependent chemical and physical properties (e.g. chemical stability, magnetic, electrical and optical properties) and catalytic applications (e.g. oxygen reduction reaction, and oxidation reactions of formic acid, methanol and carbon monoxide) of noble metal nanomaterials are also briefly introduced. Finally, based on the current research status of the crystal phase-controlled synthesis of noble metal nanomaterials, we will provide some perspectives on the challenges and opportunities in this emerging research field. PMID- 26584060 TI - Early Nerve Grafting for Facial Paralysis After Cerebellopontine Angle Tumor Resection With Preserved Facial Nerve Continuity. AB - IMPORTANCE: Preserving facial nerve function is a primary goal and a key decision factor in the comprehensive management of vestibular schwannoma and other cerebellopontine angle (CPA) tumors. OBJECTIVE: To evaluate the use of the pattern of facial paralysis recovery in the early postoperative months as a sole predictor in selecting patients for facial nerve grafting after CPA tumor resection when cranial nerve VII is uninterrupted. DESIGN, SETTING, AND PARTICIPANTS: Sixty-two patients with facial paralysis and uninterrupted cranial nerve VII who developed facial paralysis after CPA tumor resection at The Johns Hopkins Hospital were followed up prospectively to assess for spontaneous recovery and to determine candidacy for facial reanimation surgery. The study dates and dates of analysis were January 1, 2009, to March 31, 2015. INTERVENTIONS: After a minimum of 6 months of clinical follow-up and no signs of clinical recovery, patients underwent facial nerve exploration and a masseteric or hypoglossal nerve transfer. Intraoperative direct nerve stimulation was performed to assess for the presence of subclinical reinnervation. Patients were followed up for a minimum of 18 months after surgery to evaluate outcomes. MAIN OUTCOMES AND MEASURES: Facial function and recovery were studied objectively with a Smile Recovery Scale, Facial Asymmetry Index, and House-Brackmann (HB) grading system. Other outcome measures included the duration of paralysis, time to recovery, and evidence of synkinesis. RESULTS: Sixty-two patients (33 men, 29 women; mean age 51.8 years) with uninterrupted facial nerves after CPA tumor resection developed HB grade IV, V, or VI facial paralysis. Ten patients underwent nerve grafting by 12 months, 9 patients received grafting after 12 months, and 8 patients had no intervention. Thirty-five patients spontaneously recovered. In all patients who underwent nerve grafting, there were no detectable facial muscle movements or electromyographic response to direct facial nerve stimulation suggestive of occult reinnervation. Overall, early facial reanimation surgery resulted in a shorter total duration of paralysis. Masseteric nerve grafting resulted in earlier recovery compared with hypoglossal nerve grafting (5.6 vs 10.8 months, P = .005). Patients who showed no signs of recovery by 6 months after CPA surgery but declined facial reanimation surgery demonstrated at best HB grade V recovery after 18 months of observation. CONCLUSIONS AND RELEVANCE: The recovery pattern in the early postoperative period among patients who develop facial paralysis after CPA tumor resection is a useful clinical tool in selecting patients for facial reanimation surgery. Patients can be counseled for facial reanimation surgery as early as 6 months after surgery because satisfactory facial functional recovery is unlikely to occur when there is no clinical evidence of spontaneous nerve regeneration in the first 6 months. LEVEL OF EVIDENCE: 3. PMID- 26584062 TI - Excited-state annihilation reduces power dependence of single-molecule FRET experiments. AB - Single-molecule Forster resonance energy transfer (FRET) experiments are an important method for probing biomolecular structure and dynamics. The results from such experiments appear to be surprisingly independent of the excitation power used, in contradiction to the simple photophysical mechanism usually invoked for FRET. Here we show that excited-state annihilation processes are an essential cause of this behavior. Singlet-singlet annihilation (SSA) is a mechanism of fluorescence quenching induced by Forster-type energy transfer between two fluorophores while they are both in their first excited singlet states (S1S1), which is usually neglected in the interpretation of FRET experiments. However, this approximation is only justified in the limit of low excitation rates. We demonstrate that SSA is evident in fluorescence correlation measurements for the commonly used FRET pair Alexa 488/Alexa 594, with a rate comparable to the rate of energy transfer between the donor excited state and the acceptor ground state (S1S0) that is exploited in FRET experiments. Transient absorption spectroscopy shows that SSA occurs exclusively via energy transfer from Alexa 488 to Alexa 594. Excitation-power dependent microsecond correlation experiments support the conclusion based on previously reported absorption spectra of triplet states that singlet-triplet annihilation (STA) analogously mediates energy transfer if the acceptor is in the triplet state. The results indicate that both SSA and STA have a pronounced effect on the overall FRET process and reduce the power dependence of the observed FRET efficiencies. The existence of annihilation processes thus seems to be essential for using FRET as a reliable spectroscopic ruler at the high excitation rates commonly employed in single-molecule spectroscopy. PMID- 26584061 TI - Age, Sexual Dimorphism, and Disease Associations in the Developing Human Fetal Lung Transcriptome. AB - The fetal origins of disease hypothesis suggests that variations in the course of prenatal lung development may affect life-long pulmonary function growth, decline, and pathobiology. Many studies support the existence of differences in the developing lung trajectory in males and females, and sex-specific differences in the prevalence of chronic lung diseases, such as asthma and bronchopulmonary dysplasia. The objectives of this study were to investigate the early developing fetal lung for transcriptomic correlates of postconception age (maturity) and sex, and their associations with chronic lung diseases. We analyzed whole-lung transcriptome profiles of 61 females and 78 males at 54-127 days postconception (dpc) from nonsmoking mothers using unsupervised principal component analysis and supervised linear regression models. We identified dominant transcriptomic correlates for postconception age and sex with corresponding gene sets that were enriched for developing lung structural and functional ontologies. We observed that the transcriptomic sex difference was not a uniform global time shift/lag, rather, lungs of males appear to be more mature than those of females before 96 dpc, and females appear to be more mature than males after 96 dpc. The age correlate gene set was consistently enriched for asthma and bronchopulmonary dysplasia genes, but the sex correlate gene sets were not. Despite sex differences in the developing fetal lung transcriptome, postconception age appears to be more dominant than sex in the effect of early fetal lung developments on disease risk during this early pseudoglandular phase of development. PMID- 26584063 TI - Incidence of Orbital Recurrence After Enucleation or Ophthalmic Artery Chemosurgery for Advanced Intraocular Retinoblastoma--Reply. PMID- 26584064 TI - Semi-Markov Arnason-Schwarz models. AB - We consider multi-state capture-recapture-recovery data where observed individuals are recorded in a set of possible discrete states. Traditionally, the Arnason-Schwarz model has been fitted to such data where the state process is modeled as a first-order Markov chain, though second-order models have also been proposed and fitted to data. However, low-order Markov models may not accurately represent the underlying biology. For example, specifying a (time-independent) first-order Markov process involves the assumption that the dwell time in each state (i.e., the duration of a stay in a given state) has a geometric distribution, and hence that the modal dwell time is one. Specifying time dependent or higher-order processes provides additional flexibility, but at the expense of a potentially significant number of additional model parameters. We extend the Arnason-Schwarz model by specifying a semi-Markov model for the state process, where the dwell-time distribution is specified more generally, using, for example, a shifted Poisson or negative binomial distribution. A state expansion technique is applied in order to represent the resulting semi-Markov Arnason-Schwarz model in terms of a simpler and computationally tractable hidden Markov model. Semi-Markov Arnason-Schwarz models come with only a very modest increase in the number of parameters, yet permit a significantly more flexible state process. Model selection can be performed using standard procedures, and in particular via the use of information criteria. The semi-Markov approach allows for important biological inference to be drawn on the underlying state process, for example, on the times spent in the different states. The feasibility of the approach is demonstrated in a simulation study, before being applied to real data corresponding to house finches where the states correspond to the presence or absence of conjunctivitis. PMID- 26584065 TI - Insulin and Leptin Signaling in Placenta from Gestational Diabetic Subjects. AB - Insulin and leptin receptors are known to share signaling pathways, such as JAK2/STAT-3 (Janus kinase2/signal transduction and activator of transcription3), MAPK (Mitogen activated protein kinase), and PI3K (phosphoinositide 3-kinase). Both positive and negative cross-talk have been previously found in different cellular systems. Gestational diabetes (GDM) is a pathophysiological state with high circulating levels of both insulin and leptin. We have previously found that these 3 signaling pathways are activated in placenta from GDM patients to promote translation, involving the activation of leptin receptor. Now, we have tested the hypothesis that both leptin and insulin receptors might contribute to this activation in a positive way that may become negative when the system is overactivated. We studied the activation of leptin and insulin receptors in placenta from GDM and healthy pregnancies. We have also performed in vitro studies with insulin and leptin stimulation of trophoblast explants from healthy placenta. We have found that both leptin and insulin receptors are activated in placenta from GDM. In vitro stimulation of trophoblast explants with both leptin and insulin at submaximal doses (0.1 nM) potentiated the activation of signaling, whereas preincubation with maximal concentrations of insulin (10 nM) and further stimulation with leptin showed negative effect. Trophoblastic explants from GDM placenta, which presented high signaling levels, had a negative signaling effect when further incubated in vitro with leptin. In conclusion, insulin and leptin receptors have positive effects on signaling, contributing to high signaling levels in GDM placenta, but insulin and leptin have negative effects upon overstimulation. PMID- 26584066 TI - Temporal variability of pyrethroid metabolite levels in bedtime, morning, and 24 h urine samples for 50 adults in North Carolina. AB - Pyrethroid insecticides are widely used to control insects in both agricultural and residential settings worldwide. Few data are available on the temporal variability of pyrethroid metabolites in the urine of non-occupationally exposed adults. In this work, we describe the study design and sampling methodology for the Pilot Study to Estimate Human Exposures to Pyrethroids using an Exposure Reconstruction Approach (Ex-R study). Two major objectives were to quantify the concentrations of several pyrethroid metabolites in bedtime, first morning void (FMV), and 24-h urine samples as concentration (wet weight), specific-gravity (SG) corrected, creatinine (CR) corrected, and excretion rate values for 50 Ex-R adults over a six-week monitoring period and to determine if these correction approaches for urine dilution reduced the variability of the biomarker levels. The Ex-R study was conducted at the United States Environmental Protection Agency's Human Studies Facility in Chapel Hill, North Carolina USA and at participants' homes within a 40-mile radius of this facility. Recruitment of participants and field activities occurred between October 2009 and May 2011. Participants, ages 19-50 years old, provided daily food, activity, and pesticide use diaries and collected their own urine samples (bedtime, FMV, and 24-h) during weeks 1, 2, and 6 of a six-week monitoring period. A total of 2503 urine samples were collected from the study participants. These samples were analyzed for the pyrethroid metabolites 3-phenoxybenzoic acid (3-PBA), cis/trans-3-(2,2 dichlorovinyl)-2,2-dimethyl-cyclopropane carboxylic acid (cis/trans-DCCA), and 2 methyl-3-phenylbenzoic acid (MPA) using high performance liquid chromatography/tandem mass spectrometry. Only 3-PBA was frequently detected (>50%) in the adult urine samples. Median urinary 3-PBA levels were 0.88 ng/mL, 0.96 ng/mL-SG, 1.04 ng/mg, and 1.04 ng/min for concentration, SG-corrected, CR corrected, and excretion rate values, respectively, across all urine samples. The results showed that median urinary 3-PBA concentrations were consistently the lowest in FMV samples (0.77 ng/mL, 0.68 ng/mL-SG, 0.68 ng/mg, and 0.58 ng/min) and the highest in 24-h samples (0.92 ng/mL, 1.06 ng/mL-SG, 1.18 ng/mg, and 1.19 ng/min) across all four methods. Intraclass correlation coefficient (ICC) estimates for 3-PBA indicated poor reproducibility (<0.22) for all urine sample types and methods over a day, week, and six weeks. Correcting for urine sample dilution, based on either SG, CR or urine output, introduced additional measurement variability both between- and within-individuals. These results indicate that a single measure of urinary 3-PBA was not sufficient to characterize average exposure regardless of sample type, correction method, and time frame of collection. In addition, the study results can be used to inform the design of exposure characterization strategies in relevant environmental epidemiology studies in the future. PMID- 26584067 TI - Engaging Patients Across the Spectrum of Medical Product Development: View From the US Food and Drug Administration. PMID- 26584068 TI - Adipose Derived Regenerative Cell Therapy for Treating a Diabetic Wound: A Case Report. AB - BACKGROUND: Recent studies have reported on the use of adipose derived regenerative cells (ADRC) as a therapeutic method in wound healing. The present study introduces the first application of successful ADRC therapy for a diabetic foot wound. CASE REPORT: A 63-year-old woman with diabetes mellitus complaining of an opened necrotic wound in the plantar aspect of the right foot was admitted by another surgeon for debridement surgery. Despite multiple efforts, a Chopart's amputation was performed to salvage rest of the foot. In the early postoperative period, a 2 cm x 2 cm circular ulcer at the heel region and a 1 cm x 2 cm unhealed wound at the previous incision site had formed. Due to resistant diabetic ulcers, the patient was introduced to ARDC therapy (informed consent was obtained). The Celusion SystemTM (Cytori Therapeutics, Inc, San Diego, CA) was used for autologous generation of ARDC cells-1 cc of the ARDC was mixed with 40 cc of fat graft. Afterward, the ARDC-enriched fat graft was introduced to the heel and plantar region to restore the deficient glabrous tissue. The remaining 4 cc of ARDC were equally injected in a radial fashion to the wound edges. RESULTS: In the postoperative follow-up, accelerated wound healing was observed and the ulcers were completely healed after 4 weeks of ARDC treatment. CONCLUSION: ARDC therapy has the potential to be a promising new therapeutic modality for treating diabetic wounds. PMID- 26584069 TI - Combined acoustical and visual performance of noise barriers in mitigating the environmental impact of motorways. AB - This study investigated the overall performance of noise barriers in mitigating environmental impact of motorways, taking into consideration their effects on reducing noise and visual intrusions of moving traffic, but also potentially inducing visual impact themselves. A laboratory experiment was carried out, using computer-visualised video scenes and motorway traffic noise recordings to present experimental scenarios covering two traffic levels, two distances of receiver to road, two types of background landscape, and five barrier conditions including motorway only, motorway with tree belt, motorways with 3 m timber barrier, 5m timber barrier, and 5m transparent barrier. Responses from 30 participants of university students were gathered and perceived barrier performance analysed. The results show that noise barriers were always beneficial in mitigating environmental impact of motorways, or made no significant changes in environmental quality when the impact of motorways was low. Overall, barriers only offered similar mitigation effect as compared to tree belt, but showed some potential to be more advantageous when traffic level went high. 5m timber barrier tended to perform better than the 3m one at the distance of 300 m but not at 100 m possibly due to its negative visual effect when getting closer. The transparent barrier did not perform much differently from the timber barriers but tended to be the least effective in most scenarios. Some low positive correlations were found between aesthetic preference for barriers and environmental impact reduction by the barriers. PMID- 26584070 TI - Integration of an innovative biological treatment with physical or chemical disinfection for wastewater reuse. AB - In the present paper, the effectiveness of a Sequencing Batch Biofilter Granular Reactor (SBBGR) and its integration with different disinfection strategies (UV irradiation, peracetic acid) for producing an effluent suitable for agricultural use was evaluated. The plant treated raw domestic sewage, and its performances were evaluated in terms of the removal efficiency of a wide group of physical, chemical and microbiological parameters. The SBBGR resulted really efficient in removing suspended solids, COD and nitrogen with an average effluent concentration of 5, 32 and 10 mg/L, respectively. Lower removal efficiency was observed for phosphorus with an average concentration in the effluent of 3 mg/L. Plant effluent was also characterized by an average electrical conductivity and sodium adsorption ratio of 680 MUS/cm and 2.9, respectively. Therefore, according to these gross parameters, the SBBGR effluent was conformed to the national standards required in Italy for agricultural reuse. Moreover, disinfection performances of the SBBGR was higher than that of conventional municipal wastewater treatment plants and met the quality criteria suggested by WHO (Escherichia coli<1000 CFU/100 mL) for agricultural reuse. In particular, the biological treatment by SBBGR removed 3.8+/-0.4 log units of Giardia lamblia, 2.8+/-0.8 log units of E. coli, 2.5+/-0.7 log units of total coliforms, 2.0+/-0.3 log units of Clostridium perfringens, 2.0+/-0.4 log units of Cryptosporidium parvum and 1.7+/-0.7 log units of Somatic coliphages. The investigated disinfection processes (UV and peracetic acid) resulted very effective for total coliforms, E. coli and somatic coliphages. In particular, a UV radiation and peracetic acid doses of 40 mJ/cm(2) and 1 mg/L respectively reduced E. coli content in the effluent below the limit for agricultural reuse in Italy (10 CFU/100 mL). Conversely, they were both ineffective on C.perfringens spores. PMID- 26584071 TI - Impact of different colours of artificial light at night on melatonin rhythm and gene expression of gonadotropins in European perch. AB - The distribution and intensity of artificial light at night, commonly referred to as light pollution, is consequently rising and progressively also ecological implications come to light. Low intensity light is known to suppress nocturnal melatonin production in several fish species. This study aims to examine the least suppressive light colour for melatonin excreted into the holding water and the influence of different light qualities and quantities in the night on gene expression of gonadotropins in fish. European perch (Perca fluviatilis) were exposed to light of different wavelengths during the night (blue, green, and red). Melatonin concentrations were measured from water samples every 3h during a 24h period. Gene expression of gonadotropins was measured in perch exposed to different light colours and was additionally examined for perch subjected to different intensities of white light (0 lx, 1 lx, 10 lx, 100 lx) during the night. All different light colours caused a significant drop of melatonin concentration; however, blue light was least suppressive. Gene expression of gonadotropins was not influenced by nocturnal light of different light colours, but in female perch gonadotropin expression was significantly reduced by white light already at the lowest level (1 lx). We conclude that artificial light with shorter wavelengths at night is less effective in disturbing biological rhythms of perch than longer wavelengths, coinciding with the light situation in freshwater habitats inhabited by perch. Different light colours in the night showed no significant effect on gonadotropin expression, but white light in the night can disturb reproductive traits already at very low light intensities. These findings indicate that light pollution has not only the potential to disturb the melatonin cycle but also the reproductive rhythm and may therefore have implications on whole species communities. PMID- 26584072 TI - Enhanced transport of CeO2 nanoparticles in porous media by macropores. AB - This is the first study to investigate the effect of macropores on the transport of CeO2 nanoparticles (nCeO2) in quartz sand and soil. The artificial macropore types are the vertical continuous macropore (O-O), and the vertical discontinuous macropore (O-C). The results indicated that the mobility of nCeO2 was significantly enhanced by the macropore in both quartz sand and soil, and the enhancement was greater in the continuous macropore than in the discontinuous macropore. Compared with the homogeneous column, both the O-O and O-C macropores in quartz sand favored an earlier breakthrough and a larger initial effluent recovery rate of nCeO2. However, there was little influence on the plateau concentration and the total effluent recovery rate. In soil, both types of macropores significantly shortened nCeO2 breakthrough time, and favored a higher plateau concentration, and a larger initial and total effluent recovery rate. The O-O macropore which accounted for only 1% of the total pore volume had doubly increased the total mobility of nCeO2 in soil; even the mobility was increased by 30% with the O-C macropore. It was found that the effect of preferential flow on nCeO2 transport was greater in soil than it was in quartz sand. PMID- 26584073 TI - Functional trait composition of aquatic plants can serve to disentangle multiple interacting stressors in lowland streams. AB - Historically, close attention has been paid to negative impacts associated with nutrient loads to streams and rivers, but today hydromorphological alterations are considered increasingly implicated when lowland streams do not achieve good ecological status. Here, we explore if trait-abundance patterns of aquatic plants change along gradients in hydromorphological degradation and eutrophication in lowland stream sites located in Denmark. Specifically, we hypothesised that: i) changes in trait-abundance patterns occur along gradients in hydromorphological degradation and ii) trait-abundance patterns can serve to disentangle effects of eutrophication and hydromorphological degradation in lowland streams reflecting that the mechanisms behind changes differ. We used monitoring data from a total of 147 stream reaches with combined data on aquatic plant species abundance, catchment land use, hydromorphological alterations (i.e. planform, cross section, weed cutting) and water chemistry parameters. Traits related to life form, dispersal, reproduction and survival together with ecological preference values for nutrients and light (Ellenberg N and L) were allocated to 41 species representing 79% of the total species pool. We found clear evidence that habitat degradation (hydromorphological alterations and eutrophication) mediated selective changes in the trait-abundance patterns of the plant community. Specific traits could distinguish hydromorphological degradation (free-floating, surface; anchored floating leaves; anchored heterophylly) from eutrophication (free-floating, submerged; leaf area). We provide a conceptual framework for interpretation of how eutrophication and hydromorphological degradation interact and how this is reflected in trait-abundance patterns in aquatic plant communities in lowland streams. Our findings support the merit of trait-based approaches in biomonitoring as they shed light on mechanisms controlling structural changes under environmental stress. The ability to disentangle several stressors is particularly important in lowland stream environments where several stressors act in concert since the impact of the most important stressor can be targeted first, which is essential to improve the ecological status. PMID- 26584074 TI - Oropharyngeal Tularemia Outbreak Associated with Drinking Contaminated Tap Water, Turkey, July-September 2013. AB - In 2013, an oropharyngeal tularemia outbreak in Turkey affected 55 persons. Drinking tap water during the likely exposure period was significantly associated with illness (attack rate 27% vs. 11% among non-tap water drinkers). Findings showed the tap water source had been contaminated by surface water, and the chlorination device malfunctioned. PMID- 26584075 TI - Genetic Characterization of Highly Pathogenic Avian Influenza A(H5N6) Virus, Guangdong, China. PMID- 26584076 TI - Retrieval analysis of titanium nitride (TiN) coated prosthetic femoral heads articulating with polyethylene. AB - Data regarding in vivo performance of titanium nitride (TiN) coated prosthetic femoral heads is scarce, and available studies of older generations of implants demonstrated coating wear in vivo. That is why we conducted a retrieval analysis of 11 femoral heads (articulating in vivo for 1-56 months) with TiN film formed using physical vapor deposition (PVD), to verify if coating failure is a problem in contemporary implants. Retrieved implants were examined using scanning electron microscope, coating roughness was evaluated with a contact profilometer and adhesion was tested using a Rockwell HRC test according to VDI 3824 guideline. Although no gross failure of the TiN coating was observed in our retrievals, all implants had defects typical for PVD coatings, such as pinholes, small titanium droplets and blisters with delaminated coating. In some heads the coating was contaminated with small niobium (Nb) droplets uniformly scattered on the entire surface of the film. Presence of Nb contamination was associated with an increased number and area of other types of defects and poorer coating adhesion. In one component, subjected to multiple dislocations we found severe delamination and cracking of the coating, increased roughness and the presence of third bodies. Our results indicate, that although wear of the coating is lower than seen in older generations of implants, inconsistent quality of the TiN film among different implants indicates the need for strict monitoring of the manufacturing process. PMID- 26584077 TI - Enzyme-free and sensitive electrochemical determination of the FLT3 gene based on a dual signal amplified strategy: Controlled nanomaterial multilayers and a target-catalyzed hairpin assembly. AB - An isothermal, enzyme-free and sensitive electrochemical DNA sensor was developed for the detection of the FLT3 gene in acute myeloid leukemia (AML). First, aminated multi-walled carbon nanotubes (AMWNTs) and gold nanoparticles (AuNPs) were alternately self-assembled on a gold electrode using a layer-by-layer strategy. Then, the hairpin DNA probe 1 (H1), with a thiol group at the 3' end and a ferrocenyl moiety (Fc) at the 5' end, was immobilized on the AMWNTs/AuNPs multilayer films through Au-S bonding. When the target DNA (TD) appeared, it hybridized with and opened the hairpin structure of H1, and Fc was forced away from the electrode surface, leading to a significant decrease in the current peak of square wave voltammetry. Subsequently, the hairpin DNA probe 2 (H2) bound to H1, freeing the TD to trigger another reaction cycle. The combination of this target-catalyzed hairpin assembly and the LBL assembly of nanomaterials achieved a detection limit of 0.1 pM with a wide linear range of 0.1-1000 pM. The sensor discriminated between mismatched DNA and the target DNA with high selectivity. This dual signal amplification strategy is relatively simple and inexpensive because it does not need any enzymes or sophisticated equipment and successfully assayed the FLT3 gene from real samples. PMID- 26584078 TI - A new nano-worm structure from gold-nanoparticle mediated random curving of zinc oxide nanorods. AB - Creating novel nanostructures is a primary step for high-performance analytical sensing. Herein, a new worm like nanostructure with Zinc Oxide-gold (ZnO/Au) hybrid was fabricated through an aqueous hydrothermal method, by doping Au nanoparticle (AuNP) on the growing ZnO lattice. During ZnO growth, fine tuning the solution temperature expedites random curving of ZnO nanorods and forms nano worms. The nano-worms which were evidenced by morphological, physical and structural analyses, revealed elongated structures protruding from the surface (length: 1 um; diameter: ~100 nm). The appropriate peaks for the face centred cubic gold were (111) and (200), as seen from X-ray diffractogram. The strong interrelation between Au and ZnO was manifested by X-ray photoelectron spectroscopy. The combined surface area increment from the nanoparticle radii and ZnO nanorod random curving gives raise an enhancement in detection sensitivity by increasing bio-loading. 'Au-decorated hybrid nano-worm' was immobilized with a probe DNA from Vibrio Cholera and duplexed with a target which was revealed by Fourier Transform Infrared Spectroscopy. Our novel Au-decorated hybrid nano-worm is suitable for high-performance bio-sensing, as evidenced by impedance spectroscopy, having higher-specificity and attained femtomolar (10 fM) sensitivity. Further, higher stability, reproducibility and regeneration on this sensing surface were demonstrated. PMID- 26584079 TI - Aptamer induced assembly of fluorescent nitrogen-doped carbon dots on gold nanoparticles for sensitive detection of AFB1. AB - Novel fluorescent nitrogen-doped carbon dots (N,C-dots) were synthesized and assembled on aptamer modified gold nanoparticles (Aptamer/AuNPs) for the super sensitive detection of aflatoxin B1 (AFB1). Positively charged N,C-dots were synthesized by the hydrothermal treatment of pancreatin. The prepared N,C-dots were assembled on aptamer/AuNPs by electrostatic interactions. The fluorescence of the N,C-dots was efficiently quenched. When AFB1 was added to the assay solution, specific interactions between AFB1 and the aptamer caused release of the N,C-dots. The fluorescence of the N,C-dots recovered and the intensity increase could be used to calculate the amount of AFB1 added. The assay exhibits super-high sensitivity with a detection limit of 5 pg/mL (16 pM) and a wide range of linear response of 5 pg/mL to 2.00 ng/mL. A novel aptasensor is thus successfully constructed, it provides an efficient way for sensitive AFB1 sensing as well as a new technique for aptamer based novel sensor construction. PMID- 26584082 TI - Predicting Near Edge X-ray Absorption Spectra with the Spin-Free Exact-Two Component Hamiltonian and Orthogonality Constrained Density Functional Theory. AB - Orthogonality constrained density functional theory (OCDFT) provides near-edge X ray absorption (NEXAS) spectra of first-row elements within one electronvolt from experimental values. However, with increasing atomic number, scalar relativistic effects become the dominant source of error in a nonrelativistic OCDFT treatment of core-valence excitations. In this work we report a novel implementation of the spin-free exact-two-component (X2C) one-electron treatment of scalar relativistic effects and its combination with a recently developed OCDFT approach to compute a manifold of core-valence excited states. The inclusion of scalar relativistic effects in OCDFT reduces the mean absolute error of second-row elements core valence excitations from 10.3 to 2.3 eV. For all the excitations considered, the results from X2C calculations are also found to be in excellent agreement with those from low-order spin-free Douglas-Kroll-Hess relativistic Hamiltonians. The X2C-OCDFT NEXAS spectra of three organotitanium complexes (TiCl4, TiCpCl3, TiCp2Cl2) are in very good agreement with unshifted experimental results and show a maximum absolute error of 5-6 eV. In addition, a decomposition of the total transition dipole moment into partial atomic contributions is proposed and applied to analyze the nature of the Ti pre-edge transitions in the three organotitanium complexes. PMID- 26584080 TI - A novel biosensor for Escherichia coli O157:H7 based on fluorescein-releasable biolabels. AB - New techniques are required for the rapid and sensitive detection of Escherichia coli O157:H7 (E. coli O157:H7), a pathogenic bacterium responsible for serious and sometimes life-threatening diseases in humans. In this study, we developed a highly sensitive and efficient biosensor for the quantitative detection of E. coli O157:H7 by integrating fluorescein-releasable biolabels with a magnetism separable probe. Hollow silica nanospheres with a diameter of approximately 350 nm were synthesized, enriched with fluorescein, and surface-protected with macromolecule layers of poly (acrylic acid) and poly (dimethyldiallylammonium chloride). These fluorescein-enriched hollow silica nanospheres were characterized using scanning electron microscopy, transmission electron microscopy, and Fourier transform infrared spectroscopy. They were further functionalized as immune labels of E. coli O157:H7 for a sandwich-type immune reaction between this bacterium and magnetic nanoparticles (Fe3O4@SiO2). Next, the E. coli O157:H7 cells were captured, magnetically separated, and quantified based on the fluorescence intensity of the fluorescein released from the biolabels of the fluorescein-enriched hollow silica nanospheres. This analytic process can be completed within 75 min, and the biosensor showed a linear relationship ranging from 4 to 4.0 * 10(8)cfu/mL with a detection limit of 3 cfu/mL. These results show that the developed fluorescent sensor has excellent specificity, and good reproducibility and stability. This study used real spiked samples for detection, indicating that this technique has a wide range of potential applications and may be readily adapted for detecting other pathogens. PMID- 26584081 TI - Porcine Epidemic Diarrhea Virus among Farmed Pigs, Ukraine. AB - An outbreak of porcine epidemic diarrhea occurred in the summer of 2014 in Ukraine, severely affecting piglets <10 days of age; the mortality rate approached 100%. Full genome sequencing showed the virus to be closely related to strains reported from North America, showing a sequence identity of up to 99.8%. PMID- 26584083 TI - Structural Evolution from 0D Units to 3D Frameworks in Pb Oxyhalides: Unexpected Strongly Corrugated Layers in Pb7O6Br2. AB - Novel Pb7O6Br2 (1) lead oxybromide was prepared from Pb oxybromide melt by the "rapid quenching" route. Bonding scheme, thermal expansion, and structural properties were studied. The structural features of this unexpectedly complex phase are described on the basis of lone electron pair stereochemical activity and Pb-Br versus Pb-O bonding scheme. The structure of 1 contains a number of cavities, which can be assigned to the self-containments of the lone electron pairs on Pb(2+) cations. "Empty" ?Pb4 chains are observed in between of the folding sides of the adjacent strongly corrugated oxocentered [Pb7O6](2+) layers. Highly isotropic thermal expansion of 1 appeared to be unexpected. The possible explanations of such a behavior in 1 are given. The structure of 1 is an interesting example of tetrahedral framework with mixed chemical bonding and is the densest known among Pb oxyhalides with the density of 18.4 tetrahedra/1000 A(3). Current study shows that oxocentered layers derivatives from alpha-PbO can be very flexible and form rather dense three-dimensional structural topologies. The properties and structure are compared to other phases crystallizing in the anhydrous PbO-PbX2 (X = F, Cl, Br, I) systems, illustrate the complexity of lead oxyhalides, and reveal new and general pathways for the targeted synthesis of new phases with the Pb-O units of desired dimensionality. The indirect gap value of ~ 2.04 eV obtained from generalized gradient approximation calculations demonstrates potentially good photocatalytic properties of 1. PMID- 26584084 TI - Synthesis of 4-Arylthieno[2,3-b]pyridines and 4-Aminothieno[2,3-b]pyridines via a Regioselective Bromination of Thieno[2,3-b]pyridine. AB - The first regioselective, mild bromination of thieno[2,3-b]pyridine is described herein. The reaction proceeds with selectivity toward the 4-position (87% isolated yield). Subsequent cross-coupling reactions proceed in excellent yields and demonstrate the potential of 4-bromothieno[2,3-b]pyridine as a building block for use in drug discovery research. PMID- 26584085 TI - Structure-activity relationship study of anticancer thymidine-quinoxaline conjugates under the low radiance of long wavelength ultraviolet light for photodynamic therapy. AB - Thymidine quinoxaline conjugate (dT-QX) is a thymidine analog with selective cytotoxicity against different cancer cells. In this study, the structure activity relationship study of dT-QX analogs was carried out under the low radiance of black fluorescent (UVA-1) light. Significantly enhanced cytotoxicity was observed under UVA-1 activation among analogs containing both thymidine and quinoxaline moieties with different length of the linker, stereochemical configuration and halogenated substituents. Among these analogs, the thymidine dichloroquinoxaline conjugate exhibited potent activity under UVA-1 activation as the best candidate with EC50 at 0.67 MUM and 1.3 MUM against liver and pancreatic cancer cells, respectively. In contrast, the replacement of thymidine moiety with a galactosyl residue or the replacement of quinoxaline moiety with a fluorescent pyrenyl residue or a simplified diketone structure resulted in the full loss of activity. Furthermore, it was revealed that the low radiance of UVA-1 at 3 mW/cm(2) for 20 min was sufficient enough to induce the full cytotoxicity of thymidine dichloroquinoxaline conjugate and that the cytotoxic mechanism was achieved through a rapid and steady production of reactive oxygen species. PMID- 26584086 TI - Are Bond Critical Points Really Critical for Hydrogen Bonding? AB - Atoms in Molecules (AIM) theory is routinely used to assess hydrogen bond formation; however its stringent criteria controversially exclude some systems that otherwise appear to exhibit weak hydrogen bonds. We show that a regional analysis of the reduced density gradient, as provided by the recently introduced Non-Covalent Interactions (NCI) index, transcends AIM theory to deliver a chemically intuitive description of hydrogen bonding for a series of 1,n alkanediols. This regional definition of interactions overcomes the known caveat of only analyzing electron density critical points. In other words, the NCI approach is a simple and elegant generalization of the bond critical point approach, which raises the title question. Namely, is it the presence of an electron density bond critical point that defines a hydrogen bond or the general topology in the region surrounding it? PMID- 26584087 TI - Improved Angle Potentials for Coarse-Grained Molecular Dynamics Simulations. AB - Potentials routinely used in atomistic molecular dynamics simulations are not always suitable for modeling systems at coarse-grained resolution. For example, in the calculation of traditional torsion angle potentials, numerical instability is often encountered in the case of very flexible molecules. To improve the stability and accuracy of coarse-grained molecular dynamics simulations, we propose two approaches. The first makes use of improved forms for the angle potentials: the restricted bending (ReB) potential prevents torsion angles from visiting unstable or unphysical configurations and the combined bending-torsion (CBT) potential smoothly flattens the interactions when such configurations are sampled. In the second approach, dummy-assisted dihedral (DAD), the torsion potential is applied differently: instead of acting directly on the beads, it acts on virtual beads, bound to the real ones. For simple geometrical reasons, the unstable region is excluded from the accessible conformational space. The benefits of the new approaches are demonstrated in simulations of polyethylene glycol (PEG), polystyrene (PS), and polypeptide molecules described by the MARTINI coarse-grained force field. The new potentials are implemented in an in house version of the Gromacs package, publicly available. PMID- 26584088 TI - Molecular Dynamics in Strong Laser Fields: A New Algorithm for ab Initio Classical Trajectories. AB - A new, more accurate Hessian-based predictor-corrector algorithm has been developed for simulating classical trajectories of molecules in intense laser fields. The first and second derivatives of the gradient with respect to the electric field are included in the both the predictor and the corrector steps for integrating trajectories. A Taylor expansion of the gradient is used as the surface for integrating the predictor step; a distance weighted interpolant of the gradient is employed for the corrector step. Test trajectories were calculated for HCO(+) in a continuous 10 MUm, 2.9 * 10(14) W cm(-2) laser field and triplet allene dication in a 10 MUm, 5.7 * 10(13) W cm(-2) four cycle cosine pulse. The first derivative of the gradient with respect to the electric field makes a significant contribution, while the second derivative makes a smaller contribution and can be neglected. To reduce the cost, the Hessian can be updated for several steps before being recalculated. The calculations indicate that a step size of Deltat = 0.25 fs and 20 updates is efficient and reliable for these test systems. PMID- 26584089 TI - New Computational Approach to Determine Liquid-Solid Phase Equilibria of Water Confined to Slit Nanopores. AB - We devise a new computational approach to compute solid-liquid phase equilibria of confined fluids. Specifically, we extend the multibaric-multithermal ensemble method with an anisotropic pressure control to achieve the solid-liquid phase equilibrium for confined water inside slit nanopores (with slit width h ranging from 5.4 A to 7.2 A). A unique feature of this multibaric-multithermal ensemble is that the freezing points of confined water can be determined from the heat capacity peaks. The new approach has been applied to compute the freezing point of two monolayer ices, namely, a high-density flat rhombic monolayer ice (HD fRMI) and a high-density puckered rhombic monolayer ice (HD-pRMI) observed in our simulation. We find that the liquid-to-solid transition temperature (or the freezing point) of HD-pRMI is dependent on the slit width h, whereas that of HD fRMI is nearly independent of the h. PMID- 26584090 TI - Parameterization of Halogens for the Density-Functional Tight-Binding Description of Halide Hydration. AB - Parameter sets of the self-consistent-charge density-functional tight-binding model with and without its third-order extension have been developed to describe the interatomic interactions of halogen elements (X = Cl, Br, I) with hydrogen and oxygen, with the ultimate goal of investigating halide hydration with this approach. The reliability and accuracy of the model with these newly developed parameters has been evaluated by comparing the structural, energetic, and vibrational properties of small molecules containing halogen atoms with those obtained by means of standard density-functional theory. Furthermore, the newly parametrized model is found to predict equilibrium geometries, binding energies, and vibrational frequencies for small aqueous clusters containing halogen anions, X(-)(H2O)n (n = 1-4), in good agreement with those calculated with density functional theory and high-level ab initio quantum chemistry and with available experimental data. This demonstrates that the newly parametrized models might be a method of choice for investigating halide hydration in larger clusters. PMID- 26584091 TI - Density-Functional Theory with Dispersion-Correcting Potentials for Methane: Bridging the Efficiency and Accuracy Gap between High-Level Wave Function and Classical Molecular Mechanics Methods. AB - Large clusters of noncovalently bonded molecules can only be efficiently modeled by classical mechanics simulations. One prominent challenge associated with this approach is obtaining force-field parameters that accurately describe noncovalent interactions. High-level correlated wave function methods, such as CCSD(T), are capable of correctly predicting noncovalent interactions, and are widely used to produce reference data. However, high-level correlated methods are generally too computationally costly to generate the critical reference data required for good force-field parameter development. In this work we present an approach to generate Lennard-Jones force-field parameters to accurately account for noncovalent interactions. We propose the use of a computational step that is intermediate to CCSD(T) and classical molecular mechanics, that can bridge the accuracy and computational efficiency gap between them, and demonstrate the efficacy of our approach with methane clusters. On the basis of CCSD(T)-level binding energy data for a small set of methane clusters, we develop methane specific, atom-centered, dispersion-correcting potentials (DCPs) for use with the PBE0 density-functional and 6-31+G(d,p) basis sets. We then use the PBE0-DCP approach to compute a detailed map of the interaction forces associated with the removal of a single methane molecule from a cluster of eight methane molecules and use this map to optimize the Lennard-Jones parameters for methane. The quality of the binding energies obtained by the Lennard-Jones parameters we obtained is assessed on a set of methane clusters containing from 2 to 40 molecules. Our Lennard-Jones parameters, used in combination with the intramolecular parameters of the CHARMM force field, are found to closely reproduce the results of our dispersion-corrected density-functional calculations. The approach outlined can be used to develop Lennard-Jones parameters for any kind of molecular system. PMID- 26584092 TI - Orbital Analysis and Excited-State Calculations in an Energy-Based Fragmentation Method. AB - Covalently bound molecular arrays composed of porphyrins or related pigments have gained a lot of interest as components of artificial light-harvesting systems and molecular photonic devices. The large size of these arrays, however, makes their theoretical investigation employing the ab initio or density functional methodologies difficult. Energy-based fragmentation methods (EBF) represent a set of conceptually simple approaches to theoretical investigation of large systems and were therefore chosen as a tool to study these systems. Here a new approach to EBF, EBF-MO, is introduced that enables one to obtain orbitals and orbital energies and to perform population analysis and excited-state calculations of large systems composed of hundreds of atoms. This approach was implemented into a parallel program, JETT, and the benchmark calculations have shown its accuracy and applicability to the ground- and excited-state calculations of systems containing transition metals and extended pi-conjugation. EBF-MO was then applied to the density functional theory (DFT) and the time-dependent density functional theory (TDDFT) calculations of ground- and excited-state properties of a porphyrin-based molecular photonic wire composed of 472 atoms and 4265 basis functions at the B3LYP/LANL08,6-31G* level. The TDDFT calculations have revealed the character of the excited states, and the unidirectionality of the excitation energy transfer across the array relevant to its signal transfer function. The computational approaches introduced here have widened the applicability of the ab initio and density functional methodologies to calculations of extended systems such as natural and artificial light-harvesting systems and molecular photonic devices. PMID- 26584093 TI - SplitGAS Method for Strong Correlation and the Challenging Case of Cr2. AB - A new multiconfigurational quantum chemical method, SplitGAS, is presented. The configuration interaction expansion, generated from a generalized active space, GAS, wave function is split in two parts, a principal part containing the most relevant configurations and an extended part containing less relevant, but not negligible, configurations. The partition is based on an orbital criterion. The SplitGAS method has been employed to study the HF, N2, and Cr2 molecules. The results on these systems, especially on the challenging, multiconfigurational Cr2 molecule, are satisfactory. While SplitGAS is comparable with the GASSCF method in terms of memory requirements, it performs better than the complete active space method followed by second-order perturbation theory, CASPT2, in terms of equilibrium bond length, dissociation energy, and vibrational properties. PMID- 26584094 TI - Fast and Flexible Coupled Cluster Implementation. AB - A new coupled cluster singles and doubles with triples correction, CCSD(T), algorithm is presented. The new algorithm is implemented in object oriented C++, has a low memory footprint, fast execution time, low I/O overhead, and a flexible storage backend with the ability to use either distributed memory or a file system for storage. The algorithm is demonstrated to work well on single workstations, a small cluster, and a high-end Cray computer. With the new implementation, a CCSD(T) calculation with several hundred basis functions and a few dozen occupied orbitals can run in under a day on a single workstation. The algorithm has also been implemented for graphical processing unit (GPU) architecture, giving a modest improvement. Benchmarks are provided for both CPU and GPU hardware. PMID- 26584095 TI - Acceleration of Semiempirical Quantum Mechanical Calculations by Extended Lagrangian Molecular Dynamics Approach. AB - The implementation and performance of the atom-centered density matrix propagation (ADMP) [J. Chem. Phys. 2001, 114, 9758] and the curvy-steps (CURV) methods [J. Chem. Phys. 2004, 121, 1152] are described. These methods solve the electronic Schrodinger equation approximately by propagating the electronic degrees of freedom using the extended Lagrangian molecular dynamics (ELMD) simulation approach. The ADMP and CURV methods are implemented and parallelized to accelerate semiempirical quantum mechanical (QM) methods (such as the MNDO, AM1, PM3, MNDO/d, and AM1/d methods). Test calculations show that both the ADMP and the CURV methods are 2~4 times faster than the Born-Oppenheimer molecular dynamics (BOMD) method and conserve the total energy well. The accuracy of the ADMP and CURV simulations is comparable to the BOMD simulations. The parallel implementation accelerates the MD simulation by up to 28 fold for the ADMP method and 25 fold for the CURV method, respectively, relative to the speed of the single core BOMD. In addition, a multiple time scale (MTS) approach is introduced to further speed up the semiempirical QM and QM/MM ELMD simulations. Since a larger integration time step is used for the propagation of the nuclear coordinates than that for the electronic degrees of freedom, the MTS approach allows the ELMD simulation to be carried out with a time step that is larger than the time step accessible by the original ADMP and CURV methods. It renders MD simulation to be carried out about 20 times faster than the BOMD simulation, and yields results that are comparable to the single time scale simulation results. The use of the methods introduced in the present work provides an efficient way to extend the length of the QM and QM/MM molecular dynamics simulations beyond the length accessible by BOMD simulation. PMID- 26584096 TI - Assessment and Validation of Machine Learning Methods for Predicting Molecular Atomization Energies. AB - The accurate and reliable prediction of properties of molecules typically requires computationally intensive quantum-chemical calculations. Recently, machine learning techniques applied to ab initio calculations have been proposed as an efficient approach for describing the energies of molecules in their given ground-state structure throughout chemical compound space (Rupp et al. Phys. Rev. Lett. 2012, 108, 058301). In this paper we outline a number of established machine learning techniques and investigate the influence of the molecular representation on the methods performance. The best methods achieve prediction errors of 3 kcal/mol for the atomization energies of a wide variety of molecules. Rationales for this performance improvement are given together with pitfalls and challenges when applying machine learning approaches to the prediction of quantum mechanical observables. PMID- 26584097 TI - Convergence of the Interaction Energies in Noncovalent Complexes in the Coupled Cluster Methods Up to Full Configuration Interaction. AB - The CCSD(T) method stands out among various coupled-cluster (CC) approximations as the "golden standard" in computational chemistry and is widely and successfully used in the realm of covalent and noncovalent interactions. The CCSD(T) method provides reliable interaction energies, but their surprising accuracy is believed to arise partially from an error compensation. The convergence of the CC expansion has been investigated up to fully iterative pentuple excitations (CCSDTQP); for the smallest eight electron complexes, the full CI calculations have also been performed. We conclude that the convergence of interaction energy at noncovalent accuracy (0.01 kcal/mol) for the complexes studied is reached already at CCSDTQ or CCSDT(Q) levels. When even higher accuracy (spectroscopic accuracy of 1 cm(-1), or 3 cal/mol) is required, then the noniterative CCSDTQ(P) method could be used. PMID- 26584098 TI - Additive Decomposition of the Physical Components of the Magnetic Coupling from Broken Symmetry Density Functional Theory Calculations. AB - The procedure to extract and identify from broken-symmetry density functional theory (BS-DFT) calculations the various components of the magnetic couplings in diradicals [J. Chem. Phys. 2012, 137, 114106] is re-examined. It is shown that this previous decomposition scheme fails for systems exhibiting large core polarization effects and hence becomes not additive in such cases. At variance, the new scheme which differs from the previous one in the assessment of the polarization effects is perfectly additive. As done previously, the direct exchange is calculated from the MS = 1 and MS = 0 restricted solutions. We show that allowing first the delocalization of the magnetic orbitals in the field of the closed shell frozen core furnishes a good evaluation of the kinetic exchange contribution to the magnetic exchange coupling, i.e. the intersite delocalization of the magnetic electrons in the low-spin state. In a second step, allowing the polarization of the core to take place in the field of the so-revised magnetic orbitals practically leads to the same total value of the magnetic coupling obtained by the brute-force BS-DFT calculation. The success of this decomposition is illustrated on a representative series of inorganic and organic diradicals. The obtained quasi-additivity of the effects is rationalized thanks to a careful theoretical analysis of the broken-symmetry solutions. PMID- 26584099 TI - Nonlocal van der Waals Approach Merged with Double-Hybrid Density Functionals: Toward the Accurate Treatment of Noncovalent Interactions. AB - Noncovalent interactions drive the self-assembly of weakly interacting molecular systems to form supramolecular aggregates, which play a major role in nanotechnology and biochemistry. In this work, we present a thorough assessment of the performance of different double-hybrid density functionals (PBE0-DH-NL, revPBE0-DH-NL, B2PLYP-NL, and TPSS0-DH-NL), as well as their parent hybrid and (meta)GGA functionals, in combination with the most modern version of the nonlocal (NL) van der Waals correction. It is shown that this nonlocal correction can be successfully coupled with double-hybrid density functionals thanks to the short-range attenuation parameter b, which has been optimized against reference interaction energies of benchmarking molecular complexes (S22 and S66 databases). Among all the double-hybrid functionals evaluated, revPBE0-DH-NL and B2PLYP-NL behave remarkably accurate with mean unsigned errors (MUE) as small as 0.20 kcal/mol for the training sets and in the 0.25-0.42 kcal/mol range for an independent database (NCCE31). They can be thus seen as appropriate functionals to use in a broad number of applications where noncovalent interactions play an important role. Overall, the nonlocal van der Waals approach combined with last generation density functionals is confirmed as an accurate and affordable computational tool for the modeling of weakly bonded molecular systems. PMID- 26584100 TI - Is There Still Room for Parameter Free Double Hybrids? Performances of PBE0-DH and B2PLYP over Extended Benchmark Sets. AB - The performances of two double hybrids, namely B2PLYP and PBE0-DH, are tested over the large GMNTK30 benchmark and compared with the results obtained with the related global hybrids, B3LYP and PBE0 with the aim of defining if there is still room for the development on nonparametrized functionals at DH level. Beyond the intrinsic interest in figures, these functionals' pairs are chosen as representative of the parametrized (B2PLYP/B3LYP) and parameter-free (PBE0 DH/PBE0) approaches to density functional theory. The obtained results show that the behavior of the double hybrids in general parallel the performances of the corresponding global hybrids, thus showing that either using a parametrized or using a nonparameterized approach to design new double hybrids, the performances are generally ameliorated with respect to the corresponding global hybrids. Nevertheless, the accuracy of B2PLYP is still higher than that of PBE0-DH, especially for thermochemistry. Albeit a link between performances and functional physics is difficult to extricate, it could be argued that this last result is not surprising since both B3LYP and B2PLYP are tuned on this last property. PMID- 26584101 TI - Barrier Heights in Quantum Monte Carlo with Linear-Scaling Generalized-Valence Bond Wave Functions. AB - We investigate here the performance of our recently developed linear-scaling Jastrow-generalized-valence-bond (J-LGVB) wave functions based on localized orbitals, for the quantum Monte Carlo (QMC) calculation of the barrier heights and reaction energies of five prototypical chemical reactions. Using the geometrical parameters from the Minnesota database collection, we consider three hydrogen-exchanges, one heavy-atom exchange, and one association reaction and compare our results with the best available experimental and theoretical data. For the three hydrogen-exchange reactions, we find that the J-LGVB wave functions yield excellent QMC results, with average deviations from the reference values below 0.5 kcal/mol. For the heavy-atom exchange and association reactions, additional resonance structures are important, and we therefore extend our original formulation to include multiple coupling schemes characterized by different sets of localized orbitals. We denote these wave functions as J-MC LGVB, where MC indicates the multiconfiguration generalization, and show that such a form leads to very accurate barrier heights and reaction energies also for the last two reactions. We can therefore conclude that the J-LGVB theory for constructing QMC wave functions, with its multiconfiguration generalization, is valid for the study of large portions of ground-state potential energy surfaces including, in particular, the region of transition states. PMID- 26584102 TI - Resonant and Nonresonant Hyperpolarizabilities of Spatially Confined Molecules: A Case Study of Cyanoacetylene. PMID- 26584103 TI - Pair-Wise and Many-Body Dispersive Interactions Coupled to an Optimally Tuned Range-Separated Hybrid Functional. AB - We propose a nonempirical, pair-wise or many-body dispersion-corrected, optimally tuned range-separated hybrid functional. This functional retains the advantages of the optimal-tuning approach in the prediction of the electronic structure. At the same time, it gains accuracy in the prediction of binding energies for dispersively bound systems, as demonstrated on the S22 and S66 benchmark sets of weakly bound dimers. PMID- 26584104 TI - Broad Transferability of Substituent Effects in pi-Stacking Interactions Provides New Insights into Their Origin. AB - Substituent effects in model stacked homodimers and heterodimers of benzene, borazine, and 1,3,5-triazine have been examined computationally. We show that substituent effects in these dimers are strongly dependent on the identity of the unsubstituted ring, yet are independent of the ring bearing the substituent. This supports the local, direct interaction model [J. Am. Chem. Soc. 2011, 133, 10262], which maintains that substituent effects in pi-stacking interactions are dominated by through-space interactions of the substituents with the proximal vertex of the unsubstituted ring. In addition to dimers in which the unsubstituted ring is held constant, substituent effects are correlated in many other stacked dimers, including those in which neither the substituted nor unsubstituted rings are conserved. Whether substituent effects in a pair of dimers will be correlated is shown to hinge on the electrostatic components of the interaction energies, and the correlations are explained in terms of the interaction of the local dipole moments associated with the substituents and the electric fields of the unsubstituted rings. Overall, substituent effects are similar in two stacked dimers as long as the electric fields above the unsubstituted rings are similar, providing a more sound physical justification for the local, direct interaction model. PMID- 26584105 TI - Insight into Group 4 Metallocenium-Mediated Olefin Polymerization Reaction Coordinates Using a Metadynamics Approach. AB - We report here the first application of the computationally efficient metadynamics approach for analyzing single-site olefin polymerization mechanisms. The mechanism of group 4 metallocenium catalysis for ethylene homopolymerization is investigated by modeling the ethylene insertion step at the cationic (eta(5) C5H5)Zr(CH3)2(+) center using molecular dynamics simulations within the Density Functional Theory (DFT) framework. In particular, the metadynamics formalism is adopted to enable theoretical characterization of covalent bond forming/breaking processes using molecular dynamics ab initio tools. Analysis of the ethylene insertion step free energy surface indicates a slightly exoergic process (-3.2 kcal/mol) with a barrier of 8.6 kcal/mol, in good agreement with conventional ab initio static calculations. Analysis of the structural and dynamic aspects of the simulated reaction coordinate reveals a preferred olefin configuration which aligns parallel to the Zr-CH3 vector in concert with insertion and a slightly bent conformation of the product n-propyl chain to avoid nonbonded repulsion between methylene groups. It is found that the unsaturated/electrophilic CpZr(CH3)2(+) center drives the insertion step, thus promoting the formation of the Zr-alkyl bond. The metadynamics analysis uniquely encompasses all energetically possible reaction coordinates, thus providing a more detailed mechanistic picture. These results demonstrate the potential of metadynamics in the conformational and geometrical analysis of transition metal-centered homogeneous catalytic processes. PMID- 26584106 TI - A Quadratically-Converging Nudged Elastic Band Optimizer. AB - Nudged elastic band (NEB) is a well established chain-of-states method to locate the minimum energy path in configuration space. Unfortunately, existing search algorithms suffer from slow convergence. We provide an analytic derivative of the nudged elastic band force, enabling a full Newton-Raphson optimization. For molecular systems, the components of the step belonging to translations and rotations are removed with an efficient algorithm. Minimization of the NEB force is ensured by reversing components for which the Newton-Raphson step would increase the force. We achieve quadratic convergence of this optimizer when applied to simple test cases where analytic Hessians are available: one analytic two-dimensional potential and a system of Lennard-Jones particles. PMID- 26584107 TI - Evaluation of the Role of Water in the H2 Bond Formation by Ni(II)-Based Electrocatalysts. AB - We investigate the role of water in the H-H bond formation by a family of nickel molecular catalysts that exhibit high rates for H2 production in acetonitrile solvent. A key feature leading to the high reactivity is the Lewis acidity of the Ni(II) center and pendant amines in the diphosphine ligand that function as Lewis bases, facilitating H-H bond formation or cleavage. Significant increases in the rate of H2 production have been reported in the presence of added water. Our calculations show that molecular water can displace an acetonitrile solvent molecule in the first solvation shell of the metal. One or two water molecules can also participate in shuttling a proton that can combine with a metal hydride to form the H-H bond. However the participation of the water molecules does not lower the barrier to H-H bond formation. Thus these calculations suggest that the rate increase due to water in these electrocatalysts is not associated with the elementary step of H-H bond formation or cleavage but rather with the proton delivery steps. We attribute the higher barrier in the H-H bond formation in the presence of water to a decrease in direct interaction between the protic and hydridic hydrogen atoms forced by the water molecules. PMID- 26584108 TI - Electrostatic-Consistent Coarse-Grained Potentials for Molecular Simulations of Proteins. AB - We present a new generation of coarse-grained (CG) potentials that account for a simplified electrostatic description of soluble proteins. The treatment of permanent electrostatic dipoles of the backbone and polar side-chains allows to simulate proteins, preserving an excellent structural and dynamic agreement with respective reference structures and all-atom molecular dynamics simulations. Moreover, multiprotein complexes can be well described maintaining their molecular interfaces thanks to the ability of this scheme to better describe the actual electrostatics at a CG level of resolution. An efficient and robust heuristic algorithm based on particle swarm optimization is used for the derivation of CG parameters via a force-matching procedure. The ability of this protocol to deal with high dimensional search spaces suggests that the extension of this optimization procedure to larger data sets may lead to the generation of a fully transferable CG force field. At the present stage, these electrostatic consistent CG potentials are easily and efficiently parametrized, show a good degree of transferability, and can be used to simulate soluble proteins or, more interestingly, large macromolecular assemblies for which long all-atom simulations may not be easily affordable. PMID- 26584109 TI - Lennard-Jones Lattice Summation in Bilayer Simulations Has Critical Effects on Surface Tension and Lipid Properties. AB - The accuracy of electrostatic interactions in molecular dynamics advanced tremendously with the introduction of particle-mesh Ewald (PME) summation almost 20 years ago. Lattice summation electrostatics is now the de facto standard for most types of biomolecular simulations, and in particular, for lipid bilayers, it has been a critical improvement due to the large charges typically present in zwitterionic lipid headgroups. In contrast, Lennard-Jones interactions have continued to be handled with increasingly longer cutoffs, partly because few alternatives have been available despite significant difficulties in tuning cutoffs and parameters to reproduce lipid properties. Here, we present a new Lennard-Jones PME implementation applied to lipid bilayers. We confirm that long range contributions are well approximated by dispersion corrections in simple systems such as pentadecane (which makes parameters transferable), but for inhomogeneous and anisotropic systems such as lipid bilayers there are large effects on surface tension, resulting in up to 5.5% deviations in area per lipid and order parameters-far larger than many differences for which reparameterization has been attempted. We further propose an approximation for combination rules in reciprocal space that significantly reduces the computational cost of Lennard-Jones PME and makes accurate treatment of all nonbonded interactions competitive with simulations employing long cutoffs. These results could potentially have broad impact on important applications such as membrane proteins and free energy calculations. PMID- 26584110 TI - Multisite Ion Models That Improve Coordination and Free Energy Calculations in Molecular Dynamics Simulations. AB - Current ion models in molecular mechanics are simple spheres, and their interactions are solely determined from the van der Waals radius of the sphere and the total charge. Here, we introduce a model where we distribute the total charge of the ion into n-dummy centers that are placed in the direction of the coordinating atoms. We have parametrized this model for two divalent cations, Ca(2+) and Mg(2+), and have tested the model's accuracy in a variety of simulations. With this model we are not only able to correctly predict the free energies and selectivity for cation binding sites in proteins and nucleic acids, but we achieve better coordination geometries and can capture more subtle effects such as the exchange of inner shell waters. Additionally, this model does not employ higher-order electrostatics and thus can be easily used with standard force fields. PMID- 26584111 TI - Excited-State Tautomerization of 7-Azaindole in Nonpolar Solution: A Theoretical Study Based on Liquid-Phase Potential Surfaces of Mean Force. AB - Excited state tautomerization of a 7-azaindole (7AI) complex with one methanol molecule in heptane was studied using variational transition state theory including multidimensional tunneling (VTST/MT) with the dielectric continuum model for the solvent effect. Electronic structures and energies for reactants and transition state (TS) in solution were computed at the complete active space self-consistent field (CASSCF) level with second-order multireference perturbation theory (MRPT2) to take into consideration of dynamic electron correlation. The polarizable continuum model using the integral equation formalism (IEFPCM) and the SMD model were used for the excited-state solvent effect. Excited-state surfaces of potential of the mean force in solution were generated for the first time at the MRPT2//SMD/CASSCF(10,9)/6-31G(d,p) level. The position of TS on the reaction coordinate substantially depended on the dynamic electron correlation. The two protons in the excited-state tautomerization were transferred in a concerted but asynchronous process. Calculated HH/DD kinetic isotope effect (KIE) and the ratio of Arrhenius pre-exponential factors, A(HH)/A(DD), agreed very well with the corresponding experimental values. The shape of the adiabatic energy surfaces in the excited-state strongly depended on the position of isotopes due to the asynchronicity of the reaction path, and the tunneling effect was essential for reproducing experimental KIEs. The pyrrolic proton moved a twice longer distance by tunneling than the hydroxyl proton in the most probable tunneling path at 292 K. This study strongly suggests that the mechanism of the excited-state double proton transfer in heptane is triggered by proton transfer from the pyrrolic nitrogen of 7AI to alcohol (protolytic pathway), rather than by proton transfer from alcohol to the pyridine nitrogen of 7AI (solvolytic pathway). PMID- 26584112 TI - Assessment of n-Electron Valence State Perturbation Theory for Vertical Excitation Energies. AB - The multireference n-electron Valence State Perturbation Theory is applied to a benchmark set of 28 organic molecules compiled by Schreiber et al. J. Chem. Phys. (2008) 128, 13. Different types of low-lying vertical excitation energies are computed using the same geometries and TZVP basis set as in the original work. The previously published coupled cluster CC3 results are used as a reference. The complete active space second order perturbation theory (CASPT2) results, as well as the results of second order N-electron valence perturbation theory (NEVPT2) (both in their single-state variants) are evaluated against this reference set, which includes 153 singlet and 72 triplet vertical transition energies. NEVPT2 calculations are carried out in two variants: the partially contracted (PC) and the strongly contracted (SC) scheme. The statistical evaluation with respect to CC3 is found to be similar for both: the mean unsigned deviations is 0.28 eV for singlets and 0.16 eV for triplets for PC-NEVPT2, while it is 0.23 and 0.17 eV for SC-NEVPT2, respectively. Further analysis has shown that deficiencies in the zeroth-order wave functions, in particular for the subset of pi -> pi* singlet excitations, are responsible for the largest deviations from CC3. Those states have either a charge transfer or an ionic character. For the remaining singlet and all triplet excitations the general trend was established that NEVPT2 tends to slightly overestimate excitation energies while CASPT2 slightly underestimates them. However, overall, both methods are of very similar accuracy provided that the IPEA shift is used in the CASPT2 method. Interestingly, the conclusions reached in this study are independent of the orbital canonicalization scheme used in the NEVPT2 calculation. PMID- 26584113 TI - Computational Prediction of Structures and Optical Excitations for Nanoscale Ultrasmall ZnS and CdSe Clusters. AB - Small semiconductor nanoclusters are important for understanding the initial formation and growth of quantum dots and also for application, for example in the tunability provided by size. However, electronic structures and effects of capping ligands have not been systematically characterized. Thus, ground and excited state calculations using coupled-cluster methods were carried out to provide benchmarks for evaluating the applicability of density functional theory (DFT) and time-dependent DFT (TDDFT) with different functionals for the ground and excited states, respectively. Our computed data suggests that the popular B3LYP functional does not deliver optimal results for the ground and excited state. While the PBE0 functional was found to provide a good description for both the ground and excited states for small bare (ZnS)n and bare and ligated (CdSe)n clusters, the results for the hydrated (ZnS)n clusters were found to deteriorate significantly. However, the errors appear to decrease with increasing cluster size. Excitation energies obtained with the long-range hybrid CAM-B3LYP and CA B3LYP were found to provide more consistent results for both anhydrous and hydrated (ZnS)n clusters. However, their performance in spectral predictions for larger clusters requires further study. Using PBE0, electronic structures of the ground and excited states for (ZnS)n and (CdSe)n up to n = 37 using DFT and TDDFT, respectively, were re-examined. With the exception of the cage-core (ZnS)13, (CdSe)13, and (CdSe)14, small (ZnS)n and (CdSe)n are predicted to be spheroids and tubular structures (6, 8-12, 15-19) with squares and hexagons, similar to the structures of carbon single-wall nanotubes. Wurtzite (n = 23-27, 36, 37) and cage-core (n = 29-35) structures are energetically more favorable for larger clusters. We find that water and amines increase the intensities and blue shift the excitations of bare clusters. One photon absorption spectra predicted by TDDFT with the PCM solvation model for (CdSe-methylamine)13 and the larger ligated (CdSe)33 are consistent with the experimental spectra. PMID- 26584114 TI - Duschinsky, Herzberg-Teller, and Multiple Electronic Resonance Interferential Effects in Resonance Raman Spectra and Excitation Profiles. The Case of Pyrene. AB - We show that a recently developed time-independent approach for the calculation of vibrational resonance Raman (vRR) spectra is able to describe Duschinsky and Herzberg-Teller (HT) effects acting on a single resonant state, together with interferential contributions arising from multiple electronic resonances, allowing us to investigate in detail how their interplay determines both the vRR spectra at selected wavelengths and the Raman excitation profiles. We apply this methodology to the study of the spectra of pyrene in acetonitrile, an ideal system since it exhibits three close-lying electronic transitions that are bright but also subjected to HT effects. To single out the different contributions to vRR line shapes we adopted two different adiabatic models for resonant-state potential energy surfaces, namely, Adiabatic Shift (only accounting from equilibrium geometry displacements) and Adiabatic Hessian (AH, including also the Duschinsky effects), and Franck-Condon (FC) or HT approximations for the transition dipole. We show that, on balance, FC+HT calculations within the AH model provide the best agreement with experiment. Moreover, our methodology permits to individuate bands in the experimental spectra due to the simultaneous contribution of more than one resonant state and to point out and analyze interferential effects between the FC and HT terms in each resonance Raman process, together with FC-HT and HT-HT interferences between different electronic states. PMID- 26584115 TI - Diabatic Molecular Orbitals, Potential Energies, and Potential Energy Surface Couplings by the 4-fold Way for Photodissociation of Phenol. AB - Complete-active-space self-consistent-field (CASSCF) calculations provide useful reference wave functions for configuration interaction or perturbation theory calculations of excited-state potential energy surfaces including dynamical electron correlation. However, the canonical molecular orbitals (MOs) of CASSCF calculations usually have mixed character in regions of strong interaction of two or more electronic states; therefore, they are unsuitable for diabatization using the configurational uniformity approach. Here, CASSCF diabatic MOs for phenol have been obtained by the 4-fold way, and comparison to the CASSCF canonical MOs shows that they are much smoother. Using these smooth CASSCF diabatic MOs, we performed direct diabatization calculations for the three low-lying states ((1)pipi, (1)pipi*, and (1)pisigma*) and their diabatic (scalar) couplings at the dynamically correlated multiconfiguration quasidegenerate perturbation theory (MC QDPT) level. We present calculations along the O-H stretching and C-C-O-H torsion coordinates for the nonadiabatic photodissociation of phenol to the phenoxyl radical and hydrogen atom. The seams of (1)pipi*/(1)pisigma* and (1)pipi/(1)pisigma* diabatic crossings are plotted as functions of these coordinates. We also present diabatization calculations for displacements along the out-of-plane ring distortion modes 16a and 16b of the phenyl group. The dominant coupling modes of the two conical intersections ((1)pipi*/(1)pisigma* and (1)pipi/(1)pisigma*) are discussed. The present diabatization method is confirmed to be valid even for significantly distorted ring structures by diabatization calculations along a reaction path connecting the planar equilibrium geometry of phenol to its strongly distorted prefulvenic form. The present work provides insight into the mode specificity of phenol photodissociation and shows that diabatization at the MC-QDPT level employing CASSCF diabatic MOs can be a good starting point for multidimensional dynamics calculations of photochemical reactions. PMID- 26584117 TI - Fast Domain Decomposition Algorithm for Continuum Solvation Models: Energy and First Derivatives. AB - In this contribution, an efficient, parallel, linear scaling implementation of the conductor-like screening model (COSMO) is presented, following the domain decomposition (dd) algorithm recently proposed by three of us. The implementation is detailed and its linear scaling properties, both in computational cost and memory requirements, are demonstrated. Such behavior is also confirmed by several numerical examples on linear and globular large-sized systems, for which the calculation of the energy and of the forces is achieved with timings compatible with the use of polarizable continuum solvation for molecular dynamics simulations. PMID- 26584116 TI - Extension of the AMBER Force Field for Nitroxide Radicals and Combined QM/MM/PCM Approach to the Accurate Determination of EPR Parameters of DMPO-H in Solution. AB - A computational strategy that combines both time-dependent and time-independent approaches is exploited to accurately model molecular dynamics and solvent effects on the isotropic hyperfine coupling constants of the DMPO-H nitroxide. Our recent general force field for nitroxides derived from AMBER ff99SB is further extended to systems involving hydrogen atoms in beta-positions with respect to NO-moiety. The resulting force-field has been employed in a series of classical molecular dynamics simulations, comparing the computed EPR parameters from selected molecular configurations to the corresponding experimental data in different solvents. The effect of vibrational averaging on the spectroscopic parameters is also taken into account, by second-order vibrational perturbation theory involving semidiagonal third energy derivatives together first and second property derivatives. PMID- 26584118 TI - Uniform Treatment of Solute-Solvent Dispersion in the Ground and Excited Electronic States of the Solute Based on a Solvation Model with State-Specific Polarizability. AB - We present a new kind of treatment of the solute-solvent dispersion contribution to the free energy of solvation using a solvation model with state-specific polarizability (SMSSP). To evaluate the solute-solvent dispersion contribution, the SMSSP model utilizes only two descriptors, namely, the spherically averaged dipole polarizability of the solute molecule (either in its ground or excited electronic state) and the refractive index of the solvent. The model was parametrized over 643 ground-state solvation free energy data for 231 solutes in 14 nonpolar, non-hydrogen-bonding solvents. We show that the SMSSP model is applicable to solutes in both the ground and the excited electronic state. For example, in comparison to available experimental data, the model yields qualitatively accurate predictions of the solvatochromic shifts for a number of systems where solute-solvent dispersion is the dominant contributor to the shift. PMID- 26584119 TI - pH-Induced Modulation of One- and Two-Photon Absorption Properties in a Naphthalene-Based Molecular Probe. AB - Presently, there is a great demand for small probe molecules that can be used for two-photon excitation microscopy (TPM)-based monitoring of intracellular and intraorganelle activity and pH. The candidate molecules should ideally possess a large two-photon absorption cross section with optical properties sensitive to pH changes. In the present work, we investigate the potential of a methoxy napthalene (MONAP) derivative for its suitability to serve as a pH sensor using TPM. Using an integrated approach rooted in hybrid quantum mechanics/molecular mechanics, the structures, dynamics, and the one- and two-photon properties of the probe in dimethylformamide solvent are studied. It is found that the protonated form is responsible for the optical property of MONAP at moderately low pH, for which the calculated pH-induced red shift is in good agreement with experiments. A 2-fold increase in the two-photon absorption cross section in the IR region of the spectrum is predicted for the moderately low pH form of the probe, suggesting that this can be a potential probe for pH monitoring of living cells. We also propose some design principles aimed at obtaining control of the absorption spectral range of the probe by structural tuning. Our work indicates that the integrated approach employed is capable of capturing the pH-induced changes in structure and optical properties of organic molecular probes and that such in silico tools can be used to draw structure-property relationships to design novel molecular probes suitable for a specific application. PMID- 26584120 TI - Random Phase Approximation in Surface Chemistry: Water Splitting on Iron. AB - The reaction of water with zero-valent iron (anaerobic corrosion) is a complex chemical process involving physisorption and chemisorption events. We employ random phase approximation (RPA) along with gradient-corrected and hybrid density functional theory (DFT) functionals to study the reaction of water with the Fe atom and Fe(100) surface. We show that the involvement of the exact electron exchange and nonlocal correlation effects in RPA improves the description of all steps of the reaction on the Fe surface with respect to standard [meaning local density approximation (LDA) or generalized gradient approximation (GGA)] DFT methods. The reaction profile calculated by range-separated hybrid functional HSE06 agrees reasonably well with the RPA profile, which makes HSE06 a computationally less demanding alternative to RPA. We also investigate the reaction of the Fe atom with water using DFT, RPA, and coupled-cluster through the perturbative triples complete basis set [CCSD(T)-3s3p-DKH/CBS] method. Local DFT methods significantly underestimate reaction barriers, while the reaction kinetics and thermodynamics from RPA agree with the reference CCSD(T) data. Both systems, i.e., the Fe atom and Fe(100), provide the same reaction mechanism, indicating that anaerobic corrosion is a stepwise process involving one-electron steps, with the first reaction step (formation of the HFeOH intermediate) representing the rate-limiting step. PMID- 26584121 TI - Accelerating Convergence in Molecular Dynamics Simulations of Solutes in Lipid Membranes by Conducting a Random Walk along the Bilayer Normal. AB - All molecular dynamics simulations are susceptible to sampling errors, which degrade the accuracy and precision of observed values. The statistical convergence of simulations containing atomistic lipid bilayers is limited by the slow relaxation of the lipid phase, which can exceed hundreds of nanoseconds. These long conformational autocorrelation times are exacerbated in the presence of charged solutes, which can induce significant distortions of the bilayer structure. Such long relaxation times represent hidden barriers that induce systematic sampling errors in simulations of solute insertion. To identify optimal methods for enhancing sampling efficiency, we quantitatively evaluate convergence rates using generalized ensemble sampling algorithms in calculations of the potential of mean force for the insertion of the ionic side chain analog of arginine in a lipid bilayer. Umbrella sampling (US) is used to restrain solute insertion depth along the bilayer normal, the order parameter commonly used in simulations of molecular solutes in lipid bilayers. When US simulations are modified to conduct random walks along the bilayer normal using a Hamiltonian exchange algorithm, systematic sampling errors are eliminated more rapidly and the rate of statistical convergence of the standard free energy of binding of the solute to the lipid bilayer is increased 3-fold. We compute the ratio of the replica flux transmitted across a defined region of the order parameter to the replica flux that entered that region in Hamiltonian exchange simulations. We show that this quantity, the transmission factor, identifies sampling barriers in degrees of freedom orthogonal to the order parameter. The transmission factor is used to estimate the depth-dependent conformational autocorrelation times of the simulation system, some of which exceed the simulation time, and thereby identify solute insertion depths that are prone to systematic sampling errors and estimate the lower bound of the amount of sampling that is required to resolve these sampling errors. Finally, we extend our simulations and verify that the conformational autocorrelation times estimated by the transmission factor accurately predict correlation times that exceed the simulation time scale something that, to our knowledge, has never before been achieved. PMID- 26584122 TI - Robust Heterogeneous Anisotropic Elastic Network Model Precisely Reproduces the Experimental B-factors of Biomolecules. AB - A computational method called the progressive fluctuation matching (PFM) is developed for constructing robust heterogeneous anisotropic network models (HANMs) for biomolecular systems. An HANM derived through the PFM approach consists of harmonic springs with realistic positive force constants, and yields the calculated B-factors that are basically identical to the experimental ones. For the four tested protein systems including crambin, trypsin inhibitor, HIV-1 protease, and lysozyme, the root-mean-square deviations between the experimental and the computed B-factors are only 0.060, 0.095, 0.247, and 0.049 A(2), respectively, and the correlation coefficients are 0.99 for all. By comparing the HANM/ANM normal modes to their counterparts derived from both an atomistic force field and an NMR structure ensemble, it is found that HANM may provide more accurate results on protein dynamics. PMID- 26584123 TI - Intermolecular Contact Potentials for Protein-Protein Interactions Extracted from Binding Free Energy Changes upon Mutation. AB - Understanding and predicting the energetics of protein-protein interactions is fundamental to the structural modeling of protein complexes. Binding free energy can be approximated as a sum of pairwise atomic or residue contact energies, which are commonly inferred from contact frequencies observed in experimental protein structures. However, such statistically inferred potentials require certain assumptions and approximation. Here, we explore the possibility of deriving atomic and residue contact potentials directly from experimental binding free energy changes following mutation and present a number of such potentials. The first set of potentials is obtained by unweighted least-squares fitting and bootsrap aggregating. The second set is calculated using a weighting scheme optimized against absolute binding affinity data, so as to account for the over representation of certain complexes, residues, and families of interactions. The congruence of the potentials with known physical chemistry is investigated. The potentials are further validated by ranking and clustering protein-protein docking poses. PMID- 26584124 TI - Simple Method for Simulating the Mixture of Atomistic and Coarse-Grained Molecular Systems. AB - Combining fine-grained (FG) all-atom and coarse-grained (CG) systems in a single simulation in a hybrid manner is of immense interest in recent times, owing to the possibility of overcoming the limitations of both FG simulations as well as CG simulations. The existing methods for combining these two resolutions tend to require heavy parametrizations or sometimes lack in transferability to other systems of interest, and further developments toward such directions are highly required. We report here a simple protocol to combine CG and FG systems in a single simulation, using the standard FG and CG force field models by adopting a series of small proteins as test cases. Our method makes use of virtual sites as reported earlier for relatively simple butane and dialaine systems (Rzepiela et al. Phys. Chem. Chem. Phys. 2011, 13, 10437-10448), to bridge the interaction between FG protein atoms and CG water. We find that the conventional CG model (MARTINI potentials) couples too strongly with the FG model and that it leads to complete unfolding of a test protein within very short time. We find that reducing the Lennard-Jones potential between CG atoms and virtual site atoms stabilizes the secondary and tertiary structures, sometimes almost to a comparable level with the fully atomistic simulations. However, detailed inspection reveals that this reduction is not enough for satisfactory consistency of the hybrid scheme against the FG simulation. As a remedy, we observe that the addition of as small as 4 A thick position-restrained FG water layer in the hybrid simulation can further improve the structural behaviors in many respects, with its results closely mimicking those of the FG-only simulations. However, free energy landscapes reveal that this agreement with a restrained solvent layer is still accompanied by the overstabilization of the protein native structure, which will likely pose limitations for studying protein dynamics with the scheme. We show various test results that we have tried in optimizing the FG-CG mixing scheme over the course and discuss future prospects as concluding remarks of the present work. PMID- 26584125 TI - Toward an Automatic Determination of Enzymatic Reaction Mechanisms and Their Activation Free Energies. AB - We present a combination of the string method and a path collective variable for the exploration of the free energy surface associated to a chemical reaction in condensed environments. The on-the-fly string method is employed to find the minimum free energy paths on a multidimensional free energy surface defined in terms of interatomic distances, which is a convenient selection to study bond forming/breaking processes. Once the paths have been determined, a reaction coordinate is defined as a measure of the advance of the system along these paths. This reaction coordinate can be then used to trace the reaction Potential of Mean Force from which the activation free energy can be obtained. This combination of methodologies has been here applied to the study, by means of Quantum Mechanics/Molecular Mechanics simulations, of the reaction catalyzed by guanidinoacetate methyltransferase. This enzyme catalyzes the methylation of guanidinoacetate by S-adenosyl-l-methionine, a reaction that involves a methyl transfer and a proton transfer and for which different reaction mechanisms have been proposed. PMID- 26584126 TI - Reconstructing the Most Probable Folding Transition Path from Replica Exchange Molecular Dynamics Simulations. AB - The characterization of transition pathways between long-lived states, and the identification of the corresponding transition state ensembles are useful tools in the study of rare events such as protein folding. In this work we demonstrate how the most probable transition path between metastable states can be recovered from replica exchange molecular dynamic simulation data by using the dynamic string method. The local drift vector in collective variables is determined via short continuous trajectories between replica exchanges at a given temperature, and points along the string are updated based on this drift vector to produce reaction pathways between the folded and unfolded state. The method is applied to a designed beta hairpin-forming peptide to obtain information on the folding mechanism and transition state using different sets of collective variables at various temperatures. Two main folding pathways differing in the order of events are found and discussed, and the relative free energy differences for each path estimated. Finally, the structures near the transition state are found and described. PMID- 26584127 TI - Conformational Sampling by Ab Initio Molecular Dynamics Simulations Improves NMR Chemical Shift Predictions. AB - Car-Parrinello molecular dynamics simulations were performed for N-methyl acetamide as a small test system for amide groups in protein backbones, and NMR chemical shifts were calculated based on the generated ensemble. If conformational sampling and explicit solvent molecules are taken into account, excellent agreement between the calculated and experimental chemical shifts is obtained. These results represent a landmark improvement over calculations based on classical molecular dynamics (MD) simulations especially for amide protons, which are predicted too high-field shifted based on the latter ensembles. We were able to show that the better results are caused by the solute-solvents interactions forming shorter hydrogen bonds as well as by the internal degrees of freedom of the solute. Inspired by these results, we propose our approach as a new tool for the validation of force fields due to its power of identifying the structural reasons for discrepancies between the experimental and calculated data. PMID- 26584128 TI - Role of the Membrane Dipole Potential for Proton Transport in Gramicidin A Embedded in a DMPC Bilayer. AB - The membrane potential at the water/phospholipid interfaces may play a key role for proton conduction of gramicidin A (gA). Here we address this issue by Density Functional Theory-based molecular dynamics and metadynamics simulations. The calculations, performed on gA embedded in a solvated 1,2-dimyristoyl-sn-glycero-3 phosphocholine (DMPC) model membrane environment (about 2,000 atoms), indicate that (i) the membrane dipole potential rises at the channel mouth by ~0.4 V. A similar value has been measured for gA embedded in a DMPC monolayer; (ii) the calculated free energy barrier is located at the channel entrance, consistent with experiments comparing gA proton conduction in different bilayers. The electronic structures of the proton ligands (water molecules and peptide units) are similar to those in the bulk solvent. Based on these results, we suggest an important role of the membrane dipole potential for the free energy barrier of proton permeation of gA. This may provide a rationale for the large increase in the rate of proton conduction under application of a transmembrane voltage, as observed experimentally. Our calculations might suggest also a role for proton desolvation for the permeation process. This role has already emerged from EVB calculations on gA embedded in a model membrane. PMID- 26584129 TI - Convergence of QM/MM and Cluster Models for the Spectroscopic Properties of the Oxygen-Evolving Complex in Photosystem II. AB - The latest crystal structure of photosystem II at 1.9 A resolution, which resolves the topology of the Mn4CaO5 oxygen evolving complex (OEC) at atomistic detail, enables a better correlation between structural features and spectroscopic properties than ever before. Building on the refined crystallographic model of the OEC and the protein, we present combined quantum mechanical/molecular mechanical (QM/MM) studies of the spectroscopic properties of the natural catalyst embedded in the protein matrix. Focusing on the S2 state of the catalytic cycle, we examine the convergence of not only structural parameters but also of the intracluster magnetic interactions in terms of exchange coupling constants and of experimentally relevant (55)Mn, (17)O, and (14)N hyperfine coupling constants with respect to QM/MM partitioning using five QM regions of increasing size. This enables us to assess the performance of the method and to probe second sphere effects by identifying amino acid residues that principally affect the spectroscopic properties of the OEC. Comparison between QM only and QM/MM treatments reveals that whereas QM/MM models converge quickly to stable values, the QM cluster models need to incorporate significantly larger parts of the second coordination sphere and surrounding water molecules to achieve convergence for certain properties. This is mainly due to the sensitivity of the QM-only models to fluctuations in the hydrogen bonding network and ligand acidity. Additionally, a hydrogen bond that is typically omitted in QM-only treatments is shown to determine the hyperfine coupling tensor of the unique Mn(III) ion by regulating the rotation plane of the ligated D1-His332 imidazole ring, the only N-donor ligand of the OEC. PMID- 26584130 TI - Stochastic Search of Molecular Cluster Interaction Energy Surfaces with Coupled Cluster Quality Prediction. The Phenylacetylene Dimer. AB - We report a stochastic search methodology on the basis of dispersion-augmented density functional theory (DFT), aimed at finding low energy isomers of the phenylacetylene dimer as well as methane and benzene dimers. Stochastic search of the molecular cluster interaction energy surfaces was carried out with the computationally inexpensive dispersion-augmented, third-order self-consistent charge density functional tight-binding (DFTB3-D) method, and energetically low lying molecular cluster geometries were identified, including several that had previously been optimized at the MP2/cc-pVTZ level of theory and had single point interaction energies evaluated at the coupled-cluster singles, doubles, and perturbative triples (CCSD(T)) level of theory in the complete basis set limit (Maity, S. et al. Phys. Chem. Chem. Phys 2011, 13, 16706). In addition, the search procedure identifies several additional low-energy isomers that map a reaction path, rotating one monomer through a full 360 degrees relative to the first. We found that binding energies from long-range corrected functional combined with the local response dispersion correction (LC-BOP+LRD) yields binding energies that are within 1 kJ mol(-1) of the CCSD(T)/CBS results for both pi-stacked and CH...pi structures. In contrast, other functionals and second order Moller-Plesset perturbation methods favored one binding motif or the other and therefore are not ideal to describe a global potential energy surface. PMID- 26584131 TI - Squaroglitter: A 3,4-Connected Carbon Net. AB - Theoretical calculations are presented on a new hypothetical 3,4-connected carbon net (called squaroglitter) incorporating 1,4 cyclohexadiene units. The structure has tetragonal space group P4/mmm (No. 123) symmetry. The optimized geometry shows normal distances, except for some elongated bonds in the cyclobutane ring substructures in the network. Squaroglitter has an indirect bandgap of about 1.0 eV. The hypothetical lattice, whose density is close to graphite, is more stable than other 3,4-connected carbon nets. A relationship to a (4,4)nanotube is explored, as is a potential threading of the lattice with metal needles. PMID- 26584132 TI - Synthesis of Lepadiformine Using a Hydroamination Transform. AB - Dissection of lepadiformine by a double hydroamination transform affords a simple achiral amino diene. This reaction is accomplished in the forward sense by amine directed hydroboration and an oxidative alkyl shift to nitrogen, both of which occur with high stereoselectivity to generate three stereogenic centers and the lepadiformine skeleton. PMID- 26584133 TI - Tembusu-Related Flavivirus in Ducks, Thailand. AB - Since 2013, outbreaks of disease caused by duck Tembusu virus (DTMUV) have been observed in layer and broiler duck farms in Thailand. The virus is closely related to Chinese DTMUVs and belongs to the Ntaya group of mosquitoborne flaviviruses. These findings represent the emergence of DTMUV in ducks in Thailand. PMID- 26584134 TI - Subcooled-Water Nonstickiness of Condensate Microdrop Self-Propelling Nanosurfaces. AB - We report perfect humidity-tolerant subcooled-water nonstickiness on condensate microdrop self-propelling (CMDSP) surfaces. As exemplified by a CMDSP nanoneedle surface, we find that impinged subcooled drops can instantly rebound and simultaneously take away surface condensate. Remarkably, continuously poured subcooled water can also shed off on the nanosample surface. In sharp contrast, they instantly freeze on the contrast flat hydrophobic surface. Such a superior performance may be ascribed to nanostructure-induced extremely low solid-liquid interface adhesion and prevention of phase transition from the liquid subcooled water to the solid ice. These findings help in the development of low-adhesive superhydrophobic surfaces suitable for a cold and humid environment. PMID- 26584136 TI - L-Carnitine intake and high trimethylamine N-oxide plasma levels correlate with low aortic lesions in ApoE(-/-) transgenic mice expressing CETP. AB - OBJECTIVE: Dietary l-carnitine can be metabolized by intestinal microbiota to trimethylamine, which is absorbed by the gut and further oxidized to trimethylamine N-oxide (TMAO) in the liver. TMAO plasma levels have been associated with atherosclerosis development in ApoE(-/-) mice. To better understand the mechanisms behind this association, we conducted in vitro and in vivo studies looking at the effect of TMAO on different steps of atherosclerotic disease progression. METHODS: J774 mouse macrophage cells were used to evaluate the effect of TMAO on foam cell formation. Male ApoE(-/-) mice transfected with human cholesteryl ester transfer protein (hCETP) were fed l-carnitine and/or methimazole, a flavin monooxygenase 3 (FMO3) inhibitor that prevents the formation of TMAO. Following 12 week treatment, l-carnitine and TMAO plasma levels, aortic lesion development, and lipid profiles were determined. RESULTS: TMAO at concentrations up to 10-fold the Cmax reported in humans did not affect in vitro foam cell formation. In ApoE(-/-)mice expressing hCETP, high doses of l carnitine resulted in a significant increase in plasma TMAO levels. Surprisingly, and independently from treatment group, TMAO levels inversely correlated with aortic lesion size in both aortic root and thoracic aorta. High TMAO levels were found to significantly correlate with smaller aortic lesion area. Plasma lipid and lipoprotein levels did not change with treatment nor with TMAO levels, suggesting that the observed effects on lesion area were independent from lipid changes. CONCLUSION: These findings suggest that TMAO slows aortic lesion formation in this mouse model and may have a protective effect against atherosclerosis development in humans. PMID- 26584135 TI - Monoglyceride lipase deficiency modulates endocannabinoid signaling and improves plaque stability in ApoE-knockout mice. AB - BACKGROUND AND AIMS: Monoglyceride lipase (MGL) catalyzes the final step of lipolysis by degrading monoglyceride (MG) to glycerol and fatty acid. MGL also hydrolyzes and thereby deactivates 2-arachidonoyl glycerol (2-AG), the most abundant endocannabinoid in the mammalian system. 2-AG acts as full agonist on cannabinoid receptor type 1 (CB1R) and CB2R, which are mainly expressed in brain and immune cells, respectively. Thus, we speculated that in the absence of MGL, increased 2-AG concentrations mediate CB2R signaling in immune cells to modulate inflammatory responses, thereby affecting the development of atherosclerosis. METHODS AND RESULTS: We generated apolipoprotein E (ApoE)/MGL double-knockout (DKO) mice and challenged them with Western-type diet for 9 weeks. Despite systemically increased 2-AG concentrations in DKO mice, CB2R-mediated signaling remains fully functional, arguing against CB2R desensitization. We found increased plaque formation in both en face aortae (1.3-fold, p = 0.028) and aortic valve sections (1.5-fold, p = 0.0010) in DKO mice. Interestingly, DKO mice also presented reduced lipid (12%, p = 0.031) and macrophage content (18%, p = 0.061), elevated intraplaque smooth muscle staining (1.4-fold, p = 0.016) and thicker fibrous caps (1.8-fold, p = 0.0032), together with a higher ratio of collagen to necrotic core area (2.5-fold, p = 0.0003) and expanded collagen content (1.6-fold, p = 0.0007), which suggest formation of less vulnerable atherosclerotic plaques. Treatment with a CB2R inverse agonist prevents these effects in DKO mice, demonstrating that the observed plaque phenotype in DKO mice originates from CB2R activation. CONCLUSION: Loss of MGL modulates endocannabinoid signaling in CB2R-expressing cells, which concomitantly affects the pathogenesis of atherosclerosis. We conclude that despite larger lesion size loss of MGL improves atherosclerotic plaque stability. Thus, pharmacological MGL inhibition may be a novel intervention to reduce plaque rupture. PMID- 26584137 TI - Aptamer BC007 for neutralization of pathogenic autoantibodies directed against G protein coupled receptors: A vision of future treatment of patients with cardiomyopathies and positivity for those autoantibodies. AB - Cardiomyopathies such as idiopathic dilated cardiomyopathy (DCM), Chagas' cardiomyopathy and Peripartum cardiomyopathy present with autoantibodies against G-protein coupled receptors (GPCR-AABs) that agonistically activate their receptors. For the treatment of "agonistic autoantibody diseases" and in particular DCM, the removal of the GPCR-AABs by immunoadsorption (IA) has been studied with convincing patient benefit. To overcome cost and logistics problems of IA, the application of the aptamer BC007 for in vivo neutralization of GPCR AABs could help. We demonstrate here, that the aptamer neutralized, in vitro, the presently known cardiovascular-pathogenic GPCR-AABs. In spontaneously hypertensive rats, the aptamer demonstrated its GPCR-AAB neutralizing potency in vivo. In the serum of DCM patients, the same GPCR-AAB reduction was achieved when patients were either immunoadsorbed or patient's serum was ex vivo treated with the aptamer. In our view, aptamer BC007 treatment in GPCR-AAB-positive patients would have a comparable benefit as that seen after IA. Not knowing all that interfering with our idea of aptamer-dependent neutralization of GPCR-AABs, the first preliminary steps have been taken for bringing the idea closer to patients. PMID- 26584138 TI - Antiphospholipid syndrome and anticoagulation quality: a clinical challenge. AB - BACKGROUND AND AIMS: Antiphospholipid Syndrome (APS) is often complicated by ischemic vascular events. Vitamin K Antagonists (VKAs) reduce the risk of recurrent thrombosis. Quality of VKAs treatment, as assessed by the Time in Therapeutic Range (TTR), has never been investigated in APS patients. METHODS: We performed a prospective observational study including 30 APS and 30 Atrial Fibrillation (AF) patients balanced by age and gender. All patients were treated with VKAs (INR target 2.5), and TTR was calculated. RESULTS: Median TTR of APS was 53.5% vs. 68% of AF patients (p = 0.001). A multivariable linear regression analysis confirmed that the presence of APS (vs. AF) was independently associated with a worse TTR (B: -14.067, 95% Confidence Interval -25.868/-2.266, p = 0.020). The weekly dosage of VKAs was significantly higher in APS than AF patients. CONCLUSIONS: APS patients disclose a lower quality of anticoagulation compared to those with AF, requiring higher doses of VKAs. The efficacy of non-vitamin K oral anticoagulants in this high-risk patients should be tested. PMID- 26584139 TI - A novel organ culture model of aorta for vascular calcification. AB - Vascular calcification is a characteristic feature of aging, atherosclerosis, diabetes mellitus, and end-stage renal disease. The use of organ culture provides complementary information that may bridge the gap between traditional cell culture and animal models, and establishes easily controlled experimental conditions. Therefore, we investigated whether organ culture of the aorta could be used as a model of vascular calcification, applying it to animal models of other conditions. Thoracic aortas were dissected from C57BL/6 mice and cultured. To induce vascular calcification, stimulation with inorganic phosphate (Pi) was performed. Morphometric assessment of medial calcium deposition was quantitatively performed, and the amount of dissolved calcium was measured. Pi stimulation induced calcium deposition in medial layers in a time- and dose dependent manner. To investigate the phenotypic change of vascular smooth muscle cells (VSMC), the expression of Runx2, osterix, osteocalcin, and ALP activity were determined. Finally, to investigate the influence of Pi-stimulation on the cultured aorta in other models, aortas from streptozotocin (STZ)-induced diabetic mice, aged mice, and Sirt1 knockout (+/-) mice were dissected. These cultures showed a greater tendency for aortic calcification by Pi-stimulation than did control cultures. These results indicate that organ culture of the aorta from mice reflects the state of calcification and suggests that this model will be useful to explore the molecular mechanisms of vascular calcification and the pathology of senescence. PMID- 26584140 TI - Association between parental history and genetic risk scores for coronary heart disease prediction: The population-based CoLaus study. AB - BACKGROUND AND AIMS: Parental history (PH) and genetic risk scores (GRSs) are separately associated with coronary heart disease (CHD), but evidence regarding their combined effects is lacking. We aimed to evaluate the joint associations and predictive ability of PH and GRSs for incident CHD. METHODS: Data for 4283 Caucasians were obtained from the population-based CoLaus Study, over median follow-up time of 5.6 years. CHD was defined as incident myocardial infarction, angina, percutaneous coronary revascularization or bypass grafting. Single nucleotide polymorphisms for CHD identified by genome-wide association studies were used to construct unweighted and weighted versions of three GRSs, comprising of 38, 53 and 153 SNPs respectively. RESULTS: PH was associated with higher values of all weighted GRSs. After adjustment for age, sex, smoking, diabetes, systolic blood pressure, low and high density lipoprotein cholesterol, PH was significantly associated with CHD [HR 2.61, 95% CI (1.47-4.66)] and further adjustment for GRSs did not change this estimate. Similarly, one standard deviation change of the weighted 153-SNPs GRS was significantly associated with CHD [HR 1.50, 95% CI (1.26-1.80)] and remained so, after further adjustment for PH. The weighted, 153-SNPs GRS, but not PH, modestly improved discrimination [(C index improvement, 0.016), p = 0.048] and reclassification [(NRI improvement, 8.6%), p = 0.027] beyond cardiovascular risk factors. After including both the GRS and PH, model performance improved further [(C-index improvement, 0.022), p = 0.006]. CONCLUSION: After adjustment for cardiovascular risk factors, PH and a weighted, polygenic GRS were jointly associated with CHD and provided additive information for coronary events prediction. PMID- 26584141 TI - Metabolic syndrome, independent of its components, affects adversely cardiovascular morbidity in essential hypertensives. AB - BACKGROUND: The metabolic syndrome (MS) is widespread among hypertensive patients. However, the net impact of MS on major atherosclerotic events beyond the cardiovascular risk imposed by its individual components remains controversial in this group. We sought to assess both the independent and incremental prognostic role of MS for unfavorable cardiovascular events in a cohort of essential hypertensives. METHODS: We followed up 2176 essential hypertensives free of cardiovascular disease for a median period of 40 months. All subjects had at least one annual visit. MS was defined according to the updated NCEP III criteria. Endpoint of interest was the incidence of stroke, coronary artery disease (CAD) and their composite. RESULTS: MS was present at baseline in 819 hypertensives (37.6%). MS group presented increased prevalence of resistant hypertension in comparison to MS free group (18.4% versus 10.6%, p < 0.001). The incidence of the composite end-point was 3.1% (69 events) across the follow-up period. Patients with MS were more likely to experience major adverse cardiovascular events (MACE) in comparison to reference category (3.7% versus 1.9%, log rank p = 0.024). While MS was an independent predictor for MACE, none of the individual components of the syndrome was associated independently with the endpoint. MS provided incremental discriminative value (Harrell's c, p < 0.05 for all) over individual risk factors for the incidence of MACE. CONCLUSIONS: MS predicts adverse cardiovascular events in hypertensives incrementally of its individual components. Early identification of MS in this population may enable more accurate prediction of future cardiovascular risk and could implement more efficient strategies in terms of primary prevention. PMID- 26584142 TI - Trilayer Tunnel Selectors for Memristor Memory Cells. AB - An integrated memory cell with a mem-ristor and a trilayer crested barrier selector, showing repeatable nonlinear current-voltage switching loops is presented. The fully atomic-layer-deposited TaN1+x /Ta2 O5 /TaN1+x crested barrier selector yields a large nonlinearity (>10(4) ), high endurance (>10(8) ), low variability, and low temperature dependence. PMID- 26584143 TI - Complex Surface Diffusion Mechanisms of Cobalt Phthalocyanine Molecules on Ag(100). AB - We used time-lapsed scanning tunneling microscopy between 43 and 50 K and density functional theory (DFT) to explore the basic surface diffusion steps of cobalt phthalocyanine (CoPc) molecules on the Ag(100) surface. We show that the CoPc molecules translate and rotate on the surface in the same temperature range. Both processes are associated with similar activation energies; however, the translation is more frequently observed. Our DFT calculations provide the activation energies for the translation of the CoPc molecule between the nearest hollow sites and the rotation at both the hollow and the bridge sites. The activation energies are only consistent with the experimental findings, if the surface diffusion mechanism involves a combined translational and rotational molecular motion. Additionally, two channels of motion are identified: the first provides only a channel for translation, while the second provides a channel for both the translation and the rotation. The existence of the two channels explains a higher rate for the translation determined in experiment. PMID- 26584146 TI - Potential useful prognostic parameters after transcatheter aortic valve implantation: editorial. PMID- 26584145 TI - Accelerating electrostatic interaction calculations with graphical processing units based on new developments of Ewald method using non-uniform fast Fourier transform. AB - We present new algorithms to improve the performance of ENUF method (F. Hedman, A. Laaksonen, Chem. Phys. Lett. 425, 2006, 142) which is essentially Ewald summation using Non-Uniform FFT (NFFT) technique. A NearDistance algorithm is developed to extensively reduce the neighbor list size in real-space computation. In reciprocal-space computation, a new algorithm is developed for NFFT for the evaluations of electrostatic interaction energies and forces. Both real-space and reciprocal-space computations are further accelerated by using graphical processing units (GPU) with CUDA technology. Especially, the use of CUNFFT (NFFT based on CUDA) very much reduces the reciprocal-space computation. In order to reach the best performance of this method, we propose a procedure for the selection of optimal parameters with controlled accuracies. With the choice of suitable parameters, we show that our method is a good alternative to the standard Ewald method with the same computational precision but a dramatically higher computational efficiency. PMID- 26584144 TI - Development and evaluation of a multichannel endorectal RF coil for prostate MRI at 7T in combination with an external surface array. AB - PURPOSE: To develop and evaluate a sterilizable multichannel endorectal coil (ERC) for use in combination with an external surface array (ESA) for high resolution anatomical and functional studies of the prostate at 7T. MATERIALS AND METHODS: A two-loop ERC (ERC-2L) and a microstrip-loop ERC (ERC-ML) were compared at 7T in terms of transmit and receive performance. The best-performing ERC was evaluated alone and in combination with the ESA through 1) simulations on both phantom and an anatomically correct numerical human model to assess B1+ transmit and specific absorption rate (SAR) efficiencies, and 2) phantom experiments to calculate B1+ transmit efficiency and signal-to-noise ratio (SNR). Phantom studies were also performed to look at heating when using the ERC as a transmitter and for comparing the new coil against a single-channel balloon-type ERC (ERC-b). High-resolution magnetic resonance imaging (MRI) acquisitions were performed on a single healthy subject using the two-channel ERC combined with the ESA. RESULTS: Compared to the ERC-ML, the ERC-2L demonstrated 20% higher SAR efficiency and higher SNR 3 cm from the coil. The presence of a tuned and detuned ERC-2L did not alter the peak local SAR of the ESA alone; however, the detuned ERC-2L had 45% less peak local SAR around the rectum compared to the tuned ERC 2L. The receive-only version of the ERC-2L improved the SNR 4.7-fold and 1.3-fold compared to the ESA and ERC-b, respectively. In combination with the ESA, the ERC 2L supported in-plane voxel-size of 0.36 * 0.36 mm(2) in T2 -weighted anatomic imaging. CONCLUSION: The reusable ERC-2L combined with an ESA offers a high SNR imaging platform for translational studies of the prostate at 7T. J. Magn. Reson. Imaging 2016;43:1279-1287. PMID- 26584147 TI - The Nature of the Singlet and Triplet States of Cyclobutadiene as Revealed by Quantum Interference. AB - The generalized product function energy partitioning (GPF-EP) method is applied to the description of the cyclobutadiene molecule. The GPF wave function was built to reproduce generalized valence bond (GVB) and spin-coupled (SC) wave functions. The influence of quasiclassical and quantum interference contributions to each chemical bond of the system are analyzed along the automerization reaction coordinate for the lowest singlet and triplet states. The results show that the interference effect on the pi space reduces the electronic energy of the singlet cyclobutadiene relative to the second-order Jahn-Teller distortion, which takes the molecule from a D4h to a D2h structure. Our results also suggest that the pi space of the (1) B1g state of the square cyclobutadiene is composed of a weak four center-four electron bond, whereas the (3) A2g state has a four center two electron pi bond. Finally, we also show that, although strain effects are nonnegligible, the thermodynamics of the main decomposition pathway of cyclobutadiene in the gas phase is dominated by the pi space interference. PMID- 26584149 TI - Flow cytometric analysis of CD200 expression by pulmonary small cell carcinoma. AB - BACKGROUND: CD200 is a membrane bound glycoprotein that is expressed by a variety of normal tissues and hematopoietic malignancies. Flow cytometric analysis of CD200 expression has utility in the evaluation of mature B-cell neoplasms, myeloma, and acute leukemia; however, CD200 expression in nonhematopoietic malignancies has not been extensively studied. METHODS: We studied 14 cases of biopsy proven pulmonary small cell carcinoma in which a discrete CD45 negative, CD56 positive abnormal cell population was identified by flow cytometry. We retrospectively evaluated these cases for flow cytometric and immunohistochemical evidence of CD200 expression. RESULTS: Twelve of the 14 cases of pulmonary small cell carcinoma showed convincing expression of CD200 by both immunohistochemistry and flow cytometry. CONCLUSIONS: Pulmonary small cell carcinoma frequently expresses CD200 at a level that can be detected by flow cytometry and immunohistochemistry. CD200 expression therefore may be used to help identify pulmonary small cell carcinoma in flow cytometry specimens and tissue sections. CD200 may also play a role in the biology of pulmonary small cell carcinoma and is a potential target of future therapies. (c) 2015 International Clinical Cytometry Society. PMID- 26584148 TI - Correcting dynamic distortions in 7T echo planar imaging using a jittered echo time sequence. AB - PURPOSE: To develop a distortion correction method for echo planar imaging (EPI) that is able to measure dynamic changes in B0 . THEORY AND METHODS: The approach we propose is based on single-echo EPI with a jittering of the echo time between two values for alternate time points. Field maps are calculated between phase images from adjacent volumes and are used to remove distortion from corresponding magnitude images. The performance of our approach was optimized using an analytical model and by comparison with field maps from dual-echo EPI. The method was tested in functional MRI experiments at 7T with motor tasks and compared with the conventional static approach. RESULTS: Unwarping using our method was accurate even for head rotations up to 8.2 degrees , where the static approach introduced errors up to 8.2 mm. Jittering the echo time between 19 and 25 ms had no measurable effect on blood oxygenation level-dependent (BOLD) sensitivity. Our approach reduced the distortions in activated regions to <1 mm and repositioned active voxels correctly. CONCLUSION: This method yields accurate distortion correction in the presence of motion. No reduction in BOLD sensitivity was observed. As such, it is suitable for application in a wide range of functional MRI experiments. Magn Reson Med 76:1388-1399, 2016. (c) 2015 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. PMID- 26584150 TI - Use of intracardiac echocardiography during atrial fibrillation ablation to avoid complications. AB - Antral pulmonary vein isolation is the cornerstone of current catheter ablation techniques. As technology and tools for performing the ablations have evolved and improved over the past decade, the safety and efficacy of the procedure have improved. The availability of preprocedure imaging, such as MRI and CT scan and intraprocedure imaging, especially intracardiac echocardiography, gives the operator the ability to have very accurate real-time representations of the cardiac anatomy with visualization of catheter positioning and for assessing for potential complications before they become clinically manifest. Much attention has been paid to decreasing the reliance on use of fluoroscopy and the safety of both the patient as well as the operator. This chapter reviews several aspects of the utility of intracardiac echocardiography imaging in minimizing complications during atrial fibrillation ablation. PMID- 26584151 TI - Discovering the structure of nerve tissue: Part 3: From Jan Evangelista Purkyne to Ludwig Mauthner. AB - The previous works of Purkyne, Valentin, and Remak showed that the central and peripheral nervous systems contained not only nerve fibers but also cellular elements. The use of microscopes and new fixation techniques enabled them to accurately obtain data on the structure of nerve tissue and consequently in many European universities microscopes started to become widely used in histological and morphological studies. The present review summarizes important discoveries concerning the structure of neural tissue, mostly from vertebrates, during the period from 1838 to 1865. This review describes the discoveries of famous as well as less well-known scholars of the time, who contributed significantly to current understandings about the structure of neural tissue. The period is characterized by the first descriptions of different types of nerve cells and the first attempts of a cytoarchitectonic description of the spinal cord and brain. During the same time, the concept of a neuroglial tissue was introduced, first as a tissue for "gluing" nerve fibers, cells, and blood capillaries into one unit, but later some glial cells were described for the first time. Questions arose as to whether or not cells in ganglia and the central nervous system had the same morphological and functional properties, and whether nerve fibers and cell bodies were interconnected. Microscopic techniques started to be used for the examination of physiological as well as pathological nerve tissues. The overall state of knowledge was just a step away from the emergence of the concept of neurons and glial cells. PMID- 26584152 TI - Optimization of delignification of two Pennisetum grass species by NaOH pretreatment using Taguchi and ANN statistical approach. AB - In the bioconversion of lignocelluloses for bioethanol, pretreatment seems to be the most important step which improves the elimination of the lignin and hemicelluloses content, exposing cellulose to further hydrolysis. The present study discusses the application of dynamic statistical techniques like the Taguchi method and artificial neural network (ANN) in the optimization of pretreatment of lignocellulosic biomasses such as Hybrid Napier grass (HNG) (Pennisetum purpureum) and Denanath grass (DG) (Pennisetum pedicellatum), using alkali sodium hydroxide. This study analysed and determined a parameter combination with a low number of experiments by using the Taguchi method in which both the substrates can be efficiently pretreated. The optimized parameters obtained from the L16 orthogonal array are soaking time (18 and 26 h), temperature (60 degrees C and 55 degrees C), and alkali concentration (1%) for HNG and DG, respectively. High performance liquid chromatography analysis of the optimized pretreated grass varieties confirmed the presence of glucan (47.94% and 46.50%), xylan (9.35% and 7.95%), arabinan (2.15% and 2.2%), and galactan/mannan (1.44% and 1.52%) for HNG and DG, respectively. Physicochemical characterization studies of native and alkali-pretreated grasses were carried out by scanning electron microscopy and Fourier transformation Infrared spectroscopy which revealed some morphological differences between the native and optimized pretreated samples. Model validation by ANN showed a good agreement between experimental results and the predicted responses. PMID- 26584153 TI - Mortality from cystic fibrosis in Europe: 1994-2010. AB - OBJECTIVE: To date, available mortality trends due to cystic fibrosis (CF) have been limited to the analysis of certain countries in different parts of the world showing that mortality trends have been constantly decreasing. However, no studies have examined Europe as a whole. The present study aims to analyze CF mortality trends by gender within the European Union (EU) and to quantify potential years of life lost (PYLL). DESIGN: Deaths from the 27 EU countries were obtained from the statistical office of the EU from the years 1994-2010. Crude and age-standardized mortality rates (ASR) were estimated for women and men using the standard European population, expressed in deaths per 1,000,000 persons. The PYLL from ages 0 up to 30 years were estimated. Trends were studied by a joinpoint regression analysis. RESULTS: During the study period, 5,130 deaths (2,443 in males and 2,687 in females) were identified. Females had a slightly higher mortality rate than males, with a downward trend observed for both genders. In males, the ASR changed from 1.34 in 1994 to 1.03 in 2010. In females, the ASR changed from 1.42 in 1994 to 0.92 in 2010. The mean age at death and PYLL increased for both genders. The joinpoint analysis did not identify any significant joinpoint for either gender for ASR or PYLL. CONCLUSIONS: Our data suggest a continued downward trend of CF mortality throughout the EU, with differences by country and gender. PMID- 26584154 TI - Structure of tracheae and the functional implications for collapse in the American cockroach. AB - The tracheal tubes of insects are complex and heterogeneous composites with a microstructural organization that affects their function as pumps, valves, or static conduits within the respiratory system. In this study, we examined the microstructure of the primary thoracic tracheae of the American cockroach (Periplaneta americana) using a combination of scanning electron microscopy and light microscopy. The organization of the taenidia, which represents the primary source of structural reinforcement of the tracheae, was analyzed. We found that the taenidia were more disorganized in the regions of highest curvature of the tracheal tube. We also used a simple finite element model to explore the effect of cross-sectional shape and distribution of taenidia on the collapsibility of the tracheae. The eccentricity of the tracheal cross-section had a stronger effect on the collapse properties than did the distribution of taenidia. The combination of the macro-scale geometry, meso-scale heterogeneity, and microscale organization likely enables rhythmic tracheal compression during respiration, ultimately driving oxygen-rich air to cells and tissues throughout the insect body. The material design principles of these natural composites could potentially aid in the development of new bio-inspired microfluidic systems based on the differential collapse of tracheae-like networks. PMID- 26584155 TI - Avoiding Spending While Meeting Patients' Wishes: A Model of Community-Based Palliative Care Uptake in California from 2014-2022. AB - BACKGROUND: Community-based palliative care can improve outcomes and avoid unnecessary spending, but the effects of its widespread adoption on health care spending in California is unknown. OBJECTIVE: To estimate the spending avoided if, by 2022, more than 100,000 Californians received community-based palliative care (CBPC) per year. DESIGN: We estimated the 6-month per-patient spending avoided through three mature CBPC programs in California and extrapolated data to predict the total avoided spending statewide over 8 years if enrollment in the three programs proceeded according to our model. RESULTS: If Californians participated in CBPC in the numbers envisioned, in 2014 there would have been a $72 million reduction in intensive hospital based care, while still respecting patients' wishes, and nearly $1.1 billion in spending could be avoided in 2022. Overall hospital spending would be reduced by more than $5.5 billion through 2022. CONCLUSIONS: Existing CBPC programs have the potential to provide care that is both in alignment with patients' wishes and avoids substantial amounts of unnecessary hospital-based spending. PMID- 26584157 TI - Obesity Risk in Children: The Role of Acculturation in the Feeding Practices and Styles of Low-Income Hispanic Families. AB - BACKGROUND: Parent feeding has been associated with child overweight/obesity in low-income families. Because acculturation to the United States has been associated with increased adult obesity, our study aim was to determine whether acculturation was associated with feeding in these populations. METHODS: Low income Hispanic mothers of preschoolers were recruited to participate in a longitudinal study examining child eating behaviors. At baseline, mothers completed questionnaires on feeding styles, feeding practices, and acculturation. Regression analyses compared feeding styles and food parenting practices of first generation, immigrant mothers born outside the United States (n = 138) and mothers born in the United States (n = 31). The correlates of acculturation with these same constructs were also examined. RESULTS: Immigrant mothers reported using highly directive food parenting practices more often than mothers born in the United States, including pressuring their child to consume more food, using food as a reward, and controlling child food intake by limiting less-healthy foods. First-generation mothers were more likely to show authoritarian, and less likely to show indulgent, feeding styles. Greater maternal acculturation was associated with less restriction of food for weight reasons. CONCLUSIONS: Although first-generation, immigrant mothers reported using highly controlling food parenting practices with their children, those born in the United States were more indulgent with their children in the feeding context. Mechanisms that promote greater indulgence in more-acculturated mothers need to be identified. PMID- 26584158 TI - Molecular Genetic Regulation of Slc30a8/ZnT8 Reveals a Positive Association With Glucose Tolerance. AB - Zinc transporter 8 (ZnT8), encoded by SLC30A8, is chiefly expressed within pancreatic islet cells, where it mediates zinc (Zn(2+)) uptake into secretory granules. Although a common nonsynonymous polymorphism (R325W), which lowers activity, is associated with increased type 2 diabetes (T2D) risk, rare inactivating mutations in SLC30A8 have been reported to protect against T2D. Here, we generate and characterize new mouse models to explore the impact on glucose homeostasis of graded changes in ZnT8 activity in the beta-cell. Firstly, Slc30a8 was deleted highly selectively in these cells using the novel deleter strain, Ins1Cre. The resultant Ins1CreZnT8KO mice displayed significant (P < .05) impairments in glucose tolerance at 10 weeks of age vs littermate controls, and glucose-induced increases in circulating insulin were inhibited in vivo. Although insulin release from Ins1CreZnT8KO islets was normal, Zn(2+) release was severely impaired. Conversely, transgenic ZnT8Tg mice, overexpressing the transporter inducibly in the adult beta-cell using an insulin promoter-dependent Tet-On system, showed significant (P < .01) improvements in glucose tolerance compared with control animals. Glucose-induced insulin secretion from ZnT8Tg islets was severely impaired, whereas Zn(2+) release was significantly enhanced. Our findings demonstrate that glucose homeostasis in the mouse improves as beta-cell ZnT8 activity increases, and remarkably, these changes track Zn(2+) rather than insulin release in vitro. Activation of ZnT8 in beta-cells might therefore provide the basis of a novel approach to treating T2D. PMID- 26584160 TI - A high-throughput mechanofluidic screening platform for investigating tumor cell adhesion during metastasis. AB - The metastatic spread of cancer is a major barrier to effective and curative therapies for cancer. During metastasis, tumor cells intravasate into the vascular system, survive in the shear forces and immunological environment of the circulation, and then extravasate into secondary tumor sites. Biophysical forces are potent regulators of cancer biology and are key in many of the steps of metastasis. In particular, the adhesion of circulating cells is highly dependent upon competing forces between cell adhesion receptors and the shear stresses due to fluid flow. Conventional in vitro assays for drug development and the mechanistic study of metastasis are often carried out in the absence of fluidic forces and, consequently, are poorly representative of the true biology of metastasis. Here, we present a novel high-throughput approach to studying cell adhesion under flow that uses a multi-well, mechanofluidic flow system to interrogate adhesion of cancer cell to endothelial cells, extracellular matrix and platelets under physiological shear stresses. We use this system to identify pathways and compounds that can potentially be used to inhibit cancer adhesion under flow by screening anti-inflammatory compounds, integrin inhibitors and a kinase inhibitor library. In particular, we identify several small molecule inhibitors of FLT-3 and AKT that are potent inhibitors of cancer cell adhesion to endothelial cells and platelets under flow. In addition, we found that many kinase inhibitors lead to increased adhesion of cancer cells in flow-based but not static assays. This finding suggests that even compounds that reduce cell proliferation might also enhance cancer cell adhesion during metastasis. Overall, our results validate a novel platform for investigating the mechanisms of cell adhesion under biophysical flow conditions and identify several potential inhibitors of cancer cell adhesion during metastasis. PMID- 26584162 TI - 2,4,6-Triphenylphosphinine and 2,4,6-triphenylposphabarrelene revisited: synthesis, reactivity and coordination chemistry. AB - The synthesis of 2,4,6-triphenylphosphinine has been revisited and a general protocol for the preparation of such low-coordinate phosphorus compounds in good to excellent yields could be established. This allows to investigate several aspects of the chemistry of 2,4,6-triarylphosphinine, such as the reaction with in situ generated benzyne to give 2,4,6-triphenylphosphabarrelene. The corresponding 2,4,6-triphenylphosphabarrelene-selenide could be characterized crystallographically for the first time and the structural and electronic properties of this cage-compound in comparison to classical triarylphosphines could be evaluated. Moreover, [(L)W(CO)5)] complexes of both 2,4,6 triphenylphosphinine and 2,4,6-triphenylphosphabarrelene were prepared and characterized by means of X-ray crystallography. This allowed for the first time a direct structural comparison of these related phosphorus compounds, coordinated to the same metal fragment. PMID- 26584161 TI - The Impact of Feet Callosities, Arm Posture, and Usage of Electrolyte Wipes on Body Composition by Bioelectrical Impedance Analysis in Morbidly Obese Adults. AB - OBJECTIVE: This study evaluated the impact of feet callosities, arm posture, and use of electrolyte wipes on body composition measurements by bioelectrical impedance analysis (BIA) in morbidly obese adults. METHODS: 36 morbidly obese patients (13 males, aged 28-70 years, BMI 41.6 +/- 4.3 kg/m2) with moderate/severe feet callosities participated in this study. Body composition (percent body fat (%BF)) was measured while fasting using multi-frequency BIA (InBody 720(r)), before and after removal of callosities, with and without InBody(r) electrolyte wipes and custom-built auxiliary pads (to assess arm posture impact). Results from BIA were compared to air displacement plethysmography (ADP, BodPod(r)). RESULTS: Median %BF was significantly higher with auxiliary pads than without (50.1 (interquartile range 8.2) vs. 49.3 (interquartile range 9.1); p < 0.001), while no differences were found with callosity removal (49.3 (interquartile range 9.1) vs. 50.0 (interquartile range 7.9); NS) or use of wipes (49.6 (interquartile range 8.5) vs. 49.3 (interquartile range 9.1); NS). No differences in %BF were found between BIA and ADP (49.1 (IQR: 8.9) vs. 49.3 (IQR: 9.1); NS). CONCLUSION: Arm posture has a significant impact on %BF assessed by BIA, contrary to the presence of feet callosities and use of electrolyte wipes. Arm posture standardization during BIA for body composition assessment is, therefore, recommended. PMID- 26584163 TI - Millennium development goals to sustainable development goals: Journey continues for a better world. PMID- 26584164 TI - Pattern and reasons for substance use among long-distance commercial drivers in a Nigerian city. AB - OBJECTIVE: To determine the pattern and reasons for psychoactive substance use by long-distance commercial vehicle drivers in a Nigerian city. MATERIALS AND METHODS: All licensed long-distance commercial vehicle drivers who travel a distance of at least 500 km from the city metropolis were recruited. Each fourth consecutive driver who was to load his vehicle for the day was interviewed at the 10 long-distance motor parks. They responded to a sociodemographic and semi structured pro forma requesting the type of drug used and the reason and pattern of use. The data obtained were analyzed by means of descriptive statistics using the statistical package for social sciences (SPSS) version 16. RESULTS: All the respondents were males with a mean age of 43.4 years. There was no statistically significant difference between the mean age of substance users and nonusers (t = 0.491, P = 0.853). The reasons given for drug use were to keep awake while driving, for pleasure, as part of the culture, peer influence, as a substitute for food and for no obvious reason. The pattern of use tended to be related to the reason given for the use. CONCLUSION: The reason for drug use in long distance drivers could be used to modify the pattern of use to minimize the risk associated with drugged driving. PMID- 26584165 TI - Appraisal of maternity management and family planning guidelines using the agree II instrument in India. AB - INTRODUCTION: Guideline development gathered pace in India after the inception of National Rural Health Mission (NRHM) in 2005. However, there is a lack of adequate information about guideline development process, review, and update. This paper reports on the systematic appraisal of Indian guidelines related to maternity management (MM) and family planning (FP) using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument, which was one of the components of a pilot research in 2012-13. MATERIALS AND METHODS: Forty-four selected guidelines about MM and FP, identified through a consensus building workshop, were independently appraised by two appraisers with AGREE instrument having six different domains. Mean item scores, domain scores, and standardized scores were calculated by averaging the scores across the two appraisers. RESULTS: Most guidelines scored high in scope and purpose and clarity of presentation. However, they had little documentation about the development group member details, incorporation of patient views, evidence search method, method chosen for formulating recommendations, tools for application, potential barriers, cost implications, and information about the funding body. Nonclinical guidelines scored higher than clinical guidelines (P = 0.01) for MM in the domain applicability. Clinical FP guidelines scored higher than nonclinical guidelines in the domain of rigor of development (0.01). CONCLUSION: Despite being clinically sound, Indian guidelines score poorly due to weak documentation about their development process. It is recommended that the guideline development process be improved with systematic documentation for achieving standardization. PMID- 26584166 TI - Assessment of validity and reliability of Hindi version of geriatric oral health assessment index (GOHAI) in Indian population. AB - OBJECTIVE: The objective of this study was to translate the Geriatric Oral Health Assessment Index (GOHAI) into the Hindi language and assess its validity and reliability for use among people in India. MATERIALS AND METHODS: GOHAI was translated into the Hindi language and self-administered to 420 subjects aged 55 years or above. The measures for reliability, and concurrent, convergent, and discriminant validity were assessed. The questionnaire sought information about sociodemographic details, habits related to tobacco, dental visits, tooth brushing, and self-reported perceptions of general and oral health. RESULTS: Cronbach's alpha (0.774) showed high internal consistency and homogeneity between items. Low GOHAI scores were associated with the perceptions of poor oral and general health, low satisfaction with oral health, and a perceived need for dental care. Respondents with high socioeconomic status were likely to have high GOHAI scores. CONCLUSION: The Hindi version of the GOHAI demonstrated acceptable validity and reliability, and will be an important instrument to measure oral health-related quality of life (OHRQoL) for people in this region. PMID- 26584167 TI - Does Janani Shishu Suraksha Karyakram ensure cost-free institutional delivery? A cross-sectional study in rural Bankura of West Bengal, India. AB - BACKGROUND: Janani Shishu Suraksha Karyakram (JSSK) was launched in India to ensure cost-free institutional delivery. OBJECTIVES: 1) To assess the awareness of recently delivered women regarding JSSK 2) To estimate the cost of institutional delivery and its differentials. MATERIALS AND METHODS: A community based, cross-sectional study was conducted in a rural community in Bankura, West Bengal, India in 2013, among 210 women who delivered babies in the last 12 months. Information regarding sociodemographic and health service-related variables as well as item-wise costs incurred for institutional delivery were collected. Costs were expressed in Indian National Rupee (INR). A nonparametric, bivariate analysis was performed to examine the difference in median cost. RESULTS: All components of JSSK were known to 12.9% women; the highest (77.1%) for admission and lowest (29.0%) for blood transfusion. The median (+/-IQR) costs of delivery in the Block level Primary Health Center (PHC), medical college, and private facilities were INR 205.0 (+/-825.0), 900.0 (+/-1013.0), and 6600.0 (+/ 16195.0), respectively. Median cost of normal delivery in a private facility (INR 2750.0) was 3.6 times of that in a government facility (INR 765.0). Median direct cost of caesarian section (CS) in a government facility (INR 1100.0) was nearly one-fifteenth of that in a private facility (INR 16,350.0). Cash incentives under Janani Suraksha Yojana for poor and socially marginalized women could not cover the cost of CS delivery in a government facility. CONCLUSION: Gaps existed in the awareness of beneficiaries regarding entitlement under JSSK. Drugs and transport were two major causes of out-of-pocket (OOP) expenditure in public health facilities. PMID- 26584168 TI - A surveillance model for sexually transmitted infections in India. AB - The strategy for prevention and control of sexually transmitted infections (STIs) in India is based on syndromic case management delivered through designated STI/reproductive tract infection (RTI) centers (DSRCs) situated in medical colleges, district hospitals, and STI-clinics of targeted interventions programs. Laboratory tests for enhanced syndromic management are available at some sites. To ensure country-level planning and effective local implementation of STI services, reliable and consistent epidemiologic information is required on the distribution of STI cases, rate and trends of newly acquired infections, and STI prevalence in specific population groups. The present STI management information system is inadequate to meet these requirements because it is based on syndromic data and limited laboratory investigations on STIs reported passively by DSRCs and laboratories. Geographically representative information on the etiology of STI syndromes and antimicrobial susceptibility of STI pathogens although essential for optimizing available treatment options, is deficient. Surveillance must provide high quality information on: (a) prevalence of STIs such as syphilis, trichomoniasis, gonorrhea, and chlamydia among high-risk groups; syphilis in the general population and pregnant antenatal women; (b) demographic characteristics such as age, sex, new/recurrent episode, and type of syndromically diagnosed STI cases; (c) proportion of acute infections such as urethral discharge (UD) in men and nonherpetic genital ulcer disease (GUD) in men and women; (d) etiology of STI syndromes; and (e) gonococcal antimicrobial susceptibility. We describe here a framework for an STI sentinel surveillance system in India, building on the existing STI reporting systems and infrastructure, an overview of the components of the proposed surveillance system, and operational challenges in its implementation. PMID- 26584169 TI - Environmental arsenic toxicity in West Bengal, India: A brief policy review. AB - High-level arsenic contamination of drinking water in West Bengal (WB), India is a grave public health concern, with 26 million people remaining affected. Two decades of research has provided detailed information on multiple aspects of exposure assessment and risk characterization. However, policy paralysis due to lack of finances and lack of any administrative coordination between the Central and State Governments has hampered the implementation of long-term solutions. Household- and community-level arsenic removal units have provided some relief to the suffering population. In view of the increased funding through the 12th Five Year Plan period, it is the responsibility of the authorities to implement piped water supply schemes with single-point treatment facilities as the permanent solution to this three-decade-long crisis. Incorporating research evidence into policy and focusing on behavior change communication would be crucial to that end. PMID- 26584170 TI - Microbial evaluation of bottled water marketed in North India. AB - Drinking unsafe and unhygienic water can cause waterborne diseases such as diarrhea and typhoid. The present study describes the microbial evaluation of bottled water sold in North India. The samples were analyzed for total viable count and coliforms and susceptibility to different antibiotics. Though free of coliforms, the samples had a total viable count ranging from 0.01 * 10 (1) cfu/mL to 2.40 * 10 (3) cfu/mL and in 17% of the samples, total viable count was much higher than specified by the Bureau of Indian Standards (BIS), Government of India. Among the samples, 6.5% also showed fungal growth. On checking the sensitivity of bacteria isolates to different antibiotics, most of the strains were found to be resistant to a number of antibiotics. It can thus be concluded that the consumption of bottled water with a high viable count and that was bacteria-resistant to different antibiotics may have an effect on the health of the consumers, especially immune-compromised individuals. PMID- 26584171 TI - Suspected anthrax outbreak: Investigation in a rural block of west Bengal and public health response. AB - Anthrax is one of the top 10 diseases reported in India and also one of the major causes of death in livestock. This study was conducted to confirm the outbreak of suspected anthrax, determine the transmission mechanism, and implement control measures in Bhatar block of Burdwan district, West Bengal, India. A cross sectional descriptive study was conducted through house-to-house visits in Oregram and Kathaldanga villages during the period from May 30, 2013 to June 8, 2013. Out of the 93 persons exposed to anthrax, 11 persons had history of slaughtering, while 82 consumed the meat. All of the 7 cases of suspected anthrax were male (mean age 41.14 +/- 10.04 years) and involved in slaughtering the animal. Most cases presented with papule and vesicle over the upper extremity and the trunk. One patient among the suspected cases died. The outbreak was labeled as a suspected anthrax outbreak. A health awareness camp was organized to improve awareness of anthrax among villagers. PMID- 26584172 TI - A study of HIV-concordant and -discordant couples attending voluntary counselling and testing services at a tertiary care center in North India. AB - A large number of Indian couples are exposed to the risk of heterosexual human immunodeficiency virus (HIV) transmission. The present records-based study was undertaken at the voluntary counselling and testing facility of a tertiary care hospital in New Delhi, India to determine HIV prevalence among Indian couples; to assess the magnitude of seroconcordance and discordance among HIV-affected couples; and to compare the concordant and discordant partnerships for sociodemographic determinants and cluster of differentiation 4 (CD4) counts. Of the 1309 couples included in the study, 249 (19%) were HIV-affected, and of them 113 (45.4%) were concordantly and 136 (54.6%) discordantly affected by HIV. Males were the HIV-infected partners in 72% of the serodiscordant partnerships analyzed. Seroconcordance was significantly associated with the occupation status of being a housewife (P = 0.009). The contribution of discordant partnerships to the burden of HIV/acquired immune deficiency syndrome (AIDS) is significant, warranting novel couple-targeted counselling strategies and preventive measures, including safe sexual behavior and possibly preexposure HIV prophylaxis of the uninfected partner. PMID- 26584173 TI - Assessment and determinants of emotional intelligence and perceived stress among students of a medical college in south India. AB - Emotional intelligence (EI) is the ability to identify, assess, and control the emotions of oneself, of others, and of groups. Stress resulting from having to meet professional demands is common in the medical student's life. The perceived stress (PS) can be either an input or an outflow of EI or the lack thereof. This study was done to assess EI levels and to find out its association with sociodemographic variables and PS among medical students. Data were collected using a self-administered questionnaire from 198 first-year and 208 second-year medical students. EI scores were found to increase with age (r = 0.169, P = 0.004). PS scores were found to be higher among first-year students (P = 0.05). PS scores were found to decrease with increase in EI scores (r = -0.226, P < 0.001). Hence, if sufficient measures to improve EI are provided in the beginning, it would make students more stress-free during their training years at medical schools. PMID- 26584174 TI - Prevalence of iodine deficiency among adult population residing in Rural Ballabgarh, district Faridabad, Haryana. AB - Community-based surveys are essential to monitor iodine deficiency disorders (IDD) program at both the state and national levels. There is paucity of information on population iodine nutrition status in Haryana state using standard methods. A cross-sectional study was conducted in villages of Comprehensive Rural Health Services Project (CRHSP), Ballabgarh, Haryana, India. A total of 465 randomly selected individuals were assessed for urinary iodine concentration (UIC) by microplate method and household salt iodine content using iodometric titration. Of the interviewed households, 73% were using adequately iodized salt (>=15 ppm). Iodine nutrition was deficient in 17% respondents (UIC <100 MUg/L); 20.2% among males and 13.9% among females. Iodine intake of the study population as measured by UIC was adequate but nearly one-fourth of households in the study population were consuming inadequately iodized salt. The availability and access to adequately iodized salt in the study population should be improved by strengthening regulatory monitoring. PMID- 26584175 TI - Perception of sex workers of Lucknow City, Uttar Pradesh, India towards sexually transmitted infections. AB - The prevention, control, and management of sexually transmitted infections/reproductive tract infection (STI/RTI) are well-recognized cost effective strategies for controlling the spread of human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS). A cross-sectional descriptive study was done over a period of 1 year to assess the prevalence of STI, knowledge level about STI, and the STI-HIV link among the female sex workers (FSWs) of Lucknow city, Uttar Pradesh, India along with their biosocial characteristics. Most of the FSWs were illiterate, married, Hindus, and belonged to general category. The prevalence rates of STI among street-based and home based FSWs were 50.6% and 29.8%, respectively. Knowledge about the role of condom in prevention of STI and the STI-HIV link was significantly less among home-based FSWs than those who are street-based. There is a great lack in the awareness among FSWs regarding STI and their prevention. Behavior change communication (BCC) and advocacy strategy were developed, especially for the home-based group, to strengthen their knowledge regarding the STI-HIV link. PMID- 26584176 TI - Cell Phones and SAR Value. PMID- 26584177 TI - Mobile phones: Time to rethink and limit usage. PMID- 26584178 TI - Publish or perish: Are indians catching up? PMID- 26584179 TI - Comment on: Prevalence of depression and associated risk factors among the elderly in urban and rural field practice areas of a tertiary care institution in Ludhiana. PMID- 26584180 TI - Demographic Trends of Adults in New York City Opioid Treatment Programs--An Aging Population. AB - BACKGROUND: The population of adults accessing opioid treatment is growing older, but exact estimates vary widely, and little is known about the characteristics of the aging treatment population. Further, there has been little research regarding the epidemiology, healt h status, and functional impairments in this population. OBJECTIVES: To determine the utilization of opioid treatment services by older adults in New York City. METHODS: This study used administrative data from New York State licensed drug treatment programs to examine overall age trends and characteristics of older adults in opioid treatment programs in New York City from 1996 to 2012. RESULTS: We found significant increases in utilization of opioid treatment programs by older adults in New York City. By 2012, those aged 50-59 made up the largest age group in opioid treatment programs. Among older adults there were notable shifts in demographic background including gender and ethnicity, and an increase in self-reported impairments. CONCLUSIONS/IMPORTANCE: More research is needed to fully understand the specific characteristics and needs of older adults with opioid dependence. PMID- 26584181 TI - Is It Possible to Perform Less Radical Surgery for Invasive Uterine Cervical Cancer? AB - BACKGROUND/AIMS: A retrospective analysis was performed to evaluate the possibility of less radical surgery for early-stage invasive uterine cervical cancer without compromising the oncological outcome. METHODS: The analysis was performed on 175 patients with invasive uterine cervical cancer in FIGO stage IA2 IIB, all of whom underwent primary radical hysterectomy. Relationship of tumor size with the incidence of pathologic parametrial involvement and the pelvic lymph node metastasis were investigated. RESULTS: Fifty-one patients had tumor size <=2 cm and 124 had tumor size >2 cm. Patients with tumor size <=2 cm had a significantly lower incidence of parametrial invasion (p < 0.0001), lymph node metastasis (p < 0.0001), lymph vascular space involvement (p < 0.0001) and recurrence (p = 0.0002) than patients with tumor size >2 cm. Five-year relapse free survival rate was 98 and 73%, respectively (p = 0.0004). CONCLUSION: It is suggested that less radical surgery may be appropriate for some cases with tumor size <2 cm. PMID- 26584182 TI - Regulation of Early Steps of GPVI Signal Transduction by Phosphatases: A Systems Biology Approach. AB - We present a data-driven mathematical model of a key initiating step in platelet activation, a central process in the prevention of bleeding following Injury. In vascular disease, this process is activated inappropriately and causes thrombosis, heart attacks and stroke. The collagen receptor GPVI is the primary trigger for platelet activation at sites of injury. Understanding the complex molecular mechanisms initiated by this receptor is important for development of more effective antithrombotic medicines. In this work we developed a series of nonlinear ordinary differential equation models that are direct representations of biological hypotheses surrounding the initial steps in GPVI-stimulated signal transduction. At each stage model simulations were compared to our own quantitative, high-temporal experimental data that guides further experimental design, data collection and model refinement. Much is known about the linear forward reactions within platelet signalling pathways but knowledge of the roles of putative reverse reactions are poorly understood. An initial model, that includes a simple constitutively active phosphatase, was unable to explain experimental data. Model revisions, incorporating a complex pathway of interactions (and specifically the phosphatase TULA-2), provided a good description of the experimental data both based on observations of phosphorylation in samples from one donor and in those of a wider population. Our model was used to investigate the levels of proteins involved in regulating the pathway and the effect of low GPVI levels that have been associated with disease. Results indicate a clear separation in healthy and GPVI deficient states in respect of the signalling cascade dynamics associated with Syk tyrosine phosphorylation and activation. Our approach reveals the central importance of this negative feedback pathway that results in the temporal regulation of a specific class of protein tyrosine phosphatases in controlling the rate, and therefore extent, of GPVI-stimulated platelet activation. PMID- 26584183 TI - Three-dimensional multilayered fibrous constructs for wound healing applications. AB - Electrospun materials are promising scaffolds due to their light-weight, high surface-area and low-cost fabrication, however, such scaffolds are commonly obtained as ultrathin two-dimensional non-woven meshes, lacking on topographical specificity and surface side-dependent properties. Herein, it is reported the production of three-dimensional fibrous materials with an asymmetrical inner structure and engineered surfaces. The manufactured constructs evidence fibrous based microsized conical protrusions [length: (10 +/- 3) * 10(2) MUm; width: (3.8 +/- 0.8) * 10(2) MUm] at their top side, with a median peak density of 73 peaks per cm(2), while their bottom side resembles to a non-woven mesh commonly observed in the fabrication of two-dimensional electrospun materials. Regarding their thickness (3.7 +/- 0.1 mm) and asymmetric fibrous inner architecture, such materials avoid external liquid absorption while promoting internal liquid uptake. Nevertheless, such constructs also observed the high porosity (89.9%) and surface area (1.44 m(2) g(-1)) characteristic of traditional electrospun mats. Spray layer-by-layer assembly is used to effectively coat the structurally complex materials, allowing to complementary tailor features such as water vapor transmission, swelling ratio and bioactive agent release. Tested as wound dressings, the novel constructs are capable of withstanding (11.0 +/- 0.3) * 10(4) kg m(-2) even after 14 days of hydration, while actively promote wound healing (90 +/- 0.5% of wound closure within 48 hours) although avoiding cell adhesion on the dressings for a painless removal. PMID- 26584184 TI - Worse Comes to Worst: Bananas and Panama Disease--When Plant and Pathogen Clones Meet. PMID- 26584185 TI - Porcine Deltacoronavirus in Mainland China. PMID- 26584186 TI - Correction: Mutation of the Diamond-Blackfan Anemia Gene Rps7 in Mouse Results in Morphological and Neuroanatomical Phenotypes. PMID- 26584187 TI - Italian Registry of Complications associated with Regional Anesthesia (RICALOR). An incidence analysis from a prospective clinical survey. AB - BACKGROUND: Regional anesthesia (RA) is associated with many advantages, but side effects also occur. Several registries were developed to investigate such complications in many countries, which produced conflicting results. In consideration of the ongoing evolution and improvements in RA, and its widespread diffusion in Italy in the last decade (with increasing experience by anesthesiologists), a reappraisal of the incidence and the characteristics of major complications are useful to improve patient's safety. METHODS: A web-based prospective registry was developed in Italy with: 1) quarterly report of total anesthetic acts and RA procedures performed; and 2) voluntary registration of complications on dedicated forms. We evaluated incidence of complications, describing their characteristics and outcomes. RESULTS: Participants (N.=17 hospitals) registered 117,182 procedures, including 63,692 with RA (54.3%, both as primary anesthetic technique and for postoperative analgesia). A total of 34,147 neuraxial blocks (4954 epidurals/CSE, 29,193 subarachnoid blocks) and 29,545 peripheral (single shot and continuous) blocks were registered. Total incidence of complication was 4.6/10.000; incidence was 4.1/10,000 for central blocks and 5.1/10,000 for peripheral blocks, long-term neurologic deficit (at 6 months) was observed after an epidural abscess, while other complications did not lead to any long-term adverse outcomes. No hemorrhagic events or other infections have occurred. Incidence of major complications was 0.07/1000, while minor complications presented in 0.38/1000 cases. CONCLUSIONS: We confirmed RA as generally safe, but monitoring and diagnosis, together with further research efforts, are needed to improve patients' care and clarify potential risk factors. PMID- 26584188 TI - Spinal epidural abscess: stay focused, stay tuned! A clinical report with negative neurological outcome from the "Italian Registry of Complications Associated with Regional Anesthesia - RICALOR". PMID- 26584189 TI - The impact of patient-controlled analgesia on prognosis of patients receiving major abdominal surgery. AB - BACKGROUND: Postoperative pain is a major disease burden after surgery. Patient controlled analgesia has been wide used for pain management in surgical patients, yet, large-scaled studies are lacking to assess its impact on the prognosis of patients. METHODS: We prospectively enrolled patients who underwent major abdominal surgeries receiving patient-controlled analgesia (PCA) and who received non-PCA for assessment of 60-day mortality, major postoperative complications using electronic medical chart system. Pain intensity was also assessed with visual analogue scale from postoperative day 1 to day 7, chronic post-surgical pain was assessed by telephone follow-up using numerical rating scale. RESULTS: In total, 12,015 patients were included in the primary analysis. At the end of the follow-up, 1185 patients were lost to follow-up. Patients in the non-PCA group reported increased incidence of moderate-to-severe pain on postoperative day 3 (6.5% versus 9.6%, P<0.001). Patients receiving non-PCA had increased mortalities on postoperative 60-day (1.02% versus 0.47%, P<0.001). The survival probability of patients in PCA group was statistically higher than those in non PCA group (99.52% [95% CI: 99.34-99.70%] versus 98.97% [95% CI: 98.73-99.92%]). Patient receiving non-PCA reported increased in-hospital major complications compared with (2.7% versus 1.9 %, P=0.003). Pain intensity was also assessed with visual analogue scale from postoperative day 1 to day 7, chronic post-surgical pain was assessed by telephone follow-up using numerical rating scale. CONCLUSIONS: Intravenous patient-controlled analgesia was related to improved survival, less complications and chronic post-surgical pain after major abdominal surgery, reiterating the important role of pain management for the prognosis of patients who underwent surgery. PMID- 26584190 TI - Organ donation after circulatory death in Italy? Yes we can! PMID- 26584191 TI - Failure of Noninvasive Ventilation for De Novo Acute Hypoxemic Respiratory Failure: Role of Tidal Volume. AB - OBJECTIVES: A low or moderate expired tidal volume can be difficult to achieve during noninvasive ventilation for de novo acute hypoxemic respiratory failure (i.e., not due to exacerbation of chronic lung disease or cardiac failure). We assessed expired tidal volume and its association with noninvasive ventilation outcome. DESIGN: Prospective observational study. SETTING: Twenty-four bed university medical ICU. PATIENTS: Consecutive patients receiving noninvasive ventilation for acute hypoxemic respiratory failure between August 2010 and February 2013. INTERVENTIONS: Noninvasive ventilation was uniformly delivered using a simple algorithm targeting the expired tidal volume between 6 and 8 mL/kg of predicted body weight. MEASUREMENTS: Expired tidal volume was averaged and respiratory and hemodynamic variables were systematically recorded at each noninvasive ventilation session. MAIN RESULTS: Sixty-two patients were enrolled, including 47 meeting criteria for acute respiratory distress syndrome, and 32 failed noninvasive ventilation (51%). Pneumonia (n = 51, 82%) was the main etiology of acute hypoxemic respiratory failure. The median (interquartile range) expired tidal volume averaged over all noninvasive ventilation sessions (mean expired tidal volume) was 9.8 mL/kg predicted body weight (8.1-11.1 mL/kg predicted body weight). The mean expired tidal volume was significantly higher in patients who failed noninvasive ventilation as compared with those who succeeded (10.6 mL/kg predicted body weight [9.6-12.0] vs 8.5 mL/kg predicted body weight [7.6-10.2]; p = 0.001), and expired tidal volume was independently associated with noninvasive ventilation failure in multivariate analysis. This effect was mainly driven by patients with PaO2/FIO2 up to 200 mm Hg. In these patients, the expired tidal volume above 9.5 mL/kg predicted body weight predicted noninvasive ventilation failure with a sensitivity of 82% and a specificity of 87%. CONCLUSIONS: A low expired tidal volume is almost impossible to achieve in the majority of patients receiving noninvasive ventilation for de novo acute hypoxemic respiratory failure, and a high expired tidal volume is independently associated with noninvasive ventilation failure. In patients with moderate-to severe hypoxemia, the expired tidal volume above 9.5 mL/kg predicted body weight accurately predicts noninvasive ventilation failure. PMID- 26584192 TI - Does Thrombolysis Have a Place in the Cardiopulmonary Resuscitation of Patients With Acute Pulmonary Embolism? A Case of Successful Thrombolysis During Pulmonary Embolism Induced Cardiopulmonary Arrest. AB - OBJECTIVE: Pulmonary embolism often causes cardiac arrest. When this occurs, thrombolytic therapy is not routinely administered. There are multiple reasons for this, including difficulty with rapidly adequately diagnosing the embolus, the lack of good data supporting the use of thrombolytics during resuscitation, the belief that thrombolytic therapy is ineffective once a patient has already arrested, the difficulty of obtaining thrombolytics at the bedside rapidly enough to administer during a code, and the increased risks of bleeding, particularly with ongoing chest compressions. In this case report, we present a patient who was successfully treated with thrombolytic therapy during pulmonary embolism induced cardiopulmonary arrest and discuss the role of thrombolytics in cardiopulmonary resuscitation. DESIGN: Case report. SETTING: Surgical ICU in a comprehensive cancer center. PATIENT: A 56-year-old man who developed hypotension, dyspnea, hypoxia, and pulseless electrical activity 10 days after resection of a benign colon lesion with a right hemicolectomy and primary end-to end anastomosis. INTERVENTIONS: After a rapid bedside echocardiogram suggesting pulmonary embolus, thrombolytic therapy was administered during cardiopulmonary resuscitative efforts. MEASUREMENTS AND MAIN RESULTS: The patient had a return of spontaneous circulation and showed improvement in repeat echocardiographic imaging. He had a prolonged course in the ICU and hospital, but eventually made an essentially complete clinical recovery. CONCLUSION: As bedside echocardiographic technology becomes more rapidly and readily available, the rapid diagnosis of pulmonary embolism and use of thrombolytics during cardiopulmonary resuscitation may need to be more routinely considered a potential therapeutic adjunctive measure. PMID- 26584193 TI - Excellence in Intensive Care Medicine. AB - OBJECTIVE: Excellence is an important goal for all physicians. Unfortunately, it is hard to define, evaluate, and achieve. To provide a concise interpretive review of excellence in intensive care medicine, with a focus on those key characteristics that excellent physicians possess but are seldom discussed. DATA SOURCES: Electronic search of the PubMed database using the search terms "excellence," "role models," "compassion," "commitment," "dedication," and "passion." STUDY SELECTION: Publications or studies of excellence, role models, compassion, commitment, dedication, and passion. Two reviewers evaluated each term. DATA EXTRACTION: Publications or studies were abstracted independently and in duplicate. DATA SYNTHESIS: Excellence in critical care can be achieved through deliberate practice, feedback, and effective evaluation. Excellence embodies numerous characteristics, which include compassion, commitment, and passion. CONCLUSIONS: Awareness of the fundamental characteristics of excellence can help young students and doctors determine what they should strive for to become excellent physicians as well as encourage experienced doctors to rekindle the spark that initially motivated them to become physicians. PMID- 26584194 TI - Effects and Mechanisms by Which Hypercapnic Acidosis Inhibits Sepsis-Induced Canonical Nuclear Factor-kappaB Signaling in the Lung. AB - OBJECTIVE: Diverse effects of hypercapnic acidosis are mediated via inhibition of nuclear factor-kappaB, a pivotal transcription factor, in the setting of injury, inflammation, and repair, but the underlying mechanisms of action of hypercapnic acidosis on this pathway is unclear. We aim to examine the effect of hypercapnic acidosis on the nuclear factor-kappaB pathway in the setting of Escherichia coli induced lung injury and characterize the underlying mechanisms in subsequent in vitro studies. DESIGN: In vivo animal study and subsequent in vitro studies. SETTING: University Research Laboratory. SUBJECTS: Adult male Sprague-Dawley rats and pulmonary epithelial cells. INTERVENTIONS: Following pulmonary IkappaBalpha SuperRepressor transgene overexpression or sham and intratracheal E. coli inoculation, rats underwent 4 hours of mechanical ventilation under normocapnia or hypercapnic acidosis, and nuclear factor-kappaB activation, animal survival, lung injury, and cytokine profile were assessed. Subsequent in vitro studies examined the effect of hypercapnic acidosis on specific nuclear factor-kappaB canonical pathway kinases via overexpression of these components and in vitro kinase activity assays. The effect of hypercapnic acidosis on the p50/p65 nuclear factor-kappaB heterodimer was then assessed. MEASUREMENTS AND MAIN RESULTS: Hypercapnic acidosis and IkappaBalpha-SuperRepressor transgene overexpression reduced E. coli-induced lung inflammation and injury, decreased nuclear factor kappaB activity, and increased animal survival. Hypercapnic acidosis inhibited canonical nuclear factor-kappaB signaling via reduced phosphorylative activation, reducing IkappaB kinase-beta activation and intrinsic activity, thereby decreasing IkappaBalpha degradation, and subsequent nuclear factor-kappaB translocation. Hypercapnic acidosis also directly reduced DNA binding of the nuclear factor-kappaB p65 subunit, although this effect was less marked. CONCLUSIONS: Hypercapnic acidosis reduced E. coli inflammation and lung injury in vivo and reduced nuclear factor-kappaB activation predominantly by inhibiting the activation and intrinsic activity of IkappaB kinase-beta. PMID- 26584196 TI - Recruitment Maneuvers and Positive End-Expiratory Pressure Titration in Morbidly Obese ICU Patients. AB - OBJECTIVE: The approach to applying positive end-expiratory pressure in morbidly obese patients is not well defined. These patients frequently require prolonged mechanical ventilation, increasing the risk for failed liberation from ventilatory support. We hypothesized that lung recruitment maneuvers and titration of positive end-expiratory pressure were both necessary to improve lung volumes and the elastic properties of the lungs, leading to improved gas exchange. DESIGN: Prospective, crossover, nonrandomized interventional study. SETTING: Medical and surgical ICUs at Massachusetts General Hospital. PATIENTS: Critically ill, mechanically ventilated morbidly obese (body mass index > 35 kg/m(2)) patients (n = 14). INTERVENTIONS: This study evaluated two methods of titrating positive end-expiratory pressure; both trials were done utilizing positive end-expiratory pressure titration and recruitment maneuvers while measuring hemodynamics and respiratory mechanics. Measurements were obtained at the baseline positive end-expiratory pressure set by the clinicians, at zero positive end-expiratory pressure, at best positive end-expiratory pressure identified through esophageal pressure measurement before and after a recruitment maneuver, and at best positive end-expiratory pressure identified through a best decremental positive end-expiratory pressure trial. MEASUREMENTS AND MAIN RESULTS: The average body mass index was 50.7 +/- 16.0 kg/m(2). The two methods of evaluating positive end-expiratory pressure identified similar optimal positive end-expiratory pressure levels (20.7 +/- 4.0 vs 21.3 +/- 3.8 cm H2O; p = 0.40). End-expiratory pressure titration increased end-expiratory lung volumes (Delta11 +/- 7 mL/kg; p < 0.01) and oxygenation (Delta86 +/- 50 torr; p < 0.01) and decreased lung elastance (Delta5 +/- 5 cm H2O/L; p < 0.01). Recruitment maneuvers followed by titrated positive end-expiratory pressure were effective at increasing end-expiratory lung volumes while decreasing end-inspiratory transpulmonary pressure, suggesting an improved distribution of lung aeration and reduction of overdistension. The positive end-expiratory pressure levels set by the clinicians (11.6 +/- 2.9 cm H2O) were associated with lower lung volumes, worse elastic properties of the lung, and lower oxygenation. CONCLUSIONS: Commonly used positive end-expiratory pressure by clinicians is inadequate for optimal mechanical ventilation of morbidly obese patients. A recruitment maneuver followed by end-expiratory pressure titration was found to significantly improve lung volumes, respiratory system elastance, and oxygenation. PMID- 26584195 TI - Interleukin-1 Receptor Blockade Is Associated With Reduced Mortality in Sepsis Patients With Features of Macrophage Activation Syndrome: Reanalysis of a Prior Phase III Trial. AB - OBJECTIVE: To determine the efficacy of anakinra (recombinant interleukin-1 receptor antagonist) in improving 28-day survival in sepsis patients with features of macrophage activation syndrome. Despite equivocal results in sepsis trials, anakinra is effective in treating macrophage activation syndrome, a similar entity with fever, disseminated intravascular coagulation, hepatobiliary dysfunction, cytopenias, and hyperferritinemia. Hence, sepsis patients with macrophage activation syndrome features may benefit from interleukin-1 receptor blockade. DESIGN: Reanalysis of deidentified data from the phase III randomized interleukin-1 receptor antagonist trial in severe sepsis. SETTING: Multicenter study recruiting through 91 centers from 11 countries in Europe and North America. PATIENTS: Sepsis patients with multiorgan dysfunction syndrome and/or shock (original study) were regrouped based on the presence or the absence of concurrent hepatobiliary dysfunction and disseminated intravascular coagulation as features of macrophage activation syndrome. The non-hepatobiliary dysfunction/disseminated intravascular coagulation group included patients with only hepatobiliary dysfunction, only disseminated intravascular coagulation, or neither. INTERVENTION: Treatment with anakinra or placebo. MEASUREMENTS AND MAIN RESULTS: Main outcome was 28-day mortality. Descriptive and comparative statistics were performed. Data were available for 763 adults from the original study cohort, randomized to receive either anakinra or placebo. Concurrent hepatobiliary dysfunction/disseminated intravascular coagulation was noted in 43 patients (5.6% of total; 18-75 years old; 47% women). The 28-day survival was similar in both anakinra and placebo-treated non-hepatobiliary dysfunction/disseminated intravascular coagulation patients (71.4% vs 70.8%; p = 0.88). Treatment with anakinra was associated with significant improvement in the 28-day survival rate in hepatobiliary dysfunction/disseminated intravascular coagulation patients (65.4% anakinra vs 35.3% placebo), with hazard ratio for death 0.28 (0.11-0.71; p = 0.0071) for the treatment group in Cox regression. CONCLUSIONS: In this subgroup analysis, interleukin-1 receptor blockade was associated with significant improvement in survival of patients with sepsis and concurrent hepatobiliary dysfunction/disseminated intravascular coagulation. A prospective randomized trial using features of macrophage activation syndrome for mortality risk stratification should be undertaken to confirm the role of interleukin-1 blockage. PMID- 26584197 TI - Long-Term Outcome Following Tracheostomy in Critical Care: A Systematic Review. AB - OBJECTIVES: The prevalence and impact of longer-term outcomes following percutaneous tracheostomy, particularly tracheal stenosis, are unclear. Previous meta-analyses addressing this problem have been confounded by the low prevalence of tracheal stenosis and a limited number of studies. DESIGN: Embase, PubMed Medline, and the Cochrane Central Register of Clinical Trials were searched to identify all prospective studies of tracheostomy insertion in the critically ill. To reflect contemporary practice, the search was limited to studies published from 2000 onward. We scrutinized the bibliographies of returned studies for additional articles. Meta-analyses were undertaken to estimate the pooled risk difference of tracheal stenosis, bleeding, and wound infection comparing different techniques. MEASUREMENTS AND MAIN RESULTS: We identified a total of 463 studies, 29 (5,473 patients) of which met the inclusion criteria. Nine were randomized controlled trials, six were nonrandomized comparative studies, and 14 were single-arm cohort studies. Risk of wound infection was greater for the surgical tracheostomy than for the Ciaglia multiple dilator technique, pooled risk difference 0.12 (95% CI, 0.02-0.23). We did not identify significant risk differences in other meta-analyses. Pooling across all studies according to the random-effects proportion meta-analysis suggests a higher prevalence of tracheal stenosis, wound infection, and major bleeding for surgical tracheostomies. CONCLUSIONS: Considering comparative data, there was no significant difference in the prevalence of tracheal stenosis or major bleeding between percutaneous and surgical tracheostomy. In relation to wound infection, we have found a reduction associated with the original Ciaglia technique when compared with that with the surgical tracheostomy. Considering all published data reporting long-term outcomes pooled proportion meta-analysis indicates a trend toward a higher rate of tracheal stenosis and an increased risk of major bleeding and wound infection for surgical tracheostomies. This finding may be biased as a result of targeted patient selection, and further, high-quality long-term comparative data are needed to confirm these findings. PMID- 26584200 TI - Impact of Anemia and Transfusion on Readmission and Length of Stay After Spinal Surgery: A Single-center Study of 1187 Operations. AB - STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To determine whether receipt of blood transfusion and preoperative anemia are associated with increased rates of 30-day all-cause readmission, and secondarily with a prolonged hospital stay after spinal surgery. SUMMARY OF BACKGROUND DATA: Increased focus on health care quality has led to efforts to determine postsurgical readmission rates and predictors of length of postoperative hospital stay. Although there are still no defined outcome measures specific to spinal surgery to which providers are held accountable, efforts to identify appropriate measures and to determine modifiable risk factors to optimize quality are ongoing. METHODS: Records from 1187 consecutive spinal surgeries at Northwestern Memorial Hospital in 2010 were retrospectively reviewed and data were collected that described the patient, surgical procedure, hospital course, complications, and readmissions. Presence or absence of transfusion during the surgery and associated hospital course was treated as a binary variable. Multivariate negative binomial regression and logistic regression were used to model length of stay and readmission, respectively. RESULTS: Nearly one fifth (17.8%) of surgeries received transfusions, and the overall readmission rate was 6.1%. After controlling for potential confounders, we found that the presence of a transfusion was associated with a 60% longer hospital stay [adjusted incidence rate ratio=1.60 (1.34-1.91), P<0.001], but was not significantly associated with an increased rate of readmission [adjusted odds ratio=0.81 (0.39-1.70), P=0.582]. Any degree of preoperative anemia was associated with increased length of stay, but only severe anemia was associated with an increased rate of readmission. CONCLUSIONS: Both receipt of blood transfusion and any degree of preoperative anemia were associated with increased length of hospital stay after controlling for other variables. Severe anemia, but not receipt of blood transfusion, was associated with increased rate of readmission. Our findings may help define actions to reduce length of stay and decrease rates of readmission. PMID- 26584203 TI - Correction: Phase stability in nanoscale material systems: extension from bulk phase diagrams. AB - Correction for 'Phase stability in nanoscale material systems: extension from bulk phase diagrams' by Saurabh Bajaj et al., Nanoscale, 2015, 7, 9868-9877. PMID- 26584202 TI - New Osseodensification Implant Site Preparation Method to Increase Bone Density in Low-Density Bone: In Vivo Evaluation in Sheep. AB - PURPOSE: The aim of this study was to evaluate a new surgical technique for implant site preparation that could allow to enhance bone density, ridge width, and implant secondary stability. MATERIALS AND METHODS: The edges of the iliac crests of 2 sheep were exposed and ten 3.8 * 10-mm Dynamix implants (Cortex) were inserted in the left sides using the conventional drilling method (control group). Ten 5 * 10-mm Dynamix implants (Cortex) were inserted in the right sides (test group) using the osseodensification procedure (Versah). After 2 months of healing, the sheep were killed, and biomechanical and histological examinations were performed. RESULTS: No implant failures were observed after 2 months of healing. A significant increase of ridge width and bone volume percentage (%BV) (approximately 30% higher) was detected in the test group. Significantly better removal torque values and micromotion under lateral forces (value of actual micromotion) were recorded for the test group in respect with the control group. CONCLUSION: Osseodensification technique used in the present in vivo study was demonstrated to be able to increase the %BV around dental implants inserted in low-density bone in respect to conventional implant drilling techniques, which may play a role in enhancing implant stability and reduce micromotion. PMID- 26584204 TI - Dye-sensitised semiconductors modified with molecular catalysts for light-driven H2 production. AB - The development of synthetic systems for the conversion of solar energy into chemical fuels is a research goal that continues to attract growing interest owing to its potential to provide renewable and storable energy in the form of a 'solar fuel'. Dye-sensitised photocatalysis (DSP) with molecular catalysts is a relatively new approach to convert sunlight into a fuel such as H2 and is based on the self-assembly of a molecular dye and electrocatalyst on a semiconductor nanoparticle. DSP systems combine advantages of both homogenous and heterogeneous photocatalysis, with the molecular components providing an excellent platform for tuning activity and understanding performance at defined catalytic sites, whereas the semiconductor bridge ensures favourable multi-electron transfer kinetics between the dye and the fuel-forming electrocatalyst. In this tutorial review, strategies and challenges for the assembly of functional molecular DSP systems and experimental techniques for their evaluation are explained. Current understanding of the factors governing electron transfer across inorganic molecular interfaces is described and future directions and challenges for this field are outlined. PMID- 26584205 TI - Rapidly Appearing Sclerotic Vertebral Lesions in a Patient With an Infiltrative Mediastinal Mass. PMID- 26584206 TI - High-intensity interval training improves cardiovascular health, exercise capacity, and quality of life in permanent atrial fibrillation: a case study. AB - Persons with permanent atrial fibrillation experience reduced exercise tolerance, weight gain, and an associated decline in overall health. We report on a 74-year old man with permanent atrial fibrillation who underwent a 10-week high-intensity interval training program. Substantial improvements in heart rate, blood pressure, aerobic and functional capacity, and quality of life were observed. These are desirable as these patients are not candidates for other treatment options and more effective therapies for the treatment of atrial fibrillation are needed. PMID- 26584208 TI - Molecular design of electron transport with orbital rule: toward conductance decay free molecular junctions. AB - In this study, we report our viewpoint of single molecular conductance in terms of frontier orbitals. The orbital rule derived from orbital phase and amplitude is a powerful guideline for the qualitative understanding of molecular conductance in both theoretical and experimental studies. The essence of the orbital rule is the phase-related quantum interference, and on the basis of this rule a constructive or destructive pathway for electron transport is easily predicted. We have worked on the construction of the orbital rule for more than ten years and recently found from its application that pi-stacked molecular junctions fabricated experimentally are in line with the concept for conductance decay free junctions. We explain the orbital rule using benzene molecular junctions with the para-, meta- and ortho-connections and discuss linear pi conjugated chains and pi-stacked molecular junctions with respect to their small decay factors in this manuscript. PMID- 26584207 TI - Evaluating the effect of 20-hydroxyecdysone (20HE) on mechanistic target of rapamycin complex 1 (mTORC1) signaling in the skeletal muscle and liver of rats. AB - Phytoecdysteroids such as 20-hydroxyecdysone (20HE) are nutritional supplements marketed as enhancers of lean body mass. In this study the impact of 20HE ingestion on protein kinase B/Akt-mechanistic target of rapamycin complex 1 signaling in the skeletal muscle and liver of male rats was found to be limited. Bioavailability of 20HE, whether consumed alone or with leucine, also remained low at all doses ingested. Additional work is necessary to clarify 20HE mechanism of action in vivo. PMID- 26584209 TI - Chiral bifunctional ferrocenylphosphine catalyzed highly enantioselective [3 + 2] cycloaddition reaction. AB - A series of air-stable ferrocenylphosphines LB1-LB8 were designed and prepared in high yields. (R,SFc)-ferrocenylphosphine LB5 was found to efficiently promote the asymmetric [3 + 2] cycloaddition of Morita-Baylis-Hillman carbonates with maleimides to afford the corresponding bicyclic imides with 84-99% ee and 67-99% yield. Interestingly, the configuration of these products was contrary to those reported in the literature. PMID- 26584210 TI - The Royal College of Ophthalmologists' National Ophthalmology Database Study of Vitreoretinal Surgery: Report 6, Diabetic Vitrectomy. AB - IMPORTANCE: Patients and clinicians need to accurately assess the risks and benefits of pars plana vitrectomy for proliferative diabetic retinopathy, but clinical trial data may not reflect real-world experience. OBJECTIVE: To prospectively audit the complications of vitrectomy for proliferative diabetic retinopathy and help establish benchmarks. DESIGN, SETTING, AND PARTICIPANTS: Royal College of Ophthalmologists' National Ophthalmology Database study of 939 eyes of 834 patients undergoing primary vitrectomy for proliferative diabetic retinopathy at 16 different vitreoretinal units in the United Kingdom. Data were obtained for the period from January 2001 to November 2010. INTERVENTIONS: Pars plana vitrectomy with or without delamination/segmentation. MAIN OUTCOMES AND MEASURES: Descriptions of the primary procedures performed, intraoperative complication rate, and proportion of eyes undergoing further surgery. An exploratory analysis of visual outcome was undertaken, with visual success and visual loss defined as a gain or reduction of 0.3 logMAR or more, respectively (approximately 2 Snellen lines), 6 to 12 months after surgery. RESULTS: Of 420 eyes (among 408 patients) that underwent vitrectomy without delamination, the intraoperative complication rate was 13.1% (95% CI, 10.2%-16.7% [55 of 420 eyes]), with 126 eyes (30.0%) requiring an intravitreal tamponade and 49 eyes (11.7%) undergoing further vitrectomy (median follow-up, 6.9 months); 17.9% of 127 phakic eyes developed cataracts within a year, with 63.6% achieving visual success and 8.2% visual loss. Of 519 eyes (among 463 patients) that underwent vitrectomy with delamination, the intraoperative complication rate was 30.4% (95% CI, 26.6%-34.5% [158 of 519 eyes]), with 299 eyes (57.6%) requiring an intravitreal tamponade and 78 eyes (15.0%) undergoing further vitrectomy (median follow-up, 7.1 months); 21.2% of 126 phakic eyes developed cataracts within a year, with 62.8% achieving visual success and 14.9% visual loss. CONCLUSIONS AND RELEVANCE: Diabetic vitrectomy has an appreciable complication rate, particularly if delamination or segmentation are required. Nonetheless, the data available on visual acuity suggest that a majority of patients achieve clinically meaningful gains in vision. PMID- 26584211 TI - Alive SMC(2) : Bayesian model selection for low-count time series models with intractable likelihoods. AB - In this article we present a new method for performing Bayesian parameter inference and model choice for low- count time series models with intractable likelihoods. The method involves incorporating an alive particle filter within a sequential Monte Carlo (SMC) algorithm to create a novel exact-approximate algorithm, which we refer to as alive SMC2. The advantages of this approach over competing methods are that it is naturally adaptive, it does not involve between model proposals required in reversible jump Markov chain Monte Carlo, and does not rely on potentially rough approximations. The algorithm is demonstrated on Markov process and integer autoregressive moving average models applied to real biological datasets of hospital-acquired pathogen incidence, animal health time series, and the cumulative number of prion disease cases in mule deer. PMID- 26584212 TI - [Septoplasty]. PMID- 26584213 TI - [From the Expert's Office: How to Simplify the Calculation of the Hearing Loss in the Speechaudiogram According to the Scale of Boenninghaus and Roser]. PMID- 26584215 TI - Hemopoietic cell kinase (Hck) and p21-activated kinase 2 (PAK2) are involved in the down-regulation of CD1a lipid antigen presentation by HIV-1 Nef in dendritic cells. AB - Dendritic cells (DCs) play a major role in in vivo pathogenesis of HIV-1 infection. Therefore, DCs may provide a promising strategy to control and eventually overcome the fatal infection. Especially, immature DCs express all CD1s, the non-MHC lipid antigen -presenting molecules, and HIV-1 Nef down regulates CD1 expression besides MHC. Moreover, CD1d-restricted CD4(+) NKT cells are infected by HIV-1, reducing the number of these cells in HIV-1-infected individuals. To understand the exact role of DCs and CD1-mediated immune response during HIV-1 infection, Nef down-regulation of CD1a-restricted lipid/glycolipid Ag presentation in iDCs was analyzed. We demonstrated the involvement of the association of Nef with hemopoietic cell kinase (Hck) and p21-activated kinase 2 (PAK2), and that Hck, which is expressed strongly in iDCs, augmented this mutual interaction. Hck might be another therapeutic target to preserve the function of HIV-1 infected DCs, which are potential reservoirs of HIV-1 even after antiretroviral therapy. PMID- 26584216 TI - Acute Uncomplicated Diverticulitis: What to Do Until We Have Better Data. PMID- 26584217 TI - International note: Prediction of mathematics work ethic and performance from behavioral, normative, and control beliefs among Qatari adolescents. AB - Over half-a-million adolescents take part in each cycle of the Program for International Student Assessment (PISA). Yet often, researchers and policy makers across the globe tend to focus their attention primarily on the academic trajectories of adolescents hailing from highly successful education systems. Hence, a vast majority of the adolescent population who regionally and globally constitute the 'long tail of underachievement' often remain unnoticed and underrepresented in the growing literature on adolescents' academic trajectories. The present study, therefore, explored the relations of dispositions toward mathematics, subjective norms in mathematics, and perceived control of success in mathematics to mathematics work ethic as well as mathematics performance; and the mediational role of mathematics work ethic in the association between dispositional, normative, and control beliefs and mathematics performance among adolescents in one of the lowest performing education systems, Qatar. Structural equation modeling (SEM) analyses revealed that Qatari adolescents' dispositional, normative, and control beliefs about mathematics were significantly associated with their mathematics work ethic and mathematics performance, and mathematics work ethic significantly mediated the relationship between dispositional, normative, and control beliefs about mathematics and mathematics performance. However, multi-group SEM analyses indicated that these relationships were not invariant across the gender and the SES groups. PMID- 26584218 TI - Why do early adolescents bully? Exploring the influence of prestige norms on social and psychological motives to bully. AB - The present study examines psychological (e.g., Machiavellianism) and social (i.e., perceived popularity) motives for bullying, exploring the effects that classroom prestige norms for physical and relational aggression may have on these associations. A longitudinal multilevel study design was adopted, which included 978 5th to 7th graders from four Chilean schools. Participants were assessed three times over one year on self reports on bullying and Machiavellianism, and peer reports on popularity. Classroom prestige norms were calculated as the within classroom association between peer perceived coolness and aggression. Both Machiavellianism and perceived popularity were associated with bullying. However, hierarchical linear modeling analyses showed that Machiavellianism, but not perceived popularity, predicted bullying after controlling for baseline scores. Classroom prestige norms for relational aggression increased the association between Machiavellianism and bullying. Separate models were tested for boys and girls, showing no differences. Results are discussed in light of conceptual and methodological considerations. PMID- 26584219 TI - [Treatment as prevention for hepatitis C in Iceland: challenges despite optimism[Editorial]]. PMID- 26584220 TI - [Nobel prize in physiology or medicine awarded to scientists for discoveries of new antimicrobial agents[Editorial]]. PMID- 26584221 TI - [Effect of cardiac rehabilitation following coronary bypass surgery or other coronary interventions]. AB - INTRODUCTION: Cardiac rehabilitation is a well-established treatment for patients with coronary artery disease but limited information is available for Icelandic patients. The aim of this study was to investigate whether Phase II cardiac rehabilitation at the HL rehabilitation center was improving physical health and quality of life of patients. MATERIAL AND METHODS: Patients that had undergone coronary artery intervention were invited to participate. There were 64 participants (of 65 invited) that started in the study and 48 that finished. On average participants attended 2.1 sessions pr. week, for 8.4 weeks. Measurements performed: endurance (W/kg), blood pressure and pulse responses from an exercise test and body mass index (kg/m2). To measure health related quality of life the SF-36v2 questionnaire was used. RESULTS: Endurance improved by 14.4% (p<0,001) and a 6.1% increase was seen in peak pulse (p=0.001). The group was divided by age (32-64 years and 65-86 years) and both age groups improved their endurance number similarly (14.6% and 14.1%) but only the older age group improved peak pulse significantly or 7.2% (p=0.007). When the group was divided according to number of training sessions per week there was a 10.1% increase in endurance in the group that had fewer sessions but it was 19.8% in those that attended more sessions (p<0.001). Participants assessed that their physical health, measured with a questionnaire, had improved at the end of training (p=0.003). When the group was divided into two groups according to how they measured their physical health at the beginning of the study there was a significant increase of 15.1% in physical health in those that estimated worse quality of life at the beginning of the study, but the other group had an increase of 1.2%. CONCLUSION: Cardiac rehabilitation improves endurance and physical wellbeing in patients. Training magnitude is essential for improvement. PMID- 26584222 TI - [The effects of physical activity intervention on symptoms in schizophrenia, mental well-being and body composition in young adults]. AB - INTRODUCTION: Due to an unhealthy lifestyle, individuals with schizophrenia are at higher risk of morbidity compared to the general population. Studies have shown that physical activity can have positive effects on physical and mental health in these patients. The aim of the study was to evaluate the effects of a physical activity intervention on symptoms of schizophrenia, as well as on a number of physical and mental health variables. The aim was also to gain more understanding of the participants' experience of the intervention with interviews. MATERIAL AND METHODS: Seventeen individuals between the ages of 21 31, diagnosed with schizophrenia participated in the study. They exercised under professional supervision for a minimum of two sessions per week for 20 weeks and attended weekly lectures on a healthy lifestyle. The participants answered standardized questionnaires (PANSS, DASS, Rosenberg, CORE-OM, BHS, QOLS), and physical measurements (weight, height, body mass index, resting blood pressure, waist circumference and resting heart rate) were taken before and after the intervention. Six participants were interviewed after the intervention and asked about their experience. RESULTS: Negative and general psychiatric symptoms, depression, anxiety and stress scores decreased significantly whereas well-being, quality of life and physical activity increased (p<0.05). Apart from resting heart rate that decreased (p<0.05), physical measurements remained unchanged at the end of the intervention. CONCLUSION: The participants' physical activity increased, their mental well-being improved, and they did not gain weight during the intervention period. Regular exercise under supervision and education about a healthy lifestyle are a beneficial adjunct to the primary treatment of people with schizophrenia. PMID- 26584223 TI - Asymptomatic MERS-CoV Infection in Humans Possibly Linked to Infected Dromedaries Imported from Oman to United Arab Emirates, May 2015. AB - In May 2015 in United Arab Emirates, asymptomatic Middle East respiratory syndrome coronavirus infection was identified through active case finding in 2 men with exposure to infected dromedaries. Epidemiologic and virologic findings suggested zoonotic transmission. Genetic sequences for viruses from the men and camels were similar to those for viruses recently detected in other countries. PMID- 26584224 TI - Surveillance for Ebola Virus in Wildlife, Thailand. PMID- 26584225 TI - Retrospective multicenter evaluation of the "fly-catching syndrome" in 24 dogs: EEG, BAER, MRI, CSF findings and response to antiepileptic and antidepressant treatment. AB - The fly-catching syndrome (FCS) is a rare canine condition of sudden, occasional, or constant episodes of biting the air. It may be accompanied by jumping, licking, and swallowing. The etiology of FCS is unknown and controversial. Various explanations for its occurrence have included epileptoid disorders such as visual cortex epileptiform disturbances and simple and complex partial seizures as well as compulsive disorders, hallucinatory behavior, and stereotypy. A retrospective multicenter analysis of 24 dogs with clinical symptoms of FCS is presented. Clinical signs at the time of presentation, the mean age at onset of the disease, the response to treatment, and the clinical outcome were recorded and analyzed in all patients. All dogs underwent clinical, neurological, and otoscopic examinations. Complete blood cell counts (CBCs) and serum chemistry panels were obtained from each dog. Diagnostic testing included MRI and EEG examinations in 21 cases, BAER in 19 cases, and CSF analysis in 20 cases. The EEG revealed spike activity in 8 (38%) of the 21 cases, 7 of which had activity in the occipital lobes. The brainstem auditory evoked response (BAER) revealed three cases of bilateral deafness. The MRI revealed six cases of Chiari malformation (CM), one case of syringohydromyelia (SM), and one case of a falx cerebri meningioma. The dogs were divided into groups according to their treatment protocol. Group A included dogs treated with phenobarbital (PB), and group B consisted of dogs treated with fluoxetine (FLX). Thirty-six percent of the dogs in group A responded to PB, while 100% of the dogs in group B responded to FLX. The results suggest that FCS is more responsive to FLX than PB. However, the etiology of this behavior remains unclear in most cases. PMID- 26584226 TI - Diagnostic value of CT-localizer and axial low-dose computed tomography for the detection of drug body packing. AB - OBJECTIVES: The purpose of this study was to assess the diagnostic performance of CT-localizers in the detection of intracorporal containers. METHODS: This study was approved by the research ethics committee of our clinic. From March 2012 to March 2013, 108 subjects were referred to our institute with suspected body packing. The CT-localizer and the axial CT-images were compared by two blinded observers retrospectively. Presence of body packs was assessed in consensus. Sensitivity and specificity, PPV and NPV of the CT-localizer were calculated. RESULTS: Packets were detected in the CT-localizer of 19 suspects. In 28 of 108 cases packs were detected in axial CT-images. Sensitivity of CT-localizer for detection of packs was 0.68, and specificity was 1.00. There were no cases rated as false positive. The PPV was 1.0 and the NPV was 0.89. The omission of the axial CT-images would have led to a mean radiation dose reduction of 1.94 +/- 0.5 mSv. CONCLUSIONS: The value of CT-localizers lies in their high PPV. Localizers are limited by low sensitivity, compared to axial CT-images in screening of potential body packers. However, in positive cases their high PPV may possibly allow to omit the complete axial abdominal CT to achieve even lower radiation exposure. PMID- 26584227 TI - Insights into Peptoid Helix Folding Cooperativity from an Improved Backbone Potential. AB - Peptoids (N-substituted oligoglycines) are biomimetic polymers that can fold into a variety of unique structural scaffolds. Peptoid helices, which result from the incorporation of bulky chiral side chains, are a key peptoid structural motif whose formation has not yet been accurately modeled in molecular simulations. Here, we report that a simple modification of the backbone phi-angle potential in GAFF is able to produce well-folded cis-amide helices of (S)-N-(1 phenylethyl)glycine (Nspe), consistent with experiment. We validate our results against both QM calculations and NMR experiments. For this latter task, we make quantitative comparisons to sparse NOE data using the Bayesian Inference of Conformational Populations (BICePs) algorithm, a method we have recently developed for this purpose. We then performed extensive REMD simulations of Nspe oligomers as a function of chain length and temperature to probe the molecular forces driving cooperative helix formation. Analysis of simulation data by Lifson Roig helix-coil theory show that the modified potential predicts much more cooperative folding for Nspe helices. Unlike peptides, per-residue entropy changes for helix nucleation and extension are mostly positive, suggesting that steric bulk provides the main driving force for folding. We expect these results to inform future work aimed at predicting and designing peptoid peptidomimetics and tertiary assemblies of peptoid helices. PMID- 26584228 TI - Evaluation of herbicide (persistent pollutant) removal mechanisms through hybrid membrane bioreactors. AB - A laboratory-scale membrane bioreactor (MBR) combined with ultraviolet (UV) disinfection and granular activated carbon (GAC) adsorption was researched for over seven months to evaluate the removal efficiencies and mechanisms of a moderately persistent s-triazine herbicide (Ametryn), which is commonly used in Australian sugarcane farmlands. Long-term experiments showed that MBR alone (15h hydraulic retention time (HRT)) can remove 65% of Ametryn from its influent which had a concentration of 1-2mg/L. A batch study was carried out to assess the mechanisms of removal of Ametryn through MBR and found that 0.1186mg of Ametryn/g VSS is adsorbed onto sludge particles when 1mg/L of Ametryn is added to the mixed liquor and showed a 64% removal after 12h. This experiment confirmed that 99%, 92% and 83% removal of Ametryn could be achieved only from biodegradation, if the MBR maintains a HRT of 7.5, 2.5 and 1.5days respectively. PMID- 26584229 TI - Comparison of liquid and vapor hydrothermal carbonization of corn husk for the use as a solid fuel. AB - The effect of the phase during the hydrothermal carbonization (HTC) of corn husks was studied to determine whether liquid water or water vapor was the more suitable reaction medium, as well as if the HTC process could produce a solid fuel (hydrochar) from green corn husks that was comparable to coal. Using liquid water for the HTC process produced a hydrochar with an increased heating value (27.66MJkg(-1)) compared to using water vapor (25.46MJkg(-1)). HTC using liquid water removed 90% of the potassium contained in raw corn husk, whereas the water vapor HTC treatment removed 58%. The liquid water treated hydrochar contained a 29% decrease in ash content compared to the water vapor hydrochar. Using a TGA FTIR analysis the liquid treated hydrochar demonstrated a more coal-like combustion in terms of mass loss and heat production, compared to the vapor treated hydrochar. PMID- 26584230 TI - Isolation of Porcine Epidemic Diarrhea Virus during Outbreaks in South Korea, 2013-2014. PMID- 26584232 TI - Influence of Axial and Point Chirality in the Chiral Self-Assembly of Twin N Annulated Perylenecarboxamides. AB - The synthesis of three bis(N-annulated perylenecarboxamides) endowed with achiral or chiral side chains is reported. The restricted rotation of the perylene moieties yields atropisomers that can be separated by chiral HPLC. The CD spectra of the six stereoisomers show a dichroic pattern in a good solvent that changes drastically upon adding a poor solvent that favors the aggregation. The cooperative character of the supramolecular polymerization mechanism of 1-3 has been determined by denaturation experiments, which reveal that the formation of homochiral aggregates is favored over the formation of heterochiral aggregates. A complete set of amplification of chirality experiments have been carried out, revealing the preponderance of axial chirality over point chirality. The results presented herein shed relevant light on the structural conditions exhibited by molecular units endowed with different elements of asymmetry to generate chiral supramolecular structures and the supremacy of axial chirality over point chirality in the origin of homochirality. PMID- 26584231 TI - OPLS3: A Force Field Providing Broad Coverage of Drug-like Small Molecules and Proteins. AB - The parametrization and validation of the OPLS3 force field for small molecules and proteins are reported. Enhancements with respect to the previous version (OPLS2.1) include the addition of off-atom charge sites to represent halogen bonding and aryl nitrogen lone pairs as well as a complete refit of peptide dihedral parameters to better model the native structure of proteins. To adequately cover medicinal chemical space, OPLS3 employs over an order of magnitude more reference data and associated parameter types relative to other commonly used small molecule force fields (e.g., MMFF and OPLS_2005). As a consequence, OPLS3 achieves a high level of accuracy across performance benchmarks that assess small molecule conformational propensities and solvation. The newly fitted peptide dihedrals lead to significant improvements in the representation of secondary structure elements in simulated peptides and native structure stability over a number of proteins. Together, the improvements made to both the small molecule and protein force field lead to a high level of accuracy in predicting protein-ligand binding measured over a wide range of targets and ligands (less than 1 kcal/mol RMS error) representing a 30% improvement over earlier variants of the OPLS force field. PMID- 26584233 TI - The Poly Implant Prothese breast prostheses scandal: Embodied risk and social suffering. AB - This article examines the 2010 scandal surrounding the use and subsequent recall of adulterated Poly Implant Prothese (PIP) silicone breast prostheses in France. It uses a mixed method approach that includes 12 interviews with French PIP prosthesis recipients, analyses of medical literature, policy documents of French and EU regulatory agencies, and an online forum for PIP recipients. These data are used to explain how the definition of "acceptable risk" in the silicone implants controversy of the 1990s in the US influenced the PIP scandal later on in France. Additionally, PIP recipients had an embodied experience of risk that clashed with the definition of risk used by authorities and some surgeons. The coverage of re-implantation was also defined at different policy levels, leading to variation in patients' suffering. The combination of fraud and lack of recognition from part of the medical system constitutes an example of social suffering for the patients involved. The PIP scandal is a useful case for analyzing the interconnection of embodied experience and professional and public policy definitions of medical risk through the concepts of moral economy and biological citizenship. PMID- 26584234 TI - Supply of alcohol to underage drinkers: Misperceptions of community norms. AB - RATIONALE: Adult approval and acceptance of alcohol use is highly correlated with underage drinking. Social norms influence young people's decisions to drink alcohol. While there is a dearth of studies to date, it is likely that social norms also influence adults' decisions to provide adolescents with alcohol. OBJECTIVE: The current study explored the (in)consistencies between own and perceptions of others' views of underage drinking and the provision of alcohol to underage drinkers. METHODS: Computer assisted telephone survey of 1160 adults in two communities in New South Wales, Australia. RESULTS: Parents and community members were generally opposed to underage drinking and supply of alcohol to adolescents. Females, older respondents, and those who were parents were significantly more likely to disapprove of both underage drinking and supply of alcohol. However, across all of the behaviours, parents and non-parents alike perceived general community attitudes to be more liberal than their own. CONCLUSION: There is a need for community-based interventions that target parental misperceptions about the prevalence of youth drinking and the acceptability of drinking and supply of alcohol within their local community. PMID- 26584236 TI - An internet forum analysis of stigma power perceptions among women seeking fertility treatment in the United States. AB - Infertility is a condition that affects nearly 30 percent of women aged 25-44 in the United States. Though past research has addressed the stigmatization of infertility, few have done so in the context of stigma management between fertile and infertile women. In order to assess evidence of felt and enacted stigma, we employed a thematic content analysis of felt and enacted stigma in an online infertility forum, Fertile Thoughts, to analyze 432 initial threads by women in various stages of the treatment-seeking process. We showed that infertile women are frequently stigmatized for their infertility or childlessness and coped through a variety of mechanisms including backstage joshing and social withdrawal. We also found that infertile women appeared to challenge and stigmatize pregnant women for perceived immoral behaviors or lower social status. We argue that while the effects of stigma power are frequently perceived and felt in relationships between infertile women and their fertile peers, the direction of the enacted stigma is related to social standing and feelings of fairness and reinforces perceived expressions of deserved motherhood in the United States. PMID- 26584237 TI - Indium-Catalyzed [2 + 2] Cycloaddition of Allylsilanes to Internal Alkynones. AB - We have developed an indium-catalyzed [2 + 2] cycloaddition of allylsilanes to alkynones leading to selective cyclobutenone formation. The resulting cyclobutenones were readily converted to the oxidized products by Tamao-Fleming oxidation or the ring-opened products by an electrocyclic reaction. PMID- 26584235 TI - "Thinking too much": A systematic review of a common idiom of distress. AB - Idioms of distress communicate suffering via reference to shared ethnopsychologies, and better understanding of idioms of distress can contribute to effective clinical and public health communication. This systematic review is a qualitative synthesis of "thinking too much" idioms globally, to determine their applicability and variability across cultures. We searched eight databases and retained publications if they included empirical quantitative, qualitative, or mixed-methods research regarding a "thinking too much" idiom and were in English. In total, 138 publications from 1979 to 2014 met inclusion criteria. We examined the descriptive epidemiology, phenomenology, etiology, and course of "thinking too much" idioms and compared them to psychiatric constructs. "Thinking too much" idioms typically reference ruminative, intrusive, and anxious thoughts and result in a range of perceived complications, physical and mental illnesses, or even death. These idioms appear to have variable overlap with common psychiatric constructs, including depression, anxiety, and PTSD. However, "thinking too much" idioms reflect aspects of experience, distress, and social positioning not captured by psychiatric diagnoses and often show wide within cultural variation, in addition to between-cultural differences. Taken together, these findings suggest that "thinking too much" should not be interpreted as a gloss for psychiatric disorder nor assumed to be a unitary symptom or syndrome within a culture. We suggest five key ways in which engagement with "thinking too much" idioms can improve global mental health research and interventions: it (1) incorporates a key idiom of distress into measurement and screening to improve validity of efforts at identifying those in need of services and tracking treatment outcomes; (2) facilitates exploration of ethnopsychology in order to bolster cultural appropriateness of interventions; (3) strengthens public health communication to encourage engagement in treatment; (4) reduces stigma by enhancing understanding, promoting treatment-seeking, and avoiding unintentionally contributing to stigmatization; and (5) identifies a key locally salient treatment target. PMID- 26584238 TI - Japanese Macaques (Macaca fuscata) as Natural Reservoir of Bartonella quintana. AB - Bartonella quintana bacteremia was detected in 6 (13.3%) of 45 wild-caught Japanese macaques (Macaca fuscata). Multilocus sequence typing of the isolates revealed that Japanese macaques were infected with a new and specific B. quintana sequence type. Free-ranging Japanese macaques thus represent another natural reservoir of B. quintana. PMID- 26584239 TI - Evidence for Compression of Escherichia coli K12 Cells under the Effect of TiO2 Nanoparticles. AB - It has been shown that treatment with titanium dioxide nanoparticles (TiO2 NPs) combined with near-ultraviolet (UV-A) irradiation or in certain dark conditions reduced the numbers of various microorganisms, but the mechanism of this effect remains unclear. In this study to further clarify the mechanism of the antibacterial effect of TiO2 NPs the physiological state of E. coli K12 cells was estimated after incubation with the NPs (0.2 g/L) for different periods of time, with or without UV-A irradiation. Cell incubation with TiO2 NPs, combined or not combined with UV-A irradiation, showed that inactive cells were located only within cell aggregates formed after incubation with TiO2 NPs and that the larger the aggregate, the greater the number of such cells. When the formation of large aggregates was prevented, exposure to NPs under UV-A irradiation failed to result in cell inactivation. A comparative analysis of fluorescence and optical microscopic images of the same aggregates showed that the location of inactivated cells coincided with the zone of increased optical density within the aggregate. After treatment with TiO2 NPs under UV-A for 30, 60, or 120 min cells within the aggregates were the first to be inactivated. Cells on which NPs irradiated more strongly (at the periphery of large aggregates and single) remained active for a longer time than cells within the aggregates. As the time of treatment increased, so did the degree of cell compaction, with some zones of the aggregates eventually transforming into an acellular mass. After UV-A irradiation the cell aggregates spontaneously moved toward each other and gradually fused into larger structures, indicating that such exposure enhanced mutual attraction of cells treated with the NPs. Present study provides evidence for hypothesis that bacterial cells covered with TiO2 NPs are inactivated due to their mutual attraction and consequent compression. PMID- 26584241 TI - Scalable Clean Exfoliation of High-Quality Few-Layer Black Phosphorus for a Flexible Lithium Ion Battery. AB - Few-layer black phosphorus (BP) nanosheets that are clean and of high quality, are efficiently produced by exfoliating bulk BP crystals, which are prepared by a scalable gas-phase catalytic transformation method in water. They are stable enough in water for further processing and applications. As an example, these BP nanosheets are combined with graphene to give high-performance flexible lithium ion batteries. PMID- 26584242 TI - Co-occurring tobacco use and posttraumatic stress disorder: Smoking cessation treatment implications. AB - BACKGROUND AND OBJECTIVES: PTSD and cigarette smoking frequently co-occur for reasons that are not well understood. The current behavioral and pharmacological treatments and emerging new treatment targets for smoking cessation are discussed. METHODS: Here we describe recent research on PTSD and smoking with an emphasis on 1) the clinical characteristics of smokers with PTSD, 2) smoking treatment trials that specifically targeted smokers with PTSD, 3) recent research on stress-response and affect regulation pathways that might link the two disorders and 4) potential ways to leverage new findings on stress response systems and affect regulation mechanisms to improve treatment outcomes for smokers with PTSD. RESULTS: Smokers with PTSD have higher rates of smoking compared to the general population and have greater difficulty quitting compared to smokers without PTSD. There have been several studies of adjunctive and integrated smoking cessation interventions for smokers with PTSD, but fewer tailored interventions that intensively target stress-response pathways or affect regulation related to both tobacco use and PTSD. Stress-response pathways and affect regulation appear to be important mechanisms involved in the development and maintenance of smoking in individuals with PTSD. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Additional research that focuses on smokers with PTSD is warranted given that successful tobacco treatment response is low and the negative health effects of each disorder can be greatly amplified. PMID- 26584240 TI - HIV-1 and two avian retroviral 5' untranslated regions bind orthologous human and chicken RNA binding proteins. AB - Essential host cofactors in retrovirus replication bind cis-acting sequences in the 5'untranslated region (UTR). Although host RBPs are crucial to all aspects of virus biology, elucidating their roles in replication remains a challenge to the field. Here RNA affinity-coupled-proteomics generated a comprehensive, unbiased inventory of human and avian RNA binding proteins (RBPs) co-isolating with 5'UTRs of HIV-1, spleen necrosis virus and Rous sarcoma virus. Applying stringent biochemical and statistical criteria, we identified 185 RBP; 122 were previously implicated in retrovirus biology and 63 are new to the 5'UTR proteome. RNA electrophoretic mobility assays investigated paralogs present in the common ancestor of vertebrates and one hnRNP was identified as a central node to the biological process-anchored networks of HIV-1, SNV, and RSV 5' UTR-proteomes. This comprehensive view of the host constituents of retroviral RNPs is broadly applicable to investigation of viral replication and antiviral response in both human and avian cell lineages. PMID- 26584243 TI - PTSD Among Aboriginal and Torres Strait Islander People in Custody in Australia: Prevalence and Correlates. AB - Mental disorder and trauma experiences are highly prevalent among individuals in custody; however, the impact of posttraumatic stress disorder (PTSD) on functioning is rarely considered. Indigenous Australians are incarcerated at 13 times the rate of nonindigenous Australians and report high levels of trauma exposure and psychological distress. In analysis of the largest systematic study of mental disorder among indigenous Australians in custody (N = 396), we found that the 12-month prevalence of PTSD was high in both men (12.1%) and women (32.3%). Having PTSD was also associated with high rates of co-occurring mental disorders (anxiety 31.2%, depression 32.8%, psychosis 24.6%, and substance use, 75.4%), lifetime suicidal ideation (50.1%), and suicide attempts (34.4%). Individuals with PTSD, compared to those without, were more likely to experience other mental disorders, OR = 2.42, 95% CI [1.12, 5.80], p = .022; lifetime suicide thoughts, OR = 2.43, 95% CI [1.34, 4.39], p = .001, and attempts, OR = 2.56, 95% CI [1.33, 4.83], p = .002; and high rates of intoxication at the time of arrest. Despite this, most (58.9%) had not accessed any form of mental health care prior to incarceration. These findings highlight the need to identify and manage PTSD in community and custodial populations. PMID- 26584244 TI - Serum protein concentration and protein fractions in clinically healthy Lacaune and Sarda sheep using agarose gel electrophoresis. AB - BACKGROUND: Serum protein electrophoresis (SPE) provides useful information in ruminants, but reference intervals (RI) are different from other species. There have been no reports of SPE RI for dairy sheep using agarose gel electrophoresis (AGE). OBJECTIVE: The purpose of the study was to evaluate the serum concentration of total protein (TP) and protein fractions determined by AGE in mid-lactating dairy ewes, to establish RI, and to assess potential differences between Lacaune (L) and Sarda (S) sheep breeds. METHODS: Blood samples were collected from healthy, mid-lactating ewes. SPE was assessed using a semi automated AGE system. Reference intervals (90% confidence intervals) for TP and each protein fraction were determined using the nonparametric method for combined data, and the robust method for data from the single breeds. Data from S and L sheep were compared using the Mann-Whitney U test. RESULTS: The 172 sheep included 116 L and 56 S ewes, 2-6 years old. There were significant differences between S and L breeds, and RI were calculated for TP, albumin, alpha1 -globulin, alpha2 -globulin, beta1 -globulin, beta2 -globulin, gamma1 -globulin, and gamma2 globulin concentrations, and for the Albumin/Globulin ratio. Group S showed higher concentrations of TP, alpha2 -, beta1 -, beta2 -, and gamma1 -globulins, whereas L was higher for albumin and gamma2 -globulin concentrations, and A/G ratio (P < .05). CONCLUSIONS: The resolution with AGE was excellent, allowing standardization of 7 protein fractions, detection of differences between S and L ewes, and determination of RI for French (Lacaune) and Italian (Sarda) dairy sheep. PMID- 26584245 TI - Competing Insertion and External Binding Motifs in Hydrated Neurotransmitters: Infrared Spectra of Protonated Phenylethylamine Monohydrate. AB - Hydration has a drastic impact on the structure and function of flexible biomolecules, such as aromatic ethylamino neurotransmitters. The structure of monohydrated protonated phenylethylamine (H(+) PEA-H2 O) is investigated by infrared photodissociation (IRPD) spectroscopy of cold cluster ions by using rare gas (Rg=Ne and Ar) tagging and dispersion-corrected density functional theory calculations at the B3LYP-D3/aug-cc-pVTZ level. Monohydration of this prototypical neurotransmitter gives an insight into the first step of the formation of its solvation shell, especially regarding the competition between intra- and intermolecular interactions. The spectra of Rg-tagged H(+) PEA-H2 O reveal the presence of a stable insertion structure in which the water molecule is located between the positively charged ammonium group and the phenyl ring of H(+) PEA, acting both as a hydrogen bond acceptor (NH(+) ???O) and donor (OH???pi). Two other nearly equivalent isomers, in which water is externally H bonded to one of the free NH groups, are also identified. The balance between insertion and external hydration strongly depends on temperature. PMID- 26584246 TI - Sitagliptin and pancreatic cancer risk in patients with type 2 diabetes. AB - BACKGROUND: The risk of pancreatic cancer associated with incretin-based therapies is controversial. METHODS: This study retrospectively analysed the National Health Insurance database including patients with newly diagnosed type 2 diabetes mellitus at an age >= 25 years between 1999 and 2010. A total of 71 137 ever users of sitagliptin and 933 046 never users were followed for pancreatic cancer until 31 December 2011. A time-dependent approach was used to calculate incidence and estimate hazard ratios adjusted for propensity score using Cox regression. RESULTS: During follow-up, 83 ever users and 3658 never users developed pancreatic cancer, representing an incidence of 73.6 and 55.0 per 100 000 person-years, respectively. The adjusted hazard ratio (95% confidence intervals) for ever versus never users was 1.40 (1.13-1.75). The respective adjusted hazard ratio for the first, second and third tertile of cumulative dose < 14 700, 14 700-33 700 and > 33 700 mg was 1.83 (1.28-2.62), 1.97 (1.41-2.76) and 0.72 (0.45-1.15). For average daily dose of < 50, 50-99.9 and >= 100 mg, the respective hazard ratio was 3.10 (1.17-8.26), 1.01 (0.63-1.61) and 1.53 (1.18 1.97). CONCLUSIONS: Sitagliptin is significantly associated with a higher risk of pancreatic cancer, especially when the cumulative dose is < 33 700 mg. The risk diminished in users with a higher cumulative dose. The daily dose of sitagliptin should better be kept < 100 mg, and its use should be reconsidered in patients who suffer from severe renal impairment and thus a daily dose of < 50 mg is always recommended. Future studies are required to confirm the findings with more appropriate adjustment for smoking. PMID- 26584247 TI - Hyperpolarized 13C urea relaxation mechanism reveals renal changes in diabetic nephropathy. AB - PURPOSE: Our aim was to assess a novel (13) C radial fast spin echo golden ratio single shot method for interrogating early renal changes in the diabetic kidney, using hyperpolarized (HP) [(13) C,(15) N2 ]urea as a T2 relaxation based contrast bio-probe. METHODS: A novel HP (13) C MR contrast experiment was conducted in a group of streptozotocin type-1 diabetic rat model and age matched controls. RESULTS: A significantly different relaxation time (P = 0.004) was found in the diabetic kidney (0.49 +/- 0.03 s) compared with the controls (0.64 +/- 0.02 s) and secondly, a strong correlation between the blood oxygen saturation level and the relaxation times were observed in the healthy controls. CONCLUSION: HP [(13) C,(15) N2 ]urea apparent T2 mapping may be a useful for interrogating local renal pO2 status and renal tissue alterations. Magn Reson Med, 2015. (c) 2015 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. PMID- 26584248 TI - Preconditioning of mesenchymal stromal cells toward nucleus pulposus-like cells by microcryogels-based 3D cell culture and syringe-based pressure loading system. AB - To precondition mesenchymal stromal/stem cells (MSCs) with mechanical stimulation may enhance cell survival and functions following implantation in load bearing environment such as nucleus pulposus (NP) in intervertebral disc (IVD). In this study, preconditioning of MSCs toward NP-like cells was achieved in previously developed poly (ethylene glycol) diacrylate (PEGDA) microcryogels (PMs) within a syringe-based three-dimensional (3D) culture system which provided a facile and cost-effective pressure loading approach. PMs loaded with alginate and MSCs could be incubated in a sealable syringe which could be air-compressed to apply pressure loading through a programmable syringe pump. Expression levels of chondrogenic marker genes SOX9, COL II, and ACAN were significantly upregulated in MSCs when pressure loading of 0.2 MPa or 0.8 MPa was implemented. Expression levels of COL I and COL X were downregulated when pressure loading was applied. In a nude mouse model, MSCs loaded in PMs mechanically stimulated for three days were subcutaneously injected using the same culture syringe. Three weeks postinjection, more proteoglycans (PGs) were deposited and more SOX9 and COL II but less COL I and COL X were stained in 0.2 MPa group. Furthermore, injectable MSCs-loaded PMs were utilized in an ex vivo rabbit IVD organ culture model that demonstrated the leak-proof function and enhanced cell retention of PMs assisted cell delivery to a load bearing environment for potential NP regeneration. This microcryogels-based 3D cell culture and syringe-based pressure loading system represents a novel method for 3D cell culture with mechanical stimulation for better function. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 507-520, 2017. PMID- 26584250 TI - An entire universe of the Roman world's architecture found in the human skull. AB - Today's neuroanatomical terminology has its origins in the Romans' way of life, in their civil and military house architecture, as well as in the fields of engineering and technology. Despite the fact that they did not know how the nervous system worked and what the role of each neuroanatomic structure was, over time, especially in Renaissance and early modern times, the anatomists sought descriptive names for the nervous structures they have identified by way of similarity with some ancient items. This study aims to briefly review the influence of Roman architecture, engineering, and technology on neuroanatomic nomenclature, the precursor of modern neuroanatomical terminology. PMID- 26584251 TI - Surfactant deficiency in full-term newborns with transient tachypnea delivered by elective C-section. AB - INTRODUCTION: Previous studies have suggested that full-term newborns delivered by elective cesarean section who develop transient tachypnea have low gastric microbubble counts. In the present study, microbubble concentrations in oral fluid samples were used to evaluate pulmonary maturity. OBJECTIVE: To evaluate lung maturity in full-term newborns delivered by elective caesarean section using the stable microbubble test in oral aspirates collected at birth. METHOD: The study involved newborns with gestational age >37 weeks delivered by elective cesarean section. Oral fluid samples were obtained in the delivery room immediately after birth, and gastric fluid was collected within the first hour of life. Samples were frozen and analyzed by two blinded researchers. RESULTS: The sample comprised 544 newborns. Twenty-two were diagnosed with transient tachypnea of the newborn by the assisting physician, and required admission to the Neonatal Intensive or Intermediate Care Unit. The median (interquartile range) of the number of microbubbles in the oral samples of these patients was 67.5 (45-150) microbubbles/mm(2) . The remaining 498 newborns without respiratory difficulties had a count of 350 (150-750) microbubbles/mm(2) -P < 0.001. Gastric fluid tests revealed a count of 150 (82.5-700) microbubbles/mm(2) for neonates with respiratory difficulties, and of 600 (216-1125) microbubbles/mm(2) -P < 0.05 for those without respiratory symptoms. CONCLUSION: The present results suggest that transient tachypnea of the newborn is associated with surfactant dysfunction. Pediatr Pulmonol. 2016;51:596-600. (c) 2015 Wiley Periodicals, Inc. PMID- 26584252 TI - Surgical Technique for Laparoscopic Removal of a Magnetic Lower Esophageal Sphincter Augmentation Device. AB - BACKGROUND: Nissen fundoplication is the current gold standard for surgical management of gastroesophageal reflux disease; however, a magnetic antireflux device is now an alternative surgical procedure. The early literature shows good reflux control with minimal complications, and therefore placement of these devices is growing in popularity. As more of these devices are placed, there will be cases in which they will need to be removed. A laparoscopic method for removing the device is presented here. MATERIALS AND METHODS: We present a case of a 42-year-old female with history of gastroesophageal reflux who underwent a laparoscopic placement of a magnetic lower esophageal sphincter augmentation device and repair of a small hiatal hernia. She had a complicated postoperative course before presenting to our institution with a 2-year history of persistent dysphagia and requesting the device be removed. Laparoscopic removal of the device was performed. RESULTS: After laparoscopic removal of the patient's magnetic lower esophageal sphincter augmentation device, she had subjective improvement in her dysphagia but is now being medically managed for gastroesophageal reflux and for delayed gastric emptying. CONCLUSIONS: Laparoscopic removal of magnetic lower esophageal sphincter augmentation devices will sometimes be necessary and may be challenging if the surgeon encounters significant scar tissue around the gastroesophageal junction. Postoperative complications are similar to those encountered with foregut surgeries and include postoperative delayed gastric emptying. PMID- 26584249 TI - Staphylococcal adaptation to diverse physiologic niches: an overview of transcriptomic and phenotypic changes in different biological environments. AB - Host niches can differ strongly regarding, for example, oxygen tension, pH or nutrient availability. Staphylococcus aureus and other staphylococci are common colonizers of human epithelia as well as important human pathogens. The phenotypes that they show in different host environments, and the corresponding bacterial transcriptomes and proteomes, are currently under intense investigation. In this review, we examine the available literature describing staphylococcal phenotypes, such as expression of virulence factors, gross morphologic characteristics and growth patterns, in various physiological environments. Going forward, these studies will help researchers and clinicians to form an enhanced and more detailed picture of the interactions existing between the host and staphylococci as some of its most frequent colonizers and invaders. PMID- 26584253 TI - Oral delivery of liposomes. PMID- 26584254 TI - Friend and Family Support for Weight Loss in Adolescent Females. AB - BACKGROUND: Overweight and obesity rates in children and adolescents are concerning, particularly among girls. Social support from friends has been associated with healthier eating and higher levels of physical activity, yet little is known about the relationship between social support and weight loss among adolescents. This aim of this study was to prospectively examine the relationship between baseline social support from friends and family, changes in social support, and weight loss. METHODS: Sixty-five adolescent girls completed a one-year weight loss intervention trial. Data were collected at baseline, 6 months, and 12 months. RESULTS: At baseline, family support was higher compared to friend support; however, lower friend support at baseline and increases in friend support from baseline to 6 months and 12 months were associated with weight loss. When controlling for other predictors of weight loss, change in friend support for healthy eating was predictive of weight loss at 12 months. CONCLUSIONS: These findings suggest that weight loss interventions for adolescent females might consider including strategies to elicit or to create and promote social support for healthy eating from peers. Future studies are needed to test this relationship. PMID- 26584256 TI - Erratum: Vol. 62, No. 54. PMID- 26584255 TI - Tribbles Homolog 3 Promotes Foam Cell Formation Associated with Decreased Proinflammatory Cytokine Production in Macrophages: Evidence for Reciprocal Regulation of Cholesterol Uptake and Inflammation. AB - BACKGROUND: Insulin resistance is central in the pathophysiology of cardiometabolic disease; however, common mechanisms that explain the parallel development of both type 2 diabetes and atherosclerosis have not been elucidated. We have previously shown that tribbles homolog 3 (TRB3) can exert a chronic pathophysiological role in promoting insulin resistance and also has an acute physiological role to alternatively regulate glucose uptake in fat and muscle during short-term fasting and nutrient excess. Since TRB3 is expressed in human atherosclerotic plaques, we explored its role in foam cell formation to assess its potential contribution to atherogenesis. METHODS: We have used human THP-1 monocytes, which transition to lipid-laden macrophage foam cells when exposed to oxidized low-density lipoprotein (ox-LDL). RESULTS: We first observed that TRB3 was upregulated by more than twofold (P < 0.01) within 24 hr of treatment with ox LDL. To determine whether TRB3 actively participated in foam cell formation, we overexpressed TRB3 in THP-1 monocytes and found that this led to a 1.5-fold increase in cholesterol accumulation after 48 hr (P < 0.01), compared with controls. At the same time, TRB3 overexpression suppressed inflammation in macrophages as evidenced by reduced expression and secretion of tumor necrosis factor alpha (TNF-alpha) and interleukin-1 beta (IL-1beta) (both P < 0.01). CONCLUSIONS: (1) TRB3 is upregulated in macrophages upon treatment with ox-LDL; (2) TRB3 promotes lipid accumulation and suppresses cytokine expression; and (3) inflammation and foam cell formation can be reciprocally regulated, and TRB3 orients the macrophage to assume a more primary role for lipid accumulation while maintaining a secondary role as an inflammatory immune cell. PMID- 26584257 TI - Fundamentals and applications of inertial microfluidics: a review. AB - In the last decade, inertial microfluidics has attracted significant attention and a wide variety of channel designs that focus, concentrate and separate particles and fluids have been demonstrated. In contrast to conventional microfluidic technologies, where fluid inertia is negligible and flow remains almost within the Stokes flow region with very low Reynolds number (Re ? 1), inertial microfluidics works in the intermediate Reynolds number range (~1 < Re < ~100) between Stokes and turbulent regimes. In this intermediate range, both inertia and fluid viscosity are finite and bring about several intriguing effects that form the basis of inertial microfluidics including (i) inertial migration and (ii) secondary flow. Due to the superior features of high-throughput, simplicity, precise manipulation and low cost, inertial microfluidics is a very promising candidate for cellular sample processing, especially for samples with low abundant targets. In this review, we first discuss the fundamental kinematics of particles in microchannels to familiarise readers with the mechanisms and underlying physics in inertial microfluidic systems. We then present a comprehensive review of recent developments and key applications of inertial microfluidic systems according to their microchannel structures. Finally, we discuss the perspective of employing fluid inertia in microfluidics for particle manipulation. Due to the superior benefits of inertial microfluidics, this promising technology will still be an attractive topic in the near future, with more novel designs and further applications in biology, medicine and industry on the horizon. PMID- 26584258 TI - Hot Topics in Biomechanics: Hip Fracture Fixation. AB - Geriatric hip fractures continue to increase in frequency as the population ages, and intertrochanteric femur fractures are a significant part of these injuries. Plate fixation for intertrochanteric fractures of the proximal femur has been in use for many years, and application of the sliding hip screw has also been a mainstay of treatment. Recent data suggest there may be a benefit to using implants that add rotational stability to the proximal intertrochanteric fragment. Although preliminary data are promising, there is need for improved investigation to demonstrate the benefit of these new implant designs. In this era of increasing emphasis on cost, quality, and value, better data are needed to help clinicians determine the best therapy for their patients. PMID- 26584259 TI - Bone Grafting: Sourcing, Timing, Strategies, and Alternatives. AB - Acute fractures, nonunions, and nonunions with bone defects or osteomyelitis often need bone graft to facilitate union. There are several factors to consider when it is determined that a bone graft is needed. These factors include the source of the bone graft (autograft vs. allograft), proper timing for placement of the bone graft, strategies to avoid further complications (particularly in the setting of osteomyelitis), and with the development of a variety of bone graft substitutes, whether alternatives to autograft are available and appropriate for the task at hand. Autograft bone has commonly been referred to as the "gold standard" of bone grafts, against which the efficacy of other grafts has been measured. The best timing for when to place a bone graft or substitute is also somewhat controversial, particularly after an open fracture or a potentially contaminated bed. The treatment of infected nonunions, particularly those that require a graft to facilitate healing, can be quite challenging. Typically, the infection is completely eradicated before placement of a bone graft, but achieving a sterile bed and the timing of a bone graft require strategic thinking and planning. This review outlines the benefits of autografts, the most suitable sites for harvesting bone grafts, the timing of bone graft procedures, the potential risks and benefits of grafting in the face of infection, and the currently available bone graft extenders. PMID- 26584260 TI - Building Networks for Global Clinical Research: The Basics. AB - Over the last several decades, interest in global health across all fields of medicine, including orthopaedic surgery, has grown markedly. Cross-national collaborations are an effective means of conducting high-quality clinical research and offer many advantages over single-center investigations. Successful collaboration requires a well-designed research protocol, development of an effective team structure, and the funding to ensure the project is sustained to completion. Equally important, investigators must consider the social, linguistic, and cultural context in which the study is being undertaken. Although randomized clinical trials are the highest level of evidence, study designs may have to be adapted to accommodate available resources, expertise, and local contextual factors. With appropriate planning, these collaborative endeavors can generate changes in clinical practice and positively impact health policy. PMID- 26584261 TI - Infection in Orthopaedics. AB - Infection in orthopaedic trauma patients is a common problem associated with significant financial and psychosocial costs, and increased morbidity. This review outlines technologies to diagnose and prevent orthopaedic infection, examines implant-related infection and its management, and discusses the treatment of post-traumatic osteomyelitis. The gold standard for diagnosing infection has a number of disadvantages, and thus new technologies to diagnose infection are being explored, including multilocus polymerase chain reaction with electrospray ionization-mass spectrometry and optical imaging. Numerous strategies have been employed to prevent orthopaedic infection, including use of antibiotic-impregnated implant coatings and cement; however, further research is required to optimize these technologies. Biofilm formation on orthopaedic implants is attributed to the glycocalyx-mediated surface mode of bacterial growth and is usually treated through a secondary surgery involving irrigation, debridement and the appropriate use of antibiotics, or complete removal of the infected implant. Research into the treatment of post-traumatic osteomyelitis has focused on developing an optimal local antibiotic delivery vehicle, such as antibiotic-impregnated polymethylmethacrylate (PMMA) cement beads or bioabsorbable bone substitute (BBS) delivery systems. As these new technologies to diagnose, prevent and treat orthopaedic infection advance, the incidence of infection will decrease and patient care will be optimized. PMID- 26584262 TI - Stem Cell Therapies in Orthopaedic Trauma. AB - Stem cells offer great promise to help understand the normal mechanisms of tissue renewal, regeneration, and repair, and also for development of cell-based therapies to treat patients after tissue injury. Most adult tissues contain stem cells and progenitor cells that contribute to homeostasis, remodeling, and repair. Multiple stem and progenitor cell populations in bone are found in the marrow, the endosteum, and the periosteum. They contribute to the fracture healing process after injury and are an important component in tissue engineering approaches for bone repair. This review focuses on current concepts in stem cell biology related to fracture healing and bone tissue regeneration, as well as current strategies and limitations for clinical cell-based therapies. PMID- 26584264 TI - Bone Graft Substitution and Augmentation. AB - Selection of appropriate bone graft or bone graft substitute requires careful recognition of the bone healing needs of the patient's specific clinical problem and a thorough understanding of the different properties possessed by the available bone grafts and substitutes. Although autogenous iliac crest bone graft remains the gold standard of treatment for delayed unions, nonunions, and bone defects, there are a number of promising alternatives available, and emerging evidence suggests that they can be very effective when used in the proper setting. Among these, reamer-irrigator-aspirator bone graft, bone marrow concentrate, bone morphogenetic proteins, and calcium phosphate cements have received a great deal of attention in the literature. This review describes these grafts in detail along with the evidence for their use. In addition, a framework is provided for selecting the appropriate graft or substitute based on their provided properties. PMID- 26584263 TI - Biomechanical Concepts for Fracture Fixation. AB - Application of the correct fixation construct is critical for fracture healing and long-term stability; however, it is a complex issue with numerous significant factors. This review describes a number of common fracture types and evaluates their currently available fracture fixation constructs. In the setting of complex elbow instability, stable fixation or radial head replacement with an appropriately sized implant in conjunction with ligamentous repair is required to restore stability. For unstable sacral fractures with vertical or multiplanar instabilities, "standard" iliosacral screw fixation is not sufficient. Periprosthetic femur fractures, in particular Vancouver B1 fractures, have increased stability when using 90/90 fixation versus a single locking plate. Far cortical locking combines the concept of dynamization with locked plating to achieve superior healing of a distal femur fracture. Finally, there is no ideal construct for syndesmotic fracture stabilization; however, these fractures should be fixed using a device that allows for sufficient motion in the syndesmosis. In general, orthopaedic surgeons should select a fracture fixation construct that restores stability and promotes healing at the fracture site, while reducing the potential for fixation failure. PMID- 26584265 TI - Dealing With Catastrophic Outcomes and Amputations in the Mangled Limb. AB - Successful management of the mangled extremity is difficult; however, recent advancements are changing the outcomes of these difficult cases. Multiple centers are working on new bionic limbs with real-time feedback and better performance parameters. Research progress, particularly in the military sector, has aided in our understanding of heterotopic ossification after devastating limb injuries. This progress has also allowed a better treatment program for the residual limb in surgery and postsurgery. It is an exciting time in the management and rehabilitation of amputated limbs, as both biologic and technological advancements are enabling better patient satisfaction. This article looks at some of these discoveries and how they are changing the treatment of the residual limb. PMID- 26584266 TI - Bigger Data, Bigger Problems. AB - Clinical studies frequently lack the ability to reliably answer their research questions because of inadequate sample sizes. Underpowered studies are subject to multiple sources of bias, may not represent the larger population, and are regularly unable to detect differences between treatment groups. Most importantly, an underpowered study can lead to incorrect conclusions. Big data can be used to address many of these concerns, enabling researchers to answer questions with increased certainty and less likelihood of bias. Big datasets, such as The National Hip Fracture Database in the United Kingdom and the Swedish Hip Arthroplasty Registry, collect valuable clinical information that can be used by researchers to guide patient care and inform policy makers, chief executives, commissioners, and clinical staff. The range of research questions that can be examined is directly related to the quality and complexity of the data, which is positively associated with the cost of the data. However, technological advancements have unlocked new possibilities for efficient data capture and widespread opportunities to merge massive datasets, particularly in the setting of national registries and administrative data. PMID- 26584267 TI - Articular Cartilage Injury and Potential Remedies. AB - Osteoarthritis affects millions of people worldwide, is associated with joint stiffness and pain, and often causes significant disability and loss of productivity. Osteoarthritis is believed to occur as a result of ordinary "wear and tear" on joints during the course of normal activities of daily living. Posttraumatic osteoarthritis is a particular subset of osteoarthritis that occurs after a joint injury. Developing clinically relevant animal models will allow investigators to delineate the causes of posttraumatic osteoarthritis and develop means to slow or prevent its development after joint injury. Chondroprotectant compounds, which attack the degenerative pathways at a variety of steps, are being developed in an effort to prevent posttraumatic osteoarthritis and offer great promise. Often times, cartilage degradation after joint injury occurs despite our best efforts. When this happens, there are several evolving techniques that offer at least short-term relief from the effects of posttraumatic osteoarthritis. Occasionally, these traumatic lesions are so large that dramatic steps must be taken in an attempt to restore articular congruity and joint stability. Fresh osteochondral allografts have been used in these settings and offer the possibility of joint preservation. For patients presenting with neglected displaced intra-articular fractures that have healed, intra articular osteotomy techniques are being developed in an effort to restore joint congruity and function. This article reviews the results of a newly developed animal model of posttraumatic osteoarthritis, several promising chondroprotectant compounds, and also cartilage techniques that are used when degenerative cartilage lesions develop after joint injury. PMID- 26584268 TI - Osteoporotic Fracture Care: Are We Closer to Gold Standards? AB - This review summarizes symposium presentations from the OTA's Basic Science Focus Forum on care for osteoporotic fractures. The limitations of diaphyseal osteoporotic animal bone models are discussed, together with the potential benefits of using metaphyseal models to study osteoporotic fracture fixation constructs. Metaphyseal bone repair models provide better simulation of the most common osteoporotic fractures. Selection of an osteoporotic model for mechanical testing is also challenging. One should always thoroughly define the clinical problem to be addressed. The selected model should then be validated for behavior matched to known clinical behavior with known fixation configurations. The medical management of osteoporosis is directed at enhancing bone mass, improving bone quality, and lowering fracture risk. Medical strategies to achieve these goals are discussed. The medical strategy should include provision of an adequate calcium and vitamin D environment to facilitate well-mineralized bone and improve bone quality, prevent excessive bone resorption, and provide an anabolic stimulus to enhance bone formation. Atypical femur fractures continue to be a serious issue for the orthopaedic community. Risk factors, treatment modalities, and prevention strategies are discussed. A comprehensive strategy for the improved treatment of osteoporotic fractures must address both biological and mechanical issues and includes 4 specific approaches: (1) removal of inhibitors to bone healing; (2) introduction of bone healing stimulants; (3) modification of fracture fixation constructs; and (4) application of bone augmentation or substitutes. There is currently no optimal bone substitute. Substitutes should be chosen based on the most critical need when treating a particular fracture. PMID- 26584269 TI - Assessment of Fracture Repair. AB - Assessment of fracture union is a critical concept in clinical orthopaedics; however, there is no established "gold standard" for fracture healing. This review provides an overview of the problems related to the assessment of fracture healing, examines currently available tools to determine union, discusses the role of functional outcomes in the assessment of fracture healing, and finally evaluates healing outcome measures as they pertain to fracture trials. Because there is no universally accepted method to determine fracture healing, orthopaedic surgeons must rely on a range of tools that can include: radiographic assessment, mechanical assessment, serologic markers, and clinical evaluation (including functional outcomes). When used in conjunction, these tools can help to improve the sensitivity and specificity of determining fracture union. This is furthermore relevant when conducting fracture healing trials, for which there is little consensus between surgeons or the Food and Drug Administration as to optimal study endpoints. Such studies should therefore include a composite outcome measure consisting of radiographic and functional assessments to increase the quality and consistency of fracture healing trials. PMID- 26584270 TI - Inflammation, Bone Healing, and Anti-Inflammatory Drugs: An Update. AB - Fracture healing is a unique multifaceted process requiring the presence of cells, molecular mediators, and angiogenic factors. The state of inflammation dominates the initial phase, but the ideal magnitude and duration of the process for an optimal outcome remains obscure. Biological response modifiers, such as platelet-rich plasma (PRP) preparations, have been used to reconstitute the desirable early inflammatory state, but the results obtained remain inconclusive. Ongoing research to characterize and quantify the inflammatory response after bone fracture is essential in order to better understand the molecular insights of this localized reaction and to expand our armamentarium in the management of patients with an impaired fracture healing response. Non-steroidal anti inflammatory drugs frequently administered for analgesia after trauma procedures continue to be a cause of concern for a successful bone repair response. PMID- 26584271 TI - A highly selective on-off-on responsive lanthanide(iii) based probe for recognition of copper and hydrogen sulfide. AB - The development of a europium(iii) based probe (EuL1) for the detection of Cu(ii) ions and hydrogen sulphide is presented. With the addition of Cu(ii) ions, EuL1 displayed the greatest quenching among the other cations examined. The binding constant was 74,026 +/- 2899 M(-1). Once combined with Cu(ii) ions, EuL1Cu demonstrated high specificity for hydrogen sulfide compared to other organic and inorganic sulfur compounds. EuL1Cu exhibited an on-off-on type luminescence change with the alternate addition of Cu(ii) ions and H2S along with reversible forming-separating of the complex. PMID- 26584272 TI - A Qualitative Study of Smoker Identity Among College Student Smokers. AB - BACKGROUND: This research was motivated by findings that college students who smoke cigarettes often self-categorize as nonsmokers, that is, they reject the social identity of "smoker." OBJECTIVES: The goal of the present study was to shed light on college students' smoker identities beyond the smoker/nonsmoker dichotomy. METHODS: Focus groups were conducted to investigate how college students categorize their own smoking patterns and to identify what behaviors and attitudes are associated with these different categories of smoker identities. Forty-one students from a western university participated in this study in November 2011. RESULTS: The focus group results indicated that there were five distinct smoker identities on campus. Light and regular smokers were the daily smoker identities present, while stress, social, and drunk smokers were the occasional smoker identities. Moreover, each of these smoker identities was defined by a unique pattern of smoking behavior, attitudes, and motives. CONCLUSIONS/IMPORTANCE: These findings support the notion that there are different types of smokers, both daily and occasional, in the college population. We suggest that researchers, healthcare providers, and prevention/intervention programs may all benefit from distinguishing between these different types of smokers. PMID- 26584274 TI - Click and release: fluoride cleavable linker for mild bioorthogonal separation. AB - Herein, we present a water dispersable, magnetic nanoparticle supported "click and release" system. The cleavable linker has been synthesized by using a strain promoted copper-free "click" reagent to establish the specific link and a fluoride cleavable silane moiety for mild cleavage. Small organic molecules, azide-bearing dyes and functionalized enzymes have been bound to the magnetic particle and released in a bioorthogonal way. PMID- 26584276 TI - Low Dose Administration of Glutamate Triggers a Non-Apoptotic, Autophagic Response in PC12 Cells. AB - BACKGROUND/AIMS: Increasing amounts of the neurotransmitter glutamate are associated with excitotoxicity, a phenomenon related both to homeostatic processes and neurodegenerative diseases such as multiple sclerosis. METHODS: PC12 cells (rat pheochromocytoma) were treated with various concentrations of the non-essential amino acid glutamate for 0.5-24 hours. The effect of glutamate on cell morphology was monitored with electron microscopy and haematoxylin-eosin staining. Cell survival was calculated with the MTT assay. Expression analysis of chaperones associated with the observed phenotype was performed using either Western Blotting at the protein level or qRT-PCR at the mRNA level. RESULTS: Administration of glutamate in PC12 cells in doses as low as 10 MUM causes an up regulation of GRP78, GRP94 and HSC70 protein levels, while their mRNA levels show the opposite kinetics. At the same time, GAPDH and GRP75 show reduced protein levels, irrespective of their transcriptional rate. On a cellular level, low concentrations of glutamate induce an autophagy-mediated pro-survival phenotype, which is further supported by induction of the autophagic marker LC3. CONCLUSION: The findings in the present study underline a discrete effect of glutamate on neuronal cell fate depending on its concentration. It was also shown that a low dose of glutamate orchestrates a unique expression signature of various chaperones and induces cell autophagy, which acts in a neuroprotective fashion. PMID- 26584275 TI - Intradialytic Blood Pressure Abnormalities: The Highs, The Lows and All That Lies Between. AB - BACKGROUND: Frequent blood pressure (BP) measurements are necessary to ensure patient safety during hemodialysis treatments. Intradialytic BPs are not optimal tools for hypertension diagnosis and cardiovascular risk stratification, but they do have critical clinical and prognostic significance. We present evidence associating intradialytic BP phenomena including fall, rise and variability with adverse clinical outcomes and review related pathophysiologic mechanisms and potential management strategies. SUMMARY: Observational studies demonstrate associations between intradialytic hypotension, hypertension and BP variability and mortality. Lack of consensus regarding diagnostic criteria has hampered data synthesis, and prospective studies investigating optimal management strategies for BP phenomena are lacking. Mechanistic data suggest that cardiac, gut, kidney and brain ischemia may lie on the causal pathway between intradialytic hypotension and mortality, and endothelial cell dysfunction, among other factors, may be an important mediator of intradialytic hypertension and adverse outcomes. These plausible pathophysiologic links present potential therapeutic targets for future inquiry. The phenomenon of intradialytic BP variability has not been adequately studied, and practical clinical measures and treatment strategies are lacking. KEY MESSAGES: Intradialytic BP phenomena have important prognostic bearing. Clinical practice guidelines for both intradialytic hypotension and hypertension exist, but their underlying evidence is weak overall. Further research is needed to develop consensus diagnostic criteria for intradialytic hypotension, hypertension and BP variability and to elucidate optimal treatment and prevention strategies for each BP manifestation. PMID- 26584277 TI - Rapid Upregulation of Orai1 Abundance in the Plasma Membrane of Platelets Following Activation with Thrombin and Collagen Related Peptide. AB - BACKGROUND: Blood platelets accomplish primary hemostasis following vascular injury and contribute to the orchestration of occlusive vascular disease. Platelets are activated by an increase of cytosolic Ca2+-activity ([Ca2+]i), which is accomplished by Ca2+-release from intracellular stores and subsequent store operated Ca2+ entry (SOCE) through Ca2+ release activated Ca2+ channel moiety Orai1. Powerful activators of platelets include thrombin and collagen related peptide (CRP), which are in part effective by activation of small G- protein Rac1. The present study explored the influence of thrombin and CRP on Orai1 protein abundance and cytosolic Ca2+-activity ([Ca2+]i) in platelets drawn from wild type mice. METHODS: Orai1 protein surface abundance was quantified utilizing CFTM488A conjugated antibodies, and [Ca2+]i was determined with Fluo3 fluorescence. RESULTS: In resting platelets, Orai1 protein abundance and [Ca2+]i were low. Thrombin (0.02 U/ml) and CRP (5ug/ml) within 2 min increased [Ca2+]i and Orai1 protein abundance at the platelet surface. [Ca2+]i was further increased by Ca2+ ionophore ionomycin (1 uM) and by store depletion with the sarcoendoplasmatic Ca2+ ATPase inhibitor thapsigargin (1 uM). However, Orai1 protein abundance at the platelet surface was not significantly affected by ionomycin and only slightly increased by thapsigargin. The effect of thrombin and CRP on Orai1 abundance and [Ca2+]i was significantly blunted by Rac1 inhibitor NSC23766 (50 uM). CONCLUSION: The increase of [Ca2+]i following stimulation of platelets with thrombin and collagen related peptide is potentiated by ultrarapid Rac1 sensitive translocation of Orai1 into the cell membrane. PMID- 26584278 TI - Free Fatty Acids Impair FGF21 Action in HepG2 Cells. AB - BACKGROUND/AIMS: Fibroblast growth factor 21 (FGF21) is a key mediator of glucose and lipid metabolism. However, the beneficial effects of exogenous FGF21 administration are attenuated in obese animals and humans with elevated levels of circulating free fatty acids (FFA). METHODS: We investigated in vitro how FFA impact FGF21 effects on hepatic lipid metabolism. RESULTS: In the absence of FFA, FGF21 reduced lipogenesis and increased lipid oxidation in HepG2 cells. Inhibition of lipogenesis was associated with a down regulation of SREBP-1c, FAS and SCD1. The lipid-lowering effect was associated with AMPK and ACC phosphorylation, and up regulation of CPT-1alpha expression. Further, FGF21 treatment reduced TNFalpha gene expression, suggesting a beneficial action of FGF21 on inflammation. In contrast, the addition of FFA abolished the positive effects of FGF21 on lipid metabolism. CONCLUSION: In the absence of FFA, FGF21 improves lipid metabolism in HepG2 cells and reduces the inflammatory cytokine TNFalpha. However, under high levels of FFA, FGF21 action on lipid metabolism and TNFalpha gene expression is impaired. Therefore, FFA impair FGF21 action in HepG2 cells potentially through TNFalpha. PMID- 26584279 TI - Enhanced Eryptosis Following Exposure to Carnosic Acid. AB - BACKGROUND/AIMS: The phenolic abietane diterpene component of rosemary and sage, carnosic acid, may either induce or inhibit apoptosis of nucleated cells. The mechanisms involved in the effects of carnosic acid include altered mitochondrial function and gene expression. Human erythrocytes lack mitochondria and nuclei but are nevertheless able to enter suicidal death or eryptosis, which is characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Cellular mechanisms involved in the stimulation of eryptosis include oxidative stress, increase of cytosolic Ca2+ activity ([Ca2+]i), and ceramide formation. The present study explored, whether and how carnosic acid induces eryptosis. METHODS: Phosphatidylserine exposure at the cell surface was estimated from annexin V binding, cell volume from forward scatter, [Ca2+]i from Fluo3-fluorescence, ROS formation from DCFDA dependent fluorescence and ceramide abundance utilizing specific antibodies. RESULTS: A 48 hours exposure of human erythrocytes to carnosic acid significantly increased the percentage of annexin-V-binding cells (2.5 ug/ml), significantly decreased forward scatter (10 ug/ml), significantly increased Fluo3 fluorescence (10 ug/ml), significantly increased ceramide abundance (10 ug/ml), significantly increased hemolysis (10 ug/ml), but significantly decreased DCFDA fluorescence (10 ug/ml). The effect of carnosic acid on annexin-V-binding was significantly blunted, but not abolished by removal of extracellular Ca2+. CONCLUSION: Carnosic acid triggers cell shrinkage and phospholipid scrambling of the human erythrocyte cell membrane, an effect paralleled by and/or in part due to Ca2+ entry and increased ceramide abundance. PMID- 26584280 TI - Synergistic Effects of a Mixture of Glycosaminoglycans to Inhibit Adipogenesis and Enhance Chondrocyte Features in Multipotent Cells. AB - BACKGROUND/AIMS: Multipotent mesenchymal stem cells affect homeostasis of adipose and joint tissues. Factors influencing their differentiation fate are of interest for both obesity and joint problems. We studied the impact of a mixture of glycosaminoglycans (GAGs) (hyaluronic acid: dermatan sulfate 1:0.25, w/w) used in an oral supplement for joint discomfort (OralviscTM) on the differentiation fate of multipotent cells. METHODS: Primary mouse embryo fibroblasts (MEFs) were used as a model system. Post-confluent monolayer MEF cultures non-stimulated or hormonally stimulated to adipogenesis were chronically exposed to the GAGs mixture, its individual components or vehicle. The appearance of lipid laden cells, lipid accumulation and expression of selected genes at the mRNA and protein level was assessed. RESULTS: Exposure to the GAGs mixture synergistically suppressed spontaneous adipogenesis and induced the expression of cartilage extracellular matrix proteins, aggrecan core protein, decorin and cartilage oligomeric matrix protein. Hormonally-induced adipogenesis in the presence of the GAGs mixture resulted in decreased adipogenic differentiation, down-regulation of adipogenic/lipogenic factors and genes for insulin resistance-related adipokines (resistin and retinol binding protein 4), and up-regulation of oxidative metabolism-related genes. Adipogenesis in the presence of dermatan sulfate, the minor component of the mixture, was not impaired but resulted in smaller lipid droplets and the induction of a more complete brown adipocyte-related transcriptional program in the cells in the adipose state. CONCLUSIONS: The OralviscTM GAGs mixture can tip the adipogenic/chondrogenic fate balance of multipotent cells away from adipogenesis while favoring chondrocyte related gene expression. The mixture and its dermatan sulfate component also have modulatory effects of interest on hormonally-induced adipogenesis and on metabolic and secretory capabilities of adipose cells. PMID- 26584281 TI - Stimulation of Eryptosis by Narasin. AB - BACKGROUND/AIMS: Narasin, an ionophore used for the treatment of coccidiosis, has been shown to foster apoptosis of tumor cells. In analogy to apoptosis of nucleated cells, erythrocytes may enter eryptosis, the suicidal erythrocyte death characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Eryptosis may be triggered by Ca2+ entry with subsequent increase of cytosolic Ca2+ activity ([Ca2+]i), and by ceramide. The present study explored, whether and how narasin induces eryptosis. METHODS: Flow cytometry was employed to estimate phosphatidylserine exposure at the cell surface from annexin-V-binding, cell volume from forward scatter, [Ca2+]i from Fluo3-fluorescence, and ceramide abundance utilizing specific antibodies. RESULTS: A 48 hours exposure of human erythrocytes to narasin (10 and 25 ng/ml) significantly increased the percentage of annexin-V-binding cells. Forward scatter was decreased by 1 ng/ml narasin but not by higher narasin concentrations (10 and 25 ng/ml). Narasin significantly increased Fluo3-fluorescence (10 and 25 ng/ml) and slightly, but significantly increased ceramide abundance (25 ng/ml). The effect of narasin on annexin-V binding was significantly blunted, but not abolished by removal of extracellular Ca2+. CONCLUSIONS: Narasin triggers phospholipid scrambling of the erythrocyte cell membrane, an effect paralleled and partially dependent on Ca2+ entry. Narasin further leads to cell shrinkage and slight increase of ceramide abundance. PMID- 26584282 TI - SIRT1 and FOXO Mediate Contractile Differentiation of Vascular Smooth Muscle Cells under Cyclic Stretch. AB - BACKGROUND/AIMS: Physiological mechanical stretch in vivo helps to maintain the quiescent contractile differentiation of vascular smooth muscle cells (VSMCs), but the underlying mechanisms are still unclear. Here, we investigated the effects of SIRT1 in VSMC differentiation in response to mechanical cyclic stretch. METHODS AND RESULTS: Rat VSMCs were subjected to 10%-1.25Hz-cyclic stretch in vitro using a FX-4000T system. The data indicated that the expression of contractile markers, including alpha-actin, calponin and SM22alpha, was significantly enhanced in VSMCs that were subjected to cyclic stretch compared to the static controls. The expression of SIRT1 and FOXO3a was increased by the stretch, but the expression of FOXO4 was decreased. Decreasing SIRT1 by siRNA transfection attenuated the stretch-induced expression of contractile VSMC markers and FOXO3a. Furthermore, increasing SIRT1 by either treatment with activator resveratrol or transfection with a plasmid to induce overexpression increased the expression of FOXO3a and contractile markers, and decreased the expression of FOXO4 in VSMCs. Similar trends were observed in VSMCs of SIRT1 (+/ ) knockout mice. The overexpression of FOXO3a promoted the expression of contractile markers in VSMCs, while the overexpression of FOXO4 demonstrated the opposite effect. CONCLUSION: Our results indicated that physiological cyclic stretch promotes the contractile differentiation of VSMCs via the SIRT1/FOXO pathways and thus contributes to maintaining vascular homeostasis. PMID- 26584283 TI - Mesenchymal Stem Cell Conditioned Medium Promotes Proliferation and Migration of Alveolar Epithelial Cells under Septic Conditions In Vitro via the JNK-P38 Signaling Pathway. AB - BACKGROUND/AIMS: Mesenchymal stem cell (MSC) based therapies may be useful for treating acute respiratory distress syndrome (ARDS), but the underlying mechanisms are incompletely understood. We investigated the impact of human umbilical cord Wharton's jelly-derived MSC (hUC-MSC) secreted factors on alveolar epithelial cells under septic conditions and determined the relevant intracellular signaling pathways. METHODS: Human alveolar epithelial cells (AEC) and primary human small airway epithelial cells (SAEC) were subjected to lipopolysaccharide (LPS) with or without the presence of hUC-MSC-conditioned medium (CM). Proliferation and migration of AEC and SAEC were determined via an MTT assay, a wound healing assay and a transwell migration assay (only for AEC). Protein phosphorylation was determined by western blot and the experiments were repeated in presence of small-molecule inhibitors. The hMSC-secretory proteins were identified by LC-MS/MS mass spectrometry. RESULTS: MSC-CM enhanced proliferation and migration. Activation of JNK and P38, but not ERK, was required for the proliferation and migration of AEC and SAEC. Pretreatment of AEC or SAEC with SP600125, an inhibitor of JNK1 or SB200358, an inhibitor of P38, significantly reduced cell proliferation and migration. An array of proteins including TGF-beta receptor type-1, TGF-beta receptor type-2, Ras-related C3 botulinum toxin substrate 1 and Ras-related C3 botulinum toxin substrate 2 which influencing the proliferation and migration of AEC and SAEC were detected in MSC CM. CONCLUSION: Our data suggest MSC promote epithelial cell repair through releasing a repertoire of paracrine factors via activation of JNK and P38 MAPK. PMID- 26584284 TI - MicroRNA-148a Suppresses Invasion and Metastasis of Human Non-Small-Cell Lung Cancer. AB - BACKGROUND/AIMS: microRNAs (miRNAs) are noncoding RNAs that regulate multiple targets through either the degradation of mRNAs or the inhibition of protein translation, thereby altering several functions simultaneously. Growing evidence indicates that miRNAs are involved in carcinogenesis and tumor progression in non small-cell lung cancer (NSCLC). METHODS: In this study, the mRNA expression levels of miR-148a were examined in NSCLC cell lines and patient specimens using quantitative reverse transcription-PCR. The functions of miR-148a in migration/invasion and lung metastasis formation were determined by using transwell and tail vein injection assays, respectively. RESULTS: We demonstrated that miR-148a was down-regulated in NSCLC metastatic samples, and its expression was suppressed in NSCLC compared with the corresponding nonmalignant lung tissues. Clinical analysis indicated that miR-148a expression was lower in NSCLC patients compared with nonmalignant lung tissues . Decreased miR-148a was significantly associated with tumor node metastasis stage and lymph node metastasis. Furthermore, functional assays showed that miR-148a expression suppressed NSCLC cell invasive and migratory abilities in vitro and suppressed cancer metastasis in vivo, while inhibition of miR-148a enhanced NSCLC cell invasion and lung metastasis formation in a mouse model. CONCLUSIONS: Evidence from this study demonstrated that miR-148a exerts tumor-suppressive effects in NSCLC and suggests a new therapeutic option for NSCLC. PMID- 26584285 TI - Impact of Na+/Ca2+ Exchangers on Therapy Resistance of Ovary Carcinoma Cells. AB - BACKGROUND/AIMS: According to previous observations, enhanced store-operated Ca2+ entry (SOCE) accomplished by the pore forming ion channel unit Orai1 and its regulator STIM1 contribute to therapy resistance of ovary carcinoma cells. Ca2+ signaling is further shaped by Ca2+ extrusion through K+-independent (NCX) and/or K+-dependent (NCKX) Na+/Ca2+-exchangers. The present study thus explored whether therapy resistance is further paralleled by altered expression and/or function of Na+/Ca2+-exchangers. METHODS: In therapy resistant (A2780cis) and therapy sensitive (A2780sens) ovary carcinoma cells transcript levels were estimated from RT-PCR, cytosolic Ca2+-activity ([Ca2+]i) from Fura-2-fluorescence, Na+/Ca2+ exchanger activity from the increase of [Ca2+]i (x0394;[Ca2+]i) and from whole cell current (Ica) following abrupt replacement of Na+ containing (130 mM) and Ca2+ free extracellular perfusate by Na+ free and Ca2+ containing (2 mM) extracellular perfusate, as well as cell death from PI -staining in flow cytometry. RESULTS: The transcript levels of NCX3, NCKX4, NCKX5, and NCKX6, slope and peak of x0394;[Ca2+]i as well as Ica were significantly higher in therapy resistant than in therapy sensitive ovary carcinoma cells. The Na+/Ca2+-exchanger inhibitor KB-R7943 (10 uM) significantly blunted x0394;[Ca2+]i and significantly augmented the cisplatin-induced cell death of therapy resistant ovary carcinoma cells without significantly modifying cisplatin-induced cell death of therapy sensitive ovary carcinoma cells. CONCLUSION: Enhanced Na+/Ca2+-exchanger activity may contribute to the therapy sensitivity of ovary carcinoma cells. PMID- 26584286 TI - MicroRNAs as Regulators of Cisplatin Resistance in Lung Cancer. AB - Cisplatin (CDDP) is one of the most effective broad-spectrum anticancer drugs, which has been employed for the treatment of lung cancer. The development of CDDP resistance is a major problem of tumor chemotherapy. MicroRNAs (miRNAs) are an abundant class of small non-protein-coding RNAs, involved in the initiation and progression of human cancer. Increasing evidence has shown that dysregulation of miRNAs is involved in chemo resistance of tumor cells to anti-cancer drugs, including CDDP. This article summarizes current research involving miRNAs as regulators of key target genes for CDDP resistance in lung cancer. Potential use of targeting miRNAs can lead to miRNA-based therapies, which will be helpful for overcoming drug resistance and developing more effective personalized anti-cancer treatment strategies in human lung cancers. PMID- 26584287 TI - CCR4-NOT2 Promotes the Differentiation and Lipogenesis of 3T3-L1 Adipocytes via Upregulation of PPARx03B3;, CEBPalpha and Inhibition of P-GSK3alpha/beta and beta Catenin. AB - BACKGROUND/AIMS: Though CCR4-NOT2 (CNOT2), one of CCR4-NOT complex subunits, was known to be involved in metastasis and apoptosis through transcription and mRNA degradation, its other biological function is poorly understood so far. The aim of this study is to elucidate the molecular role of CNOT2 in the differentiation process of 3T3-L1 preadipocytes. METHODS AND RESULTS: CNOT2 was overexpressed during the differentiation process of 3T3-L1 preadipocytes. Consistently, mRNA levels of CNOT2, adiponectin, adiponectin 2, PPARx03B3; and CEBPalpha were enhanced in 3T3-L1 adipocytes. Conversely, CNOT2 depletion by siRNA transfection also reversed the activation of PPARx03B3; and CEBPalpha and inhibition of GSK3alpha/beta and beta-catenin at the protein level in 3T3-L1 preadipocytes. Immunofluorescence assay revealed that CNOT2 was colocalized with PPARx03B3;, but not with CEBPalpha in 3T3-L1 adipocyte. Consistently, IP western blots revealed that CNOT2 interacted with PPARx03B3; in 3T3-L1 adipocyte. CONCLUSION: Our findings demonstrate that CNOT2 promotes the differentiation of 3T3-L1 preadipocytes via upregulation of PPARx03B3;, and CEBPalpha and inhibition of GSK3alpha/beta and beta-catenin signaling as a potent molecular target for obesity. PMID- 26584288 TI - Characterization of Chondrogenic Gene Expression and Cartilage Phenotype Differentiation in Human Breast Adipose-Derived Stem Cells Promoted by Ginsenoside Rg1 In Vitro. AB - BACKGROUND/AIMS: Investigating and understanding chondrogenic gene expression during the differentiation of human breast adipose-derived stem cells (HBASCs) into chondrogenic cells is a prerequisite for the application of this approach for cartilage repair and regeneration. In this study, we aim to characterize HBASCs and to examine chondrogenic gene expression in chondrogenic inductive culture medium containing ginsenoside Rg1. METHODS: Human breast adipose-derived stem cells at passage 3 were evaluated based on specific cell markers and their multilineage differentiation capacity. Cultured HBASCs were treated either with basic chondrogenic inductive conditioned medium alone (group A, control) or with basic chondrogenic inductive medium plus 10 ug/ml (group B), 50 ug/ml (group C), or 100ug/ml ginsenoside Rg1 (group D). Cell proliferation was assessed using the CCK-8 assay for a period of 9 days. Two weeks after induction, the expression of chondrogenic genes (collagen type II, collagen type XI, ACP, COMP and ELASTIN) was determined using real-time PCR in all groups. RESULTS: The different concentrations of ginsenoside Rg1 that were added to the basic chondrogenic inductive culture medium promoted the proliferation of HBASCs at earlier stages (groups B, C, and D) but resulted in chondrogenic phenotype differentiation and higher mRNA expression of collagen type II (CO-II), collagen type XI (CO-XI), acid phosphatase (ACP), cartilage oligomeric matrix protein (COMP) and ELASTIN compared with the control (group A) at later stages. The results reveal an obvious positive dose-effect relationship between ginsenoside Rg1 and the proliferation and chondrogenic phenotype differentiation of HBASCs in vitro. CONCLUSIONS: Human breast adipose-derived stem cells retain stem cell characteristics after expansion in culture through passage 3 and serve as a feasible source of cells for cartilage regeneration in vitro. Chondrogenesis in HBASCs was found to be prominent after chondrogenic induction in conditions containing ginsenoside Rg1. PMID- 26584289 TI - Leukotriene B4 Inhibits L-Type Calcium Channels via p38 Signaling Pathway in Vascular Smooth Muscle Cells. AB - BACKGROUND/AIMS: Arachidonic acid (AA) and its metabolites are important endogenous lipid messengers. In this study, we test the effect of Leukotriene B4 (LTB4), a 5-lipoxygenase metabolite of AA, on L-type calcium channels in A7r5 rat aortic vascular smooth muscle cells. METHODS: L-type calcium channel currents were recorded by a patch-clamp technique. The mRNA expression of CaV1.2 was determined by Real-time RT-PCR. The protein expression of CaV1.2 and p38 activity was determined by Western blot analysis. RESULTS: LTB4 inhibits L-type channel currents in A7r5 cells in a dose-and time- dependent manner. LTB4 reduced the mRNA/protein expression of CaV1.2 channels in A7r5 cells. BLT1 receptor antagonist LY29311 abrogated the inhibitory effect of LTB4, while BLT2 receptor antagonist LY255283 had no effect. 5Z-7-oxozeaenol and SB203580, which block TAK1 and p38 kinase respectively, abrogated the LTB4 inhibitory effect on L-type calcium channels. LTB4 increased p38 activity in A7r5 cells. Blockage of Src, PI3K, JNK and NF-x03BA;B kinase had no effects on LTB4 inhibition of L-type calcium channel currents in A7r5 cells. CONCLUSION: We conclude that LTB4 inhibits L-type calcium channels through BLT1-TAk1-p38 signaling pathway. The LTB4 inhibitory effect on L-type calcium channels may be involved in its pathological processes such as atherosclerosis. PMID- 26584290 TI - Attenuating Hypoxia-Induced Apoptosis and Autophagy of Mesenchymal Stem Cells: the Potential of Sitagliptin in Stem Cell-Based Therapy. AB - BACKGROUND/AIMS: Dipeptidyl peptidase-4 (DPP-4) inhibitors have pleiotropic effects on cardiovascular protection beyond the antidiabetic property. However, it remains unknown that the impact of one DPP-4 inhibitor sitagliptin on the survival of mesenchymal stem cells (MSCs) in hypoxia and serum deprivation (H/SD) environment. METHODS: The apoptosis and autophagy of MSCs were analyzed in different concentrations of sitagliptin under H/SD condition. For later studies, we tested the relationship between anti-apoptotic and anti-autophagic effects of sitagliptin. The level of cell apoptosis was analyzed by Annexin V-FITC/PI staining, western blot of Bcl-2 and Bax proteins. Autophagy flux was assessed by multiple autophagy related proteins and substrates. Cell autophagy was identified by acridine orange staining, western blot of Beclin 1 and light chain 3 protein, and transmission electron microscopy. RESULTS: We demonstrated that sitagliptin attenuated hypoxia-induced apoptosis and autophagy of MSCs. Furthermore, sitagliptin regulated cell autophagy by Bcl-2/ Beclin 1 pathway in H/SD condition. CONCLUSIONS: This study provides insight into the utility of the DPP-4 inhibitor sitagliptin for MSCs transplantation in the ischemic microenvironment that extends its antidiabetic property. PMID- 26584291 TI - Role of Toll-Like Receptor 3 Gene Polymorphisms in Preeclampsia. AB - BACKGROUND/AIMS: Accumulating evidence suggests that an excessive maternal systemic inflammatory response to pregnancy with exaggerated activation of the innate immune system plays a critical role in the development of preeclampsia (PE). In this study, we investigated whether polymorphisms in the Toll-like receptor 3 (TLR3) gene are associated with susceptibility to PE in the Chinese Han population. METHODS: We recruited 987 PE patients and 1227 healthy pregnant women. Two polymorphisms (rs3775291 and rs3775296) located in TLR3 were genotyped by TaqMan allelic discrimination real-time PCR. The association between the genotype or allele frequencies and PE was examined using chi-square tests. Clinical data were compared between cases and controls using Student's t test. RESULTS: No significant difference was determined in the genetic distribution of rs3775291 and rs3775296 between cases and controls. There were also no significant differences in the genotype and allele frequencies of either SNP between healthy pregnant women and patients with late or early onset PE, or with mild or severe PE. CONCLUSION: Although this is the first study of the association between TLR3 polymorphisms and preeclampsia, we found that TLR3 polymorphisms are unlikely to play a significant role in the development of preeclampsia in the Chinese Han population. PMID- 26584292 TI - Involvement of Ca2+ Activated Cl- Channel Ano6 in Platelet Activation and Apoptosis. AB - BACKGROUND/AIMS: The ubiquitously expressed Ca2+ Activated Cl- Channel Ano6 participates in the stimulation of cell membrane scrambling. Defective Ano6 underlies the Scott syndrome, an inherited bleeding disorder with impaired scrambling of plasma membrane phospholipids. At least in theory, the bleeding disorder of Scott syndrome may result from impaired platelet function. Activators of platelets include thrombin and collagen related peptide (CRP), which trigger increase of cytosolic Ca2+-activity ([Ca2+]i), production of reactive oxygen species (ROS), degranulation, integrin activation, as well as cell shrinkage and phospholipid scrambling of the cell membrane. The present study thus explored whether Ano6 modifies activation-induced alterations of cytosolic Ca2+-activity ([Ca2+]i), degranulation (P-selectin exposure), integrin activation, phosphatidylserine exposure on the platelet surface and platelet volume. METHODS: Platelets from mice lacking Ano6 (ano6-/-) were compared to platelets from corresponding wild-type mice (ano6+/+). [Ca2+]i was estimated from Fluo-3 fluorescence, ROS from DCFDA fluorescence, degranulation from P-selectin abundance, integrin activation from alphaIIbbeta3-integrin abundance, phosphatidylserine abundance from annexin-V-binding, and cell volume from forward scatter. RESULTS: Platelet number in blood was slightly higher in ano6-/- mice than in ano6+/+ mice. Without activation [Ca2+]i and volume were similar in ano6 /- and ano6+/+ platelets as well as ROS abundance, P-selectin abundance, alphaIIbbeta3 integrin activation, and phosphatidylserine exposure were negligible in both genotypes. Thrombin (0.01 U/ml) and CRP (2 or 5 ug/ml) increased [Ca2+]i, ROS abundance, platelet degranulation, alphaIIbbeta3 integrin activation, and triggered annexin-V-binding as well as cell shrinkage, all effects less pronounced in ano6-/- than in ano6+/+ platelets. CONCLUSIONS: Genetic knockout of Ano6 blunts thrombin- and CRP-induced activation and apoptosis of blood platelets. PMID- 26584293 TI - Enhanced Store-Operated Calcium Entry in Platelets is Associated with Peripheral Artery Disease in Type 2 Diabetes. AB - BACKGROUND/AIMS: Platelet dysfunction plays an important role in thrombosis in diabetes with peripheral artery disease (PAD). Store-operated calcium entry (SOCE) and stromal interaction molecule 1 (STIM1) regulate platelet activity by modulating calcium influx. We hypothesized that enhanced SOCE in platelets is associated with diabetes with PAD. METHODS: We studied the activity of platelets from healthy participants and from type 2 diabetic patients. Platelet calcium influx and protein expression of STIM1 and sarcoendoplasmic reticulum Ca2+-ATPase 3 (SERCA3) were investigated. RESULTS: Compared with platelets from diabetic patients without PAD, platelets from diabetic patients with PAD exhibited significantly increased SOCE . Menthol administration completely inhibited calcium influx in platelets from diabetic patients without PAD, but this effect was blunted in those from diabetic patients with PAD. Furthermore, the increase in SOCE was correlated with the ankle brachial index (ABI) in diabetic patients. High glucose significantly up-regulated STIM1 and SERCA3 protein expression and induced the phosphorylation of phospholipase C (PLC) in platelets from healthy participants. This effect was attenuated in the presence of menthol or U73122, an inhibitor of PLC. Similarly, significant increases in STIM1 and SERCA3 protein expression were found in platelets from diabetic patients compared to those from healthy participants. CONCLUSION: Platelets from diabetic patients with PAD exhibited enhanced Store-operated calcium influx, which was associated with elevated STIM1/SERCA3 expression via a PLC-dependent pathway and was inhibited by menthol. PMID- 26584295 TI - Serum Procalcitonin Level and Mortality Risk in Critically ill Patients with Ventilator-Associated Pneumonia. AB - BACKGROUND/AIMS: The prognostic role of serum procalcitonin level in critically ill patients with ventilator-associated pneumonia was unclear. The aim of our study was to investigate the relationship between serum procalcitonin level and mortality risk in critically ill patients with ventilator-associated pneumonia. METHODS: Data of critically ill patients with ventilator-associated pneumonia were retrospectively collected. Demographics, comorbidities, and serum procalcitonin level were extracted from electronic medical records. The primary outcome was mortality within two months after diagnosis. Multivariable Cox regression analyses were performed to assess the prognostic role of serum procalcitonin level in those patients. RESULTS: A total of 115 critically ill patients with ventilator-associated pneumonia were enrolled in our study. Serum procalcitonin level was not associated with age, gender, or other comorbidities. Univariate Cox regression model showed that high serum procalcitonin level was associated increased risk of morality within 2 months after diagnosis (OR = 2.32, 95% CI 1.25-4.31, P = 0.008). Multivariable Cox regression model showed that high serum procalcitonin level was independently associated increased risk of morality within 2 months after diagnosis (OR = 2.38, 95% CI 1.26-4.50, P = 0.008). CONCLUSION: High serum procalcitonin level is an independent prognostic biomarker of mortality risk in critically ill patients with ventilator-associated pneumonia, and it's a promising biomarker of prognosis in critically ill patients. PMID- 26584294 TI - MiR-203 Determines Poor Outcome and Suppresses Tumor Growth by Targeting TBK1 in Osteosarcoma. AB - BACKGROUND/AIMS: Increasing evidence has shown that miR-203 plays important role in human cancer progression. However, little is known about the function of miR 203 in osteosarcoma (OS). METHODS: The expression of miR-203 in OS tissues and cell lines were examined by qRT-PCR. The biological role of miR-20 in OS cell proliferation was examined in vitro and in vivo. The targets of miR-203 were identified by a luciferase reporter gene assay. RESULTS: miR-203 was down regulated in OS tissues and cell lines; decreased miR-203 was associated with a poor overall survival in OS patients. Restoration of miR-203 expression reduced cell growth in vitro and suppressed tumorigenicity in vivo. In contrast, inhibition of miR-203 stimulated OS cell growth both in vitro and in vivo. In addition, TANK binding kinase 1 (TBK1) was identified as a direct target of miR 203; overexpression of TBK1 partly reversed the suppressive effects of miR-203. Furthermore, TBK1 was found up-regulated and inversely correlated with miR-203 in OS tissues. CONCLUSION: Taken together, these findings suggest that miR-203 acts as a tumor suppressor via regulation of TBK1 expression in OS progression, and miR-203 may be a promising therapeutic target for OS. PMID- 26584296 TI - Saquinavir Induced Suicidal Death of Human Erythrocytes. AB - BACKGROUND/AIMS: The antiretroviral protease inhibitor saquinavir is used for the treatment of HIV infections. Effects of saquinavir include induction of apoptosis, the suicidal death of nucleated cells. Saquinavir treatment may further lead to anemia. In theory, anemia could result from accelerated erythrocyte loss by enhanced suicidal erythrocyte death or eryptosis, which is characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Stimulators of eryptosis include Ca2+ entry with increase of cytosolic Ca2+ activity ([Ca2+]i), oxidative stress with increase of reactive oxygen species (ROS) and ceramide. The present study explored, whether and how saquinavir induces eryptosis. METHODS: To this end, flow cytometry was employed to estimate erythrocyte volume from forward scatter, phosphatidylserine exposure at the cell surface from annexin-V-binding, [Ca2+]i from Fluo3-fluorescence, ROS abundance from DCFDA fluorescence and ceramide abundance utilizing specific antibodies. RESULTS: A 48 hours exposure of human erythrocytes to saquinavir significantly decreased forward scatter (>= 5 ug/ml), significantly increased the percentage of annexin-V-binding cells (>= 10 ug/ml), significantly increased Fluo3-fluorescence (15 ug/ml), significantly increased DCFDA fluorescence (15 ug/ml), but did not significantly modify ceramide abundance. The effect of saquinavir on annexin-V-binding was significantly blunted, but not abolished by removal of extracellular Ca2+. CONCLUSIONS: Saquinavir triggers cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane, an effect in part due to stimulation of ROS formation and Ca2+ entry. PMID- 26584297 TI - Decreased Osteopontin Expression as a Reliable Prognostic Indicator of Improvement in Pulmonary Tuberculosis: Impact of the Level of Interferon-gamma Inducible Protein 10. AB - BACKGROUND/AIMS: Osteopontin (OPN) expression is increased during the course of various chronic inflammatory diseases, including tuberculosis (TB). However, its prognostic value in TB management remains unclear. This study aimed to determine whether OPN could associate with other cytokines serving as a reliable biomarker for evaluating the effectiveness of early anti-TB treatments. METHODS: Smear positive pulmonary TB patients (n = 20) were recruited, and the plasma levels of OPN, IP-10, TNF-alpha, and IL-12 were measured by ELISA before initiation of anti TB therapy and after sputum smear conversion. The C-reactive protein (CRP) levels and erythrocyte sedimentation rate (ESR) were also tracked during anti-TB treatment. RESULTS: OPN expression was significantly elevated in patients with smear-positive pulmonary TB, and was closely related with disease severity. Monitoring during the treatment course revealed that its expression, along with that of IFN-x03B3;-induced protein 10 (IP-10), decreased significantly only after sputum smear conversion. Moreover, OPN levels positively correlated with CRP levels before and after anti-TB treatment. Furthermore, OPN markedly promoted IP 10 expression in peripheral blood mononuclear cells. CONCLUSION: Association between OPN and IP-10 may serve as a reliable prognostic indicator for improvement during the early treatment of pulmonary TB, and may help clinicians in tailoring an effective TB treatment regimen. PMID- 26584298 TI - New Indole Alkaloids from the Bark of Rauvolfia Reflexa and their Cholinesterase Inhibitory Activity. AB - BACKGROUND/AIMS: Rauvolfia reflexa is a member of the Apocynaceae family. Plants from the Apocynaceae family have been traditionally used in the treatment of age related brain disorders Methods and Results: Two new indole alkaloids, rauvolfine C (1) and 3-methyl-10,11-dimethoxy-6-methoxycarbonyl-beta-carboline (2), along with five known, macusine B (3), vinorine (4), undulifoline (5), isoresrpiline (6) and rescinnamine (7) were isolated from the bark of Rauvolfia reflexa. Cholinesterase inhibitory assay and molecular docking were performed to get insight of the inhibitory activity and molecular interactions of the compounds. The compounds showed good to moderate cholinesterase inhibitory activity with IC50 values in the range of 8.06 to 73.23 uM. Compound 7 was found to be the most potent inhibitor of both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Compounds 1, 2, 5 and 6 were found to be selective towards BChE, while compounds 3, 4 and 7 were dual inhibitors, having almost equal inhibitory activity on both AChE and BChE. Molecular docking revealed that compounds 6 and 7 interacted differently on AChE and BChE, by means of hydrophobic interactions and hydrogen bonding. In AChE, the indole moiety of both compounds interacted with the residues lining the peripheral anionic site, whereas in BChE, their methoxy groups are primarily responsible for the strong inhibitory activity via interactions with residues at the active site of the enzyme. CONCLUSION: Two new and five known indole alkaloids were isolated from R. reflexa. Among the compounds, 7 and 6 showed the most potent and promising cholinesterase inhibitory activity, worthy for further investigations. PMID- 26584299 TI - Expression of Nodal on Bronchial Epithelial Cells Influenced by Lung Microbes Through DNA Methylation Modulates the Differentiation of T-Helper Cells. AB - BACKGROUND/AIMS: The previous study in our lab showed that Nodal molecule on bronchial epithelial cells (BECs) was modulated by all kinds of lung microbes. The present study was designed to determine the effects of Nodal on proliferation of BECs and BECs-induced differentiation of T-helper (Th) cells. The epigenetic mechanisms of Nodal expression following treatments of different lung microbes were also identified. METHODS: Real-time polymerization chain reaction (PCR) and western blot were used to determine the expression of Nodal. Flow cytometry was used to observe the effects of proliferation of BECs and subsequent BECs-induced differentiation of Th cells. Methylation levels of CpG islands in Nodal promoters were also analyzed by time of flight mass spectrometry. RESULTS: The results showed that Nodal promoted proliferation of BECs and BECs-induced differentiation of Th cell from Th1 to Th2 and Th17. Nodal promoter showed a hyper-methylation in normal BECs. Through methylation modification in the promoter, P. aeruginosa or A.baumanni inhibited the expression of Nodal while RSV promoted the expression of Nodal. CONCLUSIONS: Our data showed that Nodal promoted Th2 and Th17 differentiation and inhibited Th1 differentiation which may cause imbalance of airway microenvironment. P. aeruginosa or A.baumanni may be hopeful for the treatment of airway hyperresponsveness by inhibition Nodal expression through DNA methylation modification in the promoter. PMID- 26584300 TI - Nefiracetam Attenuates Pro-Inflammatory Cytokines and GABA Transporter in Specific Brain Regions of Rats with Post-Ischemic Seizures. AB - BACKGROUND/AIMS: Prior studies demonstrated that pro-inflammatory cytokines (PICs) including IL-1beta, IL-6 and TNF-alpha contribute to regulation of epilepsy-associated pathophysiological processes in the specific brain regions, namely the parietal cortex, hippocampus and amygdala. Moreover, GABA transporter type 1 and 3 (GAT-1 and GAT-3) modulating extracellular GABA levels are engaged in the role played by PICs in epileptogenesis. Note that brain ischemic injury also elevates cerebral PICs. Thus, in this report we examined the effects of nefiracetam (NEF), a pyrrolidone derivative, on the levels of IL-1beta, IL-6 and TNF-alpha, and expression of GAT-1 and GAT-3 in the parietal cortex, hippocampus and amygdala using a rat model of post-ischemic nonconvulsive seizure (NCS). METHODS: NCS was evoked by the middle cerebral artery occlusion (MCAO). ELISA and Western Blot analysis were employed to determine the levels of PICs and GAT-1/GAT 3, respectively. RESULTS: MCAO significantly increased IL-1beta, IL-6 and TNF alpha in the parietal cortex, hippocampus and amygdala as compared with sham control animals (P<0.05 vs. control rats). Also, in these specific brain regions expression of GAT-1 and GAT-3 was amplified; and the levels of GABA were decreased in rats following MCAO (P<0.05 vs. control rats). Systemic administration of NEF significantly attenuated the elevated PICs, amplified GAT-1 and GAT-3 as well as impaired GABA. NEF also attenuated the number of NCS events following MCAO. CONCLUSION: our data demonstrate that NEF improves post-ischemia evoked-NCS by altering PICs, GABA transporters thereby alleviating GABA in the parietal cortex, hippocampus and amygdala. This support a role for PICs and GABA in engagement of the adaptive responses associated with epileptic activity, but also suggests that NEF has anti-epileptic effects via PICs-GABA mechanisms, having pharmacological implications to target the specific PICs for neuronal dysfunction and vulnerability related to post-ischemic seizures and cognitive impairment. PMID- 26584301 TI - SPAK and OSR1 Sensitive Cell Membrane Protein Abundance and Activity of KCNQ1/E1 K+ Channels. AB - BACKGROUND/AIMS: KCNQ1/E1 channels are expressed in diverse tissues and serve a variety of functions including endolymph secretion in the inner ear, cardiac repolarization, epithelial transport and cell volume regulation. Kinases involved in regulation of epithelial transport and cell volume include SPAK (SPS1-related proline/alanine-rich kinase) and OSR1 (oxidative stress-responsive kinase 1), which are under control of WNK (with-no-K[Lys]) kinases. The present study explored whether KCNQ1/E1 channels are regulated by SPAK and/or OSR1. METHODS: cRNA encoding KCNQ1/E1 was injected into Xenopus oocytes with or without additional injection of cRNA encoding wild-type SPAK, constitutively active T233ESPAK, WNK insensitive T233ASPAK, catalytically inactive D212ASPAK, wild-type OSR1, constitutively active T185EOSR1, WNK insensitive T185AOSR1 and catalytically inactive D164AOSR1. Voltage gated K+ channel activity was quantified utilizing dual electrode voltage clamp and KCNQ1/E1 channel protein abundance in the cell membrane utilizing chemiluminescence of KCNQ1/E1 containing an extracellular Flag tag epitope (KCNQ1-Flag/E1). RESULTS: KCNQ1/E1 activity and KCNQ1-Flag/E1 protein abundance were significantly enhanced by wild-type SPAK and T233ESPAK, but not by T233ASPAK and D212ASPAK. Similarly, KCNQ1/E1 activity and KCNQ1-Flag/E1 protein abundance were significantly increased by wild-type OSR1 and T185EOSR1, but not by T185AOSR1 and D164AOSR1. CONCLUSIONS: SPAK and OSR1 participate in the regulation of KCNQ1/E1 protein abundance and activity. PMID- 26584302 TI - Extracellular Adenosine Diphosphate Ribose Mobilizes Intracellular Ca2+ via Purinergic-Dependent Ca2+ Pathways in Rat Pulmonary Artery Smooth Muscle Cells. AB - BACKGROUND/AIMS: Adenosine diphosphate ribose (ADPR), a product of beta-NAD+ metabolism generated by the multifunctional enzyme CD38, is recognized as a novel signaling molecule. The catalytic site of CD38 orients extracellularly or intracellularly, capable of generating ADPR outside and inside the cells. CD38 dependent pathways have been characterized in pulmonary artery smooth muscle cells (PASMCs); however the physiological function of extracellular ADPR is unclear. METHODS: Ca2+ mobilizing and proliferative effects of extracellular ADPR were characterized and compared with the ATP-induced responses in rat PASMCs; and the expression of purinergic receptor (P2X and P2Y) subtypes were examined in pulmonary arteries. RESULTS: ADPR elicited concentration-dependent increase in [Ca2+]i with a fast transient and a sustained phase in PASMCs. The sustained phase was abolished by Ca2+ removal and inhibited by the non-selective cation channel blocker SKF-96365, but was unaffected by TRPM2 antagonists or nifedipine. The purinergic receptor (P2X) antagonist pyridoxal-phosphate-6-azophenyl-2', 4' disulfonate inhibited partially the transient and the sustained Ca2+ response, while the P2(XY) inhibitor suramin and the phospholipase C inhibitor U73122 abolished the sustained Ca2+ influx. The P2Y1 antagonist MRS2179 had no effect on the response. By contrast, ATP and ADP activated Ca2+ response exhibited a high and a low affinity component, and the pharmacological profile of ATP-induced Ca2+ response was distinctive from that of ADPR. BrdU incorporation assay showed that ADPR caused significant inhibition whereas ATP caused slight stimulation of PASMC proliferation. RT-PCR analysis found that almost all P2X and P2Y subtypes are expressed in PAs. CONCLUSION: ADPR and ATP activate Ca2+ responses through different combinations of multiple purinergic receptor subtypes; and extracellular ADPR may exert an autocrine/paracrine action via purinergic receptors on PASMCs. PMID- 26584303 TI - Licochalcone A Induced Suicidal Death of Human Erythrocytes. AB - BACKGROUND: The anti-inflammatory, immunomodulatory, and antimicrobial Glycyrrhiza inflata extract component licochalcone A triggers apoptosis of tumor cells and is thus considered for the treatment of malignancy. Similar to apoptosis of nucleated cells, erythrocytes may enter eryptosis, the suicidal erythrocyte death characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Signaling involved in the triggering of eryptosis includes Ca2+ entry with increase of cytosolic Ca2+ activity ([Ca2+]i), and ceramide. The present study explored, whether and how licochalcone A induces eryptosis. METHODS: Human erythrocytes drawn from healthy individuals were exposed for 24 hours to 1-10 ug/ml licochalcone A. Flow cytometry was subsequently employed to estimate phosphatidylserine exposure at the cell surface from annexin V binding, cell volume from forward scatter, [Ca2+]i from Fluo3-fluorescence, and ceramide utilizing specific antibodies. In addition, hemolysis was quantified from hemoglobin release. RESULTS: Licochalcone A significantly increased the percentage of annexin-V-binding cells (>= 5 ug/ml), significantly decreased forward scatter (2.5 - 5 ug/ml), significantly increased Fluo3-fluorescence (>= 7.5 ug/ml), and significantly increased ceramide abundance (10 ug/ml). The effect of licochalcone on annexin-V-binding was not significantly modified, but hemolysis significantly enhanced by removal of extracellular Ca2+. CONCLUSIONS: Licochalcone triggers cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane, an effect independent from Ca2+ entry and presumably in part due to ceramide. PMID- 26584304 TI - Hyaluronic Acid Binding Assay Is Highly Sensitive to Select Human Spermatozoa with Good Progressive Motility, Morphology, and Nuclear Maturity. AB - OBJECTIVE: This study was performed to evaluate the correlation of hyaluronic acid binding assay (HBA) with conventional semen parameters, lipid peroxidation (LPO), intracellular reactive oxygen species (ROS), DNA fragmentation (DF), DNA maturity and mitochondrial membrane potential (MMP) level in human spermatozoa. METHODS: The semen samples were obtained from 98 patients. The seminal plasma was separated for the study of LPO, and the pellet was employed for evaluation of intracellular ROS, DF, nuclear maturity (sperm chromatin structure assay) and MMP through flowcytometry. RESULTS: The correlation and strength of HBA with respect to the studied parameters were estimated by the Pearson coefficient and multiple liner regression tests. While HBA indicated a positive correlation with progressive motility (beta-coefficients = 0.449, p < 0.05) and normal morphology (beta-coefficients = 2.722, p < 0.01), it had only negative relationship with DNA integrity (high DNA stain ability; beta-coefficients = -0.517, p < 0.05). HBA also did not show any important correlation with other conventional and intracellular sperm parameters. CONCLUSIONS: The HBA is sensitive to morphological integrity, high progressive motility and nuclear maturation. Nonetheless, HBA is not a reliable test for prediction of sperm intracellular ROS, DF and MMP risks and healthy spermatozoa selection. PMID- 26584305 TI - NADC30-like Strain of Porcine Reproductive and Respiratory Syndrome Virus, China. PMID- 26584307 TI - Fabrication of multilayered nanofluidic membranes through silicon templates. AB - We present a new fabrication method for solid-state nanoporous membranes based on sacrificial template structures made of silicon. The process consists of creating membranes by evaporating thin-films on sacrificial templates which, after their selective removal, opens the nanopores and releases the free-standing membranes. This way it is possible to define the geometry of the pore by design and to build the membrane by stacking thin-films of various materials through evaporation. Such a membrane with controlled porosity, pore geometry, thickness and nano channel composition provides new opportunities for selective chemical functionalization, gating, electrical sensing or electrical stimulation inside the nanopore. PMID- 26584308 TI - A case of Pseudomonas Aeruginosa commercial tattoo infection. PMID- 26584306 TI - Learning of Chunking Sequences in Cognition and Behavior. AB - We often learn and recall long sequences in smaller segments, such as a phone number 858 534 22 30 memorized as four segments. Behavioral experiments suggest that humans and some animals employ this strategy of breaking down cognitive or behavioral sequences into chunks in a wide variety of tasks, but the dynamical principles of how this is achieved remains unknown. Here, we study the temporal dynamics of chunking for learning cognitive sequences in a chunking representation using a dynamical model of competing modes arranged to evoke hierarchical Winnerless Competition (WLC) dynamics. Sequential memory is represented as trajectories along a chain of metastable fixed points at each level of the hierarchy, and bistable Hebbian dynamics enables the learning of such trajectories in an unsupervised fashion. Using computer simulations, we demonstrate the learning of a chunking representation of sequences and their robust recall. During learning, the dynamics associates a set of modes to each information-carrying item in the sequence and encodes their relative order. During recall, hierarchical WLC guarantees the robustness of the sequence order when the sequence is not too long. The resulting patterns of activities share several features observed in behavioral experiments, such as the pauses between boundaries of chunks, their size and their duration. Failures in learning chunking sequences provide new insights into the dynamical causes of neurological disorders such as Parkinson's disease and Schizophrenia. PMID- 26584309 TI - Primary idiopathic anetoderma. PMID- 26584310 TI - Facial involvement in pityriasis rosea: differences among Caucasian and dark skinned patients. PMID- 26584312 TI - Creating a Scheduling System on a Budget. PMID- 26584311 TI - 50 Years of Emmonsia Disease in Humans: The Dramatic Emergence of a Cluster of Novel Fungal Pathogens. PMID- 26584314 TI - The Evolutionary Soul of Jack Whitten (b.1939): April's Shark (1974). PMID- 26584317 TI - Increasing the Frequency on Spinal Cord Stimulation. PMID- 26584318 TI - A Prospective Cohort Study of Idarucizumab for Reversal of Dabigatran-Associated Hemorrhage. PMID- 26584319 TI - Succinate: A Promising Therapeutic Target for Reperfusion Injury. PMID- 26584320 TI - Neuroimaging as a Prognostication Tool for Glioblastoma. PMID- 26584321 TI - Excitotoxic SLC7A11 Expression Is a Marker of Poor Glioblastoma Survival and a Potential Therapeutic Target. PMID- 26584322 TI - The Future of Neural Recording Devices: Nanoscale, Flexible, and Injectable. PMID- 26584323 TI - Single Neuron Markers of Memory Retrieval Confidence. PMID- 26584324 TI - Neurosurgeons on the Front Line of Stroke Management: Spotting Stroke Chameleons. PMID- 26584327 TI - SHORT-TERM FLUCTUATION OF MACULAR EDEMA IN A PATIENT DIAGNOSED EARLY WITH IDIOPATHIC MACULAR TELANGIECTASIA TYPE 1: FOLLOW-UP WITH SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY. AB - PURPOSE: To present a case of idiopathic macular telangiectasia Type 1, diagnosed at early stages and its close monitoring through spectral domain optical coherence tomography. METHODS: Case report. RESULTS: A case is presented of a 43 year-old man with blurred vision in his right eye and no further symptoms. The patient did not have any history of ophthalmic disease. Imaging test with fluorescein angiography confirmed a diagnosis of idiopathic macular telangiectasia Type 1. CONCLUSION: During a close follow-up period of 6 months, spectral domain optical coherence tomography demonstrated considerable fluctuations regarding his central retinal thickness (macular edema), presence of lipid exudates, and associated visual acuity loss. PMID- 26584326 TI - Effects of levomilnacipran ER on fatigue symptoms associated with major depressive disorder. AB - The aim of this study was to evaluate the effects of levomilnacipran extended release (ER) on depression-related fatigue in adults with major depressive disorder. Post-hoc analyses of five phase III trials were carried out, with evaluation of fatigue symptoms based on score changes in four items: Montgomery Asberg Depression Rating Scale (MADRS) item 7 (lassitude), and 17-item Hamilton Depression Rating Scale (HAMD17) items 7 (work/activities), 8 (retardation), and 13 (somatic symptoms). Symptom remission was analyzed on the basis of score shifts from baseline to end of treatment: MADRS item 7 and HAMD17 item 7 (from >=2 to <=1); HAMD17 items 8 and 13 (from >=1 to 0). The mean change in MADRS total score was analyzed in patients with low and high fatigue (MADRS item 7 baseline score <4 and >=4, respectively). Patients receiving levomilnacipran ER had significantly greater mean improvements and symptom remission (no/minimal residual fatigue) on all fatigue-related items: lassitude (35 vs. 28%), work/activities (43 vs. 35%), retardation (46 vs. 39%), somatic symptoms (26 vs. 18%; all Ps<0.01 versus placebo). The mean change in MADRS total score was significantly greater with levomilnacipran ER versus placebo in both low (least squares mean difference=-2.8, P=0.0018) and high (least squares mean difference= 3.1, P<0.0001) fatigue subgroups. Levomilnacipran ER treatment was effective in reducing depression-related fatigue in adult patients with major depressive disorder and was associated with remission of fatigue symptoms. PMID- 26584328 TI - CHOROIDAL NEOVASCULARIZATION SECONDARY TO ALEXANDRITE LASER EXPOSURE. AB - PURPOSE: To report macular photic trauma after accidental occupational exposure to a 750-nm Alexandrite laser and management of secondary choroidal neovascularization. METHODS: Institutional review board-approved retrospective case report. RESULTS: A 30-year-old woman presented with immediate vision loss in her left eye after direct inadvertent exposure to a single discharge from an occupational 750-nm Alexandrite laser used for laser hair removal. Baseline Snellen visual acuity was 20/40 in the involved left eye. One week after the initial exposure, the patient experienced subjective visual decline to 20/50, was treated with oral prednisone, and then developed a subretinal hemorrhage (SRH) in the setting of choroidal neovascularization 2 weeks later, or 3 weeks after initial trauma. The patient subsequently received 5 intravitreal ranibizumab injections over 25 weeks with resolution of the SRH. Final visual acuity was 20/50. CONCLUSION: The present case documents development and management of subretinal hemorrhage associated with choroidal neovascularization following macular photic trauma after accidental occupational to a 750-nm Alexandrite laser. PMID- 26584329 TI - MULTIMODAL IMAGING OF A FAMILY WITH SPINOCEREBELLAR ATAXIA TYPE 7 DEMONSTRATING PHENOTYPIC VARIATION AND PROGRESSION OF RETINAL DEGENERATION. AB - PURPOSE: To report the variability and progression of clinical presentation in three family members with spinocerebellar ataxia Type 7 including early recognizable features on retinal imaging and magnetic resonance imaging. METHODS: Retrospective case series. RESULTS: The proband, Patient 1 (mother) presented at age 26 with light perception vision. Initial examination was significant for optic disc pallor, vascular attenuation, and central macular atrophy. Two years later, her vision declined to no light perception, and fundus examination demonstrated marked progression of macular atrophy and peripheral bone spicule formation. Seven years after the onset of vision loss, neurologic examination demonstrated ataxia, dysarthria, and slowed saccades. Genetic testing of ATXN7 identified heterozygous 61-CAG trinucleotide repeat expansion confirming the diagnosis of spinocerebellar ataxia Type 7. Patient 2 (son) presented at age 11 with visual acuity of 20/300 bilaterally and decreased color vision. Funduscopic examination was notable for disc pallor, vascular attenuation, and peripheral pigmentary changes. Electroretinography demonstrated diminished rod and cone function, and Goldmann visual field testing revealed paracentral scotoma. Patient 3 (daughter) presented at age 14 with visual acuity of 20/50 bilaterally and minimal funduscopic changes. The only significant ophthalmic finding was retinal thinning with atrophy of the outer nuclear layer and subfoveal ellipsoid zone on optical coherence tomography. Early cerebellar volume loss was also noted on magnetic resonance imaging. CONCLUSION: The clinical presentation of spinocerebellar ataxia Type 7 can vary widely even within the same family. In individuals with vision loss and normal fundus examination, careful evaluation of optical coherence tomography and brain magnetic resonance imaging facilitates early diagnosis and genetic testing. PMID- 26584330 TI - A UNIQUE POSTERIOR SEGMENT PHENOTYPIC MANIFESTATION OF COXSACKIE VIRUS INFECTION. AB - PURPOSE: To report a posterior segment phenotypic manifestation of Coxsackie virus infection that has not been previously appreciated. METHODS: The clinical course and multimodal imaging findings, including spectral domain optical coherence tomography, fluorescein angiography, near infrared reflectance, and fundus autofluorescence of two patients with Coxsackie virus infections were documented. RESULTS: A neurosensory macular detachment was present in both patients on baseline examination. Fluorescein angiography demonstrated pooling within this lesion and spectral domain optical coherence tomography identified thickening of the retinal pigment epithelial band with variable degrees of attenuation of the ellipsoid zone and interdigitation zone. Fundus autofluorescence and near infrared reflectance imaging revealed multiple satellite lesions adjacent to the neurosensory detachment. These lesions were not seen on fluorescein angiography or color photography. Satellite lesions were hyporeflective on near infrared reflectance imaging and hyperautofluorescent on fundus autofluorescence imaging. The satellite lesions correlated with sites of ellipsoid disruption on spectral domain optical coherence tomography. Both patients were observed and their condition improved over the course of time. There was total resolution of satellite lesions, reconstitution of the ellipsoid zone and interdigitation zone, and return of retinal pigment epithelial thickness to the normal range. A bull's eye pattern of macular retinal pigment epithelial disturbance persisted on color and near infrared reflectance images, despite good visual acuity. CONCLUSION: Posterior segment Coxsackie virus infection may concurrently express the clinical characteristics of acute idiopathic maculopathy and multifocal retinitis. The visual prognosis in this variant is usually favorable. The multimodal imaging features that characterize this entity should be recognized to avoid confusion with other diseases that have a similar presentation. PMID- 26584332 TI - Correction: High-surface-area mesoporous TiO2 microspheres via one-step nanoparticle self-assembly for enhanced lithium-ion storage. AB - Correction for 'High-surface-area mesoporous TiO2 microspheres via one-step nanoparticle self-assembly for enhanced lithium-ion storage' by Hsin-Yi Wang et al., Nanoscale, 2014, 6, 14926-14931. PMID- 26584333 TI - Structure vs. excitonic transitions in self-assembled porphyrin nanotubes and their effect on light absorption and scattering. AB - The optical properties of diprotonated meso-tetrakis(4-sulphonatophenyl)porphyrin (TPPS(4)) J-aggregates of elongated thin particles (nanotubes in solution and ribbons when deposited on solid interfaces) are studied by different polarimetric techniques. The selective light extinction in these structures, which depends on the alignment of the nanoparticle with respect to the polarization of light, is contributed by excitonic absorption bands and by resonance light scattering. The optical response as a function of the polarization of light is complex because, although the quasi-one-dimensional structure confines the local fields along the nanotube axis, there are two orthogonal excitonic bands, of H- and J-character, that can work in favor of or against the field confinement. Results suggest that resonance light scattering is the dominant effect in solid state preparations, i.e. in collective groups (bundles) of ribbons but in diluted solutions, i.e. with isolated nanotubes, the absorption at the excitonic transitions remains dominant and linear dichroism spectra can be a direct probe of the exciton orientations. Therefore, by analyzing scattering and absorption data we can determine the alignment of the excitonic bands within the nanoparticle, i.e. of the orientation of the basic 2D porphyrin architecture in the nanoparticle. This is a necessary first step for understanding the directions of energy transport, charge polarization and non-linear optical properties in these materials. PMID- 26584331 TI - Sae2 Function at DNA Double-Strand Breaks Is Bypassed by Dampening Tel1 or Rad53 Activity. AB - The MRX complex together with Sae2 initiates resection of DNA double-strand breaks (DSBs) to generate single-stranded DNA (ssDNA) that triggers homologous recombination. The absence of Sae2 not only impairs DSB resection, but also causes prolonged MRX binding at the DSBs that leads to persistent Tel1- and Rad53 dependent DNA damage checkpoint activation and cell cycle arrest. Whether this enhanced checkpoint signaling contributes to the DNA damage sensitivity and/or the resection defect of sae2Delta cells is not known. By performing a genetic screen, we identify rad53 and tel1 mutant alleles that suppress both the DNA damage hypersensitivity and the resection defect of sae2Delta cells through an Sgs1-Dna2-dependent mechanism. These suppression events do not involve escaping the checkpoint-mediated cell cycle arrest. Rather, defective Rad53 or Tel1 signaling bypasses Sae2 function at DSBs by decreasing the amount of Rad9 bound at DSBs. As a consequence, reduced Rad9 association to DNA ends relieves inhibition of Sgs1-Dna2 activity, which can then compensate for the lack of Sae2 in DSB resection and DNA damage resistance. We propose that persistent Tel1 and Rad53 checkpoint signaling in cells lacking Sae2 increases the association of Rad9 at DSBs, which in turn inhibits DSB resection by limiting the activity of the Sgs1-Dna2 resection machinery. PMID- 26584334 TI - Correction: Recent progress of abrasion-resistant materials: learning from nature. AB - Correction for 'Recent progress of abrasion-resistant materials: learning from nature' by Jingxin Meng et al., Chem. Soc. Rev., 2015, DOI: . PMID- 26584335 TI - For Patients With Cancer, Cure Is Not Enough. PMID- 26584336 TI - The People Have Spoken-Are Pathologists Listening? PMID- 26584337 TI - Efficient surface enhanced Raman scattering on confeito-like gold nanoparticle adsorbed self-assembled monolayers. AB - Confeito-like gold nanoparticles (AuNPs; average diameter = 80 nm) exhibiting a plasmon absorption band at 590 nm were adsorbed through immersion-adsorption on two self-assembled monolayers (SAMs) of 3-aminopropyltriethoxysilane (APTES-SAM) and polystyrene spheres coated with amine-terminated poly(amido amine) dendrimers (DEN/PS-SAM). The surface enhanced Raman scattering (SERS) effect on the SAM substrates was examined using the molecules of a probe dye, rhodamine 6G (R6G). The Raman scattering was strongly intensified on both substrates, but the enhancement factor (>10,000) of the AuNP/DEN/PS-SAM hierarchy substrate was 5-10 times higher than that of the AuNP/APTES-SAM substrate. This strong enhancement is attributed to the large surface area of the substrate and the presence of hot spots. Furthermore, analyzing the R6G concentration dependence of SERS suggested that the enhancement mechanism effectively excited the R6G molecules in the first layer on the hot spots and invoked the strong SERS effect. These results indicate that the SERS activity of confeito-like AuNPs on SAM substrates has high potential in molecular electronic devices and ultrasensitive analyses. PMID- 26584338 TI - Design and synthesis of simple, yet potent and selective non-ring-A pyripyropene A-based inhibitors of acyl-coenzyme A: cholesterol acyltransferase 2 (ACAT2). AB - A series of pyripyropene A-based compounds were designed and synthesized by opening the upper section of the A-ring, which significantly simplifies the structure and synthesis from commercially available starting materials. Representative compound (-)-3 exhibited potent activity against ACAT2 and greater selectivity for ACAT2 than for ACAT1. PMID- 26584340 TI - New directions for protease inhibitors directed drug discovery. AB - Proteases play crucial roles in various biological processes, and their activities are essential for all living organisms-from viruses to humans. Since their functions are closely associated with many pathogenic mechanisms, their inhibitors or activators are important molecular targets for developing treatments for various diseases. Here, we describe drugs/drug candidates that target proteases, such as malarial plasmepsins, beta-secretase, virus proteases, and dipeptidyl peptidase-4. Previously, we reported inhibitors of aspartic proteases, such as renin, human immunodeficiency virus type 1 protease, human T lymphotropic virus type I protease, plasmepsins, and beta-secretase, as drug candidates for hypertension, adult T-cell leukaemia, human T-lymphotropic virus type I-associated myelopathy, malaria, and Alzheimer's disease. Our inhibitors are also described in this review article as examples of drugs that target proteases. (c) 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 563-579, 2016. PMID- 26584339 TI - Effects of Prior Intensive Insulin Therapy and Risk Factors on Patient-Reported Visual Function Outcomes in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Cohort. AB - IMPORTANCE: Preservation of vision in patients with diabetes mellitus is critical. Interventions to improve glycemic control through early intensive treatment of diabetes reduce rates of severe retinopathy and preserve visual acuity. OBJECTIVE: To assess the effects of prior intensive insulin treatment and risk factors on patient-reported visual function in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort. DESIGN, SETTING, AND PARTICIPANTS: Cohort study of 1184 participants with type 1 diabetes from the DCCT/EDIC study (randomized clinical trial followed by an observational follow-up study) who completed the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) during EDIC years 17 through 20 (September 1, 2009, through April 30, 2014) in 28 institutions across the United States and Canada. MAIN OUTCOMES AND MEASURES: The primary outcome was the composite NEI-VFQ-25 score. Secondary outcomes were visual acuity (measured by the Early Treatment Diabetic Retinopathy Study protocol), retinopathy level (determined by masked grading of stereoscopic color fundus photographs), and NEI-VFQ-25 subscale scores. The composite NEI-VFQ-25 scale and its subscales were scored 0 to 100, corresponding to poor to excellent function, respectively. RESULTS: The overall average NEI-VFQ-25 score for 1184 DCCT/EDIC participants (mean [SD] age, 52.3 [6.9] years; 48% female) with a 30 year duration of diabetes was high (all participants: median, 91.7; interquartile range [IQR], 89.7-96.9; intensive treatment [n = 605]: median, 94.7; IQR, 91.0 97.2; conventional treatment [n = 579]: median, 94.0; IQR, 88.4-96.1; P = .006 for intensive vs conventional). After adjustment for sex, age, hemoglobin A1c level, and retinopathy level at DCCT baseline, the former intensive treatment group had a significant, albeit modest, improvement in overall NEI-VFQ-25 score compared with the former conventional diabetes treatment group (median difference, -1.0; 95% CI, -1.7 to -0.3; P = .006). This beneficial treatment effect was fully attributed to the prior glycemic control in DCCT (explained treatment effect: 100%). Those with visual acuity worse than 20/100 reported the largest decline in visual function (median difference, -21.0; 95% CI, -40.5 to 1.6; P = .03). CONCLUSIONS AND RELEVANCE: In the DCCT/EDIC cohort, patient reported visual function remains high in both treatment groups, comparable to previous reports of overall health-related quality of life. Intensive diabetes therapy modestly improved NEI-VFQ-25 score 30 years after the start of the DCCT, the benefit underestimated owing to more nonparticipants from the conventional treatment group. Visual acuity had the greatest effect on patient-reported visual function from among all risk factors. TRIAL REGISTRATION: clinicaltrials.gov Identifiers: NCT00360815 and NCT00360893. PMID- 26584341 TI - Editorial. PMID- 26584342 TI - Removal of N-nitrosodimethylamine precursors with powdered activated carbon adsorption. AB - The main objective of this study was to examine the roles of powdered activated carbon (PAC) characteristics (i.e., surface chemistry, pore size distribution, and surface area) in the removal of N-nitrosodimethylamine (NDMA) formation potential (FP) in surface and wastewater-impacted waters. Also, the effects of natural attenuation of NDMA precursors in surface waters, NDMA FP concentration, and carbon dose on the removal of NDMA FP by PAC were evaluated. Finally, the removal of NDMA FP by PAC at two full-scale DWTPs was monitored. Wastewater impacted and surface water samples were collected to conduct adsorption experiments using different PACs and activated carbon fibers (ACFs) with a wide range of physicochemical characteristics. The removal efficiency of NDMA FP by PAC was significantly higher in wastewater-impacted than surface waters. Adsorbable NDMA precursors showed a size distribution in the waters tested; the adsorbable fraction included precursors accessing the pore size regions of 10-20 A and <10 A. Basic carbons showed higher removal of NDMA FP than acidic carbons on a surface area basis. The overall removal of NDMA FP by PAC on a mass basis depended on the surface area, pore size distribution and pHPZC. Thus, PACs with hybrid characteristics (micro and mesoporous), higher surface areas, and basic surface chemistry are more likely to be effective for NDMA precursor control by PAC adsorption. The application of PAC in DWTPs for taste and odor control resulted in an additional 20% removal of NDMA FP for the PAC doses of 7-10 mg/L. The natural attenuation of NDMA precursors through a combination of processes (biodegradation, photolysis and adsorption) decreased their adsorbability and removal by PAC adsorption. PMID- 26584343 TI - Evolution of strategic risks under future scenarios for improved utility master plans. AB - Integrated, long-term risk management in the water sector is poorly developed. Whilst scenario planning has been applied to singular issues (e.g. climate change), it often misses a link to risk management because the likelihood of impacts in the long-term are frequently unaccounted for in these analyses. Here we apply the morphological approach to scenario development for a case study utility, Empresa Portuguesa das Aguas Livres (EPAL). A baseline portfolio of strategic risks threatening the achievement of EPAL's corporate objectives was evolved through the lens of three future scenarios, 'water scarcity', 'financial resource scarcity' and 'strong economic growth', built on drivers such as climate, demographic, economic, regulatory and technological changes and validated through a set of expert workshops. The results represent how the baseline set of risks might develop over a 30 year period, allowing threats and opportunities to be identified and enabling strategies for master plans to be devised. We believe this to be the first combined use of risk and futures methods applied to a portfolio of strategic risks in the water utility sector. PMID- 26584344 TI - Influence of wastewater sludge treatment using combined peroxyacetic acid oxidation and inorganic coagulants re-flocculation on characteristics of extracellular polymeric substances (EPS). AB - Extracellular polymeric substances (EPS) are highly hydrated biopolymers and play important roles in bioflocculation, floc stability, and solid-water separation processes. Destroying EPS structure will result in sludge reduction and release of trapped water. In this study, the effects of combined process of peracetic acid (PAA) pre-oxidation and chemical re-flocculation on morphological properties and distribution and composition of EPS of the resultant sludge flocs were investigated in detail to gain insights into the mechanism involved in sludge treatment. It was found that sludge particles were effectively solubilized and protein-like substances were degraded into small molecules after PAA oxidation. A higher degradation of protein-like substances was observed at acid environments under PAA oxidation. Microscopic analysis revealed that no integral sludge floc was observed after oxidation with PAA at high doses. The floc was reconstructed with addition of inorganic coagulants (polyaluminium chloride (PACl) and ferric chloride (FeCl3)) and PACl performed better in flocculation due to its higher charge neutralization and bridging ability. Combined oxidative lysis and chemical re-flocculation provide a novel solution for sludge treatment. PMID- 26584345 TI - Estrogenic activity in Finnish municipal wastewater effluents. AB - Effluents from wastewater treatment plants (WWTPs) are a major source of estrogenic compounds to the aquatic environment. In the present work, estrogenic activities of effluents from eight municipal WWTPs in Finland were studied. The main objectives of the study were to quantify the concentrations of selected estrogenic compounds, to evaluate their contribution to estrogenic potency and to test the feasibility of the commercial bioassays for wastewater analysis. The effluent samples were analyzed by two in vitro tests, i.e. ERalpha-CALUX((r)) and ELISA-E2, and by liquid chromatography mass spectrometry for six estrogenic compounds: estrone (E1), 17beta-estradiol (E2), estriol (E3), 17alpha ethinylestradiol (EE2), 17alpha-estradiol and bisphenol A (BPA). Estrogenic effects were found in all of the effluent samples with both of the bioassays. The concentrations measured with ELISA-E2 (8.6-61.6 ng/L) were clearly higher but exhibited a similar pattern than those with chemical analysis (E2 0.05) fresh ham or belly characteristics but decreased (P<0.01) fat in cured PC bellies. Marketing group affected (P<0.05) fresh quality, processing characteristics, and composition of hams and bellies. Immunological castration and RAC produced leaner finished products but did not alter processing yield of hams or bacon. PMID- 26584401 TI - Bipolar Patterning of Polymer Membranes by Pyroelectrification. AB - Polymer freestanding membranes with permanent bipolar patterns are fabricated by "pyroelectrification". The thermal stimulation of periodically poled lithium niobate (PPLN) crystals simultaneously generates the pyroelectric effect, the glass transition of the polymer, and therefore the periodic electric poling of the polymer. The reliability of these membranes is demonstrated for applications under both dry and wet conditions, including cell patterning. PMID- 26584402 TI - Metal-Organic Polymers Containing Discrete Single-Walled Nanotube as a Heterogeneous Catalyst for the Cycloaddition of Carbon Dioxide to Epoxides. AB - The cycloaddition of carbon dioxide to epoxides to produce cyclic carbonates is quite promising and does not result in any side products. A discrete single walled metal-organic nanotube was synthesized by incorporating a tetraphenyl ethylene moiety as the four-point connected node. The assembled complex has a large cross-section, with an exterior wall diameter of 3.6 nm and an interior channel diameter of 2.1 nm. It features excellent activity toward the cycloaddition of carbon dioxide, with a turnover number of 17,500 per mole of catalyst and an initial turnover frequency as high as 1000 per mole of catalyst per hour. Only minimal decreases in the catalytic activity were observed after 70 h under identical reaction conditions, and a total turnover number as high as 35,000 was achieved. A simple comparison of relative porous MOFs suggested that the cross-section of the channels is an important factor influencing the transport of the substrates and products through the channel. PMID- 26584403 TI - Peritraumatic Distress Mediates the Effect of Severity of Disaster Exposure on Perinatal Depression: The Iowa Flood Study. AB - Disaster exposure during pregnancy has received limited attention. This study examined the impact of the 2008 Iowa Floods on perinatal maternal depression and well-being, and the role of peritraumatic distress as a possible mechanism explaining this link. Perinatal women (N = 171) completed measures of depressive symptoms and general well-being at 5 timepoints from pregnancy to 30 months postpartum. Objectively assessed prenatal flood exposure was associated with greater depression (r = .15). Further, flood-related peritraumatic distress was uniquely associated with greater depression (r = .23), and was a key mechanism through which flood exposure led to depression. Prenatal flood exposure was also associated with general well-being (r = .18); however, a mechanism other than peritraumatic distress appears to have been responsible for the effect of flood exposure on well-being. We discuss the implications of these findings for informing etiological models and enhancing the efficacy of interventions for maternal psychopathology. PMID- 26584405 TI - Solvent-Switching Gelation and Orange-Red Emission of Ultrasmall Copper Nanoclusters. AB - By tuning the Cu???Cu and hydrogen-bonding interactions, the small cluster Cu3 L can be selectively synthesized to develop a stable and highly fluorescent material, as confirmed by matrix-assisted laser desorption ionization-time of flight mass spectroscopy. Further characterizations, including absorbance spectroscopy, XPS, and XRD demonstrate the formation of tiny Cu nanoclusters (NCs). In water, the as-prepared Cu NCs can exhibit high orange fluorescence via solution evaporation to eliminate hydrogen-bonding, and in dimethylformamide, a strong orange fluorescent gel is obtained by solvent induction to enhance the Cu???Cu and hydrogen-bonding interactions. More importantly, the Cu NCs in their substantial form exhibit nonlinear optical properties upon two-photon excitation. These results will shed light on Cu and related cluster applications in two photon biological imaging, optical power limiting, and solar energy conversion. PMID- 26584404 TI - Paracetamol (acetaminophen) protein adduct concentrations during therapeutic dosing. AB - BACKGROUND: Paracetamol protein adducts (PPA) are a biomarker of paracetamol exposure. PPA are quantified as paracetamol-cysteine (APAP-CYS), and concentrations above 1.1 MUmol l(-1) have been suggested as a marker of paracetamol-induced hepatotoxicity. However, there is little information on the range of concentrations observed during prolonged therapeutic dosing. AIM: The aim of the present study was to describe the concentration of PPA in the serum of subjects taking therapeutic doses of paracetamol for at least 16 days. METHODS: Preplanned secondary aim of a prospective randomized controlled (placebo vs. 4g day(-1) paracetamol) trial. We measured subjects' serum PPA concentrations every 3 days for a minimum of 16 days. We also measured concentrations on study days 1 3 and 16-25 in subsets of patients. PPA were quantified as APAP-CYS after gel filtration and protein digestion using liquid chromatography/mass spectrometry. RESULTS: Ninety per cent of subjects had detectable PPA after five doses. Median APAP-CYS concentrations in paracetamol-treated subjects increased to a plateau of 0.1 MUmol l(-1) on day 7, where they remained. The highest concentration measured was 1.1 MUmol l(-1) and two subjects never had detectable PPA levels. PPA were detected in the serum of 78% of subjects 9 days after their final dose. CONCLUSIONS: PPA are detectable in the vast majority of subjects taking therapeutic doses of paracetamol. While most have concentrations well below the threshold associated with hepatotoxicity, concentrations may approach 1.1 MUmol l(-1) in rare cases. Adducts are detectable after a few doses and can persist for over a week after dosing is stopped. PMID- 26584406 TI - Hypertension subtypes modify metabolic response to thiazide diuretics. AB - BACKGROUND: Blood pressure (BP) and metabolic response to thiazide diuretics might be varied in patients with different hypertension subtypes and ethnicities. This study aimed to investigate the response of BP and metabolic profiles to short-term thiazide treatment in an Asian cohort with different hypertension subtypes. DESIGN: Serial ethnic Chinese nondiabetic subjects with hypertension were evaluated. After diet instruction and lifestyle modification for 2 weeks, patients who still had elevated systolic BP (SBP>=140 mmHg) and/or diastolic BP (DBP>=90 mmHg) were given 50 mg of hydrochlorothiazide daily for 2 weeks. The responses of BP and metabolic profiles were evaluated before and after treatment according to the patient's baseline BP subtype - isolated systolic hypertension (ISH), systo-diastolic hypertension (SDH) and isolated diastolic hypertension (IDH). RESULTS: Hydrochlorothiazide treatment significantly reduced the BP in all 92 patients (62 males, aged 45.7 +/- 9.6 years), irrespective of their baseline BP subtypes. In patients with SDH (n = 39) or IDH (n = 40), hydrochlorothiazide treatment significantly increased serum adiponectin (P = 0.001 and 0.007, respectively) and reduced asymmetric dimethylarginine levels (P < 0.001, in both groups). Serum cholesterol (P = 0.027) and fasting blood sugar levels (P = 0.044) were significantly improved only in the IDH patients. Furthermore, IDH was independently associated with changes in fasting blood sugar (beta = -11.178, P = 0.022) and cholesterol (beta = -22.654, P = 0.027). CONCLUSIONS: The characteristics of the Asian hypertensive patients with diastolic hypertension can present a favourable metabolic response to the short-term hydrochlorothiazide treatment. The potential positive effect on cardiovascular risk should be validated in long-term studies in this diastolic type of hypertension. PMID- 26584407 TI - Development of hepatocellular carcinoma in patients with hepatitis C virus infection who achieved sustained virological response following interferon therapy: A large-scale, long-term cohort study. AB - BACKGROUND: We assessed the risk factors for the development of hepatocellular carcinoma (HCC) following successful eradication of hepatitis C virus (HCV) with interferon (IFN) therapy in a long-term, large-scale cohort study. METHODS: We reviewed 1094 consecutive patients with HCV who achieved sustained virological response (SVR) following IFN therapy between January 1995 and September 2013. RESULTS: During the observation period (median 50 months: range 13-224), 36 (3%) of 1094 patients developed HCC after SVR. The median period from SVR to diagnosis of HCC was 37 months (range 17-141), and the cumulative rates of HCC at 5, 10, and 15 years were 4%, 6%, and 12%, respectively. Multivariate analysis identified old age (>=60 years, HR, 3.1: 95%CI, 1.3-6.6: P = 0.009), male sex (HR, 12.0: 95%CI, 2.8-50.0: P < 0.0001), advanced fibrosis stage (F3/4, HR, 3.2: 95%CI, 1.6 7.2: P < 0.0001), and alpha-fetoprotein >=10 ng/mL at 1 year after SVR (HR, 7.8: 95%CI, 2.9-16.8: P < 0.0001) as significant and independent risk factors for post SVR HCC. CONCLUSIONS: Older age and male sex (host factors), advanced fibrosis stage (pre-IFN treatment factor), and higher alpha-fetoprotein values (post treatment factor) were significantly associated with HCC development after HCV eradication. PMID- 26584408 TI - Formulation and characterization of antimicrobial quaternary ammonium dendrimer in poly(methyl methcarylate) bone cement. AB - The use of novel antimicrobial molecules in bone cement can improve efficiency of recuperation after arthroplasty or joint replacement surgeries, avoiding the risks associated with antibiotic resistant antimicrobial agents. Nanomaterials particularly dendrimers are particularly useful for making broad spectrum killing agents owing to their large surface areas and functionalities. Therefore, we have synthesized generation 1 quaternary ammonium dendrimer of tripropylene glycol diacrylate (TPGDA) using octyl iodide (OI) [TPGDA G1.0 (=) quaternary octyl iodide (QOI)] and capitalized on their capabilities of contact killing based mechanism. We formulated different TPGDA G1.0 (=) QOI antimicrobial agent loaded liquid component composed of methyl methacrylate monomer and N,N-dimethyl-p toluidine coinitiator. Different polymethyl methacrylate (PMMA) based experimental bone cement formulations were made and dendrimer concentration was optimized. Mechanical strength and compressive modulus of modified bone cement decreased on increasing concentrations and 10% was optimized for further analysis. The mechanical strength of bone cement yield the similar trend in wet conditions bone cement immersed in artificially created stimulated body fluids. Ten percent TPGDA G1.0 (=) QOI in bone cement was sufficient to kill gram positive and negative bacteria and its property is retained even after a period of 30 days. Thus novel dendritic structures show promise for clinical antimicrobial activity while retaining mechanical properties of bone cements. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 521 530, 2017. PMID- 26584409 TI - Metronomic oral vinorelbine in advanced breast cancer and non-small-cell lung cancer: current status and future development. AB - Metronomic chemotherapy (mCT), a frequent administration of low-dose chemotherapy, allows prolonged treatment duration and minimizes the toxicity of standard-dose chemotherapy. mCT has multiple actions against cancer cells including inhibition of angiogenesis and modulation of the immune system. A number of studies lend support to the clinical efficacy of mCT in advanced breast cancer and non-small-cell lung cancer. However, further evidence is necessary to describe the optimal use of mCT and to identify suitable patients. Oral vinorelbine has emerged as a promising metronomic treatment in patients with metastatic breast cancer and non-small-cell lung cancer and is the only orally available microtubule-targeting agent. This paper reviews current evidence on metronomic oral vinorelbine, discusses its management and defines a suitable patient profile on the basis of a workshop of Italian experts. PMID- 26584410 TI - Biobanks in Oral Health: Promises and Implications of Post-Neoliberal Science and Innovation. AB - While biobanks are established explicitly as scientific infrastructures, they are de facto political-economic ones too. Many biobanks, particularly population based biobanks, are framed under the rubric of the bio-economy as national political-economic assets that benefit domestic business, while national populations are framed as a natural resource whose genomics, proteomics, and related biological material and national health data can be exploited. We outline how many biobanks epitomize this 'neoliberal' form of science and innovation in which research is driven by market priorities (e.g., profit, shareholder value) underpinned by state or government policies. As both scientific and political economic infrastructures, biobanks end up entangled in an array of problems associated with market-driven science and innovation. These include: profit trumping other considerations; rentiership trumping entrepreneurship; and applied research trumping basic research. As a result, there has been a push behind new forms of 'post-neoliberal' science and innovation strategies based on principles of openness and collaboration, especially in relation to biobanks. The proliferation of biobanks and the putative transition in both scientific practice and political economy from neoliberalism to post-neoliberalism demands fresh social scientific analyses, particularly as biobanks become further established in fields such as oral health and personalized dentistry. To the best of our knowledge, this is the first analysis of biobanks with a view to what we can anticipate from biobanks and distributed post-genomics global science in the current era of oral health biomarkers. PMID- 26584411 TI - The first reported case of equine Nocardioform placentitis in New Zealand. PMID- 26584412 TI - Initial experience with a new biodegradable airway stent in children: Is this the stent we were waiting for? AB - OBJECTIVE: To report our experience with a new type of biodegradable airway stent in the setting of severe tracheobronchial obstruction in children. DESIGN AND METHODOLOGY: We conducted a retrospective and prospective (since June 2014) study of pediatric patients with severe airway obstruction treated with biodegradable stents in our institution between 2012 and 2015. The following data were collected: demographics, indication for stenting, bronchoscopic findings, insertion technique complications, clinical outcome, stent related complications, re-stenting, and time of follow-up. RESULTS: Thirteen custom-made polydioxanone stents were placed in four infants (mean age, 4 months) with severe tracheobronchial obstruction: tracheomalacia (two patients), bronchomalacia (1), and diffuse tracheal stenosis (1). All the stents were bronchoscopically inserted uneventfully. Immediate and maintained clinical improvement was observed in every case. No major stent related complications have occurred and only mild or moderate granulation tissue was observed during surveillance bronchoscopy. Two patients required repeated stenting as expected. All the patients are alive and in a good respiratory condition with a follow-up ranging from 5 to 40 months. CONCLUSIONS: Biodegradable airway stents seem to be safe, effective, and cause fewer complications than other types of stents. They can be an alternative to the classic metallic or plastic stents for severe tracheal stenosis or malacia in small children. More experience is needed in order to establish the definite clinical criteria for their use in pediatric patients. Pediatr Pulmonol. 2016;51:607-612. (c) 2015 Wiley Periodicals, Inc. PMID- 26584413 TI - A Bayesian analysis of plutonium exposures in Sellafield workers. AB - The joint Russian (Mayak Production Association) and British (Sellafield) plutonium worker epidemiological analysis, undertaken as part of the European Union Framework Programme 7 (FP7) SOLO project, aims to investigate potential associations between cancer incidence and occupational exposures to plutonium using estimates of organ/tissue doses. The dose reconstruction protocol derived for the study makes best use of the most recent biokinetic models derived by the International Commission on Radiological Protection (ICRP) including a recent update to the human respiratory tract model (HRTM). This protocol was used to derive the final point estimates of absorbed doses for the study. Although uncertainties on the dose estimates were not included in the final epidemiological analysis, a separate Bayesian analysis has been performed for each of the 11 808 Sellafield plutonium workers included in the study in order to assess: A. The reliability of the point estimates provided to the epidemiologists and B. The magnitude of the uncertainty on dose estimates. This analysis, which accounts for uncertainties in biokinetic model parameters, intakes and measurement uncertainties, is described in the present paper. The results show that there is excellent agreement between the point estimates of dose and posterior mean values of dose. However, it is also evident that there are significant uncertainties associated with these dose estimates: the geometric range of the 97.5%:2.5% posterior values are a factor of 100 for lung dose, 30 for doses to liver and red bone marrow, and 40 for intakes: these uncertainties are not reflected in estimates of risk when point doses are used to assess them. It is also shown that better estimates of certain key HRTM absorption parameters could significantly reduce the uncertainties on lung dose in future studies. PMID- 26584414 TI - Prognostic and Safety Roles in Laparoscopic Versus Abdominal Radical Hysterectomy in Cervical Cancer: A Meta-analysis. AB - OBJECTIVE: Studies comparing the prognostic results between laparoscopic radical hysterectomy (LRH) and abdominal radical hysterectomy (ARH) in cervical cancer reported contradictory results. We aimed to evaluate the prognostic and safety roles of LRH by pooling studies in a meta-analysis. MATERIALS AND METHODS: Original articles were searched in PubMed, EMBASE, and the Cochrane Library. The survival results (5-year disease-free survival [DFS], 5-year overall survival [OS], and recurrence rate [RR]), safety parameters (intra-, peri-, and postoperative complication rates and postoperative bowel or bladder recovery days), efficiency parameters (pelvic/para-aortic lymph nodes removed), and other parameters (operative time, estimated blood loss, and hospital of stay) between the two approaches were reviewed. RESULTS: For the 2922 cases identified, DFS, OS, and RR did not differ in balanced prognostic factors, including lymph node metastasis, Stage IIB or above, non-squamous cancer histology, grade G3, lymphovascular space invasion, tumor size >=4 cm, and positive parametrial and vaginal margin rates. Meanwhile, LRH was associated with higher complication rates and a shorter time to the recovery of bowel or bladder function than for ARH. The number of removed pelvic or para-aortic lymph nodes did not significantly differ. Other parameters showed LRH was associated with a longer operative time, less blood loss, and a shorter length of hospital stay. The survival and prognostic results did not differ in balanced prognostic factors. CONCLUSIONS: LRH is safe and has lower operative complication rates than ARH. PMID- 26584415 TI - MA-CORD: Stop Ineffective Childhood Obesity Inverventions. PMID- 26584416 TI - Synthesis of Non-Natural Heteroaminopolysaccharides by alpha-Glucan Phosphorylase Catalyzed Enzymatic Copolymerization: alpha(1->4)-Linked Glucosaminoglucans. AB - Thermostable alpha-glucan phosphorylase-catalyzed enzymatic copolymerization of alpha-d-glucose 1-phosphate (Glc-1-P) with its analogue monomer, alpha-d glucosamine 1-phosphate (GlcN-1-P), from a maltotriose primer was performed to produce non-natural heteroaminopolysaccharides composed of Glc/GlcN units, that is, alpha(1->4)-linked glucosaminoglucans. The GlcN units in the products were further converted to N-acetyl-d-glucosamine (GlcNAc) units by N-acetylation. The structures of the products were evaluated by the MALDI-TOF MS, (1)H NMR, and (1)H (1)H COSY NMR measurements, which were completely different from those of the natural glycosaminoglycans. The degrees of polymerization and Glc/GlcN compositional ratios of the products were relatively dependent on the Glc-1-P/Glc 1-P/Glc3 feed ratios. The noncrystalline natures of the present materials were supported by the X-ray diffraction measurement. PMID- 26584417 TI - Targeting Two Coagulation Cascade Proteases with a Bivalent Aptamer Yields a Potent and Antidote-Controllable Anticoagulant. AB - Potent and rapid-onset anticoagulation is required for several clinical settings, including cardiopulmonary bypass surgery. In addition, because anticoagulation is associated with increased bleeding following surgery, the ability to rapidly reverse such robust anticoagulation is also important. Previously, we observed that no single aptamer was as potent as heparin for anticoagulating blood. However, we discovered that combinations of two aptamers were as potent as heparin. Herein, we sought to combine two individual anticoagulant aptamers into a single bivalent RNA molecule in an effort to generate a single molecule that retained the potent anticoagulant activity of the combination of individual aptamers. We created four bivalent aptamers that can inhibit Factor X/Xa and prothrombin/thrombin and anticoagulate plasma, as well as the combination of individual aptamers. Detailed characterization of the shortest bivalent aptamer indicates that each aptamer retains full binding and functional activity when presented in the bivalent context. Finally, reversal of this bivalent aptamer with a single antidote was explored, and anticoagulant activity could be rapidly turned off in a dose-dependent manner. These studies demonstrate that bivalent anticoagulant aptamers represent a novel and potent approach to actively and reversibly control coagulation. PMID- 26584419 TI - Importance of knowing your stimulation paradigm: methodological considerations on laser-evoked pain responses in rats and humans. PMID- 26584420 TI - Conditioned place preference and spontaneous dorsal horn neuron activity in chronic constriction injury model in rats. AB - Patients with neuropathic pain commonly present with spontaneous pain, in addition to allodynia and hyperalgesia. Although evoked responses in neuropathic pain models are well characterized, determining the presence of spontaneous pain is more challenging. We determined whether the chronic constriction injury (CCI) model could be used to measure effects of treatment of spontaneous pain, by evaluating dorsal horn neuron (DHN) spontaneous activity and spontaneous pain related behaviors. We measured conditioned place preference (CPP) to analgesia produced by sciatic nerve block with bupivacaine in rats with established CCI. We undertook another CPP experiment using hind paw incision. We also examined DHN spontaneous activity in CCI rats. Although CCI produced nocifensive responses to mechanical stimuli, CPP to analgesic nerve block was not evident 14 days after injury: Compared with baseline (314 +/- 65 seconds), CCI rats did not show a preference for the bupivacaine-paired chamber after conditioning (330 +/- 102 seconds). However, sciatic nerve block after hind paw incision produced CPP on postoperative day 1, serving as a positive control. The proportion of spontaneously active DHNs (33%) was not significantly increased in CCI rats compared with the sham (21%). The median rate of spontaneous activity in the CCI group (12.6 impulses per second) was not different from the sham group (9.2 impulses per second). Also, there was no change in DHN spontaneous activity after sciatic nerve block with bupivacaine. Our findings suggest that CCI as a neuropathic pain model should not be used to measure effects of treatment of spontaneous pain driven by the peripheral input. PMID- 26584421 TI - Epicutaneous immunotherapy for food allergy as a novel pathway for oral tolerance induction. AB - Epicutaneous immunotherapy is a developing technique, aiming at desensitizing patients with food allergy with less risks that oral ingestion or injection could generate. Several clinical trials have been performed and are currently running, in milk and peanut allergy, assessing the safety of the technique and its efficacy. Preclinical models indicate a major role in the mechanisms of desensitization, for example, Tregs and epigenetic modifications. PMID- 26584422 TI - Optofluidic tunable lenses using laser-induced thermal gradient. AB - This paper reports a new design of optofluidic tunable lens using a laser-induced thermal gradient. It makes use of two straight chromium strips at the bottom of the microfluidic chamber to absorb the continuous pump laser to heat up the moving benzyl alcohol solution, creating a 2D refractive index gradient in the entrance part between the two hot strips. This design can be regarded as a cascade of a series of refractive lenses, and is distinctively different from the reported liquid lenses that mimic the refractive lens design and the 1D gradient index lens design. CFD simulation shows that a stable thermal lens can be built up within 200 ms. Experiments were conducted to demonstrate the continuous tuning of focal length from initially infinite to the minimum 1.3 mm, as well as the off axis focusing by offsetting the pump laser spot. Data analyses show the empirical dependences of the focal length on the pump laser intensity and the flow velocity. Compared with previous studies, this tunable lens design enjoys many merits, such as fast tuning speed, aberration-free focusing, remote control, and enabling the use of homogeneous fluids for easy integration with other optofluidic systems. PMID- 26584424 TI - Dielectric response and anhydrous proton conductivity in a chiral framework containing a non-polar molecular rotor. AB - Herein, we report a chiral 3D framework with the formula [Co(HPO3)2][H2DABCO] (DABCO = 1,4-diazabicyclo[2.2.2]octane). This compound exhibits two distinct dielectric anomalies, one attributed to the transfer of protons between non-polar DABCO and the inorganic framework, and the other to the in-plane oscillatory fluctuation of the DABCO molecule. It also exhibits proton conductivity under high-temperature anhydrous conditions. PMID- 26584423 TI - School-Level Correlates of Adolescent Tobacco, Alcohol, and Marijuana Use. AB - BACKGROUND: School-level characteristics are related to students' substance use, but little research systematically examined multiple school characteristics in relation to different types of substance use across grade levels. OBJECTIVES: This study examines multiple school-level characteristics as correlates of students' tobacco, alcohol, marijuana, and combined substance use across three grade levels. METHODS: Students (N = 23,615) from 42 urban and suburban middle schools and 24 high schools in the U.S. reported on their tobacco, alcohol, and marijuana use. Students' mean age was 14 years; 47% were male, 53% African American, and 41% Caucasian. School-level data included poverty, racial composition, academic achievement, student-teacher ratio, absenteeism, and school size. Multilevel logistic and Poisson regressions tested associations between school-level predictors and adolescent substance use in middle school, early high school, and late high school. RESULTS: School-level poverty, more ethnic minority students, low achievement, and higher absenteeism were related to alcohol, marijuana, and combined substance use, particularly at lower grade levels. By contrast, cigarette smoking was more prevalent in more affluent high schools with more White students. After adjusting for other school characteristics, absenteeism emerged as the most consistent predictor of student substance use. CONCLUSIONS/IMPORTANCE: Interventions addressing absenteeism and truancy in middle and high schools may help prevent student substance use. Schools serving poor, urban, and mostly minority students may benefit from interventions targeting alcohol and marijuana use, whereas interventions focusing on tobacco use prevention may be more relevant for schools serving more affluent and predominantly White students. PMID- 26584425 TI - Serologic Evidence of Influenza A (H14) Virus Introduction into North America. PMID- 26584426 TI - Pigmentogenes Pityriasis rosea: an atypical presentation of the exanthem. PMID- 26584427 TI - PCR Real time Mismatch Amplification Mutation Assay (MAMA Real Time PCR) for evaluation of TNF-alpha promoter gene polymorphism -308 G/A in patients with psoriasis. AB - BACKGROUND: Psoriasis is a common chronic inflammatory disease, the plaques are infiltrated by leukocytes producing high levels of proinflammatory cytokines and TNF-alpha. Single-nucleotide polymorphisms within the gene promoters have been shown to affect gene expression. The -308 G/A polymorphism could affect TNF synthesis at transcriptional level. The present study develops a MAMA Real Time PCR assay, in order to identify homozygosis or heterozygosis for TNF-alpha -308 G/A polymorphism. METHODS: Seventy patients with psoriasis and 235 controls were considered for the development of the real time PCR assay. Whole blood was processed for nucleic acid extraction. RESULTS: A percentage of 36.17% controls and 38.6% patients were heterozygosis, considering Amplification-refractory mutation system (ARMS)-PCR assay while 23% and 22.85% were heterozygosis using Mismatch Amplification Mutation Assay (MAMA)-PCR. On the contrary, 1.3% and 1.4% were homozygosis A, while 75.7% and 75.75% presented homozygosis G, taking into account the MAMA-PCR results. The two assays were significantly different (P=0.0004 at chi2 Test), but MAMA-PCR showed a better performance for TNF-alpha 308 G/A gene polymorphism investigation. CONCLUSIONS: Further studies are needed for a better comprehension of the role of this polymorphism, such as MAMA real time PCR assays development for other players in cellular immune response. PMID- 26584428 TI - Charting the Course for a New Cancer Clinical Research Culture. AB - The convergence of new biological insights from sequencing, digital technologies and advanced bioinformatics tools are creating new opportunities to advance cancer care for individual patients. Fully realising this potential will require the integration and alignment of multiple stakeholders across the healthcare system. To increase the speed in which personalised medicine discoveries are translated into clinical practice and accessible to patients requires appropriately conducted clinical research with input and usage by patients, healthcare providers, regulatory authorities and policy makers. These stakeholders need to align in establishing the right evidence to facilitate clinical research and access to personalised treatments addressing the needs of targeted populations. PMID- 26584429 TI - Risk of Stroke-Associated Pneumonia and Oral Hygiene. AB - BACKGROUND: Pneumonia is a major complication of stroke, but effective prevention strategies are lacking. Since aspiration of oropharyngeal secretions is the primary mechanism for development of stroke-associated pneumonia, strategies that decrease oral colonization with pathogenic bacteria may help curtail pneumonia risk. We therefore hypothesized that systematic oral care protocols can help decrease pneumonia risk in hospitalized stroke patients. In this study, we investigated the impact of a systematic oral hygiene care (OHC) program in reducing hospital-acquired pneumonia in patients with acute-subacute stroke. METHODS: This study compared the proportion of pneumonia cases in hospitalized stroke patients before and after implementation of a systematic OHC intervention. All patients hospitalized with acute ischemic stroke or intracerebral hemorrhage admitted to a large, urban academic medical center in Boston, Mass., USA from May 31, 2008, to June 1, 2010 (epoch prior to implementation of OHC), and from January 1, 2012, to December 31, 2013 (epoch after full implementation of OHC), who were 18 years of age and hospitalized for >= 2 days were eligible for inclusion. The cohort in the first epoch constituted the control group whereas the cohort in the second epoch formed the intervention group. Multivariate logistic regression was used to control for confounders. The main outcome measure was hospital-acquired pneumonia, defined via International Classification of Diseases, Ninth Revision, Clinical Modification codes. RESULTS: The cohort comprised 1,656 admissions (707 formed historical controls; 949 were in the intervention group). The unadjusted incidence of hospital-acquired pneumonia was lower in the group assigned to OHC compared to controls (14 vs. 10.33%; p = 0.022) with an unadjusted OR of 0.68 (95% CI 0.48-0.95; p = 0.022). After adjustment for influential confounders, the OR of hospital-acquired pneumonia in the intervention group remained significantly lower at 0.71 (95% CI 0.51-0.98; p = 0.041). CONCLUSION: In this large hospital-based cohort of patients admitted with acute stroke, systematic OHC use was associated with decreased odds of hospital-acquired pneumonia. PMID- 26584431 TI - The Development of a New Medical Device for Standardized Episiotomy: A Pre Clinical Validation Study. AB - BACKGROUND: The aim of this study was to present the validation and optimization process for a new innovative medical device to create a standardized episiotomy. DESIGN: We performed a preclinical validation study. SETTING: This study was performed at the University hospital. SAMPLE: Animal, cadaver. METHODS: Together with technical engineers, we designed a new medical device that involves a knife and cuts back from buttock toward introitus, in contrast to the conventional episiotomy. We optimized the design and its performance in consecutive animal and cadaver studies. MAIN OUTCOME MEASURES: Ability to perform a standardized incision, ease of use. RESULTS: After multiple adjustments, based on the results of multiple animal and cadaver studies, a medical device was developed to perform a standardized clean-cut episiotomy of 4-6 cm length. CONCLUSION: We have shown that optimizing the technical performance and safety of an innovative device in animals, prior to opposing patients to its potential hazards, is feasible. Our design optimizing study can be used as a model for the pre-clinical validation of future innovative medical devices. PMID- 26584430 TI - Expression and Purification of Recombinant Human Basic Fibroblast Growth Factor Fusion Proteins and Their Uses in Human Stem Cell Culture. AB - To reduce the cost of cytokines and growth factors in stem cell research, a simple method for the production of soluble and biological active human basic fibroblast growth factor (hbFGF) fusion protein in Escherichia coli was established. Under optimal conditions, approximately 60-80 mg of >95% pure hbFGF fusion proteins (Trx-6xHis-hbFGF and 6xHis-hbFGF) were obtained from 1 liter of culture broth. The purified hbFGF proteins, both with and without the fusion tags, were biologically active, which was confirmed by their ability to stimulate proliferation of NIH3T3 cells. The fusion proteins also have the ability to support several culture passages of undifferentiated human embryonic stem cells and induce pluripotent stem cells. This paper describes a low-cost and uncomplicated method for the production and purification of biologically active hbFGF fusion proteins. PMID- 26584432 TI - Differences in Visual-Spatial Input May Underlie Different Compression Properties of Firing Fields for Grid Cell Modules in Medial Entorhinal Cortex. AB - Firing fields of grid cells in medial entorhinal cortex show compression or expansion after manipulations of the location of environmental barriers. This compression or expansion could be selective for individual grid cell modules with particular properties of spatial scaling. We present a model for differences in the response of modules to barrier location that arise from different mechanisms for the influence of visual features on the computation of location that drives grid cell firing patterns. These differences could arise from differences in the position of visual features within the visual field. When location was computed from the movement of visual features on the ground plane (optic flow) in the ventral visual field, this resulted in grid cell spatial firing that was not sensitive to barrier location in modules modeled with small spacing between grid cell firing fields. In contrast, when location was computed from static visual features on walls of barriers, i.e. in the more dorsal visual field, this resulted in grid cell spatial firing that compressed or expanded based on the barrier locations in modules modeled with large spacing between grid cell firing fields. This indicates that different grid cell modules might have differential properties for computing location based on visual cues, or the spatial radius of sensitivity to visual cues might differ between modules. PMID- 26584433 TI - ORACLE Stroke Study: Opinion Regarding Acceptable Outcome Following Decompressive Hemicraniectomy for Ischemic Stroke. AB - BACKGROUND: There continues to be considerable interest in the use of decompressive hemicraniectomy in the management of malignant cerebral artery infarction; however, concerns remain about long-term outcome. OBJECTIVE: To assess opinion on consent and acceptable outcome among a wide range of healthcare workers. METHODS: Seven hundred seventy-three healthcare workers at the 2 major public neurosurgical centers in Western Australia participated. Participants were asked to record their opinion on consent and acceptable outcome based on the modified Rankin Score (mRS). The evidence for clinical efficacy of the procedure was presented, and participants were then asked to reconsider their initial responses. RESULTS: Of the 773 participants included in the study, 407 (52.7%) initially felt that they would provide consent for a decompressive craniectomy as a lifesaving procedure, but only a minority of them considered an mRS score of 4 or 5 an acceptable outcome (for mRS score <=4, n = 67, 8.7%; for mRS score = 4, n = 57, 7.4%). After the introduction of the concept of the disability paradox and the evidence for the clinical efficacy of decompressive craniectomy, more participants were unwilling to accept decompressive craniectomy (18.1% vs 37.8%), but at the same time, more were willing to accept an mRS score <=4 as an acceptable outcome (for mRS score <=4, n = 92, 11.9%; for mRS score = 4, n = 79, 10.2%). CONCLUSION: Most participants felt survival with dependency to be unacceptable. However, many would be willing to provide consent for surgery in the hopes that they may survive with some degree of independence. ABBREVIATIONS: DESTINY, Decompressive Surgery for the Treatment of Malignant Infarction of the Middle Cerebral ArterymRS, modified Rankin Scale. PMID- 26584435 TI - Patient Participation Approach to Reduction of Anterior Shoulder Dislocation: P-R I-M/O-Y-E-S. AB - A variety of successful techniques are available for reduction of shoulder dislocation; none have been shown to be clearly superior to another. Analgesic methods vary as well from none to deep sedation-analgesia. The literature hints at the importance of optimal muscle relaxation as a factor of success. Yet, the literature describes only cursorily the means by which muscle relaxation is optimized. Patient-centered participation and relaxation methods have been used in other contexts to reduce pain, anxiety, and muscle tension. This article proposes to integrate a patient-centered participation approach to the reduction of anterior shoulder dislocation as a way to optimize muscular relaxation nonpharmacologically. It can be used in the field in combination with the practitioner's reduction technique of choice. It minimizes risks because it entails no deep pharmacological sedation. The mnemonic P-R-I-M/O-Y-E-S is used to respectively represent the four phases: Preparation, Rehearsal, Intervention, and Mobilization as well as the 4 repeated steps in each phase of the procedure: Observe, Yield control, Explain, and Support. The focus is on (1) securing optimal patient participation within a patient-centered approach and (2) achieving nonpharmacological muscular relaxation through a simple relaxation routine. More studies are needed to identify the factors that determine success and guide the practitioner's choice among available options in shoulder dislocation reductions. PMID- 26584434 TI - Infection-Induced Retrotransposon-Derived Noncoding RNAs Enhance Herpesviral Gene Expression via the NF-kappaB Pathway. AB - Short interspersed nuclear elements (SINEs) are highly abundant, RNA polymerase III-transcribed noncoding retrotransposons that are silenced in somatic cells but activated during certain stresses including viral infection. How these induced SINE RNAs impact the host-pathogen interaction is unknown. Here we reveal that during murine gammaherpesvirus 68 (MHV68) infection, rapidly induced SINE RNAs activate the antiviral NF-kappaB signaling pathway through both mitochondrial antiviral-signaling protein (MAVS)-dependent and independent mechanisms. However, SINE RNA-based signaling is hijacked by the virus to enhance viral gene expression and replication. B2 RNA expression stimulates IKKbeta-dependent phosphorylation of the major viral lytic cycle transactivator protein RTA, thereby enhancing its activity and increasing progeny virion production. Collectively, these findings suggest that SINE RNAs participate in the innate pathogen response mechanism, but that herpesviruses have evolved to co-opt retrotransposon activation for viral benefit. PMID- 26584436 TI - Concussion Management Practice Patterns Among Sports Medicine Physicians. AB - OBJECTIVE: The primary purpose of this study was to examine concussion management practice patterns among sports medicine physicians in the United States. DESIGN: Cross-sectional study using a web-based survey. PARTICIPANTS: Members of the American Medical Society for Sports Medicine (AMSSM). MAIN OUTCOME MEASURES: We distributed a questionnaire to physician members of the AMSSM assessing the current practices for evaluating and managing concussions sustained during sports. Specifically, we asked respondents about their use of management guidelines, medications, balance assessments, neuropsychological tests, and return-to-play strategies. RESULTS: Of the 3591 members emailed, 425 (11.8%) respondents responded. Ninety-seven percent of respondents reported basing current management of sport-related concussion on a published set of criteria, with a majority (91.9%) following the guidelines provided by the Fourth International Conference on Concussion in Sport. Seventy-six percent of respondents reported using medication beyond 48 hours postinjury. Acetaminophen was reported as the most commonly administered medication, although tricyclic antidepressants and amantadine were also commonly administered. Vitamins, minerals, and dietary supplements were also reported as commonly administered. Most respondents reported using a form of neuropsychological testing (87.1%). A majority of respondents (88.6%) reported allowing athletes to return to competition after concussion only once the athlete becomes symptom free and completes a return-to-play protocol. CONCLUSIONS: Most sports medicine physicians seem to use recently developed guidelines for concussion management, regularly use medications and neuropsychological testing in management strategies, and follow established return-to-play guidelines. CLINICAL RELEVANCE: Sports medicine physicians seem to have clinical expertise in the management of sport-related concussion. PMID- 26584437 TI - Correction: The Roles of Arabidopsis CDF2 in Transcriptional and Posttranscriptional Regulation of Primary MicroRNAs. PMID- 26584438 TI - MODIFIED CURVED ASPIRATION CANNULAS AND END-GRIPPING FORCEPS FOR 25-GAUGE VITRECTOMY ON HIGHLY MYOPIC EYES. PMID- 26584439 TI - ANALYSIS OF A CONFOCAL SCANNING LASER OPHTHALMOSCOPE NONCONTACT ULTRA-WIDE FIELD LENS SYSTEM IN RETINAL AND CHOROIDAL DISEASE. PMID- 26584440 TI - Correspondence. PMID- 26584441 TI - Reply: To PMID 25768252. PMID- 26584442 TI - Correspondence. PMID- 26584443 TI - Stereocontrol within polyketide assembly lines. AB - Most of the stereocenters of polyketide natural products are established during assembly line biosynthesis. The body of knowledge for how stereocenters are set is now large enough to begin constructing physical models of key reactions. Interactions between stereocenter-forming enzymes and polyketide intermediates are examined here at atomic resolution, drawing from the most current structural and functional information of ketosynthases (KSs), ketoreductases (KRs), dehydratases (DHs), enoylreductases (ERs), and related enzymes. While many details remain to be experimentally determined, our understanding of the chemical and physical mechanisms utilized by the chirality-molding enzymes of modular PKSs is rapidly advancing. PMID- 26584445 TI - Single-molecule fluorescence imaging to quantify membrane protein dynamics and oligomerization in living plant cells. AB - Measuring the mobility and interactions of proteins is key to understanding cellular signaling mechanisms; however, quantitative analysis of protein dynamics in living plant cells remains a major challenge. Here we describe an automated, single-molecule protocol based on total internal reflection fluorescence microscopy (TIRFM) imaging that allows protein tracking and subunit counting in living plant cells. This protocol uses TIRFM to image transgenic plant tissues expressing fluorescently tagged proteins that are localized to the plasma membrane. Next, a tracking algorithm quantifies dynamic changes in fluorescent protein motion types, temporary particle displacement and protein photobleaching steps. This protocol allows researchers to study the kinetic characteristics of heterogeneously distributed proteins. The approach has potential applications for studies of protein dynamics and subunit stoichiometry for a wide variety of plasma membrane and intracellular proteins in living plant cells and other biological specimens visualized by TIRFM or other fluorescence imaging techniques. The whole protocol can be completed in 5-6 h. PMID- 26584446 TI - Intubation-based anesthesia for long-term time-lapse imaging of adult zebrafish. AB - Zebrafish possess the remarkable ability to regenerate a vast variety of tissues, even as adults. However, direct imaging of regenerative processes in adult zebrafish remains challenging because of the lack of suitable anesthesia protocols. Here we present a description of an intubation-based anesthesia procedure that we developed to enable us to image regenerating zebrafish fins and which can be used to continuously anesthetize adult zebrafish for up to 2 d. Fish are immobilized in an imaging chamber followed by oral intubation. Subsequent delivery of anesthetic-containing water is achieved via a peristaltic pump. The setup of the system will take ~90 min for two adult zebrafish, and it requires only a little previous experience of working with zebrafish. Our protocol will enable the imaging of regenerative processes in the fin and other tissues, and the investigation of processes that require long-term anesthesia, such as immune responses and surgical procedures. PMID- 26584444 TI - Micropatterned coculture of primary human hepatocytes and supportive cells for the study of hepatotropic pathogens. AB - The development of therapies and vaccines for human hepatropic pathogens requires robust model systems that enable the study of host-pathogen interactions. However, in vitro liver models of infection typically use either hepatoma cell lines that exhibit aberrant physiology or primary human hepatocytes in culture conditions in which they rapidly lose their hepatic phenotype. To achieve stable and robust in vitro primary human hepatocyte models, we developed micropatterned cocultures (MPCCs), which consist of primary human hepatocytes organized into 2D islands that are surrounded by supportive fibroblast cells. By using this system, which can be established over a period of days, and maintained over multiple weeks, we demonstrate how to recapitulate in vitro hepatic life cycles for the hepatitis B and C viruses and the Plasmodium pathogens P. falciparum and P. vivax. The MPCC platform can be used to uncover aspects of host-pathogen interactions, and it has the potential to be used for drug and vaccine development. PMID- 26584447 TI - Extracellular protease digestion to evaluate membrane protein cell surface localization. AB - Membrane proteins have crucial roles in signaling and as anchors for cell surface display. Proper secretion of a membrane protein can be evaluated by its susceptibility to digestion by an extracellular protease, but this requires a crucial control to confirm membrane integrity during digestion. This protocol describes how to use this approach to determine how efficiently a protein is secreted to the outer surface of Gram-negative bacteria. Its success relies upon careful selection of an appropriate intracellular reporter protein that will remain undigested if the membrane barrier remains intact, but that is rapidly digested when cells are lysed before evaluation. Reporter proteins that are resistant to proteases (e.g., maltose-binding protein) do not return accurate results; in contrast, proteins that are more readily digested (e.g., SurA) serve as more sensitive reporters of membrane integrity, yielding more accurate measurements of membrane protein localization. Similar considerations apply when evaluating membrane protein localization in other contexts, including eukaryotic cells and organelle membranes. Evaluating membrane protein localization using this approach requires only standard biochemistry laboratory equipment for cell lysis, gel electrophoresis and western blotting. After expression of the protein of interest, this procedure can be completed in 4 h. PMID- 26584448 TI - Long-term Risk of Hospitalization for Somatic Diseases in Survivors of Adolescent or Young Adult Cancer. AB - IMPORTANCE: Survivors of adolescent and young adult cancers are at risk for treatment-induced late adverse effects; however, to our knowledge, the long-term risk of hospitalization in this specific group of cancer survivors has not been thoroughly evaluated. OBJECTIVE: To examine relative and absolute excess risk for hospitalizations up to 34 years after diagnosis of adolescent and young adult cancer compared with population comparisons. DESIGN, SETTING, AND PARTICIPANTS: This was a cohort study, conducted in Denmark, of 33,555 five-year survivors of adolescent or young adult cancer, diagnosed from 1943 through 2004, when they were 15 to 39 years of age, and 228,447 population comparisons, matched to the survivors by sex and year of birth. MAIN OUTCOMES AND MEASURES: Cancer survivors and comparisons were followed up for hospitalizations in the Danish Patient Register through December 2010. Standardized hospitalization rate ratios (RRs) and absolute excess risks (AERs) were calculated. RESULTS: After a median follow up of 14 years, we identified 53,032 hospitalizations in cancer survivors, whereas 38,423 were expected, resulting in an overall RR of 1.38 (95% CI, 1.37 1.39). The data analysis was started in January 2015 and ended in June 2015. Additional data analyses requested by the reviewers were conducted in August 2015. The highest risks were found for the main diagnostic groups of diseases of blood and blood-forming organs (RR, 2.00; 95% CI, 1.87-2.14), infectious and parasitic diseases (RR, 1.69; 95% CI, 1.61-1.77), and malignant neoplasms (RR, 1.63; 95% CI, 1.59-1.68). The overall AER was 2803 (95% CI, 2712-2893) per 100,000 person-years; the highest AERs were found for malignant neoplasms, diseases of digestive organs, and diseases of the circulatory system (18%, 15%, and 14% of total AER, respectively). Survivors of the 10 most common cancers in adolescents and young adults were at significantly increased risk for diseases in the 12 main diagnostic groups. The highest risks were those of survivors of leukemia (RR, 2.21; 95% CI, 2.02-2.42), brain cancer (RR, 1.93; 95% CI, 1.86 2.00), and Hodgkin lymphoma (RR, 1.87; 95% CI, 1.80-1.94). CONCLUSIONS AND RELEVANCE: The large number of survivors and the use of hospital discharge diagnoses made it possible to draw a comprehensive picture of the complex inpatient disease burden experienced by survivors of adolescent and young adult cancer. The findings underscore a great diversity of cancer-related health problems that physicians and patients should be knowledgeable about. PMID- 26584449 TI - Fluorine in fragrances: exploring the difluoromethylene (CF2) group as a conformational constraint in macrocyclic musk lactones. AB - The CF2 group is incorporated into specific positions within the lactone ring of the natural musk lactone, (12R)-(+)-12-methyl-13-tridecanolide, a constituent of Angelica root oil, Angelica archangelica L. The approach is taken as it was anticipated that CF2 groups would dictate corner locations in the macrocycle and limit the conformational space available to the lactone. Three fluorine containing lactones are prepared by organic synthesis. One (8) has CF2 groups located at the C-6 and C-9 positions, another (9) with CF2 groups at the C-5 and C-9 positions, and a third (10) with a CF2 group at C-8. Two of the fluorine containing lactones (8 and 10) were sufficiently crystalline to obtain X-ray crystal structures which revealed that the CF2 groups do adopt corner locations. All three lactones were subject to computational analysis at the B3LYP-D3/6 311+G** level to assess the relative energies of different conformers. In all cases, the global minima and most of the lowest energy minima have squared/rectangular geometries and located the CF2 groups at the corners. The lowest energy structures for 8 and 10 closely approximated the observed X-ray structures, suggesting good convergence of theory and experiment in determining relevant low energy conformations. All three compounds retained a pleasant odour suggesting the rings retained sufficient conformational flexibility to access relevant olfactory conformations. PMID- 26584450 TI - Effect of Ranibizumab on the Decision to Drive and Vision Function Relevant to Driving in Patients With Diabetic Macular Edema: Report From RESTORE, RIDE, and RISE Trials. AB - IMPORTANCE: The potential effect of treatments for diabetic macular edema (DME) on driving should be of value to patients and clinicians, such as ophthalmologists and other physicians, who treat patients with diabetes mellitus. OBJECTIVE: To determine the effect of ranibizumab on driving and patient-reported vision function relevant to driving among patients with DME. DESIGN, SETTING, AND PARTICIPANTS: This exploratory post hoc analysis was conducted between October 1, 2011, and July 25, 2015, based on deidentified data from phase 3, multicenter, randomized clinical trials (RIDE, RISE, and RESTORE trials). Individuals assigned randomly to monthly sham, 0.3-mg ranibizumab, or 0.5-mg ranibizumab in RIDE and RISE or to macular laser, macular laser plus 0.5-mg ranibizumab (3-monthly doses, then as needed), or 0.5-mg (3-monthly doses, then as needed) in RESTORE. MAIN OUTCOMES AND MEASURES: Driving items from the National Eye Institute (NEI) Visual Function Questionnaire-25 (VFQ-25) at baseline through 24 months in RIDE/RISE (pooled) and through 12 months in RESTORE. RESULTS: A total of 71.2% of 753 patients in RIDE/RISE and 50.4% of 345 patients in RESTORE reported driving at baseline; at least 55% reported still driving at follow-up. Among those not driving at baseline in RIDE/RISE, at 12 months, 7.0% (95% CI, -5.0 to 19.0) more in the 0.3-mg group and 14.4% (95% CI, 1.1 to 27.7) more in the 0.5-mg group vs the sham group reported driving. Among those not driving at baseline in RESTORE, at 12 months, 4.2% (95% CI, -7.7 to 16.1) more in the laser plus 0.5-mg group and 0.9% (95% CI, -10.3 to 12.1) more in the 0.5-mg group vs the laser group reported driving. Although balanced at baseline across treatment groups for RESTORE and RIDE/RISE, the proportion of patients with best-corrected visual acuity typically required for an unrestricted license (20/40 or better in at least 1 eye) appeared greater at month 12 in the ranibizumab groups (77 of 80 [96.3%] for 0.5 mg + laser and 91 of 93 [97.8%] for 0.5 mg) vs laser (71 of 79 [89.9%]) in RESTORE, and at months 12 (112 of 123 [91.1%] and 136 of 137 [99.3%] in 0.3- and 0.5-mg groups, respectively) and 24 (113 of 123 [91.9%] and 135 of 137 [98.5%] in the 0.3- and 0.5-mg groups, respectively) vs sham (121 of 147 [82.3%] and 122 of 147 [83.0%]) in RIDE/RISE. CONCLUSIONS AND RELEVANCE: These results suggest that 12 months after initiating ranibizumab for vision impairment from center-involved DME, patients not driving at initiation of treatment are more likely to report driving and have driving-eligible visual acuity of 20/40 or better in the better seeing eye than those treated with sham or laser. TRIAL REGISTRATION: clinicaltrials.gov Identifier: RESTORE: NCT00687804; RIDE: NCT00473382; and RISE: NCT00473330. PMID- 26584451 TI - Soft Supramolecular Nanoparticles by Noncovalent and Host-Guest Interactions. AB - Supramolecular chemistry provides a tool for the formation of highly ordered structures by means of noncovalent interactions. Soft supramolecular nanoparticles are self-assembled nanoassemblies based on small building blocks and stabilized by basic noncovalent interactions, selective host-guest interactions, or a combination of different interaction types. This review provides an overview of the existing approaches for the formation of supramolecular nanoparticles by various types of noncovalent interactions, with a strong focus on host-guest-mediated assemblies. The approaches are ordered based on the nature of the stabilizing supramolecular interaction, while focusing on the aspects that determine the particle structure. Where applicable, the use of these self-assembled nanostructures as vectors in molecular diagnostics and therapeutics is described as well. The stable yet reversible nature of supramolecular interactions and their chemical flexibility offer great prospects for the development of highly engineered nanoparticles which are compatible with the complexity of living systems. PMID- 26584452 TI - Lateralizing value of unilateral relative ictal immobility in patients with refractory focal seizures--Looking beyond unilateral automatisms. AB - PURPOSE: Ictal motor phenomena play a crucial role in the localization of seizure focus in the management of refractory focal epilepsy. While the importance of unilateral automatisms is well established, little attention is paid to the contralateral relatively immobile limb. In cases where automatisms mimic clonic or dystonic movements and in the absence of previously well-established signs, unilateral relative ictal immobility (RII) is potentially useful as a lateralizing sign. This study was carried out to examine the lateralizing value of this sign and to define its characteristics among patients of refractory focal epilepsy. METHODS: VEEGs of 69 consecutive patients of refractory focal epilepsy who had undergone epilepsy surgery at our center over last four years were reviewed and analyzed for the presence of RII. Unilateral RII was defined as a paucity of movement in one limb lasting for at least 10s while the contralateral limb showed purposive or semi-purposive movements (in the absence of tonic or dystonic posturing or clonic movements in the involved limb). The findings were seen in the light of VEEG, radiological and nuclear imaging data, and with post surgical outcome. RESULTS: Unilateral RII as a lateralizing sign was found in 24 of 69 patients (34.78%), consisting of both temporal and extra temporal epilepsy, with 100% concordance with VEEG and MRI data. All patients demonstrating this sign had a good post-surgical outcome. CONCLUSION: RII, when well characterized is a frequent and reliable lateralizing sign in patients of refractory focal epilepsy. PMID- 26584453 TI - From static micrographs to particle aggregation dynamics in three dimensions. AB - Studies on colloidal aggregation have brought forth theories on stability of colloidal gels and models for aggregation dynamics. Still, a complete link between developed frameworks and obtained laboratory observations has to be found. In this work, aggregates of silica nanoparticles (20 nm) are studied using diffusion limited cluster aggregation (DLCA) and reaction limited cluster aggregation (RLCA) models. These processes are driven by the probability of particles to aggregate upon collision. This probability of aggregation is one in the DLCA and close to zero in the RLCA process. We show how to study the probability of aggregation from static micrographs on the example of a silica nanoparticle gel at 9 wt%. The analysis includes common summary functions from spatial statistics, namely the empty space function and Ripley's K-function, as well as two newly developed summary functions for cluster analysis based on graph theory. One of the new cluster analysis functions is related to the clustering coefficient in communication networks and the other to the size of a cluster. All four topological summary statistics are used to quantitatively compare in plots and in a least-square approach experimental data to cluster aggregation simulations with decreasing probabilities of aggregation. We study scanning transmission electron micrographs and utilize the intensity-mass thickness relation present in such images to create comparable micrographs from three dimensional simulations. Finally, a characterization of colloidal silica aggregates and simulated structures is obtained, which allows for an evaluation of the cluster aggregation process for different aggregation scenarios. As a result, we find that the RLCA process fits the experimental data better than the DLCA process. PMID- 26584454 TI - In Vitro Activation of eNOS by Mangifera indica (CarelessTM) and Determination of an Effective Dosage in a Randomized, Double-Blind, Human Pilot Study on Microcirculation. AB - Mangifera indica fruit preparation (CarelessTM) activates the evolutionary conserved metabolic sensors sirtuin 1 and adenosine monophosphate-activated protein kinase, which have been identified as playing a key role in microcirculation and endothelial function. Here, an acute effect of a single dose of 100 mg or 300 mg CarelessTM on microcirculation was investigated in a randomized, double-blind, crossover pilot study in ten healthy women to determine the effective dosage. Microcirculation and endothelial function were assessed by the Oxygen-to-see system and pulse amplitude tonometry (EndoPATTM), respectively. Cutaneous blood flow was increased over time by 100 mg (54% over pre-values, p = 0.0157) and 300 mg (35% over pre-value, p = 0.209) CarelessTM. The EndoPATTM reactive hyperemia response was slightly improved 3 h after intake compared to pretesting with 300 mg CarelessTM. Furthermore, activation of endothelial nitric oxide synthase, as an important regulator for endothelial function, was tested in vitro in primary human umbilical vein endothelial cells. CarelessTM, after simulation of digestion, increased the activated form of endothelial nitric oxide synthase dose-dependently by 23% (300 ug/mL), 42% (1500 ug/mL), and 60% (3000 ug/mL) compared to the untreated control. In conclusion, the study suggests moderate beneficial effects of CarelessTM on microcirculation, which is at least partly mediated by endothelial nitric oxide synthase activation. PMID- 26584455 TI - Hypouricemic and Nephroprotective Effects of Emodinol in Oxonate-Induced Hyperuricemic Mice are Mediated by Organic Ion Transporters and OIT3. AB - Emodinol, 1beta,3beta,23-trihydroxyolean-12-en-28-acid, as the main active ingredient firstly extracted from the rhizomes of Elaeagus pungens by our research group, has been demonstrated to exhibit uricosuric activity by our previous study. The aim of this study was to evaluate the uricosuric and nephroprotective effects of emodinol and explore its possible mechanisms in potassium oxonate-induced hyperuricemic mice with renal dysfunction. Mice were orally administrated 250 mg/kg of potassium oxonate once daily for 7 consecutive days to induce hyperuricemia with renal dysfunction. Emodinol was given at doses of 25, 50, and 100 mg/kg on the same day 1 h after oxonate treatment, and allopurinol (10 mg/kg) was given as a positive control. After 1 week, serum uric acid, serum creatinine, urine uric acid, urine creatinine, blood urea nitrogen, and hepatic xanthine oxidase activity were determined. The mRNA and protein levels of urate transporter 1, glucose transporter 9, ATP-binding cassette subfamily G member 2, organic anion transporter 1, oncoprotein-induced transcript 3, and organic cation/carnitine transporters in the kidney were detected by real time polymerase chain reaction and Western blot analysis. In addition, urinary and renal Tamm-Horsfall glycoprotein concentrations were examined by ELISA assays. Emodinol significantly reduced serum urate levels, increased urinary urate levels and fractional excretion of uric acid, and inhibited hepatic xanthine oxidase activity in hyperuricemic mice. Moreover, potassium oxonate administration led to dys expressions of renal urate transporter 1, glucose transporter 9, ATP-binding cassette subfamily G member 2, organic anion transporter 1, and oncoprotein-induced transcript 3 as well as alternations of uromodulin concentrations, which could be reversed by emodinol. On the other hand, treatment of emodinol caused upregulated expressions of organic cation/carnitine transporters, resulting in an improvement of renal function characterized by decreased serum creatinine and blood urea nitrogen levels. Emodinol exhibited hypouricemic and nephroprotective actions by inhibiting xanthine oxidase activity and regulating renal ion transporters and oncoprotein induced transcript 3, which may be a potential therapeutic agent in hyperuricemia and renal dysfunction. PMID- 26584456 TI - Effectiveness of Topical Nigella sativa Seed Oil in the Treatment of Cyclic Mastalgia: A Randomized, Triple-Blind, Active, and Placebo-Controlled Clinical Trial. AB - Cyclic mastalgia is common in women and has no optimal therapy. Analgesic effects of Nigella sativa have been reported. Thus, the effect of a standardized N. sativa seed oil (600 mg applied to the site of pain bis in die for 2 months) on the 10-centimeter visual analog scale scores of pain severity in 52 women with cyclic mastalgia was compared to that of topical diclofenac (20 mg bis in die) (n = 51) and placebo (n = 53). There was no significant difference between the 1- and 2-month pain scores in the active treatment groups (p > 0.05). The pain scores of the active treatment groups did not differ significantly at 1 and 2 months (p > 0.05). The endpoint pain scores of the active treatment groups decreased significantly compared with the baseline (both p < 0.001). The pain scores of the active treatment groups at 1 and 2 months were significantly smaller than those of the placebo group (both p < 0.001). The pain scores of the placebo group at 1 and 2 months were not significantly different from the baseline (p > 0.05). No adverse effect was observed. In conclusion, topical N. sativa seed oil is safe, more effective than placebo, and has clinical effectiveness comparable to topical diclofenac in the treatment of cyclic mastalgia. PMID- 26584457 TI - Ocimum gratissimum Essential Oil and Its Isolated Compounds (Eugenol and Myrcene) Reduce Neuropathic Pain in Mice. AB - Ocimum gratissimum is used in popular medicine to treat painful diseases. The antihypernociceptive properties of O. gratissimum essential oil and two of its active components (eugenol and myrcene) were tested in a model of neuropathic pain induced by a chronic constriction injury of the sciatic nerve. In tests to determine chronic antinociception, adult male C57BL/6 J mice were treated orally with corn oil (control group), O. gratissimum essential oil at doses of 10, 20, or 40 mg/kg or eugenol or myrcene at doses of 1, 5, or 10 mg/kg for 14 days after surgery. Pregabalin (20 mg/kg) was used as a standard in this study. The treatment with 20 and 40 mg/kg of O. gratissimum essential oil and at doses of 5 and 10 mg/kg of the active components were able to promote antihypernociception in both mechanical (von Frey) and thermal (hot plate) tests. The treatment with the essential oil of the plant or eugenol was effective in reducing the levels of interleukin-1beta in the sciatic nerve. Our findings demonstrate that O. gratissimum essential oil and its isolated active components possess antihypernociceptive activity in neuropathic pain models. PMID- 26584458 TI - Characterization of the Isosteroidal Alkaloid Chuanbeinone from Bulbus of Fritillaria pallidiflora as Novel Antitumor Agent In Vitro and In Vivo. AB - Bulbus of Fritillaria pallidiflora, the dried bulb of F. pallidiflora, is widely used in Chinese folk medicine due to its powerful biological activities. The aim of this study was to investigate in vitro and in vivo antitumor activity of different fractions and isosteroidal alkaloids from bulbus of F. pallidiflora and clarify its putative mechanism of antitumor activity. Firstly, we assayed in vitro antitumor effects of different fractions from bulbus of F. pallidiflora and found that chloroform extracts and purified total alkaloids of bulbus of F. pallidiflora showed higher cytotoxic activity than other tested extracts. We further isolated four main alkaloids, chuanbeinone, imperialine-beta-N-oxide, isoverticine and isoverticine-beta-N-oxide, from the total alkaloids of bulbus of F. pallidiflora and found that they display significant cytotoxicity, whereby chuanbeinone showed the highest activity against Lewis lung carcinoma cells. Moreover, we found that chuanbeinone induced S phase arrest and further increased apoptosis of Lewis lung carcinoma cells. The results of Western blotting experiments showed that the expression of the antiapoptotic Bcl-2 was reduced by chuanbeinone treatment, while the proapoptotic protein Bax and caspase-3 were increased. Moreover, we investigated the in vivo antitumor activity of chuanbeinone and characterized its putative antitumor mechanism of action by the TUNEL assay and by histological and immunohistochemical analyses. Our results showed that chuanbeinone exhibited significant antitumor activity in vivo, while notably inhibiting tumor angiogenesis and inducing apoptosis characterized by an increased expression of caspase-3. Our findings show that chuanbeinone exhibits significant antitumor activity in vitro and in vivo, and points to possible therapeutic potential for this compound as well as for its natural source, bulbus of F. pallidiflora. PMID- 26584459 TI - Fixed Aspect Ratio Rod-to-Rod Conversion and Localized Surface Plasmon Resonance in Semiconducting I-V-VI Nanorods. AB - Fixed-aspect-ratio rod-to-rod conversion of binary V-VI Sb2 Se3 to ternary I-V-VI Cu3 SbSe3 semiconducting nano structures is reported. Capturing the inter mediate products, the insight mechanisms of the ion-diffusion process for the structural transformation are established. The final ternary structure shows localized surface plasmonresonance-induced absorption in the near-infrared regions. PMID- 26584460 TI - Graphene oxide/carbon dot composite: a new photoelectrode material for photocurrent response enhancement. AB - Low-dimensional carbon nanocomposite-based architectures and anchoring zero dimensional carbon dots on two-dimensional graphene sheets may provide an important approach to develop energy harvesting and conversion strategies. In this work, as a novel photoelectrode with a high photocurrent response performance based on a composite made with all carbon-based materials consisting of p-type graphene oxide (GO) and n-type nitrogen, sulfur co-doped carbon dot (NS CD) has been prepared via the electrophoretic deposition approach. The photoelectrochemical measurement shows that the GO/NS-CD composite greatly suppresses the charge recombination and evidently enhances the photocurrent response activity. It is anticipated that this work may pave a valuable step for the further development of all carbon-based optoelectronic devices with excellent performance. PMID- 26584461 TI - Tigriopus fulvus: The interlaboratory comparison of the acute toxicity test. AB - The paper reports the results of an interlaboratory comparison involving 11 laboratories, with the objectives of apply and validate a new standardized ecotoxicological method on marine crustacean Tigriopus fulvus. Copper was chosen as reference toxicant as indicated in the official method. The results of two independent tests performed by all the participants, demonstrated that the new method is simple, fast and easy to learn. This is confirmed even by the values of z-score index calculated for each laboratory and the relative coefficient of variation (CV) which are 6.32% after 24h, 6.56 after 48h and 35.3% after 96h, mentioned in the ISO standards for the precision of interlaboratory assays. Therefore its use could be recommended in environmental studies and monitoring. PMID- 26584462 TI - Use of the rainbow trout cell lines, RTgill-W1 and RTL-W1 to evaluate the toxic potential of benzotriazoles. AB - Epithelial cell lines, RTgill-W1 and RTL-W1 from respectively gill and liver of rainbow trout, Onchorhynchus mykiss (Walbaum), were used to evaluate the toxic potential of six benzotriazoles (BTRs) and tolytriazole (TT), which is a commercial mixture of 4-methyl-1H-benzotriazole (4MBTR) and 5-methyl-1H benzotriazole (5MBTR). The other BTRs were 1H-benzotriazole (1H-BTR), 5 chlorobenzotriazole (5CBTR), 1-hydroxybenzotriazole (1OHBTR) and 5,6-dimethyl-1H benzotriazole monohydrate (DM). Except for DM, all BTRs were cytotoxic at concentrations above 15mg/L and transitorily elevated reactive oxygen species (ROS) levels. Neither N-acetyl cysteine (NAC) nor IM-54 inhibited cytotoxicity, suggesting that ROS were not the major cause of the cell death. Cell death was not blocked by Necrostatin nor accompanied by DNA laddering, suggesting that the cell death mechanism was neither necroptosis nor apoptosis. As judged by the comet assay, DNA strand breaks were detected with three BTRs: 4MBTR, 5MBTR and 5CBTR. In RTL-W1, the BTRs weakly induced cytochrome P4501A, suggesting that they have the potential to alter xenobiotic metabolism and activate the aryl hydrocarbon receptor. In summary, the toxic potential of BTRs appears to be limited to only high concentrations, which are higher than have been measured in the environment to date. PMID- 26584463 TI - Life-Threatening Sochi Virus Infections, Russia. AB - Sochi virus was recently identified as a new hantavirus genotype carried by the Black Sea field mouse, Apodemus ponticus. We evaluated 62 patients in Russia with Sochi virus infection. Most clinical cases were severe, and the case-fatality rate was as high as 14.5%. PMID- 26584464 TI - Outbreak of Exanthematous Illness Associated with Zika, Chikungunya, and Dengue Viruses, Salvador, Brazil. PMID- 26584465 TI - Classification of image artefacts in optical coherence tomography angiography of the choroid in macular diseases. AB - BACKGROUND: To evaluate and classify image artefacts in optical coherence tomography (OCT) angiography (OCTA) of the choroid in a group of patients with macular diseases. DESIGN: Retrospective observational study. PARTICIPANTS: Five patients with age-related macular degeneration, three with central serous retinopathy, one with polypoidal choroidal vasculopathy and one with multiple evanescent white dot syndrome. METHODS: OCTA and OCT reflectivity (OCTR) maps were reviewed along with their fluorescein angiography and indocyanine green angiography. Sixty OCTA images (20 outer retina, 20 Sattler and 20 Haller layers) were graded for image artefacts by two examiners independently. MAIN OUTCOME MEASURES: OCTA artefacts and their correlation with OCTR maps, angiography and OCT B-scans. RESULTS: Artefacts (frequency) were classified into (i) motion (70 100%), (ii) fringe washout (100%), (iii) decorrelation projection (0-20%), (iv) masking and unmasking (50-65%) and (v) stromal decorrelation signal (100%). Motion artefact in OCTA is characterized by horizontal dark lines or bands not apparent on OCTR map. Fringe washout creates signal void within choroidal vessels because of fast blood flow. Decorrelation projection from retinal vasculature and choroidal new vessels above the Bruch's membrane are seen within the choroidal OCTA image. Masking and unmasking artefacts occur in regions of pigment epithelial detachment and atrophy. Decorrelation signals can also be seen in the choroidal stroma. CONCLUSIONS: Our classification system of artefact in choroidal OCTA establishes a common terminology for clinical interpretation. This is important in enhancing our understanding of the principles of OCTA acquisition, and it also serves as a bench mark for reading centres. PMID- 26584466 TI - Potent oxazoline analog of apratoxin C: Synthesis, biological evaluation, and conformational analysis. AB - In this research, the synthesis, biological evaluation, and conformational analysis of an apratoxin C oxazoline analog (3) have been demonstrated. The preparation of synthetic key intermediate 9 was achieved using an improved strategy that involves commercially available 3-methylglutaric anhydride (12), an enzymatic enantioselective alcoholysis, and a diastereoselective reduction. The Pro-Dtrina (3,7-dihydroxy-2,5,8-trimethylnonanoic acid) moiety 8 was successfully synthesized in a similar manner as our previously reported synthesis of apratoxin C (1). The cyclization precursor 5 was formed after the coupling of Pro-Dtrina 8 with a known tetrapeptide 7 to afford a linear peptide 6, the formation of an oxazoline, and the removal of the protecting groups. Finally, the macrolactamization of 5 with O-(7-aza-1H-benzotriazol-1-yl)-N,N,N',N' tetramethyluronium hexafluorophosphate (HATU)/N,N-diisopropylethylamine (DIEA) furnished an apratoxin C oxazoline analog (3), which exhibited a potent cytotoxicity against HeLa cells (IC50 value of 22 nM) that was comparable with the cytotoxicity of apratoxin C (1) (IC50 value of 4.2 nM). Conformational analyses of 1 and 3 through NMR experiments showed that oxazoline analog 3 formed a tertiary structure that was similar to the apratoxin C (1) structure in CD3 CN, which provided a probable explanation for their comparable cytotoxicities. (c) 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 404-414, 2016. PMID- 26584467 TI - Opportunistic Pulmonary Bordetella hinzii Infection after Avian Exposure. AB - We report 2 cases of pulmonary Bordetella hinzii infection in immunodeficient patients. One of these rare cases demonstrated the potential transmission of the bacteria from an avian reservoir through occupational exposure and its persistence in humans. We establish bacteriologic management of these infections and suggest therapeutic options if needed. PMID- 26584468 TI - Altered methamphetamine place conditioning in mice vaccinated with a succinyl methamphetamine-tetanus-toxoid vaccine. AB - BACKGROUND AND OBJECTIVES: We previously reported that an anti-methamphetamine (MA) vaccine attenuated drug-conditioned effects in mice, but it used a carrier protein and adjuvant not available for clinical use. Here we produced a vaccine with the same hapten (succinyl-methamphetamine, SMA) but attached to tetanus toxoid (SMA-TT) and adsorbed to aluminum hydroxide, components approved for use in humans. We then assessed the vaccine's ability to generate anti-MA antibodies, alter acquisition and reinstatement of MA place conditioning, and prevent MA brain penetration. METHODS: Mice were administered SMA-TT at weeks 0 and 3 and non-vaccinated mice received saline. Anti-MA antibody concentrations were determined at 8 and 12 weeks. Place conditioning began during week 9 in which vaccinated and non-vaccinated mice were divided into groups and conditioned with .5, or 2.0 mg/kg MA. Following acquisition training, mice were extinguished and then a reinstatement test was performed in which mice were administered their original training dose of MA. Separate groups of non-vaccinated and vaccinated mice were administered .5 and 2.0 mg/kg MA and brain MA levels determined. RESULTS AND CONCLUSIONS: Anti-MA antibody levels were elevated at week 8 and remained so through week 12. The SMA-TT vaccine attenuated acquisition and reinstatement of MA place conditioning. Significantly greater proportions of vaccinated mice during acquisition and reinstatement tests showed conditioned place aversion. Moreover, MA brain levels were decreased in vaccinated mice following administration of both doses of MA. SCIENTIFIC SIGNIFICANCE: Results support further development of anti-MA vaccines using components approved for use in humans. PMID- 26584469 TI - Spirometric reference values for Hopi Native American children ages 4-13 years. AB - Spirometry is the most important tool in diagnosing pulmonary disease and is the most frequently performed pulmonary function test. Respiratory disease is also one of the greatest causes for morbidity and mortality on the Hopi Nation, but no specific reference equations exist for this unique population. The purpose of this study was to determine if population reference equations were necessary for these children and, if needed, to create new age and race-specific pulmonary nomograms for Hopi children. Two hundred and ninety-two healthy children, ages 4 13 years, attending Hopi Nation elementary schools in Arizona, were asked to perform spirometry for a full battery of pulmonary volumes and capacities of which the following were analyzed: forced vital capacity (FVC), forced expiratory volume in 1 sec (FEV1 ), FEV1 % (FEV1 /FVC), FEF25-75% and peak expiratory flow rate (PEFR). Spirometric data from Navajo children living in the same geographical region as the Hopi children were compared as well as spirometric data from common reference values used for other ethnic groups in the USA. Spirometry tests from 165 girls and 127 boys met American Thoracic Society quality control standards. We found that the natural log of height, body mass and age were significant predictors of FEV1 , FVC, and FEF25-75% in the gender specific models and that lung function values all increased with height and age as expected. The predictions using the equations derived for Navajo, Caucasian, Mexican-American, African-American youth were significantly different (P <= 0.05) from the predictions derived from the Hopi equations for all of the variables across both genders, with the exceptions of Hopi versus Navajo FEV1 /FVC in the males and Hopi versus Caucasians FEF25-75% in the females. Thus it would appear for this population important to have specific formulae to provide more accurate reference values. PMID- 26584470 TI - Summary goodness-of-fit statistics for binary generalized linear models with noncanonical link functions. AB - Generalized linear models (GLM) with a canonical logit link function are the primary modeling technique used to relate a binary outcome to predictor variables. However, noncanonical links can offer more flexibility, producing convenient analytical quantities (e.g., probit GLMs in toxicology) and desired measures of effect (e.g., relative risk from log GLMs). Many summary goodness-of fit (GOF) statistics exist for logistic GLM. Their properties make the development of GOF statistics relatively straightforward, but it can be more difficult under noncanonical links. Although GOF tests for logistic GLM with continuous covariates (GLMCC) have been applied to GLMCCs with log links, we know of no GOF tests in the literature specifically developed for GLMCCs that can be applied regardless of link function chosen. We generalize the Tsiatis GOF statistic originally developed for logistic GLMCCs, (TG), so that it can be applied under any link function. Further, we show that the algebraically related Hosmer-Lemeshow (HL) and Pigeon-Heyse (J(2) ) statistics can be applied directly. In a simulation study, TG, HL, and J(2) were used to evaluate the fit of probit, log-log, complementary log-log, and log models, all calculated with a common grouping method. The TG statistic consistently maintained Type I error rates, while those of HL and J(2) were often lower than expected if terms with little influence were included. Generally, the statistics had similar power to detect an incorrect model. An exception occurred when a log GLMCC was incorrectly fit to data generated from a logistic GLMCC. In this case, TG had more power than HL or J(2) . PMID- 26584474 TI - Incorrect Dates in Abstract and Methods. PMID- 26584477 TI - pH-Regulated Reversible Transition Between Polyion Complexes (PIC) and Hydrogen Bonding Complexes (HBC) with Tunable Aggregation-Induced Emission. AB - The mimicking of biological supramolecular interactions and their mutual transitions to fabricate intelligent artificial systems has been of increasing interest. Herein, we report the fabrication of supramolecular micellar nanoparticles consisting of quaternized poly(ethylene oxide)-b-poly(2 dimethylaminoethyl methacrylate) (PEO-b-PQDMA) and tetrakis(4 carboxylmethoxyphenyl)ethene (TPE-4COOH), which was capable of reversible transition between polyion complexes (PIC) and hydrogen bonding complexes (HBC) with tunable aggregation-induced emission (AIE) mediated by solution pH. At pH 8, TPE-4COOH chromophores can be directly dissolved in aqueous milieu without evident fluorescence emission. However, upon mixing with PEO-b-PQDMA, polyion complexes were formed by taking advantage of electrostatic interaction between carboxylate anions and quaternary ammonium cations and the most compact PIC micelles were achieved at the isoelectric point (i.e., [QDMA(+)]/[COO(-)] = 1), as confirmed by dynamic light scattering (DLS) measurement. Simultaneously, fluorescence spectroscopy revealed an evident emission turn-on and the maximum fluorescence intensity was observed near the isoelectric point due to the restriction of intramolecular rotation of TPE moieties within the PIC cores. The kinetic study supported a micelle fusion/fission mechanism on the formation of PIC micelles at varying charge ratios, exhibiting a quick time constant (tau1) relating to the formation of quasi-equilibrium micelles and a slow time constant (tau2) corresponding to the formation of final equilibrium micelles. Upon deceasing the pH of PIC micelles from 8 to 2 at the [QDMA(+)]/[COO(-)] molar ratio of 1, TPE-4COOH chromophores became gradually protonated and hydrophobic. The size of micellar nanoparticles underwent a remarkable decrease, whereas the fluorescence intensity exhibited a further increase by approximately 7.35-fold, presumably because of the formation of HBC micelles comprising cationic PQDMA coronas and PEO/TPE-4COOH hydrogen-bonded cores, an inverted micellar structures compared to initial PIC micelles. Moreover, the pH-mediated schizophrenic micellar transition from PIC to HBC with tunable AIE characteristic was reversible. PMID- 26584476 TI - Localized signals that regulate transendothelial migration. AB - Transendothelial migration (TEM) of leukocytes is the step in leukocyte emigration in which the leukocyte actually leaves the blood vessel to carry out its role in the inflammatory response. It is therefore, arguably the most critical step in emigration. This review focuses on two of the many aspects of this process that have seen important recent developments. The adhesion molecules, PECAM (CD31) and CD99 that regulate two major steps in TEM, do so by regulating specific signals. PECAM initiates the signaling pathway responsible for the calcium flux that is required for TEM. Calcium enters through the cation channel TRPC6 and recruits the first wave of trafficking of membrane from the lateral border recycling compartment (LBRC). CD99 signals through soluble adenylate cyclase to activate protein kinase A to recruit a second wave of LBRC trafficking. Another process that is critical for TEM is transient removal of VE cadherin from the site of TEM. However, the local signaling pathways that are responsible for this appear to be different from those that open the junctions to increase vascular permeability. PMID- 26584478 TI - Acute and delayed peripheral and central neuromuscular alterations induced by a short and intense downhill trail run. AB - Downhill sections are highly strenuous likely contributing to the development of neuromuscular fatigue in trail running. Our purpose was to investigate the consequences of an intense downhill trail run (DTR) on peripheral and central neuromuscular fatigue at knee extensors (KE) and plantar flexors (PF). Twenty three runners performed a 6.5-km DTR (1264-m altitude drop) as fast as possible. The electromyographic activity of vastus lateralis (VL) and gastrocnemius lateralis (GL) was continuously recorded. Neuromuscular functions were assessed Pre-, Post-, and 2-day Post-DTR (Post2d). Maximal voluntary torques decreased Post (~ -19% for KE, ~ -25% for PF) and Post2d (~ -9% for KE, ~ -10% for PF). Both central and peripheral dysfunctions were observed. Decreased KE and PF voluntary activation (VA), evoked forces, VL M-wave amplitude, and KE low frequency fatigue were observed at Post. Changes in VL M-wave amplitude were negatively correlated to VL activity during DTR. Changes in PF twitch force and VA were negatively correlated to GL activity during DTR. The acute KE VA deficit was about a third of that reported after ultramarathons, although peripheral alterations were similar. The prolonged force loss seems to be mainly associated to VA deficit likely induced by the delayed inflammatory response to DTR-induced ultrastructural muscle damage. PMID- 26584479 TI - Reply to letter: Plasma fasting cholesterol profiles and age at onset in Parkinson's disease. PMID- 26584480 TI - Current Trends in Urolithiasis Treatment in Various European Health Systems. AB - OBJECTIVE: In spite of readily available evidence-based guidelines on urolithiasis treatment, practical applications of treatments vary from country to country, or even within countries. The choice of treatment depends not only on the evidence, but often on general non-medical decision factors such as infrastructure, expertise, trends, patient demands, industry drive and reimbursement levels. In turn, many of these factors are interdependent and a result of the individual National Health System. METHOD: In an attempt to get a crude picture of trends and practices in stone treatment across Europe, a group of well-renowned international experts in the field were asked to reply to a set of standard questions relating to stone treatments, health systems and adherence to guidelines (level of evidence D = expert opinion). RESULTS: The above mentioned interdependencies showed a varying picture in different countries. Overall, there is a trend away from lithotripsy and toward ureterorenoscopy. However, the choice of treatment is largely dependent on the affordability of infrastructure. Urologists may make choices based on the national reimbursement system, too. CONCLUSION: Without claiming to represent a scientifically sound study, this survey represents an interesting insight into a representative cross section of European urological current practices and trends in urolithiasis treatment. PMID- 26584481 TI - Cardiac Involvement in Von Hippel-Lindau Disease. AB - OBJECTIVE: The aim of this case report was to highlight the importance of ruling out pheochromocytoma in a patient with Von Hippel-Lindau disease (VHL) and cardiovascular manifestations. CLINICAL PRESENTATION AND INTERVENTION: A 22-year old woman with type IIb VHL presented with signs and symptoms of acute decompensated heart failure. Transthoracic echocardiography showed a dilated left ventricle with severely depressed ejection fraction, confirmed by MRI. Urinary catecholamine and metanephrine tests had elevated levels and an abdominal MRI showed the presence of two cystic masses at the left hypochondrium. Surgical resection of both masses was performed, confirming the diagnosis of pheochromocytoma and clear cell renal carcinoma on histology. Six-month echocardiography showed a left ventricle with normal diameters and preserved ejection fraction. Genetic analysis revealed a germline mutation (exon 3 deletion of VHL). As there was no family history of VHL, it was determined to be a de novo mutation. CONCLUSION: This case report showed an atypical manifestation in a patient with VHL and underlines the importance of screening for pheochromocytoma in such patients. PMID- 26584482 TI - Vaginal Pessary for Uterine Repositioning during High-Intensity Focused Ultrasound Ablation of Uterine Leiomyomas. AB - In order to ensure safe magnetic resonance-guided, high-intensity focused, ultrasound ablation of uterine leiomyomas, the ultrasound beam path should be free of intervening scar and bowel. Pre-treatment MRI of a 9-cm long and 7.7-cm wide leiomyomatous uterus in a 39-year-old woman with menorrhagia and abdominopelvic pain initially demonstrated a focused ultrasound treatment path without a bowel between the uterus and the abdominal wall. On the day of ablation, however, multiple loops of bowel were observed in the ultrasound beam path by MRI. Uterine repositioning was accomplished with a 76-mm donut vaginal pessary, which anteverted the fundus and successfully displaced the bowel. A vaginal pessary may aid in repositioning an axial or retroverted uterus to enable ablation of uterine leiomyomas. PMID- 26584483 TI - Correction: The Rsb Phosphoregulatory Network Controls Availability of the Primary Sigma Factor in Chlamydia trachomatis and Influences the Kinetics of Growth and Development. PMID- 26584485 TI - Detection of the Third Heart Sound Based on Nonlinear Signal Decomposition and Time-Frequency Localization. AB - This study presents a precise way to detect the third ( S3 ) heart sound, which is recognized as an important indication of heart failure, based on nonlinear single decomposition and time-frequency localization. The detection of the S3 is obscured due to its significantly low energy and frequency. Even more, the detected S3 may be misunderstood as an abnormal second heart sound with a fixed split, which was not addressed in the literature. To detect such S3, the Hilbert vibration decomposition method is applied to decompose the heart sound into a certain number of subcomponents while intactly preserving the phase information. Thus, the time information of all of the decomposed components are unchanged, which further expedites the identification and localization of any module/section of a signal properly. Next, the proposed localization step is applied to the decomposed subcomponents by using smoothed pseudo Wigner-Ville distribution followed by the reassignment method. Finally, based on the positional information, the S3 is distinguished and confirmed by measuring time delays between the S2 and S3. In total, 82 sets of cardiac cycles collected from different databases including Texas Heart Institute database are examined for evaluation of the proposed method. The result analysis shows that the proposed method can detect the S3 correctly, even when the normalized temporal energy of S3 is larger than 0.16, and the frequency of those is larger than 34 Hz. In a performance analysis, the proposed method demonstrates that the accuracy rate of S3 detection is as high as 93.9%, which is significantly higher compared with the other methods. Such findings prove the robustness of the proposed idea for detecting substantially low-energized S3 . PMID- 26584484 TI - Bihar's Pioneering School-Based Deworming Programme: Lessons Learned in Deworming over 17 Million Indian School-Age Children in One Sustainable Campaign. PMID- 26584486 TI - Tracking Neural Modulation Depth by Dual Sequential Monte Carlo Estimation on Point Processes for Brain-Machine Interfaces. AB - Classic brain-machine interface (BMI) approaches decode neural signals from the brain responsible for achieving specific motor movements, which subsequently command prosthetic devices. Brain activities adaptively change during the control of the neuroprosthesis in BMIs, where the alteration of the preferred direction and the modulation of the gain depth are observed. The static neural tuning models have been limited by fixed codes, resulting in a decay of decoding performance over the course of the movement and subsequent instability in motor performance. To achieve stable performance, we propose a dual sequential Monte Carlo adaptive point process method, which models and decodes the gradually changing modulation depth of individual neuron over the course of a movement. We use multichannel neural spike trains from the primary motor cortex of a monkey trained to perform a target pursuit task using a joystick. Our results show that our computational approach successfully tracks the neural modulation depth over time with better goodness-of-fit than classic static neural tuning models, resulting in smaller errors between the true kinematics and the estimations in both simulated and real data. Our novel decoding approach suggests that the brain may employ such strategies to achieve stable motor output, i.e., plastic neural tuning is a feature of neural systems. BMI users may benefit from this adaptive algorithm to achieve more complex and controlled movement outcomes. PMID- 26584487 TI - Real-Time Head Pose Tracking with Online Face Template Reconstruction. AB - We propose a real-time method to accurately track the human head pose in the 3 dimensional (3D) world. Using a RGB-Depth camera, a face template is reconstructed by fitting a 3D morphable face model, and the head pose is determined by registering this user-specific face template to the input depth video. PMID- 26584488 TI - Factors of Transferability for a Generic ConvNet Representation. AB - Evidence is mounting that Convolutional Networks (ConvNets) are the most effective representation learning method for visual recognition tasks. In the common scenario, a ConvNet is trained on a large labeled dataset (source) and the feed-forward units activation of the trained network, at a certain layer of the network, is used as a generic representation of an input image for a task with relatively smaller training set (target). Recent studies have shown this form of representation transfer to be suitable for a wide range of target visual recognition tasks. This paper introduces and investigates several factors affecting the transferability of such representations. It includes parameters for training of the source ConvNet such as its architecture, distribution of the training data, etc. and also the parameters of feature extraction such as layer of the trained ConvNet, dimensionality reduction, etc. Then, by optimizing these factors, we show that significant improvements can be achieved on various (17) visual recognition tasks. We further show that these visual recognition tasks can be categorically ordered based on their similarity to the source task such that a correlation between the performance of tasks and their similarity to the source task w.r.t. the proposed factors is observed. PMID- 26584489 TI - Automatic Pulmonary Artery-Vein Separation and Classification in Computed Tomography Using Tree Partitioning and Peripheral Vessel Matching. AB - We present a method for automatic separation and classification of pulmonary arteries and veins in computed tomography. Our method takes advantage of local information to separate segmented vessels, and global information to perform the artery-vein classification. Given a vessel segmentation, a geometric graph is constructed that represents both the topology and the spatial distribution of the vessels. All nodes in the geometric graph where arteries and veins are potentially merged are identified based on graph pruning and individual branching patterns. At the identified nodes, the graph is split into subgraphs that each contain only arteries or veins. Based on the anatomical information that arteries and veins approach a common alveolar sag, an arterial subgraph is expected to be intertwined with a venous subgraph in the periphery of the lung. This relationship is quantified using periphery matching and is used to group subgraphs of the same artery-vein class. Artery-vein classification is performed on these grouped subgraphs based on the volumetric difference between arteries and veins. A quantitative evaluation was performed on 55 publicly available non contrast CT scans. In all scans, two observers manually annotated randomly selected vessels as artery or vein. Our method was able to separate and classify arteries and veins with a median accuracy of 89%, closely approximating the inter observer agreement. All CT scans used in this study, including all results of our system and all manual annotations, are publicly available at "http://www.w3.org/1999/xlink">http://arteryvein.grand-challenge.org". PMID- 26584490 TI - Analysis of Lead-Free Piezoceramic-Based Power Ultrasonic Transducers for Wire Bonding. AB - Since the 1950s, lead zirconate-titanate (PZT) has been the dominant transduction material utilized in power ultrasonics, while lead-free piezoceramics have been largely neglected due to their relatively poor piezoelectric and electromechanical properties. However, the implementation of environmental directives that regulate and control the use of hazardous materials, such as lead, triggered a search for new high-performance lead-free piezoceramics. Recent advances have led to lead-free piezoceramics exhibiting properties similar to PZT, but despite this, reports utilizing these novel piezoceramics in practice are limited. This research employs a modified variant of bismuth sodium titanate (BNT) in a power ultrasonic transducer used for metal welding during the manufacture of semiconductors. The important factors for transducer reliability and performance are investigated, such as piezoceramic aging and stack preload level. It is reported that BNT-based transducers exhibit good stability, and can withstand a stack preload level of 90 MPa without depoling. Although the BNT based transducers exhibited larger dissipative losses compared to identical PZT8 based transducers, the tool displacement gain was larger under constant current conditions. Semiconductor wire bonds which satisfied the commercial quality control requirements were also formed by this BNT-based transducer. PMID- 26584491 TI - Fast Appearance Modeling for Automatic Primary Video Object Segmentation. AB - Automatic segmentation of the primary object in a video clip is a challenging problem as there is no prior knowledge of the primary object. Most existing techniques thus adapt an iterative approach for foreground and background appearance modeling, i.e., fix the appearance model while optimizing the segmentation and fix the segmentation while optimizing the appearance model. However, these approaches may rely on good initialization and can be easily trapped in local optimal. In addition, they are usually time consuming for analyzing videos. To address these limitations, we propose a novel and efficient appearance modeling technique for automatic primary video object segmentation in the Markov random field (MRF) framework. It embeds the appearance constraint as auxiliary nodes and edges in the MRF structure, and can optimize both the segmentation and appearance model parameters simultaneously in one graph cut. The extensive experimental evaluations validate the superiority of the proposed approach over the state-of-the-art methods, in both efficiency and effectiveness. PMID- 26584492 TI - A Robust Scheme for Feature-Preserving Mesh Denoising. AB - In recent years researchers have made noticeable progresses in mesh denoising, that is, recovering high-quality 3D models from meshes corrupted with noise (raw or synthetic). Nevertheless, these state of the art approaches still fall short for robustly handling various noisy 3D models. The main technical challenge of robust mesh denoising is to remove noise while maximally preserving geometric features. In particular, this issue becomes more difficult for models with considerable amount of noise. In this paper we present a novel scheme for robust feature-preserving mesh denoising. Given a noisy mesh input, our method first estimates an initial mesh, then performs feature detection, identification and connection, and finally, iteratively updates vertex positions based on the constructed feature edges. Through many experiments, we show that our approach can robustly and effectively denoise various input mesh models with synthetic noise or raw scanned noise. The qualitative and quantitative comparisons between our method and the selected state of the art methods also show that our approach can noticeably outperform them in terms of both quality and robustness. PMID- 26584493 TI - Visual Encoding of Dissimilarity Data via Topology-Preserving Map Deformation. AB - We present an efficient technique for topology-preserving map deformation and apply it to the visualization of dissimilarity data in a geographic context. Map deformation techniques such as value-by-area cartograms are well studied. However, using deformation to highlight (dis)similarity between locations on a map in terms of their underlying data attributes is novel. We also identify an alternative way to represent dissimilarities on a map through the use of visual overlays. These overlays are complementary to deformation techniques and enable us to assess the quality of the deformation as well as to explore the design space of blending the two methods. Finally, we demonstrate how these techniques can be useful in several-quite different-applied contexts: travel-time visualization, social demographics research and understanding energy flowing in a wide-area power-grid. PMID- 26584494 TI - Tone-Mapped Mean-Shift Based Environment Map Sampling. AB - In this paper, we present a novel approach for environment map sampling, which is an effective and pragmatic technique to reduce the computational cost of realistic rendering and get plausible rendering images. The proposed approach exploits the advantage of adaptive mean-shift image clustering with aid of tone mapping, yielding oversegmented strata that have uniform intensities and capture shapes of light regions. The resulted strata, however, have unbalanced importance metric values for rendering, and the strata number is not user-controlled. To handle these issues, we develop an adaptive split-and-merge scheme that refines the strata and obtains a better balanced strata distribution. Compared to the state-of-the-art methods, our approach achieves comparable and even better rendering quality in terms of SSIM, RMSE and HDRVDP2 image quality metrics. Experimental results further show that our approach is more robust to the variation of viewpoint, environment rotation, and sample number. PMID- 26584495 TI - Lightness Constancy in Surface Visualization. AB - Color is a common channel for displaying data in surface visualization, but is affected by the shadows and shading used to convey surface depth and shape. Understanding encoded data in the context of surface structure is critical for effective analysis in a variety of domains, such as in molecular biology. In the physical world, lightness constancy allows people to accurately perceive shadowed colors; however, its effectiveness in complex synthetic environments such as surface visualizations is not well understood. We report a series of crowdsourced and laboratory studies that confirm the existence of lightness constancy effects for molecular surface visualizations using ambient occlusion. We provide empirical evidence of how common visualization design decisions can impact viewers' abilities to accurately identify encoded surface colors. These findings suggest that lightness constancy aids in understanding color encodings in surface visualization and reveal a correlation between visualization techniques that improve color interpretation in shadow and those that enhance perceptions of surface depth. These results collectively suggest that understanding constancy in practice can inform effective visualization design. PMID- 26584496 TI - Switched Control of Cadence During Stationary Cycling Induced by Functional Electrical Stimulation. AB - Functional electrical stimulation (FES) can be used to activate the dysfunctional lower limb muscles of individuals with neurological disorders to produce cycling as a means of rehabilitation. However, previous literature suggests that poor muscle control and nonphysiological muscle fiber recruitment during FES-cycling causes lower efficiency and power output at the cycle crank than able-bodied cycling, thus motivating the investigation of improved control methods for FES cycling. In this paper, a stimulation pattern is designed based on the kinematic effectiveness of the rider's hip and knee joints to produce a forward torque about the cycle crank. A robust controller is designed for the uncertain, nonlinear cycle-rider system with autonomous, state-dependent switching. Provided sufficient conditions are satisfied, the switched controller yields ultimately bounded tracking of a desired cadence. Experimental results on four able-bodied subjects demonstrate cadence tracking errors of 0.05 +/-1.59 and 5.27 +/-2.14 revolutions per minute during volitional and FES-induced cycling, respectively. To establish feasibility of FES-assisted cycling in subjects with Parkinson's disease, experimental results with one subject demonstrate tracking errors of 0.43 +/- 4.06 and 0.17 +/-3.11 revolutions per minute during volitional and FES induced cycling, respectively. PMID- 26584497 TI - Non-Invasive, Temporally Discrete Feedback of Object Contact and Release Improves Grasp Control of Closed-Loop Myoelectric Transradial Prostheses. AB - Human grasping and manipulation control critically depends on tactile feedback. Without this feedback, the ability for fine control of a prosthesis is limited in upper limb amputees. Although various approaches have been investigated in the past, at present there is no commercially available device able to restore tactile feedback in upper limb amputees. Based on the Discrete Event-driven Sensory feedback Control (DESC) policy we present a device able to deliver short lasting vibrotactile feedback to transradial amputees using commercially available myoelectric hands. The device (DESC-glove) comprises sensorized thimbles to be placed on the prosthesis digits, a battery-powered electronic board, and vibrating units embedded in an arm-cuff being transiently activated when the prosthesis makes and breaks contact with objects. The consequences of using the DESC-glove were evaluated in a longitudinal study. Five transradial amputees were equipped with the device for one month at home. Through a simple test proposed here for the first time-the virtual eggs test-we demonstrate the effectiveness of the device for prosthetic control in daily life conditions. In the future the device could be easily exploited as an add-on to complement myoelectric prostheses or even embedded in prosthetic sockets to enhance their control by upper limb amputees. PMID- 26584498 TI - A UAV-Mounted Whole Cell Biosensor System for Environmental Monitoring Applications. AB - This study reports the development of a portable whole cell biosensor system for environmental monitoring applications, such as air quality control, water pollution monitoring, and radiation leakage detection. The system consists of a lightweight mechanical housing, a temperature regulating system, and a microfluidic bacterial inoculation channel. The overall system, which is less than 200 g, serves as a portable incubator for cell inoculation and can be mounted on an unmanned aerial vehicle for monitoring remote and unreachable locations. The feedback control system maintains the inoculation temperature within 0.05 degrees C. The large surface-to-volume ratio of the polydimethylsiloxane microchannel facilitates effective gas exchange for rapid bacterial growth. Molecular dynamic simulation shows effective diffusion of major gas pollutants in PDMS toward gas sensing applications. By optimizing the design, we demonstrate the operation of the system in ambient temperatures from 5 degrees C to 32 degrees C and rapid bacterial growth in microchannels compared to standard bacterial culture techniques. PMID- 26584499 TI - Predict Gram-Positive and Gram-Negative Subcellular Localization via Incorporating Evolutionary Information and Physicochemical Features Into Chou's General PseAAC. AB - In this study, we used structural and evolutionary based features to represent the sequences of gram-positive and gram-negative subcellular localizations. To do this, we proposed a normalization method to construct a normalize Position Specific Scoring Matrix (PSSM) using the information from original PSSM. To investigate the effectiveness of the proposed method we compute feature vectors from normalize PSSM and by applying support vector machine (SVM) and naive Bayes classifier, respectively, we compared achieved results with the previously reported results. We also computed features from original PSSM and normalized PSSM and compared their results. The archived results show enhancement in gram positive and gram-negative subcellular localizations. Evaluating localization for each feature, our results indicate that employing SVM and concatenating features (amino acid composition feature, Dubchak feature (physicochemical-based features), normalized PSSM based auto-covariance feature and normalized PSSM based bigram feature) have higher accuracy while employing naive Bayes classifier with normalized PSSM based auto-covariance feature proves to have high sensitivity for both benchmarks. Our reported results in terms of overall locative accuracy is 84.8% and overall absolute accuracy is 85.16% for gram positive dataset; and, for gram-negative dataset, overall locative accuracy is 85.4% and overall absolute accuracy is 86.3%. PMID- 26584500 TI - Inferring Disease Associated Phosphorylation Sites via Random Walk on Multi-Layer Heterogeneous Network. AB - As protein phosphorylation plays an important role in numerous cellular processes, many studies have been undertaken to analyze phosphorylation-related activities for drug design and disease treatment. However, although progresses have been made in illustrating the relationship between phosphorylation and diseases, no existing method focuses on disease-associated phosphorylation sites prediction. In this work, we proposed a multi-layer heterogeneous network model that makes use of the kinase information to infer disease-phosphorylation site relationship and implemented random walk on the heterogeneous network. Experimental results reveal that multi-layer heterogeneous network model with kinase layer is superior in inferring disease-phosphorylation site relationship when comparing with existing random walk model and common used classification methods. PMID- 26584501 TI - Organizing Books and Authors by Multilayer SOM. AB - This paper introduces a new framework for the organization of electronic books (e books) and their corresponding authors using a multilayer self-organizing map (MLSOM). An author is modeled by a rich tree-structured representation, and an MLSOM-based system is used as an efficient solution to the organizational problem of structured data. The tree-structured representation formulates author features in a hierarchy of author biography, books, pages, and paragraphs. To efficiently tackle the tree-structured representation, we used an MLSOM algorithm that serves as a clustering technique to handle e-books and their corresponding authors. A book and author recommender system is then implemented using the proposed framework. The effectiveness of our approach was examined in a large-scale data set containing 3868 authors along with the 10500 e-books that they wrote. We also provided visualization results of MLSOM for revealing the relevance patterns hidden from presented author clusters. The experimental results corroborate that the proposed method outperforms other content-based models (e.g., rate adapting poisson, latent Dirichlet allocation, probabilistic latent semantic indexing, and so on) and offers a promising solution to book recommendation, author recommendation, and visualization. PMID- 26584503 TI - Smartphone-Based Real-Time Indoor Location Tracking With 1-m Precision. AB - Monitoring the activities of daily living of the elderly at home is widely recognized as useful for the detection of new or deteriorating health conditions. However, the accuracy of existing indoor location tracking systems remains unsatisfactory. The aim of this study was, therefore, to develop a localization system that can identify a patient's real-time location in a home environment with maximum estimation error of 2 m at a 95% confidence level. A proof-of concept system based on a sensor fusion approach was built with considerations for lower cost, reduced intrusiveness, and higher mobility, deployability, and portability. This involved the development of both a step detector using the accelerometer and compass of an iPhone 5, and a radio-based localization subsystem using a Kalman filter and received signal strength indication to tackle issues that had been identified as limiting accuracy. The results of our experiments were promising with an average estimation error of 0.47 m. We are confident that with the proposed future work, our design can be adapted to a home like environment with a more robust localization solution. PMID- 26584502 TI - Reconstruction-Based Digital Dental Occlusion of the Partially Edentulous Dentition. AB - Partially edentulous dentition presents a challenging problem for the surgical planning of digital dental occlusion in the field of craniomaxillofacial surgery because of the incorrect maxillomandibular distance caused by missing teeth. We propose an innovative approach called Dental Reconstruction with Symmetrical Teeth (DRST) to achieve accurate dental occlusion for the partially edentulous cases. In this DRST approach, the rigid transformation between two symmetrical teeth existing on the left and right dental model is estimated through probabilistic point registration by matching the two shapes. With the estimated transformation, the partially edentulous space can be virtually filled with the teeth in its symmetrical position. Dental alignment is performed by digital dental occlusion reestablishment algorithm with the reconstructed complete dental model. Satisfactory reconstruction and occlusion results are demonstrated with the synthetic and real partially edentulous models. PMID- 26584504 TI - Incorporating Objective Function Information Into the Feasibility Rule for Constrained Evolutionary Optimization. AB - When solving constrained optimization problems by evolutionary algorithms, an important issue is how to balance constraints and objective function. This paper presents a new method to address the above issue. In our method, after generating an offspring for each parent in the population by making use of differential evolution (DE), the well-known feasibility rule is used to compare the offspring and its parent. Since the feasibility rule prefers constraints to objective function, the objective function information has been exploited as follows: if the offspring cannot survive into the next generation and if the objective function value of the offspring is better than that of the parent, then the offspring is stored into a predefined archive. Subsequently, the individuals in the archive are used to replace some individuals in the population according to a replacement mechanism. Moreover, a mutation strategy is proposed to help the population jump out of a local optimum in the infeasible region. Note that, in the replacement mechanism and the mutation strategy, the comparison of individuals is based on objective function. In addition, the information of objective function has also been utilized to generate offspring in DE. By the above processes, this paper achieves an effective balance between constraints and objective function in constrained evolutionary optimization. The performance of our method has been tested on two sets of benchmark test functions, namely, 24 test functions at IEEE CEC2006 and 18 test functions with 10-D and 30-D at IEEE CEC2010. The experimental results have demonstrated that our method shows better or at least competitive performance against other state-of-the-art methods. Furthermore, the advantage of our method increases with the increase of the number of decision variables. PMID- 26584505 TI - Simulating Kinect Infrared and Depth Images. AB - With the emergence of the Microsoft Kinect sensor, many developer communities and research groups have found countless uses and have already published a wide variety of papers that utilize the raw depth images for their specific goals. New methods and applications that use the device generally require an appropriately large ensemble of data sets with accompanying ground truth for testing purposes, as well as accurate models that account for the various systematic and stochastic contributors to Kinect errors. Current error models, however, overlook the intermediate infrared (IR) images that directly contribute to noisy depth estimates. We, therefore, propose a high fidelity Kinect IR and depth image predictor and simulator that models the physics of the transmitter/receiver system, unique IR dot pattern, disparity/depth processing technology, and random intensity speckle and IR noise in the detectors. The model accounts for important characteristics of Kinect's stereo triangulation system, including depth shadowing, IR dot splitting, spreading, and occlusions, correlation-based disparity estimation between windows of measured and reference IR images, and subpixel refinement. Results show that the simulator accurately produces axial depth error from imaged flat surfaces with various tilt angles, as well as the bias and standard lateral error of an object's horizontal and vertical edge. PMID- 26584506 TI - Constraint Co-Projections for Semi-Supervised Co-Clustering. AB - Co-clustering aims to simultaneously cluster the objects and features to explore intercorrelated patterns. However, it is usually difficult to obtain good co clustering results by just analyzing the object-feature correlation data due to the sparsity of the data and the noise. Meanwhile, most co-clustering algorithms cannot take the prior information into consideration and may produce unmeaningful results. Semi-supervised co-clustering aims to incorporate the known prior knowledge into the co-clustering algorithm. In this paper, a new technique named constraint co-projections for semi-supervised co-clustering (CPSSCC) is presented. Constraint co-projections can not only make use of two popular techniques including pairwise constraints and constraint projections, but also simultaneously perform the object constraint projections and feature constraint projections. The two popular techniques are illustrated for semi-supervised co clustering when some objects and features are believed to be in the same cluster a priori. Furthermore, we also prove that the co-clustering problem can be formulated as a typical eigen-problem and can be efficiently solved with the selected eigenvectors. To the best of our knowledge, constraint co-projections is first stated in this paper and this is the first work on using CPSSCC. Extensive experiments on benchmark data sets demonstrate the effectiveness of the proposed method. This paper also shows that CPSSCC has some favorable features compared with previous related co-clustering algorithms. PMID- 26584507 TI - Data-Distribution-Aware Fuzzy Rough Set Model and its Application to Robust Classification. AB - Fuzzy rough sets (FRSs) are considered to be a powerful model for analyzing uncertainty in data. This model encapsulates two types of uncertainty: 1) fuzziness coming from the vagueness in human concept formation and 2) roughness rooted in the granulation coming with human cognition. The rough set theory has been widely applied to feature selection, attribute reduction, and classification. However, it is reported that the classical FRS model is sensitive to noisy information. To address this problem, several robust models have been developed in recent years. Nevertheless, these models do not consider a statistical distribution of data, which is an important type of uncertainty. Data distribution serves as crucial information for designing an optimal classification or regression model. Thus, we propose a data-distribution-aware FRS model that considers distribution information and incorporates it in computing lower and upper fuzzy approximations. The proposed model considers not only the similarity between samples, but also the probability density of classes. In order to demonstrate the effectiveness of the proposed model, we design a new sample evaluation index for prototype-based classification based on the model, and a prototype selection algorithm is developed using this index. Furthermore, a robust classification algorithm is constructed with prototype covering and nearest neighbor classification. Experimental results confirm the robustness and effectiveness of the proposed model. PMID- 26584509 TI - Chemoselective Intramolecular Carbonyl Ylide Formation through Electronically Differentiated Malonate Diesters. AB - A method for chemoselective carbonyl ylide formation utilizing the Rh(II) catalyzed decomposition of electronically differentiated diazo malonates is disclosed. Treatment of ethyl, trifluoro ethyl diazo malonate with a Rh(II) catalyst selectively forms a carbonyl ylide from the relatively electron rich ethyl ester. This carbonyl ylide can be trapped by various alkynes giving highly functionalized oxabicyclic compounds in a chemo-, regio-, and diastereoselective fashion. PMID- 26584508 TI - Unilateral renal ischaemia in rats induces a rapid secretion of inflammatory markers to renal lymph and increased capillary permeability. AB - A better understanding of the inflammatory process associated with renal ischaemia-reperfusion (IR) injury may be clinically important. In this study we examined the role of the kidney in production of inflammatory mediators by analysing renal lymph after 30 min unilateral occlusion of renal artery followed by 120 min reperfusion, as well as the effect of IR on size selectivity for proteins in both glomerular and peritubular capillaries. All measured mediators increased dramatically in renal hilar lymph, plasma and renal cortical tissue samples and returned to control levels after 120 min reperfusion. The responses were differentiated; interleukin-1beta, monocyte chemoattractant protein-1 and leptin were markedly increased in plasma before reperfusion, reflecting an extrarenal response possibly induced by afferent renal nerve activity from the ischaemic kidney. Tumour necrosis factor-alpha was the only mediator showing elevated lymph-to-plasma ratio following 30 min reperfusion, indicating that most cytokines were released directly into the bloodstream. The IR-induced rise in cytokine levels was paralleled by a significant increase in high molecular weight plasma proteins in both lymph and urine. The latter was shown as a 14- to 166 fold increase in glomerular sieving coefficient of plasma proteins assessed by a novel proteomic approach, and indicated a temporarily reduced size selectivity of both glomerular and peritubular capillaries. Collectively, our data suggest that cytokines from the ischaemic kidney explain most of the rise in plasma concentration, and that the locally produced substances enter the systemic circulation through transport directly to plasma and not via the interstitium to lymph. PMID- 26584510 TI - Role of asparagine at position 562 in dimerization and immunogenicity of the hepatitis E virus capsid protein. AB - The hepatitis E virus (HEV) capsid protein, pORF2, contains 2 potential N glycosylation sites, N137 and N310, located in the S domain, and one site, N562, in the P domain. The last domain located at positions 454-606 aa forms a protruding spike from the shell, with N562 being located in the apical center of the spike, which is also a cell-attachment region and neutralizing antigenic site. Here, we expressed in Pichia pastoris a recombinant polypeptide p179 comprising the region of 439-617 aa of the HEV pORF2 as well as a set of 4 mutant proteins containing substitutions of Q, D, P and Y instead of N at position 562. All proteins were shown to be secreted from yeast. Using SDS-PAGE, Western blot analysis and tunicamycin treatment assay, we showed that the wild-type (wt) protein, p179N562, and 2 mutant variants, p179N562Q and p179N562D, formed homodimers but only the wt protein was shown to be glycosylated. As homodimers, all 3 proteins were immunoreactive with a neutralizing monoclonal antibody (5G5); however, they did not immunoreact with 5G5 after denaturation into monomers. Two other mutant variants, p179N562P and p179N562Y, did not form homodimers but were immunoreactive with the 5G5 antibody. The wt protein was shown to be less immunoreactive with 5G5 than the mutant variants in a double-antibody sandwich ELISA, suggesting a role of glycosylation at N562 in reducing antibody binding. In vitro neutralization experiments showed a more efficient neutralization with mouse antibody against p179N562P and p179N562Y than against the other 3 proteins. These findings indicate that specific substitutions at position 562 have a more measurable effect on the activity of the HEV neutralizing epitope than dimerization or glycosylation of the structural protein. Furthermore, the secretion of monomers fully immunoreactive may call into question the importance of dimerization for an effective presentation of HEV neutralization epitopes. PMID- 26584511 TI - Insectivorous bats carry host specific astroviruses and coronaviruses across different regions in Germany. AB - Recently several infectious agents with a zoonotic potential have been detected in different bat species. However, there is still a lack of knowledge on the transmission dynamics within and between bat species, as well as from bats to other mammals. To better understand these processes, it is important to compare the phylogenetic relationships between different agents to that of their respective hosts. In this study, we analysed more than 950 urine, faeces and oral swab samples collected from 653 bats from mainly four species (Myotis nattereri, Myotis bechsteinii, Myotis daubentonii, and Plecotus auritus) for the presence of coronavirus, paramyxovirus and astrovirus related nucleic acids located in three different regions of Germany. Using hemi-nested reverse transcriptase (RT)-PCR amplification of fragments within the highly conserved regions of the respective RNA dependent RNA polymerase (RdRp) genes, we detected astrovirus sequences at an overall detection rate of 25.8% of the analysed animals, with a maximum of 65% in local populations. The detection rates for coronaviruses and paramyxoviruses were distinctly lower, ranging between 1.4% and 3.1%. Interestingly, the sequence similarities in samples collected from the same bat species in different geographical areas were distinctly larger than the sequence similarities between samples from different species sampled at the same location. This indicates that host specificity may be more important than host ecology for the presence of certain viruses in bats. PMID- 26584512 TI - Toxocara malaysiensis infection in domestic cats in Vietnam--An emerging zoonotic issue? AB - Toxocara canis of canids is a parasitic nematode (ascaridoid) that infects humans and other hosts, causing different forms of toxocariasis. This species of Toxocara appears to be the most important cause of human disease, likely followed by Toxocara cati from felids. Although some studies from Malaysia and China have shown that cats can harbor another congener, T. malaysiensis, no information is available about this parasite for other countries. Moreover, the zoonotic potential of this parasite is unknown at this point. In the present study, we conducted the first investigation of domestic dogs and cats for Toxocara in Vietnam using molecular tools. Toxocara malaysiensis was identified as a common ascaridoid of domestic cats (in the absence of T. cati), and T. canis was commonly found in dogs. Together with findings from previous studies, the present results emphasize the need to explore the significance and zoonotic potential of T. malaysiensis in Vietnam and other countries where this parasite is endemic and prevalent in cats. PMID- 26584513 TI - Robust self-cleaning and micromanipulation capabilities of gecko spatulae and their bio-mimics. AB - Geckos have the extraordinary ability to prevent their sticky feet from fouling while running on dusty walls and ceilings. Understanding gecko adhesion and self cleaning mechanisms is essential for elucidating animal behaviours and rationally designing gecko-inspired devices. Here we report a unique self-cleaning mechanism possessed by the nano-pads of gecko spatulae. The difference between the velocity dependent particle-wall adhesion and the velocity-independent spatula-particle dynamic response leads to a robust self-cleaning capability, allowing geckos to efficiently dislodge dirt during their locomotion. Emulating this natural design, we fabricate artificial spatulae and micromanipulators that show similar effects, and that provide a new way to manipulate micro-objects. By simply tuning the pull off velocity, our gecko-inspired micromanipulators, made of synthetic microfibers with graphene-decorated micro-pads, can easily pick up, transport, and drop-off microparticles for precise assembling. This work should open the door to the development of novel self-cleaning adhesives, smart surfaces, microelectromechanical systems, biomedical devices, and more. PMID- 26584515 TI - Population differences in the postcrania of modern South Africans and the implications for ancestry estimation. AB - The cranium is widely recognized as the most important skeletal element to use when evaluating population differences and estimating ancestry. However, the cranium is not always intact or available for analysis, which emphasizes the need for postcranial alternatives. The purpose of this study was to quantify postcraniometric differences among South Africans that can be used to estimate ancestry. Thirty-nine standard measurements from 11 postcranial bones were collected from 360 modern black, white and coloured South Africans; the sex and ancestry distribution were equal. Group differences were explored with analysis of variance (ANOVA) and Tukey's honestly significant difference (HSD) test. Linear and flexible discriminant analysis (LDA and FDA, respectively) were conducted with bone models as well as numerous multivariate subsets to identify the model and method that yielded the highest correct classifications. Leave-one out (LDA) and k-fold (k=10; FDA) cross-validation with equal priors were used for all models. ANOVA and Tukey's HSD results reveal statistically significant differences between at least two of the three groups for the majority of the variables, with varying degrees of group overlap. Bone models, which consisted of all measurements per bone, resulted in low accuracies that ranged from 46% to 63% (LDA) and 41% to 66% (FDA). In contrast, the multivariate subsets, which consisted of different variable combinations from all elements, achieved accuracies as high as 85% (LDA) and 87% (FDA). Thus, when using a multivariate approach, the postcranial skeleton can distinguish among three modern South African groups with high accuracy. PMID- 26584516 TI - Improving Cardiovascular Disease Risk Prediction With Albuminuria and Glomerular Filtration Rate. PMID- 26584518 TI - Familial Sulcus Vergeture: Further Evidence for Congenital Origin of Type 2 Sulcus. AB - A 29-year-old otherwise healthy woman presented with a lifetime history of hoarseness because it had begun to interfere with her career. Examination of both the woman and her 60-year-old father revealed bilateral sulcus vergeture, without inflammation or lesions attributable to phonotrauma. The woman responded well to injection augmentation; the father declined treatment. Combined with existing descriptions of other family groupings, all with sulcus vergeture without signs of inflammation, clinical progression, and little or no apparent behavioral component, this report further suggests that sulcus vergeture (Ford type 2) and sulcus vocalis (Ford type 3) are entirely different entities, despite architectural similarity. PMID- 26584517 TI - Antitumor potential of a synthetic interferon-alpha/PLGF-2 positive charge peptide hybrid molecule in pancreatic cancer cells. AB - Pancreatic cancer is the most aggressive malignant disease, ranking as the fourth leading cause of cancer-related death among men and women in the United States. Interferon alpha (IFNalpha) has been used to treat pancreatic cancer, but its clinical application has been significantly hindered due to the low antitumor activity. We used a "cDNA in-frame fragment library" screening approach to identify short peptides that potentiate the antitumor activity of interferons. A short positively charged peptide derived from the C-terminus of placental growth factor-2 (PLGF-2) was selected to enhance the activity of IFNalpha. For this, we constructed a synthetic interferon hybrid molecule (SIFalpha) by fusing the positively charged PLGF-2 peptide to the C-terminus of the human IFNalpha. Using human pancreatic cell lines (ASPC and CFPAC1) as a model system, we found that SIFalpha exhibited a significantly higher activity than did the wild-type IFNalpha in inhibiting the tumor cell growth. The enhanced activity of the synthetic SIFalpha was associated with the activation of interferon pathway target genes and the increased binding of cell membrane receptor. This study demonstrates the potential of a synthetic SIFalpha as a novel antitumor agent. PMID- 26584520 TI - Accelerated cellular on- and off-target screening of bioactive compounds using microarrays. AB - In situ proteome labeling was carried out with 9 drug-like probes in live mammalian cells, with the corresponding cellular targets captured on microarrays and simultaneously screened using a diverse set of antibodies, revealing potential on- and off-targets. PMID- 26584519 TI - An element through the looking glass: exploring the Au-C, Au-H and Au-O energy landscape. AB - Gold, the archetypal "noble metal", used to be considered of little interest in catalysis. It is now clear that this was a misconception, and a multitude of gold catalysed transformations has been reported. However, one consequence of the long held view of gold as inert metal is that its organometallic chemistry contains many "unknowns", and catalytic cycles devised to explain gold's reactivity draw largely on analogies with other transition metals. How realistic are such mechanistic assumptions? In the last few years a number of key compound classes have been discovered that can provide some answers. This Perspective attempts to summarise these developments, with particular emphasis on recently discovered gold(iii) complexes with bonds to hydrogen, oxygen, alkenes and CO ligands. PMID- 26584521 TI - Art therapy among palliative cancer patients: Aesthetic dimensions and impacts on symptoms. AB - OBJECTIVE: This study aimed to explore whether aesthetic beauty and the pleasure that results from artistic activity can contribute to a reduction in the symptoms experienced by palliative care patients, and to improve the effectiveness of art therapy sessions. METHOD: A self-assessment of six symptoms (pain, anxiety, ill being, tiredness, sadness, and depression) adapted from the Edmonton Symptom Assessment System (ESAS) was completed by patients before and after a one-hour art therapy session. This assessment was completed after the session with a self assessment of aesthetic feeling. A correlation analysis was then performed. RESULTS: From July of 2012 to December of 2013, 28 patients took part in 63 art therapy sessions. On the whole, these sessions reduced the global distress of patients by 47% (p < 0.0001). There was a significant reduction in all the symptoms studied; pain (p = 0.003), anxiety (p < 0.0001), ill-being (p < 0.0001), tiredness (p < 0.0001), sadness (p < 0.0001), and depression (p < 0.0001). A study of the significant correlations (0.35 < rs < 0.52, p < 0.05) indicated that technical satisfaction, aesthetic beauty, and pleasure are all involved to varying degrees in reduction of symptoms. SIGNIFICANCE OF RESULTS: Our findings confirm the benefits of art therapy in reducing distress within the palliative context. We also make suggestions for the future direction and improvement of these sessions. PMID- 26584522 TI - Snow occurrence changes over the central and eastern United States under future warming scenarios. AB - Changes of snow occurrence across the central and eastern United States under future warming for the late 21(st) century are investigated by applying an empirical hyperbolic tangent function to both observed and downscaled high spatial resolution (~12.5 km) daily temperature and precipitation, to compare the historical (1981-2000) and future (2081-2100) snow occurrence. The observed distributions of snow frequency show that snow-rain transition zones are mainly zonally distributed, since they are largely determined by temperature, with slight shifts to the south over the Appalachian Mountains. The snow-rain transition zone is located around 38-46 degrees N for November and March, and 32 42 degrees N for winter months (DJF). These observed patterns are reproduced well for the historical period by an ensemble average of multiple general circulation models (GCMs). The probabilistic projections show that the snow-rain transition zone will shift to the north under the background of global warming at magnitudes of 2-6 degrees C, indicating that large areas will experience a partial, or even a very large, loss of snow occurrence in the future. The northward shifts are about 2 degrees latitude under the representative concentration pathways 4.5 (RCP4.5) scenario and 4 degrees latitude under the RCP8.5 scenario. The percentages of the area losing snow occurrence are also assessed. PMID- 26584523 TI - Ruminative exploration and reconsideration of commitment as risk factors for suboptimal identity development in adolescence and emerging adulthood. AB - Rather than looking at quantitative differences in exploration and commitment as indicators of (un)healthy identity formation, this study focuses on two qualitatively different forms of exploration using cross-sectional data of 4259 Belgian adolescents and emerging adults (aged 14-30 years; 64% female). First, ruminative exploration or brooding and worrying without being able to decide what you want in life, emerged as a risk factor for weak commitments and maladjustment. Its strong relationship with maladjustment was only slightly buffered by healthy forms of exploration. Second, reconsideration of commitment or feeling uncertain about current commitments and start looking for new commitments, showed similar negative relationships with commitment making and identification. Moreover, reconsideration of commitment rendered healthy forms of exploration ineffective (i.e., not predicting strong commitments or identifications with life choices). By focusing on the exact meaning and role of these two risk factors, this study sheds light on the dark side of identity formation and might be relevant for counselors working with youth that struggle with identity formation. PMID- 26584524 TI - Life on hold: Staying in identity diffusion in the late twenties. AB - This study adds to the understanding of the dark side of identity development by investigating what it means to experience long-term identity diffusion during the late twenties. In a study of change and stability in identity status between ages 25 and 29 (N = 124; 63 women), seven participants were assigned to identity diffusion at both ages. Longitudinal analysis of interviews with these participants showed that long-term experiences of identity diffusion may be described through individuals' approach to changing life conditions, the extent to which they engage in meaning making, and how they develop their personal life direction. In questionnaires, participants reported few signs of psychological distress. Even so, qualitative analyses showed a general trend among participants to keep life on hold through decreased activity or increased haphazard activity in relation to changing life conditions, to make little new meaning, and in some cases to dissolve their personal life direction. PMID- 26584525 TI - The estimated incidence of pertussis in people aged 50 years old in the United States, 2006-2010. AB - BACKGROUND: Pertussis is believed to be widely underreported and under recognized, particularly among adults. The aim of this study was to estimate the incidence of private practitioner-attended cough illness that could be attributed to Bordetella pertussis in adults aged >=50 years in the US. METHODS: Multiple linear regressions were employed to estimate the overall incidence of pertussis. Data were extracted from IMS' private practice database of longitudinal, patient level claims and IMS' commercial laboratory database during 4/1/2006-12/31/2010. Patients were >=50 years old and had >=1 ICD-9-CM claim for cough illness relating to pertussis, cough, or acute bronchitis. Pertussis positive laboratory tests, seasonal and secular variables were used for estimating the B. pertussis attributable fraction of cough illness. RESULTS: During the study period, there were 20.7 million cases of cough illness among people aged 50-64 and 27.5 million cases among those >=65; of which the model attributed 2.5 and 1.7 %, respectively, to B. pertussis. The estimated incidences of cough illness attributed to B. pertussis during the study period were on average 202 and 257/100,000 among people aged 50-64 and >=65 years, respectively, and increased over the years in both age groups. Depending on the year, estimated pertussis incidences were 42 to 105 times higher than medically attended ones in the same database. CONCLUSIONS: These findings indicate that the B. pertussis disease incidence in adults aged >=50 years is significantly higher than generally estimated. Additional research regarding pertussis reporting and diagnosis in the adult populations is needed to validate these findings. PMID- 26584527 TI - Endoscopic CO2 laser excision of a ruptured laryngocele: a novel 'blue-dye' technique to assist dissection and avoid recurrent laryngeal nerve injury. PMID- 26584526 TI - Fast evolutionary rates associated with functional loss in class I glucose transporters of Schistosoma mansoni. AB - BACKGROUND: The trematode parasite, Schistosoma mansoni, has evolved to switch from oxidative phosphorylation to glycolysis in the presence of glucose immediately after invading the human host. This metabolic switch is dependent on extracellular glucose concentration. Four glucose transporters are encoded in the genome of S. mansoni, however, only two were shown to facilitate glucose diffusion. RESULTS: By modeling the phase of human host infection, we showed that transporter transcript expression profiles of recently transformed schistosomula have two opposing responses to increased glucose concentrations. Concurring with the transcription profiles, our phylogenetic analyses revealed that S. mansoni glucose transporters belong to two separate clusters, one associated with class I glucose transporters from vertebrates and insects, and the other specific to parasitic Platyhelminthes. To study the evolutionary paths of both groups and their functional implications, we determined evolutionary rates, relative divergence times, genomic organization and performed structural analyses with the protein sequences. We finally used the modelled structures of the S. mansoni glucose transporters to biophysically (i) analyze the dynamics of key residues during glucose binding, (ii) test glucose stability within the active site, and (iii) demonstrate glucose diffusion. The two S. mansoni Platyhelminthes-specific glucose transporters, which seem to be younger than the other two, exhibit slower rates of molecular evolution, are encoded by intron-poor genes, and transport glucose. Interestingly, our molecular dynamic analyses suggest that S. mansoni class I glucose transporters are not able to transport glucose. CONCLUSIONS: The glucose transporter family in S. mansoni exhibit different evolutionary histories. Our results suggested that S. mansoni class I glucose transporters lost their capacity to transport glucose and that this function evolved independently in the Platyhelminthes-specific glucose transporters. Finally, taking into account the differences in the dynamics of glucose transport of the Platyhelminthes-specific transporters of S. mansoni compared to that of humans, we conclude that S. mansoni glucose transporters may be targets for rationally designed drugs against schistosomiasis. PMID- 26584528 TI - Do Weather Phenomena Have Any Influence on the Occurrence of Spontaneous Pneumothorax? AB - INTRODUCTION: The objective of this study was to assess the impact of weather phenomena on the occurrence of spontaneous pneumothorax (SP) in the Plzen region (Czech Republic). METHODS: A retrospective analysis of 450 cases of SP in 394 patients between 1991 and 2013. We observed changes in average daily values of atmospheric pressure, air temperature and daily maximum wind gust for each day of that period and their effect on the development of SP. RESULTS: The risk of developing SP is 1.41 times higher (P=.0017) with air pressure changes of more than+/-6.1hPa. When the absolute value of the air temperature changes by more than+/-0.9 degrees C, the risk of developing SP is 1.55 times higher (P=.0002). When the wind speed difference over the 5 days prior to onset of SP is less than 13m/sec, then the risk of SP is 2.16 times higher (P=.0004). If the pressure difference is greater than+/-6.1hPa and the temperature difference is greater than+/-0.9 degrees C or the wind speed difference during the 5 days prior to onset of SP is less than 10.7m/s, the risk of SP is 2.04 times higher (P<=.0001). CONCLUSION: Changes in atmospheric pressure, air temperature and wind speed are undoubtedly involved in the development of SP, but don't seem to be the only factors causing rupture of blebs or emphysematous bullae. PMID- 26584529 TI - Outbreak of isoniazid-resistant tuberculosis in an immigrant community in Spain. AB - BACKGROUND: Tuberculosis (TB) remains a major public health problem. In 2013, 9 million new cases of active TB were estimated globally and the proportion of reported new cases with multi-drug resistance (MDR) was 3.5%. METHODS: Contact tracing of a case of pulmonary tuberculosis was performed in a Bolivian patient. Diagnostic tests were performed according to national and local protocols. RESULTS: An outbreak of tuberculosis in an immigrant community was detected, with 5 cases originating from one index case. Genotyping and drug susceptibility testing of the sputum samples determined Mycobacterium tuberculosis resistant to isoniazid (KatG-msp unmutated/inhA 5RBS CT). Active case finding revealed a total of 39 contacts with an incidence of latent infection of 71.43%. CONCLUSIONS: The present study confirms the importance of active case finding through contact tracing as well as rapid laboratory diagnosis to achieve improvements in early detection of TB. Early diagnosis of the patient, compliance with appropriate treatment protocols and monitoring of drug resistance are considered essential for the prevention and control of TB. PMID- 26584530 TI - Recombinant vaccinia virus GLV-1h68 is a promising oncolytic vector in the treatment of cholangiocarcinoma. AB - Although early stage cholangiocarcinoma (CC) can be cured by surgical extirpation, the options for treatment of advanced stage CC are very few and suboptimal. Oncolytic virotherapy using replication-competent vaccinia virus (VACV) is a promising new strategy to treat human cancers. The ability of oncolytic VACV GLV-1h68 to infect, replicate in, and lyse three human CC cell lines was assayed in vitro and in subcutaneous flank xenografts in athymic nude mice. In this study, we have demonstrated that GLV-1h68 effectively infects and lyses three CC cell lines (KMC-1, KMBC, and KMCH-1) in vitro. Expression of the viral marker gene ruc-gfp facilitated real-time monitoring of infection and replication. Furthermore in athymic nude mice, a single dose of GLV-1h68 significantly suppressed tumor growth. The treatment was well tolerated in all animals. Recombinant VACV GLV-1h68 has significant oncolytic ability against CC both in vitro and in vivo. GLV-1h68 has the potential to be used clinically as a therapeutic agent against CC. PMID- 26584531 TI - Gene therapy for cancer: regulatory considerations for approval. AB - The rapidly changing field of gene therapy promises a number of innovative treatments for cancer patients. Advances in genetic modification of cancer and immune cells and the use of oncolytic viruses and bacteria have led to numerous clinical trials for cancer therapy, with several progressing to late-stage product development. At the time of this writing, no gene therapy product has been approved by the United States Food and Drug Administration (FDA). Some of the key scientific and regulatory issues include understanding of gene transfer vector biology, safety of vectors in vitro and in animal models, optimum gene transfer, long-term persistence or integration in the host, shedding of a virus and ability to maintain transgene expression in vivo for a desired period of time. Because of the biological complexity of these products, the FDA encourages a flexible, data-driven approach for preclinical safety testing programs. The clinical trial design should be based on the unique features of gene therapy products, and should ensure the safety of enrolled subjects. This article focuses on regulatory considerations for gene therapy product development and also discusses guidance documents that have been published by the FDA. PMID- 26584532 TI - Gene therapy for ovarian cancer using carbonyl reductase 1 DNA with a polyamidoamine dendrimer in mouse models. AB - Ovarian cancer (OC) in which carbonyl reductase 1 (CBR1) is highly expressed has good prognosis. The aims of this study were to determine the optimal conditions for delivering CBR1 DNA to OC cells via a polyamidoamine (PAMAM) dendrimer and to examine the therapeutic effectiveness of using a CBR1/PAMAM dendrimer to treat OC. The ratio for mixture of the PAMAM dendrimer and CBR1 plasmid DNA was defined as the ratio of the number of moles of phosphate groups in plasmid DNA to the number of moles of amino groups in PAMAM, which was expressed as N/P ratio. Mice were intraperitoneally injected with OC cells (HRA) to create peritoneal carcinomatosis. CBR1 DNA/PAMAM dendrimer complexes were administered on alternate days after injection of HRA cells. Cells transfected with CBR1 DNA at N/P ratio of 20:1 for 48 h produced the highest level of CBR1 expression. All the mice in control group died prior to day 25. However, all the mice administered the CBR1 DNA/PAMAM dendrimer survived (P<0.001). Use of a PAMAM dendrimer allowed CBR1 DNA to be delivered to cancer cells. The results suggested that CBR1 DNA/PAMAM dendrimer complexes may represent a potent gene therapy for the treatment of advanced OC. PMID- 26584533 TI - Non-pest prey do not disrupt aphid predation by a web-building spider. AB - A generalist predator's ability to contribute to biological control is influenced by the decisions it makes during foraging. Predators often use flexible foraging tactics, which allows them to pursue specific types of prey at the cost of reducing the likelihood of capturing other types of prey. When a pest insect has low nutritional quality or palatability for a predator, the predator is likely to reject that prey in favour of pursuing alternative, non-pest prey. This is often thought to limit the effectiveness of generalist predators in consuming aphids, which are of low nutritional quality for many generalist predators. Here, we report behavioural assays that test the hypothesis that the generalist predator, Grammonota inornata (Araneae: Linyphiidae), preferentially forages for a non-pest prey with high nutritional quality (springtails), and rejects a pest prey with low nutritional quality (aphids). In no-choice assays, molecular gut-content analysis revealed that spiders continued to feed on the low-quality aphids at high rates, even when high-quality springtails were readily available. When provided a choice between aphids and springtails in two-way choice tests, spiders did not show the expected preference for springtails. Decision-making by spiders during foraging therefore appears to be sub-optimal, possibly because of attraction to the less frequently encountered of two preys as part of a dietary diversification strategy. These results indicate that behavioural preferences alone do not necessarily compromise the pest-suppression capacity of natural enemies: even nutritionally sub-optimal pest prey can potentially be subject to predation and suppression by natural enemies. PMID- 26584534 TI - Rhinocerebral Mucormycosis with Top of Basilar Artery Syndrome. AB - AIM: Our objective is to highlight the varied forms of vascular dissemination of rhinocerebral mucormycosis resulting in ischemic arterial syndromes, especially rare posterior ischemic circulatory strokes, through dissemination of mucormycosis from sphenoid bone to clivus by bony erosion and to the basilar artery, thus causing the top of basilar artery syndrome. MATERIALS AND METHODS: We have reported a case of rhinocerebral mucormycosis in an uncontrolled diabetic patient presented to the neurointensive care unit, department of neurology. FINDINGS: A 56-year-old male diabetic patient with poorly controlled glycemic levels presented with pansinusitis resulting in rhinocerebral mucormycosis with basilar artery erosion through clivus bone erosion from sphenoid sinus. Mucormycosis is caused by fungi. Mucormycosis is commonly reported in immunocompromised patients such as poorly controlled diabetes mellitus, blood dyscrasias, malnutrition, neutropenia, iron overload, organ transplant, and immunosuppressive therapy. Mucormycosis rises with an increase in incidence of diabetes mellitus and HIV infection leading to immunocompromised status of the patient. In our case, there is invasion to the sphenoid bone and to clivus by bony erosion and to the basilar artery, thus causing the top of basilar artery syndrome, which is very unusual. CONCLUSION: Mucormycosis has a very fatal rapid progression with varied forms of cerebral dissemination with high mortality; hence early recognition and aggressive treatment are needed to increase the survival rate. PMID- 26584535 TI - Primary care visits due to injuries among the Aboriginal off-reserve population of British Columbia, Canada, 1991-2010. AB - BACKGROUND: Aboriginal people in British Columbia (BC) have higher injury incidence than the general population. This report describes variability in visits to primary care due to injury, among injury categories, time periods, geographies, and demographic groups. METHODS: We used BC's universal health care insurance plan as a population registry, linked to practitioner payment and vital statistics databases. We identified Aboriginal people by insurance premium group and birth and death record notations. Within that population we identified those residing off-reserve according to postal code. We calculated crude incidence and Standardized Relative Risk (SRR) of primary care visit due to injury, standardized for age, gender and Health Service Delivery Area (HSDA), relative to the total population of BC. RESULTS: During 1991 through 2010, the crude rate of primary care visit due to injury in BC was 3172 per 10,000 person-years. The Aboriginal off-reserve rate was 4291 per 10,000 and SRR was 1.41 (95 % confidence interval: 1.41 to 1.42). Northern and non-metropolitan HSDAs had higher SRRs, within both total BC and Aboriginal off-reserve populations. In every age and gender category, the HSDA-standardized SRR was higher among the Aboriginal off reserve than among the total population. For all injuries combined, and for the categories of trauma, poisoning, and burn, between 1991 and 2010, crude rates and SRRs declined substantially, but proportionally more rapidly among the Aboriginal off-reserve population, so the gap between the Aboriginal off-reserve and total populations is narrowing, particularly among metropolitan residents. CONCLUSIONS: These findings corroborate our previous reports regarding hospitalizations due to injury, suggesting that our observations reflect real disparities and changes in the underlying incidence of injury, and are not merely artefacts related to health care utilization. PMID- 26584536 TI - Interpreting the distinct and shared genetic characteristics between Epstein-Barr virus associated and non-associated gastric carcinoma. AB - Gastric carcinoma is one of the major causes of cancer mortality worldwide. There is a better prognosis for patients with Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) compared with those with EBV negative gastric carcinoma (EBVnGC). It is partly due to the fact that EBV infection recruits lymphocytes infiltrating the tumor. It has been reported that this infection indeed resulted in the changes in immune response genes and thus preventing the development of tumor. It is worthwhile to do a systematic study of EBVaGC and EBVnGC based on genetic characteristics and pathways. In this study, we investigated the information of gene ontology (GO) and KEGG pathway annotations to characterize EBVaGC and EBVnGC-related genes. By applying minimum redundancy maximum relevance (mRMR) algorithm, we provided an optimal set of features for identifying the EBVaGC and EBVnGC. We also employed the shortest path algorithm to probe the novel EBVaGC- and EBVnGC-related genes based on the interaction network of genes that differently expressed in them respectively. We obtained 1039 and 1003 features to identify these two types of gastric carcinoma respectively. Based on the optimal features of classification, we predicted 1881 and 2475 novel genes as additional candidates to support clinical research respectively for these two types of gastric cancers. We compared the differences and similarities of molecular traits between EBVaGC and EBVnGC, which would facilitate the understanding of gastric cancer and its therapy and was thus clinically relevant. PMID- 26584537 TI - Characterization of the complete mitochondrial genome of the storage mite pest Tyrophagus longior (Gervais) (Acari: Acaridae) and comparative mitogenomic analysis of four acarid mites. AB - Mites of the genus Tyrophagus are economically important polyphagous pest commonly living on stored products and also responsible for allergic reactions to humans. Complete mitochondrial genomes (mitogenomes) and the gene features therein are widely used as molecular markers in the study of population genetics, phylogenetics as well as molecular evolution. However, scarcity on the sequence data has greatly impeded the studies in these areas pertaining to the Acari (mites and ticks). Information on the Tyrophagus mitogenomes is quite critical for phylogenetic evaluation and molecular evolution of the mitogenomes within Acariformes. Herein, we reported the complete mitogenome of the allergenic acarid storage mite Tyrophagus longior (Astigmata: Acaridae), an important member of stored food pests, and compared with those of other three acarid mites. The complete mitogenome of T. longior was a circular molecule of 13,271 bp. Unexpectedly, only 19 transfer RNA genes (tRNAs) were present, lacking trnF, trnS1 and trnQ. Furthermore, it also contained 13 protein-coding genes (PCGs) and 2 genes for rRNA (rrnS and rrnL) commonly detected in metazoans. The four mitogenomes displayed similar characteristics with respect to the gene content, nucleotide comparison, and codon usages. Yet, the gene order of T. longior was different from that in other Acari. The J-strands of the four mitogenomes possessed high A+T content (67.4-70.0%), and exhibited positive GC-skews and negative AT-skews. Most inferred tRNAs of T. longior were extremely truncated, lacking either a D- or T-arm, as found in other acarid mites. In T. longior mitogenome the A+T-rich region was just 50 bp in length and can be folded as a stable stem-loop structure, whereas in the region some structures of microsatellite-like (AT)n and palindromic sequences was not present. Besides, reconstructing of the phylogenetic relationship based on concatenated amino acid sequences of 13 PCGs supported that monophyly of the family Acaridae and the order Astigmata, to which the former belongs. Our results were consistent with the traditional classifications. PMID- 26584538 TI - A novel gastrointestinal microbiome modulator from soy pods reduces absorption of dietary fat in mice. AB - OBJECTIVE: Simplification of diets, low in variety but high in energy, contributes to the loss in diversity observed in the obese gastrointestinal (GI) microbiome. A novel GI microbiome modulator (GIMM) as a dietary intervention was developed. METHODS: Mice were fed either an obesogenic diet (ObD) or an ObD containing 15% activated soy pod fiber (ObD-ASPF) for 30 days. The diets were isocaloric and balanced for macronutrient content. ASPF is a novel fiber preparation from whole soy pods that is activated to produce glyceollins. RESULTS: Mice fed ObD-ASPF did not gain body fat. This was associated with decreased absorption of calories (P < 0.05) and increased fecal excretion of triglycerides, which may be attributed to decreased bile acid secretion (P < 0.05). A shift (P < 0.05) in abundances of microbiota in 10 genera was observed. Mice fed ObD-ASPF had elevated plasma concentrations of the anti-inflammatory IL 10 (P < 0.05) and decreased (P < 0.05) plasma concentrations of the neutrophil chemoattractant CXCL1. CONCLUSIONS: A novel dietary intervention derived from soy pods that acts to hinder absorption of dietary fat and glucose in mice was developed. More studies with this GIMM in animal models of diet-induced nonalcoholic fatty liver diseases, type 2 diabetes, and autism are needed. PMID- 26584539 TI - Citral alleviates an accelerated and severe lupus nephritis model by inhibiting the activation signal of NLRP3 inflammasome and enhancing Nrf2 activation. AB - INTRODUCTION: Lupus nephritis (LN) is a major complication of systemic lupus erythematosus. NLRP3 inflammasome activation, reactive oxygen species (ROS) and mononuclear leukocyte infiltration in the kidney have been shown to provoke the acceleration and deterioration of LN, such as accelerated and severe LN (ASLN). Development of a novel therapeutic remedy based on these molecular events to prevent the progression of the disease is clinically warranted. METHODS: Citral (3,7-dimethyl-2,6-octadienal), a major active compound in a Chinese herbal medicine Litsea cubeba, was used to test its renoprotective effects in a lipopolysaccharide (LPS)-induced mouse ASLN model by examining NLRP3 inflammasome activation, ROS and COX-2 production as well as Nrf2 activation. The analysis of mechanisms of action of Citral also involved its effects on IL-1beta secretion and signaling pathways of NLRP3 inflammasome in LPS-primed peritoneal macrophages or J774A macrophages. RESULTS: Attenuated proteinuria, renal function impairment, and renal histopathology, the latter including intrinsic cell proliferation, cellular crescents, neutrophil influx, fibrinoid necrosis in the glomerulus, and peri-glomerular infiltration of mononuclear leukocytes as well as glomerulonephritis activity score were observed in Citral-treated ASLN mice. In addition, Citral inhibited NLRP3 inflammasome activation and levels of ROS, NAD(P)H oxidase subunit p47(phox), or COX-2, and it enhanced the activation of nuclear factor E2-related factor 2 (Nrf2). In LPS-primed macrophages, Citral reduced ATP-induced IL-1beta secretion and caspase-1 activation, but did not affect LPS-induced NLRP3 protein expression. CONCLUSION: Our data show that Citral alleviates the mouse ASLN model by inhibition of the activation signal, but not the priming signal, of NLRP3 inflammasome and enhanced activation of Nrf2 antioxidant signaling. PMID- 26584540 TI - Low resolution solution structure of an enzymatic active AhpC10:AhpF2 ensemble of the Escherichia coli Alkyl hydroperoxide Reductase. AB - The ability of bacteria to combat oxidative stress is imperative for their survival. The Alkyl hydroperoxide Reductase (AhpR) system, composed of the AhpC and AhpF proteins, is one of the dominant antioxidant defense systems required for scavenging hydrogen peroxide and organic peroxide. Therefore, it is necessary to understand the mechanism of the AhpR ensemble formation. In previous studies, we were able to elucidate conformational flexibility of Escherichia coli AhpF during the catalytic cycle and its binding site, the N-terminal domain (NTD), to AhpC. We proposed the novel binding and release mechanism of EcAhpC-AhpF, which is mediated by the well defined redox-state linked conformational changes associated with the C-terminal tail and active site regions of EcAhpC. Here, we have proceeded further to elucidate the solution structure of E. coli AhpC and the stable ensemble formation with EcAhpF using size-exclusion chromatography (SEC), dynamic light scattering (DLS) and small angle X-ray scattering (SAXS) techniques. The EcAhpC-AhpF complex structure with a stoichiometry of AhpC10:AhpF2 reveals that dimeric EcAhpF in its extended conformation enables the NTD disulphide centers to come in close proximity to the redox-active disulphide centers of EcAhpC, and provides an efficient electron transfer. Furthermore, the significance of the C-terminal tail of EcAhpC in ensemble formation is elucidated. SAXS data-based modeling revealed the flexible C-terminal tail of EcAhpC in solution, and its exposed nature, making it possible to contact the NTD of EcAhpF for stable complex formation. PMID- 26584541 TI - Discordant Growth of Monozygotic Twins Starts at the Blastocyst Stage: A Case Study. AB - Discordant growth is a common complication of monochorionic/diamniotic pregnancies; in approximately 50% of cases, the cause is unknown. The case presented here suggests that discordant growth of monozygotic twins could start during preimplantation development. Two inner cell masses (ICMs) within the same blastocyst may originate in uneven splitting of a single "parental" ICM, or the two ICMs may be formed independently de novo. We studied the transcriptomes of two morphologically distinct ICMs within a single blastocyst using high resolution RNA sequencing. The data indicated that the two ICM were at different stages of development; one was in the earliest stages of lineage commitment, while the other had already differentiated into epiblast and primitive endoderm. IGF1-mediated signaling is likely to play a key role in ICM growth and to be the major driver behind these differences. PMID- 26584542 TI - Repair of Ischemic Injury by Pluripotent Stem Cell Based Cell Therapy without Teratoma through Selective Photosensitivity. AB - Stem-toxic small molecules have been developed to induce selective cell death of pluripotent stem cells (PSCs) to lower the risk of teratoma formation. However, despite their high efficacies, chemical-based approaches may carry unexpected toxicities on specific differentiated cell types. Herein, we took advantage of KillerRed (KR) as a suicide gene, to selectively induce phototoxicity using visible light via the production of reactive oxygen species. PSCs in an undifferentiated state that exclusively expressed KR (KR-PSCs) were eliminated by a single exposure to visible light. This highly selective cell death in KR-PSCs was exploited to successfully inhibit teratoma formation. In particular, endothelial cells from KR-mPSCs remained fully functional in vitro and sufficient to repair ischemic injury in vivo regardless of light exposure, suggesting that a genetic approach in which KR is expressed in a tightly controlled manner would be a viable strategy to inhibit teratoma formation for future safe PSC-based therapies. PMID- 26584543 TI - Simultaneous Reprogramming and Gene Correction of Patient Fibroblasts. AB - The derivation of genetically modified induced pluripotent stem (iPS) cells typically involves multiple steps, requiring lengthy cell culture periods, drug selection, and several clonal events. We report the generation of gene-targeted iPS cell lines following a single electroporation of patient-specific fibroblasts using episomal-based reprogramming vectors and the Cas9/CRISPR system. Simultaneous reprogramming and gene targeting was tested and achieved in two independent fibroblast lines with targeting efficiencies of up to 8% of the total iPS cell population. We have successfully targeted the DNMT3B and OCT4 genes with a fluorescent reporter and corrected the disease-causing mutation in both patient fibroblast lines: one derived from an adult with retinitis pigmentosa, the other from an infant with severe combined immunodeficiency. This procedure allows the generation of gene-targeted iPS cell lines with only a single clonal event in as little as 2 weeks and without the need for drug selection, thereby facilitating "seamless" single base-pair changes. PMID- 26584546 TI - Enhancement of the accuracy of determination of transverse relaxation time in solution state NMR spectroscopy by using Uhrig's dynamic decoupling sequences. AB - Recently, a sequence with a set of non-equidistant pi pulses, often referred to as Uhrig's Dynamic Decoupling (UDD) sequence has been proposed which is shown to be more efficient in suppressing the time dependent systematic sources of dephasing originating from a bosonic bath. This work aims to investigate the potential of such non-equidistant sequences for more accurate measurement of the transverse relaxation time (T2) in liquid state NMR. We have shown experimentally that the dynamic decoupling schemes can estimate T2 more accurately than the equidistant pulse sequence by suppressing the dephasing effects of the field noise in the solution state. PMID- 26584544 TI - A Robust Single Primate Neuroepithelial Cell Clonal Expansion System for Neural Tube Development and Disease Studies. AB - Developing a model of primate neural tube (NT) development is important to promote many NT disorder studies in model organisms. Here, we report a robust and stable system to allow for clonal expansion of single monkey neuroepithelial stem cells (NESCs) to develop into miniature NT-like structures. Single NESCs can produce functional neurons in vitro, survive, and extensively regenerate neuron axons in monkey brain. NT formation and NESC maintenance depend on high metabolism activity and Wnt signaling. NESCs are regionally restricted to a telencephalic fate. Moreover, single NESCs can turn into radial glial progenitors (RGPCs). The transition is accurately regulated by Wnt signaling through regulation of Notch signaling and adhesion molecules. Finally, using the "NESC-TO NTs" system, we model the functions of folic acid (FA) on NT closure and demonstrate that FA can regulate multiple mechanisms to prevent NT defects. Our system is ideal for studying NT development and diseases. PMID- 26584548 TI - Exercise and cognition in multiple sclerosis: The importance of acute exercise for developing better interventions. AB - Cognitive dysfunction is highly prevalent, disabling, and poorly-managed in persons with multiple sclerosis (MS). Exercise training represents a promising approach for managing this clinical symptom of the disease. However, results from early randomized controlled trials of exercise on cognition in MS are equivocal, perhaps due to methodological concerns. This underscores the importance of considering the well-established literature in the general population that documents robust, beneficial effects of exercise training on cognition across the lifespan. The development of such successful interventions is based on examinations of fitness, physical activity, and acute exercise effects on cognition. Applying such an evidence-based approach in MS serves as a way of better informing exercise training interventions for improving cognition in this population. To that end, this paper provides a focused, updated review on the evidence describing exercise effects on cognition in MS, and develops a rationale and framework for examining acute exercise on cognitive outcomes in this population. This will provide keen insight for better developing exercise interventions for managing cognitive impairment in MS. PMID- 26584547 TI - Down-regulation of osteopontin mediates a novel mechanism underlying the cytostatic activity of TGF-beta. AB - PURPOSE: Loss of a cytostatic response to TGF-beta has been implicated in multiple hyper-proliferative disorders, including cancer. Although several key genes involved in the cytostatic activity of TGF-beta have in the past been identified, its exact mode of action is yet to be elucidated. A comprehensive understanding of the mechanisms underlying the cytostatic activity of TGF-beta may open up new avenues for the development of therapeutic strategies. METHODS: Quantitative real-time RT-PCR was used to assess osteopontin (OPN) gene expression in human hepatoma-derived Huh-7 and lung adenocarcinoma-derived A549 cells. Reporter assays using an OPN promoter-luciferase construct and its mutated counterparts were performed to assess its transcriptional activity. Binding of Smad4 to the OPN gene promoter was investigated using chromatin immunoprecipitation (CHIP). The putative role of Smad4 in OPN gene expression down-regulation was also assessed using a shRNA-mediated knockdown strategy. The anti-proliferative effect of TGF-beta on different cancer-derived cell lines was determined using the cell proliferation reagent WST-1. RESULTS: We found that the OPN expression levels dose-dependently decreased in TGF-beta-treated Huh-7 and A549 cells. Our reporter assays indicated that this TGF-beta-induced repression occurred at the transcriptional level, and could largely be abrogated by disruption of an element (TIE2) similar to the TGF-beta inhibitory element found in other TGF-beta-repressed genes. Our CHIP assay revealed that the Smad protein complex specifically binds to the OPN gene promoter, and that the TGF-beta mediated inhibition of OPN was lost upon shRNA-mediated knockdown of Smad4. Moreover, we found that the deregulation of OPN gene expression by TGF-beta occurred concomitantly with loss of the TGF-beta anti-proliferative response, whereas a neutralizing anti-OPN antibody partially restored this response. CONCLUSIONS: Our results indicate that the OPN gene is a direct target of Smad mediated TGF-beta signaling, implying that OPN expression inhibition serves as a novel mechanism underlying the cytostatic activity of TGF-beta. PMID- 26584549 TI - Type specific Real time PCR for detection of human herpes virus 6 in schizophrenia and bipolar patients: a case control study. AB - BACKGROUND: Schizophrenia (SC) and bipolar disorder (BD) are among the most devastating diseases worldwide. There are several lines of evidence suggesting that viruses may play significant roles in the etiology of these mental disorders. The aim of this study was the detection of HHV-6A/B in the peripheral blood mononuclear cells (PBMC) of SC and BD patients versus the healthy control (HC) subjects using a new method of type-specific Real time PCR analysis. METHODS: A type-specific Real time PCR was performed for simultaneous detection and typing of HHV-6A/B in the PBMCs of 120 SC and BD patients and 75 HCs. RESULTS: Only one case of HHV-6B out of 120 (0.8 %) SC and BD patients and two cases of HHV-6A (2.7 %) in 75 HCs were detected. CONCLUSIONS: The low levels of HHV-6 detection in PBMCs, severely limited the capacity of this study to investigate the association between the presence of HHV-6 and BD or SC in this population, thus no conclusions can be drawn in this regard. Meanwhile this study introduces a Real time PCR based method for type specific detection of HHV-6A/B in clinical samples. PMID- 26584550 TI - 70,489 primary care encounters: retrospective analysis of morbidity at a primary care centre in Ireland. AB - BACKGROUND: While considerable changes are happening in primary care in Ireland and considerable potential exists in intelligence derived from practice-based data to inform these changes, relatively few large-scale general morbidity surveys have been published. AIMS: To examine the most common reasons why people attend primary care, specifically 'reasons for encounter' (RFEs) among the general practice population and among specific demographic groups (i.e., young children and older adults). METHODS: We retrospectively examined clinical encounters (which had a diagnostic code) over a 4-year time period. Descriptive analyses were conducted on anonymised data. RESULTS: 70,489 RFEs consultations were recorded (mean 13.53 recorded RFEs per person per annum) and consultations involving multiple RFEs were common. RFE categories for which codes were most commonly recorded were: 'general/unspecified' (31.6 %), 'respiratory' (15.4 %) and 'musculoskeletal' (12.6 %). Most commonly recorded codes were: 'medication renewal' (6.8 %), 'cough' (6.6 %), and 'health maintenance/prevention' (5.8 %). There was considerable variation in the number of RFEs recorded per age group. 6239 RFEs (8.9 %) were recorded by children under 6 years and 15,295 RFEs (21.7 %) were recorded by adults aged over 70. RFEs recorded per calendar month increased consistently through the study period and there was a marked seasonal and temporal variation in the number of RFEs recorded. CONCLUSIONS: Practice databases can generate intelligence on morbidity and health service utilisation in the community. Future research to optimise diagnostic coding at a practice level and to promote this activity in a more representative sample of practices is a priority. PMID- 26584551 TI - Occipital cephalocele with neural crest remnants? Radiological and pathological findings in a newborn boy. AB - PURPOSE: A cephalocele is a congenital anomaly involving the herniation of intracranial tissue from a skull defect. The sac containing the central nervous system (CNS) with the ventricle system is called the encephalocystocele. An atretic cephalocele is thought to be an abortive form of cephalocele, and the essential nature is still controversial. CASE REPORT: Here, we report the case of a newborn boy with an occipital cephalocele containing a small cystic component which was composed of ependymal cells and the immature CNS tissue. A newborn boy was admitted to our hospital because of an occipital mass, which was about 2.5 cm in diameter, located at the posterior midline, and covered with alopetic skin without CSF leakage. He had a cleft palate. Magnetic resonance imaging (MRI) clearly showed an occipital cephalocele with a tiny cystic component connecting to the subarachnoid space. MRI also showed mild hydrocephalus, hypoplasia of the corpus callosum and tentorium cerebelli, dropping down of the bilateral occipital lobes and vermicular agenesis. We performed the extirpation of the subscalp module under general anesthesia and histologically examined the resected mass. On immunohistopathological examination, most part of the subscalp module was fibrous tissue with numerous vessels and meningeal origin cells. In a small part of the innermost layer, we found a small island consisting of CNS tissue and a tiny cyst lined with a single layer of ependymal cells. CONCLUSION: Based on radiological and immunohistopathological findings, we speculate that the cystic component at the base of the nodule seems to correspond to neural crest remnants but not to true herniation of the brain and cerebral ventricles. PMID- 26584552 TI - Posterior reversible encephalopathy syndrome (PRES): a rare condition after resection of posterior fossa tumors: two new cases and review of the literature. AB - INTRODUCTION: In 1996, Hinchey and colleagues coined the term "Posterior reversible encephalopathy syndrome" (PRES) to describe a condition seen in patients with acute neurological symptoms and reversible subcortical vasogenic edema predominantly involving parieto-occipital areas demonstrated in brain MRI. The occurrence of this phenomenon after surgical resection of CNS tumors is typically linked to pediatric cases. MATERIAL AND METHODS: Two new cases of PRES after posterior fossa surgery are reported. A thorough review of the literature is carried out with the purpose of updating and summarizing the main features regarding PRES in similar cases. Seven cases of PRES after resection of a posterior fossa tumor have been hitherto reported (4 patients were <20 years old). There is another pediatric case described after a ventriculoperitoneal shunting procedure in a patient with fourth ventricle ependymoma. Two resected tumors were ependymomas, 2 hemangiopericytomas in one patient, 1 pilocyticastrocytoma, 1 vestibular schwannoma, and 1 of the reported cases did not describe the final pathology diagnosis. CASE REPORTS: We present 2 new cases of PRES after surgical resection of a posterior fossa tumor (medulloblastoma in case 1 and ependymoma in case 2) in pediatric patients. Case 1 developed delayed seizures and altered mental status(10 days after surgical resection) after receiving treatment with bromocriptine for cerebellar mutism. Case 2 presented with generalized seizures and altered mental status within the first 48 postoperative hours followed by right hemiparesis. Both patients fully recovered and returned to neurological baseline status. A thorough review of the literature was carried out with the purpose of updating and summarizing the main features regarding PRES in similar cases. CONCLUSIONS: We report 2 new pediatric cases of posterior reversible encephalopathy syndrome (PRES) that developed after surgical resection of a posterior fossa tumor. Appropriate management includes supportive measures, antihypertensive agents, and antiepileptic drugs, if needed. Full recovery is the most likely outcome in line with previous articles. PMID- 26584553 TI - Multiple desmoplastic infantile gliomas--therapeutic challenges. PMID- 26584555 TI - Effect of the concentration of essential oil on orange peel waste biomethanization: Preliminary batch results. AB - The cultivation of orange (Citrus*sinensis) and its transformation is a major industry in many countries in the world, it leads to the production of about 25 30Mt of orange peel waste (OPW) per year. Until now many options have been proposed for the management of OPW but although they are technically feasible, in many cases their economic/environmental sustainability is questionable. This paper analyse at lab scale the possibility of using OPW as a substrate for anaerobic digestion. Specific objectives are testing the possible codigestion with municipal biowaste, verifying the effect on methane production of increasingly high concentration of orange essential oil (EO, that is well known to have antioxidant properties that can slower or either inhibit biomass activity) and obtaining information on the behaviour of d-limonene, the main EO component, during anaerobic digestion. The results indicate that OPW can produce up to about 370LnCH4/kgVS in mesophilic conditions and up to about 300LnCH4/kgVS in thermophilic conditions. The presence of increasingly high concentrations of EO temporary inhibits methanogenesis, but according to the results of batch tests, methane production restarts while d-limonene is partially degraded through a pathway that requires its conversion into p-cymene as the main intermediate. PMID- 26584554 TI - Paediatric clinically isolated syndromes: report of seven cases, differential diagnosis and literature review. AB - PURPOSE: Few paediatric cases of clinically isolated syndrome (CIS) have been described in literature, even though it has been increasingly recognized also in this age group. Our study retrospectively enrolled seven Italian patients (four males and three females) who met the International Paediatric Multiple Sclerosis Study Group (IPMSSG) 2012 criteria for clinically isolated syndrome over the period 2010-2014; their clinical, laboratory and imaging findings were compared with current literature and with those seen in five patients (three males and two females) with acute disseminated encephalomyelitis, who were followed in our department over the same years (mean follow-up time 2.84 +/- 1.8 years). RESULTS: In our CIS sample, male sex was prevalent, 42.8 % of patients had a multifocal presentation, MRI lesions mostly appeared confluent and with poorly defined margins, and CSF oligoclonal bands (OCBs) were identified in 28.6 %. All acute disseminated encephalomyelitis (ADEM) patients had polyfocal presentation and encephalopathy; large MRI subcortical lesions and polyclonal IgG distribution were identified. During the subsequent follow-up assessments, MRI scan revealed new lesions in three CIS patients, while in ADEM children it appeared normal. CONCLUSIONS: Paediatric CIS patients often show peculiar epidemiological, clinical and radiological features, which significantly differ from adult ones. The presence of encephalopathy and of extended MRI lesions leads to a diagnosis of ADEM, instead. In CIS patients the presence of multiple asymptomatic MRI lesions and of OCBs revealed to be the most predictive risk factors for progression to clinically definite multiple sclerosis (CDMS), so a regular long term follow-up is recommended; in ADEM, no suitable risk factors for a relapse could be identified. PMID- 26584556 TI - Effect of migration and transformation of iron on the endogenous reduction of H2S in anaerobic landfill. AB - Hydrogen sulfide (H2S) is a major odor in landfill gas and needs urgent treatment. In this study, the effect of migration and transformation of iron on the endogenous reduction of H2S was investigated in two simulated landfills. The results showed that the H2S emission concentration from the landfill cover of conventional anaerobic landfill (CL) and anaerobic landfill with leachate recirculation (RL) could reach 19.4mgm(-3) and 24.1mgm(-3), respectively. However, the migration and transformation of iron in anaerobic landfill with different operational modes results in different endogenous reduction mechanism for H2S. The proportion of precipitation-reduction mechanism and oxidation reduction mechanism in CL was 73.3% and 26.3%, respectively. But for RL, the function of oxidation was enhanced, and the sulfide content was reduced 23.1% compared with CL. The iron in landfill with leachate recirculation revealed good endogenous reduction effect on H2S control after a period of time landfilling. PMID- 26584557 TI - Bioleaching of spent Zn-Mn or Ni-Cd batteries by Aspergillus species. AB - This research explores the recovery of metals from spent Zn-Mn or Ni-Cd batteries by a bioleaching using six Aspergillus species. Two different nutrients, malt extract and sucrose, were used to produce different types of organic acids. Oxalic acid and citric acid were shown to be the dominant organic acid in malt extract and sucrose media, respectively. In the bioleaching, the metal removal was higher in sucrose media than malt extract. All species, except A. niger KUC5254, showed more than 90% removal of metals from Zn-Mn battery. For Ni-Cd battery, more than 95% of metals was extracted by A. niger KUC5254 and A. tubingensis KUC5037. As a result, A. tubingensis KUC5037 which is a non ochratoxigenic fungus was considered to have the greatest potential for improving the safety and efficiency of the bioleaching. PMID- 26584558 TI - Comparison of start-up strategies and process performance during semi-continuous anaerobic digestion of sugarcane filter cake co-digested with bagasse. AB - The anaerobic digestion of sugarcane filter cake and the option of co-digestion with bagasse were investigated in a semi-continuous feeding regime to assess the main parameters used for large-scale process designing. Moreover, fresh cattle manure was considered as alternative inoculum for the start-up of biogas reactors in cases where digestate from a biogas plant would not be available in remote rural areas. Experiments were carried out in 6 lab-scale semi-continuous stirred tank reactors at mesophilic conditions (38+/-1 degrees C) while the main anaerobic digestion process parameters monitored. Fresh cattle manure demonstrated to be appropriate for the start-up process. However, an acclimation period was required due to the high initial volatile fatty acids concentration (8.5gL(-1)). Regardless the mono-digestion of filter cake presented 50% higher biogas yield (480mLgVS(-1)) than co-digestion with bagasse (320mLgVS(-1)) during steady state conditions. A large-scale co-digestion system would produce 58% more biogas (1008m(3)h(-1)) than mono-digestion of filter cake (634m(3)h(-1)) due to its higher biomass availability for biogas conversion. Considering that the biogas production rate was the technical parameter that displayed the most relevant differences between the analyzed substrate options (0.99 1.45m(3)biogasm(3)d(-1)). The decision of which substrate option should be implemented in practice would be mainly driven by the available construction techniques, since economically efficient tanks could compensate the lower biogas production rate of co-digestion option. PMID- 26584559 TI - Environmental investigation on co-combustion of sewage sludge and coal gangue: SO2, NOx and trace elements emissions. AB - To promote the utilization of waste material as alternative fuel, the mono- and co-combustion characteristics of sewage sludge (SS) and coal gangue (CG) were systematically investigated, with emphasis on environmental influences. The emission of SO2, NOx as well as the trace elements during combustion of SS and CG were studied with regard to the effects of their chemistries, structures and interactions. Results showed that co-combustion can be beneficial for ignition performance. A synergic effect on both desulfurization and denitrification can be expected at ca. 800 degrees C. Further, an enhanced retention of trace elements during co-combustion was also observed, especially for Pb and Zn. On the basis of the results, it can be expected that, with proper operation, co-combustion of SS and CG can be a promising method for the disposal of these two wastes. PMID- 26584560 TI - ZmGOLS2, a target of transcription factor ZmDREB2A, offers similar protection against abiotic stress as ZmDREB2A. AB - GALACTINOL SYNTHASE is the first committed enzyme in the raffinose biosynthetic pathway. We have previously characterized the maize (Zea mays) GALACTINOL SYNTHASE2 gene (ZmGOLS2) as abiotic stress induced. To further investigate the regulation of ZmGOLS2 gene expression, individual luciferase expression vectors,in which the luciferase gene was controlled by different lengths of the ZmGOLS2 promoter, were co-transfected into maize protoplasts with either a ZmDREB2A- or a GFP-expression vector. Over-expression of ZmDREB2A up-regulated both the expression of the luciferase gene controlled by the ZmGOLS2 promoter and the endogenous ZmGOLS2 gene in protoplasts. Only one of the two DRE elements in the ZmGOLS2 promoter was identified as necessary for this up-regulation. Expression vectors of GFP, ZmGOLS2 or ZmDREB2A were stably transformed into Arabidopsis. Expression of ZmDREB2A up-regulated the AtGOLS3 gene but only over expression of ZmGOLS2 resulted in hyper-accumulation of galactinol and raffinose. Regardless, under drought-, heat shock-, high osmotic- or salinity-stress conditions, both the ZmGOLS2- and the ZmDREB2A- expressing plants had greater germination percentages, greater percentages of seedlings becoming autotropic, and/or greater survival percentages during/after stress than the control plants. Under normal growing conditions, transgenic Arabidopsis plants expressing the ZmGOLS2 gene had similar growth to that of untransformed wild type or GFP expressing control plants, whereas ZmDREB2A over-expressing plants exhibited retarded growth relative to either of the controls. These data suggest that over expression of ZmGOLS2, rather than the transcription factor ZmDREB2A, is a more practical target for generation of abiotic-stress tolerant crops. PMID- 26584561 TI - Beta-aminobutyric acid priming of plant defense: the role of ABA and other hormones. AB - Plants are exposed to recurring biotic and abiotic stresses that can, in extreme situations, lead to substantial yield losses. With the changing environment, the stress pressure is likely to increase and sustainable measures to alleviate the effect on our crops are sought. Priming plants for better stress resistance is one of the sustainable possibilities to reach this goal. Here, we report on the effects of beta-aminobutyric acid, a priming agent with an exceptionally wide range of action and describe its way of preparing plants to defend themselves against various attacks, among others through the modulation of their hormonal defense signaling, and highlight the special role of abscisic acid in this process. PMID- 26584562 TI - Shortness of breath and unexpected imaging findings. PMID- 26584563 TI - Validity of STONE scores in younger patients presenting with suspected uncomplicated renal colic. AB - OBJECTIVES: Recent studies have cast doubt on the routine need for emergent computed tomographic (CT) scan in patients with suspected renal colic. A clinical prediction rule, the STONE score, was recently published with the goal of helping clinicians predict obstructive kidney stones in noninfected flank pain patients before CT scan. We sought to examine the validity of this score in younger, noninfected flank pain patients. METHODS: A secondary analysis of a retrospective cohort study was performed to determine the validity of STONE scores for predicting the outcome of obstructive kidney stone in patients age 18 to 50 years presenting with flank pain suggestive of uncomplicated ureterolithiasis. Validity was measured by calculation of the area under the curve of the receiver operating characteristic curve. Sensitivity, specificity, negative predictive value, positive predictive value, and +/-likelihood ratios were calculated for various cutoff values. RESULTS: Of 134 patients who met inclusion criteria, 56.7% were female, average age was 37 years, and 52% had an obstructing kidney stone by CT scan. The receiver operating characteristic curve for the STONE score had an area under the curve of 0.87 (95% confidence interval, 0.80-0.93) and indicated that a cutoff of greater than or equal to 8 would have a sensitivity of 78.6%, specificity of 84.4%, negative predictive value of 78.3%, positive predictive value of 84.6%, and +likelihood ratio of 4.9. CONCLUSIONS: This analysis suggests that the STONE score is valid in younger populations. It can aid in determining pretest probability and help inform conversations about the likelihood of the diagnosis of renal colic before imaging, which may be useful for decision making. PMID- 26584564 TI - Rhabdomyolysis as presenting feature of acute HIV-1 seroconversion in a pediatric patient. AB - Acute rhabdomyolysis is a rare phenomenon in the emergency setting almost exclusively associated with trauma, drugs, and recent upper respiratory and gastrointestinal infection. Rare reports in the literature have highlighted adult patients presenting with rhabdomyolysis as 1 component in a constellation of symptoms in acute HIV-1 seroconversion; however, there are few reports of rhabdomyolysis as the sole presenting symptom. This case highlights the importance of investigating HIV and other sexually transmitted diseases in pediatric cases of rhabdomyolysis in the emergency care setting. PMID- 26584565 TI - In reply to: Enalapril and the VEGFA gene: personalized medicine in hypertension therapy. PMID- 26584566 TI - Free androgen index and Irisin in polycystic ovary syndrome. AB - PURPOSE: PCOS is associated with hyperandrogenism and insulin resistance (IR). Recent studies have shown that circulating Irisin levels increase in PCOS women. However, no report has demonstrated a relationship between Irisin and hyperandrogenism in PCOS women. The purpose of the study was to compare interrelationship between Irisin or androgen excess with IR in PCOS and normal subjects. METHODS: 166 PCOS and 103 control women were prospectively studied. Euglycemic- hyperinsulinemic clamps were preformed to assess their insulin sensitivity, which was expressed as M value. Circulating Irisin was determined by ELISA kit. Circulating androgens were measured using ultrasensitive assays. RESULTS: PCOS women with high FAI had significantly higher BMI, FAT%, TC, DHEA-S and HOMA-IR, and significantly lower levels of M values and SHBG than PCOS women with low FAI or the controls. Pearson correlations showed that in the entire population, FAI correlated positively with BMI, WHR, FAT%, blood pressure, TG, DHEA-S, LH/FSH, AUCinsulin, HOMA-IR and Irisin, and negatively with M values. In multiple stepwise regression analysis, only FAT%, DHEA-S and LH/FSH were independent related factors with FAI. CONCLUSION: The elevated Irisin levels in PCOS women were associated with androgen excess. Circulating Irisin is a primary predictor of hyperandrogenism, MetS and IR in PCOS women. PMID- 26584567 TI - Isolation and Characterization of a Murine Spontaneous High-Grade Follicular Lymphoma with Restricted In Vivo Spreading--a Model for Lymphatic Metastasis Via the Mesentery. AB - Spontaneous or induced malignant lymphomas in mice are valuable tools for studying human lymphoproliferative diseases, including the mechanism of migration between peripheral lymphoid organs and positioning within distinct tissue compartments. Here we report the isolation and characterization of a novel spontaneous lymphoma from BALB/c mice showing restricted tissue distribution and metastasis. The lymphoma cells display CD19, B220, MHC II, surface IgG2a/kappa chain with VH7183 rearrangement of the IgH gene, indicating their B-cell origin. Serial intraperitoneal injection of primary tumor into both BALB/c and RAG-1 deficient hosts led to the successful propagation of lymphoma. Despite the cytological characteristics of high-grade follicular B-cell lymphoma, the tumor cells (denoted as Bc-DLFL.1) showed significantly lesser spreading to extraabdominal locations upon intraperitoneal passage compared to splenic and mesenteric lymph node expansion. In mesenteric lymph nodes the high endothelial venules contained only few tumor cells, while the lymphatic vessels were almost completely filled with lymphoma cells. Similarly, the LYVE-1-positive lymphatic capillaries within the mesentery were packed with lymphoma cells. These findings suggest that Bc-DLFL.1 cells likely propagate primarily via the lymphatic circulation within the mesentery, therefore this tumor may offer an in vivo model to investigate the tumor cell migration via the lymphatic circulation from the peritoneal cavity. PMID- 26584569 TI - Bovine Medicine, 3rd Edition. PMID- 26584568 TI - The Level of ALR is Regulated by the Quantity of Mitochondrial DNA. AB - Augmenter of liver regeneration (ALR) contributes to mitochondrial biogenesis, maintenance and to the physiological operation of mitochondria. The depletion of ALR has been widely studied and had serious consequences on the mitochondrial functions. However the inverse direction, the effect of the depletion of mitochondrial electron transfer chain and mtDNA on ALR expression has not been investigated yet. Thus mtDNA depleted, rho(0) cell line was prepared to investigate the role of mitochondrial electron transfer chain and mtDNA on ALR expression. The depletion of mtDNA has not caused any difference at mRNA level, but at protein level the expression of ALR has been markedly increased. The regulatory role of ATP and ROS levels could be ruled out because the treatment of the parental cell line with different respiratory inhibitors and uncoupling agent could not provoke any changes in the protein level of ALR. The effect of mtDNA depletion on the protein level of ALR has been proved not to be liver specific, since the phenomenon could be observed in the case of two other, non-hepatic cell lines. It seems the level of mtDNA and/or its products may have regulatory role on the protein level of ALR. The up-regulation of ALR can be a part of the adaptive response in rho(0) cells that preserves the structural integrity and the transmembrane potential despite the absence of protein components encoded by the mtDNA. PMID- 26584570 TI - Osteoarthritis-like pathologic changes in the knee joint induced by environmental disruption of circadian rhythms is potentiated by a high-fat diet. AB - A variety of environmental factors contribute to progressive development of osteoarthritis (OA). Environmental factors that upset circadian rhythms have been linked to various diseases. Our recent work establishes chronic environmental circadian disruption - analogous to rotating shiftwork-associated disruption of circadian rhythms in humans - as a novel risk factor for the development of OA. Evidence suggests shift workers are prone to obesity and also show altered eating habits (i.e., increased preference for high-fat containing food). In the present study, we investigated the impact of chronic circadian rhythm disruption in combination with a high-fat diet (HFD) on progression of OA in a mouse model. Our study demonstrates that when mice with chronically circadian rhythms were fed a HFD, there was a significant proteoglycan (PG) loss and fibrillation in knee joint as well as increased activation of the expression of the catabolic mediators involved in cartilage homeostasis. Our results, for the first time, provide the evidence that environmental disruption of circadian rhythms plus HFD potentiate OA-like pathological changes in the mouse joints. Thus, our findings may open new perspectives on the interactions of chronic circadian rhythms disruption with diet in the development of OA and may have potential clinical implications. PMID- 26584572 TI - Increasing incidence of non-O157 Shiga toxin-producing Escherichia coli (STEC) in Michigan and association with clinical illness. AB - Infection with Shiga toxin-producing Escherichia coli (STEC) by serotypes other than O157 (non-O157) have been increasingly reported in the United States. This increase in reporting is primarily due to the improvements in diagnostic tests. We analysed 1497 STEC cases reported in Michigan from 2001 to 2012. A significant increase in the number of non-O157 STEC cases was observed over time, and similar incidence rates were observed for O157 and non-O157 STEC cases in certain time periods. The odds of hospitalization was two times higher in O157 STEC cases relative to non-O157 STEC cases when adjusted for age and gender, suggesting that O157 STEC causes more severe clinical outcomes in all age groups. The use of population-based surveillance to better define trends and associations with disease severity are critical to enhance our understanding of STEC infections and improve upon current prevention and control efforts. PMID- 26584571 TI - Psychotropic treatments in Prader-Willi syndrome: a critical review of published literature. AB - Prader-Willi syndrome (PWS) is a rare genetic syndrome. The phenotype includes moderate to intellectual disability, dysmorphia, obesity, and behavioral disturbances (e.g., hetero and self-injurious behaviors, hyperphagia, psychosis). Psychotropic medications are widely prescribed in PWS for symptomatic control. We conducted a systematic review of published literature to examine psychotropic medications used in PWS. MEDLINE was searched to identify articles published between January 1967 and December 2014 using key words related to pharmacological treatments and PWS. Articles with original data were included based on a standardized four-step selection process. The identification of studies led to 241 records. All selected articles were evaluated for case descriptions (PWS and behavioral signs) and treatment (type, titration, efficiency, and side effects). Overall, 102 patients were included in these studies. Treatment involved risperidone (three reports, n = 11 patients), fluoxetine (five/n = 6), naltrexone (two/n = 2), topiramate (two/n = 16), fluvoxamine (one/n = 1), mazindol (one/n = 2), N-acetyl cysteine (one/n = 35), rimonabant (one/n = 15), and fenfluramine (one/n = 15). CONCLUSION: We identified promising treatment effects with topiramate for self-injury and impulsive/aggressive behaviors, risperidone for psychotic symptoms associated with uniparental disomy (UPD), and N-acetyl cysteine for skin picking. The pharmacological approach of behavioral impairment in PWS has been poorly investigated to date. Further randomized controlled studies are warranted. WHAT IS KNOWN: Behavioral disturbances in Prader-Willi syndrome including aggressive reactions, skin picking, and hyperphagia might be very difficult to manage. Antipsychotic drugs are widely prescribed, but weight gain and increased appetite are their major side effects. WHAT IS NEW: Topiramate might be efficient for self-injury and impulsive/aggressive behaviors, N-acetyl cysteine is apromising treatment for skin picking and Antidepressants are indicated for OCD symptoms. Risperidone is indicated in case of psychotic symptoms mainly associated with uniparental disomy. PMID- 26584573 TI - Prospective Intervention of a Novel Levothyroxine Dosing Protocol Based on Body Mass Index after Thyroidectomy. AB - BACKGROUND: Weight-based postoperative levothyroxine (LT4) dosing often fails to appropriately dose overweight and underweight patients. Previously, we created an LT4-dosing algorithm based on BMI. We hypothesize that more patients will achieve euthyroidism at their postoperative visit with the use of the protocol. STUDY DESIGN: A prospective evaluation was performed of our previously published BMI based LT4 dosing. All adults who underwent thyroidectomy for benign disease between January 1, 2011 and December 31, 2013 were included; the new protocol was implemented in October 2012. Serum TSH was measured for all patients 6 to 8 weeks postoperatively, and adjustments were based on TSH. RESULTS: Three hundred and thirty patients were included, with 54% undergoing thyroidectomy after institution of the protocol. The groups were well matched. Before protocol implementation, LT4 was dosed solely by weight and 25% of patients were euthyroid at initial follow-up. After the protocol, 39% of patients were euthyroid (p = 0.01). The percentage of patients who were given too high a dose of LT4 remained the same (46% vs 42%), and there was a significant reduction in the number of patients who were given too little (29% vs 19%; p = 0.05). The effect was most profound in patients with low and normal BMI, and there were slight differences between sexes. CONCLUSIONS: Although correct initial dosing of LT4 remains challenging, this dosing protocol that we developed and implemented has improved patient care by increasing the number of patients who achieve euthyroidism at the first postoperative visit. We have made a change to our original protocol to incorporate sex differences into the calculation. PMID- 26584574 TI - Can knowledge-based DVH predictions be used for automated, individualized quality assurance of radiotherapy treatment plans? AB - BACKGROUND: Treatment plan quality assurance (QA) is important for clinical studies and for institutions aiming to generate near-optimal individualized treatment plans. However, determining how good a given plan is for that particular patient (individualized patient/plan QA, in contrast to running through a checklist of generic QA parameters applied to all patients) is difficult, time consuming and operator-dependent. We therefore evaluated the potential of RapidPlan, a commercial knowledge-based planning solution, to automate this process, by predicting achievable OAR doses for individual patients based on a model library consisting of historical plans with a range of organ-at risk (OAR) to planning target volume (PTV) geometries and dosimetries. METHODS: A 90-plan RapidPlan model, generated using previously created automatic interactively optimized (AIO) plans, was used to predict achievable OAR dose volume histograms (DVHs) for the parotid glands, submandibular glands, individual swallowing muscles and oral cavities of 20 head and neck cancer (HNC) patients using a volumetric modulated (RapidArc) simultaneous integrated boost technique. Predicted mean OAR doses were compared with mean doses achieved when RapidPlan was used to make a new plan. Differences between the achieved and predicted DVH lines were analyzed. Finally, RapidPlan predictions were used to evaluate achieved OAR sparing of AIO and manual interactively optimized plans. RESULTS: For all OARs, strong linear correlations (R(2) = 0.94-0.99) were found between predicted and achieved mean doses. RapidPlan generally overestimated the amount of achievable sparing for OARs with a large degree of OAR-PTV overlap. RapidPlan QA using predicted doses alone identified that for 50 % (10/20) of the manually optimized plans, sparing of the composite salivary glands, oral cavity or composite swallowing muscles could be improved by at least 3 Gy, 5 Gy or 7 Gy, respectively, while this was the case for 20 % (4/20) AIO plans. These predicted gains were validated by replanning the identified patients using RapidPlan. CONCLUSIONS: Strong correlations between predicted and achieved mean doses indicate that RapidPlan could accurately predict achievable mean doses. This shows the feasibility of using RapidPlan DVH prediction alone for automated individualized head and neck plan QA. This has applications in individual centers and clinical trials. PMID- 26584576 TI - Health workforce governance and oral health: Diversity and challenges in Europe. AB - Throughout the life course, oral diseases are some of the most common non communicable diseases globally, and in Europe. Human resources for oral health are fundamental to healthcare systems in general and dentistry is no exception. As political and healthcare systems change, so do forms of governance. The aim of this paper is to examine human resources for oral health in Europe, against a workforce governance framework, using England as a case study. The findings suggest that neo-liberalist philosophies are leading to multiple forms of soft governance at professional, system, organisational and individual levels, most notably in England, where there is no longer professional self-regulation. Benefits include professional regulation of a wider cadre of human resources for oral health, reorientation of care towards evidence-informed practice including prevention, and consideration of care pathways for patients. Across Europe there has been significant professional collaboration in relation to quality standards in the education of dentists, following transnational policies permitting freedom of movement of health professionals; however, the distribution of dentists is inequitable. Challenges include facilitating employment of graduates to serve the needs and demands of the population in certain countries, together with governance of workforce production and migration across Europe. Integrated trans European approaches to monitoring mobility and governance are urgently required. PMID- 26584575 TI - The objectivity of the Autism Diagnostic Observation Schedule (ADOS) in naturalistic clinical settings. AB - The Autism Diagnostic Observation Schedule (ADOS) is a first-choice diagnostic tool in autism spectrum disorder (ASD). Excellent interpersonal objectivity (interrater reliability) has been demonstrated for the ADOS under optimal conditions, i.e., within groups of highly trained "research reliable" examiners in research setting. We investigated the spontaneous interrater reliability among clinically trained ADOS users across multiple sites in clinical routine. Forty videotaped administrations of the ADOS modules 1-4 were rated by five different raters each from a pool of in total 15 raters affiliated to 13 different clinical sites. G(q,k) coefficients (analogous to intraclass correlations), kappas (K) and percent agreement (PA) were calculated. The median interrater reliability for items across the four modules was G(q,k) = .74-.83, with the single ADOS items ranging from .23 to .94. G(q,k) for total scores was .85-.92. For diagnostic classification (ASD/non-spectrum), PA was 64-82 % and Fleiss' K .19-.55. Objectivity was lower for pervasive developmental disorder not otherwise specified and non-spectrum diagnoses as compared to autism. Interrater reliabilities of the ADOS items and domain totals among clinical users across multiple sites were in the same range as previously reported for research reliable users, while the one for diagnostic classification was lower. Differences in sample characteristics, rater skills and statistics compared with previous studies are discussed. Findings endorse the objectivity of the ADOS in naturalistic clinical settings, but also pinpoint its limitations and the need and value of adequate and continuous rater training. PMID- 26584578 TI - Age-related decline and diagnostic performance of more and less prevalent clinical cases. AB - Since cognitive abilities have been shown to decrease with age, it is expected that older physicians would not perform as well as their younger counterparts on clinical cases unless their expertise can counteract the cognitive effects of aging. However, studies on the topic have shown contradictory results. This study aimed to further investigate the effect of aging on physicians' diagnostic accuracy when diagnosing prevalent and less prevalent cases based on clinical vignettes. A mixed design was used to assess the influence of case prevalence (high vs. low) as a within-subjects factor, and age group as a between subjects factor (<30; n = 23, 30-39; n = 19, 40-49; n = 27, >50 years old; n = 19) on the diagnostic accuracy of 65 family physicians and 25 residents. Repeated Measure ANOVA revealed a significant effect of case prevalence (p < .001) and age group (p < .001). Post-hoc analyses revealed that younger physicians showed the best performance. This study did not demonstrate the positive effect of experience in older physicians. In line with previous studies on expertise development, findings of the present study suggest that skills should be actively maintained to assure a high performance level throughout one's lifespan. If not, performance level could gradually decline with age. PMID- 26584577 TI - Regulation of Blood Pressure, Appetite, and Glucose by CNS Melanocortin System in Hyperandrogenemic Female SHR. AB - BACKGROUND: Hyperandrogenemia in females may be associated with sympathetic nervous system (SNS) activation and increased blood pressure (BP). However the importance of hyperandrogenemia in causing hypertension in females and the mechanisms involved are still unclear. We tested whether chronic hyperandrogenemia exacerbates hypertension in young female spontaneously hypertensive rats (SHR) and whether endogenous melanocortin-3/4 receptor (MC3/4R) activation contributes to the elevated BP. METHODS: Cardiovascular and metabolic effects of chronic MC3/4R antagonism were assessed in female SHR treated with dihydrotestosterone (DHT, beginning at 5 weeks of age) and placebo-treated female SHR. BP and heart rate (HR) were measured by telemetry and an intracerebroventricular (ICV) cannula was placed in the lateral ventricle for infusions. After control measurements, the MC3/4R antagonist (SHU-9119) was infused for 10 days (1 nmol/hour, ICV, at 15 weeks of age) followed by a 5-day recovery period. RESULTS: MC3/4R antagonism increased food intake and body weight in DHT-treated SHR (14+/-1 to 35+/-1g/day and 244+/-3 to 298+/-8g) and controls (14+/-1 to 34+/-2g/day and 207+/-4 to 269+/-8g). Compared to untreated SHR, DHT treated SHR had similar BP but lower HR (146+/-3 vs. 142+/-4mm Hg and 316+/-2 vs. 363+/-4 bpm). Chronic SHU-9119 infusion reduced BP and HR in DHT-treated SHR ( 12+/-2mm Hg and -14+/-4 bpm) and control female SHR (-19+/-2mm Hg and -21+/-6 bpm). CONCLUSION: These results indicate that hyperandrogenemia does not exacerbate hypertension in female SHR. MC3/4R antagonism reduces BP and HR despite marked increases in food intake and body weight in hyperandrogenemic and control female SHR. PMID- 26584580 TI - The health information technology safety framework: building great structures on vast voids. PMID- 26584579 TI - Incidence and clinical features of post-injection endophthalmitis according to diagnosis. AB - PURPOSE: To compare the incidence and clinical features of endophthalmitis after intravitreal antivascular endothelial growth factor (VEGF) therapy for diabetic eye disease, neovascular age-related macular degeneration (AMD) and retinal vein occlusion (RVO). METHODS: Multicentre, retrospective, consecutive case-control study. All patients treated with intravitreal bevacizumab, ranibizumab or aflibercept for diabetic eye disease, neovascular AMD or RVO between 1 January 2009 and 30 September 2013 at three retina practices were included in this study. The total number of anti-VEGF injections administered for the three indications was calculated using billing records. Endophthalmitis cases were identified using both endophthalmitis log sheets and billing records. Patient charts were reviewed to confirm that endophthalmitis was directly related to anti-VEGF injection and to record clinical features and culture results. RESULTS: During the study period, a total of 353 978 intravitreal anti-VEGF injections were performed. Presumed infectious endophthalmitis occurred in 119 of 296 017 injections performed for neovascular AMD (1/2487, 0.040%), 12 of 24 541 for diabetic eye disease (1/2045, 0.049%) and 4 of 32 418 for RVO (1/8104, 0.012%). chi(2) analysis found endophthalmitis rates to be higher in diabetic eye disease compared with RVO (p=0.010) and higher in neovascular AMD compared with RVO (p=0.014), while diabetic eye disease and neovascular AMD (p=0.517) had similar rates. The average age of the overall neovascular AMD patient population (81.9 years) was significantly older than the diabetic eye disease (64.7 years, p<0.001) and RVO (73.4 years, p<0.001) populations. CONCLUSIONS: Endophthalmitis rates appear to be lower in eyes with RVO compared with diabetic eye disease and neovascular AMD, possibly due to impaired immunity in diabetics and waning immunity in the generally older AMD population. PMID- 26584582 TI - US crackdown on cash for referrals brings more arrests. PMID- 26584581 TI - Factors Affecting the Results of Superficial Femoral Artery Stenting. AB - INTRODUCTION: The aim of this study was to assess the durability of superficial femoral artery (SFA) stents and factors that affect stent patency. METHODS: A retrospective assessment of 214 SFA stent procedures between 2003 and 2012 was conducted from a prospectively compiled database. Patency rates and patient outcomes were compiled from case notes and computerized records. Stent patency was confirmed by either duplex scan or clinical examination (palpable distal pulse). Survival and patency were compared across a range of factors using Kaplan Meier plots and log-rank tests. Factors found to be significant were further assessed by Cox regression models. RESULTS: Data were analyzed for 214 limbs in 205 patients. Inclusion criteria included those patients who received an SFA stent for treatment of claudication or critical limb ischemia (CLI) with follow up data. This gave a study group of 151 limbs divided into 76 claudicant and 75 patients with CLI (male-female ratio = 103:48, mean age 71 years, standard deviation 11.7). Seventy-one percent of procedures were elective and 29% were emergency procedures; 53% of procedures were carried out on a day case basis. Median follow-up was 11 months (range 1 day-89 months). Patency was significantly worse for patients with CLI (P = .009), with a 1- and 3-year patency of 63% and 34% compared to 79% and 60% in patients with claudication. Significant factors associated with patency included oral therapy controlled diabetes (P = .003), lesions located in either the mid-SFA (P = .029) or the mid-popliteal (P = .013), and periprocedural complications (P = .005). There was no significant difference in patency rates between insulin-dependent and nondiabetic patients (hazard ratio: 1.0, 95% confidence interval: 0.4-5.6, P = .983). The overall amputation rate for the total study group was 5%. Patients with 1- and 3-year survival were 98% and 96% in the claudication group and 74% and 51%, respectively, in the CLI group. CONCLUSION: SFA stents have superior outcomes in claudicants. Patency is related to severity of disease, diabetes, and location of disease. PMID- 26584583 TI - Assembling A Multi-Feature EEG Classifier for Left-Right Motor Imagery Data Using Wavelet-Based Fuzzy Approximate Entropy for Improved Accuracy. AB - An EEG classifier is proposed for application in the analysis of motor imagery (MI) EEG data from a brain-computer interface (BCI) competition in this study. Applying subject-action-related brainwave data acquired from the sensorimotor cortices, the system primarily consists of artifact and background removal, feature extraction, feature selection and classification. In addition to background noise, the electrooculographic (EOG) artifacts are also automatically removed to further improve the analysis of EEG signals. Several potential features, including amplitude modulation, spectral power and asymmetry ratio, adaptive autoregressive model, and wavelet fuzzy approximate entropy (wfApEn) that can measure and quantify the complexity or irregularity of EEG signals, are then extracted for subsequent classification. Finally, the significant sub features are selected from feature combination by quantum-behaved particle swarm optimization and then classified by support vector machine (SVM). Compared with feature extraction without wfApEn on MI data from two data sets for nine subjects, the results indicate that the proposed system including wfApEn obtains better performance in average classification accuracy of 88.2% and average number of commands per minute of 12.1, which is promising in the BCI work applications. PMID- 26584584 TI - Combining EEG Microstates with fMRI Structural Features for Modeling Brain Activity. AB - Combining information from Electroencephalography (EEG) and Functional Magnetic Resonance Imaging (fMRI) has been a topic of increased interest recently. The main advantage of the EEG is its high temporal resolution, in the scale of milliseconds, while the main advantage of fMRI is the detection of functional activity with good spatial resolution. The advantages of each modality seem to complement each other, providing better insight in the neuronal activity of the brain. The main goal of combining information from both modalities is to increase the spatial and the temporal localization of the underlying neuronal activity captured by each modality. This paper presents a novel technique based on the combination of these two modalities (EEG, fMRI) that allow a better representation and understanding of brain activities in time. EEG is modeled as a sequence of topographies, based on the notion of microstates. Hidden Markov Models (HMMs) were used to model the temporal evolution of the topography of the average Event Related Potential (ERP). For each model the Fisher score of the sequence is calculated by taking the gradient of the trained model parameters. The Fisher score describes how this sequence deviates from the learned HMM. Canonical Partial Least Squares (CPLS) were used to decompose the two datasets and fuse the EEG and fMRI features. In order to test the effectiveness of this method, the results of this methodology were compared with the results of CPLS using the average ERP signal of a single channel. The presented methodology was able to derive components that co-vary between EEG and fMRI and present significant differences between the two tasks. PMID- 26584586 TI - Importance of Oceanian small mountainous rivers (SMRs) in global land-to-ocean output of lignin and modern biospheric carbon. AB - The land-to-ocean export of particulate organic carbon (POC) connects carbon flow from the atmosphere through land to the ocean, of which the contemporary fraction that reaches the deep sea for burial may effectively affect atmospheric CO2. In this regard, small mountainous rivers (SMRs) in Oceania, a global erosion hotspot driven by torrential typhoon rain and active earthquakes are potentially important. Here we measured typhoon lignin discharges for Taiwan SMRs. We found that the particulate lignin export in 96 hours by a single SMR amounting to ~20% of the annual export by Mississippi River. The yearly particulate lignin discharge from Taiwan Island (35,980 km(2)) is governed by the frequency and magnitude of typhoon; thus, the historical lignin export ranged widely from 1.5 to 99.7 Gg yr(-1), which resulted in a 10-100 times higher areal yield relative to non-Oceanian rivers. The lignin-derived modern POC output from Oceania region is 37 +/- 21 Tg C yr(-1), account for approximately 20% of the annual modern POC export from global rivers. Coupled with the hyperpycnal pathway, the forested watersheds of SMRs in Oceania may serve as a giant factory to rapidly produce and efficiently convey modern POC into deep sea for sequestration. PMID- 26584587 TI - Protective features of peripheral monocytes/macrophages in stroke. AB - Hematogenous recruitment of monocytes and macrophages has traditionally been viewed as a harmful process causing exacerbation of brain injury after stroke. However, emerging findings suggest equally important protective features. Inflammatory monocytes are rapidly recruited to ischemic brain via a CCR2 dependent pathway and undergo secondary differentiation in the target tissue towards non-inflammatory macrophages, mediating neuroprotection and repair of the ischemic neurovascular unit. In contrast, independent recruitment of non inflammatory monocytes via CX3CR1 does not occur. Thus, protective features of hematogenous macrophages mainly depend on initial CCR2-dependent cell recruitment. Under therapeutic considerations, specific modulation of monocyte derived macrophages will therefore be more appropriate than non-selectively blocking their hematogenous recruitment. This article is part of a Special Issue entitled: Neuro Inflammation edited by Helga E. de Vries and Markus Schwaninger. PMID- 26584589 TI - Challenges of clinical trial design for DMD. PMID- 26584588 TI - The human decapping scavenger enzyme DcpS modulates microRNA turnover. AB - The decapping scavenger enzyme DcpS is known for its role in hydrolyzing the cap structure following mRNA degradation. Recently, we discovered a new function in miRNA degradation activation for the ortholog of DcpS in C. elegans. Here we show that human DcpS conserves its role in miRNA turnover. In human cells, DcpS is a nucleocytoplasmic shuttling protein that activates miRNA degradation independently of its scavenger decapping activity in the cytoplasmic compartment. We also demonstrate that this new function for DcpS requires the contribution of the 5'-3' exonuclease Xrn2. Our findings support a conserved role of DcpS as a modulator of miRNA turnover in animals. PMID- 26584590 TI - Waiting for a kidney from a deceased donor: an interpretative phenomenological analysis. AB - Demand for kidneys from deceased donors far outstrips supply. Despite this, there appears to be little research that focuses solely on the experience of waiting for a kidney from a deceased donor. This study uses the qualitative methodology interpretative phenomenological analysis to explore the lives of 10 people on the transplant list, with the aims of illuminating the potential psychological challenges those on the list may face during this time, and providing information to help clinicians more fully support such people in the future. Two themes connected to the experience of waiting - adjustment to the uncertainty of waiting and thinking about receiving a kidney from a living donor - are presented here. Participants describe a sense of confusion and uncertainty around life on the list, and discuss their strategies for dealing with this. Novel complexities around the ambiguous challenge of receiving an organ from a deceased donor are revealed. It is recommended that health care teams provide a forum for this patient group to work through these feelings of confusion and ambiguity. PMID- 26584591 TI - Sequence-Dependent Duplex Stabilization upon Formation of a Metal-Mediated Base Pair. AB - An artificial nucleoside surrogate with 1H-imidazo[4,5-f][1,10]phenanthroline (P) acting as an aglycone has been introduced into DNA oligonucleotide duplexes. This nucleoside surrogate can act as a bidentate ligand, and so is useful in the context of metal-mediated base pairs. Several duplexes involving a hetero base pair with an imidazole nucleoside have been investigated. The stability of DNA duplexes incorporating the respective Ag(I) -mediated base pairs strongly depends on the sequence context. Quantum mechanical/molecular mechanical (QM/MM) calculations have been performed in order to gain insight into the factors determining this sequence dependence. The results indicated that, in addition to the stabilizing effect that results from the formation of coordinative bonds, destabilizing effects may occur when the artificial base pair does not fit optimally into the surrounding B-DNA duplex. PMID- 26584592 TI - Peptide modified polymer poly (glycerol- dodecanedioate co-fumarate) for efficient control of motor neuron differentiation. AB - Neural tissue engineering is one of the most promising approaches for healing nerve damage, which bypasses the limits of contemporary conventional treatments. In a previous study, we developed a fibrous scaffold via electrospinning poly (glycerol dodecanedioate) (PGD) and gelatin that mimics the structure of a native extracellular matrix (ECM) for soft tissue engineering application. In this study, fumaric acid (FA) was incorporated into the PGD synthesis process, which produced a PGD derivative referred to as poly (glycerol dodecanedioate co fumarate) (PGDF). This introduced a new functional group, a double bond, into the polymer thus providing new modification possibilities. Arg-Gly-Asp-Cys (RGDC) and laminin peptides were chosen as biomolecules to modify the fiber and facilitate cell attachment and differentiation efficiency. The release of FA into the medium was quantified to investigate the bioreactivity of the derived scaffolds. In combination with UV crosslinking, the developed PGDF fiber mats were able to withstand degradation processes for up to 2 months, which ensures that neural tissue engineering applications are viable. Cell viability and motor neuron differentiation efficiency were demonstrated to be significantly improved with the addition of FA, RGDC and laminin peptides. PMID- 26584593 TI - Radiographic and Clinical Predictors of Cardiac Dysfunction Following Isolated Traumatic Brain Injury. AB - INTRODUCTION: Although cardiac dysfunction after traumatic brain injury (TBI) has been described, there is little data regarding the association of radiographic severity and particular lesions of TBI with the development of cardiac dysfunction. We hypothesize that the Rotterdam or Marshall scores and particular TBI lesions are associated with the development of cardiac dysfunction after isolated TBI. METHODS: We performed a retrospective cohort study. Adult patients with isolated TBI who underwent echocardiography between 2003 and 2010 were included. A board-certified neuroradiologist assessed the first computed tomography head, assigning the Rotterdam and Marshall scores and the type of TBI. Cardiac dysfunction was defined as either systolic or all cause based on the first echocardiogram after TBI. Demographic, radiological, and clinical variables were used in our analysis. RESULTS: A total of 139 patients were identified, with 20 having isolated systolic dysfunction. The Marshall and Rotterdam scores were not associated with the development of cardiac dysfunction. Only head Abbreviated Injury Scale was found to be an independent predictor of systolic cardiac dysfunction (relative risk: 2.70, 95% confidence interval: 1.19-6.13; P = .02). CONCLUSIONS: No specific radiographic variable was found to be an independent predictor of cardiac dysfunction. Further study into clinical or radiological features that would warrant an echocardiogram is warranted, as it may direct patient management. PMID- 26584594 TI - Ancillary molecular analysis in the diagnosis of soft tissue tumours: reassessment of its utility at a specialist centre. AB - AIMS: The histological diagnosis of soft tissue tumours (STTs) can be difficult, sometimes requiring a combination of morphology, immunophenotype and ancillary molecular tests. Many STTs are associated with characteristic genetic aberrations that can be assessed using fluorescence in situ hybridisation (FISH), reverse transcription-PCR (RT-PCR) or mutational analysis. We have previously assessed the practicality and sensitivity of using these modalities as part of the routine diagnosis of STT in paraffin-embedded material and now revisit the subject in light of further experience in this field. METHODS: 200 consecutive cases from 2013 that had undergone FISH, RT-PCR or mutational analysis were assessed to evaluate their diagnostic utility compared with preliminary histological assessment. RESULTS: 218 FISH, 91 RT-PCR and 43 mutational analysis tests were performed. Compared with the previous study, FISH for MDM2 amplification in possible well-differentiated/dedifferentiated liposarcomas, and mutational analysis for assessing KIT, PDGFR and BRAF mutations made up a large proportion of the workload (107 and 43 tests, respectively). As in the previous study, alveolar rhabdomyosarcoma showed the best FISH:RT-PCR concordance. Unlike previously, RT-PCR showed marginally higher sensitivity than FISH (78.9% and 76.9%), while continuing to demonstrate higher specificity (90.9% and 84.3%). RT PCR again showed an increased failure rate (5.5%; 1% for FISH). CONCLUSIONS: We demonstrate the continuing utility of RT-PCR and FISH for STT diagnosis, and that each has advantages in specific contexts. These ancillary molecular tests are important tools in both defining and excluding diagnoses of STT, which is crucial in determining prognosis and guiding appropriate management. PMID- 26584595 TI - Transcriptional and morphological effects of tamoxifen on the early development of zebrafish (Danio rerio). AB - Tamoxifen is a widely used anticancer drug with both an estrogen agonist and antagonist effect. This study focused on its endocrine disrupting effect, and overall environmental significance. Zebrafish embryos were exposed to different concentrations (0.5, 5, 50 and 500 ug l(-1) ) of tamoxifen for 96 h. The results showed a complex effect of tamoxifen on zebrafish embryo development. For the 500 ug l(-1) exposure group, the heart rate was decreased by 20% and mild defects in caudal fin and skin were observed. Expressions of a series of genes related to endocrine and morphological changes were subsequently tested through quantitative real-time polymerase chain reaction. Bisphenol A as a known estrogen was also tested as an endocrine-related comparison. Among the expression of endocrine related genes, esr1, ar, cyp19a1b, hsd3b1 and ugt1a1 were all increased by tamoxifen exposure, similar to bisphenol A. The cyp19a1b is a key gene that controls estrogen synthesis. Exposure to 0.5, 5, 50 and 500 ug l(-1) of tamoxifen caused upregulation of cyp19a1b expression to 152%, 568%, 953% and 2024% compared to controls, higher than the effects from the same concentrations of bisphenol A treatment, yet vtg1 was suppressed by 24% from exposure to 500 ug l(-1) tamoxifen. The expression of metabolic-related genes such as cyp1a, cyp1c2, cyp3a65, gpx1a, gstp1, gsr and genes related to observed morphological changes such as krt17 were also found to be upregulated by high concentrations of tamoxifen. These findings indicated the potential environmental effect of tamoxifen on teleost early development. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26584596 TI - The role of microparticles in inflammation and transfusion: A concise review. AB - Microparticles are small membrane-bound vesicles found in body fluids including peripheral blood. Microparticles are an intrinsic part of blood labile products delivered to transfused patients and have active roles in inflammation. They are delimited by a lipid bilayer composed mainly of phospholipids, cholesterol, membrane-associated proteins, intracellular components such as metabolic enzymes, proteins-involved in adhesion and fusion, cytoskeletal-associated proteins, surface glycoproteins and/or chemokines. Microparticles can trigger a pro inflammatory message to neighbouring or target cells. Microparticles originating from platelets, leukocytes, erythrocytes, and endothelial cells are associated with a variety of pathophysiological conditions. This review summarises the role of Microparticles in modulating inflammation. PMID- 26584597 TI - Anxiety and depression associated with urinary incontinence. A 10-year follow-up study from the Norwegian HUNT study (EPINCONT). AB - AIMS: Firstly, to investigate the association between depression, anxiety and urinary incontinence (UI) in a 10-year longitudinal study of women. Secondly, to investigate the association between possible differences in the stress- and urgency components of UI and different severities of depression and anxiety by age groups. METHODS: In a longitudinal, population-based survey study, the EPINCONT part of the HUNT study in Norway, we analyzed questionnaire data on UI, depression and anxiety from 16,263 women from 20 years of age. A multivariate logistic regression model was used to predict the odds of developing anxiety and depression among the women with and without UI at baseline and the odds of developing UI among the women with and without anxiety or depression at baseline. RESULTS: For women with any UI at baseline we found an association with the incidence of depression and anxiety symptoms, OR 1.45 (1.23-1.72) and 1.26 (1.8 1.47) for mild depression and anxiety respectively. For women with depression or anxiety symptoms at baseline we found an association with the incidence of any UI with OR 2.09 (1.55-2.83) and 1.65 (1.34-2.03) for moderate/severe symptom-score for depression and anxiety, respectively, for the whole sample. CONCLUSIONS: In this study, both depression and anxiety are shown to be risk factors for developing UI with a dose-dependent trend. UI is associated with increased incidence of depression and anxiety. Neurourol. Urodynam. 36:322-328, 2017. (c) 2015 The Authors. Neurourology and Urodynamics Published by Wiley Periodicals, Inc. PMID- 26584598 TI - Serum NGAL, cystatin C and urinary NAG measurements for early diagnosis of contrast-induced nephropathy in children. AB - AIM: The study investigated a number of biomarkers for the early diagnosis of contrast-induced nephropathy (CIN), which is an important cause of acute kidney injury (AKI). MATERIAL AND METHODS: The study included 91 children scheduled for elective cardiac angiography and 50 healthy controls. Biomarkers including serum (s) and urinary (u) sodium, serum and u-creatinine, s-cystatin-C, serum neutrophil gelatinase-associated lipocalin (NGAL) and urinary N-acetyl beta glucosaminidase (u-NAG)/creatinine ratio were measured 4 times sequentially in the patients and once in the controls. RESULTS: The patient group comprised 40 males (44%) and 51 females (56%) while the control group comprised 16 males (32%) and 34 females (68%). Age, gender, s-creatinine, estimated-glomerular filtration rate (eGFR), s-cystatin-C and fractional-excretion of sodium did not differ significantly between the groups. Serum sodium and s-NGAL were found to be lower in the patients than those of in the controls, while their u-NAG/creatinine ratio was found to be higher. Sequential data analysis revealed that s-NGAL and u NAG/creatinine ratio increased in the first 6 h after radiocontrast media (RCM) administration and decreased at 12 and 24 h. Serum BUN and s-cystatin-C levels also showed a significant difference during the 24-h follow-up. eGFR, s-sodium and s-creatinine levels did not change in the following period. Serum cystatin-C levels revealed a significant negative correlation with eGFR. Administered RCM doses showed a positive correlation only with u-NAG/creatinine ratios. CONCLUSION: In the first 24 h, s-cystatin-C, s-NGAL and especially u NAG/creatinine ratio showed promise as biomarkers, but eGFR is not adequate for early diagnosis of CIN. Sequential measurement of biomarkers may contribute to more accurate diagnosis of AKI. PMID- 26584599 TI - Vaping cannabis (marijuana) has the potential to reduce tobacco smoking in cannabis users. PMID- 26584600 TI - Risk of Advanced Adenomas in Siblings of Individuals With Advanced Adenomas: A Cross-Sectional Study. AB - BACKGROUND & AIMS: The risk of colorectal neoplasms among siblings of patients with advanced adenomas is not clear. We determined the prevalence of advanced adenomas in the siblings of patients with advanced adenomas and compared it with that of siblings of individuals without these lesions. METHODS: In a blinded, cross-sectional study, colonoscopies were performed (from 2010 through 2014), at 2 hospitals in Hong Kong on 200 asymptomatic siblings of patients with advanced adenomas (exposed; mean age, 58.2 +/- 6.3 years; adenomas >=10 mm, high-grade dysplasia, villous, or tubulovillous) and 400 age- and sex-matched siblings of subjects with normal findings from colonoscopies and no family history of colorectal cancer (unexposed; mean age, 58.1 +/- 6 years). We recruited 1 sibling per family. The primary outcome was prevalence of advanced adenomas. RESULTS: Baseline demographics (ie, aspirin use, smoking, body mass index, and metabolic diseases) did not differ significantly between exposed and unexposed individuals. The prevalence of advanced adenoma was 11.5% among the exposed subjects and 2.5% among the unexposed subjects (matched odds ratio [mOR] = 6.05; 95% confidence interval [CI]: 2.74-13.36; P < .001). The prevalence of adenomas >=10 mm was higher among exposed than unexposed siblings (10.5% vs 1.8%; mOR = 8.59; 95% CI: 3.44-21.45; P < .001), as was the prevalence of villous adenomas (5.5% vs 1.3% in unexposed; mOR = 6.28; 95% CI: 2.02-19.53; P = .001) and all colorectal adenomas (39.0% vs 19.0% in unexposed; mOR = 3.29; 95% CI: 2.16-5.03; P < .001). Two cancers were detected in exposed siblings and none in unexposed siblings. CONCLUSIONS: In a cross-sectional study of subjects undergoing colonoscopy in Hong Kong, siblings of individuals with at least 1 advanced adenoma had a 6-fold increased odds of advanced adenoma compared with subjects who had a sibling with a screening colonoscopy with no identified neoplasia. ClinicalTrials.gov, Number: NCT01593098. PMID- 26584602 TI - American Gastroenterological Association Institute Technical Review on the Medical Management of Microscopic Colitis. PMID- 26584603 TI - Managing Microscopic Colitis: A Patient Guide. PMID- 26584601 TI - Symptoms Have Modest Accuracy in Detecting Endoscopic and Histologic Remission in Adults With Eosinophilic Esophagitis. AB - BACKGROUND & AIMS: It is not clear whether symptoms alone can be used to estimate the biologic activity of eosinophilic esophagitis (EoE). We aimed to evaluate whether symptoms can be used to identify patients with endoscopic and histologic features of remission. METHODS: Between April 2011 and June 2014, we performed a prospective, observational study and recruited 269 consecutive adults with EoE (67% male; median age, 39 years old) in Switzerland and the United States. Patients first completed the validated symptom-based EoE activity index patient reported outcome instrument and then underwent esophagogastroduodenoscopy with esophageal biopsy collection. Endoscopic and histologic findings were evaluated with a validated grading system and standardized instrument, respectively. Clinical remission was defined as symptom score <20 (range, 0-100); histologic remission was defined as a peak count of <20 eosinophils/mm(2) in a high-power field (corresponds to approximately <5 eosinophils/median high-power field); and endoscopic remission as absence of white exudates, moderate or severe rings, strictures, or combination of furrows and edema. We used receiver operating characteristic analysis to determine the best symptom score cutoff values for detection of remission. RESULTS: Of the study subjects, 111 were in clinical remission (41.3%), 79 were in endoscopic remission (29.7%), and 75 were in histologic remission (27.9%). When the symptom score was used as a continuous variable, patients in endoscopic, histologic, and combined (endoscopic and histologic remission) remission were detected with area under the curve values of 0.67, 0.60, and 0.67, respectively. A symptom score of 20 identified patients in endoscopic remission with 65.1% accuracy and histologic remission with 62.1% accuracy; a symptom score of 15 identified patients with both types of remission with 67.7% accuracy. CONCLUSIONS: In patients with EoE, endoscopic or histologic remission can be identified with only modest accuracy based on symptoms alone. At any given time, physicians cannot rely on lack of symptoms to make assumptions about lack of biologic disease activity in adults with EoE. ClinicalTrials.gov, Number: NCT00939263. PMID- 26584604 TI - Virus-Specific CD4+ T Cells Have Functional and Phenotypic Characteristics of Follicular T-Helper Cells in Patients With Acute and Chronic HCV Infections. AB - BACKGROUND & AIMS: Follicular T-helper (Tfh) cells contribute to pathogen specific antibody responses by providing maturation signals to B cells. In mice with viral infections, virus-specific Tfh cells expand and are required to contain the infection. However, less is known about human virus-specific Tfh cells or their functions during infection. We investigated whether virus-specific CD4+ T cells from patients with hepatitis C virus (HCV) infection had phenotypic or functional features of Tfh cells and contribute to the production of HCV specific antibodies. METHODS: We collected blood samples from patients with acute and chronic HCV infection and healthy individuals (controls). We performed MHC class II tetramer analyses, assays to detect intracellular cytokines in response to HCV exposure, and analyses to quantify HCV-specific antibodies. In addition, we collected liver tissues from patients with chronic HCV infection or nonviral liver disease to analyze markers of Tfh cells. RESULTS: HCV-specific CD4+ T cells from patients with acute HCV infection expressed markers of Tfh cells and secreted interleukin 21 in response to HCV exposure. Longitudinal analyses of HCV specific T-cell responses and antibody responses showed an association between expression of inducible T-cell co-stimulator and induction of virus-specific antibodies in patients with acute HCV infection. Markers of Tfh cells were barely detectable in the peripheral blood samples from patients with chronic HCV infection, but were detected in liver tissues. CONCLUSIONS: Virus-specific Tfh cells can be detected in blood samples from patients with acute HCV infection; inducible T-cell co-stimulator expression correlates with production of HCV specific antibodies. In patients with chronic infection, Tfh cells seem to disappear from the blood but are detectable in the liver. PMID- 26584605 TI - American Gastroenterological Association Institute Guideline on the Medical Management of Microscopic Colitis. PMID- 26584606 TI - The free delivery and caesarean policy in Morocco: how much do households still pay? AB - BACKGROUND: The Free Deliveries and Caesarean Policy (FDCP) entitles all women in Morocco to deliver free of charge within public hospitals. This study assesses the policy's effectiveness by analysing household expenditures related to childbirth, by delivery type and quintile. METHODS: Structured exit survey of 973 women in six provinces at five provincial hospitals, two regional hospitals, two university hospitals and three primary health centres with maternity units. RESULTS: Households reported spending a median of US$ 59 in total for costs inside and outside of hospitals. Women requiring caesareans payed more than women with uncomplicated deliveries (P < 0.0001). The median cost was US$45 for a uncomplicated delivery, US$50 for a complicated delivery and US$65 for a caesarean section. The prescription given upon exiting the hospital comprised 62% of the total costs. Eighty-eight per cent of women from the poorest quintiles faced catastrophic expenditures. The women's perception of their hospital stay and the FDCP policy was overwhelmingly positive, but differences were noted at the various sites. CONCLUSION: The policy has been largely but not fully effective in removing financial barriers for delivery care in Morocco. More progress should also be made on increasing awareness of the policy and on easing the financial burden, which is still borne by households with lower incomes. PMID- 26584607 TI - The impact of HIV status and antiretroviral treatment on TB treatment outcomes of new tuberculosis patients attending co-located TB and ART services in South Africa: a retrospective cohort study. AB - BACKGROUND: The implementation of collaborative TB-HIV services is challenging. We, therefore, assessed TB treatment outcomes in relation to HIV infection and antiretroviral therapy (ART) among TB patients attending a primary care service with co-located ART and TB clinics in Cape Town, South Africa. METHODS: In this retrospective cohort study, all new TB patients aged >= 15 years who registered and initiated TB treatment between 1 October 2009 and 30 June 2011 were identified from an electronic database. The effects of HIV-infection and ART on TB treatment outcomes were analysed using a multinomial logistic regression model, in which treatment success was the reference outcome. RESULTS: The 797 new TB patients included in the analysis were categorized as follows: HIV- negative, in 325 patients (40.8 %); HIV-positive on ART, in 339 patients (42.5 %) and HIV positive not on ART, in 133 patients (16.7 %). Overall, bivariate analyses showed no significant difference in death and default rates between HIV-positive TB patients on ART and HIV-negative patients. Statistically significant higher mortality rates were found among HIV-positive patients not on ART compared to HIV negative patients (unadjusted odds ratio (OR) 3.25; 95 % confidence interval (CI) 1.53-6.91). When multivariate analyses were conducted, the only significant difference between the patient categories on TB treatment outcomes was that HIV positive TB patients not on ART had significantly higher mortality rates than HIV negative patients (adjusted OR 4.12; 95 % CI 1.76-9.66). Among HIV-positive TB patients (n = 472), 28.2 % deemed eligible did not initiate ART in spite of the co-location of TB and ART services. When multivariate analyses were restricted to HIV-positive patients in the cohort, we found that being HIV-positive not on ART was associated with higher mortality (adjusted OR 7.12; 95 % CI 2.95-18.47) and higher default rates (adjusted OR 2.27; 95 % CI 1.15-4.47). CONCLUSIONS: There was no significant difference in death and default rates between HIV-positive TB patients on ART and HIV negative TB patients. Despite the co-location of services 28.2 % of 472 HIV-positive TB patients deemed eligible did not initiate ART. These patients had a significantly higher death and default rates. PMID- 26584609 TI - Internalized HIV Stigma and Mindfulness: Associations With PTSD Symptom Severity in Trauma-Exposed Adults With HIV/AIDS. AB - Rates of both traumatic event exposure and posttraumatic stress disorder (PTSD; 22%-54%) are disproportionately elevated among people living with HIV/AIDS (PLHA). Trauma and related psychopathology significantly affect quality of life and disease management in this patient population. The current study examined associations between internalized HIV stigma, mindfulness skills, and the severity of PTSD symptoms in trauma-exposed PLHA. Participants included 137 PLHA (14.6% female; Mage = 48.94, SD = 8.89) who reported experiencing on average, five (SD = 2.67) traumatic events; 34% met diagnostic criteria for PTSD. Results indicate that after controlling for sex, age, education, and number of traumatic events, internalized HIV stigma was positively related to overall PTSD symptom severity (beta = .16, p < .05) and severity of re-experiencing (beta = .19, p < .05) and hyper-arousal (beta = .16, p = .05), but not avoidance, PTSD symptom clusters. Among the mindfulness facets measured, acting with awareness was uniquely negatively related to the overall severity of PTSD symptoms (beta = .25, p < .01) and the severity of re-experiencing (beta = -.25, p < .05), avoidance (beta = -.25, p < .05), and hyper-arousal (beta = -.29, p < .01) PTSD symptom clusters. These effects were observed after accounting for covariates and shared variance with other mindfulness facets. Theoretically, the present findings suggest that internalized HIV stigma may serve as a vulnerability factor for the severity of certain PTSD symptoms, whereas acting with awareness may function as a protective or resiliency factor for the severity of PTSD symptoms. Implications for the treatment of trauma-exposed PLHA are discussed. PMID- 26584608 TI - Transcriptomic characterization of the dorsal lobes after hepatectomy of the ventral lobe in zebrafish. AB - BACKGROUND: The liver possesses an ability of compensatory growth after removing three of five lobes in mammals or one of three lobes in zebrafish. The reenter of hepatocytes into the cell cycle is one of the hallmarks for the initiation of liver compensatory growth, but cellular and molecular mechanisms underlying the activation of hepatocytes remain largely unknown. RESULTS: To better understand the process, transcriptional profiles of the remaining liver dorsal lobes in female zebrafish were generated with RNA-seq. About 44 million raw reads were obtained from three sequencing libraries and 71 % of raw reads were mapped to the reference genome of zebrafish. A total number of 5652 genes were differentially expressed in at least one of two time points during the compensatory growth of liver dorsal lobes and classified into different functional categories. A number of genes encoding angiogenesis-related growth factors/ligands and apoptosis associated cytokines were strongly expressed at 6-h time point after the removal of the ventral lobe. Gene ontology enrichment analysis of genes up-regulated during early stages of liver compensatory growth revealed that small GTPase mediated signal transduction, RNA processing and intracellular protein transport were the most highly overrepresented biological processes and SNARE interactions in vesicular transport, proteasome and basal transcription factors were the most highly enriched pathways. Moreover, 477 genes differently expressed during liver compensatory growth of both female zebrafish and mice were involved in the response to stimulus, DNA replication, metabolic processes of fatty acid, lipid and steroid, multicellular organismal homeostasis and extracellular matrix constituent secretion. CONCLUSIONS: Multiple biological processes and signaling pathways are immediately activated in remaining dorsal lobes of female zebrafish right after removal of the ventral lobe and these findings provide crucial clues for further identification of cis-elements and trans-factors that are extensively involved in the initiation of liver compensatory growth. PMID- 26584610 TI - Adolescent Callous-Unemotional Traits and Parental Knowledge as Predictors of Unprotected Sex Among Youth. AB - Risky sexual behavior among adolescents is common and results in many negative consequences. The present study investigated longitudinal predictors of adolescents' likelihood of engaging in unprotected sexual intercourse. Parental knowledge, or the extent to which parents know about their children's activities, whereabouts, and friendships, is a robust predictor of youth risk behavior, including risky sexual behavior. However, parenting practices are typically less potent as predictors of subsequent behavior among youth with high levels of callous-unemotional (CU) traits. We conducted three logistic regression models, each of which examined parental knowledge in a different way (through child report, parent report, and a discrepancy score), allowing us to examine parental knowledge, CU traits, and their interaction as predictors of adolescents' subsequent engagement in sex without a condom. Results indicated that adolescents who perceived their parents to possess greater knowledge were less likely to engage in unprotected sex. Higher parent report of parental knowledge was also related to decreased likelihood of engaging in unprotected sex, but only for adolescents with high levels of CU traits. In addition, greater discrepancy between parent and adolescent reports of parental knowledge was related to increased likelihood of engaging in unprotected sex, but only for adolescents with low levels of CU traits. Results highlight the importance of considering both parent and adolescent perceptions of parental knowledge and have important implications for prevention and intervention efforts. PMID- 26584611 TI - Acculturative Stress and Risky Sexual Behavior: The Roles of Sexual Compulsivity and Negative Affect. AB - Recent syndemic models of sexual health disparities affecting racial/ethnic minorities have highlighted the role of discrimination. Yet no previous work has examined how acculturative stress (distress at the transition from one's original culture toward a new culture) associates with sexual HIV-risk behavior (SHRB). Work among other minority populations suggests sexual compulsivity (SC) may contribute to syndemic sexual health disparities as a means of coping with distress. With this in mind, the present study examined whether SC explained the relation between acculturative stress and SHRB. Separate analyses were conducted for males and females within a sample of 758 sexually initiated racial/ethnic minority college students. Among males and females, acculturative stress had an indirect effect on SHRB via SC. As the first study to examine SHRB in relation to acculturative stress, findings provide preliminary evidence that targeting SC among racial/ethnic minorities may help reduce sexual health disparities. PMID- 26584612 TI - The mediating effect of discrimination, social support and hopelessness on self rated health of Roma adolescents in Slovakia. AB - BACKGROUND: According to the EU-MIDIS report on discrimination, Roma are the most discriminated against group in Europe. Research suggests that experiencing discrimination may itself be detrimental to health. The aim of this paper is to investigate whether discrimination, hopelessness and social support mediate differences in self-rated health (SRH) between Roma and non-Roma adolescents. METHODS: We conducted a cross-sectional study among Roma from separated and segregated settlements in the eastern part of Slovakia (N = 330; mean age = 14.50; interview) and non-Roma adolescents (N = 722; mean age = 14.86; questionnaire); only non-missing data were used for analyses (n = 759). The effect of perceived discrimination, mother and father social support, and hopelessness on SRH was analysed as crude and adjusted for ethnicity, age, gender, parental education and social desirability. Mediating effects were separately assessed using the Sobel test and structural equation modelling. RESULTS: Roma adolescents reported poorer SRH and more discrimination, mother and father social support, hopelessness and social desirability. Roma ethnicity (Odds ratio/95 %-Confidence interval 3.27/2.40-4.47), discrimination (2.66/1.82-3.88), hopelessness (1.35/1.20-1.51) and mother (0.92/0.88-0.97) and father social support (0.96/0.93 - 0.997) were statistically significant predictors of poor SRH. Perceived discrimination, social support and hopelessness mediated the ethnicity-health association, with adjustment for social support increasing its strength and the other two variables decreasing it. CONCLUSIONS: Perceived discrimination, social support and hopelessness mediate a part of the association between Roma ethnicity and poor SRH, with discrimination and hopelessness being risk factors and social support a protective factor. PMID- 26584614 TI - Evaluation of a Case of Inflammatory Breast Cancer with 18F-FDG PET/CT. AB - Inflammatory breast cancer is a rare and aggressive form of cancer characterized by dermal lymphatic invasion and tumor embolization resulting in erythema and edema. In many cases, by the time of diagnosis there is already distant metastasis. Mammography, sonography, CT, and MRI are usually performed for initial staging; however, PET/CT can also be used for initial staging as it offers additional diagnostic information. PMID- 26584613 TI - Inhibition of angiogenesis by platelets in systemic sclerosis patients. AB - INTRODUCTION: Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by microvascular damage, inflammation, and fibrosis. It has become increasingly evident that platelets, beyond regulating hemostasis, are important in inflammation and innate immunity. Platelets may be an important source of proinflammatory and profibrotic cytokines in the vascular microenvironment. In this study, we sought to assess the contribution of platelet-derived factors in patients with SSc to the angiogenesis of human dermal microvascular endothelial cells (DMVECs) in a tubule formation assay and to characterize the secretion of profibrotic and proinflammatory cytokines in these platelets. METHODS: We analyzed platelets obtained from 30 patients with SSc and 12 healthy control subjects. Angiogenesis was evaluated in vitro with a DMVEC tubule formation assay on Matrigel and platelet-derived angiogenic factors such as vascular endothelial growth factor (VEGF), 165b isoform (VEGF165b), and cytokine secretion was evaluated. Platelet serotonin content was also determined. RESULTS: When DMVECs were incubated with SSc platelet releasates, tubule formation was significantly inhibited (p < 0.01, t test), and higher expression of endothelin-1 in these cells was observed compared with control subjects (p < 0.05, Mann-Whitney U test). In SSc platelet releasates, VEGF165b was significantly higher (p < 0.05, t test), and the VEGF165b/VEGF ratio was increased compared with that of control subjects. Higher secretion of transforming growth factor beta (p < 0.01, t test) and CD40L (p < 0.01, t test) was observed compared with control subjects. Also, intraplatelet serotonin levels were lower in platelets obtained from patients with diffuse SSc compared with patients with limited SSc and control subjects (p < 0.05, t test). CONCLUSIONS: Our findings suggest that antiangiogenic factors such as VEGF165b, together with proinflammatory and profibrotic factors secreted by platelets, can contribute to the progression of peripheral microvascular damage, defective vascular repair, and fibrosis in patients with SSc. PMID- 26584615 TI - Parathyroid Imaging with Simultaneous Acquisition of 99mTc-Sestamibi and 123I: The Relative Merits of Pinhole Collimation and SPECT/CT. AB - The objective of this study was to determine the relative utility of 3 state-of the-art parathyroid imaging protocols: single-time-point simultaneous acquisition of (99m)Tc-sestamibi and (123)I images with pinhole collimation in the anterior and bilateral anterior oblique projections, single-time-point simultaneous acquisition of (99m)Tc-sestamibi and (123)I images with SPECT/CT, and the combination of the first and second protocols. METHODS: Fifty-nine patients with surgical proof of parathyroid adenomas were evaluated retrospectively. All 3 protocols included perfectly coregistered subtraction images created by subtracting the (123)I images from the (99m)Tc-sestamibi images, plus an anterior parallel-hole collimator image of the neck and upper chest. The pinhole protocol was performed first, followed by the SPECT/CT protocol. Three image sets were derived from each study in each patient according to the above protocols. Two experienced observers recorded the size, location, and degree of certainty of any identified lesion. RESULTS: The 59 patients had 61 adenomas. For the 2 observers combined, the localization success rate was 88% for the pinhole protocol, 69% for the SPECT/CT protocol, and 81% for the combined protocol. The pinhole protocol detected more adenomas than the SPECT/CT protocol and missed fewer adenomas than either the SPECT/CT protocol or the combined pinhole and SPECT/CT protocol (P < 0.01). The 2 protocols that included SPECT/CT provided superior anatomic information relative to the location and size of the parathyroid adenomas. CONCLUSION: The pinhole protocol localized significantly more adenomas than the SPECT/CT protocol. However, the protocols that included SPECT/CT provided more anatomic information than pinhole imaging alone. PMID- 26584616 TI - Radiation Hormesis: Historical and Current Perspectives. AB - The purpose of this article is to provide the reader with a better understanding of radiation hormesis, the investigational research that supports or does not support the theory, and the relationship between the theory and current radiation safety guidelines and practices. The concept of radiation hormesis is known to nuclear medicine technologists, but understanding its complexities and the historical development of the theory may bring about a better understanding of radiation safety and regulations. PMID- 26584617 TI - Evaluating the Role of Routine Prone Acquisition on Visual Evaluation of SPECT Images. AB - Attenuation artifacts reduce our ability to evaluate perfusion of affected myocardial segments. The aim of this study was to evaluate the impact of routine prone-position image evaluation within a stepwise visual interpretation of myocardial perfusion studies. METHODS: We have included 279 consecutive patients who were referred for evaluation of myocardial ischemia. All patients underwent routine electrocardiogram-gated supine SPECT imaging and non-electrocardiogram gated prone-position SPECT imaging. Three nuclear medicine physicians interpreted the images in the following order: polar maps, supine images, raw images, motion frozen gated images, and prone images, using a scale of 0-4. Segments with perfusion abnormalities were noted. RESULTS: All physicians reported lower proportions of equivocal evaluations after evaluating prone images (18.3% vs. 4.7%, 19% vs. 11.1%, and 12.2% vs. 6.1%, P < 0.0001, P = 0.0077, and P = 0.0125, respectively). At the prone stage, normalcy rates were 89%, 87%, and 91%. Two physicians had significantly increased normalcy rates at the prone stage (72% 89%, P = 0.039, and 66%-87%, P = 0.006). At the prone stage, a decision reversal to normal or probably normal was observed in 40% (29/72), 33% (17/51), and 43% (21/48). In men, apical, mid, and basal inferior walls and in women apical and mid parts of anterior walls were more likely to be attributed to attenuation. The 2 steps that increased normalcy rates for interpreters were the review of raw images and of prone images. CONCLUSION: Routine prone imaging increases interpretive certainty and interobserver agreement and changes the final evaluation in a substantial number of patients and significantly decreases the number of equivocal evaluations. PMID- 26584618 TI - Evaluation of different radon guideline values based on characterization of ecological risk and visualization of lung cancer mortality trends in British Columbia, Canada. AB - BACKGROUND: There is no safe concentration of radon gas, but guideline values provide threshold concentrations that are used to map areas at higher risk. These values vary between different regions, countries, and organizations, which can lead to differential classification of risk. For example the World Health Organization suggests a 100 Bq m(-3)value, while Health Canada recommends 200 Bq m(-3). Our objective was to describe how different thresholds characterized ecological radon risk and their visual association with lung cancer mortality trends in British Columbia, Canada. METHODS: Eight threshold values between 50 and 600 Bq m(-3) were identified, and classes of radon vulnerability were defined based on whether the observed 95(th) percentile radon concentration was above or below each value. A balanced random forest algorithm was used to model vulnerability, and the results were mapped. We compared high vulnerability areas, their estimated populations, and differences in lung cancer mortality trends stratified by smoking prevalence and sex. RESULTS: Classification accuracy improved as the threshold concentrations decreased and the area classified as high vulnerability increased. Majority of the population lived within areas of lower vulnerability regardless of the threshold value. Thresholds as low as 50 Bq m(-3) were associated with higher lung cancer mortality, even in areas with low smoking prevalence. Temporal trends in lung cancer mortality were increasing for women, while decreasing for men. CONCLUSIONS: Radon contributes to lung cancer in British Columbia. The results of the study contribute evidence supporting the use of a reference level lower than the current guideline of 200 Bq m(-3) for the province. PMID- 26584619 TI - High telomerase is a hallmark of undifferentiated spermatogonia and is required for maintenance of male germline stem cells. AB - Telomerase inactivation causes loss of the male germline in worms, fish, and mice, indicating a conserved dependence on telomere maintenance in this cell lineage. Here, using telomerase reverse transcriptase (Tert) reporter mice, we found that very high telomerase expression is a hallmark of undifferentiated spermatogonia, the mitotic population where germline stem cells reside. We exploited these high telomerase levels as a basis for purifying undifferentiated spermatogonia using fluorescence-activated cell sorting. Telomerase levels in undifferentiated spermatogonia and embryonic stem cells are comparable and much greater than in somatic progenitor compartments. Within the germline, we uncovered an unanticipated gradient of telomerase activity that also enables isolation of more mature populations. Transcriptomic comparisons of Tert(High) undifferentiated spermatogonia and Tert(Low) differentiated spermatogonia by RNA sequencing reveals marked differences in cell cycle and key molecular features of each compartment. Transplantation studies show that germline stem cell activity is confined to the Tert(High) cKit(-) population. Telomere shortening in telomerase knockout strains causes depletion of undifferentiated spermatogonia and eventual loss of all germ cells after undifferentiated spermatogonia drop below a critical threshold. These data reveal that high telomerase expression is a fundamental characteristic of germline stem cells, thus explaining the broad dependence on telomerase for germline immortality in metazoans. PMID- 26584620 TI - Dynamic changes in histone modifications precede de novo DNA methylation in oocytes. AB - Erasure and subsequent reinstatement of DNA methylation in the germline, especially at imprinted CpG islands (CGIs), is crucial to embryogenesis in mammals. The mechanisms underlying DNA methylation establishment remain poorly understood, but a number of post-translational modifications of histones are implicated in antagonizing or recruiting the de novo DNA methylation complex. In mouse oogenesis, DNA methylation establishment occurs on a largely unmethylated genome and in nondividing cells, making it a highly informative model for examining how histone modifications can shape the DNA methylome. Using a chromatin immunoprecipitation (ChIP) and genome-wide sequencing (ChIP-seq) protocol optimized for low cell numbers and novel techniques for isolating primary and growing oocytes, profiles were generated for histone modifications implicated in promoting or inhibiting DNA methylation. CGIs destined for DNA methylation show reduced protective H3K4 dimethylation (H3K4me2) and trimethylation (H3K4me3) in both primary and growing oocytes, while permissive H3K36me3 increases specifically at these CGIs in growing oocytes. Methylome profiling of oocytes deficient in H3K4 demethylase KDM1A or KDM1B indicated that removal of H3K4 methylation is necessary for proper methylation establishment at CGIs. This work represents the first systematic study performing ChIP-seq in oocytes and shows that histone remodeling in the mammalian oocyte helps direct de novo DNA methylation events. PMID- 26584621 TI - Motor neurons and oligodendrocytes arise from distinct cell lineages by progenitor recruitment. AB - During spinal cord development, ventral neural progenitor cells that express the transcription factors Olig1 and Olig2, called pMN progenitors, produce motor neurons and then oligodendrocytes. Whether motor neurons and oligodendrocytes arise from common or distinct progenitors in vivo is not known. Using zebrafish, we found that motor neurons and oligodendrocytes are produced sequentially by distinct progenitors that have distinct origins. When olig2(+) cells were tracked during the peak period of motor neuron formation, most differentiated as motor neurons without further cell division. Using time-lapse imaging, we found that, as motor neurons differentiated, more dorsally positioned neuroepithelial progenitors descended to the pMN domain and initiated olig2 expression. Inhibition of Hedgehog signaling during motor neuron differentiation blocked the ventral movement of progenitors, the progressive initiation of olig2 expression, and oligodendrocyte formation. We therefore propose that the motor neuron-to oligodendrocyte switch results from Hedgehog-mediated recruitment of glial-fated progenitors to the pMN domain subsequent to neurogenesis. PMID- 26584622 TI - Elf5-centered transcription factor hub controls trophoblast stem cell self renewal and differentiation through stoichiometry-sensitive shifts in target gene networks. AB - Elf5 is a transcription factor with pivotal roles in the trophoblast compartment, where it reinforces a trophoblast stem cell (TSC)-specific transcriptional circuit. However, Elf5 is also present in differentiating trophoblast cells that have ceased to express other TSC genes such as Cdx2 and Eomes. In the present study, we aimed to elucidate the context-dependent role of Elf5 at the interface between TSC self-renewal and the onset of differentiation. We demonstrate that precise levels of Elf5 are critical for normal expansion of the TSC compartment and embryonic survival, as Elf5 overexpression triggers precocious trophoblast differentiation. Through integration of protein interactome, transcriptome, and genome-wide chromatin immunoprecipitation data, we reveal that this abundance dependent function is mediated through a shift in preferred Elf5-binding partners; in TSCs, Elf5 interaction with Eomes recruits Tfap2c to triply occupied sites at TSC-specific genes, driving their expression. In contrast, the Elf5 and Tfap2c interaction becomes predominant as their protein levels increase. This triggers binding to double- and single-occupancy sites that harbor the cognate Tfap2c motif, causing activation of the associated differentiation-promoting genes. These data place Elf5 at the center of a stoichiometry-sensitive transcriptional network, where it acts as a molecular switch governing the balance between TSC proliferation and differentiation. PMID- 26584624 TI - Epidemic myalgia and myositis associated with human parechovirus type 3 infections occur not only in adults but also in children: findings in Yamagata, Japan, 2014. AB - We previously reported an association between human parechovirus type 3 (HPeV3) and epidemic myalgia with myositis in adults during summers in which an HPeV3 outbreak occurred in children. However, this disease association has not yet been reported elsewhere. We have since continued our surveillance to accumulate data on this disease association and to confirm whether myalgia occurs in children as well as adults. Between June and August 2014, we collected 380 specimens from children with infectious diseases. We also collected clinical specimens from two adult and three paediatric patients suspected of myalgia. We then performed virus isolation and reverse-transcription-PCR using the collected specimens. We detected HPeV3 in 26 children with infectious diseases, which we regarded as indicating an outbreak. We also confirmed HPeV3 infection in all patients suspected of myalgia. In particular the symptoms in two boys, complaining of myalgia and fever, closely matched the criteria for adult myalgia. Based on our findings from 2008, 2011 and 2014, we again urge that clinical consideration be given to the relationship between myalgia and HPeV3 infections during HPeV3 outbreaks in children. Furthermore, our observations from 2014 suggest that epidemic myalgia and myositis occur not only in adults but also in children. PMID- 26584623 TI - The glucose-sensing transcription factor MLX promotes myogenesis via myokine signaling. AB - Metabolic stress and changes in nutrient levels modulate many aspects of skeletal muscle function during aging and disease. Growth factors and cytokines secreted by skeletal muscle, known as myokines, are important signaling factors, but it is largely unknown whether they modulate muscle growth and differentiation in response to nutrients. Here, we found that changes in glucose levels increase the activity of the glucose-responsive transcription factor MLX (Max-like protein X), which promotes and is necessary for myoblast fusion. MLX promotes myogenesis not via an adjustment of glucose metabolism but rather by inducing the expression of several myokines, including insulin-like growth factor 2 (IGF2), whereas RNAi and dominant-negative MLX reduce IGF2 expression and block myogenesis. This phenotype is rescued by conditioned medium from control muscle cells and by recombinant IGF2, which activates the myogenic kinase Akt. Importantly, MLX-null mice display decreased IGF2 induction and diminished muscle regeneration in response to injury, indicating that the myogenic function of MLX is manifested in vivo. Thus, glucose is a signaling molecule that regulates myogenesis and muscle regeneration via MLX/IGF2/Akt signaling. PMID- 26584625 TI - Microsatellite markers for Cryptolestes ferrugineus (Coleoptera: Laemophloeidae) and other Cryptolestes species. AB - Cryptolestes ferrugineus (Stephens, 1831) is an important insect pest of stored products. Due to its broad host range, short life cycle, and high reproductive capacity, this species has rapidly colonized temperate and tropical regions around the world. In this study, we isolated 18 novel polymorphic microsatellite loci from an enriched genomic library based on a biotin/streptavidin capture protocol. These loci will be useful tool to better understand the genetic structure and migration patterns of C. ferrugineus throughout the world. The genetic parameters were estimated based on 80 individual C. ferrugineus from two natural populations. The results revealed that 18 loci were different polymorphic levels. The numbers of alleles ranged from 3 to 12, and eleven loci demonstrated polymorphic information contents greater than 0.5. The observed (H O) and expected (H E) heterozygosities ranged from 0.051 to 0.883 and 0.173 to 0.815, respectively. Five locus/population combinations significantly deviated from Hardy-Weinberg equilibrium. We also demonstrated the potential utility of the C. ferrugineus microsatellites as population and species markers for four additional Cryptolestes species. PMID- 26584626 TI - Collimator rotation in volumetric modulated arc therapy for craniospinal irradiation and the dose distribution in the beam junction region. AB - PURPOSE: The purpose of this study was to investigate the role of beam collimator rotation in Volumetric Modulated Arc Therapy (VMAT) for craniospinal irradiation (CSI), and the impact on dose distribution in the beam junctions. METHODS: Six adult patients were selected for the study. Six VMAT plans with different collimator angles were generated for each patient. The patients were treated in supine position with two beam isocenters. The plans were evaluated by analysis of Dose-Volume Histogram (DVHs) data for planning target volume (PTV) and organs at risk (OAR), and conformity index (CI) and homogeneity index (HI) for the target. Dose distributions in the beam junctions were examined carefully and experimentally validated in phantom, with measurement using an ion chamber array and film. RESULTS: The mean values of HI and CI for the plans with different beam collimator angles were not significantly different. The numbers of segments, monitor units (MUs) and the delivery time of the plans with 45 degrees beam collimator were obviously higher than those in plans with other beam collimator angles. When collimator angle for both sets of beams were set at 0 degrees , there was a 1 mm low dose gap measured in the junction region. CONCLUSIONS: By setting the collimator angle to 45 degrees , only two isocenters were needed for the treatment of a target with the length up to 90 cm. The HI and CI of the plans were almost the same, regardless if the collimator angles were at 0 degrees . The collimator angles for at least one set of beams should be off 0 degrees in order to avoid a dose gap in the beam junction region. PMID- 26584628 TI - Investigation of the fragmentation of core-ionised deoxyribose: a study as a function of the tautomeric form. AB - We have investigated the gas phase fragmentation dynamics following the core ionisation of 2-deoxy-D-ribose (dR), a major component in the DNA chain. To that aim, we use state-of-the-art ab initio Density Functional Theory-based Molecular Dynamics simulations. The ultrafast dissociation dynamics of the core-ionised biomolecule, prior Auger decay, is first modelled for 10 fs to generate initial configurations (atomic positions and velocities) for the subsequent dynamics of the doubly ionised biomolecule in the ground state. The furanose, linear and pyranose conformations of dR were investigated. We show that fragmentation is relatively independent of the atom struck or of the duration of the core vacancy, but depends rather critically on the molecular orbital removed following Auger decay. PMID- 26584627 TI - Comparison of Tamsulosin, Nifedipine, and Placebo for Ureteric Colic. AB - Clinical question Do calcium channel blockers or alpha blockers improve renal stone passage when compared with placebo? Article chosen Pickard R, Starr K, MacLennan G, et al. Medical expulsive therapy in adults with ureteric colic: a multicentre, randomised, placebo-controlled trial. Lancet 2015;386(9991):25-31, doi: 10.1016/S0140-6736(15)60933-3. PMID- 26584629 TI - Stabilized borata-alkene formation: structural features, reactions and the role of the counter cation. AB - Dimethylbenzofulvene adds Piers' borane [HB(C6F5)2] at the indene double bond to give a mixture of regioisomeric boranes 8a,b. Subsequent isomerization under equilibrium conditions gives the isopropyl substituted 1H and 3H borylindenes 10a,b. Their treatment with the bulky LiTMP base under frustrated Lewis pair conditions resulted in a clean deprotonation reaction to give the borata-alkene 14. Its X-ray crystal structure analysis indicated a pronounced B[double bond, length as m-dash]C double bond character and thus a borata-benzofulvene description. The borata-alkene underwent (probably stepwise) [4 + 2] cycloaddition reactions with chalcone derivatives and a formal [6 + 2] cycloaddition with phenylmethylketene. Many products and derivatives were characterized by X-ray diffraction. PMID- 26584630 TI - General theory of asymmetric steric interactions in electrostatic double layers. AB - We study the mean-field Poisson-Boltzmann equation in the context of dense ionic liquids where steric effects become important. We generalise lattice gas theory by introducing a Flory-Huggins entropy for ions of differing volumes and then compare the effective free energy density to other existing lattice gas approximations, not based on the Flory-Huggins Ansatz. Within the methodology presented we also invoke more realistic equations of state, such as the Carnahan Starling approximation, that are not based on the lattice gas approximation and lead to thermodynamic functions and properties that differ strongly from the lattice gas case. We solve the Carnahan-Starling model in the high density limit, and demonstrate a slow, power-law convergence at high potentials. We elucidate how equivalent convex free energy functions can be constructed that describe steric effects in a manner which is more convenient for numerical minimisation. PMID- 26584631 TI - One-Pot Dichotomous Construction of Inside-Azayohimban and Pro-Azayohimban Systems via an Enantioselective Organocatalytic Cascade; Their Use as a Model to Probe the (Aza-)Indole Local Solvent Environment. AB - A one-pot enantioselective synthesis of 7-azaindole-octahydroisoquinolin-3-one and an inside-aza-yohimbane system containing five contiguous stereogenic centers with high enantioselectivities (>99% ee) was achieved. The prepared highly functionalized polycyclic system provides a model for probing the solvent catalyzed proton transfer reaction and mimicking the local environment of the tryptophan moiety in proteins. PMID- 26584632 TI - Cyclopropenium Cations Break the Rules of Attraction to Form Closely Bound Dimers. AB - The crystal structures of tris(ethylmethylamino)-cyclopropenium chloride and tris(diethylamino)-cyclopropenium iodide reveal the presence of closely bound dicationic dimers formed from two closed-shell monomer units. The distances between the C3 centroids of the staggered monomers are at the short end of those normally found in pi-stacked neutral arenes, let alone charged aromatic rings. Computational analysis reveals that short-range interactions are dominated by strong dispersion forces, enabling metastable dicationic dimers to form without covalent intermolecular bonding. Surrounding counterions then provide a background source of charge balance, imparting strong thermodynamic stability to the system. Additionally, these counterions form a weak but attractive electrostatic bridge between the monomer units, contributing to the surprisingly short observed intermolecular C3-C3 centroid distance. PMID- 26584633 TI - Proteomic analysis of tylosin-resistant Mycoplasma gallisepticum reveals enzymatic activities associated with resistance. AB - Mycoplasma gallisepticum is a significant pathogenic bacterium that infects poultry, causing chronic respiratory disease and sinusitis in chickens and turkeys, respectively. M. gallisepticum infection poses a substantial economic threat to the poultry industry, and this threat is made worse by the emergence of antibiotic-resistant strains. The mechanisms of resistance are often difficult to determine; for example, little is known about antibiotic resistance of M. gallisepticum at the proteome level. In this study, we performed comparative proteomic analyses of an antibiotic (tylosin)-resistant M. gallisepticum mutant and a susceptible parent strain using a combination of two-dimensional differential gel electrophoresis and nano-liquid chromatography-quadrupole-time of flight mass spectrometry. Thirteen proteins were identified as differentially expressed in the resistant strain compared to the susceptible strain. Most of these proteins were related to catalytic activity, including catalysis that promotes the formylation of initiator tRNA and energy production. Elongation factors Tu and G were over-expressed in the resistant strains, and this could promote the binding of tRNA to ribosomes and catalyze ribosomal translocation, the coordinated movement of tRNA, and conformational changes in the ribosome. Taken together, our results indicate that M. gallisepticum develops resistance to tylosin by regulating associated enzymatic activities. PMID- 26584634 TI - Promoting endothelialization on decellularized porcine aortic valve by immobilizing branched polyethylene glycolmodified with cyclic-RGD peptide: an in vitro study. AB - We functionally modify a decellularized porcine aortic valve using a novel complex biologically active cyclic- (c)-RGD modified with branched polyethylene glycol (PEG), namely, c-RDG-PEG. Human umbilical vein endothelial cell (HUVEC) adhesion and proliferation were detected for up to 8 d after seeding on the scaffold. (1)H nuclear magnetic resonance (D2O) showed signal peaks at 7.27 and 7.38 ppm associated with protons of the phenyl group in c-RGD-PEG. Attenuated total reflectance Fourier transform infrared spectroscopy showed characteristic peaks for PEG at 1100 and 1342 cm(-1). These represented vibration peaks of C-O and -CH2 bonds, suggesting successful grafting of c-RGD-PEG to a decellularized porcine aortic valve (DPAV). The tensile strengths were significantly increased in the c-RGD-PEG-DPAV group compared to the native valve and DPAV groups (P < 0.05), while the elastic modulus was sigficantly decreased in the c-RGD-PEG-DPAV group compared to the native valve and DPAV groups (P < 0.05). HUVEC proliferation was significantly higher in the c-RGD-PEG-DPAV group than in the PEG-DPAV and DPAV groups (P < 0.01). Maximum adhesion occurred at 4 h, and on the 8th day, a confluent and compact monolayer formed on the valve surface. The modified DPAV resulted in good adhesion and proliferation of endothelial cells and is an appropriate approach to modify tissue engineered heart valves for promoting endothelialization. PMID- 26584635 TI - BRAF(V600E) mutation is highly prevalent in thyroid carcinomas in the young population in Fukushima: a different oncogenic profile from Chernobyl. AB - After the accident at the Fukushima Daiichi Nuclear Power Plant, the thyroid ultrasound screening program for children aged 0-18 at the time of the accident was started from October 2011. The prevalence of thyroid carcinomas in that population has appeared to be very high (84 cases per 296,253). To clarify the pathogenesis, we investigated the presence of driver mutations in these tumours. 61 classic papillary thyroid carcinomas (PTCs), two follicular variant PTCs, four cribriform-morular variant PTCs and one poorly-differentiated thyroid carcinoma were analysed. We detected BRAF(V600E) in 43 cases (63.2%), RET/PTC1 in six (8.8%), RET/PTC3 in one (1.5%) and ETV6/NTRK3 in four (5.9%). Among classic and follicular variant PTCs, BRAF(V600E) was significantly associated with the smaller size. The genetic pattern was completely different from post-Chernobyl PTCs, suggesting non-radiogenic etiology of these cancers. This is the first study demonstrating the oncogene profile in the thyroid cancers discovered by large mass screening, which probably reflects genetic status of all sporadic and latent tumours in the young Japanese population. It is assumed that BRAF(V600E) may not confer growth advantage on paediatric PTCs, and many of these cases grow slowly, suggesting that additional factors may be important for tumour progression in paediatric PTCs. PMID- 26584636 TI - Soluble LR11/SorLA represses thermogenesis in adipose tissue and correlates with BMI in humans. AB - Thermogenesis in brown adipose tissue (BAT) is an important component of energy expenditure in mammals. Recent studies have confirmed its presence and metabolic role in humans. Defining the physiological regulation of BAT is therefore of great importance for developing strategies to treat metabolic diseases. Here we show that the soluble form of the low-density lipoprotein receptor relative, LR11/SorLA (sLR11), suppresses thermogenesis in adipose tissue in a cell autonomous manner. Mice lacking LR11 are protected from diet-induced obesity associated with an increased browning of white adipose tissue and hypermetabolism. Treatment of adipocytes with sLR11 inhibits thermogenesis via the bone morphogenetic protein/TGFbeta signalling pathway and reduces Smad phosphorylation. In addition, sLR11 levels in humans are shown to positively correlate with body mass index and adiposity. Given the need for tight regulation of a tissue with a high capacity for energy wastage, we propose that LR11 plays an energy conserving role that is exaggerated in states of obesity. PMID- 26584638 TI - Ultrathin W space layer-enabled thermal stability enhancement in a perpendicular MgO/CoFeB/W/CoFeB/MgO recording frame. AB - Perpendicularly magnetized tunnel junctions (p-MTJs) show promise as reliable candidates for next-generation memory due to their outstanding features. However, several key challenges remain that affect CoFeB/MgO-based p-MTJ performance. One significant issue is the low thermal stability (Delta) due to the rapid perpendicular magnetic anisotropy (PMA) degradation during annealing at temperatures greater than 300 degrees C. Thus, the ability to provide thermally robust PMA characteristics is a key steps towards extending the use of these materials. Here, we examine the influence of a W spacer on double MgO/CoFeB/W/CoFeB/MgO frames as a generic alternative layer to ensure thermally robust PMAs at temperatures up to 425 degrees C. The thickness-dependent magnetic features of the W layer were evaluated at various annealing temperatures to confirm the presence of strong ferromagnetic interlayer coupling at an optimized 0.55 nm W spacer thickness. Using this W layer we achieved a higher Delta of 78 for an approximately circular 20 nm diameter free layer device. PMID- 26584637 TI - Nanoliposomal Nitroglycerin Exerts Potent Anti-Inflammatory Effects. AB - Nitroglycerin (NTG) markedly enhances nitric oxide (NO) bioavailability. However, its ability to mimic the anti-inflammatory properties of NO remains unknown. Here, we examined whether NTG can suppress endothelial cell (EC) activation during inflammation and developed NTG nanoformulation to simultaneously amplify its anti-inflammatory effects and ameliorate adverse effects associated with high dose NTG administration. Our findings reveal that NTG significantly inhibits human U937 cell adhesion to NO-deficient human microvascular ECs in vitro through an increase in endothelial NO and decrease in endothelial ICAM-1 clustering, as determined by NO analyzer, microfluorimetry, and immunofluorescence staining. Nanoliposomal NTG (NTG-NL) was formulated by encapsulating NTG within unilamellar lipid vesicles (DPhPC, POPC, Cholesterol, DHPE-Texas Red at molar ratio of 6:2:2:0.2) that were ~155 nm in diameter and readily uptaken by ECs, as determined by dynamic light scattering and quantitative fluorescence microscopy, respectively. More importantly, NTG-NL produced a 70-fold increase in NTG therapeutic efficacy when compared with free NTG while preventing excessive mitochondrial superoxide production associated with high NTG doses. Thus, these findings, which are the first to reveal the superior therapeutic effects of an NTG nanoformulation, provide the rationale for their detailed investigation for potentially superior vascular normalization therapies. PMID- 26584639 TI - A new cost-effective method to mitigate ammonia loss from intensive cattle feedlots: application of lignite. AB - In open beef feedlot systems, more than 50% of dietary nitrogen (N) is lost as ammonia (NH3). Here we report an effective and economically-viable method to mitigate NH3 emissions by the application of lignite. We constructed two cattle pens (20 * 20 m) to determine the effectiveness of lignite in reducing NH3 emissions. Twenty-four steers were fed identical commercial rations in each pen. The treatment pen surface was dressed with 4.5 kg m(-2) lignite dry mass while no lignite was applied in the control pen. We measured volatilised NH3 concentrations using Ecotech EC9842 NH3 analysers in conjunction with a mass balance method to calculate NH3 fluxes. Application of lignite decreased NH3 loss from the pen by approximately 66%. The cumulative NH3 losses were 6.26 and 2.13 kg N head(-1) in the control and lignite treatment, respectively. In addition to the environmental benefits of reduced NH3 losses, the value of retained N nutrient in the lignite treated manure is more than $37 AUD head(-1) yr(-1), based on the current fertiliser cost and estimated cost of lignite application. We show that lignite application is a cost-effective method to reduce NH3 loss from cattle feedlots. PMID- 26584641 TI - mTORC2 is a tyrosine kinase. AB - The mammalian target of rapamycin (mTOR), a protein kinase, is the centre of huge attention due to its importance in intracellular signaling and in health and disease. In their recent study, Yin et al. show that mTOR can regulate signaling through the insulin-like growth factor 1 receptor and that it possesses a new enzymatic activity - the ability to phosphorylate proteins on tyrosine residues. PMID- 26584640 TI - mTORC2 promotes type I insulin-like growth factor receptor and insulin receptor activation through the tyrosine kinase activity of mTOR. AB - Mammalian target of rapamycin (mTOR) is a core component of raptor-mTOR (mTORC1) and rictor-mTOR (mTORC2) complexes that control diverse cellular processes. Both mTORC1 and mTORC2 regulate several elements downstream of type I insulin-like growth factor receptor (IGF-IR) and insulin receptor (InsR). However, it is unknown whether and how mTOR regulates IGF-IR and InsR themselves. Here we show that mTOR possesses unexpected tyrosine kinase activity and activates IGF IR/InsR. Rapamycin induces the tyrosine phosphorylation and activation of IGF IR/InsR, which is largely dependent on rictor and mTOR. Moreover, mTORC2 promotes ligand-induced activation of IGF-IR/InsR. IGF- and insulin-induced IGF-IR/InsR phosphorylation is significantly compromised in rictor-null cells. Insulin receptor substrate (IRS) directly interacts with SIN1 thereby recruiting mTORC2 to IGF-IR/InsR and promoting rapamycin- or ligand-induced phosphorylation of IGF IR/InsR. mTOR exhibits tyrosine kinase activity towards the general tyrosine kinase substrate poly(Glu-Tyr) and IGF-IR/InsR. Both recombinant mTOR and immunoprecipitated mTORC2 phosphorylate IGF-IR and InsR on Tyr1131/1136 and Tyr1146/1151, respectively. These effects are independent of the intrinsic kinase activity of IGF-IR/InsR, as determined by assays on kinase-dead IGF-IR/InsR mutants. While both rictor and mTOR immunoprecitates from rictor(+/+) MCF-10A cells exhibit tyrosine kinase activity towards IGF-IR and InsR, mTOR immunoprecipitates from rictor(-/-) MCF-10A cells do not induce IGF-IR and InsR phosphorylation. Phosphorylation-deficient mutation of residue Tyr1131 in IGF-IR or Tyr1146 in InsR abrogates the activation of IGF-IR/InsR by mTOR. Finally, overexpression of rictor promotes IGF-induced cell proliferation. Our work identifies mTOR as a dual-specificity kinase and clarifies how mTORC2 promotes IGF-IR/InsR activation. PMID- 26584642 TI - Expression analysis of the osteoarthritis genetic susceptibility locus mapping to an intron of the MCF2L gene and marked by the polymorphism rs11842874. AB - BACKGROUND: Osteoarthritis (OA) is a painful, debilitating disease characterised by loss of articular cartilage with concurrent changes in other tissues of the synovial joint. Genetic association studies have shown that a number of common variants increase the risk of developing OA. Investigating their activity can uncover novel causal pathways and potentially highlight new treatment targets. One of the reported OA association signals is marked by the single nucleotide polymorphism (SNP) rs11842874 at chromosome 13q34. rs11842874 is positioned within a small linkage disequilibrium (LD) block within intron 4 of MCF2L, a gene encoding guanine-nucleotide exchange factor DBS. There are no non-synonymous SNPs that correlate with this association signal and we therefore set out to assess whether its effect on OA susceptibility is mediated by alteration of MCF2L expression. METHODS: Nucleic acid was extracted from cartilage, synovial membrane or infrapatellar fat pad tissues from OA patients. Expression of MCF2L was measured by quantitative PCR and RNA-sequencing whilst the presence of DBS was studied using immunohistochemistry. The functional effect of SNPs within the 13q34 locus was assessed using public databases and in vitro using luciferase reporter analysis. RESULTS: MCF2L gene and protein expression are detectable in joint tissues, with quantitative differences in the expression of the gene and in the transcript isoforms expressed between the tissues tested. There is an expression quantitative trait locus (eQTL) operating within synovial membrane tissue, with possession of the risk-conferring A allele of rs11842874 correlating with increased MCF2L expression. SNPs within the rs11842874 LD block reside within transcriptional regulatory elements and their direct analysis reveals that several show quantitative differences in regulatory activity at the allelic level. CONCLUSIONS: MCF2L is subject to a cis-acting eQTL in synovial membrane that correlates with the OA association signal. This signal contains several functional SNPs that could account for the susceptibility and which therefore merit further investigation. As far as we are aware, this is the first example of an OA susceptibility locus operating as an eQTL in synovial membrane tissue but not in cartilage. PMID- 26584643 TI - Associations between nucleosome phasing, sequence asymmetry, and tissue-specific expression in a set of inbred Medaka species. AB - BACKGROUND: Transcription start sites (TSSs) with pronounced and phased nucleosome arrays downstream and nucleosome-depleted regions upstream of TSSs are observed in various species. RESULTS: We have characterized sequence variation and expression properties of this set of TSSs (which we call "Nucleocyclic TSSs") using germline and somatic cells of three medaka (Oryzias latipes) inbred isolates from different locations. We found nucleocyclic TSSs in medaka to be associated with higher gene expression and characterized by a clear boundary in sequence composition with potentially-nucleosome-destabilizing A/T-enrichment upstream (p < 10(-60)) and nucleosome- accommodating C/G-enrichment downstream (p < 10(-40)) that was highly conserved from an ancestor. A substantial genetic distance between the strains facilitated the in-depth analysis of patterns of fixed mutations, revealing a localization-specific equilibrium between the rates of distinct mutation categories that would serve to maintain the conserved sequence anisotropy around TSSs. Downstream of nucleocyclic TSSs, C to T, T to C, and other mutation rates on the sense strand increased around first nucleosome dyads and decreased around first linkers, which contrasted with genomewide mutational patterns around nucleosomes (p < 5 %). C to T rates are higher than G to A rates around nucleosome associated with germline nucleocyclic TSS sites (p < 5 %), potentially due to the asymmetric effect of transcription-coupled repair. CONCLUSIONS: Our results demonstrate an atypical evolutionary process surrounding nucleocyclic TSSs. PMID- 26584644 TI - Redox interventions to increase exercise performance. AB - Skeletal muscle continually produces reactive oxygen species (ROS) and nitric oxide (NO) derivatives. Both oxidant cascades have complex effects on muscle contraction, metabolic function and tissue perfusion. Strenuous exercise increases oxidant production by muscle, limiting performance during endurance exercise tasks. Conversely, redox interventions that modulate ROS or NO activity have the potential to improve performance. Antioxidants have long been known to buffer ROS activity and lessen oxidative perturbations during exercise. The capacity to enhance human performance varies among antioxidant categories. Vitamins, provitamins and nutriceuticals often blunt oxidative changes at the biochemical level but do not enhance performance. In contrast, reduced thiol donors have been shown to delay fatigue or increase endurance under a variety of experimental conditions. Dietary nitrate supplementation has recently emerged as a second redox strategy for increasing endurance. Purified nitrate salts and nitrate-rich foods, notably beetroot and beetroot juice, are reported to lessen the oxygen cost of exercise, increase efficiency, and enhance performance during endurance tasks. These findings are exciting but enigmatic since nitrate per se has little bioactivity and cannot be converted to NO by mammalian cells. Overall, the available data suggest exercise endurance can be augmented by redox-active supplements, either reduced thiol donors or dietary nitrates. These findings have clear implications for athletes seeking a competitive edge. More importantly, interventions that increase endurance may benefit individuals whose physical activity is limited by illness, ageing, or frailty. PMID- 26584645 TI - High frequency ultrasound of skin involvement in systemic sclerosis - a follow-up study. AB - INTRODUCTION: High-frequency ultrasound offers a potential for objective and quantitative assessment of skin thickness and skin echogenicity in systemic sclerosis (SSc). Few studies have however assessed the longitudinal changes of skin involvement using ultrasound. The aim of the study was to investigate changes in skin thickness in early SSc using high frequency ultrasound during one year of follow-up in comparison to other measurements of skin fibrosis. METHODS: This retrospective study comprised 75 consecutive patients with disease duration shorter than 3 years, in whom ultrasound examination of skin thickness was performed at baseline and at the one year follow-up at five predefined sites. RESULTS: Repeated ultrasound examination identified significant changes in a majority of patients. In 21 patients, the total sum of skin thickness (TST) increased, while TST decreased in 37 patients. On a group level there were significant decreases in skin thickness of the chest (p = 0.024) and in the TST (p = 0.011) during the observation time. Both baseline and follow-up TST correlated to serum-COMP (rS: 0.41; p = 0.001; rS: 0.49; p < 0.001), modified Rodnan skin score (mRSS; rS: 0.48; p < 0.001; rS: 0.48; p < 0.001) and hand mobility in scleroderma (HAMIS; rS: 0.30; p = 0.043; rS: 0.64; p < 0.001). Changes in TST correlated with changes in serum-COMP (rS: 0.30; p = 0.034), changes in mRSS (rS: 0.43; p < 0.001) and changes in HAMIS (rS: 0.53; p = 0.001) during follow-up. CONCLUSIONS: In early SSc, skin thickness measured by high frequency ultrasound develops in parallel with serum-COMP, mRSS and the HAMIS test. Ultrasound examination of the skin allows for objective assessment of one facet of the complex process of skin fibrosis in early SSc. PMID- 26584647 TI - Endoscopic coblator-assisted epiglottoplasty in 'obstructive sleep apnoea syndrome' patients. PMID- 26584648 TI - Widespread dispersion of the resistance element tet(B)::ISCR2 in XDR Acinetobacter baumannii isolates. AB - Acinetobacter baumannii is a significant nosocomial pathogen often associated with extreme drug resistance (XDR). In Argentina, isolates of A. baumannii resistant to tetracyclines have accounted for more than 40% of drug-resistant isolates in some hospitals. We have previously reported the dispersion of the tet(B) resistance element associated with the ISCR2 transposase in epidemiologically unrelated A. baumannii isolates recovered from 1983 to 2011. This study extends this surveillance to 77 recent (2009-2013) XDR A. baumannii isolates with different levels of minocycline susceptibility. Isolates were examined by a pan-PCR assay, which showed six different amplification patterns, and specific PCRs were used for the confirmation of the the DeltaISCR2-tet(B) tet(R)-ISCR2 element. The tet(B) gene was present in 66 isolates and the ISCR2 element in 68 isolates; the tet(B) gene was associated with ISCR2 in all tet(B) positive isolates. We conclude that this element is widespread in XDR A. baumannii isolates from Argentina and could be responsible for the emergence of tetracycline resistance in recent years. PMID- 26584650 TI - End Capping Alters the Structural Characteristics and Mechanical Properties of Transthyretin (105-115) Amyloid Protofibrils. AB - Pathological amyloid proteins are associated with degenerative and neurodegenerative diseases. These amyloid proteins develop as oligomer, fibrillar, and plaque forms, due to the denatured and unstable status of the amyloid monomers. Specifically, the development of fibrillar amyloid proteins has been investigated through several experimental studies. To understand the generation of amyloid fibrils, environmental factors such as point mutations, pH, and polymorphic characteristics have been considered. Recently, amyloid fibril studies related to end-capping effects have been conducted to understand amyloid fibril development. However, atomic-level studies to determine the stability and mechanical properties of amyloid fibrils based on end capping have not been undertaken. In this study, we show that end capping alters the structural characteristics and conformations of transthyretin (TTR) amyloid fibrils by using molecular dynamics (MD) simulations. Variation in the structural conformations and characteristics of the TTR fibrils through end capping are observed, due to the resulting electrostatic energies and hydrophobicity characteristics. Moreover, the end capping changes the mechanical properties of TTR fibrils. Our results shed light on amyloid fibril formation under end-capping conditions. PMID- 26584649 TI - Greater hunger and less restraint predict weight loss success with phentermine treatment. AB - OBJECTIVE: Phentermine is thought to cause weight loss through a reduction in hunger. It was hypothesized that higher hunger ratings would predict greater weight loss with phentermine. METHODS: This is an observational pilot study in which all subjects were treated with phentermine for 8 weeks and appetite and eating behaviors were measured at baseline and week 8. Outcomes were compared in subjects with >=5% vs. <5% weight loss, and linear regression was used to identify predictors of percent weight loss. RESULTS: Twenty-seven subjects (37 +/ 4.5 years, 93.8 +/- 12.1 kg, BMI 33.8 +/- 3.1 kg m(-2) ) completed the study, with mean weight loss of -5.4 +/- 3.3 kg (-5.7% +/- 3.2%). Subjects with >=5% weight loss had higher baseline pre-breakfast hunger (P = 0.017), desire to eat (P =0.003), and prospective food consumption (0.006) and lower baseline cognitive restraint (P = 0.01). In addition, higher baseline home prospective food consumption (P = 0.002) and lower baseline cognitive restraint (P < 0.001) were found to be predictors of weight loss. CONCLUSIONS: These results suggest that individuals reporting greater hunger and less restraint are more likely to achieve significant weight loss with phentermine. This information can be used clinically to determine who might benefit most from phentermine treatment. PMID- 26584646 TI - The twisted survivin connection to angiogenesis. AB - Survivin, a member of the inhibitor of apoptosis family of proteins (IAPs) that controls cell division, apoptosis, metastasis and angiogenesis, is overexpressed in essentially all human cancers. As a consequence, the gene/protein is considered an attractive target for cancer treatment. Here, we discuss recent findings related to the regulation of survivin expression and its role in angiogenesis, particularly in the context of hypoxia. We propose a novel role for survivin in cancer, whereby expression of the protein in tumor cells promotes VEGF synthesis, secretion and angiogenesis. Mechanistically, we propose the existence of a positive feed-back loop involving PI3-kinase/Akt activation and enhanced beta-Catenin-TCF/LEF-dependent VEGF expression followed by secretion. Finally, we elaborate on the possibility that this mechanism operating in cancer cells may contribute to enhanced tumor vascularization by vasculogenic mimicry together with conventional angiogenesis. PMID- 26584651 TI - Why are ototopical aminoglycosides still first-line therapy for chronic suppurative otitis media? A systematic review and discussion of aminoglycosides versus quinolones. AB - OBJECTIVE: This systematic review aimed to establish that quinolones are as effective as aminoglycosides when used to treat chronic suppurative otitis media. METHOD: The review included good quality, randomised, controlled trials on human subjects, published in English, that compared topical aminoglycosides with topical quinolones for the treatment of chronic suppurative otitis media. RESULTS: Nine trials met the criteria. Two studies showed a higher clinical cure rate in the quinolone group (93 per cent vs 71 per cent, p = 0.04, and 76 per cent vs 52 per cent, p = 0.009). Four studies showed no statistically significant difference in clinical outcome. A significant difference in microbiological clearance in favour of quinolones was shown in two studies (88 per cent vs 30 per cent, p < 0.001, and 88 per cent vs 30 per cent, p < 0.001). CONCLUSION: Topical quinolones do not carry the same risk of ototoxicity as aminoglycosides. Furthermore, they are equal or more effective in treating chronic suppurative otitis media and when used as prophylaxis post-myringotomy. Topical quinolones should be considered a first-line treatment for these patients. PMID- 26584652 TI - Intra-rater reliability and diagnostic accuracy of a new vaginal dynamometer to measure pelvic floor muscle strength in women with urinary incontinence. AB - AIMS: The first choice treatment in urinary incontinence (UI) is rehabilitation of the pelvic floor in order to improve muscle strength. However, no entirely reliable instruments for quantifying pelvic floor muscle (PFM) strength are currently available. Our aim was to test the intra-rater reliability and diagnostic accuracy of a new vaginal dynamometer for measuring PFM strength. METHODS: Test-retest reliability study. One hundred and four women with stress urinary incontinence (SUI) were recruited. Patients were excluded if they had a history consistent with urge urinary incontinence or pelvic organ prolapse, pregnancy, previous urogynecological surgery, severe vaginal atrophy, or neurological conditions. The examination comprised digital palpation quantified by the modified Oxford scale and by two consecutive dynamometry measurements obtained using a new prototype dynamometer. This instrument comprises a speculum in which an inductive displacement sensor (LVDTSM210.10.2.KTmodel, Schreiber) is attached to a spring of known stiffness constant (k). The intraclass correlation coefficient (ICC) was calculated to assess intra-rater reliability. Diagnostic accuracy was assessed using Receiver Operating Characteristics (ROC) curves analysis. RESULTS: Of the 104 subjects included, 59.6% presented scores between 0 2 on the Oxford scale. Intra-rater reliability was 0.98 (95%CI: 0.97-0.99). In the Bland & Altman plot, the distribution of disagreements was similar in the lowest and the highest strength values. The diagnostic accuracy of the dynamometer with regard to digital palpation showed an area under the curve of 0.85 (95%CI: 0.77-0.93). CONCLUSIONS: Our results suggest that this new vaginal dynamometer is a reliable and valid instrument for quantifying PFM strength. Neurourol. Urodynam. 36:333-337, 2017. (c) 2015 Wiley Periodicals, Inc. PMID- 26584653 TI - Solar Electricity and Solar Fuels: Status and Perspectives in the Context of the Energy Transition. AB - The energy transition from fossil fuels to renewables is already ongoing, but it will be a long and difficult process because the energy system is a gigantic and complex machine. Key renewable energy production data show the remarkable growth of solar electricity technologies and indicate that crystalline silicon photovoltaics (PV) and wind turbines are the workhorses of the first wave of renewable energy deployment on the TW scale around the globe. The other PV alternatives (e.g., copper/indium/gallium/selenide (CIGS) or CdTe), along with other less mature options, are critically analyzed. As far as fuels are concerned, the situation is significantly more complex because making chemicals with sunshine is far more complicated than generating electric current. The prime solar artificial fuel is molecular hydrogen, which is characterized by an excellent combination of chemical and physical properties. The routes to make it from solar energy (photoelectrochemical cells (PEC), dye-sensitized photoelectrochemical cells (DSPEC), PV electrolyzers) and then synthetic liquid fuels are presented, with discussion on economic aspects. The interconversion between electricity and hydrogen, two energy carriers directly produced by sunlight, will be a key tool to distribute renewable energies with the highest flexibility. The discussion takes into account two concepts that are often overlooked: the energy return on investment (EROI) and the limited availability of natural resources-particularly minerals-which are needed to manufacture energy converters and storage devices on a multi-TW scale. PMID- 26584654 TI - Black Phosphorus (BP) Nanodots for Potential Biomedical Applications. AB - Recently, the appeal of 2D black phosphorus (BP) has been rising due to its unique optical and electronic properties with a tunable band gap (~0.3-1.5 eV). While numerous research efforts have recently been devoted to nano- and optoelectronic applications of BP, no attention has been paid to promising medical applications. In this article, the preparation of BP-nanodots of a few nm to <20 nm with an average diameter of ~10 nm and height of ~8.7 nm is reported by a modified ultrasonication-assisted solution method. Stable formation of nontoxic phosphates and phosphonates from BP crystals with exposure in water or air is observed. As for the BP-nanodot crystals' stability (ionization and persistence of fluorescent intensity) in aqueous solution, after 10 d, ~80% at 1.5 mg mL(-1) are degraded (i.e., ionized) in phosphate buffered saline. They showed no or little cytotoxic cell-viability effects in vitro involving blue- and green fluorescence cell imaging. Thus, BP-nanodots can be considered a promising agent for drug delivery or cellular tracking systems. PMID- 26584655 TI - Eradicating female genital mutilation and cutting in Tanzania: an observational study. AB - BACKGROUND: Female genital mutilation and cutting (FGM/C) has long been practiced in various parts of the world. The practice is still prevalent in 29 countries on the African continent despite decades of campaigning to eradicate it. The approaches for eradication have been multi-pronged, including but not limited to, health risk campaigns teaching about the health consequences for the girls and the women, recruitment of change agents from within the communities and the enforcement of legal mechanisms. The purpose of this study was to analyse the impact of an 18 month long campaign to eradicate or reduce FGM/C in a rural predominantly Masai community. METHODS: An observational study involving mixed methods, quantitative and qualitative was conducted in Arusha region, Tanzania. A household survey, key informant interviews, focus group discussions, school children's group discussions and project document reviews for both baseline and endline assessments were used. Same tools were used for both baseline and endline assessements. Comparison of baseline and endline findings and conclusions were drawn. RESULTS: The prevalence of self reported FGM/C at endline was 69.2 %. However, physical obstetric examination of women in labour revealed a prevalence of over 95 % FGM/C among women in labour. Those in favour of FGM/C eradication were 88 %. Nearly a third of the 100 FGM practitioners had denounced the practice; they also formed a peer group that met regularly comparing baseline and endline. Knowledge about FGM/C health risks increased from 16 to 30 % (p < 0.001). The practice is currently done secretly to an uncertain extent. CONCLUSION: This multifaceted educational campaign achieved moderate success in increasing knowledge of the health risks and changing attitudes despite a short period of intervention. However, its effectiveness in reducing FGM/C prevalence was uncertain. PMID- 26584656 TI - TiO2 scaffolds in peri-implant dehiscence defects: an experimental pilot study. AB - OBJECTIVES: The primary objective was to assess osseointegration of implants with dehiscence defects grafted with a TiO2 scaffold. The secondary objective was to assess the performance of the scaffold in terms of mechanical stability and bone fill. MATERIAL AND METHODS: Five minipigs had the mandibular premolars extracted. After healing, two dental implants (SLActive(r) , Institut Straumann AG, Basel, Switzerland) with associated semi-cylindrical dehiscence defects (O = 6 mm, height = 10 mm) were installed in each quadrant. The defects were grafted with test scaffolds (n = 10) or control autologous bone blocks (n = 10). After 3 months submerged healing, the pigs were euthanized and the sites analysed by microcomputed tomography and histology. RESULTS: Four minipigs were available for second stage surgery; (n = 9) experimental and (n = 7) control sites. The mean bone-to-implant contact on the defect side was 82% (+/-10%) and 79% (+/-11%) in the test and control groups respectively. The mean level of first bone-to-implant contact was more coronal on the defect side in the test group 3.2 mm (+/-0.4 mm) than in the control group 3.6 mm (+/-1.1 mm). The defect area occupied by bone within the extent of the scaffold varied, but averaged 37% (+/-14.6%) whereas the material itself occupied 7.4% (+/-3.5%). CONCLUSIONS: Within the limitations of the study, the results suggest that the novel synthetic scaffold material perform similar to the autologous bone block control with respect to implant osseointegration. The mechanical properties of the scaffold appeared sufficient to withstand clinical load in the present experimental model. PMID- 26584657 TI - Translocation and biokinetic behavior of nanoscaled europium oxide particles within 5 days following an acute inhalation in rats. AB - Nanoscaled europium oxide (Eu2O3) particles were inhaled by rats after acute exposure and the potential translocation of particles followed by chemical analysis and transmission electron microscopy (TEM) was investigated. An aqueous dispersion (phosphate buffer/bovine serum albumin) of a commercially available Eu2O3 particle fraction consisting partially of nanoscaled particles was aerosolized with pressurized air. After rapid evaporation, rats inhaled the dry aerosol for 6 h in a single exposure resulting in an alveolar calculated dose of approximately 39.5 MUg Eu2O3. Using chemical analysis, 36.8 MUg Eu2O3 was detected 1 h after lung inhalation. The amount declined slightly to 34.5 MUg after 1 day and 35.0 MUg after 5 days. The liver showed an increase of Eu2O3 from 32.3 ng 1 h up to 294 ng 5 days after inhalation. Additionally, lung-associated lymph nodes, thymus, kidneys, heart and testis exhibited an increase of europium over the period investigated. In the blood, the highest amount of europium was found 1 h after treatment whereas feces, urine and mesenteric lymph nodes revealed the highest amount 1 day after treatment. Using TEM analysis, particles could be detected only in lungs, and in the liver, no particles were detectable. In conclusion, the translocation of Eu2O3 within 5 days following inhalation could be determined very precisely by chemical analysis. A translocation of Eu2O3 particulate matter to liver was not detectable by TEM analysis; thus, the overproportional level of 0.8% of the lung load observed in the liver after 5 days suggests a filtering effect of dissolved europium with accumulation. PMID- 26584659 TI - Helping People with Mental Illness Return to Employment: Challenging Existing Beliefs. PMID- 26584658 TI - Plantar plate radiofrequency and Weil osteotomy for subtle metatarsophalangeal joint instablity. AB - BACKGROUND: To the present day, literature has only discussed how to treat extensive plantar plate and collateral ligament lesions, with gross joint subluxation and obvious clinical instability. The treatment options for early stages of the disease with minor injuries and subtle instabilities have not been described. The main purpose of this prospective study is to evaluate the efficacy of the combination of the arthroscopic radiofrequency shrinkage and distal Weil osteotomy in the treatment of subtle metatarsophalangeal joint instability. METHOD: Prospective data (clinical, radiological, and arthroscopic findings) of 19 patients, with a total of 35 slightly unstable joints, was collected. The physical examination defined the hypothesis for plantar plate lesions (grades 0 and 1), which was confirmed during the diagnostic step of the arthroscopic procedure. RESULTS: Among our patients, 73% were females and 63% reported wearing high heels. The average age was 59 years and post-operative follow-up was 20 months. In the initial sample frame, 62% of joints showed spread-out toes with increased interdigital spacing. The mean American Orthopedic Foot and Ankle Society score rose from 53 points pre-operatively to 92 points post-operatively and a visual-analog pain scale average value of eight points pre-operatively decreased to zero post-operatively. During the pre-operative evaluation, none of the patients had stable joints and over 97% were classified as having grade 1 instability (<50% subluxation). After treatment, 83% of the joints became stable (degree of instability 0) and over 97% were congruent. All studied parameters showed statistically significant improvements in the post-operative period (p < 0.001) showing the efficiency of the treatment in pain relief, while restoring the joint stability and congruity. CONCLUSION: Arthroscopic radiofrequency shrinkage in combination with distal Weil osteotomy promotes functional improvement, pain relief, and restores the joint stability in the plantar plate lesion grades 0 and 1. PMID- 26584660 TI - A Survey on Singaporean Women's Knowledge, Perception and Practices of Mammogram Screening. AB - INTRODUCTION: Singapore is the first Asian country to establish a nationwide breast screening programme, but our breast cancer screening uptake lags behind the Western countries. This survey focused on the subject of screening mammography, to assess the reasons for non-attendance and explore ways to improve our screening uptake. MATERIALS AND METHODS: Females >=21 years old were approached at primary healthcare clinics to participate in this survey, which questioned their knowledge, perception and expectations of breast screening. RESULTS: There were 1011 respondents. Of the 740 respondents >=40 years old, 332 respondents (45.5%) went for regular mammogram screening. Women who had lower household incomes [<$2000 (OR 0.49; 95% CI, 0.28 to 0.85); $2000 to $3999 (OR 0.59; 95% CI, 0.36 to 0.97)], did not know anyone with breast cancer (OR 0.62; 95% CI, 0.42 to 0.92), did not perform breast self-examination (OR 0.42; 95% CI, 0.28 to 0.62), had lower knowledge scores (OR 0.34; 95% CI 0.22 to 0.51), did not attend other health screening (OR 0.14; 95% CI, 0.05 to 0.41), and perceived mammography as embarrassing (OR 0.55; 95% CI, 0.31 to 0.96), were less likely to attend mammographic screening. Many did not know that screening is for the asymptomatic (51.2%), or the age to start screening (46.3%). Most respondents preferred to have their mammograms in the polyclinics (62.2%) and their screening reminders to be through short messaging service (SMS) (46.0%). CONCLUSION: Our results show the current influences on Singapore women's screening practices, and also revealed that their understanding of mammogram screening is limited despite a high level of breast cancer awareness. PMID- 26584661 TI - Health Screening Behaviour among Singaporeans. AB - INTRODUCTION: This study assessed the health screening behaviour of Singaporeans and evaluated factors associated with low uptake of screening tests. MATERIALS AND METHODS: Data from the 2010 National Health Survey, which was conducted on Singapore citizens and permanent residents, was used in this analysis. Multivariate Cox regression was used to evaluate the relationship between sociodemographics and health screening behaviour for selected chronic diseases (hypertension, diabetes and hypercholesterolaemia) and cancers (cervical, breast and colorectal). National recommendations for age at which screening should be initiated and appropriate screening interval were used to define appropriate screening behaviour. RESULTS: More respondents have had their last chronic disease screening done within the recommended time period compared to cancer screening. A total of 77.8%, 63.4% and 54.9% of the respondents had their last hypertension, diabetes and hypercholesterolaemia done within the recommended time period respectively, while less than 50% of the respondents had their cervical (45.8%), breast (32.9%) and colorectal (20.2%) cancer screenings done within the recommended time period. Respondents with higher household income or more years of education were more likely to have undergone screening within the recommended time period. Indians, who are at higher risk of chronic diseases such as diabetes and hypercholesterolaemia, were also more likely to have been screened. A total of 69.9% and 79.5% of the respondents with previously undiagnosed diabetes and hypertension had reported to have done diabetes and hypertension screenings respectively, within the recommended time period. CONCLUSION: Sociodemographic factors that could be associated with a lower uptake of screening tests include: 1) low household income, 2) low education level, and 3) Malay ethnicity. Health promotion programmes and outreach to these groups can be enhanced to further improve screening uptake. PMID- 26584662 TI - Clinical Decision Rules for Paediatric Minor Head Injury: Are CT Scans a Necessary Evil? AB - INTRODUCTION: High performing clinical decision rules (CDRs) have been derived to predict which head-injured child requires a computed tomography (CT) of the brain. We set out to evaluate the performance of these rules in the Singapore population. MATERIALS AND METHODS: This is a prospective observational cohort study of children aged less than 16 who presented to the emergency department (ED) from April 2014 to June 2014 with a history of head injury. Predictor variables used in the Canadian Assessment of Tomography for Childhood Head Injury (CATCH), Children's Head Injury Algorithm for the Prediction of Important Clinical Events (CHALICE) and Pediatric Emergency Care Applied Research Network (PECARN) CDRs were collected. Decisions on CT imaging and disposition were made at the physician's discretion. The performance of the CDRs were assessed and compared to current practices. RESULTS: A total of 1179 children were included in this study. Twelve (1%) CT scans were ordered; 6 (0.5%) of them had positive findings. The application of the CDRs would have resulted in a significant increase in the number of children being subjected to CT (as follows): CATCH 237 (20.1%), CHALICE 282 (23.9%), PECARN high- and intermediate-risk 456 (38.7%), PECARN high-risk only 45 (3.8%). The CDRs demonstrated sensitivities of: CATCH 100% (54.1 to 100), CHALICE 83.3% (35.9 to 99.6), PECARN 100% (54.1 to 100), and specificities of: CATCH 80.3% (77.9 to 82.5), CHALICE 76.4% (73.8 to 78.8), PECARN high- and intermediate-risk 61.6% (58.8 to 64.4) and PECARN high-risk only 96.7% (95.5 to 97.6). CONCLUSION: The CDRs demonstrated high accuracy in detecting children with positive CT findings but direct application in areas with low rates of significant traumatic brain injury (TBI) is likely to increase unnecessary CT scans ordered. Clinical observation in most cases may be a better alternative. PMID- 26584663 TI - Hyperfamiliarity in Dementia and Mild Cognitive Impairment. AB - INTRODUCTION: Hyperfamiliarity, a phenomenon in which feelings of familiarity are evoked by novel stimuli, is well described in epilepsy and the lesioned brain. Abnormality of familiarity in Alzheimer's disease (AD) and mild cognitive impairment (MCI) have also been described in the literature, but more from a neuropsychological approach perspective. Currently, there is a lack of study on the real-life experience of familiarity abnormality in dementia and MCI. Our aim was to compare the occurrence of hyperfamiliarity among dementia and MCI. MATERIALS AND METHODS: We recruited 73 participants, 29 with AD, 10 with vascular dementia, 7 with MCI and 27 healthy controls, and administered a questionnaire to assess hyperfamiliarity frequency. RESULTS: Hyperfamiliarity was observed in real life in cognitive impairment, but was unrelated to its severity or underlying aetiology. CONCLUSION: This study highlights the similar rate of occurrence of hyperfamiliarity in the daily life of individuals with cognitive impairment. Future research should examine neuropsychological correlations and mechanisms that contribute to such observations. PMID- 26584664 TI - Localising Median Neuropathies: The Role of Different Investigations. PMID- 26584665 TI - 22nd Gordon Arthur Ransome Oration: Is Medicine Still an Art? PMID- 26584667 TI - Correction: Rosa canina L.--new possibilities for an old medicinal herb. AB - Correction for 'Rosa canina L. - new possibilities for an old medicinal herb' by Jelena Zivkovic et al., Food Funct., 2015, DOI: 10.1039/c5fo00820d. PMID- 26584668 TI - Photodissociation of medium-sized argon cluster cations in the visible region. AB - Semiclassical methods for non-adiabatic dynamics simulations, based on a semiempirical diatomics-in-molecules model of intracluster interactions and the mean-field dynamical approach with the inclusion of quantum decoherence, have been used to study the photodissociation of argon cluster cations, Ar(N)(+)(N = 6 19), at E(phot) = 2.35 eV. Time periods upto t = 200 ps have been considered and abundance of ionic and neutral fragments, their time evolution and stability have been investigated and compared with available experimental data as well as earlier theoretical studies. A good agreement has been achieved between our predictions and the experimental data and deviations from earlier dynamical calculations are discussed. PMID- 26584666 TI - CD4 count-based failure criteria combined with viral load monitoring may trigger worse switch decisions than viral load monitoring alone. AB - OBJECTIVE: CD4 count decline often triggers antiretroviral regimen switches in resource-limited settings, even when viral load testing is available. We therefore compared CD4 failure and CD4 trends in patients with viraemia with or without antiretroviral resistance. METHODS: Retrospective cohort study investigating the association of HIV drug resistance with CD4 failure or CD4 trends in patients on first-line antiretroviral regimens during viraemia. Patients with viraemia (HIV RNA >1000 copies/ml) from two HIV treatment programmes in South Africa (n = 350) were included. We investigated the association of M184V and NNRTI resistance with WHO immunological failure criteria and CD4 count trends, using chi-square tests and linear mixed models. RESULTS: Fewer patients with the M184V mutation reached immunologic failure criteria than those without: 51 of 151(34%) vs. 90 of 199 (45%) (P = 0.03). Similarly, 79 of 220 (36%) patients, who had major NNRTI resistance, had immunological failure, whereas 62 of 130 (48%) without (chi-square P = 0.03) did. The CD4 count decline among patients with the M184V mutation was 2.5 cells/mm(3) /year, whereas in those without M184V it was 14 cells/mm(3) /year (P = 0.1), but the difference in CD4 count decline with and without NNRTI resistance was marginal. CONCLUSION: Our data suggest that CD4 count monitoring may lead to inappropriate delayed therapy switches for patients with HIV drug resistance. Conversely, patients with viraemia but no drug resistance are more likely to have a CD4 count decline and thus may be more likely to be switched to a second-line regimen. PMID- 26584669 TI - An anthrax toxin variant with an improved activity in tumor targeting. AB - Anthrax lethal toxin (LT) is an A-B type toxin secreted by Bacillus anthracis, consisting of the cellular binding moiety, protective antigen (PA), and the catalytic moiety, lethal factor (LF). To target cells, PA binds to cell-surface receptors and is then proteolytically processed forming a LF-binding competent PA oligomer where each LF binding site is comprised of three subsites on two adjacent PA monomers. We previously generated PA-U2-R200A, a urokinase-activated PA variant with LF-binding subsite II residue Arg200 mutated to Ala, and PA-L1 I210A, a matrix metalloproteinase-activated PA variant with subsite III residue Ile210 mutated to Ala. PA-U2-R200A and PA-L1-I210A displayed reduced cytotoxicity when used singly. However, when combined, they formed LF-binding competent heterogeneous oligomers by intermolecular complementation, and achieved high specificity in tumor targeting. Nevertheless, each of these proteins, in particular PA-L1-I210A, retained residual LF-binding ability. In this work, we screened a library containing all possible amino acid substitutions for LF binding site to find variants with activity strictly dependent upon intermolecular complementation. PA-I207R was identified as an excellent replacement for the original clockwise-side variant, PA-I210A. Consequently, the new combination of PA-L1-I207R and PA-U2-R200A showed potent anti-tumor activity and low toxicity, exceeding the performance of the original combination, and warranting further investigation. PMID- 26584670 TI - Self-regulation of charged defect compensation and formation energy pinning in semiconductors. AB - Current theoretical analyses of defect properties without solving the detailed balance equations often estimate Fermi-level pinning position by omitting free carriers and assume defect concentrations can be always tuned by atomic chemical potentials. This could be misleading in some circumstance. Here we clarify that: (1) Because the Fermi-level pinning is determined not only by defect states but also by free carriers from band-edge states, band-edge states should be treated explicitly in the same footing as the defect states in practice; (2) defect formation energy, thus defect density, could be pinned and independent on atomic chemical potentials due to the entanglement of atomic chemical potentials and Fermi energy, in contrast to the usual expectation that defect formation energy can always be tuned by varying the atomic chemical potentials; and (3) the charged defect compensation behavior, i.e., most of donors are compensated by acceptors or vice versa, is self-regulated when defect formation energies are pinned. The last two phenomena are more dominant in wide-gap semiconductors or when the defect formation energies are small. Using NaCl and CH3NH3PbI3 as examples, we illustrate these unexpected behaviors. Our analysis thus provides new insights that enrich the understanding of the defect physics in semiconductors and insulators. PMID- 26584671 TI - First-principles study of the effect of functional groups on polyaniline backbone. AB - We present a first-principles density functional theory study focused on how the chemical and electronic properties of polyaniline are adjusted by introducing suitable substituents on a polymer backbone. Analyses of the obtained energy barriers, reaction energies and minimum energy paths indicate that the chemical reactivity of the polyaniline derivatives is significantly enhanced by protonic acid doping of the substituted materials. Further study of the density of states at the Fermi level, band gap, HOMO and LUMO shows that both the unprotonated and protonated states of these polyanilines are altered to different degrees depending on the functional group. We also note that changes in both the chemical and electronic properties are very sensitive to the polarity and size of the functional group. It is worth noting that these changes do not substantially alter the inherent chemical and electronic properties of polyaniline. Our results demonstrate that introducing different functional groups on a polymer backbone is an effective approach to obtain tailored conductive polymers with desirable properties while retaining their intrinsic properties, such as conductivity. PMID- 26584672 TI - Dairy goat kids fed liquid diets in substitution of goat milk and slaughtered at different ages: an economic viability analysis using Monte Carlo techniques. AB - The aim of this study was to analyze the economic viability of producing dairy goat kids fed liquid diets in alternative of goat milk and slaughtered at two different ages. Forty-eight male newborn Saanen and Alpine kids were selected and allocated to four groups using a completely randomized factorial design: goat milk (GM), cow milk (CM), commercial milk replacer (CMR) and fermented cow colostrum (FC). Each group was then divided into two groups: slaughter at 60 and 90 days of age. The animals received Tifton hay and concentrate ad libitum. The values of total costs of liquid and solid feed plus labor, income and average gross margin were calculated. The data were then analyzed using the Monte Carlo techniques with the @Risk 5.5 software, with 1000 iterations of the variables being studied through the model. The kids fed GM and CMR generated negative profitability values when slaughtered at 60 days (US$ -16.4 and US$ -2.17, respectively) and also at 90 days (US$ -30.8 and US$ -0.18, respectively). The risk analysis showed that there is a 98% probability that profitability would be negative when GM is used. In this regard, CM and FC presented low risk when the kids were slaughtered at 60 days (8.5% and 21.2%, respectively) and an even lower risk when animals were slaughtered at 90 days (5.2% and 3.8%, respectively). The kids fed CM and slaughtered at 90 days presented the highest average gross income (US$ 67.88) and also average gross margin (US$ 18.43/animal). For the 60-day rearing regime to be economically viable, the CMR cost should not exceed 11.47% of the animal-selling price. This implies that the replacer cannot cost more than US$ 0.39 and 0.43/kg for the 60- and 90-day feeding regimes, respectively. The sensitivity analysis showed that the variables with the greatest impact on the final model's results were animal selling price, liquid diet cost, final weight at slaughter and labor. In conclusion, the production of male dairy goat kids can be economically viable when the kids diet consists mainly of either cow milk or fermented colostrum, especially when kids are slaughtered at 90 days of age. PMID- 26584673 TI - Capacity of AIDS service organisations in Connecticut to respond to intimate partner violence. AB - Although intimate partner violence (IPV) is prevalent among women living with HIV and negatively impacts their health, few studies have examined the ability of AIDS service organisations (ASOs) to address IPV. This study used a qualitative approach to identify facilitators of and barriers to addressing IPV in female clients of ASOs in the United States. In-depth interviews were conducted between March and August 2011 with 20 ASO staff members and 19 female clients who reported a current or past history of IPV. Interviews were audio recorded, transcribed and analysed using the constant comparative method. These data identify barriers to addressing IPV at the organisation, provider and client levels, and include suggestions from both clients and providers about improving access to care. Client and provider suggestions differed in some areas. While providers emphasised structural changes such as increased training on IPV provided by their organisation, clients highlighted the importance of trusting personal relationships with staff to increase client disclosure of IPV experiences. Given the differing opinions of clients and staff, ASOs should consider involving women with histories of IPV in the process of programme and policy development. ASOs have the unique opportunity to provide comprehensive and holistic care by addressing IPV. The extent to which ASOs are able to recognise and address IPV and strategies for increasing this ability warrant greater attention from funders, ASO administrators and researchers. PMID- 26584674 TI - Synthesis of Extended Atomically Perfect Zigzag Graphene - Boron Nitride Interfaces. AB - The combination of several materials into heterostructures is a powerful method for controlling material properties. The integration of graphene (G) with hexagonal boron nitride (BN) in particular has been heralded as a way to engineer the graphene band structure and implement spin- and valleytronics in 2D materials. Despite recent efforts, fabrication methods for well-defined G-BN structures on a large scale are still lacking. We report on a new method for producing atomically well-defined G-BN structures on an unprecedented length scale by exploiting the interaction of G and BN edges with a Ni(111) surface as well as each other. PMID- 26584675 TI - Conjugation between sigma- and pi-Aromaticity in 1-C-Arylated Monocarba-closo dodecaborate Anions. AB - Conjugation between sigma- and pi-aromatic moieties in 1-C-arylated monocarba closo-dodecaborate anion derivatives 2 has been identified by means of kinetic experimental studies combined with theoretical calculations. We found that the reaction rate of iodination at the 12-B vertex of the carborane anion cage was affected by distal substituents on the benzene ring connected at the antipodal carbon vertex. Hammett and Yukawa-Tsuno plots indicated that substantial resonance effects are involved. Density functional theory calculations enabled detailed interpretation of the electronic interaction. PMID- 26584676 TI - Imaging thermal conductivity with nanoscale resolution using a scanning spin probe. AB - The ability to probe nanoscale heat flow in a material is often limited by lack of spatial resolution. Here, we use a diamond-nanocrystal-hosted nitrogen-vacancy centre attached to the apex of a silicon thermal tip as a local temperature sensor. We apply an electrical current to heat up the tip and rely on the nitrogen vacancy to monitor the thermal changes the tip experiences as it is brought into contact with surfaces of varying thermal conductivity. By combining atomic force and confocal microscopy, we image phantom microstructures with nanoscale resolution, and attain excellent agreement between the thermal conductivity and topographic maps. The small mass and high thermal conductivity of the diamond host make the time response of our technique short, which we demonstrate by monitoring the tip temperature upon application of a heat pulse. Our approach promises multiple applications, from the investigation of phonon dynamics in nanostructures to the characterization of heterogeneous phase transitions and chemical reactions in various solid-state systems. PMID- 26584678 TI - Silicon quantum dots: fine-tuning to maturity. AB - Quantum dots in semiconductor heterostructures provide one of the most flexible platforms for the study of quantum phenomena at the nanoscale. The surging interest in using quantum dots for quantum computation is forcing researchers to rethink fabrication and operation methods, to obtain highly tunable dots in spin free host materials, such as silicon. Borselli and colleagues report in Nanotechnology the fabrication of a novel Si/SiGe double quantum dot device, which combines an ultra-low disorder Si/SiGe accumulation-mode heterostructure with a stack of overlapping control gates, ensuring tight confining potentials and exquisite tunability. This work signals the technological maturity of silicon quantum dots, and their readiness to be applied to challenging projects in quantum information science. PMID- 26584677 TI - Navigational choice between reversal and curve during acidic pH avoidance behavior in Caenorhabditis elegans. AB - BACKGROUND: Under experimental conditions, virtually all behaviors of Caenorhabditis elegans are achieved by combinations of simple locomotion, including forward, reversal movement, turning by deep body bending, and gradual shallow turning. To study how worms regulate these locomotion in response to sensory information, acidic pH avoidance behavior was analyzed by using worm tracking system. RESULTS: In the acidic pH avoidance, we characterized two types of behavioral maneuvers that have similar behavioral sequences in chemotaxis and thermotaxis. A stereotypic reversal-turn-forward sequence of reversal avoidance caused an abrupt random reorientation, and a shallow gradual turn in curve avoidance caused non-random reorientation in a less acidic direction to avoid the acidic pH. Our results suggest that these two maneuvers were each triggered by a distinct threshold pH. A simulation study using the two-distinct-threshold model reproduced the avoidance behavior of the real worm, supporting the presence of the threshold. Threshold pH for both reversal and curve avoidance was altered in mutants with reduced or enhanced glutamatergic signaling from acid-sensing neurons. CONCLUSIONS: C. elegans employ two behavioral maneuvers, reversal (klinokinesis) and curve (klinotaxis) to avoid acidic pH. Unlike the chemotaxis in C. elegans, reversal and curve avoidances were triggered by absolute pH rather than temporal derivative of stimulus concentration in this behavior. The pH threshold is different between reversal and curve avoidance. Mutant studies suggested that the difference results from a differential amount of glutamate released from ASH and ASK chemosensory neurons. PMID- 26584679 TI - Electrochemical gating-induced reversible and drastic resistance switching in VO2 nanowires. AB - Reversible and drastic modulation of the transport properties in vanadium dioxide (VO2) nanowires by electric field-induced hydrogenation at room temperature was demonstrated using the nanogaps separated by humid air in field-effect transistors with planer-type gates (PG-FET). These PG-FETs allowed us to investigate behavior of revealed hydrogen intercalation and diffusion aspects with time and spatial evolutions in nanowires. These results show that air nanogaps can operate as an electrochemical reaction field, even in a gaseous atmosphere, and offer new directions to explore emerging functions for electronic and energy devices in oxides. PMID- 26584680 TI - Palladium-Catalyzed alpha-Arylation of Aryl Nitromethanes. AB - Catalytic conditions for the alpha-arylation of aryl nitromethanes have been discovered using parallel microscale experimentation, despite two prior reports of the lack of reactivity of these aryl nitromethane precursors. The method efficiently provides a variety of substituted, isolable diaryl nitromethanes. In addition, it is possible to sequentially append two different aryl groups to nitromethane. Mild oxidation conditions were identified to afford the corresponding benzophenones via the Nef reaction, and reduction conditions were optimized to afford several diaryl methylamines. PMID- 26584681 TI - Clinicopathological values of NBS1 and DNA damage response genes in epithelial ovarian cancers. AB - Epithelial ovarian cancers (EOCs) are highly lethal gynecological malignancies with a high recurrence rate. Therefore, developing prognostic markers for recurrence after chemotherapy is crucial for the treatment of ovarian cancers. As ovarian cancers frequently respond to DNA-damaging agents, we assessed the clinicopathological significance of key double-strand DNA break (DSB) repair genes, including BRCA1, BRCA2, BARD1, ATM, RAD51 and NBS1 in EOC cell lines and paraffin-embedded tissue sections from 140 EOC patients treated with cytoreductive surgery, followed by platinum-based chemotherapy. These samples were analyzed for the clinicopathological impact of DSB genes by western blot analysis, immunohistochemistry and quantitative real-time PCR. Of the DSB repair genes, BRCA1, ATM and NBS1, which are involved in the homologous recombination mediated repair pathway, were related to aggressive parameters in EOC. When survival analysis was performed, NBS1 expression exhibited an association with EOC recurrence. Specifically, increased NBS1 expression was found in 107 out of 140 cases (76.0%) and correlated with advanced stage (P=0.001), high grade (P=0.001) and serous histology (P=0.008). The median recurrence-free survival in patients with positive and negative expression of NBS1 was 30 and 78 months, respectively (P=0.0068). In multivariate analysis, NBS1 was an independent prognostic factor for the recurrence of EOC. Together, these results suggest that NBS1 is a marker of poor prognosis for the recurrence of EOC and is associated with aggressive clinicopathological parameters. PMID- 26584683 TI - 'We are looked down upon and rejected socially': a qualitative study on the experiences of trafficking survivors in Nepal. AB - BACKGROUND: The successful reintegration of sexual trafficking survivors into Nepalese society is challenging. This paper aims to explore the trafficking process, abuses faced during sexual slavery,and the challenges faced by women and girl survivors for successful reintegration. METHOD: This exploratory study used qualitative methods to identify that poverty, illiteracy, lack of opportunities, and varied social stigma initiate the victimization process, and continuity of this vicious circle increases the risk for (re)entrapment. RESULT: The reasons for sexual trafficking have also become the reasons for restricting survivors from opportunities for growth and mainstreaming. CONCLUSION: Non-existent support systems, detachment from familial ties, being outcast by society, and an uncertain livelihood make reintegration difficult for survivors. PMID- 26584684 TI - An update on clinical applications of magnetic nanoparticles for increasing the resolution of magnetic resonance imaging. AB - Today, technologies based on magnetic nanoparticles (MNPs) are regularly applied to biological systems with diagnostic or therapeutic aims. Nanoparticles made of the elements iron (Fe), gadolinium (Gd) or manganese (Mn) are generally used in many diagnostic applications performed under magnetic resonance imaging (MRI). Similar to molecular-based contrast agents, nanoparticles can be used to increase the resolution of imaging while offering well biocompatibility, poisonousness and biodistribution. Application of MNPs enhanced MRI sensitivity due to the accumulation of iron in the liver caused by discriminating action of the hepatobiliary system. The aim of this study is about the use, properties and advantages of MNPs in MRI. PMID- 26584682 TI - Electrical effects of stem cell transplantation for ischaemic cardiomyopathy: friend or foe? AB - Despite advances in other realms of cardiac care, the mortality attributable to ischaemic cardiomyopathy has only marginally decreased over the last 10 years. These findings highlight the growing realization that current pharmacological and device therapies rarely reverse disease progression and rationalize a focus on novel means to reverse, repair and re-vascularize damaged hearts. As such, multiple candidate cell types have been used to regenerate damaged hearts either directly (through differentiation to form new tissue) or indirectly (via paracrine effects). Emerging literature suggests that robust engraftment of electrophysiolgically heterogeneous tissue from transplanted cells comes at the cost of a high incidence of ventricular arrhythmias. Similar electrophysiological studies of haematological stem cells raised early concerns that transplant of depolarized, inexcitable cells that also induce paracrine-mediated electrophysiological remodelling may be pro-arrhythmic. However, meta-analyses suggest that patients receiving haematological stem cells paradoxically may experience a decrease in ventricular arrhythmias, an observation potentially related to the extremely poor long-term survival of injected cells. Finally, early clinical and preclinical data from technologies capable of differentiating to a mature cardiomyocyte phenotype (such as cardiac-derived stem cells) suggests that these cells are not pro-arrhythmic although they too lack robust long-term engraftment. These results highlight the growing understanding that as next generation cell therapies are developed, emphasis should also be placed on understanding possible anti-arrhythmic contributions of transplanted cells while vigilance is needed to predict and treat the inadvertent effects of regenerative cell therapies on the electrophysiological stability of the ischaemic cardiomyopathic heart. PMID- 26584685 TI - Assortative mixing as a source of bias in epidemiological studies of sexually transmitted infections: the case of smoking and human papillomavirus. AB - For studies examining risk factors of sexually transmitted infections (STIs), confounding can stem from characteristics of partners of study subjects, and persist after adjustment for the subjects' individual-level characteristics. Two conditions that can result in confounding by the subjects' partners are: (C1) partner choice is assortative by the risk factor examined and, (C2) sexual activity is associated with the risk factor. The objective of this paper is to illustrate the potential impact of the assortativity bias in studies examining STI risk factors, using smoking and human papillomavirus (HPV) as an example. We developed an HPV transmission-dynamic mathematical model in which we nested a cross-sectional study assessing the smoking-HPV association. In our base case, we assumed (1) no effect of smoking on HPV, and (2) conditions C1-C2 hold for smoking (based on empirical data). The assortativity bias caused an overestimation of the odds ratio (OR) in the simulated study after perfect adjustment for the subjects' individual-level characteristics (adjusted OR 1.51 instead of 1.00). The bias was amplified by a lower basic reproductive number (R 0), greater mixing assortativity and stronger association of smoking with sexual activity. Adjustment for characteristics of partners is needed to mitigate assortativity bias. PMID- 26584687 TI - The 'Toronto Meatoplasty' revisited. PMID- 26584688 TI - Association of the methylenetetrahydrofolate reductase gene C677T polymorphism with the risk of male infertility: a meta-analysis. AB - Several molecular epidemiological studies have been conducted to examine the association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and male infertility susceptibility, but the results remain inconclusive. To derive a more precise estimation of the relationship, a meta analysis was performed. In this meta-analysis, a total of 26 case-control studies including 5659 infertility cases and 5528 controls were selected to evaluate the possible association. The pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were used to assess the strength of association of C677T polymorphism with male infertility in the additive model, dominant model, recessive model and allele-frequency genetic model. In the overall analysis, the frequency of the 677T allele was significantly associated with male infertility susceptibility (OR = 2.32, 95%CI = 2.04-2.65 for TT vs. CC genotype; OR = 1.09, 95%CI = 1.00-1.19 for CT vs. CC genotype; OR = 1.19, 95%CI = 1.10-1.29 for CT/TT vs. CC genotype; OR = 1.54, 95%CI = 1.36-1.74 for TT vs. CC/TT genotype; OR = 1.22, 95%CI = 1.15 1.30 for T vs. C allele). A subgroup analysis of the subjects showed that significantly strong association between MTHFR C677T polymorphism and male infertility was present only in Asians, but not in Caucasians. Additionally, MTHFR C677T was associated with a significant increase in the risk of azoospermia in all genetic models. Meanwhile, no significantly increased risks of oligoasthenotertozoospermia (OAT) were found in most of the genetic models. In conclusion, this meta-analysis is in favor that the MTHFR C677T polymorphism is capable of causing male infertility susceptibility, especially in Asians and the subgroup of azoospermia. PMID- 26584686 TI - Facilitated long chain fatty acid uptake by adipocytes remains upregulated relative to BMI for more than a year after major bariatric surgical weight loss. AB - OBJECTIVE: This study examined whether changes in adipocyte long chain fatty acid (LCFA) uptake kinetics explain the weight regain increasingly observed following bariatric surgery. METHODS: Three groups (10 patients each) were studied: patients without obesity (NO: BMI 24.2 +/- 2.3 kg m(-2) ); patients with obesity (O: BMI 49.8 +/- 11.9); and patients classified as super-obese (SO: BMI 62.6 +/- 2.8). NO patients underwent omental and subcutaneous fat biopsies during clinically indicated abdominal surgeries; O were biopsied during bariatric surgery, and SO during both a sleeve gastrectomy and at another bariatric operation 16 +/- 2 months later, after losing 113 +/- 13 lbs. Adipocyte sizes and [(3) H]-LCFA uptake kinetics were determined in all biopsies. RESULTS: Vmax for facilitated LCFA uptake by omental adipocytes increased exponentially from 5.1 +/ 0.95 to 21.3 +/- 3.20 to 68.7 +/- 9.45 pmol/sec/50,000 cells in NO, O, and SO patients, respectively, correlating with BMI (r = 0.99, P < 0.001). Subcutaneous results were virtually identical. By the second operation, the mean BMI (SO patients) fell significantly (P < 0.01) to 44.4 +/- 2.4 kg m(-2) , similar to the O group. However, Vmax (40.6 +/- 11.5) in this weight-reduced group remained ~2X that predicted from the BMI:Vmax regression among NO, O, and SO patients. CONCLUSIONS: Facilitated adipocyte LCFA uptake remains significantly upregulated >=1 year after bariatric surgery, possibly contributing to weight regain. PMID- 26584689 TI - Cost-effectiveness of rituximab in addition to fludarabine and cyclophosphamide (R-FC) for the first-line treatment of chronic lymphocytic leukemia. AB - The cost-effectiveness of rituximab in combination with fludarabine/cyclophosphamide (R-FC) for the first line treatment of chronic lymphocytic leukemia (CLL) was evaluated. Based on long-term clinical data (follow-up of 5.9 years) from the CLL8-trial, a Markov-model with three health states (Free from disease progression, Progressive disease, Death) was used to evaluate the cost per quality-adjusted life-year (QALY) and cost per life years gained (LYG) of R-FC from the perspective of the German statutory health insurance (SHI). The addition of rituximab to FC chemotherapy results in a gain of 1.1 quality-adjusted life-years. The incremental cost-effectiveness ratio (ICER) of R-FC compared with FC was ?17,979 per QALY (?15,773 per LYG). Results were robust in deterministic and probabilistic sensitivity analyses. From the German SHI perspective, rituximab in combination with FC chemotherapy represents good value for first-line treatment of patients with CLL and compares favorably with chemotherapy alone. PMID- 26584690 TI - Taxonomic identity determines N2 fixation by canopy trees across lowland tropical forests. AB - Legumes capable of fixing atmospheric N2 are abundant and diverse in many tropical forests, but the factors determining ecological patterns in fixation are unresolved. A long-standing idea is that fixation depends on soil nutrients (N, P or Mo), but recent evidence shows that fixation may also differ among N2-fixing species. We sampled canopy-height trees across five species and one species group of N2-fixers along a landscape P gradient, and manipulated P and Mo to seedlings in a shadehouse. Our results identify taxonomy as the major determinant of fixation, with P (and possibly Mo) only influencing fixation following tree-fall disturbances. While 44% of trees did not fix N2, other trees fixed at high rates, with two species functioning as superfixers across the landscape. Our results raise the possibility that fixation is determined by biodiversity, evolutionary history and species-specific traits (tree growth rate, canopy stature and response to disturbance) in the tropical biome. PMID- 26584691 TI - Can personality close the intention-behavior gap for healthy eating? An examination with the HEXACO personality traits. AB - The aim of this study was to investigate the predictive and moderating effects of HEXACO personality factors, in addition to theory of planned behavior (TPB) variables, on fruit and vegetable consumption. American college students (N = 1036) from 24 institutions were administered the TPB, HEXACO and a self-reported fruit and vegetable consumption measure. The TPB predicted 11-17% of variance in fruit and vegetable consumption, with greater variance accounted for in healthy weight compared to overweight individuals. Personality did not significantly improve the prediction of behavior above TPB constructs; however, conscientiousness was a significant incremental predictor of intention in both healthy weight and overweight/obese groups. While support was found for the TPB as an important predictor of fruit and vegetable consumption in students, little support was found for personality factors. Such findings have implications for interventions designed to target students at risk of chronic disease. PMID- 26584692 TI - Intralesional Candida Antigen Immunotherapy for the Treatment of Recalcitrant and Multiple Warts in Children. AB - BACKGROUND: Intralesional injection of Candida antigen appears to be an effective alternative for the treatment of warts. AIM: To determine the efficacy and safety of this treatment. METHODS: We retrospectively reviewed records of all children who received intralesional injection of Candida antigen at our center from January 2008 to July 2013. RESULTS: From a total of 220 patients, 156 (70.9%) had a complete response, 37 (16.8%) had a partial response, and 27 (12.2%) had no improvement. An average of 2.73 treatments was needed. Forty-seven of the patients with more than one wart (21.3%) also noted at least partial resolution of untreated warts at distant sites. Twenty-seven of the 47 patients (57.4%) had complete resolution. All treated patients experienced some discomfort at the time of the injection, but no serious side effects were reported. DISCUSSION: We report our results using this approach in a large group of children. CONCLUSION: Intralesional injection of Candida antigen is an effective and safe therapy for children with multiple and recalcitrant cutaneous warts. PMID- 26584693 TI - Scanning Electron Microscopic Hair Shaft Analysis in Ectodermal Dysplasia Syndromes. AB - OBJECTIVES: The objective of the current study was to catalog hair shaft abnormalities in individuals with ectodermal dysplasia (ED) syndromes using scanning electron microscopy (SEM) and to compare the findings with those in unaffected controls. This is the second of a two-part study, the first of which used light microscopy as the modality and was previously published. METHODS: Scanning electron microscopy was performed in a blinded manner on hair shafts from 65 subjects with seven types of ED syndromes and 41 unaffected control subjects. Assessment was performed along the length of the shaft and in cross section. SETTING: Hair donations were collected at the 28th Annual National Family Conference held by the National Foundation for Ectodermal Dysplasia. Control subjects were recruited from a private dermatology practice and an academic children's hospital outpatient dermatology clinic. RESULTS: SEM identified various pathologic hair shaft abnormalities in each type of ED and in control patients. When hairs with all types of ED were grouped together and compared with those of control patients, the difference in the presence of small diameter and shallow and deep grooves was statistically significant (p < 0.05). When the EDs were separated according to subtype, statistically significant findings were also seen. CONCLUSION: SEM is a possible adjuvant tool in the diagnosis of ED syndromes. There are significant differences, with high specificity, between the hairs of individuals with ED and those of control subjects and between subtypes. PMID- 26584694 TI - Swollen Ears and Nose Bleeding Accompanied by Skin Papules. PMID- 26584695 TI - Developmental Delays, Fragile Hair, and Ichthyosis Since Infancy. PMID- 26584696 TI - Pediatric Dermatology Photoquiz: Localized Targetoid Plaques in a Teenager. PMID- 26584697 TI - Reticulate Pigmentation with Systemic Manifestations in a Child. PMID- 26584698 TI - Introducing: Pediatric Dermatology Procedures and Pearls. PMID- 26584699 TI - Phototherapy for Vitiligo: Skin Phototypes are Important. PMID- 26584700 TI - Varicella Within a Prior Immunization Reaction Site is Not a Wolf's Isotopic Response. PMID- 26584701 TI - Onychoheterotopia Due to a Traumatically Transplanted Nail in a Child. AB - Onychoheterotopia is a rare condition characterized by ectopic nail tissue growth. It is a digital mass that is commonly misdiagnosed. We describe a 6-year old girl who presented with onychoheterotopia after trauma to the digit. Her onychoheterotopia was incorrectly diagnosed as a common wart. It is important to include onychoheterotopia in the differential diagnosis of digital masses, especially in the setting of previous traumatic injury. PMID- 26584702 TI - Febrile Ulceronecrotic Mucha-Habermann Disease: Two Cases with Excellent Response to Methotrexate. AB - Febrile ulceronecrotic Mucha-Habermann disease (FUMHD), a severe form of pityriasis lichenoides et varioliformis acuta (PLEVA), featuring large, ulcerative, necrotic skin plaques, high fever, and other systemic symptoms, is a rare disorder of unknown etiology. No randomized controlled trials have established treatment guidelines and multiple modalities are often employed, making it difficult to assess the efficacy of any single agent. We report two cases of this condition in which treatment with methotrexate plus antibiotic treatment for superinfection led to rapid improvement. PMID- 26584703 TI - Patient Perspectives: What is acne and why do I have pimples? PMID- 26584704 TI - Patient Perspectives: What are infantile hemangiomas? PMID- 26584705 TI - Patient Perspectives: Moles and melanoma in children and teens. PMID- 26584706 TI - Patient Perspectives: Warts (verruca vulgaris) and what to do about them. PMID- 26584707 TI - Patient Perspectives: Treating acne with isotretinoin. PMID- 26584708 TI - Patient Perspectives: Molluscum Contagiosum. PMID- 26584709 TI - Patient Perspectives: What is Vitiligo? PMID- 26584710 TI - DELLA proteins interact with FLC to repress flowering transition. AB - Flowering is a highly orchestrated and extremely critical process in a plant's life cycle. Previous study has demonstrated that SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1 (SOC1) and FLOWERING LOCUS T (FT) integrate the gibberellic acid (GA) signaling pathway and vernalization pathway in regulating flowering time, but detailed molecular mechanisms remain largely unclear. In GA signaling pathway, DELLA proteins are a group of master transcriptional regulators, while in vernalization pathway FLOWERING LOCUS C (FLC) is a core transcriptional repressor that down-regulates the expression of SOC1 and FT. Here, we report that DELLA proteins interact with FLC in vitro and in vivo, and the LHRI domains of DELLAs and the C-terminus of MADS domain of FLC are required for these interactions. Phenotypic and gene expression analysis showed that mutation of FLC reduces while over-expression of FLC enhances the GA response in the flowering process. Further, DELLA-FLC interactions promote the repression ability of FLC on its target genes. In summary, these findings report that the interaction between MADS box transcription factor FLC and GRAS domain regulator DELLAs may integrate various signaling inputs in flowering time control, and shed new light on the regulatory mechanism both for FLC and DELLAs in regulating gene expression. PMID- 26584712 TI - Improving the Analytical Performance of Graphene Oxide towards the Assessment of Polyphenols. AB - The presence of oxygen functionalities on graphene surface has enormous influence on its electrochemical and electroanalytical properties. The oxygen-containing groups on graphene platforms can strongly affect the electrochemical response, being either detrimental for the heterogeneous charge transfer or promoting a favourable interaction with the specific analyte. In this study, by electrochemically reducing graphene oxide material at increasing negative potentials (from -0.25 to -1.50 V) we obtained eight electrochemically reduced graphene oxide (ERGO) platforms carrying a decreasing amount of oxygen functionalities. Subsequently, we analysed the electroanalytical response of each ERGO material for the detection of gallic acid, a standard polyphenol that is correlated to the antioxidant activity of food and beverages. The graphene platform providing the best electroanalytical performance in terms of sensitivity, selectivity and linearity of response was then employed for the analysis of commercial fruit juice samples. Herein we demonstrated that graphene materials can be electrochemically tuned to optimise their electrochemical response towards the detection of biologically important analytes. PMID- 26584711 TI - The impact of tinnitus characteristics and associated variables on tinnitus related handicap. AB - OBJECTIVE: This study aimed to determine the characteristics of tinnitus and tinnitus-related variables and explore their possible relationship with tinnitus related handicap. METHODS: Eighty-one patients with chronic tinnitus were included. The study protocol measured hearing status, tinnitus pitch, loudness, maskability and loudness discomfort levels. All patients filled in the Tinnitus Sample Case History Questionnaire, the Hyperacusis Questionnaire and the Tinnitus Handicap Inventory. The relationship of each variable with the Tinnitus Handicap Inventory score was evaluated by univariate and multivariate analyses. RESULTS: Five univariables were associated with the Tinnitus Handicap Inventory score: loudness discomfort level, subjective tinnitus loudness, tinnitus awareness, noise intolerance and Hyperacusis Questionnaire score. Multiple regression analysis showed that the Hyperacusis Questionnaire score and tinnitus awareness were independently associated with the Tinnitus Handicap Inventory score. CONCLUSION: Hyperacusis and tinnitus awareness were independently associated with the Tinnitus Handicap Inventory score. Questionnaires on tinnitus and hyperacusis are especially suited to providing additional insight into tinnitus-related handicap and are therefore useful for evaluating tinnitus patients. PMID- 26584713 TI - Cross-sectional comparison of critically ill pediatric patients across hospitals with various levels of pediatric care. AB - BACKGROUND: Inpatient administrative data sources describe the care provided to hospitalized children. The Kids' Inpatient Database (KID) provides nationally representative estimates, while the Pediatric Health Information System (PHIS, a consortium of pediatric facilities) derives more detailed information from revenue codes. The objective was to contextualize a diagnosis and procedure-based definition of critical illness to a revenue-based definition; then compare it across hospitals with different levels of pediatric care. METHODS: This retrospective, cross-sectional study utilized the 2009 KID, and 2009 inpatient discharges from the PHIS database. Patients <21 years of age (excluding neonates) were included to focus on pediatric critical illness. Critical illness was defined as: (1) critical care services (CC services) using diagnosis and procedures codes and (2) intensive care unit (ICU) care using revenue codes. Demographics, invasive procedures, and categories of critical illness were compared using Chi square and survey-weighted methods. The definitions of critical illness were compared in PHIS hospitals. CC services populations identified in General Hospitals, Pediatric Facilities, and Freestanding Children's hospitals (from KID) were compared to those in PHIS hospitals. RESULTS: Among PHIS hospitals, critically ill discharges identified by CC services accounted for 37.7% of ICU care. CC services discharges were younger and had greater proportion of respiratory illness and invasive procedure use. Critically ill patients identified by CC services in PHIS hospitals were statistically similar to those in Freestanding Children's hospitals. Pediatric Facilities and General Hospitals had more adolescents with more traumas. CC services patients in general hospitals had lower use of invasive procedures and predominance of trauma, respiratory illness, mental health issues, and general infections. Freestanding children's hospitals discharged 22% of the estimated 96,700 CC services cases. Similar proportions of critically ill patients were seen in Pediatric Facilities (31%) and General Hospitals (33%). CONCLUSION: The CC services definition captured a more severely ill fraction of critically ill children. Critically ill discharges from PHIS hospitals can likely be extrapolated to Freestanding Children's hospitals and Pediatric Facilities. General Hospitals, which provide a significant amount of pediatric critical care, are different. Studies utilizing administrative data can benefit from multiple data sources, which balance the individual strengths and weaknesses. PMID- 26584714 TI - Plasma Membrane H(+)-ATPase Regulation in the Center of Plant Physiology. AB - The plasma membrane (PM) H(+)-ATPase is an important ion pump in the plant cell membrane. By extruding protons from the cell and generating a membrane potential, this pump energizes the PM, which is a prerequisite for growth. Modification of the autoinhibitory terminal domains activates PM H(+)-ATPase activity, and on this basis it has been hypothesized that these regulatory termini are targets for physiological factors that activate or inhibit proton pumping. In this review, we focus on the posttranslational regulation of the PM H(+)-ATPase and place regulation of the pump in an evolutionary and physiological context. The emerging picture is that multiple signals regulating plant growth interfere with the posttranslational regulation of the PM H(+)-ATPase. PMID- 26584715 TI - MSH1 Is a Plant Organellar DNA Binding and Thylakoid Protein under Precise Spatial Regulation to Alter Development. AB - As metabolic centers, plant organelles participate in maintenance, defense, and signaling. MSH1 is a plant-specific protein involved in organellar genome stability in mitochondria and plastids. Plastid depletion of MSH1 causes heritable, non-genetic changes in development and DNA methylation. We investigated the msh1 phenotype using hemi-complementation mutants and transgene null segregants from RNAi suppression lines to sub-compartmentalize MSH1 effects. We show that MSH1 expression is spatially regulated, specifically localizing to plastids within the epidermis and vascular parenchyma. The protein binds DNA and localizes to plastid and mitochondrial nucleoids, but fractionation and protein protein interactions data indicate that MSH1 also associates with the thylakoid membrane. Plastid MSH1 depletion results in variegation, abiotic stress tolerance, variable growth rate, and delayed maturity. Depletion from mitochondria results in 7%-10% of plants altered in leaf morphology, heat tolerance, and mitochondrial genome stability. MSH1 does not localize within the nucleus directly, but plastid depletion produces non-genetic changes in flowering time, maturation, and growth rate that are heritable independent of MSH1. MSH1 depletion alters non-photoactive redox behavior in plastids and a sub-set of mitochondrially altered lines. Ectopic expression produces deleterious effects, underlining its strict expression control. Unraveling the complexity of the MSH1 effect offers insight into triggers of plant-specific, transgenerational adaptation behaviors. PMID- 26584716 TI - Distinguishing predictive profiles for patient-based risk assessment and diagnostics of plaque induced, surgically and prosthetically triggered peri implantitis. AB - OBJECTIVE: To investigate whether specific predictive profiles for patient-based risk assessment/diagnostics can be applied in different subtypes of peri implantitis. MATERIALS AND METHODS: This study included patients with at least two implants (one or more presenting signs of peri-implantitis). Anamnestic, clinical, and implant-related parameters were collected and scored into a single database. Dental implant was chosen as the unit of analysis, and a complete screening protocol was established. The implants affected by peri-implantitis were then clustered into three subtypes in relation to the identified triggering factor: purely plaque-induced or prosthetically or surgically triggered peri implantitis. Statistical analyses were performed to compare the characteristics and risk factors between peri-implantitis and healthy implants, as well as to compare clinical parameters and distribution of risk factors between plaque, prosthetically and surgically triggered peri-implantitis. The predictive profiles for subtypes of peri-implantitis were estimated using data mining tools including regression methods and C4.5 decision trees. RESULTS: A total of 926 patients previously treated with 2812 dental implants were screened for eligibility. Fifty six patients (6.04%) with 332 implants (4.44%) met the study criteria. Data from 125 peri-implantitis and 207 healthy implants were therefore analyzed and included in the statistical analysis. Within peri-implantitis group, 51 were classified as surgically triggered (40.8%), 38 as prosthetically triggered (30.4%), and 36 as plaque-induced (28.8%) peri-implantitis. For peri-implantitis, 51 were associated with surgical risk factor (40.8%), 38 with prosthetic risk factor (30.4%), 36 with purely plaque-induced risk factor (28.8%). The variables identified as predictors of peri-implantitis were female sex (OR = 1.60), malpositioning (OR = 48.2), overloading (OR = 18.70), and bone reconstruction (OR = 2.35). The predictive model showed 82.35% of accuracy and identified distinguishing predictive profiles for plaque, prosthetically and surgically triggered peri-implantitis. The model was in accordance with the results of risk analysis being the external validation for model accuracy. CONCLUSIONS: It can be concluded that plaque induced and prosthetically and surgically triggered peri implantitis are different entities associated with distinguishing predictive profiles; hence, the appropriate causal treatment approach remains necessary. The advanced data mining model developed in this study seems to be a promising tool for diagnostics of peri-implantitis subtypes. PMID- 26584717 TI - Identification of ANLN as ETV6 partner gene in recurrent t(7;12)(p15;p13): a possible role of deregulated ANLN expression in leukemogenesis. AB - The ETV6 gene encodes an ETS family transcription factor that is involved in a myriad of chromosomal rearrangements found in hematological malignancies and other neoplasms. A recurrent ETV6 translocation, previously described in patients with acute myeloid leukemia (AML) (Genes Chromosomes Cancer 51:328-337,2012, Leuk Res 35:e212-214, 2011), whose partner has not been identified is t(7;12)(p15;p13). We herein report that the t(7;12)(p15;p13) fuses ETV6 to ANLN, a gene not previously implicated in the pathogenesis of hematological malignancies, and we demonstrate that this translocation leads to high expression of the fusion transcript in the myeloid and lymphoid lineages. PMID- 26584718 TI - New Outpatient Management Based on a Respiratory Virtual Clinic. An Effective Measure in Times of Austerity. PMID- 26584719 TI - Carbon Monoxide Exposure During Pregnancy. AB - IMPORTANCE: Carbon monoxide (CO) is the leading cause of poisoning in the United States and is associated with high maternal and fetal mortality rates. Given the nonspecific signs and symptoms of toxicity, cases may go unsuspected or attributed to other etiologies. As CO adversely affects both mother and fetus, it is important for practitioners to recognize and treat poisoning in a timely manner. OBJECTIVE: We seek to assist practitioners with understanding the physiology and recognizing the presentations of both acute and chronic CO poisoning, as well as provide information on diagnosis and treatment options. We also conducted a review of cases described in the literature during the past half century to show varying presentations and treatment methodologies. EVIDENCE ACQUISITION: A qualitative literature search was conducted using PubMed and Google Scholar for articles published between 1970 and 2014 that assessed cases of CO poisoning during pregnancy. Excluded studies were not in English or contained nonhuman subjects. RESULTS: Nineteen published reports of CO poisoning during pregnancy described in varying levels of detail were found in the literature from 1971 to 2010. CONCLUSIONS AND RELEVANCE: Carbon monoxide poisoning requires a high degree of suspicion. Diagnosis is made based on initial history and physical evaluation and assessment of environmental CO levels; presenting carboxyhemoglobin levels may be poor indicators of severity of disease. Oxygen therapy should be initiated promptly in all possible cases with consideration of hyperbaric oxygen therapy in cases of significant maternal exposure. Treatment requires a longer duration for fetal CO elimination than in the nonpregnant patients. Importantly, practitioners should educate pregnant patients on prevention. PMID- 26584720 TI - Pubic Symphysis Rupture and Separation During Pregnancy. AB - OBJECTIVE: The aim of this study was to determine the risk factors, clinical and radiologic criteria for diagnosis, and management of this unusual complication of pregnancy. METHODS: A PubMed and Web of Science search was undertaken with no limitations on the number of years searched. RESULTS: There were 36 publications identified, with 19 articles being the basis of this review. Multiple risk factors have been identified including multiparity, macrosomia, cephalopelvic disproportion, forceps deliveries, precipitous labor, malpresentation, prior pelvic trauma, and use of the McRoberts maneuver. The diagnosis is usually made clinically, confirmed by imaging, and considered pathological when the intrapubic gap is greater than 10 mm. Magnetic resonance imaging appears to be superior to pelvic x-ray and computed tomography scan in visualization of the bone separation. Conservative treatment remains the first choice for therapy, but women who do not respond to conservative therapy or women with large separations may need surgical stabilization with external or internal fixation. CONCLUSIONS: Widening of the pubic symphysis greater than 10 mm is pathologic. The diagnosis is clinical and confirmed by imaging studies, with magnetic resonance imaging being the superior technique. Conservative treatment is the first line of therapy. Failure of conservative therapy is treated by surgical stabilization. PMID- 26584721 TI - Delivery of an Impacted Fetal Head During Cesarean: A Literature Review and Proposed Management Algorithm. AB - Effective and expedient management of an impacted fetal head (IFH) at cesarean delivery is essential to avoid maternal and neonatal morbidity. The incidence of an IFH at the time of cesarean may increase because of changing practice guidelines regarding the acceptable duration of the second stage of labor. Based on limited available evidence comparing the "push," "pull," and other methods for delivery of the IFH, we suggest the primary disengagement technique be selected based on surgeon experience and propose a management algorithm "ALERT" for clinical application. PMID- 26584722 TI - Prevalence and causes of hearing impairment in Africa. AB - OBJECTIVE: To systematically assess the data on the prevalence and causes of hearing impairment in Africa. METHODS: Systematic review on the prevalence and causes of hearing loss in Africa. We undertook a literature search of seven electronic databases (EMBASE, PubMed, Medline, Global Health, Web of Knowledge, Academic Search Complete and Africa Wide Information) and manually searched bibliographies of included articles. The search was restricted to population based studies on hearing impairment in Africa. Data were extracted using a standard protocol. RESULTS: We identified 232 articles and included 28 articles in the final analysis. The most common cut-offs used for hearing impairment were 25 and 30 dB HL, but this ranged between 15 and 40 dB HL. For a cut-off of 25 dB, the median was 7.7% for the children- or school-based studies and 17% for population-based studies. For a cut-off of 30 dB HL, the median was 6.6% for the children or school-based studies and 31% for population-based studies. In schools for the deaf, the most common cause of hearing impairment was cryptogenic deafness (50%) followed by infectious causes (43%). In mainstream schools and general population, the most common cause of hearing impairment was middle ear disease (36%), followed by undetermined causes (35%) and cerumen impaction (24%). CONCLUSION: There are very few population-based studies available to estimate the prevalence of hearing impairment in Africa. Those studies that are available use different cut-offs, making comparison difficult. However, the evidence suggests that the prevalence of hearing impairment is high and that much of it is avoidable or treatable. PMID- 26584723 TI - [Preventive withdrawal from work, psychosocial work demands and major depressive symptoms]. AB - AIM: Our study objectives were as follows: assess exposure to psychosocial work demands among working pregnant women and women on preventive withdrawal from work; and measure the association between psychosocial work demands and major depressive symptoms, according to time of withdrawal from work. METHODOLOGY: Karasek's abbreviated scale was used to measure psychosocial work demands (Job strain and "Iso-strain") and CES-D scale (Center for Epidemiological Studies Depression Scale) was used to measure major depressive symptoms (CES-D score>=23), at 24-26 weeks of pregnancy, among 3043 pregnant women in Montreal (Quebec) who worked at paid jobs at least 15 h/week and at least four consecutive weeks since the beginning of their pregnancy. Multivariate logistic regression models were built. RESULTS: At 24-26 weeks of pregnancy, 31.4% (956/3043) of pregnant women were on preventive withdrawal from work. They were more in "high strain" (31.1% vs. 21.1%) and "Iso-strain" groups (21.0% vs. 14.2%) than those who continued to work (P<0.0001). The prevalence of major depressive symptoms was higher in women on preventive withdrawal from work (10.8%; CI 95%: 8.9 to 12.9) compared to working women (7.1%; CI 95%: 6.1-8.3). After adjustment for personal and professional risk factors, "Iso-strain" remained significantly associated with major depressive symptoms in working women (adjusted OR=1.75; CI 95%: [1.05 to 2.92]) and women on preventive withdrawal from work, regardless of duration of activity before withdrawal: 4 to 12 weeks (adjusted OR=2.72; CI 95%: [1.19 6.12]), 13 to 20 weeks (adjusted OR=3.51; CI 95%: [1.54-7.97]), and >=21 weeks (adjusted OR=2.39; CI 95%: [1.10-5.20]). CONCLUSION: Psychosocial work demands are an important risk factor for the mental health of pregnant workers and require that preventive actions be put forward. PMID- 26584724 TI - Brain-targeted distribution and high retention of silver by chronic intranasal instillation of silver nanoparticles and ions in Sprague-Dawley rats. AB - The wide applications of silver nanoparticles (AgNPs) have been concerned regarding their unintentional toxicities. Different exposure modes may cause distinct accumulation, retention and elimination profiles, which are closely related with their toxicities. Unlike silver accumulation profiles through other regular administration modes, the biodistribution, accumulation and elimination of AgNPs by intranasal instillation are not fully understood. This study conducted intranasal instillation of polyvinylpyrrolidone-coated AgNPs in neonatal Sprague-Dawley rats at doses of 1 and 0.1 mg kg(-1) day(-1) for 4 and 12 weeks, respectively. The 4-week recovery was also designed after the 12-week exposure. Silver concentrations in the main tissues or organs were periodically monitored. Parallel exposures using silver ion were performed for the comparative studies. No physiological alterations were observed in AgNP exposures. In comparison, 1 mg kg(-1) day(-1) silver ions decreased body weight gain and caused mortality of 18.2%, showing ionic silver had a relatively higher toxicity than AgNPs. A relatively higher silver accumulation was observed in silver ion groups than AgNP groups. The silver ion release could not fully explain silver accumulation in AgNP exposures, showing silver distribution caused by particulate silver occurred in vivo. The highest silver concentration was in the liver at week 4, while it shifted to the brain after a 12-week exposure. Dose-related silver accumulation occurred for both AgNP and silver ion groups. The time course revealed a uniquely high concentration and retention of brain silver, implying chronic intranasal instillation caused brain-targeted silver accumulation. These findings provided substantial evidence on the potential neuronal threat from the intranasal administration of AgNPs or silver colloid-based products. PMID- 26584725 TI - Metal Containing Cytostatics and Their Interaction with Cellular Thiol Compounds Causing Chemoresistance. AB - The history of metal based cytostatics began in the 1970s by discovering the effects of cisplatin. Since then several generations of platinum based cytostatics have started to be the key weapon against tumor development and metastasis occurrence. Nevertheless, some attention has been also paid to non platinum metals, such as ruthenium, titanium, gallium, iron, cobalt, gold, and palladium. Ruthenium, titanium, and gallium complexes have been also tested in clinical studies. This boom in metal based cytostatics can be explained by great effort paid to the elucidation of mechanisms of tumor resistance to these drugs. The known mechanisms of drug resistance are: (i) down regulation, over expression, or modification of molecules of interest; (ii) increased drug efflux; (iii) induction of anti-apoptotic mechanisms or inactivation of pro-apoptotic mechanisms; (iv) changes in enzymes with an ability to activate or detoxify a drug; (v) low access of the drug to a tumor; and/or (vi) alteration in drug metabolism or excretion [1]. Often discussed but not largely reviewed and summarized is the intracellular inactivation of platinum drugs by coordination to thiol containing biomolecules glutathione (GSH) and metallothioneins (MTs). Overexpression of MT and/or GSH may cause resistance to anticancer drugs. Thus, greater attention should be paid to these interactions in case to overcome the resistance of tumor to cytostatics. PMID- 26584726 TI - A Review of the Recent Developments in Synthetic Anti-Breast Cancer Agents. AB - The perceptible decrease in the incidence of breast cancer in recent years has not influenced its societal and economic impact and it remains as the most commonly diagnosed malignancies among females. Recent reports of clinical trials in preventive settings suggested chemoprevention as an appealing strategy zeroing heavily on endocrine intervention using selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs). Unfortunately, these drugs are only effective in prevention of endocrine responsive lesions with essentially no effect in reducing the risk of estrogen-negative breast cancer. Further, the existing drugs for breast cancer treatment are invariably associated with several drawbacks such as poor oral bioavailability, non-selectivity and poor pharmacodynamics properties, limiting their clinical utility. Thus, the identification of new molecular targets and the development of agents with better pharmacological profiles will streamline the development of rational, effective and safe anticancer drugs with minimal side-effects. Over the past few years, different research groups have been actively involved in the design and synthesis of novel anti-breast cancer agents. In this review article, the recent developments (2013 onwards) made in the direction of synthesis of new scaffolds with promising anti-breast cancer activity, are briefly described. Hopefully, the data compiled in this article will update scientific community with recent endeavors in this field, and will certainly be encouraging for further research in this direction. PMID- 26584728 TI - A retrospective study of antibiotic prophylaxis value in surgical treatment of lower limb fracture. AB - BACKGROUND: Surgical site infections (SSI) are nosocomial infections that cause considerable problems in orthopaedic surgery. Antibiotic prophylaxis can be used to reduce the risk for SSI. There is no universal antibiotic that can be recommended for prophylaxis in terms of coverage of all possible pathogens because of antibiotic resistance, and there are no universal recommendations for different types of patients in terms of injury type, selected operation and risk factors for development of SSI. The aim of this study was to analyse the effectiveness of antibiotic prophylaxis in surgical treatment (ORIF) of closed lower limb fractures in young, healthy patients. PATIENTS AND METHODS: Patient details were collected from the patient histories. Inclusion criteria for participants were age 20-30 years, not suffering from any type of chronic disease or state that may affect postoperative infection and ISS<=9. Antibiotic prophylaxis use and outcome (SSI) were compared between two groups of patients. Data were analysed using descriptive statistics, Fisher's exact test and t-test for proportions. RESULTS: A total of 347 patients with closed lower limb fractures treated with ORIF met the inclusion criteria. There were 290 male and 57 female patients, with an average age of 24.47 years. Prophylactic antibiotics were given to 242 patients (69.74%); 2g ceftriaxone was administered to 88.02% of the patients who received antibiotic prophylaxis. Ten patients developed postoperative infection (eight out of 242 with antibiotic prophylaxis and two out of 105 without antibiotic prophylaxis). The difference between the two groups was not statistically significant (Fisher's exact test, P=0.749). CONCLUSION: Antibiotic prophylaxis was ineffective in preventing SSI in patients with no risk factors for SSI who were undergoing ORIF for closed lower limb fractures. PMID- 26584727 TI - Blood-Brain Barrier and Breast Cancer Resistance Protein: A Limit to the Therapy of CNS Tumors and Neurodegenerative Diseases. AB - The treatment of brain tumors and neurodegenerative diseases, represents an ongoing challenge. In Central Nervous System (CNS) the achievement of therapeutic concentration of chemical agents is complicated by the presence of distinct set of efflux proteins, such as ATP-Binding Cassette (ABC) transporters localized on the Blood-Brain Barrier (BBB). The activity of ABC transporters seems to be a common mechanism that underlies the poor response of CNS diseases to therapies. The molecular characterization of Breast Cancer Resistance Protein (BCRP/ABCG2), as an ABC transporter conferring multidrug resistance (MDR), has stimulated many studies to investigate its activity on the BBB, its involvement in physiology and CNS diseases and its role in limiting the delivery of drugs in CNS. In this review, we highlight the activity and localization of BCRP on the BBB and the action that this efflux pump has on many conventional drugs or latest generation molecules used for the treatment of CNS tumors and other neurodegenerative diseases. PMID- 26584729 TI - Internal fixation of patellar apex fractures with the basket plate: 25 years of experience. AB - INTRODUCTION: Comminution of the patellar apex is amenable to internal fixation by standard techniques and usually requires partial patellectomy. In our institution, multifragmentary fractures of the distal pole are treated with the basket plate, which is shaped to fit the geometry of the patellar apex. This implant has been used in our institution for over 25 years. The aim of this study was to evaluate long-term results of internal fixation of comminuted fractures of the patellar apex with the basket plate. MATERIALS AND METHODS: A total of 142 patients with fracture of the distal pole of the patella were treated with the basket plate between 1988 and 2013. Functional evaluation was conducted using the modified Cincinnati knee rating system. A total of 98 patients were available for late functional evaluation. RESULTS: There were no infections or implant-related problems during the follow-up period. All fractures healed within 8 to 10 weeks. There were three cases of early revision because of improper use of the implant and incorrect indication. Functional outcome following internal fixation with the basket plate was excellent in 80 patients and good in 18; there were no poor results. CONCLUSION: Internal fixation with the basket plate is recommended for management of multifragmentary fractures of the patellar apex because this method enables early, unrestricted knee motion, and provides reliable healing and good functional outcome. This method is an alternative to partial patellectomy and is considered a patella-saving procedure; therefore, the use of the basket plate is strongly recommended for the treatment of distal pole fractures. PMID- 26584731 TI - Diagnosis of occult radial head and neck fracture in adults. AB - The purpose of this study was to compare imaging modalities in the diagnosis of occult radial head and neck fractures and to assess the diagnostic value of ultrasound in diagnosing occult fractures of the radial head and neck. The study included 193 patients (101 male, 92 female) who were referred by trauma surgeons from January 2011 to July 2014 and presented with history of acute elbow trauma. The mean age of the patients was 37 years (range 15-82 years); 95 right and 98 left elbows were included in the study. Clinical examinations and standard radiograms were conducted. The anteroposterior radiographic view revealed no visible signs of fracture. The lateral radiographic view showed displacement of the anterior and posterior fat pads (fat pad sign) due to joint effusion, which is an indirect sign of fracture. In all 193 cases, ultrasound examination showed intraarticular effusion. In 176 cases (91%), there was effusion in both the olecranon bursa and the elbow joint. In 10 patients (5%), there was effusion only inside the elbow joint and in seven cases (4%) there was effusion only in the olecranon bursa. Cortical discontinuity (a direct sign of fracture) was clearly visualised in 157 cases (82%), in the radial neck in 108 cases and in the radial head in 49 cases. Ultrasound findings of fracture were questionable in 36 cases (18%). Step-off deformities, tiny avulsed bone fragments, double-line appearance of cortical margins, and diffuse irregularity of the bone surfaces were identified as auxiliary ultrasound findings (indirect signs of fracture). Standard radiograms were repeated after 7-10 days. In 184 cases (95%), there was a clearly visible fracture: a fracture of the radial neck in 111 cases (58%) and a fracture of non-displaced radial head in 73 cases (37%). In nine cases (5%), radial fracture was not confirmed on radiogram and MRI was performed in these patients. In conclusion, ultrasound imaging proved to be an effective method for diagnosing occult fractures of the radial head or neck when initial radiograms showed only intraarticular effusion. Ultrasound imaging is a cost-effective, easy to-use and radiation-free method. For these reasons we recommend it for early detection of occult fracture in the emergency room. PMID- 26584730 TI - Intentional injury against children in Sub-Saharan Africa: A tertiary trauma centre experience. AB - BACKGROUND: Intentional injuries are the result of violence. This is an important public health issue, particularly in children, and is an unaddressed problem in sub-Saharan Africa. This study sought to describe the characteristics of intentional injury, particularly physical abuse, in children presenting to our tertiary trauma centre in Lilongwe, Malawi and how they compare to children with unintentional injuries. METHODS: A retrospective analysis of children (<18 years old) with traumatic injuries presenting to Kamuzu Central Hospital (KCH) in Lilongwe, Malawi from 2009 to 2013 was performed. Children with intentional and unintentional injuries were compared with bivariate analysis and multivariate logistic regression modelling. RESULTS: 67,672 patients with traumatic injuries presented to KCH of which 24,365 were children. 1976 (8.1%) patients presented with intentional injury. Intentional injury patients had a higher mean age (11.1 +/- 5.0 vs. 7.1 +/- 4.6, p<0.001), a greater male preponderance (72.5 vs. 63.6%, p<0.001), were more often injured at night (38.3 vs. 20.7%, p<0.001), and alcohol was more often involved (7.8 vs. 1.0%, p<0.001). Multivariate logistic regression modelling showed that increasing age, male gender, and nighttime or urban setting for injury were associated with increased odds of intentional injury. Soft tissue injuries were more common in intentional injury patients (80.5 vs. 45.4%, p<0.001) and fist punches were the most common weapon (25.6%). Most patients were discharged in both groups (89.2 vs 80.9%, p<0.001) and overall mortality was lower for intentional injury patients (0.9 vs. 1.2%, p=0.001). Head injury was the most common cause of death (43.8 vs. 32.2%, p<0.001) in both groups. CONCLUSIONS: Sub-Saharan African tertiary hospitals are uniquely positioned to play a pivotal role in the identification, clinical management, and alleviation of intentional injuries to children by facilitating access to social services and through prevention efforts. PMID- 26584732 TI - Operative treatment of acute acromioclavicular dislocations Rockwood III and V Comparative study between K-wires combined with FiberTape((r)) vs. TightRope System((r)). AB - INTRODUCTION: Acromioclavicular (AC) joint dislocations usually occur in a young active population as a result of a fall on the shoulder. Rockwood divided these dislocations into six types. Optimal treatment is still a matter of discussion. Many operative techniques have been developed, but the main choice is between open and minimally-invasive arthroscopic procedures. The aim of this study was to compare two different surgical methods on two groups of patients to find out which method is superior in terms of benefit to the patient. The methods were evaluated through objective and subjective scores, with a focus on complications and material costs. MATERIAL AND METHODS: A retrospective two-centre study was conducted in patients with acute AC joint dislocation Rockwood types III and V. The two methods conducted were an open procedure using K-wires combined with FiberTape((r)) (Arthrex, Naples, USA) (Group 1) and an arthroscopic procedure using the TightRope System((r)) (Arthrex, Naples, USA) (Group 2). Groups underwent procedures during a two-year period. Diagnosis was based on the clinical and radiographic examination of both AC joints. Surgical treatment and rehabilitation were performed. RESULTS: Sixteen patients were included in this study: Group 1 comprised 10 patients, all male, average age 41.6 years (range 17 64 years), Rockwood type III (eight patients) and Rockwood type V (two patients); Group 2 had six patients, one female and five male, average age 37.8 years (range 18-58 years), Rockwood type III (two patients) and Rockwood type V (four patients). Time from injury to surgery was shorter and patients needed less time to return to daily activities in Group 1. Duration of the surgical procedure was shorter in Group 2 compared with Group 1. Complications of each method were noted. According to the measured scores and operative outcome between dislocation Rockwood type III and V, no significant difference was found. Implant material used in Group 2 was 4.7 times more expensive than that used in Group 1. CONCLUSION: Both methods offer many advantages with satisfying evaluated scores. K-wires with FiberTape((r)) offer a shorter period for complete recovery and a significantly more cost-effective outcome, whereas the TightRope System((r)) offers shorter operative procedure, better cosmetic result and avoidance of intraoperative fluoroscopy. PMID- 26584733 TI - Minimally-invasive plate osteosynthesis in distal tibial fractures: Results and complications. AB - INTRODUCTION: Distal tibial or pilon fractures are usually the result of combined compressive and shear forces, and may result in instability of the metaphysis, with or without articular depression, and injury to the soft tissue. The complexity of injury, lack of muscle cover and poor vascularity make these fractures difficult to treat. Surgical treatment of distal tibial fractures includes several options: external fixation, IM nailing, ORIF and minimally invasive plate osteosynthesis (MIPO). Management of distal tibial fractures with MIPO enables preservation of soft tissue and remaining blood supply. This is a report of a series of prospectively studied closed distal tibial and pilon fractures treated with MIPO. MATERIALS AND METHODS: A total of 21 patients with closed distal tibial or pilon fractures were enrolled in the study between March 2008 and November 2013 and completed follow-up. Demographic characteristics, mechanism of injury, time required for union, ankle range of motion and complications were recorded. Fractures were classified according to the AO/OTA classification. Nineteen patients were initially managed with an ankle-spanning external fixator. When the status of the soft tissue had improved and swelling had subsided enough, a definitive internal fixation with MIPO was performed. Patients were invited for follow-up examinations at 3 and 6 weeks and then at intervals of 6 to 8 weeks until 12 months. RESULTS: Mean age of the patients was 40.1 years (range 19-67 years). Eighteen cases were the result of high-energy trauma and three were the result of low-energy trauma. According to the AO/OTA classification there were extraarticular and intraarticular fractures, but only simple articular patterns without depression or comminution. The average time for fracture union was 19.7 weeks (range 12-38 weeks). Mean range of motion was 10 degrees of dorsiflexion (range 5-15 degrees ) and 28.3 degrees of plantar flexion (range 20-35 degrees ). Three cases were metalwork-related complications. Two patients underwent plate removal at 24 weeks because of plate impingement. There was one case of wound breakdown at 11 weeks. One patient had fracture union with tibial recurvatum of approximately 10 degrees , without functional impairment. Two patients had delayed union. CONCLUSION: MIPO is a reliable method of treatment for distal tibial fractures; it provides a high union rate and good functional outcome with minimal soft tissue complications. Skin impingement remains a common complication with MIPO, but this can be solved by timely plate removal. PMID- 26584734 TI - Methylation of an intragenic alternative promoter regulates transcription of GARP. AB - Alternative promoter usage has been proposed as a mechanism regulating transcriptional and translational diversity in highly elaborated systems like the immune system in humans. Here, we report that transcription of human glycoprotein A repetitions predominant (GARP) in regulatory CD4 T cells (Tregs) is tightly regulated by two alternative promoters. An intragenic promoter contains several CpGs and acts as a weak promoter that is demethylated and initiates transcription Treg-specifically. The strong up-stream promoter containing a CpG-island is, in contrast, fully demethylated throughout tissues. Transcriptional activity of the strong promoter was surprisingly down-regulated upon demethylation of the weak promoter. This demethylation-induced transcriptional attenuation regulated the magnitude of GARP expression and correlated with disease activity in rheumatoid arthritis. Treg-specific GARP transcription was initiated by synergistic interaction of forkhead box protein 3 (Foxp3) with nuclear factor of activated T cells (NFAT) and was underpinned by permissive chromatin remodeling caused by release of the H3K4 demethylase, PLU-1. Our findings describe a novel function of alternative promoters in regulating the extent of transcription. Moreover, since GARP functions as a transporter of transforming growth factor beta (TGFbeta), a cytokine with broad pleiotropic traits, GARP transcriptional attenuation by alternative promoters might provide a mechanism regulating peripheral TGFbeta to avoid unwanted harmful effects. PMID- 26584735 TI - Validation of a measure of health-related production loss: construct validity and responsiveness - a cohort study. AB - BACKGROUND: The aim of this study is to evaluate the construct validity and responsiveness of a Swedish measure of health-related production loss as well as to investigate if there is a difference in the level of production loss within a population suffering from persistent back/neck pain and CMDs. METHODS: The sample was drawn from a study that assessed employees' health and working capacity in 74 health care units before and after intervention. The study included 692 patients who reported working the previous six months at baseline measurement, and who were also asked to answer questions related to health-related production loss. Health-related measures were general health derived from Short Form-12, health related quality of life derived from EQ-5D, and work ability derived from the Work Ability Index (WAI). Convergent validity and external responsiveness were assessed using Spearman's Rank Correlation Coefficient and a linear regression model, respectively. RESULTS: The different measures of health showed a moderate to-strong correlation with the measure of health-related production loss and fulfilled the criteria for construct validity. Changes in health and work ability led to significant changes in health-related production loss, which demonstrates external responsiveness. This result is valid for both the total population and for the two different subgroups that were evaluated. CONCLUSIONS: The present study shows that this measure of health-related production loss is a valid measure for capturing production loss due to illness, and that work ability is more strongly correlated with health-related production loss than people's general health is. The result shows an average of about 50 % reduced production due to illness, with back pain being the most costly. PMID- 26584736 TI - An unusual medical cause of abdominal pain diagnosed by urological abnormalities. PMID- 26584739 TI - Nanoporous microscale microbial incubators. AB - Reconstruction of phylogenetic trees based on 16S rRNA gene sequencing reveals abundant microbial diversity that has not been cultured in the laboratory. Many attribute this so-called 'great plate count anomaly' to traditional microbial cultivation techniques, which largely facilitate the growth of a single species. Yet, it is widely recognized that bacteria in nature exist in complex communities. One technique to increase the pool of cultivated bacterial species is to co-culture multiple species in a simulated natural environment. Here, we present nanoporous microscale microbial incubators (NMMI) that enable high throughput screening and real-time observation of multi-species co-culture. The key innovation in NMMI is that they facilitate inter-species communication while maintaining physical isolation between species, which is ideal for genomic analysis. Co-culture of a quorum sensing pair demonstrates that the NMMI can be used to culture multiple species in chemical communication while monitoring the growth dynamics of individual species. PMID- 26584738 TI - Sodium chloride promotes pro-inflammatory macrophage polarization thereby aggravating CNS autoimmunity. AB - The increasing incidence in Multiple Sclerosis (MS) during the last decades in industrialized countries might be linked to a change in dietary habits. Nowadays, enhanced salt content is an important characteristic of Western diet and increased dietary salt (NaCl) intake promotes pathogenic T cell responses contributing to central nervous system (CNS) autoimmunity. Given the importance of macrophage responses for CNS disease propagation, we addressed the influence of salt consumption on macrophage responses in CNS autoimmunity. We observed that EAE-diseased mice receiving a NaCl-high diet showed strongly enhanced macrophage infiltration and activation within the CNS accompanied by disease aggravation during the effector phase of EAE. NaCl treatment of macrophages elicited a strong pro-inflammatory phenotype characterized by enhanced pro-inflammatory cytokine production, increased expression of immune-stimulatory molecules, and an antigen independent boost of T cell proliferation. This NaCl-induced pro-inflammatory macrophage phenotype was accompanied by increased activation of NF-kB and MAPK signaling pathways. The pathogenic relevance of NaCl-conditioned macrophages is illustrated by the finding that transfer into EAE-diseased animals resulted in significant disease aggravation compared to untreated macrophages. Importantly, also in human monocytes, NaCl promoted a pro-inflammatory phenotype that enhanced human T cell proliferation. Taken together, high dietary salt intake promotes pro inflammatory macrophages that aggravate CNS autoimmunity. Together with other studies, these results underline the need to further determine the relevance of increased dietary salt intake for MS disease severity. PMID- 26584737 TI - Global, regional, and national levels and trends in maternal mortality between 1990 and 2015, with scenario-based projections to 2030: a systematic analysis by the UN Maternal Mortality Estimation Inter-Agency Group. AB - BACKGROUND: Millennium Development Goal 5 calls for a 75% reduction in the maternal mortality ratio (MMR) between 1990 and 2015. We estimated levels and trends in maternal mortality for 183 countries to assess progress made. Based on MMR estimates for 2015, we constructed projections to show the requirements for the Sustainable Development Goal (SDG) of less than 70 maternal deaths per 100,000 livebirths globally by 2030. METHODS: We updated the UN Maternal Mortality Estimation Inter-Agency Group (MMEIG) database with more than 200 additional records (vital statistics from civil registration systems, surveys, studies, or reports). We generated estimates of maternal mortality and related indicators with 80% uncertainty intervals (UIs) using a Bayesian model. The model combines the rate of change implied by a multilevel regression model with a time series model to capture data-driven changes in country-specific MMRs, and includes a data model to adjust for systematic and random errors associated with different data sources. RESULTS: We had data for 171 of 183 countries. The global MMR fell from 385 deaths per 100,000 livebirths (80% UI 359-427) in 1990, to 216 (207-249) in 2015, corresponding to a relative decline of 43.9% (34.0-48.7), with 303,000 (291,000-349,000) maternal deaths worldwide in 2015. Regional progress in reducing the MMR since 1990 ranged from an annual rate of reduction of 1.8% (0.0 3.1) in the Caribbean to 5.0% (4.0-6.0) in eastern Asia. Regional MMRs for 2015 ranged from 12 deaths per 100,000 livebirths (11-14) for high-income regions to 546 (511-652) for sub-Saharan Africa. Accelerated progress will be needed to achieve the SDG goal; countries will need to reduce their MMRs at an annual rate of reduction of at least 7.5%. INTERPRETATION: Despite global progress in reducing maternal mortality, immediate action is needed to meet the ambitious SDG 2030 target, and ultimately eliminate preventable maternal mortality. Although the rates of reduction that are needed to achieve country-specific SDG targets are ambitious for most high mortality countries, countries that made a concerted effort to reduce maternal mortality between 2000 and 2010 provide inspiration and guidance on how to accomplish the acceleration necessary to substantially reduce preventable maternal deaths. FUNDING: National University of Singapore, National Institute of Child Health and Human Development, USAID, and the UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction. PMID- 26584740 TI - [The Brumory test, an incidental long-term memory task designed for foreign, non French-speaking people with low educational level]. AB - Cognitive assessment among foreign patients is a growing need for several reasons: foreign patients have a different culture, they have an insufficient command of the language of the consulting center, and the available cognitive tools are largely unsuitable. For these reasons, we developed a non-verbal test of long-term memory called the Brumory test. This test is based on incident encoding of 48 colored images followed by retrieval by recognition. We compared the performance of indigenous participants with that of immigrant participants (mainly from Morocco). Immigrant participants did not speak French properly and had a low educational level. The results indicate no significant difference in memory performance between the two groups of participants. Moreover, the instructions were easily understood by immigrant participants, despite the fact they do not master French. We conclude that the Brumory test is an appropriate test to assess memory among foreign non-French-speaking patients people with low educational level. PMID- 26584741 TI - Metastatic renal cell carcinoma: Contending with a sea change in therapy. PMID- 26584742 TI - Early and Midterm Outcomes of the VSSR procedure with De Paulis valsalva graft: A Chinese single-Center Experience in 38 patients. AB - BACKGROUND: This study investigated early and midterm outcomes after valve sparing aortic root replacement (VSSR procedure with De Paulis Valsalva graft) for acute aortic dissection or ascending aortic aneurysm in a single Chinese hospital center. METHODS: Between September 2005 to July 2013, 38 patients (84.2% male; mean age, 45.5 +/- 12.4) underwent VSSR procedure with De Paulis valsalva graft for acute aortic dissection or ascending aortic aneurysm and were followed up clinically and echocardiographically. RESULTS: Among the 38 cases studied, intensive care unit stay duration was 34.5 (interquartile range, 16-34.6) days; hospital stay duration was 11.7 +/- 7.9 days; operation time was 6.8 +/- 1.9 h; and cross-clamping time was 154.4 +/- 42.0 min. There was one intraoperative conversion to Bentall procedure; one re-operation for bleeding; one operative death and one case who developed complications. Mean follow-up was 39.7 +/- 21.7 months (range, 12-108 months; cumulative rate, 1483 patients-months; follow-up rate, 94%). At 5 and 10 years, overall freedom from valve replacement was 94% and 87%; freedom from aortic regurgitation grade II or higher was 94% and 91%; and freedom from reoperation was 94% and 90% years, respectively. CONCLUSIONS: The reimplantation type of valve-sparing procedure appears to be facilitated by the use of the De Paulis valsalva graft with satisfactory perioperative and midterm results. PMID- 26584743 TI - Surgical Approaches to Strabismus After Third Nerve Palsy. PMID- 26584744 TI - "Mommy, Why Is There a Big White Thing on My Eye?". PMID- 26584745 TI - It Takes Two to Make a Cell Go Right. PMID- 26584746 TI - Preservation of the Monofixation Syndrome Following Surgery for Infantile Esotropia. PMID- 26584747 TI - Surgical Correction of Consecutive Esotropia With Unilateral Medial Rectus Recession. AB - PURPOSE: Unilateral medial rectus recession is a treatment option to surgically correct consecutive esotropia. This study evaluated the surgical outcomes of patients who underwent unilateral medial rectus recession for the treatment of consecutive esotropia after surgery for intermittent exotropia. METHODS: The medical records of 16 patients who underwent surgical correction of consecutive esotropia with unilateral medial rectus recession were retrospectively reviewed. Patients with intermittent exotropia who were previously treated with one or multiple surgical procedures (8 bilateral lateral rectus recession, 7 recess resect procedure, or 1 bilateral medial rectus resection) were included in the study. Three patients were adults and 13 patients were children. The mean age was 5 years for children and 50.3 years for adults. Consecutive esotropia was defined as residual manifest esodeviation of 10 prism diopters (PD) at 6 months postoperatively. Successful correction of consecutive esotropia was defined as the lack of manifest or intermittent tropia and esophoria/exophoria within 8 PD. Patients with monofixational exotropia were excluded from the study. RESULTS: Unilateral medial rectus recession was successful in the correction of consecutive esotropia in 10 of 16 cases (62.5%). Six of 16 (37.5%) patients had unsatisfactory postoperative alignment, with 5 patients showing recurrence of exotropia. Only one patient was undercorrected. CONCLUSIONS: The success rate of surgical correction of consecutive esotropia with single muscle surgery was good. Recurrence of exotropia accounted for most of the failures, and all recurrences occurred in the group of patients initially treated surgically for intermittent exotropia with a recess-resect procedure. PMID- 26584748 TI - Indocyanine Green-Enhanced Transpupillary Thermotherapy for Retinoblastoma: Analysis of 42 Tumors. AB - PURPOSE: To evaluate the efficacy of indocyanine green-enhanced transpupillary thermotherapy (ICG-TTT) for retinoblastoma that shows suboptimal response to conventional treatments. METHODS: A single center, retrospective chart review. The technique involved ICG infusion (range: 0.3 to 0.5 mg/kg) 1 minute prior to applying TTT using the indirect ophthalmoscope technique with a spot size of 1.2 mm. RESULTS: There were 42 retinoblastomas in 30 eyes of 21 patients treated with ICG-TTT. The reasons for ICG enhancement included suboptimal response to standard TTT (n = 31, 74%), recurrence after standard TTT (n = 3, 7%), or minimally pigmented fundus with poor standard TTT uptake (n = 8, 19%). The mean patient age at treatment was 12 months (median: 11.6 months, range: 3 to 31 months). The mean tumor base was 3.5 mm (median: 3 mm), mean tumor thickness was 2.5 mm (median; 2 mm), mean distance to the foveola was 2.6 mm (median: 3 mm), and mean distance to the optic disc was 2.2 mm (median: 0.75 mm). Treatment parameters included a spot size of 1.2 mm, mean power of 760 mW (median: 800 mW, range: 400 to 1,200 mW), and mean duration of 4 minutes (median: 4 minutes, range: 0.5 to 14 minutes). Following a median of 2 sessions (range: 1 to 5 sessions) of ICG-TTT, 33 (79%) tumors demonstrated complete regression. The mean tumor thickness postoperatively was 1.7 mm. Two (5%) tumors showed minimal regression after ICG-TTT. During a mean follow-up of 46 months (median: 33 months), tumor recurrence after ICG-TTT developed in 7 (17%) cases at a mean interval of 7 months. Local complications of ICG-TTT included focal paraxial cataract (n = 2, 7%), iris atrophy (n = 1, 3%), and transient retinal hemorrhage (n = 2, 7%). Systemic problems included ICG allergy (n = 1, 5%). Overall, tumor control and globe salvage was achieved in all 30 (100%) eyes. There were no metastatic events. CONCLUSIONS: ICG-TTT is an effective alternative for reti-noblastoma control, particularly for small tumors that show suboptimal response to standard PMID- 26584749 TI - Forceps Delivery-Related Ophthalmic Injuries: A Case Series. AB - PURPOSE: To report a case series of neonatal ophthalmic trauma induced by forceps assisted vaginal delivery. METHODS: Retrospective, non-comparative case series focusing on presentation and long-term outcomes. RESULTS: Eleven cases of ophthalmic injury secondary to forceps delivery (7 male, 4 female) from October 1997 to July 2014 are presented. Eight cases were born at a single center from January 2006 to July 2014, a rate of 1 case per 413 forceps-assisted deliveries. Follow-up ranged from 2 months to 17 years. Three cases had self-limiting eyelid bruising only. There was one case each of vitreous hemorrhage and hyphema, which resolved spontaneously. There were two cases of oculomotor nerve palsy associated with intracranial hemorrhage, both requiring surgical ptosis repair at 3 and 5 weeks old, respectively. There was one case of facial nerve palsy. Four cases sustained corneal trauma, manifesting as corneal edema in three cases at birth. The fourth of these cases presented at age 4.5 years with corneal scarring and amblyopia. Resulting astigmatism in these four cases ranged from 3.5 to 7.5 diopters and best-corrected visual acuity ranged from 6/12 to 6/36 Snellen at last follow-up. CONCLUSIONS: Although rare, ophthalmic trauma secondary to forceps-assisted delivery can result in a wide spectrum of anatomical injuries, which may be self-limiting or cause significant long-term visual impairment. The authors recommend awareness among obstetricians and pediatricians of these injuries, and referral to the ophthalmologist of any newborn delivered by forceps with evidence of compressive trauma such as scalp or eyelid bruising to rule out the presence of more serious ophthalmic trauma. PMID- 26584750 TI - Outcome of a New Acrylic Intraocular Lens Implantation in Pediatric Cataract. AB - PURPOSE: To study the outcome of Hoya Clear Preloaded intraocular lens (IOL) (PC 60AD, AF Series; Hoya, Tokyo, Japan) implantation in children. METHODS: Children who underwent phacoaspiration with primary posterior capsulotomy, anterior vitrectomy, and primary IOL implantation through a 2.8-mm incision were observed prospectively. In all cases, attempts were made to implant the IOL into the capsular bag. Parameters noted were ease of implantation, synechiae formation, IOL deposits, decentration of IOL, visual axis obscuration, haptic compression, and ovalling of the rhexis. Intraoperative complications related to the IOL were also recorded. RESULTS: This series comprised 58 eyes of 38 patients with congenital/developmental cataract who underwent implantation of the Hoya IOL. Mean age of the patients was 3.27 +/- 2.69 years (range: 3 months to 8 years) and mean follow-up was 24.5 +/- 9.13 months. Visual axis obscuration occurred in 4 eyes, posterior synechiae in 5 eyes, IOL deposits in 6 eyes, haptic compression in 3 eyes, and IOL decentration in 1 eye. CONCLUSIONS: The data suggest that implantation of the Hoya IOL is a safe option in children undergoing cataract surgery. PMID- 26584751 TI - Characteristics of Children With Primary Congenital Glaucoma Receiving Trabeculotomy and Goniotomy. AB - PURPOSE: To describe the groups of patients who received trabeculotomy or goniotomy for the treatment of primary congenital glaucoma (PCG) regarding age at treatment, intraocular pressure (IOP) outcome, and medication burden. METHODS: A retrospective chart review of patients with PCG seen at Rutgers New Jersey Medical School, Newark, New Jersey, from 1998 to 2012 was conducted. Inclusion criteria were patients who received trabeculotomy or goniotomy with at least 9 months of follow-up. Presenting examination, surgical intervention, IOP, and number of medications at 1 and 2 years postoperatively were recorded. Absolute and qualified success, defined as IOP greater than 5 and less than 21 mm Hg without and with medications, respectively, was determined. RESULTS: Fifty eyes of 29 patients were diagnosed as having PCG. Of those, 25 eyes received trabeculotomy or goniotomy, with 19 fulfilling inclusion criteria. Average age at the time of trabeculotomy was 8 months versus 21 months for patients undergoing goniotomy. Mean IOP was significantly reduced (P < .001) for both trabeculotomy and goniotomy by 29.5% at 1 year and 33.3% at 2 years. There was no significant difference in IOP control between trabeculotomy and goniotomy groups. Patients in the goniotomy group were treated with significantly more medications before and after surgery compared to patients receiving trabeculotomy (P < .01), resulting in a greater rate of absolute success in trabeculotomy at 1 and 2 years. CONCLUSIONS: Patients with PCG who underwent trabeculotomy had higher IOP and were treated at an earlier age than those who had goniotomy. Both effectively lowered IOP up to 2 years with greater medication burden in patients receiving goniotomy. PMID- 26584752 TI - Metastasis of Retinoblastoma to the Nasal Mucosa Following Bilateral Enucleation. PMID- 26584753 TI - Energy levels in CaWO4:Tb(3+) at high pressure. AB - The luminescence properties of Tb(3+) in CaWO4 crystals are investigated under a hydrostatic pressure of up to 200 kbar, i.e. across scheelite-to-fergusonite phase transition. It is shown that the typical blue ((5)D3) and green ((5)D4) emissions in this material are progressively quenched at room temperature as pressure is increased. This quenching is caused by a downshift of the charge transfer (or impurity trapped exciton) state that is formed between Tb(3+) and nearby W(6+) cations in conjunction with a pressure-induced increase of the lattice relaxation experienced by this excited state. An empirical model is introduced to calculate the evolution of the (Tb(3+)-W(6+)) charge transfer energy with pressure. Combined with the pressure dependence of the energy bandgap in CaWO4, the model allows locating the 4f levels of Tb(3+) relative to the fundamental host lattice for any pressure in the range 0-200 kbar. PMID- 26584754 TI - Linear Immunoglobulin A Dermatosis of Childhood With the String of Beads Sign. PMID- 26584755 TI - Right ventricular assist device results in worse post-transplant survival. AB - BACKGROUND: To our knowledge, how the need for a right ventricular assist device (RVAD) with a left ventricular assist device (LVAD) affects outcomes after orthotopic heart transplantation has not been studied in a multi-institutional database. METHODS: The United Network for Organ Sharing (UNOS) database was queried for all adult orthotopic heart transplantations from the period 2005 2012. Patients requiring a RVAD + LVAD as a bridge to transplant were compared with patients requiring a LVAD only and patients requiring no ventricular assist device (VAD). RESULTS: During the study period, 16,955 orthotopic heart transplantations were performed. Of these, 13,209 (77.9%) patients did not require a VAD, 3,270 (19.3%) required a LVAD only, and 457 (2.7%) required a RVAD + LVAD. The RVAD + LVAD group had the longest length of stay (25.7 days) compared with the no VAD group (20.8 days) and the LVAD-only group (21.1 days) (p < 0.001). On multivariate analysis, requirement of a RVAD + LVAD before transplantation was independently associated with post-transplant mortality (hazard ratio 1.22, 95% confidence interval 1.01-1.49, p = 0.04). Other variables associated with mortality included donor age, pulsatile flow LVAD as a bridge to transplant, prolonged ischemic time, worsening renal function, black race, history of diabetes in recipient, class II panel-reactive antibody >10%, sex mismatch, and extracorporeal membrane oxygenation or mechanical ventilation as a bridge to transplant. CONCLUSIONS: The requirement of a RVAD in addition to a LVAD before orthotopic heart transplantation is associated with worse post transplant outcomes and increased mortality. PMID- 26584756 TI - Modulation of immune response, physical barrier and related signaling factors in the gills of juvenile grass carp (Ctenopharyngodon idella) fed supplemented diet with phospholipids. AB - This study was conducted to investigate the effects of dietary phospholipids (PL) on the gill immune response and physical barrier of juvenile grass carp (Ctenopharyngodon idella). A total of 1080 juvenile grass carp with an average initial weight of 9.34 +/- 0.03 g were fed six semi-purified diets containing 0.40% (unsupplemented control group), 1.43%, 2.38%, 3.29%, 4.37% and 5.42% PL for 2 months. Compared with the control group, optimal PL supplementation increased (P < 0.05): (1) the lysozyme activity, acid phosphatase activity, complement component 3 (C3) content, liver expressed antimicrobial peptide 1 (LEAP-1) and LEAP-2 mRNA expression; (2) the relative mRNA expression of interleukin 10, transforming growth factor beta1, inhibitor factor kappaBalpha (IkappaBalpha) and target of rapamycin (TOR); (3) the activities of anti-superoxide anion (ASA), anti-hydroxyl radical (AHR), copper/zinc superoxide dismutase (SOD1), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR), glutathione content and mRNA levels of SOD1, CAT, GPx, GR and NF-E2-related factor 2 (Nrf2) genes; (4) the transcription abundance of occludin, claudin b, claudin c, claudin 12 and zonula occludens 1 genes. At the same time, appropriate PL supplementation decreased (P < 0.05): (1) tumor necrosis factor alpha, interleukin 1beta, nuclear factor kappaB p65 (NF-kappaB p65), IkappaB kinase beta (IKKbeta) and IkappaB kinase gamma (IKKgamma) mRNA expression; (2) malondialdehyde (MDA), protein carbonyl (PC) and reactive oxygen species (ROS) content and the relative mRNA expression of Kelch-like-ECH-associated protein 1a (Keap1a) and Keap1b; (3) the transcription abundance of myosin light chain kinase (MLCK) and p38 mitogen activated protein kinase (p38 MAPK) genes. In conclusion, the positive effect of PL on gill health is associated with the improvement of the immunity, antioxidant status and tight junction barrier of fish gills. Finally, based on ACP activity, C3 content, PC content and ASA activity in the gills, the optimal dietary PL level for juvenile grass carp (9.34-87.50 g) was estimated to be 3.62%, 4.30%, 3.91% and 3.86%, respectively. PMID- 26584757 TI - Characterisation of a novel Type I crustin involved in antibacterial and antifungal responses in the red claw crayfish, Cherax quadricarinatus. AB - Antimicrobial peptides are important immune effectors involved in mediating innate immune responses against intruding pathogens. Here, we successfully isolated and characterized a novel Type I crustin from the red claw crayfish Cherax quadricarinatus. The full-length cDNA encoded by this gene, designated CqCrs, comprised 608 bp, containing a 5'-untranslated region (UTR) of 55 bp, a 3' UTR of 229 bp with a poly (A) tail, and an open reading frame (ORF) of 324 bp encoding a polypeptide of 107 amino acids. The deduced amino acid sequence of CqCrs exhibited a configuration typical of other crustacean Type I crustin orthologs, including one signal peptide region at the N-terminus between residues 1 and 16 and a long whey acidic protein (WAP) domain at the C-terminus between residues 60 and 107, along with a WAP-type "four-disulfide core" motif. Phylogenetic analysis showed that CqCrs was clustered first with other crustacean Type I crustins, then with other crustacean Type II crustins, and finally with other crustacean Type III crustins. Transcription of CqCrs was detected in all tissues, especially in immune tissues and was differentially induced in hemocytes post-stimulation with beta-1, 3-glucan, lipopolysaccharides (LPS) and peptidoglycans (PG) at selected time-points. To clarify the biological activity of CqCrs, the recombinant CqCrs protein (rCqCrs) was constructed and expressed in Escherichia coli BL21 (DE3). Purified rCqCrs bound to diverse bacteria and inhibited the growth of different microbes to varying degrees. These findings suggest that CqCrs is involved in a specific innate immune recognition and defense mechanisms against bacterial and fungal in C. quadricarinatus. PMID- 26584758 TI - Immunological and health-state parameters in the Patagonian rockfish Sebastes oculatus. Their relation to chemical stressors and seasonal changes. AB - We present the results of a field study that evaluates whether exposure to anthropogenic pollution impacts immunological and health-state parameters of wild marine fish during the breeding and non-breeding periods. We assessed aspects of innate immunity (bactericidal capacity, bacterial agglutination, and leukocyte profile) and general health-related parameters (neutrophil to lymphocyte ratio, hematocrit, and condition factor) in the Patagonian rockfish (Sebastes oculatus) sampled from polluted (exposed) and reference (control) sites during winter (i.e., coolest temperatures and active reproductive period) and in summer (i.e., warmest temperatures and non-reproductive period). Results showed lower bactericidal competence, hematocrit, and condition factor in fish from exposed sites independently of season, whereas lymphocytes were higher and monocytes lower at the exposed site only during summer. Moreover, fish sampled during winter displayed lower bactericidal competence, hematocrit, and condition factor than those sampled in summer independently of site, whereas the opposite pattern was found for bacterial agglutination. These results could be explained by life history theory, which predicts a re-allocation of resources between reproduction and other physiological functions (including immunity) during the most energetically demanding season. The present results show an alteration in immunological and health-state parameters of wild marine fish exposed to anthropogenic pollution independently of season, which could potentially result in higher susceptibility to disease and in turn population decline. PMID- 26584759 TI - Compact component for integrated quantum optic processing. AB - Quantum interference is indispensable to derive integrated quantum optic technologies (1-2). For further progress in large scale integration of quantum optic circuit, we have introduced first time two mode interference (TMI) coupler as an ultra compact component. The quantum interference varying with coupling length corresponding to the coupling ratio is studied and the larger HOM dip with peak visibility ~0.963 +/- 0.009 is found at half coupling length of TMI coupler. Our results also demonstrate complex quantum interference with high fabrication tolerance and quantum visibility in TMI coupler. PMID- 26584760 TI - Whole scalp resting state EEG of oscillatory brain activity shows no parametric relationship with psychoacoustic and psychosocial assessment of tinnitus: A repeated measures study. AB - Tinnitus is a perception of sound that can occur in the absence of an external stimulus. A brief review of electroencephalography (EEG) and magnetoencephalography (MEG) literature demonstrates that there is no clear relationship between tinnitus presence and frequency band power in whole scalp or source oscillatory activity. Yet a preconception persists that such a relationship exists and that resting state EEG could be utilised as an outcome measure for clinical trials of tinnitus interventions, e.g. as a neurophysiological marker of therapeutic benefit. To address this issue, we first examined the test-retest correlation of EEG band power measures in tinnitus patients (n = 42). Second we examined the evidence for a parametric relationship between numerous commonly used tinnitus variables (psychoacoustic and psychosocial) and whole scalp EEG power spectra, directly and after applying factor reduction techniques. Test-retest correlation for both EEG band power measures and tinnitus variables were high. Yet we found no relationship between whole scalp EEG band powers and psychoacoustic or psychosocial variables. We conclude from these data that resting state whole scalp EEG should not be used as a biomarker for tinnitus and that greater caution should be exercised in regard to reporting of findings to avoid confirmation bias. The data was collected during a randomised controlled trial registered at ClinicalTrials.gov (Identifier: NCT01541969). PMID- 26584761 TI - Effects of noise exposure on development of tinnitus and hyperacusis: Prevalence rates 12 months after exposure in middle-aged rats. AB - Fischer Brown Norway (FBN) rats (n = 233) were unilaterally exposed to 12 different combinations of noise intensity, duration, and spectrum, while 46 rats served as sham-exposed controls. Rats were behaviorally tested for tinnitus and hyperacusis using gap-induced inhibition of the acoustic startle reflex (Gap) and prepulse inhibition (PPI) using 60-dB SPL before noise-exposure and at regular intervals for 12 mo. 12-mo after noise exposure the middle-aged rats were then tested again for tinnitus and hyperacusis before collecting Auditory Brainstem Response (ABR) thresholds. Collapsing across all noise exposure conditions a significant tinnitus-like deficit in responding to silent gaps was observed, with the most likely tinnitus pitch around 16 kHz. Rates of tinnitus 12-mo after noise exposure were greatest in groups receiving the four least intense noise doses (110-dB for 30, 60 and 120 min, and 116-dB for 30 min), while some of the greatest rates of hyperacusis occurred in groups receiving more intense or longer exposures. The results suggest that rates for developing tinnitus in animal models may not be easily predicted based upon noise exposure dose, but that low to-moderate noise exposures may result in the greatest likelihood for producing tinnitus. PMID- 26584762 TI - Tissue oxidative stress induced by patulin and protective effect of crocin. AB - Patulin (PAT) is a secondary toxic metabolite produced principally by Penicillium expansum. This mycotoxin is known to be teratogenic, mutagenic, immunotoxic and neurotoxic, and it has been shown to cause damage in several organs in laboratory animals. This study focuses on the prevention of experimental murine PAT-induced nephrotoxicity and hepatotoxicity. We investigate the ability of a natural product, crocin (CRO), to counteract the toxic effects of PAT. Pre-treatment of mice with CRO prevented PAT-induced oxidative damage in both liver and kidney. CRO reduced lipid peroxidation, protein oxidation and restored redox status by regulating the endogenous antioxidant enzymatic system. These data corroborate and extend findings in PAT-induced nephrotoxicity and hepatotoxicity, and further suggest that preventive effect of CRO towards other forms of PAT toxicity, including neurotoxicity, may be warranted. PMID- 26584763 TI - Activation of ER stress and apoptosis by alpha- and beta-zearalenol in HCT116 cells, protective role of Quercetin. AB - Zearalenone (ZEN) and its metabolites are found in many food products and are known to induce many toxic effects. The major ZEN metabolites are alpha zearalenol (alpha-ZOL) and beta-zearalenol (beta-ZOL). The mechanisms by which they mediate their cytotoxic effects are not well known and seem to differ depending on the type of cells. We investigated the possible underlying mechanism in alpha-ZOL and beta-ZOL-induced toxicity in HCT116 cells. We showed that cell treatment with alpha-ZOL/beta-ZOL generated endoplasmic reticulum (ER) stress and activated the Unfolded Protein Response (UPR) as evidenced by XBP1 mRNA splicing and up-regulation of GADD34, GRP78, ATF4 and CHOP. Apoptosis was triggered by ZEN metabolites-induced ER stress, and executed through a mitochondria-dependent pathway, characterized by a loss of mitochondrial transmembrane potential (DeltaPsim), a downstream generation of O2*(-) and caspase 3 activation. Cellular deficiency of the pro-apoptotic proteins Bax and Bak protected cells against alpha/beta-ZOL-induced toxicity. However, treatment with alpha-ZOL or beta-ZOL combined with Quercetin (QUER), a common dietary flavonoid with well-known antioxidant activity, significantly reduced damage induced by alpha and beta-ZOL in all tested markers. We concluded that QUER protects against the cellular toxicity of alpha and beta-ZOL.*. PMID- 26584764 TI - Design and Synthesis of Near-infrared Fluorescent Probes for Imaging of Biological Nitroxyl. AB - Nitroxyl (HNO), the reduced and protonated form of nitric oxide (NO), has recently been identified as an interesting and important signaling molecule in biological systems. However, research on its biosynthesis and bioactivities are hampered by the lack of versatile HNO detection methods applicable to living cells. In this report, two new near-infrared (NIR) probes were designed and synthesized for HNO imaging in living cells. One of the probes was found to display high sensitivity towards HNO, with up to 67-fold of fluorescence increment after reaction with HNO. The detection limit was determined to be as low as 0.043 MUM. The probe displayed high selectivity towards HNO over other biologically related species including metal ions, reactive oxygen species, reactive nitrogen species and reactive sulfur species. Furthermore, the probe was shown to be suitable for imaging of exogenous and endogenous HNO in living cells. Interestingly, the probe was found to be mainly localized in lysosomes. We envision that the new NIR probe described here will serve as a useful tool for further elucidation of the intricate roles of HNO in living cells. PMID- 26584765 TI - [Diagnosis of a clear cell renal carcinoma by biopsy of an iris metastasis associated with ocular hypertension in a black man from Martinique: Case report and literature review]. PMID- 26584766 TI - [Role of intravitreal bevacizumab injection in the treatment of vascularized retinal pigment epithelial detachment]. PMID- 26584767 TI - [Spontaneous separation of epiretinal membrane: Reports of 3 cases]. AB - PURPOSE: Idiopathic epiretinal membranes most commonly develop in patients over 50 years of age. Posterior vitreous detachment seems to play a role in their formation. Epiretinal membranes are uncommon in young subjects. Surgical intervention is indicated in eyes with true functional symptoms and loss of visual acuity. METHOD: We report 3 cases with spontaneous separation of epiretinal membranes imaged by Optical Coherence Tomography. RESULTS: All patients reported improvement in functional symptoms after spontaneous separation of the epiretinal membrane. Anatomic recovery with reappearance of the foveolar depression was observed on Optical Coherence Tomography. CONCLUSION: A longer period of observation may be indicated in young patients with epiretinal membrane, due to the higher rate of spontaneous separation. PMID- 26584768 TI - Theory in Biology: Figure 1 or Figure 7? AB - The pace of modern science is staggering. The quantities of data now flowing from DNA sequencers, fluorescence and electron microscopes, mass spectrometers, and other mind-blowing instruments leave us faced with information overload. This explosion in data has brought on its heels a concomitant need for efforts at the kinds of synthesis and unification we see in theoretical physics. Often in cell biology, when theoretical modeling takes place, it is as a figure 7 reflection on experiments that have already been done, with data fitting providing a metric of success. Figure 1 theory, by way of contrast, is about living dangerously by turning our thinking into formal mathematical predictions and confronting that math with experiments that have not yet been done. PMID- 26584769 TI - [Benign chondroid syringoma of the orbit: A case report]. PMID- 26584770 TI - [Role of SD-OCT in pediatric glaucoma suspects]. PMID- 26584771 TI - [A rare cause of optic neuropathy in sarcoidosis: Acute posterior ischemic optic neuropathy, case report]. PMID- 26584772 TI - Atypical presentation of multiple sclerosis. PMID- 26584773 TI - [Ptosis in rare muscle and neuromuscular junction disorders: A literature review and diagnostic flowchart]. PMID- 26584774 TI - [Ranibizumab as a treatment for type 2 non-proliferative macular telangiectasia]. PMID- 26584775 TI - A novel multicomponent redox polymer nanobead based high performance non enzymatic glucose sensor. AB - The fabrication of a highly sensitive electrochemical non-enzymatic glucose sensor based on copper nanoparticles (Cu NPs) dispersed in a graphene (G) ferrocene (Fc) redox polymer multicomponent nanobead (MCNB) is reported. The preparation of MCNB involves three major steps, namely: i) the preparation of a poly(aniline-co-anthranilic acid)-grafted graphene (G-PANI(COOH), ii) the covalent linking of ferrocene to G-PANI(COOH) via a polyethylene imine (PEI), and iii) the electrodeposition of Cu NPs. The prepared MCNB (designated as G PANI(COOH)-PEI-Fc/Cu-MCNB), contains a conductive G-PANI(COOH), electron mediating Fc, and electrocatalytic Cu NPs that make it suitable for ultrasensitive non-enzymatic electrochemical sensing. The morphology, structure, and electro activities of MCNB were characterized. Electrochemical measurements showed that the G-PANI(COOH)-PEI-Fc/Cu-MCNB/GCE modified electrode exhibited good electrocatalytic behavior towards the detection of glucose in a wide linear range (0.50 to 15mM), with a low detection limit (0.16mM) and high sensitivity (14.3uAmM(-1)cm(-2)). Besides, the G-PANI(COOH)-PEI-Fc/Cu-MCNB/GCE sensor electrode did not respond to the presence of electroactive interferrants (such as uric acid, ascorbic acid, and dopamine) and saccharides or carbohydrates (fructose, lactose, d-isoascorbic acid, and dextrin), demonstrating its selectivity towards glucose. The fabricated NEG sensor exhibited high precision for measuring glucose in serum samples, with an average RSD of 4.3% and results comparable to those of commercial glucose test strips. This reliability and stability of glucose sensing indicates that G-PANI(COOH)-PEI-Fc/Cu-MCNB/GCE would be a promising material for the non-enzymatic detection of glucose in physiological fluids. PMID- 26584776 TI - Top-down influence on the visual cortex of the blind during sensory substitution. AB - Visual sensory substitution devices provide a non-surgical and flexible approach to vision rehabilitation in the blind. These devices convert images taken by a camera into cross-modal sensory signals that are presented as a surrogate for direct visual input. While previous work has demonstrated that the visual cortex of blind subjects is recruited during sensory substitution, the cognitive basis of this activation remains incompletely understood. To test the hypothesis that top-down input provides a significant contribution to this activation, we performed functional MRI scanning in 11 blind (7 acquired and 4 congenital) and 11 sighted subjects under two conditions: passive listening of image-encoded soundscapes before sensory substitution training and active interpretation of the same auditory sensory substitution signals after a 10-minute training session. We found that the modulation of visual cortex activity due to active interpretation was significantly stronger in the blind over sighted subjects. In addition, congenitally blind subjects showed stronger task-induced modulation in the visual cortex than acquired blind subjects. In a parallel experiment, we scanned 18 blind (11 acquired and 7 congenital) and 18 sighted subjects at rest to investigate alterations in functional connectivity due to visual deprivation. The results demonstrated that visual cortex connectivity of the blind shifted away from sensory networks and toward known areas of top-down input. Taken together, our data support the model of the brain, including the visual system, as a highly flexible task-based and not sensory-based machine. PMID- 26584777 TI - Shape-Dependent Skin Penetration of Silver Nanoparticles: Does It Really Matter? AB - Advancements in nano-structured materials have facilitated several applications of nanoparticles (NPs). Skin penetration of NPs is a crucial factor for designing suitable topical antibacterial agents with low systemic toxicity. Available reports focus on size-dependent skin penetration of NPs, mainly through follicular pathways. Herein, for the first time, we demonstrate a proof-of concept study that entails variations in skin permeability and diffusion coefficients, penetration rates and depth-of-penetration of differently shaped silver NPs (AgNPs) via intercellular pathways using both in vitro and in vivo models. The antimicrobial activity of AgNPs is known. Different shapes of AgNPs may exhibit diverse antimicrobial activities and skin penetration capabilities depending upon their active metallic facets. Consideration of the shape dependency of AgNPs in antimicrobial formulations could help developing an ideal topical agent with the highest efficacy and low systemic toxicity. PMID- 26584778 TI - Geometrically Precise Building Blocks: the Self-Assembly of beta-Peptides. AB - Peptides comprised entirely of beta-amino acids, or beta-peptides, have attracted substantial interest over the past 25 years due to their unique structural and chemical characteristics. beta-Peptides form well-defined secondary structures that exhibit different geometries compared with their alpha-peptide counterparts, giving rise to their foldamer classification. beta-Peptide foldamers can be functionalized easily and are metabolically stable and, together with the predictable side-chain topography, have led to the design of a growing number of bioactive beta-peptides with a range of biological targets. The strategic engineering of chemical and topographic properties has also led to the design of beta-peptide mimics of higher-order oligomers. More recently, the ability of these peptides to self-assemble into complex structures of controlled geometries has been exploited in materials applications. The focus of this mini-review is on how the unique structural features of beta-peptide assemblies have been exploited in the design of self-assembled proteomimetic bundles and nanomaterials. PMID- 26584779 TI - Engineering Duplex RNAs for Challenging Targets: Recognition of GGGGCC/CCCCGG Repeats at the ALS/FTD C9orf72 Locus. AB - A GGGGCC expansion within an intronic region of the C9orf72 gene forms RNA foci that are associated with one-third of familial amyotrophic lateral sclerosis and one-quarter of frontotemporal dementia. The C9orf72 locus also expresses an antisense transcript with a CCCCGG expansion that forms foci and may contribute to disease. Synthetic agents that bind these hexanucleotide repeats and block foci would be leads for therapeutic discovery. We have engineered duplex RNAs to enable them to recognize difficult C/G targets. Recognition inhibits foci formed by both GGGGCC and CCCCGG RNA. Our findings show that a single duplex RNA can be used to recognize both disease-related C9orf72 transcripts. More broadly, we extend RNAi to previously inaccessible C/G sequences and provide another example of target recognition in human cells by nuclear RNAi. PMID- 26584780 TI - Quantitative Lipoproteomics in Clostridium difficile Reveals a Role for Lipoproteins in Sporulation. AB - Bacterial lipoproteins are surface exposed, anchored to the membrane by S diacylglyceryl modification of the N-terminal cysteine thiol. They play important roles in many essential cellular processes and in bacterial pathogenesis. For example, Clostridium difficile is a Gram-positive anaerobe that causes severe gastrointestinal disease; however, its lipoproteome remains poorly characterized. Here we describe the application of metabolic tagging with alkyne-tagged lipid analogs, in combination with quantitative proteomics, to profile protein lipidation across diverse C. difficile strains and on inactivation of specific components of the lipoprotein biogenesis pathway. These studies provide the first comprehensive map of the C. difficile lipoproteome, demonstrate the existence of two active lipoprotein signal peptidases, and provide insights into lipoprotein function, implicating the lipoproteome in transmission of this pathogen. PMID- 26584781 TI - Highly tunable hybrid metamaterials employing split-ring resonators strongly coupled to graphene surface plasmons. AB - Metamaterials and plasmonics are powerful tools for unconventional manipulation and harnessing of light. Metamaterials can be engineered to possess intriguing properties lacking in natural materials, such as negative refractive index. Plasmonics offers capabilities of confining light in subwavelength dimensions and enhancing light-matter interactions. Recently, the technological potential of graphene-based plasmonics has been recognized as the latter features large tunability, higher field-confinement and lower loss compared with metal-based plasmonics. Here, we introduce hybrid structures comprising graphene plasmonic resonators coupled to conventional split-ring resonators, thus demonstrating a type of highly tunable metamaterial, where the interaction between the two resonances reaches the strong-coupling regime. Such hybrid metamaterials are employed as high-speed THz modulators, exhibiting ~60% transmission modulation and operating speed in excess of 40 MHz. This device concept also provides a platform for exploring cavity-enhanced light-matter interactions and optical processes in graphene plasmonic structures for applications including sensing, photo-detection and nonlinear frequency generation. PMID- 26584782 TI - Characterisation of haematological profiles and whole blood relative gene expression levels in Holstein-Friesian and Jersey bull calves undergoing gradual weaning. AB - Haematological profiles indicate the health status of an animal and can be used to identify sub-clinical stress responses. The objectives of the study were to examine (i) the effect of breed and plane of nutrition, on haematological profiles of artificially reared Holstein-Friesian and Jersey bull calves in response to gradual weaning, and (ii) the effect of breed on immune response genes in bovine whole blood using real-time quantitative PCR. Holstein-Friesian and Jersey bull calves were group housed indoors and individually fed using an automatic feeder. They were allocated to a high, medium or low plane of nutrition, based on milk replacer (MR) and concentrate. The nutrition treatments were calculated using National Research Council guidelines in order to achieve a high, medium or low growth rate for each respective breed. During the weaning phase MR was gradually reduced over a 14-day (d) period (d -13 to d 0). Calves were blood sampled on d -14, -6, -3, 0, 1, 3, 8 and 14 relative to weaning (d 0) for subsequent haematological analysis. On d -14, 1 and 8, a subset of eight Holstein-Friesian calves randomly selected from the medium nutrition treatment and eight Jersey calves randomly selected from the high nutrition treatment, were blood sampled for gene expression profiling, targeting biomarkers of weaning stress. These two treatment groups were chosen to examine the effect of breed on expression of the genes of interest, as energy intake and animal performance were similar. There was no effect of breed*plane of nutrition interaction nor effect of plane of nutrition on any variable measured (P>0.05). Gradual weaning produced differential biological responses in the two breeds evidenced by breed*time interactions for lymphocyte, monocyte and red blood cell number, plasma haemoglobin and haptoglobin concentrations (P<0.05). The typical stress response consisting of neutrophilia and lymphopaenia was not observed for any treatment. An immune response to gradual weaning was observed as the relative gene expression level of the pro-apoptotic gene, Fas, increased on d 1 relative to d 14 (P<0.05). Relative gene expression levels were greater in Jersey calves compared with Holstein-Friesian for the pro-inflammatory cytokine CXCL8 (P=0.05) and the glucocorticoid receptor, GRalpha (P<0.05). The increased levels of these transcripts suggest that Jersey calves may have a more sensitive immune system compared with Holstein-Friesian. PMID- 26584783 TI - Evolution of Utmost Vital Emergency (UVE) blood transfusion from 2010 to 2014 in the French establishment of the Blood Centre Atlantique. PMID- 26584784 TI - Esophageal wall dissection: an unknown adverse event of EUS. PMID- 26584785 TI - Regional center for complex colonoscopy: yield of neoplasia in patients with prior incomplete colonoscopy. AB - BACKGROUND AND AIMS: Incomplete colonoscopy increases the risk of incident proximal colon cancer postcolonoscopy. Incomplete colonoscopy is often followed by barium enema or CT colonography. We sought to describe the yield of completion colonoscopy in a regional center for complex colonoscopy. METHODS: This is a retrospective cohort study of 520 consecutive patients referred to a single colonoscopist over a 14-year period for completion colonoscopy after a previous incomplete examination. RESULTS: Colonoscopy was completed to the cecum in 506 of 520 patients (97.3%). A total of 913 conventional adenomas was removed in 277 patients (adenoma detection rate 53.3%). There were 184 adenomas >= 1 cm in size or with advanced pathology. There were 525 serrated-class lesions removed in 175 patients, including 54 sessile serrated polyps in 26 patients and 41 hyperplastic polyps greater than 1 cm in 26 patients. Nine colorectal cancers were found. We estimated that approximately 57% of the conventional adenomas, 58% of the sessile serrated polyps, 27% of the hyperplastic polyps, and all 9 cancers detected by the completion colonoscopy were beyond the extent of the previous examination. CONCLUSIONS: The yield of completion colonoscopy in a cohort of patients with previous failed cecal intubation was substantial. Regional centers for complex colonoscopy can provide high rates of cecal intubation in cases of incomplete colonoscopy and high yields of lesions in these cases. The regional center for complex colonoscopy is an important medical service. PMID- 26584786 TI - Incarcerated, retroflexed endoscope associated with a paraesophageal hernia. PMID- 26584787 TI - Comparing Tests Assessing Protein-Energy Wasting: Relation With Quality of Life. AB - OBJECTIVE: Protein-energy wasting (PEW), a state of decreased bodily protein and energy fuels, is highly prevalent among hemodialysis patients. The best method to determine PEW, however, remains debated. As an independent, negative association between PEW and quality of life (QOL) has been demonstrated, establishing which nutrition-related test correlates best with QOL may help to identify how PEW should preferably be assessed. DESIGN AND METHODS: Data were used from CONTRAST, a cohort of end-stage kidney disease patients. At baseline, Subjective Global Assessment (SGA), Malnutrition Inflammation Score (MIS), Geriatric Nutritional Risk Index, composite score on protein-energy nutritional status, normalized protein nitrogen appearance, body mass index, serum albumin, and serum creatinine were determined. QOL was assessed by the Kidney Disease Quality of Life Short Form 1.3. The present study reports on 2 general and 11 kidney disease-specific QOL scores. Spearman's rho (rho) was calculated to determine correlations between nutrition-related tests and QOL domains. Twelve months after randomization, a sensitivity analysis was performed to test the robustness of the results. RESULTS: Of 714 patients, 489 representative subjects were available for analysis. All tests correlated with the Physical Component Score, except body mass index. Only SGA and MIS correlated significantly with the Mental Component Score. SGA correlated significantly with 10 of 11 kidney disease-specific QOL domains. The MIS not only correlated significantly with all (11) kidney disease specific QOL domains but also with higher correlation coefficients. CONCLUSION: Of the 8 investigated nutrition-related tests, only MIS correlates with all QOL domains (13 of 13) with the strongest associations. PMID- 26584788 TI - Colesevelam as an Add-On Treatment for Control of Dyslipidemia and Hyperglycemia in Type 2 Diabetes. PMID- 26584789 TI - Direct Depth- and Lateral- Imaging of Nanoscale Magnets Generated by Ion Impact. AB - Nanomagnets form the building blocks for a variety of spin-transport, spin-wave and data storage devices. In this work we generated nanoscale magnets by exploiting the phenomenon of disorder-induced ferromagnetism; disorder was induced locally on a chemically ordered, initially non-ferromagnetic, Fe60Al40 precursor film using nm diameter beam of Ne(+) ions at 25 keV energy. The beam of energetic ions randomized the atomic arrangement locally, leading to the formation of ferromagnetism in the ion-affected regime. The interaction of a penetrating ion with host atoms is known to be spatially inhomogeneous, raising questions on the magnetic homogeneity of nanostructures caused by ion-induced collision cascades. Direct holographic observations of the flux-lines emergent from the disorder-induced magnetic nanostructures were made in order to measure the depth- and lateral- magnetization variation at ferromagnetic/non ferromagnetic interfaces. Our results suggest that high-resolution nanomagnets of practically any desired 2-dimensional geometry can be directly written onto selected alloy thin films using a nano-focussed ion-beam stylus, thus enabling the rapid prototyping and testing of novel magnetization configurations for their magneto-coupling and spin-wave properties. PMID- 26584790 TI - Making a difference for children and families: an appreciative inquiry of health visitor values and why they start and stay in post. AB - The study aimed to develop an understanding of health visitor recruitment and retention by examining what existing staff and new recruits wanted from their job, their professional aspirations and what would encourage them to start and stay in employment. Following a period of steady decline in numbers, the health visitor workforce in England has recently been invested in and expanded to deliver universal child public health. To capitalise on this large investment, managers need an understanding of factors influencing workforce retention and continuing recruitment of health visitors. The study was designed using an interpretive approach and involved students (n = 17) and qualified health visitors (n = 22) from the north and south of England. Appreciative inquiry (AI) exercises were used as methods of data collection during 2012. During AI exercises students and health visitors wrote about 'a practice experience you have felt excited and motivated by and briefly describe the factors that contributed to this'. Participants were invited to discuss their written accounts of practice with a peer during an audio-recorded sharing session. Participants gave consent for written accounts and transcribed recordings to be used as study data, which was examined using framework analysis. In exploring personal meanings of health visiting, participants spoke about the common aspiration to make a difference to children and families. To achieve this, they expected their job to allow them to: connect with families; work with others; use their knowledge, skills and experience; use professional autonomy. The study offers new insights into health visitors' aspirations, showing consistency with conceptual explanations of optimal professional practice. Psychological contract theory illustrates connections between professional aspirations and work commitment. Managers can use these findings as part of workforce recruitment and retention strategies and for building on the health visitor commitment to making a difference to children and families. PMID- 26584791 TI - Steroid-Derived Naphthoquinoline Asphaltene Model Compounds: Hydriodic Acid Is the Active Catalyst in I2-Promoted Multicomponent Cyclocondensation Reactions. AB - A multicomponent cyclocondensation reaction between 2-aminoanthracene, aromatic aldehydes, and 5-alpha-cholestan-3-one has been used to synthesize model asphaltene compounds. The active catalyst for this reaction has been identified as hydriodic acid, which is formed in situ from the reaction of iodine with water, while iodine is not a catalyst under anhydrous conditions. The products, which contain a tetrahydro[4]helicene moiety, are optically active, and the stereochemical characteristics have been examined by VT-NMR and VT-CD spectroscopies, as well as X-ray crystallography. PMID- 26584792 TI - Predictors of stereoacuity outcome in visually mature subjects with exotropia. AB - The purpose of this study was to determine the predictors of stereoacuity outcome in visually mature subjects with exotropia following surgical correction. Visually mature subjects who were surgically aligned and had been tested for stereoacuity in the postoperative period were studied retrospectively. Subjects were grouped with respect to their responses to Titmus or TNO stereotests. Characteristics such as amblyopia, anisometropia, and characteristics of the exodeviation such as time of onset, duration, intermittency, presence of an A or V pattern, distance-near disparity, coexisting vertical deviation, and inferior oblique overaction, were compared between the groups. One hundred and four visually mature subjects with exotropia met the inclusion criteria. Stereoacuity was achieved in 77% of the study group and only 9% of these could achieve fine stereoacuity. Negative stereoacuity was more frequently associated with larger deviation angles, higher anisometropia, inferior oblique overaction, pattern strabismus, coexisting vertical strabismus, and distance-near disparity, but not at a statistically significant level. The optimal cutoff for strabismus duration was 20 years for a positive stereoacuity outcome. Any-level visual acuity difference was found to decrease the chance for positive stereoacuity significantly. The odds ratios for the stereoacuity positivity were 4.05 for strabismus duration <20 years, 7.9 for strabismus onset >1 year of age, 3.79 for weaker eye visual acuity >20/25 and 9.85 for intermittency of strabismus. Intermittence of exotropia was the strongest predictor for positive stereoacuity. Exotropia onset after 1 year of age, absence of any-level visual acuity difference, and strabismus duration <20 years were the other predictors with decreasing power. PMID- 26584793 TI - Reply: 'Myopic foveoschisis: an ectatic retinopathy, not a schisis'. PMID- 26584794 TI - MEK inhibitors: a new class of chemotherapeutic agents with ocular toxicity. PMID- 26584795 TI - Biometric and refractive changes after orbital decompression in Korean patients with thyroid-associated orbitopathy. AB - PURPOSE: To determine the biometric and refractive changes after orbital decompression in Korean patients with thyroid-associated orbitopathy (TAO). METHODS: Retrospective, observational study (between October 2012 and September 2014) was performed. Patients with TAO undergoing orbital decompression for stable proptosis received ophthalmic examinations, including Hertel exophthalmometry, A-scan biometry, autorefraction measures, corneal topography, and wavefront aberration measures, before orbital decompression and again 2 months after surgery. RESULTS: Included in the study were 43 eyes from 23 patients. The mean exophthalmometric value decreased by 4.1 mm 2 months after orbital decompression (P<0.001). On average, axial length (AL) increased significantly by 0.08 mm (P<0.001); specifically, 37 (86%) of the 43 eyes had increased AL. Whereas anterior chamber depth and lens thickness showed no significant changes (P=0.086 and P=0.905, respectively), the mean spherical refraction and spherical equivalent (SE) decreased by 0.35 and 0.48 D, respectively (P=0.008 and P<0.001, respectively). However, cylindrical refraction and axis showed no significant changes (P=0.057 and P=0.218, respectively). The changes in AL and SE were significantly correlated (R=-0.411, P=0.009). Notably, there were no changes in corneal topography or wavefront aberration after orbital decompression. CONCLUSIONS: TAO patients who underwent orbital decompression showed myopic refractive change via increase in AL. Possible refractive changes should be considered in cases of TAO complaining of decreased visual acuity after orbital decompression. PMID- 26584797 TI - Myopic foveoschisis: an ectatic retinopathy, not a schisis. PMID- 26584796 TI - Serial evaluation of retinal vascular changes in infants treated with intravitreal bevacizumab for aggressive posterior retinopathy of prematurity in zone I. AB - PURPOSE: To evaluate the serial changes in retinal vasculature in infants treated with intravitreal bevacizumab (IVB) for aggressive posterior retinopathy of prematurity (APROP) in zone I. METHODS: Retrospective analysis of serial changes in retinal vasculature after IVB in the seven eyes of four babies with APROP in zone I. RESULTS: The initial regression, following IVB, was dramatic with reduction in vessel caliber and marked thinning and invisibility of the bridging shunts. Resurgent vascular development was very slow radially though there was continued abnormal vascular growth circumferentially. Common findings in all eyes were tangled vasculature and fine saw-toothed shunts. The variable findings were (1) new closely packed multilayered bridging shunts, long arching mature looking vessels, and finally a ridge at the periphery (n=3 eyes) at 52 weeks of postmenstrual age (PMA); (2) status quo at the stage of saw-toothed shunt and ridge in both eyes for a long time (n=2 eyes); and (3) multiple retinal hemorrhages within the vascularized retina and thick preretinal hemorrhage overlying the saw-toothed shunts and ridge that persisted for another 3 weeks and regressed 2 weeks after laser (n=1). The eyes that received bevacizumab alone (3) did not show any abnormal vascularization at 56 weeks of PMA or beyond. CONCLUSIONS: The retinal vascularization following IVB was different than normal in terms of its time, speed, and morphology; few of these changes are first to be reported in the literature (Medline search) and warrants further studies. PMID- 26584798 TI - CORR Insights((r)): Is Age or Surgical Approach Associated With Osteonecrosis in Patients With Developmental Dysplasia of the Hip? A Meta-analysis. PMID- 26584799 TI - Clinical Faceoff: Are Distal-third Diaphyseal Humerus Fractures Best Treated Nonoperatively? PMID- 26584800 TI - Classifications in Brief: Goutallier Classification of Fatty Infiltration of the Rotator Cuff Musculature. PMID- 26584801 TI - CORR Insights((r)): Outcomes of a Modular Intercalary Endoprosthesis as Treatment for Segmental Defects of the Femur, Tibia, and Humerus. PMID- 26584802 TI - How do Orthopaedic Devices Change After Their Initial FDA Premarket Approval? AB - BACKGROUND: The FDA approves novel, high-risk medical devices through the premarket approval (PMA) process based on clinical evidence supporting device safety and effectiveness. Devices subsequently may undergo postmarket modifications that are approved via one of several PMA supplement review tracks, usually without additional supporting clinical data. While orthopaedic devices cleared via the less rigorous 510(k) pathway have been studied previously, devices cleared through the PMA pathway and those receiving postmarket PMA supplements warrant further investigation. QUESTIONS/PURPOSES: We asked: What are (1) the types of original orthopaedic devices receiving FDA PMA approval, (2) the number and rate of postmarket device changes approved per device, (3) the types of PMA supplement review tracks used, (4) the types of device changes approved via the various review tracks, and (5) the number of device recalls and market withdrawals that have occurred for these devices? METHODS: All original PMA approved orthopaedic devices between January 1982 and December 2014 were identified in the publically available FDA PMA database. The number of postmarket device changes approved, the PMA supplement review track used, the types of postmarket changes, and any FDA recalls for each device were assessed. RESULTS: Seventy original orthopaedic devices were approved via the FDA PMA pathway between 1982 and 2014. These devices included 34 peripheral joint implants or prostheses, 18 spinal implants or prostheses, and 18 other devices or materials. These devices underwent a median 6.5 postmarket changes during their lifespan or 1.0 changes per device-year (interquartile range, 0.4-1.9). The rate of new postmarket device changes approved per active device, increased from less than 0.5 device changes per year in 1983 to just fewer than three device changes per year in 2014, or an increase of 0.05 device changes per device per year in linear regression analysis (95% CI, 0.04-0.07). Among the 765 total postmarket changes, 172 (22%) altered device design or components. The majority of the design changes were reviewed via either the real-time review track (n = 98; 57%), intended for minor design changes, or the 180-day review track (n = 71; 41%), intended for major design changes. Finally, a total of 12 devices had FDA recalls at some point during their lifespan, two being for hip prostheses with high revision rates. CONCLUSIONS: Relatively few orthopaedic devices undergo the FDA PMA process before reaching the market. Orthopaedic surgeons should be aware that high-risk medical devices cleared via the FDA's PMA pathway do undergo considerable postmarket device modification after reaching the market, with potential for design "drift," ie, shifting away from the initially tested and approved device designs. CLINICAL RELEVANCE: As the ultimate end-users of these devices, orthopaedic surgeons should be aware that even among high-risk medical devices approved via the FDA's PMA pathway, considerable postmarket device modification occurs. Continued postmarket device monitoring will be essential to limit patient safety risks. PMID- 26584803 TI - Protein Destabilization as a Common Factor in Diverse Inherited Disorders. AB - Protein destabilization by amino acid substitutions is proposed to play a prominent role in widespread inherited human disorders, not just those known to involve protein misfolding and aggregation. To test this hypothesis, we computationally evaluate the effects on protein stability of all possible amino acid substitutions in 20 disease-associated proteins with multiple identified pathogenic missense mutations. For 18 of the 20 proteins studied, substitutions at known positions of pathogenic mutations are significantly more likely to destabilize the native protein fold (as indicated by more positive values of ??G). Thus, positions identified as sites of disease-associated mutations, as opposed to non-disease-associated sites, are predicted to be more vulnerable to protein destabilization upon amino acid substitution. This finding supports the notion that destabilization of native protein structure underlies the pathogenicity of broad set of missense mutations, even in cases where reduced protein stability and/or aggregation are not characteristic of the disease state. PMID- 26584804 TI - Aptamers Selected by Cell-SELEX for Molecular Imaging. AB - Conventional diagnostics for cancer rely primarily on anatomical techniques. However, these techniques cannot monitor the changes at the molecular level in normal cells, which possibly signal the onset of cancer at its very earliest stages. For accurate prediction of the carcinogenesis at the molecular level, targeting ligands have been used in combination with imaging probes to monitor this biological process. Among these targeting ligands, aptamers have high binding affinity to various targets ranging from small molecules to whole organisms, and, hence, exceptional recognition ability. Many recent studies have been reported on aptamer-based molecular imaging, clearly indicating its clinical and diagnostic utility. In this review, we will discuss some key results of these studies. PMID- 26584805 TI - A genome-wide association study of n-3 and n-6 plasma fatty acids in a Singaporean Chinese population. AB - Polyunsaturated fatty acids (PUFAs) have a major impact on human health. Recent genome-wide association studies (GWAS) have identified several genetic loci that are associated with plasma levels of n-3 and n-6 PUFAs in primarily subjects of European ancestry. However, the relevance of these findings has not been evaluated extensively in other ethnic groups. The primary aim of this study was to evaluate for genetic loci associated with n-3 and n-6 PUFAs and to validate the role of recently identified index loci using data from a Singaporean Chinese population. Using a GWAS approach, we evaluated associations with plasma concentrations of three n-3 PUFAs [alphalinolenic acid (ALA), eicosapentaenoic acid and docosahexaenoic acid], four n-6 PUFAs [linoleic acid (LA), gammalinolenic acid, dihomogammalinolenic acid (DGLA) and arachidonic acid], and estimates of delta-5 desaturase and delta-6 desaturase activities among the participants (N = 1361) of the Singaporean Chinese Health Study. Our results reveal robust genome-wide associations (p value <5 * 10(-8)) with ALA, all four n 6 PUFAs, and delta-6 desaturase activity at the FADS1/FADS2 locus. We further replicated the associations between common index variants at the NTAN1/PDXDC1 locus and n-6 PUFAs LA and DGLA, and between the JMJD1C locus and n-6 PUFA LA (p value between 0.0490 and 9.88 * 10(-4)). These associations were independent of dietary intake of PUFAs. In aggregate, we show that genetic loci that influence plasma concentrations of n-3 and n-6 PUFAs are shared across different ethnic groups. PMID- 26584806 TI - Effects of ferrous carbamoyl glycine on iron state and absorption in an iron deficient rat model. AB - An iron-deficient rat model was established and used to determine the effects of different iron sources on iron metabolism and absorption. Iron-deficient rats were assigned to one of three treatment groups, and their diet was supplemented with deionized water (control), Fe-CGly, or FeSO4 for 8 days via intragastric administration. Blood samples were obtained for analysis of iron-related properties, and the small intestine and liver were removed for quantitative reverse transcription PCR of genes related to iron metabolism. The serum total iron-binding capacity (TIBC) levels of rats in Fe-CGly and FeSO4 supplementation groups was lower (P < 0.05) than that of the rats in the control group. The rats in Fe-CGly group exhibited higher (P < 0.05) plasma Fe and ferritin levels and lower (P < 0.05) TIBC levels compared with the rats in FeSO4 groups. The relative expression of liver hepcidin increased (P < 0.05) by tenfold and 80-fold in the Fe-CGly and FeSO4 groups, respectively, whereas divalent metal transporter 1, duodenal cytochrome b, and ferroportin 1 expression decreased (P < 0.05) in the duodenum in both Fe-CGly and FeSO4 group. A comparison between Fe-CGly and FeSO4 group showed that iron regulatory protein 1 (IRP1) and iron regulatory protein (IRP2) expressions were reduced (P < 0.05) in rats administered FeSO4 than in rats administered with Fe-Cgly. These results indicate that Fe-CGly rapidly improves the blood iron status and that IRP1 and IRP2 may play an important role in the intestinal absorption of Fe-CGly. PMID- 26584807 TI - Nutritional biology: a neglected basic discipline of nutritional science. AB - On the basis of a scientific-philosophical analysis, this paper tries to show that the approaches in current nutritional science-including its subdisciplines which focus on molecular aspects-are predominantly application-oriented. This becomes particularly evident through a number of conceptual problems characterized by the triad of 'dearth of theoretical foundation,' 'particularist research questions,' and 'reductionist understanding of nutrition.' The thesis presented here is that an interpretive framework based on nutritional biology is able to shed constructive light on the fundamental problems of nutritional science. In this context, the establishment of 'nutritional biology' as a basic discipline in research and education would be a first step toward recognizing the phenomenon of 'nutrition' as an oecic process as a special case of an organism environment interaction. Modern nutritional science should be substantively grounded on ecological-and therefore systems biology as well as organismic principles. The aim of nutritional biology, then, should be to develop near universal 'law statements' in nutritional science-a task which presents a major challenge for the current science system. PMID- 26584808 TI - Variation in extracellular matrix genes is associated with weight regain after weight loss in a sex-specific manner. AB - The extracellular matrix (ECM) of adipocytes is important for body weight regulation. Here, we investigated whether genetic variation in ECM-related genes is associated with weight regain among participants of the European DiOGenes study. Overweight and obese subjects (n = 469, 310 females, 159 males) were on an 8-week low-calorie diet with a 6-month follow-up. Body weight was measured before and after the diet, and after follow-up. Weight maintenance scores (WMS, regained weight as percentage of lost weight) were calculated based on the weight data. Genotype data were retrieved for 2903 SNPs corresponding to 124 ECM-related genes. Regression analyses provided us with six significant SNPs associated with the WMS in males: 3 SNPs in the POSTN gene and a SNP in the LAMB1, COL23A1, and FBLN5 genes. For females, 1 SNP was found in the FN1 gene. The risk of weight regain was increased by: the C/C genotype for POSTN in a co-dominant model (OR 8.25, 95 % CI 2.85-23.88) and the T/C-C/C genotype in a dominant model (OR 4.88, 95 % CI 2.35-10.16); the A/A genotype for LAMB1 both in a co-dominant model (OR 18.43, 95 % CI 2.35-144.63) and in a recessive model (OR 16.36, 95 % CI 2.14 124.9); the G/A genotype for COL23A1 in a co-dominant model (OR 3.94, 95 % CI 1.28-12.10), or the A-allele in a dominant model (OR 2.86, 95 % CI 1.10-7.49); the A/A genotype for FBLN5 in a co-dominant model (OR 13.00, 95 % CI 1.61 104.81); and the A/A genotype for FN1 in a recessive model (OR 2.81, 95 % CI 1.40 5.63). Concluding, variants of ECM genes are associated with weight regain after weight loss in a sex-specific manner. PMID- 26584809 TI - Skeletal muscle mitochondrial uncoupling prevents diabetes but not obesity in NZO mice, a model for polygenic diabesity. AB - Induction of skeletal muscle (SM) mitochondrial stress by expression of uncoupling protein 1 (UCP1) in mice results in a healthy metabolic phenotype associated with increased secretion of FGF21 from SM. Here, we investigated whether SM mitochondrial uncoupling can compensate obesity and insulin resistance in the NZO mouse, a polygenic diabesity model. Male NZO mice were crossed with heterozygous UCP1 transgenic (tg) mice (mixed C57BL/6/CBA background) and further backcrossed to obtain F1 and N2 offspring with 50 and 75 % NZO background, respectively. Male F1 and N2 progeny were fed a high-fat diet ad libitum for 20 weeks from weaning. Blood glucose was reduced, and diabetes (severe hyperglycemia >300 mg/dl) was fully prevented in both F1- and N2-tg progeny compared to a diabetes prevalence of 15 % in F1 and 42 % in N2 wild type. In contrast, relative body fat content and plasma insulin were decreased, and glucose tolerance was improved, in F1-tg only. Both F1 and N2-tg showed decreased lean body mass. Accordingly, induction of SM stress response including FGF21 expression and secretion was similar in both F1 and N2-tg mice. In white adipose tissue, expression of FGF21 target genes was enhanced in F1 and N2-tg mice, whereas lipid metabolism genes were induced in F1-tg only. There was no evidence for induction of browning in either UCP1 backcross. We conclude that SM mitochondrial uncoupling induces FGF21 expression and prevents diabetes in mice with a 50-75 % NZO background independent of its effects on adipose tissue. PMID- 26584810 TI - Stage 5-CKD under nephrology care: to dialyze or not to dialyze, that is the question. AB - Appropriate timing of starting chronic dialysis in patients with advanced chronic kidney disease (CKD) under nephrology care still is undefined. We systematically reviewed the most recent studies that have compared outcomes of stage 5-CKD under conservative versus substitutive treatment. Eleven studies, most in elderly patients, were identified. Results indicate no advantage of dialysis over conservative management in terms of survival, hospitalization or quality of life. This information is integrated with a case report on a middle-aged CKD patient followed in our clinic who has remained for 15 years in stage 5 despite severe disease. The patient is a diabetic woman who underwent right nephrectomy in 1994 because of renal tuberculosis. In 1999, she commenced regular nephrology care in our clinic and, since 2000, when she was 53 years old, her estimated glomerular filtration rate (eGFR) has been <=15 ml/min/1.73 m(2). Over the last decade, despite, several episodes of acute kidney injury and placement of permanent percutaneous nephrostomy in 2001, renal function has remained remarkably stable, though severely impaired (eGFR 7.7-5.6 ml/min/1.73 m(2)). Our systematic analysis of the literature and this case report highlight the need for further studies, not limited exclusively to elderly patients, to verify the efficacy of non dialysis treatment in stage 5-CKD patients. Meanwhile, nephrologists may consider that their intervention can safely prolong for several years the dialysis-free condition in ESRD independently of age. PMID- 26584811 TI - Developing a measure of medication-related quality of life for people with polypharmacy. AB - PURPOSE: To develop a measure of medication-related quality of life (MRQoL) and to validate the measure in a hospital-based population of patients with polypharmacy. METHODS: The Medication-Related Quality of Life Scale version 1.0 (MRQoLS-v1.0) included 14 items developed on the basis of interviews with elderly patients with polypharmacy, defined as taking five or more medications simultaneously. This scale was tested in 219 outpatients (99 with polypharmacy and 120 without polypharmacy). Two measures were used to establish construct validity the Psychological Distress Checklist, for convergent validity, and the Medication Adherence Behavior Scale (MABS), for discriminant validity. RESULTS: The 14-item scale was found to be both reliable and valid. Internal consistency reliability evaluated using Cronbach's alpha for this scale was 0.91. Scores on the MRQoLS-v1.0 correlated statistically significantly and negatively with those on the Psychological Distress Checklist. Discriminant validity was demonstrated by low correlation with MABS, indicating that the MRQoLS-v1.0 measured concepts different from medication adherence. Significant differences in the MRQoLS-v1.0 between patients with polypharmacy and those without polypharmacy provided evidence for known-group validity. CONCLUSIONS: The study presents a psychometric evaluation of a measure used to assess MRQoL of patients with polypharmacy. The instrument is practical to administer in clinics and provides a valuable adjunct to the outcome measurement for patients with polypharmacy. Further research on the sensitivity of this instrument to medication change in multi-medicated patients is warranted. PMID- 26584812 TI - The effects of thoracic epidural analgesia on oxygenation and pulmonary shunt fraction during one-lung ventilation: an meta-analysis. AB - BACKGROUND: The aim of our study is to compare the effects of thoracic epidural analgesia combined with general anesthesia (GA) vs. general anesthesia on oxygenation and pulmonary shunt fraction during one-lung ventilation (OLV). METHODS: Literature research was firstly conducted for studies related to comparison of epidural anesthesia combined with GA vs. GA with reporting of hemodynamic and oxygenation variables and published from Jan 1990 to Jan 2014 in EMBAS, MEDLINE and Cochrane Central Register of Controlled Trials databases. The studies were reviewed and data were extracted and analyzed using fixed-effect and random-effect models. RESULTS: There are 14 trials with 60 separate comparisons enrolling 653 patients for analysis. Regarding systemic hemodynamics, thoracic epidural analgesia decreased the mean arterial pressure and mean pulmonary arterial pressure with weighted mean difference 95% confidence interval (-6.64 [ 9.57 to -3.71] vs. -6.33 [-9.25 to -3.41] and -3.18 [-5.07 to -1.28] vs. -2.05 [ 3.35 to -0.75]) respectively at the two measurements time, however, only decreasing heart rate and systemic vascular resistance (-3.28 [-5.98 to -0.67] and -319.99 [-447.05 to -192.94]) over the first 30 min after OLV. For oxygenation variables, thoracic epidural analgesia is associated with significant reduction in partial arterial oxygen pressure, mixed arterial saturation of oxygenation and increased pulmonary venous admixture fraction compared to general anesthesia with weighted mean difference 95% confidence interval (-16.52 [-21.98 to - 11.05] vs. - 14.23 [-20.81 to - 7.65]), (0.74 [0.33 to 1.15] vs. - 0.63 [ 1.23 to -0.04]) and (2.53 [1.35 to 3.72] vs. 2.77 [1.81 to 3.74]) respectively before and after 30 min of one-lung ventilation. A decrease in mixed venous saturation of oxygenation occurred after 30 min of OLV (-2.39 [-3.73 to -0.99]). Besides, a higher mean value of airway pressure was found in the thoracic epidural analgesia with weighted mean difference 95% confidence interval (1.95 [1.61 to 2.28] vs. 0.87 [0.54 to 1.20]) at the measurements. CONCLUSION: Based on the existing limited data puts forward recommendations for cautious usage of thoracic epidural analgesia in case of underlying risks in lower systemic hemodynamics, decreased partial arterial oxygen pressure but increases pulmonary shunt during one-lung ventilation. PMID- 26584813 TI - Field Psychometric Testing of the Instrument for Assessment of Psychological Predictors of Well-Being and Quality of Life in People with HIV or AIDS. AB - The Screenphiv, a screening measure for psychological issues related to HIV, was psychometrically tested in a study involving 744 HIV-infected people in Spain. Participants ages 18-82 (M = 43.04, 72 % men, 28 % women) completed an assessment protocol that included the Screenphiv and the MOS-HIV. A trained interviewer also collected relevant illness-related clinical data and socio-demographics from the participants. A confirmatory factor analysis was used to evaluate the goodness of fit of the Screenphiv's theoretical model and confirmed six first-order factors and two second-order factors [RMSEA (IC 90 %) = 0.07 (0.07-0.08)]. No floor or ceiling effects were observed for the scores. Cronbach's alphas were acceptable for all of the factors (from 0.65 to 0.92). Criterion-related validity also achieved; Screenphiv scores were related to socio-demographic and clinical variables and MOS-HIV summary scores. The Screenphiv is a reliable and valid measure, ready to use in research and clinical settings in Spain. PMID- 26584814 TI - Refractory monogenic Crohn's disease due to X-linked inhibitor of apoptosis deficiency. PMID- 26584815 TI - Short-course radiotherapy with delayed surgery in unfit locally advanced rectal cancer patients. PMID- 26584816 TI - The thrifty phenotype hypothesis: is sirtuin 6 the solution to the enigma? PMID- 26584817 TI - Investigation of the adsorption of polymer chains on amine-functionalized double walled carbon nanotubes. AB - Molecular dynamics (MD) simulations were used to study the adsorption of different polymer chains on functionalized double-walled carbon nanotubes (DWCNTs). The nanotubes were functionalized with two different amines: NH2 (a small amine) and CH2-NH2 (a large amine). Considering three different polymer chains, all with the same number of atoms, the effect of polymer type on the polymer-nanotube interaction was studied. In general, it was found that covalent functionalization considerably improved the polymer-DWCNT interaction. By comparing the results obtained with different polymer chains, it was observed that, unlike polyethylene and polyketone, poly(styrene sulfonate) only weakly interacts with the functionalized DWCNTs. Accordingly, the smallest radius of gyration was obtained with adsorbed poly(styrene sulfonate). It was also observed that the DWCNTs functionalized with the large amine presented more stable interactions with polyketone and poly(styrene sulfonate) than with polyethylene, whereas the DWCNTs functionalized with the small amine showed better interfacial noncovalent bonding with polyethylene. PMID- 26584818 TI - Exploring the cellular and tissue uptake of nanomaterials in a range of biological samples using multimodal nonlinear optical microscopy. AB - The uptake of nanomaterials (NMs) by cells is critical in determining their potential biological impact, whether beneficial or detrimental. Thus, investigation of NM internalization by cells is a common consideration in hazard and efficacy studies. There are currently a number of approaches that are routinely used to investigate NM-cell interactions, each of which have their own advantages and limitations. Ideally, imaging modalities used to investigate NM uptake by cells should not require the NM to be labelled (e.g. with fluorophores) to facilitate its detection. We present a multimodal imaging approach employing a combination of label-free microscopies that can be used to investigate NM-cell interactions. Coherent anti-Stokes Raman scattering microscopy was used in combination with either two-photon photoluminescence or four-wave mixing (FWM) to visualize the uptake of gold or titanium dioxide NMs respectively. Live and fixed cell imaging revealed that NMs were internalized by J774 macrophage and C3A hepatocyte cell lines (15-31 MUg ml(-1)). Sprague Dawley rats were exposed to NMs (intratracheal instillation, 62 MUg) and NMs were detected in blood and lung leucocytes, lung and liver tissue, demonstrating that NMs could translocate from the exposure site. Obtained data illustrate that multimodal nonlinear optical microscopy may help overcome current challenges in the assessment of NM cellular uptake and biodistribution. It is therefore a powerful tool that can be used to investigate unlabelled NM cellular and tissue uptake in three dimensions, requires minimal sample preparation, and is applicable to live and fixed cells. PMID- 26584819 TI - In vitro and preclinical assessment of factorial design based nanoethosomes transgel formulation of an opioid analgesic. AB - CONTEXT: Tramadol is a centrally acting analgesic and requires frequent dosing. Hence, judicious selection of retarding formulations is necessary. Transdermal ethosomal gel delivery has been recognized as an alternative route to oral delivery. OBJECTIVE: The objective was to develop statistically optimized ethosomal systems for enhanced transdermal activity of tramadol vis-a-vis traditional liposomes. MATERIALS AND METHODS: Box-Behnken design was employed for optimization of nanoethosomes using phospholipon 90G (A), ethanol (B), and sonication time (C) as independent variables while dependent variables were the vesicle size (Y1), entrapment efficiency (Y2), and flux (Y3). It was prepared by rotary evaporation method and characterized for various parameters including entrapment efficiency, size and transflux. Preclinical assessments were conducted on Wistar rats to measure the performance of developed formulations. RESULTS: The optimized formulation provided mean vesicles size, reasonable entrapment efficiency and enhanced flux when compared with liposome (control). In-vivo absorption study showed a significant increase in bioavailability (7.51 times) compared with oral tramadol. The average primary irritancy index was found to be 1.4, indicating it to be non-irritant and safe for use. DISCUSSION AND CONCLUSION: The results also demonstrated that encapsulated tramadol increases its biological activity due to the superior skin penetration potential. The preclinical study indicates a significant (P < 0.05) extended analgesic effect compared to oral solution using the hot plate test method. The overall results suggest that developed formulation is an efficient carrier for transdermal delivery of tramadol. PMID- 26584820 TI - Erratum to: Olfactory dysfunction in chronic stroke patients. PMID- 26584821 TI - Effects of acute and chronic systemic methamphetamine on respiratory, cardiovascular and metabolic function, and cardiorespiratory reflexes. AB - KEY POINTS: Methamphetamine (METH) abuse is escalating worldwide, with the most common cause of death resulting from cardiovascular failure and hyperthermia; however, the underlying physiological mechanisms are poorly understood. Systemic administration of METH in anaesthetised rats reduced the effectiveness of some protective cardiorespiratory reflexes, increased central respiratory activity independently of metabolic function, and increased heart rate, metabolism and respiration in a pattern indicating that non-shivering thermogenesis contributes to the well-described hyperthermia. In animals that showed METH-induced behavioural sensitisation following chronic METH treatment, no changes were evident in baseline cardiovascular, respiratory and metabolic measures and the METH-evoked effects in these parameters were similar to those seen in saline treated or drug naive animals. Physiological effects evoked by METH were retained but were neither facilitated nor depressed following chronic treatment with METH. These data highlight and identify potential mechanisms for targeted intervention in patients vulnerable to METH overdose. Methamphetamine (METH) is known to promote cardiovascular failure or life-threatening hyperthermia; however, there is still limited understanding of the mechanisms responsible for evoking the physiological changes. In this study, we systematically determined the effects on both autonomic and respiratory outflows, as well as reflex function, following acute and repeated administration of METH, which enhances behavioural responses. Arterial pressure, heart rate, phrenic nerve discharge amplitude and frequency, lumbar and splanchnic sympathetic nerve discharge, interscapular brown adipose tissue and core temperatures, and expired CO2 were measured in urethane anaesthetised male Sprague-Dawley rats. Novel findings include potent increases in central inspiratory drive and frequency that are not dependent on METH-evoked increases in expired CO2 levels. Increases in non-shivering thermogenesis correlate with well-described increases in body temperature and heart rate. Unexpectedly, METH evoked minor effects on both sympathetic outflows and mean arterial pressure. METH modified cardiorespiratory reflex function in response to hypoxia, hypercapnia and baroreceptor unloading. Chronically METH-treated rats failed to exhibit changes in baseline sympathetic, cardiovascular, respiratory and metabolic parameters. The tonic and reflex cardiovascular, respiratory and metabolic responses to METH challenge were similar to those seen in saline treated and drug naive animals. Overall, these findings describe independent and compound associations between physiological systems evoked by METH and serve to highlight that a single dose of METH can significantly impact basic homeostatic systems and protective functions. These effects of METH persist even following chronic METH treatment. PMID- 26584822 TI - Linolenic acid improves oocyte developmental competence and decreases apoptosis of in vitro-produced blastocysts in goat. AB - The effects of alpha-linolenic acid (ALA) on developmental competence of oocytes in goats were evaluated in this study. Initially, the level of ALA in small and large antral follicles was determined to be in a range of 0.018-0.028 mg/ml (64.6 100.6 MUM, respectively). In vitro maturation was performed in the presence of various concentrations (10, 50, 100, or 200 MUM) of ALA. Cumulus expansion, meiotic maturation, levels of intracellular glutathione (GSH), embryonic cleavage, blastocyst formation following parthenogenetic activation (PA) and in vitro fertilization (IVF), number of total and apoptotic cells in blastocyst, and expression of Bax, Bcl-2, and p53 genes in blastocyst cells were determined. Compared with the control, no improvement was observed in cumulus expansion in ALA-treated groups. At 50 MUM concentration, ALA increased meiotic maturation rate but had no effect on GSH level. When oocytes treated with 50 MUM ALA were subsequently used for PA or IVF, a higher rate of blastocyst formation was observed, and these embryos had a higher total cell number and a lower apoptotic cell number. Expression analyses of genes in blastocysts revealed lesser transcript abundances for Bax gene, and higher transcript abundances for Bcl-2 gene in 50 MUM ALA group. Expression of p53 gene was also less observed in ALA treated blastocysts. Our results show that ALA treatment at 50 MUM during in vitro maturation (IVM) had a beneficial effect on maturation of goat oocytes and this, in turn, stimulated embryonic development and regulated apoptotic gene expression. PMID- 26584823 TI - Association of polymorphisms in tektin-t gene with idiopathic asthenozoospermia in Sichuan, China. AB - PURPOSE: The purpose of this research was to study the association between the single nucleotide polymorphisms (SNPs) of the tektin-t gene and idiopathic asthenozoospermia. METHODS: We conducted sequence analyses of the tektin-t gene in 104 idiopathic asthenozoospermia and 102 fertile men with normospermic parameters in Sichuan, China. RESULTS: In this study, we found that allele 136 T (odds ratio [OR] 1.745, 95 % confidence interval [CI] 1.146-2.655, P = 0.009) was significantly increased in idiopathic asthenozoospermic patients compared with fertile men. This mutation substitutes a highly conserved arginine at position 46 to cysteine. Moreover, PolyPhen-2 analysis predicted that this variant was "probably damaging". In addition, a novel heterozygous mutation, R207H (c.620G >A), was detected in five asthenozoospermic patients, while there was no detection of this genotype among the fertile candidates, indicating that the mutation was located within a conserved domain predicted by PolyPhen-2 analysis as "probably damaging" to the protein. CONCLUSIONS: These results suggested that tektin-t variants (Arg/Cys + Cys/Cys) were probably one of the high risk genetic factors for idiopathic asthenozoospermia among males in Sichuan, China, while the R207H polymorphism may be associated with idiopathic asthenozoospermia risk. PMID- 26584824 TI - Neuroprotective Effects of Icariin on Brain Metabolism, Mitochondrial Functions, and Cognition in Triple-Transgenic Alzheimer's Disease Mice. AB - AIMS: This study investigated the neuroprotective properties of icariin (an effective component of traditional Chinese herbal medicine Epimedium) on neuronal function and brain energy metabolism maintenance in a triple-transgenic mouse model of Alzheimer's disease (3 * Tg-AD). METHODS: 3 * Tg-AD mice as well as primary neurons were subjected to icariin treatment. Morris water maze assay, magnetic resonance spectroscopy (MRS), Western blotting, ELISA, and immunohistochemistry analysis were used to evaluate the effects of icariin administration. RESULTS: Icariin significantly improved spatial learning and memory retention in 3 * Tg-AD mice, promoted neuronal cell activity as identified by the enhancement of brain metabolite N-acetylaspartate level and ATP production in AD mice, preserved the expressions of mitochondrial key enzymes COX IV, PDHE1alpha, and synaptic protein PSD95, reduced Abeta plaque deposition in the cortex and hippocampus of AD mice, and inhibited beta-site APP cleavage enzyme 1 (BACE1) expression. Icariin treatment also decreased the levels of extracellular and intracellular Abeta1-42 in 3 * Tg-AD primary neurons, modulated the distribution of Abeta along the neurites, and protected against mitochondrial fragmentation in 3 * Tg-AD neurons. CONCLUSIONS: Icariin shows neuroprotective effects in 3 * Tg-AD mice and may be a promising multitarget drug in the prevention/protection against AD. PMID- 26584825 TI - Risk factor(s) related to high membrane permeability in peritoneal dialysis. AB - AIM: Peritoneal dialysis (PD) patients have different peritoneal membrane permeability (transport) characteristics. High peritoneal membrane permeability is associated with increased mortality risk in the patient population. In this study, we aimed to investigate possible risk factor(s) related to high peritoneal membrane permeability. PATIENTS AND METHOD: The study included 475 PD patients (46.1 +/- 14.5 years of mean age; 198 female and 277 male). The patients were divided two groups according to peritoneal equilibration test (PET) result: high permeability group (high and high-average) and low- permeability group (low average and low). RESULTS: In both the univariate and multivariate logistic regression analyses, it was found that diabetes mellitus and hypoalbuminemia was significantly associated with high peritoneal membrane permeability [relative risk (RR): 1.90, 95% confidence interval (CI): 1.26-2.86, p: 0.002 and RR: 2.14, 95% CI: 1.44-3.18, p<0.001, respectively]. CONCLUSION: Diabetes mellitus and hypoalbuminemia were closely associated with high peritoneal membrane permeability. Diabetic patients had 1.9 times the likelihood of having high permeability. However, the relationship between hypoalbuminemia and high peritoneal permeability appears to be a result rather than cause. PMID- 26584826 TI - One-year metreleptin improves insulin secretion in patients with diabetes linked to genetic lipodystrophic syndromes. AB - Recombinant methionyl human leptin (metreleptin) therapy was shown to improve hyperglycaemia, dyslipidaemia and insulin sensitivity in patients with lipodystrophic syndromes, but its effects on insulin secretion remain controversial. We used dynamic intravenous (i.v.) clamp procedures to measure insulin secretion, adjusted to insulin sensitivity, at baseline and after 1 year of metreleptin therapy, in 16 consecutive patients with lipodystrophy, diabetes and leptin deficiency. Patients, with a mean [+/- standard error of the mean (s.e.m.)] age of 39.2 (+/-4) years, presented with familial partial lipodystrophy (n = 11, 10 women) or congenital generalized lipodystrophy (n = 5, four women). Their mean (+/- s.e.m.) BMI (23.9 +/- 0.7 kg/m(2) ), glycated haemoglobin levels (8.5 +/- 0.4%) and serum triglycerides levels (4.6 +/- 0.9 mmol/l) significantly decreased within 1 month of metreleptin therapy, then remained stable. Insulin sensitivity (from hyperglycaemic or euglycaemic-hyperinsulinaemic clamps, n = 4 and n = 12, respectively), insulin secretion during graded glucose infusion (n = 12), and acute insulin response to i.v. glucose adjusted to insulin sensitivity (disposition index, n = 12), significantly increased after 1 year of metreleptin therapy. The increase in disposition index was related to a decrease in percentage of total and trunk body fat. Metreleptin therapy improves not only insulin sensitivity, but also insulin secretion in patients with diabetes attributable to genetic lipodystrophies. PMID- 26584827 TI - Species discrimination in the subfamily Ostertagiinae of Northern China: assessment of DNA barcode in a taxonomically challenging group. AB - Gastrointestinal nematodes within the subfamily Ostertagiinae (Teladorsagia, Ostertagia, and Marshallagia et al.) are among the most common infections of domesticated livestock. These parasites are of particular interest, as many of the species within this group are of economic importance worldwide. Traditionally, nematode species designations have been based on morphological criteria. However, this group possesses poorly defined species. There is an urgent need to develop a reliable technique that can distinguish species of Ostertagiinae. DNA barcoding has been proved to be a powerful tool to identify species of birds, mammals, and arthropods, but this technique has not yet been examined for identifying species of Ostertagiinae. In this study, a total of 138 mitochondrial DNA (mtDNA) cytochrome c oxidase subunit I (COI) sequences from individuals representing 11 species of Ostertagiinae were acquired by PCR for the first time. The specimens were collected from pastoral area of northern China. Genetic divergence analyses showed that mean interspecific Kimura two-parameter distances of COI (13.61 %) were about four times higher than the mean value of the intraspecific divergence (3.69 %). Then, the performance of the COI to identify species of Ostertagiinae was evaluated by identification success rates using nearest neighbor (NN) and BLASTn. The results indicated that the rates of correct sequence identification for COI were high (>80 %) when using the NN and BLASTn methods. Besides, the deep lineage divergences are detected in Teladorsagia circumcincta. Meanwhile, the analyses also detected no genetic differentiation between some species such as Ostertagia hahurica and Ostertagia buriatica. These results indicate that the traditional status of species within Ostertagiinae should be closely examined based on the molecular data. PMID- 26584828 TI - Intestinal spirochaetes (genus Brachyspira) colonise wild birds in the southern Atlantic region and Antarctica. AB - INTRODUCTION: The genus Brachyspira contains well-known enteric pathogens of veterinary significance, suggested agents of colonic disease in humans, and one potentially zoonotic agent. There are recent studies showing that Brachyspira are more widespread in the wildlife community than previously thought. There are no records of this genus in wildlife from the southern Atlantic region and Antarctica. Our aim was therefore, to determine whether intestinal spirochaetes of genus Brachyspira colonise marine and coastal birds in this region. METHOD: Faecal samples were collected from marine and coastal birds in the southern Atlantic region, including sub-Antarctic islands and Antarctica, in 2002, 2009, and 2012, with the aim to isolate and characterise zoonotic agents. In total, 205 samples from 11 bird species were selectively cultured for intestinal spirochaetes of genus Brachyspira. To identify isolates to species level, they were subjected to phenotyping, species-specific polymerase chain reactions, sequencing of partial 16S rRNA, NADH oxidase (nox), and tlyA genes, and phylogenetic analysis. Antimicrobial susceptibility tests were performed. RESULTS: Fourteen unique strains were obtained from 10 birds of three species: four snowy sheathbills (Chionis albus), three kelp geese (Chloephaga hybrida subsp. malvinarum), and three brown skua (Stercorarius antarcticus subsp. lonnbergi) sampled on the Falkland Islands, Tierra del Fuego in Argentina, South Georgia, South Shetland Islands, and the Antarctic Peninsula. Five Brachyspira strains were closely related to potentially enteropathogenic Brachyspira sp. of chickens: B. intermedia (n=2, from snowy sheathbills), and B. alvinipulli (n=3, from a kelp goose and two snowy sheathbills). Three strains from kelp geese were most similar to the presumed non-pathogenic species 'B. pulli' and B. murdochii, whereas the remaining six strains could not be attributed to currently known species. No isolates related to human strains were found. None of the tested strains showed decreased susceptibility to tiamulin, valnemulin, doxycycline, tylvalosin, lincomycin, or tylosin. CONCLUSIONS: This is the first report of intestinal spirochaetes from this region. Despite limitations of current diagnostic methods, our results, together with earlier studies, show that Brachyspira spp., including potentially pathogenic strains, occur globally among free-living avian hosts, and that this genus encompasses a higher degree of biodiversity than previously recognised. PMID- 26584830 TI - A study of Rift Valley fever virus in Morogoro and Arusha regions of Tanzania - serology and farmers' perceptions. AB - INTRODUCTION: Rift Valley fever (RVF) is a zoonosis primarily affecting ruminants, resulting in epidemic abortions, fever, nasal and ocular discharges, haemorrhagic diarrhoea, and a high mortality rate among young animals. Rift Valley fever virus (RVFV) is an arthropod-borne RNA virus occurring in epizootic periods associated with heavy rainfall. The last outbreak of RVF in Tanzania was in 2006-2007, resulting in severe economic losses and impaired food security due to greater number of deaths of livestock. The aim of this study was to investigate the presence of antibodies against RVFV in sheep and goats in two different regions of Tanzania during an inter-epidemic period (IEP). In addition, the perception of important diseases among livestock keepers was assessed. MATERIAL AND METHODS: A cross-sectional serological survey was conducted in three purposively selected districts in Arusha and Morogoro regions of Tanzania. Serum samples from 354 sheep and goats were analysed in a commercial RVFV competitive ELISA. At the sampling missions, a questionnaire was used to estimate the socio economic impact of infectious diseases. RESULTS AND DISCUSSION: In total, 8.2% of the analysed samples were seropositive to RVF, and most seropositive animals were younger than 7 years, indicating a continuous circulation of RVFV in the two regions. None of the livestock keepers mentioned RVF as an important livestock disease. CONCLUSIONS: This study confirms that RVFV is circulating at low levels in small ruminants during IEPs. In spite of recurring RVF outbreaks in Tanzania, livestock keepers seem to have a low awareness of the disease, making them poorly prepared and thus more vulnerable to future RVF outbreaks. PMID- 26584829 TI - Molecular and epidemiological studies of Porcine rubulavirus infection - an overview. AB - Porcine rubulavirus-La Piedad-Michoacan-Mexico virus (PorPV-LPMV) was identified as the causative agent of a viral disease that emerged spontaneously in Mexican swine in the 1980s. Since the report of the initial outbreak of the disease, only one full-length genome from a strain isolated in 1984 (PorPV-LPMV/1984) has been sequenced; sequence data are scarce from other isolates. The genetic variation of this virus that has spread throughout the main endemic region of Mexico is almost a complete mystery. The development of molecular techniques for improved diagnostics and to investigate the persistence, molecular epidemiology, and the possible reservoirs of PorPV are needed. Together, this will provide greater knowledge regarding the molecular genetic changes and useful data to establish new strategies in the control of this virus in Mexico. PMID- 26584831 TI - The experience of meditation for people with amyotrophic lateral sclerosis and their caregivers - a qualitative analysis. AB - There is a lack of studies about psychological interventions for people with amyotrophic lateral sclerosis (ALS) and their caregivers. We investigated the experience of a meditation training program tailored for ALS needs. People with ALS (pALS) and their caregivers that joined a meditation program for ALS were interviewed at the end of the program. Verbatims were analyzed with a qualitative approach. Both pALS and their caregivers reported a positive impact on their psychological well-being, promoted by an increase in acceptance and non judgmental attitude. Furthermore, coping strategies seem to improve, with a positive effect on resilience skills. The ALS meditation training program seems to be an effective psychological intervention for the promotion of well-being in pALS and their caregivers. PMID- 26584832 TI - Colombian reference growth curves for height, weight, body mass index and head circumference. AB - AIM: Published Growth studies from Latin America are limited to growth references from Argentina and Venezuela. The aim of this study was to construct reference growth curves for height, weight, body mass index (BMI) and head circumference of Colombian children in a format that is useful for following the growth of the individual child and as a tool for public health. METHODS: Prospective measurements from 27 209 Colombian children from middle and upper socio-economic level families were processed using the generalised additive models for location, scale and shape (GAMLSS). RESULTS: Descriptive statistics for length and height, weight, BMI and head circumference for age are given as raw and smoothed values. Final height was 172.3 cm for boys and 159.4 cm for girls. Weight at 18 years of age was 64.0 kg for boys and 54 kg for girls. Growth curves are presented in a +/ 3 SD format using logarithmic axes. CONCLUSION: The constructed reference growth curves are a start for following secular trends in Colombia and are also in the presented layout an optimal clinical tool for health care. PMID- 26584833 TI - Exploration of pressure ulcer and related skin problems across the spectrum of health care settings in Ontario using administrative data. AB - This is a prospective cohort study using population-level administrative data to describe the scope of pressure ulcers in terms of its prevalence, incidence risk, associating factors and the extent to which best practices were applied across a spectrum of health care settings. The data for this study includes the information of Ontario residents who were admitted to acute care, home care, long term care or continuing care and whose health care data is contained in the resident assessment instrument-minimum data set (RAI-MDS) and the health outcomes for better information and care (HOBIC) database from 2010 to 2013. The analysis included 203 035 unique patients. The overall prevalence of pressure ulcers was approximately 13% and highest in the complex continuing care setting. Over 25% of pressure ulcers in long-term care developed one week after discharge from acute care hospitalisation. Individuals with cardiovascular disease, dementia, bed mobility problems, bowel incontinence, end-stage diseases, daily pain, weight loss and shortness of breath were more likely to develop pressure ulcers. While there were a number of evidence-based interventions implemented to treat pressure ulcers, only half of the patients received nutritional interventions. PMID- 26584834 TI - The great mimicker: a rare case of head and neck inflammatory pseudotumour in the presence of human immunodeficiency virus. AB - BACKGROUND: Inflammatory pseudotumours of the head and neck are rare. A connection has been made between inflammatory pseudotumours and human immunodeficiency virus positivity. CASE REPORT: This paper reports a case of an inflammatory pseudotumour presenting with a lesion in the left tonsil and left cervical lymph node in a 49-year-old human immunodeficiency virus positive patient. A histological diagnosis was obtained after biopsy and serial radiological imaging. CONCLUSION: Diagnostic uncertainties can lead to unnecessary surgery. It is important to recognise the clinical, radiological and histological indicators of an inflammatory pseudotumour to enable a timely diagnosis and arrange appropriate treatment. In patients with co-morbidities causing immunocompromise, the potential diagnosis of an inflammatory pseudotumour should be considered. This is especially the case in human immunodeficiency virus patients, as inflammatory pseudotumours have been associated with immune reconstitution inflammatory syndrome, which can manifest up to several years after the initiation of, or change in, antiretroviral therapies. PMID- 26584835 TI - A Post-Synthetically Modified MOF for Selective and Sensitive Aqueous-Phase Detection of Highly Toxic Cyanide Ions. AB - Selective and sensitive detection of toxic cyanide (CN(-) ) by a post synthetically altered metal-organic framework (MOF) has been achieved. A post synthetic modification was employed in the MOF to incorporate the specific recognition site with the CN(-) ion over all other anions, such as Cl(-) , Br(-) , and SCN(-) . The aqueous-phase sensing and very low detection limit, the essential prerequisites for an effective sensory material, have been fulfilled by the MOF. Moreover, the present detection level meets the standard set by the World Health Organization (WHO) for the permissible limit of cyanide concentration in drinking water. The utilization of MOF-based materials as the fluorometric probes for selective and sensitive detection of CN(-) ions has not been explored till now. PMID- 26584837 TI - Transgenic expression of human CD46: does it reduce the primate T-cell response to pig endothelial cells? PMID- 26584836 TI - Thermal stability of self-assembled peptide vaccine materials. AB - The majority of current vaccines depend on a continuous "cold chain" of storage and handling between 2 and 8 degrees C. Vaccines experiencing temperature excursions outside this range can suffer from reduced potency. This thermal sensitivity results in significant losses of vaccine material each year and risks the administration of vaccines with diminished protective ability, issues that are heightened in the developing world. Here, using peptide self-assemblies based on the fibril-forming peptide Q11 and containing the epitopes OVA323-339 from ovalbumin or ESAT651-70 from Mycobacterium tuberculosis, the chemical, conformational, and immunological stability of supramolecular peptide materials were investigated. It was expected that these materials would exhibit advantageous thermal stability owing to their adjuvant-free and fully synthetic construction. Neither chemical nor conformational changes were observed for either peptide when stored at 45 degrees C for 7days. ESAT651-70-Q11 was strongly immunogenic whether it was stored as a dry powder or as aqueous nanofibers, showing undiminished immunogenicity even when stored as long as six months at 45 degrees C. This result was in contrast to ESAT651-70 conjugated to a protein carrier and adjuvanted with alum, which demonstrated marked thermal sensitivity in these conditions. Antibody titers and affinities were undiminished in mice for OVA323-339-Q11 if it was stored as assembled nanofibers, yet some diminishment was observed for material stored as a dry powder. The OVA study was done in a different mouse strain and with a different prime/boost regimen, and so it should not be compared directly with the study for the ESAT epitope. This work indicates that peptide self-assemblies can possess attractive thermal stability properties in the context of vaccine development. STATEMENT OF SIGNIFICANCE: Almost all current vaccines must be maintained within a tight and refrigerated temperature range, usually between 2 and 8 degrees C. This presents significant challenges for their distribution, especially in the developing world. Here we report on the surprisingly robust thermal stability of a self-assembled peptide vaccine. In particular a self-assembled peptide vaccine containing a tuberculosis epitope maintained all of its potency in mice when exposed to an extreme thermal treatment of six months at 45 degrees C. In a different mouse model, we investigated another model epitope and found some storage conditions where potency was diminished. Overall this study illustrates that some self-assembled peptide vaccines can have remarkable thermal stability. PMID- 26584838 TI - Immediate two-stage nipple reconstruction with a local mastectomy flap following secondary autologous breast reconstruction. AB - Because of the inevitable postoperative shrinkage, an initial hypercorrection is emphasized in nipple reconstruction with a random skin flap. However, the breast shape will be damaged if an excessively large flap is raised on the surface of the breast mound. A technique for immediate two-stage nipple reconstruction with a local mastectomy flap during the secondary breast reconstruction was reported in this study. From February 2011 to March 2014, 33 patients underwent breast reconstruction and immediate two-stage nipple reconstructions. A bipedicle deep inferior epigastric artery perforator (DIEP) flap was raised and folded upward to form the breast. Simultaneously, a deepithelialized lower mastectomy flap with a distant skin paddle was elevated and pulled throughout the reconstructed breast. The skin paddle was carefully sutured to the position of the future nipple. After 3 weeks, the pedicle of the mastectomy flap was divided, and the paddle was modeled to form the new nipple. Both the new nipple and the DIEP flaps survived postoperatively. The average projection of the reconstructed nipple was 15.4 +/- 2.7 mm immediately after the surgery, which gradually decreased to 8.2 +/- 1.1 mm during the first year of follow-up. A total of 29 patients ranked the aesthetic appearance of the reconstructed nipple and breast as "very good" or "good." On the basis of our breast-shaping techniques, the proposed immediate two-stage nipple reconstruction approach is able to maintain long-term residual projection and results in considerable patient satisfaction. LEVEL OF EVIDENCE: IV. PMID- 26584839 TI - Situational analysis of lymphatic filariasis morbidity in Ahanta West District of Ghana. AB - OBJECTIVES: Situational analysis of lymphatic filariasis (LF) morbidity and its management in Ahanta West, Ghana, to identify potential barrier to healthcare for LF patients. METHODS: Lymphoedema and hydrocoele patients were identified by community health workers from a subset of villages, and were interviewed and participated in focus group discussions to determine their attitudes and practices towards managing their morbidity, and their perceived barriers to accessing care. Local health professionals were also interviewed to obtain their views on the availability of morbidity management services in the district. RESULTS: Sixty-two patients (34 lymphoedema and 28 hydrocoeles) and 13 local health professionals were included in the study. Lymphoedema patients predominantly self-managed their conditions, which included washing with soap and water (61.8%), and exercising the affected area (52.9%). Almost 65% of patients had sought medical assistance at some stage, but support was generally limited to receiving tablets (91%). Local health professionals reported rarely seeing lymphoedema patients, citing stigma and lack of provisions to assist patients as a reason for this. Almost half of hydrocoele patients (44%) chose not to seek medical assistance despite the negative impact it had on their lives. Whilst surgery itself is free with national health insurance, 63% those who had not sought treatment stated that indirect costs of surgery (travel costs, loss of earnings, etc.) were the most prohibitive factor to seeking treatment. CONCLUSIONS: The information obtained from this study should now be used to guide future morbidity strategies in building a stronger relationship between the local health services and LF patients, to ultimately improve patients' physical, psychological and economic wellbeing. PMID- 26584840 TI - Metallosis-associated prosthetic joint infection. PMID- 26584841 TI - Pediatric invasive pneumococcal disease in Senegal. AB - OBJECTIVES: We aimed to describe the clinical, epidemiological, and outcome characteristics of IPD case patients hospitalized at the Albert-Royer National Children's Hospital (French acronym CHNEAR) to evaluate the disease burden of IPDs in a pediatric hospital of Dakar (Senegal). PATIENTS AND METHODS: All children aged 0-15 years hospitalized at the CHNEAR between January 1st, 2008 and December 31st, 2013 for a documented IPD were included in the study. Medical history, risk factors, clinical, bacteriological, and outcome data was collected. Data was then analyzed using the SPSS software, version 16 (Pearson's Chi(2) test: a P-value<0.05 was considered statistically significant). RESULTS: A total of 218 IPD patients were hospitalized at the CHNEAR during the study period (hospital prevalence: 0.79%). The mean age was 36.1 months. The male to female ratio was 1.27 (122 boys and 96 girls). Infants<2 years of age represented 61.46% of patients. Prior antibiotic therapy was found in 54% of patients but details were lacking. Infection sites were mostly meningeal (61%) and pleuropulmonary (28.9%). The main isolated serotypes were 1, 6A, 14, 5, and 23F. Case fatality was 17.4% and it was five times higher for pneumococcal meningitis. CONCLUSION: IPDs are very common in children in Senegal. Infants<2 years of age are particularly affected. The very high case fatality (17%) was significantly associated with meningeal infection sites hence the need for better access to pneumococcal vaccines. PMID- 26584842 TI - Null alleles of microsatellites for Manila clam Ruditapes philippinarum. PMID- 26584843 TI - Evaluation of blood flow and electromyographic activity in the perioral muscles. AB - BACKGROUND/OBJECTIVES: Although the electromyographic (EMG) activity of the perioral muscles, including the orbicularis oris and mentalis muscles, has been described in individuals with lip incompetence during lip sealing, blood flow through these muscles remains to be elucidated. The purpose of this study was to examine the blood flow associated with EMG activity in the perioral muscles using laser speckle imaging in individuals with lip incompetence. SUBJECTS/METHODS: Blood flow and EMG activity of the superior and inferior orbicularis oris and mentalis muscles were measured with the lips in contact (C condition) and apart (O condition) in lip incompetence (experimental) and control subjects (n = 15 in each group; mean age: 29.5 years). The change ratios of blood flow and EMG activity in the C condition versus O condition (C/O ratios) were calculated and plotted in a scattergram. The Mann-Whitney U-test, Wilcoxon signed-rank test, discriminant analysis using the Mahalanobis generalized distance, and Spearman correlation were used for statistical analysis. RESULTS: In the experimental group, blood flow and EMG activity in all muscles were significantly greater in the C condition than in the O condition. The plots of C/O ratios in the experimental group showed a distinct and wide distribution and were significantly different than those in the control group. In both groups, a significant positive correlation was observed between blood flow and EMG activity in the mentalis muscle. CONCLUSIONS/IMPLICATIONS: The present findings suggest that observing blood flow in the mentalis muscle is an effective and easily performed method of evaluating lip incompetence. PMID- 26584844 TI - Streptobacillus moniliformis bacteremia in a rheumatoid arthritis patient without a rat bite: a case report. AB - BACKGROUND: Rat bite fever is a relatively rare infectious disease due to infection with Streptobacillus moniliformis or Spirillum minus mainly via directs bite by rats, mice, or other rodents. If there is no clear bite history, the diagnosis is difficult or may not be made. CASE PRESENTATION: A 72-year-old Asian female with rheumatoid arthritis was admitted for high grade fever and walking difficulty with severe lumbago. Initially, we suspected lumber compression fracture with deterioration of rheumatoid arthritis, but Gram-negative bacilli were isolated from blood culture during hospitalization. The isolated organism was identified as S. moniliformis by 16S ribosomal ribonucleic acid (rRNA) sequencing. S. moniliformis is well known to be a primary causative organism of rat bite fever, but this patient had no history of rat bite. Had S. moniliformis bacteremia not been detected, she might have been treated for rheumatic exacerbation. CONCLUSION: We emphasize the importance of performing appropriate microbial culture testing for identifying potential infectious diseases. We also conclude that S. moniliformis infection can become established with contaminated vehicle contact alone, not only as a direct result of a bite. We must keep mind that those working in places where rodents breed or are at risk of contact with rats or mice might be at risk for contracting this unusual disease. PMID- 26584845 TI - Clarifying the management of Clostridium difficile infection. PMID- 26584846 TI - Relationship of Mitochondrial Enzymes to Fatigue Intensity in Men With Prostate Cancer Receiving External Beam Radiation Therapy. AB - PURPOSE: Mitochondrial dysfunction is a plausible biological mechanism for cancer related fatigue. Specific aims of this study were to (1) describe the levels of mitochondrial oxidative phosphorylation complex (MOPC) enzymes, fatigue, and health-related quality of life (HRQOL) before and at completion of external beam radiation therapy (EBRT) in men with nonmetastatic prostate cancer (PC); (2) examine relationships over time among levels of MOPC enzymes, fatigue, and HRQOL; and (3) compare levels of MOPC enzymes in men with clinically significant and nonsignificant fatigue intensification during EBRT. METHODS: Fatigue was measured by the revised Piper Fatigue Scale and the Functional Assessment of Cancer Therapy-Fatigue subscale (FACT-F). MOPC enzymes (Complexes I-V) and mitochondrial antioxidant superoxide dismutase 2 were measured in peripheral blood using enzyme linked immunosorbent assay at baseline and completion of EBRT. Participants were categorized into high or low fatigue (HF vs. LF) intensification groups based on amount of change in FACT-F scores during EBRT. RESULTS: Fatigue reported by the 22 participants with PC significantly worsened and HRQOL significantly declined from baseline to EBRT completion. The HF group comprised 12 men with clinically significant change in fatigue (HF) during EBRT. Although no significant changes were observed in MOPC enzymes from baseline to EBRT completion, there were important differences in the patterns in the levels of MOPC enzymes between HF and LF groups. CONCLUSION: Distinct patterns of changes in the absorbance of MOPC enzymes delineated fatigue intensification among participants. Further investigation using a larger sample is warranted. PMID- 26584847 TI - A case-control study of the relationship between a passive second stage of labor and obstetric anal sphincter injuries. AB - OBJECTIVE: To estimate the relationship between a passive second stage of labor and obstetric anal sphincter injuries (OASIS). METHODS: A retrospective, case control study was undertaken of women who delivered at a tertiary-care center in Chicago, IL, USA, between November 2005 and December 2012. Cases had sustained OASIS and were matched on the basis of parity with controls who had no OASIS. Data were obtained from an electronic repository and chart review. Participants with a passive second stage of labor lasting 60 minutes or more were deemed to have "labored down." A logistic regression model to predict OASIS was created. RESULTS: Overall, 1629 cases were compared with 1312 controls. OASIS were recorded among 1452 (57.8%) of 2510 women who did not labor down compared with 169 (40.0%) of 423 women who labored down (P<0.001). However, in binary logistic regression, the addition of laboring down to the model only increased the predictive accuracy from 80.1% to 80.7%. CONCLUSION: When known risk factors for OASIS are accounted for, the effect of laboring down on perineal outcome is negligible. PMID- 26584848 TI - Statin Use With the ATP III Guidelines Compared to the 2013 ACC/AHA Guidelines in HIV Primary Care Patients. AB - BACKGROUND: The 2013 Cholesterol Guidelines include a new atherosclerotic cardiovascular disease (ASCVD) risk calculator that determines the 10-year risk of coronary heart disease and/or stroke. The applicability of this calculator and its predecessor, the Framingham risk score (FRS) in Adult Treatment Panel (ATP) III, has been limited in patients with HIV. The objective of this study was to compare the risk scores of ASCVD and FRS in the initiation of statin therapy in patients with HIV. METHODS: We conducted a retrospective chart review of patients with HIV on statin therapy from October 1, 2013, to April 1, 2014. Data collection included patient demographics, pertinent laboratory test results, and medication list. The primary end point evaluated the level of agreement between the guidelines. RESULTS: Of 155 patients who met the inclusion criteria, 116 were treated similarly with both guidelines. This showed a moderate level of agreement ( P < .001). Forty-eight of 86 patients requiring statins were placed on the correct intensity statin using the 2013 guidelines. Regardless of which guideline, a majority of patients required statin therapy. CONCLUSION: A moderate agreement was found between both guidelines in terms of statin use when applied to an HIV patient population. Based on the 2013 guidelines and taking into account drug interactions with antiretrovirals, 44.2% of the patients were treated with an incorrect statin intensity. PMID- 26584849 TI - Comparison and concordance of health-related quality of life tests among substance users. AB - BACKGROUND: In the field of drug and alcohol abuse, health-related quality of life (HRQoL) has been used as an important clinical and research outcome. The aim of this study was to establish score linkages (concordance) among three HRQoL assessment tools: WHOQOL-BREF, DUQOL and HRQOLDA scores, applying a Rasch-based common person equating procedure. METHODS: One hundred and twenty one adults were recruited from inpatient and outpatient treatment facilities in Sydney West Area Health Service. WHOQOL-BREF, DUQOL and HRQOLDA tests were administered. Item parameters were calculated applying Rating Scale Model, a Rasch model. RESULTS: Fit statistics suggest acceptable goodness-of-fit to the RSM for three instruments. Correlations between HRQOLDA and WHOQOL-BREF and between HRQOLDA and DUQOL scores were 0.719 and 0.613, and the RiU index was 30.4 % and 20.9 %, respectively. All three tests performed adequately for differentiating between individuals whose scores are located at different points along the continuum of the HRQoL construct. CONCLUSION: The results demonstrated a higher concordance between the HRQoLDA and WHOQOL-BREF than between the HRQoLDA and the DUQOL. However, it cannot be established unequivocally that the scores of these tools are concordant. In this study, the utility of the application of the Rasch model to provide an empirical benchmark for the selection of measurement tools to be used in the context of health care and research is demonstrated. PMID- 26584850 TI - Erratum to: Studies on Immunogenicity and Antigenicity of Baculovirus-Expressed Binding Region of Plasmodium falciparum EBA-140 Merozoite Ligand. PMID- 26584851 TI - Bacterial Infections and Osteoclastogenesis Regulators in Men and Women with Cholesteatoma. AB - One of the most distinct features of middle ear cholesteatoma is bone destruction. Aetiology of cholesteatoma is thought to be multifactorial. Endotoxins produced by bacteria are thought to initiate the inflammation process in the middle ear leading to cholesteatoma. There are physiological differences in bone metabolism between men and women. The aim of our study was the immunohistochemical evaluation of the contents of two key components of the OPG/RANK/RANKL triad-RANKL and OPG in cholesteatoma, to analyse if there are any differences between the sexes and to evaluate the bacteria species isolated from cholesteatoma just before surgical treatment and to evaluate their plausible influence on the expression of OPG and RANKL in cholesteatoma. Twenty-one adult patients with acquired cholesteatoma who underwent surgery were analysed. There were no statistically significant differences in the expression of both regulators of osteoclastogenesis between the sexes. In 38.1 % patients cholesteatoma was not infected, whereas in 61.9 % patients various bacterial infections or mycosis were found. The most frequently isolated species was Pseudomonas aeruginosa (14.29 % infections) followed by Staphylococcus aureus (9.52 % infections). There were no statistically significant differences in expression of both OPG and RANKL between uninfected and infected cholesteatomas. PMID- 26584852 TI - ESRRB polymorphisms are associated with comorbidity of temporomandibular disorders and rotator cuff disease. AB - Temporomandibular disorders (TMD) are associated with comorbidity. Shoulder pain is among the symptoms associated with TMD. The purpose of this study was to investigate the association between TMD and rotator cuff disease (RCD) and related genetic aspects. All subjects underwent orofacial and shoulder examinations. The control group comprised 30 subjects with no pain. Affected subjects were divided into three groups: RCD (TMD-free, n=16), TMD (RCD-free, n=13), and TMD/RCD (patients with both RCD and TMD, n=49). A total of eight single nucleotide polymorphisms in the ESRRB gene were investigated. A chemiluminescent immunoassay was used to measure estradiol levels. Surface electromyography recorded head and cervical muscle activity. The chi(2) test and Student t-test/Mann-Whitney test were used to assess the significance of nominal and continuous variables. A P-value of <0.05 was considered significant. TMD subjects were seven times more susceptible to RCD than controls. The rs1676303 TT (P=0.02) and rs6574293 GG (P=0.04) genotypes were associated with RCD and TMD, respectively. TMD/RCD subjects showed associations with rs4903399 (P=0.02), rs10132091 (P=0.02), and CTTCTTAG/CCTCTCAG (P=0.01) haplotypes and lower muscle activity. Estradiol levels were similar among groups. This study supports TMD as a risk factor for RCD. ESRRB haplotypes and low muscle activity are common biomechanical characteristics in subjects with both diseases. PMID- 26584853 TI - Reply to: "Groin hernia repair, surgeon volume and patient reported outcome measures (PROMs)". PMID- 26584854 TI - Advances in hepatectomy technique: Toward zero transfusions in the modern era of liver surgery. AB - BACKGROUND: Perioperative blood transfusions suppress immunity and increase hospital costs. Despite multiple improvements in perioperative care, rates of transfusion during/after hepatectomy are reported to range from 25 to 50%. The purpose of this study was to determine the current risk factors for perihepatectomy transfusion by assessing the impact of recent technical advances in liver surgery on transfusion rates. METHODS: Using our prospectively maintained hepatobiliary tumor database from a high-volume center, a modern cohort of 2,249 hepatectomies (2004-2013) were identified. Patient and operative characteristics were compared between 2 time periods, 2004-2008 (n = 1,139) and 2009-2013 (n = 1,110). Throughout the study interval, transfusions were given based on clinical assessment and not triggered by laboratory thresholds. RESULTS: Compared with the early cohort, the recent cohort had more patients with an American Society of Anesthesiologists score of >= 3 (79 vs 74%), preoperative chemotherapy (73 vs 68%), and a lesser median preoperative hemoglobin (12.9 vs 13.1 mg/dL) and platelet (215,000 vs 243,000) values (all P < .001). Despite these adverse risk factors, with an increasing use of the 2-surgeon resection technique (63 vs 50%), estimated blood loss (309 vs 394 mL), transfusion rates (6 vs 15%), and duration of stay (7.0 vs 8.4 days) were decreased (all P < .001) with no change in overall morbidity or mortality. Multivariate analysis of the recent cohort determined that the independent risk factors associated with transfusion were preoperative anemia and >350 mL of blood loss. The only independent factor associated with less transfusion was use of the 2-surgeon technique for hepatic parenchymal transection. CONCLUSION: With the exception of patients with moderate to severe preoperative anemia requiring major hepatectomy, recent technical advances have decreased significantly the need for transfusion in liver surgery. PMID- 26584855 TI - Ectopic pregnancy: which treatment method least affects fertility? PMID- 26584857 TI - Inquiry of the electron density transfers in chemical reactions: a complete reaction path for the denitrogenation process of 2,3-diazabicyclo[2.2.1]hept-2 ene derivatives. AB - A detailed study on all stages associated with the reaction mechanisms for the denitrogenation of 2,3-diazabicyclo[2.2.1]hept-2-ene derivatives (DBX, with X substituents at the methano-bridge carbon atom, X = H and OH) is presented. In particular, we have characterized the processes leading to cycloalkene derivatives through migration-type mechanisms as well as the processes leading to cyclopentil-1,3-diradical species along concerted or stepwise pathways. The reaction mechanisms have been further analysed within the bonding evolution theory framework at B3LYP and M05-2X/6-311+G(2d,p) levels of theory. Analysis of the results allows us to obtain the intimate electronic mechanism for the studied processes, providing a new topological picture of processes underlying the correlation between the experimental measurements obtained by few-optical-cycle visible pulse radiation and the quantum topological analysis of the electron localization function (ELF) in terms of breaking/forming processes along this chemical rearrangement. The evolution of the population of the disynaptic basin V(N1,N2) can be related to the experimental observation associated with the N=N stretching mode evolution, relative to the N2 release, along the reaction process. This result allows us to determine why the N2 release is easier for the DBH case via a concerted mechanism compared to the stepwise mechanism found in the DBOH system. This holds the key to unprecedented insight into the mapping of the electrons making/breaking the bonds while the bonds change. PMID- 26584856 TI - Evaluation of sit-stand workstations in an office setting: a randomised controlled trial. AB - BACKGROUND: Excessive sitting time is a risk factor for cardiovascular disease mortality and morbidity independent of physical activity. This aim of this study was to evaluate the impact of a sit-stand workstation on sitting time, and vascular, metabolic and musculoskeletal outcomes in office workers, and to investigate workstation acceptability and feasibility. METHODS: A two-arm, parallel-group, individually randomised controlled trial was conducted in one organisation. Participants were asymptomatic full-time office workers aged >=18 years. Each participant in the intervention arm had a sit-stand workstation installed on their workplace desk for 8 weeks. Participants in the control arm received no intervention. The primary outcome was workplace sitting time, assessed at 0, 4 and 8 weeks by an ecological momentary assessment diary. Secondary behavioural, cardiometabolic and musculoskeletal outcomes were assessed. Acceptability and feasibility were assessed via questionnaire and interview. ANCOVA and magnitude-based inferences examined intervention effects relative to controls at 4 and 8 weeks. Participants and researchers were not blind to group allocation. RESULTS: Forty-seven participants were randomised (intervention n = 26; control n = 21). Relative to the control group at 8 weeks, the intervention group had a beneficial decrease in sitting time (-80.2 min/8-h workday (95 % CI = -129.0, -31.4); p = 0.002), increase in standing time (72.9 min/8-h workday (21.2, 124.6); p = 0.007) and decrease in total cholesterol ( 0.40 mmol/L (-0.79, -0.003); p = 0.049). No harmful changes in musculoskeletal discomfort/pain were observed relative to controls, and beneficial changes in flow-mediated dilation and diastolic blood pressure were observed. Most participants self-reported that the workstation was easy to use and their work related productivity did not decrease when using the device. Factors that negatively influenced workstation use were workstation design, the social environment, work tasks and habits. CONCLUSION: Short-term use of a feasible sit stand workstation reduced daily sitting time and led to beneficial improvements in cardiometabolic risk parameters in asymptomatic office workers. These findings imply that if the observed use of the sit-stand workstations continued over a longer duration, sit-stand workstations may have important ramifications for the prevention and reduction of cardiometabolic risk in a large proportion of the working population. TRIAL REGISTRATION: ClinicalTrials.gov NCT02496507 . PMID- 26584858 TI - Severe stress following bereavement during pregnancy and risk of pregnancy loss: results from a population-based cohort study. AB - BACKGROUND: Previous findings on the association between stress during pregnancy and pregnancy loss are inconsistent. We aimed to estimate this association using a large prospective cohort. METHODS: This population-based study included all 1 303 660 clinically recognised pregnancies in Denmark between 1995 and 2008. We categorised women as exposed to severe stress if they lost a child, sibling or parent during pregnancy. Cox Proportional Hazards models were used to study the association between exposure and rate of fetal death, starting with the follow-up on the day of completion of week 4 of pregnancy. In an attempt to control for unknown potential confounders, we also designed a pregnancy-matched analysis in which each woman had her own baseline risk of pregnancy loss and controls therefore for genetic and time-stable environmental factors. RESULTS: A total of 146 031 pregnancies ended in clinically recognised fetal loss (11.2%) and a total of 10 808 (0.8%) women were categorised as exposed. The overall risk of pregnancy loss was similar in the exposed and unexposed (aHR=1.05, 95% CI 0.95 to 1.15). Results from the pregnancy-matched analysis (performed in 423 women) showed stronger and significant associations (aHR=1.83, 95% CI 1.49 to 2.25). All the analyses indicated a stronger effect of bereavement when the mother lost a child or when the death was unexpected. CONCLUSIONS: Our main results suggested no strong association between severe stress during pregnancy and risk of pregnancy loss. Results from the pregnancy-matched analyses considered information from a selected and small group of women for whom there may exist a stronger association between stress during pregnancy and pregnancy loss. The fact that an unexpected death or the loss of a child had a stronger effect in both analyses may indicate that severe stressful situations increase the risk of pregnancy loss. PMID- 26584859 TI - Hospitalisations at the end of life in four European countries: a population based study via epidemiological surveillance networks. AB - BACKGROUND: There is a paucity of cross-national population-based research on hospitalisations of people at the end of life. We aimed to compare, in four European countries, the frequency, time, length of and factors associated with hospitalisations in the last 3 months of life. METHODS: Population-based mortality follow-back study via Sentinel Networks of general practitioners (GPs) in Belgium, the Netherlands, Italy and Spain. Using a standardised form, GPs recorded the care in the last 3 months of life of every deceased practice patient (>=18 years; 1 January 2009 to 31 December 2011). Sudden deaths were excluded. RESULTS: We studied 4791 deaths that GPs described as non-sudden (66% of all registered deaths). Between 49% (the Netherlands) and 56% (Belgium) of patients were hospitalised at least once in the last 3 months of life. Readmissions were less frequent in the Netherlands (8%) than in the other countries (15-20%, p<0.001). Chances of being hospitalised increased over the last 10 days of life across countries but remained lowest in the Netherlands (Belgium: 21-37%, the Netherlands: 15-29%, Italy: 16-37%, Spain: 14-31%). Hospitalisations in the last week of life were more likely if patients resided at home rather than in a care home (ORs and 95% CIs Belgium: 1.94 (1.28 to 2.94); the Netherlands: 2.61 (1.10 to 6.18); Spain: 4.72 (1.64 to 13.57); non-significant in Italy) and less likely if the GP knew the patient's preferred place of death (ORs and 95% CIs Belgium: 0.52 (0.36 to 0.74); the Netherlands: 0.48 (0.25 to 0.91); Spain: 0.24 (0.13 to 0.44), non-significant in Italy). CONCLUSIONS: The use of hospitals at the end-of life increased over the last weeks of life of patients in all countries studied, but remained lowest in the Netherlands, as did the rate of readmissions. This may be due to gatekeeping by GPs who are trained and supported in preventing hospital readmissions at the end of life. PMID- 26584861 TI - Noble metal nanoparticles embedding into polymeric materials: From fundamentals to applications. AB - This review covers some key concepts related to embedding of the noble metal nanoparticles in polymer surfaces. The metal nanoparticles embedded into the polymer matrix can provide high-performance novel materials that find applications in modern nanotechnology. In particular, the origin of various processes that drive the embedding phenomenon, growth of the nanostructure at the surface, factors affecting the embedding including role of surface, interface energies and thermodynamic driving forces with emphasis on the fundamental and technological applications, under different conditions (annealing and ion beams) have been discussed. In addition to the conventional thermal process for embedding which includes the measure of fundamental polymer surface properties with relevant probing techniques, this review discusses the recent advances carried out in the understanding of embedding phenomenon starting from thin metal films to growth of the nanoparticles and embedded nanostructures using novel ion beam techniques. PMID- 26584862 TI - Intention to encode boosts memory-related pre-stimulus EEG beta power. AB - Pre-stimulus oscillatory brain activity can predict the degree to which an upcoming stimulus will be remembered at a later point in time. Recently, increased pre-stimulus power in ongoing theta (5-8Hz) and low beta (13-17Hz) bands during encoding has been associated with enhanced memory performance. When a cue is presented before stimulus onset, encoding-related brain activations may be regarded as a sign of preparation for the upcoming stimulus. Here, we investigated whether the intention to encode the following stimulus into long term memory affects these preparatory pre-stimulus activations during encoding. Two groups of 18 participants took part in a subsequent memory paradigm. Electroencephalogram (EEG) was recorded while participants were presented with a series of pictures, each one preceded by a cue, which were supposed to be classified according to animacy. One group was informed about the upcoming recognition task and therefore was enabled to develop the intention to encode the stimuli (intentional encoding), whereas the other group did not receive this information (incidental encoding). Afterwards, recognition of the pictures was tested. During intentional encoding only, power in theta and low beta bands was found to be significantly increased before the onset of pictures that were later remembered compared to later forgotten ones. Group comparisons confirmed greater memory-related power increases in the low beta band for intentional than incidental encoding. These findings indicate that oscillatory states that are associated with successful encoding can be initiated voluntarily if the intention to encode the stimuli is given. We therefore suggest low beta band activation before stimulus onset to be an indicator of memory-specific preparation for an upcoming stimulus. PMID- 26584860 TI - Regulated internalization of NMDA receptors drives PKD1-mediated suppression of the activity of residual cell-surface NMDA receptors. AB - BACKGROUND: Constitutive and regulated internalization of cell surface proteins has been extensively investigated. The regulated internalization has been characterized as a principal mechanism for removing cell-surface receptors from the plasma membrane, and signaling to downstream targets of receptors. However, so far it is still not known whether the functional properties of remaining (non internalized) receptor/channels may be regulated by internalization of the same class of receptor/channels. The N-methyl-D-aspartate receptor (NMDAR) is a principal subtype of glutamate-gated ion channel and plays key roles in neuronal plasticity and memory functions. NMDARs are well-known to undergo two types of regulated internalization - homologous and heterologous, which can be induced by high NMDA/glycine and DHPG, respectively. In the present work, we investigated effects of regulated NMDAR internalization on the activity of residual cell surface NMDARs and neuronal functions. RESULTS: In electrophysiological experiments we discovered that the regulated internalization of NMDARs not only reduced the number of cell surface NMDARs but also caused an inhibition of the activity of remaining (non-internalized) surface NMDARs. In biochemical experiments we identified that this functional inhibition of remaining surface NMDARs was mediated by increased serine phosphorylation of surface NMDARs, resulting from the activation of protein kinase D1 (PKD1). Knockdown of PKD1 did not affect NMDAR internalization but prevented the phosphorylation and inhibition of remaining surface NMDARs and NMDAR-mediated synaptic functions. CONCLUSION: These data demonstrate a novel concept that regulated internalization of cell surface NMDARs not only reduces the number of NMDARs on the cell surface but also causes an inhibition of the activity of remaining surface NMDARs through intracellular signaling pathway(s). Furthermore, modulating the activity of remaining surface receptors may be an effective approach for treating receptor internalization-induced changes in neuronal functions of the CNS. PMID- 26584863 TI - Segregating attention from response control when performing a motor inhibition task: Segregating attention from response control. AB - Considerable work has demonstrated that inferior frontal gyrus (IFG), anterior insula cortex (AIC) and the supplementary motor area (SMA) are responsive during inhibitory control tasks. However, there is disagreement as to whether this relates to response selection/ inhibition or attentional processing. The current study investigates this by using a Go/No-go task with a factorial design. We observed that both left IFG and dorsal pre-SMA were responsive to no-go cues irrespective of cue frequency. This suggests a role for both in the inhibition of motor responses. Generalized psychophysiological interaction (gPPI) analyses suggest that inferior frontal gyrus may implement this function through interaction with basal ganglia and by suppressing the visual representation of cues associated with no-go responses. Anterior insula cortex and a more ventral portion of pre-SMA showed greater responsiveness to low frequency relative to higher frequency stimuli, irrespective of response type. This may reflect the hypothesized role of anterior insula cortex in marking low frequency items for additional processing (cf. Menon and Uddin, 2010). Consistent with this, the gPPI analysis revealed significantly greater anterior insula cortex connectivity with visual cortex in response to low relative to high frequency cues. PMID- 26584864 TI - Clinical feasibility of using mean apparent propagator (MAP) MRI to characterize brain tissue microstructure. AB - Diffusion tensor imaging (DTI) is the most widely used method for characterizing noninvasively structural and architectural features of brain tissues. However, the assumption of a Gaussian spin displacement distribution intrinsic to DTI weakens its ability to describe intricate tissue microanatomy. Consequently, the biological interpretation of microstructural parameters, such as fractional anisotropy or mean diffusivity, is often equivocal. We evaluate the clinical feasibility of assessing brain tissue microstructure with mean apparent propagator (MAP) MRI, a powerful analytical framework that efficiently measures the probability density function (PDF) of spin displacements and quantifies useful metrics of this PDF indicative of diffusion in complex microstructure (e.g., restrictions, multiple compartments). Rotation invariant and scalar parameters computed from the MAP show consistent variation across neuroanatomical brain regions and increased ability to differentiate tissues with distinct structural and architectural features compared with DTI-derived parameters. The return-to-origin probability (RTOP) appears to reflect cellularity and restrictions better than MD, while the non-Gaussianity (NG) measures diffusion heterogeneity by comprehensively quantifying the deviation between the spin displacement PDF and its Gaussian approximation. Both RTOP and NG can be decomposed in the local anatomical frame for reference determined by the orientation of the diffusion tensor and reveal additional information complementary to DTI. The propagator anisotropy (PA) shows high tissue contrast even in deep brain nuclei and cortical gray matter and is more uniform in white matter than the FA, which drops significantly in regions containing crossing fibers. Orientational profiles of the propagator computed analytically from the MAP MRI series coefficients allow separation of different fiber populations in regions of crossing white matter pathways, which in turn improves our ability to perform whole-brain fiber tractography. Reconstructions from subsampled data sets suggest that MAP MRI parameters can be computed from a relatively small number of DWIs acquired with high b-value and good signal-to-noise ratio in clinically achievable scan durations of less than 10min. The neuroanatomical consistency across healthy subjects and reproducibility in test-retest experiments of MAP MRI microstructural parameters further substantiate the robustness and clinical feasibility of this technique. The MAP MRI metrics could potentially provide more sensitive clinical biomarkers with increased pathophysiological specificity compared to microstructural measures derived using conventional diffusion MRI techniques. PMID- 26584865 TI - Real-time measurement and correction of both B0 changes and subject motion in diffusion tensor imaging using a double volumetric navigated (DvNav) sequence. AB - Diffusion tensor imaging (DTI) requires a set of diffusion weighted measurements in order to acquire enough information to characterize local structure. The MRI scanner automatically performs a shimming process by acquiring a field map before the start of a DTI scan. Changes in B0, which can occur throughout the DTI acquisition due to several factors (including heating of the iron shim coils or subject motion), cause significant signal distortions that result in warped diffusion tensor (DT) parameter estimates. In this work we introduce a novel technique to simultaneously measure, report and correct in real time subject motion and changes in B0 field homogeneity, both in and through the imaging plane. This is achieved using double volumetric navigators (DvNav), i.e. a pair of 3D EPI acquisitions, interleaved with the DTI pulse sequence. Changes in the B0 field are evaluated in terms of zero-order (frequency) and first-order (linear gradients) shim. The ability of the DvNav to accurately estimate the shim parameters was first validated in a water phantom. Two healthy subjects were scanned both in the presence and absence of motion using standard, motion corrected (single navigator, vNav), and DvNav DTI sequences. The difference in performance between the proposed 3D EPI field maps and the standard 3D gradient echo field maps of the MRI scanner was also evaluated in a phantom and two healthy subjects. The DvNav sequence was shown to accurately measure and correct changes in B0 following manual adjustments of the scanner's central frequency and the linear shim gradients. Compared to other methods, the DvNav produced DTI results that showed greater spatial overlap with anatomical references, particularly in scans with subject motion. This is largely due to the ability of the DvNav system to correct shim changes and subject motion between each volume acquisition, thus reducing shear distortion. PMID- 26584866 TI - Regional brain shrinkage and change in cognitive performance over two years: The bidirectional influences of the brain and cognitive reserve factors. AB - We examined relationships between regional brain shrinkage and changes in cognitive performance, while taking into account the influence of chronological age, vascular risk, Apolipoprotein E variant and socioeconomic status. Regional brain volumes and cognitive performance were assessed in 167 healthy adults (age 19-79 at baseline), 90 of whom returned for the follow-up after two years. Brain volumes were measured in six regions of interest (ROIs): lateral prefrontal cortex (LPFC), prefrontal white matter (PFw), hippocampus (Hc), parahippocampal gyrus (PhG), cerebellar hemispheres (CbH), and primary visual cortex (VC), and cognitive performance was evaluated in three domains: episodic memory (EM), fluid intelligence (Gf), and vocabulary (V). Average volume loss was observed in Hc, PhG and CbH, but reliable individual differences were noted in all examined ROIs. Average positive change was observed in EM and V performance but not in Gf scores, yet only the last evidenced individual differences in change. We observed reciprocal influences among neuroanatomical and cognitive variables. Larger brain volumes at baseline predicted greater individual gains in Gf, but differences in LPFC volume change were in part explained by baseline level of cognitive performance. In one region (PFw), individual change in volume was coupled with change in Gf. Larger initial brain volumes did not predict slower shrinkage. The results underscore the complex role of brain maintenance and cognitive reserve in adult development. PMID- 26584867 TI - Causal evidence that intrinsic beta-frequency is relevant for enhanced signal propagation in the motor system as shown through rhythmic TMS. AB - Correlative evidence provides support for the idea that brain oscillations underpin neural computations. Recent work using rhythmic stimulation techniques in humans provide causal evidence but the interactions of these external signals with intrinsic rhythmicity remain unclear. Here, we show that sensorimotor cortex follows externally applied rhythmic TMS (rTMS) stimulation in the beta-band but that the elicited responses are strongest at the intrinsic individual beta peak frequency. While these entrainment effects are of short duration, even subthreshold rTMS pulses propagate through the network and elicit significant cortico-spinal coupling, particularly when stimulated at the individual beta frequency. Our results show that externally enforced rhythmicity interacts with intrinsic brain rhythms such that the individual peak frequency determines the effect of rTMS. The observed downstream spinal effect at the resonance frequency provides evidence for the causal role of brain rhythms for signal propagation. PMID- 26584868 TI - Structural neuroplasticity in expert pianists depends on the age of musical training onset. AB - In the last decade, several studies have investigated the neuroplastic changes induced by long-term musical training. Here we investigated structural brain differences in expert pianists compared to non-musician controls, as well as the effect of the age of onset (AoO) of piano playing. Differences with non-musicians and the effect of sensitive periods in musicians have been studied previously, but importantly, this is the first time in which the age of onset of music training was assessed in a group of musicians playing the same instrument, while controlling for the amount of practice. We recruited a homogeneous group of expert pianists who differed in their AoO but not in their lifetime or present amount of training, and compared them to an age-matched group of non-musicians. A subset of the pianists also completed a scale-playing task in order to control for performance skill level differences. Voxel-based morphometry analysis was used to examine gray-matter differences at the whole-brain level. Pianists showed greater gray matter (GM) volume in bilateral putamen (extending also to hippocampus and amygdala), right thalamus, bilateral lingual gyri and left superior temporal gyrus, but a GM volume shrinkage in the right supramarginal, right superior temporal and right postcentral gyri, when compared to non-musician controls. These results reveal a complex pattern of plastic effects due to sustained musical training: a network involved in reinforcement learning showed increased GM volume, while areas related to sensorimotor control, auditory processing and score-reading presented a reduction in the volume of GM. Behaviorally, early-onset pianists showed higher temporal precision in their piano performance than late-onset pianists, especially in the left hand. Furthermore, early onset of piano playing was associated with smaller GM volume in the right putamen and better piano performance (mainly in the left hand). Our results, therefore, reveal for the first time in a single large dataset of healthy pianists the link between onset of musical practice, behavioral performance, and putaminal gray matter structure. In summary, skill-related plastic adaptations may include decreases and increases in GM volume, dependent on an optimization of the system caused by an early start of musical training. We believe our findings enrich the plasticity discourse and shed light on the neural basis of expert skill acquisition. PMID- 26584869 TI - Changes in fitness are associated with changes in hippocampal microstructure and hippocampal volume among older adults. AB - This study investigates the effects of fitness changes on hippocampal microstructure and hippocampal volume. Fifty-two healthy participants aged 59 74years with a sedentary lifestyle were randomly assigned to either of two levels of exercise intensity. Training lasted for six months. Physical fitness, hippocampal volumes, and hippocampal microstructure were measured before and after training. Hippocampal microstructure was assessed by mean diffusivity, which inversely reflects tissue density; hence, mean diffusivity is lower for more densely packed tissue. Mean changes in fitness did not differ reliably across intensity levels of training, so data were collapsed across groups. Multivariate modeling of pretest-posttest differences using structural equation modeling (SEM) revealed that individual differences in latent change were reliable for all three constructs. More positive changes in fitness were associated with more positive changes in tissue density (i.e., more negative changes in mean diffusivity), and more positive changes in tissue density were associated with more positive changes in volume. We conclude that fitness-related changes in hippocampal volume may be brought about by changes in tissue density. The relative contributions of angiogenesis, gliogenesis, and/or neurogenesis to changes in tissue density remain to be identified. PMID- 26584871 TI - A reflection of the lasting contributions from Dr. Robert Bittman to sterol trafficking, sphingolipid and phospholipid research. AB - With the passing of Dr. Robert Bittman from pancreatic cancer on the 1st October 2014, the lipid research field lost one of the most influential and significant personalities. Robert Bittman's genius was in chemical design and his contribution to the lipid research field was truly immense. The reagents and chemicals he designed and synthesised allowed interrogation of the role of lipids in constituting complex biophysical membranes, sterol transfer and in cellular communication networks. Here we provide a review of these works which serve as a lasting memory to his life. PMID- 26584870 TI - Anterior insula coordinates hierarchical processing of tactile mismatch responses. AB - The body underlies our sense of self, emotion, and agency. Signals arising from the skin convey warmth, social touch, and the physical characteristics of external stimuli. Surprising or unexpected tactile sensations can herald events of motivational salience, including imminent threats (e.g., an insect bite) and hedonic rewards (e.g., a caressing touch). Awareness of such events is thought to depend upon the hierarchical integration of body-related mismatch responses by the anterior insula. To investigate this possibility, we measured brain activity using functional magnetic resonance imaging, while healthy participants performed a roving tactile oddball task. Mass-univariate analysis demonstrated robust activations in limbic, somatosensory, and prefrontal cortical areas previously implicated in tactile deviancy, body awareness, and cognitive control. Dynamic Causal Modelling revealed that unexpected stimuli increased the strength of forward connections along a caudal to rostral hierarchy-projecting from thalamic and somatosensory regions towards insula, cingulate and prefrontal cortices. Within this ascending flow of sensory information, the AIC was the only region to show increased backwards connectivity to the somatosensory cortex, augmenting a reciprocal exchange of neuronal signals. Further, participants who rated stimulus changes as easier to detect showed stronger modulation of descending PFC to AIC connections by deviance. These results suggest that the AIC coordinates hierarchical processing of tactile prediction error. They are interpreted in support of an embodied predictive coding model where AIC mediated body awareness is involved in anchoring a global neuronal workspace. PMID- 26584872 TI - Stiffness Enhancement in Nacre-Inspired Nanocomposites due to Nanoconfinement. AB - Layered assemblies of polymers and graphene derivatives employ nacre's tested strategy of intercalating soft organic layers with hard crystalline domains. These layered systems commonly display elastic properties that exceed simple mixture rule predictions, but the molecular origins of this phenomenon are not well understood. Here we address this issue by quantifying the elastic behavior of nanoconfined polymer layers on a model layered graphene-polymer nanocomposite. Using a novel, validated coarse-grained molecular dynamics simulation approach, here we clearly show that the elastic properties of layered nanocomposites cannot be described by volume fraction considerations alone and depend strongly on both interfacial energy and nanostructure. We quantify the relative importance of polymer nanoconfinement and interfacial energy on polymer structure and elasticity, and illustrate the validity of our model for two polymers with different intrinsic elastic properties. Our theoretical model culminates in phase diagrams that accurately predict the elastic response of nacre-inspired nanocomposites by accounting for all material design parameters. Our findings provide widely applicable prescriptive guidelines for utilizing nanoconfinement to improve the mechanical properties of layer-by-layer nanocomposites. Our findings also serve to explain why the elastic properties of organic layers in nacre exhibit multifold differences from the native and extracted states. PMID- 26584873 TI - Substrate-based inhibitors exhibiting excellent protective and therapeutic effects against Botulinum Neurotoxin A intoxication. AB - Potent inhibitors to reverse Botulinum neurotoxins (BoNTs) activity in neuronal cells are currently not available. A better understanding of the substrate recognition mechanism of BoNTs enabled us to design a novel class of peptide inhibitors which were derivatives of the BoNT/A substrate, SNAP25. Through a combination of in vitro, cellular based, and in vivo mouse assays, several potent inhibitors of approximately one nanomolar inhibitory strength both in vitro and in vivo have been identified. These compounds represent the first set of inhibitors that exhibited full protection against BoNT/A intoxication in mice model with undetectable toxicity. Our findings validated the hypothesis that a peptide inhibitor targeting the two BoNT structural regions which were responsible for substrate recognition and cleavage respectively could exhibit excellent inhibitory effect, thereby providing insight on future development of more potent inhibitors against BoNTs. PMID- 26584874 TI - Failure to thrive, interstitial lung disease, and progressive digital necrosis with onset in infancy. AB - Key teaching points * SAVI is a recently described interferonopathy resulting from constitutive action of STING and up-regulation of IFN-beta signaling. * SAVI is characterized by facial erythema with telangiectasia, acral/cold-sensitive tissue ulceration and amputations, and interstitial lung disease. It has overlapping features with Aicardi-Goutieres syndrome and familial chilblain lupus. * Traditional immunosuppressive medications and biologic therapies appear to be of limited benefit, but JAK inhibitors may impact disease progression. PMID- 26584875 TI - The metabolic change of serum lysophosphatidylcholines involved in the lipid lowering effect of triterpenes from Alismatis rhizoma on high-fat diet induced hyperlipidemia mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Alismatis rhizoma (AR), a Traditional Chinese Medicine with lipid-regulating properties, is usually used to treat hyperlipidemia. Lysophosphatidylcholines (Lyso PCs) play a crucial role in lipid metabolism disorders. In this study, the triterpene fraction purified from boiling water extract of AR was evaluated for its lipid lowering activity using mice with high-fat diet (HFD) induced hyperlipidemia. The metabolic changes of individual Lyso PCs treated with the triterpene fraction were detected by ultra high performance liquid chromatography-triple quadrupole-linear ion trap mass spectrometer (UHPLC-QTRAP-MS/MS). MATERIALS AND METHODS: HFD induced hyperlipidemia mice were administrated with triterpene and non-triterpene fractions at doses of 180, 360 and 720 mg/kg body weight/day for 4 weeks, respectively. Total cholesterol (TC), low-density lipoprotein cholesterol (LDL C), high-density lipoprotein cholesterol (HDL-C) and atherogenic Index (AI) in mice serum were measured. The chemical components in the lipid-lowering fraction were characterized by ultra-high performance liquid chromatography-quadrupole time of flight tandem mass spectrometry (UHPLC-QTOF-MS/MS). The changes of Lyso PC in the serum of mice treated with the lipid-lowering fraction were quantified by UHPLC-QTRAP-MS/MS. RESULTS: A total of 18 alisol derivatives were identified in the triterpene fraction. The hyperlipidemia mice treated with the triterpene fraction showed a significant decrease in serum TC, LDL-C and AI after continuous consumption of HFD for 4 weeks. The results also showed that 27 serum Lyso PCs in mice fed with HFD were down-regulated, and 19 were up-regulated. The abnormal serum level of Lyso PCs associated with hyperlipidemia was intervened by the alisol derivatives, with increase of unsaturated Lyso PCs and decrease of saturated ones. CONCLUSIONS: The study demonstrated for the first time that triterpenes from the AR extract can lower serum lipid level in HFD induced hyperlipidemia mice. These metabolism changes of Lyso PCs could further improve our understanding of the potential mechanism of lipid lowering effect of AR. PMID- 26584876 TI - Hyperplasia of pulmonary neuroendocrine cells in infancy and childhood. AB - Pulmonary neuroendocrine cells (PNEC) are widely distributed throughout the airway mucosa of mammalian lung as solitary cells and as distinctive innervated clusters, neuroepithelial bodies (NEB). These cells differentiate early during lung development and are more prominent in fetal/neonatal lungs compared to adults. PNEC/NEB cells produce biogenic amine (serotonin) and a variety of peptides (i.e., bombesin) involved in regulation of lung function. During the perinatal period, NEB are thought to function as airway O(2)/CO(2) sensors. Increased numbers of PNEC/NEBs have been observed in a variety of perinatal and postnatal lung disorders. Recent advances in cellular and molecular biology of these cells, as they relate to perinatal and postnatal lung disorders associated with PNEC/NEB cell hyperplasia are reviewed and their possible role in pulmonary pathobiology discussed (WC 125). PMID- 26584877 TI - Posturography using the Wii Balance BoardTM: A feasibility study with healthy adults and adults post-stroke. AB - BACKGROUND: Posturography systems that incorporate force platforms are considered to assess balance and postural control with greater sensitivity and objectivity than conventional clinical tests. The Wii Balance Board (WBB) system has been shown to have similar performance characteristics as other force platforms, but with lower cost and size. OBJECTIVES: To determine the validity and reliability of a freely available WBB-based posturography system that combined the WBB with several traditional balance assessments, and to assess the performance of a cohort of stroke individuals with respect to healthy individuals. METHODS: Healthy subjects and individuals with stroke were recruited. Both groups were assessed using the WBB-based posturography system. Individuals with stroke were also assessed using a laboratory grade posturography system and a battery of clinical tests to determine the concurrent validity of the system. A group of subjects were assessed twice with the WBB-based system to determine its reliability. RESULTS: A total of 144 healthy individuals and 53 individuals with stroke participated in the study. Concurrent validity with another posturography system was moderate to high. Correlations with clinical scales were consistent with previous research. The reliability of the system was excellent in almost all measures. In addition, the system successfully characterized individuals with stroke with respect to the healthy population. CONCLUSIONS: The WBB-based posturography system exhibited excellent psychometric properties and sensitivity for identifying balance performance of individuals with stroke in comparison with healthy subjects, which supports feasibility of the system as a clinical tool. PMID- 26584878 TI - Other primary systemic cancers in patients with melanoma: Analysis of balanced acral and nonacral melanomas. AB - BACKGROUND: Although other primary systemic cancers in patients with melanoma have been studied, there have been few focusing on acral melanomas. OBJECTIVES: We assessed other primary systemic cancers in patients with acral and nonacral melanomas. METHODS: We analyzed other primary cancers in 452 patients with melanoma from 1994 to 2013. Metachronous cancers were defined as those given a diagnosis more than 2 months after diagnosis of melanoma. The others were considered prechronous or synchronous cancers. RESULTS: Among 51 cases of other primary cancers, gastrointestinal cancer (35.3%, n = 18/51) was the most common, followed by thyroid (17.6%), lung (11.8%), and breast (5.9%). Those were more prevalent in the acral melanoma group (12.8%, n = 31/243) compared with the nonacral melanoma group (9.6%, n = 20/209). Of 23 cases of metachronous cancer, the risk was the highest in bone marrow, followed by oral cavity, bladder, colon, lung, and thyroid. Among 28 cases of prechronous or synchronous cancers, gastrointestinal tract (35.7%, n = 10/28) was the most common site, followed by thyroid (17.9%), breast (10.7%), and lung (7.1%). LIMITATIONS: The study is limited by a small number of patients. CONCLUSION: Careful follow-up and imaging studies are necessary for early detection of other primary cancers and metastatic lesions in patients with melanoma. PMID- 26584879 TI - 2,30-Bis(10H-indole) heterocycles: New p53/MDM2/MDMX antagonists. AB - The protein-protein interaction of p53 and MDM2/X is a promising non genotoxic anticancer target. A rapid and efficient methodology was developed to synthesize the 2,30-bis(10H-indole) heterocyclic scaffold 2 as ester, acid and amide derivatives. Their binding affinity with MDM2 was evaluated using both fluorescence polarization (FP) assay and HSQC experiments, indicating good inhibition and a perfect starting point for further optimizations. PMID- 26584880 TI - Selective oxidation of 5-hydroxymethylcytosine with micelle incarcerated oxidants to determine it at single base resolution. AB - 5-Methylcytosine (5mC) is oxidized by ten-eleven translocation (TET) enzymes. This process followed by thymine DNA glycosylase is proposed to be the mechanism for methylcytosine demethylation. 5-Hydroxymethylcytosine (5hmC) is one of the most important key oxidative metabolites in the demethylation process, and therefore, simple and accurate method to determine 5hmC at single base resolution is desired. In the present study, we developed a mild catalytic oxidation of 5 hmC using micelle incarcerated oxidants that enables to determine the position of 5hmC at single base resolution. PMID- 26584881 TI - Synthesis and biological evaluation of pyrazolopyrimidines as potential antibacterial agents. AB - The fragment FOL7185 (compound 17) was found to be a hit against IspD and IspE enzymes isolated from bacteria, and a series of analogs containing the pyrazolopyrimidine core were synthesized. The majority of these compounds inhibited the growth of Burkholderia thailandensis (Bt) and Pseudomonas aeruginosa (Pa) in the Kirby-Bauer disk diffusion susceptibility test. Compound 29 shows inhibitory activity at 0.1 mM (32.2 lg/mL), which is comparable to the control compound kanamycin (48.5 lg/mL). Compound 29 also shows inhibitory activity at 0.5 mM against kanamycin resistant P. aeruginosa. Saturation transfer difference NMR (STD-NMR) screening of these compounds against BtIspD and BtIspE indicated that most of these compounds significantly interact with BtIspE, suggesting that the compounds may inhibit the growth of Bt by disrupting isoprenoid biosynthesis. Ligand epitope mapping of compound 29 with BtIspE indicated that hydrogens on 2,4-dichlorophenyl group have higher proximity to the surface of the enzyme than hydrogens on the pyrazolopyrimidine ring. PMID- 26584882 TI - Inhibitors of HIV-1 attachment: The discovery and structure-activity relationships of tetrahydroisoquinolines as replacements for the piperazine benzamide in the 3-glyoxylyl 6-azaindole pharmacophore. AB - 6,6-Fused ring systems including tetrahydroisoquinolines and tetrahydropyrido[3,4 d]pyrimidines have been explored as possible replacements for the piperazine benzamide portion of the HIV-1 attachment inhibitor BMS-663068. In initial studies, the tetrahydroisoquinoline compounds demonstrate sub-nanomolar activity in a HIV-1 pseudotype viral infection assay used as the initial screen for inhibitory activity. Analysis of SARs and approaches to optimization for an improved drug-like profile are examined herein. PMID- 26584883 TI - Suppression of store overload-induced calcium release by hydroxylated metabolites of carvedilol. AB - Carvedilol is a drug widely used in the treatment of heart failure and associated cardiac arrhythmias. A unique action of carvedilol is its suppression of store overload-induced calcium release (SOICR) through the cardiac ryanodine receptor (RyR2), which can trigger ventricular arrhythmias. Since the effects of carvedilol metabolites on SOICR have not yet been investigated, three carvedilol metabolites hydroxylated at the 3-, 4' and 5'-positions were synthesized and assayed for SOICR inhibition in mutant HEK 293 cells expressing the RyR2 mutant R4496C. This cell line is especially prone to SOICR and calcium release through the defective RyR2 channel was measured with a calcium-sensitive fluorescent dye. These results revealed that the 3- and 4'-hydroxy derivatives are slightly more effective than carvedilol in suppressing SOICR, while the 5'-analog proved slightly less active. Metabolic deactivation of carvedilol via these hydroxylation pathways is therefore insignificant. PMID- 26584884 TI - Photodynamic therapy via FRET following bioorthogonal click reaction in cancer cells. AB - Longer wavelength light (650-800nm) is desired to treat large tumors in photodynamic therapy (PDT). However, shorter wavelength light is needed in PDT for thin tumors, not to cause undesirable local side effects. We proposed a strategy for stepwise optical imaging and PDT using a bioorthogonal click chemistry and fluorescence resonance energy transfer (FRET). We prepared azidyl rhodamine (Rh-N3, clickable FD) and cyclooctynyl phthalocyanine [Pc-(DIBAC), clickable PS], with which, here, we demonstrate that the non-catalytic click chemistry is rapid and efficient in cancer cells and FRET from a fluorescence dye (FD) to a photosensitizer (PS) is sufficient to generate enough singlet oxygen killing cancer cells by using shorter wavelength light. PMID- 26584885 TI - Evolution of opercle shape in cichlid fishes from Lake Tanganyika - adaptive trait interactions in extant and extinct species flocks. AB - Phenotype-environment correlations and the evolution of trait interactions in adaptive radiations have been widely studied to gain insight into the dynamics underpinning rapid species diversification. In this study we explore the phenotype-environment correlation and evolution of operculum shape in cichlid fishes using an outline-based geometric morphometric approach combined with stable isotope indicators of macrohabitat and trophic niche. We then apply our method to a sample of extinct saurichthyid fishes, a highly diverse and near globally distributed group of actinopterygians occurring throughout the Triassic, to assess the utility of extant data to inform our understanding of ecomorphological evolution in extinct species flocks. A series of comparative methods were used to analyze shape data for 54 extant species of cichlids (N = 416), and 6 extinct species of saurichthyids (N = 44). Results provide evidence for a relationship between operculum shape and feeding ecology, a concentration in shape evolution towards present along with evidence for convergence in form, and significant correlation between the major axes of shape change and measures of gut length and body elongation. The operculum is one of few features that can be compared in extant and extinct groups, enabling reconstruction of phenotype environment interactions and modes of evolutionary diversification in deep time. PMID- 26584886 TI - Management of infected vascular grafts. AB - Infections of vascular grafts are associated with significant mortality and morbidity risk and cost an estimated $640 million annually in the United States. Clinical presentation varies by time elapsed from implantation and by surgical site. A thorough history and physical examination in conjunction with a variety of imaging modalities is often essential to diagnosis. For infected aortic grafts, there are several options for treatment, including graft excision with extra-anatomic bypass, in situ reconstruction, or reconstruction with the neo aortoiliac system. The management of infected endovascular aortic grafts is similar. For infected peripheral bypasses, graft preservation techniques can be utilized, but in cases where it is not possible, graft removal and revascularization through uninfected tissue planes is necessary. Infected dialysis access can be surgically treated by complete or subtotal graft excision. Diagnosis, general management, and surgical approaches to infected vascular grafts are discussed in this review. PMID- 26584887 TI - Portal vein thrombosis: When to treat and how? AB - Portal vein thrombosis is an unusual thrombotic condition not frequently seen in the general population; however, it has a higher prevalence in special circumstances such as in liver cirrhosis and hepatic or pancreatic malignancy. It also can be associated with significant morbidity and mortality. In this review, we discuss the current data available to guide therapy in the setting of different associated co-morbidities, hypercoagulable states, and associated thrombosis of the remaining splanchnic circulation. We discuss indications for anticoagulation, including the choice of anticoagulants, as well as the role of conservative 'wait and watch' and invasive therapies, such as thrombolysis, thrombectomy, and transjugular intrahepatic portosystemic shunt. PMID- 26584888 TI - Phase I study of multi-gene cell therapy in patients with peripheral artery disease. AB - Alternative treatment strategies for claudication are needed and cell-based therapies designed to induce angiogenesis are promising. The purpose of this report was to conduct a Phase I safety, dose-escalating, non-randomized, open label study of autologous, fully differentiated venous endothelial and smooth muscle cells called MultiGeneAngio (MGA) for claudication due to peripheral artery disease. Twelve subjects, at two centers, received a single intra-arterial infusion of a suspension of equal amounts of transduced autologous venous smooth muscle cells expressing vascular endothelial growth factor (VEGF165) and endothelial cells expressing angiopoietin-1 (Ang-1) (Cohort 1: 1 * 10(7), Cohort 2: 2 * 10(7), Cohort 3: 5 * 10(7), Cohort 4: 7 * 10(7)). The treatment was given unblinded and in the more symptomatic lower extremity. Transduced cells were tested for in vitro doubling time, telomerase activity, and gene expression. The main outcomes were clinical safety and tolerability. Other safety measures included ankle-brachial index (ABI) and walking time on a treadmill. All subjects were male (mean age 60 +/- 5 years) including 25% with diabetes mellitus. At 1 year follow-up, there was one serious adverse event possibly related to MGA. Safety endpoints including VEGF and Ang-1 plasma protein levels were within normal ranges in all subjects. The mean maximal walking time increased from baseline to 1 year and the index limb ABI was unchanged, indicating no safety concerns. MGA, an autologous, transduced, cell-based therapy was well tolerated and safe in this Phase I study. Further evaluation is warranted in randomized human studies. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00390767. PMID- 26584889 TI - Genetic control of morphometric diversity in the maize shoot apical meristem. AB - The maize shoot apical meristem (SAM) comprises a small pool of stem cells that generate all above-ground organs. Although mutational studies have identified genetic networks regulating SAM function, little is known about SAM morphological variation in natural populations. Here we report the use of high-throughput image processing to capture rich SAM size variation within a diverse maize inbred panel. We demonstrate correlations between seedling SAM size and agronomically important adult traits such as flowering time, stem size and leaf node number. Combining SAM phenotypes with 1.2 million single nucleotide polymorphisms (SNPs) via genome-wide association study reveals unexpected SAM morphology candidate genes. Analyses of candidate genes implicated in hormone transport, cell division and cell size confirm correlations between SAM morphology and trait-associated SNP alleles. Our data illustrate that the microscopic seedling SAM is predictive of adult phenotypes and that SAM morphometric variation is associated with genes not previously predicted to regulate SAM size. PMID- 26584890 TI - Environmental and cow-related factors affect cow locomotion and can cause misclassification in lameness detection systems. AB - To tackle the high prevalence of lameness, techniques to monitor cow locomotion are being developed in order to detect changes in cows' locomotion due to lameness. Obviously, in such lameness detection systems, alerts should only respond to locomotion changes that are related to lameness. However, other environmental or cow factors can contribute to locomotion changes not related to lameness and hence, might cause false alerts. In this study the effects of wet surfaces, dark environment, age, production level, lactation and gestation stage on cow locomotion were investigated. Data was collected at Institute for Agricultural and Fisheries Research research farm (Melle, Belgium) during a 5 month period. The gait variables of 30 non-lame and healthy Holstein cows were automatically measured every day. In dark environments and on wet walking surfaces cows took shorter, more asymmetrical strides with less step overlap. In general, older cows had a more asymmetrical gait and they walked slower with more abduction. Lactation stage or gestation stage also showed significant association with asymmetrical and shorter gait and less step overlap probably due to the heavy calf in the uterus. Next, two lameness detection algorithms were developed to investigate the added value of environmental and cow data into detection models. One algorithm solely used locomotion variables and a second algorithm used the same locomotion variables and additional environmental and cow data. In the latter algorithm only age and lactation stage together with the locomotion variables were withheld during model building. When comparing the sensitivity for the detection of non-lame cows, sensitivity increased by 10% when the cow data was added in the algorithm (sensitivity was 70% and 80% for the first and second algorithm, respectively). Hence, the number of false alerts for lame cows that were actually non-lame, decreased. This pilot study shows that using knowledge on influencing factors on cow locomotion will help in reducing the number of false alerts for lameness detection systems under development. However, further research is necessary in order to better understand these and many other possible influencing factors (e.g. trimming, conformation) of non-lame and hence 'normal' locomotion in cows. PMID- 26584891 TI - [Successful expectant management of a uterine arteriovenous malformation]. PMID- 26584892 TI - [Correlation between antenatal ultrasound and postnatal diagnosis in cleft lip or palate: A retrospective study of 44 cases]. AB - OBJECTIVES: Anomalies of the maxillofacial development concern 1 for 700 births. About 30% of prenatal diagnoses of isolated primary cleft palate or associated with a cleft of secondary palate will be corrected in postnatal. This retrospective observational study was designed to compare the antenatal data and postnatal diagnosis regarding a series of clefts. MATERIALS AND METHODS: All children born between 1 December 2009 and 31 January 2014 in a prenatal diagnostic reference center and having a cleft palate were included. Newborns with an abnormality associated with the cleft were excluded. A comparison was made between the data in the antenatal ultrasound reports and postnatal those described by the surgeon during surgery. RESULTS: Forty-four children were included and three infants were excluded due to associated anomalies. Of those 41 children, 27 children have been screened. Ultrasound and clinical diagnosis was the same for 23 cases (85.2%) and inaccurate for 4 patients (14.8%). In case of primary cleft palate prenatal diagnosis was performed to 19 cases of 21 (90.5%), but only 8 of 20 if only secondary cleft palate (42.1%) including 7 with a Pierre Robin sequence. DISCUSSION: Antenatal screening sensitivity of primary and secondary cleft palate increase in recent years with a rate of 85.2% in our series. By contrast, diagnosis of isolated secondary cleft palate seems to be more difficult and 3D ultrasound does not always improve screening performance. CONCLUSION: Ultrasound 2D seem sufficient for screening of primary and secondary cleft palate. The 3D ultrasound may be useful for a better representation of the cleft for future parents. The same language concerning the classification of the clefts facilitates harmonization of reporting and understanding between professionals. The presence of the maxillofacial surgeon ultrasound room would allow the sonographer to direct its ultrasound accurately or improve its learning curve. PMID- 26584893 TI - [Impact of the 21-gene assay in decision-making during multidisciplinary breast meeting: A French experience]. AB - OBJECTIVES: The 21-gene assay (Oncotype DX((r))) test is used to estimate the risk of recurrence and to predict the benefit of adjuvant chemotherapy at an early stage of endocrine responsive breast cancers, without HER2 overexpression or amplification. This test corresponds to a recurrence score (RS), classifying patients into three groups (low, intermediate or high risk). The objective of this two-center prospective study is to define the impact of Oncotype DX((r)) in clinical practice. METHODS: Between August 2013 and May 2015, an Oncotype DX((r)) test was decided in multidisciplinary meeting, to certain patients with an indication of adjuvant chemotherapy for HR+ and HER2 negative cancers. The therapeutic changes after knowledge of RS were collected. An estimate of the economic impact was performed and a correlation between the RS and usual breast cancer prognostic markers was investigated. RESULTS: Thirty-nine patients had a test, twenty-six (66.7%) of them have finally been no indication retaining chemotherapy. The economy obtained through the use of the test was estimated around 173,000euros. It has not been demonstrated correlation between the RS, the usual decisional and prognostic factors for breast cancer or with adjuvant! Online. CONCLUSIONS: The RS has an additional decision value compared to other common decision criteria. Use of Oncotype DX((r)) reduced in our experience the indications of adjuvant chemotherapy. The medical and economic impact could be significant. PMID- 26584894 TI - Papaverine as a replacement for pentoxifylline to select thawed testicular or epididymal spermatozoa before ICSI. AB - OBJECTIVES: Pentoxifylline has been used to improve sperm motility in Assisted Reproductive Technology mainly by initiating sperm motility in immotile spermatozoa samples obtained surgically. Indeed, as Intracytoplasmic Sperm Injection leads to very poor results when using immotile gametes, pentoxifylline gives better results by easing the selection of viable sperm mobilized after incubation. In 2011, the French Haute Autorite de sante decided that pentoxifylline used for in vivo purpose proposed Insufficient Medical Service and pentoxifylline was thus withdrawn from the French materia medica. We here assessed the efficacy on spermatozoa motility and the safety of papaverine, another phosphodiesterase inhibitor, for the replacement of pentoxifylline. METHODS: Sixteen frozen-thawed epididymal or testicular samples displaying no or very poor spontaneous motility (<=5% total motility) were subjected to both pentoxifylline (3.6mM) and papaverine (93MUM). A duplicate Mouse Embryo Assay and an In Vitro Fertilization Mouse Assay in duplo were used to discard any toxic effect of papaverine. RESULTS: Papaverine gave better results than pentoxifylline (mean total motility: 27% vs 23%, P<0.05). No Effect Level were observed in the two different Mouse Embryo Assays performed. CONCLUSION: Papaverine is a useful tool to replace pentoxifylline in ICSI programs to select viable spermatozoa in frozen-thawed sperm samples displaying no or very poor motility. PMID- 26584895 TI - Eat Right-Live Well! Supermarket Intervention Impact on Sales of Healthy Foods in a Low-Income Neighborhood. AB - OBJECTIVE: To evaluate a multifaceted supermarket intervention promoting healthier alternatives to commonly purchased foods. DESIGN: Sales of 385 foods promoted between July and October, 2012 in the Eat Right-Live Well! intervention supermarket were compared with sales in a control supermarket. SETTING: Two supermarkets in geographically separate, low-income, urban neighborhoods. PARTICIPANTS: One control and 1 intervention supermarket. INTERVENTION: Product labeling, employee training, community outreach, and in-store promotions, including taste tests. MAIN OUTCOME MEASURES: Number of items sold; absolute and percent differences in sales. ANALYSIS: Difference-in-difference analyses compared absolute and percent changes between stores and over time within stores. Sub-analyses examined taste-tested items and specific food categories, and promoted items labeled with high fidelity. RESULTS: Comparing pre- and postintervention periods, within-store difference-in-differences for promoted products in the intervention store (25,776 items; 23.1%) was more favorable than the control (9,429 items; 6.6%). The decrease in taste-tested items' sales was smaller in the intervention store (946 items; 5.5%) than the control store (14,666 items; 26.6%). Increased sales of foods labeled with high fidelity were greater in the intervention store (25,414 items; 28.0%) than the control store (7,306 items; 6.3%). CONCLUSIONS AND IMPLICATIONS: Store-based interventions, particularly high-fidelity labeling, can increase promoted food sales. PMID- 26584896 TI - Ability of the Pain Recognition and Treatment (PRT) Protocol to Reduce Expressions of Pain among Institutionalized Residents with Dementia: A Cluster Randomized Controlled Trial. AB - Many strategies have been used to improve pain management in institutionalized care settings, but there is no consensus on the effects of these methods. The study purpose was to compare the effect of a Pain Recognition and Treatment (PRT) protocol coupled with basic pain education (experimental group) versus basic pain education alone (control group) in (1) improving the pain management performance of registered nurses (RNs) and (2) reducing pain-related expressions of residents with dementia postintervention and at 3-month follow up. A double-blind cluster randomized controlled trial with a 3-month follow-up period was conducted with 195 residents of six dementia special-care units. The weekly pain management performance of RNs (e.g., use of pharmacologic and nonpharmacologic strategies, use of referral) was recorded and weekly average scores of the pain-related expressions of residents were assessed using the following: the Verbal Descriptor Scale (VDS), Pain Assessment in Advanced Dementia Scale (PAINAD), and the Cohen Mansfield Agitation Inventory (CMAI). The generalized linear mixed model analysis showed that, after intervention, the experimental group had significantly more weekly nonpharmacologic pain relief strategies and weekly referrals for pain management than the control group. Residents in the experimental group had significantly fewer verbal and behavioral expressions of pain compared to those in the control group. However, the groups did not differ significantly in the use of pharmacological strategies or the agitated behaviors expressed by residents. The PRT protocol is effective and is recommended for routine use in residents with dementia to improve the quality of pain care. PMID- 26584897 TI - A novel cell-based assay for inhibitory anti-muscarinic type 3 receptor antibodies in primary Sjogren's syndrome. AB - Inhibitory autoantibodies acting at the muscarinic acetylcholine receptor type 3 (M3R) are postulated to mediate autonomic dysfunction, including decreased salivary and lacrimal gland output and extra-glandular manifestations, in patients with primary Sjogren's syndrome. However, the contention that anti-M3R antibodies are pathogenic in patients remains untested, due to a lack of assays both sophisticated enough to detect inhibitory anti-M3R antibodies yet suitable for screening large patient cohorts. In the current study, we have established a cell-based bioassay of M3R activity, based on dual transfection of the M3R and a luciferase reporter gene. The bioassay is capable of capturing real-time agonist mediated signalling of the M3R, which is inhibited specifically by patient IgG that have previously been demonstrated to have anti-M3R activity. The assay can be run in multi-well culture plates, and analysed using simple luminescence readers. As such, the new bioassay incorporating M3R-mediated luciferase transduction is the first assay adaptable to common diagnostic platforms that is capable of determining the presence in patient serum of functionally active anti M3R autoantibodies. The new bioassay should prove useful for large cohort screening studies aiming to correlate the presence in patients of inhibitory anti M3R antibodies with symptoms of both glandular and extra-glandular autonomic dysfunction. PMID- 26584899 TI - Maternal maya ancestry and birth weight in Yucatan, Mexico. AB - OBJECTIVES: The purpose of this study was to analyze the association between maternal Maya ancestry and the birth weight of infants born in Yucatan, Mexico, during 2013. METHODS: A total of 30,435 singletons born at term (>=37 weeks) in Yucatan during 2013 were analyzed. Birth weights, gestational ages, and maternal socioeconomic data were provided by the Ministry of Health of Yucatan. Maternal Maya ancestry was defined by the presence of Maya surnames in: (1) non-Maya surnames (NM-NM), (2) one Maya surname (NM-M), and (3) two Maya surnames (M-M). Biological and socioeconomic parameters were compared between the categories of ancestry through one-way analysis of variance (ANOVA) and a multiple regression model was used to analyze the association between ancestry and infants' birth weight controlling for influence of covariates. RESULTS: Mean birth weight was 3,114 g (SD = 406) (NM-NM: 3,150 g [SD = 404], NM-M: 3,106 g [SD = 402], M-M: 3,088 g [SD = 408]). With the biological and socioeconomic variables statistically adjusted for, the presence of one and two maternal Maya surnames was associated with decreases in birth weight of 42 g and 63 g, respectively. None of the interactions between ancestry and other predictors was statistically significant. CONCLUSIONS: The lower mean birth weights of Maya infants are consistent with studies reporting poor growth and nutritional status of Maya children from Yucatan. Historically adverse socioeconomic conditions experienced by the Maya population are probably linked to the relatively lower birth weights of their infants. Am. J. Hum. Biol. 28:436-439, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26584898 TI - Discovery of Novel Plant Interaction Determinants from the Genomes of 163 Root Nodule Bacteria. AB - Root nodule bacteria (RNB) or "rhizobia" are a type of plant growth promoting bacteria, typified by their ability to fix nitrogen for their plant host, fixing nearly 65% of the nitrogen currently utilized in sustainable agricultural production of legume crops and pastures. In this study, we sequenced the genomes of 110 RNB from diverse hosts and biogeographical regions, and undertook a global exploration of all available RNB genera with the aim of identifying novel genetic determinants of symbiotic association and plant growth promotion. Specifically, we performed a subtractive comparative analysis with non-RNB genomes, employed relevant transcriptomic data, and leveraged phylogenetic distribution patterns and sequence signatures based on known precepts of symbiotic- and host-microbe interactions. A total of 184 protein families were delineated, including known factors for nodulation and nitrogen fixation, and candidates with previously unexplored functions, for which a role in host-interaction, -regulation, biocontrol, and more, could be posited. These analyses expand our knowledge of the RNB purview and provide novel targets for strain improvement in the ultimate quest to enhance plant productivity and agricultural sustainability. PMID- 26584900 TI - Misspecification in Mixed-Model-Based Association Analysis. AB - Additive genetic variance in natural populations is commonly estimated using mixed models, in which the covariance of the genetic effects is modeled by a genetic similarity matrix derived from a dense set of markers. An important but usually implicit assumption is that the presence of any nonadditive genetic effect increases only the residual variance and does not affect estimates of additive genetic variance. Here we show that this is true only for panels of unrelated individuals. In the case that there is genetic relatedness, the combination of population structure and epistatic interactions can lead to inflated estimates of additive genetic variance. PMID- 26584901 TI - Coalescence with Background and Balancing Selection in Systems with Bi- and Uniparental Reproduction: Contrasting Partial Asexuality and Selfing. AB - Uniparental reproduction in diploids, via asexual reproduction or selfing, reduces the independence with which separate loci are transmitted across generations. This is expected to increase the extent to which a neutral marker is affected by selection elsewhere in the genome. Such effects have previously been quantified in coalescent models involving selfing. Here we examine the effects of background selection and balancing selection in diploids capable of both sexual and asexual reproduction (i.e., partial asexuality). We find that the effect of background selection on reducing coalescent time (and effective population size) can be orders of magnitude greater when rates of sex are low than when sex is common. This is because asexuality enhances the effects of background selection through both a recombination effect and a segregation effect. We show that there are several reasons that the strength of background selection differs between systems with partial asexuality and those with comparable levels of uniparental reproduction via selfing. Expectations for reductions in Ne via background selection have been verified using stochastic simulations. In contrast to background selection, balancing selection increases the coalescence time for a linked neutral site. With partial asexuality, the effect of balancing selection is somewhat dependent upon the mode of selection (e.g., heterozygote advantage vs. negative frequency-dependent selection) in a manner that does not apply to selfing. This is because the frequency of heterozygotes, which are required for recombination onto alternative genetic backgrounds, is more dependent on the pattern of selection with partial asexuality than with selfing. PMID- 26584903 TI - Inexpensive Computation of the Inverse of the Genomic Relationship Matrix in Populations with Small Effective Population Size. AB - Many computations with SNP data including genomic evaluation, parameter estimation, and genome-wide association studies use an inverse of the genomic relationship matrix. The cost of a regular inversion is cubic and is prohibitively expensive for large matrices. Recent studies in cattle demonstrated that the inverse can be computed in almost linear time by recursion on any subset of ~10,000 individuals. The purpose of this study is to present a theory of why such a recursion works and its implication for other populations. Assume that, because of a small effective population size, the additive information in a genotyped population has a small dimensionality, even with a very large number of SNP markers. That dimensionality is visible as a limited number of effective SNP effects, independent chromosome segments, or the rank of the genomic relationship matrix. Decompose a population arbitrarily into core and noncore individuals, with the number of core individuals equal to that dimensionality. Then, breeding values of noncore individuals can be derived by recursions on breeding values of core individuals, with coefficients of the recursion computed from the genomic relationship matrix. A resulting algorithm for the inversion called "algorithm for proven and young" (APY) has a linear computing and memory cost for noncore animals. Noninfinitesimal genetic architecture can be accommodated through a trait-specific genomic relationship matrix, possibly derived from Bayesian regressions. For populations with small effective population size, the inverse of the genomic relationship matrix can be computed inexpensively for a very large number of genotyped individuals. PMID- 26584904 TI - On the optimal viewing position for object processing. AB - Numerous studies have shown that a visually presented word is processed most easily when participants initially fixate just to the left of the word's center. Fixating on this optimal viewing position (OVP) results in shorter response times and a lower probability of making additional within-word refixations (OVP effects), but also longer initial-fixation durations (an inverted-OVP or I-OVP effect), as compared to initially fixating at the beginning or the end of the word. Thus, typical curves are u-shaped (or inverted-u-shaped), with a leftward bias. Most researchers explain the u-shape in terms of visual constraints, and the leftward bias in terms of language constraints. Previous studies have demonstrated that (I)-OVP effects are not specific to words, but generalize to object viewing. We further investigated this by comparing the strength and (a)symmetry of (I-)OVP effects for words and objects. To this purpose, we gave participants an object- versus word-naming task in which we manipulated the position at which they initially fixated the stimulus (i.e., a line drawing or the written name of an object). Our results showed that object viewing, just as word viewing, resulted in u-shaped (I-)OVP curves. However, the effect was weaker than for words. Furthermore, for words, the curves were biased to the left, whereas they were symmetrical for objects. This might indicate that part of the (I-)OVP effect for words is language specific, and that (I-)OVP effects for objects are a purer measure of the effect of visual constraints. PMID- 26584902 TI - Coalescent Times and Patterns of Genetic Diversity in Species with Facultative Sex: Effects of Gene Conversion, Population Structure, and Heterogeneity. AB - Many diploid organisms undergo facultative sexual reproduction. However, little is currently known concerning the distribution of neutral genetic variation among facultative sexual organisms except in very simple cases. Understanding this distribution is important when making inferences about rates of sexual reproduction, effective population size, and demographic history. Here we extend coalescent theory in diploids with facultative sex to consider gene conversion, selfing, population subdivision, and temporal and spatial heterogeneity in rates of sex. In addition to analytical results for two-sample coalescent times, we outline a coalescent algorithm that accommodates the complexities arising from partial sex; this algorithm can be used to generate multisample coalescent distributions. A key result is that when sex is rare, gene conversion becomes a significant force in reducing diversity within individuals. This can reduce genomic signatures of infrequent sex (i.e., elevated within-individual allelic sequence divergence) or entirely reverse the predicted patterns. These models offer improved methods for assessing null patterns of molecular variation in facultative sexual organisms. PMID- 26584905 TI - Angioectasias on the major and accessory duodenal papillae; a unique cause of recurrent bleed in a patient with von Willebrand's disease. PMID- 26584906 TI - Bloody diarrhoea in a patient with HIV infection. PMID- 26584907 TI - Intralobar pulmonary sequestration: diagnostic expertise. AB - An obese 22-year-old man with a history of recurrent respiratory infections presented to the emergency room with left pleuritic chest pain, productive cough with mucupurulent sputum and an axillary temperature of 37.7 degrees C. Blood work showed elevated inflammatory parameters and chest X-ray was relevant for heterogeneous infiltration in the left base and opacity of the left costophrenic angle. An angio-CT scan revealed areas of bilateral consolidation with presence of an arterial branch originating from the aorta to the collected area of the left lower lobe, consistent with a respiratory infection grafted on a intralobar pulmonary sequestration of the left lung base. The infectious process was treated and the patient was planned for a lower left lobectomy. PMID- 26584908 TI - Large aortic arch mural thrombus in non-atherosclerotic thoracic aorta--a rare cause of stroke in the young. AB - A 43-year-old Indian woman was admitted to the intensive care unit, with large cerebellar infarction. A brain CT scan showed a large non-haemorrhagic infarct involving the vermis and cerebellar hemispheres. Transesophageal echocardiography and CT angiography demonstrated a large mural aortic thrombus. No evidence of cardiac or vascular pathology was present. The patient had a high risk for surgical intervention and was treated with anticoagulation. Follow-up imaging 2 weeks later showed complete resolution of the thoracic aortic thrombus. This case report emphasises that imaging of the great vessels of the neck and transesophageal echocardiography should be included in ischaemic stroke work up. A thoracic aortic thrombus should always be considered in young patients with unexplained stroke or peripheral embolism; the condition can be treated effectively with anticoagulation. PMID- 26584909 TI - Isolated renal echinococcosis: a rare disease. PMID- 26584910 TI - Fe2O3 nanoparticles suppress Kv1.3 channels via affecting the redox activity of Kvbeta2 subunit in Jurkat T cells. AB - Superparamagnetic iron oxide nanoparticles (SPIONs) are promising nanomaterials in medical practice due to their special magnetic characteristics and nanoscale size. However, their potential impacts on immune cells are not well documented. This study aims to investigate the effects of Fe2O3 nanoparticles (Fe2O3-NPs) on the electrophysiology of Kv1.3 channels in Jurkat T cells. Using the whole-cell patch-clamp technique, we demonstrate that incubation of Jurkat cells with Fe2O3 NPs dose- and time-dependently decreased the current density and shifted the steady-state inactivation curve and the recovery curve of Kv1.3 channels to a rightward direction. Fe2O3-NPs increased the NADP level but decreased the NADPH level of Jurkat cells. Direct induction of NADPH into the cytosole of Jurkat cells via the pipette abolished the rightward shift of the inactivation curve. In addition, transmission electron microscopy showed that Fe2O3-NPs could be endocytosed by Jurkat cells with relatively low speed and capacity. Fe2O3-NPs did not significantly affect the viability of Jurkat cells, but suppressed the expressions of certain cytokines (TNFalpha, IFNgamma and IL-2) and interferon responsive genes (IRF-1 and PIM-1), and the time courses of Fe2O3-NPs endocytosis and effects on the expressions of cytokines and interferon responsive genes were compatible. We conclude that Fe2O3-NPs can be endocytosed by Jurkat cells and act intracellularly. Fe2O3-NPs decrease the current density and delay the inactivation and recovery kinetics of Kv1.3 channels in Jurkat cells by oxidizing NADPH and therefore disrupting the redox activity of the Kvbeta2 auxiliary subunit, and as a result, lead to changes of the Kv1.3 channel function. These results suggest that iron oxide nanoparticles may affect T cell function by disturbing the activity of Kv1.3 channels. Further, the suppressing effects of Fe2O3-NPs on the expressions of certain inflammatory cytokines and interferon responsive genes suggest that iron oxide nanoparticles may exert modulatory effects on T cell immune activities and anti-inflammation effects. PMID- 26584911 TI - Inhibition of each module of connective tissue growth factor as a potential therapeutic target for rheumatoid arthritis. AB - We previously reported the importance of connective tissue growth factor (CTGF) in rheumatoid arthritis (RA). CTGF contains four distinct modules connected in tandem, namely insulin-like growth factor-binding protein (IGFBP)-like, von Willebrand factor (vWF) type C repeat, thrombospondin type 1 (TSP-1) repeat, and carboxyl-terminal (CT) modules. The relationships between each of these modules of CTGF and RA remain unknown. Here, we analyzed how inhibition of each CTGF module affects the pathophysiology of RA. We conducted stimulation and suppression experiments on synovial cells (MH7A) obtained from patients with RA. Moreover, we examined angiogenesis by means of a tube-formation assay performed using human umbilical vein endothelial cells (HUVECs), and we used tartrate resistant acid phosphatase (TRAP) staining to analyze osteoclastogenesis. Our results showed that M-CSF/RANKL-mediated osteoclastogenesis was enhanced when CTGF was added, but the effect of CTGF was neutralized by mAbs against CTGF modules 1-4. Furthermore, CTGF treatment of HUVECs induced formation of tubular networks, which resulted in acceleration of the angiogenesis of RA synoviocytes, and quantification showed that this tubular-network formation was also disrupted by anti-CTGF module 1-4 mAbs. Lastly, TNF-alpha enhanced the expression of CTGF and matrix metalloproteinase-3 (MMP3) in MH7A cells, and this enhancement was potently neutralized by mAbs against CTGF modules 1, 3 and 4. Thus, our results indicate that not only a mAb against CTGF but also mAbs against each specific module of CTGF might serve as potential therapeutic agents in the treatment of RA. PMID- 26584912 TI - The mechanistic basis of hyperoxaluria following gastric bypass in obese rats. AB - Roux-en-Y gastric bypass (RYGB) surgery is a popular and extremely effective procedure for sustained weight loss in the morbidly obese. However, hyperoxaluria and oxalate kidney stones frequently develop after RYGB and steatorrhea has been speculated to play a role. We examined the effects of RYGB and the role of dietary fat in an obese rat model by measuring fecal fat content and transmural oxalate fluxes across the distal colon compared to sham-operated controls (SHAM). Direct measurements of fecal fat content confirmed that RYGB on a 10 % fat diet excreted 40-fold more fecal fat than SHAM and, on a 40 % fat diet, RYGB excreted sevenfold more fecal fat than SHAM fed similarly. Results from the transport studies revealed a clear effect of high dietary fat (40 %) on colonic oxalate permeability and tissue conductance (G T) with comparable oxalate fluxes in RYGB and in SHAM. Administering a diet containing 10 % fat to both groups distinguished differences between RYGB and SHAM, revealing a 40 % increase in G T in RYGB and a reversal in the direction of net oxalate flux from absorption in SHAM to secretion in RYGB. These changes in colonic oxalate permeability were associated with a fourfold increase in urinary oxalate excretion in RYGB compared to SHAM. Therefore, oxalate solubility and permeability in the RYGB model are promoted by steatorrhea and result in enhanced passive oxalate absorption and hyperoxaluria. To our knowledge, these are the first measurements of intestinal oxalate transport in rats with RYGB. PMID- 26584913 TI - Cytotoxic and anti-inflammatory activities of phenanthrenes from the medullae of Juncus effusus L. AB - Bioactivity guided phytochemical investigation of the ethanol extract of the medullae of Juncus effusus resulted in the isolation of two new phenanthrenes, 8 hydroxymethyl-2-hydroxyl-1-methyl-5-vinyl-9,10-dihydrophenanthrene (1), and 5-(1 methoxyethyl)-1-methyl-phenanthren-2,7-diol (2) together with 15 known phenanthrenoids (3-17). The chemical structures of 1 and 2 were established by a combination of spectroscopic techniques. Compounds 1-15 and 17 were evaluated for their cytotoxic activities against five human cancer cell lines (SHSY-5Y, SMMC 7721, HepG-2, Hela and MCF-7) by CCK-8 assay, and their anti-inflammatory activities were also evaluated by inhibition on NO production in LPS-activated murine macrophage RAW 264.7 cells. PMID- 26584914 TI - Formulation of nimodipine nanocrystals for oral administration. AB - The aim of this paper is to optimize nimodipine (NMD) nanocrystals (NCs) for oral administration. The effects of independent process variables (microprecipitation temperature, shearing speed, shearing time, homogenization pressure and number of cycles) on the particle size have been studied. Experiments were conducted to optimize the formulation composition. A single factor exploration was used to screen the primary stabilizers. Then, the selected polymers/surfactants were further optimized using an L9 (3(4)) orthogonal design. The optimal formulation was composed of NMD (0.7 %, w/v), F127 (0.4 %, w/v), HPMC-E5 (0.1 %, w/v), and sodium deoxycholate (0.05 %, w/v) and was rod-shaped as shown by SEM observations, and it had a particle size of 833.3 +/- 20.6 nm, determined by laser diffraction. These aqueous NCs were physically stable for 15 days. To further improve the stability, the NCs were freeze-dried. The powder obtained exhibited acceptable flowability and was physically stable for at least 24 months. Additionally, the NMD NCs displayed much higher dissolution profiles than the bulk drug. The pharmacokinetic results showed that the relative bioavailability was 397 % in comparison with Nimotop((r)), suggesting that NCs are an efficient strategy for improving the oral bioavailability of poorly water soluble drugs. PMID- 26584915 TI - Thiol-ene-Enabled Detection of Thiophosphorylation as a Labeling Strategy for Phosphoproteins. AB - The adenosine triphosphate (ATP) analogue adenosine 5'-O-(3-thiotriphosphate) (ATPgammaS) has been applied as a tool to study kinase-substrate phosphorylation. Not only does the transfer of a thiophosphate group represent a unique modification amid the phosphoproteome, but it can also be stable to phosphatase activity. However, detection of this species is complicated due to the similar chemical reactivity of thiophosphate and proteinaceous thiols. Here, we describe a novel method for detection of protein thiophosphorylation utilizing the thiol ene reaction. By first chemoselectively capping protein thiols through radical chemistry, kinase-catalyzed thiophosphorylation can be visualized specifically. PMID- 26584916 TI - Phosphopeptide Detection with Biotin-Labeled Phos-tag. AB - Protein kinases are widely considered to be invaluable target enzymes for drug discovery and for diagnosing diseases and assessing their prognosis. Effective analytical techniques for measuring the activities of cellular protein kinases are therefore required for studies in the field of phosphoproteomics. We have recently developed a highly sensitive microarray-based technique for tracing the activities of protein kinases. A series of peptides that are specific substrates of various protein kinases are immobilized on a glass slide and subjected to phosphorylation by cell lysates. The resulting phosphorylated forms of the various peptides are then selectively and simultaneously detected by using a phosphate-binding tag molecule, biotin-labeled Phos-tag, bound to horseradish peroxidase-conjugated streptavidin. Enhanced chemiluminescence signals can then be readily detected by using an automatic image analyzer. In this chapter, we describe a standard protocol for detecting phosphopeptides by biotin-labeled Phos tag. We also describe a microarray system for high-throughput profiling of intracellular protein kinase activities. The Phos-tag-based method is expected to be useful in the rapid detection of the complex range of phosphorylation reactions involved in cellular signaling events, and it has potential applications in high-throughput screening of kinase activators or inhibitors. PMID- 26584917 TI - Phosphopeptide Enrichment by Covalent Chromatography After Solid Phase Derivatization of Protein Digests on Reversed Phase Supports. AB - The isolation of the phosphopeptide constituents from phosphoprotein digests is prerequisite to facilitate the mass spectrometric characterization of phosphorylation events. Here, we describe a chemical proteomics approach which combines solid phase derivatization of phosphoprotein digests with phosphopeptide enrichment by covalent chromatography. The use of the solid phase support for derivatization ensures for speed and completeness of reactions. The isolates proved highly suitable for mapping of the sites of phosphorylation by collisionally induced dissociation (CID). The method combines robustness with simplicity of operation using equipment available in biological laboratories, and may be readily extended to map the sites of O-glycosylation. PMID- 26584918 TI - Peptide Labeling Using Isobaric Tagging Reagents for Quantitative Phosphoproteomics. AB - Isobaric tagging reagents have become an invaluable tool for multiplexed quantitative proteomic analysis. These reagents can label multiple, distinct peptide samples from virtually any source material (e.g., tissue, cell line, purified proteins), allowing users the opportunity to assess changes in peptide abundances across many different time points or experimental conditions. Here, we describe the application of isobaric peptide labeling, specifically 8plex isobaric tags for relative and absolute quantitation (8plex iTRAQ), for quantitative phosphoproteomic analysis of cultured cells or tissue suspensions. For this particular protocol, labeled samples are pooled, fractionated by strong cation exchange chromatography, enriched for phosphopeptides, and analyzed by tandem mass spectrometry (LC-MS/MS) for both peptide identification and quantitation. PMID- 26584919 TI - Identification of Direct Kinase Substrates Using Analogue-Sensitive Alleles. AB - Identifying the substrates of protein kinases remains a major obstacle in the elucidation of eukaryotic signaling pathways. Promiscuity among kinases and their substrates coupled with the extraordinary plasticity of phosphorylation networks renders traditional genetic approaches or small-molecule inhibitors problematic when trying to determine the direct substrates of an individual kinase. Here we describe methods to label, enrich, and identify the direct substrates of analogue sensitive kinases by exploiting their steric complementarity to artificial ATP analogues. Using calcium-dependent protein kinases of Toxoplasma gondii as a model for these approaches, this protocol brings together numerous advances that enable labeling of kinase targets in semi-permeabilized cells, quantification of direct labeling over background, and highly specific enrichment of targeted phosphopeptides. PMID- 26584920 TI - Quantitative Analysis of Tissue Samples by Combining iTRAQ Isobaric Labeling with Selected/Multiple Reaction Monitoring (SRM/MRM). AB - Mass spectrometry-based phosphoproteomics is an indispensible technique used in the discovery and quantification of phosphorylation events on proteins in biological samples. The application of this technique to tissue samples is especially useful for the discovery of biomarkers as well as biological studies. We herein describe the application of a large-scale phosphoproteome analysis and SRM/MRM-based quantitation to develop a strategy for the systematic discovery and validation of biomarkers using tissue samples. PMID- 26584921 TI - Enrichment Strategies in Phosphoproteomics. AB - The comprehensive study of the phosphoproteome is heavily dependent on appropriate enrichment strategies that are most often, but not exclusively, carried out on the peptide level. In this chapter, I give an overview of the most widely used techniques. In addition to dedicated antibodies, phosphopeptides are enriched by their selective interaction with metals in the form of chelated metal ions or metal oxides. The negative charge of the phosphate group is also exploited in a variety of chromatographic fractionation methods that include different types of ion exchange chromatography, hydrophilic interaction chromatography (HILIC), and electrostatic repulsion HILIC (ERLIC) chromatography. Selected examples from the literature will demonstrate how a combination of these techniques with current high-performance mass spectrometry enables the identification of thousands of phosphorylation sites from various sample types. PMID- 26584922 TI - Phosphopeptide Enrichment by Immobilized Metal Affinity Chromatography. AB - Immobilized metal affinity chromatography (IMAC) has been the method of choice for phosphopeptide enrichment prior to mass spectrometric analysis for many years and it is still used extensively in many laboratories. Using the affinity of negatively charged phosphate groups towards positively charged metal ions such as Fe(3+), Ga(3+), Al(3+), Zr(4+), and Ti(4+) has made it possible to enrich phosphorylated peptides from peptide samples. However, the selectivity of most of the metal ions is limited, when working with highly complex samples, e.g., whole cell extracts, resulting in contamination from nonspecific binding of non phosphorylated peptides. This problem is mainly caused by highly acidic peptides that also share high binding affinity towards these metal ions. By lowering the pH of the loading buffer nonspecific binding can be reduced significantly, however with the risk of reducing specific binding capacity. After binding, the enriched phosphopeptides are released from the metal ions using alkaline buffers of pH 10-11, EDTA, or phosphate-containing buffers. Here we describe a protocol for IMAC using Fe(3+) for phosphopeptide enrichment. The principles are illustrated on a semi-complex peptide mixture. PMID- 26584923 TI - The Use of Titanium Dioxide for Selective Enrichment of Phosphorylated Peptides. AB - Titanium dioxide (TiO2) has very high affinity for phosphopeptides and in recent years it has become one of the most popular methods for phosphopeptide enrichment from complex biological samples. Peptide loading onto TiO2 resin in a highly acidic environment in the presence of 2,5-dihydroxybenzoic acid (DHB), phthalic acid, lactic acid, or glycolic acid has been shown to improve selectivity significantly by reducing unspecific binding of non-phosphorylated peptides. The phosphopeptides bound to the TiO2 are subsequently eluted from the chromatographic material using an alkaline buffer. TiO2 chromatography is extremely tolerant towards most buffers used in biological experiments, highly robust and as such it has become the method of choice in large-scale phosphoproteomics. Here we describe a batch mode protocol for phosphopeptide enrichment using TiO2 chromatographic material followed by desalting and concentration of the sample by reversed phase micro-columns prior to downstream MS and LC-MS/MS analysis. PMID- 26584924 TI - Sequential Elution from IMAC (SIMAC): An Efficient Method for Enrichment and Separation of Mono- and Multi-phosphorylated Peptides. AB - Phosphoproteomics relies on methods for efficient purification and sequencing of phosphopeptides from highly complex biological systems, especially when using low amounts of starting material. Current methods for phosphopeptide enrichment, e.g., Immobilized Metal ion Affinity Chromatography and titanium dioxide chromatography provide varying degrees of selectivity and specificity for phosphopeptide enrichment. The number of multi-phosphorylated peptides identified in most published studies is rather low. Here we describe a protocol for a strategy that separates mono-phosphorylated peptides from multiply phosphorylated peptides using Sequential elution from Immobilized Metal ion Affinity Chromatography. The method relies on the initial enrichment and separation of mono- and multi-phosphorylated peptides using Immobilized Metal ion Affinity Chromatography and a subsequent enrichment of the mono-phosphorylated peptides using titanium dioxide chromatography. The two separate phosphopeptide fractions are then subsequently analyzed by mass spectrometric methods optimized for mono phosphorylated and multi-phosphorylated peptides, respectively, resulting in improved identification of especially multi-phosphorylated peptides from a minimum amount of starting material. PMID- 26584925 TI - Improving the Phosphoproteome Coverage for Limited Sample Amounts Using TiO2 SIMAC-HILIC (TiSH) Phosphopeptide Enrichment and Fractionation. AB - Obtaining high phosphoproteome coverage requires specific enrichment of phosphorylated peptides from the often extremely complex peptide mixtures generated by proteolytic digestion of biological samples, as well as extensive chromatographic fractionation prior to liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Due to the sample loss resulting from fractionation, this procedure is mainly performed when large quantities of sample are available. To make large-scale phosphoproteomics applicable to smaller amounts of protein we have recently combined highly specific TiO2-based phosphopeptide enrichment with sequential elution from immobilized metal affinity chromatography (SIMAC) for fractionation of mono- and multi-phosphorylated peptides prior to capillary scale hydrophilic interaction liquid chromatography (HILIC) based fractionation of monophosphorylated peptides. In the following protocol we describe the procedure step by step to allow for comprehensive coverage of the phosphoproteome utilizing only a few hundred micrograms of protein. PMID- 26584926 TI - Offline High pH Reversed-Phase Peptide Fractionation for Deep Phosphoproteome Coverage. AB - Protein phosphorylation, a process in which kinases modify serines, threonines, and tyrosines with phosphoryl groups is of major importance in eukaryotic biology. Protein phosphorylation events are key initiators of signaling responses which determine cellular outcomes after environmental and metabolic stimuli, and are thus highly regulated. Therefore, studying the mechanism of regulation by phosphorylation, and pinpointing the exact site of phosphorylation on proteins is of high importance. This protocol describes in detail a phosphoproteomics workflow for ultra-deep coverage by fractionating peptide mixtures based on high pH (basic) reversed-phase chromatography prior to phosphopeptide enrichment and mass spectrometric analysis. Peptides are separated on a C18 reversed-phase column under basic conditions and fractions collected in timed intervals followed by concatenation of the fractions. Each Fraction is subsequently enriched for phosphopeptides using TiO2 followed by LC/MS analysis. PMID- 26584927 TI - Phosphopeptide Enrichment Using Various Magnetic Nanocomposites: An Overview. AB - Magnetic nanocomposites are hybrid structures consisting of an iron oxide (Fe3O4/gamma-Fe2O3) superparamagnetic core and a coating shell which presents affinity for a specific target molecule. Within the scope of phosphopeptide enrichment, the magnetic core is usually first functionalized with an intermediate layer of silica or carbon to improve dispersibility and increase specific area, and then with an outer layer of a phosphate-affinity material. Fe3O4-coating materials include metal oxides, rare earth metal-based compounds, immobilized-metal ions, polymers, and many others. This chapter provides a generic overview of the different materials that can be found in literature and their advantages and drawbacks. PMID- 26584928 TI - Two Dimensional Gel Electrophoresis-Based Plant Phosphoproteomics. AB - Phosphorylation is one of the most important reversible protein modifications and is involved in regulating signal transduction, subcellular localization and enzyme activity of target proteins. Phosphorylation or dephosphorylation of proteins is directly reflected in changed ratios of phosphoprotein abundance and total protein abundance. Two-dimensional gel electrophoresis (2-DE)-based proteomics allow quantification of both total protein abundance by Coomassie Brilliant Blue (CBB) staining and phosphoprotein abundance by fluorescence-based staining. Pro-Q diamond phosphoprotein stain (Pro-Q DPS) can bind to the phosphate moiety of the phospho-amino acid directly, regardless of the nature of the phospho-amino acid. Phosphoproteins can thus be detected using proper excitation light, quantified using image analysis software and subsequently be subjected to analysis by mass spectrometry. Here, we describe a protein phosphorylation status analysis method combining both CBB and Pro-Q DPS staining based on 2-DE gel-based phosphoproteomics, which has been widely applied to plant phosphoproteomics studies. PMID- 26584929 TI - Variable Digestion Strategies for Phosphoproteomics Analysis. AB - In recent years, mass spectrometry-based phosphoproteomics has propelled our knowledge about the regulation of cellular pathways. Nevertheless, typically applied bottom-up strategies have several limitations. Trypsin, the preferentially used proteolytic enzyme shows impaired cleavage efficiency in the vicinity of phosphorylation sites. Moreover, depending on the frequency and distribution of tryptic cleavage sites (Arg/Lys), generated peptides can be either too short or too long for confident identification using standard LC-MS approaches. To overcome these limitations, we introduce an alternative and simple approach based on the usage of the nonspecific serine protease subtilisin, which enables a fast and reproducible digestion and provides access to "hidden" areas of the proteome. Thus, in a single LC-MS experiment >1800 phosphopeptides were confidently identified and localized from 125 MUg of HeLa digest, compared to >2100 sites after tryptic digestion. While the overlap was less than 20 %, subtilisin allowed the identification of many phosphorylation sites that are theoretically not accessible via tryptic digestion, thus considerably increasing the coverage of the phosphoproteome. PMID- 26584930 TI - Online LC-FAIMS-MS/MS for the Analysis of Phosphorylation in Proteins. AB - High-field asymmetric waveform ion mobility spectrometry (FAIMS) is a gas-phase separation technique which, when coupled with liquid chromatography tandem mass spectrometry, offers benefits for analysis of complex proteomics samples such as those encountered in phosphoproteomics experiments. Results from LC-FAIMS-MS/MS are typically complementary, in terms of proteome coverage and isomer identification, to those obtained by use of solution-phase separation methods, such as prefractionation with strong cation-exchange chromatography. Here, we describe the protocol for large-scale phosphorylation analysis by LC-FAIMS-MS/MS. PMID- 26584931 TI - Simple and Reproducible Sample Preparation for Single-Shot Phosphoproteomics with High Sensitivity. AB - The traditional sample preparation workflow for mass spectrometry (MS)-based phosphoproteomics is time consuming and usually requires multiple steps, e.g., lysis, protein precipitation, reduction, alkylation, digestion, fractionation, and phosphopeptide enrichment. Each step can introduce chemical artifacts, in vitro protein and peptide modifications, and contaminations. Those often result in sample loss and affect the sensitivity, dynamic range and accuracy of the mass spectrometric analysis. Here we describe a simple and reproducible phosphoproteomics protocol, where lysis, denaturation, reduction, and alkylation are performed in a single step, thus reducing sample loss and increasing reproducibility. Moreover, unlike standard cell lysis procedures the cell harvesting is performed at high temperatures (99 degrees C) and without detergents and subsequent need for protein precipitation. Phosphopeptides are enriched using TiO2 beads and the orbitrap mass spectrometer is operated in a sensitive mode with higher energy collisional dissociation (HCD). PMID- 26584932 TI - Identification of Direct Kinase Substrates via Kinase Assay-Linked Phosphoproteomics. AB - Protein phosphorylation plays an essential role in the regulation of various cellular functions. Dysregulation of phosphorylation is implicated in the pathogenesis of certain cancers, diabetes, cardiovascular diseases, and central nervous system disorders. As a result, protein kinases have become potential drug targets for treating a wide variety of diseases. Identification of kinase substrates is vital not only for dissecting signaling pathways, but also for understanding disease pathologies and identifying novel therapeutic targets. However, identification of bona fide kinase substrates has remained challenging, necessitating the development of new methods and techniques. The kinase assay linked phosphoproteomics (KALIP) approach integrates in vitro kinase assays with global phosphoproteomics experiments to identify the direct substrates of protein kinases. This strategy has demonstrated outstanding sensitivity and a low false positive rate for kinase substrate screening. PMID- 26584933 TI - Phosphoprotein Detection by High-Throughput Flow Cytometry. AB - Phospho flow cytometry is a powerful technique for the detection of protein phosphorylation events that, like Western blotting, relies on phospho-epitope specific antibodies. In contrast to the latter, however, multidimensional and directly quantifiable data is obtained at the single-cell level allowing separate analysis of small cell populations in complex cellular mixtures. Furthermore, up to 30 phospho-specific antibodies or antibodies identifying other posttranslational modifications in combination with cell surface markers can be analyzed in a single experiment. Utilizing a technique called fluorescent cell barcoding that enables combination of up to 64 samples into one tube for multiplex analysis and later data deconvolution, phospho flow cytometry is turned into a medium- to high-throughput technology. PMID- 26584934 TI - Resources for Assignment of Phosphorylation Sites on Peptides and Proteins. AB - Reversible protein phosphorylation is a key regulatory posttranslational modification that plays a significant role in major cellular signaling processes. Phosphorylation events can be systematically identified, quantified, and localized on protein sequence using publicly available bioinformatic tools. Here we present the software tools commonly used by the phosphoproteomics community, discuss their underlying principles of operation, and provide a protocol for large-scale phosphoproteome data analysis using the MaxQuant software suite. PMID- 26584935 TI - From Phosphosites to Kinases. AB - Kinases play a pivotal role in propagating the phosphorylation-mediated signaling networks in living cells. With the overwhelming quantities of phosphoproteomics data being generated, the number of identified phosphorylation sites (phosphosites) is ever increasing. Often, proteomics investigations aim to understand the global signaling modulation that takes place in different biological conditions investigated. For phosphoproteomics data, identifying the kinases central to mediating this response is key. This has prompted several efforts to catalogue the immense amounts of phosphorylation data and known or predicted kinases responsible for the modifications. However, barely 20 % of the known phosphosites are assigned to a kinase, initiating various bioinformatics efforts that attempt to predict the responsible kinases. These algorithms employ different approaches to predict kinase consensus sequence motifs, mostly based on large scale in vivo and in vitro experiments. The context of the kinase and the phosphorylated proteins in a biological system is equally important for predicting association between the enzymes and substrates, an aspect that is also being tackled with available bioinformatics tools. This chapter summarizes the use of the larger phosphorylation databases, and approaches that can be applied to predict kinases that phosphorylate individual sites or that are globally modulated in phosphoproteomics datasets. PMID- 26584936 TI - Search Databases and Statistics: Pitfalls and Best Practices in Phosphoproteomics. AB - Advances in mass spectrometric instrumentation in the past 15 years have resulted in an explosion in the raw data yield from typical phosphoproteomics workflows. This poses the challenge of confidently identifying peptide sequences, localizing phosphosites to proteins and quantifying these from the vast amounts of raw data. This task is tackled by computational tools implementing algorithms that match the experimental data to databases, providing the user with lists for downstream analysis. Several platforms for such automated interpretation of mass spectrometric data have been developed, each having strengths and weaknesses that must be considered for the individual needs. These are reviewed in this chapter. Equally critical for generating highly confident output datasets is the application of sound statistical criteria to limit the inclusion of incorrect peptide identifications from database searches. Additionally, careful filtering and use of appropriate statistical tests on the output datasets affects the quality of all downstream analyses and interpretation of the data. Our considerations and general practices on these aspects of phosphoproteomics data processing are presented here. PMID- 26584937 TI - Systems Analysis for Interpretation of Phosphoproteomics Data. AB - Global phosphoproteomics investigations yield overwhelming datasets with up to tens of thousands of quantified phosphosites. The main challenge after acquiring such large-scale data is to extract the biological meaning and relate this to the experimental question at hand. Systems level analysis provides the best means for extracting functional insights from such types of datasets, and this has primed a rapid development of bioinformatics tools and resources over the last decade. Many of these tools are specialized databases that can be mined for annotation and pathway enrichment, whereas others provide a platform to generate functional protein networks and explore the relations between proteins of interest. The use of these tools requires careful consideration with regard to the input data, and the interpretation demands a critical approach. This chapter provides a summary of the most appropriate tools for systems analysis of phosphoproteomics datasets, and the considerations that are critical for acquiring meaningful output. PMID- 26584938 TI - Comparison between CHA2DS2-VASc and the new R2CHADS2 and ATRIA scores at predicting thromboembolic event in non-anticoagulated and anticoagulated patients with non-valvular atrial fibrillation. AB - BACKGROUND: Accurate risk stratification is considered the first and most important step in the management of patients with non-valvular atrial fibrillation (NVAF). We compared the performance of the widely used CHA2DS2-VASc and the recently developed R2CHADS2 and ATRIA scores, for predicting thromboembolic (TE) event in either non-anticoagulated or anticoagulated patients with NVAF. METHODS: The non-anticoagulated cohort was comprised of 154 patients, whereas 911 patients formed the cohort of patients on vitamin-K-antagonist. The scores were computed using the criteria mentioned in their developmental cohorts. Measures of performance for the risk scores were evaluated at predicting TE event. RESULTS: In the non-anticoagulated cohort, 9 TE events occurred during 11 +/- 2.7 months. CHA2DS2-VASc showed significant association with TE occurrence: hazard ratio (HR) = 1.58 (95 % confidence interval [95 % IC] 1.01-2.46), but R2CHADS2 and ATRIA did not (HR = 1.23 (95 % CI 0.86-1.77) and 1.20 (95 % CI 0.93 1.56), respectively. In the anticoagulated cohort, after 10 +/- 3 months of follow up, 18 TE events were developed. In that cohort, the three scores showed similar association with TE risk: HR = 1.49 (95 % CI 1.13-1.97), 1.41 (95 % CI 1.13-1.77) and 1.37 (95 % CI 1.12-1.66) for CHA2DS2-VASc, R2CHADS2 and ATRIA, respectively. In both cohorts, no TE event occurred in patients classified in the low risk category according to CHA2DS2-VASc or R2CHADS2. CONCLUSIONS: In this study of NVAF patients, CHA2DS2-VASc has better association with TE events than the new R2CHADS2 and ATRIA risk scores in the non-anticoagulated cohort. CHA2DS2 VASc and R2CHADS2 can identify patients at truly low risk regardless of the anticoagulation status. PMID- 26584939 TI - A novel L-asparaginase from Aquabacterium sp. A7-Y with self-cleavage activation. AB - We have identified a novel L-asparaginase, abASNase3, from Aquabacterium sp. A7 Y. abASNase3 is composed of 306 amino acids and exhibits 34 % sequence homology to human asparaginase (hASNase3). Further analysis revealed that abASNase3 belongs to the N-terminal nucleophile (Ntn) family of hydrolases. Previous reports about the Ntn hydrolase family and the results of our study suggest that abASNase3 must form two subunits by self-cleavage between Gly189 and Thr190 to attain catalytic activity. The two subunits remained tightly associated to build a single functional unit. The optimum pH for abASNase3 was found to be 8.0 in Tris-HCl buffer and the enzyme was found to be stable over a broad pH range from pH 6.0 to 12.0. The optimum temperature for abASNase3 was found to be approximately 40 degrees C, and the enzyme was stable below 65 degrees C. abASNase3 showed high substrate specificity toward L-asparagine and had no or only slight activity toward D-asparagine, L-glutamine and D-glutamine. abASNase3 was significantly activated by Mg(2+) and was substantially inhibited by Ni(2+), Cu(2+), Mn(2+) and Co(2+). The Michaelis-Menten constant and turnover number of abASNase3 for L-asparagine were estimated to be 3.37 * 10(-2) M and 8.72 * 10(-3) s(-1), respectively. Our results indicate that abASNase3 is a novel L asparaginase in the Ntn family of hydrolases. PMID- 26584940 TI - A 3-year long study of Staphylococcus aureus isolates from subclinical mastitis in three Azawak zebu herds at the Sahelian experimental farm of Toukounous, Niger. AB - Staphylococcus (S.) aureus is one of the most important pathogens causing bovine mastitis. The aim of the present work was to follow in three herds and during the 3 years the clonality of S. aureus isolated from California Mastitis Test (CMT) positive cows at the experimental station of Toukounous (Niger) by (i) comparing their pulsed field gel electrophoresis (PFGE) fingerprints, (ii) identifying their virulotypes by PCR amplification and (iii) assessing the production of capsule and the formation of biofilm. The 88 S. aureus isolates belonged to 14 different pulsotypes, 3 of them being predominant: A (30 %), D (27 %), B (15 %). A and B pulsotypes had the highest profile similarity coefficient (94 %), while others had similarity coefficients under 60 %. Seventy-five S. aureus isolates were further studied for their virulotypes, capsular antigens and biofilm production. Most surface factor-, leukocidin- and haemolysin-, but not the enterotoxin-encoding genes were detected in the majority (>75 %) of the isolates and were evenly distributed between the A, B and D pulsotype isolates. The majority of the 72 S. aureus positive with the cap5H or cap8H PCR produced the CP5 (82 %) or the CP8 (88 %) capsular antigen, respectively. Biofilm production by the 57 icaA-positive isolates was strong for 8 isolates, moderate for 31 isolates but weak for 18 isolates, implying that the icaA gene may not be expressed in vitro by one third of the positive isolates. Similar to other studies, those results confirm that a restricted number of S. aureus clones circulate within the three herds at Toukounous and that their specific virulence associated properties must still be further studied. PMID- 26584941 TI - Prevalence and risk factors for bovine tuberculosis in Minas Gerais State, Brazil. AB - The aim of the present study was to estimate the prevalence and regional spread of bovine tuberculosis in the state of Minas Gerais, Brazil, to identify herd level risk factors, and to provide guidance for disease control and mitigation of its impact in public health. The study comprised a large-scale random sample survey of 22,990 animals and 1586 herds, distributed in seven regions. A questionnaire was applied on each farm to collect epidemiological and herd management data. Overall, 5.04 % of herds and 0.81 % of animals were positive for bovine tuberculosis. The highest herd prevalence was found in Alto Paranaiba, an expanding dairy region. The more technologically advanced dairy herds showed a prevalence ratio of 2.83 compared to others and are obvious candidates for risk based surveillance and herd accreditation schemes. Small farms cannot be left out of disease control efforts because they are the vast majority of herds, albeit with lower individual risk. With regard to public health, there is widespread practice of producing homemade fresh cheese with raw milk and of slaughtering culled cows in places without sanitary inspection. This poses a risk to consumers and limits the efficacy of surveillance at slaughter. PMID- 26584942 TI - Population genetic structure in the Holstein breed in Brazil. AB - We evaluated the population genetic structure of the Holstein breed in Brazil through pedigree analysis with the aim of supporting genetic management of extant herds. We used data from genealogical records of 204,511 animals in farms from south and southeast Brazil. Pedigree records between 1943 and 2005 were divided into seven periods of 8 years to estimate the effective population size (N e ). N e varied during the study periods, ranging from 0.19 to 3016.25. There was an increase in the percentage of inbred animals over time, from 0.18 to 5.0 %. However, this figure may be an underestimate due to the low completeness of pedigree, primarily related to paternal pedigree. The effective number of founders (fe) was 473 animals and ancestors (fa) was 471. The genetic contribution of 260 ancestors (founders or not) accounted for 50 % of the genetic variability in the population. The average relatedness coefficient (AR) and inbreeding coefficient indicate that the Holstein breed in Brazil is being effectively managed, despite a moderate founder effect and the low number of animals that are responsible for the population variance. PMID- 26584943 TI - Assessing Affective and Deliberative Decision-Making: Adaptation of the Columbia Card Task to Brazilian Portuguese. AB - The ability to predict reward and punishment is essential for decision-making and the ability to learn about an ever-changing environment. Therefore, efforts have been made in understanding the mechanisms underlying decision-making, especially regarding how affective and deliberative processes interact with risk behavior. OBJECTIVE: To adapt to Brazilian Portuguese the Columbia Card Task (CCT) and investigate affective and deliberative processes involved in decision-making. METHODS: This study had two main phases: (1) a transcultural adaptation and (2) a pilot study. RESULTS: The feedback manipulation among the three conditions of CCT had an effect on the risk-taking level (p < .005, ES = .201). In addition, the feedback manipulation among the three conditions of CCT had an effect on the information use at both the individual and group levels. Further, a linear regression suggested that the use of information, indicated by the advantageous level of the scenarios, predict the number of cards chosen R 2 = .029, p < .001, accounting for 17% of the variance. CONCLUSIONS: The Brazilian CCT performs well and is a versatile method for the assessment of affective and deliberative decision-making under risk according to different feedback manipulation scenarios. This study goes further, comparing electrodermal activity during hot and warm conditions and addressing an advantageous level index analysis to asses deliberative processing. PMID- 26584944 TI - Myoglobin and the regulation of mitochondrial respiratory chain complex IV. AB - KEY POINTS: Mitochondrial respiration is regulated by multiple elaborate mechanisms. It has been shown that muscle specific O2 binding protein, Myoglobin (Mb), is localized in mitochondria and interacts with respiratory chain complex IV, suggesting that Mb could be a factor that regulates mitochondrial respiration. Here, we demonstrate that muscle mitochondrial respiration is improved by Mb overexpression via up-regulation of complex IV activity in cultured myoblasts; in contrast, suppression of Mb expression induces a decrease in complex IV activity and mitochondrial respiration compared with the overexpression model. The present data are the first to show the biological significance of mitochondrial Mb as a potential modulator of mitochondrial respiratory capacity. ABSTRACT: Mitochondria are important organelles for metabolism, and their respiratory capacity is a primary factor in the regulation of energy expenditure. Deficiencies of cytochrome c oxidase complex IV, which reduces O2 in mitochondria, are linked to several diseases, such as mitochondrial myopathy. Moreover, mitochondrial respiration in skeletal muscle tissue tends to be susceptible to complex IV activity. Recently, we showed that the muscle specific protein myoglobin (Mb) interacts with complex IV. The precise roles of mitochondrial Mb remain unclear. Here, we demonstrate that Mb facilitates mitochondrial respiratory capacity in skeletal muscles. Although mitochondrial DNA copy numbers were not altered in Mb-overexpressing myotubes, O2 consumption was greater in these myotubes than that in mock cells (Mock vs. Mb-Flag::GFP: state 4, 1.00 +/- 0.09 vs. 1.77 +/- 0.34; state 3, 1.00 +/- 0.29; Mock: 1.60 +/- 0.53; complex 2-3-4: 1.00 +/- 0.30 vs. 1.50 +/- 0.44; complex IV: 1.00 +/- 0.14 vs. 1.87 +/- 0.27). This improvement in respiratory capacity could be because of the activation of enzymatic activity of respiratory complexes. Moreover, mitochondrial respiration was up-regulated in myoblasts transiently overexpressing Mb; complex IV activity was solely activated in Mb-overexpressing myoblasts, and complex IV activity was decreased in the myoblasts in which Mb expression was suppressed by Mb-siRNA transfection (Mb vector transfected vs. Mb vector, control siRNA transfected vs. Mb vector, Mb siRNA transfected: 0.15 vs. 0.15 vs. 0.06). Therefore, Mb enhances the enzymatic activity of complex IV to ameliorate mitochondrial respiratory capacity, and could play a pivotal role in skeletal muscle metabolism. PMID- 26584946 TI - Long-Term Effects of Repeated Cycles of Intrathecal Triamcinolone Acetonide on Spasticity in MS Patients. AB - MAIN PROBLEM: Spasticity is a common feature in patients with multiple sclerosis (MS). Although options have broadened over the last years, there are still patients with no response to common therapeutic agents. Intrathecal administered triamcinolone acetonide (TCA) has been tested for spasticity in patients with MS. However, the long run effects are not known so far. The aim of this study was to evaluate the effects of repeated cycles of intrathecal TCA instillations on clinical parameters. METHODS: A total of 54 patients with clinically definite MS and no response to commonly utilized antispastic drugs were enrolled. TCA was administered every 3 months for a period of 9 months. Clinical assessments including spasticity, disability (EDSS), mobility (walking distance, and timed 25 foot walk), bladder function, and quality of life were carried out prior to and at the end of each treatment cycle. RESULTS: Repeated TCA treatment led to repeated effects on spasticity (P < 0.01). Bladder function improved in every 10th patient. Quality of life improved during each cycle but did not reach significance at the end of study (P = 0.09). However, long-lasting improvement on spasticity or EDSS was not shown at end of the study. Effects diminished over 3 months. CONCLUSION: Repeated TCA instillations led to replicable effects on spasticity; subgroup analyses suggest that higher spasticity, more frequent treatments, and higher EDSS may lead to pronounced effects on spasticity and EDSS. Intrathecal TCA treatment was safe and no severe side effects occurred. We hypothesize a significant time dependence of re-administration of TCA and that an interval of 3 months between the treatments might be too long. PMID- 26584947 TI - Rare presentation of adenomatoid odontogenic tumor in a pediatric patient: a case report. AB - The adenomatoid odontogenic tumor (AOT) is a painless benign tumor with slow growth, usually asymptomatic. It has three variants: follicular, extrafollicular, and peripheral. In the follicular type, the tumor is associated with an impacted tooth, and maxillary canines are the most frequently affected. Association with primary teeth is very rare. Treatment consists essentially in a total lesion enucleation. The objective of this paper is to present the clinical case of a 7 year-old female patient with an adenomatoid odontogenic tumor associated with the crown of the left lower deciduous canine (73), dislodging it to the mandibular base and consequently shifting and also impacting the permanent lower canine (33). The lesion was treated with careful enucleation, preserving the permanent canine, which then had its eruption path released favoring its migration to an ideal position. PMID- 26584948 TI - Influence of bone density and implant drill diameter on the resulting axial force and temperature development in implant burs and artificial bone: an in vitro study. AB - PURPOSE: The aim of this study was to determine how the bone density affects the temperature development in artificial bone and drill. METHODS: Ten single drills with diameters of 2.2, 2.8, 3.5, and 4.2 mm were used on four artificial bone blocks (density I-IV), with constant speed and external irrigation. Temperature measurement in blocks and drills was done by infrared camera. The resultant axial force was measured, and light microscopic examinations of the drills were performed before and after preparation. RESULTS: The block density has a greater influence on resulting axial force than the drill diameter (D1 = 2.2 mm, 4.11 +/- 0.64 N; 4.2 mm, 9.69 +/- 0.78 N vs. D4 = 2.2 mm, 0.5 +/- 0.18 N; 4.2 mm, 1.23 +/- 0.08 N). For the narrowest drill, a decrease in bone density caused a significant temperature increase in the bone and drill. However, for the thickest drill, no thermal differences were found in the bone but were seen in the drill itself (D1 = 2.8 mm vs. D4 = 2.8 mm; bone p < 0.0001, drill p < 0.0001; D1 = 4.2 mm vs. D4 = 4.2 mm; bone p = 0.5366, drill p = 0.0411). An increase in the drill diameter in the highest bone density led to a significant thermal increase in the bone and drill. However, for the lowest bone density, thermal changes were observed only in the bone (D1 = 2.8 mm vs. D1 = 4.2 mm; bone p < 0.0001, drill p < 0.0001; D4 = 2.8 mm vs. D4 = 4.2 mm; bone p < 0.0102, drill p = 0.1784). CONCLUSIONS: Thermal development depends on bone density with increasing density causing a temperature rise. However, this effect is reduced with increasing drill diameter. This may be important with regard to bone reactions and also in terms of tool wear. PMID- 26584949 TI - CD2-associated protein participates in podocyte apoptosis via PI3K/Akt signaling pathway. AB - CD2-associated protein is one of the most important slit diaphragm proteins in maintaining podocyte integrity and reducing proteinuria. In the last 15 years, progressive researches have shown that CD2AP serves as an adaptor protein, plays essential roles in the podocyte cytoskeletal structure and signaling from the extracellular SD to the intracellular dynamic actin cytoskeleton. CD2AP deficient or transcript abnormality would lead to podocyte failure and proteinuric glomerular diseases. In this study, we demonstrate that CD2AP and p85 regulatory subunit of phosphoinositide 3-OH kinase (PI3K), recruit PI3K to the plasma membrane, and stimulate PI3K-dependent AKT signaling in podocytes the CD2AP mediated AKT activity can regulate complex biological programs. PAN reduces Akt phosphorylation levels of GSK3beta, LY294002 can promote podocyte apoptosis induced by PAN. Our findings suggest that the activation of PI3K/AKT signaling represents an essential component to maintain the functional integrity of podocytes. And PI3K/Akt signaling pathway play an important role in podocyte apoptosis. PMID- 26584950 TI - Sulphonylurea receptor-1, sulphonylureas and amplification of insulin secretion by Epac activation in beta cells. AB - Amplification of insulin secretion by cyclic AMP involves activation of protein kinase A (PKA) and Epac2 in pancreatic beta cells. Recent hypotheses suggest that sulphonylurea receptor-1 (SUR1), the regulatory subunit of ATP-sensitive potassium channels, is implicated in Epac2 effects and that direct activation of Epac2 by hypoglycaemic sulphonylureas contributes to the stimulation of insulin secretion by these drugs. In the present experiments, using islets from Sur1KO mice, we show that dibutyryl-cAMP and membrane-permeant selective activators of Epac or PKA normally amplify insulin secretion in beta cells lacking SUR1. In contrast to Epac activator, sulphonylureas (glibenclamide and tolbutamide) did not increase insulin secretion in Sur1KO islets, as would be expected if they were activating Epac2 directly. Furthermore, glibenclamide and tolbutamide did not augment the amplification of insulin secretion produced by Epac activator or dibutyryl-cAMP. Collectively, the results show that SUR1 is dispensable for amplification of insulin secretion by Epac2 activation and that direct activation of Epac2 is unimportant for the action of therapeutic concentrations of sulphonylureas in beta cells. PMID- 26584951 TI - Protocol of a randomised delayed-start double-blind placebo-controlled multi centre trial for Levodopa in EArly Parkinson's disease: the LEAP-study. AB - BACKGROUND: The aim of this study is to investigate if early treatment with levodopa has a beneficial disease modifying effect on Parkinson's disease (PD) symptoms and functional health, improves the ability to (maintain) work, and reduces the use of (informal) care, caregiver burden, and costs. Additionally, cost-effectiveness and cost-utility of early levodopa treatment will be assessed. METHODS: To differentiate between the direct symptomatic effects and possible disease modifying effects of levodopa, we use a randomised delayed-start double blind placebo-controlled multi-centre trial design. Patients with early stage PD whose functional health does not yet necessitate initiation of PD-medication will be randomised to either 40 weeks of treatment with levodopa/carbidopa 100/25 mg TID including 2 weeks of dose escalation or to 40 weeks placebo TID. Subsequently, all patients receive levodopa/carbidopa 100/25 mg TID for 40 weeks. There are 8 assessments: at baseline and at 4, 22, 40, 44, 56, 68, and 80 weeks. The primary outcome measure is the difference in the mean total Unified Parkinson's Disease Rating Scale scores between the early- and delayed-start groups at 80 weeks. Secondary outcome measures are rate of progression, the AMC Linear Disability Score, side effects, perceived quality of life with the Parkinson's Disease Questionnaire-39, the European Quality of Life-5 Dimensions (EQ-5D), ability to (maintain) work, the use of (informal) care, caregiver burden, and costs. 446 newly diagnosed PD patients without impaired functional health need to be recruited in order to detect a minimal clinical relevant difference of 4 points on the total UPDRS at 80 weeks. DISCUSSION: The LEAP-study will provide insights into the possible disease modifying effects of early levodopa. TRIAL REGISTRATION: ISRCTN30518857, EudraCT number 2011-000678-72. PMID- 26584952 TI - The relationship of the musculocutaneous nerve to the brachial plexus evaluated by MRI. AB - Axillary plexus blocks (AXB) are widely used for upper limb operations. It is recommend that AXB should be performed using a multiple injection technique. Information about the course and position of the musculocutaneous nerve (MCN) is of relevance for AXB performance. The objective of this study was to examine the position of the MCN and its relationship to the axillary sheath using MRI. 54 patients underwent an AXB with 40 ml of local anaesthetic before MRI examination. The course of the MCN and the position where it left the axillary sheath and perforated the coracobrachial muscle (MCN exit point), in relation to the axillary artery and the block needle insertion point in the axillary fold, were recorded. The MCN was seen clearly in 23, partly in 26, and not identified in five patients at the MCN exit point. The mean distance from the insertion point of the block needle in the axillary fold to the MCN exit point was 36.8 mm (SD = 18.9, range: 0-90.5). In 37 patients the MCN exit point was positioned inside the Q1 quadrant (lateral anterior to the axillary artery) and in 11 patients inside the Q2 quadrant (medial anterior to the axillary artery). There is a wide variability as to where the musculocutaneous nerve (MCN) leaves the axillary sheath. Therefore multiple injection techniques, or the use of a proximally directed catheter, should be appropriate to block the MCN. PMID- 26584953 TI - Functional gastro-intestinal disorder algorithms focus on early recognition, parental reassurance and nutritional strategies. AB - Up to 50% of infants present with symptoms of regurgitation, infantile colic and/or constipation during the first 12 months of life. Although they are often classed as functional disorders, there is an overlap with cows' milk allergy. We present practical algorithms for the management of such disorders, based on existing evidence and general consensus, with a particular focus on primary health care. Management consists of early recognition of warning signs of organic disease, parental reassurance and nutritional strategies. CONCLUSION: The proposed algorithms aim to help healthcare providers manage frequent gastrointestinal and cows' milk-related symptoms in infants safely and effectively. PMID- 26584955 TI - Editorial Comment on "The Impact of Prostate Cancer Treatment on the Sexual Quality of Life for Men-Who-Have-Sex-with-Men". PMID- 26584956 TI - Top-cited articles of the last 30 years (1985-2014) in otolaryngology - head and neck surgery. AB - BACKGROUND: The frequency with which a scientific article is cited by other studies is one way to measure its academic influence. METHODS: A comprehensive search was performed to identify journal articles in the otorhinolaryngology subject category of the 2013 Journal Citation Report Science Edition over the last 30 years (1985-2014). The 100 most cited articles were reviewed and basic information including the publication year, country of origin, source journal, article type and research field was collected. RESULTS: The 100 most cited articles were published in 15 of the 44 otorhinolaryngology journals. The number of citations per article ranged between 208 and 1559. The leading research field was otology and neurotology (n = 50), followed by rhinology (n = 23) and head and neck surgery (n = 11). Most papers originated in the USA (n = 64). CONCLUSION: The possibility of an article being cited is influenced by the publication language, country of origin and source journal. PMID- 26584957 TI - Domino Carbopalladation/C-H Functionalization Sequence: An Expedient Synthesis of Bis-Heteroaryls through Transient Alkyl/Vinyl-Palladium Species Capture. AB - A microwave-assisted highly efficient intermolecular domino carbopalladation/C-H functionalization sequence has been developed to access bis-heteroaryl frameworks in a single operation. The reaction involves carbopalladation of the halogenated acrylamides or phenylpropiolamides by the Pd(0) catalysis, followed by the direct (hetero)arylation to give products with good to excellent yields. The synthetic utility of this method was also extended towards the application of the Ugi adduct as the starting material. PMID- 26584958 TI - Is laparoscopic surgery the best treatment in fistulas complicating diverticular disease of the sigmoid colon? A systematic review. AB - INTRODUCTION: Laparoscopic surgery is considered in the treatment of diverticular fistula for the possible reduction of overall morbidity and complication rate if compared to open surgery. Aim of this review is to assess the possible advantages deriving from a laparoscopic approach in the treatment of diverticular fistulas of the colon. METHODS: Studies presenting at least 10 adult patients who underwent laparoscopic surgery for sigmoid diverticular fistula were reviewed. Fistula recurrence, reintervention, Hartmann's procedure or proximal diversion, conversion to laparotomy were the outcomes considered. RESULTS: 11 non randomized studies were included. Rates of fistula recurrence (0.8%), early reintervention (30 days) (2%) and need for Hartmann's procedure or proximal diversion (1.4%) did not show significant difference between laparoscopy and open technique. DISCUSSION: there is still concern about which surgery in complicated diverticulitis should be preferred. Laparoscopic approach has led to less postoperative pain, shorter hospital stay, faster recovery and better cosmetic results. Laparoscopic resection and primary anastomosis is a possible approach to sigmoid fistulas but its advantages in terms of lower mortality rate and postoperative stay after colon resection with primary anastomosis should be interpreted with caution. When there is firm evidence supporting it, it is likely that minimally invasive surgery should become the standard approach for diverticular fistulas, thus achieving adequate exposure and better visualization of the surgical field. CONCLUSION: The lack of RCTs, the small sample size, the heterogeneity of literature do not allow to draw statistically significant conclusions on the laparoscopic surgery for fistulas despite this approach is considered safe. PMID- 26584954 TI - Reasons for late presentation to HIV care in Switzerland. AB - INTRODUCTION: Late presentation to HIV care leads to increased morbidity and mortality. We explored risk factors and reasons for late HIV testing and presentation to care in the nationally representative Swiss HIV Cohort Study (SHCS). METHODS: Adult patients enrolled in the SHCS between July 2009 and June 2012 were included. An initial CD4 count <350 cells/ul or an AIDS-defining illness defined late presentation. Demographic and behavioural characteristics of late presenters (LPs) were compared with those of non-late presenters (NLPs). Information on self-reported, individual barriers to HIV testing and care were obtained during face-to-face interviews. RESULTS: Of 1366 patients included, 680 (49.8%) were LPs. Seventy-two percent of eligible patients took part in the survey. LPs were more likely to be female (p<0.001) or from sub-Saharan Africa (p<0.001) and less likely to be highly educated (p=0.002) or men who have sex with men (p<0.001). LPs were more likely to have their first HIV test following a doctor's suggestion (p=0.01), and NLPs in the context of a regular check-up (p=0.02) or after a specific risk situation (p<0.001). The main reasons for late HIV testing were "did not feel at risk" (72%), "did not feel ill" (65%) and "did not know the symptoms of HIV" (51%). Seventy-one percent of the participants were symptomatic during the year preceding HIV diagnosis and the majority consulted a physician for these symptoms. CONCLUSIONS: In Switzerland, late presentation to care is driven by late HIV testing due to low risk perception and lack of awareness about HIV. Tailored HIV testing strategies and enhanced provider initiated testing are urgently needed. PMID- 26584959 TI - Controversies in defining prognostic relevant selection criteria that determine long-term effectiveness of liver resection for noncolorectal nonneuroendocrine liver metastasis. AB - The usefulness of liver resection in the treatment of colorectal liver metastasis and metastases from neuroendocrine tumors of the gastrointestinal tract has been studied extensively. However, the role and utility of surgery in treating patients with noncolorectal nonneuroendocrine liver metastasis (NCNNLM) is poorly defined and controversial. Despite the broadening indications of liver resection for NCNNLM, the group of patients who would benefit from surgery is still unknown. Because tumor biologies among NCNNLM vary widely, it has been difficult to determine which factors influence overall survival. Attempts have been taken in the literature to identify a variety of factors which may influence outcome following liver resection for NCNNLM. Almost all of these data are drawn from retrospective studies, and its relevance to contemporary practice is not known. Many centers have published prognostic factors which influence survival; jet the results are contradictory for these factors. There is no uniformity in the various prognostic factors reported. This review has been undertaken to provide an overview of these important controversies. PMID- 26584960 TI - Autonomic nervous responses in colorectal polypectomy: Randomized controlled trial comparing air and carbon dioxide insufflation. AB - BACKGROUND AND AIM: Carbon dioxide (CO2) insufflation devices are commonly used for endoscopic examination and treatment. In this prospective randomized controlled trial (RCT), we compared patient acceptance, cardiovascular tolerance,and autonomic nervous responses between patients receiving air insufflation and CO2 insufflation. METHODS: We initially enrolled 170 patients and, of these, 158 patients in total were analyzed (air group, 83; CO2 group, 75). Autonomic nervous responses were evaluated by analysis of heart rate variability (HRV). Primary end point was superiority in the effects of CO2 insufflation on the autonomic nervous system by HRV analysis. RESULTS: Visual analog scale disclosed significantly less abdominal pain and abdominal fullness with CO2. Percentage heart rate change rate at 1 h and 4 h after the procedure was also significantly lower in the CO2 group than in the air group (1 h after: P < 0.01, 4 h after: P < 0.05). Comparison based on age showed that % heart rate change was significantly lower in the younger CO2 patients (just after colonoscopy and 1 h after: P < 0.01, 4 h after: P < 0.05), but this difference was not apparent in an older group of patients. CONCLUSIONS: This is the first RCT showing that colorectal polypectomy using CO2 insufflation significantly decreases abdominal pain and abdominal fullness common in such patients with lowered stress to the autonomous nervous system. The effects using CO2 insufflation on the sympathetic nervous system also seemed to be more prominent among younger patients. PMID- 26584961 TI - Comparison of bacterial growth in sonication fluid cultures with periprosthetic membranes and with cultures of biopsies for diagnosing periprosthetic joint infection. AB - Total joint arthroplasty is a common operation worldwide with infection rates between 1% and 3%. In cases of suspected periprosthetic joint infection, it is very challenging to rule out the causative microorganisms. In this study, we compared the appearance of periprosthetic membranes with the microbiological results obtained from cultures of sonication fluid and the correlation between classical microbiological cultures and cultures of sonication fluid. The results confirmed a strong correlation of bacterial growth in sonication fluid cultures with bacterial growth in classical microbiological cultures. Most importantly, however, our study documented a highly significant correlation of periprosthetic membranes typical for periprosthetic joint infection (PJI) with bacterial growth in sonication fluid. Sonication fluid cultures yielded a better sensitivity than tissue cultures (72.34-60.87%). These 3 methods are useful tools in diagnosing PJIs, and even more, sonication fluid cultures should be included in the diagnostic path of PJI. PMID- 26584962 TI - Investigation of bipotent differentiation of hepatoblasts using inducible diphtheria toxin receptor-transgenic mice. AB - AIM: Hepatic progenitor cells, called hepatoblasts, are highly proliferative and exhibit bipotential differentiation into hepatocytes and cholangiocytes in the fetal liver. Thus, they are the ideal source for transplantation therapy. Although several studies have been performed in vitro, the molecular mechanisms regulating hepatoblast differentiation in vivo following transplantation remain poorly understood. The aim of this study was to investigate an in vivo model to analyze hepatoblast bipotency and proliferative ability. METHODS: Hepatic transplantation model using Cre-inducible diphtheria toxin receptor-transgenic mice (iDTR), and albafpCre mice expressing Cre under the control of albumin and alpha-fetoprotein (AFP) regulatory elements were established. Fresh hepatoblasts were transplanted into diphtheria toxin (DT)-injected iDTRalbafpCre mice and we analyzed their differentiation and proliferation abilities by immunostaining and gene expression profiles. RESULTS: Fresh hepatoblasts transplanted into DT injected iDTRalbafpCre mice engrafted and differentiated into both hepatocytes and cholangiocytes. Additionally, the number of engrafted hepatoblast-derived hepatocytes increased following partial hepatectomy and serial DT injections. Expression levels of hepatic functional genes in transplanted hepatoblast-derived hepatocytes were similar to that of normal hepatocytes. CONCLUSION: In our iDTRalbafpCre transplantation model, fresh hepatoblasts could differentiate into hepatocytes and cholangiocytes. In addition, these donor cells were induced to proliferate by the following liver injury stimulation. This result suggests that this model is valuable for investigating hepatoblast differentiation pathways in vivo. PMID- 26584963 TI - Bacillus Calmette-Guerin (BCG) Vaccination in Infancy and Risk of Childhood Diabetes. AB - BACKGROUND: A narrow time window in infancy may be relevant for the aetiology of immune-mediated type 1 diabetes. We investigated whether a non-specific immune stimulation in the first year of life, as resulting from Bacillus Calmette-Guerin (BCG) vaccination, was associated with childhood diabetes. METHODS: Using data from a birth cohort assembled through linkage of administrative databases, 78,492 subjects born in 1974 were the object of the present analysis. Information was extracted from the birth, death, and BCG vaccination registries. Diabetes-related health services were obtained from administrative health databases (physician billing claims and hospitalisation data) until 1994. Subjects were classified as having diabetes according to two validated definitions: (1) >=2 diabetes-related medical visits within 2 years or >=1 hospitalisation for diabetes; and 2) >=4 diabetes-related medical visits within 2 years. Cox proportional hazards regression was used to estimate adjusted hazard ratios (HR) and 95% confidence interval (CI), adjusted for potential confounders. RESULTS: Forty-four per cent of subjects were BCG vaccinated in the first year of life. According to the first and second definition, respectively, 293 (0.37%) and 230 (0.29%) subjects were classified as having diabetes. There was no association between BCG vaccination in the first year of life and risk of diabetes with either definition (HR(def1) = 0.92, 95% CI 0.73, 1.17; HR(def2) = 1.04, 95% CI 0.80, 1.37), and results did not differ by sex. CONCLUSIONS: Given the potentially critical importance of the exposure window and paucity of studies addressing BCG vaccination timing in relation to diabetes risk, this question deserves further investigation. PMID- 26584964 TI - Computational modeling of dynamic behaviors of human teeth. AB - Despite the importance of dynamic behaviors of dental and periodontal structures to clinics, the biomechanical roles of anatomic sophistication and material properties in quantification of vibratory characteristics remain under-studied. This paper aimed to generate an anatomically accurate and structurally detailed 3D finite element (FE) maxilla model and explore the dynamic behaviors of human teeth through characterizing the natural frequencies (NFs) and mode shapes. The FE models with different levels of structural integrities and material properties were established to quantify the effects of modeling techniques on the computation of vibratory characteristics. The results showed that the integrity of computational model considerably influences the characterization of vibratory behaviors, as evidenced by declined NFs and perceptibly altered mode shapes resulting from the models with higher degrees of completeness and accuracy. A primary NF of 889Hz and the corresponding mode shape featuring linguo-buccal vibration of maxillary right 2nd molar were obtained based on the complete maxilla model. It was found that the periodontal ligament (PDL), a connective soft tissue, plays an important role in quantifying NFs. It was also revealed that damping and heterogeneity of materials contribute to the quantification of vibratory characteristics. The study provided important biomechanical insights and clinical references for future studies on dynamic behaviors of dental and periodontal structures. PMID- 26584965 TI - Suction based mechanical characterization of superficial facial soft tissues. AB - The present study is aimed at a combined experimental and numerical investigation of the mechanical response of superficial facial tissues. Suction based experiments provide the location, time, and history dependent behavior of skin and SMAS (superficial musculoaponeurotic system) by means of Cutometer and Aspiration measurements. The suction method is particularly suitable for in vivo, multi-axial testing of soft biological tissue including a high repeatability in subsequent tests. The campaign comprises three measurement sites in the face, i.e. jaw, parotid, and forehead, using two different loading profiles (instantaneous loading and a linearly increasing and decreasing loading curve), multiple loading magnitudes, and cyclic loading cases to quantify history dependent behavior. In an inverse finite element analysis based on anatomically detailed models an optimized set of material parameters for the implementation of an elastic-viscoplastic material model was determined, yielding an initial shear modulus of 2.32kPa for skin and 0.05kPa for SMAS, respectively. Apex displacements at maximum instantaneous and linear loading showed significant location specificity with variations of up to 18% with respect to the facial average response while observing variations in repeated measurements in the same location of less than 12%. In summary, the proposed parameter sets for skin and SMAS are shown to provide remarkable agreement between the experimentally observed and numerically predicted tissue response under all loading conditions considered in the present study, including cyclic tests. PMID- 26584966 TI - Sensitivity to change and prediction of global change for the Alzheimer's Questionnaire. AB - INTRODUCTION: Longitudinal assessment of cognitive decline in amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD) often involves the use of both informant-based and objective cognitive assessments. As efforts have focused on identifying individuals in pre-clinical stages, instruments that are sensitive to subtle cognitive changes are needed. The Alzheimer's Questionnaire (AQ) has demonstrated high sensitivity and specificity in identifying aMCI and AD; however its ability to measure longitudinal change has not been assessed. The aims of this study are to assess the sensitivity to change of the AQ and to determine whether the AQ predicts change in global cognition and function in cognitively normal (CN), aMCI, and AD subjects. METHODS: Data from 202 individuals participating in a brain and body donation program were utilized for this study (101 CN, 62 aMCI, 39 AD). AD and aMCI individuals were matched on age, education, and gender to CN individuals. Sensitivity to change of the AQ was assessed in addition to the AQ's ability to predict change in global cognition and function. The Mini Mental State Exam (MMSE) and Functional Activities Questionnaire (FAQ) were used as gold standard comparisons of cognition and function. Sample size calculations for a 25% treatment effect were also carried out for all three groups. RESULTS: The AQ demonstrated small sensitivity to change in the aMCI and CN groups (d = 0.33, d = 0.23, respectively) and moderate sensitivity to change in the AD group (d = 0.43). The AQ was associated with increases in the Clinical Dementia Rating Global Score (OR = 1.20 (1.09, 1.32), P <0.001). Sample size calculations found that the AQ would require substantially fewer subjects than the MMSE given a 25% treatment effect. CONCLUSIONS: Although the AQ demonstrated small sensitivity to change in aMCI and CN individuals in terms of effect size, the AQ may be superior to objective cognitive tests in terms of required sample size for a clinical trial. As clinicians and researchers continue to identify and treat individuals in earlier stages of AD, there is a need for instruments that are sensitive to cognitive changes in these earlier stages. PMID- 26584967 TI - Use of Targeted Temperature Management After Out-of-hospital Cardiac Arrest: A Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND: Individual randomized trials have yielded variable results regarding the benefits of targeted temperature management in patients encountering out-of hospital cardiac arrest. This study aimed to systemically determine if targeted temperature management initiated after an out-of-hospital cardiac arrest was associated with improved outcomes. METHODS: Electronic databases were searched for published randomized trials that compared targeted temperature management (core body temperature 32-34 degrees C) vs control (core body temperature >=36 degrees C) after an out-of-hospital cardiac arrest. The main outcomes assessed were all-cause mortality and poor neurological outcome. RESULTS: Six trials with 1391 patients were included in the analysis. Compared with the control group, targeted temperature management was associated with a nonsignificant reduction in all-cause mortality (relative risk [RR] 0.90; 95% confidence interval [CI], 0.77 1.04; P = .15, I(2) = 34%), which was similar among those with a shockable rhythm (RR 0.89; 95% CI, 0.74-1.08, P = .25, I(2) = 46%). All-cause mortality was significantly reduced with targeted temperature management after exclusion of one trial that allowed for mild hypothermia in the control arm (RR 0.83; 95% CI, 0.71 0.96; P = .01, I(2) = 0%). There was a nonsignificant reduction in poor neurological outcome with targeted temperature management compared with control (RR 0.87; 95% CI, 0.74-1.03, P = .10, I(2) = 54%), which was similar among those with a shockable rhythm (RR 0.87; 95% CI, 0.70-1.07, P = .19, I(2) = 63%). Poor neurological outcome was significantly reduced with targeted temperature management after exclusion of one trial that allowed for mild hypothermia in the control arm (RR 0.82; 95% CI, 0.70-0.95; P = .01, I(2) = 19%). CONCLUSION: Targeted temperature management initiated after successful resuscitation in patients who encountered an out-of-hospital cardiac arrest was associated with a nonsignificant reduction in mortality and poor neurological outcome. Lack of benefit was strongly influenced by inclusion of one study that used mild hypothermia in the control arm. These results indicate that only mild hypothermia may be needed to improve outcomes among patients presenting with an out-of hospital cardiac arrest. PMID- 26584968 TI - Can the Reduction in Percent LDL Cholesterol or Attained LDL Cholesterol Levels or Both Add Incremental Prognostic Value? PMID- 26584970 TI - Are Mandatory Electronic Prescriptions in the Best Interest of Patients? PMID- 26584969 TI - Diagnosing and Treating the Syndrome of Inappropriate Antidiuretic Hormone Secretion. AB - BACKGROUND: The syndrome of inappropriate antidiuretic hormone secretion is the most common cause of hyponatremia in clinical practice, but current management of hyponatremia and outcomes in patients with syndrome of inappropriate antidiuretic hormone secretion are not well understood. The objective of the Hyponatremia Registry was to assess the current state of management of hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion in diverse hospital settings, specifically which diagnostic and treatment modalities are currently used and how rapidly and reliably they result in an increase in serum sodium concentration ([Na(+)]). A secondary objective was to determine whether treatment choices and outcomes differ across the United States and the European Union. METHODS: The Hyponatremia Registry recorded selected diagnostic measures and use, efficacy, and outcomes of therapy for euvolemic hyponatremia diagnosed clinically as syndrome of inappropriate antidiuretic hormone secretion in 1524 adult patients with [Na(+)] <=130 mEq/L (1034 from 146 US sites and 490 from 79 EU sites). A subgroup of patients with more rigorously defined syndrome of inappropriate antidiuretic hormone secretion via measurement of relevant laboratory parameters was also analyzed. RESULTS: The most common monotherapy treatments for hyponatremia in syndrome of inappropriate antidiuretic hormone secretion were fluid restriction (48%), isotonic (27%) or hypertonic (6%) saline, and tolvaptan (13%); 11% received no active agent. The mean rate of [Na(+)] change (mEq/L/d) was greater for all active therapies than no active treatment. Hypertonic saline and tolvaptan produced the greatest mean rate of [Na(+)] change (interquartile range, both 3.0 [6.0] mEq/L/d) compared with lower interquartile range rates of [Na(+)] change for isotonic saline (1.5 [3.0] mEq/L/d) and fluid restriction (1.0 [2.3] mEq/L/d). The general pattern of responses was similar in both the US and EU cohorts. At discharge, [Na(+)] was <135 mEq/L in 75% of patients and <=130 mEq/L in 43% of patients. Overly rapid correction occurred in 10.2% of patients. CONCLUSIONS: Current treatment of hyponatremia in syndrome of inappropriate antidiuretic hormone secretion often uses therapies with limited efficacy; the most commonly chosen monotherapy treatments, fluid restriction and isotonic saline, failed to increase the serum [Na(+)] by >=5 mEq/L in 55% and 64% of monotherapy treatment episodes, respectively. Appropriate laboratory tests to diagnose syndrome of inappropriate antidiuretic hormone secretion were obtained in <50% of patients; success rates in correcting hyponatremia were significantly higher when such tests were obtained. Few outcome differences were found between the United States and the European Union. A notable exception was hospital length of stay; use of tolvaptan was associated with significantly shorter length of stay in the European Union but not in the United States. Despite the availability of effective therapies, most patients with syndrome of inappropriate antidiuretic hormone secretion were discharged from the hospital still hyponatremic. PMID- 26584971 TI - Brain angiotensin-(1-7)/Mas axis: A new target to reduce the cardiovascular risk to emotional stress. AB - Emotional stress is now considered a risk factor for several diseases including cardiac arrhythmias and hypertension. It is well known that the activation of neuroendocrine and autonomic mechanisms features the response to emotional stress. However, its link to cardiovascular diseases and the regulatory mechanisms involved remain to be further comprehended. The renin-angiotensin system (RAS) plays an important role in homeostasis on all body systems. Specifically in the brain, the RAS regulates a number of physiological aspects. Recent data indicate that the activation of angiotensin-converting enzyme/angiotensin II/AT1 receptor axis facilitates the emotional stress responses. On the other hand, growing evidence indicates that its counterregulatory axis, the angiotensin-converting enzyme 2 (ACE2)/(Ang)iotensin (1-7)/Mas axis, reduces anxiety and attenuates the physiological responses to emotional stress. The present review focuses on angiotensin-(1-7)/Mas axis as a promising target to attenuate the physiological response to emotional stress reducing the risk of cardiovascular diseases. PMID- 26584972 TI - Exercise improves quality of life in androgen deprivation therapy-treated prostate cancer: systematic review of randomised controlled trials. AB - Men receiving androgen deprivation therapy (ADT) for prostate cancer (PCa) are likely to develop metabolic conditions such as diabetes, cardiovascular disease, abdominal obesity and osteoporosis. Other treatment-related side effects adversely influence quality of life (QoL) including vasomotor distress, depression, anxiety, mood swings, poor sleep quality and compromised sexual function. The objective of this study was to systematically review the nature and effects of dietary and exercise interventions on QoL, androgen deprivation symptoms and metabolic risk factors in men with PCa undergoing ADT. An electronic search of CINAHL, CENTRAL, Medline, PsychINFO and reference lists was performed to identify peer-reviewed articles published between January 2004 and December 2014 in English. Eligible study designs included randomised controlled trials (RCTs) with pre- and post-intervention data. Data extraction and assessment of methodological quality with the Cochrane approach was conducted by two independent reviewers. Seven exercise studies were identified. Exercise significantly improved QoL, but showed no effect on metabolic risk factors (weight, waist circumference, lean or fat mass, blood pressure and lipid profile). Two dietary studies were identified, both of which tested soy supplements. Soy supplementation did not improve any outcomes. No dietary counselling studies were identified. No studies evaluated androgen-deficiency symptoms (libido, erectile function, sleep quality, mood swings, depression, anxiety and bone mineral density). Evidence from RCTs indicates that exercise enhances health- and disease-specific QoL in men with PCa undergoing ADT. Further studies are required to evaluate the effect of exercise and dietary interventions on QoL, androgen deprivation symptoms and metabolic risk factors in this cohort. PMID- 26584973 TI - Benefit of statin therapy in patients with coronary spasm-induced acute myocardial infarction. AB - BACKGROUND: Coronary artery spasm is associated with vascular smooth muscle hyper reactivity. Statins suppress coronary spasm by inhibiting the vascular smooth muscle contraction. However, it is unclear whether statin therapy benefits patients with coronary spasm-induced acute myocardial infarction (AMI). METHODS AND RESULTS: We analyzed 501 (median age 57 years; male/female, 346/155) patients with coronary spasm-induced AMI with nonobstructive coronary arteries (stenosis severity <50%) from the Korea AMI Registry between November 2005 and October 2013. They were divided into two groups according to statin prescription at discharge (statin group n=292; nonstatin group n=209). The primary endpoint was the composite of 12-month major adverse cardiac events, including all causes of death, non-fatal myocardial infarction, and target vessel revascularization. The primary endpoint occurred in 17 patients during 12 months of follow-up. Statin therapy significantly reduced the risk of the composite primary endpoint [adjusted hazard ratio (HR): 0.30; 95% confidence interval (CI): 0.09-0.97; p=0.045]. Statin therapy reduced the risk of myocardial infarction (HR: 0.19; 95% CI: 0.04-0.93; p=0.040). However, we found no significant difference in the risk of the composite of all-cause death. CONCLUSION: Statin therapy in patients with coronary spasm-induced AMI with nonobstructive coronary arteries was associated with improved clinical outcome, which was predominantly accounted for by reducing the incidence of myocardial infarction. PMID- 26584974 TI - Remodeling of the intercalated disc related to aging in the mouse heart. AB - BACKGROUND: Aging is related to declined cardiac hemodynamic function. As pumping performance may be significantly related to slowed ventricular depolarization and non-synchronous contraction, we hypothesized that aging may cause dysfunction of intercalated disc (ID), which is the structure responsible for intercellular electrical communication between cardiomyocytes. METHODS: Male C57BL/6J mice were used for the study at two ages: 4 and 24 months. Electrocardiographic recording was made to analyze the time of ventricular depolarization. Then mice were killed, and the hearts were harvested for examination in transmission electron microscopy (TEM) and immunofluorescence imaging. The expression of connexin 43 (Cx43), N-cadherin, and beta-catenin in the myocardium of the left ventricle was evaluated using Western blotting. RESULTS: In senescent mice, analysis of averaged QRS complex showed its significant prolongation. At the ultrastructural level, we found frequent disruptions of the ID (affecting 29+/-5% of them), mainly at the site of adherens junction, with relatively preserved desmosomal intercellular connections and diminished number of gap junctions. Western blotting revealed significantly decreased abundance of Cx43 protein in aged animals, which may cause slowed impulse propagation through the gap junctions and contribute to the observed electrocardiographic alterations. The level of RNA for Cx43 is similar between young and old animals, which suggests a post transcriptional mechanism of Cx43 protein downregulation. CONCLUSIONS: Our study shows age-related disorganization of ID, which may be responsible for slowed conduction of the depolarization wave within the heart, and supports the hypothesis of cardiac dysfunction in senescence. PMID- 26584975 TI - Time to debate an opt-out system for organ donation in England as well as the rest of the UK. PMID- 26584976 TI - Plasmonic fluorescent CdSe/Cu2S hybrid nanocrystals for multichannel imaging and cancer directed photo-thermal therapy. AB - A simple, crude Jatropha curcas (JC) oil-based synthesis approach, devoid of any toxic phosphine and pyrophoric ligands, to produce size and shape tuned CdSe QDs and a further copper sulfide (Cu2S) encasing is presented. The QDs exhibited excellent photoluminescent properties with narrow band gap emission. Furthermore, the Cu2S shell rendered additional cytocompatibility and stability to the hybrid nanomaterial, which are major factors for translational and clinical applications of QDs. The nanocomposites were PEGylated and folate conjugated to augment their cytoamiability and enhance their specificity towards cancer cells. The nanohybrids possess potentials for visible, near infrared (NIR), photoacoustic (PA) and computed tomography (MUCT) imaging. The diverse functionality of the composite was derived from the multi-channel imaging abilities and thermal competence on NIR laser irradiation to specifically actuate the photo-thermal ablation of brain cancer cells. PMID- 26584977 TI - Development and psychometric testing of a barriers to HIV testing scale among individuals with HIV infection in Sweden; The Barriers to HIV testing scale Karolinska version. AB - BACKGROUND: Barriers to HIV testing experienced by individuals at risk for HIV can result in treatment delay and further transmission of the disease. Instruments to systematically measure barriers are scarce, but could contribute to improved strategies for HIV testing. Aims of this study were to develop and test a barriers to HIV testing scale in a Swedish context. METHODS: An 18-item scale was developed, based on an existing scale with addition of six new items related to fear of the disease or negative consequences of being diagnosed as HIV infected. Items were phrased as statements about potential barriers with a three point response format representing not important, somewhat important, and very important. The scale was evaluated regarding missing values, floor and ceiling effects, exploratory factor analysis, and internal consistencies. RESULTS: The questionnaire was completed by 292 adults recently diagnosed with HIV infection, of whom 7 were excluded (>=9 items missing) and 285 were included (>=12 items completed) in the analyses. The participants were 18-70 years old (mean 40.5, SD 11.5), 39 % were females and 77 % born outside Sweden. Routes of transmission were heterosexual transmission 63 %, male to male sex 20 %, intravenous drug use 5 %, blood product/transfusion 2 %, and unknown 9 %. All scale items had <3 % missing values. The data was feasible for factor analysis (KMO = 0.92) and a four factor solution was chosen, based on level of explained common variance (58.64 %) and interpretability of factor structure. The factors were interpreted as; personal consequences, structural barriers, social and economic security, and confidentiality. Ratings on the minimum level (suggested barrier not important) were common, resulting in substantial floor effects on the scales. The scales were internally consistent (Cronbach's alpha 0.78-0.91). CONCLUSIONS: This study gives preliminary evidence of the scale being feasible, reliable and valid to identify different types of barriers to HIV testing. PMID- 26584978 TI - Effects of ultrasonic agitation on adhesion strength of micro electroforming Ni layer on Cu substrate. AB - Micro electroforming is an important technology, which is widely used for fabricating micro metal devices in MEMS. The micro metal devices have the problem of poor adhesion strength, which has dramatically influenced the dimensional accuracy of the devices and seriously limited the development of the micro electroforming technology. In order to improve the adhesion strength, ultrasonic agitation method is applied during the micro electroforming process in this paper. To explore the effect of the ultrasonic agitation, micro electroforming experiments were carried out under ultrasonic and ultrasonic-free conditions. The effects of the ultrasonic agitation on the micro electroforming process were investigated by polarization and alternating current (a.c.) impedance methods. The real surface area of the electroforming layer was measured by cyclic voltammetry method. The compressive stress and the crystallite size of the electroforming layer were measured by X-ray Diffraction (XRD) method. The adhesion strength of the electroforming layer was measured by scratch test. The experimental results show that the imposition of the ultrasonic agitation decreases the polarization overpotential and increases the charge transfer process at the electrode-electrolyte interface during the electroforming process. The ultrasonic agitation increases the crystallite size and the real surface area, and reduces the compressive stress. Then the adhesion strength is improved about 47% by the ultrasonic agitation in average. In addition, mechanisms of the ultrasonic agitation improving the adhesion strength are originally explored in this paper. The mechanisms are that the ultrasonic agitation increases the crystallite size, which reduces the compressive stress. The lower the compressive stress is, the larger the adhesion strength is. Furthermore, the ultrasonic agitation increases the real surface area, enhances the mechanical interlocking strength and consequently increases the adhesion strength. This work contributes to fabricating the electroforming layer with large adhesion strength. PMID- 26584979 TI - Ultrasound and heat enhanced persulfate oxidation activated with Fe(0) aggregate for the decolorization of C.I. Direct Red 23. AB - Effluents from the paper printing and textile industries are often heavily contaminated with azo dyes. Azo dyes are difficult to oxidize biologically. This work investigated the decolorization of an azo dye, C.I. Direct Red 23 (DR23), by persulfate (PS) activated with Fe(0) aggregates (PS/Fe(0)). Ultrasound (US) and heat were used as enhancement tools in the PS oxidation system. Neither US activated PS nor thermally activated PS was effective in oxidizing DR23. However, the decolorization was significantly enhanced by PS/Fe(0) combined with US (PS/Fe(0)/US) or heat (PS/Fe(0)/55 degrees C). Approximately 95% decolorization of 1*10(-4) M DR23 was achieved within 15 min in the PS/Fe(0)/US system at an initial pH of 6.0, PS of 5*10(-3) M, Fe(0) of 0.5 g/L and US irradiation of 106 W/cm(2) (60 kHz). Complete decolorization was achieved within 10 min in the Fe(0)/PS/55 degrees C system. The rate of decolorization doubled when US was introduced in the PS/Fe(0) system during the treatment of different initial dye concentrations. The dependence of dye and true color (ADMI) depletion on PS concentration has been discussed. DR23 was completely degraded based on the disappearance of aromatic groups of UV-vis spectra and the variation of TOC mineralization. The observed pseudo-first-order decolorization rate was substantially enhanced by increasing temperature. The Arrhenius activation energy for the PS activated with Fe(0) was estimated as 8.98 kcal/mol, implying that higher temperature is beneficial for the DR23 decolorization. The addition of US into the PS/Fe(0) system did not incur a substantial increase in electricity, whereas the mineralization of DR23 occurred quickly. Thus, both PS/Fe(0)/US and heated PS/Fe(0) systems are practically feasible for the effective degradation of the direct azo dye in textile wastewater. PMID- 26584981 TI - Sonocatalytic degradation of Acid Blue 92 using sonochemically prepared samarium doped zinc oxide nanostructures. AB - Pure and Sm-doped ZnO nanoparticles were synthesized applying a simple sonochemical method. The nanocatalysts were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), and X-ray photoelectron spectroscopy (XPS) techniques which confirmed the successful synthesis of the doped sonocatalyst. The sonocatalytic degradation of Acid Blue 92 (AB92), a model azo dye, was more than that with sonolysis alone. The 6% Sm-doped ZnO nanoparticles had a band gap of 2.8 eV and demonstrated the highest activity. The degradation efficiency (DE%) of sonolysis and sonocatalysis with undoped ZnO and 6% Sm-doped ZnO was 45.73%, 63.9%, and 90.10%, after 150 min of treatment, respectively. Sonocatalytic degradation of AB92 is enhanced with increasing the dopant amount and catalyst dosage and with decreasing the initial AB29 concentration. DE% declines with the addition of radical scavengers such as chloride, carbonate, sulfate, and tert-butanol. However, the addition of enhancers including potassium periodates, peroxydisulfate, and hydrogen peroxide improves DE% by producing more free radicals. The results show adequate reusability of the doped sonocatalyst. Degradation intermediates were recognized by gas chromatography-mass spectrometry (GC-MS). Using nonlinear regression analysis, an empirical kinetic model was developed to estimate the pseudo-first-order constants (kapp) as a function of the main operational parameters, including the initial dye concentration, sonocatalyst dosage, and ultrasonic power. PMID- 26584980 TI - Ultrasonically enhanced extraction of luteolin and apigenin from the leaves of Perilla frutescens (L.) Britt. using liquid carbon dioxide and ethanol. AB - The present study reports on the ultrasonic enhancement of the liquid carbon dioxide (CO2) extraction of luteolin and apigenin from the leaves of Perilla frutescens (L.) Britt., to which ethanol is added as a cosolvent. The purpose of this research is also to investigate the effects of the particle size, temperature, pressure, irradiation power, irradiation time, and ethanol content in the liquid CO2 solution on the extraction yield using single-factor experiments. We qualitatively and quantitatively analyzed the yields in the extract using HPLC (high-performance liquid chromatography). The liquid CO2 mixed with ethanol was used at temperatures of 5, 20 and 25 degrees C with extraction pressures from 8 to 14 MPa. The yields of luteolin and apigenin in the extraction were clearly enhanced by the ultrasound irradiation, but the selectivity of the extract was not changed. The yields of luteolin and apigenin in the extract were also significantly improved by adjusting the operating temperature, the irradiation time, and the ethanol content in the liquid CO2 solution, but no change in the selectivity of the extract was observed. PMID- 26584983 TI - Influence of passive potential on the electronic property of the passive film formed on Ti in 0.1 M HCl solution during ultrasonic cavitation. AB - The influence of the applied passive potential on the electronic property of the passive film formed on Ti at different potentials in 0.1M HCl solution during ultrasonic cavitation, was investigated by electrochemical impedance spectra (EIS) and Mott-Schottky plot. The influence of the applied passive potential on the structure and composition of the passive film was studied by X-ray photoelectron spectroscopy (XPS) and Auger electron spectroscopy (AES). The results showed that the applied passive potential can obviously affect the electronic property of the passive film formed on Ti during ultrasonic cavitation. The resistance of the passive film increased, and the donor density of the passive film decreased with increasing the potential. The flat band potential moved to positive direction and the band gap of the passive film moved to negative direction with increasing potential. AES and XPS results indicated that the thickness of the passive film increased evidently with applying passive potential. The passive film was mainly composed of the mixture of TiO and TiO2. While the TiO2 content increased with increasing the applied passive potential, and the crystallization of the passive film increased with the increased potential. PMID- 26584982 TI - Effect of ultrasonic treatment on total phenolic extraction from Lavandula pubescens and its application in palm olein oil industry. AB - The aims of the current study were to evaluate the best technique for total phenolic extraction from Lavandula pubescens (Lp) and its application in vegetable oil industries as alternatives of synthetic food additives (TBHQ and BHT). To achieve these aims, three techniques of extraction were used: ultrasonic microwave (40 kHz, 50 W, microwave power 480 W, 5 min), ultrasonic-homogenizer (20 kHz, 150 W, 5 min) and conventional maceration as a control. By using the Folin-Ciocalteu method, the total phenolic contents (TPC) (mg gallic acid equivalent/g dry matter) were found to be 253.87, 216.96 and 203.41 for ultrasonic-microwave extract, ultrasonic-homogenizer extract and maceration extract, respectively. The ultrasonic-microwave extract achieved the higher scavenger effect of DPPH (90.53%) with EC50 (19.54 MUg/mL), and higher inhibition of beta-carotene/linoleate emulsion deterioration (94.44%) with IC50 (30.62 MUg/mL). The activity of the ultrasonic-microwave treatment could prolong the induction period (18.82 h) and oxidative stability index (1.67) of fresh refined, bleached and deodorized palm olein oil (RBDPOo) according to Rancimat assay. There was an important synergist effect between citric acid and Lp extracts in improving the oxidative stability of fresh RBDPOo. The results of this work also showed that the ultrasonic-microwave assisted extract was the most effective against Gram-positive and Gram-negative strains that were assessed in this study. The uses of ultrasonic-microwave could induce the acoustic cavitation and rupture of plant cells, and this facilitates the flow of solvent into the plant cells and enhances the desorption from the matrix of solid samples, and thus would enhance the efficiency of extraction based on cavitation phenomenon. PMID- 26584984 TI - Initial growth of sonochemically active and sonoluminescence bubbles at various frequencies. AB - The initial growth of acoustic cavitation activity is important in some applications such as therapeutic and diagnostic medicine. The initial growth of cavitation activity has been investigated using sonoluminescence and sonochemical activity (sonochemiluminescence) at 358 kHz, 647 kHz and 1062 kHz and at 5 W, 15 W and 30 W applied power levels. The growth of sonochemically active bubble population is found to be much faster than that of sonoluminescence bubble population at 358 kHz and 647 kHz whereas almost similar growth rate is observed at 1062 kHz for both bubble populations. This suggests that the cavitation bubble resonance size ranges of sonoluminescence and sonochemically active bubbles are different at 358 kHz and 647 kHz, whereas they have similar size range at 1062 kHz. At 358 kHz and 647 kHz, relatively smaller bubbles become chemically active. Possible reasons for such observations have been discussed. The data presented and discussed in this study may be useful in controlling the growth of cavitation bubble population in addition to enhancing the knowledge base in cavitation science. PMID- 26584985 TI - Enhancement effects of ultrasound on secondary wastewater effluent disinfection by sodium hypochlorite and disinfection by-products analysis. AB - Since fecal coliforms was introduced as a standard indicator of pollutants in effluents of municipal wastewater treatment plants in China in 2003, chlorine had been widely used in many wastewater treatment plants. However, concerns about the disinfection by-products (DBPs) of chlorine have been increasing. One of the effective way to reduce the production of DBPs is to reduce the effective chlorine dosage by improving the utilization rate of disinfectant. Ultrasound (US) is proved to be effective in wastewater treatment for its multiple chemical and physical effects produced by cavitation, which could favor the disinfection process accordingly. For the purpose of improving disinfection efficiency with the help of US, following points are addressed in the current study: (1) investigate the enhancement effects of US on the disinfection efficiency of sodium hypochlorite (NaClO) for real secondary effluents of municipal wastewater treatment plants; (2) evaluate the possibility of using US specific energy consumption (kJ/L) as an parameter for disinfection efficiency evaluation; and (3) quantify the reduction in chlorine-DBPs through US application. Results demonstrated that sonication could reduce two-thirds (US pretreatment) or one third (simultaneous US and NaClO disinfection) of the required concentrations of NaClO (available chlorine) for 4 log reduction of fecal coliforms, which could meet the Class 1A (fecal coliforms less than 1000 CFU/L) discharge standard of China. In addition, US pretreatment with NaClO disinfection performed better enhancement in disinfection efficiency compared with simultaneous US and NaClO disinfection. Furthermore, analysis on DBPs showed that US application as pretreatment could obviously reduce the contents of trichloromethane (TCM) and trichloroacetic acid (TCAA) by more than 85% and 50%, respectively, compared with NaClO disinfection alone for the same disinfection efficiency. Meanwhile, the experimental results also showed that the disinfection efficiency and DBPs concentration were only slightly affected under a constant US specific energy consumption, although input power density and irradiation time changed, indicating that specific energy consumption (kJ/L) could be considered as a better control parameter for disinfection efficiency evaluation. PMID- 26584986 TI - Ultrasound assisted intensification of biodiesel production using enzymatic interesterification. AB - Ultrasound assisted intensification of synthesis of biodiesel from waste cooking oil using methyl acetate and immobilized lipase obtained from Thermomyces lanuginosus (Lipozyme TLIM) as a catalyst has been investigated in the present work. The reaction has also been investigated using the conventional approach based on stirring so as to establish the beneficial effects obtained due to the use of ultrasound. Effect of operating conditions such as reactant molar ratio (oil and methyl acetate), temperature and enzyme loading on the yield of biodiesel has been investigated. Optimum conditions for the conventional approach (without ultrasound) were established as reactant molar ratio of 1:12 (oil:methyl acetate), enzyme loading of 6% (w/v), temperature of 40 degrees C and reaction time of 24 h and under these conditions, 90.1% biodiesel yield was obtained. The optimum conditions for the ultrasound assisted approach were oil to methyl acetate molar ratio of 1:9, enzyme loading of 3% (w/v), and reaction time of 3 h and the biodiesel yield obtained under these conditions was 96.1%. Use of ultrasound resulted in significant reduction in the reaction time with higher yields and lower requirement of the enzyme loading. The obtained results have clearly established that ultrasound assisted interesterification was a fast and efficient approach for biodiesel production giving significant benefits, which can help in reducing the costs of production. Reusability studies for the enzyme were also performed but it was observed that reuse of the catalyst under the optimum experimental condition resulted in reduced enzyme activity and biodiesel yield. PMID- 26584987 TI - Degradation of ibuprofen by hydrodynamic cavitation: Reaction pathways and effect of operational parameters. AB - Ibuprofen (IBP) is an anti-inflammatory drug whose residues can be found worldwide in natural water bodies resulting in harmful effects to aquatic species even at low concentrations. This paper deals with the degradation of IBP in water by hydrodynamic cavitation in a convergent-divergent nozzle. Over 60% of ibuprofen was degraded in 60 min with an electrical energy per order (EEO) of 10.77 kWh m(-3) at an initial concentration of 200 MUg L(-1) and a relative inlet pressure pin=0.35 MPa. Five intermediates generated from different hydroxylation reactions were identified; the potential mechanisms of degradation were sketched and discussed. The reaction pathways recognized are in line with the relevant literature, both experimental and theoretical. By varying the pressure upstream the constriction, different degradation rates were observed. This effect was discussed according to a numerical simulation of the hydroxyl radical production identifying a clear correspondence between the maximum kinetic constant kOH and the maximum calculated OH production. Furthermore, in the investigated experimental conditions, the pH parameter was found not to affect the extent of degradation; this peculiar feature agrees with a recently published kinetic insight and has been explained in the light of the intermediates of the different reaction pathways. PMID- 26584988 TI - Ultrasound assisted enzymatic depolymerization of aqueous guar gum solution. AB - The present work investigates the effectiveness of application of low intensity ultrasonic irradiation for the intensification of enzymatic depolymerization of aqueous guar gum solution. The extent of depolymerization of guar gum has been analyzed in terms of intrinsic viscosity reduction. The effect of ultrasonic irradiation on the kinetic and thermodynamic parameters related to the enzyme activity as well as the intrinsic viscosity reduction of guar gum using enzymatic approach has been evaluated. The kinetic rate constant has been found to increase with an increase in the temperature and cellulase loading. It has been observed that application of ultrasound not only enhances the extent of depolymerization but also reduces the time of depolymerization as compared to conventional enzymatic degradation technique. In the presence of cellulase enzyme, the maximum extent of depolymerization of guar gum has been observed at 60 W of ultrasonic rated power and ultrasonic treatment time of 30 min. The effect of ultrasound on the kinetic and thermodynamic parameters as well as the molecular structure of cellulase enzyme was evaluated with the help of the chemical reaction kinetics model and fluorescence spectroscopy. Application of ultrasound resulted in a reduction in the thermodynamic parameters of activation energy (Ea), enthalpy (DeltaH), entropy (DeltaS) and free energy (DeltaG) by 47%, 50%, 65% and 1.97%, respectively. The changes in the chemical structure of guar gum treated using ultrasound assisted enzymatic approach in comparison to the native guar gum were also characterized by FTIR. The results revealed that enzymatic depolymerization of guar gum resulted in a polysaccharide with low degree of polymerization, viscosity and consistency index without any change in the core chemical structure which could make it useful for incorporation in food products. PMID- 26584989 TI - Ultrasound-based protein determination in maize seeds. AB - The need for a simple and accurate method for protein estimation in alcoholic extracts led to the reexamination of the optimum conditions of a colorimetric assay based on the biuret reaction. Sonication time and the other experimental parameters were optimized after kinetics study on the extraction of either zein or total proteins. Zein extraction and purity were investigated by (1)H and (13)C NMR spectroscopy, SDS-PAGE electrophoresis, and UV-visible spectrophotometry (UV vis). A zein assay was proposed, which involves the reaction of copper ions in copper phosphate powder with zein extracted in ethanolic solutions under strong alkaline environment. Furthermore, we extended this procedure to determine total proteins in maize samples simultaneously with their ultrasonic-assisted (US) extraction with an alkaline-alcoholic solution. Proteins in both types of extracts were well characterized by UV-vis spectroscopy. However, the 545 nm absorbance of the violet-colored supernatants which is proportional to the protein content was found to be the key parameter of the improved biuret-based protein assay. Comparison of values obtained by this procedure and by Micro Kjeldahl method was in excellent agreement. A scaled-down procedure agreed well with the standard procedure. Enhanced accuracy and repeatability was found in protein determination in maize using the modified biuret method. The optimization of reagent concentrations and incubation times were studied as well. PMID- 26584990 TI - Sonochemistry: Science and Engineering. AB - Sonochemistry offers a simple route to nanomaterial synthesis with the application of ultrasound. The tiny acoustic bubbles, produced by the propagating sound wave, enclose an incredible facility where matter interact among at energy as high as 13 eV to spark extraordinary chemical reactions. Within each period - formation, growth and collapse of bubbles, lies a coherent phase of material formation. This effective yet highly localized method has facilitated synthesis of various chemical and biological compounds featuring unique morphology and intrinsic property. The benign processing lends to synthesis without any discrimination towards a certain group of material, or the substrates where they are grown. As a result, new and improved applications have evolved to reach out various field of science and technology and helped engineer new and better devices. Along with the facile processing and notes on the essence of sonochemistry, in this comprehensive review, we discuss the individual and mutual effect of important input parameters on the nanomaterial synthesis process as a start to help understand the underlying mechanism. Secondly, an objective discussion of the diversely synthesized nanomaterial follows to divulge the easiness imparted by sonochemistry, which finally blends into the discussion of their applications and outreach. PMID- 26584991 TI - The secondary Bjerknes force between two gas bubbles under dual-frequency acoustic excitation. AB - The secondary Bjerknes force is one of the essential mechanisms of mutual interactions between bubbles oscillating in a sound field. The dual-frequency acoustic excitation has been applied in several fields such as sonochemistry, biomedicine and material engineering. In this paper, the secondary Bjerknes force under dual-frequency excitation is investigated both analytically and numerically within a large parameter zone. The unique characteristics (i.e., the complicated patterns of the parameter zone for sign change and the combination resonances) of the secondary Bjerknes force under dual-frequency excitation are revealed. Moreover, the influence of several parameters (e.g., the pressure amplitude, the bubble distance and the phase difference between sound waves) on the secondary Bjerknes force is also investigated numerically. PMID- 26584992 TI - Development of an empirical kinetic model for sonocatalytic process using neodymium doped zinc oxide nanoparticles. AB - The degradation of Acid Blue 92 (AB92) solution was investigated using a sonocatalytic process with pure and neodymium (Nd)-doped ZnO nanoparticles. The nanoparticles were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), and X-ray photoelectron spectroscopy (XPS). The 1% Nd-doped ZnO nanoparticles demonstrated the highest sonocatalytic activity for the treatment of AB92 (10 mg/L) with a degradation efficiency (DE%) of 86.20% compared to pure ZnO (62.92%) and sonication (45.73%) after 150 min. The results reveal that the sonocatalytic degradation followed pseudo-first order kinetics. An empirical kinetic model was developed using nonlinear regression analysis to estimate the pseudo-first-order rate constant (kapp) as a function of the operational parameters, including the initial dye concentration (5-25 mg/L), doped-catalyst dosage (0.25-1 g/L), ultrasonic power (150-400 W), and dopant content (1-6% mol). The results from the kinetic model were consistent with the experimental results (R(2)=0.990). Moreover, DE% increases with addition of potassium periodate, peroxydisulfate, and hydrogen peroxide as radical enhancers by generating more free radicals. However, the addition of chloride, carbonate, sulfate, and t butanol as radical scavengers declines DE%. Suitable reusability of the doped sonocatalyst was proven for several consecutive runs. Some of the produced intermediates were also detected by GC-MS analysis. The phytotoxicity test using Lemna minor (L. minor) plant confirmed the considerable toxicity removal of the AB92 solution after treatment process. PMID- 26584993 TI - Removal of carbamazepine from aqueous solution using sono-activated persulfate process. AB - This study investigated systematically the removal of carbamazepine (CBZ) in solution using the combination of ultrasound and persulfate anions to identify the factors affecting the kinetics of the process. The effects of reaction time, initial persulfate anion concentration, initial CBZ concentration, ultrasonic power input, solution pH and temperature on CBZ removal efficiency were examined. The sulfate radical oxidation of CBZ in the presence of ultrasonic irradiation showed a significant synergistic effect on CBZ removal. It is found that up to 89.4% CBZ removal efficiency was achieved after 120 min reaction. The removal process of CBZ in solution could be described using pseudo-first-order kinetics. In this system, sulfate radicals (SO4(-)) were considered to be the mainly oxidant to remove CBZ while ultrasound power input could affect CBZ removal efficiency significantly. Changing solution pH influenced the CBZ removal efficiency and the best performance would be achieved at pH 5.0. PMID- 26584994 TI - Statistical optimization of cell disruption techniques for releasing intracellular X-prolyl dipeptidyl aminopeptidase from Lactococcus lactis spp. lactis. AB - X-prolyl dipeptidyl aminopeptidase (PepX) is an intracellular enzyme from the Gram-positive bacterium Lactococcus lactis spp. lactis NRRL B-1821, and it has commercial importance. The objective of this study was to compare the effects of several cell disruption methods on the activity of PepX. Statistical optimization methods were performed for two cavitation methods, hydrodynamic (high-pressure homogenization) and acoustic (sonication), to determine the more appropriate disruption method. Two level factorial design (2FI), with the parameters of number of cycles and pressure, and Box-Behnken design (BBD), with the parameters of cycle, sonication time, and power, were used for the optimization of the high pressure homogenization and sonication methods, respectively. In addition, disruption methods, consisting of lysozyme, bead milling, heat treatment, freeze thawing, liquid nitrogen, ethylenediaminetetraacetic acid (EDTA), Triton-X, sodium dodecyl sulfate (SDS), chloroform, and antibiotics, were performed and compared with the high-pressure homogenization and sonication methods. The optimized values of high-pressure homogenization were one cycle at 130 MPa providing activity of 114.47 mU ml(-1), while sonication afforded an activity of 145.09 mU ml(-1) at 28 min with 91% power and three cycles. In conclusion, sonication was the more effective disruption method, and its optimal operation parameters were manifested for the release of intracellular enzyme from a L. lactis spp. lactis strain, which is a Gram-positive bacterium. PMID- 26584995 TI - Sonocatalytic degradation of Rhodamine B catalyzed by beta-Bi2O3 particles under ultrasonic irradiation. AB - beta-Bi2O3 particles were synthesized by a polyacrylamide sol-gel method. The sonocatalytic activity of beta-Bi2O3 particles was evaluated by degrading Rhodamine B (RhB) under the ultrasonic irradiation, revealing that beta-Bi2O3 particles exhibit a good sonocatalytic activity. The effects of various experimental factors including ultrasonic frequency (f), solution temperature (T), catalyst dosage (Ccatalyst) and initial RhB concentration (CRhB) on the sonocatalysis efficiency were investigated. The optimum conditions for sonocatalytic degradation of RhB are obtained to be f=60 kHz, T=40 degrees C, Ccatalyst=3 g L(-1), and CRhB=5 mg L(-1). The percentage degradation of RhB after sonocatalysis for 90 min is 98.7%. Detected by the photoluminescence technique that of using terephthalic acid as a probe molecule, hydroxyl radicals (OH) are found to be produced on the irradiated by beta-Bi2O3 particles. Based on the experimental results, OH radicals are suggested to be the major active species which are responsible for the degradation reaction. PMID- 26584996 TI - SonoFenton degradation of an azo dye, Direct Red. AB - The degradation of a reactive azo dye, Direct Red 81 (DR81), by Fenton process and in conjunction with sonolysis (SonoFenton) was studied. The synergistic effect of Fenton process and sonolysis enhanced the degradation of Direct Red 81 in aqueous solutions and the reaction followed the mechanism of hydroxyl radical (HO) oxidation. The influence of the initial substrate concentration, pH and catalyst loading on the rate of decolorisation were studied. The dye decolorisation followed apparent first order kinetics. The optimum conditions for decolorisation were pH=3.0, [Fe(2+)]=0.2 g/l, [H2O2]=5.1*10(-3) mol/l and ultrasonic frequency=120 kHz, 60 W. These conditions yielded 99% decolorisation of DR81 within 75 min. The sonolytic degradation products of DR81 were identified using Electrospray Ionization-Mass Spectrometry (ESI-MS). The presence of CO3(2 ), HCO3(-), Cl(-), NO3(-), and SO4(2-) ions in the dye solution did not have a considerable effect on the decolorisation efficiency. This study demonstrates that Fenton and SonoFenton methods can effectively decolorize DR81 dye in waste water. The dye concentration used in this study is higher compared to earlier studies illustrating the effective mineralization by the SonoFenton process. The mechanism of dye degradation is also proposed. PMID- 26584997 TI - Synthesis of porous Cu-BTC with ultrasonic treatment: Effects of ultrasonic power and solvent condition. AB - Cu-BTC (BTC=1,3,5-benzenetricarboxylate) metal organic framework (MOF) was synthesized using different solvent conditions with ultrasonic treatment. Solvent mixtures of water/N,N-dimethylformamide (DMF), water/ethanol were used for the reactions with or without a variety of bases under 20 kHz ultrasonically treated conditions. Prepared crystals were purified through 30 min of sonication to remove unreacted chemicals. Treatment time and ultrasonic power effects were compared to get optimum synthetic condition. The characterization of MOF powders was performed by scanning electron microscopy, X-ray powder diffraction, infrared spectroscopy, thermo-gravimetric analysis and specific surface determination using the BET method. Isolated crystal yields varied with different solvent and applied ultrasonic power conditions. A high isolated crystal yield of 86% was obtained from water/ethanol/DMF solvent system after 120 min of ultrasonic treatment at 40% power of 750 W. Different solvent conditions led to the formation of Cu-BTC with different surface area, and an extremely high surface area of 1430 m(2)/g was obtained from the crystals taken with the solvent condition of water:DMF=70:30. PMID- 26584998 TI - Enhancement and quenching of high-intensity focused ultrasound cavitation activity via short frequency sweep gaps. AB - This letter reports on the use of frequency sweeps to probe acoustic cavitation activity generated by high-intensity focused ultrasound (HIFU). Unprecedented enhancement and quenching of HIFU cavitation activity were observed when short frequency sweep gaps were applied in negative and positive directions, respectively. It was revealed that irrespective of the frequency gap, it is the direction and frequency sweep rate that govern the cavitation activity. These effects are related to the response of bubbles generated by the starting frequency to the direction of the frequency sweep, and the influence of the sweep rate on growth and coalescence of bubbles, which in turn affects the active bubble population. These findings are relevant for the use of HIFU in chemical and therapeutic applications, where greater control of cavitation bubble population is critical. PMID- 26584999 TI - Effect of ultrasonic frequency on H2O2 sonochemical formation rate in aqueous nitric acid solutions in the presence of oxygen. AB - The influence of the ultrasonic frequency (20 kHz, 207 kHz, and 615 kHz) towards the formation kinetics of H2O2 under Ar and Ar/(20 vol.%)O2 atmospheres was evaluated in pure water and aqueous nitric solutions. Results obtained at low frequency ultrasound demonstrate that hydrogen peroxide formation is enhanced under an Ar/O2 gas mixture whatever the sonicated medium. Nevertheless, H2O2 yields are higher in aqueous nitric solutions whatever the nature of the saturating gas. These observations are consistent at high frequency ultrasound under Ar gas notwithstanding higher yields for H2O2. Surprisingly, an inverse tendency is observed for high frequency sonolysis carried out under an Ar/O2 atmosphere: higher yields of H2O2 are measured in pure water. Further studies in the presence of pure Ar revealed a more important decomposition of nitric acid under high frequency ultrasound leading to higher yields of both HNO2 in the liquid phase and NO in the gas phase. In the presence of Ar/O2 mixture, the intrabubble oxidation of NO causes cavitation bubble depletion in O2 leading to the drop of H2O2 yield. On the other hand, it was found that for Ar/(20 vol.%)O2 mixture there is no influence of oxygen on HNO2 yield whatever the ultrasonic frequency; this is most likely explained by two processes: (i) HNO2 formation results from nitrate-ion thermolysis in the liquid reaction zone surrounding the cavitation bubble, and (ii) effective intrabubble oxidation of NOx species by oxygen to nitrate-ion. PMID- 26585000 TI - SnO2-decorated multiwalled carbon nanotubes and Vulcan carbon through a sonochemical approach for supercapacitor applications. AB - Multiwalled carbon nanotubes (MWCNTs) and Vulcan carbon (VC) decorated with SnO2 nanoparticles were synthesized using a facile and versatile sonochemical procedure. The as-prepared nanocomposites were characterized by means of transmission electron microscopy, X-ray diffraction, X-ray photoelectron spectroscopy, and Fourier transform infra red spectroscopy. It was evidenced that SnO2 nanoparticles were uniformly distributed on both carbon surfaces, tightly decorating the MWCNTs and VC. The electrochemical performance of the nanocomposites was evaluated by cyclic voltammetry and galvanostatic charge/discharge cycling. The as-synthesized SnO2/MWCNTs nanocomposites show a higher capacity than the SnO2/VC nanocomposites. Concretely, the SnO2/MWCNTs electrodes exhibit a specific capacitance of 133.33 F g(-1), whereas SnO2/VC electrodes exhibit a specific capacitance of 112.14 F g(-1) measured at 0.5 mA cm(-2) in 1 M Na2SO4. PMID- 26585001 TI - Heterogeneous sono-Fenton-like process using nanostructured pyrite prepared by Ar glow discharge plasma for treatment of a textile dye. AB - The plasma-treated pyrite (PTP) nanostructures were prepared from natural pyrite (NP) utilizing argon plasma due to its sputtering and cleaning effects resulting in more active surface area. The NP and PTP were characterized using X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), Brunauer Emmett-Teller (BET) and scanning electron microscopy (SEM) methods. The performance of the PTP was greater than NP for treatment of Reactive Red 84 (RR84) by the heterogeneous sono-Fenton process. The optimum amounts of main operational parameters were obtained as PTP of 4 g/L, initial dye concentration of 10 mg/L, pH of 5, and ultrasonic power of 300 W after 120 min of reaction time. Also, the effects of enhancers, and inorganic salts and t-butanol as hydroxyl radical scavengers on the degradation efficiency were investigated. Gas chromatography-mass spectroscopy analysis (GC-MS) was applied for detection of some degradation intermediates. Environmentally friendly plasma modification of the NP, in situ production of H2O2 and OH radicals, low leached iron concentration and repeated reusability at the milder pH are the significant benefits of the PTP utilization. PMID- 26585002 TI - A simple sonochemical approach for synthesis and characterization of Zn2SiO4 nanostructures. AB - Zn2SiO4 nanoparticles have been successfully prepared via a simple sonochemical method, for the first time. The effect of various parameters including ultrasonic power, ultrasonic irradiation time and different surfactants were investigated to reach optimum condition. The as-prepared nanostructures were characterized by X ray diffraction (XRD), scanning electron microscopy (SEM), transmittance electron microscopy (TEM), Fourier transform infrared (FT-IR) spectra and energy dispersive X-ray microanalysis (EDX). The photocatalytic activity of Zn2SiO4 nano and bulk structures were compared by degradation of anionic dye methyl orange in aqueous solution under UV-light irradiation. Moreover, the cyclic voltammetry analysis of Zn2SiO4 nano and bulk structures were investigated. PMID- 26585003 TI - Variation of dissolved organic nitrogen concentration during the ultrasonic pretreatment to Microcystis aeruginosa. AB - Algae cells were the main sources of dissolved organic nitrogen (DON) in raw water with plenty of algae, and ultrasonic pretreatment was one of the algae controlling methods through the damage of algae cells. However, the variation of DON concentration during the ultrasonic treatment process was not confirmed. Variation of DON concentration during the processes of low frequency ultrasound treatment of Microcystis aeruginosa was investigated. In addition, the effect of sonication on the metabolite concentration, algae cellar activity and the subsequent coagulation performance were discussed. The results showed that after a long duration of ultrasonic (60 s), nearly 90% of the algal cells were damaged and the maximum concentration of DON attained more than 3 mg/L. In order to control the leakage extent of DON, the sonication time should be less than 30 s with power intensity of more than 1.0 W/cm(3). In the mean time, ultrasonic treatment could inhibit the reactivation and the proliferation of algal, keep the algae cell wall integrity and enhance coagulation effectively under the same condition. However, ultrasound frequency had little effect on DON at the frequency range used in this study (20-150 kHz). PMID- 26585004 TI - Simultaneous sonochemical-enzymatic coating of medical textiles with antibacterial ZnO nanoparticles. AB - The antimicrobial finishing is a must for production of medical textiles, aiming at reducing the bioburden in clinical wards and consequently decreasing the risk of hospital-acquired infections. This work reports for the first time on a simultaneous sonochemical/enzymatic process for durable antibacterial coating of cotton with zinc oxide nanoparticles (ZnO NPs). The novel technology goes beyond the "stepwise" concept we proposed recently for enzymatic pre-activation of the fabrics and subsequent sonochemical nano-coating, and is designed to produce "ready-to-use" antibacterial medical textiles in a single step. A multilayer coating of uniformly dispersed NPs was obtained in the process. The enzymatic treatment provides better adhesion of the ZnO NPs and, as a consequence, enhanced coating stability during exploitation. The NPs-coated cotton fabrics inhibited the growth of the medically relevant Staphylococcus aureus and Escherichia coli respectively by 67% and 100%. The antibacterial efficiency of these textile materials resisted the intensive laundry regimes used in hospitals, though only 33% of the initially deposited NPs remained firmly fixed onto the fabrics after multiple washings. PMID- 26585005 TI - Ultrasonic effects on the degradation kinetics, preliminary characterization and antioxidant activities of polysaccharides from Phellinus linteus mycelia. AB - In this study, a high-molecular-weight polysaccharide PL-N isolated from the alkaline extract of Phellinus linteus mycelia was degraded by ultrasound. Results showed that ultrasound treatment at different ultrasonic intensities decreased the intrinsic viscosity and molecular weight of PL-N, as well as narrowed the molecular weight distribution. A larger reduction in intrinsic viscosity and molecular weight was caused by a higher ultrasonic intensity. The degradation kinetics model was fitted to (1/Mt-1/M0)=k.t, and the reaction rate constant (k) increased with increasing ultrasonic intensity. Ultrasound degradation did not change the primary structure of PL-N, and scanning electron microscopy analysis indicated that the morphology of the original PL-N was different from that of degraded PL-N fractions. Antioxidant activity assays in vitro indicated that the degraded PL-N fraction with low molecular weight had stronger hydroxyl radical scavenging capacity and higher TEAC and FRAP values. PMID- 26585006 TI - Ultrasonic-assisted synthesis of Ce doped cubic-hexagonal ZnTiO3 with highly efficient sonocatalytic activity. AB - Ce doped ZnTiO3 as a novel catalyst with highly efficient and stable sonocatalytic activity was synthesized via an ultrasound-assisted sol-gel method using non-ionic surfactant Pluronic F127 as structure directing agent. Synthesized samples were characterized by using various techniques, such as XRD, TEM, SEM, EDX, XRF, BET, DRS, and PL, and their sonocatalytic activity studied toward degradation of p-Nitrophenol as a model organic compound. The synthesized mesoporous Ce/ZnTiO3 had mixed cubic-hexagonal phase with large surface area (118.2 m(2) g(-1)) and narrow pore size distribution (4.9 nm). The effects of cerium concentration, calcination temperature, and calcination time on the structure and the sonocatalytic activity of Ce/ZnTiO3 were studied in detail. XRD results were suggested that the relation between the phase structure and the catalytic activity is considerable. Significant decrease in band-gap and PL intensity was observed with increasing the cerium concentration in the ZnTiO3. It became clear that the Ce/ZnTiO3 (0.81 mol%) shows high sonocatalytic activity compared with pure ZnTiO3 and other Ce/ZnTiO3 samples as well as commercial TiO2 P25. The possible mechanism for the enhanced sonocatalytic activity of Ce/ZnTiO3 was discussed in details. The electrical energy consumption was also considered during sonocatalytic experiments. PMID- 26585007 TI - Ultrasound energy to accelerate dye uptake and dye-fiber interaction of reactive dye on knitted cotton fabric at low temperatures. AB - Acoustic cavitation formed due to propagation of ultrasound wave inside a dye bath was successfully used to dye cotton fabric with a reactive dye at lower temperatures. The energy input to the system during sonication was 0.7 W/cm(2). This was within the energy range that contributes towards forming cavitation during ultra-sonication. The influence of ultrasound treatment on dye particle size and fiber morphology is discussed. Particle size analysis of the dye bath revealed ultra-sonication energy was capable of de-agglomeration of hydrolyzed dye molecules during dyeing. SEM micrograph and AFM topographical image of the fiber surface revealed fiber morphology remains unchanged after the sonication. The study was extended in understanding the contribution of ultrasound method of dyeing towards achieving good color strength on the fabric, compared to the normal heating method of dyeing. Study showed color strength obtained using ultra sound method of dyeing is higher compared to normal heating dyeing. Ultrasound energy was able to achieve the good color strength on cotton fabric at very low temperature such as 30 degrees C, which was approximately 230% more than the color strength achieved in normal heating method of dyeing. This indicates that energy input to the system using ultrasound was capable of acting as an effective alternative method of dyeing knitted cotton fabrics with reactive dye. PMID- 26585008 TI - The role of passive potential in ultrasonic cavitation erosion of titanium in 1 M HCl solution. AB - The influence of the applied passive potential on the ultrasonic cavitation erosion of Ti specimen in 1 M HCl solution was investigated by mass loss experiment, scanning electron microscopy (SEM), electrochemical impedance spectra (EIS) and Mott-Schottky plot. The results showed that Ti was in the passive state within the potential region from -0.3 VSCE to 1.5 VSCE under ultrasonic cavitation erosion. The applied passive potential can obviously decrease the mass loss of Ti caused by ultrasonic cavitation erosion in 1 M HCl solution. The resistance of the passive film increased, the flat band potential moved to positive direction, and the donor density of the passive film decreased with increasing the passive potential. Finally, a physical model was provided to explain the experimental results based on energy band and semi-conductive theories. PMID- 26585009 TI - Ultrasound assisted two-stage biodiesel synthesis from non-edible Schleichera triguga oil using heterogeneous catalyst: Kinetics and thermodynamic analysis. AB - Present work deals with the ultrasound-assisted biodiesel production from low cost, substantial acid value kusum (Schleichera triguga) oil using a two-step method of esterification in presence of acid (H2SO4) catalyst followed by transesterification using a basic heterogeneous barium hydroxide (Ba(OH)2) catalyst. The initial acid value of kusum oil was reduced from 21.65 to 0.84 mg of KOH/g of oil, by acid catalyzed esterification with 4:1 methanol to oil molar ratio, catalyst concentration 1% (v/v), ultrasonic irradiation time 20 min at 40 degrees C. Then, Ba(OH)2 concentration of 3% (w/w), methanol to oil molar ratio of 9:1, ultrasonic irradiation time of 80 min, and temperature of 50 degrees C was found to be the optimum conditions for transesterification step and triglyceride conversion of 96.8% (wt) was achieved. This paper also examined the kinetics as well as the evaluation of thermodynamic parameters for both esterification and transesterification reactions. The lower value of activation energy and higher values of kinetic constants indicated a fast rate of reaction, which could be attributed to the physical effect of emulsification, in which the microturbulence generated due to radial motion of bubbles, creates an intimate mixing of the immiscible reactants causing the increase in the interfacial area, giving faster reaction kinetics. The positive values of Gibbs-free energy (DeltaG), enthalpy (DeltaH) and negative value of entropy (DeltaS) revealed that both the esterification and transesterification were non-spontaneous, endothermic and endergonic reactions. Therefore, the present work has not only established the escalation obtained due to ultrasonication but also exemplified the two-step approach for synthesis of biodiesel from non-edible kusum oil based on the use of heterogeneous catalyst for the transesterification step. PMID- 26585010 TI - Ultrasonic emulsification of parenteral valproic acid-loaded nanoemulsion with response surface methodology and evaluation of its stability. AB - Response surface methodology (RSM) was used to optimize the formulation of a nanoemulsion for central delivery following parenteral administration. A mixture of medium-chain triglyceride (MCT) and safflower seed oil (SSO) was determined as a sole phase from the emulsification properties. Similarly, a natural surfactant (lecithin) and non-ionic surfactant (Tween 80) (ratio 1:2) were used in the formulation. A central composite design (CCD) with three-factor at five-levels was used to optimize the processing method of high energy ultrasonicator. Effects of pre-sonication ultrasonic intensity (A), sonication time (B), and temperature (C) were studied on the preparation of nanoemulsion loaded with valproic acid. Influence of the aforementioned specifically the effects of the ultrasonic processing parameters on droplet size and polydispersity index were investigated. From the analysis, it was found that the interaction between ultrasonic intensity and sonication time was the most influential factor on the droplet size of nanoemulsion formulated. Ultrasonic intensity (A) significantly affects the polydispersity index value. With this optimization method, a favorable droplet size of a nanoemulsion with reasonable polydispersity index was able to be formulated within a short sonication time. A valproic acid loaded nanoemulsion can be obtained with 60% power intensity for 15 min at 60 degrees C. Droplet size of 43.21+/-0.11 nm with polydispersity index of 0.211 were produced. The drug content was then increased to 1.5%. Stability study of nanoemulsion containing 1.5% of valproic acid had a good stability as there are no significant changes in physicochemical aspects such as droplet size and polydispersity index. With the characteristisation study of pH, viscosity, transmission electron microscope (TEM) and stability assessment study the formulated nanoemulsion has the potential to penetrate blood-brain barrier in the treatment of epilepsy. PMID- 26585011 TI - Harmonic responses and cavitation activity of encapsulated microbubbles coupled with magnetic nanoparticles. AB - Encapsulated microbubbles coupled with magnetic nanoparticles, one kind of hybrid agents that can integrate both ultrasound and magnetic resonance imaging/therapy functions, have attracted increasing interests in both research and clinic communities. However, there is a lack of comprehensive understanding of their dynamic behaviors generated in diagnostic and therapeutic applications. In the present work, a hybrid agent was synthesized by integrating superparamagnetic iron oxide nanoparticles (SPIOs) into albumin-shelled microbubbles (named as SPIO albumin microbubbles). Then, both the stable and inertial cavitation thresholds of this hybrid agent were measured at varied SPIO concentrations and ultrasound parameters (e.g., frequency, pressure amplitude, and pulse length). The results show that, at a fixed acoustic driving frequency, both the stable and inertial cavitation thresholds of SPIO-albumin microbubble should decrease with the increasing SPIO concentration and acoustic driving pulse length. The inertial cavitation threshold of SPIO-albumin microbubbles also decreases with the raised driving frequency, while the minimum sub- and ultra-harmonic thresholds appear at twice and two thirds resonance frequency, respectively. It is also noticed that both the stable and inertial cavitation thresholds of SonoVue microbubbles are similar to those measured for hybrid microbubbles with a SPIO concentration of 114.7 MUg/ml. The current work could provide better understanding on the impact of the integrated SPIOs on the dynamic responses (especially the cavitation activities) of hybrid microbubbles, and suggest the shell composition of hybrid agents should be appropriately designed to improve their clinical diagnostic and therapeutic performances of hybrid microbubble agents. PMID- 26585012 TI - Synthesis, characteristics and sonocatalytic activities of calcined gamma-Fe2O3 and TiO2 nanotubes/gamma-Fe2O3 magnetic catalysts in the degradation of Orange G. AB - In this work, gamma-Fe2O3 and TiO2 NTs/gamma-Fe2O3 composites with good magnetism and sonocatalytic activity were prepared by a facile polyol method and utilize the principle of isoelectric point method, respectively. The structural and magnetic features of the prepared calcined gamma-Fe2O3 and composite catalysts were investigated by transmission electron microscopy (TEM), powder X-ray diffraction (XRD), surface analysis, UV-Vis diffuse reflectance spectra (UV-Vis DRS), vibrating sample magnetometry (VSM) and zeta potential analysis. The effects of calcination temperature on gamma-Fe2O3 phase variation, physical properties and sonocatalytic properties were investigated. The porosity, specific surface area, band gap energy and sonocatalytic activity of gamma-Fe2O3 were gradually decreased with calcination temperature increased. TiO2 NTs/gamma-Fe2O3 with appropriate composition and specific structural features possess synergetic effects such as efficient separation of charge carriers and hydroxyl radicals produced by heterogeneous fenton and fenton-like reactions. This enhanced the sonocatalytic activity for the degradation of Orange G under ultrasonic irradiation. The sonocatalytic reactions obeyed pseudo first-order kinetics. All these information provide insight into the design and development of high efficiency catalyst for wastewater treatment. PMID- 26585013 TI - Removal of selenite by zero-valent iron combined with ultrasound: Se(IV) concentration changes, Se(VI) generation, and reaction mechanism. AB - In this paper, the performance and application of zero-valent iron (ZVI) assisted by ultrasonic irradiation for the removal of selenite (Se(IV)) in wastewater was evaluated and reaction mechanism of Se(IV) with ZVI in such systems was investigated. A series of batch experiments were conducted to determine the effects of ultrasound power, pH, ZVI concentration, N2 and air on Se(IV) removal. ZVI before and after reaction with Se(IV) was characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS). Results indicated that ultrasound can lead to a significant synergy in the removal of Se(IV) by ZVI because ultrasound can promote the generation of OH and accelerate the advanced Fenton process. The primary reaction products of ZVI and Se(IV) were Se(0), ferrihydrite, and Fe2O3. PMID- 26585014 TI - Evaluation of ultrasound based sterilization approaches in terms of shelf life and quality parameters of fruit and vegetable juices. AB - The present work evaluates the performance of ultrasound based sterilization approaches for processing of different fruit and vegetable juices in terms of microbial growth and changes in the quality parameters during the storage. Comparison with the conventional thermal processing has also been presented. A novel approach based on combination of ultrasound with ultraviolet irradiation and crude extract of essential oil from orange peels has been used for the first time. Identification of the microbial growth (total bacteria and yeast content) in the juices during the subsequent storage and assessing the safety for human consumption along with the changes in the quality parameters (Brix, titratable acidity, pH, ORP, salt, conductivity, TSS and TDS) has been investigated in details. The optimized ultrasound parameters for juice sterilization were established as ultrasound power of 100 W and treatment time of 15 min for the constant frequency operation (20 kHz). It has been established that more than 5 log reduction was achieved using the novel combined approaches based on ultrasound. The treated juices using different approaches based on ultrasound also showed lower microbial growth and improved quality characteristics as compared to the thermally processed juice. Scale up studies were also performed using spinach juice as the test sample with processing at 5 L volume for the first time. The ultrasound treated juice satisfied the microbiological and physiochemical safety limits in refrigerated storage conditions for 20 days for the large scale processing. Overall the present work conclusively established the usefulness of combined treatment approaches based on ultrasound for maintaining the microbiological safety of beverages with enhanced shelf life and excellent quality parameters as compared to the untreated and thermally processed juices. PMID- 26585015 TI - An investigation of the crystallization kinetics of zeotype SAPO-34 crystals synthesized by hydrothermal and sonochemical methods. AB - The kinetics study of SAPO-34 crystallization from a gel containing morpholine as a structure directing agent (SDA) was investigated by means of X-ray diffraction (XRD) patterns in order to determine the kinetics parameters, i.e. induction times, rate constants, frequency factors, and activation energies for the induction and growth stages. The kinetics data of growth period were determined by using the Avrami-Erofeev nucleation growth model. SAPO-34 molecular sieves were synthesized by using both sonochemical-assisted hydrothermal and conventional hydrothermal heating at temperatures of 180, 200, and 220 degrees C to elucidate the influence of crystallization method on the crystallization kinetics of SAPO-34. The activation energy values indicated that the crystal growth mechanism was enhanced for samples synthesized sonochemically, whereas the induction energy was not greatly affected by using sonication process. Also, the kinetic compensation effect (KCE) was considered in order to obtain the isokinetic temperature. PMID- 26585016 TI - Ultrasonic radiation to enable improvement of direct methanol fuel cell. AB - To improve DMFC (direct methanol fuel cell) performance, a new method using ultrasonic radiation is proposed and a novel DMFC structure is designed and fabricated in the present paper. Three ultrasonic transducers (piezoelectric transducer, PZT) are integrated in the flow field plate to form the ultrasonic field in the liquid fuel. Ultrasonic frequency, acoustic power, and methanol concentration have been considered as variables in the experiments. With the help of ultrasonic radiation, the maximum output power and limiting current of cell can be independently increased by 30.73% and 40.54%, respectively. The best performance of DMFC is obtained at the condition of ultrasonic radiation (30 kHz and 4 W) fed with 2M methanol solution, because both its limiting current and output power reach their maximum value simultaneously (222 mA and 33.6 mW, respectively) under this condition. These results conclude that ultrasonic can be an alternative choice for improving the cell performance, and can facilitate a guideline for the optimization of DMFC. PMID- 26585017 TI - Sulfonated reduced graphene oxide as a highly efficient catalyst for direct amidation of carboxylic acids with amines using ultrasonic irradiation. AB - Sulfonated reduced graphene oxide nanosheets (rGO-SO3H) were prepared by grafting sulfonic acid-containing aryl radicals onto chemically reduced graphene oxide (rGO) under sonochemical conditions. rGO-SO3H catalyst was characterized by Fourier-transform infrared (FT-IR) spectroscopy, Raman spectroscopy, scanning electron microscopy (SEM), X-ray diffraction (XRD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and X-ray photoelectron spectroscopy (XPS). rGO-SO3H catalyst was successfully applied as a reusable solid acid catalyst for the direct amidation of carboxylic acids with amines into the corresponding amides under ultrasonic irradiation. The direct sonochemical amidation of carboxylic acid takes place under mild conditions affording in good to high yields (56-95%) the corresponding amides in short reaction times. PMID- 26585018 TI - Effect of high intensity ultrasound on transglutaminase-catalyzed soy protein isolate cold set gel. AB - The effects of high intensity ultrasound (HIU, 105-110 W/cm(2) for 5 or 40 min) pre-treatment of soy protein isolate (SPI) on the physicochemical properties of ensuing transglutaminase-catalyzed soy protein isolate cold set gel (TSCG) were investigated in this study. The gel strength of TSCG increased remarkably from 34.5 to 207.1 g for TSCG produced from SPI with 40 min HIU pre-treatment. Moreover, gel yield and water holding capacity also increased after HIU pre treatments. Scanning electron microscopy showed that HIU of SPI resulted in a more uniform and denser microstructure of TSCG. The content of free sulfhydryl (SH) groups was higher in HIU TSCG than non-HIU TSG, even though greater decrease of the SH groups present in HIU treated SPI was observed when the TSCG was formed, suggesting the involvement of disulfide bonds in gel formation. Protein solubility of TSCG in both denaturing and non-denaturing solvents was higher after HIU pretreatment, and changes in hydrophobic amino acid residues as well as in polypeptide backbone conformation and secondary structure of TSCG were demonstrated by Raman spectroscopy. These results suggest that increased inter molecular epsilon-(gamma-glutamyl) lysine isopeptide bonds, disulfide bonds and hydrophobic interactions might have contributed to the HIU TSCG gel network. In conclusion, HIU changed physicochemical and structural properties of SPI, producing better substrates for TGase. The resulting TSCG network structure was formed with greater involvement of covalent and non-covalent interactions between SPI molecules and aggregates than in the TSCG from non-HIU SPI. PMID- 26585019 TI - Sonochemical synthesis of Cu2O nanocubes for enhanced chemiluminescence applications. AB - A facile one-step sonochemical synthesis of Cu2O nanocubes has been developed by ultrasound irradiation of copper sulfate in the presence of polyvinylpyrrolidone and ascorbic acid at pH 11. During sonication, the reaction between acoustic cavitation-generated radicals and CuSO4 produced Cu(OH)2 intermediate which then reacted with ascorbic acid to generate Cu2O nanocubes. The products were characterized by FT-IR, XRD, HRTEM, AFM and particle size analyzer. The prepared Cu2O nanocubes were found to be very effective for enhancing chemiluminescence in the presence of luminol-H2O2 system. PMID- 26585020 TI - Study on the spatial distribution of the liquid temperature near a cavitation bubble wall. AB - A simple new model of the spatial distribution of the liquid temperature near a cavitation bubble wall (Tli) is employed to numerically calculate Tli. The result shows that Tli is almost same with the ambient liquid temperature (T0) during the bubble oscillations except at strong collapse. At strong collapse, Tli can increase to about 1510 K, the same order of magnitude with that of the maximum temperature inside the bubble, which means that the chemical reactions occur not only in gas-phase inside the collapsing bubble but also in liquid-phase just outside the collapsing bubble. Four factors (ultrasonic vibration amplitude, ultrasonic frequency, the surface tension and the viscosity) are considered to study their effects for the thin liquid layer. The results show that for the thin layer, the thickness and the temperature increase as the ultrasonic vibration amplitude rise; conversely, the thickness and the temperature decrease with the increase of the ultrasonic frequency, the surface tension or the viscosity. PMID- 26585021 TI - Multi-component electrocatalyst for low-temperature fuel cells synthesized via sonochemical reactions. AB - This review presents recent advances in multi-component electrocatalysts for low temperature fuel cells (FCs) synthesized via sonochemical reactions. As a feasible approach to develop novel electrocatalysts that can overcome the many problems of the prevailing Pt electrocatalysts, Pt- or Pd-based alloy and core shell M@Pt nanoparticles (NPs) have been pursued. Synthesizing NPs with desirable properties often turn out to be challenging. Sonochemistry generates extreme conditions via acoustic cavitation, which have been utilized in the syntheses of various Pt and Pd NPs and Pt- and Pd-based alloy NPs. Especially, it has been reported that several M@Pt core-shell NPs can be synthesized by sonochemistry, which is hard to achieve by other methods. The principles of sonochemistry are presented with examples. Also alloy NPs and core-shell NPs synthesized by sonochemistry and those by other methods are compared. PMID- 26585022 TI - Mechanisms for improving mass transfer in food with ultrasound technology: Describing the phenomena in two model cases. AB - The aim of this work was to demonstrate how ultrasound mechanisms (direct and indirect effects) improve the mass transfer phenomena in food processing, and which part of the process they are more effective in. Two model cases were evaluated: the hydration of sorghum grain (with two water activities) and the influx of a pigment into melon cylinders. Different treatments enabled us to evaluate and discriminate both direct (inertial flow and "sponge effect") and indirect effects (micro channel formation), alternating pre-treatments and treatments using an ultrasonic bath (20 kHz of frequency and 28 W/L of volumetric power) and a traditional water-bath. It was demonstrated that both the effects of ultrasound technology are more effective in food with higher water activity, the micro channels only forming in moist food. Moreover, micro channel formation could also be observed using agar gel cylinders, verifying the random formation of these due to cavitation. The direct effects were shown to be important in mass transfer enhancement not only in moist food, but also in dry food, this being improved by the micro channels formed and the porosity of the food. In conclusion, the improvement in mass transfer due to direct and indirect effects was firstly discriminated and described. It was proven that both phenomena are important for mass transfer in moist foods, while only the direct effects are important for dry foods. Based on these results, better processing using ultrasound technology can be obtained. PMID- 26585023 TI - Characterization of HIFU transducers designed for sonochemistry application: Acoustic streaming. AB - Cavitation distribution in a High Intensity Focused Ultrasound sonoreactors (HIFU) has been extensively described in the recent literature, including quantification by an optical method (Sonochemiluminescence SCL). The present paper provides complementary measurements through the study of acoustic streaming generated by the same kind of HIFU transducers. To this end, results of mass transfer measurements (electrodiffusional method) were compared to optical method ones (Particle Image Velocimetry). This last one was used in various configurations: with or without an electrode in the acoustic field in order to have the same perturbation of the wave propagation. Results show that the maximum velocity is not located at the focal but shifted near the transducer, and that this shift is greater for high powers. The two cavitation modes (stationary and moving bubbles) are greatly affect the hydrodynamic behavior of our sonoreactors: acoustic streaming and the fluid generated by bubble motion. The results obtained by electrochemical measurements show the same low hydrodynamic activity in the transducer vicinity, the same shift of the active focal toward the transducer, and the same absence of activity in the post-focal axial zone. The comparison with theoretical Eckart's velocities (acoustic streaming in non-cavitating media) confirms a very high activity at the "sonochemical focal", accounted for by wave distortion, which induced greater absorption coefficients. Moreover, the equivalent liquid velocities are one order of magnitude larger than the ones measured by PIV, confirming the enhancement of mass transfer by bubbles oscillation and collapse close to the surface, rather than from a pure streaming effect. PMID- 26585024 TI - Ultrasound assisted dispersal of a copper nanopowder for electroless copper activation. AB - This paper describes the ultrasound assisted dispersal of a low wt./vol.% copper nanopowder mixture and determines the optimum conditions for de-agglomeration. A commercially available powder was added to propan-2-ol and dispersed using a magnetic stirrer, a high frequency 850 kHz ultrasonic cell, a standard 40 kHz bath and a 20 kHz ultrasonic probe. The particle size of the powder was characterized using dynamic light scattering (DLS). Z-Average diameters (mean cluster size based on the intensity of scattered light) and intensity, volume and number size distributions were monitored as a function of time and energy input. Low frequency ultrasound was found to be more effective than high frequency ultrasound at de-agglomerating the powder and dispersion with a 20 kHz ultrasonic probe was found to be very effective at breaking apart large agglomerates containing weakly bound clusters of nanoparticles. In general, the breakage of nanoclusters was found to be a factor of ultrasonic intensity, the higher the intensity the greater the de-agglomeration and typically micron sized clusters were reduced to sub 100 nm particles in less than 30 min using optimum conditions. However, there came a point at which the forces generated by ultrasonic cavitation were either insufficient to overcome the cohesive bonds between smaller aggregates or at very high intensities decoupling between the tip and solution occurred. Absorption spectroscopy indicated a copper core structure with a thin oxide shell and the catalytic performance of this dispersion was demonstrated by drop coating onto substrates and subsequent electroless copper metallization. This relatively inexpensive catalytic suspension has the potential to replace precious metal based colloids used in electronics manufacturing. PMID- 26585025 TI - Preface to the Special Issue: Cleaning with bubbles. PMID- 26585027 TI - High rectification in organic diodes based on liquid crystalline phthalocyanines. AB - The optical and electrical properties of mesogenic metal-free and metalated phthalocyanines (PCs) with a moderately sized and regioregular alkyl periphery were investigated. In solution, the individualized molecules show fluorescence lifetimes of 4-6 ns in THF. When deposited as solid thin films the materials exhibit significantly shorter fluorescence lifetimes with bi-exponential decay (1.4-1.8 ns; 0.2-0.4 ns) that testify to the formation of aggregates viapi-pi intermolecular interactions. In diode structures, their pronounced columnar order outbalances the unfavorable planar alignment and leads to excellent rectification behavior. Field-dependent charge carrier mobilities are obtained from the J-V curves in the trap-limited space-charge-limited current regime and demonstrate that the metalated PCs display an improved electrical response with respect to the metal-free homologue. The excited-state lifetime characterization suggest that the pi-pi intermolecular interactions are stronger for the metal-free PC, confirming that the metallic centre plays an important role in the charge transport inside these materials. PMID- 26585026 TI - Molecular basis of contact inhibition of locomotion. AB - Contact inhibition of locomotion (CIL) is a complex process, whereby cells undergoing a collision with another cell cease their migration towards the colliding cell. CIL has been identified in numerous cells during development including embryonic fibroblasts, neural crest cells and haemocytes and is the driving force behind a range of phenomenon including collective cell migration and dispersion. The loss of normal CIL behaviour towards healthy tissue has long been implicated in the invasion of cancer cells. CIL is a multi-step process that is driven by the tight coordination of molecular machinery. In this review, we shall breakdown CIL into distinct steps and highlight the key molecular mechanisms and components that are involved in driving each step of this process. PMID- 26585028 TI - The association between alcohol use and depressive symptoms across socioeconomic status among 40- and 45-year-old Norwegian adults. AB - BACKGROUND: Little population-based data among middle-aged adults exists examining the relationships between depressive symptoms, alcohol use, and socio economic status (SES). This study aimed to describe the relationships between depressive symptoms and alcohol use at different levels of SES and to determine differences across SES levels among a population-based sample of 40 and 45 year old adults in Norway. METHODS: This analysis was based on data from two Norwegian health studies conducted in 2000 and 2001, and included community-dwelling Norwegian men and women aged 40 and 45 years. Self-reported frequency and quantity of alcoholic drinks was used to calculate past-year typical quantity of drinks consumed and frequency of 5+ drinks per occasion, or heavy episodic drinking (HED). Depressive symptoms were assessed with the 10-item Hopkins Symptom Checklist, and SES was measured as education level and employment status. To observe the association between depressive symptoms and alcohol use at each level of SES we fitted multinomial logistic regression models using each alcohol outcome as a dependent variable stratified by level of education and employment. To observe differences across levels of SES, we examined the interaction between depressive symptoms and SES level in multinomial logistic regression models for each alcohol measures. RESULTS: Having depressive symptoms was significantly associated with an increased risk of 5+ typical drinks among people in the lowest (RRR = 1.60, p <= 0.05) education level, and not among people in the highest. Conversely, significant associations were observed among all levels of employment. For frequency of HED, depressive symptoms was not significantly associated with frequency of HED at any education level. Depressive symptoms was associated with 13+ past year HED episodes among people with no employment (RRR = 1.97, p <= 0.05), and part-time employment (RRR = 2.33, p <= 0.01), and no association was observed among people with full-time employment. A significant interaction was observed for depressive symptoms and employment for risk of 13+ past-year HED episodes. CONCLUSIONS: The results show a variety of associations between depressive symptoms and alcohol use among people with lower SES, and suggest type of alcohol use and SES measure may influence the observation of an association between depressive symptoms and alcohol use at different SES levels. PMID- 26585029 TI - A time-calibrated phylogeny of southern hemisphere stoneflies: Testing for Gondwanan origins. AB - For more than two centuries biogeographers have attempted to explain why terrestrial or freshwater lineages have geographic distributions broken by oceans, with these disjunct distributions either attributed to vicariance associated with Gondwanan fragmentation or trans-oceanic dispersal. Stoneflies (order: Plecoptera) are a widespread order of freshwater insects whose poor dispersal ability and intolerance for salt water make them ideal candidates for Gondwanan relicts - taxa whose distribution can be explained by vicariant isolation driven by the breakup of Gondwana. Here we reconstruct the phylogenetic relationships among southern hemisphere stoneflies (5 families; 86 genera) using 2864bp of mitochondrial (COI) and nuclear (18S, H3) DNA, with a calibrated relaxed molecular clock used to estimate the chronology of diversification. Our analysis suggests that largely antitropical stonefly sub-orders, Arctoperlaria (northern hemisphere) and Antarctoperlaria (southern hemisphere), were formed approximately 121Ma (95% prior probability distribution 107-143Ma), which may reflect the vicariant rifting of the supercontinent Pangaea. Subsequently, we infer that a single Arctoperlaria lineage has dispersed into southern hemisphere 76Ma (95% range 65-98Ma). The majority of divergences between South American and Australian stonefly lineages appear to coincide with the opening of Drake Passage around 40Ma, suggesting vicariant isolation of these landmasses may be responsible for these biogeographic disjunctions. In contrast, divergences between New Zealand lineages and their sister taxa appear to post-date vicariant timeframes, implying more recent dispersal events. PMID- 26585030 TI - Divergence times, historical biogeography, and shifts in speciation rates of Myrtales. AB - We examine the eudicot order Myrtales, a clade with strong Gondwanan representation for most of its families. Although previous phylogenetic studies greatly improved our understanding of intergeneric and interspecific relationships within the order, our understanding of inter-familial relationships still remains unresolved; hence, we also lack a robust time-calibrated chronogram to address hypotheses (e.g., biogeography and diversification rates) that have implicit time assumptions. Six loci (rbcL, ndhF, matK, matR, 18S, and 26S) were amplified and sequenced for 102 taxa across Myrtales for phylogenetic reconstruction and ten fossil priors were utilized to produce a chronogram in BEAST. Combretaceae is identified as the sister clade to all remaining families with moderate support, and within the latter clade, two strongly supported groups are seen: (1) Onagraceae+Lythraceae, and (2) Melastomataceae+the Crypteroniaceae, Alzateaceae, Penaeaceae clade along with Myrtaceae+Vochysiaceae. Divergence time estimates suggest Myrtales diverged from Geraniales ~124Mya during the Aptian of the Early Cretaceous. The crown date for Myrtales is estimated at ~116Mya (Albian Aptian). BioGeoBEARS showed significant improvement in the likelihood score when the "jump dispersal" parameter was added. South America and/or Africa are implicated as important ancestral areas in all deeper nodes. BAMM analyses indicate that the best configuration included three significant shifts in diversification rates within Myrtales: near the crown of Melastomataceae (~67 64Mya), along the stem of subfamily Myrtoideae (Myrtaceae; ~75Mya), and along the stem of tribe Combreteae (Combretaceae; ~50-45Mya). Issues with conducting diversification analyses more generally are examined in the context of scale, taxon sampling, and larger sets of phylogenetic trees. PMID- 26585031 TI - A Novel Treatment for Onychomycosis in People Living With HIV Infection: Vicks VapoRubTM is Effective and Safe. PMID- 26585032 TI - Expert Consensus on the Rehabilitation Framework Guiding a Model of Care for People Living With HIV in a South African Setting. AB - Disabilities and treatments related to HIV are a focus for rehabilitation professionals in HIV-endemic countries, yet these countries lack guidance to integrate rehabilitation into a model of care for people living with HIV. We asked HIV and rehabilitation experts in South Africa to engage in a modified Delphi survey based on findings from (a) an enquiry into stakeholder perspectives of a context-specific rehabilitation framework at a semi-rural setting and (b) an analysis of international models of care-guiding rehabilitation. Consensus was determined by an a priori threshold of 70% of agreement and interquartile range (<= 1 on criterion) to be included as essential or useful in the model of care framework. Experts agreed that improving access to care, optimal communication between stakeholders, education and training for health care workers, and home based rehabilitation were essential for the model. Furthermore, task shifting and evidence-based practice were seen as fundamental for optimal care. PMID- 26585033 TI - Expression, characterisation and antigenicity of a truncated Hendra virus attachment protein expressed in the protozoan host Leishmania tarentolae. AB - Hendra virus (HeV) is an emerging zoonotic paramyxovirus within the genus Henipavirus that has caused severe morbidity and mortality in humans and horses in Australia since 1994. HeV infection of host cells is mediated by the membrane bound attachment (G) and fusion (F) glycoproteins, that are essential for receptor binding and fusion of viral and cellular membranes. The eukaryotic unicellular parasite Leishmania tarentolae has recently been established as a powerful tool to express recombinant proteins with mammalian-like glycosylation patterns, but only few viral proteins have been expressed in this system so far. Here, we describe the purification of a truncated, Strep-tag labelled and soluble version of the HeV attachment protein (sHeV G) expressed in stably transfected L. tarentolae cells. After Strep-tag purification the identity of sHeV G was confirmed by immunoblotting and mass spectrometry. The functional binding of sHeV G to the HeV cell entry receptor ephrin-B2 was confirmed in several binding assays. Generated polyclonal rabbit antiserum against sHeV G reacted with both HeV and Nipah virus (NiV) G proteins in immunofluorescence assay and efficiently neutralised NiV infection, thus further supporting the preserved antigenicity of the purified protein. PMID- 26585034 TI - Mechanical Circulatory Support in Children. AB - The field of pediatric mechanical circulatory support has undergone a significant evolution with the advent of devices designed for children and the implementation of new strategies for deployment. With the ongoing shortage of organs the demand for new devices specifically designed for children will only increase. This review discusses the evolution of mechanical circulatory support, available devices, and the implementation of new strategies for their deployment. PMID- 26585036 TI - Pharmacologic Approach to Heart Failure. AB - Heart failure may result from a wide variety of causes and present with varying degrees of severity. In large part patients present with varying degrees of congestion and compromised cardiac output. In this review a pathophysiologic construct is provided to guide the pharmacologic management of acute heart failure that leads to decreased congestion and improved cardiac output. Pharmacologic therapies that are used to treat chronic heart failure are also highlighted and provide the framework for transitioning from acute to preventative pharmacologic strategies. PMID- 26585035 TI - Acute Kidney Injury in Pediatric Heart Failure. AB - Acute kidney injury (AKI) is very common in pediatric medical and surgical cardiac patients. Not only is it an independent risk factor for increased morbidity and mortality in the short run, but repeated episodes of AKI lead to chronic kidney disease (CKD) especially in the most vulnerable hosts with multiple risk factors, such as heart transplant recipients. The cardiorenal syndrome, a term coined to emphasize the bidirectional nature of simultaneous or sequential cardiac-renal dysfunction both in acute and chronic settings, has been recently described in adults but scarcely reported in children. Despite the common occurrence and clinical and financial impact, AKI in pediatric heart failure outside of cardiac surgery populations remains poorly studied and there are no large-scale pediatric specific preventive or therapeutic studies to date. This article will review pediatric aspects of the cardiorenal syndrome in terms of pathophysiology, clinical impact and treatment options. PMID- 26585037 TI - Hemodynamic Monitoring in the Acute Management of Pediatric Heart Failure. AB - One of the basic tenets of cardiac critical care is to ensure adequate tissue oxygenation. As with other critical illness such as trauma and acute myocardial infarction studies have demonstrated that making the right diagnosis at the right time improves outcomes. The same is true for the management of patients at risk for or in a state of shock. In order to optimize outcomes an accurate and timely assessment of cardiac function, cardiac output and tissue oxygenation must be made. This review discusses the limitations of the standard assessment of cardiovascular function, and adjunctive monitoring modalities that may be used to enhance the accuracy and timely implementation of therapeutic strategies to improve tissue oxygenation. PMID- 26585038 TI - Cardiopulmonary Interactions in Children with Heart Failure. AB - Cardiopulmonary interactions are present but inconsequential in humans with normal cardiac and respiratory function; however, in the presence of significant impairment in either system, the importance of the interplay between cardiovascular and pulmonary systems cannot be overstated. This review will discuss the physiologic underpinnings and consequences of these interactions in patients with heart failure. PMID- 26585039 TI - Management of the Low Cardiac Output Syndrome Following Surgery for Congenital Heart Disease. AB - The purpose of this review is to discuss the management of the low cardiac output syndrome (LCOS) following surgery for congenital heart disease. The LCOS is a well-recognized, frequent post-operative complication with an accepted collection of hemodynamic and physiologic aberrations. Approximately 25% of children experience a decrease in cardiac index of less than 2 L/min/m2 within 6-18 hours after cardiac surgery. Post-operative strategies that may be used to manage patients as risk for or in a state of low cardiac output include the use of hemodynamic monitoring, enabling a timely and accurate assessment of cardiovascular function and tissue oxygenation; optimization of ventricular loading conditions; the judicious use of inotropic agents; an appreciation of and the utilization of positive pressure ventilation for circulatory support; and, in some circumstances, mechanical circulatory support. All interventions and strategies should culminate in improving the relationship between oxygen supply and demand, ensuring adequate tissue oxygenation. PMID- 26585040 TI - The Pathophysiology of Heart Failure in Children: The Basics. AB - Few data exist on the pathophysiologic changes in pediatric heart failure. Most of the knowledge has evolved from animal models of ischemic or idiopathic dilated cardiomyopathy. This review addresses the pathophysiologic changes that occur in the failing heart from animal models and the adult experience to unique aspects of heart failure in children. PMID- 26585041 TI - Hepatitis B virus spliced variants are associated with an impaired response to interferon therapy. AB - During hepatitis B virus (HBV) replication, spliced HBV genomes and splice generated proteins have been widely described, however, their biological and clinical significance remains to be defined. Here, an elevation of the proportion of HBV spliced variants in the sera of patients with chronic hepatitis B (CHB) is shown to correlate with an impaired respond to interferon-alpha (IFN-alpha) therapy. Transfection of the constructs encoding the three most dominant species of spliced variants into cells or ectopic expression of the two major spliced protein including HBSP and N-terminal-truncated viral polymerase protein result in strong suppression of IFN-alpha signaling transduction, while mutation of the major splicing-related sites of HBV attenuates the viral anti-IFN activities in both cell and mouse models. These results have associated the productions of HBV spliced variants with the failure response to IFN therapy and illuminate a novel mechanism where spliced viral products are employed to resist IFN-mediated host defense. PMID- 26585042 TI - Distinctive effect on nerve growth factor-induced PC12 cell neurite outgrowth by two unique neolignan enantiomers from Illicium merrillianum. AB - Merrillianoid (1), a racemic neolignan possessing the characteristic benzo-2,7 dioxabicyclo[3.2.1]octane moiety, was isolated from the branches and leaves of Illicium merrillianum. Chiral separation of 1 gave two enantiomers (+)-1 and (-) 1. The structure of 1 was established by comprehensive spectroscopic analysis and single crystal X-ray diffraction. The absolute configurations of enantiomers were determined by quantum mechanical calculation. Compound (+)-1 exhibited a better neurotrophic activity than racemate 1 by promoting nerve growth factor (NGF) induced PC12 cell neurite outgrowth, while (-)-1 showed a distinctive inhibitory effect. Furthermore, a mechanism study indicated that the two enantiomers influenced NGF-induced neurite outgrowth of PC12 cells possibly by interacting with the trkA receptor, and extracellular signal regulated kinases 1/2 (ERK1/2) and mitogen-activated protein kinase (MEK) in Ras/ERK signal cascade. But the phosphorylation level of serine/threonine kinase Akt1 and Akt2 in PI3K/Akt signal pathway showed no significant difference between (+)-1 and (-)-1. PMID- 26585043 TI - Long-term upregulation of cortical glutamatergic AMPA receptors in a mouse model of chronic visceral pain. AB - BACKGROUND: Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal disorders and it causes long-lasting visceral pain and discomfort. AMPA receptor mediated long-term potentiation (LTP) has been shown to play a critical role in animal models of neuropathic and inflammatory pain. No report is available for central changes in the ACC of mice with chronic visceral pain. RESULTS: In this study, we used integrative methods to investigate potential central plastic changes in the anterior cingulate cortex (ACC) of a visceral pain mouse model induced by intracolonic injection of zymosan. We found that visceral pain induced an increased expression of AMPA receptors (at the post synapses) in the ACC via an enhanced trafficking of the AMPA receptors to the membrane. Both GluA1 and GluA2/3 subunits were significantly increased. Supporting biochemical changes, excitatory synaptic transmission in the ACC were also significantly enhanced. Microinjection of AMPA receptor inhibitor IEM1460 into the ACC inhibited visceral and spontaneous pain behaviors. Furthermore, we found that the phosphorylation of GluA1 at the Ser845 site was increased, suggesting that GluA1 phosphorylation may contribute to AMPA receptor trafficking. Using genetically knockout mice lacking calcium-calmodulin stimulated adenylyl cyclase subtype 1 (AC1), we found that AMPA receptor phosphorylation and its membrane trafficking induced by zymosan injection were completely blocked. CONCLUSIONS: Our results provide direct evidence for cortical AMPA receptors to contribute to zymosan-induced visceral and spontaneous pain and inhibition of AC1 activity may help to reduce chronic visceral pain. PMID- 26585044 TI - A Randomized Controlled Trial of a Telephone Intervention for Alcohol Misuse With Injured Emergency Department Patients. AB - STUDY OBJECTIVE: We conduct a randomized controlled trial to test efficacy of a telephone intervention for injured emergency department (ED) patients with alcohol misuse to decrease alcohol use, impaired driving, alcohol-related injuries, and alcohol-related negative consequences. METHODS: ED patients screening positive for alcohol misuse were randomized to a 3-session telephone brief motivational intervention on alcohol, delivered by a counselor trained in motivational interviewing during 6 weeks, or a control intervention of a scripted home fire and burn safety education delivered in 3 calls. Patients were followed for 12 months and assessed for changes in alcohol use, impaired driving, alcohol related injuries, and alcohol-related negative consequences. RESULTS: Seven hundred thirty ED patients were randomized; 78% received their assigned intervention by telephone, and of those, 72% completed 12-month assessments. There were no differential benefits of telephone brief motivational intervention versus assessment and a control intervention in all 3 variables of alcohol use (frequency of binge alcohol use during the previous 30 days, maximum number of drinks at one time in the past 30 days, and typical alcohol use in the past 30 days), alcohol-impaired driving, alcohol-related injuries, and alcohol-related negative consequences. CONCLUSION: Despite the potential advantage of delivering a telephone brief motivational intervention in not disrupting ED clinical care, our study found no efficacy for it over an assessment and control intervention. Potential causes for our finding include that injury itself, alcohol assessments, or the control intervention had active ingredients for alcohol change. PMID- 26585045 TI - Effect of Decreasing County Mental Health Services on the Emergency Department. AB - STUDY OBJECTIVE: We evaluate the effect of decreasing county mental health services on the emergency department (ED). METHODS: This is a retrospective before-and-after study at a Level I academic university hospital adjacent to the county mental health treatment center. On October 1, 2009, the county decreased its inpatient psychiatric unit from 100 to 50 beds and closed its outpatient unit. Electronic health record data were collected for ED visits for the 8 months before the decrease in county services (October 2008 to May 2009) and the 8 months after the decrease (October 2009 to May 2010). Data for all adult patients (>=18 years) evaluated for a psychiatric consultation by a licensed clinical social worker were included. Outcome measures included the number of patients evaluated and the ED length of stay for those patients. RESULTS: One thousand three hundred ninety-two patient visits included a psychiatry consultation for the study period. The median age was 38 years (interquartile range [IQR] 27, 49), with no difference in age between periods. The mean number of daily psychiatry consultations increased from 1.3 (95% confidence interval [CI] 1.2 to 1.5) before closure to 4.4 (95% CI 4.1 to 4.7) afterward, with a difference in means of 3.0 visits (95% CI 2.7 to 3.3 visits). Average ED length of stay for psychiatry consultation patients was 14.1 hours (95% CI 13.1 to 15.0 hours) before closure and 21.9 hours (95% CI 20.7 to 23.2 hours) afterward, with a difference in means of 7.9 hours (95% CI 5.5 to 10.2 hours). CONCLUSION: The number of visits and length of stay for patients undergoing psychiatric consultation in the ED increased significantly after a decrease in county mental health services. This phenomenon has important implications for future policy to address the challenges of caring for patients with psychiatric needs in our communities. PMID- 26585046 TI - Can You Multitask? Evidence and Limitations of Task Switching and Multitasking in Emergency Medicine. AB - Emergency physicians work in a fast-paced environment that is characterized by frequent interruptions and the expectation that they will perform multiple tasks efficiently and without error while maintaining oversight of the entire emergency department. However, there is a lack of definition and understanding of the behaviors that constitute effective task switching and multitasking, as well as how to improve these skills. This article reviews the literature on task switching and multitasking in a variety of disciplines-including cognitive science, human factors engineering, business, and medicine-to define and describe the successful performance of task switching and multitasking in emergency medicine. Multitasking, defined as the performance of two tasks simultaneously, is not possible except when behaviors become completely automatic; instead, physicians rapidly switch between small tasks. This task switching causes disruption in the primary task and may contribute to error. A framework is described to enhance the understanding and practice of these behaviors. PMID- 26585047 TI - Type 2 diabetes mellitus as a disorder of galanin resistance. AB - The increasing prevalence of type 2 diabetes mellitus with its high morbidity and mortality becomes an important health problem. The multifactorial etiology of type 2 diabetes mellitus is relative to many gene and molecule alterations, and increased insulin resistance. Besides these, however, there are still other predisposing and risk factors accounting for type 2 diabetes mellitus not to be identified and recognized. Emerging evidence indicated that defects in galanin function played a crucial role in development of type 2 diabetes mellitus. Galanin homeostasis is tightly relative to insulin resistance and is regulated by blood glucose. Hyperglycemia, hyperinsulinism, enhanced plasma galanin levels and decreased galanin receptor activities are some of the characters of type 2 diabetes mellitus. The discrepancy between high insulin level and low glucose handling is named as insulin resistance. Similarly, the discrepancy between high galanin level and low glucose handling may be denominated as galanin resistance too. In this review, the characteristic milestones of type 2 diabetes mellitus were condensed as two analogical conceptual models, obesity-hyper-insulin-insulin resistance-type 2 diabetes mellitus and obesity-hyper-galanin-galanin resistance type 2 diabetes mellitus. Both galanin resistance and insulin resistance are correlative with each other. Conceptualizing the etiology of type 2 diabetes mellitus as a disorder of galanin resistance may inspire a new concept to deepen our knowledge about pathogenesis of type 2 diabetes mellitus, eventually leading to novel preventive and therapeutic interventions for type 2 diabetes mellitus. PMID- 26585048 TI - Linking CSF and cognition in Alzheimer's disease: Reanalysis of clinical data. AB - OBJECTIVES: Memory and executive deficits are important cognitive markers of Alzheimer's disease (AD). Moreover, in the past decade, cerebrospinal fluid (CSF) biomarkers have been increasingly utilized in clinical practice. Both cognitive and CSF markers can be used to differentiate between AD patients and healthy seniors with high diagnostic accuracy. However, the extent to which performance on specific mnemonic or executive tasks enables reliable estimations of the concentrations of different CSF markers and their ratios remains unclear. METHODS: To address the above issues, we examined the association between neuropsychological data and CSF biomarkers in 51 AD patients using hierarchical multiple regression analyses. In the first step of these analyses, age, education and sex were entered as predictors to control for possible confounding effects. In the second step, data from a neuropsychological test battery assessing episodic memory, semantic memory and executive functioning were included to determine whether these variables significantly increased (compared to step 1) the explained variance in Abeta42 concentration, p-tau concentration, t-tau concentration, Abeta42/t-tau ratio, and Abeta42/Abeta40 ratio. RESULTS: The different models explained 52% of the variance in Abeta42/t-tau ratio, 27% of the variance in Abeta42 concentration, and 28% of the variance in t-tau concentration. In particular, Abeta42/t-tau ratio was associated with verbal recognition and code shifting, with Abeta42 being related to verbal recognition and t-tau being related to code shifting. By contrast, the inclusion of neuropsychological data did not allow reliable estimations of Abeta42/Abeta40 ratio or p-tau concentration. CONCLUSION: Our results showed that strong associations exist between the cognitive key symptoms of AD and the concentrations and ratios of specific CSF markers. In addition, we revealed a specific combination of neuropsychological tests that may facilitate reliable estimations of CSF concentrations, thereby providing important diagnostic information for non-invasive early AD detection. PMID- 26585049 TI - Sex of Sexual Partners and Human Papillomavirus Vaccination Among U.S. Girls and Women. AB - INTRODUCTION: Girls and women are at risk of human papillomavirus (HPV) infection and cervical cancer from male and female sexual partners throughout the life course. However, no study has assessed how sex of sexual partners, a dimension of sexual orientation, may relate to HPV vaccination among girls and women. METHODS: In 2014, data from the 2006-2010 National Survey of Family Growth were used to conduct logistic regression analyses estimating the relationship between sex of lifetime and past-year sexual partners and HPV vaccine awareness and initiation among U.S. girls and women aged 15-25 years (N=3,253). RESULTS: Among U.S. girls and women aged 15-25 years, the prevalence of HPV vaccine awareness and HPV vaccine initiation was 84.4% and 28.5%, respectively. Adjusting for sociodemographic factors, participants with only female past-year sexual partners had significantly lower odds of initiating HPV vaccination relative to those with only male past-year sexual partners (OR=0.16, 95% CI=0.05, 0.55). Similarly, respondents with no lifetime (OR=0.65, 95% CI=0.46, 0.92) or past-year (OR=0.69, 95% CI=0.50, 0.94) sexual partners had significantly lower adjusted odds of HPV vaccine initiation compared with those with only male sexual partners. No difference was apparent in the odds of initiating HPV vaccination between participants with male and female sexual partners and those with only male sexual partners. CONCLUSIONS: Medical and public health professionals should ensure that girls and women with only female or no sexual partners are included in HPV vaccine education and promotion efforts. PMID- 26585050 TI - Low Muscle Strength Thresholds for the Detection of Cardiometabolic Risk in Adolescents. AB - INTRODUCTION: There is an association between strength and health among adolescents, yet, what remains to be determined is sex-specific cut points for low strength in the detection of risk in this population. The purpose of this study was to determine thresholds of low grip strength in a large cohort (N=1,326) of adolescents. METHODS: All data were collected between 2005 and 2008, and analyzed in 2014-2015. A cardiometabolic risk score (MetScore) was computed from the following components: percent body fat, fasting glucose, blood pressure, plasma triglyceride levels, and high-density lipoprotein cholesterol. A high-risk cardiometabolic phenotype was characterized as >=75th percentile of the MetScore. Conditional inference tree analyses were used to identify sex-specific, low normalized strength (grip strength/body mass) thresholds and risk categories. RESULTS: Lower strength was independently associated with increased odds of the high-risk cardiometabolic phenotype, such that for every 5% decrement of normalized strength, there were 1.48 and 1.45 increased odds (p<0.001) for boys and girls, even after adjusting for cardiorespiratory fitness and physical activity. Conditional tree analysis revealed a high-risk threshold for boys (<=0.33) and girls (<=0.28), as well as an intermediate threshold (boys, >0.33 and <=0.45; girls, >0.28 and <=0.36). CONCLUSIONS: These sex-specific thresholds of low strength can be incorporated into a clinical setting for identifying adolescents that would benefit from lifestyle interventions to improve muscular fitness and reduce cardiometabolic risk. PMID- 26585051 TI - Impact of New Transport Infrastructure on Walking, Cycling, and Physical Activity. AB - INTRODUCTION: Walking and cycling bring health and environmental benefits, but there is little robust evidence that changing the built environment promotes these activities in populations. This study evaluated the effects of new transport infrastructure on active commuting and physical activity. STUDY DESIGN: Quasi-experimental analysis nested within a cohort study. SETTING/PARTICIPANTS: Four hundred and sixty-nine adult commuters, recruited through a predominantly workplace-based strategy, who lived within 30 kilometers of Cambridge, United Kingdom and worked in areas of the city to be served by the new transport infrastructure. INTERVENTION: The Cambridgeshire Guided Busway opened in 2011 and comprised a new bus network and a traffic-free walking and cycling route. Exposure to the intervention was defined using the shortest distance from each participant's home to the busway. MAIN OUTCOME MEASURES: Change in weekly time spent in active commuting between 2009 and 2012, measured by validated 7-day recall instrument. Secondary outcomes were changes in total weekly time spent walking and cycling and in recreational and overall physical activity, measured using the validated Recent Physical Activity Questionnaire. Data were analyzed in 2014. RESULTS: In multivariable multinomial regression models--adjusted for potential sociodemographic, geographic, health, and workplace confounders; baseline active commuting; and home or work relocation-exposure to the busway was associated with a significantly greater likelihood of an increase in weekly cycle commuting time (relative risk ratio=1.34, 95% CI=1.03, 1.76) and with an increase in overall time spent in active commuting among the least active commuters at baseline (relative risk ratio=1.76, 95% CI=1.16, 2.67). The study found no evidence of changes in recreational or overall physical activity. CONCLUSIONS: Providing new sustainable transport infrastructure was effective in promoting an increase in active commuting. These findings provide new evidence to support reconfiguring transport systems as part of public health improvement strategies. PMID- 26585052 TI - Child Care Center Characteristics Associated With Preschoolers' Physical Activity. AB - INTRODUCTION: Despite children spending long hours in child care centers, it is unknown what center characteristics are associated with children's moderate to vigorous physical activity (MVPA) at the center and over the 24-hour day. METHODS: Mixed model ANOVA evaluated associations between 23 center characteristics (e.g., policies, facilities, practices, and staff training) and time in MVPA, measured with accelerometers, at the child care center and over the 24-hour day among 388 preschoolers from 30 randomly selected child care centers in Cincinnati, Ohio. Data collection occurred from November 2009 through January 2011; data analyses occurred in 2012-2014. RESULTS: Ninety percent of centers reported scheduling two or more outdoor sessions daily, yet only 40% of children had two or more outdoor sessions; 32% had no time outdoors. Eighty-three percent of centers reported scheduling >=60 minutes outdoors; 28% of children experienced this during observation. Children spent a mean (SE) of 2.0 (0.06) minutes/hour in MVPA. Children with >=60 minutes outdoor time had 0.6 minutes/hour more MVPA in child care (p=0.001), and 0.5 minutes/hour over the 24-hour day (p=0.001) than those who did not. Presence of an indoor play space, large outdoor playground, portable or fixed play equipment, staff PA training, weather and clothing policies, and TV/computer use were not related to children's MVPA. CONCLUSIONS: Outdoor time occurred less frequently than scheduled. Children with >=60 minutes of outdoor time at the center were more active than children without. Centers may increase preschoolers' PA by adhering to the scheduled >=60 minutes of outdoor time daily. PMID- 26585053 TI - Mortality of Youth Offenders Along a Continuum of Justice System Involvement. AB - INTRODUCTION: Black male youth are at high risk of homicide and criminal justice involvement. This study aimed to determine how early mortality among youth offenders varies based on race; gender; and the continuum of justice system involvement: arrest, detention, incarceration, and transfer to adult courts. METHODS: Criminal and death records of 49,479 youth offenders (ages 10-18 years at first arrest) in Marion County, Indiana, from January 1, 1999, to December 31, 2011, were examined. Statistical analyses were completed in November 2014. RESULTS: From 1999 to 2011 (aggregate exposure, 386,709 person-years), 518 youth offender deaths occurred. The most common cause of death was homicide (48.2%). The mortality rate of youth offenders was nearly 1.5 times greater than that among community youth (standardized mortality ratio, 1.48). The youth offender mortality rate varied depending on the severity of justice system involvement. Arrested youth had the lowest rate of mortality (90/100,000), followed by detained youth (165/100,000); incarcerated youth (216/100,000); and youth transferred to adult court (313/100,000). A proportional hazards model demonstrated that older age, male gender, and more severe justice system involvement 5 years post-arrest predicted shorter time to mortality. CONCLUSIONS: Youth offenders face greater risk for early death than community youth. Among these, black male youth face higher risk of early mortality than their white male counterparts. However, regardless of race/ethnicity, mortality rates for youth offenders increase as youth involvement in the justice system becomes more protracted and severe. Thus, justice system involvement is a significant factor to target for intervention. PMID- 26585054 TI - Malignant cerebral edema following cranioplasty. AB - Malignant cerebral edema following cranioplasty is a very rare and devastating complication. We present a case of postoperative death following cranioplasty due to malignant cerebral edema. Similar cases and possible pathogenesis are discussed. This fearsome complication should be discussed with the patients and their families as part of the informed consent procedure. PMID- 26585055 TI - Detection of Cyclooxygenase-1 in Activated Microglia During Amyloid Plaque Progression: PET Studies in Alzheimer's Disease Model Mice. AB - Cyclooxygenase (COX), a prostanoid-synthesizing enzyme, is considered to be involved in the neuroinflammatory process of neurodegenerative diseases. However, the role of COX in the progression of neurodegeneration is not well understood. We hypothesized that in vivo imaging of COX by PET will contribute to elucidation of the function of COX during the neurodegenerative process in Alzheimer's disease (AD). (11)C-labeled ketoprofen methyl ester (racemic (RS)-(11)C-KTP-Me) developed recently by our group is a useful PET probe for in vivo imaging of COX 1 during neuroinflammation. The (S)-enantiomer of ketoprofen is known to be pharmacologically more active than the (R)-enantiomer. We thus synthesized (11)C labeled (S)-ketoprofen methyl ester ((S)-(11)C-KTP-Me) as an improved PET probe specific for COX-1 and applied it for investigation of the changes in COX-1 during the progression of AD in a mouse model. METHODS: The specificity of (S) (11)C-KTP-Me for COXs was examined in PET studies with rats that had intrastriatal injection of lipopolysaccharide. To determine the details of changes in COX-1 during progression of amyloid-beta (Abeta) plaque formation in amyloid precursor protein transgenic (APP-Tg) mice, we performed immunohistochemical studies and ex vivo autoradiography with (S)-(11)C-KTP-Me. RESULTS: PET studies using hemispheric lipopolysaccharide injection into rats revealed that the sensitivity of (S)-(11)C-KTP-Me in neuroinflammation was much higher than that of (RS)-(11)C-KTP-Me and (R)-(11)C-KTP-Me; these results closely corresponded to the inhibitory activities of each enantiomer against COX-1 estimated by an in vitro assay. In APP-Tg mice, (S)-(11)C-KTP-Me administration resulted in progressive and significant increases in accumulation of radioactivity in the brain from 16 to 24 mo old in accordance with the histopathologic appearance of abundant Abeta plaques and activated microglia, whereas few changes in radioactivity accumulation and few Abeta plaques were seen in age-matched wild-type control mice. High-radioactivity accumulation by (S) (11)C-KTP-Me was markedly observed in the frontal cortex and hippocampus in which COX-1-expressing activated microglia tightly surrounded and enclosed large and more intensely stained Abeta plaques, indicating neuroinflammation that originated with Abeta. CONCLUSION: (S)-(11)C-KTP-Me is a potent PET probe that is highly selective for COX-1. Studies using APP-Tg mice demonstrated that (S)-(11)C KTP-Me could detect activated microglia that are associated with amyloid plaque progression, suggesting the involvement of COX-1 in the neuroinflammatory process in AD. PMID- 26585056 TI - Visual Versus Fully Automated Analyses of 18F-FDG and Amyloid PET for Prediction of Dementia Due to Alzheimer Disease in Mild Cognitive Impairment. AB - Biomarkers of Alzheimer disease (AD) can be imaged in vivo and can be used for diagnostic and prognostic purposes in people with cognitive decline and dementia. Indicators of amyloid deposition such as (11)C-Pittsburgh compound B ((11)C-PiB) PET are primarily used to identify or rule out brain diseases that are associated with amyloid pathology but have also been deployed to forecast the clinical course. Indicators of neuronal metabolism including (18)F-FDG PET demonstrate the localization and severity of neuronal dysfunction and are valuable for differential diagnosis and for predicting the progression from mild cognitive impairment (MCI) to dementia. It is a matter of debate whether to analyze these images visually or using automated techniques. Therefore, we compared the usefulness of both imaging methods and both analyzing strategies to predict dementia due to AD. METHODS: In MCI participants, a baseline examination, including clinical and imaging assessments, and a clinical follow-up examination after a planned interval of 24 mo were performed. RESULTS: Of 28 MCI patients, 9 developed dementia due to AD, 2 developed frontotemporal dementia, and 1 developed moderate dementia of unknown etiology. The positive and negative predictive values and the accuracy of visual and fully automated analyses of (11)C-PiB for the prediction of progression to dementia due to AD were 0.50, 1.00, and 0.68, respectively, for the visual and 0.53, 1.00, and 0.71, respectively, for the automated analyses. Positive predictive value, negative predictive value, and accuracy of fully automated analyses of (18)F-FDG PET were 0.37, 0.78, and 0.50, respectively. Results of visual analyses were highly variable between raters but were superior to automated analyses. CONCLUSION: Both (18)F-FDG and (11)C-PiB imaging appear to be of limited use for predicting the progression from MCI to dementia due to AD in short-term follow-up, irrespective of the strategy of analysis. On the other hand, amyloid PET is extremely useful to rule out underlying AD. The findings of the present study favor a fully automated method of analysis for (11)C-PiB assessments and a visual analysis by experts for (18)F-FDG assessments. PMID- 26585057 TI - In Vivo and In Vitro Characterization of a Novel MAO-B Inhibitor Radioligand, 18F Labeled Deuterated Fluorodeprenyl. AB - The aim of this study was to radiolabel a novel bis-deuterium substituted l deprenyl analog (fluorodeprenyl-D2) with (18)F and to evaluate its potential to visualize and quantify monoamine oxidase (MAO) B activity in vivo. METHODS: The precursor compound ( 5A: + 5B: ) and reference standard ( 6: ) were synthesized in multistep syntheses. Recombinant human MAO-B and MAO-A enzyme preparations were used to determine inhibitory concentrations of 50%. Radiolabeling was accomplished by a nucleophilic substitution reaction. Whole-hemisphere autoradiography was performed with (18)F-fluorodeprenyl-D2. A PET study was performed on a cynomolgus monkey. Radiometabolites were measured in monkey plasma using high-performance liquid chromatography. RESULTS: The 50% inhibitory concentration of compound 6 for MAO-B was 227 +/- 36.8 nM. Radiolabeling was accomplished with high radiochemical yield, purity, and specific radioactivity. The autoradiography binding density of (18)F-fluorodeprenyl-D2 was consistent with known MAO-B expression in the human brain. In vivo, (18)F-fluorodeprenyl-D2 showed favorable kinetic properties, with relatively fast washout from the brain. Regional time-activity curves were better described by the 2-tissue-compartment model. Administration of a 1 mg/kg dose of l-deprenyl yielded 70% inhibition of MAO-B in all regions. Radiometabolite studies demonstrated 20% unchanged radioligand at 120 min after injection. (18)F-fluorodeprenyl-D2 showed less irreversibility than did previously reported MAO-B radioligands. CONCLUSION: The results suggest that (18)F-fluorodeprenyl-D2 is a suitable PET radioligand for visualization of MAO-B activity in the human brain. PMID- 26585058 TI - Imaging the Impact of the P-Glycoprotein (ABCB1) Function on the Brain Kinetics of Metoclopramide. AB - The effects of metoclopramide on the central nervous system (CNS) in patients suggest substantial brain distribution. Previous data suggest that metoclopramide brain kinetics may nonetheless be controlled by ATP-binding cassette (ABC) transporters expressed at the blood-brain barrier. We used (11)C-metoclopramide PET imaging to elucidate the kinetic impact of transporter function on metoclopramide exposure to the brain. METHODS: (11)C-metoclopramide transport by P-glycoprotein (P-gp; ABCB1) and the breast cancer resistance protein (BCRP; ABCG2) was tested using uptake assays in cells overexpressing P-gp and BCRP. (11)C-metoclopramide brain kinetics were compared using PET in rats (n = 4-5) in the absence and presence of a pharmacologic dose of metoclopramide (3 mg/kg), with or without P-gp inhibition using intravenous tariquidar (8 mg/kg). The (11)C metoclopramide brain distribution (VT based on Logan plot analysis) and brain kinetics (2-tissue-compartment model) were characterized with either a measured or an imaged-derived input function. Plasma and brain radiometabolites were studied using radio-high-performance liquid chromatography analysis. RESULTS: (11)C-metoclopramide transport was selective for P-gp over BCRP. Pharmacologic dose did not affect baseline (11)C-metoclopramide brain kinetics (VT = 2.28 +/- 0.32 and 2.04 +/- 0.19 mL?cm(-3) using microdose and pharmacologic dose, respectively). Tariquidar significantly enhanced microdose (11)C-metoclopramide VT (7.80 +/- 1.43 mL?cm(-3)) with a 4.4-fold increase in K1 (influx rate constant) and a 2.3-fold increase in binding potential (k3/k4) in the 2-tissue compartment model. In the pharmacologic situation, P-gp inhibition significantly increased metoclopramide brain distribution (VT = 6.28 +/- 0.48 mL?cm(-3)) with a 2.0-fold increase in K1 and a 2.2-fold decrease in k2 (efflux rate), with no significant impact on binding potential. In this situation, only parent (11)C metoclopramide could be detected in the brains of P-gp-inhibited rats. CONCLUSION: (11)C-metoclopramide benefits from favorable pharmacokinetic properties that offer reliable quantification of P-gp function at the blood-brain barrier in a pharmacologic situation. Using metoclopramide as a model of CNS drug, we demonstrated that P-gp function not only reduces influx but also mediates the efflux from the brain back to the blood compartment, with additional impact on brain distribution. This PET-based strategy of P-gp function investigation may provide new insight on the contribution of P-gp to the variability of response to CNS drugs between patients. PMID- 26585059 TI - Based on the Network Degeneration Hypothesis: Separating Individual Patients with Different Neurodegenerative Syndromes in a Preliminary Hybrid PET/MR Study. AB - The network degeneration hypothesis (NDH) of neurodegenerative syndromes suggests that pathologic brain changes distribute primarily along distinct brain networks, which are characteristic for different syndromes. Brain changes of neurodegenerative syndromes can be characterized in vivo by different imaging modalities. Our aim was to test the hypothesis whether multimodal imaging based on the NDH separates individual patients with different neurodegenerative syndromes. METHODS: Twenty patients with Alzheimer disease (AD) and 20 patients with frontotemporal lobar degeneration (behavioral variant frontotemporal dementia [bvFTD, n = 11], semantic dementia [SD, n = 4], or progressive nonfluent aphasia [PNFA, n = 5]) underwent simultaneous MRI and (18)F-FDG PET in a hybrid PET/MR scanner. The 3 outcome measures were voxelwise values of degree centrality as a surrogate for regional functional connectivity, glucose metabolism as a surrogate for regional metabolism, and volumetric-based morphometry as a surrogate for regional gray matter volume. Outcome measures were derived from predefined core regions of 4 intrinsic networks based on the NDH, which have been demonstrated to be characteristic for AD, bvFTD, SD, and PNFA, respectively. Subsequently, we applied support vector machine to classify individual patients via combined imaging measures, and results were evaluated by leave-one-out cross validation. RESULTS: On the basis of multimodal voxelwise regional patterns, classification accuracies for separating patients with different neurodegenerative syndromes were 77.5% for AD versus others, 82.5% for bvFTD versus others, 97.5% for SD versus others, and 87.5% for PNFA versus others. Multimodal classification results were significantly superior to unimodal approaches. CONCLUSION: Our finding provides initial evidence that the combination of regional metabolism, functional connectivity, and gray matter volume, which were derived from disease characteristic networks, separates individual patients with different neurodegenerative syndromes. Preliminary results suggest that employing multimodal imaging guided by the NDH may generate promising biomarkers of neurodegenerative syndromes. PMID- 26585060 TI - Genetic and Environmental Influences on Regional Brain Uptake of 18F-FDG: A PET Study on Monozygotic and Dizygotic Twins. AB - Genetic or environmental influences on cerebral glucose metabolism are unknown. We attempted to reveal these influences in elderly twins by means of (18)F-FDG PET. METHODS: (18)F-FDG uptake was studied in 40 monozygotic and 18 dizygotic volunteer twin pairs aged 30 y or over. We also created 18 control pairs by pairing age- and sex-matched genetically unrelated subjects from dizygotic and monozygotic pairs. SUV images of the brain were reconstructed and analyzed by voxel-based statistical analysis with automated region-of-interest setting. The (18)F-FDG uptake in each cerebral lobe was semiquantified by taking a ratio of SUVmean in each region of interest to whole-brain SUVaverage. We calculated an intraclass correlation coefficient of SUV ratio in each region of interest for monozygotic and dizygotic pairs. By comparing differences in coefficients between monozygotic and dizygotic pairs, genetic and environmental contributions were estimated. RESULTS: The intraclass correlation coefficient in monozygotic pairs was significantly higher than that in dizygotic pairs in the parietal lobes bilaterally (P < 0.001) and in the left temporal lobe (P < 0.05) but was not significantly different in other lobes. CONCLUSION: The present study indicated that in the right and left parietal lobes and left temporal lobe, cerebral glucose metabolism is influenced more by genetics than by environment, whereas in other brain regions the influence of environment is dominant. PMID- 26585061 TI - 64Cu-ATSM Reflects pO2 Levels in Human Head and Neck Cancer Xenografts but Not in Colorectal Cancer Xenografts: Comparison with 64CuCl2. AB - The hypoxia PET tracer (64)Cu-diacetyl-bis(N(4)-methylthiosemicarbazonate) ((64)Cu-ATSM) has shown promising results in clinical studies. However, concerns have been raised with regard to the possible effect of copper metabolism and free copper on tumor uptake and thereby the robustness of (64)Cu-ATSM as a hypoxia marker. In this study, accumulation and distribution of (64)Cu-ATSM and (64)CuCl2 in tumor tissue were compared with partial pressure of oxygen (pO2) probe measurements. METHODS: One-hour dynamic PET scans were performed on nude mice bearing subcutaneous human head and neck tumors (FaDu) and human colorectal tumors (HT29) after administration of either (64)Cu-ATSM or (64)CuCl2. Subsequently, tracks were generated and track markers were positioned in tumors to allow for registration of their exact location on the high-resolution CT scan. After completion of the CT scan, pO2 probe measurements were performed along each track. PET and CT images were coregistered and ROIs drawn on the basis of the location of track markers and pO2 probe measurement depth. A linear mixed model for repeated measures was applied for the comparison of PET tracer uptake to corresponding pO2 values. RESULTS: Comparable uptake of (64)Cu-ATSM and (64)CuCl2 was found in the kidney, muscle, and liver of all animals, but (64)CuCl2 showed a higher uptake 10-60 min after injection in both tumor models. Significant differences were also found for both tumor-to-muscle and tumor-to-liver ratios. The intratumoral distribution of (64)Cu-ATSM, but not (64)CuCl2, showed a significant negative relationship with pO2 measurements in FaDu tumors. However, this relationship was not found in HT29 tumors. CONCLUSION: (64)Cu-ATSM and (64)CuCl2 displayed different uptake in tumors. In human head and neck xenografts, (64)Cu-ATSM but not (64)CuCl2 reflected pO2 measurements, indicating that (64)Cu-ATSM is a hypoxia-specific marker in this tumor type. However, data from colorectal cancer xenografts indicated that (64)Cu-ATSM may not be a hypoxia marker in all tumor types. PMID- 26585062 TI - 68Ga-PSMA-HBED-CC PET for Differential Diagnosis of Suggestive Lung Lesions in Patients with Prostate Cancer. AB - In prostate cancer (PC) patients, the differentiation between lung metastases and lesions of different origin, for example, primary lung cancer, is a common clinical question. Herein, we investigated the use of Glu-NH-CO-NH-Lys(Ahx)-HBED CC ((68)Ga-PSMA-HBED-CC) for this purpose. METHODS: PC patients (n = 1,889) undergoing (68)Ga-PSMA PET/CT or PET/MR scans were evaluated retrospectively for suggestive lung lesions. For up to 5 lesions per patient, location, CT diameter, CT morphology, and SUVmax were determined. The standard for classification was either histopathologic evaluation or, in the case of PC metastases, responsivity to antihormone therapy. A comparison of the different classes was executed by Student t test. Prostate-specific antigen and prostate-specific membrane antigen (PSMA) immunohistochemistry were performed if histologic samples were available; (68)Ga-PSMA autoradiography was performed on an exemplary case of PET-positive lung cancer. RESULTS: Eighty-nine lesions in 45 patients were identified, of which 76 were classified as PC (39 proven, 37 highly probable), 7 as primary lung cancer, and 2 as activated tuberculosis; 4 lesions remained unclear. The mean SUVmax was 4.4 +/- 3.9 for PC metastases and 5.6 +/- 1.6 for primary lung cancer (P = 0.408). Additionally, substantial differences in SUVmax intraindividually were detected. The 2 tuberculous lesions showed an SUVmax of 7.8 and 2.5. Using immunohistochemistry, we could demonstrate PSMA expression in the neovasculature of several PSMA PET-positive lung cancers as well as in tuberculous lesions from our histologic database. CONCLUSION: Quantitative (SUV) analysis of (68)Ga-PSMA PET was not able to discriminate reliably between pulmonary metastases and primary lung cancer in PC patients. The reason for the unexpectedly high tracer uptake in non-PC lesions is not completely clear. PSMA expression in neovasculature provides a possible explanation for this finding; however, other contributing factors, such as tracer binding to proteins other than PSMA, cannot be excluded at present. PMID- 26585063 TI - PET-Based Human Dosimetry of the Dimeric alphavbeta3 Integrin Ligand 68Ga-DOTA-E [c(RGDfK)]2, a Potential Tracer for Imaging Tumor Angiogenesis. AB - Peptides containing the Arg-Gly-Asp (RGD) sequence have high affinity for alphavbeta3 integrin receptors overexpressed in tumor cells. The objective of this research was to determine the biodistribution and estimate the radiation dose from (68)Ga-DOTA-E-[c(RGDfK)]2 using whole-body PET scans in humans. METHODS: Five healthy volunteers (2 women, 3 men; mean age +/- SD, 37.2 +/- 15.6 y; range, 28-65 y; mean weight, 79.2 +/- 21.0 kg; range, 64-115 kg) were included. After intravenous injection of the tracer (198.3 +/- 3.3 MBq), 3 successive whole-body (vertex to mid thigh) PET/CT scans at 3 time points (30, 60, and 120 min) were obtained on a 16-slice PET/CT scanner. The subjects did not void the bladder until the entire series of images was completed. Low-dose CT without contrast agent was used for anatomic localization and attenuation correction. OLINDA/EXM software was applied to calculate human radiation doses using the reference adult model. RESULTS: The highest uptake was in the urinary bladder, followed by the liver, kidneys, and spleen, in descending order. The critical organ was the urinary bladder wall. The mean effective doses (all subjects, men and women) were 34.1 +/- 4.9, 31.0 +/- 2.4, and 20.9 +/- 5.2 MUSv/MBq for the no-voiding, 2.5-h-voiding, and 1-h-voiding models, respectively. CONCLUSION: Of particular interest in this research was the visualization of the choroid plexus and ventricular system, which seems to be a characteristic of RGD dimeric peptides. Measured absorbed doses and effective doses are comparable to other previously reported RGD-based radiopharmaceuticals labeled with (68)Ga and (18)F. Therefore, (68)Ga-DOTA-E-[c(RGDfK)]2 can safely be used for imaging integrin alphaVbeta3 expression. PMID- 26585064 TI - WITHDRAWN: Improved therapeutic effectiveness by combining recombinant p14ARF with antisense complementary DNA of EGFR in laryngeal squamous cell carcinoma. AB - This article has been withdrawn at the request of the author(s) and/or editor. The publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 26585065 TI - Psychiatric morbidity and non-participation in breast cancer screening. AB - BACKGROUND: Organised breast cancer screening is currently one of the best strategies for early-stage breast cancer detection. However, early detection has proven challenging for women with psychiatric disease. This study aims to investigate psychiatric morbidity and non-participation in breast cancer screening. METHODS: We conducted an observational cohort study including women invited to the first organised screening round in the Central Denmark Region. Data on psychiatric diagnosis, psychoactive prescription medicine and consultation with private psychiatrists were obtained from Danish registries and assessed for a period of up to 10 years before the screening date. RESULTS: The cohort comprised 144,264 women whereof 33.0% were registered with an indication of psychiatric morbidity. We found elevated non-participation propensity among women with a psychiatric diagnosis especially for women with schizophrenia and substance abuse. Also milder psychiatric morbidity was associated with higher non participation likelihood as women who had redeemed psychoactive prescription medicine or have had minimum one consultation with a private psychiatrist were more likely not to participate. Finally, we found that the chronicity of psychiatric morbidity was associated with non-participation and that woman who had a psychiatric morbidity defined as 'persistent' had higher likelihood of non participation than women with recently active morbidity or inactive psychiatric morbidity. CONCLUSION: This study showed a strong association between psychiatric morbidity and an increased likelihood of non-participation in breast cancer screening in a health care system with universal and tax-funded health services. This knowledge may inform interventions targeting women with psychiatric morbidity as they have poorer breast cancer prognosis. PMID- 26585067 TI - 'We are dealing with it the best we can': Exploring parents' attributions regarding their child's physical disability using the 'Four Ws' framework. AB - BACKGROUND: When a child has a disability, parents' adaptation has traditionally been viewed in negative terms (e.g. grief and stress). However, recent research suggests that parents' adaptation is determined by their appraisals of their situation, both positive and negative. It would be valuable for clinicians to have a conceptual framework for exploring such cognitions. AIMS: This study aimed, first, to devise an attribution theory-based framework for understanding parental cognitions and, second, to examine its usefulness for analysing the appraisals of parents through a qualitative study. METHODS: A wide-ranging review of literature on cognitions, particularly attribution theory, was used to devise the 'Four Ws' framework: What is the problem? Who is to blame? Why did it happen? When? This was used as a scaffold to organise the data from semi-structured interviews with 36 parents of young children with physical disabilities. RESULTS: The framework proved robust, with a range of subthemes emerging through thematic analysis. Additional themes also emerged, for example, about emotions. CONCLUSION: The Four Ws framework provides a potential tool for clinicians working with parents of children with disabilities, both to guide general conversations when the child's needs are the main focus and for more in-depth clinical work with struggling parents. PMID- 26585066 TI - Establishment and Characterization of Human Germline Stem Cell Line with Unlimited Proliferation Potentials and no Tumor Formation. AB - Spermatogonial stem cells (SSCs) have significant applications in both reproductive and regenerative medicine. However, primary human SSCs are very rare, and a human SSC line has not yet been available. In this study, we have for the first time reported a stable human SSC line by stably expressing human SV40 large T antigen. RT-PCR, immunocytochemistry, and Western blots revealed that this cell line was positive for a number of human spermatogonial and SSC hallmarks, including VASA, DAZL, MAGEA4, GFRA1, RET, UCHL1, GPR125, PLZF and THY1, suggesting that these cells are human SSCs phenotypically. Proliferation analysis showed that the cell line could be expanded with significant increases of cells for 1.5 years, and high levels of PCNA, UCHL1 and SV40 were maintained for long-term culture. Transplantation assay indicated that human SSC line was able to colonize and proliferate in vivo in the recipient mice. Neither Y chromosome microdeletions of numerous genes nor tumor formation was observed in human SSC line although there was abnormal karyotype in this cell line. Collectively, we have established a human SSC line with unlimited proliferation potentials and no tumorgenesis, which could provide an abundant source of human SSCs for their mechanistic studies and translational medicine. PMID- 26585068 TI - Exploring parents' understandings of their child's journey into offending behaviours: A narrative analysis. AB - Parents are perhaps the best placed individuals to comment upon their child's life story, including early life experiences, transitions and their child's needs. However, research has rarely focussed on the views of parents of young people who have committed serious offences. This research aimed to explore parents' opinions of which factors may have led to their child becoming involved with the criminal justice system. Interviews were undertaken with six parents who were asked to narrate their child's life journey into offending behaviours. The data were then analysed using narrative analysis techniques, and a shared story was created which incorporated the main transitional stages in the children's journeys, as seen by the parents. The findings suggest that it is not just the child but the whole family who have been in a state of distress throughout the child's life. Systemic and environmental factors are argued to contribute to this distress, and the use of diagnosis for this population is critically evaluated. The research highlights a life story in which the child's and family's distress remains unheard and therefore unresolved. Clinical implications for working with this population are discussed. PMID- 26585069 TI - Adverse effects of psychological therapy: An exploratory study of practitioners' experiences from child and adolescent psychiatry. AB - The scientific knowledge about adverse effects of psychological therapies and how such effects should be detected is limited. It is possible that children and adolescents are particularly vulnerable and need specific support in order to express adverse effects. In this exploratory study, we used a qualitative approach to explore practitioners' experiences of this phenomenon. Fourteen practitioners providing psychological therapy within the Child and Adolescent Psychiatric Service were interviewed. Qualitative content analysis was applied to the data. Four overarching categories brought up by the practitioners were identified: vagueness of the concept (reflecting that the concept was novel and hard to define), psychotherapist-client interaction (encompassing aspects of the interaction possibly related to adverse effects), consequences for the young person (including a range of emotional, behavioural and social consequences) and family effects (e.g. professional complications and decreased autonomy for the parent). Professional discussions on these issues could improve psychological therapy for children and adolescents. Based on our findings and previous research, we propose three basic aspects to consider when adverse effects are detected and managed in this context: typology (form, severity and duration), aetiology (hypothesis about the causes) and perspective (adverse effects seen from the points of view of different interested parties). PMID- 26585070 TI - Antimalarials as a risk factor for elevated muscle enzymes in systemic lupus erythematosus. AB - OBJECTIVE: To investigate the relationship between antimalarials (AM) and elevated muscle enzymes in systemic lupus erythematosus (SLE). PATIENTSMETHODS: 325 lupus patients with abnormal creatine phosphokinase (CPK) for at least two consecutive clinic visits were enrolled; 54 patients on statins/fibrates (n = 43) and/or active myositis (n = 14) were excluded. The control group consisted of 1453 lupus patients with no CPK elevation during follow-up. Descriptive statistics and Cox regression analyses were performed, p < 0.05 was considered significant. RESULTS: Cases and controls did not differ regarding age at SLE diagnosis, gender ratio, or disease duration. AM use was more frequent in cases, which had more prolonged AM use. Total frequency of elevated CPK in AM users was 216/1322 (16.3%). Chloroquine was associated with a 3.3-fold, and hydroxychloroquine with a 3.1-fold, increased risk for CPK elevation. Black race was associated with higher CPK (HR = 2.941), whereas female gender was protective (HR = 0.697). 203 patients were followed for 7.3 +/- 5.6 years; 49.8% had persistent and 14.8% intermittent CPK elevation, while in 35.4% CPK was normalized. Clinical proximal muscle weakness developed in 5/203 patients. CONCLUSIONS: Chronic AM use is a potential risk factor for muscle enzyme elevation in SLE patients. CPK abnormalities persist in almost two thirds of the patients, but this remains mainly a biochemical finding, evolving to clinical myopathy in about 2.5%. PMID- 26585071 TI - Association of systemic lupus erythematosus and sleep disorders: a nationwide population-based cohort study. AB - OBJECTIVE: Using a population-based cohort study, we investigated whether sleep disorders (SDs) increase the risk of systemic lupus erythematosus (SLE). PATIENTS AND METHODS: We identified patients with SDs and a control cohort from 1998-2001 by using the Taiwan Longitudinal Health Insurance Database 2000. Two controls for each patient with an SD were selected and randomly frequency-matched according to age, gender, and index year. The follow-up person-years were estimated for the patients from the index date to SLE diagnosis, loss to follow-up, or the end of 31 December 2011. We used the Cox proportional hazards models to evaluate how SDs influence the risk of SLE after adjustments for demographic factors and comorbidities. RESULTS: A total of 144,396 subjects (48,132 SD cases and 96,264 controls) were followed for 1,477,055 person-years. The patients with SDs displayed higher incidence density rate of developing SLE than did the controls (1.03 vs. 0.46 per 10,000 person-years). After adjustment for covariates, the patients with SDs exhibited a 2.20-fold higher adjusted hazard ratio (aHR) of developing SLE than the controls (95% confidence interval (CI) = 1.44-3.36). Women exhibited a greater prevalence of SDs and SLE compared to men. Patients with SDs aged 49 years and younger exhibited a significantly increased risk of SLE compared to the controls (aHR=2.30, 95% CI = 1.33-3.98). Patients with SDs living in urban areas exhibited a significantly increased risk of SLE. CONCLUSION: This large population-based cohort study revealed that SDs increase the risk of SLE development. PMID- 26585072 TI - Primary antiphospholipid syndrome: absence of premature atherosclerosis in patients without traditional coronary artery disease risk factors. AB - OBJECTIVE: To investigate if patients with Primary Antiphospholipid Syndrome (PAPS) with venous and/or arterial thrombosis without traditional coronary artery disease (CAD) risk factors develop early atherosclerotic vascular damage. METHODS: 27 female patients with PAPS (Sidney criteria) and 27 age, body mass index (BMI), and sex matched controls were consecutively selected. Exclusion criteria were: black race, age >=55 years, traditional cardiovascular risk factors, other thrombophilias or connective tissue diseases, corticosteroids use and pregnancy. All subjects underwent Pulse Wave Velocity (PWV) and Echo-Tracking (ET), both in carotidal bed, to analyse vascular functional properties. RESULTS: Age (p = 0.92) and BMI (p = 0.91) were comparable in both groups. PAPS patients and controls had similar PWV (9.07 +/- 1.08 m/s vs 9.42 +/- 1.47 m/s, p = 0.34) as well as echo tracking parameters such as intima-media thickness (683 +/- 171 um vs 636 +/- 140 um, p = 0.52), carotideal diameter (p = 0.26), distensibility (p = 0.92), compliance coefficients (p = 0.36) and elastic modulus (p = 0.78). Patients with exclusively venous thrombosis showed lower PWV than patients with arterial thrombosis (8.55 +/- 0.70 m/s vs 9.56 +/- 0.94 m/s, p = 0.01), but no difference regarding intima-media thickness (683 +/- 171 um vs 636 +/- 140 um, p = 0.52) was observed. CONCLUSION: Patients with PAPS do not seem to be at higher risk of developing premature atherosclerosis. Patients who suffered exclusively venous thrombosis seem to be at lower risk than those with exclusively arterial events. Other studies need to confirm our findings. PMID- 26585073 TI - Orbital Compartment Syndrome: Alternative Tools to Perform a Lateral Canthotomy and Cantholysis. AB - Orbital compartment syndrome acutely threatens vision. Lateral canthotomy and cantholysis ameliorate the compartment syndrome and, to save a patient's vision, must be performed in a timely manner. This requires appropriate tools. In resource-poor settings, the straight hemostat and iris scissors that are generally used for this procedure may be unavailable. In such situations, safe alternatives include using a multitool in place of a hemostat and a #11 scalpel blade instead of the iris scissors. As when using hemostats of varying sizes, the pressure applied to the multitool must be carefully modulated. When using a scalpel blade for the lateral canthotomy, the hemostat arm remains beneath the lateral canthus as a "backstop" to protect deeper tissues. For the cantholysis, use the back of the blade to "strum" for the ligaments, reversing its direction only to cut the ligament when it is identified. PMID- 26585075 TI - Correction. PMID- 26585074 TI - Iodine supplementation of the pregnant dam alters intestinal gene expression and immunoglobulin uptake in the newborn lamb. AB - Excess iodine intake by the pregnant dam reduces lamb serum antibody concentration, specifically immunoglobulin G (IgG). An experiment was conducted to investigate the mechanisms under pinning the reduced serum IgG concentration at 24 h postpartum in the progeny of iodine supplemented dams. Forty-five mature twin bearing ewes (n=15/treatment) were allocated to one of three dietary treatments as follows: basal diet (Control); basal diet plus 26.6 mg of iodine per ewe per day as calcium iodate (CaIO3); or potassium iodide (KI). Ewes were individually housed and fed from d 119 of gestation until parturition. All lambs received colostrum at 1, 10 and 18 h postpartum via stomach tube. At 1 h postpartum lambs from the control and an iodine supplemented treatment (n=10 per treatment from control and CaIO3) were euthanised before colostrum consumption and ileal segments isolated to determine the gene expression profile of a panel of genes identified as having a role in antibody transfer. Preceding euthanasia, lambs were blood sampled for determination of serum IgG, total thyroxine and free tri-iodothyronine concentrations. Progeny of CaIO3 supplemented dams had lower tri-iodothyronine concentrations (P<0.01) at 1 h postpartum and lower serum IgG concentrations (P<0.001) at 24 h postpartum when compared with the progeny of control dams. Iodine (CaIO3) supplementation of the dam increased the relative expression (P<0.05) of the B2M, PIGR and MYC genes in the ileum of the lamb, before colostrum consumption; while the expression of THRB declined when compared with the progeny of C dams (P<0.01). In conclusion, the results of this study show that it is the actual inclusion of excess iodine in the diet of the ewe, regardless of the carrier element, that negatively affects passive transfer in the newborn lamb. This study presents novel data describing the relationship between maternal iodine nutrition and its effect on the thyroid hormone status and subsequent gene expression in the newborn lamb; which results in a failure of passive transfer and a decline in serum IgG concentration. PMID- 26585076 TI - Nurturing entrepreneurship. PMID- 26585077 TI - Better thermoelectrics through glass-like crystals. PMID- 26585083 TI - Graphene: Plasmons in moire superlattices. PMID- 26585084 TI - Spintronics: Turbulent power. PMID- 26585085 TI - Implantable electronics: A sensor web for neurons. PMID- 26585086 TI - Electrocatalysis: Powered by porphyrin packing. PMID- 26585087 TI - Material witness: Correcting errors in self-assembly. PMID- 26585088 TI - Electrical contacts to two-dimensional semiconductors. AB - The performance of electronic and optoelectronic devices based on two-dimensional layered crystals, including graphene, semiconductors of the transition metal dichalcogenide family such as molybdenum disulphide (MoS2) and tungsten diselenide (WSe2), as well as other emerging two-dimensional semiconductors such as atomically thin black phosphorus, is significantly affected by the electrical contacts that connect these materials with external circuitry. Here, we present a comprehensive treatment of the physics of such interfaces at the contact region and discuss recent progress towards realizing optimal contacts for two dimensional materials. We also discuss the requirements that must be fulfilled to realize efficient spin injection in transition metal dichalcogenides. PMID- 26585089 TI - Characterization of Lignanamides from Hemp (Cannabis sativa L.) Seed and Their Antioxidant and Acetylcholinesterase Inhibitory Activities. AB - Hemp seed is known for its content of fatty acids, proteins, and fiber, which contribute to its nutritional value. Here we studied the secondary metabolites of hemp seed aiming at identifying bioactive compounds that could contribute to its health benefits. This investigation led to the isolation of 4 new lignanamides, cannabisin M (2), cannabisin N (5), cannabisin O (8), and 3,3'-demethyl heliotropamide (10), together with 10 known lignanamides, among which 4 was identified for the first time from hemp seed. Structures were established on the basis of NMR, HR-MS, UV, and IR as well as by comparison with the literature data. Lignanamides 2, 7, and 9-14 showed good antioxidant activity, among which 7, 10, and 13 also inhibited acetylcholinesterase in vitro. The newly identified compounds in this study add to the diversity of hemp seed composition, and the bioassays implied that hemp seed, with lignanamides as nutrients, may be a good source of bioactive and protective compounds. PMID- 26585091 TI - The Effect of an Impaired Arousal on Short- and Long-Term Mortality of Elderly Patients Admitted to an Acute Geriatric Unit. AB - OBJECTIVE: Impaired arousal is associated with negative outcomes in intensive care units, but studies in acute medical wards are scanty. The study aim was to evaluate the association between impaired arousal, as measured using an ultrabrief screen, and risk of both 1- and 6-month mortality and discharge to nursing home (NH) or hospice. DESIGN: Prospective cohort study with 6-month follow-up. SETTING: An acute geriatric unit (AGU) of a university-based hospital in Northern Italy. PARTICIPANTS: All patients aged 65 years or older, admitted to the AGU between September 2012 and February 2015. MEASUREMENTS: The modified Richmond Agitation Sedation Scale (m-RASS) was used to assess patients' arousal; a score of 0 denotes normal arousal, scores ranging from +1 to +4 denote increased arousal, and scores ranging from -1 to -5 denote decreased levels. The association of m-RASS scores with 6-month mortality was assessed by a Kaplan Meier analysis. The impact of impaired arousal, defined by the m-RASS as anything other than "awake and alert," was determined using Cox proportional hazard regression for 1- and 6-month mortality after admission and logistic regressions were used for discharge to NH or hospice. The models were adjusted for age, sex, dementia, Sequential Organ Failure Assessment score, and disability. RESULTS: Patients (n = 2477) had a mean age of 84 years, and were predominantly women (59.8%). Impaired arousal on admission was present in 644 (25.9%) patients: 33 (1.3%) were comatose (m-RASS = -5), 56 (2.3%) awakened to pain only (m-RASS = 4), 43 (1.7%) were very drowsy (m-RASS = -3), 93 (3.8%) drowsy (m-RASS = -2), and 212 (8.6%) were slightly drowsy (m-RASS = -1), but there were also 110 (4.4%) patients with restlessness, 75 (3.0%) with agitation, 17 (0.7%) with severe agitation, and 3 (0.1%) with combative behavior. Globally, 337 patients died within 1 month and 689 patients within 6 months. After adjustment for covariates, patients with impaired arousal had a significantly higher chance of having died at 1-month (adjusted hazard ratio [HR] 1.56, 95% confidence interval [CI] 1.22 2.03) and 6-month follow-up (adjusted HR 1.31, 95% CI 1.10-1.57). Those with impaired arousal were more likely to be discharged to a new NH (odds ratio [OR] 1.75, 95% CI 1.19-2.57) or to hospice (OR 1.96, 95% CI 1.18-3.23) than those without impaired arousal. CONCLUSIONS: An abnormal arousal level is an independent predictor of increased risk of 1- and 6-month mortality and of discharge to a new NH or hospice. The assessment of arousal with m-RASS should be routinely performed on all older patients on admission to acute hospital wards to screen potentially critical conditions. PMID- 26585090 TI - Risk and course of motor complications in a population-based incident Parkinson's disease cohort. AB - BACKGROUND: Motor complications may become major challenges in the management of patients with Parkinson's disease. In this study, we sought to determine the incidence, risk factors, evolution, and treatment of motor fluctuations and dyskinesias in a population-representative, incident Parkinson's disease cohort. METHODS: In this prospective population-based 5-year longitudinal study, we followed 189 incident and initially drug-naive Parkinson's disease patients biannually for detailed examination of dyskinesias and motor fluctuations as defined by the Unified Parkinson's disease Rating Scale. We performed Kaplan Meier survival and Cox regression analyses to assess cumulative incidence and risk factors of these motor complications. RESULTS: The 5-year cumulative incidence of motor complications was 52.4%. Motor fluctuations occurred in 42.9% and dyskinesias in 24.3%. Besides higher motor severity predicting both motor fluctuations (p = 0.016) and dyskinesias (p < 0.001), lower age at diagnosis predicted motor fluctuations (p = 0.001), whereas female gender predicted dyskinesias (p = 0.001). Actual levodopa dose at onset of motor fluctuations (p = 0.037) or dyskinesias (p < 0.001) rather than initial treatment with levodopa (p > 0.1) independently predicted development of motor complications. Motor fluctuations reversed in 37% and dyskinesias in 49% of patients on oral treatment and remained generally mild in those with persistent complications. No patients received device-aided therapies during the study. CONCLUSIONS: More than 50% in the general Parkinson's disease population develop motor complications within 5 years of diagnosis. However, they remain mild in the vast majority and are reversible in a substantial proportion of patients. PMID- 26585092 TI - Relationship between body mass index and hippocampal glutamate/glutamine in bipolar disorder. AB - BACKGROUND: We previously reported that patients with early-stage bipolar disorder, but not healthy comparison controls, had body mass index (BMI)-related volume reductions in limbic brain areas, suggesting that the structural brain changes characteristic of bipolar disorder were more pronounced with increased weight. AIMS: To determine whether the most consistently reported neurochemical abnormality in bipolar disorder, increased glutamate/glutamine (Glx), was also more prominent with higher BMI. METHOD: We used single-voxel proton magnetic resonance spectroscopy to measure hippocampal Glx in 51 patients with first episode mania (mean BMI = 24.1) and 28 healthy controls (mean BMI = 23.3). RESULTS: In patients, but not healthy controls, linear regression demonstrated that higher BMI predicted greater Glx. Factorial ANCOVA showed a significant BMI * diagnosis interaction, confirming a distinct effect of weight on Glx in patients. CONCLUSIONS: Together with our volumetric studies, these results suggest that higher BMI is associated with more pronounced structural and neurochemical limbic brain changes in bipolar disorder, even in early-stage patients with low obesity rates. PMID- 26585093 TI - Effect of questions used by psychiatrists on therapeutic alliance and adherence. AB - BACKGROUND: Psychiatrists' questions are the mechanism for achieving clinical objectives and managing the formation of a therapeutic alliance - consistently associated with patient adherence. No research has examined the nature of this relationship and the different practices used in psychiatry. Questions are typically defined in binary terms (e.g. 'open' v 'closed') that may have limited application in practice. AIMS: To undertake a detailed examination of the types of questions psychiatrists ask patients and explore their association with the therapeutic alliance and patient adherence. METHOD: A coding protocol was developed to classify questions from 134 out-patient consultations, predominantly by syntactic form. Bivariate correlations with measures of patient adherence and the therapeutic alliance (psychiatrist-rated) were examined and assessed using generalised estimating equations, adjusting for patient symptoms, psychiatrist identity and amount of speech. RESULTS: Psychiatrists used only four of ten question types regularly: yes/no auxiliary questions, 'wh-' questions, declarative questions and tag questions. Only declarative questions predicted better adherence and perceptions of the therapeutic relationship. Conversely, 'wh ' questions - associated with positive symptoms - predicted poorer perceptions of the therapeutic relationship. Declarative questions were frequently used to propose an understanding of patients' experiences, in particular their emotional salience for the patient. CONCLUSIONS: A refined defining of questioning practices is necessary to improve communication in psychiatry. The use of declarative questions may enhance alliance and adherence, or index their manifestation in talk, e.g. better mutual understanding. The function of 'so' prefaced declaratives, also used in psychotherapy, is more nuanced than negatively connotated 'leading' questions. Hearable as displays of empathy, they attend closely to patient experience, while balancing the tasks of assessment and treatment. PMID- 26585094 TI - Longitudinal predictors of subjective recovery in psychosis. AB - BACKGROUND: Research has highlighted the importance of recovery as defined by the service user, and suggests a link to negative emotion, although little is known about the role of negative emotion in predicting subjective recovery. AIMS: To investigate longitudinal predictors of variability in recovery scores with a focus on the role of negative emotion. METHOD: Participants (n = 110) with experience of psychosis completed measures of psychiatric symptoms, social functioning, subjective recovery, depression, hopelessness and self-esteem at baseline and 6 months later. Path analysis was used to examine predictive factors for recovery and negative emotion. RESULTS: Subjective recovery scores were predicted by negative emotion, positive self-esteem and hopelessness, and to a lesser extent by symptoms and functioning. Current recovery score was not predicted by past recovery score after accounting for past symptoms, current hopelessness and current positive self-esteem. CONCLUSIONS: Psychosocial factors and negative emotion appear to be the strongest longitudinal predictors of variation in subjective recovery, rather than psychiatric symptoms. PMID- 26585095 TI - The role of the amygdala in naturalistic mentalising in typical development and in autism spectrum disorder. AB - BACKGROUND: The substantial discrepancy between mentalising in experimental settings v. real-life social interactions hinders the understanding of the neural basis of real-life social cognition and of social impairments in psychiatric disorders. AIMS: To determine the neural mechanisms underlying naturalistic mentalising in individuals with and without autism spectrum disorder. METHOD: We investigated mentalising with a new video-based functional magnetic resonance imaging task in 20 individuals with autism spectrum disorder and 22 matched healthy controls. RESULTS: Naturalistic mentalising implicated regions of the traditional mentalising network (medial prefrontal cortex, temporoparietal junction), and additionally the insula and amygdala. Moreover, amygdala activity predicted implicit mentalising performance on an independent behavioural task. Compared with controls, the autism spectrum disorder group did not show differences in neural activity within classical mentalising regions. They did, however, show reduced amygdala activity and a reduced correlation between amygdala activity and mentalising accuracy on the behavioural task, compared with controls. CONCLUSIONS: These findings highlight the crucial role of the amygdala in making accurate implicit mental state inferences in typical development and in the social cognitive impairments of individuals with autism spectrum disorder. PMID- 26585096 TI - Differences in cancer stage, treatment and in-hospital mortality between patients with and without schizophrenia: retrospective matched-pair cohort study. AB - BACKGROUND: Healthcare access and outcomes in cancer patients with schizophrenia remain unclear. AIMS: To investigate the likelihood of early diagnosis and treatment in patients with schizophrenia who have cancer and their prognosis. METHOD: A retrospective matched-pair cohort of gastrointestinal cancer patients was identified using a national in-patient database in Japan. Multivariable ordinal/binary logistic regressions was modelled to compare cancer stage at admission, invasive treatments and 30-day in-hospital mortality between patients with schizophrenia (n = 2495) and those without psychiatric disorders (n = 9980). RESULTS: The case group had a higher proportion of stage IV cancer (33.9% v. 18.1%), a lower proportion of invasive treatment (56.5% v. 70.2%, odds ratio (OR) = 0.77, 95% CI 0.69-0.85) and higher in-hospital mortality (4.2% v. 1.8%, OR = 1.35, 95% CI 1.04-1.75). CONCLUSIONS: Patients with schizophrenia who had gastrointestinal cancer had more advanced cancer, a lower likelihood of invasive treatment and higher in-hospital mortality than those without psychiatric disorders. PMID- 26585097 TI - On poverty, politics and psychology: the socioeconomic gradient of mental healthcare utilisation and outcomes. AB - Since 2008, the Improving Access to Psychological Therapies (IAPT) programme has disseminated evidence-based interventions for depression and anxiety problems. In order to maintain quality standards, government policy in England sets the expectation that 50% of treated patients should meet recovery criteria according to validated patient-reported outcome measures. Using national IAPT data, we found evidence suggesting that the prevalence of mental health problems is greater in poorer areas and that these areas had lower average recovery rates. After adjusting benchmarks for local index of multiple deprivation, we found significant differences between unadjusted (72.5%) and adjusted (43.1%) proportions of underperforming clinical commissioning group areas. PMID- 26585098 TI - Cultural differences in stigma surrounding schizophrenia: comparison between Central Europe and North Africa. AB - BACKGROUND: Exploring cultural differences may improve understanding about the social processes underlying the stigmatisation of people with mental illness. AIMS: To compare public beliefs and attitudes about schizophrenia in Central Europe and North Africa. METHOD: Representative national population surveys conducted in Germany (2011) and in Tunisia (2012), using the same interview mode (face to face) and the same fully structured interview. RESULTS: In Tunisia, respondents showed a stronger tendency to hold the person with schizophrenia responsible for the condition. At the same time they expressed more prosocial reactions and less fear than their German counterparts. In Germany, the desire for social distance was greater for more distant relationships, whereas in Tunisia this was the case for close, family-related relationships. CONCLUSIONS: Stigma differs between Tunisia and Germany more in form than in magnitude. It manifests particularly in those social roles which 'matter most' to people within a given culture. PMID- 26585099 TI - DSM-IV Axis II personality disorders and suicide and attempted suicide in China. AB - BACKGROUND: There are meagre data on Axis II personality disorders and suicidal behaviour in China. AIMS: To describe the prevalence of Axis II personality disorders in suicides and suicide attempts in China and to estimate risk for these outcomes associated with personality disorders. METHOD: People who died by suicide (n = 151), people who attempted suicide (n = 118) and living community controls (n = 140) were randomly sampled from four Chinese counties and studied using the Structured Clinical Interviews for DSM-IV-TR Axis I Disorders (SCID-I) and Axis II Personality Disorders (SCID-II). We also determined the prevalence of subthreshold versions of ten DSM-IV personality disorders. RESULTS: Axis II personality disorders were present in 7% of the suicide group, 6% of the suicide attempt group and 1% of the control group. Threshold and subthreshold personality disorders had adjusted odds ratios (point estimates) in the range of 2.7-8.0 for suicide and for suicide attempts. CONCLUSIONS: Axis II personality disorders may confer increased risk for suicidal behaviour in China, but their low prevalence in the community and among people with suicidal behaviour suggests that other personality constructs such as select dimensional traits may be a more fruitful avenue for understanding and preventing suicide in China. PMID- 26585100 TI - Cognitive ability in childhood and the chronicity and suicidality of depression. AB - BACKGROUND: There is inconsistent evidence regarding the influence of general cognitive abilities on the long-term course of depression. AIMS: To investigate the association between general childhood cognitive abilities and adult depression outcomes. METHOD: We conducted a cohort study using data from 633 participants in the New England Family Study with lifetime depression. Cognitive abilities at age 7 were measured using the Wechsler Intelligence Scale for Children. Depression outcomes were assessed using structured diagnostic interviews administered up to four times in adulthood between ages 17 and 49. RESULTS: In analyses adjusting for demographic factors and parental psychiatric illness, low general cognitive ability (i.e. IQ<85 v. IQ>115) was associated with recurrent depressive episodes (odds ratio (OR) = 2.19, 95% CI 1.20-4.00), longer episode duration (rate ratio 4.21, 95% CI 2.24-7.94), admission to hospital for depression (OR = 3.65, 95% CI 1.34-9.93) and suicide ideation (OR = 3.79, 95% CI 1.79-8.02) and attempt (OR = 4.94, 95% CI 1.67-14.55). CONCLUSIONS: Variation in cognitive abilities, predominantly within the normal range and established early in childhood, may confer long-term vulnerability for prolonged and severe depression. The mechanisms underlying this vulnerability need to be established to improve the prognosis of depression among individuals with lower cognitive abilities. PMID- 26585101 TI - Evaluation of cumulative cognitive deficits from electroconvulsive therapy. AB - BACKGROUND: Electroconvulsive therapy (ECT) is the most effective acute treatment for severe depression, but widely held concerns about memory problems may limit its use. AIMS: To find out whether repeated or maintenance courses of ECT cause cumulative cognitive deterioration. METHOD: Analysis of the results of 10 years of cognitive performance data collection from patients who have received ECT. The 199 patients had a total of 498 assessments, undertaken after a mean of 15.3 ECT sessions (range 0-186). A linear mixed-effect regression model was used, testing whether an increasing number of ECT sessions leads to deterioration in performance. RESULTS: The total number of previous ECT sessions had no effect on cognitive performance. The major factors affecting performance were age, followed by the severity of depression at the time of testing and the number of days since the last ECT session. CONCLUSIONS: Repeated courses of ECT do not lead to cumulative cognitive deficits. This message is reassuring for patients, carers and prescribers who are concerned about memory problems and confusion during ECT. PMID- 26585102 TI - Cold adaptation mechanisms in the ghost moth Hepialus xiaojinensis: Metabolic regulation and thermal compensation. AB - Ghost moths (Lepidoptera: Hepialidae) are cold-adapted stenothermal species inhabiting alpine meadows on the Tibetan Plateau. They have an optimal developmental temperature of 12-16 degrees C but can maintain feeding and growth at 0 degrees C. Their survival strategies have received little attention, but these insects are a promising model for environmental adaptation. Here, biochemical adaptations and energy metabolism in response to cold were investigated in larvae of the ghost moth Hepialus xiaojinensis. Metabolic rate and respiratory quotient decreased dramatically with decreasing temperature (15-4 degrees C), suggesting that the energy metabolism of ghost moths, especially glycometabolism, was sensitive to cold. However, the metabolic rate at 4 degrees C increased with the duration of cold exposure, indicating thermal compensation to sustain energy budgets under cold conditions. Underlying regulation strategies were studied by analyzing metabolic differences between cold-acclimated (4 degrees C for 48 h) and control larvae (15 degrees C). In cold-acclimated larvae, the energy generating pathways of carbohydrates, instead of the overall consumption of carbohydrates, was compensated in the fat body by improving the transcription of related enzymes. The mobilization of lipids was also promoted, with higher diacylglycerol, monoacylglycerol and free fatty acid content in hemolymph. These results indicated that cold acclimation induced a reorganization on metabolic structure to prioritise energy metabolism. Within the aerobic process, flux throughout the tricarboxylic acid (TCA) cycle was encouraged in the fat body, and the activity of alpha-ketoglutarate dehydrogenase was the likely compensation target. Increased mitochondrial cristae density was observed in the midgut of cold-acclimated larvae. The thermal compensation strategies in this ghost moth span the entire process of energy metabolism, including degration of metabolic substrate, TCA cycle and oxidative phosphorylation, and from an energy budget perspective explains how ghost moths sustain physiological activity in cold environments. PMID- 26585103 TI - Prolonged Electromechanical Interval Unmasks Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy in the Subclinical Stage. AB - INTRODUCTION: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is characterized by high incidence of ventricular arrhythmias. Overt ARVD/C is preceded by a subclinical stage with lack of detectable ECG and structural abnormalities. Activation delay is present before structural abnormalities and is a hallmark of arrhythmogenesis. Deformation imaging may unmask activation delay in the subclinical stage. METHODS: Three groups were compared: (1) mutation positive definite ARVD/C-patients fulfilling 2010 Task Force criteria (TFC) (n = 44); (2) asymptomatic mutation carriers not fulfilling TFC and without history of ventricular arrhythmias (n = 31); and (3) controls (n = 30). All underwent ECG and echocardiographic deformation imaging. As a surrogate for local activation delay the electromechanical interval (EMI) was measured, defined as time between onset-QRS and onset of shortening. Arrhythmic outcome (PVC-count, VT) of asymptomatic mutation carriers was correlated with EMI and ECG TFC. RESULTS: In definite ARVD/C-patients, EMI was prolonged in all lateral RV segments. In asymptomatic mutation carriers, prolonged EMI was detected in the subtricuspid area in 14/31. Terminal activation duration >=55 milliseconds (definition: supporting information) was the only ECG abnormality in this group (8/31). After a mean follow-up of 4.2 +/- 3.1 years 10/31 asymptomatic mutation carriers experienced arrhythmic outcome. Prolonged subtricuspid EMI was the only parameter significantly associated with arrhythmogenesis during follow-up. CONCLUSION: In ARVD/C-patients, EMI prolongation was present throughout the RV. In asymptomatic mutation carriers, prolonged EMI in the subtricuspid area is often detected without any additional abnormalities. These preliminary results indicate that prolonged EMI is a new parameter unmasking activation delay in the subclinical stage and may contribute to risk stratification. PMID- 26585104 TI - Control of Separation and Diameter of Ag Nanorods through Self-organized Seeds. AB - This paper proposes a mechanism of controlling the diameter and separation of metallic nanorods from physical vapor deposition through self-organized seeds and experimentally demonstrates the feasibility using Ag as the prototype metal, In as the seed, and Si the substrate. Being non-wetting on Si substrates, deposited In atoms self-organize into islands. Subsequently deposited Ag atoms attach to In islands, rather than to Si substrates, due to preferential bonding and geometrical shadowing. The experimental results show that self-organized In seeds of 5 nm nominal thickness give rise to the best separation and the smallest diameter of Ag nanorods. PMID- 26585105 TI - [Morphology of surgical complications in liver biopsies early after transplantation]. AB - Early after liver transplantation, surgical/anastomotic complications of various types are more common than in other solid organ transplants. It is not only because the complications can be related to the transplant procedure, but also due to the suboptimal quality of the graft, and/or recipient health issues. The most critical early post-transplant complication is thrombosis of the hepatic artery. Findings in peripheral core needle biopsies of allograft with a thrombosed artery can be quite variable from unremarkable features, to coagulative necrosis, marked centrilobular hepatocyte swelling and biliary features with marginal ductular proliferation and/or cholangiolitis. Therefore the differential diagnosis is broad and includes almost every syndrome associated with graft dysfunction. Biliary tract is frequently the site of minor and major complications and the majority of them are ultimately attributable to ischemic injury. Complications occurring at or near the biliary anastomosis are generally more amenable to treatment than those occurring in the liver parenchyma. PMID- 26585106 TI - [Diagnosis of rejection in a transplanted liver]. AB - Despite advances in immunosupressive therapy rejection remains the most common complication of liver transplantation in both the early and the late post transplant period. Unlike other solid organs, liver graft rejection has some specific characteristics likely attributable to the unique immunobiologic properties and the remarkable regenerative capabilities of liver parenchyma. Acute cellular rejection is the most frequent type of the rejection episode in the liver allograft, whereas chronic (ductopenic) rejection and humoral rejection are uncommon. Since the clinical findings are not entirely characteristic, histopathological evaluation of liver biopsy remains the gold standard in the diagnosis of rejection. However, the close cooperation between the pathologist and the clinician is essential for the correct interpretation of morphologic changes. PMID- 26585107 TI - [Recurrence of primary diseases after liver transplantation]. AB - A majority of primary diseases for which orthotopic liver transplantation is carried out may recur in the liver allograft, mostly in adults. As the indication criteria, transplantation surgery and post-transplantation care improve, the patients survival lengthens as well, leading to concurrently increasing incidence as well as an increase in the relevance of recurrent diseases, which are the most significant cause of late liver graft dysfunction. The frequency, clinical consequences and therapeutic options of different disease recurrence vary considerably. Even recently the worst prognosis has been associated with hepatitis C for 100% reinfection, this situation is beginning to change with new oral antiviral drugs, as has already been successfully done with hepatitis B. Among immune-mediated disorders, primary biliary cirrhosis recurrence affects 30 50% of transplant patients, albeit with mild consequences. Graft loss and subsequent necessity of retransplantation are observed in almost 10% of patients with primary sclerosing cholangitis recurrence. 30% prevalence rates for autoimmune hepatitis recurrence are reported but the frequency of graft loss has declined considerably due to maintenance of corticosteroid therapy. Excessive relapse of alcohol consumption in patients with liver transplant for alcoholic liver disease leads most commonly to extrahepatic complications. Recurrent non alcoholic steatohepatitis is rarely connected with graft loss in 5 - 10 years after transplantation. The diagnosis of a recurrent disease following liver transplantation is to a large extent based on histopathological features. In the differential diagnosis, other causes of graft dysfunction must be excluded. PMID- 26585108 TI - [Transplantations of lungs in the Czech Republic - from the perspective of the pathologist]. AB - Lung transplantation has become a standard therapeutic procedure for patients with end-stage pulmonary diseases in the Czech Republic. There were 246 lung transplantations performed from December 1997 to the end of November 2014 at the 3rd Department of Surgery, 1st Faculty of Medicine, Charles University in Prague and Motol University Hospital. The most common indications for transplantation were chronic obstructive pulmonary disease in 39.4 % of patients, idiopathic pulmonary fibrosis in 28.9 % of patients and cystic fibrosis in 19.1 % of patients. The trans-bronchial biopsy is important for monitoring patients after lung transplantation. The biopsy helps to detect acute cellular rejection, which was found within 63 % of our patients. Patients with the mild and moderate grade of acute cellular rejection got better after the anti-rejection therapy. The severe rejection in three patients led to the shock change in lung and to respiratory failure. Humoral rejection cannot be determined based on biopsy only the capillaritis and the linear binding of C4d fraction of the complement to the capillaries are inconsistent findings and are not pathognomonic. The classification of chronic rejection, which corresponds to the bronchiolitis obliterans, is limited for the common absence of bronchioli in the biopsy. Therefore, bronchiolitis obliterans in our study group was detected in only 3.7 % of patients.Since the first transplantation, 109 of our patients have survived (44.3 %). After transplantation about 90 % of patients live one year, about 70.9 % of patients live 3 years and 69.1 % live 5 years. An autopsy at our department was performed in 79 cases. The most common causes of death were mycotic infections (aspergillosis, candidiasis), bacterial infections (Klebsiela, Pseudomonas aeruginosa, Burkholderia cepacia) followed by sepsis and viral infection (CMV, varicella zoster). At the autopsy, chronic rejection was found in 13 patients and it led to chronic respiratory failure, which was often complicated by an infection. The tumors as the cause of death were mostly generalized carcinomas. PMID- 26585109 TI - Renal allograft biopsies: a guide of ins and outs for best results. AB - Renal allograft biopsies remain the best diagnostic tool to investigate the type and degree of graft injury, provide therapeutic and prognostic information and to assess the extent of irreversible chronic organ damage - if done right. This review highlights pertinent aspects relevant not only for collecting optimal tissue samples but also for rendering diagnoses. Pathologists and clinicians are provided with "take home messages" and practical tips what to do, what to avoid and what to keep in mind. PMID- 26585110 TI - [Surgical techniques of organ transplants]. AB - The list of surgical procedures of solid organ transplantations appears very interesting and colorful, even with overlap among techniques. Liver transplantation is a life-saving procedure in a majority of cases, the liver can be transplanted as a full or partial graft. The liver graft can be split for two recipients; it can also be reduced for a small recipient if splitting is not indicated. Kidney transplantation is the most common solid organ transplant procedure, the majority of kidney grafts come from brain-dead donors whereas the number of live donor transplants is increasing, also thanks to paired donation and blood group incompatible transplantation methods. The small bowel and multivisceral transplantation are rare procedures; they serve selected patients with short bowel syndrome, some patients with retroperitoneal tumors or with extensive visceral thrombosis. Solid organ transplants are well established treatment methods with good and proven outcomes. A majority of patients can return to a normal life after their transplants. PMID- 26585111 TI - [Periosteal osteosarcoma - personal experience with five cases]. AB - The authors present five cases of periosteal osteosarcoma located in the femur (4) and tibia (1) in children and young adults (1 female and 4 males) with an age range of 9 - 23 years (mean age 15 years). Radiographs in all cases showed a broad-based soft tissue mass attached to the cortex with periosteal reaction and in two of them cortical disruption with extensive medullary involvement. Follow ups were available in four cases (range 11 - 73 months) and revealed pelvic metastasis after 15 months with ultimately rapid dissemination and death in a 9 year-old girl and metastasis to the humerus after 13 months in a 15-year-old boy. The former tumor widely extended into the medullary cavity and an amputation was carried out, the latter had a pure juxtacortical position and an en block resection was performed; both of them were treated with chemotherapy. All the lesions displayed distinctive structural patterns combining a large island of tumorous cartilage and hypocellular, bland-looking myxoid mesenchymal stroma with abrupt transition between both components. Contrary to conventional osteosarcoma, the delicate flocculent osteoid deposits were produced by innocuous stromal cells lacking apparent atypia. They were strictly situated outside the prevailing chondroid areas and disclosed sometimes only after a meticulous search. Immunohistochemical detection of SATB2, S100protein and D2-40 assisted effectively not only in recognition of the real stromal histogenetic derivation, but also in distinction of true differentiation of a heavily mineralized extracellular matrix. Molecular analysis revealed no IDH1/2 mutation in four examined cases. Regardless of unique low-grade morphology in rare periosteal osteosarcoma, an aggressive therapeutical approach similar to conventional osteosarcoma is justified, particularly in the case of a medullary extension. PMID- 26585112 TI - [The autopsy of the brain and spinal cord in the diagnosis of neurodegenerative diseases - a practical approach to optimize the examination]. AB - Brain and spinal cord autopsies aimed at neuropathological diagnosis of the causes of dementia and motor abnormalities are of increasing importance. Neuropathological brain examination is often the only diagnostic modality capable of definitive diagnosis of a neurodegenerative disease and thus serves as invaluable feedback for clinicians and biochemical and imaging diagnostics. The brain and spinal cord autopsy is performed following a standardized protocol and its goal is to sample all diagnostically relevant structures. Subsequent diagnostics are then done using standard and special histologic stainings, however state-of-the-art diagnostics can be achieved only using immunohistochemical methods. The purpose of the article is to provide the pathologists with a brief and practical guideline for brain and spinal cord autopsy when diagnosis of a neurodegenerative disease is suspected. PMID- 26585113 TI - Tunable graphene metasurfaces by discontinuous Pancharatnam-Berry phase shift. AB - Metal-dielectric-graphene three-layer structures are proposed to improve the interaction of graphene micro- and nanostructures with incident waves, as the upper graphene cut-wire layer introduces a discontinuous Pancharatnam-Berry phase profile. A semi-analytical method based on the Jones calculus is conducted to investigate the conversion efficiency of cross-polarized light on this graphene metasurface for circularly polarized wave incidence, which predicts that the physical constraint (25%) of cross-coupling conversion efficiency for individual graphene layers can be overcome. Numerical simulations confirm the conclusion and demonstrate an efficiency as high as 60%. Based on this mechanism, high efficiency anomalous reflection surfaces and flat focal mirrors are designed with the tunability of reflection angles and one order of magnitude improved focusing intensity. This method paves the way to engineering high-efficiency graphene metasurfaces for tunable electromagnetic wave manipulation. PMID- 26585114 TI - Androgenetic alopecia as an indicator of metabolic syndrome and cardiovascular risk. AB - Numerous studies have investigated a probable association between androgenetic alopecia (AGA) and cardiovascular disease (CVD) by researching limited and dispersed parameters. We aimed to evaluate both traditional and non-traditional cardiovascular risk factors in male patients with early-onset AGA. This case control study included 68 participants: 51 male patients with early-onset AGA and 17 healthy male controls. Patients with AGA were classified into three groups according to the Hamilton-Norwood scale and the presence of vertex hair loss. Traditional and non-traditional cardiovascular risk factors were examined in all study subjects. Metabolic syndrome was diagnosed in 25 patients with AGA and in two control subjects (p < 0.05). The carotid intima-media thickness values were found to be significantly higher in patients with vertex pattern AGA than in patients without vertex baldness and controls (p < 0.05). The pulse-wave velocity values were also found to be significantly higher in patients (p < 0.001). A limitation of this study was the small study population. In conclusion, vertex pattern AGA appears to be a marker for early atherosclerosis. This finding supports the hypothesis that early-onset AGA alone could be an independent risk factor for CVD and metabolic syndrome. PMID- 26585115 TI - The Micro-mechanism Involved and Wollastonite Signature in the Calcareous Precipitates of Marine Isolates. AB - Micro-mechanical studies connecting the influence of extrinsic factors over intrinsic factors on 30 calcareous isolates obtained from marine sediment biofilms of the Bay of Bengal (Indian Ocean) revealed that the fate of calcareous crystal precipitation is highly dependent on factors like extracellular polysaccharides (EPS), organic carbon and nutrition. Further studies exemplified that EPS and the organic carbon secreted by the isolates controlled the dissemination of the calcareous crystals precipitated. From the study, it is evident that an EPS concentration of 7-15 mg l(-1) was found to enhance the dissemination of the calcareous crystals. Atomic force micrographs explain the nucleation behaviour and morphology of the calcareous crystals precipitated. X ray diffraction (XRD) and energy-dispersive X-ray spectroscopy (EDAX) showed that the crystals were mainly composed of calcite and partially wollastonite. PMID- 26585116 TI - On the relation between motivation and retention in educational contexts: The role of intentional and unintentional mind wandering. AB - Highly motivated students often exhibit better academic performance than less motivated students. However, to date, the specific cognitive mechanisms through which motivation increases academic achievement are not well understood. Here we explored the possibility that mind wandering mediates the relation between motivation and academic performance, and additionally, we examined possible mediation by both intentional and unintentional forms of mind wandering. We found that participants reporting higher motivation to learn in a lecture-based setting tended to engage in less mind wandering, and that this decrease in mind wandering was in turn associated with greater retention of the lecture material. Critically, we also found that the influence of motivation on retention was mediated by both intentional and unintentional types of mind wandering. Not only do the present results advance our theoretical understanding of the mechanisms underlying the relation between motivation and academic achievement, they also provide insights into possible methods of intervention that may be useful in improving student retention in educational settings. PMID- 26585117 TI - Implicit learning of a speed-contingent target feature. AB - Previous human implicit learning studies have mostly investigated implicit associations between two consecutive stimuli or between a stimulus and the subsequent response (e.g., Cleeremans, Destrebecqz, & Boyer, Trends in Cognitive Sciences, 2(10), 406-416, 1998). In the present study, participants' response speed was used as a cue to predict an upcoming target feature. We called this new type of cueing, "cueing-by-response" (CBR). We investigated whether CBR could be learned implicitly. Participants performed two tasks: participants quickly responded to a target in the simple detection task and determined the orientation of a new target in the consecutive visual search task. We applied a contingency that the target location in the visual search task was determined by the participant's response speed in the preceding simple detection task. The results demonstrated that participants learned the contingency without conscious awareness; they searched for the target more efficiently in the visual search task as the experiment progressed. But when the target appeared in a random location, this efficiency disappeared. Moreover, the experimental group exhibited faster response speeds to the target in the visual search task compared with the control groups, which had no contingency. These results suggest that individuals may use the relative speed of their own response as a predictive cue to guide spatial attention toward upcoming target locations, and CBR can be implicitly learned. PMID- 26585118 TI - Aspirin Reduces Plasma Concentrations of the Oncometabolite 2-Hydroxyglutarate: Results of a Randomized, Double-Blind, Crossover Trial. AB - BACKGROUND: Aspirin use is an effective strategy for the chemoprevention of colorectal cancer, even at low doses. However, in order to implement aspirin interventions, risk-benefit balances and biologic mechanisms need to be better defined; to further this aim, we used a metabolomics approach. METHODS: We metabolically profiled 40 healthy, nonsmoking men and women ages 20 to 45 years enrolled in a randomized, double-blind, crossover trial of 325 mg aspirin/day over a period of 60 days. Gas and liquid chromatography-mass spectrometry were used to comprehensively profile participants' plasma samples after aspirin and placebo interventions. RESULTS: A total of 363 metabolites, covering most human biochemical pathways, were measured. Compared with placebo-treated participants, plasma concentrations of the oncometabolite 2-hydroxyglutarate (R+S) decreased after aspirin treatment in both men and women (P = 0.005). This signal proved robust during 20-fold random splitting of the data using 80% of the samples in each split. We subsequently performed functional follow-up studies using targeted, enantiospecific detection in human colorectal cancer cell lines and observed an aspirin-induced reduction of (R)-2-hydroxyglutarate. We further showed that salicylate, the primary aspirin metabolite, inhibits the hydroxyacid oxoacid transhydrogenase mediated production of (R)-2-hydroxyglutarate, thereby providing mechanistic evidence for the clinically observed effects of aspirin on total-2-hydroxyglutarate. CONCLUSIONS: Using a metabolomics approach with functional follow-up, we propose that a decrease in the oncometabolite (R)-2 hydroxyglutarate may identify an additional mechanism for aspirin or its metabolites in cancer prevention. IMPACT: Reduction of the oncometabolite (R)-2 hydroxyglutarate identifies a novel, non-COX-inhibition-mediated mechanism of aspirin. PMID- 26585119 TI - Fungal Community Assembly in the Amazonian Dark Earth. AB - Here, we compare the fungal community composition and diversity in Amazonian Dark Earth (ADE) and the respective non-anthropogenic origin adjacent (ADJ) soils from four different sites in Brazilian Central Amazon using pyrosequencing of 18S ribosomal RNA (rRNA) gene. Fungal community composition in ADE soils were more similar to each other than their ADJ soils, except for only one site. Phosphorus and aluminum saturation were the main soil chemical factors contributing to ADE and ADJ fungal community dissimilarities. Differences in fungal richness were not observed between ADE and ADJ soil pairs regarding to the most sites. In general, the most dominant subphyla present in the soils were Pezizomycotina, Agaricomycotina, and Mortierellomycotina. The most abundant operational taxonomic units (OTUs) in ADE showed similarities with the entomopathogenic fungus Cordyceps confragosa and the saprobes Fomitopsis pinicola, Acremonium vitellinum, and Mortierellaceae sp., whereas OTUs similar to Aspergillus niger, Lithothelium septemseptatum, Heliocephala gracillis, and Pestalosphaeria sp. were more abundant in ADJ soils. Differences in fungal community composition were associated to soil chemical factors in ADE (P, Ca, Zn, Mg, organic matter, sum of bases, and base saturation) and ADJ (Al, potential acidity, Al saturation, B, and Fe) soils. These results contribute to a deeper view of the fungi communities in ADE and open new perspectives for entomopathogenic fungi studies. PMID- 26585121 TI - Spanish Version of the Avoidance-Endurance Questionnaire: Factor Structure and Psychometric Properties. AB - To analyze the factorial structure and psychometric properties of the Spanish adaptation of the AEQ, and to validate it by reporting relevant pain-related variables, which were not investigated in the original study. One hundred and fifty Spanish patients diagnosed with chronic back and neck pain were referred by physicians from different pain clinics in Spain; all the patients filled out the questionnaires at their clinic. A series of principal components analyses (PCA) was performed to develop the Spanish version of the AEQ. Reliability and validity were also calculated. The PCAs revealed five fear-avoidance scales (Kaiser-Meyer Olkin measures were between .60 and .88, and Bartlett's tests were significant, p .73) and suitable validity (p < .05). New results associated with pain-related cognitive/affective and behavioural responses are discussed. This instrument will probably help clinicians to identify Spanish patients at a high risk of chronicity and to develop treatments tailored to the different profiles in order to improve secondary and tertiary prevention in back and neck pain. PMID- 26585120 TI - Cerebellar Contribution to Social Cognition. AB - Emotion attribution (EA) from faces is key to social cognition, and deficits in perception of emotions from faces underlie neuropsychiatric disorders in which cerebellar pathology is reported. Here, we test the hypothesis that the cerebellum contributes to social cognition through EA from faces. We examined 57 patients with cerebellar disorders and 57 healthy controls. Thirty-one patients had complex cerebrocerebellar disease (complex cerebrocerebellar disease group (CD)); 26 had disease isolated to cerebellum (isolated cerebellar disease group (ID)). EA was measured with the Reading the Mind in the Eyes test (RMET), and informants were administered a novel questionnaire, the Cerebellar Neuropsychiatric Rating Scale (CNRS). EA was impaired in all patients (CD p < 0.001, ID p < 0.001). When analyzed for valence categories, both CD and ID missed more positive and negative stimuli. Positive targets produced the highest deficit (CD p < 0.001, ID p = 0.004). EA impairments correlated with CNRS measures of deficient social skills (p < 0.05) and autism spectrum behaviors (p < 0.005). Patients had difficulties with emotion regulation (CD p < 0.001, ID p < 0.001), autism spectrum behaviors (CD p < 0.049, ID p < 0.001), and psychosis spectrum symptoms (CD p < 0.021, ID p < 0.002). ID informants endorsed deficient social skills (CD p < 0.746, ID p < 0.003) and impaired attention regulation (CD p < 0.144, ID p < 0.001). Within the psychosis spectrum domain, CD patients were worse than controls for lack of empathy (CD p = 0.05; ID p = 0.49). Thus, patients with cerebellar damage were impaired on an EA task associated with deficient social skills and autism spectrum behaviors and experienced psychosocial difficulties on the CNRS. This has relevance for ataxias, the cerebellar cognitive affective/Schmahmann syndrome, and neuropsychiatric disorders with cerebellar pathology. PMID- 26585122 TI - The Estrogen Receptors: An Overview from Different Perspectives. AB - The estrogen receptors, ERalpha, ERbeta, and GPER, mediate the effects of estrogenic compounds on their target tissues. Estrogen receptors are located in the tissues of the female reproductive tract and breast as one would expect, but also in tissues as diverse as bone, brain, liver, colon, skin, and salivary gland. The purpose of this discussion of the estrogen receptors is to provide a brief overview of the estrogen receptors and estrogen action from perspectives such as the historical, physiological, pharmacological, pathological, structural, and ligand perspectives. PMID- 26585123 TI - Competitive Binding Assay for the G-Protein-Coupled Receptor 30 (GPR30) or G Protein-Coupled Estrogen Receptor (GPER). AB - The role of 2-methoxyestradiol is becoming a major area of investigation because of its therapeutic utility, though its mechanism is not fully explored. Recent studies have identified the G-protein-coupled receptor 30 (GPR30, GPER) as a high affinity membrane receptor for 2-methoxyestradiol. However, studies aimed at establishing the binding affinities of steroid compounds for specific targets are difficult, as the tracers are highly lipophilic and often result in nonspecific binding in lipid-rich membrane preparations with low-level target receptor expression. 2-Methoxyestradiol binding studies are essential to elucidate the underlying effects of this novel estrogen metabolite and to validate its targets; therefore, this competitive receptor-binding assay protocol was developed in order to assess the membrane receptor binding and affinity of 2 methyoxyestradiol. PMID- 26585124 TI - The Use of Real-Time Reverse Transcription-PCR for Assessing Estrogen Receptor and Estrogen-Responsive Gene Expression. AB - Real-time reverse transcription-polymerase chain reaction (RT-PCR), also known as quantitative RT-PCR (qRT-PCR), is a powerful tool for assessing gene transcription levels. The technique is especially useful for measuring estrogen receptor transcript levels as well as gene expression changes in response to estrogen stimulation as it is quick, accurate, robust, and allows the measurement of gene expression in a variety of tissues and cells. This chapter describes the protocols used for the real-time RT-PCR assay using hydrolysis (TaqMan-type) probes. PMID- 26585125 TI - Bioinformatics Analysis of Estrogen-Responsive Genes. AB - Estrogen is a steroid hormone that plays critical roles in a myriad of intracellular pathways. The expression of many genes is regulated through the steroid hormone receptors ESR1 and ESR2. These bind to DNA and modulate the expression of target genes. Identification of estrogen target genes is greatly facilitated by the use of transcriptomic methods, such as RNA-seq and expression microarrays, and chromatin immunoprecipitation with massively parallel sequencing (ChIP-seq). Combining transcriptomic and ChIP-seq data enables a distinction to be drawn between direct and indirect estrogen target genes. This chapter discusses some methods of identifying estrogen target genes that do not require any expertise in programming languages or complex bioinformatics. PMID- 26585126 TI - Electrophoretic Mobility Shift Assay (EMSA) and Supershift Assay of Cytochrome P450 2B6 in Response to Estrogen. AB - Electrophoretic mobility shift assay (EMSA) is an invaluable tool to study interaction of proteins with DNA. Estrogens are major female hormones and modulate biological function through estrogen receptor (ER). ER regulates its target gene expression via the classical mechanism in which ER directly binds to its target gene promoter or the nonclassical mechanism involving tethering of ER to other transcription factors (such as AP-1 proteins). Here, we describe the EMSA to examine the nonclassical mechanism of ER action in regulation of a gene CYP2B6 by using competition and supershift assays. PMID- 26585127 TI - Chromatin Immunoprecipitation Assay to Identify Genomic Binding Sites of Regulatory Factors. AB - DNA-protein interactions are vital to fundamental cellular events including transcription, replication, DNA repair, and recombination. Thus, their study holds the key to our understanding of mechanisms underlying normal development and homeostasis as well as disease. Transcriptional regulation is a highly complex process that involves recruitment of numerous factors resulting in formation of multi-protein complexes at gene promoters to regulate gene expression. The studied proteins can be, for example, transcription factors, epigenetic regulators, co-activators, co-repressors, or ligand-activated nuclear receptors as estrogen receptor-alpha (ERalpha) bound either directly to the DNA or indirectly by interaction with other DNA-bound factors. Chromatin immunoprecipitation (ChIP) assay is a powerful method to study interactions of proteins and a specific genomic DNA region. Recruitment of ERalpha to promoters of estrogen-dependent genes is a common mechanism to activate or enhance gene transcription in breast cancer thus promoting tumor progression. In this chapter, we demonstrate a stepwise protocol for ChIP assay using binding of ERalpha to its genomic targets after stimulation with 17beta-estradiol (E2) in breast cancer cells as an example. PMID- 26585128 TI - Chromatin Immunoprecipitation with Estrogen Receptor 1 and the Promoter of Greb1 in TM4 Sertoli Cells. AB - Chromatin immunoprecipitation (ChIP) is a technique to investigate the interaction between proteins and DNA within the natural chromatin context of the cell. There are two previously identified two canonical estrogen response elements (ERE1 and ERE2) present in the 5'-flanking region of the Greb1 gene which is a known estrogen-responsive gene. ChIP results showed the physical interaction between estrogen receptor I (ESR1) and EREs in the Greb1 promoter in TM4 mouse Sertoli cells. This chapter describes the protocol for chromatin immunoprecipitation applied to the estrogen response elements in the Greb1 promoter. PMID- 26585129 TI - Chromatin Immunoprecipitation-Sequencing (ChIP-seq) for Mapping of Estrogen Receptor-Chromatin Interactions in Breast Cancer. AB - Chromatin immunoprecipitation-sequencing (ChIP-Seq) is a powerful tool which combines the established method of ChIP with next-generation sequencing (NGS) to determine DNA-binding sites of a protein of interest on a genome-wide level, importantly, allowing for de novo discovery of binding events. Here we describe ChIP-seq using the well-established example of estrogen receptor-alpha mapping in the MCF7 breast cancer cell line. PMID- 26585130 TI - RNA-Seq Experiment and Data Analysis. AB - With the ability to obtain tens of millions of reads, high-throughput messenger RNA sequencing (RNA-Seq) data offers the possibility of estimating abundance of isoforms and finding novel transcripts. In this chapter, we describe a protocol to construct an RNA-Seq library for sequencing on Illumina NGS platforms, and a computational pipeline to perform RNA-Seq data analysis. The protocols described in this chapter can be applied to the analysis of differential gene expression in control versus 17beta-estradiol treatment of in vivo or in vitro systems. PMID- 26585131 TI - DNA Microarray Analysis of Estrogen-Responsive Genes. AB - DNA microarray is a powerful, non-biased discovery technology that allows the analysis of the expression of thousands of genes at a time. The technology can be used for the identification of differential gene expression, genetic mutations associated with diseases, DNA methylation, single-nucleotide polymorphisms, and microRNA expression, to name a few. This chapter describes microarray technology for the analysis of differential gene expression in response to estrogen treatment. PMID- 26585132 TI - Shotgun Proteomics Analysis of Estrogen Effects in the Uterus Using Two Dimensional Liquid Chromatography and Tandem Mass Spectrometry. AB - Shotgun (gel-free) proteomics is a useful approach to perform identification and relative quantification of protein in complex mixtures such as tissue homogenates, biological fluids, cell lysates, and extracellular proteins. Incorporation of separative and analytical techniques such as two-dimensional liquid chromatography at nanoscale (2D-nanoLC) coupled to tandem mass spectrometry (MS/MS analysis) into the shotgun protocol provides an excellent strategy. This chapter describes the application of the shotgun proteomics protocol to evaluate the identity and expression analysis of proteins from rat uterus after estrogen (ethinylestradiol) treatment. The steps of the protocol involve sample preparation (digestion), 2D-nanoLC-MS/MS analysis, and shotgun proteomics analysis including bioinformatics tools for data conversion, organization, and interpretation. PMID- 26585133 TI - Assessment of Protein Expression by Proximity Ligation Assay in the Nonhuman Primate Endometrium, Placenta, and Fetal Adrenal in Response to Estrogen. AB - In the field of protein biology, immunology-based techniques have been evolving for detection and quantification of protein levels, protein-protein interaction, and protein modifications in cells and tissues. The proximity ligation assay (PLA), a method of detection that combines immunologic and PCR-based approaches, was developed to overcome some of the drawbacks that are inherent to other detection methods. The PLA allows for very sensitive and discretely quantifiable measures of unmodified, native protein levels, and protein-protein interaction/modification complexes in situ in both fixed tissues and cultured cells. We describe herein the PLA method and its applicability to quantify the effects of estrogen on expression of angioregulatory factors, e.g., angiopoietin 1 (Ang-1) in the endometrium, vascular endothelial growth factor (VEGF) in the placenta, and melanocortin 2 receptor (MC2R)/accessory protein (MRAP) in the fetal adrenal of the nonhuman primate. PMID- 26585134 TI - Colocalization of Estrogen Receptors with the Fluorescent Tamoxifen Derivative, FLTX1, Analyzed by Confocal Microscopy. AB - Tamoxifen is a selective estrogen receptor modulator that competitively binds the ligand-binding domain of estrogen receptors. Binding of tamoxifen displaces its cognate ligand, 17beta-estradiol, thereby hampering the activation of estrogen receptors. Cellular labeling of ER is typically carried out using specific antibodies which require permeabilization of cells, incubation with secondary antibodies, and are expensive and time consuming. In this article, we describe the usefulness of FLTX1, a novel fluorescent tamoxifen derivative, which allows the labeling of estrogen receptors in immunocytochemistry and immunohistochemistry studies, both under permeabilized and non-permeabilized conditions. Further, besides labeling canonical estrogen receptors, this novel fluorescent probe is also suitable for the identification of unconventional targets such membrane estrogen receptors as well as other noncanonical targets, some of which are likely responsible for the number of undesired side effects reported during long-term tamoxifen treatments. PMID- 26585135 TI - Live-Cell Imaging of the Estrogen Receptor by Total Internal Reflection Fluorescence Microscopy. AB - Trafficking studies of plasma membrane-localized intracellular estrogen receptors have mainly relied on biochemical and histological techniques to locate the receptor before and after estradiol stimulation. More often than not these experiments were performed using postmortem, lysed, or fixed tissue samples, whose tissue or cellular structure is typically severely altered or at times completely lost, making the definitive localization of estrogen receptors difficult to ascertain. To overcome this limitation we began using total internal reflection fluorescence microscopy (TIRFM) to study the trafficking of plasma membrane estrogen receptors. This real-time imaging approach, described in this chapter, permits observation of live, intact cells while allowing visualization of the steps (in time and spatial distribution) involved in receptor activation by estradiol and movements on and near the membrane. TIRFM yields high-contrast real-time images of fluorescently labeled E6BSA molecules on and just below the cell surface and is ideal for studying estrogen receptor trafficking in living cells. PMID- 26585136 TI - In Situ Hybridization of Estrogen Receptors alpha and beta and GPER in the Human Testis. AB - In situ hybridization (ISH) is an excellent method for detecting RNA in histological sections, both to detect gene expression and to assign gene expression to a distinct cell population. Therefore, ISH may be used in basic cell biology to detect the expression of certain genes within a tissue containing various cell populations. Here, we describe the detection and cellular localization of three estrogen receptors, both isoforms of the genomic estrogen receptor (ERalpha and ERbeta) as well as the membrane-bound G-protein-coupled estrogen receptor 1 (GPER) in the human testis. PMID- 26585137 TI - Purification of Histone Lysine Methyltransferase SMYD2 and Co-Crystallization with a Target Peptide from Estrogen Receptor alpha. AB - Methylation of estrogen receptor alpha by the histone lysine methyltransferase SMYD2 regulates ERalpha chromatin recruitment and its target gene expression. This protocol describes SMYD2 purification and crystallization of SMYD2 in complex with an ERalpha peptide. Recombinant SMYD2 is overexpressed in Escherichia coli cells. After release from the cells by French Press, SMYD2 is purified to apparent homogeneity with multiple chromatography methods. Nickel affinity column purifies SMYD2 based on specific interaction of its 6*His tag with the bead-immobilized nickel ions. Desalting column is used for protein buffer exchange. Gel filtration column purifies SMYD2 based on molecular size. The entire purification process is monitored and analyzed by SDS-polyacrylamide gel electrophoresis. Crystallization of SMYD2 is performed with the hanging drop vapor diffusion method. Crystals of the SMYD2-ERalpha peptide complex are obtained by microseeding using seeding bead. This method can give rise to large size of crystals which are suitable for X-ray diffraction data collection. X-ray crystallographic study of the SMYD2-ERalpha complex can provide structural insight into posttranslational regulation of ERalpha signaling. PMID- 26585138 TI - Gold Nanoparticle-Based Forster Resonance Energy Transfer (FRET) Analysis of Estrogen Receptor: DNA Interaction. AB - Estrogen receptors play critical roles in regulating genes responsible for development and maintenance of reproductive tissues and other physiological function. The interaction of ERs with DNA sequences, known as estrogen response elements (EREs) (a palindromic repeat separated by three-base spacer, 5'GGTCAnnnTGACC-3'), is required for estrogen regulation of target gene expression. Here, we describe a simple "mix-and-measure"-based method for detecting ER:ERE interactions using ERE-immobilized metal nanoparticles and water soluble conjugated polyelectrolytes (CPEs) as cooperative sensing elements. This method can differentiate the distinct DNA-binding affinity between ERalpha and ERbeta, and determine ER:ERE-binding stoichiometry. This method can also accurately detect all 15 singly mutated EREs (i.e., three possible base substitutions at each of one to five positions from left to right of the 5' end half site, GGTCA) for their binding energy to ER. This method is compatible with 96-well plate format for high-throughput analysis. PMID- 26585139 TI - Analysis of Interaction of Estradiol with Estrogen Receptor by NMR Spectroscopy. AB - Following binding to estradiol, estrogen receptors (ER) alpha and ERbeta recruit a number of interacting proteins and mediate a plethora of functions. The binding of estrogen with the receptors shows changes in the resonance structure and movement of protons. We cloned ERbeta and its trans-activation domain (TAD) and ligand-binding domain (LBD), expressed them in prokaryotic expression vectors, purified them, and studied their interaction with estradiol. In this chapter, a detailed method of preparation of recombinant proteins, SDS-PAGE, silver staining, and NMR are described. Such methods are useful to check the biological activity of bacterially expressed proteins and are applicable to basic and applied research. PMID- 26585140 TI - Application of Circular Dichroism Spectroscopy to the Analysis of the Interaction Between the Estrogen Receptor Alpha and Coactivators: The Case of Calmodulin. AB - The estrogen receptor alpha ligand-binding domain (ERalpha-LBD) binds the natural hormone 17beta-estradiol (E2) to induce transcription and cell proliferation. This process occurs with the contribution of protein and peptide partners (also called coactivators) that can modulate the structure of ERalpha, and therefore its specificity of action. As with most transcription factors, ERalpha exhibits a high content of alpha helix, making it difficult to routinely run spectroscopic studies capable of deciphering the secondary structure of the different partners under binding conditions. Ca(2+)-calmodulin, a protein also highly structured in alpha-helix, is a key coactivator for ERalpha activity. Here, we show how circular dichroism can be used to study the interaction of ERalpha with Ca(2+) calmodulin. Our approach allows the determination not only of the conformational changes induced upon complex formation but also the dissociation constant (K d) of this interaction. PMID- 26585141 TI - Surface Plasmon Resonance Study of Cooperative Interactions of Estrogen Receptor alpha and Specificity Protein 1 with Composite DNA Elements. AB - Estrogen receptor alpha (ERalpha) and Specificity protein 1 (Sp1) are transcription factors (TF) that are involved in regulating progesterone receptor (PR) gene expression through cooperative interactions with DNA. The natural composite DNA +571 ERE/Sp1 site in promoter A of the progesterone receptor contains a half-site of estrogen response elements (1/2ERE) upstream of two Sp1 binding sites (the proximal Sp1 (Sp1/P) and distal Sp1 (Sp1/D)) with a 4 bp spacer. Here, we have developed a protocol for studying the cooperative interaction of Sp1 and ERalpha with the composite DNA of +571 ERE/Sp1 site using Biacore T200, a high sensitivity surface plasmon resonance spectroscopy. With this protocol, we have concluded that Sp1 binding enhances the overall ERalpha binding to the composite DNA. We have also determined the optimal spacer distance between the 1/2ERE and Sp1/D for the best cooperative protein binding. This study is pivotal in guiding the bioinformatics simulation to yield an exact model of the spacer dependency of the transcription factor/cofactor-DNA interactions, which is important for understanding the nuclear receptor regulating activity through other coactivators. PMID- 26585142 TI - Tips and Tricks for Successful Application of Statistical Methods to Biological Data. AB - This chapter discusses experimental design and use of statistics to describe characteristics of data (descriptive statistics) and inferential statistics that test the hypothesis posed by the investigator. Inferential statistics, based on probability distributions, depend upon the type and distribution of the data. For data that are continuous, randomly and independently selected, as well as normally distributed more powerful parametric tests such as Student's t test and analysis of variance (ANOVA) can be used. For non-normally distributed or skewed data, transformation of the data (using logarithms) may normalize the data allowing use of parametric tests. Alternatively, with skewed data nonparametric tests can be utilized, some of which rely on data that are ranked prior to statistical analysis. Experimental designs and analyses need to balance between committing type 1 errors (false positives) and type 2 errors (false negatives). For a variety of clinical studies that determine risk or benefit, relative risk ratios (random clinical trials and cohort studies) or odds ratios (case-control studies) are utilized. Although both use 2 * 2 tables, their premise and calculations differ. Finally, special statistical methods are applied to microarray and proteomics data, since the large number of genes or proteins evaluated increase the likelihood of false discoveries. Additional studies in separate samples are used to verify microarray and proteomic data. Examples in this chapter and references are available to help continued investigation of experimental designs and appropriate data analysis. PMID- 26585143 TI - The Synonymous Ala87 Mutation of Estrogen Receptor Alpha Modifies Transcriptional Activation Through Both ERE and AP1 Sites. AB - Estrogen receptor alpha (ERalpha) exerts regulatory actions through genomic mechanisms. In the classical pathway, ligand-activated ERalpha binds directly to DNA through estrogen response elements (ERE) located in the promoter of target genes. ERalpha can also exert indirect regulation of transcription via protein protein interaction with other transcription factors such as AP-1.S everal ERalpha synonymous polymorphisms have been identified and efforts to understand their implications have been made. Nevertheless effects of synonymous polymorphisms are still neglected. This chapter focuses on the experimental procedure employed in order to characterize the transcriptional activity of a synonymous polymorphism of the ERalpha (rs746432) called Alanine 87 (Ala87). Activity of both WT and Ala87 ERalpha isoforms on transcriptional pathways can be analyzed in transiently transfected cells using different reporter constructs. ERalpha efficiency on the classical genomic pathway can be analyzed by determining its transactivation activity on an ERE-driven thymidine kinase (TK) promoter controlling the expression of the luciferase reporter gene. Transcriptional activity through the indirect genomic pathway can be analyzed by employing an AP-1 DNA response element-driven promoter also controlling the expression of luciferase reporter gene. PMID- 26585144 TI - Selective Estrogen Receptor Modulators and the Tissue-Selective Estrogen Complex: Analysis of Cell Type-Specific Effects Using In Vivo Imaging of a Reporter Mouse Model. AB - Selective estrogen receptor modulators (SERMs) are a class of compounds that act differentially on the estrogen receptor (ER) in various tissues with a mixed agonist/antagonistic activity (agonistic in some tissues while antagonist in others). This peculiarity represents a challenge for developing new hormone replacement therapies (HRTs) and highlights the need of new tools to evaluate the specific effects of a given SERM in different organs/tissues of an entire organism and with time. Reporter mice represent invaluable tools in pharmacology to analyze specific signaling in physiological conditions and monitor the effects of drugs acting on these signals in a spatio-temporal dimension. Here, we describe an in vivo protocol to examine the effects of different SERMs on estrogen receptor activity by using the ERE-Luc reporter model, a mouse that reports ER transcriptional activity. PMID- 26585145 TI - Use of Reporter Genes to Analyze Estrogen Response: The Transgenic Zebrafish Model. AB - In vivo models to detect estrogenic compounds are very valuable for screening for endocrine disruptors. Here we describe the use of transgenic estrogen reporter zebrafish as an in vivo model for identification of estrogenic properties of compounds. Live imaging of these transgenic fish provides knowledge of estrogen receptor specificity of different ligands as well as dynamics of estrogen signaling. Coupled to image analysis, the model can provide quantitative dose response information on estrogenic activity of chemical compounds. PMID- 26585146 TI - Comparison of the Effects of the Selective Estrogen Receptor Modulators Ospemifene, Raloxifene, and Tamoxifen on Breast Tissue in Ex Vivo Culture. AB - Explant tissue culture provides a model for studying the direct effects of steroid hormones, their analogs, and novel hormonally active compounds on normal freshly isolated human breast tissues (HBTs). For this purpose, pre- and postmenopausal HBTs can be maintained in this culture system. The results demonstrate that the morphological integrity of HBT explants can be maintained in tissue culture up to 2 weeks and expression of differentiation markers, steroid hormone receptors, proliferation and apoptosis ratios can be evaluated as a response to hormonal stimulation. This chapter describes an ex vivo culture model that we have applied to study the effects of various hormonally active substances, including 17beta-estradiol and selective estrogen receptor modulators (SERMs), on normal human breast tissues. PMID- 26585147 TI - Estrogen Receptor Agonists and Antagonists in the Yeast Estrogen Bioassay. AB - Cell-based bioassays can be used to predict the eventual biological activity of a substance on a living organism. In vitro reporter gene bioassays are based on recombinant vertebrate cell lines or yeast strains and especially the latter are easy-to-handle, cheap, and fast. Moreover, yeast cells do not express estrogen, androgen, progesterone or glucocorticoid receptors, and are thus powerful tools in the development of specific reporter gene systems that are devoid of crosstalk from other hormone pathways. This chapter describes our experience with an in house developed RIKILT yeast estrogen bioassay for testing estrogen receptor agonists and antagonists, focusing on the applicability of the latter. PMID- 26585148 TI - Silencing Estrogen Receptor-alpha with siRNA in the Intact Rodent Brain. AB - The ability to silence the expression of gene products in a chemically, spatially, and temporally specific manner in the brains of animals has enabled key breakthroughs in the field of behavioral neuroscience. Using this technique, estrogen receptor alpha (ERalpha) has been specifically implicated in a multitude of behaviors in mice, including sexual, aggressive, locomotor, and maternal behaviors. ERalpha has been identified in a variety of brain regions, including the medial preoptic area, ventromedial hypothalamus, and amygdala. In this chapter we describe the techniques involved in the generation of the small hairpin RNAs (shRNAs) specifically designed to silence ERalpha, the construction of the adeno-associated viral (AAV) vector for delivery of the shRNA, the procedures to confirm the silencing of ERalpha (in vitro and in vivo) and in vivo delivery of the shRNAs to the brains of animals. PMID- 26585149 TI - Silencing Estrogen Receptor-beta with siRNA in Cultured Cells. AB - Estrogen receptors alpha and beta (ERalpha and ERbeta) are the two genomic estrogen receptors. ERbeta was the second of these receptors to be discovered; its structure is similar to that of ERalpha but they are different in histological distribution. However, the functions of ERalpha versus ERbeta are still unclear. The ability of small interfering RNAs (siRNAs) to silence gene expression has proven to be invaluable for studying gene function in cultured mammalian cells. This chapter describes the use of siRNA to inhibit the expression of ERbeta in renal cell carcinoma (RCC) and to further the understanding of ERbeta function in RCC. PMID- 26585150 TI - Experimental Procedures for Demonstration of MicroRNA Mediated Enhancement of Functional Neuroprotective Effects of Estrogen Receptor Agonists. AB - Protection of motoneurons is an important therapeutic goal in the treatment of neurological disorders. Recent reports have suggested that specific microRNAs (miRs) could modulate the expression of particular proteins for significant alterations in the pathogenesis of different neurological disorders. Thus, combination of overexpression of a specific neuroprotective miR and treatment with a neuroprotective agent could be a novel strategy for functional protection of motoneurons. The protocols described herein demonstrate that miR-7-1, a neuroprotective miR, can enhance the functional neuroprotective effects of estrogen receptor agonists such as 1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H pyrazole (PPT), Way 200070 (WAY), and estrogen (E2) in preventing apoptosis in A23187 calcium ionophore (CI) exposed VSC4.1 motoneurons. This article describes the protocols for the cell viability assay, transfection of VSC4.1 motoneurons with miRs, Annexin V/propidium iodide staining for apoptosis, Western blotting, patch-clamp recording of whole-cell membrane potential, and JC-1 staining for detection of mitochondrial membrane potential. Taken together, these protocols are used to demonstrate that miR-7-1 caused significant enhancement of the efficacy of estrogen receptor agonists for functional neuroprotection in VSC4.1 motoneurons. PMID- 26585151 TI - Expression Profiles of Estrogen-Regulated MicroRNAs in Breast Cancer Cells. AB - Molecular signaling through both estrogen and microRNAs are critical for breast cancer development and growth. The activity of estrogen is mediated by transcription factors, the estrogen receptors. Here we describe a method for robust characterization of estrogen-regulated microRNA profiles. The method details how to prepare cells for optimal estrogen response, directions for estrogen treatment, RNA extraction, microRNA large-scale profiling, and subsequent confirmations. PMID- 26585152 TI - Estradiol-Induced Transcriptional Regulation of Long Non-Coding RNA, HOTAIR. AB - HOTAIR (HOX antisense intergenic RNA) is a 2.2 kb long non-coding RNA (lncRNA), transcribed from the antisense strand of homeobox C (HOXC) gene locus in chromosome 12. HOTAIR acts as a scaffolding lncRNA. It interacts and guides various chromatin-modifying complexes such as PRC2 (polycomb-repressive complex 2) and LSD1 (lysine-specific demethylase 1) to the target gene promoters leading to their gene silencing. Various studies have demonstrated that HOTAIR overexpression is associated with breast cancer. Recent studies from our laboratory demonstrate that HOTAIR is required for viability of breast cancer cells and is transcriptionally regulated by estradiol (E2) in vitro and in vivo. This chapter describes protocols for analysis of the HOTAIR promoter, cloning, transfection and dual luciferase assays, knockdown of protein synthesis by antisense oligonucleotides, and chromatin immunoprecipitation (ChIP) assay. These protocols are useful for studying the estrogen-mediated transcriptional regulation of lncRNA HOTAIR, as well as other protein coding genes and non-coding RNAs. PMID- 26585153 TI - Detection and Functional Analysis of Estrogen Receptor alpha Phosphorylated at Serine 216 in Mouse Neutrophils. AB - Serine 216 constitutes a protein kinase C phosphorylation motif located within the DNA binding domain of estrogen receptor alpha (ERalpha). In this chapter we present experimental procedures confirming that mouse ERalpha is phosphorylated at serine 216 in peripheral blood neutrophils and in neutrophils that infiltrate the uterus, as well as the role of phosphoserine 216 in neutrophil migration. A phospho-peptide antibody (alphaP-S216) was utilized in Western blot, immunohistochemistry, and double immunofluorescence staining to detect this phosphorylation of an endogenous ERalpha. Both immunohistochemistry (with alphaP S216 or neutrophil marker Ly6G antibody) and double immunofluorescence staining of mouse uterine sections prepared from C3H/HeNCrIBR females revealed that phosphorylated ERalpha was expressed in all infiltrating neutrophils during hormonal cycles but not in any other of the other uterine cells. Neutrophils infiltrate the uterus from the blood stream. White blood cells (WBC) were prepared from peripheral blood of C3H/HeNCrIBR females or males and double immunostained. Blood neutrophils also expressed phosphorylated ERalpha but in only about 20 % of cells in both sexes. Only the neutrophils expressing phosphorylated ERalpha spontaneously migrated in in vitro Transwell migration assays and infiltrated the uterus in mice. PMID- 26585154 TI - Estrogen Receptor-alpha Knockout Mice. AB - Tissue specific knockout mice are valuable tools to study gene function in vivo. The method uses the Cre/loxP system in which loxP sites are cloned into the genome surrounding one or more exons of a gene and the targeted exon(s) are deleted when the Cre enzyme is expressed. Mouse lines that are prepared for the generation of knockout ERalpha mice have been developed independently by many research groups and the number of available transgenic mouse lines that express Cre under tissue specific promoters is large. Here, we describe how tissue specific ERalpha knockout mice are generated. PMID- 26585155 TI - Detection of Endogenous Selective Estrogen Receptor Modulators such as 27 Hydroxycholesterol. AB - The estrogen receptors (ERs) belong to the nuclear receptor superfamily, and as such act as ligand inducible transcription factors, mediating the effects of estrogens. However, their pharmacology is complex, having the ability to be differentially activated by ligands. Such ligands possess the ability to behave as either ER-agonists or ER-antagonists, depending on the cellular and tissue context, and have been termed Selective Estrogen Receptor Modulators (SERMs). Several SERMs have been identified with clinical relevance such as tamoxifen and raloxifene. Recently, 27-hydroxycholesterol has been characterized as the first identified endogenous SERM leading to the notion that other endogenous SERMs may exist, each having potential pathophysiological functions. This, coupled with the historic pharmaceutical interest as well as growing concern over chemicals in the environment with the ability to behave like SERMs, has increased the demand for assays to detect SERM-like activity. Here, we describe a common, straightforward in vitro assay investigating the induction of classic ER-target genes in MCF7 breast cancer cells, allowing one to identify ligands with SERM-like activity. PMID- 26585156 TI - Phytoestrogens Activate the Estrogen Receptor in HepG2 Cells. AB - Phytoestrogens are popular alternatives to estrogen therapy however their effects on hemostasis in postmenopausal women are unknown. This chapter describes a protocol to determine the effect of the phytoestrogens genistein, daidzein and equol, on the expression of key genes from the hemostatic system in human hepatocyte cell models and to determine the role of estrogen receptors in mediating any response seen using in vitro culture systems and Taqman((r)) gene expression analysis. PMID- 26585157 TI - Detection of the Phosphorylation of the Estrogen Receptor alpha as an Outcome of GPR30 Activation. AB - Phosphorylation of the serine residues in estrogen receptor (ER) alpha is important in transcriptional activation. Hence, methods to detect such posttranslational modification events are valuable. We describe, in detail, the analysis of the phosphorylated ERalpha by electrophoretic separation of proteins and subsequent immuno-blotting techniques. In particular, phosphorylation of the ERalpha is one possible outcome of activation of the putative membrane estrogen receptor (mER), GPR30. Hence, phosphorylation represents a cross talk event between GPR30 and ERalpha and may be important in estrogen-regulated physiology. PMID- 26585158 TI - GPER Mediates Non-Genomic Effects of Estrogen. AB - Estrogens are important modulators of a broad spectrum of physiological functions in humans. However, despite their beneficial actions, a number of lines of evidence correlate the sustained exposure to exogenous estrogen with increased risk of the onset of various cancers. Mainly these steroid hormones induce their effects by binding and activating estrogen receptors (ERalpha and ERbeta). These receptors belong to the family of ligand-regulated transcription factors, and upon activation they regulate the expression of different target genes by binding directly to specific DNA sequences. On the other hand, in recent years it has become clear that the G protein-coupled estrogen receptor 30 (GPR30/GPER) is able to mediate non-genomic action of estrogens in different cell contexts. In particular, GPER has been shown to specifically bind estrogens, and in turn to functionally cross-react with diverse cell signaling systems such as the epidermal growth factor receptor (EGFR) pathway, the Notch signaling pathway and the mitogen-activated protein kinases (MAPK) pathway. In this chapter we will present some of the different experimental techniques currently used to demonstrate the functional role of GPER in mediating non-genomic actions of estrogens, such as the dual luciferase assay, assessment of the involvement of GPER in the stimulation of cell migration in breast cancer cell lines and in cancer-associated fibroblasts, and chromatin immunoprecipitation assay. Overall, the experimental procedures described herein represent key instruments for assessing the biological role of GPER in mediating non-genomic signals of estrogen. PMID- 26585159 TI - GPER/GPR30 Knockout Mice: Effects of GPER on Metabolism. AB - Endogenous estrogens, predominantly 17beta-estradiol (E2), mediate various diverse effects throughout the body in both normal physiology and disease. Actions include development (including puberty) and reproduction as well as additional effects throughout life in the metabolic, endocrine, musculoskeletal, nervous, cardiovascular, and immune systems. The actions of E2 have traditionally been attributed to the classical nuclear estrogen receptors (ERalpha and ERbeta) that largely mediate transcriptional/genomic activities. However, more recently the G protein-coupled estrogen receptor GPER/GPR30 has become recognized as an essential mediator of certain, and particularly rapid, signaling events in response to E2. Murine genetic knockout (KO) models represent an important approach to understand the mechanisms of E2 action in physiology and disease. Studies of GPER KO mice over the last years have revealed functions for GPER in the regulation of obesity, insulin resistance and glucose intolerance, among other areas of (patho)physiology. This chapter focuses on methods for the evaluation of metabolic parameters in vivo and ex vivo with an emphasis on glucose homeostasis and metabolism through the use of glucose and insulin tolerance tests, pancreatic islet and adipocyte isolation and characterization. PMID- 26585160 TI - Analysis of G-Protein Coupled Receptor 30 (GPR30) on Endothelial Inflammation. AB - The female sex hormone estrogen (the most common form 17-beta-estradiol or E2) is known to have both anti-inflammatory and pro-inflammatory effects. Given the diversity of estrogen responses mediated through its three distinct receptors, namely, estrogen receptor alpha (ERalpha), ERbeta, and the G-protein coupled receptor 30 (GPR30), it is plausible that different receptors have specific modulatory effects on inflammation in different tissues. We have shown that activation of GPR30 exerted anti-inflammatory effects as demonstrated by significant attenuation of tumor necrosis factor (TNF)-mediated upregulation of adhesion molecules in isolated human umbilical vein endothelial cells. Interestingly, estrogen alone had no such effect and blockade of classical ERs restored the anti-inflammatory effect, suggesting that this effect was dependent on GPR30 and opposed to classical ERs. These findings were further validated by the negation of anti-inflammatory GPR30 effects by classical ER agonists. This chapter focuses on multiple pharmacological options to activate GPR30 and the use of TNF activated endothelial cells as a model system for inflammatory response as assessed by adhesion molecule detection through western blotting. PMID- 26585161 TI - Atherosclerosis and Vascular Biologic Responses to Estrogens: Histologic, Immunohistochemical, Biochemical, and Molecular Methods. AB - Atherogenesis is a multifactorial pathologic process influenced by genetics and environmental factors such as diet, exercise, stress, and other exposures. Estrogen receptors (ER) are expressed in cells of the arterial wall, suggesting that estrogen receptor ligands (estradiol, natural and pharmacologic ligands) may directly affect arterial biology and atherogenesis. Ligand bound estrogen receptor alpha and beta (ERalpha, ERbeta) can influence physiology through direct binding to estrogen response elements in the DNA, through interactions with other transcription factors such as NF-kappaB, or through rapid effects not dependent on gene expression changes but instead through non-nuclear membrane sites involving ERalpha, ERbeta, or G-coupled protein ER (GPER1). Elucidation of potential direct effects of estrogens on the artery wall requires careful evaluation of arterial biologic responses to estrogens. We have developed a comprehensive approach to understand the mechanisms of estrogen action which employs histologic measures of the size and other characteristics of atherosclerotic lesions, immunohistochemical assessments of cellular composition, evaluation of chemical, molecular, and genomic changes in the arterial environment, and determination of the relationships between arterial estrogen receptor expression and atherogenesis. This approach can provide important insights into the mechanisms of action of estrogen and other mediators of atherogenesis. PMID- 26585162 TI - Assessing Direct Vascular Actions of Estrogens. AB - Estrogens are known to affect vascular function. In order to decipher the underlying mechanisms, it is essential to study the direct actions of estrogenic substances on blood vessels. There are two widely used approaches to assess the effects of estrogenic substances directly on blood vessels, the isolated perfused intact mesenteric vascular bed (McGregor preparation) and the isolated perfused/pressurized vessel approach. The McGregor preparation relies on constant flow with vascular reactivity assessed as changes in perfusion pressure. The isolated perfused/pressurized vessel approach uses a single vessel mounted on glass micropipettes. The main readout in this approach is vascular diameter. This chapter describes these approaches which remain cornerstones in the investigation of direct vascular actions of estrogenic substances. PMID- 26585163 TI - Molecular Design, Synthesis, and Evaluation of SNIPER(ER) That Induces Proteasomal Degradation of ERalpha. AB - Manipulation of protein stability using small molecules has a great potential for both basic research and clinical therapy. Based on our protein knockdown technology, we recently developed a novel small molecule SNIPER(ER) that targets the estrogen receptor alpha (ERalpha) for degradation via the ubiquitin proteasome system. This chapter describes the design and synthesis of SNIPER(ER) compounds, and methods for the evaluation of their activity in cellular system. PMID- 26585164 TI - Regulation of Activation Induced Deaminase (AID) by Estrogen. AB - Regulation of Activation Induced Deaminase (AID) by the hormone estrogen has important implications for understanding adaptive immune responses as well as the involvement of AID in autoimmune diseases and tumorigenesis. This chapter describes the general laboratory techniques for analyzing AID expression and activity induced by estrogen, focusing on the isolation and preparation of cells for hormone treatment and the subsequent analysis of AID responsiveness to estrogen at the RNA level and for determining the regulation of AID activity via estrogen by analyzing Ig switch circle transcripts and mutations in switch region loci. PMID- 26585165 TI - Influence of milk protein cross-linking by transglutaminase on the rennet coagulation time and the gel properties. AB - BACKGROUND: Transglutaminase (TGase) modifies milk proteins by cross-linking of caseins, with increased cheese yield being the main technological benefit. In the present work the influence of TGase addition in different concentrations (0, 1, 2 and 3 U g(-1) protein in the system) and under different incubation conditions (0 h, 40 degrees C/2 h, 25 degrees C/4 h and 5 degrees C/16 h) on the rennet coagulation time (RCT) and the comprehensive rennet gel properties were investigated. RESULTS: Modification of milk proteins by TGase in a concentration dependent manner caused longer RCT and lower gel firmness. The highest TGase concentration and incubation at 40 degrees C for 2 h resulted in the longest RCT and the lowest gel firmness. Rennet gels obtained from TGase modified milk were characterised by significantly lower values of texture parameters, lower syneresis and were composed of smaller casein micelles, thinner chains and smaller clusters than those obtained from the control milk. The content of whey proteins in the gel from modified milk was higher and the content of individual casein fractions in the milk samples and rennet gels decreased upon TGase modification. CONCLUSION: Rennet cheese with modified textural and nutritional properties and improved yield can be obtained upon TGase modification but simultaneous addition of rennet and TGase is recommended. (c) 2015 Society of Chemical Industry. PMID- 26585166 TI - Erratum: Antithrombotic treatment in elderly patients with atrial fibrillation: a practical approach. PMID- 26585168 TI - Regression to the Mean Mimicking Changes in Sexual Arousal to Child Stimuli in Pedophiles. AB - The sexual preference for prepubertal children (pedophilia) is generally assumed to be a lifelong condition. Muller et al. (2014) challenged the notion that pedophilia was stable. Using data from phallometric testing, they found that almost half of 40 adult pedophilic men did not show a corresponding arousal pattern at retest. Critics pointed out that regression to the mean and measurement error might account for these results. Muller et al. contested these explanations. The present study shows that regression to the mean in combination with low reliability does indeed provide an exhaustive explanation for the results. Using a statistical model and an estimate of the retest correlation derived from the data, the relative frequency of cases with an allegedly non pedophilic arousal pattern was shown to be consistent with chance expectation. A bootstrap simulation showed that this outcome was to be expected under a wide range of retest correlations. A re-analysis of the original data from the study by Muller et al. corroborated the assumption of considerable measurement error. Therefore, the original data do not challenge the view that pedophilic sexual preference is stable. PMID- 26585167 TI - Prevalence of High-Risk Sexual Behaviors Among Monoracial and Multiracial Groups from a National Sample: Are Multiracial Young Adults at Greater Risk? AB - The present study compared the prevalence and variation in high-risk sexual behaviors among four monoracial (i.e., White, African American, Asian, Native American) and four multiracial (i.e., White/African American, White/Asian, White/Native American, African American/Native American) young adults using Wave IV data (2008-2009) from the National Longitudinal Study of Adolescent to Adult Health (N = 9724). Findings indicated differences in the sexual behavior of monoracial and multiracial young adults, but directions of differences varied depending on the monoracial group used as the referent and gender. Among males, White/African Americans had higher risk than Whites; White/Native Americans had higher risk than Native Americans. Otherwise, multiracial groups had lower risk or did not differ from the single-race groups. Among females, White/Native Americans had higher risk than Whites; White/African Americans had higher risk than African Americans. Other comparisons showed no differences or had lower risk among multiracial groups. Variations in high-risk sexual behaviors underscore the need for health research to disaggregate multiracial groups to better understand health behaviors and outcomes in the context of experiences associated with a multiracial background, and to improve prevention strategies. PMID- 26585169 TI - Men's Objectifying Media Consumption, Objectification of Women, and Attitudes Supportive of Violence Against Women. AB - A recent White House Council Report on Women and Girls called attention to sexual assault on college campuses and encouraged continued research on this important public health problem. Media that sexually objectify women have been identified by feminist scholars as encouraging of sexual assault, but some researchers question why portrayals that do not feature sexual assault should affect men's attitudes supportive of violence against women. Guided by the concepts of specific and abstract sexual scripting in Wright's (Communication Yearbook 35:343 386, 2011) sexual script acquisition, activation, application model of sexual media socialization, this study proposed that the more men are exposed to objectifying depictions, the more they will think of women as entities that exist for men's sexual gratification (specific sexual scripting), and that this dehumanized perspective on women may then be used to inform attitudes regarding sexual violence against women (abstract sexual scripting). Data were gathered from collegiate men sexually attracted to women (N = 187). Consistent with expectations, associations between men's exposure to objectifying media and attitudes supportive of violence against women were mediated by their notions of women as sex objects. Specifically, frequency of exposure to men's lifestyle magazines that objectify women, reality TV programs that objectify women, and pornography predicted more objectified cognitions about women, which, in turn, predicted stronger attitudes supportive of violence against women. PMID- 26585171 TI - Lyme Disease. AB - Occupational and environmental health nurses should educate workers about ways to prevent tick bites, which can cause Lyme disease. PMID- 26585170 TI - Management of obstructive sleep apnea in edentulous patients: an overview of the literature. AB - PURPOSE: A high prevalence of obstructive sleep apnea (OSA) is seen in edentulous individuals. Treatment options for edentulous OSA patients however are limited with continuous positive airway pressure therapy (CPAP) remaining the current therapy of choice. As CPAP is associated with high non-adherence rates and oral appliance therapy requiring sufficient dentition, there is a clinical need for effective treatment strategies aimed at edentulous OSA patients. The purpose of this study was to present a thorough overview of the literature regarding (1) the effects of nocturnal denture wearing on OSA, (2) the outcomes of oral appliance therapy, and (3) surgical treatment in edentulous OSA patients. METHODS: A computer-assisted literature search was performed in the MEDLINE database on "edentulism" and "obstructive sleep apnea." The search yielded a total of 34 original articles. RESULTS: A total of 20 studies were included after exclusion of non-relevant, duplicate, and non-English publications, comprising 4 randomized clinical trials, 12 case reports, and 4 cohort or cross-sectional studies. The outcomes of these studies were addressed in detail concerning nocturnal wearing of dentures, oral appliance therapy, and surgical treatment. CONCLUSION: Currently, there is no consensus in the literature on the effects of nocturnal wearing of dentures on OSA. Several studies report the successful use of oral appliance therapy, including implant-retained mandibular advancement devices (MADs), in selected cases of edentulous patients with varying stages of OSA. Little evidence is available regarding outcomes of surgical procedures in edentulous patients. Based on the results of this literature overview, the paucity of effective evidence-based treatment strategies for edentulous OSA patients indicates the further need of clinical studies to improve clinical management. PMID- 26585172 TI - Design Implications to Increase Utilization of Stairwells. AB - Stairwell use is a cost-effective opportunity to increase physical activity. Although stairwell use can integrate moderate physical activity in daily work routines, little information is available to guide architects and engineers on how to design facilities that promote stairwell use. This study examined the reasons behind using stairwells versus elevators through a case study at a teaching hospital. A broad range of physical design recommendations were evaluated to understand how the design of stairwells can encourage hospital staff and students to use them. An online survey was used to collect data. Findings indicated travel distance and travel direction as primary reasons for preferring elevators. Design recommendations such as motivational signs and physical movement reinforcements (e.g., cardio indicators) are discussed. PMID- 26585173 TI - Cooling Methods to Prevent Heat-Related Illness in the Workplace. AB - The common practice of workers resting in the shade to dissipate body heat can be complemented by ingestion of crushed ice or immersion in temperate water to rapidly lower core body temperature. PMID- 26585174 TI - Childhood-onset Takayasu arteritis: an update. AB - Childhood-onset Takayasu arteritis (c-TA) is a distinct subset affecting a wide age group, ranging from young infants to adolescents and it differs from adult TA in many aspects. There is scarcity of data on c-TA worldwide. The disease is classified using the European League Against Rheumatism/Pediatric Rheumatology International Trials Organization/Pediatric Rheumatology European Society criteria. The non-specific nature of presenting complaints and lack of appropriate biomarkers delay the early diagnosis of this illness and many children present with complications, which become irreversible once they set in. One of the largest cohorts of 40 children with c-TA from our center reports hypertension as the commonest presenting feature. Systemic symptoms like headache, fever and weight loss are also described. Assessment of disease in c-TA is done by correlating clinical features with raised inflammatory markers. Advanced imaging plays an important role in diagnosis. In c-TA, the role of magnetic resonance angiography is advocated, taking into consideration the enormous amount of radiation exposure with other modalities. Complications of c TA include cardiovascular, pulmonary, neurological and those arising secondary to long-term steroid and immunosuppression therapy. PMID- 26585175 TI - Diclofenac/misoprostol during early pregnancy and the risk of miscarriage: a Danish nationwide cohort study. AB - INTRODUCTION: Misoprostol can be used in the prevention of gastric ulcer in treatment with diclofenac and is used in rheumatic diseases. Since misoprostol causes contractions of the uterus, it can also be used to induce abortions when administrated vaginally. The aim of the study was to investigate if early pregnancy exposure to oral diclofenac/misoprostol was associated with miscarriage. METHOD: We conducted a nationwide cohort study identifying all registered pregnancies in Denmark from 1997 to 2011. All births were identified using the Medical Birth Registry, and all records of induced abortion and miscarriage were from the National Hospital Register. Data on drug use were from the National Prescription Register. Cox proportional hazard regression models were used to calculate the hazard of miscarriage in women exposed to diclofenac/misoprostol in early pregnancy. RESULT: We identified 1,338,824 pregnancies (970,491 births, 142,147 miscarriages, 226,145 induced abortions). One hundred sixty-six were exposed to diclofenac/misoprostol in the early pregnancy of which 28.3 % (47) ended up in a miscarriage compared to 10.6 % among unexposed. The adjusted hazard ratio of having a miscarriage after exposure to diclofenac/misoprostol in the first trimester was 3.6 (CI 95 % 2.6-4.9). CONCLUSION: We found an increased risk of miscarriage after exposure to diclofenac/misoprostol during the early pregnancy. Women in the fertile age should not be treated with the combination of diclofenac/misoprostol if other options were available. PMID- 26585176 TI - An anthraquinone derivative from Luffa acutangula induces apoptosis in human lung cancer cell line NCI-H460 through p53-dependent pathway. AB - The current study was designed to evaluate the in vitro antiproliferative activity of 1,8-dihydroxy-4-methylanthracene-9,10-dione (DHMA) isolated from the Luffa acutangula against human non-small cell lung cancer cell line (NCI-H460). Induction of apoptosis and reactive oxygen species (ROS) generation was determined through fluorescence microscopic technique. Quantitative real-time PCR and western blotting analysis was carried out to detect the expression of pro apoptotic (p53, p21, caspase-3, Bax, GADD45A, and ATM) and anti-apoptotic (NF kappaB) proteins in NCI-H460 cell line. In silico studies also performed to predict the binding mechanism of DHMA with MDM2-p53 protein. The DHMA inhibited the cell viability of NCI-H460 cells in a dose-dependent manner with an IC(50) of about 50 ug/ml. It significantly reduced cell viability correlated with induction of apoptosis, which was associated with ROS generation. The apoptotic cell death was further confirmed through dual staining and DNA fragmentation assay. DHMA significantly increased the expression of anti-apoptotic protein such as p53, p21, Bax, and caspase-3 but downregulated the expression of NF-kappaB in NCI-H460 cell line. In silico studies demonstrate that DHMA formed hydrogen bond interaction with key residues Trp26, Phe55 and Lys24 by which it disrupt the binding of p53 with MDM2 receptor. These findings suggested that DHMA induces apoptosis in NCI-H460 via a p53-dependent pathway. This the first study on cytotoxic and apoptosis inducing activity of DHMA from L. acutangula against NCI H460 cell line. Therefore, DHMA has therapeutic potential for lung cancer treatment. PMID- 26585177 TI - Fellow use of medical jargon correlates inversely with patient and observer perceptions of professionalism: results of a rheumatology OSCE (ROSCE) using challenging patient scenarios. AB - The NYC Rheumatology Objective Structured Clinical Examination (NYC-ROSCE) is held annually to assess fellow competencies. We recently redesigned our OSCE to better assess subspecialty trainee communication skills and professionalism by developing scenarios in which the patients encountered were psychosocially or medically complex. The objective of this study is to identify which types of verbal and non-verbal skills are most important in the perception of professionalism in the patient-physician interaction. The 2012-2013 NYC-ROSCEs included a total of 53 fellows: 55 MD evaluators from 7 NYC rheumatology training programs (Hospital for Special Surgery-Weill Cornell (HSS), SUNY/Downstate, NYU, Einstein, Columbia, Mount Sinai, and North Shore/Long Island Jewish (NSLIJ)), and 55 professional actors/standardized patients participated in 5 stations. Quantitative fellow performance assessments were made on the following: maintaining composure; partnering with the patient; honesty; professionalism; empathy; and accountability. Free-text comments were solicited regarding specific strengths and weaknesses. A total of 53/53 eligible (100 %) fellows were evaluated. MD evaluators rated fellows lower for professionalism than did the standardized patients (6.8 +/- 0.6 vs. 7.4 +/- 0.8, p = 0.05), suggesting that physicians and patients view professionalism somewhat differently. Fellow self evaluations for professionalism (6.6 +/- 1.2) were concordant with those of the MD evaluators. Ratings of empathy by fellows themselves (6.6 +/- 1.0), MD evaluators (6.6 +/- 0.7), and standardized patients (6.6 +/- 1.1) agreed closely. Jargon use, frequently cited by evaluators, showed a moderate association with lower professionalism ratings by both MD evaluators and patients. Psychosocially challenging patient encounters in the NYC-ROSCE permitted critical assessment of the patient-centered traits contributing to impressions of professionalism and indicate that limiting medical jargon is an important component of the competency of professionalism. PMID- 26585178 TI - A Carbohydrate Sulfotransferase-6 (CHST6) gene mutation is associated with Macular Corneal Dystrophy in Labrador Retrievers. AB - PURPOSE: To locate and identify variants associated with macular corneal dystrophy (MCD) in Labrador Retriever (LR) dogs, in the candidate gene carbohydrate sulfotransferase-6 (CHST6). METHODS: The single coding exon of canine CHST6 was sequenced in one affected LR with MCD and one control LR clinically clear of ocular disease. A further 71 control LR with unknown clinical status were sequenced for the putative causal variant in CHST6. A TaqMan SNP genotyping assay was developed and used to screen an additional 84 dogs (five affected LR and 79 clinically clear LR). Finally, the variant was screened in a third cohort of 89 unrelated LR with unknown clinical status to estimate its allele frequency in the population of LR in the United Kingdom. RESULTS: A single nucleotide polymorphism (SNP) was identified within the coding exon of CHST6, resulting in a missense mutation (c.814C>A, p.R272S). All six LR affected with MCD were homozygous for the mutant allele, while 140/151 control LR were homozygous for the wild-type allele and 11/151 were heterozygous for the mutation, indicating an association with MCD (P < 10-5 ). The mutant allele was present in the unrelated LR cohort at a frequency of 0.017, suggesting carrier and affection rates of 3.3% and 0.028%, respectively. CONCLUSIONS: A missense mutation in the CHST6 gene is strongly associated with autosomal recessive MCD in the LR. PMID- 26585179 TI - Failure to meet language milestones at two years of age is predictive of specific language impairment. AB - AIM: This study established predictive properties of single language milestones for specific language impairment (SLI) after the age of four, as these had not previously been reported in the literature. METHODS: In this nested case-control study, children attending special needs schools for severe speech and language difficulties were matched with children attending mainstream schools. Data covering the ages of zero to four years were retrieved from well-child care clinics and the outcomes of 23 language milestones in the Dutch Developmental Instrument were analysed. The predictive properties were expressed as positive likelihood ratios, sensitivity and specificity. RESULTS: We included 253 pairs of children with and without SLI, aged from four to 11 years. The mean age was eight years and three months, and 77% were boys. From the age of 18 months, cases and controls differed significantly on all milestones (p < 0.01). After 24 months, the language milestones had positive likelihood ratios that ranging from 6 to 108. In general, language milestones had a high specificity (range 77-100%), but the sensitivity was relatively low (range 0-68%). CONCLUSION: Failure to meet language milestones from the age of 24 months was predictive of SLI, but the use of separate milestones had limited value due to low sensitivity. PMID- 26585180 TI - Conceiving a national head and neck cancer screening programme. AB - BACKGROUND: This study was undertaken to determine the optimum approach to screening for head and neck cancer based on international experiences. OBJECTIVE: To determine whether or not head and neck cancer is suitable for screening, and, if so, what the ideal approach should be. METHODS: An electronic search of online databases up to and including May 2014 was conducted. Key search terms included 'head and neck', 'cancer', 'screening', 'larynx', 'oropharynx' and 'oral'. RESULTS: Subset analysis of high-risk cohorts showed statistically significant improvements in early detection of head and neck cancer via screening. CONCLUSION: Current levels of public awareness regarding head and neck cancers are suboptimal, despite increased incidence and mortality. Scheduled and opportunistic screening, coupled with efforts to enhance education and health behaviour modification, are highly recommended for pre-defined, high-risk, targeted populations. This can enable early detection and therefore improve morbidity and mortality. PMID- 26585181 TI - Sialendoscopy with the use of a syringe pump. PMID- 26585182 TI - The claim that China's fertility restrictions contributed to the use of prenatal sex selection: A sceptical reappraisal. AB - Most observers assume that China's fertility restrictions contribute to the use of prenatal sex selection. I question the logic and evidence underlying that assumption. Experts often stress that China's low fertility is largely voluntary, and that fertility restrictions are an unneeded safety valve. Others claim that China's '1.5-child' loophole, common throughout rural areas, reinforces son preference or intensifies prenatal sex discrimination by hardening fertility constraints. These claims defy logic upon closer examination. Moreover, almost two-thirds of the exceptional distortion of the sex ratio in 1.5-child areas results from excess underreporting of daughters and enforced sex-specific stopping. Prenatal sex selection may explain the remaining third but probably reflects the stronger rural son preference that led to the 1.5-child loophole itself. The recent surge in sex selection of first births that has perpetuated the distortions also seems unrelated to policy. Some son-preferring parents who formerly wanted two children may now genuinely want only one. PMID- 26585183 TI - Premarital first births: The influence of the timing of sexual onset versus post onset risks in the United States. AB - Motivated by long-standing debates between abstinence proponents and sceptics, we examine how socio-economic factors influence premarital first births via: (i) age at first sexual intercourse and (ii) the risk of a premarital first birth following the onset of sexual activity. Factors associated with an earlier age at first intercourse will imply more premarital first births owing to increased exposure to risk, but many of these same factors will also be associated with higher risks of a premarital first birth following onset. Our analyses confirm previous findings that women from disadvantaged backgrounds are younger at first intercourse and have higher premarital first-birth risks than women from more advantaged backgrounds. However, differences in onset timing have a strikingly smaller influence on premarital first-birth probabilities than do differences in post-onset risks. Our findings thus suggest that premarital first births result primarily from differences in post-onset risk behaviours as opposed to differences in onset timing. PMID- 26585184 TI - Residential proximity of parents and their adult offspring in the United Kingdom, 2009-10. AB - Using data from a large household survey representative of the UK population, we studied how closely parents and adult children live to each other. We show that residential mobility over the life course tends to increase with the physical distance between the homes of parent and child. There are large differences in intergenerational proximity between the foreign-born and UK-born, and between ethnic groups. The determinants of intergenerational proximity from the parent's viewpoint are not identical to those from the child's viewpoint. Contrary to the findings of some earlier studies, intergenerational proximity, from the child's viewpoint, does not vary with the number of siblings. But from the parent's viewpoint, having more children is unambiguously associated with a higher probability of living close to at least one child. We end with a brief discussion of some possible implications of several long-term demographic trends in the UK for intergenerational proximity. PMID- 26585187 TI - Mind-Body Medicine in the Secondary Prevention of Coronary Heart Disease. AB - BACKGROUND: In mind-body medicine (MBM), conventional lifestyle modification measures such as dietary counseling and exercise are supplemented with relaxation techniques and psychological motivational elements. This review studied the effect of MBM on cardiac events and mortality in patients with coronary heart disease (CHD). METHODS: This review is based on publications up to and including January 2015 that were retrieved by a systematic search in PubMed, the Cochrane Library, and Scopus. Randomized controlled trials of the effect of MBM programs (versus standard treatment) on cardiac events, overall mortality, and/or cardiac mortality were analyzed. Atherosclerosis, blood pressure, LDL cholesterol, and the body mass index (BMI) were chosen as secondary outcomes. Random-effects meta analyses were performed. The risk of bias was assessed with the Cochrane tool. RESULTS: Twelve trials, performed on a total of 1085 patients, were included in the analysis. Significant differences between groups were found with respect to cardiac events (odds ratio [OR]: 0.38; 95% confidence interval [CI]: 0.23-0.61; p<0.01; heterogeneity [I2]: 0%), but not overall mortality (OR: 0.82; 95% CI: 0.46-1.45; p = 0.49; I2: 0%) or cardiac mortality (OR: 0.98; 95% CI: 0.43-2.25; p = 0.97; I2: 0%). Significant differences between groups were also found with respect to atherosclerosis (mean difference [MD] = -7.86% diameter stenosis; 95% CI: -15.06-[-0.65]; p = 0.03; I2: 0%) and systolic blood pressure (MD = -3.33 mm Hg; 95% CI: -5.76-[-0.91]; p<0.01; I2: 0%), but not with respect to diastolic blood pressure, LDL cholesterol, or BMI. CONCLUSION: In patients with CHD, MBM programs can lessen the occurrence of cardiac events, reduce atherosclerosis, and lower systolic blood pressure, but they do not reduce mortality. They can be used as a complement to conventional rehabilitation programs. PMID- 26585189 TI - The Role of Tandem Double-J Ureteral Stents in the Management of Malignant Ureteral Obstruction. AB - AIM: The management of malignant ureteral obstruction (MUO) is a challenging but common problem for urologists. The different techniques currently used to address this complicated issue include percutaneous nephrostomy, extra-anatomical stents, retrograde (single) stent insertion, and metallic stents. In those situations where single ureteral stent insertion has failed, retrograde tandem or twin ureteral stent (TUS) insertion can be completed. The aim of this study was to report our clinical experience and also assess the efficacy of TUS insertion within our tertiary referral center. METHODS: Data were prospectively collected from patients requiring TUSs over an 8-year period between January 1, 2006, and December 31, 2014. A number of variables, including the improvement in renal function following TUS insertion, were recorded. RESULTS: Twenty-two TUS insertion procedures were performed on 15 patients between the period of January 1, 2006, and December 31, 2014. The mean patient age was 68.0 years (39-85 years). There were 15 primary insertions as well as 7 subsequent stent changes. The average prenephrostomy creatinine was 428 MUmol/L; an average improvement of 196 MUmol/L was observed after percutaneous drainage. Serum creatinine after TUS remained stable on discharge, 214 MUmol/L vs 227 MUmol/L preoperatively, p = 0.34. Eleven patients died at a median 131 days post-TUS insertion. TUS failure occurred in three patients; this was characterized by rising creatinine and worsening hydronephrosis. Patients with failing TUS had a median life expectancy of 45.6 days compared with 162.5 days for those with functioning TUS (p < 0.05). Overall, the patency rate at 3 months was 80%. CONCLUSION: TUS insertion is a technically efficient and effective procedure in the management of MUO, with the majority of patients treated dying of the underlying condition with functioning stents in situ. PMID- 26585190 TI - Study of the association of IL-1beta and IL-1RA gene polymorphisms with occurrence and severity of Familial Mediterranean fever. AB - Familial Mediterranean fever (FMF) is a recessive autoinflammatory disorder. The balance between the pro-inflammatory cytokine IL-1beta and its receptor antagonist IL-1RA plays an important role in the development of FMF. In order to determine a possible association of polymorphisms in IL-1beta and IL-1RA genes with occurrence and/or severity of the disease, 42 genetically confirmed FMF patients and 42 controls were genotyped for IL-1beta(-511C/T), IL-1beta(-31T/C), IL1-1beta(+3954T/C) and IL-1RA VNTR polymorphisms. IL-1beta and IL-1RA levels were evaluated by multiplex ELISA in supernatants of PBMC cultures of 30 FMF patients with and without 24h stimulation of monocytes by LPS. The CC genotype and C allele at positions -31 and + 3954 of IL-1beta gene were more frequent in FMF patients than in controls. FMF patients carriers of IL-1beta(-31) CC genotype were associated with a 2-fold increase in LPS-induced IL-1beta secretion as well as a higher disease severity score (11.2 +/- 2.9) when compared to patients carrying the TC and TT genotypes (6.1 +/- 2.1 and 4.5 +/- 2.4, respectively). These results indicate that IL-1beta gene polymorphisms at positions -31 and + 3954 may be associated with an increased risk for FMF. IL-1beta(-31) contributes also to the severity of the disease, probably by modulating IL-1beta synthesis. PMID- 26585188 TI - The Interdisciplinary Management of Acute Chest Pain. AB - BACKGROUND: Acute chest pain of non-traumatic origin is a common reason for presentation to physician's offices and emergency rooms. Coronary heart disease is the cause in up to 25% of cases. Because acute chest pain, depending on its etiology, may be associated with a high risk of death, rapid, goal-oriented management is mandatory. METHODS: This review is based on pertinent articles and guidelines retrieved by a selective search in PubMed. RESULTS: History-taking, physical examination, and a 12-lead electrocardiogram (ECG) are the first steps in the differential diagnostic process and generally allow the identification of features signifying a high risk of lifethreatening illness. If the ECG reveals ST segment elevation, cardiac catheterization is indicated. The timedependent measurement of highly sensitive troponin values is a reliable test for the diagnosis or exclusion of acute myocardial infarction. A wide variety of other potential causes (e.g., vascular, musculoskeletal, gastroenterologic, or psychosomatic) must be identified from the history if they are to be treated appropriately. Elderly patients need special attention. CONCLUSION: Acute chest pain is a major diagnostic challenge for the physician. Common errors are traceable to non-recognition of important causes and to an inadequate diagnostic work-up. Future studies should be designed to help optimize the interdisciplinary management of patients with chest pain. PMID- 26585191 TI - Robot-assisted partial nephrectomy: Superiority over laparoscopic partial nephrectomy. AB - Nephron-sparing surgery has been proven to positively impact the postoperative quality of life for the treatment of small renal tumors, possibly leading to functional improvements. Laparoscopic partial nephrectomy is still one of the most demanding procedures in urological surgery. Laparoscopic partial nephrectomy sometimes results in extended warm ischemic time and severe complications, such as open conversion, postoperative hemorrhage and urine leakage. Robot-assisted partial nephrectomy exploits the advantages offered by the da Vinci Surgical System to laparoscopic partial nephrectomy, equipped with 3-D vision and a better degree in the freedom of surgical instruments. The introduction of the da Vinci Surgical System made nephron-sparing surgery, specifically robot-assisted partial nephrectomy, safe with promising results, leading to the shortening of warm ischemic time and a reduction in perioperative complications. Even for complex and challenging tumors, robotic assistance is expected to provide the benefit of minimally-invasive surgery with safe and satisfactory renal function. Warm ischemic time is the modifiable factor during robot-assisted partial nephrectomy to affect postoperative kidney function. We analyzed the predictive factors for extended warm ischemic time from our robot-assisted partial nephrectomy series. The surface area of the tumor attached to the kidney parenchyma was shown to significantly affect the extended warm ischemic time during robot-assisted partial nephrectomy. In cases with tumor-attached surface area more than 15 cm(2) , we should consider switching robot-assisted partial nephrectomy to open partial nephrectomy under cold ischemia if it is imperative. In Japan, a nationwide prospective study has been carried out to show the superiority of robot-assisted partial nephrectomy to laparoscopic partial nephrectomy in improving warm ischemic time and complications. By facilitating robotic technology, robot assisted partial nephrectomy will be more frequently carried out as a safe, effective and minimally-invasive nephron-sparing surgery procedure. PMID- 26585192 TI - Prevention of bacterial infections in the newborn by pre-delivery administration of azithromycin: Study protocol of a randomized efficacy trial. AB - BACKGROUND: Neonatal deaths, estimated at approximately 4 million annually, now account for almost 40% of global mortality in children aged under-five. Bacterial sepsis is a leading cause of neonatal mortality. Assuming the mother is the main source for bacterial transmission to newborns, the primary objective of the trial is to determine the impact of one oral dose of azithromycin, given to women in labour, on the newborn's bacterial carriage in the nasopharynx. Secondary objectives include the impact of the intervention on bacterial colonization in the baby and the mother during the first month of life. METHODS/DESIGN: This is a Phase III, double -blind, placebo controlled randomized clinical trial in which 830 women in labour were randomized to either a single dose of 2 g oral azithromycin or placebo (ratio 1:1). The trial included pregnant women in labour aged 18 to 45 years attending study health centres in the Western Gambia. A post natal check of the mother and baby was conducted at the health centre by study clinicians before discharge and 8-10 days after delivery. Home follow up visits were conducted daily during the first week and then weekly until week 8 after delivery. Vaginal swabs and breast milk samples were collected from the mothers, and the pathogens Streptococcus pneumoniae, Group B Streptococcus (GBS) and Staphylococcus aureus were isolated from the study samples. For bacterial isolates, susceptibility pattern to azithromycin was determined using disk diffusion and E-test. Eye swabs were collected from newborns with eye discharge during the follow up period, and Chlamydial infection was assessed using molecular methods. DISCUSSION: This is a proof-of-concept study to assess the impact of antibiotic preventive treatment of women during labour on bacterial infections in the newborn. If the trial confirms this hypothesis, the next step will be to assess the impact of this intervention on neonatal sepsis. The proposed intervention should be easily implementable in developing countries. TRIAL REGISTRATION: ClinicalTrials.gov Identifier--NCT01800942--First received: February 26, 2013. PMID- 26585193 TI - Isolation of a Female-Emitted Sex Pheromone Component of the Fungus Gnat, Lycoriella ingenua, Attractive to Males. AB - Lycoriella ingenua Dufour (Diptera: Sciaridae) is acknowledged as the major pest species of the white button mushroom, Agaricus bisporus, throughout the world. Components of the female-produced sex pheromone of this species were identified previously as C15-C18 n-alkanes, with the major component n-heptadecane, and shown to be attractive to L. mali. However, a subsequent report could not repeat this work. We reinvestigated the sex pheromone of this species by confirming that virgin females were attractive to males in a Y-tube bioassay and by collection of extracts from virgin females. Extracts were analyzed by gas chromatography coupled to electroantennographic detection, and by the less widely-used technique of gas chromatography coupled to a behavioral bioassay to detect compounds causing wing-fanning and copulatory abdomen curling in males. A single, behaviorally-active pheromone component was isolated and characterized by gas chromatography coupled to mass spectrometry. This component was definitively not n-heptadecane or any of the other C15-C19 n-alkanes reported previously, but is proposed to be a sesquiterpene alcohol having analytical characteristics that closely matched those of reference germacradienols. PMID- 26585194 TI - Resident involvement in laparoscopic procedures does not worsen clinical outcomes but may increase operative times and length of hospital stay. AB - BACKGROUND: Surgical procedures have a learning curve regarding the number of cases required for proficiency. Consequently, involvement of less experienced resident surgeons may impact patients and the healthcare system. This study examines basic and advanced laparoscopic procedures performed between 2010 and 2011 and evaluates the resident surgeon participation effect. METHODS: Basic laparoscopic procedures (BL), appendectomy (LA), cholecystectomy (LC), and advanced Nissen fundoplication (LN) were queried from the American College of Surgeons National Surgical Quality Improvement Program database. Cases were identified using Current Procedural Terminology codes. Analyses were performed using IBM SPSS Statistics v.22, alpha-level = 0.05. Multiple logistic regression was used, accounting for age, race, gender, admission status, wound classification, and ASA classification. RESULTS: In total, 71,819 surgeries were reviewed, 66,327 BL (37,636 LC and 28,691 LA) and 5492 LN. Median age was 48 years for LC and 37 years for LA. In sum, 72.2 % of LC and 49.5 % of LA patients were female. LN median age was 59 years, and 67.7 % of patients were female. For BL, resident involvement was not significantly associated with mortality, morbidity, and return to the OR. Readmission was not related to resident involvement in LC. In LA, resident-involved surgeries had increased readmission and longer OR time, but decreased LOS. In LC, resident involvement was associated with longer LOS and OR time. Resident involvement was not a significant factor in the odds of mortality, morbidity, return to OR, or readmission in LN. Surgeries involving residents had increased odds of having longer LOS, and of lengthier surgery time. CONCLUSIONS: We demonstrate resident involvement is safe and does not result in poorer patient outcomes. Readmissions and LOS were higher in BL, and operative times were longer in all surgeries. Resident operations do appear to have real consequences for patients and may impact the healthcare system financially. PMID- 26585196 TI - Quality of life, diet and exercise measurements in obese individuals with and without ventilatory failure. PMID- 26585195 TI - Methods for studying human organogenesis. AB - This review details methods for utilizing D & C suction abortus specimens as a source of human fetal organs to study the morphogenetic and molecular mechanisms of human fetal organ development. By this means it is possible to design experiments elucidating the molecular mechanisms of human fetal organ development and to compare and contrast human developmental mechanisms with that of laboratory animals. Finally human fetal organs can be grown in vivo as grafts to athymic mice, thus allowing ethical analysis of potential adverse effects of environmental toxicants. PMID- 26585197 TI - The use of inhaled nitrous oxide for analgesia in adult ED patients: a pilot study. AB - BACKGROUND: Oligoanalgesia challenges emergency department (ED) health care providers and remains an area of patient dissatisfaction. Nitrous oxide (NO) is a safe, quick-acting, and well-tolerated sedative agent with analgesic and anxiolytic properties that make it ideal for ED use. OBJECTIVES: We seek to test the effectiveness of a self-administered and self-contained NO device as an analgesic agent in the ED and assess patient and staff satisfaction with this method. METHODS: We enrolled 85 patients 18 years and older in a prospective observational study of patients presenting to the ED with moderate to severe pain (>=30 mm on a 100-mm visual analog scale). Subjects received a mixture of 50% NO via a self-administered portable delivery device. Primary outcome was the reduction in baseline pain scores at 20, 40, and 60 minutes. Secondary outcomes were patient, nurse, and physician satisfaction as reported on a brief satisfaction questionnaire. RESULTS: There was a significant reduction in mean pain scores from baseline to 20 minutes that was sustained through the 60-minute period. Most subjects (93%; 95% confidence interval [CI], 85%-97%) and nurses (97%; 95% CI, 90%-99%) reported that the NO delivery system was easy to use and were satisfied with the level of pain relief and would use NO in the future (82%; 95% CI, 73%-89%). Physicians and nurses were also satisfied with the analgesic effects of NO (82%; 95% CI, 73%-89%). CONCLUSIONS: The portable NO device is an effective analgesia adjunct for ED patients presenting with painful conditions, and patients, ED nurses, and emergency physicians are satisfied with its use. Nitrous oxide coupled with a nurse-driven analgesia protocol may provide a novel solution for improvement in ED analgesia rates and overall patient satisfaction with ED pain management. PMID- 26585198 TI - Safety of laryngeal tubes. PMID- 26585199 TI - Monocyte to high-density lipoprotein ratio as a new prognostic marker in patients with STEMI undergoing primary percutaneous coronary intervention. AB - BACKGROUND: Monocyte count to high-density lipoprotein ratio (MHR) has recently emerged as an indicator of inflammation and oxidative stress in the literature. We aimed to investigate the prognostic value of MHR in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention (PCI). METHODS: A total of 513 patients who were hospitalized with diagnosis of acute ST-segment elevation myocardial infarction and treated with primary PCI were retrospectively enrolled in the study. Demographic and clinical data, admission laboratory parameters, and MHR values were recorded. Inhospital major adverse cardiac events (MACE) and mortality were reported as the clinical outcomes. RESULTS: Twenty-six patients (5%) died, and MACE was observed in 86 patients (17%) during hospital follow-up. Patients were categorized in 3 groups according to tertiles of admission MHR. The rates of inhospital mortality and MACE were significantly higher in tertile 3 group compared to tertile 1 group (10% vs 1%, 27% vs 11%; P < .01 and P < .01). In multivariate regression analysis, age, sex, presence of Killip 3 or 4, left ventricular ejection fraction, troponin I, C-reactive protein, and increased MHR levels (odds ratio, 1.03; 95% confidence interval, 1.01-1.05; P < .01) independently predicted inhospital mortality; age, presence of Killip 3 or 4, troponin I, and increased MHR levels (odds ratio, 1.02; 95% confidence interval, 1.01-1.04; P < .01) independently predicted MACE. CONCLUSION: Admission MHR values were found to be independently correlated with inhospital MACE and mortality after primary PCI. PMID- 26585200 TI - Acute Care Diagnostics Collaboration: Assessment of a Bayesian clinical decision model integrating the Prehospital Sepsis Score and point-of-care lactate. AB - Previous research demonstrated that shock index and respiratory rate are highly predictive of intensive care unit admissions. OBJECTIVE: The objective of the study is to evaluate the integration of the prehospital sepsis project score (PSP S) and point-of-care lactate in assisting prediction of severity of illness using Bayesian statistical modeling. METHODS: The PSP-S incorporates fever (38 degrees C [100.4 degrees F]) allotted with 1 point, shock index greater than or equal to 0.7 given 2 points, and a respiratory rate greater than or equal to 22 breaths per minute given 1 point for a total maximum score of 4 points. The patient population was stratified based on the PSP-S: 1 point is low risk, 2 points is moderate risk, and 3 to 4 points is high risk. Percentage risk was obtained based on intensive care unit admissions and used as pretest probability. Prehospital lactate pooled data were obtained and used to calculate likelihood ratio (LR). Percentage risk used as pretest probability and LRs for prehospital lactate were charted into the Bayesian nomogram to obtain posttest probabilities. Absolute diagnostic gain (ADG) and relative diagnostic gains (RDG) were then calculated. RESULTS: Pooled data for prehospital point of care lactate demonstrated a positive LR of 1.6 and negative LR of 0.44. Posttest probability for low risk was 16% with an ADG of 6% and RDG of 160%. Moderate risk population yielded a posttest probability of 47%, ADG of 12.5%, and RDG of 136.2%. High-risk population resulted in a posttest probability of 72%, ADG of 12%, and RDG of 120%. CONCLUSION: We found that PSP-S can be clinically complemented with the use of point-of-care lactate. PMID- 26585201 TI - Enrollment with a primary care provider does not preclude ED visits for patients with woman's health-related problems. AB - OBJECTIVE: The Affordable Care Act places primary care at the cornerstone of health maintenance. It is believed that increasing access to primary health care providers will limit emergency department (ED) use. This study examines woman's health-related ED visits by patients enrolled in an obstetric/gynecologic (OB/GYN) clinic. METHODS: A database was created combining patient information from a hospital-affiliated OB/GYN clinic and the electronic medical records from the ED of the affiliated hospital. This database was used to evaluate woman's health-related ED use by patients registered in this OB/GYN clinic compared with patients not affiliated with the clinic. RESULTS: Over an 23-month period, there were 41,791 ED visits made by 21,223 individual women >12 years of age. A total of 7251 (17.4%) of the ED visits were for OB/GYN-related conditions. There were 6430 individual women registered at the OB/GYN clinic, 1411 (22.0%) of whom made 2415 woman's health-related visits to the ED. Of the OB/GYN-related ED visits by clinic patients, 1794 (74.3%) were made during weekdays and 1023 (42.3%) were made during hours when the clinic was open for care. Study patients had diagnostic studies beyond a urine analysis or pregnancy test performed during 61% of ED visits, with an admission rate of 2%. CONCLUSION: Enrollment with a primary care provider alone does not eliminate the need for ED use in women with health related conditions. PMID- 26585202 TI - Fast separation of selected cathinones and phenylethylamines by supercritical fluid chromatography. AB - The chromatographic behaviour of eleven synthetic cathinones and four phenylethylamines under supercritical/subcritical fluid conditions was investigated. Four stationary phases with sub-2MUm particles (Waters Acquity UPC(2) BEH silica, BEH 2-ethylpyridine, CSH Fluoro-Phenyl, and HSS C18SB) were evaluated in terms of isomer resolution, chromatographic peak shape, and analysis time. Methanol, water, formic acid, ammonium hydroxide, ammonium acetate, and ammonium formate were mixed with carbon dioxide to test their influence on analyte retention and peak shapes. Methanol and ammonium cations were essential for successful separations. Efficient separations of four isomeric pairs (R>1), and most of the remaining analytes, were achieved in less than 3.3min on BEH and Fluoro-Phenyl columns with gradient of methanolic ammonium hydroxide in CO2. Drugs were detected by positive electrospray ionization-triple quadrupole mass spectrometry in selected reaction monitoring mode. Added detection specificity and faster separation of isomers on the BEH column using a steep gradient and high flow rate reduced analysis time of the mixture of 15 drugs to 1.6min. PMID- 26585203 TI - Lipidomics of tobacco leaf and cigarette smoke. AB - Detailed lipidomics experiments were performed on the extracts of cured tobacco leaf and of cigarette smoke condensate (CSC) using high-resolution liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (LC-Q-TOF MS). Following automated solid-phase extraction (SPE) fractionation of the lipid extracts, over 350 lipids could be annotated. From a large-scale study on 22 different leaf samples, it was determined that differentiation based on curing type was possible for both the tobacco leaf and the CSC extracts. Lipids responsible for the classification were identified and the findings were correlated to proteomics data acquired from the same tobacco leaf samples. Prediction models were constructed based on the lipid profiles observed in the 22 leaf samples and successfully allowed for curing type classification of new tobacco leaves. A comparison of the leaf and CSC data provided insight into the lipidome changes that occur during the smoking process. It was determined that lipids which survive the smoking process retain the same curing type trends in both the tobacco leaf and CSC data. PMID- 26585204 TI - Determination of relative enantiomer migration order using a racemic sample. AB - We developed a method that enables us to distinguish between the same or the opposite enantiomer migration order (EMO) of two enantiomers of a chiral compound with two different selectors. The method is applicable to racemic samples and thus a standard of the pure enantiomeric form(s) is not required. First, complexation constants and mobilities of complexes of the two enantiomers with the first and second selector are determined. However, for a racemic sample it is not possible to deduce whether the first migrating enantiomer with one selector is the same one as the first migrating enantiomer with the second selector. A specific mixture of the two selectors is designed to resolve this. In case the two enantiomers exhibit the same, respectively the opposite EMO in the two selectors, the mixture does, respectively does not separate the racemic sample. Thus two peaks are detected in the first case, while a single coalescent peak is recorded in the opposite case. We demonstrate the method on a racemic sample of amphetamine. Its relative EMO is determined with three cyclodextrins, heptakis(2,3,6-tri-O-methyl)-beta-cyclodextrin, (2-hydroxypropyl)-beta cyclodextrin and heptakis(2,3-di-O-acetyl-6-O-sulfo)-beta-cyclodextrin. PMID- 26585205 TI - Tailoring and recycling of deep eutectic solvents as sustainable and efficient extraction media. AB - The present study demonstrates that deep eutectic solvents (DESs) with the highest extractability can be designed by combining effective DES components from screening diverse DESs. The extraction of polar ginseng saponins from white ginseng was used as a way to demonstrate the tuneability as well as recyclability of DESs. A newly designed ternary DES (GPS-5) composed of glycerol, l-proline, and sucrose at 9:4:1 was used as a sustainable and efficient extraction medium. Based on the anti-tumor activity on HCT-116 cancer cells, it was confirmed that GPS-5 was merely an extraction solvent with no influence of the bioactivity of the ginsenosides extracted. Excellent recovery of the extracted saponins was easily achieved through solid-phase extraction (SPE). Recycling of the DES was accomplished by simple freeze-drying of the washed solutions from the SPE. The extraction efficiencies of the DESs recycled once, twice, and thrice were 92%, 85%, and 83% of that of the freshly synthesized solvent. PMID- 26585206 TI - Hyphenated and comprehensive liquid chromatography * gas chromatography-mass spectrometry for the identification of Mycobacterium tuberculosis. AB - Tuberculosis is one of the world's most emerging public health problems, particularly in developing countries. Chromatography based methods have been used to tackle this epidemic by focusing on biomarker detection. Unfortunately, interferences from lipids in the sputum matrix, particularly cholesterol, adversely affect the identification and detection of the marker compounds. The present contribution describes the serial combination of normal phase liquid chromatography (NPLC) with thermally assisted hydrolysis and methylation followed by gas chromatography-mass spectrometry (THM-GC-MS) to overcome the difficulties of biomarker evaluation. The in-series combination consists of an LC analysis where fractions are collected and then transferred to the THM-GC-MS system. This was either done with comprehensive coupling, transferring all the fractions, or with hyphenated interfacing, i.e. off-line multi heart-cutting, transferring only selected fractions. Owing to the high sensitivity and selectivity of LC as a sample pre-treatment method, and to the high specificity of the MS as a detector, this analytical approach, NPLC * THM-GC-MS, is extremely sensitive. The results obtained indicate that this analytical set-up is able to detect down to 1 * 10(3) mycobacteria/mL of Mycobacterium tuberculosis strain 124, spiked in blank sputum samples. It is a powerful analytical tool and also has great potential for full automation. If further studies demonstrate its usefulness when applied blind in real sputum specimens, this technique could compete with the current smear microscopy in the early diagnosis of tuberculosis. PMID- 26585207 TI - A fast and innovative microextraction technique, MUSPEed, followed by ultrahigh performance liquid chromatography for the analysis of phenolic compounds in teas. AB - The objective of this study was to evaluate the efficiency of a promising solid phase microextraction technique, MUSPEed, in the analysis of selected phenolic compounds from teas by ultrahigh performance liquid chromatography with photodiode array detection (MUSPEed/UHPLC-PDA). The innovative MUSPEed configuration uses 3-MUm sorbent particles tightly packed in a disposable needle equipped with a pressure-driven valve to withdraw samples in a single direction. The system was operated by the electronic pipette eVol(r) and different parameters influencing the extraction efficiency, as the nature of sorbent, pH, loading and elution conditions, and solvents were optimized. The best extracting conditions were obtained by loading twice 100MUL of tea samples through the PS/DVB-RP sorbent and eluting with 50MUL of acidified MeOH 95%. The following chromatographic separation was carried out in an Acquity C18 BEH capillary column using a gradient of 0.1% FA and acetonitrile. The optimized MUSPEed/UHPLC-PDA methodology is selective and specific and was properly validated for 8 phenolic compounds widely reported in different teas. Overall, an excellent analytical performance was obtained in the 0.2-20MUg/L linear dynamic range (LDR), with very low limits of detection (LODs) and quantification (LOQs), ranging between 3.5 16.8ng/mL and 10.6-50.6ng/mL, respectively, high recoveries (89.3-103.3%), good precision (RSD<5%) and negligible matrix effect. The methodology was used to assess the target polyphenols concentration in several tea samples. Rutin and quercetin-3-glucoside were the most abundant phenolics in all tea samples analysed and, with exception of naringenin and cinnamic acid, which are present in high amounts in the investigated citric teas, remain phenolic compounds are present in trace levels. PMID- 26585208 TI - 5-Aminobenzimidazole as new hydrophobic charge-induction ligand for expanded bed adsorption of bovine IgG. AB - Expanded bed adsorption (EBA) can capture target proteins directly from unclarified feedstock without prior solid-liquid separation. Hydrophobic charge induction chromatography (HCIC) is a promising technology for biomolecule separation with high capacity, good selectivity and relatively low cost without the pretreatment of dilution or salt addition. In this work, EBA and HCIC were combined to develop a new separation technology, hydrophobic charge-induction EBA. Two HCIC ligands, 4-mercapto-ethyl-pyridine (MEP) and 5-aminobenzimidazole (ABI), were coupled onto agarose beads containing tungsten carbide to prepare the resins for EBA, named T-MEP and T-ABI, respectively. The static adsorption and dynamic binding behaviors of bovine IgG (bIgG) were investigated. Two resins had similar saturated adsorption capacities and salt-tolerant properties, but T-ABI showed higher dynamic binding capacity than T-MEP, indicating that ABI ligand was more suitable for EBA. The performances in expanded bed were verified. With the protein mixture (2mg/ml bIgG and 10mg/ml bovine serum albumin) as the model feedstock, the effects of loading and elution pH, expansion factor and loading volume on the separation performance of bIgG were evaluated. Finally, T-ABI EBA was used to separate bIgG directly from bovine whey with optimized operation conditions. The purity and recovery of bIgG reached 90.6% and 78.2%, respectively. The purification factor was about 19.3. The results demonstrated that the combination of HCIC and EBA would be a potential platform for antibody capture with less feedstock pretreatments, high efficiency and relatively low cost. PMID- 26585209 TI - In vivo solid-phase microextraction liquid chromatography-tandem mass spectrometry for monitoring blood eicosanoids time profile after lipopolysaccharide-induced inflammation in Sprague-Dawley rats. AB - A fast and non-lethal in vivo solid-phase microextraction (SPME) sampling method for rat blood coupled to liquid chromatography and tandem mass spectrometry (LC MS/MS) was developed for monitoring rapid changes in concentrations of eicosanoids - lipid mediators involved in the development of inflammatory conditions - using diffusion-based calibration. Sampling rates of target eicosanoids were pre-determined under laboratory conditions with a precision of <=10%, and directly used for quantification of analyte concentrations in blood after lipopolysaccharide-induced inflammation in Sprague-Dawley rats. Results showed significant changes in unbound plasma concentrations of arachidonic acid (AA) and 12-hydroxyeicosatetraenoic acid (12-HETE) in response to the treatment. Next, performance of the proposed method was compared with protein precipitation (PP) of plasma, a conventional sample preparation technique. Finally, percentages of plasma protein binding (PPB) of specific eicosanoids were determined. PPB of target eicosanoids was in agreement with literature values, ranging from 99.3 to 99.9% for 12-HETE and DHA, respectively. We envision that the proposed method is a particularly suitable alternative to lethal sampling and current methods based on sample depletion in animal studies for accurate monitoring of rapid changes in blood concentrations of small molecules. PMID- 26585210 TI - Addition of PSMA ADC to enzalutamide therapy significantly improves survival in in vivo model of castration resistant prostate cancer. AB - BACKGROUND: Despite multiple new therapies available to patients with advanced castration-resistant prostate cancer (CRPC), the overall survival benefit still remains relatively short. Therefore, it is important to investigate additional treatment options that could achieve greater efficacy. Because of tumor heterogeneity and the development of resistance to treatment with single agents, combination therapies using existing drugs with new agents can potentially broaden individual therapeutic windows and achieve improved efficacy and safety profiles. The objective of the current studies was to evaluate the efficacy of combination of enzalutamide (ENZ) with prostate specific membrane antigen antibody drug conjugate (PSMA ADC) to inhibit CRPC patient-derived xenografts (PDX) in a preclinical setting. METHODS: Subcutaneous LuCaP 96CR prostate cancer PDX bearing mice were treated with a single dose of PSMA ADC (2.0 mg/kg) or 5 days a week ENZ (50 mg/kg) as monotherapy or with a combination of these two agents. The effects of the PSMA ADC+ENZ combination were compared to PSMA ADC alone, ENZ alone, and placebo control. IHC analyses were performed to determine PSMA, AR, ARV7, and GR expression and effects on proliferation. RESULTS: All treatments inhibited tumor progression but with different efficacy. At 6 weeks, in the control and ENZ groups all tumors were progressing, while in the PSMA ADC group only 5/11 were progressing, two remained unchanged and four tumors had decreased tumor volume. Moreover, all animals in the PSMA ADC+ENZ group had smaller tumors at week 6 when compared to their size at enrollment (week 0). A 14 week followup showed that all three treatments resulted in significant survival benefits but the combination effects were the most pronounced resulting in PSMA ADC+ENZ versus ENZ HR = 0.093 (P = 0.0045) and PSMA ADC+ENZ versus PSMA ADC HR = 0.051 (P = <0.0001) with no deaths observed in the combination group. CONCLUSIONS: Our results clearly indicate that the combination of PSMA ADC+ENZ possesses strong antitumor activity and significantly improves survival over ENZ monotherapy using the LuCaP 96CR PDX model. These results provide a strong rationale for clinical testing of PSMA ADC in combination with ENZ and/or other androgen-directed treatment strategies. PMID- 26585211 TI - Macular Bruch Membrane Holes in Choroidal Neovascularization-Related Myopic Macular Atrophy by Swept-Source Optical Coherence Tomography. AB - PURPOSE: To determine frequency and associations of macular Bruch membrane defects in the region of macular atrophy developing after the onset of myopic choroidal neovascularization (CNV). DESIGN: Retrospective observational case series. METHODS: The study included all patients who were consecutively examined for high myopia (axial length >=26.5mm) and CNV-related macular atrophy in the study period from June to July 2015. The patients underwent a comprehensive ophthalmologic examination including swept-source optical coherence tomography (OCT) of the macula. Main outcome measures were macular Bruch membrane defects. RESULTS: Out of 33 eyes (28 patients) with myopic CNV-related macular atrophy, 25 eyes (76%) showed macular Bruch membrane defects, which were characterized by a lack of Bruch membrane, retinal pigment epithelium, photoreceptors, and choriocapillaris. At the edges of the macular Bruch membrane defects, the ends of the Bruch membrane were upturned, and an inward protrusion of large choroidal vessels could be detected. In the center of macular Bruch membrane defects, remnants of Bruch membrane could be crumpled. In multivariate analysis, higher prevalence of secondary macular Bruch membrane defects was significantly associated with a lower prevalence of intravitreal medical therapy (P < .001) after adjusting for larger macular atrophy area size (P < .001) and longer interval between development of the CNV and final examination (P = .42). CONCLUSIONS: Macular Bruch membrane defects belong to the hallmarks of myopic CNV related macular atrophy. Since macular Bruch membrane defects lack photoreceptors and thus represent psychophysically an absolute scotoma, they are of profound importance for visual prognosis. As incidentally observed at study end, the prevalence of macular Bruch membrane defects may be lower if a previous myopic CNV was treated by intravitreal medical therapy. PMID- 26585212 TI - Sporotrichosis in the Ocular Adnexa: 21 Cases in an Endemic Area in Peru and Review of the Literature. AB - PURPOSE: To describe the clinical and epidemiologic characteristics of sporotrichosis in ocular adnexa and give an insight into factors associated with this condition. DESIGN: Retrospective case series and literature review. METHODS: We retrospectively reviewed all cases of sporotrichosis in ocular adnexa between 2004 and 2014 in the Santa Teresa Clinic of Abancay, Peru and reviewed all case reports of sporotrichosis in ocular adnexa in the literature. RESULTS: We reviewed records of 21 patients with sporotrichosis in ocular adnexa; 12 (57.1%) of them were male and their median age surrounded 9 years. In our series, 19 patients had lesions in the eyelids and 2 in the eyebrows. The lymphocutaneous form occurred in 62% of them. Ten patients (47.6%) were cured with potassium iodide. Among 65 patients with sporotrichosis in ocular adnexa (our 21 patients and 44 from the literature), the average age was 9 years, and 78% were <=15 years of age; 54% were male. The lesions were more frequent on the eyelids (n = 53 [82%]), followed by the lacrimal gland (n = 5), conjunctiva (n = 4), and eyebrows (n = 3). The lymphocutaneous clinical form (54%) was the most frequent. Fifty patients were cured: 31 of them with potassium iodide, 16 with itraconazole, and 3 with a combination including potassium iodide, itraconazole, and fluconazole. Twenty-nine patients (44.6%) resided in a hyperendemic region, and 5 patients reported contact with cats that had sporotrichosis. CONCLUSIONS: Sporotrichosis in ocular adnexa is associated with children <=15 years of age, and in 82% of these cases the disease is limited to the eyelids. PMID- 26585213 TI - Clinical Characteristics of Posterior Staphylomas in Myopic Eyes With Axial Length Shorter Than 26.5 Millimeters. AB - PURPOSE: To describe the features of posterior staphylomas in myopic eyes with an axial length shorter than 26.5 mm causing visual loss in old age. DESIGN: Retrospective, observational case series. METHODS: After reviewing cases of staphyloma, we isolated 16 eyes from 10 patients with an axial length <26.5 mm for further analysis. These patients had all undergone fundus photography and spectral-domain optical coherence tomography (SDOCT) and some had undergone 3 dimensional magnetic resonance imaging (3D-MRI). RESULTS: The mean age of the patients was 70.0 +/- 6.3 years (mean +/- standard deviation; range 59-81). The mean axial length of the eyes with a posterior staphyloma was 25.14 +/- 0.77 mm and the mean refractive error of the affected eyes was -4.28 +/- 2.65 diopters. The median visual acuity was 20/60. All eyes presented with diffuse chorioretinal atrophy, which resembles pathologic myopic maculopathy. Fuchs spots previously were detected in 3 eyes (19%) and lacquer cracks in 2 (12%). SDOCT imaging of the macula showed decreased choroidal thickness in all eyes. A macular retinoschisis was detected in 5 eyes (31%), decreased ellipsoid zone reflectivity in 4 (25%), foveal retinal detachment in 2 (12%), a dome-shaped macula in 1 (6%), a choroidal neovascularization-related subretinal scar in 3 (19%), and loss of ellipsoid zone and outer nuclear layer in 3 (19%). The 3D-MRI scans from 8 eyes showed posterior staphylomas, lateral angulation, or protrusion in all eyes. No eye featured a tilted disc syndrome. CONCLUSIONS: Posterior staphylomas in myopic eyes with an axial length shorter than 26.5 mm exhibit features resembling pathologic myopic maculopathy. This type of staphyloma might cause visual impairment in elderly patients and can be considered atypical forms of pathologic myopia in old age. PMID- 26585214 TI - Changes in first entry to out-of-home care from 1992 to 2012 among children in England. AB - Placement in out-of-home care (OHC) indicates serious childhood adversity and is associated with multiple adverse outcomes. Each year 0.5% of children in England live in OHC but evidence is lacking on the cumulative proportion who enter during childhood and how this varies over time. We measured the proportion of children born between 1992 and 2011 who entered OHC, including variation in rates of entry over time, and explored the determinants of these changes using decomposition methods. We also described changes in placement type, duration and stability. By age 18, 3.3% of children born 1992-94 entered OHC. This proportion varied by ethnicity (1.6% of White vs. 4.5% of Black children born 2001-03 entered OHC by age 9, 95% CI [1.5-1.7] and [4.4-4.6], p<0.001) and increased over time (0.8% of children born 2009-11 entered OHC by age 1 vs. 0.5% born 1992-94, 95% CI [0.7 0.9] and [0.4-0.6], p<0.001). This overall increase was driven primarily by the increased rate of entry among White children and not by concurrent changes in the population's ethnic composition. The proportion of children entering OHC in England is increasing and characteristics of the care they receive are changing with earlier intervention and longer, more stable placements. Further research is required to understand the reasons for these changes in practice and whether they are cost-effective, sustainable, and improve outcomes for children and society. PMID- 26585215 TI - Authoritarian parenting attitudes and social origin: The multigenerational relationship of socioeconomic position to childrearing values. AB - Support for authoritarian approaches to parenting, including corporal punishment, is known to be elevated among individuals with low current levels of socioeconomic attainment. The objectives of this study are: (1) to determine whether authoritarian parenting dispositions are related to disadvantages in one's social background, in addition to one's present socioeconomic standing; and (2) to distinguish, in this regard, between support for spanking and other authoritarian parenting dispositions. Ordered logit models, applied to General Social Survey data concerning a nationally representative sample of US adults, are used to examine relationships of authoritarian parenting dispositions to the socioeconomic positions that respondents currently occupy and in which they were raised. It is found that support for spanking (N=10,725) and valuing of obedience (N=10,043) are inversely related to the socioeconomic status (SES) of one's family of origin, and that these associations are robust to controls for one's current SES. A disadvantaged family background is found to increase support for spanking most among those with high current SES. Strong associations (robust to controls for SES indicators) are additionally found between African-American racial identity and support for authoritarian parenting. Prior research indicates that authoritarian parenting practices such as spanking may be harmful to children. Thus, if the parenting attitudes analyzed here translate into parenting practices, then this study's findings may point to a mechanism for the intergenerational transmission of disadvantages. PMID- 26585219 TI - Childhood trauma and clinical outcome in patients at ultra-high risk of transition to psychosis. AB - BACKGROUND: Although transition rates in 'ultra-high risk' (UHR) for psychosis samples are declining, many young individuals at UHR still experience attenuated positive symptoms and impaired functioning at follow-up. The present study examined the association between a history of childhood trauma and transition to psychosis, and symptomatic and functional outcome, in UHR patients. METHOD: Data on childhood trauma were available for 125 UHR individuals. Cox regression and linear regression analyses were used to determine the association between childhood trauma, and clinical and functional outcome, during the 24-month follow up. RESULTS: Of the 125 UHR subjects 26 individuals (20.8%) transitioned to psychosis within 24 months. Childhood trauma did not predict transition to psychosis. However, at 24-month follow-up, UHR patients with higher levels of childhood trauma had higher levels of attenuated positive symptoms (b = 0.34, t = 2.925, p < 0.01), general symptoms (b = 0.29, t = 2.707, p < 0.01) and depression (b = 0.32, t = 2.929, p < 0.01) and lower levels of global functioning (b = - 0.33, t = - 2.853, p = 0.01). Childhood trauma was not significantly associated with a differential course of symptoms over time, although in those with higher levels of childhood trauma, attenuated positive symptoms were more persistent at a trend level. CONCLUSIONS: Our results suggest that childhood trauma may contribute to a shared vulnerability for several psychopathological domains. PMID- 26585217 TI - Effect of alumina composition and surface integrity in alumina/epoxy composites on the ultrasonic attenuation properties. AB - We report a method of fabricating backing blocks for ultrasonic imaging transducers, using alumina/epoxy composites. Backing blocks contain scatterers such as alumina particles interspersed in the epoxy matrix for the effective scattering and attenuation of ultrasound. Here, the surface integrity can be an issue, where the composite material may be damaged during machining because of differences in strength, hardness and brittleness of the hard alumina particles and the soft epoxy matrix. Poor surface integrity results in the formation of air cavities between the backing block and the piezoelectric element upon assembly, hence the increased reflection off the backing block and the eventual degradation in image quality. Furthermore, with an issue of poor surface integrity due to machining, it is difficult to increase alumina as scatterers more than a specific mass fraction ratio. In this study, we increased the portion of alumina within epoxy matrix by obtaining an enhanced surface integrity using a net shape fabrication method, and verified that this method could allow us to achieve higher ultrasonic attenuation. Backing blocks were net-shaped with various mass fractions of alumina to characterize the formability and the mechanical properties, including hardness, surface roughness and the internal micro structure, which were compared with those of machined backing blocks. The ultrasonic attenuation property of the backing blocks was also measured. PMID- 26585216 TI - Does developmental timing of exposure to child maltreatment predict memory performance in adulthood? Results from a large, population-based sample. AB - Although maltreatment is a known risk factor for multiple adverse outcomes across the lifespan, its effects on cognitive development, especially memory, are poorly understood. Using data from a large, nationally representative sample of young adults (Add Health), we examined the effects of physical and sexual abuse on working and short-term memory in adulthood. We examined the association between exposure to maltreatment as well as its timing of first onset after adjusting for covariates. Of our sample, 16.50% of respondents were exposed to physical abuse and 4.36% to sexual abuse by age 17. An analysis comparing unexposed respondents to those exposed to physical or sexual abuse did not yield any significant differences in adult memory performance. However, two developmental time periods emerged as important for shaping memory following exposure to sexual abuse, but in opposite ways. Relative to non-exposed respondents, those exposed to sexual abuse during early childhood (ages 3-5), had better number recall and those first exposed during adolescence (ages 14-17) had worse number recall. However, other variables, including socioeconomic status, played a larger role (than maltreatment) on working and short-term memory. We conclude that a simple examination of "exposed" versus "unexposed" respondents may obscure potentially important within-group differences that are revealed by examining the effects of age at onset to maltreatment. PMID- 26585221 TI - White matter structural integrity differs between people with schizophrenia and healthy groups as a function of cognitive control. AB - A behavioral hallmark of schizophrenia is poor cognitive control. Recent evidence suggests that problems with cognitive control in schizophrenia are related to disconnectivity along major white matter fibers. Although deficits of cognitive control are common in schizophrenia, a proportion of otherwise healthy subjects show poor cognitive control performance. The present study sought to address this potential confound by comparing white matter integrity between a group with schizophrenia and otherwise healthy individuals with either high or low levels of cognitive control (based on working memory span performance). Diffusion tensor imaging was used to evaluate white matter integrity in 24 participants with schizophrenia, 24 healthy participants with high cognitive control (HCC), and 25 healthy participants with low cognitive control (LCC). To test for differences in fractional anisotropy (FA) across major white matter fiber tracts, a voxelwise region of interest analysis was conducted in standardized brain space. In a separate analysis, regions of interest were manually drawn in native brain space to isolate superior longitudinal fasciculus (SLF), a tract implicated in cognitive control performance. The voxelwise analysis demonstrated widespread lower FA in the schizophrenia group compared to the HCC group. With a high degree of concordance, the manual ROI analysis revealed lower FA in the schizophrenia group compared to the HCC group. Taken together, these results provide evidence to suggest that structural differences identified between healthy groups and schizophrenia may not be entirely specific to the disease process and can vary as a function of cognitive control capacity in the comparison group. PMID- 26585220 TI - A dimensional comparison between delusional disorder, schizophrenia and schizoaffective disorder. AB - INTRODUCTION: Since the early description of paranoia, the nosology of delusional disorder has always been controversial. The old idea of unitary psychosis has now gained some renewed value from the dimensional continuum model of psychotic symptoms. AIMS: 1. To study the psychopathological dimensions of the psychosis spectrum; 2. to explore the association between psychotic dimensions and categorical diagnoses; 3. to compare the different psychotic disorders from a psychopathological and functional point of view. MATERIAL AND METHODS: This is an observational study utilizing a sample of some 550 patients with a psychotic disorder. 373 participants had a diagnosis of schizophrenia, 137 had delusional disorder and 40 with a diagnosis of schizoaffective disorder. The PANSS was used to elicit psychopathology and global functioning was ascertained using the GAF measure. Both exploratory and confirmatory factor analyses of the PANSS items were performed to extract psychopathological dimensions. Associations between diagnostic categories and dimensions were subsequently studied using ANOVA tests. RESULTS: 5 dimensions - manic, negative symptoms, depression, positive symptoms and cognitive - emerged. The model explained 57.27% of the total variance. The dimensional model was useful to explained differences and similarities between all three psychosis spectrum categories. The potential clinical usefulness of this dimensional model within and between clinical psychosis spectrum categories is discussed. PMID- 26585218 TI - Differentiation of oligodendrocyte precursors is impaired in the prefrontal cortex in schizophrenia. AB - The pathophysiology of schizophrenia involves disturbances of information processing across brain regions, possibly reflecting, at least in part, a disruption in the underlying axonal connectivity. This disruption is thought to be a consequence of the pathology of myelin ensheathment, the integrity of which is tightly regulated by oligodendrocytes. In order to gain insight into the possible neurobiological mechanisms of myelin deficit, we determined the messenger RNA (mRNA) expression profile of laser captured cells that were immunoreactive for 2', 3'-cyclic nucleotide 3'-phosphodiesterase (CNPase), a marker for oligodendrocyte progenitor cells (OPCs) in addition to differentiating and myelinating oligodendrocytes, in the white matter of the prefrontal cortex in schizophrenia subjects. Our findings pointed to the hypothesis that OPC differentiation might be impaired in schizophrenia. To address this hypothesis, we quantified cells that were immunoreactive for neural/glial antigen 2 (NG2), a selective marker for OPCs, and those that were immunoreactive for oligodendrocyte transcription factor 2 (OLIG2), an oligodendrocyte lineage marker that is expressed by OPCs and maturing oligodendrocytes. We found that the density of NG2 immunoreactive cells was unaltered, but the density of OLIG2-immunoreactive cells was significantly decreased in subjects with schizophrenia, consistent with the notion that OPC differentiation impairment may contribute to oligodendrocyte disturbances and thereby myelin deficits in schizophrenia. PMID- 26585222 TI - Antisense down-regulation of the strawberry beta-galactosidase gene FabetaGal4 increases cell wall galactose levels and reduces fruit softening. AB - Strawberry softening is characterized by an increase in the solubilization and depolymerization of pectins from cell walls. Galactose release from pectin side chains by beta-galactosidase enzymes has been proposed as one reason for the increase in soluble pectins. A putative beta-galactosidase gene, FabetaGal4, has been identified using a custom-made oligonucleotide-based strawberry microarray platform. FabetaGal4 was expressed mainly in the receptacle during fruit ripening, and was positively regulated by abscisic acid and negatively regulated by auxins. To ascertain the role of FabetaGal4 in strawberry softening, transgenic plants containing an antisense sequence of this gene under the control of the CaMV35S promoter were generated. Phenotypic analyses were carried out in transgenic plants during three consecutive growing seasons, using non-transformed plants as control. Two out of nine independent transgenic lines yielded fruits that were 30% firmer than control at the ripe stage. FabetaGal4 mRNA levels were reduced by 70% in ripe fruits from these selected transgenic lines, but they also showed significant silencing of FabetaGal1, although the genes did not share significant similarity. These two transgenic lines also showed an increase in pectin covalently bound to the cell wall, extracted using Na2CO3. The amount of galactose in cell walls from transgenic fruits was 30% higher than in control; notably, the galactose increase was larger in the 1 M KOH fraction, which is enriched in hemicellulose. These results suggest that FabetaGal4 participates in the solubilization of covalently bound pectins during ripening, reducing strawberry fruit firmness. PMID- 26585224 TI - The glucose 6-phosphate shunt around the Calvin-Benson cycle. AB - It is just over 60 years since a cycle for the regeneration of the CO2-acceptor used in photosynthesis was proposed. In this opinion paper, we revisit the origins of the Calvin-Benson cycle that occurred at the time that the hexose monophosphate shunt, now called the pentose phosphate pathway, was being worked out. Eventually the pentose phosphate pathway was separated into two branches, an oxidative branch and a non-oxidative branch. It is generally thought that the Calvin-Benson cycle is the reverse of the non-oxidative branch of the pentose phosphate pathway but we describe crucial differences and also propose that some carbon routinely passes through the oxidative branch of the pentose phosphate pathway. This creates a futile cycle but may help to stabilize photosynthesis. If it occurs it could explain a number of enigmas including the lack of complete labelling of the Calvin-Benson cycle intermediates when carbon isotopes are fed to photosynthesizing leaves. PMID- 26585225 TI - Stress, strain, signaling, and adaptation--not just a matter of definition. PMID- 26585223 TI - Cavitation and water fluxes driven by ice water potential in Juglans regia during freeze-thaw cycles. AB - Freeze-thaw cycles induce major hydraulic changes due to liquid-to-ice transition within tree stems. The very low water potential at the ice-liquid interface is crucial as it may cause lysis of living cells as well as water fluxes and embolism in sap conduits, which impacts whole tree-water relations. We investigated water fluxes induced by ice formation during freeze-thaw cycles in Juglans regia L. stems using four non-invasive and complementary approaches: a microdendrometer, magnetic resonance imaging, X-ray microtomography, and ultrasonic acoustic emissions analysis. When the temperature dropped, ice nucleation occurred, probably in the cambium or pith areas, inducing high water potential gradients within the stem. The water was therefore redistributed within the stem toward the ice front. We could thus observe dehydration of the bark's living cells leading to drastic shrinkage of this tissue, as well as high tension within wood conduits reaching the cavitation threshold in sap vessels. Ultrasonic emissions, which were strictly emitted only during freezing, indicated cavitation events (i.e. bubble formation) following ice formation in the xylem sap. However, embolism formation (i.e. bubble expansion) in stems was observed only on thawing via X-ray microtomography for the first time on the same sample. Ultrasonic emissions were detected during freezing and were not directly related to embolism formation. These results provide new insights into the complex process and dynamics of water movements and ice formation during freeze-thaw cycles in tree stems. PMID- 26585226 TI - Seed vigour and crop establishment: extending performance beyond adaptation. AB - Seeds are central to crop production, human nutrition, and food security. A key component of the performance of crop seeds is the complex trait of seed vigour. Crop yield and resource use efficiency depend on successful plant establishment in the field, and it is the vigour of seeds that defines their ability to germinate and establish seedlings rapidly, uniformly, and robustly across diverse environmental conditions. Improving vigour to enhance the critical and yield defining stage of crop establishment remains a primary objective of the agricultural industry and the seed/breeding companies that support it. Our knowledge of the regulation of seed germination has developed greatly in recent times, yet understanding of the basis of variation in vigour and therefore seed performance during the establishment of crops remains limited. Here we consider seed vigour at an ecophysiological, molecular, and biomechanical level. We discuss how some seed characteristics that serve as adaptive responses to the natural environment are not suitable for agriculture. Past domestication has provided incremental improvements, but further actively directed change is required to produce seeds with the characteristics required both now and in the future. We discuss ways in which basic plant science could be applied to enhance seed performance in crop production. PMID- 26585227 TI - Nax loci affect SOS1-like Na+/H+ exchanger expression and activity in wheat. AB - Salinity stress tolerance in durum wheat is strongly associated with a plant's ability to control Na(+) delivery to the shoot. Two loci, termed Nax1 and Nax2, were recently identified as being critical for this process and the sodium transporters HKT1;4 and HKT1;5 were identified as the respective candidate genes. These transporters retrieve Na(+) from the xylem, thus limiting the rates of Na(+) transport from the root to the shoot. In this work, we show that the Nax loci also affect activity and expression levels of the SOS1-like Na(+)/H(+) exchanger in both root cortical and stelar tissues. Net Na(+) efflux measured in isolated steles from salt-treated plants, using the non-invasive ion flux measuring MIFE technique, decreased in the sequence: Tamaroi (parental line)>Nax1=Nax2>Nax1:Nax2 lines. This efflux was sensitive to amiloride (a known inhibitor of the Na(+)/H(+) exchanger) and was mirrored by net H(+) flux changes. TdSOS1 relative transcript levels were 6-10-fold lower in Nax lines compared with Tamaroi. Thus, it appears that Nax loci confer two highly complementary mechanisms, both of which contribute towards reducing the xylem Na(+) content. One enhances the retrieval of Na(+) back into the root stele via HKT1;4 or HKT1;5, whilst the other reduces the rate of Na(+) loading into the xylem via SOS1. It is suggested that such duality plays an important adaptive role with greater versatility for responding to a changing environment and controlling Na(+) delivery to the shoot. PMID- 26585229 TI - Photon upconversion in degenerately sulfur doped InP nanowires. AB - Radiative recombination in degenerately n-doped InP nanowires is studied for excitation above and below the Fermi energy of the electron gas, using photoluminescence. Laser-induced electron heating is observed, which allows absorption below the Fermi energy. We observe photon upconversion where photo excited holes recombine with high |k| electrons. This can be attributed to hole scattering to high |k|-values, and the temperature dependence of this process is measured. We show that hole relaxation via phonon scattering can be observed in continuous wave excitation luminescence measurements. PMID- 26585228 TI - Transcriptome analysis reveals the role of the root hairs as environmental sensors to maintain plant functions under water-deficiency conditions. AB - An important part of the root system is the root hairs, which play a role in mineral and water uptake. Here, we present an analysis of the transcriptomic response to water deficiency of the wild-type (WT) barley cultivar 'Karat' and its root-hairless mutant rhl1.a. A comparison of the transcriptional changes induced by water stress resulted in the identification of genes whose expression was specifically affected in each genotype. At the onset of water stress, more genes were modulated by water shortage in the roots of the WT plants than in the roots of rhl1.a. The roots of the WT plants, but not of rhl1.a, specifically responded with the induction of genes that are related to the abscisic acid biosynthesis, stomatal closure, and cell wall biogenesis, thus indicating the specific activation of processes that are related to water-stress signalling and protection. On the other hand, the processes involved in the further response to abiotic stimuli, including hydrogen peroxide, heat, and high light intensity, were specifically up-regulated in the leaves of rhl1.a. An extended period of severe stress caused more drastic transcriptome changes in the roots and leaves of the rhl1.a mutant than in those of the WT. These results are in agreement with the much stronger damage to photosystem II in the rhl1.a mutant than in its parent cultivar after 10 d of water stress. Taking into account the putative stress sensing and signalling features of the root hair transcriptome, we discuss the role of root hairs as sensors of environmental conditions. PMID- 26585230 TI - Solid pseudopapillary tumor of the pancreas (Frantz's tumor): two case reports and a review of the literature. AB - INTRODUCTION: Solid pseudopapillary tumor of the pancreas is extremely rare in children; it usually occurs in young women between 18 and 35 years of age. It comprises less than 3% of pancreatic tumors. It is of low malignancy; however, it may be locally aggressive. Surgical resection is the treatment of choice and its prognosis is excellent. CASE PRESENTATION: Two Caucasian girls, 15 and 12 years of age were diagnosed with tumor of the pancreas. The first patient had severe abdominal pain. In the second case the tumor was asymptomatic, detected incidentally during ultrasound. Computed tomography confirmed pancreatic mass. In the first case, apart from the tumor located in the head and the body of her pancreas, focal change in her right kidney was found, which was an indication to biopsy that confirmed solid pseudopapillary tumor. In the second patient the tumor was located in the body of her pancreas, with portal vein occlusion and well-developed collateral circulation. In the first patient a pancreatoduodenectomy (Traverso-Longmire) was performed; there was no mass in her right kidney. In the second case, distal pancreatectomy and splenectomy were performed. In both cases histopathology revealed solid pseudopapillary tumor resected radically. Our first patient's postoperative course was uneventful. In the second case, her postoperative course was complicated by necrosis of the remaining pancreatic head that needed pancreatoduodenectomy. Follow-up at 28 and 26 months revealed no evidence of tumor recurrence or metastases on magnetic resonance imaging. CONCLUSIONS: Typical radiological appearance of solid pseudopapillary tumor is an indication for surgery. The treatment of choice is tumor resection with sparing of pancreatic tissue. In one of our two cases we performed a preoperative biopsy because of an uncharacteristic mass in her right kidney. In our second patient, necrosis of her spared pancreatic head meant that we could not preserve pancreatic tissue. Our whole diagnostic process, treatment and possible complications analysis should be of interest and noteworthy not only to surgeons as the treatment of choice is radical resection, but also to pediatric oncologists because of differentiation from other pancreatic tumors in children. PMID- 26585231 TI - Sensitization of Pancreatic Cancers to Gemcitabine Chemoradiation by WEE1 Kinase Inhibition Depends on Homologous Recombination Repair. AB - To improve the efficacy of chemoradiation therapy for locally advanced pancreatic cancer and begin to establish patient selection criteria, we investigated the combination of the WEE1 inhibitor AZD1775 with gemcitabine-radiation in homologous recombination (HR) repair proficient and deficient pancreatic cancers. Sensitization to gemcitabine-radiation by AZD1775 was assessed in pancreatic cancer cells by clonogenic survival and in patient-derived xenografts by tumor growth. The contributions of HR repair inhibition and G2 checkpoint abrogation to sensitization were assessed by gammaH2AX, BRCA2 manipulation, and RAD51 focus formation and pHistone H3 flow cytometry, respectively. We found that AZD1775 sensitized to gemcitabine-radiation in BRCA2 wild-type but not BRCA2 mutant pancreatic cancer cells. In all cells, AZD1775 caused inhibition of CDK1 phosphorylation and G2 checkpoint abrogation. However, sensitization by AZD1775 was associated with persistent gammaH2AX and inhibition of RAD51 focus formation. In HR-proficient (BRCA2 wild-type) or -deficient (BRAC2 null) isogenic cells, AZD1775 sensitized to gemcitabine-radiation in BRCA2 wild-type, but not in BRCA2 null cells, despite significant G2 checkpoint abrogation. In patient-derived pancreatic tumor xenografts, AZD1775 significantly inhibited tumor growth and impaired RAD51 focus formation in response to gemcitabine-radiation. In conclusion, WEE1 inhibition by AZD1775 is an effective strategy for sensitizing pancreatic cancers to gemcitabine chemoradiation. Although this sensitization is accompanied by inhibition of CDK1 phosphorylation and G2 checkpoint abrogation, this mechanism is not sufficient for sensitization. Our findings demonstrate that sensitization to chemoradiation by WEE1 inhibition results from inhibition of HR repair and suggest that patient tumors without underlying HR defects would benefit most from this therapy. PMID- 26585232 TI - Identification of Metastasis-Associated Metabolic Profiles of Tumors by (1)H-HR MAS-MRS. AB - Tumors develop an abnormal microenvironment during growth, and similar to the metastatic phenotype, the metabolic phenotype of cancer cells is tightly linked to characteristics of the tumor microenvironment (TME). In this study, we explored relationships between metabolic profile, metastatic propensity, and hypoxia in experimental tumors in an attempt to identify metastasis-associated metabolic profiles. Two human melanoma xenograft lines (A-07, R-18) showing different TMEs were used as cancer models. Metabolic profile was assessed by proton high resolution magic angle spinning magnetic resonance spectroscopy ((1)H HR-MAS-MRS). Tumor hypoxia was detected in immunostained histological preparations by using pimonidazole as a hypoxia marker. Twenty-four samples from 10 A-07 tumors and 28 samples from 10 R-18 tumors were analyzed. Metastasis was associated with hypoxia in both A-07 and R-18 tumors, and (1)H-HR-MAS-MRS discriminated between tissue samples with and tissue samples without hypoxic regions in both models, primarily because hypoxia was associated with high lactate resonance peaks in A-07 tumors and with low lactate resonance peaks in R 18 tumors. Similarly, metastatic and non-metastatic R-18 tumors showed significantly different metabolic profiles, but not metastatic and non-metastatic A-07 tumors, probably because some samples from the metastatic A-07 tumors were derived from tumor regions without hypoxic tissue. This study suggests that (1)H HR-MAS-MRS may be a valuable tool for evaluating the role of hypoxia and lactate in tumor metastasis as well as for identification of metastasis-associated metabolic profiles. PMID- 26585235 TI - Morphology-controlled synthesis of monodispersed graphitic carbon coated core/shell structured Ni/NiO nanoparticles with enhanced magnetoresistance. AB - Graphitic carbon coated core/shell structured Ni/NiO nanoparticles were synthesized by a sol-gel type chemical precursor method and their structural, morphological and magnetic properties were evaluated. The synthesis method provides an improved and comparatively facile approach towards controlled growth of the composite structure of a metallic ferromagnetic (FM) core and an antiferromagnetic (AFM) metal oxide shell along with in situ growth of a supplementary surface functionalization layer of graphitic carbon. In addition, the process allows a precise control over the shape and size of this important class of core/shell type functional materials for a wide range of pertinent applications. The structural properties of the derived samples were studied with X-ray diffraction (XRD), X-ray absorption near edge structure (XANES), extended X ray absorption fine structure (EXAFS), Raman spectroscopy, energy dispersive X ray (EDX) analysis, and X-ray photoelectron spectroscopy (XPS). The microstructural features in the core/shell structured particles were evaluated using a scanning electron microscope (SEM) and a high resolution transmission electron microscope (HRTEM). Magnetic properties of the derived samples were studied using a vibrating sample magnetometer (VSM) in the 80-300 K temperature range. The surface functionalized Ni/NiO nanoparticles exhibit a distinctly enhanced magnetoresistance (MR), e.g., -10% at 290 K, than reported values in compacted Ni/NiO powders or composites. PMID- 26585234 TI - Specific TP53 Mutants Overrepresented in Ovarian Cancer Impact CNV, TP53 Activity, Responses to Nutlin-3a, and Cell Survival. AB - Evolutionary Action analyses of The Cancer Gene Atlas data sets show that many specific p53 missense and gain-of-function mutations are selectively overrepresented and functional in high-grade serous ovarian cancer (HGSC). As homozygous alleles, p53 mutants are differentially associated with specific loss of heterozygosity (R273; chromosome 17); copy number variation (R175H; chromosome 9); and up-stream, cancer-related regulatory pathways. The expression of immune related cytokines was selectively related to p53 status, showing for the first time that specific p53 mutants impact, and are related to, the immune subtype of ovarian cancer. Although the majority (31%) of HGSCs exhibit loss of heterozygosity, a significant number (24%) maintain a wild-type (WT) allele and represent another HGSC subtype that is not well defined. Using human and mouse cell lines, we show that specific p53 mutants differentially alter endogenous WT p53 activity; target gene expression; and responses to nutlin-3a, a small molecular that activates WT p53 leading to apoptosis, providing "proof of principle" that ovarian cancer cells expressing WT and mutant alleles represent a distinct ovarian cancer subtype. We also show that siRNA knock down of endogenous p53 in cells expressing homozygous mutant alleles causes apoptosis, whereas cells expressing WT p53 (or are heterozygous for WT and mutant p53 alleles) are highly resistant. Therefore, despite different gene regulatory pathways associated with specific p53 mutants, silencing mutant p53 might be a suitable, powerful, global strategy for blocking ovarian cancer growth in those tumors that rely on mutant p53 functions for survival. Knowing p53 mutational status in HGSC should permit new strategies tailored to control this disease. PMID- 26585233 TI - RNA Sequencing of Tumor-Associated Microglia Reveals Ccl5 as a Stromal Chemokine Critical for Neurofibromatosis-1 Glioma Growth. AB - Solid cancers develop within a supportive microenvironment that promotes tumor formation and growth through the elaboration of mitogens and chemokines. Within these tumors, monocytes (macrophages and microglia) represent rich sources of these stromal factors. Leveraging a genetically engineered mouse model of neurofibromatosis type 1 (NF1) low-grade brain tumor (optic glioma), we have previously demonstrated that microglia are essential for glioma formation and maintenance. To identify potential tumor-associated microglial factors that support glioma growth (gliomagens), we initiated a comprehensive large-scale discovery effort using optimized RNA-sequencing methods focused specifically on glioma-associated microglia. Candidate microglial gliomagens were prioritized to identify potential secreted or membrane-bound proteins, which were next validated by quantitative real-time polymerase chain reaction as well as by RNA fluorescence in situ hybridization following minocycline-mediated microglial inactivation in vivo. Using these selection criteria, chemokine (C-C motif) ligand 5 (Ccl5) was identified as a chemokine highly expressed in genetically engineered Nf1 mouse optic gliomas relative to nonneoplastic optic nerves. As a candidate gliomagen, recombinant Ccl5 increased Nf1-deficient optic nerve astrocyte growth in vitro. Importantly, consistent with its critical role in maintaining tumor growth, treatment with Ccl5 neutralizing antibodies reduced Nf1 mouse optic glioma growth and improved retinal dysfunction in vivo. Collectively, these findings establish Ccl5 as an important microglial growth factor for low grade glioma maintenance relevant to the development of future stroma-targeted brain tumor therapies. PMID- 26585237 TI - Low priority given to original research in the new print version of The BMJ. PMID- 26585236 TI - Intradermal microbubbles and contrast-enhanced ultrasound (CEUS) is a feasible approach for sentinel lymph node identification in early-stage breast cancer. AB - BACKGROUND: Microbubbles and contrast-enhanced ultrasound (CEUS) is a new technique for locating sentinel lymph node (SLN). The aim of this study is to explore the feasibility of SLNs tracing by CEUS using microbubbles in breast cancer patients and the value of enhancing patterns in diagnosing lymph nodes metastases. METHODS: A clinical trial was registered (trial registration: ChiCTR DDT-13003778). One hundred and one consecutive consenting patients with breast cancer undergoing SLN biopsy were enrolled. Before the surgery, microbubble was injected periareolarly. Lymphatic drainage pathway was detected by CEUS, and guidewire was deployed to locate the SLN before the operation. Blue dye was also used to help in tracing sentinel lymph node during the operation. The identification rate and the accuracy rate were recorded. Enhancing patterns of lymph nodes were recorded and compared with the pathological diagnosis. RESULTS: Of the 101 cases, SLNs in 99 cases were successfully identified by at least one tracer, including 98 cases identified by CEUS and 97 cases by blue dye. There was no significant difference between the two methods (P = 0.705). Guidewires were deployed successfully in all 98 cases, and the localized SLNs were all isolated successfully in the following operations. The status of SLNs isolated by CEUS was completely identical to that of the whole axillary lymph node while 7.1 % cases were misdiagnosed as negative by blue dye method. The sensitivity of predicting SLNs metastases by CEUS enhancing pattern was 81.8 %, the specificity was 86.2 %, and the positive and negative predictive values were 75.0 and 90.3 %, respectively. CONCLUSIONS: Microbubbles and CEUS are feasible approaches for SLN identification. The enhancing patterns on CEUS may be helpful to recognize the metastasizing SLNs. This novel method may be a promising technique for the clinical application. PMID- 26585238 TI - [Treatment of chronic itch in systemic disease. Current standards]. AB - Chronic itch (CI) is a frequent and sometimes tormenting symptom in many skin and systemic diseases. In systemic diseases, it mostly appears on primarily unaffected skin. As a sequelae of intense scratching, secondary skin lesions such as excoriations, scars, and prurigo nodularis may occur. Due to the lack of valid pathogenetic concepts and good clinical trials, the therapy of CI remains mostly symptomatic. In Europe almost all drugs used to treat CI are not approved for this indication. CI is frequent in patients with chronic kidney diseases in advanced stages. Gabapentin and pregabalin, anticonvulsants, and centrally acting calcium channel blockers have been shown to exert a profound effect in CI. Furthermore, UVB phototherapy has been proven to attenuate pruritus in uremic patients. Randomized controlled studies have recently shown that nalfurafine, a kappa-opioid receptor agonist, is able to ameliorate itch in patients with uremic itch. In patients suffering from cholestatic itch, the anion exchange resin colestyramine and rifampicin are effective antipruritic drugs. Furthermore, u opioid receptor antagonists and sertraline may be used to alleviate CI in hepatic diseases. In refractory cases, naso-biliary drainage or albumin dialysis are effective invasive procedures. For the treatment of chronic itch in hematological diseases no controlled trials have been performed so far. The mainstay in these cases is to treat the underlying disease. PMID- 26585239 TI - [Community-acquired pneumonia. New treatment concepts]. PMID- 26585240 TI - [Molecular tumour therapy]. AB - In recent years, molecular tumour therapy has dramatically improved the treatment of various types of cancer. Molecular therapy is expected to attack malignant cells more specifically with fewer side effects than conventional chemotherapy. Both kinase inhibitors and monoclonal antibodies are key components of today's molecular cancer therapy. These substances cannot fully overcome the major tumour biological problems, e.g. therapy resistance. However, as can be vividly seen with the example of immune checkpoint inhibitors, the rational design of molecularly designed drugs will considerably change therapeutic practice in oncology, albeit at the expense of exponentially growing health care costs. PMID- 26585241 TI - Histopathological analyses of murine menisci: implications for joint aging and osteoarthritis. AB - OBJECTIVE: To establish a standardized protocol for histopathological assessment of murine menisci that can be applied to evaluate transgenic, knock-out/in, and surgically induced OA models. METHODS: Knee joints from C57BL/6J mice (6-36 months) as well as from mice with surgically-induced OA were processed and cut into sagittal sections. All sections included the anterior and posterior horns of the menisci and were graded for (1) surface integrity, (2) cellularity, (3) Safranin-O staining distribution and intensity. Articular cartilage in the knee joints was also scored. RESULTS: The new histopathological grading system showed good inter- and intra-class correlation coefficients. The major age-related changes in murine menisci in the absence of OA included decreased Safranin O staining intensity, abnormal cell distribution and the appearance of acellular areas. Menisci from mice with surgically-induced OA showed severe fibrillations, partial/total loss of tissue, and calcifications. Abnormal cell arrangements included both regional hypercellularity and hypocellularity along with hypertrophy and cell clusters. In general, the posterior horns were less affected by age and OA. CONCLUSION: A new standardized protocol and histopathological grading system has been developed and validated to allow for a comprehensive, systematic evaluation of changes in aging and OA-affected murine menisci. This system was developed to serve as a standardized technique and tool for further studies in murine meniscal pathophysiology models. PMID- 26585242 TI - Importance of reference gene selection for articular cartilage mechanobiology studies. AB - OBJECTIVE: Identification of genes differentially expressed in mechano-biological pathways in articular cartilage provides insight into the molecular mechanisms behind initiation and/or progression of osteoarthritis (OA). Quantitative PCR (qPCR) is commonly used to measure gene expression, and is reliant on the use of reference genes for normalisation. Appropriate validation of reference gene stability is imperative for accurate data analysis and interpretation. This study determined in vitro reference gene stability in articular cartilage explants and primary chondrocytes subjected to different compressive loads and tensile strain, respectively. DESIGN: The expression of eight commonly used reference genes (18s, ACTB, GAPDH, HPRT1, PPIA, RPL4, SDHA and YWHAZ) was determined by qPCR and data compared using four software packages (comparative delta-Ct method, geNorm, NormFinder and BestKeeper). Calculation of geometric means of the ranked weightings was carried out using RefFinder. RESULTS: Appropriate reference gene(s) for normalisation of mechanically-regulated transcript levels in articular cartilage tissue or isolated chondrocytes were dependent on experimental set-up. SDHA, YWHAZ and RPL4 were the most stable genes whilst glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and to a lesser extent Hypoxanthine-guanine phosphoribosyltransferase (HPRT), showed variable expression in response to load, demonstrating their unsuitability in such in vitro studies. The effect of using unstable reference genes to normalise the expression of aggrecan (ACAN) and matrix metalloproteinase 3 (MMP3) resulted in inaccurate quantification of these mechano-sensitive genes and erroneous interpretation/conclusions. CONCLUSION: This study demonstrates that commonly used 'reference genes' may be unsuitable for in vitro cartilage chondrocyte mechanobiology studies, reinforcing the principle that careful validation of reference genes is essential prior to each experiment to obtain robust and reproducible qPCR data for analysis/interpretation. PMID- 26585243 TI - Teicoplanin inhibits Ebola pseudovirus infection in cell culture. AB - There is currently no approved antiviral therapy for treatment of Ebola virus disease. To discover readily available approved drugs that can be rapidly repurposed for treatment of Ebola virus infections, we screened 1280 FDA-approved drugs and identified glycopeptide antibiotic teicoplanin inhibiting Ebola pseudovirus infection by blocking virus entry in the low micromolar range. Teicoplanin could be evaluated further and incorporated into ongoing clinical studies. PMID- 26585244 TI - Combination therapy including CpG oligodeoxynucleotides and entecavir induces early viral response and enhanced inhibition of viral replication in a woodchuck model of chronic hepadnaviral infection. AB - CpG oligodeoxynucleotides (ODNs) stimulate immune cells via TLR9 and are potentially useful immunomodulators for the treatment of chronic viral infections. In the present study, different classes of CpGs were tested for their capacities for innate immune activation and antiviral activities in the woodchuck model. A class P CpG ODN was found to stimulate interferon (IFN) production in woodchuck peripheral blood mononuclear cells (PBMCs) in vitro, and following subcutaneous administration in vivo, it was observed to induce IFN and MxA expression in woodchuck PBMCs. Combination treatment with CpG ODN and entecavir (ETV) led to effective suppression of the woodchuck hepatitis virus (WHV) load in the woodchucks, with early viral responses and inhibition of replication. The woodchuck hepatitis surface antigen (WHsAg) serum concentrations were strongly decreased by CpG and ETV together but not by either agent alone, indicating synergistic effects. However, viral control post-treatment was still transient, similar to that observed with ETV alone. Significantly elevated levels of serum aspartate aminotransferase (AST) but not of alanine aminotransferase (ALT) in some of the woodchucks receiving CpG ODN were noted, but these increases were resolved before the completion of treatment and were not associated with an elevated serum bilirubin level or coagulation disorders, suggesting the absence of a significant safety concern. PMID- 26585245 TI - Atomically Sharp Interface in an h-BN-epitaxial graphene van der Waals Heterostructure. AB - Stacking various two-dimensional atomic crystals is a feasible approach to creating unique multilayered van der Waals heterostructures with tailored properties. Herein for the first time, we present a controlled preparation of large-area h-BN/graphene heterostructures via a simple chemical deposition of h BN layers on epitaxial graphene/SiC(0001). Van der Waals forces, which are responsible for the cohesion of the multilayer system, give rise to an abrupt interface without interdiffusion between graphene and h-BN, as shown by X-ray Photoemission Spectroscopy (XPS) and direct observation using scanning and High Resolution Transmission Electron Microscopy (STEM/HRTEM). The electronic properties of graphene, such as the Dirac cone, remain intact and no significant charge transfer i.e. doping, is observed. These results are supported by Density Functional Theory (DFT) calculations. We demonstrate that the h-BN capped graphene allows the fabrication of vdW heterostructures without altering the electronic properties of graphene. PMID- 26585246 TI - T1rho magnetic resonance imaging quantification of early articular cartilage degeneration in a rabbit model. AB - BACKGROUND: Osteoarthritis (OA) is a serious problem in the recent aging society, and early diagnosis and intervention of articular cartilage degeneration are very important for the onset of OA. Therefore, development of newer MRI techniques is necessary and expected for detection of early articular cartilage degeneration. METHODS: 24 rabbits were randomly divided into four equal experimental groups (Group A, B, C, D) to establish articular cartilage models in different grades of early degeneration by injecting papain into the left knee joint cavity. Another 8 rabbits were considered as blank control (Group E), and then randomized into four subgroups (EA, EB, EC, ED). T1rho and T2-weighted images of the bilateral knee joints were obtained for rabbits by using 3.0 T MRI. Group A, B, C, and D were imaged respectively at 1, 2, 3, and 4 weeks post-operation, and EA, EB, EC, ED underwent the same period imaging. Rabbits were sacrificed after scanning and the femoral condyle cartilage (FCC) was histological examined. T1rho values of the femoral condyle cartilage were measured and statistically analyzed, and contrasted with the histologic results. RESULTS: T1rho values of the left side in experimental groups were significantly higher than the right side (P < 0.05), and which increased gradually with the passage of post-operation time (P < 0.05). Histological examination demonstrated the proteoglycan content of the left side decreased, and indicated the occurrence of early degeneration. CONCLUSIONS: T1rho MRI can sensitively and quantitatively reflect the change in proteoglycans prior to the morphologic alterations of articular cartilage, and T1rho value is gradually increased with a decrease in proteoglycan content, therefore that T1rho could potentially act as a reliable tool to identify early cartilage degeneration. PMID- 26585247 TI - A Description for Rock Joint Roughness Based on Terrestrial Laser Scanner and Image Analysis. AB - Shear behavior of rock mass greatly depends upon the rock joint roughness which is generally characterized by anisotropy, scale effect and interval effect. A new index enabling to capture all the three features, namely brightness area percentage (BAP), is presented to express the roughness based on synthetic illumination of a digital terrain model derived from terrestrial laser scanner (TLS). Since only tiny planes facing opposite to shear direction make contribution to resistance during shear failure, therefore these planes are recognized through the image processing technique by taking advantage of the fact that they appear brighter than other ones under the same light source. Comparison with existing roughness indexes and two case studies were illustrated to test the performance of BAP description. The results reveal that the rock joint roughness estimated by the presented description has a good match with existing roughness methods and displays a wider applicability. PMID- 26585248 TI - Catheter-associated urinary tract infection after cardiovascular surgery: Impact of a multifaceted intervention. AB - BACKGROUND: The aims of this study were to assess the impact of a multifaceted intervention on the incidence of catheter-associated urinary tract infection (CAUTI) and on the urinary catheter utilization (UCU) ratio, evaluating adherence to recommendations for the use of indwelling urinary catheters (IUCs). METHODS: This prospective, before-and-after interventional study was conducted in three 6 month phases: preintervention (phase 1), intervention (phase 2), and postintervention (phase 3). We observed IUC insertion technique, maintenance care, and removal/nonremoval practices; provided training on CAUTI prevention measures; evaluated professional knowledge; provided adherence feedback; determined the incidence of CAUTI, and calculating the UCU ratio. RESULTS: Between phases 1 and 3, CAUTI incidence fell from 11.42 to 4.40 cases/1000 catheter-days (P = .216), whereas the UCU ratio remained constant. The risk of CAUTI was 2.6-fold higher in phase 1 than in phase 3. Adherence to hand hygiene (before and after IUC insertion) improved significantly, as did adherence to attaching the IUC to the patient and maintenance care guidelines. The reasons for IUC use (including inappropriate reasons) did not differ significantly. Professional knowledge improved significantly after training. CONCLUSION: A multifaceted intervention effectively reduced CAUTI incidence and improved the quality of care. PMID- 26585249 TI - Your Paper, Your Way: AJIC's simplified submission guidelines. PMID- 26585250 TI - Association between early influenza vaccination and the reduction of influenza like syndromes in health care providers. AB - A comparison of 2 different influenza seasons (2013-2014 and 2014-2015) where early vaccination among health care providers (HCPs) in the latter was the difference. Differences in leave of absence because of influenza-like illness (ILI) (52 vs 15 [total number of leave of absence issued], P < .001) and total days of lost work (218 vs 68, P < .001) were found for the 2013-2014 and 2014 2015 seasons, respectively. An association between earlier influenza vaccination among HCPs and a reduction in ILI, leave of absence, and days of lost work was found. PMID- 26585251 TI - Influenza vaccination competence of nurses in France: A survey in nursing schools. AB - Since 2008, French nurses have been allowed to vaccinate against influenza without medical prescription. Our survey aimed at assessing nursing students' knowledge and perception of this prerogative. Among 213 responders, 61% were aware of this matter, and 47.5% were familiar with its requirements. Most (75.6%) were positive about it. Influenza vaccination without medical prescription is well-known and validated by nursing students. This new competence may improve vaccination coverage. PMID- 26585252 TI - Intravenous C-Arm Conebeam CT Angiography following Long-Term Flow-Diverter Implantation: Technologic Evaluation and Preliminary Results. AB - BACKGROUND AND PURPOSE: A noninvasive investigation with high spatial resolution and without metal artifacts is necessary for long-term imaging follow-up after flow-diverter implantation. We aimed to evaluate the diagnostic value of conebeam CT angiography with intravenous contrast enhancement in the assessment of vascular status following implantation of the Pipeline Embolization Device and to analyze the preliminary results of vascular status following long-term Pipeline Embolization Device implantation. MATERIALS AND METHODS: This was an ongoing prospective study of consecutive patients with intracranial aneurysms treated with the Pipeline Embolization Device. Patients with a modified Rankin Scale score of 4-5 were excluded. The median and interquartile range of the time interval of Pipeline Embolization Device implantation to conebeam CT angiography with intravenous contrast enhancement were 56.6 and 42.9-62.4 months, respectively. Conebeam CT angiography with intravenous contrast enhancement was performed with the patient fully conscious, by using a C-arm CT with a flat panel detector. RESULTS: There were 34 patients and 34 vascular segments. In all 34 cases, contrast effect and image quality were good and not substantially different from those of intra-arterial conebeam CTA. Metal artifacts occurred in all 14 cases with coil masses; the Pipeline Embolization Device was obscured in 3 cases. In all 34 cases, there was no residual aneurysm, no vascular occlusion, 1 vascular stenosis (50%), good Pipeline Embolization Device apposition to the vessel, and no Pipeline Embolization Device-induced calcification. All 28 Pipeline Embolization Device-covered side branches were patent. CONCLUSIONS: Conebeam CT angiography with intravenous contrast enhancement is potentially promising and useful for effective evaluation of the vascular status following intracranial flow diverters. The Pipeline Embolization Device for intracranial aneurysms is probably safe and promising for long-term placement, with favorable morphologic outcome and without delayed complications. PMID- 26585253 TI - Sustainable Growth Rate Repealed, MACRA Revealed: Historical Context and Analysis of Recent Changes in Medicare Physician Payment Methodologies. PMID- 26585254 TI - Clinical Applications of Simultaneous PET/MR Imaging Using (R)-[11C]-Verapamil with Cyclosporin A: Preliminary Results on a Surrogate Marker of Drug-Resistant Epilepsy. AB - BACKGROUND AND PURPOSE: The development of resistance to antiepileptic drugs is explained well by the transporter hypothesis, which suggests that drug resistance is caused by inadequate penetration of drugs into the brain barrier as a result of increased levels of efflux transporter such as p-glycoprotein. To evaluate the brain expression of p-glycoprotein in patients with drug-resistant epilepsy, including neocortical epilepsy, we developed a noninvsive quantitative analysis including asymmetry indices based on (R)-[(11)C]-verapamil PET/MR imaging with cyclosporin A, a p-glycoprotein inhibitor. MATERIALS AND METHODS: Six patients with drug-resistant epilepsy, 5 patients with drug-sensitive epilepsy, and 8 healthy controls underwent dynamic (R)-[(11)C]-verapamil PET/MR imaging with an intravenous infusion of cyclosporin A. Asymmetry indices [(Right Region - Left Region)/(Right Region + Left Region) * 200%] of the standard uptake values in each of the paired lobes were calculated. RESULTS: All patients with drug resistant epilepsy had significantly different asymmetry from the healthy controls, whereas all patients with drug-sensitive epilepsy had asymmetry similar to that in healthy controls. In the temporal lobe, the asymmetry indices of patients with left temporal lobe drug-resistant epilepsy were more positive than those of healthy controls (healthy controls: 4.0413 +/- 1.7452; patients: 7.2184 +/- 1.8237; P = .048), and those of patients with right temporal drug-resistant epilepsy were more negative (patients: -1.6496 +/- 3.4136; P = .044). In addition, specific regions that had significant asymmetry were different between the lateral and medial temporal lobe epilepsy groups. In the frontal lobe, the asymmetry index of patients with right frontal lobe drug-resistant epilepsy was more negative than that in healthy controls. CONCLUSIONS: We confirmed that statistical parametric mapping analysis by using asymmetry indices of (R)-[(11)C] verapamil PET/MR imaging with cyclosporin A could be used as a surrogate marker for drug-resistant epilepsy, and this approach might be helpful for localizing or lateralizing the epileptic zone. PMID- 26585255 TI - WEB in Partially Thrombosed Intracranial Aneurysms: A Word of Caution. AB - Despite the proved safety and efficacy of Woven EndoBridge (WEB) flow disruption in conventional intracranial saccular aneurysms, the literature on its use in partially thrombosed intracranial aneurysms is scarce. We report a series of 4 patients in whom partially thrombosed intracranial aneurysms were treated with the WEB. The 2 patients who received additional intraluminal treatment with conventional stents made a good clinical recovery. Meanwhile, those patients who were treated with the WEB alone had fatal rupture of the aneurysm at short- to medium-term follow-up. This small, select case series demonstrates that WEB placement with adjunctive stent placement may be an effective treatment in the management of partially thrombosed intracranial aneurysms, which merits further validation. However, exclusive intrasaccular flow disruption may have an adverse influence on the natural history of this disease. PMID- 26585256 TI - The Cervical Spinal Canal Tapers Differently in Patients with Chiari I with and without Syringomyelia. AB - BACKGROUND AND PURPOSE: The cause of syringomyelia in patients with Chiari I remains uncertain. Cervical spine anatomy modifies CSF velocities, flow patterns, and pressure gradients, which may affect the spinal cord. We tested the hypothesis that cervical spinal anatomy differs between Chiari I patients with and without syringomyelia. MATERIALS AND METHODS: We identified consecutive patients with Chiari I at 3 institutions and divided them into groups with and without syringomyelia. Five readers measured anteroposterior cervical spinal diameters, tonsillar herniation, and syrinx dimensions on cervical MR images. Taper ratios for C1-C7, C1-C4, and C4-C7 spinal segments were calculated by linear least squares fitting to the appropriate spinal canal diameters. Mean taper ratios and tonsillar herniation for groups were compared and tested for statistical significance with a Kruskal-Wallis test. Inter- and intrareader agreement and correlations in the data were measured. RESULTS: One hundred fifty patients were included, of which 49 had syringomyelia. C1-C7 taper ratios were smaller and C4-C7 taper ratios greater for patients with syringomyelia than for those without it. C1-C4 taper ratios did not differ significantly between groups. Patients with syringomyelia had, on average, greater tonsillar herniation than those without a syrinx. However, C4-C7 taper ratios were steeper, for all degrees of tonsil herniation, in patients with syringomyelia. Differences among readers did not exceed differences among patient groups. CONCLUSIONS: The tapering of the lower cervical spine may contribute to the development of syringomyelia in patients with Chiari I. PMID- 26585257 TI - Imaging Psoas Sign in Lumbar Spinal Infections: Evaluation of Diagnostic Accuracy and Comparison with Established Imaging Characteristics. AB - BACKGROUND AND PURPOSE: Lumbar discitis-osteomyelitis has imaging characteristics than can overlap with noninfectious causes of back pain. Our aim was to determine the added accuracy of psoas musculature T2 hyperintensity (imaging psoas sign) in the MR imaging diagnosis of lumbar discitis-osteomyelitis. MATERIALS AND METHODS: This retrospective case-control study evaluated lumbar spine MR imaging examinations, during a 30-month period, that were requested for the evaluation of discitis-osteomyelitis. Of this pool, 50 age-matched control patients were compared with 51 biopsy-proved or clinically diagnosed patients with discitis osteomyelitis. Two reviewers, blinded to the clinical information, assessed the randomly organized MR imaging examinations for abnormalities of the psoas musculature, vertebral bodies, discs, and epidural space. RESULTS: Psoas T2 hyperintensity demonstrated a high sensitivity (92.1%; 95% CI, 80%-97.4%) and specificity (92%; 95% CI, 80%-97.4%), high positive likelihood ratio (11.5; 95% CI, 4.5-29.6), low negative likelihood ratio (0.09; 95% CI, 0.03-0.20), and individual area under the receiver operating characteristic curve of 0.92; 95% CI, 0.87-0.97. Identification of psoas T2 abnormality significantly improved (P = .02) the diagnostic accuracy of discitis-osteomyelitis in noncontrast examinations from an area under the receiver operator characteristic curve of the established variables (vertebral body T2 and T1 signal, endplate integrity, disc T2 signal, and disc height) from 0.93 (95% CI, 0.88-0.98) to 0.98 (95% CI, 0.96 1.0). Psoas T2 abnormalities also had the highest interobserver reliability with a kappa coefficient of 0.78 (substantial agreement). CONCLUSIONS: Psoas T2 hyperintensity, the imaging psoas sign, is highly correlated with discitis osteomyelitis. T2 hyperintensity in the psoas musculature, particularly when there is clinical suspicion of spinal infection, improves the diagnostic accuracy of discitis-osteomyelitis compared with routine noncontrast variables alone. PMID- 26585258 TI - Cerebral Blood Flow Improvement after Indirect Revascularization for Pediatric Moyamoya Disease: A Statistical Analysis of Arterial Spin-Labeling MRI. AB - BACKGROUND AND PURPOSE: The severity of Moyamoya disease is generally scaled with conventional angiography and nuclear medicine. Arterial spin-labeling MR imaging is now acknowledged for the noninvasive quantification of cerebral blood flow. This study aimed to analyze CBF modifications with statistical parametric mapping of arterial spin-labeling MR imaging in children undergoing an operation for Moyamoya disease. MATERIALS AND METHODS: We included 15 children treated by indirect cerebral revascularization with multiple burr-holes between 2011 and 2013. Arterial spin-labeling MR imaging and T1 sequences were then analyzed under SPM8, according to the general linear model, before and after the operation (3 and 12 months). Voxel-based analysis was performed at the group level, comparing all diseased hemispheres with all normal hemispheres and, at the individual level, comparing each patient with a control group. RESULTS: Group analysis showed statistically significant preoperative hypoperfusion in the MCA territory in the Moyamoya hemispheres and a significant increase of cerebral perfusion in the same territory after revascularization (P < .05 family-wise error-corrected). Before the operation, individual analysis showed significant hypoperfusion for each patient co-localized with the angiographic defect on DSA. All except 1 patient had improvement of CBF after revascularization, correlated with their clinical status. CONCLUSIONS: SPM analysis of arterial spin-labeling MR imaging offers a noninvasive evaluation of preoperative cerebral hemodynamic impairment and an objective assessment of postoperative improvement in children with Moyamoya disease. PMID- 26585259 TI - Voxel-Based Morphometry and fMRI Revealed Differences in Brain Gray Matter in Breastfed and Milk Formula-Fed Children. AB - BACKGROUND AND PURPOSE: Infant diets may have significant impact on brain development in children. The aim of this study was to evaluate brain gray matter structure and function in 8-year-old children who were predominantly breastfed or fed cow's milk formula as infants. MATERIALS AND METHODS: Forty-two healthy children (breastfed: n = 22, 10 boys and 12 girls; cow's milk formula: n = 20, 10 boys and 10 girls) were studied by using structural MR imaging (3D T1-weighted imaging) and blood oxygen level-dependent fMRI (while performing tasks involving visual perception and language functions). They were also administered standardized tests evaluating intelligence (Reynolds Intellectual Assessment Scales) and language skills (Clinical Evaluation of Language Fundamentals). RESULTS: Total brain gray matter volume did not differ between the breastfed and cow's milk formula groups. However, breastfed children had significantly higher (P < .05, corrected) regional gray matter volume measured by voxel-based morphometry in the left inferior temporal lobe and left superior parietal lobe compared with cow's milk formula-fed children. Breastfed children showed significantly more brain activation in the right frontal and left/right temporal lobes on fMRI when processing the perception task and in the left temporal/occipital lobe when processing the visual language task than cow's milk formula-fed children. The imaging findings were associated with significantly better performance for breastfed than cow's milk formula-fed children on both tasks. CONCLUSIONS: Our findings indicated greater regional gray matter development and better regional gray matter function in breastfed than cow's milk formula-fed children at 8 years of age and suggested that infant diets may have long-term influences on brain development in children. PMID- 26585260 TI - Endovascular Treatment of Intracranial Aneurysms with the WEB Device: A Systematic Review of Clinical Outcomes. AB - BACKGROUND AND PURPOSE: Despite the improvement in technology, endovascular treatment of bifurcation intracranial wide-neck aneurysms remains challenging, mainly due to the difficulty of maintaining coils within the aneurysm sac without compromising the patency of bifurcation arteries. The Woven EndoBridge (WEB) device is a recent intrasaccular braided device specifically dedicated to treating such aneurysms with a wide neck by disrupting the flow in the aneurysmal neck and promoting progressive aneurysmal thrombosis. MATERIALS AND METHODS: Using several health data bases, we conducted a systematic review of all published studies of WEB endovascular treatment in intracranial aneurysms from 2010 onward to evaluate its efficacy and safety profile. RESULTS: The literature search identified 6 relevant studies (7 articles) including wide-neck bifurcation aneurysms in >=80% of cases. Clinical data supporting the efficacy and safety of the WEB are limited to noncomparative cohort studies with large heterogeneity from a methodologic standpoint. The WEB deployment was feasible with a success rate of 93%-100%. Permanent morbidity (mRS of >1 at last follow-up) and mortality were measured at 2.2%-6.7% and 0%-17%, respectively. The adequate occlusion rate (total occlusion or neck remnant) varied between 65% and 85.4% at midterm follow up (range, 3.3-27.4 months). CONCLUSIONS: Endovascular treatment of bifurcation wide-neck aneurysms with the WEB device is feasible and allows an acceptably adequate aneurysm occlusion rate; however, the rate of neck remnants is not negligible. The WEB device needs further clinical and anatomic evaluation with long-term prospective studies, especially of the risk of WEB compression. Prospective controlled studies should be encouraged. PMID- 26585261 TI - Using Body Mass Index to Predict Needle Length in Fluoroscopy-Guided Lumbar Punctures. AB - BACKGROUND AND PURPOSE: Predicting the appropriate needle length to use in oblique interlaminar-approach fluoroscopy-guided lumbar punctures in patients with a large body mass index is difficult. Using the wrong needle length can lead to an increased radiation dose and patient discomfort. We hypothesized that body mass index could help determine the appropriate needle length to use in patients. MATERIALS AND METHODS: We randomly selected patients who underwent oblique interlaminar-approach fluoroscopy-guided lumbar punctures and had cross-sectional imaging of the lumbar spine within 1 year of imaging (n = 50). The distance from the skin to the midlumbar spinal canal (skin-canal distance) at the level of the lumbar puncture was measured by using an oblique angle of 8.6 degrees , which is an average of angles most often used to perform the procedure. A formula was devised using the skin-canal distance and body mass index to predict the appropriate needle length, subsequently confirmed in 45 patients. RESULTS: The body mass index and skin-canal distance were significantly higher (P < .001) in patients who underwent fluoroscopy-guided lumbar puncture with 5- or 7-inch needles (n = 22) than in patients requiring 3.5-inch needles (n = 28). Using linear regression, we determined the formula to predict the needle length as Skin Canal Distance (inches) = 0.077 * Body Mass Index + 0.88. We found a strong correlation (P < .001) between the predicted and actual skin canal distance in 45 patients, and our formula better predicted the skin-canal distance than others. CONCLUSIONS: We designed a formula that uses body mass index to predict the appropriate needle length in oblique interlaminar-approach fluoroscopy-guided lumbar punctures and validated it by demonstrating a strong correlation between the predicted and actual skin-canal distance. PMID- 26585262 TI - Evaluation of Subependymal Gray Matter Heterotopias on Fetal MRI. AB - BACKGROUND AND PURPOSE: Subependymal grey matter heterotopias are seen in a high proportion of children with Chiari II malformation and are potentially clinically relevant. However, despite its growing use, there is little in the literature describing its detection on fetal MRI. Our aim was to evaluate the accuracy in diagnosing subependymal gray matter heterotopias in fetuses with spinal dysraphism on fetal MR imaging. MATERIALS AND METHODS: This study is a retrospective analysis of 203 fetal MRIs performed at a single institution for spinal dysraphism during a 10-year period. Corresponding obstetric sonography, postnatal imaging, and clinical/operative reports were reviewed. RESULTS: Of the fetal MRIs reviewed, 95 fetuses were included in our analysis; 23.2% (22/95) were suspected of having subependymal gray matter heterotopias on fetal MR imaging prospectively. However, only 50% (11/22) of these cases were confirmed on postnatal brain MR imaging. On postnatal brain MR imaging, 28.4% (27/95) demonstrated imaging findings consistent with subependymal gray matter heterotopia. Only 40.7% (11/27) of these cases were prospectively diagnosed on fetal MR imaging. CONCLUSIONS: Fetal MR imaging is limited in its ability to identify subependymal gray matter heterotopias in fetuses with spinal dysraphism. It is believed that this limitation relates to a combination of factors, including artifacts from fetal motion, the very small size of fetal neuroanatomy, differences in imaging techniques, and, possibly, irregularity related to denudation of the ependyma/subependyma in the presence of spinal dysraphism and/or stretching of the germinal matrix in ventriculomegaly. PMID- 26585263 TI - Radiologic Features and Expression of Vascular Endothelial Growth Factor Stratify Survival Outcomes in Patients with Glioblastoma. AB - BACKGROUND AND PURPOSE: Vascular endothelial growth factor is a well-known tumor specific biomarker that mediates angiogenesis in glioblastoma via hypoxia dependent mechanisms. Our aim was to investigate the correlation of clinical characteristics, radiologic features, and vascular endothelial growth factor expression with survival outcomes in patients with glioblastoma. MATERIALS AND METHODS: Clinical and radiologic data of 185 patients with glioblastoma were retrospectively reviewed. Vascular endothelial growth factor expression was examined in all cases via immunohistochemical analysis. Univariate and multivariate analyses were performed to identify the prognostic factors of progression-free survival and overall survival. RESULTS: Vascular endothelial growth factor expression levels were associated with the presence of ringlike tumor contrast enhancement. Age, preoperative Karnofsky Performance Scale score, gross total resection, and adjuvant therapy were identified as prognostic factors. Among patients undergoing gross total resection, high vascular endothelial growth factor expression was associated with longer progression-free survival (P = .011) and overall survival (P = .039). For tumors with high vascular endothelial growth factor expression, both the non-contrast-enhancing tumor component and peritumoral edema could stratify overall survival (P = .039 and .018, respectively), while only the presence of the non-contrast-enhancing tumor component predicted a longer progression-free survival (P = .024). CONCLUSIONS: Vascular endothelial growth factor expression level was not an independent prognostic factor in glioblastoma. However, high vascular endothelial growth factor expression might predict longer survival in patients in whom gross total resection was achieved. Furthermore, peritumoral edema and the non-contrast enhancing tumor component could stratify survival outcomes in patients with high vascular endothelial growth factor tumors. PMID- 26585264 TI - Applicability of the Sparse Temporal Acquisition Technique in Resting-State Brain Network Analysis. AB - BACKGROUND AND PURPOSE: The ability of sparse temporal acquisition to minimize the effect of scanner background noise is of utmost importance in auditory fMRI; however, it has considerably lower temporal efficiency and resolution than the conventional continuous acquisition method. The purpose of this study was to determine whether sparse sampling could be applied to resting-state research by comparing its results with those obtained by using continuous acquisition. MATERIALS AND METHODS: We identified resting-state networks by using independent component analysis and measured their functional connectivity strength in 14 healthy subjects who underwent two 6-minute sparse (60 volumes) and continuous (360 volumes) imaging sessions. To account for the sample size difference, an additional continuous dataset was generated by temporally matching the continuous dataset to 60 volumes of the sparse dataset. RESULTS: Consistent resting-state network maps were produced through all 3 datasets. Scanner background noise did not appear to affect the spatial constitution of the networks, whereas a larger sample size influenced it substantially. The strength of the intranetwork connectivity was similar through the 3 datasets. CONCLUSIONS: Our results indicated that continuous acquisition is a recommended technique that should be applied in most of the resting-state studies due to its superior temporal efficiency and increased statistical power. The use of sparse temporal acquisition should be restricted to very particular conditions when continuous scanner noise is unacceptable. PMID- 26585265 TI - REPLY. PMID- 26585266 TI - Risk of Malignancy in Symptomatic Nodular Goiter Treated with Radiofrequency Ablation. PMID- 26585267 TI - White Matter Abnormality Correlates with Developmental and Seizure Outcomes in West Syndrome of Unknown Etiology. AB - BACKGROUND AND PURPOSE: West syndrome is an epileptic encephalopathy characterized by epileptic spasms, a specific pattern on electroencephalography of hypsarrhythmia, and developmental regression. Our aim was to assess white matter abnormalities in West syndrome of unknown etiology. We hypothesized that diffusion tensor imaging reveals white matter abnormalities, especially in patients with poor seizure and developmental outcomes. MATERIALS AND METHODS: We enrolled 23 patients with new-onset West syndrome of unknown etiology. DTI was performed at 12 and 24 months of age. Fractional anisotropy images were compared with those of controls by using tract-based spatial statistics. We compared axial, radial, and mean diffusivity between patients and controls in the fractional anisotropy skeleton. We determined correlations of these parameters with developmental quotient, electroencephalography, and seizure outcomes. We also compared DTI with hypometabolism on fluorodeoxyglucose positron-emission tomography. RESULTS: At 12 months of age, patients showed widespread fractional anisotropy reductions and higher radial diffusivity in the fractional anisotropy skeleton with a significant difference on tract-based spatial statistics. The developmental quotient at 12 months of age correlated positively with fractional anisotropy and negatively with radial and mean diffusivity. Patients with seizure and abnormal findings on electroencephalography after initial treatments had lower fractional anisotropy and higher radial diffusivity. At 24 months, although tract-based spatial statistics did not show significant differences between patients and controls, tract-based spatial statistics in the 10 patients with a developmental quotient of <70 had significant fractional anisotropy reduction. In patients with unilateral temporal lobe hypometabolism on PET, tract-based spatial statistics showed greater fractional anisotropy reduction in the temporal lobe ipsilateral to the side of PET hypometabolism. CONCLUSIONS: Diffuse abnormal findings on DTI at 12 months of age suggest delayed myelination as a key factor underlying abnormal findings on DTI. Conversely, asymmetric abnormal findings on DTI at 24 months may reflect underlying focal pathologies. PMID- 26585268 TI - Some like it hot, some like it cold: Temperature dependent biotechnological applications and improvements in extremophilic enzymes. AB - The full biotechnological exploitation of enzymes is still hampered by their low activity, low stability and high cost. Temperature-dependent catalytic properties of enzymes are a key to efficient and cost-effective translation to commercial applications. Organisms adapted to temperature extremes are a rich source of enzymes with broad ranging thermal properties which, if isolated, characterized and their structure-function-stability relationship elucidated, could underpin a variety of technologies. Enzymes from thermally-adapted organisms such as psychrophiles (low-temperature) and thermophiles (high-temperature) are a vast natural resource that is already under scrutiny for their biotechnological potential. However, psychrophilic and thermophilic enzymes show an activity stability trade-off that necessitates the use of various genetic and chemical modifications to further improve their properties to suit various industrial applications. This review describes in detail the properties and biotechnological applications of both cold-adapted and thermophilic enzymes. Furthermore, the review critically examines ways to improve their value for biotechnology, concluding by proposing an integrated approach involving thermally-adapted, genetically and magnetically modified enzymes to make biocatalysis more efficient and cost-effective. PMID- 26585270 TI - [Cluster headache and brain imagery]. AB - Cluster headache is defined on clinical international criteria developed by International Headache Society (IHS, 2013). The realization of a brain MRI with arterial angio-MRI is required according to the French recommendations (Donnet et al., 2014) based on recent the literature. Numerous causes or diseases can mimic typical or atypical AVF (Edvardsson, 2014). Identification of these causes allows an appropriate treatment in addition with symptomatic treatment. PMID- 26585271 TI - Chronic thromboembolic pulmonary hypertension. AB - Chronic thromboembolic pulmonary hypertension (CTEPH) is a form of pulmonary hypertension (PH) characterized by the persistence of thromboembolic obstructing the pulmonary arteries as an organized tissue and the presence of a variable small vessel arteriopathy. The consequence is an increase in pulmonary vascular resistance resulting in progressive right heart failure. CTEPH is classified as group IV pulmonary hypertension according to the WHO classification of pulmonary hypertension. CTEPH is defined as precapillary pulmonary hypertension (mean pulmonary artery pressure >= 25 mmHg with a pulmonary capillary wedge pressure <= 15 mmHg) associated with mismatched perfusion defects on ventilation-perfusion lung scan and signs of chronic thromboembolic disease on computed tomography pulmonary angiogram and/or conventional pulmonary angiography, in a patient who received at least 3 months of therapeutic anticoagulation. CTEPH as a direct consequence of symptomatic pulmonary embolism (PE) is rare, and a significant number of CTEPH cases develop in the absence of history of PE. Thus, CTEPH should be considered in any patient with unexplained PH. Splenectomy, chronic inflammatory conditions such as inflammatory bowel disease, indwelling catheters and cardiac pacemakers have been identified as associated conditions increasing the risk of CTEPH. Ventilation-perfusion scan (V/Q) is the best test available for establishing the thromboembolic nature of PH. When CTEPH is suspected, patients should be referred to expert centres where pulmonary angiography, right heart catheterization and high-resolution CT scan will be performed to confirm the diagnosis and to assess the operability. Pulmonary endarterectomy (PEA) remains the gold standard treatment for CTEPH when organized thrombi involve the main, lobar or segmental arteries. This operation should only be performed by experienced surgeons in specialized centres. For inoperable patients, current ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension recommend the use of riociguat and say that off-label use of drugs approved for PAH and pulmonary angioplasty may be considered in expert centres. PMID- 26585269 TI - Progesterone administration for luteal phase deficiency in human reproduction: an old or new issue? AB - Luteal phase deficiency (LPD) is described as a condition of insufficient progesterone exposure to maintain a regular secretory endometrium and allow for normal embryo implantation and growth. Recently, scientific focus is turning to understand the physiology of implantation, in particular the several molecular markers of endometrial competence, through the recent transcriptomic approaches and microarray technology. In spite of the wide availability of clinical and instrumental methods for assessing endometrial competence, reproducible and reliable diagnostic tests for LPD are currently lacking, so no type-IA evidence has been proposed by the main scientific societies for assessing endometrial competence in infertile couples. Nevertheless, LPD is a very common condition that may occur during a series of clinical conditions, and during controlled ovarian stimulation (COS) and hyperstimulation (COH) programs. In many cases, the correct approach to treat LPD is the identification and correction of any underlying condition while, in case of no underlying dysfunction, the treatment becomes empiric. To date, no direct data is available regarding the efficacy of luteal phase support for improving fertility in spontaneous cycles or in non gonadotropin induced ovulatory cycles. On the contrary, in gonadotropin in vitro fertilization (IVF) and non-IVF cycles, LPD is always present and progesterone exerts a significant positive effect on reproductive outcomes. The scientific debate still remains open regarding progesterone administration protocols, specially on routes of administration, dose and timing and the potential association with other drugs, and further research is still needed. PMID- 26585272 TI - [Should we fear the perchlorate ion in the environment?]. AB - Perchlorate ions (ClO4(-)) are present in groundwater and are then present in distribution networks of drinking water destined for human consumption. The perchlorate ion comes mainly from ammonium salt manufactured for industrial activities or from arms of the First World War. Perchlorate ion is a competitive inhibitor of the sodium-iodide symporter and inhibits the synthesis of thyroid hormones. Values of toxicity have been published by the French agency ANSES and are used by authorities to limit the consumption of drinking water of some distribution networks by children and pregnant women especially in Nord-Pas-de Calais and Picardie. Epidemiological data in other countries show no or little clinical effect in areas with similar contamination; it is therefore a precautionary principle. An effective substitution with iodine would limit the effects of the iodine deficiency itself but also would counteract the potential effects of an excess of perchlorate ions and also of other symporter inhibitors (thiocyanate, nitrate). Further studies are nevertheless needed to determine possible extra-thyroid effects of perchlorate ions. PMID- 26585273 TI - TRalpha receptor mutations extend the spectrum of syndromes of reduced sensitivity to thyroid hormone. AB - Since 2012, eight different abnormalities have been described in the THRA gene (encoding the TRalpha1 thyroid hormone receptor) of 14 patients from 9 families. These mutations induce a clinical phenotype (resistance to thyroid hormone type alpha) associating symptoms of untreated mild congenital hypothyroidism and a near-normal range of free and total thyroid hormones and TSH (the T4/T3 ratio is nevertheless usually low). The phenotype can diversely include short stature (due to growth retardation), dysmorphic syndrome (face and limb extremities), psychoneuromotor disorders, constipation and bradycardia. The identified genetic abnormalities are located within the ligand-binding domain and result in defective T3 binding, an abnormally strong interaction with corepressors and a dominant negative activity against still functional receptors. The identification of patients with consistent phenotypes and the underlying mutations are warranted to better delineate the spectrum of the syndromes of reduced sensitivity to thyroid hormone. PMID- 26585274 TI - Editorial: Aging and Metabolic Syndrome: Common Molecular Pathways. PMID- 26585276 TI - Synthesis and comparison of the biological activity of monocyclic phosphonate, difluorophosphonate and phosphate analogs of the natural AChE inhibitor cyclophostin. AB - New monocyclic phosphate, phosphonate and difluorophosphonate analogs of the natural AChE inhibitor cyclophostin were synthesized and their activity toward human AChE examined. Surprisingly, the phosphate, phosphonate, and difluorophosphonate analogs all showed diminished activity when compared with the natural product. PMID- 26585275 TI - A structure-activity relationship of non-peptide macrocyclic histone deacetylase inhibitors and their anti-proliferative and anti-inflammatory activities. AB - Inhibition of the enzymatic activity of histone deacetylase (HDAC) is a promising therapeutic strategy for cancer treatment and several distinct small molecule histone deacetylase inhibitors (HDACi) have been reported. We have previously identified a new class of non-peptide macrocyclic HDACi derived from 14- and 15 membered macrolide skeletons. In these HDACi, the macrocyclic ring is linked to the zinc chelating hydroxamate moiety through a para-substituted aryl-triazole cap group. To further delineate the depth of the SAR of this class of HDACi, we have synthesized series of analogous compounds and investigated the influence of various substitution patterns on their HDAC inhibitory, anti-proliferative and anti-inflammatory activities. We identified compounds 25b and 38f with robust anti-proliferative activities and compound 26f (IC50 47.2 nM) with superior anti inflammatory (IC50 88 nM) activity relative to SAHA. PMID- 26585277 TI - Fas-Activated Mitochondrial Apoptosis Culls Stalled Embryonic Stem Cells to Promote Differentiation. AB - The intrinsic (mitochondrial) apoptotic pathway is a conserved cell death program crucial for eliminating superfluous, damaged, or incorrectly specified cells, and the multi-domain pro-death BCL-2 family proteins BAX and BAK are required for its activation. In response to internal damage or developmental signals, BAX and/or BAK permeabilize the mitochondrial outer membrane, resulting in cytochrome c release and activation of effector caspases such as Caspase-3 (Casp3). While the mitochondrial apoptotic pathway plays a critical role during late embryonic development in mammals, its role during early development remains controversial. Here, we show that Bax(-/-)Bak(-/-) murine embryonic stem cells (ESCs) display defects during the exit from pluripotency, both in culture and during teratoma formation. Specifically, we find that when ESCs are stimulated to differentiate, a subpopulation fails to do so and instead upregulates FAS in a p53-dependent manner to trigger Bax/Bak-dependent apoptosis. Blocking this apoptotic pathway prevents the removal of these poorly differentiated cells, resulting in the retention of cells that have not exited pluripotency. Taken together, our results provide further evidence for heterogeneity in the potential of ESCs to successfully differentiate and reveal a novel role for apoptosis in promoting efficient ESC differentiation by culling cells that are slow to exit pluripotency. PMID- 26585278 TI - Target Detection Is Enhanced by Polarization Vision in a Fiddler Crab. AB - We are constantly surprised by the ability of relatively simple animals to perform precise visually guided movements within complex visual scenes, often using eyes with limited resolution. Exceptional examples include the capture of airborne prey by dragonflies, the learning flights of bees and wasps, and the tracking of conspecifics by crabs on intertidal mudflats. Most studies have focused on how animals do this using sensitivity to intensity or color. However, it is increasingly evident that a third ability, polarization vision, may contribute to such tasks. In many insects, polarization-sensitive photoreceptors are confined within an area of the eye known as the dorsal rim, which detects the polarized sky pattern specifically for navigation. However, some animals, including fiddler crabs, are sensitive to the polarization of light across the majority of their image-forming eyes, potentially allowing them to use polarization information to increase perceived contrast for general visual tasks. Investigations into the use of polarization image-parsing by animals have largely been confined to laboratory settings under artificial lighting. This approach can occasionally mislead if the lighting conditions are different from natural. This study presents the first behavioral evidence from the natural context for a function of polarization image parsing. Using experimental manipulations in wild populations of the fiddler crab Uca stenodactylus, we provide evidence that these animals use their polarization vision to enhance contrast in their visual environment, thereby increasing their ability to detect and respond to objects on the mudflat surface. PMID- 26585280 TI - Experimental Evidence that Social Relationships Determine Individual Foraging Behavior. AB - Social relationships are fundamental to animals living in complex societies. The extent to which individuals base their decisions around their key social relationships, and the consequences this has on their behavior and broader population level processes, remains unknown. Using a novel experiment that controlled where individual wild birds (great tits, Parus major) could access food, we restricted mated pairs from being allowed to forage at the same locations. This introduced a conflict for pair members between maintaining social relationships and accessing resources. We show that individuals reduce their own access to food in order to sustain their relationships and that individual foraging activity was strongly influenced by their key social counterparts. By affecting where individuals go, social relationships determined which conspecifics they encountered and consequently shaped their other social associations. Hence, while resource distribution can determine individuals' spatial and social environment, we illustrate how key social relationships themselves can govern broader social structure. Finally, social relationships also influenced the development of social foraging strategies. In response to forgoing access to resources, maintaining pair bonds led individuals to develop a flexible "scrounging" strategy, particularly by scrounging from their pair mate. This suggests that behavioral plasticity can develop to ameliorate conflicts between social relationships and other demands. Together, these results illustrate the importance of considering social relationships for explaining behavioral variation due to their significant impact on individual behavior and demonstrate the consequences of key relationships for wider processes. PMID- 26585279 TI - Aging Neural Progenitors Lose Competence to Respond to Mitogenic Notch Signaling. AB - Drosophila neural stem cells (neuroblasts) are a powerful model system for investigating stem cell self-renewal, specification of temporal identity, and progressive restriction in competence. Notch signaling is a conserved cue that is an important determinant of cell fate in many contexts across animal development; for example, mammalian T cell differentiation in the thymus and neuroblast specification in Drosophila are both regulated by Notch signaling. However, Notch also functions as a mitogen, and constitutive Notch signaling potentiates T cell leukemia as well as Drosophila neuroblast tumors. While the role of Notch signaling has been studied in these and other cell types, it remains unclear how stem cells and progenitors change competence to respond to Notch over time. Notch is required in type II neuroblasts for normal development of their transit amplifying progeny, intermediate neural progenitors (INPs). Here, we find that aging INPs lose competence to respond to constitutively active Notch signaling. Moreover, we show that reducing the levels of the old INP temporal transcription factor Eyeless/Pax6 allows Notch signaling to promote the de-differentiation of INP progeny into ectopic INPs, thereby creating a proliferative mass of ectopic progenitors in the brain. These findings provide a new system for studying progenitor competence and identify a novel role for the conserved transcription factor Eyeless/Pax6 in blocking Notch signaling during development. PMID- 26585281 TI - Circularly Polarized Light as a Communication Signal in Mantis Shrimps. AB - Animals that communicate using conspicuous body patterns face a trade-off between desired detection by intended receivers and undesired detection from eavesdropping predators, prey, rivals, or parasites. In some cases, this trade off favors the evolution of signals that are both hidden from predators and visible to conspecifics. Animals may produce covert signals using a property of light that is invisible to those that they wish to evade, allowing them to hide in plain sight (e.g., dragonfish can see their own, otherwise rare, red bioluminescence). The use of the polarization of light is a good example of a potentially covert communication channel, as very few vertebrates are known to use polarization for object-based vision. However, even these patterns are vulnerable to eavesdroppers, as sensitivity to the linearly polarized component of light is widespread among invertebrates due to their intrinsically polarization sensitive photoreceptors. Stomatopod crustaceans appear to have gone one step further in this arms race and have evolved a sensitivity to the circular polarization of light, along with body patterns producing it. However, to date we have no direct evidence that any of these marine crustaceans use this modality to communicate with conspecifics. We therefore investigated circular polarization vision of the mantis shrimp Gonodactylaceus falcatus and demonstrate that (1) the species produces strongly circularly polarized body patterns, (2) they discriminate the circular polarization of light, and (3) that they use circular polarization information to avoid occupied burrows when seeking a refuge. PMID- 26585282 TI - Specialized and Generalized Pollen-Collection Strategies in an Ancient Bee Lineage. AB - Iconic examples of insect pollination have emphasized narrowly specialized pollinator mutualisms such as figs and fig wasps and yuccas and yucca moths. However, recent attention by pollination ecologists has focused on the broad spectra of pollinated plants by generalist pollinators such as bees. Bees have great impact for formulating hypotheses regarding specialization versus generalization in pollination mutualisms. We report the pollination biology of six northern European species of an extinct tribe of pollen-basket-bearing apine bees, Electrapini, of early-middle Eocene age, examined from two deposits of 48 and 44 million years in age. These bees exhibit a pattern of generalized, incidental pollen occurring randomly on their heads, thoraces, and abdomens, obtained from diverse, nectar-bearing plants. By contrast, a more restricted suite of pollen was acquired for metatibial pollen baskets (corbiculae) of the same bee taxa from a taxonomically much narrower suite of arborescent, evergreen hosts with uniform flower structure. The stereotyped plant sources of the specialist strategy of pollen collection consisted of pentamerous, radially symmetrical flowers with a conspicuous gynoecium surrounded by prominent nectar reward, organized in structurally similar compound inflorescences. Pollen specialization in bees occurs not for efficient pollination but rather in the corbiculate Electrapini as food for bee larvae (brood) and involves packing corbiculae with moistened pollen that rapidly loses viability with age. This specialist strategy was a well-developed preference by the early Eocene, providing a geochronologic midpoint assessment of bee pollen-collection strategies. PMID- 26585283 TI - Experimental Evidence for the Population-Dynamic Mechanisms Underlying Extinction Cascades of Carnivores. AB - Species extinction rates due to human activities are high, and initial extinctions can trigger cascades of secondary extinctions, leading to further erosion of biodiversity. A potential major mechanism for secondary extinction cascades is provided by the long-standing theory that the diversity of consumer species is maintained due to the positive indirect effects that these species have on each other by reducing competition among their respective resource species. This means that the loss of one carnivore species could lead to competitive exclusion at the prey trophic level, leading to extinctions of further carnivore species. Evidence for these effects is difficult to obtain due to many confounding factors in natural systems, but extinction cascades that could be due to this mechanism have been demonstrated in simplified laboratory microcosms. We established complex insect food webs in replicated field mesocosms and found that the overharvesting of one parasitoid wasp species caused increased extinction rates of other parasitoid species, compared to controls, but only when we manipulated the spatial distribution of herbivore species such that the potential for interspecific competition at this level was high. This provides clear evidence for horizontal extinction cascades at high trophic levels due to the proposed mechanism. Our results demonstrate that the loss of carnivores can have widespread effects on other species at the same trophic level due to indirect population-dynamic effects that are rarely considered in this context. PMID- 26585284 TI - Chiral resolution of spin angular momentum in linearly polarized and unpolarized light. AB - Linearly polarized (LP) and unpolarized (UP) light are racemic entities since they can be described as superposition of opposite circularly polarized (CP) components of equal amplitude. As a consequence they do not carry spin angular momentum. Chiral resolution of a racemate, i.e. separation of their chiral components, is usually performed via asymmetric interaction with a chiral entity. In this paper we provide an experimental evidence of the chiral resolution of linearly polarized and unpolarized Gaussian beams through the transfer of spin angular momentum to chiral microparticles. Due to the interplay between linear and angular momentum exchange, basic manipulation tasks, as trapping, spinning or orbiting of micro-objects, can be performed by light with zero helicity. The results might broaden the perspectives for development of miniaturized and cost effective devices. PMID- 26585285 TI - Early pregnancy modulates survival and apoptosis pathways in the corpus luteum in sheep. AB - The corpus luteum (CL) is a transient endocrine gland. Functional and structural demise of the CL allows a new estrous cycle. On the other hand, survival of CL and its secretion of progesterone are required for the establishment of pregnancy. Survival or apoptosis of the luteal cells is precisely controlled by interactions between survival and apoptosis pathways. Regulation of these cell signaling components during natural luteolysis and establishment of pregnancy is largely unknown in ruminants. The objective of the present study was to determine the regulation of survival and apoptosis signaling protein machinery in the CL on days 12, 14, and 16 of the estrous cycle and pregnancy in sheep. Results indicate that: i) expressions of p-ERK1/2, p-AKT, beta-catenin, NFkappaB -p65, -p50, -p52, p-Src, p-beta -arrestin, p-GSK3beta, X-linked inhibitor of apoptosis protein (XIAP), and p-CREB proteins are suppressed during natural luteolysis; in contrast, their expressions are sustained or increased during establishment of pregnancy; ii) expressions of cleaved caspase-3, apoptosis inducing factor (AIF), c-Fos, c-Jun, and EGR-1 proteins are increased during natural luteolysis; in contrast, their expressions are decreased during establishment of pregnancy; and iii) expressions of Bcl-2, Bcl-XL, Bad, and Bax proteins are not modulated during natural luteolysis while expressions of Bcl2 and Bcl-XL proteins are increased during establishment of pregnancy in sheep. These proteomic changes are evident in both large and small luteal cells. These results together indicate that regression of the CL during natural luteolysis or survival of the CL during establishment of pregnancy is precisely controlled by distinct programmed suppression or activation of intraluteal cell survival and apoptosis pathways in sheep/ruminants. PMID- 26585286 TI - Animal performance and meat characteristics in steers reared in intensive conditions fed with different vegetable oils. AB - Enhancing the quality of beef meat is an important goal in terms of improving both the nutritional value for the consumer and the commercial value for producers. The aim of this work was to study the effects of different vegetable oil supplements on growth performance, carcass quality and meat quality in beef steers reared under intensive conditions. A total of 240 Blonde D' Aquitaine steers (average BW=293.7+/-38.88 kg) were grouped into 24 batches (10 steers/batch) and were randomly assigned to one of the three dietary treatments (eight batches per treatment), each supplemented with either 4% hydrogenated palm oil (PALM) or fatty acids (FAs) from olive oil (OLI) or soybean oil (SOY). No differences in growth performance or carcass quality were observed. For the meat quality analysis, a steer was randomly selected from each batch and the 6th rib on the left half of the carcass was dissected. PALM meat had the highest percentage of 16:0 (P<0.05) and the lowest n-6/n-3 polyunsaturated fatty acids (PUFA) ratio (P<0.05), OLI had the highest content of t11-18:1 (P<0.01) and c9,t11-18:2 (P<0.05) and SOY showed the lowest value of monounsaturated fatty acids (MUFA) (P<0.001), the highest percentage of PUFA (P<0.01) and a lower index of atherogenicity (P=0.07) than PALM. No significant differences in the sensory characteristics of the meat were noted. However, the results of the principal component analysis of meat characteristics enabled meat from those steers that consumed fatty acids from olive oil to be differentiated from that of steers that consumed soybean oil. PMID- 26585287 TI - A Selective Nociceptin Receptor Antagonist to Treat Depression: Evidence from Preclinical and Clinical Studies. AB - Nociceptin/Orphanin FQ (N/OFQ) is an endogenous ligand of the N/OFQ peptide (NOP) receptor, which is a G protein-coupled receptor in brain regions associated with mood disorders. We used a novel, potent, and selective orally bioavailable antagonist, LY2940094, to test the hypothesis that blockade of NOP receptors would induce antidepressant effects. In this study we demonstrate that targeting NOP receptors with LY2940094 translates to antidepressant-like effects in rodent models and, importantly, to antidepressant efficacy in patients with major depressive disorder (MDD). The proof-of-concept study (POC) was an 8-week, double blind, placebo-controlled trial that evaluated LY2940094 as a novel oral medication for the treatment of patients with MDD. Once daily oral dosing of LY2940094 at 40 mg for 8 weeks vs placebo provided some evidence for an antidepressant effect based on the change from baseline to week 8 in the GRID Hamilton Depression Rating Scale-17 item total score, although the predefined POC efficacy criterion (probability of LY2940094 being better than placebo?88%) was not met (82.9%). LY2940094 also had an early effect on the processing of emotional stimuli at Week 1 as shown by an increased recognition of positive relative to negative facial expressions in an emotional test battery. LY2940094 was safe and well tolerated. Overall, these are the first human data providing evidence that the blockade of NOP receptor signaling represents a promising strategy for the treatment of MDD. PMID- 26585288 TI - Functional Role of BDNF Production from Unique Promoters in Aggression and Serotonin Signaling. AB - Brain-derived neurotrophic factor (BDNF) regulates diverse biological functions ranging from neuronal survival and differentiation during development to synaptic plasticity and cognitive behavior in the adult. BDNF disruption in both rodents and humans is associated with neurobehavioral alterations and psychiatric disorders. A unique feature of Bdnf transcription is regulation by nine individual promoters, which drive expression of variants that encode an identical protein. It is hypothesized that this unique genomic structure may provide flexibility that allows different factors to regulate BDNF signaling in distinct cell types and circuits. This has led to the suggestion that isoforms may regulate specific BDNF-dependent functions; however, little scientific support for this idea exists. We generated four novel mutant mouse lines in which BDNF production from one of the four major promoters (I, II, IV, or VI) is selectively disrupted (Bdnf-e1, -e2, -e4, and -e6 mice) and used a comprehensive comparator approach to determine whether different Bdnf transcripts are associated with specific BDNF-dependent molecular, cellular, and behavioral phenotypes. Bdnf-e1 and -e2 mutant males displayed heightened aggression accompanied by convergent expression changes in specific genes associated with serotonin signaling. In contrast, BDNF-e4 and -e6 mutants were not aggressive but displayed impairments associated with GABAergic gene expression. Moreover, quantifications of BDNF protein in the hypothalamus, prefrontal cortex, and hippocampus revealed that individual Bdnf transcripts make differential, region-specific contributions to total BDNF levels. The results highlight the biological significance of alternative Bdnf transcripts and provide evidence that individual isoforms serve distinct molecular and behavioral functions. PMID- 26585289 TI - Cell-Type Specific Insertion of GluA2-Lacking AMPARs with Cocaine Exposure Leading to Sensitization, Cue-Induced Seeking, and Incubation of Craving. AB - Addiction is a behavioral disease, of which core components can be modeled in rodents. Much evidence implicates drug-evoked synaptic plasticity in cocaine evoked locomotor sensitization, cue-induced cocaine seeking, and incubation of cocaine craving. However, the type of plasticity evoked by different modalities of cocaine administration (eg contingent vs non-contingent) and its role in reshaping circuit function remains largely elusive. Here we exposed mice to various regimens of cocaine and recorded excitatory transmission onto identified medium-sized spiny neurons (MSN, expressing fluorescent proteins under the control of either D1R or D2R dopamine receptor promotor) in the nucleus accumbens at time points when behavioral adaptations are observed. In D1-MSN, we found the presence of GluA2-lacking alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) after single or chronic non-contingent exposure to cocaine as well as after cocaine self-administration (SA). We also report an increase in the AMPA/NMDA ratio (A/N) in D1-MSN, which was observed only after repeated passive injections associated with locomotor sensitization as well as in a condition of SA leading to seeking behavior. Remarkably, insertion of GluA2 lacking AMPARs was also detected in D2-MSN after SA of a high dose of cocaine but not regular dose (1.5 vs 0.75 mg/kg), which was the only condition where incubation of cocaine craving was observed in this study. Moreover, synapses containing GluA2-lacking AMPARs belonged to amygdala inputs in D2-MSN and to medial prefrontal cortex inputs in D1-MSN. Taken together this study allows for a refinement of a circuit model of addiction based on specific synaptic changes induced by cocaine. PMID- 26585290 TI - Role of beta4* Nicotinic Acetylcholine Receptors in the Habenulo-Interpeduncular Pathway in Nicotine Reinforcement in Mice. AB - Nicotine exerts its psychopharmacological effects by activating the nicotinic acetylcholine receptor (nAChR), composed of alpha and/or beta subunits, giving rise to a diverse population of receptors with a distinct pharmacology. beta4 containing (beta4*) nAChRs are located almost exclusively in the habenulo interpeduncular pathway. We examined the role of beta4* nAChRs in the medial habenula (MHb) and the interpeduncular nucleus (IPN) in nicotine reinforcement using behavioral, electrophysiological, and molecular techniques in transgenic mice. Nicotine intravenous self-administration (IVSA) was lower in constitutive beta4 knockout (KO) mice at all doses tested (7.5, 15, 30, and 60 MUg/kg/infusion) compared with wild-type (WT) mice. In vivo microdialysis showed that beta4KO mice have higher extracellular dopamine (DA) levels in the nucleus accumbens than in WT mice, and exhibit a differential sensitivity to nicotine induced DA outflow. Furthermore, electrophysiological recordings in the ventral tegmental area (VTA) demonstrated that DA neurons of beta4KO mice are more sensitive to lower doses of nicotine than that of WT mice. Re-expression of beta4* nAChRs in IPN neurons fully restored nicotine IVSA, and attenuated the increased sensitivity of VTA DA neurons to nicotine. These findings suggest that beta4* nAChRs in the IPN have a role in maintaining nicotine IVSA. PMID- 26585291 TI - Effect of Poly(gamma-glutamic acid) on the Physiological Responses and Calcium Signaling of Rape Seedlings (Brassica napus L.) under Cold Stress. AB - Cold stress adversely affects plant growth and development. Poly(gamma-glutamic acid) (gamma-PGA) is a potential plant growth regulator that may be an effective cryoprotectant that prevents crops from damage during cold weather. In this study, the effects of gamma-PGA on the physiological responses of rape seedlings subject to cold stress were investigated using hydroponic experiments. We determined that the malondialdehyde content was decreased by 33.4% and the proline content was increased by 62.5% by gamma-PGA after 144 h under cold stress. Antioxidant enzymes activities were also evidently enhanced after treatment with gamma-PGA. These responses counteracted increases in the fresh weight and chlorophyll content of rape seedlings, which increased by 24.5 and 50.9%, respectively, after 144 h, which meant that growth inhibition caused by cold was mitigated by gamma-PGA. Our results also showed that gamma-PGA also regulated Ca(2+) concentrations in the cytoplasm and calcium-dependent protein kinases, which are associated with cold resistance. In conclusion, we suggest that the Ca(2+)/CPKs signal pathway is involved in the gamma-PGA-mediated enhancement of cold resistance in rape seedlings. PMID- 26585292 TI - Effects of a supportive educational nursing care programme on fatigue and quality of life in patients with heart failure: a randomised controlled trial. AB - BACKGROUND: Fatigue is a common symptom in patients with heart failure that is easy to ignore. In addition, fatigue may affect patients' physical function and psychosocial conditions that can impair their quality of life. An effective nursing care programme is required to alleviate patients' fatigue and improve their quality of life. AIM: To investigate the effects of a supportive educational nursing care programme on fatigue and quality of life in patients with heart failure. METHODS: A randomised controlled trial design was used. Ninety-two patients with heart failure were randomly assigned to an intervention group (n=47) or a control group (n=45). The patients in the intervention group participated in 12 weeks of a supportive educational nursing care programme including fatigue assessment, education, coaching self-care and evaluation. The intervention was conducted by a cardiac nurse during four face-to-face interviews and three follow-up telephone interviews. Fatigue and quality of life were assessed at the baseline and 4 weeks, 8 weeks and 12 weeks after enrollment in both groups. RESULTS: The participants in the intervention group exhibited a significant decrease in the level of fatigue after 12 weeks, whereas those in the control group exhibited no significant changes. Compared with the control group, the intervention group exhibited a significantly greater decrease in the level of fatigue and significantly greater improvement in quality of life after 12 weeks of intervention. CONCLUSIONS: The supportive educational nursing care programme was recommended to alleviate fatigue and improve quality of life in patients with heart failure. PMID- 26585293 TI - The Impact of Patient Participation in Health Decisions Within Medical Encounters: A Systematic Review. AB - BACKGROUND: Although there are compelling moral arguments for patient participation in medical decisions, the link to health outcomes has not been systematically explored. OBJECTIVE: Assess the extent to which patient participation in decision making within medical encounters is associated with measured patient outcomes. METHODS: We conducted a primary search in PubMed excluding non-English and animal studies-for articles on decision making in the context of the physician-patient relationship published through the end of February 2015, using the MeSH headings (Physician-Patient Relations [MeSH] OR Patient Participation [MeSH]) and the terms (decision OR decisions OR option OR options OR choice OR choices OR alternative OR alternatives) in the title or abstract. We also conducted a secondary search of references in all articles that met the inclusion criteria. RESULTS: A thorough search process yielded 116 articles for final analysis. There was wide variation in study design, as well as measurement of patient participation and outcomes, among the studies. Eleven of the 116 studies were randomized controlled trials (RCTs). Interventions increased patient involvement in 10 (91%) of the 11 RCTs. At least one positive outcome was detected in 5 (50%) of the 10 RCTs reporting increased participation; the ratio of positive results among all outcome variables measured in these studies was much smaller. Although proportions differed, similar patterns were found across the 105 nonrandomized studies. CONCLUSIONS: Very few RCTs in the field have measures of participation in decision making and at least one health outcome. Moreover, extant studies exhibit little consistency in measurement of these variables, and results are mixed. There is a great need for well-designed, reproducible research on clinically relevant outcomes of patient participation in medical decisions. PMID- 26585294 TI - Factors associated with cervical kinematic impairments in patients with neck pain. AB - BACKGROUND AND AIM: Cervical kinematics have functional relevance and are important for assessment and management in patients with neck disorders. A better understanding of factors that might influence cervical kinematics is required. The aim of this study was to determine any relationships between altered kinematics to the symptoms and signs of sensorimotor impairments, neck pain and disability and fear of neck motion in people with neck pain. METHOD: Kinematics were measured in 39 subjects with chronic neck pain using a customized virtual reality system. Range of cervical motion, mean and peak velocity, time to peak velocity percentage, number of velocity peaks and accuracy were derived. Correlations between these measures to self-reported (neck pain intensity, disability, fear of motion, dizziness, visual disturbances) and sensorimotor measures and regression analyses were conducted. RESULTS: Range and velocity of motion of cervical rotation appeared to be most related to visual disturbances and pain or dynamic balance. Nevertheless these relationships only explained about 30% of the variance of each measure. CONCLUSION: Signs and symptoms of sensorimotor dysfunction should be considered and monitored in the management of altered cervical rotation kinematics in patients with chronic neck disorders. Future research should consider the effects of addressing these factors on neck kinematics and vice versa to aid functional recovery in those with neck pain. PMID- 26585295 TI - Effect of education on non-specific neck and low back pain: A meta-analysis of randomized controlled trials. AB - BACKGROUND: Neck and low back pain are significant health problems due to their high prevalence among the general population. Educational intervention commonly aims to reduce the symptoms and risk for additional problems by increasing the participant's knowledge, which in turn will alter the person's behavior. The primary aim of this study was to review randomize controlled trials (RCTs) to gain insights into the effectiveness of education for the prevention and treatment of non-specific neck and low back pain. METHODS: Publications were systematically searched from 1982 to March 2015 in several databases. Relevant RCTs were retrieved and assessed for methodological quality. Meta-analysis was conducted to examine the effectiveness of education for the prevention and treatment of non-specific neck and low back pain. The overall quality of evidence was assessed using the GRADE system. RESULTS: Thirty-six RCTs (30 high-quality studies) were identified. A total of 15 RCTs, which compared education programs to no education program, were included for further analysis. All studies included investigated the effectiveness of education with intermediate- and long-term follow-ups. The results showed that education programs were not effective in preventing and treating neck pain as well as treating low back pain. Conflicting evidence was found for the effectiveness of education on prevention of low back pain. CONCLUSIONS: Evidence suggests that education programs are not recommended in preventing or treating neck pain as well as treating low back pain, unless supplementary high-quality studies provide evidence to the contrary. PMID- 26585296 TI - Modular Detection of GFP-Labeled Proteins for Rapid Screening by Electron Microscopy in Cells and Organisms. AB - Reliable and quantifiable high-resolution protein localization is critical for understanding protein function. However, the time required to clone and characterize any protein of interest is a significant bottleneck, especially for electron microscopy (EM). We present a modular system for enzyme-based protein tagging that allows for improved speed and sampling for analysis of subcellular protein distributions using existing clone libraries to EM-resolution. We demonstrate that we can target a modified soybean ascorbate peroxidase (APEX) to any GFP-tagged protein of interest by engineering a GFP-binding peptide (GBP) directly to the APEX-tag. We demonstrate that APEX-GBP (1) significantly reduces the time required to characterize subcellular protein distributions of whole libraries to less than 3 days, (2) provides remarkable high-resolution localization of proteins to organelle subdomains, and (3) allows EM localization of GFP-tagged proteins, including proteins expressed at endogenous levels, in vivo by crossing existing GFP-tagged transgenic zebrafish lines with APEX-GBP transgenic lines. PMID- 26585298 TI - A Cellular System for Spatial Signal Decoding in Chemical Gradients. AB - Directional cell growth requires that cells read and interpret shallow chemical gradients, but how the gradient directional information is identified remains elusive. We use single-cell analysis and mathematical modeling to define the cellular gradient decoding network in yeast. Our results demonstrate that the spatial information of the gradient signal is read locally within the polarity site complex using double-positive feedback between the GTPase Cdc42 and trafficking of the receptor Ste2. Spatial decoding critically depends on low Cdc42 activity, which is maintained by the MAPK Fus3 through sequestration of the Cdc42 activator Cdc24. Deregulated Cdc42 or Ste2 trafficking prevents gradient decoding and leads to mis-oriented growth. Our work discovers how a conserved set of components assembles a network integrating signal intensity and directionality to decode the spatial information contained in chemical gradients. PMID- 26585297 TI - Proteomics of Primary Cilia by Proximity Labeling. AB - While cilia are recognized as important signaling organelles, the extent of ciliary functions remains unknown because of difficulties in cataloguing proteins from mammalian primary cilia. We present a method that readily captures rapid snapshots of the ciliary proteome by selectively biotinylating ciliary proteins using a cilia-targeted proximity labeling enzyme (cilia-APEX). Besides identifying known ciliary proteins, cilia-APEX uncovered several ciliary signaling molecules. The kinases PKA, AMPK, and LKB1 were validated as bona fide ciliary proteins and PKA was found to regulate Hedgehog signaling in primary cilia. Furthermore, proteomics profiling of Ift27/Bbs19 mutant cilia correctly detected BBSome accumulation inside Ift27(-/-) cilia and revealed that beta arrestin 2 and the viral receptor CAR are candidate cargoes of the BBSome. This work demonstrates that proximity labeling can be applied to proteomics of non membrane-enclosed organelles and suggests that proteomics profiling of cilia will enable a rapid and powerful characterization of ciliopathies. PMID- 26585300 TI - New insights on the phylogeny and biology of the fungal ant pathogen Aegeritella. AB - This paper evaluates the phylogenetic position of the ectoparasitic fungus Aegeritella tuberculata Balazy & Wisniewski, and broadly discusses its presence on ants in southern Poland. Field work was conducted in the Silesian Beskid Mountains in 2011-2013. The fungus was found on four species of ants: Lasius niger L., Lasius brunneus Latr., Formica lemani Bondr. and Formica fusca L. The first three species have not been noted previously in the literature as hosts of Aegeritella fungi. The infection rate ranged from 1% for Formica lemani to 21% for L. brunneus. Molecular analysis based on ITS and SSU rDNA sequences revealed close relationships between Aegeritella and Trichosporon isolates. We conclude that the genus Aegeritella-inceratae sedis until now, should be placed within the fungal group Basidiomycota, Tremellomycetes, Tremellomycetidae, Tremellales, Trichosporonaceae. PMID- 26585299 TI - Connexin Controls Cell-Cycle Exit and Cell Differentiation by Directly Promoting Cytosolic Localization and Degradation of E3 Ligase Skp2. AB - Connexins and connexin channels play important roles in cell growth/differentiation and tumorigenesis. Here, we identified a relationship between a connexin molecule and a critical cell-cycle regulator. Our data show that connexin (Cx) 50 regulated lens cell-cycle progression and differentiation by modulating expression of cyclin-dependent kinase inhibitor p27/p57 and E3 ubiquitin ligase Skp2. Cx50 directly interacted with and retained Skp2 in the cytosol by masking the nuclear targeting domain of Skp2, and this effect was supported by an increased nuclear localization of Skp2, disruption of Skp2 interaction with importin-7, and decreased levels of p27/p57 in mouse lenses lacking Cx50. As a result, Cx50 increased auto-ubiquitination and subsequent degradation of Skp2. A mutation (V362E) on the C terminus of Cx50 disrupted the interaction between Cx50 and Skp2 and completely abolished such effects. Therefore, this study identifies a role for connexins in regulating cell-cycle modulators and, consequently, cell growth and differentiation. PMID- 26585301 TI - The hyperparasite of the rickettsiales-like prokaryote, Candidatus Xenohaliotis californiensis has morphological characteristics of a Siphoviridae (Caudovirales). AB - Transmission electron microscopy analysis (TEM) of the rickettsiales-like prokaryote, Candidatus Xenohaliotis californiensis (CXc), pathogen of Haliotis spp. from the West Coast of North America, were found to be infected by a bacteriophage hyperparasite previously described in red abalone from California. The hyperparasite has an icosahedrical-like capsid with a narrow long flexible tail, this morphological characteristic tentatively place this virus in the Family Siphoviridae from the order Caudovirales. TEM images also showed the bacteriophage in different stages of assembly in the cytoplasm of CXc, demonstrating its lytic cycle. PMID- 26585302 TI - Bacterial dynamics in intestines of the black tiger shrimp and the Pacific white shrimp during Vibrio harveyi exposure. AB - The intestinal microbiota play important roles in health of their host, contributing to maintaining the balance and resilience against pathogen. To investigate effects of pathogen to intestinal microbiota, the bacterial dynamics upon a shrimp pathogen, Vibrio harveyi, exposures were determined in two economically important shrimp species; the black tiger shrimp (BT) and the Pacific white shrimp (PW). Both shrimp species were reared under the same diet and environmental conditions. Shrimp survival rates after the V. harveyi exposure revealed that the PW shrimp had a higher resistance to the pathogen than the BT shrimp. The intestinal bacterial profiles were determined by denaturing gradient gel electrophoresis (DGGE) and barcoded pyrosequencing of the 16S rRNA sequences under no pathogen challenge control and under pathogenic V. harveyi challenge. The DGGE profiles showed that the presence of V. harveyi altered the intestinal bacterial patterns in comparison to the control in BT and PW intestines. This implies that bacterial balance in shrimp intestines was disrupted in the presence of V. harveyi. The barcoded pyrosequencing analysis showed the similar bacterial community structures in intestines of BT and PW shrimp under a normal condition. However, during the time course exposure to V. harveyi, the relative abundance of bacteria belong to Vibrio genus was higher in the BT intestines at 12h after the exposure, whereas relative abundance of vibrios was more stable in PW intestines. The principle coordinates analysis based on weighted-UniFrac analysis showed that intestinal bacterial population in the BT shrimp lost their ability to restore their bacterial balance during the 72-h period of exposure to the pathogen, while the PW shrimp were able to reestablish their bacterial population to resemble those seen in the unexposed control group. This observation of bacterial disruption might correlate to different mortality rates observed between the two shrimp species. Our findings provide evidence of intestinal bacterial population altered by a presence of the pathogen in shrimp intestines and intestinal bacterial stability might provide colonization resistance against the invading pathogen in the host shrimp. Hence, intestinal microbial ecology management may potentially contribute to disease prevention in aquaculture. PMID- 26585303 TI - Understanding Pre-Eclampsia Using Alzheimer's Etiology: An Intriguing Viewpoint. AB - Characterized by hypertension and proteinuria after the 20th week of gestation, pre-eclampsia (PE) is a major cause of maternal, fetal, and neonatal morbidity and mortality. Despite being recognized for centuries, PE still lacks a reliable, early means of diagnosis or prediction, and a safe and effective therapy. We have recently reported that the event of toxic protein misfolding and aggregation is a critical etiological manifestation in PE. Using comparative proteomic analysis of gestational age-matched sera from PE and normal pregnancy, we identified several proteins that appeared to be dysregulated in PE. Our efforts so far have focused on transthyretin (TTR), a transporter of thyroxine and retinol, and amyloid precursor protein whose aggregates were detected in the PE placenta. Based on these results and detection of TTR aggregates in sera from PE patients, we proposed that PE could be a disease of protein misfolding and aggregation. Protein misfolding and aggregation have long been linked with many neurodegenerative diseases such as Alzheimer's disease. However, linkage of protein misfolding and aggregation with the PE pathogenesis is a new and novel concept. This review aims to understand the roles of aggregated proteins in PE using the cues from the Alzheimer's etiology. PMID- 26585304 TI - Prophylactic antibiotics in elective hip and knee arthroplasty: an analysis of organisms reported to cause infections and National survey of clinical practice. AB - OBJECTIVES: We wanted to investigate regional variations in the organisms reported to be causing peri-prosthetic infections and to report on prophylaxis regimens currently in use across England. METHODS: Analysis of data routinely collected by Public Health England's (PHE) national surgical site infection database on elective primary hip and knee arthroplasty procedures between April 2010 and March 2013 to investigate regional variations in causative organisms. A separate national survey of 145 hospital Trusts (groups of hospitals under local management) in England routinely performing primary hip and/or knee arthroplasty was carried out by standard email questionnaire. RESULTS: Analysis of 189 858 elective primary hip and knee arthroplasty procedures and 1116 surgical site infections found statistically significant variations for some causative organism between regions. There was a 100% response rate to the prophylaxis questionnaire that showed substantial variation between individual trust guidelines. A number of regimens currently in use are inconsistent with the best available evidence. CONCLUSIONS: The approach towards antibiotic prophylaxis in elective arthroplasty nationwide reveals substantial variation without clear justification. Only seven causative organisms are responsible for 89% of infections affecting primary hip and knee arthroplasty, which cannot justify such widespread variation between prophylactic antibiotic policies. Cite this article: Bone Joint Res 2015;4:181 189. PMID- 26585305 TI - [Traumatic pseudoaneurysm of descendent thoracic aorta solved by aortal stentgraft repair followed by development of fatal aortoesophageal fistula]. AB - Traumatic pseudoaneurysms are relatively frequently mentioned in textbooks of pathology and forensic medicine but their incidence in pathological reports is seldom documented. Our described case presented a patient who suffered from chronic alcoholism and who was repeatedly hospitalised because of various injuries including epidural and subdural hematomas. We present a case of a 69 year-old man who was hospitalised after nonspecific blunt chest injury with chest pain and dysphagia. By computed tomography the traumatic pseudoaneurysm of the descendent thoracic aorta was diagnosed pressing the oesophageal wall which was solved by implantation of aortal stent graft (TEVAR - thoracic endovascular aortic/aneurysm repair). Since after the implantation there was no blood leak, no progression of the lesion, he was soon discharged from hospital. The patient was hospitalised again after two months for newly developed haemoptysis. On suspicion of bleeding from aortal arch a carotid-carotid bypass from right to left side was performed and then re-TEVAR was implanted proximally to the first one. The man died two days following the implantation after a massive bleeding from oesophagus due to aortoesophageal fistula. The presented case deals with the etiology of the development of pseudoaneurysms, histomorphological picture of pseudoaneurysm resembling not only an isolated thoracic aortitis but slightly also the Takayashu disease. We suppose that in this case the most probable cause of necrosis and perforation of aortal wall was a decubital necrosis caused by stent graft which led to the fatal aortoesophageal necrosis. Aortoesophageal fistula belongs to the most common lethal complications of the TEVAR. PMID- 26585306 TI - [Arytmogenic ventricular cardiomyopathy]. AB - Arrhythmogenic ventricular cardiomyopathy is considered to be a primary cardiomyopathy. Over the last few decades, although being a relatively rare disease with its prevalence 1:2000 - 1:5000, there were numerous studies performed with the aim to elucidate the underlaying causes, pathogenesis, diagnostical aspects and possible treatment options of the disease. Arrhythmogenic ventricular cardiomyopathy is genetically conditioned disease where proteins of the cell-cell junctions are involved. Mutations of the myocardial intercalated dics proteins, mainly desmosomal proteins (e.g.plakoglobin), are held to be responsible for electromechanical instability of the myocardium which causes regressive changes in cardiomyocytes in most cases of arrhythmogenic ventricular cardiomyopathy. Subsequent morphological changes include fibrofatty replacement and inflammation of the myocardium. The condition results in structural changes of the heart hence arrhytmias and other signs of heart disease. There are 3 variants of this cardiomyopathy: 'classical variant with predominant right ventricular involvement, biventricular and variant with left ventricular predominance. Clinical findings in patients with arrhythmogenic ventricular cardiomyopathy suggested the most appropriate means of the diagnostics and helped to create Task Force Criteria for in vivo diagnosis of the disease. The major pitfall and significance of arrhythmogenic ventricular cardiomyopathy lies in its common presentation as sudden cardiac death affecting mostly young adults. PMID- 26585307 TI - [Bloodstain pattern analysis on examples from practice: Are calculations with application parabolic trajectory usable?]. AB - The bloodstain pattern analysis (BPA) is useful in the forensic medicine. In Czechoslovakian criminology is this method not commonly used. The objective of this work is to calculate the impact length, height and distance splashing of blood drops. The results are compared with the real values for specific cases. It is also compared to calculate the angle of incidence of blood drops, using sinalpha with a form using tgalpha. For this purposes we used two different character cases from practice with well-preserved condition and readable blood stains. Selected blood stains were documented in order to calculate the angle of incidence of blood drops and to calculateorigin splashes. For this drop of blood, the distance of impact of the drops of blood (x), the height of the sprayed blood drops (y) and the length of the flight path the drop of blood (l). The obtained data was retrospectively analysed for the two models. The first straight line is represented by the triangle (M1) and the other is the parabolic model (M2). The formulae were derived using the Euler substitution. The results show that the angle of incidence of the drop of blood can be calculated as sinalpha and the tgalpha. When applying, the triangle is appropriate to consider the application and sinalpha parabolic requires the calculation of the angle of incidence drops of blood tgalpha. Parabola is useful for the BPA. In Czechoslovakian should be providing workplace training seminars BPA primarily intended for forensic investigators.We recommend the use of this method during investigations, verification of acts in forensic practice. PMID- 26585308 TI - Traumatic asphyxia: An autopsy case. AB - Traumatic asphyxia is a form of asphyxia where respiration is prevented by external pressure on the body. A 19-year-old man was found by relatives compressed by motorboat in the garage. The death was investigated by the prosecutor; body was taken to the Morgue Department for performing autopsy. On gross physical examination; the face, neck and upper part of the chest were congested and many petechiae were observed on the conjunctivae, but not in low extremities. Autopsy macroscopic examination of lungs revealed congestion, sub pleural superficial bleeding areas. In the presented case death was reported as traumatic asphyxia by thorax compression without other lethal factors. PMID- 26585310 TI - Synthesis of Au@Pt bimetallic nanoparticles with concave Au nanocuboids as seeds and their enhanced electrocatalytic properties in the ethanol oxidation reaction. AB - Herein, a new type of uniform and well-structured Au@Pt bimetallic nanoparticles (BNPs) with highly active concave Au nanocuboids (NCs) as seeds was successfully synthesized by using the classic seed-mediated method. Electrochemical measurements were conducted to demonstrate their greatly enhanced catalytic performance in the ethanol oxidation reaction (EOR). It was found that the electrochemical performance for Au@Pt BNPs with the concave Au NCs as seeds, which were enclosed by {611} high-index facets, could be seven times higher than that of the Au@Pt bimetallic nanoparticles with regular spherical Au NPs as seeds. Furthermore, our findings show that the morphology and electrocatalytic activity of the Au@Pt BNPs can be tuned simply by changing the compositional ratios of the growth solution. The lower the amount of H2PtCl6 used in the growth solution, the thinner the Pt shell grew, and the more high-index facets of concave Au NCs seeds were exposed in Au@Pt BNPs, leading to higher electrochemical activity. These as-prepared concave Au@Pt BNPs will open up new strategies for improving catalytic efficiency and reducing the use of the expensive and scarce resource of platinum in the ethanol oxidation reaction, and are potentially applicable as electrochemical catalysts for direct ethanol fuel cells. PMID- 26585309 TI - Efficient long-term survival of cell grafts after myocardial infarction with thick viable cardiac tissue entirely from pluripotent stem cells. AB - Poor engraftment of cells after transplantation to the heart is a common and unresolved problem in the cardiac cell therapies. We previously generated cardiovascular cell sheets entirely from pluripotent stem cells with cardiomyocytes, endothelial cells and vascular mural cells. Though sheet transplantation showed a better engraftment and improved cardiac function after myocardial infarction, stacking limitation (up to 3 sheets) by hypoxia hampered larger structure formation and long-term survival of the grafts. Here we report an efficient method to overcome the stacking limitation. Insertion of gelatin hydrogel microspheres (GHMs) between each cardiovascular cell sheet broke the viable limitation via appropriate spacing and fluid impregnation with GHMs. Fifteen sheets with GHMs (15-GHM construct; >1 mm thickness) were stacked within several hours and viable after 1 week in vitro. Transplantation of 5-GHM constructs (~2 * 10(6) of total cells) to a rat myocardial infarction model showed rapid and sustained functional improvements. The grafts were efficiently engrafted as multiple layered cardiovascular cells accompanied by functional capillary networks. Large engrafted cardiac tissues (0.8 mm thickness with 40 cell layers) successfully survived 3 months after TX. We developed an efficient method to generate thicker viable tissue structures and achieve long-term survival of the cell graft to the heart. PMID- 26585311 TI - The Gas2 family protein Pigs is a microtubule +TIP that affects cytoskeleton organisation. AB - Coordination between different cytoskeletal systems is crucial for many cell biological functions, including cell migration and mitosis, and also plays an important role during tissue morphogenesis. Proteins of the class of cytoskeletal crosslinkers, or cytolinkers, have the ability to interact with more than one cytoskeletal system at a time and are prime candidates to mediate any coordination. One such class comprises the Gas2-like proteins, combining a conserved calponin-homology-type actin-binding domain and a Gas2 domain predicted to bind microtubules (MTs). This domain combination is also found in spectraplakins, huge cytolinkers that play important roles in many tissues in both invertebrates and vertebrates. Here, we dissect the ability of the single Drosophila Gas2-like protein Pigs to interact with both actin and MT cytoskeletons, both in vitro and in vivo, and illustrate complex regulatory interactions that determine the localisation of Pigs to and its effects on the cytoskeleton. PMID- 26585312 TI - The role of palmitoylation and transmembrane domain in sorting of transmembrane adaptor proteins. AB - Plasma membrane proteins synthesised at the endoplasmic reticulum are delivered to the cell surface via sorting pathways. Hydrophobic mismatch theory based on the length of the transmembrane domain (TMD) dominates discussion about determinants required for protein sorting to the plasma membrane. Transmembrane adaptor proteins (TRAP) are involved in signalling events which take place at the plasma membrane. Members of this protein family have TMDs of varying length. We were interested in whether palmitoylation or other motifs contribute to the effective sorting of TRAP proteins. We found that palmitoylation is essential for some, but not all, TRAP proteins independent of their TMD length. We also provide evidence that palmitoylation and proximal sequences can modulate sorting of artificial proteins with TMDs of suboptimal length. Our observations point to a unique character of each TMD defined by its primary amino acid sequence and its impact on membrane protein localisation. We conclude that, in addition to the TMD length, secondary sorting determinants such as palmitoylation or flanking sequences have evolved for the localisation of membrane proteins. PMID- 26585314 TI - Macrophage-derived lipid agonists of PPAR-alpha as intrinsic controllers of inflammation. AB - Macrophages are multi-faceted phagocytic effector cells that derive from circulating monocytes and undergo differentiation in target tissues to regulate key aspects of the inflammatory process. Macrophages produce and degrade a variety of lipid mediators that stimulate or suppress pain and inflammation. Among the analgesic and anti-inflammatory lipids released from these cells are the fatty acid ethanolamides (FAEs), which produce their effects by engaging nuclear peroxisome proliferator activated receptor-alpha (PPAR-alpha). Two members of this lipid family, palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), have recently emerged as important intrinsic regulators of nociception and inflammation. These substances are released from the membrane precursor, N acylphosphatidylethanolamine (NAPE), by the action of a NAPE-specific phospholipase D (NAPE-PLD), and in macrophage are primarily deactivated by the lysosomal cysteine amidase, N-acylethanolamine acid amidase (NAAA). NAPE-PLD and NAAA regulate FAE levels, exerting a tight control over the ability of these lipid mediators to recruit PPAR-alpha and attenuate the inflammatory response. This review summarizes recent findings on the contribution of the FAE-PPAR-alpha signaling complex in inflammation, and on NAAA inhibition as a novel mechanistic approach to treat chronic inflammatory disorders. PMID- 26585313 TI - p120-catenin controls contractility along the vertical axis of epithelial lateral membranes. AB - In vertebrate epithelia, p120-catenin (hereafter referred to as p120; also known as CTNND1) mediates E-cadherin stability and suppression of RhoA. Genetic ablation of p120 in various epithelial tissues typically causes striking alterations in tissue function and morphology. Although these effects could very well involve p120's activity towards Rho, ascertaining the impact of this relationship has been complicated by the fact that p120 is also required for cell cell adhesion. Here, we have molecularly uncoupled p120's cadherin-stabilizing and RhoA-suppressing activites. Unexpectedly, removing p120's Rho-suppressing activity dramatically disrupted the integrity of the apical surface, irrespective of E-cadherin stability. The physical defect was tracked to excessive actomyosin contractility along the vertical axis of lateral membranes. Thus, we suggest that p120's distinct activities towards E-cadherin and Rho are molecularly and functionally coupled and this, in turn, enables the maintenance of cell shape in the larger context of an epithelial monolayer. Importantly, local suppression of contractility by cadherin-bound p120 appears to go beyond regulating cell shape, as loss of this activity also leads to major defects in epithelial lumenogenesis. PMID- 26585315 TI - In vivo assessment of immunomodulatory activity of hydrolysed peptides from Corylus heterophylla Fisch. AB - BACKGROUND: Hazelnut dregs are by-products of hazelnut oil expression, which have not been fully exploited. This research aims to assess the immunomodulatory function of hazelnut hydrolysed peptides (HHPs). RESULTS: HHPs with a hydrolysis degree of 38.08% were divided into three fractions by ultra-filtration: the high molecular weight peptide (>10 kDa), medium molecular weight peptide (3 kDa to 10 kDa), and low molecular weight peptide (<3 kDa). Mice were fed daily with HHPs of different molecular weights at doses of 200, 400, and 800 mg kg(-1) body weight. On the 10th, 20th and 30th day of feeding, representative immune indexes were measured. Results showed that HHPs can regulate the immune system of mice, which is affected by the molecular weight of HHP and the feeding time. Generally, short term feeding (10 d to 20 d) with HHPs of different molecular weights can improve most immune indexes (organ index, spleen lymphocyte proliferation, macrophage activity, secretory immunoglobulin A content, and number of CD4(+) and CD8(+) T cells), whereas during long-term feeding (30 d), low molecular weight HHP can better sustain immune regulation. CONCLUSION: HHPs exhibit potential immunomodulatory properties, which has promising implications for the development of new functional foods. (c) 2015 Society of Chemical Industry. PMID- 26585316 TI - The 15-item Systemic Clinical Outcome and Routine Evaluation (SCORE-15) Scale: Portuguese Validation Studies. AB - This study reports on the validity of the 15-item Portuguese version of the Systemic Clinical Outcome Routine Evaluation (SCORE-15; Vilaca, Silva, & Relvas, 2014), a brief and comprehensive measure of family functioning. Previous studies with SCORE-15 show that this version replicates the three-factor solution found for the original English version: Family strengths, Family communication and Family difficulties. In addition to reviewing previous studies, this article analyses the discriminant, convergent and predictive validity of the Portuguese SCORE-15. To do so, the SCORE-15 was administered to family members attending systemic family or couple's therapy at the start of the first and fourth sessions and also to a group of non-clinical individuals. Overall, data are reported from 618 participants, including 136 from families attending systemic therapy and 482 community family members. Comparisons of community and clinical samples (discriminant validity) showed statistically significant differences for the total scale and subscales (p < .001), with the community participants presenting healthier family functioning than the clinical ones. Analyses using SCORE-15 and the Quality of Life - adult version, another family measure applied simultaneously (convergent validity), indicate that both scales are significantly (p < .01) and moderately (r = -.47) correlated. Mean score analysis of SCORE-15's therapeutic sensitivity to change (predictive validity) showed that only the Family communication subscale was sensitive to statistically significant improvement (p < .05) from session 1 to session 4, whereas the SCORE-15's reliability change index points to its ability to detect clinical improvements (RCI = 14%). PMID- 26585317 TI - Culture media for human pre-implantation embryos in assisted reproductive technology cycles. AB - BACKGROUND: Many media are commercially available for culturing pre-implantation human embryos in assisted reproductive technology (ART) cycles. It is unknown which culture medium leads to the best success rates after ART. OBJECTIVES: To evaluate the safety and effectiveness of different human pre-implantation embryo culture media in used for in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI) cycles. SEARCH METHODS: We searched the Cochrane Menstrual Disorders and Subfertility Group's Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the National Research Register, the Medical Research Council's Clinical Trials Register and the NHS Center for Reviews and Dissemination databases from January 1985 to March 2015. We also examined the reference lists of all known primary studies, review articles, citation lists of relevant publications and abstracts of major scientific meetings. SELECTION CRITERIA: We included all randomised controlled trials which randomised women, oocytes or embryos and compared any two commercially available culture media for human pre-implantation embryos in an IVF or ICSI programme. DATA COLLECTION AND ANALYSIS: Two review authors independently selected the studies, assessed their risk of bias and extracted data. We sought additional information from the authors if necessary. We assessed the quality of the evidence using Grades of Recommendation, Assessment, Development and Evaluation (GRADE) methods. The primary review outcome was live birth or ongoing pregnancy. MAIN RESULTS: We included 32 studies in this review. Seventeen studies randomised women (total 3666), three randomised cycles (total 1018) and twelve randomised oocytes (over 15,230). It was not possible to pool any of the data because each study compared different culture media.Only seven studies reported live birth or ongoing pregnancy. Four of these studies found no evidence of a difference between the media compared, for either day three or day five embryo transfer. The data from the fifth study did not appear reliable.Six studies reported clinical pregnancy rate. One of these found a difference between the media compared, suggesting that for cleavage-stage embryo transfer, Quinn's Advantage was associated with higher clinical pregnancy rates than G5 (odds ratio (OR) 1.56; 95% confidence interval (CI) 1.12 to 2.16; 692 women). This study was available only as an abstract and the quality of the evidence was low.With regards to adverse effects, three studies reported multiple pregnancies and six studies reported miscarriage. None of them found any evidence of a difference between the culture media used. None of the studies reported on the health of offspring.Most studies (22/32) failed to report their source of funding and none described their methodology in adequate detail. The overall quality of the evidence was rated as very low for nearly all comparisons, the main limitations being imprecision and poor reporting of study methods. AUTHORS' CONCLUSIONS: An optimal embryo culture medium is important for embryonic development and subsequently the success of IVF or ICSI treatment. There has been much controversy about the most appropriate embryo culture medium. Numerous studies have been performed, but no two studies compared the same culture media and none of them found any evidence of a difference between the culture media used. We conclude that there is insufficient evidence to support or refute the use of any specific culture medium. Properly designed and executed randomised trials are necessary. PMID- 26585318 TI - Nicotinic acetylcholine receptors (nAChRs) at zebrafish red and white muscle show different properties during development. AB - Nicotinic acetylcholine receptors (nAChRs) are highly expressed at the vertebrate neuromuscular junction (NMJ) where they are required for muscle activation. Understanding the factors that underlie NMJ development is critical for a full understanding of muscle function. In this study we performed whole cell and outside-out patch clamp recordings, and single-cell RT-qPCR from zebrafish red and white muscle to examine the properties of nAChRs during the first 5 days of development. In red fibers miniature endplate currents (mEPCs) exhibit single exponential time courses at 1.5 days postfertilization (dpf) and double exponential time courses from 2 dpf onwards. In white fibers, mEPCs decay relatively slowly, with a single exponential component at 1.5 dpf. By 2 and 3 dpf, mEPC kinetics speed up, and decay with a double exponential component, and by 4 dpf the exponential decay reverts back to a single component. Single channel recordings confirm the presence of two main conductance classes of nAChRs (~45 pS and ~65 pS) in red fibers with multiple time courses. Two main conductance classes are also present in white fibers (~55 pS and ~73 pS), but they exhibit shorter mean open times by 5 dpf compared with red muscle. RT-qPCR of mRNA for nicotinic receptor subunits supports a switch from gamma to epsilon subunits in white fibers but not in red. Our findings provide a developmental profile of mEPC properties from red and white fibers in embryonic and larval zebrafish, and reveal previously unknown differences between the NMJs of these muscle fibers.(c) 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 916-936, 2016. PMID- 26585319 TI - Plasma phospholipase, gamma-CEHC and antioxidant capacity in fibromyalgia. AB - OBJECTIVE: Recent studies have suggested a possible role of high levels of plasma lysophosphocholines (lysoPCs) in fibromyalgia syndrome (FMS). The aim of this study was to evaluate the content of plasma phospholipases (e.g., Platelet Activating Factor Acetyl Hydrolase [PAF-AH], secretory Phospholipase A2 [sPLA2 ], Total Antioxidant Capacity [TAOC] and 2,7,8-trimethyl-2-(2-carboxyethyl)-6 hydroxy chroman [gamma-CEHC]) in FMS patients and their association with clinical status and quality of life. METHODS: Thirty-six females meeting the 2011 American College of Rheumatology criteria for the classification of FMS and thirty-four healthy females were enrolled for the study. Plasma enzyme levels were quantified using commercial enzyme-linked-immunosorbent-assay (ELISA). In order to assess the disease severity and the functional status of patients, the Fibromyalgia Impact Questionnarie (FIQ) was used. RESULTS: Higher levels of sPLA2 and lower PAF-AH and gamma-CEHC were observed in the plasma of FMS patients compared to the controls. A decrease in PAF-AH and TAOC levels were found in severe FMS (S-FMS) compared to mild/slight (MS-FMS) forms. CONCLUSION: The results of the study indicate a possible involvement of phospholipases and gamma-CEHC in fibromyalgia syndrome. PMID- 26585320 TI - SLC6A15, a novel stress vulnerability candidate, modulates anxiety and depressive like behavior: involvement of the glutamatergic system. AB - Major depression is a multifactorial disease, involving both environmental and genetic risk factors. Recently, SLC6A15 - a neutral amino acid transporter mainly expressed in neurons - was proposed as a new candidate gene for major depression and stress vulnerability. Risk allele carriers for a single nucleotide polymorphism (SNP) in a SLC6A15 regulatory region display altered hippocampal volume, glutamate levels, and hypothalamus-pituitary-adrenal axis activity, all markers associated with major depression. Despite this genetic link between SLC6A15 and depression, its functional role with regard to the development and maintenance of depressive disorder is still unclear. The aim of the current study was therefore to characterize the role of mouse slc6a15 in modulating brain function and behavior, especially in relation to stress as a key risk factor for the development of mood disorders. We investigated the effects of slc6a15 manipulation using two mouse models, a conventional slc6a15 knock-out mouse line (SLC-KO) and a virus-mediated hippocampal slc6a15 overexpression (SLC-OE) model. Mice were tested under basal conditions and following chronic social stress. We found that SLC-KO animals displayed a similar behavioral profile to wild-type littermates (SLC-WT) under basal conditions. Interestingly, following chronic social stress SLC-KO animals showed lower levels of anxiety- and depressive-like behavior compared to stressed WT littermates. In support of these findings, SLC OE animals displayed increased anxiety-like behavior already under basal condition. We also provide evidence that GluR1 expression in the dentate gyrus, but not GluR2 or NR1, are regulated by slc6a15 expression, and may contribute to the difference in stress responsiveness observed between SLC-KO and SLC-WT animals. Taken together, our data demonstrate that slc6a15 plays a role in modulating emotional behavior, possibly mediated by its impact on glutamatergic neurotransmission. PMID- 26585321 TI - The burden and outcome of in utero transfers. AB - AIM: To quantify the number of intrauterine transfers (IUTs) arranged by Embrace Yorkshire and Humber Infant and Children's Transport Service and, to determine the outcome of when women delivered their babies, or when they were discharged following transfer. METHODS: Identification of all IUTs Embrace arranged between January 1, 2011 and February 29, 2012 with data collection to determine delivery time or date of discharge. RESULTS: There were 623 IUT referrals with a mean time taken to arrange a transfer of 109 minutes. The mean distance of IUT was 42.5 miles, and the main reason for IUT request was capacity of referring unit. 247 (52%) women delivered during the same admission and 156 delivered within 48 hours of transfer. Of those undelivered, 111 (48.7%) were discharged within 48 hours. Fibronectin test was used in 51 patients. CONCLUSION: The IUT service provided by Embrace is busy, with significant demands on administrative staff time. Neonatal cot capacity and gestation are the main reasons for transfer. There is potentially a cohort of women who may not have benefitted from IUT. We suggest the use of obstetric expertise will enhance the service, while ongoing work looking at neonatal unit cot capacity problems continues. PMID- 26585322 TI - Varying Dietary Levels of Molybdenum Inducing Cell Apoptosis of Spleen Under Cadmium Stress in Caprine. AB - The present experiment aims at evaluating chronic toxic effects of the combination of cadmium (Cd) and molybdenum (Mo) according to residual element contents, apoptosis gene expression, and ultrastructure and histopathology changes of caprine spleen. In total, 36 Boer goats were randomly divided into four groups with the equal number in each group. The control group was orally administered with deionized water while the experimental groups I, II, and III were administered with the equal quantity of CdCl2 (1 mg kg(-1) BW) and (NH4)6.Mo7O24.4H2O including 15, 30, and 45 mg.Mo kg(-1) BW, respectively. Three individuals from each group were treated with euthanasia on days 0, 25, and 50. The data showed that the content of splenic residual Mo and Cd increased (P < 0.05) in the experimental groups on days 25 and 50, while no significant difference was observed in the content of Cu. The apoptosis-related gene expression levels including Bcl-2, Bax, Caspase-3, Smac, and ceruloplasmin (CP) were also determined. Results showed that significant reductions were observed in Bcl-2 and CP expressions (P < 0.01), while Caspase-3 gene was up-regulated (P < 0.05). However, no significant difference was observed in Smac and Bax expressions. Furthermore, on day 50, spleen tissues were presented to observe ultrastructural changes in lesions by means of transmission electron microscopy, with fragmentized nucleus, vesiculation of cytoplasm, mitochondria hyperplasia, and increasing lysosomes included. In addition, histopathology results corroborated the toxicity by showing cell hemorrhage, thickening central arteries, and enhanced capsule thickness. To sum up, our study revealed that the combination of Cd and Mo could induce remarkable damage to the spleen of goats by promoting cell apoptosis in the mitochondrial pathway and affecting the deposition of Mo and Cd. PMID- 26585323 TI - The MICA-129Met/Val dimorphism affects plasma membrane expression and shedding of the NKG2D ligand MICA. AB - The MHC class I chain-related molecule A (MICA) is a ligand for the activating natural killer (NK) cell receptor NKG2D. A polymorphism causing a valine to methionine exchange at position 129 affects binding to NKG2D, cytotoxicity, interferon-gamma release by NK cells and activation of CD8(+) T cells. It is known that tumors can escape NKG2D-mediated immune surveillance by proteolytic shedding of MICA. Therefore, we investigated whether this polymorphism affects plasma membrane expression (pmMICA) and shedding of MICA. Expression of pmMICA was higher in a panel of tumor (n = 16, P = 0.0699) and melanoma cell lines (n = 13, P = 0.0429) carrying the MICA-129Val/Val genotype. MICA-129Val homozygous melanoma cell lines released more soluble MICA (sMICA) by shedding (P = 0.0015). MICA-129Met or MICA-129Val isoforms differing only in this amino acid were expressed in the MICA-negative melanoma cell line Malme, and clones with similar pmMICA expression intensity were selected. The MICA-129Met clones released more sMICA (P = 0.0006), and a higher proportion of the MICA-129Met than the MICA 129Val variant was retained in intracellular compartments (P = 0.0199). The MICA 129Met clones also expressed more MICA messenger RNA (P = 0.0047). The latter phenotype was also observed in mouse L cells transfected with the MICA expression constructs (P = 0.0212). In conclusion, the MICA-129Met/Val dimorphism affects the expression density of MICA on the plasma membrane. More of the MICA-129Met variants were retained intracellularly. If expressed at the cell surface, the MICA-129Met isoform was more susceptible to shedding. Both processes appear to limit the cell surface expression of MICA-129Met variants that have a high binding avidity to NKG2D. PMID- 26585324 TI - Assembly and characterization of the MHC class I region of the Yangtze finless porpoise (Neophocaena asiaeorientalis asiaeorientalis). AB - The Yangtze finless porpoise (Neophocaena asiaeorientalis asiaeorientalis; YFP) is the sole freshwater subspecies of N. asiaeorientalis and is now critically endangered. Major histocompatibility complex (MHC) is a family of highly polymorphic genes that play an important immunological role in antigen presentation in the vertebrates. Currently, however, little is known about MHC region in the genome of the YFP, which hampers conservation genetics and evolutionary ecology study using MHC genes. In this work, a nucleotide sequence of 774,811 bp covering the YFP MHC class I region was obtained by screening a YFP bacterial artificial chromosome (BAC) library, followed by sequencing and assembly of positive BAC clones. A total of 45 genes were successfully annotated, of which four were MHC class I genes. There are high similarities among the four YFP MHC class I genes (>94%). Divergence in the coding region of the four YFP MHC class I genes is mainly localized to exons 2 and 3, which encode the antigen binding sites of MHC class I genes. Additionally, comparison of the MHC structure in YFP to those of cattle, sheep, and pig showed that MHC class I genes are located in genome regions with regard to the conserved genes, and the YFP contains the fewest MHC class I genes among these species. This is the first report characterizing a cetacean MHC class I region and describing its organization, which would be valuable for further investigation of adaptation in natural populations of the YFP and other cetaceans. PMID- 26585325 TI - Synthesis of clinical prediction models under different sets of covariates with one individual patient data. AB - BACKGROUND: Recently, increased development of clinical prediction models has been reported in the medical literature. However, evidence synthesis methodologies for these prediction models have not been sufficiently studied, especially for practical situations such as a meta-analyses where only aggregated summaries of important predictors are available. Also, in general, the covariate sets involved in the prediction models are not common across studies. As in ordinary model misspecification problems, dropping relevant covariates would raise potentially serious biases to the prediction models, and consequently to the synthesized results. METHODS: We developed synthesizing methods for logistic clinical prediction models with possibly different sets of covariates. In order to aggregate the regression coefficient estimates from different prediction models, we adopted a generalized least squares approach with non-linear terms (a sort of generalization of multivariate meta-analysis). Firstly, we evaluated omitted variable biases in this approach. Then, under an assumption of homogeneity of studies, we developed bias-corrected estimating procedures for regression coefficients of the synthesized prediction models. RESULTS: Numerical evaluations with simulations showed that our approach resulted in smaller biases and more precise estimates compared with conventional methods, which use only studies with common covariates or which utilize a mean imputation method for omitted coefficients. These methods were also applied to a series of Japanese epidemiologic studies on the incidence of a stroke. CONCLUSIONS: Our proposed methods adequately correct the biases due to different sets of covariates between studies, and would provide precise estimates compared with the conventional approach. If the assumption of homogeneity within studies is plausible, this methodology would be useful for incorporating prior published information into the construction of new prediction models. PMID- 26585326 TI - Diversity of extracellular proteins during the transition from the 'proto apicomplexan' alveolates to the apicomplexan obligate parasites. AB - The recent completion of high-coverage draft genome sequences for several alveolate protozoans - namely, the chromerids, Chromera velia and Vitrella brassicaformis; the perkinsid Perkinsus marinus; the apicomplexan, Gregarina niphandrodes, as well as high coverage transcriptome sequence information for several colpodellids, allows for new genome-scale comparisons across a rich landscape of apicomplexans and other alveolates. Genome annotations can now be used to help interpret fine ultrastructure and cell biology, and guide new studies to describe a variety of alveolate life strategies, such as symbiosis or free living, predation, and obligate intracellular parasitism, as well to provide foundations to dissect the evolutionary transitions between these niches. This review focuses on the attempt to identify extracellular proteins which might mediate the physical interface of cell-cell interactions within the above life strategies, aided by annotation of the repertoires of predicted surface and secreted proteins encoded within alveolate genomes. In particular, we discuss what descriptions of the predicted extracellular proteomes reveal regarding a hypothetical last common ancestor of a pre-apicomplexan alveolate - guided by ultrastructure, life strategies and phylogenetic relationships - in an attempt to understand the evolution of obligate parasitism in apicomplexans. PMID- 26585327 TI - Hypoglossal nerve identification during head and neck surgery. PMID- 26585330 TI - Improvement of the respiration efficiency of Lactococcus lactis by decreasing the culture pH. AB - OBJECTIVE: The growth characteristics and intracellular hemin concentrations of Lactococcus lactis grown under different culture pH and aeration conditions were examined to investigate the effect of culture pH on the respiration efficiency of L. lactis NZ9000 (pZN8148). RESULTS: Cell biomass and biomass yield of L. lactis grown with 4 MUg hemin/ml and O2 were higher than those without aeration when the culture pH was controlled at 5-6.5. The culture pH affected the respiratory efficiency in the following order of pH: 5 > 5.5 > 6 > 6.5; the lag phase increased as the culture pH decreased. Hemin accumulation was sensitive to culture pH. Among the four pH conditions, pH 5.5 was optimal for hemin accumulation in the cells. The highest intracellular hemin level in L. lactis resting cells incubated at different pH saline levels (5-6.5) was at pH 5.5. CONCLUSION: The respiration efficiency of L. lactis under respiration-permissive conditions increases markedly as the culture pH decreases. These results may help develop high cell-density L. lactis cultures. Thus, this microorganism may be used for industrial applications. PMID- 26585331 TI - A constitutive expression system for Pichia pastoris based on the PGK1 promoter. AB - OBJECTIVES: To develop a new vector for constitutive expression in Pichia pastoris based on the endogenous glycolytic PGK1 promoter. RESULTS: P. pastoris plasmids bearing at least 415 bp of PGK1 promoter sequences can be used to drive plasmid integration by addition at this locus without affecting cell growth. Based on this result, a new P. pastoris integrative vector, pPICK2, was constructed bearing some features that facilitate protein production in this yeast: a ~620 bp PGK1 promoter fragment with three options of restriction sites for plasmid linearization prior to yeast transformation: a codon-optimized alpha factor secretion signal, a new polylinker, and the kan marker for vector propagation in bacteria and selection of yeast transformants. CONCLUSIONS: A new constitutive vector for P. pastoris represents an alternative platform for recombinant protein production and metabolic engineering purposes. PMID- 26585328 TI - Hyperoxia in intensive care, emergency, and peri-operative medicine: Dr. Jekyll or Mr. Hyde? A 2015 update. AB - This review summarizes the (patho)-physiological effects of ventilation with high FiO2 (0.8-1.0), with a special focus on the most recent clinical evidence on its use for the management of circulatory shock and during medical emergencies. Hyperoxia is a cornerstone of the acute management of circulatory shock, a concept which is based on compelling experimental evidence that compensating the imbalance between O2 supply and requirements (i.e., the oxygen dept) is crucial for survival, at least after trauma. On the other hand, "oxygen toxicity" due to the increased formation of reactive oxygen species limits its use, because it may cause serious deleterious side effects, especially in conditions of ischemia/reperfusion. While these effects are particularly pronounced during long term administration, i.e., beyond 12-24 h, several retrospective studies suggest that even hyperoxemia of shorter duration is also associated with increased mortality and morbidity. In fact, albeit the clinical evidence from prospective studies is surprisingly scarce, a recent meta-analysis suggests that hyperoxia is associated with increased mortality at least in patients after cardiac arrest, stroke, and traumatic brain injury. Most of these data, however, originate from heterogenous, observational studies with inconsistent results, and therefore, there is a need for the results from the large scale, randomized, controlled clinical trials on the use of hyperoxia, which can be anticipated within the next 2-3 years. Consequently, until then, "conservative" O2 therapy, i.e., targeting an arterial hemoglobin O2 saturation of 88-95 % as suggested by the guidelines of the ARDS Network and the Surviving Sepsis Campaign, represents the treatment of choice to avoid exposure to both hypoxemia and excess hyperoxemia. PMID- 26585332 TI - Cancer stem cells in laryngeal cancer: what we know. AB - Cancer stem cells (CSCs) are a group of cells with eternal life or infinite self renewal ability, which have high migrating, infiltrative, and metastatic abilities. Though CSCs only account for a small proportion in tumors, the high resistance to traditional therapy exempts them from therapy killing and thus they can reconstruct tumors. Previous studies found that heterogeneity of cancer cells extensively exists in head and neck cancers. Our current knowledge, about CSCs in the laryngeal cancer (LC), largely depends on head and neck studies. Given the lack of systematic data about CSCs in LC, we propose a review of the literature, reporting the evidences of CSCs in tumorigenesis of LC, with the purpose to provide new insights into the prevention and/or treatment of laryngeal carcinoma. PMID- 26585333 TI - Characterization of Plasmodium phosphatidylserine decarboxylase expressed in yeast and application for inhibitor screening. AB - Phospholipid biosynthesis is critical for the development, differentiation and pathogenesis of several eukaryotic pathogens. Genetic studies have validated the pathway for phosphatidylethanolamine synthesis from phosphatidylserine catalyzed by phosphatidylserine decarboxylase enzymes (PSD) as a suitable target for development of antimicrobials; however no inhibitors of this class of enzymes have been discovered. We show that the Plasmodium falciparum PSD can restore the essential function of the yeast gene in strains requiring PSD for growth. Genetic, biochemical and metabolic analyses demonstrate that amino acids between positions 40 and 70 of the parasite enzyme are critical for proenzyme processing and decarboxylase activity. We used the essential role of Plasmodium PSD in yeast as a tool for screening a library of anti-malarials. One of these compounds is 7 chloro-N-(4-ethoxyphenyl)-4-quinolinamine, an inhibitor with potent activity against P. falciparum, and low toxicity toward mammalian cells. We synthesized an analog of this compound and showed that it inhibits PfPSD activity and eliminates Plasmodium yoelii infection in mice. These results highlight the importance of 4 quinolinamines as a novel class of drugs targeting membrane biogenesis via inhibition of PSD activity. PMID- 26585334 TI - Investigating the Influences of Language Delay and/or Familial Risk for Dyslexia on Brain Structure in 5-Year-Olds. AB - Early language delay has often been associated with atypical language/literacy development. Neuroimaging studies further indicate functional disruptions during language and print processing in school-age children with a retrospective report of early language delay. Behavioral data of 114 5-year-olds with a retrospective report of early language delay in infancy (N = 34) and those without (N = 80) and with a familial risk for dyslexia and those without are presented. Behaviorally, children with a retrospective report of early language delay exhibited reduced performance in language/reading-related measures. A voxel-based morphometry analysis in a subset (N = 46) demonstrated an association between reduced gray matter volume and early language delay in left-hemispheric middle temporal, occipital, and frontal regions. Alterations in middle temporal cortex in children with a retrospective report of early language delay were observed regardless of familial risk for dyslexia. Additionally, while children with isolated familial risk for dyslexia showed gray matter reductions in temporoparietal and occipitotemporal regions, these effects were most profound in children with both risk factors. An interaction effect of early language delay and familial risk was revealed in temporoparietal, occipital, and frontal cortex. Our findings support a cumulative effect of early behavioral and genetic risk factors on brain development and may ultimately inform diagnosis/treatment. PMID- 26585335 TI - Enrichment of Adipose-Derived Stromal Cells for BMPR1A Facilitates Enhanced Adipogenesis. AB - BACKGROUND: Reconstruction of soft tissue defects has traditionally relied on the use of grafts and flaps, which may be associated with variable resorption and/or significant donor site morbidity. Cell-based strategies employing adipose-derived stromal cells (ASCs), found within the stromal vascular fraction (SVF) of adipose tissue, may offer an alternative strategy for soft tissue reconstruction. In this study, we investigated the potential of a bone morphogenetic protein receptor type 1A (BMPR1A)(+) subpopulation of ASCs to enhance de novo adipogenesis. METHODS: Human lipoaspirate was enzymatically digested to isolate SVF and magnetic-activated cell separation was utilized to obtain BMPR1A(+) and BMPR1A(-) cells. These cells, along with unenriched cells, were expanded in culture and evaluated for adipogenic gene expression and in vitro adipocyte formation. Cells from each group were also labeled with a green fluorescent protein (GFP) lentivirus and transplanted into the inguinal fat pads, an adipogenic niche, of immunocompromised mice to determine their potential for de novo adipogenesis. Confocal microscopy along with staining of lipid droplets and vasculature was performed to evaluate the formation of mature adipocytes by transplanted cells. RESULTS: In comparison to BMPR1A(-) and unenriched ASCs, BMPR1A(+) cells demonstrated significantly enhanced adipogenesis when cultured in an adipogenic differentiation medium, as evidenced by increased staining with Oil Red O and increased expression of peroxisome proliferator-activating receptor gamma (PPAR gamma) and fatty acid-binding protein 4 (FABP4). BMPR1A(+) cells also formed significantly more adipocytes in vivo, as demonstrated by quantification of GFP+ adipocytes. Minimal formation of mature adipocytes was appreciated by BMPR1A(-) cells. CONCLUSIONS: BMPR1A(+) ASCs show an enhanced ability for adipogenesis in vitro, as shown by gene expression and histological staining. Furthermore, within an adipogenic niche, BMPR1A(+) cells possessed an increased capacity to generate de novo fat compared to BMPR1A(-) and unenriched cells. This suggests utility for the BMPR1A(+) subpopulation in cell-based strategies for soft tissue reconstruction. PMID- 26585336 TI - A Retrospective Study to Examine Healthcare Costs Related to Cardiovascular Events in Individuals with Hyperlipidemia. AB - INTRODUCTION: Few studies have demonstrated the cost burden of cardiovascular events (CVEs) among patients with hyperlipidemia. The primary objective of this study was to determine the mean costs associated with CVEs among patients with hyperlipidemia by follow-up time period. Secondary objectives of this study included characterizing costs by CVE type and coronary heart disease (CHD) risk. METHODS: This retrospective cohort study used longitudinal claims to calculate payer costs according to CHD risk level and type of CVE, during several follow-up periods (acute and short-term, comprising year 1; plus years 2 and 3). RESULTS: There were 193,385 patients with hyperlipidemia with a CVE. Costs in the acute (30-day) period were highest ($22,404) driven by inpatient care (77%). Costs remained high ($15,133 in year 3) with ambulatory care (from 14% in acute to 37% in year 3) and pharmaceutical costs (from 2% in acute to 24% in year 3) representing a greater proportion. After second and third CVEs, acute costs were lower than for the first CVE. But in the post-acute periods, costs were higher after second and third CVEs than after first CVEs. Acute costs varied considerably by type of CVE ($9149 for transient ischemic attack to $54,251 for coronary artery bypass graft; P < 0.001), but post-acute costs were more similar across types. Costs differed by baseline CHD risk for all follow-up periods (P < 0.001), but less than by CVE type. As expected, patients without CVEs had significantly lower costs. CONCLUSION: Among patients with hyperlipidemia, the economic burden of CVEs is substantial up to 3 years after a CVE. Costs remain high after subsequent CVEs and actually increase for non-inpatient utilization. FUNDING: Amgen Inc. PMID- 26585337 TI - Value of brain MRI in infective endocarditis: a narrative literature review. AB - The nervous system is frequently involved in patients with infective endocarditis (IE). A systematic review of the literature was realized in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). This study sought to systematically evaluate the published evidence of the contribution of brain magnetic resonance imaging (MRI) in IE. The aim was to identify studies presenting the incidence and type of MRI brain lesions in IE. Fifteen relevant studies were isolated using the Medline, Embase, and Cochrane databases. Most of them were observational studies with a small number of patients. MRI studies demonstrated a wide variety and high frequency of cerebral lesions, around 80 % of which were mostly clinically occult. This review shows MRI's superiority compared to brain computed tomography (CT) for the diagnosis of neurologic complications. Recent developments of sensitive MRI sequences can detect microinfarction and cerebral microhemorrhages. However, the clinical significance of these microhemorrhages, also called cerebral microbleeds (CMBs), remains uncertain. Because some MRI neurological lesions are a distinctive IE feature, they can have a broader involvement in diagnosis and therapeutic decisions. Even if cerebral MRI offers new perspectives for better IE management, there is not enough scientific proof to recommend it in current guidelines. The literature remains incomplete regarding the impact of MRI on concerted decision making. The long-term prognosis of CMBs has not been evaluated to date and requires further studies. Today, brain MRI can be used on a case-by-case basis based on a clinician's appraisal. PMID- 26585338 TI - Epigenetics and miRNA during bacteria-induced host immune responses. AB - Various cellular processes including the pathogen-specific immune responses, host pathogen interactions and the related evasion mechanisms rely on the ability of the immune cells to be reprogrammed accurately and in many cases instantaneously. In this context, the exact functions of epigenetic and miRNA-mediated regulation of genes, coupled with recent advent in techniques that aid such studies, make it an attractive field for research. Here, we review examples that involve the epigenetic and miRNA control of the host immune system during infection with bacteria. Interestingly, many pathogens utilize the epigenetic and miRNA machinery to modify and evade the host immune responses. Thus, we believe that global epigenetic and miRNA mapping of such host-pathogen interactions would provide key insights into their cellular functions and help to identify various determinants for therapeutic value. PMID- 26585339 TI - Enhancing growth, phytochemical constituents and aphid resistance capacity in cabbage with foliar application of eckol--a biologically active phenolic molecule from brown seaweed. AB - Although foliar application of seaweed extracts on plant growth and development has and is extensively studied, reliable knowledge and understanding of the mode of action of particular compound(s) responsible for enhancing plant growth is lacking. A brown seaweed Ecklonia maxima is widely used commercially as a biostimulant to improve plant growth and crop protection. Eckol, a phenolic compound isolated from E. maxima has recently shown stimulatory effects in maize, indicating its potential use as a plant biostimulant. Cabbage is a widely cultivated vegetable crop throughout the world, which requires high input of fertilizers and is susceptible to several aphid borne diseases. This study was conducted to evaluate the effect of foliar application of eckol on the growth, phytochemical constituents and myrosinase activity (aphid resistance capacity) of commercially cultivated cabbage. Foliar application of eckol (10(-6) M) significantly enhanced shoot and root length, shoot and root fresh and dry weight, leaf area and leaf number. This treatment also showed a significant increase in photosynthetic pigments (chlorophyll 'a', chlorophyll 'b', total chlorophyll and carotenoid) compared to the untreated plants. The levels of protein, proline and iridoid glycosides were significantly higher in cabbage leaves with eckol treatment. All the control plants were severely infested with cabbage aphid (Brevicoryne brassicae) but no infestation was observed on the eckol-sprayed plants, which can be attributed to an increase in myrosinase activity. This study reveals dual effects (plant growth promoting and insect repelling) of eckol on cabbage plants that need further investigations both under field conditions and in other brassicaceous species. PMID- 26585343 TI - Comparison of diameter-axial-polar nephrometry score and RENAL nephrometry score for surgical outcomes following laparoscopic partial nephrectomy. AB - OBJECTIVES: To compare diameter-axial-polar nephrometry score with RENAL nephrometry score for surgical outcomes after laparoscopic partial nephrectomy. METHODS: We retrospectively reviewed data from 134 patients who underwent laparoscopic partial nephrectomy, using diameter-axial-polar and RENAL scores. We analyzed data for warm ischemic time and estimated blood loss intraoperatively, and percentage change in estimated glomerular filtration rate 6 months and 1 year postoperatively. Both scores were classified as low-, middle- and high-risk, and were used to compare the three analyzed parameters. RESULTS: The median tumor size was 2.3 cm (range 1.0-5.4 cm); warm ischemic time was 25.4 min (range 6.5-57 min); and at 6 months and 1 year, percentage change in estimated glomerular filtration rate was 93% (range 51.7-133.3%) and 91% (range 49.4-137.6%), respectively. There were no significant differences in warm ischemic time and estimated blood loss for RENAL between risk groups (P = 0.38 and 0.09, respectively), but significant differences between groups for diameter-axial polar score (P = 0.02 and 0.01, respectively). There were no significant differences in either score between groups for percentage change in estimated glomerular filtration rate at 6 months and 1 year. A total of 27 high-risk cases with a diameter-axial-polar score of seven points underwent laparoscopic partial nephrectomy safely; all three cases with a diameter-axial-polar score of eight points were converted to open partial nephrectomy. CONCLUSIONS: Diameter-axial polar score seems to estimate the complexity of tumor characteristics in patients undergoing laparoscopic partial nephrectomy better than RENAL score. It has a better correlation with warm ischemic time and estimated blood loss. PMID- 26585344 TI - Insight into the genome sequence of a sediment-adapted marine bacterium Neptunomonas antarctica S3-22(T) from Antarctica. AB - Neptunomonas antarctica S3-22(T) was isolated from marine sediment of the Nella Fjord, Antarctica. Here we report the draft genome sequence of N. antarctica, which comprises 4,568,828 bp with a mean G+C content of 45.7%. We found numerous genes related to resistance, motility and chemotaxis, nitrogen metabolism, aromatic compound metabolism and stress response. These metabolic features and related genes revealed genetic basis for the adaptation to the marine sediment environment in Antarctica. The genome sequence of N. antarctica S3-22(T) may also provide further insights into the ecological role of the genus Neptunomonas. PMID- 26585345 TI - Improvements in fetal heart rate analysis by the removal of maternal-fetal heart rate ambiguities. AB - BACKGROUND: Misinterpretation of the maternal heart rate (MHR) as fetal may lead to significant errors in fetal heart rate (FHR) interpretation. In this study we hypothesized that the removal of these MHR-FHR ambiguities would improve FHR analysis during the final hour of labor. METHODS: Sixty-one MHR and FHR recordings were simultaneously acquired in the final hour of labor. Removal of MHR-FHR ambiguities was performed by subtracting MHR signals from their FHR counterparts when the absolute difference between the two was less or equal to 5 beats per minute. Major MHR-FHR ambiguities were defined when they exceeded 1% of the tracing. Maternal, fetal and neonatal characteristics were evaluated in cases where major MHR-FHR ambiguities occurred and computer analysis of FHR recordings was compared, before and after removal of the ambiguities. RESULTS: Seventy-two percent of tracings (44/61) exhibited episodes of major MHR-FHR ambiguities, which were not significantly associated with any maternal, fetal or neonatal characteristics, but were associated with MHR accelerations, FHR signal loss and decelerations. Removal of MHR-FHR ambiguities resulted in a significant decrease in FHR decelerations, and improvement in FHR tracing classification. CONCLUSIONS: FHR interpretation during the final hour of labor can be significantly improved by the removal of MHR-FHR ambiguities. PMID- 26585346 TI - Sinonasal small round blue cell tumors: An approach to diagnosis. AB - The differential diagnosis for small round cell tumors in the sinonasal tract is diverse and as the body of literature documenting not only uncommon presentations but also availability of ancillary studies grows, so does the need for a reminder to take a conservative and thorough approach before rendering a diagnosis. Small tissue samples are particularly problematic, with limitations that include volume of tumor cells available for studies, lack of architectural context and a non specific gross description. Incorporation of patient history and presentation, radiologic findings, clinical impression and concurrent studies often guide the course of studies performed by the pathologist. If these are non-specific, the pathologist may need to perform ancillary studies, including a broad panel of immunohistochemical stains and molecular studies. If tissue is limited, a precise classification may not be achievable. Although the expectation to render a definitive diagnosis is high, the pathologist should never feel compelled to go further with a diagnosis than the tissue itself supports. PMID- 26585347 TI - Fused Methoxynaphthyl Phenanthrimidazole Semiconductors as Functional Layer in High Efficient OLEDs. AB - Efficient hole transport materials based on novel fused methoxynaphthyl phenanthrimidazole core structure were synthesised and characterized. Their device performances in phosphorescent organic light emitting diodes were investigated. The high thermal stability in combination with the reversible oxidation process made promising candidates as hole-transporting materials for organic light-emitting devices. Highly efficient Alq3-based organic light emitting devices have been developed using phenanthrimidazoles as functional layers between NPB [4,4-bis(N-(1-naphthyl)-N-phenylamino)biphenyl] and Alq3 [tris(8-hydroxyquinoline)aluminium] layers. Using the device of ITO/NPB/4/Alq3/LiF/Al, a maximum luminous efficiency of 5.99 cd A(-1) was obtained with a maximum brightness of 40,623 cd m(-2) and a power efficiency of 5.25 lm W(-1). PMID- 26585348 TI - Perylene Diimide Based Fluorescent Dyes for Selective Sensing of Nitroaromatic Compounds: Selective Sensing in Aqueous Medium Across Wide pH Range. AB - Water soluble perylenediimide based fluorophore salt, N,N'-bis(ethelenetrimethyl ammoniumiodide)-perylene-3,4,9,10-tetracarboxylicbisimide (PDI-1), has been used for selective fluorescence sensing of picric acid (PA) and 4-nitroaniline (4-NA) in organic as well as aqueous medium across wide pH range (1.0 to 10.0). PDI-1 showed strong fluorescence in dimethylformamide (DMF) (Phif = 0.26 (DMF) and moderate fluorescence in water. Addition of picric acid (PA) and 4-nitroaniline (4-NA) into PDI-1 in DMF/aqueous solution selectively quenches the fluorescence. The concentration dependent studies showed decrease of fluorescence linearly with increase of PA and 4-NA concentration. The interference studies demonstrate high selectivity for PA and 4-NA. Interestingly, PDI-1 showed selective fluorescence sensing of PA and 4-NA across wide pH range (1.0 to 10.0). Selective fluorescence sensing of PA and 4-NA has also been observed with trifluoroacetate (PDI-2), sulfate (PDI-3) salt of PDI-1 as well as octyl chain substituted PDI (PDI-4) without amine functionality. These studies suggest that PA and 4-NA might be having preferential interaction with PDI aromatic core and quenches the fluorescence. Thus PDI based dyes have been used for selective fluorescent sensing of explosive NACs for the first time to the best our knowledge. PMID- 26585349 TI - Chromo/Fluorogenic Detection of Co(2+), Hg(2+) and Cu(2+) by the Simple Schiff Base Sensor. AB - Herein, we reported the ditriazole Schiff base derivative 1 and evaluated its photophysical properties on induction of varieties of metal ions including Na(+), Ag(+), Ni(2+), Mn(2+), Pd(2+), Co(2+), Hg(2+), Cu(2+), Pb(2+), Cd(2+), Zn(2+), Sn(2+), Fe(2+), Fe(3+), Cr(3+) and Al(3+), in order to figure out its potential as ion sensor. The ligand 1 exhibited the strong colorimetric change in the reaction solution as well as absorption spectral shifting with the concomitant appearance of well-defined isosbestic points only upon Co(2+), Hg(2+) and Cu(2+) addition corroborates its applicability as multichannel ion detector. The different extent of spectral shifting as well as unique chromogenic change in the probe solution upon Co(2+), Hg(2+) and Cu(2+) introduction can be used as the discrimination tool for these metal ions. The ligand-metal binding stoichiometry was assessed by their optical response which was further supported by the FT-IR, NMR and mass spectrometric analysis. The association constant and the detection limits of the ligand toward Co(2+), Hg(2+) and Cu(2+) ions were calculated to be 1.52 * 10(-8), 3.26 * 10(-9), 1.16 * 10(-8) and 3.87 * 10(-10), 5.47 * 10(-11), 8.91 * 10(-11) M, respectively, employing the Benesi-Hilderbrand equation and 3 sigma slope(-1) methods. Furthermore, the successive addition of Co(2+), Hg(2+) and Cu(2+) induce the constant decline in the fluorescence emission signal intensity of the probe. The quenching efficiency of the probe upon metallic induction was fitted to the Stern-Volmer equation which yielded the upward curvature in case of all the three metals ions (Co(2+), Hg(2+) and Cu(2+)) when (Io/I-1) was plotted against the quencher concentration indicating the occurrence of both the dynamic and static quenching process in the system with the average Stern-Volmer quenching constant values of 9.25 * 10(-7), 1.14 * 10(-7), 1.829 * 10(-7), respectively. PMID- 26585350 TI - Directional distribution of chilling winds in Estonia. AB - Wind chill equivalent temperature (WCET) is used to define thermal discomfort in winter months. Directional distributions of winds, which are associated with uncomfortable weather, were composed of three climatologically different Estonian locations: Vilsandi, Kuusiku, and Johvi. Cases with wind chill equivalent temperature <-10 degrees C, which could be classified as "uncomfortable or worse," were investigated. Additional thresholds were used to measure weather risk. The 25th percentile of daily minimum WCET was tested to measure classical prevalent wind directions in Estonia: W, SW, and NW bring warm air in winter from the North Atlantic, while winds from the East-European plain (NE, E, and SE) are associated with cold air. The eastern prevalence was stronger when a lower threshold was used. A directional approach may find several applications, such as building, agricultural, landscape, or settlement planning. PMID- 26585351 TI - The Journal of Comparative Pathology Educational Trust 2015 Awards. PMID- 26585352 TI - Associations between circulating carotenoids, genomic instability and the risk of high-grade prostate cancer. AB - BACKGROUND: Carotenoids are a class of nutrients with antioxidant properties that have been purported to protect against cancer. However, the reported associations between carotenoids and prostate cancer have been heterogeneous and lacking data on interactions with nucleotide sequence variations and genomic biomarkers. OBJECTIVE: To examine the associations between carotenoid levels and the risk of high-grade prostate cancer, also considering antioxidant-related genes and tumor instability. METHODS: We measured plasma levels of carotenoids and genotyped 20 single nucleotide polymorphisms (SNP) in SOD1, SOD2, SOD3, XRCC1, and OGG1 among 559 men with non-metastatic prostate cancer undergoing radical prostatectomy. We performed copy number analysis in a subset of these men (n = 67) to study tumor instability assessed as Fraction of the Genome Altered (FGA). We examined associations between carotenoids, genotypes, tumor instability and risk of high grade prostate cancer (Gleason grade >= 4 + 3) using logistic and linear regression. RESULTS: Circulating carotenoid levels were inversely associated with the risk of high-grade prostate cancer; odds ratios (OR) and 95% confidence intervals (CI) comparing highest versus lowest quartiles were: 0.34 (95% CI: 0.18 0.66) for alpha-carotene, 0.31 (95% CI: 0.15-0.63) for beta-carotene, 0.55 (0.28 1.08) for lycopene and 0.37 (0.18-0.75) for total carotenoids. SNPs rs25489 in XRCC1, rs699473 in SOD3 and rs1052133 in OGG1 modified these associations for alpha-carotene, beta-carotene and lycopene, respectively (P <= 0.05). The proportion of men with a high degree of FGA increased with Gleason Score (P < 0.001). Among men with Gleason score <= 3 + 4, higher lycopene levels were associated with lower FGA (P = 0.04). CONCLUSION: Circulating carotenoids at diagnosis, particularly among men carrying specific somatic variations, were inversely associated with risk of high-grade prostate cancer. In exploratory analyses, higher lycopene level was associated with less genomic instability among men with low-grade disease which is novel and supports the hypothesis that lycopene may inhibit progression of prostate cancer early in its natural history. PMID- 26585353 TI - A calorimetric and spectroscopic comparison of the effects of cholesterol and its sulfur-containing analogs thiocholesterol and cholesterol sulfate on the thermotropic phase behavior and organization of dipalmitoylphosphatidylcholine bilayer membranes. AB - We performed differential scanning calorimetric (DSC) and Fourier transform infrared (FTIR) spectroscopic studies of the effects of cholesterol (Chol), thiocholesterol (tChol) and cholesterol sulfate (CholS) on the thermotropic phase behavior and organization of dipalmitoylphosphatidylcholine (DPPC) bilayer membranes. Our DSC results indicate that Chol and tChol incorporation produce small temperature increases in the main phase transition broad component while CholS markedly decreases it, but Chol decreases cooperativity and enthalpy more strongly than CholS and especially tChol. Hence, Chol and tChol thermally stabilize fluid DPPC bilayer sterol-rich domains while CholS markedly destabilizes them, and CholS and particularly tChol are less miscible in such domains. Our FTIR spectroscopic results indicate that Chol incorporation increases the rotational conformational order of fluid DPPC bilayers to a slightly and somewhat greater degree than tChol and CholS, respectively, consistent with our DSC findings. Also, Chol and CholS produce comparable degrees of H-bonding (hydration) of the DPPC ester carbonyls in fluid bilayers, whereas tChol increases H-bonding. At low temperatures, Chol is fully soluble in gel state DPPC bilayers, whereas tChol and CholS are not. Thus tChol and CholS incorporation can produce considerably different effects on DPPC bilayers. In particular, the tChol thiol group markedly reduces its lateral miscibility and increases DPPC carbonyl H-bonding without significantly affecting the other characteristic effects of Chol itself, while the CholS sulfate group significantly reduces its ability to thermally stabilize and order fluid DPPC membranes. This latter result suggests that the molecular basis for the purported ability of CholS to "stabilize" various biological membranes should be re examined. PMID- 26585354 TI - Improved cardiovascular risk factors in pediatric renal transplant recipients on steroid avoidance immunosuppression: A study of the Midwest Pediatric Nephrology Consortium. AB - Several centers have examined the implementation of immunosuppression protocols that minimize steroid exposure. This study retrospectively examined cardiovascular risk factors in 70 pediatric renal transplant recipients on steroid avoidance-based immunosuppression over three yr compared to matched pediatric patients maintained on chronic corticosteroids. Although higher rates of acute rejection were noted in the steroid-avoidant group (22% vs. 16%, p = 0.034), graft function was similar (67 + 10 mL/min/1.73 m(2) vs. 72 + 12 mL/min/1.73 m(2)) (p = 0.053). The steroid-avoidant group demonstrated improved growth (height z-score -0.41 + 5.9 vs. -1.1 + 0.041) with a decrease in the prevalence of obesity (24% vs. 34%, p = 0.021). Indexed systolic blood pressures were lower beginning at six months post-transplant in the steroid-avoidant group (1.21 + 0.15 vs. 1.51 + 0.22, p = 0.020). Indexed diastolic blood pressures were lower beginning at 12 months post-transplant (0.91 + 0.11 vs. 1.12 + 0.18, p = 0.037). Differences in total serum cholesterol values and serum glucose values were not statistically significant. Beginning at 12 months, a statistically significant decrease in left ventricular mass index (39.2 + 11.3 vs. 49.4 + 14.5, p = 0.014) was noted in patients on steroid-avoidant immunosuppression, which corresponded to a significant decrease in the prevalence of left ventricular hypertrophy in these patients by two yr post-transplant (35% vs. 48%, p = 0.012). Systolic blood pressure and BMI were independent predictors of left ventricular hypertrophy. PMID- 26585356 TI - Organophosphorus flame retardants and phthalate esters in indoor dust from different microenvironments: Bioaccessibility and risk assessment. AB - Incidental ingestion of indoor dust is an important pathway for human exposure to organophosphorus flame retardants (OPFRs) and phthalate esters (PAEs). However, little is known about their bioaccessibility in indoor dust. In this study, indoor dust samples were collected from houses, offices, public microenvironments (PMEs), and university dorms, and physiologically based extraction test (PBET) was used to measure the bioaccessibility of OPFRs and PAEs in these dust samples. Total concentrations of OPFRs in dust samples ranged from 0.01 to 63.2 MUg g(-1), with significantly lower concentrations in dorm dust (median = 0.30 MUg g(-1)) than those in houses (3.12), offices (5.94), and PMEs (11.6). Total PAEs ranged from 5.49 to 2161 MUg g(-1) with significantly lower concentrations in dorm dust (379 MUg g(-1)) than those in the other three types of dust (767, 515, and 731 MUg g(-1)). When subject to PBET, the bioaccessibility of OPFRs ranged from 8.18% (triphenyl phosphate) to 54.5% (Tris(2-chloroisopropyl) phosphate) for OPFRs, and from 1.21% (di-2-ethylhexyl phthalate, DEHP) to 81.1% (dimethyl phthalate) for PAEs. Estimated exposure doses for adults and infants to OPFRs via dust ingestion were much lower than the reference doses (RfD), but intake dose of DEHP for infants was higher than the RfD of 20 MUg kg(-1) d(-1). However, the DEHP intake dose did not exceed the RfD after incorporating bioaccessibility into risk assessment. Our data indicated the importance of considering contaminant bioaccessibility during risk assessment of indoor dust. PMID- 26585357 TI - TiO2 quantum dots as superb compact block layers for high-performance CH3NH3PbI3 perovskite solar cells with an efficiency of 16.97. AB - A compact TiO(2) layer is crucial to achieve high-efficiency perovskite solar cells. In this study, we developed a facile, low-cost and efficient method to fabricate a pinhole-free and ultrathin blocking layer based on highly crystallized TiO(2) quantum dots (QDs) with an average diameter of 3.6 nm. The surface morphology of the blocking layer and the photoelectric performance of the perovskite solar cells were investigated by spin-coating with three different materials: colloidal TiO(2) QDs, titanium precursor solution, and aqueous TiCl(4). Among these three treatments, the perovskite solar cell based on the TiO(2) QD compact layer offered the highest power conversion efficiency (PCE) of 16.97% with a photocurrent density of 22.48 mA cm(-2), a photovoltage of 1.063 V and a fill factor of 0.71. The enhancement of PCE mainly stems from the small series resistance and the large shunt resistance of the TiO(2) QD layer. PMID- 26585355 TI - Comparative Effectiveness of Vancomycin Versus Daptomycin for MRSA Bacteremia With Vancomycin MIC >1 mg/L: A Multicenter Evaluation. AB - PURPOSE: Clinical studies comparing vancomycin with alternative therapy for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia are limited. The objective of this study was to compare outcomes of early daptomycin versus vancomycin treatment for MRSA bacteremia with high vancomycin MICs in a geographically diverse multicenter evaluation. METHODS: This nationwide, retrospective, multicenter (N = 11), matched, cohort study compared outcomes of early daptomycin with vancomycin for MRSA bloodstream infection (BSI) with vancomycin MICs 1.5 to 2 ug/mL. Matching variables, based on propensity regression analysis, included age, intensive care unit (ICU), and type of BSI. Outcomes were as follows: (1) composite failure (60-day all-cause mortality, 7 day clinical or microbiologic failure, 30-day BSI relapse, or end-of-treatment failure (EOT; discontinue/change daptomycin or vancomycin because of treatment failure or adverse event]); (2) nephrotoxicity; and (2) day 4 BSI clearance. FINDINGS: A total of 170 patients were included. The median (interquartile range) age was 60 years (50-74); the median (range) Acute Physiology and Chronic Health Evaluation II score was 15 (10-18); 31% were in an ICU; and 92% had an infectious disease consultation. BSI types included endocarditis/endovascular (39%), extravascular (55%), and central catheter (6%). The median daptomycin dose was 6 mg/kg, and the vancomycin trough level was 17 mg/L. Overall composite failure was 35% (59 of 170): 15% due to 60-day all-cause mortality, 14% for lack of clinical or microbiologic response by 7 days, and 17% due to failure at end of therapy (discontinue/change because of treatment failure or adverse event). Predictors of composite failure according to multivariate analysis were age >60 years (odds ratio, 3.7; P < 0.01) and ICU stay (odds ratio, 2.64; P = 0.03). Notable differences between treatment groups were seen with: (1) end of therapy failure rates (11% vs 24% for daptomycin vs vancomycin; P = 0.025); (2) acute kidney injury rates (9% vs 23% for daptomycin vs vancomycin; P = 0.043); and (3) day 4 bacteremia clearance rates for immunocompromised patients (n = 26) (94% vs 56% for daptomycin vs vancomycin; P = 0.035). IMPLICATIONS: Results from this multicenter study provide, for the first time, a geographically diverse evaluation of daptomycin versus vancomycin for patients with vancomycin susceptible MRSA bacteremia with vancomycin MIC values >1 ug/mL. Although the overall composite failure rates did not differ between the vancomycin and daptomycin groups when intensively matched according to risks for failure, the rates of acute kidney injury were significantly lower in the daptomycin group. These findings suggest that daptomycin is a useful therapy for clinicians treating patients who have MRSA bacteremia. Prospective, randomized trials should be conducted to better assess the potential significance of elevated vancomycin MIC. PMID- 26585358 TI - Genetic polymorphisms and paclitaxel- or docetaxel-induced toxicities: A systematic review. AB - BACKGROUND: Taxanes, including paclitaxel and docetaxel, are indispensable for treatment of cancer. Development of toxicity frequently necessitates dose reduction or discontinuation of therapy, despite clinical response. OBJECTIVE: Pharmacogenetic studies were reviewed for identification of genetic variants possibly underlying individual susceptibility to adverse events. METHOD: We conducted a systematic search in Pubmed and Embase for pharmacogenetic reports with focus on commonly reported taxane-related gastrointestinal, hematological and neurological toxicities in adult patients with solid tumors. The findings from a total of 51 eligible studies are presented in a comprehensive way. RESULTS: Most frequently investigated single nucleotide polymorphisms (SNPs) were located in genes encoding proteins affecting pharmacokinetics, such as drug transporters and genes of the cytochrome P450 family. Inconclusive data for risk of toxicity as well as for effects on drug exposure were reported on variants in ABCB1, CYP3A4, CYP3A5 and, for paclitaxel, CYP2C8. Interest is also dedicated towards genes involved in pharmacodynamics, such as detoxification of reactive oxygen species, DNA repair, neuronal processes and microtubule function. Recent studies include variants in TUBB2A, EPHA5 and EPHA6 for a possible association with neurotoxicity. Variations in methodological approach, sample size, study design, treatment schedule and end-point of toxicity affect consistency of results. CONCLUSION: This review illustrates the complexity to well design pharmacogenetic studies for validation of SNPs that may clarify differences in taxane-induced toxicities among individuals. Novel genes encoding cellular targets of taxanes deserve further analysis by means of robust patient cohorts and definition of objective end-points. PMID- 26585359 TI - Silicon based radicals, radical ions, diradicals and diradicaloids. AB - Radicals are an important class of species which act as intermediates in numerous chemical and biological processes. Most of the radicals have short lifetimes. However, radicals with longer lifetimes can be isolated and stored in a pure form. They are called stable radicals. Over the last five decades, the syntheses of several stable radicals have been reported. Recently, highly unstable radicals have been successfully stabilized via strong sigma-donation of singlet carbenes. Cyclic aklyl(amino) carbene (cAAC) is regarded as a stronger sigma-donor and a better pi-acceptor when compared with that of an N-heterocyclic carbene (NHC). In this article we review preferentially the results of our group to generate stable radical centers on the carbene carbon atoms by employing the so far hidden and unique ability of the cAACs. We focus on the development of new synthetic routes to stable and isolable radicals containing silicon atoms. All the compounds have been well characterized by single crystal X-ray analysis; the mono-radicals have been distinguished by EPR spectroscpy and the ground state of the diradicals has been studied by magnetic susceptibility measurements and theoretical calculations. Many of these compounds are studied by cyclic voltammetry and are often converted to their corresponding radical cations or radical anions via electron abstraction or addition processes. Some of them are stable, having long lifetimes and hence are isolated and characterized thoroughly. Not much information has been obtained on the short lived persistent radical species. Herein, we discuss some of the examples of such a type of species and focus on what kind of chemical reactions are initiated by these short-lived radical species in solution. We also briefly mention the syntheses and charaterization of the so far reported stable silicon centered radicals. PMID- 26585360 TI - WITHDRAWN: Lack of association between the HLA-G 3'UTR 14-bp ins/del polymorphism and cancer risk: A meta-analysis of case-control study. AB - This article hashas been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 26585361 TI - Major histocompatibility complex linked databases and prediction tools for designing vaccines. AB - Presently, the major histocompatibility complex (MHC) is receiving considerable interest owing to its remarkable role in antigen presentation and vaccine design. The specific databases and prediction approaches related to MHC sequences, structures and binding/nonbinding peptides have been aggressively developed in the past two decades with their own benchmarks and standards. Before using these databases and prediction tools, it is important to analyze why and how the tools are constructed along with their strengths and limitations. The current review presents insights into web-based immunological bioinformatics resources that include searchable databases of MHC sequences, epitopes and prediction tools that are linked to MHC based vaccine design, including population coverage analysis. In T cell epitope forecasts, MHC class I binding predictions are very accurate for most of the identified MHC alleles. However, these predictions could be further improved by integrating proteasome cleavage (in conjugation with transporter associated with antigen processing (TAP) binding) prediction, as well as T cell receptor binding prediction. On the other hand, MHC class II restricted epitope predictions display relatively low accuracy compared to MHC class I. To date, pan-specific tools have been developed, which not only deliver significantly improved predictions in terms of accuracy, but also in terms of the coverage of MHC alleles and supertypes. In addition, structural modeling and simulation systems for peptide-MHC complexes enable the molecular-level investigation of immune processes. Finally, epitope prediction tools, and their assessments and guidelines, have been presented to immunologist for the design of novel vaccine and diagnostics. PMID- 26585362 TI - Expression of allograft inflammatory factor-1 in peripheral blood monocytes and synovial membranes in patients with rheumatoid arthritis. AB - OBJECTIVE: Allograft inflammatory factor-1 (AIF-1) is a cytoplasmic protein expressed in various human cells such as monocyte/macrophages and activated T lymphocytes. A recent study showed that AIF-1 is strongly expressed in infiltrating mononuclear cells and synovial fibroblasts in rheumatoid arthritis and that AIF-1 induces the proliferation of cultured synovial cells. In this study we analysed the expression of AIF-1 in peripheral blood monocytes and synovial membranes from patients with rheumatoid arthritis (RA). METHODS: We examined 71 patients with rheumatoid arthritis and 25 control subjects. RESULTS: Using flow cytometry we found significantly increased numbers of circulating AIF 1(+) monocytes in peripheral blood from RA patients compared with controls. Moreover, there were statistically significant positive correlations between AIF 1(+) monocytes, DAS28 and the Sharp erosion score. Immunofluorescence staining showed strong expression of AIF-1 by infiltrating mononuclear cells - predominantly macrophages in RA synovial tissues - compared with tissues derived from joints affected by osteoarthritis. CONCLUSION: The results of this study suggest that AIF-1 may be associated with the pathogenesis of RA and may be a novel cytokine involved in the immunological process underlying RA. PMID- 26585363 TI - TNF-alpha -238, -308, -863 polymorphisms, and brucellosis infection. AB - BACKGROUND: Brucella abortus is an intracellular bacterium that affects humans and domestic animals. Tumor necrosis factor-alpha (TNF-alpha) has been shown as a key player in the induction of cell-mediated resistance against Brucella infection. We aimed to evaluate the possible influence of the TNF-alpha promoter polymorphisms (-308 G/A, -238 G/A, and -863 C/A) on the susceptibility of human brucellosis. METHODOLOGY: A total of 153 patients with active brucellosis and 128 healthy individuals were recruited. All subjects were genotyped for the polymorphisms in the TNF-alpha gene by Allele-Specific polymerase chain reaction analysis. RESULTS: Our results showed that the TNF-alpha -308 GG genotype was significantly more frequently present in controls than in brucellosis patients (91% vs. 75%), thus was a protective factor against developing brucellosis (OR=0.313, p=0.001). In contrast, the -308 GA genotype (OR=3.026, p=0.002) and minor allele (A) (OR=3.058, p=0.001) as well as AAG haplotype (OR=4.014, p=0.001) conferred an increased risk of brucellosis. However, the -238 G/A and -863 C/A polymorphisms were not associated with the risk of brucellosis at both allelic and genotypic levels (p>0.05). CONCLUSION: Our study revealed that the TNF-alpha 308 A allele or GA heterozygosity or AAG haplotype were associated with an increased risk of brucellosis in our population. PMID- 26585364 TI - A meta-analysis of P2X7 gene-1513A/C polymorphism and pulmonary tuberculosis susceptibility. AB - OBJECTIVE: A meta-analysis was performed to determine the association between P2X7-1513A/C polymorphism and pulmonary tuberculosis susceptibility. METHODS: Based on comprehensive searches of the MEDLINE, EMBASE and ISI Web of knowledge, China National Knowledge Infrastructure (CNKI) and Wanfang Database, we identified eligible studies about the association between P2X7-1513A/C polymorphism and pulmonary tuberculosis susceptibility. RESULTS: A total of 1916 cases and 2194 controls in 10 studies were pooled together for evaluation of the overall association between P2X7-1513A/C polymorphism and susceptibility of pulmonary tuberculosis. Allele model (A vs. C: p=0.15; OR=0.86, 95% CI=0.69 1.06), homozygous model (AA vs. CC: p=0.22; OR=0.78, 95% CI=0.53-1.16), and heterozygous model (AC vs. CC: p=0.23; OR=0.80, 95% CI=0.56-1.15) did not show decreased risk of developing pulmonary tuberculosis. Similarly, dominant model (AA+AC vs. CC: p=0.19; OR=0.80, 95% CI=0.56-1.12) and recessive model (AA vs. AC+CC: p=0.21; OR=0.85, 95% CI=0.66-1.10) failed to show decreased risk of developing pulmonary tuberculosis. In Indians, allele model (A vs. C: p=0.0006; OR=0.69, 95% CI=0.55-0.85), and recessive model (AA vs. AC+CC: p=0.0003; OR=0.62, 95% CI=0.48-0.80) indicated significant association between P2X7-1513A/C polymorphism and susceptibility to pulmonary tuberculosis. CONCLUSIONS: Our pooled data suggest a association between P2X7-1513A/C polymorphism and the prevalence of pulmonary tuberculosis among Indian populations. PMID- 26585365 TI - Pituitary gigantism: Causes and clinical characteristics. AB - Acromegaly and pituitary gigantism are very rare conditions resulting from excessive secretion of growth hormone (GH), usually by a pituitary adenoma. Pituitary gigantism occurs when GH excess overlaps with the period of rapid linear growth during childhood and adolescence. Until recently, its etiology and clinical characteristics have been poorly understood. Genetic and genomic causes have been identified in recent years that explain about half of cases of pituitary gigantism. We describe these recent discoveries and focus on some important settings in which gigantism can occur, including familial isolated pituitary adenomas (FIPA) and the newly described X-linked acrogigantism (X-LAG) syndrome. PMID- 26585366 TI - Community-acquired bacteremic Streptomyces atratus pneumonia in animmunocompetent adult: a case report. AB - INTRODUCTION: Streptomyces spp. are aerobic, Gram-positive bacteria of the order Actinomycetales, known for their ability to produce antimicrobial molecules such as streptomycin. Pneumonia due to Streptomyces is considered to be rare and limited to immunocompromised patients. Streptomyces spp. are only rarely associated with invasive systemic infections. To our knowledge, we report the first documented case of community-acquired Streptomyces atratus bacteremic pneumonia in an immunocompetent patient. CASE PRESENTATION: We describe a case of Streptomyces atratus bacteremic pneumonia in an otherwise healthy, 77-year-old Spanish man. Streptomyces identified by 16S ribosomal RNA sequencing grew in multiple blood cultures and bronchoalveolar lavage cultures. The infection resolved completely after treatment with imipenem and amoxicillin/clavulanic acid for 2 months. CONCLUSIONS: The majority of cases reported in the literature make reference to the difficulty of determining the pathogenic role of Streptomyces spp. Usually considered a contaminant, the pathogenic role of Streptomyces spp. is easier to confirm when the species is isolated from a catheter tip and, in the case of blood cultures, in more than one sample with a high count of colonies. To our knowledge, we report the first documented case of Streptomyces atratus bacteremic pneumonia in an immunocompetent patient. As the experience is limited, further studies are needed to better understand the interpretation of the isolates of the genus Streptomyces; the predisposing factors for infection; and the course, treatment, and evolution of these infections. PMID- 26585367 TI - Vascular Dysfunction in Heart Failure with Preserved Ejection Fraction. PMID- 26585368 TI - Beyond ion-conduction: Channel-dependent and -independent roles of TRP channels during development and tissue homeostasis. AB - Transient receptor potential (TRP) channels comprise a family of cation channels implicated in a variety of cellular processes, including proliferation, cell migration and cell survival. As a consequence, members of this ion family play prominent roles during embryonic development, tissue maintenance and cancer progression. Although most TRP channels are non-selective, many cellular responses, mediated by TRP channels, appear to be calcium-dependent. In addition, there is mounting evidence for channel-independent roles for TRP channels. In this review, we will discuss how both these channel-dependent and -independent mechanisms affect cellular programs essential during embryonic development, and how perturbations in these pathways contribute to a variety of pathologies. This article is part of a Special Issue entitled: Calcium and Cell Fate. Guest Editors: Jacques Haiech, Claus Heizmann, Joachim Krebs, Thierry Capiod and Olivier Mignen. PMID- 26585369 TI - Gait characteristics in older adults with diabetes and impaired fasting glucose: The Rotterdam Study. AB - AIMS: To investigate the association of diabetes mellitus and impaired fasting glucose with gait in the general middle-aged and elderly population. METHODS: We performed a cross-sectional study on 3019 participants from the population-based Rotterdam Study (aged >45years, 54% women). The presence of diabetes mellitus and impaired fasting glucose was evaluated by measuring serum glucose levels and by documenting anti-diabetic treatment. Participants underwent gait analysis using an electronic walkway. Thirty gait variables were summarized into five independent gait domains for normal walking (Rhythm, Variability, Phases, Pace and Base of Support), one for turning (Turning) and one for walking heel to toe (Tandem), which were averaged into Global Gait. Linear regression analyses were performed to determine the association of diabetes, impaired fasting glucose and continuous glucose levels within the normal range with gait. RESULTS: Diabetes mellitus was associated with worse Global Gait (Z-score difference -0.19, 95% confidence interval (CI) -0.30; -0.07), worse Pace (-0.20, 95% CI -0.30; -0.10) and worse Tandem (-0.21, 95% CI -0.33; -0.09), after adjusting for age, sex, height and weight. The association with Tandem remained significant after additional adjustment for cardiovascular risk factors. Impaired fasting glucose and continuous glucose levels within the normal range were not associated with any of the gait domains. CONCLUSION: In our population-based study diabetes mellitus was associated with worse Global Gait, which was mostly reflected in Pace and Tandem. These associations were partly driven by other cardiovascular risk factors, emphasizing the importance of optimal control of cardiovascular risk factor profiles in patients with diabetes. PMID- 26585370 TI - Predictive assessment in pharmacogenetics of XRCC1 gene on clinical outcomes of advanced lung cancer patients treated with platinum-based chemotherapy. AB - Published data have shown inconsistent results about the pharmacogenetics of XRCC1 gene on clinical outcomes of advanced lung cancer patients treated with platinum-based chemotherapy. This meta-analysis aimed to summarize published findings and provide more reliable association. A total of 53 eligible studies including 7433 patients were included. Patients bearing the favorable TrpTrp and TrpArg genotypes of Arg194Trp were more likely to better response rates to platinum-based chemotherapy compared to those with the unfavorable ArgArg genotype (TrpTrp+TrpArg vs. ArgArg: odds ratio (OR) = 2.02, 95% CI, 1.66-2.45). The GlnGln and GlnArg genotypes of Arg399Gln were significantly associated with the poorer response rates compared to those with the ArgArg genotype (GlnGln +GlnArg vs. ArgArg: OR = 0.68, 95% CI, 0.54-0.86). The GlnGln genotype might be more closely associated with shorter survival time and higher risks of death for patients (GlnGln vs. ArgArg: hazard ratio (HR) = 1.14, 95% CI, 0.75-1.75). Our cumulative meta-analyses indicated a distinct apparent trend toward a better response rate for Arg194Trp, but a poorer response rate in Arg399Gln. These findings indicate a predictive role of XRCC1 polymorphisms in clinical outcomes. The use of XRCC1 polymorphisms as predictive factor of clinical outcomes in personalized chemotherapy treatment requires further verification from large well designed pharmacogenetics studies. PMID- 26585371 TI - Value of the prognostic nutritional index and weight loss in predicting metastasis and long-term mortality in nasopharyngeal carcinoma. AB - BACKGROUND: To evaluate the influence of the progonistic nutritional index (PNI) and weight loss on metastasis and long-term mortality in nasopharyngeal carcinoma (NPC). METHODS: We retrospectively reviewed 694 newly diagnosed patients with non disseminated, biopsy-proven NPC. Survival analysis was used to evaluate the predictive value of PNI and weight loss. RESULTS: Multivariate analysis demonstrated that a low pre-therapy PNI (< 55.0) was an independent predictor of poor overall survival (OS) (P = 0.012), distant metastasis-free survival (DMFS) (P = 0.011) and progression-free survival (P = 0.012). High weight loss (HWL, weight loss during treatment >=10 %) was an independent predictor of poor OS (P = 0.001) and DMFS (P = 0.014). Advanced stage disease, female gender, chemotherapy, high white blood cell count, high serum globulin concentration and pre-therapy body-mass index were predictors of HWL. CONCLUSION: Pre-therapy PNI and weight loss have significant predictive value for metastasis and mortality in patients with NPC. PMID- 26585373 TI - Larval regulation of worker reproduction in the polydomous ant Novomessor cockerelli. AB - Although workers in many ant species are capable of producing their own offspring, they generally rear the queen's offspring instead. There are various mechanisms that regulate worker reproduction including inhibitory effects of ant brood. Colonies of the ant Novomessor cockerelli are monogynous and polydomous resulting in a large portion of nest workers being physically isolated from the queen for extended periods of time. Some workers experimentally isolated from the queen in laboratory nests lay viable eggs, which develop into males. We investigate the mechanism that regulates worker fertility in subnests separated from the queen by giving queenless worker groups queen-produced larvae, queen produced eggs, or no brood. Our findings show that larvae delay the time to worker egg-laying, but eggs have no effect. Larval inhibition is a likely mechanism that contributes to the regulation of worker reproduction in N. cockerellli because larvae are easily transported to subnests that do not contain a queen. PMID- 26585372 TI - White matter structures associated with loneliness in young adults. AB - Lonely individuals may exhibit dysfunction, particularly with respect to social empathy and self-efficacy. White matter (WM) structures related to loneliness have not yet been identified. We investigated the association between regional WM density (rWMD) using the UCLA Loneliness Scale in 776 healthy young students aged 18-27 years old. Loneliness scores were negatively correlated with rWMD in eight clusters: the bilateral inferior parietal lobule (IPL), right anterior insula (AI), posterior temporoparietal junction (pTPJ), left posterior superior temporal sulcus (pSTS), dorsomedial prefrontal cortex (dmPFC), and rostrolateral prefrontal cortex (RLPFC). The bilateral IPL, right AI, left pSTS, pTPJ, and RLPFC were strongly associated with Empathy Quotient (EQ), whereas the bilateral IPL, right AI, left pTPJ, and dmPFC were associated with General Self-Efficacy Scale (GSES) score. The neural correlates of loneliness comprise widespread reduction in WMD in areas related to self- and social cognition as well as areas associated with empathy and self-efficacy. PMID- 26585374 TI - Morphology, secretion composition, and ecological aspects of stipular colleters in Rubiaceae species from tropical forest and savanna. AB - Colleters are secretory structures that produce and release mucilage or a mucilage-resin mixture protecting meristems and young structures against desiccation, herbivores, and pathogens. The secretions may vary in colleters of same or different types, indicating that the functionality of colleters may be more specific than previously thought. In this study, we compared 17 Rubiaceae species from savanna and forest environment focusing on colleter secretions and its ecological role. First, we evaluated the morphology, distribution, and histochemistry of stipular colleters using light and scanning electron microscopy. Additionally, we investigated the phenology, microclimate, and the proportion of damaged apices in the savanna and forest species. We recorded standard-type colleters, variable in distribution and size, in 14 of the 17 studied species. The secretion varied from predominantly hydrophilic, mixed to predominantly lipophilic. During the budding period, secretion covered the vegetative apices. Savanna species had a prevalence of lipid secretion in habitats with higher luminosity, which had a lower proportion of damaged apices. In contrast, forest species occurred in habitats with lower luminosity and had a higher proportion of damaged apices, in general with the absence of lipids in the colleters. These results highlight that colleters with similar morphology clearly differed in secretions among species, especially between species from savanna and forest, in which the colleters appear potentially associated with protection against irradiation in savanna, but not in the forest environment. PMID- 26585375 TI - Polystyrene nanoparticles internalization in human gastric adenocarcinoma cells. AB - The increase in the use of nanoparticles, as a promising tool for drug delivery or as a food additive, raises questions about their interaction with biological systems, especially in terms of evoked responses. In this work, we evaluated the kinetics of uptake of 44 nm (NP44) and 100 nm (NP100) unmodified polystyrene nanoparticles (PS-NPs) in gastric adenocarcinoma (AGS) cells, as well as the endocytic mechanism involved, and the effect on cell viability and gene expression of genes involved in cell cycle regulation and inflammation processes. We showed that NP44 accumulate rapidly and more efficiently in the cytoplasm of AGS compared to NP100; both PS-NPs showed an energy dependent mechanism of internalization and a clathrin-mediated endocytosis pathway. Dose response treatments revealed a non-linear curve. PS-NPs also affected cell viability, inflammatory gene expression and cell morphology. NP44 strongly induced an up regulation of IL-6 and IL-8 genes, two of the most important cytokines involved in gastric pathologies. Our study suggests that parameters such as time, size and concentration of NPs must be taken carefully into consideration during the development of drug delivery systems based on NPs and for the management of nanoparticles associated risk factors. PMID- 26585376 TI - Obstacles to establishing an NHS faecal transplant programme. PMID- 26585377 TI - [Economic impact of lung cancer screening in France: A modeling study]. AB - INTRODUCTION: The National Lung Screening Trial found that, in a selected population with a high risk of lung cancer, an annual low-dose CT-scan decreased lung cancer mortality by 20% and overall mortality by 7% compared to annual chest X-Ray. In France, a work group stated that individual screening should be considered in this setting. However, the economic impact of an organized and generalized (to all eligible individuals) screening in France was never reported. METHODS: This is a modeling study using French population demographic data and published data from randomized screening trials. We used the same selection criteria as NLST: 55-74-year-old smokers for at least 30 pack-years, current smoker or quit less than 15 years. We computed a second model including also 50 54-year-old individuals. Then, we used different participation rates: 65%, 45%, and 32%. RESULTS: According to the considered model, there would be 1,650,588 to 2,283,993 subjects eligible to screening in France. According to the model and participation rate, lung cancer screening would diagnose 3600 to 10,118 stages 1/2 lung cancer each year. There would be 5991 to 16,839 false-positives, of whom 1416 to 3981 would undergo unnecessary surgery. Screening policy would cost 105 to 215 ? million per year. However, increasing the price of a cigarette pack by 0.05 to 0.10 ? would fully cover the screening costs. CONCLUSION: Participation rate is a key point for screening impact. Screening could be easily funded by a small increase in cigarette prices. PMID- 26585379 TI - Basic detection property of an array-type CdTe detector for BNCT-SPECT - Measurement and analysis of anti-coincidence events. AB - Our research group is now investigating a BNCT-SPECT system with cadmium tellurite (CdTe) detectors, which can obtain a three-dimensional image of the BNCT treatment effect by measuring the 478keV gamma-rays emitted from an excited state of the 7Li nucleus generated by the 10B(n,alpha) reaction. The BNCT-SPECT system is composed of a collimator and an array-type CdTe detector. In this study, we produced an array detector with two CdTe elements to test the basic detection property for anti-coincidence events. Our investigation confirmed that the detector offers an improved S/N ratio by the anti-coincidence detection. We also proposed an estimation method using the MCNP5 to analyze coincidence events in the detector. PMID- 26585378 TI - A Bayesian network meta-analysis: Comparing the clinical effectiveness of local corticosteroid injections using different treatment strategies for carpal tunnel syndrome. AB - BACKGROUND: Local corticosteroid injections are commonly used to improve the short-term symptomatic severity and the functional status of the hands affected by carpal tunnel syndrome. We conducted a systematic review and Bayesian network meta-analysis to compare the clinical effectiveness of local corticosteroid injections using different injection approaches. METHODS: Electronic literature in Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Web of Science, and other sources were searched to identify clinical studies comparing different injection approaches with each other or placebo for carpal tunnel syndrome. Two review authors conducted selection of studies, data extraction, and assessment of risk of bias independently. Random-effects models were used to conduct the pairwise meta-analysis and the Bayesian network meta analysis. RESULTS: Overall, 10 studies with 633 patients were included in the systematic review. Among the injection approaches, local corticosteroid injections using the ultrasound-guided in-plane injection (Ulnar-I) approach was the best treatment strategy for clinical response (median OR versus placebo 128.30, 95% CrI 9.76 to 2299.00), change in symptom severity scale (median MD versus placebo -1.16, 95% CrI -1.95 to -0.38) , and change in functional status scale (median MD versus placebo -0.74, 95% CrI -2.00 to 0.52) at short-term follow-up period in the network meta-analysis. Local corticosteroid injections using other injection approaches were better than placebo for clinical response (for the PI approach, median OR versus placebo 8.85, 95% CrI 3.00 to 33.15; for the DI approach, median OR versus placebo 7.00, 95% CrI 0.53 to 118.80) , change in symptom severity scale (for the Ulnar-O approach, median MD versus placebo 0.78, 95% CrI -1.43 to -0.16; for the PI approach, median MD versus placebo 0.58, 95% CrI -0.95 to -0.22), and change in functional status scale (for the Ulnar-O approach, median MD versus placebo -0.63, 95% CrI -1.67 to 0.43; for the PI approach, median MD versus placebo -0.46, 95% CrI -1.11 to 0.21) at short-term follow-up period. The quality of studies is good. CONCLUSIONS: According to our analyses, the ultrasound-guided in-plane injection (Ulnar-I) approach was the most effective treatment among the injection approaches for carpal tunnel syndrome. PMID- 26585380 TI - Serum Amyloid A Protein Concentration in Blood is Influenced by Genetic Differences in the Cheetah (Acinonyx jubatus). AB - Systemic amyloid A (AA) amyloidosis is a major cause of morbidity and mortality among captive cheetahs. The self-aggregating AA protein responsible for this disease is a byproduct of serum amyloid A (SAA) protein degradation. Transcriptional induction of the SAA1 gene is dependent on both C/EBPbeta and NF kappaB cis-acting elements within the promoter region. In cheetahs, 2 alleles exist for a single guanine nucleotide deletion in the putative NF-kappaB binding site. In this study, a novel genotyping assay was developed to screen for the alleles. The results show that the SAA1A (-97delG) allele is associated with decreased SAA protein concentrations in the serum of captive cheetahs (n = 58), suggesting genetic differences at this locus may be affecting AA amyloidosis prevalence. However, there was no significant difference in the frequency of the SAA1A (-97delG) allele between individuals confirmed AA amyloidosis positive versus AA amyloidosis negative at the time of necropsy (n = 48). Thus, even though there is evidence that having more copies of the SAA1A (-97delG) allele results in a potentially protective decrease in serum concentrations of SAA protein in captive cheetahs, genotype is not associated with this disease within the North American population. These results suggest that other factors are playing a more significant role in the pathogenesis of AA amyloidosis among captive cheetahs. PMID- 26585381 TI - Shifting Thresholds: Rapid Evolution of Migratory Life Histories in Steelhead/Rainbow Trout, Oncorhynchus mykiss. AB - Expression of phenotypic plasticity depends on reaction norms adapted to historic selective regimes; anthropogenic changes in these selection regimes necessitate contemporary evolution or declines in productivity and possibly extinction. Adaptation of conditional strategies following a change in the selection regime requires evolution of either the environmentally influenced cue (e.g., size-at age) or the state (e.g., size threshold) at which an individual switches between alternative tactics. Using a population of steelhead (Oncorhynchus mykiss) introduced above a barrier waterfall in 1910, we evaluate how the conditional strategy to migrate evolves in response to selection against migration. We created 9 families and 917 offspring from 14 parents collected from the above- and below-barrier populations. After 1 year of common garden-rearing above barrier offspring were 11% smaller and 32% lighter than below-barrier offspring. Using a novel analytical approach, we estimate that the mean size at which above barrier fish switch between the resident and migrant tactic is 43% larger than below-barrier fish. As a result, above-barrier fish were 26% less likely to express the migratory tactic. Our results demonstrate how rapid and opposing changes in size-at-age and threshold size contribute to the contemporary evolution of a conditional strategy and indicate that migratory barriers may elicit rapid evolution toward the resident life history on timescales relevant for conservation and management of conditionally migratory species. PMID- 26585382 TI - Temperature measurements in trauma patients: is the ear the key to the core? AB - INTRODUCTION: It is important to monitor the core temperature in a severely injured patient. The choice of method is controversial, and different thermometers and sites for measurement are used. The aim of this study was to investigate continuous epitympanic temperature measurement using an auditory canal sensor in potentially severely injured patients and to compare this method with other commonly used devices. METHODS: In this cohort of potentially severely injured patients, the core temperature was registered continuously using an epitympanic sensor in the auditory canal, beginning at the accident scene through the first hours after admittance to the hospital. According to clinical practice, other methods of measurement were employed during pre- and in-hospital diagnostics and therapeutics. The consistency between different methods was analysed using Bland-Altman plots, and the limits of agreement (LOA) and bias between methods was estimated. RESULTS: During the study period, 18 patients were included. A total of 393 temperature measurements were obtained using seven different methods. We found that temperature measurements in the auditory canal agreed satisfactorily with most other types of measurements. The most consistent measurement was observed with bladder measurements (bias 0.43 degrees C, LOA 0.47, 1.33 degrees C), which was constant over the temperature range investigated (30.0-38.3 degrees C). CONCLUSION: Epitympanic temperature measurement in potentially severely injured patients was consistent with other methods that were commonly used to measure core temperature. The difference between measurement methods appeared to be constant over the relevant temperature range. Continuous epitympanic thermometry can be considered a reliable, cost effective and simple alternative compared with more invasive methods of thermometry. PMID- 26585383 TI - Early postoperative emergency department presentation predicts poor long-term outcomes in patients surgically treated for meningioma. AB - Previous authors have identified a number of factors that predict morbidity, mortality, and recurrence in patients undergoing resection of a meningioma. We sought to study a novel potential prognostic indicator: early postoperative visit to the emergency department (ED). We conducted a retrospective cohort study on 239 patients who underwent a meningioma resection at our institution between 2001 and 2013 with over 3 months of follow-up postoperatively. All postoperative entries in the medical record were reviewed to identify any ED visit with a neurologic or wound-related complaint within a 90 day postoperative period. The relationships between ED presentation, tumor grade, and extent of surgical resection with future risk of operative recurrence and mortality were analyzed using Fisher's exact test. Variables associated with increased risks of mortality or operative recurrence in a univariate analysis were then included in the multivariate logistic regression model. Patients with a postoperative ED visit were found to be significantly more likely to die during the follow-up period (23.0% versus 4.85%, p<0.0001) or develop an eventual operative recurrence (12.2% versus 3.0%, p=0.0131). Postoperative ED presentation was found to be associated with a higher risk of mortality and operative recurrence independent of pathological tumor grade (p<0.0001 and p=0.0102, respectively). Presentation to the ED is associated with significantly higher rates of future operative recurrence and mortality in patients with recent meningioma resections. This poor prognostic relationship is independent of tumor pathological grade. Increased vigilance and follow-up may be warranted in such patients. PMID- 26585384 TI - Role of preoperative embolization for intradural spinal hemangioblastomas. AB - Spinal hemangioblastomas (HB) are relatively rare neoplasms with a high degree of vascularity. Therapy for symptomatic tumors involves total resection when possible. Due to the enriched blood supply of these neoplasms, there is a high risk of significant intraoperative blood loss, which can lead to perioperative complications. Preoperative embolization of HB has been suggested to reduce blood loss and operative morbidity, but its use remains controversial. Data on the risks and benefits of preoperative embolization for this tumor remains limited. We identified and analyzed all 29 reported cases of preoperative embolization of intradural spinal HB within the literature. There were 18 men and nine women, and patients ranged from 24 to 61 years of age. Mean tumor size was 3.5 cm. Cervical and thoracic location was most common, accounting for 48.3% and 20% of cases, respectively. Complications from embolization and surgery were minimal, with no deaths or permanent neurological morbidity. Minimal intraoperative bleeding and excellent rates of gross total resection were reported with preoperative embolization. However, outcomes from microsurgery alone from historical series have similarly reported excellent outcomes. While there is no established standard, preoperative embolization should be reserved for particularly high risk patients with risk of intraoperative bleeding. PMID- 26585385 TI - Spatially-resolved intracellular sensing of hydrogen peroxide in living cells. AB - Understanding intracellular redox chemistry requires new tools for the site specific visualization of intracellular oxidation. We have developed a spatially resolved intracellular sensor of hydrogen peroxide, HyPer-Tau, for time-resolved imaging in live cells. This sensor consists of a hydrogen peroxide-sensing protein tethered to microtubules. We demonstrate the use of the HyPer-Tau sensor for three applications; dose-dependent response of human cells to exogenous hydrogen peroxide, a model immune response of mouse macrophages to stimulation by bacterial toxin, and a spatially-resolved response to localized delivery of hydrogen peroxide. These results demonstrate that HyPer-Tau can be used as an effective tool for tracking changes in spatially localized intracellular hydrogen peroxide and for future applications in redox signaling. PMID- 26585386 TI - Polyketide Quinones Are Alternate Intermediate Electron Carriers during Mycobacterial Respiration in Oxygen-Deficient Niches. AB - Mycobacterium tuberculosis (Mtb) adaptation to hypoxia is considered crucial to its prolonged latent persistence in humans. Mtb lesions are known to contain physiologically heterogeneous microenvironments that bring about differential responses from bacteria. Here we exploit metabolic variability within biofilm cells to identify alternate respiratory polyketide quinones (PkQs) from both Mycobacterium smegmatis (Msmeg) and Mtb. PkQs are specifically expressed in biofilms and other oxygen-deficient niches to maintain cellular bioenergetics. Under such conditions, these metabolites function as mobile electron carriers in the respiratory electron transport chain. In the absence of PkQs, mycobacteria escape from the hypoxic core of biofilms and prefer oxygen-rich conditions. Unlike the ubiquitous isoprenoid pathway for the biosynthesis of respiratory quinones, PkQs are produced by type III polyketide synthases using fatty acyl-CoA precursors. The biosynthetic pathway is conserved in several other bacterial genomes, and our study reveals a redox-balancing chemicocellular process in microbial physiology. PMID- 26585387 TI - NADP(+)-IDH Mutations Promote Hypersuccinylation that Impairs Mitochondria Respiration and Induces Apoptosis Resistance. AB - Elucidating the tumorigenic mechanism of R-2-hydroxyglutarate (R-2HG) is critical for determining how NADP(+)-IDH mutations cause cancer. Here we report that R-2HG induces cancerous metabolism and apoptosis resistance through promoting hypersuccinylation. By competitive inhibition of the mitochondrial tricarboxylic acid cycle enzyme succinate dehydrogenase (SDH), R-2HG preferentially induced succinyl-CoA accumulation and hypersuccinylation in the mitochondria. IDH1 mutation-bearing glioma samples and cells were hypersuccinylated in the mitochondria. IDH1 mutation or SDH inactivation resulted in hypersuccinylation, causing respiration inhibition and inducing cancerous metabolism and mitochondrial depolarization. These mitochondrial dysfunctions induced BCL-2 accumulation at the mitochondrial membrane, leading to apoptosis resistance of hypersuccinylated cells. Relief of hypersuccinylation by overexpressing the desuccinylase SIRT5 or supplementing glycine rescued mitochondrial dysfunctions, reversed BCL-2 accumulation, and slowed the oncogenic growth of hypersuccinylated IDH1(R132C)-harboring HT1080 cells. Thus, R-2HG-induced hypersuccinylation contributes to the tumorigenicity of NADP(+)-IDH mutations, suggesting the potential of hypersuccinylation inhibition as an intervention for hypersuccinylation-related tumors. PMID- 26585388 TI - A 3' Poly(A) Tract Is Required for LINE-1 Retrotransposition. AB - L1 retrotransposons express proteins (ORF1p and ORF2p) that preferentially mobilize their encoding RNA in cis, but they also can mobilize Alu RNA and, more rarely, cellular mRNAs in trans. Although these RNAs differ in sequence, each ends in a 3' polyadenosine (poly(A)) tract. Here, we replace the L1 polyadenylation signal with sequences derived from a non-polyadenylated long non coding RNA (MALAT1), which can form a stabilizing triple helix at the 3' end of an RNA. L1/MALAT RNAs accumulate in cells, lack poly(A) tails, and are translated; however, they cannot retrotranspose in cis. Remarkably, the addition of a 16 or 40 base poly(A) tract downstream of the L1/MALAT triple helix restores retrotransposition in cis. The presence of a poly(A) tract also allows ORF2p to bind and mobilize RNAs in trans. Thus, a 3' poly(A) tract is critical for the retrotransposition of sequences that comprise approximately one billion base pairs of human DNA. PMID- 26585390 TI - Blast from the Past: Reassessing Forgotten Translation Inhibitors, Antibiotic Selectivity, and Resistance Mechanisms to Aid Drug Development. AB - Protein synthesis is a major target within the bacterial cell for antibiotics. Investigations into ribosome-targeting antibiotics have provided much needed functional and structural insight into their mechanism of action. However, the increasing prevalence of multi-drug-resistant bacteria has limited the utility of our current arsenal of clinically relevant antibiotics, highlighting the need for the development of new classes. Recent structural studies have characterized a number of antibiotics discovered decades ago that have unique chemical scaffolds and/or utilize novel modes of action to interact with the ribosome and inhibit translation. Additionally, structures of eukaryotic cytoplasmic and mitochondrial ribosomes have provided further structural insight into the basis for specificity and toxicity of antibiotics. Together with our increased understanding of bacterial resistance mechanisms, revisiting our treasure trove of "forgotten" antibiotics could pave the way for the next generation of antimicrobial agents. PMID- 26585389 TI - Retrotransposition and Crystal Structure of an Alu RNP in the Ribosome-Stalling Conformation. AB - The Alu element is the most successful human genomic parasite affecting development and causing disease. It originated as a retrotransposon during early primate evolution of the gene encoding the signal recognition particle (SRP) RNA. We defined a minimal Alu RNA sufficient for effective retrotransposition and determined a high-resolution structure of its complex with the SRP9/14 proteins. The RNA adopts a compact, closed conformation that matches the envelope of the SRP Alu domain in the ribosomal translation elongation factor-binding site. Conserved structural elements in SRP RNAs support an ancient function of the closed conformation that predates SRP9/14. Structure-based mutagenesis shows that retrotransposition requires the closed conformation of the Alu ribonucleoprotein particle and is consistent with the recognition of stalled ribosomes. We propose that ribosome stalling is a common cause for the cis-preference of the mammalian L1 retrotransposon and for the efficiency of the Alu RNA in hijacking nascent L1 reverse transcriptase. PMID- 26585391 TI - The role of vitamin E or clay in growing Japanese quail fed diets polluted by cadmium at various levels. AB - This study was conducted to verify whether vitamin (Vit) E or natural clay as feed additives has the potential to modulate the deleterious effects resulting from exposure to cadmium (Cd) in growing Japanese quail. 648 Japanese quail chicks (1 week old) were used to evaluate the effects of dietary Cd (0, 40, 80 and 120 mg/kg diet) and two levels of Vit E (0, 250 mg/kg diet) or two levels of natural clay (0 and 100 mg/kg diet) to study the influences of Cd, Vit E, clay or their different combinations on growth performance, carcass traits, some blood biochemical components and Cd residues in muscles and liver. Live BW and weight gain of quails were linearly decreased with increasing dietary Cd levels. Moreover, feed conversion was significantly worsened with increasing Cd level. Mortality percentage was linearly increased as dietary Cd level increased up to 120 mg/kg diet. Carcass percentage was linearly decreased as dietary Cd level increased. While, giblets percentage were linearly and quadratically differed as dietary Cd level increased. Cd caused significant changes in total plasma protein, albumin, globulin, A/G ratio, creatinine, urea-N and uric acid concentrations as well as ALT, AST and ALP activities. Increasing dietary Cd level was associated with its increase in the muscles and liver. Dietary supplementation with 250 mg of Vit E/kg diet or 100 mg clay/kg improved live BW, BW gain and feed conversion when compared with the un-supplemented diet. Quails fed diet contained 250 mg Vit E/kg and those fed 100 mg clay/kg had the highest percentages of carcass and dressing than those fed the un-supplemented diet. Blood plasma biochemical components studied were better when birds received 250 mg of Vit E/kg diet and those received 100 mg clay/kg. Cd residues in the muscles and liver were significantly less in the birds had 250 mg of Vit E/kg or those received 100 mg clay/kg diet than those un-supplemented with Vit E. Growth performance traits and blood plasma biochemical components studied were significantly affected linearly by the interactions among Cd and each of Vit E and clay levels. In conclusion, the present results indicate that the deleterious effects induced by Cd plays a role in decreasing the performance of Japanese quail and that dietary supplementation with natural clay or Vit E may be useful in partly alleviating the adverse effects of Cd. PMID- 26585392 TI - Impact of Bilingualism on Cognitive Outcome After Stroke. AB - BACKGROUND AND PURPOSE: Bilingualism has been associated with slower cognitive aging and a later onset of dementia. In this study, we aimed to determine whether bilingualism also influences cognitive outcome after stroke. METHODS: We examined 608 patients with ischemic stroke from a large stroke registry and studied the role of bilingualism in predicting poststroke cognitive impairment in the absence of dementia. RESULTS: A larger proportion of bilinguals had normal cognition compared with monolinguals (40.5% versus 19.6%; P<0.0001), whereas the reverse was noted in patients with cognitive impairment, including vascular dementia and vascular mild cognitive impairment (monolinguals 77.7% versus bilinguals 49.0%; P<0.0009). There were no differences in the frequency of aphasia (monolinguals 11.8% versus bilinguals 10.5%; P=0.354). Bilingualism was found to be an independent predictor of poststroke cognitive impairment. CONCLUSIONS: Our results suggest that bilingualism leads to a better cognitive outcome after stroke, possibly by enhancing cognitive reserve. PMID- 26585393 TI - Problem-Solving Therapy During Outpatient Stroke Rehabilitation Improves Coping and Health-Related Quality of Life: Randomized Controlled Trial. AB - BACKGROUND AND PURPOSE: This study investigated whether problem-solving therapy (PST) is an effective group intervention for improving coping strategy and health related quality of life (HRQoL) in patients with stroke. METHODS: In this multicenter randomized controlled trial, the intervention group received PST as add-on to standard outpatient rehabilitation, the control group received outpatient rehabilitation only. Measurements were performed at baseline, directly after the intervention, and 6 and 12 months later. Data were analyzed using linear-mixed models. Primary outcomes were task-oriented coping as measured by the Coping Inventory for Stressful Situations and psychosocial HRQoL as measured by the Stroke-Specific Quality of Life Scale. Secondary outcomes were the EuroQol EQ-5D-5L utility score, emotion-oriented and avoidant coping as measured by the Coping Inventory for Stressful Situations, problem-solving skills as measured by the Social Problem Solving Inventory-Revised, and depression as measured by the Center for Epidemiological Studies Depression Scale. RESULTS: Included were 166 patients with stroke, mean age 53.06 years (SD, 10.19), 53% men, median time poststroke 7.29 months (interquartile range, 4.90-10.61 months). Six months post intervention, the PST group showed significant improvement when compared with the control group in task-oriented coping (P=0.008), but not stroke-specific psychosocial HRQoL. Furthermore, avoidant coping (P=0.039) and the utility value for general HRQoL (P=0.034) improved more in the PST group than in the control after 6 months. CONCLUSIONS: PST seems to improve task-oriented coping but not disease-specific psychosocial HRQoL after stroke >6-month follow-up. Furthermore, we found indications that PST may improve generic HRQoL recovery and avoidant coping. CLINICAL TRIAL REGISTRATION: URL: http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2509. Unique identifier: CNTR2509. PMID- 26585394 TI - Reperfusion Beyond 6 Hours Reduces Infarct Probability in Moderately Ischemic Brain Tissue. AB - BACKGROUND AND PURPOSE: We aimed to examine perfusion changes between 3 and 6 and 6 and 24 hours after stroke onset and their impact on tissue outcome. METHODS: Acute ischemic stroke patients underwent perfusion magnetic resonance imaging at 3, 6, and 24 hours after stroke onset and follow-up fluid-attenuated inversion recovery at 1 month to assess tissue fate. Mean transit time prolongation maps (MTTp=MTT-[median MTT of contralateral hemisphere]) were obtained at 3 (MTTp3 h), 6 (MTTp6 h), and 24 hours (MTTp24 h). Perfusion changes between 3 and 6 hours (DeltaMTTp3_6) and 6 and 24 hours (DeltaMTTp6_24) were calculated. A 2-step analysis was performed to evaluate the impact of DeltaMTTp3_6 and DeltaMTTp6_24 on tissue fate. First, a voxel-based multivariable logistic regression was performed for each individual patient with MTTp3 h, DeltaMTTp3_6, and DeltaMTT6_24 as independent variables and tissue fate as outcome. Second, Wilcoxon signed-rank tests on logistic regression coefficients were performed across patients to evaluate whether DeltaMTTp3_6 and DeltaMTT6_24 had significant impact on tissue fate for varying severities of baseline perfusion. RESULTS: Perfusion change was common during both time periods: 85% and 81% of patients had perfusion improvement during 3- to 6- and 6- and 24-hour time intervals, respectively. DeltaMTT3_6 significantly influenced 1-month infarct probability across a wide range of baseline perfusion (MTTp 0-15 s). DeltaMTT6_24 also impacted 1-month infarct probability, but its influence was restricted to tissue with milder baseline ischemia (MTTp 0-10 s). CONCLUSIONS: Brain tissue with mild to moderate ischemia can be salvaged by reperfusion even after 6 hours. Such tissue could be targeted for intervention beyond current treatment windows. PMID- 26585395 TI - Rates, Predictors, and Outcomes of Early and Late Recurrence After Stroke: The North Dublin Population Stroke Study. AB - BACKGROUND AND PURPOSE: Few recent studies have investigated the rates and predictors of early and late stroke recurrence using prospective population-based methodology. We investigated recurrent stroke at 2 years in the North Dublin Population Stroke Study (NDPSS). METHODS: Patients were ascertained from December 2005 to 2006 from overlapping community and hospital sources using hot and cold pursuit. Stroke recurrence, survival, and functional outcome were ascertained at 72 hours, 7 days, 28 days, 90 days, 1 year, and 2 years. RESULTS: Of 567 patients, cumulative 2-year stroke recurrence rate was 10.8% and case fatality was 38.6%. Recurrence subtype was associated with initial stroke subtype (P<0.001). On multivariable Cox regression, hyperlipidemia (adjusted hazard ratio, 3.32; P=0.005) and prior stroke (adjusted hazard ratio, 2.92; P=0.01) were independent predictors of 2-year recurrence in 28-day survivors. CONCLUSIONS: Despite rigorous ascertainment, recurrent stroke rates were lower in current study than in earlier studies. Our data suggest that large sample sizes may be needed for future secondary prevention trials in patients treated with modern preventive medications. PMID- 26585396 TI - Stroke Location Is an Independent Predictor of Cognitive Outcome. AB - BACKGROUND AND PURPOSE: On top of functional outcome, accurate prediction of cognitive outcome for stroke patients is an unmet need with major implications for clinical management. We investigated whether stroke location may contribute independent prognostic value to multifactorial predictive models of functional and cognitive outcomes. METHODS: Four hundred twenty-eight consecutive patients with ischemic stroke were prospectively assessed with magnetic resonance imaging at 24 to 72 hours and at 3 months for functional outcome using the modified Rankin Scale and cognitive outcome using the Montreal Cognitive Assessment (MoCA). Statistical maps of functional and cognitive eloquent regions were derived from the first 215 patients (development sample) using voxel-based lesion symptom mapping. We used multivariate logistic regression models to study the influence of stroke location (number of eloquent voxels from voxel-based lesion symptom mapping maps), age, initial National Institutes of Health Stroke Scale and stroke volume on modified Rankin Scale and MoCA. The second part of our cohort was used as an independent replication sample. RESULTS: In univariate analyses, stroke location, age, initial National Institutes of Health Stroke Scale, and stroke volume were all predictive of poor modified Rankin Scale and MoCA. In multivariable analyses, stroke location remained the strongest independent predictor of MoCA and significantly improved the prediction compared with using only age, initial National Institutes of Health Stroke Scale, and stroke volume (area under the curve increased from 0.697-0.771; difference=0.073; 95% confidence interval, 0.008-0.155). In contrast, stroke location did not persist as independent predictor of modified Rankin Scale that was mainly driven by initial National Institutes of Health Stroke Scale (area under the curve going from 0.840 to 0.835). Similar results were obtained in the replication sample. CONCLUSIONS: Stroke location is an independent predictor of cognitive outcome (MoCA) at 3 months post stroke. PMID- 26585397 TI - Comparison of Clinical Outcomes Following Single versus Multivessel Percutaneous Coronary Intervention Using Biodegradable Polymer Coated Sirolimus-Eluting Stent in an All-comers Patient Population. AB - BACKGROUND: Drug-eluting stents (DES) have been shown to reduce the rate of acute complications and the need for subsequent revascularization in cases where single vessels are treated. The performance of DES in patients with multivessel disease and complex lesions, however, remains controversial. This study assessed and compared clinical outcomes following single vs. multivessel percutaneous coronary intervention (PCI), using the Supraflex sirolimus-eluting stent (SES), in an all comers patient population. METHODS: We conducted retrospective, multicenter, all comers, observational study of 995 patients, who underwent either single-vessel PCI (n=769 patients; group-I) or multivessel PCI (n=226 patients; group-II), treated with the biodegradable polymer coated Supraflex SES, between July-2013 and May-2014 at nine different centers in India. Pre-specified primary endpoint, rate of major adverse cardiac events (MACE) [defined as composite of cardiac death, myocardial infarction (MI), target lesion revascularization (TLR) and non target lesion target vessel revascularization (non-TL TVR)], was analyzed during 12 months after the post-index procedure. We also analyzed the incidence of stent thrombosis (ST) as a safety endpoint during the follow-up period, as defined by the Academic Research Consortium (ARC). RESULTS: Of the whole study group, 1,242 lesions were treated in 995 patients (mean age 61.6+/-10.8 years; 80.0% male) with average stent length of 26.8+/-9.3 mm. Multivessel PCI patients were older, had a higher prevalence of arterial hypertension, were smoker, had a family history of coronary artery disease, previous stroke and previous PCI compared to single-vessel PCI patients. Follow-up was available in 99.0% (761/769) of patients with single-vessel intervention and 96.9% (219/226) of patients with multivessel intervention at the end of 12 months. In-hospital MACE was similar for both the groups [group-I, 3 (0.4%) vs. group-II, 1 (0.4%); p=1.000]. The observed MACE for group-I and group-II, at 30 days, 6 and 12 months follow-up were 9 (1.2%) vs. 2 (0.9%); p=1.000, 15 (2.0%) vs. 7 (3.2%); p=0.302 and 24 (3.2%) vs. 12 (5.5%); p=0.109, respectively. The cumulative incidence curves for MACE showed no significant differences between the two groups, at the end of 12 months (p=0.109). CONCLUSION: Our study shows that use of the Supraflex SES in single and multivessel coronary artery disease produces good clinical outcomes during 12 months of follow-up with a low rate of revascularization, despite complex lesion morphology. PMID- 26585399 TI - Solution Structure of Enterocin HF, an Antilisterial Bacteriocin Produced by Enterococcus faecium M3K31. AB - The solution structure of enterocin HF (EntHF), a class IIa bacteriocin of 43 amino acids produced by Enterococcus faecium M3K31, was evaluated by CD and NMR spectroscopy. Purified EntHF was unstructured in water, but CD analysis supports that EntHF adopts an alpha-helical conformation when exposed to increasing concentrations of trifluoroethanol. Furthermore, NMR spectroscopy indicates that this bacteriocin adopts an antiparallel beta-sheet structure in the N-terminal region (residues 1-17), followed by a well-defined central alpha-helix (residues 19-30) and a more disordered C-terminal end (residues 31-43). EntHF could be structurally organized into three flexible regions that might act in a coordinated manner. This is in agreement with the absence of long-range nuclear Overhauser effect signals between the beta-sheet domain and the C-terminal end of the bacteriocin. The 3D structure recorded for EntHF fits emerging facts regarding target recognition and mode of action of class IIa bacteriocins. PMID- 26585398 TI - Use of medication for cardiovascular disease during pregnancy. AB - One-third of women with heart disease use medication for the treatment of cardiovascular disease (CVD) during pregnancy. Increased plasma volume, renal clearance, and liver enzyme activity in pregnant women change the pharmacokinetics of these drugs, often resulting in the need for an increased dose. Fetal well-being is a major concern among pregnant women. Fortunately, many drugs used to treat CVD can be used safely during pregnancy, with the exception of high-dose warfarin in the first trimester, angiotensin-converting-enzyme inhibitors, angiotensin-receptor blockers, amiodarone, and spironolactone. A timely and thorough discussion between the cardiologist and the pregnant patient about the potential benefits and adverse effects of medication for CVD is important. Noncompliance with necessary treatment for cardiovascular disorders endangers not only the mother, but also the fetus. This Review is an overview of the pharmacokinetic changes in medications for CVD during pregnancy and the safety of these drugs for the fetus. The implications for maternal treatment are discussed. The Review also includes a short section on the cardiovascular effects of medication used for obstetric indications. PMID- 26585401 TI - The Type 2 dUTPase of Bacteriophage phiNM1 Initiates Mobilization of Staphylococcus aureus Bovine Pathogenicity Island 1. AB - Staphylococcus aureus pathogenicity islands (SaPIs) are genetic elements that are mobilized by specific helper phages. The initial step in mobilization is the derepression of the SaPI by the interaction of a phage protein with the SaPI master repressor Stl. Stl proteins are highly divergent between different SaPIs and respond to different phage-encoded derepressors. One such SaPI, SaPIbov1, is derepressed by the dUTPase (Dut) of bacteriophage 80alpha (Dut80alpha) and its phage phi11 homolog, Dut11. We previously showed that SaPIbov1 could also be mobilized by phage phiNM1, even though its dut gene is not homologous with that of 80alpha. Here, we show that phiNM1 dut encodes a type 2 dUTPase (DutNM1), which has an alpha-helical structure that is distinct from the type 1 trimeric, beta-sheet structure of Dut80alpha. Deletion of dutNM1 abolishes the ability of phiNM1 to mobilize SaPIbov1. Like Dut80alpha, DutNM1 forms a direct interaction with SaPIbov1 Stl both in vivo and in vitro, leading to inhibition of the dUTPase activity and Stl release from its target DNA. This work provides novel insights into the diverse mechanisms of genetic mobilization in S. aureus. PMID- 26585400 TI - Mist1 Expressing Gastric Stem Cells Maintain the Normal and Neoplastic Gastric Epithelium and Are Supported by a Perivascular Stem Cell Niche. AB - The regulation and stem cell origin of normal and neoplastic gastric glands are uncertain. Here, we show that Mist1 expression marks quiescent stem cells in the gastric corpus isthmus. Mist1(+) stem cells serve as a cell-of-origin for intestinal-type cancer with the combination of Kras and Apc mutation and for diffuse-type cancer with the loss of E-cadherin. Diffuse-type cancer development is dependent on inflammation mediated by Cxcl12(+) endothelial cells and Cxcr4(+) gastric innate lymphoid cells (ILCs). These cells form the perivascular gastric stem cell niche, and Wnt5a produced from ILCs activates RhoA to inhibit anoikis in the E-cadherin-depleted cells. Targeting Cxcr4, ILCs, or Wnt5a inhibits diffuse-type gastric carcinogenesis, providing targets within the neoplastic gastric stem cell niche. PMID- 26585402 TI - Large-Scale Analysis Exploring Evolution of Catalytic Machineries and Mechanisms in Enzyme Superfamilies. AB - Enzymes, as biological catalysts, form the basis of all forms of life. How these proteins have evolved their functions remains a fundamental question in biology. Over 100 years of detailed biochemistry studies, combined with the large volumes of sequence and protein structural data now available, means that we are able to perform large-scale analyses to address this question. Using a range of computational tools and resources, we have compiled information on all experimentally annotated changes in enzyme function within 379 structurally defined protein domain superfamilies, linking the changes observed in functions during evolution to changes in reaction chemistry. Many superfamilies show changes in function at some level, although one function often dominates one superfamily. We use quantitative measures of changes in reaction chemistry to reveal the various types of chemical changes occurring during evolution and to exemplify these by detailed examples. Additionally, we use structural information of the enzymes active site to examine how different superfamilies have changed their catalytic machinery during evolution. Some superfamilies have changed the reactions they perform without changing catalytic machinery. In others, large changes of enzyme function, in terms of both overall chemistry and substrate specificity, have been brought about by significant changes in catalytic machinery. Interestingly, in some superfamilies, relatives perform similar functions but with different catalytic machineries. This analysis highlights characteristics of functional evolution across a wide range of superfamilies, providing insights that will be useful in predicting the function of uncharacterised sequences and the design of new synthetic enzymes. PMID- 26585403 TI - HER2 Transmembrane Domain Dimerization Coupled with Self-Association of Membrane Embedded Cytoplasmic Juxtamembrane Regions. AB - Receptor tyrosine kinases of the human epidermal growth factor receptor (HER or ErbB) family transduce biochemical signals across plasma membrane, playing a significant role in vital cellular processes and in various cancers. Inactive HER/ErbB receptors exist in equilibrium between the monomeric and unspecified pre dimerized states. After ligand binding, the receptors are involved in strong lateral dimerization with proper assembly of their extracellular ligand-binding, single-span transmembrane, and cytoplasmic kinase domains. The dimeric conformation of the HER2 transmembrane domain that is believed to support the cytoplasmic kinase domain configuration corresponding to the receptor active state was previously described in lipid bicelles. Here we used high-resolution NMR spectroscopy in another membrane-mimicking micellar environment and identified an alternative HER2 transmembrane domain dimerization coupled with self-association of membrane-embedded cytoplasmic juxtamembrane region. Such a dimerization mode appears to be capable of effectively inhibiting the receptor kinase activity. This finding refines the molecular mechanism regarding the signal propagation steps from the extracellular to cytoplasmic domains of HER/ErbB receptors. PMID- 26585405 TI - Structural Change in the Dynein Stalk Region Associated with Two Different Affinities for the Microtubule. AB - Dynein is a large microtubule-based motor complex that requires tight coupling of intra-molecular ATP hydrolysis with the generation of mechanical force and track binding activity. However, the microtubule-binding domain is structurally separated by about 15nm from the nucleotide-binding sites by a coiled-coil stalk. Thus, long-range two-way communication is necessary for coordination between the catalytic cycle of ATP hydrolysis and dynein's track-binding affinities. To investigate the structural changes that occur in the dynein stalk region to produce two different microtubule affinities, here we improve the resolution limit of the previously reported structure of the entire stalk region and we investigate structural changes in the dynein stalk and strut/buttress regions by comparing currently available X-ray structures. In the light of recent crystal structures, the basis of the transition from the low-affinity to the high affinity coiled-coil registry is discussed. A concerted movement model previously reported by Carter and Vale is modified more specifically, and we proposed it as the open zipper model. PMID- 26585404 TI - Progress and Current Challenges in Modeling Large RNAs. AB - Recent breakthroughs in next-generation sequencing technologies have led to the discovery of several classes of non-coding RNAs (ncRNAs). It is now apparent that RNA molecules are not only just carriers of genetic information but also key players in many cellular processes. While there has been a rapid increase in the number of ncRNA sequences deposited in various databases over the past decade, the biological functions of these ncRNAs are largely not well understood. Similar to proteins, RNA molecules carry out a function by forming specific three dimensional structures. Understanding the function of a particular RNA therefore requires a detailed knowledge of its structure. However, determining experimental structures of RNA is extremely challenging. In fact, RNA-only structures represent just 1% of the total structures deposited in the PDB. Thus, computational methods that predict three-dimensional RNA structures are in high demand. Computational models can provide valuable insights into structure function relationships in ncRNAs and can aid in the development of functional hypotheses and experimental designs. In recent years, a set of diverse RNA structure prediction tools have become available, which differ in computational time, input data and accuracy. This review discusses the recent progress and challenges in RNA structure prediction methods. PMID- 26585406 TI - BlastKOALA and GhostKOALA: KEGG Tools for Functional Characterization of Genome and Metagenome Sequences. AB - BlastKOALA and GhostKOALA are automatic annotation servers for genome and metagenome sequences, which perform KO (KEGG Orthology) assignments to characterize individual gene functions and reconstruct KEGG pathways, BRITE hierarchies and KEGG modules to infer high-level functions of the organism or the ecosystem. Both servers are made freely available at the KEGG Web site (http://www.kegg.jp/blastkoala/). In BlastKOALA, the KO assignment is performed by a modified version of the internally used KOALA algorithm after the BLAST search against a non-redundant dataset of pangenome sequences at the species, genus or family level, which is generated from the KEGG GENES database by retaining the KO content of each taxonomic category. In GhostKOALA, which utilizes more rapid GHOSTX for database search and is suitable for metagenome annotation, the pangenome dataset is supplemented with Cd-hit clusters including those for viral genes. The result files may be downloaded and manipulated for further KEGG Mapper analysis, such as comparative pathway analysis using multiple BlastKOALA results. PMID- 26585407 TI - Resting heart rate associates with one-year risk of major adverse cardiovascular events in patients with acute coronary syndrome after percutaneous coronary intervention. AB - The study was to access the association between resting heart rate (RHR) and one year risk of major adverse cardiovascular events (MACE) in acute coronary syndrome (ACS) patients after percutaneous coronary intervention (PCI). Patients with ACS after PCI (n = 808) were prospectively followed-up for MACE. RHR was obtained from electrocardiogram. MACE was defined as a composite of cardiac death, nonfatal recurrent myocardial infarction, ischemic-driven revascularization, and ischemic stroke. The association between RHR and one-year risk of MACE was assessed using Cox proportional hazards regression model. Compared with patients with RHR >76 bpm, the adjusted hazard ratio (AHR) was 0.51 (95% confidence intervals [CI]: 0.23-1.14; P = 0.100) for patients with RHR < 61 bpm, and 0.44 (95%CI: 0.23-0.85; P = 0.014) for those with RHR 61-76 bpm. For patients with RHR >= 61 bpm, an increase of 10 bpm in RHR was associated with an increase by 38.0% in the risk of MACE (AHR: 1.38; 95% CI: 1.04-1.83; P = 0.026). ACS patients after PCI with RHR >76 bpm were at higher risk of MACE during one year follow-up compared with patients with RHR 61-76 bpm. An elevated RHR >= 61 bpm was associated with increased risk of one-year MACE in ACS patients. PMID- 26585408 TI - Association between Serum TNF-alpha Levels and Recurrent Spontaneous Miscarriage: A Meta-analysis. AB - Most recurrent spontaneous miscarriages (RSMs) are attributed to 'unexplained' factors, the majority of which are immune factors. Furthermore, clinically, only a small number of RSM patients get early diagnosis by testing for antiphospholipid antibodies, whereas most of the patients, present no specific diagnostic indicators. We performed a meta-analysis of observational studies to detect the association between RSM and TNF-alpha levels. We searched PubMed, EMBase, ScienceDirect, Web of Science, and Chinese databases (including: Wanfang Data, CNKI, and VIP databases) for articles published up to 2014. Of the 151 initially identified studies, 11 case-control studies with 1371 patients were finally analyzed. Overall, baseline TNF-alpha levels were higher in patients than in controls. The standardized mean difference of the TNF-alpha levels of the patients was 2.82 units (95% confidence interval 1.57-4.06) and the overall effect z-score was 4.42 (P < 0.0001). The heterogeneity test revealed significant differences among individual studies (P = 0.000, I(2) = 98.7%). Serum TNF-alpha levels were significantly increased in patients relative to those in controls. The heterogeneity could be attributed to the differences in the detection methods and sampling times used in the different studies. PMID- 26585409 TI - Impact of Antipsychotic Review and Nonpharmacological Intervention on Antipsychotic Use, Neuropsychiatric Symptoms, and Mortality in People With Dementia Living in Nursing Homes: A Factorial Cluster-Randomized Controlled Trial by the Well-Being and Health for People With Dementia (WHELD) Program. AB - OBJECTIVE: This study evaluated the impact of antipsychotic review, social interaction, and exercise, in conjunction with person-centered care, on antipsychotic use, agitation, and depression in people with dementia living in nursing homes. METHOD: A cluster-randomized factorial controlled trial with two replications was conducted in people with dementia in 16 U.K. nursing homes. All homes received training in person-centered care. Eight homes were randomly assigned to antipsychotic review, to a social interaction intervention, and to an exercise intervention for 9 months, with most homes assigned to more than one intervention. The primary outcome measures were antipsychotic use, agitation, and depression. Secondary outcome measures were overall neuropsychiatric symptoms and mortality. RESULTS: Antipsychotic review significantly reduced antipsychotic use by 50% (odds ratio 0.17, 95% confidence interval [CI] 0.05 to 0.60). Antipsychotic review plus the social interaction intervention significantly reduced mortality (odds ratio 0.26, 95% CI 0.13 to 0.51) compared with the group receiving neither. The group receiving antipsychotic review but not the social intervention showed significantly worse outcome in neuropsychiatric symptoms compared with the group receiving neither (score difference +7.37, 95% CI 1.53 to 13.22). This detrimental impact was mitigated by concurrent delivery of the social intervention (-0.44, CI -4.39 to 3.52). The exercise intervention significantly improved neuropsychiatric symptoms (-3.59, 95% CI -7.08 to -0.09) but not depression (-1.21, CI -4.35 to 1.93). None of the interventions had a significant impact specifically on agitation. CONCLUSIONS: While reductions in antipsychotic use can be achieved by using a "real world" intervention, this may not be of benefit to people with dementia in the current climate of more judicious prescribing unless nonpharmacological interventions such as social interaction or exercise are provided in parallel. PMID- 26585410 TI - Dexmedetomidine Inhibits TLR4/NF-kappaB Activation and Reduces Acute Kidney Injury after Orthotopic Autologous Liver Transplantation in Rats. AB - Patients who undergo orthotopic liver transplantation often sustain acute kidney injury(AKI). The toll-like receptor 4(TLR4)/Nuclear factor-kB(NF-kB) pathway plays a role in AKI. Dexmedetomidine(Dex) has been shown to attenuate AKI. The current study aimed to determine whether liver transplantation-induced AKI is associated with inflammatory response, and to assess the effects of dexmedetomidine pretreatment on kidneys in rats following orthotopic autologous liver transplantation(OALT). Seventy-seven adult male rats were randomized into 11 groups. Kidney tissue histopathology and levels of blood urea nitrogen(BUN) and serum creatinine(SCr) were evaluated. Levels of TLR4, NF-kappaB, tumor necrosis factor-alpha, and interleukin-1beta levels were measured in kidney tissues. OALT resulted in significant kidney functional impairment and tissue injury. Pre-treatment with dexmedetomidine decreased BUN and SCr levels and reduced kidney pathological injury, TLR4 expression, translocation of NF-kappaB, and cytokine production. The effects of dexmedetomidine were reversed by pre treatment with atipamezole and BRL44408, but not ARC239. These results were confirmed by using alpha2A-adrenergic receptor siRNA which reversed the protective effect of dexmedetomidine on attenuating NRK-52E cells injury induced by hypoxia reoxygenation. In conclusion, Dexmedetomidine-pretreatment attenuates OALT-induced AKI in rats which may be contributable to its inhibition of TLR4/MyD88/NF-kappaB pathway activation. The renoprotective effects are related to alpha2A-adrenergic receptor subtypes. PMID- 26585411 TI - Quizartinib elicits differential responses that correlate with karyotype and genotype of the leukemic clone. PMID- 26585412 TI - Ofatumumab in relapsed nodular lymphocyte-predominant Hodgkin lymphoma: results of a phase II study from the German Hodgkin study group. PMID- 26585413 TI - The non-genomic effects of endocrine-disrupting chemicals on mammalian sperm. AB - Exposure to toxicants present in the environment, especially the so-called endocrine-disrupting chemicals (EDCs), has been associated with decreased sperm quality and increased anomalies in male reproductive organs over the past decades. Both human and animal populations are continuously exposed to ubiquitous synthetic and natural-occurring EDCs through diet, dermal contact and/or inhalation, therefore potentially compromising male reproductive health. Although the effects of EDC are likely induced via multiple genomic-based pathways, their non-genomic effects may also be relevant. Furthermore, spermatozoa are transcriptionally inactive cells that can come in direct contact with EDCs in reproductive fluids and secretions and are therefore a good model to address non genomic effects. This review thus focuses on the non-genomic effects of several important EDCs relevant to mammalian exposure. Notably, EDCs were found to interfere with pre-existing pathways inducing a panoply of deleterious effects to sperm function that included altered intracellular Ca(2) (+) oscillations, induction of oxidative stress, mitochondrial dysfunction, increased DNA damage and decreased sperm motility and viability, among others, potentially jeopardizing male fertility. Although many studies have used non-environmentally relevant concentrations of only one compound for mechanistic studies, it is important to remember that mammals are not exposed to one, but rather to a multitude of environmental EDCs, and synergistic effects may occur. Furthermore, some effects have been detected with single compounds at environmentally relevant concentrations. PMID- 26585414 TI - Interdependency between mechanical parameters and afferent nerve discharge in hypertrophic intestine of rats. AB - Partial intestinal obstruction causes smooth muscle hypertrophy, enteric neuronal plasticity, motility disorders, and biomechanical remodeling. In this study we characterized the stimulus-response function of afferent fibers innervating the partially obstructed jejunum. A key question is whether changes in afferent firing arise from remodeled mechanical tissue properties or from adaptive afferent processes. Partial obstruction was created by placing a polyethylene ring for 2 wk in jejunum of seven rats. Sham obstruction was made in six rats and seven rats served as normal controls. Firing from mesenteric afferent nerve bundles was recorded during mechanical ramp, relaxation, and creep tests. Stress strain, spike rate increase ratio (SRIR), and firing rate in single units were assessed for evaluation of interdependency of the mechanical stimulations, histomorphometry data, and afferent nerve discharge. Partial intestinal obstruction resulted in hypertrophy and jejunal stiffening proximal to the obstruction site. Low SRIR at low strains during fast distension and at high stresses during slow distension was found in the obstructed rats. Single unit analysis showed increased proportion of mechanosensitive units but absent high threshold (HT) units during slow stimulation, decreased number of HT units during fast stimulation, and shift from HT sensitivity towards low threshold sensitivity in the obstructed jejunum. Biomechanical remodeling and altered afferent response to mechanical stimulations were found in the obstructed jejunum. Afferents from obstructed jejunum preserved their function in encoding ongoing mechanical stimulation but showed changes in their responsiveness. The findings support that mechanical factors rather than adaption are important for afferent remodeling. PMID- 26585416 TI - Effect of N-glycosylation on the transport activity of the peptide transporter PEPT1. AB - The intestinal peptide transporter PEPT1 provides bulk quantities of amino acids to epithelial cells. PEPT1 is a high-capacity and low-affinity solute carrier of the SLC15 family found in apical membranes of enterocytes in small intestine and distal colon. Surprisingly, murine PEPT1 (mPEPT1) has an apparent molecular mass of ~95 kDa in the small intestine but ~105 kDa in the large intestine. Here we describe studies on mPEPT1 protein glycosylation and how glycans affect transport function. Putative N-glycosylation sites of mPEPT1 were altered by site-directed mutagenesis followed by expression in Xenopus laevis oocytes. Replacement of six asparagine residues (N) at positions N50, N406, N439, N510, N515, and N532 by glutamine (Q) resulted in a decrease of the mPEPT1 mass by around 35 kDa. Electrophysiology revealed all glycosylation-deficient transporters to be functional with comparable expression levels in oocyte membranes. Strikingly, the mutant protein with N50Q exhibited a twofold decreased affinity for Gly-Sar but a 2.5-fold rise in the maximal inward currents compared with the wild-type protein. Elevated maximal transport currents were also recorded for cefadroxil and tri-l alanine. Tracer flux studies performed with [(14)C]-Gly-Sar confirmed the reduction in substrate affinity and showed twofold increased maximal transport rates for the N50Q transporter. Elimination of individual N-glycosylation sites did not alter membrane expression in oocytes or overall transport characteristics except for the mutant protein N50Q. Because transporter surface density was not altered in N50Q, removal of the glycan at this location appears to accelerate the substrate turnover rate. PMID- 26585415 TI - Defect of mitochondrial respiratory chain is a mechanism of ROS overproduction in a rat model of alcoholic liver disease: role of zinc deficiency. AB - Morphological and functional alterations of hepatic mitochondria have been documented in patients with alcoholic liver disease (ALD). Our recent study demonstrated that zinc level was decreased in whole liver and mitochondria by chronic alcohol feeding. The present study was undertaken to determine whether zinc deficiency mediates alcohol-induced mitochondrial electron transport chain (ETC) defect and whether defective ETC function may lead to generation of reactive oxygen species (ROS). Male Wistar rats were pair fed with the Lieber DeCarli control or ethanol diet for 5 mo. Chronic alcohol exposure increased hepatic triglyceride, free fatty acid, and 4-hydroxynonenal (4HNE) levels; meanwhile hepatic mitochondrial 4HNE level was also increased. Moreover, hepatic mitochondrial respiratory complexes I, III, IV, and V and hepatic ATP production were decreased by chronic alcohol exposure. Chronic alcohol feeding decreased peroxisome proliferator-activated receptor gamma coactivator-1-alpha (PGC1alpha), nuclear respiratory factor 1 (NRF1), mitochondrial transcription factor A (TFAM), and mitochondrial DNA. HepG2 cells were treated with N,N,N',N'-tetrakis (2 pyridylmethyl) ethylenediamine (TPEN) for 6 h. Zinc deficiency significantly decreased mitochondrial respiratory complexes I, III, and IV. In addition, PGC1alpha, NRF1, and TFAM levels as well as mitochondrial DNA were significantly decreased by TPEN treatment. Knockdown of mitochondrial respiratory complexes I, III, or IV by shRNA caused a decrease in mitochondrial membrane potential and an increase in ROS production. These results suggest that alcohol-induced hepatic zinc deficiency could inactivate mitochondrial biogenesis pathway and decrease mitochondrial DNA replication, which, in turn, decreases mitochondrial complex protein expression. The defect of mitochondrial respiratory complexes may worsen alcohol-induced ROS production. PMID- 26585417 TI - The old knee in the young athlete: knowns and unknowns in the return to play conversation. PMID- 26585418 TI - A comparison of reconstruction methods for undersampled atomic force microscopy images. AB - Non-raster scanning and undersampling of atomic force microscopy (AFM) images is a technique for improving imaging rate and reducing the amount of tip-sample interaction needed to produce an image. Generation of the final image can be done using a variety of image processing techniques based on interpolation or optimization. The choice of reconstruction method has a large impact on the quality of the recovered image and the proper choice depends on the sample under study. In this work we compare interpolation through the use of inpainting algorithms with reconstruction based on optimization through the use of the basis pursuit algorithm commonly used for signal recovery in compressive sensing. Using four different sampling patterns found in non-raster AFM, namely row subsampling, spiral scanning, Lissajous scanning, and random scanning, we subsample data from existing images and compare reconstruction performance against the original image. The results illustrate that inpainting generally produces superior results when the image contains primarily low frequency content while basis pursuit is better when the images have mixed, but sparse, frequency content. Using support vector machines, we then classify images based on their frequency content and sparsity and, from this classification, develop a fast decision strategy to select a reconstruction algorithm to be used on subsampled data. The performance of the classification and decision test are demonstrated on test AFM images. PMID- 26585420 TI - Levothyroxine liquid solution versus tablet form for replacement treatment in pregnant women. AB - OBJECTIVE: To evaluate the need and the magnitude of levothyroxine (LT4) increase in hypothyroid pregnant women on liquid compared to tablet formulations. METHODS: Patients were recruited by searching our "thyroid patients" database. The selection criteria were as follows: a) pregnant women on treatment for hypothyroidism (both liquid and tablet LT4) who gave birth at our hospital between February 2012 and January 2014; b) thyroid stimulating hormone (TSH) and free thyroxine (FT4) levels obtained at least 3 months before missed menstrual cycle, with a TSH value less than 2.5 mIU/L and c) TSH and FT4 obtained within 12 weeks of pregnancy, and each month subsequently. RESULTS: During pregnancy, 8/31 (25.5%) of the women had to increase the dosage of LT4. Of these, 7/17 (41.2%) were on LT4 replacement therapy with tablets, and 1/14 (7.1%) with liquid formulation (p = 0.038). Daily LT4 was significantly increased in the liquid group only (52.9 +/- 19.5 versus 67.5 +/- 19.2 mcg/day (p = 0.013). A logistic regression analysis showed that the treatment with LT4 tablets was the only predictor of LT4 increase (OR: 0.44; 95% CI: 0.04-0.83; p = 0.031). CONCLUSION: Pregnant women on optimal replacement therapy before pregnancy require an increase of LT4 dosage more often when on a tablet than liquid formulation. PMID- 26585421 TI - Trimethoprim-induced aseptic meningitis: a reminder case review. PMID- 26585422 TI - Different pathogenicities of Rice stripe virus from the insect vector and from viruliferous plants. AB - Persistent plant viruses usually depend on insects for their transmission; they cannot be transmitted between plants or through mechanical inoculation. However, the mechanism by which persistent viruses become pathogenic in insect vectors remains unknown. In this study, we used Rice stripe virus (RSV), its insect vector Laodelphax striatellus and host plant (Oryza sativa) to explore how persistent viruses acquire pathogenicity from insect vectors. RSV acquired phytopathogenicity in both the alimentary tract and the salivary gland of L. striatellus. We mechanically inoculated RSV into rice O. sativa leaves through midrib microinjection. Insect-derived RSV induced a typical stripe symptom, whereas plant-derived RSV only produced chlorosis in rice leaves. Insect-derived RSV had higher expression of genes rdrp, ns2, nsvc2, sp and nsvc4 than plant derived RSV, and the latter had higher expression of genes cp and ns3 than the former in rice leaves. Different from plant-derived RSV, insect-derived RSV damaged grana stacks within the chloroplast and inhibited photosynthesis by suppressing the photosystem II subunit psbp. This study not only presented a convenient method to mechanically inoculate RSV into plants, but also provided insights into the different pathogenic mechanisms of RSV from the insect vector and from viruliferous plants. PMID- 26585419 TI - AMPK, a metabolic sensor, is involved in isoeugenol-induced glucose uptake in muscle cells. AB - Isoeugenol exerts various beneficial effects on human health. However, the mechanisms underlying these effects are poorly understood. In this study, we observed that isoeugenol activated AMP-activated protein kinase (AMPK) and increased glucose uptake in rat L6 myotubes. Isoeugenol-induced increase in intracellular calcium concentration and glucose uptake was inhibited by STO-609, an inhibitor of calcium/calmodulin-dependent protein kinase kinase (CaMKK). Isoeugenol also increased the phosphorylation of protein kinase C-alpha (PKCalpha). Chelation of calcium with BAPTA-AM blocked isoeugenol-induced AMPK phosphorylation and glucose uptake. Isoeugenol stimulated p38MAPK phosphorylation that was inhibited after pretreatment with compound C, an AMPK inhibitor. Isoeugenol also increased glucose transporter type 4 (GLUT4) expression and its translocation to the plasma membrane. GLUT4 translocation was not observed after the inhibition of AMPK and CaMKK. In addition, isoeugenol activated the Akt substrate 160 (AS160) pathway, which is downstream of the p38MAPK pathway. Knockdown of the gene encoding AS160 inhibited isoeugenol-induced glucose uptake. Together, these results indicate that isoeugenol exerts beneficial health effects by activating the AMPK/p38MAPK/AS160 pathways in skeletal muscle. PMID- 26585423 TI - Vitamin D represses rhinovirus replication in cystic fibrosis cells by inducing LL-37. AB - Vitamin D has immunomodulatory properties in the defence against pathogens. Its insufficiency is a widespread feature of cystic fibrosis (CF) patients, which are repeatedly suffering from rhinovirus (RV)-induced pulmonary exacerbations.To investigate whether vitamin D has antiviral activity, primary bronchial epithelial cells from CF children were pre-treated with vitamin D and infected with RV16. Antiviral and anti-inflammatory activity of vitamin D was assessed. RV and LL-37 levels were measured in bronchoalveolar lavage (BAL) of CF children infected with RV.Vitamin D reduced RV16 load in a dose-dependent manner in CF cells (10(-7 )M, p<0.01). The antiviral response mediated by interferons remained unchanged by vitamin D in CF cells. Vitamin D did not exert anti-inflammatory properties in RV-infected CF cells. Vitamin D increased the expression of the antimicrobial peptide LL-37 up to 17.4-fold (p<0.05). Addition of exogenous LL-37 decreased viral replication by 4.4-fold in CF cells (p<0.05). An inverse correlation between viral load and LL-37 levels in CF BAL (r=-0.48, p<0.05) was observed.RV replication in primary CF bronchial cells was reduced by vitamin D through the induction of LL-37. Clinical studies are needed to determine the importance of an adequate control of vitamin D for prevention of virus-induced pulmonary CF exacerbations. PMID- 26585424 TI - European IPF Patient Charter: unmet needs and a call to action for healthcare policymakers. AB - Patient advocacy groups play an important role in supporting patients with chronic diseases and promoting better care. The aim of this patient-physician initiative was to gather perceptions from European idiopathic pulmonary fibrosis (IPF) patient advocacy groups regarding inequalities and unmet needs in IPF care, in order to develop a Patient Charter to advocate for better care.In total, 11 European patient advocacy groups were interviewed regarding the care of patients with IPF in their countries. Interview feedback was presented to a Working Group including patient advocacy group representatives and IPF specialists; key areas of agreement were developed into the European IPF Patient Charter.The interviews identified five key themes that fed into the final Charter: the need for improved diagnosis, treatment access, holistic care, disease awareness and palliative care. The final Charter was endorsed by patient advocacy groups and presented to 26 Members of the European Parliament in September 2014. It has received >8900 signatures to date.This patient-physician initiative highlights the inequalities and unmet needs in IPF care across Europe, and demonstrates how this insight can inform the development of a Patient Charter, designed as a call to action for healthcare policymakers to drive improvement in European IPF care. PMID- 26585425 TI - QuantiFERON-TB performance enhanced by novel Mycobacterium tuberculosis-specific antigens. PMID- 26585426 TI - Transfer factor, lung volumes, resistance and ventilation distribution in healthy adults. AB - Monitoring of chronic lung disease requires reference values of lung function indices, including putative markers of small airway function, spanning a wide age range.We measured spirometry, transfer factor of the lung for carbon monoxide (TLCO), static lung volume, resistance and ventilation distribution in a healthy population, studying at least 20 subjects per sex and per decade between the ages of 20 and 80 years.With respect to the Global Lung Function Initiative reference data, our subjects had average z-scores for forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC of -0.12, 0.04 and -0.32, respectively. Reference equations were obtained which could account for a potential dependence of index variability on age and height. This was done for (but not limited to) indices that are pertinent to asthma and chronic obstructive pulmonary disease studies: forced expired volume in 6 s, forced expiratory flow, TLCO, specific airway conductance, residual volume (RV)/total lung capacity (TLC), and ventilation heterogeneity in acinar and conductive lung zones.Deterioration in acinar ventilation heterogeneity and lung clearance index with age were more marked beyond 60 years, and conductive ventilation heterogeneity showed the greatest increase in variability with age. The most clinically relevant deviation from published reference values concerned RV/TLC values, which were considerably smaller than American Thoracic Society/European Respiratory Society-endorsed reference values. PMID- 26585427 TI - Ertapenem in the treatment of multidrug-resistant tuberculosis: first clinical experience. PMID- 26585428 TI - Predicting mortality in bronchiectasis using bronchiectasis severity index and FACED scores: a 19-year cohort study. AB - The clinical course of bronchiectasis is unpredictable, posing a challenge both in clinical practice and in research. Two mortality prediction scores, the bronchiectasis severity index (BSI) and FACED scores, have recently been developed. The aim of this study was to assess the ability of these scores to predict long-term mortality and to compare the two scores.The study was a single centre retrospective cohort analysis consisting of 91 subjects originally recruited in 1994. BSI and FACED scores were calculated at the time of enrolment and long-term mortality ascertained. Data was available for 74 patients with a median of 18.8 years of follow-up.Both scoring systems had similar predictive power for 5-year mortality (area under receiver operator characteristic curve (AUC) 0.79 for BSI and 0.8 for FACED). Both scores were able to predict 15-year mortality with the FACED score showing slightly superior predictive power (AUC 0.82 versus 0.69, p=0.0495).This study provides further validation of the FACED and BSI scores for the prediction of mortality in bronchiectasis and demonstrates their utility over a longer period than originally described. Whilst both scores had excellent predictive power, the FACED score was superior for 15-year mortality. PMID- 26585429 TI - Predictors of mortality in rheumatoid arthritis-associated interstitial lung disease. AB - Interstitial lung disease (ILD) is a common pulmonary manifestation of rheumatoid arthritis. There is lack of clarity around predictors of mortality and disease behaviour over time in these patients.We identified rheumatoid arthritis-related interstitial lung disease (RA-ILD) patients evaluated at National Jewish Health (Denver, CO, USA) from 1995 to 2013 whose baseline high-resolution computed tomography (HRCT) scans showed either a nonspecific interstitial pneumonia (NSIP) or a "definite" or "possible" usual interstitial pneumonia (UIP) pattern. We used univariate, multivariate and longitudinal analytical methods to identify clinical predictors of mortality and to model disease behaviour over time.The cohort included 137 subjects; 108 had UIP on HRCT (RA-UIP) and 29 had NSIP on HRCT (RA NSIP). Those with RA-UIP had a shorter survival time than those with RA-NSIP (log rank p=0.02). In a model controlling for age, sex, smoking and HRCT pattern, a lower baseline % predicted forced vital capacity (FVC % pred) (HR 1.46; p<0.0001) and a 10% decline in FVC % pred from baseline to any time during follow up (HR 2.57; p<0.0001) were independently associated with an increased risk of death.Data from this study suggest that in RA-ILD, disease progression and survival differ between subgroups defined by HRCT pattern; however, when controlling for potentially influential variables, pulmonary physiology, but not HRCT pattern, independently predicts mortality. PMID- 26585430 TI - T-cell receptor-HLA-DRB1 associations suggest specific antigens in pulmonary sarcoidosis. AB - In pulmonary sarcoidosis, CD4(+) T-cells expressing T-cell receptor Valpha2.3 accumulate in the lungs of HLA-DRB1*03(+) patients. To investigate T-cell receptor-HLA-DRB1*03 interactions underlying recognition of hitherto unknown antigens, we performed detailed analyses of T-cell receptor expression on bronchoalveolar lavage fluid CD4(+) T-cells from sarcoidosis patients.Pulmonary sarcoidosis patients (n=43) underwent bronchoscopy with bronchoalveolar lavage. T cell receptor alpha and beta chains of CD4(+) T-cells were analysed by flow cytometry, DNA-sequenced, and three-dimensional molecular models of T-cell receptor-HLA-DRB1*03 complexes generated.Simultaneous expression of Valpha2.3 with the Vbeta22 chain was identified in the lungs of all HLA-DRB1*03(+) patients. Accumulated Valpha2.3/Vbeta22-expressing T-cells were highly clonal, with identical or near-identical Valpha2.3 chain sequences and inter-patient similarities in Vbeta22 chain amino acid distribution. Molecular modelling revealed specific T-cell receptor-HLA-DRB1*03-peptide interactions, with a previously identified, sarcoidosis-associated vimentin peptide, (Vim)429-443 DSLPLVDTHSKRTLL, matching both the HLA peptide-binding cleft and distinct T-cell receptor features perfectly.We demonstrate, for the first time, the accumulation of large clonal populations of specific Valpha2.3/Vbeta22 T-cell receptor expressing CD4(+) T-cells in the lungs of HLA-DRB1*03(+) sarcoidosis patients. Several distinct contact points between Valpha2.3/Vbeta22 receptors and HLA DRB1*03 molecules suggest presentation of prototypic vimentin-derived peptides. PMID- 26585431 TI - A randomised trial of glucocorticoids in acute-stage allergic bronchopulmonary aspergillosis complicating asthma. AB - Whether use of high-dose steroids in acute-stage allergic bronchopulmonary aspergillosis (ABPA) is associated with superior outcomes is not known. Herein, we compare the efficacy and safety of two glucocorticoid protocols in ABPA.Treatment-naive ABPA subjects randomly received either high-dose or medium dose oral prednisolone. The primary outcomes were exacerbation rates and glucocorticoid-dependent ABPA after 1 and 2 years, respectively, of treatment. The secondary end-points were composite response rates after 6 weeks, improvement in lung function, time to first exacerbation, cumulative dose and adverse effects.92 subjects (high-dose n=44, medium-dose n=48) were included in the study. The numbers of subjects with exacerbation after 1 year (high-dose 40.9% versus medium-dose 50%, p=0.59) and glucocorticoid-dependent ABPA after 2 years (high-dose 11.4% versus medium-dose 14.6%, p=0.88) were similar in the two groups. Although composite response rates were significantly higher in the high dose group, improvement in lung function and time to first exacerbation were similar in the two groups. Cumulative glucocorticoid dose and side-effects were significantly higher in the high-dose group.Medium-dose oral glucocorticoids are as effective and safer than high-dose in treatment of ABPA. PMID- 26585432 TI - Changes in airway inflammation during pulmonary exacerbations in patients with cystic fibrosis and primary ciliary dyskinesia. AB - Lung disease in patients with both primary ciliary dyskinesia (PCD) or cystic fibrosis (CF) is associated with impaired mucociliary clearance; however, clinical outcomes are typically worse in CF patients. We assessed whether CF and PCD patients differ in inflammatory response in the airways during pulmonary exacerbation.We first studied clinically stable PCD patients with a spectrum of bacterial pathogens to assess inflammatory response to different pathogens. Subsequently, PCD and CF patients with similar bacterial pathogens were studied at the time of a pulmonary exacerbation and after 21 days of antibiotics treatment. Qualitative and quantitative microbiology, cell counts, interleukin-8 concentrations, and neutrophil elastase activity were assessed in sputum samples obtained before and after treatment.In stable PCD patients, no significant differences were found in sputum inflammatory markers between individuals colonised with different bacterial pathogens. Pulmonary exacerbation severity assessed by a pulmonary exacerbation score and lung function decline from their previous baseline did not differ between CF and PCD patients. Bacterial density for Staphylococcus aureus and Haemophilus influenzae was higher in CF versus PCD (p<0.05), but absolute neutrophil counts were higher in PCD patients (p=0.02). While sputum elastase activity was similar in PCD and CF at the time of exacerbation, it decreased with antibiotic therapy in PCD (p<0.05) but not CF patients.PCD patients differ from those with CF in their responses to treatment of pulmonary exacerbations, with higher neutrophil elastase activity persisting in the CF airways at the end of treatment. PMID- 26585433 TI - Lung function changes over time following withdrawal of inhaled corticosteroids in patients with severe COPD. PMID- 26585434 TI - COPD and risk of venous thromboembolism and mortality in a general population. AB - The relationship between chronic obstructive pulmonary disease (COPD) and risk of venous thromboembolism (VTE) has been scarcely studied in the general population. We aimed to investigate the association between COPD and risk of VTE and mortality in a population-based cohort.Spirometry was conducted in 8646 males and females, participating in the fifth (2001-02) and sixth (2007-08) surveys of the Tromso Study. Incident VTE events during follow-up were registered from the date of inclusion to December 31, 2011. Cox-regression models with COPD stages and confounders as time varying covariates were used to calculate hazard ratios with 95% confidence intervals for VTE and all-cause mortality.During a median follow up of 6.2 years, 215 subjects developed VTE. Subjects with COPD stage III/IV had a two-fold higher risk of secondary VTE compared to subjects with normal airflow (HR 2.05, 95% CI 1.02-4.10). COPD patients, particularly those with stage III/IV disease, with VTE had a higher mortality rate than COPD patients without VTE (50.2% versus 5.6% per year).Our findings suggest that patients with severe COPD may have increased risk of secondary VTE, and that COPD patients with VTE have a higher mortality rate than COPD patients without VTE. PMID- 26585435 TI - Blood basophil activation is a reliable biomarker of allergic bronchopulmonary aspergillosis in cystic fibrosis. AB - The diagnosis of cystic fibrosis (CF) patients with allergic bronchopulmonary aspergillosis (ABPA) is clinically challenging, due to the absence of an objective biological test. Since blood basophils play a major role in allergic responses, we hypothesised that changes in their surface activation pattern discriminate between CF patients with and without ABPA.We conducted a prospective longitudinal study (Stanford cohort) comparing basophil activation test CD203c levels by flow cytometry before and after activation with Aspergillus fumigatus allergen extract or recombinant Asp f1 in 20 CF patients with ABPA (CF-ABPA) and in two comparison groups: CF patients with A. fumigatus colonisation (AC) but without ABPA (CF-AC; n=13) and CF patients without either AC or ABPA (CF; n=12). Patients were tested every 6 months and when ill with pulmonary exacerbation. We also conducted cross-sectional validation in a separate patient set (Dublin cohort).Basophil CD203c surface expression reliably discriminated CF-ABPA from CF AC and CF over time. Ex vivo stimulation with A. fumigatus extract or recombinant Asp f1 produced similar results within the Stanford (p<0.0001) and the Dublin cohorts. CF-ABPA patients were likelier to have elevated specific IgE to A. fumigatus and were less frequently co-infected with Staphylococcus aureus.Basophil CD203c upregulation is a suitable diagnostic and stable monitoring biomarker of ABPA in CF. PMID- 26585436 TI - Sp8 expression in putative neural progenitor cells in guinea pig and human cerebrum. AB - Neural stem/progenitor cells have been characterized at neurogenic sites in adult mammalian brain with various molecular markers. Here it has been demonstrated that Sp8, a transcription factor typically expressed among mature GABAergic interneurons, also labels putative neural precursors in adult guinea pig and human cerebrum. In guinea pigs, Sp8 immunoreactive (Sp8+) cells were localized largely in the superficial layers of the cortex including layer I, as well as the subventricular zone (SVZ) and subgranular zone (SGZ). Sp8+ cells at the SGZ showed little colocalization with mature and immature neuronal markers, but co expressed neural stem cell markers including Sox2. Some layer I Sp8+ cells also co-expressed Sox2. The amount of Sp8+ cells in the dentate gyrus was maintained 2 weeks after X-ray irradiation, while that of doublecortin (DCX+) cells was greatly reduced. Mild ischemic insult caused a transient increase of Sp8+ cells in the SGZ and layer I, with the subgranular Sp8+ cells exhibited an increased colabeling for the mitotic marker Ki67 and pulse-chased bromodeoxyuridine (BrdU). Sp8+ cells in the dentate gyrus showed an age-related decline in guinea pigs, in parallel with the loss of DCX+ cells in the same region. In adult humans, Sp8+ cells exhibited comparable morphological features as seen in guinea pigs, with those at the SGZ and some in cortical layer I co-expressed Sox2. Together, these results suggested that Sp8 may label putative neural progenitors in guinea pig and human cerebrum, with the labeled cells in the SGZ appeared largely not mitotically active under normal conditions. (c) 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 939-955, 2016. PMID- 26585437 TI - Profiles of Mild Cognitive Impairment (MCI) in the Elderly. AB - We applied latent class analysis (LCA) to a set of neuropsychological data with the aim of corroborating the three cognitive profiles of mild cognitive impairment (MCI) described in the literature, namely: healthy, amnestic, non amnestic, and multidomain. The ultimate purpose of the LCA was to try to find the underlying classification of MCI and related pathologies by means of the participants' response patterns, rather than on more classical psychometric criteria, such as the standard deviation of the mean. We computed 547 neuropsychological assessments derived from 223 participants who were assessed annually for three consecutive years. The battery included tests of memory, language, executive function, and praxis. The results obtained by means of LCA, with a four-group solution and using the 40th percentile as the criterion, confirm prior classifications obtained with more questionable psychometric criteria, while providing longitudinal data on the course of MCI and the stability of group assignment over time. PMID- 26585438 TI - Clinical Features and Surgical Results of Right Atrial Myxoma. AB - BACKGROUND: We retrospectively analyzed 367 patients receiving surgical resection of cardiac myxomas in our center over six years, and analyzed the incidence and surgical results of 28 cases of right atrial myxomas. We also compared the age, gender, and attached sites between left atrial myxoma and right atrial myxoma. METHODS: Between January 2007 and December 2012, 28 patients with right atrial myxomas underwent surgical resection. There were 16 males and 12 females. The mean age was 47.77 +/- 13.20 years (range: 8.00-79.00 years). Associated cardiac lesions included moderate and severe tricuspid regurgitation in four, coronary atherosclerotic heart disease in five, and pulmonary embolism in one. Twenty seven patients (96.43%) were followed from 26 to 94 months (mean 55.78 +/- 21.10 months). RESULTS: There was no early death after operation. The incidence of right atrial myxomas among sporadic cardiac myxomas was 7.89%. One patient died of lung cancer 34 months after myxoma resection. Two patients underwent coronary artery stent implantation due to coronary atherosclerotic heart disease during the follow-up period. One patient underwent myxoma resection due to recurrence in the left atrium four years after the first operation. There was no significant difference in the age between left atrial myxoma and right atrial myxoma (p > 0.05). There was a significant difference in the gender between left atrial myxomas and right atrial myxomas (p < 0.05). The most common attached sites of left atrial myxomas and right atrial myxomas are the atrial septum. CONCLUSIONS: Surgical resection of the right atrial myxoma results in good clinical outcomes and a decreased incidence of recurrence. PMID- 26585440 TI - DECISION-MAKING ALIGNED WITH RAPID-CYCLE EVALUATION IN HEALTH CARE. AB - BACKGROUND: Availability of real-time electronic healthcare data provides new opportunities for rapid-cycle evaluation (RCE) of health technologies, including healthcare delivery and payment programs. We aim to align decision-making processes with stages of RCE to optimize the usefulness and impact of rapid results. Rational decisions about program adoption depend on program effect size in relation to externalities, including implementation cost, sustainability, and likelihood of broad adoption. METHODS: Drawing on case studies and experience from drug safety monitoring, we examine how decision makers have used scientific evidence on complex interventions in the past. We clarify how RCE alters the nature of policy decisions; develop the RAPID framework for synchronizing decision-maker activities with stages of RCE; and provide guidelines on evidence thresholds for incremental decision-making. RESULTS: In contrast to traditional evaluations, RCE provides early evidence on effectiveness and facilitates a stepped approach to decision making in expectation of future regularly updated evidence. RCE allows for identification of trends in adjusted effect size. It supports adapting a program in midstream in response to interim findings, or adapting the evaluation strategy to identify true improvements earlier. The 5 step RAPID approach that utilizes the cumulating evidence of program effectiveness over time could increase policy-makers' confidence in expediting decisions. CONCLUSIONS: RCE enables a step-wise approach to HTA decision-making, based on gradually emerging evidence, reducing delays in decision-making processes after traditional one-time evaluations. PMID- 26585439 TI - Inclusion of brain volume loss in a revised measure of 'no evidence of disease activity' (NEDA-4) in relapsing-remitting multiple sclerosis. AB - BACKGROUND: 'No evidence of disease activity' (NEDA), defined as absence of magnetic resonance imaging activity (T2 and/or gadolinium-enhanced T1 lesions), relapses and disability progression ('NEDA-3'), is used as a comprehensive measure of treatment response in relapsing multiple sclerosis (RMS), but is weighted towards inflammatory activity. Accelerated brain volume loss (BVL) occurs in RMS and is an objective measure of disease worsening and progression. OBJECTIVE: To assess the contribution of individual components of NEDA-3 and the impact of adding BVL to NEDA-3 ('NEDA-4') METHODS: We analysed data pooled from two placebo-controlled phase 3 fingolimod trials in RMS and assessed NEDA-4 using different annual BVL mean rate thresholds (0.2%-1.2%). RESULTS: At 2 years, 31.0% (217/700) of patients receiving fingolimod 0.5 mg achieved NEDA-3 versus 9.9% (71/715) on placebo (odds ratio (OR) 4.07; p < 0.0001). Adding BVL (threshold of 0.4%), the respective proportions of patients achieving NEDA-4 were 19.7% (139/706) and 5.3% (38/721; OR 4.41; p < 0.0001). NEDA-4 status favoured fingolimod across all BVL thresholds tested (OR 4.01-4.41; p < 0.0001). CONCLUSION: NEDA-4 has the potential to capture the impact of therapies on both inflammation and neurodegeneration, and deserves further evaluation across different compounds and in long-term studies. PMID- 26585441 TI - Practical guide to sample size calculations: an introduction. AB - A sample size justification is a vital step when designing any trial. However, estimating the number of participants required to give a meaningful result is not always straightforward. A number of components are required to facilitate a suitable sample size calculation. In this paper, the general steps are summarised for conducting sample size calculations with practical advice and guidance on how to utilise the app SampSize. PMID- 26585442 TI - Clinicopathologic and cytogenetic characterization of therapy-related acute T lymphoblastic leukemia in adult population. PMID- 26585443 TI - Batch affinity adsorption of His-tagged proteins with EDTA-based chitosan. AB - Affinity adsorption purification of hexahistidine-tagged (His-tagged) proteins using EDTA-chitosan-based adsorption was designed and carried out. Chitosan was elaborated with ethylenediaminetetraacetic acid (EDTA), and the resulting polymer was characterized by FTIR, TGA, and TEM. Different metals including Ni(2+), Cu(2+), and Zn(2+) were immobilized with EDTA-chitosan, and their capability to the specific adsorption of His-tagged proteins were then investigated. The results showed that Ni(2+)-EDTA-chitosan and Zn(2+)-EDTA-chitosan had high affinity toward the His-tagged proteins, thus isolating them from protein mixture. The target fluorescent-labeled hexahistidine protein remained its fluorescent characteristic throughout the purification procedure when Zn(2+)-EDTA chitosan was used as a sorbent, wherein the real-time monitor was performed to examine the immigration of fluorescent-labeled His-tagged protein. Comparatively, Zn(2+)-EDTA-chitosan showed more specific binding ability for the target protein, but with less binding capacity. It was further proved that this purification system could be recovered and reused at least for 5 times and could run on large scales. The presented M(2+)-EDTA-chitosan system, with the capability to specifically bind His-tagged proteins, make the purification of His-tagged proteins easy to handle, leaving out fussy preliminary treatment, and with the possibility of continuous processing and a reduction in operational cost in relation to the costs of conventional processes. PMID- 26585444 TI - Enhancement of UDPG synthetic pathway improves ansamitocin production in Actinosynnem pretiosum. AB - Ansamitocin P-3 (AP-3), an amacrocyclic lactam compound, is produced by Actinosynnema pretiosum. As a group of maytansinoid antibiotics, ansamitocins have an extraordinary antitumor activity by blocking the assembly of tubulin forming into functional microtubules. The biosynthesis of ansamitocins is initialized by the formation of UDP-glucose (UDPG) which is converted from glucose-1-phosphate (G1P). In this study, we focused on the influence of enhancement of UDPG biosynthesis on the production of ansamitocins in A. pretiosum. The homologous overexpressions of phosphoglucomutase, starch phosphorylase, and UTP-G1P uridylyltransferase, respectively, could largely increase the pool sizes of G1P and UDPG and result in improved AP-3 production. The elevated intracellular glucose-6-phosphate (G6P) level provided by the enhanced glyconeogenesis had, however, no significant effects on the biosynthesis of AP-3. The G6P-G1P-UDPG pathway was therefore systematically engineered by multiple genetic modifications, and a significant increase in AP-3 production was achieved (168 mg/L of AP-3 in flask culture, 40 % higher than the control strain). We also found that the enhancement of starch assimilation pathway could also improve the assembly of AP-3 to some extent. In addition, heterologous gene overexpression from Actinosynnema mirum could result in more AP-3 biosynthesis in comparison to the corresponding homologous overexpression, suggesting an alternative and promising avenue of metabolic engineering strategy for improving AP-3 production. PMID- 26585445 TI - Cinnamaldehyde inhibits fungal growth and aflatoxin B1 biosynthesis by modulating the oxidative stress response of Aspergillus flavus. AB - Cinnamaldehyde (CIN) is a promising natural preservative and generally recognized as safe for commodities as well as consumers. In this work, the antifungal effects of CIN on Aspergillus flavus were evaluated both in solid and in liquid culture conditions. Our results indicated that CIN effectively inhibited radial growth, spore production, mycelium formation, and aflatoxin B1 biosynthesis by A. flavus in a dose-dependent manner. At the concentration of 104 mg L(-1), CIN exposure was able to completely inhibit fungal growth as well as aflatoxin B1 production. Furthermore, the inhibitory activities of CIN were closely connected with the treatment period and the tested fungal species. Compared with the control strains, CIN dose dependently changed the morphology and ultrastructure of mycelium in different degree. Especially, the reduction of hydrogen peroxide was considered to follow the destruction of mitochondrial. Meanwhile, CIN significantly cut the levels of lipid peroxidation and reduced glutathione. The activity of total superoxide dismutase was significantly inhibited after CIN treatment at the end of incubation, whereas the activities of catalase and glutathione peroxidase were opposite. These results indicated that the inhibitory effect of CIN could attribute to oxidative stress alleviation possibly induced by modifications of cellular structure as well as redox status. PMID- 26585446 TI - A synergistic interaction between salt-tolerant Pseudomonas and Mesorhizobium strains improves growth and symbiotic performance of liquorice (Glycyrrhiza uralensis Fish.) under salt stress. AB - Chinese liquorice (Glycyrrhiza uralensis Fish.) is a salt-tolerant medicinal legume that could be utilized for bioremediation of salt-affected soils. We studied whether co-inoculation of the symbiotic Mesorhizobium sp. strain NWXJ19 or NWXJ31 with the plant growth-promoting Pseudomonas extremorientalis TSAU20 could restore growth, nodulation, and shoot/root nitrogen contents of salt stressed G. uralensis, which was grown in potting soil and irrigated with 0, 50, and 75 mM NaCl solutions under greenhouse conditions. Irrigation with NaCl solutions clearly retarded the growth of uninoculated liquorice, and the higher the NaCl concentration (75 and 100 mM NaCl), the more adverse is the effect. The two Mesorhizobium strains, added either alone or in combination with P. extremorientalis TSAU20, responded differently to the salt levels used. The strain NWXJ19 was a good symbiont for plants irrigated with 50 mM NaCl, whereas the strain NWXJ31 was more efficient for plants irrigated with water or 75 mM NaCl solution. P. extremorientalis TSAU20 combined with single Mesorhizobium strains alleviated the salt stress of liquorice plants and improved yield and nodule numbers significantly in comparison with single-strain-inoculated liquorice. Both salt stress and inoculation raised the nitrogen content of shoots and roots. The nitrogen contents were at their highest, i.e., 30 and 35 % greater compared to non-stressed uninoculated plants, when plants were inoculated with P. extremorientalis TSAU20 and Mesorhizobium sp. NWXJ31 as well as irrigated with 75 mM NaCl solution. From this study, we conclude that dual inoculation with plant growth-promoting rhizobacteria could be a new approach to improve the tolerance of G. uralensis to salt stress, thereby improving its suitability for the remediation of saline lands. PMID- 26585448 TI - Conchal bowl reconstruction with collagen matrix xenograft in cartilage transfer rhinoplasty. PMID- 26585447 TI - Point-of-care testing with CRP in primary care: a registry-based observational study from Norway. AB - BACKGROUND: Norwegian primary health care is maintained on the regular general practitioners (RGPs), GP's contracted to the municipalities in a list patient system, working at daytime and at out-of-hours services (OOH services). Respiratory disease is most prevalent during OOH services, and in more than 50 % of the consultations, a CRP test is performed. Children in particular have a high consultation rate, and the CRP test is frequently conducted, but the contributing factors behind its frequent use are not known. This study compares the RGPs rate of CRP use at daytime and OOH in consultations with children and how this rate is influenced by characteristics of the RGPs. METHODS: A cross-sectional register study was conducted based on all (N = 2,552,600) electronic compensation claims from consultations with children <= 5 year during the period 2009-2011 from primary health care. Consultation rates and CRP use were estimated and analysed using descriptive methods. Being among the 20% of RGPs with the highest rate of CRP use at daytime or OOH was an outcome measure in regression analyses using RGP , and RGP list characteristics as explanatory variables. RESULTS: One third of all RGPs work regularly in OOH services, and they use CRP 1.42 times more frequently in consultations with children in OOH services than in daytime services even when the distribution of diagnosis according to ICPC-2 chapters is similar. Not being approved specialist, have a large number at their patient lists but relatively few children on their list and a large number of consultations with children were significantly associated with frequent use of CRP in daytime services. The predictors for frequent CRP use in OOH services were being a young doctor, having many consultations with children during OOH and a frequent use of CRP in daytime services. CONCLUSIONS: The increase in the frequency of CRP test use from daytime to OOH occurs in general for RGPs and for all most used diagnoses. The RGPs who use the CRP test most frequently in their daytime practice have the highest rate of CRP in OOH services. PMID- 26585449 TI - Cyclic-di-AMP synthesis by the diadenylate cyclase CdaA is modulated by the peptidoglycan biosynthesis enzyme GlmM in Lactococcus lactis. AB - The second messenger cyclic-di-adenosine monophosphate (c-di-AMP) plays important roles in growth, virulence, cell wall homeostasis, potassium transport and affects resistance to antibiotics, heat and osmotic stress. Most Firmicutes contain only one c-di-AMP synthesizing diadenylate cyclase (CdaA); however, little is known about signals and effectors controlling CdaA activity and c-di AMP levels. In this study, a genetic screen was employed to identify components which affect the c-di-AMP level in Lactococcus. We characterized suppressor mutations that restored osmoresistance to spontaneous c-di-AMP phosphodiesterase gdpP mutants, which contain high c-di-AMP levels. Loss-of-function and gain-of function mutations were identified in the cdaA and gdpP genes, respectively, which led to lower c-di-AMP levels. A mutation was also identified in the phosphoglucosamine mutase gene glmM, which is commonly located within the cdaA operon in bacteria. The glmM I154F mutation resulted in a lowering of the c-di AMP level and a reduction in the key peptidoglycan precursor UDP-N acetylglucosamine in L. lactis. C-di-AMP synthesis by CdaA was shown to be inhibited by GlmM(I154F) more than GlmM and GlmM(I154F) was found to bind more strongly to CdaA than GlmM. These findings identify GlmM as a c-di-AMP level modulating protein and provide a direct connection between c-di-AMP synthesis and peptidoglycan biosynthesis. PMID- 26585450 TI - Characterization of a Novel Collagen Scaffold for Corneal Tissue Engineering. AB - Globally millions are blind due to corneal disease, yet tissue for transplantation is a limited resource. This study characterizes the physical and biological properties of a novel collagen-based scaffold. Transparency, optical coherence tomography (OCT), and scanning electron microscopy (SEM) were used to analyze the structure of the scaffold, synthesized using rat tail collagen I. Water content was determined. The tensile strength was assessed using a micro mechanical analyzer. In vitro biocompatibility was assessed by culturing the scaffold with epithelial or keratocyte spheres. The mean scaffold transmittance was 0.72 at 358 nm, 0.88 at 570 nm, and 0.92 at 900 nm. OCT imaging confirmed that the scaffold maintained a corneal shape, with a central thickness of 502 MUm and a reflectivity profile comparable to that of a normal human cornea. SEM of the scaffold revealed multiple lamellae on cross section. The mean water content was 88.7% +/- 0.7%. Ultimate tensile strength for the noncross-linked scaffold was 1.23 +/- 0.27 MPa compared with 2.21 +/- 0.70 MPa for the cross-linked scaffold (human corneal anterior stroma 1.53 +/- 0.86 MPa) at a strain rate of 0.5%/s. Epithelial cells migrated over the scaffold to confluence. Keratocytes populated the scaffold and maintained a lamellar arrangement. The properties of this novel scaffold suggest that it has potential to be developed into a corneal tissue substitute for human transplantation. PMID- 26585451 TI - Design a cadA-targeted DNA probe for screening of potential bacterial cadmium biosorbents. AB - Due to their metal removal ability, bacterial biosorbents can be effectively used for the treatment of wastewaters containing heavy metals. Searching for bacterial biosorbents for hazardous heavy metals like cadmium is a pivotal for remediation efforts. The gene cadA, that mediates resistance to cadmium over an ATP-dependent efflux mechanism, provides a good target for the selection of potential cadmium biosorbents. For this reason, in this study, a 36-mer-oligonucleotide DNA probe based on the entire 3.5-kb BglII-XbaI fragment of cadA operon from staphylococcal plasmid pI258 was prepared by using Vector NTI Express software. Under the hybridization conditions of 46 degrees C, 50 % formamide, and 0.028 M NaCl, the designed cadA probe appeared to be highly specific to the cadA-positive Staphylococcus warneri and Delftia acidovorans isolates tested. The results indicated that the newly designed cadA-targeted DNA probe has potential as a specific, sensitive, and quantitative tool in selecting and in situ screening of potential cadmium biosorbents. PMID- 26585452 TI - Metal toxicity differently affects the Iris pseudacorus-arbuscular mycorrhiza fungi symbiosis in terrestrial and semi-aquatic habitats. AB - Phytoremediation offers an environmental friendly alternative to conventional cleanup techniques. In this study, mycorrhizal fungi isolated from the roots of Mentha longifolia grown in the basin of the Centuria River (S Poland) were used. Iris pseudacorus was grown in substratum from an industrial waste, enriched in Pb, Fe, Zn, and Cd in a terrestrial and water-logged habitat. Plant yield and photosynthetic performance was the highest in the aquatic environment; however, the presence of toxic metals (TM) negatively affected photosystem II (PSII) photochemistry as shown by the JIP test. Fungi colonization and Cd accumulation within plant tissues was decreased. In the terrestrial habitat, neither arbuscular mycorrhizal fungi (AMF) nor metal toxicity affected plant growth, although metal uptake, Cd in particular, as well as photosynthesis were affected. Inoculated plants accumulated significantly more Cd, and photosynthesis was downregulated. The results presented in this study clearly indicate that the I. pseudacorus-AMF symbiosis adapts itself to the presence of toxic metals in the environment, optimizing resource supply, energy fluxes, and possibly stress tolerance mechanisms. Plant/AMF consortia grown in terrestrial and water-logged habitats utilize different strategies to cope with metal toxicity. The use of AMF in improving the phytoremediation potential of I. pseudacorus needs, however, further research. PMID- 26585453 TI - Effects of phosphorus on chemical forms of Cd in plants of four spinach (Spinacia oleracea L.) cultivars differing in Cd accumulation. AB - In order to clarify how cadmium (Cd) chemical forms in planta relate to the genotype difference in Cd accumulation of spinach (Spinacia oleracea L.), two low Cd and two high-Cd cultivars were compared under a hydroponic experiment with two concentrations of Cd (8.98 or 44.71 MUmol Cd L(-1)). The concentrations of phosphorus in the hydroponic system were also adjusted to two levels (0.5 and 1.0 mmol L(-1)) to investigate the influence of phosphorus on the forms and accumulation of Cd in the tested cultivars. Average Cd concentrations in shoots were 8.50-10.06 mg kg(-1) for high-Cd cultivars and 6.11-6.64 mg kg(-1) for low Cd cultivars a under lower Cd treatment and were as high as 24.41-31.35 mg kg(-1) and 19.65-25.76 mg kg(-1), respectively, under a higher treatment. Phosphorus significantly decreased Cd accumulation in the tested cultivars, and the effect had superiority over the cultivar alternation under higher Cd stress. Cadmium in the NaCl-extractable fraction of the plant tissues showed the greatest relationship to genotype difference of Cd accumulation. The difference in the capacity to binding Cd into F HAc, F HCl, or F Residue was another important mechanism involving in the genotype difference in Cd accumulation of spinach. Among them, average proportion of Cd in F HAc in low-Cd cultivars was higher than that in high-Cd cultivars in association with the effect of phosphorus. PMID- 26585454 TI - Oxidative stress and spermatogenesis suppression in the testis of cadmium-treated Bombyx mori larvae. AB - Bombyx mori L. (B. mori) were exposed to cadmium chloride (CdCl2) incorporated in an artificial diet (0, 6.25, 12.5, 25, and 50 mg kg(-1)) throughout the larval stage. Changes in malondialdehyde (MDA) and reduced glutathione (GSH) contents and activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), as well as their corresponding messenger RNA (mRNA) levels in the testes of the fifth instar larvae were evaluated. Additionally, spermatozoon deformation in the testes was examined. Upon Cd treatment, the MDA content in the testes was significantly increased in a concentration-dependent manner. Cd-exposed larvae had increased levels of glutathione. Pearson's correlation analysis revealed that SOD and CAT activities were positively correlated (R (2) = 0.605, P = 0.017). The changing trends in the mRNA levels of these enzymes were not always consistent with those of enzymatic activities. Alterations in GSH-Px activities and mRNA levels were positively correlated (R (2) = 0.771, P < 0.01). Morphological analysis revealed that Cd deformed and affected the maturation of spermatozoa. Our results collectively support a relationship between Cd and alterations in the levels of antioxidant enzymes in B. mori testes. PMID- 26585455 TI - Passive sampling of polybrominated diphenyl ethers in indoor and outdoor air in Shanghai, China: seasonal variations, sources, and inhalation exposure. AB - Ninety-seven seasonal, passive indoor and outdoor air samples were collected in Shanghai to study polybrominated diphenyl ethers (SigmaPBDEs, 16 congeners including BDE-209), their concentrations, composition profiles, seasonal variations, influencing factors, emission sources, and human inhalation exposure. In summer, median indoor concentrations of Sigma 15 PBDEs (excluding BDE-209) were 82 pg m(-3) in offices and 30 pg m(-3) in homes, ~3 times the winter concentrations. The average summer concentration of 130 pg m(-3) BDE-209 in homes was higher than that in offices (which was 90 pg m(-3)); in winter, home and office concentrations were similar (46 and 47 pg m(-3), respectively). For outdoor air, the median concentration of Sigma 15 PBDEs in summer (12 pg m(-3)) was twice the winter concentration (6 pg m(-3)), while the summer median concentration of BDE-209 (398 pg m(-3)) was half the winter concentration (794 pg m(-3)). Higher concentrations of Sigma 15 PBDEs indoors compared with outdoors showed that the lower brominated BDEs found were mainly from indoor sources. Meanwhile, the much lower indoor concentration of BDE-209 compared with the outdoors showed that BDE-209 came mainly from outdoor sources. The data set also indicated that electric/electronic appliances were the main sources of indoor SigmaPBDEs, and old appliances emitted more lower brominated BDEs, while industrial emissions should be the main source of the outdoor BDE-209. Median daily human exposures to Sigma 15 PBDEs and BDE-209 through inhalation were estimated to be 0.23 and 1.73 ng day(-1) in winter and 0.65 and 2.28 ng day(-1) in summer for adults. The human inhalation exposure to SigmaPBDEs (3.44 ng day( 1) for adults and 1.33 ng day(-1) for toddlers) was comparable to that from eating contaminated fish for both toddlers and adults in Shanghai. PMID- 26585456 TI - Depth profile of persistent and emerging organic pollutants upstream of the Three Gorges Dam gathered in 2012/2013. AB - Persistent and emerging organic pollutants were sampled in September 2012 and 2013 at a sampling site in front of the Three Gorges Dam near Maoping (China) in a water depth between 11 and 61 m to generate a depth profile of analytes. A novel compact water sampling system with self-packed glass cartridges was employed for the on-site enrichment of approximately 300 L of water per sample to enable the detection of low analytes levels in the picogram per liter-scale in the large water body. The overall performance of the sampling system was acceptable for the qualitative detection of polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), perfluoroalkylic acids (PFAAs), pharmaceutical residues and polar pesticides. Strongly particle-associated analytes like PAHs and PCBs resided mainly in the glass wool filter of the sampling system, whereas all other compounds have mainly been enriched on the XAD-resin of the self-packed glass cartridges. The sampling results revealed qualitative information on the presence, depth distribution and origin of the investigated compounds. Although the depth profile of PAHs, PCBs, OCPs, and PFAAs appeared to be homogeneous, pharmaceuticals and polar pesticides were detected in distinct different patterns with water depth. Source analysis with diagnostic ratios for PAHs revealed their origin to be pyrogenic (burning of coal, wood and grass). In contrast, most PCBs and OCPs had to be regarded as legacy pollutants which have been released into the environment in former times and still remain present due to their persistence. The abundance of emerging organic pollutants could be confirmed, and their most abundant compounds could be identified as perfluorooctanoic acid, diclofenac and atrazine among investigated PFAAs, pharmaceuticals and polar pesticides, respectively. PMID- 26585457 TI - Functional MRI activation in response to panic-specific, non-panic aversive, and neutral pictures in patients with panic disorder and healthy controls. AB - There is evidence that besides limbic brain structures, prefrontal and insular cortical activations and deactivations are involved in the pathophysiology of panic disorder. This study investigated activation response patterns to stimulation with individually selected panic-specific pictures in patients with panic disorder with agoraphobia (PDA) and healthy control subjects using functional magnetic resonance imaging (fMRI). Structures of interest were the prefrontal, cingulate, and insular cortex, and the amygdalo-hippocampal complex. Nineteen PDA subjects (10 females, 9 males) and 21 healthy matched controls were investigated using a Siemens 3-Tesla scanner. First, PDA subjects gave Self Assessment Manikin (SAM) ratings on 120 pictures showing characteristic panic/agoraphobia situations, of which 20 pictures with the individually highest SAM ratings were selected. Twenty matched pictures showing aversive but not panic specific stimuli and 80 neutral pictures from the International Affective Picture System were chosen for each subject as controls. Each picture was shown twice in each of four subsequent blocks. Anxiety and depression ratings were recorded before and after the experiment. Group comparisons revealed a significantly greater activation in PDA patients than control subjects in the insular cortices, left inferior frontal gyrus, dorsomedial prefrontal cortex, the left hippocampal formation, and left caudatum, when PA and N responses were compared. Comparisons for stimulation with unspecific aversive pictures showed activation of similar brain regions in both groups. Results indicate region-specific activations to panic-specific picture stimulation in PDA patients. They also imply dysfunctionality in the processing of interoceptive cues in PDA and the regulation of negative emotionality. Therefore, differences in the functional networks between PDA patients and control subjects should be further investigated. PMID- 26585458 TI - Isolation of nucleated red blood cells in maternal blood for Non-invasive prenatal diagnosis. AB - This paper introduces a two-step cascade enrichment method for isolating nucleated red blood cells (NRBCs) in maternal blood. The two-step enrichment platform consists of a positive enrichment process based on a red blood cell (RBC) hyperaggregation method and a negative enrichment process using microfluidic technology. An analytical evaluation using blood samples from patients with leukemia showed that the while blood cell (WBC) depletion and NRBC loss rates of the positive enrichment process were 93.98 % and 6.02 %, respectively. Through the two-step cascade enrichment method, 1-396 NRBCs and only 0-6 WBCs were isolated from 1 mL of 18 maternal blood samples. Experimental results also showed that the WBC depletion rate of the proposed two-step method was more than 625,000-fold, and the purity of enriched NRBCs ranged from 20 % to 100 %. Furthermore, SRY (the sex-determining region of the Y chromosome) genes were detected in enriched NRBCs, thereby demonstrating that enriched NRBCs contain fetus-derived NRBCs. PMID- 26585460 TI - A Fusarium graminearum strain-comparative proteomic approach identifies regulatory changes triggered by agmatine. AB - Plant pathogens face different environmental clues depending on the stage of the infection cycle they are in. Fusarium graminearum infects small grain cereals producing trichothecenes type B (TB) that act as virulence factor in the interaction with the plant and have important food safety implications. This study addresses at the proteomic level the effect of an environmental stimulus (such as the presence of a polyamine like agmatine) possibly encountered by the fungus when it is already within the plant. Because biological diversity affects the proteome significantly, a multistrain (n=3) comparative approach was used to identify consistent effects caused on the fungus by the nitrogen source (agmatine or glutamic acid). Proteomics analyses were performed by the use of 2D-DIGE. Results showed that agmatine augmented TB production but not equally in all strains. The polyamine reshaped drastically the proteome of the fungus activating specific pathways linked to the translational control within the cell. Chromatin restructuring, ribosomal regulations, protein and mRNA processing enzymes were modulated by the agmatine stimulus as well as metabolic, structural and virulence related proteins, suggesting the need to reshape specifically the fungal cell for TB production, a key step for the pathogen spread within the spike. BIOLOGICAL SIGNIFICANCE: Induction of toxin synthesis by plant compounds plays a crucial role in toxin contamination of food and feed, in particular trichothecenes type B produced mainly by F. graminearum on wheat. This work describes the level of diversity of 3 strains facing 2 toxin inducing plant derived compounds. This knowledge is of use for the research community on toxigenic Fusarium strains in cereals for understanding the role of fungal diversity in toxin inducibility. This work also suggests that environmental clues that can be found within the plant during infection (like different nitrogen compounds) are crucial stimuli for reshaping the proteome profile and consequently the specialization profiling of the fungus, ultimately leading to very different toxin contamination levels in the plant. PMID- 26585459 TI - Neurobehavior related to epigenetic differences in preterm infants. AB - Preterm birth is associated with medical problems affecting the neuroendocrine system, altering cortisol levels resulting in negative effects on newborn neurobehavior. Newborn neurobehavior is regulated by DNA methylation of NR3C1 and HSD11B2. AIM: Determine if methylation of HSD11B2 and NR3C1 is associated with neurobehavioral profiles in preterm infants. PATIENTS & METHODS: Neurobehavior was measured before discharge from the hospital in 67 preterm infants. Cheek swabs were collected for DNA extraction. RESULTS: Infants with the high-risk neurobehavioral profile showed more methylation than infants with the low-risk neurobehavioral profile at CpG3 for NR3C1 and less methylation of CpG3 for HSD11B2. Infants with these profiles were more likely to have increased methylation of NR3C1 and decreased methylation of HSD11B2 at these CpG sites. CONCLUSION: Preterm birth is associated with epigenetic differences in genes that regulate cortisol levels related to high-risk neurobehavioral profiles. PMID- 26585461 TI - Benchmarking quantitative label-free LC-MS data processing workflows using a complex spiked proteomic standard dataset. AB - Proteomic workflows based on nanoLC-MS/MS data-dependent-acquisition analysis have progressed tremendously in recent years. High-resolution and fast sequencing instruments have enabled the use of label-free quantitative methods, based either on spectral counting or on MS signal analysis, which appear as an attractive way to analyze differential protein expression in complex biological samples. However, the computational processing of the data for label-free quantification still remains a challenge. Here, we used a proteomic standard composed of an equimolar mixture of 48 human proteins (Sigma UPS1) spiked at different concentrations into a background of yeast cell lysate to benchmark several label free quantitative workflows, involving different software packages developed in recent years. This experimental design allowed to finely assess their performances in terms of sensitivity and false discovery rate, by measuring the number of true and false-positive (respectively UPS1 or yeast background proteins found as differential). The spiked standard dataset has been deposited to the ProteomeXchange repository with the identifier PXD001819 and can be used to benchmark other label-free workflows, adjust software parameter settings, improve algorithms for extraction of the quantitative metrics from raw MS data, or evaluate downstream statistical methods. BIOLOGICAL SIGNIFICANCE: Bioinformatic pipelines for label-free quantitative analysis must be objectively evaluated in their ability to detect variant proteins with good sensitivity and low false discovery rate in large-scale proteomic studies. This can be done through the use of complex spiked samples, for which the "ground truth" of variant proteins is known, allowing a statistical evaluation of the performances of the data processing workflow. We provide here such a controlled standard dataset and used it to evaluate the performances of several label-free bioinformatics tools (including MaxQuant, Skyline, MFPaQ, IRMa-hEIDI and Scaffold) in different workflows, for detection of variant proteins with different absolute expression levels and fold change values. The dataset presented here can be useful for tuning software tool parameters, and also testing new algorithms for label-free quantitative analysis, or for evaluation of downstream statistical methods. PMID- 26585462 TI - Three-dimensional spectral domain optical coherence tomography and light microscopy of an intravitreal parasite. AB - BACKGROUND: Various imaging modalities play a role in diagnosing parasitic infections of the eye. We describe the spectral domain optical coherence tomography (SD-OCT) findings of an intravitreal parasite with subsequent evaluation by light microscopy. FINDINGS: This is a case report of a 37-year-old Ecuadorian man who presented with uveitic glaucoma and a new floater in his left eye for 1 week's duration. Full ophthalmic examination revealed an intravitreal parasite. Color fundus photography, fluorescein angiography (FA), ocular ultrasonography (US), and SD-OCT were performed. The parasite was removed via 23 gauge pars plana vitrectomy and sent to pathology for evaluation. Color fundus photography and ocular ultrasonography demonstrated an elongated foreign body within the vitreous above the retina. FA demonstrated minimal vascular changes in the vicinity of the parasite. SD-OCT was utilized to visualize the parasite and to create a three-dimensional (3D) image. The parasite was determined to be most consistent with Gnathostoma spp. by morphologic analysis. CONCLUSIONS: This is the first reported case of SD-OCT of an intravitreal parasite with corresponding evaluation by pathology. SD-OCT allows non-invasive, high-resolution visualization and 3D reconstruction of parasitic anatomy which may help establish tomographic criteria for species identification. PMID- 26585463 TI - Investigation of each histological type in undifferentiated early gastric cancer and validity of diagnosis of the disease range. PMID- 26585464 TI - A Bifunctional Interlayer Material for Modifying Both the Anode and Cathode in Highly Efficient Polymer Solar Cells. AB - A novel polymer-solar-cell architecture using the conjugated polymer PFS as both the anode and cathode interlayers is constructed, and a high power conversion efficiency of 9.48% is achieved using the corresponding photovoltaic device. PMID- 26585465 TI - Correlation of Global Strain Rate and Left Ventricular Filling Pressure in Patients with Coronary Artery Disease: A 2-D Speckle-Tracking Study. AB - The aim of the present study was to evaluate the role of 2-D speckle-tracking imaging in the prediction of left ventricular filling pressure in patients with coronary artery disease (CAD) and normal left ventricular ejection fraction (LVEF). Eighty-four patients with CAD and 30 healthy controls were recruited prospectively. The longitudinal strain rate (SR) curves were determined in three apical views of the left ventricle long axis. Circumferential and radial SR curves were determined in three short-axis views. Left ventricular end-diastolic pressure (LVEDP) was invasively obtained by left heart catheterization. Compared with the 30 controls, the patients with CAD had significantly lower global SR during early diastole (SRe) and higher E/SRe in three directions of myocardial deformation. CAD patients with elevated LVEDP had significantly lower SRe and higher E/SRe of three deformations. Pearson's correlation analysis revealed that LVEDP correlated positively with E/E' ratio, radial SRe and longitudinal and circumferential E/SRe. LVEDP correlated negatively with longitudinal and circumferential SRe and radial E/SRe. Receiver operating characteristic curve analysis revealed that these SR indexes predicted elevated LVEDP (areas under the curve: longitudinal E/SRe = 0.74, circumferential E/SRe = 0.74, circumferential SRe = 0.70, longitudinal SRe = 0.69, radial E/SRe = 0.68, radial SRe = 0.65), but neither was superior to the tissue Doppler imaging index E/E' (area under the curve = 0.84). The present study indicates that 2-D speckle-tracking imaging is a practical method for evaluating LV filling pressure, but it might not provide additional advantages compared with E/E' in CAD patients. PMID- 26585466 TI - Reply to: Is there survival benefit from increased intensity for CEA monitoring after primary resection of colorectal cancer? PMID- 26585467 TI - Aberrant GSTP1 promoter methylation is associated with increased risk and advanced stage of breast cancer: a meta-analysis of 19 case-control studies. AB - BACKGROUND: Glutathione S-transferase P1 (GSTP1) has been reported to function as a tumor suppressor gene in various types of human cancers. Aberrant methylation of tumor-related genes at the promoter regions can inactivate genes, which is important in the carcinogenesis of breast cancer. However, the role of GSTP1 promoter methylation in the occurrence of breast cancer and its relationship with tumor stage and histological grade has not been fully elucidated. Thus, we carried out a meta-analysis to yield a more accurate association. METHODS: A systematically literature search was made on PubMed, EMBASE and Web of Science databases for eligible studies. The odds ratio (OR) and 95 % confidence interval (95 % CI) were calculated by RevMan 5.2 software. Subgroup and sensitivity analyses were conducted to explore the source of heterogeneity. RESULTS: Eventually, 17 articles involving 19 case-control studies were included in the present meta-analysis. Overall, the pooled results indicated that aberrant GSTP1 promoter methylation was significantly associated with the risk of breast cancer (OR = 7.85, 95 % CI = 5.12-12.01; Caucasians OR = 7.23, 95 % CI = 3.76-13.90 and Asians OR = 11.71, 95 % CI = 5.69-24.07). Furthermore, our results revealed that GSTP1 promoter methylation was more often observed in late-stage breast cancer patients compared with early-stage ones (OR = 1.84, 95 % CI = 1.32-2.58). However, no significant association was identified between GSTP1 promoter methylation and histological grade (OR = 0.74, 95 % CI = 0.43-1.26). CONCLUSIONS: The results indicated that GSTP1 promoter methylation probably plays an important role in breast carcinogenesis, which could serve as an effective biomarker for the diagnosis and monitor of breast cancer. PMID- 26585468 TI - Effect of increasing dietary nonfiber carbohydrate with starch, sucrose, or lactose on rumen fermentation and productivity of lactating dairy cows. AB - The objective of this study was to investigate effects of increasing dietary nonfiber carbohydrate (NFC) with starch, sucrose, or lactose on rumen fermentation, volatile fatty acid absorption, and milk production of lactating dairy cows. Twenty-eight multiparous, lactating Holstein cows (141 +/- 50 d in milk; 614 +/- 53 kg of body weight) including 8 ruminally cannulated cows were used in this study. Cows were assigned to 4 dietary treatments in a 4 * 4 Latin square design with 21-d periods. The treatments were control [27% starch and 4% sugar on a dry matter (DM) basis], a high-NFC diet by increasing dietary starch content (STA; 32% starch and 4% sugar on a DM basis), and 2 more high-NFC diets by increasing dietary sugar content (27% starch and 9% sugar on a DM basis) in which sucrose (SUC) or lactose (LAC) was supplemented. Dry matter intake was greater for cows fed high-NFC diets compared with control diet (27.1 vs. 26.3 kg/d), but rumen pH and milk production did not differ between cows fed control and high-NFC diets. However, cows fed high-disaccharide diets had lower mean rumen pH than those fed STA diet (6.19 vs. 6.32). Although molar proportion of butyrate was greater for high-disaccharide treatments than STA treatment (15.2 vs. 13.7 mol/100 mol), absorption rate of volatile fatty acid in the rumen was not affected by treatment. In addition, cows fed high-disaccharide diets had higher energy-corrected milk yield than cows fed STA diet (39.6 vs. 38.0 kg/d). Dry matter intake did not differ between cows fed 2 high-disaccharide diets. Although cows fed the SUC diet had lower molar proportion of butyrate in the rumen compared with those fed the LAC diet (14.4 vs. 15.9 mol/100 mol), the SUC diet did not decrease rumen pH. In addition, cows fed the SUC diet had lower nutrient digestibility of organic matter than did those fed the LAC diet (59.7 vs. 64.4%), but milk component yields did not differ between the 2 high disaccharide diet treatments. The results of the present study suggested that partially replacing dietary starch with disaccharides increased DM intake and energy-corrected milk, although rumen pH decreased for high-disaccharide diets, and that the rumen pH responses cannot be attributed to difference in absorption rate of volatile fatty acids in the rumen. In addition, type of sugars affected nutrient digestibility and rumen fermentation, but the effects were not large enough to affect rumen pH and milk production. PMID- 26585469 TI - Staphylococcus aureus genotype B and other genotypes isolated from cow milk in European countries. AB - Staphylococcus aureus is globally one of the most important pathogens causing contagious mastitis in cattle. Previous studies, however, have demonstrated in Swiss cows that Staph. aureus isolated from bovine intramammary infection is genetically heterogeneous, with Staph. aureus genotype B (GTB) and GTC being the most prominent genotypes. In addition, Staph. aureus GTB was found to be contagious, whereas Staph. aureus GTC and all the remaining genotypes were involved in individual cow disease. The aim of this study was to subtype strains of Staph. aureus isolated from bovine mastitic milk and bulk tank milk to obtain a unified view of the presence of bovine staphylococcal subtypes in 12 European countries. A total of 456 strains of Staph. aureus were subjected to different typing methods: ribosomal spacer PCR, detection of enterotoxin genes, and detection of gene polymorphisms (lukE, coa). Major genotypes with their variants were combined into genotypic clusters (CL). This study revealed 5 major CL representing 76% of all strains and comprised CLB, CLC, CLF, CLI, and CLR. The clusters were characterized by the same genetic properties as the Swiss isolates, demonstrating high clonality of bovine Staph. aureus. Interestingly, CLB was situated in central Europe whereas the other CL were widely disseminated. The remaining 24% of the strains comprised 41 genotypes and variants, some of which (GTAM, GTBG) were restricted to certain countries; many others, however, were observed only once. PMID- 26585470 TI - Short communication: Drug residues in goat milk after prophylactic use of antibiotics in intravaginal sponges for estrus synchronization. AB - The aim of this study was to determine whether the prophylactic use of antibiotics in intravaginal sponges used for estrus synchronization in goats may result in the presence of inhibitors in milk and, therefore, of positive results by microbial screening tests. Ninety-eight Murciano-Granadina goats were used, divided into 7 groups of 14 animals. Intravaginal sponges were placed in 6 groups using 2 concentrations of 3 different antibiotics: doxycycline, oxytetracycline, and sulfathiazole-framycetin. The sponges of the control group were placed without antibiotics. Milk samples were collected daily until 7 d posttreatment and analyzed using 3 microbial tests. Positive samples were retested by specific receptor-binding assays to confirm the positive results. Vaginal status was evaluated by visual assessment of the external aspect of the sponges after removal. The microbial test response was not affected by either day posttreatment or dose of antibiotic used, except for oxytetracycline at the higher concentration. Moreover, no positive results were obtained using receptor-binding assays, suggesting that residues, if present in milk, did not exceed the regulatory (safety) levels established for these drugs. The occurrence of soiled sponges was higher in the control group. With respect to the dose of antibiotics used, no significant differences were found for the lower dose administered. However, a significant increase in the percentage of clean sponges was observed for the higher dose of doxycycline. We conclude that the prophylactic use of low doses of doxycycline, oxytetracycline, or sulfathiazole in intravaginal sponges used for synchronization of estrus helps to reduce clinical vaginitis in dairy goats and does not seem to be the cause of positive results in microbial inhibitor tests used to detect antibiotics in goat milk. PMID- 26585471 TI - Randomized noninferiority study evaluating the efficacy of 2 commercial dry cow mastitis formulations. AB - The study objective was to compare the efficacy of 2 commercial dry cow mastitis formulations containing cloxacillin benzathine or ceftiofur hydrochloride. Quarter-level outcomes included prevalence of intramammary infection (IMI) postcalving, risk for cure of preexisting infections, risk for acquiring a new IMI during the dry period, and risk for clinical mastitis between dry off and 100 d in milk (DIM). Cow-level outcomes included the risk for clinical mastitis and the risk for removal from the herd between dry off and 100 DIM, as well as Dairy Herd Improvement Association (DHIA) test-day milk component and production measures between calving and 100 DIM. A total of 799 cows from 4 Wisconsin dairy herds were enrolled at dry off and randomized to 1 of the 2 commercial dry cow therapy (DCT) treatments: cloxacillin benzathine (DC; n=401) or ceftiofur hydrochloride (SM; n=398). Aseptic quarter milk samples were collected for routine bacteriological culture before DCT at dry off and again at 0 to 10 DIM. Data describing clinical mastitis cases and DHIA test-day results were retrieved from on-farm electronic records. The overall crude quarter-level prevalence of IMI at dry off was 34.7% and was not different between treatment groups. Ninety six percent of infections at dry off were of gram-positive organisms, with coagulase-negative Staphylococcus and Aerococcus spp. isolated most frequently. Mixed logistic regression analysis showed no difference between treatments as to the risk for presence of IMI at 0 to 10 DIM (DC=22.4%, SM=19.9%) or on the risk for acquiring a new IMI between dry off and 0 to 10 DIM (DC=16.6%, SM=14.1%). Noninferiority analysis and mixed logistic regression analysis both showed no treatment difference in risk for a cure between dry off and 0 to 10 DIM (DC=84.8%, SM=85.7%). Cox proportional hazards regression showed no difference between treatments in quarter-level risk for clinical mastitis (DC=1.99%, SM=2.96%), cow-level risk for clinical mastitis (DC=17.0%, SM=15.3%), or on risk for removal from the herd (DC=10.7%, SM=10.3%) between dry off and 100 DIM. Finally, multivariable linear regression with repeated measures showed no overall no difference between treatments in DHIA test-day somatic cell count linear score (DC=2.19, SM=2.22), butterfat test (DC=3.84%, SM=3.86%), protein test (DC=3.02%, SM=3.02%), or 305-d mature-equivalent milk production (DC=11,817 kg, SM=11,932 kg) between calving and 100 DIM. In conclusion, DC was noninferior to SM in effecting a cure, and there was no difference in efficacy between these 2 DCT formulations as related to all other udder health or cow performance measures evaluated between dry off and 100 DIM. PMID- 26585472 TI - Quantification of whey proteins by reversed phase-HPLC and effectiveness of mid infrared spectroscopy for their rapid prediction in sweet whey. AB - In the dairy industry, membrane filtration is used to reduce the amount of whey waste and, simultaneously, to recover whey proteins (WP). The composition of WP can strongly affect the filtration treatment of whey, and rapid determination of WP fractions would be of interest for dairy producers to monitor WP recovery. This study aimed to develop mid-infrared spectroscopy (MIRS) prediction models for the rapid quantification of protein in sweet whey, using a validated rapid reversed phase (RP)-HPLC as a reference method. Quantified WP included alpha lactalbumin (alpha-LA), beta-lactoglobulin (beta-LG) A and B, bovine serum albumin, caseinomacropeptides, and proteose peptone. Validation of RP-HPLC was performed by calculating the relative standard deviation (RSD) in repeatability and reproducibility tests for WP retention time and peak areas. Samples of liquid whey (n=187) were analyzed by RP-HPLC and scanned through MIRS to collect spectral information (900 to 4,000 cm(-1)); statistical analysis was carried out through partial least squares regression and random cross-validation procedure. Retention times in RP-HPLC method were stable (RSD between 0.03 and 0.80%), whereas the RSD of peak area (from 0.25 to 8.48%) was affected by WP relative abundance. Higher coefficients of determination in validation for MIRS model were obtained for protein fractions present in whey in large amounts, such as beta-LG (0.58), total identified WP (0.58), and alpha-LA (0.56). Results of this study suggest that MIRS is an easy method for rapid quantification of detail protein in sweet whey, even if better resolution was achieved with the method based on RP HPLC. The prediction of WP in sweet whey by MIRS might be used for screening and for classifying sweet whey according to its total and individual WP contents. PMID- 26585473 TI - Milk production responses to different strategies for feeding supplements to grazing dairy cows. AB - Milk production responses of grazing cows offered supplements in different ways were measured. Holstein-Friesian cows, averaging 45 d in milk, were allocated into 8 groups of 24, with 2 groups randomly assigned to each of 4 feeding strategies. These were control: cows grazed a restricted allowance of perennial ryegrass pasture supplemented with milled wheat grain fed in the milking parlor and alfalfa hay offered in the paddock; FGM: same pasture and allowance as the control supplemented with a formulated grain mix containing wheat grain, corn grain, and canola meal fed in the parlor and alfalfa hay fed in the paddock; PMRL: same pasture and allowance as the control, supplemented with a PMR consisting of the same FGM but mixed with alfalfa hay and presented on a feed pad after each milking; and PMRH: same PMR fed in the same way as PMRL but with a higher pasture allowance. For all strategies, supplements provided the same metabolizable energy and grain:forage ratio [75:25, dry matter (DM) basis]. Each group of 24 cows was further allocated into 4 groups of 6, which were randomly assigned to receive 8, 12, 14, or 16 kg of DM supplement/cow per d. Thus, 2 replicated groups per supplement amount per dietary strategy were used. The experiment had a 14-d adaptation period and a 14-d measurement period. Pasture allowance, measured to ground level, was approximately 14 kg of DM/d for control, FGM, and PMRL cows, and 28 kg of DM/d for the PMRH cows, and was offered in addition to the supplement. Positive linear responses to increasing amounts of supplement were observed for yield of milk, energy-corrected milk, fat, and protein for cows on all 4 supplement feeding strategies. Production of energy corrected milk was greatest for PMRH cows, intermediate for FGM and PMRL cows, and lowest for control cows. Some of these differences in milk production related to differences in intake of pasture and supplement. Milk fat concentration decreased with increasing amount of supplement for all feeding strategies, but the decline was most marked for the control cows. Milk protein concentration increased for all groups as the amount of supplement increased, but was greater for FGM, PMRL, and PMRH cows than control cows. It is concluded that when supplements are fed to grazing dairy cows, inclusion of corn grain and canola meal can increase milk production even at similar metabolizable energy intakes, and that it does not matter whether these supplements are fed as a PMR or in the parlor and paddock. PMID- 26585474 TI - Inter-relationships among alternative definitions of feed efficiency in grazing lactating dairy cows. AB - International interest in feed efficiency, and in particular energy intake and residual energy intake (REI), is intensifying due to a greater global demand for animal-derived protein and energy sources. Feed efficiency is a trait of economic importance, and yet is overlooked in national dairy cow breeding goals. This is due primarily to a lack of accurate data on commercial animals, but also a lack of clarity on the most appropriate definition of the feed intake and utilization complex. The objective of the present study was to derive alternative definitions of energetic efficiency in grazing lactating dairy cows and to quantify the inter relationships among these alternative definitions. Net energy intake (NEI) from pasture and concentrate intake was estimated up to 8 times per lactation for 2,693 lactations from 1,412 Holstein-Friesian cows. Energy values of feed were based on the French Net Energy system where 1 UFL is the net energy requirements for lactation equivalent of 1kg of air-dry barley. A total of 8,183 individual feed intake measurements were available. Energy balance was defined as the difference between NEI and energy expenditure. Efficiency traits were either ratio-based or residual-based; the latter were derived from least squares regression models. Residual energy intake was defined as NEI minus predicted energy to fulfill the requirements for the various energy sinks. The energy sinks (e.g., NEL, metabolic live weight) and additional contributors to energy kinetics (e.g., live weight loss) combined, explained 59% of the variation in NEI, implying that REI represented 41% of the variance in total NEI. The most efficient 10% of test-day records, as defined by REI (n=709), on average were associated with a 7.59 UFL/d less NEI (average NEI of the entire population was 16.23 UFL/d) than the least efficient 10% of test-day records based on REI (n=709). Additionally, the most efficient 10% of test-day records, as defined by REI, were associated with superior energy conversion efficiency (ECE, i.e., NEL divided by NEI; ECE=0.55) compared with the least efficient 10% of test-day records (ECE=0.33). Moreover, REI was positively correlated with energy balance, implying that more negative REI animals (i.e., deemed more efficient) are expected to be, on average, in greater negative energy balance. Many of the correlations among the 14 defined efficiency traits differed from unity, implying that each trait is measuring a different aspect of efficiency. PMID- 26585475 TI - Short communication: Typing and tracking Bacillaceae in raw milk and milk powder using pyroprinting. AB - Contamination of fluid and processed milk products with endospore-forming bacteria, such as Bacillaceae, affect milk quality and longevity. Contaminants come from a variety of sources, including the dairy farm environment, transportation equipment, or milk processing machinery. Tracking the origin of bacterial contamination to allow specifically targeted remediation efforts depends on a reliable strain-typing method that is reproducible, fast, easy to use, and amenable to computerized analysis. Our objective was to adapt a recently developed genotype-based Escherichia coli strain-typing method, called pyroprinting, for use in a microbial source-tracking study to follow endospore forming bacillus bacteria from raw milk to powdered milk. A collection of endospores was isolated from both raw milk and its finished powder, and, after germination, the vegetative cells were subject to the pyroprinting protocol. Briefly, a ribosomal DNA intergenic transcribed spacer present in multiple copies in Bacillaceae genomes was amplified by the PCR. This multicopy locus generated a mixed PCR product that was subsequently subject to pyrosequencing, a quantitative real-time sequencing method. Through a series of enzymatic reactions, each nucleotide incorporation event produces a photon of light that is quantified at each nucleotide dispensation. The pattern of light peaks generated from this mixed template reaction is called a pyroprint. Isolates with pyroprints that match with a Pearson correlation of 0.99 or greater are considered to be in the same group. The pyroprint also contains some sequence data useful for presumptive species-level identification. This method identified groups with isolates from raw milk only, from powdered milk only, or from both sources. This study confirms pyroprinting as a rapid, reproducible, automatically digitized tool that can be used to distinguish bacterial strains into taxonomically relevant groups and, thus, indicate probable origins of bacterial contamination in powdered milk. PMID- 26585476 TI - A sensory- and consumer-based approach to optimize cheese enrichment with grape skin powders. AB - The present study aimed to present a sensory- and consumer-based approach to optimize cheese enrichment with grape skin powders (GSP). The combined sensory evaluation approach, involving a descriptive and an affective test, respectively, was applied to evaluate the effect of the addition of grape skin powders from 2 grape varieties (Barbera and Chardonnay) at different levels [0.8, 1.6, and 2.4%; weight (wt) powder/wt curd] on the sensory properties and consumer acceptability of innovative soft cow milk cheeses. The experimental plan envisaged 7 products, 6 fortified prototypes (at rates of Barbera and Chardonnay of 0.8, 1.6, and 2.4%) and a control sample, with 1 wk of ripening. By means of a free choice profile, 21 cheese experts described the sensory properties of prototypes. A central location test with 90 consumers was subsequently conducted to assess the acceptability of samples. The GSP enrichment strongly affected the sensory properties of innovative products, mainly in terms of appearance and texture. Fortified samples were typically described with a marbling aspect (violet or brown as function of the grape variety) and with an increased granularity, sourness, saltiness, and astringency. The fortification also contributed certain vegetable sensations perceived at low intensity (grassy, cereal, nuts), and some potential negative sensations (earthy, animal, winy, varnish). The white color, the homogeneous dough, the compact and elastic texture, and the presence of lactic flavors resulted the positive drivers of preference. On the contrary, the marbling aspect, granularity, sandiness, sourness, saltiness, and astringency negatively affected the cheese acceptability for amounts of powder, exceeding 0.8 and 1.6% for the Barbera and Chardonnay prototypes, respectively. Therefore, the amount of powder resulted a critical parameter for liking of fortified cheeses and a discriminant between the 2 varieties. Reducing the GSP particle size and improving the GSP dispersion in the curd would reduce the effect of powder addition on sensory properties, thereby encouraging the use of these polyphenol based fortifiers in cheeses. The proposed approach allowed the identification of sensory properties critical for product acceptability by consumers, thus helping the optimization of both fortifier characteristics and new cheese production and composition. PMID- 26585477 TI - Transformation of serum-susceptible Escherichia coli O111 with p16Slux plasmid to allow for real-time monitoring of complement-based inactivation of bacterial growth in bovine milk. AB - Complement activity has only recently been characterized in raw bovine milk. However, the activity of this component of the innate immune system was found to diminish as milk was subjected to heat or partitioning during cream separation. Detection of complement in milk relies on a bactericidal assay. This assay exploits the specific growth susceptibility of Escherichia coli O111 to the presence of complement. Practical application of the assay was demonstrated when a reduction in complement activity was recorded in the case of pasteurized and reduced-fat milks. This presented an opportunity to improve the functionality of the bactericidal assay by incorporating bioluminescence capability into the target organism. Following some adaptation, the strain was transformed by correctly integrating the p16Slux plasmid. Growth properties of the transformed strain of E. coli O111 were unaffected by the modification. The efficacy of the strain adaptation was correlated using the LINEST function analysis [r=0.966; standard error of prediction (SEy)=0.957] bioluminescence with that of bactericidal assay total plate counts within the range of 7.5 to 9.2 log cfu/mL using a combination of raw and processed milk samples. Importantly, the transformed E. coli O111 p16Slux strain could be identified in milk and broth samples using bioluminescence measurement, thus enabling the bactericidal assay viability test to be monitored in real time throughout incubation. PMID- 26585478 TI - Hepatic global DNA and peroxisome proliferator-activated receptor alpha promoter methylation are altered in peripartal dairy cows fed rumen-protected methionine. AB - The availability of Met in metabolizable protein (MP) of a wide range of diets for dairy cows is low. During late pregnancy and early lactation, in particular, suboptimal Met in MP limits its use for mammary and liver metabolism and also for the synthesis of S-adenosylmethionine, which is essential for many biological processes, including DNA methylation. The latter is an epigenetic modification involved in the regulation of gene expression, hence, tissue function. Thirty nine Holstein cows were fed throughout the peripartal period (-21 d to 30 d in milk) a basal control (CON) diet (n=14) with no Met supplementation, CON plus MetaSmart (MS; Adisseo NA, Alpharetta, GA; n=12), or CON plus Smartamine M (SM; Adisseo NA; n=13). The total mixed ration dry matter for the close-up and lactation diets was measured weekly, then the Met supplements were adjusted daily and top-dressed over the total mixed ration at a rate of 0.19 (MS) or 0.07% (SM) on a dry matter basis. Liver tissue was collected on -10, 7, and 21 d for global DNA and peroxisome proliferator-activated receptor alpha (PPARalpha) promoter region-specific methylation. Several PPARalpha target and putative target genes associated with carnitine synthesis and uptake, fatty acid metabolism, hepatokines, and carbohydrate metabolism were also studied. Data were analyzed using PROC MIXED of SAS (SAS Institute Inc., Cary, NC) with the preplanned contrast CON versus SM + MS. Global hepatic DNA methylation on d 21 postpartum was lower in Met-supplemented cows than CON. However, of 2 primers used encompassing 4 to 12 CpG sites in the promoter region of bovine PPARA, greater methylation occurred in the region encompassing -1,538 to -1,418 from the transcription start site in cows supplemented with Met. Overall expression of PPARA was greater in Met-supplemented cows than CON. Concomitantly, PPARA-target genes, such as ANGPTL4, FGF21, and PCK1, were also upregulated overall by Met supplementation. The upregulation of PPARalpha target genes indicates that supplemental Met, likely through the synthesis of S-adenosylmethionine, activated PPARA-regulated signaling pathways. Upregulation of hepatic PPARA has been associated with improved lipid metabolism and immune function, both of which were reported in companion publications from this study. In turn, those positive effects resulted in improved postpartal health and performance. Further research is needed to study more closely the mechanistic connections between global DNA and promoter region-specific PPARA methylation with PPARA expression and functional outcomes in liver. PMID- 26585479 TI - Effect of the absence of the CcpA gene on growth, metabolic production, and stress tolerance in Lactobacillus delbrueckii ssp. bulgaricus. AB - The catabolite control protein A (CcpA) is a kind of multi-effect regulatory protein. In the study, the effect of the inactivation of CcpA and aerobic conditions on the growth, metabolic production, and stress tolerance to heat, oxidative, and cold stresses in Lactobacillus delbrueckii ssp. bulgaricus was investigated. Results showed that inactivation of CcpA distinctly hindered growth. Total lactic acid concentration was significantly lower in aerobiosis for both strains and was lower for the mutant strain than L. bulgaricus. Acetic acid production from the mutant strain was higher than L. bulgaricus in aerobiosis compared with anaerobiosis. Enzyme activities, lactate dehydrogenase (LDH), phosphate fructose kinase (PFK), pyruvate kinase (PK), and pyruvic dehydrogenase (PDH), were significantly lower in the mutant strain than L. bulgaricus. The diameters of inhibition zone were 13.59 +/- 0.02 mm and 9.76 +/- 0.02 mm for L. bulgaricus in anaerobiosis and aerobiosis, respectively; and 8.12 +/- 0.02 mm and 7.38 +/- 0.02 mm for the mutant in anaerobiosis and aerobiosis, respectively. For both strains, cells grown under aerobic environment possess more stress tolerance. This is the first study in which the CcpA-negative mutant of L. bulgaricus is constructed and the effect of aerobic growth on stress tolerance of L. bulgaricus is evaluated. Although aerobic cultivation does not significantly improve growth, it does improve stress tolerance. PMID- 26585480 TI - Economic values for health and feed efficiency traits of dual-purpose cattle in marginal areas. AB - Economic values of clinical mastitis, claw disease, and feed efficiency traits along with 16 additional production and functional traits were estimated for the dairy population of the Slovak Pinzgau breed using a bioeconomic approach. In the cow-calf population (suckler cow population) of the same breed, the economic values of feed efficiency traits along with 15 further production and functional traits were calculated. The marginal economic values of clinical mastitis and claw disease incidence in the dairy system were -? 70.65 and -? 26.73 per case per cow and year, respectively. The marginal economic values for residual feed intake were -? 55.15 and -? 54.64/kg of dry matter per day for cows and breeding heifers in the dairy system and -? 20.45, -? 11.30, and -? 6.04/kg of dry matter per day for cows, breeding heifers, and fattened animals in the cow-calf system, respectively, all expressed per cow and year. The sums of the relative economic values for the 2 new health traits in the dairy system and for residual feed intake across all cattle categories in both systems were 1.4 and 8%, respectively. Within the dairy production system, the highest relative economic values were for milk yield (20%), daily gain of calves (20%), productive lifetime (10%), and cow conception rate (8%). In the cow-calf system, the most important traits were weight gain of calves from 120 to 210 d and from birth to 120 d (19 and 14%, respectively), productive lifetime (17%), and cow conception rate (13%). Based on the calculation of economic values for traits in the dual-purpose Pinzgau breed, milk production and growth traits remain highly important in the breeding goal, but their relative importance should be adapted to new production and economic conditions. The economic importance of functional traits (especially of cow productive lifetime and fertility) was sufficiently high to make the inclusion of these traits into the breeding goal necessary. An increased interest of consumers in animal welfare and quality of dairy farm products should probably lead to the incorporation of health traits (clinical mastitis incidence and somatic cells score) into the breeding goal. However, keeping carcass traits in the breeding goal of the Slovak Pinzgau breed does not seem to be relevant to the long-term market situation. PMID- 26585481 TI - Predicting extraction and uptake of arterial energy metabolites by the mammary glands of lactating cows when blood flow is perturbed. AB - Previous work shows that mammary uptake of milk precursors from blood can be affected by the rate of blood flow (F) to the glands. The purpose of the current work was to test the ability of compartmental and cylindrical capillary models to account for the variation in mammary extraction and net uptake of plasma metabolites produced by perturbation of mammary F. The data for model fitting were obtained from a previous experiment in which mammary arteriovenous differences of acetate + beta-hydroxybutyrate (2C), glucose, triacylglycerol (TAG), and long-chain fatty acids (LCFA) were measured in 4 cows before, during, and after intraarterial infusion of inhibitors of endothelial nitric oxide synthase and cyclooxygenase, which are 2 major systems of F control in the mammary glands. The 4 models tested were (1) constant extraction within each cow, (2) clearance from an extracellular compartment is a linear function of F with an intercept, (3) total capillary volume in a cylindrical representation is a linear function of F with an intercept, and (4) uptake from an extracellular compartment obeys Henri-Michaelis-Menten kinetics, where maximum velocity (Vmax) is a linear function of F with an intercept. According to prediction errors, model 4 fitted 2C extraction data best, accounting for 82% of the observed variation. The estimated Km (Henri-Michaelis-Menten constant) for venous 2C was 0.4 mM. For glucose clearance, a variant of model 2 with a positive effect of 2C uptake on clearance was identified as best, producing a coefficient of determination (R(2)) of 0.31. For TAG, model 2 with a positive effect of arterial TAG concentration on TAG clearance was best, with an R(2) of 0.22. For LCFA, model 2 with a positive effect of arterial LCFA on LCFA clearance was best, with an R(2) of 0.29. Models 2 and 3 fitted the extraction data with the same R(2)-values and prediction errors, so both compartmental and cylindrical approaches to describing the vascular bed were equally capable of describing the effect of F on mammary uptakes. A combined fit of all best-fit models to extraction data for all 4 metabolites at once explained 52, 42, 73, and 77% of variation in net uptakes of 2C, glucose, TAG, and LCFA, respectively. According to the fitted model, each 1 L/min increase in F increased the mammary volumes of distribution of 2C, glucose, TAG, and LCFA by 13, 14, 18, and 7%, respectively. PMID- 26585482 TI - Effect of calving interval and parity on milk yield per feeding day in Danish commercial dairy herds. AB - The idea of managing cows for extended lactations rather than lactations of the traditional length of 1 yr primarily arose from observations of increasing problems with infertility and cows being dried off with high milk yields. However, it is vital for the success of extended lactation practices that cows are able to maintain milk yield per feeding day when the length of the calving interval (CInt) is increased. Milk yield per feeding day is defined as the cumulated lactation milk yield divided by the sum of days between 2 consecutive calvings. The main objective of this study was to investigate the milk production of cows managed for lactations of different lengths, and the primary aim was to investigate the relationship between CInt, parity, and milk yield. Five measurements of milk yield were used: energy-corrected milk (ECM) yield per feeding day, ECM yield per lactating day, cumulative ECM yield during the first 305 d of lactation, as well as ECM yield per day during early and late lactation. The analyses were based on a total of 1,379 completed lactations from cows calving between January 2007 and May 2013 in 4 Danish commercial dairy herds managed for extended lactation for several years. Herd-average CInt length ranged from 414 to 521 d. The herds had Holstein, Jersey, or crosses between Holstein, Jersey, and Red Danish cows with average milk yields ranging from 7,644 to 11,286 kg of ECM per cow per year. A significant effect of the CInt was noted on all 5 measurements of milk yield, and this effect interacted with parity for ECM per feeding day, ECM per lactating day and ECM per day during late lactation. The results showed that cows were at least able to produce equivalent ECM per feeding day with increasing CInt, and that first- and second-parity cows maintained ECM per lactating day. Cows with a CInt between 17 and 19 mo produced 476 kg of ECM more during the first 305 d compared with cows with a CInt of less than 13 mo. Furthermore, early-lactation ECM yield was greater for all cows and late lactation ECM yield was less for second-parity and older cows when undergoing an extended compared with a shorter lactation. Increasing CInt increased the dry period length with 3 to 5d. In conclusion, the group of cows with longer CInt were able to produce at least equivalent amounts of ECM per feeding day when the CInt was up to 17 to 19 mo on these 4 commercial dairy farms. PMID- 26585483 TI - Effect of maturity and hybrid on ruminal and intestinal digestion of corn silage in dry cows. AB - The aim of this study was to evaluate the effect of stage of maturity at harvest on extent of starch, neutral detergent fiber (NDF), and protein digestion, and rumen fermentation in dry cows fed whole-plant corn silage from different hybrids. Four nonlactating Holstein cows cannulated at the rumen and proximal duodenum were fed 4 corn silages differing in hybrid (flint vs. flint-dent) and maturity stage (early vs. late) in a 4 * 4 Latin square design. From early to late maturity, starch content increased (from 234.5 to 348.5 g/kg), whereas total tract (99.7 to 94.5%) and ruminal starch digestibility (91.3 to 86.5%) decreased significantly. The decrease in ruminal starch digestibility with increasing maturity was similar between hybrids. No effects were found of maturity, hybrid, or maturity * hybrid interaction on total-tract NDF digestibility, ruminal NDF digestibility, true digestibility of N and organic matter in the rumen, or microbial synthesis. Harvesting at later maturity led to increased ruminal ammonia, total volatile fatty acid concentrations, and acetate/propionate ratio but not pH. This study concludes that delaying date of harvest modifies the proportions of digestible starch and NDF supplied to cattle. Adjusting date of corn harvest to modulate amount of rumen-digested starch could be used as a strategy to control nutrient delivery to ruminants. PMID- 26585484 TI - Phenotypic associations between gestation length and production, fertility, survival, and calf traits. AB - Gestation length may be a useful selection criterion in the genetic evaluation of fertility for New Zealand's predominantly seasonally calving dairy herd. However, it is unknown if calves born following shorter gestation lengths have lower survival or are compromised in their subsequent performance as a milking cow. In this study, data from a large number (~38,000) of cows were first analyzed to determine if those animals born following a short (shortest 5%) or a long (longest 5%) gestation length differed in their subsequent fertility, milk production, and survival compared with intermediate-gestation-length animals. To determine the effect of gestation length on calving difficulty and perinatal mortality, the gestation records of the calves born to these cows (from their heifer and subsequent 6 parities) were also analyzed. Animals born following short gestation lengths had improved fertility (specifically, their probability of being presented for mating in the first 21 d of the mating season was increased by 4 to 5 percentage points and the day of the calving season at which they calved was 2 to 5d earlier), whereas those born following long gestation lengths had decreased fertility (3 to 4% less likely to be presented for mating in the first 21 d of the calving season and calved 3 to 5d later) compared with animals with average gestation lengths. Both short- and long-gestation-length animals produced significantly less milk and solids (e.g., 1.3 to 1.4 kg of protein over a standardized 270-d lactation) relative to intermediate-gestation length cows, after adjusting for the day of the year they were born. However, for short-gestation-length cows, this effect disappeared when the earlier birth advantage was retained. Short-gestation-length cows did not exhibit a significant reduction in survival compared with intermediate-gestation-length cows. Short gestation length did not affect calving difficulty but long gestation length was negatively associated with this trait (i.e., about 2% higher incidence). Calves gestated for shorter or longer periods were more likely to die in the perinatal period than other calves (3 and 7% higher incidence of mortality, respectively). Overall, the net effects of shortened gestation lengths are likely to be economically positive. PMID- 26585485 TI - Housing system may affect behavior and growth performance of Jersey heifer calves. AB - Social pressure is increasing to adopt alternative housing and management practices that allow farm animals more opportunity to exercise and demonstrate social behavior. The present study investigated the effect of pair housing on the behavior and growth performance of Jersey heifer calves. Forty female Jersey calves were allocated to individual or pair housing at birth and monitored for 9 wk. Calves were provided with a single hutch, and those allocated to the pair housing treatment were provided a pen enclosure twice the size of individually housed calves and only one hutch was provided per pair. All calves were fed milk replacer via bucket twice per day (1.89 L/feeding first 7 d; 2.27 L/feeding until weaned) and had ad libitum access to grain and water. Gradual weaning commenced on d 49 by reducing the calves' milk allowance to one feeding per day, and weaning occurred on d 56. Grain consumption was monitored daily and calves were weighed weekly. Direct behavioral observations were conducted twice per week. Calves housed in pairs tended to have greater average daily gain compared with calves housed individually (0.63 vs. 0.59 +/- 0.02 kg/d, respectively). Pair housing also increased final body weight compared with individual housing (64.9 vs. 61.7 +/- 0.59 kg, respectively). During observation periods, calves housed individually spent more time engaging in nonnutritive sucking than calves housed in pairs (21.5 vs. 8.15 +/- 0.03% of total observations). Calves housed in pairs were observed cross sucking 13.5% of the time during observational periods. Although housing Jersey calves in pairs may increase measures of growth performance, future research should aim to reduce cross-sucking behavior within the Jersey breed through alternative feeding systems or environmental enrichment. PMID- 26585486 TI - Activation of mTORC1 under nutrient starvation conditions increases cellular radiosensitivity in human liver cancer cell lines, HepG2 and HuH6. AB - BACKGROUND: The presence of unperfused regions containing cells under hypoxic and nutrient starvation conditions contributes to radioresistance in solid human tumors. It is well known that the hypoxia causes cellular radioresistance. However, the effects of nutrient starvation conditions on cellular radiosensitivity remain unclear. METHODS: Human liver cancer cell lines, HepG2 and HuH6, and a SV40-transformed human fibroblast cell line, LM217 were used to examine the effects of nutrient starvation conditions on cellular radiosensitivity and on activity of mammalian target of rapamycin complex 1 (mTORC1) that senses cellular nutrient conditions and affects radiosensitivity. RESULTS: In contrast to suppressed mTORC1 activity under nutrient starvation conditions in LM217, HepG2 and HuH6 cells showed increased mTORC1 activity under nutrient starvation conditions. Both AMP-activated protein kinase (AMPK) and Akt were activated under nutrient starvation conditions in all the three cell lines. Under starvation conditions, increased radiosensitivity was observed in HepG2 and HuH6 cells, in contrast to decreased radiosensitivity in LM217 cells. Knockdown of mTOR using siRNA for mTOR or treatment with a mTOR inhibitor, rapamycin, suppressed the increased radiosensitivity under starvation conditions in HepG2 cells. CONCLUSION: Our data show for the first time that nutrient starvation conditions activate mTORC1 and increase radiosensitivity through mTORC1 activation in liver cancer cell lines, HepG2 and HuH6. PMID- 26585487 TI - miR-4792 inhibits epithelial-mesenchymal transition and invasion in nasopharyngeal carcinoma by targeting FOXC1. AB - Through analysis of a published micro-array-based high-throughput assessment, we discovered that miR-4792 was markedly down-regulated in nasopharyngeal carcinoma (NPC) tissues. However, little is known about its effect and mechanism involved in NPC development and progression. Here, we reported the role of miR-4792 in epithelial-mesenchymal transition (EMT) and invasion in NPC. We identified an inverse correlation between miR-4792 expression level and NPC cell EMT and invasion, and up-regulation of miR-4792 inhibited NPC cell EMT and invasion. Moreover, we identified and validated that FOXC1 was a direct target of miR-4792, and miR-4792 regulated EMT and invasion in NPC by acting directly on the 3'UTR of FOXC1 mRNA. We also performed the animal experiments to explore the anti-tumor effect of miR-4792, and found that overexpression of miR-4792 inhibited the growth of nasopharyngeal tumors in vivo. These findings suggest that miR-4792 functions as a tumor suppressor in NPC development and progression by targeting FOXC1, which could act as a novel potential therapeutic target for NPC treatment, and miR-4792/FOXC1 pathway that we studied might be used for NPC treatment in future. PMID- 26585488 TI - MiR-661 inhibits glioma cell proliferation, migration and invasion by targeting hTERT. AB - In this study, we analyzed the functional role of miR-661 in glioma cell proliferation, migration and invasion. We found that overexpression of miR-661 obviously suppressed the proliferation, migration and invasion of glioma cells. MiRNA target prediction algorithms implied that hTERT is a candidate target gene for miR-661. A fluorescent reporter assay confirmed that miR-661 could lead to hTERT gene silencing by recognizing and specifically binding to the predicted site of the hTERT mRNA 3' untranslated region (3'UTR) specifically. Furthermore, hTERT knockdown significantly decreased the growth and viability of glioma cells. These results indicate that miR-661 can inhibit glioma cell proliferation, migration and invasion by targeting hTERT. PMID- 26585489 TI - Autocrine insulin increases plasma membrane K(ATP) channel via PI3K-VAMP2 pathway in MIN6 cells. AB - Regulation of ATP-sensitive inwardly rectifying potassium (KATP) channel plays a critical role in metabolism-secretion coupling of pancreatic beta-cells. Released insulin from beta-cells inhibits insulin and glucagon secretion with autocrine and paracrine modes. However, molecular mechanism by which insulin inhibits hormone secretion remains elusive. Here, we investigated the effect of autocrine insulin on surface abundance of KATP channel in mouse clonal beta-cell line, MIN6. High glucose increased plasmalemmal sulfonylurea receptor 1 (SUR1), a component of KATP channel as well as exogenous insulin treatment. SUR1 trafficking by high glucose or insulin was blocked by inhibition of phosphoinositide 3-kinase (PI3K) with wortmannin. Pretreatment with brefeldin A or silencing of vesicle-associated membrane protein 2 (VAMP2) abolished insulin mediated upregulation of surface SUR1. Functionally, glucose-stimulated cytosolic Ca(2+) ([Ca(2+)]i) increase was blunted by insulin or diazoxide, a KATP channel opener. Insulin-induced suppression of [Ca(2+)]i oscillation was prevented by an insulin receptor blocker. These results provide a novel molecular mechanism for autocrine negative feedback regulation of insulin secretion. PMID- 26585490 TI - Arctigenin reduces blood pressure by modulation of nitric oxide synthase and NADPH oxidase expression in spontaneously hypertensive rats. AB - Arctigenin is a bioactive constituent from dried seeds of Arctium lappa L., which was traditionally used as medicine. Arctigenin exhibits various bioactivities, but its effects on blood pressure regulation are still not widely studied. In this study, we investigated antihypertensive effects of arctigenin by long-term treatment in spontaneously hypertensive rats (SHRs). Arctigenin (50 mg/kg) or vehicle was administered to SHRs or Wistar rats as negative control by oral gavage once a day for total 8 weeks. Nifedipine (3 mg/kg) was used as a positive drug control. After treatment, hemodynamic and physical parameters, vascular reactivity in aorta, the concentration of plasma arctigenin and serum thromboxane B2, NO release and vascular p-eNOS, p-Akt, caveolin-1 protein expression, and vascular superoxide anion generation and p47phox protein expression were detected and analyzed. The results showed that arctigenin significantly reduced systolic blood pressure and ameliorated endothelial dysfunction of SHRs. Arctigenin reduced the levels of thromboxane B2 in plasma and superoxide anion in thoracic aorta of SHRs. Furthermore, arctigenin increased the NO production by enhancing the phosphorylation of Akt and eNOS (Ser 1177), and inhibiting the expression of NADPH oxidase in thoracic aorta of SHRs. Our data suggested that antihypertensive mechanisms of arctigenin were associated with enhanced eNOS phosphorylation and decreased NADPH oxidase-mediated superoxide anion generation. PMID- 26585491 TI - Proteomics applications in Caenorhabditis elegans research. AB - The free-living nematode Caenorhabditis elegans is one of the most studied models in a wide variety of research fields with applications in agro- or pharmaceutical industries. It has been used for the development of new anthelminthic drugs and was proven to yield key insights in neurodegenerative diseases and metabolic syndromes. Due to its suitability for high-throughput genetic screens, efficiency for RNA interference approaches and the availability of thousands of mutants, most studies were carried out at the genetic level. However, determining the cellular function of each gene product remains an unfinished goal in this post genomic era. A systems biology approach focusing on the actual gene products (i.e. proteins) can help unraveling this puzzle. A fundamental pillar in this research is mass spectrometry-based proteomics. We here provide an in-depth overview of proteomics-related studies in C. elegans research, with special emphasis on the methodologies and biological applications. PMID- 26585492 TI - Prolactin-Induced Protein regulates cell adhesion in breast cancer. AB - Prolactin-Induced Prolactin (PIP) is widely expressed in breast cancer and has key cellular functions in this disease that include promoting invasion and cell cycle progression. Notably, we have recently identified a strong association between PIP-binding partners and a number of cell functions that are involved in cell adhesion. Therefore in this study, we investigated the effect of PIP on the regulation of cell adhesion using PIP-silencing in breast cancer cell lines T 47D, BT-474, and MFM-223. Our findings suggest that PIP expression is necessary for cell adhesion in a process that shows variation in the pattern of PIP regulation of cell-matrix and cell-cell adhesions based on the types of adhesion surface and breast cancer cell line. In this respect, we observed that PIP silencing markedly reduced cell adhesion to uncoated plates in all three cell lines. In addition, in T-47D and MFM-223 cells fibronectin matrix induced baseline adhesion and reversed the PIP-silencing mediated reduction of cell adhesion. However, in BT-474 cells we did not observe an induction of baseline adhesion by fibronectin and PIP-silencing led to a marked reduction in cell adhesion to both uncoated and fibronectin-coated plates. Furthermore, we observed a significant reduction in cell-cell adhesion of BT-474 cell line following PIP silencing. To explain an underlying mechanism for PIP regulation of cell adhesion, we found that PIP expression is necessary for the formation of alpha actinin/actin-rich podosomes at the adhesion-sites of breast cancer cells. In summary, this study suggests that PIP expression regulates the process of cell adhesion in breast cancer. PMID- 26585493 TI - Oral health needs in individuals with trisomy 18 and trisomy 13: Implications for dental professionals. AB - The purpose of this study was to examine oral health needs and dental care in individuals with trisomy 18 and trisomy 13 (full, mosaic, partial and other, mixed types). Primary feeding method was also examined. Data was collected from a parent-completed, mixed method survey (TRIS Survey). Mean age in months was 120.2 (range 38 to 394 months) and 133 (range 36 to 405 months), respectively, for trisomy 18 and trisomy 13 individuals. Results indicated the majority of individuals received routine dental care from their family dentist. Approximately 80% in both groups needed some form of specialized dental care. Close to 25% and 30% of trisomy 18 and trisomy 13 individuals, respectively, required hospital admission for specialized dental care. Responses indicated the presence of excessive plaque and tooth decay across the groups with a higher incidence for individuals with trisomy 13. Although not the primary form of intake, over half of the individuals received oral feedings. Implications for dental care and management are provided along with the need for additional research to confirm or disconfirm this study's findings. PMID- 26585496 TI - 2020 Vision: Genetic Counselors as Acknowledged Leaders in Integrating Genetics and Genomics into Healthcare. PMID- 26585495 TI - Optical Control of Insulin Secretion Using an Incretin Switch. AB - Incretin mimetics are set to become a mainstay of type 2 diabetes treatment. By acting on the pancreas and brain, they potentiate insulin secretion and induce weight loss to preserve normoglycemia. Despite this, incretin therapy has been associated with off-target effects, including nausea and gastrointestinal disturbance. A novel photoswitchable incretin mimetic based upon the specific glucagon-like peptide-1 receptor (GLP-1R) agonist liraglutide was designed, synthesized, and tested. This peptidic compound, termed LirAzo, possesses an azobenzene photoresponsive element, affording isomer-biased GLP-1R signaling as a result of differential activation of second messenger pathways in response to light. While the trans isomer primarily engages calcium influx, the cis isomer favors cAMP generation. LirAzo thus allows optical control of insulin secretion and cell survival. PMID- 26585497 TI - Clinical outcome of maraviroc-containing therapy in heavily pre-treated HIV-1 infected patients. AB - Available data on the use of maraviroc (MVC) in clinical settings are limited. In this cohort study, the clinical outcomes of HIV-1-infected patients treated with MVC were analysed and the predictive values of different tropism assays were compared. Baseline viral tropism was assessed and compared by phenotypic (Trofile and MT-2) and genotypic assays. Virological and immunological responses were evaluated. In total, 62 predominantly extensively pre-treated patients started MVC [median GSS 2.0 (IQR 2.0-2.5)]. Tropism assays were performed on baseline samples of 58 patients (93.5%). Thirty-two samples (80.0%) were classified as R5 by Trofile, 41 (80.4%) by genotypic tropism test (GTT) and 17 (81.0%) by MT-2. At least two types of tropism assay were performed on samples from 39 patients, whereas in 15 patients all three assays were performed (concordance 84.8-94.1%). Plasma HIV-RNA was <50 copies/mL in 82.1%, 85.0% and 68.8% of patients after 12, 24 and 36 months, respectively; median CD4 cell increase was 199 (IQR 108-283), 291 (IQR 187-413) and 234 (IQR 106-444)cells/MUL. The predictive values of different tropism assays were comparably high: at Month 24, 92.9% (Trofile and GTT) and 100.0% (MT-2) of patients had plasma HIV-RNA <50 copies/mL. Three patients stopped MVC treatment because of suspected side effects. Five patients died during follow-up. In this heavily pre-treated cohort, treatment with MVC was well tolerated and resulted in good immunological and virological responses. Results generated by the different tropism assays correlated well with each other and had a high predictive value. PMID- 26585498 TI - Syntheses and applications of periodic mesoporous organosilica nanoparticles. AB - Periodic Mesoporous Organosilica (PMO) nanomaterials are envisioned to be one of the most prolific subjects of research in the next decade. Similar to mesoporous silica nanoparticles (MSN), PMO nanoparticles (NPs) prepared from organo-bridged alkoxysilanes have tunable mesopores that could be utilized for many applications such as gas and molecule adsorption, catalysis, drug and gene delivery, electronics, and sensing; but unlike MSN, the diversity in chemical nature of the pore walls of such nanomaterials is theoretically unlimited. Thus, we expect that PMO NPs will attract considerable interest over the next decade. In this review, we will present a comprehensive overview of the synthetic strategies for the preparation of nanoscaled PMO materials, and then describe their applications in catalysis and nanomedicine. The remarkable assets of the PMO structure are also detailed, and insights are provided for the preparation of more complex PMO nanoplatforms. PMID- 26585499 TI - Magnetic structures of the low temperature phase of Mn3(VO4)2 - towards understanding magnetic ordering between adjacent Kagome layers. AB - In this article we report on a detailed analysis of the magnetic structures of the magnetic phases of the low temperature (lt-) phase of Mn3(VO4)2 (=Mn3V2O8) with a Kagome staircase structure determined by means of powder neutron diffraction. Two magnetic transitions were found at ~25 K (HT1 phase, Cmc'a') and ~17 K (LT1 phase, Pmc'a'), in excellent agreement with previous reports. The LT1 phase is characterized by commensurate magnetic ordering of the magnetic moments on two magnetic sites of the Mn1a/b (2a + 2d) and Mn2 (8i) ions of the nuclear structure (where for the latter site two different overall orientations of magnetic moments within the ab-plane (Mn2a and Mn2b) can be distinguished. This results in mainly antiferromagnetic interactions between edge-sharing Mn octahedra within the Kagome planes. The HT1 phase is characterised by strong spin frustration resulting from the loss of ordering of the magnetic moments of Mn2a/b ions along the b-axis. Both magnetic structures are in agreement with the previously reported ferrimagnetic properties of lt-Mn3(VO4)2 and shed light on the magnetic phase diagram of the compound reported previously. The magnetic structures are discussed with respect to superexchange interaction pathways within the Kagome layers, which appear to be predominantly antiferromagnetic. The magnetic structures of Mn3(VO4)2 are different compared to those reported for Ni3(VO4)2 and Co3(VO4)2 and represent an unique commensurate way out of spin frustration for compounds with strong antiferromagnetic superexchange interactions within the Kagome layers. Additionally, we derive a superexchange model, which will be called redox-mediated M-M(')(d(0))-M superexchange and which can help to understand the exclusively ferromagnetic ordering of adjacent Kagome layers found only for lt-Mn3(VO4)2. PMID- 26585500 TI - Development of a recombinant, chimeric tetravalent dengue vaccine candidate. AB - Dengue is a significant threat to public health worldwide. Currently, there are no licensed vaccines available for dengue. Takeda Vaccines Inc. is developing a live, attenuated tetravalent dengue vaccine candidate (TDV) that consists of an attenuated DENV-2 strain (TDV-2) and three chimeric viruses containing the prM and E protein genes of DENV-1, -3 and -4 expressed in the context of the attenuated TDV-2 genome backbone (TDV-1, TDV-3, and TDV-4, respectively). TDV has been shown to be immunogenic and efficacious in nonclinical animal models. In interferon-receptor deficient mice, the vaccine induces humoral neutralizing antibody responses and cellular immune responses that are sufficient to protect from lethal challenge with DENV-1, DENV-2 or DENV-4. In non-human primates, administration of TDV induces innate immune responses as well as long lasting antibody and cellular immunity. In Phase 1 clinical trials, the safety and immunogenicity of two different formulations were assessed after intradermal or subcutaneous administration to healthy, flavivirus-naive adults. TDV administration was generally well-tolerated independent of dose and route. The vaccine induced neutralizing antibody responses to all four DENV serotypes: after a single administration of the higher formulation, 24-67%% of the subjects seroconverted to all four DENV and >80% seroconverted to three or more viruses. In addition, TDV induced CD8(+) T cell responses to the non-structural NS1, NS3 and NS5 proteins of DENV. TDV has been also shown to be generally well tolerated and immunogenic in a Phase 2 clinical trial in dengue endemic countries in adults and children as young as 18 months. Additional clinical studies are ongoing in preparation for a Phase 3 safety and efficacy study. PMID- 26585501 TI - The use of volumetric projections in Digital Human Modelling software for the identification of Large Goods Vehicle blind spots. AB - The aim of the study is to understand the nature of blind spots in the vision of drivers of Large Goods Vehicles caused by vehicle design variables such as the driver eye height, and mirror designs. The study was informed by the processing of UK national accident data using cluster analysis to establish if vehicle blind spots contribute to accidents. In order to establish the cause and nature of blind spots six top selling trucks in the UK, with a range of sizes were digitized and imported into the SAMMIE Digital Human Modelling (DHM) system. A novel CAD based vision projection technique, which has been validated in a laboratory study, allowed multiple mirror and window aperture projections to be created, resulting in the identification and quantification of a key blind spot. The identified blind spot was demonstrated to have the potential to be associated with the scenarios that were identified in the accident data. The project led to the revision of UNECE Regulation 46 that defines mirror coverage in the European Union, with new vehicle registrations in Europe being required to meet the amended standard after June of 2015. PMID- 26585503 TI - Ethical Considerations in Pediatric Stem Cell Donation. PMID- 26585502 TI - Effect of alternative video displays on postures, perceived effort, and performance during microsurgery skill tasks. AB - Physical work demands and posture constraint from operating microscopes may adversely affect microsurgeon health and performance. Alternative video displays were developed to reduce posture constraints. Their effects on postures, perceived efforts, and performance were compared with the microscope. Sixteen participants performed microsurgery skill tasks using both stereo and non stereoscopic microscopes and video displays. Results showed that neck angles were 9-13 degrees more neutral and shoulder flexion were 9-10 degrees more elevated on the video display than the microscope. Time observed in neck extension was higher (30% vs. 17%) and neck movements were 3x more frequent on the video display than microscopes. Ratings of perceived efforts did not differ among displays, but usability ratings were better on the microscope than the video display. Performance times on the video displays were 66-110% slower than microscopes. Although postures improved, further research is needed to improve task performance on video displays. PMID- 26585504 TI - Engineered in-situ depot-forming hydrogels for intratumoral drug delivery. AB - Chemotherapy is the traditional treatment for intermediate and late stage cancers. The search for treatment options with minimal side effects has been ongoing for several years. Drug delivery technologies that result in minimal or no side effects with improved ease of use for the patients are receiving increased attention. Polymer drug conjugates and nanoparticles can potentially offset the volume of drug distribution while enhancing the accumulation of the active drug in tumors thereby reducing side effects. Additionally, development of localized drug delivery platforms is being investigated as another key approach to target tumors with minimal or no toxicity. Development of in-situ depot forming gel systems for intratumoral delivery of immuno-oncology actives can enhance drug bioavailability to the tumor site and reduce systemic toxicity. This field of drug delivery is critical to develop given the advent of immunotherapy and the availability of novel biological molecules for treating solid tumors. This article reviews the advances in the field of engineered in-situ gelling platforms as a practical tool for local delivery of active oncolytic agents to tumor sites. PMID- 26585505 TI - Novel antisense therapeutics delivery systems: In vitro and in vivo studies of liposomes targeted with anti-CD20 antibody. AB - Antisense gene therapy using molecules such as antisense oligodeoxynucleotides, siRNA or miRNA is a very promising strategy for the treatment of neoplastic diseases. It can be combined with other treatment strategies to enhance therapeutic effect. In acute leukemias, overexpression of the antiapoptotic gene BCL2 is observed in more than 70% of cases. Therefore, reduction of the Bcl-2 protein level could, in itself, prevent the development of cancer or could possibly help sensitize cancer cells to apoptosis inducers. The main objective of our work is to develop therapeutic liposome formulations characterized by high transfection efficiency, stability in the presence of serum, as well as specificity and toxicity for target (leukemic) cells. Each of our liposomal formulations consists of a core composed of antisense oligonucleotides complexed by either cationic lipid, DOTAP, or a synthetic polycation, polyethyleneimine, encapsulated within liposomes modified with polyethylenoglycol. In addition, the liposomal shells are enriched with covalently-bound antibodies recognizing a well characterized bio-marker, CD20, exposed on the surface of leukemia cells. The resulting immunoliposomes selectively and effectively reduced the expression of BCL2 in target cells. Model animal experiments carried out on mice-engrafted tumors expressing the specific marker showed high efficiency of the liposome formulations against specific tumor development. In conclusion, we show that lipid formulations based on a polyplex or lipoplex backbone additionally equipped with antibodies are promising non-viral vectors for specific oligonucleotide transfer into human tumor cells. PMID- 26585506 TI - Clinical outcomes of immunoglobulin use in solid organ transplant recipients: protocol for a systematic review and meta-analysis. AB - BACKGROUND: Transplantation improves survival and the quality of life of patients with end-stage organ failure. Infection, due to surgical issues, host factors such as diabetes, immunosuppression, and hypogammaglobulinemia, is a major post transplant complication. Clinical outcomes of prophylaxis or treatment of hypogammaglobulinemia in solid organ transplant recipients are not well established and are in need of further study. METHODS/DESIGN: We will conduct a systematic review of studies investigating clinically relevant outcomes of immunoglobulin use either as prophylaxis or treatment of hypogammaglobulinemia after solid organ transplantation. Both randomized and non-randomized studies (excluding case reports and case series of less than 20 subjects) will be included. Outcomes of interest will include the overall rate of infection, hospital admission, hospital length of stay, intensive care unit admission, 1 year all-cause mortality, incidence of acute organ rejection, allograft survival within 1 year, and adverse events. We will search MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, Transplant library, and the International Clinical Trials Registry Platform for randomized and non-randomized studies on adult solid organ transplant patients who received prophylactic immunoglobulin or immunoglobulin treatment. Two reviewers will conduct all screening and data collection independently. We will assess study level of risk of bias using the Cochrane Risk of Bias Assessment Tool for randomized controlled trials and for non-randomized studies. If meta-analysis of outcome data is deemed appropriate, we will use random effects models to combine data for continuous and dichotomous measures. DISCUSSION: The results of this systematic review may inform guideline development for measuring immunoglobulin level and use of immunoglobulin in solid organ transplant patients and highlight areas for further research. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015017620. PMID- 26585507 TI - Sperm Associated Antigen 6 (SPAG6) Regulates Fibroblast Cell Growth, Morphology, Migration and Ciliogenesis. AB - Mammalian Spag6 is the orthologue of Chlamydomonas PF16, which encodes a protein localized in the axoneme central apparatus, and regulates flagella/cilia motility. Most Spag6-deficient mice are smaller in size than their littermates. Because SPAG6 decorates microtubules, we hypothesized that SPAG6 has other roles related to microtubule function besides regulating flagellar/cilia motility. Mouse embryonic fibroblasts (MEFs) were isolated from Spag6-deficient and wild type embryos for these studies. Both primary and immortalized Spag6-deficient MEFs proliferated at a much slower rate than the wild-type MEFs, and they had a larger surface area. Re-expression of SPAG6 in the Spag6-deficient MEFs rescued the abnormal cell morphology. Spag6-deficient MEFs were less motile than wild type MEFs, as shown by both chemotactic analysis and wound-healing assays. Spag6 deficient MEFs also showed reduced adhesion associated with a non-polarized F actin distribution. Multiple centrosomes were observed in the Spag6-deficient MEF cultures. The percentage of cells with primary cilia was significantly reduced compared to the wild-type MEFs, and some Spag6-deficient MEFs developed multiple cilia. Furthermore, SPAG6 selectively increased expression of acetylated tubulin, a microtubule stability marker. The Spag6-deficient MEFs were more sensitive to paclitaxel, a microtubule stabilizer. Our studies reveal new roles for SPAG6 in modulation of cell morphology, proliferation, migration, and ciliogenesis. PMID- 26585508 TI - Unrecognized myocardial infarctions assessed by cardiovascular magnetic resonance are associated with the severity of the stenosis in the supplying coronary artery. AB - BACKGROUND: A previous study has shown an increased prevalence of late gadolinium enhancement cardiovascular magnetic resonance (LGE CMR) detected unrecognized myocardial infarction (UMI) with increasing extent and severity of coronary artery disease. However, the coronary artery disease was evaluated on a patient level assuming normal coronary anatomy. Therefore, the aims of the present study were to investigate the prevalence of UMI identified by LGE CMR imaging in patients with stable angina pectoris and no known previous myocardial infarction; and to investigate whether presence of UMI is associated with stenotic lesions in the coronary artery supplying the segment of the myocardium in which the UMI is located, using coronary angiography to determine the individual coronary anatomy in each patient. METHODS: In this prospective multicenter study, we included patients with stable angina pectoris and without prior myocardial infarction, scheduled for coronary angiography. A LGE CMR examination was performed prior to the coronary angiography. The study cohort consisted of 235 patients (80 women, 155 men) with a mean age of 64.8 years. RESULTS: UMIs were found in 25% of patients. There was a strong association between stenotic lesions (>=70% stenosis) in a coronary artery and the presence of an UMI in the myocardial segments supplied by the stenotic artery; it was significantly more likely to have an UMI downstream a stenosis >= 70% as compared to < 70% (OR 5.1, CI 3.1 8.3, p < 0.0001). 56% of the UMIs were located in the inferior and infero-lateral myocardial segments, despite predominance for stenotic lesions in the left anterior descending artery. CONCLUSION: UMI is common in patients with stable angina and the results indicate that the majority of the UMIs are of ischemic origin due to severe coronary atherosclerosis. In contrast to what is seen in recognized myocardial infarctions, UMIs are predominately located in the inferior and infero-lateral myocardial segments. TRIAL REGISTRATION: The PUMI study is registered at ClinicalTrials.gov (NCT01257282). PMID- 26585509 TI - Vertically aligned InGaN nanowires with engineered axial In composition for highly efficient visible light emission. AB - We report on the fabrication of novel InGaN nanowires (NWs) with improved crystalline quality and high radiative efficiency for applications as nanoscale visible light emitters. Pristine InGaN NWs grown under a uniform In/Ga molar flow ratio (UIF) exhibited multi-peak white-like emission and a high density of dislocation-like defects. A phase separation and broad emission with non-uniform luminescent clusters were also observed for a single UIF NW investigated by spatially resolved cathodoluminescence. Hence, we proposed a simple approach based on engineering the axial In content by increasing the In/Ga molar flow ratio at the end of NW growth. This new approach yielded samples with a high luminescence intensity, a narrow emission spectrum, and enhanced crystalline quality. Using time-resolved photoluminescence spectroscopy, the UIF NWs exhibited a long radiative recombination time (taur) and low internal quantum efficiency (IQE) due to strong exciton localization and carrier trapping in defect states. In contrast, NWs with engineered In content demonstrated three times higher IQE and a much shorter taur due to mitigated In fluctuation and improved crystal quality. PMID- 26585510 TI - Plasma fetuin-A does not correlate with monocyte TLR4 in humans. PMID- 26585511 TI - H95 Is a pH-Dependent Gate in Aquaporin 4. AB - Aquaporin 4 (AQP4) is a transmembrane protein from the aquaporin family and is the predominant water channel in the mammalian brain. The regulation of permeability of this protein could be of potential therapeutic use to treat various forms of damage to the nervous tissue. In this work, based on data obtained from in silico and in vitro studies, a pH sensitivity that regulates the osmotic water permeability of AQP4 is demonstrated. The results indicate that AQP4 has increased water permeability at conditions of low pH in atomistic computer simulations and experiments carried out on Xenopus oocytes expressing AQP4. With molecular dynamics simulations, this effect was traced to a histidine residue (H95) located in the cytoplasmic lumen of AQP4. A mutant form of AQP4, in which H95 was replaced with an alanine (H95A), loses sensitivity to cytoplasmic pH changes in in vitro osmotic water permeability, thereby substantiating the in silico work. PMID- 26585512 TI - Protein Kinase A Catalytic Subunit Primed for Action: Time-Lapse Crystallography of Michaelis Complex Formation. AB - The catalytic subunit of the cyclic AMP-dependent protein kinase A (PKAc) catalyzes the transfer of the gamma-phosphate of bound Mg2ATP to a serine or threonine residue of a protein substrate. Here, time-lapse X-ray crystallography was used to capture a series of complexes of PKAc with an oligopeptide substrate and unreacted Mg2ATP, including the Michaelis complex, that reveal important geometric rearrangements in and near the active site preceding the phosphoryl transfer reaction. Contrary to the prevailing view, Mg(2+) binds first to the M1 site as a complex with ATP and is followed by Mg(2+) binding to the M2 site. Concurrently, the target serine hydroxyl of the peptide substrate rotates away from the active site toward the bulk solvent, which breaks the hydrogen bond with D166. Lastly, the serine hydroxyl of the substrate rotates back toward D166 to form the Michaelis complex with the active site primed for phosphoryl transfer. PMID- 26585513 TI - Cryoelectron Tomography of the NAIP5/NLRC4 Inflammasome: Implications for NLR Activation. AB - Inflammasomes are high molecular weight protein complexes that play a crucial role in innate immunity by activating caspase-1. Inflammasome formation is initiated when molecules originating from invading microorganisms activate nucleotide-binding domain and leucine-rich repeat-containing receptors (NLRs) and induce NLR multimerization. Little is known about the conformational changes involved in NLR activation and the structural organization of NLR multimers. Here, we show by cryoelectron tomography that flagellin-induced NAIP5/NLRC4 multimers form right- and left-handed helical polymers with a diameter of 28 nm and a pitch of 6.5 nm. Subtomogram averaging produced an electron density map at 4 nm resolution, which was used for rigid body fitting of NLR subdomains derived from the crystal structure of dormant NLRC4. The resulting structural model of inflammasome-incorporated NLRC4 indicates that a prominent rotation of the LRR domain of NLRC4 is necessary for multimer formation, providing unprecedented insight into the conformational changes that accompany NLR activation. PMID- 26585514 TI - Kite Proteins: a Superfamily of SMC/Kleisin Partners Conserved Across Bacteria, Archaea, and Eukaryotes. AB - SMC/kleisin complexes form elongated annular structures, which are critical for chromosome segregation, genome maintenance, and the regulation of gene expression. We describe marked structural similarities between bacterial and eukaryotic SMC/kleisin partner proteins (designated here as "kite" proteins for kleisin interacting tandem winged-helix (WH) elements of SMC complexes). Kite proteins are integral parts of all prokaryotic SMC complexes and Smc5/6 but not cohesin and condensin. They are made up of tandem WH domains, form homo- or heterodimers via their amino-terminal WH domain, and they associate with the central part of a kleisin subunit. In placental mammals, the kite subunit NSE3 gave rise to several (>60) kite-related proteins, named MAGE, many of which encode tumor- and testis-specific antigens. Based on architectural rather than sequence similarity, we propose an adapted model for the evolution of the SMC protein complexes and discuss potential functional similarities between bacterial Smc/ScpAB and eukaryotic Smc5/6. PMID- 26585515 TI - Government motion on plain packaging for cigarettes undermines intellectual property rights. PMID- 26585516 TI - A new animal model for delayed osseous union secondary to osteitis. AB - BACKGROUND: The treatment of infection-related delayed bone unions is still very challenging for the orthopedic surgeon. The prevalence of such infection-related types of osteitis is high in complex fractures, particularly in open fractures with extensive soft-tissue damage. The aim of this study was to develop a new animal model for delayed union due to osteitis. METHODS: After randomization to infected or non-infected groups 20 Sprague-Dawley rats underwent a transverse fracture of the midshaft tibia. After intramedullary inoculation with staphylococcus aureus (10(3) CFU) fracture stabilization was done by intramedullary titanium K-wires. After 5 weeks all rats were euthanized and underwent biomechanical testing to evaluate bone consolidation or delayed union, respectively. Micro-CT scans were additionally used to quantitatively evaluate the callus formation by the score of Lane and Sandhu. Blood samples were taken to analyze infectious disease markers (day 1, 14 and 35). RESULTS: Biomechanical testing showed a significant higher maximum torque in the non-infected group 5 weeks postoperatively compared with the infected group (p < 0.001). According to the Lane and Sandhu score a significantly higher callus formation was found in the non-infected group (p < 0.001). Similarly, the leucocyte count in the infected group was significantly higher than in the non-infected group (p < 0.05). CONCLUSIONS: Here we have established a new animal model for delayed osseous union secondary to osteitis. The animal model appears to be appropriate for future experimental studies to test new therapeutic strategies in these difficult to treat bone healing complications. PMID- 26585518 TI - OrthoANI: An improved algorithm and software for calculating average nucleotide identity. AB - Species demarcation in Bacteria and Archaea is mainly based on overall genome relatedness, which serves a framework for modern microbiology. Current practice for obtaining these measures between two strains is shifting from experimentally determined similarity obtained by DNA-DNA hybridization (DDH) to genome-sequence based similarity. Average nucleotide identity (ANI) is a simple algorithm that mimics DDH. Like DDH, ANI values between two genome sequences may be different from each other when reciprocal calculations are compared. We compared 63 690 pairs of genome sequences and found that the differences in reciprocal ANI values are significantly high, exceeding 1 % in some cases. To resolve this problem of not being symmetrical, a new algorithm, named OrthoANI, was developed to accommodate the concept of orthology for which both genome sequences were fragmented and only orthologous fragment pairs taken into consideration for calculating nucleotide identities. OrthoANI is highly correlated with ANI (using BLASTn) and the former showed approximately 0.1 % higher values than the latter. In conclusion, OrthoANI provides a more robust and faster means of calculating average nucleotide identity for taxonomic purposes. The standalone software tools are freely available at http://www.ezbiocloud.net/sw/oat. PMID- 26585517 TI - Prehospital intravenous epinephrine may boost survival of patients with traumatic cardiac arrest: a retrospective cohort study. AB - BACKGROUND: Prehospital resuscitation for patients with major trauma emphasizes a load-and-go principle. For traumatic cardiac arrest (TCA) patients, the administration of vasopressors remains under debate. This study evaluated the effectiveness of epinephrine in the prehospital setting for patients with TCA. METHODS: We conducted a retrospective cohort study using a prospectively collected registry for out-of-hospital cardiac arrest in Taipei. Enrollees were >=18 years of age with TCA. Patients with signs of obvious death like decapitation or rigor mortis were excluded. Patients were grouped according to prehospital administration, or lack thereof, of epinephrine. Outcomes were sustained (>=2 h) recovery of spontaneous circulation (ROSC) and survival to discharge. A subgroup analysis was performed by stratified total prehospital time. RESULTS: From June 1 2010 to May 31 2013, 514 cases were enrolled. Epinephrine was administered in 43 (8.4%) cases. Among all patients, sustained ROSC and survival to discharge was 101 (19.6%) and 20 (3.9%), respectively. The epinephrine group versus the non-epinephrine group had higher sustained ROSC (41.9% vs. 17.6%, p < 0.01) and survival to discharge (14.0% vs. 3.0%, p < 0.01). The adjusted odds ratios (ORs) of epinephrine effect were 2.24 (95% confidence interval (CI) 1.05-4.81) on sustained ROSC, and 2.94 (95% CI 0.85-10.15) on survival to discharge. Subgroup analysis showed increased ORs of epinephrine effect on sustained ROSC with a longer prehospital time. CONCLUSION: Among adult patients with TCA in an Asian metropolitan area, administration of epinephrine in the prehospital setting was associated with increased short-term survival, especially for those with a longer prehospital time. PMID- 26585519 TI - Antiphospholipid Antibody Syndrome With Valvular Vegetations in Acute Q Fever. AB - BACKGROUND: Coxiella burnetii endocarditis is considered to be a late complication of Q fever in patients with preexisting valvular heart disease (VHD). We observed a large transient aortic vegetation in a patient with acute Q fever and high levels of IgG anticardiolipin antibodies (IgG aCL). Therefore, we sought to determine how commonly acute Q fever could cause valvular vegetations associated with antiphospholipid antibody syndrome, which would be a new clinical entity. METHODS: We performed a consecutive case series between January 2007 and April 2014 at the French National Referral Center for Q fever. Age, sex, history of VHD, immunosuppression, and IgG aCL assessed by enzyme-linked immunosorbent assay were tested as potential predictors. RESULTS: Of the 759 patients with acute Q fever and available echocardiographic results, 9 (1.2%) were considered to have acute Q fever endocarditis, none of whom had a previously known VHD. After multiple adjustment, very high IgG aCL levels (>100 immunoglobulin G-type phospholipid units; relative risk [RR], 24.9 [95% confidence interval {CI}, 4.5 140.2]; P = .002) and immunosuppression (RR, 10.1 [95% CI, 3.0-32.4]; P = .002) were independently associated with acute Q fever endocarditis. CONCLUSIONS: Antiphospholipid antibody syndrome with valvular vegetations in acute Q fever is a new clinical entity. This would suggest the value of systematically testing for C. burnetii in antiphospholipid-associated cardiac valve disease, and performing early echocardiography and antiphospholipid dosages in patients with acute Q fever. PMID- 26585520 TI - Investing in Immunity: Prepandemic Immunization to Combat Future Influenza Pandemics. AB - We are unlikely, with current technologies, to have sufficient pandemic influenza vaccine ready in time to impact the first wave of the next pandemic. Emerging data show that prior immunization with an immunologically distinct hemagglutinin of the same subtype offers the potential to "prime" recipients for rapid protection with a booster dose, years later, of a vaccine then manufactured to match the pandemic strain. This article proposes making prepandemic priming vaccine(s) available for voluntary use, particularly to those at high risk of early occupational exposure, such as first responders and healthcare workers, and to others maintaining critical infrastructure. In addition to providing faster protection and potentially reducing social disruption, being able, early in a pandemic, to immunize those who had received prepandemic vaccine with one dose of the pandemic vaccine, rather than the 2 doses typically required, would reduce the total doses of pandemic vaccine then needed, extending vaccine supplies. PMID- 26585521 TI - Editorial Commentary: Is Prepandemic Vaccination a Wise Investment? PMID- 26585522 TI - Profiling of Brevibacillus borstelensis transcriptome exposed to high temperature shock. AB - To understand the molecular mechanisms underlying the ability of the bacteria to survive at high temperature, gene expression profile of Brevibacillusborstelensis at 55 degrees C during 5 and 10min heat shock period was carried out by high throughput sequencing technology. A total of 2555 non-redundant transcripts were annotated. A total of 575 genes at 5min and 400 genes at 10min exhibited significant differential expression in response to temperature upshift from 50 to 55 degrees C. Genes up-regulated under heat shock were associated with metabolism (mtnE), membrane transport, signal transduction, transcriptional regulation (ycxD, codY) and folding and sorting (hsp90). A larger number of genes encoding hypothetical proteins were identified. RT-PCR experimental results carried out on genes expressed under heat shock were found to be consistent with transcriptome data. The results enhance our understanding of adaptation strategy of thermophilic bacteria thereby providing a strong background for in depth research in thermophiles. PMID- 26585525 TI - Blood eosinophils and inhaled corticosteroid/long-acting beta-2 agonist efficacy in COPD. AB - OBJECTIVE: We performed a review of studies of fluticasone propionate (FP)/salmeterol (SAL) (combination inhaled corticosteroid (ICS)/long-acting beta2 agonist (LABA)) in patients with COPD, which measured baseline (pretreatment) blood eosinophil levels, to test whether blood eosinophil levels >=2% were associated with a greater reduction in exacerbation rates with ICS therapy. METHODS: Three studies of >=1-year duration met the inclusion criteria. Moderate and severe exacerbation rates were analysed according to baseline blood eosinophil levels (<2% vs >=2%). At baseline, 57-75% of patients had >=2% blood eosinophils. Changes in FEV1 and St George's Respiratory Questionnaire (SGRQ) scores were compared by eosinophil level. RESULTS: For patients with >=2% eosinophils, FP/SAL was associated with significant reductions in exacerbation rates versus tiotropium (INSPIRE: n=719, rate ratio (RR)=0.75, 95% CI 0.60 to 0.92, p=0.006) and versus placebo (TRISTAN: n=1049, RR=0.63, 95% CI 0.50 to 0.79, p<0.001). No significant difference was seen in the <2% eosinophil subgroup in either study (INSPIRE: n=550, RR=1.18, 95% CI 0.92 to 1.51, p=0.186; TRISTAN: n=354, RR=0.99, 95% CI 0.67 to 1.47, p=0.957, respectively). In SCO30002 (n=373), no significant effects were observed (FP or FP/SAL vs placebo). No relationship was observed in any study between eosinophil subgroup and treatment effect on FEV1 and SGRQ. DISCUSSION: Baseline blood eosinophil levels may represent an informative marker for exacerbation reduction with ICS/LABA in patients with COPD and a history of moderate/severe exacerbations. PMID- 26585526 TI - Maternal Caffeine Intake During Pregnancy and Child Cognition and Behavior at 4 and 7 Years of Age. AB - Although caffeine is commonly consumed during pregnancy, there are few reports on the association of in utero caffeine exposure with offspring cognition or behavior during childhood. We evaluated the association of maternal serum paraxanthine, caffeine's primary metabolite, at <20 and >=26 weeks' gestation with the child's intelligence quotient (IQ) and problem behaviors at ages 4 and 7 years among 2,197 mother-child pairs. The mothers were controls from a case control study of caffeine metabolites and spontaneous abortion that was nested within the Collaborative Perinatal Project (multiple US sites, 1959-1974). Associations of paraxanthine (adjusted for maternal age, race, education, smoking, prepregnancy weight, gestational age at blood draw, and child sex) with mean IQ were assessed by linear regression and associations with problem behaviors by logistic regression. Paraxanthine concentration at >=26 weeks' gestation manifested an inverted-J-shaped association with child's IQ at age 7 years, with a peak difference (vs. undetectable) of 0.65 points at 750 ug/L (66th percentile) and a decrement thereafter. Paraxanthine at <20 weeks was linearly associated with internalizing behavior at age 4 years (for a 500-ug/L increase, odds ratio = 1.3, 95% confidence interval: 1.1, 1.5). None of the remaining 12 associations approached statistical significance. We conclude that over a range of values applicable to most pregnant women, there was no meaningful association of serum paraxanthine level with childhood IQ or problem behaviors. PMID- 26585523 TI - Current Pharmaceutical Treatments and Alternative Therapies of Parkinson's Disease. AB - Over the decades, pharmaceutical treatments, particularly dopaminergic (DAergic) drugs have been considered as the main therapy against motor symptoms of Parkinson's disease (PD). It is proposed that DAergic drugs in combination with other medications, such as monoamine oxidase type B inhibitors, catechol-O-methyl transferase inhibitors, anticholinergics and other newly developed non-DAergic drugs can make a better control of motor symptoms or alleviate levodopa-induced motor complications. Moreover, non-motor symptoms of PD, such as cognitive, neuropsychiatric, sleep, autonomic and sensory disturbances caused by intrinsic PD pathology or drug-induced side effects, are gaining increasing attention and urgently need to be taken care of due to their impact on quality of life. Currently, neuroprotective therapies have been investigated extensively in pre clinical studies, and some of them have been subjected to clinical trials. Furthermore, non-pharmaceutical treatments, including deep brain stimulation (DBS), gene therapy, cell replacement therapy and some complementary managements, such as Tai chi, Yoga, traditional herbs and molecular targeted therapies have also been considered as effective alternative therapies to classical pharmaceutics. This review will provide us updated information regarding the current drugs and non-drugs therapies for PD. PMID- 26585524 TI - Interobserver agreement for the ATS/ERS/JRS/ALAT criteria for a UIP pattern on CT. AB - OBJECTIVES: To establish the level of observer variation for the current ATS/ERS/JRS/ALAT criteria for a diagnosis of usual interstitial pneumonia (UIP) on CT among a large group of thoracic radiologists of varying levels of experience. MATERIALS AND METHODS: 112 observers (96 of whom were thoracic radiologists) categorised CTs of 150 consecutive patients with fibrotic lung disease using the ATS/ERS/JRS/ALAT CT criteria for a UIP pattern (3 categories- UIP, possibly UIP and inconsistent with UIP). The presence of honeycombing, traction bronchiectasis and emphysema was also scored using a 3-point scale (definitely present, possibly present, absent). Observer agreement for the UIP categorisation and for the 3 CT patterns in the entire observer group and in subgroups stratified by observer experience, were evaluated. RESULTS: Interobserver agreement across the diagnosis category scores among the 112 observers was moderate, ranging from 0.48 (IQR 0.18) for general radiologists to 0.52 (IQR 0.20) for thoracic radiologists of 10-20 years' experience. A binary score for UIP versus possible or inconsistent with UIP was examined. Observer agreement for this binary score was only moderate. No significant differences in agreement levels were identified when the CTs were stratified according to multidisciplinary team (MDT) diagnosis or patient age or when observers were categorised according to experience. Observer agreement for each of honeycombing, traction bronchiectasis and emphysema were 0.59+/-0.12, 0.42+/-0.15 and 0.43+/ 0.18, respectively. CONCLUSIONS: Interobserver agreement for the current ATS/ERS/JRS/ALAT CT criteria for UIP is only moderate among thoracic radiologists, irrespective of their experience, and did not vary with patient age or the MDT diagnosis. PMID- 26585527 TI - Understanding flow patterns and inflammatory status in intracranial aneurysms: Towards a personalized medicine. AB - Unruptured intracranial aneurysms are frequently and incidentally discovered with noninvasive imaging and the decision for preventive treatment is supported by epidemiologic and statistics data, lacking personalized argumentation about individual aneurysm behavior and inflammatory status of its wall. After a review of hemodynamic forces leading to aneurysm genesis and interaction with inflammation onset within aneurysmal wall, we will successively detail routine imaging methods for the aneurysmal wall and their respective contribution. Then, we will draw up the inventory of different experimental imaging and in vitro methods for future investigation of the aneurysmal wall. We emphasize the need for cooperation with various specialties: histopathology, genetics, and immunology in order to understand the natural history of the aneurysmal sac leading most often to stability but elsewhere to aneurysmal growth, thrombosis or rupture. A description of a research protocol devoted to aneurysmal wall inflammation and recently accepted in our university is introduced. PMID- 26585528 TI - Did an eighteen-century anatomist provide the first known description of a spinal cord vascular malformation? PMID- 26585529 TI - Prediction of the consistency of pituitary adenoma: A comparative study on diffusion-weighted imaging and pathological results. AB - OBJECTIVES: This study aims to evaluate the role of BLADE magnetic resonance (MR) diffusion-weighted imaging (DWI) and other traditional MRI parameters to predict pituitary adenoma consistency in combination with pathological results. METHODS: Thirty-four patients with surgery and pathological diagnosis of pituitary adenomas were included in this study. All exams were performed at 3.0T with traditional MRI sequences and BLADE DWI to acquire MRI parameters, then the consistency and collagen content of pituitary adenomas were evaluated at and after surgery respectively to explore the capacity of MRI technique to predict consistency or its correlation with collagen content. RESULTS: According to consistency evaluated at surgery, 29 pituitary adenomas were categorised as soft while others were regarded as hard. SI ratio of pre- or post-enhanced T1-weighted images, T2-weighted images or ADC values exhibited no significant relationship with adenoma consistency. To some extent, the ADC ratio had diagnostic value to predict hard consistency for ADC<1.077, while the AUC was 0.7724 for the ROC curve. H.E. staining and Masson staining were used to assess collagen content qualitatively and quantitatively. Adenoma consistency was relevant to collagen content while the cut-off value for collagen content between soft and hard tumours was 15.39%; the ADC ratio exhibited close relationship with collagen content, showing a lower ADC ratio for increasing collagen content. CONCLUSIONS: This study revealed that the ADC ratio decreased with increasing collagen content and predicted hard consistency of tumours for ADC<1.077. Correlation between ADC ratio and tumour consistency needs further exploration. PMID- 26585530 TI - Diagnostic accuracy of diffusion-weighted MR imaging versus delayed gadolinium enhanced T1-weighted imaging in middle ear recurrent cholesteatoma: A retrospective study of 39 patients. AB - OBJECTIVE: MR imaging using diffusion-weighted (DW) images and delayed gadolinium enhanced T1-weighted images is evolving into an alternative to second look surgery in detection of recurrent cholesteatomas. The aim of this study was to retrospectively compare the DW images, the post-gadolinium T1-weighted images and the combination of both methods in this indication. PATIENTS AND METHODS: We retrospectively evaluated the MR examination of 39 patients clinically suspected for a recurrent cholesteatoma. Patients in the study underwent DW sequences, delayed gadolinium enhanced T1-weighted sequences as well as standard uninjected protocol using T1 and T2 sequences. Three blinded radiologists evaluated three data sets: a set of post-gadolinium T1-weighted images, a set of DW images and a set of the combination of both methods. The interobserver agreement was evaluated and the diagnostic accuracy of each method was described by sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). The performances of the three techniques were also evaluated using ROC curves, from which the AUC were compared. Results were compared with surgical results or a two-year follow-up. RESULTS: The overall sensitivity and specificity were respectively 63% and 71% for the post-gadolinium T1-weighted images, 88% and 75% for the DW images and 84% and 75% for the combined images. The PPV and NPV were respectively 89% and 33% for the post-gadolinium T1-weighted images, 93% and 62% for the DW images and 93% and 55% for the combined images. The sensitivity and the NPV were significantly different between the three methods (P<0.0001 and P=0.027). There was no statistically significant difference in specificity or PPV between the three methods (P=0.931 and P=0.650). The diagnostic accuracy evaluated with the AUC showed no statistically significant difference between the DW images and the combined images (P=0.433). CONCLUSION: MR imaging reliably identifies those patients suspected for recurrent cholesteatoma who require a surgical second look by using DW MR imaging. The combination with delayed gadolinium enhanced T1-weighted sequences does not significantly increase the diagnostic accuracy of the examination. PMID- 26585531 TI - Corinebacterium urealyticum: increased incidence of infection and encrusted uropathy. AB - INTRODUCTION: Corynebacterium urealyticum (CU) affects patients who are immunosuppressed, chronically ill or have undergone numerous operations. Obstructive uropathy (OU) is a complication of infection. STUDY OBJECTIVE: To demonstrate the growing increase in cases of infection by CU and OU in the past 5 years. MATERIAL AND METHODS: A descriptive study was conducted of urological patients with CU-positive urine cultures (January 2009-December 2014). We calculated the annual distribution and clinical characteristics of infection by CU and OU. Minimum follow-up: 6 months. We obtained the statistical means and ranges of clinical parameters pre/post-therapy. RESULTS: The total number of patients with CU was 115 (men, 87; women, 28). The mean age was 67.9 years (range, 6-95 years), and the annual distribution of cases for 2009, 2010, 2011, 2012, 2013 and 2014 was 9 (7.8%), 13 (11.3%), 9 (7.8%), 20 (17.4%), 31 (27%) and 33 (28.7%), respectively. The increase in cases for 2009-2014 was 300%. Multiple urological surgeries were performed in 89 cases (77.3%), with surgical complications in 77 cases (66.9%). Eighteen (15.6%) patients had OU (men, 13; women, 5), 12 had pyelitis (66.7%), 3 had cystopathy (16.6%), 2 had prostatic capsule disease (11.2%) and 1 had mesh calcification (5.5%). The analysis of the 18 cases with OU showed pre/postantibiotic therapy urine pHs of 8 (r, 6-9) vs. 6 (r, 5-7). All postantibiotic cultures were negative. Acidifying solution was applied in 5 cases, and surgery was performed in 13 cases (72.2%). The results from before/after the multimodal therapy showed renal impairment in 12 (66.6%) vs. 9 cases (50%) and glomerular filtration rates (GFR) of 45.8 (r, 6->90) vs. 52.7 (r, 13->90). The improvement in GFR was 6.94 points (T Wilcoxon; P=.102). The radiology results (incrustations) showed improvement in 13 patients (72.2%) and no change in 5 (27.8%). There was no specific mortality for CU. CONCLUSIONS: The prevalence of infection by CU and OU is increasing. Antibiotic treatment is highly effective. Acidifying solutions are an acceptable option for reducing calcifications. PMID- 26585532 TI - Cancer: Xenograft encyclopaedia identifies drug combination opportunities. PMID- 26585534 TI - Towards a hit for every target. AB - Technological advances coupled with novel collaborative strategies for compound sourcing and management are poised to transform the utility of high-throughput screening. PMID- 26585533 TI - Pioneering government-sponsored drug repositioning collaborations: progress and learning. AB - A new model for translational research and drug repositioning has recently been established based on three-way partnerships between public funders, the pharmaceutical industry and academic investigators. Through two pioneering initiatives - one involving the Medical Research Council in the United Kingdom and one involving the National Center for Advancing Translational Sciences of the National Institutes of Health in the United States - new investigations of highly characterized investigational compounds have been funded and are leading to the exploration of known mechanisms in new disease areas. This model has been extended beyond these first two initiatives. Here, we discuss the progress to date and the unique requirements and challenges for this model. PMID- 26585535 TI - Infectious disease: Glutamine analogue reverses cerebral malaria. PMID- 26585536 TI - Two decades of new drug development for central nervous system disorders. PMID- 26585537 TI - Lead identification: Shedding light on dark chemical matter. PMID- 26585538 TI - A general method for the definition of margin recipes depending on the treatment technique applied in helical tomotherapy prostate plans. AB - PURPOSE: To obtain specific margin recipes that take into account the dosimetric characteristics of the treatment plans used in a single institution. METHODS: We obtained dose-population histograms (DPHs) of 20 helical tomotherapy treatment plans for prostate cancer by simulating the effects of different systematic errors (Sigma) and random errors (sigma) on these plans. We obtained dosimetric margins and margin reductions due to random errors (random margins) by fitting the theoretical results of coverages for Gaussian distributions with coverages of the planned D99% obtained from the DPHs. RESULTS: The dosimetric margins obtained for helical tomotherapy prostate treatments were 3.3 mm, 3 mm, and 1 mm in the lateral (Lat), anterior-posterior (AP), and superior-inferior (SI) directions. Random margins showed parabolic dependencies, yielding expressions of 0.16sigma(2), 0.13sigma(2), and 0.15sigma(2) for the Lat, AP, and SI directions, respectively. When focusing on values up to sigma = 5 mm, random margins could be fitted considering Gaussian penumbras with standard deviations (sigmap) equal to 4.5 mm Lat, 6 mm AP, and 5.5 mm SI. CONCLUSIONS: Despite complex dose distributions in helical tomotherapy treatment plans, we were able to simplify the behaviour of our plans against treatment errors to single values of dosimetric and random margins for each direction. These margins allowed us to develop specific margin recipes for the respective treatment technique. The method is general and could be used for any treatment technique provided that DPHs can be obtained. PMID- 26585539 TI - Microscopic endometriosis: impact on our understanding of the disease and its surgery. PMID- 26585541 TI - Extraordinary clinical success of a single-embryo transfer policy. What comes next? PMID- 26585542 TI - Transmission of human immunodeficiency virus Type-1 by fresh-frozen plasma treated with methylene blue and light. AB - BACKGROUND: The risk of transfusion-transmitted infection (TTI) has been minimized by introduction of nucleic acid testing (NAT) and pathogen inactivation (PI). This case report describes transmission of human immunodeficiency virus Type 1 (HIV-1) to two recipients despite these measures. STUDY DESIGN AND METHODS: In March 2009 a possible TTI of HIV-1 was identified in a patient that had received pooled buffy coat platelet concentrate (BC-PLT) in November 2005. The subsequent lookback study found two more patients who had received methylene blue (MB)-treated fresh-frozen plasma (FFP) and red blood cells (RBCs) from the same donation. In November 2005 the donor had tested negative for both HIV antibodies and HIV-1 RNA by 44 minipool (44 MP) NAT. Repository samples of this donation and samples from the recipients were used for viral load (VL) and sequence analysis. RESULTS: HIV-1 RNA was detectable by individual donation (ID) NAT in the repository sample from the 2005 window period donation and a VL of 135 copies/mL was measured. HIV-1 infection was confirmed in both recipients of both BC-PLT (65 mL of plasma) and MB-FFP (261 mL of plasma), but not in the patient that had received 4-week-old RBCs (20 mL of plasma). The sequence analysis revealed a close phylogenetic relationship between the virus strains isolated from the donor and recipients, compatible with TTI. CONCLUSIONS: Approximately 17,600 and 4400 virions in the MB-FFP and BC-PLT were infectious, but 1350 virions in the RBCs were not. ID-NAT would have prevented this transmission, but the combination of MP-NAT and MB-PI did not. PMID- 26585544 TI - Mozambioside Is an Arabica-Specific Bitter-Tasting Furokaurane Glucoside in Coffee Beans. AB - Sensory-guided fractionation of a roasted coffee beverage revealed a highly polar, bitter-tasting subfraction, from which the furokaurane glucoside mozambioside was isolated and identified in its chemical structure by means of HDMS and NMR spectra. Sensory evaluation revealed a bitter taste recognition threshold of 60 (+/- 10) MUmol/L. UPLC-HDMS quantitation of raw coffee beans showed that Arabica coffees contained 396-1188 nmol/g mozambioside, whereas only traces (<5 nmol/g) were detected in Robusta coffees, thus suggesting that mozambioside can be used as an analytical marker for Arabica coffee. Roasted Arabica contained a substantially reduced concentration (232 +/- 37 nmol/g), indicating partial degradation of mozambioside during coffee roasting. Mozambioside was nearly quantitatively extracted into the aqueous brew during coffee-making (86-98%). PMID- 26585543 TI - A multicentre study of the evidence for customized margins in photon breast boost radiotherapy. AB - OBJECTIVE: To determine if subsets of patients may benefit from smaller or larger margins when using laser setup and bony anatomy verification of breast tumour bed (TB) boost radiotherapy (RT). METHODS: Verification imaging data acquired using cone-beam CT, megavoltage CT or two-dimensional kilovoltage imaging on 218 patients were used (1574 images). TB setup errors for laser-only setup (dlaser) and for bony anatomy verification (dbone) were determined using clips implanted into the TB as a gold standard for the TB position. Cases were grouped by centre , patient- and treatment-related factors, including breast volume, TB position, seroma visibility and surgical technique. Systematic (Sigma) and random (sigma) TB setup errors were compared between groups, and TB planning target volume margins (MTB) were calculated. RESULTS: For the study population, Sigmalaser was between 2.8 and 3.4 mm, and Sigmabone was between 2.2 and 2.6 mm, respectively. Females with larger breasts (p = 0.03), easily visible seroma (p <= 0.02) and open surgical technique (p <= 0.04) had larger Sigmalaser. Sigmabone was larger for females with larger breasts (p = 0.02) and lateral tumours (p = 0.04). Females with medial tumours (p < 0.01) had smaller Sigmabone. CONCLUSION: If clips are not used, margins should be 8 and 10 mm for bony anatomy verification and laser setup, respectively. Individualization of TB margins may be considered based on breast volume, TB and seroma visibility. ADVANCES IN KNOWLEDGE: Setup accuracy using lasers and bony anatomy is influenced by patient and treatment factors. Some patients may benefit from clip-based image guidance more than others. PMID- 26585545 TI - A New MRI Masking Technique Based on Multi-Atlas Brain Segmentation in Controls and Schizophrenia: A Rapid and Viable Alternative to Manual Masking. AB - Brain masking of MRI images separates brain from surrounding tissue and its accuracy is important for further imaging analyses. We implemented a new brain masking technique based on multi-atlas brain segmentation (MABS) and compared MABS to masks generated using FreeSurfer (FS; version 5.3), Brain Extraction Tool (BET), and Brainwash, using manually defined masks (MM) as the gold standard. We further determined the effect of different masking techniques on cortical and subcortical volumes generated by FreeSurfer. METHODS: Images were acquired on a 3 Tesla MR Echospeed system General Electric scanner on five control and five schizophrenia subjects matched on age, sex, and IQ. Automated masks were generated from MABS, FS, BET, and Brainwash, and compared to MM using these metrics: a) volume difference from MM; b) Dice coefficients; and c) intraclass correlation coefficients. RESULTS: Mean volume difference between MM and MABS masks was significantly less than the difference between MM and FS or BET masks. Dice coefficient between MM and MABS was significantly higher than Dice coefficients between MM and FS, BET, or Brainwash. For subcortical and left cortical regions, MABS volumes were closer to MM volumes than were BET or FS volumes. For right cortical regions, MABS volumes were closer to MM volumes than were BET volumes. CONCLUSIONS: Brain masks generated using FreeSurfer, BET, and Brainwash are rapidly obtained, but are less accurate than manually defined masks. Masks generated using MABS, in contrast, resemble more closely the gold standard of manual masking, thereby offering a rapid and viable alternative. PMID- 26585546 TI - Vitamin D deficiency prevalence and risk factors among pregnant Chinese women. AB - OBJECTIVE: To evaluate vitamin D deficiency prevalence and risk factors among pregnant Chinese women. DESIGN: A descriptive cross-sectional analysis. SETTING: China National Nutrition and Health Survey (CNNHS) 2010-2013. SUBJECTS: A total of 1985 healthy pregnant women participated. Possible predictors of vitamin D deficiency were evaluated via multiple logistic regression analyses. RESULTS: The median serum 25-hydroxyvitamin D level was 15.5 (interquartile range 11.9-20.0, range 3.0-51.5) ng/ml, with 74.9 (95 % CI 73.0, 76.7) % of participants being vitamin D deficient (25-hydroxyvitamin D <20 ng/ml). According to the multivariate logistic regression analyses, vitamin D deficiency was positively correlated with Hui ethnicity (P=0.016), lack of vitamin D supplement use (P=0.021) and low ambient UVB level (P<0.001). In the autumn months, vitamin D deficiency was related to Hui ethnicity (P=0.012) and low ambient UVB level (P<0.001). In the winter months, vitamin D deficiency was correlated with younger age (P=0.050), later gestational age (P=0.035), higher pre-pregnancy BMI (P=0.019), low ambient UVB level (P<0.001) and lack of vitamin D supplement use (P=0.007). CONCLUSIONS: Vitamin D deficiency is prevalent among pregnant Chinese women. Residing in areas with low ambient UVB levels increases the risk of vitamin D deficiency, especially for women experiencing advanced stages of gestation, for younger pregnant women and for women of Hui ethnicity; therefore, vitamin D supplementation and sensible sun exposure should be encouraged, especially in the winter months. Further studies must determine optimal vitamin D intake and sun exposure levels for maintaining sufficient vitamin D levels in pregnant Chinese women. PMID- 26585547 TI - Modeling predicts a connection between sinus vortex effects and aortic compliance. AB - We submit this letter in order to clarify some methodological issues and concerns raised by Spronck et al. (2015) related to our mathematical modeling of aortic valve dynamics during systole Aboelkassem et al. (2015). It is important to note at the outset that these clarifications do not impact the simulation output or conclusions we originally reported in that paper. However, Spronck et al. have led us to recognize some unfortunate omissions and minor typographical errors in the methods portion of our report that, once corrected, will allow others to more easily reproduce and understand our results. PMID- 26585548 TI - Switch from anakinra to canakinumab in a severe case of CINCA syndrome. PMID- 26585549 TI - No-Report Paradigms: Extracting the True Neural Correlates of Consciousness. AB - The goal of consciousness research is to reveal the neural basis of phenomenal experience. To study phenomenology, experimenters seem obliged to ask reports from the subjects to ascertain what they experience. However, we argue that the requirement of reports has biased the search for the neural correlates of consciousness over the past decades. More recent studies attempt to dissociate neural activity that gives rise to consciousness from the activity that enables the report; in particular, no-report paradigms have been utilized to study conscious experience in the full absence of any report. We discuss the advantages and disadvantages of report-based and no-report paradigms, and ask how these jointly bring us closer to understanding the true neural basis of consciousness. PMID- 26585550 TI - Neurotic Individuals are not Creative Thinkers. PMID- 26585551 TI - Chelator-Free Labeling of Layered Double Hydroxide Nanoparticles for in Vivo PET Imaging. AB - Layered double hydroxide (LDH) nanomaterial has emerged as a novel delivery agent for biomedical applications due to its unique structure and properties. However, in vivo positron emission tomography (PET) imaging with LDH nanoparticles has not been achieved. The aim of this study is to explore chelator-free labeling of LDH nanoparticles with radioisotopes for in vivo PET imaging. Bivalent cation (64)Cu(2+) and trivalent cation (44)Sc(3+) were found to readily label LDH nanoparticles with excellent labeling efficiency and stability, whereas tetravalent cation (89)Zr(4+) could not label LDH since it does not fit into the LDH crystal structure. PET imaging shows that prominent tumor uptake was achieved in 4T1 breast cancer with (64)Cu-LDH-BSA via passive targeting alone (7.7 +/- 0.1%ID/g at 16 h post-injection; n = 3). These results support that LDH is a versatile platform that can be labeled with various bivalent and trivalent radiometals without comprising the native properties, highly desirable for PET image-guided drug delivery. PMID- 26585552 TI - Atomic force microscopy measurements of bacterial adhesion and biofilm formation onto clay-sized particles. AB - Bacterial adhesion onto mineral surfaces and subsequent biofilm formation play key roles in aggregate stability, mineral weathering, and the fate of contaminants in soils. However, the mechanisms of bacteria-mineral interactions are not fully understood. Atomic force microscopy (AFM) was used to determine the adhesion forces between bacteria and goethite in water and to gain insight into the nanoscale surface morphology of the bacteria-mineral aggregates and biofilms formed on clay-sized minerals. This study yields direct evidence of a range of different association mechanisms between bacteria and minerals. All strains studied adhered predominantly to the edge surfaces of kaolinite rather than to the basal surfaces. Bacteria rarely formed aggregates with montmorillonite, but were more tightly adsorbed onto goethite surfaces. This study reports the first measured interaction force between bacteria and a clay surface, and the approach curves exhibited jump-in events with attractive forces of 97 +/- 34 pN between E. coli and goethite. Bond strengthening between them occurred within 4 s to the maximum adhesion forces and energies of -3.0 +/- 0.4 nN and -330 +/- 43 aJ (10( 18) J), respectively. Under the conditions studied, bacteria tended to form more extensive biofilms on minerals under low rather than high nutrient conditions. PMID- 26585553 TI - Massive localized lymphedema: a clinicopathologic study of 46 patients with an enrichment for multiplicity. AB - Massive localized lymphedema is a monstrous tumefactive pseudosarcoma seen in middle-aged morbidly obese adults. Since its initial description in 1998, the etiology remains unknown, although associations with trauma, surgeries, and hypothyroidism have been reported. Herein, we report the largest study of massive localized lymphedema and expand upon its clinicopathologic features. Fifty-four cases from 46 patients were retrospectively identified from the institutional archives of The Ohio State University Wexner Medical Center between 2002 and 2015. Forty-six patients (21 males and 25 females, mean age 50 years) presented with large masses developing over a 5-60-month period. The majority of patients were Caucasian (n=39). All patients were obese with a mean weight of 384.7 lb and a mean body mass index of 59.6 kg/m(2). Thirty-six patients had a history of atherosclerotic cardiovascular disease and diabetes mellitus type 2 was present in 22 patients. Eight patients had multifocal massive localized lymphedema. The sites included thigh (n=33), abdomen (n=17), suprapubic region (n=1), mons pubis (n=6), scrotum (n=2), perianal region (n=1), and right flank (n=1). Mostly, the clinical impression was benign processes, including pannus or lymphedema pseudotumor. Grossly, the mean weight was 8237 g and the mean size was 53.2 cm. Histologically, eight cases showed a unique pattern of dystrophic calcifications mimicking hyperchromatic, atypical nuclei that might lead to misdiagnosis of liposarcoma, four cases showed focal metaplastic ossification, and three cases showed multinucleated cells in addition to prototypic features of massive localized lymphedema. We report that this is the largest series of massive localized lymphedema. This is a lesion mostly seen in morbidly obese patients and the thigh is the most common site of involvement. We note a marked racial predilection for Caucasians and a tendency towards multiplicity. We suggest that obesity itself and the related metabolic syndrome have an important role in its pathogenesis. PMID- 26585554 TI - Loss of H3K27 trimethylation distinguishes malignant peripheral nerve sheath tumors from histologic mimics. AB - The diagnosis of malignant peripheral nerve sheath tumor is challenging, particularly in the sporadic setting. Inactivation of the polycomb repressive complex 2 (PRC2), resulting from inactivating mutations of its constituents SUZ12 or EED1, has recently been identified in 70-90% of malignant peripheral nerve sheath tumors. Homozygous PRC2 inactivation results in loss of histone H3K27 trimethylation (H3K27me3). PRC2 inactivation promotes tumor progression and may render patients sensitive to epigenetic-based targeted therapies. H3K27me3 loss has not yet been validated as a diagnostic marker. We evaluated immunohistochemistry for H3K27me3 in 100 malignant peripheral nerve sheath tumors (70 sporadic, 10 neurofibromatosis type 1-associated, 10 radiation-associated, 10 epithelioid) and 200 other spindle cell neoplasms representing potential mimics (20 each monophasic synovial sarcoma, leiomyosarcoma, dedifferentiated liposarcoma, malignant solitary fibrous tumor, low-grade fibromyxoid sarcoma, cellular schwannoma, spindle cell melanoma, unclassified postradiation sarcoma; 10 each atypical neurofibroma, spindle cell rhabdomyosarcoma, gastrointestinal stromal tumor, fibrosarcomatous dermatofibrosarcoma protuberans). In total, 51 (51%) malignant peripheral nerve sheath tumors, including 34 (49%) sporadic, 7 (70%) neurofibromatosis type 1-associated, and 10 (100%) radiation-associated, but no epithelioid malignant peripheral nerve sheath tumors, were negative for H3K27me3. An additional 6 (6%) tumors showed heterogeneous H3K27me3 expression. Among the 90 sporadic, neurofibromatosis type 1-associated, and radiation associated malignant peripheral nerve sheath tumors, complete H3K27me3 loss was observed in 29% of low-grade, 59% of intermediate-grade, and 83% of high-grade tumors (low vs intermediate/high grade, P=0.0003). Among other tumor types, 4 (20%) unclassified postradiation sarcomas were negative for H3K27me3, whereas all other neoplasms were positive. Loss of H3K27me3 is highly specific for malignant peripheral nerve sheath tumor (although only modestly more sensitive than S-100 protein and SOX10) and may be a useful diagnostic marker. Our findings suggest that PRC2 inactivation in malignant peripheral nerve sheath tumor may occur during progression to higher grades. PMID- 26585555 TI - Minimally Invasive Temporary Right Ventricular Assist Device for Acute Right Ventricular Failure. AB - Minimally invasive approaches to acute mechanical circulatory support are needed to reduce hemorrhagic and other complications. We describe our minimally invasive approach to right ventricular assist device placement in patients with acute, non postcardiotomy, right ventricular failure. PMID- 26585557 TI - Flubromazolam--A new life-threatening designer benzodiazepine. AB - CONTEXT: In addition to designer benzodiazepines such as etizolam, deschloroetizolam, pyrazolam, diclazepam, nifoxipam, or clonazolam, a new psychoactive substance like flubromazolam, triazole of flubromazepam has become available. Flubromazolam is currently not marketed as a medication but rather as a research chemical and recreational drug. It mostly causes sedative effects but also has moderate anti-anxiety and muscle relaxant effects. A case of a severe intoxication of flubromazolam has been reported. CASE DETAILS: A 27-year-old man, presented with deep coma, bilateral pinpoint unreactive pupils, acute respiratory failure and hypotension, complicated by hypoxic ischemic changes in the central nervous system. A positive result of a urine screening test confirmed the presence of benzodiazepines, which resulted in administration of flumazenil and improved patient consciousness. Quantitative method of liquid chromatography indicated flubromazolam in the patient's serum at 59 ng/mL and urine at 105 ng/mL about 19 h after ingestion of 3 mg dose. On admission, serum creatine kinase was 15,960 U/L. The patient was treated with mechanical ventilation, intravenous fluids, flumazenil and continuous infusion of norepinephrine at a dose of 0.12 ug/kg/min. The patient survived and on the ninth day of hospitalization he was transferred to the Department of Neurology. DISCUSSION: Flubromazolam is a new designer drug. Recreational use may be a cause of prolonged, severe intoxication associated with coma, hypotension, and rhabdomyolysis. PMID- 26585556 TI - Image-guided tumor surgery: will there be a role for fluorescent nanoparticles? AB - Image-guided surgery (IGS) using fluorescent nanoparticles (NPs) has the potential to substantially impact patient treatment. The use of fluorescence imaging provides surgeons with real-time feedback on the location of diseased tissue using safe, low-cost imaging agents and instrumentation. Fluorescent NPs are likely to play a role as they are capable of taking advantage of the enhanced permeability and retention (EPR) effect and can be modified to avoid clearance, increase circulation time, and specifically target tumors. Clinical trials of IGS using the FDA-approved fluorophores indocyanine green and methylene blue have already shown preliminary successes, and incorporation of fluorescent NPs will likely improve detection by providing higher signal to background ratio and reducing false-positive rates through active targeting. Preclinical development of fluorescent NP formulations is advancing rapidly, with strategies ranging from passive targeting to active targeting of cell surface receptors, creating pH responsive NPs, and increasing cell uptake through cleavable proteins. This collective effort could lead to clinical trials using fluorescent NPs in the near future. WIREs Nanomed Nanobiotechnol 2016, 8:498-511. doi: 10.1002/wnan.1381 For further resources related to this article, please visit the WIREs website. PMID- 26585558 TI - Insights into the smooth-to-rough transitioning in Mycobacterium bolletii unravels a functional Tyr residue conserved in all mycobacterial MmpL family members. AB - In mycobacteria, MmpL proteins represent key components that participate in the biosynthesis of the complex cell envelope. Whole genome analysis of a spontaneous rough morphotype variant of Mycobacterium abscessus subsp. bolletii identified a conserved tyrosine that is crucial for the function of MmpL family proteins. Isogenic smooth (S) and rough (R) variants differed by a single mutation linked to a Y842H substitution in MmpL4a. This mutation caused a deficiency in glycopeptidolipid production/transport in the R variant and a gain in the capacity to produce cords in vitro. In zebrafish, increased virulence of the M. bolletii R variant over the parental S strain was found, involving massive production of serpentine cords, abscess formation and rapid larval death. Importantly, this finding allowed us to demonstrate an essential role of Tyr842 in several different MmpL proteins, including Mycobacterium tuberculosis MmpL3. Structural homology models of MmpL4a and MmpL3 identified two additional critical residues located in the transmembrane regions TM10 and TM4 that are facing each other. We propose that these central residues are part of the proton-motive force that supplies the energy for substrate transport. Hence, we provide important insights into mechanistic/structural aspects of MmpL proteins as lipid transporters and virulence determinants in mycobacteria. PMID- 26585559 TI - Lipid transport to avian oocytes and to the developing embryo. AB - Studies of receptor-mediated lipoprotein metabolic pathways in avian species have revealed that physiological intricacies of specific cell types are highly analogous to those in mammals. A prime example for the power of comparative studies across different animal kingdoms, elucidated in the chicken, is that the expression of different lipoprotein receptors in somatic cells and oocytes are the key to oocyte growth. In avian species, yolk precursor transport from the hen's liver to rapidly growing oocytes and the subsequent transfer of yolk nutrients via the yolk sac to the developing embryo are highly efficient processes. Oocytes grow from a diameter of 5 mm to 2.5-3 cm in only 7 days, and the yolk sac transfers nutrients from the yolk stored in the mature oocyte to the embryo within just 2 weeks. The underlying key transport mechanism is receptor mediated endocytosis of macromolecules, i.e., of hepatically synthesized yolk precursors for oocyte growth, and of mature yolk components for embryo nutrition, respectively. Recently, the receptors involved, as well as the role of lipoprotein synthesis in the yolk sac have been identified. As outlined here, lipoprotein degradation/resynthesis cycles and the expression of lipoprotein receptors are not only coordinated with the establishment of the follicular architecture embedding the oocyte, but also with the generation of the yolk sac vasculature essential for nutrient transfer to the embryo. PMID- 26585560 TI - Animal models of coronary heart disease. AB - Cardiovascular disease, predominantly coronary heart disease and stroke, leads to high morbidity and mortality not only in developed worlds but also in underdeveloped regions. The dominant pathologic foundation for cardiovascular disease is atherosclerosis and as to coronary heart disease, coronary atherosclerosis and resulting lumen stenosis, even total occlusions. In translational research, several animals, such as mice, rabbits and pigs, have been used as disease models of human atherosclerosis and related cardiovascular disorders. However, coronary lesions are either naturally rare or hard to be fast induced in these models, hence, coronary heart disease induction mostly relies on surgical or pharmaceutical interventions with no or limited primary coronary lesions, thus unrepresentative of human coronary heart disease progression and pathology. In this review, we will describe the progress of animal models of coronary heart disease following either spontaneous or diet-accelerated coronary lesions. PMID- 26585561 TI - Practical guide to sample size calculations: superiority trials. AB - A sample size justification is a vital part of any investigation. However, estimating the number of participants required to give meaningful results is not always straightforward. A number of components are required to facilitate a suitable sample size calculation. In this paper, the steps for conducting sample size calculations for superiority trials are summarised. Practical advice and examples are provided illustrating how to carry out the calculations by hand and using the app SampSize. PMID- 26585562 TI - POTENTIAL FOR PATIENTS AND PATIENT-DRIVEN ORGANIZATIONS TO IMPROVE EVIDENCE FOR HEALTH TECHNOLOGY ASSESSMENT. AB - This article gives a patient organization's perspective on health technology assessments (HTAs) and the role that such organizations can, and should, play in them. PMID- 26585563 TI - A manoeuvre to enhance subglottic view during flexible laryngoscopy. PMID- 26585564 TI - Stability of niosomes with encapsulated vitamin D3 and ferrous sulfate generated using a novel supercritical carbon dioxide method. AB - Niosomes were prepared using a novel supercritical carbon dioxide based method to simultaneously encapsulate ferrous sulfate and vitamin D3 as hydrophilic and hydrophobic cargo, respectively. Vesicle particle size was determined to be bimodal with peak diameters of 1.44 +/- 0.16 MUm and 7.21 +/- 0.64 MUm, with the smaller peak comprising 98.8% of the total niosomal volume. Encapsulation efficiency of ferrous sulfate was 25.1 +/- 0.2% and encapsulation efficiency of vitamin D3 was 95.9 +/- 1.47%. Physical stability of the produced niosomes was assessed throughout a storage period of 21 days. Niosomes showed good physical stability at 20 degrees C, but storage at 4 degrees C showed an initial burst release, indicating possible rupture of the niosomal membrane. The Korsmeyer Peppas equation was used to model the release of ferrous sulfate over time at both storage temperatures. PMID- 26585565 TI - The pivotal role of high glucose-induced overexpression of PKCbeta in the appearance of glucagon-like peptide-1 resistance in endothelial cells. AB - Recently, it has been demonstrated that Glucagon-like peptide-1 (GLP-1) has a protective effect on endothelial cells. Our hypothesis is that this GLP-1 protective effect is partly lost when the cells are exposed to sustained high glucose concentrations. Human umbilical vein endothelial cells (HUVECs) were cultured for 21 days in normal glucose (5 mmol/L, NG) or high glucose (25 mmol/L glucose, HG). GLP-1 (7-37) and Ruboxistaurin were added at 50 and 500 nM, respectively, alone or in combination, 1 h before cell harvesting. Analysis of GLP-1 receptor protein levels, as well as of the gene expression of different ER stress-related genes, proliferation markers, antioxidant cell response-related genes, and PKA subunits, was performed. ROS production was also measured in HUVECs exposed to mentioned treatments. GLP-1 receptor expression was reduced in HUVECs exposed to chronic high glucose concentrations but was partially restored by a chemical PKCbeta-specific inhibitor. GLP-1, added as an acute treatment in endothelial cells, had the capacity to induce the expression of Nrf2-detoxifying enzyme targets, to increase transcription levels of scavenger genes, to attenuate the expression of high glucose-induced PKA subunits, ER stress and also the apoptotic phenotype of HUVECs; these effects occured only when high glucose induced PKCbeta overexpression was reduced by Ruboxistaurin. In a similar manner, ROS production induced by high glucose was reduced by GLP-1 in the presence of PKCbeta inhibitor. This study suggests that an increase in PKCbeta, induced by high glucose, could have a role in endothelial GLP-1 resistance, reducing GLP-1 receptor levels and disrupting the GLP-1 canonical pathway. PMID- 26585566 TI - Periostin on the road to nonalcoholic fatty liver disease. PMID- 26585567 TI - Rejection of organic micro-pollutants from water by a tubular, hydrophilic pervaporative membrane designed for irrigation applications. AB - The links between chemical properties, including those relating to molecular size, solubility, hydrophobicity and vapour pressure, and rejection of model aromatic micro-pollutants by a tubular, hydrophilic polymer pervaporation membrane designed for irrigation applications were investigated. Open air experiments were conducted at room temperature for individual solutions of fluorene, naphthalene, phenol, 1,2-dichlorobenzene, 1,2-diethylbenzene and 2 phenoxyethanol. Percentage rejection generally increased with increased molecular size for the model micro-pollutants (47-86%). Molecular weight and log Kow had the strongest positive relationships with rejection, as demonstrated by respective correlation coefficients of r = 0.898 and 0.824. Rejection was also strongly negatively correlated with aqueous solubility and H-bond delta. However, properties which relate to vapour phase concentrations of the micro-pollutants were not well correlated with rejection. Thus, physicochemical separation processes, rather than vapour pressure, drive removal of aromatic contaminants by the investigated pervaporation tube. This expanded knowledge could be utilized in considering practical applications of pervaporative irrigation systems for treating organic-contaminated waters such as oilfield-produced waters. PMID- 26585568 TI - Rapidly growing giant cell tumor of bone in a skeletally immature girl. AB - Giant cell tumor of bone (GCTB) in skeletally immature patients is rare, and little is known regarding how fast GCTB can grow. We report a case of a 10-year old skeletally immature girl with pathologically proven GCTB with obvious growth plate invasion that showed surprisingly rapid growth over only 14 days. A radiograph of the left knee revealed well-circumscribed, geographic bone destruction at the distal metaphysis of the femur with a focal cortical defect, suggesting a pathologic fracture. No abnormal mineralization or periosteal reaction was seen. A CT without contrast and an MRI demonstrated a homogeneous lesion with cortical disruption posteriorly and laterally with a slight soft tissue extension. Biopsy showed numerous multinucleated giant cells and spindle shaped mononuclear cells without any sign of malignancy, suggesting GCTB. However, rapid lesion enlargement and destruction of the surrounding cortex were noted 14 days after biopsy. Considering the amount of bone destruction, traditional treatment of curettage and bone cement would not suffice to sustain structural strength. In addition, considering the patient's age, the tumor location, and the aggressive course, a malignant tumor, especially a giant cell rich osteosarcoma, could not be excluded. Therefore, en bloc resection, including the growth plate and prosthetic replacement, were performed. Confirmation of GCTB was made from a pathologic evaluation, and a breach to the growth plate was identified. Since very little inflammatory reaction, degenerative change, or aneurysmal, bone, cyst-like change was found, the growth plate invasion was confirmed as due to GCTB extension, not due to the preoperative biopsy. PMID- 26585570 TI - Epigenetic regulation of UBE3A and roles in human neurodevelopmental disorders. AB - The E3 ubiquitin ligase UBE3A, also known as E6-AP, has a multitude of ascribed functions and targets relevant to human health and disease. Epigenetic regulation of the UBE3A gene by parentally imprinted noncoding transcription within human chromosome 15q11.2-q13.3 is responsible for the maternal-specific effects of 15q11.2-q13.3 deletion or duplication disorders. Here, we review the evidence for diverse and emerging roles for UBE3A in the proteasome, synapse and nucleus in regulating protein stability and transcription as well as the current mechanistic understanding of UBE3A imprinting in neurons. Angelman and Dup15q syndromes as well as experimental models of these neurodevelopmental disorders are highlighted as improving understanding of UBE3A and its complex regulation for improving therapeutic strategies. PMID- 26585571 TI - Dinaciclib, a Cyclin-Dependent Kinase Inhibitor Promotes Proteasomal Degradation of Mcl-1 and Enhances ABT-737-Mediated Cell Death in Malignant Human Glioma Cell Lines. AB - The prognosis for malignant glioma, the most common brain tumor, is still poor, underscoring the need to develop novel treatment strategies. Because glioma cells commonly exhibit genomic alterations involving genes that regulate cell-cycle control, there is a strong rationale for examining the potential efficacy of strategies to counteract this process. In this study, we examined the antiproliferative effects of the cyclin-dependent kinase inhibitor dinaciclib in malignant human glioma cell lines, with intact, deleted, or mutated p53 or phosphatase and tensin homolog on chromosome 10; intact or deleted or p14ARF or wild-type or amplified epidermal growth factor receptor. Dinaciclib inhibited cell proliferation and induced cell-cycle arrest at the G2/M checkpoint, independent of p53 mutational status. In a standard 72-hour 3-[4,5 dimethylthiazol- 2yl]-5-[3-carboxymethoxyphenyl]-2-[4-sulfophenyl]-2H, tetrazolium (MTS) assay, at clinically relevant concentrations, dose-dependent antiproliferative effects were observed, but cell death was not induced. Moreover, the combination of conventional chemotherapeutic agents and various growth-signaling inhibitors with dinaciclib did not yield synergistic cytotoxicity. In contrast, combination of the Bcl-2/Bcl-xL inhibitors ABT-263 (4 [4-[[2-(4-chlorophenyl)-5,5-dimethylcyclohexen-1-yl]methyl]piperazin-1-yl]-N-[4 [[(2R)-4-morpholin-4-yl-1-phenylsulfanylbutan-2-yl]amino]-3 (trifluoromethylsulfonyl)phenyl]sulfonylbenzamide) or ABT-737 (4-[4-[[2-(4 chlorophenyl)phenyl]methyl]piperazin-1-yl]-N-[4-[[(2R)-4-(dimethylamino)-1 phenylsulfanylbutan-2-yl]amino]-3-nitrophenyl]sulfonylbenzamide) with dinaciclib potentiated the apoptotic response induced by each single drug. The synergistic killing by ABT-737 with dinaciclib led to cell death accompanied by the hallmarks of apoptosis, including an early loss of the mitochondrial transmembrane potential; the release of cytochrome c, smac/DIABLO, and apoptosis-inducing factor; phosphatidylserine exposure on the plasma membrane surface and activation of caspases and poly ADP-ribose polymerase. Mechanistic studies revealed that dinaciclib promoted proteasomal degradation of Mcl-1. These observations may have important clinical implications for the design of experimental treatment protocols for malignant human glioma. PMID- 26585573 TI - Understanding the Health Risks of Lower Olefins. PMID- 26585569 TI - An open-label prospective randomized multicenter study of intensive versus weekly granulocyte and monocyte apheresis in active crohn's disease. AB - BACKGROUND: Granulocyte and monocyte adsorptive apheresis (GMA) has shown efficacy in patients with active Crohn's disease (CD). However, with routine weekly therapy, it may take several weeks to achieve remission. This study was performed to assess clinical efficacy and safety of intensive GMA in patients with active CD. METHODS: In an open-label, prospective, randomized multicentre setting, 104 patients with CD activity index (CDAI) of 200 to 450 received intensive GMA, at two sessions per week (n = 55) or one session per week (n = 49). Clinical remission was defined as a CDAI score <150. Patients in each arm could receive up to 10 GMA sessions. However, GMA treatment could be discontinued when CDAI decreased to <150 (clinical remission level). RESULTS: Of the 104 patients, 99 were available for efficacy evaluation as per protocol, 45 in the weekly GMA group, and 54 in the intensive GMA group. Remission was achieved in 16 of 45 patients (35.6 %) in the weekly GMA and in 19 of 54 (35.2 %) in the intensive GMA (NS). Further, the mean time to remission was 35.4 +/- 5.3 days in the weekly GMA and 21.7 +/- 2.7 days in the intensive GMA (P = 0.0373). Elevated leucocytes and erythrocyte sedimentation rate were significantly improved by intensive GMA, from 8005/MUL to 6950/MUL (P = 0.0461) and from 54.5 mm/hr to 30.0 mm/hr (P = 0.0059), respectively. In both arms, GMA was well tolerated and was without safety concern. CONCLUSIONS: In this study, with respect to remission rate, intensive GMA was not superior to weekly GMA, but the time to remission was significantly shorter in the former without increasing the incidence of side effects. UMIN registration # 000003666. PMID- 26585572 TI - Dual A1/A2B Receptor Blockade Improves Cardiac and Renal Outcomes in a Rat Model of Heart Failure with Preserved Ejection Fraction. AB - Heart failure with preserved ejection fraction (HFpEF) is prevalent and often accompanied by metabolic syndrome. Current treatment options are limited. Here, we test the hypothesis that combined A1/A2B adenosine receptor blockade is beneficial in obese ZSF1 rats, an animal model of HFpEF with metabolic syndrome. The combined A1/A2B receptor antagonist 3-[4-(2,6-dioxo-1,3-dipropyl-7H-purin-8 yl)-1-bicyclo[2.2.2]octanyl]propanoic acid (BG9928) was administered orally (10 mg/kg/day) to obese ZSF1 rats (n = 10) for 24 weeks (from 20 to 44 weeks of age). Untreated ZSF1 rats (n = 9) served as controls. After 24 weeks of administration, BG9928 significantly lowered plasma triglycerides (in mg/dl: control group, 4351 +/- 550; BG9928 group, 2900 +/- 551) without adversely affecting plasma cholesterol or activating renin release. BG9928 significantly decreased 24-hour urinary glucose excretion (in mg/kg/day: control group, 823 +/- 179; BG9928 group, 196 +/- 80) and improved oral glucose tolerance, polydipsia, and polyuria. BG9928 significantly augmented left ventricular diastolic function in association with a reduction in cardiac vasculitis and cardiac necrosis. BG9928 significantly reduced 24-hour urinary protein excretion (in mg/kg/day: control group, 1702 +/- 263; BG9928 group, 1076 +/- 238), and this was associated with a reduction in focal segmental glomerulosclerosis, tubular atrophy, tubular dilation, and deposition of proteinaceous material in the tubules. These findings show that, in a model of HFpEF with metabolic syndrome, A1/A2B receptor inhibition improves hyperlipidemia, exerts antidiabetic actions, reduces HFpEF, improves cardiac histopathology, and affords renal protection. We conclude that chronic administration of combined A1/A2B receptor antagonists could be beneficial in patients with HFpEF, in particular those with comorbidities such as obesity, diabetes, and dyslipidemias. PMID- 26585574 TI - The Effects of Prone with Respect to Supine Position on Stress Relaxation, Respiratory Mechanics, and the Work of Breathing Measured by the End-Inflation Occlusion Method in the Rat. AB - PURPOSE: The working hypothesis is that the prone position with respect to supine may change the geometric configuration of the lungs inside the chest wall, thus their reciprocal mechanical interactions, leading to possible effects on stress relaxation phenomena and respiratory mechanics. METHOD: The effects of changing body posture from supine to prone on respiratory system mechanics, particularly on stress relaxation, were investigated in the rat by the end-inflation occlusion method. RESULTS: In the prone with respect to supine position, an increment of the frictional resistance of the airway (from 0.13 +/- 0.01 to 0.19 +/- 0.02 cm H2O/l sec(-1), p < 0.05) and a decrement of the stress relaxation-linked pressure dissipation (from 0.51 +/- 0.05 to 0.45 +/- 0.05 cm H2O/l sec(-1), p < 0.01) were found. Respiratory system elastance and total resistive pressure dissipation did not change significantly. Accordingly, a significant increase of the frictional "ohmic" mechanical inspiratory work of breathing and a decrease of the visco elastic work of inspiration were demonstrated, while no significant changes occurred for the total mechanical work of breathing and its total resistive and elastic components. CONCLUSION: It is concluded that postural changes affect the visco-elastic characteristics of the respiratory system and the related stress relaxation phenomena by influencing the disposition and relation of the lungs inside the chest wall and their relative geometrical configuration, and the interaction phenomena of the constitutive parenchymal structures, i.e., elastin and collagen fibers. Since the prone position resulted in no serious or disadvantageous respiratory system mechanical derangement, it is suggested it may be usefully applied in nursing or for therapeutic goals. PMID- 26585577 TI - Red-Emitting Mitochondrial Probe with Ultrahigh Signal-to-Noise Ratio Enables High-Fidelity Fluorescent Images in Two-Photon Microscopy. AB - Herein, we reported a red-emitting probe (E)-4-(2-(8-hydroxy-julolidine-9 yl)vinyl)-1-methylpyridin-1-ium iodide (HJVPI) on a rotor mechanism with an ultrahigh signal-to-noise ratio. HJVPI could give high-fidelity fluorescent images of mitochondria in living immortalized and normal cells and be suitable for IR excitation source of two-photon microscopy and various excitation sources of confocal microscopy. As a rotor, its single/two-photon fluorescence intensities directly depended on environmental viscosity. And, as a mitochondrial probe, it displayed much larger two-photon absorption cross sections in comparison with commercial MitoTracker Green FM and MitoTracker Red FM. Moreover, the fact that living cells stained by HJVPI still possessed physiological function could also be confirmed: (1) MTT assay demonstrated that the mitochondria of cells stained retained their electron mediating ability and (2) double assay of HJVPI and SYTOX Blue nucleic acid stain (S-11348) showed that the plasma membrane of the cells stained was still intact. In addition, HJVPI possessed a number of beneficial properties in bioimaging such as good membrane permeability, high photostability, and excellent counterstain compatibility with Hoechst 33342. Related mechanism research suggested that its localization property was dependent on the mitochondrial membrane potential in living cells. All its remarkable properties can extend the investigation on mitochondria in a biological context. PMID- 26585578 TI - Gene expression alterations associated with outcome in aromatase inhibitor treated ER+ early-stage breast cancer patients. AB - Aromatase inhibitors (AI), either alone or together with chemotherapy, have become the standard adjuvant treatment for postmenopausal, estrogen receptor positive (ER+) breast cancer. Although AIs improve overall survival, resistance is still a major clinical problem, thus additional biomarkers predictive of outcome of ER+ breast cancer patients treated with AIs are needed. Global gene expression analysis was performed on ER+ primary breast cancers from patients treated with adjuvant AI monotherapy; half experienced recurrence (median follow up 6.7 years). Gene expression alterations were validated by qRT-PCR, and functional studies evaluating the effect of siRNA-mediated gene knockdown on cell growth were performed. Twenty-six genes, including TFF3, DACH1, RGS5, and GHR, were shown to exhibit altered expression in tumors from patients with recurrence versus non-recurrent (fold change >=1.5, p < 0.05), and the gene expression alterations were confirmed using qRT-PCR. Ten of these 26 genes could be linked in a network associated with cellular proliferation, growth, and development. TFF3, which encodes for trefoil factor 3 and is an estrogen-responsive oncogene shown to play a functional role in tamoxifen resistance and metastasis of ER+ breast cancer, was also shown to be upregulated in an AI-resistant cell line model, and reduction of TFF3 levels using TFF3-specific siRNAs decreased the growth of both the AI-resistant and -sensitive parental cell lines. Moreover, overexpression of TFF3 in parental AI-sensitive MCF-7/S0.5 cells resulted in reduced sensitivity to the AI exemestane, whereas TFF3 overexpression had no effect on growth in the absence of exemestane, indicating that TFF3 mediates growth and survival signals that abrogate the growth inhibitory effect of exemestane. We identified a panel of 26 genes exhibiting altered expression associated with disease recurrence in patients treated with adjuvant AI monotherapy, including TFF3, which was shown to exhibit a growth- and survival promoting effect in the context of AI treatment. PMID- 26585579 TI - Long-term outcomes among breast cancer patients with extensive regional lymph node involvement: implications for locoregional management. AB - Extensive lymph node (LN) involvement portends significant risk for distant metastasis (DM) among breast cancer patients. As a result, local management may be of secondary import to systemic control in this population. We analyzed patients with >=10 involved LNs (N3) to evaluate the feasibility of breast conserving therapy (BCT) vs modified radical mastectomy (MRM) in this high-risk cohort. Among 98 women with N3 disease 46 (46.9%) underwent BCT and 52 (53.1%) received MRM. Nearly all patients (92%) received comprehensive radiotherapy (RT) including axillary and supraclavicular fields. The Kaplan-Meier method and Cox regression analyses were used to analyze time-to-event outcomes. Median follow-up was 76 months, with a 5-year DFS of 64.9% and OS of 71.9% among the cohort. Poorly differentiated (p = 0.007), ER-negative tumors (p = 0.015) had adverse DFS outcomes. Treatment groups did not differ with regard to 10-year DFS (45.4% for MRM vs. 57.6% for BCT; p = 0.31), or OS (61.4 vs. 63.7%; p = 0.79). DM-free survival was 48.9% following MRM and 60.6% following BCT (p = 0.19). Patients with >=10 involved LNs have similar outcomes following BCT or MRM, suggesting that RT may obviate the need for more-extensive surgery. While local control is comparably favorable regardless of surgical approach, systemic control remains a challenge in this population. PMID- 26585580 TI - Simple, Inexpensive, and Rapid Approach to Fabricate Cross-Shaped Memristors Using an Inorganic-Nanowire-Digital-Alignment Technique and a One-Step Reduction Process. AB - A rapid, scalable, and designable approach to produce a cross-shaped memristor array is demonstrated using an inorganic-nanowire digital-alignment technique and a one-step reduction process. Two-dimensional arrays of perpendicularly aligned, individually conductive Cu-nanowires with a nanometer-scale Cux O layer sandwiched at each cross point are produced. PMID- 26585576 TI - Guanfacine Extended Release: A New Pharmacological Treatment Option in Europe. AB - Children/adolescents with attention-deficit/hyperactivity disorder (ADHD) may have a poor or inadequate response to psychostimulants or be unable to tolerate their side-effects; furthermore, stimulants may be inappropriate because of co existing conditions. Only one non-stimulant ADHD pharmacotherapy, the noradrenaline transporter inhibitor atomoxetine, is currently approved for use in Europe. We review recent advances in understanding of the pathophysiology of ADHD with a focus on the roles of catecholamine receptors in context of the alpha2A adrenergic receptor agonist guanfacine extended release (GXR), a new non stimulant treatment option in Europe. Neuroimaging studies of children/adolescents with ADHD show impaired brain maturation, and structural and functional anomalies in brain regions and networks. Neurobiological studies in ADHD and medication response patterns support involvement of monoaminergic neurotransmitters (primarily dopamine and noradrenaline). Guanfacine is a selective alpha2A-adrenergic receptor agonist that has been shown to improve prefrontal cortical cognitive function, including working memory. The hypothesized mode of action of guanfacine centres on direct stimulation of post synaptic alpha2A-adrenergic receptors to enhance noradrenaline neurotransmission. Preclinical data suggest that guanfacine also influences dendritic spine growth and maturation. Clinical trials have demonstrated the efficacy of GXR in ADHD, and it is approved as monotherapy or adjunctive therapy to stimulants in Canada and the USA (for children and adolescents). GXR was approved recently in Europe for the treatment of ADHD in children and adolescents for whom stimulants are not suitable, not tolerated or have been shown to be ineffective. GXR may provide particular benefit for children/adolescents who have specific co-morbidities such as chronic tic disorders or oppositional defiant disorder (or oppositional symptoms) that have failed to respond to first-line treatment options. PMID- 26585581 TI - The Ongoing Challenges of Targeting the Androgen Receptor. PMID- 26585582 TI - Structured and Modular Training Pathway for Robot-assisted Radical Prostatectomy (RARP): Validation of the RARP Assessment Score and Learning Curve Assessment. AB - BACKGROUND: Use of robot-assisted radical prostatectomy (RARP) for prostate cancer is increasing. Structured surgical training and objective assessment are critical for outcomes. OBJECTIVE: To develop and validate a modular training and assessment pathway via Healthcare Failure Mode and Effect Analysis (HFMEA) for trainees undertaking RARP and evaluate learning curves (LCs) for procedural steps. DESIGN, SETTING, AND PARTICIPANTS: This multi-institutional (Europe, Australia, and United States) observational prospective study used HFMEA to identify the high-risk steps of RARP. A specialist focus group enabled validation. Fifteen trainees who underwent European Association of Urology robotic surgery curriculum training performed RARP and were assessed by mentors using the tool developed. Results produced LCs for each step. A plateau above score 4 indicated competence. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We used a modular training and assessment tool (RARP Assessment Score) to evaluate technical skills. LCs were constructed. Multivariable Kruskal-Wallis, Mann Whitney U, and kappa coefficient analyses were used. RESULTS AND LIMITATIONS: Five surgeons were observed for 42 console hours to map steps of RARP. HFMEA identified 84 failure modes and 46 potential causes with a hazard score >=8. Content validation created the RARP Assessment Score: 17 stages and 41 steps. The RARP Assessment Score was acceptable (56.67%), feasible (96.67%), and had educational impact (100%). Fifteen robotic surgery trainees were assessed for 8 mo. In 426 RARP cases (range: 4-79), all procedural steps were attempted by trainees. Trainees were assessed with the RARP Assessment Score by their expert mentors, and LCs for individual steps were plotted. LCs demonstrated plateaus for anterior bladder neck transection (16 cases), posterior bladder neck transection (18 cases), posterior dissection (9 cases), dissection of prostatic pedicle and seminal vesicles (15 cases), and anastomosis (17 cases). Other steps did not plateau during data collection. CONCLUSIONS: The RARP Assessment Score based on HFMEA methodology identified critical steps for focused RARP training and assessed surgeons. LCs demonstrate the experience necessary to reach a level of competence in technical skills to protect patients. PATIENT SUMMARY: We developed a safety and assessment tool to gauge the technical skills of surgeons performing robot-assisted radical prostatectomy. Improvement was monitored, and measures of progress can be used in future to guide mentors when training surgeons to operate safely. PMID- 26585583 TI - Neurobehavioral and self-awareness changes after traumatic brain injury: Towards new multidimensional approaches. AB - Neurobehavioral and self-awareness changes are frequently observed following traumatic brain injury (TBI). These disturbances have been related to negative consequences on functional outcomes, caregiver distress and social reintegration, representing therefore a challenge for clinical research. Some studies have recently been conducted to specifically explore apathetic and impulsive manifestations, as well as self-awareness impairments in patients with TBI. These findings underlined the heterogeneity of clinical manifestations for each behavioral disturbance and the diversity of psychological processes involved. In this context, new multidimensional approaches taking into account the various processes at play have been proposed to better understand and apprehend the complexity and dynamic nature of these problematic behaviors. In addition, the involvement of social and environmental factors as well as premorbid personality traits have increasingly been addressed. These new multidimensional frameworks have the potential to ensure targeted and effective rehabilitation by allowing a better identification and therefore consideration of the various mechanisms involved in the onset of problematic behaviors. In this context, the main objective of this position paper was to demonstrate the interest of multidimensional approaches in the understanding and rehabilitation of problematic behaviors in patients with TBI. PMID- 26585584 TI - Use of psychotropic drugs in physically disabled patients: One-shot prevalence and medical practice assessment in a physical and rehabilitation medicine ward. PMID- 26585585 TI - Adipose-Derived Mesenchymal Stem Cells With Microfracture Versus Microfracture Alone: 2-Year Follow-up of a Prospective Randomized Trial. AB - PURPOSE: To compare the clinical and radiologic efficacy of adipose-derived stem cells (ADSCs) with fibrin glue and microfracture (MFX) versus MFX alone in patients with symptomatic knee cartilage defects. METHODS: Patients who were aged 18 to 50 years and had a single International Cartilage Repair Society grade III/IV symptomatic cartilage defect (>=3 cm(2)) on the femoral condyle were randomized to receive ADSCs with fibrin glue and MFX treatment (group 1, n = 40) or MFX treatment alone (group 2, n = 40). There was a lack of blinding for patients because of the additional intervention method (liposuction). The cartilage defect was diagnosed using preoperative magnetic resonance imaging (MRI), and quantitative and qualitative assessments of the repair tissue were carried out at 24 months by using the Magnetic Resonance Observation of Cartilage Repair Tissue scoring system with follow-up MRI. Clinical results were evaluated using the Lysholm score, the Knee Injury and Osteoarthritis Outcome Score (KOOS), and a 10-point visual analog scale for pain (0 points, no pain; 10 points, worst possible pain) preoperatively and postoperatively at 3 months, 12 months, and the last follow-up visit. RESULTS: The 2 groups had similar baseline patient characteristics. Follow-up MRI was performed at 24 months (mean, 24.3 months; range, 24.0 to 25.1 months) after the operation. Group 1 included 26 patients (65%) who had complete cartilage coverage of the lesion at follow-up compared with 18 patients (45%) in group 2. Significantly better signal intensity was observed for the repair tissue in group 1, with 32 patients (80%) having normal or nearly normal signal intensity (i.e., complete cartilage coverage of the lesion) compared with 28 patients (72.5%) in group 2. The mean clinical follow-up period was 27.4 months (range, 26 to 30 months). The improvements in the mean KOOS pain and symptom subscores were significantly greater at follow-up in group 1 than in group 2 (pain, 36.6 +/- 11.9 in group 1 and 30.1 +/- 14.7 in group 2 [P = .034]; symptoms, 32.3 +/- 7.2 in group 1 and 27.8 +/- 6.8 in group 2 [P = .005]). However, the improvements in the other subscores were not significantly different between group 1 and group 2 (activities of daily living, 38.5 +/- 12.8 and 37.6 +/- 12.9, respectively [P = .767]; sports and recreation, 33.9 +/- 10.3 and 31.6 +/- 11.0, respectively [P = .338]; quality of life, 38.4 +/- 13.1 and 37.8 +/- 12.0, respectively [P = .650]). Among the 80 patients, second-look arthroscopies were performed in 57 knees (30 in group 1 and 27 in group 2), and biopsy procedures were performed during these arthroscopies for 18 patients in group 1 and 16 patients in group 2. The second-look arthroscopies showed good repair tissue quality, although no significant intergroup difference was observed. The mean total histologic score was 1,054 for group 1 compared with 967 for group 2 (P = .036). Age, lesion size, duration of symptoms before surgery, mechanism of injury, and combined procedures were not correlated with clinical results, Magnetic Resonance Observation of Cartilage Repair Tissue scores, and histologic outcomes at short-term follow-up. CONCLUSIONS: Compared with MFX alone, MFX and ADSCs with fibrin glue provided radiologic and KOOS pain and symptom subscore improvements, with no differences in activity, sports, or quality-of-life subscores, in symptomatic single cartilage defects of the knee that were 3 cm(2) or larger, with similar structural repair tissue. LEVEL OF EVIDENCE: Level II, prospective comparative study. PMID- 26585587 TI - Inheritance and Variation of Genomic DNA Methylation in Diploid and Triploid Pacific Oyster (Crassostrea gigas). AB - DNA methylation is an important epigenetic mechanism that could be responsive to environmental changes indicating a potential role in natural selection and adaption. In order to evaluate an evolutionary role of DNA methylation, it is essential to first gain a better insight into inheritability. To address this question, this study investigated DNA methylation variation from parents to offspring in the Pacific oyster Crassostrea gigas using fluorescent-labeled methylation-sensitive amplified polymorphism (F-MSAP) analysis. Most of parental methylated loci were stably transmitted to offspring segregating following Medelian expectation. However, methylated loci deviated more often than non methylated loci and offspring showed a few de novo methylated loci indicating DNA methylation changes from parents to offspring. Interestingly, some male-specific methylated loci were found in this study which might help to explore sex determination in oyster. Despite environmental stimuli, genomic stresses such as polyploidization also can induce methylation changes. This study also compared global DNA methylation level and individual methylated loci between diploid and triploid oysters. Results showed no difference in global methylation state but a few ploidy-specific loci were detected. DNA methylation variation during polyploidization was less than autonomous methylation variation from parents to offspring. PMID- 26585588 TI - Enzyme-Assisted Preparation of Furcellaran-Like kappa-/beta-Carrageenan. AB - Carrageenans are sulfated galactans that are widely used in industrial applications for their thickening and gelling properties, which vary according to the amount and distribution of ester sulfate groups along the galactan backbone. To determine and direct the sulfation of kappa-carrageenan moieties, we purified an endo-kappa-carrageenan sulfatase (Q15XH1 accession in UniprotKB) from Pseudoalteromonas atlantica T6c extracts. Based on sequence analyses and exploration of the genomic environment of Q15XH1, we discovered and characterized a second endo-kappa-carrageenan sulfatase (Q15XG7 accession in UniprotKB). Both enzymes convert kappa-carrageenan into a hybrid, furcellaran-like kappa-/beta carrageenan. We compared the protein sequences of these two new kappa-carrageenan sulfatases and that of a previously reported iota-carrageenan sulfatase with other predicted sulfatases in the P. atlantica genome, revealing the existence of additional new carrageenan sulfatases. PMID- 26585589 TI - BMP-7 attenuated silica-induced pulmonary fibrosis through modulation of the balance between TGF-beta/Smad and BMP-7/Smad signaling pathway. AB - OBJECTIVE: To investigate the anti-fibrotic effects and possible mechanisms of bone morphogenetic protein-7 (BMP-7) on silica induced fibrosis in RLE-6TN cells, and compare the preventive treatment of experimental silicosis with BMP-7 with therapeutic treatment of silicosis in vitro models. METHODS: RLE-6TN cells were incubated with the supernatant of RAW264.7, treated by 50 MUg/mL silica in either presence or absence of BMP-7 in different phases. Morphological changes and the cellular wound-healing assays were used to evaluate the process of EMT. By using Western Blotting, the epithelial marker E-cadherin (E-cad), and the mesenchymal markers Vimentin (Vim), Snail, and fibronectin (FN) were detected as well as the Smad signaling pathway proteins, including phosphorylated Smad1/5(P-Smad1/5), phosphorylated Smad2/3(P-Smad2/3), and non-phosphorylated Smad1, Smad8, and Smad2. The progress of fibrosis was assessed by the content of hydroxyproline (Hyp) and collagen I and III protein levels. In addition, MTT assay was used to explore the toxic effects of silica as well as BMP-7. RESULTS: The EMT model of RLE-6TN cells was established successfully, the cells had a fibroblast-like morphology with increasing migration activity. The expressions of Vim, Snail, FN, collagen I and collagen III were up-regulated with the increase of silica concentration. BMP-7 could attenuate the decrease of P-Smad1/5 and the increase of P-Smad2/3, collagen I, collagen III, and FN via Smad signaling pathway. BMP-7 inhibited the mesenchymal-like responses in RLE-6TN cells, including cell migration, expression of fibrosis markers, and secretion of Hyp. Furthermore, the anti-fibrotic effects in the prevention group were more effective than treatment group. CONCLUSION: The restoration of BMP signaling with BMP-7 is associated with inhibiting silica-induced fibrosis through the mechanisms of activated BMP-7/Smad and suppressed TGF-beta/Smad pathways. Preventive treatment of pulmonary fibrosis progression with BMP-7 may expect to be the optimized strategy than therapeutic therapy of fibrosis. PMID- 26585590 TI - Monoclonal antibodies to human butyrylcholinesterase reactive with butyrylcholinesterase in animal plasma. AB - Five mouse anti-human butyrylcholinesterase (BChE) monoclonal antibodies bind tightly to native human BChE with nanomolar dissociation constants. Pairing analysis in the Octet system identified the monoclonal antibodies that bind to overlapping and independent epitopes on human BChE. The nucleotide and amino acid sequences of 4 monoclonal antibodies are deposited in GenBank. Our goal was to determine which of the 5 monoclonal antibodies recognize BChE in the plasma of animals. Binding of monoclonal antibodies 11D8, B2 18-5, B2 12-1, mAb2 and 3E8 to BChE in animal plasma was measured using antibody immobilized on Pansorbin cells and on Dynabeads Protein G. A third method visualized binding by the shift of BChE activity bands on nondenaturing gels stained for BChE activity. Gels were counterstained for carboxylesterase activity. The three methods agreed that B2 18 5 and mAb2 have broad species specificity, but the other monoclonal antibodies interacted only with human BChE, the exception being 3E8, which also bound chicken BChE. B2 18-5 and mAb2 recognized BChE in human, rhesus monkey, horse, cat, and tiger plasma. A weak response was found with rabbit BChE. Monoclonal mAb2, but not B2 18-5, bound pig and bovine BChE. Gels stained for carboxylesterase activity confirmed that plasma from humans, monkey, pig, chicken, and cow does not contain carboxylesterase, but plasma from horse, cat, tiger, rabbit, guinea pig, mouse, and rat has carboxylesterase. Rabbit plasma carboxylesterase hydrolyzes butyrylthiocholine. In conclusion monoclonal antibodies B2 18-5 and mAb2 can be used to immuno extract BChE from the plasma of humans, monkey and other animals. PMID- 26585591 TI - Pathway underlying small intestine apoptosis by dietary nickel chloride in broiler chickens. AB - The aims of this study were to investigate the pathways which dietary nickel chloride (NiCl2) affects small intestine apoptosis in broiler chickens by observing the ultrastructure, and bcl-2, bax, and caspase-3 protein expression and mRNA expression, and cytochrome C, bak and caspase-9 mRNA expression of the small intestine. A total of 240 one-day-old avian broilers were divided into four groups and fed a corn-soybean basal diet as the control diet or three experimental diets supplemented with 300, 600, and 900 mg/kg of NiCl2 for 42 days. Ultrastructurally, the microvilli were apparently exfoliated, and the mitochondria were swollen and the number of lysosomes increased in the intestinal cells of three experimental groups. As measured by TUNEL and flow cytometry (FCM), the percentage of apoptotic cells in the small intestine and the lymphocytes in the ileum were significantly increased in three experimental groups when compared with those of the control group. Meanwhile, immunohistochemistry, quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immuno-sorbent assay (ELISA) tests showed that the protein expression, mRNA expression levels were decreased in the bcl-2, whereas those of bax and caspase-3, and the cytochrome C, bak and caspase-9 mRNA expression levels were increased in three experimental groups. The abovementioned results show that pathway of dietary NiCl2-induced small intestine apoptosis is related to the mitochondrial damage and promotion of the cytochrome C release from mitochondria, which activates the mitochondrion-mediated apoptosis pathway. PMID- 26585592 TI - New cytotoxic butyltin complexes with 2-sulfobenzoic acid: Molecular interaction with lipid bilayers and DNA as well as in vitro anticancer activity. AB - New butyltin complexes with 2-sulfobenzoic acid: [Sn(C4H9)2{O3SC6H4COO 2}(H2O)].(C2H5OH) (DBTsbz), [Sn(C4H9)3{O3SC6H4COOH-2}] (TBTsbz) and [Sn2(C4H9)6{MU-O3SC6H4COO-2}] (DTBTsbz) are very effective cytotoxic agents against tumor cells. The molecular interaction of these complexes with lipid membranes and DNA has been investigated. The IR spectra and changes of (1)H, (13)C chemical shifts suggest that SO3 and COO groups of 2-sulfobenzoato ligand interact with O atom of glycerin fragment of DPPC. Moreover, the compounds form Sn-OP bonds with phosphate groups of DPPC, which was shown by the lower frequency shift of the nus(PO2(-)) and nuas(PO2(-)) band, by change of (31)P NMR signals and by DFT calculation. Another possibility is the interaction of the phosphate group of DPPC owing to formation of hydrogen bond O-H...O-P between water molecule coordinated to Sn and oxygen atom from the phosphate group. Using TCSPC FCS we characterized DNA supramolecular assemblies' formation upon increasing TBTsbz, DTBTsbz and DBTsbz concentration. Diffusion time, lifetime and particle number changes are altered systematically with increasing Ccomp/CDNAbp ratio in following effectiveness order DBTsbz > TBTsbz > DTBTsbz. From those parameters we can conclude that all these compounds lead to a change of DNA winding, strand but not to DNA compaction. Investigated compounds show very high cytotoxic activity against cancer cell lines. All compounds exhibit efficient in vitro antitumor activity toward Jurkat (T-cell leukemia), CL-1 (T-lymphoblastoid cell line), GL-1 (B cell lymphoma cell line) and D-17 (canine osteosarcoma). The DBTsbz is more effective then carboplatin against canine osteosarcoma. PMID- 26585593 TI - An Exclusively trans-Selective Chlorocarbamoylation of Alkynes Enabled by a Palladium/Phosphaadamantane Catalyst. AB - Pharmaceutically relevant methylene oxindoles are synthesized by a palladium(0) catalyzed intramolecular chlorocarbamoylation reaction of alkynes. A relatively underexplored class of caged phosphine ligands is uniquely suited for this transformation, enabling high levels of reactivity and exquisite trans selectivity. This report entails the first transition-metal-catalyzed atom economic addition of a carbamoyl chloride across an alkyne. PMID- 26585595 TI - Is Post-Graduate Training Essential for Practice Readiness? AB - Few things are more fundamental to the purpose of health professions training than to prepare practice-ready health professionals. The Accreditation Council of Pharmacy Education (ACPE) Standards 2016 address graduate readiness to 1) provide direct patient care in a variety of health care settings (practice-ready) and 2) contribute as a member of an interprofessional collaborative patient care team (team-ready). ACPE Standards 2007 states that graduates should be prepared to deliver direct patient care. This includes the ability to design, implement, monitor, evaluate, and adjust pharmacy care plans that are patient specific and to function effectively as a member of an interprofessional team. Yet, controversy remains within the profession regarding the practice-readiness of PharmD graduates, which has been further fueled by the recent ACCP White Paper on Collaborative Drug Therapy Management and Comprehensive Medication Management - 2015. This commentary makes the case that PharmD graduates are practice-ready and it offers a solution that may settle this lingering controversy. PMID- 26585594 TI - Pan-Bcl-2 inhibitor Obatoclax is a potent late stage autophagy inhibitor in colorectal cancer cells independent of canonical autophagy signaling. AB - BACKGROUND: Colorectal cancer is the third most common malignancy in humans and novel therapeutic approaches are urgently needed. Autophagy is an evolutionarily highly conserved cellular process by which cells collect unnecessary organelles or misfolded proteins and subsequently degrade them in vesicular structures in order to refuel cells with energy. Dysregulation of the complex autophagy signaling network has been shown to contribute to the onset and progression of cancer in various models. The Bcl-2 family of proteins comprises central regulators of apoptosis signaling and has been linked to processes involved in autophagy. The antiapoptotic members of the Bcl-2 family of proteins have been identified as promising anticancer drug targets and small molecules inhibiting those proteins are in clinical trials. METHODS: Flow cytometry and colorimetric assays were used to assess cell growth and cell death. Long term 3D cell culture was used to assess autophagy in a tissue mimicking environment in vitro. RNA interference was applied to modulate autophagy signaling. Immunoblotting and q-RT PCR were used to investigate autophagy signaling. Immunohistochemistry and fluorescence microscopy were used to detect autophagosome formation and autophagy flux. RESULTS: This study demonstrates that autophagy inhibition by obatoclax induces cell death in colorectal cancer (CRC) cells in an autophagy prone environment. Here, we demonstrate that pan-Bcl-2 inhibition by obatoclax causes a striking, late stage inhibition of autophagy in CRC cells. In contrast, ABT-737, a Mcl-1 sparing Bcl-2 inhibitor, failed to interfere with autophagy signaling. Accumulation of p62 as well as Light Chain 3 (LC3) was observed in cells treated with obatoclax. Autophagy inhibition caused by obatoclax is further augmented in stressful conditions such as starvation. Furthermore, our data demonstrate that inhibition of autophagy caused by obatoclax is independent of the essential pro autophagy proteins Beclin-1, Atg7 and Atg12. CONCLUSIONS: The objective of this study was to dissect the contribution of Bcl-2 proteins to autophagy in CRC cells and to explore the potential of Bcl-2 inhibitors for autophagy modulation. Collectively, our data argue for a Beclin-1 independent autophagy inhibition by obatoclax. Based on this study, we recommend the concept of autophagy inhibition as therapeutic strategy for CRC. PMID- 26585596 TI - Are implantable cardiac monitors the 'gold standard' for atrial fibrillation detection? A prospective randomized trial comparing atrial fibrillation monitoring using implantable cardiac monitors and DDDRP permanent pacemakers in post atrial fibrillation ablation patients. AB - AIMS: Implantable devices are widely accepted, but not proven, to be the most reliable monitoring method to assess atrial fibrillation (AF) therapies. We compared REVEAL((r))XT implantable cardiac monitors (ICMs) and permanent pacemakers (PPMs). METHODS AND RESULTS: Fifty patients with paroxysmal AF were randomized to ICM or PPM implant 6 weeks prior to pulmonary vein isolation. Permanent pacemakers were programmed to monitoring only (ODO). Device downloads were performed at 0, 3, 6, 9, and 12 months. All patients underwent 7-day external loop recorder. Device ECGs and EGMs were compared for AF burden. A total of 20 744 and 11 238 arrhythmia episodes were identified in the ICM and PPM groups, respectively. Correct identification of AF was significantly better in the PPM group (97 vs. 55% P < 0.001). In the ICM group, 26% of ECGs were un interpretable. Sensitivity and specificity for each episode of AF was significantly better in the PPM group (100 vs. 79% and 98 vs. 66%, respectively, P < 0.001). The positive predictive value for the detection of any AF was significantly better in the PPM than the ICM (100 vs. 58%, P = 0.03). The negative predictive value for the absence of all AF was not significantly different between the PPM and ICM (100% vs. 92%, P = 0.76). CONCLUSION: Permanent pacemakers Holters are the most accurate method of evaluating arrhythmia burden and the therapeutic efficacy of novel AF therapies. ICM has a high degree of artefact, which reduces its specifity and sensitivity. Despite the deficiencies of ICM monitoring the negative predictive value of the ICM is satisfactory if zero AF burden is the aim of therapy. PMID- 26585597 TI - Geometrical considerations in cardiac electrophysiology and arrhythmogenesis. AB - The rate of repolarization (RRepol) and so the duration of the cardiac action potential are determined by the balance of inward and outward currents across the cardiac membrane (net ionic current). Plotting action potential duration (APD) as a function of the RRepol reveals an inverse non-linear relationship, arising from the geometric association between these two factors. From the RRepol-APD relationship, it can be observed that a longer action potential will exhibit a greater propensity to shorten, or prolong, for a given change in the RRepol (i.e. net ionic current), when compared with one that is initially shorter. This observation has recently been used to explain why so many interventions that prolong the action potential exert a greater effect at slow rates (reverse rate dependence). In this article, we will discuss the broader implications of this simple principle and examine how common experimental observations on the electrical behaviour of the myocardium may be explained in terms of the RRepol APD relationship. An argument is made, with supporting published evidence, that the non-linear relationship between the RRepol and APD is a fundamental, and largely overlooked, property of the myocardium. The RRepol-APD relationship appears to explain why interventions and disease with seemingly disparate mechanisms of action have similar electrophysiological consequences. Furthermore, the RRepol-APD relationship predicts that prolongation of the action potential, by slowing repolarization, will promote conditions of dynamic electrical instability, exacerbating several electrophysiological phenomena associated with arrhythmogenesis, namely, the rate dependence of dispersion of repolarization, APD restitution, and electrical alternans. PMID- 26585598 TI - 2015 HRS/EHRA/APHRS/SOLAECE expert consensus statement on optimal implantable cardioverter-defibrillator programming and testing. PMID- 26585600 TI - Behavioural addiction-A rising tide? AB - The term 'addiction' was traditionally used in relation to centrally active substances, such as cocaine, alcohol, or nicotine. Addiction is not a unitary construct but rather incorporates a number of features, such as repetitive engagement in behaviours that are rewarding (at least initially), loss of control (spiralling engagement over time), persistence despite untoward functional consequences, and physical dependence (evidenced by withdrawal symptoms when intake of the substance diminishes). It has been suggested that certain psychiatric disorders characterized by maladaptive, repetitive behaviours share parallels with substance addiction and therefore represent 'behavioural addictions'. This perspective has influenced the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), which now has a category 'Substance Related and Addictive Disorders', including gambling disorder. Could other disorders characterised by repetitive behaviours, besides gambling disorder, also be considered 'addictions'? Potential examples include kleptomania, compulsive sexual behaviour, 'Internet addiction', trichotillomania (hair pulling disorder), and skin-picking disorder. This paper seeks to define what is meant by 'behavioural addiction', and critically considers the evidence for and against this conceptualisation in respect of the above conditions, from perspectives of aetiology, phenomenology, co-morbidity, neurobiology, and treatment. Research in this area has important implications for future diagnostic classification systems, neurobiological models, and novel treatment directions. PMID- 26585599 TI - Profiling of circulating microRNAs in patients with Barrett's esophagus and esophageal adenocarcinoma. AB - BACKGROUND: Circulating microRNAs (miRNAs) have been suggested as novel markers for various diseases. The goal of this pilot study was to identify circulating miRNAs differentially expressed comparing Barrett's esophagus (BE), esophageal adenocarcinoma (EAC), and controls. METHODS: MicroRNA expression profiling was performed by qPCR array using plasma from six controls and eight BE and eight EAC patients. Validation was performed by analyzing the expression of six selected miRNAs, by qRT-PCR in 115 plasma samples of controls, BE, and EAC patients. Diagnostic accuracy was evaluated by area under the curve (AUC) analysis. RESULTS: We identified three miRNAs that were elevated in EAC and four miRNAs that were elevated in BE. Further validation showed that miRNA-382-5p was significantly increased and miRNA-133a-3p significantly decreased in EAC. miRNA 194-5p and miRNA-451a were significantly increased and miRNA-136-5p significantly decreased in BE versus controls. A combination of three or more miRNAs was found to have a good diagnostic performance in discriminating BE from controls (AUC: 0.832), EAC from controls (AUC: 0.846), and BE from EAC (AUC: 0.797). CONCLUSION: Our data suggest that circulating miRNAs are differentially expressed in BE and EAC. The miRNAs identified may be used for future non-invasive screening of BE and EAC. PMID- 26585601 TI - Is Gerontology in Crisis? PMID- 26585602 TI - Gerontology in India. AB - India, with a population of 1.22 billion, has a predominantly agriculture-based economy. Its 90 million elderly population heavily depend on their children for financial support and caregiving. Research on aging in India today is focused on the medical, biological, behavioral, and social sciences. Aging as an independent subject is only taught at a few institutions. Several national and state agencies and many nongovernmental organizations offer housing, day care, and health care services. The 1999 National Policy on Older Persons is being revised, 2 National Institutes on Aging have been designated, and a pilot health program targeting seniors has been implemented. India's greatest concern is how to provide adequate health care and income security for its huge elderly population, especially the uneducated rural poor. PMID- 26585609 TI - Patient Test Preference for Colorectal Cancer Screening and Screening Uptake in an Insured Urban Minority Population. AB - The study examines the role of patient colorectal cancer (CRC) screening test preference and CRC screening uptake in an insured, urban minority population. Study subjects were enrolled in a randomized controlled trial to promote CRC screening. The interventions were educational, with an emphasis on colonoscopy screening. Subjects were 50+ years of age, fully insured for CRC screening, and out of compliance with current CRC screening recommendations. This paper includes those who answered a question about CRC screening test preference and indicated that they intended to receive such a test in the coming year (n = 453). CRC screening uptake was ascertained from medical claims data. Regardless of test preference, few received CRC screening (22.3 %). Those preferring the home stool test (HST) were less likely to get tested than those preferring a colonoscopy (16.6 vs 29.9 %, chi(2) = 9.9, p = .002). Preference for HST was more strongly associated with beliefs about colonoscopy than with knowledge about colonoscopy. In the context of an RCT emphasizing colonoscopy screening for CRC, patients expressing a preference for HST are at heightened risk of remaining unscreened. Colonoscopy should be recommended as the preferred CRC test, but HSTs should be accessible and encouraged for patients who are averse to colonoscopy.Clinical trials.gov: Identifier: NCT02392143. PMID- 26585610 TI - Letter to the editor. Commentary to the article: LaMoreaux B, Barbar-smiley F, Ardoin S, Madhoun H. Two cases of thrombosis in patients with antiphospholipid antibodies during treatment of immune thrombocytopenia with romiplostin, a thrombopoietin receptor agonist. Semin Arthritis Rheum 2015 Jul 29.pii: S0049 0172(15)00196-1. DOI:10.1016/j.semarthrit.2015.07-008. [Epub ahead of print]. PMID- 26585611 TI - Direct coating of mesoporous titania on CTAB-capped gold nanorods. AB - We demonstrate a CTAB-templated approach towards direct coating of mesoporous titania on gold nanorods in aqueous solutions. The formation of the mesoporous shell is found to be closely correlated with CTAB concentration and the amount of the titania precursor. This approach can be readily extended to form mesoporous titania shells on other CTAB-capped nanoparticles. PMID- 26585612 TI - The role of dyad-level factors in shaping sexual and drug-related HIV/STI risks among sex workers with intimate partners. AB - BACKGROUND: Despite high HIV burden among sex workers (SWs) globally, and relatively high prevalence of client condom use, research on potential HIV/STI risk pathways of intimate partnerships is limited. This study investigated partner/dyad-level factors associated with inconsistent condom use among SWs with intimate partners in Vancouver, Canada. METHODS: Baseline data (2010-2013) were drawn from a community-based prospective cohort of women SWs. Multivariable generalized estimating equations logistic regression examined dyad-level factors associated with inconsistent condom use (<100% in last six months) with up to three male intimate partners per SW. Adjusted odds ratios and 95% confidence intervals were reported (AOR[95%CI]). RESULTS: Overall, 369 SWs reported having at least one intimate partner, with 70.1% reporting inconsistent condom use. Median length of partnerships was 1.8 years, with longer duration linked to inconsistent condom use. In multivariable analysis, dyad factors significantly associated with increased odds of inconsistent condom use included: having a cohabiting (5.43[2.53-11.66]) or non-cohabiting intimate partner (2.15[1.11 4.19]) (versus casual partner), providing drugs (3.04[1.47-6.30]) or financial support to an intimate partner (2.46[1.05-5.74]), physical intimate partner violence (2.20[1.17-4.12]), and an intimate partner providing physical safety (2.08[1.11-3.91]); non-injection drug use was associated with a 68% reduced odds (0.32[0.17-0.60]). CONCLUSIONS: Our study highlights the complex role of dyad level factors in shaping sexual and drug-related HIV/STI risk pathways for SWs from intimate partners. Couple and gender-focused interventions efforts are needed to reduce HIV/STI risks to SWs through intimate partnerships. This research supports further calls for integrated violence and HIV prevention within broader sexual/reproductive health efforts for SWs. PMID- 26585613 TI - Independent and interactive effects of real-time risk factors on later temptations and lapses among smokers trying to quit. AB - PURPOSE: The current study sought to expand our understanding of relapse mechanisms by identifying the independent and interactive effects of real-time risk factors on temptations and the ability to resist temptations in smokers during a quit attempt. PROCEDURES: This study was a secondary analysis of data from 109 adult, treatment-seeking daily smokers. Ecological momentary assessment data was collected 4 times a day for 21 days following a quit attempt and was used to assess affect, urge, impulsiveness, recent cigarette exposure, and alcohol use as predictors of temptations to smoke and smoking up to 8h later. All smokers received nicotine replacement therapy and smoking cessation counseling. FINDINGS: In multinomial hierarchical linear models, there were significant main (agitation odds ratio (OR)=1.22, 95% CI=1.02-1.48; urge OR=1.60, 95% CI=1.35 1.92; nicotine dependence measured by WISDM OR=1.04, 95% CI=1.01-1.08) and interactive effects (agitation*urge OR=1.12, 95% CI=1.01-1.27; urge*cigarette exposure OR=1.38, 95% CI=1.10-1.76; positive affect*impulsiveness OR=2.44, 95% CI=1.02-5.86) on the odds of temptations occurring, relative to abstinence without temptation. In contrast, prior smoking (OR=3.46, 95% CI=2.58-4.63), higher distress (OR=1.30, 95% CI=1.06-1.60), and recent alcohol use (OR=3.71, 95% CI=1.40-9.89) predicted smoking versus resisting temptation, and momentary impulsiveness was related to smoking for individuals with higher baseline impulsiveness (OR=1.12, 95% CI=1.04-1.22). CONCLUSIONS: The risk factors and combinations of factors associated with temptations and smoking lapses differ, suggesting a need for separate models of temptation and lapse. PMID- 26585614 TI - Clinical Trials Versus Clinical Practice: When Evidence and Practice Diverge- Should Nondiabetic Patients With 3-Vessel Disease and Stable Ischemic Heart Disease Be Preferentially Treated With CABG? PMID- 26585615 TI - Comparative Effectiveness and Safety of New-Generation Versus Early-Generation Drug-Eluting Stents According to Complexity of Coronary Artery Disease: A Patient Level Pooled Analysis of 6,081 Patients. AB - OBJECTIVES: The purpose of this study was to compare the 2-year safety and effectiveness of new- versus early-generation drug-eluting stents (DES) according to the severity of coronary artery disease (CAD) as assessed by the SYNTAX (Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery) score. BACKGROUND: New-generation DES are considered the standard-of care in patients with CAD undergoing percutaneous coronary intervention. However, there are few data investigating the effects of new- over early-generation DES according to the anatomic complexity of CAD. METHODS: Patient-level data from 4 contemporary, all-comers trials were pooled. The primary device-oriented clinical endpoint was the composite of cardiac death, myocardial infarction, or ischemia driven target-lesion revascularization (TLR). The principal effectiveness and safety endpoints were TLR and definite stent thrombosis (ST), respectively. Adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated at 2 years for overall comparisons, as well as stratified for patients with lower (SYNTAX score <=11) and higher complexity (SYNTAX score >11). RESULTS: A total of 6,081 patients were included in the study. New-generation DES (n = 4,554) compared with early-generation DES (n = 1,527) reduced the primary endpoint (HR: 0.75 [95% CI: 0.63 to 0.89]; p = 0.001) without interaction (p = 0.219) between patients with lower (HR: 0.86 [95% CI: 0.64 to 1.16]; p = 0.322) versus higher CAD complexity (HR: 0.68 [95% CI: 0.54 to 0.85]; p = 0.001). In patients with SYNTAX score >11, new-generation DES significantly reduced TLR (HR: 0.36 [95% CI: 0.26 to 0.51]; p < 0.001) and definite ST (HR: 0.28 [95% CI: 0.15 to 0.55]; p < 0.001) to a greater extent than in the low-complexity group (TLR pint = 0.059; ST pint = 0.013). New-generation DES decreased the risk of cardiac mortality in patients with SYNTAX score >11 (HR: 0.45 [95% CI: 0.27 to 0.76]; p = 0.003) but not in patients with SYNTAX score <=11 (pint = 0.042). CONCLUSIONS: New generation DES improve clinical outcomes compared with early-generation DES, with a greater safety and effectiveness in patients with SYNTAX score >11. PMID- 26585616 TI - Moore's Law: Apples and Oranges. PMID- 26585617 TI - Diagnostic and Prognostic Implications of Coronary Flow Capacity: A Comprehensive Cross-Modality Physiological Concept in Ischemic Heart Disease. AB - OBJECTIVES: The purpose of this study is to evaluate whether coronary flow capacity (CFC) improves discrimination of patients at risk for major adverse cardiac events (MACE) compared with coronary flow reserve (CFR) alone, and to study the diagnostic and prognostic implications of CFC in relation to contemporary diagnostic tests for ischemic heart disease (IHD), including fractional flow reserve (FFR). BACKGROUND: Although IHD results from a combination of focal obstructive, diffuse, and microcirculatory involvement of the coronary circulation, its diagnosis remains focused on focal obstructive causes. CFC comprehensively documents flow impairment in IHD, regardless of its origin, by interpreting CFR in relation to maximal flow (hyperemic average peak flow velocity [hAPV]), and overcomes the limitations of using CFR alone. This is governed by the understanding that ischemia occurs in vascular beds with substantially reduced hAPV and CFR, whereas ischemia is unlikely when hAPV or CFR is high. METHODS: Intracoronary pressure and flow were measured in 299 vessels (228 patients), where revascularization was deferred in 154. Vessels were stratified as having normal, mildly reduced, moderately reduced, or severely reduced CFC using CFR thresholds derived from published data and corresponding hAPV percentiles. The occurrence of MACE after deferral of revascularization was recorded during 11.9 years of follow-up (quartile 1: 10.0 years, quartile 3: 13.4 years). RESULTS: Combining CFR and hAPV improved the prediction of MACE over CFR alone (p = 0.01). After stratification in CFC, MACE rates throughout follow-up were strongly associated with advancing impairment of CFC (p = 0.002). After multivariate adjustment, mildly and moderately reduced CFC were associated with a 2.1-fold (95% confidence interval: 1.1 to 4.0; p = 0.017), and 7.1-fold (95% confidence interval: 2.9 to 17.1; p < 0.001) increase in MACE hazard, respectively, compared with normal CFC. Severely reduced CFC was identified by FFR <=0.80 in 90% of cases, although >=40% of vessels with normal or mildly reduced CFC still had an FFR <=0.80. CONCLUSIONS: CFC provides a cross-modality platform for the diagnosis and risk-stratification of IHD and enriches the interpretation of contemporary diagnostic tests in IHD. PMID- 26585618 TI - Combining Baseline Distal-to-Aortic Pressure Ratio and Fractional Flow Reserve in the Assessment of Coronary Stenosis Severity. AB - OBJECTIVES: This study sought to understand the physiological basis of baseline distal-to-aortic pressure ratio (Pd/Pa) and fractional flow reserve (FFR) agreement and discordance, using coronary flow reserve (CFR), stenosis resistance, and microcirculatory resistance measurements, and form there, to investigate the potential value of combining Pd/Pa with FFR in the diagnostic rationale. BACKGROUND: Pd/Pa is always available before FFR assessment, and emerging data supports the notion that baseline indices can determine the ischemic potential of coronary stenosis in selected subsets. METHODS: A total of 467 stenosed vessels from 363 patients were investigated with pressure and flow sensors during baseline and hyperemia: 168 vessels (135 patients) with thermodilution-derived flow, and 299 vessels (228 patients) with Doppler-derived flow. RESULTS: Pd/Pa correlated more strongly with CFR than FFR (rho difference = 0.129; p for rho comparison <0.001). Although Pd/Pa and FFR were closely correlated (rho = 0.798; 95% confidence interval: 0.767 to 0.828), categorical discordance was observed in 19.3% of total vessels. Such discordance was associated with the patients' clinical profile and was characterized by contrastive changes in stenosis resistance, microcirculatory resistance, and the underlying CFR. Notably, all stenosis with Pd/Pa <=0.83 (n = 74, 15.8%) progressed to FFR <=0.80, and although no Pd/Pa cutoff was able to exclude the development of FFR <=0.80 in the high end of values, only 15 (10.1%) vessels with Pd/Pa >=0.96 (n = 149, 31.9%) developed FFR <=0.80, from which none had definite ischemia, as defined by CFR <=1.74. CONCLUSIONS: Combining baseline Pd/Pa with FFR seems to provide a more comprehensive physiological examination of stenosed coronary arteries and a closer pressure-based appraisal of the flow reserve of the downstream myocardial bed. PMID- 26585619 TI - How Can We Further Optimize the Invasive Evaluation of Coronary Physiology? PMID- 26585620 TI - Paclitaxel-Coated Balloon for Recalcitrant In-Drug-Eluting Stent Restenosis. PMID- 26585621 TI - Comparison of Stent Expansion Guided by Optical Coherence Tomography Versus Intravascular Ultrasound: The ILUMIEN II Study (Observational Study of Optical Coherence Tomography [OCT] in Patients Undergoing Fractional Flow Reserve [FFR] and Percutaneous Coronary Intervention). AB - OBJECTIVES: The present study sought to determine whether optical coherence tomography (OCT) guidance results in a degree of stent expansion comparable to that with intravascular ultrasound (IVUS) guidance. BACKGROUND: The most important predictor of adverse outcomes (thrombosis and restenosis) after stent implantation with IVUS guidance is the degree of stent expansion achieved. METHODS: We compared the relative degree of stent expansion (defined as the minimal stent area divided by the mean of the proximal and distal reference lumen areas) after OCT-guided stenting in patients in the ILUMIEN (Observational Study of Optical Coherence Tomography [OCT] in Patients Undergoing Fractional Flow Reserve [FFR] and Percutaneous Coronary Intervention) (N = 354) and IVUS-guided stenting in patients in the ADAPT-DES (Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents) study (N = 586). Stent expansion was examined in all 940 patients in a covariate-adjusted analysis as well as in 286 propensity matched pairs (total N = 572). RESULTS: In the matched-pair analysis, the degree of stent expansion was not significantly different between OCT and IVUS guidance (median [first, third quartiles] = 72.8% [63.3, 81.3] vs. 70.6% [62.3, 78.8], respectively, p = 0.29). Similarly, after adjustment for baseline differences in the entire population, the degree of stent expansion was also not different between the 2 imaging modalities (p = 0.84). Although a higher prevalence of post PCI stent malapposition, tissue protrusion, and edge dissections was detected by OCT, the rates of major malapposition, tissue protrusion, and dissections were similar after OCT- and IVUS-guided stenting. CONCLUSIONS: In the present post-hoc analysis of 2 prospective studies, OCT and IVUS guidance resulted in a comparable degree of stent expansion. Randomized trials are warranted to compare the outcomes of OCT- and IVUS-guided coronary stent implantation. PMID- 26585623 TI - Transcatheter Valve Sizing and the Rigid Aortic Root: An Ongoing Dilemma to Avoid the Worst. PMID- 26585622 TI - Relation Between Bioresorbable Scaffold Sizing Using QCA-Dmax and Clinical Outcomes at 1 Year in 1,232 Patients From 3 Study Cohorts (ABSORB Cohort B, ABSORB EXTEND, and ABSORB II). AB - OBJECTIVES: This study sought to investigate the clinical outcomes based on the assessment of quantitative coronary angiography-maximal lumen diameter (Dmax). BACKGROUND: Assessment of pre-procedural Dmax of proximal and distal sites has been used for Absorb scaffold size selection in the ABSORB studies. METHODS: A total of 1,248 patients received Absorb scaffolds in the ABSORB Cohort B (ABSORB Clinical Investigation, Cohort B) study (N = 101), ABSORB EXTEND (ABSORB EXTEND Clinical Investigation) study (N = 812), and ABSORB II (ABSORB II Randomized Controlled Trial) trial (N = 335). The incidence of major adverse cardiac events (MACE) (a composite of cardiac death, any myocardial infarction [MI], and ischemia-driven target lesion revascularization) was analyzed according to the Dmax subclassification of scaffold oversize group versus scaffold nonoversize group. RESULTS: Of 1,248 patients, pre-procedural Dmax was assessed in 1,232 patients (98.7%). In 649 (52.7%) patients, both proximal and distal Dmax values were smaller than the nominal size of the implanted scaffold (scaffold oversize group), whereas in 583 (47.3%) of patients, the proximal and/or distal Dmax were larger than the implanted scaffold (scaffold nonoversize group). The rates of MACE and MI at 1 year were significantly higher in the scaffold oversize group than in the scaffold nonoversize group (MACE 6.6% vs. 3.3%; log-rank p < 0.01, all MI: 4.6% vs. 2.4%; log-rank p = 0.04), mainly driven by a higher MI rate within 1 month post-procedure (3.5% vs. 1.9%; p = 0.08). The independent MACE determinants were both Dmax smaller than the scaffold nominal size (odds ratio [OR]: 2.13, 95% confidence interval [CI]: 1.22 to 3.70; p < 0.01) and the implantation of overlapping scaffolds (OR: 2.10, 95% CI: 1.17 to 3.80; p = 0.01). CONCLUSIONS: Implantation of an oversized Absorb scaffold in a relatively small vessel appears to be associated with a higher 1-year MACE rate driven by more frequent early MI. (ABSORB Clinical Investigation, Cohort B [ABSORB Cohort B], NCT00856856; ABSORB EXTEND Clinical Investigation [ABSORB EXTEND], NCT01023789; ABSORB II Randomized Controlled Trial [ABSORB II], NCT01425281). PMID- 26585624 TI - New Ways of Thinking About Senescent Bioprosthetic Heart Valve Therapy. PMID- 26585625 TI - Safety and Efficacy of Stent Retrievers for the Management of Acute Ischemic Stroke. PMID- 26585626 TI - Embolization of Left Atrial Appendage Thrombus During Transcatheter Aortic Valve Replacement: A Potential Mechanism of Periprocedural Stroke. PMID- 26585627 TI - Trends in the Use of Mechanical Circulatory Support Devices in Patients Presenting With ST-Segment Elevation Myocardial Infarction. PMID- 26585628 TI - Publications From the Interventional Council. PMID- 26585629 TI - First-in-Man Implantation of a Tricuspid Annular Remodeling Device for Functional Tricuspid Regurgitation. PMID- 26585630 TI - Percutaneous Correction of Right Superior Vena Cava to Left Atrium. PMID- 26585631 TI - Magneto-structural versatility of copper(II)-3-phenylpropionate coordination polymers with N-donor coligands. AB - A novel series of copper(II) coordination polymers [Cu2(O2CC8H9)4(pyz)]n (1), [Cu2(O2CC8H9)4(dps)]n (2), {[Cu(O2CC8H9)2(dps)(H2O)].H2O}n (3), {[NaCu(O2CC8H9)2(bpm)(NO3)].H2O}n (4), and [Cu4(O2CC8H9)6(OH)2(bpp)2]n (5) [O2CC8H9- = 3-phenylpropionate anion, pyz = pyrazine, dps = di(4-pyridyl)sulfide, bpm = 2,2'-bipyrimidine, and bpp = 1,3-bis(4-pyridyl)propane] have been synthesized and magneto-structurally investigated. Compounds 1 and 2 belong to a large group of copper(II) carboxylates where bis-monodentate pyz (1) and dps (2) ligands connect the paddle-wheel [CuII2(MU-O2CC8H9)4] units leading to alternating copper(II) chains. The structure of 3 consists of uniform chains of trans-[CuII(O2CC8H9)2] units linked by the bis-monodentate dps ligand. Compound 4 consists of heterobimetallic chains where [NaI2CuII2(MU-O2CC8H9)4(NO3)2] units are doubly bridged by bis-bidentate bpm ligands. Compound 5 is also a chain compound whose structure is made up by tetranuclear [CuII4(MU3-OH)2(MU O2CC8H9)4(O2CC8H9)2] units which are doubly bridged by bis-monodentate bpp ligands. The magnetic properties were investigated in the temperature range 1.8 300 K. Strong antiferromagnetic interactions across the quadruple syn-syn carboxylate are observed in 1 and 2 [J = -378 (1) and -348 cm-1 (2)] whereas a weak ferromagnetic coupling through the double out-of-plane oxo(carboxylate) bridge occurs in 4 [J = +2.66 cm-1], the spin Hamiltonian being defined as H = JS1.S2 with S1 = S2 = SCu = 1/2. A quasi Curie law is observed for 3 (theta = 0.36 cm-1), the bis-monodentate dps ligand being a very poor mediator of magnetic interactions. The analysis of the magnetic properties of 5 is quite complex because of the presence of two crystallographically independent tetracopper(II) units with single-MU-hydroxo, di-MU-hydroxo, MU3-hydroxo and single-MU-hydroxo plus double syn,syn carboxylate bridges in each one. The nature and values of the magnetic couplings for 5 obtained by fitting (intermediate, strong and weak antiferromagnetic interactions for the three former exchange pathways respectively, and intermediate ferromagnetic interactions for the latter one) were substantiated by DFT type calculations. PMID- 26585633 TI - Healthy eating habits protect against temptations. AB - Can healthy food-choice habits protect people against temptations of consuming large portion sizes and unhealthy foods? In two studies, we show that the answer is yes, good habits serve this protective role, at least in contexts in which people are not deliberating and thus fall back on habitual responses. In the first study, participants trained with unhealthy habits to approach eating chocolate, but not those trained with healthy habits, succumbed to temptation and ate more chocolates when their self-control resources were depleted. Study 2 extended and clarified these findings by demonstrating the role of environmental cues in eliciting healthy habits when self-control resources are depleted. Participants who had been trained to choose carrots habitually to a pictorial stimulus (i.e., habit cue) subsequently resisted choosing M&Ms as long as the cue was present. This effect of habit cues on healthy food choices suggests the usefulness of manipulating such cues as a means of meeting self-regulatory goals such as portion control. PMID- 26585632 TI - Sibling feeding behavior: Mothers as role models during mealtimes. AB - Siblings may act as caregivers and role models during mealtimes, and develop caregiving skills by observing and imitating the behavior of their mothers. The objective of this study was to examine the association between maternal feeding behaviors and encouragements to eat delivered from the sibling to the index child during mealtimes. Index children aged 4-8 years (n = 69) were videotaped while eating a routine evening meal at home with one sibling present. Encouragements to eat delivered from the sibling to the index child were coded from the videotapes. Mothers completed the Child Feeding Questionnaire and the Caregiver's Feeding Styles Questionnaire. Poisson regression was used to examine the association of maternal Pressure to Eat, Restriction, Monitoring, Verbal Direction, and Coercion with number of encouragements to eat delivered from the sibling to the index child. Models were adjusted for index child's age, sex, and race/ethnicity, and maternal education. Results showed that maternal Pressure to Eat (Rate Ratio (RR): 1.39, 95% confidence interval (CI): 1.19, 1.69), Restriction (RR: 1.31, 95% CI: 1.07, 1.60), Verbal Direction (RR: 2.04, 95% CI: 1.68, 2.47), and Coercion (RR: 1.58, 95% CI: 1.29, 1.92) were each positively associated with the number of encouragements to eat delivered from the sibling to the index child. Maternal Monitoring was not associated with the number of encouragements to eat delivered from the sibling to the index child (RR: 0.92, 97% CI: 0.78, 1.09). Findings suggest that maternal behavior during mealtimes may affect the index child indirectly by shaping the behavior of siblings. Since controlling feeding behaviors have been associated with greater child obesity risk, future studies may evaluate the compounded effect of experiencing controlling feeding behaviors from both mothers and siblings. PMID- 26585634 TI - Combining food type(s) and food quantity choice in a new food choice paradigm based on vice-virtue bundles. AB - Given the prevalence and rising rates of obesity in many countries, including the United States, much food decision-making research ultimately aims at understanding how consumers can make healthier choices. The two predominant choice paradigms used in food decision-making research ask consumers to choose (a) between a "vice" (or unhealthy food) and a "virtue" (or healthy food) or (b) among varying portion sizes of "vice." We propose a new food choice paradigm that encourages consumers to jointly consider both food type(s) choice and food portion size at each decision point. The purpose of this paradigm is two-fold. First, it aims to allow examination of more comprehensive eating behavior (e.g., to examine the overall composition of a plate of food rather than choice of a single food). Second, it aims to shift consumers towards including large proportions of virtues and smaller proportions of vice in their overall consumption portfolios. For this paradigm, we draw upon a recently introduced food product innovation called "vice-virtue bundles" (Liu et al., 2015) that illustrates the basis of this new food choice paradigm, in which food type(s) and portion decisions are made simultaneously. Accordingly, we first discuss relevant findings on vice-virtue bundles as well as the differences between simultaneous and sequential choice of multiple products. Second, we examine the benefits for managing and controlling one's consumption that are provided by vice-virtue bundles and this joint food choice paradigm more generally. Third and finally, we point out opportunities for future research by discussing (a) multiple factors that influence food choices, (b) decision processes affected by food choice paradigms, and (c) issues of generalizability related to the presence of vice virtue bundles. PMID- 26585635 TI - Meals and snacks: Children's characterizations of food and eating cues. AB - This study examined preschoolers' and their parents' categorizations of eating episodes based on cues used for defining these occasions (i.e., time, portion size, preparation, content, and emotion) as a meal or snack. Thirty-four children aged 4 to 6 saw pictorial representations of each cue, along with a short verbal description, and were asked to place the picture in one of three boxes: "meal", "snack", or "either meal or snack". One parent per child (85% mothers, Mean age = 35.1 years) separately categorized the same items in an online survey. Results illustrated which cues play a role in how parents and children categorize eating occasions as meals or snacks. Parents used 24 of the 32 cue-related items to distinguish between eating occasions as a meal or a snack, while children used only four. Parents and preschoolers were consistent in using cartoon character packaging to indicate a snack, and also used several of the same content cues. The current study highlights the various cues used to categorize an eating occasion, and the unhealthy character of snacks, as participants associated some unhealthy foods and very few healthy foods with snacks. Future research should focus on the role of parents, the home environment, and advertising media in shaping children's characterizations of eating occasions towards development of healthy eating habits and away from problematic eating behaviors that may persist later in life. PMID- 26585636 TI - Highly Stretchable Electrodes on Wrinkled Polydimethylsiloxane Substrates. AB - This paper demonstrates a fabrication technology of Ag wrinkled electrodes with application in highly stretchable wireless sensors. Ag wrinkled thin films that were formed by vacuum deposition on top of pre-strained and relaxed polydimethylsiloxane (PDMS) substrates which have been treated using an O2 plasma and a surface chemical functionalization process can reach a strain limit up to 200%, while surface adhesion area can reach 95%. The electrical characteristics of components such as resistors, inductors and capacitors made from such Ag conductors have remained stable under stretching exhibiting low temperature and humidity coefficients. This technology was then demonstrated for wireless wearable electronics using compatible processing with established micro/nano fabrication technology. PMID- 26585637 TI - High-frequency and high-quality silicon carbide optomechanical microresonators. AB - Silicon carbide (SiC) exhibits excellent material properties attractive for broad applications. We demonstrate the first SiC optomechanical microresonators that integrate high mechanical frequency, high mechanical quality, and high optical quality into a single device. The radial-breathing mechanical mode has a mechanical frequency up to 1.69 GHz with a mechanical Q around 5500 in atmosphere, which corresponds to a fm . Qm product as high as 9.47 * 10(12) Hz. The strong optomechanical coupling allows us to efficiently excite and probe the coherent mechanical oscillation by optical waves. The demonstrated devices, in combination with the superior thermal property, chemical inertness, and defect characteristics of SiC, show great potential for applications in metrology, sensing, and quantum photonics, particularly in harsh environments that are challenging for other device platforms. PMID- 26585639 TI - Increased risks of tic disorders in children with epilepsy: A nation-wide population-based case-control study in Taiwan. AB - Both epilepsy and tic disorders may share common mechanisms with the involvement of abnormal cortical-basal ganglion circuit connection and dopaminergic dysfunction. However, the association between epilepsy and tic disorders has never been studied. This study investigated the risks of developing tic disorders among children with epilepsy using databases of a universal health insurance system in Taiwan. The data analyzed in this study were retrieved from the National Health Insurance Research Database in Taiwan. The study cohort included children with epilepsy between 2001 and 2007 (n=2629) and a three-fold age- and gender-matched controls (n=7887). All subjects were followed up for 3 years from the date of cohort entry to identify their admissions due to tic disorders (ICD-9 CM codes 307.2, 307.20-307.23). Cox hazard regression analysis was performed to estimate the effect of epilepsy on the occurrence of tics. The epilepsy cohort had a higher prevalence of tics (1.7% vs. 0.2%), and a 8.70-fold increased risk of developing a tic disorder compared with the controls (adjusted hazard ratio (AHR) 8.70, 95% confidence interval (CI) 4.26-16.37, p<0.001). Male patients were observed to have a higher risk of developing a tic disorder (AHR 1.90, 95% CI=1.04-3.46, p<0.001) compared to female individuals. Patients with multiple antiepileptic drugs treatment also exhibited higher crude OR for developing tic disorders. This nationwide population-based cohort study, for the first time, demonstrated that there is a significantly increased risk for tic disorders among children with epilepsy. We also found males, attention deficit disorder and the use of multiple AEDs to be independent risk factors of tic disorders. Closely evaluating possible tic disorders would be crucial for improving the outcome and life quality in children with epilepsy. PMID- 26585638 TI - Physician versus non-physician delivery of alcohol screening, brief intervention and referral to treatment in adult primary care: the ADVISe cluster randomized controlled implementation trial. AB - BACKGROUND: Unhealthy alcohol use is a major contributor to the global burden of disease and injury. The US Preventive Services Task Force has recommended alcohol screening and intervention in general medical settings since 2004. Yet less than one in six US adults report health care professionals discussing alcohol with them. Little is known about methods for increasing implementation; different staffing models may be related to implementation effectiveness. This implementation trial compared delivery of alcohol screening, brief intervention and referral to specialty treatment (SBIRT) by physicians versus non-physician providers receiving training, technical assistance, and feedback reports. METHODS: The study was a cluster randomized implementation trial (ADVISe [Alcohol Drinking as a Vital Sign]). Within a private, integrated health care system, 54 adult primary care clinics were stratified by medical center and randomly assigned in blocked groups of three to SBIRT by physicians (PCP arm) versus non physician providers and medical assistants (NPP and MA arm), versus usual care (Control arm). NIH-recommended screening questions were added to the electronic health record (EHR) to facilitate SBIRT. We examined screening and brief intervention and referral rates by arm. We also examined patient-, physician-, and system-level factors affecting screening rates and, among those who screened positive, rates of brief intervention and referral to treatment. RESULTS: Screening rates were highest in the NPP and MA arm (51 %); followed by the PCP arm (9 %) and the Control arm (3.5 %). Screening increased over the 12 months after training in the NPP and MA arm but remained stable in the PCP arm. The PCP arm had higher brief intervention and referral rates (44 %) among patients screening positive than either the NPP and MA arm (3.4 %) or the Control arm (2.7 %). Higher ratio of MAs to physicians was related to higher screening rates in the NPP and MA arm and longer appointment times to screening and intervention rates in the PCP arm. CONCLUSION: Findings suggest that time frames longer than 12 months may be required for full SBIRT implementation. Screening by MAs with intervention and referral by physicians as needed can be a feasible model for increasing the implementation of this critical and under-utilized preventive health service within currently predominant primary care models. TRIAL REGISTRATION: Clinical Trials NCT01135654. PMID- 26585640 TI - Erratum to: A role for human brain pericytes in neuroinflammation. PMID- 26585641 TI - Comparison of (14)C liquid scintillation counting at NIST and NRC Canada. AB - An informal bilateral comparison of (14)C liquid scintillation (LS) counting at the National Research Council of Canada (NRC) and the National Institute of Standards and Technology (NIST) has been completed. Two solutions, one containing (14)C-labeled sodium benzoate and one containing (14)C-labeled n-hexadecane, were measured at both laboratories. Despite observed LS cocktail instabilities, the two laboratories achieved accord in their standardizations of both solutions. At the conclusion of the comparison, the beta spectrum used for efficiency calculations was identified as inadequate and the data were reanalyzed with different inputs, improving accord. PMID- 26585642 TI - Micellar phase boundaries under the influence of ethyl alcohol. AB - The Compton spectrum quenching technique is used to monitor the effect of ethyl alcohol (EtOH) additions on phase boundaries in two systems. In toluenic solutions of the nonionic surfactant, Triton X-100, EtOH shifts the boundary separating the first clear phase from the first turbid phase to higher water:surfactant ratios. In a commonly used scintillant, Ultima Gold AB, the critical micelle concentration is not shifted. The molecular interactions behind the observations and implications for liquid scintillation counting are discussed. PMID- 26585643 TI - Comparisons organized by Ionizing Radiation Metrology Laboratory of FTMC, Lithuania. AB - The newly established Ionizing Radiation Metrology Laboratory of the National Metrology Institute (FTMC) in Lithuania organized four comparisons in the field of low-level radioactivity measurements in water. For gamma-ray emitters, the activity concentration in the samples was in the range 1-25Bq/kg, while for tritium it was around 2Bq/g. The assigned values of all comparisons were traceable to the primary standards of the Czech Metrology Institute (CMI). PMID- 26585644 TI - Decay Data Evaluation Project (DDEP): Updated decay data evaluations for (24)Na, (46)Sc, (51)Cr, (54)Mn, (57)Co, (59)Fe, (88)Y, (198)Au. AB - Updated DDEP evaluations have been presented for the decay characteristics of the radionuclides (24)Na, (46)Sc, (51)Cr, (54)Mn, (57)Co, (59)Fe, (88)Y and (198)Au. Previous DDEP evaluations for these radionuclides were published in the BIPM-5 monographie in 2004. The experimental data published during the intervening period of 2004-2014 were taken into account in the current evaluations as well as other information: new compilations, analyses, and corrections. The updated evaluations are compared to previous results. PMID- 26585645 TI - Acute Toxicity of Water-Accommodated Fraction and Chemically Enhanced WAF of Bunker C Oil and Dispersant to a Microalga Tetraselmis tetrathele. AB - This study assessed the toxicity of water-accommodated fraction (WAF) and chemically enhanced WAF (CEWAF) of bunker C oil and dispersant (DISP) to a microalga, Tetraselmis tetrathele. The 72-h median effective concentration (72-h EC50) of CEWAF and DISP were determined at 3.30% and 2.40%, respectively. The no observed effect concentration (NOEC) of CEWAF to T. tetrathele was at 2.0% and lowest observed effect concentration (LOEC) was at 3.0% while NOEC and LOEC of DISP to T. tetrathele were determined at 1.0% and 2.0%, respectively. The addition of dispersant to oil increased the amount of total PAH present in the CEWAF test solutions. DISP alone was highly toxic, and the toxicity of CEWAF was primarily caused by the presence of dispersant. PMID- 26585646 TI - The Effect of Water Hardness on Mortality of Zebrafish (Danio rerio) During Exposure to Oxytetracycline. AB - Marking of fish otoliths with oxytetracycline and tetracycline is a widely used method to evaluate the effectiveness of stocking operations. Available protocols for the labeling of fish specify a number of factors influencing mark quality and potential risk for fish during marking. This study investigates the influence of water hardness on mortality of freshwater fish during marking with OTC. In order to pursue this question complexation of OTC with Mg(2+) and Ca(2+) cations was measured spectrophotometrically. Furthermore, zebrafish (Danio rerio) were immersed in OTC solutions (1200 mg/L; 48 h immersion) combined with varying levels of water hardness (5.5, 15.5, 25.5, 32.5 degrees dH). The amount of OTC-Mg Ca-complexes was positively correlated to water hardness. Moreover, it could be demonstrated that mortality of zebrafish during marking varied as a factor of water hardness. Highest mortalities occurred at the lowest (5.5 degrees dH) and the highest (32.5 degrees dH) tested levels during marking with OTC. PMID- 26585647 TI - Spatial and Temporal Variations of Taste and Odor Compounds in Surface Water, Overlying Water and Sediment of the Western Lake Chaohu, China. AB - The seasonal variations of taste and odor (T&O) compounds in western Lake Chaohu were evaluated from July to December 2013. High values were detected in particulate fractions, with peak values 28.25 ng/L for geosmin (GEO), 45.18 ng/L for dimethyltrisulfide (DMTS), 714.77 ng/L for beta-cyclocitral, 11.23 ng/L for beta-ionone in surface water, and 14.21 ng/L for GEO, 103.68 ng/L for DMTS, 11.97 ng/L for beta-ionone in overlying water, all exceeding their odor thresholds. The maximum off-flavor concentrations in sediment ranged from 2010.76 ng/kg for GEO to 1.7 ng/kg for beta-ionone. Positive correlations could be found not only between Anabaena and particulate GEO (r = 0.813, p < 0.01), but also between Microcystis and total beta-cyclocitral (r = 0.652, p < 0.01) or beta-ionone (r = 0.560, p < 0.01) in surface water. TP, TN, PO4-P, Chl-a and organic matter contributed significantly to the variations of T&O compounds in water or sediment. The cause of the variations of T&O compounds was the accumulation and degradation of cyanobacteria in water rather than nutrient-rich sediment. PMID- 26585648 TI - Intermediate Outcomes of Femoropopliteal Stenting in Women: 3-Year Results of the DURABILITY II Trial. AB - BACKGROUND: This study investigated the effects of gender on the 3-year outcomes of the StuDy for EvalUating EndovasculaR TreAtments of Lesions in the Superficial Femoral Artery and Proximal Popliteal By usIng the Protege EverfLex NitInol STent System II (DURABILITY II) trial. METHODS: A total of 287 patients enrolled in the DURABILITY II trial (prospective and nonrandomized trial) were stratified by gender and evaluated for primary, primary assisted, and secondary patency at 3 years. Clinical scores including changes in ankle-brachial index (ABI) and walking impairment questionnaire (WIQ) scores were evaluated. RESULTS: Overall 190 male and 97 female patients were included for analysis. The 3-year primary, assisted primary, and secondary patency rates for women versus men were 62.5% vs. 58.8%, 68.5% vs. 64.9%, and 72.1% vs. 67.2%, respectively (P < 0.05). Although ABIs at presentation were similar between women versus men (0.64 vs. 0.65, P < 0.05), women had lower ABI scores at 3 years compared with men (0.85 vs. 0.92, P = 0.03). Women versus men had inferior walking distance scores at presentation (13.6 vs. 25.7, P < 0.001), scores were equalized by 2 years (51.6 vs. 60.8, P < 0.05); however, 3-year follow-up demonstrated less durable results for women versus men (37.3 vs. 58.8, P < 0.05). In addition, women had worse WIQ scores for pain, walking speed, and stair climbing. However, the relative change in scores between men and women were comparable, with both groups seeing similar improvements from baseline for these parameters. CONCLUSIONS: Women continue to see clinical improvement after intervention, achieving comparable ABIs and walking distance to men at 2 years. These benefits are diminished at 3-year follow-up with women achieving lower absolute ABI and WIQ parameters compared with men, but improved overall compared with scores at presentation. PMID- 26585650 TI - Problems with preference and place of death for children too. PMID- 26585649 TI - Transarticular fixation by hook plate versus coracoclavicular stabilization by single multistrand titanium cable for acute Rockwood grade-V acromioclavicular joint dislocation: a case-control study. AB - BACKGROUND: Hook plate (HP) is popularly used for acute and severely displaced acromioclavicular (AC) dislocations. However, subacromial impingement and acromion osteolysis induced by transarticular fixation are notorious. The current case-control study was to compare transarticular fixation by HP to coracoclavicular (CC) stabilization by single multistrand titanium cable (MSTC). METHODS: Between January 2006 and August 2009, 24 patients with acute AC dislocations were surgically treated by open reduction and transarticular fixation with HP. These patients were matched to a series of 24 patients, who were managed by CC stabilization with MSTC in the same period. All AC dislocations were graded as Rockwood type V. Implant was removed 8-12 months after the primary operation in all patients, and 12 months at least were needed to assess the maintenance of AC joint. Functional results were evaluated before implant removal as well as in the last follow-up based on Constant-Murley criteria. RESULTS: There were no differences of demographic data including age, dominant gender and side, injury-to-surgery interval, operation time and follow up period. In terms of functionality, Constant score was 95.8 +/- 4.1 in MSTC group, while 76.7 +/- 8.0 in HP group before implant removal (P < 0.001). In detail, MSTC was superior to HP in pain, ROM and activities. Constant score was significantly improved to 86.1 +/- 5.7 after hardware removal for patients in HP (P < 0.001). Degenerative change of acromioclavicular joint presented in 16 patients (66.7%) in patients treated by HP, while it was found in only 3 patients (12.5%) treated by MSTC (P < 0.001). CONCLUSIONS: MSTC is superior to HP for the treatment of Rockwood type-V acromioclavicular dislocation both before and after removal of the implant. Hardware removal is of great benefits for functional improvement in patients treated by HP. PMID- 26585652 TI - Conference Report: Nanotechnology Congress & Expo 2015, Frankfurt, Germany August 11-13, 2015. PMID- 26585651 TI - [Squamous cell carcinoma secondary to Buruli ulcer in West Africa]. AB - BACKGROUND: Buruli ulcer is an infection caused by Mycobacterium ulcerans occurring in tropical areas. In West Africa, it is an emerging threat mainly affecting children aged under 15years. This chronic disease is complicated by dystrophic scars in which squamous cell carcinoma can occur in the long term. PATIENTS AND METHODS: This is a retrospective study of squamous cell carcinomas in Buruli ulcer scars seen at the Treichville University Hospital (Abidjan, Ivory Coast) over a five-year period. RESULTS: During the study period, 8cases were observed and concerned young adults presenting Buruli ulcer in their childhood. Tumours were restricted to the limbs, with loco-regional invasion. Treatment was primarily surgical. Four of the patients died. DISCUSSION: The risk of recurrence of cancer in these scars remains poorly evaluated, highlighting the importance of long-term monitoring strategies for human patients in order to ensure rapid identification of any changes in Buruli ulcer scars. PMID- 26585653 TI - Editorial (Thematic Issue:Neuroscience of Exercise: Focus on Cognitive and Brain Functioning). PMID- 26585654 TI - Neuroscience of Exercise: Association Among Neurobiological Mechanisms and Mental Health. AB - Neuroscience is an emergent research field that comprises many multidisciplinary investigations, searches for explanations about the relationship between the body and the brain. Here, we will give a little summary of this field showing the main current findings. We discuss the lack of consistent data about the relationship among exercise for neurodegenerative diseases and psychiatric disorders, sports performance and rehabilitation, and therefore, the difficult to describe cause effect associations or to describe in detail the neurobiological mechanisms underlying these associations. PMID- 26585655 TI - [Hypertension and dementia: A complex relationship]. PMID- 26585656 TI - Endocrine disruptors in 2015: Epigenetic transgenerational inheritance. PMID- 26585657 TI - Nutrition: Breaking the fructose habit. PMID- 26585658 TI - Diabetes: Extreme increases in sleep duration raise T2DM risk. PMID- 26585659 TI - Metabolism: Fasting induces FGF21 in humans. PMID- 26585662 TI - Diabetes: Time to rethink intensive treatment for all? PMID- 26585663 TI - Therapy: Unexplained infertility - ongoing transatlantic debate. PMID- 26585665 TI - Reproductive endocrinology: Don't be so quick to stop hormone-replacement therapy. PMID- 26585666 TI - [Self-amputation of the penis treated immediately: Case report and review of the literature]. AB - Self-amputation of the penis treated immediately: case report and review of the literature. Self-amputation of the penis is rare in urological practice. It occurs more often in a context psychotic disease. It can also be secondary to alcohol or drugs abuse. Treatment and care vary according on the severity of the injury, the delay of consultation and the patient's mental state. The authors report a case of self-amputation of the penis in an alcoholic context. The authors analyze the etiological and urological aspects of this trauma. PMID- 26585667 TI - Delayed clamping of the umbilical cord after delivery and implications for public cord blood banking. AB - BACKGROUND: Public banking of umbilical cord blood units (CBUs) containing higher numbers of cells ensures timely engraftment after transplantation for increasing numbers of patients. Delayed clamping of the umbilical cord after birth may benefit some infants by preventing iron deficiency. Implications of delayed cord clamping for public cord blood banking remains unclear. STUDY DESIGN AND METHODS: CBUs collected by Canadian Blood Services at one collection site between November 1, 2014, and March 17, 2015, were analyzed. The delay in cord clamping after birth was timed and classified as "no delay," 20 to 60 seconds, more than 60 seconds, or more than 120 seconds. RESULTS: Of 367 collections, 100 reported no delay in clamping while clamping was delayed by 20 to 60 seconds (n = 69), more than 60 seconds (n = 98), or more than 120 seconds (n = 100) in the remaining cases. The mean volume and total nucleated cells (TNCs) in units with no delay in clamping were significantly greater than mean volumes for all categories of delayed clamping (Tukey's test, p < 0.05 for each comparison). The proportion of units with more than 1.5 * 10(9) TNCs was significantly reduced when clamping was delayed (p = 5.5 * 10(-8) ). The difference was most marked for cords that were clamped more than 120 seconds after delivery (6.2% compared with 39%). CONCLUSIONS: Delayed cord clamping greatly diminishes the volume and TNC count of units collected for a public cord blood bank. Creating an inventory of CBUs with high TNC content may take more time than expected. PMID- 26585668 TI - Human Amniotic Membrane-Derived Products in Sports Medicine: Basic Science, Early Results, and Potential Clinical Applications. AB - BACKGROUND: Amniotic membrane (AM)-derived products have been successfully used in ophthalmology, plastic surgery, and wound care, but little is known about their potential applications in orthopaedic sports medicine. PURPOSE: To provide an updated review of the basic science and preclinical and clinical data supporting the use of AM-derived products and to review their current applications in sports medicine. STUDY DESIGN: Systematic review. METHODS: A systematic search of the literature was conducted using the Medline, EMBASE, and Cochrane databases. The search term amniotic membrane was used alone and in conjunction with stem cell, orthopaedic, tissue engineering, scaffold, and sports medicine. RESULTS: The search identified 6870 articles, 80 of which, after screening of the titles and abstracts, were considered relevant to this study. Fifty-five articles described the anatomy, basic science, and nonorthopaedic applications of AM-derived products. Twenty-five articles described preclinical and clinical trials of AM-derived products for orthopaedic sports medicine. Because the level of evidence obtained from this search was not adequate for systematic review or meta-analysis, a current concepts review on the anatomy, physiology, and clinical uses of AM-derived products is presented. CONCLUSION: Amniotic membranes have many promising applications in sports medicine. They are a source of pluripotent cells, highly organized collagen, antifibrotic and anti inflammatory cytokines, immunomodulators, and matrix proteins. These properties may make it beneficial when applied as tissue engineering scaffolds, improving tissue organization in healing, and treatment of the arthritic joint. The current body of evidence in sports medicine is heavily biased toward in vitro and animal studies, with little to no human clinical data. Nonetheless, 14 companies or distributors offer commercial AM products. The preparation and formulation of these products alter their biological and mechanical properties, and a thorough understanding of these differences will help guide the use of AM-derived products in sports medicine research. PMID- 26585669 TI - Histidine oxidation photosensitized by pterin: pH dependent mechanism. AB - Aromatic pterins accumulate in the skin of patients suffering from vitiligo, a chronic depigmentation disorder, due to the oxidation of tetrahydrobiopterin, the biologically active form of pterins. In this work, we have investigated the ability of pterin, the parent compound of aromatic pterins, to photosensitize the oxidation of histidine in aqueous solutions under UV-A irradiation. Histidine is an alpha-amino acid with an imidazole functional group, and is frequently present at the active sites of enzymes. The results highlight the role of the pH in controlling the competition between energy and electron transfer mechanisms. It has been previously demonstrated that pterins participate as sensitizers in photosensitized oxidations, both by type I (electron-transfer) and type II mechanisms (singlet oxygen ((1)O2)). By combining different analytical techniques, we could establish that a type I photooxidation was the prevailing mechanism at acidic pH, although a type II mechanism is also present, but it is more important in alkaline solutions. PMID- 26585670 TI - Recurrent endometrial hyperplasia as a presentation of estrogen-secreting thecoma - case report and minireview of the literature. AB - Thecoma is a rare ovarian tumor, presenting usually in postmenopausal women as unilateral, benign, solid lesion. About 15% of affected patients develop endometrial hyperplasia (EH) and 20% are diagnosed with endometrial cancer. In this case report, we present 60-year-old women admitted because of recurrent spotting of 5 years duration, which started 1 year after menopause. In history, the patient underwent three times curettage procedures and once (1 year before admission) had estradiol levels typical for reproductive-age women. At admission, we found elevated serum levels of estradiol (222.5 pg/ml) and a small mass in the right ovary. The markers of germ cell tumors were negative. After the initial diagnosis, the patient was qualified for total abdominal hysterectomy with bilateral salpingo-oophorectomy. The histopathological examination and immunohistochemical staining confirmed the thecoma diagnosis. In follow-up examination after 8 weeks, we found decreased serum estradiol levels and relief of the symptoms. In conclusion, we want to underline that in cases of EH, especially in patients with a history of recurrences, the special attention should be paid for differential diagnosis. In such cases, the estrogen-secreting tumors should be excluded. PMID- 26585671 TI - Enhancing Nutraceutical Bioavailability from Raw and Cooked Vegetables Using Excipient Emulsions: Influence of Lipid Type on Carotenoid Bioaccessibility from Carrots. AB - The influence of the nature of the lipid phase in excipient emulsions on the bioaccessibility and transformation of carotenoid from carrots was investigated using a gastrointestinal tract (GIT) model. Excipient emulsions were fabricated using whey protein as an emulsifier and medium-chain triglycerides (MCT), fish oil, or corn oil as the oil phase. Changes in particle size, charge, and microstructure were measured as the carrot-emulsion mixtures were passed through simulated mouth, stomach, and small intestine regions. Carotenoid bioaccessibility depended on the type of lipids used to form the excipient emulsions (corn oil > fish oil ? MCT), which was attributed to differences in the solubilization capacity of mixed micelles formed from different lipid digestion products. The transformation of carotenoids was greater for fish oil and corn oil than for MCT, which may have been due to greater oxidation or isomerization. The bioaccessibility of the carotenoids was higher from boiled than raw carrots, which was attributed to greater disruption of the plant tissue facilitating carotenoid release. In conclusion, excipient emulsions are highly effective at increasing carotenoid bioaccessibility from carrots, but lipid type must be optimized to ensure high efficacy. PMID- 26585672 TI - Neutrophil Activation Promotes Fibrinogen Oxidation and Thrombus Formation in Behcet Disease. AB - BACKGROUND: Behcet disease (BD) is a systemic vasculitis with a broad range of organ involvement, characterized by a multisystemic, immune-inflammatory disorder involving vessels of all sizes and often complicated by thrombosis. Systemic redox imbalance and circulating neutrophil hyperactivation have been observed in BD patients and are thought to be responsible for impaired coagulation. We here focused on the pathogenetic mechanisms potentially linking immune cell activation and thrombosis, and specifically examined whether neutrophil activation can affect fibrinogen modifications and consequently elicit thrombosis. METHODS AND RESULTS: Blood samples were collected from 98 consecutive BD patients attending our dedicated Center and from 70 age- and sex-matched healthy controls; in all patients fibrinogen function and structure, fibrin susceptibility to plasmin lysis, plasma redox status, leukocyte oxidative stress markers, and possible reactive oxygen species sources were examined. Thrombin-catalyzed fibrin formation and fibrin susceptibility to plasmin-induced lysis were significantly impaired in BD patients (P<0.001). These findings were associated with increased plasma oxidative stress markers (P<0.001) and with a marked carbonylation of fibrinogen (P<0.001), whose secondary structure appeared deeply modified. Neutrophils displayed an enhanced NADPH oxidase activity and increased reactive oxygen species production (P<0.001), which significantly correlated with fibrinogen carbonylation level (r(2)=0.33, P<0.0001), residual beta-band intensity (r(2)=0.07, P<0.01), and fibrinogen clotting ability (r(2)=0.073, P<0.01) CONCLUSIONS: In BD patients, altered fibrinogen structure and impaired fibrinogen function are associated with neutrophil activation and enhanced reactive oxygen species production whose primary source is represented by neutrophil NADPH oxidase. PMID- 26585674 TI - Experiences and desired nursing assistance of women on out-patient breast cancer chemotherapy in Southeastern Nigeria. AB - OBJECTIVE: This study explored the experiences and nursing support needs of women undergoing out-patient breast cancer chemotherapy in two teaching hospitals in Southeastern Nigeria. METHODS: Using a qualitative descriptive design, based on grounded theory approach and focus group discussion (FGD) methodology, 20 histological confirmed breast cancer patients at different stages of combination chemotherapy (cyclophosphamide, doxorubicin, and fluorouracil ) were purposively selected and engaged in FGDs at two surgical oncology clinics. Data saturation was reached at the fourth FGD. The audio-taped and transcribed data were content analyzed using thematic approach. RESULTS: Participants were all christians of the Igbo-speaking ethnic group, and aged between 36 and 66 years. Most were married and had at least primary education. Five themes emerged from the FGDs: inadequate preparation for chemotherapy; chemotherapy scary, distressful, and financially demanding; hope, faith and courage sustained treatment; self-care actions initiated to 'weather the storm'; and nursing assistance desired to foster hope and enhance patients' acceptance of, adjustment and adherence to breast cancer chemotherapy in Nigeria. Culture influenced their chemotherapy perspectives and coping. CONCLUSION: Women with breast cancer in southeastern Nigeria desired but were inadequately prepared to cope with chemotherapy distress they experienced. Nurses could help patients to accept and navigate through chemotherapy by initiating and supporting effective and efficient self-care actions that are culturally congruent.Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26585673 TI - MiR-125b Is Critical for Fibroblast-to-Myofibroblast Transition and Cardiac Fibrosis. AB - BACKGROUND: Cardiac fibrosis is the pathological consequence of stress-induced fibroblast proliferation and fibroblast-to-myofibroblast transition. MicroRNAs have been shown to play a central role in the pathogenesis of cardiac fibrosis. We identified a novel miRNA-driven mechanism that promotes cardiac fibrosis via regulation of multiple fibrogenic pathways. METHODS AND RESULTS: Using a combination of in vitro and in vivo studies, we identified that miR-125b is a novel regulator of cardiac fibrosis, proliferation, and activation of cardiac fibroblasts. We demonstrate that miR-125b is induced in both fibrotic human heart and murine models of cardiac fibrosis. In addition, our results indicate that miR 125b is necessary and sufficient for the induction of fibroblast-to-myofibroblast transition by functionally targeting apelin, a critical repressor of fibrogenesis. Furthermore, we observed that miR-125b inhibits p53 to induce fibroblast proliferation. Most importantly, in vivo silencing of miR-125b by systemic delivery of locked nucleic acid rescued angiotensin II-induced perivascular and interstitial fibrosis. Finally, the RNA-sequencing analysis established that miR-125b altered the gene expression profiles of the key fibrosis-related genes and is a core component of fibrogenesis in the heart. CONCLUSIONS: In conclusion, miR-125b is critical for induction of cardiac fibrosis and acts as a potent repressor of multiple anti-fibrotic mechanisms. Inhibition of miR-125b may represent a novel therapeutic approach for the treatment of human cardiac fibrosis and other fibrotic diseases. PMID- 26585675 TI - [Total duration of ventilation in the prone position in patients with acute respiratory distress syndrome]. PMID- 26585676 TI - Seasonality and household diets in Ethiopia. AB - OBJECTIVE: To revisit seasonality by assessing how household diets vary across agricultural seasons in rural and urban Ethiopia. The role of seasonality on the sources and intake of energy (per capita) and household dietary diversity score (HDDS) was analysed. DESIGN: The use of nationally representative household-level data collected each month over one year to study the seasonal changes in the sources and intake of energy and HDDS. SETTING: Eleven regions of Ethiopia, including rural and urban settings. SUBJECTS: Total of 27 835 households were interviewed between July 2010 and July 2011 in all eleven regions of the country. On average each month saw 2300 household interviews, yielding nationally representative data for each calendar month. RESULTS: For rural households, the mean daily per capita energy intake was 10 288 kJ (2459 kcal) in February (post harvest period) and lower in the lean season: 9703 kJ (2319 kcal) in June (P<0.05) and 9552 kJ (2283 kcal) in July (P<0.001). HDDS for rural households was highest in February (6.73) and lowest in June (5.98; P<0.001) but high again in July (6.57). Urban energy intake was also lower in the lean season but HDDS varied less by season. Considerable seasonal variation was also found in energy sources in rural areas, less so in urban areas. CONCLUSIONS: Household diets in Ethiopia remain subjected to significant seasonal stress. HDDS and food security measured using energy intake do not always agree. Preferably, HDDS and energy intake data should be used together to assess food security. PMID- 26585677 TI - Characterization of Prohibitins in Male Reproductive System and their Expression under Oxidative Stress. AB - PURPOSE: We investigated the expression and location of prohibitin 1 and 2 of the prohibitin family in the male reproductive system and their potential roles during the oxidative stress response in a rat model. MATERIALS AND METHODS: Semiquantitative polymerase chain reaction, Western blot, immunohistochemistry and indirect immunofluorescence were performed to examine the expression and localization of prohibitins. Oxidative damage was evaluated using a commercially available malondialdehyde kit. Histological damage induced by doxorubicin injection was examined by hematoxylin and eosin staining. RESULTS: Prohibitin 1 and 2 were ubiquitously expressed in various human tissues with distinct high expression in the epididymis. In the human testis and epididymis they were localized in the cytoplasm of diverse cell types. Prohibitin 1 was located on the entire tail region of human ejaculated spermatozoa while prohibitin 2 was specifically localized on the equatorial region. In spermatozoa from young men with asthenozoospermia the percent of spermatozoa with positive staining as well as the fluorescence intensity of prohibitin 2 was much lower than in the spermatozoa of healthy donors. Uniform expression of prohibitins in the testis and epididymis of the rat during postnatal development suggested conserved and vital biological functions. Moreover under oxidative stress induced by doxorubicin injection the expression of prohibitin 1 and 2 was significantly down regulated in the rat testis with significant histomorphological changes. CONCLUSIONS: To our knowledge this research represents the first systematic study of prohibitins in the male reproductive system. It lays the foundation for further functional studies and provides potential therapeutic targets for infertility induced by oxidative stress. PMID- 26585678 TI - Prevention, Diagnosis and Treatment of Rhabdomyolysis after Urological Surgery. PMID- 26585680 TI - Natural History, Complications and Re-Intervention Rates of Asymptomatic Residual Stone Fragments after Ureteroscopy: a Report from the EDGE Research Consortium. AB - PURPOSE: Fragments 4 mm or smaller after ureteroscopy historically have been considered clinically insignificant but there is a reported 20% event rate on followup even with stones 4 mm or smaller. In this study we examine the natural history, complications and re-intervention rates of fragments after ureteroscopy. MATERIALS AND METHODS: Data from 6 centers were collected retrospectively from members of the Endourology Disease Group for Excellence in 232 patients who had residual fragments after ureteroscopy between 2006 and 2013. Patients with fragment(s) of any size on imaging within 12 months were eligible. The primary outcome measured was stone events, and secondary outcomes included stone growth, stone passage, re-intervention and complications. RESULTS: Of the 232 subjects with fragments 131 (56%) required no further intervention and remained asymptomatic, 34 (15%) experienced complications requiring no intervention and 67 (29%) required intervention, ie the primary outcome stone event rate was 44%. Fragments larger than 4 mm were more likely to grow with time (p <0.001) and were associated with more complications (p=0.039). Fragments larger than 2 mm were more likely to grow (p <0.001) but were not associated with complications or re intervention. Re-intervention was predictable based on fragment size (p=0.017). In a multivariable logistic regression model there was no significant difference between the techniques of dusting stones or basket extraction. CONCLUSIONS: This study suggests that fragment size larger than 4 mm after ureteroscopy is associated with significantly higher rates of stone growth, complications and the need for re-intervention. Ensuring complete stone-free status is the most effective strategy to reduce stone events after ureteroscopy. PMID- 26585679 TI - Pain and Urinary Symptoms Should Not be Combined into a Single Score: Psychometric Findings from the MAPP Research Network. AB - PURPOSE: The purpose of this study was to create symptom indexes, that is scores derived from questionnaires to accurately and efficiently measure symptoms of interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome, collectively referred to as urological chronic pelvic pain syndromes. We created these indexes empirically by investigating the structure of symptoms using exploratory factor analysis. MATERIALS AND METHODS: As part of the MAPP (Multi-Disciplinary Approach to the Study of Chronic Pelvic Pain) Research Network 424 participants completed questionnaires, including GUPI (Genitourinary Pain Index), ICSI (Interstitial Cystitis Symptom Index) and ICPI (Interstitial Cystitis Problem Index). Individual items from questionnaires about bladder and pain symptoms were evaluated by principal component and exploratory factor analyses to identify indexes with fewer questions to comprehensively quantify symptom severity. Additional analyses included correlating symptom indexes with symptoms of depression, which is a known comorbidity of patients with pelvic pain. RESULTS AND CONCLUSIONS: Exploratory factor analyses suggested that the 2 factors pain severity and urinary severity provided the best psychometric description of items in GUPI, ICSI and ICPI. These factors were used to create 2 symptom indexes for pain and urinary symptoms. Pain, but not urinary symptoms, was associated with symptoms of depression on multiple regression analysis, suggesting that these symptoms may impact patients with urological chronic pelvic pain syndromes differently (B +/- SE for pain severity = 0.24 +/- 0.04, 95% CI 0.16-0.32, beta = 0.32, p <0.001). Our results suggest that pain and urinary symptoms should be assessed separately rather than combined into 1 total score. Total scores that combine the separate factors of pain and urinary symptoms into 1 score may be limited for clinical and research purposes. PMID- 26585681 TI - Should Clinicians Use Ultrasensitive Prostate Specific Antigen Measurements for Patient Evaluation? PMID- 26585683 TI - Positive Margins after Radical Nephrectomy with Venous Thrombectomy: Controversies and Treatment Options. PMID- 26585682 TI - TAT-peroxiredoxin 2 Fusion Protein Supplementation Improves Sperm Motility and DNA Integrity in Sperm Samples from Asthenozoospermic Men. AB - PURPOSE: We compared levels of peroxiredoxin 2 in semen samples from normozoospermic and asthenozoospermic men. The potential effects of TAT peroxiredoxin 2 fusion protein on sperm motility and DNA integrity were also evaluated. MATERIALS AND METHODS: Semen samples were obtained from 50 normozoospermic and 50 asthenozoospermic men. Lipid peroxidation of semen was determined using a commercial malondialdehyde kit. Sperm DNA fragmentation was evaluated by TUNEL assay. Western blot and immunofluorescence were performed to detect the amount of peroxiredoxin 2 protein in seminal plasma and spermatozoa. Sperm motility, DNA damage and levels of reactive oxygen species were evaluated after TAT-peroxiredoxin 2 fusion protein supplementation to the sperm suspension for 2 and 12 hours of incubation. RESULTS: In asthenozoospermic semen samples a significantly higher level of malondialdehyde and DNA damage was discovered. However, the expression of peroxiredoxin 2 was significantly lower in seminal plasma and spermatozoa compared with that of normozoospermic men. TAT peroxiredoxin 2 fusion protein was successfully prepared and delivered to the spermatozoa. Interestingly adding TAT-peroxiredoxin 2 in asthenozoospermic sperm suspension effectively defended against the decrease in progressive motility and the increase in DNA damage. CONCLUSIONS: This study shows that supplementation of TAT-peroxiredoxin 2 fusion protein in the sperm suspension from asthenozoospermic men effectively improved sperm motility and DNA integrity by reducing levels of reactive oxygen species. Therefore, we speculate that peroxiredoxin 2 may have an important role as an antioxidant defense in semen and would provide new prevention and therapy alternatives for asthenozoospermia. PMID- 26585684 TI - Mesh rather than Autologous Tissue should be Used for Transvaginal Repair of Pelvic Organ Prolapse. PRO FOR NATIVE TISSUE. PMID- 26585685 TI - Mesh Rather than Autologous Tissue Should be Used for Transvaginal Repair of Pelvic Organ Prolapse. PRO FOR MESH. PMID- 26585686 TI - Purposes of Internet use and problematic Internet use among Turkish high school students. AB - INTRODUCTION: After the emergence of the Internet, the sudden increase in its use soon attracted attention to this phenomenon. Studies have shown that there is a relationship between problematic Internet use (PIU) and the purposes of Internet use. METHODS: The aims of this study are to examine the purposes of Internet use among Turkish high school students according to their gender, frequency of Internet use (FIU), grade point average (GPA) and family income (F-income), and to investigate whether all these variables predict PIU. The participants in the study were 375 high school students (185 girls and 190 boys), and verbal consent was obtained from the subjects before application. The participants' ages ranged between 14 and 18 (Mean = 15.6, SD = 1.26). One-way analysis of variance was used to identify the purposes of Internet use in terms of demographic variables. Also, hierarchical multiple regression analyses were conducted to explore whether demographic variables and purposes of Internet use affected PIU. RESULTS AND DISCUSSION: Finally, the results demonstrate that male gender, high FIU, low GPA, and high levels of F-income correlate significantly with PIU. Also, the social, leisure and virtual-emotional purposes of Internet use, besides demographic variables, were significantly correlated with PIU. PMID- 26585687 TI - Mitotic index and multipolar mitosis in routine histologic sections as prognostic markers of pancreatic cancers: A clinicopathological study. AB - OBJECTIVES: Pancreatic cancer is characterized by genomic complexity and chromosomal instability, and atypical mitotic figures are morphological features of this phenotype. In the present study, we determined the frequency and the clinicopathological and prognostic significance of mitotic figures in pancreatic cancers. METHODS: We surveyed the mitotic figures of the normal ductal epithelium, acinar cells, pancreatic intraepithelial neoplasias, and pancreatic cancers on hematoxylin-and-eosin-stained tissue specimens (n = 121). RESULTS: Pancreatic cancer cells showed significantly higher mitotic indices as compared with the ductal cells, acinar cells, and pancreatic intraepithelial neoplasias. Both normal and atypical mitosis were significantly elevated only in pancreatic cancers. In pancreatic cancers, approximately 30% of total mitosis was atypical including multipolar, lag-type, ring and asymmetrical mitosis, and anaphase bridges. The Kaplan-Meier curves in pancreatic cancers showed significant correlations between total mitosis and disease free survival. Furthermore, the cases with multipolar mitosis showed poorer prognosis than those without. Lymph node metastasis and multipolar mitosis were independent prognostic factors for overall survival of patients with pancreatic cancer. In addition, lymph node metastasis and total mitosis were independent factors for disease free survival. CONCLUSION: These findings suggest that routinely obtained pathological specimens, even small biopsy or cytological specimens, can provide valuable information concerning the prognosis of pancreatic cancers. PMID- 26585688 TI - Erratum. PMID- 26585690 TI - Additional Arctic observations improve weather and sea-ice forecasts for the Northern Sea Route. AB - During ice-free periods, the Northern Sea Route (NSR) could be an attractive shipping route. The decline in Arctic sea-ice extent, however, could be associated with an increase in the frequency of the causes of severe weather phenomena, and high wind-driven waves and the advection of sea ice could make ship navigation along the NSR difficult. Accurate forecasts of weather and sea ice are desirable for safe navigation, but large uncertainties exist in current forecasts, partly owing to the sparse observational network over the Arctic Ocean. Here, we show that the incorporation of additional Arctic observations improves the initial analysis and enhances the skill of weather and sea-ice forecasts, the application of which has socioeconomic benefits. Comparison of 63 member ensemble atmospheric forecasts, using different initial data sets, revealed that additional Arctic radiosonde observations were useful for predicting a persistent strong wind event. The sea-ice forecast, initialised by the wind fields that included the effects of the observations, skilfully predicted rapid wind-driven sea-ice advection along the NSR. PMID- 26585689 TI - Mesenchymal Stem Cells Induce Directional Migration of Invasive Breast Cancer Cells through TGF-beta. AB - Mesenchymal stem cells (MSCs) are recruited to the tumor microenvironment and influence tumor progression; however, how MSCs induce the invasion of cancer cells is not completely understood. Here, we used a 3D coculture model to determine how MSCs affect the migration of invasive breast cancer cells. Coculture with MSCs increases the elongation, directional migration, and traction generation of breast cancer cells. MSC-induced directional migration directly correlates with traction generation and is mediated by transforming growth factor beta (TGF-beta) and the migratory proteins rho-associated kinase, focal adhesion kinase, and matrix metalloproteinases. Treatment with MSC conditioned media or recombinant TGF-beta1 elicits a similar migration response to coculture. Taken together, this work suggests TGF-beta is secreted by MSCs, leading to force dependent directional migration of invasive breast cancer cells. These pathways may be potential targets for blocking cancer cell invasion and subsequent metastasis. PMID- 26585692 TI - Successful Repair of Acute Type A Aortic Dissection 15 Years Following Bilateral Lung Transplantation. AB - This report describes a patient treated for acute type A aortic dissection 15 years after undergoing bilateral lung transplantation by a clamshell thoracotomy. PMID- 26585691 TI - PTH Induces Systemically Administered Mesenchymal Stem Cells to Migrate to and Regenerate Spine Injuries. AB - Osteoporosis affects more than 200 million people worldwide leading to more than 2 million fractures in the United States alone. Unfortunately, surgical treatment is limited in patients with low bone mass. Parathyroid hormone (PTH) was shown to induce fracture repair in animals by activating mesenchymal stem cells (MSCs). However, it would be less effective in patients with fewer and/or dysfunctional MSCs due to aging and comorbidities. To address this, we evaluated the efficacy of combination i.v. MSC and PTH therapy versus monotherapy and untreated controls, in a rat model of osteoporotic vertebral bone defects. The results demonstrated that combination therapy significantly increased new bone formation versus monotherapies and no treatment by 2 weeks (P < 0.05). Mechanistically, we found that PTH significantly enhanced MSC migration to the lumbar region, where the MSCs differentiated into bone-forming cells. Finally, we used allogeneic porcine MSCs and observed similar findings in a clinically relevant minipig model of vertebral defects. Collectively, these results demonstrate that in addition to its anabolic effects, PTH functions as an adjuvant to i.v. MSC therapy by enhancing migration to heal bone loss. This systemic approach could be attractive for various fragility fractures, especially using allogeneic cells that do not require invasive tissue harvest. PMID- 26585693 TI - Controlled release tablet formulation containing natural Delta(9) tetrahydrocannabinol. AB - Cannabinoids are increasingly being used in the treatment of chemotherapy-induced nausea and vomiting (CINV) because of their action on the cannabinoid receptors, CB1 and CB2. The currently marketed capsule formulations (sesame oil based and crystalline powder) are required to be administered frequently to maintain therapeutic levels, which leads to non-compliance. In the present study, oral controlled release tablet formulations of Delta(9)-tetrahydrocannabinol (THC) were prepared using the lipids Precirol(r) and Compritol(r). Release profiles using THC-lipid matrices and/or with the lipids in the external phase (blend) were evaluated. The effect of directly compressible diluents lactose mixture (Ludipress(r)), dicalcium phosphate anhydrous (Emcompress(r)) and microcrystalline cellulose (Avicel(r) 102) on tablet characteristics and in vitro drug release was also investigated. Further, in vitro THC release in the presence of a lipase inhibitor, Pluronic(r) F68, was also studied. A 24 h zero-order THC release profile was obtained with a combination of Precirol(r) and Compritol(r) in the compression blend. Addition of Pluronic(r) F68 did not alter THC release in vitro. These optimized tablets were chemically and physically stable for 3 months, the last time point tested, at 25 degrees C/60% RH. The overall results demonstrate the feasibility of preparing oral THC tablets for once a day administration which can improve CINV management. PMID- 26585694 TI - Circumcision with "no-flip Shang Ring" and "Dorsal Slit" methods for adult males: a single-centered, prospective, clinical study. AB - This paper was aimed to compare the clinical effectiveness and safety of adult male circumcision using the Shang RingTM (SR) with the no-flip technique compared with Dorsal Slit (DS) surgical method. A single-centered, prospective study was conducted at the West China Hospital, where patients were circumcised using the no-flip SR (n = 408) or the DS (n = 94) procedure. The adverse events (AEs) and satisfaction were recorded for both groups, and ring-removal time and percentage of delayed removals were recorded for the SR group. Finally, complete follow-up data were collected for 76.1% of patients (SR: n = 306; DS: n = 76). The average ring-removal time for the SR group was 17.62 +/- 6.30 days. The operation time (P < 0.001), pain scores during the procedure (P < 0.001) and at 24 h postoperatively (P < 0.001), bleeding (P = 0.001), infection (P = 0.034), and satisfaction with penile appearance (P < 0.001) in the SR group were superior to those in the DS group. After two postoperative weeks, the percentage of patients with edema in the SR group (P = 0.029) was higher but no differences were found at 4 weeks (P = 0.185) between the two groups. In conclusions, the no-flip SR method was found to be superior to the DS method for its short operation time (<5 min), involving less pain, bleeding, infection, and resulting in a satisfactory appearance. However, the time for recovery from edema took longer, and patients may wear device for 2-3 weeks after the procedure. PMID- 26585695 TI - Claudin-11 and occludin are major contributors to Sertoli cell tight junction function, in vitro. AB - The Sertoli cell tight junction (TJ) is the key component of the blood-testis barrier, where it sequesters developing germ cells undergoing spermatogenesis within the seminiferous tubules. Hormonally regulated claudin-11 is a critical transmembrane protein involved in barrier function and its murine knockout results in infertility. We aimed to assess quantitatively the significance of the contribution of claudin-11 to TJ function, in vitro, using siRNA-mediated gene silencing. We also conducted an analysis of the contribution of occludin, another intrinsic transmembrane protein of the TJ. Silencing of claudin-11 and/or occludin was conducted using siRNA in an immature rat Sertoli cell culture model. Transepithelial electrical resistance was used to assess quantitatively TJ function throughout the culture. Two days after siRNA treatment, cells were fixed for immunocytochemical localization of junction proteins or lyzed for RT-PCR assessment of mRNA expression. Silencing of claudin-11, occludin, or both resulted in significant decreases in TJ function of 55% (P < 0.01), 51% (P < 0.01), and 62% (P < 0.01), respectively. Data were concomitant with significant decreases in mRNA expression and marked reductions in the localization of targeted proteins to the Sertoli cell TJ. We provide quantitative evidence that claudin-11 contributes significantly (P < 0.01) to Sertoli cell TJ function in vitro. Interestingly, occludin, which is hormonally regulated but not implicated in infertility until late adulthood, is also a significant (P < 0.01) contributor to barrier function. Our data are consistent with in vivo studies that clearly demonstrate a role for these proteins in maintaining normal TJ barrier structure and function. PMID- 26585697 TI - Commentary on "morphological characteristics and initial genetic study of multiple morphological anomalies of the flagella in China". PMID- 26585696 TI - Demethylation treatment restores erectile function in a rat model of hyperhomocysteinemia. AB - Methylation modification is an important cellular mechanism of gene expression regulation. Dimethylarginine dimethylaminohydrolase-2 (DDAH-2) protein is a pivotal molecular for endothelium function. To explore the effects of 5-aza deoxycytidine (5-aza), a demethylation agent, in hyperhomocysteinemia (hhcy) related erectile dysfunction (ED) rats, 5-aza (1 mg kg-1 ) was administrated to Sprague-Dawley hhcy-rats induced by supplemented methionine chow diet. Erectile function, nitric oxide-cyclic guanosine monophosphate (NO-cGMP) levels, expression of DDAH-2 protein and promoter methylation status of DDAH-2 were studied in the corpora cavernosa. We found that supplemented methionine diet induced a high homocysteine level after 6 weeks of treatment. DDAH-2 protein was down-regulated in the corpora cavernosa while the administration of 5-aza up regulated DDAH-2 expression and restored erectile function. The methionine-fed rats showed high methylation levels of DDAH-2 promoter region while the group treated with 5-aza demonstrated lower-methylation levels when compared to the methionine-fed group. Besides, the administration of 5-aza improved NO and cGMP levels in methionine-fed rats. Therefore, the methylation mechanism involves in ED pathogenesis, and demethylation offers a potential new strategy for ED treatment. PMID- 26585698 TI - Association of time to prostate-specific antigen nadir and logarithm of prostate specific antigen velocity after progression in metastatic prostate cancer with prior primary androgen deprivation therapy. AB - We investigated the association of time to prostate-specific antigen nadir (TTPN) and logarithm of prostate-specific antigen velocity after progression Log(PSAVAP) in metastatic prostate cancer with prior primary androgen deprivation therapy (ADT). All metastatic prostate cancer patients treated with primary ADT from 2000 to 2009 were reviewed. Patients who developed disease progression were included in the subsequent analyses. Patients were categorized into three groups according to their TTPN: TTPN of <3 months, 3-17 months, and >17 months. We compared the Log(PSAVAP) between the different TTPN groups using Mann-Whitney U-test and Kruskal-Wallis test. Further multiple linear regression analyses on Log(PSAVAP) were performed to adjust for other potential confounding factors. Among 419 patients who were treated with primary ADT, 306 patients developed disease progression with a median follow-up of 28 months. Longer TTPN was associated with lower Log(PSAVAP) (P = 0.008) within all subgroup analyses (TTPN of <3 vs 3-17 months, P= 0.020; TTPN of 3-17 vs >17 months, P= 0.009; and TTPN of <3 vs >17 months, P= 0.001). Upon multiple linear regression analyses, baseline PSA (regression coefficient 0.001, P= 0.045), PSA nadir (regression coefficient 0.002, P= 0.040), and TTPN (regression coefficient -0.030, P= 0.001) were the three factors that were significantly associated with Log(PSAVAP). In conclusion, a longer TTPN was associated with lower Log(PSAVAP) in metastatic prostate cancer patients following primary ADT. TTPN cut-offs at 3 months and 17 months appeared to have prognostic significance in predicting Log(PSAVAP). TTPN may serve as a good prognostic indicator in deciding the treatment strategy in patients with disease progression. PMID- 26585700 TI - Air quality control in the ART laboratory is a major determinant of IVF success. PMID- 26585699 TI - Regulation of epithelial function, differentiation, and remodeling in the epididymis. AB - The epididymis is a single convoluted tubule lined by a pseudostratified epithelium. Specialized epididymal epithelial cells, the so-called principal, basal, narrow, and clear cells, establish a unique luminal environment for the maturation and storage of spermatozoa. The epididymis is functionally and structurally divided into several segments and sub-segments that create regionally distinct luminal environments. This organ is immature at birth, and epithelial cells acquire their fully differentiated phenotype during an extended postnatal period, but the factors involved in this complex process remain incompletely characterized. In the adult epididymis, the establishment of an acidic luminal pH and low bicarbonate concentration in the epididymis contributes to preventing premature activation of spermatozoa during their maturation and storage. Clear cells are proton-secreting cells throughout the epididymis, but principal cells have distinct acid/base transport properties, depending on their localization within the epididymis. Basal cells are located in all epididymal segments, but they have a distinct morphology depending on the segment and species examined. How this structural plasticity of basal cells is regulated is discussed here. Also, the role of luminal factors and androgens in the regulation of epithelial cells is reviewed in relation to their respective localization in the proximal versus distal regions of the epididymis. Finally, we describe a novel role for CFTR in tubulogenesis and epithelial cell differentiation. PMID- 26585701 TI - Healthcare utilization and costs in patients with benign prostatic hyperplasia: a population-based study. AB - This study aimed to investigate differences in healthcare service utilization between patients with and those without benign prostatic hyperplasia (BPH) using Taiwan's National Health Insurance population-based database. A total of 7413 patients with BPH and 7413 age-matched patients without BPH were included. The outcome variable was 1-year utilization of healthcare services including the number of outpatient visits, inpatient days, and the costs of outpatient and inpatient treatments. In addition, we separated healthcare services into urology services and nonurology services for analysis. We found that as to the utilization of outpatient urological services, patients with BPH had more outpatient services (7.84 vs 0.52, P< 0.001), higher outpatient costs (US$372 vs US$34, P< 0.001), a longer length of inpatient stay (0.55 vs 0.11, P< 0.001), higher in-patients costs (US$149 vs US$32, P< 0.001), and higher total costs (US$521 vs US$67, P< 0.001) than the comparison group. As for nonurological services, patients with BPH also had more outpatient services (49.11 vs 24.79, P< 0.001), higher outpatient costs (US$1794 vs US$1014, P< 0.001), a longer length of in-patient stay (3.72 vs 2.04, P< 0.001), higher inpatient costs (US$874 vs US$486, P< 0.001), and higher total costs (US$2668 vs US$1500, P< 0.001) compared to comparison patients. We also found that the average total cost was about 2 fold greater for patients with BPH than comparison patients. We concluded that patients with BPH had higher healthcare utilization than comparison patients without BPH. PMID- 26585702 TI - Prognostic Impact of Intensified Maintenance Therapy on Children With Advanced Lymphoblastic Lymphoma: A Report From the Japanese Pediatric Leukemia/Lymphoma Study Group ALB-NHL03 Study. AB - BACKGROUND: Childhood advanced lymphoblastic lymphoma (LBL) has a favorable outcome with an event-free survival (EFS) rate of over 80% in response to treatment strategies for acute lymphoblastic leukemia (ALL). However, no progress has been made in this outcome over the past 10 years. PROCEDURE: We conducted the first nationwide prospective study of childhood advanced LBL to assess the efficacy and safety of ALL-directed therapy with an intensified maintenance phase. We omitted local radiotherapy including prophylactic cranial radiotherapy except for patients with initial central nervous system disease. The total duration of the treatment was 24 months. RESULTS: For the 136 patients analyzed in this study, 5-year overall survival (OS) was 82.9% and 5-year EFS was 77.9%. Thirty events were observed and 14 occurred before the initiation of intensified maintenance phase. Of 14 events, nine were observed as mediastinal enlargement. There was no significant difference in outcome when stratified according to gender or by immunophenotype. The 5-year EFS according to clinical stage in patients with T-cell LBL (T-LBL) was 70.6% for stage III and 88.9% for stage IV (P = 0.037). CONCLUSIONS: Our first nationwide study provided about 80% cure rate with only one case of toxic death in childhood advanced LBL. However, our intensified maintenance therapy could not improve the survival outcome. There was a trend of better EFS in Japanese patients with T-LBL stage IV than T-LBL stage III. PMID- 26585703 TI - RESPONSIVENESS, LANGUAGE, AND ALIGNMENT: REFLECTIONS ON SOME CHALLENGES FOR HEALTH TECHNOLOGY ASSESSMENT. AB - Health systems around the world cope with the challenge of difficult economic times, and the value of health technology assessment (HTA) is increasing. Making the right choices, with limited resources, in the face of increasingly complex technologies requires decisions informed by data and analyses that help us to manage the risks involved. Those who undertake and use HTA can play a greater role in helping decision makers meet these challenges; they need to think how to define innovation and respond to it, how to communicate their analyses, and, critically, how to align their work with the ambitions of their health systems. HTA can become a key health system enabler without compromising its objectivity or independence. It can say that it is too early to determine the value of a new technology when the data simply will not support a safe decision. However, it can also be bold and recommend the managed introduction of new technologies, even when the when the data is immature, provided that the health system understands the risks and there is a plausible case for believing that further research will support the value proposition. The goal for HTA is to be able confidently to do both. PMID- 26585704 TI - From the bathroom to the bone-anchored hearing aid: an idea on how to remove a stripped abutment screw from a bone-anchored hearing aid. PMID- 26585705 TI - Tobacco control and the World Trade Organization: mapping member states' positions after the framework convention on tobacco control. AB - OBJECTIVE: To note the frequency of discussions and disputes about tobacco control measures at the World Trade Organization (WTO) before and after the coming into force of the Framework Convention on Tobacco Control (FCTC). To review trends or patterns in the positions taken by members of the WTO with respect to tobacco control measures. To discuss possible explanations for these observed trends/patterns. METHODS: We gathered data on tobacco-related disputes in the WTO since its establishment in 1995 and its forerunner, the General Agreement on Tariffs and Trade (GATT), prior-FCTC and post-FCTC. We also looked at debates on tobacco control measures within the WTO more broadly. To this end, we classified and coded the positions of WTO member states during discussions on tobacco control and the FCTC, from 1995 until 2013, within the Technical Barriers to Trade (TBT) Committee and the Trade-Related Aspects of Intellectual Property Rights (TRIPS) Council. RESULTS: There is a growing interest within the WTO for tobacco-related issues and opposition to tobacco control measures is moving away from high-income countries towards low(er) income countries. CONCLUSIONS: The growing prominence of tobacco issues in the WTO can be attributed at least in part to the fact that during the past decade tobacco firms have been marginalised from the domestic policy-making process in many countries, which has forced them to look for other ways and forums to influence decision-making. Furthermore, the finding that almost all recent opposition within the WTO to stronger tobacco regulations came from developing countries is consistent with a relative shift of transnational tobacco companies' lobbying efforts from developed to developing countries. PMID- 26585706 TI - The smoke-free legislation in Hong Kong: its impact on mortality. AB - OBJECTIVES: To examine trends in deaths for conditions associated with secondhand smoke exposure over the years prior to and following the implementation of a smoke-free policy in Hong Kong. DESIGN: Time-series study. SETTING: Death registration data from Hong Kong Special Administrative Region (SAR) Government Census and Statistics Department. PARTICIPANTS: All deaths registered from 1 January 2001 to 31 December 2011. MAIN OUTCOME MEASURES: Deaths for conditions associated with passive smoking include cardiovascular disease (CVD), respiratory disease and other causes. RESULTS: There was a decline in the annual proportional change for ischaemic heart disease (IHD), acute myocardial infarction (AMI) and CVD mortality in the year after the intervention for all ages and those aged 65 years or older. There were also clear declines in the cool season peaks for these three conditions in the first postintervention year. There was a further drop in the cool season peak for AMI among all ages in the year after the exemptions ceased. No declines in annual proportional change or changes in seasonal peaks of mortality were found for any of the control conditions. CONCLUSIONS: The findings in this study add to the evidence base, as summarised in the Surgeon General's report, extending the impact of effective smoke-free legislation to those aged 65 years or older and to cerebrovascular events in younger age groups. They also reinforced the need for comprehensive, enforced and effective smoke-free laws if the full extent of the health gains are to be achieved. PMID- 26585707 TI - Retailer compliance with tobacco control laws in New York City before and after raising the minimum legal purchase age to 21. AB - OBJECTIVES: New York City (NYC) is the first large city to increase the legal minimum age for possessing tobacco products from 18 to 21 (Tobacco 21) and establish a minimum price law to reduce smoking rates among youth. However, retailer compliance with these regulations is unknown. METHODS: Youthful investigators purchased cigarettes pre and post-Tobacco 21 implementation in 92 NYC neighbourhoods. Investigators recorded whether their ID was checked, the pack's purchase price, and observed compliance with additional regulations. Multivariable OLS and Poisson regression models assess pre and post Tobacco 21 compliance with ID checks and purchase prices, controlling for retailer type, location and compliance with other laws. RESULTS: Retailer compliance with ID checks declined from 71% to 62% (p<0.004) between periods, and holding constant other factors, compliance with ID checks and sales at legal prices declined significantly after the laws changed. Compared to chain stores, independent retailers had significantly lower compliance rates (p<0.01). CONCLUSIONS: Several aspects of tobacco control appear to have deteriorated in NYC. Greater attention to monitoring retailer compliance with all tobacco regulations will be important for Tobacco 21 laws to be effective in reducing youth access to tobacco products. PMID- 26585708 TI - Microbial assemblages for environmental quality assessment: Knowledge, gaps and usefulness in the European Marine Strategy Framework Directive. AB - The EU Marine Strategy Framework Directive 2008/56/EC (MSFD) defines a framework for Community actions in the field of marine environmental policy in order to achieve and/or maintain the Good Environmental Status (GES) of the European seas by 2020. Microbial assemblages (from viruses to microbial-sized metazoa) provide a major contribution to global biodiversity and play a crucial role in the functioning of marine ecosystems, but are largely ignored by the MSFD. Prokaryotes are only seen as "microbial pathogens," without defining their role in GES indicators. However, structural or functional prokaryotic variables (abundance, biodiversity and metabolism) can be easily incorporated into several MSFD descriptors (i.e. D1. biodiversity, D4. food webs, D5. eutrophication, D8. contaminants and D9. contaminants in seafood) with beneficial effects. This review provides a critical analysis of the current MSFD descriptors and illustrates the reliability and advantages of the potential incorporation of some prokaryotic variables within the set of indicators of marine environmental quality. Following a cost/benefit analysis against scientific and economic criteria, we conclude that marine microbial components, and particularly prokaryotes, are highly effective for detecting the effects of anthropogenic pressures on marine environments and for assessing changes in the environmental health status. Thus, we recommend the inclusion of these components in future implementations of the MSFD. PMID- 26585709 TI - Quaternized pine sawdust in the treatment of mining wastewater. AB - Mining wastewater was treated using quaternized pine sawdust (QPSD) anion exchanger. The wastewater contained heavy metals (e.g. Sb, As, Co, Cr, Ni, V, U), NO3(-), among others, and a high concentration of SO4(2-). A series of column cycles imitating a real treatment process was conducted (three sorption/desorption cycles, a maintenance cycle with HCl and two sorption/desorption cycles). The effects of contact time and temperature (5 degrees C and 23 degrees C) were studied to assess the applicability of QPSD in the treatment of cold mining effluents. At 5 degrees C, 85% of nickel was removed but the sorption was slower than at 23 degrees C (initial Ni concentration was about 39 ug/l). Nickel was also removed in column efficiently (85-100% reduction). Treatment with HCl during the maintenance cycles did not hinder nickel sorption. Nickel was desorbed with both NaCl and HCl. Contrary to expectations, nitrate was not sorbed. QPSD showed selectivity towards nickel. However, uptake of uranium and cobalt was detected in column. Neutron activation analysis was used to detect metals sorbed onto the QPSD, and uptake of several metals was confirmed. PMID- 26585710 TI - Metabolic-epigenetic crosstalk in macrophage activation. AB - Epigenetic enzymes are emerging as crucial controllers of macrophages, innate immune cells that determine the outcome of many inflammatory diseases. Recent studies demonstrate that the activity of particular chromatin-modifying enzymes is regulated by the availability of specific metabolites like acetyl-coenzyme A, S-adenosylmethionine, alpha-ketoglutarate, nicotinamide adenine dinucleotide and polyamines. In this way chromatin-modifying enzymes could sense the macrophage's metabolic status and translate this into gene expression and phenotypic changes. Importantly, distinct macrophage activation subsets display particular metabolic pathways. IFNgamma/lipopolysaccharide-activated macrophages (MIFNgamma/LPS or M1) display high glycolysis, which directly drives their inflammatory phenotype. In contrast, oxidative mitochondrial metabolism and enhanced polyamine production are hallmarks and requirements for IL-4-induced macrophage activation (MIL-4 or M2). Here we report how epigenetics could serve as a bridge between altered macrophage metabolism, macrophage activation and disease. PMID- 26585711 TI - NSDF: Neuroscience Simulation Data Format. AB - Data interchange is emerging as an essential aspect of modern neuroscience. In the areas of computational neuroscience and systems biology there are multiple model definition formats, which have contributed strongly to the development of an ecosystem of simulation and analysis tools. Here we report the development of the Neuroscience Simulation Data Format (NSDF) which extends this ecosystem to the data generated in simulations. NSDF is designed to store simulator output across scales: from multiscale chemical and electrical signaling models, to detailed single-neuron and network models, to abstract neural nets. It is self documenting, efficient, modular, and scalable, both in terms of novel data types and in terms of data volume. NSDF is simulator-independent, and can be used by a range of standalone analysis and visualization tools. It may also be used to store variety of experimental data. NSDF is based on the widely used HDF5 (Hierarchical Data Format 5) specification and is open, platform-independent, and portable. PMID- 26585712 TI - Groupwise Image Registration Guided by a Dynamic Digraph of Images. AB - For groupwise image registration, graph theoretic methods have been adopted for discovering the manifold of images to be registered so that accurate registration of images to a group center image can be achieved by aligning similar images that are linked by the shortest graph paths. However, the image similarity measures adopted to build a graph of images in the extant methods are essentially pairwise measures, not effective for capturing the groupwise similarity among multiple images. To overcome this problem, we present a groupwise image similarity measure that is built on sparse coding for characterizing image similarity among all input images and build a directed graph (digraph) of images so that similar images are connected by the shortest paths of the digraph. Following the shortest paths determined according to the digraph, images are registered to a group center image in an iterative manner by decomposing a large anatomical deformation field required to register an image to the group center image into a series of small ones between similar images. During the iterative image registration, the digraph of images evolves dynamically at each iteration step to pursue an accurate estimation of the image manifold. Moreover, an adaptive dictionary strategy is adopted in the groupwise image similarity measure to ensure fast convergence of the iterative registration procedure. The proposed method has been validated based on both simulated and real brain images, and experiment results have demonstrated that our method was more effective for learning the manifold of input images and achieved higher registration accuracy than state-of-the-art groupwise image registration methods. PMID- 26585713 TI - Nuclear medicine training in the European Union: 2015 update. PMID- 26585714 TI - Perceived food intolerance and irritable bowel syndrome in a population 3 years after a giardiasis-outbreak: a historical cohort study. AB - BACKGROUND: Studies have shown an increased prevalence of irritable bowel syndrome (IBS) after acute gastroenteritis. Food as a precipitating and perpetuating factor in IBS has gained recent interest, but food intolerance following gastroenteritis is less investigated. The aims of this study were firstly, to compare perceived food intolerance in a group previously exposed to Giardia lamblia with a control group; secondly, to explore the relation with IBS status; and thirdly, to investigate associations with content of fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) in foods reported. METHODS: This is a historical cohort study with mailed questionnaire to 1252 Giardia exposed and a control cohort matched by gender and age. Differences between groups were investigated using bivariate and multivariate analyses. RESULTS: The questionnaire response rate in the exposed group was 65.3 % (817/1252) and in the control group 31.4 % (1128/3598). The adjusted odds ratio (OR) for perceived food intolerance for the exposed group was 2.00 with 95 % confidence interval (CI): 1.65 to 2.42, as compared with the control group. Perceived intolerance for dairy products was the most frequently reported intolerance, with an adjusted OR for the exposed of 1.95 (95 % CI: 1.51 to 2.51). Perceived intolerance for fatty foods, vegetables, fruit, cereals and alcohol was also significantly higher in the exposed group. The groups did not differ in perceived intolerance to spicy foods, coffee or soda. The association between exposure to Giardia infection and perceived food intolerance differed between the IBS group and the no-IBS group, but IBS was not a significant effect modifier for the association. Perceived intolerance for high FODMAP foods (adjusted OR 1.91) and low FODMAP foods (adjusted OR 1.55) was significantly associated with exposure status. CONCLUSION: Exposure to Giardia infection was associated with perceived food intolerance 3 years after giardiasis. IBS status did not alter the association between exposure status and perceived food intolerance. Perceived intolerance to high FODMAP foods and low FODMAP foods were both statistically significantly associated with exposure to Giardia infection. PMID- 26585715 TI - December 2015. PMID- 26585716 TI - Effect of obesity on the effectiveness of hormonal contraceptives. PMID- 26585717 TI - Response to Contraception Letter to the Editor (CONTRACEPTION_2015_94). PMID- 26585718 TI - Factors That Affect Physiologic Tremor and Dexterity During Surgery: A Primer for Neurosurgeons. AB - INTRODUCTION: All individuals have a physiologic tremor that may become more pronounced in periods of stress, stimulant use, or caffeine. There are few publications measuring the effects of these factors on surgeons or trainees and no comprehensive reviews. We sought to review the representative literature. MATERIALS AND METHODS: An exhaustive literature search to identify journal articles evaluating factors that affect surgical tremor or dexterity was performed. RESULTS: Our search identified 34 studies. All included manuscripts are from small, single-center studies and the vast majority evaluated procedural skills on the basis of laparoscopic simulators. Only one study in which the authors evaluated microsurgical procedural performance was identified. CONCLUSIONS: The literature evaluating tremor and its relationship to surgical performance is limited. Surgeons wishing to optimize surgical dexterity may benefit from avoiding caffeine use or fasting before operating and avoiding sleep deprivation or alcohol use the night before procedures. Those surgeons prone to anxiety or stress-related tremor may obtain a benefit from certain beta-blockers. Finally, the use of appropriate surgical ergonomics with hand or wrist steadying may improve surgical tremor and reduce fatigue. PMID- 26585719 TI - Development of Glioblastoma after Treatment of Brain Abscess. AB - OBJECTIVE: Abscess formation within a glioblastoma has been reported rarely. In the few reported cases, after aspiration to treat a presumed abscess, lesions recurred over a short period and, consequently, glioblastoma was recognized. We present a case of a glioblastoma that developed 1.5 years after successful treatment of a brain abscess. A latency of 1.5 years before symptom development seems overly long, even if the glioblastoma was present at the time of the initial brain abscess. Hence, we consider this a possible de novo glioblastoma arising from glial scar tissue. We also discuss possible mechanisms underlying malignant transformation. CASE DESCRIPTION: A 78-year-old man was admitted to our hospital with progressive gait disturbance caused by a brain abscess. Aspiration of the cyst and systematic antibiotic therapy cured the abscess. However, 1.5 years later, the patient presented to our hospital with generalized convulsions due to recurrence of the cystic lesion. He underwent craniotomy for removal of the cystic lesion, which was found to be a glioblastoma rather than a recurrent brain abscess. Glial scar tissue was detected in the cyst wall. CONCLUSIONS: Development of glioblastoma after treatment of a brain abscess is rare; the pathogenesis is open to speculation. Based on the clinical course, the pathologic findings, and comparison with previous reports, de novo glioblastoma arising from glial scar tissue may be the most likely explanation of the current case. If so, to our knowledge, this is the first report of this condition. PMID- 26585720 TI - Re-do Craniotomy for Recurrent Grade IV Glioblastomas: Impact and Outcomes from the National Neuroscience Institute Singapore. AB - AIM: We hypothesize that re-do craniotomy for recurrent grade IV glioblastomas improves survival while preserving outcome in selected patients. METHODS: A retrospective analysis was conducted of 141 patients, from a prospectively collected database from 2004-2014, with grade IV glioblastomas who underwent craniotomy and excision. Sixty-five patients were included in our analysis. Twenty patients underwent re-do craniotomy at recurrence and were compared with 45 patients who received nonsurgical therapy for recurrences. Primary end point was overall survival from time of diagnosis. Demographic and disease factors were analyzed using Cox regression analysis for significance. RESULTS: The median survival for those with re-do craniotomy was 25.4 months compared with 11.6 months (P < 0.001) in the group that underwent nonsurgical therapy. The mean age for this group was 53.5 years. This group had a higher postsurgical/treatment median Karnofsky performance scale (KPS) of 80 compared with 60 (P < 0.001) showing better functional outcome. A Cox regression analysis of factors determined that age, KPS at recurrence, extent of resection at initial surgery and re-do craniotomy were significant for positive outcomes. CONCLUSION: Our results show that in a select group of patients with recurrent grade IV glioblastomas, repeated excision, aiming for gross total resection where safely possible, has significant survival benefit without severely compromising functionality and should be considered. PMID- 26585721 TI - Frameless Stereotactic Robot-Assisted Subthalamic Nucleus Deep Brain Stimulation: Case Report. AB - BACKGROUND: Electrode implantation for deep brain stimulation (DBS) can be performed in numerous ways, but the current "gold standard" is the use of frame based systems for accuracy. Robotic stereotactic procedures, however, have gained increased interest because of their ease of use and reliability, but there could be concern about their safety in the United States as the result of recent lawsuits (e.g., the da Vinci Surgical System). We report the first DBS implantation performed using a robot (ROSA robotic device) approved by Food and Drug Administration for use in North America. CASE DESCRIPTION: A 56-year-old, right-handed woman with a 12-year history of Parkinson disease is described. She was offered bilateral subthalamic nucleus DBS placement to address motor fluctuations and dyskinesias. DBS electrode implantation was implemented successfully with ROSA robotic stereotactic assistance. Using preoperative magnetic resonance imaging scan acquisitions, we targeted the patient's subthalamic nucleus bilaterally. Bone fiducials were placed and intraoperative computed tomography (CT) imaging was obtained. The magnetic resonance imaging and CT were fused, and the patient was registered to the ROSA software. Trajectories were obtained and a microdrive device was fixed to the robotic arm to advance the electrode to the correct location. Electrodes were then placed bilaterally. Intraoperative CT showed good placement with no complications encountered. CONCLUSIONS: The advantages of robotic assistance in stereotactic procedures are as follows: 1) improved accuracy, 2) "arc-less" approach, and 3) minor adjustments can be made in multiple planes to the entry point without adjustment of a frame. The case demonstrates robotic stereotactic assistance viability as an alternative to traditional frame-based or frameless systems in U.S. hospitals. PMID- 26585722 TI - Isolated Oculomotor Nerve Palsy as Presenting Symptom of Bilateral Chronic Subdural Hematomas: Two Consecutive Case Report and Review of the Literature. AB - BACKGROUND: Isolated oculomotor nerve palsy (ONP) is caused most commonly by vascular disease, posterior circulation aneurysms, and inflammatory or traumatic injury. ONP usually occurs in chronic subdural hematoma (CSDH) as a common sign of cerebral herniation that typically is associated with a deterioration of consciousness. CASE DESCRIPTION: We report 2 cases of bilateral CSDH who presented with ONP without deterioration of consciousness. An extensive literature review revealed this is an extremely rare finding. We also investigated all the possible pathogenic mechanisms producing nerve impairment and found a strong association with bilateral subdural hematoma. Vascular compression between posterior circulation arteries and tentorial edge abnormalities also could be involved. Vulnerability of the oculomotor nerve seems to be a necessary condition leading to clinical onset and is caused by predisposing factors to nerve damage, including vascular disease, head trauma, or herpes zoster infection. CONCLUSIONS: Although isolated ONP is a very rare presentation of CSDH, a differential diagnosis is absolutely necessary, because surgical treatment allows good recovery of third nerve palsy in most of the cases. PMID- 26585723 TI - Renaissance Neurosurgery: Italy's Iconic Contributions. AB - Various changes in the sociopolitical milieu of Italy led to the increasing tolerance of the study of cadavers in the late Middle Ages. The efforts of Mondino de Liuzzi (1276-1326) and Guido da Vigevano (1280-1349) led to an explosion of cadaver-centric studies in centers such as Bologna, Florence, and Padua during the Renaissance period. Legendary scientists from this era, including Leonardo Da Vinci, Andreas Vesalius, Bartolomeo Eustachio, and Costanzo Varolio, furthered the study of neuroanatomy. The various texts produced during this period not only helped increase the understanding of neuroanatomy and neurophysiology but also led to the formalization of medical education. With increased understanding came new techniques to address various neurosurgical problems from skull fractures to severed peripheral nerves. The present study aims to review the major developments in Italy during the vibrant Renaissance period that led to major progress in the field of neurosurgery. PMID- 26585724 TI - Pretreatment of Anxiety Before Cervical Spine Surgery Improves Clinical Outcomes: A Prospective, Single-Institution Experience. AB - BACKGROUND: Affective disorders such as depression and anxiety have been shown to contribute to inferior outcomes after spine surgery. A high baseline level of anxiety is associated with refractory postoperative pain and patient dissatisfaction with surgery. The aim of this prospective study is to assess whether the pretreatment of anxiety before spine surgery improves patient reported outcomes 1-year after an anterior cervical discectomy and fusion (ACDF) procedure. METHODS: A total of 27 adult patients with a known history of anxiety disorder (pretreated cohort: 11 patients, control cohort: 16 patients) undergoing ACDF at Duke University Medical Center were included in this study. All patients were diagnosed with an anxiety disorder at least 6 months before surgery by a board-certified psychiatrist. Enrollment criteria included available demographic, surgical, and clinical outcomes data. All patients had prospectively collected patient reported outcomes measures and a minimum 1-year follow-up. Patients completed the Neck Disability Index (NDI), Short-Form 12 (SF-12), and visual analog scale (VAS) before surgery then at 6 weeks, and 3, 6, and 12 months after surgery. Clinical outcomes and complication rates were compared between both patient cohorts. RESULTS: Baseline characteristics were similar between both cohorts. At baseline, there were no significant differences between cohorts in NDI (P = 0.11), SF-12 PCS (P = 0.63), SF-12 MCS (P = 0.90), and VAS neck pain (P = 0.80). There was no nerve root injury or incidental durotomy in either cohort. At 6 months after surgery, patients in the pretreated cohort reported significantly lower postoperative pain compared to the control cohort (P = 0.01). These results were durable through 1 year (P = 0.02). At 1 year, patients who were pretreated for anxiety before surgery reported significantly lower postoperative neck pain scores compared with the control cohort (P = 0.02). CONCLUSION: Our study demonstrates that pretreatment of anxiety before cervical spine surgery results in a significant reduction in postoperative neck pain scores and may be a viable management strategy for patients with coexisting affective disorders and cervical spine pathology. Patients awaiting spine surgery should routinely be assessed for anxiety before surgery, and interventions to reduce and treat anxiety should be provided. PMID- 26585725 TI - Review of the Management of Infected Subdural Hematoma. AB - OBJECTIVE: Infection of a subdural hematoma is an unusual cause of subdural empyema, with fewer than 50 cases reported in the literature. The appropriate surgical option for this entity has not been determined because of its rarity. We present a case report of a post-traumatic subdural hematoma infected with Escherichia coli that was successfully treated with craniotomy. In addition, we performed a PubMed search to comprehensively illustrate the causative organism, source of infection, clinical picture, surgical treatment, and outcome for this condition. This article presents an update on the condition. CASE DESCRIPTION: A 55-year-old man was admitted to our hospital complaining of headache, seizure, and urinary incontinence. He had a history of alcoholism and several hospitalizations for mild head trauma. Neuroimaging studies revealed a chronic hematic collection in the left frontal-parietal region. Laboratory tests showed increased C-reactive protein levels. In addition, surgical results revealed an infected subdural hematoma. A bacterial culture of the purulent specimen identified E. coli. In view of the urinary complaint and leukocyturia, the cause of the infected subdural hematoma was postulated as a urinary tract infection. CONCLUSIONS: Infected subdural hematoma is an unusual disorder. We must keep in mind the possibility of this complication when seeing a patient who presents with any of the 3 most common symptoms in this review. In these patients, craniotomy should be the method of surgical drainage, especially in adults. It ensures maximal drainage of the loculated pus and allows the total removal of the infected hematoma capsule. PMID- 26585726 TI - Neurosurgical Care in the Elderly: Increasing Demands Necessitate Future Healthcare Planning. AB - OBJECTIVES: The worldwide elderly population is steadily increasing. It has been recommended that age-appropriate information should be available for older patients, but little exists in neurosurgery. We aim to better understand the clinical characteristics, bed occupancy and outcomes of elderly patients admitted to a UK neurosurgical unit. METHODS: Retrospective review of medical records of all patients aged 75 years and older admitted for at least 1 night to the Southwest Neurosurgery Centre from 2007 to 2010. Mortality data up to 31 December 2012 were obtained from a national registry. RESULTS: Eight hundred and eighty six elderly patients were admitted, for whom 877 records were available. Three hundred and eighty-nine patients were admitted electively; 488 were emergency or urgent; 48.8% had cranial pathology and 50.7% had spinal disease. Emergency cases were significantly older and more likely to be male than elective patients. The median length of stay for emergency patients was significantly longer than that of elective patients (P < 0.0001, 3 vs. 8 days). One elective patient died as an inpatient, compared with 46 emergency patients. Of emergency and elective patients, 25.6% and 3.6%, respectively, had died by 6 months after discharge. Age and length of stay were not associated with early death. CONCLUSIONS: The demographics and outcomes of the elderly admitted to a UK neurosurgical center are discussed. Differences between elective and emergency groups are attributable to both the pathologic processes and case selection. Neurosurgical treatment should not be denied based on age, however the high risks of emergency surgery in this age group should be acknowledged. PMID- 26585727 TI - Predictors of Outcome in Nontraumatic Spontaneous Acute Spinal Subdural Hematoma: Case Report and Literature Review. AB - OBJECTIVES: To analyze the clinical presentation and outcome of nontraumatic spontaneous acute spinal subdural hematoma by observing the predictors of outcome. METHODS/RESULTS: This study was based on a case report and systematic review of the international literature. Among the 151 patients, 80 were female and 65 were male (1.25 female/1.0 male). The age distribution ranged from 6 months to 87 years, with a small increase in incidence between the first and second decade of life and a major peak at age 60 years. The difference of proportion of good results between patients with and without established neurologic deficits was: 0.488, 95% confidence interval (95% CI) 0.237-0.648, P = 2.71e-08; coagulopathy was 0.335, 95% CI 0.163-0.508, P = 0.0002; SAH was 0.0539, 95% CI -0.119 to 0.226, P = 0.6529; lumbar puncture/associated diseases was 0.149 95% CI -0.032 to 0.330, P = 0.1171; surgery was 0.0593, 95% CI -0.114 to 0.233, P = 0.5838; and hematoma extension equal or longer than 5 levels was 0.010 95% CI 0.178 to 0.197, P = 1. CONCLUSIONS: Although mortality and morbidity associated with nontraumatic spontaneous acute spinal subdural hematoma has decreased during the last 2 decades, the disease still carries a mortality rate of approximately1.3% and a morbidity (permanent neurologic deficits) rate of 28%. The main factors affecting the outcome are neurologic status at presentation and coagulopathies. PMID- 26585728 TI - Comparison of Conventional and Kilohertz Frequency Epidural Stimulation in Patients Undergoing Trialing for Spinal Cord Stimulation: Clinical Considerations. AB - OBJECTIVE: Compare therapeutic response of patients to conventional versus high frequency spinal cord stimulation (SCS). METHODS: Twelve patients with back and leg pain who met standard clinical criteria for a trial of conventional SCS (low frequency stimulation [LFS]) participated in a half-day session of high-frequency stimulation (HFS) during their weeklong conventional trial. HFS consisted of frequencies ranging from 50 Hz to 4 kHz, or 100 Hz to10 kHz, at constant voltage settings increasing from 0.5 V to 10 V. Visual Analog Scale scores from 0 to10 were recorded, along with notes of any clinical discomfort and open patient comments. RESULTS: Two of 12 patients had no benefit from either LFS or HFS. In the remaining 10 patients, paresthesias were significantly altered by HFS, and four experienced complete elimination of paresthesias. Five patients preferred HFS to LFS, with an additional three preferring both equally. Abrupt sensation to the onset of HFS was described in six patients, and in ten patients, HFS allowed maximum voltage stimulation of 10 V without discomfort. The four patients who did not have a successful trial of stimulation had significantly longer duration of pain compared to the eight patients who went on to permanent implant (11.2 vs. 4.3 years, P = 0.04). CONCLUSIONS: HFS significantly altered the feeling of paresthesias in the majority of patients (ten of 12), was preferred to LFS in five of 12 patients, and non-inferior to LFS in eight of 12 patients. Both 4 kHz and 10 kHz stimulation allowed patients to benefit from HFS. HFS allowed maximum voltage stimulation without discomfort. PMID- 26585729 TI - Communicating Hydrocephalus Associated with Intracranial Schwannoma Treated by Gamma Knife Radiosurgery. AB - OBJECTIVE: Gamma knife radiosurgery (GKRS) has been established as an effective and safe treatment for intracranial schwannoma. However, serious complications can occur after GKRS, including hydrocephalus. The pathophysiology and risk factors of this disorder are not yet fully understood. The objective of the study was to assess potential risk factors for hydrocephalus after GKRS. METHODS: We retrospectively reviewed the medical radiosurgical records of 244 patients who underwent GKRS to treat intracranial schwannoma. The following parameters were analyzed as potential risk factors for hydrocephalus after GKRS: age, sex, target volume, irradiation dose, prior tumor resection, treatment technique, and tumor enhancement pattern. The tumor enhancement pattern was divided into 2 groups: group A (homogeneous enhancement) and group B (heterogeneous or rim enhancement). RESULTS: Of the 244 patients, 14 of them (5.7%) developed communicating hydrocephalus. Communicating hydrocephalus occurred within 2 years after GKRS in most patients (92.8%). No significant association was observed between any of the parameters investigated and the development of hydrocephalus, with the exception of tumor enhancement pattern. Group B exhibited a statistically significant difference by univariate analysis (P = 0.002); this difference was also significant by multivariate analysis (P = 0.006). CONCLUSION: Because hydrocephalus is curable, patients should be closely monitored for the development of this disorder after GKRS. In particular, patients with intracranial schwannomas with irregular enhancement patterns or cysts should be meticulously observed. PMID- 26585730 TI - Nuances in Localization and Surgical Treatment of Syringomyelia Associated with Fenestrated and Webbed Intradural Spinal Arachnoid Cyst: A Retrospective Analysis. AB - INTRODUCTION: Intradural spinal arachnoid cysts (SACs) are among many etiologies for syringomyelia. Consequentially, neurologic symptoms arise such as pain, gait disturbance, and bladder dysfunction. Identification of SAC on magnetic resonance imaging (MRI) can be challenging, as SACs can be fenestrated or in the form of fine webs. METHODS: Imaging and clinical data for 7 patients who underwent surgical treatment for SAC associated with syringomyelia were reviewed. All previous publications of this pathology were reviewed via MEDLINE search. RESULTS: Seven patients with a mean age 59 years were found to have a SAC causing syringomyelia. Intraoperative exploration confirmed SAC appearances of fine webs or a fluid-filled loculation impinging on the spinal cord. Common presentations were back pain, gait disturbance, and bladder incontinence. Diagnosis was made by MRI, although in 3 cases, the SAC was not identified on the initial review. Computed tomography myelogram was performed in one case due to the enlarged syringomyelia and lack of obvious spinal cord compression. Thoracic laminectomy/laminoplasty was performed for all patients, centered at the level of a subtle indentation of the cord; the syringomyelia proper was not directly addressed. Postoperatively, all patients had complete resolution of their symptoms with MRI demonstrating resolution of the syringomyelia. CONCLUSIONS: Careful evaluation of the MRI can demonstrate subtle indentation of the cord at the caudal or cephalad end of the syringomyelia and may obviate the need for additional imaging. Meticulous arachnoid dissection and establishment of good CSF flow is sufficient for resolution of the syringomyelia, averting the need for more aggressive procedures. PMID- 26585731 TI - Long Segment Spinal Dural Cyst: A Case Report. AB - BACKGROUND: Spinal meningeal cysts are a rare benign disease that can cause myelopathy. In most cases, spinal meningeal cysts consist of an arachnoid membrane. To the best of our knowledge, few articles have report on intradural spinal meningeal cyst consisting of dura mater. CASE DESCRIPTION: A 58-year-old man presented to our institute with aggravation of clumsy hands and dysesthesia of the feet. Magnetic resonance imaging of the entire spine revealed a cystic lesion compressing the spinal cord posteriorly. Cyst fenestration and placement of the cyst-subarachnoid shunt was performed via an anterior approach. Postoperatively, the histopathologic results revealed that the cyst wall consisted of a dura mater-like membrane. The patient's symptoms resolved without the appearance of any new neurologic deficits. CONCLUSIONS: The etiology of spinal meningeal cysts remains unclear. Spinal meningeal cysts consisting of dura mater (spinal dural cysts) are extremely rare. Treatment with only decompression with laminectomy causes enlargement of the dural cyst later. Cyst fenestration and placement of a cyst-subarachnoid shunt for the spinal dural cyst resulted in the resolution of myelopathy and cyst shrinkage. PMID- 26585732 TI - Flow-Diverting Devices versus Coil Embolization for Intracranial Aneurysms: A Systematic Literature Review and Meta-analysis. AB - OBJECTIVE: To review the literature on flow-diverting device (FDD) treatments for intracranial aneurysms (IAs) and to compare the safety and efficacy of FDDs with coil embolization treatment (CET) for IAs using a meta-analysis of published studies. METHODS: A systematic electronic search was conducted of PubMed, Springer Link, EBSCO, and the Cochrane Database on all accessible published articles through September 2015. Abstracts, full-text manuscripts, and the reference lists of retrieved articles were analyzed. Studies that explicitly compared FDD and CET approaches to the treatment of IAs were included. Odds ratios (ORs) and 95% CIs were calculated for the complete occlusion rate and the morbidity rate using a random-effects model. RESULTS: Nine studies were included in the analysis, containing retrospectively collected data for 863 patients. FDD treatment showed a significantly higher complete occlusion rate than CET (OR = 3.13; 95% confidence interval [CI], 2.11-4.65) and the subgroup of stent-assisted coiling did (OR = 2.08; 95% CI, 1.34-3.24). FDDs did not achieve a significantly lower overall morbidity rate compared with CET (OR = 0.87; 95% CI, 0.45-1.69) or the SAC (stent-assisted coiling) subgroup (OR = 0.86; 95% CI, 0.33-2.26), and our results did not show a significant difference in mortality between the two techniques. CONCLUSIONS: FDD treatment of IAs yielded satisfactory results in complete occlusion rate compared with CET. The FDD procedure is feasible and has no significant difference in morbidity risk. Despite the findings reported herein, further validation with well-designed, multicenter randomized controlled trials is needed. PMID- 26585733 TI - Meningocele and Meningoencephalocele of the Lateral Wall of Sphenoidal Sinus: The Role of the Endoscopic Endonasal Surgery. AB - BACKGROUND: Meningocele and meningoencephalocele of the lateral wall of the sphenoidal sinus (LWSS) are rare lesions, crossing the borders of multiple disciplines such as ear-nose-throat, maxillofacial, and neurologic surgery. We reviewed our surgical experience to analyze the role of the endoscopic endonasal approach and consider these pathologies from different perspectives. METHODS: All consecutive cases of meningocele and meningoencephalocele of LWSS operated through an endoscopic endonasal approach from 1998 to 2015 in our institutions were collected. Medical history, focusing on previous episodes of cerebrospinal fluid leak, meningitis or seizures, was considered. The outcome was assessed considering the medical condition and the postoperative neuroimaging. RESULTS: The series includes 23 patients (7 male, 16 female). Mean age was 52 years (26-73 years). Eleven cases were meningoencephaloceles and 12 meningoceles. A clear cerebrospinal fluid leak occurred on in 19 patients and was associated with meningitis in 3. Two were presenting a history of epilepsy. No complications were observed, but 1 case presented seizures on waking. At follow-up (mean 84 months, 4-167) each patient is in good clinical condition with no further episodes of leaking or seizures. CONCLUSIONS: Endoscopic endonasal surgery is a safe and effective approach for meningocele and meningoencephalocele of LWSS; it allows resection of herniated tissue and repair of the osteodural defect. The favorable clinical outcome and the possible effectiveness on seizures lead us to support this approach as first minimally invasive treatment also in presence of epilepsy, as a first low risk epilepsy surgical procedure. PMID- 26585734 TI - The Current Use of Social Media in Neurosurgery. AB - OBJECTIVE: To measure the presence and popularity of neurosurgical departments, journals, and nonprofit organizations on 3 major social networks. METHODS: A systematic 2-pronged search strategy was used in June 2015 to identify all accounts on Facebook, Twitter, and YouTube that were relevant to neurosurgery. Online search was conducted by 2 independent authors. All accounts were ranked according to their popularity data. RESULTS: Our search yielded 158 social media accounts (86 Facebook, 59 Twitter, and 13 YouTube) of neurosurgical private and academic practice departments. Of the 158 accounts we retrieved, 117 were for private practice centers (74%). Accounts of academic and private departments had a similar median number of "likes" and "followers" on Facebook and Twitter, respectively. Seven neurosurgical journals only had active Facebook and Twitter accounts (of 20 screened journals). When compared with studies of social media in other medical subspecialties, the use of these networks in neurosurgery followed a similar pattern in their presence and popularity. CONCLUSIONS: The current study shows different uses of social media platforms and numbers of users of the online neurosurgical community. Content optimization, advanced metrics of user engagement, and their subsequent effects on academic impact remain unanswered queries and require further prospective study. PMID- 26585735 TI - Ultrasensitive Cytosensor Based on Self-Enhanced Electrochemiluminescent Ruthenium-Silica Composite Nanoparticles for Efficient Drug Screening with Cell Apoptosis Monitoring. AB - The self-enhanced electrochemiluminescence (ECL) with high sensitivity could be an effective method for anticancer drug screening with cell apoptosis monitoring. Here we reported an ultrasensitive ECL cytosensor for cell apoptosis monitoring by using self-enhanced electrochemiluminescent ruthenium-silica composite nanoparticles (Ru-N-SiNPs) labeled annexin V as signal probes. The Ru-N-SiNPs were first synthesized through simple hydrolysis of a novel precursor containing luminescent and intracoreactant groups in one molecule, which presented higher emission efficiency and enhanced ECL intensity due to the shorter electron transfer path and less energy loss. Moreover, the as-proposed ECL cytosensor was successfully used to investigate efficiency of paclitaxel toward MDA-MB-231 breast cancer cell in the range from 1 nM to 200 nM with a detection limit of 0.3 nM and a correlation coefficient of 0.9917. The improved accuracy and excellent dynamic range revealed the potential applications in biomolecules diagnostics and cells detections, especially in living and complex systems. PMID- 26585736 TI - Ultrasound-assisted external fixation: a technique for austere environments. AB - INTRODUCTION: Ultrasound-assisted external fixation of long bones has the potential to enhance extremity damage control surgery in locations without fluoroscopy, such as forward surgical elements, the intensive care unit, and spacecraft. This pre-clinical study specifically sought to evaluate orthopaedic surgeons' ability to sonographically define fracture patterns and the associated zone of injury in order to improve surgical decision-making and safely insert Schanz pin percutaneously. METHODS: We encased small composite femurs in a cylindrical echogenic gelatin matrix to simulate a human thigh. Three orthopaedic trauma surgeons with no prior ultrasound experience were taught to use sonography to diagnose fractures and assist external fixation. The surgeons were then presented with five specimens in a randomized sequence: three diaphyseal fractures (32-A2, 32-C2 and 32-C3); a distal femur fracture (33-A1.2); and an intact femur, all encased in an opaque black gelatin matrix to blind the participants to the underlying pathology. If they diagnosed a diaphyseal fracture, the surgeons were instructed to insert two Schanz pins proximal and two distal to the fracture, no closer than 40 mm from the fracture edges. RESULTS: Fracture diagnosis and surgical decision-making were correct in all cases. All intact femurs were recognized as such. The need for a knee-spanning external fixator was recognized for all distal femur fractures. The three surgeons performed appropriate ultrasound-assisted pin placement in every case of diaphyseal fracture. The pins adjacent to the fracture site were on average 58 mm (SD +/-11 mm) from the edge of the fracture. No pins were inserted in the fracture or in the knee joint. CONCLUSIONS: The current study results suggest that with minimal training, orthopaedic surgeons can use portable ultrasound to diagnose femur fractures, decide the appropriate external fixator configuration, and safely insert Schanz pins outside the zone of injury. PMID- 26585737 TI - Bone beveling caused by blunt trauma: a case report. AB - The authors report a fatal case of blunt trauma to the skull caused by a rib of a beach umbrella. The skull displayed a round hole in the right temporal bone with typical internal beveling. Blunt trauma mimicking a gunshot wound (round perforation of the skull with internal beveling) is very rarely reported in the forensic literature. PMID- 26585740 TI - A Cable-Shaped Lithium Sulfur Battery. AB - A carbon nanostructured hybrid fiber is developed by integrating mesoporous carbon and graphene oxide into aligned carbon nanotubes. This hybrid fiber is used as a 1D cathode to fabricate a new cable-shaped lithium-sulfur battery. The fiber cathode exhibits a decent specific capacity and lifespan, which makes the cable-shaped lithium-sulfur battery rank far ahead of other fiber-shaped batteries. PMID- 26585738 TI - Identification of rare variants of DSP gene in sudden unexplained nocturnal death syndrome in the southern Chinese Han population. AB - Sudden unexplained nocturnal death syndrome (SUNDS) is a perplexing disorder to both forensic pathologists and clinic physicians. Desmoplakin (DSP) gene was the first desmosomal gene linked to arrhythmogenic right ventricular cardiomyopathy (ARVC) which was associated with sudden death. To identify the genetic variants of the DSP gene in SUNDS in the southern Chinese Han population, we genetically screened the DSP gene in 40 sporadic SUNDS victims, 16 Brugada syndrome (BrS) patients, and 2 early repolarization syndrome (ERS) patients using next generation sequencing (NSG) and direct Sanger sequencing. A total of 10 genetic variants of the DSP gene were detected in 11 cases, comprised of two novel missense mutations (p.I125F and p.D521A) and eight previously reported rare variants. Of eight reported variants, two were previously considered pathogenic (p.Q90R and p.R2639Q), three were predicted in silico to be pathogenic (p.R315C, p.E1357D and p.D2579H), and the rest three were predicted to be benign (p.N1234S, p.R1308Q, and p.T2267S). This is the first report of DSP genetic screening in Chinese SUNDS and Brugada syndrome. Our results imply that DSP mutations contribute to the genetic cause of some SUNDS victims and maybe a new susceptible gene for Brugada syndrome. PMID- 26585741 TI - [Congenital radio-ulnar synostosis]. PMID- 26585742 TI - Risk assessment and management of high and intermediate risk pulmonary embolism. PMID- 26585743 TI - Diagnosis of pulmonary embolism. AB - Pulmonary embolism is the third cause of mortality by cardiovascular disease after coronary artery disease and stroke, and its incidence is around 1/1000 per year. During the last two decades, many different non-invasive diagnostic tests have been developed and validated. For hemodynamically stable outpatients, the diagnosis of acute pulmonary embolism mainly rests on the sequential use of clinical assessment, D-dimer measurement and multidetector CT. In patients with a contraindication to CT, lower limb venous ultrasonography and ventilation perfusion scintigraphy remain valid options. Massive pulmonary embolism is a distinct clinical entity with a specific diagnostic approach. In unstable patients with suspected pulmonary embolism, echocardiography should be the initial test. PMID- 26585744 TI - [Benefits and risks for primary prevention with statins in the elderly]. AB - CONTEXT: Statins in primary prevention before 75 years old reduce cardiovascular events from 20 to 30% and mortality from 10% with acceptable side effects. We investigated whether these results persisted for patients aged 75 and older taking statin. METHOD: Methodic review of large randomized clinical trials and meta-analyzes that included patients 75 years and older treated with statins in primary prevention. RESULTS: Since the 1990s, a score of randomized controlled trials studying statins versus placebo in primary prevention were published and studied in meta-analyses. Exclusion criteria, including persons older than 70 years, are often restrictive. The impact on all-cause mortality in the four main studies and meta-analyses in over 75 years has not been demonstrated. On the other hand, a recent meta-analyses of observational studies including subjects between 70 and 89 years treated with statins found that low total cholesterol was associated with a moderate decrease in cardiovascular mortality, with no decrease in all-cause mortality. Moreover, in a common context of comorbidities in this age group, statins may be responsible for many adverse effects, drug interactions and impaired quality of life. CONCLUSION: Given the lack of formal evidence of effectiveness in terms of all-cause mortality and a high level of adverse effects, the benefit/risk of primary prevention with statins is not established in the elderly. The economic weight of statin prescriptions and their possible impact on quality of life justify an economic analysis of discontinuing statin therapy for people 75 years and older. PMID- 26585745 TI - [Giant cell arteritis and unexplained hypoxemia]. PMID- 26585746 TI - [Acute necrotizing pancreatitis secondary to post-traumatic fat embolism "a case report"]. PMID- 26585747 TI - A Stochastic Model for the Interbreeding of Two Populations Continuously Sharing the Same Habitat. AB - We propose and solve a stochastic mathematical model of general applicability to interbreeding populations which share the same habitat. Resources are limited so that the total population size is fixed by environmental factors. Interbreeding occurs during all the time of coexistence until one of the two population disappears by a random fluctuation. None of the two populations has a selective advantage. We answer the following questions: How long the two populations coexist and how genetically similar they become before the extinction of one of the two? how much the genetic makeup of the surviving population changes by the contribution of the disappearing one? what it is the number of interbreeding events given the observed introgression of genetic material? The model was originally motivated by a paleoanthropological problem concerning the interbreeding of Neanderthals and African modern humans in Middle East which is responsible for the fraction of Neanderthal genes (1-4%) in present Eurasian population. PMID- 26585748 TI - The Potential Impact of Vaccination on the Dynamics of Dengue Infections. AB - Dengue, classified as a 'neglected topical disease', is currently regarded globally as the most important mosquito-borne viral disease, which inflicts substantial socioeconomic and health burden in many tropical and subtropical regions of the world. While efforts continue towards developing and improving the efficacy of a tetravalent vaccine to protect individuals against all dengue virus serotypes, the long-term epidemiological impact of vaccination remains elusive. We develop a serotype-specific, vector-host compartmental model to evaluate the effect of vaccination in the presence of antibody-dependent enhancement and cross protection following recovery from primary infection. Reproducing the reported multi-annual patterns of dengue infection, our model projects that vaccination can dramatically reduce the overall incidence of the disease. However, if the duration of vaccine-induced protection is shorter than the average lifetime of the human population, vaccination can potentially increase the incidence of severe infection of dengue haemorrhagic fever due to the effects of antibody dependent enhancement. The magnitude and timelines for this increase depend strongly on the efficacy and duration of the vaccine-induced protection. Corresponding to the current estimates of vaccine efficacy, we show that dengue eradication is infeasible using an imperfect vaccine. Furthermore, for a vaccine that induces lifetime protection, a nearly full coverage of infant vaccination is required for dengue elimination. Our findings suggest that other vector control measures may still play a significant role in dengue prevention even when a vaccine with high protection efficacy becomes available. PMID- 26585749 TI - Are changes in the extent of left ventricular dyssynchrony as assessed by speckle tracking associated with response to cardiac resynchronization therapy? AB - Echocardiographic assessment of left ventricular (LV) dyssynchrony is used to predict response to cardiac resynchronization therapy (CRT). However, the association between reduction in the extent of speckle tracking based LV dyssynchrony and echocardiographic response to CRT has not been explored yet. The aim of this study was to assess the changes in the extent of LV dyssynchrony as a result of CRT and its association with echocardiographic response to CRT in a large consecutive series of patients. We studied 138 patients with standard CRT indication. Time-based speckle tracking longitudinal strain (maximal delay between 6-segments in 4-chamber view) was performed to assess LV-dyssynchrony at baseline and after a mean follow-up of 22 +/- 8 months. Echocardiographic CRT response was defined as a reduction in LV end-systolic volume >=15 %. Mean age was 68 +/- 8 years (30 % female). Mean LV ejection fraction (LVEF) was 26 +/- 7 %. Ninety six patients (70 %) were classified as echocardiographic responders. In the total study group, LV-dyssynchrony decreased from 196 +/- 89 ms at baseline to 180 +/- 105 ms during follow-up, P = 0.01. Of note, in responders there was a pronounced reduction in LV dyssynchrony (198 +/- 88 ms at baseline vs 154 +/- 50 ms after CRT, P < 0.001), whereas in non-responders there was a significant increase (191 +/- 92 ms at baseline vs 243 +/- 160 ms after CRT, P = 0.04). After multivariate analysis, decreased in LV-dyssynchrony, wider QRS duration and non ischemic etiology were independently and significantly associated with CRT response. Changes in the extent of LV dyssynchrony as measured by speckle tracking after CRT are independently associated with response to CRT. PMID- 26585750 TI - Epicardial fat thickness: distribution and association with diabetes mellitus, hypertension and the metabolic syndrome in the ELSA-Brasil study. AB - Epicardial fat thickness (EFT) has emerged as a marker of cardiometabolic risk, but its clinical use warrants proper knowledge of its distribution and associations in populations. We aimed to describe the distribution of EFT, its demographic correlates and independent associations with diabetes, hypertension and metabolic syndrome (MS) in free-living Brazilian adults. From the baseline echocardiography of the Brazilian Longitudinal Study of Adult Health (ELSA Brasil)-a cohort study of civil servants aged 35-74 years-EFT was measured from a randomly selected sample of 998 participants as the mean of two paraesternal windows obtained at end systole (EFTsyst) and end diastole (EFTdiast). From the 421 individuals free of diabetes, hypertension and MS, we defined EFT reference values and the EFTsyst 75th percentile cut-off. Median EFTsyst was 1.5 (IQR 0 2.6) mm; a large proportion (84 %) had EFTdiast = 0. EFT was higher in women and lower in blacks, and increased with age and BMI. Although EFT was higher in those with diabetes, hypertension, and MS, EFT associations were reduced when adjusted for age, sex and ethnicity, and were non-significant after adjusting for obesity measures. In conclusion, the amount of EFT in this large multiethnic population is smaller than reported in other populations. EFT reference values varied across demographic and clinical variables, EFT associations with cardiometabolic variables being largely explained by age, sex, ethnicity and central obesity. Although EFT can help identify individuals at increased cardiometabolic risk, it will likely have a limited additional role compared to current risk stratification strategies. PMID- 26585751 TI - Reproducibility of serial optical coherence tomography measurements for lumen area and plaque components in humans (The CLI-VAR [Centro per la Lotta Contro l'Infarto-variability] II study). AB - Frequency-domain optical coherence tomography (FD-OCT) is a promising intracoronary imaging technique to study atherosclerosis. Indeed, its unprecedented spatial resolution allows the assessment of fibrous cap thickness, lipid pool and features of plaque vulnerability. Aim of this study was to determine the reproducibility of the in vivo FD-OCT measurements of lumen area and plaque components in serial studies. Twenty-six patients undergoing FD-OCT assessment of intermediate lesion during coronary angiography were included in this study. FD-OCT pullbacks were acquired twice from the same coronary segment at interval of 5 min without additional intervention and analyzed off-line at an independent imaging core laboratory. Lumen diameter (LD), lumen area (LA), fibrous cap (FC) thickness and lipid pool (LP) arc extension measurements were compared in 440 matched frames. Both the per-segment and per-frame analyses showed excellent correlation coefficients for the inter-pullback comparisons for all parameters explored (R > 0.95 and p < 0.001 in all cases). Accordingly, the Bland-Altman estimates of bias showed non-significant differences in the inter pullback comparisons at all levels. Per-frame analysis showed a slightly variations of LA in 45.8% of cases with changes greater than 2% likely related to different phases of cardiac cycle. Nevertheless, nor FC thickness or circumferential arc of LP were affected by LA changes during serial FD-OCT acquisition. This study showed an excellent reproducibility of lumen and plaque component measurements obtained with FD-OCT in vivo. Thus, this intracoronary imaging technique could be used to assess atherosclerosis progression and describe accurate plaque evolution in repeated serial studies. PMID- 26585752 TI - Urinary metallomics as a novel biomarker discovery platform: Breast cancer as a case study. AB - BACKGROUND: Urinary metallomics is presented here as a new "omics" approach that aims to facilitate personalized cancer screening and prevention by improving our understanding of urinary metals in disease. METHODS: Twenty-two urinary metals were examined with inductively-coupled plasma-mass spectrometry in 138 women newly diagnosed with breast cancer and benign conditions. Urinary metals from spot urine samples were adjusted to renal dilution using urine specific gravity. RESULTS: Two urinary metals, copper (P-value=0.036) and lead (P-value=0.003), were significantly increased in the urine of breast cancer patients. A multivariate model that comprised copper, lead, and patient age afforded encouraging discriminatory power (AUC: 0.728, P-value<0.0005), while univariate models of copper (61.7% sensitivity, 50.0% specificity) and lead (76.6% sensitivity, 51.2% specificity) at optimized cutoff thresholds compared favorably with other breast cancer diagnostic modalities such as mammography. Correlations found among various metals suggested potential geographic and dietary influences on the urine metallome that warrant further investigation. CONCLUSIONS: This proof-of-concept work introduces urinary metallomics as a noninvasive, potentially transformative "omics" approach to early cancer detection. Urinary copper and lead have also been preliminarily identified as potential breast cancer biomarkers. PMID- 26585753 TI - Method evaluation of pepsinogen I/II assay based on chemiluminescent immunoassays and comparison with other test methods. AB - BACKGROUND: Serum pepsinogen (PG) I and the PG I/PG II ratio have been used for atrophic gastritis (AG) diagnosis for decades. Low levels of PG I and/or PG I/PG II are closely related to AG and predict the risk of gastric cancer. We evaluated the performance of the chemiluminescent immunoassay-based Architect Pepsinogen I/II assay. METHODS: The evaluation consisted of determination of the precision, linearity, limit of blank (LoB), limit of detection (LoD) and method comparison with Eiken and Biohit assays. RESULTS: The total CVs were below 5% for both PG I and PG II. Acceptable linearity was observed for PG I and PG II in their respective reportable ranges. The PG I LoB was 0.317ng/mL and the PG II LoB was 0.418ng/mL, and LoDs were 0.412ng/mL and 0.497ng/mL, respectively. Correlation analysis indicated that results of the Architect assay were comparable to those of the Eiken and Biohit assays, but the three methods lead to different estimations of the cancer risk. CONCLUSION: The overall analytical performance of Architect Pepsinogen I/II assay is acceptable for the detection of patients with suspected AG. The categorization results of gastric cancer risk showed some difference among test methods suggesting the need for harmonization among the methods from vendors. PMID- 26585754 TI - Rapid quantitative analysis of human serum sphingomyelin species using MALDI-TOF mass spectrometry with lipid hydrolase treatment. AB - BACKGROUND: Sphingomyelin (SM) is a key component of extracellular membranes and lipoproteins, and plays roles in cell signaling and as a component of lipoproteins. SM species differ in terms of fatty acid (FA) composition. However, no simple, rapid, quantitative assay for identifying different SM species has yet been reported. In this study, lipid hydrolase treatment and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) were used to identify serum SM species. METHODS: Sera were collected from healthy young individuals. To identify SM species, sera were treated with phospholipase A2 and lipoprotein lipase, and lipids were extracted using the standard chloroform/methanol (2/1 v/v) method. RESULTS: We detected 15 peaks from serum using MALDI-TOF MS, which were assigned to SM species bound with FA components ranging from C15:0 to C24:2. The most prominent serum SM species was SM [C16:0], which accounted for approximately 26% of serum SM. Some SM species contained an odd-carbon FA (C15, C21, and C23), and these accounted for approximately 4% of serum SM. The reproducibility of major SM species within and between application positions on MS-sample plate was CV=3.0%-7.9% and CV=3.1%-6.8%, respectively. The concentration and dilution ratio were linearly related. The SM species composition of 10 healthy young subjects showed a similar profile. CONCLUSIONS: We developed a rapid, and quantitative method for identifying serum SM species using lipid hydrolase treatment and MALDI-TOF MS. This method will be suitable for clinical laboratory studies to examine the associations between SM species and disease states. PMID- 26585755 TI - Stimuli-Responsive Reversible Fluorescence Switching in a Crystalline Donor Acceptor Mixture Film: Mixed Stack Charge-Transfer Emission versus Segregated Stack Monomer Emission. AB - We report on a molecularly tailored 1:1 donor-acceptor (D-A) charge-transfer (CT) cocrystal that manifests strongly red-shifted CT luminescence characteristics, as well as noteworthy reconfigurable self-assembling behaviors. A loosely packed molecular organization is obtained as a consequence of the noncentrosymmetric chemical structure of molecule A1, which gives rise to considerable free volume and weak intermolecular interactions. The stacking features of the CT complex result in an external stimuli-responsive molecular stacking reorganization between the mixed and demixed phases of the D-A pair. Accordingly, high-contrast fluorescence switching (red<->blue) is realized on the basis of the strong alternation of the electronic properties between the mixed and demixed phases. A combination of structural, spectroscopic, and computational studies reveal the underlying mechanism of this stimuli-responsive behavior. PMID- 26585756 TI - Covariance estimators for generalized estimating equations (GEE) in longitudinal analysis with small samples. AB - Generalized estimating equations (GEE) is a general statistical method to fit marginal models for longitudinal data in biomedical studies. The variance covariance matrix of the regression parameter coefficients is usually estimated by a robust "sandwich" variance estimator, which does not perform satisfactorily when the sample size is small. To reduce the downward bias and improve the efficiency, several modified variance estimators have been proposed for bias correction or efficiency improvement. In this paper, we provide a comprehensive review on recent developments of modified variance estimators and compare their small-sample performance theoretically and numerically through simulation and real data examples. In particular, Wald tests and t-tests based on different variance estimators are used for hypothesis testing, and the guideline on appropriate sample sizes for each estimator is provided for preserving type I error in general cases based on numerical results. Moreover, we develop a user friendly R package "geesmv" incorporating all of these variance estimators for public usage in practice. PMID- 26585759 TI - A 10-year restrospective evaluation of ultrasound in pregnant abdominal trauma patients. AB - The pregnant abdominal trauma patient presents a unique diagnostic challenge. This study aimed to evaluate the accuracy of abdominal sonography for the detection of clinically important injuries in pregnant abdominal trauma patients. A retrospective review was performed of a trauma center database from 2001 to 2011. Medical records were reviewed to determine initial abdominal imaging test results and clinical course. Sensitivity, specificity, positive predictive value, and negative predictive value of ultrasound for detection of traumatic injury were calculated. Of 19,128 patients with suspected abdominal trauma, 385 (2 %) were pregnant. Of these, 372 (97 %) received ultrasound as the initial abdominal imaging test. All 13 pregnant patients who did not receive ultrasound received abdominal CT. Seven pregnant patients underwent both ultrasound and CT. Seven ultrasound examinations were positive, leading to one therapeutic Cesarean section and one laparotomy. One ultrasound was considered false positive (no injury was seen on subsequent CT). There were 365 negative ultrasound examinations. Of these, 364 were true negative (no abdominal injury subsequently found). One ultrasound was considered false negative (a large fetal subchorionic hemorrhage seen on subsequent dedicated obstetrical ultrasound). Sensitivity and positive predictive value were 85.7 %. Specificity and negative predictive value were 99.7 %. Abdominal sonography is an effective and sufficient imaging examination in pregnant abdominal trauma patients. When performed as part of the initial assessment using an abbreviated trauma protocol with brief modifications for pregnancy, ultrasound minimizes diagnostic delay, obviates radiation risk, and provides high sensitivity for injury in the pregnant population. PMID- 26585760 TI - Residual pulmonary obstruction and the risk of late complications in patients with pulmonary embolism. PMID- 26585761 TI - Thrombophilia testing in young patients with ischemic stroke. AB - INTRODUCTION: The possible significance of thrombophilia in ischemic stroke remains controversial. We aimed to study inherited and acquired thrombophilias as risk factors for ischemic stroke, transient ischemic attack (TIA) and amaurosis fugax in young patients. MATERIALS AND METHODS: We included patients aged 18 to 50 years with ischemic stroke, TIA or amaurosis fugax referred to thrombophilia investigation at Aarhus University Hospital, Denmark from 1 January 2004 to 31 December 2012 (N=685). Clinical information was obtained from the Danish Stroke Registry and medical records. Thrombophilia investigation results were obtained from the laboratory information system. Absolute thrombophilia prevalences and associated odds ratios (OR) with 95% confidence intervals (95% CI) were reported for ischemic stroke (N=377) and TIA or amaurosis fugax (N=308). Thrombophilia prevalences for the general population were obtained from published data. RESULTS: No strong associations were found between thrombophilia and ischemic stroke, but patients with persistent presence of lupus anticoagulant (3%) had an OR at 2.66 (95% CI 0.84-9.15) for ischemic stroke. A significantly higher risk of TIA/amaurosis fugax was found for factor V Leiden heterozygote (12%) (OR: 1.99 (95% CI 1.14-3.28)). No other inherited or acquired thrombophilia was associated with ischemic stroke, TIA or amaurosis fugax. CONCLUSIONS: In young patients, thrombophilia did not infer an increased risk of ischemic stroke. Only factor V Leiden heterozygote patients had an increased risk of TIA/amaurosis fugax, and persistent presence of lupus anticoagulant was likely associated with ischemic stroke. We suggest the testing restricted to investigation of persistent presence of lupus anticoagulant. PMID- 26585762 TI - Assessment of algorithms to identify patients with thrombophilia following venous thromboembolism. AB - INTRODUCTION: Routine testing for thrombophilia following venous thromboembolism (VTE) is controversial. The use of large datasets to study the clinical impact of thrombophilia testing on patterns of care and patient outcomes may enable more efficient analysis of this practice in a wide range of settings. We set out to examine how accurately algorithms using International Classification of Diseases 9th Revision (ICD-9) codes and/or pharmacy data reflect laboratory-confirmed thrombophilia diagnoses. MATERIALS AND METHODS: A random sample of adult Kaiser Permanente Colorado patients diagnosed with unprovoked VTE between 1/2004 and 12/2010 underwent medical record abstraction of thrombophilia test results. Algorithms using "ICD-9" (positive if a thrombophilia ICD-9 code was present), "Extended anticoagulation (AC)" (positive if AC therapy duration was >6 months), and "ICD-9 & Extended AC" (positive for both) criteria to identify possible thrombophilia cases were tested. Using positive thrombophilia laboratory results as the gold standard, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value of each algorithm were calculated, along with 95% confidence intervals (CIs). RESULTS: In our cohort of 636 patients, sensitivities were low (<50%) for each algorithm. "ICD-9" yielded the highest PPV (41.5%, 95% CI 26.3-57.9%) and a high specificity (95.9%, 95% CI 94.0-97.4%). "Extended AC" had the highest sensitivity but lowest specificity, and "ICD-9 & Extended AC" had the highest specificity but lowest sensitivity. CONCLUSIONS: ICD 9 codes for thrombophilia are highly specific for laboratory-confirmed cases, but all algorithms had low sensitivities. Further development of methods to identify thrombophilia patients in large datasets is warranted. PMID- 26585764 TI - Combined flame and solution synthesis of nanoscale tungsten-oxide and zinc/tin oxide heterostructures. AB - Heterostructures of tungsten-oxide nanowires decorated with zinc/tin-oxide nanostructures are synthesized via a combined flame and solution synthesis approach. Vertically well-aligned tungsten-oxide nanowires are grown on a tungsten substrate by a flame synthesis method. Here, tetragonal WO(2.9) nanowires (diameters of 20-50 nm, lengths >10 MUm, and coverage density of 10(9) 10(10) cm(-2)) are produced by the vapor-solid mechanism at 1720 K. Various kinds of Zn/Sn-oxide nanostructures are grown or deposited on the WO(2.9) nanowires by adjusting the Sn(2+) : Zn(2+) molar ratio in an aqueous ethylenediamine solution at 65 degrees C. With WO(2.9) nanowires serving as the base structures, sequential growth or deposition on them of hexagonal ZnO nanoplates, Zn(2)SnO(4) nanocubes, and SnO(2) nanoparticles are attained for Sn(2+) : Zn(2+) ratios of 0 : 1, 1 : 10, and 10 : 1, respectively, along with different saturation conditions. High-resolution transmission electron microscopy of the interfaces at the nanoheterojunctions shows abrupt interfaces for ZnO/WO(2.9) and Zn(2)SnO(4)/WO(2.9), despite lattice mismatches of >20%. PMID- 26585763 TI - Revisiting the mechanistic basis of the French Paradox: Red wine inhibits the activity of protein disulfide isomerase in vitro. AB - INTRODUCTION: Although epidemiologic evidence points to cardioprotective activity of red wine, the mechanistic basis for antithrombotic activity has not been established. Quercetin and related flavonoids are present in high concentrations in red but not white wine. Quercetin-glycosides were recently shown to prevent thrombosis in animal models through the inhibition of extracellular protein disulfide isomerase (PDI). We evaluated whether red or white wine inhibited PDI activity in vitro. METHODS: Quercetin levels in red and white wines were measured by HPLC analysis. Inhibition of PDI activity by red and white wines was assessed by an insulin reduction turbidity assay at various concentrations of wine. PDI inhibition was confirmed using a reduced peptide that contained a disulfide containing peptide as a substrate. The inhibition of PDI related thiol isomerases ERp5 and ERp57 was also assessed. RESULTS: We observed a dose-dependent decrease of PDI activity for a variety of red but not white wines. Red wine diluted to 3% final concentration resulted in over 80% inhibition of PDI activity by insulin reductase assay for all varieties tested. This inhibition was also observed in the peptide based assay. Red grape juice yielded similar results but ethanol alone did not affect PDI activity. Interestingly, red wine also inhibited the PDI related thiol isomerases ERp5 and ERp57, albeit to a lesser degree than PDI. CONCLUSIONS: PDI activity is inhibited by red wine and grape juice, identifying a potentially novel mechanism underlying the cardiovascular benefits attributed to wine consumption. PMID- 26585765 TI - Socioeconomic disparities in breast cancer incidence and survival among parous women: findings from a population-based cohort, 1964-2008. AB - BACKGROUND: Socioeconomic position (SEP) has been associated with breast cancer incidence and survival. We examined the associations between two socioeconomic indicators and long-term breast cancer incidence and survival in a population based cohort of parous women. METHODS: Residents of Jerusalem who gave birth between 1964-1976 (n = 40,586) were linked to the Israel Cancer Registry and Israel Population Registry to determine breast cancer incidence and vital status through mid-2008. SEP was assessed by husband's occupation and the woman's education. We used log ranks tests to compare incidence and survival curves by SEP, and Cox proportional hazard models to adjust for demographic, reproductive and diagnostic factors and assess effect modification by ethnic origin. RESULTS: In multivariable models, women of high SEP had a greater risk of breast cancer compared to women of low SEP (Occupation: HR 1.18, 95 % CI 1.03-1.35; Education: HR 1.39, 95 % CI 1.21-1.60) and women of low SEP had a greater risk of mortality after a breast cancer diagnosis (Occupation: HR 1.33, 95 % CI 1.04-1.70; Education: HR 1.37, 95 % CI 1.06-1.76). The association between education and survival was modified by ethnic origin, with a gradient effect observed only among women of European origin. Women of Asian, North African and Israeli origin showed no such trend. CONCLUSIONS: SEP was associated with long-term breast cancer incidence and survival among Israeli Jews. Education had a stronger effect on breast cancer outcomes than occupation, suggesting that a behavioral mechanism may underlie disparities. More research is needed to explain the difference in the effect of education on survival among European women compared to women of other ethnicities. PMID- 26585767 TI - Rethinking general anesthesia for cesarean section. AB - In this review, we describe the current consensus surrounding general anesthetic management for cesarean section. For induction of anesthesia, rapid-sequence induction using thiopental and suxamethonium has been the recommended standard for a long time. In recent years, induction of anesthesia using propofol, rocuronium, and remifentanil have been gaining popularity. To prevent aspiration pneumonia, a prolonged preoperative fasting and an application of cricoid pressure during induction of anesthesia have been recommended, but these practices may require revision. Guidelines for difficult airway management were developed first in obstetric anesthesia, and the use of a supraglottic airway is now recognized as an effective rescue device. After the delivery of a fetus, switching from volatile anesthetics to intravenous anesthetics has been recommended to avoid uterine atony. At the same time, intraoperative awareness should be avoided. The rate of persistent wound pain is higher when only general anesthesia was used during cesarean section than with regional anesthesia, and thus it is necessary to provide a sufficient postoperative analgesia using multimodal analgesia, including intravenous patient-controlled analgesia (IV PCA), transversus abdominis plane (TAP) block, non-steroidal inflammatory drugs, and acetaminophen. PMID- 26585769 TI - Pedagogy and the Art of Death: Reparative Readings of Death and Dying in Margaret Edson's Wit. AB - Wit explores modes of reading representations of death and dying, both through the play's sustained engagement with Donne's Holy Sonnets and through Vivian's self-reflexive approach to her illness and death. I argue that the play dramatizes reparative readings, a term coined by Eve Kosofsky Sedgwick to describe an alternative to the paranoid reading practices that have come to dominate literary criticism. By analyzing the play's reparative readings of death and dying (as well as its representation of the shortcomings of paranoid readings), I show how Wit provides lessons about knowledge-making and reading practices in the field of health humanities. PMID- 26585768 TI - Clinical usefulness of urinary liver-type fatty-acid-binding protein as a perioperative marker of acute kidney injury in patients undergoing endovascular or open-abdominal aortic aneurysm repair. AB - PURPOSE: Acute kidney injury (AKI) is common after cardiovascular surgery and is usually diagnosed on the basis of the serum creatinine (SCr) level and urinary output. However, SCr is of low sensitivity in patients with poor renal function. Because urinary liver-type fatty-acid-binding protein (L-FABP) reflects renal tubular injury, we evaluated whether perioperative changes in urinary L-FABP predict AKI in the context of abdominal aortic repair. METHODS: Study participants were 95 patients who underwent endovascular abdominal aortic aneurysm repair (EVAR) and 42 who underwent open repair. We obtained urine samples before surgery, after anesthesia induction, upon stent placement, before aortic cross-clamping (AXC), 1 and 2 h after AXC, at the end of surgery, 4 h after surgery, and on postoperative days (PODs) 1, 2, and 3, for measurement of L FABP. We obtained serum samples before surgery, immediately after surgery, and on PODs 1, 2, and 3, for measurement of SCr. We also plotted receiver-operating characteristic (ROC) curves to identify cutoff laboratory values for predicting the onset of AKI. RESULTS: With EVAR, urinary L-FABP was significantly increased 4 h after the procedure (P = 0.014). With open repair, urinary L-FABP increased significantly to its maximum by 2 h after AXC (P = 0.007). With AKI, SCr significantly increased (P < 0.001, P = 0.001) by POD 2. ROC analysis showed urinary L-FABP to be more sensitive than SCr for early detection of AKI. CONCLUSION: Urinary L-FABP appears to be a sensitive biomarker of AKI in patients undergoing abdominal aortic repair. PMID- 26585770 TI - Meanwhile. PMID- 26585771 TI - Identification, structural characterization and transformations of the high temperature Zn9-deltaSb7 phase in the Zn-Sb system. AB - The Zn9-deltaSb7 phase has been identified via high-temperature powder diffraction studies. Zn9-deltaSb7 adopts two modifications: an alpha form stable between 514 degrees C and 539 degrees C and a Zn-poorer beta form stable from 539 degrees C till its melting temperature of 581 degrees C. The Zn9-deltaSb7 structure was solved from the powder data using the simulated annealing approach. Both modifications adopt the same hexagonal structure (P6/mmm) but with slightly different lattice parameters. The alpha-to-beta transformation is abrupt and first-order in nature. The Zn atoms occupy the tetrahedral holes created by Sb atoms. The ideal Zn9Sb7 composition can be explained by its tendency to adopt a charge balance configuration. Out of 7 Sb atoms, 3 Sb atoms form dimers (Sb(2-) ions) and 4 Sb atoms are isolated (Sb(3-) ions), which require 9 Zn(2+) cations for charge neutrality. PMID- 26585772 TI - Microlunatus endophyticus sp. nov., an endophytic actinobacterium isolated from bark of Bruguiera sexangula. AB - A Gram-stain-positive, aerobic, coccoid, non-motile, non-spore-forming bacterium, designated strain S3Af-1T, was isolated from surface-sterilized bark of Bruguiera sexangula collected from Dongzhaigang National Nature Reserve in Hainan, China, and examined using a polyphasic approach to clarify its taxonomic position. This bacterium did not produce substrate mycelia or aerial hyphae, and no diffusible pigments were observed on the media tested. Strain S3Af-1T grew optimally without NaCl, at 28-30 degrees C and at pH 7.0.Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain S3Af-1T belonged to the genus Microlunatus and shared highest similarity with 'Microlunatus terrae' BS6 (97.43 %) and Microlunatus soli CC-12602T (97.08 %). DNA-DNA hybridization results indicated that the level of relatedness between strain S3Af-1T and M. soli CC-12602T was less than 70 %. The DNA G+C content of strain S3Af-1T was 67.1 mol%. The cell wall peptidoglycan contained ll-2,6-diaminopimelic acid. MK-9(H6) and MK-9(H4) were the predominant menaquinones. Phosphatidylglycerol, diphosphatidylglycerol, an unidentified glycolipid, two unidentified phospholipids and other lipids were detected in the polar lipid extracts. The major fatty acids were iso-C16 : 0, anteiso-C17 : 0 and anteiso-C15 : 0. On the basis of phylogenetic analysis, and phenotypic and chemotaxonomic characteristics, strain S3Af-1T represents a novel species of the genus Microlunatus, for which the name Microlunatus endophyticus sp. nov. is proposed. The type strain is S3Af-1T ( = DSM 100019T = CGMCC 4.7306T). PMID- 26585773 TI - Intrahepatic hepatitis B virus replication and liver histology in subjects with occult hepatitis B infection. AB - We studied the intrahepatic hepatitis B virus (HBV) replicative status in 40 people with occult hepatitis B infection (OBI) and 40 patients with chronic hepatitis B (CHB). Intrahepatic HBV DNA, covalently closed circular DNA (cccDNA), and pre-genomic RNA (pgRNA) were quantified. Patients with OBI had median necroinflammation and fibrosis scores of 1 and 0, respectively. Intrahepatic total HBV DNA, cccDNA and pgRNA were detectable in 30 (77%), one (3%) and five (13%) of the participants with OBI, respectively. People with OBI had lower median intrahepatic total HBV DNA than the patients with CHB (p < 0.0001). They had nearly normal liver histology and low intrahepatic HBV replication. PMID- 26585774 TI - Similar virus spectra and seasonality in paediatric patients with acute respiratory disease, Ghana and Germany. AB - Epidemiological differences between tropical and temperate regions regarding viruses causing acute respiratory infection are poorly understood. This is in part because methodological differences limit the comparability of data from these two regions. Using identical molecular detection methods, we tested 1174 Ghanaian and 539 German children with acute respiratory infections sampled over 12 months for the 15 most common respiratory viruses by PCR. A total 43.2% of the Ghanaian and 56.6% of the German children tested positive for at least one respiratory virus. The pneumoviruses respiratory syncytial virus and human metapneumovirus were most frequently detected, in 13.1% and 25.1% within the Ghanaian and German children, respectively. At both study sites, pneumoviruses were more often observed at younger ages (p <0.001). In the Ghanaian rainy season, enveloped viruses were detected twice as often as non-enveloped viruses (prevalence rate ratio (PR) 2.0, 95% CI 1.7-2.4). In contrast, non-enveloped viruses were more frequent during the Ghanaian dry season (PR 0.6, 95% CI 0.4 0.8). In Germany, enveloped viruses were also more frequently detected during the relatively colder winter season (PR 1.6, 95% CI 1.2-2.1) and non-enveloped viruses during summer (PR 0.7, 95% CI 0.5-0.9). Despite a distance of about 5000 km and a difference of 44 degrees latitude separating Germany and Ghana, virus spectra, age associations and seasonal fluctuation showed similarities between sites. Neither respiratory viruses overall, nor environmentally stable (non enveloped) viruses in particular were more frequent in tropical Ghana. The standardization of our sampling and laboratory testing revealed similarities in acute respiratory infection virus patterns in tropical and temperate climates. PMID- 26585775 TI - Allele Frequencies Net Database: Improvements for storage of individual genotypes and analysis of existing data. AB - The Allele Frequencies Net Database (AFND) is a freely accessible database which stores population frequencies for alleles or genes of the immune system in worldwide populations. Herein we introduce two new tools. We have defined new classifications of data (gold, silver and bronze) to assist users in identifying the most suitable populations for their tasks. The gold standard datasets are defined by allele frequencies summing to 1, sample sizes >50 and high resolution genotyping, while silver standard datasets do not meet gold standard genotyping resolution and/or sample size criteria. The bronze standard datasets are those that could not be classified under the silver or gold standards. The gold standard includes >500 datasets covering over 3 million individuals from >100 countries at one or more of the following loci: HLA-A, -B, -C, -DPA1, -DPB1, DQA1, -DQB1 and -DRB1 - with all loci except DPA1 present in more than 220 datasets. Three out of 12 geographic regions have low representation (the majority of their countries having less than five datasets) and the Central Asia region has no representation. There are 18 countries that are not represented by any gold standard datasets but are represented by at least one dataset that is either silver or bronze standard. We also briefly summarize the data held by AFND for KIR genes, alleles and their ligands. Our second new component is a data submission tool to assist users in the collection of the genotypes of the individuals (raw data), facilitating submission of short population reports to Human Immunology, as well as simplifying the submission of population demographics and frequency data. PMID- 26585776 TI - Association of HLA-G*01:01:02:01/G*01:04:01 polymorphism with gastric adenocarcinoma. AB - Human leukocyte antigen-G (HLA-G) plays an important role in tumor cell escape from immune surveillance and HLA-G polymorphisms might service as a potential risk factor for clinical outcomes in GAC (gastric adenocarcinoma). We investigated the association between HLA-G polymorphisms as well as soluble HLA-G level and accordance of GAC. This case-control study included 100 GAC patients and 102 unrelated Iranian individual's samples as control. The clinical stages ranged from I to IV. PCR-RFLP method was carried out in order to specify the genotypes of the HLA-G gene. Concentrations of sHLA-G in serum were determined with the sHLA-G-specific enzyme linked immunosorbent assay (ELISA) kit. The G*01:04:01 and G*01:01:02:01 alleles were the predominant alleles in GAC patients and healthy controls. The G*01:01:03:01 and G*01:01:08 allele distributions are significantly higher among controls comparing to cases and seem to have protective effect (P value=0.026 and 0.007 respectively). There is a substantial differences in G*01:01:02:01/G*01:04:01 genotype frequencies between cases and controls (OR=2.8, P value<0.001). The G*01:01:03:01/G*01:04:01 and G*01:01:02:01/G*01:01:08 genotypes frequency are higher among controls in comparison to patients (P value=0.028 and 0.007 respectively). The polymorphisms in HLA-G could affect GAC induction and its outcome. Also, increased sHLA-G levels in serum might be a useful biomarker for diagnosis. PMID- 26585777 TI - Immunosuppressive drugs affect induction of IFNy+ Treg in vitro. AB - BACKGROUND: We reported previously that patients with poor long-term graft function are able to form IFNy+ Treg in vitro pretransplant, but late posttransplant have more frequently undetectable or lower levels of IFNy+ Treg in the peripheral blood than patients with good long-term graft outcome. In the present study, we investigated the induction of IFNy+ and Tbet+ Treg subsets in the presence of immunosuppressants in vitro. METHODS: PBL of 10 healthy individuals were stimulated with PMA/Ionomycin in the presence of different immunosuppressive drugs at 2 different concentrations that were chosen to approximately mirror the blood levels in renal transplant recipients. IFNy+, Tbet+, CD119+, and Helios+ CD4+CD25+CD127-Foxp3+ Treg subsets were analyzed using 8-color-fluorescence-flow-cytometry. RESULTS: Cyclosporine (p<0.01) and 6alpha methylprednisolone (p<0.05) at both concentrations as well as high doses of azathioprine (p<0.05) and mycophenolate mofetil (p<0.05) inhibited the induction of IFNy+ and Tbet+ Treg, whereas lower concentrations of azathioprine and mycophenolate mofetil tended to increase IFNy+, Tbet+ and CD119+ Treg (p?0.05). CONCLUSIONS: Drug-induced inhibition of Treg induction might result in low IFNy+ Treg levels with the consequence of T effector activation and impaired graft function. Further studies will show whether monitoring of IFNy+ Treg might help to prevent clinical complications provoked by an inappropriate immunosuppressive protocol. PMID- 26585778 TI - Detection of Infertility-related Neutralizing Antibodies with a Cell-free Microfluidic Method. AB - The unwanted emergence of neutralizing antibodies (nAbs) against an endogenous or a therapeutic protein can result in deficiency diseases or therapy failure. Here, we developed a cell-free microfluidic method for the sensitive detection and quantification of nAbs in human serum that are associated with infertility. We used cell-derived vesicles containing the luteinizing hormone (LH)/choriogonadotropin receptor (LHHCGR) to detect nAbs against LH. The method exploits the entire cellular signal amplification mechanism, and facilitates the detection of as little as 0.44 nM of LH-nAb (Kd 1.5 nM) in human serum matrix within only 15 minutes. In addition, dose-response curves can be generated in less than 2 hours to evaluate the nAB concentration and dissociation constant. The developed system is devoid of problems associated with cell-based assays and we believe that this simple effect-directed analysis can be used in clinical environments, and is adaptable to other hormones or cytokines and their respective nAbs. PMID- 26585779 TI - Long-distance quantum information transfer with strong coupling hybrid solid system. AB - In this paper, we demonstrate how information can be transferred among the long distance memory units in a hybrid solid architecture, which consists the nitrogen vacancy (NV) ensemble acting as the memory unit, the LC circuit acting as the transmitter (receiver), and the flux qubit acting as the interface. Numerical simulation demonstrates that the high-fidelity quantum information transfer between memory unit and transmitter (receiver) can be implemented, and this process is robust to both the LC circuit decay and NV ensemble spontaneous emission. PMID- 26585780 TI - Behavior, Social Competence, and Voice Disorders in Childhood and Adolescence. AB - OBJECTIVES/HYPOTHESIS: This study aimed to verify the relationships among voice change complaints, indicators of competence, and behavioral problems in children and adolescents. STUDY DESIGN: This is a prospective study. METHODS: A sample of 103 parents/guardians completed the Child Behavior Checklist for ages 6-18 years. The mean age and gender were very similar between the participants with and without voice complaints. RESULTS: Regarding the competences, no differences were found between the participants with and without voice complaints. The group with voice complaints presented higher total scores and T-scores in the both anxiety/depression and somatic complaints domains and in the internalising, externalizing, and total scales. The total scores and T-scores on the internalising, externalizing, and total scales, as well as those of their domains (anxiety/depression, somatic complaints, social problems, thought problems, attention problems, rule-breaking behavior, and aggressive behavior), differed between children and adolescents with and without voice complaints. CONCLUSIONS: Children and adolescents with complaints of voice disorder demonstrate a potential risk of developing emotional/behavioral problems. PMID- 26585781 TI - New insights into posture and locomotion. PMID- 26585782 TI - Differential expression of inflammation-related genes in IL-4 transgenic mice before and after the onset of atopic dermatitis skin lesions. AB - IL-4 plays an important role in the pathogenesis of atopic dermatitis (AD), a common chronic inflammatory skin disease. We have generated IL-4 transgenic (Tg) mice by over-expressing IL-4 in the epidermis. These mice spontaneously develop chronic pruritic inflammatory skin lesions, which meet the clinical and histological diagnostic criteria for human AD. Systemic survey of immune-related genes in this mouse model, however, has not been performed. In this study, we utilize PCR array technique to examine hundreds of inflammation-related genes in the IL-4 Tg mice before and after the onset of skin lesions as well as in their wild type (WT) littermates. Only those genes with at least 2-fold up-regulation or down-regulation and with a P-value of less than 0.05 in comparison to WT controls were identified and analyzed. In the skin lesions, many chemokines, pro inflammatory cytokines, and other AD-related factors are dysregulated compared to the wild type mice. Particularly, CXCL5, IL-1beta, IL-24, IL-6, oncostatin M, PTGS2, FPR1 and REG3gamma are up-regulated several hundred-fold. In the pre lesional group that shows no obvious skin abnormality on clinical observation, 30 dysregulated genes are nevertheless identified though the fold changes are much less than that of the lesional group, including CCL6, CCL8, CCL11, CCL17, CXCL13, CXCL14, CXCR3 and IL-12Rbeta2. Finally using ELISA, we demonstrate that 4 most dramatically up-regulated factors in the skin are also elevated in the peripheral blood of the IL-4 Tg mice. Taken together, our data have identified hundreds of dysregulated factors in the IL-4 Tg mice before and after the onset of skin lesions. Future detailed examination of these factors will shed light on our understanding of the development and progression of AD and help to discover important biomarkers for clinical AD diagnosis and treatment. PMID- 26585783 TI - Disentangling the relative importance of different socioeconomic resources for myocardial infarction incidence and survival: a longitudinal study of over 300,000 Finnish adults. AB - BACKGROUND: Lower socioeconomic position (SEP) is associated with an increased risk of myocardial infarction (MI) incidence and mortality, but the relative importance of different socioeconomic resources at different stages of the disease remains unclear. METHODS: A nationally representative register-based sample of 40- to 60-year-old Finnish men and women in 1995 (n= 302 885) were followed up for MI incidence and mortality in 1996-2007. We compared the effects of education, occupation, income and wealth on first MI incidence, first-day and long-term fatality. Cox's proportional hazards regression and logistic regression models were estimated adjusting for SEP covariates simultaneously to assess independent effects. RESULTS: Fully adjusted models showed greatest relative inequalities of MI incidence by wealth in both sexes, with an increased risk also associated with manual occupations. Education was a significant predictor of incidence in men. Low income was associated with a greater risk of death on the day of MI incidence [odds ratio (OR) = 1.40 in men and 1.95 in women when comparing lowest and highest income quintiles], and in men, with long-term fatality [hazard ratio (HR) = 1.74]. Wealth contributed to inequalities in first day fatality in men and in long-term fatality in both sexes. CONCLUSION: The results show that different socioeconomic resources have diverse effects on the disease process and add new evidence on the significant association of wealth with heart disease onset and fatality. Targeting those with the least resources could improve survival in MI patients and help reduce social inequalities in coronary heart disease mortality. PMID- 26585784 TI - Social disparities in hazardous alcohol use: self-report bias may lead to incorrect estimates. AB - BACKGROUND: Self-report bias in surveys of alcohol consumption is widely documented; however, less is known about the distribution of such bias by socioeconomic status (SES) and about the possible impact on social disparities. This study aims to assess social disparities in hazardous drinking (HD) and to analyze how correcting alcohol consumption data for self-report bias may affect estimates of disparities. METHODS: National survey data from 13 countries, Canada, England, Finland, France, Germany, Hungary, Ireland, Japan, Korea, New Zealand, Spain, Switzerland and USA, are used to examine social disparities in HD by SES and education level. Defining HD as drinking above 3 drinks/day for men and 2 for women, social disparities were assessed by calculating country-level concentration indexes. Aggregate consumption data were used to correct survey based estimates for self-report bias. RESULTS: Survey data show that more educated women are more likely than less-educated women to engage in HD, while the opposite is observed in men in most countries. Large discrepancies in alcohol consumption between survey-based and aggregate estimates were found. Correcting for self-report bias increased estimates of social disparities in women, and decreased them in men, to the point that gradients were reversed in several countries (from higher rates in low education/SES men to an opposite pattern). CONCLUSION: This study provides evidence of a likely misestimation of social disparities in HD, in both men and women, due to self-report bias in alcohol consumption surveys. This study contributes to a better knowledge of the social dimensions of HD and to the targeting of alcohol policies. PMID- 26585785 TI - Supply/Demand in Radiology: A Historical Perspective and Comparison to other Labor Markets. AB - RATIONALE AND OBJECTIVES: There has been attention on the job market recently and on radiology's supply/demand calculus. Supply is influenced by the number of trained radiologists, while demand is driven by demographics and technological innovation. We analyze the supply of radiologists historically and compare to other labor markets-medical and non-medical, domestic and foreign. MATERIALS AND METHODS: We review National Resident Matching Program data in radiology and several other specialties from 1991 to 2015. We also review surveys, physician recruitment data, and peer-reviewed commentaries on medical specialty job markets. Trends are compared across specialties. The regulation of American medical training is compared to that in the United Kingdom and to a nonmedical labor market, unionized theatrical stage employees. RESULTS: Radiology residency positions have increased since 1998 despite a downturn in the job market. This expansion coincides with a decreasing percentage of positions filled by domestic graduates. A similar trend has been seen in pathology, a notoriously oversupplied specialty. Conversely, other specialties have maintained their proportion of domestic graduates by way of limited supply or implicit demand. CONCLUSIONS: The radiology job market is currently oversupplied, primarily a result of increasing residency positions despite indicators of decreasing demand. The percentage of residency positions filled by domestic graduates has decreased during the same period, suggesting that medical student interest is responsive to the market. Other specialties, particularly pathology, demonstrate the dangers of chronic oversupply. We advocate a reduction of radiology residency positions such that supply closely approximates demand without exceeding it. Additional measures may be taken, if necessary, to restore market equilibrium in the event of a mild undersupply. PMID- 26585786 TI - Centering the Patient in Radiology Research. PMID- 26585787 TI - An Aneurysm by Any Other Name. PMID- 26585789 TI - Acute bioprosthetic mitral valve thrombosis. PMID- 26585790 TI - Anne Marie's Christmas. PMID- 26585791 TI - Septic shock from community-onset pneumonia: is there a role for aspirin plus macrolides combination? PMID- 26585788 TI - PKR deficiency alters E. coli-induced sickness behaviors but does not exacerbate neuroimmune responses or bacterial load. AB - BACKGROUND: Systemic inflammation induces neuroimmune activation, ultimately leading to sickness (e.g., fever, anorexia, motor impairments, exploratory deficits, and social withdrawal). In this study, we evaluated the role of protein kinase R (PKR), a serine-threonine kinase that can control systemic inflammation, on neuroimmune responses and sickness. METHODS: Wild-type (WT) PKR+/+ mice and PKR-/- mice were subcutaneously injected with live Escherichia coli (E. coli) or vehicle. Food consumption, rotarod test performance, burrowing, open field activity, object investigation, and social interaction were monitored. Plasma TNF alpha and corticosterone were measured by ELISA. The percentage of neutrophils in blood was deduced from blood smears. Inflammatory gene expression (IL-1beta, TNF alpha, IL-6, cyclooxygenase (COX)-2, iNOS) in the liver and the brain (hypothalamus and hippocampus) were quantified by real-time PCR. Blood and lavage fluid (injection site) were collected for microbiological plate count and for real-time PCR of bacterial 16S ribosomal DNA (rDNA). Corticotrophin-releasing hormone (CRH) expression in the hypothalamus was also determined by real-time PCR. RESULTS: Deficiency of PKR diminished peripheral inflammatory responses following E. coli challenge. However, while the core components of sickness (anorexia and motor impairments) were similar between both strains of mice, the behavioral components of sickness (reduced burrowing, exploratory activity deficits, and social withdrawal) were only observable in PKR-/- mice but not in WT mice. Such alteration of behavioral components was unlikely to be caused by exaggerated neuroimmune activation, by an impaired host defense to the infection, or due to a dysregulated corticosterone response, because both strains of mice displayed similar neuroimmune responses, bacterial titers, and plasma corticosterone profiles throughout the course of infection. Nevertheless, the induction of hypothalamic corticotrophin-releasing hormone (CRH) by E. coli was delayed in PKR-/- mice relative to WT mice, suggesting that PKR deficiency may postpone the CRH response during systemic inflammation. CONCLUSIONS: Taken together, our findings show that (1) loss of PKR could alter E. coli-induced sickness behaviors and (2) this was unlikely to be due to exacerbated neuroimmune activation, (3) elevated bacterial load, or (4) dysregulation in the corticosterone response. Further studies can address the role of PKR in the CRH response together with its consequence on sickness. PMID- 26585792 TI - Programming cell death in the 1960s: developmental biology beyond dichotomy. AB - Programmed cell death (PCD) has been one of the most significant topics in modern biomedical research. Its broad importance in many biological and pathological phenomena, including morphogenesis, autoimmune disease, and cancer, demonstrates that its origin deserves a historical examination. By analyzing the role of developmental biology of the 1960s in shaping the notion of a program, this paper explains the emergence of a close correlation between not only life and death, but also the normal and the pathological in the postwar study of cell death. PMID- 26585793 TI - Microscopic polyangiitis in a patient with primary biliary cirrhosis: Treatment complications. PMID- 26585794 TI - Dental erosion in French adolescents. AB - BACKGROUND: Since the 2000s, different epidemiological studies focusing on the prevalence or the aetiology of DE in adolescents recognised them as an at-risk population due to their eating behaviours. None was carried out in French adolescents. The primary objective of this study was to assess the prevalence of dental erosion (DE) using the total BEWE score among adolescents in the department of Alpes Maritimes, France. The secondary objectives were to observe changes in prevalence estimates depending on both the cutoffvalue of total BEWE score with different teeth/dental surfaces examined, and to identify the related risk factors. METHODS: A cross-sectional study in a multistage random sample of 339 14-yr-old schoolchildren was carried out in 2014. The children completed a self-administered questionnaire concerning diet and oral habits. Caries was assessed with ICDAS-II (International Caries Detection and Assessment System-II) criteria and erosion with BEWE (Basic Erosive Wear Examination) index. The total BEWE score was calculated to assess the DE prevalence with two cutoff values (3 and 1). Data were analysed using descriptive statistics and logistic regression models. RESULTS: The 331 children were aged 14.4 +/- 0.5 years. The DE prevalence was 39 % using a total BEWE score >= 3. With a cutoff total BEWE score of 1 (at least one affected tooth), the prevalence varied from 3.9 to 56.8 % depending on the teeth/surfaces that were used for the analysis. The DE prevalence, assessed with only first molars and maxillary incisors, was about 54 %. The risk factors for DE (total BEWE score >= 3) were daily consumption of acidic beverages (OR: 4.0; 95 % CI: 2.1-7.6) and acidic sweets (OR: 3.2; 95 % CI: 1.2-8.0), low socio economic category (OR: 2.4; 95 % CI: 1.1-5.0) and visible dental biofilm (OR: 2.0; 95 % CI: 1.2-3.4). CONCLUSION: Depending on the method chosen, the prevalence varied from 3.9 to 56.8 % among these adolescents. Thus, a consensus on choice of index, teeth to examine and age at assessment is necessary to standardise measurement of DE prevalence. PMID- 26585796 TI - Neurodegenerative disease: The plot thickens. PMID- 26585795 TI - Rapid characterization of CRISPR-Cas9 protospacer adjacent motif sequence elements. AB - To expand the repertoire of Cas9s available for genome targeting, we present a new in vitro method for the simultaneous examination of guide RNA and protospacer adjacent motif (PAM) requirements. The method relies on the in vitro cleavage of plasmid libraries containing a randomized PAM as a function of Cas9-guide RNA complex concentration. Using this method, we accurately reproduce the canonical PAM preferences for Streptococcus pyogenes, Streptococcus thermophilus CRISPR3 (Sth3), and CRISPR1 (Sth1). Additionally, PAM and sgRNA solutions for a novel Cas9 protein from Brevibacillus laterosporus are provided by the assay and are demonstrated to support functional activity in vitro and in plants. PMID- 26585797 TI - Psychiatric disorders: Modelling lithium responsiveness in a dish. PMID- 26585798 TI - Neural circuits: Consumption control. PMID- 26585801 TI - Incidence of sexually transmitted infections jumps in US, CDC reports. PMID- 26585800 TI - A new mechanism of nervous system plasticity: activity-dependent myelination. AB - The synapse is the focus of experimental research and theory on the cellular mechanisms of nervous system plasticity and learning, but recent research is expanding the consideration of plasticity into new mechanisms beyond the synapse, notably including the possibility that conduction velocity could be modifiable through changes in myelin to optimize the timing of information transmission through neural circuits. This concept emerges from a confluence of brain imaging that reveals changes in white matter in the human brain during learning, together with cellular studies showing that the process of myelination can be influenced by action potential firing in axons. This Opinion article summarizes the new research on activity-dependent myelination, explores the possible implications of these studies and outlines the potential for new research. PMID- 26585802 TI - [Leon Bouchacourt (1865-1949): How an obstetrician pointed out individual radiosensitivity]. AB - Leon Bouchacourt (1865-1949) was a misknown pioneer of radiology and radiotherapy from Lyon, France. While he was resident in obstetrics in Hopitaux de Paris from 1892 to 1898, he met Charcot, the future polar explorer, and wrote the first thesis dissertation about X-rays. He invented a new radiology technique for cavitary organs such as vagina, rectum and mouth, the endodiascopy, which permitted him to perform the first pelvimetry and dental radiographies in France. While he undertook the first trials of contact-radiotherapy, he was confronted with radiation-induced reactions. In 1911, he wrote the first paper about individual radiosensitivity. During the First World War, he commanded one of the radiology vehicles, he met Irene Curie and developed his " radiological helmet ", which will hold his name and became essential for interventional radiology. After the war, with Beclere and ten others, Leon Bouchacourt funded the French Radiology Society. He ended his career by thinking about public health and the different aspects of the duties of radiologists. PMID- 26585799 TI - The endocannabinoid system in guarding against fear, anxiety and stress. AB - The endocannabinoid (eCB) system has emerged as a central integrator linking the perception of external and internal stimuli to distinct neurophysiological and behavioural outcomes (such as fear reaction, anxiety and stress-coping), thus allowing an organism to adapt to its changing environment. eCB signalling seems to determine the value of fear-evoking stimuli and to tune appropriate behavioural responses, which are essential for the organism's long-term viability, homeostasis and stress resilience; and dysregulation of eCB signalling can lead to psychiatric disorders. An understanding of the underlying neural cell populations and cellular processes enables the development of therapeutic strategies to mitigate behavioural maladaptation. PMID- 26585803 TI - Cytopenias + mutations - dysplasia = what? PMID- 26585804 TI - ATF4, a new player in fetal HSC expansion. PMID- 26585805 TI - Factor V: an active player in inflammation. PMID- 26585806 TI - Is there a best TKI for chronic phase CML? AB - The development of BCR/ABL1 tyrosine kinase inhibitors (TKIs) over the past 20 years has dramatically improved the outcomes for patients with every stage of Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML). Clinicians now have access to 5 oral, generally well-tolerated, and highly effective TKIs. How should these agents be used for an individual patient to ensure the best possible duration and quality-of-life, to avoid treatment-related complications, and potentially to achieve a cure at an affordable cost? Because CML patients may need to continue TKI therapy indefinitely, the long-term safety of each treatment option must be considered. Evidence-based care requires an understanding of the optimal use of these drugs, their specific early and late toxicities, the prognostic significance of achieving treatment milestones, and the critical importance of molecular monitoring. Efficacy is important, but treatment choice does not depend only on efficacy. Choosing among various treatment options is informed by understanding the distinct benefits and risks of each agent, along with careful consideration of patient-specific factors, such as risk status, age, and comorbidities. PMID- 26585807 TI - Current challenges in diagnostic imaging of venous thromboembolism. AB - Because the clinical diagnosis of deep-vein thrombosis and pulmonary embolism is nonspecific, integrated diagnostic approaches for patients with suspected venous thromboembolism have been developed over the years, involving both non-invasive bedside tools (clinical decision rules and D-dimer blood tests) for patients with low pretest probability and diagnostic techniques (compression ultrasound for deep-vein thrombosis and computed tomography pulmonary angiography for pulmonary embolism) for those with a high pretest probability. This combination has led to standardized diagnostic algorithms with proven safety for excluding venous thrombotic disease. At the same time, it has become apparent that, as a result of the natural history of venous thrombosis, there are special patient populations in which the current standard diagnostic algorithms are not sufficient. In this review, we present 3 evidence-based patient cases to underline recent developments in the imaging diagnosis of venous thromboembolism. PMID- 26585809 TI - Heart rate complexity: A novel approach to assessing cardiac stress reactivity. AB - Correlation dimension (D2), a measure of heart rate (HR) complexity, has been shown to decrease in response to acute mental stress and relate to adverse cardiovascular health. However, the relationship between stress-induced changes in D2 and HR has yet to be established. The present studies aimed to assess this relationship systematically while controlling for changes in respiration and autonomic activity. In Study 1 (N = 25) D2 decreased during stress and predicted HR reactivity even after adjusting for changes in respiration rate, and cardiac vagal tone. This result was replicated in Study 2 (N = 162) and extended by including a measure of cardiac sympathetic activity; correlation dimension remained an independent predictor of HR reactivity in a hierarchical linear model containing measures of cardiac parasympathetic and sympathetic activity and their interaction. These results suggest that correlation dimension may provide additional information regarding cardiac stress reactivity above that provided by traditional measures of cardiac autonomic function. PMID- 26585810 TI - Editorial: Modifying Cardiovascular Risk Factors: Current Opinion and Future Trends. PMID- 26585811 TI - A novel structural risk index for primary spontaneous pneumothorax: Ankara Numune Risk Index. AB - BACKGROUND: In this study, we aimed to reveal a novel risk index as a structural risk marker for primary spontanoeus pneumothorax using body mass index and chest height, structural risk factors for pneumothorax development. METHODS: Records of 86 cases admitted between February 2014 and January 2015 with or without primary spontaneous pneumothorax were analysed retrospectively. The patients were allocated to two groups as Group I and Group II. The patients were evaluated with regard to age, gender, pneumothorax side, duration of hospital stay, treatment type, recurrence, chest height and transverse diameter on posteroanterior chest graphy and body mass index. Body mass index ratio per cm of chest height was calculated by dividing body mass index with chest height. We named this risk index ratio which is defined first as 'Ankara Numune Risk Index'. Diagnostic value of Ankara Numune Risk Index value for prediction of primary spontaneous pneumothorax development was analysed with Receiver Operating Characteristics curver. RESULTS: Of 86 patients, 69 (80.2%) were male and 17 (19.8%) were female. Each group was composed of 43 (50%) patients. When Receiver Operating Characteristics curve analysis was done for optimal limit value 0.74 of Ankara Numune Risk Index determined for prediction of pneumothorax development risk, area under the curve was 0.925 (95% Cl, 0.872-0.977, p < 0.001). CONCLUSIONS: Ankara Numune Risk Index is one of the structural risk factors for prediction of primary spontaneous pneumothorax development however it is insufficient for determining recurrence. PMID- 26585812 TI - Curcumin Suppresses Phthalate-Induced Metastasis and the Proportion of Cancer Stem Cell (CSC)-like Cells via the Inhibition of AhR/ERK/SK1 Signaling in Hepatocellular Carcinoma. AB - Recent evidence indicating that phthalates promote cancer development, including cell proliferation, migration, and invasion, has raised public health concerns. Here, we show that bis(2-ethylhexyl) phthalate promotes the migration, invasion, and epithelial-mesenchymal transition of hepatocellular carcinoma cells. In addition, bis(2-ethylhexyl) phthalate increased the proportion of cancer stem cell (CSC)-like cells and stemness maintenance in vitro as well as tumor growth and metastasis in vivo. The various activities of curcumin, including anticancer, anti-inflammation, antioxidation, and immunomodulation, have been investigated extensively. Curcumin suppressed phthalate-induced cell migration, invasion, and epithelial-mesenchymal transition, decreased the proportion of CSC-like cells in hepatocellular carcinoma cell lines in vitro, and inhibited tumor growth and metastasis in vivo. We also reveal that curcumin suppressed phthalate-induced migration, invasion, and CSC-like cell maintenance through inhibition of the aryl hydrocarbon receptor/ERK/SK1/S1P3 signaling pathway. Our results suggest that curcumin may be a potential antidote for phthalate-induced cancer progression. PMID- 26585813 TI - Metacognitions as Mediators of Gender Identity-related Anxiety. AB - OBJECTIVE: Research has found that the prevalence of psychological distress is substantially higher in transgender compared to cisgender populations. This study explored the role of metacognitions as mediators of anxiety in a sample comprising of cisgender and transgender individuals. METHOD: One-hundred and twenty-five individuals (19 trans-male; 24 male; 25 trans-female; 57 female) completed a series of measures that assessed metacognitions, worry and anxiety. RESULTS: Correlation analyses were used to identify potential mediators of the relationship between gender identity and anxiety. A mediation model indicated that beliefs about thoughts concerning uncontrollability and danger entirely mediated the relationship between gender identity and anxiety (b = 2.00, bias corrected and accelerated confidence interval [0.68, 3.49]). CONCLUSIONS: Metacognitions play an important role in anxiety in transgender individuals. HIGHLIGHTS: -Metacognitions were found to mediate anxiety in transgender and cisgender individuals. -The exploration of metacognitions in transgender individuals experiencing psychological distress may have clinical utility. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26585814 TI - [Meningitis, lumbar puncture and procalcitonin]. PMID- 26585815 TI - Endophthalmitis after intravitreal treatment with ranibizumab. PMID- 26585816 TI - High prevalence of asymptomatic carriers of Tropheryma whipplei in different populations from the North of Spain. AB - INTRODUCTION: Tropheryma whipplei is the causative agent of Whipple disease. T. whipplei has also been detected in asymptomatic carriers with a very different prevalence. To date, in Spain, there are no data regarding the prevalence of T. whipplei in a healthy population or in HIV-positive patients, or in chronic fatigue syndrome (CFS). Therefore, the aim of this work was to assess the prevalence of T. whipplei in stools in those populations. METHODS: Stools from 21 HIV-negative subjects, 65 HIV-infected, and 12 CFS patients were analysed using real time-PCR. HIV-negative and positive subjects were divided into two groups, depending on the presence/absence of metabolic syndrome (MS). Positive samples were sequenced. RESULTS: The prevalence of T. whipplei was 25.51% in 98 stool samples analysed. Prevalence in HIV-positive patients was significantly higher than in HIV-negative (33.8% vs. 9.09%, p=0.008). Prevalence in the control group with no associated diseases was 20%, whereas no positive samples were observed in HIV-negative patients with MS, or in those diagnosed with CFS. The prevalence observed in HIV-positive patients without MS was 30.35%, and with MS it was 55.5%. The number of positive samples varies depending on the primers used, although no statistically significant differences were observed. CONCLUSIONS: There is a high prevalence of asymptomatic carriers of T. whipplei among healthy and in HIV-infected people from Spain. The role of T. whipplei in HIV patients with MS is unclear, but the prevalence is higher than in other populations. PMID- 26585817 TI - Scarlet fever: A not so typical exanthematous pharyngotonsillitis (based on 171 cases). AB - AIM: To describe the age, signs and clinical symptoms of children with scarlet fever at the present time, and to check whether they are equivalent to those with traditional streptococcal pharyngotonsillitis. STUDY DESIGN: An observational, retrospective study was conducted on the clinical records of 5500 children aged from 0 to 15 years attending a primary health care center. A record was made of the percentage of the cases in which signs and symptoms appear and the Centor score was calculated. Microbiological diagnosis of the disease was made using the rapid antigen-detection test or traditional culture. RESULTS: A total of 171 out of 252 scarlet fever diagnoses were microbiologically verified in 158 patients. The median age was 3.8 years (interquartile range: 2.91-4.78), with the majority (57%) under the age of 4 years. There was fever in 89% of the processes (95% CI: 84-94%), with a temperature of >38 degrees C in 73% (95% CI: 65-80%), enlarged lymph nodes in 70% (95% CI: 58-82%), absence of cough in 73% (95% CI: 65-80%), and tonsillar exudate in only 24% (95% CI: 17-31%). The Centor score (n=105) was <=2 points in 86% (95% CI: 79-92%). The only difference regarding age is that episodes in patients under the age of 4 years old have significantly higher fever (>38 degrees C) than the older ones (80% versus 63%. OR 3.13; 95% CI: 1.46-6.71). CONCLUSION: Scarlet fever pharyngotonsillitis differs from the traditional streptococcal pharyngotonsillitis, and its evaluation using clinical prediction rules such as Centor or McIsaac is questionable. The main diagnostic key must certainly be rash, regardless of patient age. PMID- 26585818 TI - [Hepatitis A: High susceptibility in our young population]. PMID- 26585819 TI - [The applying of a Royal Decree-Law 16/2012 to HIV-infected people. An example showing that it should be repealed as it is unfair and inefficient]. PMID- 26585820 TI - Native valve endocarditis caused by Kocuria kristinae. PMID- 26585821 TI - Antioxidants and vascular health. AB - Oxygen free radicals and other reactive oxygen species (ROS) are common products of normal aerobic cellular metabolism, but high levels of ROS lead to oxidative stress and cellular damage. Increased production of ROS favors vascular dysfunction, inducing altered vascular permeability and inflammation, accompanied by the loss of vascular modulatory function, the imbalance between vasorelaxation and vasoconstriction, and the aberrant expression of inflammatory adhesion molecules. Inflammatory stimuli promote oxidative stress generated from the increased activity of mitochondrial nicotinamide adenine dinucleotide phosphate oxidase, particularly of the Nox4 isoform, with the consequent impairment of mitochondrial beta-oxidation. Vascular dysfunction due to the increase in Nox4 activity and ROS overproduction leads to the progression of cardiovascular diseases, diabetes, inflammatory bowel disease, and neurological disorders. Considerable research into the development of effective antioxidant therapies using natural derivatives or new synthetic molecules has been conducted. Antioxidants may prevent cellular damage by reducing ROS overproduction or interfering in reactions that involve ROS. Vitamin E and ascorbic acid are well known as natural antioxidants that counteract lipid peroxidative damage by scavenging oxygen-derived free radicals, thus restoring vascular function. Recently, preliminary studies on natural antioxidants such as goji berries, thymus, rosemary, green tea ginseng, and garlic have been conducted for their efficacy in preventing vascular damage. N-acetyl-cysteine and propionyl-L carnitine are synthetic compounds that regulate ROS production by replacing endogenous antioxidants in both endothelial and smooth muscle cells. In this review, we consider the molecular mechanisms underlying the generation of oxidative stress-induced vascular dysfunction as well as the beneficial effects of antioxidant therapies. PMID- 26585822 TI - Genetic variations in the PI3K/AKT pathway predict platinum-based neoadjuvant chemotherapeutic sensitivity in squamous cervical cancer. AB - AIMS: Cervical cancer is one of the most frequent malignant tumours in women. The PI3K/Akt pathway plays a role in chemoresistance to platinum-based neoadjuvant chemotherapy (NAC). The objective of this study was to evaluate the association between genetic polymorphisms in the PI3K/Akt pathway and chemotherapeutic outcomes following platinum-based NAC in Northwestern Chinese Han patients with squamous cervical cancer (SCC). MAIN METHODS: In total, 17 tagging single nucleotide polymorphisms (tSNPs) in four genes (PIK3CA, Akt1, Akt2, PTEN) were identified as being associated with chemotherapeutic response in 259 patients with stage IB2-IIB SCC. Each of these patients received more than two cycles of NAC. These tSNPs were genotyped by the Sequenom MassArray system. KEY FINDINGS: The heterozygous genotype of two loci in the PIK3CA gene (rs3729679: uncorrected P=0.022 and rs12494623: uncorrected P=0.018) was associated with an increased risk of chemoresistance in SCC patients. The stratified analysis also showed that these same SNP polymorphisms were associated with a poor response to NAC in the cisplatin-based subgroup. Furthermore, NAC non-responders had a higher frequency of the rs10416620 and rs62107593 G alleles in the Akt2 gene (rs10416620 and rs62107593: uncorrected P=0.037). The rs34716810 A allele was associated with a poor response to chemotherapy (uncorrected P=0.037). Moreover, rs2498786 (uncorrected P=0.036) and the GGCC haplotype of polymorphisms in Akt1 showed a high risk for non-response to NAC (uncorrected P=0.018). SIGNIFICANCE: The findings from this study demonstrate that genetic polymorphisms in the PI3K/Akt pathway are associated with sensitivity to platinum-based chemotherapy in SCC patients. PMID- 26585823 TI - Food avoidance in an Australian adult population sample: the case of dairy products. AB - OBJECTIVE: To assess the prevalence of and explanations for the avoidance of dairy foods, including symptoms attributed to their consumption, diagnoses and psychological predictors of avoidance. Also considered were comparisons with symptom-related avoidance of wheat in the same sample. DESIGN: Cross-sectional population survey. SETTING: The study was conducted in Australia using a national postal omnibus survey. SUBJECTS: Adults aged 18 years and over (n 1184; 52.9 % female) selected at random from the Australian Electoral Roll. RESULTS: Despite few claims of formally diagnosed allergy or intolerance, 11.8 % of the sample reported avoiding dairy products because of adverse physiological effects, which commonly included gastrointestinal symptoms. Unlike wheat (3.5 %) or wheat-and dairy (3.6 %) avoidance, dairy avoidance (8.2 %) was predicted by age (negatively) and worry about illness (positively). CONCLUSIONS: The findings are further evidence of a widespread tendency for consumers to exercise control over their health by eliminating dietary factors considered suspect without medical evidence or oversight. Unanswered questions include the decision processes underlying dairy avoidance, whether symptoms are attributed correctly, the agents and physiological mechanism(s) involved, the relative contributions of symptom severity and vigilance to the association with illness worry, and the nutritional adequacy of dairy avoiders' diets. Irrespective of the accuracy of self diagnoses, if the elimination of suspect foods is an end in itself the paradoxical possibility for nutritional imbalances may have significant public health implications. PMID- 26585824 TI - Identification of a Novel Nematotoxic Protein by Challenging the Model Mushroom Coprinopsis cinerea with a Fungivorous Nematode. AB - The dung of herbivores, the natural habitat of the model mushroom Coprinopsis cinerea, is a nutrient-rich but also very competitive environment for a saprophytic fungus. We showed previously that C. cinerea expresses constitutive, tissue-specific armories against antagonists such as animal predators and bacterial competitors. In order to dissect the inducible armories against such antagonists, we sequenced the poly(A)-positive transcriptome of C. cinerea vegetative mycelium upon challenge with fungivorous and bacterivorous nematodes, Gram-negative and Gram-positive bacteria and mechanical damage. As a response to the fungivorous nematode Aphelenchus avenae, C. cinerea was found to specifically induce the transcription of several genes encoding previously characterized nematotoxic lectins. In addition, a previously not characterized gene encoding a cytoplasmic protein with several predicted Ricin B-fold domains, was found to be strongly upregulated under this condition. Functional analysis of the recombinant protein revealed a high toxicity toward the bacterivorous nematode Caenorhabditis elegans. Challenge of the mycelium with A. avenae also lead to the induction of several genes encoding putative antibacterial proteins. Some of these genes were also induced upon challenge of the mycelium with the bacteria Escherichia coli and Bacillus subtilis. These results suggest that fungi have the ability to induce specific innate defense responses similar to plants and animals. PMID- 26585825 TI - Mitochondrial-Nuclear Epistasis Impacts Fitness and Mitochondrial Physiology of Interpopulation Caenorhabditis briggsae Hybrids. AB - In order to identify the earliest genetic changes that precipitate species formation, it is useful to study genetic incompatibilities that cause only mild dysfunction when incompatible alleles are combined in an interpopulation hybrid. Such hybridization within the nematode species Caenorhabditis briggsae has been suggested to result in selection against certain combinations of nuclear and mitochondrial alleles, raising the possibility that mitochondrial-nuclear (mitonuclear) epistasis reduces hybrid fitness. To test this hypothesis, cytoplasmic-nuclear hybrids (cybrids) were created to purposefully disrupt any epistatic interactions. Experimental analysis of the cybrids suggests that mitonuclear discord can result in decreased fecundity, increased lipid content, and increased mitochondrial reactive oxygen species levels. Many of these effects were asymmetric with respect to cross direction, as expected if cytoplasmic nuclear Dobzhansky-Muller incompatibilities exist. One such effect is consistent with the interpretation that disrupting coevolved mitochondrial and nuclear loci impacts mitochondrial function and organismal fitness. These findings enhance efforts to study the genesis, identity, and maintenance of genetic incompatibilities that precipitate the speciation process. PMID- 26585826 TI - Genomic Analysis of ATP Efflux in Saccharomyces cerevisiae. AB - Adenosine triphosphate (ATP) plays an important role as a primary molecule for the transfer of chemical energy to drive biological processes. ATP also functions as an extracellular signaling molecule in a diverse array of eukaryotic taxa in a conserved process known as purinergic signaling. Given the important roles of extracellular ATP in cell signaling, we sought to comprehensively elucidate the pathways and mechanisms governing ATP efflux from eukaryotic cells. Here, we present results of a genomic analysis of ATP efflux from Saccharomyces cerevisiae by measuring extracellular ATP levels in cultures of 4609 deletion mutants. This screen revealed key cellular processes that regulate extracellular ATP levels, including mitochondrial translation and vesicle sorting in the late endosome, indicating that ATP production and transport through vesicles are required for efflux. We also observed evidence for altered ATP efflux in strains deleted for genes involved in amino acid signaling, and mitochondrial retrograde signaling. Based on these results, we propose a model in which the retrograde signaling pathway potentiates amino acid signaling to promote mitochondrial respiration. This study advances our understanding of the mechanism of ATP secretion in eukaryotes and implicates TOR complex 1 (TORC1) and nutrient signaling pathways in the regulation of ATP efflux. These results will facilitate analysis of ATP efflux mechanisms in higher eukaryotes. PMID- 26585827 TI - SNPTracker: A Swift Tool for Comprehensive Tracking and Unifying dbSNP rs IDs and Genomic Coordinates of Massive Sequence Variants. AB - The reference single nucleotide polymorphism (rs) ID in dbSNP (http://www.ncbi.nlm.nih.gov/SNP/) is a key resource identifier, which is widely used in human genetics and genomics studies. However, its application is often complicated by the varied IDs of different versions. Here, we developed a user friendly tool, SNPTracker, for comprehensively tracking and unifying the rs IDs and genomic coordinates of massive sequence variants at a time. It worked perfectly, and had much higher accuracy and capacity than two alternative utilities in our proof-of-principle examples. SNPTracker will greatly facilitate genetic data exchange and integration in the postgenome-wide association study era. PMID- 26585828 TI - Comparison between Thermal Desorption Tubes and Stainless Steel Canisters Used for Measuring Volatile Organic Compounds in Petrochemical Factories. AB - OBJECTIVE: The purpose of this study was to compare thermal desorption tubes and stainless steel canisters for measuring volatile organic compounds (VOCs) emitted from petrochemical factories. METHODS: Twelve petrochemical factories in the Mailiao Industrial Complex were recruited for conducting the measurements of VOCs. Thermal desorption tubes and 6-l specially prepared stainless steel canisters were used to simultaneously perform active sampling of environmental air samples. The sampling time of the environmental air samples was set up on 6 h close to a full work shift of the workers. A total of 94 pairwise air samples were collected by using the thermal adsorption tubes and stainless steel canisters in these 12 factories in the petrochemical industrial complex. To maximize the number of comparative data points, all the measurements from all the factories in different sampling times were lumped together to perform a linear regression analysis for each selected VOC. Pearson product-moment correlation coefficient was used to examine the correlation between the pairwise measurements of these two sampling methods. A paired t-test was also performed to examine whether the difference in the concentrations of each selected VOC measured by the two methods was statistically significant. RESULTS: The correlation coefficients of seven compounds, including acetone, n-hexane, benzene, toluene, 1,2 dichloroethane, 1,3-butadiene, and styrene were >0.80 indicating the two sampling methods for these VOCs' measurements had high consistency. The paired t-tests for the measurements of n-hexane, benzene, m/p-xylene, o-xylene, 1,2-dichloroethane, and 1,3-butadiene showed statistically significant difference (P-value < 0.05). This indicated that the two sampling methods had various degrees of systematic errors. Looking at the results of six chemicals and these systematic errors probably resulted from the differences of the detection limits in the two sampling methods for these VOCs. CONCLUSIONS: The comparison between the concentrations of each of the 10 selected VOCs measured by the two sampling methods indicted that the thermal desorption tubes provided high accuracy and precision measurements for acetone, benzene, and 1,3-butadiene. The accuracy and precision of using the thermal desorption tubes for measuring the VOCs can be improved due to new developments in sorbent materials, multi-sorbent designs, and thermal desorption instrumentation. More applications of thermal desorption tubes for measuring occupational and environmental hazardous agents can be anticipated. PMID- 26585829 TI - Synthesis and Biopharmaceutical Evaluation of Imatinib Analogues Featuring Unusual Structural Motifs. AB - A convenient synthesis of imatinib, a potent inhibitor of ABL1 kinase and widely prescribed drug for the treatment of a variety of leukemias, was devised and applied to the construction of a series of novel imatinib analogues featuring a number of non-aromatic structural motifs in place of the parent molecule's phenyl moiety. These analogues were subsequently evaluated for their biopharmaceutical properties (e.g., ABL1 kinase inhibitory activity, cytotoxicity). The bicyclo[1.1.1]pentane- and cubane-containing analogues were found to possess higher themodynamic solubility, whereas cubane- and cyclohexyl-containing analogues exhibited the highest inhibitory activity against ABL1 kinase and the most potent cytotoxicity values against cancer cell lines K562 and SUP-B15. Molecular modeling was employed to rationalize the weak activity of the compounds against ABL1 kinase, and it is likely that the observed cytotoxicity of these agents arises through off-target effects. PMID- 26585830 TI - Peripheral Cannulation for Cardiopulmonary Bypass in Resection of Renal Cell Carcinomas with Level 3 Tumour Thrombus. AB - BACKGROUND: In renal cell carcinomas with tumour thrombus involving the intrahepatic vena cava or above (Level 3+), the urologist will often require the assistance of a cardiothoracic surgeon to establish cardiopulmonary bypass to safely perform a cavotomy for complete resection - this is traditionally through a sternotomy and central cannulation approach. METHODS: We present two cases of patients with Level 3 tumour thrombus involvement, in whom resection was performed with bypass established through peripheral cannulation, thus avoiding the added morbidity of a sternotomy. RESULTS: The cases were performed without any major adverse events, with bypass times of 55 and 200minutes respectively. CONCLUSIONS: Peripheral cannulation is a useful tool in the cardiothoracic surgeon's armamentarium, whose utility should be remembered outside of its traditional setting. We describe two cases, where peripheral cannulation for CPB has been shown to be a safe and minimally invasive alternative to sternotomy for resection of locally advanced renal cell carcinomas. PMID- 26585831 TI - Impact of Obstructive Sleep Apnoea on Heart Failure with Preserved Ejection Fraction. AB - BACKGROUND: The impact of obstructive sleep apnoea on heart failure with preserved ejection fraction is unknown. METHODS: Fifty-eight patients who had heart failure with a left ventricular ejection fraction; >=50% underwent a sleep study. Brain natriuretic peptide (BNP) levels were determined at enrolment and at one, six, 12 and 36 months after enrolment. RESULTS: Obstructive sleep apnoea was found in 39 patients (67%), and they were all subsequently treated with continuous positive airway pressure. Echocardiography at admission showed that E/E' tended to be higher in the 39 patients with, than in the 19 patients without, obstructive sleep apnoea (15.0+/-3.6 vs 12.1+/-1.9, respectively, P=0.05). The median BNP levels at enrolment were similar in patients with and without obstructive sleep apnoea [median (interquartile range): 444 (233-752) vs 316 (218-703) pg/ml]. Although BNP levels decreased over time in both groups, the reduction was less pronounced in patients with obstructive sleep apnoea (P<0.05). Consequently, BNP levels were higher in patients with sleep apnoea at six months, [221 (137-324) vs 76 (38-96) pg/ml, P<0.05], 12 months [123 (98-197) vs 52 (38 76) pg/ml, P<0.05] and 36 months [115 (64-174) vs 56 (25-74) pg/ml, P<0.05]. CONCLUSION: Obstructive sleep apnoea, even when treated appropriately, may worsen long-term cardiac function and outcomes in patients who have heart failure with preserved ejection fraction. PMID- 26585832 TI - Pulmonary Protective Effects of Remote Ischaemic Preconditioning with Postconditioning in Patients Undergoing Cardiac Surgery Involving Cardiopulmonary Bypass: A Substudy of the Remote Ischaemic Preconditioning with Postconditioning Outcome trial. AB - BACKGROUND: The RISPO (Remote Ischemic Preconditioning with Postconditioning Outcome) trial evaluated whether remote ischaemic preconditioning (RIPC) combined with remote ischaemic postconditioning (RIPostC) improves the clinical outcomes of patients undergoing cardiac surgery. This substudy of the RISPO trial aimed to evaluate the effect of RIPC with RIPostC on pulmonary function in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). METHODS: Sixty-five patients were enrolled (32: control and 33: RIPC-RIPostC). In the RIPC-RIPostC group, four cycles of 5min ischaemia and 5min reperfusion were administered before and after CPB to the upper limb. Peri-operative PaO2/FIO2 ratio, intra operative pulmonary shunt, and dynamic and static lung compliance were determined. RESULTS: The mean PaO2/ FIO2 was significantly higher in the RIPC RIPostC group at 24h after surgery [290 (96) vs. 387 (137), p=0.001]. The incidence of mechanical ventilation for longer than 48h was significantly higher in the control group (23% vs. 3%, p<0.05). However, there were no significant differences in other pulmonary profiles, post-operative mechanical ventilation time, and duration of intensive care unit stay. CONCLUSIONS: In our study, RIPC RIPostC improved the post-operative 24h PaO2/FIO2 ratio. Remote ischaemic preconditioning-Remote ischaemic postconditioning has limited and delayed pulmonary protective effects in cardiac surgery patients with CPB. PMID- 26585833 TI - Position-specific automated processing of V3 env ultra-deep pyrosequencing data for predicting HIV-1 tropism. AB - HIV-1 coreceptor usage must be accurately determined before starting CCR5 antagonist-based treatment as the presence of undetected minor CXCR4-using variants can cause subsequent virological failure. Ultra-deep pyrosequencing of HIV-1 V3 env allows to detect low levels of CXCR4-using variants that current genotypic approaches miss. However, the computation of the mass of sequence data and the need to identify true minor variants while excluding artifactual sequences generated during amplification and ultra-deep pyrosequencing is rate limiting. Arbitrary fixed cut-offs below which minor variants are discarded are currently used but the errors generated during ultra-deep pyrosequencing are sequence-dependant rather than random. We have developed an automated processing of HIV-1 V3 env ultra-deep pyrosequencing data that uses biological filters to discard artifactual or non-functional V3 sequences followed by statistical filters to determine position-specific sensitivity thresholds, rather than arbitrary fixed cut-offs. It allows to retain authentic sequences with point mutations at V3 positions of interest and discard artifactual ones with accurate sensitivity thresholds. PMID- 26585835 TI - Corrigendum: IRAK1 is a therapeutic target that drives breast cancer metastasis and resistance to paclitaxel. PMID- 26585834 TI - Repetitive transcranial magnetic stimulation induces long-lasting changes in protein expression and histone acetylation. AB - The use of non-invasive brain stimulation like repetitive transcranial magnetic stimulation (rTMS) is an increasingly popular set of methods with promising results for the treatment of neurological and psychiatric disorders. Despite great enthusiasm, the impact of non-invasive brain stimulation on its neuronal substrates remains largely unknown. Here we show that rTMS applied over the frontal cortex of awaken mice induces dopamine D2 receptor dependent persistent changes of CDK5 and PSD-95 protein levels specifically within the stimulated brain area. Importantly, these modifications were associated with changes of histone acetylation at the promoter of these genes and prevented by administration of the histone deacetylase inhibitor MS-275. These findings show that, like several other psychoactive treatments, repeated rTMS sessions can exert long-lasting effects on neuronal substrates. This underscores the need of understanding these effects in the development of future clinical applications as well as in the establishment of improved guidelines to use rTMS in non-medical settings. PMID- 26585836 TI - Studying citizen science through adaptive management and learning feedbacks as mechanisms for improving conservation. AB - Citizen science has generated a growing interest among scientists and community groups, and citizen science programs have been created specifically for conservation. We examined collaborative science, a highly interactive form of citizen science, which we developed within a theoretically informed framework. In this essay, we focused on 2 aspects of our framework: social learning and adaptive management. Social learning, in contrast to individual-based learning, stresses collaborative and generative insight making and is well-suited for adaptive management. Adaptive-management integrates feedback loops that are informed by what is learned and is guided by iterative decision making. Participants engaged in citizen science are able to add to what they are learning through primary data collection, which can result in the real-time information that is often necessary for conservation. Our work is particularly timely because research publications consistently report a lack of established frameworks and evaluation plans to address the extent of conservation outcomes in citizen science. To illustrate how our framework supports conservation through citizen science, we examined how 2 programs enacted our collaborative science framework. Further, we inspected preliminary conservation outcomes of our case-study programs. These programs, despite their recent implementation, are demonstrating promise with regard to positive conservation outcomes. To date, they are independently earning funds to support research, earning buy-in from local partners to engage in experimentation, and, in the absence of leading scientists, are collecting data to test ideas. We argue that this success is due to citizen scientists being organized around local issues and engaging in iterative, collaborative, and adaptive learning. PMID- 26585837 TI - Loco-regional administration of nanomedicines for the treatment of lung cancer. AB - Lung cancer poses one of the most significant challenges to modern medicine, killing thousands every year. Current therapy involves surgical resection supplemented with chemotherapy and radiotherapy due to high rates of relapse. Shortcomings of currently available chemotherapy protocols include unacceptably high levels of systemic toxicity and low accumulation of drug at the tumor site. Loco-regional delivery of nanocarriers loaded with anticancer agents has the potential to significantly increase efficacy, while minimizing systemic toxicity to anticancer agents. Local drug administration at the tumor site using nanoparticulate drug delivery systems can reduce systemic toxicities observed with intravenously administered anticancer drugs. In addition, this approach presents an opportunity for sustained delivery of anticancer drug over an extended period of time. Herein, the progress in the development of locally administered nanomedicines for the treatment of lung cancer is reviewed. Administration by inhalation, intratumoral injection and means of direct in situ application are discussed, the benefits and drawbacks of each modality are explored. PMID- 26585838 TI - Recurrent Penile Squamous Cell Carcinoma Successfully Treated With Cetuximab, Chemotherapy, and Radiotherapy. PMID- 26585839 TI - Association Between N-acetyltransferase 2 Polymorphism and Bladder Cancer Risk: Results From Studies of the Past Decade and a Meta-Analysis. AB - Numerous studies have identified that the slow acetylation status of N acetyltransferase 2 (NAT2) is associated with an elevated bladder cancer risk. However, the results remain inconclusive. The aim of our study was to evaluate the effect of NAT2 acetylation status in patients with bladder cancer. Electronic databases were searched to retrieve related studies published in the past decade. The pooled odds ratio (OR) with its 95% confidence interval (CI) was used to calculate the strength of this relationship. Overall, a total of 18 studies were selected for the analysis, which included 4473 bladder cancer cases and 7204 matched controls. Our result showed that the NAT2 slow acetylation phenotypes were significantly associated with an increased risk of bladder cancer compared with the rapid phenotypes (OR, 1.56; 95% CI, 1.33-1.82; P < .00001) in a random effect model. This significant association was also found in a subgroup analysis of ethnicity (P < .05). Furthermore, the NAT2 slow phenotypes also significantly increased the risk of bladder cancer in smokers (OR, 0.75; 95% CI, 0.62-0.90; P = .002). However, no correlation was found between the combined effect of NAT2 slow phenotypes and gender with bladder cancer risk (OR, 0.89; 95% CI, 0.28-2.78; P = .84). In conclusion, our results suggest that the NAT2 slow acetylator, in particular, the NAT2 slow acetylator combined with smoking, are associated with an increased bladder cancer risk. Future well-designed studies with large populations and more ethnicities are needed to clarify this association further. PMID- 26585840 TI - Is rate-pressure product of any use in the isolated rat heart? Assessing cardiac 'effort' and oxygen consumption in the Langendorff-perfused heart. AB - NEW FINDINGS: What is the central question of this study? Rate-pressure product (RPP) is commonly used as an index of cardiac 'effort'. In canine and human hearts (which have a positive force-frequency relationship), RPP is linearly correlated with oxygen consumption and has therefore been widely adopted as a species-independent index of cardiac work. However, given that isolated rodent hearts demonstrate a negative force-frequency relationship, its use in this model requires validation. What is the main finding and its importance? Despite its widespread use, RPP is not correlated with oxygen consumption (or cardiac 'effort') in the Langendorff-perfused isolated rat heart. This lack of correlation was also evident when perfusions included a range of metabolic substrates, insulin or beta-adrenoceptor stimulation. Langendorff perfusion of hearts isolated from rats and mice has been used extensively for physiological, pharmacological and biochemical studies. The ability to phenotype these hearts reliably is, therefore, essential. One of the commonly used indices of function is rate-pressure product (RPP); a rather ill-defined index of 'work' or, more correctly, 'effort'. Rate-pressure product, as originally described in dog or human hearts, was shown to be correlated with myocardial oxygen consumption (MVO2). Despite its widespread use, the application of this index to rat or mouse hearts (which, unlike the dog or human, have a negative force-frequency relationship) has not been characterized. The aim of this study was to examine the relationship between RPP and MVO2 in Langendorff-perfused rat hearts. Paced hearts (300-750 beats min(-1)) were perfused either with Krebs-Henseleit (KH) buffer (11 mm glucose) or with buffer supplemented with metabolic substrates and insulin. The arteriovenous oxygen consumption (MVO2) was recorded. Metabolic status was assessed using (31) P magnetic resonance spectroscopy and lactate efflux. Experiments were repeated in the presence of isoprenaline and in unpaced hearts where heart rate was increased by cumulative isoprenaline challenge. In KH buffer-perfused hearts, MVO2 increased with increasing heart rate, but given that left ventricular developed pressure decreased with increases in rate, RPP was not correlated with MVO2, lactate production or phosphocreatine/ATP ratio. Although the provision of substrates or beta-adrenoceptor stimulation changed the shape of the RPP-MVO2 relationship, neither intervention resulted in a positive correlation between RPP and oxygen consumption. Rate-pressure product is therefore an unreliable index of oxygen consumption or 'cardiac effort' in the isolated rat heart. PMID- 26585841 TI - Paediatric necrolytic migratory erythema as a presenting sign of glucagonoma syndrome. AB - Glucagonoma syndrome is an extremely rare pancreatic neuroendocrine tumour often associated with necrolytic migratory erythema. While glucagonomas are neoplasms of adulthood, we report the first case in a paediatric patient. We present the case of a 15-year-old girl with a 4-year history of a rash, consistent with necrolytic migratory erythema, found to have a localized glucagonoma. Immediately following resection of the tumour, there was complete resolution of her rash and systemic symptoms. Detection of the cutaneous rash of necrolytic migratory erythema can aid in the early diagnosis of a glucagonoma, as well as the prevention of metastatic disease. To our knowledge, this is the first reported paediatric patient with glucagonoma syndrome. PMID- 26585843 TI - Profile of Indian patients with premature canities. AB - BACKGROUND: Premature canities is a common yet incompletely understood dermatological entity with scarce demographic and clinical data. AIM: Evaluation of the demographic and clinical profile of cases with premature canities and to look for systemic associations. METHODS: Fifty two self-reported cases of premature canities (onset before 20 years of age) and an equal number of healthy controls were recruited from the outpatient department of the Department of Dermatology, Guru Teg Bahadur Hospital Delhi, India from November 2011 to March 2013. A detailed history including onset, duration and pattern of involvement, a family history with pedigree charting and scalp examination were recorded on a predesigned proforma. A history of atopy was looked for in all study subjects and they were screened for thyroid disorder and diabetes. RESULTS: The mean age of cases and controls was comparable. The mean age of onset of graying was 11.6 +/- 3.6 years. The mean duration at the time of presentation was 39.8 +/- 37.2 months. The frontal region was the earliest affected area in 25 (48.1%) cases. Positive family history of premature canities was reported in 39 (75%) cases with an equal prevalence on paternal and maternal sides. More than half of the cases, 29 (55.8%) reported having a first degree relative affected by premature canities, 13 (25%) had a second degree and 20 (38.5%) had a third degree relative affected. Atopy was found to be strongly associated with premature canities with an odds ratio of 3.8. No association with thyroid abnormality or diabetes mellitus was seen. LIMITATION: The study suffered from the limitation of a small sample size. CONCLUSION: It was observed that the process of graying mostly starts in the frontal region. It was also found to be associated with a strong family history and atopic predisposition. Larger studies are recommended to arrive at a definite conclusion. PMID- 26585842 TI - Extended Sedation With Continuous Midazolam or Dexmedetomidine Infusion for Young Children Receiving 131 I-MIBG Radiopharmaceutical Therapy for Advanced Neuroblastoma. AB - BACKGROUND: (131) I-MIBG is increasingly used for treating neuroblastoma; however, administration requires careful adherence to radiation safety guidelines. We describe our experience using continuous sedation to facilitate safe (131) I-MIBG therapy for young children. PROCEDURE: Patients were included in this case series if they received continuous midazolam or dexmedetomidine infusion for sedation during (131) I-MIBG therapy from November 1, 2012, to October 1, 2014. Key outcomes included adequacy of sedation for both (131) I-MIBG infusion and the duration of radioactive isolation, as well as sedative-related toxicities. Additionally, nuclear medicine scans before and after (131) I-MIBG therapy were assessed using the Curie score. These scores were compared qualitatively between midazolam, dexmedetomidine, and control (no sedative infusion) groups. RESULTS: Of the 13 patients receiving continuous sedation for (131) I-MIBG therapy, seven achieved adequate sedation with midazolam, five achieved adequate sedation with dexmedetomidine, one patient (1.6 years old) failed to achieve adequate sedation with either medication and did not receive (131) I-MIBG therapy. Sedation was generally well tolerated. Common side effects for dexmedetomidine infusion included hypotension and relative bradycardia. Both treatment and control groups had multiple patients with increased Curie scores post-(131) I-MIBG therapy. However, one patient in the midazolam group and two in the dexmedetomidine group had decreased Curie scores after (131) I-MIBG therapy, while none decreased in the control group. CONCLUSIONS: Although we cannot exclude the possibility of some inhibition of (131) I-MIBG uptake by midazolam or dexmedetomidine, this case series suggests that continuous infusions of either agent can provide effective sedation to allow safe administration of (131) I-MIBG to young patients. PMID- 26585844 TI - The controversy of hepatitis C and rituximab: A multidisciplinary dilemma with implications for patients with pemphigus. PMID- 26585845 TI - Multiple giant clear cell acanthomas. PMID- 26585846 TI - Afatinib-induced hypertrichosis of the eyelashes and eyebrows. PMID- 26585851 TI - Patch testing in children: An experience from Kashmir. PMID- 26585852 TI - Vulvovaginal-gingival syndrome and esophageal involvement in lichen planus. PMID- 26585854 TI - Infantile cholestasis presenting as recurrent pruritus. PMID- 26585856 TI - How children aged 2;6 tailor verbal expressions to interlocutor informational needs. AB - Although preschoolers are pervasively underinformative in their actual usage of verbal reference, a number of studies have shown that they nonetheless demonstrate sensitivity to listener informational needs, at least when environmental cues to this are obvious. We investigated two issues. The first concerned the types of visual cues to interlocutor informational needs which children aged 2;6 can process whilst producing complex referring expressions. The second was whether performance in experimental tasks related to naturalistic conversational proficiency. We found that 2;6-year-olds used fewer complex expressions when the objects were dissimilar compared to highly similar objects, indicating that they tailor their verbal expressions to the informational needs of another person, even when the cue to the informational need is relatively opaque. We also found a correlation between conversational skills as rated by the parents and the degree to which 2;6-year-olds could learn from feedback to produce complex referring expressions. PMID- 26585857 TI - Transoral orthodromic temporalis muscle transfer technique for dynamic reanimation of the paralysed face. PMID- 26585858 TI - Alcohol intake and Helicobacter pylori infection: a dose-response meta-analysis of observational studies. AB - : Background Alcohol intake has been suggested to have an impact on the development of many chronic diseases. How alcohol intake may modulate risk of Helicobacter pylori (H. pylori) infection, however, remains a subject open for investigation. A dose-response meta-analysis was performed of epidemiological studies to better quantify this relationship. Materials and methods Twelve observational articles were identified. The summary odds ratio (OR) and confidence intervals (CI) were calculated for alcohol drinkers vs non-drinkers. The summary OR estimates were obtained using the random-effects model and dose response meta-analysis. Sub-group and sensitivity analysis were also conducted. Results The summary OR was 0.78 (95% CI = 0.69-0.89). The dose-response analysis demonstrated that for drinkers of 10, 15, 30, 60 and 96 g/day alcohol intake, the estimated ORs were 0.80 (95% CI = 0.76-0.85), 0.79 (95% CI = 0.75-0.84), 0.83 (95% CI = 0.78-0.87), 0.85 (95% CI = 0.78-0.93) and 0.87 (95% CI = 0.70-1.06), respectively, compared to non-drinkers. The inverse relationship between alcohol intake and H. pylori infection was consistent, regardless of sex, age, geographic areas, detection methods or beverage types. CONCLUSION: Evidence from these observational studies suggests that moderate alcohol intake is associated with a reduction in H. pylori infection of ~ 22% and may facilitate elimination of H. pylori. PMID- 26585859 TI - Different substrates and starter inocula govern microbial community structures in biogas reactors. AB - The influence of different starter inocula on the microbial communities in biogas batch reactors fed with fresh maize and maize silage as substrates was investigated. Molecular biological analysis by Denaturing Gradient Gel Electrophoresis (DGGE) of 16S rRNA gene fragments showed that each inoculum bore specific microbial communities with varying predominant phylotypes. Both, bacterial and archaeal DGGE profiles displayed three distinct communities that developed depending on the type of inoculum. Although maize and silage are similar substrates, different communities dominated the lactate-rich silage compared to lactate-free fresh maize. Cluster analysis of DGGE gels showed the communities of the same substrates to be stable with their respective inoculum. Bacteria-specific DGGE analysis revealed a rich diversity with Firmicutes being predominant. The other abundant phylotypes were Bacteroidetes and Synergistetes. Archaea-specific DGGE analysis displayed less diverse community structures, identifying members of the Methanosarcinales as the dominant methanogens present in all the three biogas digesters. In general, the source of inoculum played a significant role in shaping microbial communities. Adaptability of the inoculum to the substrates fed also influenced community compositions which further impacted the rates of biogas production. PMID- 26585860 TI - The relationship between early-life environment, the epigenome and the microbiota. AB - Children exposed to early-life adversity carry a greater risk of poor health and disease into adulthood. This increased disease risk is shadowed by changes in the epigenome. Epigenetics can change gene expression to modify disease risk; unfortunately, how epigenetics are changed by the environment is unclear. It is known that the environment modifies the microbiota, and recent data indicate that the microbiota and the epigenome interact and respond to each other. Specifically, the microbiome may alter the epigenome through the production of metabolites. Investigating the relationship between the microbiome and the epigenome may provide novel understanding of the impact of early-life environment on long-term health. PMID- 26585861 TI - Theoretical implications addressing rural college students' organ donation behaviors. AB - The current study used the theory of planned behavior to examine rural college students' attitudes, normative beliefs, and perceived behavioral control regarding intent to register as organ donors. This effort is done in light of a need to increase intervention efforts among college students, particularly those in rural areas where these undertakings may need to be tailored in grassroots approaches. The study made use of perceived behavioral control as a moderator and found partial support for the model. Findings offer results that scholars, practitioners, and educators can utilize for interventions. PMID- 26585862 TI - Illness representation and sense of coherence in dementia caregiving. AB - The objectives of this study were to describe illness representations in dementia caregiving and examine the relationship between illness perceptions and carers' sense of coherence. Illness perceptions were assessed by the Brief Illness Perception Questionnaire. We measured sense of coherence, symptoms of anxiety and depression and carer burden. Regression analyses indicated that after controlling for demographic factors, burden and psychological distress in carers, illness coherence and emotional responses to the disease independently contributed towards explaining variance in carers' sense of coherence. Results provide support for the usefulness of the self-regulation model in understanding dementia caregiving. PMID- 26585863 TI - Parathyroid Lipoadenoma: a Clinicopathological Diagnosis and Possible Trap for the Unaware Pathologist. AB - The authors present clinicopathological features of parathyroid lipoadenoma in a 48-year-old woman who presented with symptomatic primary hyperparathyroidism manifesting with pathological fractures and osteoporosis. Preoperative sestamibi scan failed to localize the source of her disease. Exploratory surgery identified an enlarged parathyroid gland with abundant fat tissue. The significant drop of intraoperative serum parathyroid hormone after the removal of this gland and postoperative biochemical cure justified the presence of a single gland disease presenting as parathyroid lipoadenoma. From an educational perspective, the presented case emphasizes why the historical approach to parathyroid proliferations by assessing alone the ratio of parenchymal cells to adipocytes is not a reliable method in the diagnostic evaluation of parathyroid disease. While the accurate size and weight of a parathyroid gland are defining parameters of an abnormal gland, intraoperative and postoperative biochemical workup distinguishes uniglandular disease (adenoma) from multiglandular disease (hyperplasia). The authors also provide a brief review of the previously published cases of parathyroid lipoadenomas to highlight their clinicopathological characteristics of relevance to surgical pathologists. PMID- 26585864 TI - Anatomical and histological study of the dorsal and ventral nasal conchal bullae in normal horses. AB - The morphology of the dorsal conchal bulla (DCB) and ventral conchal bulla (VCB) are poorly described. The recent recognition that these bullae can become infected, causing chronic unilateral nasal discharge, has stimulated interest in these structures. Fourteen cadaveric horse heads were transected sagittally midline and dissected to expose the nasal conchal bullae. The dimensions of each bulla, the number and orientation of drainage apertures, and cellulae septae were recorded. Randomly selected samples were examined histologically. The mean DCB and VCB lengths were 78 and 57 mm, respectively; equivalent to 13.9 per cent and 10.2 per cent of skull length, respectively. The mean DCB and VCB heights were 29 and 28 mm, respectively; equivalent to 5.2 per cent and 5 per cent of skull length, respectively. The DCB was larger than the VCB, containing more septae, cellulae and drainage apertures. No communications were identified between the bullae and the immediately adjacent paranasal sinuses. Histology revealed that the bullae consist of ciliated, pseudostratified, columnar epithelium over glandular submucosa often overlying turbinate bone and, variably, hyaline cartilage. This more detailed description of equine DCB and VCB anatomy will hopefully facilitate successful treatment of their disorders. PMID- 26585865 TI - Prevalence of subscapularis tears and accuracy of shoulder ultrasound in pre operative diagnosis. AB - PURPOSE: Subscapularis tears can be difficult to diagnose and their treatment requires advanced arthroscopic skills. The objective of this study was to find the prevalence of subscapularis tears on arthroscopic examination of shoulders with rotator cuff pathology and to determine the accuracy of pre-operative ultrasound in diagnosing these tears. METHOD: Ultrasound and intra-operative reports of 236 patients who underwent shoulder arthroscopy for rotator cuff pathology by the senior author at his institution were compared. Prevalence of subscapularis tear was noted and classified using Lafosse classification system. Ultrasound reports and intra-operative findings were compared to determine the accuracy, sensitivity and specificity of ultrasound in detecting subscapularis tears. RESULTS: The prevalence of subscapularis tears in patients needing rotator cuff repair was found to be 31.4 %. A total of 6.4 % of patients needing a rotator cuff repair had an isolated subscapularis tear. The sensitivity of ultrasound was 39.5 % and specificity 93.1 % in detection of these tears. The overall accuracy of ultrasound was 75.8 %. Sensitivity of ultrasound was low (42.8 %) for smaller (type 1 and 2) tears and higher (79 %) for larger (types 3, 4, 5) tears. The overall positive predictive value of USS was 73.1 % and negative predictive value 76.4 %. CONCLUSION: The shoulder surgeon should be skilled in diagnosing and repairing subscapularis tendon tears arthroscopically and cannot completely rely on pre-operative ultrasound scans in ruling out smaller tears as its sensitivity in diagnosing smaller tears is quite low. Unsettling anterior shoulder pain with a normal ultrasound may need further arthroscopic evaluation to rule out missed subscapularis tears. PMID- 26585866 TI - Authorities and foundation of the orthopaedic school in Germany in the 19th century: part II: Richard von Volkmann, Julius Wolff, Albert Hoffa, Friedrich Trendelenburg and other German authors. AB - The national achievements of the orthopaedic school of Germany became international in the second part of the 19th century, and from 1860 through 1914 its educational system attracted many physicians and surgeons from all over the world. During this period of 50 years, German surgeons asserted their dominance in orthopaedic surgery, particularly with four famous surgeons: Richard von Volkmann, Julius Wolff, Albert Hoffa, and Friedrich Trendelenburg. They held annual meetings, during which papers were read and discussed. We also present contributions to orthopaedic sciences of the other German authors during 19th century according to different cities. PMID- 26585867 TI - Evaluation of a clinical risk index for advanced colorectal neoplasia among a North American population of screening age. AB - BACKGROUND: A clinical risk index employing age, sex, family history of colorectal cancer (CRC), smoking history and body mass index (BMI) may be useful for prioritizing screening with colonoscopy. The aim of this study was to conduct an external evaluation of a previously published risk index for advanced neoplasia (AN) in a large, well-characterized cohort. METHODS: Five thousand one hundred thirty-seven asymptomatic persons aged 50 to 74 (54.9 % women) with a mean age (SD) of 58.3 (6.2) years were recruited for the study from a teaching hospital and colorectal cancer screening centre between 2003 and 2011. All participants underwent a complete screening colonoscopy and removal of all polyps. AN was defined as cancer or a tubular adenoma, traditional serrated adenoma (TSA), or sessile serrated adenoma (SSA) with villous characteristics (>=25% villous component), and/or high-grade dysplasia and/or diameter >=10 mm. Risk scores for each participant were summed to derive an overall score (0-8). The c-statistic was used to measure discriminating ability of the risk index. RESULTS: The prevalence of AN in the study cohort was 6.8 %. The likelihood of detecting AN increased from 3.6 to 13.1 % for those with a risk score of 1 to 6 respectively. The c-statistic for the multivariable logistic model in our cohort was 0.64 (95 % CI = 0.61-067) indicating modest overlap between risk scores. CONCLUSIONS: The risk index for AN using age, sex, family history, smoking history and BMI was found to be of limited discriminating ability upon external validation. The index requires further refinement to better predict AN in average risk persons of screening age. PMID- 26585868 TI - Concurrent Merkel cell carcinoma and squamous cell carcinoma in a chest nodule. PMID- 26585869 TI - Special Issue on Genome Engineering. PMID- 26585872 TI - Creating Ribo-T: (Design, Build, Test)n. AB - Engineering biology is especially challenging given our relatively poor ability to rationally design within life's complex design landscape. Thus, moving through the engineering "design, build, test" cycle multiple times accumulates system knowledge and hopefully yields a successful design. Here I discuss the engineering process behind our recently published work creating a ribosome with tethered subunits, Ribo-T. PMID- 26585873 TI - Doping-Induced Carrier Density Modulation in Polymer Field-Effect Transistors. AB - Controlled device parameters of high-mobility polymer field-effect transistors (FETs) are demonstrated by modest doping and charge compensation. Through fleeting chemical vapor treatments of aligned poly[4-(4,4-dihexadecyl-4H cyclopenta[1,2-b:5,4-b']dithiophen-2-yl)-alt-[1,2,5]thiadiazolo-[3,4-c]pyridine] (PCDTPT) thin films as the charge transport layer in the FET channel, the FET properties are tailored by controlling doping concentration of the PCDTPT adjacent to metal electrodes. PMID- 26585874 TI - Risks of Cardiac Valve Regurgitation and Heart Failure Associated with Ergot- and Non-Ergot-Derived Dopamine Agonist Use in Patients with Parkinson's Disease: A Systematic Review of Observational Studies. AB - BACKGROUND: Dopamine agonists (DAs) are commonly used in the therapy of Parkinson's disease (PD). However, several observational studies have suggested a putative association between DAs and specific cardiac adverse events. OBJECTIVES: The aim of this study was to systematically review and summarize the available epidemiologic evidence on the association between use of ergot- and non-ergot derived DAs and the risk of valvular heart disease, specifically cardiac valve regurgitation (CVR) and heart failure (HF) in patients with PD. METHODS: The databases MEDLINE/PubMed and EMBASE were searched for all relevant articles published before February 2015. Studies were eligible if they met the following inclusion criteria: exposure to any approved non-ergot- or ergot-derived DA, presentation of original data, inclusion of an unexposed reference group, and valvular heart disease or heart failure as the primary outcome of interest. RESULTS: Thirteen publications for CVR were identified (two nested case-control, one cohort and ten cross-sectional studies). Compared with non-ergot DAs or other anti-parkinsonian drugs, exposure to ergot-derived DAs pergolide and cabergoline was associated with an increased risk of CVR among PD patients. Incidence rate ratios (IRR) in the nested case-control and cohort studies ranged from 2.00 to 7.10 and 4.58 to 4.90, respectively. Longer treatment duration and higher dose of those DAs was also associated with a higher risk of CVR. Risk of HF was estimated in three nested case-control studies and one cohort study. Use of cabergoline (IRR range 1.30-2.39) and the non-ergot-derived DA pramipexole (IRR range 1.40 1.81) was associated with a higher HF risk among patients with PD. Pergolide may also be associated with a higher risk of HF. CONCLUSION: Despite the heterogeneous methodological approaches of the included studies, there is strong evidence that treatment with pergolide and cabergoline is associated with a higher risk of CVR, and moderate evidence that treatment with pramipexole and cabergoline is associated with a higher risk of HF in patients with Parkinson's disease. PMID- 26585875 TI - The Pharmacokinetics of Second-Generation Long-Acting Injectable Antipsychotics: Limitations of Monograph Values. AB - Product monographs (also known by terms such as Summary of Product Characteristics and Highlights of Prescribing Information, depending on the jurisdiction) provide essential information to ensure the safe and effective use of a drug. Medical practitioners often rely on these monographs for guidance on matters related to pharmacokinetics as well as indications, contraindications, clinical pharmacology, and adverse reactions. The clinical and scientific information found within these documents, forming the basis for decision making, are presumed to be derived from well-designed studies. The objective of this review is to examine the source and validity of the pharmacokinetic data used in establishing the half-lives and times to steady-state reported in the product monographs of second-generation long-acting injectable antipsychotics. Thus, we have critically evaluated the clinical trials from which the pharmacokinetic parameters listed in the product monographs were determined. In many cases, the pharmacokinetic information presented in product monographs is of limited use to clinicians wishing to optimize the effectiveness and tolerability of second generation long-acting injectable antipsychotics. Under such circumstances, off label prescribing practices may actually produce better clinical outcomes than if decisions were made based on the product monographs alone. PMID- 26585877 TI - [A rare but classical cause of a left posterior basal thoracic mass]. PMID- 26585876 TI - [Comorbidities of COPD]. AB - COPD is a slowly progressive chronic respiratory disease causing an irreversible decrease in air flow. The main cause is smoking, which provokes inflammatory phenomena in the respiratory tract. COPD is a serious public health issue, causing high morbidity, mortality and disability. Related comorbidities are linked to ageing, common risk factors and genetic predispositions. A combination of comorbidities increases healthcare costs. For instance, patients with more than two comorbidities represent a quarter of all COPD sufferers but account for half the related health costs. Our review describes different comorbidities and their impact on the COPD prognosis. The comorbidities include: cardiovascular diseases, osteoporosis, denutrition, obesity, ageing, anemia, sleeping disorders, diabetes, metabolic syndrome, anxiety-depression and lung cancer. The prognosis worsens with one or more comorbidities. Clinicians are faced with the challenge of finding practical and appropriate ways of treating these comorbidities, and there is increasing interest in developing a global, multidisciplinary approach to management. Managing this chronic disease should be based on a holistic, patient-centred approach and smoking cessation remains the key factor in the care of COPD patients. PMID- 26585879 TI - A novel multimodal computational system using near-infrared spectroscopy to monitor cerebral oxygenation during assisted ventilation in CDH patients. AB - BACKGROUND/PURPOSE: The aim of this study was to create a computational simulator to serve as an early alert system for cerebral hypoxemia prior to the onset of clinical symptoms. METHODS: Neonates with congenital diaphragmatic hernia (Jan 2010-Dec 2014) were recruited to collect continuous measurements of cerebral tissue oxygen saturation (cStO2) using a near-infrared spectroscopy (NIRS) device (FORE-SIGHT(r), CASMED). Clinicians were blinded to NIRS data and treated infants based on pre-established clinical protocols. Charts were reviewed retrospectively to identify clinical events of hypoxemia (spontaneous, sustained decrease in preductal SpO2<85% leading to ventilator changes). We developed a computational algorithm that determined baseline values, variability and event data for each patient. RESULTS: Twenty-three of 36 patients enrolled met data criteria. The algorithm anticipated an event at least 15 minutes prior to the event in 77% of cases, with an average pre-event detection of 47 minutes (range 16-122 minutes). Post-event StO2 (SpO2<85%) was determined to be 63.7% +/- 11.7. In this computational model, the sensitivity to distinguish low states of cerebral perfusion was 94% with a specificity of 96%. CONCLUSION: We have developed a computational algorithm with an early warning system that has the potential of being translated into a real-time clinical interface that may improve management of neonates. PMID- 26585880 TI - Cumulative sum: An individualized proficiency metric for laparoscopic fundamentals. AB - BACKGROUND: A reliable metric of technical proficiency is indispensable to the training of fellows and residents. The purpose of this study was to determine whether cumulative sum (Cusum) has predictive validity in laparoscopic training. We hypothesized that Cusum would be a better predictor of technical ability in fundamentals of laparoscopic surgery (FLS) than traditional practice volume metrics. METHODS: Twenty medical students were recruited to practice three FLS tasks: peg transfer, circle cut, and intracorporeal knot tie. Up to 7hours of self-directed practice was allotted to each participant. Practice attempts were scored by standard FLS criteria and monitored via Cusum. Each participant's terminal Cusum performance was analyzed retrospectively. Posttests were conducted by faculty blinded to practice performance. RESULTS: Eighteen participants completed the study (90%). Median adjusted posttest scores were 102.3, 84.1, and 78.6 for peg transfer, circle cut, and knot tie, respectively. For the knot tie task, participants who exceeded the Cusum decision interval during their final practice attempts performed significantly higher on posttesting (81.2 vs 71.5, p=0.015). Knot tie terminal Cusum score was positively associated with posttest performance after adjusting for practice volume (p=0.031). Total practice volume and practice time were not significantly associated with posttest performance for any FLS task. CONCLUSION: Cusum score is a more valid representation of FLS proficiency than practice volume or practice time. Incorporating Cusum in a clinical setting may promote more efficient allocation of time resources and operative volume. PMID- 26585881 TI - Elective pediatric surgical care in a forward deployed setting: What is feasible vs. what is reasonable. AB - OBJECTIVE: To describe the scope and outcomes of elective pediatric surgical procedures performed during combat operations. BACKGROUND: The care of patients in Operation Enduring Freedom (OEF) includes elective humanitarian surgery on Afghan children. Unlike military reports of pediatric trauma care, there is little outcome data on elective pediatric surgical care during combat operations to guide treatment decisions. METHODS: All elective surgical procedures performed on patients<=16years of age from May 2012 through April 2014 were reviewed. Procedures were grouped by surgical specialty and were further classified as single-stage (SINGLE) or multi-stage (MULTI). The primary endpoint was post operative complications requiring further surgery, and the secondary endpoint was post-operative follow up. RESULTS: A total of 311 elective pediatric surgical procedures were performed on 239 patients. Surgical specialties included general surgery, orthopedics, otolaryngology, ophthalmology, neurosurgery and urology. 178 (57%) were SINGLE while 133 (43%) were MULTI. Fifteen patients required 32 procedures for post-operative complications. Approximately half of all procedures were performed as outpatient surgery. Median length of stay for inpatient was 2.2days, and all patients survived to discharge. The majority of patients returned for outpatient follow-up (207, 87%), and 4 patients (1.7%) died after discharge. CONCLUSIONS: Elective pediatric surgical care in a forward deployed setting is feasible; however, limitations in resources for perioperative care and rehabilitation mandate prudent patient selection particularly with respect to procedures that require prolonged post-operative care. Formal guidance on the process of patient selection for elective humanitarian surgery in these settings is needed. PMID- 26585882 TI - Vulnerability, therapeutic misconception and informed consent: is there a need for special treatment of pregnant women in fetus-regarding clinical trials? AB - Historically, pregnant women have generally been excluded from clinical trials. One of the reasons for this exclusion has been the belief that pregnant women are vulnerable as research participants. Although this view has now largely fallen into disfavour, this article argues that in the situation where the pregnant woman is newly diagnosed with a fetal condition for which the only option, other than watchful waiting, is enrolment in a clinical trial, she should be considered a cognitively and medically vulnerable research participant. This is because she is in a highly stressed emotional state and so less able to decide completely freely whether or not to participate in the clinical trial. In other words, she is under a higher risk of therapeutic misconception and of not understanding what she is consenting to. This article suggests that in order for the consent of these women to be given freely and without emotional pressure, it has to be ensured that strategies are developed to ensure they are fully informed and actually understand the information. This surpasses the requirements of the English law of informed consent and also of General Medical Council (GMC) guidance on consent to research but such an approach would help safeguard that, despite these women's poor bargaining position, their trial participation is really free, voluntary and informed. PMID- 26585883 TI - Engineering and characterization of simplified vaginal and seminal fluid simulants. AB - BACKGROUND: Reported vaginal and seminal fluid simulants have complex compositions with multiple preparatory steps that contribute to physical instability. We report the design and characterization of stable and simplified buffers that mimic the salient physical/chemical properties of the physiological fluids. STUDY DESIGN/METHODS: Human cervicovaginal and seminal fluid samples were collected and buffering capacity was determined. The major buffering species were identified from published compositions of reproductive tract fluids. These values were used to compute the composition of vaginal and seminal fluid simulants. Ionic strength, buffering capacities, pH and osmolalities were then calculated or experimentally determined. Finally, cytotoxicity was evaluated in HEC-1-A cells and 3D reconstructed EpiVaginalTM tissue (VEC-100-FT) using naive cells/tissue and nonoxynol-9 as controls. RESULTS: The use of calculated amounts of conjugate acid and base for buffer development resulted in compositions that did not require endpoint pH adjustment and could be formulated as stable 10* concentrates. Furthermore, due to the absence of complex divalent salts, all our proposed simulants were stable at 4 degrees C for 1 month whereas precipitation and pH and osmolality changes were noted in reported buffers. Experimental determination of buffering capacities yielded similar values for undiluted cervicovaginal fluid (beta4.2-5.2=35.6 +/- 12.3 mM, N=7) and human seminal fluid (beta7-6=37.5 +/- 5 mM, N=3). All neat simulants showed significant cytotoxicity in HEC-1-A cells but were well tolerated by organotypic vaginal tissue. CONCLUSIONS: We report revised and improved compositions of buffers mimicking salient properties of vaginal and seminal fluid necessary for in vitro product evaluation. IMPLICATIONS: To support research in reproductive health and in particular drug delivery, we have designed and characterized stable new media to mimic these important fluids that can be used in a variety of in vitro studies. PMID- 26585885 TI - Trans-Balloon Visualisation During Dilatation (TBVD) of Oesophageal Strictures: a Novel Innovation. AB - BACKGROUND: Hydrostatic balloon dilatation of upper gastrointestinal strictures is associated with a risk of perforation that varies with the underlying pathology and with the technique employed. We present a technique of trans balloon visualisation of the stricture during dilatation (TBVD) that allows direct 'real-time' observation of the effect of dilatation on the stricture, facilitating early recognition of mucosal abruption, thereby reducing the perforation rate. PATIENTS AND METHODS: We retrospectively analysed 100 consecutive patients, undergoing balloon dilatation of oesophageal strictures between 1st of January 2011 and 1st of July 2014. RESULTS: One hundred patients underwent 186 dilatations, with 34 having multiple procedures (mean 1.86). All had oesophageal strictures (mean diameter 8.49 mm, range 5-11 mm) and most underwent dilatation up to a maximum of 17 mm (mean 14.7 mm). Fifty-six percent were male and the average age was 62.5 years (17-89 years). Only one patient (0.5% of all procedures) had a full-thickness perforation requiring intervention while just one further patient had a deep mucosal tear that did not require intervention. CONCLUSIONS: TBVD is a safe technique with a short learning curve and is one of the important factors that allow potentially difficult dilatations to be performed safely with an exceptionally low rate of adverse events of less than 1%. PMID- 26585886 TI - Raising clinical awareness for better dengue fever outbreak control. PMID- 26585887 TI - AUTHOR Reply. PMID- 26585888 TI - Author Reply. PMID- 26585889 TI - Editorial Comment. PMID- 26585890 TI - Editorial Comment. PMID- 26585891 TI - Oestrogen receptor positive breast cancer metastasis to bone: inhibition by targeting the bone microenvironment in vivo. AB - Clinical trials have shown that adjuvant Zoledronic acid (ZOL) reduces the development of bone metastases irrespective of ER status. However, post menopausal patients show anti-tumour benefit with ZOL whereas pre-menopausal patients do not. Here we have developed in vivo models of spontaneous ER+ve breast cancer metastasis to bone and investigated the effects of ZOL and oestrogen on tumour cell dissemination and growth. ER+ve (MCF7, T47D) or ER-ve (MDA-MB-231) cells were administered by inter-mammary or inter-cardiac injection into female nude mice +/- estradiol. Mice were administered saline or 100 MUg/kg ZOL weekly. Tumour growth, dissemination of tumour cells in blood, bone and bone turnover were monitored by luciferase imaging, histology, flow cytometry, two photon microscopy, micro-CT and TRAP/P1NP ELISA. Estradiol induced metastasis of ER+ve cells to bone in 80-100 % of animals whereas bone metastases from ER-ve cells were unaffected. Administration of ZOL had no effect on tumour growth in the fat pad but significantly inhibited dissemination of ER+ve tumour cells to bone and frequency of bone metastasis. Estradiol and ZOL increased bone volume via different mechanisms: Estradiol increased activity of bone forming osteoblasts whereas administration of ZOL to estradiol supplemented mice decreased osteoclast activity and returned osteoblast activity to levels comparable to that of saline treated mice. ER-ve cells require increased osteoclast activity to grow in bone whereas ER+ve cells do not. Zol does not affect ER+ve tumour growth in soft tissue, however, inhibition of bone turnover by ZOL reduced dissemination and growth of ER+ve breast cancer cells in bone. PMID- 26585893 TI - Spherical nitrogen-doped hollow mesoporous carbon as an efficient bifunctional electrocatalyst for Zn-air batteries. AB - Materials based upon porous carbon have gained considerable attention due to their high surface area, electric conductivity, thermal and chemical stability, low density, and availability. These superior properties make them ideal for diverse applications. Doping these carbon nanostructures holds promise of designing the properties of these structures and opening the door to practical applications. Herein, we report the preparation of hollow N-doped mesoporous carbon (HMC) spheres fabricated via polymerization and carbonization of dopamine on a sacrificial spherical SiO(2) template that is removed upon hydrofluoric acid etching. The morphology and structural features of these HMCs were evaluated using scanning electron microscopy and transmission electron microscopy and the N doping (7.1 at%) was confirmed by X-ray photoelectron spectroscopy (XPS). The oxygen reduction/evolution reaction (ORR/OER) performance of N-doped HMC was evaluated using rotating disk electrode (RDE) voltammetry in an alkaline electrolyte. N-doped HMC demonstrated a high ORR onset potential of -0.055 V (vs. Hg/HgO) and excellent stability. The outstanding bifunctional activity was implemented in a practical Zn-air battery (ZAB), which exhibited a small charge discharge voltage polarization of 0.89 V and high stability over repeated cycling. PMID- 26585892 TI - Oncogenic role of SIRT1 associated with tumor invasion, lymph node metastasis, and poor disease-free survival in triple negative breast cancer. AB - The aim of this study is to evaluate the biological role and clinical implications of silent mating type information regulation 2 homolog 1 (SIRT1) as a novel candidate for target therapy in triple negative breast cancer (TNBC) for which there is no specific agent. 344 patients who received surgical resection for TNBC from January 2003 to December 2006 at Seoul National University Hospital were enrolled, and the role of SIRT1 protein was evaluated via immunohistochemistry on tissue samples. In vivo experiments to evaluate tumor invasiveness were carried out with three human TNBC cell lines following SIRT1 siRNA transfection. Expression of SIRT1 significantly correlated with lymph node metastasis (p = 0.008). In multivariate analysis, SIRT1 expression (p = 0.011), T stage (p = 0.014), and lymphatic invasion (p < 0.001) were revealed to be independent predictive factors for lymph node metastasis. Combination of these three parameters revealed predictive performance for lymph node metastasis with an area under the curve (AUC) of 0.689 on receiver operating characteristics (ROC) curves analysis. SIRT1 expression correlated with shorter disease-free survival (P = 0.003) but not with overall survival. Inhibition of SIRT1 with small interfering RNA (siRNA) conspicuously suppressed the invasiveness of TNBC cell lines. This study reveals the role of SIRT1 on tumor invasiveness and unfavorable clinical outcomes, and we suggest its potential role as a prognostic indicator as well as a novel therapeutic target in TNBC. PMID- 26585894 TI - Patients predict their own outcome with CRT. PMID- 26585895 TI - Knockdown of NLRP5 arrests early embryogenesis in sows. AB - NLRP (NLR family, Pyrin domain containing) genes have both immunization- and reproduction-related clades in mammals. Nlrp5 is a reproduction-related gene, originally identified in the mouse, which plays a key role in mouse early embryogenesis. Previous studies estimated that the porcine NLRP5 gene is assigned to the long arm of chromosome 6 and expressed in oocytes. However, the expression pattern of the NLRP5 gene in the porcine reproductive tract, and the localization and function of NLRP5 protein in porcine preimplantation embryos are still unknown. Here, we show that NLRP5 transcripts and protein are detected exclusively in the ovary in the porcine reproductive tract. Furthermore, the transcripts display a sharp decline in porcine preimplantation embryos before zygotic genome activation, but the protein remains present through to the blastocyst stage, localize in the cytoplasm and close to the subcortex of porcine oocytes and preimplantation embryos. Moreover, the knockdown of NLRP5 expression in zygotes using RNA interference arrested early embryonic development. These results provide the first evidence that the NLRP5 gene is required for early embryogenesis in sows, suggesting that this gene might play an essential role in zygotic genome activation. PMID- 26585896 TI - Preoperative predictive factors and further risk stratification of biochemical recurrence in clinically localized high-risk prostate cancer. AB - BACKGROUND: To identify preoperative predictive factors for biochemical recurrence (BCR) and to further stratify its risk in high-risk localized prostate cancer patients receiving radical prostatectomy (RP). METHODS: Subjects included 195 high-risk prostate cancer patients undergoing RP from 2000 to 2012. RP consisted of retropubic radical prostatectomy and robot-assisted radical prostatectomy, involving 84 cases and 111 cases, respectively. BCR was defined as a prostate serum antigen (PSA) level >=0.2 ng/mL. BCR-free survival (BCRFS) was calculated using the Kaplan-Meier method. Preoperative predictors of BCR were assessed with Cox's proportional hazard regression analysis. RESULTS: Eighty-nine patients (45.6 %) experienced recurrence. BCRFS rates 3 and 5 years after RP were 58 and 50 %, respectively. Prostate volume, transition zone volume, and Gleason score were not significantly associated with BCR. Patients with higher preoperative PSA, PSA density (PSAD), PSA density of the transition zone, percentage of positive cores (PPC), and PPC from the dominant side showed significantly lower BCRFS. The PPC from the dominant side and PSAD were significant independent prognostic factors for BCR. Using these variables, the hazard ratio of BCR could be calculated and patients stratified into three risk groups. The 5-year BCRFS rates for Groups 1, 2, and 3 were 64.9 %, 48.1 %, and 21.3 %, respectively. CONCLUSIONS: Patients with high-risk localized prostate cancer as currently defined do not have uniformly poor prognosis after RP. PPC from the dominant side and PSAD are significant predictors of BCR. These factors can identify high-risk patients with very poor prognosis. PMID- 26585897 TI - Macrophage traits in cancer cells are induced by macrophage-cancer cell fusion and cannot be explained by cellular interaction. AB - BACKGROUND: Cell fusion is a natural process in normal development and tissue regeneration. Fusion between cancer cells and macrophages generates metastatic hybrids with genetic and phenotypic characteristics from both maternal cells. However, there are no clinical markers for detecting cell fusion in clinical context. Macrophage-specific antigen CD163 expression in tumor cells is reported in breast and colorectal cancers and proposed being caused by macrophages-cancer cell fusion in tumor stroma. The purpose of this study is to examine the cell fusion process as a biological explanation for macrophage phenotype in breast. METHODS: Monocytes, harvested from male blood donor, were activated to M2 macrophages and co-cultured in ThinCert transwell system with GFP-labeled MCF-7 cancer cells. MCF7/macrophage hybrids were generated by spontaneous cell fusion, isolated by fluorescence-activated cell sorting and confirmed by fluorescence microscopy, short tandem repeats analysis and flow cytometry. CD163 expression was evaluated in breast tumor samples material from 127 women by immunohistochemistry. RESULTS: MCF-7/macrophage hybrids were generated spontaneously at average rate of 2 % and showed phenotypic and genetic traits from both maternal cells. CD163 expression in MCF-7 cells could not be induced by paracrine interaction with M2-activated macrophages. CD163 positive cancer cells in tumor sections grew in clonal collection and a cutoff point >25 % of positive cancer cells was significantly correlated to disease free and overall survival. CONCLUSIONS: In conclusion, macrophage traits in breast cancer might be caused by cell fusion rather than explained by paracrine cellular interaction. These data provide new insights into the role of cell fusion in breast cancer and contributes to the development of clinical markers to identify cell fusion. PMID- 26585898 TI - Water management, rice varieties and mycorrhizal inoculation influence arsenic concentration and speciation in rice grains. AB - A pot experiment was carried out to investigate the effects of water management and mycorrhizal inoculation on arsenic (As) uptake by two rice varieties, the As resistant BRRI dhan 47 (B47) and As-sensitive BRRI dhan 29 (B29). Grain As concentration of B47 plants was significantly lower than that of B29, and grain As concentration of B47 was higher under flooding conditions than that under aerobic conditions. In general, mycorrhizal inoculation (Rhizophagus irregularis) had no significant effect on grain As concentrations, but decreased the proportion of inorganic arsenic (iAs) in grains of B47. The proportion of dimethylarsinic acid (DMA) in the total grain As was dramatically higher under flooding conditions. Results demonstrate that rice variety selection and appropriate water management along with mycorrhizal inoculation could be practical countermeasures to As accumulation and toxicity in rice grains, thus reducing health risks of As exposure in rice diets. PMID- 26585899 TI - Stochastic nonlinear mixed effects: a metformin case study. AB - In nonlinear mixed effect (NLME) modeling, the intra-individual variability is a collection of errors due to assay sensitivity, dosing, sampling, as well as model misspecification. Utilizing stochastic differential equations (SDE) within the NLME framework allows the decoupling of the measurement errors from the model misspecification. This leads the SDE approach to be a novel tool for model refinement. Using Metformin clinical pharmacokinetic (PK) data, the process of model development through the use of SDEs in population PK modeling was done to study the dynamics of absorption rate. A base model was constructed and then refined by using the system noise terms of the SDEs to track model parameters and model misspecification. This provides the unique advantage of making no underlying assumptions about the structural model for the absorption process while quantifying insufficiencies in the current model. This article focuses on implementing the extended Kalman filter and unscented Kalman filter in an NLME framework for parameter estimation and model development, comparing the methodologies, and illustrating their challenges and utility. The Kalman filter algorithms were successfully implemented in NLME models using MATLAB with run time differences between the ODE and SDE methods comparable to the differences found by Kakhi for their stochastic deconvolution. PMID- 26585901 TI - Morphological distribution of thyroid cancer from Cancer Incidence in Five Continents Vol. X. PMID- 26585900 TI - Brevibacillus gelatini sp. nov., isolated from a hot spring. AB - Two Gram-stain-positive, moderately thermophilic, endospore-forming, rod-shaped, motile bacteria designated PDF4T and PDF10, were isolated from Camkoy hot spring in the provinces of Aydin, Turkey and were characterized in order to determine their phylogenetic position. 16S rRNA gene sequence analysis revealed that the two strains belonged to the genus Brevibacillus. Strain PDF4T showed highest 16S rRNA gene sequence similarity to strain PDF10 (99.5 %), Brevibacillus brevis DSM 30T (98.9 %), Brevibacillus parabrevis DSM 8376T (98.6 %) and Brevibacillus formosus DSM 9885T (98.5 %); similarities to other species of the genus Brevibacillus were less than 98.5 %. The predominant fatty acids of strain PDF4T were anteiso-C15 : 0 (60.0 %) and iso-C15 : 0 (22.3 %). The polar lipids of strain PDF4T consisted of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylmonomethylethanolamine, an unknown phospholipid, two unknown lipid, an unknown aminophospholipid and two unknown aminolipids. MK-7 was detected as a sole respiratory quinone, and the cell wall of strain PDF4T contained meso-diaminopimelic acid. The DNA G+C content of strain PDF4T was 51.7 mol%. DNA-DNA hybridization showed less than 60 % relatedness between strain PDF4T and type strains of the most closely related species given above. Based on these data, the two strains are considered to represent a novel species of the genus Brevibacillus, for which the name Brevibacillus gelatini sp. nov. is proposed. The type strain is PDF4T ( = NCCB 100559T = DSM 100115T). PMID- 26585904 TI - Quantum Process Tomography of an Optically-Controlled Kerr Non-linearity. AB - Any optical quantum information processing machine would be comprised of fully characterized constituent devices for both single state manipulations and tasks involving the interaction between multiple quantum optical states. Ideally for the latter, would be an apparatus capable of deterministic optical phase shifts that operate on input quantum states with the action mediated solely by auxiliary signal fields. Here we present the complete experimental characterization of a system designed for optically controlled phase shifts acting on single-photon level probe coherent states. Our setup is based on a warm vapor of rubidium atoms under the conditions of electromagnetically induced transparency with its dispersion properties modified through the use of an optically triggered N-type Kerr non-linearity. We fully characterize the performance of our device by sending in a set of input probe states and measuring the corresponding output via time-domain homodyne tomography and subsequently performing the technique of coherent state quantum process tomography. This method provides us with the precise knowledge of how our optical phase shift will modify any arbitrary input quantum state engineered in the mode of the reconstruction. PMID- 26585905 TI - Methane attenuates myocardial ischemia injury in rats through anti-oxidative, anti-apoptotic and anti-inflammatory actions. AB - Myocardial infarction (MI) remains the most frequent cardiovascular disease with high mortality. Recently, methane has been shown protective effects on small intestinal ischemia-reperfusion injury. We hypothesized that methane-rich saline (MS) could protect the myocardium again MI via its anti-oxidative, anti-apoptotic and anti-inflammatory effects. In experiment 1, tetrazolium chloride staining and detection of myocardial enzymes and oxidative and inflammatory parameters were performed at 12h after MI to determine the optimal dose at which intraperitoneal MS exerted the best protective effects on MI. In experiment 2, rats were treated with 10 ml/kg MS. Myocyte apoptosis was detected 72 h after MI, and cardiac function and myocardial remodeling were evaluated 4 weeks after MI. Results showed different dose of MS reduced infarct area, decreased myocardial enzymes, inhibited inflammation and oxidative stress following MI. The optimal dose of MS was 10 mg/kg. Moreover, treatment with 10mg/kg MS for 3 days significantly reduced myocyte apoptosis, improved cardiac function and inhibited myocardial remodeling (reduced anterior wall thickness, attenuated myocyte hypertrophy, and decreased myocardial collagen). MS protects the myocardium of MI rats via its anti-oxidative, anti-inflammatory, anti-apoptotic and anti-remodeling activities. Thus, MS provides a novel and promising strategy for the treatment of ischemic heart diseases. PMID- 26585906 TI - DHA-induced stress response in human colon cancer cells - Focus on oxidative stress and autophagy. AB - Polyunsaturated fatty acids (PUFAs) are important constituents of the diet and health benefits of omega-3/n-3 PUFAs, especially eicosapentaenoic acid (EPA, 20:5 n-3) and docosahexaenoic acid (DHA, 22:6 n-3) have been well documented in relation to several diseases. Increasing evidence suggests that n-3 PUFAs may have anticancer activity and improve the effect of conventional cancer therapy. The mechanisms behind these effects are still unclear and need to be elucidated. We have examined the DHA-induced stress response in two human colon cancer cell lines, SW620 and Caco-2. SW620 cells are growth-inhibited at early time points by DHA, while the growth of Caco-2 cells almost remains unaffected by the same treatment. Gene expression analysis of SW620 cells treated with DHA revealed changes at early time points; transcripts involved in oxidative stress and autophagy were among the first to be differentially expressed. We find that oxidative stress is induced in both cell lines, although at different time points and to different extent. DHA induced nuclear translocation of the oxidative stress sensor NFE2L2 in both cell lines, indicating an induction of an anti oxidative response. However, vitamin E did not counteract ROS-production or the translocation of NFE2L2 to the nucleus. Neither vitamin E nor the antioxidants butylated hydoxyanisole (BHA) and butylated hydoxytoluene (BHT) did affect the growth inhibition in SW620 cells after DHA-treatment. Also, siRNA-mediated down regulation of NFE2L2 did not sensitize SW620 and Caco-2 cells to DHA. These results indicate that oxidative stress response is not the cause of DHA-induced cytotoxicity in SW620 cells. Using biochemical and imaging based functional assays, we found a low basal level of autophagy and no increase in autophagic flux after adding DHA to the SW620 cells. However, Caco-2 cells displayed a higher level of autophagy, both in the absence and presence of DHA. Inhibition of autophagy by siRNA mediated knock down of ATG5 and ATG7 sensitized both SW620 and Caco-2 cells to DHA. Stimulation of autophagy by rapamycin in SW620 and Caco-2 cells resulted in decreased DHA-sensitivity and inhibition of autophagy in Caco-2 cells by chloroquine resulted in increased DHA-sensitivity. These results suggest that autophagy is important for the DHA sensitivity of colon cancer cells and imply possible therapeutic effects of this fatty acid against cancer cells with low autophagy. PMID- 26585907 TI - Lack of a significant impact of Gag-Protease-mediated HIV-1 replication capacity on clinical parameters in treatment-naive Japanese individuals. AB - BACKGROUND: HLA class I-associated escape mutations in HIV-1 Gag can reduce viral replication, suggesting that associated fitness costs could impact HIV-1 disease progression. Previous studies in North American and African cohorts have reported reduced Gag-Protease mediated viral replication capacity (Gag-Pro RC) in individuals expressing protective HLA class I alleles including HLA-B*57:01, B*27:05, and B*81:01. These studies also reported significant positive associations between Gag-Pro RCs and plasma viral load (pVL). However, these HLA alleles are virtually absent in Japan, and the importance of Gag as an immune target is not clearly defined in this population. RESULTS: We generated chimeric NL4-3 viruses carrying patient-derived Gag-Protease from 306 treatment-naive Japanese individuals chronically infected with HIV-1 subtype B. We analyzed associations between Gag-Pro RC and clinical markers of HIV-1 infection and host HLA expression. We observed no significant correlation between Gag-Pro RC and pVL in Japan in the overall cohort. However, upon exclusion of individuals expressing Japanese protective alleles HLA-B*52:01 and B*67:01, Gag-Pro RC correlated positively with pVL and negatively with CD4 T-cell count. Our results thus contrast with studies from other global cohorts reporting significantly lower Gag Pro RC among persons expressing protective HLA alleles, and positive relationships between Gag-Pro RC and pVL in the overall study populations. We also identified five amino acids in Gag-Protease significantly associated with Gag-Pro RC, whose effects on RC were confirmed by site-directed mutagenesis. However, of the four mutations that decreased Gag-Pro RC, none were associated with reductions in pVL in Japan though two were associated with lower pVL in North America. CONCLUSIONS: These data indicate that Gag fitness does not affect clinical outcomes in subjects with protective HLA class I alleles as well as the whole Japanese population. Moreover, the impact of Gag fitness costs on HIV-1 clinical parameters in chronic infection is likely low in Japan compared to other global populations. PMID- 26585908 TI - Patient-specific instrumentation in total knee arthroplasty: simpler, faster and more accurate than standard instrumentation-a randomized controlled trial. AB - PURPOSE: This randomized controlled trial was conducted to compare patient specific instrumentation (PSI) to standard instrumentation regarding efficacy to achieve a good coronal alignment and differences in surgical time, blood loss and length of stay. METHODS: Ninety-five of 100 randomized patients eligible for total knee arthroplasty were analysed. PSI with magnetic resonance and long-leg radiograph was performed in 47 patients, while 48 patients received standard instrumentation. Primary outcome measure was coronal alignment, evaluated with long-leg radiograph. Deviation >3 degrees varus/valgus was considered an outlier. Surgical time was compared from skin to skin. Length of stay was a post hoc analysis. Blood loss was evaluated comparing the number of blood units spent, fall in haemoglobin and haematocrit levels. RESULTS: Standard instrumentation had a higher number of outliers in the coronal alignment with a relative risk of 3.015, compared to PSI. Surgical time was reduced by 18 min (24.8 %) with the PSI, as well as length of stay, with a half-day reduction. Number of blood units spent was significantly less in the PSI group. Relative risk of transfusion was 7.09 for patients in the standard instrumentation group. Difference in Hg and Htc levels were not significant. No patient had to abandon PSI. Minor changes to preoperative plan occurred in 14.9 % of the patient: cut review in 4.3 % and insert change in 10.6 %. CONCLUSIONS: Patient-specific instrumentation (PSI) is able to provide important advantages over standard instrumentation in total knee arthroplasty: it lowers the risk of outliers and transfusion, is a faster procedure and enables a shorter length of stay with a low rate of intraoperative adjustments. LEVEL OF EVIDENCE: I. PMID- 26585909 TI - Cross-sectional area of hamstring tendon autograft after anatomic triple-bundle ACL reconstruction. AB - PURPOSE: The purpose was to evaluate the cross-sectional area changes in hamstring tendon autografts up to 5 years after the anatomic triple-bundle anterior cruciate ligament (ACL) reconstruction. METHODS: A total of 178 MRI scans from 139 patients (35 males, 104 females, mean age 30.4 years) with the anatomic triple-bundle ACL reconstructions were obtained to evaluate the cross sectional area of the ACL grafts. They were classified into seven groups according to the period from reconstruction to MRI evaluation: Group -2 months (m.), Group 3-6 m., Group 7-12 m, Group 1-2 years (y.), Group 2-3 y., Group 3-4 y., and Group 4 y.-. Intra-operatively, the cross-sectional area of the graft was measured directly using a custom-made area micrometre. Post-operatively, the cross-sectional area of the grafts' mid-substance was measured with oblique axial MRI slices perpendicular to the long axis of the grafts using a digital radiology viewing program. The percent increase in the cross-sectional area was calculated by dividing the post-operative cross-sectional area by the intra-operative cross sectional area. RESULTS: The mean percent increase in the cross-sectional area in Groups -2 m., 3-6 m., 7-12 m., 1-2 y., 2-3 y., 3-4 y., and 4 y.- was 105.7 +/- 14.0, 134.9 +/- 20.0, 137.3 +/- 27.8, 129.4 +/- 22.2, 124.1 +/- 20.4, 117.8 +/- 16.9, and 117.1 +/- 17.2 %, respectively. The percent increase in Groups 3-6 m., 7-12 m., and 1-2 y. was significantly greater than in Group -2 m., while that in Group 4 y.- was significantly less than in Group 7-12 m. CONCLUSIONS: The cross sectional area of the hamstring tendon autografts after the anatomic triple bundle ACL reconstruction increases over time up to 1 year post-operatively, decreases gradually thereafter, and reaches plateau at around 3 years. LEVEL OF EVIDENCE: Retrospective case series, Level IV. PMID- 26585910 TI - Transcriptome responses to heat- and cold-stress in ladybirds (Cryptolaemus montrouzieri Mulasnt) analyzed by deep-sequencing. AB - BACKGROUND: Changed temperature not only threaten agricultural production, but they also affect individual biological behavior, population and community of many insects, and consequently reduce the stability of our ecosystem. Insect's ability to respond to temperature stress evolved through a complex adaptive process, thus resulting in varied temperature tolerance among different insects. Both high and low extreme temperatures are detrimental to insect development since they constitute an important abiotic stress capable of inducing abnormal biological responses. Many studies on heat or cold tolerance of ladybirds have focused on measurements of physiological and biochemical indexes such as supercooling point, higher/lower lethal temperatures, survival rate, dry body weight, water content, and developmental duration. And studies of the molecular mechanisms of ladybird responses to heat or cold stress have focused on single genes, such as those encoding heat shock proteins, but has not been analyzed by transcriptome profiling. RESULTS: In this study, we report the use of Digital Gene Expression (DGE) tag profiling to gain insight into transcriptional events associated with heat- and cold-stress in C. montrouzieri. About 6 million tags (49 bp in length) were sequenced in a heat stress group, a cold stress group and a negative control group. We obtained 687 and 573 genes that showed significantly altered expression levels following heat and cold shock treatments, respectively. Analysis of the global gene expression pattern suggested that 42 enzyme-encoding genes mapped to many Gene Ontology terms are associated with insect's response to heat- and cold stress. CONCLUSIONS: These results provide a global assessment of genes and molecular mechanisms involved in heat and cold tolerance. PMID- 26585911 TI - Chronic renal disease is not chronic kidney disease: implications for use of the QRISK and Joint British Societies risk scores. AB - BACKGROUND: Chronic kidney disease (CKD) is a major risk factor for cardiovascular disease (CVD) and European guidelines advocate assessment of CVD risk. QRISK and JBS3 risk calculators do not use the consensus definition of CKD stages 3-5 but instead use a definition referring to renal pathologies and CKD stages 4 and 5. Consequently, there is potential for doctors to misclassify their patients when using these risk calculators. OBJECTIVES: To quantify the number of people who may be affected by such misclassifications. METHODS: Database analysis using the Clinical Practice Research Datalink (CPRD).We identified 2512053 adults aged 25-84 without prior history of CVD on 1st January 2014. We identified those with 'chronic renal disease' and/or CKD by searching medical event history data. RESULTS: The study population was 48.7% male with mean age of 50.2 years. A total of 80718 had diagnostic READ codes for CKD stages 3, 4 or 5. Of these, 6585 individuals (8.2%) were classified as having 'chronic renal disease' according to the updated QRISK 2014, up from 3365 according to QRISK 2013. Whilst the updated QRISK definition of 'chronic renal disease' in total identified 62% more people than previously and had improved sensitivity for CKD stages 3 to 5, sensitivity remained poor (8.16%; 95% CI: 7.97-8.35%). CONCLUSION: Misuse of risk scores by general practitioners could result in clinically important differences in risk estimates. Users of risk scores should recognize the potential for error and developers should aim to label risk factors more clearly. PMID- 26585912 TI - Latent class analysis suggests four distinct classes of complementary medicine users among women with breast cancer. AB - BACKGROUND: Breast cancer patients commonly report using >1 form of complementary and alternative medicine (CAM). However, few studies have attempted to analyze predictors and outcomes of multiple CAM modalities. We sought to group breast cancer patients by clusters of type and intensity of complementary and alternative medicine (CAM) use following diagnosis. METHODS: Detailed CAM use following breast cancer diagnosis was assessed in 2002-2003 among 764 female residents of Long Island, New York diagnosed with breast cancer in 1996-1997. Latent class analysis (LCA) was applied to CAM modalities while taking into account frequency and intensities. RESULTS: Four distinct latent classes of CAM use emerged: 1) "Low-dose supplement users" (40%), who used only common nutritional supplements; 2) "Vitamin/mineral supplement users" (39%), using an abundance of supplements in addition to other practices; 3) "Mind-body medicine users" (12%), with near-universal use of supplements, mind-body medicine techniques, and massage; and 4) "Multi-modality high-dose users" (9%), who were highly likely to use nearly all types of CAM. Predictors of membership in classes with substantial CAM use included younger age, more education, higher income, Jewish religion, ideal body mass index, higher fruit and vegetable intake, higher levels of physical activity, receipt of adjuvant chemotherapy, and prior use of oral contraceptives. CONCLUSIONS: LCA identified important subgroups of breast cancer patients characterized by varying degrees of complementary therapy use. Further research should explore the reproducibility of these classes and investigate the association between latent class membership and breast cancer outcomes. PMID- 26585913 TI - Boosting plant immunity with CRISPR/Cas. AB - CRISPR/Cas has recently been transferred to plants to make them resistant to geminiviruses, a damaging family of DNA viruses. We discuss the potential and the limitations of this method.See related Research: http://www.genomebiology.com/2015/16/1/238. PMID- 26585914 TI - Low Tidal Volume Ventilation: Trust but Verify. PMID- 26585915 TI - Humidification During Invasive Mechanical Ventilation: Less Lung Inflammation With Optimal Gas Conditioning. PMID- 26585916 TI - Reducing Unplanned Extubations in the Pediatric ICU: Are We Seeing the Whole Picture? PMID- 26585917 TI - Reducing Unplanned Extubations in the Pediatric ICU: Are We Seeing the Whole Picture?--Reply. PMID- 26585919 TI - Overwhelming majority of junior doctors vote for strike action. PMID- 26585920 TI - A Dy2 single-molecule magnet with benzoate anions and phenol-O(-) bridging groups. AB - A Dy2 single-molecule magnet, namely [Dy2(H3L)2(PhCOO)4].4H2O (1), was obtained from the reaction of Dy(PhCOO)3 with 1,5-bis(2-hydroxy-3 methoxybenzylidene)carbonohydrazide (H4L). Each Dy(III) ion is located in the chelating pocket [DyO8N] formed by the carboxyl-O, phenol-O, carbohydrazide-O and carbohydrazide-N, forming a tricapped trigonal prism configuration. The Dy(III) centers are bridged by the benzoate anions with MU2:eta(1),eta(2) coordination mode and the phenol-O(-) groups in the form of MU1:eta(2), respectively. The appearance of frequency-dependent out-of-phase (chi''M) signals indicates that 1 displays single-molecule magnet (SMM) behaviour. Fits of the ac data gave an energy barrier (Ueff) of 42.7 K with a pre-exponential factor (tau0) of 1.31 * 10(-7) s. The structure-property relationship of some selected Dy2 paradigmatic compounds was further discussed. PMID- 26585921 TI - Children's diets, pesticide uptake, and implications for risk assessment: An Israeli case study. AB - The presence of pesticides in the Israeli food supply is well documented but little is known about the risks posed by children's diets for potential exposures. We investigated potential exposures to food-borne pesticides in a sample of 301 urban Israeli children (2008-10). Data from a food frequency questionnaire, 24 hour food recall, and Israel's national pesticide monitoring program were used to estimate uptake factors for 26 compounds in 27 fruits and vegetables. A pilot risk assessment was performed and the findings were compared with the Israel Ministry of Health's 2012 pesticide risk assessment for the general population. The surveyed children had higher potential exposures than the general population for over one third of the compounds, and uptake factors exceeded the Acceptable Daily Intake in ten compounds. Methamidophos, exceeded the ADI at the 25th percentile and fenamiphos, iprodione, and oxydemethon methyl, exceeded the ADI at the 50 percentile. ADIs for several compounds were exceeded even though the residues detected were below the statutory limit. Improved monitoring, enforcement, and revision of the Maximum Residue Limit for certain food/pesticide pairs are indicated as is the need to incorporate data on children's actual food consumption in national risk assessments. PMID- 26585922 TI - A comprehensive toxicological safety assessment of an aqueous extract of Polypodium leucotomos (Fernblock((r))). AB - A battery of toxicological studies was conducted in accordance with internationally accepted standards to investigate the genotoxicity and repeated dose oral toxicity of Fernblock((r)), a commercial aqueous extraction of the leaves of the tropical fern Polypodium leucotomos used for its oral and topical photoprotective properties. No evidence of mutagenicity was observed in a bacterial reverse mutation test or in vitro mammalian chromosomal aberration test nor was any genotoxic activity observed in an in vivo mouse micronucleus test. Two repeated-dose oral toxicity studies were conducted in male and female Wistar rats. In the first study, no mortality or toxic effects were observed and no target organs were identified at doses administered for 14 days by gavage up to the maximum dose of 5000 mg/kg bw/day. Based on these results, a 90-day study was conducted at 0, 300, 600, and 1200 mg/kg bw/day. No mortality or treatment related adverse effects were observed and no target organs were identified. The NOAEL from the 90-day study was determined to be 1200 mg/kg bw/day, the highest dose tested. PMID- 26585923 TI - Automated Multiplex LC-MS/MS Assay for Quantifying Serum Apolipoproteins A-I, B, C-I, C-II, C-III, and E with Qualitative Apolipoprotein E Phenotyping. AB - BACKGROUND: Direct and calculated measures of lipoprotein fractions for cardiovascular risk assessment suffer from analytical inaccuracy in certain dyslipidemic and pathological states, most commonly hypertriglyceridemia. LC MS/MS has proven suitable for multiplexed quantification and phenotyping of apolipoproteins. We developed and provisionally validated an automated assay for quantification of apolipoprotein (apo) A-I, B, C-I, C-II, C-III, and E and simultaneous qualitative assessment of apoE phenotypes. METHODS: We used 5 value assigned human serum pools for external calibration. Serum proteins were denatured, reduced, and alkylated according to standard mass spectrometry-based proteomics procedures. After trypsin digestion, peptides were analyzed by LC MS/MS. For each peptide, we measured 2 transitions. We compared LC-MS/MS results to those obtained by an immunoturbidimetric assay or ELISA. RESULTS: Intraassay CVs were 2.3%-5.5%, and total CVs were 2.5%-5.9%. The LC-MS/MS assay correlated (R = 0.975-0.995) with immunoturbidimetric assays with Conformite Europeenne marking for apoA-I, apoB, apoC-II, apoC-III, and apoE in normotriglyceridemic (n = 54) and hypertriglyceridemic (n = 46) sera. Results were interchangeable for apoA-I <=3.0 g/L (Deming slope 1.014) and for apoB-100 <=1.8 g/L (Deming slope 1.016) and were traceable to higher-order standards. CONCLUSIONS: The multiplex format provides an opportunity for new diagnostic and pathophysiologic insights into types of dyslipidemia and allows a more personalized approach for diagnosis and treatment of lipid abnormalities. PMID- 26585924 TI - Sulfatide Analysis by Mass Spectrometry for Screening of Metachromatic Leukodystrophy in Dried Blood and Urine Samples. AB - BACKGROUND: Metachromatic leukodystrophy (MLD) is an autosomal recessive disorder caused by deficiency in arylsulfatase A activity, leading to accumulation of sulfatide substrates. Diagnostic and monitoring procedures include demonstration of reduced arylsulfatase A activity in peripheral blood leukocytes or detection of sulfatides in urine. However, the development of a screening test is challenging because of instability of the enzyme in dried blood spots (DBS), the widespread occurrence of pseudodeficiency alleles, and the lack of available urine samples from newborn screening programs. METHODS: We measured individual sulfatide profiles in DBS and dried urine spots (DUS) from MLD patients with LC MS/MS to identify markers with the discriminatory power to differentiate affected individuals from controls. We also developed a method for converting all sulfatide molecular species into a single species, allowing quantification in positive-ion mode upon derivatization. RESULTS: In DBS from MLD patients, we found up to 23.2-fold and 5.1-fold differences in total sulfatide concentrations for early- and late-onset MLD, respectively, compared with controls and pseudodeficiencies. Corresponding DUS revealed up to 164-fold and 78-fold differences for early- and late-onset MLD patient samples compared with controls. The use of sulfatides converted to a single species simplified the analysis and increased detection sensitivity in positive-ion mode, providing a second option for sulfatide analysis. CONCLUSIONS: This study of sulfatides in DBS and DUS suggests the feasibility of the mass spectrometry method for newborn screening of MLD and sets the stage for a larger-scale newborn screening pilot study. PMID- 26585925 TI - MALDI-TOF-MS Assay to Detect the Hemizygous 22q11.2 Deletion in DNA from Dried Blood Spots. AB - BACKGROUND: A hemizygous deletion of 1.5-3 Mb in 22q11.2 causes a distinct clinical syndrome with variable congenital defects. Current diagnostic methods use fluorescent in situ hybridization (FISH) or comparative genomic hybridization by microarray to detect the deletion. Neither method is suitable for newborn screening (NBS), since they cannot be performed on dried blood spots (DBS). We developed a MALDI-TOF-MS assay that uses DBS to measure the hemizygous deletion of UFD1L, located within the 22q11.2 region. METHODS: We used DBS from 54 affected patients, previously tested by FISH or microarray, and 100 cord blood samples to evaluate the performance of the MALDI-TOF-MS assay. With a single primer pair, a 97-base oligonucleotide within UFD1L was amplified, as was a sequence on chromosome 18 that differs by 2 nucleotides. A multiplexed, single base extension reaction created allele-specific products for MALDI-TOF-MS detection. The products were spotted onto a silicon chip, and the height of the spectral peaks identified the relative amounts of target and reference gene. RESULTS: The median ratio of the spectral peak for each UFD1L target:reference base was 0.96 and 0.99 for controls, compared with 0.35 and 0.53 for 22q11 deletion syndrome patients. There was 100% concordance between FISH/microarray and MALDI-TOF-MS in all patients with 22q11.2 deletion syndrome. CONCLUSIONS: This method can be reliably performed with DBS and is suitable for high sample throughput. This assay may be considered for use in population-based NBS for 22q11.2 deletion. PMID- 26585926 TI - Protein-Specific Glycoprofiling for Patient Diagnostics. PMID- 26585928 TI - Ion Mobility in Clinical Analysis: Current Progress and Future Perspectives. AB - BACKGROUND: Ion mobility spectrometry (IMS) is a rapid separation tool that can be coupled with several sampling/ionization methods, other separation techniques (e.g., chromatography), and various detectors (e.g., mass spectrometry). This technique has become increasingly used in the last 2 decades for applications ranging from illicit drug and chemical warfare agent detection to structural characterization of biological macromolecules such as proteins. Because of its rapid speed of analysis, IMS has recently been investigated for its potential use in clinical laboratories. CONTENT: This review article first provides a brief introduction to ion mobility operating principles and instrumentation. Several current applications will then be detailed, including investigation of rapid ambient sampling from exhaled breath and other volatile compounds and mass spectrometric imaging for localization of target compounds. Additionally, current ion mobility research in relevant fields (i.e., metabolomics) will be discussed as it pertains to potential future application in clinical settings. SUMMARY: This review article provides the authors' perspective on the future of ion mobility implementation in the clinical setting, with a focus on ambient sampling methods that allow IMS to be used as a "bedside" standalone technique for rapid disease screening and methods for improving the analysis of complex biological samples such as blood plasma and urine. PMID- 26585927 TI - Quantification of Anaplastic Lymphoma Kinase Protein Expression in Non-Small Cell Lung Cancer Tissues from Patients Treated with Crizotinib. AB - BACKGROUND: Crizotinib has antitumor activity in ALK (anaplastic lymphoma receptor tyrosine kinase)-rearranged non-small cell lung cancer (NSCLC). The current diagnostic test for ALK rearrangement is breakapart fluorescence in situ hybridization (FISH), but FISH has low throughput and is not always reflective of protein concentrations. The emergence of multiple clinically relevant biomarkers in NSCLC necessitates efficient testing of scarce tissue samples. We developed an anaplastic lymphoma kinase (ALK) protein assay that uses multiplexed selected reaction monitoring (SRM) to quantify absolute amounts of ALK in formalin-fixed paraffin-embedded (FFPE) tumor tissue. METHODS: After validation in formalin fixed cell lines, the SRM assay was used to quantify concentrations of ALK in 18 FFPE NSCLC samples that had been tested for ALK by FISH and immunohistochemistry. Results were correlated with patient response to crizotinib. RESULTS: We detected ALK in 11 of 14 NSCLC samples with known ALK rearrangements by FISH. Absolute ALK concentrations correlated with clinical response in 5 of 8 patients treated with crizotinib. The SRM assay did not detect ALK in 3 FISH-positive patients who had not responded to crizotinib. In 1 of these cases, DNA sequencing revealed a point mutation that predicts a nonfunctional ALK fusion protein. The SRM assay did not detect ALK in any tumor tissue with a negative ALK status by FISH or immunohistochemistry. CONCLUSIONS: ALK concentrations measured by SRM correlate with crizotinib response in NSCLC patients. The ALK SRM proteomic assay, which may be multiplexed with other clinically relevant proteins, allows for rapid identification of patients potentially eligible for targeted therapies. PMID- 26585929 TI - LC-MS/MS for Identifying Patients with CYP24A1 Mutations. AB - BACKGROUND: Patients have been described with loss-of-function CYP24A1 (cytochrome P450, family 24, subfamily A, polypeptide 1) mutations that cause a high ratio of 25-hydroxyvitamin D to 24,25-dihydroxyvitamin D [25(OH)D/24,25(OH)2D], increased serum 1,25-dihydroxyvitamin D, and resulting hypercalcemia, hypercalciuria and nephrolithiasis. A 25(OH)D/24,25(OH)2D ratio that can identify patients who are candidates for confirmatory CYP24A1 genetic testing would be valuable. We validated an LC-MS/MS assay for 24,25(OH)2D (D3 and D2) and determined a 25(OH)D/24,25(OH)2D cutoff to identify candidates for confirmatory genetic testing. METHODS: After addition of isotope-labeled internal standard, serum samples were extracted by solid-phase extraction, derivatized with 4-phenyl-1,2,4,-triazoline-3,5-dione, and quantified by LC-MS/MS. We measured 25(OH)D/24,25(OH)2D in 91 healthy patients and 34 patients with clinically suspected CYP24A1-mediated hypercalcemia. RESULTS: The limits of detection and quantification were 0.03 (0.2) and 0.1 (0.24) nmol/L, respectively, for 24,25(OH)2D3, and 0.1 (0.23) and 0.5 (1.16) nmol/L for 24,25(OH)2D2. Intra- and interassay imprecision was 4%-15% across the analytical measurement range of 0.1-25 ng/mL (0.2-60 nmol/L). No interference was observed with 25(OH)D and 1,25(OH)2D. 25(OH)D/24,25(OH)2D of 7-35 was observed in healthy patients, whereas in 2 patients with CYP24A1 mutations, 25(OH)D/24,25(OH)2D was significantly increased (99-467; P < 0.001). A 25(OH)D/24,25(OH)2D ratio >=99 identified patients who were candidates for CYP24A1 genetic testing. CONCLUSIONS: Increased 25(OH)D/24,25(OH)2D supports the diagnosis of reduced CYP24A1 activity due to mutations in CYP24A1. Measurement of 25(OH)D/24,25(OH)2D should be considered a part of the clinical workup in patients with hypercalcemia of otherwise unknown etiology. PMID- 26585930 TI - Applications of MALDI Mass Spectrometry in Clinical Chemistry. AB - BACKGROUND: MALDI-TOF mass spectrometry (MS) is set to make inroads into clinical chemistry because it offers advantages over other analytical platforms. These advantages include low acquisition and operating costs, ease of use, ruggedness, and high throughput. When coupled with innovative front-end strategies and applied to important clinical problems, it can deliver rapid, sensitive, and cost effective assays. CONTENT: This review describes the general principles of MALDI TOF MS, highlights the unique features of the platform, and discusses some practical methods based upon it. There is substantial potential for MALDI-TOF MS to make further inroads into clinical chemistry because of the selectivity of mass detection and its ability to independently quantify proteoforms. SUMMARY: MALDI-TOF MS has already transformed the practice of clinical microbiology and this review illustrates how and why it is now set to play an increasingly important role in in vitro diagnostics in particular, and clinical chemistry in general. PMID- 26585931 TI - New Non-Nucleocide NS5B Protein Inhibitors for the Treatment of Chronic Hepatitis C Infection. AB - Hepatitis C virus is one of the major causative pathogens of chronic hepatitis and the second most common cause of hepatocellular cancer. The virally encoded NS5B RNA-dependent RNA polymerase is a vital component of the replicase complex that orchestrates the replication process leading to the production of progeny virus. In recent years, developing novel drugs to target NS5B polymerase has become one of the important strategies for the treatment of chronic hepatitis C infection. This review highlights the structure and scaffold of the non nucleoside NS5B inhibitors represented in the past five years. PMID- 26585932 TI - In Silico Approaches to the Design of NS5A Inhibitors. AB - In recent years, nonstructural protein 5A (NS5A) has rapidly emerged as a promising therapeutic target for Hepatitis C (HCV) virus therapy. It is involved in both viral RNA replication and virus assembly and NS5A plays a critical role in the regulation of HCV life cycle. NS5A replication complex inhibitors (NS5A RCIs) have demonstrated strong antiviral activity in vitro and in vivo. However, wild-type resistance mutations and a wide range of genotypes significantly reduce their clinical efficacy. The exact mechanism of NS5A action still remains elusive, therefore several in silico models have been constructed to gain insight into the drug binding and subsequent structural optimization to overcome resistance. This paper provides a comprehensive overview of the computational studies towards NS5A mechanism of action and the design of novel small-molecule inhibitors. PMID- 26585933 TI - A Comprehensive Insight into the Chemical Space and ADME Features of Small Molecule NS5A Inhibitors. AB - Non-structural 5A (NS5A) protein plays a crucial role in the replication of hepatitis C virus (HCV) and during the past decade has attracted increasing attention as a promising biological target for the treatment of viral infections and related disorders. Small-molecule NS5A inhibitors have shown significant antiviral activity in vitro and in vivo. Several lead molecules are reasonably regarded as novel highly potent drug candidates with favorable ADME features and tolerable side effects. The first-in-class daclatasvir has recently been launched into the market and 14 novel molecules are currently under evaluation in clinical trials. From this perspective, we provide an overview of the available chemical space of small-molecule NS5A inhibitors and their PK properties, mainly focusing on the diversity in structure and scaffold representation. PMID- 26585934 TI - HCV Inhibitors: Role of Compounds from Botanical Sources. AB - The developing number of hepatitis C virus infected cases worldwide has threatened people's health. The available therapeutic options have low specificity, side effects and high rate of drug resistance and thus potentiate the need for novel effective anti-HCV drugs. Agents obtained from natural sources offer an enormous scope of structural diversity and broad therapeutic range of coverage. This review summarizes the research and development of anti-HCV agents (plant extracts/isolated components) obtained from various natural sources along with the associated mechanism of HCV inhibition. Some of the reported examples include triterpenes, naringenin, Proanthocyanidin, curcumin, Epigallocatechin-3 gallate, quercetin and abrogates having diverse anti-HCV properties. The compiled knowledge regarding anti-HCV agents from natural sources will provide considerable information for developing novel safe and effective anti-HCV drugs. PMID- 26585935 TI - Current Drug Discovery for Anti-hepatitis C Virus Targeting NS4B. AB - Hepatitis C virus (HCV) infection is a major worldwide epidemic disease. It is estimated that more than 170 million individuals are infected with HCV and with three to four million new cases each year. Many new direct-acting antiviral (DAA) agents that specifically target HCV NS3 protease or NS5B polymerase inhibitors are therefore in development, with a significant effect for the patient and for the market recently. The non-structural 4B (NS4B) protein, is among the least characterized of the HCV proteins. A variety of functions have been recognized for NS4B, such as the ability to induce the membranous web replication platform, RNA binding and NTPase activity. In order to maximize antiviral efficacy and prevent the emergence of resistance, novel NS4B inhibitors have been subjected to pharmacological studies. In this review, we discussed current understanding of the structure and function of NS4B, and novel drug discoveries targeting NS4B as anti-hepatitis C virus such as sulfonamide, piperidine, carboxamide, piperazinone and quinoline derivatives within the last three years. PMID- 26585936 TI - Computational Modelling in Studies for Hepatitis C Virus (HCV) NS3 Protease. AB - Hepatitis C virus (HCV) infected up to 3% of global human population. More than 350 thousand die annually due to liver cirrhosis and hepatocellular carcinoma, developed at the late stages of the disease. The typical ways of HCV transmission are: transfusion of contaminated blood and blood products; sharing syringes among intravenous drug users; use of poorly sterilized medical instruments in certain countries with bad sterilization practice. HCV is hard to identify, at early stages the disease is asymptomatic and progresses slowly. HCV RNA genome is highly variable, and thus interferes developing of a vaccine. HCV NS3 protease has received close attention as the promising drug target. Recent approval of Boceprevir and Telaprevir, the first inhibitors of HCV NS3 protease, has let increase effectiveness of anti-HCV therapy. Though these new medicines show drawbacks in drug resistance and genotype coverage, second and third generation of HCV protease inhibitors will overcome them. Computational modelling had an impact role in these discoveries. Involvement of modelling in studies for Hepatitis C (HCV) NS3 protease is considered in this review. PMID- 26585937 TI - Folding of newly translated membrane protein CCR5 is assisted by the chaperonin GroEL-GroES. AB - The in vitro folding of newly translated human CC chemokine receptor type 5 (CCR5), which belongs to the physiologically important family of G protein coupled receptors (GPCRs), has been studied in a cell-free system supplemented with the surfactant Brij-35. The freshly synthesized CCR5 can spontaneously fold into its biologically active state but only slowly and inefficiently. However, on addition of the GroEL-GroES molecular chaperone system, the folding of the nascent CCR5 was significantly enhanced, as was the structural stability and functional expression of the soluble form of CCR5. The chaperonin GroEL was partially effective on its own, but for maximum efficiency both the GroEL and its GroES lid were necessary. These results are direct evidence for chaperone assisted membrane protein folding and therefore demonstrate that GroEL-GroES may be implicated in the folding of membrane proteins. PMID- 26585938 TI - Improving safety of autologous haematopoietic stem cell transplantation in patients with Crohn's disease. AB - OBJECTIVE: To evaluate the feasibility and toxicity of autologous haematopoietic stem cell transplantation (HSCT) for the treatment of refractory Crohn's disease (CD). DESIGN: In this prospective study, patients with refractory CD suffering an aggressive disease course despite medical treatment, impaired quality of life and in whom surgery was not an acceptable option underwent HSCT. Toxicity and complications during the procedure and within the first year following transplantation were evaluated, along with the impact of the introduction of supportive measures on safety outcomes. RESULTS: 26 patients were enrolled. During mobilisation, 16 patients (62%) presented febrile neutropaenia, including one bacteraemia and two septic shocks. Neutropaenia median time after mobilisation was 5 days. 5 patients withdrew from the study after mobilisation and 21 patients entered the conditioning phase. Haematopoietic recovery median time for neutrophils (>0.5*10(9)/L) was 11 days and for platelets (>20*10(9)/L) 4 days. Twenty patients (95%) suffered febrile neutropaenia and three patients (27%) presented worsening of the perianal CD activity during conditioning. Among non-infectious complications, 6 patients (28.5%) presented antithymocyte globulin reaction, 12 patients (57%) developed mucositis and 2 patients (9.5%) had haemorrhagic complications. Changes in supportive measures over the study, particularly antibiotic prophylaxis regimes during mobilisation and conditioning, markedly diminished the incidence of severe complications. During the first 12 month follow-up, viral infections were the most commonly observed complications, and one patient died due to systemic cytomegalovirus infection. CONCLUSIONS: Autologous HSCT for patients with refractory CD is feasible, but extraordinary supportive measures need to be implemented. We suggest that this procedure should only be performed in highly experienced centres. PMID- 26585939 TI - [Nivolumab, a new hope in non-small cell lung cancer]. AB - Lung cancer accounts for 10% of cancer cases, but leads to 20% of cancer-specific mortality. Therapeutic options are limited, especially in tumors, which do not harbour druggable oncogenic alterations, and overall survival falls short of twoyears in the metastatic setting. The arrival of immunotherapy is a new hope for the achievement of an improved and sustainable survival in lung cancer patients. The approval of Nivolumab in this setting will lead to drastic changes in clinical practice. For optimal patient care, it will be essential to integrate the benefits and risks of such treatment. This review aims at discussing the role of nivolumab in lung cancer, in consideration of updated clinical data for safety and efficacy. PMID- 26585940 TI - Non-inferiority of mammalian cell-derived quadrivalent subunit influenza virus vaccines compared to trivalent subunit influenza virus vaccines in healthy children: a phase III randomized, multicenter, double-blind clinical trial. AB - OBJECTIVES: The safety and immunogenicity of mammalian cell-derived quadrivalent influenza vaccine (QIVc) as compared with trivalent influenza vaccines (TIV1c/TIV2c) was evaluated in children aged >=4 to <18 years. METHODS: Two thousand three hundred and thirty-three subjects were randomized 2:1:1 to receive either one or two doses of study vaccine depending on previous vaccination status. Hemagglutination inhibition antibody responses for all four influenza strains were performed 3 weeks after the last dose. Reactogenicity and safety were also assessed (ClinicalTrials.gov: NCT01992107). RESULTS: QIVc met the non inferiority criteria against all four vaccine strains and demonstrated superiority for both influenza B strains over the unmatched B lineage included in the comparator vaccines, when geometric mean titers and seroconversion rates were compared at 3 weeks after the last vaccination. Similar percentages of subjects experienced solicited and unsolicited adverse events (AEs) across all subgroups. Unsolicited AEs, serious AEs, medically attended AEs, and new onset chronic disease were reported in comparable percentages of subjects in all study groups. No vaccine-related serious AEs or deaths occurred. CONCLUSIONS: QIVc demonstrated a similar safety profile and immunogenicity responses against all four vaccine strains without signs of immune interference on addition of an alternate lineage B strain compared with TIV1c/TIV2c and may provide broader protection against both influenza B lineages in children. PMID- 26585941 TI - A modeling study of human infections with avian influenza A H7N9 virus in mainland China. AB - OBJECTIVES: Since February 2013, more than 400 laboratory-confirmed human cases of avian influenza A H7N9 infection have been reported in mainland China. Little is known of the dynamics of this novel virus in poultry and human populations, which is essential for developing effective long-term control strategies for this zoonosis. The aim of this study was to evaluate the impact of screening and culling of infected poultry on the evolution of the H7N9 epidemic. METHODS: A mathematical model for transmission dynamics of avian influenza A H7N9 virus in human and poultry populations was constructed. Parameters in the model were estimated using publicly available nationwide surveillance data on animal and human infections. RESULTS: By fitting a two-host model, it was shown that screening for H7N9 in poultry and culling could effectively decrease the number of new human H7N9 cases. Furthermore, the elimination of circulating H7N9 virus is possible if an intensive, but technically feasible, poultry screening and culling policy is adopted. CONCLUSIONS: Screening and culling infected poultry is a critical measure for preventing human H7N9 infections in the long term. This model may provide important insights for decision-making on a national intervention strategy for the long-term control of the H7N9 virus epidemic. PMID- 26585942 TI - An embodied biologically constrained model of foraging: from classical and operant conditioning to adaptive real-world behavior in DAC-X. AB - Animals successfully forage within new environments by learning, simulating and adapting to their surroundings. The functions behind such goal-oriented behavior can be decomposed into 5 top-level objectives: 'how', 'why', 'what', 'where', 'when' (H4W). The paradigms of classical and operant conditioning describe some of the behavioral aspects found in foraging. However, it remains unclear how the organization of their underlying neural principles account for these complex behaviors. We address this problem from the perspective of the Distributed Adaptive Control theory of mind and brain (DAC) that interprets these two paradigms as expressing properties of core functional subsystems of a layered architecture. In particular, we propose DAC-X, a novel cognitive architecture that unifies the theoretical principles of DAC with biologically constrained computational models of several areas of the mammalian brain. DAC-X supports complex foraging strategies through the progressive acquisition, retention and expression of task-dependent information and associated shaping of action, from exploration to goal-oriented deliberation. We benchmark DAC-X using a robot-based hoarding task including the main perceptual and cognitive aspects of animal foraging. We show that efficient goal-oriented behavior results from the interaction of parallel learning mechanisms accounting for motor adaptation, spatial encoding and decision-making. Together, our results suggest that the H4W problem can be solved by DAC-X building on the insights from the study of classical and operant conditioning. Finally, we discuss the advantages and limitations of the proposed biologically constrained and embodied approach towards the study of cognition and the relation of DAC-X to other cognitive architectures. PMID- 26585943 TI - Downregulated Expression of E-cadherin and TP53 in Patients with Gastric Diseases: the Involvement of H. pylori Infection and Its Virulence Markers. AB - PURPOSE: Gastritis caused by infection with Helicobacter pylori is characterized by chronic inflammation and damage in gastric tissue, which is a main risk factor for gastric cancer. Associated with H. pylori, the TP53 gene tumor suppressor and the cell adhesion glycoprotein epithelial cadherin develop a relevant role in the integrity and carcinogenesis of the epithelium. We aimed to detection of H. pylori and its main virulence markers and measured the messenger RNA (mRNA) expression levels of E-cadherin and TP53 genes. METHODS: The detection of H. pylori and its virulence markers, as well as the mRNA expression levels of E cadherin and TP53 genes, were obtained for 161 samples of gastric biopsies including 37 with normal gastric tissue, 70 with gastritis, 24 from neoplastic tissue, and 27 from adjacent non-neoplastic by means of a quantitative real-time polymerase chain reaction. RESULTS: The mRNA expression levels of E-cadherin and TP53 were found to be decreased in patients with gastritis, independently of H. pylori infection. In samples from gastric patients, the neoplastic tissue showed an accentuated decrease of expression; on the other hand, the expression of E cadherin was normal in adjacent non-neoplastic. CONCLUSIONS: No evidence was found of the involvement of the cagA and vacA genes in the decreased expression of E-cadherin and TP53. The process of carcinogenesis is complex, and the decrease of the E-cadherin gene expression and TP53 gene expression appears to contribute significantly. PMID- 26585944 TI - Epidemiological Study of Gallbladder Cancer Patients from North Indian Gangetic Planes--a High-Volume Centre's Experience. AB - PURPOSE: Gallbladder carcinoma (GBC) is characterized by a dismal prognosis owing to the paucity of early signs and symptoms. North India reports high incidence of GBC possibly due to environmental, dietary and reproductive factors. Understanding the epidemiology of gallbladder cancer has and will continue to provide valuable insights into determining causes and risk factors for gallbladder cancer. METHODS: Prospective study of gallbladder carcinoma patients, presenting in our department, was undertaken over three year period to evaluate the epidemiological profile of gallbladder carcinoma patients from our region. RESULTS: The peak incidence of GBC was in 31-50 years age group (58 %). Male to female ratio was 1:4.83, with mean age for females (mean 49.1 years) significantly lower than male counterpart (mean 54.9 years) (p value = 0.000423). Majority of patients were non-vegetarians (67%) and 84% of them consumed mustard oil (home made/loose packed) as predominant cooking medium. Majority of the patients of GBC in our study were from low socioeconomic strata (68%) (Kuppuswamy classes IV, V (lower class)). GBC was more commonly seen in females with the age of menarche less than 14 years (83%) and the age of the first child birth less than 20 years (56%). Females with more than two children had higher incidence (57%). Majority of the female patients (71%) were postmenopausal. Gallstones were present in 390 out of 490 patients (80%). Incidental gallbladder carcinoma was detected in 158 out of 490 patients (32%). Pain abdomen was the most common presenting complaint (98%). Significant proportion of the patients with GBC presented with distant metastasis (stage IVB) (52%). The most common histological subtype was adenocarcinoma (78%). CONCLUSION: Current data suggest that the epidemiology of gallbladder cancer is constantly evolving, with much of this change caused by lifestyle, cultural and dietary factors. Balanced diet, prevention of malnutrition/adulteration, tobacco prevention and early intervention for cholelithiasis may help in decreasing the incidence of this dreaded disease. More structured studies need to be carried out to ascertain risk factors for GBC in our population subgroup. PMID- 26585945 TI - Searching for candidate genes in familial BRCAX mutation carriers with prostate cancer. AB - OBJECTIVE: A family history of prostate cancer (PC) is a well-recognized high risk factor for the development of clinically significant PC. To date, traditional linkage and association studies have identified only a limited number of genes and specific gene variants that account for only a small proportion of PC risk. To identify novel PC predisposition genes we performed whole-exome sequencing of PC-affected men from families with a significant history of PC. METHODS AND MATERIALS: Exome sequencing was performed on 5 PC-affected men from 3 families where there were multiple cases of PCs and where diagnostic testing returned a negative result for BRCA1 and BRCA2 mutations. Genotyping was performed for all potentially predisposing variants detected within each family on the affected and unaffected male participants. RESULTS: Essential splice site, missense, and stop-lost variants were filtered against a recently published candidate gene list. A total of 19 truncating variants and 17 missense variants were identified for genotyping in all prostate-affected and unaffected male participants. In all, 3 missense variants, PCTP, MCRS1, and ATRIP, demonstrated complete segregation and 1 missense variant, PARP2, demonstrated partial segregation with PC. In addition, 3 truncating variants, CYP3A43, DOK3, and PLEKHH3, demonstrated complete segregation and 3 truncation mutations, HEATR5B, GPR124, and HKR1, demonstrated partial segregation with PC. No segregating variants between the 3 families were shared. CONCLUSIONS: In all, 10 truncating or missense variants showed either complete or partial segregation with PC in the relevant families. CYP3A43 and PARP2 variants have been shown to occur in other familial PCs and our findings add to the contribution that these variants potentially have in the risk and development of PC in BRCAX cases. PMID- 26585946 TI - ERG overexpression and multifocality predict prostate cancer in subsequent biopsy for patients with high-grade prostatic intraepithelial neoplasia. AB - PURPOSE: The most important clinical significance of an isolated high-grade prostatic intraepithelial neoplasia (HGPIN) diagnosis is the risk of missed prostate cancer (PCa) in subsequent biopsies. Because most patients with HGPIN do not harbor or develop PCa, clinical, pathological, or molecular markers that predict of PCa risk are of clinical significance. MATERIALS AND METHODS: Overall, 155 men with a diagnosis of isolated HGPIN, which was based on the results of extended biopsy, and who underwent at least one repeat biopsy were analyzed for ERG oncoprotein (ERG) expression and clinicopathological parameters to determine the risk of finding PCa in subsequent biopsies. RESULTS: Of 155 patients diagnosed with HGPIN on initial biopsy, 39 (25%) had PCa on subsequent biopsies. For men with only one repeat biopsy, the cancer detection rate was 22%. Most (54%) PCas were detected in<=6 months of rebiopsy. ERG expression was present in 15 patients with HGPIN (9.6%). Patients with ERG expression in HGPIN were more likely to have PCa in repeat biopsy, with 9 (60%) ERG-positive and 30 (21%) of ERG-negative patients having PCa (P = 0.001). Multifocal involvement (P = 0.0001), cribriform morphology (P = 0.004), and bilaterality (P = 0.0075) of HGPIN were other significant risk factors. On multivariable analysis, only the presence of ERG positivity and multifocality remained significant parameters in detecting PCa on a repeat biopsy. The presence of ERG-negative focal HGPIN involving one core, which accounted for 46% of patients, had minimal (16%) PCa risk on subsequent biopsy. In total, 8 patients (89%) ERG-positive HGPIN had PCa identified at identical sites on subsequent biopsy, of which 5 (71%) were ERG positive. CONCLUSIONS: The status of ERG expression in HGPIN along with other histological parameters stratifies patients into low- and high-risk groups for having PCa on subsequent biopsy. Our results further support molecular characterization of HGPIN as a means to improve risk stratification and optimize surveillance strategies. PMID- 26585947 TI - Are we doing "better"? The discrepancy between perception and practice of enhanced recovery after cystectomy principles among urologic oncologists. AB - PURPOSE: The concept of enhanced recovery after surgery has been around since the 1990s when it was first introduced as a means to improve postoperative recovery of general surgical patients. In the field of urology, the uptake of enhanced recovery pathways has been slow for unclear reasons. Recently, interest in enhanced recovery after cystectomy (ERAC) has been increasing, but the current urologic oncology practice patterns remain unclear. In this study, we investigate modern perioperative patterns of care and rates of application of ERAC principles by cystectomy surgeons. MATERIALS AND METHODS: ERAC principles were identified by reviewing urology and general surgery literature. An adapted version of The Royal College of Surgeons of England fast-track surgical principles survey was used. Preoperative education, bowel preparation avoidance, nasogastric tubes avoidance, normothermia, opioid avoidance, early ambulation, and early feeding were all practices queried with the survey. Surveys were distributed electronically to faculty of Society of Urologic Oncology fellowships with bladder cancer as a special area of interest. Additional participants were identified by recent publications on cystectomies for bladder cancer. In total, 128 surveys were e mailed to the previously identified experts. Of these, 61 (48%) completed the survey. Responses were classified as congruent with commonly accepted ERAC principles (ERAC group) or noncongruent (non-ERAC group). Chi-square test was used for categorical variables and Wilcoxon-Mann-Whitney for ordinal variables. RESULTS: Of the urologists who classified themselves in the ERAC group (64%), the average length of stay was reported to be 6.1 days and 7.2 days in the non-ERAC group (P = 0.02). Only 20% were practicing all interventions. Among the ERAC surgeons 1, 2 or 3 of the interventions were omitted by 13%, 25%, and 23% of the respondents, respectively. Significant differences were found between the self reported ERAC adopters and nonadopters in the use of bowel preparation (P = 0.01), nasogastric tubes (P = 0.007), alvimopan (P<0.001), and the average day of advancement to clear liquids (P<0.001). There were no differences in postoperative ambulation and opiate or nonsteroidal anti-inflammatory drug use. Lack of convincing evidence was cited as the main reason for the non-ERAC group not yet implementing an ERAC pathway followed by lack of resource availability. CONCLUSION: Urologists who consider themselves as practicing ERAC do not universally practice all of the pathway tenets. A significant gap exists between self-perception and practice of enhanced recovery. ERAC implementation is challenging but represents a significant opportunity to improve the quality of care for cystectomy patients. PMID- 26585949 TI - Isolated Resection of Segment VIII: A Technique for Drainage Through the Couinaud Space to Prevent Postoperative Collections. PMID- 26585950 TI - Determining the Learning Curve of Transcutaneous Laryngeal Ultrasound in Vocal Cord Assessment by CUSUM Analysis of Eight Surgical Residents: When to Abandon Laryngoscopy. AB - Transcutaneous laryngeal ultrasonography (TLUSG) is a promising alternative to laryngoscopy in vocal cords (VCs) assessment which might be challenging in the beginning. However, it remains unclear when an assessor can provide proficient TLUSG enough to abandon direct laryngoscopy . Eight surgical residents (SRs) without prior USG experience were recruited to determine the learning curve. After a standardized training program, SRs would perform 80 consecutive peri operative VCs assessment using TLUSG. Performances of SRs were quantitatively evaluated by a composite performance score (lower score representing better performance) which comprised total examination time (in seconds), VCs visualization, and assessment accuracy. Cumulative sum (CUSUM) chart was then used to evaluate learning curve. Diagnostic accuracy and demographic data between every twentieth TLUSG were compared. 640 TLUSG examinations had been performed by 8 residents. 95.1% of VCs could be assessed by SRs. The CUSUM curve showed a rising pattern (learning phase) until 7th TLUSG and then flattened. The curve declined continuously after 42nd TLUSG (after reaching a plateau). Rates of assessable VCs were comparable in every twentieth cases performed. It took a longer time to complete TLUSG in 1st-20th than 21st-40th examinations. (45 vs. 32s, p = 0.001). Although statistically not significant, proportion of false negative results was higher in 21st-40th (2.5%) than 1(st)-20th (0.6%), 41(st) 60th (0.7%), and 61(st)-80th (0.7%) TLUSG performed. After a short formal training, surgeons could master skill in TLUSG after seven examination and assess vocal cord function consistently and accurately after 40 TLUSG. PMID- 26585951 TI - Practical Approaches to Definitive Reconstruction of Complex Abdominal Wall Defects. AB - With advances in abdominal surgery and the management of major trauma, complex abdominal wall defects have become the new surgical disease, and the need for abdominal wall reconstruction has increased dramatically. Subsequently, how to reconstruct these large defects has become a new surgical question. While most surgeons use native abdominal wall whenever possible, evidence suggests that synthetic or biologic mesh needs to be added to large ventral hernia repairs. One particular group of patients who exemplify "complex" are those with contaminated wounds, enterocutaneous fistulas, enteroatmospheric fistulas, and/or stoma(s), where synthetic mesh is to be avoided if at all possible. Most recently, biologic mesh has become the new standard in high-risk patients with contaminated and dirty-infected wounds. While biologic mesh is the most common tissue engineered used in this field of surgery, level I evidence is needed on its indication and long-term outcomes. Various techniques for reconstructing the abdominal wall have been described, however the long-term outcomes for most of these studies, are rarely reported. In this article, I outline current practical approaches to perioperative management and definitive abdominal reconstruction in patients with complex abdominal wall defects, with or without fistulas, as well as those who have lost abdominal domain. PMID- 26585953 TI - Hoxa cluster genes determine the proliferative activity of adult mouse hematopoietic stem and progenitor cells. AB - Determination of defined roles for endogenous homeobox (Hox) genes in adult hematopoietic stem and progenitor cell (HSPC) activity has been hampered by a combination of embryonic defects and functional redundancy. Here we show that conditional homozygous deletion of the Hoxa cluster (Hoxa(-/-)) results in a marked reduction of adult HSPC activity, both in vitro and in vivo. Specifically, proliferation of Hoxa(-/-) HSPCs is reduced compared with wild-type (WT) cells in vitro and they are less competitive in vivo. Notably, the loss of Hoxa genes had little impact on HSPC differentiation. Comparative RNA sequencing analyses of Hoxa(-/-) and WT hematopoietic stem cells (CD150(+)/CD48(-)/Lineage(-)/c kit(+)/Sca-1(+)) identified a large number of differentially expressed genes, three of which (Nr4a3, Col1a1, and Hnf4a) showed >10-fold reduced levels. Engineered overexpression of Hoxa9 in Hoxa(-/-) HSPCs resulted in partial phenotypic rescue in vivo with associated recovery in expression of a large proportion of deregulated genes. Together, these results provide definitive evidence linking Hoxa gene expression to proliferation of adult HSPCs. PMID- 26585952 TI - Vitamin D supplementation to prevent depression and poor physical function in older adults: Study protocol of the D-Vitaal study, a randomized placebo controlled clinical trial. AB - BACKGROUND: Depressive symptoms and decreased physical functioning are interrelated conditions and common in older persons, causing significant individual and societal burden. Evidence suggests that vitamin D supplementation may be beneficial for both mental and physical functioning. However, previous randomized controlled trials have yielded inconsistent results and often had suboptimal designs. This study examines the effect of vitamin D supplementation on both depressive symptoms and physical functioning in a high-risk population of older persons with low vitamin D status. METHODS/DESIGN: The D-Vitaal study is a randomized, double-blind, placebo-controlled trial investigating the effects of a daily dose of 1200 IU vitamin D3 versus placebo for one year on depressive symptoms and physical functioning (primary outcomes) in older adults. Participants (N = 155, age 60-80 years) were recruited from the general population. Eligibility criteria included the presence of depressive symptoms, >=1 functional limitation and serum 25-hydroxyvitamin D levels between 15 and 50/70 nmol/L (depending on season). Secondary outcomes include incidence of major depressive disorder, anxiety symptoms, health-related quality of life, cognitive function and cost-effectiveness of the intervention. DISCUSSION: With this study, we aim to elucidate the effects of vitamin D supplementation on depressive symptoms and physical functioning in older persons who are at high risk of developing more substantial mental and physical problems. If effective, vitamin D supplementation can be a preventive intervention strategy that is easy to implement in the primary care setting. TRIAL REGISTRATION: Netherlands Trial Register NTR3845. Registered 6 February 2013. PMID- 26585954 TI - Signaling-mediated cooperativity between glycoprotein Ib-IX and protease activated receptors in thrombin-induced platelet activation. AB - Thrombin-induced cellular response in platelets not only requires protease activated receptors (PARs), but also involves another thrombin receptor, the glycoprotein Ib-IX complex (GPIb-IX). It remains controversial how thrombin binding to GPIb-IX stimulates platelet responses. It was proposed that GPIb-IX serves as a dock that facilitates thrombin cleavage of protease-activated receptors, but there are also reports suggesting that thrombin binding to GPIb-IX induces platelet activation independent of PARs. Here we show that GPIb is neither a passive thrombin dock nor a PAR-independent signaling receptor. We demonstrate a novel signaling-mediated cooperativity between PARs and GPIb-IX. Low-dose thrombin-induced PAR-dependent cell responses require the cooperativity of GPIb-IX signaling, and conversely, thrombin-induced GPIb-IX signaling requires cooperativity of PARs. This mutually dependent cooperativity requires a GPIb-IX specific 14-3-3-Rac1-LIMK1 signaling pathway, and activation of this pathway also requires PAR signaling. The cooperativity between GPIb-IX signaling and PAR signaling thus drives platelet activation at low concentrations of thrombin, which are important for in vivo thrombosis. PMID- 26585955 TI - FOXO1 activation is an effector of SYK and AKT inhibition in tonic BCR signal dependent diffuse large B-cell lymphomas. AB - Inhibition of spleen tyrosine kinase (SYK) in tonic B-cell receptor (BCR) signal dependent diffuse large B-cell lymphomas (DLBCLs) inhibits cellular proliferation, decreases cholesterol biosynthesis, and triggers apoptosis, at least in part via a mechanism involving decreased activity of phosphatidylinositol 3-kinase/AKT axis. Because forkhead box O1 (FOXO1) is a major effector of this pathway, we investigated the role of FOXO1 in toxicity of BCR pathway inhibition. Inhibition of SYK in DLBCL cells with tonic BCR signaling decreased phospho-AKT and phospho-FOXO1 levels and triggered FOXO1-driven gene expression. Introduction of constitutively active FOXO1 mutant triggered cell cycle arrest and apoptosis, indicating that increased FOXO1 activity is toxic to these DLBCL cells. Depletion of FOXO1 with short hairpin RNA led to almost complete resistance to chemical SYK inhibitor R406, demonstrating that FOXO1 is also required for R406-induced cell death. FOXO1 in these cells is also involved in regulation of expression of the critical master regulator of cholesterol biosynthesis, SREBP1. Because HRK is the key effector of SYK inhibition, we characterized a mechanism linking FOXO1 activation and HRK induction that involves caspase-dependent cleavage of HRK's transcriptional repressor DREAM. Because AKT in lymphoma cells can be regulated by other signals than BCR, we assessed the combined effects of the AKT inhibitor MK-2206 with R406 and found markedly synergistic FOXO1-dependent toxicity. In primary DLBCLs, FOXO1 expression was present in 80% of tumors, correlated with SYK activity, and was associated with longer overall survival. These results demonstrate that FOXO1 is required for SYK and AKT inhibitor-induced toxicity. PMID- 26585956 TI - Prostaglandin E synthase is upregulated by Gas6 during cancer-induced venous thrombosis. AB - Venous thromboembolism is a common complication of cancer. Based on recent evidence that (1) growth arrest-specific 6 (Gas6) regulates the expression of tissue factor during venous thrombosis, and (2) cancer promotes a procoagulant milieu, we hypothesize that Gas6 may be involved in cancer-induced coagulopathy. Venous thrombi were induced in both wild-type (WT) and Gas6-deficient ((-/-)) mice with cancer. WT mice with cancer developed larger thrombi than their healthy counterparts; these larger thrombi induced by cancer were not seen in Gas6(-/-) mice. Whole genome microarray analysis of differential gene expression in WT and Gas6(-/-) endothelial cells exposed to M27 murine lung carcinoma cells reveal that Gas6 increases prostaglandin E synthase (Ptges) expression in endothelial cells. This was confirmed using real-time polymerase chain reaction and immunofluorescence staining. Culture of WT endothelial cells with M27 increases the secretion of prostaglandin E2 (PGE2), the enzymatic product of Ptges, in WT but not in Gas6(-/-) endothelial cells. In WT endothelial cells, Ptges expression was regulated through extracellular signal-regulated kinase 1/2 phosphorylation (ERK1/2). In vitro, PGE2 activates platelets after binding to its receptor, EP3. In vivo, EP3 receptor antagonism reversed the effect of cancer-induced thrombosis in WT mice. These results show that Gas6, through upregulation of PGE2, contributes to cancer-induced venous thrombosis. PMID- 26585957 TI - Two Randomized Controlled Pilot Trials of Social Forces to Improve Statin Adherence among Patients with Diabetes. AB - BACKGROUND: Medication nonadherence is an important obstacle to cardiovascular disease management. OBJECTIVE: To improve adherence through real-time feedback based on theories of how social forces influence behavior. DESIGN: Two randomized controlled pilot trials called PROMOTE and SUPPORT. Participants stored statin medication in wireless-enabled pill bottles that transmitted adherence data to researchers. PARTICIPANTS: Adults with diabetes and a history of low statin adherence based on pharmacy refills (i.e., Medication Possession Ratio [MPR] <80% in the pre-randomization screening period). INTERVENTION: In PROMOTE, each participant was randomized to 1) weekly messages in which that participant's statin adherence was compared to that of other participants (comparison), 2) weekly summaries of that participant's statin adherence (summary), or 3) control. In SUPPORT, each participant identified another person (the Medication Adherence Partner [MAP]) to receive reports about that participant's adherence, and was randomized to 1) daily reports to MAP, 2) weekly reports to MAP, 3) reports to MAP only if dose was missed, or 4) control. MAIN OUTCOMES MEASURE: Adherence measured by pill bottle. KEY RESULTS: Among 45,000 health plan members contacted by mail, <1% joined the trial. Participants had low baseline MPRs (median = 60%, IQR 41-72%) but high pill-bottle adherence (90% in PROMOTE, 92% in SUPPORT) during the trial. In PROMOTE (n = 201) and SUPPORT (n = 200), no intervention demonstrated significantly better adherence vs. CONTROL: In a subgroup of PROMOTE participants with the lowest pre-study MPR, pill-bottle-measured adherence in the comparison arm (89%) was higher than the control (86%) and summary (76%) arms, but differences were non-significant (p = 0.10). CONCLUSIONS: Interventions based on social forces did not improve medication adherence vs. control over a 3-month period. Given the low percentage of invited individuals who enrolled, the studies may have attracted participants who required little encouragement to improve adherence other than study participation. PMID- 26585958 TI - Impact of wastewater irrigation on the dynamics of metal concentration in the vadose zone: simulation with NETPATH--part II. AB - Understanding and quantification of geochemical processes in vadose zone of sewage-effluent-irrigated soils are helpful in predicting the transference of metals and other ions to food chain and groundwater. Hence, an attempt has been made to simulate various geochemical processes occurring in the flow path of infiltrating sewage water down the vadose zone with the help of Net Geochemical Reaction Along the Flow Path (NETPATH). This study area was located in Western Delhi, India, where sewage effluents originating from Keshopur Sewage Treatment plant have been used for irrigation since 1979. Agricultural lands receiving irrigation through sewage and tube well water were selected for this study. The results indicated that groundwater of 20- and 10-year sewage-irrigated lands was slightly oversaturated in respect of calcite and dolomite, and undersaturated in respect of gypsum. The shallow groundwater of 5-year sewage-irrigated field was undersaturated in case of calcite, dolomite, and gypsum. Among the metals, major focus was given on Fe and Mn as these two metals are redox prone and relatively more mobile than other metals under saturated conditions. There was reduction in concentration of Fe and Mn in groundwater samples of 20-year sewage-irrigated field as compared to that in sewage effluent. Such reduction in concentration of Fe and Mn could be ascribed to the formation of goethite and manganite in vadose zone, respectively, as revealed by simulation with NETPATH. Similarly, in case of 10- and 5-year sewage-irrigated fields, increase in Fe and Mn concentrations in groundwater was due to dissolution of siderite and pyrulusite, respectively. NETPATH software could explain the variation in diethylene triamine pentaacetic acid (DTPA)-extractable Fe and Mn content in vadose zone to the extent of 94 and 65%, respectively. PMID- 26585959 TI - A calcified amorphous tumor that developed on both sides of the atrioventricular valve annulus. AB - We report a rare case of a hemodialysis patient with a calcified amorphous tumor (CAT) on both sides of the atrioventricular valve annulus. A 70-year-old female who had received hemodialysis for 23 years because of chronic glomerulonephritis presented to our hospital with acute heart failure. Echocardiography indicated the presence of mobile cardiac masses on the mitral valve and tricuspid valve annulus. We suspected the presence of a cardiac tumor or vegetation. The patient received 3 g/day sulbactam-ampicillin and 60 mg/day gentamicin. Surgery was performed on the 14th day after hospital admission. The patient underwent mitral valve replacement, tricuspid annuloplasty, and tumor resection. Based on the pathological findings, the cardiac tumor was diagnosed as a CAT. PMID- 26585960 TI - Towards the development of simultaneous two-field robotic surgery. PMID- 26585961 TI - Calsequestrins in skeletal and cardiac muscle from adult Danio rerio. AB - Calsequestrin (Casq) is a high capacity, low affinity Ca(2+)-binding protein, critical for Ca(2+)-buffering in cardiac and skeletal muscle sarcoplasmic reticulum. All vertebrates have multiple genes encoding for different Casq isoforms. Increasing interest has been focused on mammalian and human Casq genes since mutations of both cardiac (Casq2) and skeletal muscle (Casq1) isoforms cause different, and sometime severe, human pathologies. Danio rerio (zebrafish) is a powerful model for studying function and mutations of human proteins. In this work, expression, biochemical properties cellular and sub-cellular localization of D. rerio native Casq isoforms are investigated. By quantitative PCR, three mRNAs were detected in skeletal muscle and heart with different abundances. Three zebrafish Casqs: Casq1a, Casq1b and Casq2 were identified by mass spectrometry (Data are available via ProteomeXchange with identifier PXD002455). Skeletal and cardiac zebrafish calsequestrins share properties with mammalian Casq1 and Casq2. Skeletal Casqs were found primarily, but not exclusively, at the sarcomere Z-line level where terminal cisternae of sarcoplasmic reticulum are located. PMID- 26585962 TI - First complete genome sequence of European turkey coronavirus suggests complex recombination history related with US turkey and guinea fowl coronaviruses. AB - A full-length genome sequence of 27,739 nt was determined for the only known European turkey coronavirus (TCoV) isolate. In general, the order, number and size of ORFs were consistent with other gammacoronaviruses. Three points of recombination were predicted, one towards the end of 1a, a second in 1b just upstream of S and a third in 3b. Phylogenetic analysis of the four regions defined by these three points supported the previous notion that European and American viruses do indeed have different evolutionary pathways. Very close relationships were revealed between the European TCoV and the European guinea fowl coronavirus in all regions except one, and both were shown to be closely related to the European infectious bronchitis virus (IBV) Italy 2005. None of these regions of sequence grouped European and American TCoVs. The region of sequence containing the S gene was unique in grouping all turkey and guinea fowl coronaviruses together, separating them from IBVs. Interestingly the French guinea fowl virus was more closely related to the North American viruses. These data demonstrate that European turkey and guinea fowl coronaviruses share a common genetic backbone (most likely an ancestor of IBV Italy 2005) and suggest that this recombined in two separate events with different, yet related, unknown avian coronaviruses, acquiring their S-3a genes. The data also showed that the North American viruses do not share a common backbone with European turkey and guinea fowl viruses; however, they do share similar S-3a genes with guinea fowl virus. PMID- 26585963 TI - Epileptogenic zone localization and seizure control in coupled neural mass models. AB - Exact localization of the epileptogenic zone (EZ) is the first priority for ensuring epilepsy treatments and reducing side effects. The results of traditional visual methods for localizing the origin of seizures are far from satisfactory in some cases. Signal processing methods could extract substantial information that may complement visual inspection of EEG signals. In this study, EZ localization is changed into a driver identification problem, and a nonlinear interdependence measure, the weighted rank interdependence, is proposed and used as a driver indicator because it can detect coupling information, especially directionality, from EEG signals. A proportional integral derivative (PID) controller is then explored, using simulations, to establish its suitability for seizure control. The seizure control we propose rests on identifying the EZ using nonlinear interdependence measures of directed functional connectivity. Two directionally coupled neural mass models are employed for simulation investigation. Two parameters can adjust the sensitivity and completeness of the weighted rank interdependence for different applications, and their effect is discussed in the context of neural mass models. Simulation results demonstrate that use of the weighted rank interdependence for EZ identification can be applied to different EZ types, and the approach achieves an overall identification rate of 98.84 % for several EZ types. Simulations also indicate that PID control can effectively regulate synchronization between neural masses. PMID- 26585964 TI - Neurocomputational model of moral behaviour. AB - Our understanding of human morality has dramatically improved in the last decades, thanks to efforts carried out with scientific methods, in addition to the traditional speculative approach. Substantial contributions and relevant empirical data have come from neuroscience, psychology, genetics, comparative ethology, anthropology, and the social sciences. In this fruitful synergy, one useful approach is still missing: computational modeling. More precisely, a neurocomputational model aimed at simulating forms of moral behavior, to our knowledge, has not yet been designed. The purpose of this work is to start filling this gap, proposing MOral Neural Engine (MONE), a model that simulates the emergence of moral cognition. The neural engine in this model is assumed to be based in frontal areas, specifically the orbitofrontal and the ventromedial prefrontal cortex, and in connections to limbic areas involved in emotions and reward, such as the ventral striatum and the amygdala. Moral cognition is probably the result of a collection of several different neural processes, activated depending on the type of moral problem, each associated with a variety of emotions. This model, in its first implementation, deals with only a single moral situation: stealing someone's food, a transgression that typically elicits guilt, learned in the model from the angry facial expressions of the victim. PMID- 26585966 TI - Prolapse or incontinence: what affects sexual function the most? AB - INTRODUCTION AND HYPOTHESIS: Pelvic organ prolapse (POP) and stress urinary incontinence (SUI) adversely affect sexual function in women. Comparative studies of the two subgroups are few and results are conflicting. The aim of this study was to compare the effect of POP and SUI on the sexual function of women undergoing surgery for these conditions. METHODS: The study population comprised women with POP or SUI in a tertiary referral hospital in the UK. Women who underwent SUI surgery had no symptoms of POP and had urodynamically proven stress incontinence. Patients with POP had >= stage 2 prolapse, without bothersome urinary symptoms. Pre-operative data on sexual function were collected and compared using an electronic pelvic floor assessment questionnaire (ePAQ). The incidence of sexual dysfunction and comparison of symptoms in both groups were calculated using the Mann-Whitney U test. RESULTS: Three hundred and forty-three women undergoing surgery for either SUI or POP were included. Patients were age matched, with 184 undergoing SUI surgery (age range 33-77 years) and 159 POP surgery (age range 27-78 years; p = 0.869). The overall impact of POP and SUI was not significantly different in the two subgroups (p = 0.703). However, both patients (73 % vs 36 %; p = 0.00) and partners (50 % vs 24 %; p = 0.00) avoid intercourse significantly more frequently in cases with POP compared with SUI. This did not have a significant impact on quality of life. CONCLUSIONS: The impact of bothersome SUI or POP on sexual function was found to be similar, but patient and partner avoidance in women with POP was greater than those with SUI. PMID- 26585967 TI - Polypropylene mesh slings and cancer: An incidental finding or association? PMID- 26585965 TI - Learning to grasp and extract affordances: the Integrated Learning of Grasps and Affordances (ILGA) model. AB - The activity of certain parietal neurons has been interpreted as encoding affordances (directly perceivable opportunities) for grasping. Separate computational models have been developed for infant grasp learning and affordance learning, but no single model has yet combined these processes in a neurobiologically plausible way. We present the Integrated Learning of Grasps and Affordances (ILGA) model that simultaneously learns grasp affordances from visual object features and motor parameters for planning grasps using trial-and-error reinforcement learning. As in the Infant Learning to Grasp Model, we model a stage of infant development prior to the onset of sophisticated visual processing of hand-object relations, but we assume that certain premotor neurons activate neural populations in primary motor cortex that synergistically control different combinations of fingers. The ILGA model is able to extract affordance representations from visual object features, learn motor parameters for generating stable grasps, and generalize its learned representations to novel objects. PMID- 26585968 TI - Does a transition in education equate to a transition in practice? Thai stakeholder's perceptions of the introduction of the Doctor of Pharmacy programme. AB - BACKGROUND: Pharmacy education and pharmacy practice are facing remarkable changes following new scientific discoveries, evolving patient needs and the requirements of advanced pharmacy competency for practices. Many countries are introducing or undertaking major transformations in pharmacy education. The Thai pharmacy curriculum has been changed from a 5-year BPharm and a 6-year PharmD to only a 6-year PharmD programme. Curriculum change processes usually involve stakeholders, including both internal and external educational institutions, at all levels. This study aims to understand the experiences and perceptions of stakeholders regarding the transition to an all-PharmD programme in Thailand. METHODS: Semi-structured interviews were conducted in Thailand with 130 stakeholders (e.g., policy makers, pharmacy experts, educators, health care providers, patients, students and parents) from August-October 2013. The interviews were audio recorded, transcribed verbatim and analysed using an inductive thematic analysis. RESULTS: Three main themes were derived from the findings: 1. influences on curriculum change (e.g., the needs of pharmacists to provide better patient care, the US-Thai consortium for the development of pharmacy education); 2. perceived benefits (e.g., improve pharmacy competencies from generalists to specialists, ready to work after graduation, providing a high quality of patient care); and 3. concerns (e.g., the higher costs of study for a longer period of time, the mismatch between the pharmacy graduates' competency and the job market's needs, insufficient preceptors and training sites, lack of practical experience of the faculty members and issues related to the separate licenses that are necessary due to the difference in the graduates' specialties). CONCLUSIONS: This is the first study to highlight the issues surrounding the transition to the 6-year PharmD programme in Thailand, which was initiated due to the need for higher levels of competency among the nation's pharmacists. The transition was influenced by many factors. Many participants perceived benefits from the new pharmacy curriculum. However, some participants were concerned about this transition. Although most of the respondents accepted the need to go forward to the 6-year PharmD programme, designing an effective curriculum, providing a sufficient number of qualified PharmD preceptors, determining certain competencies of pharmacists in different practices and monitoring the quality of pharmacy education still need to be addressed during this transitional stage of pharmacy education in Thailand. PMID- 26585970 TI - Accelerating research through reagent repositories: the genome editing example. AB - Keith Joung, Dan Voytas and Joanne Kamens share insights into how the genome editing field was advanced by early access to biological resources and the role in this process that plasmid repositories play. PMID- 26585969 TI - Collis-Nissen gastroplasty for short oesophagus. AB - The Collis-Nissen procedure is performed for the surgical treatment of 'true short oesophagus'. When this condition is strongly suspected radiologically, the patient is placed in the 45 degrees left lateral position on the operating table with the left chest and arm lifted to perform a thoracostomy in the V-VI space, posterior to the axillary line. The hiatus is opened and the distal oesophagus is widely mobilized. With intraoperative endoscopy, the position of the oesophago gastric junction in relationship to the hiatus is determined and the measurement of the length of the intra-abdominal oesophagus is performed to decide either to carry out a standard anti-reflux procedure or to lengthen the oesophagus. If the oesophagus is irreversibly short ('true short oesophagus'), the short gastric vessels are divided and the gastric fundus is mobilized. An endostapler is introduced into the left chest. The left thoracoscopic approach is suitable to control effectively the otherwise blind passage of the endostapler into the mediastinum and upper abdomen (if a second optic is not used). The tip of the stapler is clearly visible while 'walking' on the left diaphragm. The Collis gastroplasty is performed over a 46 Maloney bougie. A floppy Nissen fundoplication and the hiatoplasty complete the procedure. PMID- 26585971 TI - Down-regulation of the Th1, Th17, and Th22 pathways due to anti-TNF-alpha treatment in psoriasis. AB - BACKGROUND: Psoriasis is a T-cell-mediated chronic inflammatory dermatosis. Th1, Th17 and Th22 cells are suggested to contribute to the pathogenesis of psoriasis. OBJECTIVE: To determine whether treatment with the anti-tumor-necrosis-factor antagonist, adalimumab, induces significant modulation of the Th1, Th17 and Th22 pathways, and correlates cellular activity with clinical response. METHODS: This study included 21 patients with moderate-to-severe psoriasis who were treated with adalimumab, and 10 healthy control subjects. Blood samples were collected at baseline and at week 12. Flow cytometry was used to analyze the frequency of circulating Th1, Th17 and Th22 cells. Real-time polymerase chain reaction was used to analyze the expression of T-bet (Th1-related), retinoid-acid receptor related orphan receptor gamma t (RORgammat, Th17-related) and aryl hydrocarbon receptor (AHR, Th22-related). An enzyme-linked immunosorbent assay was used to analyze the serum levels of IFN-gamma, IL-17, IL-22, IL-6 and tumor necrosis factor-alpha (TNF-alpha). RESULTS: At baseline, the frequencies of Th1, Th17 and Th22 cells were higher in psoriasis patients compared to the healthy controls. The expression of transcription factors T-bet, RORgammat and AHR, and the serum levels of IFN-gamma, IL-17, IL-22, IL-6 and TNF-alpha were higher in psoriasis patients compared to the healthy controls. After adalimumab therapy, there was a significant decline in the frequencies of Th1, Th17 and Th22 cells, and a concomitant decrease in the levels of their associated transcription factors and cytokines. CONCLUSION: The results suggest that the anti-tumor-necrosis-factor antagonist, adalimumab, disrupts the Th1, Th17 and Th22 pathways, resulting in clinical improvement of psoriasis. PMID- 26585972 TI - Unveiling the anti-inflammatory activity of Sutherlandia frutescens using murine macrophages. AB - Sutherlandia frutescens is a botanical widely used in southern Africa for treatment of inflammatory and other conditions. Previously, an ethanolic extract of S. frutescens (SFE) has been shown to inhibit the production of reactive oxygen species (ROS) and nitric oxide (NO) by murine neurons and a microglia cell line (BV-2 cells). In this study we sought to confirm the anti-inflammatory activities of SFE on a widely used murine macrophage cell line (i.e., RAW 264.7 cells) and primary mouse macrophages. Furthermore, experiments were conducted to investigate the anti-inflammatory activity of the flavonol and cycloartanol glycosides found in high quantities in S. frutescens. While the SFE exhibited anti-inflammatory activities upon murine macrophages similar to that reported with the microglia cell line, this effect does not appear to be mediated by sutherlandiosides or sutherlandins. In contrast, chlorophyll in our extracts appeared to be partly responsible for some of the activity observed in our macrophage-dependent screening assay. PMID- 26585973 TI - First case of primary intraocular natural killer t-cell lymphoma. AB - BACKGROUND: Natural killer cell tumors can be broadly divided by origin into mature-cell and progenitor-cell types. The invasion of nasal-origin natural killer cells into the ophthalmologic field is sometimes observed in patients, but primary ocular natural killer cell tumors are a rare occurrence. CASE PRESENTATION: A 66 year-old woman without any systemic disease presented with blurred vision due to a severe vitreous opacity in the right eye. Flow cytometric analysis of the vitreous fluid suggested a natural killer cell tumor. Moreover, cytologic examination of vitreal and retinal specimens revealed the infiltration of a natural killer cell tumor, while PCR and immunocytochemistry revealed Epstein-Barr virus infection. The results of a gene rearrangement analysis were positive for IGH, while TCR beta chains were all negative. We examined the patient with whole-body magnetic resonance imaging and positron emission tomography, and performed a bone marrow examination. These examinations returned no abnormal results. CONCLUSION: Thorough analysis of vitreal samples is essential when performing vitrectomies for vitreous opacities of unknown cause. Flow cytometric, cytologic, and PCR analysis of vitreal and retinal samples may reveal the presence and cause of severe illness. PMID- 26585974 TI - Posterior instrumented fusion suppresses the progression of ossification of the posterior longitudinal ligament: a comparison of laminoplasty with and without instrumented fusion by three-dimensional analysis. AB - PURPOSE: There is no definitive evidence that additional instrumented fusion following laminoplasty suppresses the progression of ossification of the posterior longitudinal ligament (OPLL). Recently, we reported a novel method involving the creation of three-dimensional (3D) model from computed tomography images to measure the volume of OPLL accurately. The study aim was to evaluate whether laminoplasty with instrumented fusion suppresses the progression of OPLL in comparison with stand-alone laminoplasty by our novel 3D analysis. METHODS: The present study comprised of a group of 19 patients (14 men, five women) with OPLL treated with posterior decompression and fusion (PDF group), and a group of 22 patients (14 men, eight women) treated with laminoplasty alone (LP group). The volume of OPLL was evaluated three times during the follow-up period, and the volume change of OPLL was compared between the two groups. RESULTS: The PDF group (2.0 +/- 1.7 %/year; range, -3.0 to 5.3) demonstrated lower annual rate of lesion increase compared to the LP group (7.5 +/- 5.6 %/year; range, 1.0-19.2) (p < 0.001). In a notable thing, the annual rate of increase from the 2nd to the 3rd measurement significantly decreased compared with that from the 1st to the 2nd measurement in the PDF group (p < 0.05). CONCLUSION: This is the first study to prove a possible suppressant effect of additional posterior instrumented fusion on OPLL progression using novel 3D analysis. PMID- 26585975 TI - Outcome of conservative and surgical treatment of pyogenic spondylodiscitis: a systematic literature review. AB - BACKGROUND: Spondylodiscitis is a spinal infection affecting primarily the intervertebral disk and the adjacent vertebral bodies. Currently many aspects of the treatment of pyogenic spondylodiscitis are still a matter of debate. PURPOSE: The aim of this study was to review the currently available literature systematically to determine the outcome of patients with pyogenic spondylodiscitis for conservative and surgical treatment strategies. METHODS: A systematic electronic search of MEDLINE, EMBASE, Cochrane Collaboration, and Web of Science regarding the treatment of pyogenic spondylodiscitis was performed. Included articles were assessed on risk of bias according the Cochrane Handbook for Systematic Reviews of Interventions, and the quality of evidence and strength of recommendation was evaluated according the GRADE approach. RESULTS: 25 studies were included. Five studies had a high or moderate quality of evidence. One RCT suggest that 6 weeks of antibiotic treatment of pyogenic spondylodiscitis results in a similar outcome when compared to longer treatment duration. However, microorganism-specific studies suggest that at least 8 weeks of treatment is required for S. aureus and 8 weeks of Daptomycin for MRSA. The articles that described the outcome of surgical treatment strategies show that a large variety of surgical techniques can successfully treat spondylodiscitis. No additional long-term beneficial effect of surgical treatment could be shown in the studies comparing surgical versus antibiotic only treatment. CONCLUSION: There is a strong level of recommendation for 6 weeks of antibiotic treatment in pyogenic spondylodiscitis although this has only been shown by one recent RCT. If surgical treatment is indicated, it has been suggested by two prospective studies with strong level of recommendation that an isolated anterior approach could result in a better clinical outcome. PMID- 26585979 TI - Neuro-oncology: Astrocytoma cells interconnect to resist radiotherapy. PMID- 26585977 TI - Remote ischaemic conditioning-a new paradigm of self-protection in the brain. AB - Remote ischaemic conditioning (RIC) triggers endogenous protective pathways in distant organs such as the kidney, heart and brain, and represents an exciting new paradigm in neuroprotection. RIC involves repetitive inflation and deflation of a blood pressure cuff on the limb, and is safe and feasible. The exact mechanism of signal transmission from the periphery to the brain is not known, but both humoral factors and an intact nervous system seem to have critical roles. Early-phase clinical trials have already been conducted to test RIC in the prehospital setting in acute ischaemic stroke, and in subarachnoid haemorrhage for the prevention of delayed cerebral ischaemia. Furthermore, two small randomized clinical trials in patients with symptomatic intracranial atherosclerosis have shown that RIC can reduce recurrence of stroke and have neuroprotective activity. RIC represents a highly practical and translatable therapy for acute, subacute, and chronic neurological diseases with an ischaemic or inflammatory basis. In this Review, we consider the principles and mechanisms of RIC, evidence from preclinical models and clinical trials that RIC is beneficial in neurological disease, and how the procedure might be used in the future in disorders such as vascular cognitive impairment and traumatic brain injury. PMID- 26585980 TI - Disorders of consciousness: Functional connectivity could be a prognostic neuroimaging marker for recovery from coma. PMID- 26585982 TI - Stroke: Proteomics chip yields three new markers that predict ischaemic stroke. PMID- 26585978 TI - Synaptopathy connects inflammation and neurodegeneration in multiple sclerosis. AB - Multiple sclerosis (MS) has long been regarded as a chronic inflammatory disease of the white matter that leads to demyelination and eventually to neurodegeneration. In the past decade, several aspects of MS pathogenesis have been challenged, and degenerative changes of the grey matter, which are independent of demyelination, have become a topic of interest. CNS inflammation in MS and experimental autoimmune encephalomyelitis (EAE; a disease model used to study MS in rodents) causes a marked imbalance between GABAergic and glutamatergic transmission, and a loss of synapses, all of which leads to a diffuse 'synaptopathy'. Altered synaptic transmission can occur early in MS and EAE, independently of demyelination and axonal loss, and subsequently causes excitotoxic damage. Inflammation-driven synaptic abnormalities are emerging as a prominent pathogenic mechanism in MS-importantly, they are potentially reversible and, therefore, represent attractive therapeutic targets. In this Review, we focus on the connection between inflammation and synaptopathy in MS and EAE, which sheds light not only on the pathophysiology of MS but also on that of primary neurodegenerative disorders in which inflammatory processes contribute to disease progression. PMID- 26585984 TI - Results of surgical treatment for juvenile myasthenia gravis. AB - INTRODUCTION: Radical or extended thymectomy is an effective treatment for myasthenia gravis in the adult population. There are few reports to demonstrate the effectiveness of this treatment in patients with juvenile myasthenia gravis. OBJECTIVE: The main objective of this study was to show that extended transsternal thymectomy is a valid option for treating this disease in paediatric patients. RESULTS: Twenty-three patients with juvenile myasthenia gravis underwent this surgical treatment in the period between April 2003 and April 2014; mean age was 12.13 years and the sample was predominantly female. The main indication for surgery, in 22 patients, was the generalised form of the disease (Osserman stage II) together with no response to 6 months of medical treatment. The histological diagnosis was thymic hyperplasia in 22 patients and thymoma in one patient. There were no deaths and no major complications in the postoperative period. After a mean follow-up period of 58.87 months, 22 patients are taking no medication or need less medication to manage myasthenic symptoms. CONCLUSIONS: Extended (radical) transsternal thymectomy is a safe and effective surgical treatment for juvenile myasthenia gravis. PMID- 26585986 TI - Diagnosis and New Treatment Modalities for Glioblastoma: Do They Improve Patient Survival? AB - Central nervous system (CNS) malignances include tumors of the brain and spinal cord. Taking into account the cell type where they originate from, there are almost 120 different types of CNS tumors. Benign tumors are not aggressive and normally do not invade other organs; however, they require surgical removal before they alter the surrounding brain functions. Primary malignant brain tumors commonly include astrocytomas, oligodendrogliomas, and ependimomas, where astrocytomas represent around 76%. The World Health Organization (WHO) has defined four histological grades of astrocytomas that range from the less aggressive tumors (grade I) to highly malignant tumors (grade IV). These grade IV tumors, also called glioblastoma (GBM), are the most aggressive of the primary malignant brain tumors. Patients with GBM have a median survival of 12 to 15 months. Current treatment for GBM includes surgery, radiotherapy and chemotherapy. Although there have been some advances in diagnosis and treatment, there is still no optimal treatment available for GBMs. In this review, we will discuss the approaches for GBM diagnosis and treatment, with a special emphasis to post-treatment imaging, and whether novel targeted therapies have impacted the survival of GBM patients. In addition, we will discuss clinical trials and the future of GBM diagnosis and treatment. PMID- 26585985 TI - Anti-CD20 Antibodies for Idiopathic Nephrotic Syndrome in Children. AB - Rituximab, a chimeric anti-CD20 monoclonal antibody originally licensed for lymphoma, is emerging as a novel steroid-sparing agent for idiopathic nephrotic syndrome in children. The potential use of anti-CD20 monoclonal antibodies in idiopathic nephrotic syndrome has contributed to shifting the view of podocytopathies from T cell-mediated to more complex immunomediated disorders that can benefit from targeting B cells and other mediators of the early immune response. Clinical data on the use of rituximab also have implications on disease management and classification. In this review, we present results of clinical studies that support rituximab as an effective steroid-sparing agent in steroid dependent idiopathic nephrotic syndrome. Recent randomized controlled trials suggest that potential benefits of rituximab therapy in steroid-dependent forms of idiopathic nephrotic syndrome vary depending on whether children are dependent on steroids alone or on both steroids and calcineurin inhibitors, with greater probabilities to achieve drug-free remission in the former group. Multiple-drug dependence may identify a different disease state with different prognosis and treatment options. Insufficient data are available on optimal use of rituximab as a maintenance steroid-sparing agent in these steroid-sensitive forms of the disease, including how often and for how long rituximab infusions should be repeated to maximize expected benefits and minimize potential harms. Finally, one randomized controlled trial in children with steroid-resistant idiopathic nephrotic syndrome yielded negative results. New anti-CD20 antibodies are under study in this patient population. PMID- 26585987 TI - Physiological and clinical relevance of anomalous right coronary artery originating from left sinus of Valsalva in adults. AB - OBJECTIVE: To examine physiological and clinical relevance of an anomalous right coronary artery originating from left sinus of Valsalva (right ACAOS) with interarterial course in adults. METHODS AND RESULTS: For physiological assessment, fractional flow reserve (FFR) during dobutamine challenge was measured in 37 consecutive adult patients with lone right ACAOS with interarterial course. At baseline, mean FFR was 0.91+/-0.06, declining to 0.89+/ 0.06 upon dobutamine infusion (p<0.001). Dobutamine stress FFR was significant (<=0.8) in three patients (8.1%), two of whom were surgically treated. Following surgery, dobutamine stress FFR rose from 0.76 to 0.94 and 0.76 to 0.98. Remodelling index (r=0.583, p=0.002), minimal lumen area (diastole: r=0.580, p=0.002; systole: r=0.0618, p<0.001) and per cent area stenosis (r=-0.550, p=0.004), measured by intravascular ultrasound, correlated with dobutamine stress FFR. To assess the clinical relevance, follow-up data of 119 patients with lone right ACAOS with interarterial course were analysed retrospectively. Two deaths occurred during a median follow-up period of 4 years, for a mortality rate of 0.34 per 100 person-year. No instances of myocardial infarction were recorded and one patient did undergo surgical revascularisation in the course follow-up. CONCLUSIONS: Most instances of lone right ACAOS with interarterial course discovered in adults were physiologically insignificant and ran benign clinical courses. Conservative management may thus suffice in this setting if no definitive signs of myocardial ischaemia are evident. PMID- 26585988 TI - Effect of denosumab on Japanese patients with rheumatoid arthritis: a dose response study of AMG 162 (Denosumab) in patients with RheumatoId arthritis on methotrexate to Validate inhibitory effect on bone Erosion (DRIVE)-a 12-month, multicentre, randomised, double-blind, placebo-controlled, phase II clinical trial. AB - OBJECTIVES: To evaluate efficacy and safety of three different regimens of denosumab, a fully human monoclonal antibody to receptor activator of nuclear factor kappa B (RANK) ligand (RANKL), for Japanese patients with rheumatoid arthritis (RA). METHODS: In this multicentre, randomised, placebo-controlled phase II study, 350 Japanese patients with RA between 6 months and <5 years, stratified by glucocorticoid use and rheumatoid factor status, were randomly assigned to subcutaneous injections of placebo or denosumab 60 mg every 6 months (Q6M), every 3 months (Q3M) or every 2 months (Q2M). All patients basically continued methotrexate treatment and had a supplement of calcium and vitamin D throughout the study. The primary endpoint was change in the modified Sharp erosion score from baseline to 12 months. RESULTS: Denosumab significantly inhibited the progression of bone erosion at 12 months compared with the placebo, and the mean changes of the modified Sharp erosion score at 12 months from baseline were 0.99, 0.27 (compared with placebo, p=0.0082), 0.14 (p=0.0036) and 0.09 (p<0.0001) in the placebo, Q6M, Q3M and Q2M, respectively. Secondary endpoint analysis revealed that denosumab also significantly inhibited the increase of the modified total Sharp score compared with the placebo, with no obvious evidence of an effect on joint space narrowing for denosumab. As shown in previous studies, denosumab increased bone mineral density. No apparent difference was observed in the safety profiles of denosumab and placebo. CONCLUSIONS: Addition of denosumab to methotrexate has potential as a new therapeutic option for patients with RA with risk factors of joint destruction. TRIAL REGISTRATION NUMBER: JapicCTI-101263. PMID- 26585989 TI - Short Chemical Ischemia Triggers Phosphorylation of eIF2alpha and Death of SH SY5Y Cells but not Proteasome Stress and Heat Shock Protein Response in both SH SY5Y and T98G Cells. AB - Both translation arrest and proteasome stress associated with accumulation of ubiquitin-conjugated protein aggregates were considered as a cause of delayed neuronal death after transient global brain ischemia; however, exact mechanisms as well as possible relationships are not fully understood. The aim of this study was to compare the effect of chemical ischemia and proteasome stress on cellular stress responses and viability of neuroblastoma SH-SY5Y and glioblastoma T98G cells. Chemical ischemia was induced by transient treatment of the cells with sodium azide in combination with 2-deoxyglucose. Proteasome stress was induced by treatment of the cells with bortezomib. Treatment of SH-SY5Y cells with sodium azide/2-deoxyglucose for 15 min was associated with cell death observed 24 h after treatment, while glioblastoma T98G cells were resistant to the same treatment. Treatment of both SH-SY5Y and T98G cells with bortezomib was associated with cell death, accumulation of ubiquitin-conjugated proteins, and increased expression of Hsp70. These typical cellular responses to proteasome stress, observed also after transient global brain ischemia, were not observed after chemical ischemia. Finally, chemical ischemia, but not proteasome stress, was in SH-SY5Y cells associated with increased phosphorylation of eIF2alpha, another typical cellular response triggered after transient global brain ischemia. Our results showed that short chemical ischemia of SH-SY5Y cells is not sufficient to induce both proteasome stress associated with accumulation of ubiquitin-conjugated proteins and stress response at the level of heat shock proteins despite induction of cell death and eIF2alpha phosphorylation. PMID- 26585990 TI - Exercise Therapy in Spinobulbar Muscular Atrophy and Other Neuromuscular Disorders. AB - There is no curative treatment for most neuromuscular disorders. Exercise, as a treatment for these diseases, has therefore received growing attention. When executed properly, exercise can maintain and improve health and reduce the risk of cardiovascular disease, obesity, and diabetes. In persons with muscle wasting due to neuromuscular conditions, however, a common belief has been that physical activity could accelerate degeneration of the diseased muscle and a careful approach to training has therefore been suggested. In this review, we describe the current knowledge about physical training in patients with neuromuscular diseases associated with weakness and wasting. We review studies that have investigated different types of exercise in both myopathies and motor neuron diseases, with particular emphasis on training of persons affected by spinobulbar muscular atrophy (SBMA). Finally, we provide suggestions for future investigations of training in this condition. PMID- 26585991 TI - Indwelling Stent Embedded with Light-Emitting Diodes for Photodynamic Therapy of Malignant Biliary Obstruction. AB - PURPOSE: We describe the design and preliminary characterization of a stent incorporating light-emitting diodes (LEDs) for photodynamic therapy (PDT) of malignant biliary obstruction. METHODS: A prototype was constructed with red (640 nm) LEDs embedded in a 14.5 French polyurethane tube. The device was evaluated for optical power and subjected to physical and electrical tests. PDT-induced reactive oxygen species were imaged in a gel phantom. RESULTS: The stent functioned at a 2.5-cm bend radius and illuminated for 6 months in saline. No stray currents were detected, and it was cool after 30 minutes of operation. Optical power of 5-15 mW is applicable to PDT. Imaging of a reactive oxygen indicator showed LED-stent activation of photosensitizer. CONCLUSIONS: The results motivate biological testing and design optimization. PMID- 26585992 TI - Factors associated with early resumption of sexual intercourse among postnatal women in Uganda. AB - BACKGROUND: Despite being a key component to be addressed during postnatal period, sexuality has long been a subject of secrecy and taboo in Africa. Resumption of sexual intercourse after giving birth has been shown to reduce extramarital affairs and consequently reduce risk of sexually transmitted infections like HIV/AIDS. Consequences of early resumption of sexual intercourse include unwanted pregnancy, genital trauma and puerperal infection. The objective of the study was to assess prevalence and factors associated with early resumption of sexual intercourse among postnatal mothers attending postnatal clinic at a National referral Hospital in Uganda. METHODOLOGY: A cross-sectional study that employed an interviewer-administered questionnaire was conducted among 374 women who delivered six months prior to conducting the study. The independent variables included socio-demographic characteristics of the participant, socio demographic characteristics of the spouse, perceived cultural norms, medical history, mode of delivery, and postpartum complications. The dependent variable was timing of resumption of sexual intercourse after childbirth (before or after six weeks postpartum). Data were analysed using SPSS version 16.0. RESULTS: The study showed that 105 participants (21.6%) had resumed sexual intercourse before 6 weeks after childbirth. The participants' education level, occupation, and parity; education level of the spouse, age of baby and use of family planning were the factors associated with early resumption of sexual intercourse after child birth (before six weeks postpartum) (p < 0.05). CONCLUSION: Many women resumed sexual intercourse after six weeks. Women with high income, low parity, who ever-used contraception or had a spouse with high education level were more likely to have early resumption of sexual intercourse. PMID- 26585993 TI - Dissociative Experiences and Psychopathology Among Inmates in Italian and Portuguese Prisons. AB - The association between dissociation and psychopathological symptoms is well established, yet studies with inmates are lacking. If higher rates of dissociation and psychiatric symptoms are reported in inmate samples, it is not clear whether they represent two separate, albeit related, characteristics. We examined the association between dissociation and psychopathological symptoms among 320 Italian subjects (122 inmates and 198 community participants) and a Portuguese inmate sample ( n = 67). Then, we tested whether dissociation and psychopathology levels were higher among inmates. Both hypotheses were supported, confirming the relevance of dissociative, paranoid, and psychotic symptoms among inmates, as well as their interrelations. Notably, the group difference in dissociation remained significant after partialing out the variance associated with other psychopathological symptoms. Conversely, only the difference in paranoid symptoms remained-marginally-significant when controlling for the influence of dissociation. This finding suggests that dissociation may have unique relevance for the psychological functioning of inmates. PMID- 26585994 TI - Binding of Reactive Oxygen Species at Fe-S Cubane Clusters. AB - Reactive oxygen species (ROS) play an important role in the biochemistry of the cell and occur in degenerative processes as well as in signal transduction. Iron sulfur proteins are particularly oxygen-sensitive and their inorganic cofactors frequently undergo ROS-induced decomposition reactions. As experimental knowledge about these processes is still incomplete we present here a quantum chemical study of the relative energetics for the binding of the most relevant ROS to [Fe4S4] clusters. We find that cubane clusters with one uncoordinated Fe atom (as found, for instance, in aconitase) bind all oxygen derivatives considered, whereas activation of triplet O2 to singlet O2 is required for binding to valence saturated iron centers in these clusters. The radicals NO and OH feature the most exothermic binding energies to Fe atoms. Direct sulfoxidation of coordinating cysteine residues is only possible by OH or H2O2 as attacking agents. The thermodynamic picture of ROS binding to iron-sulfur clusters established here can serve as a starting point for studying reactivity-modulating effects of the cluster-embedding protein environment on ROS-induced decomposition of iron-sulfur proteins. PMID- 26585995 TI - The Association among Feeding Mode, Growth, and Developmental Outcomes in Infants with Complex Congenital Heart Disease at 6 and 12 Months of Age. AB - OBJECTIVE: To assess the association between early anthropometric measurements, device-assisted feeding, and early neurodevelopment in infants with complex congenital heart diseases (CHDs). STUDY DESIGN: Bayley Scales of Infant Development II were used to assess cognitive and motor skills in 72 infants with CHD at 6 and 12 months of age. Linear regression models were used to assess the association between mode of feeding and anthropometric measurements with neurodevelopment at 6 and 12 months of age. RESULTS: Of the 72 infants enrolled in the study, 34 (47%) had single-ventricle physiology. The mean Mental Developmental Index (MDI) and Psychomotor Developmental Index (PDI) scores at 6 months of age were 92 +/- 10 and 81 +/- 14, respectively. At 12 months of age, the mean MDI and PDI scores were 94 +/- 12 and 80 +/- 16, respectively. Lower length-for-age z score (P < .01) and head circumference-for-age z score (P < .05) were independently associated with lower MDI at 6 months, and both increased hospital length of stay (P < .01) and lower length-for-age z score (P = .04) were associated independently with lower MDI at 12 months. Device-assisted feeding at 3 months (P = .04) and lower length-for-age z score (P < .05) were independently associated with lower PDI at 6 months. Both lower weight-for-age z score (P = .04) and lower length-for-age z score (P = .04) were associated independently with PDI at 12 months. CONCLUSION: Neonates with complex CHD who required device assisted feeding and those with lower weight and length and head circumference z scores at 3 months were at risk for neurodevelopmental delay at 6 and 12 months of age. PMID- 26585996 TI - Chemokine receptor CXCR3 in turbot (Scophthalmus maximus): cloning, characterization and its responses to lipopolysaccharide. AB - Chemokine (C-X-C motif) receptor 3, a member of the G protein-coupled receptors superfamily, regulates the responses of many immune responses. In this experiment, we cloned and characterized the cDNA of CXCR3 in Scophthalmus maximus (turbot). A 5'-UTR of 216-bp, a 259-bp 3'-UTR with a poly (A) tail and a 1089-bp CDS encoding 362 amino acids form the cDNA of CXCR3, which is 1564-bp long. Phylogenetic analyses indicated that turbot CXCR3 shared a high similarity with other CXCR3s and shared more similarity with CXCR5 than the other subfamilies of chemokines. The CXCR3 protein in turbot showed the highest similarity with the CXCR3b from rainbow trout (44.5%), which indicated that this CXCR3 gene/protein may be a CXCR3b isoform. Quantitative real-time PCR analysis showed that CXCR3 transcripts were constitutively expressed in all the tissues of the non-injected turbot used in this study, with the highest expression occurring in blood. Several immune-related tissues of fish, such as the spleen, head kidney, liver and blood, tissues, which were abundant of lymphocyte, were investigated in this study. CXCR3 gene was expressed at the highest level in blood than the other tested tissues. The injection experiment suggested that the CXCR3 expression level after LPS injection was significantly up-regulated in all immune-related tissues in turbot. These results improve our understanding of the functions of CXCR3 in the turbot immune response. PMID- 26585997 TI - In situ experiments to assess effects of constraints linked to caging on ecotoxicity biomarkers of the three-spined stickleback (Gasterosteus aculeatus L.). AB - The aim of this study was to evaluate the effects of caging constraints on multiple fish biomarkers used during ecotoxicological studies (biometric data, immune and antioxidant systems, and energetic status). Two of these constraints were linked to caging: starvation and fish density in cages, and one in relation to the post-caging handling: a short transport. Three in situ experiments were conducted with three-spined sticklebacks (Gasterosteus aculeatus). The first experiment compared the effects of three densities (low, medium, and high). The second experiment compared effects of starvation in fish fed every two days with fish that were not fed. Finally comparisons between sticklebacks which have suffered a short car transport after caging and sticklebacks killed without preliminary transport were made. The lack of food had no effect on fish energetic reserves but negatively affected their condition index and their immune system. Transport and high density induced oxidative stress, defined as an overproduction of reactive oxygen species and a stimulation of the antioxidant system. These two constraints also harmed the leucocyte viability. In order not to have any impact on ecotoxicity biomarkers during in situ experiments, it is preferable to decrease fish density in cages, prevent transport before dissections, and feed fish when the caging lasts more than two weeks. PMID- 26585998 TI - Brachial plexus endoscopic dissection and correlation with open dissection. AB - Shoulder endoscopy is evolving and becoming extra-articular. More and more procedures are taking place in the area of the brachial plexus (BP). We carried out an anatomical study to describe the endoscopic anatomy of the BP and the technique used to dissect and expose the BP endoscopically. Thirteen fresh cadavers were dissected. We first performed an endoscopic dissection of the BP, using classical extra-articular shoulder arthroscopy portals. Through each portal, we dissected as many structures as possible and identified them. We then did an open dissection to corroborate the endoscopic findings and to look for damage to the neighboring structures. In the supraclavicular area, we were able to expose the C5, C6 and C7 roots, and the superior and middle trunks in 11 of 13 specimens through two transtrapezial portals by following the suprascapular nerve. The entire infraclavicular portion of the BP (except the medial cord and its branches) was exposed in 11 of 13 specimens. The approach to the infraclavicular portion of the BP led directly to the lateral and posterior cords, but the axillary artery hid the medial cord. The musculocutaneous nerve was the first nerve encountered when dissecting medially from the anterior aspect of the coracoid process. The axillary nerve was the first nerve encountered when following the anterior border of the subscapularis medially from the posterior aspect of the coracoid process. Knowledge of the endoscopic anatomy of the BP is mandatory to expose and protect this structure while performing advanced arthroscopic shoulder procedures. PMID- 26586000 TI - Water spray-induced grooming is negatively correlated with depressive behavior in the forced swimming test in rats. AB - Rodents show grooming, a typical self-care behavior, under stress and non-stress conditions. Previous studies revealed that grooming under stress conditions such as the open-field test (OFT) or the elevated plus-maze test (EPM) is associated with anxiety, but the roles of grooming under non-stress conditions are not well understood. Here, we examined spray-induced grooming as a model of grooming under a non-stress condition to investigate the relationship between this grooming and depression-like behavior in the forced swim test (FST) and tail suspension test, and we compared spray-induced grooming with OFT- and EPM-induced grooming. The main finding was that the duration of spray-induced grooming, but not that of OFT/EPM-induced grooming, was negatively correlated with the duration of immobility in the FST, an index of depression-like behavior. The results suggest that spray-induced grooming is functionally different from the grooming in the OFT and EPM and is related to reduction of depressive behavior. PMID- 26585999 TI - Efficacy and safety of extracorporeal shock wave therapy for orthopedic conditions: a systematic review on studies listed in the PEDro database. AB - BACKGROUND: Extracorporeal shock wave therapy (ESWT) is an effective and safe non invasive treatment option for tendon and other pathologies of the musculoskeletal system. SOURCES OF DATA: This systematic review used data derived from the Physiotherapy Evidence Database (PEDro; www.pedro.org.au, 23 October 2015, date last accessed). AREAS OF AGREEMENT: ESWT is effective and safe. An optimum treatment protocol for ESWT appears to be three treatment sessions at 1-week intervals, with 2000 impulses per session and the highest energy flux density the patient can tolerate. AREAS OF CONTROVERSY: The distinction between radial ESWT as 'low-energy ESWT' and focused ESWT as 'high-energy ESWT' is not correct and should be abandoned. GROWING POINTS: There is no scientific evidence in favour of either radial ESWT or focused ESWT with respect to treatment outcome. AREAS TIMELY FOR DEVELOPING RESEARCH: Future randomized controlled trials should primarily address systematic tests of the aforementioned optimum treatment protocol and direct comparisons between radial and focused ESWT. PMID- 26586002 TI - AN EVALUATION OF THE BASIC CHARACTERISTICS OF A PLASTIC SCINTILLATING FIBRE DETECTOR IN CT RADIATION FIELDS. AB - The ionisation chamber for computed tomography (CT) is an instrument that is most commonly used to measure the computed tomography dose index. However, it has been reported that the 10 cm effective detection length of the ionisation chamber is insufficient due to the extent of the dose distribution outside the chamber. The purpose of this study was to estimate the basic characteristics of a plastic scintillating fibre (PSF) detector with a long detection length of 50 cm in CT radiation fields. The authors investigated position dependence using diagnostic X ray equipment and dependencies for energy, dose rate and slice thickness using an X-ray CT system. The PSF detector outputs piled up at a count rate of 10 000 counts ms-1 in dose rate dependence study. With calibration, this detector may be useful as a CT dosemeter with a long detection length except for the measurement at high dose rate. PMID- 26586001 TI - Somato-axodendritic release of oxytocin into the brain due to calcium amplification is essential for social memory. AB - Oxytocin (OT) is released into the brain from the cell soma, axons, and dendrites of neurosecretory cells in the hypothalamus. Locally released OT can activate OT receptors, form inositol-1,4,5-trisphosphate and elevate intracellular free calcium (Ca(2+)) concentrations [(Ca(2+)) i ] in self and neighboring neurons in the hypothalamus, resulting in further OT release: i.e., autocrine or paracrine systems of OT-induced OT release. CD38-dependent cyclic ADP-ribose (cADPR) is also involved in this autoregulation by elevating [Ca(2+)] i via Ca(2+) mobilization through ryanodine receptors on intracellular Ca(2+) pools that are sensitive to both Ca(2+) and cADPR. In addition, it has recently been reported that heat stimulation and hyperthermia enhance [Ca(2+)] i increases by Ca(2+) influx, probably through TRPM2 cation channels, suggesting that cADPR and TRPM2 molecules act as Ca(2+) signal amplifiers. Thus, OT release is not simply due to depolarization-secretion coupling. Both of these molecules play critical roles not only during labor and milk ejection in reproductive females, but also during social behavior in daily life in both genders. This was clearly demonstrated in CD38 knockout mice in that social behavior was impaired by reduction of [Ca(2+)] i elevation and subsequent OT secretion. Evidence for the associations of CD38 with social behavior and psychiatric disorder is discussed, especially in subjects with autism spectrum disorder. PMID- 26586003 TI - Comorbidities, bone-sparing agent prescription history and their determinants among postmenopausal women in UK primary care settings: a retrospective database study. AB - SUMMARY: Distinguishing oral bisphosphonates from other bone-sparing therapies, this retrospective observational study, first, characterized treated osteoporosis patients in the UK, and secondly, explored factors associated with the risk of discontinuation or switching between therapies. The latter should be considered when evaluating real-world data. PURPOSE: This retrospective observational study evaluated the characteristics of women with postmenopausal osteoporosis, including comorbidities and determinants of treatment patterns with bone-sparing agents. METHODS: The UK Clinical Practice Research Datalink was used to identify postmenopausal women (aged >=50 years) treated with a bone-sparing agent or diagnosed with osteoporosis between 1 January 1993 and 31 December 2008. Two non mutually-exclusive subpopulations were defined: (1) patients active in the database on 31 December 2008; (2) patients treated with a bone-sparing agent since 1 January 1993. Subpopulation 1 was used to describe patient comorbidities and osteoporosis treatment history, and subpopulation 2 was used to explore the characteristics associated with bone-sparing treatment patterns use via multivariable regression for repeated multinomial responses. RESULTS: A total of 62,657 individuals met the inclusion criteria; subpopulation 1 comprised 38,469 women (61.4%), of whom 21,687 received a bone-sparing agent in 2008 (99.7% oral bisphosphonates and the remainder other agents). Those receiving other agents were more likely to have had previous treatment with bone-sparing agents, to have experienced previous fractures, and to have visited their doctor more frequently. Analyses also identified several comorbidities associated with an increased risk of discontinuation of bone-sparing agents, including heart disease, gastrointestinal disease, and renal failure. Anticonvulsant use was associated with a dramatic increase in the risk of switching. CONCLUSIONS: Several patient characteristics were associated with discontinuation of, or switching between, bone-sparing treatments. Patients receiving bone-sparing medication other than oral bisphosphonates were more likely to have comorbid conditions and a history of fracture and to have taken an oral bisphosphonate previously. PMID- 26586004 TI - Trends in food and beverage television brand appearances viewed by children and adolescents from 2009 to 2014 in the USA. AB - OBJECTIVE: Public health experts raise concerns about marketing unhealthy products to young people through television (TV) product placements. Coca-Cola brand appearances (product placements) reached a substantial child and adolescent audience in 2008, but additional brands now sponsor popular programming. We aimed to quantify child and adolescent exposure to food and beverage appearances since 2008. DESIGN: In 2015, we purchased Nielsen data on occurrences and child/adolescent exposure to food, beverage and restaurant brand appearances on US prime-time TV from 2009 to 2014, and analysed appearances by product category, company, brand and year. We compared exposure to appearances with exposure to traditional commercials for top brands. SETTING: Nationally representative panel of approximately 20 000 TV-viewing households. SUBJECTS: Children (2-11 years) and adolescents (12-17 years). RESULTS: Exposure to food and beverage brand appearances peaked in 2012 and declined through 2014. Whereas full-calorie soda brands dominated before 2012, other sugary drink and quick-serve restaurant brands contributed over one-third of appearances viewed by children in 2013 and 2014. Nine hundred and fifty-four companies had brand appearances from 2009 to 2014, but just four were responsible for over half of exposures: The Coca-Cola Company, Dr Pepper Snapple Group, PepsiCo and Starbucks. Approximately half were viewed on reality TV programmes and one sitcom. Each year from 2009 to 2013, brand appearance exposure exceeded traditional advertising exposure for at least one brand. CONCLUSIONS: Despite recent reductions in brand appearances viewed by young people, some unhealthy branded products continue to be marketed via this method. We suggest policy options to reduce child and adolescent exposure to such appearances. PMID- 26586005 TI - In Reply to "The effect of tolvaptan on kidney function in patients with autosomal dominant polycystic kidney disease". PMID- 26586006 TI - Klotho attenuates renal hypertrophy and glomerular injury in Ins2Akita diabetic mice. AB - BACKGROUND: Expression of klotho, the renoprotective anti-aging gene, is decreased in diabetic model kidneys. We hypothesized that klotho protein attenuates renal hypertrophy and glomerular injury in a mouse model of diabetic nephropathy. METHODS: Klotho transgenic (KLTG) mice were crossed with spontaneously diabetic Ins2Akita (AKITA) mice. Glomerular morphology, macrophage infiltration, urinary albumin excretion and urinary 8-hydroxy-2-deoxy guanosine excretion were examined. In vitro, human glomerular endothelial cells were stimulated with high glucose with or without recombinant klotho, and calpain activity and proinflammatory cytokine expressions were measured. RESULTS: We found that klotho protein overexpression attenuates renal hypertrophy and glomerular injury in this mouse model of diabetic nephropathy. Klotho overexpression attenuated renal hypertrophy, albuminuria, glomerular mesangial expansion, and endothelial glycocalyx loss in the AKITA mice. AKITA mice exhibit high levels of urinary 8-hydroxy-2-deoxy guanosine excretion. In the presence of klotho overexpression, this effect was reversed. In addition, the glomerular macrophage infiltration characteristic of AKITA mice was attenuated in KLTG-AKITA mice. In human glomerular endothelial cells, high glucose induced calpain activity. This effect was suppressed by expression of recombinant klotho, which also suppressed the induction of proinflammatory cytokines. CONCLUSION: Our data suggest klotho protein protects against diabetic nephropathy through multiple pathways. PMID- 26586007 TI - Atypical clinical and radiological course of a patient with Canavan disease. AB - Canavan disease (CD) is a rare metabolic disorder caused by aspartoacylase (ASPA) deficiency. It leads to severe neurological degeneration with spongiform brain degeneration. Accumulation of N-acetylaspartate (NAA) in brain and urine is specific to the disease and guides diagnosis. Magnetic resonance imaging (MRI) usually shows diffuse white matter abnormalities with involvement of the basal ganglia. Mild forms of the disease with a more favorable clinical course and radiological involvement of the basal ganglia without white matter abnormalities have also been reported. Here we report an atypical case of a girl aged nine years with CD. The disease started at the classical age of five months. Classical elevation of NAA in brain and urine was present and genetic analysis identified mutations in the ASPA gene. However, clinical evolution was milder than typical CD, with partial motor impairment and relatively well-preserved cognitive skills. MRI was also atypical with low white matter involvement and unusual topography and evolution of abnormalities in the basal ganglia. PMID- 26586009 TI - Mixed method integrative review exploring nurses' recognition and response to unsafe practice. AB - AIM: To determine how nurses recognize and respond to unsafe practice. BACKGROUND: Practice guidelines and standards outline safe practice. Nurses face challenges in recognizing and responding unsafe practice. DESIGN: Whittemore and Knafl's revised framework for integrative reviews guided the analysis. DATA SOURCES: A comprehensive search of literature exploring the identification and response to unsafe practice, was undertaken in CINAHL, Medline, Embase and PsychoINFO databases for the period 2004-2014. REVIEW METHODS: Nineteen articles from 15 studies were included in the review. A mixed method integrative approach was used to review data and draw conclusions. RESULTS: Behaviours and cues that indicate unsafe practice are influenced by organizational and individual characteristics. Individual nurses responses are variable and there are professional and personal costs associated with being reported or reporting unsafe practice. CONCLUSION: The small number of studies reviewed limits the conclusions that can be drawn from the review but suggest that nurses can identify unsafe practice in their peers. Individual nurses' recognition and response to unsafe practice in their peers contributes to patient outcomes and safety. Nurses need awareness training and strategies to respond to unsafe practice and reporting systems that protect reporters from repercussions. Further research investigating organizational factors and individual factors that contribute to a shift in practice across safety boundaries is required. PMID- 26586008 TI - Intracerebroventricular administration of alpha-ketoisocaproic acid decreases brain-derived neurotrophic factor and nerve growth factor levels in brain of young rats. AB - Maple syrup urine disease (MSUD) is an inherited aminoacidopathy resulting from dysfunction of the branched-chain keto acid dehydrogenase complex, leading to accumulation of the branched-chain amino acids (BCAA) leucine, isoleucine and valine as well as their corresponding transaminated branched-chain alpha ketoacids. This disorder is clinically characterized by ketoacidosis, seizures, coma, psychomotor delay and mental retardation whose pathophysiology is not completely understood. Recent studies have shown that oxidative stress may be involved in neuropathology of MSUD. However, the effect of accumulating alpha ketoacids in MSUD on neurotrophic factors has not been investigated. Thus, the objective of the present study was to evaluate the effects of acute intracerebroventricular administration of alpha-ketoisocaproic acid (KIC) on brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) levels in the brains of young male rats. Ours results showed that intracerebroventricular administration of KIC decreased BDNF levels in hippocampus, striatum and cerebral cortex, without induce a detectable change in pro-BDNF levels. Moreover, NGF levels in the hippocampus were reduced after intracerebroventricular administration of KIC. In conclusion, these data suggest that the effects of KIC on demyelination and memory processes may be mediated by reduced trophic support of BDNF and NGF. Moreover, lower levels of BDNF and NGF are consistent with the hypothesis that a deficit in this neurotrophic factor may contribute to the structural and functional alterations of brain underlying the psychopathology of MSUD, supporting the hypothesis of a neurodegenerative process in MSUD. PMID- 26586010 TI - Effects of skeleton structure on necrosis targeting and clearance properties of radioiodinated dianthrones. AB - Necrosis avid agents (NAAs) can be used for diagnose of necrosis-related diseases, evaluation of therapeutic responses and targeted therapeutics of tumor. In order to probe into the effects of molecular skeleton structure on necrosis targeting and clearance properties of radioiodinated dianthrones, four dianthrone compounds with the same substituents but different skeletal structures, namely Hypericin (Hyp), protohypericin (ProHyp), emodin dianthrone mesomer (ED-1) and emodin dianthrone raceme (ED-2) were synthesized and radioiodinated. Then radioiodinated dianthrones were evaluated in vitro for their necrosis avidity in A549 lung cancer cells untreated and treated with H2O2. Their biodistribution and pharmacokinetic properties were determined in rat models of induced necrosis. In vitro cell assay revealed that destruction of rigid skeleton structure dramatically reduced their necrosis targeting ability. Animal studies demonstrated that destruction of rigid skeleton structure dramatically reduced the necrotic tissue uptake and speed up the clearance from the most normal tissues for the studied compounds. Among these (131)I-dianthrones, (131)I-Hyp exhibited the highest uptake and persistent retention in necrotic tissues. Hepatic infarction could be clearly visualized by SPECT/CT using (131)I-Hyp as an imaging probe. The results suggest that the skeleton structure of Hyp is the lead structure for further structure optimization of this class of NAAs. PMID- 26586011 TI - [Sciatic nerve intraneural perineurioma]. AB - Intraneural perineurioma is a benign tumor developed from the perineurium and responsible for localized nerve hypertrophy. This uncommon tumor is characterized by a proliferation of perineural cells with a "pseudo-onion bulb" pattern. We report a sciatic nerve intraneural perineurioma in a 39-year-old patient. PMID- 26586012 TI - [Specific morphology of a rare ovarian tumor]. PMID- 26586013 TI - A new contemporary prostate cancer grading system. PMID- 26586014 TI - [A deep-seated haemorrhagic tumor with spindle cells]. PMID- 26586015 TI - [A testis with a misleading clinical aspect]. PMID- 26586016 TI - [Eosinophilic cellulitis: About a new pediatric case]. AB - Wells' syndrome or "eosinophilic cellulitis" is characterized by clinical features of cellulitis and histological pictures of eosinophils infiltrate of the dermis with some " flame " figures. This is a very rare disease in the pediatric age. We report the case of a 14-month-old boy, presented with two farms painful nodular brownish lesions in the thigh and back of the foot as well as multiple erythematous papular and vesicular lesions on the forehead, cheeks, limbs and trunk. Biological analysis and histological examination confirmed the diagnosis of Wells' syndrome. The outcome was favorable with dermocorticoid. PMID- 26586017 TI - [Gastro-intestinal neuroectodermal tumor (GNET): A case report of a small intestine tumor with hepatic metastases]. AB - The gastro-intestinal neuroectodermal tumor (GNET) is a rare sarcoma of the digestive tract, which was recently recognised. The knowledge of the morphological, immunohistochemical and molecular diagnostic criteria is necessary to not mistake it for the metastasis of a melanoma or for another sarcoma of the digestive tract as the gastro-intestinal clear cells sarcoma or the malignant peripheral nervous system tumor (MPNST). We report the case of a 41-year-old patient with a GNET of the small intestine with hepatic metastasis. The histological examination showed a diffuse proliferation of epithelioid cells, which only express PS100. The presence EWSR1-ATF1 gene fusions with any melanocytic differentiation leads to the diagnosis of GNET. PMID- 26586018 TI - Treatment rates of paediatric acute myeloid leukaemia: a view from three tertiary centres in India. PMID- 26586019 TI - Current tobacco use is associated with higher rates of implant revision and deep infection after total hip or knee arthroplasty: a prospective cohort study. AB - BACKGROUND: Tobacco smoking is a risk factor for several adverse post-operative outcomes. We aimed to compare the rates of complications in current tobacco users and non-users who underwent primary total hip arthroplasty (THA) or total knee arthroplasty (TKA). METHODS: All patients who underwent primary THA or TKA at the Mayo Clinic from 2010-2013 were included in the study. Current tobacco use was defined as the use of cigarettes, cigars, pipes, or smokeless tobacco reported at the time of index THA or TKA; current non-users were former users or never users. We used Cox proportional hazards regression to assess the association of current tobacco use status with each post-THA/TKA complication, using hazard ratios and 95% confidence intervals (CI). RESULTS: Tobacco use status was available for 7926 patients (95%) and not available for 446 patients (5%); 565 (7%) were current tobacco users. Compared to non-users, current tobacco users were more likely to be male (p < 0.001), and less likely to be obese (p <= 0.008), be older than 60 years, have Charlson score >0 or have undergone TKA rather than THA (p < 0.001 each). The hazard ratios for deep infection (2.37; 95% CI 1.19, 4.72; p = 0.01) and implant revision (1.78; 95% CI 1.01, 3.13; p = 0.04) were higher in current tobacco users than in non-users. No significant differences were noted for periprosthetic fractures or superficial infections. CONCLUSIONS: We noted that current tobacco use was associated with high risk of deep infection and implant revision after primary THA or TKA. Future studies should determine the optimal time for tobacco use cessation before elective surgeries such as THA and TKA to improve short-term and long-term arthroplasty outcomes. PMID- 26586020 TI - Adipose-derived Stem Cell Conditioned Media Extends Survival time of a mouse model of Amyotrophic Lateral Sclerosis. AB - Adipose stromal cells (ASC) secrete various trophic factors that assist in the protection of neurons in a variety of neuronal death models. In this study, we tested the effects of human ASC conditional medium (ASC-CM) in human amyotrophic lateral sclerosis (ALS) transgenic mouse model expressing mutant superoxide dismutase (SOD1(G93A)). Treating symptomatic SOD1(G93A) mice with ASC-CM significantly increased post-onset survival time and lifespan. Moreover, SOD1(G93A) mice given ASC-CM treatment showed high motor neuron counts, less activation of microglia and astrocytes at an early symptomatic stage in the spinal cords under immunohistochemical analysis. SOD1(G93A) mice treated with ASC CM for 7 days showed reduced levels of phosphorylated p38 (pp38) in the spinal cord, a mitogen-activated protein kinase that is involved in both inflammation and neuronal death. Additionally, the levels of alpha-II spectrin in spinal cords were also inhibited in SOD1(G93A) mice treated with ASC-CM for 3 days. Interestingly, nerve growth factor (NGF), a neurotrophic factor found in ASC-CM, played a significant role in the protection of neurodegeneration inSOD1(G93A) mouse. These results indicate that ASC-CM has the potential to develop into a novel and effective therapeutic treatment for ALS. PMID- 26586021 TI - High exposure to inorganic arsenic by food: the need for risk reduction. AB - Arsenic is a human carcinogen that occurs ubiquitously in soil and water. Based on epidemiological studies, a benchmark dose (lower/higher bound estimate) between 0.3 and 8 MUg/kg bw/day was estimated to cause a 1 % increased risk of lung, skin and bladder cancer. A recently published study by EFSA on dietary exposure to inorganic arsenic in the European population reported 95th percentiles (lower bound min to upper bound max) for different age groups in the same range as the benchmark dose. For toddlers, a highly exposed group, the highest values ranged between 0.61 and 2.09 ug arsenic/kg bw/day. For all other age classes, the margin of exposure is also small. This scenario calls for regulatory action to reduce arsenic exposure. One priority measure should be to reduce arsenic in food categories that contribute most to exposure. In the EFSA study the food categories 'milk and dairy products,' 'drinking water' and 'food for infants' represent major sources of inorganic arsenic for infants and also rice is an important source. Long-term strategies are required to reduce inorganic arsenic in these food groups. The reduced consumption of rice and rice products which has been recommended may be helpful for a minority of individuals consuming unusually high amounts of rice. However, it is only of limited value for the general European population, because the food categories 'grain-based processed products (non rice-based)' or 'milk and dairy products' contribute more to the exposure with inorganic arsenic than the food category 'rice.' A balanced regulatory activity focusing on the most relevant food categories is required. In conclusion, exposure to inorganic arsenic represents a risk to the health of the European population, particularly to young children. Regulatory measures to reduce exposure are urgently required. PMID- 26586022 TI - Dicaffeoylquinic Acid-Enriched Fraction of Cichorium glandulosum Seeds Attenuates Experimental Type 1 Diabetes via Multipathway Protection. AB - Chicory has a major geographical presence in Europe and Asia. Cichorium glandulosum Boiss. et Huet, a genus Cichorium, is used for medicinal and food purposes in Asia. In this study, a dicaffeoylquinic acid-enriched fraction of C. glandulosum seeds n-BuOH fraction (CGSB) could ameliorate type 1 diabetes mellitus (T1DM) in streptozotocin (STZ)-induced diabetic mice with continuous administration for 2 weeks. CGSB treatment showed significantly higher plasma insulin levels but lower free fatty acids in adipose tissue and liver. Moreover, CGSB improved pancreatic islet mass. In vitro, different fractions of C. glandulosum seed (CGS) induced the differentiation of 3T3-L1 preadipocytes. The mRNA level for peroxisome proliferator-activated receptor alpha increased in high glucose treatment group in HepG2 cells, while CGSB significantly down-regulated the mRNA expression. The main compound of CGSB, 3,5-dicaffeoylquinic acid, was isolated and identified, which exhibited alpha-glucosidase inhibitory activity. These findings demonstrated that CGSB attenuated experimental T1DM via multipathway protection. PMID- 26586025 TI - Leisure-activity participation to prevent later-life cognitive decline: a systematic review. AB - OBJECTIVE: A systematic literature review was conducted to characterise the current state of knowledge concerning the definition, categorisation, and operationalisation of leisure activity in studies examining its possible role in preventing later-life cognitive decline. Following PRISMA guidelines for a systematic review, the study examined peer-reviewed empirical research publications focused on leisure activity, cognitive decline, and prevention. METHODS: Searches in the PubMed/Medline reSEARCH, CINHAL, Ovid MEDLINE, Embase, Web of Science, PsychoINFO, ERIC Proquest, the Cochrane library, and PsycARTICLES databases for the years 2000 to 2011 identified 52 publications for inclusion. RESULTS: The results are discussed and based on these findings are further interpreted using the Model of Human Occupation, which focuses on key factors identified in the review that are salient to associations between participation in leisure activities and prevention of dementia. CONCLUSIONS: While the findings support a growing consensus that participation in leisure activities might significantly contribute to prevention of dementia, it also identifies major hindrances to progress. Important limitations detected include a lack of theoretical underpinnings, and little consensus and standardisation in the measured key variables. The study reinforces the critical need to overcome these limitations to enable health care professionals (e.g. occupational therapists) to make evidence-based recommendations for increased participation in activities as a means of promoting health and preventing cognitive decline. PMID- 26586023 TI - N-Docosahexaenoylethanolamine ameliorates ethanol-induced impairment of neural stem cell neurogenic differentiation. AB - Previous studies demonstrated that prenatal exposure to ethanol interferes with embryonic and fetal development, and causes abnormal neurodevelopment. Docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid highly enriched in the brain, was shown to be essential for proper brain development and function. Recently, we found that N-docosahexenoyethanolamine (synaptamide), an endogenous metabolite of DHA, is a potent PKA-dependent neurogenic factor for neural stem cell (NSC) differentiation. In this study, we demonstrate that ethanol at pharmacologically relevant concentrations downregulates cAMP signaling in NSC and impairs neurogenic differentiation. In contrast, synaptamide reverses ethanol-impaired NSC neurogenic differentiation through counter-acting on the cAMP production system. NSC exposure to ethanol (25-50 mM) for 4 days dose dependently decreased the number of Tuj-1 positive neurons and PKA/CREB phosphorylation with a concomitant reduction of cellular cAMP. Ethanol-induced cAMP reduction was accompanied by the inhibition of G-protein activation and expression of adenylyl cyclase (AC) 7 and AC8, as well as PDE4 upregulation. In contrast to ethanol, synaptamide increased cAMP production, GTPgammaS binding, and expression of AC7 and AC8 isoforms in a cAMP-dependent manner, offsetting the ethanol-induced impairment in neurogenic differentiation. These results indicate that synaptamide can reduce ethanol-induced impairment of neuronal differentiation by counter-affecting shared targets in G-protein coupled receptor (GPCR)/cAMP signaling. The synaptamide-mediated mechanism observed in this study may offer a possible avenue for ameliorating the adverse impact of fetal alcohol exposure on neurodevelopment. PMID- 26586026 TI - Copper-Mediated Cross-Dehydrogenative Coupling of 2-Methylpyridine and 8 Methylquinoline with Methyl Ketones and Benzamides. AB - A synthetic method to prepare (E)-(pyridin-2-yl)enones and (E)-(quinolin-8 yl)enones that relies on the respective copper(I)-catalyzed formal cross dehydrogenative coupling (CDC) reaction of 2-methylpyridine and 8-methylquinoline with methyl ketones has been discovered. The mechanism was delineated to follow a pathway involving oxidation of the N-heterocycle to its corresponding aldehyde adduct prior to reaction with the methyl ketone. The versatility and substrate dependent divergence in the reactivity of the copper-mediated CDC strategy was exemplified by its application to the synthesis of N-(quinolin-8-ylmethyl)amide and N-(quinolin-8-ylmethyl)aniline adducts on switching the cross-coupling partner to benzamides or an aniline derivative. PMID- 26586024 TI - Associations with HIV testing in Uganda: an analysis of the Lot Quality Assurance Sampling database 2003-2012. AB - Beginning in 2003, Uganda used Lot Quality Assurance Sampling (LQAS) to assist district managers collect and use data to improve their human immunodeficiency virus (HIV)/AIDS program. Uganda's LQAS-database (2003-2012) covers up to 73 of 112 districts. Our multidistrict analysis of the LQAS data-set at 2003-2004 and 2012 examined gender variation among adults who ever tested for HIV over time, and attributes associated with testing. Conditional logistic regression matched men and women by community with seven model effect variables. HIV testing prevalence rose from 14% (men) and 12% (women) in 2003-2004 to 62% (men) and 80% (women) in 2012. In 2003-2004, knowing the benefits of testing (Odds Ratio [OR] = 6.09, 95% CI = 3.01-12.35), knowing where to get tested (OR = 2.83, 95% CI = 1.44 5.56), and secondary education (OR = 3.04, 95% CI = 1.19-7.77) were significantly associated with HIV testing. By 2012, knowing the benefits of testing (OR = 3.63, 95% CI = 2.25-5.83), where to get tested (OR = 5.15, 95% CI = 3.26-8.14), primary education (OR = 2.01, 95% CI = 1.39-2.91), being female (OR = 3.03, 95% CI = 2.53 3.62), and being married (OR = 1.81, 95% CI = 1.17-2.8) were significantly associated with HIV testing. HIV testing prevalence in Uganda has increased dramatically, more for women than men. Our results concurred with other authors that education, knowledge of HIV, and marriage (women only) are associated with testing for HIV and suggest that couples testing is more prevalent than other authors. PMID- 26586027 TI - Cardiac GR and MR: From Development to Pathology. AB - The efficacy of mineralocorticoid receptor (MR) antagonism in the treatment of certain patients with heart failure has highlighted the pivotal role of aldosterone and MR in heart disease. The glucocorticoid (GC) receptor (GR) is also expressed in heart, but the role of cardiac GR had received much less attention until recently. GR and MR are highly homologous in both structure and function, although not in cellular readout. Recent evidence in animal models has uncovered a tonic role for GC action via GR in cardiomyocytes in prevention of heart disease. Here, we review this evidence and the implications for a balance between GR and MR activation in the early life maturation of the heart and its subsequent health and disease. PMID- 26586028 TI - [Accidental gamma-hydroxybutyrate poisoning in an infant]. PMID- 26586029 TI - [Are the ophthalmology items of the French health record realistic?]. AB - PURPOSE: Since 2006, French general practitioners have had to carry out an ophthalmological screening for children, using a methodology contained within the child's health record (carnet de sante). The purpose of this screening is to allow an early diagnosis of sight-threatening as well as potentially life threatening conditions (e.g., retinoblastoma). The aim of the present study was to evaluate the theoretical knowledge and the clinical skills of practitioners implementing the screening, with regards to two specific items of the health record screening schedule, by means of a questionnaire. MATERIAL AND METHODS: From December 2013 to September 2014, 42 practitioners (16 general practitioners, 14 pediatricians, 12 resident physicians) from four distinct locations in Normandy, France, were questioned using a questionnaire on two ophthalmological items of the French health record: one on red reflex and one on eyeball size. RESULTS: Only four of 42 practitioners provided correct answers on the red reflex color. Thirty of 42 practitioners reported difficulties performing the red reflex test, mostly because they did not know the normality criteria and the purpose served by this test. Thirty-three of 42 practitioners declared that they found it difficult to know whether or not eyeball sizes were normal, mostly because they were unaware of the normality criteria. None of the practitioners provided the correct (to within +/- 1 mm) mean horizontal cornea diameter in full-term newborns and adults. CONCLUSION: This study demonstrates that there is poor theoretical knowledge and a low level of clinical skill for practitioners performing the ophthalmological screening based on the French health record schedule. This schedule therefore does not seem to meet its purpose. PMID- 26586030 TI - Familial risk and protective factors in alcohol intoxicated adolescents: psychometric evaluation of the family domain of the Communities That Care Youth Survey (CTC) and a new short version of the Childhood Trauma Questionnaire (CTQ). AB - BACKGROUND: Alcohol intoxicated adolescents (AIA) in emergency department are an important target group for prevention and valid information on their familial risk and protective factors (RPF) is crucial for implementing customized family based counseling in hospitals. We therefore, examined the psychometric characteristics of scales which assess familial RPF. METHODS: We used seven family scales from the Communities That Care Youth Survey Instrument (CTC-F7); four assess risk factors: family conflicts, poor family management, parental attitudes favorable towards drug use/antisocial behavior; three assess protective factors: family attachment, opportunities and rewards for prosocial involvement. To assess physical and emotional abuse and emotional neglect, we created a new scale composed of six items from the Childhood Trauma Questionnaire (CTQ-6). We tested these eight scales on 342 AIA aged 13-17. Based on the classical test theory we calculated descriptive item and scale statistics and internal consistency. We assessed construct validity by confirmatory factor analysis with Maximum Likelihood (ML) estimation in a sample with imputed missing values (EM Algorithm). To check robustness, we repeated the analyses with complete cases, with multiple imputed data, and with methods suitable for categorical data. We used SPSS 21, AMOS 21 and R (randomForrest and lavaan package). RESULTS: Three of seven CTC-F scales showed poor psychometric properties in the descriptive analysis. A ML-confirmatory model with five latent factors fitted the remaining CTC-F scales best (CTC-F5). The latent structure of the CTQ-6 is characterized by three first-order factors (physical abuse, emotional abuse, emotional neglect) and one second-order factor. The global goodness-of-fit indices for the CTC-F5 and the CTQ-6 demonstrated acceptable fit (for both models: TLI and CFI>0.97, RMSEA<0.05). The confirmatory evaluation based on complete cases (n=266), on multiple imputed data, and with alternative estimation methods produces global and local model-fit indices that are comparable to those from the main analysis. The final subscales CTC-F5 and CTQ-6 show acceptable to good internal consistency (alpha>0.7). CONCLUSIONS: The final CTC-F5 and the newly developed CTQ-6 demonstrate acceptable to good psychometric properties for the AIA sample. The CTC-F5 and the CTQ-6 facilitate a psychometrically sound assessment of familial RPF for this vulnerable and important target group for prevention. PMID- 26586031 TI - Paroxysmal eyelid movements in patients with visual-sensitive reflex seizures. AB - AIM: Paroxysmal eyelid movements (PEM) are non-epileptic episodes characterized by eyelid closure, upturning of the eyes, and rapid eyelid flutter. The aim of this study was to report clinical and EEG data of patients with PEM and its relationship with visual sensitivity. METHODS: We studied 26 patients with epilepsy (12 males and 14 females; mean age: 14.0+/-6.9 years) who presented PEM. The epilepsy was idiopathic generalized (eight cases), idiopathic focal (six cases), symptomatic focal (five cases), and reflex epilepsy (seven cases). PEM and blinking were analysed by video-EEG recordings at rest and during intermittent photic stimulation, pattern stimulation, and TV watching. Blink rate was evaluated during three different conditions: at rest, during a TV-viewing period, and at the occurrence of PEM. Analysis of variance (ANOVA) was used for statistical comparisons. RESULTS: Repeated episodes of PEM were recorded in all patients. The frequency of PEM ranged from 8 to 12.5 Hz (average: 9.6+/-1.5). PEM were accompanied by a significant increase in blinking compared to the rest condition and TV watching (blink rate: 56.5+/-21.1 vs 25.0+/-16.2 vs 11.3+/-11.8, respectively; p<0.0001). Photoparoxysmal EEG responses (measured as sensitivity to photic stimulation) were found in 25 cases, associated with pattern sensitivity in 22; only one patient was sensitive to pattern but not photic stimulation. Visually-induced seizures were recorded in 20 cases, triggered by both stimuli (photic and pattern stimulation) in 11 patients; seizures were triggered by pattern stimulation (but not photic stimulation) in five, photic stimulation (but not pattern stimulation) in three, and TV watching (but not photic or pattern stimulation) in one. Epileptic eyelid myoclonia was noted in 17 patients. CONCLUSION: The coexistence of PEM, photoparoxysmal EEG responses, increased blinking, and epileptic eyelid myoclonia suggests an underlying dysfunction involving cortical-subcortical neural networks, according to the recent concept of system epilepsies. [Published with video sequences]. PMID- 26586032 TI - Traumatic experiences, alexithymia, and Internet addiction symptoms among late adolescents: A moderated mediation analysis. AB - The association between traumatic experiences, alexithymia, and substance abuse is well established. Less is known about the role of traumatic experiences and alexithymia in the onset and maintenance of Internet-related disorders. In the present study, self-report measures on traumatic experiences, alexithymia, and problematic Internet use were administered to 358 high school students (57% females) aged 18-19years old, to test whether alexithymic traits mediated the relationship between traumatic experiences and Internet addiction symptoms, and whether gender moderated the proposed mediation in the sample. While partial mediation occurred in the entire sample, gender directly affected the relationship between the investigated constructs: Internet addiction symptoms were independently related to traumatic experiences among males, and to alexithymic traits among females. Therefore, the results of this study suggest that trauma memories among males, and problems with affect regulation among females, may increase the risk of problematic Internet use during late adolescence. Such findings might have relevant implications to inform any treatment plan for late adolescent students who are overinvolved with online activities, pointing out that tailored approaches to their problems and difficulties are particularly needed in clinical practice. PMID- 26586033 TI - Placental anastomoses in monochorionic diamniotic twin pregnancy: not always a source of complication. PMID- 26586034 TI - Pancreas-preserving management in reinterventions for severe pancreatic fistula after pancreatoduodenectomy: a systematic review. AB - BACKGROUND: Life-threatening postoperative pancreatic fistula (LTPOPF) is the most feared complication after pancreatoduodenectomy (PD). Although completion pancreatectomy (CP) is usually performed when radiological management fails, the associated morbidity and mortality rates remain high. Here, we reviewed pancreas preserving alternatives to CP. METHODS: The PubMed database was systematically searched for publications between 1983 and 2014, describing pancreas-preserving surgical treatment of the pancreas remnant (PR) after reintervention in a context of post-PD LTPOPF. RESULTS: A total of 12 articles including 140 patients were reviewed. Six different types of pancreas-preserving treatment were described: external wirsungostomy, simple drainage of the PF, closure of pancreatic stump, internal wirsungostomy, partial CP, and salvage pancreatogastrostomy after major leakage of a pancreatojejunostomy. The overall median survival rate was 75 % but rose to 83 % when patients undergoing only surgical drainage of the fistula were excluded. The median complication rate was 75 %, and the median length of hospital stay was 41.5 days. Further reintervention was required for 25 % of the patients. The median incidence of late diabetes was 22.5 %. The incidence of exocrine insufficiency ranged from 0 to 100 % depending on the intervention. CONCLUSION: Pancreas-preserving surgical management of the PR after LTPOPF can be performed with acceptable mortality and morbidity. These data suggest that CP should have a more precisely specified role in the management algorithm and should not be performed systematically. PMID- 26586035 TI - How to apply the LEAP study. PMID- 26586036 TI - Myeloid differentiation protein 2 facilitates pollen- and cat dander-induced innate and allergic airway inflammation. AB - BACKGROUND: The National Health and Nutrition Examination Survey identified several pollens and cat dander as among the most common allergens that induce allergic sensitization and allergic diseases. We recently reported that ragweed pollen extract (RWPE) requires Toll-like receptor 4 (TLR4) to stimulate CXCL mediated innate neutrophilic inflammation, which in turn facilitates allergic sensitization and airway inflammation. Myeloid differentiation protein 2 (MD2) is a TLR4 coreceptor, but its role in pollen- and cat dander-induced innate and allergic inflammation has not been critically evaluated. OBJECTIVE: We sought to elucidate the role of MD2 in inducing pollen- and cat dander-induced innate and allergic airway inflammation. METHODS: TCM(Null) (TLR4(Null), CD14(Null), MD2(Null)), TLR4(Hi), and TCM(Hi) cells and human bronchial epithelial cells with small interfering RNA-induced downregulation of MD2 were stimulated with RWPE, other pollen allergic extracts, or cat dander extract (CDE), and activation of nuclear factor kappaB (NF-kappaB), secretion of the NF-kappaB-dependent CXCL8, or both were quantified. Wild-type mice or mice with small interfering RNA knockdown of lung MD2 were challenged intranasally with RWPE or CDE, and innate and allergic inflammation was quantified. RESULTS: RWPE stimulated MD2-dependent NF kappaB activation and CXCL secretion. Likewise, Bermuda, rye, timothy, pigweed, Russian thistle, cottonwood, walnut, and CDE stimulated MD2-dependent CXCL secretion. RWPE and CDE challenge induced MD2-dependent and CD14-independent innate neutrophil recruitment. RWPE induced MD2-dependent allergic sensitization and airway inflammation. CONCLUSIONS: MD2 plays an important role in induction of allergic sensitization to cat dander and common pollens relevant to human allergic diseases. PMID- 26586037 TI - Incident asthma and Mycoplasma pneumoniae: A nationwide cohort study. AB - BACKGROUND: Previous studies investigating the relationship between Mycoplasma pneumoniae and incident asthma in the general population have been inconclusive. OBJECTIVE: We conducted a nationwide cohort study to clarify this relationship. METHODS: Using the National Health Insurance Research Database of Taiwan, we identified 1591 patients with M pneumoniae infection (International Classification of Diseases, Ninth Revision, Clinical Modification code 4830) given diagnoses between 2000 and 2008. We then frequency matched 6364 patients without M pneumoniae infection from the general population according to age, sex, and index year. Cox proportional hazards regression analysis was performed to determine the adjusted hazard ratio (aHR) of the occurrence of asthma in the M pneumoniae cohort compared with that in the non-M pneumoniae cohort. RESULTS: Regardless of comorbidities and the use of antibiotic or steroid therapies, patients with M pneumonia infection had a higher risk of incident asthma than those without it. The aHR of asthma was 3.35 (95% CI, 2.71-4.15) for the M pneumoniae cohort, with a significantly higher risk when patients were stratified by age, sex, follow-up time, and comorbidities, including allergic rhinitis, atopic dermatitis, or allergic conjunctivitis. Patients with M pneumoniae infection had a higher risk of having early-onset (age, <12 years; aHR, 2.87) and late-onset (age, >=12 years; aHR, 3.95) asthma. The aHR was also higher within the less than 2-year follow-up in the M pneumoniae cohort (aHR, 4.41; 95% CI, 3.40-5.74) than in the cohort without the infection. CONCLUSION: This study found that incident cases of early-onset and late-onset asthma are closely related to M pneumoniae infection, even in nonatopic patients. PMID- 26586038 TI - Early or not delayed complementary feeding?: This is the question. PMID- 26586039 TI - Reply. PMID- 26586041 TI - Postural adjustments in young ballet dancers compared to age matched controls. AB - OBJECTIVES: The purpose of the study was to use photogrammetry to evaluate the posture of ballet practitioners compared to an age-matched control group. DESIGN: One hundred and eleven 7- to 24-year-old female volunteers were evaluated and were divided into two groups: the ballet practising group (n = 52) and the control group (n = 59), divided into three subgroups according to age and years of ballet experience. RESULTS: Dancers with 1-3 years experience compared to controls of the same age shows alterations in External Rotation Angle (P < 0.05). Dancers 4-9 years experience show alterations in Lumbar Lordosis, Pelvis Tilt Angle and Navicular Angle Right and Left (P < 0.05). Dancers with over 9 years experience show alterations in External Rotation and Navicular Angle Left (P < 0.05). CONCLUSIONS: Research shows there are differences between dancers and controls. In the groups 1-3 years and over 9 years of experience, the External Rotation Angle is greater. In the group 4-9 years of experience the Lumbar Lordosis Angle is greater and Pelvis Tilt, Navicular Angle Left and Right are smaller. In more than 9 years of ballet experience, the Navicular Angle Left is smaller. PMID- 26586042 TI - Dynamic postural stability differences between male and female players with and without ankle sprain. AB - OBJECTIVES: To evaluate dynamic stability index (DSI) differences between males and females for different jump directions. To examine both preseason DSI differences between players with and without a history of ankle sprain, and between players with and without an ankle sprain during the subsequent season. DESIGN: Prospective cohort design. SETTING: Laboratory. PARTICIPANTS: 47 male (22.9 +/- 3.9 y) and 19 female (21.5 +/- 2.9 y) sub-elite and elite team sport players. MAIN OUTCOME MEASURES: Ankle sprain history was collected using an injury history questionnaire. DSI of a single-leg hop-stabilization task measured preseason was collected using force plates and calculated using a Matlab program. Ankle sprains were reported during the subsequent season. RESULTS: Male players demonstrated larger DSI than female players on forward medial/lateral stability index (MLSI) and vertical stability index (VSI), diagonal VSI, and lateral anterior/posterior stability index (APSI) and VSI. Forward, diagonal and lateral dynamic postural stability indices (DPSI) were larger for males (p < 0.001). No significant differences were found between players with and without a previous ankle sprain nor between players with and without an ankle sprain during the subsequent season. CONCLUSION: Male players showed larger DSI scores than female players, indicating lower dynamic stability. Sex-specific training sessions or prevention programs should be developed. PMID- 26586040 TI - Changes in IgE sensitization and total IgE levels over 20 years of follow-up. AB - BACKGROUND: Cross-sectional studies have reported a lower prevalence of sensitization in older adults, but few longitudinal studies have examined whether this is an aging or a year-of-birth cohort effect. OBJECTIVE: We sought to assess changes in sensitization and total IgE levels in a cohort of European adults as they aged over a 20-year period. METHODS: Levels of serum specific IgE to common aeroallergens (house dust mite, cat, and grass) and total IgE levels were measured in 3206 adults from 25 centers in the European Community Respiratory Health Survey on 3 occasions over 20 years. Changes in sensitization and total IgE levels were analyzed by using regression analysis corrected for potential differences in laboratory equipment and by using inverse sampling probability weights to account for nonresponse. RESULTS: Over the 20-year follow-up, the prevalence of sensitization to at least 1 of the 3 allergens decreased from 29.4% to 24.8% (-4.6%; 95% CI, -7.0% to -2.1%). The prevalence of sensitization to house dust mite (-4.3%; 95% CI, -6.0% to -2.6%) and cat (-2.1%; 95% CI, -3.6% to 0.7%) decreased more than sensitization to grass (-0.6%; 95% CI, -2.5% to 1.3%). Age-specific prevalence of sensitization to house dust mite and cat did not differ between year-of-birth cohorts, but sensitization to grass was most prevalent in the most recent ones. Overall, total IgE levels decreased significantly (geometric mean ratio, 0.63; 95% CI, 0.58-0.68) at all ages in all year-of-birth cohorts. CONCLUSION: Aging was associated with lower levels of sensitization, especially to house dust mite and cat, after the age of 20 years. PMID- 26586043 TI - Contribution of Corticospinal Modulation and Total Electrical Energy for Peripheral-Nerve-Stimulation-Induced Neuroplasticity as Indexed by Additional Muscular Force. AB - BACKGROUND: Protocols to induce motor related neuroplasticity are usually directed to central neural structures such as the motor cortex or the spinal cord. OBJECTIVE: Herein, we aimed to evaluate the effects of peripheral nerve stimulation using a current intensity (stimulation intensity) approach to understand the contribution of the corticospinal system and total energy to electrically-induced neuroplasticity. METHODS: Electrical stimulation trains of lower intensity, interlaced with 2-s bursts of higher intensity, were applied to anesthetized rabbits. Nerve blocks were applied to the proximal side of the stimulation site with identical stimulation trains in a different session to block the contribution of corticospinal volleys during intensity-modulated electrical stimulation. RESULTS: Additional force corresponding to additional recruitment of motoneurons was observed when a 2-s burst of high intensity was present (burst/constant: 24.7 +/- 3.6%/2.09 +/- 4.8%; p < .001). Additional force was absent in sessions when the neural pathway to the spinal cord was blocked (unblocked/blocked: 29.3 +/- 3.8%/-2.49 +/- 4.8%; p < .001). CONCLUSIONS: The results suggest that induced neuroplasticity indexed by the additional force is dependent on the total energy applied and connectivity to central structures. These results give additional evidence for the contribution of two factors for induced neuroplasticity: (i) modulation by corticospinal structures and (ii) total energy of stimulation. Further protocols should explore simultaneous peripheral and central stimulation. PMID- 26586045 TI - Benefits and implementation of home hemodialysis: A narrative review. AB - Home hemodialysis (HD) is a modality of renal replacement therapy that can be safely and independently performed at home by end-stage renal disease (ESRD) patients. Home HD can be performed at the convenience of the patients on a daily basis, every other day and overnight (nocturnal). Despite the great and many perceived benefits of home HD, including the significant improvements in health outcomes and resource utilization, the adoption of home HD has been limited; lack or inadequate pre-dialysis education and training constitute a major barrier. The lack of self-confidence and/or self-efficacy to manage own therapy, lack of family and/or social support, fear of machine and cannulation of blood access and worries of possible catastrophic events represent other barriers for the implementation of home HD besides inadequate competence and/or expertise in caring for home HD patients among renal care providers (nephrologists, dialysis nurses, educators). A well-studied, planned and prepared and carefully implemented central country program supported by adequate budget can play a positive role in overcoming the challenges to home HD. Healthcare authorities, with the increasingly financial and logistic demands and the relatively higher mortality and morbidity rates of the conventional in-center HD, should tackle home HD as an attractive and cost-effective modality with more freedom, quality of life and improvement of clinical outcomes for the ESRD patients. PMID- 26586044 TI - Transcriptional analysis of micronutrient zinc-associated response for enhanced carbohydrate utilization and earlier solventogenesis in Clostridium acetobutylicum. AB - The micronutrient zinc plays vital roles in ABE fermentation by Clostridium acetobutylicum. In order to elucidate the zinc-associated response for enhanced glucose utilization and earlier solventogenesis, transcriptional analysis was performed on cells grown in glucose medium at the exponential growth phase of 16 h without/with supplementary zinc. Correspondingly, the gene glcG (CAC0570) encoding a glucose-specific PTS was significantly upregulated accompanied with the other two genes CAC1353 and CAC1354 for glucose transport in the presence of zinc. Additionally, genes involved in the metabolisms of six other carbohydrates (maltose, cellobiose, fructose, mannose, xylose and arabinose) were differentially expressed, indicating that the regulatory effect of micronutrient zinc is carbohydrate-specific with respects to the improved/inhibited carbohydrate utilization. More importantly, multiple genes responsible for glycolysis (glcK and pykA), acidogenesis (thlA, crt, etfA, etfB and bcd) and solventogenesis (ctfB and bdhA) of C. acetobutylicum prominently responded to the supplementary zinc at differential expression levels. Comparative analysis of intracellular metabolites revealed that the branch node intermediates such as acetyl-CoA, acetoacetyl-CoA, butyl-CoA, and reducing power NADH remained relatively lower whereas more ATP was generated due to enhanced glycolysis pathway and earlier initiation of solventogenesis, suggesting that the micronutrient zinc-associated response for the selected intracellular metabolisms is significantly pleiotropic. PMID- 26586046 TI - Transplant nephrectomy - A single-center experience. AB - Transplant nephrectomy (TN) is associated with significant morbidity and mortality and influences the outcome of subsequent renal transplantation. The aim of this study was to identify the reasons for TN in a single transplant center in the United Kingdom and to determine the complication rate, effect on relisting and re-transplantation. We studied all the TNs in our center from January 2000 to December 2011. Detailed information including cause of allograft failure and reason for TN were analyzed. Of 602 renal transplants performed at our center during the period of the study, 42 TNs were performed on 38 (6%) patients (24 men and 14 women). The median age of the patients at the time of transplantation who subsequently underwent TN was 56 years (range: 28-73 years) and 71% of the allografts were donated after circulatory death. The mean human leucocyte antigen mismatch for these patients was 2.3. The most commonly used immunosuppression was a combination of prednisolone, mycophenolate and tacrolimus, which was used in 50% of the patients. Twenty-five (60%) of the TNs in this series were for allografts failing during the first month of transplantation. The most common indication for the TN was graft thrombosis (50%), with an overall in-hospital mortality rate of 9.5% and a morbidity rate of 31%. Seven of 19 patients listed underwent successful re-transplantation. Although TN is associated with a risk of significant morbidity and mortality, it does not preclude from listing for re transplantation. The difficulty of access to complete information about transplant failures and TN highlights the need for a national registry. PMID- 26586047 TI - Is there a genetic predisposition to new-onset diabetes after kidney transplantation? AB - Kidney transplant recipients may develop new-onset diabetes after transplantation (NODAT) and transplant-associated hyperglycemia (TAH) (NODAT or new-onset impaired glucose tolerance-IGT). We studied 251 consecutive renal transplant South Asian recipients for incidence of NODAT and its risk factors between June 2004 and January 2009. Pre-transplant glucose tolerance test (GTT) identified non diabetics (n = 102, IGT-24, NGT-78) for analysis. Baseline immunosuppression along with either cyclosporine (CsA) (n = 70) or tacrolimus (Tac) (n = 32) was given. Patients underwent GTT 20 days (mean) post-transplant to identify NODAT, normal (N) or IGT. TAH was observed in 40.2% of the patients (40% in CsA and 40.6% in Tac) (P = 0.5). NODAT developed in 13.7% of the patients (12.9% in CsA and 15.6% in Tac) (P = 0.5). Overall, Hepatitis C (P = 0.007), human leukocyte antigen (HLA) B52 (P = 0.03) and lack of HLA A28 (A68/69) (P = 0.03) were associated with TAH. In the Tac group, higher Day 1 dosage (P <0.001), HLA A1 (P = 0.04), B13 (P = 0.03) and lack of DR2 (P = 0.004) increased the risk of TAH. In the CsA group, HLA A10 (P = 0.03), failure of triglyceride (P = 0.001) or low density lipoprotein (LDL) (P = 0.03) to lower or high-density lipoprotein to rise (P = 0.001), and higher post-transplant LDL (P <0.001) and cholesterol levels (P = 0.02) were associated with NODAT or TAH. Post-transplant fasting plasma glucose on Day 1 had sensitivity-54.5%, specificity-50.1%, positive predictive value 18.1% and negative predictive value-84.8% for detecting NODAT. In conclusion, there is a genetic predisposition to NODAT and TAH in South Asia as seen by the HLA associations, and a predisposition exists to the individual diabetogenic effects of Tac and CsA based on HLA type. This could lead to more careful selection of calcineurin inhibitors based on HLA types in the South Asian population. PMID- 26586048 TI - Outpatient parenteral antibiotic therapy in a renal transplant population: A single-center experience. AB - Outpatient parenteral antimicrobial therapy (OPAT) is a well-established method in medical specialties. Its use in renal transplant recipients has not been thoroughly explored. No guidelines within this patient subset exist. This study describes OPAT outcomes within a UK teaching hospital renal transplant population. Renal function, mapped by estimated glomerular filtration rate (eGFR), and clinical response to infection were collected retrospectively. A total of 635 antimicrobial episodes were administered to nine renal transplant patients over 12 discrete OPAT courses during the study period. Eleven of 12 OPAT courses (91.67%) produced a clinical improvement in infection. One course was terminated due to immunosuppressive-related neutropenia. No patient required admission due to failure of OPAT or adverse events. There was no significant change in graft function throughout the OPAT courses compared with baseline renal function (ANOVA, P = 0.06). One minor line infection was reported. This was treated conservatively and did not interrupt the OPAT. OPAT is safe and clinically effective in our renal transplant recipients with no significant deterioration in eGFR. The incidence of adverse events, specifically line complications, was lower in our population than those reported in the literature. Future work should develop OPAT guidelines designed for transplant recipients to outline the degree of monitoring required. PMID- 26586049 TI - Predictive factors for increased aortic pulse wave velocity in renal transplant recipients and its relation to graft outcome. AB - To evaluate aortic stiffness in renal transplant patients and to determine the correlation of renal insufficiency and estimated glomerular filtration rate (eGFR) with aortic pulse wave velocity (APWV), we studied 96 renal transplant patients followed-up at our center. We measured the APWV using transcutaneous Doppler flow recordings and the foot-to-foot method, and calculated the eGFR using the Modification of Diet in Renal Disease equation. The study included 81 (84.4%) males and 15 (15.6%) females. The mean age of the patients was 37.84 +/- 10.10 years. The mean duration of transplant was 47.90 +/- 34.40 months. The eGFR of the patients ranged from 1 to 120 mL/min, with a mean GFR of 72.6 +/- 23.2 mL/min. Sixty-seven (69.8%) patients had eGFR > 60 mL/min and hence had stages 1 and 2 chronic kidney disease (CKD), 27 (28.1%) patients had eGFR 30-60 mL/min and hence had stage 3 CKD and two (2.1%) patients had eGFR <30 mL/min and hence had stages 4 and 5 CKD. The APWV of the patients ranged from 4 to 14.2 m/s, with a mean of 7.49 +/- 2.47 m/s. A significant inverse correlation was found between the APWV and eGFR (Pearson correlation coefficient, -0.427, P = 0.00). The mean APWV was significantly higher among patients with higher CKD stage, P = 0.004. We conclude that the APWV is related to the renal graft dysfunction as measured by eGFR. The poorer the renal function, the higher was the APWV. Determination of the APWV may be helpful in predicting the outcome in renal transplant recipients. PMID- 26586050 TI - Tolerance and efficacy of a low dose of the calcimimetic agent cinacalcet in controlling moderate to severe secondary hyperparathyroidism in hemodialysis patients. AB - Secondary hyperparathyroidism is almost a constant feature in chronic kidney disease (CKD) patients maintained on hemodialysis (HD). Calcimimetic agents appear to offer an alternative to surgery in controlling secondary hyperparathyroidism in these patients. Recent studies provide conflicting data on the benefits, efficacy and tolerance of cinacalcet as first-line therapy for the treatment of secondary hyperparathyroidism in CKD. This study was designed to investigate the efficacy and tolerance of a low dose of the calcimimetic agent cinacalcet in patients on long-term HD having moderate to severe secondary hyperparathyroidism. Twenty five adult male patients on HD for more than three years were included in the study. All had moderate to severe secondary hyperparathyroidism with serum intact parathyroid hormone (iPTH) >50 pmol/L, resistant to conventional treatment. We used the targets of Chronic Kidney Disease: Outcomes Quality Initiative (K/DOQI) clinical guidelines as optimal target of serum iPTH, calcium and phosphate. Patients were administered cinacalcet as a single oral daily dose of 30 mg and were followed-up for six months. Cinacalcet treatment for six months resulted in a significant reduction in the serum phosphate and iPTH levels while the serum calcium levels remained unchanged. Thirty-six percent of the patients attained the recommended serum iPTH levels, 40% achieved significant reduction of the serum iPTH levels and 24% showed no favorable response. Only one patient dropped out because of severe gastrointestinal symptoms. Our results suggest that treatment of CKD patients, having moderate to severe secondary hyperparathyroidism, with low-dose cinacalcet is effective and well tolerated. PMID- 26586051 TI - The effect of gabapentin on muscle cramps during hemodialysis: A double-blind clinical trial. AB - Hemodialysis-associated muscle cramps (HAMC) are a common complication during hemodialysis (HD) sessions. A number of pharmacologic agents have been evaluated to prevent and or diminish HAMC; however, none of them has an established role. To the best of our knowledge, this is the first study to evaluate the possible effect of gabapentin on HAMC. In a double-blinded clinical trial, we compared the possible effect of gabapentin with a placebo in prevention and or diminishing episodes of HAMC in HD patients who had experienced frequent intradialytic muscle cramps. At first, placebo was given before each dialysis session for four weeks and then, after a two-week washout period, 300 mg of gabapentin was given before each dialysis session for four weeks to verify the effect of gabapentin on HAMC. Overall, 15 patients (seven men and eight women; mean age, 52.02 years) with frequent intradialytic muscle cramps were enrolled in the study. The incidence of symptomatic muscle cramp decreased in the gabapentin group compared with the placebo group, with a significant difference between them (P = 0.001). The intensity of muscle cramps also decreased in the gabapentin group (P = 0.001). There was no significant association between HAMC in male and female patients (P = 0. 397), mean age of HD patients (P = 0.226) and cause of end-stage renal disease (P = 0.551). According to the results of our study, gabapentin prescription before each HD session significantly reduced the frequency and the intensity of muscle cramps during HD without any major side-effects. PMID- 26586052 TI - Erythrocyte sedimentation rate in stable patients on chronic hemodiaysis. AB - The objective of this study was to assess the value and determinants of erythrocyte sedimentation rate (ESR) in stable patients on regular hemodialysis (HD). Pre-dialysis and post-dialysis ESR was measured in a group of stable adult patients on regular HD and the results were compared. The results were also correlated with the patients' demographic and laboratory data. Only stable patents were included in the study. Patients with evidence of current infection, active inflammatory processor malignancy and severe anemia were excluded. We recruited 161 patients in the study of whom 44.1% were males, 53.4% had diabetes mellitus and 40.4% had an episode of sepsis previously. Only 15.5% of the patients had less than one year of dialysis and 54.3% were over the age of 60 years. The mean post-dialysis ESR was significantly higher than the pre-dialysis ESR (55.6 +/- 30.4 and 49.8 +/- 28.5, respectively; P = 0.003). Pre-dialysis, 79.5% of the patients had raised ESR. ESR was significantly correlated with C reactive protein, serum ferritin, plasma albumin and fibrinogen (P <0.05). Patient factors (age, gender, duration of dialysis, previous renal transplantation, type of dialysis access and sepsis or thrombosis of dialysis access site) and blood laboratory parameters (hemoglobin, serum creatinine and serum parathormone) had no statistically significant correlation with ESR ( P >= 0.05). Post-dialysis the ESR was raised in most of the stable patients on regular HD and was significantly higher than the pre-dialysis ESR (by, on average, 5.8 mm/h). ESR had variable correlation with different blood factors. PMID- 26586053 TI - Association of dialysis adequacy with nutritional and inflammatory status in patients with chronic kidney failure. AB - The number of patients with dialysis-dependent renal failure has increased in the past years worldwide. Several parameters have been introduced for the quantitative assessment of dialysis adequacy. The National Cooperative Dialysis Study results indicated that Kt/V and time-averaged concentration of urea (TAC) are predictors of mortality in patients who receive maintenance hemodialysis (HD). Also, the protein catabolic ratio (PCR), which is an indicator of nutritional status, can predict patients' mortality. Our aim was to assess the impact of parameters that show dialysis adequacy on indices of nutrition or inflammation. A total of 46 patients were included in the study; eight patients were excluded during the course of the study and 38 patients were enrolled in the final analysis. All patients were receiving HD for at least for three months. HD was administered three times per week and the study lasted for two months. Kt/V, TAC and PCR were assessed at the beginning of the study based on patients' urea and blood urea nitrogen in the first week of our study; these calculations were repeated at the end of the first and second months using the mean of the mentioned values in the month. Both adequacy indices significantly and positively correlated with changes in PCR (P <0.001). However, no significant correlation was detectable between Kt/V and TAC with either body mass index and albumin or C reactive protein. Based on the Kt/V values, patients with adequate dialysis had slower decrease in the PCR (P <0.001). Our results indicate that adequacy of dialysis is correlated with patients' nutritional status. No correlation was observed between dialysis adequacy and inflammatory status. PMID- 26586054 TI - Lactate dehydrogenase as a biomarker for early renal damage in patients with sickle cell disease. AB - Among many complications of sickle cell disease, renal failure is the main contributor to early mortality. It is present in up to 21% of patients with sickle cell disease. Although screening for microalbuminuria and proteinuria is the current acceptable practice to detect and follow renal damage in patients with sickle cell disease, there is a crucial need for other, more sensitive biomarkers. This becomes especially true knowing that those biomarkers start to appear only after more than 60% of the kidney function is lost. The primary purpose of this study is to determine whether lactate dehydrogenase (LDH) correlates with other, direct and indirect bio-markers of renal insufficiency in patients with sickle cell disease and, therefore, could be used as a biomarker for early renal damage in patients with sickle cell disease. Fifty-five patients with an established diagnosis of sickle cell disease were recruited to in the study. Blood samples were taken and 24-h urine collection samples were collected. Using Statcrunch, a data analysis tool available on the web, we studied the correlation between LDH and other biomarkers of kidney function as well as the distribution and relationship between the variables. Regression analysis showed a significant negative correlation between serum LDH and creatinine clearance, R (correlation coefficient) = -0.44, P = 0.0008. This correlation was more significant at younger age. This study shows that in sickle cell patients LDH correlates with creatinine clearance and, therefore, LDH could serve as a biomarker to predict renal insufficiency in those patients. PMID- 26586055 TI - Morbidity and mortality associated with Plasmodium vivax and Plasmodium falciparum infection in a tertiary care kidney hospital. AB - Malaria is a disease of tropical regions and both types of plasmodia, i.e. Plasmodium falciparum and Plasmodium vivax, cause significant morbidity and mortality. P. vivax was thought to be benign and cause less morbidity and mortality. Many reports showed the devastating effect of vivax malaria too. We compared the clinical symptoms, laboratory markers, treatment and outcome of both the plasmodia. This is a retrospective analysis of 95 patients admitted to The Kidney Center, Karachi in a duration of 15 years (1997-2012); 45 patients with falciparum malaria and 50 patients with vivax malaria, and compared the clinical presentation, laboratory workup, treatment and outcome in both groups. The two groups constitute a mixed population of diabetes, chronic kidney disease (CKD) and hemodialysis patients. Both plasmodia have an equal clinical impact in terms of fever and rigors, anorexia, nausea, feeling of dyspnea, change in the mental status, changes in the urine color, diarrhea, volume depletion and pedal edema. However, patients with falciparum had significantly more vomiting (P = 0.02), oliguria (P = 0.003) and jaundice (P = 0.003). Laboratory parameters also showed a severe impact of falciparum, as there was more severe anemia and kidney and liver dysfunction. More patients were treated with dialysis and blood transfusion in the falciparum group. The outcome in the two groups was not significantly different in terms of death and days of hospitalization. Falciparum malaria has a higher clinical impact than the vivax malaria, but vivax is not as benign as it was once thought to be. It also has devastating effects on vulnerable populations like patients with CKD and diabetes. PMID- 26586056 TI - Profile of acute kidney injury after open heart surgeries in a tertiary care hospital. AB - Our objective is to determine the incidence, etiology, risk factors and outcome of acute kidney injury (AKI) after open heart surgery. A prospective study was conducted on 62 patients who underwent open heart surgery and were followed-up for the development of AKI and to determine its incidence, etiology and outcome. Post-operative AKI was considered when the post-operative serum creatinine was >1.5 mg/dL or there was doubling of serum creatinine above the baseline (pre operative) with a prior normal renal function. The incidence of AKI in the post operative period in our study was 17.7%. The common etiological factors for AKI in our study were sepsis, hypotension, prolonged need for ventilator and inotropic support and drugs given in the post-operative period. The important risk factors for the development of AKI in the post-operative period were hypertension, diabetes mellitus, gout, prolonged total bypass time and prolonged aortic cross-clamp time. The overall mortality in our study subjects was 11.3% (seven of 62 died) and the mortality in the patients who developed post-operative AKI was 71.4%. PMID- 26586057 TI - Microalbuminuria and pegylated interferon in hepatitis-C patients. AB - To determine the relation between hepatitis C virus (HCV) genotype 4 and microalbuminuria in relation to hepatic histology and viremia in the absence of cryoglobulinemia and to examine the effect of treatment on microalbuminuria, we studied 400 HCV genotype-4-infected patients who were tested for microalbuminuria, albumin creatinine ratio (ACR), urea, creatinine and estimated glomerular filtration rate (eGFR). The parameters were measured again in the HCV patients after six months of treatment with pegylated interferon and ribavirin. Microalbuminuria was detected in 56 (14%) HCV-positive patients. There was a highly significant reduction in the microalbuminuria levels among the HCV positive individuals after six months of therapy (P <0.001). Microalbuminuria was significantly associated with older age [Odds Ratio (OR): 1.1, 95% confidence interval (CI): 1.0-1.2, P = 0.01], elevated creatinine (OR: 0.09, 95% CI: 0.01- 0.7, P = 0.02), high modified Histological Activity Index score (OR: 1.5, 95% CI: 1.1-1.5, P = 0.004) and increased viral load (OR: 2.8, 95% CI: 1.1-6.6, P = 0.01). Sustained virological response (SRV) was achieved in 272 (86%) patients. The individuals with SVR had lower microalbuminuria post-treatment (P = 0.56). We conclude that HCV infection can be associated with microalbuminuria, which can be reduced by the use of a combination therapy of pegylated interferon-ribavirin. PMID- 26586058 TI - Adiponectin gene expression in human primary adipocyte culture treated with uremic serum. AB - End-stage renal disease (ESRD) is accompanied by an increased rate of morbidity and mortality due to cardiovascular disease (CVD). Although renal replacement therapy is required at this stage, it is associated with additional complications such as inflammation and dyslipidemia. It has been suggested that adiponectin has anti-inflammatory properties. We studied the potential role of uremic mileu on the adiponectin expression in human primary adipocyte culture. A cohort of 18 patients with ESRD (hemo-and peritoneal dialysis) and nine healthy controls were analyzed in a prospective cross-sectional study. Single blood samples were taken pre-and post-hemodialysis and in peritoneal dialysis patients. Serum concentrations of total adiponectin (7.95 +/- 1.44 MUg/mL; 6.73 +/- 1.2 MUg/mL; 13.7 +/- 3.04 MUg/mL, respectively) and high molecular weight adiponectin (3.03 +/- 1.95 MUg/mL; 3.57 +/- 2.44 14 MUg/mL; 8.02 +/- 5 MUg/mL respectively) were measured. Other biochemical parameters (cholesterol, low-density lipoprotein cholesterol and triglycerides) were assessed in all groups of patients. Adiponectin gene expression was determined using real-time polymerase chain reaction, and was found to be lower in ESRD patients compared with healthy controls with low dose but not with high-dose treatments. Serum concentrations of total adiponectin and high molecular weight adiponectin were significantly higher in the ESRD versus control group. These results provide an initial insight into understanding the putative role of adipose tissue in contributing to the association of CVD risk in patients with chronic kidney disease. PMID- 26586059 TI - Kinetics of parathyroid hormone after parathyroidectomy in chronic hemodialysis patients. AB - Secondary hyperparathyroidism is a common complication in chronic renal failure. The treatment in some cases requires parathyroidectomy. The kinetics of the parathyroid hormone (PTH) levels after surgery helps to evaluate the efficacy of parathyroidectomy. Prospective analysis was made of the kinetics of intact PTH (iPTH) after parathyroidectomy in 10 chronic hemodialysis (HD) patients who had secondary hyperparathyroidism. We determined the levels of iPTH before surgery and its evolution after parathyroidectomy at regular intervals: Day 0, D7, D15, D30 and D90. The mean age of our patients was 40 +/- 13 years, with a sex ratio of 1. The mean duration on HD was 122 +/- 63 months. The duration of secondary hyperparathyroidism varied from one year to 12 years. All patients had received medical treatment for hyperparathyroidism. The indications for parathyroidectomy included resistance to medical treatment in seven cases, development of brown tumors in two cases and soft tissue calcifications in one case. All patients had radiographic evidence of hyperparathyroidism. The parathyroidectomy was sub-total in all patients, 6/8 in four cases and 7/8 in six cases. The mean iPTH level was 2341 +/- 1946 pg/mL before surgery. A sharp drop in this level was noticed on D0, with a median of 92 pg/mL and, thereafter, the levels were 79 pg/mL on D7, 25 pg/mL on D15 and 36 pg/mL after 1 month. At 3 months post-surgery, the mean iPTH level was 302 pg/mL. Histological examination of the resected gland showed parathyroid hyperplasia in all patients. In our series, the efficacy of sub-total parathyroidectomy was satisfactory with rapid normalization of PTH, which is consistent with the literature data. Sub-total parathyroidectomy still has a place in the treatment of secondary hyperparathyroidism in chronic renal failure. Its indications should be limited to cases resistant to medical treatment and, in particular, in cases with occurrence of complications. PMID- 26586060 TI - The correlation between attention deficit hyperactivity disorder and steroid dependent nephrotic syndrome. AB - Nephrotic syndrome (NS) is characterized by nephritic-range proteinuria and the triad of clinical findings associated with large urinary losses of protein, hypoalbuminemia, edema and hyperlipidemia. More than 80% of children below 13 years of age with primary NS have steroid-responsive forms. There is no identifiable cause of attention-deficit hyperactivity disorder (ADHD). It is likely that the symptoms of ADHD represent a final common pathway of diverse causes, including genetic, organic and environmental etiologies. This case control study was performed on 130 children aged between 5 and 13 years who were followed-up for two years. Sixty-five children with steroid-dependent nephrotic syndrome (SDNS) as the case group and 65 healthy children as the control group were included in the study. Patients with minimal change NS were treated with prednisolone for at least six months. Conner's Parent Rating Scale - 48 (CPRS-48) was completed by the parents and the children were identified with any form of ADHD. Then, children were referred to an expert psychiatrist. The collected data were analyzed with SPSS software. The result showed that there was no significant relationship between different types of ADHD in both groups. Thus, based on current study, one may conclude that there are no significant differences between prevalence of ADHD in children with SDNS and the control group. PMID- 26586061 TI - Outcome of upper limb vascular access for hemodialysis. AB - The aim of this study was to investigate the outcome of vascular access procedures for hemodialysis and factors affecting access survival and complication rates. A retrospective review was carried out on 276 patients who underwent 404 consecutive vascular access operations performed over seven-years. The overall primary failure rate was 9.2%, while the oneand five-year cumulative access patency rates were 63.8% and 40.6%, respectively. Diabetes mellitus status significantly influenced access survival (P = 0.022). Autogenous arteriovenous fistulas (AVFs) are reliable procedures with access sites often available in the upper limb proximally and distally. Patients with diabetes mellitus have significantly worse patency rates of upper limb AVFs. PMID- 26586062 TI - Transfusion-transmitted virus infection in hemodialysis patients in Arar, Saudi Arabia: Prevalence, predictors and genotyping. AB - Transfusion-transmitted virus (TTV) is a single-stranded DNA virus that was identified in patients with post-transfusion hepatitis of non-A-to-G type. Patients with chronic renal failure on maintenance hemodialysis (HD) have a higher risk of viral infections, and the prevalence of TTV infection is common. The aim of our study was to detect TTV-DNA and its genotype in HD patients. A case-control study compromising of 63 patients on maintenance HD therapy at the Nephrology Center of Central Arar Hospital and 100 healthy individuals who were tested for TTVDNA and its genotype by semi nested-polymerase chain reaction with primers derived from the conserved open reading frame 1 (ORF1) region followed by digestion with NdeI and PstI restriction enzyme. The results show that the prevalence of TTV in HD patients was high and statistically significant; 42.9% compared with 19% in the control group. History of blood transfusion was the only significant predictor, and we found that age of patients, duration of HD, hepatitis B and C infection, aspartate aminotransferase and alanine aminotransferase levels were not significant predictors of TT virus positivity in HD patients. TTV genotype 1 (G1) was found to be the most common genotype among both HD and healthy controls. The prevalence of TTV among HD patients was significantly higher than that in healthy individuals. History of blood transfusion was the only significant predictor of TTV positivity among them. Genotype 1 was the most predominant type among HD and healthy individuals. Further studies on TTV in peritoneal dialysis patients and transplant patients are needed. PMID- 26586063 TI - Analysis of histopathological pattern of kidney biopsy specimens in Kuwait: A single-center, five-year prospective study. AB - Glomerulonephritis (GN) varies in incidence in different geographical areas due to different socioeconomic conditions and ethnicity, genetic variability and environmental factors. Our study is aimed to determine the histopathological pattern of kidney biopsies in Kuwait over the preceding five years. In a prospective study, we analyzed the clinical and pathological data of 214 kidney biopsies that were performed during the period from November 2009 to November 2014 at the Al-Khezam Dialysis Center, Al-Adan Hospital, Kuwait. Kidney biopsies were performed percutaneously using an automated gun guided by ultrasound. The biopsy samples were processed for light microscopy and immunofluorescence. Electron microscopy was performed only in selected cases. Age, gender, serum creatinine, 24-h urinary protein, virology, immunology profiles, indication for renal biopsy and histopathological findings were recorded for analysis. Primary GN was reported in 46.7%, secondary GN was reported in 42.9% and tubulointerstitial disease was reported in 10.3% of the 214 kidney biopsies studied. Among primary GN, membranous GN (MGN) was the most common lesion (12.1%), followed by immunoglobulin A nephropathy (IgAN, 11.7%), minimal change disease (9.8%), focal and segmental glomerulosclerosis (9.3%), membranoproliferative GN (1.9%), Alport's syndrome (1.4%) and fibrillary GN (0.46%). Among biopsies that showed secondary GN, lupus nephritis was the most common (11.7%), followed by hypertensive glomerulosclerosis (10.3%), crescentic GN (7.1%), diabetic nephropathy (3.3%), thrombotic microangiopathy (2.3%), amyloidosis (2.3%), post-infectious GN (1.4%) and myeloma kidney (0.9%). Among biopsies that showed tubulointerstitial disease, acute interstitial nephritis was the most common lesion (6.1%), followed by chronic interstitial nephritis (2.8%) and acute tubular necrosis (1.4%). Our study indicates that MGN was the most common primary GN, followed by IgAN, while lupus nephritis was the most common secondary GN, followed by hypertensive glomerulosclerosis. PMID- 26586064 TI - Immuno-histological assessment of sub-clinical acute and borderline rejection in renal allograft recipients: Data from a transplant center in India. AB - This single-center study was carried out on living related and unrelated renal transplant recipients (RTRs) to evaluate the usefulness of surveillance biopsies in monitoring stable renal allografts using immuno-histological markers for immune-activation. This is a prospective, longitudinal study. Protocol biopsies of 60 RTRs with stable graft function were evaluated at three, six and 12 months post-transplant. Immuno-histological evaluation was carried out using immune activation markers (perforins, granzyme and interleukin-2R), phenotypic markers (CD-3 and CD-20), viral markers and C4d. The demographic and clinical profile was recorded for each patient. All cases of acute sub-clinical rejection (SCR) were treated and borderline SCR cases were followed-up without treatment. SCR at three and six months post-transplant was evident in 16.7% and 3.7% of RTRs, respectively. Positive statistical association of SCR was seen with HLA-DR mismatches, whereas patients receiving induction therapy and tacrolimus-based immunosuppression exhibited a lower incidence of SCR. T cell phenotype with persistent expression of immune-activation markers exhibited positive statistical association with interstitial fibrosis and tubular atrophy at 12-month follow-up biopsy. The mean creatinine levels were significantly lower in the protocol biopsy group than the non-protocol biopsy group. No significant difference was found between the mean creatinine levels of the SCR group after treatment and the non-SCR cases within the protocol biopsy group. Early treatment of sub-clinical acute rejection leads to better functional outcomes. However, persistent immune activation is associated with chronicity and may have implications on long-term graft survival. PMID- 26586065 TI - Urinary screening for asymptomatic renal disorders in pre-school children in Enugu metropolis, South-east Nigeria: Useful or useless. AB - To evaluate the usefulness of simple screening tests such as urinalysis and blood pressure measurement in the early detection of renal disorders in pre-School children, we used a multi-staged random sampling method to select subjects from registered nursery schools within Enugu metropolis in south-east Nigeria. We selected 630 children for this cohort study. There was a prevalence of 2.7%, 0% and 1.9% for asymptomatic proteinuria, hematuria and hypertension, respectively. There was no age, gender or social class preponderance (P = 0.44). Hypertension seemed to be limited to children close to the age group of five years (P <0.001). No correlations could be documented between asymptomatic proteinuria, hematuria or hypertension. The prevalence of persistent proteinuria was found to be 1.6% and the mean urinary protein excretion estimation (spot urine protein/creatinine) was 1.88 g/mg +/- 0.53, with a mean glomerular filtration rate of 78.7 +/- 12.6 mL/min/1.73 m3 . Renal ultrasonography revealed abnormal findings in 30% of the children with persistent proteinuria. Asymptomatic persistent proteinuria with or without hematuria and hypertension could be a presumptive evidence of an underlying renal parenchymal disease and should be properly investigated and followed-up. PMID- 26586066 TI - Cross-cultural adaptation, validation and reliability of the South Indian (Kannada) version of the Kidney Disease and Quality of Life (KDQOL-36) instrument. AB - Health-related quality of life is an essential aspect concerned with the treatment outcomes. The main objective of the study is to evaluate the validity and reliability of the South Indian (Kannada) version of the Kidney Disease and Quality of Life-36 (KDQOL-36) instrument for hemodialysis (HD) patients. The KDQOL-36 instrument was validated by the committee of experts consisting of healthcare providers such as nephrologists (three), senior HD staff nurse (one) and clinical pharmacist (one). The measurement properties such as variability, reliability and validity were determined by administering the questionnaire to 82 patients on HD who were randomly selected from the HD units of three hospitals. The test and retest methods were used for reliability. Test-re-test reliability was assessed with a subsample of 45 patients by two administrations of the KDQOL 36 seven days apart. Data were collected through a face-to-face interview. It was evaluated computing intraclass correlation coefficients (ICC) and internal consistency estimated by computing Cronbach's-alfa. Reliability of each Kannada version of the KDQOL-36 sub-scale (symptoms/problems, burden of kidney disease, effects of kidney disease, physical component score [PCS] and mental component score [MCS] was good (Cronbach's-alfa >0.7, ranging from 0.72 to 0.77). The ICC ranged from 0.83 to 0.99 and the 95% confidence interval was 0.76-0.99 for test retest of the KDQOL-36. The reliability measured with Cronbach's alfa, which was more than 0.72 and ICC ranged from 0.83 to 0.99, indicating that the Kannada version of the KDQOL-36 is reliable and valid for evaluating the health-related quality of life in Kannada-speaking HD patients. PMID- 26586067 TI - Scedosporium apiospermum causing brain abscess in a renal allograft recipient. AB - Scedosporium apiospermum is the asexual form of a rare fungus Pseudallescheria boydii that is usually present in the soil, sewage and dirty water. In immunocompromised patients, it is a rare infection involving multiple organs. We present a case of renal allograft recipient who developed fever two weeks post renal transplant. He was initially found to have dengue fever. After five days, he became drowsy and developed right-sided hemiparesis. Magnetic resonance imaging of the brain revealed multiple irregular masses with associated edema consistent with fungal brain abscesses. Left parietal abscess was drained and he was started on voriconazole. His cyclosporine was stopped. Drained pus revealed fungal hyphae on potassium hydroxide stain and Scedosporium apiospermum on culture. Unfortunately, the patient died after five days. Scedosporium infections should be kept as a possibility in transplant recipients with disseminated infections, especially with a brain abscess. Despite antifungal therapy and surgical drainage, mortality rates are high. PMID- 26586068 TI - Fournier's gangrene due to perioperative iatrogenic colon perforation in a renal transplant recipient. AB - Fournier's gangrene is not a common cause of morbidity in renal transplant recipients, but, if it occurs, it is difficult to treat because of the immunosuppression and associated increased mortality rate. We describe the case of a male patient who underwent renal transplantation with complicated post operative course, resulting in cecum perforation (thermal injury due to cautery use during transplantation) requiring exploratory laparotomy and cecostomy. A few days later, he developed Fournier's gangrene and urgent radical surgical debridement of the scrotum was performed, along with aggressive antibiotic regimen and the immunosuppressive treatment was modified. Subsequently, the patient underwent scheduled cecostomy closure (right hemicolectomy), while the scrotum trauma healed with tertiary intention. Epidemiologic characteristics, clinical presentation, diagnostic workup, therapeutic options and morbidity mortality rates of Fournier's gangrene are reviewed, emphasizing the role of immunosuppression in renal transplant recipients to disease development. PMID- 26586069 TI - Wegner's granulomatosis developing for the first time in a patient eight years after starting maintenance hemodialysis. AB - Wegener's granulomatosis is a serious autoimmune disorder characterized by necrotizing small-vessel vasculitis. It is a multisystem disease that primarily affects the lung and kidneys. Previous studies indicated few relapses of vasculitis after hemodialysis due to uremic immunosuppression. Our case report describes an end-stage renal failure patient who had developed non-caseating lung granulomata with giant cell formation and fibrinoid necrosis of arterial media that is consistent with Wegner's granulomatosis for the first time and eight years after initiation of maintenance hemodialysis. We believe that such a phenomenon has rarely been reported. PMID- 26586070 TI - Dizziness and renal failure revealing the Von Hippel Lindau disease. AB - The germinal mutation of the Von Hippel Lindeau (VHL) tumor suppressor gene predisposes to the development of benign or malignant richly vascularized tumors. VHL disease is an autosomal-dominant disorder with complete penetrance at the age of 60 years. Screening for people at risk is strongly recommended, and careful monitoring allows treatment of the tumor lesions as early as possible. A 42-year old man sought medical consult for hematuria, disabling dizziness and balance disorders lasting for two months. The neurological examination revealed the presence of a kinetic cerebellar syndrome. The cerebro-spinal magnetic resonance imaging revealed multiple hemangioblastomas, both encephalic and medullar. Abdominal computed tomography revealed a big solid mass in the left kidney and multiple intra-parenchymal cystic lesions in the right kidney and the pancreas. The diagnosis of VHL disease was strongly suspected. The operative indication of brain damage and renal mass have been submitted. The pathological study of the renal surgical specimen revealed a clear cell carcinoma. The post-operative course was uneventful and all the symptoms have disappeared. Genetic study and close follow-up are recommended for this disease. PMID- 26586071 TI - Meningitis and intracranial bleed in a child with steroid-resistant nephrotic syndrome. AB - Meningitis and associated intracranial bleeding have been rarely reported in patients with steroid-resistant nephrotic syndrome. We present such a case with raised intracranial tension in a 13-year-old child and discuss the management issues. Prompt recognition and appropriate treatment of these complications can be life saving in a child with nephrotic syndrome. PMID- 26586072 TI - C1q nephropathy and isolated CD59 deficiency manifesting as necrotizing crescentic glomerulonephritis: A rare association of two diseases. AB - C1q nephropathy is a recently described clinico-pathologic entity with a variable clinical presentation and pathology. Crescentic glomerulonephritis (GN) has been reported in only two patients in the available literature. CD59 deficiency, along with lack of CD55, is responsible for paroxysmal nocturnal hemoglobinuria (PNH). Few cases of isolated CD59 deficiency have been described with PNH-like features. A middle-aged adult male presented with rapidly progressive renal failure. Serological investigations were negative. A renal biopsy revealed necrotizing crescentic GN with rupture of Bowman's capsule. Immunofluorescence on the frozen sections showed dominant mesangial deposits of C1q along with IgM. Hematological work-up of the patient revealed isolated CD59 deficiency. Hence, a final diagnosis of C1q nephropathy and CD59 deficiency manifesting as crescentic GN and hemolytic anemia was made. The co-existence of two rare disorders, C1q nephropathy and CD59 deficiency, in a patient with necrotizing crescentic GN is described for the first time to the best of our knowledge. The pathogenetic link of these two entities with the clinical manifestation requires further study. PMID- 26586073 TI - Acute kidney injury in a child: A case of Munchausen syndrome by proxy. AB - Renal and urologic problems in pediatric condition falsification (PCF) or Munchausen by proxy (MSP) can result in serious diagnostic dilemma. Symptoms of hematuria, pyuria and recurrent urinary tract infections have occasionally been described. However, MSP presenting as azotemia has not been previously reported. We describe the case of an unfortunate boy who had to undergo unnecessary hemodialysis for persistent hyperkalemia and azotemia before a final diagnosis of the falsification of investigations by the parents was made. PMID- 26586074 TI - Immunoglobin G4-related disease: Two case reports and review of the recent literature. AB - IgG4-related disease (IgG4-RD) is a new, multiorgan and constantly evolving disease characterized by IgG4-positive plasma cells in the affected organ. This disease often affects the elderly. The pancreas is the main target organ affected, with almost all organs in the body being affected. A large amount of studies have been conducted to understand the pathogenesis of the disease and its spectrum. For accurate diagnosis of the condition, an adequate knowledge of imaging findings, clinical presentations and laboratory reports is essential. We report two cases of the IgG4-RD and review the recent literature about this increasingly recognized entity. PMID- 26586075 TI - Membranous nephropathy and severe acute kidney injury following influenza vaccination. AB - Immunization with influenza vaccine remains an important global health strategy to prevent outbreaks and epidemics of seasonal influenza. Influenza vaccine has rarely been associated with vasculitis, acute kidney injury (AKI) and nephrotic syndrome (NS). Glomerular diseases following influenza vaccination have also been rarely reported. We report a patient who developed acute-onset massive proteinuria with NS and severe AKI soon after receiving the 2009 H1N1 influenza vaccine. Kidney biopsy showed membranous nephropathy (MN) and acute interstitial nephritis (AIN). Optimal management of glomerular diseases or AIN following influenza vaccination is not known. Our patient responded well to an initial course of oral corticosteroid therapy with normalization of serum creatinine level but had a relapse of NS with AKI soon after completion of corticosteroid therapy. A repeat kidney biopsy revealed MN and resolved AIN. A subsequent prolonged course of oral corticosteroids resulted in complete clinical remission of the NS as well as normalization of renal function. Long-term response to corticosteroid therapy in such cases is not known. However, our patient continued to remain in clinical remission with normal renal function, five years after the initial treatment. PMID- 26586076 TI - Everolimus with low-dose cyclosporine in de novo renal transplant recipients: A single center Indian experience. PMID- 26586077 TI - Circulating bacterial DNA fragments in chronic hemodialysis patients. PMID- 26586078 TI - Dialysatoma - A complication of continuous ambulatory peritoneal dialysis. PMID- 26586079 TI - Epidemiology of chronic kidney disease in a Pakistani population. PMID- 26586080 TI - Non-invasive screening tool for chronic kidney disease. PMID- 26586081 TI - Evaluation of biological, psychosocial, and interventional predictors for success of a smoking cessation programme in Hong Kong. AB - INTRODUCTION: Predictors for smoking cessation have been identified in different studies but some of the predictors have been variable and inconsistent. In this study, we reviewed all the potential variables including medication, counselling, and others not commonly studied to identify the robust predictors of smoking cessation. METHODS: This historical cohort study was conducted in smoking cessation clinics in Hong Kong. Subjects who volunteered to come for free treatment between January 2010 and December 2011 were reviewed. Those under the age of 18 years, or who were mentally unstable or cognitively impaired were excluded. Counselling and quit-smoking medications were provided to the participants. The outcome measure was self-reported 7-day point prevalence abstinence rate at week 26. RESULTS: Univariate analysis showed that the following were significant predictors of quitting: (1) psychosocial variables such as feeling stressed, feeling depressed, confidence in quitting, difficulty in quitting, importance of quitting, Smoking Self-Efficacy Questionnaire score; (2) smoking-related variables such as number of cigarettes smoked per day, Fagerstrom Test for Nicotine Dependence score, number of high-risk situations encountered; (3) health-related variable of having mental illness; (4) basic demographics such as age, marital status, and household income; and (5) interventional variables such as counselling and pharmacotherapy. Multiple logistic regression showed that the independent predictors were age, having mental illness, daily cigarette consumption, Fagerstrom Test for Nicotine Dependence score, reasons for quitting, confidence in quitting, depressed mood, external self-efficacy, intervention with counselling and medications. CONCLUSIONS: This clinic-based local study offers a different perspective on the predictors of quitting. It reminds us to adopt a holistic approach to deal with nicotine withdrawal, to enhance external self-efficacy to resist temptation and social influences, to provide adequate counselling, and to help smokers to cope with mood problems. PMID- 26586082 TI - Removal of Anabaena flos-aquae in water treatment process using Moringa oleifera and assessment of fatty acid profile of generated sludge. AB - This study aimed to evaluate the efficiency of the coagulation/flocculation/dissolved air flotation (C/F/DAF) process using the coagulant Moringa oleifera (MO) seed powder, and to analyse the profile of fatty acids present in the generated sludge after treatment. For the tests, deionized water artificially contaminated with cell cultures of Anabaena flos-aquae was used, with a cell density in the order of 10(4) cells mL(-1). C/F/DAF tests were conducted using 'Flotest' equipment. For fatty acid profile analyses, a gas chromatograph equipped with a flame ionization detector was used. It was seen that the optimal dosage (100 mg L(-1)) of MO used in the C/F/DAF process was efficient at removing nearly all A. flos-aquae cells (96.4%). The sludge obtained after treatment contained oleic acid (61.7%) and palmitic acid (10.8%). Thus, a water treatment process using C/F/DAF linked to integral MO powder seed was found to be efficient in removing cells of cyanobacteria, and produced a sludge rich in oleic acid that is a precursor favourable for obtaining quality biodiesel, thus becoming an alternative application for the recycling of such biomass. PMID- 26586083 TI - A Y527A mutation in the fusion protein of Newcastle disease virus strain LaSota leads to a hyperfusogenic virus with increased replication and immunogenicity. AB - Newcastle disease is a highly contagious and economically important disease of poultry. Low-virulence Newcastle disease virus (NDV) strains such as B1 and LaSota have been used as live vaccines, with a proven track record of safety and efficacy. However, these vaccines do not completely prevent infection or virus shedding. Therefore, there is a need to enhance the immunogenicity of these vaccine strains. In this study, the effect of mutations in the conserved tyrosine residues of the F protein of vaccine strain LaSota was investigated. Our results showed that substitution of tyrosine at position 527 by alanine resulted in a hyperfusogenic virus with increased replication and immunogenicity. Challenge study with highly virulent NDV strain Texas GB showed that immunization of chickens with Y527A mutant virus provided 100% protection and no shedding of the challenge virus. This study suggests that the strain LaSota harbouring the Y527A mutation may represent a more efficacious vaccine. PMID- 26586085 TI - Single Center Outcomes of Status Epilepticus at a Paediatric Intensive Care Unit. AB - BACKGROUND: Status epilepticus (SE) is a frequent admission diagnosis to paediatric intensive care units (PICUs) and is associated with variable outcomes. We have audited our experience of patients presenting in SE at a Canadian PICU to determine unfavorable outcome variables. METHODS: Charts of patients <18 years of age presenting in SE to a tertiary care PICU over a 10-year period were audited. Data were analyzed at three care-points: transport, the emergency department (ED) and the PICU. Patient outcome before PICU discharge was categorized as "favorable" for return to pre-status functioning level or "unfavorable" for new deficit/death. Student's t-test and the Kruskal-Wallis test were used for analysis of normal and skewed continuous variables, respectively, and either Chi square test or Fisher's exact test for categorical variables. RESULTS: 189 patients (54% males) were identified with a median age of 1.9 years. Idiopathic SE had the highest incidence; infectious/vascular etiologies were associated with more unfavorable outcomes. Progression to refractory SE in the ED had a higher incidence of death (p<0.05). Patients with an unfavorable outcome had a higher incidence of apnea during transport (p=0.01), longer hospital stays (p<0.05), need for therapeutic coma (p=0.01), longer duration of therapeutic coma (p<0.05), need for mechanical ventilation (p<0.05), and recurrent or refractory seizures during inpatient stay (p<0.05). Multivariate analysis of unfavorable outcomes of patients in SE presenting to the PICU included renal failure, cerebral edema, apnea during transport, refractory seizures, and recurrent seizures. CONCLUSIONS: Refractory seizures in children presenting with SE are associated with worsened outcomes in the PICU. PMID- 26586084 TI - The role of cognitive effort in subjective reward devaluation and risky decision making. AB - Motivation is underpinned by cost-benefit valuations where costs-such as physical effort or outcome risk-are subjectively weighed against available rewards. However, in many environments risks pertain not to the variance of outcomes, but to variance in the possible levels of effort required to obtain rewards (effort risks). Moreover, motivation is often guided by the extent to which cognitive-not physical-effort devalues rewards (effort discounting). Yet, very little is known about the mechanisms that underpin the influence of cognitive effort risks or discounting on motivation. We used two cost-benefit decision-making tasks to probe subjective sensitivity to cognitive effort (number of shifts of spatial attention) and to effort risks. Our results show that shifts of spatial attention when monitoring rapidly presented visual stimuli are perceived as effortful and devalue rewards. Additionally, most people are risk-averse, preferring safe, known amounts of effort over risky offers. However, there was no correlation between their effort and risk sensitivity. We show for the first time that people are averse to variance in the possible amount of cognitive effort to be exerted. These results suggest that cognitive effort sensitivity and risk sensitivity are underpinned by distinct psychological and neurobiological mechanisms. PMID- 26586086 TI - [A rare tumor of the Ampulla of Vater]. PMID- 26586087 TI - [A bilateral epithelial myoepithelial carcinoma of the parotid gland]. AB - We report the case of a 52-year-old man, who was admitted in the department of otorhinolaryngology for a mass of the right parotid gland. The radiological and clinical hypothesis was a squamous cell carcinoma. Histopathological examination revealed a biphasic proliferation composed of epithelial cells arranged in a tubular pattern stained with cytokeratins 5-6 and 7 and EMA surrounded by clear myoepithelial cells stained with smooth muscle actin and p63. Ki-67 labeling index was low. The diagnosis of epithelial myoepithelial carcinoma was proposed. One year after, the patient noticed a centimetric mass of the left parotid gland. The radiological hypothesis was the presence of an intraparotidian lymph node. Histopathological examination showed a second epithelial myoepithelial carcinoma. This is an uncommon neoplasm comprising approximately 1% of all salivary gland tumours, affecting mainly the parotid gland. It is occurring preferably in patients older than 60years old. This is a low-grade malignant tumour with tendency to local recurrence and lymph node metastatic potential. We describe an exceptional bilateral epithelial myoepithelial carcinoma of the parotid gland. PMID- 26586088 TI - [Unusual cause of intussusception in adult]. PMID- 26586089 TI - [A colonic mucosae with brushing border]. PMID- 26586090 TI - [The Gleason score: A more accurate grading system]. PMID- 26586092 TI - Systematic review and meta-analysis reveals acutely elevated plasma cortisol following fasting but not less severe calorie restriction. AB - Elevated plasma cortisol has been reported following caloric restriction, and may contribute to adverse effects including stress-induced overeating, but results from published studies are inconsistent. To clarify the effects of caloric restriction on plasma cortisol, and to assess cortisol as an indicator of stress during caloric restriction, we conducted a systematic review and meta-analysis of published studies in which cortisol was measured following caloric restriction without other manipulations in humans. We further compared effects of fasting, very low calorie diet (VLCD), and other less intense low calorie diet (LCD), as well as the duration of caloric restriction by meta-regression. Overall, caloric restriction significantly increased serum cortisol level in 13 studies (357 total participants). Fasting showed a very strong effect in increasing serum cortisol, while VLCD and LCD did not show significant increases. The meta-regression analysis showed a negative association between the serum cortisol level and the duration of caloric restriction, indicating serum cortisol is increased in the initial period of caloric restriction but decreased to the baseline level after several weeks. These results suggest that severe caloric restriction causes activation of the hypothalamic-pituitary-adrenal axis, which may be transient, but results in elevated cortisol which could mediate effects of starvation on brain and metabolic function as well as ameliorate weight loss. PMID- 26586093 TI - Clinical efficacy of metronomic chemotherapy after cool-tip radiofrequency ablation in the treatment of hepatocellular carcinoma. AB - PURPOSE: Anti-angiogenic agents have shown promise for treating advanced hepatocellular carcinoma (HCC), and the primary mechanism of low-dose metronomic chemotherapy using traditional cytotoxic drugs is anti-angiogenic. This study evaluated the efficacy of metronomic capecitabine and thalidomide after cool-tip radiofrequency ablation (RFA), relative to RFA alone, for treating patients with HCC. METHODS AND MATERIALS: Patients with HCC were randomly apportioned to a test group (n = 22) receiving metronomic chemotherapy with capecitabine and thalidomide after RFA, or a control group (n = 28) receiving RFA only. Serum circulating endothelial cells (CECs) and vascular endothelial growth factor (VEGF) were measured in all patients before and 1 month after RFA treatment. Enhanced computed tomography or ultrasound imaging was performed to evaluate efficacy during 12 months of follow-up. The treatment groups were further stratified as HCC within or outside the Milan criteria for transplantation. RESULTS: One month post-treatment, the tumour response rate (TRR), including complete response and partial response rate, of the test and control groups was statistically similar. At 12 months, the TRR of the test group (68.2%) was significantly higher than that of the control group (35.7%). In the test group, the TRR of patients whose tumour burdens were outside the Milan criteria was significantly higher than that of the control group. One month post-treatment, CECs and VEGF levels of the test group were significantly lower than baseline, while those of the control group were significantly higher. At the end of the 12 month follow-up, there was a progression-free survival (PFS) benefit of 2 months in the test group. CONCLUSION: Metronomic capecitabine and thalidomide after RFA significantly reduced recurrence of HCC and extended PFS, especially for HCC outside the Milan criteria, perhaps via reduction of serum CECs and VEGF levels and inhibition of tumour angiogenesis. PMID- 26586091 TI - Novel RNA- and FMRP-binding protein TRF2-S regulates axonal mRNA transport and presynaptic plasticity. AB - Despite considerable evidence that RNA-binding proteins (RBPs) regulate mRNA transport and local translation in dendrites, roles for axonal RBPs are poorly understood. Here we demonstrate that a non-telomeric isoform of telomere repeat binding factor 2 (TRF2-S) is a novel RBP that regulates axonal plasticity. TRF2-S interacts directly with target mRNAs to facilitate their axonal delivery. The process is antagonized by fragile X mental retardation protein (FMRP). Distinct from the current RNA-binding model of FMRP, we show that FMRP occupies the GAR domain of TRF2-S protein to block the assembly of TRF2-S-mRNA complexes. Overexpressing TRF2-S and silencing FMRP promotes mRNA entry to axons and enhances axonal outgrowth and neurotransmitter release from presynaptic terminals. Our findings suggest a pivotal role for TRF2-S in an axonal mRNA localization pathway that enhances axon outgrowth and neurotransmitter release. PMID- 26586094 TI - Clinical Characteristics and Long-term Predictors of Persistent Left Ventricular Systolic Dysfunction in Peripartum Cardiomyopathy. AB - BACKGROUND: Peripartum cardiomyopathy (PPCM) is a potentially life-threatening dilated cardiomyopathy that occurs in previously well women during pregnancy or postpartum. The predictors of persistent left ventricular (LV) systolic dysfunction (LVSD) in PPCM are poorly understood and were the subject of this study. METHODS: Patients with PPCM (n = 71), who were admitted to Beijing Friendship Hospital from 2004 to 2011, were retrospectively analyzed. Data including electrocardiographic and echocardiographic measurements at diagnosis (baseline) and at the last follow-up visit were collected. Data on plasma brain natriuretic peptide (BNP) and C-reactive protein (CRP) levels were also collected at baseline. A receiver operating characteristic curve was used to determine the cutoff values. Univariate and multivariate analyses were used to assess the significant predictive variables for persistent LVSD. RESULTS: Thirty-one patients (44%) did not recover completely at the last follow-up visit (LV nonrecovery group), and 40 patients (56%) had good LV recovery (LV recovery group). Baseline BNP level was positively correlated with LV end-diastolic diameter (r = 0.559; P < 0.001), and inversely correlated with LV ejection fraction (LVEF) (r = -0.548; P < 0.001) and fractional shortening (r = -0.542; P < 0.001). There was no difference in CRP levels between the 2 groups. Receiver operating characteristic curves indicated the cutoff value in terms of predicting persistent LVSD was 34% for LVEF, 64 mm for LV end-diastolic diameter, 16% for fractional shortening, and 1860 pg/mL for BNP. Univariate and multivariate analyses confirmed that LVEF < 34% (95% CI, 1.38-7.30; P = 0.007) and BNP > 1860 pg/mL (95% CI, 1.18-6.99; P = 0.020) were independent prognostic factors in predicting persistent LVSD. CONCLUSIONS: LVEF and plasma BNP levels have good predictive value in long-term cardiac dysfunction. PMID- 26586095 TI - Altered fraction of regulatory B and T cells is correlated with autoimmune phenomena and splenomegaly in patients with CVID. AB - Common variable immunodeficiency (CVID) is a heterogeneous primary immunodeficiency disease, leading to recurrent bacterial airway infections and often also autoimmune complications. To shed light on the regulatory lymphocytes from these patients, we analyzed the levels of regulatory B (pro-B10) cell and regulatory T (Treg) cell subpopulations in PBMCs from twenty-six patients diagnosed with CVID using multi-color flowcytometry. Pro-B10 cells were induced by 48h in vitro stimulation prior to analysis. Suppressor function was measured on a subset of patients with splenomegaly and autoimmune complications. The levels of regulatory B and T cells were correlated to clinical manifestations, including autoimmunity, splenomegaly and CVID EUROclass subgroups. We demonstrate a significant association between elevated levels of pro-B10 cells, decreased levels of Tregs and autoimmune phenomena in CVID patients. The finding of marked abnormalities in regulatory lymphocyte populations contribute to our understanding of the pathogenesis of CVID and potentially be valuable in the clinical management and treatment of patients. PMID- 26586096 TI - Effect of dietary protein on plasma insulin-like growth factor-1, growth, and body composition in healthy term infants: a randomised, double-blind, controlled trial (Early Protein and Obesity in Childhood (EPOCH) study). AB - The effect of protein intake on growth velocity in infancy may be mediated by insulin-like growth factor-1 (IGF-1). This study aimed to determine the effects of formulae containing 1.8 (F1.8) or 2.7 g (F2.7) protein/418.4 kJ (100 kcal) on IGF-1 concentrations and growth. Healthy term infants were randomly assigned to receive F1.8 (n 74) or F2.7 (n 80) exclusively for the first 4 months of life. A group of breast-fed infants (n 84) was followed-up simultaneously (reference). Growth and body composition were measured at 0.5, 4, 6, 12, 36, 48 and 60 months of life. The IGF-1 concentrations at 4 months (primary outcome) were similar in the F1.8 (67.1 (sd 20.8) ng/l; n 70) and F2.7 (71.2 (sd 27.5) ng/l; n 73) groups (P=0.52). Both formula groups had higher IGF-1 concentrations than the breast-fed group at 4 and 9 months of age (P<=0.0001). During the first 60 months of life, anthropometric parameters in the F1.8 group were lower compared with the F2.7 group, and the differences were significant for head circumference from 2 to 60 months, body weight at 4 and 6 months and length at 9, 12 and 36 months of age. There were no significant differences in body composition between these two groups at any age. We conclude that, in formula-fed infants, although increased protein intake did not affect the IGF-1 concentration during the first 12 months of life, it did affect length and head circumference growth, suggesting that factors other than IGF-1 could play roles in determining growth velocity. PMID- 26586097 TI - Effect of protective agents and previous acclimation on ethanol resistance of frozen and freeze-dried Lactobacillus plantarum strains. AB - The aim of this work was to study the protective effect of sucrose, trehalose and glutamate during freezing and freeze-drying of three oenological Lactobacillus plantarum strains previously acclimated in the presence of ethanol. The efficiency of protective agents was assessed by analyses of membrane integrity and bacterial cultivability in a synthetic wine after the preservation processes. No significant differences in the cultivability, with respect to the controls cells, were observed after freezing at -80 degrees C and -20 degrees C, and pre acclimated cells were more resistant to freeze-drying than non-acclimated ones. The results of multiparametric flow cytometry showed a significant level of membrane damage after freeze-drying in two of the three strains. The cultivability was determined after incubation in wine-like medium containing 13 or 14% v/v ethanol at 21 degrees C for 24 h and the results were interpreted using principal component analysis (PCA). Acclimation was the most important factor for preservation, increasing the bacterial resistance to ethanol after freezing and freeze-drying. Freeze-drying was the most drastic method of preservation, followed by freezing at -20 degrees C. The increase of ethanol concentration from 6 to 10% v/v in the acclimation medium improved the recovery of two of the three strains. In turn, the increase of ethanol content in the synthetic wine led to a dramatic decrease of viable cells in the three strains investigated. The results of this study indicate that a successful inoculation of dehydrated L. plantarum in wine depends not only on the use of protective agents, but also on the cell acclimation process prior to preservation, and on the ethanol content of wine. PMID- 26586098 TI - A new method for temperature-field reconstruction during ultrasound-monitored cryosurgery using potential-field analogy. AB - The current study aims at developing computational tools in order to gain information about the thermal history in areas invisible to ultrasound imaging during cryosurgery. This invisibility results from the high absorption rate of the ultrasound energy by the frozen region, which leads to an apparent opacity in the cryotreated area and a shadow behind it. A proof-of-concept for freezing front estimation is demonstrated in the current study, using the new potential field analogy method (PFAM). This method is further integrated with a recently developed temperature-field reconstruction method (TFRM) to estimate the temperature distribution within the frozen region. This study uses prostate cryosurgery as a developmental model and trans-rectal ultrasound imaging as a choice of practice. Results of this study indicate that the proposed PFAM is a viable and computationally inexpensive solution to estimate the extent of freezing in the acoustic shadow region. Comparison of PFAM estimations and experimental data shows an average mismatch of less than 2 mm in freezing-front location, which is comparable to the uncertainty in ultrasound imaging. Comparison of the integrated PFAM + TFRM scheme with a full-scale finite-elements analysis (FEA) indicates an average mismatch of 0.9 mm for the freezing front location and 0.1 mm for the lethal temperature isotherm of -45 degrees C. Comparison of the integrated PFAM + TFRM scheme with experimental temperature measurements show a difference in the range of 2 degrees C and 6 degrees C for selected points of measurement. Results of this study demonstrate the integrated PFAM + TFRM scheme as a viable and computationally inexpensive means to gain information about the thermal history in the frozen region during ultrasound monitored cryosurgery. PMID- 26586099 TI - Three dimensional in vitro culture of preantral follicles following slow-freezing and vitrification of mouse ovarian tissue. AB - To evaluate the effects slow-freezing and vitrification on three dimensional in vitro culture of preantral follicles, ovaries of 12-14 days old female NMRI mice were isolated and randomly assigned to fresh control, slow-freezing and vitrification groups. Slow-freezing was performed using programmable freezer. Vitrification was carried out in a medium consisting of ethylene glycol (EG) and dimethyl sulphoxide (Me2SO) by needle immersion method. middle sized preantral follicles were mechanically isolated and cultured for 12 days in 0.7% sodium alginate gel. The follicles development and quantitative expression of oocyte specific genes (Bmp15, Gdf9, Fgf8) and the growth related genes (Igf1, Kit, Kit l) were assessed after 1, 8 and 12 days of culture. Both cryopreserved groups showed reduction of follicular survival rates compared to the control group on days 8 and 12 of culture (P < 0.05). Antrum formation rates reduced in slow freezing after 12 days of culture (P < 0.05). Evaluation of gene expression showed reduction of Bmp15, Gdf9, Fgf8, Kit and Kit-l during 12 days of culture (P < 0.05). Kit and Kit-l expression in slow-freezing group significantly reduced on day 8 of culture (p < 0.05). Igf1 expression was lower in slow-freezing group on 1st day of culture than vitrification and control groups (P < 0.05). Finally, intergroup comparison showed same expression pattern of genes after 12 days of culture. Thus, cryopreservation of mouse ovaries by both methods can preserve most developmental parameters and expression of maturation genes. However, vitrification is a better method for cryopreservation of mouse ovaries due to greater antrum formation and expression of growth related markers. PMID- 26586100 TI - Should the search for bilingual advantages in executive functioning continue? PMID- 26586101 TI - Rural-Urban Differences in Costs of End-of-Life Care for Elderly Cancer Patients in the United States. AB - PURPOSE: The objective of this study was to examine the rural-urban differences in Medicare expenditures on end-of-life care for elderly cancer patients in the United States. METHODS: We analyzed Medicare claims data for 175,181 elderly adults with lung, colorectal, female breast, or prostate cancer diagnosis who died in 2008. The end-of-life costs were quantified as total Medicare expenditures for the last 12 months of care including inpatient, outpatient, physician services, hospice, home health, skilled nursing facilities (SNF), and durable medical expenditure. Linear regression models were used to estimate rural urban differences in log-transformed end-of-life costs and logistic regressions were used to estimate probability of service use, adjusting for demographics, socioeconomic status, and comorbidities. FINDINGS: On average, elderly cancer patients cost Medicare $51,273, $50,274, $62,815, and $50,941 in the last year for breast, prostate, colorectal, and lung cancer, respectively. Rural patients cost Medicare about 10%, 6%, 8%, and 4% less on end-of-life care than their urban counterparts for breast, prostate, colorectal, and lung cancer, respectively. Rural cancer patients were less likely to use hospice and home health, more likely to use outpatient and SNF, and they cost Medicare less on inpatient and physician services and more on outpatient care conditional on service use. CONCLUSIONS: The lower Medicare spending on end-of-life care for the rural cancer patients suggests disparities based on place of residence. A future study that delineates the source of the rural-urban difference can help us understand whether it indicates inappropriate level of palliative care and find effective policies to reduce the urban-rural disparities. PMID- 26586102 TI - High DNA-Binding Affinity and Gene-Transfection Efficacy of Bioreducible Cationic Nanomicelles with a Fluorinated Core. AB - During the last two decades, cationic polymers have become one of the most promising synthetic vectors for gene transfection. However, the weak interactions formed between DNA and cationic polymers result in low transfection efficacy. Furthermore, the polyplexes formed between cationic polymers and DNA generally exhibit poor stability and toxicity because of the large excess of cationic polymer typically required for complete DNA condensation. Herein, we report the preparation of a novel class of bioreducible cationic nanomicelles by the use of disulfide bonds to connect the cationic shell to the fluorocarbon core. These bioreducible nanomicelles form strong interactions with DNA and completely condense DNA at an N/P ratio of 1. The resulting nanomicelle/DNA polyplexes exhibited high biocompatibility and performed very effectively as a gene-delivery system. PMID- 26586103 TI - Talking about trans fatty acids. PMID- 26586104 TI - Nut consumption and age-related disease. AB - Current knowledge on the effects of nut consumption on human health has rapidly increased in recent years and it now appears that nuts may play a role in the prevention of chronic age-related diseases. Frequent nut consumption has been associated with better metabolic status, decreased body weight as well as lower body weight gain over time and thus reduce the risk of obesity. The effect of nuts on glucose metabolism, blood lipids, and blood pressure is still controversial. However, significant decreased cardiovascular risk has been reported in a number of observational and clinical intervention studies. Thus, findings from cohort studies show that increased nut consumption is associated with a reduced risk of cardiovascular disease and mortality (especially that due to cardiovascular-related causes). Similarly, nut consumption has been also associated with reduced risk of certain cancers, such as colorectal, endometrial, and pancreatic neoplasms. Evidence regarding nut consumption and neurological or psychiatric disorders is scarce, but a number of studies suggest significant protective effects against depression, mild cognitive disorders and Alzheimer's disease. The underlying mechanisms appear to include antioxidant and anti inflammatory actions, particularly related to their mono- and polyunsaturated fatty acids (MUFA and PUFA, as well as vitamin and polyphenol content). MUFA have been demonstrated to improve pancreatic beta-cell function and regulation of postprandial glycemia and insulin sensitivity. PUFA may act on the central nervous system protecting neuronal and cell-signaling function and maintenance. The fiber and mineral content of nuts may also confer health benefits. Nuts therefore show promise as useful adjuvants to prevent, delay or ameliorate a number of chronic conditions in older people. Their association with decreased mortality suggests a potential in reducing disease burden, including cardiovascular disease, cancer, and cognitive impairments. PMID- 26586105 TI - Palliative care and dementia--A time and place? AB - The current focus in dementia care places emphasis on the potential of people to live well with the condition. Given the historical tendency to neglect the full rights and citizenship of people with dementia, such an emphasis gives hope and optimism that there is life after diagnosis. This paper seeks to explore the potential compromise of effective preparation for the complexities of advanced illness that may be presented by this consistently up-beat message. Dementia is a life limiting condition, currently without cure. Therefore, the appropriateness of palliative care may seem obvious. Yet, until relatively recently, palliative care was seen as an adjunct to oncology in the minds of professionals and public alike. However, there is a growing recognition that specialist palliative care has much to offer people with a range of long term conditions, including people with dementia. So, whilst 'living well' is an important message-especially following diagnosis-planning for advanced dementia and dying well is equally important. The aim of this paper is to highlight policy on the living well and the palliative care approach for people with dementia. A word limited narrative literature review was conducted to explore how policies have or have not informed the literature on both messages. The findings emphasise the need for a continuum approach to dementia care, with discussion on when, where, and how can palliative care be delivered for people with dementia. PMID- 26586106 TI - High-Performance Flexible All-Solid-State Supercapacitor from Large Free-Standing Graphene-PEDOT/PSS Films. AB - Although great attention has been paid to wearable electronic devices in recent years, flexible lightweight batteries or supercapacitors with high performance are still not readily available due to the limitations of the flexible electrode inventory. In this work, highly flexible, bendable and conductive rGO-PEDOT/PSS films were prepared using a simple bar-coating method. The assembled device using rGO-PEDOT/PSS electrode could be bent and rolled up without any decrease in electrochemical performance. A relatively high areal capacitance of 448 mF cm(-2) was achieved at a scan rate of 10 mV s(-1) using the composite electrode with a high mass loading (8.49 mg cm(-2)), indicating the potential to be used in practical applications. To demonstrate this applicability, a roll-up supercapacitor device was constructed, which illustrated the operation of a green LED light for 20 seconds when fully charged. PMID- 26586107 TI - Different methods to analyze stepped wedge trial designs revealed different aspects of intervention effects. AB - OBJECTIVES: Within epidemiology, a stepped wedge trial design (i.e., a one-way crossover trial in which several arms start the intervention at different time points) is increasingly popular as an alternative to a classical cluster randomized controlled trial. Despite this increasing popularity, there is a huge variation in the methods used to analyze data from a stepped wedge trial design. STUDY DESIGN AND SETTING: Four linear mixed models were used to analyze data from a stepped wedge trial design on two example data sets. The four methods were chosen because they have been (frequently) used in practice. Method 1 compares all the intervention measurements with the control measurements. Method 2 treats the intervention variable as a time-independent categorical variable comparing the different arms with each other. In method 3, the intervention variable is a time-dependent categorical variable comparing groups with different number of intervention measurements, whereas in method 4, the changes in the outcome variable between subsequent measurements are analyzed. RESULTS: Regarding the results in the first example data set, methods 1 and 3 showed a strong positive intervention effect, which disappeared after adjusting for time. Method 2 showed an inverse intervention effect, whereas method 4 did not show a significant effect at all. In the second example data set, the results were the opposite. Both methods 2 and 4 showed significant intervention effects, whereas the other two methods did not. For method 4, the intervention effect attenuated after adjustment for time. CONCLUSION: Different methods to analyze data from a stepped wedge trial design reveal different aspects of a possible intervention effect. The choice of a method partly depends on the type of the intervention and the possible time-dependent effect of the intervention. Furthermore, it is advised to combine the results of the different methods to obtain an interpretable overall result. PMID- 26586108 TI - Idaein chloride induced p53 dependent apoptosis in cervical cancer cells through inhibition of viral oncoproteins. AB - Host dependent expression of early HPV oncoproteins, E6 and E7 play central role in the formation of cervical carcinoma. Presently, we have shown that the cyanidin analog, idaein chloride treatment induced dose dependent apoptosis (IC50 = 2.579 MUg/ml) in HPV positive - HeLa cells. Flow cytometric analysis showed arrest of cell cycle at G1 phase with an increased sub G1 cell population on 12th h of exposure. The recorded reduced expression levels of cell cycle proteins - cyclin D, cdk 4 and cdk 6 confirmed the occurrence of cell cycle arrest at G1 phase. In addition, the idaein chloride significantly inhibited the expression of E6 and E7 proteins, resulting in p53 re-expression and hence triggering of p53 dependent apoptosis. This has been further supported by the recorded variations in the expression patterns of p21/WAF, pRb and E2F regulatory proteins. In case of mitochondrial apoptotic markers, the expression of Bax was restored and Bcl-2 level got decreased at 12th h. Cleaved caspases 3 & 9 and PARP were also observed after 3 h of treatment. Interestingly, the epigenetic regulatory enzymes (DNMTs) were inhibited by idaein chloride. Thus, idaein chloride could be a potent source for developing a drug against cervical carcinoma. PMID- 26586109 TI - AFM studies in diverse ionic environments of nucleosomes reconstituted on the 601 positioning sequence. AB - Atomic force microscopy (AFM) was used to study mononucleosomes reconstituted from a DNA duplex of 353 bp containing the strong 601 octamer positioning sequence, together with recombinant human core histone octamers. Three parameters were measured: 1) the length of DNA wrapped around the core histones; 2) the number of superhelical turns, calculated from the total angle through which the DNA is bent, and 3) the volume of the DNA-histone core. This approach allowed us to define in detail the structural diversity of nucleosomes caused by disassembly of the octasome to form subnucleosomal structures containing hexasomes, tetrasomes and disomes. At low ionic strength (TE buffer) and in the presence of physiological concentrations of monovalent cations, the majority of the particles were subnucleosomal, but physiological concentrations of bivalent cations resulted in about half of the nucleosomes being canonical octasomes in which the exiting DNA duplexes cross orthogonally. The dominance of this last species explains why bivalent but not monovalent cations can induce the initial step towards compaction and convergence of neighboring nucleosomes in nucleosomal arrays to form the chromatin fiber in the absence of linker histone. The observed nucleosome structural diversity may reflect the functional plasticity of nucleosomes under physiological conditions. PMID- 26586110 TI - Absorption and blood/cellular transport of folate and cobalamin: Pharmacokinetic and physiological considerations. AB - The systems involving folate and cobalamin have several features in common: 1) their dietary forms require luminal digestion for absorption; 2) intestinal bacteria in the upper intestine synthesize and utilize both vitamins, creating possible competition for the nutrients; 3) there is one major intestinal brush border protein essential for absorption; 4) both are subject to extensive entero hepatic circulation. Finally, human mutations have confirmed the role of specific transporters and receptors in these processes. There are other features, however, that distinguish the metabolism of these vitamins: 1) upper intestinal bacteria tend to produce folate, while cobalamin (cbl) utilization is more common; 2) cbl absorption requires a luminal binding protein, but folate does not; 3) folate absorption can occur throughout the small bowel, but the cbl receptor, cubilin, is restricted to the distal half of the small bowel; 4) movement into cells uses transporters, exchangers, and symporters, whereas cbl is transferred by receptor mediated endocytosis; 5) folate is carried in the blood mostly in red blood cells, whereas cbl is carried on specific binding-proteins; 6) folate can enter cells via multiple systems, but cbl uptake into all tissues use the transcobalamin receptor (TC-R), with the asialoglycoprotein receptor (ASGP-R) present in hepatocytes for uptake of haptocorrin-cbl (HC-cbl) complexes. In summary, the systems for absorption and distribution of folate and cobalamin are complex. These complexities help to explain the variable clinical responses after oral administration of the vitamins, especially when provided as supplements. PMID- 26586111 TI - Age-dependent accumulation of mitochondrial DNA deletions in the aortic root of atherosclerosis-prone apolipoprotein E-knockout mice. AB - PURPOSE: To investigate whether mitochondrial DNA (mtDNA) damage, specifically deletion, contributes to the development of atherosclerosis or is simply a secondary effect of the primary factors causing atherosclerosis. MATERIALS AND METHODS: mtDNA deletion was detected by PCR in the aortic root of atherosclerosis prone C57BL/6J apolipoprotein (Apo) E gene deficient (-/-) mice and control C57BL/6J mice at different ages. Atherosclerotic plaques in the Apo E-/- mice were assessed using frozen sections of the aortic root. The protein levels of COX III and 8-oxoguanine glycosylase (OGG1) were determined. RESULTS: while mtDNA deletions accumulated significantly in mice as young as 2- month-old, atherosclerotic plaques were not detected until mice were 6 months old or older, suggesting that mtDNA deletion occurs prior to the formation of atherosclerotic plaques in the aortic root of these mice. Moreover, the expression levels of mtDNA-encoded COX III protein in both 2-month-old and 16-month-old C57BL/6J ApoE /- mice were significantly lower than those in C57BL/6J mice (p<0.05). Additionally, the protein level of 8-oxoguanine glycosylase (OGG1), a mitochondrial enzyme that functions in DNA excision repair, decreased with age in these mice, indicating that age-related down-regulation of mtDNA excision repair also contributes to atherosclerosis in C57BL/6J ApoE-/- mice. CONCLUSION: These results reveal that mtDNA deletions occur during the early "initiation" stage of atherosclerosis in C57BL/6J ApoE-/- mice and have the potential to promote atherosclerosis. PMID- 26586112 TI - Association between reproductive variables and metabolic syndrome in chinese community elderly women. AB - OBJECTIVE: This study aimed to evaluate the association between reproductive variables and metabolic syndrome (MetS) among Chinese community elderly women. METHODS: We conducted a cross-sectional study in a Beijing urban district. A two stage stratified clustering sampling method was used and 1251 elderly women were included. RESULTS: The prevalence of MetS was 65.1% in this population. Women with MetS had younger menarche age, a greater number of years after menopause, higher gravidity and parity. The prevalence of MetS showed an increasing trend for tertiles of years after menopause (p=0.002) and number of children (p<0.001), while decreasing trend for menarche age (p=0.021). Logistic regression showed ORs of age at menarche, years after menopause and number of children for MetS were 0.94, 1.40, and 1.36 for second and 0.63, 1.58, and 1.75 for last tertiles. CONCLUSION: There is strong association between reproductive variables and higher risk of MetS. Simple information on timing of menarche and menopause could help identify women who may have higher risk of getting MetS and take early action to prevent related chronic diseases. PMID- 26586113 TI - Application of the clinical version of the narrow path walking test to identify elderly fallers. AB - INTRODUCTION: Falling during walking is a common problem among the older population. Hence, the challenge facing clinicians is identifying who is at risk of falling during walking, for providing an effective intervention to reduce that risk. We aimed to assess whether the clinical version of the narrow path walking test (NPWT) could identify older adults who are reported falls. MATERIALS AND METHODS: A total of 160 older adults were recruited and asked to recall fall events during the past year. Subjects were instructed to walk in the laboratory at a comfortable pace within a 6 meter long narrow path, 3 trials under single task (ST) and 3 trials dual task (DT) conditions without stepping outside the path (i.e., step errors). The average trial time, number of steps, trial velocity, number of step errors, and number of cognitive task errors were calculated for ST and DT. Fear of falling, performance oriented mobility assessment (POMA) and mini-metal state examination (MMSE) were measured as well. RESULTS: Sixty-one subjects reported that they had fallen during the past year and 99 did not. Fallers performed more steps, and were slower than non-fallers. There were no significant differences, however, in the number of steps errors, the cognitive task errors in ST and DT in POMA and MMSE. CONCLUSION: Our data demonstrates slower gait speed and more steps during the NPWT in ST and DT in fallers. There is no added value of DT over the ST for identification of faller's older adults. PMID- 26586114 TI - Soil mulching significantly enhances yields and water and nitrogen use efficiencies of maize and wheat: a meta-analysis. AB - Global crop yields are limited by water and nutrient availability. Soil mulching (with plastic or straw) reduces evaporation, modifies soil temperature and thereby affects crop yields. Reported effects of mulching are sometimes contradictory, likely due to differences in climatic conditions, soil characteristics, crop species, and also water and nitrogen (N) input levels. Here we report on a meta-analysis of the effects of mulching on wheat and maize, using 1310 yield observations from 74 studies conducted in 19 countries. Our results indicate that mulching significantly increased yields, WUE (yield per unit water) and NUE (yield per unit N) by up to 60%, compared with no-mulching. Effects were larger for maize than wheat, and larger for plastic mulching than straw mulching. Interestingly, plastic mulching performed better at relatively low temperature while straw mulching showed the opposite trend. Effects of mulching also tended to decrease with increasing water input. Mulching effects were not related to soil organic matter content. In conclusion, soil mulching can significantly increase maize and wheat yields, WUE and NUE, and thereby may contribute to closing the yield gap between attainable and actual yields, especially in dryland and low nutrient input agriculture. The management of soil mulching requires site specific knowledge. PMID- 26586115 TI - The Control of Conjugation Lengths and Steric Hindrance to Modulate Aggregation Induced Emission with High Electroluminescence Properties and Interesting Optical Properties. AB - A series of novel AIE-active (aggregation-induced emission) molecules, named SAF 2-TriPE, SAF-3-TriPE, and SAF-4-TriPE, were designed and synthesized through facile reaction procedures. We found that incorporation of the spiro-acridine fluorene (SAF) group, which is famous for its excellent hole-transporting ability and rigid structure, at different substitution positions on the phenyl ring affected the conjugation lengths of these compounds. Consequently, we have obtained molecules with different emission colors and properties without sacrificing good EL (electroluminescence) characteristics. Accordingly, a device that was based on compound SAF-2-TriPE displayed superior EL characteristics: it emitted green light with etac, max =10.5 cd A(-1) and etaext, max =4.22 %, whereas a device that was based on compound SAF-3-TriPE emitted blue-green light with etac, max =3.9 cd A(-1) and etaext, max = 1.71 %. These compounds also displayed different AIE performances: when the fraction of water in the THF solutions of these compounds was increased, we observed a significant improvement in the PhiF of compounds SAF-2-TriPE and SAF-3-TriPE; in contrast, compound SAF-4 TriPE showed an abnormal phenomenon, in that it emitted a strong fluorescence in both pure THF solution and in the aggregated state without a significant change in PhiF . Overall, this systematic study confirmed a relationship between the regioisomerism of the luminophore structure and its AIE activity and the resulting electroluminescent performance in non-doped devices. PMID- 26586116 TI - Expression of serum miR-218 in hepatocellular carcinoma and its prognostic significance. AB - BACKGROUND: Several recent studies have revealed that microRNAs (miRNAs) are stably detectable in the circulation and can be used as biomarkers for diagnosis and prognosis of malignancy. The aim of this manuscript is to investigate serum miR-218 expression in patients with hepatocellular carcinoma (HCC) and to analyze its potential diagnostic and prognostic value in HCC. METHODS: Quantitative real time quantitative PCR (qPCR) was conducted to detect serum miR-218 expression from 156 HCC and 98 benign liver diseases (BLD) as well as 64 healthy controls. The relevance of serum miR-218 expression to the clinicopathological factors was assessed. In addition, the prediction of cutoff values of the markers was performed by the receiver operating characteristic (ROC) curve. Moreover, the Kaplan-Meier method was used to plot survival curves and univariable and multivariable Cox regression analyses were used to evaluate independent prognostic factors. RESULTS: Consequently, our findings revealed that serum miR 218 levels were remarkably underexpressed in HCC patients as compared to BLD patients and healthy controls. And its low level was obviously related to tumor size (p = 0.048), tumor number (p = 0.018), vascular invasion (p = 0.039), Edmondson grade (p = 0.042), and higher TNM stage (III-IV). ROC curve analysis showed that miR-218 had a significant diagnostic accuracy, yielded an AUC (the areas under the ROC curve) of 0.734 (95 % confidence interval (CI) 0.68-0.789, p < 0.01), thus providing a sensitivity of 66.7 % and a specificity of 69.1 % in discriminating HCC from BLD and healthy controls. Meanwhile, miR-218 can act as a useful biomarker in distinguishing the patients with large tumors (>5 cm) from patients with small tumors (<5 cm) (p < 0.01). In addition, the combination of miR-218 and AFP had greater diagnosis capacity with an AUC of 0.908 (95 % CI 0.876-0.940; p < 0.01). Both log-rank test and Cox regression analysis demonstrated that the decreased serum expression of miR-218 had a significant impact on overall survival of the patients with HCC (HR = 3.049, 95 % CI 2.028 4.585, p < 0.01). CONCLUSION: Taken together, this study suggested that serum expression of miR-218 might be a potential noninvasive tumor biomarker in the diagnosis and assessment of prognosis of HCC. PMID- 26586117 TI - SEOM clinical guidelines for the treatment of follicular non-Hodgkin's lymphoma. AB - Follicular non-Hodgkin's lymphoma (FL) is a nodal B lymphoid malignancy that originates from the germinal center of a lymph node. FL is the second most frequent lymphoma subtype. The course of the disease is usually characterised by a typically indolent clinical course, with a median survival rate of 8-10 years, although most patients relapse after treatment. Diagnosis should always be based on a surgical specimen like an excisional node lymph biopsy. The first-line treatment of FL will depend of extension disease, tumour burden, patient symptoms, performance status and also patient decision. The addition of rituximab to conventional chemotherapy has improved ORR, PFS and OS. As first line in patients that need treatment, a combination of chemotherapy with rituximab induction followed by 2 years of rituximab maintenance is the best option. High dose chemotherapy with autologous stem-cell transplantation in first line has not shown improvement and is not recommended as first-line therapy. Before any treatment decision in relapsed patients, a repeat biopsy is mandatory to rule out a transformation into large cell aggressive lymphoma. Standard treatment is controversial, depends on the efficacy of prior treatment, duration of the time to-relapse, patient's age and histological findings at relapse. PMID- 26586119 TI - Is There a Role for Antiangiogenic Therapy in Renal Medullary Carcinoma? PMID- 26586118 TI - Clinical guideline seom: hereditary colorectal cancer. AB - Genetic mutations have been identified as the cause of inherited cancer risk in some colon cancer; these mutations are estimated to account for only 5-6 % of colorectal cancer (CRC) cases overall. Up to 25-30 % of patients have a family history of CRC that suggests a hereditary component, common exposures among family members, or a combination of both. Cancers in people with a hereditary predisposition typically occur at an earlier age than in sporadic cases. A predisposition to CRC may include a predisposition to other cancers, such as endometrial cancer. We describe genetics, current diagnosis and management of CRC hereditary syndromes pointing to a multidisciplinary approach to achieve the best results in patients and family outcomes. PMID- 26586120 TI - LRP1B, BRD2 and CACNA1D: new candidate genes in fetal metabolic programming of newborns exposed to maternal hyperglycemia. AB - AIM: To assess the associations between gestational diabetes mellitus (GDM) and DNA methylation levels at genes related to energy metabolism. PATIENTS & METHODS: Ten loci were selected from our recent epigenome-wide association study on GDM. DNA methylation levels were quantified by bisulfite pyrosequencing in 80 placenta and cord blood samples (20 exposed to GDM) from an independent birth cohort (Gen3G). RESULTS: We did not replicate association between DNA methylation and GDM. However, in normoglycemic women, glucose levels were associated with DNA methylation changes at LRP1B and BRD2 and at CACNA1D and LRP1B gene loci in placenta and cord blood, respectively. CONCLUSION: These results suggest that maternal glucose levels, within the normal range, are associated with DNA methylation changes at genes related to energy metabolism and previously associated with GDM. Maternal glycemia might thus be involved in fetal metabolic programming. PMID- 26586121 TI - The canonical equation of adaptive dynamics for life histories: from fitness returns to selection gradients and Pontryagin's maximum principle. AB - This paper should be read as addendum to Dieckmann et al. (J Theor Biol 241:370 389, 2006) and Parvinen et al. (J Math Biol 67: 509-533, 2013). Our goal is, using little more than high-school calculus, to (1) exhibit the form of the canonical equation of adaptive dynamics for classical life history problems, where the examples in Dieckmann et al. (J Theor Biol 241:370-389, 2006) and Parvinen et al. (J Math Biol 67: 509-533, 2013) are chosen such that they avoid a number of the problems that one gets in this most relevant of applications, (2) derive the fitness gradient occurring in the CE from simple fitness return arguments, (3) show explicitly that setting said fitness gradient equal to zero results in the classical marginal value principle from evolutionary ecology, (4) show that the latter in turn is equivalent to Pontryagin's maximum principle, a well known equivalence that however in the literature is given either ex cathedra or is proven with more advanced tools, (5) connect the classical optimisation arguments of life history theory a little better to real biology (Mendelian populations with separate sexes subject to an environmental feedback loop), (6) make a minor improvement to the form of the CE for the examples in Dieckmann et al. and Parvinen et al. PMID- 26586122 TI - Phenolics and Terpenoids; the Promising New Search for Anthelmintics: A Critical Review. AB - Ailments caused by helminth parasites are global causing different types of clinical complications with permanent and long term morbidity in humans. Although huge advances have been made in medical sciences the effectiveness of available anthelmintics are still quite limited. Starting from the 50's, most importance was given to synthetic compounds for developing remedies from them, however, the traditional knowledge of medicine of different countries continued to provide us clues against this widespread health problem. Natural products or structural analogs with diverse structures are always been the major sources for discovering new therapeutics and in recent past different active compounds have also been identified form these plant sources having anthelmintic properties. Although compounds of diverse chemical nature and classes were identified, most active ones belong to either phenol or terpene in broad chemical nature. The mechanism of action of these phytotherapeutics is usually multi-targeted and can act against the helminth parasites through diverse spectrum of activities. In this review we summarized the effective anthelmintics belong to either phenolics or terpenoids and highlighted the major way of their effectiveness. This also highlights the recent development of new therapeutic strategies against helminth parasites in the light of recent advances of knowledge. In addition, developing efficient strategies to promote apoptosis and disturbing redox status in them by natural products can provide us a clue in antifilarial drug developmental research and crucial unmet medical need. PMID- 26586123 TI - Recent Advances on Dark and Light-Activated Cytotoxity of Imidazole-Containing Ruthenium Complexes. AB - Imidazole derivatives have known to possess a diverse range of pharmacological activity. In particular, one of ruthenium-based derivatives, imidazolium [trans RuCl4(1H-imidazole)(DMSOS)] (NAMI-A) which is now in clinical trials, opens a new avenue for developing promising ruthenium-based anticancer drugs alternative to Cisplatin. This mini-review overviews some representative examples of imidazole containing ruthenium complexes (ICRCs) with in vitro anticancer activities. Special attention is paid on ICRCs with the activities more potent than Cisplatin, and their correlation with their DNA binding properties in the context of possible cancer chemotherapeutic applications. The ICRCs are divided into two main categories according to their dark and light activated cytotoxicity; the former case is further clarified into mononuclear complexes including tris(bidentate polypyridyl) ruthenium complexes and those containing monodentatively coordinative imidazole ligands as well as polynuclear complexes. The perspective, challenges and future efforts for investigations into ICRCs are pointed out or suggested. PMID- 26586124 TI - Targeted Drug Delivery System for Platinum-based Anticancer Drugs. AB - Platinum-based (Pt-based) anticancer drugs have been recognised as one of the most effective drugs for clinical treatment of malignant tumors due to its unique mechanism of action and broad range of anticancer spectrum. But, there are still some limitations such as side effects, drug resistance/cross resistance, no specific targeting, becoming obstacles to restrict its expanding of clinical application. Targeted drug delivery system (TDDS) is a promising strategy for the research of novel Pt-based anticancer drugs. A variety of TDDS have been explored to improve the antitumor activity of Pt-based drugs such as nanoparticle drug systems, polymer-drug systems, drugs-macrocyclic compounds systems, etc. The review concentrates on recent development of various targeted drug delivery techniques, which could provide more opportunities for the development of Pt based drugs with better efficiency, lower toxicity and less resistance. PMID- 26586125 TI - Advances on Semisynthesis, Total Synthesis, and Structure-Activity Relationships of Honokiol and Magnolol Derivatives. AB - Honokiol and magnolol (an isomer of honokiol) are small-molecule polyphenols isolated from the barks of Magnolia officinalis, which have been widely used in traditional Chinese and Japanese medicines. In the last decade, a variety of biological properties of honokiol and magnolol (e.g., anti-oxidativity, antitumor activity, anti-depressant activity, anti-inflammatory activity, neuroprotective activity, anti-diabetic activity, antiviral activity, and antimicrobial activity) have been reported. Meanwhile, certain mechanisms of action of some biological activities were also investigated. Moreover, many analogs of honokiol and magnolol were prepared by structural modification or total synthesis, and some exhibited very potent pharmacological activities with improved water solubility. Therefore, the present review will provide a systematic coverage on recent developments of honokiol and magnolol derivatives in regard to semisynthesis, total synthesis, and structure-activity relationships from 2000 up to now. PMID- 26586126 TI - Therapeutic Outlook of Pyrazole Analogs: A Mini Review. AB - BACKGROUND: Pyrazole is one of the excellent structural motifs in medicinal chemistry. Various physiological and therapeutic possibilities have been exploited by incorporating different pharmacophoric groups in the pyrazole moiety. OBJECTIVE: This has opened a new arena of pyrazole analogs that can be developed into medicinal agents such as anti-inflammatory, analgesic, antipyretic, antiviral, antibacterial, anticancer, anticonvulsant, hypoglycemic, carbonic anhydrase inhibitors, mono amino oxidase (MAO) inhibitors, etc. Though, pyrazole analogs have proven their clinical efficacy as different pharmacological agents, a few of them have been withdrawn from the market due to their side effects. Thus, research on potential new drug candidates bearing the pyrazole moiety with lesser side effects has fairly increased over the last few years. CONCLUSION: This review explores diverse pharmacological activities exhibited by pyrazole analogs reported recently, which may be of great help for researchers in the area of drug discovery to understand the current scenario of pyrazole based compounds and to design and develop newer drug candidates with improved efficacy. PMID- 26586127 TI - Hormetic Potential of Sulforaphane (SFN) in Switching Cells' Fate Towards Survival or Death. AB - Epidemiological evidences establish sulforaphane (SFN), a hormetic dietary isothiocyanate to be a promising chemopreventive, anti-inflammatory and anti cancer agent. Beyond a concentration threshold SFN exerts pro-death activities (cell cycle arrest, epigenetic modifications and apoptosis) and below the threshold it either promotes prosurvival autophagy or remains latent. There is a significant lacuna in understanding the underpinning dynamic molecular networks that alternate the pharmacological responses with respect to the intracellular concentration and exposure time that renders SFN to be a characteristic hormetic molecule (display characteristic biphasic dose response curve). Unraveling this multi-targeted SFN triggered molecular interplay between apoptosis and pro survival autophagy may have great therapeutic implications. From the available literature, here we present a review that illustrates the existence of a hormetic window and briefly discussed its role in the spectrum of activity of SFN in different pathological conditions (cancer and immune-mediated diseases). Further, we hypothesize a hormetic signaling event on how SFN triggers mutually exclusive molecular pathways such as cell survival or death signals depending on its pathophysiological environment, exposure time and in vitro working concentrations. By better understanding these altered events and underpinning mechanisms in different combinations such as concentrations and time a proper therapeutic can be designed. PMID- 26586128 TI - The Role Oxidative Stress in the Pathogenesis of Eye Diseases: Current Status and a Dual Role of Physical Activity. AB - Extensive research during the past three decades has demonstrated the mechanisms by which an imbalance in the redox status of prooxidant/antioxidant reactions in cells with advantage of prooxidant reactions (oxidative stress, OS) can cause peroxidation of nucleic acids, bases, lipids, proteins and carbohydrates, thus resulting in their damage. These actions result in stimulation of signal transduction pathways and activation of transcription factors that can lead to chronic inflammation and cause tissue dysfunction. The most important oxidants are reactive oxygen species (ROS) and reactive nitrogen species (RNS) generated by various metabolic pathways, physical, chemical and biological factors, and pathological conditions. The eye is one of the major target of the ROS/RNS attack due to exposition on several environmental factors like high pressure of oxygen, light exposure, ultraviolet rays, ionizing radiation, chemical pollutants, irritant, and pathogenic microbes, which are able to shift the redox status of a cell towards oxidizing conditions. There is increasing evidence indicating that persistent OS contributes to the development of many ocular diseases. Increases in the accumulation of hydrogen peroxide and markers of the oxidative damage to DNA, lipids, proteins observed in several eye diseases and usage of antioxidants in their treatment and prevention emphasize the involvement of OS pathways. This paper summarizes the present state of knowledge in the involvement of OS in the etiology of non-cancer ocular diseases (dry eye syndrome; corneal and conjunctive diseases; cataract; glaucoma; age-related macular degeneration; retinitis pigmentosa; diabetic retinopathy, autoimmune and inflammatory uveitis) and cancer ocular diseases (melanoma; retinoblastoma; lymphoma). The paper also discusses the potential applications of antioxidants in the prevention of eye diseases and shows a duality of physical exercise actions: protection against the ROS/RNS damage by regular-moderate physical activity and damaging effect through mediation of OS by endurance exercise without adaptable physical training. PMID- 26586131 TI - Carbon for engineering of a water-oxidizing catalyst. AB - Herein we report that the reaction of KMnO4 with cobalt nanoparticles coated with multiple graphene layers forms a promising catalyst toward water oxidation. The compound was characterized by scanning electron microscopy, energy-dispersive spectroscopy, high resolution transmission electron microscopy, X-ray diffraction, electronic spectroscopy, Fourier transform infrared spectroscopy, and atomic absorption spectroscopy. In addition to the Mn oxide-based characteristics of the catalyst, it is a conductive, self-healing, recycling, highly dispersible, magnetically separable, environmentally friendly, and nano sized catalyst for water oxidation. The turnover frequency for the catalyst toward water oxidation is 0.1 and 0.05 (mmol O2 per mol Mn s) in the presence of cerium(iv) ammonium nitrate and photo-produced Ru(bpy)3(3+). PMID- 26586130 TI - Exercise self-efficacy and the relation with physical behavior and physical capacity in wheelchair-dependent persons with subacute spinal cord injury. AB - BACKGROUND: Since physical activity and exercise levels are known to be generally low in persons with spinal cord injury (SCI), there seems to be a need for intervention. Exercise self-efficacy (ESE), the confidence persons have in their ability to be physically active and exercise, is an important and modifiable predictor of physical behavior. The goal of this study was to 1) describe ESE in persons with subacute SCI, 2) to assess ESE in subgroups based on demographic and lesion characteristics, and 3) to explore the relation between ESE and physical behavior and physical capacity. METHODS: Thirthy-seven persons with subacute SCI who are wheelchair dependent participated. Participants completed the Exercise Self-Efficacy Scale. We recorded age and lesion characteristics, measured physical behavior (physical activity, motility and sedentary day time, n = 35) with an accelerometer-based activity monitor and measured physical capacity (peak power output, n = 28 and peak oxygen uptake, n = 24) during a maximal hand cycling test. Measurements were performed 2 months prior to discharge from inpatient rehabilitation. Mann-Whitney tests were used to test for differences between subgroups based on age and lesion characteristics and spearman correlations were used to assess the relation between ESE and physical activity and physical capacity. RESULTS: Persons with tetraplegia had lower ESE compared to persons with paraplegia (Z = -1.93, p = 0.05). No differences in ESE were found between subgroups based on age and motor completeness of the lesion. In persons with paraplegia, ESE was positively related to peak power output (rho = 0.58, p = 0.02). The relation of ESE with wheeled physical activity was rho = 0.36, p = 0.09. CONCLUSIONS: In persons with SCI who are dependent on a manual wheelchair, lesion level when categorized as paraplegic and tetraplegic affected ESE whereas age categories and completeness categories did not. Persons with tetraplegia were found to have lower confidence with regard to physical activity and exercise indicating that this subgroup can benefit from extra attention in the promotion of physical activity and exercise. In persons with paraplegia, ESE seemed to be lower in persons with less peak power output and less daily physical activity. PMID- 26586129 TI - Invasive cutaneous Neoscytalidium infections in renal transplant recipients: a series of five cases. AB - BACKGROUND: Neoscytalidium species (formerly Scytalidium species) are black fungi that usually cause cutaneous infections mimicking dermatophytes lesions. Very few publications have reported invasive or disseminated infections. CASE PRESENTATION: In this paper, we report the clinical presentations, treatments and outcomes of five cases of invasive Neoscytalidium infections with cutaneous involvement, including two cases with disseminated infection, in five renal transplant recipients. To our knowledge, this is the first report of a series albeit small-of renal transplant patients in whom this infection was identified. All cases occurred in a single hospital in Paris, France, between 2001 and 2011. Patients all originate from tropical area. CONCLUSION: Treatments of Neoscytalidium infection varied greatly, underlining the lack of a recommendation for a standardized treatment. All patients were cured after long-term antifungal therapy and/or surgical excision. Interestingly, one patient with disseminated infection involving the left elbow, the right leg, the lungs and the nasal septum was cured by medical therapy only without surgery. This may suggest that in contrast to others mycoses (such as mucormycosis), an adequate medical treatment could be sufficient for treating Neoscytalidium. We also point out the difficulties we had in diagnosing two patients with Kaposi's sarcoma because of the similarity of the lesions. Furthermore, our report underlines the need to check for this rare infection in immunocompromised kidney transplant recipients originating from tropical areas. PMID- 26586132 TI - Yeast reveals similar molecular mechanisms underlying alpha- and beta-synuclein toxicity. AB - Synucleins belong to a family of intrinsically unstructured proteins that includes alpha-synuclein (aSyn), beta-synuclein (bSyn) and gamma-synuclein (gSyn). aSyn is the most studied member of the synuclein family due to its central role in genetic and sporadic forms of Parkinson's disease and other neurodegenerative disorders known as synucleionopathies. In contrast, bSyn and gSyn have been less studied, but recent reports also suggest that, unexpectedly, these proteins may also cause neurotoxicity. Here, we explored the yeast toolbox to investigate the cellular effects of bSyn and gSyn. We found that bSyn is toxic and forms cytosolic inclusions that are similar to those formed by aSyn. Moreover, we found that bSyn shares similar toxicity mechanisms with aSyn, including vesicular trafficking impairment and induction of oxidative stress. We demonstrate that co-expression of aSyn and bSyn exacerbates cytotoxicity, due to increased dosage of toxic synuclein forms, and that they are able to form heterodimers in both yeast and in human cells. In contrast, gSyn is not toxic and does not form inclusions in yeast cells. Altogether, our findings shed light into the question of whether bSyn can exert toxic effects and confirms the occurrence of aSyn/bSyn heterodimers, opening novel perspectives for the development of novel strategies for therapeutic intervention in synucleinopathies. PMID- 26586134 TI - Three-dimensional colour Doppler imaging for evaluating perforators of the anterolateral thigh flap. PMID- 26586133 TI - Neck motion, motor control, pain and disability: A longitudinal study of associations in neck pain patients in physiotherapy treatment. AB - BACKGROUND: Neck pain is associated with several alterations in neck motion and motor control, but most of the findings are based on cross-sectional studies. OBJECTIVE: The aim of this study was to investigate associations between changes in neck motion and motor control, and changes in neck pain and disability in physiotherapy patients during a course of treatment. DESIGN: Prospective cohort study. METHOD: Subjects with non-specific neck pain (n = 71) participated in this study. Neck flexibility, joint position error (JPE), head steadiness, trajectory movement control and postural sway were recorded before commencement of physiotherapy (baseline), at 2 weeks, and at 2 months. Numerical Rating Scale and Neck Disability Index were used to measure neck pain and disability at the day of testing. To analyze within subjects effects in neck motion and motor control, neck pain, and disability over time we used fixed effects linear regression analysis. RESULTS: Changes in neck motion and motor control occurred primarily within 2 weeks. Reduction in neck pain was associated with increased cervical range of motion in flexion-/extension and increased postural sway when standing with eyes open. Decreased neck disability was associated with some variables for neck flexibility and trajectory movement control. Cervical range of motion in flexion-/extension was the only variable associated with changes in both neck pain and neck disability. CONCLUSIONS: This study shows that few of the variables for neck motion and motor control were associated with changes neck pain and disability over a course of 2 months with physiotherapy treatment. PMID- 26586136 TI - Embolization of direct carotid cavernous fistulas with the novel double-balloon technique. AB - Multiple endovascular management of direct carotid cavernous fistula (CCF) has been widely accepted as a treatment option. Embolization of the fistula with detachable balloons or thrombogenic coil-based occlusion has been the main choice to treat direct CCF, with good safety and efficacy. This study investigated the safety and efficacy of embolization of direct CCF with the novel double-balloon technique. A retrospective review of a prospective database on cerebral vascular disease was performed. We identified a total of five patients presenting with high-flow direct CCF. All patients were managed with transarterial embolization with the novel double-balloon technique. Three of the five patients were treated with two detachable balloons, and a completely occluded fistula with preservation of the internal carotid artery was achieved. Of the remaining two patients treated with more detachable balloons, one patient achieved a perfect outcome and the other one suffered from recurrent fistula due to balloon migration 3 weeks after embolization. During a follow-up period of 12-18 months, no symptoms reoccurred in any patient. Thus, the double-balloon treatment may be a promising method for CCF complete occlusion. This novel technique may bring more benefits in the following two cases: 1). A single inflated detachable balloon fails to completely occlude the CCF, which causing the next balloon can not pass into the fistula. 2). A giant CCF needs more balloons for fistula embolization. PMID- 26586137 TI - The impact of selection on population genetic structure in the clam Meretrix petechialis revealed by microsatellite markers. AB - The aim of our work is to evaluate the impact of mass selection on genetic structure in artificially closed populations of the clam Meretrix petechialis. In the present study, we performed mass selection over four generations (from 2004 to 2010) on two clam populations [shell features of purple lines (SP) and black dots (SB)] and analyzed their temporal genetic variation and structure using microsatellite makers. The two closed populations originated from the natural Shandong population (SD); thus, a natural SD population (10SD) was used to detect the current genetic structure after 6 years of natural selection. The results showed that the genetic diversity of the four generations of SB and SP was gradually reduced but remained at relatively high levels (SB, A = 18.9.4-16.8, Ho = 0.7389-0.6971, and He = 0.8897-0.8591; SP, A = 20.0-17.8, Ho = 0.7512-0.7043, and He = 0.8938-0.8625), which has not been reduced compared with that of the 10SD population (A = 17.8, Ho = 0.6803, and He = 0.8302). The Ne estimates for the two populations were almost at the same levels as the actual numbers of parental individuals. In addition, a low inbreeding coefficient was detected in the two populations (SB, 0.00201-0.00639; SP, 0.00176-0.00541). Based on the results, the present mass selection has not made a large impact on the population genetic structure of the closed populations. The present investigation provides important information for the development of management strategies for genetic breeding of the clam. PMID- 26586138 TI - Anatomy, Histochemistry, and Antifungal Activity of Anacardium humile (Anacardiaceae) Leaf. AB - Leaves of Anacardium humile are used in Brazilian traditional medicine for the treatment of intestinal disturbances and skin lesions. This study aimed to define leaf diagnostic structural characters, to propose a new method of phytochemical analysis of secretions, prospect flavonoids and alkaloids, and to evaluate their inhibitory activity on Candida albicans. Common anatomical, phytochemical, and microbiological methods were used. Leaves of Anacardium occidentale were used as a reference for the structural analyses. The main structural characters were closed vascular system, absence of ducts at the medulla, bilateral mesophyll, absence of bundle sheath extension, and secretory idioblasts at the xylem. The ducts present schizogenous origin, and secreting activity is restricted to the initial phases of leaf blade expansion. The proposed new phytochemical method is practical and inexpensive and has potential for wide application. The abundance of tannins and flavonoids is related to medicinal use. A single peak in high performance liquid chromatography indicated the presence of a pure substance not previously reported. The extract had a strong inhibitory effect on C. albicans. The obtained results confirm the potential of A. humile for the prospection of new bioactive compounds. PMID- 26586140 TI - Efforts to limit antimicrobial resistance are threatened by lack of evidenced control policies, review warns. PMID- 26586139 TI - Clinical profile of PanIN lesions in tropical chronic pancreatitis. AB - BACKGROUND: Chronic pancreatitis (CP) found in the tropical countries is known to have a higher risk for carcinoma of the pancreas. This study aimed to explore the clinical profile of pancreatic intraepithelial neoplasia (PanIN), one of the precursors of carcinoma of the pancreas, in tropical CP and to identify the possible clinical predictors of the same. METHODOLOGY: A retrospective study was done enrolling patients who underwent either Frey's procedure or pancreatic resection for symptomatic CP, between January 2008 and December 2012. They were grouped into PanIN positive and PanIN negative based on histopathology. Their clinical and laboratory parameters were compared statistically to identify the predictors of the PanIN status. RESULTS: Sixty-two tropical CP patients who had Frey's procedure or pancreatic resection were enrolled into this study; 38.7 % cases showed PanIN changes and 61.29 % had no PanIN changes. Majority of the clinical and laboratory parameters were found comparable between the two groups except obstructive jaundice and CA 19-9 value >137.5 which were there in 54.2 % of PanIN-positive cases. On histopathology, 54.83 % cases were benign CP and 45.16 % were malignant CP. Among the benign CP, 33.3 % were PanIN positive and among those with malignancy 66.7 % were PanIN positive. Low-grade PanINs were seen in 73 % cases of benign CP and in 26.1 % of malignancy whereas high-grade PanIN-3 lesions were seen exclusively in patients with malignancy. CONCLUSION: High-grade PanIN-3 lesions showed significant association with pancreatic malignancy. Obstructive jaundice and CA 19-9 >= 137.5 could predict PanIN positivity. PMID- 26586141 TI - Predictors of the new criteria for probable PTSD among older adults. AB - The definition of post-traumatic stress disorder (PTSD) changed in the fifth edition of the Diagnostic and Statistical Manual (DSM-5) and it is yet unclear how these changes affect the diagnosis of PTSD among older adults. The present study examined the contribution of demographic characteristics, functioning status, health related factors, as well as exposure to rocket attacks to prediction of probable PTSD in older adults. Three-hundred and thirty-nine community-dwelling adults (age range 50-90; M=65.44, SD=9.77) were sampled through random dialing to Jewish residents in the south of Israel. Participants completed a phone-questionnaire that collected background information and reports of relevant symptoms. Analyses showed that self-rated health, incidence of depression episodes, and exposure to rocket attacks predicted the DSM-5 definition of PTSD as well as the subscale of negative alternations in cognition and mood. The current study delineates the unique set of predictors of probable PTSD in older adults, with an emphasis on negative alternations in cognition and mood. Greater attention to unique predictors of PTSD in the second half of life is called for. PMID- 26586143 TI - Improving Pregnancy Outcomes through Maternity Care Coordination: A Systematic Review. AB - BACKGROUND: Care during pregnancy is multifaceted and often goes beyond traditional prenatal care from an obstetrical care provider. Coordinating care between multiple providers can be challenging, but is beneficial for providers and patients. Care coordination is associated with decreased costs, greater patient satisfaction, and a reduction in medical errors. To our knowledge, no previous review has examined maternity care coordination (MCC) programs and their association with pregnancy outcomes. METHODS: Using a search algorithm comprised of relevant MCC terminology, studies were identified through a systematic search of PubMed, Scopus, ClinicalTrials.gov, and Google Scholar. Studies meeting eligibility criteria (e.g., defining the care coordination components and examining at least one quantitative outcome) were fully abstracted and quality rated using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist. MAIN FINDINGS: Thirty-three observational studies of MCC were included in this review. Quality scores ranged from 27% to 100%. Most studies included strategies with a team approach to decision making and/or individual case management. Social service referrals to outside organizations were also common. Twenty-seven studies reported infant birth weight as a main outcome; 12 found a significant improvement in birth weights among care coordination participants. CONCLUSIONS: Roughly one-third of the included studies reported improved birth weights among care coordination participants. However, it remains unknown what effect care coordination strategies have on patient and provider satisfaction in the prenatal care setting, two aspects of maternity care that may advance the quality and utilization of prenatal health services. PMID- 26586144 TI - Utilizing multiple scale models to improve predictions of extra-axial hemorrhage in the immature piglet. AB - Traumatic brain injury (TBI) is a leading cause of death and disability in the USA. To help understand and better predict TBI, researchers have developed complex finite element (FE) models of the head which incorporate many biological structures such as scalp, skull, meninges, brain (with gray/white matter differentiation), and vasculature. However, most models drastically simplify the membranes and substructures between the pia and arachnoid membranes. We hypothesize that substructures in the pia-arachnoid complex (PAC) contribute substantially to brain deformation following head rotation, and that when included in FE models accuracy of extra-axial hemorrhage prediction improves. To test these hypotheses, microscale FE models of the PAC were developed to span the variability of PAC substructure anatomy and regional density. The constitutive response of these models were then integrated into an existing macroscale FE model of the immature piglet brain to identify changes in cortical stress distribution and predictions of extra-axial hemorrhage (EAH). Incorporating regional variability of PAC substructures substantially altered the distribution of principal stress on the cortical surface of the brain compared to a uniform representation of the PAC. Simulations of 24 non-impact rapid head rotations in an immature piglet animal model resulted in improved accuracy of EAH prediction (to 94 % sensitivity, 100 % specificity), as well as a high accuracy in regional hemorrhage prediction (to 82-100 % sensitivity, 100 % specificity). We conclude that including a biofidelic PAC substructure variability in FE models of the head is essential for improved predictions of hemorrhage at the brain/skull interface. PMID- 26586142 TI - Neuropsychological profile in adult schizophrenia measured with the CMINDS. AB - Schizophrenia neurocognitive domain profiles are predominantly based on paper-and pencil batteries. This study presents the first schizophrenia domain profile based on the Computerized Multiphasic Interactive Neurocognitive System (CMINDS((r))). Neurocognitive domain z-scores were computed from computerized neuropsychological tests, similar to those in the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB), administered to 175 patients with schizophrenia and 169 demographically similar healthy volunteers. The schizophrenia domain profile order by effect size was Speed of Processing (d=-1.14), Attention/Vigilance (d=-1.04), Working Memory (d=-1.03), Verbal Learning (d=-1.02), Visual Learning (d=-0.91), and Reasoning/Problem Solving (d=-0.67). There were no significant group by sex interactions, but overall women, compared to men, showed advantages on Attention/Vigilance, Verbal Learning, and Visual Learning compared to Reasoning/Problem Solving on which men showed an advantage over women. The CMINDS can readily be employed in the assessment of cognitive deficits in neuropsychiatric disorders; particularly in large-scale studies that may benefit most from electronic data capture. PMID- 26586145 TI - Burst and Tonic Spinal Cord Stimulation: Different and Common Brain Mechanisms. AB - OBJECTIVE: Spinal cord stimulation is commonly used to treat medically intractable pain. Different stimulation designs are used to obtain pain suppression such as tonic stimulation, high frequency stimulation, and burst stimulation. Preliminary analysis of the same data used in this study demonstrated that burst stimulation likely modulates the medial pain pathways in contrast to tonic stimulation. The question arises what different and common supraspinal mechanisms burst and tonic stimulation use. MATERIALS AND METHODS: The clinical and electroencephalography (EEG) data of five patients undergoing tonic, burst, and sham stimulation were analyzed to look at the commonalities and differences between burst and tonic stimulation. A source-localized (sLORETA) EEG substraction and conjunction analysis is performed in each condition for both activity and functional connectivity. A ratio between the dorsal anterior cingulate cortex (dACC) and pregenual anterior cingulate cortex/ventromedial prefrontal cortex (pgACC/vmPFC) is calculated to reflect a balance between pain supporting and pain suppressing systems. RESULTS: Differences are noted in the dACC, dorsolateral prefrontal cortex, the primary somatosensory cortex, and the posterior cingulate cortex (PCC). Burst and tonic stimulation share activation in the pgACC, inferior parietal area, which encompasses the inferior secondary somatosensory cortex, PCC, and the parahippocampus. Burst suppression normalizes the pain supporting/pain suppressing balance in contrast to tonic stimulation. DISCUSSION AND CONCLUSION: These data suggest that burst and tonic stimulation both modulate the descending pain inhibitory system (via pgACC), as well as a self-referential contextual (via PCC) aversive memory system (via parahippocampus). However, burst normalizes the pain supporting/suppressing balance in contrast to tonic mode by a greater effect on the dACC. PMID- 26586146 TI - Circumstances surrounding the onset of stroke: a qualitative study. AB - AIM: To document perceptions of circumstances spontaneously associated with the occurrence of the stroke on that particular day. BACKGROUND: Known triggers of stroke include birthday or negative emotions. However, specific circumstances relating to that birthday or emotion have not yet been documented. DESIGN: Phenomenological perspective where data were collected between October 2011-June 2012. METHOD: In-depth interviews conducted 5-8 weeks post stroke with 37 participants, with a mean age of 56.3 years (sd 11.9) and 40.5% (14/37) of whom were female. An interview guide composed of open-ended questions and developed with experts was used to explore in detail free associations surrounding the stroke. All interviews were audiotaped and transcribed. Data were rigorously analysed by two team members and discussed in team meetings until reaching consensus on essential themes. FINDINGS: Relationships emerged as being the overarching theme related to stroke triggers with the interrelated subthemes of: (1) birthday or anniversary; (2) parenting; (3) being sick seen as a benefit; and (4) alcohol or drug abuse. The stroke happened on a day which was related in some way to a relationship with a significant other affected by tension, a lack of transparency or an overinvestment of emotional/affective state. CONCLUSIONS: There is a need to address individuals' beliefs as a part of secondary prevention interventions to be truly client-centred, which the phenomenological perspective allows. Relationships as a potential source of stress should be added as a theme to discuss with patients for a holistic approach to stroke prevention including psychosocial factors. PMID- 26586147 TI - Formulation and evaluation of anti-rheumatic dexibuprofen transdermal patches: a quality-by-design approach. AB - Dexibuprofen (DXIBN) transdermal patches were formulated using various concentrations of selected polymeric excipients (matrix material; ethyl cellulose and polyvinylpyrrolidone, plasticizer (di-N-butyl phthalate), and a conventional permeation enhancer (almond oil)). Initial patch formulations were evaluated for their physiochemical properties (thickness, moisture uptake, final moisture content, and DXIBN content). Also, impact of patch components on resulting tensile strength and in vitro permeation were used to predict an optimal patch formulation using a quality-by-design (QbD) approach, which was subsequently evaluated and further compared with a commercial oral tablet dosage form for in vitro and in vivo release (rabbit model). Initially formulated patches demonstrated uniform thickness (0.44 +/- 0.02 cm), relatively low moisture uptake (7.87 +/- 1.11 w/w %), and highly acceptable drug loading values (100.0 +/- 0.026%). The tensile strength of patches increased significantly with matrix polymer concentration and to a lesser degree with increase in plasticizer and permeation enhancer content, although these affected the permeation of DXIBN. Predicted properties (tensile strength and DXIBN steady-state flux) for the QbD optimized formulation were in close agreement to experimental results. The QbD optimal patch formulation behavior differed significantly from the commercial tablet formulation in vivo. Such model-based predictions (QbD approach) will reduce cost and time in formulation development sciences. PMID- 26586148 TI - [Overmedicalization: When too much medicine harms]. AB - Overmedicalization refers to non-validated medical practices, with no clear benefits, potentially harmful and therefore unnecessarily costly. Awareness is growing with respect to this serious public health problem. Permanent expansion of diagnostic or therapeutic interventions, disease mongering, inadequate management of diagnostic uncertainty, conflict of interest or lack of commitment by physicians and patients in shared decision making. Overmedicalization is made possible by a lack of training of health professionals and users on medical decision process. Only a multidisciplinary research program, involving medical and non-medical worlds, will allow the implementation of corrective actions. PMID- 26586149 TI - Encapsulation of Aconitine in Self-Assembled Licorice Protein Nanoparticles Reduces the Toxicity In Vivo. AB - Many herbal medicines and compositions are clinically effective but challenged by its safety risks, i.e., aconitine (AC) from aconite species. The combined use of Radix glycyrrhizae (licorice) with Radix aconite L. effectively eliminates toxicity of the later while increasing efficacy. In this study, a boiling-stable 31-kDa protein (namely GP) was purified from licorice and self-assembled into nanoparticles (206.2 +/- 2.0 nm) at pH 5.0, 25 degrees C. The aconitine encapsulated GP nanoparticles (238.2 +/- 1.2 nm) were prepared following the same procedure and tested for its toxicity by intraperitoneal injection on ICR mouse (n = 8). Injection of GP-AC nanoparticles and the mixed licorice-aconite decoction, respectively, caused mild recoverable toxic effects and no death, while the aconitine, particle-free GP-AC mixture and aconite decoction induced sever toxic effects and 100 % death. Encapsulation of poisonous alkaloids into self-assembled herbal protein nanoparticles contributes to toxicity attenuation of combined use of herbs, implying a prototype nanostructure and a universal principle for the safer clinical applications of herbal medicines. PMID- 26586150 TI - A Free-Standing Sulfur/Nitrogen-Doped Carbon Nanotube Electrode for High Performance Lithium/Sulfur Batteries. AB - A free-standing sulfur/nitrogen-doped carbon nanotube (S/N-CNT) composite prepared via a simple solution method was first studied as a cathode material for lithium/sulfur batteries. By taking advantage of the self-weaving behavior of N CNT, binders and current collectors are rendered unnecessary in the cathode, thereby simplifying its manufacturing and increasing the sulfur weight ratio in the electrode. Transmission electronic microscopy showed the formation of a highly developed core-shell tubular structure consisting of S/N-CNT composite with uniform sulfur coating on the surface of N-CNT. As a core in the composite, the N-CNT with N functionalization provides a highly conductive and mechanically flexible framework, enhancing the electronic conductivity and consequently the rate capability of the material. PMID- 26586151 TI - Low grade glioma guidelines: Foreword. PMID- 26586152 TI - Value of MRI olfactory bulb evaluation in the assessment of olfactory dysfunction in Bardet-Biedl syndrome. AB - Olfactory bulb (OB) volume evaluation by magnetic resonance imaging (MRI) has been demonstrated to be related to olfactory dysfunction in many different diseases. Olfactory dysfunction is often overlooked in Bardet-Biedl syndrome (BBS) patients and is rarely objectively evaluated by MRI. We present a series of 20 BBS patients with olfactory dysfunction. The OB was evaluated separately and blindly by two radiologists (SR and SM) with 3 Tesla MRI imaging comparatively to 12 normal control subjects by global visual evaluation and by quantitative measurement of OB volume. In the 12 control cases OB visual evaluation was considered as normal in all cases for radiologist (SR) and in 10 cases for radiologist (SM). In the 20 BBS patients, OB visual evaluation was considered as abnormal in 18 cases for SR and in all cases for SM. OB volumetric evaluation for SR and SM in BBS patients was able to provide significant correlation between BBS and olfactory dysfunction. This study indicates that OB volume evaluation by MRI imaging like structural MRI scan for gray matter modifications demonstrates that olfactory dysfunction in BBS patients is a constant and cardinal symptom integrated in a genetical syndrome with peripheral and central olfactory structure alterations. PMID- 26586153 TI - Disposable optics for microscopy diagnostics. AB - The point-of-care testing (POCT) is having increasing role on modern health care systems due to a possibility to perform tests for patients conveniently and immediately. POCT includes lot of disposable devices because of the environment they are often used. For a disposable system to be reasonably utilized, it needs to be high in quality but low in price. Optics based POCT systems are interesting approach to be developed, and here we describe a low-cost fabrication process for microlens arrays for microscopy. Lens arrays having average lens diameter of 222 MUm with 300 MUm lens pitch were fabricated. The lenses were characterized to have standard deviation of 0.06 MUm in height and 4.61 MUm in diameter. The resolution limit of 3.9MUm is demonstrated with real images, and the images were compared with ones made with glass and polycarbonate lens arrays. The image quality is at the same level than with the glass lenses and the manufacturing costs are very low, thus making them suitable for POCT applications. PMID- 26586154 TI - Sodium Nitrate Induces Reactive Oxygen Species That Lower the Antioxidant Power, Damage the Membrane, and Alter Pathways of Glucose Metabolism in Human Erythrocytes. AB - Nitrate salts are widely used as food additives and nitrogenous fertilizers and are present as contaminants in drinking water supplies. The effect of different concentrations (1-15 mM) of sodium nitrate (NaNO3) on human erythrocytes was studied under in vitro conditions. Treatment of erythrocytes with NaNO3 resulted in increases in methemoglobin levels, lipid peroxidation, and protein oxidation and a decrease in glutathione content. There were changes in the activities of all major antioxidant defense enzymes, and the pathways of glucose metabolism were also affected. Increased generation of reactive oxygen species (ROS) took place while the antioxidant power was impaired. The osmotic fragility of cells was increased, and membrane-bound enzymes were greatly inhibited. All changes were statistically significant at a probability level of P < 0.05 at all concentrations of NaNO3 except the lowest (1 mM). Thus, NaNO3 generates ROS that cause significant damage to human erythrocytes and interfere in normal cellular pathways. PMID- 26586155 TI - A selective impairment of perception of sound motion direction in peripheral space: A case study. AB - It is still an open question if the auditory system, similar to the visual system, processes auditory motion independently from other aspects of spatial hearing, such as static location. Here, we report psychophysical data from a patient (female, 42 and 44 years old at the time of two testing sessions), who suffered a bilateral occipital infarction over 12 years earlier, and who has extensive damage in the occipital lobe bilaterally, extending into inferior posterior temporal cortex bilaterally and into right parietal cortex. We measured the patient's spatial hearing ability to discriminate static location, detect motion and perceive motion direction in both central (straight ahead), and right and left peripheral auditory space (50 degrees to the left and right of straight ahead). Compared to control subjects, the patient was impaired in her perception of direction of auditory motion in peripheral auditory space, and the deficit was more pronounced on the right side. However, there was no impairment in her perception of the direction of auditory motion in central space. Furthermore, detection of motion and discrimination of static location were normal in both central and peripheral space. The patient also performed normally in a wide battery of non-spatial audiological tests. Our data are consistent with previous neuropsychological and neuroimaging results that link posterior temporal cortex and parietal cortex with the processing of auditory motion. Most importantly, however, our data break new ground by suggesting a division of auditory motion processing in terms of speed and direction and in terms of central and peripheral space. PMID- 26586156 TI - Community engagement among men who have sex with men living with HIV/AIDS in Taiwan. AB - Community engagement was developed as a global principle in the provision of HIV/AIDS services, yet evidence-based research of implementation of the principle is lacking in Taiwan. This short report aims to understand factors associated with engagement in two types of activities with varying levels of visibility: HIV related community events and HIV-related community action, in Taiwanese men who have sex with men (MSM) living with HIV. A cross-sectional survey was distributed to a purposive sample of participants recruited from AIDS service organizations (ASOs). Among participants (n = 178), 63.6% were involved in HIV-related community events, while less than half (47.7%) were involved in HIV-related community action. In multivariable analysis, age, involvement in ASOs, and AIDS knowledge were positively associated with engagement in community events, and living in the north of Taiwan, years of infection, and self-stigma were negatively associated with this type of engagement. Few factors, with the exception of involvement in ASOs, were positively associated with engagement in HIV-related community action. To this end, ASOs appear to play a strong role in improving and organizing both types of community engagement in Taiwan. Future studies should evaluate tailored programs delivered through ASOs for strengthening community connectedness among younger, stigmatized, and longer diagnosed MSM living with HIV. PMID- 26586157 TI - Differential variability and correlation of gene expression identifies key genes involved in neuronal differentiation. AB - BACKGROUND: Understanding the dynamics of stem cell differentiation processes at the molecular level is a central challenge in developmental biology and regenerative medicine. Although the dynamic behaviors of differentiation regulators have been partially characterized, the architecture regulating the underlying molecular systems remains unclear. RESULT: System-level analysis of transcriptional data was performed to characterize the dynamics of molecular networks in neural differentiation of stem cells. Expression of a network module of genes tightly co-expressed in mouse embryonic stem (ES) cells fluctuated greatly among cell populations before differentiation, but became stable following neural differentiation. During the neural differentiation process, genes exhibiting both differential variance and differential correlation between undifferentiated and differentiating states were related to developmental functions such as body axis development, neuronal movement, and transcriptional regulation. Furthermore, these genes were genetically associated with neuronal differentiation, providing support for the idea they are not only differentiation markers but could also play important roles in neural differentiation. Comparisons with transcriptional data from human induced pluripotent stem (iPS) cells revealed that the system of genes dynamically regulated during neural differentiation is conserved between mouse and human. CONCLUSIONS: The results of this study provide a systematic analytical framework for identifying key genes involved in neural differentiation by detecting their dynamical behaviors, as well as a basis for understanding the dynamic molecular mechanisms underlying the processes of neural differentiation. PMID- 26586158 TI - Primary breast sarcoma: A retrospective study over 35 years from a single institution. AB - AIM: The aim of this study was to contribute to the collected knowledge of prognostic factors in primary breast sarcomas (PBS) to the benefit of possible future prospective studies and therapeutic guidelines. METHOD: All patients with pathologically verified PBS in the period of 1979-2014 were extracted from a hospital-based database at Aarhus University Hospital. All records were reviewed for patient and tumor characteristics. Primary endpoints were overall survival, disease-free survival (DFS) and disease-specific survival (DSS). Adjustments were made for age, tumor location, surgical strategy, size, histological classification, prior radiation and grade. Prognostic factors were determined by the use of Cox proportional hazard ratio. RESULTS: In total 42 patients were identified. Surgical resection was the main method of treatment. Nineteen (45%) patients were initially selected for lumpectomy, of these 68% needed at least one re-excision to attain wide margins. In total 55% experienced recurrence, loco regional in 43%. Five-years overall survival was 49%, five-year DFS was 48% and five-year DSS was 40%. Significant prognostic factors were size and grade. A trend towards better survival in those with superficial tumors was observed as well as an increased incidence in radiation-induced angiosarcoma (AS) of the breast, however, prognosis was no different from non-radiation-induced AS. CONCLUSION: Prognostic factors in PBS patients were size and grade with a trend towards better survival in those with superficial tumors. There was no difference in survival between radiation-induced and spontaneous breast sarcomas. High rate of local recurrence suggests the need for aggressive surgical approach or the routine addition of postoperative radiotherapy in those selected for breast conserving surgery (BCS). PMID- 26586159 TI - beta-Conglutin dual aptamers binding distinct aptatopes. AB - An aptamer was previously selected against the anaphylactic allergen beta conglutin (beta-CBA I), which was subsequently truncated to an 11-mer and the affinity improved by two orders of magnitude. The work reported here details the selection and characterisation of a second aptamer (beta-CBA II) selected against a second aptatope on the beta-conglutin target. The affinity of this second aptamer was similar to that of the 11-mer, and its affinity was confirmed by three different techniques at three independent laboratories. This beta-CBA II aptamer in combination with the previously selected beta-CBA I was then exploited to a dual-aptamer approach. The specific and simultaneous binding of the dual aptamer (beta-CBA I and beta-CBA II) to different sites of beta-conglutin was confirmed using both microscale thermophoresis and surface plasmon resonance where beta-CBA II serves as the primary capturing aptamer and beta-CBA I or the truncated beta-CBA I (11-mer) as the secondary signalling aptamer, which can be further exploited in enzyme-linked aptamer assays and aptasensors. PMID- 26586160 TI - Nanosensors for neurotransmitters. AB - Neurotransmitters are an important class of messenger molecules. They govern chemical communication between cells for example in the brain. The spatiotemporal propagation of these chemical signals is a crucial part of communication between cells. Thus, the spatial aspect of neurotransmitter release is equally important as the mere time-resolved measurement of these substances. In conclusion, without tools that provide the necessary spatiotemporal resolution, chemical signaling via neurotransmitters cannot be studied in greater detail. In this review article we provide a critical overview about sensors/probes that are able to monitor neurotransmitters. Our focus are sensing concepts that provide or could in the future provide the spatiotemporal resolution that is necessary to 'image' dynamic changes of neurotransmitter concentrations around cells. These requirements set the bar for the type of sensors we discuss. The sensor must be small enough (if possible on the nanoscale) to provide the envisioned spatial resolution and it should allow parallel (spatial) detection. In this article we discuss both optical and electrochemical concepts that meet these criteria. We cover techniques that are based on fluorescent building blocks such as nanomaterials, proteins and organic dyes. Additionally, we review electrochemical array techniques and assess limitations and possible future directions. PMID- 26586161 TI - Pentavalent antimony uptake pathway through erythrocyte membranes: molecular and atomic fluorescence approaches. AB - Previous studies by our group have shown that Sb(V) is able to enter red blood cells in a dynamic process and is reduced to Sb(III) by glutathione. The present study aims to investigate a possible entry pathway for Sb(V) through the erythrocyte membrane. Applying fluorescence spectroscopy studies with Laurdan and diphenylhexatriene (DPH) probes, it was found that there was no interaction between Sb(V) and membrane lipids. By comparing the Sb(V) entry percentages through lipid vesicles and sealed erythrocyte membranes, it was found that Sb(V) required protein channels to pass through the membrane. The competitive inhibition results using HCO3 (-) and Cl(-) showed that the Sb(V) uptake rate through the membrane fell approximately 50-70 % until full inhibition was reached, which was possibly due to the inhibition of the anion exchanger 1 (AE1) channel. Finally, the fluorescence measurements with the 5 iodoacetamidofluorescein (5-IAF) probe showed that Sb(V) interacted with membrane protein SH groups during this process. PMID- 26586162 TI - Photoluminescence imaging of solitary dopant sites in covalently doped single wall carbon nanotubes. AB - Covalent dopants in semiconducting single wall carbon nanotubes (SWCNTs) are becoming important as routes for introducing new photoluminescent emitting states with potential for enhanced quantum yields, new functionality, and as species capable of near-IR room-temperature single photon emission. The origin and behavior of the dopant-induced emission is thus important to understand as a key requirement for successful room-T photonics and optoelectronics applications. Here, we use direct correlated two-color photoluminescence imaging to probe how the interplay between the SWCNT bright E(11) exciton and solitary dopant sites yields the dopant-induced emission for three different dopant species: oxygen, 4 methoxybenzene, and 4-bromobenzene. We introduce a route to control dopant functionalization to a low level as a means for introducing spatially well separated solitary dopant sites. Resolution of emission from solitary dopant sites and correlation to their impact on E(11) emission allows confirmation of dopants as trapping sites for localization of E(11) excitons following their diffusive transport to the dopant site. Imaging of the dopant emission also reveals photoluminescence intermittency (blinking), with blinking dynamics being dependent on the specific dopant. Density functional theory calculations were performed to evaluate the stability of dopants and delineate the possible mechanisms of blinking. Theoretical modeling suggests that the trapping of free charges in the potential well created by permanent dipoles introduced by dopant atoms/groups is likely responsible for the blinking, with the strongest effects being predicted and observed for oxygen-doped SWCNTs. PMID- 26586163 TI - Rectal Cancer Magnetic Resonance Imaging: Imaging Beyond Morphology. AB - Magnetic resonance imaging (MRI) has in recent years progressively established itself as one of the most valuable modalities for the diagnosis, staging and response assessment of rectal cancer and its use has largely focused on accurate morphological assessment. The potential of MRI, however, extends beyond detailed anatomical depiction: aspects of tissue physiology, such as perfusion, oxygenation and water molecule diffusivity, can be assessed indirectly. Functional MRI is rapidly evolving as a promising non-invasive assessment tool for tumour phenotyping and assessment of response to new therapeutic agents. In spite of promising experimental data, the evidence base for the application of functional MRI techniques in rectal cancer remains modest, reflecting the relatively poor agreement on technical protocols, image processing techniques and quantitative methodology to date, hampering routine integration into clinical management. This overview outlines the established strengths and the critical limitations of anatomical MRI in rectal cancer; it then introduces some of the functional MRI techniques and quantitative analysis methods that are currently available, describing their applicability in rectal cancer and reviewing the relevant literature; finally, it introduces the concept of a multi-parametric quantitative approach to rectal cancer. PMID- 26586164 TI - Imaging mass spectrometry of the visual system: Advancing the molecular understanding of retina degenerations. AB - Visual sensation is fundamental for quality of life, and loss of vision to retinal degeneration is a debilitating condition. The eye is the only part of the central nervous system that can be noninvasively observed with optical imaging. In the clinics, various spectroscopic methods provide high spatial resolution images of the fundus and the developing degenerative lesions. However, the currently utilized tools are not specific enough to establish the molecular underpinnings of retinal diseases. In contrast, mass spectrometric imaging (MSI) is a powerful tool to identify molecularly specific disease indicators and classification markers. This technique is particularly well suited to the eye, where molecular information can be correlated with clinical data collected via noninvasive diagnostic imaging modalities. Recent studies during the last few recent years have uncovered a plethora of new spatially defined molecular information on several vision-threatening diseases, including age-related macular degeneration, Stargardt disease, glaucoma, cataract, as well as lipid disorders. Even though MS inside the eye cannot be performed noninvasively, by linking diagnostic and molecular information, these studies are the first step toward the development of smart ophthalmic diagnostic and surgical tools. Here, we provide an overview of current approaches applying MSI technology to ocular pathology. PMID- 26586165 TI - Posttranscriptional regulation of cytokine expression. AB - Expression of cytokines and chemokines is regulated at multiple steps during the transfer of the genetic information from DNA sequence to the functional protein. The multilayered control of cytokine expression reflects the need of the immune system to precisely and rapidly adjust the magnitude and duration of immune responses to external cues. Common features of the regulation of cytokine expression are temporal and highly dynamic changes in cytokine mRNA stability. Failures in the timing and extent of mRNA decay can result in disease. Recent advances in transcriptome-wide approaches began to shed light into the complex network of cis-acting sequence elements and trans-acting factors controlling mRNA stability. These approaches led to the discovery of novel unexpected paradigms but they also revealed new questions. This review will discuss the control of cytokine mRNA stability both in the context of high content approaches as well as focused mechanistic studies and animal models. The article highlights the need for systems biology approaches as important means to understand how cytokine mRNA decay helps maintain the immune and tissue homeostasis, and to explore options for therapeutical exploitation of mRNA stability regulation. PMID- 26586166 TI - Peri-ictal water drinking: a rare automatic behaviour in temporal lobe epilepsy. AB - Peri-ictal water drinking (PIWD) has been reported as the action of drinking during or within two minutes of an electroclinical seizure. It is considered a peri-ictal vegetative symptom, evident both during childhood and adulthood epilepsy. The aim of this paper was to describe the clinical and electroencephalographic features of two new adult subjects suffering from symptomatic temporal lobe epilepsy with episodes of PIWD recorded by VIDEO-EEG and to review literature data in order to better define this peculiar event during seizures, a rare and probably underestimated semiological sign. To date, 51 cases with focal epilepsy and seizures associated with PIWD have been reported. All patients presented with temporal lobe epilepsy. All cases but one had symptomatic epilepsy. Most of the patients had an involvement of the right hemisphere. Water drinking was reported as an ictal sign in the majority of patients, and less frequently was reported as postictal. We believe that PIWD might be considered a rare automatic behaviour, like other automatisms. Automatisms are more frequently described in patients with temporal lobe epilepsy. PIWD was reported also to have lateralizing significance in the non dominant temporal lobe, however, because of its rarity, this finding remains unclear. PMID- 26586167 TI - A case of MUC5AC-positive intraductal neoplasm of the pancreas classified as an intraductal tubulopapillary neoplasm? AB - This report describes a unique case of intraductal tubulopapillary neoplasm (ITPN) of the pancreas in order to clarify its oncogenesis and more precisely classify pancreatic intraductal neoplasms. A 74-year-old man visited our institution for follow-up of acute pancreatitis. Imaging examinations revealed a hypovascular intraductal mass in the head of the pancreas with progressive dilation of the pancreatic duct, atrophy of the pancreatic parenchyma, and a non mucinous appearance. A pancreatoduodenectomy was performed to identify this pancreatic intraductal neoplasm. Macroscopically, the tumor was a solid nodular mass with no visibly secreted mucin obstructing the dilated ducts. Histologically, it had a homogeneous appearance with nodules of back-to-back tubular glands and occasional papillary elements, and there were no apparent transitions to areas with less marked cytoarchitectural atypia. Although the intraductal neoplastic growth corresponded to an ITPN, immunohistochemical staining revealed partial positivity for MUC5AC, for which ITPNs are characteristically negative. Somatic mutations in KRAS, GNAS, BRAF, and PIK3CA were not detected. A loss of MUC5AC expression and mutations in KRAS and GNAS are key elements in the diagnosis of ITPN. Thus, it was difficult to distinguish the present case as a pancreatobiliary-type (PB-type) intraductal papillary mucinous neoplasm (IPMN) or a phenotypic variant of ITPN. As it is possible that some cases of PB-type IPMN and ITPN overlap, the precise classification of these rare lesions may require re-evaluation. PMID- 26586168 TI - Frontal space distance in facial clefts and retrognathia at 11-13 weeks' gestation. AB - OBJECTIVE: To examine the frontal space (FS) distance in first-trimester fetuses with bilateral, unilateral or median cleft lip and palate and in those with retrognathia. METHODS: This was a retrospective study using stored two dimensional ultrasound images of fetal profiles that were recorded at the time of the nuchal translucency (NT) scan at three prenatal medical centers. Images of 300 normal fetuses and 53 fetuses with facial defects were obtained. To measure the FS distance, a line was drawn between the anterior edge of the mental protuberance of the mandible and anterior edge of the maxilla (MM line) and extended upwards in front of the forehead. The perpendicular distance (FS distance) between the MM line and the skin at the point of largest excursion of the fetal forehead was measured. In cases in which the MM line was located anteriorly to the forehead, the distance was measured in the same fashion but was multiplied by -1. Two operators measured the FS distance twice, independently of each other. FS distances were transformed into Z-scores based on the linear relationship with crown-rump length (CRL) in normal fetuses. The distribution of FS distances in fetuses with bilateral, unilateral or median cleft lip and palate and those with retrognathia were compared with that in the normal group using Student's t-test. RESULTS: A search of the centers' databases identified 53 abnormal cases including 20, nine and eight with a bilateral, unilateral and median cleft lip and palate, respectively, and 16 cases of retrognathia. In fetuses with bilateral, unilateral and median clefts and those with retrognathia, median delta NT was 1.00 mm, 0.37 mm, 4.00 mm and 0.26 mm, respectively. Among these affected groups, 12 (60.0%), six (66.7%), two (25.0%) and eight (50.0%) fetuses had an abnormal karyotype. In the normal population, FS distance was dependent on CRL measurement (FS = 6.62 - (0.08 * CRL); r = -0.539; P < 0.0001). In fetuses with a bilateral and median cleft and in those with retrognathia, FS distance was significantly different from that in the normal population (all P < 0.0001), however, the difference was not significant in fetuses with unilateral clefts (P = 0.103). The respective Z-scores of FS distance for fetuses with bilateral, unilateral and median clefts and retrognathia were -9.7 +/- 2.0, -3.1 +/- 5.1, 8.2 +/- 3.4 and -7.3 +/- 2.3. Measurements were >= 99(th) and <= 1(st) centiles in all but one (98.1%) case. CONCLUSION: The FS distance appears to be a helpful tool in the detection of facial clefts at 11-13 weeks' gestation. Copyright (c) 2015 ISUOG. Published by John Wiley & Sons Ltd. PMID- 26586169 TI - Acutely deteriorated extravascular volume overload during peripheral blood stem cell mobilization in POEMS syndrome: A case series with cytokine analysis. AB - We describe two cases of polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes (POEMS) syndrome patients with deteriorated extravascular volume overload without increased levels of vascular endothelial growth factor after the administration of cyclophosphamide + granulocyte colony stimulating factor for stem cell mobilization. We then measured the serum levels of 27 cytokines from these cases using a multiplex suspension array system. The analysis revealed the changes of cytokine profiles before cyclophosphamide + granulocyte colony-stimulating factor and after the development of capillary leak symptoms in both cases. This may improve our current level of understanding of the pathogenesis of POEMS syndrome not driven by vascular endothelial growth factor. PMID- 26586170 TI - Blood cell-derived microvesicles with potential pathogenic roles in therapeutic blood components and specialized diagnostic tools in diseases. PMID- 26586171 TI - Translation and validation of the Farsi version of the Wheelchair Outcome Measure (WhOM-Farsi) in individuals with spinal cord injury. AB - BACKGROUND: The Wheelchair Outcome Measure (WhOM) evaluates participation outcomes associated with wheelchair use. While English and French versions of this measure have shown appropriate psychometric properties, it is not clear whether this measure is valid and reliable when used in a culture significantly different from the western culture. OBJECTIVE: To establish validity and reliability for the WhOM-Farsi. METHODS: After a forward-backward translation using the International Quality of Life Assessment process, the WhOM-Farsi was administered to 75 Farsi speakers with spinal cord injury. The WhOM-Farsi was administered on two occasions to examine test-retest reliability. Two therapists rated the measure to evaluate inter-rater reliability. Construct validity was assessed by measuring associations between scores of the WhOM-Farsi, the 12-item short-form health survey (SF-12), the Beck Depression Index (BDI-II) and the Spinal Cord Independence Measure (SCIM-III). RESULTS: The intra class correlation coefficient (ICC) for inter-rater reliability for all scores was 0.99. For test retest, the ICC was 0.91, 0.94 and 0.83 for Sat, Imp * Sat and body function, respectively. As hypothesized the scores were positively correlated with the SF 12 and SCIM-III scores and negatively correlated with the BDI-II scores. CONCLUSIONS: The results illustrated there is evidence to support the validity and reliability of the WhOM-Farsi scores. PMID- 26586172 TI - Factors affecting malnutrition in children and the uptake of interventions to prevent the condition. AB - BACKGROUND: Malnutrition is a major cause of child morbidity and mortality. There are several interventions to prevent the condition but it is unclear how well they are taken up by both malnourished and well nourished children and their mothers and the extent to which this is influenced by socio-economic factors. We examined socio-economic factors, health outcomes and the uptake of interventions to prevent malnutrition by mothers of malnourished and well-nourished in under fives attending Princess Marie Louise Children's Hospital (PML). METHODS: An unmatched case control study of malnourished and well-nourished children and their mothers was conducted at PML, the largest facility for managing malnutrition in Ghanaian children. Malnourished children with moderate and severe acute malnutrition were recruited and compared with a group of well-nourished children attending the hospital. Weight-for-height was used to classify nutritional status. Record forms and a semi-structured questionnaire were used for data collection, which was analysed with Stata 11.0 software. RESULTS: In all, 182 malnourished and 189 well-nourished children and their mothers/carers participated in the study. Children aged 6-12 months old formed more than half of the malnourished children. The socio-demographic factors associated with malnutrition in the multivariate analysis were age <=24 months and a monthly family income of <=200 GH Cedis. Whereas among the health outcomes, low birth weight, an episode of diarrhoea and the presence of developmental delay were associated with malnutrition. Among the interventions, inadequate antenatal visits, faltering growth and not de-worming one's child were associated with malnutrition in the multivariate analysis. Immunisation and Vitamin A supplementation were not associated with malnutrition. Missed opportunities for intervention were encountered. CONCLUSION: Poverty remains an important underlying cause of malnutrition in children attending Princess Marie Louise Children's Hospital. Specific and targeted interventions are needed to address this and must include efforts to prevent low birthweight and diarrhoea, and reduce health inequalities. Regular antenatal clinic attendance, de-worming of children and growth monitoring should also be encouraged. However, further studies are needed on the timing and use of information on growth faltering to prevent severe forms of malnutrition. PMID- 26586173 TI - Chloroplast avoidance movement is not functional in plants grown under strong sunlight. AB - Chloroplast movement in nine climbing plant species was investigated. It is thought that chloroplasts generally escape from strong light to avoid photodamage but accumulate towards weak light to perform photosynthesis effectively. Unexpectedly, however, the leaves of climbing plants grown under strong sunlight showed very low or no chloroplast photorelocation responses to either weak or strong blue light when detected by red light transmittance through leaves. Direct observations of Cayratia japonica leaves, for example, revealed that the average number of chloroplasts in upper periclinal walls of palisade tissue cells was only 1.2 after weak blue-light irradiation and almost all of the chloroplasts remained at the anticlinal wall, the state of chloroplast avoidance response. The leaves grown under strong light have thin and columnar palisade tissue cells comparing with the leaves grown under low light. Depending on our analyses and our schematic model, the thinner cells in a unit leaf area have a wider total plasma membrane area, such that more chloroplasts can exist on the plasma membrane in the thinner cells than in the thicker cells in a unit leaf-area basis. The same strategy might be used in other plant leaves grown under direct sunlight. PMID- 26586174 TI - Plasma proteomic analysis of active and torpid greater mouse-eared bats (Myotis myotis). AB - Hibernation is a physiological adaptation to overcome extreme environmental conditions. It is characterized by prolonged periods of torpor interrupted by temporary arousals during winter. During torpor, body functions are suppressed and restored rapidly to almost pre-hibernation levels during arousal. Although molecular studies have been performed on hibernating rodents and bears, it is unclear how generalizable the results are among hibernating species with different physiology such as bats. As targeted blood proteomic analysis are lacking in small hibernators, we investigated the general plasma proteomic profile of European Myotis myotis and hibernation associated changes between torpid and active individuals by two-dimensional gel electrophoresis. Results revealed an alternation of proteins involved in transport, fuel switching, innate immunity and blood coagulation between the two physiological states. The results suggest that metabolic changes during hibernation are associated with plasma proteomic changes. Further characterization of the proteomic plasma profile identified transport proteins, coagulation proteins and complement factors and detected a high abundance of alpha-fetoprotein. We were able to establish for the first time a basic myotid bat plasma proteomic profile and further demonstrated a modulated protein expression during torpor in Myotis myotis, indicating both novel physiological pathways in bats in general, and during hibernation in particular. PMID- 26586176 TI - DNA-binding protein phosphatase AtDBP1 acts as a promoter of flowering in Arabidopsis. AB - MAIN CONCLUSION: We provide evidence that AtDBP1 promotes flowering by regulating the transcript levels of several important integrators and floral meristem identity genes, including FLC, CO, SOC1, LFY, FT and FD. DNA-binding protein phosphatases (DBP) which exhibit both sequence specific DNA-binding and protein phosphatase 2C activities are important regulators that are involved in both the transcriptional and post-translational regulations. DBP factors are known to mediate susceptibility to potyviruses; however, whether they are involved in other processes is still unclear. In this study, under both long day (LD) and short day conditions, AtDBP1 overexpressing plants displayed early flowering, while the knock out mutants, atdbp1, exhibited a delay in flowering relative to the wild-type plants; both the overexpressing lines and atdbp1 mutants remained photoperiodic sensitive, indicating that AtDBP1 was involved in the autonomous pathway. AtDBP1 does not respond to vernalization at transcript level, and both AtDBP1 overexpressing plants and atdbp1 mutants remain responsive to vernalization, indicating that AtDBP1 may not be directly involved in vernalization. Real-time PCR analysis showed that AtDBP1 can suppress FLOWERING LOCUC C (FLC) expression, a key integrator of the autonomous and vernalization pathways, and enhance the expression levels of CONSTANS and FLOWERING LOCUC T, key regulators of the LD pathway. Furthermore, expression of floral meristem identity genes including SUPPRESSOR OF OVEREXPRESSION OF CO 1, LEAFY and FD was also promoted in AtDBP1 overexpressing plants. AtDBP1 transcription can be detected in root, leaf, stem, flower and silique. AtDBP1-GFP and YFP-AtDBP1 fusion protein were localized in the cytosol and nucleus. Our results provide the evidence demonstrating the effective role of AtDBP1 for flowering time regulation and report a novel function of DBP factors in planta besides in plant defense. PMID- 26586175 TI - Tonsillectomy in a European Cohort of 1,147 Patients with IgA Nephropathy. AB - BACKGROUND: Tonsillectomy has been considered a treatment for IgA nephropathy (IgAN). It is aimed at removing a source of pathogens, reducing mucosa-associated lymphoid tissue and decreasing polymeric IgA synthesis. However, its beneficial effect is still controversial. In Asia, favorable outcomes have been claimed mostly in association with corticosteroids. In Europe, small, single-center uncontrolled studies have failed to show benefits. METHODS: The European validation study of the Oxford classification of IgAN (VALIGA) collected data from 1,147 patients with IgAN over a follow-up of 4.7 years. We investigated the outcome of progression to end-stage renal disease (ESRD) and/or 50% loss of estimated glomerular filtration rate (eGFR) and the annual loss of eGFR in 61 patients who had had tonsillectomy. RESULTS: Using the propensity score, which is a logistic regression model, we paired 41 patients with tonsillectomy and 41 without tonsillectomy with similar risk of progression (gender, age, race, mean blood pressure, proteinuria, eGFR at renal biopsy, previous treatments and Oxford MEST scores). No significant difference was found in the outcome. Moreover, we performed an additional propensity score pairing 17 patients who underwent tonsillectomy after the diagnosis of IgAN and 51 without tonsillectomy with similar risk of progression at renal biopsy and subsequent treatments. No significant difference was found in changes in proteinuria, or in the renal end point of 50% reduction in GFR and/or ESRD, or in the annual loss of eGFR. CONCLUSION: In the large VALIGA cohort of European subjects with IgAN, no significant correlation was found between tonsillectomy and renal function decline. PMID- 26586177 TI - Cisgenic Rvi6 scab-resistant apple lines show no differences in Rvi6 transcription when compared with conventionally bred cultivars. AB - MAIN CONCLUSION: The expression of the apple scab resistance gene Rvi6 in different apple cultivars and lines is not modulated by biotic or abiotic factors. All commercially important apple cultivars are susceptible to Venturia inaequalis, the causal organism of apple scab. A limited number of apple cultivars were bred to express the resistance gene Vf from the wild apple genotype Malus floribunda 821. Positional cloning of the Vf locus allowed the identification of the Rvi6 (formerly HcrVf2) scab resistance gene that was subsequently used to generate cisgenic apple lines. It is important to understand and compare how this resistance gene is transcribed and modulated during infection in conventionally bred cultivars and in cisgenic lines. The aim of this work was to study the transcription pattern of Rvi6 in three classically bred apple cultivars and six lines of 'Gala' genetically modified to express Rvi6. Rvi6 transcription was analyzed at two time points using quantitative real-time PCR (RT-qPCR) following inoculation with V. inaequalis conidia or water. Rvi6 transcription was assessed in relation to five reference genes. beta-Actin, RNAPol, and UBC were the most suited to performing RT-qPCR experiments on Malus * domestica. Inoculation with V. inaequalis conidia under conditions conducive to scab infection failed to produce any significant changes to the transcription level of Rvi6. Rvi6 expression levels were inconsistent in response to external treatments in the different apple cultivars, and transgenic, intragenic or cisgenic lines. PMID- 26586178 TI - Delaminated montmorillonite with iron(III)-TiO2 species as a photocatalyst for removal of a textile azo-dye from aqueous solution. AB - A set of mesoporous delaminated montmorillonites containing iron(III)-titanium oxide species was synthesized using two minerals: a bentonite as support and an ilmenite as source of Fe-TiO2 species. Several values of both sulphuric acid concentration and temperature were employed to extract Fe-TiO2 species from an ilmenite. Analyses by X-ray fluorescence, X-ray diffraction, scanning electron microscopy and nitrogen adsorption-desorption confirmed the successful formation of delaminated (or exfoliated) mesoporous structures. Optical properties of solids were determined by UV-Vis diffuse reflectance spectroscopy, and their band gap energy values were also calculated. A small UV-shift of band gap values regarding that of commercial photo-active TiO2 was detected as consequence of the quantum size effect, suggesting that photocatalytic experiments should be performed under UV-radiation assistance. The synthesized solids showed good activity in the photocatalytic oxidation of a textile dye (reactive yellow 145: RY 145), achieving conversions higher than 70% and chemical oxygen demand removal between 60% and 80%. PMID- 26586180 TI - Delayed Unilateral Coronal Synostosis Following Metopic Synostosis Repair. PMID- 26586179 TI - Mycobacterial infection induces a specific human innate immune response. AB - The innate immune system provides the first response to infection and is now recognized to be partially pathogen-specific. Mycobacterium tuberculosis (MTB) is able to subvert the innate immune response and survive inside macrophages. Curiously, only 5-10% of otherwise healthy individuals infected with MTB develop active tuberculosis (TB). We do not yet understand the genetic basis underlying this individual-specific susceptibility. Moreover, we still do not know which properties of the innate immune response are specific to MTB infection. To identify immune responses that are specific to MTB, we infected macrophages with eight different bacteria, including different MTB strains and related mycobacteria, and studied their transcriptional response. We identified a novel subset of genes whose regulation was affected specifically by infection with mycobacteria. This subset includes genes involved in phagosome maturation, superoxide production, response to vitamin D, macrophage chemotaxis, and sialic acid synthesis. We suggest that genetic variants that affect the function or regulation of these genes should be considered candidate loci for explaining TB susceptibility. PMID- 26586181 TI - Flexible Sensory Representations in Auditory Cortex Driven by Behavioral Relevance. AB - Animals require the ability to ignore sensory stimuli that have no consequence yet respond to the same stimuli when they become useful. However, the brain circuits that govern this flexibility in sensory processing are not well understood. Here we show in mouse primary auditory cortex (A1) that daily passive sound exposure causes a long-lasting reduction in representations of the experienced sound by layer 2/3 pyramidal cells. This habituation arises locally in A1 and involves an enhancement in inhibition and selective upregulation in the activity of somatostatin-expressing inhibitory neurons (SOM cells). Furthermore, when mice engage in sound-guided behavior, pyramidal cell excitatory responses to habituated sounds are enhanced, whereas SOM cell responses are diminished. Together, our results demonstrate the bidirectional modulation of A1 sensory representations and suggest that SOM cells gate cortical information flow based on the behavioral relevance of the stimulus. PMID- 26586182 TI - Sufficiency of Mesolimbic Dopamine Neuron Stimulation for the Progression to Addiction. AB - The factors causing the transition from recreational drug consumption to addiction remain largely unknown. It has not been tested whether dopamine (DA) is sufficient to trigger this process. Here we use optogenetic self-stimulation of DA neurons of the ventral tegmental area (VTA) to selectively mimic the defining commonality of addictive drugs. All mice readily acquired self-stimulation. After weeks of abstinence, cue-induced relapse was observed in parallel with a potentiation of excitatory afferents onto D1 receptor-expressing neurons of the nucleus accumbens (NAc). When the mice had to endure a mild electric foot shock to obtain a stimulation, some stopped while others persevered. The resistance to punishment was associated with enhanced neural activity in the orbitofrontal cortex (OFC) while chemogenetic inhibition of the OFC reduced compulsivity. Together, these results show that stimulating VTA DA neurons induces behavioral and cellular hallmarks of addiction, indicating sufficiency for the induction and progression of the disease. PMID- 26586184 TI - Developmental Axon Pruning Requires Destabilization of Cell Adhesion by JNK Signaling. AB - Developmental axon pruning is essential for normal brain wiring in vertebrates and invertebrates. How axon pruning occurs in vivo is not well understood. In a mosaic loss-of-function screen, we found that Bsk, the Drosophila JNK, is required for axon pruning of mushroom body gamma neurons, but not their dendrites. By combining in vivo genetics, biochemistry, and high-resolution microscopy, we demonstrate that the mechanism by which Bsk is required for pruning is through reducing the membrane levels of the adhesion molecule Fasciclin II (FasII), the NCAM ortholog. Conversely, overexpression of FasII is sufficient to inhibit axon pruning. Finally, we show that overexpressing other cell adhesion molecules, together with weak attenuation of JNK signaling, strongly inhibits pruning. Taken together, we have uncovered a novel and unexpected interaction between the JNK pathway and cell adhesion and found that destabilization of cell adhesion is necessary for efficient pruning. PMID- 26586183 TI - Convergence, Divergence, and Reconvergence in a Feedforward Network Improves Neural Speed and Accuracy. AB - One of the proposed canonical circuit motifs employed by the brain is a feedforward network where parallel signals converge, diverge, and reconverge. Here we investigate a network with this architecture in the Drosophila olfactory system. We focus on a glomerulus whose receptor neurons converge in an all-to-all manner onto six projection neurons that then reconverge onto higher-order neurons. We find that both convergence and reconvergence improve the ability of a decoder to detect a stimulus based on a single neuron's spike train. The first transformation implements averaging, and it improves peak detection accuracy but not speed; the second transformation implements coincidence detection, and it improves speed but not peak accuracy. In each case, the integration time and threshold of the postsynaptic cell are matched to the statistics of convergent spike trains. PMID- 26586185 TI - The early acquisition of viable knowledge: A use of recursive model as an analytical devise (methodolosocial). AB - In nurse education typically, information is presented to students within the classroom and then applied within a clinical situation. Acquisition of the knowledge required to inform the student's early practice is the focus of this research. This paper centres upon the construction of a cognitive model that is recursive in nature, and forms an integral part of a qualitative research study. The primary study investigated how first year student nurses use the information received in the classroom to underpin their early practice. Data were collected from 10 students and 4 of their lecturers, via blogs and interviews and used iteratively to create a model that is recursive in nature. Recursion is a process of repeatedly revisiting the same thing, in this case the data, which are considered in an iterative or progressive way. Recursion thus facilitated the development of a model, which was seen to change and develop in sophistication as more data were considered and evaluated. Visual devices were used throughout to bring clarity during the construction of the model. This visual process was pivotal to the analysis. This paper chronicles the development of an analytical device through the medium of the study presented. Viable knowledge is represented as the synthesis of concepts, as presented in the classroom, and practice, as experienced within the clinical area. It illustrates how conceptual material delivered within the classroom has become embedded within an individual student's consciousness and is used during a clinical placement to make sense of a specific situation. The study identifies how students use information and makes recommendations as to how appropriate curricula integrate all the facets of the recursive model. The process of recursive modelling is thus offered as an analytical devise, which may be applied by researchers to other qualitative data. PMID- 26586186 TI - C. elegans maximum velocity correlates with healthspan and is maintained in worms with an insulin receptor mutation. AB - Ageing is marked by physical decline. Caenorhabditis elegans is a valuable model for identifying genetic regulatory mechanisms of ageing and longevity. Here we report a simple method to assess C. elegans' maximum physical ability based on the worms' maximum movement velocity. We show maximum velocity declines with age, correlates well with longevity, accurately reports movement ability and, if measured in mid-adulthood, is predictive of maximal lifespan. Contrary to recent findings, we observe that maximum velocity of worm with mutations in daf-2(e1370) insulin/IGF-1 signalling scales with lifespan. Because of increased odorant receptor expression, daf-2(e1370) mutants prefer food over exploration, causing previous on-food motility assays to underestimate movement ability and, thus, worm health. Finally, a disease-burden analysis of published data reveals that the daf-2(e1370) mutation improves quality of life, and therefore combines lifespan extension with various signs of an increased healthspan. PMID- 26586187 TI - Oscillatory stress stimulation uncovers an Achilles' heel of the yeast MAPK signaling network. AB - Cells must interpret environmental information that often changes over time. In our experiment, we systematically monitored the growth of yeast cells under various frequencies of oscillating osmotic stress. Growth was severely inhibited at a particular resonance frequency, at which cells show hyperactivated transcriptional stress responses. This behavior represents a sensory misperception: The cells incorrectly interpret oscillations as a staircase of ever-increasing osmolarity. The misperception results from the capacity of the osmolarity-sensing mitogen-activated protein kinase (MAPK) network to retrigger with sequential osmotic stresses. Although this feature is critical for coping with natural challenges, such as continually increasing osmolarity, it results in a trade-off of fragility to non-natural oscillatory inputs that match the retriggering time. These findings demonstrate the value of non-natural dynamic perturbations in exposing hidden sensitivities of cellular regulatory networks. PMID- 26586188 TI - High-speed recording of neural spikes in awake mice and flies with a fluorescent voltage sensor. AB - Genetically encoded voltage indicators (GEVIs) are a promising technology for fluorescence readout of millisecond-scale neuronal dynamics. Previous GEVIs had insufficient signaling speed and dynamic range to resolve action potentials in live animals. We coupled fast voltage-sensing domains from a rhodopsin protein to bright fluorophores through resonance energy transfer. The resulting GEVIs are sufficiently bright and fast to report neuronal action potentials and membrane voltage dynamics in awake mice and flies, resolving fast spike trains with 0.2 millisecond timing precision at spike detection error rates orders of magnitude better than previous GEVIs. In vivo imaging revealed sensory-evoked responses, including somatic spiking, dendritic dynamics, and intracellular voltage propagation. These results empower in vivo optical studies of neuronal electrophysiology and coding and motivate further advancements in high-speed microscopy. PMID- 26586189 TI - Cell nonautonomous activation of flavin-containing monooxygenase promotes longevity and health span. AB - Stabilization of the hypoxia-inducible factor 1 (HIF-1) increases life span and health span in nematodes through an unknown mechanism. We report that neuronal stabilization of HIF-1 mediates these effects in Caenorhabditis elegans through a cell nonautonomous signal to the intestine, which results in activation of the xenobiotic detoxification enzyme flavin-containing monooxygenase-2 (FMO-2). This prolongevity signal requires the serotonin biosynthetic enzyme TPH-1 in neurons and the serotonin receptor SER-7 in the intestine. Intestinal FMO-2 is also activated by dietary restriction (DR) and is necessary for DR-mediated life-span extension, which suggests that this enzyme represents a point of convergence for two distinct longevity pathways. FMOs are conserved in eukaryotes and induced by multiple life span-extending interventions in mice, which suggests that these enzymes may play a critical role in promoting health and longevity across phyla. PMID- 26586191 TI - International expert consensus conference on testosterone deficiency and its treatment held in Prague, Czech Republic. AB - An international expert consensus conference regarding testosterone deficiency (TD) (also known as hypogonadism) and its treatment was held on 1 October 2015, in Prague, Czech Republic. The impetus for this meeting was to address several key scientific issues that have been misunderstood or distorted during the recent intense media attention to this topic. Eighteen experts from 11 countries participated, from the disciplines of urology, endocrinology, andrology, diabetology, and basic science research. The goal was to identify scientific concepts for which there was broad agreement. It was noted that recent public controversies regarding testosterone therapy have been anchored by two retrospective studies reporting increased cardiovascular (CV) risks. Both these studies contained major flaws, and are contradicted by a large body of evidence suggesting CV benefits with testosterone therapy. Other topics discussed included the negative impact of TD on male health; the questionable validity of restrictions on treatment based on age-specific cut-offs, presence of identified underlying conditions, or application of rigid biochemical thresholds; and the lack of evidence regarding prostate cancer risks. Final consensus statements (resolutions) are under development. It is hoped these will serve as a scientific foundation for further discussion, and will thereby reduce misinformation regarding TD and its treatment. PMID- 26586190 TI - Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway. AB - Eukaryotic cells coordinate growth with the availability of nutrients through the mechanistic target of rapamycin complex 1 (mTORC1), a master growth regulator. Leucine is of particular importance and activates mTORC1 via the Rag guanosine triphosphatases and their regulators GATOR1 and GATOR2. Sestrin2 interacts with GATOR2 and is a leucine sensor. Here we present the 2.7 angstrom crystal structure of Sestrin2 in complex with leucine. Leucine binds through a single pocket that coordinates its charged functional groups and confers specificity for the hydrophobic side chain. A loop encloses leucine and forms a lid-latch mechanism required for binding. A structure-guided mutation in Sestrin2 that decreases its affinity for leucine leads to a concomitant increase in the leucine concentration required for mTORC1 activation in cells. These results provide a structural mechanism of amino acid sensing by the mTORC1 pathway. PMID- 26586192 TI - Biofilms produced by Burkholderia cenocepacia: influence of media and solid supports on composition of matrix exopolysaccharides. AB - Bacteria usually grow forming biofilms, which are communities of cells embedded in a self-produced dynamic polymeric matrix, characterized by a complex three dimensional structure. The matrix holds cells together and above a surface, and eventually releases them, resulting in colonization of other surfaces. Although exopolysaccharides (EPOLs) are important components of the matrix, determination of their structure is usually performed on samples produced in non-biofilm conditions, or indirectly through genetic studies. Among the Burkholderia cepacia complex species, Burkholderia cenocepacia is an important pathogen in cystic fibrosis (CF) patients and is generally more aggressive than other species. In the present investigation, B. cenocepacia strain BTS2, a CF isolate, was grown in biofilm mode on glass slides and cellulose membranes, using five growth media, one of which mimics the nutritional content of CF sputum. The structure of the matrix EPOLs was determined by 1H-NMR spectroscopy, while visualization of the biofilms on glass slides was obtained by means of confocal laser microscopy, phase-contrast microscopy and atomic force microscopy. The results confirmed that the type of EPOLs biosynthesized depends both on the medium used and on the type of support, and showed that mucoid conditions do not always lead to significant biofilm production, while bacteria in a non-mucoid state can still form biofilm containing EPOLs. PMID- 26586193 TI - Telepsychiatry: Benefits and costs in a changing health-care environment. AB - In the USA, the high cost and inefficiencies of the health care system have prompted widespread demand for a better value on investment. Reform efforts, focused on increasing effective, cost-efficient, and patient-centred practices, are inciting lasting changes to health care delivery. Integrated care, providing team-based care that addresses both physical and behavioural health needs is growing as an evidence-based way to provide improved care with lower overall costs. This in turn, is leading to an increasing demand for psychiatrists to work with primary care physicians in delivering integrated care. Telepsychiatry is an innovative platform that has a variety of benefits to patients, providers, and systems. Associated costs are changing as technology advances and policies shift. The purpose of this article is to describe the changing role of psychiatry within the environment of U.S. healthcare reform, and the benefits (demonstrated and potential) and costs (fixed, variable, and reimbursable) of telepsychiatry to providers, patients and systems. PMID- 26586194 TI - Surgical results of metastatic spinal cord compression (MSCC) from non-small cell lung cancer (NSCLC): analysis of functional outcome, survival time, and complication. AB - BACKGROUND CONTEXT: A number of studies have reported favorable surgical results for metastatic spinal tumors from various solid tumors. However, there are few data available on metastatic spinal cord compression (MSCC) from lung cancer despite its considerable frequency. PURPOSE: The study aims to present the functional outcomes, survival time, and complications after surgical treatment for MSCC from non-small cell lung cancer (NSCLC). STUDY DESIGN/SETTING: This is a longitudinal observational study. PATIENT SAMPLE: The study includes 50 patients who had neurologic deficit and underwent surgical treatment for MSCC from NSCLC. OUTCOME MEASURES: The Eastern Cooperative Oncology Group performance status (ECOG PS), ambulatory status, overall survival, factors associated with survival time, and perioperative complications were analyzed. METHODS: The postoperative changes of ECOG-PS and ambulatory status were assessed. The factors affecting postoperative ambulatory status were evaluated using logistic regression analysis. Survival time was calculated using the Kaplan-Meier method. To identify the prognostic factors, log-rank test and Cox hazards regression model were used for univariate and multivariate analyses, respectively. Major complications within postoperative 30 days and mortality rate were recorded. RESULTS: The study cohort consisted of 27 males and 23 females with a mean age of 58.0+/-11.3 years at the time of surgery. An ECOG-PS improvement by at least one grade was observed in 33 of 50 cases (66.0%). Among 39 patients who were not ambulatory before surgery, 23 patients (59.0%) regained ambulatory ability after surgery. Patients who were preoperatively ambulant and those who underwent surgery within 72 hours from neurologic deficit had an increased chance of postoperative ambulation. The median for overall survival after surgery was 5.2 months. Five prognostic factors were identified on univariate analysis: time from neurologic deficit, responsiveness to preoperative chemotherapy, postoperative chemotherapy, postoperative ECOG-PS, and postoperative ambulatory status. Multivariate analysis revealed that time to neurologic deficit (risk ratio [RR]: 2.28, p=.023), postoperative chemotherapy (RR: 6.58, p<.001), and postoperative ECOG-PS (RR: 2.73, p=.040) were independent prognostic factors of survival time. Major complications developed in 34.0% of patients (17 of 50), and the 30-day mortality rate was 10.0% (5 of 50). CONCLUSIONS: Functional improvements were observed through surgical treatment even with relatively high complication rates for MSCC from NSCLC. Earlier surgical treatment could act as an adjuvant therapy for prolonging survival by improving functional status. PMID- 26586195 TI - Cervical digit: a rare developmental anomaly. PMID- 26586196 TI - Effect of in ovo feeding of folic acid on the folate metabolism, immune function and epigenetic modification of immune effector molecules of broiler. AB - This study was conducted to investigate the effect of in ovo feeding (IOF) of folic acid on the folate metabolism, immune function and the involved epigenetic modification of broilers. A total of 400 (Cobb) hatching eggs were randomly divided into four groups (0, 50, 100 and 150 ug injection of folic acid at embryonic age 11 d), and chicks hatched from each treatment were randomly divided into six replicates with 12 broilers/replicate after incubation. The results indicated that, in ovo, 100- and 150-ug folic acid injections improved the hatchability. The average daily gain and feed conversion ratio increased in the 150-ug group during the late growth stage. Simultaneously, in the 100- and 150-ug groups, an increase was observed in hepatic folate content and the expression of methylenetetrahydrofolate reductase (d1 and 42) and methionine synthase reductase (d21). IgG and IgM concentrations, as well as plasma lysozyme activity of broilers, showed a marked increase along with increasing folic acid levels. The splenic expression levels of IL-2 and IL-4 were up-regulated, whereas that of IL 6 was down-regulated, in the 100- and 150-ug folic acid treatment groups. In addition, histone methylation in IL-2 and IL-4 promoters exhibited an enrichment of H3K4m2 but a loss of H3K9me2 with the increased amount of folic acid additive. In contrast, a decrease in H3K4m2 and an increase in H3K9me2 were observed in the IL-6 promoter in folic acid treatments. Furthermore, in ovo, the 150-ug folic acid injection improved the chromatin tightness of the IL-2 and IL-4 promoter regions. Our findings suggest that IOF of 150 ug of folic acid can improve the growth performance and folate metabolism of broilers, and enhance the relationship between immune function and epigenetic regulation of immune genes, which are involved with the alterations in chromatin conformation and histone methylation in their promoters. PMID- 26586198 TI - Overview of current surgical strategies for aortic disease in patients with Marfan syndrome. AB - Marfan syndrome is a heritable, systemic disorder of the connective tissue with a high penetrance, named after Dr. Antoine Marfan. The most clinically important manifestations of this syndrome are cardiovascular pathologies which cause life threatening events, such as acute aortic dissections, aortic rupture and regurgitation of the aortic valve or other artrioventricular valves leading to heart failure. These events play important roles in the life expectancy of patients with this disorder, especially prior to the development of effective surgical approaches for proximal ascending aortic disease. To prevent such catastrophic aortic events, a lower threshold has been recommended for prophylactic interventions on the aortic root. After prophylactic root replacement, disease in the aorta beyond the root and distal to the arch remains a cause for concern. Multiple surgeries are required throughout a patient's lifetime that can be problematic due to distal lesions complicated by dissection. Many controversies in surgical strategies remain, such as endovascular repair, to manage such complex cases. This review examines the trends in surgical strategies for the treatment of cardiovascular disease in patients with Marfan syndrome, and current perspectives in this field. PMID- 26586200 TI - The brain expressed x-linked gene 1 (Bex1) regulates myoblast fusion. AB - Skeletal muscle development (myogenesis) is a complex but precisely orchestrated process involving spatiotemporal regulation of the proliferation, differentiation and fusion of myogenic progenitor cells (myoblasts). Here we identify brain expressed x-linked gene 1 (Bex1) as a transient, developmentally regulated gene involved in myoblast fusion. Bex1 expression is undetectable in adult muscles or in quiescent muscle stem cells (satellite cells). During embryonic myogenesis, however, Bex1 is robustly expressed by myogenin(+) differentiating myoblasts, but not by Pax7(+) proliferating myoblasts. Interestingly, Bex1 is initially localized in the cytoplasm and then translocates into the nucleus. During adult muscle regeneration, Bex1 is highly expressed in newly regenerated myofibers and the expression is rapidly downregulated during maturation. Consistently, in cultured myoblasts, Bex1 is not expressed at the proliferation stage but transiently expressed upon induction of myogenic differentiation, following a similar cytoplasm to nucleus translocation pattern as seen in vivo. Using gain- and loss-of-function studies, we found that overexpression of Bex1 promotes the fusion of primary myoblasts without affecting myogenic differentiation and myogenin expression. Conversely, Bex1 knockout myoblasts exhibit obvious fusion defects, even though they express normal levels of myogenin and differentiate normally. These results elucidate a novel role of Bex1 in myogenesis through regulating myoblast fusion. PMID- 26586199 TI - Complex regulation of HSC emergence by the Notch signaling pathway. AB - Hematopoietic stem cells are formed during embryonic development, and serve as the foundation of the definitive blood program for life. Notch signaling has been well established as an essential direct contributor to HSC specification. However, several recent studies have indicated that the contribution of Notch signaling is complex. HSC specification requires multiple Notch signaling inputs, some received directly by hematopoietic precursors, and others that occur indirectly within neighboring somites. Of note, proinflammatory signals provided by primitive myeloid cells are needed for HSC specification via upregulation of the Notch pathway in hemogenic endothelium. In addition to multiple requirements for Notch activation, recent studies indicate that Notch signaling must subsequently be repressed to permit HSC emergence. Finally, Notch must then be reactivated to maintain HSC fate. In this review, we discuss the growing understanding of the dynamic contributions of Notch signaling to the establishment of hematopoiesis during development. PMID- 26586202 TI - Do you have the nerves to regenerate? The importance of neural signalling in the regeneration process. AB - The importance of nerve-derived signalling for correct regeneration has been the topic of research for more than a hundred years, but we are just beginning to identify the underlying molecular pathways of this process. Within the current review, we attempt to provide an extensive overview of the neural influences during early and late phases of both vertebrate and invertebrate regeneration. In general, denervation impairs limb regeneration, but the presence of nerves is not essential for the regeneration of aneurogenic extremities. This observation led to the "neurotrophic factor(s) hypothesis", which states that certain trophic factors produced by the nerves are necessary for proper regeneration. Possible neuron-derived factors which regulate regeneration as well as the denervation affected processes are discussed. PMID- 26586201 TI - Ibuprofen slows migration and inhibits bowel colonization by enteric nervous system precursors in zebrafish, chick and mouse. AB - Hirschsprung Disease (HSCR) is a potentially deadly birth defect characterized by the absence of the enteric nervous system (ENS) in distal bowel. Although HSCR has clear genetic causes, no HSCR-associated mutation is 100% penetrant, suggesting gene-gene and gene-environment interactions determine HSCR occurrence. To test the hypothesis that certain medicines might alter HSCR risk we treated zebrafish with medications commonly used during early human pregnancy and discovered that ibuprofen caused HSCR-like absence of enteric neurons in distal bowel. Using fetal CF-1 mouse gut slice cultures, we found that ibuprofen treated enteric neural crest-derived cells (ENCDC) had reduced migration, fewer lamellipodia and lower levels of active RAC1/CDC42. Additionally, inhibiting ROCK, a RHOA effector and known RAC1 antagonist, reversed ibuprofen effects on migrating mouse ENCDC in culture. Ibuprofen also inhibited colonization of Ret+/- mouse bowel by ENCDC in vivo and dramatically reduced bowel colonization by chick ENCDC in culture. Interestingly, ibuprofen did not affect ENCDC migration until after at least three hours of exposure. Furthermore, mice deficient in Ptgs1 (COX 1) and Ptgs2 (COX 2) had normal bowel colonization by ENCDC and normal ENCDC migration in vitro suggesting COX-independent effects. Consistent with selective and strain specific effects on ENCDC, ibuprofen did not affect migration of gut mesenchymal cells, NIH3T3, or WT C57BL/6 ENCDC, and did not affect dorsal root ganglion cell precursor migration in zebrafish. Thus, ibuprofen inhibits ENCDC migration in vitro and bowel colonization by ENCDC in vivo in zebrafish, mouse and chick, but there are cell type and strain specific responses. These data raise concern that ibuprofen may increase Hirschsprung disease risk in some genetically susceptible children. PMID- 26586204 TI - Functionalizations of Mixtures of Regioisomeric Aryllithium Compounds by Selective Trapping with Dichlorozirconocene. AB - The reaction of mixtures of aryllithium regioisomers obtained either by directed lithiation or by Br/Li exchange with substoichiometric amounts of Cp2ZrCl2 proceeds with high regioselectivity. The least sterically hindered regioisomeric aryllithium is selectively transmetalated to the corresponding arylzirconium species leaving the more hindered aryllithium ready for various reactions with electrophiles. As an application, these regioselective transmetalations from Li to Zr were used to prepare all three lithiated regioisomers of 1,3 bis(trifluoromethyl)benzene. PMID- 26586203 TI - Clinical Utility of Diagnostic Laboratory Tests in Dogs with Acute Pancreatitis: A Retrospective Investigation in a Primary Care Hospital. AB - BACKGROUND: Acute pancreatitis (AP) occurs frequently in dogs, but most previous studies examining the diagnosis of AP have used data from secondary care hospitals. HYPOTHESIS/OBJECTIVES: The aim of this study was to investigate the clinical utility of diagnostic laboratory tests in dogs with AP in a primary care hospital. ANIMALS: Sixty-four dogs with clinical signs suggestive of AP diagnosed with nonpancreatic disease (NP) or AP. METHODS: Medical records were retrospectively reviewed, including diagnostic laboratory tests considered potentially useful in the diagnosis of AP. The diagnostic accuracy of amylase and FUJI DRI-CHEM lipase (FDC lip) were investigated using receiver operating characteristics (ROC). In addition, we verified whether diagnostic laboratory tests were useful for evaluating duration of hospitalization and as biomarkers for monitoring recovery. RESULTS: Activities of amylase and FDC lip were significantly higher in the AP group than in the NP group (P = .001, P < .001, respectively). The sensitivity of FDP lip activity for diagnosing AP was 100% (95% confidence interval [CI], 87.7-100%); the specificity was 89.5% (95% CI, 66.9-98.7%). Area under the ROC curve for FDC lip activity was 0.98 (95% CI, 0.93 1). High alanine aminotransferase (ALT) activity was associated with extended duration of hospitalization (P = .04). A significant difference in C-reactive protein (CRP) concentration before and 5 days after treatment was found (P = .001). CONCLUSIONS AND CLINICAL IMPORTANCE: Measurement of FDC lip activity appears useful for diagnosing AP. High ALT activity might be associated with prolonged duration of hospitalization, and CRP might be useful as a biomarker for monitoring recovery from AP. PMID- 26586205 TI - Majorana zero modes in the hopping-modulated one-dimensional p-wave superconducting model. AB - We investigate the one-dimensional p-wave superconducting model with periodically modulated hopping and show that under time-reversal symmetry, the number of the Majorana zero modes (MZMs) strongly depends on the modulation period. If the modulation period is odd, there can be at most one MZM. However if the period is even, the number of the MZMs can be zero, one and two. In addition, the MZMs will disappear as the chemical potential varies. We derive the condition for the existence of the MZMs and show that the topological properties in this model are dramatically different from the one with periodically modulated potential. PMID- 26586206 TI - Obestatin promotes proliferation and survival of adult hippocampal progenitors and reduces amyloid-beta-induced toxicity. AB - The ghrelin gene-derived peptide obestatin promotes survival in different cell types through a yet undefined receptor; however, its potential neuroprotective activities are still unknown. Here, obestatin effects were investigated on proliferation and survival of adult rat hippocampal progenitor cells (AHPs). Obestatin immunoreactivity was found in AHPs; moreover, obestatin binding to AHPs was displaced by the GLP-1R agonist Ex-4 and antagonist Ex-9. Furthermore, obestatin increased cell proliferation and survival in growth factor deprived medium and inhibited apoptosis; these effects were blocked by Ex-9. The underlying mechanisms involved Galphas/cAMP/PKA/CREB signaling, phosphorylation of ERK1/2 and PI3K/Akt, and the PI3K targets GSK-3beta/beta-catenin and mTOR. Obestatin also counteracted Abeta1-42-induced detrimental effects through inhibition of GSK-3beta activity and Tau hyperphosphorylation, main hallmarks of neuronal death in Alzheimer's disease. These findings indicate a novel protective role for obestatin in AHPs and candidate this peptide as potential therapeutic target for increasing neurogenesis and for approaching neurodegenerative disorders. PMID- 26586207 TI - Anandamide acts via kisspeptin in the regulation of testicular activity of the frog, Pelophylax esculentus. AB - In the frog Pelophylax esculentus, the endocannabinoid anandamide (AEA) modulates Gonadotropin Releasing Hormone (GnRH) system in vitro and down-regulates steroidogenic enzymes in vivo. Thus, male frogs were injected with AEA +/- SR141716A, a cannabinoid receptor 1 (CB1) antagonist, to evaluate possible effects on GnRH and Kiss1/Gpr54 systems, gonadotropin receptors and steroid levels. In frog diencephalons, AEA negatively affected both GnRH and Kiss1/Gpr54 systems. In testis, AEA induced the expression of gonadotropin receptors, cb1, gnrh2 and gnrhr3 meanwhile reducing gnrhr2 mRNA and Kiss1/Gpr54 proteins. Furthermore, aromatase (Cyp19) expression increased in parallel to testosterone decrease and estradiol increase. In vitro treatment of testis with AEA revealed direct effects on Cyp19 and induced the expression of the AEA-degrading enzyme Faah. Lastly, AEA effects on Faah were counteracted by the antiestrogen ICI182780, indicating estradiol mediated effect. In conclusion, for the first time we show in a vertebrate that AEA regulates testicular activity through kisspeptin system. PMID- 26586208 TI - Scrutinising the regulators of syncytialization and their expression in pregnancy related conditions. AB - The placenta is important for the success of gestation and foetal development. In fact, this specialized pregnancy organ is essential for foetal nourishment, support, and protection. In the placenta, there are different cell populations, including four subtypes of trophoblasts. Cytotrophoblasts fuse and differentiate into the multinucleated syncytiotrophoblast (syncytialization). Syncytialization is a hallmark of placentation and is highly regulated by numerous molecules with distinct roles. Placentas from pregnancies complicated by preeclampsia, intrauterine growth restriction or trisomy 21 have been associated with a defective syncytialization and an altered expression of its modulators. This work proposes to review the molecules that promote or inhibit both fusion and biochemical differentiation of cytotrophoblasts. Moreover, it will also analyse the syncytialization modulators abnormally expressed in pathological placentas, highlighting the molecules that may contribute to the aetiology of these diseases. PMID- 26586209 TI - Comprehensive transcriptomic analysis of the process of gonadal sex differentiation in the turbot (Scophthalmus maximus). AB - The turbot is a flatfish with a ZW/ZZ sex determination system but with a still unknown sex determining gene(s), and with a marked sexual growth dimorphism in favor of females. To better understand sexual development in turbot we sampled young turbot encompassing the whole process of gonadal differentiation and conducted a comprehensive transcriptomic study on its sex differentiation using a validated custom oligomicroarray. Also, the expression profiles of 18 canonical reproduction-related genes were studied along gonad development. The expression levels of gonadal aromatase cyp19a1a alone at three months of age allowed the accurate and early identification of sex before the first signs of histological differentiation. A total of 56 differentially expressed genes (DEG) that had not previously been related to sex differentiation in fish were identified within the first three months of age, of which 44 were associated with ovarian differentiation (e.g., cd98, gpd1 and cry2), and 12 with testicular differentiation (e.g., ace, capn8 and nxph1). To identify putative sex determining genes, ~4.000 DEG in juvenile gonads were mapped and their positions compared with that of previously identified sex- and growth-related quantitative trait loci (QTL). Although no genes mapped to the previously identified sex related QTLs, two genes (foxl2 and 17betahsd) of the canonical reproduction related genes mapped to growth-QTLs in linkage group (LG) 15 and LG6, respectively, suggesting that these genes are related to the growth dimorphism in this species. PMID- 26586210 TI - The oxytocin receptor antagonist, Atosiban, activates pro-inflammatory pathways in human amnion via G(alphai) signalling. AB - Oxytocin (OT) plays an important role in the onset of human labour by stimulating uterine contractions and promoting prostaglandin/inflammatory cytokine synthesis in amnion via oxytocin receptor (OTR) coupling. The OTR-antagonist, Atosiban, is widely used as a tocolytic for the management of acute preterm labour. We found that in primary human amniocytes, Atosiban (10 MUM) signals via PTX-sensitive Galphai to activate transcription factor NF-kappaB p65, ERK1/2, and p38 which subsequently drives upregulation of the prostaglandin synthesis enzymes, COX-2 and phospho-cPLA2 and excretion of prostaglandins (PGE2) (n = 6; p < 0.05, ANOVA). Moreover, Atosiban treatment increased expression and excretion of the inflammatory cytokines, IL-6 and CCL5. We also showed that OT-simulated activation of NF-kappaB, ERK1/2, and p38 and subsequent prostaglandin and inflammatory cytokine synthesis is via Galphai-2 and Galphai-3 but not Galphaq, and is not inhibited by Atosiban. Activation or exacerbation of inflammation is not a desirable effect of tocolytics. Therefore therapeutic modulation of the OT/OTR system for clinical management of term/preterm labour should consider the effects of differential G-protein coupling of the OTR and the role of OT or selective OTR agonists/antagonists in activating proinflammatory pathways. PMID- 26586211 TI - Osteoblasts promote castration-resistant prostate cancer by altering intratumoral steroidogenesis. AB - The skeleton is the preferred site for prostate cancer (PC) metastasis leading to incurable castration-resistant disease. The increased expression of genes encoding steroidogenic enzymes found in bone metastatic tissue from patients suggests that up-regulated steroidogenesis might contribute to tumor growth at the metastatic site. Because of the overall sclerotic phenotype, we hypothesize that osteoblasts regulate the intratumoral steroidogenesis of castration resistant prostate cancer (CRPC) in bone. We here show that osteoblasts alter the steroidogenic transcription program in CRPC cells, closely mimicking the gene expression pattern described in CRPC. Osteoblast-stimulated LNCaP-19 cells displayed an increased expression of genes encoding for steroidogenic enzymes (CYP11A1, HSD3B1, and AKR1C3), estrogen signaling-related genes (CYP19A1, and ESR2), and genes for DHT-inactivating enzymes (UGT2B7, UGT2B15, and UGT2B17). The observed osteoblast-induced effect was exclusive to osteogenic CRPC cells (LNCaP 19) in contrast to osteolytic PC-3 and androgen-dependent LNCaP cells. The altered steroid enzymatic pattern was specific for the intratibial tumors and verified by immunohistochemistry in tissue specimens from LNCaP-19 xenograft tumors. Additionally, the overall steroidogenic effect was reflected by corresponding levels of progesterone and testosterone in serum from castrated mice with intratibial xenografts. A bi-directional interplay was demonstrated since both proliferation and Esr2 expression of osteoblasts were induced by CRPC cells in steroid-depleted conditions. Together, our results demonstrate that osteoblasts are important mediators of the intratumoral steroidogenesis of CRPC and for castration-resistant growth in bone. Targeting osteoblasts may therefore be important in the development of new therapeutic approaches. PMID- 26586212 TI - Isolation and molecular characterization of bovine enteroviruses in Egypt. AB - Enteroviruses belong to the Picornaviridae family and infect a wide range of mammals including cattle. Bovine enterovirus (BEV) has recently been reclassified into E and F serotypes. BEV was first isolated in Egypt in 1966 although it has been known in other countries since the 1950s. In this study, BEV-F2 was isolated from calves with severe diarrhea and the isolated viruses were subjected to molecular characterization. Illumina sequencing of one of the isolates revealed the presence of a complete BEV-F genome sequence. The phylogenetic analysis revealed nucleotide substitutions along the genome in comparison with other known strains of BEV-F (HQ663846, AY508697 and DQ092795). Two primer sets were designed from the 3D and 5'NTR regions and used for the examination of the remaining isolates, which were confirmed to be of the BEV-F2 serotype. The availability of the complete genome sequence of this virus adds to the sequence database of the members of Picornaviridae and should be useful in future molecular studies of BEV. PMID- 26586213 TI - Developmental pathways and endothelial to mesenchymal transition in canine myxomatous mitral valve disease. AB - Epithelial to mesenchymal transition (EMT) and the cardiovascular equivalent, endothelial to mesenchymal transition (EndoMT), contribute to a range of chronic degenerative diseases and cancer metastasis. Chronic valvulopathies exhibit some features of EndoMT and activation of developmental signalling pathways, such as osteogenesis and chondrogenesis, expression of cell differentiation markers, basement membrane damage and endothelial transformation. The aim of the present study was to investigate the potential role of developmental mechanisms in canine myxomatous mitral valve disease (MMVD) using a combination of transcriptomic array technology, RT-PCR and immunohistochemistry. There was significant differential expression for genes typically associated with valvulogenesis and EndoMT, including markers of inflammation (IL6, IL18 and TLR4), basement membrane disarray (NID1, LAMA2 and CTSS), mesenchymal and endothelial cell differentiation (MYH11 and TAGLN) and EndoMT (ACTA2, SNAI1, CTNNB1, HAS2, CDH5, and NOTCH1), with fold changes from +15.35 (ACTA2) to -5.52 (LAMA2). These changes in gene expression were confirmed using RT-PCR, except for HAS2. In silico analysis identified important gene networks and canonical pathways in MMVD that have associations with development and organogenesis, including inflammation, valve morphogenesis and EMT, as well as components of the basement membrane and extra cellular matrix. Immunohistochemistry identified changes in the expression of hyaluronic acid synthase (Has2), Snai1, alpha-smooth muscle actin (alpha-SMA) and VE-cadherin (CDH5), and co-expression of Has2 with alpha-SMA. These research findings strongly suggest involvement of developmental signalling pathways and mechanisms, including EndoMT, in the pathogenesis of canine MMVD. PMID- 26586214 TI - Chlamydia pecorum infections in sheep and cattle: A common and under-recognised infectious disease with significant impact on animal health. AB - There is a growing recognition that infections of livestock by the obligate intracellular bacterium, Chlamydia pecorum, are more widespread than was previously thought. A range of diseases have been associated with this pathogen, with the most important manifestations including infectious arthritis, infertility, enteritis, reduced growth rates, mastitis, and pneumonia. C. pecorum infections have also been associated with sub-clinical disease, highlighting our lack of knowledge about its true economic impact on livestock producers. Diagnosis of C. pecorum infection is based on clinical findings, serology and histopathology, which are not necessarily implemented in subclinical or early stages of infection, thus potentially contributing to under-diagnosis and under reporting of infections associated with this bacterium. Recent molecular epidemiology studies have revealed that C. pecorum is genetically diverse and that there may be an association between certain strains and disease in sheep and cattle. Antimicrobial treatment of affected animals has questionable efficacy, justifying development of chlamydia vaccines for livestock. This review summarises current knowledge of the prevalence and impact of C. pecorum infections in sheep and cattle and provides an update on attempts to improve detection, management and treatment of infections by this important obligate intracellular pathogen. PMID- 26586215 TI - An update on the treatment of canine atopic dermatitis. AB - Canine atopic dermatitis is a common skin disease seen in veterinary clinical practice. Several factors appear to contribute to the cutaneous inflammation and pruritus. The therapeutic strategy should focus on control of those factors that can be identified and for which interventional measures are feasible; these include ectoparasites, bacterial/fungal infection and dietary hypersensitivity. Ectoparasites, particularly fleas, are not the cause of atopic dermatitis, but they are a confounding factor, which can exacerbate pruritus, and preventative measures are therefore indicated. Bacterial and yeast infections are frequently associated with atopic dermatitis and initial systemic and/or topical therapy should be considered, followed by regular topical treatment for preventing relapse. Concurrent dietary hypersensitivity should be investigated by undertaking an elimination/provocation trial, followed by feeding of a hypoallergenic diet where appropriate. Depending on the severity of the clinical signs of atopic dermatitis and the willingness and expectations of owners, symptomatic treatment and/or specific interventional therapy for environmental allergy (allergen avoidance, allergen-specific immunotherapy) may be implemented. Symptomatic treatment includes use of glucocorticoids (systemically or topically), ciclosporin and oclacitinib. Other treatment modalities of lower or less proven efficacy include antihistamines, dextromethorphan, fatty acids, feline interferon-omega, misoprostol, pentoxifylline, specific serotonin re uptake inhibitors and tricyclic antidepressant drugs. The therapeutic approach should be reviewed at regular intervals and tailored to the individual's needs. A successful long-term outcome can usually be achieved by combining the various treatment approaches in a way that maximises their benefits and minimises their drawbacks. PMID- 26586216 TI - Genetic parameters and estimated breeding values of insect bite hypersensitivity in Belgian Warmblood horses. AB - Genetic factors involved in susceptibility to insect bite hypersensitivity (IBH) in Belgian Warmblood horses (BWP) were investigated. Data relating to 3409 horses were collected using a questionnaire, administered to owners during sport competitions, BWP breeding days, breeder visits and after phone calls. Horses were classified as IBH-affected or unaffected, based on two 'disease classifiers': a lifetime record, based on owner information (life_status) and another based on whether or not the horse was showing clinical signs at the time of questioning (clin_status). IBH prevalence was 10% based on life_status, and 6.2% based on clin_status. The heritabilities estimated using threshold animal models varied from 0.65 to 0.78 on the underlying scale (0.18-0.26 on the observed scale). These research findings indicate that susceptibility to IBH is a heritable trait in BWP. PMID- 26586217 TI - Acute coronary syndrome among patients with chest pain: Prevalence, incidence and risk factors. AB - BACKGROUND: Urbanization and adoption of new diet and lifestyles had increased the cardiovascular risk factor (CVRF) rate and therefore, acute coronary syndrome (ACS) in developing countries such as Tunisia. We aimed at determining ACS prevalence among a sample of Tunisian patients with chest pain, at establishing the standardized incidence rate (SIR) of ACS, and at quantifying the relationship between ASC and CVRF in this population. METHODS: We studied 3158 patients admitted to a chest pain unit for non-traumatic chest pain collected in Emergency Data from January 2012 to December 2014. For all patients, the data were collected using a standardized form. We performed univariate rather than multivariate logistic regression analyses to identify age and gender-related CVRF in ACS. Linear interpolation was used for curve estimation. RESULTS: 707 (22.3%) chest pain patients were classified as ACS. The age-SIR per 10(-5)personyear (PY) was 85.7; it was 112.6 in men and 45.3 in women. Eighty one percent of patient with ACS cumulated 2 CVRF and more. The highest odds ratio were 2.00 (95% CI 1.64 2.44) for diabetes and 1.81 (95% CI 1.50-2.18) for active smoking. ACS in elderly patients was significantly associated with active smoking (OR: 2.36), diabetes (OR: 1.72) and personal ACS history (OR: 1.71). We found a significant and very high linear relation between the number of CVRF and ACS odds ratio (R(2)=0.958). CONCLUSION: Our results showed that the incidence of ACS in a Tunisian population is not very different from what is observed in developed countries; with a close relation with CVRF especially diabetes and smoking. PMID- 26586218 TI - HMGB1 induced endothelial permeability promotes myocardial fibrosis in diabetic cardiomyopathy. PMID- 26586219 TI - Non-centrosomal epidermal microtubules act in parallel to LET-502/ROCK to promote C. elegans elongation. AB - C. elegans embryonic elongation is a morphogenetic event driven by actomyosin contractility and muscle-induced tension transmitted through hemidesmosomes. A role for the microtubule cytoskeleton has also been proposed, but its contribution remains poorly characterized. Here, we investigate the organization of the non-centrosomal microtubule arrays present in the epidermis and assess their function in elongation. We show that the microtubule regulators gamma tubulin and NOCA-1 are recruited to hemidesmosomes and adherens junctions early in elongation. Several parallel approaches suggest that microtubule nucleation occurs from these sites. Disrupting the epidermal microtubule array by overexpressing the microtubule-severing protein Spastin or by inhibiting the C. elegans ninein homolog NOCA-1 in the epidermis mildly affected elongation. However, microtubules were essential for elongation when hemidesmosomes or the activity of the Rho kinase LET-502/ROCK were partially compromised. Imaging of junctional components and genetic analyses suggest that epidermal microtubules function together with Rho kinase to promote the transport of E-cadherin to adherens junctions and myotactin to hemidesmosomes. Our results indicate that the role of LET-502 in junctional remodeling is likely to be independent of its established function as a myosin II activator, but requires a microtubule dependent pathway involving the syntaxin SYX-5. Hence, we propose that non centrosomal microtubules organized by epidermal junctions contribute to elongation by transporting junction remodeling factors, rather than having a mechanical role. PMID- 26586220 TI - Expanding the power of recombinase-based labeling to uncover cellular diversity. AB - Investigating the developmental, structural and functional complexity of mammalian tissues and organs depends on identifying and gaining experimental access to diverse cell populations. Here, we describe a set of recombinase responsive fluorescent indicator alleles in mice that significantly extends our ability to uncover cellular diversity by exploiting the intrinsic genetic signatures that uniquely define cell types. Using a recombinase-based intersectional strategy, these new alleles uniquely permit non-invasive labeling of cells defined by the overlap of up to three distinct gene expression domains. In response to different combinations of Cre, Flp and Dre recombinases, they express eGFP and/or tdTomato to allow the visualization of full cellular morphology. Here, we demonstrate the value of these features through a proof-of principle analysis of the central noradrenergic system. We label previously inaccessible subpopulations of noradrenergic neurons to reveal details of their three-dimensional architecture and axon projection profiles. These new indicator alleles will provide experimental access to cell populations at unprecedented resolution, facilitating analysis of their developmental origin and anatomical, molecular and physiological properties. PMID- 26586221 TI - Selection and dynamics of embryonic stem cell integration into early mouse embryos. AB - The process by which pluripotent cells incorporate into host embryos is of interest to investigate cell potency and cell fate decisions. Previous studies suggest that only a minority of the embryonic stem cell (ESC) inoculum contributes to the adult chimaera. How incoming cells are chosen for integration or elimination remains unclear. By comparing a heterogeneous mix of undifferentiated and differentiating ESCs (serum/LIF) with more homogeneous undifferentiated culture (2i/LIF), we examine the role of cellular heterogeneity in this process. Time-lapse ex vivo imaging revealed a drastic elimination of serum/LIF ESCs during early development in comparison with 2i/LIF ESCs. Using a fluorescent reporter for naive pluripotency (Rex1-GFP), we established that the acutely eliminated serum/LIF ESCs had started to differentiate. The rejected cells were apparently killed by apoptosis. We conclude that a selection process exists by which unwanted differentiating cells are eliminated from the embryo. However, occasional Rex1(-) cells were able to integrate. Upregulation of Rex1 occurred in a proportion of these cells, reflecting the potential of the embryonic environment to expedite diversion from differentiation priming to enhance the developing embryonic epiblast. PMID- 26586222 TI - Phosphotyrosyl phosphatase activator facilitates localization of Miranda through dephosphorylation in dividing neuroblasts. AB - The mechanism for the basal targeting of the Miranda (Mira) complex during the asymmetric division of Drosophila neuroblasts (NBs) is yet to be fully understood. We have identified conserved Phosphotyrosyl phosphatase activator (PTPA) as a novel mediator for the basal localization of the Mira complex in larval brain NBs. In mutant Ptpa NBs, Mira remains cytoplasmic during early mitosis and its basal localization is delayed until anaphase. Detailed analyses indicate that PTPA acts independent of and before aPKC to localize Mira. Mechanistically, our data show that the phosphorylation status of the T591 residue determines the subcellular localization of Mira and that PTPA facilitates the dephosphorylation of T591. Furthermore, PTPA associates with the Protein phosphatase 4 complex to mediate localization of Mira. On the basis of these results, a two-step process for the basal localization of Mira during NB division is revealed: cortical association of Mira mediated by the PTPA-PP4 complex is followed by apical aPKC-mediated basal restriction. PMID- 26586223 TI - Neuropilin 1 balances beta8 integrin-activated TGFbeta signaling to control sprouting angiogenesis in the brain. AB - Angiogenesis in the developing central nervous system (CNS) is regulated by neuroepithelial cells, although the genes and pathways that couple these cells to blood vessels remain largely uncharacterized. Here, we have used biochemical, cell biological and molecular genetic approaches to demonstrate that beta8 integrin (Itgb8) and neuropilin 1 (Nrp1) cooperatively promote CNS angiogenesis by mediating adhesion and signaling events between neuroepithelial cells and vascular endothelial cells. beta8 integrin in the neuroepithelium promotes the activation of extracellular matrix (ECM)-bound latent transforming growth factor beta (TGFbeta) ligands and stimulates TGFbeta receptor signaling in endothelial cells. Nrp1 in endothelial cells suppresses TGFbeta activation and signaling by forming intercellular protein complexes with beta8 integrin. Cell type-specific ablation of beta8 integrin, Nrp1, or canonical TGFbeta receptors results in pathological angiogenesis caused by defective neuroepithelial cell-endothelial cell adhesion and imbalances in canonical TGFbeta signaling. Collectively, these data identify a paracrine signaling pathway that links the neuroepithelium to blood vessels and precisely balances TGFbeta signaling during cerebral angiogenesis. PMID- 26586226 TI - Deterioration of the coercivity due to the diffusion induced interface layer in hard/soft multilayers. AB - Hard/soft permanent magnets have aroused many interests in the past two decades because of their potential in achieving giant energy products as well as their rich variety of magnetic behaviors. Nevertheless, the experimental energy products are much smaller than the theoretical ones due to the much smaller coercivity measured in the experiments. In this paper, the deterioration of the coercivity due to the interface atomic diffusion is demonstrated based on a three dimensional (3D) micromagnetic software (OOMMF) and a formula derived for the pinning field in a hard/soft multilayer, which can be applied to both permanent magnets and exchange-coupled-composite (ECC) media. It is found that the formation of the interface layer can decrease the coercivity by roughly 50%, which is responsible for the observed smaller coercivity in both composite and single-phased permanent magnets. A method to enhance the coercivity in these systems is proposed based on the discussions, consistent with recent experiments where excellent magnetic properties are achieved. PMID- 26586224 TI - Tropomodulin 1 directly controls thin filament length in both wild-type and tropomodulin 4-deficient skeletal muscle. AB - The sarcomeric tropomodulin (Tmod) isoforms Tmod1 and Tmod4 cap thin filament pointed ends and functionally interact with the leiomodin (Lmod) isoforms Lmod2 and Lmod3 to control myofibril organization, thin filament lengths, and actomyosin crossbridge formation in skeletal muscle fibers. Here, we show that Tmod4 is more abundant than Tmod1 at both the transcript and protein level in a variety of muscle types, but the relative abundances of sarcomeric Tmods are muscle specific. We then generate Tmod4(-/-) mice, which exhibit normal thin filament lengths, myofibril organization, and skeletal muscle contractile function owing to compensatory upregulation of Tmod1, together with an Lmod isoform switch wherein Lmod3 is downregulated and Lmod2 is upregulated. However, RNAi depletion of Tmod1 from either wild-type or Tmod4(-/-) muscle fibers leads to thin filament elongation by ~15%. Thus, Tmod1 per se, rather than total sarcomeric Tmod levels, controls thin filament lengths in mouse skeletal muscle, whereas Tmod4 appears to be dispensable for thin filament length regulation. These findings identify Tmod1 as the key direct regulator of thin filament length in skeletal muscle, in both adult muscle homeostasis and in developmentally compensated contexts. PMID- 26586227 TI - RNA Detection in Urine: From RNA Extraction to Good Normalizer Molecules. AB - RNA detection in liquid urine biopsy specimens could be an optimal method for noninvasive diagnostic and prognostic procedures in urologic disorders; however, there are no standardized procedures for implementing it in the clinic. We present a systematic evaluation of the best storage conditions and purification methods using four commercially available extraction kits to purify RNA from void urine. We measured different RNA molecules to select good and stable biomarkers and normalizers for analyses in liquid urine biopsy specimens. We have established a new combined procedure for RNA isolation from urine and found good performance in 25 urine samples from healthy volunteers of both sexes. Associations were tested using the t-test for paired samples, and miRNA specimens were selected as the more stable molecules. Stability analysis was performed, and we found miR193a and miR448 as the best normalizers to be used in this biofluid. This is a highly reproducible method that could be used to evaluate urine samples for diagnostic and prognostic purposes. PMID- 26586225 TI - The development and plasticity of alveolar type 1 cells. AB - Alveolar type 1 (AT1) cells cover >95% of the gas exchange surface and are extremely thin to facilitate passive gas diffusion. The development of these highly specialized cells and its coordination with the formation of the honeycomb like alveolar structure are poorly understood. Using new marker-based stereology and single-cell imaging methods, we show that AT1 cells in the mouse lung form expansive thin cellular extensions via a non-proliferative two-step process while retaining cellular plasticity. In the flattening step, AT1 cells undergo molecular specification and remodel cell junctions while remaining connected to their epithelial neighbors. In the folding step, AT1 cells increase in size by more than 10-fold and undergo cellular morphogenesis that matches capillary and secondary septa formation, resulting in a single AT1 cell spanning multiple alveoli. Furthermore, AT1 cells are an unexpected source of VEGFA and their normal development is required for alveolar angiogenesis. Notably, a majority of AT1 cells proliferate upon ectopic SOX2 expression and undergo stage-dependent cell fate reprogramming. These results provide evidence that AT1 cells have both structural and signaling roles in alveolar maturation and can exit their terminally differentiated non-proliferative state. Our findings suggest that AT1 cells might be a new target in the pathogenesis and treatment of lung diseases associated with premature birth. PMID- 26586228 TI - Sensing Small Changes in Protein Abundance: Stimulation of Caco-2 Cells by Human Whey Proteins. AB - Mass spectrometry (MS)-based proteomic approaches have largely facilitated our systemic understanding of cellular processes and biological functions. Cutoffs in protein expression fold changes (FCs) are often arbitrarily determined in MS based quantification with no demonstrable determination of small magnitude changes in protein expression. Therefore, many biological insights may remain veiled due to high FC cutoffs. Herein, we employ the intestinal epithelial cell (IEC) line Caco-2 as a model system to demonstrate the dynamicity of tandem-mass tag (TMT) labeling over a range of 5-40% changes in protein abundance, with the variance controls of +/- 5% FC for around 95% of TMT ratios when sampling 9-12 biological replicates. We further applied this procedure to examine the temporal proteome of Caco-2 cells upon exposure to human whey proteins (WP). Pathway assessments predict subtle effects due to WP in moderating xenobiotic metabolism, promoting proliferation and various other cellular functions in differentiating enterocyte-like Caco-2 cells. This demonstration of a sensitive MS approach may open up new perspectives in the system-wide exploration of elusive or transient biological effects by facilitating scrutiny of narrow windows of proteome abundance changes. Furthermore, we anticipate this study will encourage more investigations of WP on infant gastrointestinal tract development. PMID- 26586229 TI - Significant Gas Adsorption and Catalytic Performance by a Robust Cu(II) -MOF Derived through Single-Crystal to Single-Crystal Transmetalation of a Thermally Less-Stable Zn(II) -MOF. AB - By using a bent tetracarboxylic acid ligand that incorporates a pendent-NH2 functional group, a 3D Zn(II)-framework (1) based on Zn2 (CO2)4 secondary building units and Zn12 (CO2)24 supramolecular building blocks has been synthesized. Framework 1 is thermally less stable, which precludes its application as a porous framework for gas adsorption or catalytic studies. This framework undergoes single-crystal to single-crystal transmetalation to give isostructural 1Cu. Unlike 1, the Cu(II) analogue is very stable and can be activated by removing metal-bound lattice solvent molecules by heating to afford 1Cu'. The activated 1Cu' exhibits excellent H2 storage (2.29 wt%) at 77 K and a high 32.1 wt% CO2 uptake at 273 K. Additionally, it displays significant selectivity for CO2 adsorption over N2 and H2 and can catalyse size-selective Knoevenagel condensation reactions. PMID- 26586230 TI - Diverse Cutaneous Presentations of Langerhans Cell Histiocytosis in Children: A Retrospective Cohort Study. AB - BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare disease, frequently affecting young children. PROCEDURE: We performed a retrospective study in patients younger than 16 years old manifesting with skin symptoms, and documented their different cutaneous lesions and systemic symptoms. We compared subgroups of children with single-system, skin-only, and multisystem disease and sought signs predictive for multisystem disease. In a small sample of patients, BRAF mutations were analyzed in archived biopsies. RESULTS: A wide spectrum of cutaneous presentations varying from crusted nodules and papules, blisters, vascular tumor like lesions, scaling orange to red macules (frequently in seborrheic regions) to purpuric macules, and papules was documented in our cohort of 32 children. Otitis externa was a common manifestation and mucosal lesions were seen in three patients. A novel manifestation was a red-blue nodule that appeared in a patient after a vaccination. None of the cutaneous lesions was predictive for the classification or final outcome as a single-system or multisystem disease. However, later onset and a more protracted course of skin lesions were more frequent findings in multisystem LCH. Mucosal lesions and otitis externa were almost exclusively seen in patients with multisystem disease, a finding that warrants further investigation. Both wild-type (WT) and mutated BRAF were found not only in multisystem LCH, but also in skin-only LCH. Two cases with rapidly resolving congenital lesions had WT BRAF. CONCLUSIONS: Late onset and a protracted course of skin lesions are associated with MS-LCH, whereas WT BRAF is found in rapidly resolving skin lesions. PMID- 26586231 TI - Investigations of the unsaturated zone at two radioactive waste disposal sites in Lithuania. AB - The unsaturated zone is an important part of the water cycle, governed by many hydrological and hydrogeological factors and processes and provide water and nutrients to the terrestrial ecosystem. Besides, the soils of the unsaturated zone are regarded as the first natural barrier to a large extent and are able to limit the spread of contaminants depending on their properties. The unsaturated zone provides a linkage between atmospheric moisture, groundwater, and seepage of groundwater to streams, lakes, or other surface water bodies. The major difference between water flow in saturated and unsaturated soils is that the hydraulic conductivity, which is conventionally assumed to be a constant in saturated soils, is a function of the degree of saturation or matrix suction in the unsaturated soils. In Lithuania, low and intermediate level radioactive wastes generated from medicine, industry and research were accumulated at the Maisiagala radioactive waste repository. Short-lived low and intermediate levels radioactive waste, generated during the operation of the Ignalina Nuclear Power Plant (INPP) and arising after the INPP decommissioning will be disposed of in the near surface repository close to the INPP (Stabatiske site). Extensive data sets of the hydraulic properties and water content attributed to unsaturated zone soil profiles of the two radioactive waste disposal sites have been collected and summarized. Globally widespread radionuclide tritium ((3)H) and stable isotope ratio ((18)O/(16)O and (2)H/(1)H) distribution features were determined in precipitation, unsaturated zone soil moisture profiles and groundwater. PMID- 26586233 TI - Tuned synthesis of two coordination polymers of Cd(II) using substituted bent 3 pyridyl linker and succinate: structures and their applications in anion exchange and sorption properties. AB - Two new Cd(II) coordination polymers, namely [Cd(3-bpdh)2(ClO4)2]n (1) and {[Cd(3 bpdh)(suc)(H2O)].3(H2O)}n (2), have been synthesized using a substituted bent N,N'-donor ligand 2,5-bis-(3-pyridyl)-3,4-diaza-2,4-hexadiene (3-bpdh) and aliphatic dicarboxylate disodium succinate (suc) with Cd(II) perchlorate salts at room temperature by a slow diffusion technique for the exploration of our previous reported work. Both the structures were determined by single-crystal X ray diffraction analysis and also by other physicochemical methods. Structure analysis revealed that complex 1 is a 1D chain structure containing coordinated perchlorate with a metal centre, and complex 2 shows a porous 3D framework with encapsulation of lattice water molecules into the void along the crystallographic a-axis. The PXRD study shows the bulk purity of both the complexes and TGA analysis of 2 exhibits that the structure is thermally stable up to 250 degrees C. Complex 1 shows a nice anion exchange property with replacement of weakly coordinated perchlorate with the inclusion of new anions; and the anion exchanged solids were characterised by FT-IR, PXRD and photoluminescence properties. The desolvated framework of 2 exhibits sorption of CO2 and water vapor and surface adsorption of N2 corroborating with the nature of the pore environment present in 2. The photoluminescence study has been also done for both complexes in the solid state which exhibits ligand based emissions at room temperature. PMID- 26586232 TI - Schistosomiasis in the Democratic Republic of Congo: a literature review. AB - Schistosomiasis is a poverty-related parasitic infection, leading to chronic ill health. For more than a century, schistosomiasis has been known to be endemic in certain provinces of the Democratic Republic of Congo (DRC). However, a clear overview on the status of the disease within the country is currently lacking, which is seriously hampering control. Here, we review the available information on schistosomiasis in DRC of the past 60 years. Findings and data gaps are discussed in the perspective of upcoming control activities.An electronic literature search via PubMed complemented by manual search of non-peer-reviewed articles was conducted up to January 2015. The search concerned all relevant records related to schistosomiasis in the DRC from January 1955 onwards. A total of 155 records were found, of which 30 met the inclusion criteria. Results were summarized by geographical region, mapped, and compared with those reported sixty years ago. The available data reported schistosomiasis in some areas located in 10 of the 11 provinces of DRC. Three species of Schistosoma were found: S. mansoni, S. haematobium and S. intercalatum. The prevalence of schistosomiasis varied greatly between regions and between villages, with high values of up to 95 % observed in some communities. The overall trend over 60 years points to the spread of schistosomiasis to formerly non-endemic areas. The prevalence of schistosomiasis has increased in rural endemic areas and decreased in urban/peri urban endemic areas of Kinshasa. Hepatosplenomegaly, urinary tract lesions and anaemia were commonly reported in schistosomiasis endemic areas but not always associated with infection status.The present review confirms that schistosomiasis is still endemic in DRC. However, available data are scattered across time and space and studies lack methodological uniformity, hampering a reliable estimation of the current status of schistosomiasis in DRC. There is a clear need for updated prevalence data and well-designed studies on the epidemiology and transmission of schistosomiasis in DRC. This will aid the national control program to adequately design and implement strategies for sustainable and comprehensive control of schistosomiasis throughout the country. PMID- 26586234 TI - NUT Carcinoma of the Sublingual Gland. AB - NUT carcinoma (NC) is a recently described, rare and extremely aggressive cancer primarily located to supradiaphragmatic structures and affecting young individuals. NC is characterized by translocations involving the NUT gene on 15q14 with the most common translocation partner gene being BRD4 on 19p13, resulting in the t(15;19)(q14;p13) karyotype. NC is poorly differentiated and is likely to be overlooked and misdiagnosed as poorly differentiated squamous cell carcinoma (SCC) when immunohistochemical evaluation of NUT protein expression is omitted. Previously, NC has been found in the parotid and submandibular glands and we present the first case in the sublingual gland arising in a 40-year-old woman. We discuss the diagnostic considerations for poorly differentiated carcinomas of the salivary glands and advocate the inclusion of NUT immunohistochemistry in this setting. Not only does the NC diagnosis confer a grave prognosis when treated as SCC as illustrated by the present case, but is important for the inclusion of patients in ongoing clinical trials. PMID- 26586236 TI - An alternative approach to pharyngeal and hypopharyngeal foreign body removal in the clinic: a successful five case series. PMID- 26586235 TI - Preserved cardiorespiratory function and NT-proBNP levels before and during exercise in patients with recent onset of rheumatoid arthritis: the clinical challenge of stratifying the patient cardiovascular risks. AB - Rheumatoid arthritis (RA) is associated with an increased risk of myocardial infarction and congestive heart failure. In RA patients, elevated NT-proBNP levels have been reported to be a prognostic marker of left ventricular dysfunction. In this study, we evaluated cardiorespiratory functional capacity and NT-proBNP levels before and during cardiopulmonary exercise test in early RA (ERA) patients. Twenty ERA patients and 10 healthy controls were studied by color Doppler echocardiography to evaluate ventricular systolic and diastolic function. Arterial stiffness and wave reflections were quantified non-invasively using applanation tonometry of the radial artery. Cardiopulmonary treadmill test was performed to measure peak VO2 and VE/VCO2 parameters. NT-proBNP plasma levels were measured before and at the exercise peak during cardiopulmonary exercise. The peak oxygen uptake [VO2 (ml/min/kg)], the ventilatory equivalents for carbon dioxide (EqCO2), respiratory exchange ratio and arterial stiffness were similar between patients and controls during cardiopulmonary exercise test. Basal and peak cardiopulmonary exercise NT-proBNP plasma levels were comparable in ERA patients with respect to healthy controls. When we analyzed patients according to disease characteristics and cardiovascular risk factors, ERA patients with high disease activity, BMI > 25 kg/m2 and ACPA positivity presented significantly higher baseline and exercise peak NT-proBNP levels. Cardiorespiratory function is preserved in patients with recent onset of rheumatoid arthritis. The increased basal and exercise peak NT-proBNP plasma levels in patients with negative disease prognostic factors represent a possible marker to stratify the cardiovascular risk in patients with early rheumatoid arthritis. PMID- 26586237 TI - An affinity-structure database of helix-turn-helix: DNA complexes with a universal coordinate system. AB - BACKGROUND: Molecular interactions between proteins and DNA molecules underlie many cellular processes, including transcriptional regulation, chromosome replication, and nucleosome positioning. Computational analyses of protein-DNA interactions rely on experimental data characterizing known protein-DNA interactions structurally and biochemically. While many databases exist that contain either structural or biochemical data, few integrate these two data sources in a unified fashion. Such integration is becoming increasingly critical with the rapid growth of structural and biochemical data, and the emergence of algorithms that rely on the synthesis of multiple data types to derive computational models of molecular interactions. DESCRIPTION: We have developed an integrated affinity-structure database in which the experimental and quantitative DNA binding affinities of helix-turn-helix proteins are mapped onto the crystal structures of the corresponding protein-DNA complexes. This database provides access to: (i) protein-DNA structures, (ii) quantitative summaries of protein-DNA binding affinities using position weight matrices, and (iii) raw experimental data of protein-DNA binding instances. Critically, this database establishes a correspondence between experimental structural data and quantitative binding affinity data at the single basepair level. Furthermore, we present a novel alignment algorithm that structurally aligns the protein-DNA complexes in the database and creates a unified residue-level coordinate system for comparing the physico-chemical environments at the interface between complexes. Using this unified coordinate system, we compute the statistics of atomic interactions at the protein-DNA interface of helix-turn-helix proteins. We provide an interactive website for visualization, querying, and analyzing this database, and a downloadable version to facilitate programmatic analysis. CONCLUSIONS: This database will facilitate the analysis of protein-DNA interactions and the development of programmatic computational methods that capitalize on integration of structural and biochemical datasets. The database can be accessed at http://ProteinDNA.hms.harvard.edu. PMID- 26586238 TI - Association of patterns of methadone use with antiretroviral therapy discontinuation: a prospective cohort study. AB - BACKGROUND: Methadone maintenance therapy (MMT) is a proven treatment strategy for opioid dependent patients. Although studies have demonstrated that MMT increases contact with the medical system and improves adherence to antiretroviral therapy (ART) in HIV-positive people who inject drugs (PWID), the effect of MMT discontinuation on ART discontinuation has not been well described. METHODS: We examined the impact of continuous MMT use, MMT non-use and MMT discontinuation on the time to ART discontinuation (defined as 90 days of continuous non-use following previous enrolment) in a community-recruited prospective cohort of HIV-positive PWID followed between May 1996 and May 2013 in Vancouver, Canada. Multivariate Cox proportional hazards regression was used to examine the association between MMT use patterns and time to ART discontinuation while adjusting for socio-demographic confounders. RESULTS: A total of 794 HIV positive PWID were included during the study period. In an adjusted analysis, in comparison to those who were continuously on MMT, MMT non-use (Adjusted Hazard Ratio [AHR] = 1.44, 95 % Confidence Interval [CI]: 1.19-1.73) as well as discontinuing MMT (AHR = 1.82, 95 % CI: 1.27-2.60) were both found to be independently associated with time to ART discontinuation. CONCLUSIONS: This study reinforces the known benefits of MMT use on ART adherence and demonstrates how discontinuation of MMT is independently associated with an increased risk of ART cessation. These data highlight the importance of retaining PWID on MMT. PMID- 26586239 TI - More on hepatic granulomas. AB - We have read the case report of Nihon-Yanagi et al. The patient they described developed hepatic granuloma two times and the granulomatous lesion was surrounding metal staples/clips suggesting that the granuloma was due to surgical staples/clips. Hepatic granulomas (HGs) are reported in around 5% of patient who undergo a liver biopsy and caused by several diseases including sarcoidosis, tuberculosis, hydatid cyst, brucellosis, typhoid fever, chronic hepatitis B and C and primary biliary cirrhosis (PBC). Chronic hepatitis B and C infections are the most common and serious causes of liver damage in patient with renal failure. Their prevalence is a higher than people without renal failure. We have previously reported that the prevalences of HGs in patients with chronic hepatitis B and C are 1.5 and 1.3% respectively. The described patient was on hemodialysis for 12 years. The other causes of HG seem excluded; however hepatitis B and C infections and PBC should have been tested and excluded before ascribing the HGs to surgical staples/clipping material. PMID- 26586240 TI - Developing Brief Opportunistic Interactions: practitioners facilitate patients to identify and change health risk behaviours at an early preventive stage. AB - Aim To identify shortcomings in existing models of patient behaviour change, and present the development and testing of a novel approach using practitioner facilitation and person-focussed conversations that identifies and addresses behaviours at an earlier stage than current models. BACKGROUND: Systematic strategies used by health professionals to change patient behaviours began with motivational interviewing and brief intervention approaches for serious addictive behaviours. Practitioners typically presume they should drive the process of patient behaviour change. Attempts to transfer these approaches to primary care, and a broader range of health risk behaviours, have been less successful. The TADS programme (Tobacco, Alcohol and Other Drugs, later Training and Development Services) began teaching motivational interviewing and brief interventions to practitioners in New Zealand in 1996. Formal and informal evaluations showed that practitioners used screening tools that patients rejected and that led to incomplete disclosure, used language that did not engage patients, failed to identify the behaviours patients wished to address and therefore misdirected interventions. METHODS: Iterative development of new tools with input from patients and primary care clinicians. Findings The TADS programme developed a questionnaire whose results remained private to the patient, which enabled the patient to identify personal behaviours that they might choose to change (the TADS Personal Assessment Choice Tool). This was assisted by a brief conversation that facilitated and supported any change prioritised by the patient (the TADS Brief Opportunistic Interaction). The need for this approach, and its effectiveness, appeared to be similar across adults, youth, different ethnic groups and people in different socio-economic circumstances. Behaviours patients identified were often linked to other health risk behaviours or early-stage mental health disorders that were not easily detected by practitioner-driven screening or inquiry. The long-term effectiveness of this approach in different populations in primary health care settings requires further evaluation. PMID- 26586241 TI - The ICSI procedure from past to future: a systematic review of the more controversial aspects. AB - BACKGROUND: ICSI is currently the most commonly used assisted reproductive technology, accounting for 70-80% of the cycles performed. This extensive use, even excessive, is partly due to the high level of standardization reached by the procedure. There are, however, some aspects that deserve attention and can still be ameliorated. The aim of this systematic review was to evaluate the results of available publications dealing with the management of specific situations during ICSI in order to support embryologists in trying to offer the best laboratory individualized treatment. METHODS: This systematic review is based on material obtained by searching PUBMED between January 1996 and March 2015. We included peer-reviewed, English-language journal articles that have evaluated ICSI outcomes in the case of (i) immature oocytes, (ii) oocyte degeneration, (iii) timing of the various phases, (iv) polar body position during injection, (v) zona free oocytes, (vi) fertilization deficiency, (vii) round-headed sperm, (viii) immotile sperm and (ix) semen samples with high DNA fragmentation. RESULTS: More than 1770 articles were obtained, from which only 90 were specifically related to the issues developed for female gametes and 55 for the issues developed for male gametes. The studies selected for this review were organized in order to provide a guide to overcome roadblocks. According to these studies, the injection of rescue metaphase I oocytes should be discouraged due to poor clinical outcomes and a high aneuploidy rates; laser-assisted ICSI represents an efficient method to solve the high oocyte degeneration rate; the optimal ICSI timing and the best polar body position during the injection have not been clarified; injected zona free oocytes, if handled carefully, can develop up to blastocyst stage and implant; efficient options can be offered to patients who suffered fertilization failure in previous conventional ICSI cycles. Most controversial and inconclusive are data on the best method to select a viable spermatozoa when only immotile spermatozoa are available for ICSI and, to date, there is no reliable approach to completely filter out spermatozoa with fragmented DNA from an ejaculate. However, most of the studies do not report essential clinical outcomes, such as live birth, miscarriage and fetal abnormality rate, which are essential to establish the safety of a procedure. CONCLUSIONS: This review provides the current knowledge on some controversial technical aspects of the ICSI procedures in order to improve its efficacy in specific contexts. Notwithstanding that embryologists might benefit from the approaches presented herein in order to improve ICSI outcomes, this area of expertise still demands a greater number of well-designed studies, especially in order to solve open issues about the safety of these procedures. PMID- 26586242 TI - Adalimumab: A Review in Chronic Plaque Psoriasis. AB - Adalimumab (Humira((r))) is a fully human monoclonal antibody against tumour necrosis factor (TNF), formulated for subcutaneous administration. It is well established in the treatment of adults with moderate-to-severe chronic plaque psoriasis and has recently received approval in the EU for the treatment of severe chronic plaque psoriasis in children and adolescents from 4 years of age. In a phase III trial in paediatric patients, a significantly greater proportion of patients receiving adalimumab 0.8 mg/kg (to a maximum of 40 mg) every other week (eow) achieved a >=75 % improvement from baseline in Psoriasis Area and Severity Index than those receiving methotrexate after 16 weeks of treatment. In adults, well-designed randomized clinical trials demonstrated that adalimumab 40 mg eow effectively reduced the signs and symptoms of psoriasis and improved dermatology-specific and general measures of health-related quality of life, with these benefits sustained during long-term treatment. Adalimumab was generally well tolerated, compared with placebo or methotrexate, during clinical trials in paediatric and adult patients with chronic plaque psoriasis. Thus, adalimumab remains an important treatment strategy in adults with moderate-to-severe chronic plaque psoriasis and provides a promising new systemic treatment option for children and adolescents from 4 years of age with severe psoriasis. PMID- 26586243 TI - Rabbit model of tracheal stenosis induced by prolonged endotracheal intubation using a segmented tube. AB - OBJECTIVE: Animal model of tracheal stenosis based on pathophysiology of prolonged endotracheal intubation has been rarely reported. We sought to verify the feasibility of inducing an animal model of tracheal stenosis by segmented endotracheal tube insertion in the New Zealand white rabbit model. METHODS: Tracheal stenosis was induced by inserting a segmented endotracheal tube of 1.5cm length which was wrapped with a commercialized absorbable hemostat in 15 New Zealand white rabbits, while sham surgery controls (n=3) underwent tracheotomy and direct closure of tracheal exposure. The tube was removed transorally, 1 week after tube insertion. All rabbits were evaluated endoscopically at 1 week, 2 weeks and 3 weeks after the tube insertion. The rabbits were sacrificed 3 weeks after the surgery, and the excised tissue of trachea was processed along with the procedure of standard hematoxylin eosin staining and observed under a microscope. RESULTS: Tracheal stenosis was induced in all rabbits (range 32-84% stenosis) with no death of rabbits during the study. The histological features of tracheal stenosis demonstrated thickening and fibrosis of lamina propria and submucosa with relatively intact cartilage framework. CONCLUSIONS: We developed a rabbit model of tracheal stenosis induced by endotracheal intubation using a segmented tracheal tube. Since the model is based on the physiologic condition of prolonged endotracheal intubation, it may be used in variable studies related to tracheal stenosis. PMID- 26586244 TI - Investigation of pepsin in tears of children with laryngopharyngeal reflux disease. AB - OBJECTIVES: Numerous investigations postulated that laryngopharyngeal reflux (LPR) is implicated in the pathogenesis of various upper airway inflammatory diseases as sinusitis or dacryostenosis. The presence of pepsin in tears might be confirmed the presuntive hypothesis of the arrival in the nasolacrimal ducts and precorneal tears film through the laryngopharyngeal reflux of either gastric acid or stomach secretions (pepsin) with inflammatory potentialities. The aim of this preliminary study was to identify the presence or absence of pepsin in the tears collected from children with a high suspicion of LPR who underwent 24-h pH (MII pH) monitoring to confirm the disease. METHODS: This study enrolled 20 patients suffering from symptoms of laryngopharyngeal reflux that underwent 24-h multichannel intraluminal impedance (MII)-pH monitoring to confirm the disease. The findings of the study group were compared with those of a control group of patients with negative pH monitoring. The quantitative analysis of human pepsin concentration in the tear samples was performed by ELISA method in both groups. RESULTS: Four children (20%) of the study group showed pepsin in the tears. All of the subjects belonging to the control group were negative for its presence. No difference differences in the total number of reflux episodes and the number of weakly basic reflux in the pepsin positive patients vs. pepsin negative children were present. CONCLUSIONS: 20% of the children with diagnosed LPR showed pepsin in the tears. Our specific investigation might provide information regarding sinusitis or dacryostenosis. PMID- 26586245 TI - Polymorphic variants near 1p22 and 20q11.2 loci and the risk of non-syndromic cleft lip and palate in South Indian population. AB - BACKGROUND: Recent genome-wide association studies (GWAS) have reported multiple genetic risk loci for non-syndromic orofacial clefts (NSOFCs) in many populations. However, the contribution of these loci to NSOFC in India, which comprises one-fifth of the global population, is completely lacking. Our aim was to replicate the association of the SNPs located on 1p22 chromosomal loci (rs540026, rs481931) and 20q11.2 (rs13041247, rs11696257) in the aetiology of NSOFCs, in South Indian populations. METHODS: The SNPs were genotyped by using KBiosciences KASPar SNP genotyping chemistry in 173 cases and 176 controls for NSOFCs in South India. To estimate the association between these SNPs and NSOFCs, chi-square test was adopted. Odds ratios (OR) with 95% confidence intervals (CI) were also calculated in order to assess the risk. RESULTS: Single nucleotide polymorphisms located at chromosomal region 1p22 are not found to be associated with cleft lip with or without non-syndromic cleft palate (NSCL/P) and non syndromic cleft palate only (NSCPO) at either the genotype or allele levels. Further, there is no LD observed between these variants. The polymorphic variants near 20q11.2 (rs13041247, rs11696257) are in complete linkage disequilibrium (LD) and are significantly associated with only NSCL/P in genotypic (p=0.013) and allelic models (p=0.029). In the genotypic model significance persisted even after Bonferroni correction (p<0.016). CONCLUSION: These results suggest that 20q11.2 SNPs could play a contributory role in the pathophysiology and risk of NSCL/P, while the variations in 1p22 do not underlie the pathophysiology of NSOFCs in South Indian populations. PMID- 26586246 TI - Speech task effects on acoustic measure of fundamental frequency in Cantonese speaking children. AB - OBJECTIVES: Speaking fundamental frequency (F0) is a voice measure frequently used to document changes in vocal performance over time. Knowing the intra subject variability of speaking F0 has implications on its clinical usefulness. The present study examined the speaking F0 elicited from three speech tasks in Cantonese-speaking children. The study also compared the variability of speaking F0 elicited from different speech tasks. METHODS: Fifty-six vocally healthy Cantonese-speaking children (31 boys and 25 girls) aged between 7.0 and 10.11 years participated. For each child, speaking F0 was elicited using speech tasks at three linguistic levels (sustained vowel /a/ prolongation, reading aloud a sentence and passage). Two types of variability, within-session (trial-to-trial) and across-session (test-retest) variability, were compared across speech tasks. RESULTS AND CONCLUSIONS: Significant differences in mean speaking F0 values were found between speech tasks. Mean speaking F0 value elicited from sustained vowel phonations was significantly higher than those elicited from the connected speech tasks. The variability of speaking F0 was higher in sustained vowel prolongation than that in connected speech. PMID- 26586247 TI - Characterization of N-glycosylation and amino acid sequence features of immunoglobulins from swine. AB - The primary goal of this study was to develop a method to study the N glycosylation of IgG from swine in order to detect epitopes containing N glycolylneuraminic acid (Neu5Gc) and/or terminal galactose residues linked in alpha1-3 susceptible to cause xenograft-related problems. Samples of immunoglobulin were isolated from porcine serum using protein-A affinity chromatography. The eluate was then separated on electrophoretic gel, and bands corresponding to the N-glycosylated heavy chains were cut off the gel and subjected to tryptic digestion. Peptides and glycopeptides were separated by reversed phase liquid chromatography and fractions were collected for matrix assisted laser desorption/ionization time-of-flight mass spectrometric (MALDI-TOF MS) analysis. Overall no alpha1-3 galactose was detected, as demonstrated by complete susceptibility of terminal galactose residues to beta-galactosidase digestion. Neu5Gc was detected on singly sialylated structures. Two major N glycopeptides were found, EEQFNSTYR and EAQFNSTYR as determined by tandem MS (MS/MS), as previously reported by Butler et al. (Immunogenetics, 61, 2009, 209 230), who found 11 subclasses for porcine IgG. Out of the 11, ten include the sequence corresponding to EEQFNSTYR, and only one codes for EAQFNSTYR. In this study, glycosylation patterns associated with both chains were slightly different, in that EEQFNSTYR had a higher content of galactose. The last step of this study consisted of peptide-mapping the 11 reported porcine IgG sequences. Although there was considerable overlap, at least one unique tryptic peptide was found per IgG sequence. The workflow presented in this manuscript constitutes the first study to use MALDI-TOF-MS in the investigation of porcine IgG structural features. PMID- 26586248 TI - Nerve Fiber Activation During Peripheral Nerve Field Stimulation: Importance of Electrode Orientation and Estimation of Area of Paresthesia. AB - INTRODUCTION AND AIM: Low back pain is one of the indications for using peripheral nerve field stimulation (PNFS). However, the effect of PNFS varies between patients; several stimulation parameters have not been investigated in depth, such as orientation of the nerve fiber in relation to the electrode. While placing the electrode parallel to the nerve fiber may give lower activation thresholds, anodal blocking may occur when the propagating action potential passes an anode. METHODS: A finite element model was used to simulate the extracellular potential during PNFS. This was combined with an active cable model of Abeta and Adelta nerve fibers. It was investigated how the angle between the nerve fiber and electrode affected the nerve activation and whether anodal blocking could occur. Finally, the area of paresthesia was estimated and compared with any concomitant Adelta fiber activation. RESULTS: The lowest threshold was found when nerve and electrode were in parallel, and that anodal blocking did not appear to occur during PNFS. The activation of Abeta fibers was within therapeutic range (<10V) of PNFS; however, within this range, Adelta fiber activation also may occur. The combined area of activated Abeta fibers (paresthesia) was at least two times larger than Adelta fibers for similar stimulation intensities. CONCLUSION: No evidence of anodal blocking was observed in this PNFS model. The thresholds were lowest when the nerves and electrodes were parallel; thus, it may be relevant to investigate the overall position of the target nerve fibers prior to electrode placement. PMID- 26586249 TI - Exploring Problems in Following the Hemodialysis Diet and Their Relation to Energy and Nutrient Intakes: The BalanceWise Study. AB - OBJECTIVE: To identify the problems experienced by hemodialysis (HD) patients in attempting to follow the HD diet and their relation to energy and nutrient intakes. DESIGN: Cross-sectional analysis of baseline data from the BalanceWise Study. SUBJECTS: Participants included community-dwelling adults recruited from outpatient HD centers. After excluding participants with incomplete dietary analyses (n = 50), 140 African American and white (40/60%) men and women (52/48%) on chronic intermittent HD for at least 3 months (median 3 years) were included. INTERVENTION: Participant responses, on a 5-point Likert scale ranging from "not at all a problem" to "a very important problem for me," to 34 questions pertaining to potential barriers to following the HD diet in the previous 2 months were classified as either a problem (1) or not a problem (2-5). MAIN OUTCOME MEASURE: Energy and nutrient intakes determined using the Nutrition Data System for Research(r) based on 3, non-consecutive, unscheduled, 2-pass 24-hour dietary recalls collected on 1 dialysis and 1 non-dialysis weekday, and 1 non dialysis weekend day. RESULTS: More than half of participants reported having problems related to specific behavioral factors (e.g., feeling deprived), technical difficulties (e.g., tracking nutrients), and physical condition (e.g., appetite), but issues of time and food preparation and behavioral factors tended to be most deterministic of reported dietary intakes. Longer duration of HD was associated with lower intakes of protein, potassium, and phosphorus (P < .05). CONCLUSION: Registered dietitian nutritionists should consider issues of time and food preparation, and behavioral factors in their nutrition assessment of HD patients and should continually monitor HD patients for changes in protein intake that may occur over time. PMID- 26586250 TI - Learning from experience: improving the process of internationally educated nurses' application for registration - a study protocol. AB - AIM: This study aims to improve the efficiency of the application for registration process for internationally educated nurses seeking licensure to practice. BACKGROUND: The licensure and employment of internationally educated nurses has been one strategy to address the global nursing shortage. However, little is known about which application characteristics relate to success in obtaining licensure. DESIGN: This project uses evidence from a retrospective statistical analysis of four years of internationally educated nurse application data to inform the development and implementation of changes to policies and practices at the College and Association of Registered Nurses of Alberta. Analysis of application data will also be conducted to evaluate the impact of the changes on outcomes and timelines. METHODS: The project encompasses four phases, with funding from Health Canada's Internationally Educated Health Professionals Initiative approved in March 2011. Phase One focuses on a statistical analysis of application data to identify characteristics associated with success in the application process and quantify timelines for the phases of the process. The resulting knowledge will inform Phase Two, the development and implementation of policy and practice changes. Further analysis will be completed in Phase Three, comparing outcomes and timelines between pre- and postimplementation data using statistical analyses and exemplar-based statistics. Phase Four will focus on dissemination and knowledge transfer, potentially leading to further changes. DISCUSSION: Findings, policy and practice adaptations and implementation evaluation will provide evidence about the internationally educated nurse application for registration process to Registered Nurse regulators, educational institutions, internationally educated nurses, employers and governments. PMID- 26586251 TI - Development of a Medium-Throughput Targeted LCMS Assay to Detect Endogenous Cellular Levels of Malonyl-CoA to Screen Fatty Acid Synthase Inhibitors. AB - The fatty acid synthase (FAS) enzyme in mammalian cells is a large multidomain protein responsible for de novo synthesis of fatty acids. The steps catalyzed by FAS involve the condensation of acetyl-CoA and malonyl-CoA moieties in the presence of NADPH until palmitate is formed. Inhibition of FAS causes an accumulation of intracellular malonyl-CoA, as this metabolite is essentially committed to fatty acid synthesis once formed. Detection of intracellular metabolites for screening can be problematic due to a lack of appropriate tools, but here we describe a targeted liquid chromatography-mass spectroscopy (LCMS) method to directly measure endogenous levels of malonyl-CoA to drive a drug development structure-activity relationship (SAR) screening cascade. Our process involves preparation of samples at 96-well scale, normalization postpermeabilization via use of a whole-well imaging platform, and the LCMS detection methodology. The assay is amenable to multiplexing cellular endpoints, has a typical Z' of >0.6, and has high reproducibility of EC50 values. PMID- 26586252 TI - Is GETUP Helpful and Relevant in a Resource Poor Setting Like Nepal? PMID- 26586253 TI - Case Presentations from the Addiction Academy. AB - In this article, a case-based format is used to address complex clinical issues in addiction medicine. The cases were developed from the authors' practice experience, and were presented at the American College of Medical Toxicology Addiction Academy in 2015. Section I: Drug and Alcohol Dependence and Pain explores cases of patients with co-occurring pain and substance use disorders. Section II: Legal and Policy Issues in Substance Use Disorders highlights difficult legal and policy questions in addiction medicine. Section III: Special Populations and Addictive Disorders delves into the complexity of addiction in special populations (pregnant, pediatric, and geriatric patients). PMID- 26586254 TI - Synthesis and carbonic anhydrase inhibitory properties of amino acid - coumarin/quinolinone conjugates incorporating glycine, alanine and phenylalanine moieties. AB - N-Protected amino acids (Gly, Ala and Phe) were reacted with amino substituted coumarin and quinolinone derivatives, leading to the corresponding N-protected amino acid-coumarin/quinolinone conjugates. The carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activity of the new compounds was assessed against various human (h) isoforms, such as hCA I, hCA II, hCA IV and hCA XII. The quinolinone conjugates were inactive as enzyme inhibitors, whereas the coumarins were ineffective hCA I/II inhibitors (KIs > 50 MUM) but were submicromolar hCA IV and XII inhibitors, with inhibition constants ranging between 92 nM and 1.19 MUM for hCA IV, and between 0.11 and 0.79 MUM for hCA XII. These coumarin derivatives, as many others reported earlier, thus show an interesting selective inhibitory profile for the membrane-bound over the cytosolic CA isoforms. PMID- 26586255 TI - Comparison of communication skills between trained and untrained students using a culturally sensitive nurse-client communication guideline in Indonesia. AB - BACKGROUND: A communication guideline that is sensitive to the local culture is influential in the process of nursing care. The Gadjah Mada nurse-client communication guideline, the "Ready-Greet-Invite-Discuss," was meant (1) to strengthen the relationship between the nurse and the client despite of socio culturally hierarchical gap between health providers and clients in Indonesian context, (2) to provide attention to the unspoken concerns especially in the context of indirect communication which mostly using non-verbal signs and politeness etiquettes, and (3) to initiate dialog in the society which hold a more community-oriented decision making. OBJECTIVE: Our aim is to compare the communication skills of nursing students who had and had not received a training using a culture-sensitive Gadjah Mada nurse-client communication guideline. METHODS: This was a quasi experimental randomized control study to the fifth semester students of a nursing school at Yogyakarta, Indonesia. The intervention group was trained by the Gadjah Mada nurse-client communication guideline. Both intervention and the control group had learned general nurse-client communication guidelines. The training was 4h with role-plays, supportive information and feedback sessions. An objective-structured clinical examination (OSCE) was conducted 1week after the training, in seven stations, with seven simulated clients. Observers judged the communication skills of the students using a checklist of 5-point Likert scale, whereas simulated clients judged their satisfaction using 4-point Likert scale represented in colorful ribbons. RESULTS: There were significant mean differences in each domain of communication guideline observed between the trained and the control groups as judged by the teachers (p<=0.05) and simulated clients. CONCLUSIONS: Training using a culture-sensitive communication skills guideline could improve the communication skills of the nursing students and may increase satisfaction of the clients. PMID- 26586256 TI - The Nurse Professional Competence (NPC) Scale: Self-reported competence among nursing students on the point of graduation. AB - BACKGROUND: International organisations, e.g. WHO, stress the importance of competent registered nurses (RN) for the safety and quality of healthcare systems. Low competence among RNs has been shown to increase the morbidity and mortality of inpatients. OBJECTIVES: To investigate self-reported competence among nursing students on the point of graduation (NSPGs), using the Nurse Professional Competence (NPC) Scale, and to relate the findings to background factors. METHODS AND PARTICIPANTS: The NPC Scale consists of 88 items within eight competence areas (CAs) and two overarching themes. Questions about socio economic background and perceived overall quality of the degree programme were added. In total, 1086 NSPGs (mean age, 28.1 [20-56]years, 87.3% women) from 11 universities/university colleges participated. RESULTS: NSPGs reported significantly higher scores for Theme I "Patient-Related Nursing" than for Theme II "Organisation and Development of Nursing Care". Younger NSPGs (20-27years) reported significantly higher scores for the CAs "Medical and Technical Care" and "Documentation and Information Technology". Female NSPGs scored significantly higher for "Value-Based Nursing". Those who had taken the nursing care programme at upper secondary school before the Bachelor of Science in Nursing (BSN) programme scored significantly higher on "Nursing Care", "Medical and Technical Care", "Teaching/Learning and Support", "Legislation in Nursing and Safety Planning" and on Theme I. Working extra paid hours in healthcare alongside the BSN programme contributed to significantly higher self-reported scores for four CAs and both themes. Clinical courses within the BSN programme contributed to perceived competence to a significantly higher degree than theoretical courses (93.2% vs 87.5% of NSPGs). SUMMARY AND CONCLUSION: Mean scores reported by NSPGs were highest for the four CAs connected with patient-related nursing and lowest for CAs relating to organisation and development of nursing care. We conclude that the NPC Scale can be used to identify and measure aspects of self-reported competence among NSPGs. PMID- 26586257 TI - 'Why don't nurses like students?'. PMID- 26586258 TI - The learning environment as a mediating variable between self-directed learning readiness and academic performance of a sample of saudi nursing and medical emergency students. AB - BACKGROUND: There has been some ground-breaking research on self-directed learning (SDL) in nursing education which reveals the superiority of SDL to traditional learning methods in terms of students' academic performance and the development of positive attitudes toward the learning process on the part of both students and teachers. OBJECTIVES: The relationship between students' self directed learning readiness (SDLR) and students' academic performance, and the mediating role of students' perceptions of the learning environment needs further investigation. In this study, it is proposed that students' perceptions of their learning environment could enhance their SDLR and thus boost their academic performance (in terms of their GPA). DESIGN: A descriptive design was used to examine the relationships between the domains of SDLR, which are self-management, desire to learn and self-control and students' perceptions of the learning environment (SPLE) and students' GPA. DATA SOURCE: A survey involving 342 [Corrected] Saudi students from nursing and emergency medical services undergraduate programs in King Saud University was used for this research. RESULTS: The results showed that SDLR level positively influenced students' academic performance positively, and that students' perceptions of their learning environment played a significant role in determining their level of SDLR and academic performance. CONCLUSION: It is recommended that nursing and emergency medical services educators provide a supportive learning environment in terms of good teaching, clear goals and standards, appropriate assessment, appropriate workload, and emphasis on independence to encourage students to engage in the process of SDL which can, in turn, enhance their academic performance. PMID- 26586259 TI - Pressure and protective factors influencing nursing students' self-esteem: A content analysis study. AB - BACKGROUND: A review of the literature shows that the range of self-esteem in nursing students ranges from normal to low. It is hypothesized that different contextual factors could affect levels of self-esteem. OBJECTIVE: The main aim of this study was to explore these factors from the viewpoint of Iranian nursing students using a qualitative approach. DESIGN: A qualitative content analysis study. SETTING: Faculty of Nursing and Midwifery, 2014. PARTICIPANTS: Fourteen student nurses and two qualified nurses. METHODS: This study has been applied to various depths of interpretation. Semi-structured interviews were used to collect the data. Fourteen student nurses and two qualified nurses were interviewed. RESULTS: Two main themes of the "pressure factors" with subthemes: low self efficacy, sense of triviality, ineffective instructor-student interaction, low self-confidence and "protective factors" with subthemes: knowledge acquisition, mirror of valuability, professional autonomy, religious beliefs, and choosing the nursing field with interest was extracted in this study. Results showed that these themes have interaction with each other like a seesaw, as pressure factors decrease, the effect of protective factors on the self-esteem are increased. CONCLUSION: Nurse educators not only should try to improve the students' skills and knowledge, but should also try to enhance the protective factors and decrease pressure factors by enhancing the nursing students' feeling of being important, using participatory teaching methods, considering students' feedback, and attempting to improve facilities at the clinics are also recommended. PMID- 26586260 TI - Gaps in antenatal care are found in most stillbirths. PMID- 26586261 TI - Glutamate functions in stomatal closure in Arabidopsis and fava bean. AB - Guard cells are indispensable for higher plants because they control gas exchange and water balance to maintain photosynthetic activity. The signaling processes that govern their movement are controlled by several factors, such as abscisic acid (ABA), blue light, pathogen-associated molecular patterns (PAMPs), and carbon dioxide. Herein, we demonstrated that the amino acid glutamate (Glu), a well-known mammalian neurotransmitter, functions as a novel signaling molecule in stomatal closure in both Arabidopsis and fava bean (Vicia faba L.). Pharmacological and electrophysiological analyses provided important clues for the participation of Glu-receptors, Ca(2+), and protein phosphorylation during the signaling process. Genetic analyses using Arabidopsis ABA-deficient (aba2-1) and ABA-insensitive (abi1-1 and abi2-1) mutants showed that ABA is not required for Glu signaling. However, loss-of-function of the Arabidopsis gene encoding Slow Anion Channel-Associated 1 (SLAC1) and Calcium-Dependent Protein Kinase 6 (CPK6) impaired the Glu response. Moreover, T-DNA knockout mutations of the Arabidopsis Glu receptor-like gene (GLR), GLR3.5, lost their sensitivity to Glu dependent stomatal closure. Our results strongly support functional Glu-signaling in stomatal closure and the crucial roles of GLRs in this signaling process. PMID- 26586262 TI - Subgroup characteristics of insular low-grade glioma based on clinical and molecular analysis of 42 cases. AB - Although the classification of insular glioma has been established based on the anatomical location in order to facilitate personalized surgical resection, the diagnosis based on anatomical and functional characteristics becomes more complex when insular tumors extend into either the frontobasal brain region and/or the temporal lobe, as part of the limbic system. Moreover, prognosis of insular tumor resection is still controversial. Further analysis of subgroup characteristics of insular grade II gliomas based on clinical and molecular analysis is required to reliably determine patients' survival rates. In this retrospective study 20 purely insular grade II gliomas patients and 22 paralimbic grade II gliomas that involved frontal and/or temporal lobes were compared with regard to epidemiological and clinical characteristics. The molecular profiles including Isocitrate dehydrogenase 1 (IDH1), telomerase reverse transcriptase (TERT) promoter, and P53 mutations, 1p19q co-deletion were analyzed, and microRNA profiles were assessed by microarray and bioinformatics analysis. Purely insular grade II gliomas displayed a high frequency of IDH1 mutations with favorable outcome. IDH1 mutated paralimbic glioma shared many parameters with the purely insular glioma in respect to growth patterns, survival, and microRNA profile, but differed significantly from the IDH1 wild type paralimbic gliomas. Our findings suggest that IDH1 mutations can define subpopulations of insular gliomas with distinct disease entities regardless of tumor extension patterns. These findings could be useful to develop a customized treatment strategy for insular glioma patients. PMID- 26586263 TI - Neural basis of individual differences in the response to mental stress: a magnetoencephalography study. AB - Stress is a risk factor for the onset of mental disorders. Although stress response varies across individuals, the mechanism of individual differences remains unclear. Here, we investigated the neural basis of individual differences in response to mental stress using magnetoencephalography (MEG). Twenty healthy male volunteers completed the Temperament and Character Inventory (TCI). The experiment included two types of tasks: a non-stress-inducing task and a stress inducing task. During these tasks, participants passively viewed non-stress inducing images and stress-inducing images, respectively, and MEG was recorded. Before and after each task, MEG and electrocardiography were recorded and subjective ratings were obtained. We grouped participants according to Novelty seeking (NS) - tendency to be exploratory, and Harm avoidance (HA) - tendency to be cautious. Participants with high NS and low HA (n = 10) assessed by TCI had a different neural response to stress than those with low NS and high HA (n = 10). Event-related desynchronization (ERD) in the beta frequency band was observed only in participants with high NS and low HA in the brain region extending from Brodmann's area 31 (including the posterior cingulate cortex and precuneus) from 200 to 350 ms after the onset of picture presentation in the stress-inducing task. Individual variation in personality traits (NS and HA) was associated with the neural response to mental stress. These findings increase our understanding of the psychological and neural basis of individual differences in the stress response, and will contribute to development of the psychotherapeutic approaches to stress-related disorders. PMID- 26586265 TI - Evaluation of different CT lung anatomies for proton therapy with pencil beam scanning delivery, using a validated non-rigid image registration method. PMID- 26586264 TI - Malaria surveillance in low-transmission areas of Zambia using reactive case detection. AB - BACKGROUND: Repeat national household surveys suggest highly variable malaria transmission and increasing coverage of high-impact malaria interventions throughout Zambia. Many areas of very low malaria transmission, especially across southern and central regions, are driving efforts towards sub-national elimination. CASE DESCRIPTION: Reactive case detection (RCD) is conducted in Southern Province and urban areas of Lusaka in connection with confirmed incident malaria cases presenting to a community health worker (CHW) or clinic and suspected of being the result of local transmission. CHWs travel to the household of the incident malaria case and screen individuals living in adjacent houses in urban Lusaka and within 140 m in Southern Province for malaria infection using a rapid diagnostic test, treating those testing positive with artemether lumefantrine. DISCUSSION: Reactive case detection improves access to health care and increases the capacity for the health system to identify malaria infections. The system is useful for targeting malaria interventions, and was instrumental for guiding focal indoor residual spraying in Lusaka during the 2014/2015 spray season. Variations to maximize impact of the current RCD protocol are being considered, including the use of anti-malarials with a longer lasting, post treatment prophylaxis. CONCLUSION: The RCD system in Zambia is one example of a malaria elimination surveillance system which has increased access to health care within rural communities while leveraging community members to build malaria surveillance capacity. PMID- 26586266 TI - Do determinants of burden and emotional distress in dementia caregivers change over time? AB - OBJECTIVES: Caring for a patient with dementia is a real challenge and can have considerable psychological consequences in the long run. Many caregivers, mostly relatives, feel highly burdened. To develop effective caregiver support to prevent caregivers from getting overburdened, insight is needed into the determinants of burden. The objective of this study is to explore which patient and caregiver characteristics determine the different kinds of caregiver burden over time, both in the short and in the long run. METHOD: The study was longitudinal. Data on patients and caregivers, general burden and emotional distress were collected at three times: at baseline, at the end of treatment and at nine months. The study was conducted in a psychiatric skilled nursing home with a unit for integrative reactivation and rehabilitation (IRR) and at different sites of home-/day care, assisted living arrangements and nursing home wards (usual care). RESULTS: General burden is shown to be determined by severity of patient's neuropsychiatric symptoms, caregiver's sense of competence, health related quality of life. Emotional distress is determined by severity of patient's neuropsychiatric symptoms, caregiver's sense of competence, high affiliation and patient gender. CONCLUSION: In preventing or treating caregiver burden, professional interventions need to aim specifically at diminishing the neuropsychiatric symptoms in dementia patients and improving the sense of competence in caregivers. PMID- 26586267 TI - Automated Code Engine for Graphical Processing Units: Application to the Effective Core Potential Integrals and Gradients. AB - We present an automated code engine (ACE) that automatically generates optimized kernels for computing integrals in electronic structure theory on a given graphical processing unit (GPU) computing platform. The code generator in ACE creates multiple code variants with different memory and floating point operation trade-offs. A graph representation is created as the foundation of the code generation, which allows the code generator to be extended to various types of integrals. The code optimizer in ACE determines the optimal code variant and GPU configurations for a given GPU computing platform by scanning over all possible code candidates and then choosing the best-performing code candidate for each kernel. We apply ACE to the optimization of effective core potential integrals and gradients. It is observed that the best code candidate varies with differing angular momentum, floating point precision, and type of GPU being used, which shows that the ACE may be a powerful tool in adapting to fast evolving GPU architectures. PMID- 26586268 TI - The impact of probabilistic feature cueing depends on the level of cue abstraction. AB - Allocation of attentional resources rests on predictions about the likelihood of events. While this effect has been extensively studied in the spatial attention domain where the location of a target stimulus is pre-cued, less is known about the cueing of stimulus features such as the color of a behaviorally relevant target. Moreover, there is disagreement about which types of color cues are effective for biasing attention. Here we investigated the effects of probabilistic context (percentage of cue validity, %CV) for different levels of cue abstraction to elucidate how feature-based search information is processed and used to direct attention. The color of a target was cued by presenting the perceptual color, the color word, or two-letter abbreviations. %CV, i.e., the probability that the cue indicated the color correctly, changed unpredictably between 50, 70, and 90%. Response times (RTs) for valid and invalid trials in each %CV condition were recorded in 60 datasets and analyzed with analyses of variance. The results showed that all cues were associated with comparable RT costs after invalid cueing. The modulation of RT costs by probabilities, however, depended upon level of cue abstraction and time on task: While a strong, immediate impact of %CV was found for two-letter cueing, the effect was solely observed in the second half of the experiment for perceptual and word cues. These results demonstrate that probabilistic feature-based information is processed differently for different levels of cue abstraction. Moreover, the modulatory effect of the environmental statistics differentially depends on the time on task for different feature cues. PMID- 26586269 TI - The effects of body exposure on self-body image and esthetic appreciation in anorexia nervosa. AB - Repeated exposures to thin-idealized body shapes may alter women's perceptions of what normal (e.g., accepted) and ideal (e.g., desired) bodies in a cultural environment look like. The aim of the present study was to investigate whether exposure to thin and round body shapes may change the subsequent esthetic appreciation of others' bodies and the perceptual and cognitive-affective dimensions of self-body image in patients suffering from anorexia nervosa (AN). Thirteen AN patients and 13 matched healthy controls were exposed to pictures of either thin or round unfamiliar body models and, before and after exposure, they were required to either express liking judgments about round and slim figures of unfamiliar bodies (esthetic task) or to adjust distorted pictures of their own body to their perceptual (How do you see yourself?), affective (How do you feel yourself?), metacognitive (How do others see you?) and ideal (How would you like to look like?) body image (self-body adjustment task). Brief exposures to round models increased liking judgments of round figures in both groups. However, only in AN patients, exposure to round models induced an increase in thin figures liking, which positively correlated with their preoccupation with dieting. Furthermore, exposure to round bodies in AN patients, but not in controls, increased the distortion for the perceptual body image and decreased the size of the ideal one. No differences between the two groups were obtained after adaptation to thin models. Our results suggest that AN patients' perception of their own and others' body is more easily malleable by exposure to round figures as compared to controls. Crucially, this mechanism may strongly contribute to the development and maintenance of self-body image disturbances. PMID- 26586270 TI - Phase-locking index and power of 40-Hz auditory steady-state response are not related to major personality trait dimensions. AB - Although a number of studies have demonstrated state-related dependence of auditory steady-state responses (ASSRs), the investigations assessing trait related ASSR changes are limited. Five consistently identified major trait dimensions, also referred to as "big five" (Neuroticism, Extraversion, Openness, Agreeableness and Conscientiousness), are considered to account for virtually all personality variances in both healthy people and those with psychiatric disorders. The purpose of the present study was, for the first time, to establish the link between 40-Hz ASSR and "big five" major personality trait dimensions in young healthy adults. Ninety-four young healthy volunteers participated (38 males and 56 females; mean age +/- SD 22.180 +/- 2.75). The 40-Hz click trains were presented for each subject 30 times with an inter-train interval of 1-1.5 s. The EEG responses were recorded from F3, Fz, F4, C3, Cz, C4, P3, Pz and P4 locations according to 10/20 electrode placement system. Phase-locking index (PLI) and event-related power perturbation (ERSP) were calculated, each providing the following characteristics: peak time, entrainment frequency, peak value and mean value. For assessing "big five" personality traits, NEO Personality Inventory Revised (NEO-PI-R) was used. No significant correlation between 40-Hz ASSR PLI or ERSP and "big five" personality traits was observed. Our results indicate that there is no dependence between 40-Hz ASSR entrainment and personality traits, demonstrating low individual 40-Hz variability in this domain. Our results support further development of 40-Hz ASSR as a neurophysiological marker allowing distinguishing between healthy population and patients with psychiatric disorders. PMID- 26586271 TI - The impact of extraversion on attentional bias to pleasant stimuli: neuroticism matters. AB - The present study explored whether neuroticism modulates the impact of extraversion on attention orienting to pleasant and unpleasant pictures of diverse emotional intensities. We measured event-related potentials for highly emotional, mildly emotional, and neutral stimuli in both pleasant and unpleasant blocks, while subjects (16 stable ambiverts, 15 stable extraverts, 17 neurotic ambiverts, and 17 neurotic extraverts) were asked to perform a standard/deviant categorization task, irrespective of the emotionality of the deviants. The results revealed a modulation effect of neuroticism in the impact of extraversion on emotional attention. On the one hand, irrespective of extraversion, emotionally stable samples showed increased N200 amplitudes for highly unpleasant (HN) stimuli relative to mildly unpleasant (MN) and neutral stimuli, while these samples exhibited no significant emotion magnitude effect in the pleasant block. On the other hand, although neurotic samples, both extraverts and ambiverts, showed enhanced N2 amplitudes for HN stimuli than neutral stimuli, neurotic extraverts displayed increased N2 amplitudes for highly pleasant (HP) and mildly pleasant (MP) stimuli than neutral stimuli, which was absent in neurotic ambiverts. These results extend our understanding of the relationship between extraversion and emotion by showing that neuroticism amplifies the positive emotional bias of extraverts. PMID- 26586272 TI - Characterization of circulating APOL1 protein complexes in African Americans. AB - APOL1 gene renal-risk variants are associated with nephropathy and CVD in African Americans; however, little is known about the circulating APOL1 variant proteins which reportedly bind to HDL. We examined whether APOL1 G1 and G2 renal-risk variant serum concentrations or lipoprotein distributions differed from nonrisk G0 APOL1 in African Americans without nephropathy. Serum APOL1 protein concentrations were similar regardless of APOL1 genotype. In addition, serum APOL1 protein was bound to protein complexes in two nonoverlapping peaks, herein referred to as APOL1 complex A (12.2 nm diameter) and complex B (20.0 nm diameter). Neither of these protein complexes associated with HDL or LDL. Proteomic analysis revealed that complex A was composed of APOA1, haptoglobin related protein (HPR), and complement C3, whereas complex B contained APOA1, HPR, IgM, and fibronectin. Serum HPR was less abundant on complex B in individuals with G1 and G2 renal-risk variant genotypes, relative to G0 (P = 0.0002-0.037). These circulating complexes may play roles in HDL metabolism and susceptibility to CVD. PMID- 26586273 TI - A Wireless Intracranial Brain Deformation Sensing System for Blast-Induced Traumatic Brain Injury. AB - Blast-induced traumatic brain injury (bTBI) has been linked to a multitude of delayed-onset neurodegenerative and neuropsychiatric disorders, but complete understanding of their pathogenesis remains elusive. To develop mechanistic relationships between bTBI and post-blast neurological sequelae, it is imperative to characterize the initiating traumatic mechanical events leading to eventual alterations of cell, tissue, and organ structure and function. This paper presents a wireless sensing system capable of monitoring the intracranial brain deformation in real-time during the event of a bTBI. The system consists of an implantable soft magnet and an external head-mounted magnetic sensor that is able to measure the field in three dimensions. The change in the relative position of the soft magnet WITH respect to the external sensor as the result of the blast wave induces changes in the magnetic field. The magnetic field data in turn is used to extract the temporal and spatial motion of the brain under the blast wave in real-time. The system has temporal and spatial resolutions of 5 MUs and 10 MUm. Following the characterization and validation of the sensor system, we measured brain deformations in a live rodent during a bTBI. PMID- 26586276 TI - The Divergent Cardiovascular Effects of Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers on Myocardial Infarction and Death. AB - The renin angiotensin aldosterone system (RAAS) plays a central role in the pathophysiology of hypertension and vascular disease. Angiotensin converting enzyme inhibitors (ACEis) suppress angiotensin II (ANG II) concentrations, whereas angiotensin receptor blockers (ARBs) block the binding of ANG II to AT1 receptors. ACEis and ARBs are both effective anti-hypertensive agents and have similar risk reductions in stroke - a blood pressure dependent phenomenon. ACEis also reduce the risk of myocardial infarction (MI) and mortality in high risk hypertensive patients, as well as in diabetics, the elderly, those with vascular disease, and in congestive heart failure. ARBs, in contrast, do not reduce the risk of MI or death in clinical trials where the comparator has been another active therapy or even a placebo. Systematic reviews of ARBs that include meta analyses or meta-regression analyses confirm that ARBs lack the cardiovascular protective effects of ACEis, which in part are "independent" of blood pressure lowering. Practice guidelines, especially those in high risk hypertensive patients, should reflect the evidence that ACEis and ARBs have divergent cardiovascular effects - ACEis reduce mortality, whereas ARBs do not. ACEis should be the preferred RAAS inhibitor in high risk patients. PMID- 26586277 TI - Body condition loss and increased serum levels of nonesterified fatty acids enhance progesterone levels at estrus and reduce estrous activity and insemination rates in postpartum dairy cows. AB - Data from 96 Holstein Friesian cows on a commercial dairy farm were used to investigate whether body condition and serum levels of nonesterified fatty acids (NEFAs) postpartum (pp) affect progesterone (P4) levels, estrous activity, and fertility in dairy cows. The examination period started 14 days before the expected calving date and ended either when a cow was inseminated or at a maximum of 90 days pp. Body condition score (BCS; 1-5 scale) and backfat thickness (BFT) were determined every 2 weeks. Blood for analysis of NEFA and P4 concentrations was sampled weekly during the first 35 days pp and then every 48 hours until an ovulation was observed. Transrectal ultrasonography of the ovaries started at 21 days pp and was performed after blood sampling. If cows were not inseminated because of silent ovulation, sampling and ultrasonography continued on Days 7, 14, and 18 after ovulation and again every 48 hours until the next ovulation. Estrous activity was continuously measured with the Heatime estrus detection system. Pregnancy controls were performed ultrasonographically 28 and 42 days after AI. Cows with increased NEFA levels at 28 days pp had an increased risk of maintaining minimum P4 levels above 0.4 ng/mL at first recognized estrus (P = 0.03). Higher NEFA levels at Day 7 were associated with lower probability for a cow to have elevated P4 levels (>=2 ng/mL) by Day 35 pp, indicating delayed commencement of luteal activity (C-LA). Estrous activity was not influenced (P > 0.10) by minimum P4 concentrations at estrus, but more animals with C-LA until Day 35 pp showed estrous activity compared to cows without C-LA throughout this period (P = 0.006). Estrous activity was lower in cows with a low BCS 14 days pp (P = 0.02) and with a low BFT 42 days pp (P = 0.03). Moreover, the probability to exhibit estrus was reduced with higher NEFA levels at 21 days pp (P = 0.01). Eighty-five cows were inseminated and 37 (44%) got pregnant after insemination. Higher NEFA levels, especially 14, 28, and 42 days pp, were associated with lower probability to inseminate a cow. Regarding the cows that were inseminated, no influence of BCS, BFT, or NEFA levels on pregnancy per artificial insemination was found. In conclusion, cows with higher loss of body condition and elevated NEFA concentrations had higher P4 concentrations during estrus, a reduced estrous activity and insemination rate, but no depression in pregnancy per artificial insemination. PMID- 26586278 TI - Effects on the equine endometrium of cervical occlusion after insemination. AB - Cervical patency is considered to be important for uterine drainage after mating or artificial insemination (AI), and failure to relax or premature tightening of the cervix can lead to persistent endometritis. This study investigated the hypothesis that cervical occlusion after AI increases accumulation of fluid, polymorphonuclear leukocytes (PMNs), and cytokines in the uterine lumen. Endometrial swabs were obtained from 29 normal cyclic mares during the first, third, and fifth estrus and biopsies during the first and fifth estrus. All mares were inseminated during the second and fourth estrus. In either the second or fourth estrus, a clamped catheter was inserted into the uterus immediately after AI. Accumulation of intrauterine fluid was evaluated by transrectal ultrasonography at 0, 6, 25, and 48 hours. Fluid was drained from the catheter at either 25 hours (TxA) or 6 and 25 hours after AI (TxB). In the control estrus (TxC, no catheters), fluid was obtained by a tampon at 25 hours after AI. The uteri were then lavaged with Ringer's solution, after which the catheters were withdrawn. Sequences of treatments in the second and fourth estrus were A followed by C, C followed by A, B followed by C, and C followed by B in groups AC, CA, BC, and CB, respectively. Five mares lost their catheters and were excluded from the study. Scores for total inflammation, gland dilation, and lymphatic lacunae in the uterine biopsies did not differ significantly between groups or estrous periods. In contrast, periglandular fibrosis scores increased in all groups during the experiment. At 25 hours after AI in the second estrus, the mares with the catheters had larger accumulations of fluid (P < 0.05) and higher concentrations and total numbers of PMNs in uterine fluid (P < 0.05) than the mares without catheters. In the fourth estrus, the total number of PMNs was lower in TxB than in TxA at 25 hours (P < 0.05). Concentrations of PMNs in TxC were 10 times higher in the fourth estrus than the second. Within mare groups AC and BC, total numbers of PMNs in treatment C (fourth estrus) were as high as in TxA and B (second estrus). Expression of IL-1beta, IL-6, IL-10 and TNF-alpha, analyzed by Western blotting, did not differ significantly between the treatments or estrous periods. It is concluded that a closed cervix after insemination results in pronounced inflammation of the mare's endometrium. Furthermore, this kind of severe insult may lead to permanent pathologic changes in the endometrium, including fibrosis. PMID- 26586275 TI - The Evidence for Saturated Fat and for Sugar Related to Coronary Heart Disease. AB - Dietary guidelines continue to recommend restricting intake of saturated fats. This recommendation follows largely from the observation that saturated fats can raise levels of total serum cholesterol (TC), thereby putatively increasing the risk of atherosclerotic coronary heart disease (CHD). However, TC is only modestly associated with CHD, and more important than the total level of cholesterol in the blood may be the number and size of low-density lipoprotein (LDL) particles that contain it. As for saturated fats, these fats are a diverse class of compounds; different fats may have different effects on LDL and on broader CHD risk based on the specific saturated fatty acids (SFAs) they contain. Importantly, though, people eat foods, not isolated fatty acids. Some food sources of SFAs may pose no risk for CHD or possibly even be protective. Advice to reduce saturated fat in the diet without regard to nuances about LDL, SFAs, or dietary sources could actually increase people's risk of CHD. When saturated fats are replaced with refined carbohydrates, and specifically with added sugars (like sucrose or high fructose corn syrup), the end result is not favorable for heart health. Such replacement leads to changes in LDL, high-density lipoprotein (HDL), and triglycerides that may increase the risk of CHD. Additionally, diets high in sugar may induce many other abnormalities associated with elevated CHD risk, including elevated levels of glucose, insulin, and uric acid, impaired glucose tolerance, insulin and leptin resistance, non-alcoholic fatty liver disease, and altered platelet function. A diet high in added sugars has been found to cause a 3-fold increased risk of death due to cardiovascular disease, but sugars, like saturated fats, are a diverse class of compounds. The monosaccharide, fructose, and fructose-containing sweeteners (e.g., sucrose) produce greater degrees of metabolic abnormalities than does glucose (either isolated as a monomer, or in chains as starch) and may present greater risk of CHD. This paper reviews the evidence linking saturated fats and sugars to CHD, and concludes that the latter is more of a problem than the former. Dietary guidelines should shift focus away from reducing saturated fat, and from replacing saturated fat with carbohydrates, specifically when these carbohydrates are refined. To reduce the burden of CHD, guidelines should focus particularly on reducing intake of concentrated sugars, specifically the fructose-containing sugars like sucrose and high-fructose corn syrup in the form of ultra-processed foods and beverages. PMID- 26586279 TI - Low ensemble disorder in quantum well tube nanowires. AB - We have observed very low disorder in high quality quantum well tubes (QWT) in GaAs-Al(0.4)Ga(0.6)As core-multishell nanowires. Room-temperature photoluminescence spectra were measured from 150 single nanowires enabling a full statistical analysis of both intra- and inter-nanowire disorder. By modelling individual nanowire spectra, we assigned a quantum well tube thickness, a core disorder parameter and a QWT disorder parameter to each nanowire. A strong correlation was observed between disorder in the GaAs cores and disorder in the GaAs QWTs, which indicates that variations in core morphology effectively propagate to the shell layers. This highlights the importance of high quality core growth prior to shell deposition. Furthermore, variations in QWT thicknesses for different facet directions was found to be a likely cause of intra-wire disorder, highlighting the need for accurate shell growth. PMID- 26586280 TI - Oxidative damage and histopathological changes in lung of rat chronically exposed to nicotine alone or associated to ethanol. AB - Smoking is the most important preventable risk factor of chronic obstructive pulmonary disease and lung cancer. This study was designed to investigate oxidative damage and histopathological changes in lung tissue of rats chronically exposed to nicotine alone or supplemented with ethanol. Twenty-four male Wistar rats divided into three groups were used for the study. The nicotine group received nicotine (2.5mg/kg/day); the nicotine-ethanol group was given simultaneously same dose of nicotine plus ethanol (0.2g/kg/day), while the control group was administered only normal saline (1 ml/kg/day). The treatment was administered by subcutaneous injection once daily for a period of 18 weeks. Chronic nicotine administration alone or combined to ethanol caused a significant increase in malondialdehyde (MDA) level, superoxide dismutase (SOD) activity and catalase (CAT) activity in lung tissue compared to control rats suggesting an oxidative damage. However, these increases were mostly prominent in nicotine group. The histopathological examination of lung tissue of rats in both treated groups revealed many alterations in the pulmonary structures such as emphysema change (disappearance of the alveolar septa, increased irregularity and size of air sacs) and marked lymphocytic infiltration in perivascular and interstitial areas. However, the changes characterized in the nicotine group (pulmonary congestion, hemorrhage into alveoli and interstitial areas, edema) were more drastic than those observed in the nicotine-ethanol group, and they can be attributed to a significant degree of capillary endothelial permeability and microvascular leak. Conversely, the ethanol supplementation caused an appearance of fatty change and fibrosis in pulmonary tissue essentially due to a metabolism of ethanol. Finally, the lung damage illustrated in nicotine group was more severe than that observed in the nicotine-ethanol group. We conclude that the combined administration of nicotine and ethanol may moderate the effect of nicotine administered independently by counteractive interactions between these two drugs. PMID- 26586281 TI - Forecasting the Incidence of Dementia and Dementia-Related Outpatient Visits With Google Trends: Evidence From Taiwan. AB - BACKGROUND: Google Trends has demonstrated the capability to both monitor and predict epidemic outbreaks. The connection between Internet searches for dementia information and dementia incidence and dementia-related outpatient visits remains unknown. OBJECTIVE: This study aimed to determine whether Google Trends could provide insight into trends in dementia incidence and related outpatient visits in Taiwan. We investigated and validated the local search terms that would be the best predictors of new dementia cases and outpatient visits. We further evaluated the nowcasting (ie, forecasting the present) and forecasting effects of Google Trends search trends for new dementia cases and outpatient visits. The long-term goal is to develop a surveillance system to help early detection and interventions for dementia in Taiwan. METHODS: This study collected (1) dementia data from Taiwan's National Health Insurance Research Database and (2) local Internet search data from Google Trends, both from January 2009 to December 2011. We investigated and validated search terms that would be the best predictors of new dementia cases and outpatient visits. We then evaluated both the nowcasting and the forecasting effects of Google Trends search trends through cross correlation analysis of the dementia incidence and outpatient visit data with the Google Trends data. RESULTS: The search term "dementia + Alzheimer's disease" demonstrated a 3-month lead effect for new dementia cases and a 6-month lead effect for outpatient visits (r=.503, P=.002; r=.431, P=.009, respectively). When gender was included in the analysis, the search term "dementia" showed 6-month predictive power for new female dementia cases (r=.520, P=.001), but only a nowcasting effect for male cases (r=.430, P=.009). The search term "neurology" demonstrated a 3-month leading effect for new dementia cases (r=.433, P=.008), for new male dementia cases (r=.434, P=.008), and for outpatient visits (r=.613, P<.001). CONCLUSIONS: Google Trends established a plausible relationship between search terms and new dementia cases and dementia-related outpatient visits in Taiwan. This data may allow the health care system in Taiwan to prepare for upcoming outpatient and dementia screening visits. In addition, the validated search term results can be used to provide caregivers with caregiving-related health, skills, and social welfare information by embedding dementia-related search keywords in relevant online articles. PMID- 26586282 TI - Preliminary validation and reliability of the Short Form Chronic Respiratory Disease Questionnaire in a lung cancer population. AB - The Short Form Chronic Respiratory Questionnaire (SF-CRQ) is frequently used in patients with obstructive pulmonary disease and it has demonstrated excellent psychometric properties. Since there is no psychometric information for its use with lung cancer patients, this study explored its validity and reliability in this population. Forty-six patients were assessed at two time points (with a 4 week interval) using the SF-CRQ, the modified Borg Scale, five numerical rating scales related to Perceived Severity of Breathlessness, and the Hospital Anxiety and Depression Scale. Internal consistency reliability was investigated by Cronbach's alpha reliability coefficient, test-retest reliability by Spearman Brown reliability coefficient (P), content validity as well as convergent validity by Pearson's correlation coefficient between the SF-CRQ, and the conceptual similar scales mentioned above were explored. A principal component factor analysis was performed. The internal consistency was high [alpha = 0.88 (baseline) and 0.91 (after 1 month)]. The SF-CRQ had good stability with test retest reliability ranging from r = 0.64 to 0.78, P < 0.001. Factor analysis suggests a single construct in this population. The preliminary data analyses supported the convergent, content, and construct validity of the SF-CRQ providing promising evidence that this can be a valid and reliable instrument for the assessment of quality of life related to breathlessness in lung cancer patients. PMID- 26586283 TI - Development, characterization and optimization of a new suspension chicken induced pluripotent cell line for the production of Newcastle disease vaccine. AB - Traditionally, substrates for production of viral poultry vaccines have been embryonated eggs or adherent primary cell cultures. The difficulties and cost involved in scaling up these substrates in cases of increased demand have been a limitation for vaccine production. Here, we assess the ability of a newly developed chicken-induced pluripotent cell line, BA3, to support replication and growth of Newcastle disease virus (NDV) LaSota vaccine strain. The characteristics and growth profile of the cells were also investigated. BA3 cells could grow in suspension in different media to a high density of up to 7.0 * 10(6) cells/mL and showed rapid proliferation with doubling time of 21 h. Upon infection, a high virus titer of 1.02 * 10(8) EID50/mL was obtained at 24 h post infection using a multiplicity of infection (MOI) of 5. In addition, the cell line was shown to be free of endogenous and exogenous Avian Leukosis viruses, Reticuloendotheliosis virus, Fowl Adenovirus, Marek's disease virus, and several Mycoplasma species. In conclusion, BA3 cell line is potentially an excellent candidate for vaccine production due to its highly desirable industrially friendly characteristics of growing to high cell density and capability of growth in serum free medium. PMID- 26586284 TI - All-Iron Redox Flow Battery Tailored for Off-Grid Portable Applications. AB - An all-iron redox flow battery is proposed and developed for end users without access to an electricity grid. The concept is a low-cost battery which the user assembles, discharges, and then disposes of the active materials. The design goals are: (1) minimize upfront cost, (2) maximize discharge energy, and (3) utilize non-toxic and environmentally benign materials. These are different goals than typically considered for electrochemical battery technology, which provides the opportunity for a novel solution. The selected materials are: low-carbon steel negative electrode, paper separator, porous-carbon-paper positive electrode, and electrolyte solution containing 0.5 m Fe2 (SO4 )3 active material and 1.2 m NaCl supporting electrolyte. With these materials, an average power density around 20 mW cm(-2) and a maximum energy density of 11.5 Wh L(-1) are achieved. A simple cost model indicates the consumable materials cost US$6.45 per kWh(-1) , or only US$0.034 per mobile phone charge. PMID- 26586285 TI - Resistive expressions in preschool children during peripheral vein cannulation in hospitals: a qualitative explorative observational study. AB - BACKGROUND: Children may resist common medical procedures, and this may lead to the use of restraint. This can be challenging to all of the involved parties, but empirical research is scarce on children's expressions during these procedures. METHODS: To explore preschool children's resistive expressions during peripheral vein cannulation we video recorded and performed an in-depth analysis of naturally occurring situations with six newly hospitalized preschool children. RESULTS: Fourteen attempts of peripheral vein cannulation were recorded. A typology of resistive expressions was developed consisting of: protest, escape, and endurance. During the expression of protest, the children showed an insistent attitude where they were maintaining their view. The expression of escape was when children were panicked, avoiding hands of adults when being approached. When expressing endurance the children were stiff, motionless and introverted. Less physical restraint is required during endurance, but children still appear to refuse participation. CONCLUSIONS: We identified three types of resistive expressions that can be used to better understand the individual child and inform clinical judgment in challenging procedural situations. This knowledge can help to sensitize health care providers in their attempt to arrange for children's participation. PMID- 26586286 TI - Management of patients with type 2 diabetes and multiple chronic conditions: A Delphi consensus of the Spanish Society of Internal Medicine. AB - AIMS: To develop consensus-based recommendations for the management of chronic complex patients with type 2 diabetes mellitus using a two round Delphi technique. METHODS: Experts from the Diabetes and Obesity Working Group (DOWG) of the Spanish Society of Internal Medicine (SEMI) reviewed MEDLINE, PubMed, SCOPUS and Cochrane Library databases up to September 2014 to gather information on organization and health care management, stratification of therapeutic targets and therapeutic approach for glucose control in chronic complex patients with type 2 diabetes mellitus. A list of 6 recommendations was created and rated by a panel of 75 experts from the DOWG by email (first round) and by open discussion (second round). A written document was produced and sent back to DOWG experts for clarification purposes. RESULTS: A high degree of consensus was achieved for all recommendations summarized as 1) there is a need to redesign and test new health care programs for chronic complex patients with type 2 diabetes mellitus; 2) therapeutic targets in patients with short life expectancy should be individualized in accordance to their personal, clinical and social characteristics; 3) patients with chronic complex conditions and type 2 diabetes mellitus should be stratified by hypoglycemia risk; 4) age and specific comorbidities should guide the objectives for glucose control; 5) the risk of hypoglycemia should be a key factor when choosing a treatment; and 6) basal insulin analogs compared to human insulin are cost-effective options. CONCLUSION: The assessment and recommendations provided herein represent our best professional judgment based on current data and clinical experience. PMID- 26586287 TI - D-dimer and histamine in early stage bacteremia: A prospective controlled cohort study. AB - INTRODUCTION: Plasma histamine levels and D-dimer predict disease severity and mortality in advanced septic shock. We hypothesized that increased plasma histamine levels parallel coagulation activation and yield prognostic significance already at a very early stage of bacteremia. PATIENTS AND METHODS: This prospective controlled cohort study enrolled 72 consecutive non-surgical non ICU-ward inpatients with newly culture-diagnosed bacteremia and a Pitt Bacteremia score <=2 to determine the extent of histamine and D-dimer release and their predictive role on outcome at the earliest stage of blood stream infection. Age matched healthy adults served as internal controls (n=36). A binominal logistic regression and a Cox proportional hazards regression analysis were performed to ascertain the effects of D-dimer and histamine on in-hospital mortality. RESULTS: In contrast to plasma histamine, D-dimer levels were significantly higher within hours of culture-proven bacteremia. In-hospital mortality occurred in 17%. Histamine levels were neither associated with D-dimer level (r=0.04; p>0.05) nor with ICU admissions (r=0.06; p>0.05) and outcome (crude OR 0.8, 95% CI 0.3-1.9; p=0.6). In contrast, early-elevated D-dimer levels predicted mortality: the odds to die increased with the D-dimer level, and was 12.6 (crude OR, 95% CI 3-52; p=0.001) in patients with a D-dimer >=4MUg/mL (n=13). CONCLUSION: Histamine levels are elevated in only few patients (4%) with newly diagnosed bacteremia. Our findings suggest that D-dimer, but not plasma histamine, could be a promising marker of lethality already at a very early stage of blood stream infection. PMID- 26586288 TI - Groove sign. PMID- 26586289 TI - Nopaline-type Ti plasmid of Agrobacterium encodes a VirF-like functional F-box protein. AB - During Agrobacterium-mediated genetic transformation of plants, several bacterial virulence (Vir) proteins are translocated into the host cell to facilitate infection. One of the most important of such translocated factors is VirF, an F box protein produced by octopine strains of Agrobacterium, which presumably facilitates proteasomal uncoating of the invading T-DNA from its associated proteins. The presence of VirF also is thought to be involved in differences in host specificity between octopine and nopaline strains of Agrobacterium, with the current dogma being that no functional VirF is encoded by nopaline strains. Here, we show that a protein with homology to octopine VirF is encoded by the Ti plasmid of the nopaline C58 strain of Agrobacterium. This protein, C58VirF, possesses the hallmarks of functional F-box proteins: it contains an active F-box domain and specifically interacts, via its F-box domain, with SKP1-like (ASK) protein components of the plant ubiquitin/proteasome system. Thus, our data suggest that nopaline strains of Agrobacterium have evolved to encode a functional F-box protein VirF. PMID- 26586290 TI - Women gaze behaviour in assessing female bodies: the effects of clothing, body size, own body composition and body satisfaction. AB - Often with minimally clothed figures depicting extreme body sizes, previous studies have shown women tend to gaze at evolutionary determinants of attractiveness when viewing female bodies, possibly for self-evaluation purposes, and their gaze distribution is modulated by own body dissatisfaction level. To explore to what extent women's body-viewing gaze behaviour is affected by clothing type, dress size, subjective measurements of regional body satisfaction and objective measurements of own body composition (e.g., chest size, body mass index, waist-to-hip ratio), in this self-paced body attractiveness and body size judgement experiment, we compared healthy, young women's gaze distributions when viewing female bodies in tight and loose clothing of different dress sizes. In contrast to tight clothing, loose clothing biased gaze away from the waist-hip to the leg region, and subsequently led to enhanced body attractiveness ratings and body size underestimation for larger female bodies, indicating the important role of clothing in mediating women's body perception. When viewing preferred female bodies, women's higher satisfaction of a specific body region was associated with an increased gaze towards neighbouring body areas, implying satisfaction might reduce the need for comparison of confident body parts; furthermore undesirable body composition measurements were correlated with a gaze avoidance process if the construct was less changeable (i.e. chest size) but a gaze comparison process if the region was more changeable (i.e. body mass index, dress size). Clearly, own body satisfaction and body composition measurements had an evident impact on women's body-viewing gaze allocation, possibly through different cognitive processes. PMID- 26586291 TI - Action induction due to visual perception of linear motion in depth. AB - Visually perceived motion can affect observers' motor control in such a way that an intended action can be activated automatically when it contains similar spatial features. So far, effects have been mostly demonstrated with simple displays where objects were moving in a two-dimensional plane. However, almost all actions we perform and visually perceive in everyday life are much more complex and take place in three-dimensional space. The purpose of this study was to examine action inductions due to visual perception of motion in depth. Therefore, we conducted two Simon experiments where subjects were presented with video displays of a sphere (simple displays, experiment 1) and a real person (complex displays, experiment 2) moving in depth. In both experiments, motion direction towards and away from the observer served as task irrelevant information whereas a color change in the video served as relevant information to choose the correct response (close or far positioned response key). The results show that subjects reacted faster when motion direction of the dynamic stimulus was corresponding to the spatial position of the demanded response. In conclusion, this direction-based Simon effect is modulated by spatial position information, higher sensitivity of our visual system for looming objects, and a high salience of objects being on a collision course. PMID- 26586292 TI - Observation and physical practice: different practice contexts lead to similar outcomes for the acquisition of kinematic information. AB - This study differentiated the contributions of physical and observational practice to the learning of a single-limb multi-joint coordination pattern. Three groups (physical-practice, observation-practice, observation-physical) practiced for 2 days and were given two performance tests 24 h after the second practice session. The performance tests revealed that physical and observational practice contributed similarly to identifying and using kinematic information related to the relative motion direction between joints (lead/lag relationship) and to the to-be-learned relative phase pattern (phi = 90 degrees ). Physical practice resulted in more stable coordination during performance tests and in the ability to produce different joint amplitudes with less variability. A serendipitous finding was that maximum elbow flexion (point of movement reversal) emerged as a kinematic event around which elbow and wrist coordination were organized. Movement reversals often serve to anchor the movement dynamics, and this anchoring effect was evident following both physical and observational practice, yet physical practice resulted in an advantage with regard to this anchor point on several kinematic measures. The results are discussed within the context of contemporary behavioral theories (coordination dynamics, visual perception perspective) of observational learning. PMID- 26586293 TI - Prescriptions and proscriptions: moralising sleep medicines. AB - The pharmaceuticalisation of sleep is a contentious issue. Sleep medicines get a 'bad press' due to their potential for dependence and other side effects, including studies reporting increased mortality risks for long-term users. Yet relatively little qualitative social science research has been conducted into how people understand and negotiate their use/non-use of sleep medicines in the context of their everyday lives. This paper draws on focus group data collected in the UK to elicit collective views on and experiences of prescription hypnotics across different social contexts. Respondents, we show, drew on a range of moral repertoires which allowed them to present themselves and their relationships with hypnotics in different ways. Six distinct repertoires about hypnotic use are identified in this regard: the 'deserving' patient, the 'responsible' user, the 'compliant' patient, the 'addict', the 'sinful' user and the 'noble' non user. These users and non-users are constructed drawing on cross-cutting themes of addiction and control, ambivalence and reflexivity. Such issues are in turn discussed in relation to recent sociological debates on the pharmaceuticalisation/de-pharmaceuticalisation of everyday life and the consumption of medicines in the UK today. PMID- 26586294 TI - Effects of PTEN gene alteration in patients with gallbladder cancer. AB - Gallbladder cancer (GBC) is an aggressive malignancy usually diagnosed in an advanced stage. We investigated the effects of alterations of the phosphatase and tensin homologue (PTEN) gene on the occurrence and development of GBC, which has not been previously reported. A total 141 cases of GBC were analyzed for mutation, expression, and methylation across the nine exons of the PTEN gene. DNA sequencing methods were applied for mutation detection, whereas protein expression and methylation status were evaluated by immunohistochemical and methylation-specific PCR analysis, respectively. Novel PTEN mutations were observed in 6.3% of cases (9/141), and they included two silent mutations. In mutant cases, according to changes in codons, the respective amino acid sequences were also changed, which caused of proteins. A high percentage (72%) of loss of protein expression was observed more often in cases than in control samples. Interestingly, all nine cases with mutations showed loss of PTEN expression, whereas four of these nine cases showed positive promoter methylation. Hypermethylation was significantly more common in older patients than in younger ones (P<0.02). These findings suggest that PTEN mutations and inactivation may play an important role in the development and progression of gallbladder carcinoma. PMID- 26586295 TI - Non-biological determinants of paediatric bladder bowel dysfunction: A pilot study. AB - OBJECTIVES: Children with bladder and bowel dysfunction (BBD) constitute a significant proportion of referrals at paediatric urology clinics worldwide, presenting with a wide range of symptom severity that may significantly affect quality of life. Non-biological factors may play a key role in triggering BBD severity, but these underpinning causes of BBD during childhood are still unknown. The aim of this study was to identify the effects of personal, family related and environmental variables on the severity of BBD symptoms in school aged children. STUDY DESIGN: A pilot, prospective, observational study was conducted on 53 children diagnosed with BBD, and their legal guardian(s), on their first referred visit to a paediatric BBD clinic led by nurse practitioners. Upon receiving consent, patients and their legal guardian(s) completed three study questionnaires, with the guidance of research coordinators. The first questionnaire was the Dysfunctional Voiding Scoring System (DVSS); the second, a three-part questionnaire used to collect demographic information and data on the patient, their family and environmental characteristics; and the third gathered a detailed history of the child's lifestyle regimen, focusing on their bowel and bladder function. RESULTS: Most of the children were female (66%), with an average age of 8.35 years. Most children attended public schools (74%) and none reported failing a grade. The mean parental age was 41.4 years (SD = 4.9 years), 62% of the families had two children and 53% were Caucasian. The mean DVSS score for this sample was 9.9 (SD = 4.2, range 2-21). Daycare attendance, school problems and unplanned pregnancy showed statistically significant influences on the severity of BBD and were associated with higher DVSS scores according to the Table below. CONCLUSIONS: Children with BBD attending urology outpatient clinics as new referrals had more severe symptoms when they were born from an unplanned pregnancy, attended daycare and/or had school problems. These findings suggest that interventions aimed at decreasing BBD severity, or preventing its onset in school-aged children, should focus on the environment surrounding them, specifically on the interaction between personal, familial and environmental factors. These factors seem to have an important effect on paediatric continence, as children grow and develop under numerous societal influences and social interactions. PMID- 26586296 TI - 'Targeted top down' approach for the investigation of UTI: A 10-year follow-up study in a cohort of 1000 children. AB - INTRODUCTION: Investigations following urinary tract infection (UTI) aim to identify children who are prone to renal scarring, which may be preventable. In 2002, in an attempt to reduce unnecessary intervention, the present institution standardised the investigation of children with a confirmed UTI. OBJECTIVE: This study aimed to identify the significance of urological abnormalities on investigations following a UTI in children, prior to the introduction of the National Institute for Health and Care Excellence (NICE) guidelines. METHODS: Clinical information on the first 1000 patients was retrieved from a prospective UTI hospital database. The follow-up period was 10 years. RESULTS: There were 180 males and 820 females (M:F = 1:4.5). The median age of presentation was 5 years (range 11 days-16 years). A renal ultrasound (US) was performed on all patients, and was normal in 93% of cases (n = 889) (see Figure). Of the 7% who had an abnormal US (n = 71), 54 were female and 17 male (M:F = 1:3). A total of 372 DMSA scans were requested and 350 attended their appointment. Of these, 278 cases (79%) were reported as normal, while 72 had an abnormality documented. Of these 72 patients with abnormalities on DMSA scan, 49 had a repeat DMSA scan: 30 demonstrated permanent scarring, while the DMSA scan became normal in 19. Sixteen of the 278 patients whose DMSA scan was initially normal had a repeat DMSA scan due to symptoms, and all scans were normal. Twelve (1.2%) patients required surgical intervention: three underwent circumcision for recurrent UTIs; three underwent endoscopic treatment of VUR; one had a PUV resection; one underwent a cystoscopy; three had a pyeloplasty for pelvi-ureteric junction obstruction; and one had a ureteric reimplantation for vesico-ureteric junction obstruction. After initial investigations and management, 936 patients were discharged from the UTI clinic: 47 of them re-presented - 40 with recurrent UTIs and seven with dysuria. Thirty-five of the 47 children who re-presented with urological symptoms underwent a DMSA scan, which showed scarring in three (6%). DISCUSSION: Only 12% of children have a significant radiological abnormality picked up on investigation following a UTI. The present investigation approach differed from the NICE guidelines, where imaging is based on patient age and characteristics of the UTI. All children had a renal US, while DMSA scans were reserved for those children <1 year of age or those with upper tract symptoms. The present protocol recommended a renal US in all children presenting with a UTI. This promptly identified those with pelvi-ureteric junction obstruction and those with PUV, who all presented >6 months of age with a single UTI and, therefore, based on the NICE guidelines would not have undergone a renal US. Of the children who re presented with further UTIs, a significant number were found to have dysfunctional voiding. As this link is well reported, it may be appropriate to screen for this in older children at initial presentation. Only three patients, who had a US at presentation, were subsequently found to have scarring on DMSA. After 10 years of follow-up, this could represent a false negative rate of 0.3% for the screening programme. None of the girls were found to have VUR or needed any surgical intervention, which suggested that early identification of the scarring might not have altered management. Few patients required surgical intervention, all of whom were identified early. No patient who re-presented required intervention. This would suggest that the present protocol is effective at picking up abnormalities that require surgical management. CONCLUSION: This study suggested that after a childhood UTI, the liberal use of renal ultrasound and a focused 'top down' approach to investigation is likely to identify the vast majority of children who require intervention. PMID- 26586297 TI - Multidrug resistance protein 1 reduces the aggregation of mutant huntingtin in neuronal cells derived from the Huntington's disease R6/2 model. AB - Mutant huntingtin (mHtt) aggregation in the nucleus is the most readily apparent phenotype and cause of neuronal death in Huntington's disease (HD). Inhibiting mHtt aggregation reduces cell death in the brain and is thus a promising therapeutic approach. The results of the present study demonstrated that mHtt aggregation in the nucleus was altered by the activity of multidrug resistance protein 1 (MDR1), which was experimentally modulated by verapamil, siRNA and an expression vector. MDR1 detoxifies drugs and metabolites through its excretory functions in the membrane compartment, thereby protecting cells against death or senescence. When they were treated with verapamil, R6/2 mice showed a progressive decline in rotarod performance and increased mHtt aggregation in the brain. Using neuronal stem cells from R6/2 mice, we developed an in vitro HD model to test mHtt accumulation in the nuclei of neurons. When MDR1 activity in cells was decreased by verapamil or siRNA, mHtt aggregation in the nuclei increased, whereas the induction of MDR1 resulted in a decrease in mHtt aggregation. Thus, our data provide evidence that MDR1 plays an important role in the clearance of mHtt aggregation and may thus be a potential target for improving the survival of neurons in Huntington's disease. PMID- 26586298 TI - Photoreactive helical nanoaggregates exhibiting morphology transition on thermal reconstruction. AB - The supramolecular design of photochromic molecules has produced various smart molecular assemblies that can switch their structures and/or functions in response to light stimuli. However, most of these assemblies require large structural changes of the photochromic molecules for an efficient conversion of assembled states, which often suppresses the photoreactivity within the self assemblies. Here we report molecular assemblies, based on a photo-cross-linkable chromophoric dyad, in which a small amount of ultraviolet-generated photochemical product can guide the entire system into different assembly processes. In apolar solution, the intact dyad self-assembles into right-handed superhelical fibrils. On ultraviolet-irradiation of these fibrils, an effective photoreaction affords a sole photo-cross-linked product. When right-handed helical fibrils, containing a minor amount of the photoproduct, are thermally reconstructed, the intact molecule and the photoproduct undergo a co-assembly process that furnishes superhelical fibrils with different molecular packing structures. This molecular design principle should afford new paradigms for smart molecular assemblies. PMID- 26586299 TI - Mechanical resistance of the periorbita and the orbital floor complex--are isolated orbital floor fractures only a soft tissue problem? AB - The primary aims of orbital floor reconstruction are to prevent enophthalmos and herniation of the orbital contents in order to achieve correct globe position. Theoretically, the mechanical load of the orbital floor is approximately 0.0005N/mm(2) (30g orbital content onto 600mm(2) of orbital floor area). Therefore, low mechanical stress from orbital floor reconstruction materials is expected. The periorbita and orbital floor complex (bony orbital floor with periorbita) of 12 human cadavers were investigated for their mechanical resistance to distortion and compared to different absorbable pliable reconstruction materials after modification with pores (Bio-Gide, Creos, and PDS). The human periorbita resistance (approximately 1.4N/mm(2)) was comparable to that of the absorbable membranes (Creos, Bio-Gide), and the resistance of PDS (approximately 2.3N/mm(2)) was comparable to that of the orbital floor complex. The periorbita has a higher stability than the bony orbital floor. Therefore, in isolated orbital floor fractures with a traumatized bony orbital floor and periorbita, reconstruction of the soft tissue as a periorbita equivalent with a resorbable membrane appears to be adequate to prevent enophthalmos and herniation of the orbital contents. PMID- 26586300 TI - Effects of pulsed electromagnetic fields on swelling and pain after implant surgery: a double-blind, randomized study. AB - The aim of this split-mouth, double-blind, randomized study was to determine whether pulsed electromagnetic field therapy (PEMF) can improve swelling and the management of pain after full-arch immediate loading implant surgery. Eleven patients were selected for the study. Each patient received four distal tilted implants in the upper or lower jaw and underwent full-arch immediate loading rehabilitation. After surgery, two PEMF devices were applied to each patient, one on each cheek. In a random manner, one of these PEMF devices was switched on (test side); the other served as a placebo (control side). Forty-eight hours after surgery clinicians estimated postoperative swelling through photographic documentation, comparing the condition before and after surgery, while pain was assessed using a verbal rating scale. The patient's degree of comfort in relation to the PEMF devices was analyzed by questionnaire using a numerical rating scale. No statistically significant difference was observed between the test and control sides for swelling or pain (P>0.05). Most of the patients did not present swelling or pain at 48h after surgery, regardless of whether the PEMF device was activated or not. Various outcomes were found in the comfort evaluation. Within the limitations of this study, PEMF does not reduce postoperative swelling or pain after implant surgery. PMID- 26586301 TI - Anthropomorphic assessment of the retromolar foramen and retromolar nerve: anomaly or variation of normal anatomy? AB - The retromolar foramen, retromolar canal, and retromolar nerve constitute a variation of the inferior alveolar nerve (IAN) with a prevalence of 12-75%; this represents type 1 bifidity of the IAN. The aim of this study was to assess the prevalence of the retromolar nerve in our population and to obtain related data. One hundred and thirty-six mandibles of fresh cadavers aged 20-75 years were dissected. The buccolingual location, diameter, and distance from the third molar, and their associations with sex, were measured. The area of innervation and demographic data were also documented and analysed statistically. The retromolar foramen and retromolar nerve were observed in 55 cases (40.4%). The mean diameter of the retromolar foramen was 1.7 mm (range 1.1-2.1 mm); the mean diameter was 1.8 mm in males and 1.5mm in females. Histological findings showed that the retromolar nerve extended from the anterior border of the ramus, innervating the retromolar pad and continuing to the buccal gingiva of up to two teeth anteriorly (first molar region). This high percentage of IAN type 1 bifidity (40.4%) suggests it to be a normal anatomical variation of the IAN rather than an anomaly. PMID- 26586302 TI - Economy matters to fight against malnutrition: Results from a multicenter survey. AB - BACKGROUND AND AIM: Malnutrition represents a serious health care threat, as it increases morbidity, mortality and health care cost. The effective screening and treatment with enteral (EN) or parenteral (PN) nutrition are the key elements of the policy called Optimal Nutrition Care for All (ONCA). The study tried to analyze the impact of the state's economy on the implementation of EN and PN to define its role in ONCA. MATERIAL AND METHODS: an international survey in twenty two European countries was performed between January and December 2014. An electronic questionnaire was distributed to 22 representatives of clinical nutrition (PEN) societies. The questionnaire comprised questions regarding country economy, reimbursement, education and the use EN and PN. Return rate was 90.1% (n = 20). RESULTS: EN and PN were used in all countries surveyed (100%), but to different extent. The country's income significantly influenced the reimbursement for EN and PN (p < 0.05). It was also associated with the overall use of tube feeding and PN (p = 0.05), but not with the use of oral nutritional supplements (p = 0.165). The use of both, EN and PN at hospitals was not depended on the economy (p > 0.05). Education was actively carried out in all countries, however the teaching at the pre-graduate level was the least widespread, and also correlated with the country income (p = 0.042). CONCLUSIONS: Results indicated that economic situation influences all aspects of ONCA, including education and treatment. The reimbursement for EN and PN seemed to be the key factor of effective campaign against malnutrition. PMID- 26586304 TI - Novel strategies for diagnosing the cause of short-term organic fouling in ultrafiltration. AB - The main objective of this study was to demonstrate the usefulness of a multi strategic approach for identifying the extent and mechanism of fouling in the ultrafiltration (UF) of wastewater effluent organic matter (EfOM). In this study, we combined EfOM fractionation with spectroscopic autopsies for clean and fouled UF membranes. The EfOM fractions were sequentially removed from the wastewater effluent using relatively gentle techniques (neutral pH and no extractions). The residual EfOM samples were then used in UF tests. This work showed that resistance to filtration was partially reduced with the removal of particles (>20 nm), but almost all of the short-term fouling was eliminated with the removal of organic acids, which constitute 22% of the total organic carbon. The membrane autopsies were conducted using attenuated reflectance infrared spectroscopy for the top and bottom fouled membranes, and comparison was made with the infrared spectra of a clean membrane. Hydrophilic base/neutrals were the dominant EfOM constituents at the top of the fouled membranes. Hydrophobic acids were adsorbed onto the pore walls deep inside the membranes, which coincided with the permeability recovery of fouled membranes. The fouling mechanisms were examined by measuring the resistance to filtration as a function of permeate flux using various operational conditions and by investigating the effectiveness of hydraulic and chemical cleaning on the restoration of membrane permeability. PMID- 26586303 TI - The metabolism and disposition of GSK2140944 in healthy human subjects. AB - 1. GSK2140944 is a novel bacterial topoisomerase inhibitor in development for the treatment of bacterial infections. The metabolism and disposition in healthy human subjects was investigated. 2. Six male subjects received [(14)C] GSK2140944 orally (2000 mg) and as a single 2-hour i.v. infusion (1000 mg). Urinary elimination (59%) was major by the i.v. route, whereas fecal elimination (53%) pre-dominated via the oral route. Accelerator mass spectrometry (AMS) was used for the analysis of plasma and bile samples due to the low level of radioactivity in samples (low specific activity of the doses). Unchanged GSK2140944 was the predominant circulating component (>60% DRM), with the main circulating metabolite M4 formed by oxidation of the triazaacenaphthylene moiety representing 10.8% (considered major) and 8.6% drug-related material by the oral and i.v. route, respectively. Approximately 50% of the oral dose was absorbed and eliminated mainly as unchanged GSK2140944 in urine (~20% of dose). Elimination via metabolism (~13% of dose) was relatively minor. The facile oxidation of GSK2140944 to metabolite M4 was believed to be a result of activation by adjacent electron withdrawing groups. 3. This study demonstrates the use of AMS to overcome radioprofiling challenges presented by low specific activity resulted from high doses administration. PMID- 26586305 TI - Are ready-to-eat salads ready to eat? An outbreak of Salmonella Coeln linked to imported, mixed, pre-washed and bagged salad, Norway, November 2013. AB - We investigated a nationwide outbreak of Salmonella Coeln in Norway, including 26 cases identified between 20 October 2013 and 4 January 2014. We performed a matched case-control study, environmental investigation and detailed traceback of food purchases to identify the source of the outbreak. In the case-control study, cases were found to be more likely than controls to have consumed a ready-to-eat salad mix (matched odds ratio 20, 95% confidence interval 2.7-infinity). By traceback of purchases one brand of ready-to-eat salad was indicated, but all environmental samples were negative for Salmonella. This outbreak underlines that pre-washed and bagged salads carry a risk of infection despite thorough cleaning procedures by the importer. To further reduce the risk of infection by consumption of ready-to-eat salads product quality should be ensured by importers. Outbreaks linked to salads reinforce the importance of implementation of appropriate food safety management systems, including good practices in lettuce production. PMID- 26586306 TI - Fish oil improves lipid profile in juvenile rats with intrauterine growth retardation by altering the transcriptional expression of lipid-related hepatic genes. AB - OBJECTIVE: To determine whether maternal intrauterine undernutrition and post weaning fish oil intake influence lipid profile in juvenile offspring, and explore the possible mechanisms at transcriptional levels. METHODS: After weaning, 32 control offspring and 24 intrauterine growth retardation (IUGR) offspring were randomly allocated to standard chow or fish oil diet. At 10 weeks, fasting plasma glucose, triglycerides, total cholesterol and expressions of related hepatic genes were examined. RESULTS: IUGR offspring without catch-up growth tended to develop hyperglycemia, dyslipidemia and hepatic steatosis. Down regulation of CPT-1 and LDLR at transcriptional levels were found in IUGR offspring. Early short-term fish oil intervention reversed these unfavorable changes in juvenile rats with IUGR. The mechanisms might be mediated by decreased expression of ACC-1, increased expression of CPT-1, LDLR and ABCG5. CONCLUSION: These data suggest that IUGR offspring already present lipid abnormality in juvenile stage, and early short-term fish oil consumption is beneficial to prevent these unfavorable changes. PMID- 26586307 TI - Atrial Switch Operation in a Late Presenter With d-Transposed Great Arteries, Juxtaposed Atrial Appendages, and Bilateral Superior Caval Veins. AB - A 26-year-old patient with d-transposition of great arteries (d-TGA), bilateral superior vena cava, and juxtaposed atrial appendages underwent a successful atrial switch operation. It is extremely uncommon to encounter a previously unpalliated patient with d-TGA at this age. Unusual morphologic features in this patient necessitated technical modifications to successfully accomplish an atrial switch procedure. PMID- 26586308 TI - Novel Technique to Evaluate Pulmonary Vascular Resistance in a Patient With Aortopulmonary Window. AB - We report a case of a 15-month-old female presenting with a large aortopulmonary window during a medical mission. The optimal surgical correction for this patient would be based on an estimation of her pulmonary vascular reactivity. This report details the use of antegrade/retrograde flow ratios using Doppler measurements in the proximal descending aorta at baseline and while receiving 100% oxygen. A large increase in the proportion of retrograde flow under the 100% oxygen condition suggested a reactive pulmonary vascular bed. She underwent a complete repair with patch closure of the aortopulmonary window. A postoperative echocardiographic assessment showed near normal right ventricular pressures. PMID- 26586309 TI - Helping Adolescents with Type 1 Diabetes "Figure It Out". AB - The aim of this study was to gain an understanding of adolescent's experiences living with diabetes and build a theoretical paradigm for future interventions in adolescents with type 1 diabetes mellitus (T1DM). The adolescent's quest for independence, balancing blood sugars, and integrating diabetes led to increased conflict with parents which contributed to difficulty coping. One code in this study, "figuring it out", is the focus of this manuscript. METHODS: Grounded theory with 15 in depth interviews were conducted with adolescents ages 11 to 15 with T1DM. RESULTS: A theoretical model about the concept of "normalizing" was identified. Normalizing was defined as the ability to integrate diabetes into the background of one's daily life to make diabetes 'part of me'. The fifth phase of normalizing was "Figuring it out" which had 4 sub codes: (1) learning to accept diabetes, (2) believing it's possible to manage their diabetes, (3) showing responsibility, and (4) staying on track, and the normalizing task was "accepting the new normal". CONCLUSIONS: Adolescents with T1DM develop the understanding that diabetes is their 'new normal'. The use of motivational interviewing, goal setting, and promotion of self-management may be important interventions in supporting adolescents with T1DM to normalize their life. PMID- 26586310 TI - Human Papillomavirus Infection and Vaccination. AB - Human papillomavirus (HPV) is an infection that can be sexually transmitted and result in health consequences including genital warts and cancers. Two vaccines, Gardasil(r) [Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant] and CervarixTM [Human Papillomavirus Bivalent (Types 16 and 18) Vaccine], have been approved for the prevention of HPV and HPV-related diseases. OBJECTIVES: To explore facilitators and barriers associated with HPV vaccine utilization and compliance regarding vaccine series completion in school-aged, adolescent, and young adult females in the United States; to discuss HPV infection and highlight the safety and efficacy of the HPV vaccine; and to illustrate delivery strategies that can improve immunization rates and review implications for healthcare providers. METHODS: A literature review was performed using health-related online databases (CINAHL, MEDLINE, PubMED, Web of Science, EBSCOHost and Google Scholar) and archival searching to identify current vaccination rates and factors associated with vaccine uptake. RESULTS: Despite the availability of vaccines that prevent cancer, acceptance and utilization rates of both HPV vaccines are less than recommended by the Advisory Committee for Immunization Practices (ACIP). Some of the barriers to HPV vaccination include lack of provider recommendation, negative parent or patient attitudes and beliefs, cost, and missed clinical opportunities. The primary facilitator to HPV vaccination is a strong provider recommendation. CONCLUSIONS: Healthcare providers can enhance HPV vaccine utilization by taking an active role with patients. Strategies include education and advocacy for receiving the vaccine, maximizing access to the HPV vaccine, and implementing new strategies for vaccine delivery. PMID- 26586311 TI - 5-HT2 receptor blockade exhibits 5-HT vasodilator effects via nitric oxide, prostacyclin and ATP-sensitive potassium channels in rat renal vasculature. AB - The aim of this study was to determine whether orally sarpogrelate (selective 5 HT2 antagonist) treatment (30 mg/kg/day; 14 days) could modify 5-HT renal vasoconstrictor responses, characterizing 5-HT receptors and mediator mechanisms involved in serotonergic responses in the in situ autoperfused rat kidney. Intra arterial (i.a.) injections of 5-HT (0.00000125 to 0.1 MUg/kg) decreased renal perfusion pressure (RPP) but did not affect the mean blood pressure (MBP). i.a. agonists 5-CT (5-HT1/7), CGS-12066B (5-HT1B), L-694,247 (5-HT1D) or AS-19 (5-HT7) mimicked renal 5-HT vasodilator effect. However, neither 8-OH-DPAT (5-HT1A) nor 1 phenylbiguanide (5-HT3) modified RPP. Moreover: (i) GR-55562 (5-HT1B antagonist) and L-NAME (nitric oxide synthase [NOS] inhibitor) blocked CGS-12066B-induced vasodilator response, (ii) LY310762 (5-HT1D antagonist) and indomethacin (non selective cyclooxygenase inhibitor) blocked L-694,247-induced vasodilator response; (iii) SB-258719 (5-HT7 antagonist) and glibenclamide (ATP-sensitive K+ channel blocker) blocked AS-19-induced vasodilator response; and (iv) 5-HT- or 5 CT-elicited renal vasodilation was significantly blocked by the mixture of GR 55562 + LY310762 + SB-258719. Furthermore, eNOS and iNOS proteins and prostacyclin levels are overexpressed in sarpogrelate-treated rats. Our data suggest that 5-HT exerts renal vasodilator effect in the in situ autoperfused sarpogrelate-treated rat kidney, mediated by 5-HT1D, 5-HT1B and 5-HT7 receptors, involving cyclooxygenase-derived prostacyclin, nitric oxide synthesis/release and ATP-sensitive K+ channels, respectively. PMID- 26586312 TI - Soluble N-cadherin: A novel inhibitor of VSMC proliferation and intimal thickening. AB - Reoccurrence of symptoms occurs in 30-50% of coronary artery disease patients receiving vein grafts or bare-metal stents due to intimal thickening (restenosis). Restenosis is caused by vascular smooth muscle cell (VSMC) migration and proliferation. New therapeutic approaches that reduce VSMC migration and proliferation while promoting endothelial cell (EC) coverage are required. We assessed the effect of a soluble form of N-cadherin (SNC-Fc, a fusion of the extracellular portion of N-Cadherin to a mutated Fc fragment of IgG), a cell-cell junction molecule, on human saphenous VSMC proliferation and migration in vitro. We also assessed its effect on intimal thickening in a validated human ex vivo organ culture model. We observed that SNC-Fc significantly inhibited VSMC proliferation and to a lesser extent migration. The anti-proliferative effect of SNC-Fc was mediated by the interaction of SNC-Fc with the FGFR, rather than through inhibition of beta-catenin signalling. SNC-Fc also significantly reduced intimal thickening by ~85% in the ex vivo organ culture model. SNC-Fc treatment inhibited proliferation of the intimal cells but did not affect migration. SNC-Fc reduced EC apoptosis, without detrimental effects on EC proliferation and migration in vitro. Importantly SNC-Fc increased EC coverage in the ex vivo model of intimal thickening. In conclusion, we suggest that SNC-Fc may have potential as an anti-proliferative therapeutic agent for reducing restenosis which has no detrimental effects on endothelial cells. PMID- 26586313 TI - The vasodilator papaverine stimulates L-type Ca(2+) current in rat tail artery myocytes via a PKA-dependent mechanism. AB - Papaverine is an opium alkaloid, primarily used as an antispasmodic drug and as a cerebral and coronary vasodilator. Its phosphodiesterase inhibitory activity promotes increase of cAMP levels mainly in the cytosol. As cAMP is known to modulate L-type Ca(2+) channel activity, here we tested the proposition that papaverine could affect vascular channel function. An in-depth analysis of the effect of papaverine on Ba(2+) or Ca(2+) current through L-type Ca(2+) channel [IBa(L) or ICa(L)], performed in rat tail artery myocytes using either the whole cell or the perforated patch-clamp method, was accompanied by a functional study on rat aorta rings. Papaverine increased current amplitude under both the perforated or whole-cell configuration. Stimulation of the current by papaverine was concentration-, Vh-, frequency-, and charge carrier-dependent, and fully reverted by drug washout. The PKA inhibitor H89, but not the PKG inhibitor Rp-8 Br-cGMPS, antagonised papaverine- as well as IBMX- (another phosphodiesterase inhibitor) induced IBa(L) stimulation. In cells pre-treated with IBMX, application of papaverine failed to increase current amplitude. Papaverine sped up the inactivation kinetics of IBa(L), though only at concentrations >= 30 MUM, and shifted the voltage dependence of the inactivation curve to more negative potentials. In rings, the vasorelaxing activity of papaverine was enhanced by previous treatment with nifedipine. In conclusion, papaverine stimulates vascular L-type Ca(2+) channel via a PKA-dependent mechanism, thus antagonising its main vasodilating activity. PMID- 26586315 TI - Correction. PMID- 26586314 TI - Postprandial nutrient-sensing and metabolic responses after partial dietary fishmeal replacement by soyabean meal in turbot (Scophthalmus maximus L.). AB - In this study, we chose a carnivorous fish, turbot (Scophthalmus maximus L.), to examine its nutrient-sensing and metabolic responses after ingestion of diets with fishmeal (FM), or 45% of FM replaced by soyabean meal (34.6% dry diet) balanced with or without essential amino acids (EAA) to match the amino acid profile of FM diet for 30 d. After a 1-month feeding trial, fish growth, feed efficiency and nutrient retention were markedly reduced by soyabean meal incorporated (SMI) diets. Compared with the FM diet, SMI led to a reduction of postprandial influx of free amino acids, hypoactivated target of rapamycin signalling and a hyperactivated amino acid response pathway after refeeding, a status associated with reduced protein synthesis, impaired postprandial glycolysis and lipogenesis. These differential effects were not ameliorated by matching an EAA profile of soyabean meal to that of the FM diet through dietary amino acid supplementation. Therefore, this study demonstrated that the FM diet and SMI diets led to distinct nutrient-sensing responses, which in turn modulated metabolism and determined the utilisation efficiency of diets. Our results provide a new molecular explanation for the role of nutrient sensing in the inferior performance of aquafeeds in which FM is replaced by soyabean meal. PMID- 26586316 TI - Correction. PMID- 26586318 TI - Correction. PMID- 26586317 TI - Chiropractic spinal manipulative therapy for migraine: a study protocol of a single-blinded placebo-controlled randomised clinical trial. AB - INTRODUCTION: Migraine affects 15% of the population, and has substantial health and socioeconomic costs. Pharmacological management is first-line treatment. However, acute and/or prophylactic medicine might not be tolerated due to side effects or contraindications. Thus, we aim to assess the efficacy of chiropractic spinal manipulative therapy (CSMT) for migraineurs in a single-blinded placebo controlled randomised clinical trial (RCT). METHOD AND ANALYSIS: According to the power calculations, 90 participants are needed in the RCT. Participants will be randomised into one of three groups: CSMT, placebo (sham manipulation) and control (usual non-manual management). The RCT consists of three stages: 1 month run-in, 3 months intervention and follow-up analyses at the end of the intervention and 3, 6 and 12 months. The primary end point is migraine frequency, while migraine duration, migraine intensity, headache index (frequency x duration x intensity) and medicine consumption are secondary end points. Primary analysis will assess a change in migraine frequency from baseline to the end of the intervention and follow-up, where the groups CSMT and placebo and CSMT and control will be compared. Owing to two group comparisons, p values below 0.025 will be considered statistically significant. For all secondary end points and analyses, a p value below 0.05 will be used. The results will be presented with the corresponding p values and 95% CIs. ETHICS AND DISSEMINATION: The RCT will follow the clinical trial guidelines from the International Headache Society. The Norwegian Regional Committee for Medical Research Ethics and the Norwegian Social Science Data Services have approved the project. Procedure will be conducted according to the declaration of Helsinki. The results will be published at scientific meetings and in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT01741714. PMID- 26586319 TI - Does COPD have a clinically relevant impact on hearing loss? A retrospective matched cohort study with selection of patients diagnosed with COPD. AB - OBJECTIVES: Chronic obstructive pulmonary disease (COPD) as a multisystemic disease has a measurable and biologically explainable impact on the auditory function detectable in the laboratory. This study tries to clarify if COPD is also a significant and clinically relevant risk factor for hearing impairment detectable in the general practice setting. DESIGN: Retrospective matched cohort study with selection of patients diagnosed with COPD. SETTING: 12 general practices in Lower Austria. PARTICIPANTS: Consecutive patients >35 years with a diagnosis of COPD who consulted 1 of 12 single-handed GPs in 2009 and 2010 were asked to participate. Those who agreed were individually 1:1 matched with controls according to age, sex, hypertension, diabetes, coronary heart disease and chronic heart failure. MAIN OUTCOME MEASURES: Sensorineural hearing impairment as assessed by pure tone audiometry, answers of three questions concerning a self-perceived hearing problem, application of the whispered voice test and the score of the Hearing Inventory for the Elderly, Screening Version (HHIE-S). RESULTS: 194 patients (97 pairs of 194 cases and controls) with a mean age of 65.5 (SD 10.2) were tested. Univariate conditional logistic regression resulted in significant differences in the mean bone conduction hearing loss and in the total score of HHIE-S, in the multiple conditional regression model, only smoking (p<0.0001) remained significant. CONCLUSIONS: The results of this study do not support the hypothesis that there is an association between COPD and hearing impairment which, if found, would have allowed better management of patients with COPD. PMID- 26586320 TI - Correction. PMID- 26586321 TI - Correction. PMID- 26586322 TI - A pilot, quasi-experimental, mixed methods investigation into the efficacy of a group psychotherapy intervention for caregivers of outpatients with cancer: the COPE study protocol. AB - INTRODUCTION: Despite the rising trend of cancer prevalence and increase in family caregiving, little attention has been paid to the efficacy of psychosocial interventions among Asian caregiver samples, particularly support groups, given the benefits that have been shown in studies on Western populations. This trial aims to evaluate the effectiveness of a pilot 4-week group psychotherapy for Singaporean family caregivers of patients receiving outpatient care. METHODS AND ANALYSIS: Facilitated by a clinical psychologist, this intervention is primarily based on the brief integrative psychological therapy with a supportive-expressive intent. Participants will be recruited while they are accompanying their care recipients for outpatient consultations. Since this is a pilot study, a sample size of 120 participants is targeted on the basis of sample sizes of previous studies. The study adopts a quasi-experimental design, as participants are assigned the intervention or control arms based on their availability to attend the intervention. A mixed methods approach is used to evaluate the outcomes of the intervention. A self-administered battery of tests is completed at four time points: baseline, postintervention and follow-up at 1-month and 2-month postinterventions; semi-structured interviews are conducted at baseline and post intervention. Primary outcomes are quality of life and anxious and depressive symptoms; secondary outcomes are stress and basic psychological needs. Analysis using analysis of covariance would be conducted to determine the effectiveness of the intervention. ETHICS AND DISSEMINATION: This study protocol has ethics approval from the National Healthcare Group Domain Specific Review Board (NHG DSRB Ref: 2013/00662). Written informed consent is obtained from every participant. Results will be disseminated through journals and conferences, and will be particularly relevant for clinicians intending to implement similar support groups to address the psychosocial concerns of caregivers, as well as for researchers seeking to refine the structure and evaluate the effectiveness of such programmes. TRIAL REGISTRATION NUMBER: Current Controlled Trials NCT02120183 (https://clinicaltrials.gov/show/NCT02120183). PMID- 26586323 TI - Role of context in care transition interventions for medically complex older adults: a realist synthesis protocol. AB - INTRODUCTION: Approximately 30-50% of older adults have two or more conditions and are referred to as multimorbid or complex patients. These patients often require visits to various healthcare providers in a number of settings and are therefore susceptible to fragmented healthcare delivery while transitioning to receive care. Care transition interventions have been implemented to improve continuity of care, however, current evidence suggests that some interventions or components of interventions are only effective within certain contexts. There is therefore a need to unpack the mechanisms of how and within which contexts care transition interventions and their components are effective. Realist review is a synthesis method that explains how complex programmes work within various contexts. The purpose of this study is to explain the effect of context on the activities and mechanisms of care transition interventions in medically complex older adults using a realist review approach. METHODS AND ANALYSIS: This synthesis will be guided by Pawson and colleagues' 2004 and 2005 protocols for conducting realist reviews. The underlying theories of care transition interventions were determined based on an initial literature search using relevant databases. English language peer-reviewed studies published after 1993 will be included. Several relevant databases will be searched using medical subject headings and text terms. A screening form will be piloted and titles, abstracts and full text of potentially relevant articles will be screened in duplicate. Abstracted data will include study characteristics, intervention type, contextual factors, intervention activities and underlying mechanisms. Patterns in Context-Activity-Mechanism-Outcome (CAMO) configurations will be reported. ETHICS AND DISSEMINATION: Internal knowledge translation activities will occur throughout the review and existing partnerships will be leveraged to disseminate findings to frontline staff, hospital administrators and policymakers. Finalised results will be presented at local, national and international conferences, and disseminated via peer-reviewed publications in relevant journals. PMID- 26586324 TI - Perceptions of emergency care in Kenyan communities lacking access to formalised emergency medical systems: a qualitative study. AB - OBJECTIVES: We undertook this study in Kenya to understand the community's emergency care needs and barriers they face when trying to access care, and to seek community members' thoughts regarding high impact solutions to expand access to essential emergency services. DESIGN: We used a qualitative research methodology to conduct 59 focus groups with 528 total Kenyan community member participants. Data were coded, aggregated and analysed using the content analysis approach. SETTING: Participants were uniformly selected from all eight of the historical Kenyan provinces (Central, Coast, Eastern, Nairobi, North Eastern, Nyanza, Rift Valley and Western), with equal rural and urban community representation. RESULTS: Socioeconomic and cultural factors play a major role both in seeking and reaching emergency care. Community members in Kenya experience a wide range of medical emergencies, and seem to understand their time critical nature. They rely on one another for assistance in the face of substantial barriers to care-a lack of: system structure, resources, transportation, trained healthcare providers and initial care at the scene. CONCLUSIONS: Access to emergency care in Kenya can be improved by encouraging recognition and initial treatment of emergent illness in the community, strengthening the pre-hospital care system, improving emergency care delivery at health facilities and creating new policies at a national level. These community generated solutions likely have a wider applicability in the region. PMID- 26586325 TI - Managing uncertainty in advanced liver disease: a qualitative, multiperspective, serial interview study. AB - OBJECTIVE: To understand the experiences and support needs of people with advanced liver disease and those of their lay and professional carers to inform improvements in the supportive and palliative care of this rapidly growing but currently neglected patient group. DESIGN: Multiperspective, serial interviews. We conducted up to three qualitative in-depth interviews with each patient and lay carer over 12 months and single interviews with case-linked healthcare professionals. Data were analysed using grounded theory techniques. PARTICIPANTS: Patients with advanced liver disease of diverse aetiologies recruited from an inpatient hepatology ward, and their lay carers and case-linked healthcare professionals nominated by the patients. SETTING: Primary and secondary care in South-East Scotland. RESULTS: 37 participants (15 patients, 11 lay and 11 professional carers) completed 51 individual and 13 joint patient-carer interviews. Nine patients died during the study. Uncertainty dominated experiences throughout the course of the illness, across patients' considerable physical, psychological, social and existential needs and affected patients, lay carers and professionals. This related to the nature of the condition, the unpredictability of physical deterioration and prognosis, poor communication and information-sharing, and complexities of care. The pervasive uncertainty also shaped patients' and lay carers' strategies for coping and impeded care planning. While patients' acute medical care was usually well coordinated, their ongoing care lacked structure and focus. CONCLUSIONS: Living, dying and caring in advanced liver disease is dominated by pervasive, enduring and universally shared uncertainty. In the face of high levels of multidimensional patient distress, professionals must acknowledge this uncertainty in constructive ways that value its contribution to the person's coping approach. Pervasive uncertainty makes anticipatory care planning in advanced liver disease challenging, but planning 'just in case' is vital to ensure that patients receive timely and appropriate supportive and palliative care alongside effective management of this unpredictable illness. PMID- 26586326 TI - Mesh fixation methods in open inguinal hernia repair: a protocol for network meta analysis and trial sequential analysis of randomised controlled trials. AB - INTRODUCTION: Randomised clinical trials (RCTs) have been used to compare and evaluate different types of mesh fixation usually employed to repair open inguinal hernia. However, there is no consensus among surgeons on the best type of mesh fixation method to obtain optimal results. The choice often depends on surgeons' personal preference. This study aims to compare different types of mesh fixation methods to repair open inguinal hernias and their role in the incidences of chronic groin pain, risk of hernia recurrence, complications, operative time, length of hospital stay and postoperative pain, using Bayesian network meta analysis and trial sequential analysis of RCTs. METHODS AND ANALYSIS: A systematic search will be performed using PubMed, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Chinese Biomedical Literature Database (CBM) and Chinese Journal Full-text Database, to include RCTs of different mesh fixation methods (or fixation vs no fixation) during open inguinal hernia repair. The risk of bias in included RCTs will be evaluated according to the Cochrane Handbook V.5.1.0. Standard pairwise meta-analysis, trial sequential analysis and Bayesian network meta-analysis will be performed to compare the efficacy of different mesh fixation methods. ETHICS AND DISSEMINATION: Ethical approval and patient consent are not required since this study is a meta-analysis based on published studies. The results of this network meta-analysis and trial sequential analysis will be submitted to a peer-reviewed journal for publication. PROTOCOL REGISTRATION NUMBER: PROSPERO CRD42015023758. PMID- 26586328 TI - A new tobamovirus infecting tomato crops in Jordan. AB - In this study, we completed the whole genome sequence of a new tobamovirus isolated from tomato plants grown in greenhouses in Jordan during the spring of 2015. The 6393-nt single-stranded RNA (ssRNA) genome encodes four proteins, as do other tobamoviruses: two replication-related proteins of 126 kDa and 183 kDa, a 30-kDa movement protein (MP) and a 17.5-kDa coat protein (CP). Phylogenetic analysis showed that this virus does not group with either the tomato mosaic virus (ToMV) or the tobacco mosaic virus (TMV) clades. Instead, it stems from a branch leading to the TMV clade. Analysis of possible recombination events between this virus and representative isolates of closely related tomato infecting tobamoviruses showed that at least one region originated by recombination. We provide evidence that we have identified a new tobamovirus, for which we propose the name "tomato brown rugose fruit virus". PMID- 26586329 TI - Complete genome sequence of a strain of Actinidia virus X detected in Ribes nigrum cv. Baldwin showing unusual symptoms. AB - A Ribes-infecting strain of the potexvirus Actinidia virus X (AVX-RV3124) was isolated from black currant plants (Ribes nigrum cv. Baldwin, accession 3124 03D1) showing symptoms of leaf chlorosis and deformity. This is the first description of the complete genome sequence of an isolate of this virus and the first detection of a potexvirus in Ribes. The genome of AVX-RV3124 consists of 6,888 nucleotides (nt) excluding the poly(A) tail at the 3' terminus. When AVX RV3124 was compared to the available sequence of the AVX isolate in GenBank (accession no. KC568202), two large indel events (72 nt and 33 nt) were identified in the replicase coding region of RV3124. Evidence of recombination was detected upstream of the 3' terminus of the replicase gene of both virus isolates, providing further evidence of a common origin. PMID- 26586327 TI - Cardiovascular, renal and gastrointestinal effects of incretin-based therapies: an acute and 12-week randomised, double-blind, placebo-controlled, mechanistic intervention trial in type 2 diabetes. AB - INTRODUCTION: Incretin-based therapies, that is, glucagon-like peptide (GLP)-1 receptor agonists and dipeptidyl peptidase (DPP)-4 inhibitors, are relatively novel antihyperglycaemic drugs that are frequently used in type 2 diabetes management. Apart from glucose-lowering, these agents exhibit pleiotropic actions that may have favourable and unfavourable clinical consequences. Incretin-based therapies have been associated with heart rate acceleration, heart failure, acute renal failure and acute pancreatitis. Conversely, these agents may reduce blood pressure, glomerular hyperfiltration, albuminuria and hepatic steatosis. While large-sized cardiovascular safety trials can potentially identify the clinical significance of some of these pleiotropic actions, small-sized mechanistic studies are important to understand the (patho)physiological rationale of these findings. The current protocol describes a mechanistic study to assess cardiovascular, renal and gastrointestinal effects, and mechanisms of incretin based therapies in type 2 diabetes. METHODS AND ANALYSES: 60 patients with type 2 diabetes will undergo acute and prolonged randomised, double-blind, intervention studies. The acute intervention will consist of intravenous administration of the GLP-1 receptor agonist exenatide or placebo. For the prolonged intervention, patients will be randomised to 12-week treatment with the GLP-1 receptor agonist liraglutide, the DPP-4 inhibitor sitagliptin or matching placebos. For each examined organ system, a primary end point is defined. Primary cardiovascular end point is change in resting heart rate variability assessed by beat-to-beat heart rate monitor and spectral analyses software. Primary renal end point is change in glomerular filtration rate assessed by the classic inulin clearance methodology. Primary gastrointestinal end points are change in pancreatic exocrine function assessed by MRI-techniques (acute intervention) and faecal elastase-1 levels (12 week intervention). Secondary end points include systemic haemodynamics, microvascular function, effective renal plasma flow, renal tubular function, pancreatic volume and gallbladder emptying-rate. MEDICAL ETHICS AND DISSEMINATION: The study is approved by the local Ethics Review Board (VU University Medical Center, Amsterdam) and conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. TRIAL REGISTRATION NUMBER: NCT01744236. PMID- 26586330 TI - Abrupt emergence and predominance in Vietnam of rotavirus A strains possessing a bovine-like G8 on a DS-1-like background. AB - An apparently single rotavirus A strain possessing a genotype constellation of G8 P[8]-I2-R2-C2-M2-A2-N2-T2-E2-H2 abruptly emerged, caused diarrhoea in children requiring hospitalisation, and increased to reach 27 % of strains detected during the first half of 2015 in Vietnam. PMID- 26586331 TI - Characterization of siRNAs derived from cucumber green mottle mosaic virus in infected cucumber plants. AB - Virus-derived small interfering RNAs (vsiRNAs) of cucumber green mottle mosaic virus (CGMMV), a member of the genus Tobamovirus, were characterised in cucumber plants by deep sequencing. CGMMV vsiRNAs of 21-22 nt in length predominated, suggesting that there might be a conserved mechanism of DCL2 and DCL4 involvement in the biogenesis of vsiRNAs, as well as a common RNA silencing pathway in CGMMV infected cucumber plants. The 5'-terminal base of vsiRNAs was biased towards C/A/U, suggesting that CGMMV vsiRNAs might be loaded into diverse AGO-containing RISCs to disturb the gene expression of host plants. Possible targets for some of the vsiRNAs were also predicted. PMID- 26586332 TI - Noncytopathic bovine viral diarrhea virus 2 impairs virus control in a mouse model. AB - Bovine viral diarrhea virus (BVDV) is an economically important pathogen that causes development of mild to severe clinical signs in wild and domesticated ruminants. We previously showed that mice could be infected by BVDV. In the present study, we infected mice intraperitoneally with non-cytopathic (ncp) BVDV1 or ncp BVDV2, harvested the blood and organs of the infected mice at days 4, 7, 10 and 14 postinfection (pi), and performed immunohistochemical analyses to confirm BVDV infection. Viral antigens were detected in the spleens of all infected mice from days 4 through 14 and were also found in the mesenteric lymph nodes, gut-associated lymphoid tissue (GALT), heart, kidney, intestine, and bronchus-associated lymphoid tissue (BALT) of some infected mice. In ncp BVDV2 infected mice, flow cytometric analysis revealed markedly fewer CD4(+) and CD8(+) T lymphocytes and lower expression of costimulatory molecules CD80 (B7-1) and CD86 (B7-2) and major histocompatibility complex (MHC) class II (I-A/I-E) than those in ncp BVDV1-infected mice. Production of the cytokines interleukin (IL)-6 and monocyte chemotactic protein (MCP)-1 was higher in the plasma of ncp BVDV2 infected mice than that in that of ncp BVDV1-infected mice. Our results demonstrate that ncp BVDV1 and ncp BVDV2 interact differently with the host innate immune response in vivo. These findings highlight an important distinction between ncp BVDV1 and ncp BVDV2 and suggest that ncp BVDV2 impairs the host's ability to control the infection and enhances virus dissemination. PMID- 26586333 TI - Bioinformatics analysis of codon usage patterns and influencing factors in Penaeus monodon nudivirus. AB - Penaeus monodon nudivirus (PmNV) is one of the most important and most commonly reported shrimp viruses. In the present study, codon usage of PmNV was studied in detail. Based on effective number of codons (ENC) values, strong to low codon usage bias was observed in PmNV genes. Nucleotide composition-ENC correlation analysis and the GC3 versus ENC relationship indicated that compositional constraint has a major effect on codon usage of PmNV. At the whole-genome level, relative synonymous codon usage (RSCU) analysis showed almost complete antagonism between the codon usage pattern of PmNV and its host P. monodon. However, codon adaptive index (CAI) values indicated that forces of selective/translational constraints have been able to overcome this antagonism in some genes. PMID- 26586334 TI - Effects of repeated quetiapine treatment on conditioned avoidance responding in rats. AB - The present study characterized the behavioral mechanisms of avoidance-disruptive effect of quetiapine in the conditioned avoidance response test under two behavioral testing (2 warning signals vs. 1 warning signal) and two drug administration conditions (subcutaneous vs. intravenous). In Experiments 1 and 2, well-trained adult male Sprague-Dawley rats were tested under the subcutaneous (s.c.) quetiapine treatment (5.0, 15.0, 25.0, 50.0mg/kg) for 7 days in a novel procedure consisting of two conditioned stimuli (CS) (white noise serving as CS1 and pure tone as CS2). Only the highest dose (50.0mg/kg) produced a persistent suppression of the avoidance response without impairing the escape response. The magnitude of suppression of the CS1 avoidance was similar to that of CS2 avoidance. No significant group difference was found in the quetiapine (15.0mg/kg, s.c.) challenge test, indicating a lack of a long-term quetiapine effect. In Experiment 3, well-trained rats were tested under the intravenous (i.v.) quetiapine treatment (3.0, 9.0, 15.0mg/kg) for 5 days and challenged with quetiapine (6.0mg/kg, i.v. followed by 9.0mg/kg, s.c.). Only the white noise was used as the CS. Similar to what was being observed in Experiments 1 and 2, intravenously administered quetiapine dose-dependently suppressed avoidance responding during the drug test days, but did not alter drug sensitivity in the challenge days. Thus, quetiapine does not appear to show a preferential inhibition of the avoidance response to a less salient stimulus; and prior quetiapine treatment (s.c. and i.v.) does not cause a sensitization or tolerance to quetiapine. PMID- 26586335 TI - Downregulation of ERRalpha inhibits angiogenesis in human umbilical vein endothelial cells through regulating VEGF production and PI3K/Akt/STAT3 signaling pathway. AB - The human estrogen related receptor alpha (ERRalpha) is a pivotal regulator involved in energy homeostasis and mitochondrial biogenesis. It has been demonstrated that activation of ERRalpha in various breast cancer cells results in a significant increase of vascular endothelial growth factor (VEGF) mRNA and protein secretion. However, little is known about the relationship between ERRalpha and angiogenesis. Thus, the present study is aimed to investigate the effects and mechanism of ERRalpha suppression on the angiogenesis in human umbilical vein endothelial cells (HUVECs). Here we show that ERRalpha suppression powerfully inhibits proliferation, migration and capillary-like structures formation of HUVECs. Importantly, we demonstrate that these inhibitory effects are associated with the significantly reduced expression and production of VEGF. Results from further experiments using western blot and luciferase reporter assay exhibit that ERRalpha suppression inhibits hypoxia-inducible factor 1alpha (HIF 1alpha) expression, and phosphorylation of protein kinase B (Akt) and signal transducer and activator of transcription (STAT3) which up-regulated VEGF expression. In summary, we show that ERRalpha suppression inhibits angiogenesis in HUVECs and deserves further studies for application of rationale therapeutic target for patient with diseases related with aberrant angiogenesis. PMID- 26586337 TI - Potentially inappropriate prescribing in children. PMID- 26586338 TI - Role of the Symmetry of Multipoint Hydrogen Bonding on Chelate Cooperativity in Supramolecular Macrocyclization Processes. AB - Herein, we analyze the intrinsic chelate effect that multipoint H-bonding patterns exert on the overall energy of dinucleoside cyclic systems. Our results indicate that the chelate effect is regulated by the symmetry of the H-bonding pattern, and that the effective molarity is reduced by about three orders of magnitude when going from the unsymmetric ADD-DAA or DDA-AAD patterns to the symmetric DAD-ADA pattern. PMID- 26586336 TI - Homeobox A9 directly targeted by miR-196b regulates aggressiveness through nuclear Factor-kappa B activity in non-small cell lung cancer cells. AB - MicroRNAs (miRNAs) are recognized as crucial posttranscriptional regulators of gene expression, and play critical roles as oncogenes or tumor suppressors in various cancers. Here, we show that miR-196b is upregulated in mesenchymal-like state non-small cell lung cancer (NSCLC) cells and lung cancer tissues. Moreover, miR-196b upregulation stimulates cell invasion and a change in cell morphology to a spindle shape via loss of cell-to-cell contacts. We identified homeobox A9 (HOXA9) as a target gene of miR-196b by using public databases such as TargetScan, miRDB, and microRNA.org. HOXA9 expression is inversely correlated with miR-196b levels in clinical NSCLC samples as compared to that in corresponding control samples, and with the migration and invasion of NSCLC cells. Ectopic expression of HOXA9 resulted in a suppression of miR-196b-induced cell invasion, and HOXA9 reexpression increased E-cadherin expression. Furthermore, HOXA9 potently attenuated the expression of snail family zinc finger 2 (SNAI2/SLUG) and matrix metallopeptidase 9 (MMP9) by controlling the binding of nuclear factor-kappa B to the promoter of SLUG and MMP9 genes, respectively. Therefore, we suggest that HOXA9 plays a central role in controlling the aggressive behavior of lung cancer cells and that miR-196b can serve as a potential target for developing anticancer agents. (c) 2015 Wiley Periodicals, Inc. PMID- 26586339 TI - Evolution of the statistical distribution in a topological defect network. AB - The complex networks of numerous topological defects in hexagonal manganites are highly relevant to vastly different phenomena from the birth of our cosmos to superfluidity transition. The topological defects in hexagonal manganites form two types of domain networks: type-I without and type-II with electric self poling. A combined phase-field simulations and experimental study shows that the frequencies of domains with N-sides, i.e. of N-gons, in a type-I network are fitted by a lognormal distribution, whereas those in type-II display a scale-free power-law distribution with exponent ~2. A preferential attachment process that N gons with a larger N have higher probability of coalescence is responsible for the emergence of the scale-free networks. Since the domain networks can be observed, analyzed, and manipulated at room temperature, hexagonal manganites provide a unique opportunity to explore how the statistical distribution of a topological defect network evolves with an external electric field. PMID- 26586340 TI - MRI-imaging and clinical findings of eleven children with tick-borne encephalitis and review of the literature. AB - OBJECTIVES: The incidence of tick-borne encephalitis (TBE) is increasing in many countries. Magnetic resonance imaging (MRI) in the course of TBE is not regularly performed in children. The aim of our study was evaluating MRI-findings of children and adolescents with TBE. PATIENTS AND METHODS: Retrospective evaluation of the charts and MRIs of patients who had been treated for TBE in the four participating hospitals in the last twenty years. RESULTS: 11 patients (5 male; age at TBE 3 weeks-15 9/12 years; mean 104.9 months) were included. MRI (within the first week after admission) revealed symmetric or asymmetric T2 hyperintensities in both thalami in 7/11 patients with additional bilateral lesions in putamen and/or caudate nucleus in 3 patients, and additional cortical lesions in 2 patients. Our youngest patient presented with T2-hyperintensities affecting the whole left cerebral hemisphere including white and grey matter and both cerebellar hemispheres. One patient had a minimal reversible T2 hyperintensity in the splenium of the corpus callosum (RHSCC). 3/11 patients had a normal MRI. 4/11 patients showed complete neurological recovery (2/4 with a normal MRI, RHSCC patient). 6/11 children survived with significant sequelae: hemiparesis (n = 4); cognitive deficits (n = 4); pharmacoresistant epilepsy (n = 2). One patient died of a malignant brain edema. DISCUSSION: A spectrum of MRI findings can be found in children with TBE, often showing involvement of the subcortical deep grey matter structures. In children presenting with a meningoencephalitis and bilateral thalamic involvement TBE should be included in the differential diagnosis. PMID- 26586341 TI - Musical outgroups and the paradox of social bonding: Comment on "Music, empathy and cultural understanding" by E. Clark et al. PMID- 26586342 TI - Dissolution enhancement of active pharmaceutical ingredients by therapeutic deep eutectic systems. AB - A therapeutic deep eutectic system (THEDES) is here defined as a deep eutectic solvent (DES) having an active pharmaceutical ingredient (API) as one of the components. In this work, THEDESs are proposed as enhanced transporters and delivery vehicles for bioactive molecules. THEDESs based on choline chloride (ChCl) or menthol conjugated with three different APIs, namely acetylsalicylic acid (AA), benzoic acid (BA) and phenylacetic acid (PA), were synthesized and characterized for thermal behaviour, structural features, dissolution rate and antibacterial activity. Differential scanning calorimetry and polarized optical microscopy showed that ChCl:PA (1:1), ChCl:AA (1:1), menthol:AA (3:1), menthol:BA (3:1), menthol:PA (2:1) and menthol:PA (3:1) were liquid at room temperature. Dissolution studies in PBS led to increased dissolution rates for the APIs when in the form of THEDES, compared to the API alone. The increase in dissolution rate was particularly noticeable for menthol-based THEDES. Antibacterial activity was assessed using both Gram-positive and Gram-negative model organisms. The results show that all the THEDESs retain the antibacterial activity of the API. Overall, our results highlight the great potential of THEDES as dissolution enhancers in the development of novel and more effective drug delivery systems. PMID- 26586343 TI - SVEPM 2015-Controlling disease across species using emerging techniques in epidemiology and economics applied to animal health, Society of Veterinary Epidemiology and Preventive Medicine conference Ghent, Belgium 25-27 March 2015. PMID- 26586344 TI - Spatial and temporal epidemiology of porcine epidemic diarrhea (PED) in the Midwest and Southeast regions of the United States. AB - Emergence of porcine epidemic diarrhea virus (PEDV) in the US in 2013 caused a major impact in the swine industry due to its high mortality and rapid spread through the country. Even though the role of potential sources of infection in the epidemiology of the disease at the farm level (feed, fomites) has been extensively investigated, there is a lack of knowledge about the dynamics of disease spread at the regional level. Here, we investigated the dissemination of PEDV infection in two areas located in the regions with the highest swine density in the country (Southeast and Midwest) including more than 2400 farms. Location and date of outbreaks were used to assess the spatial and temporal clustering of cases using global (Cuzick-Edwards, Knox and directional tests) and local (Bernouilli model of the spatial scan statistic) techniques in the first 10 months of the epidemic. A strong spatio-temporal pattern was detected in both areas of study, with an increased risk of disease at <2km distances of recently (<7 days) infected farms, although extent of clustering was higher in the Southeast. Results, computed for two different locations in the first months of the epidemic, suggest that local transmission from infected farms into neighboring PEDV-free sites is a likely explanation for a substantial proportion of the reported PEDV-positive farms and consistent with the rapid spread of a highly infectious disease in the absence of immunity. PMID- 26586346 TI - [Recent Advances in the Management of Recurrent Bile Duct Stones]. AB - Approximately 3-15% of patients who have undergone removal of bile duct stones with endoscopic sphincterotomy have recurrence of stones which often presents as acute cholangitis. Despite better understanding on the factors and mechanisms underlying the recurrence of bile duct stones achieved during the past few decades, endoscopic removal still remains the mainstay of management for recurrent bile duct stones. Recently investigated and suggested management of recurrent bile duct stones are highlighted in this review. PMID- 26586345 TI - Encorafenib (LGX818), a potent BRAF inhibitor, induces senescence accompanied by autophagy in BRAFV600E melanoma cells. AB - Encorafenib (LGX818) is a new-generation BRAF inhibitor that is under evaluation in clinical trials. However, the underlying mechanism remains to be elucidated. Here we show that LGX818 potently decreased ERK phosphorylation and inhibited proliferation in BRAFV600E melanoma cell lines. Moreover, LGX818 downregulated CyclinD1 in a glycogen synthase kinase 3beta-independent manner and induced cell cycle arrest in the G1 phase, Surprisingly, LGX818 triggered cellular senescence in BRAFV600E melanoma cells, as evidenced by increased beta-galactosidase staining, while no appreciable induction of apoptosis was detected, as determined by Annexin V and propidium iodide staining and immunoblot analysis of caspase-3 processing and poly (ADP-ribose) polymerase cleavage. Increased p27KIP1 expression and retinoblastoma protein activation were detected during LGX818 induced senescence. Additionally, inhibition of dual-specificity tyrosine phosphorylation-regulated kinase 1B by AZ191 reversed LGX818-induced CyclinD1 turnover and senescence. Interestingly, autophagy is triggered through inhibition of the mTOR/70S6K pathway during LGX818-induced senescence. Moreover, autophagy inhibition by pharmacological and genetic regulation attenuates LGX818-induced senescence. Notably, combining LGX818 with autophagy modulators has anti proliferative effect in LGX818-resistant BRAF mutant melanoma cells. Altogether, we uncovered a mechanism by which LGX818 exerts its anti-tumor activity in BRAFV600E melanoma cells. PMID- 26586347 TI - [Incidence and Clinical Features of Esophageal Perforation Caused by Ingested Foreign Body]. AB - BACKGROUND/AIMS: Esophageal perforation is a rare but often a life-threatening condition. However, the incidence and clinical features of esophageal perforation caused by ingested foreign body are unknown. This study investigated the incidence of esophageal perforation caused by ingested foreign body and evaluated the clinical features and outcome of patients with esophageal perforation. METHODS: Among a total of 196 adult patients with confirmed esophageal foreign body and complained of at least one of the related symptoms at the emergency department between January 2000 and July 2008, 18 patients with esophageal perforation due to esophageal foreign body ingestion were included in the study. Data were collected by retrospectively reviewing the electric medical records. RESULTS: The incidence of esophageal foreign body and esophageal perforation in adults was 19.4% (196/1,009) and 1.8% (18/1,009), respectively. Chest pain was the most common symptom and fishbone was the most common foreign body causing esophageal perforation. Mediastinitis or mediastinal abscess occurred in 13 patients (13/18, 72.2%). About half (8/18) of the patients were admitted to the intensive care unit but there was no in-hospital mortality. CONCLUSIONS: The incidence of esophageal perforation in patients with foreign body ingestion was low but it increased up to 9.2% in patients with esophageal foreign body. However, prognosis was favorable with timely proper treatment. Chest pain can be an ominous sign indicating the presence of esophageal perforation in patients with esophageal foreign body. PMID- 26586348 TI - [Ten-day Sequential Therapy versus Bismuth Based Quadruple Therapy as Second Line Treatment for Helicobacter pylori Infection]. AB - BACKGROUND/AIMS: Ten-day sequential therapy has been evaluated as the first line therapy for Helicobacter pylori eradication but studies on sequential therapy as a second line therapy is lacking. The aim of this study was to compare the efficacy of 10-day sequential therapy and quadruple therapy as second line treatment for H. pylori eradication after failure of standard triple therapy. METHODS: Patients who did not respond to standard triple therapy for H. pylori eradication were assigned to either 10-day sequential or bismuth based quadruple therapy as second line treatment from January 2009 to December 2014 at Yeungnam University Medical Center. Post treatment H. pylori status was determined by rapid urease test, giemsa staining, or (13)C-urea breath test. Eradication rate and side effects of both therapies were compared. RESULTS: A total of 158 H. pylori infected patients were included and 70 patients were treated by bismuth based quadruple therapy and 88 patients by 10-day sequential therapy. Age and sex were not significantly different between the two groups. Eradication rate was 84.3% (59/70) in quadruple group and 56.8% (50/88) in sequential group. Side effects occurred significantly higher in quadruple group than sequential group (27.1% vs. 11.4%, p=0.011). CONCLUSIONS: For second line H. pylori eradication after failure of standard triple therapy, bismuth based quadruple therapy showed significantly higher H. pylori eradication rate than 10-day sequential therapy. Further prospective studies are needed to evaluate the efficacy of 10-day sequential therapy as a second line H. pylori eradication treatment. PMID- 26586349 TI - Is the Prevalence of Gallbladder Polyp Different between Vegetarians and General Population? AB - BACKGROUND/AIMS: Gallbladder polyps (GBP) are a common clinical finding that can express malignant potential. The aim of this study was to evaluate whether vegetarianism protects against GBP, together with other putative risk factors. METHODS: A retrospective, cross-sectional study was conducted with subjects who received a health check-up from July 2005 to December 2011. Korean Buddhist priests, who are obligatory vegetarians by religious belief, were identified as vegetarians (vegetarian group) and compared with a non-vegetarian control group sampled from those coming for health check-ups at the same institution. RESULTS: Out of 18,483 subjects, GBP were found in 810 (4.4%). Al though GBP tended to be less common in the vegetarian group (23 [3.5%] out of 666) than in control group (787 [4.4%] out of 17,817), the difference was insignificant statistically (p=0.233). By logistic regression, old age (OR=1.61, 95% CI=1.1 9-2.26 for 30-39 years; OR=1.47, 95% CI=1.08-1.98 for 40-49 years), male gender (OR=1.51, 95% CI=1.31-1.75), high BMI (OR=1.18, 95% CI=1.00-1.39 for >= 23.0 kg/m(2) and < 25.0 kg/m(2) ) and HBsAg positivity (OR=1.53, 95% CI=1.19-1.98) were independent risk factors of GBP. CONCLUSIONS: GBP was significantly associated with old age, male gender , high BMI and HBsAg positivity, but not with vegetarianism. PMID- 26586350 TI - Prevalence of Gastric Subepithelial Tumors in Korea: A Single Center Experience. AB - BACKGROUND/AIMS: The incidental finding of gastrointestinal subepithelial tumors (SETs) is increasing with national cancer screening endoscopy. In a Swedish population, screening endoscopy found a prevalence of SETs of 0.36%. However, the prevalence of gastric SETs in Korean patients has not been described. Therefore, this study evaluated the prevalence of SETs of the stomach in a Korean patient population. METHODS: We reviewed endoscopic reports of 11,712 subjects who underwent screening esophagogastroduodenoscopy (EGD) at Hanyang University Hospital between July 2012 and June 2013. RESULTS: Among 11,712 patients, 194 (1.7%) had SET of the stomach. Of these, 71 (prevalence, 0.6%) were male and 123 (prevalence, 1.1%) were female. When grouped by age, the prevalence of SET was as follows: 1.0% for patients in their twenties, 6.2% for those in their thirties, 19.1% for those in their forties, 33.0% for those in their fifties, 30.4% for those in their sixties, and 10.3% for those over 70 years of age. CONCLUSIONS: The overall prevalence of gastric SET among healthy examinees was 1.7%. The prevalence of gastric SET increased with age and was higher in female. PMID- 26586351 TI - [Esophageal Hemangioma Treated by Endoscopic Mucosal Resection: A Case Report and Review of the Literature]. AB - Hemangioma of the esophagus is a rare form of benign esophageal tumor. It usually presents as a single lesion located in the lower third of the esophagus and is mostly asymptomatic. However, it may occasionally cause hematemesis and/or obstruction. Surgical resection is the conventional treatment modality for managing esophageal hemangioma, but less invasive approaches such as endoscopic therapy are recently becoming more widely employed. Herein, we report a case of a 54-year-old man who presented with an esophageal hemangioma that was successfully treated by endoscopic mucosal resection without any complications. PMID- 26586352 TI - A Case of Aerophagia Diagnosed by Multichannel Intraluminal Impedance Monitoring. AB - Aerophagia is a disorder caused by abnormal accumulation of air in the gastrointestinal tract as a result of repetitive and frequent inflow of air through the mouth. For the diagnosis of this condition, it is difficult to objectively measure the air swallowing. However, multichannel intraluminal impedance monitoring facilitates the differential diagnosis between normal air swallowing and pathologic aerophagia, and can aid in the determination of the frequency and amount of air swallowed. In this report, in addition to a literature review, we describe a case of 36-year-old man with abdominal distension who was diagnosed with aerophagia using esophageal impedance monitoring and was treated with clonazepam. PMID- 26586353 TI - Successful Treatment of Bleeding Duodenal Varix by Percutaneous Transsplenic Embolization. AB - Variceal bleeding occurs primarily in the esophagus or stomach in patients with liver cirrhosis, but can also occur rarely in the duodenum. Duodenal variceal bleeding has a high mortality and poor prognosis due to heavy blood flow originating from the portal vein (PV) and the technical difficulty of hemostatic procedures. Treatments including endoscopic sclerotherapy, endoscopic ligations, endoscopic clipping and transjugular intrahepatic portosystemic shunt have been tried, with only moderate and variable success. A percutaneous transsplenic approach offers another way of accessing the PV. Here we report a case of successfully treated duodenal variceal bleeding by percutaneous transsplenic embolization. PMID- 26586354 TI - Primary Adenocarcinoma with Focal Choriocarcinomatous Differentiation in the Sigmoid Colon. AB - Primary colorectal choriocarcinoma is a rare neoplasm. Only 19 cases have been reported worldwide, most of which involved adenocarcinomas. The prognosis is usually poor, and the standard therapy for this tumor has not been established. A 61-year-old woman presented with constipation and lower abdominal discomfort. She was diagnosed with primary adenocarcinoma with focal choriocarcinomatous differentiation in the sigmoid colon and liver metastasis. Because the serum beta human chorionic gonadotropin level was not significantly elevated, and because only focal choriocarcinomatous differentiation was diagnosed, we selected the chemotherapy regimen that is used for the treatment of metastatic colorectal adenocarcinoma. The patient survived for 13 months after the initial diagnosis. This is the first case in Korea to assess the suppressive effects of the standard chemotherapy for colorectal adenocarcinoma against coexisting colorectal choriocarcinoma and adenocarcinoma. PMID- 26586355 TI - Preparation of Mesoporous Bimetallic Au-Pt with a Phase-Segregated Heterostructure Using Mesoporous Silica. AB - Mesoporous bimetallic Au-Pt with a phase-segregated heterostructure has been prepared by using mesoporous silica SBA-15 as a template. Au nanoparticles were prepared as a seed metal within the mesopores, and subsequently Pt was deposited, sandwiching the Au seeds. Energy-dispersive X-ray (EDX) spectral mapping showed that the framework of mesoporous bimetallic Au-Pt, prepared by removing the silica template with HF, was composed of Au nanoparticles joined with Pt nanowires. The Au/Pt ratio of the mesoporous bimetallic Au-Pt could be varied by controlling the number of Au deposition cycles. Pre-adsorbed CO (COad) stripping voltammetry of the mesoporous bimetallic Au-Pt showed that the surfaces of the joined bimetallic structure were electrochemically active. This could be attributed to the open framework structure having a high ratio of exposed bimetallic mesopore surfaces. The described preparative approach, involving a mesoporous silica template and stepwise deposition within the mesopores, enables control of the nanostructure of the bimetallic material, which is greatly promising for the further development of synthetic methodologies for bimetallic structures. PMID- 26586356 TI - Discussion. PMID- 26586357 TI - Going the distance with success: An attempted argument that less is not always more. PMID- 26586359 TI - Reaching the full potential of MEP monitoring during surgery of the thoracoabdominal aorta. PMID- 26586358 TI - Anticoagulation with apixaban in a patient with a left ventricular assist device and gastrointestinal bleeding: A viable alternative to warfarin? PMID- 26586361 TI - SMART or simply bold? PMID- 26586360 TI - Nonselective carotid artery ultrasound screening in patients undergoing coronary artery bypass grafting: Is it necessary? AB - OBJECTIVES: To determine whether nonselective preoperative carotid artery ultrasound screening alters management of patients scheduled for coronary artery bypass grafting (CABG), and whether such screening affects neurologic outcomes. METHODS: From March 2011 to September 2013, preoperative carotid artery ultrasound screening was performed on 1236 of 1382 patients (89%) scheduled to undergo CABG. Carotid artery stenosis (CAS) was classified as none or mild (any type 0%-59% stenosis), moderate (unilateral 60%-79% stenosis), or severe (bilateral 60%-79% stenosis or unilateral 80%-100% stenosis). RESULTS: A total of 1069 (86%) had =moderate CAS, 1 of 19 (5.3%) undergoing CABG + CEA and 3 of 148 (2.0%) undergoing CABG alone experienced stroke (P = .4). In patients with moderate CAS, stroke occurred in 1 of 11 (9.1%) off-pump and 1 of 79 (1.3%) on pump patients (P = .2). In patients with severe CAS, stroke occurred in 1 of 6 (17%) off-pump and 1 of 71 (1.4%) on-pump patients (P = .15). CONCLUSIONS: Routine preoperative carotid artery evaluation altered the management of a minority of patients undergoing CABG; this did not translate into perioperative stroke risk. Hence, a more targeted approach for preoperative carotid artery evaluation should be adopted. PMID- 26586362 TI - Uncertain behaviours of integrated circuits improve computational performance. AB - Improvements to the performance of conventional computers have mainly been achieved through semiconductor scaling; however, scaling is reaching its limitations. Natural phenomena, such as quantum superposition and stochastic resonance, have been introduced into new computing paradigms to improve performance beyond these limitations. Here, we explain that the uncertain behaviours of devices due to semiconductor scaling can improve the performance of computers. We prototyped an integrated circuit by performing a ground-state search of the Ising model. The bit errors of memory cell devices holding the current state of search occur probabilistically by inserting fluctuations into dynamic device characteristics, which will be actualised in the future to the chip. As a result, we observed more improvements in solution accuracy than that without fluctuations. Although the uncertain behaviours of devices had been intended to be eliminated in conventional devices, we demonstrate that uncertain behaviours has become the key to improving computational performance. PMID- 26586363 TI - Whole exome sequencing identified a novel COL2A1 mutation that causes mild Spondylo-epiphyseal dysplasia mimicking autosomal dominant brachyolmia. PMID- 26586364 TI - Two bisthienylethene-Ir(III) complexes showing acid/base-induced structural transformation and on-off luminescence switching in solution. AB - Complexes [Ir(dfppy)2(pbdtiH)](PF6).2CHCl3 (1-H) and [Ir(dfppy)2(pbdti)] (1) were synthesized by the reaction of bisthienylethene pbdtiH and an [Ir(dfppy)2Cl]2 dimer under neutral and basic conditions, respectively. Thus, the {Ir(dfppy)2}(+) unit is coordinated by pbdtiH in 1-H, and by pbdti(-) in 1, which are confirmed by their crystal structures. The structures of 1-H and 1 could be interconverted in solution, upon alternately adding NEt3 and TFA, thus resulting in reversible luminescence switching between the on-state of 1-H and the off-state of 1 at room temperature. In addition, both 1-H and 1 show solid-state luminescence, with a broad emission at 534 nm and 525 nm, respectively. The free pbdtiH ligand shows photochromic behavior in CH2Cl2 solution. However, no photochromism has been observed in 1-H and 1, indicating that the coordination of the pbdtiH/pbdti(-) ligand to the {Ir(dfppy)2}(+) unit could suppress their photochromic behaviors. PMID- 26586365 TI - A novel combination of fipronil and permethrin (Frontline Tri-Act(r)/Frontect(r)) reduces risk of transmission of Babesia canis by Dermacentor reticulatus and of Ehrlichia canis by Rhipicephalus sanguineus ticks to dogs. AB - BACKGROUND: The ability of Frontline Tri-Act(r)/Frontect(r), a topical ectoparasiticide containing fipronil and permethrin for dogs, to prevent the transmission of Babesia canis as well as Ehrlichia canis was evaluated by infesting dogs with infected vector ticks. METHODS: For the Babesia canis study, 16 dogs were randomly allocated to two groups. Eight dogs were treated on day 0 with a topical spot-on formulation containing 6.76 % w/v fipronil plus 50.48 % w/v permethrin and eight dogs served as the untreated control group. Dermacentor reticulatus ticks, with a B. canis infection rate ranging between 2 and 10 %, were placed onto dogs on days 7, 14, 21 and 28. In situ tick counts were performed on Days 9, 16 and 23. Ticks were counted and removed on Day 30. Infection of the dogs with B. canis was monitored by rectal temperature readings, clinical examinations and blood smears as well as PCR and IFA (indirect fluorescent antibody assay). For the Ehrlichia canis study, another 16 dogs were allocated to two groups. Eight dogs were treated with the fipronil and permethrin combination on days 0 and 28 and eight dogs served as untreated controls. Rhipicephalus sanguineus ticks, carrying an infection rate of 13 % for E. canis, were released in the sleeping kennels of the dogs on days 7, 14, 21, 28, 35, 42, 49 and 56. Ticks were counted in situ on the dogs on a weekly basis. All ticks were removed and counted on the final assessment day 58. Infection of the dogs with E. canis was monitored by rectal temperature, clinical examinations, and testing of blood samples by PCR, IFA and platelet counts. RESULTS: B. canis was transmitted by D. reticulatus ticks to all eight untreated control dogs and to one treated dog, which was confirmed by blood smears, PCR and IFA. E.canis was transmitted by R. sanguineus ticks to all eight untreated control dogs. Two of the dogs in the treated group were found positive based on PCR and/or IFA. CONCLUSIONS: Frontline Tri-Act(r)/Frontect(r) significantly lowered the risk for dogs to acquire a B. canis infection by 87.5 % over a challenge period of 28 days. The risk for dogs to acquire E. canis was reduced by 75 % over a period of 56 days. PMID- 26586366 TI - Synthesis of deuterium-labelled halogen derivatives of L-tryptophan catalysed by tryptophanase. AB - The isotopomers of halogen derivatives of l-tryptophan (l-Trp) (4'-F-, 7'-F-, 5' Cl- and 7'-Br-l-Trp), specifically labelled with deuterium in alpha-position of the side chain, were obtained by enzymatic coupling of the corresponding halogenated derivatives of indole with S-methyl-l-cysteine in (2)H2O, catalysed by enzyme tryptophanase (EC 4.1.99.1). The positional deuterium enrichment of the resulting tryptophan derivatives was controlled using (1)H NMR. In accordance with the mechanism of the lyase reaction, a 100% deuterium labelling was observed in the alpha-position; the chemical yields were between 23 and 51%. Furthermore, beta-F-l-alanine, synthesized from beta-F-pyruvic acid by the l-alanine dehydrogenase reaction, has been tested as a coupling agent to obtain the halogenated deuterium-labelled derivatives of l-Trp. The chemical yield (~30%) corresponded to that as observed with S-methyl-l-cysteine but the deuterium label was only 63%, probably due to the use of a not completely deuterated incubation medium. PMID- 26586367 TI - Outcomes by area of residence deprivation in a cohort of oral cancer patients: Survival, health-related quality of life, and place of death. AB - OBJECTIVES: Oral cancer patients from lower socio-economic backgrounds have worse outcomes of survival and health related quality of life. The mechanism of cause is not fully understood. The purpose of the paper is to report treatment selection, survival, health related quality of life, cause and place of death in relation to deprivation status. MATERIALS AND METHODS: 553 patients treated for oral cancer between 2008 and 2012 were identified from records at University hospital. Mortality was tracked via the Office of National Statistics (ONS) and health-related quality of life was measured using the University Washington quality of life questionnaire (UW-QoLv4). Postcodes of residence at diagnosis were used to obtain index of multiple deprivation (IMD) 2010 scores. RESULTS: Nearly half of the sample (47%) lived in the 'most deprived' IMD 2010 quartile of residential areas in England and such patients when treated with curative intent using surgery with or without adjuvant radiotherapy had worse survival than patients living elsewhere, p=0.01 after adjusting for pathological staging and age group. There were no notable differences by IMD group in cancer being mentioned anywhere in part 1 or part 2 of the death certificate or in place of death. After adjustment for patient and clinical factors patients residing in more deprived areas had worse quality of life outcomes in regard to social emotional functioning and overall quality of life but not in regard to physical oral function. CONCLUSION: Addressing inequalities in health care related to deprivation is a priority for patients with oral cancer. PMID- 26586368 TI - Use of Provisc(r) eye protection during FESS. PMID- 26586369 TI - Creating a 'reverse' integrated primary and mental healthcare clinic for those with serious mental illness. AB - Individuals with serious mental illness (SMI) are more likely to experience preventable medical health issues, such as diabetes, hyperlipidemia, obesity, and cardiovascular disease, than the general population. To further compound this issue, these individuals are less likely to seek preventative medical care. These factors result in higher usage of expensive emergency care, lower quality of care, and lower life expectancy. This manuscript presents literature that examines the health disparities this population experiences, and barriers to accessing primary care. Through the identification of these barriers, we recommend that the field of family medicine work in collaboration with the field of mental health to implement 'reverse' integrated care (RIC) systems, and provide primary care services in the mental health settings. By embedding primary care practitioners in mental health settings, where individuals with SMI are more likely to present for treatment, this population may receive treatment for somatic care by experts. This not only would improve the quality of care received by patients, but would also remove the burden of managing complex somatic care from providers trained in mental health. The rationale for this RIC system, as well as training and policy reforms, are discussed. PMID- 26586370 TI - A preliminary report of breast cancer screening by positron emission mammography. AB - OBJECTIVE: Fluorine-18 fluorodeoxyglucose (FDG)-positron emission tomography (PET) and PET/computed tomography (PET/CT) have had a considerable impact on the detection of various malignancies. PET and PET/CT are minimally invasive methods that can provide whole-body imaging at one time. Therefore, an FDG-PET cancer screening program has been widely used in Japan. However, the breast cancer detection rate of FDG-PET cancer screening is relatively low. Therefore, FDG-PET screening is not recommended for breast cancer screening. Positron emission mammography (PEM) is a high-resolution molecular breast imaging technology. PEM can detect small breast cancers that cannot be detected on PET or PET/CT images due to limited spatial resolution. We have performed opportunistic breast cancer screening using PEM since 2011. To the best of our knowledge, this is the first report regarding PEM breast cancer screening. METHODS: This study enrolled 265 women. PEM images were analyzed by agreement of 2 experienced nuclear medicine physicians. The readers were given information from medical interview sheet. US findings were interpreted holistically. The number of participants, patient recall rate, further examination rate, and cancer detection rate by year were calculated. RESULTS: The overall recall rate was 8.3%; the work-up examination rate was 77.3%, and cancer detection rate was 2.3%. The positive predictive value of PEM was 27.3%. Six cancers were found by PEM screening. Five were invasive cancers and one was ductal carcinoma in situ. Histological tumor sizes were reported in three cases: 0.7, 1.2, and 2 cm. CONCLUSION: PEM screening appears to have potential for breast cancer screening. PMID- 26586371 TI - Plasticizer DBP Activates NLRP3 Inflammasome through the P2X7 Receptor in HepG2 and L02 Cells. AB - Ditubyl phthalate (DBP), one of the most widely used plasticizers, can migrate out to contaminate our bodies and environment. A number of studies have showed that DBP is closely related to liver pathological changes and diseases. Inflammasomes are multiprotein complexes composed of procaspase and pattern recognition receptors such as Nucleotide oligomerization domain (NOD) like receptor family, pyrin domain containing 3 (NLRP3). Activation of NLRP3 inflammasome is implicated in the pathogeneses of liver damage. The aim of this study was to determine the effects of DBP on NLRP3 inflammasome. We found that DBP triggered the activation of NLRP3 inflammasome in hepatocyte cell lines. By using Ca-074-Me, N-acetylcysteine and KN-62, we observed that the P2X7 receptor participated in the DBP-induced activation of NLRP3 inflammasome. DBP could also trigger the ATP release. In conclusion, we demonstrated that DBP is one of the activator of NLRP3 inflammasome and may play an important role in liver damage. PMID- 26586372 TI - Large scale patterns of genetic variation and differentiation in sugar maple from tropical Central America to temperate North America. AB - BACKGROUND: Geological events in the latter Cenozoic have influenced the distribution, abundance and genetic structure of tree populations in temperate and tropical North America. The biogeographical history of temperate vegetation that spans large ranges of latitude is complex, involving multiple latitudinal shifts that might have occurred via different migration routes. We determined the regional structuring of genetic variation of sugar maple (Acer saccharum subsp. saccharum) and its only subspecies in tropical America (Acer saccharum subsp. skutchii) using nuclear and chloroplast data. The studied populations span a geographic range from Maine, USA (46 degrees N), to El Progreso, Guatemala (15 degrees N). We examined genetic subdivisions, explored the locations of ancestral haplotypes, analyzed genetic data to explore the presence of a single or multiple glacial refugia, and tested whether genetic lineages are temporally consistent with a Pleistocene or older divergence. RESULTS: Nuclear and chloroplast data indicated that populations in midwestern USA and western Mexico were highly differentiated from populations in the rest of the sites. The time of the most recent common ancestor of the western Mexico haplotype lineage was dated to the Pliocene (5.9 Ma, 95% HPD: 4.3-7.3 Ma). Splits during the Pleistocene separated the rest of the phylogroups. The most frequent and widespread haplotype occurred in half of the sites (Guatemala, eastern Mexico, southeastern USA, and Ohio). Our data also suggested that multiple Pleistocene refugia (tropics-southeastern USA, midwestern, and northeastern USA), but not western Mexico (Jalisco), contributed to post-glacial northward expansion of ranges. Current southern Mexican and Guatemalan populations have reduced population sizes, genetic bottlenecks and tend toward homozygosity, as indicated using nuclear and chloroplast markers. CONCLUSIONS: The divergence of western Mexican populations from the rest of the sugar maples likely resulted from orographic and volcanic barriers to gene flow. Past connectivity among populations in the southeastern USA and eastern Mexico and Guatemala possible occurred through gene flow during the Pleistocene. The time to the most common ancestor values revealed that populations from the Midwest and Northeast USA represented different haplotype lineages, indicating major divergence of haplotypes lineages before the Last Glacial Maximum and suggesting the existence of multiple glacial refugia. PMID- 26586373 TI - Relationship between Inflammation and Aspirin and Clopidogrel Antiplatelet Responses in Acute Ischemic Stroke. AB - OBJECTIVE: We measured serum levels of proinflammatory/prothrombotic markers P selectin, CD40L, matrix metalloproteinase 9 (MMP-9), intracellular adhesion molecule 1 (ICAM-1), and interleukin (IL)-6 in ischemic stroke patients, correlating their levels with the results of aspirin (ASA) and clopidogrel antiplatelet responses, using 3 "point of care" platelet function instruments, thromboelastograph (TEG), Accumetrics (ACU), and impedance aggregometer (IMP). METHODS: Patients on chronic ASA regimen at the time of stroke were switched to 300 mg clopidogrel loading dose and 75 mg clopidogrel maintenance dose. Serum levels of the aforementioned inflammatory mediators were measured in 51 patients at baseline (on ASA regimen), and at 26 +/- 5 hours and 64 +/- 18 hours postclopidogrel administration by enzyme-linked immunosorbent assay. RESULTS: P selectin, CD40L, and MMP-9 serum levels were reduced; ICAM-1 and IL-6 serum levels showed no difference postclopidogrel administration relative to baseline. Patients' stratification based on ASA dose showed more significant reductions in P-selectin, CD40L, and MMP-9 serum levels postclopidogrel administration in patients who were on baseline 81 mg ASA, as compared to patients on 325 mg ASA. Measurement with TEG was sensitive for correlating ASA antiplatelet responses to serum levels of inflammatory markers, whereas measurements with ACU and IMP were sensitive for correlating clopidogrel antiplatelet responses to serum levels of inflammatory markers. CONCLUSION: Clopidogrel exerts both platelet-dependent and platelet-independent anti-inflammatory effects. The association between platelet function and inflammation depends on the platelet function analyzer, the type of antiplatelet agent, the nature of the inflammatory marker, and the time of measurement relative to the time of drug administration. PMID- 26586375 TI - The effect of dose escalation on gastric toxicity when treating lower oesophageal tumours: a radiobiological investigation. AB - PURPOSE: Using radiobiological modelling to estimate normal tissue toxicity, this study investigates the effects of dose escalation for concurrent chemoradiation therapy (CRT) in lower third oesophageal tumours on the stomach. METHODS AND MATERIALS: 10 patients with lower third oesophageal cancer were selected from the SCOPE 1 database (ISCRT47718479) with a mean planning target volume (PTV) of 348 cm(3). The original 3D conformal plans (50 Gy3D) were compared to newly created RapidArc plans of 50 GyRA and 60 GyRA, the latter using a simultaneous integrated boost (SIB) technique using a boost volume, PTV2. Dose-volume metrics and estimates of normal tissue complication probability (NTCP) were compared. RESULTS: There was a significant increase in NTCP of the stomach wall when moving from the 50 GyRA to the 60 GyRA plans (11-17 %, Wilcoxon signed rank test, p = 0.01). There was a strong correlation between the NTCP values of the stomach wall and the volume of the stomach wall/PTV 1 and stomach wall/PTV2 overlap structures (R = 0.80 and R = 0.82 respectively) for the 60 GyRA plans. CONCLUSION: Radiobiological modelling suggests that increasing the prescribed dose to 60 Gy may be associated with a significantly increased risk of toxicity to the stomach. It is recommended that stomach toxicity be closely monitored when treating patients with lower third oesophageal tumours with 60 Gy. PMID- 26586376 TI - Glucocorticoid Clearance and Metabolite Profiling in an In Vitro Human Airway Epithelium Lung Model. AB - The emergence of microphysiologic epithelial lung models using human cells in a physiologically relevant microenvironment has the potential to be a powerful tool for preclinical drug development and to improve predictive power regarding in vivo drug clearance. In this study, an in vitro model of the airway comprising human primary lung epithelial cells cultured in a microfluidic platform was used to establish a physiologic state and to observe metabolic changes as a function of glucocorticoid exposure. Evaluation of mucus production rate and barrier function, along with lung-specific markers, demonstrated that the lungs maintained a differentiated phenotype. Initial concentrations of 100 nM hydrocortisone (HC) and 30 nM cortisone (C) were used to evaluate drug clearance and metabolite production. Measurements made using ultra-high-performance liquid chromatography and high-mass-accuracy mass spectrometry indicated that HC metabolism resulted in the production of C and dihydrocortisone (diHC). When the airway model was exposed to C, diHC was identified; however, no conversion to HC was observed. Multicompartmental modeling was used to characterize the lung bioreactor data, and pharmacokinetic parameters, including elimination clearance and elimination half-life, were estimated. Polymerse chain reaction data confirmed overexpression of 11-beta hydroxysteroid dehydrogenase 2 (11betaHSD2) over 11betaHSD1, which is biologically relevant to human lung. Faster metabolism was observed relative to a static model on elevated rates of C and diHC formation. Overall, our results demonstrate that this lung airway model has been successfully developed and could interact with other human tissues in vitro to better predict in vivo drug behavior. PMID- 26586377 TI - Physiologically-Based Pharmacokinetic-Pharmacodynamic Modeling of 1alpha,25 Dihydroxyvitamin D3 in Mice. AB - 1alpha,25-Dihydroxyvitamin D3 [1,25(OH)2D3] concentrations are regulated by renal CYP27B1 for synthesis and CYP24A1 for degradation. Published plasma and tissue 1,25(OH)2D3 concentrations and mRNA fold change expression of Cyp24a1 and Cyp27b1 following repetitive i.p. injections to C57BL/6 mice (2.5 MUg * kg(-1) every 2 days for 4 doses) were fitted with a minimal and full physiologically-based pharmacokinetic-pharmacodynamic models (PBPK-PD). The minimal physiologically based pharmacokinetic-pharmacodynamic linked model (mPBPK-PD) related Cyp24a1 mRNA fold changes to linear changes in tissue/tissue baseline 1,25(OH)2D3 concentration ratios, whereas the full physiologically-based pharmacokinetic pharmacodynamic model (PBPK-PD) related measured tissue Cyp24a1 and Cyp27b1 fold changes to tissue 1,25(OH)2D3 concentrations with indirect response, sigmoidal maximal stimulatory effect/maximal inhibitory effect functions. Moreover, the intestinal segregated flow model (SFM) that describes a low and partial intestinal (blood/plasma) flow to enterocytes was nested within both models for comparison with the traditional model for intestine (TM) where the entire flow perfuses the intestine. Both the mPBPK(SFM)-PD and full PBPK(SFM)-PD models described the i.p. plasma and tissue 1,25(OH)2D3 concentrations and fold changes in mRNA expression significantly better than the TM counterparts with F test comparisons. The full PBPK(SFM)-PD fits showed estimates with good precision (lower percentage of coefficient of variation), and the model was more robust in predicting data from escalating i.v. doses (2, 60, and 120 pmol) and the rebound in 1,25(OH)2D3 tissue concentrations after dosing termination. The full PBPK(SFM) PD model performed the best among the tested models for describing the complex pharmacokinetic-pharmacodynamic interplay among Cyp27b1, Cyp24a1, and 1,25(OH)2D3. PMID- 26586379 TI - Best Practices for Drug Prescribing in Older Adults: A Call for Action. AB - Achievement of a good quality of prescribing is one of the major challenges for physicians caring for older persons, because of aging-related changes in pharmacokinetics and pharmacodynamics of drugs, the large number of co-occurring chronic diseases affecting older adults and consequent polypharmacy. Several approaches are available and have been used to tackle over-prescription of drugs, such as medication review, application of appropriateness criteria and computerized prescription support systems, but, one by one, they have shown limited effectiveness with respect to patient-centred outcomes. We propose to test a multicomponent intervention with the goal of achieving the best-tailored pharmacotherapy for each patient at a specific point in time. The intervention should start with identification of patients at risk of drug-related problems and identification of their priorities, followed by medication review over time, supported by the use of inappropriateness criteria and computerized systems, and also necessarily embedded in the Comprehensive Geriatric Assessment. PMID- 26586378 TI - Regulation of Hepatic Drug-Metabolizing Enzymes in Germ-Free Mice by Conventionalization and Probiotics. AB - Little is known regarding the effect of intestinal microbiota modifiers, such as probiotics and conventionalization with exogenous bacteria, on host hepatic drug metabolism. Therefore, the goal of this study was to determine the effect of these modifiers on the expression of various drug-metabolizing enzymes of the host liver. VSL3 is a probiotic that contains eight live strains of bacteria. Five groups of mice were used: 1) conventional mice (CV), 2) conventional mice treated with VSL3 in drinking water, 3) germ-free (GF) mice, 4) GF mice treated with VSL3, and 5) GF mice exposed to the conventional environment for 2 months. All mice were 3 months old at tissue collection. GF conditions markedly downregulated the cytochrome P450 (P450) 3a gene cluster, but upregulated the Cyp4a cluster, whereas conventionalization normalized their expression to conventional levels [reverse-transcription quantitative polymerase chain reaction (qPCR) and western blot]. Changes in the Cyp3a and 4a gene expression correlated with alterations in the pregnane X receptor and peroxisome proliferator-activated receptor alpha-DNA binding, respectively (chromatin immunoprecipitation-qPCR). VSL3 increased each bacterial component in the large intestinal content of the CV mice, and increased these bacteria even more in GF mice, likely due to less competition for growth in the GF environment. VSL3 given to conventional mice increased the mRNAs of Cyp4v3, alcohol dehydrogenase 1, and carboxyesterase 2a, but decreased the mRNAs of multiple phase II glutathione-S-transferases. VSL3 given to germ-free mice decreased the mRNAs of UDP-glucuronosyltransferases 1a9 and 2a3. In conclusion, conventionalization and VSL3 alter the expression of many drug-metabolizing enzyme s in the liver, suggesting the importance of considering "bacteria-drug" interactions for various adverse drug reactions in patients. PMID- 26586381 TI - Synthesis of N-alkyl (aril)-tetra pyrimidine thiones and investigation of their human carbonic anhydrase I and II inhibitory effects. AB - Tetrahydropyrimidine thiones, which are cyclic thiocarbamides derivatives, were synthesised from thiourea, beta-diketones and substituted benzaldehydes. A tautomeric form of these derivatives incorporates the thiol functionality, which is known to interact with metal ions from metalloenzymes active sites, such as the carbonic anhydrases (CAs, EC 4.2.1.1) among others. This is a superfamily of widespread enzymes, which catalyses a crucial biochemical reaction, the reversible hydration of carbon dioxide to bicarbonate and protons (H(+)). The newly synthesised N-alkyl (aril)-tetrahydropyrimidine thiones were tested for inhibition of the cytosolic human isoforms I and II (hCA I and II). Both isoforms were effectively inhibited by the newly synthesised thiones. Ki values were in the range of 218.5 +/- 23.9-261.0 +/- 41.5 pM for hCA I, and of 181.8 +/- 41.9 273.6 +/- 41.4 pM for hCA II, respectively. This under-investigated class of derivatives may bring interesting insights in the field of non-sulphonamide CA inhibitors. PMID- 26586374 TI - The basolateral amygdala gamma-aminobutyric acidergic system in health and disease. AB - The brain comprises an excitatory/inhibitory neuronal network that maintains a finely tuned balance of activity critical for normal functioning. Excitatory activity in the basolateral amygdala (BLA), a brain region that plays a central role in emotion and motivational processing, is tightly regulated by a relatively small population of gamma-aminobutyric acid (GABA) inhibitory neurons. Disruption in GABAergic inhibition in the BLA can occur when there is a loss of local GABAergic interneurons, an alteration in GABAA receptor activation, or a dysregulation of mechanisms that modulate BLA GABAergic inhibition. Disruptions in GABAergic control of the BLA emerge during development, in aging populations, or after trauma, ultimately resulting in hyperexcitability. BLA hyperexcitability manifests behaviorally as an increase in anxiety, emotional dysregulation, or development of seizure activity. This Review discusses the anatomy, development, and physiology of the GABAergic system in the BLA and circuits that modulate GABAergic inhibition, including the dopaminergic, serotonergic, noradrenergic, and cholinergic systems. We highlight how alterations in various neurotransmitter receptors, including the acid-sensing ion channel 1a, cannabinoid receptor 1, and glutamate receptor subtypes, expressed on BLA interneurons, modulate GABAergic transmission and how defects of these systems affect inhibitory tonus within the BLA. Finally, we discuss alterations in the BLA GABAergic system in neurodevelopmental (autism/fragile X syndrome) and neurodegenerative (Alzheimer's disease) diseases and after the development of epilepsy, anxiety, and traumatic brain injury. A more complete understanding of the intrinsic excitatory/inhibitory circuit balance of the amygdala and how imbalances in inhibitory control contribute to excessive BLA excitability will guide the development of novel therapeutic approaches in neuropsychiatric diseases. PMID- 26586382 TI - Challenges in Screening and Diagnosing Frailty Syndrome: Which Tool to be used? PMID- 26586383 TI - Diagnostic Test of a Scoring System for Frailty Syndrome in the Elderly According to Cardiovascular Health Study, Study of Osteoporotic Fracture and Comprehensive Geriatric Assessment Based Frailty Index Compared with Frailty Index 40 Items. AB - AIM: to get a recommendation on the best frailty syndrome diagnostic tools, that will be able to be practiced on a daily setting in Indonesia. METHODS: this is a cross-sectional study with diagnostic test approach, conducted to patients in the Geriatric Outpatient Clinic of Cipto Mangunkusumo National Referral Hospital on May-June 2013. Each subject underwent a frailty evaluation using CHS, SOF, FI-CGA and FI-40 scoring systems. Then, we calculate the sensitivity, specificity, PPV, NPV, LR+ and LR- of each scoring system compared to FI-40. RESULTS: the proportion of frail, pre-frail and fit according to FI-40 are 25.3%, 71% and 3.7% respectively. In terms of differentiation frail to non-frail, CHS had 41.2% sensitivity, 95% specificity, PPV 73.7%, NPV 82.7%, LR+ 8.41 and LR- 0.62. SOF scoring system had 17.6% sensitivity, 99.5% specificity, PPV 92.3%, NPV 78.1%, LR+ 35.2 and LR- 0.83. Furthermore FI-CGA had 8.8% sensitivity, 100% specificity, PPV 100%, NPV 76.4%, LR+ and LR- 0.91. CONCLUSION: There is no better scoring system that could be implemented to screen for frailty syndrome other than FI-40 items. However, other scoring systems could be used as a good diagnostic tool for the syndrome. PMID- 26586384 TI - Effectiveness of Short Term Percutaneous Tibial Nerve Stimulation for Non neurogenic Overactive Bladder Syndrome in Adults: A Meta-analysis. AB - AIM: to evaluate the effectiveness of short-term PTNS for non-neurogenic OAB in adults systematically by comparing with sham procedure and other treatments. METHODS: we performed a systematic review of cohort study. Data sources were MEDLINE, EMBASE, CINAHL, National Library for Health, Cochrane, and google scholar from 2005 through 2015. Meta-analysis was performed using the random effects model. Heterogeneity of effects was assessed by calculating I2 statistic. Statistical analysis was performed using Review Manager 5.3 for RCT meta analysis. RESULTS: we analized 11 randomised controlled trial (RCT) and five prospective non-comparative studies with variable success rate. Based on percentage of responders, the results were 37.3% - 81.8% in PTNS group, 0% - 20.9% in sham group, 54.8% in anti-muscarinic group, and 89.7% in multimodal group. The decrease of voiding symptoms episodes per day was found in PTNS (0.7 4.5), sham (0.3-1.5), and anti-muscarinic (0.6-2.9) groups. In meta-analysis of four RCTs, the results favour PTNS over sham procedure with overall risk ratio of 7.32 (95% CI of 1.69-32.16), p=0.09, I2=54%. CONCLUSION: there is an evidence of effectiveness of short term PTNS in treatment of non-neurogenic OAB. PTNS is proven significantly better than sham procedure. PMID- 26586385 TI - Efficacy of Probiotic Escherichia coli Nissle 1917 in Patients with Irritable Bowel Syndrome: a Double Blind Placebo-controlled Randomized Trial. AB - AIM: to evaluate potential improvement effect for probiotic E. coliNissle 1917 in the management of refractory IBS in an Iranian population. METHODS: a double blind placebo controlled approach has been used in the current clinical trial. 139 confirmed IBS patients were included into the study, and were given probiotic E.coli Nissle 1917 for 6 weeks. 11 items Birmingham IBS Symptom Questionnairehas been used for evaluation of changes in the symptoms every 2 weeks. RESULTS: sixty eight subjects (49%) were males. Mean+/-SD age of the participants was 38+/-13.3 years. 49(35.3%) of the patients were diarrhea-predominant. The total scores showed no significant difference between the intervention vs. control group( 6.7+/-6.8 vs. -6.7+/-6.5, respectively; p=0.95); neither did any of the questionnaire items any significant alterations in the two groups. After stratification of patients based on their IBS type, diarrhea-predominant patients showed a positive response to the probiotic improving their sleep (p=0.05 and 0.03 at weeks 2 and 6, respectively). Patients with constipation-predominant IBS showed no response to the probiotic; while patients with diarrhea-constipation mixed IBS showed unfavorable response to the probiotic in the need for strain to pass a motion compared to the placebo (p=0.03 and 0.02 at weeks 4 and 6, respectively). CONCLUSION: probiotic therapy with E.coli Nissle 1917 was not able to induce significant improvement in the symptoms of patients with non categorized IBS. Nevertheless, when IBS patients were recategorized to subgroups according to their main symptoms, evaluation of the efficacy of the probiotic on some individual items in the symptom list reached the significance level. Prospective clinical trials are recommended to confirm our findings. PMID- 26586386 TI - Factors Associated with In-stent Restenosis in Patients Following Percutaneous Coronary Intervention. AB - AIM: to determine factors associated with In-Stent Restenosis (ISR) in patients following Percutaneous Coronary Intervention (PCI). METHODS: a retrospective cross-sectional study was conducted using secondary information from medical records of post-PCI patients who underwent follow-up of angiography PCI between January 2009 and March 2014 at The Integrated Cardiovascular Service Unit, Cipto Mangunkusumo Hospital, Jakarta. Angiographic ISR was defined when the diameter of stenosis 50% at follow-up angiography including the diameter inside the stent and diameter with five-mm protrusion out of the proximal and distal ends of the stent. RESULTS: there were 289 subjects including 133 subjects with and 156 subjects without ISR. The incidence of ISR in patients using of bare-metal stent (BMS) and drug-eluting stent (DES) were 61.3% and 40.7%, respectively. Factors associated with ISR are stent-type (OR=4.83, 95% CI 2.51-9.30), stent length (OR=3.71, 95% CI 1.99-6.90), bifurcation lesions (OR=2.43, 95% CI 1.16-5.10), smoking (OR=2.30, 95% CI 1.33-3.99), vascular diameter (OR=2.18, 95% CI 1.2 3.73), hypertension (OR=2.16, 95% CI 1.16-4.04) and diabetes mellitus (OR=2.14, 95% CI 1.23-3.70). CONCLUSION: stent type, stent length, bifurcation lesions, smoking, vascular diameter, hypertension and DM are factors associated with ISR in patients following PCI. PMID- 26586387 TI - Performance of Alpha Fetoprotein in Combination with Alpha-1-acid Glycoprotein for Diagnosis of Hepatocellular Carcinoma Among Liver Cirrhosis Patients. AB - AIM: to evaluate the use of alpha-1-acid glycoprotein (AAG) for diagnosing hepatocellular carcinoma (HCC), and to combine with alpha fetoprotein (AFP) as part of routine examination in liver cirrhosis patients. METHODS: this is a diagnostic study using cross-sectional design. A hundred and six patients were included in this study. Baseline data such as age, gender, AFP, AAG, peripheral blood count, AST and ALT were consecutively collected from liver cirrhosis patients with or without HCC. Serum AAG were measured quantitatively using immunoturboditimetric assay and AFP with enzyme immune assay (EIA). Statistical analysis were done using SPSS 13.0. Data comparisons between group were done using Mann-Whitney test. Diagnostic performance for each marker alone was compared to the surrogate use of both markers (combined parallel approach) in HCC cases. RESULTS: receiver operating characteristic (ROC) analysis showed that area under the curve for AFP-AAG combination was 88.1% and higher than AFP only (86.2%) or AAG only (76.5%) with sensitivity of 83%, 73% and 44%, respectively, at specificity of >80%. CONCLUSION: our study showed that combination of AFP and AAG is superior than either marker alone in diagnosing HCC in liver cirrhosis patients. Combination of AFP and AAG may be used to prompt early diagnosis screening of HCC. PMID- 26586388 TI - Clinical Effectiveness, Safety and Tolerability of Amlodipine/Valsartan in Hypertensive Patients: the Indonesian Subset of the EXCITE Study. AB - AIM: to assess the effectiveness, safety and tolerability of amlodipine/valsartan (Aml/Val) single-pill combination (SPC) in hypertensive patients in a real-world setting. METHODS: the Indonesian subset of the EXCITE (clinical EXperience of amlodIpine and valsarTan in hypErtension) study, which was a multinational, prospective, observational, open study in hypertensive patients treated with Aml/Val SPC for 26 weeks. Aml/Val SPCs (5/80, 5/160, 10/160 mg) were administered as monotherapy or as add-on therapy to other antihypertensive medications in patients not controlled by prior monotherapy. The effectiveness outcomes were (1) mean decrease in sitting systolic blood pressure and diastolic blood pressure (msSBP and msDBP) from baseline to week 26; (2) proportion of patients achieving BP goal (<140/90 mmHg for nondiabetics, or <130/80 mmHg for diabetics); (3) proportion of patients who were responders (achieving BP goal or BP reduction of >20/10 mmHg). The safety variables were the incidence of AEs and SAEs, and the incidence of edema. RESULTS: a total of 500 patients from Indonesia received Aml/Val SPC, 487 patients were analyzed for efficacy (by LOCF), and 464 patients completed the study. At study end (week 26), the overall msSBP and msDBP(95% CI) reductions from baseline were -33.7 (-35.2, -32.1) mmHg and -14.8 (-15.7, -13.8) mmHg, respectively. Among the 487 patients, 52.4% achieved BP goal and 80.5% were responders (LOCF). Among 464 patients who completed the study, 53.7% achieved BP goal and 84.5% were responders. Aml/Val SPC was effective in decreasing BP in Indonesian patients. AEs, including SAEs, were reported in 11.4% patients, with SAEs in 1% of patients, and death in 0.8% of patients. SAEs and deaths were considered unrelated to the study drug. Edema was reported by 9.4% of patients at baseline, and in 3.7% patients at end of study. Effectiveness, tolerability and compliance were rated good and very good in 90.8%, 92.2%, and 89.2% of patients, respectively, according to the investigators. CONCLUSION: Aml/Val SPC was effective for BP reductions and well tolerated in hypertensive patients, not adequately controlled by monotherapy, in a daily clinical setting in Indonesia. PMID- 26586389 TI - Septic Pulmonary Embolism Following Appendectomy Surgery. AB - Septic Pulmonary embolism is a rare condition where there were numerous pulmonary infarcts resulting from blood clot emboli that also contains microorganism. This disorder is insidious onset, Its clinical features usually unspecific and the diagnosis usually difficult to establish. A 43 old woman who underwent an appendicitis surgery, reentered the hospital at the sixth day after surgery presented with fever, pain at the surgical site, progressive severe dyspnea and chest tightness. From the physical examination finding there were tachycardia, tachypneu, wet rough basal rhonki on the right rear and tenderness at right lower region of the abdomen. The thorax-abdomen CT scan result was pleuropneumonial with minimal effusion in the right side. A CT angiography scan of the chest and abdomen showed intralumen emboli in medial lobe segmen of right pulmonary artery, right pleuropneumonia with segmental lession in segmen 10 right lobe and inflammation process along right lateral wall of the abdomen. Laboratory results that also supported diagnosis were D dimer 3442 ng/mL and culture result from surgical site pus showed E. Coli ESBL (+). Base on these findings, this case was established as a septic pulmonary embolism. PMID- 26586390 TI - Traumatic Inhalation due to Merapi Volcanic Ash. AB - Pneumonoultramicroscopicsilicovolcanoconiosis is fibrotic lung diseases of the pulmonary parenchyma following chronic inhalation of inorganic dusts containing crystalline silicon dioxide. The acute manifestations observed after heavy ashfalls include attacks of asthma and bronchitis, with an increased reporting of cough, breathlessness, chest tightness, and wheezing due to irritation of the lining of the airways. The chronic health condition of most concern is silicosis, a diffuse nodular fibrosis of the lungs, develops slowly, usually appearing 10 to 30 years after first exposure. A 35 years old male was admitted to Sardjito Hospital, Yogyakarta with complaints of progressive dyspnoea, right side chest pain since last 3 month and periodic episodes of dry cough. He had history of exposure to volcanic ash at the location around volcano eruption for about 10 month. Examination revealed hyperresonant note, diminished vesicular breath sounds in lower right side of the chest. The chest X-ray presence leads to bleb. Based on the clinical and radiological suspicion of pneumoconiosis the patient was submitted to computed tomography of the chest and revealed bilateral multiple bullae mainly at the right lung field. The biopsy specimen verified the diagnosis of anthrocosilicosis. There is no proven specific therapy for any form of silicosis. Symptomatic therapy should include treatment of airflow limitation with bronchodilators, aggressive management of respiratory tract infection with antibiotics, and use of supplemental oxygen (if indicated) to prevent complications of chronic hypoxemia. PMID- 26586391 TI - Opioid Use in Cancer Pain Management in Indonesia: a Call For Attention. AB - Severe pain is a major problem for cancer patients, and pain management often requires the use of opioids. Indonesia is one of the countries where the use of opioids for cancer patients is extremely low, and this calls for attention, as many cancer patients in the country undergo unnecessary suffering as the consequence of this opioid underuse. The inability to assess pain correctly, failure to determine the correct dose, fear of addiction, overly tight regulation, all contribute to the failure to implement rational use of opioids for cancer patients. Breakthrough pain, a problem which requires special attention not only because it is commonly found but also requires proper knowledge to handle them. These hurdles are discussed in the present review, in order to bring a better understanding about the correct use of opioids in severe cancer pain. Some examples where opiods are used inappropriately in cancer pain management are also discussed. PMID- 26586392 TI - Successful Treatment of Unstageable Pressure Ulcer by Using Advanced Wound Dressing. PMID- 26586393 TI - Extended Dual Antiplatelet for Diabetic Elderly Patients After Drug-eluting Stent Implantation: an Evidence-based Clinical Review. AB - Antiplatelet is an important drug for patients with coronary heart disease undergoing drug-eluting stent implantation. Current guidelines recommend dual antiplatelet with aspirin and a P2Y12 inhibitor for at least 12 months. Continuation of DAPT beyond 12 months may be considered for preventing very late stent thrombosis. Several patient-related factors that contribute to stent thrombosis have been recognized, including diabetes and advanced age, but the optimal DAPT duration for these patients is still controversial. This article reviews the efficacy of extended (>12 months) compared to standard (12 months) DAPT for reducing myocardial infarction and stent thrombosis rates, especially in diabetic elderly patients. Literature screening was conducted at PubMed and Cochrane database using "dual antiplatelet", "duration", "adult-onset diabetes mellitus", "elderly" and, "drug-eluting stent" as keywords. Article types were limited to meta-analysis, systematic review, randomized clinical trial, or clinical trial that compared the efficacy of extended to standard duration of DAPT. Clinical outcomes used were myocardial infarction and stent thrombosis. The initial search was done to find relevant studies specifically assessing diabetic and elderly patients, then widened to diabetic and non-diabetic patients of any age above eighteen years. A total of 5 clinical trials and 1 meta-analysis were reviewed, showing an overall risk reduction of stent thrombosis and myocardial infarction. This review has several limitations, such as its potential selection bias and under-represented proportion of diabetic and elderly patients. High-risk subgroups like diabetes mellitus has a tendency of increased ischemic risk, while advanced age could have both increased ischemic risk and bleeding risk. This review suggests that it is better to reserve extended dual antiplatelet therapy for patients with high ischemic risk and low bleeding risk (tailored therapy). PMID- 26586394 TI - Managing Hypertriglyceridemia in Daily Practice. AB - Hypertriglyceridemia is a form of dyslipidemia, which usually occurs in combination with hypercholesterolemia, high-LDL or low-HDL cholesterol level. Most studies suggest that hypertriglyceridemia is associated with many metabolic disorders such as metabolic syndrome, diabetes, obesity, and also cardio cerebrovascular diseases. Treatment of hypertriglyceridemia is often not comprehensively addressed by many physicians, who usually only include prescribing drugs without encouraging patients to perform physical activity, to take a true healthy diet for dyslipidemia and to stop smoking. This review article discusses evaluation, diagnosis and a comprehensive, yet simple management of hypertriglyceridemia, which can be easily applied in daily clinical practice. PMID- 26586395 TI - Glabridin arrests cell cycle and inhibits proliferation of hepatocellular carcinoma by suppressing braf/MEK signaling pathway. AB - Glabridin, an isoflavone isolated from licorice, owns a variety of pharmacological effects. Several reports have demonstrated that glabridin could regulate multiple cellular signaling pathways to inhibit the progression of cancer. However, the target proteins have not been elucidated yet. We used shape screening and induced fit docking to screen the protein data bank against glabridin. Braf and MEK1/2, important intermediate molecules of the braf/MEK cascade, were identified as the potential targets of glabridin. The experimental data showed that glabridin could inhibit the phosphorylation of MEK1/2 and the phosphorylation levels of downstream molecules including ERK1/2 and transcription factors ATF1 and CREB, but had no effect on the phosphorylation of braf. In particular, the in vitro pull-down assay indicated that glabridin selectively bound to braf and MEK1/2. What is more, exposure to glabridin significantly suppressed the proliferation of hepatocellular carcinoma HepG2 cell line. In addition, glabridin might arrest cell cycle in G1 through downregulation of cyclinD3, CDK2, and CDK4. In conclusion, glabridin is a potential multi-molecule targeting inhibitor in the field of clinical prevention or treatment of cancer. PMID- 26586397 TI - The construction and proliferative effects of a lentiviral vector capable of stably overexpressing SPINK1 gene in human pancreatic cancer AsPC-1 cell line. AB - This study aims to design and generate recombinant lentiviral vector containing the complete coding sequence (CDS) region of human serine protease inhibitor Kazal type 1 gene (SPINK1) and establish a human pancreatic cancer cell line (AsPC-1) stably overexpressing SPINK1. Then, to assess the proliferative and oncogenic effects of upregulated SPINK1 gene on pancreatic cancer AsPC-1 cells using different methods. Initially, the target coding sequence (CDS) of SPINK1 was amplified by polymerase chain reaction (PCR) and the synthesized product was subsequently subcloned into the lentiviral vector. The construction of recombinant SPINK1 gene was verified by the restriction digestion and sequencing analysis. The lentiviral particles carrying SPINK1 gene were produced by co transfection of the recombination lentiviral vector and the packaging mix plasmids into 293 T cells and filtered and concentrated before AsPC-1 cells were infected by the virus particles. The cells transduced were differentially selected with puromycin, and the clones that highly expressed SPINK1 were chosen by real-time PCR and confirmed by Western blot after 7 weeks. The stably transduced AsPC-1 cell line showed significantly increased metabolic and proliferative capability using CCK-8 and Trypan Blue assays (P < 0.001). Cell cycle and DNA content analysis by flow cytometry showed that upregulated SPINK1 elicited significant increase in the percentage of AsPC-1 cells in the S and G2/M phase (P < 0.001). Clone formation assay demonstrated that the number of the colonies formed in the experimental group was greater than that in the control parental cells (P < 0.001). It was concluded that a stable AsPC-1 cell line capable of overexpressing SPINK1 had been successfully created, and that the proliferative capacity of AsPC-1 pancreatic cancer cells was significantly raised by SPINK1 upregulation as well as the ability of a single AsPC-1 cell to grow into a colony. PMID- 26586398 TI - Irradiation induces glioblastoma cell senescence and senescence-associated secretory phenotype. AB - Glioblastoma multiforme (GBM) is one of the most aggressive and fatal primary brain tumors in humans. The standard therapy for the treatment of GBM is surgical resection, followed by radiotherapy and/or chemotherapy. However, the frequency of tumor recurrence in GBM patients is very high, and the survival rate remains poor. Delineating the mechanisms of GBM recurrence is essential for therapeutic advances. Here, we demonstrate that irradiation rendered 17-20 % of GBM cells dead, but resulted in 60-80 % of GBM cells growth-arrested with increases in senescence markers, such as senescence-associated beta-galactosidase-positive cells, H3K9me3-positive cells, and p53-p21(CIP1)-positive cells. Moreover, irradiation induced expression of senescence-associated secretory phenotype (SASP) mRNAs and NFkappaB transcriptional activity in GBM cells. Strikingly, compared to injection of non-irradiated GBM cells into immune-deficient mice, the co-injection of irradiated and non-irradiated GBM cells resulted in faster growth of tumors with the histological features of human GBM. Taken together, our findings suggest that the increases in senescent cells and SASP in GBM cells after irradiation is likely one of main reasons for tumor recurrence in post radiotherapy GBM patients. PMID- 26586396 TI - Long noncoding RNAs and tumorigenesis: genetic associations, molecular mechanisms, and therapeutic strategies. AB - The human genome contains a large number of nonprotein-coding sequences. Recently, new discoveries in the functions of nonprotein-coding sequences have demonstrated that the "Dark Genome" significantly contributes to human diseases, especially with regard to cancer. Of particular interest in this review are long noncoding RNAs (lncRNAs), which comprise a class of nonprotein-coding transcripts that are longer than 200 nucleotides. Accumulating evidence indicates that a large number of lncRNAs exhibit genetic associations with tumorigenesis, tumor progression, and metastasis. Our current understanding of the molecular bases of these lncRNAs that are associated with cancer indicate that they play critical roles in gene transcription, translation, and chromatin modification. Therapeutic strategies based on the targeting of lncRNAs to disrupt their expression or their functions are being developed. In this review, we briefly summarize and discuss the genetic associations and the aberrant expression of lncRNAs in cancer, with a particular focus on studies that have revealed the molecular mechanisms of lncRNAs in tumorigenesis. In addition, we also discuss different therapeutic strategies that involve the targeting of lncRNAs. PMID- 26586399 TI - Sodium glycididazole enhances the radiosensitivity of laryngeal cancer cells through downregulation of ATM signaling pathway. AB - The purpose of this study was to evaluate the radiation-enhancing effect of sodium glycididazole, and the corresponding mechanisms of action on laryngeal cancer cells. Two laryngeal cancer cell lines (Hep-2 and UT-SCC-19A) were irradiated with X-rays in the presence or absence of sodium glycididazole. Cell survival, DNA damage and repair, cell apoptosis, cell cycle distribution, expression of proteins related to cell cycle checkpoint, and apoptosis were measured. Significantly increased DNA damages, decreased cells in the G1 phase, arrested cells at G2/M phase, decreased DNA repair protein XRCC1 foci formation, and enhanced cell apoptosis were observed in laryngeal cell lines treated by sodium glycididazole combined with irradiation compared with the irradiation alone. The combined treatment downregulated the protein expressions of ataxia telangiectasia mutated (ATM), p-ATM, CHK2, and P53 but upregulated the protein expressions of MDM2 and Cdk2. This study indicates that sodium glycididazole enhances the radiosensitivity of laryngeal cancer cells through downregulation of ATM signaling pathway in vitro and in vivo. PMID- 26586400 TI - Aberrant regulation of miR-15b in human malignant tumors and its effects on the hallmarks of cancer. AB - MicroRNAs encoded by the miR-15b/16-2 cluster act as tumor suppressors. Aberrant regulation of miR-15b in human malignant tumors is reportedly involved in cancer development, contributing to cell death, reduced proliferation, angiogenesis and metastasis resistance, metabolism reprogramming, genome instability, and tumor associated inflammation. In this review, we summarize the mechanisms involved in regulating miR-15b expression in mammalian tumors and discuss the effects of miR 15b dysregulation on the hallmarks of cancer and highlight its role as a potentially valuable target for future cancer therapeutic strategies. PMID- 26586401 TI - Clinicopathological characteristics and liver stem cell marker expression in hepatocellular carcinoma involving bile duct tumor thrombi. AB - The aim of this study was to analyze the clinicopathological characteristics and expression of liver stem cell markers of hepatocellular carcinoma (HCC) involving bile duct tumor thrombi (BDTT). A total of 35 patients with HCC and BDTT in a consecutive series of HCC patients who underwent surgical treatment were studied retrospectively and compared with 916 patients without BDTT from the same series. Clinicopathological characteristics, overall survival (OS), and tumor expression of liver stem cell markers CD133, CD90, EpCAM, CK19, VEGF, and C-kit were compared between the two patient groups. Analysis was performed for the entire patient groups as well as for 35 pairs of patients with or without BDTT matched by propensity score. HCC patients with BDTT tended to have smaller tumors than those without BDTT, as well as a higher probability of having poorly differentiated tumor, Child-Pugh class B, liver cirrhosis, and microvascular invasion. Tumor tissue in patients with BDTT showed significantly higher expression rates of all liver stem cell markers examined. OS was significantly lower for patients with BDTT at 1 year (69 vs 84 %), 3 years (37 vs 64 %), and 5 years (20 vs 55 %) (P < 0.001). Patients with HCC and BDTT show lower OS than patients without BDTT. The higher frequency of liver stem cell marker expression in the presence of BDTT suggests that such stem cells may play a role in the pathogenesis of this form of HCC. PMID- 26586402 TI - Glutathione production by recombinant Escherichia coli expressing bifunctional glutathione synthetase. AB - Glutathione (GSH) is an important bioactive substance applied widely in pharmaceutical and food industries. Due to the strong product inhibition in the GSH biosynthetic pathway, high levels of intracellular content, yield and productivity of GSH are difficult to achieve. Recently, a novel bifunctional GSH synthetase was identified to be less sensitive to GSH. A recombinant Escherichia coli strain expressing gshF encoding the bifunctional glutathione synthetase of Streptococcus thermophilus was constructed for GSH production. In this study, efficient GSH production using this engineered strain was investigated. The cultivation process was optimized by controlling dissolved oxygen (DO), amino acid addition and glucose feeding. 36.8 mM (11.3 g/L) GSH were formed at a productivity of 2.06 mM/h when the amino acid precursors (75 mM each) were added and glucose was supplied as the sole carbon and energy source. PMID- 26586403 TI - Anti-tuberculosis lead molecules from natural products targeting Mycobacterium tuberculosis ClpC1. AB - Tuberculosis (TB) is a serious and potentially fatal disease caused by Mycobacterium tuberculosis (M. tb). The occurrence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) M. tb is a significant public health concern because most of the anti-TB drugs that have been in use for over 40 years are no longer effective for the treatment of these infections. Recently, new anti-TB lead compounds such as cyclomarin A, lassomycin, and ecumicin, which are cyclic peptides from actinomycetes, have shown potent anti-TB activity against MDR and XDR M. tb as well as drug-susceptible M. tb in vitro. The target molecule of these antibiotics is ClpC1, a protein that is essential for the growth of M. tb. In this review, we introduce the three anti-TB lead compounds as potential anti TB therapeutic agents targeting ClpC1 and compare them with the existing anti-TB drugs approved by the US Food and Drug Administration. PMID- 26586404 TI - Culture-independent discovery of natural products from soil metagenomes. AB - Bacterial natural products have proven to be invaluable starting points in the development of many currently used therapeutic agents. Unfortunately, traditional culture-based methods for natural product discovery have been deemphasized by pharmaceutical companies due in large part to high rediscovery rates. Culture independent, or "metagenomic," methods, which rely on the heterologous expression of DNA extracted directly from environmental samples (eDNA), have the potential to provide access to metabolites encoded by a large fraction of the earth's microbial biosynthetic diversity. As soil is both ubiquitous and rich in bacterial diversity, it is an appealing starting point for culture-independent natural product discovery efforts. This review provides an overview of the history of soil metagenome-driven natural product discovery studies and elaborates on the recent development of new tools for sequence-based, high throughput profiling of environmental samples used in discovering novel natural product biosynthetic gene clusters. We conclude with several examples of these new tools being employed to facilitate the recovery of novel secondary metabolite encoding gene clusters from soil metagenomes and the subsequent heterologous expression of these clusters to produce bioactive small molecules. PMID- 26586405 TI - Mitochondrial Respiration Chain Enzymatic Activities in the Human Brain: Methodological Implications for Tissue Sampling and Storage. AB - Mitochondrial respiratory chain complexes enzymatic (MRCCE) activities were successfully evaluated in frozen brain samples. Epilepsy surgery offers an ethical opportunity to study human brain tissue surgically removed to treat drug resistant epilepsies. Epilepsy surgeries are done with hemodynamic and laboratory parameters to maintain physiology, but there are no studies analyzing the association among these parameters and MRCCE activities in the human brain tissue. We determined the intra-operative parameters independently associated with MRCCE activities in middle temporal neocortex (Cx), amygdala (AMY) and head of hippocampus (HIP) samples of patients (n = 23) who underwent temporal lobectomy using multiple linear regressions. MRCCE activities in Cx, AMY and HIP are differentially associated to trans-operative mean arterial blood pressure, O2 saturation, hemoglobin, and anesthesia duration to time of tissue sampling. The time-course between the last seizure occurrence and tissue sampling as well as the sample storage to biochemical assessments were also associated with enzyme activities. Linear regression models including these variables explain 13-17 % of MRCCE activities and show a moderate to strong effect (r = 0.37-0.82). Intraoperative hemodynamic and laboratory parameters as well as the time from last seizure to tissue sampling and storage time are associated with MRCCE activities in human samples from the Cx, AMYG and HIP. Careful control of these parameters is required to minimize confounding biases in studies using human brain samples collected from elective neurosurgery. PMID- 26586407 TI - Bilateral avascular necrosis of the femoral head following treatment of Ewing's sarcoma. PMID- 26586406 TI - Characteristic Changes of Astrocyte and Microglia in Rat Striatum Induced by 3-NP and MCAO. AB - Our previous studies had confirmed that both 3-NP and MCAO induced the behavioral defect as well as striatal neuronal injury and loss in experimental rats. This study aimed to examine different response forms of striatal astrocyte and microglia in 3-NP and MCAO rat models. The present results showed that the immunoreaction for GFAP was extremely weak in the lesioned core of striatum, but in the transition zone of 3-NP model and the penumbra zone of MCAO model, GFAP+ cells showed strong hypertrophic and proliferative changes. Statistical analysis for the number, size and integral optical density (IOD) of GFAP+ cells showed significant differences when compared with their controls and compared between the core and the transition zone or the penumbra zone, respectively, but no differences between the 3-NP and MCAO groups. However, Iba-1+ cells showed obvious hypertrophy and proliferation in the injured striatum in the 3-NP and the MCAO models, especially in the transition zone of 3-NP model and the penumbra zone of MCAO model. These Iba-1+ cells displayed two characteristic forms as branching cells with thick processes and amoeboid cells with thin processes. Statistical analysis showed that the number, size and IOD of Iba-1+ cells were significantly increased in the cores and the transition zone of 3-NP group and the penumbra zone of MCAO group than that of the controls, and the immune response of Iba-1 was stronger in the MCAO group than in the 3-NP group. The present results suggested that characteristic responses of astrocyte and microglia in the 3-NP and the MCAO models display their different effects on the pathological process of brain injury. PMID- 26586408 TI - Associations between bone mineral density and urinary phthalate metabolites among post-menopausal women: a cross-sectional study of NHANES data 2005-2010. AB - Bone mineral density (BMD) decreases with age, especially among post-menopausal women. Exposures to endocrine disruptors, such as phthalate diesters, could alter BMD through a variety of unidentified mechanisms. A hypothesis-generating study investigated associations between urinary phthalate metabolites and BMD at the femoral neck and spine in post-menopausal women (n = 480) participating in the National Health and Nutrition Examination Survey, from 2005 to 2010. Mono-ethyl phthalate (MEP), molar sum of low molecular weight metabolites (mono-n-butyl phthalate (MNBP), mono-isobutyl phthalate (MIBP), MEP), molar sum of estrogenic metabolites (MNBP, MIBP, MEP, mono-benzyl phthalate (MBZP)), and an estrogenic equivalency factor were negatively associated with spinal BMD. Some associations were modified by age or BMI. The cross-sectional study design, uncertainty regarding the critical time window of exposure, the potential for exposure misclassification, and residual confounding limit our abilities to draw causal conclusions regarding phthalate metabolites and BMD in post-menopausal women. Future studies should address these limitations. PMID- 26586409 TI - Pulmonary artery sarcoma presenting as an isolated lung mass. AB - We report a very rare case of pulmonary artery sarcoma that presented as an isolated lung mass, which we attempted to resect via lobectomy, although this resulted in incomplete resection due to unnoticed latent proximal presentations. A 54-year-old man complained of a dry cough that had persisted for 2 months. Enhanced chest computed tomography revealed a lobular mass in his left lower lobe. Therefore, left lower lobectomy was performed as a radical surgery, and the tumor was ultimately diagnosed as pulmonary artery sarcoma. However, follow-up computed tomography at 16 months revealed proximal presentations in the pulmonary trunk and right pulmonary artery, which we retrospectively discovered were present before the surgery. This case highlights the importance of evaluating the lumen of the pulmonary artery, to accurately determine the required extent of any radical surgery, even in cases of pulmonary artery sarcoma that presents as an isolated lung mass. PMID- 26586410 TI - Authors' reply to Mawer and Wilcox and Mullish and Williams. PMID- 26586411 TI - Holomorphic Hartree-Fock Theory: An Inherently Multireference Approach. AB - We investigate the existence of holomorphic Hartree-Fock solutions using a revised SCF algorithm. We use this algorithm to study the Hartree-Fock solutions for H2 and H42+ and report the emergence of holomorphic solutions at points of symmetry breaking. Finally, we find these holomorphic solutions for H4 and use them as a basis for Non-Orthogonal Configuration Interaction at a range of rectangular geometries and show them to produce energies in good agreement with Full Configuration Interaction. PMID- 26586412 TI - Quantum secret sharing via local operations and classical communication. AB - We investigate the distinguishability of orthogonal multipartite entangled states in d-qudit system by restricted local operations and classical communication. According to these properties, we propose a standard (2, n)-threshold quantum secret sharing scheme (called LOCC-QSS scheme), which solves the open question in [Rahaman et al., Phys. Rev. A, 91, 022330 (2015)]. On the other hand, we find that all the existing (k, n)-threshold LOCC-QSS schemes are imperfect (or "ramp"), i.e., unauthorized groups can obtain some information about the shared secret. Furthermore, we present a (3, 4)-threshold LOCC-QSS scheme which is close to perfect. PMID- 26586413 TI - Cohort study of neurocognitive functioning and adaptive behaviour in children and adolescents with Niemann-Pick Disease type C1. AB - AIM: To describe the neurocognitive and adaptive behavior profile of children and adolescents with Niemann-Pick Disease type C1 (NPC1), a rare genetic disease that frequently presents in childhood, with variable onset and symptom complex involving neurodegeneration. METHOD: Thirty-eight participants (20 males, 18 females; mean age 8y 10mo, SD 4y 8mo, range 1-18y) with NPC1 were evaluated through a natural history protocol. RESULTS: NPC1 severity was in the mild to moderate range for most participants. Cognitive scores (n=32) ranged from very low to above average; about half of the participants exhibited a clinically significant advantage of Verbal IQ over Non-verbal IQ. Adaptive behavior scores (n=21) were generally in the borderline to impaired range. Longitudinal cognitive data (n=19) suggested a pattern of decreasing scores over time. However, most participants remained at the same general level of functioning throughout the study. INTERPRETATION: This study begins to systematically describe the neurocognitive phenotype of children and adolescents with NPC1, identifying heterogeneity and decline, aiding in understanding the natural history of the disease to plan treatment studies. PMID- 26586414 TI - Trends in incidence for gestational trophoblastic disease over the last 20 years in a population-based study. AB - BACKGROUND: Gestational trophoblastic disease (GTD) represents a heterogeneous group of disorders. Wide variations in incidence rates are reported worldwide, probably explained by a lack of centralized databases and heterogeneity in case definition. The aim of the present study was to determine the trends in incidence of GTD in the last 20 years with the use of population-based data. PATIENTS AND METHODS: Data on patients with pathologically confirmed diagnosis of GTD between 1994 and 2013 were obtained from PALGA, a nationwide archive containing all pathology reports in the Netherlands. RESULTS: In the 20-year period 6343 cases were registered with GTD, representing an overall incidence rate of 1.67 per 1000 deliveries per year. An initial rise in incidence rate was seen over the first 10 years (0.075 per year, 95% CI 0.040-0.109), followed by a stabilization from 2004 to 2013 (increase per year 0.011, 95% CI -0.017-0.040). Although partial hydatidiform mole (HM) was more common in earlier years, complete and partial HM reached comparable incidence rates of 0.68 and 0.64 per 1000 deliveries respectively from 2009 onwards. In the last decade, unspecified HM diagnosis declined significantly from 0.14 per 1000 deliveries in 2003 to 0.03 per 1000 deliveries (per year -0.011, CI -0.016-0.06), suggesting improved diagnostic analyses. CONCLUSION: After an initial rise in GTD incidence in the Netherlands rates remained steady from 2004 onwards. As pathological confirmation is currently the norm and advanced pathological techniques are now widely available, true steady incidence rates may have been reached. PMID- 26586415 TI - Is the NCI MATCH trial a match for gynecologic oncology? AB - The Precision Medicine Initiative is an NCI driven program in cancer to generate the scientific evidence needed to move the concept of precision medicine into clinical practice. The rapid development and widespread availability of next generation sequencing and other molecular interrogation of tumors has heralded a new era of knowledge about each individual's tumor at a point in time. In some instances, this information has led to new therapeutic discoveries, in most instances, this information has been uninformative or of unclear significance. The NCI Molecular Analysis for Therapy Choice (MATCH) trial [NCT02465060] which screens for molecular features that may predict response to a drug with a given mechanism of action, is a multi-study, collaborative effort between the NCI and many pharmaceutical companies to begin to clarify the significance of molecular alterations in tumors not previously studied. This trial design is in response to the recent appreciation that certain driver mutations which may be common in a particular tumor type are mutated in other diseases at low frequency (<10%). In low frequency mutations, testing the utility of certain targeted therapy requires screening large numbers of patients. This review article will discuss the types of novel trial designs that led to the development and launch of the NCI MATCH. PMID- 26586416 TI - Phonetic complexity of words immediately following utterance-initial productions in children who stutter. AB - PURPOSE: The purpose of the present study was to analyze phonetic complexity in the speech of children who stutter in a manner distinct from previous research with specific emphasis on three methodological considerations: (1) analysis of the word immediately following the initial word in the utterance; (2) accounting for other additional linguistic and lexical factors; and (3) discrimination of disfluency types produced. METHODS: Parent-child conversations were transcribed for 14 children who stutter (mean age=3 years, 7 months; SD=11.20 months) and coded for phonetic complexity using the Word Complexity Measure (WCM). Phonetic complexity of words immediately following the initial fluent or stuttered words of an utterance were included within binomial regression analyses, along with additional linguistic and lexical factors. RESULTS: Analyses indicate that the phonetic complexity of the second word of an utterance was not a significant contributor to the likelihood of whole- or part-word repetitions on the preceding initial word of the utterance. CONCLUSION: Findings support previous data that suggest the phonetic complexity of speech, at least as measured by the WCM, does not distinctly influence stuttered speech in preschool-age children. PMID- 26586417 TI - The dual aptamer approach: rational design of a high-affinity FAD aptamer. AB - A design strategy for high-affinity aptamers of complex biomolecules is presented. We developed an RNA with FAD-binding properties by combining known ATP and FMN-aptamers. Cooperative binding of FAD was shown by SPR spectroscopy and fluorescence assays. The strategy should be transferable to several other biomolecules. PMID- 26586418 TI - Use of the Fitbit to Measure Adherence to a Physical Activity Intervention Among Overweight or Obese, Postmenopausal Women: Self-Monitoring Trajectory During 16 Weeks. AB - BACKGROUND: Direct-to-consumer trackers and devices have potential to enhance theory-based physical activity interventions by offering a simple and pleasant way to help participants self-monitor their behavior. A secondary benefit of these devices is the opportunity for investigators to objectively track adherence to physical activity goals across weeks or even months, rather than relying on self-report or a small number of accelerometry wear periods. The use of consumer trackers for continuous monitoring of adherence has considerable potential to enhance physical activity research, but few studies have been published in this rapidly developing area. OBJECTIVE: The objective of the study was to assess the trajectory of physical activity adherence across a 16-week self-monitoring intervention, as measured by the Fitbit tracker. METHODS: Participants were 25 overweight or obese, postmenopausal women enrolled in the intervention arm of a randomized controlled physical activity intervention trial. Each participant received a 16-week technology-based intervention that used the Fitbit physical activity tracker and website. The overall study goal was 150 minutes/week of moderate to vigorous intensity physical activity (MVPA) and 10,000 steps/day; however, goals were set individually for each participant and updated at Week 4 based on progress. Adherence data were collected by the Fitbit and aggregated by Fitabase. Participants also wore an ActiGraph GT3X+ accelerometer for 7 days prior to the intervention and again during Week 16. RESULTS: The median participant logged 10 hours or more/day of Fitbit wear on 95% of the 112 intervention days, with no significant decline in wear over the study period. Participants averaged 7540 (SD 2373) steps/day and 82 minutes/week (SD 43) of accumulated "fairly active" and "very active" minutes during the intervention. At Week 4, 80% (20/25) of women chose to maintain/increase their individual MVPA goal and 72% (18/25) of participants chose to maintain/increase their step goal. Physical activity levels were relatively stable after peaking at 3 weeks, with only small declines of 8% for steps (P=.06) and 14% for MVPA (P=.05) by 16 weeks. CONCLUSIONS: These data indicate that a sophisticated, direct-to-consumer activity tracker encouraged high levels of self-monitoring that were sustained over 16 weeks. Further study is needed to determine how to motivate additional gains in physical activity and evaluate the long-term utility of the Fitbit tracker as part of a strategy for chronic disease prevention. TRIAL REGISTRATION: Clinicaltrials.gov NCT01837147; http://clinicaltrials.gov/ct2/show/NCT01837147 (Archived by WebCite at http://www.webcitation.org/6d0VeQpvB). PMID- 26586419 TI - Dual-Phase Oxygen Transport Membranes for Stable Operation in Environments Containing Carbon Dioxide and Sulfur Dioxide. AB - Dual-phase membranes are appealing candidates for oxygen transport membranes owing to their unique combination of ambipolar electron-ion transport and endurance. However, O2 separation in industrial environments demands very high stability and effectiveness in the presence of CO2- and SO2-bearing process gases. Here, the composition of dual-phase membranes based on NiFe2O4-Ce(0.8) Tb(0.2)O(2-delta) (NFO-CTO) was optimized and the effective performance of catalytically-activated membranes was assessed in presence of CO2 and SO2. Further insight into the limiting mechanisms in the permeation was gained through electrical conductivity studies, permeation testing in several conditions and impedance spectroscopy analysis. The dual-phase membranes were prepared by one pot sol-gel method and their permeability increases with increasing fluorite content. An O2 flux of 0.25 (ml min(-1) cm(-2)) mm at 1000 degrees C was obtained for a thick self-standing membrane with 40:60 NFO/CTO composition. An in depth study mimicking typical harsh conditions encountered in oxyfuel flue gases was performed on a 50:50 NFO/CTO membrane. CO2 content as well as SO2 presence in the sweep gas stream were evaluated in terms of O2 permeation. O2 fluxes of 0.13 and 0.09 mL min(-1) cm(-2) at 850 degrees C were obtained for a 0.59 mm thick membrane under CO2 and 250 ppm SO2 in CO2 sweep conditions, respectively. Extended periods at work under CO2- and SO2-containing atmospheres revealed good permeation stability over time. Additionally, XRD, backscattered electrons detector (BSD)-SEM, and energy-dispersive X-ray spectroscopy (EDS) analysis of the spent membrane confirmed material stability upon prolonged exposure to SO2. PMID- 26586420 TI - Effect of ultrasonication on anaerobic degradability of solid waste digestate. AB - This paper evaluates the effect of ultrasonication on anaerobic biodegradability of lignocellulosic residues. While ultrasonication has been commonly applied as a pre-treatment of the feed substrate, in the present study a non-conventional process configuration based on recirculation of sonicated digestate to the biological reactor was evaluated at the lab-scale. Sonication tests were carried out at different applied energies ranging between 500 and 50,000kJ/kg TS. Batch anaerobic digestion tests were performed on samples prepared by mixing sonicated and untreated substrate at two different ratios (25:75 and 75:25 w/w). The results showed that when applied as a post-treatment of digestate, ultrasonication can positively affect the yield of anaerobic digestion, mainly due to the dissolution effect of complex organic molecules that have not been hydrolyzed by biological degradation. A good correlation was found between the CH4 production yield and the amount of soluble organic matter at the start of digestion tests. The maximum gain in biogas production was 30% compared to that attained with the unsonicated substrate, which was tentatively related to the type and concentration of the metabolic products. PMID- 26586421 TI - Giant optical enhancement of strain gradient in ferroelectric BiFeO3 thin films and its physical origin. AB - Through mapping of the spatiotemporal strain profile in ferroelectric BiFeO3 epitaxial thin films, we report an optically initiated dynamic enhancement of the strain gradient of 10(5)-10(6) m(-1) that lasts up to a few ns depending on the film thickness. Correlating with transient optical absorption measurements, the enhancement of the strain gradient is attributed to a piezoelectric effect driven by a transient screening field mediated by excitons. These findings not only demonstrate a new possible way of controlling the flexoelectric effect, but also reveal the important role of exciton dynamics in photostriction and photovoltaic effects in ferroelectrics. PMID- 26586422 TI - Burnout and Work Engagement in Nurses: A Comment on Sinclair et al. (2015) "Bad versus good, what matters more on the treatment floor? Relationships of positive and negative events with nurses' burnout and engagement". PMID- 26586423 TI - Single-cell analysis and stochastic modelling unveil large cell-to-cell variability in influenza A virus infection. AB - Biochemical reactions are subject to stochastic fluctuations that can give rise to cell-to-cell variability. Yet, how this variability affects viral infections, which themselves involve noisy reactions, remains largely elusive. Here we present single-cell experiments and stochastic simulations that reveal a large heterogeneity between influenza A virus (IAV)-infected cells. In particular, experimental data show that progeny virus titres range from 1 to 970 plaque forming units and intracellular viral RNA (vRNA) levels span three orders of magnitude. Moreover, the segmentation of IAV genomes seems to increase the susceptibility of their replication to noise, since the level of different genome segments can vary substantially within a cell. In addition, simulations suggest that the abortion of virus entry and random degradation of vRNAs can result in a large fraction of non-productive cells after single-hit infection. These results challenge current beliefs that cell population measurements and deterministic simulations are an accurate representation of viral infections. PMID- 26586424 TI - FGF21-Mediated Improvements in Glucose Clearance Require Uncoupling Protein 1. AB - Fibroblast growth factor 21 (FGF21)-mediated weight loss and improvements in glucose metabolism correlate with increased uncoupling protein 1 (Ucp1) levels in adipose tissues, suggesting that UCP1-dependent thermogenesis may drive FGF21 action. It was reported that FGF21 is equally effective at reducing body weight and improving glucose homeostasis without UCP1. We find while FGF21 can lower body weight in both wild-type and Ucp1 knockout mice, rapid clearance of glucose by FGF21 is defective in the absence of UCP1. Furthermore, in obese wild-type mice there is a fall in brown adipose tissue (BAT) temperature during glucose excursion, and FGF21 improves glucose clearance while preventing the fall in BAT temperature. In Ucp1 knockout mice, the fall in BAT temperature during glucose excursion and FGF21-mediated changes in BAT temperature are lost. We conclude FGF21-mediated improvements in clearance of a glucose challenge require UCP1 and evoke UCP1-dependent thermogenesis as a method to increase glucose disposal. PMID- 26586425 TI - Acetylation of an NB-LRR Plant Immune-Effector Complex Suppresses Immunity. AB - Modifications of plant immune complexes by secreted pathogen effectors can trigger strong immune responses mediated by the action of nucleotide binding leucine-rich repeat immune receptors. Although some strains of the pathogen Pseudomonas syringae harbor effectors that individually can trigger immunity, the plant's response may be suppressed by other virulence factors. This work reveals a robust strategy for immune suppression mediated by HopZ3, an effector in the YopJ family of acetyltransferases. The suppressing HopZ3 effector binds to and can acetylate multiple members of the RPM1 immune complex, as well as two P. syringae effectors that together activate the RPM1 complex. These acetylations modify serine, threonine, lysine, and/or histidine residues in the targets. Through HopZ3-mediated acetylation, it is possible that the whole effector-immune complex is inactivated, leading to increased growth of the pathogen. PMID- 26586426 TI - Non-redundant Functions of ATM and DNA-PKcs in Response to DNA Double-Strand Breaks. AB - DNA double-strand breaks (DSBs) elicit the so-called DNA damage response (DDR), largely relying on ataxia telangiectasia mutated (ATM) and DNA-dependent protein kinase (DNA-PKcs), two members of the PI3K-like kinase family, whose respective functions during the sequential steps of the DDR remains controversial. Using the DIvA system (DSB inducible via AsiSI) combined with high-resolution mapping and advanced microscopy, we uncovered that both ATM and DNA-PKcs spread in cis on a confined region surrounding DSBs, independently of the pathway used for repair. However, once recruited, these kinases exhibit non-overlapping functions on end joining and gammaH2AX domain establishment. More specifically, we found that ATM is required to ensure the association of multiple DSBs within "repair foci." Our results suggest that ATM acts not only on chromatin marks but also on higher order chromatin organization to ensure repair accuracy and survival. PMID- 26586427 TI - ATM Kinase Is Required for Telomere Elongation in Mouse and Human Cells. AB - Short telomeres induce a DNA damage response, senescence, and apoptosis, thus maintaining telomere length equilibrium is essential for cell viability. Telomerase addition of telomere repeats is tightly regulated in cells. To probe pathways that regulate telomere addition, we developed the ADDIT assay to measure new telomere addition at a single telomere in vivo. Sequence analysis showed telomerase-specific addition of repeats onto a new telomere occurred in just 48 hr. Using the ADDIT assay, we found that ATM is required for addition of new repeats onto telomeres in mouse cells. Evaluation of bulk telomeres, in both human and mouse cells, showed that blocking ATM inhibited telomere elongation. Finally, the activation of ATM through the inhibition of PARP1 resulted in increased telomere elongation, supporting the central role of the ATM pathway in regulating telomere addition. Understanding this role of ATM may yield new areas for possible therapeutic intervention in telomere-mediated disease. PMID- 26586428 TI - SRSF10 Plays a Role in Myoblast Differentiation and Glucose Production via Regulation of Alternative Splicing. AB - Alternative splicing is a major mechanism of controlling gene expression and protein diversity in higher eukaryotes. We report that the splicing factor SRSF10 functions during striated muscle development, myoblast differentiation, and glucose production both in cells and in mice. A combination of RNA-sequencing and molecular analysis allowed us to identify muscle-specific splicing events controlled by SRSF10 that are critically involved in striated muscle development. Inclusion of alternative exons 16 and 17 of Lrrfip1 is a muscle-specific event that is activated by SRSF10 and essential for myoblast differentiation. On the other hand, in mouse primary hepatocytes, PGC1alpha is a key target of SRSF10 that regulates glucose production by fasting. SRSF10 represses inclusion of PGC1alpha exon 7a and facilitates the production of functional protein. The results highlight the biological significance of SRSF10 and regulated alternative splicing in vivo. PMID- 26586430 TI - The Tumor Suppressor Cdkn3 Is Required for Maintaining the Proper Number of Centrosomes by Regulating the Centrosomal Stability of Mps1. AB - Supernumerary centrosomes promote the assembly of abnormal spindles in many human cancers. The observation that modest changes in the centrosomal levels of Mps1 kinase can cause centrosome overduplication in human cells suggests the existence of a regulatory system that may tightly control its centrosomal stability. Here, we show that Cdkn3, a Cdk-associated phosphatase, prevents Mps1-mediated centrosome overduplication. We identify Cdkn3 as a direct binding partner of Mps1. The interaction between Mps1 and Cdkn3 is required for Mps1 to recruit Cdkn3 to centrosomes. Subsequently, Mps1-bound Cdkn3 forms a regulatory system that controls the centrosomal levels of Mps1 through proteasome-mediated degradation and thereby prevents Mps1-mediated centrosome overduplication. Conversely, knockdown of Cdkn3 stabilizes Mps1 at centrosomes, which promotes centrosome overduplication. We suggest that Mps1 and Cdkn3 form a self-regulated feedback loop at centrosomes to tightly control the centrosomal levels of Mps1, which prevents centrosome overduplication in human cells. PMID- 26586429 TI - Transcriptional Landscape of Cardiomyocyte Maturation. AB - Decades of progress in developmental cardiology has advanced our understanding of the early aspects of heart development, including cardiomyocyte (CM) differentiation. However, control of the CM maturation that is subsequently required to generate adult myocytes remains elusive. Here, we analyzed over 200 microarray datasets from early embryonic to adult hearts and identified a large number of genes whose expression shifts gradually and continuously during maturation. We generated an atlas of integrated gene expression, biological pathways, transcriptional regulators, and gene regulatory networks (GRNs), which show discrete sets of key transcriptional regulators and pathways activated or suppressed during CM maturation. We developed a GRN-based program named MatStat(CM) that indexes CM maturation status. MatStat(CM) reveals that pluripotent-stem-cell-derived CMs mature early in culture but are arrested at the late embryonic stage with aberrant regulation of key transcription factors. Our study provides a foundation for understanding CM maturation. PMID- 26586431 TI - Combined Loss of Tet1 and Tet2 Promotes B Cell, but Not Myeloid Malignancies, in Mice. AB - TET1/2/3 are methylcytosine dioxygenases that regulate cytosine hydroxymethylation. Tet1/2 are abundantly expressed in HSC/HPCs and are implicated in hematological malignancies. Tet2 deletion in mice causes myeloid malignancies, while Tet1-null mice develop B cell lymphoma after an extended period of latency. Interestingly, TET1/2 are often concomitantly downregulated in acute B-lymphocytic leukemia. Here, we investigated the overlapping and non redundant functions of Tet1/2 using Tet1/2 double-knockout (DKO) mice. DKO and Tet2(-/-) HSC/HPCs show overlapping and unique 5 hmC and 5 mC profiles. DKO mice exhibit strikingly decreased incidence and delayed onset of myeloid malignancies in comparison to Tet2(-/-) mice and in contrast develop lethal B cell malignancies. Transcriptome analysis of DKO tumors reveals expression changes in many genes dysregulated in human B cell malignancies, including LMO2, BCL6, and MYC. These results highlight the critical roles of TET1/2 individually and together in the pathogenesis of hematological malignancies. PMID- 26586432 TI - Gut-Resident Lactobacillus Abundance Associates with IDO1 Inhibition and Th17 Dynamics in SIV-Infected Macaques. AB - Gut microbes can profoundly modulate mucosal barrier-promoting Th17 cells in mammals. A salient feature of HIV/simian immunodeficiency virus (SIV) immunopathogenesis is the loss of Th17 cells, which has been linked to increased activity of the immunomodulatory enzyme, indoleamine 2,3-dioxygenase 1 (IDO 1). The role of gut microbes in this system remains unknown, and the SIV-infected rhesus macaque provides a well-described model for HIV-associated Th17 loss and mucosal immune disruption. We observed a specific depletion of gut-resident Lactobacillus during acute and chronic SIV infection of rhesus macaques, which was also seen in early HIV-infected humans. This depletion in rhesus macaques correlated with increased IDO1 activity and Th17 loss. Macaques supplemented with a Lactobacillus-containing probiotic exhibited decreased IDO1 activity during chronic SIV infection. We propose that Lactobacillus species inhibit mammalian IDO1 and thus may help to preserve Th17 cells during pathogenic SIV infection, providing support for Lactobacillus species as modulators of mucosal immune homeostasis. PMID- 26586433 TI - ATM and ATR Signaling Regulate the Recruitment of Human Telomerase to Telomeres. AB - The yeast homologs of the ATM and ATR DNA damage response kinases play key roles in telomerase-mediated telomere maintenance, but the role of ATM/ATR in the mammalian telomerase pathway has been less clear. Here, we demonstrate the requirement for ATM and ATR in the localization of telomerase to telomeres and telomere elongation in immortal human cells. Stalled replication forks increased telomerase recruitment in an ATR-dependent manner. Furthermore, increased telomerase recruitment was observed upon phosphorylation of the shelterin component TRF1 at an ATM/ATR target site (S367). This phosphorylation leads to loss of TRF1 from telomeres and may therefore increase replication fork stalling. ATM and ATR depletion reduced assembly of the telomerase complex, and ATM was required for telomere elongation in cells expressing POT1DeltaOB, an allele of POT1 that disrupts telomere-length homeostasis. These data establish that human telomerase recruitment and telomere elongation are modulated by DNA-damage transducing kinases. PMID- 26586434 TI - Adenoviral Vector Vaccination Induces a Conserved Program of CD8(+) T Cell Memory Differentiation in Mouse and Man. AB - Following exposure to vaccines, antigen-specific CD8(+) T cell responses develop as long-term memory pools. Vaccine strategies based on adenoviral vectors, e.g., those developed for HCV, are able to induce and sustain substantial CD8(+) T cell populations. How such populations evolve following vaccination remains to be defined at a transcriptional level. We addressed the transcriptional regulation of divergent CD8(+) T cell memory pools induced by an adenovector encoding a model antigen (beta-galactosidase). We observe transcriptional profiles that mimic those following infection with persistent pathogens, murine and human cytomegalovirus (CMV). Key transcriptional hallmarks include upregulation of homing receptors and anti-apoptotic pathways, driven by conserved networks of transcription factors, including T-bet. In humans, an adenovirus vaccine induced similar CMV-like phenotypes and transcription factor regulation. These data clarify the core features of CD8(+) T cell memory following vaccination with adenovectors and indicate a conserved pathway for memory development shared with persistent herpesviruses. PMID- 26586435 TI - Direct Visualization of HIV-1 Replication Intermediates Shows that Capsid and CPSF6 Modulate HIV-1 Intra-nuclear Invasion and Integration. AB - Direct visualization of HIV-1 replication would improve our understanding of the viral life cycle. We adapted established technology and reagents to develop an imaging approach, ViewHIV, which allows evaluation of early HIV-1 replication intermediates, from reverse transcription to integration. These methods permit the simultaneous evaluation of both the capsid protein (CA) and viral DNA genome (vDNA) components of HIV-1 in both the cytosol and nuclei of single cells. ViewHIV is relatively rapid, uses readily available reagents in combination with standard confocal microscopy, and can be done with virtually any HIV-1 strain and permissive cell lines or primary cells. Using ViewHIV, we find that CA enters the nucleus and associates with vDNA in both transformed and primary cells. We also find that CA's interaction with the host polyadenylation factor, CPSF6, enhances nuclear entry and potentiates HIV-1's depth of nuclear invasion, potentially aiding the virus's integration into gene-dense regions. PMID- 26586436 TI - Burn Induces Browning of the Subcutaneous White Adipose Tissue in Mice and Humans. AB - Burn is accompanied by long-lasting immuno-metabolic alterations referred to as hypermetabolism that are characterized by a considerable increase in resting energy expenditure and substantial whole-body catabolism. In burned patients, the length and magnitude of the hypermetabolic state is the highest of all patients and associated with profoundly increased morbidity and mortality. Unfortunately, the mechanisms involved in hypermetabolism are essentially unknown. We hypothesized that the adipose tissue plays a central role for the induction and persistence of hypermetabolism post-burn injury. Here, we show that burn induces a switch in the phenotype of the subcutaneous fat from white to beige, with associated characteristics such as increased mitochondrial mass and UCP1 expression. Our results further demonstrate the significant role of catecholamines and interleukin-6 in this process. We conclude that subcutaneous fat remodeling and browning represent an underlying mechanism that explains the elevated energy expenditure in burn-induced hypermetabolism. PMID- 26586437 TI - Structural Basis for a Switch in Receptor Binding Specificity of Two H5N1 Hemagglutinin Mutants. AB - Avian H5N1 influenza viruses continue to spread in wild birds and domestic poultry with sporadic infection in humans. Receptor binding specificity changes are a prerequisite for H5N1 viruses and other zoonotic viruses to be transmitted among humans. Previous reported hemagglutinin (HA) mutants from ferret transmissible H5N1 viruses of A/Vietnam/1203/2004 and A/Indonesia/5/2005 showed slightly increased, but still very weak, binding to human receptors. From mutagenesis and glycan array studies, we previously identified two H5N1 HA mutants that could more effectively switch receptor specificity to human-like alpha2-6-linked sialosides with avidity comparable to wild-type H5 HA binding to avian-like alpha2-3-linked sialosides. Here, crystal structures of these two H5 HA mutants free and in complex with human and avian glycan receptor analogs reveal the structural basis for their preferential binding to human receptors. These findings suggest continuous surveillance should be maintained to monitor and assess human-to-human transmission potential of H5N1 viruses. PMID- 26586438 TI - Crystal Structures of SecYEG in Lipidic Cubic Phase Elucidate a Precise Resting and a Peptide-Bound State. AB - The bacterial SecYEG translocon functions as a conserved protein-conducting channel. Conformational transitions of SecYEG allow protein translocation across the membrane without perturbation of membrane permeability. Here, we report the crystal structures of intact SecYEG at 2.7-A resolution and of peptide-bound SecYEG at 3.6-A resolution. The higher-resolution structure revealed that the cytoplasmic loop of SecG covers the hourglass-shaped channel, which was confirmed to also occur in the membrane by disulfide bond formation analysis and molecular dynamics simulation. The cytoplasmic loop may be involved in protein translocation. In addition, the previously unknown peptide-bound crystal structure of SecYEG implies that interactions between the cytoplasmic side of SecY and signal peptides are related to lateral gate opening at the first step of protein translocation. These SecYEG structures therefore provide a number of structural insights into the Sec machinery for further study. PMID- 26586439 TI - Expansion of Interstitial Telomeric Sequences in Yeast. AB - Telomeric repeats located within chromosomes are called interstitial telomeric sequences (ITSs). They are polymorphic in length and are likely hotspots for initiation of chromosomal rearrangements that have been linked to human disease. Using our S. cerevisiae system to study repeat-mediated genome instability, we have previously shown that yeast telomeric (Ytel) repeats induce various gross chromosomal rearrangements (GCR) when their G-rich strands serve as the lagging strand template for replication (G orientation). Here, we show that interstitial Ytel repeats in the opposite C orientation prefer to expand rather than cause GCR. A tract of eight Ytel repeats expands at a rate of 4 * 10(-4) per replication, ranking them among the most expansion-prone DNA microsatellites. A candidate-based genetic analysis implicates both post-replication repair and homologous recombination pathways in the expansion process. We propose a model for Ytel repeat expansions and discuss its applications for genome instability and alternative telomere lengthening (ALT). PMID- 26586440 TI - A Diet-Sensitive BAF60a-Mediated Pathway Links Hepatic Bile Acid Metabolism to Cholesterol Absorption and Atherosclerosis. AB - Dietary nutrients interact with gene networks to orchestrate adaptive responses during metabolic stress. Here, we identify Baf60a as a diet-sensitive subunit of the SWI/SNF chromatin-remodeling complexes in the mouse liver that links the consumption of fat- and cholesterol-rich diet to elevated plasma cholesterol levels. Baf60a expression was elevated in the liver following feeding with a western diet. Hepatocyte-specific inactivation of Baf60a reduced bile acid production and cholesterol absorption, and attenuated diet-induced hypercholesterolemia and atherosclerosis in mice. Baf60a stimulates expression of genes involved in bile acid synthesis, modification, and transport through a CAR/Baf60a feedforward regulatory loop. Baf60a is required for the recruitment of the SWI/SNF chromatin-remodeling complexes to facilitate an activating epigenetic switch on target genes. These studies elucidate a regulatory pathway that mediates the hyperlipidemic and atherogenic effects of western diet consumption. PMID- 26586441 TI - A DNMT3A2-HDAC2 Complex Is Essential for Genomic Imprinting and Genome Integrity in Mouse Oocytes. AB - Maternal genomic imprints are established during oogenesis. Histone deacetylases (HDACs) 1 and 2 are required for oocyte development in mouse, but their role in genomic imprinting is unknown. We find that Hdac1:Hdac2(-/-) double-mutant growing oocytes exhibit global DNA hypomethylation and fail to establish imprinting marks for Igf2r, Peg3, and Srnpn. Global hypomethylation correlates with increased retrotransposon expression and double-strand DNA breaks. Nuclear associated DNMT3A2 is reduced in double-mutant oocytes, and injecting these oocytes with Hdac2 partially restores DNMT3A2 nuclear staining. DNMT3A2 co immunoprecipitates with HDAC2 in mouse embryonic stem cells. Partial loss of nuclear DNMT3A2 and HDAC2 occurs in Sin3a(-/-) oocytes, which exhibit decreased DNA methylation of imprinting control regions for Igf2r and Srnpn, but not Peg3. These results suggest seminal roles of HDAC1/2 in establishing maternal genomic imprints and maintaining genomic integrity in oocytes mediated in part through a SIN3A complex that interacts with DNMT3A2. PMID- 26586442 TI - Chromatin Dynamics and the RNA Exosome Function in Concert to Regulate Transcriptional Homeostasis. AB - The histone variant H2A.Z is a hallmark of nucleosomes flanking promoters of protein-coding genes and is often found in nucleosomes that carry lysine 56 acetylated histone H3 (H3-K56Ac), a mark that promotes replication-independent nucleosome turnover. Here, we find that H3-K56Ac promotes RNA polymerase II occupancy at many protein-coding and noncoding loci, yet neither H3-K56Ac nor H2A.Z has a significant impact on steady-state mRNA levels in yeast. Instead, broad effects of H3-K56Ac or H2A.Z on RNA levels are revealed only in the absence of the nuclear RNA exosome. H2A.Z is also necessary for the expression of divergent, promoter-proximal noncoding RNAs (ncRNAs) in mouse embryonic stem cells. Finally, we show that H2A.Z functions with H3-K56Ac to facilitate formation of chromosome interaction domains (CIDs). Our study suggests that H2A.Z and H3-K56Ac work in concert with the RNA exosome to control mRNA and ncRNA expression, perhaps in part by regulating higher-order chromatin structures. PMID- 26586443 TI - Pharmacological Activation of Thyroid Hormone Receptors Elicits a Functional Conversion of White to Brown Fat. AB - The functional conversion of white adipose tissue (WAT) into a tissue with brown adipose tissue (BAT)-like activity, often referred to as "browning," represents an intriguing strategy for combating obesity and metabolic disease. We demonstrate that thyroid hormone receptor (TR) activation by a synthetic agonist markedly induces a program of adaptive thermogenesis in subcutaneous WAT that coincides with a restoration of cold tolerance to cold-intolerant mice. Distinct from most other browning agents, pharmacological TR activation dissociates the browning of WAT from activation of classical BAT. TR agonism also induces the browning of white adipocytes in vitro, indicating that TR-mediated browning is cell autonomous. These data establish TR agonists as a class of browning agents, implicate the TRs in the browning of WAT, and suggest a profound pharmacological potential of this action. PMID- 26586444 TI - Association of intraoperative vasopressin administration with acute postoperative kidney injury and outcomes after coronary artery bypass surgery. PMID- 26586445 TI - Do cost savings from reductions in nosocomial infections justify additional costs of single-bed rooms in intensive care units? A simulation case study. AB - PURPOSE: Evidence shows that single-patient rooms can play an important role in preventing cross-transmission and reducing nosocomial infections in intensive care units (ICUs). This case study investigated whether cost savings from reductions in nosocomial infections justify the additional construction and operation costs of single-bed rooms in ICUs. MATERIALS AND METHODS: We conducted deterministic and probabilistic return-on-investment analyses of converting the space occupied by open-bay rooms to single-bed rooms in an exemplary ICU. We used the findings of a study of an actual ICU in which the association between the locations of patients in single-bed vs open-bay rooms with infection risk was evaluated. RESULTS: Despite uncertainty in the estimates of costs, infection risks, and length of stay, the cost savings from the reduction of nosocomial infections in single-bed rooms in this case substantially outweighed additional construction and operation expenses. The mean value of internal rate of return over a 5-year analysis period was 56.18% (95% credible interval, 55.34%-57.02%). CONCLUSIONS: This case study shows that although single-patient rooms are more costly to build and operate, they can result in substantial savings compared with open-bay rooms by avoiding costs associated with nosocomial infections. PMID- 26586446 TI - Determinants of changes in vitamin D status postpartum in Swedish women. AB - Low vitamin D status has been associated with unfavourable health outcomes. Postpartum, it is speculated that maternal vitamin D status decreases due to transfer of vitamin D from mother to child through breast milk. A few studies have investigated changes in maternal vitamin D postpartum and possible determinants. Thus, the aims of the present study were to determine changes in serum concentrations of 25-hydroxyvitamin D (25(OH)D) between 2 weeks and 12 months postpartum in Swedish women and to evaluate lactation and other determinants for changes in 25(OH)D concentration postpartum. In total, seventy eight women were studied at 2 weeks, 4 months and 12 months postpartum. Data collection included measurements of weight and height as well as information about lactation, sun exposure, use of oestrogen contraceptives and physical activity level. Blood samples were collected and serum 25(OH)D levels were analysed using liquid chromatography-tandem MS. Dietary intake of vitamin D was recorded using 4-d food diaries. For all the women studied, mean serum 25(OH)D did not change between 2 weeks and 12 months postpartum (67 (SD 23) v. 67 (SD 19) nmol/l). No association was found between lactation and changes in serum 25(OH)D concentration postpartum. Significant determinants for postpartum changes in 25(OH)D concentration were use of vitamin D supplements (P=0.003), use of oestrogen contraceptives (P=0.013) and season (P=0.005). In conclusion, no changes were observed in 25(OH)D concentrations during the 1st year postpartum in these women and no association was found between lactation and changes in 25(OH)D concentration postpartum. The main determinants for the variation in changes in 25(OH)D concentrations postpartum were use of vitamin D supplements, use of oestrogen contraceptives and season. PMID- 26586447 TI - Investigating the effect of autoinduction in cynomolgus monkeys of a novel anticancer MDM2 antagonist, idasanutlin, and relevance to humans. AB - 1. Idasanutlin (RG7388) is a potent p53-MDM2 antagonist currently in clinical development for treatment of cancer. The purpose of the present studies was to investigate the cause of marked decrease in plasma exposure after repeated oral administration of RG7388 in monkeys and whether the autoinduction observed in monkeys is relevant to humans. 2. In monkey liver and intestinal microsomes collected after repeated oral administration of RG7388 to monkeys, significantly increased activities of homologue CYP3A8 were observed (ex vivo). Investigation using a physiologically based pharmacokinetic (PBPK) model suggested that the loss of exposure was primarily due to induction of metabolism in the gut of monkeys. 3. Studies in monkey and human primary hepatocytes showed that CYP3A induction by RG7388 only occurred in monkey hepatocytes but not in human hepatocytes, which suggests the observed CYP3A induction is monkey specific. 4. The human PK data obtained from the first cohorts confirmed the lack of relevant induction as predicted by the human hepatocytes and the PBPK modelling based on no induction in humans. PMID- 26586448 TI - Population differences and the effect of vaginal progesterone on preterm birth in women with threatened preterm labor (.). AB - OBJECTIVE: Threatened preterm labor (tPTL) is a complication of pregnancy. Identification of women and clinical definition differs between countries. This study investigated differences in tPTL and effectiveness of vaginal progesterone to prevent preterm birth (PTB) between two countries. METHODS: Secondary analysis of a randomized controlled trial (RCT) from Argentina and Switzerland comparing vaginal progesterone to placebo in women with tPTL (n = 379). Cox proportional hazards analysis was performed to compare placebo groups of both countries and to compare progesterone to placebo within each country. We adjusted for baseline differences. Iatrogenic onset of labor or pregnancy beyond gestational age of interest was censored. RESULTS: Swiss and Argentinian women were different on baseline. Risks for delivery <14 days and PTB < 34 and < 37 weeks were increased in Argentina compared to Switzerland, HR 3.3 (95% CI 0.62-18), 54 (95% CI 5.1 569) and 3.1 (95% CI 1.1-8.4). In Switzerland, progesterone increased the risk for delivery <14 days [HR 4.4 (95% CI 1.3-15.7)] and PTB <37 weeks [HR 2.5 (95% CI 1.4-4.8)], in Argentina there was no such effect. CONCLUSION: In women with tPTL, the effect of progesterone may vary due to population differences. Differences in populations should be considered in multicenter RCTs. PMID- 26586450 TI - Vertical distribution of sediment phosphorus in Lake Hachirogata related to the effect of land reclamation on phosphorus accumulation. AB - The focus of this work is the change in sediment properties and chemical characteristics that occur after land reclamation projects. The results indicate a higher sedimentation rate in Lake Hachirogata after reclamation, with the rate increasing with proximity to the agricultural zone. In the west-side water samples, higher levels of dissolved total nitrogen and dissolved total phosphorus (DTP) were found in both surface and bottom waters. The increase in P (39-80%) was generally greater than that for N (12-16%), regarding the nutrient supply from reclaimed farmland in the western part of the lake. In the eastern part of the lake, the pore-water Cl- profile showed a decreasing vertical gradient in the sediment core. This indicates desalination of the lake water after construction of a sluice gate in 1961. In the western sediment-core sample, a uniform Cl- profile indicates the mixing of lake water and pore water after reclamation. Considering the sedimentation of P in the last 100 years, there is a trend of increasing accumulation of P and P-activities after the reclamation project. This appears to be an impact from change in the lake environment as a result of increased agricultural nutrients, desalination, and residence. A large amount of mobile phosphorus (42-72% of TP in the western core sample) trapped in sediment increases the risk of phosphorus release and intensification of algal blooms. High sediment phosphorus and phosphorus mobility should be considered a source of pollution in the coastal environment. PMID- 26586449 TI - The structural neural substrate of subjective happiness. AB - Happiness is a subjective experience that is an ultimate goal for humans. Psychological studies have shown that subjective happiness can be measured reliably and consists of emotional and cognitive components. However, the neural substrates of subjective happiness remain unclear. To investigate this issue, we used structural magnetic resonance imaging and questionnaires that assessed subjective happiness, the intensity of positive and negative emotional experiences, and purpose in life. We found a positive relationship between the subjective happiness score and gray matter volume in the right precuneus. Moreover, the same region showed an association with the combined positive and negative emotional intensity and purpose in life scores. Our findings suggest that the precuneus mediates subjective happiness by integrating the emotional and cognitive components of happiness. PMID- 26586451 TI - A prevalence study of Salmonella spp., Yersinia spp., Toxoplasma gondii and porcine reproductive and respiratory syndrome virus in UK pigs at slaughter. AB - An abattoir-based study was undertaken between January and May 2013 to estimate the prevalence of Salmonella spp. and Yersinia spp. carriage and seroprevalence of antibodies to Toxoplasma gondii and porcine reproductive and respiratory syndrome virus (PRRSv) in UK pigs at slaughter. In total, 626 pigs were sampled at 14 abattoirs that together process 80% of the annual UK pig slaughter throughput. Sampling was weighted by abattoir throughput and sampling dates and pig carcasses were randomly selected. Rectal swabs, blood samples, carcass swabs and the whole caecum, tonsils, heart and tongue were collected. Salmonella spp. was isolated from 30.5% [95% confidence interval (CI) 26.5-34.6] of caecal content samples but only 9.6% (95% CI 7.3-11.9) of carcass swabs, which was significantly lower than in a UK survey in 2006-2007. S. Typhimurium and S. 4,[5],12:i:- were the most commonly isolated serovars, followed by S. Derby and S. Bovismorbificans. The prevalence of Yersinia enterocolitica carriage in tonsils was 28.7% (95% CI 24.8-32.7) whereas carcass contamination was much lower at 1.8% (95% CI 0.7-2.8). The seroprevalence of antibodies to Toxoplasma gondii and PRRSv was 7.4% (95% CI 5.3-9.5) and 58.3% (95% CI 53.1-63.4), respectively. This study provides a comparison to previous abattoir-based prevalence surveys for Salmonella and Yersinia, and the first UK-wide seroprevalence estimates for antibodies to Toxoplasma and PRRSv in pigs at slaughter. PMID- 26586452 TI - Ice formation in the left mainstem bronchus during cryoballoon ablation for the treatment of atrial fibrillation. PMID- 26586453 TI - Impact of ventricular ectopic burden in a premature ventricular contraction induced cardiomyopathy animal model. AB - BACKGROUND: Frequent premature ventricular contractions (PVCs) have been associated with PVC-induced cardiomyopathy (CM) in some patients. OBJECTIVE: The purpose of this study was to understand the cardiac consequences of different PVC burdens and the minimum burden required to induce left ventricular (LV) dysfunction. METHODS: Right ventricular apical PVCs at a coupling interval of 240 ms were introduced at different PVC burdens in 9 mongrel canines. A stepwise increase in PVC burden was implemented every 8 weeks from 0% (baseline), 7%, 14%, 25%, 33% to 50% using our premature pacing algorithm. Echocardiogram and 24-hour Holter were obtained at 4- and 8-week period for each PVC burden with a single blinded reader assessing all echocardiographic parameters including those assessed by speckle tracking imaging (EchoPAC workstation, General Electric). CM was defined as left ventricular ejection fraction (LVEF) <50% or LVEF drop >10% points. Interleukin-6 and pro-brain natriuretic peptide levels were obtained at the end of each PVC burden. RESULTS: The mean LVEF (mean heart rate) at 8 weeks for each PVC burden (0%, 7%, 14%, 33%, and 50%) were 57% +/- 2.9% (85 +/- 13 beats/min), 54.4% +/- 3% (81 +/- 10 beats/min), 53.3% +/- 5% (77 +/- 12 beats/min), 51.1% +/- 4.2% (79 +/- 14 beats/min), 47.7% +/- 3.8% (80 +/- 14 beats/min), and 44.7% +/- 1.9% (157 +/- 43 beats/min). PVC-induced CM was present in 11.1%, 44.4%, and 100% of animals with 25%, 33%, and 50% PVC burden, respectively. E/A ratio and radial strain decreased while left atrial size increased beyond 33% PVC burden. No changes in pro-brain natriuretic peptide and interleukin-6 levels were noted at any PVC burden. CONCLUSION: LV systolic function (LVEF and radial strain) declined linearly as PVC burden increased. PVC induced CM developed in some canines with 25% and 33% PVC burden, but developed in all animals with 50% PVC burden. PMID- 26586454 TI - Embryonic development of the right ventricular outflow tract and arrhythmias. PMID- 26586455 TI - Direct Measurement of Optical Force Induced by Near-Field Plasmonic Cavity Using Dynamic Mode AFM. AB - Plasmonic nanostructures have attracted much attention in recent years because of their potential applications in optical manipulation through near-field enhancement. Continuing experimental efforts have been made to develop accurate techniques to directly measure the near-field optical force induced by the plasmonic nanostructures in the visible frequency range. In this work, we report a new application of dynamic mode atomic force microscopy (DM-AFM) in the measurement of the enhanced optical force acting on a nano-structured plasmonic resonant cavity. The plasmonic cavity is made of an upper gold-coated glass sphere and a lower quartz substrate patterned with an array of subwavelength gold disks. In the near-field when the sphere is positioned close to the disk array, plasmonic resonance is excited in the cavity and the induced force by a 1550 nm infrared laser is found to be increased by an order of magnitude compared with the photon pressure generated by the same laser light. The experiment demonstrates that DM-AFM is a powerful tool for the study of light induced forces and their enhancement in plasmonic nanostructures. PMID- 26586456 TI - Association of mitochondrial mutations with the age of patients having atherosclerotic lesions. AB - Mitochondrial genome mutations are associated with different pathologies. Earlier the authors of the study found an association of some mitochondrial genome mutations with atherosclerosis. In the present study, an attempt to analyze a connection of detected mutations with the age of patients with atherosclerosis was made. The investigated sample included 700 individuals, examined by ultrasonography in polyclinics of Moscow and the Moscow region. The sample was divided approximately into two equal parts. The first part included patients with carotid atherosclerosis. The second part included conventionally healthy study participants. In PCR-fragments of individuals' DNA the heteroplasmy level of investigated mutations was quantitatively measured by the method, developed by members of our laboratory on the basis of pyrosequencing technology. According to the obtained results mutations G12315A, G14459A and G15059A were significantly associated with the age of the study participants. The same time one nucleotide replacements A1555G and G14846A correlated negatively with the age at a high level of significance. Thus, in the present study an association of atherogenic mitochondrial genome mutations with age was found. Antiatherogenic mutations were correlated with the age negatively. This prompts a suggestion about common mechanisms of atherogenesis and aging. PMID- 26586457 TI - Blood pressure in the Congolese adult population of South Kivu, Democratic Republic of Congo: Preliminary results from the Bukavu Observ Cohort Study. AB - BACKGROUND: Providing factual data about non-communicable diseases (NCDs) is of utmost importance in the sub-Saharan African countries where NCDs and arterial hypertension data remain scattered, scarce, and less representative given the region's heterogeneous population. Within this context, the interuniversity cooperation VLIR-UOS/Catholic University of Bukavu (Democratic Republic of Congo) has established an integrated project for monitoring hypertension and cardiovascular risk factors in the population of South Kivu. The aim of the study was to present the basic results of the determinants of blood pressure in the cohort studied. METHODS: In 2013 and 2014, trained interviewers collected the anthropometric parameters, blood pressure, and medical history of 7405 adults (3060 in urban areas and 4345 in rural areas) including 3162 males and 4243 females; the cohort is expected to be followed for 9 years. RESULTS: The average age of the entire group was 33.0+/-16.7 years. Compared to men, women had significantly higher obesity indices (P<0.0001), lower blood pressure between 20 and 39 years of age (P<0.0001) but higher blood pressure at 60 years of age and older (P<0.0001). Blood pressure was positively correlated with body mass index, waist circumference, and paradoxically with consumption of vegetables, but negatively correlated with the consumption of fruit, intense physical activity, and relaxation at home. CONCLUSIONS: These results show that a cohort study is feasible in the Democratic Republic of Congo. The factual data analysis can contribute to health policy orientation and setting up of preventive measures. Since most correlated risk factors are preventable, recommendations can already be made in the fight against high blood pressure in this population. PMID- 26586458 TI - Expression and Clinical Pathological Significance of miR-200a in Concurrent Cholangiocarcinoma Associated with Hepatolithiasis. AB - BACKGROUND Approximately 2-10% of the patients with hepatolithiasis may develop cholangiocarcinoma (CCA). Despite recent advances in the treatment of cancers, the 5-year survival rate for CCA patients currently remains poor, primarily due to early local invasion and distant metastasis of the cancer. This study aimed to investigate miR-200a expression in combined hepatolithiasis and CCA as well as its correlation with the clinical features of CCA. MATERIAL AND METHODS miR-200a expression in combined hepatolithiasis and CCA was detected by real-time reverse transcription PCR (qRT-PCR). Its correlation with the clinicopathology of CCA was analyzed by t-tests. The effect of miR-200a on the proliferation CCA cells was determined by MTT assay. The effect of miR-200a on the invasive ability of CCA cells was assessed by Boyden chamber test. RESULTS The expression level of MiR 200a in patients with combined hepatolithiasis and CCA was significantly decreased compared with patients with only hepatolithiasis (P<0.01). Furthermore, miR-200a expression in hepatic duct cancer RBE cells was substantially reduced compared with hepatolithiasis group (P<0.01). Correlation analysis showed that abnormal expression of miR-200a was only associated with the differentiation degree and metastasis of CCA. MiR-200a transfection significantly inhibited the proliferation and invasion of REB cells (P<0.01). CONCLUSIONS MiR-200a may suppress the proliferative and invasive ability of REB cells. The reduced miR 200a expression might be correlated with the development and progression of CCA. PMID- 26586459 TI - Relationships between the lean mass index and bone mass and reference values of muscular status in healthy Chinese children and adolescents. AB - This study aimed to analyze the relationships between the lean mass index (LMI) and bone outcomes in Chinese children and adolescents using dual-energy X-ray absorptiometry (DXA) and to establish sex-specific reference percentile curves for the assessment of muscle status. A total of 1541 Chinese children and adolescents between the ages of 5 and 19 years were recruited from southern China. Body composition was measured by DXA (Lunar Prodigy) to acquire total body and total body less head (TBLH) measures. LMI was calculated as the LM (kg) divided by the height in meters squared. Strong sex gaps were observed after age 14 in total body LMI and appendicular LMI (p < 0.001). LM and LMI values continued to increase for boys up to age 14 compared to girls who plateaued after age 12. For each sex group, total body bone mineral content (BMC) and TBLH BMC were highly correlated with total body LMI and appendicular LMI (r = 0.856-0.916 in boys, and r = 0.651-0.804 in girls, p < 0.001). The appendicular LMI was more strongly associated with total body BMC and TBLH BMC than was total body LMI. The correlations between the BMC values and the LM measures were stronger than the fat mass results. We also present sex-specific percentile curves for LM-age and LMI-age relationships, which could be useful for identifying the LM deficits in this population. PMID- 26586460 TI - High expression of Bcl-2 predicts poor outcome in diffuse large B-cell lymphoma patients with low international prognostic index receiving R-CHOP chemotherapy. AB - The prognostic significance of Bcl-2, Bcl-6, p53, topoisomerase II, and beta tubulin expression was evaluated in diffuse large B-cell lymphoma (DLBCL) patients treated with cyclophosphamide, doxorubicin, vincristine, prednisolone, and rituximab. Eight-year progression-free survival (PFS, P = 0.006) and overall survival (OS, P = 0.001) of patients with high Bcl-2 expression were significantly inferior to those of patients with low expression without prognostic significance of Bcl-6, p53, topoisomerase II, and beta-tubulin expression. High expression of Bcl-2 was associated with poor PFS (P = 0.045) and OS (P = 0.004) only in patients with low international prognostic index (IPI). In multivariate analysis, high expression of Bcl-2 was a significant independent prognostic factor of poor PFS (P = 0.026) and OS (P = 0.007) along with high IPI. In conclusion, the expression of Bcl-2 may be a useful prognostic factor, especially in DLBCL patients with low IPI. PMID- 26586461 TI - Thrombin generation and other coagulation parameters in a patient with homozygous congenital protein S deficiency on treatment with rivaroxaban. AB - Rivaroxaban, which targets factor Xa and does not reduce proteins C/S, was chosen to treat a 6-year-old girl with homozygous protein S (PS) deficiency who developed skin necrosis while on warfarin. Owing to the lack of experience with rivaroxaban in children, the girl was started with 5 mg once-daily, which was gradually increased to 40 mg daily. The increasing dosage was driven by the need to avoid recurrence of skin necrosis. During dose-escalation, four pharmacokinetics assays were carried out measuring drug plasma concentrations and their effect on hemostatic parameters. We report the laboratory work-up, with special reference to parameters of thrombin-generation. Rivaroxaban concentrations by HPLC were correlated with those by the anti-factor Xa assay (r(2) = 0.92, p < 0.01), but there was an overestimation by HPLC. Thrombin generation parameters, such as the area under the curve (referred to as ETP), peak-thrombin, and velocity-index, when measured after addition of thrombomodulin, showed unexpected changes: ETP decreased, but peak-thrombin and velocity-index increased. Similar patterns were obtained in a PS-depleted plasma and in plasma from patients with heterozygous PS deficiency, but not in plasma from controls. In conclusion, these preliminary results suggest that PS may be a determinant of velocity and peak-thrombin, but not of the total amount of thrombin generated. PMID- 26586462 TI - Intrathecal donor lymphocyte infusion for isolated leukemia relapse in the central nervous system following allogeneic stem cell transplantation: a case report and literature review. AB - An 8-year-old boy with a bone marrow relapse of T cell acute lymphoblastic leukemia underwent stem-cell transplantation from a human leukocyte antigen (HLA) haploidentical mother. Five months later, he relapsed with central nervous system (CNS) involvement. Systemic chemotherapy and repeated intrathecal chemotherapy induced consciousness disturbances and frequent arrhythmia, prompting us to discontinue the chemotherapy. He had already received an 18-Gy prophylactic cranial irradiation, an 8-Gy total body irradiation, and a 15-Gy local irradiation for pituitary gland involvement. We therefore performed five intrathecal donor lymphocyte infusions (IDLIs) in escalating doses from 1 * 10(4) up to 1 * 10(6) cells/kg. All IDLIs were safe without infusion reactions or graft versus-host disease. After the second and later IDLIs, donor mononuclear cells were continuously detected in cerebrospinal fluid; however, he did not achieve donor-dominant chimerism. Based on our case and four cases reported in the literature, the efficacy of IDLI therapy is limited for CNS relapse of hematological malignancies. However, we suggest that IDLI remains a feasible and safe option, as no GVHD or other adverse effects occurred, even in the HLA haploidentical setting. We will make further efforts to increase the efficacy. PMID- 26586464 TI - Detection of mycobacteria in MGG-stained bone marrow smears. PMID- 26586463 TI - Effective VCR/DEX pulse maintenance therapy in the KYCCSG ALL-02 protocol for pediatric acute lymphoblastic leukemia. AB - In a previous study of childhood acute lymphoblastic leukemia (ALL) by the Kyushu Yamaguchi Children's Cancer Study Group, ALL-96, we achieved a 72.1 % 5-year event-free survival (EFS) and an 84.8 % 5-year overall survival (OS). In a subsequent study, ALL-02, we adopted a vincristine dexamethasone (VCR/DEX) pulse regimen as maintenance therapy in the context of the ALL-96 study using the same risk classification and treatment schedule. A total of 156 pediatric cases of ALL were treated with ALL-02. All of the patients were classified as standard-risk or high-risk. Risk stratification was based on white cell counts, immunophenotype, the presence of central nervous system (CNS) disease at diagnosis, organomegaly, and early treatment response (day 14 bone marrow status). The 7-year EFS and OS rates were 77.7 % (95 % CI 70.6-84.8 %) and 89.5 % (95 % CI 84.6-94.4 %), respectively. CNS 3 status [hazard ratio (HR) = 5.0, p = 0.009] and high white blood cell count at diagnosis (HR = 2.6, p = 0.047) were risk factors for poor EFS in multivariate analysis. Our strategies to categorize patients into two risk groups, and to treat with a VCR/DEX pulse were feasible and reasonably effective treatments for pediatric ALL. PMID- 26586465 TI - Chemical composition of the essential oil from the leaves of Anaxagorea brevipes (Annonaceae) and evaluation of its bioactivity. AB - The essential oil obtained by hydrodistillation from leaves of Anaxagorea brevipes was analysed by gas chromatography fitted with a flame ionisation detector (GC-FID) and coupled to mass spectrometry (GC-MS). Thirty one components were identified, representing around 75.7% of total oil. The major components were beta-eudesmol (13.16%), alpha-eudesmol (13.05%), gamma-eudesmol (7.54%), guaiol (5.12%), caryophyllene oxide (4.18%) and beta-bisabolene (4.10%). The essential oil showed antimicrobial activity against Gram-positive bacteria and yeast with the MIC values between 25.0 and 100 MUg/mL. The highest antiproliferative activity was observed for the oil against MCF-7 (breast, TGI = 12.8 MUg/mL), NCI-H460 (lung, TGI = 13.0 MUg/mL) and PC-3 (prostate, TGI = 9.6 MUg/mL) cell lines, while against no cancer cell line HaCat (keratinocyte) the TGI was 38.8 MUg/mL. The oil exhibited a small antioxidant activity assessed through ORAC-FL assay (517 MUmol TE/g). This is the first report regarding the chemical composition and bioactivity of A. brevipes essential oil. PMID- 26586466 TI - Reactions of alkynes with cis-RuCl2(dppm)2: exploring the interplay of vinylidene, alkynyl and eta(3)-butenynyl complexes. AB - Reactions of cis-RuCl2(dppm)2 with various terminal alkynes, of the type HC=CC6H4 4-R (1 equiv.), in the presence of TlBF4 have resulted in the formation of cationic vinylidene complexes trans-[RuCl(=C=CHC6H4-4-R)(dppm)2]BF4 ([1]BF4). These complexes can be isolated, or treated in situ with a suitable base (Proton Sponge, 1,8-bis(dimethylamino)naphthalene) to yield the mono-alkynyl complexes trans-RuCl(C=CC6H4-4-R)(dppm)2 (2). Through similar reactions between cis RuCl2(dppm)2 with 2 equiv. of alkyne, TlBF4 and base, trans-bis(alkynyl) complexes, trans-Ru(C=CC6H4-4-R)2(dppm)2 (3), can be isolated when R is an electron withdrawing substituent (R = NO2, COOMe, C=CSiMe3), whereas reactions with alkynes bearing electron donating substituents (R = OMe and Me) form cationic eta(3)-butenynyl complexes [Ru(eta(3)-{HC(C6H4-4-R)=CC=CC6H4-4 R})(dppm)2](+) ([4](+)). This work highlights the importance of the electronic character of the alkyne in influencing product outcome. PMID- 26586467 TI - The prototoxin LYPD6B modulates heteromeric alpha3beta4-containing nicotinic acetylcholine receptors, but not alpha7 homomers. AB - Prototoxins are a diverse family of membrane-tethered molecules expressed in the nervous system that modulate nicotinic cholinergic signaling, but their functions and specificity have yet to be completely explored. We tested the selectivity and efficacy of leukocyte antigen, PLAUR (plasminogen activator, urokinase receptor) domain-containing (LYPD)-6B on alpha3beta4-, alpha3alpha5beta4-, and alpha7 containing nicotinic acetylcholine receptors (nAChRs). To constrain stoichiometry, fusion proteins encoding concatemers of human alpha3, beta4, and alpha5 (D and N variants) subunits were expressed in Xenopus laevis oocytes and tested with or without LYPD6B. We used the 2-electrode voltage-clamp method to quantify responses to acetylcholine (ACh): agonist sensitivity (EC50), maximal agonist-induced current (Imax), and time constant (tau) of desensitization. For beta4-alpha3-alpha3-beta4-alpha3 and beta4-alpha3-beta4-alpha3-alpha3, LYPD6B decreased EC50 from 631 to 79 MUM, reduced Imax by at least 59%, and decreased tau. For beta4-alpha3-alpha5D-beta4-alpha3 and beta4-alpha3-beta4-alpha-alpha5D, LYPD6B decreased Imax by 63 and 32%, respectively. Thus, LYPD6B acted only on (alpha3)3(beta4)2 and (alpha3)2(alpha5D)(beta4)2 and did not affect the properties of (alpha3)2(beta4)3, alpha7, or (alpha3)2(alpha5N)(beta4)2 nAChRs. Therefore, LYPD6B acts as a mixed modulator that enhances the sensitivity of (alpha3)3(beta4)2 nAChRs to ACh while reducing ACh-induced whole-cell currents. LYPD6B also negatively modulates alpha3beta4 nAChRs that include the alpha5D common human variant, but not the N variant associated with nicotine dependence. PMID- 26586469 TI - A Light-Activated Olefin Metathesis Catalyst Equipped with a Chromatic Orthogonal Self-Destruct Function. AB - A sulfur-chelated photolatent ruthenium olefin metathesis catalyst has been equipped with supersilyl protecting groups on the N-heterocyclic carbene ligand. The silyl groups function as an irreversible chromatic kill switch, thus decomposing the catalyst when it is irradiated with 254 nm UV light. Therefore, different types of olefin metathesis reactions may be started by irradiation with 350 nm UV light and prevented by irradiation with shorter wavelengths. The possibility to induce and impede catalysis just by using light of different frequencies opens the pathway for stereolithographic applications and novel light guided chemical sequences. PMID- 26586468 TI - Changes in poly(A) tail length dynamics from the loss of the circadian deadenylase Nocturnin. AB - mRNA poly(A) tails are important for mRNA stability and translation, and enzymes that regulate the poly(A) tail length significantly impact protein profiles. There are eleven putative deadenylases in mammals, and it is thought that each targets specific transcripts, although this has not been clearly demonstrated. Nocturnin (NOC) is a unique deadenylase with robustly rhythmic expression and loss of Noc in mice (Noc KO) results in resistance to diet-induced obesity. In an attempt to identify target transcripts of NOC, we performed "poly(A)denylome" analysis, a method that measures poly(A) tail length of transcripts in a global manner, and identified 213 transcripts that have extended poly(A) tails in Noc KO liver. These transcripts share unexpected characteristics: they are short in length, have long half-lives, are actively translated, and gene ontology analyses revealed that they are enriched in functions in ribosome and oxidative phosphorylation pathways. However, most of these transcripts do not exhibit rhythmicity in poly(A) tail length or steady-state mRNA level, despite Noc's robust rhythmicity. Therefore, even though the poly(A) tail length dynamics seen between genotypes may not result from direct NOC deadenylase activity, these data suggest that NOC exerts strong effects on physiology through direct and indirect control of target mRNAs. PMID- 26586470 TI - Facile Installation of 2-Reverse Prenyl Functionality into Indoles by a Tandem N Alkylation-Aza-Cope Rearrangement Reaction and Its Application in Synthesis. AB - An unprecedented tandem N-alkylation-ionic aza-Cope (or Claisen) rearrangement hydrolysis reaction of readily available indolyl bromides with enamines is described. Due to the complicated nature of the two processes, an operationally simple N-alkylation and subsequent microwave-irradiated ionic aza-Cope rearrangement-hydrolysis process has been uncovered. The tandem reaction serves as a powerful approach to the preparation of synthetically and biologically important, but challenging, 2-reverse quaternary-centered prenylated indoles with high efficiency. Notably, unusual nonaromatic 3-methylene-2,3-dihydro-1H-indole architectures, instead of aromatic indoles, are produced. Furthermore, the aza Cope rearrangement reaction proceeds highly regioselectively to give the quaternary-centered reverse prenyl functionality, which often produces a mixture of two regioisomers by reported methods. The synthetic value of the resulting nonaromatic 3-methylene-2,3-dihydro-1H-indole architectures has been demonstrated as versatile building blocks in the efficient synthesis of structurally diverse 2 reverse prenylated indoles, such as indolines, indole-fused sultams and lactams, and the natural product bruceolline D. PMID- 26586471 TI - Determination of affinity and efficacy of acetylcholinesterase inhibitors using isothermal titration calorimetry. AB - BACKGROUND: Acetylcholinesterase (AChE), an enzyme rapidly terminating nerve signals at synapses of cholinergic neurons is an important drug target in treatment of Alzheimer's disease and related memory loss conditions. Here we present comprehensive use of isothermal titration calorimetry (ITC) for investigation of AChE kinetics and AChE-inhibitor interactions. METHODS: Acetylcholinesterase (AChE, EC 3.1.1.7) from Electrophorus electricus was assayed for interactions with five well known AChE inhibitors, galanthamine, tacrine, donepezil, edrophonium and ambenonium. In ITC experiments the inhibitors were injected to the enzyme solution solely (for thermodynamic characterization of binding) or in presence of the substrate, acetylcholine (for determination of inhibitors potency). RESULTS: Detailed description of various experimental protocols is presented, allowing evaluation of inhibitors potency (in terms of IC50 and Ki) and thermodynamic parameters of the binding. The potency of tested inhibitors was in nano to micromolar range which corresponded to activities determined in conventional method. Binding of all inhibitors showed to be enthalpy driven and obtained Ka values demonstrated good correlation with the data from standard Ellman's assay. CONCLUSIONS: Obtained results confirmed the usability of the ITC technique for comprehensive characterization of AChE inhibitor interactions and AChE kinetics. The method reduced the complexity of reaction mixture and interference problems with the advantage of using natural substrates. GENERAL SIGNIFICANCE: The work reports complete thermodynamic characteristics of the AChE - inhibitor complexes. Due to the universal character of ITC measurements, described protocols can be easily adapted to other enzymatic systems. PMID- 26586472 TI - V-type ATPase proton pump expression during enamel formation. AB - Several diseases such as proximal and distal renal tubular acidosis and osteoporosis are related to intracellular pH dysregulation resulting from mutations in genes coding for ion channels, including proteins comprising the proton-pumping V-type ATPase. V-type ATPase is a multi-subunit protein complex expressed in enamel forming cells. V-type ATPase plays a key role in enamel development, specifically lysosomal acidification, yet our understanding of the relationship between the endocytotic activities and dental health and disease is limited. The objective of this study is to better understand the ameloblast associated pH regulatory networks essential for amelogenesis. Quantitative RT-PCR was performed on tissues from secretory-stage and maturation-stage enamel organs to determine which of the V-type ATPase subunits are most highly upregulated during maturation-stage amelogenesis: a time when ameloblast endocytotic activity is highest. Western blot analyses, using specific antibodies to four of the V type ATPase subunits (Atp6v0d2, Atp6v1b2, Atp6v1c1 and Atp6v1e1), were then applied to validate much of the qPCR data. Immunohistochemistry using these same four antibodies was also performed to identify the spatiotemporal expression profiles of individual V-type ATPase subunits. Our data show that cytoplasmic V type ATPase is significantly upregulated in enamel organ cells during maturation stage when compared to secretory-stage. These data likely relate to the higher endocytotic activities, and the greater need for lysosomal acidification, during maturation-stage amelogenesis. It is also apparent from our immunolocalization data, using antibodies against two of the V-type ATPase subunits (Atp6v1c1 and Atp6v1e1), that significant expression is seen at the apical membrane of maturation-stage ameloblasts. Others have also identified this V-type ATPase expression profile at the apical membrane of maturation ameloblasts. Collectively, these data better define the expression and role of the V-type ATPase proton pump in the enamel organ during amelogenesis. PMID- 26586474 TI - Does comorbidity interact with prostate cancer to increase mortality? A Danish cohort study of 45 326 prostate cancer patients diagnosed during 1995-2011. AB - BACKGROUND: Many prostate cancer patients die of other causes, but it remains unknown whether comorbidity interacts synergistically with prostate cancer to increase the mortality rate beyond that explained by the individual risks of comorbidity and prostate cancer. METHODS: A nationwide cohort study of 45 326 Danish prostate cancer patients diagnosed during 1995-2011, each matched to approximately five men from the general population on age and individual comorbidities in the Charlson Comorbidity Index (CCI). We calculated five-year mortality rates and interaction contrasts as a measure of the excess mortality rate explained by synergy between prostate cancer and comorbidity. RESULTS: Five year mortality was 46.8% in prostate cancer patients and 25.8% in matched men from the general population. For prostate cancer patients with a CCI score of 2 3, the mortality rate was 250 per 1000 person-years [95% confidence interval (CI): 236, 263], and interaction between comorbidity and prostate cancer accounted for 20% of the total mortality rate (50 deaths per 1000 person-years, 95% CI 35, 65) in the first year following cancer diagnosis. The interaction was mainly present for patients with metastatic disease and those not treated with prostatectomy. CONCLUSION: Up to 20% of all deaths among men who had both prostate cancer and comorbidities could be explained by the comorbidity-prostate cancer interaction. The mortality attributable to comorbidity itself and the mortality attributable to the interaction may be reduced by successful treatment of the comorbidity. PMID- 26586473 TI - Glutamine and hyperammonemic crises in patients with urea cycle disorders. AB - Blood ammonia and glutamine levels are used as biomarkers of control in patients with urea cycle disorders (UCDs). This study was undertaken to evaluate glutamine variability and utility as a predictor of hyperammonemic crises (HACs) in UCD patients. METHODS: The relationships between glutamine and ammonia levels and the incidence and timing of HACs were evaluated in over 100 adult and pediatric UCD patients who participated in clinical trials of glycerol phenylbutyrate. RESULTS: The median (range) intra-subject 24-hour coefficient of variation for glutamine was 15% (8-29%) as compared with 56% (28%-154%) for ammonia, and the correlation coefficient between glutamine and concurrent ammonia levels varied from 0.17 to 0.29. Patients with baseline (fasting) glutamine values >900 MUmol/L had higher baseline ammonia levels (mean [SD]: 39.6 [26.2]MUmol/L) than patients with baseline glutamine <= 900 MUmol/L (26.6 [18.0]MUmol/L). Glutamine values >900 MUmol/L during the study were associated with an approximately 2-fold higher HAC risk (odds ratio [OR]=1.98; p=0.173). However, glutamine lost predictive significance (OR=1.47; p=0.439) when concomitant ammonia was taken into account, whereas the predictive value of baseline ammonia >= 1.0 upper limit of normal (ULN) was highly statistically significant (OR=4.96; p=0.013). There was no significant effect of glutamine >900 MUmol/L on time to first HAC crisis (hazard ratio [HR]=1.14; p=0.813), but there was a significant effect of baseline ammonia >= 1.0 ULN (HR=4.62; p=0.0011). CONCLUSIONS: The findings in this UCD population suggest that glutamine is a weaker predictor of HACs than ammonia and that the utility of the predictive value of glutamine will need to take into account concurrent ammonia levels. PMID- 26586475 TI - Does the onset of bone metastasis in sunitinib-treated renal cell carcinoma patients impact the overall survival? AB - PURPOSE: To evaluate the impact of bone metastasis (BM) onset toward prognosis in metastatic renal cell carcinoma (mRCC) patients treated with sunitinib. METHODS: mRCC patients with BM and sunitinib as first targeted therapy between May 2005 and December 2012 were retrospectively analyzed. Patients with synchronous (s) BM or metachronous (m) BM were compared with regard to treatment and outcome [time to clinical progression (TTcP), overall survival (OS), skeletal-related events (SRE)]. Descriptive statistics, Kaplan-Meier estimation of TTcP and OS, Cox regression analyses, and a landmark analysis were administered. RESULTS: BM was identified in 127 mRCC patients; thereof, 82 sunitinib-treated patients were analyzed [sBM n = 57 (69.5 %), mBM n = 25 (30.5 %)]. Higher tumor grading (p = 0.029), male predominance (p = 0.02), and less second-line therapy (p = 0.001) were detected in sBM compared to mBM. SRE remained similar between subgroups (p = 0.462). TTcP during sunitinib was similar [median sBM 8.1 (95 % CI 3.9-12.3) vs. mBM 8.7 (95 % CI 2.7-14.8) months, p = 0.903]. OS remained significantly inferior in sBM patients compared to mBM [median sBM 21.1 (95 % CI 16-26.2) months vs. mBM 38.5 (95 % CI 15-62) months, p = 0.001], which was confirmed by landmark analyses at 1.5, 3, 6, 9, and 12 months. However, OS after occurrence of BM was similar in both groups [median sBM 24.2 (95 % CI 17.3-31.1) months vs. mBM 17.2 (95 % CI 8.4 26) months, p = 0.519]. CONCLUSIONS: mBM is associated with an improved OS compared to sBM in mRCC with sunitinib treatment, despite similar efficacy of sunitinib treatment in both groups of patients. PMID- 26586476 TI - Open radical cystectomy: still the gold standard for muscle invasive bladder cancer. AB - INTRODUCTION: Muscle invasive bladder cancer is an unforgiving disease, and if untreated, it leads to death within 2 years of the diagnosis in >85 % of the patients. Long-term oncologic efficacy remains the ultimate standard that all procedures have to be measured by. In the past decades, open radical cystectomy (RC), extended pelvic lymph node dissection (PLND), and urinary diversion have been established as the gold standard. In the last few years, however, growing attention has been set on robotic-assisted radical cystectomy (RARC). RESULTS: Even in the very long term, open RC has good oncological results and if an ileal neobladder is performed excellent functional results. Follow-up of patients after open RC exceeds more than a decade which is unsurpassed by any other technique. Its outcomes have been proven to be durable and cost-effective. Least perioperative complications as well as best oncological and functional results can be achieved if open RC and urinary diversion were performed in a high-volume hospital by high-volume surgeons and an experienced team. CONCLUSIONS: Despite upcoming new technologies such as RARC, open RC following extended (PLND) remains the gold standard treatment for high-grade muscle invasive bladder cancer. PMID- 26586477 TI - A signal processing based analysis and prediction of seizure onset in patients with epilepsy. AB - One of the main areas of behavioural neuroscience is forecasting the human behaviour. Epilepsy is a central nervous system disorder in which nerve cell activity in the brain becomes disrupted, causing seizures or periods of unusual behaviour, sensations and sometimes loss of consciousness. An estimated 5% of the world population has epileptic seizure but there is not any method to cure it. More than 30% of people with epilepsy cannot control seizure. Epileptic seizure prediction, refers to forecasting the occurrence of epileptic seizures, is one of the most important but challenging problems in biomedical sciences, across the world. In this research we propose a new methodology which is based on studying the EEG signals using two measures, the Hurst exponent and fractal dimension. In order to validate the proposed method, it is applied to epileptic EEG signals of patients by computing the Hurst exponent and fractal dimension, and then the results are validated versus the reference data. The results of these analyses show that we are able to forecast the onset of a seizure on average of 25.76 seconds before the time of occurrence. PMID- 26586479 TI - SUV420H1 enhances the phosphorylation and transcription of ERK1 in cancer cells. AB - The oncogenic protein ERK, a member of the extracellular signal-regulated kinase (ERK) cascade, is a well characterized signaling molecule involved in tumorigenesis. The ERK signaling pathway is activated in a large proportion of cancers and plays a critical role in tumor development. Functional regulation by phosphorylation of kinases in the ERK pathway has been extensively studied, however methylation of the ERK protein has not been reported to date. Here, we demonstrated that the protein lysine methyltransferase SUV420H1 tri-methylated ERK1 at lysines 302 and 361, and that substitution of methylation sites diminished phosphorylation levels of ERK1. Concordantly, knockdown of SUV420H1 reduced phosphorylated ERK1 and total ERK1 proteins, and interestingly suppressed ERK1 at the transcriptional level. Our results indicate that overexpression of SUV420H1 may result in activation of the ERK signaling pathway through enhancement of ERK phosphorylation and transcription, thereby providing new insights in the regulation of the ERK cascade in human cancer. PMID- 26586478 TI - Angiogenic gene signature in human pancreatic cancer correlates with TGF-beta and inflammatory transcriptomes. AB - Pancreatic ductal adenocarcinomas (PDACs) are hypovascular, but overexpress pro angiogenic factors and exhibit regions of microvasculature. Using RNA-seq data from The Cancer Genome Atlas (TCGA), we previously reported that ~12% of PDACs have an angiogenesis gene signature with increased expression of multiple pro angiogenic genes. By analyzing the recently expanded TCGA dataset, we now report that this signature is present in ~35% of PDACs but that it is mostly distinct from an angiogenesis signature present in pancreatic neuroendocrine tumors (PNETs). These PDACs exhibit a transcriptome that reflects active TGF-beta signaling, and up-regulation of several pro-inflammatory genes, and many members of JAK signaling pathways. Moreover, expression of SMAD4 and HDAC9 correlates with endothelial cell abundance in PDAC tissues. Concomitantly targeting the TGF beta type I receptor (TbetaRI) kinase with SB505124 and JAK1-2 with ruxolitinib suppresses JAK1 phosphorylation and blocks proliferative cross-talk between human pancreatic cancer cells (PCCs) and human endothelial cells (ECs), and these anti proliferative effects were mimicked by JAK1 silencing in ECs. By contrast, either inhibitor alone does not suppress their enhanced proliferation in 3D co-cultures. These findings suggest that targeting both TGF-beta and JAK1 signaling could be explored therapeutically in the 35% of PDAC patients whose cancers exhibit an angiogenesis gene signature. PMID- 26586480 TI - Maternal care in Acanthosomatinae (Insecta: Heteroptera: Acanthosomatidae)- correlated evolution with morphological change. AB - BACKGROUND: Maternal care (egg-nymph guarding behavior) has been recorded in some genera of Acanthosomatidae. However, the origin of the maternal care in the family has remained unclear due to the lack of phylogenetic hypotheses. Another reproductive mode is found in non-caring species whose females smear their eggs before leaving them. They possess pairs of complex organs on the abdominal venter called Pendergrast's organ (PO) and spread the secretion of this organ onto each egg with their hind legs, which is supposed to provide a protective function against enemies. Some authors claim that the absence of PO may be associated with the presence of maternal care. No study, however, has tested this hypothesis of a correlated evolution between the two traits. RESULTS: We reconstructed the molecular phylogeny of the subfamily Acanthosomatinae using five genetic markers sequenced from 44 species and one subspecies with and without maternal care. Eight additional species from the other two acanthosomatid subfamilies were included as outgroups. Our results indicated that maternal care has evolved independently at least three times within Acanthosomatinae and once in the outgroup species. Statistical tests for correlated evolution showed that the presence of maternal care is significantly correlated with the secondary loss or reduction of PO. Ancestral state reconstruction for the node of Acanthosoma denticaudum (a non-caring species in which egg smearing with developed POs occurs) and A. firmatum (a caring species with reduced POs) suggested egg smearing was still present in their most recent common ancestor and that maternal care in A. firmatum has evolved relatively recently. CONCLUSIONS: We showed that maternal care is an apomorphic trait that has arisen multiple times from the presence of PO within the subfamily Acanthosomatinae. The acquisition of maternal care is correlated with the reduction or loss of PO, which suggests an evolutionary trade-off between the two traits resulting from physiological costs. This prediction also implies that presence of maternal care can be highly expected for those groups lacking behavioral data, which invariably also lack the organ. No secondary loss of maternal care was detected in the present tree. We suggest that the loss of maternal care may be suppressed due to the vulnerability of the PO-free condition, which thus maintains maternal care. PMID- 26586481 TI - SGTB Promotes the Caspase-Dependent Apoptosis in Chondrocytes of Osteoarthritis. AB - The purpose of this study is to investigate the expression of small glutamine rich tetratricopeptide repeat (TPR)-containing beta (SGTB) in articular cartilage of osteoarthritis (OA) and analyze the relationship between SGTB and chondrocyte apoptosis. We established an OA rat model by the meniscal/ligamentous injury (MLI) modeling method and observed the expression of SGTB in articular cartilage by immunohistochemistry and RT-PCR. Human SW1353 chondrosarcoma cells were treated with interleukin-1beta (IL-1beta) to mimic the OA-like chondrocyte injury in vitro, and Western blot was employed to examine the IL-1beta-induced expression of SGTB and active caspase-3. The co-localization of SGTB and active caspase-3 was confirmed by immunofluorescence. We knocked down SGTB expression by RNA interference (RNAi) and overexpressed SGTB by plasmid transfection. Western blot was carried out to detect the knockdown/overexpressing efficiency of SGTB and evaluate its effects on IL-1beta-stimulated expression of active caspase-3 in SW1353 cells. Annexin V/propidium iodide staining was used to detect chondrocyte apoptosis. Then, Western blot was carried out to examine the IL-1beta-induced expression of Hsp70 and evaluate SGTB effects on IL-1beta-stimulated expression of Hsp70 in SW1353 cells. SGTB expression was significantly up-regulated in articular cartilage of OA rat model. IL-1beta stimulation increased the expression of SGTB and active caspase-3 in SW1353 cells. SGTB co-localized with active caspase-3 in IL-1beta-treated SW1353 cells. SGTB inhibition significantly reduced IL-1beta-stimulated expression of active caspase-3 in SW1353 cells. In line with this, overexpressing SGTB via Myc-SGTB transfection increased the active caspase-3 level in IL-1beta-stimulated SW1353 cells. Moreover, flow cytometry assay demonstrated that SGTB knockdown alleviated IL-1beta-induced apoptosis, but it was increased in SW1353 cells that overexpressed SGTB. Overexpressing SGTB via Myc-SGTB transfection decreased the Hsp70 level in IL 1beta-stimulated SW1353 cells. Our results suggested that SGTB positively regulate the activation of caspase-3 by negatively regulating the activity of Hsp70 and might promote chondrocyte apoptosis in OA. This study may provide a novel insight into the pathophysiology of OA and a potential therapeutic target for its treatment. PMID- 26586483 TI - Effects of various antimicrobial stewardship programs on antimicrobial usage and resistance among common gram-negative bacilli causing health care-associated infections: A multicenter comparison. AB - BACKGROUND: The effects of various antimicrobial stewardship programs (ASPs) on both antibiotic consumption and resistance among different hospitals within the same insurance system have rarely been investigated. METHODS: This 6-year retrospective study included three medical centers with similar facilities and infection control measures in Taiwan. These hospitals used different types of ASPs: one had a hospital-wide preauthorization requirement by infectious diseases physicians for all broad-spectrum antibiotics, covering all intensive care units; the second used the same program, but excluded all intensive care units; and the third used postprescription review only. The nonsusceptibility of unduplicated isolates of gram-negative bacilli causing health care-associated infections and consumption of broad-spectrum antibiotics were analyzed. RESULTS: Overall, the usage of broad-spectrum antibiotics of all classes escalated significantly over time in all three hospitals, but consumption was lowest under the hospital-wide preauthorization program. Under this ASP, despite a 2-fold increase in the total broad-spectrum antibiotic consumption during study period, some declining trends of resistance were found, including ciprofloxacin-resistant Pseudomonas aeruginosa and Acinetobacter baumannii, and carbapenem-resistant P. aeruginosa. By contrast, the other two hospitals with preauthorization program excluding all intensive care units and postprescription review had similar high broad-spectrum antibiotic consumption, comparable growing trends of resistant strains in general, and the correlations of antibiotic consumption and resistance were basically positive. Carbapenem-resistant A. baumannii increased significantly over time in all three hospitals. CONCLUSION: This interhospital comparison suggested that hospital-wide preauthorization program is the most effective to reduce key gram-negative bacilli resistance, with the exception of carbapenem resistant A. baumannii. PMID- 26586482 TI - Trimester-Specific Population Pharmacokinetics and Other Correlates of Variability in Sulphadoxine-Pyrimethamine Disposition Among Ugandan Pregnant Women. AB - BACKGROUND: Sulphadoxine-pyrimethamine (SP) is widely used as an intermittent preventive treatment for malaria in pregnancy (IPTp). However, pharmacokinetic studies in pregnancy show variable and often contradictory findings. We describe population and trimester-specific differences in SP pharmacokinetics among Ugandan women. METHODS: SP (three tablets) were administered to 34 nonpregnant and 87 pregnant women in the second trimester. Seventy-eight pregnant women were redosed in the third trimester. Blood was collected over time points ranging from 0.5 h to 42 days postdose. Data on the variables age, body weight, height, parity, gestational age, and serum creatinine, alanine transaminase and albumin levels were collected at baseline. Plasma drug assays were performed using high performance liquid chromatography with ultraviolet detection. Population pharmacokinetic analysis was done using NONMEM software. RESULTS: A two compartment model with first-order absorption and a lag time best described both the sulphadoxine and pyrimethamine data. Between trimesters, statistically significant differences in central volumes of distribution (V(2)) were observed for both drugs, while differences in the distribution half-life and the terminal elimination half-life were observed for pyrimethamine and sulphadoxine, respectively. Significant covariate relationships were identified on clearance (pregnancy status and serum albumin level) and V(2) (gestational age) for sulphadoxine. For pyrimethamine, clearance (pregnancy status and age) and V(2) (gestational age and body weight) were significant. Considering a 25 % threshold for clinical relevance, only differences in clearance of both drugs between pregnant and nonpregnant women were significant. CONCLUSION: While clinically relevant differences in SP disposition between trimesters were not seen, increased clearance with pregnancy and the increasing volume of distribution in the central compartment with gestational age lend support to the revised World Health Organization guidelines advocating more frequent dosing of SP for IPTp. PMID- 26586485 TI - Syntheses of halogen derivatives of L-tryptophan, L-tyrosine and L-phenylalanine labeled with hydrogen isotopes. AB - Halogenated, labeled with tritium and doubly with deuterium and tritium, derivatives of L-tryptophan, i.e. 5'-bromo-[2-(3)H]-, 5'-bromo-[2-(2)H/(3)H]-, 5' fluoro-[2-(3)H]-5'-fluoro-[2-(2)H/(3)H]-, 6'-fluoro-[2-(3)H]-, 6'-fluoro-[2 (2)H/(3)H]-L-tryptophan, as well as, L-tyrosine, i.e. 3'-fluoro-[2-(3)H]-, 3' fluoro-[2-(2)H/(3)H]-, 3'-chloro-[2-(3)H]-, and 3'-chloro-[2-(2)H/(3)H]-L tyrosine, and also L-phenylalanine, i.e. 2'-fluoro-[(3S)-(3)H]-, 2'-fluoro-[(3S) (2)H/(3) H]-, 2'-chloro-[(3S)-(3)H]-, 2'-chloro-[(3S)-(2)H/(3)H]-, 4'-chloro [(3S)-(3)H]-, and 4'-chloro-[(3S)-(2)H/(3)H]-L-phenylalanine were synthesized using enzymatic methods. Isotopomers of L-tryptophan were synthesized by coupling of halogenated indoles with S-methyl-L-cysteine carried out in deuteriated or tritiated incubation media. Labeled halogenated derivatives of L-tyrosine were obtained by the enzymatically supported exchange between halogenated L-tyrosine and isotopic water. Labeled halogenated isotopologues of L-Phe were synthesized by the enzymatic addition of ammonia to halogenated cinnamic acid. As a source of hydrogen tritiated water (HTO) and heavy water (D2O) with addition of HTO were used. PMID- 26586487 TI - Fontan-associated liver disease: Implications for heart transplantation. AB - Chronic liver diseases are associated with multiple complications, including cirrhosis, portal hypertension, ascites, synthetic dysfunction and hepatocellular carcinoma, and these processes are increasingly recognized in post-Fontan patients. Fontan-associated liver disease (FALD) can be defined as abnormalities in liver structure and function that result from the Fontan circulation and are not related to another disease process. FALD arises due to chronic congestion of the liver created by the elevated venous pressure and low cardiac output of the Fontan circulation, which may be superimposed on previous liver injury. Pathology studies have generally shown that FALD worsens as time post-Fontan increases, but the prevalence of FALD is not well defined because the majority of Fontan patients, even those with significant hepatic fibrosis, appear to be asymptomatic and biochemical or functional hepatic abnormalities are usually subtle or absent. Alternate non-invasive investigations, derived from the study of other chronic liver diseases, have been tested in small series of pediatric and adult Fontan patients, but they have been confounded by congestion and do not correlate well with liver biopsy findings. Liver disease can complicate Fontan circulatory failure and may even be significant enough to be considered a contraindication to heart transplantation or require combined heart-liver transplantation. The search for the optimal management strategy continues in the setting of increasing numbers of Fontan patients surviving to adulthood and being referred for heart transplantation. Thus, in this review we attempt to define the scope and significance of FALD and address transplant-related assessment and management of this challenging disorder. PMID- 26586486 TI - Immunotherapies for Immune-Mediated Myopathies: A Current Perspective. AB - Until recently, the treatment of immune-mediated inflammatory myopathies has largely been empirical with glucocorticoids, steroid-sparing immunosuppressive drugs, and intravenous immunoglobulin. However, a proportion of patients are only partially responsive to these therapies, and there has been a need to consider alternative treatment approaches. In particular, patients with inclusion body myositis are resistant to conventional immunotherapies or show only a transient response, and remain a major challenge. With increasing recognition of the different subtypes of immune-mediated inflammatory myopathies, and improved understanding of their pathogenesis, more targeted treatments are now being trialled. The overall approach to treatment, and novel therapies targeting B cells, T cells, and specific cytokines are discussed in this review. PMID- 26586488 TI - Elevated pulmonary arterial and systemic plasma aldosterone levels associate with impaired cardiac reserve capacity during exercise in left ventricular systolic heart failure patients: A pilot study. AB - BACKGROUND: Elevated levels of aldosterone are a modifiable contributor to clinical worsening in heart failure with reduced ejection fraction (HFrEF). Endothelin-1 (ET-1), which is increased in HFrEF, induces pulmonary endothelial aldosterone synthesis in vitro. However, whether transpulmonary aldosterone release occurs in humans or aldosterone relates to functional capacity in HFrEF is not known. Therefore, we aimed to characterize ET-1 and transpulmonary aldosterone levels in HFrEF and determine if aldosterone levels relate to peak volume of oxygen uptake (pVO2). METHODS: Data from 42 consecutive HFrEF patients and 18 controls referred for invasive cardiopulmonary exercise testing were analyzed retrospectively. RESULTS: Radial ET-1 levels (median [interquartile range]) were higher in HFrEF patients compared with controls (17.5 [11.5-31.4] vs 11.5 [4.4-19.0] pg/ml, p = 0.04). A significant ET-1 transpulmonary gradient (pulmonary arterial [PA] - radial arterial levels) was present in HFrEF (p < 0.001) but not in controls (p = 0.24). Compared with controls, aldosterone levels (median [interquartile range]) were increased in HFrEF patients in the PA (364 [250-489] vs 581 [400-914] ng/dl, p < 0.01) and radial compartments (366 [273 466] vs 702 [443-1223] ng/dl, p < 0.001). Akin to ET-1, a transpulmonary increase (median [interquartile range]) in aldosterone concentration was also observed between controls and HFrEF patients at rest (7.5 [-54 to 40] vs 61.6 [-13.6 to 165] ng/dl, p = 0.01) and peak exercise (-20.7 [-39.6 to 79.1] vs 25.8 [-29.2 to 109.3] ng/dl, p = 0.02). The adjusted pVO2 correlated inversely with aldosterone levels at peak activity in the PA (r = -0.31, p = 0.01) and radial artery (r = 0.32, p = 0.01). CONCLUSIONS: These data provide preliminary evidence in support of increased transpulmonary aldosterone levels in HFrEF and suggest an inverse relationship between circulating aldosterone and pVO2. Future prospective studies are needed to characterize the functional effects of transpulmonary and circulating aldosterone on cardiac reserve capacity in HFrEF. PMID- 26586490 TI - Hospital readmissions after discharge to home with the Total Artificial Heart Freedom driver: Readmission reasons, clinical outcomes, and health care costs. PMID- 26586489 TI - Mixed cellular and antibody-mediated rejection in heart transplantation: In-depth pathologic and clinical observations. AB - BACKGROUND: Little is known about mixed cellular and antibody-mediated rejection (MR) in heart transplantation. It remains unclear whether cardiac MR has distinctive pathologic and clinical features beyond those of simultaneous cellular rejection (CR) and antibody-mediated rejection (AMR). In this study we systematically explore the pathologic and clinical characteristics of MR in heart transplantation. METHODS: The UTAH Cardiac Transplant Program database was queried for transplant recipients who survived long enough to have at least one endomyocardial biopsy (EMB) between 1985 and 2014. Only EMBs with both CR and AMR scores documented were included. In addition to detailed pathologic analyses, we also examined the incidence and prevalence of MR, the likelihood to transition from and to MR, and mortality associated with MR. RESULTS: Patients (n = 1,207) with a total of 28,484 EMBs met the study inclusion criteria. The overall prevalence of MR was 7.8% and it was nearly twice as frequent within the first year post-transplant. Mild MR was by far the most common occurrence and was typically preceded by an immune active state. When CR increased in severity, AMR tended to follow, but the reverse was not true. On pathology, individual features of CR and AMR were more easily separated in cases of mild MR, whereas they substantially overlapped in more severe cases. MR was associated with a significant cardiovascular death risk that was incremental with severity. CONCLUSIONS: MR is not common, usually occurs early after transplant, and is associated with worse outcomes. MR reflects a complex interplay between cellular and humoral processes, which varies with rejection severity. PMID- 26586491 TI - Injuries to the head and neck in Homer's Odyssey. AB - The Odyssey and the Iliad are the most prominent works of ancient Greek epic poetry, and we have retrieved injuries to the head and neck mentioned in the Odyssey. We studied the texts both in ancient Greek and the translations in modern Greek and English and searched for references to trauma to the head and neck. We recorded the injuries, the attacker and defender, the weapons used, the site, and the result. There were 11 injuries of the head and neck, nine of which were fatal. PMID- 26586492 TI - Self-retaining retraction of the tongue. PMID- 26586494 TI - Randomized controlled pilot trial of mindfulness-based stress reduction for breast and colorectal cancer survivors: effects on cancer-related cognitive impairment. AB - PURPOSE: Cancer-related cognitive impairment (CRCI) is a common, fatigue-related symptom that disrupts cancer survivors' quality of life. Few interventions for CRCI exist. As part of a randomized pilot study targeting cancer-related fatigue, the effects of mindfulness-based stress reduction (MBSR) on survivors' cognitive outcomes were investigated. METHODS: Breast and colorectal cancer survivors (n = 71) with moderate-to-severe fatigue were randomized to MBSR (n = 35) or a fatigue education and support (ES; n = 36) condition. The Attentional Function Index (AFI) and the Stroop test were used to assess survivors' cognitive function at baseline (T1), after the 8-week intervention period (T2), and 6 months later (T3) using intent-to-treat analysis. Mediation analyses were performed to explore mechanisms of intervention effects on cognitive functioning. RESULTS: MBSR participants reported significantly greater improvement on the AFI total score compared to ES participants at T2 (d = 0.83, p = 0.001) and T3 (d = 0.55, p = 0.021). MBSR also significantly outperformed ES on most AFI subscales, although both groups improved over time. MBSR produced greater Stroop accuracy rates relative to ES at T2 (r = 0.340, p = 0.005) and T3 (r = 0.280, p = 0.030), with improved accuracy over time only for the MBSR group. There were no significant differences in Stroop reaction time between groups. Improvements in mindfulness mediated the effect of group (e.g., MBSR vs. ES) on AFI total score at T2 and T3. CONCLUSIONS: Additional randomized trials with more comprehensive cognitive measures are warranted to definitively assess the efficacy of MBSR for CRCI. IMPLICATIONS FOR CANCER SURVIVORS: This pilot study has important implications for all cancer survivors as it is the first published trial to show that MBSR offers robust and durable improvements in CRCI. PMID- 26586496 TI - Depression and hyperactivity in two patients with craniofrontonasal syndrome. PMID- 26586495 TI - Higher-intensity exercise helps cancer survivors remain motivated. AB - PURPOSE: The aim of the present study was to determine if exercise intensity impacts upon the psychosocial responses of breast and prostate cancer survivors to a rehabilitation program. METHODS: Eighty-seven prostate and 72 breast cancer survivors participated in an 8-week exercise and supportive group psychotherapy intervention (n = 84) or control (n = 75) group. Intervention participants were randomized to low-to-moderate intensity exercise (LIG; n = 44; 60-65 % VO2peak, 50-65 % one repetition maximum (1RM)) or moderate-to-high intensity exercise (HIG; n = 40; 75-80 % VO2peak, 65-80 % 1RM) while controls continued usual care. Before and after the 8 weeks, all participants completed the Functional Assessment of Cancer Therapy-Breast or -Prostate to assess quality of life (QOL) and Behavioural Regulations of Exercise Version 2 for exercise motivation. Intervention participants also completed a follow-up assessment 4 months post intervention. RESULTS: All three groups improved in QOL from baseline to post intervention, with no significant differences. From post-intervention to follow up, the LIG and HIG similarly maintained QOL scores. Between baseline and post intervention, both intervention arms improved their motivation to exercise compared to the controls (p = 0.004). At the 4-month follow-up, the HIG had maintained their overall exercise motivation (p < 0.001) and both domains of intrinsic motivation (identified regulation, p = 0.047; intrinsic regulation, p = 0.007); however, the LIG had regressed. CONCLUSIONS: The structured intervention was successful at improving autonomous exercise motivation, regardless of exercise intensity. However, only those participants who had exercised at a higher intensity sustained their improvement. Intervention participation did not improve QOL more than controls. IMPLICATIONS FOR CANCER SURVIVORS: Higher intensity exercise is more likely to result in more sustainable increases in motivation to exercise among cancer survivors. PMID- 26586497 TI - Carotid intima media thickness and subclinical early atherosclerosis. PMID- 26586499 TI - Prevalence of disability in Australian elderly: Impact of trends in obesity and diabetes. AB - OBJECTIVE: We aimed to estimate the impact of past and future changes in obesity and diabetes prevalence in mid-life on disability prevalence for adult Australians. METHODS: We analysed data from the Australian Diabetes, Obesity and Lifestyle study (AusDiab) including participants aged 45-64years, disability-free at baseline (1999/2000) with disability information at follow-up (2011/12) (n=2107). We used coefficients from multinomial logistic regression to predict 10 year probabilities of disability and death from baseline predictors (age, sex, obesity, smoking, diabetes and hypertension). We estimated the prevalence of disability attributable to past (1980) and expected future (2025) changes in obesity and diabetes prevalence using the life table approach. RESULTS: We estimated that the prevalence of disability for those aged between 55 and 74years would have been 1697 cases per 100,000 persons less in 2010 (10.3% less) if the rates of obesity and diabetes observed in 2000 had been as low as the levels observed in 1980. However, if instead the prevalence of obesity and diabetes had been as high as the levels expected in 2025, then the prevalence of disability would have been an additional 2173 per 100,000 persons (an additional 13.2%). CONCLUSIONS: We demonstrate, for the first time, a substantial potential impact of obesity and diabetes trends on disability amongst those aged 55-74years. In Australian adults by 2025 we estimate that around 26% of disability cases would have been avoidable if there had been no change in obesity and diabetes prevalence since 1980. A similar impact is likely around the world in developed countries. PMID- 26586498 TI - Predictors and Survival Impact of False-Negative Sentinel Nodes in Melanoma. AB - BACKGROUND: The status of the sentinel lymph node in melanoma is an important prognostic factor. The clinical predictors and implications of false-negative (FN) biopsy remain debatable. METHODS: We compared patients with positive sentinel lymph node biopsy (SNB) [true positive (TP)] and negative SNB with and without regional recurrence [FN, true negative (TN)] from our prospective institutional database. RESULTS: Among 2986 patients (84 FN, 494 TP, and 2408 TN; median follow-up 93 months), the incidence of FN-SNB was 2.8%. While calculated FN rate was 14.5% [84 FN/(494 TP + 84 FN) * 100], when we accounted for local/in transit recurrence (LITR) this rate was 8.5% [46 FN/(494 TP + 46 FN) * 100 %]. On multivariate analysis, male gender (OR 2.0, 95% CI 1.1-3.6, p = 0.018), head/neck primaries (OR 2.5, 95% CI 1.3-4.8, p < 0.006), and LITR (OR 3.5, 95% CI 2.1-5.8, p < 0.001) were associated with FN-SNB. Melanoma-specific survival (MSS) for the FN group was similar to the TP group at 5 years (68 vs. 73%, p = 0.539). However, MSS declined more for the FN group with a longer follow up and was significantly worse at 10 years (44 vs. 64%, p < 0.001). On multivariate analysis, FN-SNB was a significant predictor of worse MSS in melanomas <4 mm in Breslow thickness (HR 1.6; 95% CI 1.1-2.5, p = 0.021). CONCLUSIONS: Male gender, LITR, and head and neck tumors were associated with FN-SNB. FN-SNB was an independent predictor of worse MSS in melanomas <4 mm in thickness, but this survival difference did not become apparent until after 5 years of follow-up. PMID- 26586500 TI - Patients' and carers' views and expectations about intensive management for moderate rheumatoid arthritis: a qualitative study. AB - Intensive management for rheumatoid arthritis (RA) involves frequent hospital visits and adjusted doses or combinations of medication. Research is currently underway to test whether or not intensive management strategies are valuable in moderately active disease, however, patient views on intensive management in this disease group are unknown. The objectives of this study were to explore the views and expectations of patients with moderately active RA and of carers of patients with moderately active RA. We conducted focus groups and one-to-one interviews in 2014 with 14 participants (9 patients, 5 carers) from 4 rheumatology clinics across 3 London Hospital NHS Trusts. Non-English-speaking patients were included with the assistance of a professional translator. Focus groups and interviews were audio recorded and transcribed and transcripts analysed using a framework analysis approach. Four main themes were identified: 'Hopes and Expectations of Intensive Management', 'Acceptability of Intensive Management', 'Patient Education' and 'The Importance of Continuity of Care'. Our main findings were that attendance at frequent clinic appointments was largely acceptable to patients and carers. Views on taking higher doses of medication depended on how stable patients were on their current treatment regime. Continuity of care from the rheumatologist and the provision of written/verbal information about intensive management were important to patients and carers. PMID- 26586501 TI - Prevention of postoperative ear canal stenosis using stents made of dental impression material: a rapid, cost-effective solution. PMID- 26586502 TI - Special Issue on Free Energy. PMID- 26586503 TI - Practical Aspects of Free-Energy Calculations: A Review. AB - Free-energy calculations in the framework of classical molecular dynamics simulations are nowadays used in a wide range of research areas including solvation thermodynamics, molecular recognition, and protein folding. The basic components of a free-energy calculation, that is, a suitable model Hamiltonian, a sampling protocol, and an estimator for the free energy, are independent of the specific application. However, the attention that one has to pay to these components depends considerably on the specific application. Here, we review six different areas of application and discuss the relative importance of the three main components to provide the reader with an organigram and to make nonexperts aware of the many pitfalls present in free energy calculations. PMID- 26586504 TI - An Overview of Electrostatic Free Energy Computations for Solutions and Proteins. AB - Free energy simulations for electrostatic and charging processes in complex molecular systems encounter specific difficulties owing to the long-range, 1/r Coulomb interaction. To calculate the solvation free energy of a simple ion, it is essential to take into account the polarization of nearby solvent but also the electrostatic potential drop across the liquid-gas boundary, however distant. The latter does not exist in a simulation model based on periodic boundary conditions because there is no physical boundary to the system. An important consequence is that the reference value of the electrostatic potential is not an ion in a vacuum. Also, in an infinite system, the electrostatic potential felt by a perturbing charge is conditionally convergent and dependent on the choice of computational conventions. Furthermore, with Ewald lattice summation and tinfoil conducting boundary conditions, the charges experience a spurious shift in the potential that depends on the details of the simulation system such as the volume fraction occupied by the solvent. All these issues can be handled with established computational protocols, as reviewed here and illustrated for several small ions and three solvated proteins. PMID- 26586505 TI - Diffusive Models of Membrane Permeation with Explicit Orientational Freedom. AB - Accurate calculation of permeabilities from first-principles has been a long standing challenge for computer simulations, notably in the context of drug discovery, as a route to predict the propensity of small, organic molecules to spontaneously translocate biological membranes. Of equal importance is the understanding of the permeation process and the pathway followed by the permeant from the aqueous medium to the interior of the lipid bilayer, and back out again. A convenient framework for the computation of permeabilities is provided by the solubility-diffusion model, which requires knowledge of the underlying free energy and diffusivity landscapes. Here, we develop a formalism that includes an explicit description of the orientational motion of the solute as it diffuses across the membrane. Toward this end, we have generalized a recently proposed method that reconciles thermodynamics and kinetics in importance-sampling simulations by means of a Bayesian-inference scheme to reverse-solve the underlying Smoluchowski equation. Performance of the proposed formalism is examined in the model cases of a water and an ethanol molecule crossing a fully hydrated lipid bilayer. Our analysis reveals a conspicuous dependence of the free energy and rotational diffusivity on the orientation of ethanol when it lies within the headgroup region of the bilayer. Specifically, orientations for which the hydroxyl group lies among the polar lipid head groups, while the ethyl group recedes toward the hydrophobic interior are associated with free-energy minima ~2kBT deep, as well as significantly slower orientational kinetics compared to the bulk solution or the core of the bilayer. The conspicuous orientational anisotropy of ethanol at the aqueous interface is suggestive of a complete rotation of the permeant as it crosses the hydrophobic interior of the membrane. PMID- 26586506 TI - Free Energy Calculation of Nanodiamond-Membrane Association-The Effect of Shape and Surface Functionalization. AB - Nanodiamonds (NDs) are nanoscale diamond particles with broad applications in biosensing, drug delivery, and long-term tracking. Their interactions with a membrane dictate both the endocytosis process and subsequent intracellular fate of the nanoparticles. However, details of ND-membrane association and the energetics of this process remain largely unknown. In this work, we use all-atom molecular dynamics (MD) simulations to determine the free energy profile and molecular details of ND-membrane association, with a focus on the impact of shape and surface functionalization. Through altogether 6.5 MUs umbrella sampling on six atomistic ND models of different shapes (spherical or pyramidal) and surface functionalization (5%, 35%, and 55%), we show that nanodiamonds associate favorably with the membrane, which is largely driven by ND-lipid interactions. During its membrane association, the shape of a nanodiamond plays a key role in determining the location of the free energy minimum, while its surface functionalization modulates the depth of the minimum. Of the six models studied here, all spherical NDs adhere to the bilayer surface, whereas pyramidal NDs, with the exception of the most functionalized P55, anchor inside the membrane. Shape also dominates the height of the free energy barrier: the sharp pyramidal NDs have much lower barriers against penetrating a POPC bilayer than spherical ones. Our all-atom ND models and their bilayer association strength determined here can be combined with future coarse-grained or continuum models to further explore ND-membrane interactions on larger length scales. PMID- 26586507 TI - Absolute Organic Crystal Thermodynamics: Growth of the Asymmetric Unit into a Crystal via Alchemy. PMID- 26586508 TI - Fast Switching Alchemical Transformations in Molecular Dynamics Simulations. AB - We present an efficient and rigorous implementation of the fast switching alchemical transformation for systems where electrostatic interactions are treated using the smooth particle mesh Ewald method. Free energies are computed using bidirectional nonequilibrium alchemical trajectories by applying the Crooks fluctuation theorem and the Bennett acceptance ratio to the collection of the final alchemical works. The technique is used for the evaluation of the 1 octanol/water partition coefficients for some selected organic molecules. Fast switching alchemical tranformations appear to be competitive, both in accuracy and in efficiency, with respect to the traditional methods based on independent equilibrium simulations of intermediate states. PMID- 26586509 TI - Free Energy Calculations for the Peripheral Binding of Proteins/Peptides to an Anionic Membrane. 1. Implicit Membrane Models. AB - The binding of peptides and proteins to the surface of complex lipid membranes is important in many biological processes such as cell signaling and membrane remodeling. Computational studies can aid experiments by identifying physical interactions and structural motifs that determine the binding affinity and specificity. However, previous studies focused on either qualitative behaviors of protein/membrane interactions or the binding affinity of small peptides. Motivated by this observation, we set out to develop computational protocols for bimolecular binding to charged membranes that are applicable to both peptides and large proteins. In this work, we explore a method based on an implicit membrane/solvent model (generalized Born with a simple switching in combination with the Gouy-Chapman-Stern model for a charged interface), which we expect to lead to useful results when the binding does not implicate significant membrane deformation and local demixing of lipids. We show that the binding free energy can be efficiently computed following a thermodynamic cycle similar to protein ligand binding calculations, especially when a Bennett acceptance ratio based protocol is used to consider both the membrane bound and solution conformational ensembles. Test calculations on a series of peptides show that our computational approach leads to binding affinities in encouraging agreement with experimental data, including for the challenging example of the bringing of flexible MARCKS-ED peptides to membranes. The calculations highlight that for a membrane with a significant fraction of anionic lipids, it is essential to include the effect of ion adsorption using the Stern model, which significantly modifies the effective surface charge. This implicit membrane model based computational protocol helps lay the groundwork for more systematic analysis of protein/peptide binding to membranes of complex shape and composition. PMID- 26586510 TI - Assessing the Accuracy of Two Enhanced Sampling Methods Using EGFR Kinase Transition Pathways: The Influence of Collective Variable Choice. AB - Structurally elucidating transition pathways between protein conformations gives deep mechanistic insight into protein behavior but is typically difficult. Unbiased molecular dynamics (MD) simulations provide one solution, but their computational expense is often prohibitive, motivating the development of enhanced sampling methods that accelerate conformational changes in a given direction, embodied in a collective variable. The accuracy of such methods is unclear for complex protein transitions, because obtaining unbiased MD data for comparison is difficult. Here, we use long-time scale, unbiased MD simulations of epidermal growth factor receptor kinase deactivation as a complex biological test case for two widely used methods-steered molecular dynamics (SMD) and the string method. We found that common collective variable choices, based on the root-mean square deviation (RMSD) of the entire protein, prevented the methods from producing accurate paths, even in SMD simulations on the time scale of the unbiased transition. Using collective variables based on the RMSD of the region of the protein known to be important for the conformational change, however, enabled both methods to provide a more accurate description of the pathway in a fraction of the simulation time required to observe the unbiased transition. PMID- 26586511 TI - POPs monitoring in Australia and New Zealand using plastic resin pellets, and International Pellet Watch as a tool for education and raising public awareness on plastic debris and POPs. AB - Persistent organic pollutants (i.e. PCBs, DDTs, and HCHs) were analyzed along Australia and New Zealand North Island coastlines. PCB concentrations were high in urban areas (107-294 ng/g-pellet), with Sydney Harbour the most polluted. Hepta-chlorinated PCB was abundant, with ~30% in urban areas suggesting legacy pollution. DDT concentrations showed similar pattern except in rural agricultural sites, Taupo Bay and Ahipara, New Zealand (23 and 47 ng/g-pellet). p,p'-DDE predominance at these 2 sites suggested historical input; they also had high HCH concentrations (17 and 29 ng/g-pellet). The role of International Pellet Watch (IPW) in science communication was studied through feedbacks from IPW volunteers, case studies and examples. IPW data were categorized into understandable terms and tailored reports based on volunteers' backgrounds complemented with pollution maps. The effectiveness of IPW science communication has led to its use in awareness and education activities focusing on both POPs and plastic debris issues. PMID- 26586512 TI - Efficacy of single and multi-metric fish-based indices in tracking anthropogenic pressures in estuaries: An 8-year case study. AB - Facing a generalized increase in water degradation, several programmes have been implemented for protecting and enhancing the water quality and associated wildlife, which rely on ecological indicators to assess the degree of deviation from a pristine state. Here, single (species number, Shannon-Wiener H', Pielou J') and multi-metric (Estuarine Fish Assessment Index, EFAI) community-based ecological quality measures were evaluated in a temperate estuary over an 8-year period (2005-2012), and established their relationships with an anthropogenic pressure index (API). Single metric indices were highly variable and neither concordant amongst themselves nor with the EFAI. The EFAI was the only index significantly correlated with the API, indicating that higher ecological quality was associated with lower anthropogenic pressure. Pressure scenarios were related with specific fish community composition, as a result of distinct food web complexity and nursery functioning of the estuary. Results were discussed in the scope of the implementation of water protection programmes. PMID- 26586513 TI - Detection of human-derived fecal contamination in Puerto Rico using carbamazepine, HF183 Bacteroides, and fecal indicator bacteria. AB - The level of fecal pollution in 17 sites in Puerto Rico was determined by Escherichia coli (E.coli) enumeration using an enzyme substrate medium and Quanti Tray(r)/2000. Human fecal pollution was identified using an enzyme-linked immunosorbent assay for the detection of carbamazepine (CBZ) and quantitative polymerase chain reaction (qPCR) detection of the human Bacteroides marker, HF183. Carbamazepine was detected in 16 out of 17 sites, including Condado Lagoon, a popular recreational area. Elevated E.coli levels (>410 CFU 100 mL(-1)) were detected in 13 sites. Average CBZ concentrations ranged from 0.005 MUg L(-1) to 0.482 MUg L(-1) and 7 sites were positive for HF183. Higher CBZ concentrations were associated with the detection of HF183 (Mann-Whitney test; U=42.0; df=7; 1 tailed P value=0.013). This was the second study to determine surface water concentrations of CBZ in the Caribbean and the first in Puerto Rico. PMID- 26586514 TI - The variability of EEG functional connectivity of young ADHD subjects in different resting states. AB - OBJECTIVE: To assess ADHD from global measures of EEG functional connectivity and their temporal variability in different resting states. METHODS: EEGs from sixteen cortical regions were recorded at rest during eyes-closed (EC) and eyes open (EO) in 10 male combined-type ADHD subjects and 12 healthy male controls. The mean global connectivity (CM) of each region and its temporal variability (CV) were estimated from a number of EEG segments recorded in both states. Connectivity indices between regions were calculated using the magnitude squared coherence (Coh) in the delta(delta)/theta(theta)/alpha(alpha)/beta(beta) frequency bands and the nonlinear index (L) of generalized synchronization. RESULTS: The CM did not present between-group differences in any region or state. However, the CV exhibited state-independent differences between both groups (ADHD>controls) mainly in frontal and parieto-occipital regions for all indices except Coh(alpha). Within group, only the CV-Coh(theta) of the centro-temporal region increased significantly for the ADHD subjects from EC to EO (p<0.001) and was greater than controls in EO (p<0.001). CONCLUSIONS: The CV of index-L and of Coh(theta) seem to be the best state-independent and -dependent measurements, respectively, to discriminate ADHDs from control subjects using resting state EEG data. SIGNIFICANCE: The underlying neural dysfunctions producing the ADHD seem better reflected by the CV measurements. PMID- 26586516 TI - A protocol for amide bond formation with electron deficient amines and sterically hindered substrates. AB - A protocol for amide coupling by in situ formation of acyl fluorides and reaction with amines at elevated temperature has been developed and found to be efficient for coupling of sterically hindered substrates and electron deficient amines where standard methods failed. PMID- 26586515 TI - Nosocomial transmission of avian influenza A (H7N9) virus in China: epidemiological investigation. AB - STUDY QUESTION: Can avian influenza A (H7N9) virus be transmitted between unrelated individuals in a hospital setting? METHODS: An epidemiological investigation looked at two patients who shared a hospital ward in February 2015, in Quzhou, Zhejiang Province, China. Samples from the patients, close contacts, and local environments were examined by real time reverse transcriptase (rRT) polymerase chain reaction (PCR) and viral culture. Haemagglutination inhibition and microneutralisation assays were used to detect specific antibodies to the viruses. Primary outcomes were clinical data, infection source tracing, phylogenetic tree analysis, and serological results. STUDY ANSWER AND LIMITATIONS: A 49 year old man (index patient) became ill seven days after visiting a live poultry market. A 57 year old man (second patient), with a history of chronic obstructive pulmonary disease, developed influenza-like symptoms after sharing the same hospital ward as the index patient for five days. The second patient had not visited any poultry markets nor had any contact with poultry or birds within 15 days before the onset of illness. H7N9 virus was identified in the two patients, who both later died. Genome sequences of the virus isolated from both patients were nearly identical, and genetically similar to the virus isolated from the live poultry market. No specific antibodies were detected among 38 close contacts. Transmission between the patients remains unclear, owing to the lack of samples collected from their shared hospital ward. Although several environmental swabs were positive for H7N9 by rRT-PCR, no virus was cultured. Owing to delayed diagnosis and frequent hospital transfers, no serum samples were collected from the patients, and antibodies to H7N9 viruses could not be tested. WHAT THIS STUDY ADDS: Nosocomial H7N9 transmission might be possible between two unrelated individuals. Surveillance on patients with influenza-like illness in hospitals as well as chickens in live poultry markets should be enhanced to monitor transmissibility and pathogenicity of the virus. FUNDING, COMPETING INTERESTS, DATA SHARING: Funding support from the Program of International Science and Technology Cooperation of China (2013DFA30800), Basic Work on Special Program for Science and Technology Research (2013FY114600), National Natural Science Foundation of China (81402730), Special Program for Prevention and Control of Infectious Diseases in China (2013ZX10004218), US National Institutes of Health (1R01-AI108993), Zhejiang Province Major Science and Technology Program (2014C03039), and Quzhou Science and Technology Program (20111084). The authors declare no other interests and have no additional data. PMID- 26586518 TI - Torsional and Cyclic Fatigue Resistance of a New Nickel-Titanium Instrument Manufactured by Electrical Discharge Machining. AB - INTRODUCTION: The purpose of this study was to evaluate the torsional and cyclic fatigue resistance of the new Hyflex EDM OneFile (Coltene/Whaledent AG, Altstatten, Switzerland) manufactured by electrical discharge machining and compare the findings with the ones of Reciproc R25 (VDW, Munich, Germany) and WaveOne Primary (Dentsply Maillefer, Ballaigues, Switzerland). METHODS: One hundred-twenty new Hyflex EDM OneFile (#25/0.08), Reciproc R25, and WaveOne Primary files were used. Torque and angle of rotation at failure of new instruments (n = 20) were measured according to ISO 3630-1 for each brand. Cyclic fatigue resistance was tested measuring the number of cycles to failure in an artificial stainless steel canal with a 60 degrees angle and a 3-mm radius of curvature. Data were analyzed using the analysis of variance test and the Student Newman-Keuls test for multiple comparisons. The fracture surface of each fragment was examined with a scanning electron microscope. RESULTS: The cyclic fatigue of Hyflex EDM was significantly higher than the one of Reciproc R25 and WaveOne Primary (P < .05 and P < .001, respectively). Hyflex EDM showed a lower maximum torque load (P < .05) but a significantly higher angular rotation (P < .0001) to fracture than Reciproc R25 and WaveOne Primary. No significant difference was found comparing the maximum torque load, angular rotation, and cyclic fatigue of Reciproc R25 and WaveOne Primary (P > .05). CONCLUSIONS: The new Hyflex EDM instruments (controlled memory wire) have higher cyclic fatigue resistance and angle of rotation to fracture but lower torque to failure than Reciproc R25 and WaveOne Primary files (M-wire for both files). PMID- 26586517 TI - Non-cultured dermal-derived mesenchymal cells attenuate sepsis induced by cecal ligation and puncture in mice. AB - Sepsis remains a threat to critically ill patients and carries a high morbidity and mortality. Cell-based therapies have risen in prominence in recent years. Dermal-derived mesenchymal cells (DMCs) are attractive as one of the abundant sources from which to isolate mesenchymal cells for therapeutic applications and can be easily accessed with minimal harm to the donor. In this study, we described for the first time the use of non-cultured DMCs for treating sepsis in a cecal ligation and puncture (CLP) mouse model and investigated their immunomodulatory effects. We found that non-cultured DMCs administration provides a beneficial effect to improve survival in CLP-induced sepsis. This effect is partly mediated by the ability of DMCs to home to sites of injury, to reduce the inflammatory response, to inhibit apoptosis, and to stimulate macrophage migration and phagocytosis. Our further findings suggest that DMCs treatment modulates the beneficial cytoprotective effects exhibited during sepsis, at least in part, by altering miRNA expression. These discoveries provide important evidence that non-cultured DMCs therapy has a specific anti-inflammatory effect on sepsis, and provide the basis for the development of a new therapeutic strategy for managing clinical sepsis. PMID- 26586520 TI - Towards evidence based medicine for paediatricians. PMID- 26586519 TI - Question 1: Does prophylactic paracetamol prevent fever after vaccination in infants? PMID- 26586521 TI - Question 2: Do standing frames and other related physical therapies reduce the risk of fractures in children with cerebral palsy? PMID- 26586523 TI - Noble-Metal-Free Molybdenum Disulfide Cocatalyst for Photocatalytic Hydrogen Production. AB - Photocatalytic water splitting using powered semiconductors as photocatalysts represents a promising strategy for clean, low-cost, and environmentally friendly production of H2 utilizing solar energy. The loading of noble-metal cocatalysts on semiconductors can significantly enhance the solar-to-H2 conversion efficiency. However, the high cost and scarcity of noble metals counter their extensive utilization. Therefore, the use of alternative cocatalysts based on non precious metal materials is pursued. Nanosized MoS2 cocatalysts have attracted considerable attention in the last decade as a viable alternative to improve solar-to-H2 conversion efficiency because of its superb catalytic activity, excellent stability, low cost, availability, environmental friendliness, and chemical inertness. In this perspective, the design, structures, synthesis, and application of MoS2 -based composite photocatalysts for solar H2 generation are summarized, compared, and discussed. Finally, this Review concludes with a summary and remarks on some challenges and opportunities for the future development of MoS2 -based photocatalysts. PMID- 26586524 TI - Evaluation of ventricular wall stress and cardiac function in patients with dilated cardiomyopathy. AB - Dilated cardiomyopathy is a heart disease characterized by both left ventricular dilatation and left ventricular systolic dysfunction, leading to cardiac remodeling and ultimately heart failure. We aimed to investigate the effect of dilated cardiomyopathy on the pump performance and myocardial wall mechanics using patient-specific finite element analysis. Results evinced pronounced end systolic wall stress on left ventricular wall of patients with dilated cardiomyopathy as compared to that of normal hearts. In dilated cardiomyopathy, both end-diastolic and end-systolic pressure-volume relationships of left ventricle and right ventricle were shifted to the right compared to controls, suggesting reduced myocardial contractility. We hereby propose that finite element analysis represents a useful tool to assess the myocardial wall stress and cardiac work, which are responsible for progressive left ventricular deterioration and poor clinical course. PMID- 26586525 TI - Individual and combined effects of noise-like whole-body vibration and parathyroid hormone treatment on bone defect repair in ovariectomized mice. AB - The effectiveness of intermittent administration of parathyroid hormone and exposure to whole-body vibration on osteoporotic fracture healing has been previously investigated, but data on their concurrent use are lacking. Thus, we evaluated the effects of intermittent administration of parathyroid hormone, whole-body vibration, and their combination on bone repair in osteoporotic mice. Noise-like whole-body vibration with a broad frequency range was used instead of conventional sine-wave whole-body vibration at a specific frequency. Mice were ovariectomized at 9 weeks of age and subjected to drill-hole surgery in the right tibial diaphysis at 11 weeks. The animals were divided into four groups (n = 12 each): a control group, and groups treated with intermittent administration of parathyroid hormone, noise-like whole-body vibration, and both. From postoperative day 2, the groups treated with intermittent administration of parathyroid hormone and groups treated with both intermittent administration of parathyroid hormone and noise-like whole-body vibration were subcutaneously administered parathyroid hormone at a dose of 30 ug/kg/day. The groups treated with noise-like whole-body vibration and groups treated with both intermittent administration of parathyroid hormone and noise-like whole-body vibration were exposed to noise-like whole-body vibration at a root mean squared acceleration of 0.3g and frequency components of 45-100 Hz for 20 min/day. Following 18 days of interventions, the right tibiae were harvested, and the regenerated bone was analyzed by micro-computed tomography and nanoindentation testing. Compared with the control group, callus volume fraction was 40% higher in groups treated with intermittent administration of parathyroid hormone and 73% higher in groups treated with both intermittent administration of parathyroid hormone and noise like whole-body vibration, and callus thickness was 35% wider in groups treated with both intermittent administration of parathyroid hormone and noise-like whole body vibration. Indentation modulus was 46% higher in groups treated with noise like whole-body vibration and 43% higher in groups treated with both intermittent administration of parathyroid hormone and noise-like whole-body vibration, and hardness was 31% higher in groups treated with both intermittent administration of parathyroid hormone and noise-like whole-body vibration compared with the control group. There was no interaction between the two treatments for both structure and mechanical indexes. The main effects of intermittent administration of parathyroid hormone and noise-like whole-body vibration on bone repair included increased bone formation and enhanced mechanical function of regenerated bone, respectively. The combined treatment resulted in further regeneration of bone with high indentation modulus and hardness, suggesting the therapeutic potential of the combined use of noise-like whole-body vibration and intermittent administration of parathyroid hormone for enhancing osteoporotic bone healing. PMID- 26586526 TI - A biomechanical comparison of four different fixation methods for midshaft clavicle fractures. AB - Clavicle fractures may occur in all age groups, and 70%-80% of clavicle fractures occur in the midshaft. Many methods for treating midshaft clavicular fractures have been reported and remain controversial. To provide some guidance for clinical treatment, 30 artificial polymethyl methacrylate models of the clavicle were sewn obliquely at the midshaft to simulate the most common type of clavicular fractures, and the fracture models were divided into five groups randomly and were fixed as follows: the reconstruction plates were placed at the superior position of the fracture model (R-S group), the reconstruction plates were placed at the anteroinferior position of the fracture model (R-AI group), the locking plates were placed at the superior position (L-S group), the locking plates were placed at the anteroinferior position (L-AI group); and the control models were unfixed (control group). The strain gauges were attached to the bone surface near the fracture fragments, and then, the biomechanical properties of the specimens were measured using the compression test, torsion test and three point bending test. The results showed that plate fixation can provide a stable construct to help with fracture healing and is the preferred method in the treatment of clavicle fractures. The locking plate provides the best biomechanical stability when placed at the anteroinferior position, and this surgical method can reduce the operation time and postoperative complications; thus, it would be a better choice in clinical practice. PMID- 26586527 TI - Effect of friction and clearance on kinematics and contact mechanics of dual mobility hip implant. AB - The dual mobility hip implant has been introduced recently and increasingly used in total hip replacement to maintain the stability and reduce the risk of post surgery dislocation. However, the kinematics and contact mechanisms of dual mobility hip implants have not been investigated in detail in the literature. Therefore, finite element method was adopted in this study to investigate dynamics and contact mechanics of a typical metal-on-polymer dual mobility hip implant under different friction coefficient ratios between the inner and the outer articulations and clearances/interferences between the ultra-high-molecular weight polyethylene liner and the metal back shell. A critical ratio of friction coefficients between the two pairs of contact interfaces was found to mainly determine the rotating surfaces. Furthermore, an initial clearance between the liner and the back shell facilitated the rotation of the liner while an initial interference prevented such a motion at the outer articulating interface. In addition, the contact area and the sliding distance at the outer articulating surface were markedly greater than those at the inner cup-head interface, potentially leading to extensive wear at the outer surface of the liner. PMID- 26586528 TI - Pulse-echo ultrasound transit time spectroscopy: A comparison of experimental measurement and simulation prediction. AB - Considering ultrasound propagation through complex composite media as an array of parallel sonic rays, a comparison of computer-simulated prediction with experimental data has previously been reported for transmission mode (where one transducer serves as transmitter, the other as receiver) in a series of 10 acrylic step-wedge samples, immersed in water, exhibiting varying degrees of transit time inhomogeneity. In this study, the same samples were used but in pulse-echo mode, where the same ultrasound transducer served as both transmitter and receiver, detecting both 'primary' (internal sample interface) and 'secondary' (external sample interface) echoes. A transit time spectrum was derived, describing the proportion of sonic rays with a particular transit time. A computer simulation was performed to predict the transit time and amplitude of various echoes created, and compared with experimental data. Applying an amplitude-tolerance analysis, 91.7% +/- 3.7% of the simulated data were within +/ 1 standard deviation of the experimentally measured amplitude-time data. Correlation of predicted and experimental transit time spectra provided coefficients of determination (R(2)%) ranging from 100.0% to 96.8% for the various samples tested. The results acquired from this study provide good evidence for the concept of parallel sonic rays. Furthermore, deconvolution of experimental input and output signals has been shown to provide an effective method to identify echoes otherwise lost due to phase cancellation. Potential applications of pulse-echo ultrasound transit time spectroscopy include improvement of ultrasound image fidelity by improving spatial resolution and reducing phase interference artefacts. PMID- 26586529 TI - Abnormal mitochondrial transport and morphology as early pathological changes in human models of spinal muscular atrophy. AB - Spinal muscular atrophy (SMA), characterized by specific degeneration of spinal motor neurons, is caused by mutations in the survival of motor neuron 1, telomeric (SMN1) gene and subsequent decreased levels of functional SMN. How the deficiency of SMN, a ubiquitously expressed protein, leads to spinal motor neuron specific degeneration in individuals affected by SMA remains unknown. In this study, we examined the role of SMN in mitochondrial axonal transport and morphology in human motor neurons by generating SMA type 1 patient-specific induced pluripotent stem cells (iPSCs) and differentiating these cells into spinal motor neurons. The initial specification of spinal motor neurons was not affected, but these SMA spinal motor neurons specifically degenerated following long-term culture. Moreover, at an early stage in SMA spinal motor neurons, but not in SMA forebrain neurons, the number of mitochondria, mitochondrial area and mitochondrial transport were significantly reduced in axons. Knocking down of SMN expression led to similar mitochondrial defects in spinal motor neurons derived from human embryonic stem cells, confirming that SMN deficiency results in impaired mitochondrial dynamics. Finally, the application of N-acetylcysteine (NAC) mitigated the impairment in mitochondrial transport and morphology and rescued motor neuron degeneration in SMA long-term cultures. Furthermore, NAC ameliorated the reduction in mitochondrial membrane potential in SMA spinal motor neurons, suggesting that NAC might rescue apoptosis and motor neuron degeneration by improving mitochondrial health. Overall, our data demonstrate that SMN deficiency results in abnormal mitochondrial transport and morphology and a subsequent reduction in mitochondrial health, which are implicated in the specific degeneration of spinal motor neurons in SMA. PMID- 26586530 TI - Urine-sample-derived human induced pluripotent stem cells as a model to study PCSK9-mediated autosomal dominant hypercholesterolemia. AB - Proprotein convertase subtilisin kexin type 9 (PCSK9) is a critical modulator of cholesterol homeostasis. Whereas PCSK9 gain-of-function (GOF) mutations are associated with autosomal dominant hypercholesterolemia (ADH) and premature atherosclerosis, PCSK9 loss-of-function (LOF) mutations have a cardio-protective effect and in some cases can lead to familial hypobetalipoproteinemia (FHBL). However, limitations of the currently available cellular models preclude deciphering the consequences of PCSK9 mutation further. We aimed to validate urine-sample-derived human induced pluripotent stem cells (UhiPSCs) as an appropriate tool to model PCSK9-mediated ADH and FHBL. To achieve our goal, urine sample-derived somatic cells were reprogrammed into hiPSCs by using episomal vectors. UhiPSC were efficiently differentiated into hepatocyte-like cells (HLCs). Compared to control cells, cells originally derived from an individual with ADH (HLC-S127R) secreted less PCSK9 in the media (-38.5%; P=0.038) and had a 71% decrease (P<0.001) of low-density lipoprotein (LDL) uptake, whereas cells originally derived from an individual with FHBL (HLC-R104C/V114A) displayed a strong decrease in PCSK9 secretion (-89.7%; P<0.001) and had a 106% increase (P=0.0104) of LDL uptake. Pravastatin treatment significantly enhanced LDL receptor (LDLR) and PCSK9 mRNA gene expression, as well as PCSK9 secretion and LDL uptake in both control and S127R HLCs. Pravastatin treatment of multiple clones led to an average increase of LDL uptake of 2.19 +/- 0.77-fold in HLC S127R compared to 1.38 +/- 0.49 fold in control HLCs (P<0.01), in line with the good response to statin treatment of individuals carrying the S127R mutation (mean LDL cholesterol reduction=60.4%, n=5). In conclusion, urine samples provide an attractive and convenient source of somatic cells for reprogramming and hepatocyte differentiation, but also a powerful tool to further decipher PCSK9 mutations and function. PMID- 26586532 TI - Burnout and Work Engagement in Nurses: Reply to Bianchi. PMID- 26586531 TI - TP53 alterations in pancreatic acinar cell carcinoma: new insights into the molecular pathology of this rare cancer. AB - The molecular alterations of pancreatic acinar cell carcinomas (ACCs) are poorly understood and have been reported as being different from those in ductal adenocarcinomas. Loss of TP53 gene function in the pathogenesis of ACCs is controversial since contradictory findings have been published. A comprehensive analysis of the different possible genetic and epigenetic mechanisms leading to TP53 alteration in ACC has never been reported and hence the role of TP53 in the pathogenesis and/or progression of ACC remains unclear. We investigated TP53 alterations in 54 tumor samples from 44 patients, including primary and metastatic ACC, using sequencing analysis, methylation-specific multiplex ligation probe amplification, fluorescence in situ hybridization, and immunohistochemistry. TP53 mutations were found in 13 % of primary ACCs and in 31 % of metastases. Primary ACCs and metastases showed the same mutational profile, with the exception of one case, characterized by a wild-type sequence in the primary carcinoma and a mutation in the corresponding metastasis. FISH analysis revealed deletion of the TP53 region in 53 % of primary ACCs and in 50 % of metastases. Promoter hypermethylation was found in one case. The molecular alterations correlated well with the immunohistochemical findings. A statistically significant association was found between the combination of mutation of one allele and loss of the other allele of TP53 and worse survival. PMID- 26586533 TI - Availability of Early, Intensive, and Continuous Nutrition Management for Fournier's Gangrene with Rectal Cancer: A Case Report. PMID- 26586534 TI - Comparison of Living and Bedrooms in Terms of House Dust Mites in the Province of Erzincan, Turkey. AB - The most important factors in development of symptoms such as allergic asthma, rhinitis, conjunctivitis, and dermatitis in atopic persons are the allergens of house dust mites. The objective of this study was to compare living rooms and bedrooms, and woolen and spring mattresses in terms of the number and species of mites in houses in the province of Erzincan, Turkey. In total, 74 dust samples were collected from living rooms and bedrooms of 37 randomly selected houses from various districts of the city. All examined houses were positive for house dust mites. In total, 5,210 mites were isolated, 1,058 from the living rooms and 4,152 from the bedrooms, and the differences were statistically significant (P < 0.05). Of 4,152 mites detected in bedrooms, 1,330 (32%) were isolated from 31 spring mattresses and 2,822 (68%) from 6 woolen mattresses (P < 0.001). The study identified 14 families, 17 genera, and 16 species belonging to Astigmata, Prostigmata, and Oribatida. Of these, Dermatophagoides pteronyssinus (Trouessart) was the dominant species: living rooms, 63.3%; bedrooms, 74.4%; woolen mattresses, 84.6%; and spring mattresses, 52.8%. This was followed by Lepidoglyphus destructor (Schrank) (9.8%), Dermatophagoides farinae Hughes (5.1%), Tyrophagus putrescentiae (Schrank) (4.3%), and Acarus siro L. (2.5%) in living rooms; L. destructor (11.2%), Euroglyphus maynei (Cooreman) (4.2%), D. farinae (3.8%), and T. putrescentiae (1.0%) in bedrooms; L. destructor (11.8%), D. farinae (2.1%), E. maynei (0.3%), and T. putrescentiae (0.2%) in woolen mattresses; and E. maynei (12.5%), L. destructor (9.9%), D. farinae (7.5%), and T. putrescentiae (2.7%) in spring mattresses. PMID- 26586535 TI - New Records of Ixodes affinis (Acari: Ixodidae) Parasitizing Avian Hosts in Southeastern Virginia. AB - Ixodes affinis Neumann (Acari: Ixodidae) is a hard-bodied tick species distributed throughout much of the southeastern United States. Although I. affinis does not parasitize humans, it is a competent vector of Borrelia burgdorferi sensu stricto, the causative-agent of Lyme disease, and thus contributes to the enzootic maintenance of this pathogen. This study presents evidence of I. affinis parasitizing five new host passerine species. During 2012 2014, 1,888 birds were captured and examined for ticks, and 18 immature I. affinis were collected from 12 birds-six Carolina Wrens (Thyrothorus ludovicianus); two Brown Thrashers (Toxostoma rufum); and one American Robin (Turdus migratorius), Eastern Towhee (Pipilo erythrophthalmus), Northern Cardinal (Cardinalis cardinalis), and White-throated Sparrow (Zonotrichia albicollis). Of 15 larvae and 3 nymphs collected, one nymph tested positive for B. burgdorferi DNA. I. affinis was found co-feeding on birds with immature Amblyomma americanum (L.), Ixodes brunneus Koch, Ixodes dentatus Marx, Ixodes scapularis Say, and Haemaphysalis leporispalustris Packard. The results of this research provide a better understanding of I. affinis hosts and identify avian taxa that may play a role in the maintenance and dispersal of this tick species. PMID- 26586536 TI - Clean Chemistry for Elemental Impurities Analysis of Pharmaceuticals in Compliance with USP 232. AB - United States Pharmacopeia updated its 100 years old metal analysis method with inductively coupled plasma mass spectrometry (ICP-MS) and inductively coupled plasma optical emission spectrometry (ICP-OES). These sensitive instruments require that sample preparation be at least as sophisticated as the instrumentation used in the analysis. Sample contamination during sample preparation has to be controlled to an acceptable level given the low detection limit of these instruments and the ubiquitous presence of elements. This article focused on sample contamination during sample preparation. Contaminations from environment, reagents, and lab apparatus were investigated for their impact on trace element analysis. Advice on clean lab practice was offered to the pharmaceutical industry in regard to contamination control in elemental analysis labs at a time when the industry is preparing for compliance with elemental impurities in drug products. PMID- 26586537 TI - Design, Optimization, and Evaluation of Lurasidone Hydrochloride Nanocrystals. AB - The present investigation was carried out to design, optimize, and evaluate lurasidone hydrochloride nanocrystals for improving its solubility and dissolution characteristics. Nanocrystals were prepared by media milling technique using zirconium oxide beads with 0.1 mm diameter. Various stabilizers, viz. poloxamer 188, PVP K30, SLS, HPMC E15, and PVP S 630 D, were evaluated to stabilize the nanocrystals. The Pareto chart obtained through Plackett-Burman screening design revealed that HPMC E 15 showed the highest standardized effect (p value <0.05) on percent dissolution efficiency at 2 min. In subsequent studies, a 3(2) factorial design was employed to quantify the effect of two independent variables, namely amount of stabilizer and milling time on predetermined response variables mean particle size, saturation solubility, and percent dissolution efficiency at 2 min. Statistical analysis of the factorial design revealed that all predetermined response variables were significantly dependent (p value <0.05) on the independent variables. The observed response of the optimized batch prepared as per the desirability function was in close agreement with predicted response, and mathematical model generated was validated. The optimized batch was lyophilized, and X-ray powder diffraction studies indicated that there was no substantial change in crystallinity of the drug. The optimized formulation showed mean particle size of 228 nm and released almost all the drug within first 5 min. Since the crystallinity of the drug is maintained, improvement in saturation solubility and dissolution efficiency could be attributed to decrease in mean particle size of the drug. PMID- 26586538 TI - Biological nitrogen removal from sewage via anammox: Recent advances. AB - Biological nitrogen removal from sewage via anammox is a promising and feasible technology to make sewage treatment energy-neutral or energy-positive. Good retention of anammox bacteria is the premise of achieving sewage treatment via anammox. Therefore the anammox metabolism and its factors were critically reviewed so as to form biofilm/granules for retaining anammox bacteria. A stable supply of nitrite for anammox bacteria is a real bottleneck for applying anammox in sewage treatment. Nitritation and partial-denitrification are two promising methods of offering nitrite. As such, the strategies for achieving nitritation in sewage treatment were summarized by reviewing the factors affecting nitrite oxidation bacteria growth. Meanwhile, the methods of achieving partial denitrification have been developed through understanding the microorganisms related with nitrite accumulation and their factors. Furthermore, two cases of applying anammox in the mainstream sewage treatment plants were documented. PMID- 26586539 TI - Invasive cervical cancer in pregnancy. AB - Detection of invasive cervical cancer during pregnancy is rare, with reported incidence rates ranging from 0.05% to 0.1%. However, cervical cancer is one of the most common malignancies diagnosed during pregnancy. The management of invasive cervical cancer in pregnancy is extremely challenging and requires a multidisciplinary team approach to optimise the treatment for the patient by simultaneously providing the best chance of survival for the foetus. The approach is based mainly on the following factors: gestational age at the time of the diagnosis, stage, histological subtype, desire regarding fertility and quality of life. The gold standard treatment for this condition in pregnancy is not yet established. This is due to the absence of prospective studies and clinical trials. Therefore, its management presents a dilemma that requires individualisation of care. The various factors that need to be considered for obtaining a good outcome for both mother and child are described in this study. PMID- 26586540 TI - Adhesions are the major cause of complications in operative gynecology. AB - Adhesion formation has been found to be highly prevalent in patients with a history of operations or inflammatory peritoneal processes. These patients are at a high risk of serious intraoperative complications during a subsequent operation if adhesiolysis is performed. These complications include bowel perforation, ureteral or bladder injury, and vascular injury. In order to minimize the risk of these complications, adhesiolysis should only be performed by experienced surgeons, and intraoperative strategies must be adopted. The reduction of the overall incidence of adhesions is essential for subsequent surgical treatments. Anti-adhesion strategies must be adopted for preventing the reoccurrence of adhesions after abdominopelvic operations. The strategies employed to reduce the risk and the overall incidence of adhesions have been elucidated in this article. PMID- 26586541 TI - Difficulties with diagnosis of malignancies in pregnancy. AB - Diagnosis and staging of cancer during pregnancy may be difficult due to overlap in physical signs, uncertainties on safety and accuracy of diagnostic tests and histopathology in pregnant women. Tumour markers should be used with caution due to pregnancy-induced elevation. Ionizing imaging and staging techniques such as computed tomography (CT) or positron emission tomography (PET) scans and sentinel node procedures are safe during pregnancy when fetal radiation threshold of 100 mGy is maintained. Ionizing imaging techniques can increasingly be avoided with the technical devolvement of non-ionizing techniques such as magnetic resonance imaging (MRI), including whole body MRI and diffusion-weighted imaging, which hold potentially great opportunities for the diagnostic management of pregnant cancer patients. Pathological evaluation and establishing a diagnosis of malignancy can be difficult in pregnant women, and a note to the pathologist of the pregnant status is essential for accurate diagnosis. This chapter will give an overview of possibilities and difficulties in diagnosing pregnant women with cancer. PMID- 26586542 TI - Quality and fertilizing capacity of boar spermatozoa during liquid storage in extender supplemented with different antibiotics. AB - The aim of the study was to determine the effect of antibiotics on quality parameters and fertilizing capacity of boar sperm during liquid preservation. In the first experiment, semen was diluted in an extender containing 200 MUg/mL of gentamicin as a control and diluted in a modified extenders: Ext I (contained 200 MUg/mL florfenicol), Ext II (contained 200 MUg/mL polymyxin B), Ext III (contained 100 MUg/mL gentamicin and 100 MUg/mL florfenicol) and Ext IV (contained 100 MUg/mL gentamicin and 100 MUg/mL polymyxin B). The semen was stored for ten days. Sperm quality was evaluated based on the motility (CASA; TM: total motility; PM: progressive motility), membrane integrity (YO-PRO-1/PI assay), mitochondrial activity (JC-1) and DNA integrity (TUNEL). The highest PM% (62.5 +/- 9.6) was observed in Ext III at Day 6 of storage. The highest sperm viability and mitochondrial transmembrane potential was noticed at the end of the storage period in Ext III. Long-term storage did not induce DNA fragmentation in the extenders analyzed. In the second experiment, semen diluted in the control extender and in the extender providing the highest quality spermatozoa on Day 10 (Ext III) was used for artificial insemination (AI) of synchronized gilts. Our studies showed that the highest reproductive performance of inseminated gilts (pregnant gilts: 97.0%, litter size: 11.4 +/- 1.2) occurred with Ext III semen dilution. The combination of 100 MUg/mL gentamicin and 100 MUg/mL florfenicol in the extender maintained sperm motility, membrane integrity and mitochondrial activity and enhanced the higher reproduction success. PMID- 26586543 TI - Superfluidity in topologically nontrivial flat bands. AB - Topological invariants built from the periodic Bloch functions characterize new phases of matter, such as topological insulators and topological superconductors. The most important topological invariant is the Chern number that explains the quantized conductance of the quantum Hall effect. Here we provide a general result for the superfluid weight Ds of a multiband superconductor that is applicable to topologically nontrivial bands with nonzero Chern number C. We find that the integral over the Brillouin-zone of the quantum metric, an invariant calculated from the Bloch functions, gives the superfluid weight in a flat band, with the bound Ds?|C|. Thus, even a flat band can carry finite superfluid current, provided the Chern number is nonzero. As an example, we provide Ds for the time-reversal invariant attractive Harper-Hubbard model that can be experimentally tested in ultracold gases. In general, our results establish that a topologically nontrivial flat band is a promising concept for increasing the critical temperature of the superconducting transition. PMID- 26586545 TI - [Underdiagnosed asthma in third-grade children]. AB - Undiagnosed asthma has been poorly studied before adolescence since it can go unnoticed by parents and doctors. Moreover, it is unusual to look for undiagnosed asthma by directly questioning children on the presence of current respiratory symptoms. Epidemiologic studies show that more adolescents quote symptoms suggestive of asthma than the prevalence of doctor-diagnosed asthma, but respiratory symptoms compatible with asthma remain undetected by parents of younger children more frequently than doctors diagnose asthma in their children. We attempted to evaluate the relevance of a questionnaire used since 2011 by school doctors in Paris to detect asthma. In this questionnaire, the family history of atopy and asthma were completed by the parents when they met the school doctor (last year of preschool) and questions on current respiratory symptoms were answered by third-grade children seen alone by the school doctor. One hundred and thirty-one children out of 1135 children questioned had a positive questionnaire for suspected asthma. In three-quarters of the cases, questionnaires were positive based on the children's answers on their respiratory symptoms (without a positive answer on personal or family history being necessary). The outcome of 41 children screened by the questionnaire was known. Twenty (49%) children had received a final diagnosis of asthma, of whom 12 were put on asthma controllers. Among these 20 children, two children underwent lung function testing and two others underwent tests for allergy. In eight children, tests had been requested by the child's GP, but no final diagnosis was reported by the parents. None of the 13 children in whom asthma was ruled out had any test performed. It was concluded that it is possible to detect undiagnosed asthma in children as young as 8 years by directly asking them about their respiratory symptoms. The knowledge of personal and family history can improve screening for asthma in these children. A more thorough evaluation of all children with a positive questionnaire is necessary to better understand the properties of the questionnaire. Finally, the best way to implement this screening program remains to be established (school health, GPs). PMID- 26586544 TI - Assessing vertebrate biodiversity in a kelp forest ecosystem using environmental DNA. AB - Preserving biodiversity is a global challenge requiring data on species' distribution and abundance over large geographic and temporal scales. However, traditional methods to survey mobile species' distribution and abundance in marine environments are often inefficient, environmentally destructive, or resource-intensive. Metabarcoding of environmental DNA (eDNA) offers a new means to assess biodiversity and on much larger scales, but adoption of this approach for surveying whole animal communities in large, dynamic aquatic systems has been slowed by significant unknowns surrounding error rates of detection and relevant spatial resolution of eDNA surveys. Here, we report the results of a 2.5 km eDNA transect surveying the vertebrate fauna present along a gradation of diverse marine habitats associated with a kelp forest ecosystem. Using PCR primers that target the mitochondrial 12S rRNA gene of marine fishes and mammals, we generated eDNA sequence data and compared it to simultaneous visual dive surveys. We find spatial concordance between individual species' eDNA and visual survey trends, and that eDNA is able to distinguish vertebrate community assemblages from habitats separated by as little as ~60 m. eDNA reliably detected vertebrates with low false-negative error rates (1/12 taxa) when compared to the surveys, and revealed cryptic species known to occupy the habitats but overlooked by visual methods. This study also presents an explicit accounting of false negatives and positives in metabarcoding data, which illustrate the influence of gene marker selection, replication, contamination, biases impacting eDNA count data and ecology of target species on eDNA detection rates in an open ecosystem. PMID- 26586546 TI - [Acute diarrhea in infants: Evaluation of general practitioner practices]. PMID- 26586547 TI - [Motivations for a consultation before adoption: A multicenter study]. AB - INTRODUCTION: While the number of international adoptions in France is decreasing, adopted children are older and in poorer health than they used to be. This phenomenon has resulted in an increase in the demand for preadoption consultations over the past several years. This study analyses the reasons for these consultations. METHOD: Prospective multicenter study conducted from 1 January to 31 December 2013. RESULTS: Ten centers contributed to the study, i.e., 196 preadoption consultations. Seeking medical advice was the reason for 88% of the consultations, whether the advice was based on the study of an identified child's medical file (32%) or a country's healthcare characteristics, whether the country was identified (34%) or not (23%). In 6% of cases, the motive for preadoption consultations was social and familial, and in the last 5% it was to obtain general information about adoption and its procedures. In more than 40% of the cases, whether the child or the country identified, Russia is the subject of the consultation because of the complexity of the files and because of the dreaded but rarely mentioned fetal alcohol syndrome. CONCLUSION: The deterioration of adopted children's health is an additional worry for future adoption applicants. To provide them with the best information possible without making choices for them, specialists should have substantial experience in adoption before going into these preadoption consultations. PMID- 26586548 TI - Timed performance weaknesses on computerized tasks in pediatric brain tumor survivors: A comparison with sibling controls. AB - With more children surviving a brain tumor, insight into the late effects of the disease and treatment is of high importance. This study focused on profiling the neurocognitive functions that might be affected after treatment for a pediatric brain tumor, using a broad battery of computerized tests. Predictors that may influence neurocognitive functioning were also investigated. A total of 82 pediatric brain tumor survivors (PBTSs) aged 8-18 years (M = 13.85, SD = 3.15, 49% males) with parent-reported neurocognitive complaints were compared to a control group of 43 siblings (age M = 14.27, SD = 2.44, 40% males) using linear mixed models. Neurocognitive performance was assessed using measures of attention, processing speed, memory, executive functioning, visuomotor integration (VMI), and intelligence. Tumor type, treatment, tumor location, hydrocephalus, gender, age at diagnosis, and time since diagnosis were entered into regression analyzes as predictors for neurocognitive functioning. The PBTSs showed slower processing speeds and lower intelligence (range effect sizes .71 .82, p < .001), as well as deficits in executive attention, short-term memory, executive functioning, and VMI (range effect sizes .40-.57, p < .05). Older age at assessment was associated with better neurocognitive functioning (B = .450, p < .001) and younger age at diagnosis was associated with lower intelligence (B = .328, p < .05). Medical risk factors, e.g., hydrocephalus, did not show an association with neurocognitive functioning. Late effects in PBTSs include a broad range of neurocognitive deficits. The results suggest that even PBTSs that were traditionally viewed as low risk for neurocognitive problems (e.g., surgery only, no hydrocephalus) may suffer from decreased neurocognitive functioning. PMID- 26586549 TI - Maternal psychiatric disorders and risk of preterm birth. AB - PURPOSE: To study the effect of maternal psychiatric disorders (depression, anxiety disorder, bipolar disease, schizophrenia, unspecified psychiatric disorder, and comorbid conditions) and odds of preterm birth. METHODS: The Consortium on Safe Labor (2002-2008), an observational cohort with 12 centers from across the United States included 223,394 singleton pregnancies with clinical data obtained from electronic medical records and maternal diagnoses of psychiatric disorders from maternal discharge summaries. Length of gestation was based on the best clinical estimate and categorized as birth less than 39, less than 37, less than 34, and less than 28 weeks' gestation. The adjusted odds ratios (ORs) with 95% confidence intervals of birth were estimated by logistic regression with generalized estimating equations. RESULTS: Any maternal psychiatric disorder was associated with odds of birth less than 39 weeks' gestation (odds ratio [OR] = 1.32, 95% confidence interval = 1.28-1.37), less than 37 weeks' gestation (OR = 1.45, 1.38-1.52), less than 34 weeks' gestation (OR = 1.47, 1.35-1.59), and less than 28 weeks' gestation (OR = 1.57, 1.36-1.82). Specifically, odds of birth less than 37 weeks' gestation were associated with maternal depression (OR = 1.31, 1.23-1.40), anxiety disorder (OR = 1.68, 1.41 2.01), depression with anxiety disorder (OR = 2.31, 1.93-2.78), bipolar disease (OR = 1.54, 1.22-1.94), bipolar disease with depression and/or anxiety disorder (OR = 1.70, 1.30-2.22), and unspecified psychiatric disorder (OR = 1.52, 1.41 1.64). CONCLUSIONS: Maternal psychiatric disorders, especially comorbid psychiatric conditions, were associated with increased likelihood of preterm birth. PMID- 26586550 TI - [Ophthalmologic reading charts : Part 2: Current logarithmically scaled reading charts]. AB - PURPOSE: To analyze currently available reading charts regarding print size, logarithmic print size progression, and the background of test-item standardization. METHODS: For the present study, the following logarithmically scaled reading charts were investigated using a measuring microscope (iNexis VMA 2520; Nikon, Tokyo): Eschenbach, Zeiss, OCULUS, MNREAD (Minnesota Near Reading Test), Colenbrander, and RADNER. Calculations were made according to EN-ISO 8596 and the International Research Council recommendations. RESULTS: Modern reading charts and cards exhibit a logarithmic progression of print sizes. The RADNER reading charts comprise four different cards with standardized test items (sentence optotypes), a well-defined stop criterion, accurate letter sizes, and a high print quality. Numbers and Landolt rings are also given in the booklet. The OCULUS cards have currently been reissued according to recent standards and also exhibit a high print quality. In addition to letters, numbers, Landolt rings, and examples taken from a timetable and the telephone book, sheet music is also offered. The Colenbrander cards use short sentences of 44 characters, including spaces, and exhibit inaccuracy at smaller letter sizes, as do the MNREAD cards. The MNREAD cards use sentences of 60 characters, including spaces, and have a high print quality. CONCLUSION: Modern reading charts show that international standards can be achieved with test items similar to optotypes, by using recent technology and developing new concepts of test-item standardization. Accurate print sizes, high print quality, and a logarithmic progression should become the minimum requirements for reading charts and reading cards in ophthalmology. PMID- 26586552 TI - Thymic pathology in placental abruption: an autopsy study of third trimester stillborns in a predominantly African-American population. AB - OBJECTIVE: Complete placental abruption results rapidly in fetal death through acute asphyxia, and identification of thymic lesions at autopsy may help in confirming this diagnosis. Thymic petechiae are a marker for acute asphyxia, while absence of histologically identifiable acute thymic involution (ATI), which requires several hours to develop, may help in exclusion. METHODS: We identified autopsies on 17 3rd trimester stillborns with clinical abruption; 58 stillborns with unexplained demise comprised the control group. Eighty-nine percent of the mothers were African-American. ATI was graded 0-4 (grades 0-1 and 3-4 were combined for analysis), and thymic petechiae were recorded. RESULTS: In the abruption group, ATI grade 0-1 was more frequent than higher grades: 13 (77%) had ATI grade 0-1 compared to 1 (6%) with ATI grade 3-4 (p < 0.001). In contrast, in the control group, ATI grade 3-4 was more frequent than lower grades: 9 (16%) had ATI grade 0-1 compared to 30 (52%) with ATI grade 3-4 (p < 0.001). Thymic petechiae were more frequent in the abruption compared to control group [10 (59%) versus 2 (3%)] (p < 0.001), and were frequently seen with low ATI grade: 10 (83%) had ATI grade 0-1 (p < 0.001). CONCLUSIONS: The presence of thymic petechiae and ATI grade 0-1 correlates significantly with a clinical diagnosis of placental abruption. PMID- 26586551 TI - Development of exosome-encapsulated paclitaxel to overcome MDR in cancer cells. AB - Exosomes have recently come into focus as "natural nanoparticles" for use as drug delivery vehicles. Our objective was to assess the feasibility of an exosome based drug delivery platform for a potent chemotherapeutic agent, paclitaxel (PTX), to treat MDR cancer. Herein, we developed different methods of loading exosomes released by macrophages with PTX (exoPTX), and characterized their size, stability, drug release, and in vitro antitumor efficacy. Reformation of the exosomal membrane upon sonication resulted in high loading efficiency and sustained drug release. Importantly, incorporation of PTX into exosomes increased cytotoxicity more than 50 times in drug resistant MDCKMDR1 (Pgp+) cells. Next, our studies demonstrated a nearly complete co-localization of airway-delivered exosomes with cancer cells in a model of murine Lewis lung carcinoma pulmonary metastases, and a potent anticancer effect in this mouse model. We conclude that exoPTX holds significant potential for the delivery of various chemotherapeutics to treat drug resistant cancers. FROM THE CLINICAL EDITOR: Exosomes are membrane derived natural vesicles of ~40 - 200 nm size. They have been under extensive research as novel drug delivery vehicles. In this article, the authors developed exosome-based system to carry formulation of PTX and showed efficacy in the treatment of multi-drug resistant cancer cells. This novel system may be further developed to carry other chemotherapeutic agents in the future. PMID- 26586553 TI - Effects of Maternal Iodine Nutrition and Thyroid Status on Cognitive Development in Offspring: A Pilot Study. AB - BACKGROUND AND OBJECTIVE: Maternal iodine nutrition and thyroid status may influence neurocognitive development in offspring. This study investigated the effects on the intelligence quotient (IQ) of children born to mothers with different levels of iodine supplementation, with or without the administration of levothyroxine (LT4), prior to and during pregnancy. PATIENTS AND METHODS: This pilot, prospective, observational study included four study groups, each comprising 15 mother-child pairs, identified on the basis of maternal histories of iodized salt consumption and LT4 treatment prior to and during pregnancy. The groups were labeled as follows: iodine (I), no iodine (no-I), iodine + LT4 (I + T4), and no iodine + LT4 (no-I + T4). IQ tests were administered to children at 6 12 years of age with the Wechsler Intelligence Scale for Children-3rd Edition (WISC-III), with full-scale IQ (FSIQ), verbal IQ (VIQ), and performance IQ (PIQ) being evaluated. RESULTS: Children of I and I + T4 mothers had similar verbal, performance, and FSIQs, which were 14, 10, and 13 points higher, respectively, than children born to no-I and no-I + T4 mothers. A positive association was found between VIQ and maternal urinary iodine (beta = 1.023 [confidence interval (CI) 1.003-1.043]; p = 0.028), but not with maternal free thyroxine concentrations at any stage of pregnancy. Overall, the prevalence of borderline or defective cognitive function was more than threefold higher in the children of mothers not using iodized salt than of those mothers using it (76.9% vs. 23.1%, odds ratio 7.667 [CI 2.365-24.856], chi2 = 12.65; p = 0.0001). CONCLUSIONS: Neuro intellectual outcomes in children appear to be more dependent on their mothers' nutritional iodine status than on maternal thyroid function. These results support the growing body of evidence that prenatal, mild-to-moderate iodine deficiency adversely affects cognitive development later in life, with a seemingly greater impact on verbal abilities. PMID- 26586554 TI - Evaluation of Liver Metastases Using Contrast-Enhanced Ultrasound: Enhancement Patterns and Influencing Factors. AB - BACKGROUND/AIMS: To evaluate the enhancement patterns of liver metastases and their influencing factors using dynamic contrast-enhanced ultrasound (CEUS). METHODS: A total of 240 patients (139 male and 101 female; 58.5 +/- 11.2 years of age) diagnosed with liver metastases in our hospital were enrolled in this study to evaluate tumor characteristics using CEUS. A comparison of enhancement patterns with tumor size and primary tumor type was performed using the chi square test. The differences between quantitative variables were evaluated with the independent-sample t-test and one-way analysis of variance. RESULTS: The enhancement patterns of liver metastases on CEUS were categorized as diffuse homogeneous hyperenhancement (133/240, 55.4%), rim-like hyperenhancement (80/240, 33.3%), heterogeneous hyperenhancement (10/240, 4.2%), and isoenhancement (17/240, 7.1%). There were significant differences in the enhancement patterns during the arterial phase based on the nodule size (p=0.001). A total of 231 of the nodules showed complete washout during the portal phase, and 237 nodules were hypoenhanced during the delayed phase. The washout time was correlated with tumor vascularity, with a longer washout time observed in hypervascular metastases compared to hypovascular metastases (p=0.033). CONCLUSIONS: Diffuse homogeneous hyperenhancement followed by rapid washout was the most common enhancement pattern of liver metastases on CEUS and was affected by the nodule size and tumor vascularity. Small metastases were prone to show diffuse homogeneous hyperenhancement. Hypervascular metastases showed a significantly longer washout time compared to hypovascular metastases. PMID- 26586555 TI - Uh, Um, and Autism: Filler Disfluencies as Pragmatic Markers in Adolescents with Optimal Outcomes from Autism Spectrum Disorder. AB - Filler disfluencies--uh and um--are thought to serve distinct discourse functions. We examined fillers in spontaneous speech by youth with autism spectrum disorder (ASD), who struggle with pragmatic language, and by youth with ASD who have achieved an 'optimal outcome' (OO), as well as in peers with typical development (TD). While uh rates did not differ, participants with ASD produced um less frequently than OO or TD groups. Um rate was associated with autism symptom severity, but not executive function or language abilities, suggesting that um serves a pragmatic, listener-oriented function. Moreover, in contrast to minimal production in ASD, the typical OO um production substantiates the normalization of subtle social communication in this population. PMID- 26586556 TI - Social-Emotional Inhibition of Return in Children with Autism Spectrum Disorder Versus Typical Development. AB - In typical development there is a bias to orient visual attention to social information. Children with ASD do not reliably demonstrate this bias, and the role of attention orienting has not been well studied. We examined attention orienting via the inhibition of return (IOR) mechanism in a spatial cueing task using social-emotional cues; we studied 8- to 17-year-old children with ASD (n = 41) and typically developing controls (TDC) (n = 25). The ASD group exhibited a significantly stronger IOR effect than the TDC group, and the IOR effect correlated positively with social impairments but was unrelated to co-occurring ADHD or anxiety symptoms. The results provide evidence of an early altered attention mechanism that is associated with to core social deficits in ASD. PMID- 26586557 TI - Endurance Exercise and the Heart: Friend or Foe? AB - Although low- to moderate-intensity exercise has well-known cardiovascular benefits, it has been increasingly suggested that prolonged strenuous endurance exercise (SEE) could have potential deleterious cardiac effects. In effect, the term 'cardiac overuse injury' (or 'over-exercise') has been recently reported to group all the possible deleterious cardiac consequences of repeated exposure to SEE or 'over-exercise'. In this article, we provide a balanced overview of the current state of knowledge regarding the 'pros' and 'cons' of SEE from a cardiological point of view. PMID- 26586558 TI - Effects of L-dopa priming on cortical high beta and high gamma oscillatory activity in a rodent model of Parkinson's disease. AB - Prolonged L-dopa treatment in Parkinson's disease (PD) often leads to the expression of abnormal involuntary movements known as L-dopa-induced dyskinesia. Recently, dramatic 80 Hz oscillatory local field potential (LFP) activity within the primary motor cortex has been linked to dyskinetic symptoms in a rodent model of PD and attributed to stimulation of cortical dopamine D1 receptors. To characterize the relationship between high gamma (70-110 Hz) cortical activity and the development of L-dopa-induced dyskinesia, cortical LFP and spike signals were recorded in hemiparkinsonian rats treated with L-dopa for 7 days, and dyskinesia was quantified using the abnormal involuntary movements (AIMs) scale. The relationship between high gamma and dyskinesia was further probed by assessment of the effects of pharmacological agents known to induce or modulate dyskinesia expression. Findings demonstrate that AIMs and high gamma LFP power increase between days 1 and 7 of L-dopa priming. Notably, high beta (25-35 Hz) power associated with parkinsonian bradykinesia decreased as AIMs and high gamma LFP power increased during priming. After priming, rats were treated with the D1 agonist SKF81297 and the D2 agonist quinpirole. Both dopamine agonists independently induced AIMs and high gamma cortical activity that were similar to that induced by L-dopa, showing that this LFP activity is neither D1 nor D2 receptor specific. The serotonin 1A receptor agonist 8-OH-DPAT reduced L-dopa- and DA agonist-induced AIMs and high gamma power to varying degrees, while the serotonin 1A antagonist WAY100635 reversed these effects. Unexpectedly, as cortical high gamma power increased, phase locking of cortical pyramidal spiking to high gamma oscillations decreased, raising questions regarding the neural substrate(s) responsible for high gamma generation and the functional correlation between high gamma and dyskinesia. PMID- 26586559 TI - Pathogenesis of severe ataxia and tremor without the typical signs of neurodegeneration. AB - Neurological diseases are especially devastating when they involve neurodegeneration. Neuronal destruction is widespread in cognitive disorders such as Alzheimer's and regionally localized in motor disorders such as Parkinson's, Huntington's, and ataxia. But, surprisingly, the onset and progression of these diseases can occur without neurodegeneration. To understand the origins of diseases that do not have an obvious neuropathology, we tested how loss of CAR8, a regulator of IP3R1-mediated Ca(2+)-signaling, influences cerebellar circuit formation and neural function as movement deteriorates. We found that faulty molecular patterning, which shapes functional circuits called zones, leads to alterations in cerebellar wiring and Purkinje cell activity, but not to degeneration. Rescuing Purkinje cell function improved movement and reducing their Ca(2+) influx eliminated ectopic zones. Our findings in Car8(wdl) mutant mice unveil a pathophysiological mechanism that may operate broadly to impact motor and non-motor conditions that do not involve degeneration. PMID- 26586560 TI - Temozolomide for aggressive ACTH pituitary tumors: failure of a second course of treatment. AB - INTRODUCTION: Temozolomide (TMZ) is an oral alkylating agent that has been used over the past 8 years to treat aggressive pituitary tumors resistant to conventional therapy. To date, only 25 patients treated with TMZ for ACTH producing pituitary tumors (14 adenomas and 11 carcinomas) have been reported. MATERIALS AND METHODS: We present a retrospective review of the medical records of three patients with aggressive ACTH producing adenomas treated with TMZ. In the three cases there was evidence of progression to conventional therapy before starting TMZ. We used the conventional scheme for the treatment of gliomas until completing 7, 12 and 6 cycles respectively. Reduction in tumor size was evident after the 3rd, 5th and 4th cycle of TMZ and progression free survival was 25, 19 and more than 12 months in the three patients respectively. Improvement of the ocular and visual symptoms was evident after the 4th cycle of treatment in all cases. Normalization of urinary free cortisol levels was achieved after the 3rd and 9th cycle in the two cases with hypercortisolism. Two of the three patients received a second course of treatment when the disease progressed but it did not stop tumor progression. The principal side effects were G3 neutropenia, G1 and G2 thrombocytopenia, G1 lymphopenia, asthenia and nausea. CONCLUSION: The treatment with TMZ is effective and safe in patients with aggressive corticotrophin tumors resistant to conventional therapy. Nevertheless once the disease progresses, a second course of treatment does not seem to be effective. PMID- 26586561 TI - Trichoderma species occurring on wood with decay symptoms in mountain forests in Central Europe: genetic and enzymatic characterization. AB - The aim of this study was to explore the species diversity of Trichoderma obtained from samples of wood collected in the forests of the Gorce Mountains (location A), Karkonosze Mountains (location B) and Tatra Mountains (location C) in Central Europe and to examine the cellulolytic and xylanolytic activity of these species as an expression of their probable role in wood decay processes. The present study has led to the identification of the following species and species complex: Trichoderma atroviride P. Karst., Trichoderma citrinoviride Bissett, Trichoderma cremeum P. Chaverri & Samuels, Trichoderma gamsii Samuels & Druzhin., Trichoderma harzianum complex, Trichoderma koningii Oudem., Trichoderma koningiopsis Samuels, C. Suarez & H.C. Evans, Trichoderma longibrachiatum Rifai, Trichoderma longipile Bissett, Trichoderma sp. (Hypocrea parapilulifera B.S. Lu, Druzhin. & Samuels), Trichoderma viride Schumach. and Trichoderma viridescens complex. Among them, T. viride was observed as the most abundant species (53 % of all isolates) in all the investigated locations. The Shannon's biodiversity index (H), evenness (E), and the Simpson's biodiversity index (D) calculations for each location showed that the highest species diversity and evenness were recorded for location A-Gorce Mountains (H' = 1.71, E = 0.82, D = 0.79). The preliminary screening of 119 Trichoderma strains for cellulolytic and xylanolytic activity showed the real potential of all Trichoderma species originating from wood with decay symptoms to produce cellulases and xylanases-the key enzymes in plant cell wall degradation. PMID- 26586562 TI - Germline ablation of dermatan-4O-sulfotransferase1 reduces regeneration after mouse spinal cord injury. AB - Chondroitin/dermatan sulfate proteoglycans (CSPGs/DSPGs) are major components of the extracellular matrix. Their expression is generally upregulated after injuries to the adult mammalian central nervous system, which is known for its low ability to restore function after injury. Several studies support the view that CSPGs inhibit regeneration after injury, whereas the functions of DSPGs in injury paradigms are less certain. To characterize the functions of DSPGs in the presence of CSPGs, we studied young adult dermatan-4O-sulfotransferase1-deficient (Chst14(-/-)) mice, which express chondroitin sulfates (CSs), but not dermatan sulfates (DSs), to characterize the functional outcome after severe compression injury of the spinal cord. In comparison to their wild-type (Chst14(+/+)) littermates, regeneration was reduced in Chst14(-/-) mice. No differences between genotypes were seen in the size of spinal cords, numbers of microglia and astrocytes neither in intact nor injured spinal cords after injury. Monoaminergic innervation and re-innervation of the spinal cord caudal to the lesion site as well as expression levels of glial fibrillary acidic protein (GFAP) and myelin basic protein (MBP) were similar in both genotypes, independent of whether they were injured and examined 6weeks after injury or not injured. These results suggest that, in contrast to CSPGs, DSPGs, being the products of Chst14 enzymatic activity, promote regeneration after injury of the adult mouse central nervous system. PMID- 26586563 TI - Fixation of skin grafts in total and extensive defects of the scalp. PMID- 26586564 TI - Association between funding, risk of bias, and outcome of randomised controlled trials in oral and maxillofacial surgery. AB - The influence of funding on the main outcome of a random control trial (RCT) is important, as it could potentially lead to bias towards industry, and results that are too optimistic. We investigated the association between funding, the published outcome, and the risk of bias in trials in oral and maxillofacial surgery (OMFS) published from January 2000 to May 2013 listed in PubMed. The methods used were scored using the risk of bias items given in a Delphi List. Sources of funding were recorded and categorised five ways: not funded, funded by industry, not funded by industry, supported by industry, and source of funds not clear. A total of 390 RCT met the inclusion criteria, and there was a correlation between funding and favourable main outcomes, although this was not significant. There was no correlation between the risk of bias and favourable results of the main outcome of a trial, or between the risk of bias and the reported source of funding in post-hoc analysis. We were unable to show a significant correlation between funding and a higher likelihood of a favourable result for the primary outcome in RCT in OMFS. We also failed to show a significant correlation between the risk of bias of a trial and its main outcome. In contrast, the source of funding proved to affect the risk of bias of a trial significantly, although not in post-hoc analysis. Funded trials were better organised, and so had a lower risk of bias. PMID- 26586565 TI - Role of lipid rafts in neuronal differentiation of dental pulp-derived stem cells. AB - Human dental pulp-derived stem cells (hDPSCs) are characterized by a typical fibroblast-like morphology. They express specific markers for mesenchymal stem cells and are capable of differentiation into osteoblasts, adipoblasts and neurons in vitro. Previous studies showed that gangliosides are involved in the induction of early neuronal differentiation of hDPSCs. This study was undertaken to investigate the role of lipid rafts in this process. Lipid rafts are signaling microdomains enriched in glycosphingolipids, cholesterol, tyrosine kinase receptors, mono- or heterotrimeric G proteins and GPI-anchored proteins. We preliminary showed that established cells expressed multipotent mesenchymal stromal-specific surface antigens. Then, we analyzed the distribution of lipid rafts, revealing plasma membrane microdomains with GM2 and EGF-R enrichment. Following stimulation with EGF/bFGF, neuronal differentiation was observed. To analyze the functional role of lipid rafts in EGF/bFGF-induced hDPSCs differentiation, cells were preincubated with lipid raft affecting agents, i.e. [D]-PDMP or methyl-beta-cyclodextrin. These compounds significantly prevented neuronal-specific antigen expression, as well as Akt and ERK 1/2 phosphorylation, induced by EGF/bFGF, indicating that lipid raft integrity is essential for EGF/bFGF-induced hDPSCs differentiation. These results suggest that lipid rafts may represent specific chambers, where multimolecular signaling complexes, including lipids (gangliosides, cholesterol) and proteins (EGF-R), play a role in hDPSCs differentiation. PMID- 26586566 TI - Identification and interplay of sequence specific DNA binding proteins involved in regulation of human Pregnane and Xenobiotic Receptor gene. AB - Pregnane and Xenobiotic Receptor (PXR), a member of nuclear receptor superfamily, acts as a 'xenosensor' in our body and modulates a network of genes involved in xenobiotic metabolism and elimination. Expression levels of PXR in certain metabolic disorders including cancer are reported to be altered and its induced expression is associated with the development of resistance towards chemotherapy and adverse drug-drug interactions. Though the transcriptional regulation of PXR target genes have been elucidated in significant details, the structure and functional control of PXR promoter itself remains inadequately explored. In this work, we identify a Composite Element (CE) located within the proximal PXR promoter region that consists of multiple overlapping cis-elements and demonstrated that CE interacts specifically with some critical nuclear proteins. Subsequent DNA-protein interaction studies revealed mutually exclusive interactions on CE occurring between Sp1 and two unidentified DNA binding proteins with molecular masses of 50 and 54kDa. Here, we report the identification of 54kDa CE binding protein as a heterogeneous nuclear ribonucleoprotein K (hnRNPK) and demonstrate the effect of hnRNP K and Sp1 on PXR promoter transcriptional activity. Overall, the study indicates that PXR gene is tightly regulated to maintain a low receptor level. PMID- 26586567 TI - Impact of QTL minor allele frequency on genomic evaluation using real genotype data and simulated phenotypes in Japanese Black cattle. AB - BACKGROUND: Genetic variance that is not captured by single nucleotide polymorphisms (SNPs) is due to imperfect linkage disequilibrium (LD) between SNPs and quantitative trait loci (QTLs), and the extent of LD between SNPs and QTLs depends on different minor allele frequencies (MAF) between them. To evaluate the impact of MAF of QTLs on genomic evaluation, we performed a simulation study using real cattle genotype data. METHODS: In total, 1368 Japanese Black cattle and 592,034 SNPs (Illumina BovineHD BeadChip) were used. We simulated phenotypes using real genotypes under different scenarios, varying the MAF categories, QTL heritability, number of QTLs, and distribution of QTL effect. After generating true breeding values and phenotypes, QTL heritability was estimated and the prediction accuracy of genomic estimated breeding value (GEBV) was assessed under different SNP densities, prediction models, and population size by a reference test validation design. RESULTS: The extent of LD between SNPs and QTLs in this population was higher in the QTLs with high MAF than in those with low MAF. The effect of MAF of QTLs depended on the genetic architecture, evaluation strategy, and population size in genomic evaluation. In genetic architecture, genomic evaluation was affected by the MAF of QTLs combined with the QTL heritability and the distribution of QTL effect. The number of QTL was not affected on genomic evaluation if the number of QTL was more than 50. In the evaluation strategy, we showed that different SNP densities and prediction models affect the heritability estimation and genomic prediction and that this depends on the MAF of QTLs. In addition, accurate QTL heritability and GEBV were obtained using denser SNP information and the prediction model accounted for the SNPs with low and high MAFs. In population size, a large sample size is needed to increase the accuracy of GEBV. CONCLUSION: The MAF of QTL had an impact on heritability estimation and prediction accuracy. Most genetic variance can be captured using denser SNPs and the prediction model accounted for MAF, but a large sample size is needed to increase the accuracy of GEBV under all QTL MAF categories. PMID- 26586568 TI - Autophagy is dispensable for B-cell development but essential for humoral autoimmune responses. AB - To gain new insight into the role of B-cell autophagy, we generated two novel mouse models deficient for the autophagy-related gene (Atg)5, one from the outset pro-B cell stage (Atg5(f/-) Mb1 cre) and the other in mature B cells only (Atg5(f/-) CD21 cre). We show that autophagy is dispensable for pro- to pre-B cell transition, but necessary at a basal level to maintain normal numbers of peripheral B cells. It appears non-essential for B-cell activation under B-cell receptor stimulation but required for their survival after lipopolysaccharide stimulation that drives plasmablast differentiation and for specific IgM production after immunization. Results obtained using Atg5(f/-) CD21 cre * C57BL/6(lpr/lpr) autoimmune-prone mice show that B-cell autophagy is involved in the maintenance of anti-nuclear antibody secretion, elevated number of long-lived plasma cells, and sustains IgG deposits in the kidneys. Thus, treatments specifically targeting autophagy might be beneficial in systemic autoimmune diseases. PMID- 26586569 TI - Downregulation of COMMD1 by miR-205 promotes a positive feedback loop for amplifying inflammatory- and stemness-associated properties of cancer cells. AB - Sustained activation of nuclear factor-kappaB (NF-kappaB) in cancer cells has been shown to promote inflammation, expansion of cancer stem cell (CSC) population, and tumor development. In contrast, recent studies reveal that CSCs exhibit increased inflammation due to constitutive NF-kappaB activation; however, the underlying molecular mechanism remains unclear. In the present study, the analysis of microarray data revealed upregulation of NF-kappaB-regulated pro inflammatory genes and downregulation of copper metabolism MURR1 domain containing 1 (COMMD1) during the enrichment for stemness in SAS head and neck squamous-cell carcinoma (HNSCC) cells. The 3'-UTR of COMMD1 mRNA contains microRNA (miR)-205 target site. Parallel studies with HNSCC and NSCLC cells indicated that miR-205 is upregulated upon NF-kappaB activation and suppresses COMMD1 expression in stemness-enriched cancer cells. COMMD1 negatively regulates the inflammatory responses induced by TLR agonists, IL-1beta, and TNF-alpha by targeting RelA for degradation. The shRNA-mediated downregulation of COMMD1 in cancer cells enhanced inflammatory response, generating favorable conditions for macrophage recruitment. In addition, genes associated with stemness were also upregulated in these cells, which exhibited increased potential for anchorage independent growth. Furthermore, COMMD1 downregulation promoted in vivo tumorigenesis and tumor growth, and tumors derived from COMMD1-knockdown cells displayed elevated level of NF-kappaB activation, increased expression of inflammatory- and stemness-associated genes, and contain expanded population of tumor-associated leukocytes and stemness-enriched cancer cells. These results suggest that COMMD1 downregulation by miR-205 promotes tumor development by modulating a positive feedback loop that amplifies inflammatory- and stemness associated properties of cancer cells. PMID- 26586570 TI - Activation of SK2 channels preserves ER Ca2+ homeostasis and protects against ER stress-induced cell death. AB - Alteration of endoplasmic reticulum (ER) Ca(2+) homeostasis leads to excessive cytosolic Ca(2+) accumulation and delayed neuronal cell death in acute and chronic neurodegenerative disorders. While our recent studies established a protective role for SK channels against excessive intracellular Ca(2+) accumulation, their functional role in the ER has not been elucidated yet. We show here that SK2 channels are present in ER membranes of neuronal HT-22 cells, and that positive pharmacological modulation of SK2 channels with CyPPA protects against cell death induced by the ER stressors brefeldin A and tunicamycin. Calcium imaging of HT-22 neurons revealed that elevated cytosolic Ca(2+) levels and decreased ER Ca(2+) load during sustained ER stress could be largely prevented by SK2 channel activation. Interestingly, SK2 channel activation reduced the amount of the unfolded protein response transcription factor ATF4, but further enhanced the induction of CHOP. Using siRNA approaches we confirmed a detrimental role for ATF4 in ER stress, whereas CHOP regulation was dispensable for both, brefeldin A toxicity and CyPPA-mediated protection. Cell death induced by blocking Ca(2+) influx into the ER with the SERCA inhibitor thapsigargin was not prevented by CyPPA. Blocking the K(+) efflux via K(+)/H(+) exchangers with quinine inhibited CyPPA-mediated neuroprotection, suggesting an essential role of proton uptake and K(+) release in the SK channel-mediated neuroprotection. Our data demonstrate that ER SK2 channel activation preserves ER Ca(2+) uptake and retention which determines cell survival in conditions where sustained ER stress contributes to progressive neuronal death. PMID- 26586571 TI - Catch me if you can: targeting the mitochondrial permeability transition pore in myocardial infarction. PMID- 26586572 TI - Cleavage of DAP5 by coxsackievirus B3 2A protease facilitates viral replication and enhances apoptosis by altering translation of IRES-containing genes. AB - Cleavage of eukaryotic translation initiation factor 4G (eIF4G) by enterovirus proteases during infection leads to the shutoff of cellular cap-dependent translation, but does not affect the initiation of cap-independent translation of mRNAs containing an internal ribosome entry site (IRES). Death-associated protein 5 (DAP5), a structural homolog of eIF4G, is a translation initiation factor specific for IRES-containing mRNAs. Coxsackievirus B3 (CVB3) is a positive single stranded RNA virus and a primary causal agent of human myocarditis. Its RNA genome harbors an IRES within the 5'-untranslated region and is translated by a cap-independent, IRES-driven mechanism. Previously, we have shown that DAP5 is cleaved during CVB3 infection. However, the protease responsible for cleavage, cleavage site and effects on the translation of target genes during CVB3 infection have not been investigated. In the present study, we demonstrated that viral protease 2A but not 3C is responsible for DAP5 cleavage, generating 45- and 52-kDa N- (DAP5-N) and C-terminal (DAP5-C) fragments, respectively. By site directed mutagenesis, we found that DAP5 is cleaved at amino acid G434. Upon cleavage, DAP5-N largely translocated to the nucleus at the later time points of infection, whereas the DAP5-C largely remained in the cytoplasm. Overexpression of these DAP5 truncates demonstrated that DAP5-N retained the capability of initiating IRES-driven translation of apoptosis-associated p53, but not the prosurvival Bcl-2 (B-cell lymphoma 2) when compared with the full-length DAP5. Similarly, DAP5-N expression promoted CVB3 replication and progeny release; on the other hand, DAP5-C exerted a dominant-negative effect on cap-dependent translation. Taken together, viral protease 2A-mediated cleavage of DAP5 results in the production of two truncates that exert differential effects on protein translation of the IRES-containing genes, leading to enhanced host cell death. PMID- 26586573 TI - The NAD(+) salvage pathway modulates cancer cell viability via p73. AB - The involvement of the nicotinamide adenine dinucleotide (NAD(+)) salvage pathway in cancer cell survival is poorly understood. Here we show that the NAD(+) salvage pathway modulates cancer cell survival through the rarely mutated tumour suppressor p73. Our data show that pharmacological inhibition or knockdown of nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting enzyme in the NAD(+) salvage pathway, enhances autophagy and decreases survival of cancer cells in a p53-independent manner. Such NAMPT inhibition stabilizes p73 independently of p53 through increased acetylation and decreased ubiquitination, resulting in enhanced autophagy and cell death. These effects of NAMPT inhibition can be effectively reversed using nicotinamide mononucleotide (NMN), the enzymatic product of NAMPT. Similarly, knockdown of p73 also decreases NAMPT inhibition induced autophagy and cell death, whereas overexpression of p73 alone enhances these effects. We show that the breast cancer cell lines (MCF-7, MDA-MB-231 and MDA-MB-468) harbour significantly higher levels of NAMPT and lower levels of p73 than does the normal cell line (MCF-10A), and that NAMPT inhibition is cytotoxic exclusively to the cancer cells. Furthermore, data from 176 breast cancer patients demonstrate that higher levels of NAMPT and lower levels of p73 correlate with poorer patient survival, and that high-grade tumours have significantly higher NAMPT/p73 mRNA ratios. Therefore, the inverse relationship between NAMPT and p73 demonstrable in vitro is also reflected from the clinical data. Taken together, our studies reveal a new NAMPT-p73 nexus that likely has important implications for cancer diagnosis, prognosis and treatment. PMID- 26586574 TI - Tissue-specific control of midbody microtubule stability by Citron kinase through modulation of TUBB3 phosphorylation. AB - Cytokinesis, the physical separation of daughter cells at the end of cell cycle, is commonly considered a highly stereotyped phenomenon. However, in some specialized cells this process may involve specific molecular events that are still largely unknown. In mammals, loss of Citron-kinase (CIT-K) leads to massive cytokinesis failure and apoptosis only in neuronal progenitors and in male germ cells, resulting in severe microcephaly and testicular hypoplasia, but the reasons for this specificity are unknown. In this report we show that CIT-K modulates the stability of midbody microtubules and that the expression of tubulin beta-III (TUBB3) is crucial for this phenotype. We observed that TUBB3 is expressed in proliferating CNS progenitors, with a pattern correlating with the susceptibility to CIT-K loss. More importantly, depletion of TUBB3 in CIT-K dependent cells makes them resistant to CIT-K loss, whereas TUBB3 overexpression increases their sensitivity to CIT-K knockdown. The loss of CIT-K leads to a strong decrease in the phosphorylation of S444 on TUBB3, a post-translational modification associated with microtubule stabilization. CIT-K may promote this event by interacting with TUBB3 and by recruiting at the midbody casein kinase 2alpha (CK2alpha) that has previously been reported to phosphorylate the S444 residue. Indeed, CK2alpha is lost from the midbody in CIT-K-depleted cells. Moreover, expression of the nonphosphorylatable TUBB3 mutant S444A induces cytokinesis failure, whereas expression of the phospho-mimetic mutant S444D rescues the cytokinesis failure induced by both CIT-K and CK2alpha loss. Altogether, our findings reveal that expression of relatively low levels of TUBB3 in mitotic cells can be detrimental for their cytokinesis and underscore the importance of CIT-K in counteracting this event. PMID- 26586575 TI - Tripartite containing motif 32 modulates proliferation of human neural precursor cells in HIV-1 neurodegeneration. AB - In addition to glial cells, HIV-1 infection occurs in multipotent human neural precursor cells (hNPCs) and induces quiescence in NPCs. HIV-1 infection of the brain alters hNPC stemness, leading to perturbed endogenous neurorestoration of the CNS following brain damage by HIV-1, compounding the severity of dementia in adult neuroAIDS cases. In pediatric neuroAIDS cases, HIV-1 infection of neural stem cell can lead to delayed developmental milestones and impaired cognition. Using primary cultures of human fetal brain-derived hNPCs, we gained novel insights into the role of a neural stem cell determinant, tripartite containing motif 32 (TRIM32), in HIV-1 Tat-induced quiescence of NPCs. Acute HIV-1 Tat treatment of hNPCs resulted in proliferation arrest but did not induce differentiation. Cellular localization and levels of TRIM32 are critical regulators of stemness of NPCs. HIV-1 Tat exposure increased nuclear localization and levels of TRIM32 in hNPCs. The in vitro findings were validated by studying TRIM32 localization and levels in frontal cortex of HIV-1-seropositive adult patients collected at post mortem as well as by infection of hNPCs by HIV-1. We observed increased percentage of cells with nuclear localization of TRIM32 in the subventricular zone (SVZ) as compared with age-matched controls. Our quest for probing into the mechanisms revealed that TRIM32 is targeted by miR-155 as downregulation of miR-155 by HIV-1 Tat resulted in upregulation of TRIM32 levels. Furthermore, miR-155 or siRNA against TRIM32 rescued HIV-1 Tat-induced quiescence in NPCs. Our findings suggest a novel molecular cascade involving miR-155 and TRIM32 leading to HIV-1 Tat-induced attenuated proliferation of hNPCs. The study also uncovered an unidentified role for miR-155 in modulating human neural stem cell proliferation, helping in better understanding of hNPCs and diseased brain. PMID- 26586576 TI - Resequencing of the common marmoset genome improves genome assemblies and gene coding sequence analysis. AB - The first draft of the common marmoset (Callithrix jacchus) genome was published by the Marmoset Genome Sequencing and Analysis Consortium. The draft was based on whole-genome shotgun sequencing, and the current assembly version is Callithrix_jacches-3.2.1, but there still exist 187,214 undetermined gap regions and supercontigs and relatively short contigs that are unmapped to chromosomes in the draft genome. We performed resequencing and assembly of the genome of common marmoset by deep sequencing with high-throughput sequencing technology. Several different sequence runs using Illumina sequencing platforms were executed, and 181 Gbp of high-quality bases including mate-pairs with long insert lengths of 3, 8, 20, and 40 Kbp were obtained, that is, approximately 60* coverage. The resequencing significantly improved the MGSAC draft genome sequence. The N50 of the contigs, which is a statistical measure used to evaluate assembly quality, doubled. As a result, 51% of the contigs (total length: 299 Mbp) that were unmapped to chromosomes in the MGSAC draft were merged with chromosomal contigs, and the improved genome sequence helped to detect 5,288 new genes that are homologous to human cDNAs and the gaps in 5,187 transcripts of the Ensembl gene annotations were completely filled. PMID- 26586577 TI - Type II Anion Relay Chemistry: Exploiting Bifunctional Weinreb Amide Linchpins for the One-Pot Synthesis of Differentiated 1,3-Diketones, Pyrans, and Spiroketals. AB - The design, synthesis, and validation of new highly effective bifunctional linchpins for type II anion relay chemistry (ARC) has been achieved. The mechanistically novel negative-charge migration that comprises the Brook rearrangement is now initiated by a stabilized tetrahedral intermediate, which is generated by nucleophilic addition to a Weinreb amide, rather than by a simple oxyanion that is generated from an epoxide. As a result, the linchpin preserves the carbonyl functionality in the ARC adducts, thus permitting access to functionally complex systems in a single flask without the need for further chemical manipulations. This tactic was validated with the one-pot preparation of monoprotected 1,3-diketones as well as pyran and spiroketal scaffolds, depending on the choice of nucleophile, electrophile, and work-up conditions. PMID- 26586578 TI - The role of brain-derived neurotrophic factor in learned fear processing: an awake rat fMRI study. AB - Brain-derived neurotrophic factor (BDNF) signaling is implicated in the etiology of many psychiatric disorders associated with altered emotional processing. Altered peripheral (plasma) BDNF levels have been proposed as a biomarker for neuropsychiatric disease risk in humans. However, the relationship between peripheral and central BDNF levels and emotional brain activation is unknown. We used heterozygous BDNF knockdown rats (BDNF(+/-)) to examine the effects of genetic variation in the BDNF gene on peripheral and central BDNF levels and emotional brain activation as assessed by awake functional magnetic resonance imaging (fMRI). BDNF(+/-) and control rats were trained to associate a flashing light (conditioned stimulus; CS) with foot-shock, and brain activation in response to the CS was measured 24 h later in awake rats using fMRI. Central and peripheral BDNF levels were decreased in BDNF(+/-) rats compared with control rats. Activation of fear circuitry (amygdala, periaqueductal gray, granular insular) was seen in control animals; however, activation of this circuitry was absent in BDNF(+/-) animals. Behavioral experiments confirmed impaired conditioned fear responses in BDNF(+/-) rats, despite intact innate fear responses. These data confirm a positive correlation [r = 0.86, 95% confidence interval (0.55, 0.96); P = 0.0004] between peripheral and central BDNF levels and indicate a functional relationship between BDNF levels and emotional brain activation as assessed by fMRI. The results demonstrate the use of rodent fMRI as a sensitive tool for measuring brain function in preclinical translational studies using genetically modified rats and support the use of peripheral BDNF as a biomarker of central affective processing. PMID- 26586580 TI - A Comparison of PECS and iPad to Teach Requesting to Pre-schoolers with Autistic Spectrum Disorders. AB - Few studies have compared the efficacy of the Picture Exchange Communication System (PECS) and iPads used as speech generating devices (SGDs), and none have targeted preschoolers. This study compares the relative efficacy of PECS and an iPad/SGD with three preschool-aged children with autism spectrum disorder and limited functional speech who lived in Malta. The study utilized an adapted alternating treatment design embedded in a multiple baseline design, with requesting of reinforcers as the dependent variable. Visual analysis of the results indicated that all participants required more prompted trials and sessions for the iPad/SGD condition. All participants learned a three step navigational sequence on the iPad. Participant preference probes were inconclusive and were not linked to speed of acquisition of requesting skills. Results suggest that both PECS and an iPad could be appropriate for teaching requesting skills to beginning communicators. PMID- 26586581 TI - A carpet-like polyposis: An unusual endoscopic image of stomach in patients with familial adenomatous polyposis. PMID- 26586579 TI - Diagnostic accuracy and clinical relevance of an inflammatory biomarker panel for sepsis in adult critically ill patients. AB - The objective of this study was to assess the diagnostic accuracy of C-reactive protein (CRP), procalcitonin (PCT), and cellular immune markers levels in sepsis. This was a prospective observational study in adult intensive care unit (ICU) patients, between 2012 and 2014. The 8-color flow cytometric biomarker panel included CD64, CD163, and HLA-DR. Index test results were compared with sepsis, using receiver operating characteristic curve analyses. Multivariate logistic regression assessed the relationship of sets of markers with the probability of sepsis. Of 219 enrolled patients, 120 had sepsis. C-statistic was the highest for CRP (0.86) followed by neutrophil CD64 expression (0.83), procalcitonin (0.82), and Acute Physiology and Chronic Health Evaluation (APACHE) IV (0.72). After adjustment for APACHE IV, the combination of CRP, PCT, and neutrophil CD64 measure remained a significant predictor of sepsis with an excellent AUC (0.90). In a targeted ICU population at increased risk of sepsis, CRP, PCT, and neutrophil CD64 combined improve the diagnostic accuracy of sepsis. PMID- 26586582 TI - Hematotoxic and biochemical effects of UVA on the Egyptian toad (Bufo regularis). AB - PURPOSE: To study the adverse impacts of ultraviolet radiation-A (UVA 320-400 nm) on some hematological and biochemical parameters of Bufo regularis was considered. MATERIALS AND METHODS: Samples were classified into four groups: (i) Control; (ii) ultraviolet radiation (UVR)-treated group (for 3 days/for 15 min/day); (iii) UVR-treated group (for 3 days/for 30 min/day); and (iv) (for 3 days/for 60 min/day). The destructive effects of UVA radiation was evaluated by red blood cells (RBC) count, hemoglobin content (Hb), hematocrite (Ht), erythrocytic indices, white blood cells (WBC) count, total protein, glucose, aspartic amino transferase (AST), alanine amino transferase (ALT), alkaline phosphatase (ALP), lactate dehyderogenase (LDH), glucose-6-phosphate dehyderogenase (G6PDH) and total bilribuin. RESULTS: No mortality was observed. However, some physiological effects after the exposure to UVA were reported. The UVA-induced malformations recorded in the red blood cells included crenated cells (Cr), Acanthocytes (Ac), tear drop-like cells (Tr) and sickle cells (Sk). CONCLUSION: The present study revealed the exposure to UVA from 15-60 min/day for three days could promote several biochemical and physiological disturbances as well as some changes in RBC. PMID- 26586583 TI - Effects of ankle foot orthoses on body functions and activities in people with floppy paretic ankle muscles: a systematic review. AB - BACKGROUND: People with floppy ankle muscles paresis use ankle foot orthoses to improve their walking ability. Ankle foot orthoses also limit ankle range of motion thereby introducing additional problems. Insight in effects of ankle foot orthoses on body functions and activities in people with floppy paretic ankle muscles aids in clinical decision making and may improve adherence. METHODS: Studies published before October 27th, 2014, were searched in Pubmed, Embase, Cinahl, and Cochrane Library. Studies evaluating effects of ankle foot orthoses on body functions and/or activities in people with floppy paretic ankle muscles were included. Studies solely focusing on people with spastic paretic ankle muscles were excluded. Study quality was assessed using a custom-made scale. Body functions and activities were defined according to the International Classification of Functioning, Disability and Health. FINDINGS: Twenty-four studies were included, evaluating 394 participants. Participants were grouped according to paresis type (i) dorsiflexor paresis, (ii) plantar flexor paresis, (iii) both dorsiflexor and plantar flexor paresis. Dorsal, circular, and elastic ankle foot orthoses increased dorsiflexion during swing (by 4-6 degrees , group i). Physical comfort with dorsal ankle foot orthoses was lower than that with circular ankle foot orthoses (groups i and iii). Dorsal ankle foot orthoses increased push-off moment (by 0.2-0.5 Nm/kg), increased walking efficiency, and decreased ankle range of motion (by 12-30 degrees , groups ii and iii). INTERPRETATION: People with dorsiflexor paresis benefit more from circular and elastic ankle foot orthoses while people with plantar flexor paresis (and dorsiflexor paresis) benefit more from dorsal ankle foot orthoses. PMID- 26586584 TI - [Ultrasound-guided techniques, also a very useful tool for nursing]. PMID- 26586585 TI - [Bullous haemorrhagic dermatosis at distant sites due to enoxaparin: An uncommon secondary effect in an anticoagulated oncology patient]. PMID- 26586587 TI - Arthroscopic osteochondroplasty in patients with mild slipped capital femoral epiphysis after in situ fixation. AB - PURPOSE: Mild slipped capital femoral epiphyses (SCFE) nevertheless show significant femoral head-neck deformities which may put cartilage and acetabular labrum at risk. Whether this deformity can be restored to normal has not yet been described in the literature. METHODS: In a prospective follow-up study, 14 patients with mild SCFE underwent in situ fixation with a single 6.5-mm cancellous, partially threaded screw. In 14 patients arthroscopic osteochondroplasty was performed, and in 13 patients pre- and postoperative measurements of the alpha-angle were made using antero-superior radial magnetic resonance imaging. RESULTS: After arthroscopic osteochondroplasty, the mean alpha angle decreased from 57 degrees (range 50 degrees -74 degrees ) to 37 degrees (range 32 degrees -47 degrees ; p < 0.001). Six patients showed beginning degenerative intra-articular changes (four antero-superior cartilage and three antero-superior labrum lesions) at the time of hip arthroscopy. No intra operative complications occurred. In one patient, arthroscopic debridement was necessary due to arthrofibrosis and persistent pain. CONCLUSION: Arthroscopic osteochondroplasty can successfully correct the antero-superior alpha-angle in patients with mild SCFE to normal values. Clinical randomized controlled studies with long-term follow-up are required to find evidence of improved functional and radiographic mid- and long-term outcome compared to in situ fixation alone. PMID- 26586588 TI - Biological Evaluation (In Vitro and In Vivo) of Bilayered Collagenous Coated (Nano Electrospun and Solid Wall) Chitosan Membrane for Periodontal Guided Bone Regeneration. AB - The application of barrier membranes in guided bone regeneration (GBR) has become a commonly used surgical technique in periodontal research. The objectives of this study were to evaluate the in vitro biocompatibility and osteogenic differentiation of mesenchymal stem cells (MSCs) on two different collagenous coatings (nano electrospun fibrous vs. solid wall) of bilayered collagen/chitosan membrane and their histological evaluation on bone regeneration in rabbit calvarial defects. It was found that chitosan-nano electrospun collagen (CNC) membranes had higher proliferation/metabolic activity compared to the chitosan collagen (CC) and pristine chitosan membranes. The qRT-PCR analysis demonstrated the CNC membranes induced significant expression of osteogenic genes (Osteocalcin, RUNX2 and Col-alpha1) in MSCs. Moreover, higher calcium content and alkaline phosphatase activity of MSCs were observed compared to the other groups. Histologic and histomorphometric evaluations were performed on the uncovered (negative control) as well as covered calvarial defects of ten adult white rabbits with different membranes (CNC, CC, BioGide (BG, positive control)) at 1 and 2 months after surgery. More bone formation was detected in the defects covered with CNC and BG membranes than those covered by CC and the negative control. No inflammation and residual biomaterial particles were observed on the membrane surface or in the surrounding tissues in the surgical areas. These results suggest that bilayer CNC membrane can have the potential for use as a GBR membrane material facilitating bone formation. PMID- 26586589 TI - Hydrolysis of whey lactose by immobilized beta-galactosidase in a bioreactor with a spirally wound membrane. AB - The beta-galactosidase was covalently immobilized onto a modified polypropylene membrane, using glutaraldehyde. The optimal conditions for hydrolysis of lactose (4.7%) by immobilized beta-galactosidase in a batch process were determined 13.6 U enzyme activity, 40 degrees C, pH 6.8 and 10h. The obtained degree of hydrolysis was compared with results received by a free enzyme. It was found, that the lactose hydrolysis by an immobilized enzyme was 1.6 times more effective than the lactose hydrolysis by a free enzyme. It was determined that the stability of the immobilized enzyme was 2 times higher in comparison with the stability of free enzyme. The obtained immobilized system beta galactosidase/polypropylene membrane was applied to produce glucose-galactose syrup from waste whey. The whey characteristics and the different preliminary treatments of the whey were investigated. Then the whey lactose hydrolysis in a bioreactor by an immobilized enzyme on a spirally wound membrane was performed. The optimal membrane surface and the optimal flow rate of the whey through the membrane module were determined, respectively 100 cm(2) and 1.0 mL min(-1). After 10h, the degree of lactose hydrolysis was increased to 91%. The operation stability was studied. After 20th cycle the yield of bioreactor was 69.7%. PMID- 26586590 TI - Property enhancement of soy protein isolate-based films by introducing POSS. AB - To enhance the mechanical and water-resistant properties of soy protein isolate (SPI) based films, hydrophobic TriSilanolPhenyl polyhedral oligomeric silsesquioxanes (POSS) was incorporated to modify the SPI films. POSS has three SiOH groups in a molecular, which is employed to cross-link SPI with the help of 3-glycidoxypropyltrimethoxysilane (GPTMS). POSS is a structure of eight phenol groups, playing a critical role in improving the physical and mechanical properties. The X-ray diffraction (XRD) and attenuated total reflectance (ATR) Fourier transform infrared spectroscopy (FT-IR) were used to characterize the films. The degree of reaction of SiOH groups in the POSS was estimated to be 53.0% according with the absorbance of ATR FT-IR spectra. Although the elongation at break was reduced by 52.6%, the tensile modulus, tensile strength and 10% offset yield strength were significantly increased by 86.6%, 34.0% and 56.8%, respectively, due to the cross-linking reactions among SPI, GPTMS and POSS. The results of water-resistant tests showed that the 24-hour water absorption was dramatically reduced by 54.7%. PMID- 26586591 TI - Measurement and relevance of maximum metabolic rate in fishes. AB - Maximum (aerobic) metabolic rate (MMR) is defined here as the maximum rate of oxygen consumption (MO2max ) that a fish can achieve at a given temperature under any ecologically relevant circumstance. Different techniques exist for eliciting MMR of fishes, of which swim-flume respirometry (critical swimming speed tests and burst-swimming protocols) and exhaustive chases are the most common. Available data suggest that the most suitable method for eliciting MMR varies with species and ecotype, and depends on the propensity of the fish to sustain swimming for extended durations as well as its capacity to simultaneously exercise and digest food. MMR varies substantially (>10 fold) between species with different lifestyles (i.e. interspecific variation), and to a lesser extent (10 MUM) and non-ischemic metabolic crisis (lactate/pyruvate ratio [LPR] >40) as important components of secondary damage in severe traumatic brain injury (TBI). Spreading depolarizations (SD) are pathological waves that occur in many patients in the days following TBI and, in animal models, cause elevations in extracellular glutamate, increased anaerobic metabolism, and energy substrate depletion. Here, we examined the association of SD with changes in cerebral neurochemistry by placing a microdialysis probe alongside a subdural electrode strip in peri-lesional cortex of 16 TBI patients requiring neurosurgery. In 107 h (median; range: 76-117 h) of monitoring, 135 SDs were recorded in six patients. Glutamate (50 MUmol/L) and lactate (3.7 mmol/L) were significantly elevated on day 0 in patients with SD compared with subsequent days and with patients without SD, whereas pyruvate was decreased in the latter group on days 0 and 1 (two-way analysis of variance [ANOVA], p values <0.05). In patients with SD, both glutamate and LPR increased in a dose-dependent manner with the number of SDs in the microdialysis sampling period (0, 1, >=2 SD) [glutamate: 2.1->7.0->52.3 MUmol/L; LPR: 27.8->29.9->45.0, p values <0.05]. In these patients, there was a 10% probability of SD occurring when glutamate and LPR were in normal ranges, but a 60% probability when both variables were abnormal (>10 MUmol/L and >40 MUmol/L, respectively). Taken together with previous studies, these preliminary clinical results suggest SDs are a key pathophysiological process of secondary brain injury associated with non-ischemic glutamate excitotoxicity and severe metabolic crisis in severe TBI patients. PMID- 26586608 TI - A small n sequential multiple assignment randomized trial design for use in rare disease research. AB - BACKGROUND: Clinical trials in rare diseases are difficult to conduct due to the limited number of patients available with each disorder. We developed a Phase 2 trial which is a small n sequential multiple assignment randomized trial (snSMART) design to test several treatments for a rare disease for which no standard therapy exists. PURPOSE: This paper illustrates the design, sample size estimation and operating characteristics of an snSMART. METHODS: We investigate the performance of a class of weighted Z statistics via computer simulations. RESULTS: We demonstrate the increase in power over traditional single stage designs, and indicate how the power changes as a function of the weight given to each stage. CONCLUSION: The snSMART design is promising in a rare disease setting where several alternative treatments are under consideration and small sample sizes are necessary. PMID- 26586609 TI - Unconditional reference values for the amniotic fluid index measurement between 26w0d and 41w6d of gestation in low-risk pregnancies. AB - OBJECTIVE: To establish reference values for the amniotic fluid index (AFI) measurement between 26w0d and 41w6d of gestation in a Brazilian population. METHODS: We performed a cross-sectional study with 1984 low-risk singleton pregnant women between 26w0d and 41w6d of gestation. AFI was measured according to the technique proposed by Phelan et al. Maternal abdomen was divided into four quadrants using the umbilicus and linea nigra as landmarks. Single vertical pocket in each quadrant was measured and the AFI was generated by the sum of these four values without umbilical cord or fetal parts. All ultrasound exams were performed by only two experienced examiners. AFI was expressed as median, interquartile range, mean and ranges in each gestational age (GA) interval. Polynomial regressions were performed to obtain the best fit with adjustment by the determination coefficient (R(2)). RESULTS: Mean of AFI ranged from 14.0 +/- 4.1 cm (range, 9.7-14.0) at 26w0d to 8.3 +/- 4.7 cm (range, 1.9-16.5) at 41w6d, respectively. The best polynomial regression fit curve was a first-degree: AFI = 16.29-0.125*GA (R(2) = 0.01). According the scatterplot, AFI values practically did not vary with advancing GA. CONCLUSION: Reference values for the AFI measurement between 26w0d and 41w6d of gestation in a low-risk Brazilian population were established. PMID- 26586610 TI - A Double-Blind Placebo-Controlled Trial of Liquid Thyroxine Ingested at Breakfast: Results of the TICO Study. AB - BACKGROUND: Levothyroxine (LT4) is the recommended treatment for millions of hypothyroid patients. Current guidelines recommend that LT4 tablets be taken in a fasting state, but inability to adhere to this often leads to poor therapy compliance. METHODS: A randomized, double-blind, placebo-controlled, crossover trial was conducted in previously untreated hypothyroid patients randomly assigned to receive an oral solution of LT4 either at least 30 minutes before breakfast or directly at breakfast time. Each patient completed two six-week treatment periods, with different timing of active LT4 administration: placebo before breakfast and active LT4 at breakfast, or vice versa. At the end of each period, thyrotropin (TSH), free thyroxine (fT4), and free triiodothyronine (fT3) were measured. The primary endpoint was to verify any difference in serum TSH levels whether consuming liquid LT4 at breakfast or 30 minutes prior to breakfast. RESULTS: A total of 77 patients (64 females; median age 45.4 +/- 3.7 years) completed the study. No statistically significant differences in serum TSH, fT4, or fT3 levels were observed whether LT4 was taken at breakfast or 30 minutes before, in a fasting state. No significant effect from the sequence of regimens, breakfast composition, and/or concomitantly administered drugs was observed on the dose of LT4 administered, or on the post-treatment serum TSH values. CONCLUSIONS: The TICO study suggests that a liquid LT4 formulation can be ingested directly at breakfast, thus potentially improving therapeutic compliance. This observation is of considerable clinical relevance, since non adherence to LT4 therapy requirements is more likely to cause variability in serum TSH concentrations. PMID- 26586611 TI - The effects of different cross-linking conditions on collagen-based nanocomposite scaffolds-an in vitro evaluation using mesenchymal stem cells. AB - Nanocomposite scaffolds which aimed to imitate a bone extracellular matrix were prepared for bone surgery applications. The scaffolds consisted of polylactide electrospun nano/sub-micron fibres, a natural collagen matrix supplemented with sodium hyaluronate and natural calcium phosphate nano-particles (bioapatite). The mechanical properties of the scaffolds were improved by means of three different cross-linking agents: N-(3-dimethylamino propyl)-N'-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide in an ethanol solution (EDC/NHS/EtOH), EDC/NHS in a phosphate buffer saline solution (EDC/NHS/PBS) and genipin. The effect of the various cross-linking conditions on the pore size, structure and mechanical properties of the scaffolds were subsequently studied. In addition, the mass loss, the swelling ratio and the pH of the scaffolds were determined following their immersion in a cell culture medium. Furthermore, the metabolic activity of human mesenchymal stem cells (hMSCs) cultivated in scaffold infusions for 2 and 7 days was assessed. Finally, studies were conducted of cell adhesion, proliferation and penetration into the scaffolds. With regard to the structural stability of the tested scaffolds, it was determined that EDC/NHS/PBS and genipin formed the most effectively cross-linked materials. Moreover, it was discovered that the genipin cross-linked scaffold also provided the best conditions for hMSC cultivation. In addition, the infusions from all the scaffolds were found to be non-cytotoxic. Thus, the genipin and EDC/NHS/PBS cross-linked scaffolds can be considered to be promising biomaterials for further in vivo testing and bone surgery applications. PMID- 26586612 TI - Cloning and high level expression of the biologically active extracellular domain of Macaca mulatta CD40 in Pichia pastoris. AB - The CD40-mediated immune response contributes to a wide variety of chronic inflammatory diseases. CD40 antagonists have potential as novel therapies for immune disorders. However, the CD40 pathway has not been well characterized in the rhesus monkey Macaca mulatta, which is a valuable animal model for human immune disease. An 834 bp transcript was cloned from peripheral blood mononuclear cells (PBMCs) of rhesus monkey using specific primers designed according to the predicted sequence of M. mulatta CD40 (mmCD40) in GenBank. Sequence analysis demonstrated that mmCD40 is highly homologous to human CD40 (hCD40), with an amino acid sequence identity of 94%. Genes encoding the extracellular domain of mmCD40 and the Fc fragment of the hIgG1 were inserted into a pPIC9K plasmid to produce mmCD40Ig by Pichia pastoris. Approximately 15-20 mg of the mmCD40Ig protein with ~90% purity could be recovered from 1 L of culture. The purified mmCD40Ig protein can form dimers and can specifically bind CD40L-positive cells. Additionally, the mmCD40Ig protein can bind hCD40L protein in phosphate buffered saline and form a stable combination in a size-exclusion chromatography assay using a Superdex 200 column. Moreover, mmCD40Ig is as efficient as M. mulatta CTLA4Ig (mmCTLA4Ig) to suppress Con A-stimulated lymphocyte proliferation. Additionally, mmCD40Ig only showed mild immunosuppressive activity in a one-way mixed lymphocyte reaction (MLR) system. These results suggest that mmCD40Ig secreted by P. pastoris was productive and functional, and it could be used as a tool for pathogenesis and therapies for chronic inflammatory diseases in a M. mulatta model. PMID- 26586613 TI - Expression of a novel bacteriocin-the plantaricin Pln1-in Escherichia coli and its functional analysis. AB - A potential bacteriocin gene was isolated from 18575 ORFs by bioinformatics methods. It was named pln1, and cloned into pET32a. Then, it was expressed as a thioredoxin-Pln1 fusion protein in Escherichia coli BL21 (DE3). The fusion protein was purified by Ni-NTA, and thioredoxin was removed by enterokinase. Finally, Pln1 was purified using a cation affinity column. The yields of fused and cleaved Pln1 peptides were 100-110 mg/l and 9-11 mg/l, respectively. Pln1 was stable in an acidic environment and at temperatures below 60 degrees C, but was easily degraded under alkaline conditions and by protease treatment. The cleaved and purified Pln1 showed strong antimicrobial activity against gram-positive bacteria such as Micrococcus luteus CMCC 63202, Staphylococcus epidermidis, Lactococcus lactis NZ3900, Lactobacillus paracasei CICC 20241, and Listeria innocua CICC 10417. In particular, Pln1 had a better activity against methicillin resistant S. epidermidis (MRSE) than nisin, thereby offering an attractive approach to counter bacterial antibiotic resistance. PMID- 26586614 TI - Cohort effects on the need for health care and implications for health care planning in Canada. AB - The sustainability of publicly funded health care systems is an issue for governments around the world. The economic climate limits governments' fiscal capacity to continue to devote an increasing share of public funds to health care. Meanwhile the demands for health care within populations continue to increase. Planning the future requirements for health care is typically based on applying current levels of health service use by age to demographic projections of the population. But changes in age-specific levels of health over time would undermine this 'constant use by age' assumption. We use representative Canadian survey data (Canadian Community Health Survey) covering the period 2001-2012, to identify the separate trends in demography (population ageing) and epidemiology (population health) on self-reported health. We propose an approach to estimating future health care requirements that incorporates cohort trends in health. Overall health care requirements for the population increase as the size and mean age of the population increase, but these effects are mitigated by cohort trends in health-we find the estimated need for health care is lower when models account for cohort effects in addition to age effects. PMID- 26586615 TI - Building a Global Mental Health Research Workforce: Perspectives from the National Institute of Mental Health. PMID- 26586616 TI - Transforming Psychiatry: A Curriculum on Recovery-Oriented Care. PMID- 26586617 TI - Lignans from the roots of Acorus tatarinowii Schott ameliorate beta amyloid induced toxicity in transgenic Caenorhabditis elegans. AB - A novel tetralignan, tatarinan T (1) with the rare C8-C7' linkage pattern, along with a known monolignan (2) were isolated from the roots of Acorus tatarinowii Schott. Their chemical structures were elucidated on the basis of NMR and X-ray diffraction analysis. We evaluated the protective effects of two rare lignans against beta-amyloid toxicity by using CL4176 transgenic C. elegans model for the first time, and found that they significantly delayed paralysis of worms at the concentration of 100 MUM. Compound 2 exhibited the more potential protective effect against beta-amyloid toxicity, its value of PT50 extended up to 62.3% at 100 MUM compared with control, especially, it still has 30.8% extension at 10 MUM. PMID- 26586618 TI - New triterpenoids from the latex of Euphorbia resinifera Berg. AB - Nine novel compounds, six euphane triterpenes, Euphorol A-D (1-4), H (8) and I (9), and three tirucallane triterpenes, Euphorol E-G (5-7) including four nortriterpenes, together with seven known compounds (10-16) have been isolated from the methanol extraction of Euphorbium. Their structures were established on the basis of extensive analyses of their HR-ESI-MS, UV, IR, 1D and 2D NMR methods. A putative biogenetic relationship to these compounds was proposed. The cytotoxicity of all these isolates against MCF-7, U937 and C6 cancer cell lines was evaluated. Compounds 1-3, 10, 11 and 13-16 exhibited moderate cytotoxic activities. PMID- 26586619 TI - Inhibition of algal bromophenols and their related phenols against glucose 6 phosphate dehydrogenase. AB - A novel bromophenol, n-butyl 2,3-dibromo-4,5-dihydroxybenzyl ether, and known bromophenols were isolated from Rhodomelaceae algae as glucose 6-phosphate dehydrogenase (G6PD) inhibitors. Among them, bromophenol dimers showed stronger inhibitory activity against Leuconostoc mesenteroides and Saccharomyces cerevisiae G6PDs than the corresponding monomers. The dibenzyl ether-type dimers had lower IC50 values than the diarylmethane-type dimers against L. mesenteroides G6PD among the bromophenols examined. In contrast, the inhibitory activities of diarylmethane-type dimers against S. cerevisiae G6PD were stronger than those of dibenzyl ether-type dimers. Especially, 3-bromo-2-(2,3-dibromo-4,5 dihydroxybenzyl)-4,5-dihydroxybenzyl methyl ether selectively inhibited S. cerevisiae G6PD compared to L. mesenteroides G6PD. PMID- 26586620 TI - Suppressive effects of polyozellin on endothelial protein C receptor shedding via inhibiting TACE activity and MAP kinases. AB - Beyond its role in the activation of protein C, the endothelial cell protein C receptor (EPCR) plays an important role in the cytoprotective pathway. EPCR can be shed from the cell surface, which is mediated by tumor necrosis factor-alpha converting enzyme (TACE). Polyozellin, a major constituent of a Korea edible mushroom Polyozellus multiplex, has been known to exhibit the biological activities such as anti-oxidative and anti-inflammatory effects. However, little is known about the effects of polyozellin on EPCR shedding. We investigated this issue by monitoring the effects of polyozellin on phorbol-12-myristate 13-acetate (PMA)-, tumor necrosis factor (TNF)-alpha-, interleukin (IL)-1beta-induced EPCR shedding in human umbilical vein endothelial cells (HUVECs), and cecal ligation and puncture (CLP)-mediated EPCR shedding in mice and underlying mechanism. Data demonstrate that polyozellin induced potent inhibition of PMA-, TNF-alpha-, IL 1beta- (in HUVECs), and CLP-induced EPCR shedding (in mice) via inhibition of phosphorylation of mitogen-activated protein kinases (MAPKs) such as p38, janus kinase (JNK), and extracellular signal-regulated kinase (ERK) 1/2. Polyozellin also inhibited the expression and activity of PMA-induced TACE in HUVECs suggesting that p38, ERK1/2, and JNK could be the molecular targets of POZ. These results demonstrate the potential of polyozellin as an anti-EPCR shedding reagent against PMA-mediated and CLP-mediated EPCR shedding. PMID- 26586621 TI - Hydroxycinnamic acid amides from Scopolia tangutica inhibit the activity of M1 muscarinic acetylcholine receptor in vitro. AB - Scopolia tangutica Maxim (S. tangutica) extracts have been traditionally used as antispasmodic, sedative, and analgesic agents in Tibet and in the Qinghai province of China. Their active compositions are however poorly understood. We have recently isolated five new hydroxycinnamic acid (HCA) amides along with two known HCA amides, one cinnamic acid amide from these extracts. In this study, we evaluate their abilities to inhibit carbacol-induced activity of M1 muscarinic acetylcholine receptor along with the crude extracts. Chinese hamster ovary cells stably expressing the recombinant human M1 receptor (CHO-M1 cells) were employed to evaluate the anticholinergic potentials. Intracellular Ca(2+) changes were monitored using the FLIPR system. Five HCA amides as well as the crude S. tangutica extract displayed dose-dependent inhibitory effects against M1 receptor. These findings demonstrate that HCA amides are part of the M1 receptor inhibiting principles of S. tangutica. Since blockade of parasympathetic nerve impulse transmission through the inhibition of the M1 receptor lessens smooth muscle spasms, our findings provided a molecular explanation for the traditional use of S. tangutica against spasm. PMID- 26586622 TI - 6(17)-Epoxylathyrane diterpenes from Euphorbia sogdiana Popov with cytotoxic activity. AB - Phytochemical analysis of Euphorbia sogdiana Popov, Euphorbiaceae, afforded the isolation of three new diterpenes based on the rare 6(17)-epoxylathyrane skeleton (1-3), along with a lathyrane (4), a myrsinane (5) and a tigliane (6) diterpenoids, previously isolated from Euphorbia aellenii. Their chemical structures were established through a combination of nuclear magnetic resonance spectroscopy and mass spectrometric methods. The epoxylathyranes 1-4 were tested to evaluate their cytotoxic activity against Jurkat T-leukemia and EJ-138 bladder cancer cells and their chemical analogy allowed to propose some structure activity relationships. PMID- 26586623 TI - Isolation and identification of metabolites of bakuchiol in rats. AB - Bakuchiol, the main active component of Psoralea corylifolia, showed a range of significant pharmacological activities, including antimicrobial, antiinflammatory, reduction of bone loss and estrogenic activities. In this research, 12 metabolites, including 11 new compounds, were isolated from the urine and feces of rats after oral administration of bakuchiol, and their structures were elucidated by extensive spectroscopic analysis. The possible metabolic pathways of bakuchiol in rats were proposed, and a rare bile acid conjugation reaction was found. In addition, bakuchiol and its metabolites M1-M3 were studied for their alkaline phosphatase (ALP) activities on MC3T3-E1 cells and cytotoxicity on HKC-8 cells. The data showed that bakuchiol exerted significant effects on ALP activity of MC3T3-E1 cells and cytotoxicity on HKC-8 cells, while M1-M3 only showed ALP activities at 10(-5)M on MC3T3-E1 cells and no cytotoxicity on HKC-8 cells. PMID- 26586628 TI - The total and freely dissolved polycyclic aromatic hydrocarbons content in residues from biogas production. AB - In the situation of increasing agricultural utilization of residues from biogas production (RBP) it is important to determine the concentration of contaminants, which could occur in these materials. The group of contaminants that requires special attention are polycyclic aromatic hydrocarbons (PAH). The objective of the study was to determine the total and freely dissolved (Cfree) of PAHs in RBP from 6 different biogas plants operating under various temperature conditions and without or with the separation into the solid and liquid fractions. The freely dissolved PAHs were determined using polyoxymethylene (POM method). The total content of the Sigma16 PAHs in RBP varied from 449 to 6147 MUg/kgdw, while that of Cfree PAHs was at the level from 57 to 653 ng/L. No significant differences were noted in the content of the Sigma16 PAHs (total) between the solid and the liquid fractions. This indicates that in the course of the separation, the PAHs are distributed proportionally between the fractions. However in the case of Cfree, PAHs content in the solid fraction was over twice as high as in the liquid fraction. This was probably due to the greater affinity of the particles present in the liquid fraction to the analysed PAHs than to the particles of the solid fraction. Higher affinity to liquid fraction was also confirmed by the distribution coefficients KTOC determined on the basis of Cfree. PMID- 26586629 TI - Morphological and molecular characterization of Choleoeimeria pogonae n. sp. coccidian parasite (Apicomplexa: Eimeriidae, 1989, Paperna and Landsberg) in a western bearded dragon (Pogona minor minor). AB - A new species, Choleoeimeria pogonae n. sp. is described from a Western bearded dragon (Pogona minor minor) in Western Australia. Sporulated oocysts (n = 48) were cylindroidal in shape. Oocyst length, 27.0 (26.0-28.3) MUm, oocyst width, 15.2 (14.0-16.5) MUm, oocyst length/width ratio (L/W) 1.8 (1.6-1.9), each with 4 sporocysts (Eimeria-like) and a polar granule, but lacking a micropyle and oocyst residuum. Sporocysts are ovoidal in shape, sporocyst length, 10.0 (9.0-11.0) MUm, sporocyst width 8.5 (7.0-9.5) MUm, sporocyst L/W ratio, 1.2 (1.1-1.3). Stieda, substieda and parasubstieda bodies were all absent. Molecular analysis was conducted at the 18S rRNA and cytochrome c oxidase I (COI) loci. Phylogenetic analysis of 18S sequences revealed that C. pogonae n. sp. grouped together with another four Choleoeimeria spp. and exhibited 99.1%-99.4% genetic similarity. At the COI locus, C. pogonae n. sp. was in an independent clade and had the highest similarity (80.4%) to Eimeria cf. mivati from a chicken (Gallus gallus domesticus). According to the morphological and molecular data, this isolate is a new species of coccidian parasite. This study further supports the taxonomy of Choleoeimeria spp. as a new genus based on molecular phylogenetic analysis. PMID- 26586630 TI - Analysis of long-term monomer elution from bulk-fill and conventional resin composites using high performance liquid chromatography. AB - OBJECTIVE: The aim of this study was to assess monomer elution from bulk-fill and conventional resin-composites stored in different media using high performance liquid chromatography (HPLC) for up to 3 months. METHODS: Six bulk-fill (SureFil SDR, Venus Bulk Fill, X-tra base, Filtek Bulk Fill flowable, Sonic Fill, and Tetric EvoCeram Bulk Fill) and eight conventional resin-composites (Grandioso Flow, Venus Diamond Flow, X-Flow, Filtek Supreme XTE, Grandioso, Venus Diamond, TPH Spectrum, and Filtek Z250) were tested. Cylindrical samples (n=5) were immersed in water, 70% ethanol/water solution (70% E/W), and artificial saliva and stored at 37 degrees C for 24h, 1 month, and 3 months. The storage solutions were analysed with HPLC. Data were analysed with repeated measures ANOVA, one-way ANOVA, and Tukey post hoc test at alpha=0.05. RESULTS: Monomers detected in water and artificial saliva were TEGDMA, DEGDMA, UDMA, and TCD-DI-HEA. No eluted monomers were detected from X-tra base and Sonic fill in these media. All monomers showed a variable extent of elution into 70% E/W with significantly higher amounts than those detected in water and artificial saliva. Significantly higher elution was detected from UDMA-BisEMA based composites compared to BisGMA and BisGMA-BisEMA based systems in 70% E/W. The rate of elution into different media varied between different monomers and was highly dependent on the molecular weight of the eluted compounds. SIGNIFICANCE: Elution from bulk-fill resin composites is comparable to that of conventional materials despite their increased increment thickness. Monomer elution is highly dependent on the hydrophobicity of the base monomers and the final network characteristics of the resin-matrix. PMID- 26586631 TI - Committee on air pollution effects research: 40 years of UK air pollution. AB - The UK Committee on Air Pollution Effects Research (CAPER) was established 40 years ago. This special section was compiled to mark this anniversary. During this time there have been dramatic changes in the composition of the air over the UK. The four papers in this special section of Environmental Pollution represent the current air pollution effects research focus on ozone and nitrogen deposition, two related issues and are proving from a policy perspective to be quite intractable issues. The UK CAPER research community continues to advance the underpinning science and engages closely with the user community in government departments. PMID- 26586632 TI - How much crude oil can zooplankton ingest? Estimating the quantity of dispersed crude oil defecated by planktonic copepods. AB - We investigated and quantified defecation rates of crude oil by 3 species of marine planktonic copepods (Temora turbinata, Acartia tonsa, and Parvocalanus crassirostris) and a natural copepod assemblage after exposure to mechanically or chemically dispersed crude oil. Between 88 and 100% of the analyzed fecal pellets from three species of copepods and a natural copepod assemblage exposed for 48 h to physically or chemically dispersed light crude oil contained crude oil droplets. Crude oil droplets inside fecal pellets were smaller (median diameter: 2.4-3.5 MUm) than droplets in the physically and chemically dispersed oil emulsions (median diameter: 6.6 and 8.0 MUm, respectively). This suggests that copepods can reject large crude oil droplets or that crude oil droplets are broken into smaller oil droplets before or during ingestion. Depending on the species and experimental treatments, crude oil defecation rates ranged from 5.3 to 245 ng-oil copepod(-1) d(-1), which represent a mean weight-specific defecation rate of 0.026 MUg-oil MUg-Ccopepod(1) d(-1). Considering a dispersed crude oil concentration commonly found in the water column after oil spills (1 MUl L(-1)) and copepod abundances in high productive coastal areas, copepods may defecate ~ 1.3-2.6 mg-oil m(-3) d(-1), which would represent ~ 0.15%-0.30% of the total dispersed oil per day. Our results indicate that ingestion and subsequent defecation of crude oil by planktonic copepods has a small influence on the overall mass of oil spills in the short term, but may be quantitatively important in the flux of oil from surface water to sediments and in the transfer of low solubility, toxic petroleum hydrocarbons into food webs after crude oil spills in the sea. PMID- 26586633 TI - Reliability and stability of immobilization remediation of Cd polluted soils using sepiolite under pot and field trials. AB - Long-term effectiveness and persistence are two important criterias to evaluate alternative remediation technology of heavy metal polluted soils. Pot and field studies showed addition of sepiolite was effective in immobilizing Cd in polluted soils, with significant reduction in TCLP extracts (0.6%-49.6% and 4.0%-32.5% reduction in pot and field experiments, respectively) and plant uptake (14.4% 84.1% and 22.8%-61.4% declines in pot and field studies, correspondingly). However, the applications of sepiolite offered a limited guarantee for the safety of edible vegetables in Cd-polluted soils, depending on the soil type, the Cd pollution type and level, and the dose and application frequency of chemical amendments. Bioassays, such as plant growth, soil enzymatic activities and microbial community diversity, indicated a certain degree of recovery of soil metabolic function. Therefore, sepiolite-assisted in situ remediation is cost effective, environmentally friendly, and technically applicable, and can be successfully used to reduce Cd enter into the food chain on field scale. PMID- 26586634 TI - Redox activity and in vitro bioactivity of the water-soluble fraction of urban particulate matter in relation to particle size and chemical composition. AB - Chemical and toxicological characterization of the water-soluble fraction of size segregated urban particulate matter (PM) (<0.49, 0.49-0.97, 0.97-1.5, 1.5-3.0, 3.0-7.2 and >7.2 MUm) was carried out at two urban sites, traffic and urban background, during the cold and the warm period. Chemical analysis of the water soluble PM fraction included ionic species (NO3(-), SO4(2-), Cl(-), Na(+), NH4(+), K(+), Mg(2+), Ca(2+)), water-soluble organic carbon (WSOC), and trace elements (Al, As, Ba, Cd, Cr, Cu, Fe, Pb, Mn, Ni, Zn, Pt, Pd, Rh, Ru, Ir, Ca, and Mg). The dithiothreitol (DTT) assay was employed for the abiotic assessment of the oxidative PM activity. Cytotoxic responses were investigated in vitro by applying the mitochondrial dehydrogenase (MTT) and the lactate dehydrogenase (LDH) bioassays on human lung cells (MRC-5), while DNA damage was estimated by the single cell gel electrophoresis assay, known as Comet assay. The correlations between the observed bioactivity responses and the concentrations of water soluble chemical PM constituents in the various size ranges were investigated. The results of the current study corroborate that short-term bioassays using lung human cells and abiotic assays, such as the DTT assay, could be relevant to complete the routine chemical analysis and to obtain a preliminary screening of the potential effects of PM-associated airborne pollutants on human health. PMID- 26586635 TI - Concern-driven integrated approaches for the grouping, testing and assessment of nanomaterials. AB - NM's potential to induce adverse effects in humans or the environment is being addressed in numerous research projects, and methods and tools for NM hazard identification and risk assessment are advancing. This article describes how integrated approaches for the testing and assessment of NMs can ensure the safety of nanomaterials, while adhering to the 3Rs principle. PMID- 26586636 TI - [Reply to: Non-pharmacological analgesia in spanish neonatal units]. PMID- 26586637 TI - [Half-day case robotic radical prostatectomy. Surgery of the future? A case report]. AB - INTRODUCTION: Robotics and ambulatory are modern applications of surgery. This case study proves the feasibility of robot-assisted radical prostatectomy as an outpatient procedure. METHOD: This report highlights the first, half-day, robotic prostatectomy performed on a 57-year-old man with localized prostate cancer. This operation was proposed to the subject because of his excellent physical condition and favorable environmental factors. He chose to undergo the surgery voluntarily. He underwent a nerve sparing radical prostatectomy. Target-controlled infusion propofol was used in perioperative sedation and analgesia. Postoperative evaluation criteria was made with the Visual Analog Scale of Pain Intensity (VASPI), Chung score and a patient satisfaction survey. RESULTS: No perioperative or postoperative complications were reported. Blood loss was low (75 mL). The patient stayed less than 12 hours in the ambulatory unit thanks to a rapid recovery. The patient returned home after reporting a Chung score of 10. No hospital readmission was necessary. Functional results were: a bowel movement on day 1, back to work on day 2, normal urinary continence on day 8, a correct erectile function on day 9. Oncological results revealed negative surgical margins for cancer and PSA postoperative<0.03 ng/mL. CONCLUSION: Ambulatory robotic radical prostatectomies can be performed on voluntarily-selected patients without affecting the high quality of urological surgery outcomes. PMID- 26586638 TI - [Sexual function after transobturator tape procedure for stress urinary incontinence and overall patients' satisfaction]. AB - OBJECTIVE: To evaluate the quality of sexual activity after a transobturator tape procedure for urinary incontinence and to examine the global satisfaction reported by patients. MATERIALS AND METHODS: This is a bicentric retrospective study, postoperative questionnaires were sent to 247 women operated for urinary incontinence by TOT/TVT-O surgery, after 1 year, prolaps were excluded. Patients' overall improvement was assessed using the French version of Patient Global Impression and Improvement (PGI-I), urinary symptoms were assessed with the use of ICIQ-Fluts and quality of sexual function using Lemack and Zimmern questionnaire and ICIQ-Fluts-Sex. A logistic regression analysis was run to analyse the factors associated with women overall improvement. RESULTS: One hundred and sixty-five patients answered the questionnaire (66.8%). Average age was 55 (+/-11), and the average postoperative period was 39 months (+/-17.9). After surgery, according to the PGI-I: 135 women (81.8%) found an overall improvement, 22 (13.4%) found their condition unchanged and 8 (4.8%) women found it worse. Among the 165 women, 118 were sexually active, 37 (31.4%) reported improvement in intercourse satisfaction whereas 11 (9.3%) complained about sexual function deterioration and 70 (59.3%) felt unchanged. The 37 women who reported sexual improvement described decreased coital incontinence in 54% of the cases. Eleven women who felt sexually worse, reported dyspareunia. Results of the logistic regression analysis suggested that overall improvement after surgery depended not only on the incontinence score (OR 0.83) but also on the quality of the postoperative sexual activity (OR 12.96). CONCLUSION: One third of the women reported improvement of their sexuality after transobturator tape procedure. In fact, global satisfaction after surgery was as related to the improvement of urinary symptoms as it was to the quality of the sexual activity. LEVEL OF EVIDENCE: 5. PMID- 26586640 TI - Advanced glycation end-products induce skeletal muscle atrophy and dysfunction in diabetic mice via a RAGE-mediated, AMPK-down-regulated, Akt pathway. AB - Diabetic myopathy, a less studied complication of diabetes, exhibits the clinical observations characterized by a less muscle mass, muscle weakness and a reduced physical functional capacity. Accumulation of advanced glycation end-products (AGEs), known to play a role in diabetic complications, has been identified in ageing human skeletal muscles. However, the role of AGEs in diabetic myopathy remains unclear. Here, we investigated the effects of AGEs on myogenic differentiation and muscle atrophy in vivo and in vitro. We also evaluated the therapeutic potential of alagebrium chloride (Ala-Cl), an inhibitor of AGEs. Muscle fibre atrophy and immunoreactivity for AGEs, Atrogin-1 (a muscle atrophy marker) and phosphorylated AMP-activated protein kinase (AMPK) expressions were markedly increased in human skeletal muscles from patients with diabetes as compared with control subjects. Moreover, in diabetic mice we found increased blood AGEs, less muscle mass, lower muscular endurance, atrophic muscle size and poor regenerative capacity, and increased levels of muscle AGE and receptor for AGE (RAGE), Atrogin-1 and phosphorylated AMPK, which could be significantly ameliorated by Ala-Cl. Furthermore, in vitro, AGEs (in a dose-dependent manner) reduced myotube diameters (myotube atrophy) and induced Atrogin-1 protein expression in myotubes differentiated from both mouse myoblasts and primary human skeletal muscle-derived progenitor cells. AGEs exerted a negative regulation of myogenesis of mouse and human myoblasts. Ala-Cl significantly inhibited the effects of AGEs on myotube atrophy and myogenesis. We further demonstrated that AGEs induced muscle atrophy/myogenesis impairment via a RAGE-mediated AMPK-down regulation of the Akt signalling pathway. Our findings support that AGEs play an important role in diabetic myopathy, and that an inhibitor of AGEs may offer a therapeutic strategy for managing the dysfunction of muscle due to diabetes or ageing. PMID- 26586641 TI - Neutrophils of Scophthalmus maximus produce extracellular traps that capture bacteria and inhibit bacterial infection. AB - Neutrophils constitute an essential part of the innate immune system. Recently, neutrophils have been found to produce a complex extracellular structure called neutrophil extracellular traps (NETs) that capture bacteria, fungi, and parasites. In fish, a few studies on NETs production have been reported, however, the function of fish NETs is unknown. In this study, we examined the ability of turbot (Scophthalmus maximus) neutrophils to produce NETs and investigated the effect of turbot NETs on bacterial infection. We found that upon lipopolysaccharides treatment, turbot head kidney neutrophils produced typical NETs structures that contained DNA and histones. Bacteria treatment also induced production of NETs, which in turn entrapped the bacterial cells and inhibited bacterial replication. Furthermore, when introduced into turbot, NETs-trapped bacteria exhibited significantly weakened ability of tissue dissemination and colonization. These results indicate for the first time that teleost NETs possess apparent antibacterial effect both in vitro and in vivo. PMID- 26586642 TI - Molecular cloning and functional characterization of duck mitochondrial antiviral signaling protein (MAVS). AB - Mitochondrial antiviral-signaling protein (MAVS), also called IPS-1/VISA/Cardif, is an important molecule involved in host defense and triggers a signal for producing type I IFN. Currently the function of MAVS in ducks (duMAVS) remains largely unclear while significant progress has been made in mammals. In this study, the full-length duMAVS cDNA was cloned from duck embryo fibroblasts (DEFs) for the first time. Tissue specificity analysis showed duMAVS was universally expressed in all detected tissues. DEFs transfected with duMAVS were able to induce interferon-beta (IFN-beta) expression through activating interferon regulatory factor 1 (IRF1) and nuclear factor kappa B (NF-kappaB). Both the CARD like domain and transmembrane domain were required for duMAVS signaling via deletion mutant analysis. In addition, poly(I:C)- or Sendai virus (SeV)-induced IFN-beta expression in DEFs were significantly decreased by knock-down of duMAVS with siRNA. Altogether, these results indicate that MAVS is a critical immunoregulator in duck innate immune system. PMID- 26586643 TI - Renal transplantation in the elderly. PMID- 26586644 TI - Do elderly recipients really benefit from kidney transplantation? AB - Data from the nineties showed that even older individuals had a survival advantage with kidney transplantation compared to dialysis. Consequently, we are increasingly wait-listing high-risk patients in terms of age and co-morbidities. However, times are changing. Due to severe organ shortage we now use more often expanded criteria donor kidneys with less favorable outcomes, while at the same time survival on dialysis is improving. The question therefore rises again if elderly patients really benefit from transplantation nowadays. At least for the U.S., recent data still suggest an overall survival benefit with transplantation in older recipients but the risks vary greatly with the health status of the recipient and with the type of donor. Especially for transplant centers outside of the U.S., recent large studies are lacking. Because of continuing changes in both donor and recipient characteristics as well as dialysis outcomes, a permanent area-specific reassessment of data is needed. In this review we describe the important evolutions in transplant and dialysis care over the last 20 years and provide an overview on recent data comparing survival on dialysis versus transplantation in the elderly. PMID- 26586645 TI - Allocation strategies for elderly kidney transplant recipients. AB - In all modern societies, the percentage of elderly people is increasing. However, this does not necessary reflect the percentage of patients waiting for a new kidney and the availability of organs for this entity differs markedly between countries. Thus, allocation strategies for elderly kidney recipients should be based on the characteristics of the specific countries and take into account: access to the waiting list and availability of living as well as marginal and conventional post-mortem donors. PMID- 26586646 TI - Lipoarabinomannan, and its related glycolipids, induce divergent and opposing immune responses to Mycobacterium tuberculosis depending on structural diversity and experimental variations. AB - Exposure to Mycobacterium tuberculosis (Mtb) may lead to active or latent tuberculosis, or clearance of Mtb, depending essentially on the quality of the host's immune response. This response is initiated through the interaction of Mtb cell wall surface components, mostly glycolipids, with cells of the innate immune system, particularly macrophages (Mphis) and dendritic cells (DCs). The way Mphis and DC alter their cytokine secretome, activate or inhibit different microbicidal mechanisms and present antigens and consequently trigger the T cell-mediated immune response impacts the host immune response against Mtb. Lipoarabinomannan (LAM) is one of the major cell wall components of Mtb. Mannosyl-capped LAM (ManLAM), and its related cell wall-associated types of glycolipids/lipoglycans, namely phosphatidylinositol mannosides (PIMs) and lipomannan (LM), exhibit important and distinct immunomodulatory properties. The structure, internal heterogeneity and abundance of these molecules vary between Mtb strains exhibiting distinct degrees of virulence. Thus ManLAM, LM and PIMs may be considered crucial Mtb-associated virulence factors in the pathogenesis of tuberculosis. Of particular relevance for this review, there is controversy about the specific immunomodulatory properties of these distinct glycolipids, particularly when tested as purified molecules in vitro. In addition to the variability in the glycolipid composition conflicting reports may also result from differences in the protocols used for glycolipid isolation and for in vitro experiments including immune cell types and procedures to generate them. Understanding the immunomodulatory properties of these cell wall glycolipids, how they differ between distinct Mtb strains, and how they influence the degree of Mtb virulence, is of utmost relevance to understand how the host mounts a protective or otherwise pathologic immune response. This is essential for the design of preventive strategies against tuberculosis. Thus, since clarifying the controversy on this matter is crucial we here review, summarize and discuss reported data from in vitro stimulation with the three major Mtb complex cell wall glycolipids (ManLAM, PIMs and LM) in an attempt to conciliate the conflicting findings. PMID- 26586647 TI - A review of the use of ethionamide and prothionamide in childhood tuberculosis. AB - Ethionamide (ETH) and prothionamide (PTH), both thioamides, have proven efficacy in clinical studies and form important components for multidrug-resistant tuberculosis treatment regimens and for treatment of tuberculous meningitis in adults and children. ETH and PTH are pro-drugs that, following enzymatic activation by mycobacterial EthA inhibit InhA, a target shared with isoniazid (INH), and subsequently inhibit mycolic acid synthesis of Mycobacterium tuberculosis. Co-resistance to INH and ETH is conferred by mutations in the mycobacterial inhA promoter region; mutations in the ethA gene often underlie ETH and PTH monoresistance. An oral daily dose of ETH or PTH of 15-20 mg/kg with a maximum daily dose of 1000 mg is recommended in children to achieve adult equivalent serum concentrations shown to be efficacious in adults, although information on optimal pharmacodynamic targets is still lacking. Gastrointestinal disturbances, and hypothyroidism during long-term therapy, are frequent adverse effects observed in adults and children, but are rarely life-threatening and seldom necessitate cessation of ETH therapy. More thorough investigation of the therapeutic effects and toxicity of ETH and PTH is needed in childhood TB while child-friendly formulations are needed to appropriately dose children. PMID- 26586648 TI - Primary mouse lung fibroblasts help macrophages to tackle Mycobacterium tuberculosis more efficiently and differentiate into myofibroblasts up on bacterial stimulation. AB - Keeping with their classical role in wound healing, fibroblasts of the lung take part in the resolution of tubercular granulomas. They are totally absent in nascent granulomas, but surround necrotizing granulomas, and are the majority of cells in healed granulomas. Lung fibroblasts may become infected with Mycobacterium tuberculosis (Mtb). Two previous studies suggested an immunomodulatory effect of fibroblasts on infected macrophages. In the present study, we looked at the role of primary mouse lung fibroblasts on naive or activated mouse bone marrow macrophages infected with Mtb and the effect of infection on fibroblast properties. We observed that with fibroblasts in the vicinity, infected naive macrophages restricted the bacterial growth, while activated macrophages turned more bactericidal with concomitant increase in nitrite production. Neutralizing IL-1alpha in fibroblast supernatant reduced the nitrite production by infected macrophages. Secretion of IL-6 and MCP-1 was down regulated, while TNF-alpha was up-regulated in infected naive macrophages. In infected activated macrophages, the secretion of IL-6 was up-regulated, while that of MCP-1 and TNF-alpha was unaffected. The 'fibroblast effects' were enhanced when the fibroblasts too were infected. Mtb induced IL-1 secretion and pro-fibrotic responses by fibroblasts. Mtb-induced myofibroblast conversion was blocked by rapamycin suggesting cell signalling via mTOR. PMID- 26586649 TI - Strength training, but not endurance training, reduces motor unit discharge rate variability. AB - This study evaluates and compares the effects of strength and endurance training on motor unit discharge rate variability and force steadiness of knee extensor muscles. Thirty sedentary healthy men (age, 26.0+/-3.8yrs) were randomly assigned to strength training, endurance training or a control group. Conventional endurance and strength training was performed 3days per week, over a period of 6weeks. Maximum voluntary contraction (MVC), time to task failure (at 30% MVC), coefficient of variation (CoV) of force and of the discharges rates of motor units from the vastus medialis obliquus and vastus lateralis were determined as subjects performed 20% and 30% MVC knee extension contractions before and after training. CoV of motor unit discharges rates was significantly reduced for both muscles following strength training (P<0.001), but did not change in the endurance (P=0.875) or control group (P=0.995). CoV of force was reduced after the strength training intervention only (P<0.01). Strength training, but not endurance training, reduces motor unit discharge rate variability and enhances force steadiness of the knee extensors. These results provide new insights into the neuromuscular adaptations that occur with different training methods. PMID- 26586650 TI - Nosocomial transmission of avian influenza virus A (H7N9). PMID- 26586652 TI - Cerebral autoregulation during cardiopulmonary bypass. PMID- 26586653 TI - Commentary: Never Forget Your Old Toys When You Get New Ones. PMID- 26586654 TI - Commentary: Inside of the Interaction Between the Plaque and the Stent: Optical Coherence Tomography During Carotid Artery Stenting. PMID- 26586655 TI - Bone engineering by phosphorylated-pullulan and beta-TCP composite. AB - A multifunctional biomaterial with the capacity bond to hard tissues, such as bones and teeth, is a real need for medical and dental applications in tissue engineering and regenerative medicine. Recently, we created phosphorylated pullulan (PPL), capable of binding to hydroxyapatite in bones and teeth. In the present study, we employed PPL as a novel biocompatible material for bone engineering. First, an in vitro evaluation of the mechanical properties of PPL demonstrated both PPL and PPL/beta-TCP composites have higher shear bond strength than materials in current clinical use, including polymethylmethacrylate (PMMA) cement and alpha-tricalcium phosphate (TCP) cement, Biopex-R. Further, the compressive strength of PPL/beta-TCP composite was significantly higher than Biopex-R. Next, in vivo osteoconductivity of PPL/beta-TCP composite was investigated in a murine intramedular injection model. Bone formation was observed 5 weeks after injection of PPL/beta-TCP composite, which was even more evident at 8 weeks; whereas, no bone formation was detected after injection of PPL alone. We then applied PPL/beta-TCP composite to a rabbit ulnar bone defect model and observed bone formation comparable to that induced by Biopex-R. Implantation of PPL/beta-TCP composite induced new bone formation at 4 weeks, which was remarkably evident at 8 weeks. In contrast, Biopex-R remained isolated from the surrounding bone at 8 weeks. In a pig vertebral bone defect model, defects treated with PPL/beta-TCP composite were almost completely replaced by new bone; whereas, PPL alone failed to induce bone formation. Collectively, our results suggest PPL/beta-TCP composite may be useful for bone engineering. PMID- 26586656 TI - Reevaluating Musculoskeletal Linkages in Suction-Feeding Fishes with X-Ray Reconstruction of Moving Morphology (XROMM). PMID- 26586657 TI - Cerebral Vasoreactivity, Apolipoprotein E, and the Risk of Dementia: A Population Based Study. AB - OBJECTIVE: Cerebral vasoreactivity (CVR) is a key factor in maintenance of continuous cerebral perfusion and a marker of (micro)vascular damage. We aimed to determine the longitudinal relation between CVR and the risk of dementia in the general population. APPROACH AND RESULTS: We determined CVR in nondemented participants who underwent transcranial Doppler with induced hypercapnia from 1997 to 1999, as part of the ongoing population-based Rotterdam Study. We used a Cox model to determine the risk of dementia in relation to CVR, adjusted for age, sex, cardiovascular risk factors, and carotid intima-media thickness. We furthermore determined decline on a cognitive test battery in relation to CVR, using linear mixed models. Among 1629 participants (mean +/- SD age 70.6 +/- 6.2 years, 46.2% female) with a mean follow-up of 11.5 years, 209 were diagnosed with dementia, of whom 171 had Alzheimer disease. Higher CVR at baseline was associated with lower risk of dementia (adjusted hazard ratio, 95% confidence interval, per SD increase: 0.87, 0.75-1.00) and Alzheimer disease (adjusted hazard ratio, 0.84; 0.71-0.99). This association was more profound in APOEepsilon4 carriers than in noncarriers (adjusted hazard ratio for all dementia: 0.77, 0.60-0.98 versus 0.89, 0.73-1.07). Performance on cognitive tests at baseline was better with higher CVR (g-factor: P=0.02), but during 3 cognitive assessments over 11 years of follow-up, higher CVR at baseline was associated with less decline in test scores on the Stroop reading and interference tasks in APOEepsilon4 carriers only (P=0.01 and 0.02, respectively). CONCLUSIONS: Impaired CVR is associated with an increased risk of dementia in the general population. PMID- 26586658 TI - Serum Ferritin Relates to Carotid Intima-Media Thickness in Offspring of Fathers With Higher Serum Ferritin Levels. AB - OBJECTIVE: Body iron status has been linked to atherosclerosis in adults. The purposes of our study were to determine (1) the association between circulating ferritin levels and carotid intima-media thickness (cIMT) in a cohort of apparently healthy children and (2) the association between cIMT and parental ferritin levels. APPROACH AND RESULTS: Circulating ferritin levels (microparticle enzyme immunoassay), metabolic parameters, and cIMT (ultrasonography) were analyzed cross-sectionally in a cohort of 692 healthy white children with a mean age of 8 +/- 2 years (52% girls and 48% boys). In consecutive 123 children from the cross-sectional sample, the same serum assessments were also performed at baseline in their parents, and the cIMT was repeated after 3 years of follow-up in the children at a mean age of 11 +/- 2 years (53% girls and 47% boys). Weak but significant positive associations were evident between children's circulating ferritin levels and cIMT (r=0.123; P=0.001) and with the change in cIMT 3 years later a tendency was also observed (r=0.185; P=0.048). In multiple regression analyses, circulating ferritin levels contributed independently to cIMT variance (beta=0.090; P=0.026; R(2)=10%) and cIMT change variance (beta=0.216; P=0.019; R(2)= 3.4%) after controlling for body mass index, high-sensitivity C-reactive protein, age, sex, and low-density lipoprotein-cholesterol levels. This association was, however, remarkably significant (beta=0.509; P=0.001; R(2)= 20.4%) in children whose fathers had ferritin levels above the median value (122.5 ng/mL).The latter association remained significant after correction for multiple testing. Maternal's ferritin levels showed no interaction in this association. CONCLUSIONS: These results suggest a paternal-specific effect on cIMT partially reflected by father's ferritin levels. PMID- 26586660 TI - Uncoupling of Endothelial Nitric Oxide Synthase in Perivascular Adipose Tissue of Diet-Induced Obese Mice. AB - OBJECTIVE: The present study was conducted to investigate the contribution of perivascular adipose tissue (PVAT) to vascular dysfunction in a mouse model of diet-induced obesity. APPROACH AND RESULTS: Obesity was induced in male C57BL/6J mice with a high-fat diet for 20 weeks, and vascular function was studied with myograph. In PVAT-free aortas isolated from obese mice, the endothelium dependent, nitric oxide-mediated vasodilator response to acetylcholine remained normal. In contrast, a clear reduction in the vasodilator response to acetylcholine was observed in aortas from obese mice when PVAT was left in place. Adipocytes in PVAT were clearly positive in endothelial nitric oxide synthase (eNOS) staining, and PVAT nitric oxide production was significantly reduced in obese mice. High-fat diet had no effect on eNOS expression but led to eNOS uncoupling, evidenced by diminished superoxide production in PVAT after eNOS inhibition. As mechanisms for eNOS uncoupling, arginase induction and l-arginine deficiency were observed in PVAT. Obesity-induced vascular dysfunction could be reversed by ex vivo l-arginine treatment and arginase inhibition. CONCLUSIONS: Diet-induced obesity leads to l-arginine deficiency and eNOS uncoupling in PVAT. The combination therapy with l-arginine and arginase inhibitors may represent a novel therapeutic strategy for obesity-induced vascular disease. PMID- 26586659 TI - Hypoxia-Inducible Factor 1alpha Is a Critical Downstream Mediator for Hypoxia Induced Mitogenic Factor (FIZZ1/RELMalpha)-Induced Pulmonary Hypertension. AB - OBJECTIVE: Pulmonary hypertension (PH) is characterized by progressive elevation of pulmonary vascular resistance, right ventricular failure, and ultimately death. We have shown that in rodents, hypoxia-induced mitogenic factor (HIMF; also known as FIZZ1 or resistin-like molecule-beta) causes PH by initiating lung vascular inflammation. We hypothesized that hypoxia-inducible factor-1 (HIF-1) is a critical downstream signal mediator of HIMF during PH development. APPROACH AND RESULTS: In this study, we compared the degree of HIMF-induced pulmonary vascular remodeling and PH development in wild-type (HIF-1alpha(+/+)) and HIF-1alpha heterozygous null (HIF-1alpha(+/-)) mice. HIMF-induced PH was significantly diminished in HIF-1alpha(+/-) mice and was accompanied by a dysregulated vascular endothelial growth factor-A-vascular endothelial growth factor receptor 2 pathway. HIF-1alpha was critical for bone marrow-derived cell migration and vascular tube formation in response to HIMF. Furthermore, HIMF and its human homolog, resistin-like molecule-beta, significantly increased interleukin (IL)-6 in macrophages and lung resident cells through a mechanism dependent on HIF 1alpha and, at least to some extent, on nuclear factor kappaB. CONCLUSIONS: Our results suggest that HIF-1alpha is a critical downstream transcription factor for HIMF-induced pulmonary vascular remodeling and PH development. Importantly, both HIMF and human resistin-like molecule-beta significantly increased IL-6 in lung resident cells and increased perivascular accumulation of IL-6-expressing macrophages in the lungs of mice. These data suggest that HIMF can induce HIF-1, vascular endothelial growth factor-A, and interleukin-6, which are critical mediators of both hypoxic inflammation and PH pathophysiology. PMID- 26586661 TI - Injury-Mediated Vascular Regeneration Requires Endothelial ER71/ETV2. AB - OBJECTIVE: Comprehensive understanding of the mechanisms regulating angiogenesis might provide new strategies for angiogenic therapies for treating diverse physiological and pathological ischemic conditions. The E-twenty six (ETS) factor Ets variant 2 (ETV2; aka Ets-related protein 71) is essential for the formation of hematopoietic and vascular systems. Despite its indispensable function in vessel development, ETV2 role in adult angiogenesis has not yet been addressed. We have therefore investigated the role of ETV2 in vascular regeneration. APPROACH AND RESULTS: We used endothelial Etv2 conditional knockout mice and ischemic injury models to assess the role of ETV2 in vascular regeneration. Although Etv2 expression was not detectable under steady-state conditions, its expression was readily observed in endothelial cells after injury. Mice lacking endothelial Etv2 displayed impaired neovascularization in response to eye injury, wounding, or hindlimb ischemic injury. Lentiviral Etv2 expression in ischemic hindlimbs led to improved recovery of blood perfusion with enhanced vessel formation. After injury, fetal liver kinase 1 (Flk1), aka VEGFR2, expression and neovascularization were significantly upregulated by Etv2, whereas Flk1 expression and vascular endothelial growth factor response were significantly blunted in Etv2-deficient endothelial cells. Conversely, enforced Etv2 expression enhanced vascular endothelial growth factor-mediated endothelial sprouting from embryoid bodies. Lentiviral Flk1 expression rescued angiogenesis defects in endothelial Etv2 conditional knockout mice after hindlimb ischemic injury. Furthermore, Etv2(+/-); Flk1(+/-) double heterozygous mice displayed a more severe hindlimb ischemic injury response compared with Etv2(+/-) or Flk1(+/-) heterozygous mice, revealing an epistatic interaction between ETV2 and FLK1 in vascular regeneration. CONCLUSIONS: Our study demonstrates a novel obligatory role for the ETV2 in postnatal vascular repair and regeneration. PMID- 26586662 TI - Deletion of Hyaluronan Synthase 3 Inhibits Neointimal Hyperplasia in Mice. AB - OBJECTIVE: Hyaluronan (HA) is a polymeric glucosaminoglycan that forms a provisional extracellular matrix in diseased vessels. HA is synthesized by 3 different HA synthases (HAS1, HAS2, and HAS3). Aim of this study was to unravel the role of the HAS3 isoenzyme during experimental neointimal hyperplasia. APPROACH AND RESULTS: Neointimal hyperplasia was induced in Has3-deficient mice by ligation of the carotid artery. HA in the media of Has3-deficient mice was decreased 28 days after ligation, and neointimal hyperplasia was strongly inhibited. However, medial and luminal areas were unaffected. Cell density, proliferation, and apoptosis were not altered, suggesting a proportional decrease of both, the number of cells and extracellular matrix. In addition, endothelial function as determined by acetylcholine-induced relaxation of aortic rings, immunoblotting of endothelial nitric oxide synthase, and arterial blood pressure were not affected. Furthermore, the oxidative stress response was not affected as determined in total protein extracts from aortae. Transcriptome analysis comparing control versus ligated carotid arteries hinted toward a mitigated differential regulation of various signaling pathways in Has3-deficient mice in response to ligation that were related to vascular smooth muscle cell (VSMC) migration, including focal adhesions, integrins, mitogen-activated protein kinase, and phosphatidylinositol signaling system. Lentiviral overexpression of HAS3 in VSMC supported the migratory phenotype of VSMC in response to platelet derived growth factor BB in vitro. Accordingly, knockdown of HAS3 reduced the migratory response to platelet-derived growth factor BB and in addition decreased the expression of PDGF-B mRNA. CONCLUSIONS: HAS3-mediated HA synthesis after vessel injury supports seminal signaling pathways in activation of VSMC, increases platelet-derived growth factor BB-mediated migration, and in turn enhances neointimal hyperplasia in vivo. PMID- 26586663 TI - Cardiomyocyte VEGF Regulates Endothelial Cell GPIHBP1 to Relocate Lipoprotein Lipase to the Coronary Lumen During Diabetes Mellitus. AB - OBJECTIVE: Lipoprotein lipase (LPL)-mediated triglyceride hydrolysis is the major source of fatty acid for cardiac energy. LPL, synthesized in cardiomyocytes, is translocated across endothelial cells (EC) by its transporter glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1). Previously, we have reported an augmentation in coronary LPL, which was linked to an increased expression of GPIHBP1 following moderate diabetes mellitus. We examined the potential mechanism by which hyperglycemia amplifies GPIHBP1. APPROACH AND RESULTS: Exposure of rat aortic EC to high glucose induced GPIHBP1 expression and amplified LPL shuttling across these cells. This effect coincided with an elevated secretion of heparanase. Incubation of EC with high glucose or latent heparanase resulted in secretion of vascular endothelial growth factor (VEGF). Primary cardiomyocytes, being a rich source of VEGF, when cocultured with EC, restored EC GPIHBP1 that is lost because of cell passaging. Furthermore, recombinant VEGF induced EC GPIHBP1 mRNA and protein expression within 24 hours, an effect that could be prevented by a VEGF neutralizing antibody. This VEGF-induced increase in GPIHBP1 was through Notch signaling that encompassed Delta-like ligand 4 augmentation and nuclear translocation of the Notch intracellular domain. Finally, cardiomyocytes from severely diabetic animals exhibiting attenuation of VEGF were unable to increase EC GPIHBP1 expression and had lower LPL activity at the vascular lumen in perfused hearts. CONCLUSION: EC, as the first responders to hyperglycemia, can release heparanase to liberate myocyte VEGF. This growth factor, by activating EC Notch signaling, is responsible for facilitating GPIHBP1-mediated translocation of LPL across EC and regulating LPL-derived fatty acid delivery to the cardiomyocytes. PMID- 26586666 TI - Disaggregating Within- and Between-Person Effects of Social Identification on Subjective and Endocrinological Stress Reactions in a Real-Life Stress Situation. AB - Several experimental and cross-sectional studies have established the stress buffering effect of social identification, yet few longitudinal studies have been conducted within this area of research. This study is the first to make use of a multilevel approach to disaggregate between- and within-person effects of social identification on subjective and endocrinological stress reactions. Specifically, we conducted a study with 85 prospective students during their 1-day aptitude test for a university sports program. Ad hoc groups were formed, in which students completed several tests in various disciplines together. At four points in time, salivary cortisol, subjective strain, and identification with their group were measured. Results of multilevel analyses show a significant within person effect of social identification: The more students identified with their group, the less stress they experienced and the lower their cortisol response was. Between-person effects were not significant. Advantages of using multilevel approaches within this field of research are discussed. PMID- 26586667 TI - Nanorod mediated collagen scaffolds as extra cellular matrix mimics. AB - Creating collagen scaffolds that mimic extracellular matrices without using toxic exogenous materials remains a big challenge. A new strategy to create scaffolds through end-to-end crosslinking through functionalized nanorods leading to well designed architecture is presented here. Self-assembled scaffolds with a denaturation temperature of 110 degrees C, porosity of 70%, pore size of 0.32 MUm and Young's modulus of 231 MPa were developed largely driven by imine bonding between 3-mercapto-1-propanal (MPA) functionalized ZnO nanorods and collagen. The mechanical properties obtained were much higher than that of native collagen, collagen-MPA, collagen-3-mercapto-1-propanol (3MPOH) or collagen- 3-MPOH-ZnO, clearly bringing out the relevance of nanorod mediated assembly of fibrous networks. This new strategy has led to scaffolds with mechanical properties much higher than earlier reports and can provide support for cell growth and facilitation of cell attachment. PMID- 26586668 TI - Bioactive borate glass promotes the repair of radius segmental bone defects by enhancing the osteogenic differentiation of BMSCs. AB - Bioactive borate glass (BG) has emerged as a promising alternative for bone regeneration due to its high osteoinductivity, osteoconductivity, compressive strength, and biocompatibility. However, the role of BG in large segmental bone repair is unclear and little is known about the underlying mechanism of BG's osteoinductivity. In this study, we demonstrated that BG possessed pro-osteogenic effects in an experimental model of critical-sized radius defects. Transplanting BG to radius defects resulted in better repair of bone defects as compared to widely used beta-TCP. Histological and morphological analysis indicated that BG significantly enhanced new bone formation. Furthermore, the degradation rate of the BG was faster than that of beta-TCP, which matched the higher bone regeneration rate. In addition, ions from BG enhanced cell viability, ALP activity, and osteogenic-related genes expression. Mechanistically, the critical genes Smad1/5 and Dlx5 in the BMP pathway and p-Smad1/5 proteins were significantly elevated after BG transplantation, and these effects could be blocked by the BMP/Smad specific inhibitor. Taken together, our findings suggest that BG could repair large segmental bone defects through activating the BMP/Smad pathway and osteogenic differentiation in BMSCs. PMID- 26586669 TI - Mast Cells Produce a Unique Chondroitin Sulfate Epitope. AB - The granules of mast cells contain a myriad of mediators that are stored and protected by the sulfated glycosaminoglycan (GAG) chains that decorate proteoglycans. Whereas heparin is the GAG predominantly associated with mast cells, mast cell proteoglycans are also decorated with heparan sulfate and chondroitin sulfate (CS). This study investigated a unique CS structure produced by mast cells that was detected with the antibody clone 2B6 in the absence of chondroitinase ABC digestion. Mast cells in rodent tissue sections were characterized using toluidine blue, Leder stain and the presence of mast cell tryptase. The novel CS epitope was identified in rodent tissue sections and localized to cells that were morphologically similar to cells chemically identified as mast cells. The rodent mast cell-like line RBL-2H3 was also shown to express the novel CS epitope. This epitope co-localized with multiple CS proteoglycans in both rodent tissue and RBL-2H3 cultured cells. These findings suggest that the novel CS epitope that decorates mast cell proteoglycans may play a role in the way these chains are structured in mast cells. PMID- 26586671 TI - A Nonrandomized Trial of Progressive Resistance Training Intervention in Women With Polycystic Ovary Syndrome and Its Implications in Telomere Content. AB - BACKGROUND: Physical activity is known to relieve the metabolic complications of polycystic ovary syndrome (PCOS), and exercise is also associated with telomere biology. We investigated the changes induced by progressive resistance training (PRT) in telomere content and metabolic disorder in women with PCOS and controls. PARTICIPANTS AND METHODS: Forty-five women with PCOS and 52 healthy women aged 18 to 37 years were submitted to PRT. A linear periodization of PRT was prepared based on a trend of decreasing volume and intensity throughout the training period. The volunteers performed PRT 3 times a week for 4 months. The participants' physical characteristics and hormonal concentrations were measured before and after PRT, as telomere content that was measured using quantitative real-time polymerase chain reaction. RESULTS: Briefly, Progressive resistance training reduced waist circumference, body fat percentage, plasma testosterone and sex hormone-binding globulin concentrations, glycemia, and free androgen index. Fasting insulin and insulin resistance index were greater in women with PCOS. Androstenedione and homocysteine increased after PRT. There were no differences in telomere content between controls (0.96 +/- 0.3 before vs 0.85 +/- 0.21 after) and women with PCOS (0.94 +/- 0.33 before vs 0.88 +/- 0.39 after). Adjusted analysis showed telomere shortening after PRT in all women (0.95 +/- 0.31 before vs 0.86 +/- 0.31 after; P = .03). In women with PCOS, increased homocysteine levels were related to telomere reduction and increased androstenedione was positively correlated with telomere content after PRT. CONCLUSIONS: Progressive resistance training had positive effects on the hormonal and physical characteristics of women with PCOS and controls, but telomere content was reduced and homocysteine level increased in all participants. PMID- 26586665 TI - BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers. AB - BACKGROUND: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. METHODS: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. RESULTS: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10(-) (6)) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10(-3)). These associations were stronger for serous ovarian cancer and for estrogen receptor-negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10(-5) and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10(-5), respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. CONCLUSIONS: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations. PMID- 26586670 TI - The Role of Prolactin in Bone Metastasis and Breast Cancer Cell-Mediated Osteoclast Differentiation. AB - BACKGROUND: Metastasis to the bone is a deleterious aspect of breast cancer and is a preferred site that results in bone loss. Hormones such as prolactin (PRL) have not yet been studied for their role in modulating the secondary tumor bone microenvironment. METHODS: We used quantitative immunohistochemistry with 134 samples of human primary breast cancer and 17 matched primary breast cancers and bone metastases. A Cox proportional hazards regression model was fitted to evaluate the associations between high prolactin receptor (PRLR) expression and time to bone metastasis, adjusting for estrogen receptor status, lymph node status, and chemotherapy status. We assessed osteoclast differentiation, osteoclast size, and measured pit formation in dentine slices. Statistical tests were two-sided. RESULTS: High PRLR expression in the primary breast tumor was associated with a shorter time to metastasis that includes bone (PRLRAQUA Max-per 100 unit hazard ratio = 1.04, 95% confidence interval = 1.00 to 1.07, P = .03). We observed the PRLR in rare samples of bone metastases and matched primary breast cancer. PRL treatment of breast cancer cells induced osteoclast differentiation and bone lysis via secreted factors and was abrogated by a PRLR antagonist (delta1-9-G129R-hPRL). We demonstrated that sonic hedgehog is a PRL regulated cytokine in breast cancer cells and part of the mechanism that induces osteoclast differentiation. CONCLUSIONS: Our evidence indicates that PRL-PRLR can escalate the impact of breast cancer on bone metastasis and that the presence of the PRLR in the tumor microenvironment of breast cancer bone metastasis has the potential to modulate the microenvironment to induce lytic osteoclast formation. PMID- 26586672 TI - Study on size effect of the silica nanospheres with solid core and mesoporous shell on cellular uptake. AB - The properties of mesoporous silica nanoparticles including large surface area, large pore volume, easy surface functionalization and control of structure and pore size has made them promising drug carriers. In this study, the effect of different diameters (50 nm, 70 nm, 90 nm, 110 nm and 140 nm) of silica nanospheres with a solid core and mesoporous shell (mSiO2/SiO2) on cellular internalization in mouse fibroblast cells (L929) was evaluated. The physical properties of the nanostructures were characterized with various methods, such as transmission electron microscopy with x-ray dispersion spectroscopy, thermogravimetric analysis, Fourier transform infrared spectroscopy and zeta potential. In order to define the cellular uptake, the nanostructures were labelled with fluorescent dye Alexa647, and imaging and quantitative methods were applied: laser scanning confocal microscopy, flow cytometry and thermogravimetry. Our results indicate that cellular uptake of the studied nanospheres is size dependent, and nanospheres of 90 nm in diameter showed the most efficient cell internalization. Thus, particle size is an important parameter that determines cellular uptake of nanoparticles and should be considered in designing drug delivery carriers. PMID- 26586673 TI - Partnership with UK health bodies is to bring 11 new institutes to India. PMID- 26586674 TI - Safety and efficacy of hysteroscopic sterilization compared with laparoscopic sterilization: an observational cohort study. PMID- 26586675 TI - Endoscopic-assisted minimally invasive resection of a papillary muscle blood cyst in an adult patient. AB - We describe endoscopic-assisted minimally invasive resection of a blood cyst originating from the papillary muscle that caused severe mitral regurgitation and necessitated mitral valve replacement in an active adult woman, as well as a review of the relevant literature. An endoscopic view increases the visibility of the surgical target and facilitates a precise observation of the tumour and dissection at the appropriate layer. The On-X mechanical valve was chosen for mitral valve repair to minimize thromboembolic risk. This patient additionally benefited from endoscopic-assisted right minithoracotomy in terms of both cosmetic and functional aspects. PMID- 26586676 TI - Chest wall resection for multifocal osseous haemangioma. AB - Intraosseous haemangioma is a rare and benign primary tumour of the bone. We report the case of a 76-year old woman who presented the exceptional condition of multifocal cavernous haemangiomas involving the spine and the ribs, requiring spinal and chest wall resections to confirm the diagnosis and treat the symptoms. PMID- 26586677 TI - Lung ultrasound in adult and paediatric cardiac surgery: is it time for routine use? AB - Respiratory complications are common causes of morbidity and the need of repeated X-ray examinations after cardiac surgery. Ultrasound of the chest, including the lung parenchyma, has been recently introduced as a new tool to detect many pulmonary abnormalities. Despite this, the use of lung ultrasound (LUS) in adult and congenital cardiac surgery remains limited. In particular, lung ultrasound has been mainly used in the evaluation of pleural effusion (PLE), but no consensus exists on methods to quantify the volume of the effusion. Usefulness of LUS for the assessment of diaphragmatic motion in children has also been highlighted, but no clear recommendation exists regarding its routine use. Accuracy of LUS in detecting pulmonary congestion after adult cardiac surgery has been demonstrated, whereas studies in children are still scarce, and data on pneumothorax and lung consolidations are limited in the paediatric population. There are methodological and practicality issues regarding diagnostic protocols (i.e. image views and their sequential order) and instrumentation (transducers and their setting) used in different studies. It also remains unclear which practitioner-the cardiologist, intensivist, pulmonologist or the radiologist, should perform the examination. Cost analysis pertaining to extensive clinical application of lung ultrasound in cardiac surgery has never been performed. Guidelines and recommendations are warranted for a systematic and extensive use of this technique in cardiac surgery at different ages, as it could serve as a useful, versatile tool that could potentially decrease time, radiation exposure and costs. PMID- 26586678 TI - Defining the palliative care patient: its challenges and implications for service delivery. AB - BACKGROUND: Within the UK, general practitioners (GPs) are required to maintain a register of palliative patients under their care. The term 'palliative' when applied to patients encompasses a highly heterogeneous population with varying meanings amongst health professionals. We explored GPs views of what defines a palliative care patient in the context of identifying clinical service needs. METHODS: Audiotaped semi-structured interviews were conducted with GPs to explore how they identify patients requiring inclusion on a palliative care register. Thematic analysis was undertaken and emerging themes identified. RESULTS: Major themes suggested GPs found it difficult to define the palliative care patient. The decision to include a patient on the palliative care register was made as a multidisciplinary team. Patients not identified as 'palliative' were often discussed unofficially if care requirements were significant or prognosis uncertain. The needs of patients with non-malignant disease were considered equal to those with cancer but the challenges of identifying such patients greater. More emphasis was placed on intensity of care required than prognosis. Inclusion on a register triggered greater professional input and was considered beneficial to patient care. CONCLUSIONS: No definition of the palliative care patient exists in working practice and without one there is a risk that some patients with palliative needs will not receive the necessary support, while others may access valuable resources before time. Achieving health policy targets which require identification of palliative patients will continue to be a challenge until a workable and reliable definition of the term 'palliative' is agreed upon. PMID- 26586680 TI - Incurable, but treatable: how to address challenges for an emerging group. PMID- 26586682 TI - Exploring the transition from curative care to palliative care: a systematic review of the literature. AB - BACKGROUND: UK policy guidance on treatment and care towards the end of life identifies a need to better recognise patients who are likely to be in the last 12 months of life. Health and social care professionals have a key role in initiating and managing a patient's transition from 'curative care' to palliative care. The aim of this paper is to provide a systematic review of evidence relating to the transition from curative care to palliative care within UK settings. METHOD: Four electronic databases were searched for studies published between 1975 and March 2010. Inclusion criteria were all UK studies relating to the transition from curative care to palliative care in adults over the age of 18. Selected studies were independently reviewed, data were extracted, quality was assessed and data were synthesised using a descriptive thematic approach. RESULTS: Of the 1464 articles initially identified, 12 papers met the criteria for inclusion. Four themes emerged from the literature: (1) patient and carer experiences of transitions; (2) recognition and identification of the transition phase; (3) optimising and improving transitions; and (4) defining and conceptualising transitions. CONCLUSIONS: The literature suggests that little is known about the potentially complex transition to palliative care. Evidence suggests that continuity of care and multidisciplinary collaboration are crucial in order to improve the experience of patients making the transition. An important role is outlined for generalist providers of palliative care. Incorporating palliative care earlier in the disease trajectory and implementing a phased transition appear key components of optimum care. PMID- 26586683 TI - Defining chronic cancer: patient experiences and self-management needs. AB - OBJECTIVE: Chronic cancer is poorly defined and strategies for supporting patients during this disease phase are lacking. This research defines chronic cancer, explores patient experiences and reviews patients' support needs against those described in the 2007 Department of Health Generic Choice Model for Long term Conditions (DoH-GCM). DESIGN: Semistructured interviews were audio recorded, transcribed and data explored for emergent themes. The a priori themes from DoH GCM were applied: clinical support; self-care and self-management; supporting independence; psychological support; and social and economic factors. RESULTS: 56 patients >12 months postdiagnosis of advanced cancer were recruited from five clinics at a Yorkshire cancer centre: breast (n=11); renal (n=11); colorectal/gastrointestinal (n=12); gynaecological (n=12); and prostate (n=10). Most patients aspired to living normal lives. Challenges included frequent and lengthy hospital appointments, long-term symptom control and uncertainty. Only renal and prostate patients reported routine access to specialist nursing. Uptake of support services was varied and there was generally poor understanding of support pathways for non-medical problems and issues occurring when patients were not receiving active treatment. There was variation in coping strategies and ability of patients to attain a positive outlook on life. CONCLUSIONS: For patients to do well in this cancer phase requires good self-management of symptoms plus taking an active role in accessing appropriate services as needed. Care planning at the point of transition to the chronic phase of cancer should focus on evaluating patients' needs, clarifying support pathways, increasing the profile and involvement of community services and organisations, and supporting patients and families develop effective self-management skills. PMID- 26586684 TI - Development of Prognosis in Palliative care Study (PiPS) predictor models to improve prognostication in advanced cancer: prospective cohort study. AB - OBJECTIVE: To develop a novel prognostic indicator for use in patients with advanced cancer that is significantly better than clinicians' estimates of survival. DESIGN: Prospective multicentre observational cohort study. SETTING: 18 palliative care services in the UK (including hospices, hospital support teams, and community teams). PARTICIPANTS: 1018 patients with locally advanced or metastatic cancer, no longer being treated for cancer, and recently referred to palliative care services. MAIN OUTCOME MEASURES: Performance of a composite model to predict whether patients were likely to survive for "days" (0-13 days), "weeks" (14-55 days), or "months+" (>55 days), compared with actual survival and clinicians' predictions. RESULTS: On multivariate analysis, 11 core variables (pulse rate, general health status, mental test score, performance status, presence of anorexia, presence of any site of metastatic disease, presence of liver metastases, C reactive protein, white blood count, platelet count, and urea) independently predicted both two week and two month survival. Four variables had prognostic significance only for two week survival (dyspnoea, dysphagia, bone metastases, and alanine transaminase), and eight variables had prognostic significance only for two month survival (primary breast cancer, male genital cancer, tiredness, loss of weight, lymphocyte count, neutrophil count, alkaline phosphatase, and albumin). Separate prognostic models were created for patients without (PiPS-A) or with (PiPS-B) blood results. The area under the curve for all models varied between 0.79 and 0.86. Absolute agreement between actual survival and PiPS predictions was 57.3% (after correction for over optimism). The median survival across the PiPS-A categories was 5, 33, and 92 days and survival across PiPS-B categories was 7, 32, and 100.5 days. All models performed as well as, or better than, clinicians' estimates of survival. CONCLUSIONS: In patients with advanced cancer no longer being treated, a combination of clinical and laboratory variables can reliably predict two week and two month survival. PMID- 26586685 TI - Accuracy of prognosis prediction by PPI in hospice inpatients with cancer: a multi-centre prospective study. AB - The Palliative Prognostic Index (PPI) is a prognostication tool for palliative care patients based on clinical indices developed in Japan and further validated by one study in the UK. The aim of this study was to test its prediction accuracy in a large inpatient hospice sample. The admitting doctor in three inpatient hospices calculated the PPI score on admission. Two hundred and sixty-two patients were included in this study. Based on the PPI score, three subgroups were identified. Group 1 corresponded to patients with PPI <=4 and the median survival of 53 days (95% CI 40 to 80 days). Group 2 corresponded to those with PPI >4 and <=6 and the median survival 15 days (95% CI 12 to 26 days) and Group 3 corresponded to patients with PPI >6 and the median survival of 5 days (95% CI 3 to 7 days). In this study, PPI was able to identify patients' likelihood of dying within 3 weeks with a sensitivity of 64% and specificity of 83%. It was able to identify a 6-week survival chance with a sensitivity of 62% and specificity of 86%. A one-unit increase in PPI score was estimated to increase the hazard for death by a factor of 1.33 (95% CI 1.26 to 1.40), based on fitting a stratified Cox proportional hazards model. The authors conclude that PPI can be used to predict prognosis for patients with advanced cancer. PMID- 26586686 TI - Improving care for patients whose recovery is uncertain. The AMBER care bundle: design and implementation. AB - INTRODUCTION: Despite preferences to the contrary, 53% of deaths in England occur in hospital. Difficulties in managing clinical uncertainty can result in delayed recognition that a person may be approaching the end of life, and a failure to address his/her preferences. Planning and shared decision-making for hospital patients need to improve where an underlying condition responds poorly to acute medical treatment and there is a risk of dying in the next 1-2 months. This paper suggests an approach to improve this care. INTERVENTION: A care bundle (the AMBER care bundle) was designed by a multiprofessional development team, which included service users, utilising the model for improvement following an initial scoping exercise. The care bundle includes two identification questions, four subsequent time restricted actions and systematic daily follow-up. CLINICAL IMPACT: This paper describes the development and implementation of a care bundle. From August 2011 to July 2012, 638 patients received care supported by the AMBER care bundle. In total 42.8% died in hospital and a further 14.5% were readmitted as emergencies within 30 days of discharge. Clinical outcome measures are in development. CONCLUSIONS: It has been possible to develop a care bundle addressing a complex area of care which can be a lever for cultural change. The implementation of the AMBER care bundle has the potential to improve care of clinically uncertain hospital patients who may be approaching the end of life by supporting their recognition and prompting discussion of their preferences. Outcomes associated with its use are currently being formally evaluated. PMID- 26586687 TI - Quality indicators for palliative and end of life care: a review of Swedish policy documents. AB - BACKGROUND: All patients with palliative and end of life care needs should be guaranteed equal and safe treatment and care, regardless of their disease or site of care. The inclusion of quality indicators in national guidelines and other guiding documents supports quality assurance and improvement in provision of care. The aim of this paper was to review existing quality indicators in national Swedish policy documents relevant to palliative and end of life care. METHODS: We reviewed existing guidelines for diseases expected to require palliative care issued by the National Board of Health and Welfare, existing regional clinical practice guidelines and the annual report of the Swedish Register of Palliative Care (SRPC) up until 2010. RESULTS: We found 11 quality indicators pertinent to palliative and end of life care in the guidelines for cancer diseases and 'The care and nursing of the elderly'. The indicators included assessment and treatment of pain, communication with the patient and the family, documentation in the patient record and registration in the SRPC. In the national guidelines for cardiology, pulmonary diseases, stroke, diabetes and dementia, there were no indicators relevant for palliative or end of life care. CONCLUSIONS: In the existing Swedish national guidelines for many different diseases, there is still a great need to define clinically relevant and feasible outcome measures of quality of palliative and end of life care. PMID- 26586689 TI - Imaging in carpal instability. AB - Carpal instability is a complex and heterogeneous clinical condition. Management requires accurate identification of structural injury with an understanding of the resultant movement (kinematic) and load transfer (kinetic) failure. Static imaging techniques, such as plain film radiography, stress views, ultrasound, magnetic resonance, MR arthrography and computerized tomography arthrography, may accurately depict major wrist ligamentous injury. Dynamic ultrasound and videofluoroscopy may demonstrate dynamic instability and kinematic dysfunction. There is a growing evidence base for the diagnostic accuracy of these techniques in detecting intrinsic ligament tears, but there are limitations. Evidence of their efficacy and relevance in detection of non-dissociative carpal instability and extrinsic ligament tears is weak. Further research into the accuracy of existing imaging modalities is still required. Novel techniques, including four dimensional computerized tomography and magnetic resonance, can evaluate both cross-sectional and functional carpal anatomy. This is a narrative review of level-III studies evaluating the role of imaging in carpal instability. PMID- 26586690 TI - A method of stabilization of the fingers for intraoperative lateral radiographs. PMID- 26586691 TI - Human Induced Pluripotent Stem Cell-Derived Podocytes Mature into Vascularized Glomeruli upon Experimental Transplantation. AB - Glomerular podocytes express proteins, such as nephrin, that constitute the slit diaphragm, thereby contributing to the filtration process in the kidney. Glomerular development has been analyzed mainly in mice, whereas analysis of human kidney development has been minimal because of limited access to embryonic kidneys. We previously reported the induction of three-dimensional primordial glomeruli from human induced pluripotent stem (iPS) cells. Here, using transcription activator-like effector nuclease-mediated homologous recombination, we generated human iPS cell lines that express green fluorescent protein (GFP) in the NPHS1 locus, which encodes nephrin, and we show that GFP expression facilitated accurate visualization of nephrin-positive podocyte formation in vitro These induced human podocytes exhibited apicobasal polarity, with nephrin proteins accumulated close to the basal domain, and possessed primary processes that were connected with slit diaphragm-like structures. Microarray analysis of sorted iPS cell-derived podocytes identified well conserved marker gene expression previously shown in mouse and human podocytes in vivo Furthermore, we developed a novel transplantation method using spacers that release the tension of host kidney capsules, thereby allowing the effective formation of glomeruli from human iPS cell-derived nephron progenitors. The human glomeruli were vascularized with the host mouse endothelial cells, and iPS cell-derived podocytes with numerous cell processes accumulated around the fenestrated endothelial cells. Therefore, the podocytes generated from iPS cells retain the podocyte-specific molecular and structural features, which will be useful for dissecting human glomerular development and diseases. PMID- 26586693 TI - Margaret McCartney: Juniors vote to strike--a profession united for the NHS. PMID- 26586692 TI - Six Months of Hydroxyurea Reduces Albuminuria in Patients with Sickle Cell Disease. AB - The earliest symptom of glomerular injury in patients with sickle cell disease (SCD) is microalbuminuria. The effect of hydroxyurea (HU) on urine albumin-to creatinine ratio (ACR) is unclear and should be determined, because increasing numbers of patients with SCD take this drug to improve red blood cell function. In this cohort study of 58 SS-homozygous adults with SCD who initiated HU therapy, we evaluated ACR changes and relationships of these changes with demographic, clinical, and biologic parameters at HU initiation (baseline) and 6 months later (follow-up). Between baseline and follow-up, ACR declined significantly for the entire population (3.0-1.7 mg/mmol; P<0.01), but this was primarily driven by the ACR reduction in the microalbuminuria subgroup (8.1-2.3 mg/mmol; P=0.03; n=23). According to bivariate analyses on 39 patients who did not receive a blood transfusion during the study period, the baseline to follow up ACR decline was strongly associated with decreases in levels of hemolysis markers, percentage of dense red blood cells, and systolic BP. Bivariate analysis also revealed a close association between the ACR decrease and high baseline levels of hemolysis markers and percentage of dense red blood cells. These results show that urine ACR decreased significantly after 6 months of HU and confirm a close relationship between ACR and hemolysis evolution in patients with SCD. PMID- 26586694 TI - Bordetella biofilms: a lifestyle leading to persistent infections. AB - Bordetella bronchiseptica and B. pertussis are Gram-negative bacteria that cause respiratory diseases in animals and humans. The current incidence of whooping cough or pertussis caused by B. pertussis has reached levels not observed since the 1950s. Although pertussis is traditionally known as an acute childhood disease, it has recently resurged in vaccinated adolescents and adults. These individuals often become silent carriers, facilitating bacterial circulation and transmission. Similarly, vaccinated and non-vaccinated animals continue to be carriers of B. bronchiseptica and shed bacteria resulting in disease outbreaks. The persistence mechanisms of these bacteria remain poorly characterized. It has been proposed that adoption of a biofilm lifestyle allows persistent colonization of the mammalian respiratory tract. The history of Bordetella biofilm research is only a decade long and there is no single review article that has exclusively focused on this area. We systematically discuss the role of Bordetella factors in biofilm development in vitro and in the mouse respiratory tract. We further outline the implications of biofilms to bacterial persistence and transmission in humans and for the design of new acellular pertussis vaccines. PMID- 26586696 TI - Differences in Transitional Care Provided to Mexican American and Non-Hispanic White Older Adults. AB - BACKGROUND: Transitional care, assisting patients to move safely through multiple health care settings, may be insufficient for older Hispanic patients. PURPOSE: Describe home health care services referral rates for Hispanic and non-Hispanic White (NHW) patients and factors that influence case managers' (CMs') discharge planning processes. DESIGN: Organized by the Ethno-Cultural Gerontological Nursing Model, health records were reviewed ( n = 33,597 cases) and supplemented with qualitative description ( n = 8 CMs). FINDINGS: Controlling for gender, insurance type, age, and hospital length of stay, NHW older adults received more home health care services referrals (odds ratio = 1.23). Insurance coverage was the most frequent determinant of CMs' post-hospital care choices, rather than patients' being Hispanic. NHW older adults were more likely to have insurance than Hispanic older adults. IMPLICATIONS: Insurance coverage being CMs' primary consideration in determining patients' dispositions is a form of systems-level discrimination for Hispanic vulnerable groups, which combined with other hospital level constraints, should be addressed with policy-level interventions. PMID- 26586695 TI - Cascading network failure across the Alzheimer's disease spectrum. AB - Complex biological systems are organized across various spatiotemporal scales with particular scientific disciplines dedicated to the study of each scale (e.g. genetics, molecular biology and cognitive neuroscience). When considering disease pathophysiology, one must contemplate the scale at which the disease process is being observed and how these processes impact other levels of organization. Historically Alzheimer's disease has been viewed as a disease of abnormally aggregated proteins by pathologists and molecular biologists and a disease of clinical symptoms by neurologists and psychologists. Bridging the divide between these scales has been elusive, but the study of brain networks appears to be a pivotal inroad to accomplish this task. In this study, we were guided by an emerging systems-based conceptualization of Alzheimer's disease and investigated changes in brain networks across the disease spectrum. The default mode network has distinct subsystems with unique functional-anatomic connectivity, cognitive associations, and responses to Alzheimer's pathophysiology. These distinctions provide a window into the systems-level pathophysiology of Alzheimer's disease. Using clinical phenotyping, metadata, and multimodal neuroimaging data from the Alzheimer's Disease Neuroimaging Initiative, we characterized the pattern of default mode network subsystem connectivity changes across the entire disease spectrum (n = 128). The two main findings of this paper are (i) the posterior default mode network fails before measurable amyloid plaques and appears to initiate a connectivity cascade that continues throughout the disease spectrum; and (ii) high connectivity between the posterior default mode network and hubs of high connectivity (many located in the frontal lobe) is associated with amyloid accumulation. These findings support a system model best characterized by a cascading network failure--analogous to cascading failures seen in power grids triggered by local overloads proliferating to downstream nodes eventually leading to widespread power outages, or systems failures. The failure begins in the posterior default mode network, which then shifts processing burden to other systems containing prominent connectivity hubs. This model predicts a connectivity 'overload' that precedes structural and functional declines and recasts the interpretation of high connectivity from that of a positive compensatory phenomenon to that of a load-shifting process transiently serving a compensatory role. It is unknown whether this systems-level pathophysiology is the inciting event driving downstream molecular events related to synaptic activity embedded in these systems. Possible interpretations include that the molecular-level events drive the network failure, a pathological interaction between the network-level and the molecular-level, or other upstream factors are driving both. PMID- 26586697 TI - Tobacco Use Among Arab Immigrants Living in Colorado: Prevalence and Cultural Predictors. AB - PURPOSE: The authors determined the prevalence of smoking among Arab immigrants living in Colorado. The authors also evaluated the relationship between acculturation and tobacco use, including both cigarettes and hookah among Arab immigrants. METHOD: A cross-sectional survey of 100 adult Arab immigrants living in Colorado was carried out. RESULTS: The results revealed that 19% of the study participants were current cigarette smokers and 21% were current hookah smokers. Participants who were more integrated into Arab culture were more likely to use tobacco products ( p = .03) and to have family members ( p = .02) and friends who use tobacco products ( p = .007). CONCLUSIONS: Acculturation plays a major role in affecting the health habits of Arab immigrants living in Colorado, especially in the area of hookah smoking. IMPLICATIONS FOR PRACTICE: Understanding some culturally relevant predictors of tobacco use might assist health care providers in designing successful smoking cessation programs. PMID- 26586698 TI - Immune Activity of BCG Infected Mouse Macrophages Treated with a Novel Recombinant Mouse Lactoferrin. AB - Lactoferrin has been investigated for its adjuvant action to boost the BCG vaccine. Previous studies demonstrated that lactoferrin (LF) enhanced efficacy of the Bacillus Calmette-Guerin (BCG) vaccine to protect mice against the virulent Erdman Mycobacterium tuberculosis challenge. The studies here investigate the hypothesis that a novel CHO-derived recombinant mouse LF can modify cytokine production and antigen presentation molecules on macrophages. The mouse LF (rmLF) was examined for effects on bone marrow derived macrophage (BMM) activities when cultured with BCG. Comparisons were made to CHO-derived recombinant human LF (rhLF). Inflammatory cytokine responses were investigated, as were antigen presentation and associated co-stimulatory molecules. Cytokine responses were subsequently measured when these cells were co-cultured with naive or BCG sensitized CD4+ lymphocytes. While overall responses were similar between mouse, human, and bovine forms, the homologous rmLF treated infected BMMs showed unique activation patterns of cytokine production. These results indicate that species specific LF can have different effects on mouse macrophages exposed to BCG, thus potentially affecting adjuvant activity when used in models of vaccination in mice. PMID- 26586699 TI - Inhibition of HBV Replication in HepG2.2.15 Cells by Human Peripheral Blood Mononuclear Cell-Derived Dendritic Cells. AB - Anti-HBV therapy is essential for patients awaiting liver transplantation. This study aimed to explore the effects of dendritic cells (DCs) derived from the peripheral blood of hepatitis B patients on the replication of HBV in vivo and to evaluate the biosafety of DCs in clinical therapy. Peripheral blood mononuclear cells (PBMCs) were isolated from HBV-infected patients and maturation-promoting factors and both HBsAg and HBcAg were used to induce DC maturation. Mature DCs and lymphocytes were co-cultured with human hepatocyte cell HL-7702 or HBV producing human hepatocellular carcinoma cell HepG2.2.15. We found that mature lymphocytes exposed to DCs in vitro did not influence morphology or activities of HL-7702 and HepG2.2.15 cells. Liver function indexes and endotoxin levels in the cell supernatants did not change in these co-cultures. Additionally, supernatant and intracellular HBV DNA levels were reduced when HepG2.2.15 cells were co cultured with mature lymphocytes that had been cultured with DCs, and HBV covalently closed circular DNA (cccDNA) levels in HepG2.2.15 cells also decreased. Importantly, DC-mediated immunotherapy had no mutagenic effect on HBV genomic DNA by gene sequencing of the P, S, X, and C regions of HBV genomic DNA. We conclude that PBMC-derived DCs from HBV-infected patients act on autologous lymphocytes to suppress HBV replication and these DC clusters showed favorable biosafety. PMID- 26586700 TI - Optimization PCR for Detection CTG/CCTG-Repeat Expansions in the Diagnosis of Myotonic Dystrophies. AB - CONTEXT: Myotonic dystrophies (DMs) are a group of autosomal dominant neuromuscular disorders which are caused by large CTG/CCTG-repeat expansions in untranslated regions of DMPK/ZNF9 gene. The "phenotypic overlap" in DMs creates complication in distinguishing patients with DM1 from patients with DM2 and underscores the need for these patients to undergo genetic test; therefore, detection and accurate sizing of the CTG/CCTG-repeat expansions are necessary. Templates with long CTG/CCTG tandem repeats are difficult to amplify by convention PCR. AIMS: The aim of our study was to develop an efficient, economic amplification method which based on combination of primer design, modified annealing, and extension conditions in PCR amplification. SETTINGS AND DESIGN: We detected and analyzed the CTG-repeat expansions in patients having clinical, electrophysiological, and muscle pathology features indicative of DMs by optimization PCR. If no CTG-repeat expansions were detected, we subsequently analyzed the CCTG-repeat expansions in the remaining patients. RESULTS: 42 participants included 25 DMs patients and 17 family members. 22 patients showed CTG-repeat expansions, the CTG-repeat ranged from 53 to 683 and the average was 535; 3 patients showed CCTG-repeat expansions, the CCTG-repeat ranged from 400 to 450 and the average was 416. CONCLUSIONS: Molecular genetic tests are essential for DMs diagnosis; Optimization PCR under the optimal conditions of primer design, modified annealing, and extension conditions can be used for efficient PCR in DMs diagnosis; Optimization PCR can greatly improve the positive detection of DMs, provide an economic, accurate, and rapid method for routine diagnostic use. PMID- 26586701 TI - Protective Effect of Thalidomide on Liver Injury in Rats with Acute Pancreatitis via Inhibition of Oxidative Stress. AB - This study was designed to investigate the preventive effect of thalidomide on acute pancreatitis-associated liver injury in the rat and analyze its relationship with oxidative stress. The acute pancreatitis of rats was induced by the retrograde injection of 5% sodium taurocholate into the biliopancreatic duct. Thalidomide (100 mg/kg) was given daily via the intragastric route for 8 days before this injection. The levels of oxidative stress parameters including superoxide dismutase (SOD), glutathione peroxidase (GSHpx), and malondialdehyde (MDA) in the liver were detected by biochemical assay. Nuclear factor-kappaB p65 (NF-kappaBp65), tumor necrosis factor alpha (TNF-alpha), and intercellular adhesion molecule-1 (ICAM-1) protein and mRNA levels in the liver were detected using western blots and reverse transcriptase polymerase chain reaction, respectively. Compared with the untreated model group, liver histopathology, SOD, GSHpx, MDA levels, NF-kappaBp65, TNF-alpha, ICAM-1 protein, and mRNA levels in the liver of rats given thalidomide were improved significantly. Results demonstrate that thalidomide may exert its effects on oxidative stress to attenuate the progression of acute pancreatitis-associated liver injury in rats. PMID- 26586702 TI - Bioinformatics Analysis to Determine Prognostic Mutations of 72 de novo Acute Myeloid Leukemia Cases from the Cancer Genome Atlas (TCGA) with 23 Most Common Mutations and no Abnormal Cytogenetics. AB - OBJECTIVES: Up to 40% of acute myeloid leukemia (AML) patients have normal cytogenetics (CN-AML) but they may have gene mutations. An important issue in the treatment of CN-AML is how gene mutation patterns may help with patient management. The Cancer Genome Atlas (TCGA) database has data from 200 cases of de novo AML including cytogenetics, gene mutations, and survival duration (prognosis). METHODS: Cases with the most common mutations and no cytogenetic abnormalities were selected from the TCGA. Unsupervised neural network analysis was performed to group them into clusters according to their pattern of mutations and survival. RESULTS: 72 cases of CN-AML with the 23 most common mutations were obtained from TCGA. Clustering was found to be based on 6 mutations, with the following prognostic groups: (a) good: NPM1, CEBPA, or TET2, (b) intermediate: NPM1/DNMT3A, or other mutations, (c) poor: RUNX1, FLT3-ITD, FLT3-ITD/NPM1, or FLT3-ITD/CEBPA. Some discrepancy between our results and those from previous studies is most likely due to inclusion of AML cases transformed from myeloproliferative neoplasms or myelodysplastic syndrome in previous studies. CONCLUSIONS: This study provides further molecular characterization and prognostic data most specific for the de novo subgroup of CN-AML patients. PMID- 26586703 TI - Inducible Nitric Oxide Synthase in the Duodenal Mucosa Is Associated with Mast Cell Degranulation in Patients with Functional Dyspepsia. AB - AIM: Functional dyspepsia (FD) is a clinical syndrome with chronic gastroduodenal symptoms without noticeable organic or systemic diseases. According to the Rome III consensus, FD can be subdivided into PDS (postprandial distress syndrome) and EPS (epigastric pain syndrome). Neurotransmitters are involved in the development and pathology of FD. However, the expression profiles of neurotransmitters in FD patients are not clear. This study aimed to investigate the expression profile of neurotransmitters in the duodenal mucosa of FD patients. METHODS: A total of 48 FD patients treated at our hospital were included in this study: 23 patients with PDS and 25 patients with EPS. Another 21 healthy volunteers served as normal controls. The duodenal mucosa was biopsied with gastroscopy and examined with immunohistochemical staining against serotonin, substance P, inducible nitric oxide synthase (iNOS), and vasoactive intestinal peptide (VIP). Mast cells were identified with toluidine blue staining. RESULTS: The duodenal iNOS levels were significantly higher in PDS patients than the normal controls (P<0.05). The expression of serotonin, substance P, and VIP did not differ significantly among the groups. Mast cell counts and the percentage of mast cells with degranulation were significantly higher in PDS and EPS patients than normal controls (P<0.001) In addition, iNOS expression levels were positively correlated with percentage of degranulating mast cells (r=0.321, P=0.008). CONCLUSIONS: In conclusion, duodenal iNOS may be involved in the pathogenesis of PDS. PMID- 26586704 TI - Advanced Lung Cancer Is Associated with Decreased Expression of Perforin, CD95, CD38 by Circulating CD3+CD8+ T Lymphocytes. AB - It is known that dysregulation of the immune system is closely related to the development of lung cancer and that CD8+T lymphocytes play a critical role in antitumor immunity. We analyzed the percentage of CD3+CD8+ T cells in peripheral blood, and expressions of the activated molecules, perforin, CD95, CD28, HLA-DR and CD38 in circulating CD3+CD8+ T cells from 68 lung cancer cases with stage I~II and 61 lung cancer cases with stage III~IV by flow cytometry. 61 lung cancer cases with stage III~IV were followed up for more than 6 months and survival time was recorded. The percentages of perforin+ cells, CD95+ cells and CD38+ cells in fresh CD3+CD8+ T lymphocytes of stage III~IV group were lower than those of stage I~II group (p=0.021; p=0.043; p=0.036). And an increased percentage of CD3+CD8+perforin+ cells was shown to have a positive effect on the survival time in stage III~IV lung cancer patients (p=0.043). Advanced lung cancer patients have characteristics of impairment in the cytotoxicity of circulating CD3+CD8+ T lymphocytes and perforin expression in circulating CD3+CD8+ T cells might be used as a prognostic biomarker for the advanced lung cancer. PMID- 26586705 TI - Diagnosis of Drug Resistance to Fluoroquinolones, Amikacin, Capreomycin, Kanamycin and Ethambutol with Genotype MTBDRsl Assay: a Meta-Analysis. AB - BACKGROUND: The Genotype MTBDRsl is a new-generation PCR-based line-probe assay for rapid identification of the resistance to the second-line antituberculosis drugs with a single strip. The aim of this meta-analysis was to evaluate the performance of Genotype MTBDRsl in detecting drug resistance to fluoroquinolones, amikacin, capreomycin, kanamycin and ethambutol in comparison with the phenotypic drug susceptibility test. DESIGN: We searched Pubmed, Embase and the Cochrane Library and calculated the sensitivity, the specificity, the positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), corresponding 95% confidence interval (CI), and the area under the summary receiver operating characteristic (SROC) curves (AUC), and tested heterogeneity in accuracy estimates with the Spearman correlation coefficient and Chi-square. RESULTS: The summarized sensitivity (95% CI), specificity (95% CI), and AUC (standard error) were 0.869 (0.847-0.890), 0.973 (0.965-0.979) and 0.9690 (0.0188) for fluoroquinolones, 0.868 (0.829-0.900), 0.998 (0.994-0.999) and 0.9944 (0.0050) for amikacin, 0.879 (0.838-0.914), 0.970 (0.958-0.978) and 0.9791 (0.0120) for capreomycin, 0.501 (0.461-0.541), 0.991 (0.983-0.996) and 0.9814 (0.0114) for kanamycin and 0.686 (0.663-0.709), 0.871 (0.852-0.888) and 0.7349 (0.0639) for ethambutol, respectively. CONCLUSION: The genotype MTBDRsl demonstrate excellent accuracy for detecting drug resistance to fluoroquinolones, amikacin, and capreomycin, but it may not be an appropriate choice for detection of kanamycin and ethambutol. PMID- 26586706 TI - The Effect of Colchicine on Mean Platelet Volume in Behcet's Disease. AB - BACKGROUND: Patients with Behcet's Disease are recognized to be at an increased risk for venous and/or arterial thrombosis. Colchicine reduces the initiation and amplification of inflammation and is believed to suppress secretion of cytokines and chemokines and in vitro platelet aggregation. OBJECTIVES: To evaluate the effect of colchicine on levels of mean platelets volume, platelets, erythrocyte sedimentation rate, and C-reactive protein in patients with Behcet's Disease. METHODS: Patients with Behcet's Disease were evaluated for mean platelets volume before colchicine therapy (Group 1) and after 6-month from beginning of colchicine treatment (Group 2). RESULTS: Fifty-two subjects were evaluated. The mean age was 38.3 years and the female/male ratio was 28/24=1.16. Laboratory tests were evaluated in Group 1 and Group 2. The median level of mean platelets volume was 9.2+/-0.8 fl in Group 1 and 8.9+/-0.9 fl in Group 2. Levels of mean platelets volume was found as significant between Group 1 and 2 (p=0.001). CONCLUSIONS: Given the proposed relationship between MPV and platelet activity, MPV may serve as a surrogate essay for Behcet's response to colchicine. Colchicine might suppress platelet function and be used in vascular involvement together with immunosuppressant agents in Behcet's Disease. Further studies in large population are needed to evaluate the role of colchicine in platelet function and the effect of colchicine on thrombosis in BD. PMID- 26586707 TI - Mir-181b Functions as Anti-Apoptotic Gene in Post-Status Epilepticus via Modulation of Nrarp and Notch Signaling Pathway. AB - BACKGROUND: The expression pattern and function of miRs in the post-status epilepticus (SE) rat are still unclear. This study aimed to investigate the role and mechanism of miR-181b in the post- SE rat. METHODS: The lithium-pilocarpine induced SE model was established in Sprague-Dawley rats. The expression of miR 181b in rat blood and hippocampus was confirmed by RT-PCR at 24 hous and 7 days post-SE. The expression of Nrarp, Hes-1, and Bcl-2 was detected by RT-PCR and western blot. After the rat model was treated with LV-rno-mir181b and LV-anti 181b-5p, the expression change of miR-181b, Nrarp, Hes-1, and Bcl-2 was examined again. The effects of altering the expression of miR-181b on neurone cell apoptosis post-SE were assessed. RESULTS: The expression of miR-181b significantly decreased both in post-SE rat hippocampus and peripheral blood at 24 hours and 7 days (p<0.05). Nrarp is up-regulated, however, Hes-1 and Bcl-2 are down-regulated (p<0.05). LV-miR-181b treatment induced down-regulation of Nrarp and up-regulation of Hes-1 and Bcl-2 (p<0.05). Neurone cell apoptosis decreased in miR-181b group and post-SE rat hippocampal (p<0.05). CONCLUSIONS: Our study showed the low-expression of miR-181b in the hippocampus in a post-SE rat model. MiR-181b negatively regulated Nrarp as an anti-apoptotic gene via Notch signaling pathway. PMID- 26586708 TI - Elevated Local and Serum CX3CL1(Fractalkine) Expression and Its Association with Disease Severity in Patients with Psoriasis. AB - BACKGROUND AND OBJECTIVE: Psoriasis is a chronic immune and inflammatory skin disease. Fractalkine (FKN, CX3CL1), a membrane-bound CX3C chemokine, has been identified to play an important role in the pathogenesis of psoriasis. However, whether it is elevated in the tissue or peripheral blood of patients with psoriasis and is associated with disease severity is unclear. This study was carried out to explore local and serum FKN expression in patients with psoriasis and investigate the relationship with the disease severity. METHODS: Serum samples were collected from 47 plaque psoriasis patients and 49 healthy individuals. Serum FKN levels were measured by an enzymelinked immunosorbent assay. The PASI scores of patients with psoriasis and their correlation with serum FKN levels were evaluated. 16 cases of local skin tissues were collected from psoriasis patients and controls who underwent traumatic incidents needing autologous skin grafting, respectively. FKN protein and mRNA expression were examined using Western blotting and RT-PCR, respectively. RESULTS: Local and serum expression of FKN were significantly higher than the expression in the controls (P<0.05), serum FKN levels were positively associated with Psoriasis Area and Severity Index (PASI) scores, (P<0.001) and levels of IL-22 (P<0.001) and IFN-gamma (P<0.001). CONCLUSION: These results suggest that FKN may play an important role in the pathogenesis of psoriasis and represent a reliable biomarker to reflect disease severity. Therapeutic interventions that target FKN in psoriasis deserve further study. PMID- 26586709 TI - Evaluation of the Lipid Interference for Siemens BN ProSpec Cystatin C Assay Using Pediatric Samples. AB - Endogenous interferents (lipids, hemoglobin and bilirubin) are a common cause of pre-analytical laboratory errors. We evaluated the effect of lipemia on Siemens cystatin C assay using pediatric samples. Lipemic samples were prepared by adding various concentrations of triglycerides into low and high cystatin C sample pools. Cystatin C concentrations were then measured on Siemens BN ProSpec analyzer and change of the analyte concentrations was determined. Low and high cystatin C sample pools were not affected by additions of lower lipid concentrations (150, 500 and 750 mg/dL), while the negative bias of <10% was seen with additions of higher lipid concentrations (1000 and 1500 mg/dL). Our results suggest that the BN ProSpec assay is a good alternative for cystatin C measurements in our pediatric population with no major interference from lipemia. PMID- 26586710 TI - Clinicopathologic Findings of Hematological Malignancy: a Retrospective Autopsy Study. AB - Hematological malignancies exhibit many clinical presentations, from ambiguous systemic symptoms to rapid multi-organ failure. By identifying common clinical, laboratory, and autopsy findings in patients with a hematological malignancy, living patients may be diagnosed and treated earlier. We retrospectively reviewed our institution's 2003-2013 autopsy and respective medical records for patients with a hematological malignancy. Clinical, laboratory and autopsy findings were retrieved. 30 patients with hematological malignancy were identified, including 14 "new" cases, defined here as diagnosed either post-mortem (n=6) or within 4 weeks of death (n=8). 16 patients had a known prior diagnosis of greater than 4 weeks and/or received treatment. "New" patients most frequently presented with pain, dyspnea and gastrointestinal symptoms. Common laboratory findings for new lymphoma patients included elevated aspartate aminotransferase, prothrombin time (PT), lactate dehydrogenase (LDH), lactic acidosis, and cytopenia. New leukemia patients had peripheral smear findings, thrombocytopenia, elevated PT, lactic acidosis and elevated LDH. Patients with a prior diagnosis of hematological malignancy had similar findings to new patients with increased thrombocytopenia in prior lymphoma cases. Immediate causes of death were most frequently multi organ failure through malignant organ infiltration and/or septic shock. With an increased awareness of hematological malignancy in a differential diagnosis, a timely diagnosis or clinical interventions can eventually save lives. PMID- 26586711 TI - Childhood de novo CD5+ Diffuse Large B-cell Lymphoma: a Separate Entity? AB - De novo CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) is a subtype of DLBCL found predominantly in older individuals. This particular subtype has been associated with a female predominance and a more aggressive clinical course. Conversely, this entity has not been described in the pediatric population. We report a case of a 12 year-old boy who presented with an ileocecal intussusception. Radiologic, morphologic, and immunophenotypic analysis revealed an isolated extranodal mass consistent with a CD5+ DLBCL, germinal center cell phenotype. Fluorescent in situ hybridization analysis was negative for cMYC, BCL6, BCL2, MLL, and IGH/CCND1 rearrangement and showed loss of one copy of MLL in 32% cells. The patient was treated with four cycles of cyclophosphamide, vincristine, prednisolone, methotrexate, and doxorubicin and achieved complete remission. To the best of our knowledge, this is the first detailed report of a de novo CD5+ DLBCL occurring in a child. PMID- 26586712 TI - One Novel Frameshift Mutation on Exon 64 of COL7A1 Gene in an Iranian Individual Suffering Recessive Dystrophic Epidermolysis Bullosa. AB - Recessive dystrophic epidermolysis bullosa (RDEB) is an extremely rare subtype of bullous dermatosis caused by the COL7A1 gene mutation. After genomic DNA extraction from the peripheral blood sample of all subjects (3 pedigree members and 3 unrelated control individuals), COL7A1 gene screening was performed by PCR amplification and direct DNA sequencing of all of the coding exons and flanking intronic regions. Genetic analysis of the COL7A1 gene in an affected individual revealed a novel mutation: c.5493delG (p.K1831Nfs*10) in exon 64 of the COL7A1 gene in homozygous state. This mutation was not discovered in 3 unrelated Iranian control individuals. These data suggest that c.5493delG may influence the phenotype of RDEB. The result of this case report contributes to the expanding database on COL7A1 mutations. PMID- 26586713 TI - Coccidioidomycosis Presented as a Pelvic Mass in an Otherwise Healthy Female. AB - We present a case of a 32 year old female with a past medical history of hypertension who presented with several years of chronic back pain and was ultimately diagnosed with isolated pelvic coccidioidomycosis. She was initially seen by gynecologic oncology for assessment of possible metastatic cancer by image study, but a cytopathologic diagnosis of coccidioidomycosis lead to a cancellation of the planned surgery and extensive antifungal treatment managed by the infectious disease team. She had no known previous pulmonary disease or immunodeficiency. Pelvic coccidioidomycosis without known pulmonary disease is very rare, and disseminated infection typically only occurs in those who are severely immunocompromised. Our case presented with several years of back pain and a pelvic mass mistaken for possible malignancy by image study. PMID- 26586714 TI - Identification of a Novel Deletion in AVP-NPII Gene in a Patient with Central Diabetes Insipidus. AB - Central Diabetes Insipidus (CDI) is caused by a deficiency of antidiuretic hormone and characterized by polyuria, polydipsia and inability to concentrate urine. Our objective was to present the results of the molecular analyses of AVP neurophysin II (AVP-NPII) gene in a large familial neurohypophyseal (central) DI pedigree. A male patient and his family members were analyzed and the prospective clinical data were collected. The proband applied to hospital for eligibility to be a recruit in Armed Forces. The patient had severe polyuria (20 L/day), polydipsia (20.5 L/day), fatique, and deep thirstiness. CDI was confirmed with the water deprivation-desmopressin test according to an increase in urine osmolality from 162 mOsm/kg to 432 mOsm/kg after desmopressin acetate injection. To evaluate the coding regions of AVP-NPII gene, polymerase chain reactions were performed and amplified regions were submitted to direct sequence analysis. We detected a heterozygous three base pair deletion at codon 69-70 (207_209delGGC) in exon 2, which lead to a deletion of the amino acid alanine. A three dimensional protein structure prediction was shown for the deleted AVP-NPII and compared with the wild type. The three base pair deletion may yield an abnormal AVP precursor in neurophysin moiety, but further functional analyses are needed to understand the function of the deleted protein. PMID- 26586715 TI - A Rare Case of Waldenstrom Macroglobulinemia/Lymphoplasmacytic Lymphoma with Light Chain Discrepancy between B Lymphocyte Population and Serum Paraprotein. AB - Waldenstrom macroglobulinemia (WM) is a subset of lymphoplasmacytic lymphoma with bone marrow involvement, monotypic immunoglobulin (Ig) M and a light chain of neoplastic cells. A 68-year-old woman presented with fever, nausea, vomiting, and pancytopenia. Her serum albumin/globulin ratio was reversed, and monoclonal gammopathy of IgM, lambda type (23.20%, 1.58 g/dL) was detected. In her bone marrow, increased small lymphocytes were admixed with plasmacytoid lymphocytes and plasma cells. She was diagnosed as having lymphoplasmacytic variant of WM. Immunohistochemical stains and flow cytometic analysis revealed two distinct populations; monoclonal B cells (kappa+) and abnormal plasma cells (CD19 /CD56+/lambda+). She expired 19 days after admission due to septic shock. This is a rare case of WM exhibiting a light chain discrepancy between monoclonal B lymphocytes and paraprotein-secreting plasma cells. Light chain restriction may occur distinctly between lymphocyte and plasma cell populations in WM. PMID- 26586716 TI - Effect of Decitabine Combined with Unrelated Cord Blood Transplantation in an Adult Patient with -7/EVI1+ Acute Myeloid Leukemia: a Case Report and Literature Review. AB - Patients with relapsed or refractory acute myeloid leukemia (rAML) have a poor prognosis if they do not undergo hematopoietic stem cell transplantation (HSCT). We describe a case herein of acute myeloid leukemia (AML) with monosomy 7 and EVI1(+)(-7/EVI1(+)) in a patient who failed to achieve a complete remission (CR) after two cycles of standard induction chemotherapy. He subsequently received decitabine (DAC) as "bridge therapy" and directly underwent unrelated cord blood transplantation (UCBT) due to the absence of an available sibling donor. Although DAC treatment did not induce CR, it did produce hematologic improvement and control disease progression with acceptable side effects, thus effectively bridging the time of donor search. Following UCBT, the marrow showed complete hematologic and cytogenetic remission. At present, 18 months after the transplantation, the patient's general condition is still good. PMID- 26586717 TI - Case report: Concomitant Chronic Lymphocytic Leukaemia and Cytogenetically Normal de novo Acute Leukaemia in a Patient. AB - The simultaneous occurrence of acute myeloid leukaemia with untreated chronic lymphocytic leukemia is extremely rare. We report a case of a 74-year-old man who was evaluated for macrocytic anaemia. Based on the morphology and immunophenotyping analysis of peripheral blood, a diagnosis of chronic lymphocytic leukemia was established. Subsequently, the bone marrow examination revealed the presence of two distinct, coexisting CLL and AML clones. Cytogenetic and molecular genetic analysis detected deletion 13q14.3 and unmutated immunoglobulin variable heavy-chain in the CLL clone, only. The AML and CLL clones did not share clonality, and the AML did not involve the peripheral blood. A diagnosis of cytogenetically normal de novo AML occurring concurrently with untreated CLL has not been reported previously in English literature. PMID- 26586718 TI - Lysinibacillus spp. Endophthalmitis: a First Reported Case. AB - Post-traumatic endophthalmitis (PTE) is an uncommon sequela of open globe injuries. In cases involving an intraocular foreign body (IOFB), the risk of PTE increases by up to four-fold. Typically, presentation occurs in the acute timeframe. Only three reported cases of delayed-onset PTE currently exist in the literature (two cases caused by Proprionibacterium acnes and one by Phaeoacremonium parasiticum, a fungal pathogen). We describe a case of delayed onset post-traumatic endophthalmitis (PTE) caused by Lysinibacillus spp., an organism not previously reported in the ophthalmic literature. PMID- 26586720 TI - Arthropod genomics beyond fruit flies: bridging the gap between proximate and ultimate causation. PMID- 26586719 TI - State injury prevention policies and variation in death from injury. AB - OBJECTIVES: Death from injury is frequently preventable, but injury remains a leading cause of death in the USA. While evidence-based strategies exist to prevent many types of injuries, effective policies for implementing these strategies at the population level are needed to reduce injury deaths. We identified promising injury prevention policies and evaluated their association with injury death rate (IDR). METHODS: We identified 11 injury prevention policies and accessed data on 2013 state and county IDRs. States were divided into strong, moderate and weak tertiles based on total number of policies in place. Adjusted regression modelling compared the strength of state prevention policies with IDRs at the state level and then at the county level to account for variability within states. RESULTS: The strength of state prevention policies (tertile) was not significantly associated with IDR in US states. However, counties in strong policy states had a 11.8-point lower IDR compared with those in weak policy states (p=0.001). CONCLUSIONS: States with more injury prevention policies in place have lower rates of death from injury, particularly when evaluated at the county level. Implementing recommended prevention policies holds potential to prevent injury death in the USA. PMID- 26586721 TI - GC1118, an Anti-EGFR Antibody with a Distinct Binding Epitope and Superior Inhibitory Activity against High-Affinity EGFR Ligands. AB - The EGFR-targeted monoclonal antibodies are a valid therapeutic strategy for patients with metastatic colorectal cancer (mCRC). However, only a small subset of mCRC patients has therapeutic benefits and there are high demands for EGFR therapeutics with a broader patient pool and more potent efficacy. In this study, we report GC1118 exhibiting a different character in terms of binding epitope, affinity, mode of action, and efficacy from other anti-EGFR antibodies. Structural analysis of the EGFR-GC1118 crystal complex revealed that GC1118 recognizes linear, discrete N-terminal epitopes of domain III of EGFR, critical for EGF binding but not overlapping with those of other EGFR-targeted antibodies. GC1118 exhibited superior inhibitory activity against high-affinity EGFR ligands in terms of EGFR binding, triggering EGFR signaling, and proliferation compared with cetuximab and panitumumab. EGFR signaling driven by low-affinity ligands, on the contrary, was well inhibited by all the antibodies tested. GC1118 demonstrated robust antitumor activity in tumor xenografts with elevated expression of high-affinity ligands in vivo, whereas cetuximab did not. Considering the significant role of high-affinity EGFR ligands in modulating tumor microenvironment and inducing resistance to various cancer therapeutics, our study suggests a potential therapeutic advantage of GC1118 in terms of efficacy and a range of benefited patient pool. Mol Cancer Ther; 15(2); 251-63. (c)2015 AACR. PMID- 26586722 TI - Translation Inhibition by Rocaglates Is Independent of eIF4E Phosphorylation Status. AB - Rocaglates are natural products that inhibit protein synthesis in eukaryotes and exhibit antineoplastic activity. In vitro biochemical assays, affinity chromatography experiments coupled with mass spectrometry analysis, and in vivo genetic screens have identified eukaryotic initiation factor (eIF) 4A as a direct molecular target of rocaglates. eIF4A is the RNA helicase subunit of eIF4F, a complex that mediates cap-dependent ribosome recruitment to mRNA templates. The eIF4F complex has been implicated in tumor initiation and maintenance through elevated levels or increased phosphorylation status of its cap-binding subunit, eIF4E, thus furthering the interest toward developing rocaglates as antineoplastic agents. Recent experiments have indicated that rocaglates also interact with prohibitins 1 and 2, proteins implicated in c-Raf-MEK-ERK signaling. Because increased ERK signaling stimulates eIF4E phosphorylation status, rocaglates are also expected to inhibit eIF4E phosphorylation status, a point that has not been thoroughly investigated. It is currently unknown whether the effects on translation observed with rocaglates are solely through eIF4A inhibition or also a feature of blocking eIF4E phosphorylation. Here, we show that rocaglates inhibit translation through an eIF4E phosphorylation-independent mechanism. PMID- 26586724 TI - Nanoconjugation of PSMA-Targeting Ligands Enhances Perinuclear Localization and Improves Efficacy of Delivered Alpha-Particle Emitters against Tumor Endothelial Analogues. AB - This study aims to evaluate the effect on killing efficacy of the intracellular trafficking patterns of alpha-particle emitters by using different radionuclide carriers in the setting of targeted antivascular alpha-radiotherapy. Nanocarriers (lipid vesicles) targeted to the prostate-specific membrane antigen (PSMA), which is unique to human neovasculature for a variety of solid tumors, were loaded with the alpha-particle generator actinium-225 and were compared with a PSMA-targeted radiolabeled antibody. Actinium-225 emits a total of four alpha-particles per decay, providing highly lethal and localized irradiation of targeted cells with minimal exposure to surrounding healthy tissues. Lipid vesicles were derivatized with two types of PSMA-targeting ligands: a fully human PSMA antibody (mAb) and a urea-based, low-molecular-weight agent. Target selectivity and extent of internalization were evaluated on monolayers of human endothelial cells (HUVEC) induced to express PSMA in static incubation conditions and in a flow field. Both types of radiolabeled PSMA-targeted vesicles exhibit similar killing efficacy, which is greater than the efficacy of the radiolabeled control mAb when compared on the basis of delivered radioactivity per cell. Fluorescence confocal microscopy demonstrates that targeted vesicles localize closer to the nucleus, unlike antibodies which localize near the plasma membrane. In addition, targeted vesicles cause larger numbers of dsDNAs per nucleus of treated cells compared with the radiolabeled mAb. These findings demonstrate that radionuclide carriers, such as PSMA-targeted lipid-nanocarriers, which localize close to the nucleus, increase the probability of alpha-particle trajectories crossing the nuclei, and, therefore, enhance the killing efficacy of alpha-particle emitters. PMID- 26586725 TI - Segmentation of Breast Lesions in Ultrasound Images through Multiresolution Analysis Using Undecimated Discrete Wavelet Transform. AB - Earliest detection and diagnosis of breast cancer reduces mortality rate of patients by increasing the treatment options. A novel method for the segmentation of breast ultrasound images is proposed in this work. The proposed method utilizes undecimated discrete wavelet transform to perform multiresolution analysis of the input ultrasound image. As the resolution level increases, although the effect of noise reduces, the details of the image also dilute. The appropriate resolution level, which contains essential details of the tumor, is automatically selected through mean structural similarity. The feature vector for each pixel is constructed by sampling intra-resolution and inter-resolution data of the image. The dimensionality of feature vectors is reduced by using principal components analysis. The reduced set of feature vectors is segmented into two disjoint clusters using spatial regularized fuzzy c-means algorithm. The proposed algorithm is evaluated by using four validation metrics on a breast ultrasound database of 150 images including 90 benign and 60 malignant cases. The algorithm produced significantly better segmentation results (Dice coef = 0.8595, boundary displacement error = 9.796, dvi = 1.744, and global consistency error = 0.1835) than the other three state of the art methods. PMID- 26586723 TI - Identification of Selective Lead Compounds for Treatment of High-Ploidy Breast Cancer. AB - Increased ploidy is common in tumors but treatments for tumors with excess chromosome sets are not available. Here, we characterize high-ploidy breast cancers and identify potential anticancer compounds selective for the high-ploidy state. Among 354 human breast cancers, 10% have mean chromosome copy number exceeding 3, and this is most common in triple-negative and HER2-positive types. Women with high-ploidy breast cancers have higher risk of recurrence and death in two patient cohorts, demonstrating that it represents an important group for improved treatment. Because high-ploidy cancers are aneuploid, rather than triploid or tetraploid, we devised a two-step screen to identify selective compounds. The screen was designed to assure both external validity on diverse karyotypic backgrounds and specificity for high-ploidy cell types. This screen identified novel therapies specific to high-ploidy cells. First, we discovered 8 azaguanine, an antimetabolite that is activated by hypoxanthine phosphoribosyltransferase 1 (HPRT1), suggesting an elevated gene-dosage of HPRT1 in high-ploidy tumors can control sensitivity to this drug. Second, we discovered a novel compound, 2,3-diphenylbenzo[g]quinoxaline-5,10-dione (DPBQ). DPBQ activates p53 and triggers apoptosis in a polyploid-specific manner, but does not inhibit topoisomerase or bind DNA. Mechanistic analysis demonstrates that DPBQ elicits a hypoxia gene signature and its effect is replicated, in part, by enhancing oxidative stress. Structure-function analysis defines the core benzo[g]quinoxaline-5,10 dione as being necessary for the polyploid-specific effects of DPBQ. We conclude that polyploid breast cancers represent a high-risk subgroup and that DPBQ provides a functional core to develop polyploid-selective therapy. Mol Cancer Ther; 15(1); 48-59. (c)2015 AACR. PMID- 26586730 TI - Health services should collect feedback from inpatients at the point of service: opinions from patients and staff in acute and subacute facilities. AB - OBJECTIVE: Point of service feedback (POSF) enables patients to give health services feedback about their experiences during or immediately after care. Despite the increasing use of POSF, little is known regarding patients' and staffs' opinions of this practice and whether they consider it acceptable or useful. The study aimed to determine patient and staff opinions regarding POSF. DESIGN: A cross-sectional survey. SETTING: Acute and subacute healthcare facilities. PARTICIPANTS: Two hundred and forty-seven patients and 221 staff. RESULTS: Participants indicated that patients should be invited to evaluate health services when they are in hospital or subacute care and improving services was the most important reason for doing so. Staff indicated that: collecting patients' feedback during their stay was an important part of providing care and not an interruption to it (n = 187 of 221, 85%); collecting patients' feedback was best done with a variety of methods; talking directly with patients during their stay was the preferred option (n = 161 of 219, 74%). More patients preferred to: give feedback during their stay (51%) than after discharge from care (15%); give feedback by talking with someone (45%) than completing a questionnaire (31%). Some patients (14%) were concerned about reprisals from staff if they gave negative feedback. CONCLUSIONS: POSF can be acceptable and useful for evaluating health services and should be incorporated into a person centred approach that allows patients to choose from a variety of feedback options both during and after their stay. To be most useful, feedback should be incorporated into a quality improvement system. PMID- 26586733 TI - PCSK9 Inhibition: Does Lipoprotein Size Matter? PMID- 26586734 TI - Neonatal onychomadesis. PMID- 26586735 TI - America's science legacy. PMID- 26586731 TI - In the loop: promoter-enhancer interactions and bioinformatics. AB - Enhancer-promoter regulation is a fundamental mechanism underlying differential transcriptional regulation. Spatial chromatin organization brings remote enhancers in contact with target promoters in cis to regulate gene expression. There is considerable evidence for promoter-enhancer interactions (PEIs). In the recent years, genome-wide analyses have identified signatures and mapped novel enhancers; however, being able to precisely identify their target gene(s) requires massive biological and bioinformatics efforts. In this review, we give a short overview of the chromatin landscape and transcriptional regulation. We discuss some key concepts and problems related to chromatin interaction detection technologies, and emerging knowledge from genome-wide chromatin interaction data sets. Then, we critically review different types of bioinformatics analysis methods and tools related to representation and visualization of PEI data, raw data processing and PEI prediction. Lastly, we provide specific examples of how PEIs have been used to elucidate a functional role of non-coding single nucleotide polymorphisms. The topic is at the forefront of epigenetic research, and by highlighting some future bioinformatics challenges in the field, this review provides a comprehensive background for future PEI studies. PMID- 26586732 TI - Effect of PCSK9 Inhibition by Alirocumab on Lipoprotein Particle Concentrations Determined by Nuclear Magnetic Resonance Spectroscopy. AB - BACKGROUND: In patients with discordance between low-density lipoprotein (LDL) cholesterol and LDL particle (LDL-P) concentrations, cardiovascular risk more closely correlates with LDL-P. METHODS AND RESULTS: We investigated the effect of alirocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9, on lipoprotein particle concentration and size in hypercholesterolemic patients, using nuclear magnetic resonance spectroscopy. Plasma samples were collected from patients receiving alirocumab 150 mg every 2 weeks (n=26) or placebo (n=31) during a phase II, double-blind, placebo controlled trial in patients (LDL cholesterol >=100 mg/dL) on a stable atorvastatin dose. In this post hoc analysis, percentage change in concentrations of LDL-P, very-low-density lipoprotein particles, and high-density lipoprotein particles from baseline to week 12 was determined by nuclear magnetic resonance. Alirocumab significantly reduced mean concentrations of total LDL-P (-63.3% versus -1.0% with placebo) and large (-71.3% versus -21.8%) and small (-54.0% versus +17.8%) LDL-P subfractions and total very-low-density lipoprotein particle concentrations (-36.4% versus +33.4%; all P<0.01). Total high-density lipoprotein particles increased with alirocumab (+11.2% versus +1.4% with placebo; P<0.01). There were greater increases in large (44.6%) versus medium (17.7%) or small high density lipoprotein particles (2.8%) with alirocumab. LDL-P size remained relatively unchanged in both groups; however, very-low-density and high-density lipoprotein particle sizes increased to a significantly greater extent with alirocumab. CONCLUSIONS: Alirocumab significantly reduced LDL-C and LDL-P concentrations in hypercholesterolemic patients receiving stable atorvastatin therapy. These findings may be of particular relevance to patients with discordant LDL-C and LDL-P concentrations. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier: NCT01288443. PMID- 26586737 TI - Space physics. LISA Pathfinder tests spacetime sensor. PMID- 26586738 TI - Neuroscience. A faster, brighter picture of brain cells in action. PMID- 26586739 TI - Funding. NIH program fails to launch blacks in biotech. PMID- 26586740 TI - Q&A. Europe's research chief wants scientists to speak up. PMID- 26586741 TI - Archaeology. Humans may have reached Chile by 18,500 years ago. PMID- 26586742 TI - Biomaterials. Crystalline eyes of chitons inspire materials scientists. PMID- 26586744 TI - How to hijack a journal. PMID- 26586743 TI - What does a disease deserve? PMID- 26586745 TI - Tissue engineering. Restoring voice. PMID- 26586746 TI - Neuroscience. Mapping the birth of the sleep connectome. PMID- 26586747 TI - Energy and environment. Transport: A roadblock to climate change mitigation? PMID- 26586748 TI - Molecular biology. Putting the breaks on meiosis. PMID- 26586749 TI - Physics. Magnetic fields make waves in cuprates. PMID- 26586750 TI - Geology. 100 years of continental drift. PMID- 26586751 TI - Solar cells. Perovskite solar cells join the major league. PMID- 26586752 TI - Batteries. Opening the window for aqueous electrolytes. PMID- 26586753 TI - Wildfires: Weigh policy effectiveness. PMID- 26586754 TI - Wildfires: Systemic changes required. PMID- 26586755 TI - Wildfires--Response. PMID- 26586756 TI - Errata. AB - ERRATUM FOR THE REPORT "Recruitment of RNA polymerase II by the pioneer transcription factor PHA-4" by H.-T. Hsu et al., Science 350, aad5928 (2015). Published online 16 October 2015; 10.1126/science.aad5928. ERRATUM FOR THE REPORT "Spreading depression triggers headache by activating neuronal Panx1 channels" by H. Karatas et al., Science 350, aad5166 (2015). Published online 2 October 2015; 10.1126/science.aad5166. ERRATUM FOR THE REPORT "A neoplastic gene fusion mimics trans-splicing of RNAs in normal human cells" by H. Li et al., Science 350, aad3463 (2015). Published online 2 October 2015; 10.1126/science.aad3463 PMID- 26586757 TI - Stable recombination hotspots in birds. AB - The DNA-binding protein PRDM9 has a critical role in specifying meiotic recombination hotspots in mice and apes, but it appears to be absent from other vertebrate species, including birds. To study the evolution and determinants of recombination in species lacking the gene that encodes PRDM9, we inferred fine scale genetic maps from population resequencing data for two bird species: the zebra finch, Taeniopygia guttata, and the long-tailed finch, Poephila acuticauda. We found that both species have recombination hotspots, which are enriched near functional genomic elements. Unlike in mice and apes, most hotspots are shared between the two species, and their conservation seems to extend over tens of millions of years. These observations suggest that in the absence of PRDM9, recombination targets functional features that both enable access to the genome and constrain its evolution. PMID- 26586758 TI - Nonparadoxical evolutionary stability of the recombination initiation landscape in yeast. AB - The nonrandom distribution of meiotic recombination shapes heredity and genetic diversification. Theoretically, hotspots--favored sites of recombination initiation--either evolve rapidly toward extinction or are conserved, especially if they are chromosomal features under selective constraint, such as promoters. We tested these theories by comparing genome-wide recombination initiation maps from widely divergent Saccharomyces species. We find that hotspots frequently overlap with promoters in the species tested, and consequently, hotspot positions are well conserved. Remarkably, the relative strength of individual hotspots is also highly conserved, as are larger-scale features of the distribution of recombination initiation. This stability, not predicted by prior models, suggests that the particular shape of the yeast recombination landscape is adaptive and helps in understanding evolutionary dynamics of recombination in other species. PMID- 26586759 TI - "Water-in-salt" electrolyte enables high-voltage aqueous lithium-ion chemistries. AB - Lithium-ion batteries raise safety, environmental, and cost concerns, which mostly arise from their nonaqueous electrolytes. The use of aqueous alternatives is limited by their narrow electrochemical stability window (1.23 volts), which sets an intrinsic limit on the practical voltage and energy output. We report a highly concentrated aqueous electrolyte whose window was expanded to ~3.0 volts with the formation of an electrode-electrolyte interphase. A full lithium-ion battery of 2.3 volts using such an aqueous electrolyte was demonstrated to cycle up to 1000 times, with nearly 100% coulombic efficiency at both low (0.15 coulomb) and high (4.5 coulombs) discharge and charge rates. PMID- 26586760 TI - Multifunctionality of chiton biomineralized armor with an integrated visual system. AB - Nature provides a multitude of examples of multifunctional structural materials in which trade-offs are imposed by conflicting functional requirements. One such example is the biomineralized armor of the chiton Acanthopleura granulata, which incorporates an integrated sensory system that includes hundreds of eyes with aragonite-based lenses. We use optical experiments to demonstrate that these microscopic lenses are able to form images. Light scattering by the polycrystalline lenses is minimized by the use of relatively large, crystallographically aligned grains. Multiscale mechanical testing reveals that as the size, complexity, and functionality of the integrated sensory elements increase, the local mechanical performance of the armor decreases. However, A. granulata has evolved several strategies to compensate for its mechanical vulnerabilities to form a multipurpose system with co-optimized optical and structural functions. PMID- 26586761 TI - Operational redundancy in axon guidance through the multifunctional receptor Robo3 and its ligand NELL2. AB - Axon pathfinding is orchestrated by numerous guidance cues, including Slits and their Robo receptors, but it remains unclear how information from multiple cues is integrated or filtered. Robo3, a Robo family member, allows commissural axons to reach and cross the spinal cord midline by antagonizing Robo1/2-mediated repulsion from midline-expressed Slits and potentiating deleted in colorectal cancer (DCC)-mediated midline attraction to Netrin-1, but without binding either Slits or Netrins. We identified a secreted Robo3 ligand, neural epidermal growth factor-like-like 2 (NELL2), which repels mouse commissural axons through Robo3 and helps steer them to the midline. These findings identify NELL2 as an axon guidance cue and establish Robo3 as a multifunctional regulator of pathfinding that simultaneously mediates NELL2 repulsion, inhibits Slit repulsion, and facilitates Netrin attraction to achieve a common guidance purpose. PMID- 26586762 TI - Open-ocean fish reveal an omnidirectional solution to camouflage in polarized environments. AB - Despite appearing featureless to our eyes, the open ocean is a highly variable environment for polarization-sensitive viewers. Dynamic visual backgrounds coupled with predator encounters from all possible directions make this habitat one of the most challenging for camouflage. We tested open-ocean crypsis in nature by collecting more than 1500 videopolarimetry measurements from live fish from distinct habitats under a variety of viewing conditions. Open-ocean fish species exhibited camouflage that was superior to that of both nearshore fish and mirrorlike surfaces, with significantly higher crypsis at angles associated with predator detection and pursuit. Histological measurements revealed that specific arrangements of reflective guanine platelets in the fish's skin produce angle dependent polarization modifications for polarocrypsis in the open ocean, suggesting a mechanism for natural selection to shape reflectance properties in this complex environment. PMID- 26586764 TI - A doctor's dilemma. AB - Deniz Kirik was drawn to medicine by his desire to better understand the human brain, but he found that doctors in his native Turkey have little opportunity for research. Nonetheless, he has turned what first felt like a failed career choice into an advantage. Now a neuroscience professor at Lund University in Sweden and co-founder of a spinoff company, Kirik uses his medical background to develop novel gene-based therapies for Parkinson's disease and bring them to the clinic. In October, Kirik secured a partnership with his regional government in southern Sweden to build a hospital specialized for testing and implementing gene therapies. --This interview was edited for brevity and clarity. PMID- 26586763 TI - Helminth infection, fecundity, and age of first pregnancy in women. AB - Infection with intestinal helminths results in immunological changes that influence co-infections, and might influence fecundity by inducing immunological states affecting conception and pregnancy. We investigated associations between intestinal helminths and fertility in women, using 9 years of longitudinal data from 986 Bolivian forager-horticulturalists, experiencing natural fertility and 70% helminth prevalence. We found that different species of helminth are associated with contrasting effects on fecundity. Infection with roundworm (Ascaris lumbricoides) is associated with earlier first births and shortened interbirth intervals, whereas infection with hookworm is associated with delayed first pregnancy and extended interbirth intervals. Thus, helminths may have important effects on human fertility that reflect physiological and immunological consequences of infection. PMID- 26586765 TI - Stem cell regulation. Bidirectional Notch signaling regulates Drosophila intestinal stem cell multipotency. AB - Drosophila intestinal stem cells (ISCs) generate enterocytes (ECs) and enteroendocrine (ee) cells. Previous work suggests that different levels of the Notch ligand Delta (Dl) in ISCs unidirectionally activate Notch in daughters to control multipotency. However, the mechanisms driving different outcomes remain unknown. We found that during ee cell formation, the ee cell marker Prospero localizes to the basal side of dividing ISCs. After asymmetric division, the ee daughter cell acts as a source of Dl that induces low Notch activity in the ISC to maintain identity. Alternatively, ISCs expressing Dl induce high Notch activity in daughter cells to promote EC formation. Our data reveal a conserved role for Notch in Drosophila and mammalian ISC maintenance and suggest that bidirectional Notch signaling may regulate multipotency in other systems. PMID- 26586767 TI - Study Reveals Seeds of Metastases. AB - Rare tumor cells thought to initiate metastasis possess unique gene signatures that distinguish them from cells in primary tumors, a recent study concludes. The findings may help in developing drugs that specifically target metastasis in patients with different types of cancer. PMID- 26586766 TI - Stromal Expression of miR-143/145 Promotes Neoangiogenesis in Lung Cancer Development. AB - The two unrelated miRNAs miR-143 and miR-145, coexpressed from the miR-143/145 cluster, have been proposed to act as tumor suppressors in human cancer, and therapeutic benefits of delivering miR-143 and miR-145 to tumors have been reported. In contrast, we found that tumor-specific deletion of miR-143/145 in an autochthonous mouse model of lung adenocarcinoma did not affect tumor development. This was consistent with the lack of endogenous miR-143/145 expression in normal and transformed lung epithelium. Surprisingly, miR-143/145 in the tumor microenvironment dramatically promoted tumor growth by stimulating the proliferation of endothelial cells. Loss of miR-143/145 in vivo led to derepression of the miR-145 target CAMK1D, an inhibitory kinase, which when overexpressed prevents mitotic entry of endothelial cells. As a consequence, tumors in miR-143/145-deficient animals exhibited diminished neoangiogenesis, increased apoptosis, and their expansion was limited by the tumor's ability to co opt the alveolar vasculature. These findings demonstrate that stromal miR-143/145 promotes tumorigenesis and caution against the use of these miRNAs as agents in cancer therapeutics. SIGNIFICANCE: This study shows that miR-143/145 expressed from the tumor microenvironment stimulates neoangiogenesis and supports tumor expansion in the lung, demonstrating a surprising role for the putative tumor suppressor miRNA cluster in promoting tumorigenesis. We propose inhibition of miR 143/145 as a therapeutic avenue to modulate tumor neoangiogenesis. PMID- 26586773 TI - IL17A-Mediated Endothelial Breach Promotes Metastasis Formation. AB - The role of the IL23/IL17A axis in tumor-immune interactions is a matter of controversy. Although some suggest that IL17A-producing T cells (TH17) can suppress tumor growth, others report that IL17A and IL23 accelerate tumor growth. Here, we systematically assessed the impact of IL17A-secreting lymphocytes in several murine models of tumor lung metastasis. Genetic fate mapping revealed that IL17A was secreted within lung metastases predominantly by gammadelta T cells, whereas TH17 cells were virtually absent. Using different tumor models, we found Il17a(-/-) mice to consistently develop fewer pulmonary tumor colonies. IL17A specifically increased blood vessel permeability and the expression of E selectin and VCAM-1 by lung endothelial cells in vivo. In transgenic mice, specific targeting of IL17A to the endothelium increased the number of tumor foci. Moreover, the direct impact of IL17A on lung endothelial cells resulted in impaired endothelial barrier integrity, showing that IL17A promotes the formation of lung metastases through tumor-endothelial transmigration. PMID- 26586774 TI - Mesenchymal Stem Cells and Cardiomyocytes Interplay to Prevent Myocardial Hypertrophy. AB - Bone marrow-derived mesenchymal stem cells (BMSCs) have emerged as a promising therapeutic strategy for cardiovascular disease. However, there is no evidence so far that BMSCs can heal pathological myocardial hypertrophy. In this study, BMSCs were indirectly cocultured with neonatal rat ventricular cardiomyocytes (NRVCs) in vitro or intramyocardially transplanted into hypertrophic hearts in vivo. The results showed that isoproterenol (ISO)-induced typical hypertrophic characteristics of cardiomyocytes were prevented by BMSCs in the coculture model in vitro and after BMSC transplantation in vivo. Furthermore, activation of the Ca(2+)/calcineurin/nuclear factor of activated T cells cytoplasmic 3 (NFATc3) hypertrophic pathway in NRVCs was abrogated in the presence of BMSCs both in vitro and in vivo. Interestingly, inhibition of vascular endothelial growth factor (VEGF) release from BMSCs, but not basic fibroblast growth factor and insulin-like growth factor 1, abolished the protective effects of BMSCs on cardiomyocyte hypertrophy. Consistently, VEGF administration attenuated ISO induced enlargement of cellular size; the upregulation of atrial natriuretic peptide, brain natriuretic peptide, and beta-myosin heavy chain expression; and the activation of Ca2+/calcineurin/NFATc3 hypertrophic pathways, and these pathways can be abrogated by blocking VEGFR-1 in cardiomyocytes, indicating that VEGF receptor 1 is involved in the antihypertrophic role of VEGF. We further found that the ample VEGF secretion contributing to the antihypertrophic effects of BMSCs originates from the crosstalk of BMSCs and cardiac cells but not BMSCs or cardiomyocytes alone. Interplay of mesenchymal stem cells with cardiomyocytes produced synergistic effects on VEGF release. In summary, crosstalk between mesenchymal stem cells and cardiomyocytes contributes to the inhibition of myocardial hypertrophy via inhibiting Ca2+/calcineurin/NFATc3 hypertrophic pathways in cardiac cells. These results provide the first evidence for the treatment of myocardial hypertrophy using BMSCs. SIGNIFICANCE: This study found that mesenchymal stem cells may crosstalk with cardiomyocytes, which causes a synergistic vascular endothelial growth factor (VEGF) release from both kinds of cells and then inhibits pathological cardiac remodeling following hypertrophic stimulation in cardiomyocytes in vitro and in vivo. Blockage of VEGF release from bone marrow-derived mesenchymal stem cells (BMSCs) abolishes the antihypertrophic actions of BMSCs in vitro and in vivo. On the contrary, VEGF administration attenuates hypertrophic signaling of calcineurin/ nuclear factor of activated T cell cytoplasmic 3 signal pathways. This study provides the first evidence for the treatment of myocardial hypertrophy using BMSCs. PMID- 26586775 TI - Propranolol and Mesenchymal Stromal Cells Combine to Treat Traumatic Brain Injury. AB - More than 6.5 million patients are burdened by the physical, cognitive, and psychosocial deficits associated with traumatic brain injury (TBI) in the U.S. Despite extensive efforts to develop neuroprotective therapies for this devastating disorder, there have been no successful outcomes in human clinical trials to date. Retrospective studies have shown that beta-adrenergic receptor blockers, specifically propranolol, significantly decrease mortality of TBI through mechanisms not yet fully elucidated but are thought to counterbalance a hyperadrenergic state resulting from a TBI. Conversely, cellular therapies have been shown to improve long-term behavior following TBI, likely by reducing inflammation. Given the nonredundancy in their therapeutic mechanisms, we hypothesized that a combination of acute propranolol followed by mesenchymal stem cells (MSCs) isolated from human bone marrow would have additive effects in treating a rodent model of TBI. We have found that the treatments are well tolerated individually and in combination with no adverse events. MSCs decrease BBB permeability at 96 hours after injury, inhibit a significant accumulation of activated microglia/macrophage in the thalamic region of the brain both short and long term, and enhance neurogenesis short term. Propranolol decreases edema and reduces the number of fully activated microglia at 7 days and the number of semiactivated microglia at 120 days. Combinatory treatment improved cognitive and memory functions 120 days following TBI. Therefore, the results here suggest a new, efficacious sequential treatment for TBI may be achieved using the beta blocker propranolol followed by MSC treatment. SIGNIFICANCE: Despite continuous efforts, traumatic brain injury (TBI) remains the leading cause of death and disability worldwide in patients under the age of 44. In this study, an animal model of moderate-severe TBI was treated with an acute dose of propranolol followed by a delayed dose of human mesenchymal stem cells (MSCs), resulting in improved short- and long-term measurements. These results have direct translational application. They reinforce the inevitable clinical trial of MSCs to treat TBI by demonstrating, among other benefits, a notable decrease in chronic neuroinflammation. More importantly, these results demonstrate that MSCs and propranolol, which is increasingly being used clinically for TBI, are compatible treatments that improve overall outcome. PMID- 26586777 TI - Cervicitis aetiology and case definition: a study in Australian women attending sexually transmitted infection clinics. AB - OBJECTIVES: Studies examining cervicitis aetiology and prevalence lack comparability due to varying criteria for cervicitis. We aimed to outline cervicitis associations and suggest a best case definition. METHODS: A cross sectional study of 558 women at three sexually transmitted infection clinics in Sydney, Australia, 2006-2010, examined pathogen and behavioural associations of cervicitis using three cervicitis definitions: 'microscopy' (>30 pmnl/hpf (polymorphonuclear leucocytes per high-powered field on cervical Gram stain)), 'cervical discharge' (yellow and/or mucopurulent cervical discharge) or 'micro+cervical discharge' (combined 'microscopy' and 'cervical discharge'). RESULTS: Chlamydia trachomatis (CT), Mycoplasma genitalium (MG), Trichomonas vaginalis (TV) and Neisseria gonorrhoeae (NG) had the strongest associations with cervicitis definitions 'micro+cervical discharge': CT adjusted prevalence ratio (APR)=2.13 (95% CI 1.38 to 3.30) p=0.0006, MG APR=2.21 (1.33 to 3.69) p=0.002, TV APR=2.37 (1.44 to 3.90) p=0.0007 NG PR=4.42 (3.79 to 5.15) p<0.0001 and 'cervical discharge': CT APR=1.90 (1.25 to 2.89) p=0.003, MG APR=1.93 (1.17 to 3.19) p=0.011, TV APR=2.02 (1.24 to 3.31) p=0.005 NG PR=3.88 (3.36 to 4.48) p<0.0001. Condom use for vaginal sex 'always/sometimes' reduced cervicitis risk: ('micro+cervical discharge') APR=0.69 (0.51 to 0.93) p=0.016. Combined population attributable risk % (PAR%) of these four pathogens was only 18.0% with a protective PAR% of condoms of 25.7%. Exposures not associated with cervicitis included bacterial vaginosis, Mycoplasma hominis, Ureaplasma urealyticum, herpes simplex virus 1&2, cytomegalovirus, Candida, age, smoking and hormonal contraception. CONCLUSIONS: Cervicitis was associated with CT, MG, TV and NG with combined PAR% of these pathogens only 18% in this setting, suggesting other factors are involved. Condoms significantly reduced cervicitis risk. Cervicitis definitions with best clinical utility and pathogen prediction were 'cervical discharge' and 'micro+cervical discharge'. PMID- 26586778 TI - A 35-year journey to evidence-based medicine: a personal story. PMID- 26586776 TI - Patient-Derived Human Induced Pluripotent Stem Cells From Gingival Fibroblasts Composited With Defined Nanohydroxyapatite/Chitosan/Gelatin Porous Scaffolds as Potential Bone Graft Substitutes. AB - Human embryonic stem cells and adult stem cells have always been the cell source for bone tissue engineering. However, their limitations are obvious, including ethical concerns and/or a short lifespan. The use of human induced pluripotent stem cells (hiPSCs) could avoid these problems. Nanohydroxyapatite (nHA) is an important component of natural bone and bone tissue engineering scaffolds. However, its regulation on osteogenic differentiation with hiPSCs from human gingival fibroblasts (hGFs) is unknown. The purpose of the present study was to investigate the osteogenic differentiation of hiPSCs from patient-derived hGFs regulated by nHA/chitosan/gelatin (HCG) scaffolds with different nHA ratios, such as HCG-111 (1 wt/vol% nHA) and HCG-311 (3 wt/vol% nHA). First, hGFs were reprogrammed into hiPSCs, which have enhanced osteogenic differentiation capability. Second, HCG-111 and HCG-311 scaffolds were successfully synthesized. Finally, hiPSC/HCG complexes were cultured in vitro or subcutaneously transplanted into immunocompromised mice in vivo. The osteogenic differentiation effects of two types of HCG scaffolds on hiPSCs were assessed for up to 12 weeks. The results showed that HCG-311 increased osteogenic-related gene expression of hiPSCs in vitro proved by quantitative real-time polymerase chain reaction, and hiPSC/HCG-311 complexes formed much bone-like tissue in vivo, indicated by cone beam computed tomography imaging, H&E staining, Masson staining, and RUNX-2, OCN immunohistochemistry staining. In conclusion, our study has shown that osteogenic differentiation of hiPSCs from hGFs was improved by HCG-311. The mechanism might be that the nHA addition stimulates osteogenic marker expression of hiPSCs from hGFs. Our work has provided an innovative autologous cell-based bone tissue engineering approach with soft tissues such as clinically abundant gingiva. SIGNIFICANCE: The present study focused on patient-personalized bone tissue engineering. Human induced pluripotent stem cells (hiPSCs) were established from clinically easily derived human gingival fibroblasts (hGFs) and defined nanohydroxyapatite/chitosan/gelatin (HCG) scaffolds. hiPSCs derived from hGFs had better osteogenesis capability than that of hGFs. More interestingly, osteogenic differentiation of hiPSCs from hGFs was elevated significantly when composited with HCG-311 scaffolds in vitro and in vivo. The present study has uncovered the important role of different nHA ratios in HCG scaffolds in osteogenesis induction of hiPSCs derived from hGFs. This technique could serve as a potential innovative approach for bone tissue engineering, especially large bone regeneration clinically. PMID- 26586779 TI - Cardioband, a transcatheter surgical-like direct mitral valve annuloplasty system: early results of the feasibility trial. AB - AIMS: Cardioband system is a direct annuloplasty adjustable device that is implanted in the beating heart on the posterior annulus under fluoroscopic and transoesophageal echocardiographic (TEE) guidance. We report the early (1 month) outcomes of the first-in-man pre-CE-mark feasibility and safety trial. METHODS AND RESULTS: The study enrolled high-risk adult individuals at five institutions in Europe with symptomatic secondary mitral regurgitation (MR) despite optimal medical therapy. The primary efficacy endpoints included the technical success rate of implantation, feasibility of the Cardioband adjustment (technical performance), and ability to reduce the annular septolateral dimension and MR grade at hospital discharge and at 30 days. The study group included 31 consecutively enrolled high-risk patients with moderate-to-severe or severe secondary MR with at least 1 month of follow-up (mean age 71.8 +/- 6.9 years). All patients received the full implant of a Cardioband. Adjustment of the Cardioband resulted in a significant reduction in the septolateral dimension in all but two patients (septolateral dimension from 36.8 +/- 4.8 to 29 +/- 5.5 mm after the procedure, P < 0.01). Following Cardioband adjustment (29 of 31 patients) MR was none or trace in 6 (21%), mild in 21 (72%), and moderate in 2 (7%). No patient had severe MR after adjustment. Procedural mortality was zero and in-hospital mortality was 6.5% (2 of 31 patients, neither procedure- nor device-related). At 30 days, 22 of the 25 patients (88%) had MR <=2+. CONCLUSIONS: This study demonstrates the feasibility and safety of percutaneous direct mitral annuloplasty with the Cardioband device in high-risk patients with MR. PMID- 26586781 TI - Patients with familial hypercholesterolaemia are characterized by presence of cardiovascular disease at the time of death. AB - AIMS: Untreated familial hypercholesterolaemia (FH) increases the risk of premature atherosclerosis and cardiovascular disease (CVD). This study investigated the presence of CVD in FH patients at the time of death. METHODS AND RESULTS: The presence of CVD, lipid profile, medical treatment, and cause of death was characterized in all deceased Norwegian FH patients, of whom we had access to medical records (n = 79, from 1989 to 2010). The mean age at first CVD event was 44 years. The mean age at the time of death was 60 years. Cardiovascular disease was the cause of 50% of the deaths. At the time of death, 93% of the FH patients had established CVD and 69% had experienced myocardial infarction. The FH patients were divided into two groups (cut-off 60 years); FH patients who died at a younger age (mean age 51 years) and at an older age (mean age 71 years). More of the younger FH patients received statins (98 vs. 81%, P = 0.038), and fewer received niacin (0 vs. 17%, P = 0.019) compared with the older patients. The last measured low-density lipoprotein cholesterol level was higher in the younger patients compared with the older FH patients (5.3 vs. 4.4 mmol/L, P = 0.033). There were more current smokers among the younger FH patients compared with the older patients (55 vs. 10%, P = 0.001). Interestingly, there were no sex differences in age at the first CVD event or age at the time of death. CONCLUSION: Cardiovascular disease is present in most FH patients at the time of death, underscoring the severity of FH and the need for early diagnosis and treatment. PMID- 26586780 TI - Causes of late mortality with dual antiplatelet therapy after coronary stents. AB - AIMS: In the dual antiplatelet therapy (DAPT) study, continued thienopyridine beyond 12 months after drug-eluting stent placement was associated with increased mortality compared with placebo. We sought to evaluate factors related to mortality in randomized patients receiving either drug-eluting or bare metal stents in the DAPT study. METHODS AND RESULTS: Patients were enrolled after coronary stenting, given thienopyridine and aspirin for 12 months, randomly assigned to continued thienopyridine or placebo for an additional 18 months (while taking aspirin), and subsequently treated with aspirin alone for another 3 months. A blinded independent adjudication committee evaluated deaths. Among 11 648 randomized patients, rates of all-cause mortality rates were 1.9 vs. 1.5% (continued thienopyridine vs. placebo, P = 0.07), cardiovascular mortality, 1.0 vs. 1.0% (P = 0.97), and non-cardiovascular mortality, 0.9 vs. 0.5% (P = 0.01) over the randomized period (Months 12-30). Rates of fatal bleeding were 0.2 vs. 0.1% (P = 0.81), and deaths related to any prior bleeding were 0.3 vs. 0.2% (P = 0.36), Months 12-33). Cancer incidence did not differ (2.0 vs. 1.6%, P = 0.12). Cancer-related deaths occurred in 0.6 vs. 0.3% (P = 0.02) and were rarely related to bleeding (0.1 vs. 0, P = 0.25). After excluding those occurring in patients with cancer diagnosed before enrolment, rates were 0.4 vs. 0.3% (P = 0.16). CONCLUSION: Bleeding accounted for a minority of deaths among patients treated with continued thienopyridine. Cancer-related death in association with thienopyridine therapy was mainly not related to bleeding and may be a chance finding. Caution is warranted when considering extended thienopyridine in patients with advanced cancer. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00977938. PMID- 26586782 TI - T-wave subtleties in screened athletes: sharpening the lead or whittling the pencil away? PMID- 26586784 TI - Development and maintenance of the arterial valves. PMID- 26586783 TI - Early ST elevation myocardial infarction in non-capable percutaneous coronary intervention centres: in situ fibrinolysis vs. percutaneous coronary intervention transfer. AB - AIMS: The preferred reperfusion strategy for early ST elevation myocardial infarction (STEMI, defined as time from symptoms onset <=120 min) in non-capable percutaneous coronary intervention (PCI) centres remains controversial. We sought to compare mortality of in situ fibrinolysis vs. PCI transfer in a real-life consecutive cohort of early STEMI. METHODS AND RESULTS: Prospective multicentre STEMI registry (Catalonia 'Codi IAM' network) of all-comers in a non-capable PCI centre with symptom onset to first medical contact (FMC) <120 min. Two groups were identified: in situ fibrinolysis and transfer to a PCI-capable centre. Primary endpoint was 30-day mortality. We included 2470 patients, of whom 2227 (90.2%) and 243 (9.8%) comprised the transfer and fibrinolysis groups, respectively. In the fibrinolysis group, diagnostic and system delays were shorter (24 vs. 31 min, P < 0.001; 45 vs. 119 min, P < 0.001, respectively). Thirty-day mortality was 7.7 and 5.1% in fibrinolysis and transfer groups, respectively (P = 0.09). However, patients in the transfer group whose time FMC device was achieved within 140 min were associated with significantly lower mortality (2.0% for FMC-device <99 min, and 4.6% for FMC-device 99-140 min; P < 0.01 and P = 0.03, respectively vs. fibrinolysis). In multivariable logistic regression analysis, reperfusion with fibrinolysis was an independent 30-day mortality predictive factor (odds ratio: 1.91, 95% confidence interval: 1.01 3.50; P = 0.04), together with age and Killip-Kimball class (both P < 0.001). CONCLUSIONS: In early STEMI patients assisted in non-capable PCI centres, in situ fibrinolysis had worse prognosis than patient transfer. Transfer to a PCI-capable centre seems recommended in patients with FMC-device delay <140 min. PMID- 26586786 TI - EMBRACE STEMI study: a Phase 2a trial to evaluate the safety, tolerability, and efficacy of intravenous MTP-131 on reperfusion injury in patients undergoing primary percutaneous coronary intervention. AB - AIMS: Among patients with ST-elevation myocardial infarction (STEMI), reperfusion injury contributes to additional myocardial damage. MTP-131 is a cell-permeable peptide that preserves the integrity of cardiolipin, enhances mitochondrial energetics, and improves myocyte survival during reperfusion. METHODS AND RESULTS: EMBRACE STEMI is a multicentre, randomized, double-blind Phase 2a trial that evaluated the efficacy and safety of MTP-131 vs. placebo infused at a rate of 0.05 mg/kg/h for 1 h among first-time anterior STEMI subjects undergoing primary percutaneous coronary intervention (PCI) for a proximal or mid left anterior descending (LAD) artery occlusion. Administration of MTP-131 was not associated with a significant reduction in the primary endpoint, infarct size by creatine kinase-myocardial band (CK-MB) area under the curve (AUC) over 72 h (5785 +/- 426 ng h/mL in placebo vs. 5570 +/- 486 ng h/mL in MTP-131; ITALIC! P = NS). MTP-131 was not associated with an improvement in pre-specified magnetic resonance imaging, angiographic, electrocardiographic, or clinical outcomes. CONCLUSION: Among subjects with first-time anterior STEMI due to a proximal or mid LAD lesion who undergo successful PCI, administration of MTP-131 was safe and well tolerated. Treatment with MTP-131 was not associated with a decrease in myocardial infarct size as assessed by AUC0-72 of CK-MB. PMID- 26586787 TI - Mitochondrial DNA Repair through OGG1 Activity Attenuates Breast Cancer Progression and Metastasis. AB - Production of mitochondrial reactive oxygen species and integrity of mitochondrial DNA (mtDNA) are crucial in breast cancer progression and metastasis. Therefore, we evaluated the role of mtDNA damage in breast cancer by genetically modulating the DNA repair enzyme 8-oxoguanine DNA glycosylase (OGG1) in the PyMT transgenic mouse model of mammary tumorigenesis. We generated mice lacking OGG1 (KO), mice overexpressing human OGG1 subunit 1alpha in mitochondria (Tg), and mice simultaneously lacking OGG1 and overexpressing human OGG1 subunit 1alpha in mitochondria (KO/Tg). We found that Tg and KO/Tg mice developed significantly smaller tumors than KO and wild-type (WT) mice after 16 weeks. Histologic analysis revealed a roughly 2-fold decrease in the incidence of lung metastases in Tg mice (33.3%) compared to WT mice (62.5%). Furthermore, lungs from Tg mice exhibited nearly a 15-fold decrease in the average number of metastatic foci compared with WT mice (P <= 0.05). Primary tumors isolated from Tg mice also demonstrated reduced total and mitochondrial oxidative stress, diminished mtDNA damage, and increased mitochondrial function. Targeting hOGG1 to the mitochondria protected cells from mtDNA damage, resulting in downregulation of HIF1alpha and attenuated phosphorylation of Akt. Collectively, we demonstrate proof of concept that mtDNA damage results in breast cancer progression and metastasis in vivo. Moreover, our findings offer new therapeutic strategies for modulating the levels of mtDNA repair enzymes to delay or stall metastatic progression. PMID- 26586789 TI - Perspectives from the Field: HIV Testing and Linkage to Care in North Carolina. AB - BACKGROUND: HIV testing and linkage to care are critical first steps along the care continuum. Targeted efforts are needed in the South to achieve the goals of the National HIV/AIDS Strategy, and qualitative examination of testing and linkage to care from the perspective of professionals in the field can provide nuanced insight into the strengths and limitations of a care system to inform improvement efforts. These issues are explored in North Carolina (NC), with potential applicability to other Southern states. METHODS: Twenty-one interviews were conducted with professionals in the HIV prevention and care systems in NC. Interviews were analyzed for emergent themes. RESULTS: Individuals' access barriers, aspects of clinics and clinical care, challenges for community-based organizations, stigma, and the role of the NC Department of Health and Human Services were identified as themes affecting testing and linkage. DISCUSSION: These findings can inform efforts to address HIV testing and linkage to care in NC. This approach may provide beneficial insight for other systems of care. PMID- 26586788 TI - Suicidal Behavior and Associations with Quality of Life among HIV-Infected Patients in Ibadan, Nigeria. AB - BACKGROUND: Suicidality has rarely been studied in HIV-infected patients in sub Saharan Africa. This study explored suicidal behavior in a clinic sample of people living with HIV, in Nigeria. METHODS: Consecutive patients were interviewed using the Composite International Diagnostic Interview (CIDI-10.0) and the World Health Organization Quality of Life (WHO-QOL-HIV-BREF). Associations of suicidal behavior were explored using logistic regression models. RESULTS: In this sample of 828 patients (71% female, mean age 41.3 +/- 10 years), prevalence of suicidal behaviors were 15.1%, 5.8%, and 3.9% for suicidal ideation, plans, and attempts, respectively. Women were more likely than men to report suicidal ideation (odds ratio 1.7; 95% confidence interval 1.05-2.64). Depression and/or anxiety disorder was associated with increased odds of all suicidal behaviors. Suicidal behavior was associated with significantly lower overall and domain scores on the WHO-QOL. CONCLUSION: Suicidal behaviors were common and significantly associated with the presence of mental disorders and lower quality of life. PMID- 26586790 TI - A comparison of survival between on-pump and off-pump left internal mammary artery bypass graft surgery for isolated left anterior descending coronary artery disease: an analysis of the UK National Adult Cardiac Surgery Audit Registry. AB - OBJECTIVES: To determine if the use of cardiopulmonary bypass is associated with all-cause in-hospital and mid-term survival for patients undergoing left internal mammary artery (LIMA) to left anterior descending (LAD) coronary artery bypass grafting (CABG) for single coronary vessel disease. METHODS: Data from the National Adult Cardiac Surgery Audit registry for all elective and urgent isolated CABG procedures performed between April 2003 and March 2013 in first time cardiac surgery patients were extracted. Experienced surgeons (those with >=300 records) were classified by their technique preference (as 'off-pump preference', 'mixed practice', 'on-pump preference') based on their entire isolated CABG data. In-hospital mortality and time to death were analysed using logistic and Cox proportional hazards regression models, respectively. RESULTS: From a total of 3402 records, 65.5% were performed off-pump. There were 16 (0.47%) in-hospital deaths: 6 (0.51%) in the on-pump group and 10 (0.45%) in the off-pump group. The risk-adjusted odds ratio of in-hospital mortality in the direction of on-pump was 1.09 [95% confidence interval (CI): 0.39-3.04; P = 0.86]. The overall 5-year survival in the on- and off-pump groups was 93.1 and 93.4%, respectively. The adjusted hazard ratio (HR) for mortality in the direction of on-pump CABG was 1.15 (95% CI: 0.89-1.49; P = 0.28). Comparing off pump cases performed by experienced CABG surgeons with a preference for the off pump technique with on-pump cases performed by surgeons with a preference for the on-pump technique indicated a significant difference (HR for on-pump = 1.72; 95% CI: 1.19-2.47; P = 0.004). CONCLUSIONS: Elective and urgent first-time CABG for isolated LAD disease is associated with excellent mid-term survival in the England and Wales population, conferring a 5-year survival rate of 93.1 and 93.4% in the on-pump and off-pump groups, respectively. There was no difference in risk adjusted survival between the on-pump and off-pump techniques when analysing all procedures; however, supportive analysis demonstrated that off-pump surgery performed by experienced surgeons with a preference for the off-pump technique in their CABG caseload is associated with improved mid-term survival when compared with on-pump surgery performed by surgeons with a preference for the on-pump technique. PMID- 26586791 TI - Impact of levosimendan and ischaemia-reperfusion injury on myocardial subsarcolemmal mitochondrial respiratory chain, mitochondrial membrane potential, Ca2+ cycling and ATP synthesis. AB - OBJECTIVES: Levosimendan (LS) is increasingly used in case of myocardial failure after cardiac surgery. The impact of LS on myocardial mitochondrial functions, such as respiratory chain function (RCF), mitochondrial membrane potential (DeltaPsim), Ca(2+) handling, mitochondrial permeability transition pore (mPTP) opening and ATP during ongoing ischaemia/reperfusion (IR) injury, is not well understood. Depending on LS, I/R injury or the combination of both, we analysed myocardial functions in a retrograde Langendorff-model followed by the analysis of subsarcolemmal mitochondrial (SSM) functions. METHODS: Rat hearts were divided into four study groups; two were subjected to 30 min of perfusion without (control) or with the application of 1.4 umol/20 min LS (Levo). Experiments were repeated with hearts being subjected to 40 min of normothermic stop-flow ischaemia and 30 min of reperfusion without (IR) or with LS application (Levo IR). Systolic left ventricular pressure (LVPsys), left ventricular contractility (LVdp/dtmax) and coronary flow were determined. SSM were analysed regarding RCF, DeltaPsim, ATP, and Ca(2+) retention capacity (CRC), Ca(2+)-induced swelling and Ca(2+) fluxes after (re)perfusion. RESULTS: I/R injury suppressed LVdp/dtmax (1381 +/- 927 vs 2464 +/- 913 mmHg/s; P = 0.01 at 30 min (re-)perfusion time). IR revealed complex I-V state3 (19.1 +/- 7.4 vs 27.6 +/- 11.0 nmolO2/min; P < 0.044) and II-V state3 (20.6 +/- 6.8 vs 37.3 +/- 9.10 molO2/min; P < 0.0001) suppression and Levo limited I-V (14.8 +/- 11.1 vs 27.6 +/- 11.0 nmolO2/min; P < 0.001) and II-V (24.1 +/- 6.4 vs 37.3 +/- 9.10 molO2/min; P < 0.0001) function. After energizing, DeltaPsim hypopolarization was observed in Levo (0.76 +/- 0.04 vs 0.84 +/- 0.04; P = 0.02), IR (0.75 +/- 0.06 vs 0.84 +/- 0.04; P = 0.007) and Levo IR (0.75 +/- 0.06 vs 0.06 +/- 0.04; P = 0.01). IR (AUC: 626 vs 292; P = 0.023) and Levo-IR (AUC: 683 vs 292, P = 0.003) increased Ca(2+)-induced mPTP-opening susceptibility. CRC declined in IR (6.4 +/- 2.1 vs 10.5 +/- 2.6; P = 0.04) or Levo (6.5 +/- 2.0 vs 10.5 +/- 2.6; P = 0.023). Ca(2+) uptake was delayed in IR and Levo-IR without LS impact (P < 0.0001). Ca(2+) liberation was increased in Levo-IR. ATP synthesis was reduced in Levo (0.49 +/- 0.14 vs 0.74 +/- 0.14; P = 0.002) and Levo-I/R (0.34 +/- 0.18 vs 0.74 +/- 0.14; P < 0.002). CONCLUSION: LS limited RCF at complex IV and V with DeltaPsim hypopolarization suggesting a specific [Formula: see text]-dependent pathway. Ca(2+) redistribution from SSM by LS during I/R injury possibly prevents from Ca(2+) overload due to mPTP flickering. LS-induced mPTP flickering did not promote permanent Ca(2+)-induced mPTP opening. LS-dependent inhibition of ATP generation presumably resulted from complex IV and V limitations and lowered DeltaPsim. However, a resulting impact of limited ATP synthesis on myocardial recovery remains arguable. PMID- 26586792 TI - Genetic deletion of TNFalpha inhibits ultraviolet radiation-induced development of cutaneous squamous cell carcinomas in PKCepsilon transgenic mice via inhibition of cell survival signals. AB - Protein kinase C epsilon (PKCepsilon), a Ca(2+)-independent phospholipid dependent serine/threonine kinase, is among the six PKC isoforms (alpha, delta, epsilon, eta, MU, zeta) expressed in both mouse and human skin. Epidermal PKCepsilon level dictates the susceptibility of PKCepsilon transgenic (TG) mice to the development of cutaneous squamous cell carcinomas (SCC) elicited either by repeated exposure to ultraviolet radiation (UVR) or by using the DMBA initiation TPA (12-O-tetradecanoylphorbol-13-acetate) tumor promotion protocol (Wheeler,D.L. et al. (2004) Protein kinase C epsilon is an endogenous photosensitizer that enhances ultraviolet radiation-induced cutaneous damage and development of squamous cell carcinomas. Cancer Res., 64, 7756-7765). Histologically, SCC in TG mice, like human SCC, is poorly differentiated and metastatic. Our earlier studies to elucidate mechanisms of PKCepsilon-mediated development of SCC, using either DMBA-TPA or UVR, indicated elevated release of cytokine TNFalpha. To determine whether TNFalpha is essential for the development of SCC in TG mice, we generated PKCepsilon transgenic mice/TNFalpha-knockout (TG/TNFalphaKO) by crossbreeding TNFalphaKO with TG mice. We now present that deletion of TNFalpha in TG mice inhibited the development of SCC either by repeated UVR exposures or by the DMBA-TPA protocol. TG mice deficient in TNFalpha elicited both increase in SCC latency and decrease in SCC incidence. Inhibition of UVR-induced SCC development in TG/TNFalphaKO was accompanied by inhibition of (i) the expression levels of TNFalpha receptors TNFRI and TNFRII and cell proliferation marker ornithine decarboxylase and metastatic markers MMP7 and MMP9, (ii) the activation of transcription factors Stat3 and NF-kB and (iii) proliferation of hair follicle stem cells and epidermal hyperplasia. The results presented here provide the first genetic evidence that TNFalpha is linked to PKCepsilon-mediated sensitivity to DMBA-TPA or UVR-induced development of cutaneous SCC. PMID- 26586793 TI - Clinicopathological and prognostic significance of RECQL5 helicase expression in breast cancers. AB - RECQL5 is a member of the RecQ family of DNA helicases and has key roles in homologous recombination, base excision repair, replication and transcription. The clinicopathological significance of RECQL5 expression in breast cancer is unknown. In this study, we have evaluated RECQL5 mRNA expression in 1977 breast cancers, and RECQL5 protein level in 1902 breast cancers [Nottingham Tenovus series (n = 1650) and ER- cohort (n = 252)]. Expression levels were correlated to aggressive phenotypes and survival outcomes. High RECQL5 mRNA expression was significantly associated with high histological grade (P = 0.007), HER2 overexpression (P = 0.032), ER+/HER2-/high proliferation genefu subtype (P < 0.0001), integrative molecular clusters (intClust 1and 9) (P < 0.0001) and poor survival (P < 0.0001). In subgroup analysis, high RECQL5 mRNA level remains significantly associated with poor BCSS in ER+ cohort (P < 0.0001) but not in ER- cohort (P = 0.116). At the protein level, in tumours with low RAD51, high RECQL5 level was significantly associated with high histological grade (P < 0.0001), higher mitotic index (P = 0.008), dedifferentiation (P = 0.025), pleomorphism (P = 0.027) and poor survival (P = 0.003). In subgroup analysis, high RECQL5/low RAD51 remains significantly associated with poor BCSS in ER+ cohort (P = 0.010), but not in ER- cohort (P = 0.628). In multivariate analysis, high RECQL5 mRNA and high RECQL5/low RAD51 nuclear protein coexpression independently influenced survival (P = 0.022) in whole cohort and in the ER+ subgroup. Preclinically, we show that exogenous expression of RECQL5 in MCF10A cells can drive proliferation supporting an oncogenic function for RECQL5 in breast cancer. We conclude that RECQL5 is a promising biomarker in breast cancer. PMID- 26586794 TI - The presence of the intron 3 16 bp duplication polymorphism of p53 (rs17878362) in breast cancer is associated with a low Delta40p53:p53 ratio and better outcome. AB - Breast cancer is the most common female cancer, but it has relatively low rates of p53 mutations, suggesting other mechanisms are responsible for p53 inactivation. We have shown that the p53 isoform, Delta40p53, is highly expressed in breast cancer, where it may contribute to p53 inactivation. Delta40p53 can be produced by alternative splicing of p53 in intron 2 and this is regulated by the formation of G-quadruplex structures in p53 intron 3, from which the nucleotides forming these structures overlap with a common polymorphism, rs17878362. rs17878362 alters p53 splicing to decrease fully spliced p53 messenger RNA (mRNA) in vitro following ionizing radiation and this in turn alters Delta40p53:p53. Hence, the presence of rs17878362 may be important in regulating Delta40p53:p53 in breast cancer. This study aimed to determine if rs17878362 was associated with altered Delta40p53 and p53 expression and outcome in breast cancer. We sequenced p53 in breast tumours from 139 patients and compared this with Delta40p53 and p53 mRNA expression. We found that the ratio of Delta40p53:p53 was significantly lower in tumours homozygous for the polymorphic A2 allele compared with those who were wild-type (A1/A1). Furthermore, there was a lower proportion of breast cancers carrying the A2 allele from patients who subsequently developed metastasis compared with those that did not. Finally, we show that patients whose tumours carried the polymorphic A2 allele had significantly better disease-free survival. These results show that rs17878362 is associated with a low Delta40p53:p53 ratio in breast cancer and that this is associated with better outcome. PMID- 26586796 TI - Factors predicting pasireotide responsiveness in somatotroph pituitary adenomas resistant to first-generation somatostatin analogues: an immunohistochemical study. AB - AIM: To gather data regarding factors predicting responsiveness to pasireotide in acromegaly. PATIENTS AND METHODS: SSTR2a, SSTR3, SSTR5, AIP, Ki-67 and the adenoma subtype were evaluated in somatotroph adenomas from 39 patients treated post-operatively with somatostatin analogues (SSAs). A standardized SSTR scoring system was applied (scores 0-3). All patients received first-generation SSAs, and 11 resistant patients were subsequently treated with pasireotide LAR. RESULTS: None of the patients with negative or cytoplasmic-only SSTR2a expression (scores 0-1) were responsive to first-generation SSAs, as opposed to 20% (score 2) and 50% of patients with a score of 3 (P=0.04). None of the patients with an SSTR5 score of 0-1 were responsive to pasireotide, as opposed to 5/7 cases with a score of 2 or 3 (P=0.02). SSTR3 expression did not influence first-generation SSAs or pasireotide responsiveness. Tumours with low AIP were resistant to first generation SSAs (100 vs 60%; P=0.02), while they had similar responsiveness to pasireotide compared to tumours with conserved AIP expression (50 vs 40%; P=0.74). Tumours with low AIP displayed reduced SSTR2 (SSTR2a scores 0-1 44.4 vs 6.7%; P=0.006) while no difference was seen in SSTR5 (SSTR5 scores 0-1 33.3 vs 23.3%; P=0.55). Sparsely granulated adenomas responded better to pasireotide compared to densely granulated ones (80 vs 16.7%; P=0.04). CONCLUSION: The expression of SSTR5 might predict responsiveness to pasireotide in acromegaly. AIP deficient and sparsely granulated adenomas may benefit from pasireotide treatment. These results need to be confirmed in larger series of pasireotide treated patients. PMID- 26586795 TI - Common genetic variation and survival after colorectal cancer diagnosis: a genome wide analysis. AB - Genome-wide association studies have identified several germline single nucleotide polymorphisms (SNPs) significantly associated with colorectal cancer (CRC) incidence. Common germline genetic variation may also be related to CRC survival. We used a discovery-based approach to identify SNPs related to survival outcomes after CRC diagnosis. Genome-wide genotyping arrays were conducted for 3494 individuals with invasive CRC enrolled in six prospective cohort studies (median study-specific follow-up = 4.2-8.1 years). In pooled analyses, we used Cox regression to assess SNP-specific associations with CRC-specific and overall survival, with additional analyses stratified by stage at diagnosis. Top findings were followed-up in independent studies. A P value threshold of P < 5*10(-8) in analyses combining discovery and follow-up studies was required for genome-wide significance. Among individuals with distant-metastatic CRC, several SNPs at 6p12.1, nearest the ELOVL5 gene, were statistically significantly associated with poorer survival, with the strongest associations noted for rs209489 [hazard ratio (HR) = 1.8, P = 7.6*10(-10) and HR = 1.8, P = 3.7*10(-9) for CRC-specific and overall survival, respectively). No SNPs were statistically significantly associated with survival among all cases combined or in cases without distant metastases. SNPs in 6p12.1/ELOVL5 were associated with survival outcomes in individuals with distant-metastatic CRC, and merit further follow-up for functional significance. Findings from this genome-wide association study highlight the potential importance of genetic variation in CRC prognosis and provide clues to genomic regions of potential interest. PMID- 26586797 TI - DIANA-miRGen v3.0: accurate characterization of microRNA promoters and their regulators. AB - microRNAs (miRNAs) are small non-coding RNAs that actively fine-tune gene expression. The accurate characterization of the mechanisms underlying miRNA transcription regulation will further expand our knowledge regarding their implication in homeostatic and pathobiological networks. Aim of DIANA-miRGen v3.0 (http://www.microrna.gr/mirgen) is to provide for the first time accurate cell line-specific miRNA gene transcription start sites (TSSs), coupled with genome wide maps of transcription factor (TF) binding sites in order to unveil the mechanisms of miRNA transcription regulation. To this end, more than 7.3 billion RNA-, ChIP- and DNase-Seq next generation sequencing reads were analyzed/assembled and combined with state-of-the-art miRNA TSS prediction and TF binding site identification algorithms. The new database schema and web interface facilitates user interaction, provides advanced queries and innate connection with other DIANA resources for miRNA target identification and pathway analysis. The database currently supports 276 miRNA TSSs that correspond to 428 precursors and >19M binding sites of 202 TFs on a genome-wide scale in nine cell-lines and six tissues of Homo sapiens and Mus musculus. PMID- 26586798 TI - CPPsite 2.0: a repository of experimentally validated cell-penetrating peptides. AB - CPPsite 2.0 (http://crdd.osdd.net/raghava/cppsite/) is an updated version of manually curated database (CPPsite) of cell-penetrating peptides (CPPs). The current version holds around 1850 peptide entries, which is nearly two times than the entries in the previous version. The updated data were curated from research papers and patents published in last three years. It was observed that most of the CPPs discovered/ tested, in last three years, have diverse chemical modifications (e.g. non-natural residues, linkers, lipid moieties, etc.). We have compiled this information on chemical modifications systematically in the updated version of the database. In order to understand the structure-function relationship of these peptides, we predicted tertiary structure of CPPs, possessing both modified and natural residues, using state-of-the-art techniques. CPPsite 2.0 also maintains information about model systems (in vitro/in vivo) used for CPP evaluation and different type of cargoes (e.g. nucleic acid, protein, nanoparticles, etc.) delivered by these peptides. In order to assist a wide range of users, we developed a user-friendly responsive website, with various tools, suitable for smartphone, tablet and desktop users. In conclusion, CPPsite 2.0 provides significant improvements over the previous version in terms of data content. PMID- 26586799 TI - NONCODE 2016: an informative and valuable data source of long non-coding RNAs. AB - NONCODE (http://www.bioinfo.org/noncode/) is an interactive database that aims to present the most complete collection and annotation of non-coding RNAs, especially long non-coding RNAs (lncRNAs). The recently reduced cost of RNA sequencing has produced an explosion of newly identified data. Revolutionary third-generation sequencing methods have also contributed to more accurate annotations. Accumulative experimental data also provides more comprehensive knowledge of lncRNA functions. In this update, NONCODE has added six new species, bringing the total to 16 species altogether. The lncRNAs in NONCODE have increased from 210 831 to 527,336. For human and mouse, the lncRNA numbers are 167,150 and 130,558, respectively. NONCODE 2016 has also introduced three important new features: (i) conservation annotation; (ii) the relationships between lncRNAs and diseases; and (iii) an interface to choose high-quality datasets through predicted scores, literature support and long-read sequencing method support. NONCODE is also accessible through http://www.noncode.org/. PMID- 26586800 TI - CRISPR interference and priming varies with individual spacer sequences. AB - CRISPR-Cas (clustered regularly interspaced short palindromic repeats-CRISPR associated) systems allow bacteria to adapt to infection by acquiring 'spacer' sequences from invader DNA into genomic CRISPR loci. Cas proteins use RNAs derived from these loci to target cognate sequences for destruction through CRISPR interference. Mutations in the protospacer adjacent motif (PAM) and seed regions block interference but promote rapid 'primed' adaptation. Here, we use multiple spacer sequences to reexamine the PAM and seed sequence requirements for interference and priming in the Escherichia coli Type I-E CRISPR-Cas system. Surprisingly, CRISPR interference is far more tolerant of mutations in the seed and the PAM than previously reported, and this mutational tolerance, as well as priming activity, is highly dependent on spacer sequence. We identify a large number of functional PAMs that can promote interference, priming or both activities, depending on the associated spacer sequence. Functional PAMs are preferentially acquired during unprimed 'naive' adaptation, leading to a rapid priming response following infection. Our results provide numerous insights into the importance of both spacer and target sequences for interference and priming, and reveal that priming is a major pathway for adaptation during initial infection. PMID- 26586801 TI - HOCOMOCO: expansion and enhancement of the collection of transcription factor binding sites models. AB - Models of transcription factor (TF) binding sites provide a basis for a wide spectrum of studies in regulatory genomics, from reconstruction of regulatory networks to functional annotation of transcripts and sequence variants. While TFs may recognize different sequence patterns in different conditions, it is pragmatic to have a single generic model for each particular TF as a baseline for practical applications. Here we present the expanded and enhanced version of HOCOMOCO (http://hocomoco.autosome.ru and http://www.cbrc.kaust.edu.sa/hocomoco10), the collection of models of DNA patterns, recognized by transcription factors. HOCOMOCO now provides position weight matrix (PWM) models for binding sites of 601 human TFs and, in addition, PWMs for 396 mouse TFs. Furthermore, we introduce the largest up to date collection of dinucleotide PWM models for 86 (52) human (mouse) TFs. The update is based on the analysis of massive ChIP-Seq and HT-SELEX datasets, with the validation of the resulting models on in vivo data. To facilitate a practical application, all HOCOMOCO models are linked to gene and protein databases (Entrez Gene, HGNC, UniProt) and accompanied by precomputed score thresholds. Finally, we provide command-line tools for PWM and diPWM threshold estimation and motif finding in nucleotide sequences. PMID- 26586802 TI - Estimate of within population incremental selection through branch imbalance in lineage trees. AB - Incremental selection within a population, defined as limited fitness changes following mutation, is an important aspect of many evolutionary processes. Strongly advantageous or deleterious mutations are detected using the synonymous to non-synonymous mutations ratio. However, there are currently no precise methods to estimate incremental selection. We here provide for the first time such a detailed method and show its precision in multiple cases of micro evolution. The proposed method is a novel mixed lineage tree/sequence based method to detect within population selection as defined by the effect of mutations on the average number of offspring. Specifically, we propose to measure the log of the ratio between the number of leaves in lineage trees branches following synonymous and non-synonymous mutations. The method requires a high enough number of sequences, and a large enough number of independent mutations. It assumes that all mutations are independent events. It does not require of a baseline model and is practically not affected by sampling biases. We show the method's wide applicability by testing it on multiple cases of micro-evolution. We show that it can detect genes and inter-genic regions using the selection rate and detect selection pressures in viral proteins and in the immune response to pathogens. PMID- 26586804 TI - : a database of ciliate genome rearrangements. AB - Ciliated protists exhibit nuclear dimorphism through the presence of somatic macronuclei (MAC) and germline micronuclei (MIC). In some ciliates, DNA from precursor segments in the MIC genome rearranges to form transcriptionally active genes in the mature MAC genome, making these ciliates model organisms to study the process of somatic genome rearrangement. Similar broad scale, somatic rearrangement events occur in many eukaryotic cells and tumors. The (http://oxytricha.princeton.edu/mds_ies_db) is a database of genome recombination and rearrangement annotations, and it provides tools for visualization and comparative analysis of precursor and product genomes. The database currently contains annotations for two completely sequenced ciliate genomes: Oxytricha trifallax and Tetrahymena thermophila. PMID- 26586803 TI - Foreign DNA acquisition by the I-F CRISPR-Cas system requires all components of the interference machinery. AB - CRISPR immunity depends on acquisition of fragments of foreign DNA into CRISPR arrays. For type I-E CRISPR-Cas systems two modes of spacer acquisition, naive and primed adaptation, were described. Naive adaptation requires just two most conserved Cas1 and Cas2 proteins; it leads to spacer acquisition from both foreign and bacterial DNA and results in multiple spacers incapable of immune response. Primed adaptation requires all Cas proteins and a CRISPR RNA recognizing a partially matching target. It leads to selective acquisition of spacers from DNA molecules recognized by priming CRISPR RNA, with most spacers capable of protecting the host. Here, we studied spacer acquisition by a type I-F CRISPR-Cas system. We observe both naive and primed adaptation. Both processes require not just Cas1 and Cas2, but also intact Csy complex and CRISPR RNA. Primed adaptation shows a gradient of acquisition efficiency as a function of distance from the priming site and a strand bias that is consistent with existence of single-stranded adaption intermediates. The results provide new insights into the mechanism of spacer acquisition and illustrate surprising mechanistic diversity of related CRISPR-Cas systems. PMID- 26586805 TI - COLOMBOS v3.0: leveraging gene expression compendia for cross-species analyses. AB - COLOMBOS is a database that integrates publicly available transcriptomics data for several prokaryotic model organisms. Compared to the previous version it has more than doubled in size, both in terms of species and data available. The manually curated condition annotation has been overhauled as well, giving more complete information about samples' experimental conditions and their differences. Functionality-wise cross-species analyses now enable users to analyse expression data for all species simultaneously, and identify candidate genes with evolutionary conserved expression behaviour. All the expression-based query tools have undergone a substantial improvement, overcoming the limit of enforced co-expression data retrieval and instead enabling the return of more complex patterns of expression behaviour. COLOMBOS is freely available through a web application at http://colombos.net/. The complete database is also accessible via REST API or downloadable as tab-delimited text files. PMID- 26586806 TI - BreCAN-DB: a repository cum browser of personalized DNA breakpoint profiles of cancer genomes. AB - BreCAN-DB (http://brecandb.igib.res.in) is a repository cum browser of whole genome somatic DNA breakpoint profiles of cancer genomes, mapped at single nucleotide resolution using deep sequencing data. These breakpoints are associated with deletions, insertions, inversions, tandem duplications, translocations and a combination of these structural genomic alterations. The current release of BreCAN-DB features breakpoint profiles from 99 cancer-normal pairs, comprising five cancer types. We identified DNA breakpoints across genomes using high-coverage next-generation sequencing data obtained from TCGA and dbGaP. Further, in these cancer genomes, we methodically identified breakpoint hotspots which were significantly enriched with somatic structural alterations. To visualize the breakpoint profiles, a next-generation genome browser was integrated with BreCAN-DB. Moreover, we also included previously reported breakpoint profiles from 138 cancer-normal pairs, spanning 10 cancer types into the browser. Additionally, BreCAN-DB allows one to identify breakpoint hotspots in user uploaded data set. We have also included a functionality to query overlap of any breakpoint profile with regions of user's interest. Users can download breakpoint profiles from the database or may submit their data to be integrated in BreCAN-DB. We believe that BreCAN-DB will be useful resource for genomics scientific community and is a step towards personalized cancer genomics. PMID- 26586807 TI - The anatomical distribution of genetic associations. AB - Deeper understanding of the anatomical intermediaries for disease and other complex genetic traits is essential to understanding mechanisms and developing new interventions. Existing ontology tools provide functional, curated annotations for many genes and can be used to develop mechanistic hypotheses; yet information about the spatial expression of genes may be equally useful in interpreting results and forming novel hypotheses for a trait. Therefore, we developed an approach for statistically testing the relationship between gene expression across the body and sets of candidate genes from across the genome. We validated this tool and tested its utility on three applications. First, we show that the expression of genes in associated loci from GWA studies implicates specific tissues for 57 out of 98 traits. Second, we tested the ability of the tool to identify novel relationships between gene expression and phenotypes. Specifically, we experimentally confirmed an underappreciated prediction highlighted by our tool: that white blood cell count--a quantitative trait of the immune system--is genetically modulated by genes expressed in the skin. Finally, using gene lists derived from exome sequencing data, we show that human genes under selective constraint are disproportionately expressed in nervous system tissues. PMID- 26586808 TI - A novel role for the histone acetyltransferase Hat1 in the CENP-A/CID assembly pathway in Drosophila melanogaster. AB - The incorporation of CENP-A into centromeric chromatin is an essential prerequisite for kinetochore formation. Yet, the molecular mechanisms governing this process are surprisingly divergent in different organisms. While CENP-A loading mechanisms have been studied in some detail in mammals, there are still large gaps to our understanding of CENP-A/Cid loading pathways in Drosophila. Here, we report on the characterization and delineation of at least three different CENP-A preloading complexes in Drosophila. Two complexes contain the CENP-A chaperones CAL1, FACT and/or Caf1/Rbap48. Notably, we identified a novel complex consisting of the histone acetyltransferase Hat1, Caf1 and CENP-A/H4. We show that Hat1 is required for proper CENP-A loading into chromatin, since knock down in S2 cells leads to reduced incorporation of newly synthesized CENP-A. In addition, we demonstrate that CENP-A/Cid interacts with the HAT1 complex via an N terminal region, which is acetylated in cytoplasmic but not in nuclear CENP-A. Since Hat1 is not responsible for acetylation of CENP-A/Cid, these results suggest a histone acetyltransferase activity-independent escort function for Hat1. Thus, our results point toward intriguing analogies between the complex processing pathways of newly synthesized CENP-A and canonical histones. PMID- 26586809 TI - probeBase--an online resource for rRNA-targeted oligonucleotide probes and primers: new features 2016. AB - probeBase http://www.probebase.net is a manually maintained and curated database of rRNA-targeted oligonucleotide probes and primers. Contextual information and multiple options for evaluating in silico hybridization performance against the most recent rRNA sequence databases are provided for each oligonucleotide entry, which makes probeBase an important and frequently used resource for microbiology research and diagnostics. Here we present a major update of probeBase, which was last featured in the NAR Database Issue 2007. This update describes a complete remodeling of the database architecture and environment to accommodate computationally efficient access. Improved search functions, sequence match tools and data output now extend the opportunities for finding suitable hierarchical probe sets that target an organism or taxon at different taxonomic levels. To facilitate the identification of complementary probe sets for organisms represented by short rRNA sequence reads generated by amplicon sequencing or metagenomic analysis with next generation sequencing technologies such as Illumina and IonTorrent, we introduce a novel tool that recovers surrogate near full-length rRNA sequences for short query sequences and finds matching oligonucleotides in probeBase. PMID- 26586810 TI - Vessel wall MRI and intracranial aneurysms. AB - : Vessel wall magnetic resonance imaging (MRI) is a novel imaging technique that allows the intracranial vessel walls to be imaged directly. This state-of the art imaging modality may potentially change the way aneurysms are evaluated and managed. In this short review we discuss the current knowledge with illustrative cases. PMID- 26586811 TI - Sex, Impulsivity, and Anxiety: Interplay between Ventral Striatum and Amygdala Reactivity in Sexual Behaviors. PMID- 26586812 TI - Automatic and Controlled Semantic Retrieval: TMS Reveals Distinct Contributions of Posterior Middle Temporal Gyrus and Angular Gyrus. AB - Semantic retrieval involves both (1) automatic spreading activation between highly related concepts and (2) executive control processes that tailor this activation to suit the current context or goals. Two structures in left temporoparietal cortex, angular gyrus (AG) and posterior middle temporal gyrus (pMTG), are thought to be crucial to semantic retrieval and are often recruited together during semantic tasks; however, they show strikingly different patterns of functional connectivity at rest (coupling with the "default mode network" and "frontoparietal control system," respectively). Here, transcranial magnetic stimulation (TMS) was used to establish a causal yet dissociable role for these sites in semantic cognition in human volunteers. TMS to AG disrupted thematic judgments particularly when the link between probe and target was strong (e.g., a picture of an Alsatian with a bone), and impaired the identification of objects at a specific but not a superordinate level (for the verbal label "Alsatian" not "animal"). In contrast, TMS to pMTG disrupted thematic judgments for weak but not strong associations (e.g., a picture of an Alsatian with razor wire), and impaired identity matching for both superordinate and specific-level labels. Thus, stimulation to AG interfered with the automatic retrieval of specific concepts from the semantic store while stimulation of pMTG impaired semantic cognition when there was a requirement to flexibly shape conceptual activation in line with the task requirements. These results demonstrate that AG and pMTG make a dissociable contribution to automatic and controlled aspects of semantic retrieval. SIGNIFICANCE STATEMENT: We demonstrate a novel functional dissociation between the angular gyrus (AG) and posterior middle temporal gyrus (pMTG) in conceptual processing. These sites are often coactivated during neuroimaging studies using semantic tasks, but their individual contributions are unclear. Using transcranial magnetic stimulation and tasks designed to assess different aspects of semantics (item identity and thematic matching), we tested two alternative theoretical accounts. Neither site showed the pattern expected for a "thematic hub" (i.e., a site storing associations between concepts) since stimulation disrupted both tasks. Instead, the data indicated that pMTG contributes to the controlled retrieval of conceptual knowledge, while AG is critical for the efficient automatic retrieval of specific semantic information. PMID- 26586813 TI - Downregulation of Spermine Augments Dendritic Persistent Sodium Currents and Synaptic Integration after Status Epilepticus. AB - Dendritic voltage-gated ion channels profoundly shape the integrative properties of neuronal dendrites. In epilepsy, numerous changes in dendritic ion channels have been described, all of them due to either their altered transcription or phosphorylation. In pilocarpine-treated chronically epileptic rats, we describe a novel mechanism that causes an increased proximal dendritic persistent Na(+) current (INaP). We demonstrate using a combination of electrophysiology and molecular approaches that the upregulation of dendritic INaP is due to a relief from polyamine-dependent inhibition. The polyamine deficit in hippocampal neurons is likely caused by an upregulation of the degrading enzyme spermidine/spermine acetyltransferase. Multiphoton glutamate uncaging experiments revealed that the increase in dendritic INaP causes augmented dendritic summation of excitatory inputs. These results establish a novel post-transcriptional modification of ion channels in chronic epilepsy and may provide a novel avenue for treatment of temporal lobe epilepsy. SIGNIFICANCE STATEMENT: In this paper, we describe a novel mechanism that causes increased dendritic persistent Na(+) current. We demonstrate using a combination of electrophysiology and molecular approaches that the upregulation of persistent Na(+) currents is due to a relief from polyamine-dependent inhibition. The polyamine deficit in hippocampal neurons is likely caused by an upregulation of the degrading enzyme spermidine/spermine acetyltransferase. Multiphoton glutamate uncaging experiments revealed that the increase in dendritic persistent Na current causes augmented dendritic summation of excitatory inputs. We believe that these results establish a novel post transcriptional modification of ion channels in chronic epilepsy. PMID- 26586814 TI - Default Mode Dynamics for Global Functional Integration. AB - The default mode network (DMN) has been traditionally assumed to hinder behavioral performance in externally focused, goal-directed paradigms and to provide no active contribution to human cognition. However, recent evidence suggests greater DMN activity in an array of tasks, especially those that involve self-referential and memory-based processing. Although data that robustly demonstrate a comprehensive functional role for DMN remains relatively scarce, the global workspace framework, which implicates the DMN in global information integration for conscious processing, can potentially provide an explanation for the broad range of higher-order paradigms that report DMN involvement. We used graph theoretical measures to assess the contribution of the DMN to global functional connectivity dynamics in 22 healthy volunteers during an fMRI-based n back working-memory paradigm with parametric increases in difficulty. Our predominant finding is that brain modularity decreases with greater task demands, thus adapting a more global workspace configuration, in direct relation to increases in reaction times to correct responses. Flexible default mode regions dynamically switch community memberships and display significant changes in their nodal participation coefficient and strength, which may reflect the observed whole-brain changes in functional connectivity architecture. These findings have important implications for our understanding of healthy brain function, as they suggest a central role for the DMN in higher cognitive processing. SIGNIFICANCE STATEMENT: The default mode network (DMN) has been shown to increase its activity during the absence of external stimulation, and hence was historically assumed to disengage during goal-directed tasks. Recent evidence, however, implicates the DMN in self-referential and memory-based processing. We provide robust evidence for this network's active contribution to working memory by revealing dynamic reconfiguration in its interactions with other networks and offer an explanation within the global workspace theoretical framework. These promising findings may help redefine our understanding of the exact DMN role in human cognition. PMID- 26586815 TI - Layer-Specific fMRI Responses to Excitatory and Inhibitory Neuronal Activities in the Olfactory Bulb. AB - High-resolution functional magnetic resonance imaging (fMRI) detects localized neuronal activity via the hemodynamic response, but it is unclear whether it accurately identifies neuronal activity specific to individual layers. To address this issue, we preferentially evoked neuronal activity in superficial, middle, and deep layers of the rat olfactory bulb: the glomerular layer by odor (5% amyl acetate), the external plexiform layer by electrical stimulation of the lateral olfactory tract (LOT), and the granule cell layer by electrical stimulation of the anterior commissure (AC), respectively. Electrophysiology, laser-Doppler flowmetry of cerebral blood flow (CBF), and blood oxygenation level-dependent (BOLD) and cerebral blood volume-weighted (CBV) fMRI at 9.4 T were performed independently. We found that excitation of inhibitory granule cells by stimulating LOT and AC decreased the spontaneous multi-unit activities of excitatory mitral cells and subsequently increased CBF, CBV, and BOLD signals. Odor stimulation also increased the hemodynamic responses. Furthermore, the greatest CBV fMRI responses were discretely separated into the same layers as the evoked neuronal activities for all three stimuli, whereas BOLD was poorly localized with some exception to the poststimulus undershoot. In addition, the temporal dynamics of the fMRI responses varied depending on the stimulation pathway, even within the same layer. These results indicate that the vasculature is regulated within individual layers and CBV fMRI has a higher fidelity to the evoked neuronal activity compared with BOLD. Our findings are significant for understanding the neuronal origin and spatial specificity of hemodynamic responses, especially for the interpretation of laminar-resolution fMRI. SIGNIFICANCE STATEMENT: Functional magnetic resonance imaging (fMRI) is a noninvasive, in vivo technique widely used to map function of the entire brain, including deep structures, in animals and humans. However, it measures neuronal activity indirectly by way of the vascular response. It is currently unclear how finely the hemodynamic response is regulated within single cortical layers and whether increased inhibitory neuronal activities affect fMRI signal changes. Both laminar specificity and the neural origins of fMRI are important to interpret functional maps properly, which we investigated by activating discrete rat olfactory bulb circuits. PMID- 26586817 TI - Amperometric Monitoring of Sensory-Evoked Dopamine Release in Awake Larval Zebrafish. AB - Dopamine plays crucial roles in a broad spectrum of brain functions, and neural circuit mechanisms underlying dopaminergic regulation have been intensively studied in the past decade. As larval zebrafish have relatively simple and highly conserved dopaminergic systems, it can serve as an ideal vertebrate animal model to tackle this issue at a whole-brain scale. For this purpose, it is important to develop methods for monitoring endogenous dopamine release in intact larval zebrafish. Here, we developed a real-time method to monitor dopamine release at high spatiotemporal resolution in the brain of awake larval zebrafish using carbon fiber microelectrodes. As an example for application, we combined this method with genetic tools and in vivo calcium imaging and found that food extract can activate pretectal dopaminergic neurons, which in turn release dopamine at the visual center through their projection, providing a dopaminergic circuit mechanism for olfactory modulation of visual functions. Thus, our study demonstrates, for the first time, the utility of carbon fiber microelectrodes for monitoring sensory-evoked dopamine release in the brain of an awake small organism. SIGNIFICANCE STATEMENT: With carbon fiber microelectrodes, we have succeeded in monitoring sensory-evoked dopamine release in the brain of an awake small organism for the first time. By elucidating the circuitry origin of the dopamine release, we illustrated the potential application of this method in dissection of the neural circuitry mechanisms underlying dopaminergic neuromodulation. PMID- 26586816 TI - Interneuron Transcriptional Dysregulation Causes Frequency-Dependent Alterations in the Balance of Inhibition and Excitation in Hippocampus. AB - Circuit dysfunction in complex brain disorders such as schizophrenia and autism is caused by imbalances between inhibitory and excitatory synaptic transmission (I/E). Short-term plasticity differentially alters responses from excitatory and inhibitory synapses, causing the I/E ratio to change as a function of frequency. However, little is known about I/E ratio dynamics in complex brain disorders. Transcriptional dysregulation in interneurons, particularly parvalbumin interneurons, is a consistent pathophysiological feature of schizophrenia. Peroxisome proliferator activated receptor gamma coactivator 1alpha (PGC-1alpha) is a transcriptional coactivator that in hippocampus is highly concentrated in inhibitory interneurons and regulates parvalbumin transcription. Here, we used PGC-1alpha(-/-) mice to investigate effects of interneuron transcriptional dysregulation on the dynamics of the I/E ratio at the synaptic and circuit level in hippocampus. We find that loss of PGC-1alpha increases the I/E ratio onto CA1 pyramidal cells in response to Schaffer collateral stimulation in slices from young adult mice. The underlying mechanism is enhanced basal inhibition, including increased inhibition from parvalbumin interneurons. This decreases the spread of activation in CA1 and dramatically limits pyramidal cell spiking, reducing hippocampal output. The I/E ratio and CA1 output are partially restored by paired-pulse stimulation at short intervals, indicating frequency-dependent effects. However, circuit dysfunction persists, indicated by alterations in kainate-induced gamma oscillations and impaired nest building. Together, these results show that transcriptional dysregulation in hippocampal interneurons causes frequency-dependent alterations in I/E ratio and circuit function, suggesting that PGC-1alpha deficiency in psychiatric and neurological disorders contributes to disease by causing functionally relevant alterations in I/E balance. SIGNIFICANCE STATEMENT: Alteration in the inhibitory and excitatory synaptic transmission (I/E) balance is a fundamental principle underlying the circuit dysfunction observed in many neuropsychiatric and neurodevelopmental disorders. The I/E ratio is dynamic, continuously changing because of synaptic short-term plasticity. We show here that transcriptional dysregulation in interneurons, particularly parvalbumin interneurons, causes frequency-dependent alterations in the I/E ratio and in circuit function in hippocampus. Peroxisome proliferator activated receptor gamma coactivator 1alpha (PGC-1alpha-deficient) mice have enhanced inhibition in CA1, the opposite of what is seen in cortex. This study fills an important gap in current understanding of how changes in inhibition in complex brain disorders affect I/E dynamics, leading to region specific circuit dysfunction and behavioral impairment. This study also provides a conceptual framework for analyzing the effects of short-term plasticity on the I/E balance in disease models. PMID- 26586818 TI - Functional Deficiencies in Fragile X Neurons Derived from Human Embryonic Stem Cells. AB - Fragile X syndrome (FXS), the most common form of inherited mental retardation, is a neurodevelopmental disorder caused by silencing of the FMR1 gene, which in FXS becomes inactivated during human embryonic development. We have shown recently that this process is recapitulated by in vitro neural differentiation of FX human embryonic stem cells (FX-hESCs), derived from FXS blastocysts. In the present study, we analyzed morphological and functional properties of neurons generated from FX-hESCs. Human FX neurons can fire single action potentials (APs) to depolarizing current commands, but are unable to discharge trains of APs. Their APs are of a reduced amplitudes and longer durations than controls. These are reflected in reduced inward Na(+) and outward K(+) currents. In addition, human FX neurons contain fewer synaptic vesicles and lack spontaneous synaptic activity. Notably, synaptic activity in these neurons can be restored by coculturing them with normal rat hippocampal neurons, demonstrating a critical role for synaptic mechanisms in FXS pathology. This is the first extensive functional analysis of human FX neurons derived in vitro from hESCs that provides a convenient tool for studying molecular mechanisms underlying the impaired neuronal functions in FXS. SIGNIFICANCE STATEMENT: Fragile X syndrome (FXS), the most common form of inherited mental retardation, is caused by silencing of the FMR1 gene. In this study, we describe for the first time the properties of neurons developed from human embryonic stem cells (hESCs) that carry the FMR1 mutation and are grown in culture for extended periods. These neurons are retarded compared with controls in several morphological and functional properties. In vitro neural differentiation of FX hESCs can thus serve as a most relevant system for the analysis of molecular mechanisms underlying the impaired neuronal functions in FXS. PMID- 26586819 TI - Mindfulness Meditation-Based Pain Relief Employs Different Neural Mechanisms Than Placebo and Sham Mindfulness Meditation-Induced Analgesia. AB - Mindfulness meditation reduces pain in experimental and clinical settings. However, it remains unknown whether mindfulness meditation engages pain-relieving mechanisms other than those associated with the placebo effect (e.g., conditioning, psychosocial context, beliefs). To determine whether the analgesic mechanisms of mindfulness meditation are different from placebo, we randomly assigned 75 healthy, human volunteers to 4 d of the following: (1) mindfulness meditation, (2) placebo conditioning, (3) sham mindfulness meditation, or (4) book-listening control intervention. We assessed intervention efficacy using psychophysical evaluation of experimental pain and functional neuroimaging. Importantly, all cognitive manipulations (i.e., mindfulness meditation, placebo conditioning, sham mindfulness meditation) significantly attenuated pain intensity and unpleasantness ratings when compared to rest and the control condition (p < 0.05). Mindfulness meditation reduced pain intensity (p = 0.032) and pain unpleasantness (p < 0.001) ratings more than placebo analgesia. Mindfulness meditation also reduced pain intensity (p = 0.030) and pain unpleasantness (p = 0.043) ratings more than sham mindfulness meditation. Mindfulness-meditation-related pain relief was associated with greater activation in brain regions associated with the cognitive modulation of pain, including the orbitofrontal, subgenual anterior cingulate, and anterior insular cortex. In contrast, placebo analgesia was associated with activation of the dorsolateral prefrontal cortex and deactivation of sensory processing regions (secondary somatosensory cortex). Sham mindfulness meditation-induced analgesia was not correlated with significant neural activity, but rather by greater reductions in respiration rate. This study is the first to demonstrate that mindfulness-related pain relief is mechanistically distinct from placebo analgesia. The elucidation of this distinction confirms the existence of multiple, cognitively driven, supraspinal mechanisms for pain modulation. SIGNIFICANCE STATEMENT: Recent findings have demonstrated that mindfulness meditation significantly reduces pain. Given that the "gold standard" for evaluating the efficacy of behavioral interventions is based on appropriate placebo comparisons, it is imperative that we establish whether there is an effect supporting meditation-related pain relief above and beyond the effects of placebo. Here, we provide novel evidence demonstrating that mindfulness meditation produces greater pain relief and employs distinct neural mechanisms than placebo cream and sham mindfulness meditation. Specifically, mindfulness meditation-induced pain relief activated higher-order brain regions, including the orbitofrontal and cingulate cortices. In contrast, placebo analgesia was associated with decreased pain-related brain activation. These findings demonstrate that mindfulness meditation reduces pain through unique mechanisms and may foster greater acceptance of meditation as an adjunct pain therapy. PMID- 26586820 TI - Competition between the Brain and Testes under Selenium-Compromised Conditions: Insight into Sex Differences in Selenium Metabolism and Risk of Neurodevelopmental Disease. AB - Selenium (Se) is essential for both brain development and male fertility. Male mice lacking two key genes involved in Se metabolism (Scly(-/-)Sepp1(-/-) mice), selenoprotein P (Sepp1) and Sec lyase (Scly), develop severe neurological dysfunction, neurodegeneration, and audiogenic seizures that manifest beginning in early adulthood. We demonstrate that prepubescent castration of Scly(-/ )Sepp1(-/-) mice prevents behavioral deficits, attenuates neurodegeneration, rescues maturation of GABAergic inhibition, and increases brain selenoprotein levels. Moreover, castration also yields similar neuroprotective benefits to Sepp1(-/-) and wild-type mice challenged with Se-deficient diets. Our data show that, under Se-compromised conditions, the brain and testes compete for Se utilization, with concomitant effects on neurodevelopment and neurodegeneration. SIGNIFICANCE STATEMENT: Selenium is an essential trace element that promotes male fertility and brain function. Herein, we report that prepubescent castration provides neuroprotection by increasing selenium-dependent antioxidant activity in the brain, revealing a competition between the brain and testes for selenium utilization. These findings provide novel insight into the interaction of sex and oxidative stress upon the developing brain and have potentially significant implications for the prevention of neurodevelopmental disorders characterized by aberrant excitatory/inhibitory balance, such as schizophrenia and epilepsy. PMID- 26586821 TI - Astroglial Connexin 43 Hemichannels Modulate Olfactory Bulb Slow Oscillations. AB - An emergent concept in neurosciences consists in considering brain functions as the product of dynamic interactions between neurons and glial cells, particularly astrocytes. Although the role played by astrocytes in synaptic transmission and plasticity is now largely documented, their contribution to neuronal network activity is only beginning to be appreciated. In mouse olfactory bulb slices, we observed that the membrane potential of mitral cells oscillates between UP and DOWN states at a low frequency (<1 Hz). Such slow oscillations are correlated with glomerular local field potentials, indicating spontaneous local network activity. Using a combination of genetic and pharmacological tools, we showed that the activity of astroglial connexin 43 hemichannels, opened in an activity dependent manner, increases UP state amplitude and impacts mitral cell firing rate. This effect requires functional adenosine A1 receptors, in line with the observation that ATP is released via connexin 43 hemichannels. These results highlight a new mechanism of neuroglial interaction in the olfactory bulb, where astrocyte connexin hemichannels are both targets and modulators of neuronal circuit function. SIGNIFICANCE STATEMENT: An emergent concept in neuroscience consists in considering brain function as the product of dynamic interactions between neurons and glial cells, particularly astrocytes. A typical feature of astrocytes is their high expression level of connexins, the molecular constituents of gap junction channels and hemichannels. Although hemichannels represent a powerful medium for intercellular communication between astrocytes and neurons, their function in physiological conditions remains largely unexplored. Our results show that in the olfactory bulb, connexin 43 hemichannel function is promoted by neuronal activity and, in turn, modulates neuronal network slow oscillations. This novel mechanism of neuroglial interaction could influence olfactory information processing by directly impacting the output of the olfactory bulb. PMID- 26586822 TI - Structural Organization of the Corpus Callosum Predicts Attentional Shifts after Continuous Theta Burst Stimulation. AB - Repetitive transcranial magnetic stimulation (rTMS) applied over the right posterior parietal cortex (PPC) in healthy participants has been shown to trigger a significant rightward shift in the spatial allocation of visual attention, temporarily mimicking spatial deficits observed in neglect. In contrast, rTMS applied over the left PPC triggers a weaker or null attentional shift. However, large interindividual differences in responses to rTMS have been reported. Studies measuring changes in brain activation suggest that the effects of rTMS may depend on both interhemispheric and intrahemispheric interactions between cortical loci controlling visual attention. Here, we investigated whether variability in the structural organization of human white matter pathways subserving visual attention, as assessed by diffusion magnetic resonance imaging and tractography, could explain interindividual differences in the effects of rTMS. Most participants showed a rightward shift in the allocation of spatial attention after rTMS over the right intraparietal sulcus (IPS), but the size of this effect varied largely across participants. Conversely, rTMS over the left IPS resulted in strikingly opposed individual responses, with some participants responding with rightward and some with leftward attentional shifts. We demonstrate that microstructural and macrostructural variability within the corpus callosum, consistent with differential effects on cross-hemispheric interactions, predicts both the extent and the direction of the response to rTMS. Together, our findings suggest that the corpus callosum may have a dual inhibitory and excitatory function in maintaining the interhemispheric dynamics that underlie the allocation of spatial attention. SIGNIFICANCE STATEMENT: The posterior parietal cortex (PPC) controls allocation of attention across left versus right visual fields. Damage to this area results in neglect, characterized by a lack of spatial awareness of the side of space contralateral to the brain injury. Transcranial magnetic stimulation over the PPC is used to study cognitive mechanisms of spatial attention and to examine the potential of this technique to treat neglect. However, large individual differences in behavioral responses to stimulation have been reported. We demonstrate that the variability in the structural organization of the corpus callosum accounts for these differences. Our findings suggest novel dual mechanism of the corpus callosum function in spatial attention and have broader implications for the use of stimulation in neglect rehabilitation. PMID- 26586823 TI - Modulation of Saccade Vigor during Value-Based Decision Making. AB - During value-based decision-making, individuals consider the various options and select the one that provides the maximum subjective value. Although the brain integrates abstract information to compute and compare these values, the only behavioral outcome is often the decision itself. However, if the options are visual stimuli, during deliberation the brain moves the eyes from one stimulus to the other. Previous work suggests that saccade vigor, i.e., peak velocity as a function of amplitude, is greater if reward is associated with the visual stimulus. This raises the possibility that vigor during the free viewing of options may be influenced by the valuation of each option. Here, humans chose between a small, immediate monetary reward and a larger but delayed reward. As the deliberation began, vigor was similar for the saccades made to the two options but diverged 0.5 s before decision time, becoming greater for the preferred option. This difference in vigor increased as a function of the difference in the subjective values that the participant assigned to the delayed and immediate options. After the decision was made, participants continued to gaze at the options, but with reduced vigor, making it possible to infer timing of the decision from the sudden drop in vigor. Therefore, the subjective value that the brain assigned to a stimulus during decision-making affected the motor system via the vigor with which the eyes moved toward that stimulus. SIGNIFICANCE STATEMENT: We find that, as individuals deliberate between two rewarding options and arrive at a decision, the vigor with which they make saccades to each option reflects a real-time evaluation of that option. With deliberation, saccade vigor diverges between the two options, becoming greater for the option that the individual will eventually choose. The results suggest a shared element between the network that assigns value to a stimulus during the process of decision making and the network that controls vigor of movements toward that stimulus. PMID- 26586825 TI - Head-Directional Tuning and Theta Modulation of Anatomically Identified Neurons in the Presubiculum. AB - The presubiculum provides a major input to the medial entorhinal cortex (MEC) and contains cells that encode for the animal's head direction (HD), as well as other cells likely to be important for navigation and memory, including grid cells. To understand the mechanisms underlying HD cell firing and its effects on other parts of the circuit, it is important to determine the anatomical identity of these functionally defined cells. Therefore, we juxtacellularly recorded single cells in the presubiculum in freely moving rats, finding two classes of cells based on firing patterns and juxtacellular labeling (of a subset). Regular-firing cells had the anatomical characteristics of pyramidal cells and included most recorded HD cells. Therefore, HD cells are likely to be excitatory pyramidal cells. For one HD cell, we could follow an axon projecting directly to the MEC. Fast-spiking (FS) cells had the anatomical characteristics of interneurons and displayed weak HD tuning. Furthermore, FS cells displayed a surprising lack of theta-rhythmic firing, in strong contrast to the FS cells that we recorded in the MEC. Overall, we show that HD cells in the presubiculum are pyramidal cells, with FS interneurons only showing weak HD tuning; therefore, MEC may receive an excitatory HD input, as previously assumed by many models. The lack of theta rhythmicity in FS interneurons suggests that different mechanisms may underlie theta in different parts of the hippocampal formation. SIGNIFICANCE STATEMENT: In freely moving rats, we recorded and labeled single neurons in the presubiculum, an area providing one of the major inputs to the medial entorhinal cortex and part of a network involved in spatial navigation and memory. Post hoc identification of labeled cells showed that (fast-spiking, FS) interneurons and pyramidal cells in the presubiculum can be distinguished based on physiological criteria. We found that both moderately and strongly tuned head-direction (HD) cells are pyramidal cells and therefore likely to provide an excitatory HD input to the entorhinal cortex. FS interneurons were weakly head directional and, surprisingly, showed no theta-rhythmic firing. Therefore, the presubiculum appears to encode HD information via excitatory pyramidal cells, possibly also involving FS interneurons, without using a theta-rhythmic temporal code. PMID- 26586824 TI - Reliable Genetic Labeling of Adult-Born Dentate Granule Cells Using Ascl1 CreERT2 and Glast CreERT2 Murine Lines. AB - Newly generated dentate granule cells (GCs) are relevant for input discrimination in the adult hippocampus. Yet, their precise contribution to information processing remains unclear. To address this question, it is essential to develop approaches to precisely label entire cohorts of adult-born GCs. In this work, we used genetically modified mice to allow conditional expression of tdTomato (Tom) in adult-born GCs and characterized their development and functional integration. Ascl1(CreERT2);CAG(floxStopTom) and Glast(CreERT2);CAG(floxStopTom) mice resulted in indelible expression of Tom in adult neural stem cells and their lineage upon tamoxifen induction. Whole-cell recordings were performed to measure intrinsic excitability, firing behavior, and afferent excitatory connectivity. Developing GCs were also staged by the expression of early and late neuronal markers. The slow development of adult-born GCs characterized here is consistent with previous reports using retroviral approaches that have revealed that a mature phenotype is typically achieved after 6-8 weeks. Our findings demonstrate that Ascl1(CreERT2) and Glast(CreERT2) mouse lines enable simple and reliable labeling of adult-born GC lineages within restricted time windows. Therefore, these mice greatly facilitate tagging new neurons and manipulating their activity, required for understanding adult neurogenesis in the context of network remodeling, learning, and behavior. SIGNIFICANCE STATEMENT: Our study shows that Ascl1(CreERT2) and Glast(CreERT2) mice lines can be used to label large cohorts of adult-born dentate granule cells with excellent time resolution. Neurons labeled in this manner display developmental and functional profiles that are in full agreement with previous findings using thymidine analogs and retroviral labeling, thus providing an alternative approach to tackle fundamental questions on circuit remodeling. Because of the massive neuronal targeting and the simplicity of this method, genetic labeling will contribute to expand research on adult neurogenesis. PMID- 26586826 TI - S6 Kinase Reflects and Regulates Ethanol-Induced Sedation. AB - Alcohol use disorders (AUDs) affect people at great individual and societal cost. Individuals at risk for AUDs are sensitive to alcohol's rewarding effects and/or resistant to its aversive and sedating effects. The molecular basis for these traits is poorly understood. Here, we show that p70 S6 kinase (S6k), acting downstream of the insulin receptor (InR) and the small GTPase Arf6, is a key mediator of ethanol-induced sedation in Drosophila. S6k signaling in the adult nervous system determines flies' sensitivity to sedation. Furthermore, S6k activity, measured via levels of phosphorylation (P-S6k), is a molecular marker for sedation and overall neuronal activity: P-S6k levels are decreased when neurons are silenced, as well as after acute ethanol sedation. Conversely, P-S6k levels rebound upon recovery from sedation and are increased when neuronal activity is enhanced. Reducing neural activity increases sensitivity to ethanol induced sedation, whereas neuronal activation decreases ethanol sensitivity. These data suggest that ethanol has acute silencing effects on adult neuronal activity, which suppresses InR/Arf6/S6k signaling and results in behavioral sedation. In addition, we show that activity of InR/Arf6/S6k signaling determines flies' behavioral sensitivity to ethanol-induced sedation, highlighting this pathway in acute responses to ethanol. SIGNIFICANCE STATEMENT: Genetic factors play a major role in the development of addiction. Identifying these genes and understanding their molecular mechanisms is a necessary first step in the development of targeted therapeutic intervention. Here, we show that signaling from the insulin receptor in Drosophila neurons determines flies' sensitivity to ethanol-induced sedation. We show that this signaling cascade includes the small GTPase Arf6 and S6 kinase (S6k). In addition, activity of S6k is regulated by acute ethanol exposure and by neuronal activity. S6k activity is therefore both an acute target of ethanol exposure and a regulator of ethanol's effects on behavior. PMID- 26586828 TI - Role of the Suprachiasmatic and Arcuate Nuclei in Diurnal Temperature Regulation in the Rat. AB - In mammals, daily changes in body temperature (Tb) depend on the integrity of the suprachiasmatic nucleus (SCN). Fasting influences the Tb in the resting period and the presence of the SCN is essential for this process. However, the origin of this circadian/metabolic influence is unknown. We hypothesized that, not only the SCN but also the arcuate nucleus (ARC), are involved in the Tb setting through afferents to the thermoregulatory median preoptic nucleus (MnPO). Therefore, we investigated by neuronal tracing and microdialysis experiments the possible targeting of the MnPO by the SCN and the ARC in male Wistar rats. We observed that vasopressin release from the SCN decreases the temperature just before light onset, whereas alpha-melanocyte stimulating hormone release, especially at the end of the dark period, maintains high temperature. Both peptides have opposite effects on the brown adipose tissue activity through thermoregulatory nuclei such as the dorsomedial nucleus of the hypothalamus and the dorsal raphe nucleus. The present study indicates that the coordination between circadian and metabolic signaling within the hypothalamus is essential for an adequate temperature control. SIGNIFICANCE STATEMENT: When circadian and metabolic systems are not well synchronized, individuals may develop metabolic diseases. The underlying mechanisms are unknown. Here, we demonstrate that the balance between the releases of neuropeptides derived from the biological clock and from a metabolic sensory organ as the arcuate nucleus, are essential for an adequate temperature control. These observations show that brain areas involved in circadian and metabolic functions of the body need to interact to produce a coherent arrangement of physiological processes associated with temperature control. PMID- 26586827 TI - Comprehensive Corticospinal Labeling with mu-crystallin Transgene Reveals Axon Regeneration after Spinal Cord Trauma in ngr1-/- Mice. AB - Spinal cord injury interrupts descending motor tracts and creates persistent functional deficits due to the absence of spontaneous axon regeneration. Of descending pathways, the corticospinal tract (CST) is thought to be the most critical for voluntary function in primates. Even with multiple tracer injections and genetic tools, the CST is visualized to only a minor degree in experimental studies. Here, we identify and validate the mu-crystallin (crym) gene as a high fidelity marker of the CST. In transgenic mice expressing green fluorescent protein (GFP) under crym regulatory elements (crym-GFP), comprehensive and near complete CST labeling is achieved throughout the spinal cord. Bilateral pyramidotomy eliminated the 17,000 GFP-positive CST axons that were reproducibly labeled in brainstem from the spinal cord. We show that CST tracing with crym-GFP is 10-fold more efficient than tracing with biotinylated dextran amine (BDA). Using crym-GFP, we reevaluated the CST in mice lacking nogo receptor 1 (NgR1), a protein implicated in limiting neural repair. The number and trajectory of CST axons in ngr1(-/-) mice without injury was indistinguishable from ngr1(+/+) mice. After dorsal hemisection in the midthoracic cord, CST axons did not significantly regenerate in ngr1(+/+) mice, but an average of 162 of the 6000 labeled thoracic CST axons (2.68%) regenerated >100 MUm past the lesion site in crym-GFP ngr1(-/-) mice. Although traditional BDA tracing cannot reliably visualize regenerating ngr1(-/-) CST axons, their regenerative course is clear with crym-GFP. Therefore the crym-GFP transgenic mouse is a useful tool for studies of CST anatomy in experimental studies of motor pathways. SIGNIFICANCE STATEMENT: Axon regeneration fails in the adult CNS, resulting in permanent functional deficits. Traditionally, inefficient extrinsic tracers such a biotinylated dextran amine (BDA) are used to label regenerating fibers after therapeutic intervention. We introduce crym-green fluorescent protein (GFP) transgenic mice as a comprehensive and specific tool with which to study the primary descending motor tract, the corticospinal tract (CST). CST labeling with crym-GFP is 10 times more efficient compared with BDA. The enhanced sensitivity afforded by crym-GFP revealed significant CST regeneration in NgR1 knock-out mice. Therefore, crym-GFP can be used as a standardized tool for future CST spinal cord injury studies. PMID- 26586830 TI - There and Back Again: Hippocampus and Retrosplenial Cortex Track Homing Distance during Human Path Integration. AB - Path integration, the updating of position and orientation during movement, often involves tracking a home location. Here, we examine processes that could contribute to successful location tracking in humans. In particular, we investigate a homing vector model of path integration, whereby a navigator continuously tracks a trajectory back to the home location. To examine this model, we developed a loop task for fMRI, in which participants viewed movement that circled back to a home location in a sparse virtual environment. In support of a homing vector system, hippocampus, retrosplenial cortex, and parahippocampal cortex were responsive to Euclidean distance from home. These results provide the first evidence of a constantly maintained homing signal in the human brain. In addition, hippocampus, retrosplenial cortex, and parahippocampal cortex, as well as medial prefrontal cortex, were recruited during successful path integration. These findings suggest that dynamic processes recruit hippocampus, retrosplenial cortex, and parahippocampal cortex in support of path integration, including a homing vector system that tracks movement relative to home. SIGNIFICANCE STATEMENT: Path integration is the continual updating of position and orientation during navigation. Animal studies have identified place cells and grid cells as important for path integration, but underlying models of path integration in humans have rarely been studied. The results of our novel loop closure task are the first to suggest that a homing vector tracks Euclidean distance from the home location, supported by the hippocampus, retrosplenial cortex, and parahippocampal cortex. These findings suggest a potential homing vector mechanism supporting path integration, which recruits hippocampus and retrosplenial cortex to track movement relative to home. These results provide new avenues for computational and animal models by directing attention to homing vector models of path integration, which differ from current movement-tracking models. PMID- 26586829 TI - The Role of Motion Extrapolation in Amphibian Prey Capture. AB - Sensorimotor delays decouple behaviors from the events that drive them. The brain compensates for these delays with predictive mechanisms, but the efficacy and timescale over which these mechanisms operate remain poorly understood. Here, we assess how prediction is used to compensate for prey movement that occurs during visuomotor processing. We obtained high-speed video records of freely moving, tongue-projecting salamanders catching walking prey, emulating natural foraging conditions. We found that tongue projections were preceded by a rapid head turn lasting ~ 130 ms. This motor lag, combined with the ~ 100 ms phototransduction delay at photopic light levels, gave a ~ 230 ms visuomotor response delay during which prey typically moved approximately one body length. Tongue projections, however, did not significantly lag prey position but were highly accurate instead. Angular errors in tongue projection accuracy were consistent with a linear extrapolation model that predicted prey position at the time of tongue contact using the average prey motion during a ~ 175 ms period one visual latency before the head movement. The model explained successful strikes where the tongue hit the fly, and unsuccessful strikes where the fly turned and the tongue hit a phantom location consistent with the fly's earlier trajectory. The model parameters, obtained from the data, agree with the temporal integration and latency of retinal responses proposed to contribute to motion extrapolation. These results show that the salamander predicts future prey position and that prediction significantly improves prey capture success over a broad range of prey speeds and light levels. SIGNIFICANCE STATEMENT: Neural processing delays cause actions to lag behind the events that elicit them. To cope with these delays, the brain predicts what will happen in the future. While neural circuits in the retina and beyond have been suggested to participate in such predictions, few behaviors have been explored sufficiently to constrain circuit function. Here we show that salamanders aim their tongues by using extrapolation to estimate future prey position, thereby compensating for internal delays from both visual and motor processing. Predictions made just before a prey turn resulted in the tongue being projected to a position consistent with the prey's pre-turn trajectory. These results define the computations and operating regimen for neural circuits that predict target motion. PMID- 26586831 TI - Functional and Physical Interaction of Diacylglycerol Kinase zeta with Protein Kinase Calpha Is Required for Cerebellar Long-Term Depression. AB - The balance between positive and negative regulators required for synaptic plasticity must be well organized at synapses. Protein kinase Calpha (PKCalpha) is a major mediator that triggers long-term depression (LTD) at synapses between parallel fibers and Purkinje cells in the cerebellum. However, the precise mechanisms involved in PKCalpha regulation are not clearly understood. Here, we analyzed the role of diacylglycerol kinase zeta (DGKzeta), a kinase that physically interacts with PKCalpha as well as postsynaptic density protein 95 (PSD-95) family proteins and functionally suppresses PKCalpha by metabolizing diacylglycerol (DAG), in the regulation of cerebellar LTD. In Purkinje cells of DGKzeta-deficient mice, LTD was impaired and PKCalpha was less localized in dendrites and synapses. This impaired LTD was rescued by virus-driven expression of wild-type DGKzeta, but not by a kinase-dead mutant DGKzeta or a mutant lacking the ability to localize at synapses, indicating that both the kinase activity and synaptic anchoring functions of DGKzeta are necessary for LTD. In addition, experiments using another DGKzeta mutant and immunoprecipitation analysis revealed an inverse regulatory mechanism, in which PKCalpha phosphorylates, inactivates, and then is released from DGKzeta, is required for LTD. These results indicate that DGKzeta is localized to synapses, through its interaction with PSD-95 family proteins, to promote synaptic localization of PKCalpha, but maintains PKCalpha in a minimally activated state by suppressing local DAG until its activation and release from DGKzeta during LTD. Such local and reciprocal regulation of positive and negative regulators may contribute to the fine-tuning of synaptic signaling. SIGNIFICANCE STATEMENT: Many studies have identified signaling molecules that mediate long-term synaptic plasticity. In the basal state, the activities and concentrations of these signaling molecules must be maintained at low levels, yet be ready to be boosted, so that synapses can undergo synaptic plasticity only when they are stimulated. However, the mechanisms involved in creating such conditions are not well understood. Here, we show that diacylglycerol kinase zeta (DGKzeta) creates optimal conditions for the induction of cerebellar long-term depression (LTD). DGKzeta works by regulating localization and activity of protein kinase Calpha (PKCalpha), an important mediator of LTD, so that PKCalpha effectively responds to the stimulation that triggers LTD. PMID- 26586832 TI - Hand Shape Representations in the Human Posterior Parietal Cortex. AB - Humans shape their hands to grasp, manipulate objects, and to communicate. From nonhuman primate studies, we know that visual and motor properties for grasps can be derived from cells in the posterior parietal cortex (PPC). Are non-grasp related hand shapes in humans represented similarly? Here we show for the first time how single neurons in the PPC of humans are selective for particular imagined hand shapes independent of graspable objects. We find that motor imagery to shape the hand can be successfully decoded from the PPC by implementing a version of the popular Rock-Paper-Scissors game and its extension Rock-Paper Scissors-Lizard-Spock. By simultaneous presentation of visual and auditory cues, we can discriminate motor imagery from visual information and show differences in auditory and visual information processing in the PPC. These results also demonstrate that neural signals from human PPC can be used to drive a dexterous cortical neuroprosthesis. SIGNIFICANCE STATEMENT: This study shows for the first time hand-shape decoding from human PPC. Unlike nonhuman primate studies in which the visual stimuli are the objects to be grasped, the visually cued hand shapes that we use are independent of the stimuli. Furthermore, we can show that distinct neuronal populations are activated for the visual cue and the imagined hand shape. Additionally we found that auditory and visual stimuli that cue the same hand shape are processed differently in PPC. Early on in a trial, only the visual stimuli and not the auditory stimuli can be decoded. During the later stages of a trial, the motor imagery for a particular hand shape can be decoded for both modalities. PMID- 26586833 TI - Arabidopsis PHL2 and PHR1 Act Redundantly as the Key Components of the Central Regulatory System Controlling Transcriptional Responses to Phosphate Starvation. AB - When confronted with inorganic phosphate (Pi) starvation, plants activate an array of adaptive responses to sustain their growth. These responses, in a large extent, are controlled at the transcriptional level. Arabidopsis (Arabidopsis thaliana) PHOSPHATE RESPONSE1 (PHR1) and its close homolog PHR1-like 1 (PHL1) belong to a 15-member family of MYB-CC transcription factors and are regarded as the key components of the central regulatory system controlling plant transcriptional responses to Pi starvation. The knockout of PHR1 and PHL1, however, causes only a partial loss of the transcription of Pi starvation-induced genes, suggesting the existence of other key components in this regulatory system. In this work, we used the transcription of a Pi starvation-induced acid phosphatase, AtPAP10, to study the molecular mechanism underlying plant transcriptional responses to Pi starvation. We first identified a DNA sequence on the AtPAP10 promoter that is critical for the transcription of AtPAP10. We then demonstrated that PHL2 and PHL3, two other members of the MYB-CC family, specifically bind to this DNA sequence and activate the transcription of AtPAP10. Unlike PHR1 and PHL1, the transcription and protein accumulation of PHL2 and PHL3 are upregulated by Pi starvation. RNA-sequencing analyses indicated that the transcription of most Pi starvation-induced genes is impaired in the phl2 mutant, indicating that PHL2 is also a key component of the central regulatory system. Finally, we showed that PHL2, and perhaps also PHL3, acts redundantly with PHR1 to regulate plant transcriptional response to Pi starvation. PMID- 26586834 TI - Identification of Arabidopsis GPAT9 (At5g60620) as an Essential Gene Involved in Triacylglycerol Biosynthesis. AB - The first step in the biosynthesis of nearly all plant membrane phospholipids and storage triacylglycerols is catalyzed by a glycerol-3-phosphate acyltransferase (GPAT). The requirement for an endoplasmic reticulum (ER)-localized GPAT for both of these critical metabolic pathways was recognized more than 60 years ago. However, identification of the gene(s) encoding this GPAT activity has remained elusive. Here, we present the results of a series of in vivo, in vitro, and in silico experiments in Arabidopsis (Arabidopsis thaliana) designed to assign this essential function to AtGPAT9. This gene has been highly conserved throughout evolution and is largely present as a single copy in most plants, features consistent with essential housekeeping functions. A knockout mutant of AtGPAT9 demonstrates both male and female gametophytic lethality phenotypes, consistent with the role in essential membrane lipid synthesis. Significant expression of developing seed AtGPAT9 is required for wild-type levels of triacylglycerol accumulation, and the transcript level is directly correlated to the level of microsomal GPAT enzymatic activity in seeds. Finally, the AtGPAT9 protein interacts with other enzymes involved in ER glycerolipid biosynthesis, suggesting the possibility of ER-localized lipid biosynthetic complexes. Together, these results suggest that GPAT9 is the ER-localized GPAT enzyme responsible for plant membrane lipid and oil biosynthesis. PMID- 26586835 TI - A G-Box-Like Motif Is Necessary for Transcriptional Regulation by Circadian Pseudo-Response Regulators in Arabidopsis. AB - PSEUDO-RESPONSE REGULATORs (PRRs) play overlapping and distinct roles in maintaining circadian rhythms and regulating diverse biological processes, including the photoperiodic control of flowering, growth, and abiotic stress responses. PRRs act as transcriptional repressors and associate with chromatin via their conserved C-terminal CCT (CONSTANS, CONSTANS-like, and TIMING OF CAB EXPRESSION 1 [TOC1/PRR1]) domains by a still-poorly understood mechanism. Here, we identified genome-wide targets of PRR9 using chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) and compared them with PRR7, PRR5, and TOC1/PRR1 ChIP-seq data. We found that PRR binding sites are located within genomic regions of low nucleosome occupancy and high DNase I hypersensitivity. Moreover, conserved noncoding regions among Brassicaceae species are enriched around PRR binding sites, indicating that PRRs associate with functionally relevant cis-regulatory regions. The PRRs shared a significant number of binding regions, and our results indicate that they coordinately restrict the expression of target genes to around dawn. A G-box-like motif was overrepresented at PRR binding regions, and we showed that this motif is necessary for mediating transcriptional regulation of CIRCADIAN CLOCK ASSOCIATED 1 and PRR9 by the PRRs. Our results further our understanding of how PRRs target specific promoters and provide an extensive resource for studying circadian regulatory networks in plants. PMID- 26586837 TI - Mass spectrometry methods measured androgen and estrogen concentrations during pregnancy and in newborns of mothers with polycystic ovary syndrome. AB - OBJECTIVE: Little is known about the aetiology of polycystic ovary syndrome (PCOS). Some suggest that elevated maternal androgens during gestation play a causative role. This implies placental passage of androgens during pregnancy. The aim of this study is to compare androgen and estrogen concentrations in maternal serum during pregnancy and in umbilical cord blood, between mothers with PCOS and their offspring compared to controls. DESIGN: Prospective case-control study. METHODS: Maternal blood samples were collected around 20 weeks of gestation and at delivery. Umbilical cord blood was also taken at delivery. Androgens (testosterone (T), androstenedione (ADION), dehydroepiandrostenedione (DHEA)) and estrogens (estrone (E1), estradiol (E2), estriol (E3)) were measured using the liquid chromatography tandem mass spectrometry (LC-MS/MS) methods. RESULTS: At 20 weeks of gestation: T (P=0.019) and ADION (P=0.034) were higher in the PCOS mothers (pregnant with a girl), whereas DHEA, E1, E2, and E3 were not different. Maternal concentration at birth: T (P=0.004) and ADION (P=0.009) were also higher in the subgroup of PCOS mothers that were pregnant with a girl compared to the girl pregnancy controls. DHEA, E1, E2 and E3 were not different. In umbilical cord blood, no differences were found for T, ADION, DHEA, E2, E3, and AMH between the PCOS mothers and the controls respectively. E1 was lower in girls from PCOS mothers (P=0.007). CONCLUSIONS: Despite elevated maternal androgen concentrations during pregnancy in PCOS mothers, offspring showed no signs of elevated androgen concentrations in cord blood at birth using the latest highly specific LC-MS/MS methods. PMID- 26586836 TI - Functional Analysis of the Hsp93/ClpC Chaperone at the Chloroplast Envelope. AB - The Hsp100-type chaperone Hsp93/ClpC has crucial roles in chloroplast biogenesis. In addition to its role in proteolysis in the stroma, biochemical and genetic evidence led to the hypothesis that this chaperone collaborates with the inner envelope TIC complex to power preprotein import. Recently, it was suggested that Hsp93, working together with the Clp proteolytic core, can confer a protein quality control mechanism at the envelope. Thus, the role of envelope-localized Hsp93, and the mechanism by which it participates in protein import, remain unclear. To analyze the function of Hsp93 in protein import independently of its ClpP association, we created a mutant of Hsp93 affecting its ClpP-binding motif (PBM) (Hsp93[P-]), which is essential for the chaperone's interaction with the Clp proteolytic core. The Hsp93[P-] construct was ineffective at complementing the pale-yellow phenotype of hsp93 Arabidopsis (Arabidopsis thaliana) mutants, indicating that the PBM is essential for Hsp93 function. As expected, the PBM mutation negatively affected the degradation activity of the stromal Clp protease. The mutation also disrupted association of Hsp93 with the Clp proteolytic core at the envelope, without affecting the envelope localization of Hsp93 itself or its association with the TIC machinery, which we demonstrate to be mediated by a direct interaction with Tic110. Nonetheless, Hsp93[P-] expression did not detectably improve the protein import efficiency of hsp93 mutant chloroplasts. Thus, our results do not support the proposed function of Hsp93 in protein import propulsion, but are more consistent with the notion of Hsp93 performing a quality control role at the point of import. PMID- 26586838 TI - Morphometric changes correlate with poor psychological outcomes in patients with acromegaly. AB - OBJECTIVE: Acromegaly is frequently associated with altered facial appearance at the time of diagnosis. Furthermore, acromegaly is also associated with adverse psychological outcomes. We conducted a single-centre, cross-sectional study comparing patients with growth hormone vs non-functioning pituitary adenomas (NFA) to assess the association between morphometric changes and psychological outcomes and illness perception of patients with acromegaly. METHODS: A seven step scale was developed to grade morphometric changes based on facial photographs. In addition, all patients were asked to draw an image of their own body and an image of what they considered to be an average healthy body and complete seven psychological questionnaires. We recruited 55 consecutive patients in each of the two groups who had undergone surgery with or without radiation therapy (RT). RESULTS: Our data showed that the clinician-rated morphometric scale was highly reliable in assessing facial changes, with 93/99 (Intraclass correlation coefficient (ICC)=0.95 (0.93-0.97)) graded as similar by independent raters. The mean (s.d.) grading for Acro and NFA patients on the clinician-rated morphometric scale were 3.5 (1.3) and 0.41 (0.35) respectively (P<0.0001). A higher clinician-rated morphometric score was also predictive of a poorer score on the drawing test. CONCLUSIONS: Our study demonstrates a correlation between physical changes associated with acromegaly and poor psychological outcomes, whereas no such correlation existed with modes of therapy, disease control status, RT, malignancy, initial or recent GH/IGF1 or secondary hormonal deficiency. Our data support the utility of the morphometric scale as a clinical tool for grading facial changes. PMID- 26586840 TI - Gender-specific medicine in the genomic era. AB - This article is intended to illuminate several important changes in our concept of gender-specific medicine in the genomic era. It reviews the history of gender specific medicine, pointing out the changes in our perception of the nature of biological sex and our expanding knowledge of how it affects the phenotype. The old debate about 'nature versus nurture' is now largely resolved; the two are inextricably intertwined as a result of epigenomic regulation of gene expression; many of the resulting phenotypic changes are inherited and affect future generations. More accurate, rapid and cheaper methods of editing genomic composition are implementing a more sophisticated understanding of how genes function and how individual components of the genome might be added or eliminated to maintain health and prevent disease. As Venter predicted, the new discipline of synthetic biology, based on the creation and use of novel 'designer' chromosomes is an inevitable expansion of our ability to decipher the naturally occurring genome and the factors that control its expression. As we move with unexpected and stunning rapidity into our exploration and manipulation of the genetic code, our investigations must acknowledge the solidly established fact that biological sex will have a profound impact on the interventions we have made and will make in the future. Unfortunately, in spite of the recent urging of the National Institutes of Health (NIH) that sex be included as an essential variable in all levels of scientific investigation, genuine issues remain to be resolved before all scientists accept not only the importance of doing this, but also how to implement it. PMID- 26586839 TI - Maternal hypothyroxinaemia in pregnancy is associated with obesity and adverse maternal metabolic parameters. AB - OBJECTIVE: Subclinical hypothyroidism and isolated hypothyroxinaemia in pregnancy have been associated with an increased risk of gestational diabetes. We aimed to ascertain if these women have a worse metabolic phenotype than euthyroid pregnant women. DESIGN, SUBJECTS AND METHODS: We recruited 956 healthy Caucasian women with singleton, non-diabetic pregnancies from routine antenatal clinics. Detailed anthropometric measurements (including BMI and skinfold thickness) and fasting blood samples (for TSH, free thyroxine (FT4), free triiodothyronine (FT3), HbA1c, lipid profile, plasma glucose and insulin resistance (HOMA-IR) analysis) were obtained at 28 weeks gestation. RESULTS: In comparison to euthyroid women (n=741), women with isolated hypothyroxinaemia (n=82) had significantly increased BMI (29.5 vs 27.5 kg/m(2), P<0.001), sum of skinfolds (57.5 vs 51.3 mm, P=0.002), fasting plasma glucose (4.5 vs 4.3 mmol/l, P=0.01), triglycerides (2.3 vs 2.0 mmol/l, P<0.001) and HOMA-IR (2.0 vs 1.3, P=0.001). Metabolic parameters in women with subclinical hypothyroidism (n=133) were similar to those in euthyroid women. Maternal FT4 was negatively associated with BMI (r=-0.22), HbA1c (r=-0.14), triglycerides (r=-0.17), HOMA-IR (r=-0.15) but not total/HDL cholesterol ratio (r=-0.03). Maternal FT3:FT4 ratio was positively associated with BMI (r=0.4), HbA1c (r=0.21), triglycerides (r=0.2), HOMA-IR (r=0.33) and total/HDL cholesterol ratio (r=0.07). TSH was not associated with the metabolic parameters assessed. CONCLUSIONS: Isolated hypothyroxinaemia, but not subclinical hypothyroidism, is associated with adverse metabolic phenotype in pregnancy, as is decreasing maternal FT4 and increasing FT3:FT4 ratio. These associations may be a reflection of changes in the thyroid hormone levels secondary to increase in BMI rather than changes in thyroid hormone levels affecting body weight and related metabolic parameters. PMID- 26586842 TI - Persistent Requirement and Alteration of the Key Targets of PRDM1 During Primordial Germ Cell Development in Mice. AB - Primordial germ cells (PGCs) are the foundation of totipotency and vital for reproduction and heredity. PGCs in mice arise from the epiblast around Embryonic Day (E) 7.0, migrate through the hindgut endoderm, and colonize and proliferate in the embryonic gonads until around E13.5 prior to their differentiation either into prospermatogonia or oogonia. PRDM1, a transcriptional repressor, plays an essential role in PGC specification that includes robustly repressing a somatic mesodermal program. Using an inducible conditional knockout system, we show here that PRDM1 is critically required throughout PGC development. When Prdm1 was deleted in migrating PGCs at E9.5 or E10.5, or in male gonadal PGCs at E11.5, PGCs were eliminated by apoptosis from around E10.5, E11.5, or E13.5, respectively. When Prdm1 was deleted in female gonadal PGCs at E11.5, PGCs progressed into the first meiotic prophase in an apparently normal fashion, but the oogonia exhibited an aberrant pachytene phenotype, undergoing abrupt apoptosis from around E16.5. The escape of a fraction of PGCs (~10%) from the Prdm1 deletion was sufficient to recover fairly normal germ cell pools, both in male and female adults. The key targets of PRDM1 in migrating and/or gonadal PGCs, including genes for development, apoptosis, and prospermatogonial differentiation, showed only a modest overlap with those upon PGC specification, and were enriched with histone H3 lysine 27 trimethylation (H3K27me3). Our findings provide critical insight into the mechanism for maintaining the transcriptional integrity of PGCs. PMID- 26586841 TI - Prenatal Testosterone Exposure Leads to Gonadal Hormone-Dependent Hyperinsulinemia and Gonadal Hormone-Independent Glucose Intolerance in Adult Male Rat Offspring. AB - Elevated testosterone levels during prenatal life lead to hyperandrogenism and insulin resistance in adult females. This study evaluated whether prenatal testosterone exposure leads to the development of insulin resistance in adult male rats in order to assess the influence of gonadal hormones on glucose homeostasis in these animals. Male offspring of pregnant rats treated with testosterone propionate or its vehicle (control) were examined. A subset of male offspring was orchiectomized at 7 wk of age and reared to adulthood. At 24 wk of age, fat weights, plasma testosterone, glucose homeostasis, pancreas morphology, and gastrocnemius insulin receptor (IR) beta levels were examined. The pups born to testosterone-treated mothers were smaller at birth and remained smaller through adult life, with levels of fat deposition relatively similar to those in controls. Testosterone exposure during prenatal life induced hyperinsulinemia paralleled by an increased HOMA-IR index in a fasting state and glucose intolerance and exaggerated insulin responses following a glucose tolerance test. Prenatal androgen-exposed males had more circulating testosterone during adult life. Gonadectomy prevented hyperandrogenism, reversed hyperinsulinemia, and attenuated glucose-induced insulin responses but did not alter glucose intolerance in these rats. Prenatal androgen-exposed males had decreased pancreatic islet numbers, size, and beta-cell area along with decreased expression of IR in gastrocnemius muscles. Gonadectomy restored pancreatic islet numbers, size, and beta-cell area but did not normalize IRbeta expression. This study shows that prenatal testosterone exposure leads to a defective pancreas and skeletal muscle function in male offspring. Hyperinsulinemia during adult life is gonad-dependent, but glucose intolerance appears to be independent of postnatal testosterone levels. PMID- 26586843 TI - Lentiviral Vector-Mediated Complementation Restored Fetal Viability but Not Placental Hyperplasia in Plac1-Deficient Mice. AB - The X-linked Plac1 gene is maternally expressed in trophoblast cells during placentation, and its disruption causes placental hyperplasia and intrauterine growth restriction. In contrast, Plac1 is also reported to be one of the upregulated genes in the hyperplastic placenta generated by nuclear transfer. However, the effect of overexpressed Plac1 on placental formation and function remained unaddressed. We complemented the Plac1 knockout placental dysfunction by lentiviral vector-mediated, placenta-specific Plac1 transgene expression. Whereas fetal development and the morphology of maternal blood sinuses in the labyrinth zone improved, placental hyperplasia remained, with an expanded the junctional zone that migrated and encroached into the labyrinth zone. Further experiments revealed that wild-type placenta with transgenically expressed Plac1 resulted in placental hyperplasia without the encroaching of the junctional zone. Our findings suggest that Plac1 is involved in trophoblast cell proliferation, differentiation, and migration. Its proper expression is required for normal placentation and fetal development. PMID- 26586845 TI - On the repeated measures designs and sample sizes for randomized controlled trials. AB - For the analysis of longitudinal or repeated measures data, generalized linear mixed-effects models provide a flexible and powerful tool to deal with heterogeneity among subject response profiles. However, the typical statistical design adopted in usual randomized controlled trials is an analysis of covariance type analysis using a pre-defined pair of "pre-post" data, in which pre (baseline) data are used as a covariate for adjustment together with other covariates. Then, the major design issue is to calculate the sample size or the number of subjects allocated to each treatment group. In this paper, we propose a new repeated measures design and sample size calculations combined with generalized linear mixed-effects models that depend not only on the number of subjects but on the number of repeated measures before and after randomization per subject used for the analysis. The main advantages of the proposed design combined with the generalized linear mixed-effects models are (1) it can easily handle missing data by applying the likelihood-based ignorable analyses under the missing at random assumption and (2) it may lead to a reduction in sample size, compared with the simple pre-post design. The proposed designs and the sample size calculations are illustrated with real data arising from randomized controlled trials. PMID- 26586844 TI - Cumulus Cell Transcripts Transit to the Bovine Oocyte in Preparation for Maturation. AB - So far, the characteristics of a good quality egg have been elusive, similar to the nature of the physiological, cellular, and molecular cues leading to its production both in vivo and in vitro. Current understanding highlights a strong and complex interdependence between the follicular cells and the gamete. Secreted factors induce cellular responses in the follicular cells, and direct exchange of small molecules from the cumulus cells to the oocyte through gap junctions controls meiotic arrest. Studying the interconnection between the cumulus cells and the oocyte, we previously demonstrated that the somatic cells also contribute transcripts to the gamete. Here, we show that these transcripts can be visualized moving down the transzonal projections (TZPs) to the oocyte, and that a time course analysis revealed progressive RNA accumulation in the TZPs, indicating that RNA transfer occurs before the initiation of meiosis resumption under a timetable fitting with the acquisition of developmental competence. A comparison of the identity of the nascent transcripts trafficking in the TZPs, with those in the oocyte increasing in abundance during maturation, and that are present on the oocyte's polyribosomes, revealed transcripts common to all three fractions, suggesting the use of transferred transcripts for translation. Furthermore, the removal of potential RNA trafficking by stripping the cumulus cells caused a significant reduction in maturation rates, indicating the need for the cumulus cell RNA transfer to the oocyte. These results offer a new perspective to the determinants of oocyte quality and female fertility, as well as provide insight that may eventually be used to improve in vitro maturation conditions. PMID- 26586846 TI - Sexually transmitted infections in the military: new challenges for an old problem. PMID- 26586847 TI - The BASHH MSM special interest group. PMID- 26586848 TI - How to set up a remotely supported hub and spoke sexual health service for a military population. PMID- 26586849 TI - Sexually transmitted infections and sexual behaviour of deploying shipboard US military personnel: a cross-sectional analysis. AB - OBJECTIVES: Sexually transmitted infection (STI) prevalence and risk behaviour may differ at different phases of deployment. We examined STI prevalence and sexual behaviour in the predeployment time period (12 months prior) among recently deployed shipboard US Navy and Marine Corps military personnel. METHODS: Data were collected from 1938 male and 515 female service members through an anonymous, self-completed survey assessing sexual behaviours and STI acquisition characteristics in the past 12 months. Cross-sectional sex-stratified descriptive statistics are reported. RESULTS: Overall, 67% (n=1262/1896) reported last sex with a military beneficiary (spouse, n=931, non-spouse service member, n=331). Among those with a sexual partner outside their primary partnership, 24% (n=90/373) reported using a condom the last time they had sex and 30% (n=72/243) reported their outside partner was a service member. In total, 90% (n=210/233) reported acquiring their most recent STI in the USA (88%, n=126/143 among those reporting >=1 deployments and an STI >=1 year ago) and a significantly higher proportion (p<0.01) of women than men acquired the STI from their regular partner (54% vs 21%) and/or a service member (50% vs 26%). CONCLUSIONS: Findings suggest a complex sexual network among service members and military beneficiaries. Findings may extend to other mobile civilian and military populations. Data suggest most STI transmission within the shipboard community may occur in local versus foreign ports but analyses from later time points in deployment are needed. These data may inform more effective STI prevention interventions. PMID- 26586850 TI - Different values of urinary fractionated metanephrines after unilateral adrenalectomy for pheochromocytoma according to time intervals after surgery. AB - Background After adrenalectomy, urinary fractionated metanephrine concentrations are expected to be reduced. However, there are few studies suggesting cut-offs for adrenalectomy patients. Methods Urinary metanephrine and normetanephrine concentrations in adrenalectomy patients and two controls were compared and hormonal concentrations were evaluated via time intervals after surgery. Results The median urinary metanephrine level after unilateral adrenalectomy was lower than that of the non-pheochromocytoma controls but comparable to healthy controls. Urinary normetanephrine concentrations did not differ between adrenalectomy patients and non-pheochromocytoma controls, although both group had levels higher than those of healthy controls. The median urinary normetanephrine level in the immediate postoperative period was higher than in the later period. Conclusions Urinary metanephrine concentrations were lower after adrenalectomy, but urinary normetanephrine concentrations were not changed compared with the non pheochromocytoma controls. However, urinary normetanephrine concentrations in the patient group were higher than levels in the heathy controls. PMID- 26586851 TI - The predictive value of low plasma copper and high plasma zinc in detecting zinc induced copper deficiency. AB - BACKGROUND: Zinc-induced copper deficiency is a condition whose diagnosis is often delayed allowing severe and usually irreversible neurology symptoms to develop. Plasma copper concentrations are usually low and plasma zinc concentrations high. The aim of this study was to measure the predictive value of this combination of results as a means of facilitating its early diagnosis. METHODS: Low plasma copper (<=6 umol/L) and high plasma zinc results (>18 umol/L) were retrieved from the laboratory database from 2000 to 2014. Medical records and laboratory notes of the corresponding 20 patients found were accessed to determine which were likely to have zinc-induced copper deficiency. RESULTS: Fifteen (75%) patients were diagnosed with zinc-induced copper deficiency which was symptomatic in 13. Of the five remaining patients, two were treated with zinc because of Wilson's disease which was the cause of hypocupraemia, two were treated parenterally with zinc, and insufficient information was available in the final patient. CONCLUSIONS: The combination of a low plasma copper and high plasma zinc is strongly predictive for the diagnosis of zinc-induced copper deficiency. There is the therefore an opportunity for the reporting biochemist to facilitate in its earlier diagnosis so enabling treatment to be implemented before the condition deteriorates. PMID- 26586852 TI - Evaluation of combined Gd-EOB-DTPA and gadobutrol magnetic resonance imaging for the prediction of hepatocellular carcinoma grading. AB - BACKGROUND: Tumor biopsy is not essential for the diagnosis of hepatocellular carcinoma (HCC); however, grading remains important for the prognosis. PURPOSE: To investigate whether combined Gd-EOB-DTPA and gadobutrol liver magnetic resonance imaging (MRI) can predict HCC grading. MATERIAL AND METHODS: Thirty patients (66.6 +/- 7.3 years) with histologically confirmed HCC (grade 1, n = 5; grade 1-2, n = 6; grade 2, n = 13; grade 2-3, n = 2; grade 3, n = 4) underwent two liver MRIs, one with gadobutrol and one with Gd-EOB-DTPA, on consecutive days. Blinded to grading, two radiologists reviewed the gadobutrol and Gd-EOB DTPA images in consensus with respect to: (i) HCC hyper-/iso-/hypointensity in the arterial, portal-venous/delayed, and Gd-EOB-DTPA hepatocellular phase; and (ii) morphologic tumor features (encapsulated growth, vessel invasion, heterogeneity, liver capsule infiltration, satellite metastases). RESULTS: A significant correlation with grading was not found for either the combined dynamic information of all gadobutrol phases (r = -0.187, P = 0.331) or all the Gd-EOB-DTPA phases (r = 0.052, P = 0.802). No correlation with grading was found for a combination of arterial and hepatocellular phase in Gd-EOB-DTPA MRI (r = 0.209, P = 0.305), a combination of both arterial phases (gadobutrol and Gd-EOB DTPA) with the Gd-EOB-DTPA hepatocellular phase (r = 0.240, P = 0.248), or a combination of all available gadobutrol and Gd-EOB-DTPA phases (r = 0.086, P = 0.691). For all gadobutrol information (dynamic phases and morphology; r = 0.049, P = 0.801) and for all Gd-EOB-DTPA information (r = 0.040, P = 0.845), no correlation with grading was found. Hepatocellular Gd-EOB-DTPA phase iso /hyperintensity never occurred in grade 3 HCCs. CONCLUSION: Histological HCC grading cannot be predicted by combined Gd-EOB-DTPA/gadobutrol MRI. However, Gd EOB-DTPA hepatocellular phase iso-/hyperintensity was never detected in grade 3 HCCs. PMID- 26586853 TI - Combined Effect of Blood Cadmium and Lead Levels on Coronary Heart Disease Prediction Risk in Korean Men. AB - This study was designed to investigate the combined effects of cadmium (Cd) and lead (Pb) on 10-year coronary heart disease (CHD) risk calculated using the Framingham risk score. The heavy metal data set of the Korean National Health and Nutrition Examination Survey IV and V (2008-2010) was analyzed. The 10-year CHD risk was significantly associated with the log-transformed blood Cd and Pb levels in Korean men. For the highest quartile of Cd and Pb, the odds ratio (OR) of the intermediate risk and beyond for CHD (10-year risk >=10%) compared to the lowest quartile was 6.870 (Cd, 95% confidence interval [CI]: 4.58-10.30) and 3.127 (Pb, 95% CI: 2.09-4.69) after adjusting for confounders, respectively. The adjusted OR of the intermediate risk and beyond for CHD (10-year risk >=10%) in the fourth quartile of both Cd and Pb was 12.2 (95% CI: 8.0-18.5) compared to the reference group (first and second quartiles of Cd and Pb). However, the association between log-transformed blood Cd and Pb and the 10-year CHD risk was not significant in Korean women. PMID- 26586854 TI - Impact of Vitamin K Administration on INR Changes and Bleeding Events Among Patients With Cirrhosis. AB - BACKGROUND: The efficacy of vitamin K in lowering an elevated INR in the setting of cirrhosis is not well established. OBJECTIVES: The purpose of this investigation is to determine the effect of vitamin K administration on the INR and bleeding eventsamong hospitalized patients with cirrhosis. METHODS: This is a retrospective investigation of patients hospitalized at an academic institution from 2010 to 2012. Adults with an ICD9 code supporting cirrhosis were segregated into matched cohorts based on provision of vitamin K. Multivariable logistic regression of factors associated with INR decrease and bleeding events was completed. RESULTS: The final matched cohort (n = 276) contained 130 patients who received vitamin K and 146 who did not receive this therapy. ICU care (adjusted odds ratio [AOR] = 2.91; 95% CI = 1.54-5.49; P = 0.01), receipt of a blood product (AOR = 2.40; 95%CI = 1.35-4.24; P = 0.03), and baseline INR > 1.6 (AOR = 1.72; 95% CI = 1.00-2.95; P = 0.05), but not vitamin K administration (AOR = 1.17; 95% CI = 0.66-2.08; P = 0.59), were associated with INR decrease. Bleeding events occurred more frequently among patients with a history of esophageal varices (AOR = 6.35; 95% CI = 1.21-33.4; P = 0.03), but vitamin K administration did not have an impact on these events (AOR = 4.90; 95% CI = 0.56-43.0; P = 0.15). CONCLUSIONS: Administration of vitamin K did not affect INR changes or bleeding events in this cohort of hospitalized patients with cirrhosis. PMID- 26586855 TI - How Well Do You Expect to Recover, and What Does Recovery Mean, Anyway? Qualitative Study of Expectations After a Musculoskeletal Injury. AB - BACKGROUND: Expecting to recover from a musculoskeletal injury is associated with actual recovery. Expectations are potentially modifiable, although it is not well understood how injured people formulate expectations. A better understanding of how expectations are formulated may lead to better knowledge about how interventions might be implemented, what to intervene on, and when to intervene. OBJECTIVES: The objective of this study was to explore what "recovery" meant to participants, whether they expected to "recover," and how they formed these expectations. METHODS: This qualitative study used interpretive phenomenological analysis. Eighteen semistructured interviews were conducted with people seeking treatment for recent musculoskeletal injuries. RESULTS: Recovery was conceptualized as either (1) complete cessation of symptoms or pain-free return to function or (2) return to function despite residual symptoms. Expectations were driven by desire for a clear diagnosis, belief (or disbelief) in the clinician's prognosis, prior experiences, other people's experiences and attitudes, information from other sources such as the Internet, and a sense of self as resilient. CONCLUSIONS: Expectations appear to be embedded in both hopes and fears, suggesting that clinicians should address both when negotiating realistic goals and educating patients. This approach is particularly relevant for cases of nonspecific musculoskeletal pain, where diagnoses are unclear and treatment may not completely alleviate pain. PMID- 26586856 TI - Reliability of Physical Activity Measures During Free-Living Activities in People After Total Knee Arthroplasty. AB - BACKGROUND: Few instruments that measure physical activity (PA) can accurately quantify PA performed at light and moderate intensities, which is particularly relevant in older adults. The evidence of their reliability in free-living conditions is limited. OBJECTIVE: The study objectives were: (1) to determine the test-retest reliability of the Actigraph (ACT), SenseWear Armband (SWA), and Community Healthy Activities Model Program for Seniors (CHAMPS) questionnaire in assessing free-living PA at light and moderate intensities in people after total knee arthroplasty; (2) to compare the reliability of the 3 instruments relative to each other; and (3) to determine the reliability of commonly used monitoring time frames (24 hours, waking hours, and 10 hours from awakening). DESIGN: A one group, repeated-measures design was used. METHODS: Participants wore the activity monitors for 2 weeks, and the CHAMPS questionnaire was completed at the end of each week. Test-retest reliability was determined by using the intraclass correlation coefficient (ICC [2,k]) to compare PA measures from one week with those from the other week. RESULTS: Data from 28 participants who reported similar PA during the 2 weeks were included in the analysis. The mean age of these participants was 69 years (SD=8), and 75% of them were women. Reliability ranged from moderate to excellent for the ACT (ICC=.75-.86) and was excellent for the SWA (ICC=.93-.95) and the CHAMPS questionnaire (ICC=.86-.92). The 95% confidence intervals (95% CI) of the ICCs from the SWA were the only ones within the excellent reliability range (.85-.98). The CHAMPS questionnaire showed systematic bias, with less PA being reported in week 2. The reliability of PA measures in the waking-hour time frame was comparable to that in the 24-hour time frame and reflected most PA performed during this period. LIMITATIONS: Reliability may be lower for time intervals longer than 1 week. CONCLUSIONS: All PA measures showed good reliability. The reliability of the ACT was lower than those of the SWA and the CHAMPS questionnaire. The SWA provided more precise reliability estimates. Wearing PA monitors during waking hours provided sufficiently reliable measures and can reduce the burden on people wearing them. PMID- 26586857 TI - Which Children Are Not Getting Their Needs for Therapy or Mobility Aids Met? Data From the 2009-2010 National Survey of Children With Special Health Care Needs. AB - BACKGROUND: Pediatric rehabilitation therapy services and mobility aids have an important role in the health of children with special health care needs, and the Affordable Care Act (ACA) may increase coverage for these needs. Identifying the prevalence of and factors associated with therapy and mobility aid needs and unmet needs prior to the full implementation of the ACA will be useful for future evaluation of its impact. OBJECTIVE: The purpose of this study was to identify the prevalence of and factors associated with caregiver perceived needs and unmet needs for therapy or mobility aids among children with special health care needs living in the United States. DESIGN: A cross-sectional, descriptive, multivariate analysis was conducted. METHODS: The 2009-2010 National Survey of Children With Special Health Care Needs was used to identify a nationally representative sample of children with special health care needs with needs for therapy (weighted n=2,603,605) or mobility aids (weighted n=437,971). Odds of having unmet needs associated with child and family characteristics were estimated. RESULTS: Nearly 1 in 5 children with therapy needs had unmet needs, and nearly 1 in 10 children with mobility aid needs had unmet needs. Unmet needs were most strongly associated with how frequently the condition affected function and being uninsured in the previous year. LIMITATIONS: Data were caregiver reported and not verified by clinical assessment. Survey data grouped physical therapy, occupational therapy, and speech therapy; analysis was not discipline specific. CONCLUSIONS: This evidence serves as a baseline about the future impact of the ACA. Pediatric rehabilitation professionals should be aware that children with special health care needs whose condition more frequently affects function and who have insurance discontinuity may need more support to meet therapy or mobility aid needs. PMID- 26586858 TI - Does More Therapy in Skilled Nursing Facilities Lead to Better Outcomes in Patients With Hip Fracture? AB - BACKGROUND: Skilled nursing facilities (SNFs) have increasingly been providing more therapy hours to beneficiaries of Medicare. It is not known whether these increases have improved patient outcomes. OBJECTIVE: The study objectives were: (1) to examine temporal trends in therapy hour volumes and (2) to evaluate whether more therapy hours are associated with improved patient outcomes. DESIGN: This was a retrospective cohort study. METHODS: Data sources included the Minimum Data Set, Medicare inpatient claims, and the Online Survey, Certification, and Reporting System. The study population consisted of 481,908 beneficiaries of Medicare fee-for-service who were admitted to 15,496 SNFs after hip fracture from 2000 to 2009. Linear regression models with facility and time fixed effects were used to estimate the association between the quantity of therapy provided in SNFs and the likelihood of discharge to home. RESULTS: The average number of therapy hours increased by 52% during the study period, with relatively little change in case mix at SNF admission. An additional hour of therapy per week was associated with a 3.1-percentage-point (95% confidence interval=3.0, 3.1) increase in the likelihood of discharge to home. The effect of additional therapy decreased as the Resource Utilization Group category increased, and additional therapy did not benefit patients in the highest Resource Utilization Group category. LIMITATIONS: Minimum Data Set assessments did not cover details of therapeutic interventions throughout the entire SNF stay and captured only a 7-day retrospective period for measures of the quantity of therapy provided. CONCLUSIONS: Increases in the quantity of therapy during the study period cannot be explained by changes in case mix at SNF admission. More therapy hours in SNFs appear to improve outcomes, except for patients with the greatest need. PMID- 26586859 TI - Improvement of Physical Therapist Assessment of Risk of Falls in the Hospital and Discharge Handover Through an Intervention to Modify Clinical Behavior. AB - BACKGROUND: Discharge from the hospital is a high risk transition period for older adults at risk of falls. Guidelines relevant to physical therapists for managing this risk are well documented, but commonly not implemented. PURPOSE: This project implemented an intervention to improve physical therapists' adherence to key guideline recommendations for managing risk of falls on discharge from one hospital. DATA SOURCES: A pretest-posttest study design was undertaken and was underpinned by the Theoretical Domains Framework (TDF) to aid in the design of interventions to increase physical therapists' adherence to guideline recommendations and to identify barriers to these interventions. DATA EXTRACTION: A multifaceted intervention was implemented, including the establishment of a governance committee, education sessions, development of a "pathway" to guide practice, modification of an existing standardized assessment proforma, development of standardized processes and indicators for handover, increasing availability of educational handouts, audit and feedback processes, and allocation of dedicated staffing to oversee falls prevention within the physical therapy department. DATA SYNTHESIS: There were significant improvements in physical therapist behavior leading to key guideline recommendations being met, including: the proportion of patients who were identified to be at risk of falls (6.3% preintervention versus 94.8% postintervention) prior to discharge, an increase in documentation of clinical handover at discharge (68.6% preintervention versus 90.9% postintervention), and improvement in the quality of this documented clinical handover (34.9% of case notes met 5 criteria preintervention versus 92.9% postintervention). LIMITATIONS: The approach was resource intensive and consequently may be difficult to replicate at other sites. CONCLUSIONS: A multifaceted intervention underpinned by the TDF, designed to modify physical therapists' behavior to improve adherence to guideline recommendations for managing risk of falls on discharge from one hospital, was successful. PMID- 26586860 TI - Vestibular Rehabilitation After Traumatic Brain Injury: Case Series. AB - BACKGROUND AND PURPOSE: There has been an increasing focus on vestibular rehabilitation (VR) after traumatic brain injury (TBI) in recent years. However, detailed descriptions of the content of and patient responses to VR after TBI are limited. The purposes of this case series are (1) to describe a modified, group based VR intervention and (2) to examine changes in self-reported and performance based outcome measures. CASE DESCRIPTION: Two women and 2 men (aged 24-45 years) with mild TBI, dizziness, and balance problems participated in an 8-week intervention consisting of group sessions with guidance, individually modified VR exercises, a home exercise program, and an exercise diary. Self-reported and performance-based outcome measures were applied to assess the impact of dizziness and balance problems on functions related to activity and participation. OUTCOMES: The intervention caused no adverse effects. Three of the 4 patients reported reduced self-perceived disability because of dizziness, diminished frequency and severity of dizziness, improved health-related quality of life, reduced psychological distress, and improved performance-based balance. The change scores exceeded the minimal detectable change, indicating a clinically significant change or improvement in the direction of age-related norms. The fourth patient did not change or improve in most outcome measures. DISCUSSION: A modified, group-based VR intervention was safe and appeared to be viable and beneficial when addressing dizziness and balance problems after TBI. However, concurrent physical and psychological symptoms, other neurological deficits, and musculoskeletal problems might influence the course of central nervous system compensation and recovery. The present case series may be useful for tailoring VR interventions to patients with TBI. Future randomized controlled trials are warranted to evaluate the short- and long-term effects of VR after TBI. PMID- 26586861 TI - Interdisciplinary Management of Complex Regional Pain Syndrome of the Face. AB - BACKGROUND AND PURPOSE: Orofacial pain disorders are relatively uncommon and pose a substantial diagnostic challenge. This case report documents the diagnosis and management of hemifacial pain in a patient who was referred to an interdisciplinary pain medicine unit. The purpose of this case report is twofold. First, it presents complex regional pain syndrome (CRPS) as a potential differential diagnosis in cases of facial pain. Second, it describes the successful adaption of contemporary management approaches for distal-extremity CRPS to treat people with CRPS of the facial region. CASE DESCRIPTION: The patient had hemifacial pain and concomitant motor and autonomic symptoms after a small laceration of the eyelid. Extensive specialist medical evaluations were undertaken to exclude an underlying structural pathology. After detailed clinical assessments by a physical therapist, pain physician, and clinical psychologist, a diagnosis of CRPS involving the face was made. OUTCOMES: The patient's pain was largely unresponsive to pharmacological agents. A modified graded motor imagery program, together with desensitization and discrimination training, was commenced by the physical therapist and clinical psychologist. A positive clinical response was indicated by a decrease in allodynia, normalization of motor control, and regained function in activities of daily living. DISCUSSION: Complex regional pain syndrome is an infrequently reported differential diagnosis that can be considered in patients with persistent facial pain. This case report highlights how careful examination and clinical decision making led to the use of an innovative therapeutic strategy to manage a challenging condition. PMID- 26586862 TI - Structural Validity of the Dutch Version of the Patient-Rated Wrist Evaluation (PRWE-NL) in Patients With Hand and Wrist Injuries. AB - BACKGROUND: Hand and wrist injuries are one of the most common injuries seen in adults. The Patient-Rated Wrist Evaluation (PRWE) questionnaire has been developed as a patient-report outcome measure of pain and disability to evaluate the outcome after hand and wrist injuries. OBJECTIVE: The aims of this study were (1) to evaluate the structural validity of the existing Dutch version of the PRWE (PRWE-NL) in patients with hand or wrist injuries and (2) to investigate the appropriateness of reporting subscale scores. DESIGN: This was a retrospective analysis of cross-sectional data of 368 adult patients. METHODS: Patients aged 18 to 65 years and treated either surgically or conservatively for an isolated hand or wrist injury were recruited. Patients were excluded if they were unable to speak or read Dutch. Confirmatory factor analyses were used to investigate structural validity, and Cronbach alpha (alpha) and omega (omega) coefficients were used to investigate internal consistency. RESULTS: A series of confirmatory factor analyses revealed that all models (ie, a single-factor model, correlated 2 and 3-factor models, and 2 bifactor models) were associated with adequate model fit. However, inspection of the factor loadings, the explained common variance (ECV), and the different coefficient omega values revealed that the PRWE-NL should be considered a measure of a unidimensional trait. In addition, PRWE-NL subscales were associated with unacceptably low levels of reliability independently of the global PRWE-NL factor. LIMITATIONS: Although the sample size was adequate, the response rate was 37.1%. Participants were mainly patients with fractures of the wrist or hand, predominantly treated nonsurgically. CONCLUSION: This study suggests that the PRWE-NL measures a unidimensional trait. A single score should be used for the PRWE-NL, without subscale scores. PMID- 26586863 TI - Effect of Continuous-Wave Low-Intensity Ultrasound in Inflammatory Resolution of Arthritis-Associated Synovitis. AB - BACKGROUND: Low-intensity ultrasound (LIUS) can reduce pain and improve function in arthritic joints. Neutrophils are first-line actors in host defense that recruit macrophages. Dead neutrophils are removed during resolution of inflammation. Delayed neutrophil clearance can lead to extended inflammation or even chronic autoimmune disease. Although neutrophil extracellular traps (NETs) in arthritic tissue are involved in the pathogenesis of arthritis, their functional role has not been clarified. OBJECTIVES: This study aimed to investigate the effect of LIUS on synovial inflammation and its resolution via neutrophil clearance. METHODS: Synovitis was induced by intra-articular injection of complete Freund's adjuvant (CFA) into the left knee joint of 58 adult male Sprague-Dawley rats. Low-intensity ultrasound (1 MHz, 200 mW/cm(2)) was applied for 10 minutes daily. Neutrophil clearance was assessed with the expression of myeloperoxidase (MPO). In addition, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and NET formation in the synovium were observed. In neutrophil and macrophage cultures from peripheral blood, the effect of NET clearance by LIUS was investigated. RESULTS: In CFA-induced synovitis, MPO positive neutrophils peaked after 2 to 3 days, filling the inflammatory core. Monocytes and macrophages in the periphery later infiltrated the core and were reduced thereafter. Low-intensity ultrasound reduced synovial hyperplasia and induced earlier MPO clearance. Neutrophils in the core of the inflamed synovium exhibited NET formation, which LIUS increased. Low-intensity also induced NETs in peripheral polymorphonuclear cells in an intensity-dependent manner and potentiated phorbol myristate acetate (PMA)-induced NETosis. The PMA-induced NETs were cleared by macrophages; clearance was enhanced by LIUS. LIMITATIONS: The effect of LIUS on CFA-induced inflammation was observed only during the acute phase. Although the effect of LIUS on NETosis in the in vitro neutrophil culture system was clear, the in vivo NETosis cannot be quantified. CONCLUSIONS: Neutrophil extracellular traps act in inflammatory synovitis, and LIUS enhanced the NETs and resulted in neutrophil clearance by enhancing the phagocytosis of macrophages, which might be a factor underlying the therapeutic effect of LIUS in arthritic synovium. PMID- 26586864 TI - Reliability and Structural and Construct Validity of the Functional Strength Measurement in Children Aged 4 to 10 Years. AB - BACKGROUND: Adequate muscle strength, power, and endurance are important in children's daily activities and sports. Various instruments have been developed for the assessment of muscle function; each measures different aspects. The Functional Strength Measurement (FSM) was developed to measure performance in activities in which strength is required. OBJECTIVE: The study objective was to establish the test-retest reliability and structural and construct validity of the FSM. DESIGN: A cross-sectional descriptive study was conducted. METHODS: The performance of 474 children with typical development on the FSM was examined. Test-retest reliability (n=47) was calculated with the intraclass correlation coefficient (2.1A) for agreement. Structural validity was examined with exploratory factor analysis, and internal consistency was established with the Cronbach alpha. Construct validity was determined by calculating correlations between FSM scores and scores obtained with a handheld dynamometer (HHD) (n=252) (convergent validity) and between FSM scores and scores on the Movement Assessment Battery for Children-2 (MABC-2) (n=77) (discriminant validity). RESULTS: The test-retest reliability of the FSM total score ranged from .91 to .94. The structural validity revealed one dimension, containing all 8 FSM items. The Cronbach alpha was .74. The convergent validity with the HHD ranged from .42 to .74. The discriminant validity with MABC-2 items revealed correlations that were generally lower than .39, and most of the correlations were not significant. Exploratory factor analysis of a combined data set (FSM, HHD, and MABC-2; n=77) revealed 2 factors: muscle strength/power and muscle endurance with an agility component. LIMITATIONS: Discriminant validity was measured only in children aged 4 to 6 years. CONCLUSIONS: The FSM, a norm-referenced test for measuring functional strength in children aged 4 to 10 years, has good test-retest reliability and good construct validity. PMID- 26586867 TI - Draft Genome Sequence of Porphyrobacter mercurialis (sp. nov.) Strain Coronado. AB - Here, we present the draft genome of Porphyrobacter mercurialis strain Coronado, the proposed type strain for this species. The assembly contains 3,482,341 bp in 10 contigs. PMID- 26586865 TI - Group Versus Individual Physical Therapy for Veterans With Knee Osteoarthritis: Randomized Clinical Trial. AB - BACKGROUND: Efficient approaches are needed for delivering nonpharmacological interventions for management of knee osteoarthritis (OA). OBJECTIVE: This trial compared group-based versus individual physical therapy interventions for management of knee OA. DESIGN AND METHODS: Three hundred twenty patients with knee OA at the VA Medical Center in Durham, North Carolina, (mean age=60 years, 88% male, 58% nonwhite) were randomly assigned to receive either the group intervention (group physical therapy; six 1-hour sessions, typically 8 participants per group) or the individual intervention (individual physical therapy; two 1-hour sessions). Both programs included instruction in home exercise, joint protection techniques, and individual physical therapist evaluation. The primary outcome measure was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC; range=0-96, higher scores indicate worse symptoms), measured at baseline, 12 weeks, and 24 weeks. The secondary outcome measure was the Short Physical Performance Battery (SPPB; range=0-12, higher scores indicate better performance), measured at baseline and 12 weeks. Linear mixed models assessed the difference in WOMAC scores between arms. RESULTS: At 12 weeks, WOMAC scores were 2.7 points lower in the group physical therapy arm compared with the individual physical therapy arm (95% confidence interval [CI]=-5.9, 0.5; P=.10), indicating no between-group difference. At 24 weeks, WOMAC scores were 1.3 points lower in the group physical therapy arm compared with the individual physical therapy arm (95% CI=-4.6, 2.0; P=.44), indicating no significant between-group difference. At 12 weeks, SPPB scores were 0.1 points lower in the group physical therapy arm compared with the individual physical therapy arm (95% CI=-0.5, 0.2; P=.53), indicating no difference between groups. LIMITATIONS: This study was conducted in one VA medical center. Outcome assessors were blinded, but participants and physical therapists were not blinded. CONCLUSIONS: Group physical therapy was not more effective than individual physical therapy for primary and secondary study outcomes. Either group physical therapy or individual physical therapy may be a reasonable delivery model for health care systems to consider. PMID- 26586868 TI - Draft Genome Sequence of the Ant-Associated Fungus Phialophora attae (CBS 131958). AB - The black yeast Phialophora attae was isolated from the cuticle of tropical ant gynes. The ant-fungus association is sustained due to symbiotic evolutionary adaptations that allow fungal assimilation and tolerance of toxic compounds produced by the ant. The genome sequence of the first ant-associated fungus, P. attae, is presented here. PMID- 26586869 TI - Draft Genome Sequence of a European Isolate of the Apple Canker Pathogen Neonectria ditissima. AB - The Sordariomycetes fungus Neonectria ditissima is a major pathogen of apples, causing canker on trees and fruit spoilage. We report here the draft genome sequence of a European strain isolated from cankerous tissue. PMID- 26586870 TI - Draft Genome Sequences of Facultative Methylotrophs, Gemmobacter sp. Strain LW1 and Mesorhizobium sp. Strain 1M-11, Isolated from Movile Cave, Romania. AB - Facultative methylotrophs belonging to the genera Gemmobacter and Mesorhizobium were isolated from microbial mat and cave water samples obtained from the Movile Cave ecosystem. Both bacteria can utilize methylated amines as their sole carbon and nitrogen source. Here, we report the draft genome sequences of Gemmobacter sp. strain LW1 and Mesorhizobium sp. strain IM1. PMID- 26586871 TI - Complete Genome Sequence of the Gut Commensal and Laboratory Strain Enterococcus faecium 64/3. AB - The genome sequence of the commensal and widely used laboratory strain Enterococcus faecium 64/3 was resolved by means of PacificBioscience and Illumina whole-genome sequencing. The genome comprises 2,575,333 bp with 2,382 coding sequences as assigned by NCBI. PMID- 26586872 TI - Draft Genome Sequence of the Fungus Trametes hirsuta 072. AB - A standard draft genome sequence of the white rot saprotrophic fungus Trametes hirsuta 072 (Basidiomycota, Polyporales) is presented. The genome sequence contains about 33.6 Mb assembled in 141 scaffolds with a G+C content of ~57.6%. The draft genome annotation predicts 14,598 putative protein-coding open reading frames (ORFs). PMID- 26586873 TI - Genomic Sequence of Burkholderia multivorans NKI379, a Soil Bacterium That Inhibits the Growth of Burkholderia pseudomallei. AB - Burkholderia multivorans NKI379 is a soil bacterium that exhibits an antagonistic effect against the growth of Burkholderia pseudomallei, the causative agent of the infectious disease melioidosis. We report the draft genomic sequence of B. multivorans NKI379, which has a G+C content of 67% and 5,203 candidate protein encoding genes. PMID- 26586874 TI - Draft Genome Sequence of Gulbenkiania mobilis Strain MB1, a Sulfur-Metabolizing Thermophile Isolated from a Hot Spring in Central India. AB - This paper reports the draft genome sequence of the proteobacterium Gulbenkiania mobilis strain MB1, a sulfur-metabolizing thermophile isolated from a hot spring located in Pachmarhi, India. This study reports the first draft genome sequence of any species from the genus Gulbenkiania. PMID- 26586875 TI - Genome Sequence of Streptococcus phocae subsp. phocae Strain ATCC 51973T Isolated from a Harbor Seal (Phoca vitulina). AB - Streptococcus phocae subsp. phocae is a pathogen that affects different pinniped and mammalian species. This announcement reports the genome sequence of the type strain ATCC 51973 isolated in Norway from clinical specimens of harbor seal (Phoca vitulina), revealing interesting genes related to possible virulence factors. PMID- 26586876 TI - Complete Genome Sequence of Enterococcus Bacteriophage EFLK1. AB - We previously isolated EFDG1, a lytic phage against enterococci for therapeutic use. Nevertheless, EFDG1-resistant bacterial strains (EFDG1(r)) have evolved. EFLK1, a new highly effective phage against EFDG1(r) strains, was isolated in this study. The genome of EFLK1 was fully sequenced, analyzed, and deposited in GenBank. PMID- 26586877 TI - Draft Genome Sequence of Amantichitinum ursilacus IGB-41, a New Chitin-Degrading Bacterium. AB - Amantichitinum ursilacus IGB-41 is a new species of chitin-degrading bacterium isolated from soil, which secretes potential industrial enzymes. The genome of A. ursilacus was sequenced, and the gene set encoding chitinases was identified. Here, we present the draft genome of 4.9 Mb, comprising 38 contigs, and the corresponding annotation. PMID- 26586878 TI - Draft Genome Sequences of Two South African Bacillus anthracis Strains. AB - Bacillus anthracis is a Gram-positive bacterium that causes anthrax, mainly in herbivores through exotoxins and capsule produced on plasmids, pXO1 and pXO2. This paper compares the whole-genome sequences of two B. anthracis strains from an endemic region and a sporadic outbreak in South Africa. Sequencing was done using next-generation sequencing technologies. PMID- 26586879 TI - Whole-Genome Sequence and Classification of 11 Endophytic Bacteria from Poison Ivy (Toxicodendron radicans). AB - Here, we report the whole-genome sequences and annotation of 11 endophytic bacteria from poison ivy (Toxicodendron radicans) vine tissue. Five bacteria belong to the genus Pseudomonas, and six single members from other genera were found present in interior vine tissue of poison ivy. PMID- 26586880 TI - Draft Genome Sequences from Cyclospora cayetanensis Oocysts Purified from a Human Stool Sample. AB - The parasite Cyclospora cayetanensis causes foodborne diarrheal illness. Here, we report draft genome sequences obtained from C. cayetanensis oocysts purified from a human stool sample. The genome assembly consists of 865 contigs with a total length of 44,563,857 bases. These sequences can facilitate the development of subtyping tools to aid outbreak investigations. PMID- 26586881 TI - High-Quality Draft Genome Sequence of Bacillus amyloliquefaciens Strain 629, an Endophyte from Theobroma cacao. AB - Bacillus amyloliquefaciens strain 629 is an endophyte isolated from Theobroma cacao L. Here, we report the draft genome sequence (3.9 Mb) of B. amyloliquefaciens strain 629 containing 16 contigs (3,903,367 bp), 3,912 coding sequences, and an average 46.5% G+C content. PMID- 26586882 TI - Genome Sequences of Three Turkey Orthoreovirus Strains Isolated in Hungary. AB - We have investigated the genomic properties of three turkey reovirus strains 19831M09, D1246, and D1104-isolated in Hungary in 2009. Sequence identity values and phylogenetic calculations indicated genetic conservativeness among the studied Hungarian strains and a close relationship with strains isolated in the United States. PMID- 26586883 TI - Draft Genome Sequence of the Moderately Heat-Tolerant Lactococcus lactis subsp. lactis bv. diacetylactis Strain GL2 from Algerian Dromedary Milk. AB - Lactococcus lactis subsp. lactis bv. diacetylactis GL2 is a moderately thermotolerant lactic acid bacterium isolated from dromedary raw milk. Here, we present the draft genome sequence of this potential new dairy starter strain, which combines thermotolerance and the capacity to metabolize lactose, casein, and citrate. PMID- 26586884 TI - Complete Genome Sequence of Potential Probiotic Lactobacillus sp. HFC8, Isolated from Human Gut Using PacBio SMRT Sequencing. AB - We report a 3.07-Mb complete genome sequence of a lactic acid bacterium, Lactobacillus sp. HFC8. The gene-coding clusters are predicated for probiotic characteristics, like bacteriocin production, cell adhesion, bile salt hydrolysis, lactose metabolism, autoaggregation, and tolerance to oxidative stress. PMID- 26586885 TI - Draft Genome Sequence of Pseudoalteromonas sp. Strain R3, a Red-Pigmented l-Amino Acid Oxidase-Producing Bacterium. AB - Here, we report a draft 5.58-Mb genome sequence of Pseudoalteromonas sp. strain R3, isolated from an intertidal-zone sludge sample, which has l-amino acid oxidase activity. The genomics information of this strain will facilitate the study of l-amino acid oxidase, quorum sensing, and the relationship of the two. PMID- 26586886 TI - Draft Genome Sequence of the Serratia rubidaea CIP 103234T Reference Strain, a Human-Opportunistic Pathogen. AB - We provide here the first genome sequence of a Serratia rubidaea isolate, a human opportunistic pathogen. This reference sequence will permit a comparison of this species with others of the Serratia genus. PMID- 26586887 TI - Draft Genome Sequence of Ardenticatena maritima 110S, a Thermophilic Nitrate- and Iron-Reducing Member of the Chloroflexi Class Ardenticatenia. AB - We report here the draft genome sequence of Ardenticatena maritima 110S, the first sequenced member of class Ardenticatenia of the phylum Chloroflexi. This thermophilic organism is capable of a range of physiologies, including aerobic respiration and iron reduction. It also encodes a complete denitrification pathway with a novel nitric oxide reductase. PMID- 26586888 TI - Draft Genome Sequences of Two Isolates of the Plant-Pathogenic Fungus Neonectria ditissima That Differ in Virulence. AB - Neonectria ditissima is the causal agent of apple canker. Here, we present the draft genome sequences of two isolates of N. ditissima that differ in virulence. Comparative genomics will enable pathogenicity determinants to be identified in this plant-pathogenic fungus. PMID- 26586889 TI - Draft Genome Sequence of Herpetosiphon geysericola GC-42, a Nonphototrophic Member of the Chloroflexi Class Chloroflexia. AB - We report here the draft genome sequence of Herpetosiphon geysericola GC-42, a predatory nonphototrophic member of the class Chloroflexia in the phylum Chloroflexi. This genome provides insight into the evolution of phototrophy and aerobic respiration within the Chloroflexi. PMID- 26586890 TI - Draft Genome Sequence of Ornatilinea apprima P3M-1, an Anaerobic Member of the Chloroflexi Class Anaerolineae. AB - We report the draft genome sequence of Ornatilinea apprima P3M-1, a strictly anaerobic member of the Chloroflexi class Anaerolineae. This genome provides insight into the diversity of metabolism within the Anaerolineae, and the evolution of respiration within the Chloroflexi. PMID- 26586891 TI - Draft Genome of Thermanaerothrix daxensis GNS-1, a Thermophilic Facultative Anaerobe from the Chloroflexi Class Anaerolineae. AB - We present the draft genome of Thermanaerothrix daxensis GNS-1, a thermophilic member of the Chloroflexi phylum. This organism was initially characterized as a nonmotile, strictly anaerobic fermenter; however, genome analysis demonstrates that it encodes genes for a flagellum and multiple pathways for aerobic and anaerobic respiration. PMID- 26586892 TI - Draft Genome Sequence of Prosthecomicrobium hirschii ATCC 27832T. AB - We report the draft genome sequence of Prosthecomicrobium hirschii ATCC 27832(T), an alphaproteobacterium with remarkable cellular morphologies. The chromosome comprises 6,484,983 bp in six scaffolds with a G+C content of 69%, and 6,066 potential coding sequences. PMID- 26586893 TI - Draft Genome Sequence of Leptolinea tardivitalis YMTK-2, a Mesophilic Anaerobe from the Chloroflexi Class Anaerolineae. AB - We present the draft genome sequence of Leptolinea tardivitalis YMTK-2, a member of the Chloroflexi phylum. This organism was initially characterized as a strictly anaerobic nonmotile fermenter; however, genome analysis demonstrates that it encodes for a flagella and might be capable of aerobic respiration. PMID- 26586894 TI - Draft Genome Sequence of Levilinea saccharolytica KIBI-1, a Member of the Chloroflexi Class Anaerolineae. AB - We report the draft genome sequence of Levilinea saccharolytica KIBI-1, a facultative anaerobic member of the Chloroflexi class Anaerolineae. While L. saccharolytica was characterized as an obligate anaerobe, genome analysis provides evidence for the presence of both aerobic respiration and partial denitrification pathways. PMID- 26586895 TI - Draft Genome Sequence of Bacillus safensis JPL-MERTA-8-2, Isolated from a Mars Bound Spacecraft. AB - Here, we present the draft genome of Bacillus safensis JPL-MERTA-8-2, a strain found in a spacecraft assembly cleanroom before launch of the Mars Exploration Rovers. The assembly contains 3,671,133 bp in 14 contigs. PMID- 26586896 TI - Draft Genome Sequence of Amikacin- and Kanamycin-Resistant Mycobacterium tuberculosis MT433 without rrs and eis Mutations. AB - We announce the draft genome sequence of amikacin- and kanamycin-resistant Mycobacterium tuberculosis MT433, which has been previously described as the strain carrying an unknown resistance mechanism. PMID- 26586897 TI - Complete Genome Sequences of Two Outbreak Strains of Salmonella enterica subsp. enterica Serovar Thompson Associated with Cilantro. AB - Salmonella enterica subsp. enterica serovar Thompson strains RM1984 (CADPH 99A2334) and RM1986 (CADPH-99A2345) are associated with a 1999 outbreak in contaminated cilantro. We report here the complete genome sequences and annotation of these two S. Thompson strains. These genomes are distinct and provide additional data for our understanding of S. enterica. PMID- 26586898 TI - Genome Sequences of Three Strains of the Pseudomonas aeruginosa PA7 Clade. AB - Draft genome sequences of three P. aeruginosa strains from the PA7 clade are presented here. Their lengths are 6.36 (EML528), 6.44 (EML545), and 6.33 Mb (EML548). Comparisons with the PA7 genome showed 5,113 conserved coding sequences (CDSs), and significant numbers of strain-specific CDSs. Their analysis will improve our understanding of this highly divergent clade. PMID- 26586899 TI - Complete Genome Sequence of Spiroplasma turonicum Strain Tab4cT, a Parasite of a Horse Fly, Haematopota sp. (Diptera: Tabanidae). AB - Spiroplasma turonicum was isolated from a Haematopota sp. fly in France. We report the nucleotide sequence of the circular chromosome of strain Tab4c(T). The genome information will facilitate evolutionary studies of spiroplasmas, including symbionts of insects and ticks and pathogens of plants, insects, crustaceans, and humans. PMID- 26586900 TI - Draft Genome Sequence of Mycobacterium mucogenicum Strain CSUR P2099. AB - Mycobacterium mucogenicum is a rapid-growing, nontuberculosis Mycobacterium species. The draft genome of M. mucogenicum CSUR P2099 comprises 6,210,127 bp exhibiting a 67.2% G+C content, 6,003 protein-coding genes, and 91 predicted RNA genes. PMID- 26586901 TI - Draft Genome Sequence of Bacillus vietnamensis Strain UCD-SED5 (Phylum Firmicutes). AB - Here, we present the draft genome sequence of Bacillus vietnamensis UCD-SED5 (phylum Firmicutes). This strain was isolated from sediment surrounding Zostera marina roots near the UC Davis Bodega Marine Laboratory (Bodega Bay, California) and represents the second genome of this species. The assembly consists of 4,325,707 bp, in 108 contigs. PMID- 26586902 TI - First Draft Genome Sequence of the Acidovorax caeni sp. nov. Type Strain R-24608 (DSM 19327). AB - We report the draft genome sequence of the Acidovorax caeni type strain R-24608 that was isolated from activated sludge of an aerobic-anaerobic wastewater treatment plant. The closest strain to Acidovorax caeni strain R-24608 is Acidovorax sp. strain MR-S7 with a 55.4% (amino-acid sequence) open reading frames (ORFs) average similarity. PMID- 26586903 TI - Erratum for Erill and Caruso, Complete Genome Sequence of Bacillus cereus Group Phage TsarBomba. PMID- 26586904 TI - Maternal protein restriction compromises myocardial contractility in the young adult rat by changing proteins involved in calcium handling. AB - Maternal protein restriction (MPR) during pregnancy is associated with increased cardiovascular risk in the offspring in adulthood. In this study we evaluated the cardiac function of young male rats born from mothers subjected to MPR during pregnancy, focusing on the myocardial mechanics and calcium-handling proteins. After weaning, rats received normal diet until 3 mo old, when the following parameters were assessed: arterial and left ventricular hemodynamics and in vitro cardiac contractility in isolated papillary muscles. The body weight was lower and arterial pressure higher in the MPR group compared with young adult offspring of female rats that received standard diet (controls); and left ventricle time derivatives increased in the MPR group. The force developed by the cardiac muscle was similar; but time to peak and relaxation time were longer, and the derivatives of force were depressed in the MPR. In addition, MPR group exhibited decreased post-pause potentiation of force, suggesting reduced reuptake function of the sarcoplasmic reticulum. Corroborating, the myocardial content of SERCA-2a and phosphorylated PLB-Ser16/total PLB ratio was decreased and sodium-calcium exchanger was increased in the MPR group. The contraction dependent on transsarcolemmal influx of calcium was higher in MPR if compared with the control group. In summary, young rats born from mothers subjected to protein restriction during pregnancy exhibit changes in the myocardial mechanics with altered expression of calcium-handling proteins, reinforcing the hypothesis that maternal malnutrition is related to increased cardiovascular risk in the offspring, not only for hypertension, but also cardiac dysfunction. PMID- 26586905 TI - Increased expression of telomere-regulating genes in endurance athletes with long leukocyte telomeres. AB - Leukocyte telomeres shorten with age, and excessive shortening is associated with age-related cardiometabolic diseases. Exercise training may prevent disease through telomere length maintenance although the optimal amount of exercise that attenuates telomere attrition is unknown. Furthermore, the underlying molecular mechanisms responsible for the enhanced telomere maintenance observed in endurance athletes is poorly understood. We quantified the leukocyte telomere length and analyzed the expression of telomere-regulating genes in endurance athletes and healthy controls (both n = 61), using quantitative PCR. We found endurance athletes have significantly longer (7.1%, 208-416 nt) leukocyte telomeres and upregulated TERT (2.0-fold) and TPP1 (1.3-fold) mRNA expression compared with controls in age-adjusted analysis. The telomere length and telomere regulating gene expression differences were no longer statistically significant after adjustment for resting heart rate and relative VO(2 max) (all P > 0.05). Resting heart rate emerged as an independent predictor of leukocyte telomere length and TERT and TPP1 mRNA expression in stepwise regression models. To gauge whether volume of exercise was associated with leukocyte telomere length, we divided subjects into running and cycling tertiles (distance covered per week) and found individuals in the middle and highest tertiles had longer telomeres than individuals in the lowest tertile. These data emphasize the importance of cardiorespiratory fitness and exercise training in the prevention of biological aging. They also support the concept that moderate amounts of exercise training protects against biological aging, while higher amounts may not elicit additional benefits. PMID- 26586906 TI - Impact of ventilation strategies during chest compression. An experimental study with clinical observations. AB - The optimal ventilation strategy during cardiopulmonary resuscitation (CPR) is unknown. Chest compression (CC) generates circulation, while during decompression, thoracic recoil generates negative pressure and venous return. Continuous flow insufflation of oxygen (CFI) allows noninterrupted CC and generates positive airway pressure (Paw). The main objective of this study was to assess the effects of positive Paw compared with the current recommended ventilation strategy on intrathoracic pressure (P(IT)) variations, ventilation, and lung volume. In a mechanical model, allowing compression of the thorax below an equilibrium volume mimicking functional residual capacity (FRC), CC alone or with manual bag ventilation were compared with two levels of Paw with CFI. Lung volume change below FRC at the end of decompression and P(IT), as well as estimated alveolar ventilation, were measured during the bench study. Recordings were obtained in five cardiac arrest patients to confirm the bench findings. Lung volume was continuously below FRC, and as a consequence P(IT) remained negative during decompression in all situations, including with positive Paw. Compared with manual bag or CC alone, CFI with positive Paw limited the fall in lung volume and resulted in larger positive and negative P(IT) variations. Positive Paw with CFI significantly augmented ventilation induced by CC. Recordings in patients confirmed a major loss of lung volume below FRC during CPR, even with positive Paw. Compared with manual bag ventilation, positive Paw associated with CFI limits the loss in lung volume, enhances CC-induced positive P(IT), maintains negative P(IT) during decompression, and generates more alveolar ventilation. PMID- 26586907 TI - Relationship between blood pressure and cerebral blood flow during supine cycling: influence of aging. AB - The cerebral pressure-flow relationship can be quantified as a high-pass filter, where slow oscillations are buffered (<0.20 Hz) and faster oscillations are passed through relatively unimpeded. During moderate intensity exercise, previous studies have reported paradoxical transfer function analysis (TFA) findings (altered phase or intact gain). This study aimed to determine whether these previous findings accurately represent this relationship. Both younger (20-30 yr; n = 10) and older (62-72 yr; n = 9) adults were examined. To enhance the signal to-noise ratio, large oscillations in blood pressure (via oscillatory lower body negative pressure; OLBNP) were induced during steady-state moderate intensity supine exercise (~45-50% of heart rate reserve). Beat-to-beat blood pressure, cerebral blood velocity, and end-tidal Pco2 were monitored. Very low frequency (0.02-0.07 Hz) and low frequency (0.07-0.20 Hz) range spontaneous data were quantified. Driven OLBNP point estimates were sampled at 0.05 and 0.10 Hz. The OLBNP maneuvers augmented coherence to >0.97 at 0.05 Hz and >0.98 at 0.10 Hz in both age groups. The OLBNP protocol conclusively revealed the cerebrovascular system functions as a high-pass filter during exercise throughout aging. It was also discovered that the older adults had elevations (+71%) in normalized gain (+0.46 +/- 0.36%/%: 0.05 Hz) and reductions (-34%) in phase (-0.24 +/- 0.22 radian: 0.10 Hz). There were also age-related phase differences between resting and exercise conditions. It is speculated that these age-related changes in the TFA metrics are mediated by alterations in vasoactive factors, sympathetic tone, or the mechanical buffering of the compliance vessels. PMID- 26586908 TI - iNOS-dependent sweating and eNOS-dependent cutaneous vasodilation are evident in younger adults, but are diminished in older adults exercising in the heat. AB - Nitric oxide synthase (NOS) contributes to sweating and cutaneous vasodilation during exercise in younger adults. We hypothesized that endothelial NOS (eNOS) and neuronal NOS (nNOS) mediate NOS-dependent sweating, whereas eNOS induces NOS dependent cutaneous vasodilation in younger adults exercising in the heat. Further, aging may upregulate inducible NOS (iNOS), which may attenuate sweating and cutaneous vasodilator responses. We hypothesized that iNOS inhibition would augment sweating and cutaneous vasodilation in exercising older adults. Physically active younger (n = 12, 23 +/- 4 yr) and older (n = 12, 60 +/- 6 yr) adults performed two 30-min bouts of cycling at a fixed rate of metabolic heat production (400 W) in the heat (35 degrees C). Sweat rate and cutaneous vascular conductance (CVC) were evaluated at four intradermal microdialysis sites with: 1) lactated Ringer (control), 2) nNOS inhibitor (nNOS-I, NPLA), 3) iNOS inhibitor (iNOS-I, 1400W), or 4) eNOS inhibitor (eNOS-I, LNAA). In younger adults during both exercise bouts, all inhibitors decreased sweating relative to control, albeit a lower sweat rate was observed at iNOS-I compared with eNOS-I and nNOS-I sites (all P < 0.05). CVC at the eNOS-I site was lower than control in younger adults throughout the intermittent exercise protocol (all P < 0.05). In older adults, there were no differences between control and iNOS-I sites for sweating and CVC during both exercise bouts (all P > 0.05). We show that iNOS and eNOS are the main contributors to NOS-dependent sweating and cutaneous vasodilation, respectively, in physically active younger adults exercising in the heat, and that iNOS inhibition does not alter sweating or cutaneous vasodilation in exercising physically active older adults. PMID- 26586910 TI - Effects of carbon monoxide-releasing molecules on pulmonary vasoreactivity in isolated perfused lungs. AB - In addition to its renowned poisonous effects, carbon monoxide (CO) is being recognized for its beneficial actions on inflammatory and vasoregulatory pathways, particularly when applied at low concentrations via CO-releasing molecules (CO-RMs). In the lung, CO gas and CO-RMs are suggested to decrease pulmonary vascular tone and hypoxic pulmonary vasoconstriction (HPV). However, the direct effect of CO-RMs on the pulmonary vasoreactivity in isolated lungs has not yet been investigated. We assessed the effect of CORM-2 and CORM-3 on the pulmonary vasculature during normoxia and acute hypoxia (1% oxygen for 10 min) in isolated ventilated and perfused mouse lungs. The effects were compared with those of inhaled CO gas (10%). The interaction of CORM-2 or CO with cytochrome P 450 (CYP) was measured simultaneously by tissue spectrophotometry. Inhaled CO decreased HPV and vasoconstriction induced by the thromboxane mimetic U-46619 but did not alter KCl-induced vasoconstriction. In contrast, concentrations of CORM-2 and CORM-3 used to elicit beneficial effects on the systemic circulation did not affect pulmonary vascular tone. High concentration of CO-RMs or long-term application induced a continuous increase in normoxic pressure. Inhaled CO showed spectral alterations correlating with the inhibition of CYP. In contrast, during application of CORM-2 spectrophotometric signs of interaction with CYP could not be detected. Application of CO-RMs in therapeutic doses in isolated lungs neither decreases pulmonary vascular tone and HPV nor does it induce spectral alterations that are characteristic of CO-inhibited CYP. High doses, however, may cause pulmonary vasoconstriction. PMID- 26586909 TI - Interindividual variability in the dose-specific effect of dopamine on carotid chemoreceptor sensitivity to hypoxia. AB - Human studies use varying levels of low-dose (1-4 MUg.kg(-1).min(-1)) dopamine to examine peripheral chemosensitivity, based on its known ability to blunt carotid body responsiveness to hypoxia. However, the effect of dopamine on the ventilatory responses to hypoxia is highly variable between individuals. Thus we sought to determine 1) the dose response relationship between dopamine and peripheral chemosensitivity as assessed by the ventilatory response to hypoxia in a cohort of healthy adults, and 2) potential confounding cardiovascular responses at variable low doses of dopamine. Young, healthy adults (n = 30, age = 32 +/- 1, 24 male/6 female) were given intravenous (iv) saline and a range of iv dopamine doses (1-4 MUg.kg(-1).min(-1)) prior to and throughout five hypoxic ventilatory response (HVR) tests. Subjects initially received iv saline, and after each HVR the dopamine infusion rate was increased by 1 MUg.kg(-1).min(-1). Tidal volume, respiratory rate, heart rate, blood pressure, and oxygen saturation were continuously measured. Dopamine significantly reduced HVR at all doses (P < 0.05). When subjects were divided into high (n = 13) and low (n = 17) baseline chemosensitivity, dopamine infusion (when assessed by dose) reduced HVR in the high group only (P < 0.01), with no effect of dopamine on HVR in the low group (P > 0.05). Dopamine infusion also resulted in a reduction in blood pressure (3 MUg.kg(-1).min(-1)) and total peripheral resistance (1-4 MUg.kg(-1).min(-1)), driven primarily by subjects with low baseline chemosensitivity. In conclusion, we did not find a single dose of dopamine that elicited a nadir HVR in all subjects. Additionally, potential confounding cardiovascular responses occur with dopamine infusion, which may limit its usage. PMID- 26586912 TI - Altering fatty acid availability does not impair prolonged, continuous running to fatigue: evidence for carbohydrate dependence. AB - We determined the effect of suppressing lipolysis via administration of nicotinic acid (NA) on fuel substrate selection and half-marathon running capacity. In a single-blinded, Latin square design, 12 competitive runners completed four trials involving treadmill running until volitional fatigue at a pace based on 95% of personal best half-marathon time. Trials were completed in a fed or overnight fasted state: 1) carbohydrate (CHO) ingestion before (2 g CHO.kg(-1).body mass( 1)) and during (44 g/h) [CFED]; 2) CFED plus NA ingestion [CFED-NA]; 3) fasted with placebo ingestion during [FAST]; and 4) FAST plus NA ingestion [FAST-NA]. There was no difference in running distance (CFED, 21.53 +/- 1.07; CFED-NA, 21.29 +/- 1.69; FAST, 20.60 +/- 2.09; FAST-NA, 20.11 +/- 1.71 km) or time to fatigue between the four trials. Concentrations of plasma free fatty acids (FFA) and glycerol were suppressed following NA ingestion irrespective of preexercise nutritional intake but were higher throughout exercise in FAST compared with all other trials (P < 0.05). Rates of whole-body CHO oxidation were unaffected by NA ingestion in the CFED and FAST trials, but were lower in the FAST trial compared with the CFED-NA trial (P < 0.05). CHO was the primary substrate for exercise in all conditions, contributing 83-91% to total energy expenditure with only a small contribution from fat-based fuels. Blunting the exercise-induced increase in FFA via NA ingestion did not impair intense running capacity lasting ~85 min, nor did it alter patterns of substrate oxidation in competitive athletes. Although there was a small but obligatory use of fat-based fuels, the oxidation of CHO-based fuels predominates during half-marathon running. PMID- 26586911 TI - A method to test contractility of the supraspinatus muscle in mouse, rat, and rabbit. AB - The rotator cuff (RTC) muscles not only generate movement but also provide important shoulder joint stability. RTC tears, particularly in the supraspinatus muscle, are a common clinical problem. Despite some biological healing after RTC repair, persistent problems include poor functional outcomes with high retear rates after surgical repair. Animal models allow further exploration of the sequela of RTC injury such as fibrosis, inflammation, and fatty infiltration, but there are few options regarding contractility for mouse, rat, and rabbit. Histological findings can provide a "direct measure" of damage, but the most comprehensive measure of the overall health of the muscle is contractile force. However, information regarding normal supraspinatus size and contractile function is scarce. Animal models provide the means to compare muscle histology, imaging, and contractility within individual muscles in various models of injury and disease, but to date, most testing of animal contractile force has been limited primarily to hindlimb muscles. Here, we describe an in vivo method to assess contractility of the supraspinatus muscle and describe differences in methods and representative outcomes for mouse, rat, and rabbit. PMID- 26586913 TI - Advanced Glycation End Products (AGE) Potently Induce Autophagy through Activation of RAF Protein Kinase and Nuclear Factor kappaB (NF-kappaB). AB - Advanced glycation end products (AGE) accumulate in diabetic patients and aging people because of high amounts of three- or four-carbon sugars derived from glucose, thereby causing multiple consequences, including inflammation, apoptosis, obesity, and age-related disorders. It is important to understand the mechanism of AGE-mediated signaling leading to the activation of autophagy (self eating) that might result in obesity. We detected AGE as one of the potent inducers of autophagy compared with doxorubicin and TNF. AGE-mediated autophagy is inhibited by suppression of PI3K and potentiated by the autophagosome maturation blocker bafilomycin. It increases autophagy in different cell types, and that correlates with the expression of its receptor, receptor for AGE. LC3B, the marker for autophagosomes, is shown to increase upon AGE stimulation. AGE mediated autophagy is partially suppressed by inhibitor of NF-kappaB, PKC, or ERK alone and significantly in combination. AGE increases sterol regulatory element binding protein activity, which leads to an increase in lipogenesis. Although AGE mediated lipogenesis is affected by autophagy inhibitors, AGE-mediated autophagy is not influenced by lipogenesis inhibitors, suggesting that the turnover of lipid droplets overcomes the autophagic clearance. For the first time, we provide data showing that AGE induces several cell signaling cascades, like NF-kappaB, PKC, ERK, and MAPK, that are involved in autophagy and simultaneously help with the accumulation of lipid droplets that are not cleared effectively by autophagy, therefore causing obesity. PMID- 26586914 TI - Leishmania donovani Encodes a Functional Selenocysteinyl-tRNA Synthase. AB - The synthesis of selenocysteine, the 21st amino acid, occurs on its transfer RNA (tRNA), tRNA(Sec). tRNA(Sec) is initially aminoacylated with serine by seryl-tRNA synthetase and the resulting seryl moiety is converted to phosphoserine by O phosphoseryl-tRNA kinase (PSTK) in eukaryotes. The selenium donor, selenophosphate is synthesized from selenide and ATP by selenophosphate synthetase. Selenocysteinyl-tRNA synthase (SepSecS) then uses the O-phosphoseryl tRNA(Sec) and selenophosphate to form Sec-tRNA(Sec) in eukaryotes. Here, we report the characterization of selenocysteinyl-tRNA synthase from Leishmania donovani. Kinetoplastid SepSecS enzymes are phylogenetically closer to worm SepSecS. LdSepSecS was found to exist as a tetramer. Leishmania SepSecS enzyme was found to be active and able to complement the DeltaselA deletion in Escherichia coli JS1 strain only in the presence of archaeal PSTK, indicating the conserved nature of the PSTK-SepSecS pathway. LdSepSecS was found to localize in the cytoplasm of the parasite. Gene deletion studies indicate that Leishmania SepSecS is dispensable for the parasite survival. The parasite was found to encode three selenoproteins, which were only expressed in the presence of SepSecS. Selenoproteins of L. donovani are not required for the growth of the promastigotes. Auranofin, a known inhibitor of selenoprotein synthesis showed the same sensitivity toward the wild-type and null mutants suggesting its effect is not through binding to selenoproteins. The three-dimensional structural comparison indicates that human and Leishmania homologs are structurally highly similar but their association modes leading to tetramerization seem different. PMID- 26586915 TI - Mitochondrial Ribosomal Protein L12 Is Required for POLRMT Stability and Exists as Two Forms Generated by Alternative Proteolysis during Import. AB - To translate the 13 mtDNA-encoded mRNAs involved in oxidative phosphorylation (OXPHOS), mammalian mitochondria contain a dedicated set of ribosomes comprising rRNAs encoded by the mitochondrial genome and mitochondrial ribosomal proteins (MRPs) that are encoded by nuclear genes and imported into the matrix. In addition to their role in the ribosome, several MRPs have auxiliary functions or have been implicated in other cellular processes like cell cycle regulation and apoptosis. For example, we have shown that human MRPL12 binds and activates mitochondrial RNA polymerase (POLRMT), and hence has distinct functions in the ribosome and mtDNA transcription. Here we provide concrete evidence that there are two mature forms of mammalian MRPL12 that are generated by a two-step cleavage during import, involving efficient cleavage by mitochondrial processing protease and a second inefficient or regulated cleavage by mitochondrial intermediate protease. We also show that knock-down of MRPL12 by RNAi results in instability of POLRMT, but not other primary mitochondrial transcription components, and a corresponding decrease in mitochondrial transcription rates. Knock-down of MRPL10, the binding partner of MRPL12 in the ribosome, results in selective degradation of the mature long form of MRPL12, but has no effect on POLRMT. We propose that the two forms of MRPL12 are involved in homeostatic regulation of mitochondrial transcription and ribosome biogenesis that likely contribute to cell cycle, growth regulation, and longevity pathways to which MRPL12 has been linked. PMID- 26586916 TI - Peptide Bond Synthesis by a Mechanism Involving an Enzymatic Reaction and a Subsequent Chemical Reaction. AB - We recently reported that an amide bond is unexpectedly formed by an acyl-CoA synthetase (which catalyzes the formation of a carbon-sulfur bond) when a suitable acid and l-cysteine are used as substrates. DltA, which is homologous to the adenylation domain of nonribosomal peptide synthetase, belongs to the same superfamily of adenylate-forming enzymes, which includes many kinds of enzymes, including the acyl-CoA synthetases. Here, we demonstrate that DltA synthesizes not only N-(d-alanyl)-l-cysteine (a dipeptide) but also various oligopeptides. We propose that this enzyme catalyzes peptide synthesis by the following unprecedented mechanism: (i) the formation of S-acyl-l-cysteine as an intermediate via its "enzymatic activity" and (ii) subsequent "chemical" S -> N acyl transfer in the intermediate, resulting in peptide formation. Step ii is identical to the corresponding reaction in native chemical ligation, a method of chemical peptide synthesis, whereas step i is not. To the best of our knowledge, our discovery of this peptide synthesis mechanism involving an enzymatic reaction and a subsequent chemical reaction is the first such one to be reported. This new process yields peptides without the use of a thioesterified fragment, which is required in native chemical ligation. Together with these findings, the same mechanism-dependent formation of N-acyl compounds by other members of the above mentioned superfamily demonstrated that all members most likely form peptide/amide compounds by using this novel mechanism. Each member enzyme acts on a specific substrate; thus, not only the corresponding peptides but also new types of amide compounds can be formed. PMID- 26586917 TI - The Relay/Converter Interface Influences Hydrolysis of ATP by Skeletal Muscle Myosin II. AB - The interface between relay and converter domain of muscle myosin is critical for optimal myosin performance. Using Drosophila melanogaster indirect flight muscle S1, we performed a kinetic analysis of the effect of mutations in the converter and relay domain. Introduction of a mutation (R759E) in the converter domain inhibits the steady-state ATPase of myosin S1, whereas an additional mutation in the relay domain (N509K) is able to restore the ATPase toward wild-type values. The R759E S1 construct showed little effect on most steps of the actomyosin ATPase cycle. The exception was a 25-30% reduction in the rate constant of the hydrolysis step, the step coupled to the cross-bridge recovery stroke that involves a change in conformation at the relay/converter domain interface. Significantly, the double mutant restored the hydrolysis step to values similar to the wild-type myosin. Modeling the relay/converter interface suggests a possible interaction between converter residue 759 and relay residue 509 in the actin-detached conformation, which is lost in R759E but is restored in N509K/R759E. This detailed kinetic analysis of Drosophila myosin carrying the R759E mutation shows that the interface between the relay loop and converter domain is important for fine-tuning myosin kinetics, in particular ATP binding and hydrolysis. PMID- 26586918 TI - Increased Glucose-induced Secretion of Glucagon-like Peptide-1 in Mice Lacking the Carcinoembryonic Antigen-related Cell Adhesion Molecule 2 (CEACAM2). AB - Carcinoembryonic antigen-related cell adhesion molecule 2 (CEACAM2) regulates food intake as demonstrated by hyperphagia in mice with the Ceacam2 null mutation (Cc2(-/-)). This study investigated whether CEACAM2 also regulates insulin secretion. Ceacam2 deletion caused an increase in beta-cell secretory function, as assessed by hyperglycemic clamp analysis, without affecting insulin response. Although CEACAM2 is expressed in pancreatic islets predominantly in non-beta cells, basal plasma levels of insulin, glucagon and somatostatin, islet areas, and glucose-induced insulin secretion in pooled Cc2(-/-) islets were all normal. Consistent with immunofluorescence analysis showing CEACAM2 expression in distal intestinal villi, Cc2(-/-) mice exhibited a higher release of oral glucose mediated GLP-1, an incretin that potentiates insulin secretion in response to glucose. Compared with wild type, Cc2(-/-) mice also showed a higher insulin excursion during the oral glucose tolerance test. Pretreating with exendin(9-39), a GLP-1 receptor antagonist, suppressed the effect of Ceacam2 deletion on glucose induced insulin secretion. Moreover, GLP-1 release into the medium of GLUTag enteroendocrine cells was increased with siRNA-mediated Ceacam2 down-regulation in parallel to an increase in Ca(2+) entry through L-type voltage-dependent Ca(2+) channels. Thus, CEACAM2 regulates insulin secretion, at least in part, by a GLP-1-mediated mechanism, independent of confounding metabolic factors. PMID- 26586920 TI - A Novel Simulation Method for Binary Discrete Exponential Families, with Application to Social Networks. AB - Stochastic models for finite binary vectors are widely used in sociology, with examples ranging from social influence models on dichotomous behaviors or attitudes to models for random graphs. Exact sampling for such models is difficult in the presence of dependence, leading to the use of Markov chain Monte Carlo (MCMC) as an approximation technique. While often effective, MCMC methods have variable execution time, and the quality of the resulting draws can be difficult to assess. Here, we present a novel alternative method for approximate sampling from binary discrete exponential families having fixed execution time and well-defined quality guarantees. We demonstrate the use of this sampling procedure in the context of random graph generation, with an application to the simulation of a large-scale social network using both geographical covariates and dyadic dependence mechanisms. PMID- 26586921 TI - Integration, Disintegration, and Self-Similarity: Characterizing the Scales of Shape Variation in Landmark Data. AB - The biologist examining samples of multicellular organisms in anatomical detail must already have an intuitive concept of morphological integration. But quantifying that intuition has always been fraught with difficulties and paradoxes, especially for the anatomically labelled Cartesian coordinate data that drive today's toolkits of geometric morphometrics. Covariance analyses of interpoint distances, such as the Olson-Miller factor approach of the 1950's, cannot validly be extended to handle the spatial structure of complete morphometric descriptions; neither can analyses of shape coordinates that ignore the mean form. This paper introduces a formal parametric quantification of integration by analogy with how time series are approached in modern paleobiology. Over there, a finding of trend falls under one tail of a distribution for which stasis comprises the other tail. The null hypothesis separating these two classes of finding is the random walks, which are self similar, meaning that they show no interpretable structure at any temporal scale. Trend and stasis are the two contrasting ways of deviating from this null. The present manuscript introduces an analogous maneuver for the spatial aspects of ontogenetic or phylogenetic organismal studies: a subspace within the space of shape covariance structures for which the standard isotropic (Procrustes) model lies at one extreme of a characteristic parameter and the strongest growth gradient models at the other. In-between lies the suggested new construct, the spatially self-similar processes that can be generated within the standard morphometric toolkit by a startlingly simple algebraic manipulation of partial warp scores. In this view, integration and "disintegration" as in the Procrustes model are two modes of organismal variation according to which morphometric data can deviate from this common null, which, as in the temporal domain, is formally featureless, incapable of supporting any summary beyond a single parameter for amplitude. In practice the classification can proceed by examining the regression coefficient for log partial warp variance against log bending energy in the standard thin-plate spline setup. The self-similarity model, for which the regression slope is precisely [Formula: see text] corresponds well to the background against which the evolutionist's or systematist's a-priori notion of "local shape features" can be delineated. Integration as detected by the regression slope can be visualized by the first relative intrinsic warp (first relative eigenvector of the nonaffine part of a shape coordinate configuration with respect to bending energy) and may be summarized by the corresponding quadratic growth gradient. The paper begins with a seemingly innocent toy example, uncovers an unexpected invariance as an example of the general manipulation proposed, then applies the new modeling tactic to three data sets from the existing morphometric literature. Conclusions follow regarding findings and methodology alike. PMID- 26586919 TI - Magnetic Nanoparticles: Material Engineering and Emerging Applications in Lithography and Biomedicine. AB - We present an interdisciplinary overview of material engineering and emerging applications of iron oxide nanoparticles. We discuss material engineering of nanoparticles in the broadest sense, emphasizing size and shape control, large area self-assembly, composite/hybrid structures, and surface engineering. This is followed by a discussion of several non-traditional, emerging applications of iron oxide nanoparticles, including nanoparticle lithography, magnetic particle imaging, magnetic guided drug delivery, and positive contrast agents for magnetic resonance imaging. We conclude with a succinct discussion of the pharmacokinetics pathways of iron oxide nanoparticles in the human body -- an important and required practical consideration for any in vivo biomedical application, followed by a brief outlook of the field. PMID- 26586922 TI - Local Heterozygosity Effects on Nestling Growth and Condition in the Great Cormorant. AB - Under inbreeding, heterozygosity at neutral genetic markers is likely to reflect genome-wide heterozygosity and, thus, is expected to correlate with fitness. There is, however, growing evidence that some of heterozygosity-fitness correlations (HFCs) can be explained by 'local effects', where noncoding loci are at linkage disequilibrium with functional genes. The aim of this study was to investigate correlations between heterozygosity at seven microsatellite loci and two fitness-related traits, nestling growth rate and nutritional condition, in a recently bottlenecked population of great cormorant Phalacrocorax carbo sinensis. We found that heterozygosity was positively associated with both nestling traits at the between-brood level, but the individual (within-brood) effects of heterozygosity were non-significant. We also found that only one locus per trait was primarily responsible for the significant multi-locus HFCs, suggesting a linkage disequilibrium with non-identified functional loci. The results give support for 'local effect' hypothesis, confirming that HFCs may not only be interpreted as evidence of inbreeding and that genetic associations between functional and selectively neutral markers could be much more common in natural populations than previously thought. PMID- 26586923 TI - The Color of AIDS: An Analysis of newspaper coverage of HIV/AIDS in the United States from 1992-2007. AB - Although overall HIV rates have declined in the U.S. over the past two decades, these declines have been accompanied by steady growth in infection rates among African Americans, creating persistent racial disparities in HIV infection. News media have been instrumental in educating and informing the public about the epidemic. This content analytic study examines the frequency and content of coverage of HIV/AIDS in national and local U.S. daily newspapers from December 1992 through December 2007 with a focus on the presentation of risk by population subgroups. A computerized search term was used to identify HIV/AIDS-related news coverage from 24 daily U.S. newspapers and one wire service across a 15-year period (N = 53,934 stories). Human and computerized coding methods were used to examine patterns in frequency and content in the sample. Results indicate a decline in coverage of the epidemic over the study period. There was also a marked shift in the portrayal of risk in the U.S., from a domestic to an international focus. When coverage did address HIV/AIDS among groups with disproportionately high risk in the U.S., it typically failed to provide context for the disparity beyond individual behavioral risk factors. The meta-message of news coverage of HIV during this period may have reduced the visibility of the impact of HIV/AIDS on Americans. The practice of reporting the racial disparity without providing context may have consequences for the general public's ability to interpret these disparities. PMID- 26586924 TI - The Role of Circulating Tight Junction Proteins in Evaluating Blood Brain Barrier Disruption following Intracranial Hemorrhage. AB - Brain injury after intracranial hemorrhage (ICH) results in significant morbidity and mortality. Blood brain barrier (BBB) disruption is a hallmark of ICH-induced brain injury; however, data mirroring BBB disruption in human ICH are scarce. The aim of this study was to assess the significance of circulating biomarkers in evaluating BBB disruption after ICH. Twenty-two patients with ICH were recruited in this study. Concentrations of the tight junction proteins (TJs) Claudin-5 (CLDN5), Occludin (OCLN), and zonula occludens 1 (ZO-1) and vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) were measured by using enzyme-linked immunosorbent assay in serum and cerebrospinal fluid (CSF) samples obtained from patients with ICH. The white blood cell (WBC) count in blood and CSF, albumin (ALB) levels in the CSF (ALBCSF), and the BBB ratio were significantly higher in the ICH than in controls (p < 0.05). Significantly higher levels of CLDN5, OCLN, ZO-1, MMP-9, and VEGF in CSF were observed in the ICH group; these biomarkers were also positively associated with BBB ratio (p < 0.05). Our data revealed that circulating TJs could be considered the potential biomarkers reflecting the integrity of the BBB in ICH. PMID- 26586925 TI - Among-year variation in the repeatability, within- and between-individual, and phenotypic correlations of behaviors in a natural population. AB - When mean behaviors correlate among individuals, they form behavioral syndromes. One way to understand the evolution of such a group-level phenomenon is to compare horizontally patterns of correlations among populations (or species) or follow longitudinally the same population over years in the light of parallel differences in the environment. We applied the longitudinal approach to 8-year field data and analyzed phenotypic correlations, and their within- and between individual components, among three behaviors (novelty avoidance, aggression, and risk-taking) in male collared flycatchers, Ficedula albicollis, in a meta analytic framework. The phenotypic correlation between novelty avoidance and aggression varied heterogeneously (it was positive in some years, while it was negative in other years), while the other pair-wise correlations were consistently positive over the study period. We investigated four potential socio ecological factors, and found evidence that the among-year alterations in the demographic structure of the population (density, age composition) can be responsible for the heterogeneous effect sizes. Comparing within- and between individual correlations across pairs of traits, we found that the correlation between aggression and risk-taking at the among-individual level was the strongest suggesting that this relationship has the highest potential to form a behavioral syndrome. Within-year repeatabilities varied among traits, but were systematically higher than between-year repeatabilities. Our study highlights on an empirical basis that there can be several biological and statistical reasons behind detecting a phenotypic correlation in a study, but only few of these imply that fixed behavioral syndromes are maintained in a natural population. In fact, some correlations seem to be shaped by environmental fluctuations. PMID- 26586926 TI - Social anxiety and cannabis cravings: The influences of parent injunctive norms and tension reduction expectancies. AB - OBJECTIVES: Socially anxious cannabis users are influenced by cannabis expectancies and normative perceptions. The present study examines the influence of psychosocial factors on cannabis use vulnerability factors as the result of interactions between norms perceptions, social anxiety, and expectancies. METHODS: Participants were 149 (36.2% female) current cannabis users aged 18-36 (M=21.01, SD=3.09). Hierarchical multiple regressions were employed to investigate the predictive value of the social anxiety X injunctive norms X expectancies interaction on cannabis cravings. RESULTS: A three-way interaction emerged in the prediction of cannabis cravings. Simple slopes analyses showed that among individuals with perceptions of greater parent approval of cannabis use (higher injunctive norms), social anxiety was associated with greater cannabis craving when expectancies regarding relaxation and tension reduction were greater (t=2.54, p=.01, beta=1.12). CONCLUSIONS: Among cannabis users with perceptions of greater injunctive norms, social anxiety was associated with greater cannabis craving when tension reduction expectancies were greater. However, social anxiety was unrelated to cannabis craving when expectances were low. This suggests that cannabis craving among socially anxious adults was greatest when cannabis use was viewed as acceptable and expected to reduce tension, and highlights the importance of considering norms, expectancies, and social anxiety in understanding cannabis-related behaviors. PMID- 26586927 TI - Autism-Like Behavior and Epigenetic Changes Associated with Autism as Consequences of In Utero Exposure to Environmental Pollutants in a Mouse Model. AB - We tested the hypothesis that in utero exposure to heavy metals increases autism like behavioral phenotypes in adult animals and induces epigenetic changes in genes that have roles in the etiology of autism. Mouse dams were treated with cadmium, lead, arsenate, manganese, and mercury via drinking water from gestational days (E) 1-10. Valproic acid (VPA) injected intraperitoneally once on (E) 8.5 served as a positive control. Young male offspring were tested for behavioral deficits using four standardized behavioral assays. In this study, in utero exposure to heavy metals resulted in multiple behavioral abnormalities that persisted into adulthood. VPA and manganese induced changes in perseverative/impulsive behavior and social dominance behavior, arsenic caused changes only in perseverative/impulsive behavior, and lead induced abnormalities in social interaction in comparison to the control animals. Brain samples from Mn, Pb, and VPA treated and control animals were evaluated for changes in CpG island methylation in promoter regions and associated changes in gene expression. The Chd7 gene, essential for neural crest cell migration and patterning, was found to be hypomethylated in each experimental animal tested compared to water treated controls. Furthermore, distinct patterns of CpG island methylation yielded novel candidate genes for further investigation. PMID- 26586928 TI - Functional Performance and Associations between Performance Tests and Neurological Assessment Differ in Men and Women with Parkinson's Disease. AB - BACKGROUND: Neurological assessment of a patient with Parkinson's disease (PD) is expected to reflect upon functional performance. As women are known to report more limitations even for same observed functional performance level, present study was designed to examine whether associations between neurological assessments and functional performance differ across genders. METHODS: 14 men and 14 women with PD participated. Functional performance was assessed by measuring walking speeds on 10-meter walk test (10MWT) and by performing timed-up-and-go test (TUG). Neurological assessment included Hoehn and Yahr Scale (HY), Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Schwab and England Activities of Daily Living Scale (S-E), and Mini Mental State Examination (MMSE). RESULTS: In women with PD, Kendall's tau-b correlation analyses revealed significant correlations between functional performance tests and neurological assessment measures, with the exception in MMSE. No corresponding associations were found for men, although they demonstrated better functional performance, as expected. CONCLUSION: Men in similar clinical stage of the PD perform better on functional tests than women. Disease severity reflects upon functional performance differently in men and women with PD. Results indicate that when interpreting the assessment results of both functional performance and neurological assessment tests, the gender of the patient should be taken into consideration. PMID- 26586930 TI - Risk assessment's New Era: Part 1: Challenges for Industrial Hygiene. PMID- 26586929 TI - Effect of Endometrial Injury on Secretion of Endometrial Cytokines and IVF Outcomes in Women with Unexplained Subfertility. AB - In order to determine the effect of endometrial injury (EI) on in vitro fertilization (IVF) outcomes in women with unexplained subfertility and explore the relationship between EI and endometrial inflammatory cytokines, 66 women with unexplained subfertility undergoing IVF treatment were recruited. 38 patients in the EI group underwent EI in the mid-luteal phase of the cycle and 28 patients in the non-EI (NEI) group. According to the pregnancy outcome, the NEI and EI groups were divided into NEI-nonpregnant (NEI-NP), NEI-pregnant (NEI-P), EI-NP, and EI P. All patients underwent aspiration of endometrial secretions immediately before embryo transfer. The concentrations of ten mediators were measured using Milliplex Magnetic Bead assay. The clinical pregnancy was significantly higher in the EI than in the NEI group. The concentrations of interleukin- (IL-) 6, IL-8, IL-12 (p70), IL-13, interferon- (IFN-) gamma, monocyte chemotactic protein- (MCP ) 1, and vascular endothelial growth factor (VEGF) were significantly higher in the EI than the NEI group. The expression of IFN-gamma and VEGF in the EI-P was significantly increased compared to the EI-NP group. These findings suggest that, in women with unexplained subfertility, endometrial injury might be a potential method to improve clinical pregnancy rates by promoting the expression of IFN gamma and VEGF. PMID- 26586931 TI - Risk Assessment's New Era: part 2: Evolving Methods and Future Directions. PMID- 26586932 TI - Reassessment of pneumatic retinopexy for primary treatment of rhegmatogenous retinal detachment. AB - BACKGROUND: Pneumatic retinopexy (PR) remains a popular technique for the treatment of rhegmatogenous retinal detachment (RRD). OBJECTIVE: To evaluate the single operation and final success rate of PR for primary treatment of RRD and to determine factors associated with anatomical and visual outcomes. METHODS: This retrospective case review study analyzed the data of patients who underwent PR for primary treatment of RRD. Patients with a follow-up period of <2 months were excluded. Single operation success was defined as successful retinal reattachment following a single PR throughout 2 months of follow-up. RESULTS: Eighty-four eyes met the inclusion criteria. Single operation success was achieved in 50 eyes (59.5%), while 82 obtained anatomical success at the final follow-up visit (97.6%). An average of 0.702+/-1.095 additional retinal detachment operations was necessary to achieve final anatomical success in the entire cohort (n=84) and 1.4+/-1.3 in the single operation failure group (n=34). Both groups (single operation success vs failure) did not differ significantly in any of the preoperative variables. Multivariate analysis of pseudophakic patients (n=22) revealed that 52.65% of the variation in single operation outcome was explained by the number of clock-hours detached (partial R (2)=43.76%, P=0.001). The final best-corrected visual acuity was significantly better in the single operation success group (logarithm of minimum angle [logMAR] 0.229+/-0.249 vs logMAR 0.747+/-0.567, P<0.001). CONCLUSION: Careful patient selection is warranted before performing PR in RRD, particularly in pseudophakic patients with large detachments. Ultimately 60% of the cases will attach after the procedure with the rest requiring on average 1.4 additional procedures to achieve final anatomical success. PMID- 26586933 TI - Tear film osmolarity and dry eye disease: a review of the literature. AB - OBJECTIVE: To evaluate the evidence in the peer-reviewed literature regarding the use of tear osmolarity as a physiological marker to diagnose, grade severity, and track therapeutic response in dry eye disease (DED). In addition, to review the evidence for the role of tear osmolarity in the pathophysiology of DED and ocular surface disease. METHODS: A literature review of all publications after the year 2000, which included the keywords "tear osmolarity", was conducted. Relevant articles were graded according to quality of evidence and research, using the University of Michigan Practice Guideline and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) rating systems. Articles were further categorized by the nature of any reported financial support and by the overall impression they provided related to tear osmolarity. RESULTS: A total of 164 articles were identified as relevant to the search criteria, although some were editorials, and some were written in a foreign language. Of the total, it was possible to grade 159, and an overall impression was generated for 163. A positive impression of tear osmolarity in DED diagnosis was evident in 72% (117/163) of all articles, with a neutral impression in a further 21% (35/163); 7% had a negative impression. The percentage of positive impressions appeared independent of the quality of research; 73% (38/52) of articles graded high/moderate quality supported the use of tear film osmolarity measurement in DED diagnosis. Impressions were also independent of the source of financial support, with 72% (75/104) of independent studies positive. CONCLUSION: The literature broadly supports the use of tear film osmolarity as an objective numerical measure for diagnosing, grading severity, and managing treatment of DED. PMID- 26586934 TI - Reductive metabolism of oxymatrine is catalyzed by microsomal CYP3A4. AB - Oxymatrine (OMT) is a pharmacologically active primary quinolizidine alkaloid with various beneficial and toxic effects. It is confirmed that, after oral administration, OMT could be transformed to the more toxic metabolite matrine (MT), and this process may be through the reduction reaction, but the study on the characteristics of this transformation is limited. The aim of this study was to investigate the characteristics of this transformation of OMT in the human liver microsomes (HLMs) and human intestinal microsomes (HIMs) and the cytochrome P450 (CYP) isoforms involved in this transformation. The current studies demonstrated that OMT could be metabolized to MT rapidly in HLMs and HIMs and CYP3A4 greatly contributed to this transformation. All HLMs, HIMs, and CYP3A4 isoform mediated reduction reaction followed typical biphasic kinetic model, and Km, Vmax, and CL were significant higher in HLMs than those in HIMs. Importantly, different oxygen contents could significantly affect the metabolism of OMT, and with the oxygen content decreased, the formation of metabolite was increased, suggesting this transformation was very likely a reduction reaction. Results of this in vitro study elucidated the metabolic pathways and characteristics of metabolism of OMT to MT and would provide a theoretical basis and guidance for the safe application of OMT. PMID- 26586935 TI - Empagliflozin in the treatment of type 2 diabetes: evidence to date. AB - In the last decade, researchers have gained a greater understanding of the pathophysiologic mechanisms of type 2 diabetes as a chronic and progressive disease. One of the more recent treatment targets is the kidney. The kidneys become maladaptive in diabetes by increasing the reabsorption of glucose above the normal physiologic renal threshold. This discovery has led to the development of the sodium/glucose cotransporter 2 inhibitors (SGLT2). These agents readjust the renal threshold for glucose reabsorption to a lower level and decrease glucose reabsorption, while increasing urinary glucose when the glucose is above the renal threshold and subsequently lowering plasma glucose. The mechanism of action of the SGLT2 inhibitors is insulin independent, which makes them a novel treatment of diabetes. At the time of preparation of this manuscript, there were three SGLT2 inhibitors available in the US. This manuscript focuses on empagliflozin, the newest SGLT2 inhibitor, the trials in its development, and the clinical data available to date. Further, the authors propose future applications of empagliflozin, including in the treatment of type 1 diabetes, and its potential role in renoprotection. PMID- 26586936 TI - Arsenic sulfide combined with JQ1, chemotherapy agents, or celecoxib inhibit gastric and colon cancer cell growth. AB - BACKGROUND: Arsenic compounds have modest cytotoxic activity in solid tumors. We investigated if arsenic sulfide (As4S4) in combination with other distinct agents could enhance its cytotoxic activity. METHODS: We used gastric and colon cancer cell lines to study the synergistic effect of As4S4 in combination with BRD4 inhibitor JQ1, or with chemotherapy drug cisplatin and irinotecan or with COX2 inhibitor celecoxib. We investigated the mechanism of the cytotoxic effect of these novel combinations. RESULTS: We found that when As4S4 was combined with JQ1, cisplatin, irinotecan or celecoxib, its cytotoxic activity was dramatically enhanced in both gastric and colon cancer cell lines. As4S4 and JQ1 inhibited BRD4 and c-Myc while activating p53 expression synergistically. As4S4 inhibited COX2 and cyclin D1 expression. When As4S4 was combined with chemotherapy drug cisplatin or COX2 inhibitor celecoxib, its inhibition of COX2, BCL2, and p38 expression was enhanced. As4S4 and cisplatin synergistically stimulated p53, phosphor-p38 (p-p38), and increased cleaved caspase 3 (c-caspase 3). CONCLUSION: As4S4 in combination with JQ1, cisplatin, irinotecan or celecoxib showed enhanced cytotoxic effect on gastric and colon cancer cells, indicating the potential application of these novel drug combinations as part of treatment strategy that warrants further investigation. As4S4 and JQ1 demonstrate synergistic activation of p53 and inhibition of c-Myc. As4S4 and cisplatin and celecoxib activated multiple apoptosis pathways. PMID- 26586938 TI - Evaluation of the efficacy and safety of three dosing regimens of agalsidase alfa enzyme replacement therapy was underpowered. PMID- 26586937 TI - Efficacy and tolerability of oral oxycodone and oxycodone/naloxone combination in opioid-naive cancer patients: a propensity analysis. AB - BACKGROUND: World Health Organization step III opioids are required to relieve moderate-to-severe cancer pain; constipation is one of the most frequent opioid induced side effects. A fixed combination, prolonged-release oxycodone/naloxone (OXN), was developed with the aim of reducing opioid-related gastrointestinal side effects. The objective of this study was to compare the efficacy and safety of prolonged-release oxycodone (OXY) alone to OXN in opioid-naive cancer patients with moderate-to-severe pain. METHODS: Propensity analysis was utilized in this observational study, which evaluated the efficacy, safety, and quality of life. RESULTS: Out of the 210 patients recruited, 146 were matched using propensity scores and included in the comparative analysis. In both groups, pain intensity decreased by ~3 points after 60 days, indicating comparable analgesic efficacy. Responder rates were similar between groups. Analgesia was achieved and maintained with similarly low and stable dosages over time (12.0-20.4 mg/d for OXY and 11.5-22.0 mg/d for OXN). Bowel Function Index (BFI) and laxative use per week improved from baseline at 30 days and 60 days in OXN recipients (-16, P<0.0001 and -3.5, P=0.02, respectively); BFI worsened in the OXY group. The overall incidence of drug-related adverse events was 28.9% in the OXY group and 8.2% in the OXN group (P<0.01); nausea and vomiting were two to five times less frequent with OXN. Quality of life improved to a significantly greater extent in patients receiving OXN compared to OXY (increase in Short Form-36 physical component score of 7.1 points vs 3.2 points, respectively; P<0.001). CONCLUSION: In patients with chronic cancer pain, OXN provided analgesic effectiveness that is similar to OXY, with early and sustained benefits in tolerability. The relationship between responsiveness to OXN and clinical characteristics is currently being investigated. PMID- 26586939 TI - Elderly women who received Helicobacter pylori-eradicating therapy have reduced risk of low skeletal muscle mass. AB - BACKGROUND: Sarcopenia is associated with adverse outcomes such as physical disability, poorer quality of life, and death. Helicobacter pylori (HP) eradication increases ghrelin secretion, which may be a possible treatment for sarcopenia. We investigated whether HP eradication reduces the risk of low muscle mass (LMM), which is an integral component of sarcopenia. MATERIALS AND METHODS: Healthy, asymptomatic women aged >=60 years who participated in a health screening program were enrolled. Subjects with a history of HP eradication were compared with those who were HP IgG(+), but had not received HP-eradicating therapy. Body composition was measured by multifrequency bioelectrical impedance analysis. LMM was defined as body muscle mass 2 standard deviations below the mean muscle mass of healthy women aged 20-39 years from the same program. Multivariable analysis was used to identify sarcopenia risk factors. RESULTS: Three hundred seventy-two women had received HP eradication, while 689 HP IgG(+) women had not. The prevalence of LMM was significantly lower in those who received HP eradication (13.7% vs 21.6%, P=0.002). Multivariable analysis identified risk factors for LMM as age, white blood cell count, serum total protein concentration, and the metabolic syndrome. HP eradication (odds ratio: 0.632, 95% confidence interval: 0.440-0.824, P=0.013) was a significant preventive factor, and exercise (odds ratio: 0.710, 95% confidence interval: 0.504-1.002, P=0.051) had a preventive tendency. CONCLUSION: HP eradication might reduce LMM risk. This finding should be confirmed in prospective longitudinal studies to determine the long-term effects of HP eradication on sarcopenia. PMID- 26586940 TI - Combined bronchodilators (tiotropium plus olodaterol) for patients with chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease (COPD), a respiratory disease characterized by a progressive decline in lung function, is considered to be a leading cause of morbidity and mortality. Long-acting inhaled bronchodilators, such as long-acting beta2 agonists (LABAs) or long-acting muscarinic antagonists (LAMAs), are the cornerstone of maintenance therapy for patients with moderate-to-very-severe COPD. For patients not sufficiently controlled on a single long-acting bronchodilator, a combination of different bronchodilators has shown a significant increase in lung function. Tiotropium, a once-daily dosing LAMA, demonstrated sustained improvements in lung function as well as improved health related quality of life, reduced exacerbations, and increased survival without altering the rate of decline in the mean forced expiratory volume in 1 second (FEV1) with fairly tolerable side effects. Olodaterol is a once-daily dosing LABA that has proven to be effective in improving lung function, reducing rescue medication use, and improving dyspnea and health-related quality of life, as well as improving exercise endurance with an acceptable safety profile. The combination of olodaterol and tiotropium provided additional improvements in lung function greater than monotherapy with each drug alone. Several well-designed randomized trials confirmed that the synergistic effect of both drugs in combination was able to improve lung function and health-related quality of life without a significant increase in adverse effects. The objective of this paper is to review available evidence on the clinical efficacy and safety of tiotropium, olodaterol, and their combination in patients with COPD. PMID- 26586941 TI - Prevalence of chronic obstructive pulmonary disease in asymptomatic smokers. AB - BACKGROUND: Physicians do not routinely recommend smokers to undergo spirometry unless they are symptomatic. OBJECTIVE: To test the hypothesis that there are a significant number of asymptomatic smokers with chronic obstructive pulmonary disease (COPD), we estimated the prevalence of COPD in a group of asymptomatic smokers. METHODS: Two thousand nine hundred and sixty-one smokers with a cumulative consumption history of at least 10 pack-years, either smokers with symptoms or smokers without symptoms (WOS) were invited to perform a spirometry and complete a symptom questionnaire. RESULTS: Six hundred and thirty-seven (21.5%) smokers had no symptoms, whereas 2,324 (78.5%) had at least one symptom. The prevalence of COPD in subjects WOS was 1.5% when considering the whole group of smokers (45/2,961) and 7% when considering only the group WOS (45/637). From 329 smokers with COPD, 13.7% were WOS. Subjects WOS were younger, had better lung function and lower cumulative consumption of cigarettes, estimated as both cigarettes per day and pack-years. According to severity of airflow limitation, 69% vs 87% of subjects were classified as Global Initiative for Chronic Obstructive Lung Disease stages I-II in the WOS and smokers with symptoms groups, respectively (P<0.001). A multivariate analysis showed that forced expiratory volume in 1 second (mL) was the only predictive factor for COPD in asymptomatic smokers. CONCLUSION: Prevalence of COPD in asymptomatic smokers is 1.5%. This number of asymptomatic smokers may be excluded from the benefit of an "early" intervention, not just pharmacological but also from smoking cessation counseling. The higher forced expiratory volume in 1 second may contribute to prevent early diagnosis. PMID- 26586942 TI - PLGA-encapsulated tea polyphenols enhance the chemotherapeutic efficacy of cisplatin against human cancer cells and mice bearing Ehrlich ascites carcinoma. AB - The clinical success of the applicability of tea polyphenols awaits efficient systemic delivery and bioavailability. Herein, following the concept of nanochemoprevention, which uses nanotechnology for enhancing the efficacy of chemotherapeutic drugs, we employed tea polyphenols, namely theaflavin (TF) and epigallocatechin-3-gallate (EGCG) encapsulated in a biodegradable nanoparticulate formulation based on poly(lactide-co-glycolide) (PLGA) with approximately 26% and 18% encapsulation efficiency, respectively. It was observed that TF/EGCG encapsulated PLGA nanoparticles (NPs) offered an up to ~7-fold dose advantage when compared with bulk TF/EGCG in terms of exerting its antiproliferative effects and also enhanced the anticancer potential of cisplatin (CDDP) in A549 (lung carcinoma), HeLa (cervical carcinoma), and THP-1 (acute monocytic leukemia) cells. Cell cycle analysis revealed that TF/EGCG-NPs were more efficient than bulk TF/EGCG in sensitizing A549 cells to CDDP-induced apoptosis, with a dose advantage of up to 20-fold. Further, TF/EGCG-NPs, alone or in combination with CDDP, were more effective in inhibiting NF-kappaB activation and in suppressing the expression of cyclin D1, matrix metalloproteinase-9, and vascular endothelial growth factor, involved in cell proliferation, metastasis, and angiogenesis, respectively. EGCG and TF-NPs were also found to be more effective than bulk TF/EGCG in inducing the cleavage of caspase-3 and caspase-9 and Bax/Bcl2 ratio in favor of apoptosis. Further, in vivo evaluation of these NPs in combination with CDDP showed an increase in life span (P<0.05) in mice bearing Ehrlich's ascites carcinoma cells, with apparent regression of tumor volume in comparison with mice treated with bulk doses with CDDP. These results indicate that EGCG and TF-NPs have superior cancer chemosensitization activity when compared with bulk TF/EGCG. PMID- 26586943 TI - Detection of fluorescent organic nanoparticles by confocal laser endomicroscopy in a rat model of Barrett's esophageal adenocarcinoma. AB - For many years, novel strategies for cancer detection and treatment using nanoparticles (NPs) have been developed. Esophageal adenocarcinoma is the sixth leading cause of cancer-related deaths in Western countries, and despite recent advances in early detection and treatment, its prognosis is still very poor. This study investigated the use of fluorescent organic NPs as potential diagnostic tool in an experimental in vivo model of Barrett's esophageal adenocarcinoma. NPs were made of modified polysaccharides loaded with [4-(dicyanomethylene)-2-methyl 6-(4-dimethylaminostyryl)-4H-pyran] (DCM), a well-known fluorescent dye. The NP periphery might or might not be decorated with ASYNYDA peptide that has an affinity for esophageal cancer cells. Non-operated and operated rats in which gastroesophageal reflux was surgically induced received both types of NPs (NP-DCM and NP-DCM-ASYNYDA) by intravenous route. Localization of mucosal NPs was assessed in vivo by confocal laser endomicroscopy, a technique which enables a "real time" and in situ visualization of the tissue at a cellular level. After injection of NP-DCM and NP-DCM-ASYNYDA, fluorescence was observed in rats affected by esophageal cancer, whereas no signal was observed in control non operated rats, or in rats with simple esophagitis or Barrett's esophagus mucosa. Fluorescence was observable in vivo 30 minutes after the administration of NPs. Interestingly, NP-DCM-ASYNYDA induced strong fluorescence intensity 24 hours after administration. These observations suggested that NPs could reach the tumor cells, likely by enhanced permeability and retention effect, and the peptide ASYNYDA gave them high specificity for esophageal cancer cells. Thus, the combination of NP platform and confocal laser endomicroscopy could play an important role for highlighting esophageal cancer conditions. This result supports the potential of this strategy as a targeted carrier for photoactive and bioactive molecules in esophageal cancer diagnosis and treatment. PMID- 26586944 TI - An in vitro and in vivo study of gemcitabine-loaded albumin nanoparticles in a pancreatic cancer cell line. AB - BACKGROUND AND OBJECTIVES: Gemcitabine (Gem) is far from satisfactory as the first-line regimen for pancreatic cancer, and the emergence of albumin nanoparticles offers new hope for the delivery of Gem. In this study, Gem-loaded human serum albumin nanoparticles (Gem-HSA-NPs) were successfully synthesized, characterized, and tested on a BxPC-3 cell line both in vitro and in vivo. MATERIALS AND METHODS: 4-N-myristoyl-gemcitabine (Gem-C14) was obtained first by coupling myristoyl with the 4-amino group of Gem. The Gem-HSA-NPs were then prepared by nanoparticle albumin-bound technology and characterized for particle size, zeta potential, morphology, encapsulation efficiency, drug-loading efficiency, and release characteristics. Using both in vitro and in vivo studies, Gem-C14 and Gem-HSA-NPs were tested on the human pancreatic cancer cell line BxPC 3. RESULTS: Gem-HSA-NPs showed an average particle size of 150+/-27 nm, and with an encapsulation rate of 82.99%+/-3.5% and a drug-loading rate of 10.42%+/-3.5%, they exhibited a favorable controlled- and sustained-release nature. In in vitro, Gem-C14 was equivalent in cytotoxicity to Gem. In in vivo, the Gem-HSA-NPs exhibited the strongest inhibitory effect on tumor growth but the lowest toxicity among the four groups. CONCLUSION: The enhanced in vivo efficacy of Gem-HSA-NPs toward the pancreatic cancer cell line suggests their potential role for use in the clinical field. PMID- 26586945 TI - Nanoencapsulation of natural triterpenoid celastrol for prostate cancer treatment. AB - Celastrol (CL), a triterpenoid extracted from the Chinese herb Tripterygium wilfordii, has recently attracted interest for its potential antitumor effects. However, unfavorable physicochemical and pharmacokinetics properties such as low solubility, poor bioavailability, and systemic toxicity, are limiting its therapeutic application. In this context, the development of innovative nanocarriers can be useful to overcome these issues, and nanoencapsulation would represent a powerful strategy. In this study, we developed novel CL-loaded poly(epsilon-caprolactone) nanoparticles (NPs), and investigated their antiproliferative efficacy on prostate cancer cells. CL-NPs were prepared using a nanoprecipitation method and fully characterized by physicochemical techniques. The antiproliferative effects on LNCaP, DU-145, and PC3 cell lines of CL-NPs, compared to those of free CL at different concentrations (0.5, 1.0, and 2.0 uM), were investigated. Moreover, fluorescence microscopy was utilized to examine the cellular uptake of the nanosystems. Furthermore, to elucidate impact of nanoencapsulation on the mechanism of action, Western analyses were conducted to explore apoptosis, migration, proliferation, and angiogenesis alteration of prostate cancer cells. The results confirmed that CL-NPs inhibit proliferation dose dependently in all prostate cancer cells, with inhibitory concentration50 less than 2 uM. In particular, the NPs significantly increased cytotoxicity at lower/medium dose (0.5 and 1.0 uM) on DU145 and PC3 cell lines with respect to free CL, with modulation of apoptotic and cell cycle machinery proteins. To date, this represents the first report on the development of biocompatible polymeric NPs encapsulating CL. Our findings offer new perspectives for the exploitation of developed CL-NPs as suitable prototypes for prostate cancer treatment. PMID- 26586946 TI - Graphene oxide-silver nanocomposite as a promising biocidal agent against methicillin-resistant Staphylococcus aureus. AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) has been responsible for serious hospital infections worldwide. Nanomaterials are an alternative to conventional antibiotic compounds, because bacteria are unlikely to develop microbial resistance against nanomaterials. In the past decade, graphene oxide (GO) has emerged as a material that is often used to support and stabilize silver nanoparticles (AgNPs) for the preparation of novel antibacterial nanocomposites. In this work, we report the synthesis of the graphene-oxide silver nanocomposite (GO-Ag) and its antibacterial activity against relevant microorganisms in medicine. MATERIALS AND METHODS: GO-Ag nanocomposite was synthesized through the reduction of silver ions (Ag(+)) by sodium citrate in an aqueous GO dispersion, and was extensively characterized using ultraviolet visible absorption spectroscopy, X-ray diffraction, thermogravimetric analysis, X ray photoelectron spectroscopy, and transmission electron microscopy. The antibacterial activity was evaluated by microdilution assays and time-kill experiments. The morphology of bacterial cells treated with GO-Ag was investigated via transmission electron microscopy. RESULTS: AgNPs were well distributed throughout GO sheets, with an average size of 9.4+/-2.8 nm. The GO-Ag nanocomposite exhibited an excellent antibacterial activity against methicillin resistant S. aureus, Acinetobacter baumannii, Enterococcus faecalis, and Escherichia coli. All (100%) MRSA cells were inactivated after 4 hours of exposure to GO-Ag sheets. In addition, no toxicity was found for either pristine GO or bare AgNPs within the tested concentration range. Transmission electronic microscopy images offered insights into how GO-Ag nanosheets interacted with bacterial cells. CONCLUSION: Our results indicate that the GO-Ag nanocomposite is a promising antibacterial agent against common nosocomial bacteria, particularly antibiotic-resistant MRSA. Morphological injuries on MRSA cells revealed a likely loss of viability as a result of the direct contact between bacteria and the GO Ag sheets. PMID- 26586947 TI - Double encephalitis with herpes simplex virus type II and cytomegalovirus in an elder Chinese: a case report. AB - Herpes simplex encephalitis is a rare disease. In adults, most of the reported cytomegalovirus (CMV) infections are seen in immunocompromised patients. We present a case of 67-year-old Chinese male with the coinfection of CMV and herpes simplex virus type II (HSV-II). He had no history of being treated with immunosuppressants, showed symptoms of psychosis and was scored 109 on the Positive and Negative Syndrome Scale. This patient presented with a rare case of coinfection of CMV and herpes simplex virus type II with psychotic symptoms. PMID- 26586948 TI - The relationships between blood pressure, blood glucose, and bone mineral density in postmenopausal Turkish women. AB - BACKGROUND: Hypertension, diabetes mellitus, and osteoporosis are important comorbidities commonly seen in postmenopausal women. The aim of the present study was to investigate the relationships between blood pressure, blood glucose, and bone mineral density (BMD) in postmenopausal Turkish women. METHODS: In this cross-sectional study, 270 consecutive patients who were admitted to an outpatient clinic with vasomotor symptoms and/or at least 1 year of amenorrhea were included. The patients were categorized into three groups according to their blood pressure and metabolic status as follows: normotensive, hypertensive nondiabetics, and hypertensive diabetics. The T- and z-scores of the proximal femur and lumbar vertebrae were measured with the dual-energy X-ray absorptiometry method to assess the BMD of the study groups. RESULTS: Lumbar vertebral T-scores (P<0.001), lumbar vertebral z-scores (P<0.003), and proximal femoral T-scores (P<0.001) were demonstrated to be significantly lower in the hypertensive diabetic group compared to the hypertensive nondiabetic and normotensive groups. Systolic blood pressure was significantly inversely correlated with lumbar vertebral T-scores (r=-0.382; P=0.001), lumbar vertebral z scores (r=-0.290; P=0.001), and proximal femoral T-scores (r=-0.340; P=0.001). Moreover, diastolic blood pressure was significantly inversely correlated with lumbar vertebral T-scores (r=-0.318; P=0.001), lumbar vertebral z-scores (r= 0.340; P=0.001), and proximal femoral T-scores (r=-0.304; P=0.001). Hypertension (odds ratio [OR]: 2.541, 95% confidence interval [CI]: 1.46-3.48, P=0.003), diabetes mellitus (OR: 2.136, 95% CI: 1.254-3.678, P=0.006), and age (OR: 1.069, 95% CI: 1.007-1.163, P=0.022) were found to be significant independent predictors of osteopenia in a multivariate analysis, after adjusting for other risk parameters. CONCLUSION: The present study is the first to evaluate the relationships between blood pressure, blood glucose, and BMD in postmenopausal Turkish women. Moreover, both hypertension and diabetes were demonstrated as significant independent predictors of osteopenia in postmenopausal Turkish women. Clinicians should be aware of the high risk of developing osteopenia in diabetic hypertensive postmenopausal women. PMID- 26586949 TI - Managing gastroesophageal reflux disease - comparative efficacy and outcomes of dexlansoprazole MR. AB - The management of gastroesophageal reflux disease (GERD) has been revolutionized with the development of proton pump inhibitors (PPIs). Unfortunately, due to the inherent pharmacokinetic and pharmacodynamic profiles of conventional PPIs, many patients continue to suffer from symptoms related to GERD despite appropriate use of PPIs. Dexlansoprazole MR is a PPI with a unique dual delayed-release delivery system that has been designed to address the unmet needs in GERD management. Specifically, dexlansoprazole MR addresses limitations with short plasma half life and need for meal-associated dosing, characteristic of conventional PPIs. In addition, dexlansoprazole MR has been shown to be effective in several specific clinical situations. These include coadministration with clopidogrel, healing of all grades of erosive esophagitis, improvement in reflux-related quality of life, step down to once-per-day dosing, and treatment of Helicobacter pylori infections. Furthermore, dexlansoprazole MR has been found to induce symptom improvement in patients with nonerosive esophageal reflux disease, nocturnal heartburn and GERD-related sleep disturbance, and regurgitation. Overall, dexlansoprazole MR is a unique and useful tool in the management of GERD. PMID- 26586950 TI - New developments in the management of schizophrenia and bipolar disorder: potential use of cariprazine. AB - Cariprazine is a recently developed antipsychotic drug with a partial agonism for the D2 and D3 receptors. It shows a tenfold greater affinity for the D3 receptor. In clinical trials, its therapeutic effect has been tested in patients with an acute exacerbation of schizophrenia and in patients with acute mania in bipolar disorder. Like risperidone, cariprazine improves positive and negative schizophrenic symptoms, and ameliorates cognitive functions. Cariprazine induces extrapyramidal symptoms less often than risperidone and can cause acute akathisia. It is a prolactin-sparing antipsychotic drug and has a favorable metabolic profile. In acute mania in bipolar disorder, it treats manic symptoms significantly better than placebo. As a consequence of its improved adverse effects, cariprazine improves patients' quality of life to a greater extent than other second-generation antipsychotic drugs. Cariprazine is a promising antipsychotic drug in the treatment of schizophrenia, acute mania in bipolar disorder, and in schizophrenia with mania. In these patients, its long-term therapeutic effect and its action in comparison with other second-generation antipsychotic drugs, above all aripiprazole, remain to be tested in clinical trials. PMID- 26586951 TI - The fascial system and exercise intolerance in patients with chronic heart failure: hypothesis of osteopathic treatment. AB - Chronic heart failure is a progressive, debilitating disease, resulting in a decline in the quality of life of the patient and incurring very high social economic costs. Chronic heart failure is defined as the inability of the heart to meet the demands of oxygen from the peripheral area. It is a multi-aspect complex disease which impacts negatively on all of the body systems. Presently, there are no texts in the modern literature that associate the symptoms of exercise intolerance of the patient with a dysfunction of the fascial system. In the first part of this article, we will discuss the significance of the disease, its causes, and epidemiology. The second part will explain the pathological adaptations of the myofascial system. The last section will outline a possible osteopathic treatment for patients with heart failure in order to encourage research and improve the general curative approach for the patient. PMID- 26586952 TI - Combination of cetuximab and PP242 synergistically suppress the progression of wild-type KRAS colorectal carcinoma. AB - Mammalian target of rapamycin (mTOR) has been shown to be overactive in human colorectal cancer, but the first-generation mTOR inhibitor, rapamycin, has failed to show clinical efficacy against colorectal cancer. On the other hand, although the second-generation mTOR inhibitor, PP242, has exerted substantial efficacy, it was revealed that independent inhibition by PP242 was transient, which could lead to positive-feedback loop to EGFR. Using wild-type KRAS colorectal cancer cells as models, we investigate the treatment efficacy of a widely used anti-EGFR monoclonal antibody, cetuximab, and PP242, alone or in combination in vitro and in vivo. Results of cell viability assays confirmed the synergistic inhibitory effect of PP242 and cetuximab on the survival of Caco-2 and HT-29 cells. Moreover, the ability of cancer-cell invasion and proliferation was also significantly inhibited by the combination therapy when compared with cetuximab or PP242 alone. Interestingly, the percentage of CD44-positive cancer cells was substantially decreased by the combination therapy in comparison with PP242 alone through fluorescence-activated cell sorting. The growth of cancer stem-like cell spheres in vitro was also maximally inhibited by combination therapy, in terms of either diameter or number. More importantly, the efficacy of combination therapy was more prominent than either drug alone in established tumor xenografts. These findings supported the potential use of combination therapy of PP242 and cetuximab against wild-type KRAS colorectal carcinomas. PMID- 26586953 TI - Impact of more detailed categorization of shrinkage or progression ratio at initial imaging response after sorafenib treatment in advanced hepatocellular carcinoma patients. AB - BACKGROUND: Sorafenib therapy improves survival in unresectable hepatocellular carcinoma (HCC) patients without an objective response. The present study investigated whether the initial imaging response might be a prognostic indicator after administration of sorafenib therapy in HCC patients. PATIENTS AND METHODS: This retrospective study reviewed unresectable HCC patients undergoing sorafenib therapy. Patients evaluated without complete response, partial response (PR), or progressive disease (PD) at the initial imaging response evaluation by modified Response Evaluation Criteria in Solid Tumors were divided into three groups according to more detailed categorization of the shrinkage/progression ratio in initial imaging response. A comparison of progression-free and overall survival among these groups was performed. RESULTS: Of the 43 non-PR non-PD patients with target lesions, ten (23.3%) exhibited mild response (MR; -30% to -5%), 14 (32.6%) exhibited no change (NC; -5% to +5%), and 19 (44.2%) exhibited mild-PD (MPD; +5% to +20%). There was no statistical difference in progression-free or overall survival between MR and NC patients. The median progression-free survivals in NC+MR and mild-PD patients were 15.0 and 5.3 months, respectively (P<0.01), and the median survival times were 31.9 and 17.1 months, respectively (P<0.001). In multivariate analysis, etiology (hepatitis C virus) and initial imaging response (MR+NC) was identified as an independently good prognostic factor. CONCLUSION: More detailed categorization of shrinkage or progression at the initial imaging response evaluation may be a useful marker for predicting sorafenib treatment outcomes in HCC patients. If the initial imaging response is not progression but stability, sorafenib may have a survival benefit. PMID- 26586954 TI - Correlation of C-X-C chemokine receptor 2 upregulation with poor prognosis and recurrence in human glioma. AB - C-X-C chemokine receptor 2 (CXCR2), a member of the G-protein-coupled receptor family, is an interleukin-8 receptor and results in the activation of neutrophils. To date, CXCR2 has been identified with many cell events, including inflammation, neovascularization, metastasis, and cell carcinogenesis. This study aimed to investigate alterations in the expression of CXCR2 in patients with brain gliomas and relationships with pathological grades and clinicopathological characteristics. Brain tissue specimens from 60 patients with glioma and 15 patients undergoing surgery for epilepsy (controls) were detected using streptavidin-perosidase immunohistochemistry. Western blotting was used to evaluate CXCR2 protein levels with fresh tissues derived from glioma cases or controls. Correlations between CXCR2 expression and clinicopathological characteristics were analyzed using SPSS software. The results showed high-grade gliomas with high CXCR2 expression as compared with normal tissues. The expression of CXCR2 was significantly related to high grades and recurrence of tumor but not to age or sex. During an in vitro wound healing assay, U251 migration was reduced when the CXCR2-specific inhibitor SB225002 was applied. Our results suggested that the high expression of CXCR2 in gliomas was closely correlated to the degree of malignancy and recurrence and that CXCR2 inhibition decreased the migration of glioma cells. Therefore, CXCR2 may serve as a potential therapeutic target for the recurrence and migration of gliomas. PMID- 26586956 TI - New developments in the treatment of drug-resistant tuberculosis: clinical utility of bedaquiline and delamanid. AB - The current treatment for drug-resistant tuberculosis (TB) is long, complex, and associated with severe and life-threatening side effects and poor outcomes. For the first time in nearly 50 years, there have been two new drugs registered for use in multidrug-resistant TB (MDR-TB). Bedaquiline, a diarylquinoline, and delamanid, a nitromidoxazole, have received conditional stringent regulatory approval and have World Health Organization interim policy guidance for their use. As countries improve and scale up their diagnostic services, increasing number of patients with MDR-TB and extensively drug-resistant TB are identified. These two new drugs offer a real opportunity to improve the outcomes of these patients. This article reviews the evidence for these two new drugs and discusses the clinical questions raised as they are used outside clinical trial settings. It also reviews the importance of the accompanying drugs used with these new drugs. It is important that barriers hindering the use of these two new drugs are addressed and that the existing clinical experience in using these drugs is shared, such that their routine-use programmatic conditions is scaled up, ensuring maximum benefit for patients and countries battling the MDR-TB crisis. PMID- 26586955 TI - From bench to bedside: use of human adipose-derived stem cells. AB - Since the discovery of adipose-derived stem cells (ASC) in human adipose tissue nearly 15 years ago, significant advances have been made in progressing this promising cell therapy tool from the laboratory bench to bedside usage. Standardization of nomenclature around the different cell types used is finally being adopted, which facilitates comparison of results between research groups. In vitro studies have assessed the ability of ASC to undergo mesenchymal differentiation as well as differentiation along alternate lineages (transdifferentiation). Recently, focus has shifted to the immune modulatory and paracrine effects of transplanted ASC, with growing interest in the ASC secretome as a source of clinical effect. Bedside use of ASC is advancing alongside basic research. An increasing number of safety-focused Phase I and Phase IIb trials have been published without identifying any significant risks or adverse events in the short term. Phase III trials to assess efficacy are currently underway. In many countries, regulatory frameworks are being developed to monitor their use and assure their safety. As many trials rely on ASC injected at a distant site from the area of clinical need, strategies to improve the homing and efficacy of transplanted cells are also being explored. This review highlights each of these aspects of the bench-to-bedside use of ASC and summarizes their clinical utility across a variety of medical specialties. PMID- 26586957 TI - Red cell distribution width in type 2 diabetic patients. AB - OBJECTIVE: To study the indices of some elements of the complete blood count, in type 2 diabetic patients, in comparison with nondiabetic healthy controls; and to find out the effects of glycemic control and different medications on these indices. To the best of our knowledge, this study is novel in our environment and will serve as a foundation for other researchers in this field. METHODS: This retrospective study included 260 type 2 diabetic patients on treatment and 44 healthy control subjects. Sex, age, weight, height, blood pressure, complete blood count, fasting plasma glucose, hemoglobin A1c (HbA1c), and lipid profile data, were available for all of the study population. For diabetic patients, data on duration of diabetes and all medications were also available. RESULTS: Red cell distribution width (RDW) was significantly higher in diabetic patients than in control subjects (P=0.008). It was also higher in patients with uncontrolled glycemia (HbA1c >7%) than those with good control (HbA1c <=7%; P=0.035). Mean platelet volume (MPV) was comparable in both diabetic patients and healthy controls (P=0.238). RDW and MPV did not significantly correlate with fasting plasma glucose, HbA1c, or duration of diabetes. Both aspirin and clopidogrel did not show a significant effect on MPV. Both insulin and oral hypoglycemic agents did not show a significant effect on RDW, mean corpuscular volume, MPV, platelet count, or white blood cell count. Diabetic patients treated with indapamide or the combined thiazides and angiotensin receptor blockers showed no significant difference in RDW when compared with the control subjects. CONCLUSION: RDW, which is recently considered as an inflammatory marker with a significant predictive value of mortality in diseased and healthy populations, is significantly higher in diabetic patients than healthy subjects and is particularly higher in uncontrolled glycemia. None of the studied hypoglycemic agents showed a significant effect on RDW. Diabetic hypertensive patients receiving antihypertensive therapy in the form of indapamide or the combined therapy of thiazides and angiotensin receptor blockers have RDW values comparable to those of the healthy population. PMID- 26586958 TI - Relationship between chronic complications, hypertension, and health-related quality of life in Portuguese patients with type 2 diabetes. AB - BACKGROUND: The aim of this study was to assess the relationship between health related quality of life (HRQoL) and the presence or absence of hypertension and diabetes-related chronic complications in type 2 diabetes, and also the association between HRQoL and the number of chronic complications. METHODS: One hundred patients with type 2 diabetes were interviewed. HRQoL was evaluated using the age-adjusted Short-Form 36 dimensions (physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health). RESULTS: The mean age of the study population was 62.7+/-8.7 years; 54.0% were male, and 51.0% were receiving only oral hypoglycemic agents. Chronic complications were related to worse HRQoL in different dimensions: peripheral neuropathy and cardiovascular disease (all, except bodily pain), retinopathy (physical functioning, general health, vitality, and mental health), peripheral arterial disease (physical functioning, role-physical, and general health), and nephropathy (general health and vitality). Hypertension was related to worse general health and vitality. An increased number of chronic complications was associated with worse HRQoL in all dimensions of Short-Form 36 except for the bodily pain dimension. CONCLUSION: The presence and increased number of diabetes-related chronic complications, and the presence of hypertension were related to worse age-adjusted HRQoL. Peripheral neuropathy and cardiovascular disease were more strongly related to age-adjusted HRQoL. PMID- 26586959 TI - Diagnostic and treatment strategies in mucopolysaccharidosis VI. AB - Mucopolysaccharidosis VI (MPS VI) is a very rare autosomal recessive disorder caused by mutations in the ARSB gene, which lead to deficient activity of the lysosomal enzyme ASB. This enzyme is important for the breakdown of the glycosaminoglycans (GAGs) dermatan sulfate and chondroitin sulfate, which accumulate in body tissues and organs of MPS VI patients. The storage of GAGs (especially dermatan sulfate) causes bone dysplasia, joint restriction, organomegaly, heart disease, and corneal clouding, among several other problems, and reduced life span. Despite the fact that most cases are severe, there is a spectrum of severity and some cases are so attenuated that diagnosis is made late in life. Although the analysis of urinary GAGs and/or the measurement of enzyme activity in dried blood spots are useful screening methods, the diagnosis is based in the demonstration of the enzyme deficiency in leucocytes or fibroblasts, and/or in the identification of pathogenic mutations in the ARSB gene. Specific treatment with enzyme replacement has been available since 2005. It is safe and effective, bringing measurable benefits and increased survival to patients. As several evidences indicate that early initiation of therapy may lead to a better outcome, newborn screening is being considered for this condition, and it is already in place in selected areas where the incidence of MPS VI is increased. However, as enzyme replacement therapy is not curative, associated therapies should be considered, and research on innovative therapies continues. The management of affected patients by a multidisciplinary team with experience in MPS diseases is highly recommended. PMID- 26586960 TI - ROCK2 and MYLK variants under hypobaric hypoxic environment of high altitude associate with high altitude pulmonary edema and adaptation. AB - OBJECTIVE: To date, a major class of kinases, serine-threonine kinase, has been scantly investigated in stress-induced rare, fatal (if not treated early), and morbid disorder, high altitude pulmonary edema (HAPE). This study examined three major serine-threonine kinases, ROCK2, MYLK, and JNK1, along with six other genes, tyrosine hydroxylase, G-protein subunits GNA11 and GNB3, and alpha1 adrenergic receptor isoforms 1A, 1B, and 1D as candidate gene markers of HAPE and adaptation. METHODS: For this, 57 variants across these nine genes were genotyped in HAPE patients (n=225), HAPE controls (n=210), and highlanders (n=259) by Sequenom MS (TOF)-based MassARRAY(r) platform using iPLEXTM Gold technology. In addition, to study the gene expression, quantitative real-time polymerase chain reaction was performed in human peripheral blood mononuclear cells of the three study groups. RESULTS: A significant association was observed for C allele (ROCK2 single-nucleotide polymorphism, rs10929728) with HAPE (P=0.03) and C, T, and A alleles (MYLK single-nucleotide polymorphisms, rs11717814, rs40305, and rs820336) with both HAPE and adaptation (P=0.001, P=0.006, and P=0.02, respectively). ROCK2 88 kb GGGTTGGT haplotype was associated with lower risk of HAPE (P=0.0009). MYLK 7 kb haplotype CTA, composed of variant alleles, was associated with higher risk of HAPE (P=0.0006) and lower association with adaptation (P=1E-06), whereas haplotype GCG, composed of wild-type alleles, was associated with lower risk of HAPE (P=0.001) and higher association with adaptation (P=1E-06). Haplotype haplotype and gene-gene interactions demonstrated a correlation in working of ROCK2 and MYLK. CONCLUSION: The data suggest the association of ROCK2 with HAPE and MYLK with HAPE and adaptation in Indian population. The outcome has provided new insights into the physiology of HAPE and adaptation. PMID- 26586961 TI - Impact of inpatient caseload, emergency department duties, and online learning resource on General Medicine In-Training Examination scores in Japan. AB - BACKGROUND: Both clinical workload and access to learning resource are important components of educational environment and may have effects on clinical knowledge of residents. METHODS: We conducted a survey with a clinical knowledge evaluation involving postgraduate year (PGY)-1 and -2 resident physicians at teaching hospitals offering 2-year postgraduate training programs required for residents in Japan, using the General Medicine In-Training Examination (GM-ITE). An individual-level analysis was conducted to examine the impact of the number of assigned patients and emergency department (ED) duty on the residents' GM-ITE scores by fitting a multivariable generalized estimating equations. In hospital level analysis, we evaluated the relationship between for the number of UpToDate reviews for each hospital and for the hospitals' mean GM-ITE score. RESULTS: A total of 431 PGY-1 and 618 PGY-2 residents participated. Residents with four or five times per month of the ED duties exhibited the highest mean scores compared to those with greater or fewer ED duties. Those with largest number of inpatients in charge exhibited the highest mean scores compared to the residents with fewer inpatients in charge. Hospitals with the greater UpToDate topic viewing showed significantly greater mean score. CONCLUSION: Appropriate ED workload and inpatient caseload, as well as use of evidence-based electronic resources, were associated with greater clinical knowledge of residents. PMID- 26586962 TI - Reflections on osteopathic fascia treatment in the peripheral nervous system. AB - The peripheral nerve is composed of several layers of fascia tissue, which can become a source of pain if the way they slide is impeded. It is only recently that fascial osteopathy research has been aimed at understanding what happens to the fascia following treatment, and as a result of previous studies, we are able to highlight some of the benefits, including a reduction in local pain and inflammation. The osteopathic approach to the fascial system of the peripheral nerve does not have a grounding in scientific research, being based instead on the clinical experience of individual operators, despite peripheral nerve palpation being used as a method to evaluate and test its function. The authors wish to encourage the initiation of new research in the fields of academic and clinical osteopathy that is aimed at quantifying the possible benefits a patient may derive from osteopathic treatment of the peripheral nerve. PMID- 26586963 TI - Analysis of opioid-mediated analgesia in Phase III studies of methylnaltrexone for opioid-induced constipation in patients with chronic noncancer pain. AB - BACKGROUND: Subcutaneous methylnaltrexone is efficacious and well tolerated for opioid-induced constipation (OIC) but may theoretically disrupt opioid-mediated analgesia. METHODS: Opioid use, pain intensity, and opioid withdrawal (Objective Opioid Withdrawal Scale [OOWS] and Subjective Opiate Withdrawal Scale [SOWS] scores) were reported in a randomized, double-blind trial with an open-label extension (RCT) and an open-label trial (OLT) evaluating safety in adults with chronic noncancer pain. In the RCT, patients taking >=50 mg of oral morphine equivalents daily with <3 rescue-free bowel movements weekly received methyl naltrexone 12 mg once daily (n=150), every other day (n=148), or placebo (n=162) for 4 weeks, followed by open-label methylnaltrexone 12 mg (as needed [prn]; n=364) for 8 weeks. In the OLT, patients (n=1,034) on stable opioid doses with OIC received methylnaltrexone 12 mg prn for up to 48 weeks. RESULTS: Minimal fluctuations of median morphine equivalent dose from baseline (BL) were observed in the RCT double-blind period (BL, 154.8-161.0 mg/d; range, 137.1-168.0 mg/d), RCT open-label period (BL, 156.3-174.6; range, 144.0-180.0) and OLT (BL, 120 mg/d; range, 117.3-121.1 mg/d). No significant change from BL in pain intensity score occurred in any group at weeks 2 or 4 (both P>=0.1) of the RCT double-blind period, and scores remained stable during the open-label period and in the OLT (mean change, -0.2 to 0.1). Changes from BL in OOWS and SOWS scores during the double-blind period were not significantly impacted by methylnaltrexone exposure at weeks 2 or 4 (P>0.05 for all). CONCLUSION: Methylnaltrexone did not affect opioid-mediated analgesia in patients with chronic noncancer pain and OIC. PMID- 26586964 TI - The safety of liposome bupivacaine following various routes of administration in animals. AB - BACKGROUND: This report presents results from four preclinical studies evaluating safety and pharmacokinetics (PKs) of liposome bupivacaine following intravascular (intravenous [IV], intra-arterial [IA]), epidural, and intrathecal administration in dogs. METHODS: Intravascular administration was initially tested in a pilot study to determine maximum tolerated doses, and then in an expanded study of systemic adverse effects and PKs. An epidural study compared properties of liposome bupivacaine alone and in combination with lidocaine/epinephrine vs bupivacaine HCl. Another study assessed effects after intrathecal administration. RESULTS: In the initial intravascular studies, maximum doses at which no meaningful adverse events were observed with liposome bupivacaine were higher than for bupivacaine HCl (4.5 mg/kg IV vs 0.75 mg/kg IV, and 1.5 mg/kg IA vs 0.1 mg/kg IA, respectively). In the expanded intravascular study, there was no mortality or changes in pathology; adverse clinical signs included convulsions, lying on side, and decreased muscle tone (all were transient). In the epidural study, liposome bupivacaine was well tolerated at doses up to the highest dose tested (40 mg), with no evidence of spinal cord damage and with less motor blockade than bupivacaine HCl 15 mg. Intrathecal administration of liposome bupivacaine 40 mg was not associated with meaningful safety concerns and resulted in less motor blockade than bupivacaine HCl 15 mg. PK analyses showed that maximum plasma bupivacaine levels following administration of liposome bupivacaine (4.5 mg/kg IV and 40 mg epidural) were similar to maximum plasma bupivacaine levels following a threefold lower dose of bupivacaine HCl (1.5 mg/kg IV and 15 mg epidural). CONCLUSION: Liposome bupivacaine has a favorable safety profile compared with bupivacaine HCl when administered to dogs via intravascular, epidural, and intrathecal routes. This favorable safety profile is likely related to the liposome-bound nature of bupivacaine in the liposome bupivacaine formulation. PMID- 26586966 TI - A case of choroidal osteoma in a 10-year-old child. AB - Choroidal osteoma is a rare, benign tumor, usually diagnosed in healthy adult women in their second or third decade of life. Though its etiology and pathogenesis are unclear, it is usually diagnosed due to its typical clinical features of yellowish-orange colored subretinal lesion at posterior pole and a dense echogenic plaque persisting even in lower gains on B-scan ultrasonography. Mostly unilateral (79%), the median age of diagnosis is 26 years. It is relatively rare in children. We report a case of choroidal osteoma in a 10-year old boy. PMID- 26586965 TI - Mayer-Rokitansky-Kuster-Hauser syndrome: a review. AB - The congenital aplasia or severe hypoplasia of mullerian structures is infrequent. However, the features of normal female endocrine function paired with the absence of a functional uterus and vagina makes it a fascinating entity. The diagnosis and work-up in these patients has become very efficient, thanks to the use of imaging, and there are multiple successful procedures for the creation of a neovagina. In recent years, infertility treatment options through in vitro fertilization have also become available as part of the long-term care of these patients. PMID- 26586967 TI - Synergistic effect of regenerating agent plus cord blood serum eye drops for the treatment of resistant neurotrophic keratitis: a case report and a hypothesis for pathophysiologic mechanism. AB - This report describes a case of a 72-year-old Caucasian woman presenting with a large neurotrophic keratitis with a large persistent epithelial defect, with a longest linear diameter of 7 mm and greatest perpendicular width of 5 mm, affecting epithelium, Bowman membrane, and anterior stroma. Corneal disease was resistant to conventional treatment and classified as stage 2 according to Mackie classification. Patient was instructed to instill regenerating agent (RGTA) eye drops in the morning, as the first eye drop, once every 5 days in combination with daily cord blood serum (CBS) eye drops 6 times/day. The patient was asked to visit after 1 week (V1), 2 weeks (V2), 3 weeks (V3), and 4 weeks (V4) of study treatment. In V4 treatment, corneal sensitivity improved, and keratitis healed with resolution of stromal inflammation. Global treatment tolerance was very satisfactory. Patient continued the therapy for a further month after complete healing. Currently, the patient has been followed up for 3 months without any sign of keratitis recurrence. To the best of our knowledge, this case report describes for the first time the successful combined use of RGTA and CBS eye drops for the treatment of neurotrophic keratitis resistant to conventional treatment. We hypothesize that RGTA eye drops could provide an optimal migration substrate and that growth factors supplied by CBS eye drops could strengthen the repair process by promoting cell growth over the matrix. Combined RGTA and CBS eye drop therapy could be a new potential option for the successful treatment of resistant neurotrophic keratitis, particularly when each drug alone is not effective. PMID- 26586968 TI - Interferon-free combination therapies for the treatment of hepatitis C: current insights. AB - The hepatitis C virus (HCV) treatment landscape has rapidly changed over the past 5 years. The development of direct-acting antiviral (DAA) agents that specifically target various steps in the HCV lifecycle has revolutionized therapeutic options for patients with HCV, with the development of highly effective and well-tolerated oral interferon-free regimens. There are many DAAs that are currently in development or have recently been approved, which target different nonstructural HCV proteins and host targets that are essential for HCV replication. This review will focus on the different classes of DAAs and the various combinations that are in advanced development for the treatment of chronic HCV infection and will focus on the different regimens in specific patient populations. PMID- 26586969 TI - Association of cytokine gene polymorphisms with hepatitis C virus infection in a population from Rio de Janeiro, Brazil. AB - BACKGROUND: The host immune response is an important indicator of the outcome of hepatitis C virus (HCV) infection and disease progression. The aim of this study was to explore cytokine gene polymorphisms as a candidate for susceptibility to persistent HCV infection or HCV spontaneous clearance in a population from Rio de Janeiro, Brazil. METHODS: Genetic polymorphisms in the cytokines, tumor necrosis factor-alpha (-308), transforming growth factor-beta 1 (codons 10 and 25), interleukin-10 (IL-10; -1082 and -592), IL-6 (-174), and interferon-gamma (+874) were analyzed by polymerase chain reaction sequence-specific primers in 245 patients with chronic hepatitis C (CHC), 41 spontaneous recovery (SR) patients, and 189 healthy volunteers. Further, polymorphisms in IL-28B (rs12979860, rs12980275, and rs8099917) were assessed by real-time polymerase chain reaction in all groups. RESULTS: The IL-28B rs12979860 CC and rs12980275 AA genotypes were significantly associated with SR of HCV infection and response to therapy, whereas the C allele of IL-6 (-174) was associated with protection to CHC. A multivariate analysis showed that the male sex and IL-28B rs12979860 CT and TT and transforming growth factor-beta 1 (codon 10) TC genotypes were factors associated with CHC. Additionally, IL-6 (-174) C allele was increased in SR patients compared with patients with CHC. CONCLUSION: IL-28B polymorphisms are associated with spontaneous clearance of HCV and response to therapy in a Brazilian population. Also, IL-6 (-174) C allele is involved in SR and decreased inflammation scores. PMID- 26586970 TI - Beyond expectation: a case for nonpersonal contextual factors in a more comprehensive approach to the placebo effect and the contribution of environmental psychology. AB - Creating an optimized health care environment to maximize the probability and magnitude of placebo effects draws on a number of well-researched mechanisms such as the patient's positive expectation toward treatment outcome. Patient-centered communication styles influence expectations and can thus be considered as a form of supplemental treatment. Unconsciously processed contextual triggering and facilitating placebo effects are omnipresent in clinical settings as well as in all other social and physical environments. Contextual cues in both the social and physical domain exert influences on the recipient's emotional state and recreational experiences. While the majority of research focuses on improving the patients' expectations, classical conditioning effects of nonsocial contextual factors have been largely neglected in discussions on practical implementation of placebo-enhancing environments. Built on the empirically well-supported argument that conditioning processes act as a powerful tool to mobilize self-healing resources just as verbally induced expectations do, we argue for a stronger consideration of the effects of permanent, nonsocial and nonverbal environmental contexts. Environmental psychology is a new field of research within the psychological domain and offers a toolbox of opportunities for medical psychological research and health care practitioners to improve the treatment outcomes and benefits of health care environments. PMID- 26586971 TI - Barriers to health care for undocumented immigrants: a literature review. AB - With the unprecedented international migration seen in recent years, policies that limit health care access have become prevalent. Barriers to health care for undocumented immigrants go beyond policy and range from financial limitations, to discrimination and fear of deportation. This paper is aimed at reviewing the literature on barriers to health care for undocumented immigrants and identifying strategies that have or could be used to address these barriers. To address study questions, we conducted a literature review of published articles from the last 10 years in PubMed using three main concepts: immigrants, undocumented, and access to health care. The search yielded 341 articles of which 66 met study criteria. With regard to barriers, we identified barriers in the policy arena focused on issues related to law and policy including limitations to access and type of health care. These varied widely across countries but ultimately impacted the type and amount of health care any undocumented immigrant could receive. Within the health system, barriers included bureaucratic obstacles including paperwork and registration systems. The alternative care available (safety net) was generally limited and overwhelmed. Finally, there was evidence of widespread discriminatory practices within the health care system itself. The individual level focused on the immigrant's fear of deportation, stigma, and lack of capital (both social and financial) to obtain services. Recommendations identified in the papers reviewed included advocating for policy change to increase access to health care for undocumented immigrants, providing novel insurance options, expanding safety net services, training providers to better care for immigrant populations, and educating undocumented immigrants on navigating the system. There are numerous barriers to health care for undocumented immigrants. These vary by country and frequently change. Despite concerns that access to health care attracts immigrants, data demonstrates that people generally do not migrate to obtain health care. Solutions are needed that provide for noncitizens' health care. PMID- 26586972 TI - Intraocular lens implants: Do they come with a life time guaranty? PMID- 26586973 TI - Corneal collagen crosslinking for progressive keratoconus in Saudi Arabia: One year controlled clinical trial analysis. AB - AIMS: To determine the short-term efficacy of corneal collagen crosslinking (CXL) treatment in patients with progressive Keratoconus (KCN) in comparison with no treatment. SETTINGS AND DESIGN: This controlled clinical trial study was carried out at a tertiary eye hospital, Eastern Province, Saudi Arabia. METHODS AND MATERIAL: A prospective controlled clinical study of patients being treated for Keratoconus at a tertiary eye care hospital in the Eastern province of Saudi Arabia. 51 eyes of 43 patients with progressive KCN who received corneal collagen crosslinking (treatment group) and 50 eyes of 34 patients with KCN and no treatment (control group) were included in our study. A one year clinical data were collected preoperatively as well as at 1, 3, 6 and 12 months postoperatively for the treatment group patients. A baseline and 1 year clinical data were collected for the control group patients. The short-term efficacy of the treatment in preventing progression of KCN in comparison with no treatment was analysed at one year. RESULTS: At one year after crosslinking there was significant flattening of the average keratometry by 0.61 D (p = 0.001) [95% CI: 0.25, 0.97] compared to 0.40 D (p = 0.210) steepening in the control group; difference between treatment and control was 1.01 D (p = 0.006) [95%CI: 0.29, 1.72]. Pachymetry in treatment group thinned by 20.21 MUm (p < 0.0001) [95% CI: 12.77, 27.66] compared to 0.32 MUm (p = 0.912) in the control group. Visual acuity remained stable at the preoperative level of 20/30 (p = 0.397) in the treatment group and 20/40 (p = 0.553) in the control group at one year. CONCLUSIONS: Corneal CXL is an effective treatment for halting the progression of KCN as shown by reduced keratometry and stability of vision. PMID- 26586974 TI - Is there is an association between the presence of Staphylococcus species and occurrence of vernal keratoconjunctivitis? AB - PURPOSE: The aim of this study was to identify the association of normal bacterial flora with vernal keratoconjunctivitis (VKC) occurrence in VKC and non VKC groups. METHODS: Conjunctival specimens were collected from 18 VKC patients and 22 healthy controls, cultured and identified following standard methods. The association between the presence of bacteria and occurrence of VKC was analyzed using Chi square statistic. RESULTS: Comparable bacterial growth was observed in VKC (77.8%) as well as control group (77.2%) (p = 0.970). Analysis of individual bacterial revealed that Staphylococcus aureus was detected more frequently in VKC (27.78% vs. 4.55% in control, p = 0.041) and Staphylococcus epidermidis was found much more commonly in the control eyes (45.45% in control vs. 5.56% in VKC, p = 0.005). CONCLUSIONS: An aggravating role of S. aureus colonization in the occurrence of VKC, and a possible role of S. epidermidis against the occurrence of VKC were concluded. PMID- 26586975 TI - Decreased visual acuity resulting from glistening and sub-surface nano-glistening formation in intraocular lenses: A retrospective analysis of 5 cases. AB - BACKGROUND: To report on five patients with decreased visual acuity due to glistening and severe sub-surface nano-glistening (SSNG) formation within their intraocular lenses (IOLs). DESIGN: Case reports and analysis of extracted IOLs. PARTICIPANTS AND SAMPLES: We report improved visual acuity when IOLs with severe glistening and SSNG were exchanged for clear IOLs in five patients. METHODS: Case reports. MAIN OUTCOME MEASURES: The main outcome measure was visual acuity. The secondary outcome measure was light transmission. Explanted IOLs were subjected to investigation. Pre- and postoperative slit lamp images of the anterior eye and microscopic images of the extracted IOLs were taken and compared. Light transmission of the IOL was measured using a double beam type spectrophotometer. An integrated value of the percentage light transmittance in the visible light spectrum was calculated. RESULTS: We report on five patients whose visual acuity improved when IOLs were exchanged because of severe glistening and SSNG. All of the affected IOLs were MA60BM (Alcon, Forth Wroth Texas, USA) and the original implantation had occurred over a range of 6-15 years prior to the IOL exchange. Light transmission was decreased in all affected lenses compared to a similar control IOL. CONCLUSIONS: Although only a few reports of cases in which glistening and SSNG have progressed to the level of decreased visual function have been published, the likelihood is that this phenomena will increase as the severity and incidence of these inclusions have been shown to increase with time. Appropriate evaluations of visual function in such patients are needed and consideration should be given to IOL exchange in symptomatic patients. PMID- 26586976 TI - Management of moderate and severe corneal astigmatism with AcrySof(r) toric intraocular lens implantation - Our experience. AB - PURPOSE: Visual performance following toric intraocular lens implantation for cataract with moderate and severe astigmatism. SETTING: Cataract services, Shroff Eye Centre, New Delhi, India. DESIGN: Case series. METHOD: This prospective study included 64 eyes of 40 patients with more than 1.50 dioptre (D) of pre-existing corneal astigmatism undergoing phacoemulsification with implantation of the AcrySof(r) toric IntraOcular Lens (IOL). The unaided visual acuity (UCVA), best corrected visual acuity (BCVA), residual refractive sphere and refractive cylinders were evaluated. Toric IOL axis and alignment error was measured by slit lamp method and Adobe Photoshop (version 7) method. Patient satisfaction was evaluated using a satisfaction questionnaire at 3 months. RESULTS: The mean residual refractive astigmatism was 0.57 D at the final follow-up of 3 months. Mean alignment error was 3.44 degrees (SD = 2.60) by slit lamp method and 3.88 degrees (SD = 2.86) by Photoshop method. Forty-six (71.9%) eyes showed misalignment of 5 degrees or less, and 60 (93.8%) eyes showed misalignment of 10 degrees or less. The mean log MAR UCVA at 1st post-op day was 0.172 (SD = 0.02), on 7th post-op day was 0.138 (SD = 0.11), and on 30th post-op day was 0.081 (SD = 0.11). The mean log MAR BCVA at three months was -0.04 (SD = 0.76). CONCLUSION: We believe that implantation of AcrySof(r) toric IOL is an effective, safe and predictable method to correct high amounts of corneal astigmatism during cataract surgery. PMID- 26586977 TI - Posterior sub-tenon's bevacizumab injection in diabetic macular edema; a pilot study. AB - PURPOSE: To evaluate the short-term results of sub-tenon's injection of bevacizumab in patients with clinically significant macular edema (CSME). METHODS: In this prospective non-comparative interventional case series, sub tenon's injection of 2.5 mg/0.1 ml bevacizumab was performed for eyes with CSME. Macular thickness and best corrected visual acuity measurements were performed before and one month after injections. RESULTS: Nineteen eyes of twelve patients with a mean age of 59.8 +/- 5.7 years were evaluated. Thirteen eyes (68.4%) had center-involving macular edema. No significant difference was observed between pre- and post-injection central subfield retinal thickness measurements (P = 0.3). Central subfield thickness measurements improved or remained unchanged in 13 eyes (68.4%). Baseline BCVA of 0.48 +/- 0.35 LogMAR improved to 0.36 +/- 0.26 LogMAR after injection (P = 0.01). Improvement of >2 lines in BCVA was found in 5 eyes (26.3%), and no eye lost >2 lines of BCVA. No complication associated with sub-tenon's injection was observed. CONCLUSION: Sub-tenon's injection of bevacizumab resulted in significant short-term visual improvement in eyes with CSME. Retinal thickness changes were not significant. PMID- 26586978 TI - Primary canaliculitis: The incidence, clinical features, outcome and long-term epiphora after snip-punctoplasty and curettage. AB - PURPOSE: To study the incidence, clinical features and outcome of primary canaliculitis with special reference to long-term epiphora after Snip punctoplasty and curettage. METHODS: Single center, retrospective, telephonic questionnaire study. The medical records of patients who visited Orbit and Oculoplasty clinic, Tertiary Eye Hospital, India from 01 July 2011 to 31 June 2012 were analyzed. Records of the patients with primary canaliculitis were reviewed for clinical profile and management. Post-surgical patients thus identified were telephonically contacted in December 2012. Questionnaire was used to assess the postsurgical epiphora. Symptomatic patients were given clinic appointment, reassessed and managed. RESULTS: 2245 patients visited Orbit and Oculoplasty clinic during the study period. The incidence of primary canaliculitis was 1.4% (31 patients). The median age of the patients with canaliculitis was 65 years (range, 14-80 yrs). Sixteen patients were male. All cases were unilateral and four eyes showed both upper and lower canalicular involvement. The commonest clinical presentations were pus or concretion from punctum (28), mucous discharge (23), epiphora (18) and conjunctival injection (18). Three snip punctoplasty and canalicular curettage was performed in 30 of these patients. Twenty of the 25 available culture results were positive and streptococcus species was the most common isolated organism. Records revealed that five (22%) of these patients had persistence of symptoms. Twenty-three patients could be contacted telephonically. The median follow-up of these patients was 11 months. On telephonic communication we found that two (8.7%) patients had epiphora. Munk epiphora score in these patients was three and one respectively. CONCLUSIONS: Incidence of canaliculitis was 1.4%. Most common isolate was streptococcus species. Snip-punctoplasty and curettage is a safe and efficacious modality of treatment of canaliculitis. Post-operative epiphora occurred in 8.7% patients. PMID- 26586981 TI - Intravitreal bevacizumab in congenital retinal macrovessel with retinal arteriolar macroaneurysm. AB - Congenital retinal macrovessel (CRM) refers to an aberrant vessel, usually a vein, which traverses the macula and supplies both sides of the horizontal raphe. It is a rare condition, mostly asymptomatic and discovered on routine examination. We describe a case of both arterial and venous CRM with a macroaneurysm along the arterial CRM that presented with decreased vision due to prominent lipid exudation at the macula. Treatment with intravitreal bevacizumab resulted in a favourable anatomical as well as functional outcome. To the best of our knowledge, this is the first report of this unusual presentation of CRM, and its successful management with intravitreal bevacizumab. PMID- 26586980 TI - Platelet derived growth factor inhibitors: A potential therapeutic approach for ocular neovascularization. AB - Retinochoroidal vascular diseases are the leading causes of blindness in the developed world. They include diabetic retinopathy (DR), retinal vein occlusion, retinopathy of prematurity, age-related macular degeneration (AMD), and pathological myopia, among many others. Several different therapies are currently under consideration for the aforementioned disorders. In the following section, agents targeting platelet-derived growth factor (PDGF) are discussed as a potential therapeutic option for retinochoroidal vascular diseases. PDGF plays an important role in the angiogenesis cascade that is activated in retinochoroidal vascular diseases. The mechanism of action, side effects, efficacy, and the potential synergistic role of these agents in combination with other treatment options is discussed. The future of treatment of retinochoroidal vascular diseases, particularly AMD, has become more exciting due to agents such as PDGF antagonists. PMID- 26586979 TI - Advances in the treatment of central serous chorioretinopathy. AB - Central serous chorioretinopathy is a disease that is partly understood. Novel advancements have led to further understanding of the disease, and have identified choroidal dysfunction as the principal element in CSCR development. New imaging tools have aided in better monitoring disease response to various treatment models. Enhanced depth imaging optical coherence tomography, in particular, has helped in observing choroidal thickness changes after various treatment models. To date, photodynamic therapy and focal laser remain the main stay of treatment. More understanding of disease pathophysiology in the future will help in determining the drug of choice and the best management option for such cases. PMID- 26586982 TI - Idiopathic multiple retinal pigment epithelial detachments - A case report. AB - Retinal pigment epithelial detachment, often asymptomatic is a common retinal finding. Multiple serous retinal pigment epithelial detachment especially in a female is very uncommon. We describe a case of multiple retinal pigment epithelial detachments throughout the fundus in a 51-year old female otherwise asymptomatic. Indocyanine green angiography and fundus auto fluorescence showed abnormalities with a normal systemic work-up. This is the first report of an asymptomatic patient correlating angiogram with auto fluorescence in multiple serous retinal pigment epithelial detachments. PMID- 26586983 TI - Bilateral optic neuritis in a patient with Behcet's disease who respond to therapeutic plasma exchange. AB - Bilateral optic neuritis has been reported very rarely as a manifestation of neuro-Behcet's disease. We present a 50 year old woman who had 20-year history of Behcet's disease presented with acutely blurred vision associated with orbital pain in both eyes. Visual acuity was 0.4 in the right eye and light perception in the left eye; afferent pupillary defect was detected in the left eye. Bilateral swelling of the optic disk was found. The cerebrospinal fluid sample tests were within normal limits. Brain magnetic resonance imaging, magnetic resonance venography and fundus fluorescein angiography were normal. She was diagnosed with bilateral optic neuritis and treated with intravenous methyl prednisolone for 10 days. As there was no response to the treatment, therapeutic plasma exchange was started and the patient's visual acuities improved moderately. We suggest that when high dose steroid is failed to treat ON in BD, treatment with TPE may be considered. PMID- 26586984 TI - Spontaneously resolving descemet's membrane detachment caused by an ophthalmic viscosurgical device during cataract surgery. AB - We present a case of a central Descemet's membrane detachment (DMD) induced by an Ophthalmic Viscosurgical Device during phacoemulsification surgery that resolved spontaneously, leaving a best spectacle corrected visual acuity of 20/20. The detachment was monitored with serial anterior segment optical coherence tomography images. Most cases of central DMD reported in the literature have been managed surgically to facilitate rapid visual recovery and minimize the risk of scarring. Our case adds to the literature in providing an alternative management strategy where surgical intervention may not be possible. PMID- 26586985 TI - Candida parapsilosis corneal graft infection from a single eye center: Histopathologic report of 2 cases. AB - Fungal keratitis accounts for 6-53% of all cases of ulcerative keratitis in variable studies. The majority of cases are due to septate fungi. The abnormal cornea in cases of dry eye syndrome, chronic ulceration, erythema multiform and possibly HIV infection is infected more commonly with Candida, most commonly Candida albicans. Candida parapsilosis affects neonates and intensive care unit (ICU) patients and it has been recently found with increasing frequency. In a previous study on mycotic keratitis in our tertiary eye hospital, filamentous fungi were more commonly isolated than yeasts. We are presenting 2 successive cases of corneal graft infection by Candida parapsilosis referred to us from another eye center to attract the attention of ophthalmologists and health workers to such an infection. PMID- 26586986 TI - Clinical variability in hereditary optic neuropathies: Two novel mutations in two patients with dominant optic atrophy and Wolfram syndrome. AB - Dominant optic atrophy (DOA) and Wolfram syndrome share a great deal of clinical variability, including an association with hearing loss and the presence of optic atrophy at similar ages. The objective of this paper was to discuss the phenotypic variability of these syndromes with respect to the presentation of two clinical cases. We present two patients, each with either DOA or Wolfram syndrome, and contribute to the research literature through our findings of two novel mutations. The overlapping of several clinical characteristics in hereditary optic neuropathies can complicate the differential diagnosis. Future studies are needed to better determine the genotype-phenotype correlation for these diseases. PMID- 26586987 TI - An unusual eyelid mass: Tarsal dermoid cyst. AB - We report the case of a 15-month-old boy who presented with a mass lesion of the right upper eyelid that had been present since birth and had slowly enlarged over the last 3 months. The lesion had minimal surrounding erythema simulating the appearance of a chalazion. Intraoperatively the lesion was noted to be firmly adherent to the underlying tarsus. The lesion was excised completely through an eyelid crease approach leaving the tarsus intact. The histopathology was consistent with dermoid cyst. To our knowledge, this is the third case of a tarsal dermoid cyst reported in the literature. Dermoid cyst should be included in the differential diagnosis of eyelid mass lesions, and particulary differentiated from a chalazion to avoid mismanagement that may lead to scarring, recurrence and inflammation. The excision of these lesions sparing the underlying tarsus can be possible. PMID- 26586988 TI - Foreign body in ocular coats causing a pseudo optic nerve head shadow. AB - Small intraocular foreign body in the outer coats of the eye may be wrongly interpreted as optic nerve head on ultrasound imaging. Such errors can be avoided by performing multiple sonography scans in different axes. PMID- 26586989 TI - Lost drill bit during medial canthoplasty for a blepharophimosis syndrome. PMID- 26586990 TI - Special Issue on Molecular Biology and Biophysics of Eukaryotic Cells. PMID- 26586991 TI - Phenomenology and energetics of diffusion across cell phase states. AB - Cell based transport properties have been mathematically addressed. Cell contained cross boundary diffusion of materials has been explained using valid formalisms and related analytical expressions have been developed. Various distinguishable physical structures and their properties raise different general structure specific diffusion mechanisms and controlled transport related parameters. Some of these parameters play phenomenological roles and some cause regulatory effects. The cell based compartments may be divided into three major physical phase states namely liquid, plasma and solid phase states. Transport of ions, nutrients, small molecules like proteins, etc. across inter phase states and intraphase states follows general transport related formalisms. Creation of some localized permanent and/or temporary structures e.g., ion channels, clustering of constituents, etc. and the transitions between such structures appear as regulators of the transport mechanisms. In this article, I have developed mainly a theoretical analysis of the commonly observed cell transport phenomena. I have attempted to develop formalisms on general cell based diffusion followed by a few numerical computations to address the analytical expression phenomenologically. I have then extended the analysis to adopting with the local structure originated energetics. Independent or correlated molecular transport naturally relies on some general parameters that define the nature of local cell environment as well as on some occasionally raised or transiently active stochastic resonance due to localized interactions. Short and long range interaction energies play crucial roles in this regard. Physical classification of cellular compartments has led us developing analytical expressions on both biologically observed diffusion mechanisms and the diffusions's occasional stochasticity causing energetics. These analytical expressions help us address the diffusion phenomena generally considering the physical properties of the biostructures across the diffusion pathways. A specific example case of single molecule transport and localized interaction energetics in a specific cell phase has been utilized to address the diffusion quite clearly. This article helps to address the mechanisms of cell based diffusion and nutrient movements and thus helps develop strategic templates to manipulate the diffusion mechanisms. Application of the theoretical knowledge into designing or discovering drugs or small molecule inhibitors targeting cell based structures may open up new avenues in biomedical sciences. PMID- 26586992 TI - Entropic analysis reveals a connection between the recurrence of cancer and chemotherapy. AB - In this study, we proposed an entropic analysis to overcome limitations of conventional statistical methods to analyze clinical data for cancer patients who experienced relapse of tumors following chemotherapy. We have applied this entropic method to reveal potential mechanisms that lead to a relapse of Wilms' tumor in pediatric patients. Results indicate beta-tubulin isotype III up regulation is likely the primary cause of the relapse. PMID- 26586993 TI - ZnO nanoparticles augment ALT, AST, ALP and LDH expressions in C2C12 cells. AB - The present study aimed to investigate the effect of ZnO nanoparticles on alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) enzyme expressions in C2C12 cells. ZnO nanoparticles are widely used in the several cosmetic lotions and other biomedical products. Several studies report on ZnO nanoparticle mediated cytotoxicity. However, there are no reports on the effect of ZnO nanoparticles on ALT, AST, ALP and LDH enzyme expressions in C2C12 cells. A cytotoxicity assay was carried out to determine the effect of ZnO nanoparticles (1-5 mg/ml) on C2C12 cell viability at 48 and 72 h. ZnO nanoparticles increased ALT, AST, ALP and LDH enzyme mRNA expression and their activities in C2C12 cells. In conclusion, the present study showed that ZnO nanoparticles increased these enzyme activities and its mRNA expression in C2C12 cells in a dose-dependent manner. PMID- 26586994 TI - Effect of acetone extract from stem bark of Acacia species (A. dealbata, A. ferruginea and A. leucophloea) on antioxidant enzymes status in hydrogen peroxide induced HepG2 cells. AB - Acacia species are multipurpose trees, widely used in the traditional systems of medicine to treat various ailments. The major objective of the present study was to determine the gene expression of enzymatic antioxidants by acetone extract from the stem bark of three Acacia species (Acacia dealbata, Acacia ferruginea and Acacia leucophloea) in hydrogen peroxide (H2O2)-induced human hepatoma (HepG2) cells. The expression of antioxidant enzymes such as superoxide dismutase containing copper-zinc (CuZnSOD)/manganese (MnSOD), catalase (CAT) and glutathione peroxidase (GPx) in HepG2 cells was evaluated by real-time PCR. The results of antioxidant enzyme expression in real-time PCR study revealed that the H2O2 (200 MUM) challenged HepG2 cells reduced the expression of enzymes such as SOD, GPx and CAT. However, the cells pre-treated with acetone extracts of all the three Acacia species significantly (P > 0.05) up-regulated the expression of antioxidant enzymes in a concentration dependent manner (25, 50 and 75 MUg/mL). In conclusion, the findings of our study demonstrated that the acetone extract of Acacia species effectively inhibited H2O2 mediated oxidative stress and may be useful as a therapeutic agent in preventing oxidative stress mediated diseases. PMID- 26586995 TI - Induction of primitive streak and mesendoderm formation in monolayer hESC culture by activation of TGF-beta signaling pathway by Activin B. AB - Human embryonic stem cells (hESCs) have the ability to differentiate into all human cells, however controlling the differentiation has always been a challenge. In the present study we have investigated the direct differentiation of hESCs on MEFs by using TGF-beta signaling pathway activators Activin A and Activin B. Activation of the TGF-beta pathway with Activin B in low serum highly induced primitive streak and mesendoderm formation after 24 h, which included up regulation of SOX 17 and BRACHYURY protein and gene expression. Continuous stimulation with Activin B in 2% serum further induced mesendoderm formation by increased gene expression of Brachyury, SOX17, MEOX and FOX at the same time we found down-regulation of neuroectodermal marker genes. Further, by stimulating the mesodermal cells by BMP-2 we succeeded to induce mesenchymal like cells with high expression of mesenchymal markers including; MEOX, FOX, RUNX2, COL1 and OSTEOPONTIN. In conclusion we have directed the differentiation of hESCs as monolayer to primitive streak like cells with Activin B and further into pure mesoderm and mesenchymal like cells by BMP-2. PMID- 26586996 TI - The natural diet of the mud crab Scylla olivacea (Herbst, 1896) in Pichavaram mangroves, India. AB - Food and feeding habits of mud crab Scylla olivacea (Herbst, 1896) in Pichavaram mangroves was investigated quantitatively and qualitatively for a period of two years from June 2010 to May 2012. Gut contents from 1737 specimens comprising 843 males and 894 females in the size range between 45 mm and 148 mm were examined. Crustaceans form the predominant food item in a majority of size groups in terms of percentage wet weight and frequency of occurrence, while molluscs showed a preference in few size groups. The other dietary items includes fishes, detritus, mud and sand and miscellaneous. Gut content analysis revealed no significant variation between the quantities of food consumed by both sexes. Feeding intensity was higher in juveniles and subadults of both sexes than that of adults, revealing a greater preference to feed on fast moving prey such as crustaceans and fishes. The results of the present study indicate that S. olivacea in Pichavaram mangroves exhibited a clear preference for crustaceans. PMID- 26586997 TI - Quercetin-3-O-beta-d-glucopyranosyl-(1 -> 6)-beta-d-glucopyranoside suppresses melanin synthesis by augmenting p38 MAPK and CREB signaling pathways and subsequent cAMP down-regulation in murine melanoma cells. AB - In this study, the effect of purified quercetin-3-O-beta-d-glucopyranosyl-(1 -> 6)-beta-d-glucopyranosid (QCGG) on melanogenesis was investigated. QCGG was isolated from the calyx of a traditional Korean medicinal herb, Persimmon (Diospyros kaki). The hypopigmentation effects of QCGG were determined by examination of cellular melanin contents, tyrosinase activity assay, cAMP assay, and Western blotting of alpha-MSH-stimulated B16F10 mouse melanoma cells. Our results showed that QCGG inhibited both melanin synthesis and tyrosinase activity in a concentration-dependent manner as well as significantly reduced the expression of melanogenic proteins such as microphthalmia-associated transcription factor (MITF), tyrosinase-related protein-1, tyrosinase-related protein-2, and tyrosinase. Moreover, QCGG inhibited intracellular cAMP levels, cAMP response element-binding protein (CREB), and p38 MAPK expression in alpha MSH-stimulated B16F10 cells. Taken together, the suppressive effects of QCGG on melanogenesis may involve down-regulation of MITF and its downstream signaling pathway via phosphorylation of p38 MAPK and CREB along with reduced cAMP levels. These results indicate that QCGG reduced melanin synthesis by reducing expression of tyrosine and tyrosine-related proteins via extracellular signal-related protein kinase (ERK) activation, followed by down-regulation of CREB, p38, and MITF. PMID- 26586998 TI - Membrane-drug interactions studied using model membrane systems. AB - The direct interaction of drugs with the cell membrane is often neglected when drug effects are studied. Systematic investigations are hindered by the complexity of the natural membrane and model membrane systems can offer a useful alternative. Here some examples are reviewed of how model membrane architectures including vesicles, Langmuir monolayers and solid supported membranes can be used to investigate the effects of drug molecules on the membrane structure, and how these interactions can translate into effects on embedded membrane proteins. PMID- 26586999 TI - Theoretical investigation of the interactions in binding pocket of Reverse Transcriptase. AB - Interactions in proteins have been studied using several chemical information techniques including quantum chemical methods that are applied to truncated systems composed of the ligand molecule and the surrounding amino acids of the receptor. In this work we adopt an approach to study these interactions accounting for as many as possible explicit solvent molecules and without the need of a fragmented calculation. Furthermore, we embed our quantum chemical calculations within a molecular dynamics framework that enables a fundamentally fast system for quantum molecular dynamic simulations (QCMD). Central to this new system for QCMD is the tight binding QC system, newly developed in our laboratories, and which combined with the MD paradigm results in an ultra accelerated QCMD method for protein-ligand interaction evaluations. We have applied our newly developed method to the Nevirapine (NVP)-Reverse Transcriptase (RT) system. We show how the proposed method leads us to new findings. The advanced QCMD was applied to a system of RT with NVP and it has led to the knowledge of specific groups and atoms that interact with surrounding amino acids of RT and help in drug binding. The information derived from this calculation may be used in designing drugs for NVP resistant virus strains that have binding capability like NVP. PMID- 26587000 TI - Molecular characterization of Escherichia coli O157:H7 recovered from meat and meat products relevant to human health in Riyadh, Saudi Arabia. AB - Raw meat can harbor pathogenic bacteria, potentially harmful to humans such as Escherichia coli O157:H7 causing diarrhea and hemolytic-uremic syndrome (HS). Therefore, the current study was carried out to evaluate the prevalence and the molecular detection characterization of E. coli serotype O157:H7 recovered from raw meat and meat products collected from Saudi Arabia. During the period of 25th January 2013 to 25th March 2014, 370 meat samples were collected from abattoirs and markets located in Riyadh, Saudi Arabia "200 raw meat samples and 170 meat products". Bacteriological analysis of the meat samples and serotyping of the isolated E. coli revealed the isolation of 11 (2.97%) strains of E. coli O157:H7. Isolation of E. coli O157:H7 in raw beef, chicken and mutton were 2%, 2.5%, and 2.5%, respectively, however, there was no occurrence in raw turkey. The incidences of E. coli O157:H7 in ground beef, beef burgers, beef sausage, ground chicken and chicken burgers were 5%, 10%, 0.0%, 5% and 0.0%, respectively. The multiplex PCR assay revealed that 3 (27.27%) out of 11 E. coli O157:H7 isolates from raw beef, chicken and mutton had stx1, stx2, and eae while 5 (45.45%) E. coli O157:H7 isolates from ground beef, ground chicken, and raw beef had both stx1 and stx2. However, from beef burgers, only one E. coli O157:H7 isolate had stx1 while two were positive for hlyA gene. These results call for urgent attention toward appropriate controls and good hygienic practices in dealing with raw meat. PMID- 26587001 TI - Development of interspecific Solanum lycopersicum and screening for Tospovirus resistance. AB - Tospovirus has emerged as a serious viral pathogen for several crops including tomato. The tomato production is being severely affected worldwide by Tospovirus. Some reports have been published about the association of plant virus and development of human disease either by direct or indirect consumption. Resistance to this virus has been identified as good source in wild tomato species (Lycopersicum peruvianum). But the introgression of resistance genes into cultivated tomato lines and the development of interspecific hybrid are hampered due to incompatibility, fertilization barriers and embryo abortion. But this barrier has been broken by applying the embryo rescue methods. This study describes the development of interspecific hybrid tomato plants by highly efficient embryo rescue method and screening for Tospovirus resistance. The interspecific hybrid tomato plants were developed by making a cross between wild tomato species (L. peruvianum) and cultivated tomato (Solanum lycopersicum). The immature embryos were cultured in standardized medium and interspecific hybrids were developed from embryogenic callus. The immature embryos excised from 7 to 35 days old fruits were used for embryo rescue and 31 days old embryos showed very good germination capabilities and produced the highest number of plants. Developed plants were hardened enough and shifted to green house. The hybrid nature of interspecific plants was further confirmed by comparing the morphological characters from their parents. The F1, F2 and F3 plants were found to have varying characters especially for leaf type, color of stem, fruits, size, shapes and they were further screened for virus resistance both in lab and open field followed by Enzyme linked Immunosorbant Assay confirmation. Finally, a total of 11 resistant plants were selected bearing red color fruits with desired shape and size. PMID- 26587002 TI - Determination of potential role of antioxidative status and circulating biochemical markers in the pathogenesis of ethambutol induced toxic optic neuropathy among diabetic and non-diabetic patients. AB - The present study was designed to explore the antioxidative status and circulating biochemical markers having a potential role in the pathogenesis of ethambutol (EMB) induced toxic optic neuropathy (TON) among diabetic and non diabetic patients. Fifty patients under complete therapy of EMB for tuberculosis were included in the present study. Inclusion criteria for patients were to receive EMB everyday during treatment, a dose of 25 mg/kg for initial 2 months and 15 mg/kg during the rest of therapy period. We conducted color vision and visual acuity test for all patients. Fifteen out of fifty EMB induced TON patients, were found to be diabetic. Color vision and visual acuity test results were evaluated for diabetic and non-diabetic as well as twenty age matched controls. The results demonstrated a significant pattern of circulating biochemical markers between the studied groups. Data regarding hematological (RBC, p value = 0.02; Hemoglobin, p value = 0.02), hepatic (total bilirubin, p value = 0.01), renal (urea, p value = 0.03; creatinine, p value = 0.007), lipid (total cholesterol, p value = 0.01; total triglycerides, p value = 0.03) and antioxidative (superoxide dismutase, p value = 0.005; glutathione, p value = 0.02; catalase, p value = 0.02) profile showed a highly significant difference among the studied groups specially patients with diabetes. Malondialdehyde (MDA) level had gone significantly up in diabetic TON patients (p value = 0.02), in comparison to other antioxidants and vitamins (Vit). Vit-A, E, B1, B12 and Zinc seem to be playing a major role in the pathogenesis of TON, specially Vit-E and B1 surpassed all the antioxidants as having highly significant inverse relationships with MDA (MDA vs Vit-E, r = -0.676(**) and MDA vs Vit-B1, r = 0.724(**) respectively). We conclude that during the ethambutol therapy the decreased levels of Vit-E and Vit-B1 possibly play a role in the development of TON and may be used as therapeutic agents to lessen the deleterious effects of ethambutol. PMID- 26587003 TI - Glutathione S-transferase pi (GST-pi) inhibition and anti-inflammation activity of the ethyl acetate extract of Streptomyces sp. strain MJM 8637. AB - To investigate the anti-cancer properties of soil-borne actinobacteria, MJM 8637, the glutathione S-transferase pi (GST-pi) assay, anti-tumor necrosis factor (TNF) alpha assay, the level of antioxidant potential by DPPH radical scavenging activity, NO scavenging activity, and ABTS radical scavenging activity in ethyl acetate extract were determined. The 16S rDNA sequencing analysis revealed that Streptomyces sp. strain MJM 8637, which was isolated from Hambak Mountain, Korea, has 99.5% similarity to Streptomyces atratus strain NBRC 3897. The physiological and the morphological characteristics of the strain MJM 8637 were also identified. The ethyl acetate extract of MJM 8637 inhibited TNF-alpha production approximately 61.8% at concentration 100 MUg/ml. The IC50 value of the strain MJM 8637 extract on GST-pi was identified to be 120.2 +/- 1.6 MUg/ml. In DPPH, NO, and ABTS radical scavenging assays, the IC50 values of the strain MJM 8637 extract were found to be 977.2 MUg/ml, 1143.7 MUg/ml, and 454.4 MUg/ml, respectively. The ethyl acetate extract of the strain MJM 8637 showed 97.2 +/- 1.3% of cell viability at 100 MUg/ml in RAW 264.7 cell viability assay. The results obtained from this study suggest that the ethyl acetate extract of Streptomyces sp. strain MJM 8637 could be considered as a potential source of drug for the cancers that have multidrug resistance with its GST-pi inhibition and anti-inflammation activities, and low cytotoxicity. PMID- 26587004 TI - The cytotoxic nature of Acanthopanax sessiliflorus stem bark extracts in human breast cancer cells. AB - Acanthopanax sessiliflorus, a small woody shrub has traditionally been referred to have anticancer activity, but it has not been scientifically explored so far. Therefore, to investigate the anticancer effects of A. sessiliflorus stem bark extracts (ASSBE), MDA-MB-231 and MCF-7 human breast cancer cells were treated with one of its bioactive fractions, n-hexane (ASSBE-nHF). Cytotoxicity (24 h) was determined by MTT assay and antiproliferative effect was assessed by counting cell numbers after 72 h treatment using hemocytometer. The role of ASSBE-nHF on apoptosis was analysed by annexin V-FITC/PI, Hoechst 33342 staining, DNA fragmentation pattern and immunoblotting of apoptosis markers. For the assay of enhanced production of ROS and mitochondrial membrane depolarization, specific stains such as DCFH-DA and JC-1 were used, respectively. To understand the mode of action of ASSBE-nHF on MCF-7 cells, cells were pre-treated with antioxidant, n acetylcysteine. The hexane fraction of ASSBE showed maximum activity towards human breast cancer cells compared to other two fractions at a minimal concentration of 50 MUg/ml. The annexin V-FITC/PI, Hoechst 33342 staining, DNA fragmentation and immunoblotting assays showed that ASSBE-nHF induces non apoptotic cell death in MCF-7 and MDA-MB-231 cells. ASSBE-nHF significantly increased the production of ROS and decreased the mitochondrial membrane potential (MMP) in MCF-7 cells. Similarly, it decreased the MMP in MDA-MB-231 cells, but had no effect on ROS production. Further, the cytotoxic effect of ASSBE-nHF in MCF-7 cells was not significantly reversed even in the presence of n acetylcysteine, an antioxidant. These findings revealed that ASSBE-nHF induces non-apoptotic cell death via mitochondria associated with both ROS dependent and independent pathways in human breast cancer cells. PMID- 26587006 TI - Pseudomonas induces salinity tolerance in cotton (Gossypium hirsutum) and resistance to Fusarium root rot through the modulation of indole-3-acetic acid. AB - Abiotic stresses cause changes in the balance of phytohormones in plants and result in inhibited root growth and an increase in the susceptibility of plants to root rot disease. The aim of this work was to ascertain whether microbial indole-3-acetic acid (IAA) plays a role in the regulation of root growth and microbially mediated control of root rot of cotton caused by Fusarium solani. Seed germination and seedling growth were improved by both NaCl and Mg2SO4 (100 mM) solutions when treated with root-associated bacterial strains Pseudomonas putida R4 and Pseudomonas chlororaphis R5, which are able to produce IAA. These bacterial strains were also able to reduce the infection rate of cotton root rot (from 70 to 39%) caused by F. solani under gnotobiotic conditions. The application of a low concentration of IAA (0.01 and 0.001 MUg/ml) stimulated plant growth and reduced disease incidence caused by F. solani (from 70 to 41 56%, respectively). Shoot and root growth and dry matter increased significantly and disease incidence was reduced by bacterial inoculants in natural saline soil. These results suggest that bacterial IAA plays a major role in salt stress tolerance and may be involved in induced resistance against root rot disease of cotton. PMID- 26587005 TI - Regulation of ceramide channel formation and disassembly: Insights on the initiation of apoptosis. AB - Sphingolipid research has surged in the past two decades and has produced a wide variety of evidence supporting the role of this class of molecules in mediating cellular growth, differentiation, senescence, and apoptosis. Ceramides are a subgroup of sphingolipids (SLs) that are directly involved in the process of initiation of apoptosis. We, and others, have recently shown that ceramides are capable of the formation of protein-permeable channels in mitochondrial outer membranes under physiological conditions. These pores are indeed good candidates for the pathway of release of pro-apoptotic proteins from the mitochondrial intermembrane space (IMS) into the cytosol to initiate intrinsic apoptosis. Here, we review recent findings on the regulation of ceramide channel formation and disassembly, highlighting possible implications on the initiation of the intrinsic apoptotic pathway. PMID- 26587007 TI - Evaluation of propolis, honey, and royal jelly in amelioration of peripheral blood leukocytes and lung inflammation in mouse conalbumin-induced asthma model. AB - Bee products have been used since ancient times to treat many diseases, including respiratory ailments. The present study aimed to examine the modulatory effect of honey, royal jelly, and propolis extract on peripheral blood leukocytes and lung inflammation in a mouse conalbumin-induced asthma model. The mice in group I were not sensitised or treated; they were kept as controls. The mice in group II were sensitised and challenged with conalbumin. Twenty-four hours after the first challenge with antigen, the mice in group III received 0.5 mg/kg of dexamethasone intraperitoneally per day for 18 consecutive days and kept as positive controls. The mice in groups IV, V, and VI received 650, 1000, and 30 mg/kg of honey, royal jelly, and propolis (aqueous and ethanolic extract), respectively, once per day for 18 consecutive days. Blood was collected from all of the mice for white blood cell differentiation, and the lungs were removed for histopathological studies. The groups treated with propolis extract exhibited considerable ameliorative effects against asthma, which might be explained by the flavonoids and phenolics found in propolis, which might have antioxidative effects. Otherwise, the sensitised and honey- or royal jelly-treated groups exhibited an increased incidence of asthma cascade events due to increased inflammatory cells. These results might be due to the immunostimulatory and vasodilatory effects of royal jelly and honey, which are antagonistic to bronchial asthma cases. Histopathological examination revealed that the sensitised treated propolis extract groups had significant decreases in inflammatory scores compared with other treatments and the sensitised untreated group. These results confirmed the previous data of peripheral blood cells. PMID- 26587008 TI - Reproductive biology of the Suez Canal spider crab Schizophrys aspera (H. Milne Edwards, 1834: Crustacea: Brachyura: Majidae). AB - A reproductive biology study of the spider crab Schizophrys aspera (H. Milne Edwards, 1834) was conducted in the Suez Canal from July 2012 to June 2013. The annual sex ratio (Male:Female) of S. aspera was female biased with values of 1:1.25. Out of the four ovarian development stages of this crab, two stages were observed in the Suez Canal throughout the whole year. The ovigerous crab's carapace width varied from 28 to 52 mm. This crab species can spawn during most of the year in the canal water, with a peak during late spring and early winter. The fecundity of ovigerous females ranged between 2349 and 13600 eggs with a mean of 5494 +/- 1486 eggs. Female crabs that reached sexual maturity exhibited a minimum carapace width varying between 22 and 46 mm, and fifty percentage of all ovigerous females showed a carapace width of 36 mm. PMID- 26587009 TI - Adsorptive removal of cadmium ions by Spirulina platensis dry biomass. AB - Cadmium is one of the most toxic substances found in aquatic ecosystems. This metal tends to accumulate in photosynthetic plants and fish and is transferred to humans causing many diseases. It has to be removed from our environment to reduce any health risks. Dry biomass of the microalga (cyanobacterium) Spirulina platensis was used as biosorbent for the removal of cadmium ions (Cd(2+)) from aqueous solutions. The effects of different levels of pH (3-9), biomass concentration (0.25-2 g), temperature (18-46 degrees C), metal concentration (40 200 mg/l) and contact time (30-120 min) were tested. Batch cultures were carried out in triplicate in an orbital shaker at 150 rpm. After centrifuging the biomass, the remaining levels of cadmium ions were measured in the supernatant by Atomic Absorption Spectrometer. Very high levels of removal, reaching up to 87.69% were obtained. The highest percentage of removal was reached at pH 8, 2 g of biosorbent, 26 degrees C, and 60 mg/l of cadmium concentration after 90 min of contact time. Langmuir and Freundlich isotherm models were applied to describe the adsorption isotherm of the metal ions by S. platensis. Langmuir model was found to be in better correlation with experimental data (R (2) = 0.92). Results of this study indicated that S. platensis is a very good candidate for the removal of heavy metals from aquatic environments. The process is feasible, reliable and eco-friendly. PMID- 26587010 TI - Erratum to: Zn (II) and Cu (II) adsorption and retention onto iron oxyhydroxide nanoparticles: effects of particle aggregation and salinity. AB - [This corrects the article DOI: 10.1186/1467-4866-15-6.]. PMID- 26587011 TI - Comparison of targeted next-generation sequencing and Sanger sequencing for the detection of PIK3CA mutations in breast cancer. AB - BACKGROUND: Phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha, PIK3CA, is one of the most frequently mutated genes in breast cancer, and the mutation status of PIK3CA has clinical relevance related to response to therapy. The aim of our study was to investigate the mutation status of PIK3CA gene and to evaluate the concordance between NGS and SGS for the most important hotspot regions in exon 9 and 20, to investigate additional hotspots outside of these exons using NGS, and to correlate the PIK3CA mutation status with the clinicopathological characteristics of the cohort. METHODS: In the current study, next-generation sequencing (NGS) and Sanger Sequencing (SGS) was used for the mutational analysis of PIK3CA in 186 breast carcinomas. RESULTS: Altogether, 64 tumors had PIK3CA mutations, 55 of these mutations occurred in exons 9 and 20. Out of these 55 mutations, 52 could also be detected by Sanger sequencing resulting in a concordance of 98.4 % between the two sequencing methods. The three mutations missed by SGS had low variant frequencies below 10 %. Additionally, 4.8 % of the tumors had mutations in exons 1, 4, 7, and 13 of PIK3CA that were not detected by SGS. PIK3CA mutation status was significantly associated with hormone receptor-positivity, HER2-negativity, tumor grade, and lymph node involvement. However, there was no statistically significant association between the PIK3CA mutation status and overall survival. CONCLUSIONS: Based on our study, NGS is recommended as follows: 1) for correctly assessing the mutation status of PIK3CA in breast cancer, especially for cases with low tumor content, 2) for the detection of subclonal mutations, and 3) for simultaneous mutation detection in multiple exons. PMID- 26587012 TI - A quantitative shotgun proteomics analysis of germinated rice embryos and coleoptiles under low-temperature conditions. AB - BACKGROUND: At low temperatures, rice grains have a reduced germination rate and grow more slowly, which delays the emergence of rice seedlings from the paddy water surface and significantly increases seedling mortality. In this study, we conducted a shotgun proteomics analysis of geminated embryos and coleoptiles to compare the proteome expression pattern between the low-temperature resistant variety, Tong 88-7, and the low-temperature susceptible variety, Milyang 23. RESULTS: In a shotgun proteomics analysis of low-temperature resistant and susceptible embryos and coleoptiles in both cold and control temperatures, we discovered a total of 2626 non-redundant proteins, with a 0.01 false discovery rate. A comparison of protein expression patterns between resistant and susceptible embryos and coleoptiles under low-temperature and normal conditions revealed that 85 proteins and 196 proteins were expressed by the resistant and susceptible strains, respectively, in response to low temperature. Among them, 12 proteins overlapped. Proteins involved in stress responses, metabolism, and gene expression were expressed in both strains. CONCLUSIONS: Similar molecular functions of the response were detected, suggesting that the resistant and susceptible strain have a similar proteome response to cold temperatures. The resistance of Tong 88-7 to cold-water germination may result from the efficiency of these proteins, rather than activation of additional or different molecular processes. A comparison of protein expression between the resistant and susceptible strains' responses revealed that the more successful low-temperature germination of Tong 88-7 was associated with gibberellin signaling, protein trafficking, and the ABA-mediated stress response. PMID- 26587013 TI - Clinical utility of tadalafil in the treatment of pulmonary arterial hypertension: an evidence-based review. AB - Pulmonary arterial hypertension (PAH) is a chronic and disabling condition characterized by an elevated pulmonary vascular resistance and an elevated mean pulmonary arterial pressure. Despite recent improvements in treatment availability, PAH remains challenging to treat, burdensome for patients, and ultimately incurable. Tadalafil is a phos-phodiesterase-5 inhibitor that is administered once daily by mouth for the treatment of PAH. Current treatment guidelines recommend tadalafil as an option for patients with World Health Organization functional class II or III PAH. In a placebo-controlled clinical trial, patients taking tadalafil demonstrated significantly improved exercise capacity as measured by the 6-minute walk distance. Patients also experienced decreased incidence of clinical worsening, increased quality of life, and improved cardiopulmonary hemodynamics. Uncontrolled studies and smaller trials have indicated a possible role for tadalafil as a suitable alternative to sildenafil and as a beneficial add-on option when used in combination with other treatments for PAH. Tadalafil is generally safe and well tolerated. Adverse events are typically mild-to-moderate in intensity, and discontinuation rates are usually low. The purpose of this review is to provide an evidence-based evaluation of the clinical utility of tadalafil in the treatment of PAH. PMID- 26587014 TI - Computing interaction probabilities in signaling networks. AB - Biological networks inherently have uncertain topologies. This arises from many factors. For instance, interactions between molecules may or may not take place under varying conditions. Genetic or epigenetic mutations may also alter biological processes like transcription or translation. This uncertainty is often modeled by associating each interaction with a probability value. Studying biological networks under this probabilistic model has already been shown to yield accurate and insightful analysis of interaction data. However, the problem of assigning accurate probability values to interactions remains unresolved. In this paper, we present a novel method for computing interaction probabilities in signaling networks based on transcription levels of genes. The transcription levels define the signal reachability probability between membrane receptors and transcription factors. Our method computes the interaction probabilities that minimize the gap between the observed and the computed signal reachability probabilities. We evaluate our method on four signaling networks from the Kyoto Encyclopedia of Genes and Genomes (KEGG). For each network, we compute its edge probabilities using the gene expression profiles for seven major leukemia subtypes. We use these values to analyze how the stress induced by different leukemia subtypes affects signaling interactions. PMID- 26587016 TI - Therapeutic Actions of the Thiazolidinediones in Alzheimer's Disease. AB - Alzheimer's disease (AD) is a multifactorial metabolic brain disorder characterized by protein aggregates, synaptic failure, and cognitive impairment. In the AD brain is common to observe the accumulation of senile plaques formed by amyloid-beta (Abeta) peptide and the neurofibrillary tangles composed of modified tau protein, which both lead to cellular damage and progressive neurodegeneration. Currently, there is no effective therapy for AD; however several studies have shown that the treatments with the peroxisome proliferators activated receptor-gamma (PPARgamma) agonists known as thiazolidinedione drugs (TZDs), like rosiglitazone and pioglitazone, attenuate neurodegeneration and improve cognition in mouse models and patients with mild-to-moderate AD. Furthermore, studies on animal models have shown that TZDs inhibit neuroinflammation, facilitate amyloid-beta plaque clearance, enhance mitochondrial function, improve synaptic plasticity, and, more recently, attenuate tau hyperphosphorylation. How TZDs may improve or reduce these pathologic signs of AD and what the mechanisms and the implicated pathways in which these drugs work are are questions that remain to be answered. However, in this review, we will discuss several cellular targets, in which TZDs can be acting against the neurodegeneration. PMID- 26587017 TI - Explore Awareness of Information Security: Insights from Cognitive Neuromechanism. AB - With the rapid development of the internet and information technology, the increasingly diversified portable mobile terminals, online shopping, and social media have facilitated information exchange, social communication, and financial payment for people more and more than ever before. In the meantime, information security and privacy protection have been meeting with new severe challenges. Although we have taken a variety of information security measures in both management and technology, the actual effectiveness depends firstly on people's awareness of information security and the cognition of potential risks. In order to explore the new technology for the objective assessment of people's awareness and cognition on information security, this paper takes the online financial payment as example and conducts an experimental study based on the analysis of electrophysiological signals. Results indicate that left hemisphere and beta rhythms of electroencephalogram (EEG) signal are sensitive to the cognitive degree of risks in the awareness of information security, which may be probably considered as the sign to assess people's cognition of potential risks in online financial payment. PMID- 26587018 TI - Minimally Invasive Necrosectomy Techniques in Severe Acute Pancreatitis: Role of Percutaneous Necrosectomy and Video-Assisted Retroperitoneal Debridement. AB - Consensus advocating a principle of early organ support, nutritional optimisation, followed ideally by delayed minimally invasive intervention within a "step-up" framework where possible has radically changed the surgical approach to complications of acute pancreatitis in the last 20 years. The 2012 revision of the Atlanta Classification incorporates these changes, and provides a background which underpins the complexities of individual patient management decisions. This paper discusses the place for delayed minimally invasive surgical intervention (percutaneous necrosectomy, video-assisted retroperitoneal debridement (VARD)), and the rationale for opting to adopt a percutaneous approach over endoscopic or laparoscopic approaches in different clinical situations. PMID- 26587015 TI - Peroxisome Proliferator-Activated Receptors and the Heart: Lessons from the Past and Future Directions. AB - Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear family of ligand activated transcriptional factors and comprise three different isoforms, PPAR-alpha, PPAR-beta/delta, and PPAR-gamma. The main role of PPARs is to regulate the expression of genes involved in lipid and glucose metabolism. Several studies have demonstrated that PPAR agonists improve dyslipidemia and glucose control in animals, supporting their potential as a promising therapeutic option to treat diabetes and dyslipidemia. However, substantial differences exist in the therapeutic or adverse effects of specific drug candidates, and clinical studies have yielded inconsistent data on their cardioprotective effects. This review summarizes the current knowledge regarding the molecular function of PPARs and the mechanisms of the PPAR regulation by posttranslational modification in the heart. We also describe the results and lessons learned from important clinical trials on PPAR agonists and discuss the potential future directions for this class of drugs. PMID- 26587019 TI - Reduced Cardiovascular Capacity and Resting Metabolic Rate in Men with Prostate Cancer Undergoing Androgen Deprivation: A Comprehensive Cross-Sectional Investigation. AB - Objectives. To investigate if androgen deprivation therapy exposure is associated with additional risk factors for cardiovascular disease and metabolic treatment related toxicities. Methods. One hundred and seven men (42-89 years) with prostate cancer undergoing androgen deprivation therapy completed a maximal graded objective exercise test to determine maximal oxygen uptake, assessments for resting metabolic rate, body composition, blood pressure and arterial stiffness, and blood biomarker analysis. A cross-sectional analysis was undertaken to investigate the potential impact of therapy exposure with participants stratified into two groups according to duration of androgen deprivation therapy (<3 months and >=3 months). Results. Maximal oxygen uptake (26.1 +/- 6.0 mL/kg/min versus 23.2 +/- 5.8 mL/kg/min, p = 0.020) and resting metabolic rate (1795 +/- 256 kcal/d versus 1647 +/- 236 kcal/d, p = 0.005) were significantly higher in those with shorter exposure to androgen deprivation. There were no differences between groups for peripheral and central blood pressure, arterial stiffness, or metabolic profile. Conclusion. Three months or longer exposure to androgen deprivation therapy was associated with reduced cardiorespiratory capacity and resting metabolic rate, but not in a range of blood biomarkers. These findings suggest that prolonged exposure to androgen deprivation therapy is associated with negative alterations in cardiovascular outcomes. Trial registry is: ACTRN12609000200280. PMID- 26587020 TI - Four-Point Preprandial Self-Monitoring of Blood Glucose for the Assessment of Glycemic Control and Variability in Patients with Type 2 Diabetes Treated with Insulin and Vildagliptin. AB - The study explored the utility of four-point preprandial glucose self-monitoring to calculate several indices of glycemic control and variability in a study adding the DPP-4 inhibitor vildagliptin to ongoing insulin therapy. This analysis utilized data from a double-blind, randomized, placebo-controlled crossover study in 29 patients with type 2 diabetes treated with vildagliptin or placebo on top of stable insulin dose. During two 4-week treatment periods, self-monitoring of plasma glucose was undertaken at 4 occasions every day. Glucose values were used to assess several indices of glycemic control quality, such as glucose mean, GRADE, M-VALUE, hypoglycemia and hyperglycemia index, and indices of glycemic variability, such as standard deviation, CONGA, J-INDEX, and MAGE. We found that vildagliptin improved the glycemic condition compared to placebo: mean glycemic levels, and both GRADE and M-VALUE, were reduced by vildagliptin (P < 0.01). Indices also showed that vildagliptin reduced glycemia without increasing the risk for hypoglycemia. Almost all indices of glycemic variability showed an improvement of the glycemic condition with vildagliptin (P < 0.02), though more marked differences were shown by the more complex indices. In conclusion, the study shows that four-sample preprandial glucose self-monitoring is sufficient to yield information on the vildagliptin effects on glycemic control and variability. PMID- 26587021 TI - Measles Virus: Identification in the M Protein Primary Sequence of a Potential Molecular Marker for Subacute Sclerosing Panencephalitis. AB - Subacute Sclerosing Panencephalitis (SSPE), a rare lethal disease of children and young adults due to persistence of measles virus (MeV) in the brain, is caused by wild type (wt) MeV. Why MeV vaccine strains never cause SSPE is completely unknown. Hypothesizing that this phenotypic difference could potentially be represented by a molecular marker, we compared glycoprotein and matrix (M) genes from SSPE cases with those from the Moraten vaccine strain, searching for differential structural motifs. We observed that all known SSPE viruses have residues P64, E89, and A209 (PEA) in their M proteins whereas the equivalent residues for vaccine strains are either S64, K89, and T209 (SKT) as in Moraten or PKT. Through the construction of MeV recombinants, we have obtained evidence that the wt MeV-M protein PEA motif, in particular A209, is linked to increased viral spread. Importantly, for the 10 wt genotypes (of 23) that have had their M proteins sequenced, 9 have the PEA motif, the exception being B3, which has PET. Interestingly, cases of SSPE caused by genotype B3 have yet to be reported. In conclusion, our results strongly suggest that the PEA motif is a molecular marker for wt MeV at risk to cause SSPE. PMID- 26587022 TI - Evaluating Andrographolide as a Potent Inhibitor of NS3-4A Protease and Its Drug Resistant Mutants Using In Silico Approaches. AB - Current combination therapy of PEG-INF and ribavirin against the Hepatitis C Virus (HCV) genotype-1 infections is ineffective in maintaining sustained viral response in 50% of the infection cases. New compounds in the form of protease inhibitors can complement the combination therapy. Asunaprevir is new to the drug regiment as the NS3-4A protease inhibitor, but it is susceptible to two mutations, namely, R155K and D168A in the protein. Thus, in our study, we sought to evaluate Andrographolide, a labdane-diterpenoid from the Andrographis paniculata plant as an effective compound for inhibiting the NS3-4A protease as well as its concomitant drug-resistant mutants by using molecular docking and dynamic simulations. Our study shows that Andrographolide has best docking scores of -15.0862, -15.2322, and -13.9072 compared to those of Asunaprevir -3.7159, 2.6431, and -5.4149 with wild-type R155K and D168A mutants, respectively. Also, as shown in the MD simulations, the compound was good in binding the target proteins and maintains strong bonds causing very less to negligible perturbation in the protein backbone structures. Our results validate the susceptibility of Asunaprevir to protein variants as seen from our docking studies and trajectory period analysis. Therefore, from our study, we hope to add one more option in the drug regiment to tackle drug resistance in HCV infections. PMID- 26587023 TI - Development of a Portable Single Photon Ionization-Photoelectron Ionization Time of-Flight Mass Spectrometer. AB - A vacuum ultraviolet lamp based single photon ionization- (SPI-) photoelectron ionization (PEI) portable reflecting time-of-flight mass spectrometer (TOFMS) was designed for online monitoring gas samples. It has a dual mode ionization source: SPI for analyte with ionization energy (IE) below 10.6 eV and PEI for IE higher than 10.6 eV. Two kinds of sampling inlets, a capillary inlet and a membrane inlet, are utilized for high concentration and trace volatile organic compounds, respectively. A mass resolution of 1100 at m/z 64 has been obtained with a total size of 40 * 31 * 29 cm, the weight is 27 kg, and the power consumption is only 70 W. A mixture of benzene, toluene, and xylene (BTX), SO2, and discharging products of SF6 were used to test its performance, and the result showed that the limit of quantitation for BTX is as low as 5 ppbv (S/N = 10 : 1) with linear dynamic ranges greater than four orders of magnitude. The portable TOFMS was also evaluated by analyzing volatile organic compounds from wine and decomposition products of SF6 inside of a gas-insulated switchgear. PMID- 26587024 TI - Nosocomial Isolates and Their Drug Resistant Pattern in ICU Patients at National Institute of Neurological and Allied Sciences, Nepal. AB - Multidrug resistant organisms are increasing day by day and the cause is poorly known. This study was carried out from June 2011 to May 2012 at National Institute of Neurological and Allied Sciences Kathmandu, Nepal, with a view to determining drug resistant pathogens along with detection of extended spectrum beta-lactamase (ESBL), AmpC beta-lactamase (ABL), and metallo-beta-lactamase (MBL) producing bacteria causing infection to ICU patients. A standard methodology was used to achieve these objectives as per recommendation of American Society for Microbiology. ESBL was detected by combined disc assay using cefotaxime and cefotaxime clavulanic acid, ABL by inhibitor based method using cefoxitin and phenylboronic acid, and MBL by imipenem-EDTA combined disk method. Two hundred and ninety-four different clinical samples such as tracheal aspirates, urine, pus, swabs, catheter tips, and blood were processed during the study. Most common bacteria were Acinetobacter spp. Of the total 58 Acinetobacter spp., 46 (79%) were MDR, and 27% were positive for ABL and 12% were for MBL. Of the 32 cases of Staphylococcus aureus, 18 (56%) were MDR. Findings of this study warrant routine beta-lactamase testing in clinical isolates. PMID- 26587025 TI - Serum hCG Levels following the Ovulatory Injection: Associations with Patient Weight and Implantation Time. AB - Objective. To test if serum hCG levels the morning after the ovulatory hCG injection correlate with (1) retrieval efficiency, (2) oocyte maturity, (3) embryo quality, (4) pregnancy, and/or (5) time to implantation in patients undergoing in vitro fertilization (IVF) with intracytoplasmic sperm injection (ICSI). Design. Retrospective cohort analysis. Setting. University-based IVF clinic. Patient(s). All IVF/ICSI cycles from April 2005 to February 2008 whose hCG administration was confirmed (n = 472 patients). Intervention(s). Serum hCG was measured the morning following the ovulatory injection, on the 16th day following retrieval, and repeated on day 18 for those with positive results. Main Outcome Measure(s). Number of follicles on the day of hCG injection, number of oocytes retrieved, maturity of oocytes, embryo quality, pregnancy outcome, and time to implantation. Result(s). hCG levels did not correlate with retrieval efficiency, oocyte maturity, embryo quality, or pregnancy. Postinjection hCG levels were inversely associated with patient weight and time to implantation. Conclusion(s). No correlation was found between hCG level and any parameter of embryo quality. Patient weight affected hCG levels following hCG injection and during the early period of pregnancy following implantation. No association between postinjection hCG level and time of implantation (adjusted for patient weight) was apparent. PMID- 26587026 TI - Memory Profiles after Unilateral Paramedian Thalamic Stroke Infarction: A Comparative Study. AB - We performed extensive neuropsychological assessment of two male patients (matched for age and educational level) with similar (localization and size) unilateral paramedian ischemic thalamic lesions (AB on the left and SD on the right). Both patients showed severe memory impairments as well as other cognitive deficits. In comparison to SD, AB showed severe impairment of executive functions and a more severe deficit of episodic/anterograde memory, especially in the verbal modality. The findings of this single case study suggest the possibility that the profile and severity of the executive dysfunction are determinant for the memory deficits and depend on from the side of the lesion. In addition to a material-side-specific (verbal versus visual) deficit hypothesis, the differential diencephalo-prefrontal contributions in mnestic-processing, in case of paramedian thalamic stroke, might also be explained in terms of their stage specificity (encoding versus retrieval). PMID- 26587027 TI - Comment on "Trichobezoar Causing Airway Compromise during Esophagogastroduodenoscopy". PMID- 26587028 TI - Effect of Low Glycemic Index Diet Versus Metformin on Metabolic Syndrome. AB - BACKGROUND: Metabolic syndrome (MetS) continues to be highly prevalent and contributes to a rapidly growing problem worldwide. The most important therapeutic intervention for metabolic syndrome is diet modification, an intervention whose efficacy has been proven for metabolic syndrome. OBJECTIVES: The aim of the present study was to compare the effects of low glycemic index diet versus metformin on MetS components in adults with MetS. PATIENTS AND METHODS: Fifty-one adults with MetS participated in this randomized controlled clinical trial. Patients were randomly allocated to two groups of metformin and low glycemic index diet. The intervention period was eight weeks. The studied participants were compared at baseline and the end of the trial, regarding the following factors: weight, blood pressure, waist circumference, fasting blood sugar, hemoglobin A1c and lipid profiles (Triglyceride (TG), Total Cholesterol (TC), Low-Density Lipoprotein (LDL) cholesterol, and High-Density Lipoprotein (HDL) cholesterol). RESULTS: The anthropometric measurements, Fasting Blood Sugar (FBS), Hemoglobin A1c, serum lipid profiles (TG, TC, LDL-C, HDL-C) and lipoprotein ratio (LDL/HDL) showed a significant decrease after the intervention in both groups (P < 0.05). Comparison of the difference between the two groups was not significant, except for the mean reduction in FBS, which was more in the metformin group although this was not clinically significant. CONCLUSIONS: This study supports the assumption that low glycemic index diet as well as metformin can positively affect metabolic syndrome components. PMID- 26587029 TI - Hormone Inhibition During Mini-Puberty and Testicular Function in Male Rats. AB - BACKGROUND: The mini-pubertal period of almost six hours in neonatal male rats is thought to be an important stage in sexual development. OBJECTIVES: The aim of this study was to investigate the effect of hormone inhibition during mini puberty on testicular function in male rats. MATERIALS AND METHODS: We measured serum testosterone (T), luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in male rats at different time points after birth by enzyme linked immunosorbent assay (ELISA) and established a "no mini-puberty" model by ether inhalation. The mRNA expression levels of testicular androgen receptor (AR), insulin-like growth factor 3 (INSL3), anti-Mullerian hormone (AMH), and ghrelin were determined by real-time polymerase chain reaction (PCR) assays on postnatal days 45 and 75. Testicular tissue biopsies were stained with hematoxylin and eosin (H & E) and the structure, number and maturity of testis cells (including spermatogenic, Sertoli, and Leydig cells) were observed under microscopy at the same time. RESULTS: Serum T and LH levels peaked at two hours after birth, while FSH peaked at hour 0, and bilateral testicular weight peaked at four hours after birth. The rats that underwent ether inhalation five minutes after birth had markedly reduced serum hormone levels. The mini-puberty model group revealed visible morphologic alterations in the tests on postnatal day 45. Then, on postnatal day 75, the mRNA expression level of AMH significantly decreased (P < 0.05) in the same group. CONCLUSIONS: The inhibition of mini-puberty period in male rats was demonstrated to have an effect on their testicular function to some extent. PMID- 26587030 TI - Underestimating the Effect of Lipids on Cardiovascular Events: Regression Dilution Bias in the Population-Based Cohort of Tehran Lipid and Glucose Study. AB - BACKGROUND: Random errors in the measurement of risk factors lead to bias in the exposure-disease association. OBJECTIVES: This study aimed to examine the extent of underestimation in the association of total cholesterol (TC), high density lipoprotein cholesterol (HDL-C) and triglyceride (TG) with cardiovascular disease (CVDs) in the Tehran Lipid and Glucose Study. PATIENTS AND METHODS: Of 6327 eligible people in the original cohort followed for about 10 years to detect CVD events, 3063 (1224 men and 1839 women) had replicate measurements for blood lipids. Two regression dilution ratios were calculated by nonparametric and parametric methods, using replicate data from reexaminations three and six years after baseline. Adjusted and unadjusted hazard ratios (HR) were corrected for regression dilution bias. RESULTS: By parametric method, based on reexamination three years after baseline, the strength of real association of usual levels of TC, TG and HDL-C with cardiovascular disease, considering beta coefficients of related models, were underestimated about 42%, 51% and 81% in men and 40%, 43% and 62% in women, respectively. Underestimations were relatively independent of age, sex and body mass index. Correction for regression dilution bias led to more than 60% increase in estimated HR for TC adjusted for confounders. CONCLUSIONS: Using baseline measurements of lipids led to considerable underestimation in the association of these factors with CVD outcome in TLGS. The underestimation increased with time interval between baseline and follow-up measurements for TC and TG. TC had more attenuation on estimated HR due to stronger relation with CVD risk. PMID- 26587031 TI - Heating Process in Pasteurization and not in Sterilization Decreases the Iodine Concentration of Milk. AB - BACKGROUND: Iodine is a vital component of the thyroid hormones and is required for normal growth, development, and tissue metabolism in humans and animals. OBJECTIVES: This study for the first time compares the effects of heating during pasteurization and sterilization on the iodine concentration of milk for an adequate provision of dietary iodine. MATERIALS AND METHODS: This study was carried out on multiparous Holstein Friesian lactating cows. Thirty Holstein dairy cows were fed with a diet containing 10 mg of potassium iodide (KI) per kilogram dry matter of diet. Milk samples were obtained on days 4 and 2 before and again on days 2, 4, 6, and 8 after the inclusion of KI into the total mixed ration diet of the dairy cows. The milk samples were sterilized using ultra-high temperature, following which the effect of the heating process during sterilization on the cows' iodine concentration was compared to that in the only previous documented study from Iran in which milk supplementation with KI was the same as ours. Milk in that study was pasteurized via the high-temperature short time method, a method which involves temperatures in excess of 73 degrees C for durations longer than 15 seconds. RESULTS: The inclusion of KI in the diet of the dairy cows in these 2 separate experiments increased their milk iodine levels. Pasteurization decreased the iodine content of the milk (P < 0.05), while no significant difference was observed in the iodine concentration of the sterilized milk. CONCLUSIONS: The present study showed that the iodine concentration is not decreased during the heating process in sterilization, indicating that supplemented sterilized milk could be a good alternative vehicle for dietary iodine in the prevention of iodine deficiency. PMID- 26587032 TI - Hepatitis C Virus Infection in Iran; Viral Spread Routes in General Population and Safety Measures. PMID- 26587033 TI - FAS and FAS-Ligand Promoter Polymorphisms in Hepatitis B Virus Infection. AB - BACKGROUND: The FAS and FAS-Ligand (FASL) system is an important apoptosis pathway in the liver. The FAS-mediated pathway functions by binding the FASL on the activated cytotoxic T lymphocytes and Natural Killer (NK) cells to the FAS receptor on infected hepatocytes. FAS and FASL polymorphisms, which are related to apoptosis, might influence the outcome of Hepatitis B Virus (HBV) infection. OBJECTIVES: Thus, the present study aimed to determine if FAS and FASL promoter polymorphisms are associated with the clinical outcome of HBV infection. PATIENTS AND METHODS: DNA samples were obtained from the infected individuals including chronic carrier (n = 50), chronic hepatitis (n = 50), cirrhosis (n = 25), naturally recovered (n = 26) and compared with those of their matched healthy controls (n = 100). Genotyping for polymorphisms of FAS-670 A/G and -1377 G/A, and FASL -844 C/T was performed using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assays. RESULTS: Multiple analyses for genetic association of FAS and FASL polymorphisms were not statistically different between HBV patients (n = 125) and healthy controls (n = 100). However, genotype and allele frequencies of FASL-844 C/T were significantly different between recovered individuals and patients with cirrhosis (P = 0.02 and P=0.01, respectively). Whereas, FAS-670A/G and -1377G/A polymorphisms were similarly distributed in these two groups (P = 0.8 and P = 0.47, respectively). CONCLUSIONS: The current study results showed that bearing -844T allele in FASL promoter region has a protective effect on cirrhosis and is involved in recovery from infection. In conclusion, it is proposed that HBV infection outcome might be influenced by FASL-844C/T polymorphism through alteration in apoptosis of hepatocytes. PMID- 26587034 TI - Hepatic Shock Differential Diagnosis and Risk Factors: A Review Article. AB - CONTEXT: Liver as an important organ has a vital role in physiological processes in the body. Different causes can disrupt normal function of liver. Factors such as hypo-perfusion, hypoxemia, infections and some others can cause hepatic injury and hepatic shock. EVIDENCE ACQUISITION: Published research resources from 2002 to May 2015 in some databases (PubMed, Scopus, Index Copernicus, DOAJ, EBSCO CINAHL, Science direct, Cochrane library and Google scholar and Iranian search database like SID and Iranmedex) were investigated for the present study. RESULTS: Different causes can lead to hepatic shock. Most of these causes can be prevented by early resuscitation and treatment of underlying factors. CONCLUSIONS: Hepatic shock is detected in ill patients, especially those with hemodynamic disorders. It can be prevented by early treatment of underlying disease. There is no definite treatment for hepatic shock and should be managed conservatively. Hepatic shock in patients can increase the mortality rate. PMID- 26587035 TI - Identification and Characterization of Liver MicroRNAs of the Chinese Tree Shrew via Deep Sequencing. AB - BACKGROUND: Chinese tree shrew (Tupaia belangeri chinensis) is a small animal that possess many features, which are valuable in biomedical research, as experimental models. Currently, there are numerous attempts to utilize tree shrews as models for hepatitis C virus (HCV) infection. OBJECTIVES: This study aimed to construct a liver microRNA (miRNA) data of the tree shrew. MATERIALS AND METHODS: Three second filial generation tree shrews were used in this study. Total RNA was extracted from each liver of the tree shrew and equal quality mixed, then reverse-transcribed to complementary DNA (cDNA). The cDNAs were amplified by polymerase chain reaction and subjected to high-throughput sequencing. RESULTS: A total of 2060 conserved miRNAs were identified through alignment with the mature miRNAs in miRBase 20.0 database. The gene ontology and Kyoto encyclopedia of genes and genomes analyses of the target genes of the miRNAs revealed several candidate miRNAs, genes and pathways that may involve in the process of HCV infection. The abundance of miR-122 and Let-7 families and their other characteristics provided us more evidences for the utilization of this animal, as a potential model for HCV infection and other related biomedical research. Moreover, 80 novel microRNAs were predicted using the software Mireap. The top 3 abundant miRNAs were validated in other tree samples, based on stem loop quantitative reverse transcription-polymerase chain reaction. CONCLUSIONS: According to the liver microRNA data of Chinese tree shrew, characteristics of the miR-122 and Let-7 families further highlight the suitability of tree shrew as the animal model in HCV research. PMID- 26587037 TI - Extending the Debate on Poor Response to Hepatitis B Virus Vaccination in Children With Celiac Disease: Which Question Remains? PMID- 26587036 TI - Serum Levels of Annexin A2 as a Candidate Biomarker for Hepatic Fibrosis in Patients With Chronic Hepatitis B. AB - BACKGROUND: Hepatologists have studied serologic markers of liver injury for decades. Annexins are a prominent group of such markers and annexin A2 (AnxA2) is one of the best characterized annexins. AnxA2 inhibits HBV polymerase among other functions. Its expression is up-regulated in regenerative hepatocytes. OBJECTIVES: To determine if serum AnxA2 level has a role in estimating liver damage in chronic HBV infection and investigate whether AnxA2 levels correlate with hepatic fibrosis. PATIENTS AND METHODS: This study included 173 patients with chronic hepatitis B (CHB) and 51 healthy controls. Liver fibrosis was graded histologically on liver biopsy samples. Blood samples were taken from patients during biopsy and serum AnxA2 levels were measured with ELISA. RESULTS: In a group of adult patients with CHB, AnxA2 values were far higher than those of the control group (P = 0.001). When we assessed AnxA2 levels based on fibrosis stages, serum AnxA2 levels of patients with early stage fibrosis (stages 1 - 3) were significantly higher than those of patients with advanced stage fibrosis (stages 4 - 5; P = 0.001). CONCLUSIONS: AnxA2 is a useful biomarker for early stage fibrosis in patients with CHB. PMID- 26587038 TI - Genetic Variants in the SAMM50 Gene Create Susceptibility to Nonalcoholic Fatty Liver Disease in a Chinese Han Population. AB - BACKGROUND: Genome-wide association studies have shown that rs738491, rs2143571, and rs3761472 in the sorting and assembly machinery component 50 homolog (SAMM50) gene are significantly associated with susceptibility to nonalcoholic fatty liver disease (NAFLD). OBJECTIVES: The present study evaluated the association between the three genetic variants in the SAMM50 gene and susceptibility to NAFLD in a Chinese Han population. PATIENTS AND METHODS: Genotypes for 3 single nucleotide polymorphisms (SNPs), viz rs738491, rs2143571, and rs3761472, in the SAMM50 gene were determined using an improved multiplex ligation detection reaction technique in 340 B-type ultrasonography-diagnosed NAFLD patients and 452 healthy controls. Meanwhile, serum lipid profiles and liver enzymes were estimated using standard clinical laboratory methods. The SNP-SNP interactions were analyzed by performing multifactor dimensionality reduction (MDR) and generalized multifactor dimensionality reduction (GMDR). RESULTS: The genotype and allele frequencies of the SAMM50 polymorphisms between the NAFLD group and the control group were significantly different (all Ps < 0.05). In the multivariate analysis adjusted for gender, age, and body mass index, the carriers of the rs738491 T allele, rs2143571 A allele, and rs3761472 G allele had significantly increased susceptibility to NAFLD (OR, 1.507; 95% CI, 1.035 to 2.195; P = 0.032; OR, 1.761; 95% CI, 1.232 to 2.517; P = 0.002; OR, 1.483; 95% CI, 1.039 to 2.115; P = 0.030, respectively). Moreover, the rs738491 T allele carriers had significantly higher levels of alanine aminotransferase (ALT) (P = 0.017) than did the noncarriers. However, differences in the levels of serum triglyceride (TG) and aspartate aminotransferase (AST) were not statistically significant (P = 0.123; P = 0.107). The Rs2143571 A allele and the rs3761472 G allele were both deeply associated with increased levels of serum TG, ALT, and AST (all Ps < 0.05). Furthermore, the MDR and GMDR showed that a synergistic relationship might exist between rs738491, rs2143571, and rs3761472 in the SAMM50 gene and the pathophysiology and genetics of NAFLD. CONCLUSIONS: We first demonstrated that the rs738491 T allele, rs2143571 A allele, and rs3761472 G allele in the SAMM50 gene created susceptibility to NAFLD in a Chinese Han population. The combination of the three SNPs in the SAMM50 gene may have synergism to predict the predisposition to NAFLD. PMID- 26587039 TI - Effect of Aerobic and Resistance Exercise Training on Liver Enzymes and Hepatic Fat in Iranian Men With Nonalcoholic Fatty Liver Disease. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) has different prevalence rates in various parts of the world and is a risk factor for diabetes and cardiovascular disease that could progress to nonalcoholic steatohepatitis, cirrhosis, and liver failure. OBJECTIVES: The current study aimed to investigate the effect of Aerobic Training (AT) and resistance training (RT) on hepatic fat content and liver enzyme levels in Iranian men. PATIENTS AND METHODS: In a randomized clinical trial study, 30 men with clinically defined NAFLD were allocated into three groups (aerobic, resistance and control). An aerobic group program consisted of 45 minutes of aerobic exercise at 60% - 75% maximum heart rate intensity, a resistance group performed seven resistance exercises at intensity of 50% - 70% of 1 repetition maximum (1RM ) and the control group had no exercise training program during the study. Before and after training, anthropometry, insulin sensitivity, liver enzymes and hepatic fat were elevated. RESULTS: After training, hepatic fat content was markedly reduced, to a similar extent, in both the aerobic and resistance exercise training groups (P <= 0.05). In the two exercise training groups, alanine amino transferase and aspartate amino transferase serum levels were significantly decreased compared to the control group (P = 0.002) and (P = 0.02), respectively. Moreover, body fat (%), fat mass (kg), homeostasis model assessment insulin resistance (HOMI-IR) were all improved in the AT and RT. These changes in the AT group were independent of weight loss. CONCLUSIONS: This study demonstrated that RT and AT are equally effective in reducing hepatic fat content and liver enzyme levels among patients with NAFLD. However, aerobic exercise specifically improves NAFLD independent of any change in body weight. PMID- 26587040 TI - G1896A Precore Mutation and Association With HBeAg Status, Genotype and Clinical Status in Patients With Chronic Hepatitis B. AB - BACKGROUND: Precore stop codon (G1896A) mutation is one of the commonest mutations found in patients with chronic hepatitis B. However, over the years, this mutation was not reported much in Malaysia. OBJECTIVES: We therefore investigated the presence of G1896A mutation in Malaysian population and its association with HBeAg status, clinical stage, hepatitis B virus (HBV) genotype and e-seroconversion rate. PATIENTS AND METHODS: Serum samples from 93 patients confirmed as hepatitis B carriers were collected for molecular assay. The whole genome of HBV was amplified by polymerase chain reaction and directly sequenced. The precore and basal core promoter regions were analyzed for presence of mutations. RESULTS: The most commonly observed mutation in the precore region was C1858T with 64.5% prevalence. The precore mutation of interest (G1896A) was identified in 25.8% of isolates. The basal core promoter mutations detected were A1762T-G1764A (26.9%), C1653T (8.6%), A1752G (10.8%) and C1766T (2.2%). No significant association was observed between G1896A mutation and HBeAg negativity. Nonetheless, G1896A was highly prevalent among HBV genotype B. Clinical association revealed that subjects with G1896A mutations were mainly detected in asymptomatic chronic hepatitis B (58.3%) and liver cirrhosis (41.7%). One subject was diagnosed with fulminant hepatitis (4.2%) and 8.3% had hepatocellular carcinoma (HCC). CONCLUSIONS: Our data suggested an intermediate prevalence of G1896A mutation among Malaysian hepatitis B carriers. The stop codon mutation has a significant association with genotype B and patients with chronic hepatitis B and liver cirrhosis. PMID- 26587041 TI - The Association of Ala133Ser Polymorphism and Methylation in Ras Association Domain Family 1A Gene With Unfavorable Prognosis of Hepatocellular Carcinoma. AB - BACKGROUND: The functional and prognostic significance of Ras association domain family 1A gene (RASSF1A) on hepatocellular carcinoma (HCC) has not been well characterized. OBJECTIVES: This study aimed to investigate the association between Ala133Ser polymorphism or promoter methylation in RASSF1A and the prognosis of HCC in Nantong City, one of the areas with the highest incidence of cancer in China. PATIENTS AND METHODS: Using peripheral blood plasma, the incidence rate of RASSF1A Ala133Ser in 235 controls and subjects with 260 HCC was analyzed by the polymerase chain reaction and sequencing. We further investigated the RASSF1A methylation status in HCC and corresponding peri-tumorous normal tissues using the methylation-specific polymerase chain reaction approach. RESULTS: It was found that the frequency of the RASSF1A Ala133Ser T allele (Ala/Ser and Ser/Ser) genotype in HCC cases was observably higher than that of normal subjects (P < 0.001). In comparison to the Ala/Ala genotype, the T allele genotype improved the susceptibility to HCC. The study also found that RASSF1A methylation improves the risk of HCC. Furthermore, in contrast with the corresponding peri-tumorous normal tissues, we observed that the RASSF1A methylation status was markedly higher in HCC tissues (P < 0.001). The Kaplan Meier and multivariate analyses suggested that the poor survival of HCC patients was closely connected with hepatocirrhosis, Barcelona Clinic Liver Cancer stage, Edmondson division, RASSF1A methylation and Ala133Ser polymorphism (P < 0.001). CONCLUSIONS: The polymorphism and promoter methylation of RASSF1A may be a significant factor in HCC, and can be an indicator for poor prognosis in patients with HCC. PMID- 26587042 TI - Prevalence of Hepatitis B, Hepatitis C and HIV and Related Risk Factors in Contact Sportsmen in Zanjan: A Letter to Editor. PMID- 26587044 TI - Microbial and Heavy Metal Contaminant of Antidiabetic Herbal Preparations Formulated in Bangladesh. AB - The aim of the current study was to evaluate microbial contamination in terms of microbial load (total aerobic count and total coliform count) and specific pathogenic bacteria (Salmonella spp., Escherichia coli, particularly Escherichia coli 0157) in thirteen antidiabetic herbal preparations (ADHPs) from Dhaka City. All the thirteen ADHPs had been found contaminated with fungi and different pathogenic bacteria. From the data, it is found that only two of these preparations (ADHP-1 and ADHP-12) complied with the safety limit (as stated in different Pharmacopoeias and WHO guidelines) evaluated by all different microbial counts. None of these herbal preparations could assure the safety as all of them were contaminated by fungi. The overall safety regarding heavy metal content (Zn, Cu, Mn, Cr, Cd, and Pb) was assured as none of them exceeded the safety limit of the daily intake. Microbial contaminants in these herbal preparations pose a potential risk for human health and care should be taken in every step involved in the preparation of these herbal preparations to assure safety. PMID- 26587043 TI - MicroRNAs' Involvement in Osteoarthritis and the Prospects for Treatments. AB - Osteoarthritis (OA) is a chronic disease and its etiology is complex. With increasing OA incidence, more and more people are facing heavy financial and social burdens from the disease. Genetics-related aspects of OA pathogenesis are not well understood. Recent reports have examined the molecular mechanisms and genes related to OA. It has been realized that genetic changes in articular cartilage and bone may contribute to OA's development. Osteoclasts, osteoblasts, osteocytes, and chondrocytes in joints must express appropriate genes to achieve tissue homeostasis, and errors in this can cause OA. MicroRNAs (miRNAs) are small noncoding RNAs that have been discovered to be overarching regulators of gene expression. Their ability to repress many target genes and their target-binding specificity indicate a complex network of interactions, which is still being defined. Many studies have focused on the role of miRNAs in bone and cartilage and have identified numbers of miRNAs that play important roles in regulating bone and cartilage homeostasis. Those miRNAs may also be involved in the pathology of OA, which is the focus of this review. Future studies on the role of miRNAs in OA will provide important clues leading to a better understanding of the mechanism(s) of OA and, more particularly, to the development of therapeutic targets for OA. PMID- 26587045 TI - Salutary Effects of Cepharanthine against Skeletal Muscle and Kidney Injuries following Limb Ischemia/Reperfusion. AB - Limb ischemia/reperfusion (I/R) causes oxidation and inflammation and subsequently induces muscle and kidney injuries. Cepharanthine, a natural plant alkaloid, possesses anti-inflammatory and antioxidative properties. We elucidated the salutary effects of cepharanthine against muscle and kidney injuries following limb I/R. Adult male rats were randomized to receive I/R or I/R plus cepharanthine. I/R was achieved by applying tourniquet high around each thigh for 3 hours followed by reperfusion for 24 hours. Cepharanthine (10 mg/kg, intraperitoneal) was injected immediately before reperfusion. After euthanization, degrees of tissue injury, inflammation, and oxidation were examined. Our data revealed that the I/R group had significant increases in injury biomarker concentrations of muscle (creatine kinase and lactate dehydrogenase) and kidney (creatinine, neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1). Histological assays revealed moderate muscle and kidney injury characteristics in the I/R group. The I/R group also had significant increases in concentrations of inflammatory molecules (interleukin-6, macrophage inflammatory protein-2, and prostaglandin E2) and reactive nitrogen species (nitric oxide) as well as lipid peroxidation (malondialdehyde). Of note, these effects of limb I/R could be mitigated by cepharanthine. These data confirmed that cepharanthine attenuated muscle and kidney injuries induced by limb I/R. The mechanisms may involve its anti-inflammatory and antioxidative capacities. PMID- 26587046 TI - Association between Albuminuria and Different Body Constitution in Type 2 Diabetes Patients: Taichung Diabetic Body Constitution Study. AB - Objective. Albuminuria in type 2 diabetes mellitus (T2DM) patients increases the risk of diabetic nephropathy, the leading cause of end-stage renal disease worldwide. Because albuminuria is modifiable, identifying relevant risk factors could facilitate prevention and/or management. This cross-sectional study investigated whether body constitution (BC) independently predicts albuminuria. Method. Patients with T2DM (n = 846) received urinalysis, a blood test, and diabetic retinopathy examination. Albuminuria was defined by an elevated urinary albumin/creatinine ratio (>=30 MUg/mg). BC type (Yang deficiency, Yin deficiency, and Phlegm stasis) was assessed using a body constitution questionnaire (BCQ). Traditional risk factors for albuminuria were also recorded. Odds ratios (ORs) of albuminuria for BC were estimated using multivariate logistic regression. Results. Albuminuria was more prevalent in patients with Yang deficiency or Phlegm stasis (both P < 0.01). After adjustment, patients with both Yang deficiency and Phlegm stasis exhibited a significantly higher risk of albuminuria (OR = 3.037; 95% confidence interval = 1.572-5.867, and P < 0.001). Conclusion. BC is strongly associated with albuminuria in T2DM patients. Using a BCQ to assess BC is noninvasive, convenient, and inexpensive and can provide information for health care professionals to identify T2DM patients who are at a high risk of albuminuria. PMID- 26587048 TI - Gastrodin Reduces Blood Pressure by Intervening with RAAS and PPARgamma in SHRs. AB - Gastrodin is a bioactive compound extracted from traditional Chinese medicine, Gastrodia elata Bl. It has a definite effect on reducing blood pressure in hypertensive patients. However, the mechanisms of gastrodin in lowering blood pressure still remain unclear. In this study, 4 weeks of administration of gastrodin (100 mg/kg/d intraperitoneally injected) decreased the systolic blood pressure (SBP) in spontaneously hypertensive rats (SHRs) (190.2 +/- 8.9 versus 169.8 +/- 6.4, P < 0.01). Among SHRs receiving gastrodin treatment, angiotensin II (Ang II) and aldosterone (ALD) in serum were significantly decreased (2022.1 +/- 53.0 versus 1528.7 +/- 93.9, 213.33 +/- 35.17 versus 179.65 +/- 20.31, and P < 0.01, P < 0.05, resp.) and dramatically downregulated expression of angiotensin type 1 receptor (AT1R) (4.9 +/- 0.9 versus 2.6 +/- 0.9, P < 0.05) in myocardium in both mRNA and protein levels compared with their corresponding groups without gastrodin treatment. Additionally, gastrodin increased the mRNA expression (0.18 +/- 0.07 versus 0.82 +/- 0.10, P < 0.01) and protein synthesis (0.40 +/- 0.10 versus 0.34 +/- 0.10, P < 0.01) of peroxisome proliferator-activated receptor gamma (PPARgamma) in myocardium tissues. Overall, our data demonstrated that gastrodin was able to decrease the SBP in SHR. Furthermore, this study showed that gastrodin intervened with the renin-angiotensin-aldosterone system (RAAS) and PPARgamma effectively, which indicates its antihypertensive mechanism. PMID- 26587047 TI - Plant-Derived Compounds Targeting Pancreatic Beta Cells for the Treatment of Diabetes. AB - Diabetes is a global health problem and a national economic burden. Although several antidiabetic drugs are available, the need for novel therapeutic agents with improved efficacy and few side effects remains. Drugs derived from natural compounds are more attractive than synthetic drugs because of their diversity and minimal side effects. This review summarizes the most relevant effects of various plant-derived natural compounds on the functionality of pancreatic beta cells. Published data suggest that natural compounds directly enhance insulin secretion, prevent pancreatic beta cell apoptosis, and modulate pancreatic beta cell differentiation and proliferation. It is essential to continuously investigate natural compounds as sources of novel pharmaceuticals. Therefore, more studies into these compounds' mechanisms of action are warranted for their development as potential anti-diabetics. PMID- 26587049 TI - Correlates of the Quality of life of Adolescents in families affected by HIV/AIDS in Benue State, Nigeria. AB - It was estimated that over 260,000 children are living with HIV/AIDS while close to 2 million are directly or indirectly affected by the disease in Nigeria. Improvements in treatments for infected children have been documented in the literature but there is a gross knowledge gap on the impact of HIV/AIDS on the quality of life and psychosocial functioning (PSF) of affected children in Nigeria. We comparatively explored the association of quality of life with PSF and other factors among adolescents in families affected by HIV/AIDS (FAHA) and in families not affected by HIV/AIDS (FNAHA). Data was extracted for 960 adolescents from a State wide cross-sectional study in which participants were selected through multistage sampling techniques. Data was collected using questionnaires consisting of demographic information, adapted WHO-QOL BREF and the Strength & Difficulty Questionnaire (SDQ). The quality of life scores were categorized into Poor, Moderate and High based on the amount of standard deviation away from the mean while the SDQ scores were categorized into normal, borderline and abnormal based on the SDQ scoring systems. Chi-square test and independent t-test were used for bivariate analyses while logistic regression was used for multivariate analyses at 5% level of significance. Proportion with poor quality of life (27.0%) was significantly higher among adolescents in FAHA than in FNAHA (p=0.0001). Adolescents in FAHA (OR:2.32; 95%CI:1.67-4.09) were twice more likely to have poor quality of life than those in FNAHA. In FAHA, adolescents on the borderline of PSF (OR:2.19; 95%CI:1.23-3.89) were twice more likely to have poor quality of life than those with normal PSF. Adolescents in FAHA have poorer quality of life than those in FNAHA and also face additional burdens of psychosocial dysfunctions. Interventions focusing on functional social support and economic empowerment will benefit adolescents in FAHA in the studied location. PMID- 26587051 TI - An Overview of Biomolecular Event Extraction from Scientific Documents. AB - This paper presents a review of state-of-the-art approaches to automatic extraction of biomolecular events from scientific texts. Events involving biomolecules such as genes, transcription factors, or enzymes, for example, have a central role in biological processes and functions and provide valuable information for describing physiological and pathogenesis mechanisms. Event extraction from biomedical literature has a broad range of applications, including support for information retrieval, knowledge summarization, and information extraction and discovery. However, automatic event extraction is a challenging task due to the ambiguity and diversity of natural language and higher-level linguistic phenomena, such as speculations and negations, which occur in biological texts and can lead to misunderstanding or incorrect interpretation. Many strategies have been proposed in the last decade, originating from different research areas such as natural language processing, machine learning, and statistics. This review summarizes the most representative approaches in biomolecular event extraction and presents an analysis of the current state of the art and of commonly used methods, features, and tools. Finally, current research trends and future perspectives are also discussed. PMID- 26587052 TI - Early weaning in idiopathic scoliosis. AB - BACKGROUND: Many years of bracing represent a burden to the patients. Early weaning may be the result of poor compliance, but may also be planned in patients with a long expected treatment time and a reduced stable primary curve during bracing. The aim of the present cohort study was to compare curve size, health related quality of life and surgical rates at long-term follow-up after ordinary bracing, planned and unplanned early weaning. METHODS: Three hundred eighty-one patients (353 girls/28 boys) with late-onset juvenile (n = 30) and adolescent (n = 351) idiopathic scoliosis and a mean primary major curve of 33.1 (range 20-57) degrees were treated with Boston brace and followed prospectively. RESULTS: Ordinary brace treatment was completed in 290 (76 %) patients, planned early weaning at bone age <14 years in 59 (16 %), and unplanned early weaning in 32 (8 %), while 14 (5 %), 1 (2 %), and 12 (38 %) had surgery, respectively. Forty-eight (81 %) of the patients had a primary curve <= 25 degrees at planned early weaning. Six-teen (27 %) of those who had planned early weaning, resumed bracing after a mean time of 2.0 years. The mean curve size at long-term follow-up in average 23.4 years after weaning, was smaller (p < 0.001) in patients with planned early weaning (25.1 degrees ) compared with ordinary bracing (34.0 degrees ) and unplanned early weaning (34.8 degrees ). Patient satisfaction and self-image at long-term was better in the planned early weaning group (p < 0.05), but differences were small. CONCLUSION: The benefit of planned early weaning was the shortened bracing time and good clinical results. This procedure may be attempted if curve reduction is stable over time and the primary curve is 25 degrees or less in patients with several years of expected bracing. The patients should be monitored carefully and regularly at 4-6 months intervals until maturity, and a new brace should be prepared if the curve increases significantly. PMID- 26587050 TI - Refining the approach to vaccines against influenza A viruses with pandemic potential. AB - Vaccination is the most effective strategy for prevention and control of influenza. Timely production and deployment of seasonal influenza vaccines is based on an understanding of the epidemiology of influenza and on global disease and virologic surveillance. Experience with seasonal influenza vaccines guided the initial development of pandemic influenza vaccines. A large investment in pandemic influenza vaccines in the last decade has resulted in much progress and a body of information that can now be applied to refine the established paradigm. Critical and complementary considerations for pandemic influenza vaccines include improved assessment of the pandemic potential of animal influenza viruses, proactive development and deployment of pandemic influenza vaccines, and application of novel platforms and strategies for vaccine production and administration. PMID- 26587053 TI - Occult fractures of the proximal femur: imaging diagnosis and management of 82 cases in a regional trauma center. AB - BACKGROUND: Occult hip fractures are often difficult to identify in busy trauma units. We aimed to present our institutions experience in the diagnosis and treatment of occult fractures around the hip and to help define a clinical and radiological management algorithm. METHOD: We conducted a seven-year retrospective hospital medical record analysis. The electronic database was searched for ICD-10 CM codes S72.0 and S72.1 used for proximal femoral fractures upon patient discharge. We identified 34 (4.83 %) femoral neck fractures and 48 (4.42 %) trochanteric fractures labeled as occult. RESULTS: The majority of the cases were diagnosed by primary MRI scan (57.4 %) and 12 were diagnosed by emergency CT scan (14.6 %). For the remaining cases the final diagnosis was confirmed by 72 h CT scan in 9 patients (representing 39 % of the false negative cases) or by MRI in the rest of 14 patients. MRI was best at detecting incomplete pertrochanteric fracture patterns (13.45 % of total) and incomplete fractures of the greater trochanter (3.65 % of total) respectively. It also detected the majority of Garden I femoral neck fractures (20.7 % of total). CT scanning accurately detected 100 % of Garden 2 fractures (2.44 %) and 25 % (3.65 %) of the complete pertrochanteric fractures (false negative 25 %). CONCLUSION: Occult fractures should be suspected in all patients with traumatic onset of hip pain that is inconsistent with normal radiographic findings. MRI is the golden standard but not as readily available not as cheap and not quite as quick to perform as as a CT scan. The latter which in turn can provide falsely negative results in the first 24 h. Improved imaging protocols could expedite management and improve treatment. PMID- 26587054 TI - PyPedia: using the wiki paradigm as crowd sourcing environment for bioinformatics protocols. AB - BACKGROUND: Today researchers can choose from many bioinformatics protocols for all types of life sciences research, computational environments and coding languages. Although the majority of these are open source, few of them possess all virtues to maximize reuse and promote reproducible science. Wikipedia has proven a great tool to disseminate information and enhance collaboration between users with varying expertise and background to author qualitative content via crowdsourcing. However, it remains an open question whether the wiki paradigm can be applied to bioinformatics protocols. RESULTS: We piloted PyPedia, a wiki where each article is both implementation and documentation of a bioinformatics computational protocol in the python language. Hyperlinks within the wiki can be used to compose complex workflows and induce reuse. A RESTful API enables code execution outside the wiki. Initial content of PyPedia contains articles for population statistics, bioinformatics format conversions and genotype imputation. Use of the easy to learn wiki syntax effectively lowers the barriers to bring expert programmers and less computer savvy researchers on the same page. CONCLUSIONS: PyPedia demonstrates how wiki can provide a collaborative development, sharing and even execution environment for biologists and bioinformaticians that complement existing resources, useful for local and multi center research teams. AVAILABILITY: PyPedia is available online at: http://www.pypedia.com. The source code and installation instructions are available at: https://github.com/kantale/PyPedia_server. The PyPedia python library is available at: https://github.com/kantale/pypedia. PyPedia is open source, available under the BSD 2-Clause License. PMID- 26587055 TI - Effective management of attention-deficit/hyperactivity disorder (ADHD) through structured re-assessment: the Dundee ADHD Clinical Care Pathway. AB - Attention-deficit/hyperactivity disorder (ADHD) has become a major aspect of the work of child and adolescent psychiatrists and paediatricians in the UK. In Scotland, Child and Adolescent Mental Health Services were required to address an increase in referral rates and changes in evidence-based medicine and guidelines without additional funding. In response to this, clinicians in Dundee have, over the past 15 years, pioneered the use of integrated psychiatric, paediatric, nursing, occupational therapy, dietetic and psychological care with the development of a clearly structured, evidence-based assessment and treatment pathway to provide effective therapy for children and adolescents with ADHD. The Dundee ADHD Clinical Care Pathway (DACCP) uses standard protocols for assessment, titration and routine monitoring of clinical care and treatment outcomes, with much of the clinical work being nurse led. The DACCP has received international attention and has been used as a template for service development in many countries. This review describes the four key stages of the clinical care pathway (referral and pre-assessment; assessment, diagnosis and treatment planning; initiating treatment; and continuing care) and discusses translation of the DACCP into other healthcare systems. Tools for healthcare professionals to use or adapt according to their own clinical settings are also provided. PMID- 26587056 TI - Segmental paleotetraploidy revealed in sterlet (Acipenser ruthenus) genome by chromosome painting. AB - BACKGROUND: Acipenseriformes take a basal position among Actinopteri and demonstrate a striking ploidy variation among species. The sterlet (Acipenser ruthenus, Linnaeus, 1758; ARUT) is a diploid 120-chromosomal sturgeon distributed in Eurasian rivers from Danube to Enisey. Despite a high commercial value and a rapid population decline in the wild, many genomic characteristics of sterlet (as well as many other sturgeon species) have not been studied. RESULTS: Cell lines from different tissues of 12 sterlet specimens from Siberian populations were established following an optimized protocol. Conventional cytogenetic studies supplemented with molecular cytogenetic investigations on obtained fibroblast cell lines allowed a detailed description of sterlet karyotype and a precise localization of 18S/28S and 5S ribosomal clusters. Localization of sturgeon specific HindIII repetitive elements revealed an increased concentration in the pericentromeric region of the acrocentric ARUT14, while the total sterlet repetitive DNA fraction (C0t30) produced bright signals on subtelomeric segments of small chromosomal elements. Chromosome and region specific probes ARUT1p, 5, 6, 7, 8 as well as 14 anonymous small sized chromosomes (probes A-N) generated by microdissection were applied in chromosome painting experiments. According to hybridization patterns all painting probes were classified into two major groups: the first group (ARUT5, 6, 8 as well as microchromosome specific probes C, E, F, G, H, and I) painted only a single region each on sterlet metaphases, while probes of the second group (ARUT1p, 7 as well as microchromosome derived probes A, B, D, J, K, M, and N) marked two genomic segments each on different chromosomes. Similar results were obtained on male and female metaphases. CONCLUSIONS: The sterlet genome represents a complex mosaic structure and consists of diploid and tetraploid chromosome segments. This may be regarded as a transition stage from paleotetraploid (functional diploid) to diploid genome condition. Molecular cytogenetic and genomic studies of other 120- and 240 chromosomal sturgeons are needed to reconstruct genome evolution of this vertebrate group. PMID- 26587057 TI - Chemozart: a web-based 3D molecular structure editor and visualizer platform. AB - BACKGROUND: Chemozart is a 3D Molecule editor and visualizer built on top of native web components. It offers an easy to access service, user-friendly graphical interface and modular design. It is a client centric web application which communicates with the server via a representational state transfer style web service. Both client-side and server-side application are written in JavaScript. A combination of JavaScript and HTML is used to draw three dimensional structures of molecules. RESULTS: With the help of WebGL, three dimensional visualization tool is provided. Using CSS3 and HTML5, a user-friendly interface is composed. More than 30 packages are used to compose this application which adds enough flexibility to it to be extended. Molecule structures can be drawn on all types of platforms and is compatible with mobile devices. No installation is required in order to use this application and it can be accessed through the internet. This application can be extended on both server-side and client-side by implementing modules in JavaScript. Molecular compounds are drawn on the HTML5 Canvas element using WebGL context. CONCLUSIONS: Chemozart is a chemical platform which is powerful, flexible, and easy to access. It provides an online web-based tool used for chemical visualization along with result oriented optimization for cloud based API (application programming interface). JavaScript libraries which allow creation of web pages containing interactive three dimensional molecular structures has also been made available. The application has been released under Apache 2 License and is available from the project website https://chemozart.com. PMID- 26587058 TI - A new compound heterozygosis for inactivating mutations in the glucokinase gene as cause of permanent neonatal diabetes mellitus (PNDM) in double-first cousins. AB - BACKGROUND: Permanent neonatal diabetes mellitus (PNDM) is a rare disorder, characterized by uncontrolled hyperglycemia diagnosed during the first 6 months of life. In general, PNDM has a genetic origin and most frequently it results from heterozygous mutations in KCNJ11, INS and ABCC8 genes. Homozygous or compound heterozygous inactivating mutations in GCK gene as cause of PNDM are rare. In contrast, heterozygosis for GCK inactivating mutations is frequent and results in the maturity-onset diabetes of young (MODY), manifested by a mild fasting hyperglycemia usually detected later in life. Therefore, as an autosomal recessive disorder, GCK-PNDM should be considered in families with history of glucose intolerance or MODY in first relatives, especially when consanguinity is suspected. RESULTS: Here we describe two patients born from non-consanguineous parents within a family. They presented low birth weight with persistent hyperglycemia during the first month of life. Molecular analyses for KCNJ11, INS, ABCC8 did not show any mutation. GCK gene sequencing, however, revealed that both patients were compound heterozygous for two missense combined in a novel GCK-PNDM genotype. The p.Asn254His and p.Arg447Gly mutations had been inherited from their mothers and fathers, respectively, as their mothers are sisters and their fathers are brothers. Parents had been later diagnosed as having GCK-MODY. CONCLUSIONS: Mutations' in silico analysis was carried out to elucidate the role of the amino acid changes on the enzyme structure. Both p.Asn254His and p.Arg447Gly mutations appeared to be quite damaging. This is the first report of GCK-PNDM in a Brazilian family. PMID- 26587059 TI - The Effectiveness of Corticosteroid Injection for De Quervain's Stenosing Tenosynovitis (DQST): A Systematic Review and Meta-Analysis. AB - De Quervain's stenosing tenosynovitis (DQST) treatments include corticosteroid injection around the tendon sheath; however there is some ambiguity concerning the efficacy of this treatment. The aim of this systematic review and meta analysis is to examine the totality of evidence relating to the use of corticosteroid injection in DQST when compared to placebo or other active treatments. A systematic literature search was conducted in July 2014. Only randomized control trials (RCTs) were included. Outcome measures included impairment, activity limitation and participation restriction. Five RCTs were identified with 165 patients, 88 in the treatment group and 77 in the control group.Patients who received corticosteroid injection (n=142) had a higher rate of resolution of symptoms [RR 2.59, 95% CI: 1.25 to 5.37, p=0.05, I2=62%]. This group reported greater pain relief as assessed by Visual Analogue Scale (VAS) at first assessment [mean difference -2.51, 95% CI: -3.11 to -1.90, p=0.0003, I2=65%] and demonstrated a statistically significant improvement in function (n=78) as measured by the DASH score and Dutch AIMS-HFF score [SMD -0.83, 95% CI: -1.54 to -0.12, p=0.02, I2=48]. This review confirms that corticosteroid injection results in a statistically significant increase in resolution of symptoms, pain relief and increased function in the treatment of DQST. PMID- 26587060 TI - Bacterial and Hematological Findings in Infected Total Hip Arthroplasties in Norway Assessment of 278 Revisions Due to Infection in the Norwegian Arthroplasty Register. AB - Our aim was to assess the bacterial findings in infected total hip arthroplasties (THAs) in Norway. We also wanted to investigate the relationship between causal bacteria and hematological findings. Revisions reported to the Norwegian Arthroplasty Register (NAR) due to infection after total hip arthroplasty during the period 1993 through September 2007 were identified. One single observer visited ten representative hospitals where clinical history, preoperative blood samples and the bacterial findings of intraoperative samples were collected. Bacterial growth in two or more samples was found in 278 revisions, and thus included. The following bacteria were identified: Coagulase-negative staphylococci (CoNS) (41%), Staphylococcus aureus (S. aureus) (19%), streptococci (11%), polymicrobial infections (10%), enterococci (9%), Gram-negative bacteria (6%) and others (4%). CoNS were the most common bacteria throughout the period but in the acute postoperative infections (< 3 weeks) S. aureus was the most frequent bacterial finding. We found no change in the distribution of the bacterial groups over time. S. aureus appears correlated with a higher C-reactive protein value (CRP) (mean 140 (95% Confidence interval (CI): 101-180)) than CoNS (mean 42 (CI: 31-53)). S. aureus also correlated with a higher erythrocyte sedimentation rate value (ESR) (mean 67 (CI: 55-79)) than CoNS (mean 47 (CI: 39 54)). PMID- 26587061 TI - The Effect of Foam Rolling Duration on Hamstring Range of Motion. AB - Musculoskeletal health benefits from flexibility training and maintaining a functional, or sport specific, range of motion is important to one's overall fitness. Commercial foam rollers are commonly used in gyms, therapy clinics and homes, yet data are lacking on the optimal rolling duration and effect on range of motion. PURPOSE: The purpose of this study was to examine the effect of varied durations of a commercial foam roller treatment on hamstring range of motion. METHODS: The knee extension range of motion of 33 college aged men and women (age= 20+/-1.5y, mass= 72.2+/-10.8 kg) was assessed after a short (2 sets of 10s) and long (4 sets of 30s) duration of hamstring self-administered myofascial release using a commercial foam roller. A one way ANOVA was performed to compare the mean knee extension angle for each condition to baseline measures. RESULTS: Results indicated that neither the short duration (67.30 +/- 10.60 deg) nor long duration (67.41 +/- 10.81 deg) rolling condition produced significant increases in knee extension compared to baseline (67.70 +/- 9.90 deg). CONCLUSION: Self administered foam rolling for a total duration of up to 2 minutes is not adequate to induce improvements in knee joint flexibility. Contributing factors may include the amount of pressure imparted by the commercial roller as well as duration of treatment. PMID- 26587062 TI - Editorial The Role of Surgery in Osteoarthritis, Rheumatoid Arthritis and Ankylosing Spondylitis. PMID- 26587064 TI - A Novel Minimally Invasive Technique for Treatment of Unicameral Bone Cysts. AB - Management of unicameral bone cysts (UBC) remain controversial. These cysts seldom heal spontaneously or even after pathological fracture. Sometimes these cysts can be very large and incredibly troublesome to the patient. Various treatments exist with variable success rates. We present our experience of treating these lesions by continuous drainage. Over a seven year period, six patients with unicameral bone cysts were treated by inserting a modified drain into the wall of the cyst. The aim of surgery was to place the drain in a dependent area of the cyst, through the cortex allowing for continuous drainage. This was achieved through a small incision under radiographic control. A cement restrictor (usually used for femoral canal plugging during total hip replacements) was modified and inserted to prevent closure of the drain site. A redivac drain was passed through the plug into the cyst. The drain was left in place for a week to establish an epithelialized pathway which hopefully would remain patent, into the subcutaneous tissues, after the drain had been removed. There were four males and two females in the group and the age range was 6 -12 years. Four of the lesions were in the upper humerus, one in the proximal femur and the other one in the proximal tibia. Healing was rated according to the modified Neer classification. Grade 1 (healed) and Grade 2 (healed with defect) was defined as excellent outcome. Persistent /Recurrent cysts (Grade 3 and 4) were noted as unsatisfactory. Five cases were completely healed. Only one had a further fracture and there were no recurrent fractures. All the patients reported complete comfort and they all were able to re-engage in recreational activities without restriction. We think that reducing the intra-medullary pressure in these lesions will lead to healing. We report a safe and minimally invasive technique for the management of UBC. PMID- 26587065 TI - First Metatarsalphalangeal Joint Arthrodesis: A Retrospective Comparison of Two Methods of Fixation. AB - First metatarsalphalangeal joint arthrodesis is a well established and successful treatment; however there still remains controversy over the best choice of construct. We performed a retrospective study of patients undergoing first metatarsalphalangeal fusion over eighteen months (n=52) using either dorsal non locking plate with additional compression lag screw fixation or dorsal non locking plate alone. We found when assessing clinical criteria, patients with dorsal non-locking plates and additional compression lag screw fixation had a significantly higher rate of fusion (100% vs 77.8%), significantly higher rate of fusion within the first two months (55.6% vs 83.3%), significantly earlier time to fusion (52.2 days vs 75.6 days), and significantly lower rate of non-union (0% vs 22.2%). When blindly assessing radiographic criteria, the patients treated with the plate and compression screw had a significantly higher rate of fusion and lower rate of non-union (0% vs 33%). There was no statistically significant difference between the frequencies of complications in the groups. We believe that the interfragmentary compression is a crucial factor in achieving good union rates and recommend the use of non-locking pre-contoured plating with additional interfragmentary compression screw as the fixation method of choice for these procedures. PMID- 26587063 TI - Acute Osteochondral Fractures in the Lower Extremities - Approach to Identification and Treatment. AB - Chondral and osteochondral fractures of the lower extremities are important injuries because they can cause pain and dysfunction and often lead to osteoarthritis. These injuries can be misdiagnosed initially which may impact on the healing potential and result in poor long-term outcome. This comprehensive review focuses on current pitfalls in diagnosing acute osteochondral lesions, potential investigative techniques to minimize diagnostic errors as well as surgical treatment options. Acute osteochondral fractures are frequently missed and can be identified more accurately with specific imaging techniques. A number of different methods can be used to fix these fractures but attention to early diagnosis is required to limit progression to osteoarthritis. These fractures are common with joint injuries and early diagnosis and treatment should lead to improved long term outcomes. PMID- 26587066 TI - A Literature Review of Total Hip Arthroplasty in Patients with Ankylosing Spondylitis: Perioperative Considerations and Outcome. AB - Ankylosing spondylitis is a spondyloarthropathy affecting the sacro-iliac joints with subsequent progression to the spine and the hip joints. The hip joints are affected by synovitis, enthesial inflammation, involvement of medullary bone, progressive degeneration and secondary osteoarthritis. Clinical presentation is usually in the form of pain and stiffness progressing to disabling fixed flexion contractures and in some instances, complete ankylosis. Hip arthroplasty should be considered for hip pain, postural and functional disability, or pain in adjacent joints due to hip stiffness. We conducted a literature review to determine peri-operative considerations and outcome in ankylosing spondylitis patients undergoing hip arthroplasty. In this review, we have discussed pre operative surgical planning, thromboprophylaxis, anaesthetic considerations and heterotopic ossification. Outcomes of arthroplasty include range of movement, pain relief, survivorship and complications. PMID- 26587067 TI - Current Controversies of Alignment in Total Knee Replacements. AB - Total knee replacement is an increasingly popular operation for end stage knee arthritis. In the majority it alleviates pain and improves function. However up to 20% of patients remain dissatisfied, even with well-aligned and secure implants. Restoration of a neutral mechanical axis has traditionally been strived for, to improve both function and implant survival and there is historical data to support this. More recently this view has been questioned and some surgeons are trying to improve the function and outcomes by moving away from standard alignment principles in an attempt to reproduce the kinematics of the pre arthritic knee of that individual. Others are using computers, robots and patient specific guides to improve accuracy. This article aims to review the traditional alignment concept and the newer techniques, along with the evidence behind it. PMID- 26587068 TI - Current Evidence for the Use of Laminar Flow in Reducing Infection Rates in Total Joint Arthroplasty. AB - Since the introduction of laminar air flow in orthopaedic theatres by Sir John Charnley, it has widely become accepted as the standard during orthopaedic procedures such as joint arthroplasty. We present a review of available current literature for the use of laminar flow operating theatre ventilation during total joint arthroplasty and examines the effectiveness of laminar flow ventilated operating theatres in preventing post-operative wound infection. Results of our findings suggest that while bacterial and air particulate is reduced by laminar air flow systems, there is no conclusive effect on the reduction of post operative wound infections following total joint arthroplasty. We conclude that a combination of strict aseptic technique, prophylactic antibiotics and good anaesthetic control during surgery remains crucial to reduce post-operative surgical infections. PMID- 26587069 TI - Bilateral Simultaneous Total Knee Arthroplasty: A Patient-Matched Retrospective Observational Study. AB - Bilateral total knee arthroplasty can be performed either as a staged or simultaneous procedure. We conducted a retrospective comparative study to compare the need for transfusion, the length of procedure, the length of stay, and complications of bilateral simultaneous knee arthroplasty with those of unilateral knee arthroplasty. Sixty-nine patients who underwent bilateral simultaneous knee arthroplasty procedures were compared with a matched control group of 69 patients who underwent unilateral knee arthroplasty. Receiver Operating Characteristic (ROC) curve was used to determine optimum cut-off values. Both groups of patients had a similar age and gender distribution, preoperative haemoglobin and ASA scores. Cumulative transfusion episodes were lower in the bilateral group than twice that of the unilateral group. In multivariate analysis the preoperative haemoglobin level and bilateral procedures were independent factors predicting the need for transfusion. The average length of procedure and length of hospital stay in the bilateral group was less than twice than that of the unilateral group. Advanced age and bilateral procedures were independent predictors of prolonged length of stay. A haemoglobin level of 12.5 g/dL and age of 70 were most suitable cut-off points to predict need for transfusion and occurrence of medical complications respectively. We conclude that bilateral simultaneous knee arthroplasties are safe and cost effective in appropriately selected patients. We recommend avoiding bilateral simultaneous procedures in patients over the age of 70 years and with significant comorbidities. PMID- 26587070 TI - Single Stage Knee Arthroplasty Revision Surgery: A Systematic Review of the Literature. AB - Total Knee Arthroplasty is an increasingly common procedure and revision surgery, particularly for infection, is associated with significant morbidity and healthcare costs. The current gold standard is a two stage revision procedure but single stage revision is increasingly being used in some departments to improve patient outcomes. We conducted a systematic review of the literature to determine the up-to-date evidence underlying the use of a single stage knee approach in revision surgery. A total of 12 studies were included in this review amounting to 433 revision surgeries. This is the largest review of single stage knee revision surgery. The procedures described were heterogenous and included the 'two-in-one' technique as well as other single stage revision procedures. There were also differences in implants and antibiotic regimens. The mean re-infection rates described in 10 studies was 9.4% (range 0-19.2%) after a mean follow-up of 40.3 months (range 7-180 months). The re-infection rates in the studies published over the last 30 years are falling, and this is not accounted for by any significant change in duration of follow-up during this period. The outcome scores varied, but patients generally showed an improvement. The Knee Society Score and the Oxford Knee Score were the most commonly used in five and three studies respectively. We conclude that the current evidence for single stage revision is variable and there is a lack of good quality evidence to address whether single stage revisions is thorough enough to eradicate deep infection and is able to restore adequate function. There is a need for larger prospective studies with standardised procedures and protocol, and with adequate follow-up. Till then, patients considered for a single stage approach should be thoroughly assessed and the surgery should be performed by a senior surgeon with experience in single stage knee revisions. PMID- 26587071 TI - Impact of Weekend Physiotherapy Service on the Cost Effectiveness of Elective Orthopaedic Hip and Knee Arthroplasty. AB - We performed a prospective correlational study to evaluate the efficiency and cost effectiveness of weekend physiotherapy in accelerating rehabilitation, reducing hospital stay as well as hospital costs for joint arthroplasty patients in a busy Scottish district general hospital. Patients that underwent elective hip (470) and knee (321) arthroplasty were analysed over a 12 month period. A four month period with weekend physiotherapy provision was arranged to ascertain its effectiveness on the length of stay and the achievement of set physiotherapy milestones. Data collected included length of stay and progression in a defined set of physiotherapy milestones. The relationship between time to discharge, mobilisation with sticks, straight leg raise, 90o knee flexion and cost effectiveness of service were used to determine the correlation, and analysis of the interactions of these factors separately. Our Outcome data demonstrate a statistical significance for the time to mobilisation with two sticks for hip (p=0.0030) and knee (p= 0.0037) arthroplasty patients. There was a trend towards earlier discharge times for all patients receiving weekend physiotherapy, but this was not statistically significant. We conclude that the provision of a continuous programme of weekend physiotherapy for all arthroplasty patients has the potential benefit of a quicker rehabilitation that would results in a cost saving. PMID- 26587072 TI - Risk Factors of Cardiovascular Diseases in HIV/AIDS Patients on HAART. AB - BACKGROUND: The introduction and widespread use of combination antiretroviral therapy referred to as highly active antiretroviral therapy (HAART) in the mid 1990's, has led HIV-infected individuals to experience a dramatic decline in immunodeficiency-related events and death. There is growing concern on metabolic complications associated with HIV and HAART which may increase cardiovascular risk and disease. The aim of this study was to investigate the cardiovascular risk profile of HIV/AIDS patients receiving HAART and those not receiving HAART at HIV/AIDS treatment centres in the South West Region of Cameroon. METHODS: Consenting participants, who had been receiving HAART, were compared with HAART naive participants. A questionnaire was administered; anthropometric and blood pressure measurements were recorded under standard conditions. Blood samples were obtained for the determination of plasma glucose and lipid levels. RESULTS: Two hundred and fifteen participants were recruited, 160 (74.4%) were on HAART and 55 (25.6%) were HAART naive. Among the individual lipid abnormalities, increased total cholesterol was the most prevalent (40.0%). Participants on HAART were significantly about 8 times at risk of developing hypercholesterolemia when compared to the HAART inexperienced group (OR 8.17; 95% CI: 3.31-20.14; p<0.001). Hypertension had a prevalence of 25.6% (95% CI: 15.3%-35.9%) and was about 2 times significantly higher in the HAART treated than the HAART untreated group (p=0.033). The prevalence of low HDL-c was significantly higher in males (24.1%) compared to females (11.2%) (p=0.0196). Many females (27.3%) were obese compared to males (7.4%) (p=0.0043). HAART use and treatment duration of more than five years were significantly associated with higher prevalence of CVD risk factors. CONCLUSION: HAART treatment was associated with significantly higher prevalence of hypercholesterolemia, increased LDL-c and hypertension, hence the risk of cardiovascular diseases. PMID- 26587073 TI - Editorial Physical Activity and HIV in Africa. PMID- 26587074 TI - Cardiac Disease and HIV in Africa: A Case for Physical Exercise. AB - AIDS-related deaths and new HIV infections have declined globally, but continue to be a major problem in Africa. Prior to the advent of antiretroviral treatment (ART) HIV patients died of immunodeficiency and associated opportunistic infections; Highly Active Antiretroviral Therapy (HAART) has resulted in increased survival of these patients and has transformed this illness into a chronic condition. Cardiovascular, respiratory, neurological and muscular problems interfere with exercise in HIV-infected patients. Particularly cardiovascular disease may be associated with direct damage by the virus, by antiretroviral therapy and by malnutrition and chronic lung disease, resulting in physical and psychological impairment. Recent studies have shown the benefits of exercise training to improvement of physiologic and functional parameters, with the gains being specific to the type of exercise performed. Exercise should be recommended to all HIV patients as an effective prevention and treatment for metabolic and cardiovascular syndromes associated with HIV and HAART exposure in sub-Saharan Africa. PMID- 26587075 TI - A Systematic Review of the Effects of Exercise Interventions on Body Composition in HIV+ Adults. AB - Over the years, physical activity and exercise have been used to positively impact the health and quality of life of persons infected with HIV and, more recently, has been associated with a spectrum of body composition changes. The aim of this review was to examine the effects of various exercise interventions on body composition in HIV positive adults, using a search strategy of randomized, controlled trials (RCTs). A systematic review was performed by five independent reviewers using a predetermined protocol adapted from previous research for assessing the articles for inclusion, the extracted data, and methodological quality. Eight RCTs involving 430 (26% female) HIV positive adults performing exercise a minimum of thrice weekly for at least six weeks were finally selected: Four were progressive resistance training (PRT) studies, three were aerobic training (AT) studies, and one involved yoga. In the PRT studies, there were significant increases in three anthropometric measures, namely, body mass, sum of skinfolds and sum of limb girths. In the AT studies, significant decreases were found in seven anthropometric measures, namely, body mass index, waist-hip ratio, body mass, triceps skinfold, waist circumference and sum of skinfolds. With yoga, the changes were non-significant. Exercise contributes to improved body composition and, when applied safely, appears to be beneficial for adults living with HIV/AIDS. However, these findings should be interpreted cautiously due to the relatively few RCTs published to date. Future studies would benefit from increased attention to sample size, female participants, participant follow-up, complete statistical analysis and intention-to-treat analysis. PMID- 26587076 TI - Effects of a 2-Year Supervised Exercise Program Upon the Body Composition and Muscular Performance of HIV-Infected Patients. AB - BACKGROUND: There is a lack of research investigating long-term effects of exercise training upon the body composition and muscle function in HIV-infected patients (PHIV). The study investigated the influence of a 2-year supervised exercise program on body composition and strength of PHIV under highly active antiretroviral therapy (HAART). METHODS: A training program including aerobic, strength and flexibility exercises was performed by 27 PHIV (17 men/ 10 women; age: 48.7+/-7.0 years; HAART: 150.7+/-65.3 months) during 1 year and 18 PHIV (10 men/ 8 women; age: 50.6+/-5.2 years; HAART: 176.6+/-53.1 months) during 2 years. Body composition and knee isokinetic strength were assessed at baseline and at the end of each year of intervention. RESULTS: Body composition remained stable along the whole experiment vs baseline (1-year - total muscle mass: Delta men=1.1%, P=0.21; Delta women=1.4%, P=0.06; trunk fat: Delta men=-0.1%, P=0.65; Delta women=-1.5%, P=0.45; 2 years - total muscle mass: Delta men=2.7%, P=0.54; Delta women=-1.9%, P=0.71; trunk fat: Delta men=4.4%, P=0.96; Delta women=10.0%, P=0.30). After 1-year, peak torque increased in men (Delta extension=4.2%, P=0.01; Delta flexion=12.2%, P=0.04) and total work reduced in women (Delta extension=-15.4%, P=0.01, Delta flexion=-17.5%, P=0.05). All strength markers remained stable vs baseline after 2 years of intervention (P>0.05). Only men showed significant reduction in the risk of disability due to sarcopenia (P=0.05) after 1 year of intervention, which remained stable after 2 years. CONCLUSION: Long-term exercise training preserved strength and muscle mass in PHIV under HAART. Exercise programs should be part of HIV therapy to prevent sarcopenia of this population along the years. TRIAL REGISTRATION: ACTRN12610000683033; UTN U1111-1116-4416. PMID- 26587077 TI - Effect of Different Types of Exercise in HIV + Mozambican Women Using Antiretroviral Therapy. AB - The aim of this study was to evaluate and compare the effect of two types of exercises interventions on the regularity and health-related physical fitness in HIV-infected individuals who use antiretroviral therapy (ART). A total of 53 HIV+ African women (mean age=39.5+/-8.4 years) on ART participated in the study. Subjects were randomly divided into 3 groups, namely, formal exercise (FEG), playful exercise (PEG) and control (CG). During 12 weeks, the exercise groups underwent a program of 1-hour duration with a frequency of 3 times a week. The FEG performed a protocol that included 20 minutes of exercise, cycling at 60 % of VO2peak, increasing to 75 % and 85 % in the 4th and 8th weeks, respectively, and a muscular endurance circuit consisted of 6 exercises at 15 repetitions per minute (RM). The PEG followed a program consisting of active games. Before and after the intervention the participants were submitted to a clinical evaluation including immunological parameters (CD4+), cardiovascular risk factors, physical fitness and anthropometry. Comparison of somatic variables before and after the program showed no exercise effect. Immunological and cardiovascular variables were also independent of the exercise group. The main effect was found in cardiorespiratory fitness: exercise groups increased significantly in VO2peak (FEG=14.7 %; PEG=11.1 %) with no significant differences in CG. The percentage of high attendance was identical between the two groups. It was concluded that there is no contraindication for exercise in this type of population and the beneficial effect was mainly in cardiorespiratory fitness, regardless of the type of exercise performed. PMID- 26587078 TI - Social-Ecological, Motivational and Volitional Factors for Initiating and Maintaining Physical Activity in the Context of HIV. AB - Sport and exercise can have several health benefits for people living with HIV. These benefits can be achieved through different types of physical activity, adapting to disease progression, motivation and social-ecological options. However, physical activity levels and adherence to exercise are generally low in people living with HIV. At the same time, high drop-out rates in intervention studies are prevalent; even though they often entail more favourable conditions than interventions in the natural settings. Thus, in the framework of an intervention study, the present study aims to explore social-ecological, motivational and volitional correlates of South African women living with HIV with regard to physical activity and participation in a sport and exercise health promotion programme. The qualitative data was produced in the framework of a non randomised pre-post intervention study that evaluated structure, processes and outcomes of a 10-week sport and exercise programme. All 25 participants of the programme were included in this analysis, independent of compliance. Data was produced through questionnaires, participatory group discussions, body image pictures, research diaries and individual semi-structured interviews. All participants lived in a low socioeconomic, disadvantaged setting. Hence, the psychological correlates are contextualised and social-ecological influences on perception and behaviour are discussed. The results show the importance of considering social-cultural and environmental influences on individual motives, perceptions and expectancies, the fear of disclosure and stigmatisation, sport and exercise-specific group dynamics and self-supporting processes. Opportunities and strategies to augment physical activity and participation in sport and exercise programmes in the context of HIV are discussed. PMID- 26587079 TI - Scribe Impacts on Provider Experience, Operations, and Teaching in an Academic Emergency Medicine Practice. AB - INTRODUCTION: Physicians dedicate substantial time to documentation. Scribes are sometimes used to improve efficiency by performing documentation tasks, although their impacts have not been prospectively evaluated. Our objective was to assess a scribe program's impact on emergency department (ED) throughput, physician time utilization, and job satisfaction in a large academic emergency medicine practice. METHODS: We evaluated the intervention using pre- and post-intervention surveys and administrative data. All site physicians were included. Pre- and post intervention data were collected in four-month periods one year apart. Primary outcomes included changes in monthly average ED length of stay (LOS), provider specific average relative value units (RVUs) per hour (raw and normalized to volume), self-reported estimates of time spent teaching, self-reported estimates of time spent documenting, and job satisfaction. We analyzed data using descriptive statistics and appropriate tests for paired pre-post differences in continuous, categorical, and ranked variables. RESULTS: Pre- and post-survey response rates were 76.1% and 69.0%, respectively. Most responded positively to the intervention, although 9.5% reported negative impressions. There was a 36% reduction (25%-50%; p<0.01) in time spent documenting and a 30% increase (11% 46%, p<0.01) in time spent in direct patient contact. No statistically significant changes were seen in job satisfaction or perception of time spent teaching. ED volume increased by 88 patients per day (32-146, p=0.04) pre- to post- and LOS was unchanged; rates of patients leaving against medical advice dropped, and rates of patients leaving without being seen increased. RVUs per hour increased 5.5% and per patient 5.3%; both were statistically significant. No statistically significant changes were seen in patients seen per hour. There was moderate correlation between changes in ED volume and changes in productivity metrics. CONCLUSION: Scribes were well received in our practice. Documentation time was substantially reduced and redirected primarily to patient care. Despite an ED volume increase, LOS was maintained, with fewer patients leaving against medical advice but more leaving without being seen. RVUs per hour and per patient both increased. PMID- 26587080 TI - Identifying Patient Door-to-Room Goals to Minimize Left-Without-Being-Seen Rates. AB - INTRODUCTION: Emergency department (ED) patients in the leave-without-being-seen (LWBS) group risk problems of inefficiency, medical risk, and financial loss. The goal at our hospital is to limit LWBS to <1%. This study's goal was to assess the influence on LWBS associated with prolonging intervals between patient presentation and placement in an exam room (DoorRoom time). This study's major aim was to identify DoorRoom cutoffs that maximize likelihood of meeting the LWBS goal (i.e. <1%). METHODS: We conducted the study over one year (8/13-8/14) using operations data for an ED with annual census~50,000. For each study day, the LWBS endpoint (i.e. was LWBS<1%: "yes or no") and the mean DoorRoom time were recorded. We categorized DoorRoom means by intervals starting with <=10min and ending at >60 min. Multivariate logistic regression was used to assess for DoorRoom cutoffs predicting high LWBS, while adjusting for patient acuity (triage scores and admission %) and operations parameters. We used predictive marginal probability to assess utility of the regression-generated cutoffs. We defined statistical significance at p<0.05 and report odds ratio (OR) and 95% confidence intervals (CI). RESULTS: Univariate results suggested a primary DoorRoom cutoff of 20', to maintain a high likelihood (>85%) of meeting the LWBS goal. A secondary DoorRoom cutoff was indicated at 35', to prevent a precipitous drop-off in likelihood of meeting the LWBS goal, from 61.1% at 35' to 34.4% at 40'. Predictive marginal analysis using multivariate techniques to control for operational and patient-acuity factors confirmed the 20' and 35' cutoffs as significant (p<0.001). Days with DoorRoom between 21-35' were 74% less likely to meet the LWBS goal than days with DoorRoom<=20' (OR 0.26, 95% CI [0.13-0.53]). Days with DoorRoom>35' were a further 75% less likely to meet the LWBS goal than days with DoorRoom of 21-35' (OR 0.25, 95% CI [0.15-0.41]). CONCLUSION: Operationally useful DoorRoom cutoffs can be identified, which allow for rational establishment of performance goals for the ED attempting to minimize LWBS. PMID- 26587081 TI - Identify-Isolate-Inform: A Modified Tool for Initial Detection and Management of Middle East Respiratory Syndrome Patients in the Emergency Department. AB - Middle East respiratory syndrome (MERS) is a novel infectious disease caused by a coronavirus (MERS-CoV) first reported in Saudi Arabia in September 2012. MERS later spread to other countries in the Arabian Peninsula, followed by an outbreak in South Korea in 2015. At least 26 countries have reported MERS cases, and these numbers may increase over time. Due to international travel opportunities, all countries are at risk of imported cases of MERS, even if outbreaks do not spread globally. Therefore, it is essential for emergency department (ED) personnel to be able to rapidly assess MERS risk and take immediate actions if indicated. The Identify-Isolate-Inform (3I) tool, originally conceived for initial detection and management of Ebola virus disease patients in the ED and later adjusted for measles, can be adapted for real-time use for any emerging infectious disease. This paper reports a modification of the 3I tool for use in initial detection and management of patients under investigation for MERS. Following an assessment of epidemiologic risk factors, including travel to countries with current MERS transmission and contact with patients with confirmed MERS within 14 days, patients are risk stratified by type of exposure coupled with symptoms of fever and respiratory illness. If criteria are met, patients must be immediately placed into airborne infection isolation (or a private room until this type of isolation is available) and the emergency practitioner must alert the hospital infection prevention and control team and the local public health department. The 3I tool will facilitate rapid categorization and triggering of appropriate time-sensitive actions for patients presenting to the ED at risk for MERS. PMID- 26587082 TI - Tuberculoma-Induced Seizures. AB - Seizures in human immunodeficiency virus (HIV) patients can be caused by a wide variety of opportunistic infections, and, especially in developing countries, tuberculosis (TB) should be high on the differential. In India, TB is the most common opportunistic infection in HIV and it can have several different central nervous system manifestations, including intracranial tuberculomas. In this case, an HIV patient presenting with new-onset seizure and fever was diagnosed with tuberculous meningitis and multiple intracranial tuberculomas. The patient received standard TB medications, steroids, and anticonvulsants in the emergency department and was admitted for further care. PMID- 26587083 TI - Diagnosis of Aortic Dissection in Emergency Department Patients is Rare. AB - INTRODUCTION: Aortic dissection is a rare event. While the most frequent symptom is chest pain, that is a common emergency department (ED) chief complaint and other diseases causing chest pain occur much more often. Furthermore, 20% of dissections are without chest pain and 6% are painless. For these reasons, diagnosing dissections may be challenging. Our goal was to determine the number of total ED and atraumatic chest pain patients for every aortic dissection diagnosed by emergency physicians. METHODS: DESIGN: Retrospective cohort. SETTING: 33 suburban and urban New York and New Jersey EDs with annual visits between 8,000 and 80,000. PARTICIPANTS: Consecutive patients seen by emergency physicians from 1-1-1996 through 12-31-2010. OBSERVATIONS: We identified aortic dissection and atraumatic chest pain patients using the International Classification of Diseases 9th Revision and Clinical Modification codes. We then calculated the number of total ED and atraumatic chest pain patients for every aortic dissection, along with 95% confidence intervals (CIs). RESULTS: From a database of 9.5 million ED visits, we identified 782 aortic dissections or one for every 12,200 (95% CI [11,400-13,100]) visits. The mean age of dissection patients was 66+/-16 years and 38% were female. There were 763,000 (8%) with atraumatic chest pain diagnoses. Thus, there is one dissection for every 980 (95% CI [910-1,050]) atraumatic chest pain patients. CONCLUSION: The diagnosis of aortic dissections by emergency physicians is rare and challenging. An emergency physician seeing 3,000 to 4,000 patients a year would diagnose an aortic dissection approximately every three to four years. PMID- 26587084 TI - Not Just an Urban Phenomenon: Uninsured Rural Trauma Patients at Increased Risk for Mortality. AB - INTRODUCTION: National studies of largely urban populations showed increased risk of traumatic death among uninsured patients, as compared to those insured. No similar studies have been done for major trauma centers serving rural states. METHODS: We performed retrospective analyses using trauma registry records from adult, non-burn patients admitted to a single American College of Surgeons certified Level 1 trauma center in a rural state (2003-2010, n=13,680) and National Trauma Data Bank (NTDB) registry records (2002-2008, n=380,182). Risk of traumatic death was estimated using multivariable logistic regression analysis. RESULTS: We found that 9% of trauma center patients and 27% of NTDB patients were uninsured. Overall mortality was similar for both (~4.5%). After controlling for covariates, uninsured trauma center patients were almost five times more likely to die and uninsured NTDB patients were 75% more likely to die than commercially insured patients. The risk of death among Medicaid patients was not significantly different from the commercially insured for either dataset. CONCLUSION: Our results suggest that even with an inclusive statewide trauma system and an emergency department that does not triage by payer status, uninsured patients presenting to the trauma center were at increased risk of traumatic death relative to patients with commercial insurance. PMID- 26587085 TI - Treatment Failure Outcomes for Emergency Department Patients with Skin and Soft Tissue Infections. AB - INTRODUCTION: Skin and soft tissue infections (SSTIs) are commonly evaluated in the emergency department (ED). Our objectives were to identify predictors of SSTI treatment failure within one week post-discharge in patients with cutaneous abscesses, as well as to identify predictors of recurrence within three months in that proportion of participants. METHODS: This was a sub-analysis of a parent study, conducted at two EDs, evaluating a new, nucleic acid amplification test (NAAT) for Staphylococcus aureus in ED patients. Patients>=18 years receiving incision and drainage (I&D) were eligible. Patient-reported outcome data on improvement of fever, swelling, erythema, drainage, and pain were collected using a structured abstraction form at one week, one month, and three months post ED visit. RESULTS: We enrolled 272 participants (20 from a feasibility study and 252 in this trial), of which 198 (72.8%) completed one-week follow up. Twenty-seven additional one-week outcomes were obtained through medical record review rather than by the one-week follow-up phone call. One hundred ninety-three (73%) patients completed either the one- or three-month follow up. Most patients recovered from their initial infection within one week, with 10.2% of patients reporting one-week treatment failure. The odds of treatment failure were 66% lower for patients who received antibiotics following I&D at their initial visit. Overall SSTI recurrence rate was 28.0% (95% CI [21.6%-34.4%]) and associated with contact with someone infected with methicillin resistant S. aureus (MRSA), previous SSTI history, or clinician use of wound packing. CONCLUSION: Treatment failure was reduced by antibiotic use, whereas SSTI recurrence was associated with prior contact, SSTI, or use of packing. PMID- 26587086 TI - Accuracy of 'My Gut Feeling:' Comparing System 1 to System 2 Decision-Making for Acuity Prediction, Disposition and Diagnosis in an Academic Emergency Department. AB - INTRODUCTION: Current cognitive sciences describe decision-making using the dual process theory, where a System 1 is intuitive and a System 2 decision is hypothetico-deductive. We aim to compare the performance of these systems in determining patient acuity, disposition and diagnosis. METHODS: Prospective observational study of emergency physicians assessing patients in the emergency department of an academic center. Physicians were provided the patient's chief complaint and vital signs and allowed to observe the patient briefly. They were then asked to predict acuity, final disposition (home, intensive care unit (ICU), non-ICU bed) and diagnosis. A patient was classified as sick by the investigators using previously published objective criteria. RESULTS: We obtained 662 observations from 289 patients. For acuity, the observers had a sensitivity of 73.9% (95% CI [67.7-79.5%]), specificity 83.3% (95% CI [79.5-86.7%]), positive predictive value 70.3% (95% CI [64.1-75.9%]) and negative predictive value 85.7% (95% CI [82.0-88.9%]). For final disposition, the observers made a correct prediction in 80.8% (95% CI [76.1-85.0%]) of the cases. For ICU admission, emergency physicians had a sensitivity of 33.9% (95% CI [22.1-47.4%]) and a specificity of 96.9% (95% CI [94.0-98.7%]). The correct diagnosis was made 54% of the time with the limited data available. CONCLUSION: System 1 decision-making based on limited information had a sensitivity close to 80% for acuity and disposition prediction, but the performance was lower for predicting ICU admission and diagnosis. System 1 decision-making appears insufficient for final decisions in these domains but likely provides a cognitive framework for System 2 decision-making. PMID- 26587087 TI - Central Venous Catheter Intravascular Malpositioning: Causes, Prevention, Diagnosis, and Correction. AB - Despite the level of skill of the operator and the use of ultrasound guidance, central venous catheter (CVC) placement can result in CVC malpositioning, an unintended placement of the catheter tip in an inadequate vessel. CVC malpositioning is not a complication of central line insertion; however, undiagnosed CVC malpositioning can be associated with significant morbidity and mortality. The objectives of this review were to describe factors associated with intravascular malpositioning of CVCs inserted via the neck and chest and to offer ways of preventing, identifying, and correcting such malpositioning. A literature search of PubMed, Cochrane Library, and MD Consult was performed in June 2014. By searching for "Central line malposition" and then for "Central venous catheters intravascular malposition," we found 178 articles written in English. Of those, we found that 39 were relevant to our objectives and included them in our review. According to those articles, intravascular CVC malpositioning is associated with the presence of congenital and acquired anatomical variants, catheter insertion in left thoracic venous system, inappropriate bevel orientation upon needle insertion, and patient's body habitus variants. Although plain chest radiography is the standard imaging modality for confirming catheter tip location, signs and symptoms of CVC malpositioning even in presence of normal or inconclusive conventional radiography findings should prompt the use of additional diagnostic methods to confirm or rule out CVC malpositioning. With very few exceptions, the recommendation in cases of intravascular CVC malpositioning is to remove and relocate the catheter. Knowing the mechanisms of CVC malpositioning and how to prevent, identify, and correct CVC malpositioning could decrease harm to patients with this condition. PMID- 26587088 TI - Pediatric Tape: Accuracy and Medication Delivery in the National Park Service. AB - INTRODUCTION: The objective is to evaluate the accuracy of medication dosing and the time to medication administration in the prehospital setting using a novel length-based pediatric emergency resuscitation tape. METHODS: This study was a two-period, two-treatment crossover trial using simulated pediatric patients in the prehospital setting. Each participant was presented with two emergent scenarios; participants were randomized to which case they encountered first, and to which case used the National Park Service (NPS) emergency medical services (EMS) length-based pediatric emergency resuscitation tape. In the control (without tape) case, providers used standard methods to determine medication dosing (e.g. asking parents to estimate the patient's weight); in the intervention (with tape) case, they used the NPS EMS length-based pediatric emergency resuscitation tape. Each scenario required dosing two medications (Case 1 [febrile seizure] required midazolam and acetaminophen; Case 2 [anaphylactic reaction] required epinephrine and diphenhydramine). Twenty NPS EMS providers, trained at the Parkmedic/Advanced Emergency Medical Technician level, served as study participants. RESULTS: The only medication errors that occurred were in the control (no tape) group (without tape: 5 vs. with tape: 0, p=0.024). Time to determination of medication dose was significantly shorter in the intervention (with tape) group than the control (without tape) group, for three of the four medications used. In case 1, time to both midazolam and acetaminophen was significantly faster in the intervention (with tape) group (midazolam: 8.3 vs. 28.9 seconds, p=0.005; acetaminophen: 28.6 seconds vs. 50.6 seconds, p=0.036). In case 2, time to epinephrine did not differ (23.3 seconds vs. 22.9 seconds, p=0.96), while time to diphenhydramine was significantly shorter in the intervention (with tape) group (13 seconds vs. 37.5 seconds, p<0.05). CONCLUSION: Use of a length-based pediatric emergency resuscitation tape in the prehospital setting was associated with significantly fewer dosing errors and faster time-to medication administration in simulated pediatric emergencies. Further research in a clinical field setting to prospectively confirm these findings is needed. PMID- 26587089 TI - Sensitivity of a Clinical Decision Rule and Early Computed Tomography in Aneurysmal Subarachnoid Hemorrhage. AB - INTRODUCTION: Application of a clinical decision rule for subarachnoid hemorrhage, in combination with cranial computed tomography (CT) performed within six hours of ictus (early cranial CT), may be able to reasonably exclude a diagnosis of aneurysmal subarachnoid hemorrhage (aSAH). This study's objective was to examine the sensitivity of both early cranial CT and a previously validated clinical decision rule among emergency department (ED) patients with aSAH and a normal mental status. METHODS: Patients were evaluated in the 21 EDs of an integrated health delivery system between January 2007 and June 2013. We identified by chart review a retrospective cohort of patients diagnosed with aSAH in the setting of a normal mental status and performance of early cranial CT. Variables comprising the SAH clinical decision rule (age>=40, presence of neck pain or stiffness, headache onset with exertion, loss of consciousness at headache onset) were abstracted from the chart and assessed for inter-rater reliability. RESULTS: One hundred fifty-five patients with aSAH met study inclusion criteria. The sensitivity of early cranial CT was 95.5% (95% CI [90.9 98.2]). The sensitivity of the SAH clinical decision rule was also 95.5% (95% CI [90.9-98.2]). Since all false negative cases for each diagnostic modality were mutually independent, the combined use of both early cranial CT and the clinical decision rule improved sensitivity to 100% (95% CI [97.6-100.0]). CONCLUSION: Neither early cranial CT nor the SAH clinical decision rule demonstrated ideal sensitivity for aSAH in this retrospective cohort. However, the combination of both strategies might optimize sensitivity for this life-threatening disease. PMID- 26587090 TI - Triple Rule Out versus CT Angiogram Plus Stress Test for Evaluation of Chest Pain in the Emergency Department. AB - INTRODUCTION: Undifferentiated chest pain in the emergency department (ED) is a diagnostic challenge. One approach includes a dedicated chest computed tomography (CT) for pulmonary embolism or dissection followed by a cardiac stress test (TRAD). An alternative strategy is a coronary CT angiogram with concurrent chest CT (Triple Rule Out, TRO). The objective of this study was to describe the ED patient course and short-term safety for these evaluation methods. METHODS: This was a retrospective observational study of adult patients presenting to a large, community ED for acute chest pain who had non-diagnostic electrocardiograms (ECGs) and normal biomarkers. We collected demographics, ED length of stay, hospital costs, and estimated radiation exposures. We evaluated 30-day return visits for major adverse cardiac events. RESULTS: A total of 829 patients underwent TRAD, and 642 patients had TRO. Patients undergoing TRO tended to be younger (mean 52.3 vs 56.5 years) and were more likely to be male (42.4% vs. 30.4%). TRO patients tended to have a shorter ED length of stay (mean 14.45 vs. 21.86 hours), to incur less cost (median $449.83 vs. $1147.70), and to be exposed to less radiation (median 7.18 vs. 16.6 mSv). No patient in either group had a related 30-day revisit. CONCLUSION: Use of TRO is feasible for assessment of chest pain in the ED. Both TRAD and TRO safely evaluated patients. Prospective studies investigating this diagnostic strategy are needed to further assess this approach to ED chest pain evaluation. PMID- 26587091 TI - Comparing an Unstructured Risk Stratification to Published Guidelines in Acute Coronary Syndromes. AB - INTRODUCTION: Guidelines are designed to encompass the needs of the majority of patients with a particular condition. The American Heart Association (AHA) in conjunction with the American College of Cardiology (ACC) and the American College of Emergency Physicians (ACEP) developed risk stratification guidelines to aid physicians with accurate and efficient diagnosis and management of patients with acute coronary syndrome (ACS). While useful in a primary care setting, in the unique environment of an emergency department (ED), the feasibility of incorporating guidelines into clinical workflow remains in question. We aim to compare emergency physicians' (EP) clinical risk stratification ability to AHA/ACC/ACEP guidelines for ACS, and assessed each for accuracy in predicting ACS. METHODS: We conducted a prospective observational cohort study in an urban teaching hospital ED. All patients presenting to the ED with chest pain who were evaluated for ACS had two risk stratification scores assigned: one by the treating physician based on clinical evaluation and the other by the AHA/ACC/ACEP guideline aforementioned. The patient's ACS risk stratification classified by the EP was compared to AHA/ACC/ACEP guidelines. Patients were contacted at 30 days following the index ED visit to determine all cause mortality, unscheduled hospital/ED revisits, and objective cardiac testing performed. RESULTS: We enrolled 641 patients presenting for evaluation by 21 different EPs. There was a difference between the physician's clinical assessment used in the ED, and the AHA/ACC/ACEP task force guidelines. EPs were more likely to assess patients as low risk (40%), while AHA/ACC/ACEP guidelines were more likely to classify patients as intermediate (45%) or high (45%) risk. Of the 119 (19%) patients deemed high risk by EP evaluation, 38 (32%) were diagnosed with ACS. AHA/ACC/ACEP guidelines classified only 57 (9%) patients low risk with 56 (98%) of those patients diagnosed with no ACS. CONCLUSION: In the ED, physicians are more efficient at correctly placing patients with underlying ACS into a high risk category. A small percentage of patients were considered low risk when applying AHA/ACC/ACEP guidelines, which demonstrates how clinical insight is often required to make an efficient assessment of cardiac risk and established criteria may be overly conservative when applied to an acute care population. PMID- 26587092 TI - Interposed Abdominal Compression CPR for an Out-of-Hospital Cardiac Arrest Victim Failing Traditional CPR. AB - Interposed abdominal compression cardiopulmonary resuscitation (IAC-CPR) is an alternative technique to traditional cardiopulmonary resuscitation (CPR) that can improve perfusion and lead to restoration of circulation in patients with chest wall deformity either acquired through vigorous CPR or co-morbidity such as chronic obstructive pulmonary disease. We report a case of out-of-hospital cardiac arrest where IAC-CPR allowed for restoration of spontaneous circulation and eventual full neurologic recovery when traditional CPR was failing to generate adequate pulses with chest compression alone. PMID- 26587093 TI - Injuries Following Segway Personal Transporter Accidents: Case Report and Review of the Literature. AB - The Segway(r) self-balancing personal transporter has been used as a means of transport for sightseeing tourists, military, police and emergency medical personnel. Only recently have reports been published about serious injuries that have been sustained while operating this device. This case describes a 67-year old male who sustained an oblique fracture of the shaft of the femur while using the Segway(r) for transportation around his community. We also present a review of the literature. PMID- 26587094 TI - Invasive Mechanical Ventilation in California Over 2000-2009: Implications for Emergency Medicine. AB - INTRODUCTION: Patients who require invasive mechanical ventilation (IMV) often represent a sequence of care between the emergency department (ED) and intensive care unit (ICU). Despite being the most populous state, little information exists to define patterns of IMV use within the state of California. METHODS: We examined data from the masked Patient Discharge Database of California's Office of Statewide Health Planning and Development from 2000-2009. Adult patients who received IMV during their stay were identified using the International Classification of Diseases 9th Revision and Clinical Modification procedure codes (96.70, 96.71, 96.72). Patients were divided into age strata (18-34 yr, 35-64 yr, and >65 yr). Using descriptive statistics and regression analyses, for IMV discharges during the study period, we quantified the number of ED vs. non-ED based admissions; changes in patient characteristics and clinical outcome; evaluated the marginal costs for IMV; determined predictors for prolonged acute mechanical ventilation (PAMV, i.e. IMV>96 hr); and projected the number of IMV discharges and ED-based admissions by year 2020. RESULTS: There were 696,634 IMV discharges available for analysis. From 2000-2009, IMV discharges increased by 2.8%/year: n=60,933 (293/100,000 persons) in 2000 to n=79,868 (328/100,000 persons) in 2009. While ED-based admissions grew by 3.8%/year, non-ED-based admissions remained stable (0%). During 2000-2009, fastest growth was noted for 1) the 35-64 year age strata; 2) Hispanics; 3) patients with non-Medicare public insurance; and 4) patients requiring PAMV. Average total patient cost-adjusted charges per hospital discharge increased by 29% from 2000 (from $42,528 to $60,215 in 2014 dollars) along with increases in the number of patients discharged to home and skilled nursing facilities. Higher marginal costs were noted for younger patients (ages 18-34 yr), non-whites, and publicly insured patients. Some of the strongest predictors for PAMV were age 35-64 years (OR=1.12; 95% CI [1.09-1.14], p<0.05); non-Whites; and non-Medicare public insurance. Our models suggest that by 2020, IMV discharges will grow to n=153,153 (377 IMV discharges/100,000 persons) with 99,095 admitted through the ED. CONCLUSION: Based on sustained growth over the past decade, by the year 2020, we project a further increase to 153,153 IMV discharges with 99,095 admitted through the ED. Given limited ICU bed capacities, ongoing increases in the number and type of IMV patients have the potential to adversely affect California EDs that often admit patients to ICUs. PMID- 26587095 TI - Patient Admission Preferences and Perceptions. AB - INTRODUCTION: Understanding patient perceptions and preferences of hospital care is important to improve patients' hospitalization experiences and satisfaction. The objective of this study was to investigate patient preferences and perceptions of hospital care, specifically differences between intensive care unit (ICU) and hospital floor admissions. METHODS: This was a cross-sectional survey of emergency department (ED) patients who were presented with a hypothetical scenario of a patient with mild traumatic brain injury (TBI). We surveyed their preferences and perceptions of hospital care related to this scenario. A closed-ended questionnaire provided quantitative data on patient preferences and perceptions of hospital care and an open-ended questionnaire evaluated factors that may not have been captured with the closed-ended questionnaire. RESULTS: Out of 302 study patients, the ability for family and friends to visit (83%), nurse availability (80%), and physician availability (79%) were the factors most commonly rated "very important," while the cost of hospitalization (62%) and length of hospitalization (59%) were the factors least commonly rated "very important." When asked to choose between the ICU and the floor if they were the patient in the scenario, 33 patients (10.9%) choose the ICU, 133 chose the floor (44.0%), and 136 (45.0%) had no preference. CONCLUSION: Based on a hypothetical scenario of mild TBI, the majority of patients preferred admission to the floor or had no preference compared to admission to the ICU. Humanistic factors such as the availability of doctors and nurses and the ability to interact with family appear to have a greater priority than systematic factors of hospitalization, such as length and cost of hospitalization or length of time in the ED waiting for an in-patient bed. PMID- 26587096 TI - Evaluation of Social Media Use by Emergency Medicine Residents and Faculty. AB - INTRODUCTION: Clinicians and residency programs are increasing their use of social media (SM) websites for educational and promotional uses, yet little is known about the use of these sites by residents and faculty. The objective of the study is to assess patterns of SM use for personal and professional purposes among emergency medicine (EM) residents and faculty. METHODS: In this multi-site study, an 18-question survey was sent by e-mail to the residents and faculty in 14 EM programs and to the Council of Emergency Medicine Residency Directors (CORD) listserv via the online tool SurveyMonkeyTM. We compiled descriptive statistics, including assessment with the chi-square test or Fisher's exact test. StatsDirect software (v 2.8.0, StatsDirect, Cheshire, UK) was used for all analyses. RESULTS: We received 1,314 responses: 63% of respondents were male, 40% were <30 years of age, 39% were between the ages 31 and 40, and 21% were older than 40. The study group consisted of 772 residents and 542 faculty members (15% were program directors, 21% were assistant or associate PDs, 45% were core faculty, and 19% held other faculty positions. Forty-four percent of respondents completed residency more than 10 years ago. Residents used SM markedly more than faculty for social interactions with family and friends (83% vs 65% [p<0.0001]), entertainment (61% vs 47% [p<0.0001]), and videos (42% vs 23% [p=0.0006]). Residents used FacebookTM and YouTubeTM more often than faculty (86% vs 67% [p<0.001]; 53% vs 46% [p=0.01]), whereas residents used TwitterTM (19% vs 26% [p=0.005]) and LinkedInTM (15% vs 32% [p<0.0001]) less than faculty. Overall, residents used SM sites more than faculty, notably in daily use (30% vs 24% [p<0.001]). For professional use, residents were most interested in its use for open positions/hiring (30% vs 18% [p<0.0001]) and videos (33% vs 26% [p=0.005]) and less interested than faculty with award postings (22% vs 33% [p<0.0001]) or publications (30% vs 38% [p=0.0007]). CONCLUSION: EM residents and faculty have different patterns and interests in the personal and professional uses of social media. Awareness of these utilization patterns could benefit future educational endeavors. PMID- 26587097 TI - Effectiveness of a 40-minute Ophthalmologic Examination Teaching Session on Medical Student Learning. AB - INTRODUCTION: Emergency physicians are among the few specialists besides ophthalmologists who commonly perform ophthalmologic examinations using the slit lamp and other instruments. However, most medical schools in the United States do not require an ophthalmology rotation upon completion. Teaching procedural skills to medical students can be challenging due to limited resources and instructor availability. Our study assesses the effectiveness of a 40-minute hands-on teaching session on ophthalmologic examination for medical students using only two instructors and low-cost equipment. METHODS: We performed an interventional study using a convenience sample of subjects. Pre- and post-workshop questionnaires on students' confidence in performing ophthalmologic examination were administered. We used a paired t-test and Wilcoxon rank test to analyze the data. RESULTS: Of the 30 participants in the study, the mean age was 25 and the majority were first-year medical students. The students' confidence in performing every portion of the ophthalmologic exam increased significantly after the teaching session. We found that the average confidence level before the teaching session were below 2 on a 1-5 Likert scale (1 being the least confident). Confidence levels in using the slit lamp had the highest improvement among the skills taught (2.17 95% CI [1.84-2.49]). Students reported the least improvement in their confidence in assessing extraocular movements (0.73, 95% CI [0.30-1.71]) and examining pupillary function (0.73, 95% CI [0.42-1.04]). We observed the biggest difference in median confidence level in the use of the tonometer (4 with a p-value of <0.05). CONCLUSION: A 40-minute structured hands-on training session can significantly improve students' confidence levels in ophthalmologic skills. PMID- 26587098 TI - Hand Washing Practices Among Emergency Medical Services Providers. AB - INTRODUCTION: Hand hygiene is an important component of infection control efforts. Our primary and secondary goals were to determine the reported rates of hand washing and stethoscope cleaning in emergency medical services (EMS) workers, respectively. METHODS: We designed a survey about hand hygiene practices. The survey was distributed to various national EMS organizations through e-mail. Descriptive statistics were calculated for survey items (responses on a Likert scale) and subpopulations of survey respondents to identify relationships between variables. We used analysis of variance to test differences in means between the subgroups. RESULTS: There were 1,494 responses. Overall, reported hand hygiene practices were poor among pre-hospital providers in all clinical situations. Women reported that they washed their hands more frequently than men overall, although the differences were unlikely to be clinically significant. Hygiene after invasive procedures was reported to be poor. The presence of available hand sanitizer in the ambulance did not improve reported hygiene rates but improved reported rates of cleaning the stethoscope (absolute difference 0.4, p=0.0003). Providers who brought their own sanitizer were more likely to clean their hands. CONCLUSION: Reported hand hygiene is poor amongst pre-hospital providers. There is a need for future intervention to improve reported performance in pre-hospital provider hand washing. PMID- 26587099 TI - Telephone CPR Instructions in Emergency Dispatch Systems: Qualitative Survey of 911 Call Centers. AB - INTRODUCTION: Out-of-hospital cardiac arrest (OHCA) is a leading cause of death. The 2010 American Heart Association Emergency Cardiovascular Care (ECC) Guidelines recognize emergency dispatch as an integral component of emergency medical service response to OHCA and call for all dispatchers to be trained to provide telephone cardiopulmonary resuscitation (T-CPR) pre-arrival instructions. To begin to measure and improve this critical intervention, this study describes a nationwide survey of public safety answering points (PSAPs) focusing on the current practices and resources available to provide T-CPR to callers with the overall goal of improving survival from OHCA. METHODS: We conducted this survey in 2010, identifying 5,686 PSAPs; 3,555 had valid e-mail addresses and were contacted. Each received a preliminary e-mail announcing the survey, an e-mail with a link to the survey, and up to three follow-up e-mails for non-responders. The survey contained 23 primary questions with sub-questions depending on the response selected. RESULTS: Of the 5,686 identified PSAPs in the United States, 3,555 (63%) received the survey, with 1,924/3,555 (54%) responding. Nearly all were public agencies (n=1,888, 98%). Eight hundred seventy-eight (46%) responding agencies reported that they provide no instructions for medical emergencies, and 273 (14%) reported that they are unable to transfer callers to another facility to provide T-CPR. Of the 1,924 respondents, 975 (51%) reported that they provide pre-arrival instructions for OHCA: 67 (3%) provide compression-only CPR instructions, 699 (36%) reported traditional CPR instructions (chest compressions with rescue breathing), 166 (9%) reported some other instructions incorporating ventilations and compressions, and 92 (5%) did not specify the type of instructions provided. A validation follow up showed no substantial difference in the provision of instructions for OHCA by non-responders to the survey. CONCLUSION: This is the first large-scale, nationwide assessment of the practices of PSAPs in the United States regarding T-CPR for OHCA. These data showing that nearly half of the nation's PSAPs do not provide T-CPR for OHCA, and very few PSAPs provide compression-only instructions, suggest that there is significant potential to improve the implementation of this critical link in the chain of survival for OHCA. PMID- 26587100 TI - Variability in Criteria for Emergency Medical Services Routing of Acute Stroke Patients to Designated Stroke Center Hospitals. AB - INTRODUCTION: Comprehensive stroke systems of care include routing to the nearest designated stroke center hospital, bypassing non-designated hospitals. Routing protocols are implemented at the state or county level and vary in qualification criteria and determination of destination hospital. We surveyed all counties in the state of California for presence and characteristics of their prehospital stroke routing protocols. METHODS: Each county's local emergency medical services agency (LEMSA) was queried for the presence of a stroke routing protocol. We reviewed these protocols for method of stroke identification and criteria for patient transport to a stroke center. RESULTS: Thirty-three LEMSAs serve 58 counties in California with populations ranging from 1,175 to nearly 10 million. Fifteen LEMSAs (45%) had stroke routing protocols, covering 23 counties (40%) and 68% of the state population. Counties with protocols had higher population density (1,500 vs. 140 persons per square mile). In the six counties without designated stroke centers, patients meeting criteria were transported out of county. Stroke identification in the field was achieved using the Cincinnati Prehospital Stroke Screen in 72%, Los Angeles Prehospital Stroke Screen in 7% and a county-specific protocol in 22%. CONCLUSION: California EMS prehospital acute stroke routing protocols cover 68% of the state population and vary in characteristics including activation by symptom onset time and destination facility features, reflecting matching of system design to local geographic resources. PMID- 26587102 TI - Focused Cardiac Ultrasound Diagnosis of Cor Triatriatum Sinistrum in Pediatric Cardiac Arrest. AB - Cardiac arrest in the adolescent population secondary to congenital heart disease (CHD) is rare. Focused cardiac ultrasound (FoCUS) in the emergency department (ED) can yield important clinical information, aid in resuscitative efforts during cardiac arrest and is commonly integrated into the evaluation of patients with pulseless electrical activity (PEA). We report a case of pediatric cardiac arrest in which FoCUS was used to diagnose a critical CHD known as cor triatriatum sinistrum as the likely cause for PEA cardiac arrest and help direct ED resuscitation. PMID- 26587101 TI - Access to and Use of Point-of-Care Ultrasound in the Emergency Department. AB - INTRODUCTION: Growing evidence supports emergency physician (EP)-performed point of-care ultrasound (PoC US). However, there is a utilization gap between academic emergency departments (ED) and other emergency settings. We elucidated barriers to PoC US use in a multistate sample of predominantly non-academic EDs to inform future strategies to increase PoC US utilization, particularly in non-academic centers. METHODS: In 2010, we surveyed ED directors in five states (Arkansas, Hawaii, Minnesota, Vermont, and Wyoming; n=242 EDs) about general ED characteristics. In four states we determined barriers to PoC US use, proportion of EPs using PoC US, use privileges, and whether EPs can bill for PoC US. RESULTS: Response rates were >80% in each state. Overall, 47% of EDs reported PoC US availability. Availability varied by state, from 34% of EDs in Arkansas to 85% in Vermont. Availability was associated with higher ED visit volume, and percent of EPs who were board certified/board eligible in emergency medicine. The greatest barriers to use were limited training (70%), expense (39%), and limited need (perceived or real) (32%). When PoC US was used by EPs, 50% used it daily, 44% had privileges not requiring radiology confirmation, and 34% could bill separately for PoC US. Only 12% of EPs used it >=80% of the time when placing central venous lines. CONCLUSION: Only 47% of EDs in our five-state sample of predominantly non-academic EDs had PoC US immediately available. When available, the greatest barriers to use were limited training, expense, and limited need. Recent educational and technical advancements may help overcome these barriers. PMID- 26587103 TI - Bedside Ultrasound Evaluation Uncovering a Rare Urological Emergency Secondary to Neurofibromatosis. PMID- 26587104 TI - Splenic Rupture Diagnosed with Bedside Ultrasound in a Patient with Shock in the Emergency Department Following Colonoscopy. PMID- 26587105 TI - Elderly Woman with Abdominal Pain: Bedside Ultrasound Diagnosis of Diverticulitis. PMID- 26587106 TI - Ruptured Splenic Artery Aneurysm: Rare Cause of Shock Diagnosed with Bedside Ultrasound. AB - Splenic artery aneurysm rupture is rare and potentially fatal. It has largely been reported in pregnant patients and typically not diagnosed until laparotomy. This case reports a constellation of clinical and sonographic findings that may lead clinicians to rapidly diagnose ruptured splenic artery aneurysm at the bedside. We also propose a rapid, but systematic sonographic approach to patients with atraumatic hemoperitoneum causing shock. It is yet another demonstration of the utility of bedside ultrasound in critically ill patients, specifically with undifferentiated shock. PMID- 26587107 TI - Not What It Seems: Deep Tissue Infection Presenting as Cellulitis. PMID- 26587108 TI - Emergency Physician Attitudes, Preferences, and Risk Tolerance for Stroke as a Potential Cause of Dizziness Symptoms. AB - INTRODUCTION: We evaluated emergency physicians' (EP) current perceptions, practice, and attitudes towards evaluating stroke as a cause of dizziness among emergency department patients. METHODS: We administered a survey to all EPs in a large integrated healthcare delivery system. The survey included clinical vignettes, perceived utility of historical and exam elements, attitudes about the value of and requisite post-test probability of a clinical prediction rule for dizziness. We calculated descriptive statistics and post-test probabilities for such a clinical prediction rule. RESULTS: The response rate was 68% (366/535). Respondents' median practice tenure was eight years (37% female, 92% emergency medicine board certified). Symptom quality and typical vascular risk factors increased suspicion for stroke as a cause of dizziness. Most respondents reported obtaining head computed tomography (CT) (74%). Nearly all respondents used and felt confident using cranial nerve and limb strength testing. A substantial minority of EPs used the Epley maneuver (49%) and HINTS (head-thrust test, gaze evoked nystagmus, and skew deviation) testing (30%); however, few EPs reported confidence in these tests' bedside application (35% and 16%, respectively). Respondents favorably viewed applying a properly validated clinical prediction rule for assessment of immediate and 30-day stroke risk, but indicated it would have to reduce stroke risk to <0.5% to be clinically useful. CONCLUSION: EPs report relying on symptom quality, vascular risk factors, simple physical exam elements, and head CT to diagnose stroke as the cause of dizziness, but would find a validated clinical prediction rule for dizziness helpful. A clinical prediction rule would have to achieve a 0.5% post-test stroke probability for acceptability. PMID- 26587109 TI - Tension Pneumoperitoneum Caused by Obstipation. AB - Emergency physicians are often required to evaluate and treat undifferentiated patients suffering acute hemodynamic compromise (AHC). It is helpful to apply a structured approach based on a differential diagnosis including all causes of AHC that can be identified and treated during a primary assessment. Tension pneumoperitoneum (TP) is an uncommon condition with the potential to be rapidly fatal. It is amenable to prompt diagnosis and stabilization in the emergency department. We present a case of a 16-year-old boy with TP to demonstrate how TP should be incorporated into a differential diagnosis when evaluating an undifferentiated patient with AHC. PMID- 26587110 TI - ST-Elevation Myocardial Infarction After Sumitriptan Ingestion in Patient with Normal Coronary Arteries. AB - Sumitriptan has been used by millions as a migraine abortant; however, there have been studies showing angina pectoris, coronary vasospasm, and even myocardial infarction in patients with predisposing cardiac risk factors. The majority are patients using the injectable form subcutaneously. We present the case of a patient who presents with ST-elevation myocardial infarction, with no cardiovascular risk factors, after ingesting oral sumitriptan for her typical migraine. PMID- 26587111 TI - A Surprising Finding of Remote Ischial Avulsion. PMID- 26587112 TI - Hydrocele of the Canal of Nuck. PMID- 26587113 TI - Fatal Tension Pneumoperitoneum Due to Non-Accidental Trauma. PMID- 26587114 TI - Uterine Incarceration: Rare Cause of Urinary Retention in Healthy Pregnant Patients. AB - Gravid uterine incarceration (GUI) is a condition that is well discussed in literature; however, there are few acute diagnoses in the emergency department (ED). We present a case series where three multiparous females presented to the ED with non-specific urinary symptoms. On bedside ultrasound, each patient was noted to have a retroverted uterus and inferior bladder entrapment under the sacral promontory. GUI is a rare condition that can lead to uremia, sepsis, peritonitis, and ultimately maternal death. Emergency physicians should include GUI in their differential diagnosis in this patient population and use bedside ultrasound as an adjunct to diagnosis. PMID- 26587115 TI - Severe Hemorrhage from Cervical Cancer Managed with Foley Catheter Balloon Tamponade. PMID- 26587116 TI - Comments on "High Altitude Pulmonary Edema in an Experienced Mountaineer. Possible Genetic Predisposition". PMID- 26587117 TI - Response to Comments on "High Altitude Pulmonary Edema in an Experienced Mountaineer. Possible Genetic Predisposition". PMID- 26587118 TI - Low rate of non-compliance to antituberculous therapy under the banner of directly observed treatment short course (DOTS) strategy and well organized retrieval system: a call for implementation of this strategy at all DOTS centers in Saudi Arabia. AB - INTRODUCTION: The objective of this study was to show the effectiveness of revised retrieval system on non-compliance. METHODS: We retrospectively evaluated the effectiveness of a revised retrieval system on non-compliance during continuous phase of antituberculous treatment (Jan-2005 to Dec-2010) compared to baseline non-compliance (Jan-2002 to Dec-2004). RESULTS: In the baseline period, 141 of 501 (28%) patients did not attend their first appointment. Of these 141 patients, 63 (45%) patients could be brought back to treatment while 78 patients (16%) dropped out and could not be retrieved. During the 2nd phase after launching a revised retrieval system, 98 of 835 (13%) patients did not attend their first appointment. Using the retrieval system, 79 (81%) patients were brought back for regular follow up, and 19 patients could not be retrieved, a dropout rate of 2.27%. By virtue of revised retrieval system, there was a significant drop in non-compliance by 15% and a decline in net dropout rate by 14%. The number of those brought back to treatment by revised retrieval system almost doubled (81%) compared to 44% retrieval in initial period. CONCLUSION: The revised retrieval system had a significant impact on the reduction of dropout rate and significant improvement in the retrieval of those patients. PMID- 26587119 TI - [Glanzmann thrombasthenia: about 11 cases]. PMID- 26587120 TI - [Ascites and fever in women: do not rule out Krukenberg tumor]. PMID- 26587121 TI - Acoustic assessment of erygmophonic speech of Moroccan laryngectomized patients. AB - INTRODUCTION: Acoustic evaluation of alaryngeal voices is among the most prominent issues in speech analysis field. In fact, many methods have been developed to date to substitute the classic perceptual evaluation. The Aim of this study is to present our experience in erygmophonic speech objective assessment and to discuss the most widely used methods of acoustic speech appraisal. through a prospective case-control study we have measured acoustic parameters of speech quality during one year of erygmophonic rehabilitation therapy of Moroccan laryngectomized patients. METHODS: We have assessed acoustic parameters of erygmophonic speech samples of eleven laryngectomized patients through the speech rehabilitation therapy. Acoustic parameters were obtained by perturbation analysis method and linear predictive coding algorithms also through the broadband spectrogram. RESULTS: Using perturbation analysis methods, we have found erygmophonic voice to be significantly poorer than normal speech and it exhibits higher formant frequency values. However, erygmophonic voice shows also higher and extremely variable Error values that were greater than the acceptable level. And thus, live a doubt on the reliability of those analytic methods results. CONCLUSION: Acoustic parameters for objective evaluation of alaryngeal voices should allow a reliable representation of the perceptual evaluation of the quality of speech. This requirement has not been fulfilled by the common methods used so far. Therefore, acoustical assessment of erygmophonic speech needs more investigations. PMID- 26587122 TI - [Hydatid cyst of the adrenal: about a case]. PMID- 26587123 TI - [Pancreatic hydatid cyst: a case about]. PMID- 26587124 TI - Perceived barriers to physical activity among Nigerian stroke survivors. AB - INTRODUCTION: Benefits of physical activity in the prevention and management of stroke are well documented in the literature. There is increasing evidence that stroke survivors in South-West Nigeria are physically inactive. Data on barriers to the achievement of the recommended physical activity levels including its differences along socio-demographic characteristics among stroke survivors in South-West Nigeria are needed. METHODS: The Exercise Benefits and Barrier Scale and the International Physical Activity Questionnaire were administered on 121 stroke survivors to determine their perceived barriers to physical activity and physical activity levels respectively. Information on socio-demographic data and clinical variables were also collected. RESULTS: The sample included 70.2% males, with majority of the participants reporting low physical activity levels (80.2%) and high perceived barriers (Mean = 48.13, SD = 7.88). The four most reported common barriers among stroke survivors were access to exercise facilities (95.0%), being embarrassed to exercise (94.2%), economic cost demands of exercise (94.2%) and notion that people in exercise clothes look funny (94.2%) respectively. There were no significant differences found in barriers to physical activity between gender (U = 1471.00, P = 0.74) and across each of: occupational status (H = 4.37, P = 0.22), age group (H = 0.82, P = 0.84) and educational levels (H = 4.56, P = 0.33). Significant difference however existed in perceived barriers across marital status categories (H = 12.87, P = 0.05). CONCLUSION: Stroke survivors indicated high perceived barriers to physical activity and these barriers were associated with marital status. PMID- 26587125 TI - Colon bypass with a colon-flap augmentation pharyngoesophagoplasty. AB - Extensive caustic stricture of the upper aero-digestive system (oro- and hypo pharynx) is a severe injury with limited surgical options. We adopted augmentation of the cicatrized upper aero-digestive tract with colon as our preferred management option. The aim of this report is to describe our initial experience with the technique of colon-flap augmentation pharyngo-esophagoplasty (CFAP) for selected patients with severe pharyngo-esophageal stricture. Between October 2011 and June 2013, three male patients (aged 16, 4 and 18 years respectively) underwent CFAP following extensive pharyngo-esophageal stricture. Postoperative recovery was uneventful in all three cases and all started swallowing within 7-10 days after surgery without significant dysphagia. Colon flap augmentation pharyngo-esophagoplasty is an effective procedure for reconstruction of the pharynx and the hypopharynx after extensive caustic pharyngoesophageal structure in selected cases. PMID- 26587126 TI - [Hematological and nutritional profile of homozygous sickle cell SS aged 6 to 59 months in Lubumbashi, Democratic Republic of Congo]. PMID- 26587127 TI - [Severe hemorrhage in the peripartum in intensive care unit in a level 3 Tunisian university center: epidemiology and risk factors for maternal mortality]. PMID- 26587128 TI - [Thyroidectomy performed under local anesthesia at the University Hospital of Antananarivo]. PMID- 26587129 TI - [Osteo articular tuberculosis (Pott disease excluded): about 120 cases in Abidjan]. PMID- 26587130 TI - [Perceived stress: validation of the translation of a stress measuring scale in Moroccan dialect]. PMID- 26587131 TI - Aneurysmal dilatation of the pulmonary artery trunk and its major branches. PMID- 26587133 TI - [Neonatal unilateral paralysis of the radial nerve]. PMID- 26587132 TI - Locally recurrent subcutaneous and muscular hydatid cysts of the leg: an unusual case report. AB - We report a rare case of 50-year-old Moroccan woman with local recurrence of a subcutaneous hydatid cyst in proximity to the medial surface of the tibia and another cyst at the tibialis posterior muscle in the absence of liver, lung und spleen involvement. The first surgery was done in another hospital three years ago; no adjuvant treatment was performed after surgery. Recurrence was diagnosed according to the MRI appearance, serological and pathological findings. The patient underwent complete excision of the subcutaneous cyst with two centimeters of the medial gastrocnemius muscle; the tibialis posterior muscle cyst was intraoperatively drained and irrigated with scolicidal agent as it was next to the posterior tibial pedicle. A periopertive anthelmintic chemotherapy was administered. Two years after the patient showed no recurrence. This case report and literature review describe an approach to the diagnosis and management of this pathological entity. PMID- 26587134 TI - A fragment of Foley catheter balloon as a cause of Bladder stone in woman. AB - Urinary bladder calculi are rarely seen in women and any history of previous pelvic surgery must, therefore, raise suspicion of an iatrogenic etiology. According to the literature, fewer than 2% of all bladder calculi occur in female subjects and, thus, their presence should provoke careful assessment of the etiology. We report one case of a fragment of Foley catheter balloon as a cause of Bladder stone in 28 years old woman. We analyzed the diagnosis, aspect and therapeutic management of this case which is the first described in literature to our knowledge. PMID- 26587135 TI - An unusual recurrence of pruritic creeping eruption after treatment of cutaneous larva migrans in an adult Ghanaian male: a case report with a brief review of literature. AB - The hookworm related Cutaneous Larva Migrans is a common disease present in the tropic and subtropical areas of the world. The disease is self limiting and would naturally resolve within weeks. However, an unusual recurrence of the disease in a Ghanaian male after standard treatment was observed and is herein reported. A 52 year old Ghanaian male of Akan dissent was diagnosed with Cutaneous Larva Migrans in a clinic in Accra, Ghana. Symptoms of the disease persisted for three days after treatment with a 400mg single dose Albendazole and was only resolved after re-dosing with 400 mg daily of the same drug for three days. Two months post-treatment, the usual pruritic creeping eruption typical with the disease re appeared even though the victim has not been re-exposed to any possible larva contaminated source. This could possibly be a case of hookworm-related larva resistance to a standard anti-helminthic therapy and host immunity. PMID- 26587136 TI - Huge plastic bezoar: a rare cause of gastrointestinal obstruction. AB - Bezoars are rare causes of gastrointestinal obstruction. Basically, they are of four types: trichobezoars, phytobezoars, pharmacobezoars, and lactobezoars. Some rare types of bezoars are also known. In this article a unique case of plastic bezoars is presented. We describe a girl aged 14 years who ingested large amounts of plastic material used for knitting chairs and charpoys. The conglomerate of plastic threads, entrapped food material and other debris, formed a huge mass occupying the whole stomach and extended into small bowel. PMID- 26587137 TI - [Arthroscopy assisted treatment of fractures of the external plate by percutaneous screw fixation]. PMID- 26587138 TI - Open lunate enucleation. PMID- 26587139 TI - [Posttraumatic carotid-cavernous fistulas--about a case and review of literature]. PMID- 26587140 TI - Assessment of the magnitude and associated factors of immunological failure among adult and adolescent HIV-infected patients in St. Luke and Tulubolo Hospital, Oromia Region, Ethiopia. AB - INTRODUCTION: The use of antiretroviral therapy (ART) has become a standard of care for the treatment of HIV infection. However, cost and resistance to ART are major obstacles for access to treatment especially in resource-limited settings. In this study, we aimed to assess the magnitude and associated factors of Immunological failure among adult and adolescent HIV infected Patients (with age '15 yrs) on Highly Active Antiretroviral Therapy (HAART) in St. Luke and Tulu Bolo Hospitals, Oromia Region, Ethiopia. METHODS: A retrospective follow-up study was conducted among HIV-infected patients initiated 1st line ART at St. Luke and Tulu Bolo Hospitals, South West Shoa Zone, Oromia, Ethiopia. RESULTS: A total of 828 patient charts were reviewed. 477(57.6%) were female and the median age was 32 years. The median baseline CD4 count was 148cells/mm3. The most common prescribed ART was TDF based (36.7%). Out of 828 patients chart reviewed 6.8% (56) were developed immunological failure. Out of them only 20 (2.4%) were detected and put on second line regimen. The incidence of immunological failure was 1.8 cases per 100 person years of follow-up. Patients who had not disclosed their HIV status to any one had high risk of immunological failure compared with patients those who had disclosed their HIV status (AHR, 0.429; 95% CI 0.206 - 0.893; P-value=0.024). CONCLUSION: Non disclosures of HIV status and with ambulatory of baseline functional status were found to be predictors of immunological failure. Most of the immunological failure cases were not detected early and not switched to second line ARV regimen. So patients with the above risk factors should be considered for a timely switch to second line HAART. PMID- 26587141 TI - [Amyopathic dermatomyositis revealing a thymic carcinoma]. PMID- 26587142 TI - [Ruptured aneurysms of the infrarenal abdominal aorta: surgical aspects in Dakar about 6 observations]. PMID- 26587143 TI - Poland's syndrome. PMID- 26587144 TI - [Interim prosthesis complication]. PMID- 26587145 TI - [Central retinal vein occlusion in young patients revealing hyperhomocysteinemia: about a case]. PMID- 26587146 TI - Acalculous cholecystitis in patient with hepatic hypogenesis and chilaiditi sign. PMID- 26587147 TI - [Retroperitoneal paraganglioma: report of a case and literature review]. PMID- 26587148 TI - [Epidermal necrolysis linked to the dermal application of a potassium hydroxide solution]. PMID- 26587149 TI - [Perioperative management of a retroperitoneal paraganglioma]. PMID- 26587150 TI - Distribution of Kell phenotype among pregnant women in Sokoto, North Western Nigeria. AB - INTRODUCTION: Kell antigen is highly immunogenic and is the common cause of antibody production in mismatched blood transfusions, haemolytic transfusion reaction (HTR) and maternal alloimmunization, which causes severe anaemia in neonates. The aim of this study is to determine the prevalence and ethnic variation of the Kell phenotype among pregnant women in Sokoto, Nigeria. METHODS: Kell antigen status of 150 pregnant women aged 18-45 years and mean age 27.19 +/ 4.69 years attending antenatal clinic in UDUTH Sokoto Nigeria was determined using the conventional tube method and anti-Kell reagents (Lorne Laboratories, UK). RESULTS: Among the 150 subjects studied, 3 (2.0%) of subjects were positive and 147 (98.0) were negative for K antigen. Of the 150 pregnant subjects; 32 (21.3%) were primigravidae while 118 (78.7%) were multigravidae. Kell phenotype was more prevalent among primigravidae (3.1%) compared to multigravidae (1.7%) women. The distribution of Kell phenotype among the pregnant subjects was compared based on ethnicity. The prevalence of Kell antigen was significantly higher among the Hausa ethnic group (3.2%) compared to other ethnic groups which indicated zero prevalence (p = 0.001). Kell negative phenotype was >= 96.8% among all the ethnic groups. CONCLUSION: Our observed prevalence of Kell phenotype is consistent with previous studies among Blacks and Asians but significantly lower than values observed in previous studies among Caucasians. We recommend that all pregnant women should be screened for the presence clinically significant red cell antigens including Kell antigen on their first antenatal visit. Kell negative red cell should be routinely provided for all pregnant women and women with child bearing potential to reduce the risk of Kell-associated HDFN. There is need to introduce routine screening of pregnant women for clinically significant red cell antibodies to facilitate the effective management of HDFN as well as prevent HTR. There is also need for sustained health education of pregnant women in the area to encourage early booking for antenatal care. PMID- 26587151 TI - Living with epilepsy in Lubumbashi (Democratic Republic of Congo): epidemiology, risk factors and treatment gap. AB - INTRODUCTION: Epilepsy is the most common of serious neurological disorders, yet despite considerable efforts, good access to medication, appropriate social and societal acceptance and acceptable quality of life (QoL) are difficult to achieve especially in developing countries. It is estimated that over 500,000 people suffer from epilepsy in the DRC. There is no report, in our knowledge on the epilepsy in Lubumbashi. METHODS: A descriptive study was undertaken in individuals with a clinical diagnosis of epilepsy who presented at the CNPJG outpatient clinic in Lubumbashi over a 12 months period. A 64-item questionnaire was used to collect information from the patients. Case records were reviewed and relevant demographic, social, professional, medical history, medical condition data were extracted. RESULTS: Among 3,540 patients who presented to a neuropsychiatric clinic run by the Fracarita charity over a 1-year period, 423 (11.9%) were identified as having epilepsy, and 179 were subsequently included in the survey after they (or their parent/guardian) provided informed consent and completed an EEG investigation. Data were collected using a standardized, 64-item questionnaire. Epilepsy had negative impact on the lives of individuals with the condition; 40.8% had either no education or had completed primary education only, 38.0% were unemployed and the majority (64.6%; n = 113) were unmarried or divorced. Family history of epilepsy (first or second degree) was present in 23.5% of cases. Other reported factors that could potentially precipitate epilepsy included obstetric and perinatal factors (15.1%) and central nervous system infections during infancy (8.4%). Consumption of alcohol or recreational drugs accounted for 10.6%. The treatment gap was above 67% and the delay between first seizure and first consultation was 15 months. When asked to describe their condition, or its cause, 55.3% of participants (or their families) considered epilepsy to be of spiritual/ religious origin, while 25.1% had almost no insight and could not provide any description. CONCLUSION: This first epidemiological study shows a high prevalence of epilepsy among patients presenting to the clinic in Lubumbashi, DRC, and reveals a significant treatment gap. PMID- 26587152 TI - [Prevalence of complications of corticosteroid therapy among West African consulting in rheumatology]. PMID- 26587153 TI - [Prognostic factors of disease-free survival in patients with uterine cervix tumor]. PMID- 26587154 TI - [Mesenteric stromal tumor: report of a rare case and review of literature]. PMID- 26587155 TI - [Sciatica revealing peri-neural cyst of the sacral bone]. PMID- 26587156 TI - Towards task shifting? A comparison of the accuracy of acute trauma-radiograph reporting by medical officers and senior radiographers in an African hospital. AB - INTRODUCTION: Due to the universal shortage of radiologists, medical officers are largely responsible for acute trauma radiograph reporting in public sector healthcare facilities in well-resourced countries. In poorly-resourced countries, a shortage of medical officers results in most acute trauma radiographs being unreported. In the European Union (EU), experienced radiographers with no specific training have been shown to be more accurate than medical officers in trauma radiograph reporting, while EU radiographers who receive additional training can reach accuracies comparable to radiologists. In some EU countries, the role of the radiographer has been extended to include trauma reporting. However, there has been no study of the accuracy of trauma radiograph reporting by radiographers in Africa, where task-shifting could yield potentially greater benefits, due to shortages of both radiologists and medical officers. The aim of this study was therefore to compare the accuracy of acute trauma-radiograph reporting by medical officers and senior radiographers in an African setting. METHODS: A prospective study was conducted at a South African hospital from November 2013-April 2014. Medical officers and senior radiographers reported the same set of appendicular skeleton trauma radiographs. Reporting accuracy, sensitivity and specificity were calculated using a consultant radiologist's report as the reference standard. Differences were evaluated using the Mann Whitney U test, with p < 0.05 significant. RESULTS: Senior radiographers achieved significantly higher reporting accuracy and sensitivity than medical officers (81.5% vs 67.8%, p = 0.002). CONCLUSION: Senior radiographers represent a potentially important resource for acute trauma-radiograph reporting in the public healthcare sector in Africa. PMID- 26587157 TI - Exclusive breastfeeding and HIV/AIDS: a crossectional survey of mothers attending prevention of mother-to-child transmission of HIV clinics in southwestern Nigeria. AB - INTRODUCTION: Prevention of Mother-To-Child-Transmission (PMTCT) of Human Immunodeficiency Virus (HIV) guideline recommends replacement feeding where it is acceptable, feasible, affordable, sustainable and safe. Where this is un achievable, exclusive breastfeeding (EBF) is recommended during the first six months of life. METHODS: A hospital-based cross-sectional study was conducted among 600 HIV-positive using a two-stage sampling technique. Data on socio demographics, infant feeding choice and factors influencing these choices were collected using semi-structured questionnaires. RESULTS: Majority of the mothers (86.0%) were married and aged 31.0 +/- 5.7 years. Slightly above half (53.0%) had <=2 children and more than two-third had disclosed their HIV status to their spouses. About two-third (61.0%) were traders with 75.0% earning monthly income <=N5,000.00k. Half of the mothers had >=4 antenatal care visits and 85.0% had infant feeding counselling. Infant feeding choices among the mothers were EBF (61.0%), ERF (26.0%) and MF (13.0%). The choice of EBF was influenced by spouse influence (84.0%), family influence (81.0%) and fear of stigmatisation (53.0%). Predictors of EBF were; monthly income (AOR = 2.6, C.I. =1.4-4.5), infant feeding counselling (AOR = 2.7, C.I. = 1.6-6.9) and fear of stigmatisation (AOR = 7. 2, C.I. = 2.1-23.6). CONCLUSION: HIV positive mothers are faced with multiple challenges as they strive to practice exclusive breastfeeding. More extensive and comprehensive approach of infant feeding counseling with emphasis on behavioural change programmes in the context of HIV/AIDS within communities is advocated. PMID- 26587158 TI - [Predictors of morbidity and mortality in patients undergoing intra-aortic counterpulsation balloon in cardiac surgery]. PMID- 26587159 TI - [Laparoscopic cholecystectomy for acute cholecystitis gallstones: about 22 cases compiled at the Rebirth hospital of Ndjamena]. PMID- 26587160 TI - Spontaneous splenic rupture in pregnancy. AB - Splenic rupture during pregnancy is a rare and can frequently be a misdiagnosed pathology. This rupture is associated with a high maternal and fetal mortality rate. A 26 years old Moroccan woman para II gravida II presented at the third stage of pregnancy with acute onset of severe abdominal pain. She developed immediately a hypovolemic shock. After both a physical and sonographical exam, it was revealed that it was due to a massive hemoperitoneum. Therefore, an emergent laparotomy and cesarean delivery with abdominal exploration were performed; also, an active bleeding was identified at the splenic hilum consistent with splenic rupture. Through this case report, we want to raise awareness of this surgical emergency that requires immediate recognition because any delay can lead to catastrophic consequences. PMID- 26587161 TI - [Deceptive masks of bipolarity: study 100 cases]. PMID- 26587162 TI - [Post Traumatic rupture of Bruch membrane: about a case]. PMID- 26587163 TI - [Bilateral intraosseous synovial cyst of the carpal scaphoid revealed by pathological fracture: report of a case and review the literature]. PMID- 26587164 TI - [Orthopedic manifestations of neurofibromatosis type 1 or Recklinghausen disease]. PMID- 26587165 TI - [Contribution of radio-guided biopsy in the histopathological diagnosis of childhood tumors of: experience of Rabat Child Hospital]. PMID- 26587166 TI - [The management of pain in the child with cancer]. PMID- 26587167 TI - Wrist disarticulation associated with Monteggia fracture. PMID- 26587168 TI - Determinants of antenatal care, institutional delivery and postnatal care services utilization in Nigeria. AB - INTRODUCTION: Utilization of antenatal care, institutional delivery and postnatal care services in Nigeria are poor even by african average. METHODS: We analysed the 2013 Nigeria DHS to determine factors associated with utilization of these health MCH indicators by employing both bivariate and multivariate logistic regressions. RESULTS: Overall, 54% of women had at least four ANC visits, 37% delivered in health facility and 29% of new born had postnatal care within two of births. Factors that consistently predict the utilization of the three MCH services are maternal and husband's level education, place of residence, wealth level and parity. Antenatal care strongly predicts both health facility delivery (OR = 2.16, 95%CI: 1.99-2.34) and postnatal care utilization (OR = 4.67, 95%CI: 3.95-5.54); while health facility delivery equally predicting postnatal care (OR = 2.84, 95%CI: 2.20-2.80). CONCLUSION: Improving utilization of these three MCH indicators will require targeting women in the rural areas and those with low level of education as well as creating demand for health facility delivery. Improving ANC use by making it available and accessible will have a multiplier effect of improving facility delivery which will lead to improved postnatal care utilization. PMID- 26587169 TI - [Intestinal parasites simulating appendicitis on ultrasound: about two cases]. PMID- 26587170 TI - Sepsis in Africa: practical steps to stem the tide. PMID- 26587171 TI - [Accidental ingestion of a coin]. PMID- 26587172 TI - Dual intersection syndrome of the forearm: a case report. AB - The intersection syndrome, described since the 19(th) century, is an uncommon disorder associated with rubbing at the crossing point between the first dorsal compartment muscles and the radial wrist extensor muscles. Imaging modalities used to diagnosis this syndrome includes ultrasonography and magnetic resonance imaging. We reported a case of a 60-year-old man presented to our formation with painful swelling on the dorsum of the wrist and forearm. An MRI and an ultrasound were performed, and objectified a dual cross syndrome of the forearm. PMID- 26587173 TI - [An unusual intrabronchial foreign body - the scarf pin: presentation and management]. PMID- 26587174 TI - [Evaluation of residency training in general and digestive surgery in Tunisia]. PMID- 26587175 TI - [Hospital management of severe acute malnutrition in children with F-75 and F-100 alternative local preparations: results and challenges]. PMID- 26587176 TI - Impalement injury by glass shard with delayed colonic perforation. AB - A 66-year-old man experienced a traumatic injury after a fall on top of a glass tea table, which caused some superficial lacerations all around the body. He was examined in the emergency room by a physician. The physician could not feel any foreign body upon wound exploration and sutured the laceration. Fourteen months after the injury, he developed progressive abdominal pain. On emergency room and abdominal x-ray showed a foreign body, which a CT scan revealed as an intraabdominal glass shard. The glass presumably impaled his abdominal wall as a result of his previous traumatic injury. The patient underwent laparotomy, which revealed a large glass (16x1cm) perforating the transverse colon. It was extracted and the perforation closed with a lineal stapler. There was no need of bowel resection and the patient was discharged home nine days after the intervention. PMID- 26587177 TI - Epidemiological profile of the Ebola virus disease outbreak in Nigeria, July September 2014. AB - INTRODUCTION: In July 2014, Nigeria experienced an outbreak of Ebola virus disease following the introduction of the disease by an ill Liberian Traveler. The Government of Nigeria with the support of Technical and Development Partners responded quickly and effectively to contain the outbreak. The epidemiological profile of the outbreak that majorly affected two States in the country in terms of person, place and time characteristics of the cases identified is hereby described. METHODS: Using field investigation technique, all confirmed and probable cases were identified, line-listed and analysed using Microsoft Excel 2007 by persons, time and place. RESULTS: A total of 20 confirmed and probable cases; 16 in Lagos (including the index case from Liberia) and 4 in Port Harcourt were identified. The mean age was 39.5 +/- 12.4 years with over 40% within the age group 30-39 years. The most frequent exposure type was direct physical contact in 70% of all cases and 73% among health care workers. The total case fatality was 40%; higher among healthcare workers (46%) compared with non healthcare workers (22%). The epidemic curve initially shows a typical common source outbreak, followed by a propagated pattern. CONCLUSION: Investigation revealed the size and spread of the outbreak and provided information on the characteristics of persons, time and place. Enhanced surveillance measures, including contact tracing and follow- up proved very useful in early case detection and containment of the outbreak. PMID- 26587178 TI - Using giant African pouched rats to detect human tuberculosis: a review. AB - Despite its characteristically low sensitivity, sputum smear microscopy remains the standard for diagnosing tuberculosis (TB) in resource-poor countries. In an attempt to develop an alternative or adjunct to microscopy, researchers have recently examined the ability of pouched rats to detect TB-positive human sputum samples and the microbiological variables that affect their detection. Ten published studies, reviewed herein, suggest that the rats are able to detect the specific odor of Mycobacterium tuberculosis, which causes TB, and can substantially increase new-case detections when used for second-line TB screening following microscopy. Further research is needed to ascertain the rats' ability to detect TB in children and in HIV-positive patients, to detect TB when used for first-line screening, and to be useful in broad-scale applications where cost effectiveness is a major consideration. PMID- 26587179 TI - Aesthetic Dermatologic Treatments: Consensus from the Experts. PMID- 26587180 TI - Nitric Oxide Regulates Neurogenesis in the Hippocampus following Seizures. AB - Hippocampal neurogenesis is changed by brain injury. When neuroinflammation accompanies injury, activation of resident microglial cells promotes the release of inflammatory cytokines and reactive oxygen/nitrogen species like nitric oxide (NO). In these conditions, NO promotes proliferation of neural stem cells (NSC) in the hippocampus. However, little is known about the role of NO in the survival and differentiation of newborn cells in the injured dentate gyrus. Here we investigated the role of NO following seizures in the regulation of proliferation, migration, differentiation, and survival of NSC in the hippocampus using the kainic acid (KA) induced seizure mouse model. We show that NO increased the proliferation of NSC and the number of neuroblasts following seizures but was detrimental to the survival of newborn neurons. NO was also required for the maintenance of long-term neuroinflammation. Taken together, our data show that NO positively contributes to the initial stages of neurogenesis following seizures but compromises survival of newborn neurons. PMID- 26587181 TI - Draft genome sequence of Cellulomonas carbonis T26(T) and comparative analysis of six Cellulomonas genomes. AB - Most Cellulomonas strains are cellulolytic and this feature may be applied in straw degradation and bioremediation. In this study, Cellulomonas carbonis T26(T), Cellulomonas bogoriensis DSM 16987(T) and Cellulomonas cellasea 20108(T) were sequenced. Here we described the draft genomic information of C. carbonis T26(T) and compared it to the related Cellulomonas genomes. Strain T26(T) has a 3,990,666 bp genome size with a G + C content of 73.4 %, containing 3418 protein coding genes and 59 RNA genes. The results showed good correlation between the genotypes and the physiological phenotypes. The information are useful for the better application of the Cellulomonas strains. PMID- 26587182 TI - Surgery versus Conservative Treatment for Spontaneous Supratentorial Intracerebral Hemorrhage in Spot Sign Positive Patients. AB - OBJECTIVE: An advantage of surgical treatment over conservative treatment of spontaneous intracerebral hemorrhage (ICH) is controversial. Recent reports suggest that contrast extravasations on CT angiography (CTA) might serve as a crucial predictor of hematoma expansion and mortality. The purpose of this study was aimed at investigating the efficacy of surgical treatment in patients with spot sign positive ICH. METHODS: We used our institutional medical data search system to identify all adult patients who admitted for treatment of ICH between January 1, 2007 and January 31, 2012. Patients were classified two groups into a surgical group (n=27) and a conservative treatment group (n=28). Admission criteria were the following: age 20-79 years, spontaneous supratentorial ICH, Glasgow Coma Score Ranging from 9 to 14, ICH volume >=20 mL, and treatment within 24 hours. RESULTS: Fifty-five patients were analyzed. There was no significant difference in the ICU stay between the conservative treatment group (7.36+/-3.66 days) and the surgical treatment group (6.93+/-2.20 days; p=0.950). There was a significant difference in the in-hospital stay between the conservative treatment group (13.93+/-8.87 days) and the surgical treatment group (20.33+/-6.37 days; p=0.001). Overall mortality at day 90 after ICH was 36.4%; this included 16 of 28 patients (57.1%) in the conservative group and 4 of 27 patients (14.8%) in the surgical group. In univariate analysis, there was a positive effect of the surgical treatment in reducing mortality at 90 days (p=0.002), Glasgow Outcome Scale (GOS) at 90-day (p=0.006), and modified Rankin Scale (mRS) at 90-day (p=0.023). In multivariate logistic analysis, there was a significant difference in mortality (odds ratio, 0.211; 95% confidence interval, 0.049-0.906; p=0.036) between the groups at 90-day follow-up. However, there was no significant difference in GOS (odds ratio, 0.371; 95% confidence interval, 0.031-4.446; p=0.434) and mRS (odds ratio, 1.041; 95% confidence interval, 0.086-12.637; p=0.975) between the groups at 90-day follow-up. CONCLUSION: In this study of surgical treatment of supratentorial ICH in patients with spot sign positive in CTA was associated with less mortality despite of long duration of in-hospital stay. We failed to show that clinical outcome benefit of surgical treatment compared with conservative treatment in patients with spot sign positive ICH. PMID- 26587183 TI - Clinical Analysis Comparing Efficacy between a Distal Filter Protection Device and Proximal Balloon Occlusion Device during Carotid Artery Stenting. AB - OBJECTIVE: The main concern during transfemoral carotid artery stenting (CAS) is preventing cerebral embolus dislodgement. We compared clinical outcomes and intraprocedural embolization rates of CAS using a distal filter protection device or proximal balloon occlusion device. METHODS: From January 2011 to March 2015, a series of 58 patients with symptomatic or asymptomatic internal carotid artery stenosis >=70% were treated with CAS with embolic protection device in single center. All patients underwent post-CAS diffusion-weighted magnetic resonance imaging (DW-MRI) to detect new ischemic lesions. We compared clinical outcomes and postprocedural embolization rates. RESULTS: CAS was performed in all 61 patients. Distal filter protection success rate was 96.6% (28/29), whose mean age was 70.9 years, and mean stenosis was 81%. Their preprocedural infarction rate was 39% (11/28). Subsequent DW-MRI revealed 96 new ischemic lesions in 71% (20/28) patients. In contrast, the proximal balloon occlusion device success rate was 93.8% (30/32), whose mean age was 68.8 years and mean stenosis was 86%. Preprocedure infarction rate was 47% (14/30). DW-MRI revealed 45 new ischemic lesions in 57% (17/30) patients. Compared with distal filter protection device, proximal balloon occlusion device resulted in fewer ischemic lesions per patient (p=0.028). In each group, type of stent during CAS had no significant effect on number of periprocedural embolisms. Only 2 neurologic events occurred in the successfully treated patients (one from each group). CONCLUSION: Transfemoral CAS with proximal balloon occlusion device achieves good results. Compared with distal filter protection, proximal balloon occlusion might be more effective in reducing cerebral embolism during CAS. PMID- 26587184 TI - Extent of Contrast Enhancement on Non-Enhanced Computed Tomography after Intra Arterial Thrombectomy for Acute Infarction on Anterior Circulation: As a Predictive Value for Malignant Brain Edema. AB - OBJECTIVE: To determine whether the use of contrast enhancement (especially its extent) predicts malignant brain edema after intra-arterial thrombectomy (IAT) in patients with acute ischemic stroke. METHODS: We reviewed the records of patients with acute ischemic stroke who underwent IAT for occlusion of the internal carotid artery or the middle cerebral artery between January 2012 and March 2015. To estimate the extent of contrast enhancement (CE), we used the contrast enhancement area ratio (CEAR)-i.e., the ratio of the CE to the area of the hemisphere, as noted on immediate non-enhanced brain computed tomography (NECT) post-IAT. Patients were categorized into two groups based on the CEAR values being either greater than or less than 0.2. RESULTS: A total of 39 patients were included. Contrast enhancement was found in 26 patients (66.7%). In this subgroup, the CEAR was greater than 0.2 in 7 patients (18%) and less than 0.2 in the other 19 patients (48.7%). On univariate analysis, both CEAR >=0.2 and the presence of subarachnoid hemorrhage were significantly associated with progression to malignant brain edema (p<0.001 and p=0.004), but on multivariate analysis, only CEAR >=0.2 showed a statistically significant association (p=0.019). In the group with CEAR >=0.2, the time to malignant brain edema was shorter (p=0.039) than in the group with CEAR <0.2. Clinical functional outcomes, based on the modified Rankin scale, were also significantly worse in patients with CEAR >=0.2 (p=0.003). CONCLUSION: The extent of contrast enhancement as noted on NECT scans obtained immediately after IAT could be predictive of malignant brain edema and a poor clinical outcome. PMID- 26587185 TI - High-Dose Simvastatin Is Effective in Preventing Cerebral Vasospasm after Aneurysmal Subarachnoid Hemorrhage: A Prospective Cohort Study in Korean Patients. AB - OBJECTIVE: The goal of this study was to assess the effect of high-dose simvastatin on cerebral vasospasm and its clinical outcome after aneurysmal subarachnoid hemorrhage (SAH) in Korean patients. METHODS: This study was designed as a prospective observational cohort study. Its subjects were aneurysmal SAH patients who had undergone aneurysm clipping or coiling. They were assigned to 1 of 3 groups : the 20 mg, 40 mg, and 80 mg simvastatin groups. The primary end-point was the occurrence of symptomatic vasospasm. The clinical outcome was assessed with the modified Rankin Scale (mRS) score after 1 month and 3 months. The risk factors of the development of vasospasm were assessed by logistic regression analysis. RESULTS: Ninety nine patients with aneurysmal SAH were treated and screened. They were sequentially assigned to the 20 mg (n=22), 40 mg (n=34), and 80 mg (n=31) simvastatin groups. Symptomatic vasospasm occurred in 36.4% of the 20 mg group, 8.8% of the 40 mg group, and 3.2% of the 80 mg group (p=0.003). The multiple logistic regression analysis showed that poor Hunt-Hess grades (OR=5.4 and 95% CI=1.09-26.62) and high-dose (80 mg) simvastatin (OR=0.09 and 95% CI=0.1-0.85) were independent factors of symptomatic vasospasm. The clinical outcomes did not show a significant difference among the three groups. CONCLUSION: This study demonstrated that 80 mg simvastatin treatment was effective in preventing cerebral vasospasm after aneurysmal SAH, but did not improve the clinical outcome in Korean patients. PMID- 26587186 TI - Upfront Stereotactic Radiosurgery for Pineal Parenchymal Tumors in Adults. AB - OBJECTIVE: Pineal parenchymal tumors (PPTs) in adults are rare, and knowledge regarding their optimal management and treatment outcome is limited. Herein, we present the clinical results of our series of PPTs other than pineoblastomas managed by stereotactic radiosurgery (SRS) at upfront setting. METHODS: Between 1997 and 2014, nine consecutive adult patients with the diagnosis of PPTs, either pineocytoma or pineal parenchymal tumor of intermediate differentiation, were treated with SRS. There were 6 men and 3 women. The median age was 39 years (range, 31-53 years). All of the patients presented with symptoms of hydrocephalus. Endoscopic third ventriculostomy and biopsy was done for initial management. After histologic diagnosis, patients were treated with Gamma Knife with the mean dose of 13.3 Gy (n=3) or fractionated Cyberknife with 32 Gy (n=6). RESULTS: After a mean follow-up of 78.6 months (range, 14-223 months), all patients were alive and all of their tumors were locally controlled except for one instance of cerebrospinal fluid seeding metastasis. On magnetic resonance images, tumor size decreased in all patients, resulting in complete response in 3 patients and partial response in 6. One patient had experienced temporary memory impairment after SRS, which improved spontaneously. CONCLUSION: SRS is effective and safe for PPTs in adults and can be considered as a useful alternative to surgical resection at upfront setting. PMID- 26587187 TI - The Effect of the Pedicle-Facet Angle on Degenerative Cervical Spondylolisthesis. AB - OBJECTIVE: To measure the orientation of the facet joints of cervical spine (C spine) segments in the sagittal plane, known as the pedicle-facet (P-F) angle, and to use these measurements to evaluate the relationship between the P-F angle and the amount of vertebral anterolisthesis in patients with degenerative cervical spondylolisthesis (DCS). METHODS: A retrospective case-control study was performed including 30 age- and sex-matched patients with DCS and 30 control participants. Anterior-posterior and lateral view radiographs of the C-spine were obtained in a standing position. The P-F angle at all cervical levels and the amount of anterolisthesis at C4-5 were measured from lateral view plain radiographs. RESULTS: The P-F angles at C4-5 were 141.14+/-7.14 degrees for the DCS group and 130.53+/-13.50 degrees (p=0.012) for the control group, and at C5 6 were 137.46+/-8.53 degrees for the DCS group and 128.53+/-16.01 degrees for the control group (p=0.001). The mean P-F angle at C4-5 did not correlate with the amount of anterolisthesis (p=0.483). The amount of anterior slippage did correlate with age (p<0.001). CONCLUSION: The P-F angle was intrinsically higher at C4-5, compared to C5-6, in both the DCS and control groups, which might explain the increased likelihood for anterolisthesis of C4. Higher P-F angles in the DCS group may be a predisposing factor to slippage. The P-F angle may interact with age to increase incidence of anterolisthesis with increasing age. PMID- 26587188 TI - Usefulness of Fracture Risk Assessment Tool Using Lumbar Bone Mineral Density in Prediction of Osteoporotic Vertebral Fracture. AB - OBJECTIVE: To investigate the value of lumbar bone mineral density (BMD) in fracture risk assessment (FRAX) tool. METHODS: One hundred and ten patients aged over 60 years were enrolled and divided into 2 groups as non-osteoporotic vertebral fracture (OVF) and OVF groups. The 10-year-risk of major osteoporotic vertebral fracture of each group was calculated by FRAX tool with femoral and lumbar spine BMDs to compare the usefulness of lumbar spine BMD in prediction of OVF. The blood level of osteocalcin and C-terminal telopeptide (CTX) as markers of activities of osteoblast and osteoclast, respectively were analyzed using the institutional database. RESULTS: In the OVF group, the ratio of patients with previous fracture history or use of glucocorticoid was higher than those in non OVF group (p=0.000 and 0.030, respectively). The levels of T-score of femur neck and lumbar spine in OVF group were significantly lower than those in non-OVF group (p=0.001 and 0.000, respectively). The risk of OVF in FRAX using femur BMD in non-OVF and OVF groups was 6.7+/-6.13 and 11.4+/-10.06, respectively (p=0.007). The risk of using lumbar BMD in the 2 groups was 6.9+/-8.91 and 15.1+/ 15.08, respectively (p=0.002). The areas under the receiver operator characteristic curve in the FRAX risk with lumbar and femur neck BMD were 0.726 and 0.684, respectively. The comparison of osteocalcin and CTX was not significant (p=0.162 and 0.369, respectively). CONCLUSION: In our study, the 10 year risk of major osteoporotic fracture in the OVF group of our study was lower than the recommended threshold of intervention for osteoporosis. Hence, a lower threshold for the treatment of osteoporosis may be set for the Korean population to prevent OVF. In the prediction of symptomatic OVF, FRAX tool using lumbar spine BMD may be more useful than that using femur neck BMD. PMID- 26587189 TI - Acute Contralateral Radiculopathy after Unilateral Transforaminal Lumbar Interbody Fusion. AB - OBJECTIVE: Cases of contralateral radiculopathy after a transforaminal lumbar interbody fusion with a single cage (unilateral TLIF) had been reported, but the phenomenon has not been explained satisfactorily. The purpose of this study was to determine its incidence, causes, and risk factors. METHODS: We did retrospective study with 546 patients who underwent a unilateral TLIF, and used CT and MRI to study the causes of contralateral radicular symptoms that appeared within a week postoperatively. Clinical and radiological results were compared by dividing the patients into the symptomatic group and asymptomatic group. RESULTS: Contralateral symptoms occurred in 32 (5.9%) of the patients underwent unilateral TLIF. The most common cause of contralateral symptoms was a contralateral foraminal stenosis in 22 (68.8%), screw malposition in 4 (12.5%), newly developed herniated nucleus pulposus in 3 (9.3%), hematoma in 1 (3.1%), and unknown origin in 2 patients (6.3%). 16 (50.0%) of the 32 patients received revision surgery. There was no difference in visual analogue scale and Oswestry disability index between the two groups at discharge. Both preoperative and postoperative contralateral foraminal areas were significantly smaller, and postoperative segmental angle was significantly greater in the symptomatic group comparing to those of the asymptomatic group (p<0.05). CONCLUSION: The incidence rate is not likely to be small (5.9%). If unilateral TLIF is performed for cases when preoperative contralateral foraminal stenosis already exists or when a large restoration of segmental lordosis is required, the probability of developing contralateral radiculopathy is increased and caution from the surgeon is needed. PMID- 26587190 TI - The Effects of Spinopelvic Parameters and Paraspinal Muscle Degeneration on S1 Screw Loosening. AB - OBJECTIVE: To investigate risk factors for S1 screw loosening after lumbosacral fusion, including spinopelvic parameters and paraspinal muscles. METHODS: We studied with 156 patients with degenerative lumbar disease who underwent lumbosacral interbody fusion and pedicle screw fixation including the level of L5 S1 between 2005 and 2012. The patients were divided into loosening and non loosening groups. Screw loosening was defined as a halo sign larger than 1 mm around a screw. We checked cross sectional area of paraspinal muscles, mean signal intensity of the muscles on T2 weight MRI as a degree of fatty degeneration, spinopelvic parameters, bone mineral density, number of fusion level, and the characteristic of S1 screw. RESULTS: Twenty seven patients showed S1 screw loosening, which is 24.4% of total. The mean duration for S1 screw loosening was 7.3+/-4.1 months after surgery. Statistically significant risk factors were increased age, poor BMD, 3 or more fusion levels (p<0.05). Among spinopelvic parameters, a high pelvic incidence (p<0.01), a greater difference between pelvic incidence and lumbar lordotic angle preoperatively (p<0.01) and postoperatively (p<0.05). Smaller cross-sectional area and high T2 signal intensity in both multifidus and erector spinae muscles were also significant muscular risk factors (p<0.05). Small converging angle (p<0.001) and short intraosseous length (p<0.05) of S1 screw were significant screw related risk factors (p<0.05). CONCLUSION: In addition to well known risk factors, spinopelvic parameters and the degeneration of paraspinal muscles also showed significant effects on the S1 screw loosening. PMID- 26587191 TI - Clinical Utility of an Automated Pupillometer in Patients with Acute Brain Lesion. AB - OBJECTIVE: The purpose of this study was to evaluate the clinical utility and validity of using a pupillometer to assess patients with acute brain lesions. METHODS: Pupillary examinations using an automated pupillometer (NeurOptics(r)NPiTM-100 Pupillometer) were performed every 4 hours and were simultaneously assessed using the Glasgow Coma Scale (GCS) and for intracranial pressure (ICP), from admission to discharge or expire in neuro-intensive care unit (NICU). Manual pupillary examinations were also recorded for comparison. By comparing these data, we evaluated the validity of using automated pupillometers to predict clinical outcomes. RESULTS: The mean values of the Neurologic Pupillary index (NPi) were different in the groups examined manually. The GCS correlated well with NPi values, especially in severe brain injury patients (GCS below 9). However, the NPi values were weakly correlated with intracranial pressure (ICP) when the ICP was lower than 30 cm H2O. The NPi value was not affected by age or intensity of illumination. In patients with a "poor" prognosis who had a Glasgow Outcome Scale (GOS) of 1 or 2, the mean initial NPi score was 0.88+/-1.68, whereas the value was 3.89+/-0.97 in patients with a "favorable" prognosis who had a GOS greater than 2 (p<0.001). For predicting clinical outcomes, the initial NPi value of 3.4 had the highest sensitivity and specificity. CONCLUSION: An automated pupillometer can serve as a simple and useful tool for the accurate measurement of pupillary reactivity in patients with acute brain lesions. PMID- 26587192 TI - Chronological Changes of C-Reactive Protein Levels Following Uncomplicated, Two Staged, Bilateral Deep Brain Stimulation. AB - OBJECTIVE: The occurrence of acute cerebral infection following deep brain stimulation (DBS) is currently being reported with elevation of C-reactive protein (CRP) level. The aim of the present study was to establish normal range of the magnitude and time-course of CRP increases following routine DBS procedures in the absence of clinical and laboratory signs of infection. METHODS: A retrospective evaluation of serial changes of plasma CRP levels in 46 patients undergoing bilateral, two-staged DBS was performed. Because DBS was performed as a two-staged procedure involving; implantation of lead and internal pulse generator (IPG), CRP was measured preoperatively and postoperatively every 2 days until normalization of CRP (post-lead implantation day 2 and 4, post-IPG implantation day 2, 4, and 6). RESULTS: Compared with preoperative CRP levels (0.12+/-0.17 mg/dL, n=46), mean CRP levels were significantly elevated after lead insertion day 2 and 4 (1.68+/-1.83 mg/dL, n=46 and 0.76+/-0.38 mg/dL, n=16, respectively, p<0.001). The mean CRP levels at post-lead implantation day 2 were further elevated at post-IPG implantation day 2 (3.41+/-2.56 mg/dL, n=46, respectively, p<0.01). This elevation in post-IPG day 2 rapidly declined in day 4 (1.24+/-1.29 mg/dL, n=46, p<0.05) and normalized to preoperative value at day 6 (0.42+/-0.33 mg/dL, n=46, p>0.05). Mean CRP levels after IPG implantation were significantly higher in patients whose IPGs were implanted at post-lead day 3 than those at post-lead day 5-6 (3.99+/-2.80 mg/dL, n=30, and 2.31+/-1.56 mg/dL, n=16, respectively, p<0.05). However, there was no difference in post-IPG day 2 and 4 between them (p>0.05). CONCLUSION: The mean postoperative CRP levels were highest on post-IPG insertion day 2 and decreased rapidly, returning to the normal range on post-IPG implantation day 6. The duration of post-lead implantation period influenced the magnitude of CRP elevation at post-IPG insertion day 2. Information about the normal response of CRP following DBS could help to avoid unnecessary diagnostic and therapeutic efforts. PMID- 26587193 TI - Stereotactic Hematoma Removal of Spontaneous Intracerebral Hemorrhage through Parietal Approach. AB - OBJECTIVE: To determine the advantages of parietal approach compared to Kocher's point approach for spontaneous, oval-shaped intracerebral hemorrhage (ICH) with expansion to the parietal region. METHODS: We divided patients into two groups : group A had burr holes in the parietal bone and group B had burr holes at Kocher's point. The hematoma volume, Glasgow coma scale (GCS) score, and modified Barthel Index (mBI) score were calculated. At discharge, we evaluated the patients' Glasgow outcome scale (GOS) score, modified Rankin Scale (mRS) score, motor grade, and hospitalization duration. We evaluated the patients' mBI scores and motor grades at 6 months after surgery. RESULTS: The hematoma volume in group A was significantly less than that in group B on postoperative days 1, 3, 5, 7, 14, and 21. Group A had significantly higher GCS scores than did group B on postoperative days 1 and 3. Group A had higher mBI scores postoperatively than did group B, but the scores were not significantly different. No differences were observed for the GOS score, mRS score, motor grade at discharge, or duration of hospitalization. The mBI score of group A at 6 months after surgery was significantly higher, and more patients in group A showed muscle strength improvement. CONCLUSION: In oval-shaped ICH with expansion to the parietal region, the parietal approach is considered to improve the clinical symptoms at the acute phase by removing the hematoma more effectively in the early stages. The parietal approach might help promote the long-term recovery of motor power. PMID- 26587194 TI - Peritumoral Brain Edema after Stereotactic Radiosurgery for Asymptomatic Intracranial Meningiomas: Risks and Pattern of Evolution. AB - OBJECTIVE: To investigate the risks and pattern of evolution of peritumoral brain edema (PTE) after stereotactic radiosurgery (SRS) for asymptomatic intracranial meningiomas. METHODS: A retrospective study was conducted on 320 patients (median age 56 years, range 24-87 years) who underwent primary Gamma Knife radiosurgery for asymptomatic meningiomas between 1998 and 2012. The median tumor volume was 2.7 cc (range 0.2-10.5 cc) and the median follow-up was 48 months (range 24-168 months). Volumetric data sets for tumors and PTE on serial MRIs were analyzed. The edema index (EI) was defined as the ratio of the volume of PTE including tumor to the tumor volume, and the relative edema indices (rEIs) were calculated from serial EIs normalized against the baseline EI. Risk factors for PTE were analyzed using logistic regression. RESULTS: Newly developed or increased PTE was noted in 49 patients (15.3%), among whom it was symptomatic in 28 patients (8.8%). Tumor volume larger than 4.2 cc (p<0.001), hemispheric tumor location (p=0.005), and pre-treatment PTE (p<0.001) were associated with an increased risk of PTE. rEI reached its maximum value at 11 months after SRS and decreased thereafter, and symptoms resolved within 24 months in most patients (85.7%). CONCLUSION: Caution should be exercised in decision-making on SRS for asymptomatic meningiomas of large volume (>4.2 cc), of hemispheric location, or with pre-treatment PTE. PTE usually develops within months, reaches its maximum degree until a year, and resolves within 2 years after SRS. PMID- 26587195 TI - Low Grade Myofibroblastic Sarcoma Occurred in the Scalp. AB - Low-grade myofibroblastic sarcoma (LGMS) is a rare sarcoma with myofibroblastic differentiation. LGMS has a propensity for local recurrence and is associated with a low risk of metastatic spread. A 26-year-old man presented with a 12-month history of a slow growing palpable hard mass in the right parietal scalp. Enhanced CT scan of head showed a 3*4 cm sized well-defined and heterogeneously enhancing scalp mass. The patient underwent excision of the tumor. The histological and immunohistochemical features were consistent with a LGMS. We performed re-operation for remnant tumor removal after diagnosis. After 14 months of surgery, the patient was well-being state. PMID- 26587196 TI - Brown Tumor of the Thoracic Spine: First Manifestation of Primary Hyperparathyroidism. AB - Brown tumors also called as osteoclastomas, are rare nonneoplastic lesions that arise in the setting of primary or secondary hyperparathyroidism. Parathyroid adenomas or hyperplasia constitute the major Brown tumor source in primary hyperparathyroidism while chronic renal failure is the leading cause in secondary hyperparathyroidism. Most of the patients with the diagnosis of primary hyperparathyroidism present with kidney stones or isolated hypercalcemia. However, nearly one third of patients are asymptomatic and hypercalcemia is found incidentally. Skeletal involvement such as generalized osteopenia, bone resorption, bone cysts and Brown tumors are seen on the late phase of hyperparathyroidism. The symptoms include axial pain, radiculopathy, myelopathy and myeloradiculopathy according to their locations. Plasmocytoma, lymphoma, giant cell tumors and metastates should be ruled out in the differential diagnosis of Brown tumors. Treatment of Brown tumors involve both the management of hyperparathyroidism and neural decompression. The authors report a very rare spinal Brown tumor case, arisen as the initial manifestation of primary hyperparathyroidism that leads to acute paraparesis. PMID- 26587197 TI - Radiculopathy as Delayed Presentations of Retained Spinal Bullet. AB - Bullet injuries to the spine may cause injury to the anatomical structures with or without neurologic deterioration. Most bullet injuries are acute, resulting from direct injury. However, in rare cases, delayed injury may occur, resulting in claudication. We report a case of intradural bullet at the L3-4 level with radiculopathy in a 30-year-old male. After surgical removal, radicular and claudicating pain were improved significantly, and motor power of the right leg also improved. We report the case of intradural bullet, which resulted in delayed radiculopathy. PMID- 26587198 TI - Spinal Subdural Hematoma Associated with Intracranial Subdural Hematoma. AB - The simultaneous occurrence of an intracranial and a spinal subdural hematoma (SDH) is rare. We describe a case of cranial SDH with a simultaneous spinal SDH. An 82-year-old woman visited the emergency room because of drowsiness and not being able to walk 6 weeks after falling down. A neurological examination showed a drowsy mentality. Brain computed tomography showed bilateral chronic SDH with an acute component. The patient underwent an emergency burr-hole trephination and hematoma removal. She exhibited good recovery after the operation. On the fourth postoperative day, she complained of low-back pain radiating to both lower limbs, and subjective weakness of the lower limbs. Spine magnetic resonance imaging revealed a thoracolumbosacral SDH. A follow-up spinal magnetic resonance imaging study that was performed 16 days later showed a significant decrease in the size of the spinal SDH. We discuss the pathogenesis of this simultaneous occurrence of spinal and cranial SDH. PMID- 26587199 TI - Ophthalmology in Persian medicine. AB - Despite the fact that ophthalmology is one of the foremost branches of medicine, conceptualization of the structure and function of the eye barely advanced in ancient Western civilizations. At the early recovery of Persian civilization (9(th) century AD) after the extinction of the Sassanid Empire (7(th) century AD), translations of Greek medical textbooks played an important role in the development of medicine and the emergence of great Persian physicians such as Rhazes, Avicenna and others. Rhazes was a leading Persian physician whose medical teachings have as yet not been thoroughly explored. In addition to numerous books and articles in various fields, he authored a great medical Encyclopedia (al-Hawi al-Kabir) in 25 volumes. In this article, we are going to compare Rhazes' particular viewpoints about ophthalmology with those of other famous Persian physicians and some recent essays and textbooks. For this purpose we reviewed Rhazes' second volume of al-Hawi that is dedicated exclusively to ophthalmology and contains some major topics of ophthalmology including anatomy, physiology, pathology, diseases, disorders and treatments. Important themes were carefully extracted and compared with the tenets of modern ophthalmology. After collating Rhazes' viewpoints with the latest findings in this field, it was concluded that he had brilliantly written about the signs and symptoms, etiology and treatment of many eye disorders more than a thousand years ago. The amazing point is that there was no accurate equipment at the time to help him in his investigations. This study proved that Rhazes' theories conform to recent knowledge about ophthalmology in many aspects, and could therefore be the subject of further investigations. PMID- 26587200 TI - Status of human dignity of adult patients admitted to hospitals of Tehran. AB - Maintaining dignity and respect is among patients' most fundamental rights. The importance of patient dignity, the status quo, patients' needs, and a shortage of survey studies in this area were the underlying incentives for conducting this study. This was a cross-sectional descriptive study in which data were collected through Patient Dignity Inventory (PDI). The questionnaire was completed by 280 inpatients in 2012 to determine their perspectives on their personal state of human dignity. In this study, the mean score of patients' dignity was 1.89 out of 5 (SD = 0.81). Results indicated a significant relationship between type of hospital and the distress caused by disease symptoms, peace of mind, and social support (P < 0.05). There were also relationship between type of ward and dependency (P < 0.05), type of disease and dependency (P < 0.05), gender and social support (P < 0.05), household size and peace of mind (P < 0.05). The person's satisfaction with household income showed significant relationship with symptom distress, dependency and existential distress (P < 0.05). Results showed a significant inverse correlation between age and patient dignity (P = 0.005, r = - 0.166). However, the relationship between employment status, health insurance, education level and the above factors were insignificant. Studies indicate that there is a relationship between patients' dignity and mental distress, and therefore policy makers and health services officials should establish and implement plans to maintain and enhance patients' dignity in hospitals. Educating the health team, particularly the nurses can be very effective in maintaining patients' dignity and respect. PMID- 26587201 TI - The influence of theory on the formation of the infirmary during antiquity and the Middle Ages in the West. AB - The modern infirmary is the evolutional product of the dialectic interface between medical theories at each time and the outcome of their application in clinical practice. The infirmary as we know it today did not exist during antiquity, but the different precursors of the modern hospital emerged as a result of the interaction between medical theory and practice. During antiquity the Hippocratic work decisively contributed to the creation of the Asklipieion, an institution with predetermined structure created to heal diseases. Later in antiquity new types of infirmaries appeared along with the evolution of private practice for physicians. Establishment of the first modern hospitals was an outstanding contribution of Islamic medicine during reign of the Islamic Empire. Although there was little progress in the development of medical theory in medieval West, evolution of the infirmary continued and was mostly influenced by Christian religion and charity. In Constantinople large medieval infirmaries were built, but patient care was frequently offered in monasteries by clergymen. Later on medicine and treatment of diseases were taken over by physicians and taught in universities, and medical theory continued on its course of evolution. It is obvious that the modern infirmary is not only a place for treating diseases, but rather the upshot of a series of advancements in science, the relations between people or even countries, and the way humanity perceives its nature and the future. Our research is focused on the interactive relationship between the evolution of medical theory and the infirmary as an institution during antiquity and the Middle Ages with particular emphasis on the Western World. PMID- 26587202 TI - Continuing review of ethics in clinical trials: a surveillance study in Iran. AB - In recent years, notable measures have been taken to protect the rights of participants in biomedical research in Iran. The present study examines possible trends in adherence to ethical codes regarding informed consent after the development of the National Code of Ethics in Biomedical Research (NCEBR) and establishment of research ethics committees. In this retrospective study, 126 dissertations from Tehran University of Medical Sciences were evaluated for adherence to ethical codes. These dissertations were all in clinical trial design and had been presented in the years 1999 and 2009, that is, precisely before and after the development of the NCEBR. A checklist was developed to evaluate the ethical issues associated with informed consent. A single investigator retrieved and evaluated the consent forms from the dissertations. Borderline cases were discussed with other investigators to reach a consensus decision. Based on the checklist, the Standardized Ethical Score (SES) was calculated for each consent form. The mean SES and the rate of consent form attachment were compared between the two years. In total, 70 dissertations had reported obtaining informed consent from study participants, whereas consent forms were attached in only 22 dissertations (17.50%). The percentage of dissertations with the consent form attached increased over time from 12.2% in 1999 to 20.8% in 2009 (P > 0.05), but the majority still did not include a consent form. Moreover, the mean SES of consent forms was significantly higher in 1999 (0.746) than in 2009 (0.428), highlighting the need for more training of researchers and improved surveillance by the ethics committees. A great amount of effort is still needed to make the consent process more ethical, especially for dissertations as a less visible part of academic research. As for students, more systematic training focused on research ethics should be implemented prior to thesis submission. PMID- 26587203 TI - Organizing Hematoma of the Maxillary Sinus Mimicking Malignancy Diagnosed by Fluorodeoxyglucose Positron-Emission Tomography (FDG PET/CT): A Case Report. AB - Organizing hematoma of the paranasal sinuses is a diagnostic dilemma clinically and radiographically, mimicking benign or malignant neoplastic processes. Although the diagnostic rate of this disease has increased as characteristic imaging findings are somewhat elucidated, endoscopic examination, preoperative biopsy, and computed tomography (CT) imaging do not give helpful information in differentiating these lesions from malignant neoplastic processes. A 55-year-old man presented with a 4-month history of recurrent nasal bleeding. He also complained of a left-sided nasal obstruction. CT findings were highly suggestive of a malignant tumor of the maxillary sinus. However, based on fluorodeoxyglucose F(18) positron-emission tomography (PET/CT) and magnetic resonance imaging (MRI), the provisional diagnosis of benign tumor rather than malignancy was made. Complete resection of the mass was achieved by simple transnasal endoscopic surgery using the Caldwell-Luc approach. Organizing hematoma of the maxillary sinus was diagnosed by histopathologic evaluation. The clinical, radiological, and histopathologic findings of the patient are presented. In this report, we have presented (18)FDG-PET findings of organized hematoma of the maxillary sinus (OHMS) that showed an increased FDG uptake in the peripheral rim of the mass with central photopenia. To our knowledge, this is the first case report in the literature reporting FDG-PET/CT findings of OHMS. Careful interpretation of metabolic (FDG-PET/CT) and anatomic (CT and MRI) images should be performed to accurately characterize the expansile lesion of the maxillary sinus in order to increase specificity and reduce equivocal findings significantly. PMID- 26587204 TI - Chondromyxoid Fibroma of Two Cervical Vertebrae with Involvement of Surrounding Soft Tissue: Radiologic Diagnostic Dilemma. AB - Chondromyxoid fibroma is a rare benign cartilaginous neoplasm that mostly affects the metaphyseal region of the long bones. The tibia, small tubular bones of the foot, the distal femur and pelvis are common locations, but involvement of the vertebral bones, especially the cervical vertebra, is very rare. Radiographic features show typical characteristics and this tumor often presents as a lobulated, eccentric radiolucent lesion with no periosteal reaction. In addition, geographic bone destruction is seen in all cases. We present an adult female with a one-year history of neck pain, and ultrasound findings that suggest a right paravertebral muscular lesion due to inflammatory or neoplastic origins. The histopathological studies confirmed that the biopsied specimen was a chondromyxoid fibroma of the cervical vertebrae laminae and spinous processes (C3 and C4) with abutting soft tissue. Despite the unusual location and soft tissue presentation, a chondromyxoid fibroma should be considered in the differential diagnosis of a cervical bone lesion. PMID- 26587205 TI - Biofilm Formation and Virulence Factors Among Pseudomonas aeruginosa Isolated From Burn Patients. AB - BACKGROUND: Pseudomonas aeruginosa possesses a variety of virulence factors and infections caused by multidrug-resistant P. aeruginosa (MDRPA) in burn patients are a public health problem. OBJECTIVES: The aim of this study was to determine the antibiotic resistance pattern, the biofilm formation, the prevalence of MDRPA and two virulence genes (nan1 and exoA) among P. aeruginosa isolated from burn patients. PATIENTS AND METHODS: A total of 144 isolates of P. aeruginosa were collected from burn patient at the Burn Centre of Tehran, Iran, between March 2013 and July 2013. Antibiotic susceptibility test was performed via agar disk diffusion method. The ability of producing biofilm was examined by crystal violet microtiter plate assay and the prevalence of the exoA and nan1 genes among the isolates was determined by polymerase chain reaction (PCR). RESULTS: A high rate of resistance was seen against ciprofloxacin (93.7%), aztreonam (86.8%), piperacillin (85.4%), ceftazidime (82.6%), amikacin (82%) and imipenem (79.2%). In total, 93.1% of the isolates were characterized as MDRPA. Biofilm formation was seen in 92.4% of the isolates. The prevalence of the exoA and nan1 genes were 75% and 11.8% among the isolates, respectively. CONCLUSIONS: The high rate of MDRPA and its ability to produce biofilm is an alarm for public health. The statistical analysis showed that biofilm production in the MDRPA isolates was significantly higher than that in the non-MDRPA isolates (P < 0.001). PMID- 26587206 TI - Vaginal Protection by H2O2-Producing Lactobacilli. AB - BACKGROUND: Peroxide-producing lactobacilli provide protection from infection for the female reproductive tract. However, in vitro studies demonstrated that H2O2 produced by Lactobacillus is not the cause of inhibition of pathogens. It is not exactly known how H2O2-producing lactobacilli are involved in the protection of the vaginal environment. OBJECTIVES: This study aimed to evaluate the importance of the interaction between H2O2-producing lactobacilli and their host for the resistance of the vaginal biotope. MATERIALS AND METHODS: In this study, we used vaginal lactobacilli (11 H2O2-roducing strains and 11 non-H2O2-producing strains). The influence of epithelial cells on the growth and antibacterial activity of lactobacilli were evaluated. The effects of lactobacilli on the antibacterial activity of the epithelial cells, muramidase and lactoferrin were also determined. RESULTS: Vaginal epithelial cells stimulated the growth and antibacterial activity of H2O2-producing lactobacilli in a greater extent than that of the non-H2O2-producing lactobacilli. Mainly, the H2O2-producing lactobacilli were capable of increasing the activity of the host antimicrobial peptides (muramidase and lactoferrin) as well as the antibacterial activity of the epithelial cells. CONCLUSIONS: The involvement of the peroxide-producing lactobacilli in the protection of vagina was due to their ability to effectively interact with the host. This is expressed on one side to stimulate the growth and antagonistic activity of lactobacilli and on the other side to increase the antibacterial activity of the host defense factors (muramidase, lactoferrin and metabolites of epithelial cells). PMID- 26587207 TI - High Recovery Rate of Non-albicans Candida Species Isolated From Burn Patients With Candidemia in Iran. AB - BACKGROUND: Blood stream infections (BSIs) are major causes of morbidity and mortality in burn patients. Microorganisms responsible for BSI are generally bacteria; however, Candida spp. are the infection agents in as many as 8% of all cases. Burn wound colonization and infections are generally the first steps to systemic infection. Candidemia in burn patients has been associated with high mortality and a prolonged hospital stay. OBJECTIVES: Candidemia in burn patients has been defined as a preterminal event, leading to high morbidity and mortality rates among these patients. The aim of this study was to establish the incidence of candidemia in burn patients in Iran. PATIENTS AND METHODS: We consecutively collected 405 blood samples from 113 burn patients. The yeast isolates were identified to the species level using conventional procedures. In vitro antifungal susceptibility of the Candida isolates to amphotericin B, fluconazole, voriconazole and caspofungin was performed using the Etest. RESULTS: Twenty-seven samples (6.7%) of the blood cultures from 13 patients (12%) were positive for Candida species. Candida parapsilosis (38%) and C. tropicalis (38%) were the most commonly found Candida species, followed by C. albicans (15%) and C. guilliermondii (15%) in the patients. The incidence of candidemia was significantly correlated with increased duration of hospitalization, increased time of stay in the intensive care unit, and higher mortality. The antifungal susceptibility tests demonstrated that amphotericin B and voriconazole had the lowest minimum inhibitory concentrations (MICs) against Candida spp. CONCLUSIONS: Non-albicans Candida should be considered as significant pathogens in burned patients with candidemia. PMID- 26587208 TI - Antibiotic Resistance and Biofilm Formation of Enterococcus faecalis in Patient and Environmental Samples. AB - BACKGROUND: Enterococci are opportunistic pathogens and are a major factor in nosocomial infections. They may contain ebp operon, which upon expression makes them highly prone to biofilm formation on biotic and abiotic surfaces. OBJECTIVES: The aim of the current study was to detect the polymorphism of ebp genes in Enterococcus faecalis. MATERIALS AND METHODS: Samples were isolated from patients (n = 58) and hospital environments (n = 32) of two hospitals in Tehran, Iran. All enterococcal species were identified by species-specific polymerase chain reaction (PCR); the antibiotic resistance pattern against nine antibiotics was determined. The ebp A, ebp B, ebp C and srt C genes were detected by PCR and the biofilm formation by the isolates was evaluated using the microtiter plate method. The genetic diversity of ebp genes was analyzed by restriction fragment length polymorphism (RFLP). RESULTS: The results indicated that, 86% of patient and 29% of environmental isolates carried ebp genes. The ability of the isolates to strongly attach was 62% and 71% for patient and environmental samples, respectively. The RFLP of the ebp showed no genetic variations amongst the isolates. CONCLUSIONS: The results of the antibiotic resistance and other data suggest that there is a possible common clone of E. faecalis, which could rapidly disseminate in patients and the environment. PMID- 26587209 TI - Appropriate Genotyping of Hepatitis B Virus in Iran. PMID- 26587210 TI - Designing and Construction Pcdna3.1 Vector Encoding Cfp10 Gene of Mycobacterium tuberculosis. AB - BACKGROUND: Pathogenic mycobacteria are a major cause of human morbidity and mortality. Mycobacterium tuberculosis is an etiological agent of human tuberculosis (TB). Designing new vaccines, including DNA vaccines, may be a useful strategy for preventing TB. OBJECTIVES: The purpose of this study was to design and construct an eukaryotic expression vector containing M. tuberculosis. MATERIALS AND METHODS: Genomic DNA of M. tuberculosis H37Rv cultured on Lowenstein Jensen medium was extracted, and cfp10 was amplified by PCR. After digesting the PCR product and the plasmid, the cfp10 fragment was ligated into the vector pcDNA3.1 (+). Correct insertion was confirmed by colony PCR, restriction enzyme digestion, and sequencing. RESULTS: Electrophoresis of the PCR product on gel showed a 303-bp target fragment. Colony PCR, restriction enzyme digestion, and Sequencing methods confirmed the accuracy of the gene cloning. Colony PCR and restriction enzyme digestion confirmed the cloning. CONCLUSIONS: Cloning of cfp10 of M. tuberculosis into an eukaryotic expression vector was performed successfully. We propose this recombinant plasmid for inducing immunity in animal models in future studies. This recombinant vector can also be used in the construction of fusion proteins. PMID- 26587211 TI - Exploring the In Vitro Thrombolytic Activity of Nattokinase From a New Strain Pseudomonas aeruginosa CMSS. AB - BACKGROUND: Thrombolytic therapy has become a conventional treatment for acute myocardial infarction (AMI), yet currently, clinically prescribed thrombolytic drugs have problems such as delayed action and other side effects. Fibrinolytic enzymes have attracted interest as thrombolytic agents because of their efficiency in the fibrinolytic process, including plasmin activation. Nattokinase (NK) is a potent fibrinolytic agent for thrombosis therapy. OBJECTIVES: The aim of this study was to enhance the production of NK from Pseudomonas aeruginosa CMSS by media optimization and strain improvement. MATERIALS AND METHODS: In the present study, a potent NK-producing strain was isolated from cow milk and identified. To enhance the yield of NK, effect of various parameters such as pH, temperature, carbon source, nitrogen source and inoculum size were optimized. Strain improvement of P. aeruginosa CMSS was done by random UV-mutagenesis. Nattokinase was partially purified and the activity was determined by the casein digestion method, blood clot lysis and fibrin degradation assay. RESULTS: Based on morphological, biochemical and molecular characterization, the strain was confirmed as P. aeruginosa (GenBank accession number: JX112657), designated as P. aeruginosa CMSS. The optimum condition at pH 7 and temperature at 25C showed activity of NK as 1514 U mL(-1) and 1532 U mL(-1), respectively. Sucrose as the carbon source and shrimp shell powder (SSP) as the nitrogen source expressed NK activity of 1721 U mL(-1) and 2524 U mL(-1), respectively. At 1% inoculum size, the maximum rate of enzyme production was achieved with 2581 U mL(-1). The NK activity of the mutant strain UV60 was 4263 U mL(-1), indicating a two-fold increase in activity compared to the wild strain (2581 UmL(-1)). Nattokinase produced from mutant strain P. aeruginosa CMSS UV60 showed 94% blood clot lysis at ten minutes. The degradation of fibrin clot by the produced NK was observed after two hours of incubation. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) confirmed the molecular mass of CMSS UV60 NK to be 21kDa. CONCLUSIONS: The current study demonstrated the enhanced production of NK by P. aeruginosa CMSS. This study is unique and the findings are the first report on the production of NK from P. aeruginosa CMSS isolated from cow milk. PMID- 26587212 TI - Molecular Characterization of Pre-Core/Core and S Region of Hepatitis B Virus in Hemodialysis Patients With Occult Hepatitis B Infection. AB - BACKGROUND: Occult hepatitis B infection (OBI) is a major public health problem worldwide, which harbors potential risk of hepatitis B virus (HBV) transmission through blood transfusion and transplantation. OBI is characterized by the presence of HBV-DNA in the blood or liver tissue without detectable hepatitis B surface antigen (HBsAg) in the serum. An important cause of OBI is the occurrence of mutations in the HBV genome, especially in the S region. OBJECTIVES: The study aims to analyze mutations in S and pre-core/core regions of HBV-DNA in hemodialysis patients. PATIENTS AND METHODS: Sera of 216 hemodialysis patients were tested for HBsAg and hepatitis B core antibody (HBcAb) by ELISA. Sera of patients that tested negative for HBsAg were evaluated by PCR for the detection of HBV-DNA in the S and pre-core/core regions. In total, six PCR products were sequenced, aligned, and compared with the HBV reference sequence. Amino acid deletion and nucleotide substitution were considered mutations in S and pre core/core regions of HBV-DNA. RESULTS: Among 216 patients, 203 (93.98%) and 175 (81.01%) sera samples tested negative for HBsAg and HBcAb, respectively. Among all HBsAg-negative samples, six (2.9%) tested positive for HBV-DNA, including four (1.97%) for S and two (0.98%) for pre-core regions. All four (1.97%) samples that tested positive for the S region belonged to HBV-subtype awy. The amino acid sequence of all four samples showed the YMDD motif in position 204 (rtM204). There were three amino acid substitutions in the S region (T127P, P153L, and F170S) and one substitution in the RT region (Y135S). Moreover, two (0.98%) pre core/core positive patients had an unexpected stop codon in position 1896. CONCLUSIONS: This study indicates that 2.9% of hemodialysis patients had OBI, which is considered as a major public health problem worldwide. Moreover, we observed three mutations in S region, including T127P, P153L, and F170S, which caused OBI. This study is first to report a mutation analysis of HBV in hemodialysis patients in southwestern Iran. These results indicate that current screening tests based on HBsAg detection are not reliable for detection of HBV infection in dialysis patients. PMID- 26587213 TI - Prevalence and Genotype Characterization of Blastocystis hominis Among the Baghmalek People in Southwestern Iran in 2013 - 2014. AB - BACKGROUND: Blastocystis hominis is a common globally distributed parasite. The prevalence of this parasite has been shown to vary among different countries. Molecular studies have also shown that there is a high level of genetic diversity among Blastocystis spp. isolated from humans and animals. Extensive information on parasitic genotypes will aid in devising more effective strategies for the identification and potential control of these pathogenic parasites. OBJECTIVES: This study aimed to gain information on the prevalence and abundance of Blastocystis subtypes in Iran. MATERIALS AND METHODS: Over a period of 3 months, 1,410 stool samples were collected and examined by microscopy. Samples found to be positive for B. hominis were concentrated and phylogenetic analysis was subsequently performed. A questionnaire was completed by all study participants. RESULTS: Blastocystis hominis was found to have a prevalence of 3.33% in the study population. There was no significant association of Blastocystis infection with age (P = 0.3) or gender (P = 0.57). The Blastocystis subtypes (ST) identified in this study were ST3, ST4, ST5, and ST7 with the most prevalent being ST4 (40.9%). CONCLUSIONS: The prevalence of B. hominis in the study area was lower than that reported for most developed countries, and unlike in other countries in the Middle East, ST4 was the most prevalent subtype. PMID- 26587214 TI - Evaluation of the Antimicrobial Effect of Chitosan/Polyvinyl Alcohol Electrospun Nanofibers Containing Mafenide Acetate. AB - BACKGROUND: Chitosan, an important biodegradable and biocompatible polymer, has demonstrated wound-healing and antimicrobial properties. OBJECTIVES: This study aimed to evaluate the antimicrobial properties of mafenide acetate-loaded nanofibrous films, prepared by the electrospinning technique, using chitosan and polyvinyl alcohol (PVA). MATERIALS AND METHODS: A 3(2) full factorial design was used for formulating electrospinning solutions. The chitosan percentage in chitosan/PVA solutions (0%, 10%, and 30%) and the drug content (0%, 20%, and 40%) were chosen as independent variables. The release rate of mafenide acetate from nanofibrous films and their microbial penetration were evaluated. The antimicrobial activity of different nanofibrous film formulations against Staphylococcus aureus and Pseudomonas aeruginosa was studied. RESULTS: The results indicated that all nanofibrous films, with and without drug, can prevent bacterial penetration. Incorporation of mafenide acetate into chitosan/PVA nanofibers enhanced their antimicrobial activity against P. aeruginosa and S. aureus. CONCLUSIONS: Overall, the results showed that chitosan/polyvinyl alcohol (PVA) nanofibrous films are applicable for use as a wound dressing with protective, healing, and antimicrobial effects. PMID- 26587215 TI - The Prevalence of Demodex Species and Its Relationship With the Metabolic Syndrome in Women of Malatya Province, Turkey. AB - BACKGROUND: Demodex species are ectoparasites living in the hair follicles and sebaceous glands in human. Only two species, Demodex folliculorum and D. brevis were identified in human. While the D. folliculorum is settling in infundibular part of the hair follicles mostly, D. brevis settles into the sebaceous glands and ducts, which are deeper. These parasites live preferentially in hair follicles on the face and in the sebaceous glands, although they have also been reported to reside in seborrheic parts of the human body. The Demodex species have the highest rate on the face which has thesignificant number of sebaceous glands and sebum production in the skin. However, the rate of infestation increases with age in healthy skin. OBJECTIVES: The aim of this study was to determine the prevalence of Demodex species in healthy women and the relationship between the incidence of Demodex and metabolic syndrome (MetS). PATIENTS AND METHODS: This study consisted of 151,498 women aged >= 20 years who reside in the central district of Malatya province, Turkey. In 5% confidence interval of sample size, while the design effect was 1.5 it was calculated as 552 individuals and while the design effect was 2 it was calculated as 736 individuals. The World Health Organization 30 cluster sampling method was used to select the samples. Women aged >= 20 years who were not pregnant or lactating were included in the study. From a total of 669 subjects included in this study, 90.89% of the largest sample was accessed. RESULTS: Parasites were detected in 263 (39.3%) of 669 subjects and 3 of them were D. brevis. In chi-square analysis, nosignificant relationship was found between the incidence of the parasite, age, education level, occupation, marital status, family type, and MetS. However, a significant relationship was found between the diastolic pressure and those who fed with fatty foods and the incidence of parasite's occurrence. CONCLUSIONS: According to the results of this study, MetS has no effect on the frequency of occurrence of the parasite; however, weight, fatty foods, and high diastolic pressure are effective in the frequency of occurrence of the parasite. The effects of these factors on the incidence of parasites should be supported by further study designs. PMID- 26587216 TI - Serotype Replacement and Nasopharyngeal Carriage Due to the Introduction of New Pneumococcal Conjugate Vaccine to National Routine Immunization. PMID- 26587217 TI - Blood Culture Bottle and Standard Culture Bottle Methods for Detection of Bacterial Pathogens in Parapneumonic Pleural Effusion. AB - BACKGROUND: Bacterial parapneumonic pleural effusions (PPEs) have high morbidity. The accurate identification of pathogens is vital for initiating the appropriate treatment. A previous study suggested that the use of blood culture bottles might improve the bacterial yield in PPEs. OBJECTIVES: The aim of this study was to compare the culture positivity rate by the blood culture bottles and the standard culture bottles in bacterial PPEs. PATIENTS AND METHODS: Patients diagnosed with PPEs at the Khon Kaen Hospital, Khon Kaen, Thailand, which is an endemic area of melioidosis, were enrolled consecutively and prospectively. The study period was from June first, 2012 to December 31st, 2013. The inclusion criteria were adult patients aged > 18 years, with exudative, neutrophilic parapneumonic effusion. Of the pleural fluid samples, 5 mL from all the eligible patients were collected in both blood culture bottles and the standard culture bottles. Patient baseline characteristics, laboratory results, and culture results were collected and analyzed. RESULTS: During the study period, 129 patients met the study criteria. The bacteria-positive rate of pleural fluid culture using the standard culture bottle was 14.0%, whereas the positive rate using blood culture bottles was 24.0% (P < 0.001). CONCLUSIONS: The blood culture bottle method is more effective than the standard culture bottle method for the detection of bacterial pathogens in PPE. PMID- 26587218 TI - Analysis of Naturally Occurring Resistant Mutations to Hepatitis C Virus NS3 Protease Inhibitors: A Preliminary Study in South of Iran. AB - BACKGROUND: Exploring the rate of naturally occurring NS3 protease mutants in HCV infected population is influential in the future therapeutic approaches. OBJECTIVES: This study explored naturally occurring resistant mutations to protease inhibitors in a pilot study. PATIENTS AND METHODS: We analyzed NS3 gene sequences in 7 HCV infected patients, referred to the central liver center, south of Iran. The protease domain was amplified by PCR followed by product extraction. Amplified NS3 genes were cloned by TA/cloning system. For each patient, clonal sequencing was performed to improve mutation detection sensitivity. Then, the obtained sequences were compared with the reference sequences and final phylogenic tree was constructed. Afterwards, the sequences were studied to investigate point mutations. RESULTS: Phylogenetic analysis between reference and amplified sequences demonstrated high similarity of all sequences with genotype 1. Interestingly, crucial protease resistant mutations were detected in V36 and R155 positions in one patient's sequence. Checking different clones of this patient confirmed V36L, as the dominant mutation while R155K was detected only in a few cases. CONCLUSIONS: As revealed, naturally occurring resistant mutations, especially R155K in protease sequence were identified in 1 out of the 7 patients, so the rate of such mutations is estimated to be high. It seems that checking HCV patients before protease inhibitor treatment are necessary in the region. PMID- 26587219 TI - Evaluation of Prognostic Values of Tissue Plasminogen Activator and Plasminogen Activator Inhibitor-1 in Crimean-Congo Hemorrhagic Fever Patients. AB - BACKGROUND: Crimean-Congo hemorrhagic fever (CCHF) is a widespread disease in Turkey, and was responsible for many deaths in endemic regions during the last decade. The pathogenesis of the disease is not fully understood yet. OBJECTIVES: In this study we aimed to determine the levels of tissue plasminogen activator (tPA) and Plasminogen activator inhibitor-1 (PAI-1) as predictors of prognosis in CCHF. PATIENTS AND METHODS: Patients who were diagnosed by the polymerase chain reaction (PCR) and IgM positivity in the reference laboratory were included in this study. Tissue Plasminogen activator and PAI-1 levels were measured by the enzyme linked immunosorbent assay (ELISA) using a commercial kit (human t-PA ELISA and human PAL-1 ELISA; BioVendor research and diagnostic products, BioVendor-Laboratorni medicina a.s., Brno, Czech Republic). RESULTS: A total of 46 patients participated in this study. The significant differences between recovering patients and the patients who died, regarding Aspartate aminotransferase (AST), Creatine Phosphokinase (CPK), Lactate Dehydrogenase (LDH), Prothrombin Time (PT), activated Partial Thromboplastin time (aPTT), and thrombocyte and fibrinogen levels, were consistent with many clinical studies in the literature. The fatal cases were found to have higher tPA and PAI-1 levels in contrast to the patients who completely recovered. CONCLUSIONS: We think that these findings may help the progress of understanding of CCHF pathogenesis. PMID- 26587220 TI - Multidrug-Resistant Escherichia coli and Klebsiella pneumoniae Isolated From Patients in Kashan, Iran. AB - BACKGROUND: Escherichia coli and Klebsiella pneumoniae are common human pathogens that cause a wide spectrum of infections. Antimicrobial resistance is a basic obstacle in the management of these infections which has different patterns in various regions. OBJECTIVES: In this study, the antibiotic resistance patterns and risk factors for multidrug-resistant (MDR) E. coli and K. pneumoniae were determined. PATIENTS AND METHODS: In this cross-sectional study, a total of 250 isolates (134 E. coli and 116 K. pneumoniae) were collected and antimicrobial resistances to ampicillin, amoxicillin-clavulanic acid, amikacin, gentamycin, ceftriaxone, ceftazidime, ciprofloxacin and imipenem were evaluated by disc diffusion method and confirmed by E-test. Moreover, risk factors for MDR E. coli and K. pneumoniae were also detected. RESULTS: The mean ages of the culture positive cases of E. coli and K. pneumoniae were 33.39 +/- 24.42 and 36.54 +/- 24.66 years, respectively (P = 0.31); 137 (54.8%) cases were male and 113 (45.2%) were female (P = 0.53). Nineteen (14.2%) isolates of E. coli and 12 (10.3%) isolates of K. pneumoniae were sensitive to all the evaluated antibiotics. The prevalence of MDR E. coli and MDR K. pneumoniae was 50% and 46.6%, respectively (P = 0.59). The highest resistance for both strains was to ampicillin and no imipenem resistance was seen. The risk factors for MDR E. coli were admission history during the recent three months (P = 0.043) and antibiotic use in the previous month (P = 0.03); for MDR K. pneumoniae, they were admission in the pediatric ward (P = 0.016), surgical ward (P = 0.019), or gynecology ward (P = 0.12), admission duration of > seven days, and antibiotic use during the past month (P = 0.04). CONCLUSIONS: The prevalence of multidrug resistance was high compared with developed countries, and history of admission, antibiotic use, admission duration and admission wards were the risk factors for multidrug resistance. PMID- 26587221 TI - Characterization of CTX-M-Type Extend-Spectrum beta-Lactamase Producing Klebsiella spp. in Kashan, Iran. AB - CONTEXT: The CTX-M family consists of more than 50 beta-lactamases, which are grouped on the basis of sequences into five subtypes including CTX-M-1, CTX-M-2, CTX-M-8, CTX-M-9 and CTX-M-25. OBJECTIVES: The current study aimed to detect subtypes of CTX-M extended-spectrum beta-lactamases (ESBLs) among ESBL positive Klebsiella isolates from patients in Kashan, Iran. MATERIALS AND METHODS: A total of 100 clinical isolates of Klebsiella were collected and the isolates, which showed resistance or reduced susceptibility to cefotaxime, ceftazidime and/or aztreonam by the disk diffusion method were selected. These isolates were identified as ESBL-producing isolates by double disk synergy tests using clavulanic acid, cefotaxime, ceftazidime and aztreonam. The blaCTX-M type determinants were identified by the Polymerase Chain Reaction (PCR) method followed by DNA sequencing. RESULTS: Of the 100 Klebsiella isolates, 41 (41%) demonstrated resistance or reduced susceptibility to ceftazidime and/or aztreonam and 35% (n = 35) were ESBL-producers. Twenty-eight (8o%) of the ESBL-producing isolates carried the blaCTX-M type genes. Based on PCR assays and sequencing of blaCTX-M genes, CTX-M-1, CTX-M-2 and CTX-M-9 were identified in 21 (60%), 15 (42%) and nine (34%) of these isolates, respectively (GenBank accession numbers KJ803828-KJ803829). CONCLUSIONS: Our study showed that the frequency of blaCTX-M genes among Klebsiella isolates in our region is at an alarming rate. Also, we found a high prevalence of blaCTX-M-1 beta-lactamase in Klebsiella isolates in Kashan. PMID- 26587222 TI - Alveolar rhabdomyosarcoma confined to the bone marrow with no identifiable primary tumour using FDG-PET/CT. AB - BACKGROUND: Rhabdomyosarcoma (RMS), a malignant tumour of mesenchymal origin which can occur at various sites in the body, is one of the most common soft tissue sarcomas in both children and adolescents, but is rare in adults with a prevalence of less than 1 %. The alveolar subtype of rhabdomyosarcoma (ARMS) is typically characterized by a specific reciprocal chromosomal translocation involving the PAX3 and FKHR or PAX7 and FKHR genes, respectively. ARMS is most frequently seen in childhood, and typically affects the sinuses and soft tissue of the extremities, with approximately 23 % exhibiting metastasis to the marrow. Non-invasive F-18-fluorodeoxyglucose positron-emission tomography (FDG-PET) scans have a high ability to detect lymph nodes, bone, and bone marrow involvement in patients with metastatic RMS, often with higher sensitivity and specificity compared with conventional modalities. CASE PRESENTATION: Here, we report an unusual case of ARMS confined to the bone marrow in an older adult that lacked an identifiable primary tumour using FDG-PET/CT and mimicked a haematological disease with pancytopenia but without abnormal findings by FDG-PET/CT. The patient was initially treated with topotecan/cyclophosphamide and subsequently switched to vinorelbine. Due to severe toxicity the treatment was discontinued, however after 7-months follow-up, the patient is still alive with an improved general state of health and only a mild pancytopenia with no need for blood transfusions. CONCLUSION: Rhabdomyosarcoma can be limited to the bone marrow with no identifiable primary tumour. This case shows that the use of a bone marrow biopsy in suspected malignancies affecting the bone marrow is irreplaceable. PMID- 26587223 TI - Ouabain prevents pathological cardiac hypertrophy and heart failure through activation of phosphoinositide 3-kinase alpha in mouse. AB - BACKGROUND: Use of low doses of digitalis to prevent the development of heart failure was advocated decades ago, but conflicting results of early animal studies dissuaded further research on this issue. Recent discoveries of digitalis effects on cell signal pathways prompted us to reexamine the possibility of this prophylactic action of digitalis. The specific aim of the present study was to determine if subinotropic doses of ouabain would prevent pressure overload induced cardiac remodeling in the mouse by activating phosphoinositide 3-kinase alpha (PI3Kalpha). RESULTS: Studies were done on an existing transgenic mouse deficient in cardiac PI3Kalpha (p85-KO) but with normal cardiac contractility, a control mouse (Con), and on cultured adult cardiomyocytes. In Con myocytes, but not in p85-KO myocytes, ouabain activated PI3Kalpha and Akt, and caused cell growth. This occurred at low ouabain concentrations that did not activate the EGFR-Src/Ras/Raf/ERK cascade. Con and p85-KO mice were subjected to transverse aortic constriction (TAC) for 8 weeks. A subinotropic dose of ouabain (50 ug/kg/day) was constantly administrated by osmotic mini-pumps for the first 4 weeks. All mice were monitored by echocardiography throughout. Ouabain early treatment attenuated TAC-induced cardiac hypertrophy and fibrosis, and improved cardiac function in TAC-operated Con mice but not in TAC-operated p85-KO mice. TAC downregulated alpha2-isoform of Na(+)/K(+)-ATPase but not its alpha1-isoform in Con hearts, and ouabain treatment prevented the downregulation of alpha2 isoform. TAC-induced reduction of alpha2-isoform did not occur in p85-KO hearts. CONCLUSIONS: Our results show that (a) safe doses of ouabain prevent or delay cardiac remodeling of pressure overloaded mouse heart; and (b) these prophylactic effects are due to ouabain binding to alpha2-isoform resulting in the selective activation of PI3Kalpha. Our findings also suggest that potential prophylactic use of digitalis for prevention of heart failure in man deserves serious consideration. PMID- 26587224 TI - Career perspective: Victor A. Convertino. AB - This review focuses on a career of unique opportunities to participate in various areas of research related to extreme physiology and medicine. My experience as a volunteer subject in exercise experiments conducted at NASA included the study of acute and chronic physiological responses and adaptations to exercise in environments of hypoxia, heat stress, and simulated microgravity (bed rest), and eventually to my doctoral work on mechanisms underlying expansion of plasma and blood volume with acute and repeated exercise and heat exposure. My career has taken me to research positions at NASA, the Stanford University School of Medicine, the University of Arizona, and the U.S. Air Force Research Laboratory before assuming my present location at the U.S. Army Institute of Surgical Research. As a result of these multiple experiences across a period of 45 years, I have had opportunities to translate basic research to astronauts, high performance aircraft pilots, and critically ill patients who are challenged by conditions of extreme physiology and medicine. PMID- 26587225 TI - Genetics of Paget's disease of bone. AB - Paget's disease of bone (PDB) is a common metabolic bone disease characterised by focal areas of increased bone turnover, which primarily affects people over the age of 55 years. Genetic factors have a fundamental role in the pathogenesis of PDB and are probably the main predisposing factor for the disease. The genetic contribution to PDB susceptibility ranges from rare pathogenic mutations in the single gene SQSTM1 to more common, small effect variants in at least seven genetic loci that predispose to the disease. These loci have additive effects on disease susceptibility and interact with SQSTM1 mutations to affect disease severity, making them a potentially useful tool in predicting disease risk and complication and in managing treatments. Many of these loci harbour genes that have important function in osteoclast differentiation such as CSF1, DCSTAMP and TNFRSF11A. Other susceptibility loci have highlighted new molecular pathways that have not been previously implicated in regulation of bone metabolism such as OPTN, which was recently found to negatively regulate osteoclast differentiation. PDB-susceptibility variants exert their effect either by affecting the protein coding sequence such as variants found in SQSTM1 and RIN3 or by influencing gene expression such as those found in OPTN and DCSTAMP. Epidemiological studies indicate that environmental triggers also have a key role in PDB and interact with genetic factors to influence manifestation and severity of the disease; however, further studies are needed to identify these triggers. PMID- 26587226 TI - Sclerostin inhibits osteoblast differentiation without affecting BMP2/SMAD1/5 or Wnt3a/beta-catenin signaling but through activation of platelet-derived growth factor receptor signaling in vitro. AB - Sclerostin inhibits bone formation mostly by antagonizing LRP5/6, thus inhibiting Wnt signaling. However, experiments with genetically modified mouse models suggest that a significant part of sclerostin-mediated inhibition of bone formation is due to interactions with other binding partners. The objective of the present work was to identify signaling pathways affected by sclerostin in relation with its inhibitory action on osteogenic differentiation of C3H10T1/2 cells, MC3T3-E1 cells and primary osteoblasts. Sclerostin inhibited BMP2-induced osteoblast differentiation without altering SMAD1/5 phosphorylation and transcriptional activity. Moreover, sclerostin prevented Wnt3a-mediated osteoblastogenesis without affecting LRP5/6 phosphorylation or beta-catenin transcriptional activity. In addition, sclerostin inhibited mineralization promoted by GSK3 inhibition, which mimics canonical Wnt signaling without activation of LRP5/6, suggesting that sclerostin can prevent osteoblast differentiation without antagonizing LRP5/6. Finally, we found that sclerostin could activate platelet-derived growth factor receptor (PDGFR) and its downstream signaling pathways PLCgamma, PKC, Akt and ERK1/2. PDGFR inhibition could reverse sclerostin-mediated inhibitory activity on BMP2-induced osteoblast differentiation. Therefore, our data suggest that sclerostin can activate PDGFR signaling by itself, and this functional interaction may be involved in the negative effect of sclerostin on osteoblast differentiation. PMID- 26587227 TI - Bone mineral density and cardiovascular risk factors in postmenopausal women with coronary artery disease. AB - It has been suggested that osteoporosis and coronary artery disease (CAD) have overlapping pathophysiological mechanisms and related risk factors. The aim of this study was to investigate the association between several traditional cardiovascular risk factors and measures of bone mineral density (BMD) in postmenopausal women with and without clinically significant CAD defined angiographically. A case-control study was undertaken of 180 postmenopausal women (aged between 48 and 88 years) who were recruited from King Abdulaziz University Hospital, Saudi Arabia. Study subjects underwent dual-energy x-ray absorptiometry and coronary angiography. The presence of hypertension, diabetes, dyslipidemia, obesity, smoking and physical activity was identified from clinical examination and history. Demographic, anthropometric and biochemical characteristics were measured. Univariate and multivariate analyses were employed to explore the relationships between cardiovascular risk factors, including BMD, and the presence of CAD. CAD patients were more likely to have a lower BMD and T-score at the femoral neck than those without CAD (P<0.05). Significant differences were found between the groups for fasting lipid profile, fasting blood glucose and anthropometric measures (P<0.05). Conditional logistic regression showed that 3 risk factors were significantly related with the presence of CAD: high-density lipoprotein-cholesterol (odds ratio, OR: 0.226, 95% confidence interval, CI: 0.062-0.826), fasting plasma glucose (OR: 1.154, 95% CI: 1.042-1.278) and femoral neck T-score (OR: 0.545, 95% CI: 0.374-0.794). This study suggests an association of low BMD and elevated CAD risk. Nevertheless, additional longitudinal studies are needed to determine the temporal sequence of this association. PMID- 26587228 TI - Open tuber calcaneus fracture caused by a meat cleaver: A case report. AB - INTRODUCTION: Avulsion fractures of the tuber calcanei classically occur after falling on the foot, due to the forced dorsiflexion and the sudden contraction of the Achilles tendon. Direct trauma to the back of the leg and a direct penetrating injury are also infrequent causes and may be observed predominantly in younger patients. PRESENTATION OF CASE: We present a case of an open tuber calcaneus fracture resulting from a penetrating trauma in a 37-year-old patient. The fracture was reduced through the open wound and fixed using two cannulated screws. Bone union was radiologically and clinically observed at the end of the first year. DISCUSSION: During a physical altercation, the posterior of the patient's heel was struck directly with a meat cleaver. The position of the patient during the trauma can be considered to have increased the severity and depth of the injury. In addition, even though the injury radiologically resembled an avulsion fracture and was caused by direct trauma, the fact that it was open and that the mechanism of injury differed from the norm means that it should not be evaluated as a classic avulsion fracture in the full sense. Emergency open reduction and internal fixation were applied to an open calcaneal tuberosity fracture, and the patient was started on intravenous antibiotic therapy. CONCLUSION: Surgical techniques are successful in the treatment of open tuber calcanei fractures and an open intervention is usually required. Using cannulated screws is a good treatment option. PMID- 26587229 TI - Step-up approach and video assisted retroperitoneal debridement in infected necrotizing pancreatitis: A case complicated by retroperitoneal bleeding and colonic fistula. AB - INTRODUCTION: Infected Necrotizing Pancreatitis carries a high mortality and necessitates intervention to achieve sepsis control. The surgical strategy for proven infected necrosis has evolved, with abandonment of open necrosectomy to a step-up approach consisting of percutaneous drains and Video-assisted retroperitoneal debridement (VARD). We present a case that underwent VARD complicated by bleeding and colonic perforation and describe its management. PRESENTATION OF CASE: A 38 year-old male with acute pancreatitis developed infected necrotizing pancreatitis. Initial treatment was by percutaneous drainage under radiological guidance and intravenous antibiotics. The infected retroperitoneal necrosis was then debrided using gasless laparoscopy through a mini-incision. Post-operatively, he developed peripancreatic bleeding which was controlled with angioembolisation. He also developed a descending colon fistula which was treated with laparotomy and defunctioning loop ileostomy. He recovered and subsequently had his ileostomy closed twelve months later. The colonic fistula recurred and was treated with endoscopic clips and histoacryl glue injection and finally closed. DISCUSSION: Step-up approach consists of the 3 D's: Delay, drain and debride. VARD is recommended as it is replicable in general surgical units using standard laparoscopic instruments. Bleeding and colon perforation are potential complications which must have multi-disciplinary input, aggressive resuscitation and timely radiologic intervention. Defunctioning ileostomy is recommended to control sepsis in colonic fistulation. Novel fistula closing methods using endoscopic clips and histoacryl glue are potential treatment options. CONCLUSION: Step-up approach and VARD is the new paradigm to treat necrotizing pancreatitis. Complications of bleeding and colon fistula are uncommon and require multi-disciplinary management. PMID- 26587230 TI - Isolated pancreatic tail injury: A rare presentation. AB - INTRODUCTION: Pancreatic injuries occur in up to 10% of all major blunt abdominal trauma events. Due to the retroperitoneal location of the pancreas, isolated pancreatic injury occurs in less than 5% of cases. PRESENTATION OF CASE: A 12 year old male child was brought to the emergency department with epigastric pain 12 days after alleged history of fall from bicycle. On admission, he had tenderness in the epigastrium. CT scan revealed a transection through the tail of the pancreas with no injury to any other organ. As there was no evidence of duct injury, he was treated conservatively. DISCUSSION: Morbidity and mortality rates for isolated pancreatic trauma are directly related to the presence of damage to the pancreatic duct. Helical multislice CT scan represents the best noninvasive diagnostic method for the detection of pancreatic injury. Hyperamylasemia should at least be considered as a sign of probable pancreatic injury in the setting of blunt abdominal trauma. CONCLUSION: Trauma to the pancreas is not common, and isolated pancreatic trauma is even less common. An isolated pancreatic injury may be missed or the diagnosis may be delayed because the initial symptoms and signs of pancreatic injury are subtle. PMID- 26587231 TI - Commentary on "Inhibition of interleukin-1beta decreases aneurysm formation and progression in a novel model of thoracic aortic aneurysms". AB - Aortic aneurysm is a silent but life-threatening disease, whose pathogenesis remains poorly understood. Aneurysm models have been induced in small animals to study its pathogenesis, Johnston WF et al. successfully induced a novel model of thoracic aortic aneurysms (TAA) by periadventitial application of elastase in mice. We comment on this model according to our experiment. We hypothesize that endogenous MMPs, especially MMP2, play a vital role in complex repair process of aneurysmal wall, which should be a key target in the investigation and treatment of aortic aneurysms. PMID- 26587232 TI - Isolated scapula fracture: Ice hockey player without trauma. AB - INTRODUCTION: Scapular fractures are generally occur from in high-energy traumas and are associated with a high incidence of morbidity and mortality. PRESENTATION OF CASE: We present an unusual scapular fracture that occurred with a rare mechanism. A 23-year-old male patient who led an active sports life for 10 years and played ice hockey for the last 5 years. In a competition, he felt a sudden pain in his right scapula after hit the puck. He did not experience any direct trauma to his shoulder and there was no evidence of any pathological fracture. The fracture was isolated in the scapular body and it was classified as type 4, according to Hardegger classification. The was patient immobilized with a Velpau bandage for three weeks and then treated with physiotherapy for shoulder rehabilitation. DISCUSSION: The fracture mechanism was likely a disharmonius contracture of the agonist and antagonist muscles of the shoulder joint while hitting the puck. CONCLUSION: Scapular fractures are generally seen along with other injuries, but in this case we wanted to emphasize that care has to been taken to diagnose an isolated scapular fracture while assessing shoulder pain. PMID- 26587233 TI - Unnoticed biloma due to liver puncture after Veress needle insertion. AB - Laparoscopic surgery has become more widespread in the last years. Creating the pneumoperitoneum is the first surgical procedure but it is still responsible for many of the adverse events described in this field. Until now, liver puncture producing a delayed biloma has not been described. We present a case where a biloma was developed after liver puncture by the Veress needle, during a laparoscopic procedure, and detected on the 3rd day. It was detected by CT scan and treated by laparoscopy. Biloma due to Veress needle is a new entity in the context of adverse events related to Veress needle insertion, which needs a high suspicious index. We recommend to do Palmer's test and to check the insertion and to look for possible lesions below with the camera in order to minimize incidence of such injuries. Should this happen, laparoscopic or percutaneous drainage are both suitable alternatives to solve this complication. PMID- 26587234 TI - Antioxidant capacity and concentration of redox-active trace mineral in fully weaned intra-uterine growth retardation piglets. AB - BACKGROUND: The redox status of intra-uterine growth retardation (IUGR) piglets post-weaning has been poorly studied. METHODS: Newborns from twenty-four sows were weighted, weaned at 21 d and fed a starter diet until sampling. Sampling was done at 14 d post-weaning. A piglet was defined as IUGR when its birth weight was 2 SD below the mean birth weight of the total population. At weaning, eighteen piglets with nearly equal body weight from each category (i.e. IUGR or normal birth weight (NBW) piglets) were selected and then allocated to two treatments, consisted of six replicates with each pen having three piglets. RESULTS: Compared with NBW group, IUGR significantly decreased average daily gain (P < 0.001), average daily feed intake (P = 0.003), and feed efficiency (P < 0.001) of piglets during the first two weeks post-weaning. IUGR decreased the activities of total antioxidant capacity (P = 0.019), total superoxide dismutase (T-SOD, P = 0.023), and ceruloplasmin (P = 0.044) but increased the levels of malondialdehyde (P = 0.040) and protein carbonyl (P = 0.010) in plasma. Similarly, the decreased activities of T-SOD (P = 0.005), copper- and zinc-containing superoxide dismutase (Cu/Zn-SOD, P = 0.002), and catalase (P = 0.049) was observed in the liver of IUGR piglets than these of NBW piglets. IUGR decreased hepatic Cu/Zn-SOD activity (P = 0.023) per unit of Cu/Zn-SOD protein in piglets when compared with NBW piglets. In addition, IUGR piglets exhibited the decreases in accumulation of copper in both plasma (P = 0.001) and liver (P = 0.014), as well as the concentrations of iron (P = 0.002) and zinc (P = 0.048) in liver. Compared with NBW, IUGR down-regulated mRNA expression of Cu/Zn-SOD (P = 0.021) in the liver of piglets. CONCLUSIONS: The results indicated that IUGR impaired antioxidant capacity and resulted in oxidative damage in fully weaned piglets, which might be associated with the decreased levels of redox-active trace minerals. This study highlights the importance of redox status in IUGR offspring and provides a rationale for alleviating oxidative damage by dietary interventions aiming to supplement trace minerals and to restore redox balance in the future. PMID- 26587235 TI - Management of a microprolactinoma with aripiprazole in a woman with cabergoline induced mania. AB - A previously healthy 32-year-old woman developed cyclical mood swings after being prescribed cabergoline for a pituitary microprolactinoma. These mood swings persisted for over 2 years, at which point she developed an acute manic episode with psychotic features and was admitted to a psychiatry unit. Cabergoline was discontinued and replaced with aripiprazole 10 mg/day. Her manic episode quickly resolved, and she was discharged within 6 days of admission. The aripiprazole suppressed her prolactin levels for over 18 months of follow-up, even after the dose was lowered to 2 mg/day. There was no significant change in tumor size over 15 months, treatment was well tolerated and the woman remained psychiatrically stable. LEARNING POINTS: Dopamine agonists such as cabergoline, which are a standard treatment for microprolactinomas, can have serious adverse effects such as psychosis or valvular heart disease.Aripiprazole is a well-tolerated atypical antipsychotic that, unlike other antipsychotics, is a partial dopamine agonist capable of suppressing prolactin levels.Adjunctive, low-dose aripiprazole has been utilized to reverse risperidone-induced hyperprolactinemia.This case report demonstrates how aripiprazole monotherapy, in doses ranging from 2 to 10 mg/day, was effective in suppressing prolactin in a woman with a microprolactinoma who developed psychiatric side effects from cabergoline. PMID- 26587236 TI - Differences in ball speed and three-dimensional kinematics between male and female handball players during a standing throw with run-up. AB - BACKGROUND: The purpose of this paper was to examine differences in ball release speed and throwing kinematics between male and female team-handball players in a standing throw with run-up. Other research has shown that this throwing type produces the highest ball release speeds and comparing groups with differences in ball release speed can suggest where this difference might come from. If throwing technique differs, perhaps gender-specific coordination- and strength-training guidelines are in order. METHODS: Measurements of three-dimensional kinematics were performed with a seven-camera VICON motion capture system and subsequent joint angles and angular velocities calculations were executed in Mathcad. Data analysis with Statistical Parametric Mapping allowed us to examine the entire time-series of every variable without having to reduce the data to certain scalar values such as minima/maxima extracted from the time-series. RESULTS: Statistical Parametric Mapping enabled us to detect several differences in the throwing kinematics (12 out of 20 variables had one or more differences somewhere during the motion). The results indicated two distinct strategies in generating and transferring momentum through the kinematic chain. Male team-handball players showed more activity in the transverse plane (pelvis and trunk rotation and shoulder horizontal abduction) whereas female team-handball players showed more activity in the sagital plane (trunk flexion). Also the arm cocking maneuver was quite different. CONCLUSIONS: The observed differences between male and female team handball players in the motions of pelvis, trunk and throwing arm can be important information for coaches to give feedback to athletes. Whether these differences contribute to the observed difference in ball release speed is at the present unclear and more research on the relation with anthropometric profile needs to be done. Kinematic differences might suggest gender-specific training guidelines in team-handball. PMID- 26587238 TI - Effects of ethanol on the electrochemical removal of Bacillus subtilis spores from water. AB - This study aimed to characterize the effects of ethanol on the monopolar electrochemical process to remove Bacillus subtilis spores from drinking water. In particular, spores' destruction was tested by applying 20-100 mA current for 15-60 min to B. subtilis spores (10(2)-10(4) CFU/mL density), with stainless steel electrodes. The experimental results showed electrochemical removal of spores in the presence of 0.4 M ethanol at 15, 45, and 60 min and 5 mA/cm(2) current density. However, the use of ethanol or the electrochemical process alone did not eliminate B. subtilis spores at these time points. Overall, this study suggests that adding ethanol to the electrochemical process successfully removes B. subtilis spores from drinking water. PMID- 26587237 TI - Noncontiguous finished genome sequence and description of Necropsobacter massiliensis sp. nov. AB - Strain FF6(T) was isolated from the cervical abscess of a 4-year-old Senegalese boy, in Dakar, Senegal. MALDI-TOF MS did not provide any identification. This strain exhibited a 95.17% 16S rRNA sequence identity with Necropsobacter rosorum. Using a polyphasic study including phenotypic and genomic analyses, strain FF6(T) was an aero-anaerobic Gram-negative cocobacillus, oxidase positive, and exhibited a genome of 2,493,927 bp (1 chromosome but no plasmid) with a G+C content of 46.2% that coded 2,309 protein-coding and 53 RNA genes. On the basis of these data, we propose the creation of Necropsobacter massiliensis sp. nov. PMID- 26587239 TI - Sources of metal pollution in the urban atmosphere (A case study: Tuzla, Istabul). AB - In this study, Istanbul-Tuzla Region atmosphere was selected as the working area for atmospheric pollution. Although the study area seems too local, this region contains shipyards and shipyard-related side product industries. It is also surrounded by aluminum (ASSAN) and copper (SARKUYSAN) facilities and tannery organized industrial district. For determined the atmospheric inputs, the sample collection was carried out as monthly in 2010. Particulate matter was filtered from aerosols via a high volume air sampler. The collected 46 ambient air samples were analyzed for Cr, Fe, Cu, Zn, Cd, Pb and Al using Atomic Absorption Spectrometry (AAS), Flame unit. Additionally, the volume of the air was drawn and meteorological data recorded. Average individual heavy metal concentrations were found as Cd (0.06 ng/m(3)) < Cr (0.09 ng/m(3)) < Zn (0.21 ng/m(3)) < Pb (0.23 ng/m(3)) < Cu (0.48 ng/m(3)). The concentrations of crustal elements Fe and Al were changed between 5.48 ng/m(3), 74 ng/m(3) and 14 ng/m(3), 284 ng/m(3) respectively during the sampling period. Except Cr and Fe anthropogenic contribution was seen on the concentrations of Zn, Cu, Pb and Cd in an increasing order. While the crustal element Fe was not show an appreciable change in concentration, but the Al concentration was display an important change in concentration depending on the wind transportation. PMID- 26587240 TI - Acceptance and effects of a therapeutic renal food in pet cats with chronic kidney disease. AB - INTRODUCTION: Renal foods are used to manage chronic kidney disease (CKD) in dogs and cats, but their effectiveness may be limited by the ability to transition animals to them. MATERIAL AND METHODS: In a prospective study, pet cats with previously undiagnosed kidney disease (20 International Renal Interest Society (IRIS) 1, 61 IRIS 2, 14 IRIS 3/4, 33 at risk for CKD) were transitioned to a renal food. Markers of renal function were measured and owners answered questionnaires about their pet over one year. RESULTS: All but eight cats (120/128; 94 per cent) successfully transitioned to the renal food. Most of the time, cats moderately or extremely liked the food (89 per cent), ate at least half (73 per cent) and were moderately or extremely enthusiastic while eating (68 per cent). Cats rarely disliked the food (2 per cent) or refused to eat it (1 per cent). Markers of renal function were unchanged in IRIS 1 and 2 cats and changed little in IRIS 3/4 cats. In all groups, owner-assessed quality of life improved initially and then remained stable. Mean bodyweight did not change in cats with CKD. CONCLUSIONS: Most cats with CKD successfully transitioned to the renal food. The results also support previous studies that the renal food can help stabilise cats with CKD. PMID- 26587241 TI - The ice-breaker effect: singing mediates fast social bonding. AB - It has been proposed that singing evolved to facilitate social cohesion. However, it remains unclear whether bonding arises out of properties intrinsic to singing or whether any social engagement can have a similar effect. Furthermore, previous research has used one-off singing sessions without exploring the emergence of social bonding over time. In this semi-naturalistic study, we followed newly formed singing and non-singing (crafts or creative writing) adult education classes over seven months. Participants rated their closeness to their group and their affect, and were given a proxy measure of endorphin release, before and after their class, at three timepoints (months 1, 3 and 7). We show that although singers and non-singers felt equally connected by timepoint 3, singers experienced much faster bonding: singers demonstrated a significantly greater increase in closeness at timepoint 1, but the more gradual increase shown by non singers caught up over time. This represents the first evidence for an 'ice breaker effect' of singing in promoting fast cohesion between unfamiliar individuals, which bypasses the need for personal knowledge of group members gained through prolonged interaction. We argue that singing may have evolved to quickly bond large human groups of relative strangers, potentially through encouraging willingness to coordinate by enhancing positive affect. PMID- 26587242 TI - Angled multimode interferometer for bidirectional wavelength division (de)multiplexing. AB - We have demonstrated a bidirectional wavelength division (de)multiplexer (WDM) on the silicon-on-insulator platform using two 4-channel angled multimode interferometers (AMMIs) sharing the same multimode interference waveguide. An excellent match of the peak transmission wavelength of each channel between the two AMMIs was achieved. The input and output access waveguides were arranged in a configuration such that the propagation of light of one AMMI in the multimode interference waveguide suffered minimal perturbation by the input and output waveguides of the other AMMI. This type of device is ideal for the WDM system for datacom or telecom applications, e.g. an integrated optical transceiver, where the transmission wavelengths are required to match with the receiving wavelengths. The device also benefits from simple fabrication (as only a single lithography and etching step is required), improved convenience for the transceiver layout design, a reduction in tuning power and circuitry and efficient use of layout space. A low insertion loss of 3-4 dB, and low crosstalk of -15 to -20 dB, was achieved. PMID- 26587243 TI - Using prediction markets to forecast research evaluations. AB - The 2014 Research Excellence Framework (REF2014) was conducted to assess the quality of research carried out at higher education institutions in the UK over a 6 year period. However, the process was criticized for being expensive and bureaucratic, and it was argued that similar information could be obtained more simply from various existing metrics. We were interested in whether a prediction market on the outcome of REF2014 for 33 chemistry departments in the UK would provide information similar to that obtained during the REF2014 process. Prediction markets have become increasingly popular as a means of capturing what is colloquially known as the 'wisdom of crowds', and enable individuals to trade 'bets' on whether a specific outcome will occur or not. These have been shown to be successful at predicting various outcomes in a number of domains (e.g. sport, entertainment and politics), but have rarely been tested against outcomes based on expert judgements such as those that formed the basis of REF2014. PMID- 26587244 TI - Omura's whales (Balaenoptera omurai) off northwest Madagascar: ecology, behaviour and conservation needs. AB - The Omura's whale (Balaenoptera omurai) was described as a new species in 2003 and then soon after as an ancient lineage basal to a Bryde's/sei whale clade. Currently known only from whaling and stranding specimens primarily from the western Pacific and eastern Indian Oceans, there exist no confirmed field observations or ecological/behavioural data. Here we present, to our knowledge, the first genetically confirmed documentation of living Omura's whales including descriptions of basic ecology and behaviour from northwestern Madagascar. Species identification was confirmed through molecular phylogenetic analyses of biopsies collected from 18 adult animals. All individuals shared a single haplotype in a 402 bp sequence of mtDNA control region, suggesting low diversity and a potentially small population. Sightings of 44 groups indicated preference for shallow-water shelf habitat with sea surface temperature between 27.4 degrees C and 30.2 degrees C. Frequent observations were made of lunge feeding, possibly on zooplankton. Observations of four mothers with young calves, and recordings of a song-like vocalization probably indicate reproductive behaviour. Social organization consisted of loose aggregations of predominantly unassociated single individuals spatially and temporally clustered. Photographic recapture of a female re-sighted the following year with a young calf suggests site fidelity or a resident population. Our results demonstrate that the species is a tropical whale without segregation of feeding and breeding habitat, and is probably non migratory; our data extend the range of this poorly studied whale into the western Indian Ocean. Exclusive range restriction to tropical waters is rare among baleen whale species, except for the various forms of Bryde's whales and Omura's whales. Thus, the discovery of a tractable population of Omura's whales in the tropics presents an opportunity for understanding the ecological factors driving potential convergence of life-history patterns with the distantly related Bryde's whales. PMID- 26587245 TI - Modality-specific attention in foraging bumblebees. AB - Attentional demands can prevent humans and other animals from performing multiple tasks simultaneously. Some studies, however, show that tasks presented in different sensory modalities (e.g. visual and auditory) can be processed simultaneously. This suggests that, at least in these cases, attention might be modality-specific and divided differently between tasks when present in the same modality compared with different modalities. We investigated this possibility in bumblebees (Bombus terrestris) using a biologically relevant experimental set-up where they had to simultaneously choose more rewarding flowers and avoid simulated predatory attacks by robotic 'spiders'. We found that when the tasks had to be performed using visual cues alone, bees failed to perform both tasks simultaneously. However, when highly rewarding flowers were indicated by olfactory cues and predators were indicated by visual cues, bees managed to perform both tasks successfully. Our results thus provide evidence for modality specific attention in foraging bees and establish a novel framework for future studies of crossmodal attention in ecologically realistic settings. PMID- 26587246 TI - The contribution of seed dispersers to tree species diversity in tropical rainforests. AB - Tropical rainforests are known for their extreme biodiversity, posing a challenging problem in tropical ecology. Many hypotheses have been proposed to explain the diversity of tree species, yet our understanding of this phenomenon remains incomplete. Here, we consider the contribution of animal seed dispersers to the species diversity of trees. We built a multi-layer lattice model of trees whose animal seed dispersers are allowed to move only in restricted areas to disperse the tree seeds. We incorporated the effects of seed dispersers in the traditional theory of allopatric speciation on a geological time scale. We modified the lattice model to explicitly examine the coexistence of new tree species and the resulting high biodiversity. The results indicate that both the coexistence and diversified evolution of tree species can be explained by the introduction of animal seed dispersers. PMID- 26587247 TI - Differential responses of coral larvae to the colour of ambient light guide them to suitable settlement microhabitat. AB - Reef-building corals produce planktonic planula larvae that must select an appropriate habitat to settle and spend the rest of their life, a behaviour that plays a critical role in survival. Here, we report that larvae obtained from a deep-water population of Pseudodiploria strigosa settled more readily under blue light and in the dark, which aligns well with the light field characteristics of their natal habitat. By contrast, larvae of the shallow-water coral Acropora millepora settled in high proportions under blue and green light while settlement was less in the dark. Acropora millepora larvae also showed reduced settlement under red light, which should be abundant at shallow depth. Hypothesizing that this might be a mechanism preventing the larvae from settling on the exposed upwards-facing surfaces, we quantified A. millepora settlement in manipulated light chambers in situ on the reef. While A. millepora larvae naturally preferred settling on vertical rather than exposed horizontal surfaces, swapping the colours of upwards-facing and sideways-facing light fields was sufficient to invert this preference. We also tested if the variation in intrinsic red fluorescence in A. millepora larvae correlates with settlement rates, as has been suggested previously. We observed this correlation only in the absence of light, indicating that larval red fluorescent protein is probably not directly involved in light sensing. Our study reveals previously under-appreciated light-sensory capabilities in coral larvae, which could be an important axis of ecological differentiation between coral species and/or populations. PMID- 26587248 TI - Histological evidence for a supraspinous ligament in sauropod dinosaurs. AB - Supraspinous ossified rods have been reported in the sacra of some derived sauropod dinosaurs. Although different hypotheses have been proposed to explain the origin of this structure, histological evidence has never been provided to support or reject any of them. In order to establish its origin, we analyse and characterize the microstructure of the supraspinous rod of two sauropod dinosaurs from the Upper Cretaceous of Argentina. The supraspinous ossified rod is almost entirely formed by dense Haversian bone. Remains of primary bone consist entirely of an avascular tissue composed of two types of fibre-like structures, which are coarse and longitudinally (parallel to the main axis of the element) oriented. These structures are differentiated on the basis of their optical properties under polarized light. Very thin fibrous strands are also observed in some regions. These small fibres are all oriented parallel to one another but perpendicular to the element main axis. Histological features of the primary bone tissue indicate that the sacral supraspinous rod corresponds to an ossified supraspinous ligament. The formation of this structure appears to have been a non pathological metaplastic ossification, possibly induced by the continuous tensile forces applied to the element. PMID- 26587249 TI - Fossil evidence and stages of elongation of the Giraffa camelopardalis neck. AB - Several evolutionary theories have been proposed to explain the adaptation of the long giraffe neck; however, few studies examine the fossil cervical vertebrae. We incorporate extinct giraffids, and the okapi and giraffe cervical vertebral specimens in a comprehensive analysis of the anatomy and elongation of the neck. We establish and evaluate 20 character states that relate to general, cranial and caudal vertebral lengthening, and calculate a length-to-width ratio to measure the relative slenderness of the vertebrae. Our sample includes cervical vertebrae (n=71) of 11 taxa representing all seven subfamilies. We also perform a computational comparison of the C3 of Samotherium and Giraffa camelopardalis, which demonstrates that cervical elongation occurs disproportionately along the cranial-caudal vertebral axis. Using the morphological characters and calculated ratios, we propose stages in cervical lengthening, which are supported by the mathematical transformations using fossil and extant specimens. We find that cervical elongation is anisometric and unexpectedly precedes Giraffidae. Within the family, cranial vertebral elongation is the first lengthening stage observed followed by caudal vertebral elongation, which accounts for the extremely long neck of the giraffe. PMID- 26587250 TI - Prolonged transition time between colostrum and mature milk in a bear, the giant panda, Ailuropoda melanoleuca. AB - Bears produce the most altricial neonates of any placental mammal. We hypothesized that the transition from colostrum to mature milk in bears reflects a temporal and biochemical adaptation for altricial development and immune protection. Comparison of bear milks with milks of other eutherians yielded distinctive protein profiles. Proteomic and metabolomic analysis of serial milk samples collected from six giant pandas showed a prolonged transition from colostrum to main-phase lactation over approximately 30 days. Particularly striking are the persistence or sequential appearance of adaptive and innate immune factors. The endurance of immunoglobulin G suggests an unusual duration of trans-intestinal absorption of maternal antibodies, and is potentially relevant to the underdeveloped lymphoid system of giant panda neonates. Levels of certain milk oligosaccharides known to exert anti-microbial activities and/or that are conducive to the development of neonatal gut microbiomes underwent an almost complete changeover around days 20-30 postpartum, coincident with the maturation of the protein profile. A potential metabolic marker of starvation was detected, the prominence of which may reflect the natural postpartum period of anorexia in giant panda mothers. Early lactation in giant pandas, and possibly in other ursids, appears to be adapted for the unique requirements of unusually altricial eutherian neonates. PMID- 26587251 TI - Modelling mass and heat transfer in nano-based cancer hyperthermia. AB - We derive a sophisticated mathematical model for coupled heat and mass transport in the tumour microenvironment and we apply it to study nanoparticle delivery and hyperthermic treatment of cancer. The model has the unique ability of combining the following features: (i) realistic vasculature; (ii) coupled capillary and interstitial flow; (iii) coupled capillary and interstitial mass transfer applied to nanoparticles; and (iv) coupled capillary and interstitial heat transfer, which are the fundamental mechanisms governing nano-based hyperthermic treatment. This is an improvement with respect to previous modelling approaches, where the effect of blood perfusion on heat transfer is modelled in a spatially averaged form. We analyse the time evolution and the spatial distribution of particles and temperature in a tumour mass treated with superparamagnetic nanoparticles excited by an alternating magnetic field. By means of numerical experiments, we synthesize scaling laws that illustrate how nano-based hyperthermia depends on tumour size and vascularity. In particular, we identify two distinct mechanisms that regulate the distribution of particle and temperature, which are characterized by perfusion and diffusion, respectively. PMID- 26587252 TI - Reduced entomopathogen abundance in Myrmica ant nests-testing a possible immunological benefit of myrmecophily using Galleria mellonella as a model. AB - Social insects such as ants have evolved collective rather than individual immune defence strategies against diseases and parasites at the level of their societies (colonies), known as social immunity. Ants frequently host other arthropods, so called myrmecophiles, in their nests. Here, we tested the hypothesis that myrmecophily may partly arise from selection for exploiting the ants' social immunity. We used larvae of the wax moth Galleria mellonella as 'model myrmecophiles' (baits) to test this hypothesis. We found significantly reduced abundance of entomopathogens in ant nests compared with the surrounding environment. Specific entomopathogen groups (Isaria fumosorosea and nematodes) were also found to be significantly less abundant inside than outside ant nests, whereas one entomopathogen (Beauveria brongniartii) was significantly more abundant inside nests. We therefore hypothesize that immunological benefits of entering ant nests may provide us a new explanation of why natural selection acts in favour of such a life-history strategy. PMID- 26587253 TI - Seasonal and ontogenetic variation of skin microbial communities and relationships to natural disease dynamics in declining amphibians. AB - Recently, microbiologists have focused on characterizing the probiotic role of skin bacteria for amphibians threatened by the fungal disease chytridiomycosis. However, the specific characteristics of microbial diversity required to maintain health or trigger disease are still not well understood in natural populations. We hypothesized that seasonal and developmental transitions affecting susceptibility to chytridiomycosis could also alter the stability of microbial assemblages. To test our hypothesis, we examined patterns of skin bacterial diversity in two species of declining amphibians (Lithobates yavapaiensis and Eleutherodactylus coqui) affected by the pathogenic fungus Batrachochytrium dendrobatidis (Bd). We focused on two important transitions that affect Bd susceptibility: ontogenetic (from juvenile to adult) shifts in E. coqui and seasonal (from summer to winter) shifts in L. yavapaiensis. We used a combination of community-fingerprinting analyses and 16S rRNA amplicon sequencing to quantify changes in bacterial diversity and assemblage composition between seasons and developmental stages, and to investigate the relationship between bacterial diversity and pathogen load. We found that winter-sampled frogs and juveniles, two states associated with increased Bd susceptibility, exhibited higher diversity compared with summer-sampled frogs and adult individuals. Our findings also revealed that hosts harbouring higher bacterial diversity carried lower Bd infections, providing support for the protective role of bacterial communities. Ongoing work to understand skin microbiome resilience after pathogen disturbance has the potential to identify key taxa involved in disease resistance. PMID- 26587254 TI - Sexual reproduction with variable mating systems can resist asexuality in a rock paper-scissors dynamics. AB - While sex can be advantageous for a lineage in the long term, we still lack an explanation for its maintenance with the twofold cost per generation. Here we model an infinite diploid population where two autosomal loci determine, respectively, the reproductive mode, sexual versus asexual and the mating system, polygynous (costly sex) versus monogamous (assuming equal contribution of parents to offspring, i.e. non-costly sex). We show that alleles for costly sex can spread when non-costly sexual modes buffer the interaction between asexual and costly sexual strategies, even without twofold benefit of recombination with respect to asexuality. The three interacting strategies have intransitive fitness relationships leading to a rock-paper-scissors dynamics, so that alleles for costly sex cannot be eliminated by asexuals in most situations throughout the parameter space. Our results indicate that sexual lineages with variable mating systems can resist the invasion of asexuals and allow for long-term effects to accumulate, thus providing a solution to the persisting theoretical question of why sex was not displaced by asexuality along evolution. PMID- 26587256 TI - Study of coupled nonlinear partial differential equations for finding exact analytical solutions. AB - Exact solutions of nonlinear partial differential equations (NPDEs) are obtained via the enhanced (G'/G)-expansion method. The method is subsequently applied to find exact solutions of the Drinfel'd-Sokolov-Wilson (DSW) equation and the (2+1) dimensional Painleve integrable Burgers (PIB) equation. The efficiency of this method for finding these exact solutions is demonstrated. The method is effective and applicable for many other NPDEs in mathematical physics. PMID- 26587255 TI - Happy hamsters? Enrichment induces positive judgement bias for mildly (but not truly) ambiguous cues to reward and punishment in Mesocricetus auratus. AB - Recent developments in the study of animal cognition and emotion have resulted in the 'judgement bias' model of animal welfare. Judgement biases describe the way in which changes in affective state are characterized by changes in information processing. In humans, anxiety and depression are characterized by increased expectation of negative events and negative interpretation of ambiguous information. Positive wellbeing is associated with enhanced expectation of positive outcomes and more positive interpretation of ambiguous information. Mood congruent judgement biases for ambiguous information have been demonstrated in a range of animal species, with large variation in the way tests are administered and in the robustness of analyses. We highlight and address some issues using a laboratory species not previously tested: the Syrian hamster (Mesocricetus auratus). Hamsters were tested using a spatial judgement go/no-go task in enriched and unenriched housing. We included a number of controls and additional behavioural tests and applied a robust analytical approach using linear mixed effects models. Hamsters approached the ambiguous cues significantly more often when enriched than unenriched. There was no effect of enrichment on responses to the middle cue. We discuss these findings in light of mechanisms underlying processing cues to reward, punishment and true ambiguity, and the implications for the welfare of laboratory hamsters. PMID- 26587257 TI - Regional differentiation and extensive hybridization between mitochondrial clades of the Southern Ocean giant sea spider Colossendeis megalonyx. AB - Assessing the enormous diversity of Southern Ocean benthic species and their evolutionary histories is a central task in the era of global climate change. Based on mitochondrial markers, it was recently suggested that the circumpolar giant sea spider Colossendeis megalonyx comprises a complex of at least six cryptic species with mostly small and non-overlapping distribution ranges. Here, we expand the sampling to include over 500 mitochondrial COI sequences of specimens from around the Antarctic. Using multiple species delimitation approaches, the number of distinct mitochondrial OTUs increased from six to 15-20 with our larger dataset. In contrast to earlier studies, many of these clades show almost circumpolar distributions. Additionally, analysis of the nuclear internal transcribed spacer region for a subset of these specimens showed incongruence between nuclear and mitochondrial results. These mito-nuclear discordances suggest that several of the divergent mitochondrial lineages can hybridize and should not be interpreted as cryptic species. Our results suggest survival of C. megalonyx during Pleistocene glaciations in multiple refugia, some of them probably located on the Antarctic shelf, and emphasize the importance of multi-gene datasets to detect the presence of cryptic species, rather than their inference based on mitochondrial data alone. PMID- 26587258 TI - The effects of precipitation, river discharge, land use and coastal circulation on water quality in coastal Maine. AB - Faecal pollution in stormwater, wastewater and direct run-off can carry zoonotic pathogens to streams, rivers and the ocean, reduce water quality, and affect both recreational and commercial fishing areas of the coastal ocean. Typically, the closure of beaches and commercial fishing areas is governed by the testing for the presence of faecal bacteria, which requires an 18-24 h period for sample incubation. As water quality can change during this testing period, the need for accurate and timely predictions of coastal water quality has become acute. In this study, we: (i) examine the relationship between water quality, precipitation and river discharge at several locations within the Gulf of Maine, and (ii) use multiple linear regression models based on readily obtainable hydrometeorological measurements to predict water quality events at five coastal locations. Analysis of a 12 year dataset revealed that high river discharge and/or precipitation events can lead to reduced water quality; however, the use of only these two parameters to predict water quality can result in a number of errors. Analysis of a higher frequency, 2 year study using multiple linear regression models revealed that precipitation, salinity, river discharge, winds, seasonality and coastal circulation correlate with variations in water quality. Although there has been extensive development of regression models for freshwater, this is one of the first attempts to create a mechanistic model to predict water quality in coastal marine waters. Model performance is similar to that of efforts in other regions, which have incorporated models into water resource managers' decisions, indicating that the use of a mechanistic model in coastal Maine is feasible. PMID- 26587259 TI - Growth patterns and life-history strategies in Placodontia (Diapsida: Sauropterygia). AB - Placodontia is a clade of durophagous, near shore marine reptiles from Triassic sediments of modern-day Europe, Middle East and China. Although much is known about their primary anatomy and palaeoecology, relatively little has been published regarding their life history, i.e. ageing, maturation and growth. Here, growth records derived from long bone histological data of placodont individuals are described and modelled to assess placodont growth and life-history strategies. Growth modelling methods are used to confirm traits documented in the growth record (age at onset of sexual maturity, age when asymptotic length was achieved, age at death, maximum longevity) and also to estimate undocumented traits. Based on these growth models, generalized estimates of these traits are established for each taxon. Overall differences in bone tissue types and resulting growth curves indicate different growth patterns and life-history strategies between different taxa of Placodontia. Psephoderma and Paraplacodus grew with lamellar-zonal bone tissue type and show growth patterns as seen in modern reptiles. Placodontia indet. aff. Cyamodus and some Placodontia indet. show a unique combination of fibrolamellar bone tissue regularly stratified by growth marks, a pattern absent in modern sauropsids. The bone tissue type of Placodontia indet. aff. Cyamodus and Placodontia indet. indicates a significantly increased basal metabolic rate when compared with modern reptiles. Double lines of arrested growth, non-annual rest lines in annuli, and subcycles that stratify zones suggest high dependence of placodont growth on endogenous and exogenous factors. Histological and modelled differences within taxa point to high individual developmental plasticity but sexual dimorphism in growth patterns and the presence of different taxa in the sample cannot be ruled out. PMID- 26587260 TI - Environmental offsets, resilience and cost-effective conservation. AB - Conservation management agencies are faced with acute trade-offs when dealing with disturbance from human activities. We show how agencies can respond to permanent ecosystem disruption by managing for Pimm resilience within a conservation budget using a model calibrated to a metapopulation of a coral reef fish species at Ningaloo Reef, Western Australia. The application is of general interest because it provides a method to manage species susceptible to negative environmental disturbances by optimizing between the number and quality of migration connections in a spatially distributed metapopulation. Given ecological equivalency between the number and quality of migration connections in terms of time to recover from disturbance, our approach allows conservation managers to promote ecological function, under budgetary constraints, by offsetting permanent damage to one ecological function with investment in another. PMID- 26587261 TI - Balance and coordination after viewing stereoscopic 3D television. AB - Manufacturers and the media have raised the possibility that viewing stereoscopic 3D television (S3D TV) may cause temporary disruption to balance and visuomotor coordination. We looked for evidence of such effects in a laboratory-based study. Four hundred and thirty-three people aged 4-82 years old carried out tests of balance and coordination before and after viewing an 80 min movie in either conventional 2D or stereoscopic 3D, while wearing two triaxial accelerometers. Accelerometry produced little evidence of any change in body motion associated with S3D TV. We found no evidence that viewing the movie in S3D causes a detectable impairment in balance or in visuomotor coordination. PMID- 26587262 TI - Coordination nano-space as stage of hydrogen ortho-para conversion. AB - The ability to design and control properties of nano-sized space in porous coordination polymers (PCPs) would provide us with an ideal stage for fascinating physical and chemical phenomena. We found an interconversion of nuclear-spin isomers for hydrogen molecule H2 adsorbed in a Hofmann-type PCP, {Fe(pz)[Pd(CN)4]} (pz=pyrazine), by the temperature dependence of Raman spectra. The ortho (o)-para (p) conversion process of H2 is forbidden for an isolated molecule. The charge density study using synchrotron radiation X-ray diffraction reveals the electric field generated in coordination nano-space. The present results corroborate similar findings observed on different systems and confirm that o-p conversion can occur on non-magnetic solids and that electric field can induce the catalytic hydrogen o-p conversion. PMID- 26587263 TI - The growth threshold conjecture: a theoretical framework for understanding T-cell tolerance. AB - Adaptive immune responses depend on the capacity of T cells to target specific antigens. As similar antigens can be expressed by pathogens and host cells, the question naturally arises of how can T cells discriminate friends from foes. In this work, we suggest that T cells tolerate cells whose proliferation rates remain below a permitted threshold. Our proposal relies on well-established facts about T-cell dynamics during acute infections: T-cell populations are elastic (they expand and contract) and they display inertia (contraction is delayed relative to antigen removal). By modelling inertia and elasticity, we show that tolerance to slow-growing populations can emerge as a population-scale feature of T cells. This result suggests a theoretical framework to understand immune tolerance that goes beyond the self versus non-self dichotomy. It also accounts for currently unexplained observations, such as the paradoxical tolerance to slow growing pathogens or the presence of self-reactive T cells in the organism. PMID- 26587264 TI - To what extent do human-altered landscapes retain population connectivity? Historical changes in gene flow of wetland fish Pungitius pungitius. AB - Understanding how human-altered landscapes affect population connectivity is valuable for conservation planning. Natural connectivity among wetlands, which is maintained by floods, is disappearing owing to farmland expansion. Using genetic data, we assessed historical changes in the population connectivity of the ninespine stickleback within a human-altered wetland system. We predicted that: (i) the contemporary gene flow maintained by the artificial watercourse network may be restricted to a smaller spatial scale compared with the gene flow preceding alteration, and (ii) the contemporary gene flow is dominated by the downstream direction owing to the construction of low-head barriers. We evaluated the potential source population in both timescales. Seventeen studied populations were grouped into four genetically different clusters, and we estimated the migration rates among these clusters. Contemporary migration was restricted to between neighbouring clusters, although a directional change was not detected. Furthermore, we consistently found the same potential source cluster, from past to present, characterized by large amounts of remnant habitats connected by artificial watercourses. These findings highlight that: (i) artificial connectivity can sustain the short-distance connectivity of the ninespine stickleback, which contributes to maintaining the potential source populations; however, (ii) population connectivity throughout the landscape has been prevented by agricultural developments. PMID- 26587265 TI - MiFish, a set of universal PCR primers for metabarcoding environmental DNA from fishes: detection of more than 230 subtropical marine species. AB - We developed a set of universal PCR primers (MiFish-U/E) for metabarcoding environmental DNA (eDNA) from fishes. Primers were designed using aligned whole mitochondrial genome (mitogenome) sequences from 880 species, supplemented by partial mitogenome sequences from 160 elasmobranchs (sharks and rays). The primers target a hypervariable region of the 12S rRNA gene (163-185 bp), which contains sufficient information to identify fishes to taxonomic family, genus and species except for some closely related congeners. To test versatility of the primers across a diverse range of fishes, we sampled eDNA from four tanks in the Okinawa Churaumi Aquarium with known species compositions, prepared dual-indexed libraries and performed paired-end sequencing of the region using high-throughput next-generation sequencing technologies. Out of the 180 marine fish species contained in the four tanks with reference sequences in a custom database, we detected 168 species (93.3%) distributed across 59 families and 123 genera. These fishes are not only taxonomically diverse, ranging from sharks and rays to higher teleosts, but are also greatly varied in their ecology, including both pelagic and benthic species living in shallow coastal to deep waters. We also sampled natural seawaters around coral reefs near the aquarium and detected 93 fish species using this approach. Of the 93 species, 64 were not detected in the four aquarium tanks, rendering the total number of species detected to 232 (from 70 families and 152 genera). The metabarcoding approach presented here is non invasive, more efficient, more cost-effective and more sensitive than the traditional survey methods. It has the potential to serve as an alternative (or complementary) tool for biodiversity monitoring that revolutionizes natural resource management and ecological studies of fish communities on larger spatial and temporal scales. PMID- 26587266 TI - Tiarajudens eccentricus and Anomocephalus africanus, two bizarre anomodonts (Synapsida, Therapsida) with dental occlusion from the Permian of Gondwana. AB - Anomodontia was a highly successful tetrapod clade during the Permian and the Triassic. New morphological information regarding two bizarre basal anomodonts is provided and their palaeoecological significance is explored. The osteology of the recently discovered Tiarajudens eccentricus Cisneros et al. 2011, from the Brazilian Permian, is described in detail. The taxon exhibits unusual postcranial features, including the presence of gastralia. Additional preparation and computed tomography scans of the holotype of Anomocephalus africanus Modesto et al. 1999 discovered in the Karoo Basin of South Africa allow a reappraisal of this genus. Anomocephalus is similar to Tiarajudens with regard to several traits, including a battery of large, transversally expanded, palatal teeth. Molariform teeth are present in the mandible of the African taxon, providing additional insight into the function of the earliest tooth-occlusion mechanism known in therapsids. At least two waves of tooth replacement can be recognized in the palate of Anomocephalus. The outsized, blade-like caniniforms of the herbivorous Tiarajudens allow several non-exclusive ecological interpretations, among which we favour intraspecific display or combat. This behaviour was an alternative to the head-butting practised by the contemporary dinocephalians. Combat specializations that are considered typical of Cenozoic herbivores likely evolved during the Middle Permian, at the time the first communities with diverse, abundant tetrapod herbivores were being assembled. PMID- 26587267 TI - An empirical investigation into the role of subjective prior probability in searching for potentially missing items. AB - There are many examples from the scientific literature of visual search tasks in which the length, scope and success rate of the search have been shown to vary according to the searcher's expectations of whether the search target is likely to be present. This phenomenon has major practical implications, for instance in cancer screening, when the prevalence of the condition is low and the consequences of a missed disease diagnosis are severe. We consider this problem from an empirical Bayesian perspective to explain how the effect of a low prior probability, subjectively assessed by the searcher, might impact on the extent of the search. We show how the searcher's posterior probability that the target is present depends on the prior probability and the proportion of possible target locations already searched, and also consider the implications of imperfect search, when the probability of false-positive and false-negative decisions is non-zero. The theoretical results are applied to two studies of radiologists' visual assessment of pulmonary lesions on chest radiographs. Further application areas in diagnostic medicine and airport security are also discussed. PMID- 26587268 TI - A global optimization paradigm based on change of measures. AB - A global optimization framework, COMBEO (Change Of Measure Based Evolutionary Optimization), is proposed. An important aspect in the development is a set of derivative-free additive directional terms, obtainable through a change of measures en route to the imposition of any stipulated conditions aimed at driving the realized design variables (particles) to the global optimum. The generalized setting offered by the new approach also enables several basic ideas, used with other global search methods such as the particle swarm or the differential evolution, to be rationally incorporated in the proposed set-up via a change of measures. The global search may be further aided by imparting to the directional update terms additional layers of random perturbations such as 'scrambling' and 'selection'. Depending on the precise choice of the optimality conditions and the extent of random perturbation, the search can be readily rendered either greedy or more exploratory. As numerically demonstrated, the new proposal appears to provide for a more rational, more accurate and, in some cases, a faster alternative to many available evolutionary optimization schemes. PMID- 26587269 TI - Nest inundation from sea-level rise threatens sea turtle population viability. AB - Contemporary sea-level rise will inundate coastal habitats with seawater more frequently, disrupting the life cycles of terrestrial fauna well before permanent habitat loss occurs. Sea turtles are reliant on low-lying coastal habitats worldwide for nesting, where eggs buried in the sand remain vulnerable to inundation until hatching. We show that saltwater inundation directly lowers the viability of green turtle eggs (Chelonia mydas) collected from the world's largest green turtle nesting rookery at Raine Island, Australia, which is undergoing enigmatic decline. Inundation for 1 or 3 h reduced egg viability by less than 10%, whereas inundation for 6 h reduced viability by approximately 30%. All embryonic developmental stages were vulnerable to mortality from saltwater inundation. Although the hatchlings that emerged from inundated eggs displayed normal physical and behavioural traits, hypoxia during incubation could influence other aspects of the physiology or behaviour of developing embryos, such as learning or spatial orientation. Saltwater inundation can directly lower hatching success, but it does not completely explain the consistently low rates of hatchling production observed on Raine Island. More frequent nest inundation associated with sea-level rise will increase variability in sea turtle hatching success spatially and temporally, due to direct and indirect impacts of saltwater inundation on developing embryos. PMID- 26587270 TI - Functional morphology and efficiency of the antenna cleaner in Camponotus rufifemur ants. AB - Contamination of body surfaces can negatively affect many physiological functions. Insects have evolved different adaptations for removing contamination, including surfaces that allow passive self-cleaning and structures for active cleaning. Here, we study the function of the antenna cleaner in Camponotus rufifemur ants, a clamp-like structure consisting of a notch on the basitarsus facing a spur on the tibia, both bearing cuticular 'combs' and 'brushes'. The ants clamp one antenna tightly between notch and spur, pull it through, and subsequently clean the antenna cleaner itself with the mouthparts. We simulated cleaning strokes by moving notch or spur over antennae contaminated with fluorescent particles. The notch removed particles more efficiently than the spur, but both components eliminated more than 60% of the particles with the first stroke. Ablation of bristles, brush and comb strongly reduced the efficiency, indicating that they are essential for cleaning. To study how comb and brush remove particles of different sizes, we contaminated antennae of living ants, and anaesthetized them immediately after they had performed the first cleaning stroke. Different-sized beads were trapped in distinct zones of the notch, consistent with the gap widths between cuticular outgrowths. This suggests that the antenna cleaner operates like a series of sieves that remove the largest objects first, followed by smaller ones, down to the smallest particles that get caught by adhesion. PMID- 26587271 TI - Yes, it turns: experimental evidence of pearl rotation during its formation. AB - Cultured pearls are human creations formed by inserting a nucleus and a small piece of mantle tissue into a living shelled mollusc, usually a pearl oyster. Although many pearl observations intuitively suggest a possible rotation of the nucleated pearl inside the oyster, no experimental demonstration of such a movement has ever been done. This can be explained by the difficulty of observation of such a phenomenon in the tissues of a living animal. To investigate this question of pearl rotation, a magnetometer system was specifically engineered to register magnetic field variations with magnetic sensors from movements of a magnetic nucleus inserted in the pearl oyster. We demonstrated that a continuous movement of the nucleus inside the oyster starts after a minimum of 40 days post-grafting and continues until the pearl harvest. We measured a mean angular speed of 1.27 degrees min(-1) calculated for four different oysters. Rotation variability was observed among oysters and may be correlated to pearl shape and defects. Nature's ability to generate so amazingly complex structures like a pearl has delivered one of its secrets. PMID- 26587272 TI - Proximate causes of the red face of the bald uakari monkey (Cacajao calvus). AB - In social species, such as primates, facial appearances transmit a variety of social signals. Although it is suggested that the intense red colour of the face of the bald uakari monkey might be an indicator of health, this hypothesis still has not been verified. This study describes the histological structure of the skin of the face in the bald uakari, compared with other non-red neotropical primates, to better understand the maintenance of its colour. The facial skin of the bald uakari monkey is characterized by a thinner epidermis, absence of melanin pigments and a high density of vascular capillaries that spread below the epidermis. These vascular capillaries are larger and more tortuous than in other neotropical primates. The skin of the face of the bald uakari monkey allows a direct external assessment of haematological status, suggesting that the colour of the face would be an honest indicator of health, but could also signal sexual or behavioural states. PMID- 26587273 TI - How visual perceptual grouping influences foot placement. AB - Everybody would agree that vision guides locomotion; but how does vision influence choice when there are different solutions for possible foot placement? We addressed this question by investigating the impact of perceptual grouping on foot placement in humans. Participants performed a stepping stone task in which pathways consisted of target stones in a spatially regular path of foot falls and visual distractor stones in their proximity. Target and distractor stones differed in shape and colour so that each subset of stones could be easily grouped perceptually. In half of the trials, one target stone swapped shape and colour with a distractor in its close proximity. We show that in these 'swapped' conditions, participants chose the perceptually groupable, instead of the spatially regular, stepping location in over 40% of trials, even if the distance between perceptually groupable steps was substantially larger than normal step width/length. This reveals that the existence of a pathway that could be traversed without spatial disruption to periodic stepping is not sufficient to guarantee participants will select it and suggests competition between different types of visual input when choosing foot placement. We propose that a bias in foot placement choice in favour of visual grouping exists as, in nature, sudden changes in visual characteristics of the ground increase the uncertainty for stability. PMID- 26587274 TI - The relationship between pond habitat depth and functional tadpole diversity in an agricultural landscape. AB - One of the most important goals of biodiversity studies is to identify which characteristics of local habitats act as filters that determine the diversity of functional traits along environmental gradients. In this study, we investigated the relationship between the environmental variables of ponds and the functional trait diversity distribution of anuran tadpoles in an agricultural area in southeastern Brazil. Our results show that the functional trait diversity of frog tadpoles has a bell-curve-shaped relationship with the depths of ponds inserted in a pasture matrix. Because we are witnessing increasing human pressure on land use, simple acts (e.g. maintaining reproductive habitats with medium depth) can be the first steps towards preserving the diversity of Neotropical frog tadpole traits in agricultural landscapes. PMID- 26587276 TI - What's the catch? Validity of whaling data for Japanese catches of sperm whales in the North Pacific. AB - The failure of international efforts to manage commercial whaling was exemplified by revelations of large-scale illegal whale catches by the USSR over a 30 year period following World War II. Falsifications of catch data have also been reported for Japanese coastal whaling, but to date there has been no investigation of the reliability of catch statistics for Japanese pelagic (factory fleet) whaling operations. Here, we use data of known reliability from Soviet whaling industry reports to show that body lengths reported to the International Whaling Commission (IWC) by Japanese factory fleets for female sperm whales caught in the North Pacific are not credible. In 1968/1969, Japanese whaling fleets in the North Pacific killed 1568 females, of which 1525 (97.3%) were reported as being at or above the IWC's minimum length of 11.6 m (legal sized females, LSFs). By contrast, Soviet fleets operating during this period killed 12 578 females; only 824 (6.6%) were LSFs. Adjusting for effort, catches of LSFs were up to 9.1 times higher for Japan compared with the USSR, and even higher for very large females. Dramatic differences in body length statistics were evident when both nations operated in the same area. Significantly, the frequency of LSFs and very large females in the Japanese catch markedly declined after the IWC's International Observer Scheme in 1972 made illegal whaling more difficult. We conclude that the Japanese length data reflect systematic falsification of catch statistics submitted to the IWC, with serious implications for the reliability of data used in current population assessments. The apparent ease with which catch data were falsified in the past underscores the necessity of transparent and independent inspection procedures in any future commercial whaling. PMID- 26587275 TI - Symbiotic bacteria enable olive fly larvae to overcome host defences. AB - Ripe fruit offer readily available nutrients for many animals, including fruit fly larvae (Diptera: Tephritidae) and their associated rot-inducing bacteria. Yet, during most of their ontogeny, fruit remain chemically defended and effectively suppress herbivores and pathogens by high levels of secondary metabolites. Olive flies (Bactrocera oleae) are uniquely able to develop in unripe olives. Unlike other frugivorous tephritids, the larvae maintain bacteria confined within their midgut caeca. We examined the interaction between larvae, their associated bacteria, and fruit chemical defence, hypothesizing that bacterial contribution to larval development is contingent on the phenology of fruit defensive chemistry. We demonstrate that larvae require their natural complement of bacteria (Candidatus Erwinia dacicola: Enterobacteriaceae) in order to develop in unripe olives. Conversely, when feeding on ripe fruit, larval development proceeds independently of these bacteria. Our experiments suggest that bacteria counteract the inhibitory effect of oleuropein-the principal phenolic glycoside in unripe olives. In light of these results, we suggest that the unique symbiosis in olive flies, compared with other frugivorous tephritids, is understood by considering the relationship between the fly, bacteria and fruit chemistry. When applied in an evolutionary context, this approach may also point out the forces which shaped symbioses across the Tephritidae. PMID- 26587277 TI - Keep up or drown: adjustment of western Pacific coral reefs to sea-level rise in the 21st century. AB - Since the Mid-Holocene, some 5000 years ago, coral reefs in the Pacific Ocean have been vertically constrained by sea level. Contemporary sea-level rise is releasing these constraints, providing accommodation space for vertical reef expansion. Here, we show that Porites microatolls, from reef-flat environments in Palau (western Pacific Ocean), are 'keeping up' with contemporary sea-level rise. Measurements of 570 reef-flat Porites microatolls at 10 locations around Palau revealed recent vertical skeletal extension (78+/-13 mm) over the last 6-8 years, which is consistent with the timing of the recent increase in sea level. We modelled whether microatoll growth rates will potentially 'keep up' with predicted sea-level rise in the near future, based upon average growth, and assuming a decline in growth for every 1 degrees C increase in temperature. We then compared these estimated extension rates with rates of sea-level rise under four Representative Concentration Pathways (RCPs). Our model suggests that under low-mid RCP scenarios, reef-coral growth will keep up with sea-level rise, but if greenhouse gas concentrations exceed 670 ppm atmospheric CO2 levels and with +2.2 degrees C sea-surface temperature by 2100 (RCP 6.0 W m(-2)), our predictions indicate that Porites microatolls will be unable to keep up with projected rates of sea-level rise in the twenty-first century. PMID- 26587278 TI - Membrane shrinkage and cortex remodelling are predicted to work in harmony to retract blebs. AB - Numerous cell types undergo an oscillatory form of dynamics known as blebbing, whereby pressure-driven spherical protrusions of membrane (known as blebs) expand and contract over the cell's surface. Depending on the cell line, blebs play important roles in many different phenomena including mitosis and locomotion. The expansion phase of cellular blebbing has been mathematically modelled in detail. However, the active processes occurring during the retraction phase are not so well characterized. It is thought that blebs retract because a cortex reforms inside, and adheres to, the bleb membrane. This cortex is retracted into the cell and the attached bleb membrane follows. Using a computational model of a cell's membrane, cortex and interconnecting adhesions, we demonstrate that cortex retraction alone cannot account for bleb retraction and suggest that the mechanism works in tandem with membrane shrinking. Further, an emergent hysteresis loop is observed in the intracellular pressure, which suggests a potential mechanism through which a secondary bleb can be initiated as a primary bleb contracts. PMID- 26587279 TI - A two-state hysteresis model from high-dimensional friction. AB - In prior work (Biswas & Chatterjee 2014 Proc. R. Soc. A 470, 20130817 (doi:10.1098/rspa.2013.0817)), we developed a six-state hysteresis model from a high-dimensional frictional system. Here, we use a more intuitively appealing frictional system that resembles one studied earlier by Iwan. The basis functions now have simple analytical description. The number of states required decreases further, from six to the theoretical minimum of two. The number of fitted parameters is reduced by an order of magnitude, to just six. An explicit and faster numerical solution method is developed. Parameter fitting to match different specified hysteresis loops is demonstrated. In summary, a new two-state model of hysteresis is presented that is ready for practical implementation. Essential Matlab code is provided. PMID- 26587280 TI - The presence of lateral photophores correlates with increased speciation in deep sea bioluminescent sharks. AB - The vast majority of species within the lanternshark genus Etmopterus harbour complex luminescent markings on their flanks, whose functional significance has long remained obscure. Recent studies, however, suggest these enigmatic photophore aggregations to play a role in intraspecific communication. Using visual modelling based on in vivo luminescence measurements from a common lanternshark species, we show that etmopterid flank markings can potentially work as a medium range signal for intraspecific detection/recognition. In addition, using molecular phylogenetic analyses, we demonstrate that the Etmopterus clade exhibits a greater than expected species richness given its age. This is not the case for other bioluminescent shark clades with no (or only few) species with flank markings. Our results therefore suggest that etmopterid flank markings may provide a way for reproductive isolation and hence may have facilitated speciation in the deep-sea. PMID- 26587281 TI - Clear Corneal Phacovitrectomy with Posterior Capsulorhexis and IOL Implantation in Management of Selective Vitreoretinal Cases. AB - Purpose. To describe our technique, clear corneal phacovitrectomy with posterior capsulorhexis (CCPV), for the management of selected posterior segment intraocular foreign body (IOFB), posteriorly dislocated lens fragments (PDLF), and proliferative diabetic retinopathy (PDR) cases. Methods. This was a single center retrospective interventional case series. In 21 patients (21 eyes) we performed phacovitrectomy through three clear corneal tunnel incisions (CCTI) and posterior capsulorhexis to remove IOFB (n = 8), PDLF from the vitreous cavity after complicated phacoemulsification (n = 6), and vitreous hemorrhage and epiretinal membranes in PDR (n = 7). The procedure was completed with implantation of a hydrophobic acrylic IOL through the CCTI. Results. The mean visual acuity (logMAR) was 0.90 preoperative and improved to 0.26 over a mean follow-up of 8.7 months (range, 6-12 months). The intraocular lens was implanted into the capsular bag (n = 12) or onto the anterior capsule (n = 9). One PDR patient experienced an intraprocedural complication, hemorrhage from isolated fibrovascular adhesions. One IOFB patient developed apparent anterior proliferative vitreoretinopathy and required a repeat intervention. Conclusion. Selected vitreoretinal IOFB, PDLF, and PDR cases can be successfully managed by a combined surgical approach involving clear corneal phacovitrectomy with posterior capsulorhexis and implantation of an IOL, with good visual outcome and a low complication rate. PMID- 26587282 TI - Micro-Bypass Implantation for Primary Open-Angle Glaucoma Combined with Phacoemulsification: 4-Year Follow-Up. AB - Purpose. To report the long-term follow-up results in patients with cataract and primary open-angle glaucoma (POAG) randomly assigned to cataract surgery combined with micro-bypass stent implantation or phacoemulsification alone. Methods. 36 subjects with cataract and POAG were randomized in a 1 : 2 ratio to either iStent implantation and cataract surgery (combined group) or cataract surgery alone (control group). 24 subjects agreed to be evaluated again 48 months after surgery. Patients returned one month later for unmedicated washout assessment. Results. At the long-term follow-up visit we reported a mean IOP of 15,9 +/- 2,3 mmHg in the iStent group and 17 +/- 2,5 mmHg in the control group (p = NS). After washout, a 14,2% between group difference in favour of the combined group was statistically significant (p = 0,02) for mean IOP reduction. A significant reduction in the mean number of medications was observed in both groups compared to baseline values (p = 0,005 in the combined group and p = 0,01 in the control group). Conclusion. Patients in the combined group maintained low IOP levels after long-term follow-up. Cataract surgery alone showed a loss of efficacy in controlling IOP over time. Both treatments reduced the number of ocular hypotensive medications prescribed. This trial is registered with: NCT00847158. PMID- 26587283 TI - Lactose Hydrolysis in Milk and Dairy Whey Using Microbial beta-Galactosidases. AB - This work aimed at evaluating the influence of enzyme concentration, temperature, and reaction time in the lactose hydrolysis process in milk, cheese whey, and whey permeate, using two commercial beta-galactosidases of microbial origins. We used Aspergillus oryzae (at temperatures of 10 and 55 degrees C) and Kluyveromyces lactis (at temperatures of 10 and 37 degrees C) beta galactosidases, both in 3, 6, and 9 U/mL concentrations. In the temperature of 10 degrees C, the K. lactis beta-galactosidase enzyme is more efficient in the milk, cheese whey, and whey permeate lactose hydrolysis when compared to A. oryzae. However, in the enzyme reaction time and concentration conditions evaluated, 100% lactose hydrolysis was not reached using the K. lactis beta-galactosidase. The total lactose hydrolysis in whey and permeate was obtained with the A. oryzae enzyme, when using its optimum temperature (55 degrees C), at the end of a 12 h reaction, regardless of the enzyme concentration used. For the lactose present in milk, this result occurred in the concentrations of 6 and 9 U/mL, with the same time and temperature conditions. The studied parameters in the lactose enzymatic hydrolysis are critical for enabling the application of beta-galactosidases in the food industry. PMID- 26587284 TI - Hospitalization Events among Children and Adolescents with Sickle Cell Disease in Basra, Iraq. AB - Objectives. Despite improvements in the management of sickle cell disease (SCD), many patients still experience disease-related complications requiring hospitalizations. The objectives of this study were to identify causes of hospitalization among these patients and factors associated with the length of hospital stay (LOS) and readmission. Methods. Data from 160 patients (<14 years old) with SCD who were admitted to the Basra Maternity and Children's Hospital from the first of January 2012 through July 2012 were analyzed. Results. The main causes of hospitalization were acute painful crises (73.84%), infections (9.28%), acute chest syndrome (8.02%), and acute splenic sequestration crisis (6.32%). The mean LOS was 4.34 +/- 2.85 days. The LOS for patients on hydroxyurea (3.41 +/- 2.64 days) was shorter than that for patients who were not (4.59 +/- 2.86 days), P < 0.05. The readmission rate (23.1%) was significantly higher among patients with frequent hospitalizations in the previous year (OR 9.352, 95% CI 2.011 43.49), asthma symptoms (OR 4.225, 95% CI 1.125-15.862), and opioid use (OR 6.588, 95% CI 1.104-30.336). Patients on hydroxyurea were less likely to be readmitted (OR 0.082, 95% CI 0.10-0.663). Conclusions. There is a relatively high readmission rate among patients with SCD in Basra. The use of hydroxyurea significantly decreases the LOS and readmission rate. PMID- 26587285 TI - Knowledge Level of the Primary Healthcare Providers on Chronic Obstructive Pulmonary Disease and Pulmonary Rehabilitation. AB - INTRODUCTION: Awareness of the healthcare providers on chronic obstructive pulmonary disease (COPD), which is an important cause of mortality and morbidity in our country and all over the world, and on pulmonary rehabilitation (PR) which plays an important role in its nonpharmacological treatment will provide effectiveness in diagnosis and treatment of COPD. The present study aimed at determining knowledge level of the healthcare providers about COPD and PR. MATERIALS AND METHODS: In this cross-sectional study, family practitioners and staff of home-care in central county of Manisa City were applied a questionnaire in order to determine their knowledge level on COPD and pulmonary rehabilitation during the in-service training on "pulmonary rehabilitation, home-care services for the pulmonary diseases, and respiratory exercises." RESULTS: 65.5% of the healthcare providers responded to the survey. Rate of those correctly knowing at least one of four items was 97.2%. No responder knew all items correctly. Average value for correct answers was 5.30 +/- 2.1 (range: 1-10). The physicians, men, and those working in family health centers had higher level of knowledge on COPD compared to nonphysician healthcare providers (p = 0.006), women (p = 0.002), and those working in other practices (p = 0.019), respectively. CONCLUSION: Knowledge level of the primary healthcare providers on COPD and PR remains inadequate. Dynamic postgraduate training on this topic will be useful in referring the patients to centers giving service for this condition. PMID- 26587286 TI - A Multicenter Trial Defining a Serum Protein Signature Associated with Pancreatic Ductal Adenocarcinoma. AB - Background. Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with rapid tumor progression and poor prognosis. This study was motivated by the lack of sensitive and specific PDAC biomarkers and aimed to identify a diagnostic, serum protein signature for PDAC. Methods. To mimic a real life test situation, a multicenter trial comprising a serum sample cohort, including 338 patients with either PDAC or other pancreatic diseases (OPD) and controls with nonpancreatic conditions (NPC), was analyzed on 293-plex recombinant antibody microarrays targeting immunoregulatory and cancer-associated antigens. Results. Serum samples collected from different hospitals were analyzed and showed that (i) sampling from five different hospitals could not be identified as a preanalytical variable and (ii) a multiplexed biomarker signature could be identified, utilizing up to 10 serum markers that could discriminate PDAC from controls, with sensitivities and specificities in the 91-100% range. The first protein profiles associated with the location of the primary tumor in the pancreas could also be identified. Conclusions. The results demonstrate that robust enough serum signatures could be identified in a multicenter trial, potentially contributing to the development of a multiplexed biomarker immunoassay for improved PDAC diagnosis. PMID- 26587287 TI - Randomized, Placebo-Controlled, Double-Blind Pilot Study of D-Cycloserine in Chronic Stroke. AB - Stroke is a leading cause of death and disability in the USA. Up to 60% of patients do not fully recover despite intensive physical therapy treatment. N Methyl-D-aspartate receptors (NMDA-R) have been shown to play a role in synaptic plasticity when activated. D-Cycloserine promotes NMDA receptor function by binding to receptors with unoccupied glycine sites. These receptors are involved in learning and memory. We hypothesized that D-cycloserine, when combined with robotic-assisted physiotherapy (RAP), would result in greater gains compared with placebo + RAP in stroke survivors. Participants (n = 14) were randomized to D cycloserine plus RAP or placebo plus RAP. Functional, cognitive, and quality-of life measures were used to assess recovery. There was significant improvement in grip strength of the affected hand within both groups from baseline to 3 weeks (95% confidence interval for mean change, 3.95 +/- 2.96 to 4.90 +/- 3.56 N for D cycloserine and 5.72 +/- 3.98 to 8.44 +/- 4.90 N for control). SIS mood domain showed improvement for both groups (95% confidence interval for mean change, 72.6 +/- 16.3 to 82.9 +/- 10.9 for D-cycloserine and 82.9 +/- 13.5 to 90.3 +/- 9.9 for control). This preliminary study does not provide evidence that D-cycloserine can provide greater gains in learning compared with placebo for stroke survivors. PMID- 26587288 TI - Pain Levels after Local Anaesthetic with or without Hyaluronidase in Carpal Tunnel Release: A Randomised Controlled Trial. AB - Purpose. Hyaluronidase is an enzyme that temporarily liquefies the interstitial barrier, allowing easy dispersal of local anaesthetic through cleavage of tissue planes. This prospective, blinded, randomised controlled study investigates the utility of adding hyaluronidase to local anaesthetic in the setting of carpal tunnel release. Methods. 70 consecutive carpal tunnel release patients were recruited and randomised into a control group only receiving local anaesthetic and a hyaluronidase group receiving both hyaluronidase and local anaesthetic. Pain scores were rated using the visual analogue scale (VAS) by patients immediately after local anaesthetic injection and again immediately after the carpal tunnel release. Results. Preoperative VAS scores, taken after local anaesthetic injection, were greater than postoperative VAS scores. Postoperative VAS scores were significantly lower in the hyaluronidase group and tourniquet times were significantly shorter in the hyaluronidase group. Conclusion. Hyaluronidase addition to local anaesthetic in carpal tunnel release resulted in significant reductions in operative time and pain immediately after operation. PMID- 26587290 TI - Use of Peripheral Nerve Blocks with Sedation for Total Knee Arthroplasty in a Patient with Contraindication for General Anesthesia. AB - Although peripheral nerve blocks are commonly used to provide postoperative analgesia after total knee arthroplasty (TKA) and other lower extremity procedures, these blocks are rarely used for intraoperative anesthesia. Most TKAs are performed under general anesthesia (GA) or neuraxial anesthesia (NA). The knee has a complex sensory innervation that makes surgical anesthesia difficult with peripheral nerve blocks alone. Rarely are both GA and NA relatively contraindicated and alternatives are considered. We present a patient who underwent TKA performed under peripheral nerve block and sedation alone. PMID- 26587289 TI - The Plasticity of Brain Gray Matter and White Matter following Lower Limb Amputation. AB - Accumulating evidence has indicated that amputation induces functional reorganization in the sensory and motor cortices. However, the extent of structural changes after lower limb amputation in patients without phantom pain remains uncertain. We studied 17 adult patients with right lower limb amputation and 18 healthy control subjects using T1-weighted magnetic resonance imaging and diffusion tensor imaging. Cortical thickness and fractional anisotropy (FA) of white matter (WM) were investigated. In amputees, a thinning trend was seen in the left premotor cortex (PMC). Smaller clusters were also noted in the visual-to motor regions. In addition, the amputees also exhibited a decreased FA in the right superior corona radiata and WM regions underlying the right temporal lobe and left PMC. Fiber tractography from these WM regions showed microstructural changes in the commissural fibers connecting the bilateral premotor cortices, compatible with the hypothesis that amputation can lead to a change in interhemispheric interactions. Finally, the lower limb amputees also displayed significant FA reduction in the right inferior frontooccipital fasciculus, which is negatively correlated with the time since amputation. In conclusion, our findings indicate that the amputation of lower limb could induce changes in the cortical representation of the missing limb and the underlying WM connections. PMID- 26587291 TI - Small Bowel Obstruction Masquerading as Acute ST Elevation Myocardial Infarction. AB - ST segment elevation on EKG remains among the most important presentations of acute myocardial infarction. Due to the urgency of intervention for this finding, other clinical scenarios causing ST elevations on EKG may sometimes go unaddressed and can lead to fatal complications. We present a case of an 86-year old male presenting with small bowel obstruction leading to EKG findings of ST segment elevation in the absence of critical coronary obstruction. The EKG finding resolved after the improvement of small bowel obstruction reflecting the reversible cause of the changes. PMID- 26587292 TI - Pacing and Sensing of Human Heart for over 31 Years with the Same Apparatus (Generator and Lead). AB - Several patients receive a permanent pacemaker in a relatively young age, with multiple subsequent reoperations for pacemaker replacement. Pulse generator replacement is an invasive procedure, associated with the risk of various complications, mainly infection and skin erosion. A case of an extremely long lasting pacemaker with a totally uneventful longevity period over 31 years is presented. The explanation for this quite rare pacemaker longevity (possibly unique) is analyzed and discussed. PMID- 26587293 TI - Ciprofloxacin-Induced Thrombotic Thrombocytopenic Purpura: A Case of Successful Treatment and Review of the Literature. AB - A 49-year-old African American woman was admitted to our hospital with abdominal pain, nausea, vomiting, lethargy, and confusion. She was receiving ciprofloxacin for a urinary-tract infection prior to admission. Laboratory examination revealed anemia, thrombocytopenia, elevated lactate dehydrogenase, and serum creatinine. Peripheral smear showed numerous schistocytes, and the patient was diagnosed with thrombotic thrombocytopenic purpura (TTP). Ciprofloxacin was identified as the offending agent. The patient received treatment with steroids and plasmapheresis, which led to rapid clinical recovery. This is the first case to our knowledge of successfully treated ciprofloxacin-induced TTP; previously reported cases had fulminant outcomes. Quinolones are an important part of the antibiotic armamentarium, and this case can raise awareness of the association between quinolones and TTP. A high index of suspicion for detection and early and aggressive management are vitally important for a successful outcome. PMID- 26587294 TI - Evaluation of Low-Level Laser Therapy in TMD Patients. AB - Light amplification by stimulated emission of radiation (laser) is one of the most recent treatment modalities in dentistry. Low-level laser therapy (LLLT) is suggested to have biostimulating and analgesic effects through direct irradiation without causing thermal response. There are few studies that have investigated the efficacy of laser therapy in temporomandibular disorders (TMD), especially in reduced mouth opening. The case report here evaluates performance of LLLT with a diode laser for temporomandibular clicking and postoperative findings were evaluated in two cases of TMD patients. First patient had a history of limited mouth opening and pain in temporomandibular joint (TMJ) region since nine months. Second patient's main complaint was his restricted mouth opening, which was progressed in one year. LLLT was performed with a 685 nm red probed diode laser that has an energy density of 6.2 J/cm(2), three times a week for one month, and application time was 30 seconds (685 nm, 25 mW, 30 s, 0.02 Hz, and 6.2 J/cm(2)) (BTL-2000, Portative Laser Therapy Device). The treatment protocol was decided according to the literature. One year later patients were evaluated and there were no changes. This application suggested that LLLT is an appropriate treatment for TMD related pain and limited mouth opening and should be considered as an alternative to other methods. PMID- 26587295 TI - Combined Periodontal, Orthodontic, and Prosthetic Treatment in an Adult Patient. AB - A 41-year-old man had a significant loss of bone and supporting tissues with pathologic migration of several teeth and several missing teeth. He was treated with an interdisciplinary therapeutic protocol that included nonsurgical periodontal therapy based on strict control of supragingival plaque, subgingival periodontal therapy, orthodontic and endodontic treatment, and replacement of restorations. The orthodontic therapy was performed in a severely reduced bone support and the presence of pathological tooth migration after periodontal disease control. The interdisciplinary treatment protocol was the key to achieve a significant improvement in his facial and dental esthetics, masticatory function, and quality of life. PMID- 26587296 TI - Reestablishment of Occlusal Vertical Dimension in Complete Denture Wearing in Two Stages. AB - The assessment and reestablishment of the occlusal vertical dimension (OVD) are considered important factors in the treatment of complete denture wearers. The long-time use of a complete denture can result in jaw displacement due to abrasion of the artificial teeth and residual ridge resorption, causing esthetic complications. Most patients with old dentures and incorrect OVD accept reestablishment of the OVD with new complete dentures, even if they were used to their old dentures. The present clinical report describes a method of gradual reestablishment of OVD using a diagnostic acrylic splint on artificial teeth in old complete dentures before the manufacture of new complete dentures. Clinical Significance. The use of a reversible treatment for reestablishment of the OVD in old complete dentures with a diagnostic occlusal acrylic splint allows for the reestablishment of the intermaxillary relationship, providing physiological conditions of masticatory performance associated with the recovery of facial esthetics in edentulous patients. PMID- 26587297 TI - Elevated Intracranial Pressure Diagnosis with Emergency Department Bedside Ocular Ultrasound. AB - Bedside sonographic measurement of optic nerve sheath diameter can aid in the diagnosis of elevated intracranial pressure in the emergency department. This case report describes a 21-year-old female presenting with 4 months of mild headache and 2 weeks of recurrent, transient binocular vision loss. Though limited by patient discomfort, fundoscopic examination suggested the presence of blurred optic disc margins. Bedside ocular ultrasound (BOUS) revealed wide optic nerve sheath diameters and bulging optic discs bilaterally. Lumbar puncture demonstrated a cerebrospinal fluid (CSF) opening pressure of 54 cm H2O supporting the suspected diagnosis of idiopathic intracranial hypertension. Accurate fundoscopy can be vital to the appropriate diagnosis and treatment of patients with suspected elevated intracranial pressure, but it is often technically difficult or poorly tolerated by the photophobic patient. BOUS is a quick and easily learned tool to supplement the emergency physician's fundoscopic examination and help identify patients with elevated intracranial pressure. PMID- 26587298 TI - A Case of Palytoxin Poisoning in a Home Aquarium Enthusiast and His Family. AB - Inhalational exposure to palytoxin is an extremely rare cause of respiratory distress. This little-known marine toxin has the potential to cause significant morbidity and mortality. Toxicity has been best documented in cases of ingestion but has also been seen in cases of dermal exposure and inhalation of vapors. Palytoxin has been found in several coral species, some of which are favored by home aquarium enthusiasts and are commercially available. We report a case of a family who were exposed to the aerosolized toxin following the cleaning of a coral in their home aquarium. It is important that clinicians be aware of this source of toxic exposure to provide necessary care to these patients. PMID- 26587299 TI - Disabling Orthostatic Headache after Penetrating Stonemason Pencil Injury to the Sacral Region. AB - Penetrating injuries to the spine, although less common than motor vehicle accidents and falls, are important causes of injury to the spinal cord. They are essentially of two varieties: gunshot or stab wounds. Gunshot injuries to the spine are more commonly described. Stab wounds are usually inflicted by knife or other sharp objects. Rarer objects causing incidental spinal injuries include glass fragments, wood pieces, chopsticks, nailguns, and injection needles. Just few cases of penetrating vertebral injuries caused by pencil are described. The current case concerns a 42-year-old man with an accidental penetrating stonemason pencil injury into the vertebral canal without neurological deficit. After the self-removal of the foreign object the patient complained of a disabling orthostatic headache. The early identification and treatment of the intracranial hypotension due to the posttraumatic cerebrospinal fluid (CSF) sacral fistulae were mandatory to avoid further neurological complications. In the current literature acute pattern of intracranial hypotension immediately after a penetrating injury of the vertebral column has never been reported. PMID- 26587300 TI - Whole Exome Sequencing Reveals Compound Heterozygosity for Ethnically Distinct PEX7 Mutations Responsible for Rhizomelic Chondrodysplasia Punctata, Type 1. AB - We describe two brothers who presented at birth with bone growth abnormalities, followed by development of increasingly severe intellectual and physical disability, growth restriction, epilepsy, and cerebellar and brain stem atrophy, but normal ocular phenotypes. Case 1 died at 19 years of age due to chronic respiratory illnesses without a unifying diagnosis. The brother remains alive but severely disabled at 19 years of age. Whole exome sequencing identified compound heterozygous stop mutations in the peroxisome biogenesis factor 7 gene in both individuals. Mutations in this gene cause rhizomelic chondrodysplasia punctata, type 1 (RCDP1). One mutation, p.Arg232 (*) , has only been documented once before in a Japanese family, which is of interest given these two boys are of European descent. The other mutation, p.Leu292 (*) , is found in approximately 50% of RCDP1 patients. These are the first cases of RCDP1 that describe the coinheritance of the p.Arg232 (*) and p.Leu292 (*) mutations and demonstrate the utility of WES in cases with unclear diagnoses. PMID- 26587301 TI - Langerhans Cell Histiocytosis in an Infant Mimicking a Lymphoma at Presentation. AB - Langerhans cell histiocytosis (LCH) is a rare disorder characterized by proliferation and accumulation of clonal dendritic cells with varied clinical presentation and an unpredictable course. We report a 5-month-old infant with LCH who presented with severe respiratory distress, a large mediastinal mass, significant generalized lymphadenopathy, and hepatosplenomegaly. Lymphoma, especially T cell lymphoblastic lymphoma, can present with superior mediastinal syndrome needing urgent empirical therapy without biopsy. However, lack of response prompted a biopsy which confirmed it to be a case of LCH and that leads to appropriate therapy and survival. There have been reports of LCH presenting with isolated mediastinal mass or with generalized lymphadenopathy, but the combined presentation of generalized lymphadenopathy with large mediastinal mass, hepatosplenomegaly, and fever in an infant has rarely been reported. Conclusion. LCH should also be considered in the differential diagnosis of an infant presenting with generalized lymphadenopathy, mediastinal mass, hepatosplenomegaly, and fever. PMID- 26587302 TI - Diaphragmatic Amyloidosis Causing Respiratory Failure: A Case Report and Review of Literature. AB - Neuromuscular respiratory failure is a rare complication of systemic immunoglobulin light chain amyloidosis. We describe a case of a 70-year-old Caucasian man with multiple myeloma who presented with worsening dyspnea. The patient was diagnosed with and treated for congestive heart failure but continued to suffer from hypercapnic respiratory insufficiency. He had restrictive physiology on pulmonary function tests and abnormal phrenic nerve conduction studies, consistent with neuromuscular respiratory failure. The diagnosis of systemic immunoglobulin light chain amyloidosis was made based on the clinical context and a cardiac biopsy. Despite treatment attempts, the patient passed away in the intensive care unit from hypercapnic respiratory failure. Autopsy revealed dense diaphragmatic amyloid deposits without phrenic nerve infiltration or demyelination or lung parenchymal involvement. Only 5 cases of neuromuscular respiratory failure due to amyloid infiltration of the diaphragm have been described. All cases, including this, were characterized by rapid progression and high mortality. Therefore, diaphragmatic amyloidosis should be on the differential for progressive neuromuscular respiratory failure in patients with multiple myeloma or any other monoclonal gammopathy. Given its poor prognosis, early recognition of this condition is essential in order to address goals of care and encourage pursuit of palliative measures. PMID- 26587303 TI - Klippel-Trenaunay Syndrome with Extensive Lymphangiomas. AB - Klippel-Trenaunay syndrome (KTS) is a rare disorder characterized by the triad of vascular malformations, venous varicosities, and bone and soft-tissue hypertrophy. We present a case of Klippel-Trenaunay syndrome with limb hypertrophy, port-wine stains, lymphangiomas, and venous varicosities in the limbs. PMID- 26587304 TI - Two Unusual Aspects of Posterior Reversible Encephalopathy Syndrome Mimicking Primary and Secondary Brain Tumor Lesions. AB - The posterior reversible encephalopathy syndrome (PRES) is a rare clinical radiological entity well described with typical clinical and radiological manifestations. Atypical presentation, especially in imaging, exists. The authors report here two cases of posterior reversible encephalopathy in which imaging aspects were atypical, mimicking, in the first case, hemorrhagic cerebral metastasis of cholangiocarcinoma and, in the second case, a brain tumor. The diagnosis has been retrospectively rectified due to clinical and radiological outcome. PMID- 26587306 TI - Primary Gallbladder Lymphoma in a Male Patient with No Risk Factors Detected Incidentally by CT Colonography. AB - Primary gallbladder lymphoma, although rare, usually presents in females with symptoms mimicking cholecystitis. We present a rare case of primary gallbladder in an 81-year-old male with no risk factors whose only symptom was weight loss. Routine blood tests including liver function tests were unremarkable. A CT colonography was carried out to exclude colonic malignancy. Unilateral gallbladder wall thickening and lymphadenopathy were incidentally detected and confirmed by ultrasound and a decision for the patient to undergo laparoscopic cholecystectomy and intraoperative cholangiogram was made. Histology confirmed extranodal marginal zone lymphoma with follow-up staging and biopsy of the bone marrow not demonstrating spread. Cholecystectomy was therefore deemed curative and no adjuvant therapy was necessary. Thickening of the gallbladder wall on any imaging with or without symptoms should not be ignored or assumed to be cholecystitis, even in males with no risk factors. In these patients urgent cholecystectomy with intraoperative cholangiogram is indicated with histology and haematology follow-up. PMID- 26587305 TI - Laparoscopic Distal Pancreatectomy with or without Preservation of the Spleen for Solid Pseudopapillary Neoplasm. AB - Solid pseudopapillary neoplasm (SPN) is a rare tumor of the pancreas. Laparoscopic distal pancreatectomy (DP) is a feasible and safe procedure, and successful spleen preservation rates are higher using a laparoscopic approach. We hypothesized that certain patients with SPN would be good candidates for laparoscopic surgery; however, few surgeons have reported laparoscopic DP for SPN. We discuss the preoperative assessment and surgical simulation for two SPN cases. A simulation was designed because we consider that a thorough preoperative understanding of the procedure based on three-dimensional image analysis is important for successful laparoscopic DP. We also discuss the details of the actual laparoscopic DP with or without splenic preservation that we performed for our two SPN cases. It is critical to use appropriate instruments at appropriate points in the procedure; surgical instruments are numerous and varied, and surgeons should maximize the use of each instrument. Finally, we discuss the key techniques and surgical pitfalls in laparoscopic DP with or without splenic preservation. We conclude that experience alone is inadequate for successful laparoscopic surgery. PMID- 26587307 TI - Development of an HPLC Method for Absolute Quantification and QAMS of Flavonoids Components in Psoralea corylifolia L. AB - The seeds of Psoralea corylifolia L. (Fabaceae) are a commonly used medicinal herb in eastern Asia with many beneficial effects in clinical therapies. In this study, a simple, sensitive, precise, and specific reverse phase high-performance liquid chromatography (HPLC) method was established for quantification of 9 flavonoids in P. corylifolia, including isobavachin, neobavaisoflavone, bavachin, corylin, bavachalcone, bavachinin, isobavachalcone, corylifol A, and 4'-O methylbavachalcone. Based on this method, a quantitative analysis of multicomponents by single marker (QAMS) was carried out, and the relative correction factors (RCFs) were calculated for determining the contents of other flavonoids. The accuracy of QAMS method was verified by comparing with the results of external standard method, as well as the feasibility and adaptability of the method applied on quality control of P. corylifolia. The 9 compounds were baseline separated in 60 min with a good linearity of regression coefficient (R (2)) over 0.9991. The accuracies of QAMS were between 92.89% and 109.5%. The RSD values of f in different injection volume were between 2.3% and 3.6%. The results obtained from QAMS suggested that it was a convenient and accurate method to determine multicomponents especially when some authentic standard substances were unavailable. It can be used to control the quality of P. corylifolia. PMID- 26587308 TI - Simultaneous Determination of Six Active Compounds in Yixin Badiranjibuya Granules, a Traditional Chinese Medicine, by RP-HPLC-UV Method. AB - In this study, a sensitive, precise, and accurate HPLC-UV method was developed and validated to simultaneously determine the six analytes (luteolin-7-O-beta-D glucuronide, apigenin-7-O-beta-D-glucuronide, diosmetin-7-O-beta-D-glucuronide, acacetin-7-O-beta-D-glucuronide, tilianin, and rosmarinic acid) in Yixin Badiranjibuya Granules, in which five analytes (i.e., luteolin-7-O-beta-D glucuronide, apigenin-7-O-beta-D-glucuronide, diosmetin-7-O-beta-D-glucuronide, acacetin-7-O-beta-D-glucuronide, and rosmarinic acid) were determined for the first time in Yixin Badiranjibuya Granules, the content of tilianin in Yixin Badiranjibuya Granules was reported in other literatures, and the content of tilianin in our work was higher than that of the literature reports. The quality of 11 batch samples from four different manufacturers was evaluated using the proposed determination method. The contents of the six analytes were largely different among samples from various manufacturers. Therefore, this determination method can provide a scientific basis for quality evaluation and control of Yixin Badiranjibuya Granules. PMID- 26587309 TI - Pharmacology and Phytochemistry of Oleo-Gum Resin of Commiphora wightii (Guggulu). AB - Guggulu is an oleo-gum resin which exudes out as a result of injury from the bark of Commiphora wightii (Arnott) Bhandari [syn. Commiphora mukul (Hook. Ex Stocks) Engl; Balsamodendron mukul (Hook. Ex Stocks); Family, Burseraceae]. It has been used in the Ayurveda since time immemorial for the treatment of variety of disorders such as inflammation, gout, rheumatism, obesity, and disorders of lipids metabolism. It is a mixture of phytoconstituents like volatile oil which contains terpenoidal constituents such as monoterpenoids, sesquiterpenoids, diterpenoids, and triterpenoids; steroids; flavonoids; guggultetrols; lignans; sugars; and amino acids. This review is an effort to compile all the information available on all of its chemical constituents which are responsible for its therapeutic potential. The wild occurrence of this species is restricted mainly to the dry regions of Rajasthan and Gujarat States of India, and the bordering regions of Pakistan. Oleo-gum resin, guggulu, tapped from the stems of this species, is consumed in high volumes by the Indian herbal industries. There has been a decline in its wild population over the last several decades, as a result of habitat loss and degradation, coupled with unregulated harvesting and tapping of oleo-gum resin. This species is consequently assessed as Critically Endangered and enlisted in the IUCN red list of threatened species. PMID- 26587310 TI - Study of Collagen Birefringence in Different Grades of Oral Squamous Cell Carcinoma Using Picrosirius Red and Polarized Light Microscopy. AB - Objectives. The present study was done to evaluate birefringence pattern of collagen fibres in different grades of oral squamous cell carcinoma using Picrosirius red stain and polarization microscopy and to determine if there is a change in collagen fibres between different grades of oral squamous cell carcinoma. Materials and Methods. Picrosirius red stained 5 MUm thick sections of previously diagnosed different grades of squamous cell carcinoma and normal oral mucosa were studied under polarization microscopy for arrangement as well as birefringence of collagen fibres around tumour islands. Results. It was found that thin collagen fibres increased and thick collagen fibres decreased with dedifferentiation of OSCC (P < 0.0001). It was observed that there was change in polarization colours of thick fibres from yellowish orange to greenish yellow with dedifferentiation of OSCC indicating loosely packed fibres (P < 0.0001). Conclusion. There was a gradual change of birefringence of collagen from yellowish orange to greenish yellow from well to poorly differentiated squamous cell carcinoma, indicating that there is a change from mature form of collagen to immature form as tumour progresses. Studying collagen fibres with Picrosirius red for stromal changes around tumour islands along with routine staining may help in predicting the prognosis of tumour. PMID- 26587312 TI - CD4+ T helper cell responses to NY-ESO-1 tumor antigen in ovarian cancer resist perversion into immunosuppressive Tregs. AB - In a recent study, we have demonstrated that T helper type 1 (TH1) cells specific for the tumor antigen NY-ESO-1 are amplified at ovarian tumor sites but are not "perverted" into immunosuppressive FOXP3+ regulatory T cells (Tregs). These findings encourage the development of protocols aiming to eliminate, or inactivate, FOXP3+ Tregs and reinforce Type I anticancer immunity, to improve clinical outcomes. PMID- 26587311 TI - Safety and Immunogenicity of a Recombinant Adenovirus Serotype 35-Vectored HIV-1 Vaccine in Adenovirus Serotype 5 Seronegative and Seropositive Individuals. AB - BACKGROUND: Recombinant adenovirus serotype 5 (rAd5)-vectored HIV-1 vaccines have not prevented HIV-1 infection or disease and pre-existing Ad5 neutralizing antibodies may limit the clinical utility of Ad5 vectors globally. Using a rare Ad serotype vector, such as Ad35, may circumvent these issues, but there are few data on the safety and immunogenicity of rAd35 directly compared to rAd5 following human vaccination. METHODS: HVTN 077 randomized 192 healthy, HIV uninfected participants into one of four HIV-1 vaccine/placebo groups: rAd35/rAd5, DNA/rAd5, and DNA/rAd35 in Ad5-seronegative persons; and DNA/rAd35 in Ad5-seropositive persons. All vaccines encoded the HIV-1 EnvA antigen. Antibody and T-cell responses were measured 4 weeks post boost immunization. RESULTS: All vaccines were generally well tolerated and similarly immunogenic. As compared to rAd5, rAd35 was equally potent in boosting HIV-1-specific humoral and cellular immunity and responses were not significantly attenuated in those with baseline Ad5 seropositivity. Like DNA, rAd35 efficiently primed rAd5 boosting. All vaccine regimens tested elicited cross-clade antibody responses, including Env V1/V2 specific IgG responses. CONCLUSIONS: Vaccine antigen delivery by rAd35 is well tolerated and immunogenic as a prime to rAd5 immunization and as a boost to prior DNA immunization with the homologous insert. Further development of rAd35 vectored prime-boost vaccine regimens is warranted. PMID- 26587313 TI - Elevated core-fucosylated IgG is a new marker for hepatitis B virus-related hepatocellular carcinoma. AB - Immunoglubulin G (IgG) and its abnormal glycosylations are associated with carcinogenesis. The present study investigates the relationship between cancer derived IgG and clinicopathological characteristics in hepatocellular carcinoma (HCC) and assesses the value of serum N-glycosylated IgG in diagnosing and monitoring hepatitis B virus (HBV)-related HCC. Tissue microarray analysis of 90 HCC tissues showed that HCC patients with IgG immunopositivity had higher levels of core-fucosylated alpha fetoprotein (AFP-L3), larger tumors, and a higher incidence of portal vein tumor thrombus. HCC-derived IgG stimulated the growth of liver cancer cells in vitro. HCC patients presented a significantly increased fraction of Lens culinaris agglutinin binding IgG (core-fucosylated IgG, IgG-L3) among total serum IgG. The clinical diagnostic performance of serum IgG-L3% was evaluated in 3 case-control studies (1 training set and 2 validation cohorts), including 293 patients with HCC, 131 with liver cirrhosis, 132 HBV carriers, and 151 healthy controls. IgG-L3% had better general diagnostic performance than AFP in the training set and validation cohort 1 (accuracy: 81.33-85.11% versus 63.33 78.61%). In validation cohort 2, where we aimed to assess the efficiency of IgG L3% in patients with AFP-negative HCC, the diagnostic accuracy of IgG-L3% was 72.54-73.60%. Finally, a longitudinal evaluation based on 31 HCC patients demonstrated that IgG-L3% decreased in 24 patients after curative surgery. The remaining 7 patients showed elevated IgG-L3% and post-operative recurrence. HCC patients with higher IgG-L3% had poor survival during a 3-year follow up. We conclude that HCC-derived IgG is correlated with progressive behavior of HCC. Therefore, elevated core-fucosylated IgG is a new diagnostic and prognostic marker in HBV-related HCC. PMID- 26587314 TI - Triggering co-stimulation directly in melanoma tumor fragments drives CD8+ tumor infiltrating lymphocyte expansion with improved effector-memory properties. AB - TIL from solid tumors can express activation/co-stimulatory molecules like 4 1BB/CD137, a sign of recent antigenic stimulation in the tumor microenvironment (TME). This activated state can be exploited ex vivo to enhance the expansion of tumor-reactive CD8+ TIL for adoptive cell therapy through direct addition of immunomodulators to tumor fragments in culture. PMID- 26587315 TI - Can dendritic cells improve whole cancer cell vaccines based on immunogenically killed cancer cells? AB - Immunogenic cell death (ICD) offers interesting opportunities in cancer cell (CC) vaccine manufacture, as it increases the immunogenicity of the dead CC. Furthermore, fusion of CCs with dendritic cells (DCs) is considered a superior method for generating whole CC vaccines. Therefore, in this work, we determined in naive mice whether immunogenically killed CCs per se (CC vaccine) elicit an antitumoral immune response different from the response observed when immunogenically killed CCs are associated with DCs through fusion (fusion vaccine) or through co-incubation (co-incubation vaccine). After tumor inoculation, the type of immune response in the prophylactically vaccinated mice differed between the groups. In more detail, fusion vaccines elicited a humoral anticancer response, whereas the co-incubation and CC vaccine mainly induced a cellular response. Despite these differences, all three approaches offered a prophylactic protection against tumor development in the murine mammary carcinoma model. In summary, it can be concluded that whole CC vaccines based on immunogenically killed CCs may not necessarily require association with DCs to elicit a protective anticancer immune response. If this finding can be endorsed in other cancer models, the manufacture of CC vaccines would greatly benefit from this new insight, as production of DC-based vaccines is laborious, time-consuming and expensive. PMID- 26587317 TI - Designing CAR T cells for glioblastoma. AB - Chimeric antigen receptor (CAR)-modified T cells directed against CD19 can mediate long-term durable remissions in B cell malignancies, but bringing a new target antigen to the clinic requires extensive modeling to avoid on-target and off-target toxicity. We recently described a systematic approach to test a new CAR directed against EGFR variant III. PMID- 26587316 TI - Carving out its niche: A role for carbonic anhydrase IX in pre-metastatic niche development. AB - Primary tumor-associated hypoxia stimulates the production of secreted factors that mobilize bone marrow-derived cells, including immunomodulatory myeloid derived suppressor cells (MDSCs) to pre-metastatic niches. We recently found that the hypoxia-induced enzyme carbonic anhydrase IX (CAIX) promotes metastasis by stimulating the G-CSF dependent mobilization of granulocytic MDSCs to the lung pre-metastatic niche. PMID- 26587319 TI - Interaction of tumor cells with infiltrating lymphocytes via CD70 and CD27 in clear cell renal cell carcinoma. AB - CD70 upregulation by hypoxia-inducible factor and CD27+ lymphocyte tumor infiltration are associated with worse survival in von Hippel-Lindau gene (VHL) mutated clear cell renal cell carcinoma (ccRCC). CD70/CD27 interaction is accompanied by high soluble CD27 levels in the sera of ccRCC patients suggesting that soluble CD27 is a potential predictive tool for anti-CD70 therapy. PMID- 26587318 TI - Prognostic and theranostic impact of molecular subtypes and immune classifications in renal cell cancer (RCC) and colorectal cancer (CRC). AB - Molecular and immune classifications powerfully predict cancer patient's survival and response to therapies. We herein describe the immune tumor microenvironment of molecular subgroups of colorectal and renal cell cancers, revealing a strong correlation between tumor subtypes and distinct immune profiles. PMID- 26587320 TI - Absence of myeloperoxidase and CD8 positive cells in colorectal cancer infiltrates identifies patients with severe prognosis. AB - Colorectal cancer (CRC) infiltration by cells expressing myeloperoxidase (MPO) or CD8 positive T lymphocytes has been shown to be independently associated with favorable prognosis. We explored the relationship occurring between CD8+ and MPO+ cell CRC infiltration, its impact on clinical-pathological features and its prognostic significance in a tissue microarray (TMA) including 1,162 CRC. We observed that CRC showing high MPO+ cell infiltration are characterized by a prognosis as favorable as that of cancers with high CD8+ T cell infiltration. However, MPO+ and CD8+ CRC infiltrating cells did not synergize in determining a more favorable outcome, as compared with cancers showing MPOhigh/CD8low or MPOlow/CD8high infiltrates. Most importantly, we identified a subgroup of CRC with MPOlow/CD8low tumor infiltration characterized by a particularly severe prognosis. Intriguingly, although MPO+ and CD8+ cells did not co-localize in CRC infiltrates, an increased expression of TIA-1 and granzyme-B was detectable in T cells infiltrating CRC with high MPO+ cell density. PMID- 26587321 TI - GITR engagement in combination with CTLA-4 blockade completely abrogates immunosuppression mediated by human liver tumor-derived regulatory T cells ex vivo. AB - In liver cancer tumor-infiltrating regulatory T cells (Ti-Treg) are potent suppressors of tumor-specific T-cell responses and express high levels of the Treg-associated molecules cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and glucocorticoid-induced tumor necrosis factor receptor (GITR). In this study, we have evaluated the capacity of GITR-ligation, CTLA-4-blockade and a combination of both treatments to alleviate immunosuppression mediated by Ti Treg. Using ex vivo isolated cells from individuals with hepatocellular carcinoma (HCC) or liver metastases from colorectal cancer (LM-CRC) we show that treatment with a soluble form of the natural ligand of GITR (GITRL), or with blocking antibodies to CTLA-4, reduces the suppression mediated by human liver tumor infiltrating CD4+Foxp3+ Treg, thereby restoring proliferation and cytokine production by effector T cells. Importantly, combined treatment with low doses of both molecules exhibited stronger recovery of T cell function compared with either treatment alone. Our data suggest that in patients with primary and secondary liver cancer both GITR-ligation and anti-CTLA-4 mAb can improve the antitumor immunity by abrogating Ti-Treg mediated suppression. PMID- 26587322 TI - A high density of tertiary lymphoid structure B cells in lung tumors is associated with increased CD4+ T cell receptor repertoire clonality. AB - T and B cell receptor (TCR and BCR, respectively) Vbeta or immunoglobulin heavy chain complementarity-determining region 3 sequencing allows monitoring of repertoire changes through recognition, clonal expansion, affinity maturation, and T or B cell activation in response to antigen. TCR and BCR repertoire analysis can advance understanding of antitumor immune responses in the tumor microenvironment. TCR and BCR repertoires of sorted CD4+, CD8+ or CD19+ cells in tumor, non-tumoral distant tissue (NT), and peripheral compartments (blood/draining lymph node [P]) from 47 non-small cell lung cancer (NSCLC) patients (agemedian = 68 y) were sequenced. The clonotype spectra were assessed among different tissues and correlated with clinical and immunological parameters. In all tissues, CD4+ and CD8+ TCR repertoires had greater clonality relative to CD19+ BCR. CD4+ T cells exhibited greater clonality in NT compared to tumor (p = 0.002) and P (p < 0.001), concentrated among older patients (age > 68). Younger patients exhibited greater CD4+ T cell diversity in P compared to older patients (p = 0.05), and greater CD4+ T cell clonality in tumor relative to P (p < 0.001), with fewer shared clonotypes between tumor and P than older patients (p = 0.04). More interestingly, greater CD4+ and CD8+ T cell clonality in tumor and P, respectively (both p = 0.05), correlated with high density of tumor-associated tertiary lymphoid structure (TLS) B cells, a biomarker of higher overall survival in NSCLC. Results indicate distinct adaptive immune responses in NSCLC, where peripheral T cell diversity is modulated by age, and tumor T cell clonal expansion is favored by the presence of TLSs in the tumor microenvironment. PMID- 26587324 TI - The macrophage: Switches from a passenger to a driver during anticancer therapy. AB - We have recently discovered that BRAF inhibitors induce potent macrophage responses that confer melanoma resistance to therapy. Our studies lay a foundation for the hypothesis that macrophages switch their role from a passenger to a driver for tumor survival during therapeutic treatment, suggesting that agents that target macrophages can be an important component of "cocktail" anticancer therapy. PMID- 26587325 TI - Lung specific X protein as a novel therapeutic target for lung cancer. AB - The identification of novel therapeutic targets in lung cancer is an urgent challenge. We found lung-specific X protein (LunX) is overexpressed in lung cancer and promotes primary tumor growth and metastatic colonization. The antibody against LunX appears to be potentially applicable for therapeutic use in the future, given its efficacy in preclinical models. PMID- 26587323 TI - Natural Killer (NK)/melanoma cell interaction induces NK-mediated release of chemotactic High Mobility Group Box-1 (HMGB1) capable of amplifying NK cell recruitment. AB - In this study we characterize a new mechanism by which Natural Killer (NK) cells may amplify their recruitment to tumors. We show that NK cells, upon interaction with melanoma cells, can release a chemotactic form of High Mobility Group Box-1 (HMGB1) protein capable of attracting additional activated NK cells. We first demonstrate that the engagement of different activating NK cell receptors, including those mainly involved in tumor cell recognition can induce the active release of HMGB1. Then we show that during NK-mediated tumor cell killing two HMGB1 forms are released, each displaying a specific electrophoretic mobility possibly corresponding to a different redox status. By the comparison of normal and perforin-defective NK cells (which are unable to kill target cells) we demonstrate that, in NK/melanoma cell co-cultures, NK cells specifically release an HMGB1 form that acts as chemoattractant, while dying tumor cells passively release a non-chemotactic HMGB1. Finally, we show that Receptor for Advanced Glycation End products is expressed by NK cells and mediates HMGB1-induced NK cell chemotaxis. Proteomic analysis of NK cells exposed to recombinant HMGB1 revealed that this molecule, besides inducing immediate chemotaxis, also promotes changes in the expression of proteins involved in the regulation of the cytoskeletal network. Importantly, these modifications could be associated with an increased motility of NK cells. Thus, our findings allow the definition of a previously unidentified mechanism used by NK cells to amplify their response to tumors, and provide additional clues for the emerging role of HMGB1 in immunomodulation and tumor immunity. PMID- 26587326 TI - Tumors induce immune tolerance through activation of beta-catenin/TCF4 signaling in dendritic cells: A novel therapeutic target for cancer immunotherapy. AB - Tumors promote immune suppression and dendritic cells (DCs) play a key role in this. However, signaling networks that program DCs to induce immune suppression are unknown. In our recent study, we showed that tumors activate beta catenin/TCF4 in DCs programming them to a regulatory state, which promotes T regulatory responses while suppresses effector T cell responses. Thus, targeting DCs-beta-catenin pathway represents a promising target for anticancer immunotherapy. PMID- 26587327 TI - Retargeted oncolytic viruses provoke tumor-directed T-cell responses. AB - Intratumoral application of oncolytic viruses effectively induce tumor-directed immune responses. However, their systemic application is typically insufficient to stimulate the required extent of tumor tissue inflammation to elicit antitumor immunity. We recently discovered evidence that this barrier can be overcome by effective molecular retargeting of viral infection. PMID- 26587328 TI - Oxygenation to improve cancer vaccines, adoptive cell transfer and blockade of immunological negative regulators. AB - Oxygenation of tumors weakens the tumor-protecting immunosuppressive signaling by A2A adenosine receptors in hypoxic and extracellular adenosine-rich microenvironments. This, in turn, unleashes the otherwise inhibited tumor reactive T and natural killer (NK) cells. Oxygenation of tumors thus emerges as a novel checkpoint inhibitor of potential therapeutic value, but only in combination with cancer immunotherapies. PMID- 26587329 TI - ISG15: A double edged sword in cancer. AB - Interferon-Stimulated Gene 15 (ISG15) transcript is aberrantly expressed in most human malignancies, suggesting that it has a protumor function. However, at the protein level ISG15 has both protumor and immunomodulatory antitumor functions. Therapeutic strategies to maximize the latter may benefit cancer patients overexpressing the ISG15 pathway. PMID- 26587330 TI - CAR-T cells are serial killers. AB - Chimeric antigen receptor (CAR) T cells have enjoyed unprecedented clinical success against haematological malignancies in recent years. However, several aspects of CAR T cell biology remain unknown. We recently compared CAR and T cell receptor (TCR)-based killing in the same effector cell and showed that CAR T cells can not only efficiently kill single tumor targets, they can also kill multiple tumor targets in a sequential manner. Single and serial killing events were not sustained long term due to CAR down-regulation after 20 hours. PMID- 26587331 TI - Functional expression of CD137 (4-1BB) on T helper follicular cells. AB - CD137 (4-1BB) is a surface protein initially discovered to mark activated T lymphocytes. However, its broader expression pattern also encompasses activated NK cells, B cells and myeloid cells, including mature dendritic cells. In this study, we have immunostained for CD137 on paraffin-embedded lymphoid tissues including tonsils, lymph nodes, ectopic tertiary lymphoid tissue in Hashimoto thyroiditis and cancer. Surprisingly, immunostaining mainly decorated intrafollicular lymphocytes in the tissues analyzed, with only scattered staining in interfollicular areas. Moreover, pathologic lymphoid follicles in follicular lymphoma and tertiary lymphoid tissue associated with non-small cell lung cancer showed a similar pattern of immunostaining. Multispectral fluorescence cytometry demonstrated that CD137 expression was restricted to CD4+ CXCR5+ follicular T helper lymphocytes (TFH cells) in tonsils and lymph nodes. Short-term culture of lymph node cell suspensions in the presence of either an agonistic anti-CD137 monoclonal antibody (mAb) or CD137-ligand stimulated the functional upregulation of TFH cells in 3 out of 6 cases, as indicated by CD40L surface expression and cytokine production. As a consequence, immunostimulatory monoclonal antibodies targeting CD137 (such as urelumab and PF-05082566) should be expected to primarily act on this lymphocyte subset, thus modifying ongoing humoral immune responses in patients with autoimmune disease and cancer. PMID- 26587332 TI - Immunomodulation of the tumor microenvironment by neutralization of Semaphorin 4D. AB - Semaphorin 4D is highly expressed at the invasive tumor margin and acts as a guidance molecule, restricting movement of tumoricidal immune cells into the tumor microenvironment. We recently showed that antibody neutralization of SEMA4D augmented activated monocyte and anticancer T-cell tumor penetration and that anti-SEMA4D antibody potentiated other immunomodulatory therapies in murine tumor models. PMID- 26587333 TI - Melanoma targeting with the loco-regional chemotherapeutic, Melphalan: From cell death to immunotherapeutic efficacy. AB - All immunoregulatory chemotherapeutics are chiefly applied in a systemic setting for anticancer therapy. However, immune responses following loco-regional application of chemotherapy may differ from those after systemic application. We recently found that Melphalan, a prototypical loco-regionally applied chemotherapeutic agent, exhibits the ability to increase the immunogenicity of dying melanoma cells. PMID- 26587334 TI - Targeting STING pathways for the treatment of cancer. AB - Recently, we demonstrated that stimulator of interferon genes (STING) ligand cyclic di-guanylate (c-di-GMP) is an excellent adjuvant in cancer vaccination but also induces immunogenic tumor cell death. Combination of both pathways resulted in a nearly complete elimination of the metastases in a breast cancer model. This study is discussed below. PMID- 26587335 TI - miR-181a modulates acute myeloid leukemia susceptibility to natural killer cells. AB - Although daunorubicin (DNR) is the most widely used anthracycline to treat acute myeloid leukemia (AML), resistance to this drug remains a critical problem. The aim of this study was to investigate the relationship between AML resistance to daunorubicin and susceptibility to natural killer (NK) cell-mediated cell lysis, and the putative expression of miRs. For this purpose, we used the parental AML cell lines U-937 and KG-1 and their equivalent resistant U937(R) and KG-1(R) cell lines. We demonstrate for the first time that the acquisition of resistance to DNR by the parental cell lines resulted in the acquisition of cross-resistance to NK cell-mediated cytotoxicity. miR microarray analysis revealed that this cross resistance was associated with miR-181a downregulation and the subsequent regulation of MAP3K10 and MAP2K1 tyrosine kinases and the BCL-2 (BCL-2 and MCL-1) family. Overexpression of miR-181a in AML blasts resulted in the attenuation of their resistance to DNR and to NK-cell-mediated killing. These data point to a determinant role of miR-181a in the sensitization of leukemic resistant cells to DNR and NK cells and suggest that miR-181a may provide a promising option for the treatment of immuno- and chemo-resistant blasts. PMID- 26587336 TI - Factors affecting the identification of individual mountain bongo antelope. AB - The recognition of individuals forms the basis of many endangered species monitoring protocols. This process typically relies on manual recognition techniques. This study aimed to calculate a measure of the error rates inherent within the manual technique and also sought to identify visual traits that aid identification, using the critically endangered mountain bongo, Tragelaphus eurycerus isaaci, as a model system. Identification accuracy was assessed with a matching task that required same/different decisions to side-by-side pairings of individual bongos. Error rates were lowest when only the flanks of bongos were shown, suggesting that the inclusion of other visual traits confounded accuracy. Accuracy was also higher for photographs of captive animals than camera-trap images, and in observers experienced in working with mountain bongos, than those unfamiliar with the sub-species. These results suggest that the removal of non essential morphological traits from photographs of bongos, the use of high quality images, and relevant expertise all help increase identification accuracy. Finally, given the rise in automated identification and the use of citizen science, something our results would suggest is applicable within the context of the mountain bongo, this study provides a framework for assessing their accuracy in individual as well as species identification. PMID- 26587337 TI - Use of video surveillance to measure the influences of habitat management and landscape composition on pollinator visitation and pollen deposition in pumpkin (Cucurbita pepo) agroecosystems. AB - Pumpkin (Cucurbita pepo) production relies on insect-mediated pollination, which is provided by managed and wild pollinators. The goals of this study were to measure the visitation frequency, longevity and temporal activity patterns of pumpkin pollinators and to determine if local habitat management and landscape composition affected this pollination service. We used video surveillance to monitor bee acitivty within male and female pumpkin flowers in 2011 and 2012 across a pollination window of 0600-1200 h. We also quantified the amount of pollen deposited in female flowers across this time period. In 2011, A. mellifera made significantly more floral visits than other bees, and in 2012 Bombus spp. was the dominant pumpkin pollinator. We found variation in visitation among male and female pumpkin flowers, with A. mellifera visiting female flowers more often and spending longer per visit within them than male flowers in both 2011 and 2012. The squash bee P. pruinosa visited male flowers more frequently in 2012, but individuals spent equal time in both flower sexes. We did not find variation in the timing of flower visitation among species across the observed pollination window. In both 2011 and 2012 we found that the majority of pollen deposition occurred within the first two hours (0600-0800 h) of observation; there was no difference between the pollen deposited during this two-hour period and full pollination window (0600-1200 h). Local additions of sweet alyssum floral strips or a field buffer strip of native wildflowers did not have an effect on the foraging activity of bees or pollen deposition. However, semi-natural and urban habitats in the surrounding landscape were positively correlated with the frequency of flower visitation by wild pollinators and the amount of pollen deposited within female flowers. PMID- 26587338 TI - Ecological drivers and habitat associations of estuarine bivalves. AB - Community composition of the infaunal bivalve fauna of the St. Lucie Estuary and southern Indian River Lagoon, eastern Florida was sampled quarterly for 10 years as part of a long-term benthic monitoring program. A total of 38,514 bivalves of 137 taxa were collected and identified. We utilized this data, along with sediment samples and environmental measurements gathered concurrently, to assess the community composition, distribution, and ecological drivers of the infaunal bivalves of this estuary system. Salinity had the strongest influence on bivalve assemblage across the 15 sites, superseding the influences of sediment type, water turbidity, temperature and other environmental parameters. The greatest diversity was found in higher salinity euhaline sites, while the greatest abundance of individual bivalves was found in medium salinity mixohaline sites, the lowest diversity and abundances were found in the low salinity oligohaline sites, demonstrating a strong positive association between salinity and diversity/abundance. Water management decisions for the estuary should incorporate understanding of the role of salinity on bivalve diversity, abundance, and ecosystem function. PMID- 26587339 TI - The diagnostic and prognostic importance of oxidative stress biomarkers and acute phase proteins in Urinary Tract Infection (UTI) in camels. AB - The present study aimed to investigate the diagnostic and prognostic importance of oxidative stress biomarkers and acute phase proteins in urinary tract infection (UTI) in camels. We describe the clinical, bacteriological and biochemical findings in 89 camels. Blood and urine samples from diseased (n = 74) and control camels (n = 15) were submitted to laboratory investigations. The urine analysis revealed high number of RBCS and pus cells. The concentrations of serum and erythrocytic malondialdehyde (sMDA & eMDA), Haptoglobin (Hp), serum amyloid A (SAA), Ceruloplasmin (Cp), fibrinogen (Fb), albumin, globulin and interleukin 6 (IL-6) were higher in diseased camels when compared to healthy ones. Catalase, super oxide dismutase and glutathione levels were lower in diseased camels when compared with control group. Forty one of 74 camels with UTI were successfully treated. The levels of malondialdehyde, catalase, super oxide dismutase, glutathione, Hp, SAA, Fb, total protein, globulin and IL-6 were associated with the odds of treatment failure. The MDA showed a great sensitivity (Se) and specificity (Sp) in predicting treatment failure (Se 85%/Sp 100%) as well as the SAA (Se 92%/Sp 87%) and globulin levels (Se 85%/Sp 100%) when using the cutoffs that maximizes the sum of Se + Sp. Multivariate logistic regression analysis revealed that two models had a high accuracy to predict failure with the first model including sex, sMDA and Hp as covariates (area under the receiver operating characteristic curve (AUC) = 0.92) and a second model using sex, SAA and Hp (AUC = 0.89). Conclusively, the oxidative stress biomarkers and acute phase proteins could be used as diagnostic and prognostic biomarkers in camel UTI management. Efforts should be forced to investigate such biomarkers in other species with UTI. PMID- 26587340 TI - Multiphasic strain differentiation of atypical mycobacteria from elephant trunk wash. AB - Background. Two non-tuberculous mycobacterial strains, UM_3 and UM_11, were isolated from the trunk wash of captive elephants in Malaysia. As they appeared to be identical phenotypes, they were investigated further by conventional and whole genome sequence-based methods of strain differentiation. Methods. Multiphasic investigations on the isolates included species identification with hsp65 PCR-sequencing, conventional biochemical tests, rapid biochemical profiling using API strips and the Biolog Phenotype Microarray analysis, protein profiling with liquid chromatography-mass spectrometry, repetitive sequence-based PCR typing and whole genome sequencing followed by phylogenomic analyses. Results. The isolates were shown to be possibly novel slow-growing schotochromogens with highly similar biological and genotypic characteristics. Both strains have a genome size of 5.2 Mbp, G+C content of 68.8%, one rRNA operon and 52 tRNAs each. They qualified for classification into the same species with their average nucleotide identity of 99.98% and tetranucleotide correlation coefficient of 0.99999. At the subspecies level, both strains showed 98.8% band similarity in the Diversilab automated repetitive sequence-based PCR typing system, 96.2% similarity in protein profiles obtained by liquid chromatography mass spectrometry, and a genomic distance that is close to zero in the phylogenomic tree constructed with conserved orthologs. Detailed epidemiological tracking revealed that the elephants shared a common habitat eight years apart, thus, strengthening the possibility of a clonal relationship between the two strains. PMID- 26587341 TI - Malaria prevalence and incidence in an isolated, meso-endemic area of Mozambique. AB - Isolated areas, such as the 2 * 7 km peninsula of Linga Linga in Mozambique, are the places where malaria might be most easily eliminated. Currently available control strategies include long-lasting insecticidal bednets impregnated with pyrethroid insecticides (LLINs), rapid diagnostic tests (RDTs) for diagnosis and artemisinin based combination therapy (ACT) for treatment and these were applied on the peninsula. In 2007, following a census of the population and mapping of 500 households, five annual all-age prevalence surveys were conducted. Information on LLIN use, house construction, and animal ownership was obtained. A spatially structured generalized additive model indicated that malaria risk was greatest towards the northern end of the peninsula and that people living in houses with grass or thatch roofs had a greater risk of malaria than those living in houses with corrugated iron roofs. Incidence peaked nine weeks after rainfall (r (2) = 0.34, p = 0.0002). From 2009 incidence was measured at a centrally based project clinic. The proportion of under nine-year-old resident attendees diagnosed with malaria decreased significantly from 48% in 2009, to 35% in 2010 and 25% in 2011. At the same time, there was a shift in the peak age of cases from 1-4 year olds to 5-9 year olds. Nevertheless, in order to further reduce malaria transmission in an area such as Linga Linga, additional vector control measures need to be considered. PMID- 26587342 TI - Characterization of the salivary microbiome in patients with pancreatic cancer. AB - Clinical manifestations of pancreatic cancer often do not occur until the cancer has undergone metastasis, resulting in a very low survival rate. In this study, we investigated whether salivary bacterial profiles might provide useful biomarkers for early detection of pancreatic cancer. Using high-throughput sequencing of bacterial small subunit ribosomal RNA (16S rRNA) gene, we characterized the salivary microbiota of patients with pancreatic cancer and compared them to healthy patients and patients with other diseases, including pancreatic disease, non-pancreatic digestive disease/cancer and non-digestive disease/cancer. A total of 146 patients were enrolled at the UCSD Moores Cancer Center where saliva and demographic data were collected from each patient. Of these, we analyzed the salivary microbiome of 108 patients: 8 had been diagnosed with pancreatic cancer, 78 with other diseases and 22 were classified as non diseased (healthy) controls. Bacterial 16S rRNA sequences were amplified directly from salivary DNA extractions and subjected to high-throughput sequencing (HTS). Several bacterial genera differed in abundance in patients with pancreatic cancer. We found a significantly higher ratio of Leptotrichia to Porphyromonas in the saliva of patients with pancreatic cancer than in the saliva of healthy patients or those with other disease (Kruskal-Wallis Test; P < 0.001). Leptotrichia abundances were confirmed using real-time qPCR with Leptotrichia specific primers. Similar to previous studies, we found lower relative abundances of Neisseria and Aggregatibacter in the saliva of pancreatic cancer patients, though these results were not significant at the P < 0.05 level (K-W Test; P = 0.07 and P = 0.09 respectively). However, the relative abundances of other previously identified bacterial biomarkers, e.g., Streptococcus mitis and Granulicatella adiacens, were not significantly different in the saliva of pancreatic cancer patients. Overall, this study supports the hypothesis that bacteria abundance profiles in saliva are useful biomarkers for pancreatic cancer though much larger patient studies are needed to verify their predictive utility. PMID- 26587343 TI - Lung ultrasound in the diagnosis of pneumonia in children: proposal for a new diagnostic algorithm. AB - Background. Despite guideline recommendations, chest radiography (CR) for the diagnosis of community-acquired pneumonia (CAP) in children is commonly used also in mild and/or uncomplicated cases. The aim of this study is to assess the reliability of lung ultrasonography (LUS) as an alternative test in these cases and suggest a new diagnostic algorithm. Methods. We reviewed the medical records of all patients admitted to the pediatric ward from February 1, 2013 to December 31, 2014 with respiratory signs and symptoms. We selected only cases with mild/uncomplicated clinical course and in which CR and LUS were performed within 24 h of each other. The LUS was not part of the required exams recorded in medical records but performed independently. The discharge diagnosis, made only on the basis of history and physical examination, laboratory and instrumental tests, including CR (without LUS), was used as a reference test to compare CR and LUS findings. Results. Of 52 selected medical records CAP diagnosis was confirmed in 29 (55.7%). CR was positive in 25 cases, whereas LUS detected pneumonia in 28 cases. Four patients with negative CR were positive in ultrasound findings. Instead, one patient with negative LUS was positive in radiographic findings. The LUS sensitivity was 96.5% (95% CI [82.2%-99.9%]), specificity of 95.6% (95% CI [78.0%-99.9%]), positive likelihood ratio of 22.2 (95% CI [3.2-151.2]), and negative likelihood ratio of 0.04 (95% CI [0.01-0.25]) for diagnosing pneumonia. Conclusion. LUS can be considered as a valid alternative diagnostic tool of CAP in children and its use must be promoted as a first approach in accordance with our new diagnostic algorithm. PMID- 26587344 TI - Chemotaxis and degradation of organophosphate compound by a novel moderately thermo-halo tolerant Pseudomonas sp. strain BUR11: evidence for possible existence of two pathways for degradation. AB - An organophosphate (OP) degrading chemotactic bacterial strain BUR11 isolated from an agricultural field was identified as a member of Pseudomonas genus on the basis of its 16S rRNA gene sequence. The strain could utilize parathion, chlorpyrifos and their major hydrolytic intermediates as sole source of carbon for its growth and exhibited positive chemotactic response towards most of them. Optimum concentration of parathion for its growth was recorded to be 200 ppm and 62% of which was degraded within 96 h at 37 degrees C. Growth studies indicated the strain to be moderately thermo-halo tolerant in nature. Investigation based on identification of intermediates of parathion degradation by thin layer chromatography (TLC), high performance liquid chromatography (HPLC), gas chromatography (GC) and liquid chromatography mass spectrometry (LC-MS/MS) provided evidence for possible existence of two pathways. The first pathway proceeds via 4-nitrophenol (4-NP) while the second proceeds through formation of 4-aminoparathion (4-APar), 4-aminophenol (4-AP) and parabenzoquinone (PBQ). This is the first report of chemotaxis towards organophosphate compound by a thermo halo tolerant bacterium. PMID- 26587345 TI - Kisspeptin receptor agonist (FTM080) increased plasma concentrations of luteinizing hormone in anestrous ewes. AB - Kisspeptin receptor (KISS1R) agonists with increased half-life and similar efficacy to kisspeptin in vitro may provide beneficial applications in breeding management of many species. However, many of these agonists have not been tested in vivo. These studies were designed to test and compare the effects of a KISS1R agonist (FTM080) and kisspeptin on luteinizing hormone (LH) in vivo. In experiment 1 (pilot study), sheep were treated with FTM080 (500 pmol/kg BW) or sterile water (VEH) intravenosuly. Blood was collected every 15 min before (1 h) and after (1 h) treatment. In experiment 2, sheep were treated with KP-10 (human Metastin 45-54; 500 pmol/kg BW), one of three dosages of FTM080 (500 (FTM080:500), 2500 (FTM080:2500), or 5000 (FTM080:5000) pmol/kg BW), or VEH intravenously. Blood was collected every 15 min before (1 h) and after (4 h) treatment. In experiment 1, FTM080:500 increased (P < 0.05) plasma LH concentrations when compared to VEH. The area under the curve (AUC) of LH following FTM080:500 treatment was also increased (P < 0.05). In experiment 2, plasma LH concentrations increased (P < 0.05) following treatment with KP-10 and FTM080:5000 when compared to VEH and FTM080:500. The AUC of LH following KP-10 was greater than (P < 0.05) all other treatments and the AUC of LH following FTM080:5000 was greater than (P < 0.05) all treatments except KP-10. These data provide evidence to suggest that FTM080 stimulates the gonadotropic axis of ruminants in vivo. Any increased half-life and comparable efficacy of FTM080 to KP-10 in vitro does not appear to translate to in vivo in sheep. PMID- 26587346 TI - The Bulimulidae (Mollusca: Pulmonata) from the Region de Atacama, northern Chile. AB - The bulimulid genus Bostryx Troschel, 1847 is the most species-rich genus of land snails found in Chile, with the majority of its species found only in the northern part of the country, usually in arid coastal zones. This genus has been sparsely studied in Chile and there is little information on their distribution, diversity or ecology. Here, for the first time, a formal analysis of the diversity of bulimulids in the Region de Atacama, northern Chile, is reported. Of the seventeen species recorded for the area, most of them were efectively found in the field collections and one record was based on literature. Five taxa are described as new: Bostryx ancavilorum sp. nov., Bostryx breurei sp. nov., Bostryx calderaensis sp. nov., Bostryx ireneae sp. nov. and Bostryx valdovinosi sp. nov., and the known geographic distribution of seven species is extended. Results reveal that the Region de Atacama is the richest region in terrestrial snails in Chile, after the Juan Fernandez Archipelago. All of the terrestrial molluscan species occurring in the area are endemic to Chile, most of them with restricted geographic distributions along the coastal zones, and none of them are currently protected by law. Further sampling in northern Chile will probably reveal more snail species to be discovered and described. PMID- 26587347 TI - Variation in species diversity and functional traits of sponge communities near human populations in Bocas del Toro, Panama. AB - Recent studies have renewed interest in sponge ecology by emphasizing the functional importance of sponges in a broad array of ecosystem services. Many critically important habitats occupied by sponges face chronic stressors that might lead to alterations in their diversity, relatedness, and functional attributes. We addressed whether proximity to human activity might be a significant factor in structuring sponge community composition, as well as potential functional roles, by monitoring sponge diversity and abundance at two structurally similar sites that vary in distance to areas of high coastal development in Bocas Del Toro, Panama. We surveyed sponge communities at each site using belt transects and differences between two sites were compared using the following variables: (1) sponge species richness, Shannon diversity, and inverse Simpson's diversity; (2) phylogenetic diversity; (3) taxonomic and phylogenetic beta diversity; (4) trait diversity and dissimilarity; and (5) phylogenetic and trait patterns in community structure. We observed significantly higher sponge diversity at Punta Caracol, the site most distant from human development (~5 km). Although phylogenetic diversity was lower at Saigon Bay, the site adjacent to a large village including many houses, businesses, and an airport, the sites did not exhibit significantly different patterns of phylogenetic relatedness in species composition. However, each site had a distinct taxonomic and phylogenetic composition (beta diversity). In addition, the sponge community at Saigon included a higher relative abundance of sponges with high microbial abundance and high chlorophyll a concentration, whereas the community at Punta Caracol had a more even distribution of these traits, yielding a significant difference in functional trait diversity between sites. These results suggest that lower diversity and potentially altered community function might be associated with proximity to human populations. This study highlights the importance of evaluating functional traits and phylogenetic diversity in addition to common diversity metrics when assessing potential environmental impacts on benthic communities. PMID- 26587348 TI - Overexpression of centromere protein K (CENPK) in ovarian cancer is correlated with poor patient survival and associated with predictive and prognostic relevance. AB - Ovarian cancer has a poor prognosis. Most patients are diagnosed with ovarian cancer when the disease has reached an advanced stage and cure rates are generally under 30%. Hence, early diagnosis of ovarian cancer is the best means to control the disease in the long term and abate mortality. So far, cancer antigen 125 (CA125) and human epididymis protein 4 (HE4) are the gold-standard tumor markers for ovarian cancer; however, these two markers can be elevated in a number of conditions unrelated to ovarian cancer, resulting in decreased specifically and positive predictive value. Therefore, it is urgent to identify novel biomarkers with high reliability and sensitivity for ovarian cancer. In this study for the first time, we identified a member of the centromere protein (CENP) family, CENPK, which was specifically upregulated in ovarian cancer tissues and cell lines and the overexpression of which was associated with poor prognoses in patients with ovarian cancer. In addition, the presence of CENPK significantly improved the sensitivity of CA125 or HE4 for predicting clinical outcomes of ovarian cancer patients. In conclusion, we identified that CENPK was specifically upregulated in ovarian cancer cells and can be used as a novel tumor marker of ovarian cancer. PMID- 26587349 TI - Ketoreductase TpdE from Rhodococcus jostii TMP1: characterization and application in the synthesis of chiral alcohols. AB - Background. Production of highly pure enantiomers of vicinal diols is desirable, but difficult to achieve. Enantiomerically pure diols and acyloins are valuable bulk chemicals, promising synthones and potential building blocks for chiral polymers. Enzymatic reduction of ketones is a useful technique for the synthesis of the desired enantiomeric alcohols. Here, we report on the characterization of a ketoreductase TpdE from Rhodococcus jostii TMP1 that is a prospective tool for the synthesis of such compounds. Results. In this study, NADPH-dependent short chain dehydrogenase/reductase TpdE from Rhodococcus jostii TMP1 was characterized. The enzyme exhibited broad substrate specificity towards aliphatic 2,3-diketones, butan-3-one-2-yl alkanoates, as well as acetoin and its acylated derivatives. TpdE stereospecifically reduced alpha-diketones to the corresponding diols. The GC-MS analysis of the reduction products of 2,3- and 3,4-diketones indicated that TpdE is capable of reducing both keto groups in its substrate leading to the formation of two new chiral atoms in the product molecule. Bioconversions of diketones to corresponding diols occurred using either purified enzyme or a whole-cell Escherichia coli BL21 (DE3) biocatalyst harbouring recombinant TpdE. The optimum temperature and pH were determined to be 30-35 degrees C and 7.5, respectively. Conclusions. The broad substrate specificity and stereoselectivity of TpdE from Rhodococcus jostii TMP1 make it a promising biocatalyst for the production of enantiomerically pure diols that are difficult to obtain by chemical routes. PMID- 26587350 TI - Can we measure beauty? Computational evaluation of coral reef aesthetics. AB - The natural beauty of coral reefs attracts millions of tourists worldwide resulting in substantial revenues for the adjoining economies. Although their visual appearance is a pivotal factor attracting humans to coral reefs current monitoring protocols exclusively target biogeochemical parameters, neglecting changes in their aesthetic appearance. Here we introduce a standardized computational approach to assess coral reef environments based on 109 visual features designed to evaluate the aesthetic appearance of art. The main feature groups include color intensity and diversity of the image, relative size, color, and distribution of discernable objects within the image, and texture. Specific coral reef aesthetic values combining all 109 features were calibrated against an established biogeochemical assessment (NCEAS) using machine learning algorithms. These values were generated for ~2,100 random photographic images collected from 9 coral reef locations exposed to varying levels of anthropogenic influence across 2 ocean systems. Aesthetic values proved accurate predictors of the NCEAS scores (root mean square error < 5 for N >= 3) and significantly correlated to microbial abundance at each site. This shows that mathematical approaches designed to assess the aesthetic appearance of photographic images can be used as an inexpensive monitoring tool for coral reef ecosystems. It further suggests that human perception of aesthetics is not purely subjective but influenced by inherent reactions towards measurable visual cues. By quantifying aesthetic features of coral reef systems this method provides a cost efficient monitoring tool that targets one of the most important socioeconomic values of coral reefs directly tied to revenue for its local population. PMID- 26587351 TI - First description of underwater acoustic diversity in three temperate ponds. AB - The past decade has produced an increased ecological interest in sonic environments, or soundscapes. However, despite this rise in interest and technological improvements that allow for long-term acoustic surveys in various environments, some habitats' soundscapes remain to be explored. Ponds, and more generally freshwater habitats, are one of these acoustically unexplored environments. Here we undertook the first long term acoustic monitoring of three temperate ponds in France. By aural and visual inspection of a selection of recordings, we identified 48 different sound types, and according to the rarefaction curves we calculated, more sound types are likely present in one of the three ponds. The richness of sound types varied significantly across ponds. Surprisingly, there was no pond-to-pond daily consistency of sound type richness variation; each pond had its own daily patterns of activity. We also explored the possibility of using six acoustic diversity indices to conduct rapid biodiversity assessments in temperate ponds. We found that all indices were sensitive to the background noise as estimated through correlations with the signal-to-noise ratio (SNR). However, we determined that the AR index could be a good candidate to measure acoustic diversities using partial correlations with the SNR as a control variable. Yet, research is still required to automatically compute the SNR in order to apply this index on a large data set of recordings. The results showed that these three temperate ponds host a high level of acoustic diversity in which the soundscapes were variable not only between but also within the ponds. The sources producing this diversity of sounds and the drivers of difference in daily song type richness variation both require further investigation. Such research would yield insights into the biodiversity and ecology of temperate ponds. PMID- 26587352 TI - Detection of diabetic macular oedema: validation of optical coherence tomography using both foveal thickness and intraretinal fluid. AB - No studies have yet evaluated jointly central foveal thickness (CFT) and the presence of intraretinal fluid (PIF) to diagnose diabetic macular oedema (DMO) using optic coherence tomography (OCT). We performed a cross-sectional observational study to validate OCT for the diagnosis of DMO using both CFT and PIF assessed by OCT (3D OCT-1 Maestro). A sample of 277 eyes from primary care diabetic patients was assessed in a Spanish region in 2014. OUTCOME: DMO diagnosed by stereoscopic mydriatic fundoscopy. OCT was used to measure CFT and PIF. A binary logistic regression model was constructed to predict the outcome using CFT and PIF. The area under the ROC curve (AUC) of the model was calculated and non-linear equations used to determine which CFT values had a high probability of the outcome (positive test), distinguishing between the presence or absence of PIF. Calculations were made of the sensitivity, specificity, and the positive (PLR) and negative (NLR) likelihood ratios. The model was validated using bootstrapping methodology. A total of 37 eyes had DMO. AUC: 0.88. Positive test: CFT >=90 um plus PIF (>=310 um if no PIF). Clinical parameters: sensitivity, 0.83; specificity, 0.89; PLR, 7.34; NLR, 0.19. The parameters in the validation were similar. In conclusion, combining PIF and CFT provided a tool to very precisely discriminate the presence of DMO. Similar studies are needed to provide greater scientific evidence for the use of PIF in the diagnosis of DMO. PMID- 26587353 TI - Metabolic and genomic analysis elucidates strain-level variation in Microbacterium spp. isolated from chromate contaminated sediment. AB - Hexavalent chromium [Cr(VI)] is a soluble carcinogen that has caused widespread contamination of soil and water in many industrial nations. Bacteria have the potential to aid remediation as certain strains can catalyze the reduction of Cr(VI) to insoluble and less toxic Cr(III). Here, we examine Cr(VI) reducing Microbacterium spp. (Cr-K1W, Cr-K20, Cr-K29, and Cr-K32) isolated from contaminated sediment (Seymore, Indiana) and show varying chromate responses despite the isolates' phylogenetic similarity (i.e., identical 16S rRNA gene sequences). Detailed analysis identified differences based on genomic metabolic potential, growth and general metabolic capabilities, and capacity to resist and reduce Cr(VI). Taken together, the discrepancies between the isolates demonstrate the complexity inter-strain variation can have on microbial physiology and related biogeochemical processes. PMID- 26587354 TI - Current nutrition promotion, beliefs and barriers among cancer nurses in Australia and New Zealand. AB - Rationale. Many cancer patients and survivors do not meet nutritional and physical activity guidelines, thus healthier eating and greater levels of physical activity could have considerable benefits for these individuals. While research has investigated cancer survivors' perspective on their challenges in meeting the nutrition and physical guidelines, little research has examined how health professionals may assist their patients meet these guidelines. Cancer nurses are ideally placed to promote healthy behaviours to their patients, especially if access to dieticians or dietary resources is limited. However, little is known about cancer nurses' healthy eating promotion practices to their patients. The primary aim of this study was to examine current healthy eating promotion practices, beliefs and barriers of cancer nurses in Australia and New Zealand. A secondary aim was to gain insight into whether these practices, beliefs and barriers were influenced by the nurses' hospital or years of work experience. Patients and Methods. An online questionnaire was used to obtain data. Sub-group cancer nurse comparisons were performed on hospital location (metropolitan vs regional and rural) and years of experience (<25 or >=25 years) using ANOVA and chi square analysis for continuous and categorical data respectively. Results. A total of 123 Australasian cancer nurses responded to the survey. Cancer nurses believed they were often the major provider of nutritional advice to their cancer patients (32.5%), a value marginally less than dieticians (35.9%) but substantially higher than oncologists (3.3%). The majority promoted healthy eating prior (62.6%), during (74.8%) and post treatment (64.2%). Most cancer nurses felt that healthy eating had positive effects on the cancer patients' quality of life (85.4%), weight management (82.9%), mental health (80.5%), activities of daily living (79.7%) and risk of other chronic diseases (79.7%), although only 75.5% agreed or strongly agreed that this is due to a strong evidence base. Lack of time (25.8%), adequate support structures (17.3%) nutrition expertise (12.2%) were cited by the cancer nurses as the most common barriers to promoting healthy eating to their patients. Comparisons based on their hospital location and years of experience, revealed very few significant differences, indicating that cancer nurses' healthy eating promotion practices, beliefs and barriers were largely unaffected by hospital location or years of experience. Conclusion. Australasian cancer nurses have favourable attitudes towards promoting healthy eating to their cancer patients across multiple treatment stages and believe that healthy eating has many benefits for their patients. Unfortunately, several barriers to healthy eating promotion were reported. If these barriers can be overcome, nurses may be able to work more effectively with dieticians to improve the outcomes for cancer patients. PMID- 26587355 TI - Homeotic transformations and number changes in the vertebral column of Triturus newts. AB - We explored intraspecific variation in vertebral formulae, more specifically the variation in the number of thoracic vertebrae and frequencies of transitional sacral vertebrae in Triturus newts (Caudata: Salamandridae). Within salamandrid salamanders this monophyletic group shows the highest disparity in the number of thoracic vertebrae and considerable intraspecific variation in the number of thoracic vertebrae. Triturus species also differ in their ecological preferences, from predominantly terrestrial to largely aquatic. Following Geoffroy St. Hilaire's and Darwin's rule which states that structures with a large number of serially homologous repetitive elements are more variable than structures with smaller numbers, we hypothesized that the variation in vertebral formulae increases in more elongated species with a larger number of thoracic vertebrae. We furthermore hypothesized that the frequency of transitional vertebrae will be correlated with the variation in the number of thoracic vertebrae within the species. We also investigated potential effects of species hybridization on the vertebral formula. The proportion of individuals with a number of thoracic vertebrae different from the modal number and the range of variation in number of vertebrae significantly increased in species with a larger number of thoracic vertebrae. Contrary to our expectation, the frequencies of transitional vertebrae were not correlated with frequencies of change in the complete vertebrae number. The frequency of transitional sacral vertebra in hybrids did not significantly differ from that of the parental species. Such a pattern could be a result of selection pressure against transitional vertebrae and/or a bias towards the development of full vertebrae numbers. Although our data indicate relaxed selection for vertebral count changes in more elongated, aquatic species, more data on different selective pressures in species with different numbers of vertebrae in the two contrasting, terrestrial and aquatic environments are needed to test for causality. PMID- 26587357 TI - Porphyrobacter mercurialis sp. nov., isolated from a stadium seat and emended description of the genus Porphyrobacter. AB - A novel, Gram-negative, non-spore-forming, pleomorphic yellow-orange bacterial strain was isolated from a stadium seat. Strain Coronado(T) falls within the Erythrobacteraceae family and the genus Porphyrobacter based on 16S rRNA phylogenetic analysis. This strain has Q-10 as the predominant respiratory lipoquinone, as do other members of the family. The fatty acid profile of this strain is similar to other Porphyrobacter, however Coronado(T) contains predominately C18:1omega7cis and C16:0, a high percentage of the latter not being observed in any other Erythrobacteraceae. This strain is catalase-positive and oxidase-negative, can grow from 4 to 28 degrees C, at NaCl concentrations 0.1 1.5%, and at pH 6.0-8.0. On the basis of phenotypic and phylogenetic data presented in this study, strain Coronado(T) represents a novel species in the Porphyrobacter genus for which the name Porphyrobacter mercurialis sp. nov. is proposed; the type strain is Coronado(T) (=DSMZ 29971, =LMG 28700). PMID- 26587358 TI - Demographic and genetic factors in the recovery or demise of ex situ populations following a severe bottleneck in fifteen species of Hawaiian tree snails. AB - Wild populations of endangered Hawaiian tree snails have declined precipitously over the last century due to introduced predators and other human impacts. Life history traits, such as very low fecundity (<5 offspring per year across taxa) and maturity at approximately four years of age have made recovery difficult. Conservation efforts such as in situ predator-free enclosures may increase survival to maturity by protecting offspring from predation, but no long-term data existed prior to this study demonstrating the demographic and genetic parameters necessary to maintain populations within those enclosures. We evaluated over 20 years of evidence for the dynamics of survival and extinction in captive ex situ populations of Hawaiian tree snails established from wild collected individuals. From 1991 to 2006, small numbers of snails (<15) from fifteen species were collected from the wild to initiate captive-reared populations as a hedge against extinction. This small number of founders resulted in a severe bottleneck in each of the captive-reared populations. We identified key demographic parameters that predicted population recovery from this bottleneck. Species with captive populations that produced between two and four offspring per adult per year and had 20-50% of those offspring survive to maturity recovered to numbers above 100 individuals, and maintained viable populations following a decline that occurred between 2009 and 2014. Those populations that had less than two offspring per adult per year and less than 20% survival to maturity did not reach 100 individuals in captivity, and many of these populations died out during the recent decline. We suggest that small reductions in fitness may contribute to extirpation in taxa with inherently low fecundity, by keeping populations below a threshold number essential to long-term recovery. Future ex situ populations should be founded with no less than 15 adults, and maintained in conditions closely approximating the temperature and humidity of source locations to optimize fitness. Permanent translocations of wild populations for conservation purposes will be more likely to succeed with greater than 100 adults, and should be limited to locations with a similar climate to source locations. PMID- 26587356 TI - Effects of sex and site on amino acid metabolism enzyme gene expression and activity in rat white adipose tissue. AB - Background and Objectives. White adipose tissue (WAT) shows marked sex- and diet dependent differences. However, our metabolic knowledge of WAT, especially on amino acid metabolism, is considerably limited. In the present study, we compared the influence of sex on the amino acid metabolism profile of the four main WAT sites, focused on the paths related to ammonium handling and the urea cycle, as a way to estimate the extent of WAT implication on body amino-nitrogen metabolism. Experimental Design. Adult female and male rats were maintained, undisturbed, under standard conditions for one month. After killing them under isoflurane anesthesia. WAT sites were dissected and weighed. Subcutaneous, perigonadal, retroperitoneal and mesenteric WAT were analyzed for amino acid metabolism gene expression and enzyme activities. Results. There was a considerable stability of the urea cycle activities and expressions, irrespective of sex, and with only limited influence of site. Urea cycle was more resilient to change than other site-specialized metabolic pathways. The control of WAT urea cycle was probably related to the provision of arginine/citrulline, as deduced from the enzyme activity profiles. These data support a generalized role of WAT in overall amino N handling. In contrast, sex markedly affected WAT ammonium-centered amino acid metabolism in a site-related way, with relatively higher emphasis in males' subcutaneous WAT. Conclusions. We found that WAT has an active amino acid metabolism. Its gene expressions were lower than those of glucose-lipid interactions, but the differences were quantitatively less important than usually reported. The effects of sex on urea cycle enzymes expression and activity were limited, in contrast with the wider variations observed in other metabolic pathways. The results agree with a centralized control of urea cycle operation affecting the adipose organ as a whole. PMID- 26587359 TI - New craniodental remains of Wakaleo alcootaensis (Diprotodontia: Thylacoleonidae) a carnivorous marsupial from the late Miocene Alcoota Local Fauna of the Northern Territory, Australia. AB - New jaws and teeth referable to the rare thylacoleonid marsupial Wakaleo alcootaensis are figured and described. The species is the geologically youngest known member of the genus and is only known from the late Miocene Alcoota Local Fauna of the Northern Territory, Australia. A revised diagnosis of the species is presented which is found to be morphologically distinct from its congeners. W. alcootaensis can be distinguished from other species of Wakaleo by its greater size, deeply recessed masseteric fossa, more steeply angled I1, loss of P2, greater P3 to M1 ratio and loss of M3. Several characters of W. alcootaensis, including the increase in size, steeply angled I1, increase of the relative size of P3, and reduction of the molar row are present in at least some species of Thylacoleo. Phylogenetic analysis suggests that these character states are convergences and that there was parallel evolution in these two thylacoleonid lineages. PMID- 26587360 TI - Barriers to breast self examination practice among Malaysian female students: a cross sectional study. AB - INTRODUCTION: Breast cancer is the most frequent cancer and the second reason of cancer deaths among woman worldwide, including Malaysia. The objective of this paper is to assess the practice of breast self-examination (BSE) and identify the barriers of BSE practice among undergraduate female students in Malaysia. METHODS: A cross-sectional study conducted among 810 female undergraduate students in Klang Valley, Malaysia between April-Jun 2012. Data was collected via self-administered questionnaire which was developed and pre-tested for this study. RESULTS: The majority of respondents were Malay 709 (95.6 %) and single 719 (96.9 %) with a mean age of 21.7 (1.1). Only hundred eleven (15 %) of the participants had a family history of breast cancer. 70.5 % of the respondents do not practice breast self-examination, 70.5 % do not know how to do it, 64.7 and 61.5 % reported no symptoms of breast cancer and worries to detect breast cancer, respectively. Univariate analysis showed that age, marital status and personal history of breast disease were statistically associated with the practice of breast self-examination. CONCLUSION: In this study, a high percentage of respondents were aware of breast cancer but do not perform breast self examination. Knowledge, socio-cultural and environmental factors were identified as barriers; so it is recommended that knowledge among the public about breast cancer and promotion of public breast health awareness campaigns through the media should be carried out. PMID- 26587361 TI - Kikuchi-Fujimoto disease associated with community acquired pneumonia showing intrathoratic lymphadenopathy without cervical lesions. AB - INTRODUCTION: Kikuchi-Fujimoto disease (KFD), or histiocytic necrotizing lymphadenitis, is a rare entity of unknown etiology in young adults that is typically characterized by cervical lymphadenopathy and persistent fever. The pathogenesis of KFD has been suggested to be an abnormal immune response, and infections or autoimmune diseases are considered to be involved in KFD. However, KFD associated with community acquired pneumonia (CAP) has not been reported. CASE DESCRIPTION: A 35-year-old male was admitted due to high fever, diffuse air space consolidation in the right lung with ipsilateral pleural effusion and massive mediastinal and hilar lymphadenopathy without cervical lesions. On clinical suspicion of malignant lymphoma complicated with pneumonia, we performed a video-assisted thoracoscopic lymph node biopsy, and the diagnosis of KFD was established. Complete cure of the intrathoratic lesions was observed by administration of beta-lactam antibiotics alone without steroid therapy. DISCUSSION AND EVALUATION: Previous large case series have identified no pathogenic relationship between KFD and pneumonia. The hilar adenopathy could have caused airway compression leading to pneumonia. CONCLUSIONS: KFD should be considered in the differential diagnosis of massive mediastinal and hilar lymphadenopathy, even when there are no superficial lesions. In addition, we need to bear in mind that unexpected disorders occasionally coexist with common diseases. PMID- 26587362 TI - A comprehensive review on privacy preserving data mining. AB - Preservation of privacy in data mining has emerged as an absolute prerequisite for exchanging confidential information in terms of data analysis, validation, and publishing. Ever-escalating internet phishing posed severe threat on widespread propagation of sensitive information over the web. Conversely, the dubious feelings and contentions mediated unwillingness of various information providers towards the reliability protection of data from disclosure often results utter rejection in data sharing or incorrect information sharing. This article provides a panoramic overview on new perspective and systematic interpretation of a list published literatures via their meticulous organization in subcategories. The fundamental notions of the existing privacy preserving data mining methods, their merits, and shortcomings are presented. The current privacy preserving data mining techniques are classified based on distortion, association rule, hide association rule, taxonomy, clustering, associative classification, outsourced data mining, distributed, and k-anonymity, where their notable advantages and disadvantages are emphasized. This careful scrutiny reveals the past development, present research challenges, future trends, the gaps and weaknesses. Further significant enhancements for more robust privacy protection and preservation are affirmed to be mandatory. PMID- 26587363 TI - Zoometric measures and their utilization in prediction of live weight of local goats in southern Mexico. AB - Objectives of this study were: (a) to compare live weight (LW) and zoometric measures (ZM) of local goats in two locations, (b) to fit the best regression equation for goat LW prediction using ZM. LW, body length (BL), trunk length (TL), withers height (WH), hearth girth (HG), rump width (RW), rump length (RL), head length (HL), head width (HW), and ear length (EL) were measured in 318 Local does in Amatepec and Tejupilco, State of Mexico. Statistical methods included student's "t" tests for comparison of means, and correlation, principal components (PC), and multiple linear regression analyses. To evaluate the goodness of fit for LW prediction models the R(2) value was used as a criterion. Differences (P <= 0.05) were found between does of Amatepec and Tejupilco in LW, BL, TL, HG, RL, HL, HW, and EL. In Amatepec, LW was correlated with HG, BL, and HW (P <= 0.01), whereas in Tejupilco LW was correlated with HG, BL, TL, and HW (P <= 0.01). From the Amatepec measures 5 PC were extracted, and which in a multiple regression analysis explained 83.3 % of the total variance, whereas from Tejupilco 4 PC were extracted, and which in a multiple regression analysis explained 82.4 % of the total variance. The best regression model to predict doe LW in Amatepec included TL, HG, RW, and HW, whereas for Tejupilco the best model included BL, HG, HW, and EL. It is concluded that: (1) Amatepec does surpass those of Tejupilco in LW and most ZM, (2) there are reliable ZM for predicting LW of local does in both locations, HG, and HW being common measures for both populations. PMID- 26587364 TI - Extreme value modelling of Ghana stock exchange index. AB - Modelling of extreme events has always been of interest in fields such as hydrology and meteorology. However, after the recent global financial crises, appropriate models for modelling of such rare events leading to these crises have become quite essential in the finance and risk management fields. This paper models the extreme values of the Ghana stock exchange all-shares index (2000 2010) by applying the extreme value theory (EVT) to fit a model to the tails of the daily stock returns data. A conditional approach of the EVT was preferred and hence an ARMA-GARCH model was fitted to the data to correct for the effects of autocorrelation and conditional heteroscedastic terms present in the returns series, before the EVT method was applied. The Peak Over Threshold approach of the EVT, which fits a Generalized Pareto Distribution (GPD) model to excesses above a certain selected threshold, was employed. Maximum likelihood estimates of the model parameters were obtained and the model's goodness of fit was assessed graphically using Q-Q, P-P and density plots. The findings indicate that the GPD provides an adequate fit to the data of excesses. The size of the extreme daily Ghanaian stock market movements were then computed using the value at risk and expected shortfall risk measures at some high quantiles, based on the fitted GPD model. PMID- 26587365 TI - Optimized heart rate for 320-row cardiac CT can be feasibly predicted from prescan parameters. AB - To evaluate the degree of heart rate (HR) changes at rest (HRrest), during breath hold (HRtest), and during cardiac CT examinations (HRscan) in a large group of patients , and to derive and asses the feasibility of a predictive formula for HRscan. HRrest, HRtest, and HRscan were retrospectively compared in a total of 563 consecutive patients who underwent 320-row cardiac CT. Multiple regression analysis was performed to derive predictive formulae for HRscan in the entire study population and, in each group of patients with decreased (Dec) or increased (Inc) HR during breath hold. The predictive formula was evaluated as accurate when less than 5 % of the actual HRscan exceeded the predicted HRscan by +/-5 beats per minute (bpm). The average values of the HRtest (65.3 +/- 12.0 bpm) and HRscan (63.7 +/- 11.9 bpm) significantly decreased from those of the HRrest (68.4 +/- 11.9 bpm) (p < 0.0001). The predictive formula (HRscan = 3.601 + 0.113HRrest + 0.8HRtest) was determined to be accurate only in Group Dec. The HRtest significantly decreased from the HRrest, and the HRscan significantly decreased from the HRtest. An accurate predictive formula for HRscan could be built only for Group Dec. PMID- 26587366 TI - The role of chemotherapy and operation on lymphocytes accumulation in peripheral blood obtained from patients with oral squamous cell carcinoma. AB - The "Cancer Immunoediting" concept has provided critical insights suggesting dual functions of immune system during the cancer initiation and development. However, the dynamics and roles of CD4(+) and CD8(+) T cells, CD19(+) B cells, and CD56(+) NK cells in the patients with oral squamous cell carcinoma during treatment remain unclear. A total of 43 patients with OSCC were divided into different groups according to different clinical factors (TNM staging, pathological patterns, age and genders) for assessment of relations with CD3(+)CD4(+) T cells, CD3(+)CD8(+) T cells, CD3(-)CD19(+) B cells and CD3(-)CD16(+)CD56(+) NK cells and different chemotherapy and radical operation. The expression of CD3(+)CD4(+) T cells were significantly increased in advanced tumor stage, large tumor size and positive lymph nodes metastasis, compared to that in early groups. The accumulation of CD3(+)CD4(+) T cells were significantly increased in OSCC patients received 2 cycles CT and radical operation. Moreover, the accumulation of CD3(+)CD8(+) T cells were significantly decreased in OSCC patients received 2 cycles CT and radical operation. The distribution of circulating CD3(-)CD19(+) B cells was related with radical operation in patients with OSCC. This study indicate that CD4(+) T cells have opposing roles in OSCC progression and outcomes, which provides new insights relevant for the development of effective cancer immunotherapeutic approaches. 2 cycles TP regime chemotherapy and radical therapy may contribute to increase the effects of anti-tumor immunity on patients with OSCC. PMID- 26587367 TI - Materialism, affective states, and life satisfaction: case of Croatia. AB - In recent years, a number of studies have used Material Values Scale (MVS) to assess beliefs about importance to own material things. The aims of this study were to validate the MVS scale and to explore the relationships between materialistic values and well-being of Croatian citizens. The study was carried out on a representative sample of N = 1129 Croatian citizens. We used the short 9 item version of the MVS, life satisfaction rating, ratings of two positive (Positive affect) and four negative emotions (Negative affect) over the past month, and demographic variables (age, gender, income). The original dimensionality of the MVS was not confirmed; confirmatory factor analyses yielded two instead of three factors, Happiness and Centrality/Success. When controlled for income, gender and age, the Happiness dimension predicted Life satisfaction and both Positive and Negative affect, indicating that people who believed that the material goods in ones life leads to happiness reported to have lower life satisfaction, lower level of positive affect and higher level of negative affect over the past month. The Centrality/Success dimension was positively related to Positive affect, indicating that the belief that possessions play a central role in enjoyment leads to more frequent experiences of happiness and satisfaction over the past month. PMID- 26587368 TI - Methods to Estimate the Comparative Effectiveness of Clinical Strategies that Administer the Same Intervention at Different Times. AB - Clinical guidelines that rely on observational data due to the absence of data from randomized trials benefit when the observational data or its analysis emulates trial data or its analysis. In this paper, we review a methodology for emulating trials that compare the effects of different timing strategies, that is, strategies that vary the frequency of delivery of a medical intervention or procedure. We review trial emulation for comparing (i) single applications of the procedure at different times, (ii) fixed schedules of application, and (iii) schedules adapted to the evolving clinical characteristics of the patients. For illustration, we describe an application in which we estimate the effect of surveillance colonoscopies in patients who had an adenoma detected during the Norwegian Colorectal Cancer Prevention (NORCCAP) trial. PMID- 26587369 TI - Sphingolipids, Lipid Rafts, and Giardial Encystation: The Show Must Go On. AB - Sphingolipids are sphingosine-based phospholipids, which are present in the plasma and endomembranes of many eukaryotic cells. These lipids are involved in various cellular functions, including cell growth, differentiation, and apoptosis. In addition, sphingolipid and cholesterol-enriched membrane microdomains (also called "lipid rafts") contain a set of proteins and lipids, which take part in the signaling process in response to intra- or extracellular stimuli. Recent findings suggest that sphingolipids, especially glucosylceramide, play a critical role in inducing encystation and maintaining the cyst viability in Giardia. Similarly, the assembly/disassembly of lipid rafts modulates the encystation and cyst production of this ubiquitous enteric parasite. In this review article, we discuss the overall progress in the field and examine whether sphingolipids and lipid rafts can be used as novel targets for designing therapies to control infection by Giardia, which is rampant in developing countries, where children are especially vulnerable. PMID- 26587370 TI - Female Athlete Triad Awareness Among Multispecialty Physicians. AB - BACKGROUND: The female athlete triad (Triad) is a serious condition with lifelong consequences seen in physically active females. Prior studies assessing Triad knowledge among coaches/athletic trainers reported surprisingly low awareness results. Our aims were to (1) determine the percentage of physicians across multiple specialties who had heard of the phrase "female athlete triad" and (2) determine the percentage who can properly diagnose or have a high comfort level appropriately referring these patients. METHODS: Via electronic survey, we recruited medical staff, residents, and fellows at three large academic institutions across specialties to answer an eight-item test on Triad awareness and knowledge. RESULTS: A total of 931 physician participants were recorded. Of the total responders (40 % male and 60 % female), 23 % were residents, 12 % were fellows, and 65 % were attending physicians. Overall, 37 % had heard of the Triad. Of these respondents, an average of 2.1 +/- 1.1 of the three components were properly identified with an overall average score on the Triad awareness test of 71 +/- 18 % out of a possible 100 %. Fifty-one percent reported feeling either comfortable treating or referring a patient with the Triad. When assessing awareness among specialties, the awareness rates were highest among orthopedic surgery (80 %), followed by obstetrics and gynecology (55 %) and physical medicine and rehabilitation/rheumatology (52 %). The three with the lowest awareness were anesthesia (9 %), radiology (10 %), and psychiatry (11 %). CONCLUSIONS: Our findings suggest that approximately one third of the physicians surveyed have heard of the Triad. Approximately one half of physicians were comfortable treating or referring a patient with the Triad. Increased awareness through education to properly identify and manage the Triad is essential for all physicians. PMID- 26587371 TI - Production and characterization of neurosecretory protein GM using Escherichia coli and Chinese Hamster Ovary cells. AB - Neurosecretory protein GL (NPGL) and neurosecretory protein GM (NPGM) are paralogs recently discovered in birds and in mammals. The post-translational products of NPGL and of NPGM genes include a signal peptide sequence, a glycine amidation signal, and a dibasic amino acid cleavage site. This suggests that the mature forms of NPGL and of NPGM are small proteins secreted in the hypothalamus and containing an amidated C-terminus. However, endogenous NPGL and NPGM have not yet been identified. Chicken NPGL and NPGM have two highly conserved Cys residues that are likely to form a disulfide bond, while mammalian NPGM has one additional Cys residue located between the two conserved Cys residues and the correct disulfide bond pattern is unclear. In this study, we prepared rat NPGM to elucidate the structure of its mature form. We first expressed the predicted mature NPGM, containing an extra C-terminal Gly, in Escherichia coli SHuffle cells, which are engineered to promote the formation of native disulfide bridges in recombinant proteins. We observed the presence of a disulfide bond between the N-terminal Cys residue and the second Cys residue, while the C-terminal Cys residue was free. Secondly, we transfected a construct containing the entire NPGM open reading frame into Chinese Hamster Ovary cells, and observed that NPGM was cleaved immediately after the signal peptide and that it was secreted into the medium. Furthermore, the protein presented a disulfide bond at the same location observed in recombinant NPGM. PMID- 26587372 TI - Osteonecrosis of the jaw during biyearly treatment with zoledronic acid for aromatase inhibitor associated bone loss in early breast cancer: A literature review. AB - Osteonecrosis of the jaw (ONJ) is one of the most relevant and specific complication of biphosphonates. ONJ in patients receiving zoledronic acid every 3 to 4 weeks is frequently described, but the ONJ biyearly regimen used to reduce aromatase inhibitor associated bone loss (AIBL), is rarely reported. A literature review, focusing on the important trials using zoledronic acid to reduce AIBL, found that the mean risk of developing ONJ when zoledronic acid is used biyearly varies between 0.12% and 0.7%. PMID- 26587373 TI - Pre-treatment serum lactate dehydrogenase and alkaline phosphatase as predictors of metastases in extremity osteosarcoma. AB - BACKGROUND: The prognosis of patients with metastatic osteosarcoma remains poor. However, the chance of survival can be improved by surgical resection of all metastases. In this study we investigate the value of serum alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) in predicting the presence of metastatic disease at time of diagnosis. METHODS: Sixty-one patients with histologically confirmed conventional osteosarcoma of the extremity were included in the study. Only 19.7% of cases presented without evidence of systemic spread of the disease. Pre-treatment serum ALP and LDH were analysed in patients with and without skeletal or pulmonary metastases. RESULTS: Serum LDH and ALP levels were not significantly different in patients with or without pulmonary metastases (p=0.88 and p=0.47, respectively). The serum LDH and ALP levels did however differ significantly in patients with or without skeletal metastases (p<0.001 and p=0.02, respectively). The optimal breakpoint for serum LDH as a marker of skeletal metastases was 849 IU/L (AUC 0.839; Sensitivity=0.88; Specificity=0.73). LDH >454 IU/L equated to 100% sensitivity for detected bone metastases (positive diagnostic likelihood ratio (DLR)=1.32). With a cut-off of 76 IU/L a sensitivity of 100% was reached for serum ALP predicting the presence of skeletal metastases (positive DLR=1.1). In a multivariate analysis both LDH >=850 IU/L (odds ratio [OR]=9; 95% confidence interval (CI) 1.8-44.3) and ALP >=280 IU/L (OR=10.3; 95% CI 2.1-50.5) were predictive of skeletal metastases. LDH however lost its significance in a multivariate model which included pre-treatment tumour volume. CONCLUSION: In cases of osteosarcoma with LDH >850 IU/L and/or ALP >280 IU/L it may be prudent to consider more sensitive staging investigations for detection of skeletal metastases. Further research is required to determine the value and the most sensitive cut-off points of serum ALP and LDH in the prediction of skeletal metastases. PMID- 26587374 TI - Diagnostic and prognostic validity of serum bone turnover markers in bone metastatic non-small cell lung cancer patients. PMID- 26587375 TI - The role of 18F-NaF PET/CT in metastatic bone disease. AB - AIM: To investigate the role of 18F-NaF PET/CT and compare it with 99m Tc-MDP whole body bone scintigraphy and 18F-FDG PET/CT in detecting the extent of metastatic bone disease and to present our first experience with 18F-NaF PET/CT in our country. MATERIALS AND METHODS: A total of 37 histopathologically proven cancer patients (22 male, 15 female) with bone metastasis detected on Tc-99m MDP whole body bone scan were prospectively enrolled Cebeci, following ethics committee approval. 18F-NaF PET/CT was performed to the participants in Ankara University Medical Faculty Nuclear Medicine Department for evaluation of symptomatic skeletal sites which were negative on Tc-99m MDP whole body bone scan. A lesion based comparison was made between 18F-NaF PET/CT and Tc-99m MDP whole body bone scan for each patient and between 18F-NaF PET/CT and 18F-FDG PET/CT in 12/37 patients. RESULTS: The number of lesions demonstrated by 99m Tc MDP bone scan and 18F-NaF PET/CT was equal in 4/37 (%11) of the cases. 18F-NaF PET/CT showed a greater number of pathological foci in 89% of participants. 18F NaF PET/CT was able to show both lytic and blastic lesions and small lesions were better visualized due to the advantage of sectional imaging with much better resolution and higher target/background ratio. 18F-NaF PET/CT demonstrated a greater number of metastases in 10/12 (83%) of the patients when compared to 18F FDG PET/CT. In the other two patients, bone metastasis could be demonstrated only by 18F-NaF PET/CT. The uptake of 18F-FDG was variable in blastic lesions and cranial bone involvement was missed by 18F-FDG PET/CT in some cases due to physiological brain metabolism. CONCLUSION: Although further prospective clinical studies in specific cancer populations are indicated to set the place of 18F-NaF PET/CT in diagnostic scheme, the results of this pilot study from our country support the superiority of 18F-NaF PET/CT in investigation of bone metastasis over 99mTc-MDP bone scan and 18F-FDG PET/CT in various malignancies. 18F-NaF PET/CT is coming forward as a single step bone seeking study, considering all the advantages, but especially potential of detecting occult metastases and reliably directing patient management. PMID- 26587376 TI - Dosing of zoledronic acid with its anti-tumor effects in breast cancer. AB - Bisphosphonates have played an important role in the treatment of breast cancer, mainly in patients with bone metastasis, by reducing the risk of fracture, spinal cord compression, and hypercalcemia. Zoledronic acid, the most frequently used intravenous agent, has been traditionally administered on a monthly dosing schedule. Preclinical studies have demonstrated that zoledronic acid can inhibit angiogenesis, invasion, and adhesion of tumor cells. Several clinical studies of different timings and schedules of zoledronic acid therapy have demonstrated its anti-tumor effects, as well as its protective effect on bone health, in postmenopausal women during adjuvant breast cancer therapy. In general, early initiation of zoledronic acid, concomitantly with adjuvant therapy, has been found to be most beneficial. However, questions remain over the most effective schedule of treatment and relative potency of zoledronic acid. Therefore, we review the existing clinical studies to examine the influence of dosing of zoledronic acid therapy on clinical outcomes in patients with breast cancer. PMID- 26587377 TI - Epidemiology of substance abuse in the population of Lucknow. AB - BACKGROUND: Habit of consuming tobacco and areca-nut containing substances is in vogue in Lucknow as a part of the Nawabi culture. Hence, this study was planned with an aim to generate evidence for the prevalence of habits of substance abuse by the population of Lucknow and know their socio-demographic profile. METHODOLOGY: Population based cross-sectional study was conducted by organizing oral health check-up camps in randomly selected rural and urban parts of Lucknow, the capital city of Uttar Pradesh, which is the most populated state of India. Patients were enrolled after obtaining informed consent. A structured and validated questionnaire based tool was administered by a team of trained dental surgeons for collecting the desired information through interview and their oral cavity examination. RESULTS: A total of 3437 subjects were enrolled in the study, out of which 82.9% were male and 17.1% were female. Among them, 64.6% subjects belonged to rural domiciliary status, by religion, 80.6% and 18.5% of the subjects were Hindu and Muslims respectively. The most prevalent habit was consumption of smokeless tobacco substances, of which pan masala with tobacco (gutkha) was the most prevalent substance of abuse. CONCLUSION: Smokeless tobacco consumption was highly prevalent in the population surveyed. It is recommended to formulate and implement strong preventive strategies. Also, steps should be taken to increase the awareness of the harmful consequences of these habits. PMID- 26587378 TI - Evaluation of trapezoidal-shaped 3-D plates for internal fixation of mandibular subcondylar fractures in adults. AB - AIMS: The purpose of this study is to evaluate the clinical results and to assess the efficacy, stability, and rigidity of trapezoidal 3-D plates for osteosynthesis in adult mandibular subcondylar fracture patients. METHODS: This study included 15 cases of trauma having mandibular subcondylar fractures, in which open reduction and internal fixation are indicated. After selecting patient according to the inclusion criteria, all patients underwent open reduction and rigid fixation. Fracture was then stabilized using 4 hole, 2.0 mm trapezoidal shaped 3-D titanium plates using retromandibular incision. Postoperative clinical examination was carried out on 3rd day; 1st, 2nd, and 4th weeks; and 3rd and 6th months. RESULTS: The results of this study suggest that the fixation of mandibular subcondylar fracture with trapezoidal-shaped 3-D plates provides three dimensional stability and carries low morbidity. CONCLUSION: Patients with gross displacement of condylar fragment, major reduction in posterior facial height, and deranged occlusion can be successfully managed by open reduction of condylar fracture and its fixation using 3-D plates. PMID- 26587379 TI - Incidence and pattern of mandibular fractures in Rohilkhand region, Uttar Pradesh state, India: A retrospective study. AB - AIMS: To understand and evaluate the significance of various aetiological factors in determining the incidence and dictating the patterns of mandibular fractures in Rohilkhand region. METHODS: The patient records and radiographs for 144 patients treated for mandibular fractures were reviewed between the time periods from January 2012 to December 2013. Data on age, gender, aetiology, use of intoxicants, head injury, associated injuries, days of the week, anatomic site and multiple fractures within the mandible were recorded and assessed. RESULTS: Maximum incidence of fractures was observed among the individuals in 3rd decade (35.4%) followed by 2nd and 4th decades, which exhibited 32 and 30 cases (22.2% and 20.8%), respectively. Male to female ratio was biased (4:1) portraying a male predominance. Road traffic accidents (RTAs) were observed to be the predominant aetiological factor responsible accounting for 79.2% of the total injuries followed by assaults (11.8%) and falls (9%). Parasymphysis exhibited the highest incidence (32.63%) amongst the anatomic sites, followed by body (18.75%), angle (16.66%), condyle (15.27%), symphysis (12.50%), ramus (2.77%) and coronoid (1.38%). CONCLUSION: The study reveals that majority of affected patients were in the 2nd and 3rd decades. A definitive relationship existed between RTA and the incidence of mandibular fractures. The frequency further increased with consumption of social intoxicants. The most commonly fractured site was parasymphysis either isolated or associated with other fractures in the mandible. PMID- 26587380 TI - Pre-arthroplastic and simultaneous mandibular distraction for correction of facial deformity in temporomandibular joint ankylosis. AB - INTRODUCTION: In cases of temporomandibular joint (TMJ) ankylosis, interposition arthroplasty allows return of functional jaw movements. In order to improve the facial appearance, distraction osteogenesis is the treatment of choice, and may be timed either as a pre-arthroplastic, simultaneous or post-arthroplastic procedure. This study was planned to compare the treatment outcomes of pre arthroplastic distraction (PAD) and simultaneous arthroplastic distraction (SAD) to establish the better treatment modality in terms of improvement in function and aesthetics. MATERIALS AND METHODS: This prospective randomized experimental study included 20 children and adolescents suffering from facial deformity due to long standing unilateral TMJ ankylosis. They were randomly allocated to the two surgical groups with ten in each group. RESULT: Both groups resulted in good facial symmetry and aesthetics. Initially, during the distraction period, mouth opening of SAD group scored less than that of PAD group but became comparable in 30 days. More pain at the distraction site and over the normal TMJ was observed in PAD group. The excursive movements were almost comparable in both the groups. CONCLUSION: We conclude that both procedures are effective in correcting the post ankylotic deformity and improving function. Although PAD has better control over movement of the distracting segment, the contralateral TMJ may experience pain. SAD requires a shorter management period but is associated with a temporary decrease in function. Also, control of distraction may be difficult and chances of reankylosis are always there. PMID- 26587381 TI - Reliability of India-specific regression formula for age estimation of population in and around Bahadurgarh, Haryana (India). AB - OBJECTIVES: The study was conducted to check the reliability of India-specific regression formula for age estimation of population in and around Bahadurgarh, Haryana (India). MATERIALS AND METHODS: The study was conducted using digital orthopantomograms (OPGs) of 464 subjects (253 males and 211 females). Chronologic age (CA) was derived from that mentioned on the OPG. Each tooth in the left mandibular segment was scored using Demirjian's scoring and age was calculated using the regression formulas derived by Acharya. The difference of the chronologic and estimated age was used to check the reliability of India-specific regression formula. RESULTS: The mean estimated age was found to be significantly higher as compared to CA for overall as well as both the genders independently (p < 0.001). Difference (in +/-) between estimated and CA ranged from 0 to 4.2 years. Mean difference in age was 0.85 +/- 0.73 years for males and 0.87 +/- 0.76 years for females. CONCLUSION: The published India-specific regression formula does not have reliability in the population of Bahadurgarh, Haryana and hence cannot be universally applied. PMID- 26587382 TI - Periodontal associations in cardiovascular diseases: The latest evidence and understanding. AB - Periodontal and cardiovascular diseases (CVD) are inflammatory diseases. Recent epidemiological studies have associated the effect of periodontitis on CVD progression. Findings of oral pathogens in carotid atheromas provided a plausible relationship between these two diseases. One possible mechanism is the infiltration of oral/periodontal pathogens through inflamed and ulcerated gingival epithelium. This results in translocation of oral pathogens throughout the systemic circulation affecting vascular tissues, and initiating a cascade of inflammatory reactions detrimental to the cardiovascular system. In addition, leakage of pro-inflammatory cytokines/chemokines from the ulcerated periodontium into the bloodstream may cause the production of hepatic acute-phase proteins. Moreover, as chronic bacteremia occurs, the adaptive immune system is activated. Antibodies produced in response to periodontal pathogens trigger a cross-reaction between endothelial cells and modified low-density lipoprotein to enhance the movement of lipids into cells within the vessel wall. Some antibodies and inflammatory cytokines promote the Th1 response, thereby further activating macrophages within the atheroma. These plausible mechanisms are contributing factors in initiating and propagating atherogenesis. This review discusses the current understanding of CVD pathology/periodontitis, potential underlying mechanisms regarding this association, and general guidelines for treating patients with CVD risks. PMID- 26587383 TI - Nanodentistry: Is just a fiction or future. AB - Nanotechnology creates incredibly useful structures from individual atoms or molecules, which provides a new alternative and a possibly superior approach for the identification of oral health related problems and also in designing of more biocompatible dental materials with better properties and anticaries potential. Nanodentistry is striving its best to apply new advances in dental practice. The present article discusses the use of nanotechnology in dentistry and also the latest innovations in oral health care, nanoincorporated products, and issues of patient safety and occupational health. PMID- 26587384 TI - Glandular odontogenic cyst - Literature review and report of a paediatric case. AB - Glandular odontogenic cyst (GOC) is an extremely rare lesion occurring in the jawbones. The present paper is a review of 181 cases of GOCs reported in English literature, since it was first reported by Padayache and Van Wyk in 1987. Mandible was involved in 130 cases and maxilla in 51 cases. Anterior mandible was the most common area of involvement. Radiographic appearance was that of a unilocular radiolucency in 98 of 176 reported cases. Rest presented as multilocular radiolucency. Cortical expansion was observed in 136 of the 180 reported cases while cortex breach or perforation was seen in 81 cases. The treatment of choice was that of minor procedures that included enucleation with or without curettage, peripheral ostectomy, cryotherapy, etc. in 157 of the total 177 reported cases. Marginal jaw resection, segmental mandibulectomy etc. was reported in 20 cases. Although minor surgical procedures were the treatment of choice in most studies, two major studies of Kaplan et al. and Fowler et al. involving 111 and 46 cases, recorded a recurrence rate of 35.9 and 19.6%, respectively. The age range was between 11 and 82 years. The respective mean age of patients in the above mentioned studies was 45.7 for Kaplan's and 51 years for Fowler's whereas in our study, the mean age was 45.9 years. Very rarely does GOC presents itself in a paediatric patient. The paper also reports a case of an 11 year-old child whose histopathogy came out to be a case of a GOC. PMID- 26587385 TI - Trefoils: An unexplored natural protective shield of oral cavity. AB - The new mammalian growth factor peptide family consists of three peptides, TFF1, TFF2, and TFF3, which are secreted mainly from mucous epithelia with mucus gel. The predominant secretion of trefoil factor (TFF) occurs from gastric mucosal lining, small and large intestine, oral mucosal cells, and salivary glands. Research regarding trefoil factors is an immerging aspect in the dental field. The mucosal healing and restitution function describes about its novel role in case of chronic inflammatory conditions, but its expression from different tissue at different pathological condition shows its importance in immune response. At present, TFF expression has been detected from the severe periodontal diseased tissue samples. Future research from mild to moderate chronic periodontal diseased condition should be carried out to assess the protective response of TFF in gingival tissues. In future, assessment of TFF levels and its expression in oral mucosal tissues and oral secretions, such as saliva and gingival crevicular fluid, will provide a negative biomarker for chronic periodontal diseases and a novel therapeutic agent in oral mucosal healing. PMID- 26587386 TI - Detection of immunoglobulin (Ig) A antibodies against porcine epidemic diarrhea virus (PEDV) in fecal and serum samples. AB - Many assays for detection of antibodies against porcine epidemic diarrhea virus (PEDV) are based on detection of neutralizing antibodies or immunoglobulin (Ig) G in serum samples. However, due to the particular features of the mucosal immune system, presence of serum antibodies against enteric pathogens, such as PEDV, not always correlates with protection. In contrast, anti-PEDV IgA antibodies correlate with protection against subsequent challenges. An indirect PEDV IgA ELISA was previously developed to monitor IgA levels in colostrum and milk samples. In the present paper we describe an adaptation of the protocol for detection of IgA antibodies in serum and fecal samples.*The adapted protocol will aid in future assessment of protective levels of humoral response against PEDV infection by measuring IgA levels in serum and fecal samples.*Fecal samples are non-invasive and easy to collect at any time by animal caretakers and therefore offering advantages over the serum sample collection procedure.*A strong positive correlation between the anti-PEDV levels in fecal and serum samples was identified; however, detection of IgA antibodies was often more successful in serum than in paired fecal samples due to overall lower sample-to-positive (S/P) ratios for the latter sample type. PMID- 26587387 TI - Obtaining full contact for measuring polydimethylsiloxane mechanical properties with flat punch nanoindentation. AB - Procedure to establish full contact between the sample and the 1 mm diameter cylindrical flat punch tip to measure polydimethylsiloxane (PDMS) mechanical properties using the Hysitron TriboIndenter is described. This procedure differs from the standard automated indentation because each indent has to be performed manually after establishing full contact with the sample surface. Incomplete contact happens because of the sample tilt with respect to the flat punch surface and results in incorrect elastic modulus values.*Automated indentation results in incorrect values of the elastic modulus due to initial incomplete contact between the flat punch and the PDMS sample surface, caused by the tilt, and using the unloading slope, which is affected by viscoelastic soft polymer deformation.*Correct procedure requires establishing the full contact between the tip and the sample. This is achieved by moving the tip into the sample in 1-2 MUm increments, up to 40-80 MUm maximum combined displacement, until the loading stiffness no longer increases.*The elastic modulus is calculated from the loading stiffness and the diameter of the flat punch, instead of the unloading stiffness, which is larger due to viscoelastic unloading. After establishing the full contact, other mechanical testing can be conducted. PMID- 26587388 TI - An optimised method for the production of MERS-CoV spike expressing viral pseudotypes. AB - The production and use of pseudotyped viral particles are widely established for many viruses, and applications in the fields of serology and vaccine development are manifold. Viral pseudotypes have proven to be powerful tools to study the effects of viral evolution on serological outcomes, viral tropism and immunogenicity studies. Pseudotyped viruses are chimeric constructs in which the outer (surface) glycoprotein(s) of one virus is combined with the replication defective viral "core" of another virus. Pseudotypes allow for accurate, sequence directed, sensitive antibody neutralisation assays and antiviral screening to be conducted within a low biosecurity facility and offer a safe and efficient alternative to wildtype virus use. The protocol outlined here represents a rapid and reliable method for the generation of high-titre pseudotype viral particles with the MERS-CoV spike protein on a lentiviral core, and is adapted from previously published protocols. This protocol is optimised for transfection in a 100 mm Petri dish with 7 ml of supernatant harvested, however it can be readily scaled to different production volumes. This protocol has a number of advantages including:*Use of readily available reagents.*Consistent, high virus titres.*Rapid generation of novel glycoproteins for research into strain variation. PMID- 26587389 TI - Soma Crisis. PMID- 26587391 TI - Revisiting reflexology: Concept, evidence, current practice, and practitioner training. AB - Reflexology is basically a study of how one part of the human body relates to another part of the body. Reflexology practitioners rely on the reflexes map of the feet and hands to all the internal organs and other human body parts. They believe that by applying the appropriate pressure and massage certain spots on the feet and hands, all other body parts could be energized and rejuvenated. This review aimed to revisit the concept of reflexology and examine its effectiveness, practices, and the training for reflexology practitioners. PubMed, SCOPUS, Google Scholar, and SpringerLink databases were utilized to search the following medical subject headings or keywords: foot massage, reflexology, foot reflexotherapy, reflexological treatment, and zone therapy. The articles published for the last 10 years were included. Previous systematic reviews failed to show concrete evidence for any specific effect of reflexology in any conditions. Due to its non invasive, non-pharmacological complementary nature, reflexology is widely accepted and anecdotal evidence of positive effect reflexology in a variety of health conditions are available. Adequate training for practitioners is necessary to ensure the consistency of service provided. PMID- 26587390 TI - Traditional Chinese medicine in patients with osteoarthritis of the knee. AB - To evaluate whether the use of traditional Chinese medicine (TCM; zhong yi) influences symptoms or functional outcomes in patients with osteoarthritis (OA) of the knee ( xi guan jie yan). A systematic review of randomized control trials was conducted. Searches for studies in PubMed that were performed between 1965 and August 2013, and retrieved studies were subjected to reference screening. The types of studies included in our review were 1) placebo-based or comparative studies; 2) open label, single-blinded or double-blinded studies; 3) studies evaluating the efficacy of TCM for treating OA of the knee; and 4) studies evaluating only TCM or combination preparations. Trials were conducted with participants over 18 years of age with knee pain and at least three of the following characteristics: 1) an age greater than 50 years; 2) morning stiffness lasting for fewer than 30 min; 3) a crackling or grating sensation; 4) bony tenderness of the knee; 5) bony enlargement of the knee; or 6) no detectable warmth of the joint to the touch. Studies were rated for risk of bias and graded for quality. After screening, 104 studies that satisfied the eligibility requirements were identified, and only 18 randomized control trials were included in the quantitative and qualitative synthesis. Upon review, we found "moderate quality" evidence of effects from acupuncture ( zhen jiu) on pain, which was measured using a visual analogue scale, and physical function, which was measured using qigong ( qi gong) with motion. "Low-quality" evidence was found regarding the effects of acupuncture on physical function, and no evidence was found regarding the effects of herbal medicine on pain or physical function. Herbal patches ( yao bu) appeared to affect pain and physical and function, but these effects were not found to be significant. The initial findings included in this review suggest that acupuncture is a promising intervention according to the primary outcome measure, pain, and qigong with motion is an effective method for treating physical function. However, according to the Grades of Recommendation, Assessment, Development, and Evaluation criteria, only moderate-quality evidence was found in these studies. Further rigorous studies are warranted to investigate the application of TCM in treating OA of knee. PMID- 26587392 TI - Pharmacokinetic profile of phytoconstituent(s) isolated from medicinal plants-A comprehensive review. AB - Herbal medicine, the backbone of traditional medicine, has played an important role in human health and welfare for a long period. Traditional therapeutic approaches of regional significance are found in Africa, South and Central America, China, India, Tibet, Indonesia, and the Pacific Islands. The considerable scientific significance and commercial potential of traditional medicines have resulted in increased international attention and global market demands for herbal medicines, especially Chinese herbal medicines. Herbal medicines currently are the primary form of health care for the poor in the developing countries, and also are widely used as a supplement or substitute for conventional drugs in developed countries. These traditional medicines have a pivotal role in the treatment of various ailments and more than 50% of drugs used in Western pharmacopoeia are isolated from herbs or derived from modifications of chemicals found in plants. Herbal medicines usually contain a complex mixture of various bioactive molecules, which make its standardization complicated, and there is little information about all compounds responsible for pharmacological activity. Several research papers have been published that claim pharmacological activity of herbal medicines but few are discussing the role of the exact phytoconstituent. Understanding the pharmacokinetic profile of such phytoconstituents is essential. Although there are research papers that deal with pharmacokinetic properties of phytoconstituents, there are a number of phytoconstituents yet to be explored for their kinetic properties. This article reviews the pharmacokinetic profile of 50 different therapeutically effective traditional medicinal plants from the year 2003 onward. PMID- 26587393 TI - Ayurnutrigenomics: Ayurveda-inspired personalized nutrition from inception to evidence. AB - Ayurveda proclaims food and drugs are intersecting concepts that are vital for human survival and for the prevention and mitigation of diseases. Food interferes with the molecular mechanisms of an organism's "physiome". It is consumed in large amounts compared to any drug. Hence, research on its effect and interaction with genome is highly relevant toward understanding diseases and their therapies. Ayurgenomics presents a personalized approach in the predictive, preventive, and curative aspects of stratified medicine with molecular variability, which embodies the study of interindividual variability due to genetic variability in humans for assessing susceptibility, and establishing diagnosis and prognosis, mainly on the basis of the constitution type of a person's Prakriti. Ayurnutrigenomics is an emerging field of interest pervading Ayurveda systems biology, where the selection of a suitable dietary, therapeutic, and lifestyle regime is made on the basis of clinical assessment of an individual maintaining one's Prakriti. This Ayurveda-inspired concept of personalized nutrition is a novel concept of nutrigenomic research for developing personalized functional foods and nutraceuticals suitable for one's genetic makeup with the help of Ayurveda. Here, we propose and present this novel concept of Ayurnutrigenomics and its emerging areas of research, which may unfold future possibilities toward smart yet safe therapeutics. PMID- 26587394 TI - Integration between orthodox medicine, homeopathy and acupuncture for inpatients: Three years experience in the first hospital for Integrated Medicine in Italy. AB - The hospital in Pitigliano (Tuscany) is the first hospital in Italy to put into practice a model of Integrated Medicine. This clinical setting caters for the use of complementary medicine (homeopathy and acupuncture ( zhen jiu)) alongside orthodox therapies (conventional medicine). The therapeutic model implicates doctors who are experts in complementary and alternative medicine (CAM; bu chong yu ti dai yi xue) and the rest of the hospital personnel working together as equals. This contribution explains the difficulties, critical aspects and potential of this innovative setting. The clinical setting for Integrated Medicine was evaluated in part through observation and in part through the analysis of approval questionnaires. The writers of the questionnaires were the orthodox medical personnel and the hospital patients. The project is still evolving today in spite of the initial partial contrariety of some doctors in the hospital and some external doctors in the area. However, it can already be considered a positive experience, as confirmed by the high approval gained from many health workers and most of the hospital patients. Moreover, the follow-up carried out through specific surgeries dedicated to CAM is extremely positive. Up to now 532 inpatients suffering from acute illnesses, relapse of a chronic illness or neurological or orthopaedic rehabilitation following strokes, brain haemorrhage, neurological illness or limb prosthesis operations have been treated. This work has tried to illustrate the innovative and positive experience for the Italian public health authorities so that it may also be useful to anyone who would like to promote similar initiatives within its public health Institution. PMID- 26587395 TI - Effect of acupressure with valerian oil 2.5% on the quality and quantity of sleep in patients with acute coronary syndrome in a cardiac intensive care unit. AB - The purpose of this three-group double-blind clinical trial study was to investigate the effect of acupressure ( zhi ya) with valerian ( xie cao) oil 2.5% on the quality and quantity of sleep in patients with acute coronary syndrome (ACS) in a coronary intensive care unit (CCU). This study was conducted on 90 patients with ACS in Mazandaran Heart Center (Sari, Iran) during 2013. The patients were randomly assigned to one of three groups. Patients in the acupressure with valerian oil 2.5% group (i.e., valerian acupressure group) received bilateral acupoint ( xue wei) massage with two drops of valerian oil for 2 minutes for three nights; including every point this treatment lasted in total 18 minutes. Patients in the acupressure group received massage at the same points with the same technique but without valerian oil. Patients in the control group received massage at points that were 1-1.5 cm from the main points using the same technique and for the same length of time. The quality and quantity of the patients' sleep was measured by the St. Mary's Hospital Sleep Questionnaire (SMHSQ). After the intervention, there was a significant difference between sleep quality and sleep quantity in the patients in the valerian acupressure group and the acupressure group, compared to the control group (p < 0.05). Patients that received acupressure with valerian oil experienced improved sleep quality; however, this difference was not statistically significant in comparison to the acupressure only group. Acupressure at the ear spirit gate ( shen men), hand Shenmen, glabella ( yin tang), Wind Pool ( feng chi), and Gushing Spring ( yong quan) acupoints can have therapeutic effects and may improve the quality and quantity of sleep in patients with ACS. Using these techniques in combination with herbal medicines such valerian oil can have a greater impact on improving sleep and reducing waking during the night. PMID- 26587396 TI - Phytochemical, analgesic, antibacterial, and cytotoxic effects of Alpinia nigra (Gaertn.) Burtt leaf extract. AB - This research evaluated the phytochemical contents as well as the analgesic, cytotoxic, and antimicrobial effects of the methanolic extract of Alpinia nigra leaf. Phytochemical analysis was carried out using established methods. The analgesic effects of the extract were measured with the formalin test and tail immersion test. The antibacterial activity of the extract was evaluated using the disc diffusion technique. Cytotoxicity was assessed with the brine shrimp lethality bioassay. Data were analyzed with one-way analysis of variance using statistical software (SPSS, Version 19.0). The qualitative phytochemical screening of A. nigra leaf extract showed the presence of medicinally active secondary metabolites such as alkaloids, glycosides, cardiac glycosides, flavonoids, steroids, tannins, anthraquinone glycosides, and saponins. The extract at a dose of 200 mg/kg revealed a prevailed central nociception increasing the reaction time in response to thermal stimulation. The extract also showed a response to chemical nociceptors, causing pain inhibition in the late phase. The leaf extract (2 mg/disc) showed mild antibacterial activity compared to tetracycline (50 MUg/disc). In the brine shrimp lethality bioassay, the LC50 (lethal concentration 50) value of the extract was found to be 57.12 MUg/mL, implying a promising cytotoxic effect. The results evidenced the moderate analgesic and antibacterial effects with pronounced cytotoxic capability. PMID- 26587397 TI - Literature analysis of Acanthopanax anaphylactic shock in China. AB - The aims of this study are to investigate the occurrence characteristics of Acanthopanax ( ci wu jia) anaphylactic shock and to provide objective evidence for the rational use of the medicine. Fifty-seven cases of Acanthopanax anaphylactic shock were collected from several professional databases in China. The statistical data of the patients were analyzed with Visual FoxPro 6.0 and Office Excel 2003 by Microsoft (Redmond, WA, USA). The male:female incidence ratio was 0.5:1. Fifty-six (98.25%) patients were older than 30 years. Thirty nine (68.42%) patients had an unknown allergy history. Nine (15.79%) patients used Acanthopanax for unlabeled indications. In most (98.25 %) patients, Acanthopanax was used in the form of dosage injection. Anaphylactic shock occurred within 30 minutes after treatment in 52 (94.54%) patients, and all episodes occurred during the infusion process. In two (3.51%) patients, the episode occurred when they used Acanthopanax for the second time. In one (1.75%) patient, the episode occurred during the third time of use. The clinical symptoms of anaphylactic shock are diversified, but all patients presented with cardiovascular and respiratory system symptoms. Acanthopanax injections that led to anaphylactic shock were produced exclusively by four manufacturers. Four (7.02%) patients died and 49 (85.96%) patients were cured, but the status of four patients is unknown. Because an Acanthopanax injection may cause anaphylactic shock and can be fatal in severe cases, physicians and patients must pay close attention to using it rationally. Clinicians should carefully consult the allergic constitution of their patients, strictly follow the guidelines of the drug, use Acanthopanax in the oral dosage form as much as possible, and strengthen therapeutic monitoring. PMID- 26587398 TI - Clinical efficacy and tolerability of two Japanese traditional herbal medicines, Hachimi-jio-gan and Gosha-jinki-gan, for lower urinary tract symptoms with cold sensitivity. AB - We evaluated the efficacy and tolerability of Hachimi-jio-gan (HJG; ba wei di huang wan) and Gosha-jinki-gan (GJG; ji sheng shen qi wan), two traditional Japanese medicines, in 60 patients with lower urinary tract symptoms (LUTS) having cold sensitivity unresponsive to alpha1-blockers or antimuscarinic drugs. All patients received a mixture of HJG or GJG for 12 weeks in addition to alpha1 blockers or antimuscarinic drugs as add-on therapy. International Prostate Symptom Score, International Prostate Symptom Score-Quality of Life, Benign Prostatic Hyperplasia Impact Index, and the number of nocturnal voids were statistically much improved. However, there was no change in maximal urinary flow rate and post-void residual urine. Urinary 8-hydroxy-2-deoxyguanosine was statistically greatly improved from baseline after treatment in the HJG group compared to the GJG group. Adverse reactions were observed in 8.3% of patients, but all reactions were mild. Both HJG and GJG mixtures can serve as safe and effective potential therapeutic alternatives in patients with LUTS and cold sensitivity unresponsive to alpha1-blockers or antimuscarinic drugs. Additionally, HJG mixture was found to have anti-oxidative activity, and therefore further long-term clinical investigations are needed to examine its anti-aging effects in addition to its effect on urinary symptoms. PMID- 26587399 TI - Successful Treatment of Chronic Donor Site Pain. AB - INTRODUCTION: This is a case presentation of a 45-year-old male with chronic donor site pain following autologous iliac crest bone harvest successfully treated with superior cluneal nerve blockade. Donor site pain following autologous bone harvest is a common postoperative complication of lumbar fusion procedures that can cause significant morbidity and diminish quality of life, even in the context of an otherwise successful surgery. Dysfunction of the superior cluneal nerves is an etiology of this chronic pain. The patient's medical history, attempted treatments, and literature were reviewed. CASE PRESENTATION: A 45-year-old male with a six year history of severe pain over the right iliac crest following an otherwise successful lumbar laminectomy and fusion underwent two sets of superior cluneal nerve blocks, with sustained relief of more than 80% at seven months follow up. CONCLUSIONS: Donor site pain following autologous iliac crest bone harvest is a common surgical complication that is often resistant to conservative treatments such as physical therapy and oral medications. Blockade of the superior cluneal nerves is a safe and technically simple procedure that may result in long-term pain relief, obviating the need to consider more invasive options. PMID- 26587400 TI - Comparison of Transforaminal and Parasagittal Epidural Steroid Injections in Patients With Radicular Low Back Pain. AB - BACKGROUND: Epidural steroid injection (ESI), including transforaminal (TF) epidural injections and interlaminar (IL) epidural steroid injections are commonly performed procedures for the management of lumbosacral radicular pain. Parasagittal interlaminar (PIL) approach could enable higher ventral epidural spread, with fewer complications than TF. OBJECTIVES: This study aims to compare the effectiveness of PIL and TF ESI in relieving the pain and disability of patients with lumbosacral pain. PATIENTS AND METHODS: This prospective study enrolled 64 patients, aged between 18 to 75 years, with a diagnosis of low back pain and unilateral lumbosacral radicular pain. The patients were randomized to receive fluoroscopically guided epidural injection, through either the PIL or TF approach. Patients were evaluated for effective pain relief [numerical rating scale (NRS) < 3] by 0 - 10 numeric rating scale (NRS) and functional improvement by the Oswestry Disability Index (ODI). RESULTS: Effective pain relief [numeric rating scale (NRS) < 3] was observed in 77.3% (95% CI: 67-90.5%) of patients in PIL group and 74.2% (95% CI: 62.4 - 89.4%) of patients in the TF group (P = 0.34), at 4 weeks. Mean NRS score was not significantly different between the PIL group compared to the TF group, at 4 weeks (P = 0.19). Number of patients with improved disability (measured by ODI < 20%) was not significantly different in PIL group (78% of cases) compared to the TF group (76% of cases), at 4 weeks (P = 0.21). There were no adverse effects observed in any of our patients. CONCLUSIONS: The PIL epidural injection is as effective as TF epidural injection in improving pain and functional status, in patients with chronic lumbosacral low back pain, due to disc degeneration. PMID- 26587401 TI - The Effects of Prolotherapy With Hypertonic Dextrose Versus Prolozone (Intraarticular Ozone) in Patients With Knee Osteoarthritis. AB - BACKGROUND: Knee osteoarthritis (KOA) is a common disabling disease. Limited studies have demonstrated that prolotherapy with dextrose or with prolozone can be helpful in the treatment of patients with KOA. OBJECTIVES: In the current study, we compared the results between these two treatment methods. PATIENTS AND METHODS: In the current randomized clinical trial, 80 patients with mild to moderate KOA were randomly assigned equally into two groups (ozone group and dextrose group). In each group, injections were repeated three times with 10-day intervals. Before the treatment and 3 months after the injections, the pain intensity was measured by using a visual analogue scale and the Western Ontario and McMaster university arthritis index scores. Finally, the results were compared between the two groups. RESULTS: In the two groups, the pain intensity and WOMAC scores significantly decreased and increased, respectively (P < 0.001). However, there was no significant difference between the two groups. CONCLUSIONS: Prolotherapy with dextrose and with prolozone result in the same pain relief or functional improvement in patients with mild to moderate KOA. PMID- 26587402 TI - Efficacy of Conversational Hypnosis and Propofol in Reducing Adverse Effects of Endoscopy. AB - BACKGROUND: As pain and nausea is usually associated with endoscopy procedure, its management is important to alleviate patients' anxious in this regard. OBJECTIVES: The present study aimed to examine the effectiveness of conversational hypnosis in reducing anxiety and endoscopy-related complications as well as its role in increasing the satisfaction of patients exposed to endoscopic procedures. PATIENTS AND METHODS: The participants of upper GI endoscopy procedure were randomly assigned to an experiment group (with conversational hypnosis intervention, n = 93) and a control group (n = 47). The participants' hemodynamic indexes (HR, blood pressure, pulse oximetry), anxiety, satisfaction level, and complications resulted from the procedure were monitored and included in the self-administered questionnaire. RESULTS: The results indicated that the participants in experiment group had a significant reduction of anxiety in the posttest. The adverse side effects such as vomiting, nausea, and hiccups in the experimental group was less than the control group, though this difference was not significant (P = 0.54). CONCLUSIONS: The results suggested that conversational hypnosis technique could reduce anxiety as well as the sedation process in invasive procedures such as endoscopy. PMID- 26587403 TI - Influence of Ketamine on Early Postoperative Cognitive Function After Orthopedic Surgery in Elderly Patients. AB - BACKGROUND: Postoperative cognitive dysfunction (POCD) is a serious and frequent complication after surgery, especially in elderly patients. Ketamine is an N methyl D-aspartic acid receptor antagonist with demonstrated neuroprotective effects. An intravenous bolus of a sub-anesthetic dose (0.5 mg/kg) of ketamine can reduce postoperative delirium (POD) and POCD after cardiac surgery. But, the influence of ketamine on early POCD after non-cardiac surgery is unclear. OBJECTIVES: The current study aimed to evaluate the influence of ketamine on early postoperative cognitive function after orthopedic surgery in elderly patients. PATIENTS AND METHODS: Fifty six elderly patients (> 60-years-old), scheduled for elective orthopedic surgery during general anesthesia (duration of anesthesia > two hours) were enrolled. Patients received intravenous bolus, a total of 3 mL mixed with 0.9% normal saline and 0.5 mg/kg ketamine (K group) or 3 mL of 0.9% normal saline (N group). Three neurocognitive function tests (mini mental status examination, trail-making test, digit substitution test), and c reactive protein (CRP) concentration were determined before surgery and on postoperative day one (POD 1) and postoperative day six (POD 6). RESULTS: The two groups had similar demographic characteristics except for the gender. Surgical and anesthetic data were not significantly different. A statistically significant difference was observed in comparison of trail-making test score. Trail-making test score increased more in the N group (52.5 points) than the K group (13 points) at POD 1 (P = 0.047) compared with baseline scores. There were no significant differences in the mini-mental status examination, digit substitution test and CRP concentration at POD 1 and POD 6 between the two groups. POCD (the two Z-scores in more than two tests or the combined Z-score was 1.96 or more) was present in one patient (4%) in the K group at POD 6 (P = 0.98). CONCLUSIONS: The incidence of POCD was not significantly influenced by a bolus dose of ketamine (0.5 mg/kg) after orthopedic surgery in elderly patients. There were no negative effects of ketamine on early POCD. PMID- 26587404 TI - The Role of NMDARs Ligands on Antinociceptive Effects of Pregabalin in the Tail Flick Test. AB - BACKGROUND: Pregabalin as a new anticonvulsant has been used in different pain treatments. OBJECTIVES: The aim of this study was to investigate the role of N methyl-D-aspartate (NMDA) ligands in antinociceptive effect of pregabalin in mice using tail flick. MATERIALS AND METHODS: NMDA (15 and 30 mg/kg) as an agonist or MK801 (0.02 and 0.05 mg/kg) as an antagonist were injected intraperitoneally either alone or 15 minutes before antinociceptive dose of pregabalin (100 mg/kg). Then the latency times and %MPE were measured in the tail flick assay during 75 minutes. RESULTS: NMDA and MK801 had no effects alone. NMDA pretreatment significantly decreased the latency times of pregabalin till 75(th) minutes. In NMDA pretreated groups, %MPE30 unlike %MPE75 decreased significantly compared to those of pregabalin. MK801 delayed the latency times in pretreated groups, but %MPE30 and %MPE75 did not change significantly compared to pregabalin alone. CONCLUSIONS: Our findings support the role of NMDARs in pregabalin antinociception, because the NMDAR agonist, unlike the antagonist, decreased the antinociceptive effect of pregabalin, even if tail flick is not an adequate pain assessment method in this regard. PMID- 26587405 TI - Comparison of Transcutaneous Electrical Nerve Stimulation and Pulsed Radiofrequency Sympathectomy for Treating Painful Diabetic Neuropathy. AB - BACKGROUND: Painful diabetic peripheral neuropathy (DPN) is a long-term complication of type 1 and type 2 diabetes that majorly impacts quality of life. Its prevalence increases with age and duration of diabetes. It is more common in patients who have suboptimal glycemic control over several years. Because DPN may be resistant to conventional treatments, it is common for patients to only have partial pain relief. Therefore, new therapeutic options are needed for the condition. OBJECTIVES: The aim of the present study was to compare the efficacy of transcutaneous electrical nerve stimulation (TENS) and pulsed radiofrequency (PRF) lumbar sympathectomy in treating painful DPN. PATIENTS AND METHODS: Sixty five patients with painful DPN refractory to conventional treatment were randomly and evenly assigned to either the TENS or PRF lumbar sympathectomy groups. Pain evaluations were based on the 10-point numerical rating scale (NRS). Subjects were followed for three months and had a total of four study visits (baseline and 1 week, 1 month, and 3 months after treatment). RESULTS: Sixty patients completed all study visits. In both groups, the NRS rating significantly decreased after treatment, with a marked pain reduction observed at the first follow-up evaluation. In the PRF group, the NRS decreased from 6.46 at baseline to 2.76 at the 1 week visit. One and 3 months after treatment, the NRS was 4.30 and 5.13, respectively (P < 0.0001). In the TENS group, the NRS decreased from 6.10 at baseline to 3.96 at the 1 week visit. One and 3 months after treatment, the NRS was 5.23 and 5.90, respectively (P < 0.0001). Unfortunately, the NRS steady increased almost back to baseline levels in the TENS group. The NRS only slightly increased during the follow-up period in the PRF group, but did not reach baseline levels. CONCLUSIONS: Both TENS and PRF lumbar sympathectomy are promising pain relief treatments for painful DNP. However, PRF lumbar sympathectomy seems to have a superior efficacy. Further studies with a larger sample size and a longer follow-up period are needed. PMID- 26587406 TI - A Comparison of Patient Controlled Epidural Analgesia With Intravenous Patient Controlled Analgesia for Postoperative Pain Management After Major Gynecologic Oncologic Surgeries: A Randomized Controlled Clinical Trial. AB - BACKGROUND: Postoperative pain after major open gynecologic surgeries requires appropriate pain management. OBJECTIVES: This study aimed at comparing perioperative patient controlled epidural analgesia (PCEA) and patient controlled intravenous analgesia (PCA) after gynecologic oncology surgeries. PATIENTS AND METHODS: In this clinical trial study, 90 patients with American society of anesthesiologists (ASA) class I or II scheduled for gynecologic oncologic surgeries were randomly allocated to two groups (45 patients each group) to receive: patient-controlled epidural analgesia with bupivacaine and fentanyl (PCEA group), or patient controlled intravenous analgesia (IV PCA group) with fentanyl, pethidine and ondansetron. Postoperative pain was assessed over 48 hours using the visual analog scale (VAS). The frequency of rescue analgesia was recorded. Occurrence of any concomitant events such as nausea, vomiting, ileus, purities, sedation and respiratory complications were recorded postoperatively. RESULTS: There were no statistically significant differences in demographic data including; age, weight, ASA physical status, duration of surgery, intraoperative bleeding, and the amount of blood transfusion (P > 0.05), between the two studied groups. Severity of postoperative pain was not significantly different between the two groups (P > 0.05); however, after first patient mobilization, pain was significantly lower in the epidural group than the IV group (P < 0.001). There was no significant difference between the two groups regarding the incidence of complications such as nausea, vomiting, purities or ileus (P > 0.05). Nevertheless, the incidence and severity of sedation was significantly higher in the IV group (P < 0.001). Respiratory depression was higher in the IV group than the epidural group; this difference, however, was not significant (P = 0.11). In the epidural group, only 10 patients (22.2%) had mild and transient lower extremities parenthesis. CONCLUSIONS: Both intravenous and epidural analgesic techniques with combination of analgesics provide proper postoperative pain control after major gynecologic cancer surgeries without any significant complications. Regarding lower sedative and respiratory depressant effects of epidural analgesia, it seems that this method is a safer technique for postoperative pain relief in these patients. PMID- 26587407 TI - The Assessment of Addition of Either Intravenous Paracetamol or Diclofenac Suppositories to Patient-Controlled Morphine Analgesia for Postgastrectomy Pain Control. AB - BACKGROUND: Major surgical procedures, such as gastrectomy, result in extensive postoperative pain, which can lead to increased morbidity, discomfort and dissatisfaction among the patients. OBJECTIVES: The aim of this study was to evaluate the effect of adding diclofenac suppositories or intravenous paracetamol, on morphine consumption and on the quality of postgastrectomy pain control. PATIENTS AND METHODS: This randomized double blinded clinical trial was carried out in 90 patients with gastric cancer, who were candidates for gastrectomy, which were divided into three similar groups. The patients were transferred to an intensive care unit after the operation and received patient controlled analgesia (PCA) with morphine, morphine PCA plus intravenous paracetamol 1 g, every 6 hours, and morphine PCA plus diclofenac suppositories, 100 mg every 8 hours. The patients were evaluated for up to 24 hours after the operation for the severity of pain, alertness, and opioid complications. RESULTS: There was no significant difference in pain scores among the three groups (P values, after extubation, at 2, 4, 6, 12, 18 and 24 hours were 0.72, 0.19, 0.21, 0.66, 0.54, 0.56, and 0.25, respectively), although morphine consumption was greater in the morphine group, compared with the other two groups (21.4 +/- 7.7 mg in morphine group vs. 14.3 +/- 5.8 mg in morphine-paracetamol group and 14.3 +/- 3.9 in morphine-diclofenac group; P = 0.001). In morphine group, during the first 24 hours, the patients had lower levels of consciousness (P values, after extubation, at 2, 4, 6, 12, 18 and 24 hour were 0.6, 0.95, 0.28, 0.005, 0.027, 0.022 and 0.004 respectively), even though the incidence of complications was similar among the three groups. CONCLUSIONS: In this study, intravenous paracetamol or diclofenac suppositories, administered for postgastrectomy pain control, decreased morphine consumption by almost 32% and also improved alertness. Nevertheless, the amount of opioids did not affect the incidence of complications. PMID- 26587408 TI - A Survey on the Effect of Oral Gabapentin on Hemodynamic Changes During Direct Laryngoscopy and Tracheal Intubation and Intraoperative Bleeding in Patients Undergoing Septorhinoplasty. AB - BACKGROUND: In patients undergoing septorhinoplasty, control of bleeding and hemodynamic variables is of great importance and laryngoscopy and tracheal intubation could be followed by a specific and transient increase in systemic blood pressure and heart rate. OBJECTIVES: This study aimed to examine the effects of oral gabapentin on hemodynamic changes, during direct laryngoscopy, and the amount of bleeding in the patients undergoing septorhinoplasty. PATIENTS AND METHODS: In a double-blind clinical trial, 103 patients (American society of anesthesiologists class I, II) aged 18 - 45 years old, who were septorhinoplasty candidates, were randomly assigned into two groups, a 900 mg gabapentin group and placebo, in Amir-Al-Momenin academic hospital. The drug was prescribed to the patients orally, 2 hours before the operation. Anesthetic technique was similar for all the patients. Heart rate (HR), systolic (SBP) and diastolic blood pressures (DBP), mean arterial blood pressure (MAP), oxygen saturation percentage of arterial blood (SaO2), before induction of anesthesia, 3, 5, 10, and 15 minutes after the intubation and tracheal extubation, and the amount of bleeding during operation were measured. Statistical analysis was performed with the SPSS (v. 16) software. RESULTS: Variations in the HR, DBP and SaO2, in the specified time intervals, did not show any statistically significant difference, although variations in SBP were statistically significant (higher in gabapentin group). Regarding the average amount of bleeding volume, although there was a lower amount of bleeding in the gabapentin group, the difference was not statistically significant. Also, regarding the pain, there was no significant difference between the two groups in terms of visual analog scale (VAS) average and the received analgesic. CONCLUSIONS: The present study showed that premedication with 900 mg gabapentin did not affect the hemodynamic changes induced by laryngoscopy and the amount of bleeding. However, the decreased amount of bleeding was observed in the gabapentin group. PMID- 26587409 TI - Persistent Spinal Headache After Removal of Intrathecal Drug Delivery System: A Case Report and Review of Literature. AB - INTRODUCTION: To report and discuss the spinal headache following insertion and removal of intrathecal drug delivery system in patients with chronic pain disorders. CASE PRESENTATION: Intrathecal drug delivery system (IDDS) was initially used for the management of chronic malignant pain; it has since been used to manage pain from other nonmalignant conditions as well. Spinal headache is one of the complications during the trial, permanent placement and after removal of intrathecal drug delivery catheter systems. A 48-year-male patient with chronic pain disorder developed a refractory spinal headache after removing the intrathecal drug delivery system requiring a surgical intervention to resolve the problem. CONCLUSIONS: Conservative management is successful in the vast majority of patients with spinal headache. Interventional procedures are required in a small fraction of patients for symptomatic relief. PMID- 26587410 TI - The effect of different drinks on the color stability of different restorative materials after one month. AB - OBJECTIVES: The aim of this study was to evaluate the effect of three different drinks on the color parameters of four different restorative materials. MATERIALS AND METHODS: Three different composites (Filtek Ultimate Universal Restorative, Filtek Ultimate Flowable, and Filtek Silorane, 3M ESPE) and a polyacid-modified composite resin material (Dyract XP, Dentsply DeTrey GmbH) were evaluated. Eighty four disc-shaped specimens of 8 mm in diameter and 2 mm in thickness were prepared (n = 21 each). Color coordinates (L*a*b*, DeltaL*, Deltaa*, Deltab*, and DeltaE*) were measured using a VITA Easyshade Compact (VITA Zahnfabrik) after 24 hr of storage (baseline) and after 30 day of storage in three different beverages of black tea, Coca cola, or water (control) (n = 7). In each beverage, the specimens were stored three times a day, one hr each, for 30 day. The color changes (DeltaE) were calculated and were analyzed by Kruskal-Wallis and Dunn multiple comparison test. RESULTS: The color difference (DeltaE*) of the resin materials ranged between 1.31 and 15.28 after 30 day of immersion in the staining solutions. Dyract XP in Coca cola (15.28 +/- 2.61) and black tea (12.22 +/- 2.73) showed the highest mean DeltaE* value after 30 day, followed by Filtek Ultimate Universal Restorative (5.99 +/- 1.25) and Filtek Ultimate Flowable (4.71 +/- 1.40) in black tea (p < 0.05). CONCLUSIONS: The compomers displayed unacceptable color changes at the end of 30 day in all beverages. Among resin composites, the silorane based composite exhibited relatively good color stability than the others. Filtek Ultimate Universal Restorative and Filtek Flowable showed similar color changes in all beverages. PMID- 26587411 TI - Comparison of mechanical properties of a new fiber reinforced composite and bulk filling composites. AB - OBJECTIVES: The aim of this study was to evaluate the mechanical and physical properties of a newly developed fiber reinforced dental composite. MATERIALS AND METHODS: Fiber reinforced composite EverX Posterior (EXP, GC EUROPE), and other commercially available bulk fill composites, including Filtek Bulk Fill (FB, 3M ESPE), SonicFill (SF, Kerr Corp.), SureFil (SDR, Dentsply), Venus Bulk Fill (VB, HerausKultzer), Tetric evoceram bulk fill (TECB, Ivoclar Vivadent), and Xtra Base (XB, Voco) were characterized. Composite samples light-cured with a LED device were evaluated in terms of flexural strength, flexural modulus (ISO 4049, n = 6), fracture toughness (n = 6), and Vickers hardness (0, 2, and 4 mm in depth at 24 hr, n = 5). The EXP samples and the fracture surface were observed under a scanning electron microscopy. Data were statistically analyzed using one-way ANOVA and unpaired t-test. RESULTS: EXP, FB, and VB had significantly higher fracture toughness value compared to all the other bulk composite types. SF, EXP, and XB were not statistically different, and had significantly higher flexural strength values compared to other tested composite materials. EXP had the highest flexural modulus, VB had the lowest values. Vickers hardness values revealed SF, EXP, TECB, and XB were not statistically different, and had significantly higher values compared to other tested composite materials. SEM observations show well dispersed fibers working as a reinforcing phase. CONCLUSIONS: The addition of fibers to methacrylate-based matrix results in composites with either comparable or superior mechanical properties compared to the other bulk fill materials tested. PMID- 26587412 TI - Effect of immersion into solutions at various pH on the color stability of composite resins with different shades. AB - OBJECTIVES: This study examined the color changes of a resin composite with different shades upon exposure to water with different pH. MATERIALS AND METHODS: Nanohybrid resin composites (Filtek Z350XT, 3M ESPE) with four different shades (A2, A3, B1, and B2) were immersed in water with three different pH (pH 3, 6, and 9) for 14 day. The CIE L*a*b* color coordinates of the specimens were evaluated before and after immersion in the solutions. The color difference (DeltaE*) and the translucency parameter (TP) were calculated using the color coordinates. RESULTS: DeltaE* ranged from 0.33 to 1.58, and the values were affected significantly by the pH. The specimens immersed in a pH 6 solution showed the highest DeltaE* values (0.87 - 1.58). The specimens with a B1 shade showed the lowest DeltaE* change compared to the other shades. TP ranged from 7.01 to 9.46 depending on the pH and resin shade. The TP difference between before and after immersion in the pH solutions was less than 1.0. CONCLUSIONS: The resulting change of color of the tested specimens did not appear to be clinically problematic because the color difference was < 1.6 in the acidic, neutral, and alkaline solutions regardless of the resin shade, i.e., the color change was imperceptible. PMID- 26587413 TI - Clinical and radiographical evaluation of mineral trioxide aggregate, biodentine and propolis as pulpotomy medicaments in primary teeth. AB - OBJECTIVES: The purpose of this study was to evaluate the efficacy of mineral trioxide aggregate (MTA), Biodentine and Propolis as pulpotomy medicaments in primary dentition, both clinically and radiographically. MATERIALS AND METHODS: A total of 75 healthy 3 to 10 yr old children each having at least one carious primary molar tooth were selected. Random assignment of the pulpotomy medicaments was done as follows: Group I, MTA; Group II, Biodentine; Group III, Propolis. All the pulpotomized teeth were evaluated at 3, 6, and 9 mon clinically and radiographically, based on the scoring criteria system. RESULTS: The clinical success rates were found to be similar among the three groups at 3 and 6 mon where as a significant decrease in success rate was observed in Group III (84%) compared to both Group I (100%) and Group II (100%) at 9 mon. Radiographic success rates over a period of 9 mon in Groups I, II, and III were 92, 80, and 72%, respectively. CONCLUSIONS: Teeth treated with MTA and Biodentine showed more favorable clinical and radiographic success as compared to Propolis at 9 mon follow-up. PMID- 26587414 TI - Influence of a glide path on the dentinal crack formation of ProTaper Next system. AB - OBJECTIVES: The aim was to evaluate dentinal crack formation after root canal preparation with ProTaper Next system (PTN) with and without a glide path. MATERIALS AND METHODS: Forty-five mesial roots of mandibular first molars were selected. Fifteen teeth were left unprepared and served as controls. The experimental groups consist of mesiobuccal and mesiolingual root canals of remaining 30 teeth, which were divided into 2 groups (n = 15): Group PG/PTN, glide path was created with ProGlider (PG) and then canals were shaped with PTN system; Group PTN, glide path was not prepared and canals were shaped with PTN system only. All roots were sectioned perpendicular to the long axis at 1, 2, 3, 4, 6, and 8 mm from the apex, and the sections were observed under a stereomicroscope. The presence/absence of cracks was recorded. Data were analyzed with chi-square tests with Yates correction. RESULTS: There were no significant differences in crack formation between the PTN with and without glide path preparation. The incidence of cracks observed in PG/PTN and PTN groups was 17.8% and 28.9%, respectively. CONCLUSIONS: The creation of a glide path with ProGlider before ProTaper Next rotary system did not influence dentinal crack formation in root canals. PMID- 26587415 TI - Effect of dentin treatment on proliferation and differentiation of human dental pulp stem cells. AB - OBJECTIVES: Sodium hypochlorite (NaOCl) is an excellent bactericidal agent, but it is detrimental to stem cell survival, whereas intracanal medicaments such as calcium hydroxide (Ca[OH]2) promote the survival and proliferation of stem cells. This study evaluated the effect of sequential NaOCl and Ca[OH]2 application on the attachment and differentiation of dental pulp stem cells (DPSCs). MATERIALS AND METHODS: DPSCs were obtained from human third molars. All dentin specimens were treated with 5.25% NaOCl for 30 min. DPSCs were seeded on the dentin specimens and processed with additional 1 mg/mL Ca[OH]2, 17% ethylenediaminetetraacetic acid (EDTA) treatment, file instrumentation, or a combination of these methods. After 7 day of culture, we examined DPSC morphology using scanning electron microscopy and determined the cell survival rate with 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. We measured cell adhesion gene expression levels after 4 day of culture and odontogenic differentiation gene expression levels after 4 wk using quantitative real-time polymerase chain reaction. RESULTS: DPSCs did not attach to the dentin in the NaOCl-treated group. The gene expression levels of fibronectin-1 and secreted phosphoprotein-1 gene in both the Ca[OH]2- and the EDTA-treated groups were significantly higher than those in the other groups. All Ca[OH]2-treated groups showed higher expression levels of dentin matrix protein-1 than that of the control. The dentin sialophosphoprotein level was significantly higher in the groups treated with both Ca[OH]2 and EDTA. CONCLUSIONS: The application of Ca[OH]2 and additional treatment such as EDTA or instrumentation promoted the attachment and differentiation of DPSCs after NaOCl treatment. PMID- 26587416 TI - The effect of saliva decontamination procedures on dentin bond strength after universal adhesive curing. AB - OBJECTIVES: The purpose of this study was to investigate the effectiveness of multiple decontamination procedures for salivary contamination after curing of a universal adhesive on dentin bond strength according to its etch modes. MATERIALS AND METHODS: Forty-two extracted bovine incisors were trimmed by exposing the labial dentin surfaces and embedded in cylindrical molds. A universal adhesive (All-Bond Universal, Bisco) was used. The teeth were randomly divided into groups according to etch mode and decontamination procedure. The adhesive was applied according to the manufacturer's instructions for a given etch mode. With the exception of the control groups, the cured adhesive was contaminated with saliva for 20 sec. In the self-etch group, the teeth were divided into three groups: control, decontamination with rinsing and drying, and decontamination with rinsing, drying, and adhesive. In the etch-and-rinse group, the teeth were divided into four groups: control, decontamination with rinsing and drying, decontamination with rinsing, drying, and adhesive, and decontamination with rinsing, drying, re-etching, and reapplication of adhesive. A composite resin (Filtek Z350XT, 3M ESPE) was used for filling and was cured on the treated surfaces. Shear bond strength was measured, and failure modes were evaluated. The data were subjected to one-way analysis of variation and Tukey's HSD test. RESULTS: The etch-and-rinse subgroup that was decontaminated by rinse, drying, re etching, and reapplication of adhesive showed a significantly higher bond strength. CONCLUSIONS: When salivary contamination occurs after curing of the universal adhesive, additional etching improves the bond strength to dentin. PMID- 26587417 TI - Identification of Enterococcus faecalis antigens specifically expressed in vivo. AB - OBJECTIVES: Molecular mechanism of the pathogenicity of Enterococcus faecalis (E. faecalis), a suspected endodontic pathogen, has not yet been adequately elucidated due to limited information on its virulence factors. Here we report the identification of in vivo expressed antigens of E. faecalis by using a novel immunoscreening technique called change-mediated antigen technology (CMAT) and an experimental animal model of endodontic infection. MATERIALS AND METHODS: Among 4,500 E. coli recombinant clones screened, 19 positive clones reacted reproducibly with hyperimmune sera obtained from rabbits immunized with E. faecalis cells isolated from an experimental endodontic infection. DNA sequences from 16 of these in vivo-induced (IVI) genes were determined. RESULTS: Identified protein antigens of E. faecalis included enzymes involved in housekeeping functions, copper resistance protein, putative outer membrane proteins, and proteins of unknown function. CONCLUSIONS: In vivo expressed antigens of E. faecalis could be identified by using a novel immune-screening technique CMAT and an experimental animal model of endodontic infection. Detailed analysis of these IVI genes will lead to a better understanding of the molecular mechanisms involved in the endodontic infection of E. faecalis. PMID- 26587418 TI - Management of apicomarginal defect in esthetic region associated with a tooth with anomalies. AB - Tooth related factors such as palatoradicular groove can be one of the causes for localized periodontal destruction. Such pathological process may result in apicomarginal defect along with inflammation of pulp. This creates challenging situation which clinician must be capable of performing advanced periodontal regenerative procedures for the successful management. This case report discusses clinical management of apicomarginal defect associated with extensive periradicular destruction in a maxillary lateral incisor, along with histopathologic aspect of the lesion. PMID- 26587419 TI - Treatment of non-vital immature teeth with amoxicillin-containing triple antibiotic paste resulting in apexification. AB - A recent treatment option for non-vital immature teeth in young patients is revascularization with triple antibiotic paste (TAP). However, tooth discoloration was reported with the use of conventional minocycline-containing TAP. In this case report, amoxicillin-containing TAP was used for revascularization of non-vital immature teeth to prevent tooth discoloration. At the 1 yr follow up, the teeth were asymptomatic on clinical examination and showed slight discoloration of the crown due to mineral trioxide aggregate (MTA) filling rather than amoxicillin-containing TAP. Radiographic examination revealed complete resolution of the periapical radiolucency, and closed apex with obvious periodontal ligament space. However, the root growth was limited, and the treatment outcome was more like apexification rather than revascularization. These results may be due to unstable blood clot formation which could not resist the condensation force of MTA filling, whether or not a collagen matrix was in place. These cases showed that although revascularization was not successful, apexification could be expected, resulting in the resolution of the periapical radiolucency and the closure of the apex. Therefore, it is worthwhile attempting revascularization of non-vital immature teeth in young patients. PMID- 26587420 TI - Statistical notes for clinical researchers: effect size. PMID- 26587421 TI - Simple methods to enhance bond strength of self-adhesive resin cements. PMID- 26587422 TI - Working width, a deserted aspect of Endodontics. PMID- 26587423 TI - Pulse: Revived in 'The Pulse of Asia'. PMID- 26587424 TI - Pulse Wave Velocity in Postmenopausal Women. AB - Cardiovascular disease (CVD) and osteoporosis are major causes of morbidity and mortality in postmenopausal women. The relationship between atherosclerosis and osteoporosis has been established by studies of the underlying pathophysiological mechanisms and biochemical pathways that seem to overlap in many places. Pulse wave velocity (PWV) is one of the known predictors of cardiovascular and all cause mortality. Studies indicate that PWV in hypertensive postmenopausal women is increased, and hormone replacement therapy (HRT) attenuates this increase. In addition, recently, many studies have suggested a role for arterial stiffness in the association between CVD and osteoporosis. From these findings, it appears that estrogen deficiency combined with production of inflammatory cytokines plays a role in increased PWV closely associated with CVD and osteoporosis, although the mechanisms of arterial stiffness in postmenopausal women may be more complex. Accordingly, a possible role for PWV as a surrogate marker of CVD as well as osteoporosis in postmenopausal women is discussed in this review. First, menopause leads to increased arterial stiffness with aging in females. Further, epidemiological data evaluating arterial stiffness assessed by PWV provided evidence that most of the established CVD risk factors are determinants of PWV, and these risk factors are increased in patients with CVD. In turn, contrary to expectation, HRT did not always contribute to a lower incidence of CVD in postmenopausal women. By reviewing the current data available, it becomes clear that, at present, the effects of menopause including HRT on PWV remain controversial, and further studies are needed to clarify these associations. PMID- 26587426 TI - Blood Pressure Variability and Cognitive Function in the Elderly. AB - With the increase in the aging population, it is important to understand the individual diseases and their interactions which are prevalent and have a great impact on the health status of the elderly. Hypertension is one of the most common diseases in older age and may impact the health status because it is the main risk factor for cardiovascular and cerebrovascular diseases such as heart failure and stroke. Recently, much evidence has been accumulated showing that hypertension plays an important role in the development and progression of cognitive impairment and dementia. Cerebral hypoperfusion secondary to severe atherosclerosis resulting from long-standing hypertension may be a major biological pathway linking high blood pressure (BP) to cognitive decline and dementia. Furthermore, increased BP variability has also been reported to be significantly associated with white matter hyperintensities and brain atrophy, which are predisposing conditions of dementia, depression, and falls in the elderly even after adjusting for BP levels and other confounding variables. Several mechanisms have been shown to be involved in the association between BP variability and cognitive impairment in elderly individuals. In addition to an increased cerebral blood flow fluctuation, neurohumoral activation, endothelial dysfunction, inflammation, and oxidative stress have been suggested to be the underlying mechanisms. However, clinical trials provide limited evidence for a protective effect of antihypertensive therapy against dementia and stroke-related cognitive decline. In this article, we aimed to review the existing evidence of the connection between BP variability and cognitive impairment in elderly people. PMID- 26587425 TI - Arterial Stiffness. AB - Stiffness of large arteries has been long recognized as a significant determinant of pulse pressure. However, it is only in recent decades, with the accumulation of longitudinal data from large and varied epidemiological studies of morbidity and mortality associated with cardiovascular disease, that it has emerged as an independent predictor of cardiovascular risk. This has generated substantial interest in investigations related to intrinsic causative and associated factors responsible for the alteration of mechanical properties of the arterial wall, with the aim to uncover specific pathways that could be interrogated to prevent or reverse arterial stiffening. Much has been written on the haemodynamic relevance of arterial stiffness in terms of the quantification of pulsatile relationships of blood pressure and flow in conduit arteries. Indeed, much of this early work regarded blood vessels as passive elastic conduits, with the endothelial layer considered as an inactive lining of the lumen and as an interface to flowing blood. However, recent advances in molecular biology and increased technological sophistication for the detection of low concentrations of biochemical compounds have elucidated the highly important regulatory role of the endothelial cell affecting vascular function. These techniques have enabled research into the interaction of the underlying passive mechanical properties of the arterial wall with the active cellular and molecular processes that regulate the local environment of the load-bearing components. This review addresses these emerging concepts. PMID- 26587427 TI - The Reality of Aging Viewed from the Arterial Wall: An Interview with Dr. Edward Lakatta, Founder and Director of the Laboratory of Cardiovascular Science, National Institute on Aging. AB - An exclusive interview conducted by Professors Jeong Bae Park and Sungha Park with Dr. Edward Lakatta in Seoul while he was visiting for the Pulse of Asia 2013 in Seoul. In this interview, Dr. Lakatta explains and describes vascular aging and aging. PMID- 26587428 TI - Role of Pulsatile Hemodynamics in Acute Heart Failure: Implications for Type 1 Cardiorenal Syndrome. AB - Heart failure has become a major health problem worldwide with a substantial financial burden mainly from hospitalization due to acute heart failure syndrome (AHFS). A considerable number of patients hospitalized for the treatment of AHFS experience significant worsening of renal function, which is now recognized as type 1 cardiorenal syndrome (CRS) and is associated with worse outcomes. Currently known risk factors for acute CRS in AHFS include obesity, cachexia, hypertension, diabetes, proteinuria, uremic solute retention, anemia, and repeated subclinical acute kidney injury events. Venous renal congestion due to hemodynamic changes also contributes to type 1 CRS. Vascular aging and its aggravated pulsatile hemodynamics have been shown to be involved in the pathogenesis of AHFS. Suboptimal recovery of the perturbation of the pulsatile hemodynamics may predict 6-month post-discharge cardiovascular outcomes in patients hospitalized due to AHFS. Furthermore, on-admission pulsatile hemodynamics may also be helpful to identify and stratify patients with aggravated pulsatile hemodynamics who may benefit from customized therapy. There are close interplays and feedback loops between heart and kidney dysfunction. Increased arterial stiffness accelerates pulse wave velocity and causes an earlier return of the reflected wave, resulting in higher systolic, lower diastolic, and higher pulse pressure in the central aorta and renal arteries. Increased pulsatile hemodynamics have been associated with deterioration of renal function in subjects with a high coronary risk and patients with hypertension or chronic kidney disease. Thus, there is a potential role of vascular aging/pulsatile hemodynamics in the pathophysiological pathways of acute CRS in AHFS. PMID- 26587430 TI - Image-Based Evaluation of Vascular Function and Hemodynamics. AB - The noticeable characteristics of the blood vascular structure are the inconsistent viscosity of blood and the stiffness of the vascular wall. If we can control these two factors, we can solve more problems related to hemodynamics and vascular wall function. Understanding the properties of hemodynamics and vascular wall function may provide more information applicable to clinical practice for cardiovascular disease. The bedside techniques evaluating vascular function usually measure indirect parameters. In contrast, some medical imaging techniques provide clear and direct depictions of functional cardiovascular characteristics. In this review, image-based evaluation of hemodynamic and vascular wall functions is discussed from the perspective of blood flow velocity, flow volume, flow pattern, peripheral vascular resistance, intraluminal pressure, vascular wall stress, and wall stiffness. PMID- 26587429 TI - Effects of Various Antihypertensive Drugs on Arterial Stiffness and Wave Reflections. AB - We reviewed trials that tested the efficacy of antihypertensive drugs in reducing arterial stiffness and wave reflections as assessed by pulse wave velocity and augmentation index, respectively. Regardless of cross-over or parallel-group comparison design, placebo-controlled trials demonstrated that antihypertensive drugs were effective in reducing pulse wave velocity. In actively-controlled parallel-group comparison studies, this effect on arterial stiffness was more evident for angiotensin-converting enzyme inhibitors or angiotensin receptor blockers than other classes of antihypertensive drugs, particularly when brachial ankle pulse wave velocity was measured. Regardless of cross-over or parallel group comparison or placebo- or actively-controlled design, the reviewed trials showed that beta-blockers were inferior to all the other classes of antihypertensive drugs in reducing augmentation index. However, these studies had a small sample size and a short follow-up time and did not link the changes in measurements of arterial function with cardiovascular events. Whether the superiority or inferiority is clinically relevant for cardiovascular protection and prevention remains to be investigated. PMID- 26587431 TI - Arterial Stiffness, Kidney Function, and Chronic Kidney Disease Progression. AB - Arterial stiffness can nowadays be measured easily and noninvasively around the globe. Although well established as an independent predictor of cardiovascular events, less is known about the role of arterial stiffness in the progressive loss of kidney function once chronic kidney disease (CKD) is established. In addition to measures of arterial stiffness, a number of devices now noninvasively record the pulse profile from sites such as the radial artery and, using internal algorithms, are able to estimate central pressure profiles. Although these devices have generated much data on the prediction of cardiovascular events, e.g. measures of arterial stiffness, there is much less known about the predictive utility of these measures in CKD progression. In this review, we cover approaches to arterial stiffness as measured by pulse wave velocity and discuss measures of the systolic and diastolic contour of the pulse waveform vis-a-vis their relationship to declines in kidney function over time. We restrict our coverage to studies that have longitudinal data, but we also include a table of studies, which, to our knowledge, have only published cross-sectional data at this time. PMID- 26587432 TI - Combination of Echocardiography and Pulse Wave Velocity Provides Clues for the Differentiation between White Coat Hypertension and Hypertension in Postmenopausal Women. AB - OBJECTIVE: To determine whether or not noninvasive assessment of the cardiovascular system can discriminate white coat hypertension and hypertension in postmenopausal women. The major reason is the high prevalence of white coat hypertension in these subjects and the uncertain associations of white coat hypertension with cardiovascular risk. PATIENTS AND METHODS: Selected women were required to be naturally or surgically menopausal for at least 1 year but not more than 5 years past their menstrual period. White coat hypertension patients were defined as subjects who had office blood pressures >150/90 mm Hg but who had both systolic and diastolic ambulatory pressures <120/80 mm Hg. In total, 44 subjects with a mean age of 52 years were recruited from the outpatient clinic and examined. Office and home blood pressures were measured using the HEM 401C (Omron Life Science Co. Ltd., Tokyo, Japan), a semi-automatic device that operates on the cuff-oscillometric principle and generates a digital display of the systolic (SBP) and diastolic blood pressure as well as the pulse rate. The pulse wave velocity (PWV) was recorded, and the left ventricular (LV) diameter, septal wall thickness, and left posterior wall thickness were assessed by M-mode echocardiography after selecting the measurement section by B-mode echocardiography. RESULTS: Twenty patients were diagnosed as having white coat hypertension based on the criteria in the trial. Pulse wave patterns were different between subjects with white coat hypertension and those with hypertension. PWV of subjects with white coat hypertension was 1.32 +/- 0.33 m/s and that of patients with hypertension was 1.46 +/- 0.37 m/s (p < 0.01). In addition to these findings, there was a significant association between the values of home SBP and PWV and the LV mass index. However, this association was not seen for office SBP. When the data of the LV mass index and PWV were combined, white coat hypertension could be easily differentiated from hypertension. CONCLUSIONS: The combination of blood pressure self-monitoring, echocardiographic data, and PWV can be a powerful indicator for the treatment of hypertension in postmenopausal women. PMID- 26587433 TI - Cardio-Ankle Vascular Index and Its Potential Clinical Implications for Sleep Apnea. AB - Sleep apnea is a prevalent disorder associated with an increased risk of cardiovascular disease (CVD). While arterial stiffness is a surrogate marker for the development of CVD, the cardio-ankle vascular index (CAVI) is a recently developed metric for evaluating arterial stiffness. Clinical studies have shown that the CAVI is higher in patients with the sleep apnea syndrome. In particular, a reduction in the CAVI can clearly be seen during short-term therapy for these patients. Although clinical evidence on sleep apnea using the CAVI is currently limited, the CAVI is expected to be useful for identifying patients with an increased risk of CVD and for monitoring treatment effectiveness in sleep apnea practice. PMID- 26587434 TI - Pulse Pressure Is Useful for Determining the Choice of Antihypertensive Drugs in Postmenopausal Women. AB - OBJECTIVE: To assess the efficacy of various classes of antihypertensive drugs in postmenopausal women with hypertension using pulse pressure (PP) as an index. PATIENTS AND METHODS: Selected women were required to be naturally menopausal for at least 1 year but not more than 5 years past their menstrual period. Exclusion criteria were a history of preeclampsia or eclampsia, a severe illness such as myocardial infarction or stroke within 6 months, the use of estrogens or progestins within 3 months, proteinuric nephropathy, and surgically induced menopause. There were 114 women who participated in this study after having given informed consent. These women were diagnosed as having hypertension based on an office blood pressure >140/90 mm Hg as well as a self-measured blood pressure at home >130/85 mm Hg. If both levels of blood pressure were not fulfilled, the patients were excluded. All antihypertensive medications were withdrawn 6 weeks before the initiation of the study. The patients were randomly assigned in equal numbers to the following groups: (1) combination therapy with losartan (angiotensin receptor blocker) 50 mg daily + trichlormethiazide (diuretic) 2 mg twice a week, and (2) combination therapy with cilnidipine (calcium channel blocker) 5 mg + arotinolol (alphabeta-blocker) 10 mg daily. RESULTS: The patients were retrospectively divided into three groups according to their PP at the start of the study: Group I (n = 24), >65 mm Hg; Group II (n = 58), 65-45 mm Hg, and Group III (n = 32), <45 mm Hg. In Group I, combination therapy with cilnidipine + arotinolol resulted in a greater reduction in the systolic blood pressure than the combination therapy with losartan + trichlormethiazide (from 169/88 +/- 2/5 to 133/73 +/- 2/5 mm Hg vs. from 169/88 +/- 2/5 to 149/66 +/- 2/5 mm Hg, p < 0.05). On the other hand, in Group III, losartan + trichlormethiazide decreased diastolic as well as systolic blood pressures (from 152/106 +/- 2/2 to 123/78 +/- 1/1 mm Hg vs. from 149/107 +/- 2/2 to 129/84 +/- 2/1 mm Hg, p < 0.05). In Group II, there were no differences between the two antihypertensive regimens. Laboratory findings were not influenced by any type of treatment. CONCLUSIONS: PP measurement before starting medication for hypertension may be useful for determining the choice of antihypertensive drugs. PMID- 26587436 TI - The Efficacy of Fimasartan for Cardiovascular Events and Metabolic Syndrome (K MetS Study): Rationale, Design and Participant Characteristics. AB - Fimasartan, the eighth angiotensin receptor blocker, was launched in March 2011 and was found to have an excellent efficacy and safety profile in a large cross sectional population study [Safety and Efficacy of Fimasartan in Patients with Arterial Hypertension (Safe-KanArb); Park et al.: Am J Cardiovasc Drugs 2013;13:47-56]. However, there is no long-term study to evaluate its efficacy for major adverse cardiovascular events (MACE) and other effects. The purpose of this study (K-MetS study) was to evaluate whether the early reduction of blood pressure (BP) and/or correction of metabolic derangements with fimasartan will affect MACE and the development of diabetes after long-term use in patients with hypertension. A total of 10,734 patients were screened between October 2011 and October 2012. Of these, 10,601 patients from 582 private clinics and 11 university hospitals were enrolled and are currently treated with fimasartan. The primary endpoints are MACE (cardiovascular mortality, stroke, myocardial infarction, and hospitalization for heart failure) and the development of diabetes after 3 years of follow-up. In addition to BP monitoring in the clinic, home BP monitoring is performed in about two thirds of patients. The patients were 56.2 +/- 10.9 years old (mean +/- SD), with 48.4% being women. The mean clinic and home systolic/diastolic BP at baseline were 145.0 +/- 17.0/88.8 +/- 11.4 and 138.6 +/- 14.8/82.6 +/- 9.9 mm Hg, respectively. The metabolic syndrome was found in 56.4%, increased abdominal circumference in 52.8%, elevated fasting glucose in 46.8%, hypertriglyceridemia in 44.7%, and low high-density lipoprotein cholesterol in 33.3% of patients. Further, complicated hypertension with diabetes occurred in 15.1%, ischemic heart disease in 3.3%, stroke in 0.9%, heart failure in 0.7%, and atrial fibrillation in 0.4% of patients. Most participants in this study had a low-to-moderate risk for hypertension. The K-MetS study is expected to provide valuable information about the effects of early BP control and correction of metabolic abnormalities on future cardiovascular outcomes relative to low-risk hypertension. PMID- 26587437 TI - Editorial. PMID- 26587435 TI - Exercise Hypertension. AB - Irrespective of apparent 'normal' resting blood pressure (BP), some individuals may experience an excessive elevation in BP with exercise (i.e. systolic BP >=210 mm Hg in men or >=190 mm Hg in women or diastolic BP >=110 mm Hg in men or women), a condition termed exercise hypertension or a 'hypertensive response to exercise' (HRE). An HRE is a relatively common condition that is identified during standard exercise stress testing; however, due to a lack of information with respect to the clinical ramifications of an HRE, little value is usually placed on such a finding. In this review, we discuss both the clinical importance and underlying physiological contributors of exercise hypertension. Indeed, an HRE is associated with an increased propensity for target organ damage and also predicts the future development of hypertension, cardiovascular events and mortality, independent of resting BP. Moreover, recent work has highlighted that some of the elevated cardiovascular risks associated with an HRE may be related to high-normal resting BP (pre-hypertension) or ambulatory 'masked' hypertension and that an HRE may be an early warning signal of abnormal BP control that is otherwise undetected with clinic BP. Whilst an HRE may be amenable to treatment via pharmacological and lifestyle interventions, the exact physiological mechanism of an HRE remains elusive, but it is likely a manifestation of multiple factors including large artery stiffness, increased peripheral resistance, neural circulatory control and metabolic irregularity. Future research focus may be directed towards determining threshold values to denote the increased risk associated with an HRE and further resolution of the underlying physiological factors involved in the pathogenesis of an HRE. PMID- 26587438 TI - Role of Pulse Wave Velocity in Patients with Chronic Kidney Disease Stages 3-5 on Long-Term Follow-Up. AB - BACKGROUND: The relationship between arterial stiffness and kidney function has not been clearly demonstrated although observations of higher arterial stiffness in patients with advanced stages of chronic kidney disease (CKD) were reported. In longitudinal analyses, there was no close association between basal arterial stiffness and progression of kidney function in the general population. In the present study, we assessed the relationship between arterial stiffness and progression of renal dysfunction in patients with CKD stages 3-5 using two types of measures of arterial stiffness, i.e., carotid-femoral pulse wave velocity (cfPWV) and brachial-ankle pulse wave velocity (baPWV), over a 10-year period. METHODS: 110 patients with CKD stages 3-5 (aged 57.8 +/- 10.6 years; female/male: 72/38) were followed for 10 years. Before and at the end of the 10-year period, cfPWV and baPWV were measured using form PWV/ABI (Omron Colin Co. Ltd.). RESULTS: Throughout the study, systolic blood pressure was well-controlled in all patients. Twenty-nine patients (26%) received renal replacement therapy, 12 patients (11%) developed cardiovascular diseases (CVDs), 5 patients were found to have neoplasm, and 9 patients dropped out of the study during the 10-year observation period. In patients who developed end-stage renal disease, the baseline estimated glomerular filtration rate (eGFR) was significantly lower, and in patients who developed CVD, the basal value of baPWV was significantly higher (p < 0.05). Throughout the study, blood pressures were controlled (136.1/77.0 +/- 15.6/7.1 to 137.5/77.6 +/- 14.9/11.2), kidney function worsened (eGFR, 30.8 +/- 16.5 to 22.9 +/- 17.6 ml/min/1.73 m(2); p < 0.01), and baPWV but not cfPWV showed a significant change [1, 672.2 +/- 209.6 vs. 1,753.1 +/- 333.2 cm/s (p = 0.04) and 918.9 +/- 153.2 vs. 939.4 +/- 133.2 cm/s]. Moreover, the difference in PWV between the start and the end of the 10-year observation period was positively correlated with the difference in eGFR. CONCLUSION: With moderate progression of renal dysfunction and under well-controlled blood pressure, peripheral but not central arterial stiffness is possibly one of the strongest predictors of CVD in patients with CKD stages 3-5. PMID- 26587439 TI - Gender Difference in Arterial Stiffness in a Multicenter Cross-Sectional Study: The Korean Arterial Aging Study (KAAS). AB - Elevated arterial stiffness has emerged as an important risk factor for future cardiovascular (CV) events in men and women. However, gender-related differences in arterial stiffness have not been clearly demonstrated. We thus determine whether gender affects arterial stiffness in subjects with and without CV risk factors. We consecutively enrolled 1,588 subjects aged 17-87 years (mean age: 46.5; 51% women) from the Korean Arterial Aging Study (KAAS), which is a multicenter registry from 13 university hospitals in Korea for the evaluation of arterial stiffness. We compared markers of arterial stiffness - central augmentation index (AIx), aortic pulse wave velocity (PWV), and pulse pressure (PP) amplification - in apparently healthy men and women without risk factors with those in high-risk subjects with a smoking habit, hypertension, diabetes, and dyslipidemia but without drug treatment. Aortic PWV and PP amplification were significantly higher in men than in women (7.78 +/- 1.16 vs. 7.64 +/- 1.15 m/s, p = 0.015, and 1.39 +/- 0.22 vs. 1.30 +/- 0.18, p < 0.001, respectively). However, women had a significantly higher central AIx than men (23.5 +/- 11.9 vs. 16.1 +/- 12.6%, p < 0.001). The central AIx and aortic PWV values were significantly higher in the high-risk group than in the healthy group for both men and women. In men, central AIx and aortic PWV were associated positively with age and blood pressure, and negatively with body mass index. In women, central AIx was positively related to age, diastolic blood pressure, and serum cholesterol levels. Aortic PWV was positively related to age, systolic blood pressure, fasting glucose, and heart rate. PP amplification was associated negatively with age and blood pressure and positively with heart rate in both men and women. In conclusion, arterial stiffness is mainly determined by sex, age, and blood pressure. Markers of arterial stiffness differ between men and women. Dyslipidemia and glucose contribute to a modest increase in arterial stiffness only in women. Therefore, the arteries of women may be more vulnerable to CV risk factors than those of men. PMID- 26587440 TI - Common Carotid Artery Stiffness Is Associated with Left Ventricular Structure and Function and Predicts First Hospitalization for Acute Heart Failure. AB - AIMS: Proximal aortic stiffness may be more important than carotid-femoral pulse wave velocity (cf-PWV) in the pathogenesis of heart failure. The present study investigated the associations of common carotid artery (CCA) stiffness, which might be a surrogate for proximal aortic stiffness, with left ventricular (LV) structure and function, and the development of acute heart failure (AHF). METHODS AND RESULTS: Outpatients without a history of heart failure (114 subjects aged 63.5 +/- 17.5 years) were enrolled for comprehensive noninvasive cardiovascular examinations. The LV mass index, the LV ejection fraction (EF), and the ratio of the early diastolic transmitral flow velocity to the early septal mitral annular diastolic velocity (E/E') were measured by echocardiography. CCA mechanical properties, including the incremental elastic modulus (Einc), beta stiffness index, CCA distensibility (CD) and circumferential strain (CS), were assessed by carotid artery ultrasonography. cf-PWV was measured by arterial tonometry. CD was significantly associated with the LV mass index, and all CCA stiffness indices were significantly associated with EF and E/E' independently of age, mean blood pressure, and cf-PWV. During a mean follow-up of 265 +/- 106 days, 9 patients presented with AHF. Einc (hazard ratio 6.56, 95% confidence interval 1.64-26.26, by quartile analysis), CS (6.82, 1.70-27.35), and beta stiffness index (3.91, 1.05-14.57) but not cf-PWV (1.62, 0.41-6.51) significantly predicted the events. CONCLUSIONS: In patients at risk for heart failure, CCA stiffness was significantly associated with LV structure and function independently of cf-PWV. In addition, CCA stiffness but not cf-PWV predicted first AHF. PMID- 26587441 TI - Decline of Renal Function and Progression of Left Ventricular Hypertrophy Are Independently Determined in Chronic Kidney Disease Stages 3-5. AB - Invasive and noninvasive methods for evaluating the effects of hemodynamics on progression of left ventricular hypertrophy (LVH) in patients with chronic kidney disease (CKD) have been proposed. Central aortic pressure (CAP) has been reported to be the best among selected measures of hemodynamics for predicting LVH. However, there are few studies examining the relation between longitudinal changes in CAP and renal dysfunction in patients with CKD. METHODS: Sixty-seven patients with CKD stages 3-5 (female/male ratio: 26/41, age: 61.5 +/- 13.1 years) were followed for 5 years. Before and at the end of the 5-year period, CAP was recorded by an automated tonometric system (HEM-9000 AI; Omron Healthcare, Kyoto, Japan). Second systolic aortic blood pressure (SBP2) was employed as an index of CAP. RESULTS: Throughout the study, systolic blood pressure (SBP) was well controlled. Renal function followed by estimated glomerular filtration rate (eGFR) gradually worsened as a whole. Ten patients had renal replacement therapy, 3 patients developed cardiovascular diseases and 2 patients were found to have a neoplasm during the 5-year observation period. SBP2 increased from 120 +/- 19 to 125 +/- 33 mm Hg and eGFR decreased from 38.2 +/- 18.2 to 29.5 +/- 16.3 ml/min/1.73 m(2); however, these differences did not achieve significance. The left ventricular mass (LVM) index significantly increased from 115.5 +/- 10.5 to 131.2 +/- 11.7 g/m(2) (p < 0.05). Although the changes in SBP2 and eGFR looked like a mirror image, there was no significant correlation between the two factors. Moreover, multivariate regression analysis did not reveal a close correlation between SBP2 and CKD progression. In contrast to the decline of renal function, the baseline value of SBP2 predicted an increase in the LVM index. CONCLUSION: Worsening of renal dysfunction is not solely dependent on hemodynamics. Other factors might be involved in a complex manner. PMID- 26587442 TI - Hypertensive Vasculopathy: An Exclusive Interview with Dr. Rhian M. Touyz, President of the International Society of Hypertension. AB - An exclusive interview by Prof. Jeong Bae Park conducted with Dr. Rhian M. Touyz in Seoul while she was visiting for the Korean Society of Hypertension, May 10, 2014. In this interview, Dr. Touyz explains and describes hypertensive vasculopathy. PMID- 26587443 TI - Risk Associated with Pulse Pressure on Out-of-Office Blood Pressure Measurement. AB - BACKGROUND: Longitudinal studies have demonstrated that the risk of cardiovascular disease increases with pulse pressure (PP). However, PP remains an elusive cardiovascular risk factor with findings being inconsistent between studies. The 2013 ESH/ESC guideline proposed that PP is useful in stratification and suggested a threshold of 60 mm Hg, which is 10 mm Hg higher compared to that in the 2007 guideline; however, no justification for this increase was provided. METHODOLOGY: Published thresholds of PP are based on office blood pressure measurement and often on arbitrary categorical analyses. In the International Database on Ambulatory blood pressure in relation to Cardiovascular Outcomes (IDACO) and the International Database on HOme blood pressure in relation to Cardiovascular Outcome (IDHOCO), we determined outcome-driven thresholds for PP based on ambulatory or home blood pressure measurement, respectively. RESULTS: The main findings were that for people aged <60 years, PP did not refine risk stratification, whereas in older people the thresholds were 64 and 76 mm Hg for the ambulatory and home PP, respectively. However, PP provided little added predictive value over and beyond classical risk factors. PMID- 26587444 TI - Noninvasive and Invasive Assessments of the Functional Significance of Intermediate Coronary Artery Stenosis: Is This a Matter of Right or Wrong? AB - Coronary computed tomographic angiography (cCTA) has emerged in recent years as a noninvasive modality to evaluate coronary artery disease. Many studies have revealed the excellent diagnostic accuracy of cCTA when compared with invasive coronary angiography (ICA) or intravascular ultrasound (IVUS). It is generally accepted that the functional significance of coronary artery stenosis is important to make treatment decisions; however, cCTA, ICA, and IVUS are limited in the ability to determine the physiologic significance of coronary stenosis. The FIGURE-OUT study compared the noninvasive and invasive assessment of the functional significance of intermediate coronary artery stenosis. PMID- 26587445 TI - Pulsatile and Steady-State Pressure Trends in Children: A Window into the Future? AB - The aorta has limited ability to accommodate increasing body size by remodeling. The dramatic rise in pediatric obesity threatens to overwhelm this intrinsic remodeling program and lead to abnormal aortic function. As hypothesized, pulse pressure, as an index of aortic function, has indeed risen dramatically in parallel with the rise of pediatric obesity, while at the same time mean arterial pressure, as an index of small resistance artery function, has fallen. These divergent large-artery-versus-small-artery indices may combine to explain the counterintuitive decrease in systolic blood pressure in children and adults during the global obesity pandemic. The pathophysiologic mechanisms underpinning these contrasting trends are not yet known. PMID- 26587446 TI - Pulsatile and Steady-State Pressure Trends in Children: Is the Future Now?: Comment on the Paper by Zachariah and Kovacikova [Pulse 2014;2:57-62]. PMID- 26587448 TI - Clinical Considerations for the Association between Vascular Damage and Chronic Kidney Disease. AB - Chronic kidney disease (CKD) is an independent risk factor for cardiovascular disease. Recently, noninvasive and simple morphological and functional methods have been introduced to assess atherosclerotic vascular damage. This review describes the association of CKD with vascular damage as assessed by these methods. Carotid intima-media thickness (IMT) and coronary artery calcium score (CACS) are morphological parameters of vascular damage, and an ankle-brachial index (ABI) <0.90 suggests the presence of peripheral arterial disease (i.e., it represents advanced atherosclerosis). Several prospective studies have demonstrated that CKD is a risk factor for an increased IMT, an increased CACS and a decreased ABI. While it has not been clarified whether measuring the IMT or CACS might be useful to predict the progression of renal function decline, a reduced ABI has been demonstrated as a predictor of accelerated renal function decline. On the other hand, pulse wave velocity (PWV) is a marker of arterial stiffness rather than atherosclerosis, reflecting functional abnormalities caused by vascular damage, and moderate-to-severe CKD may be a risk factor for the progression of arterial stiffness. The measurement of functional markers, especially of PWV or pulse pressure, has been demonstrated to be useful to predict the rate of progression of renal function decline. Thus, renal dysfunction and atherogenic states may be components of a vicious cycle, and vascular function abnormalities associated with atherosclerosis may accelerate this cycle. As the next step, we propose to examine whether improvement of vascular function abnormalities can interrupt this vicious cycle. PMID- 26587447 TI - Arterial Stiffness in Children: Pediatric Measurement and Considerations. AB - BACKGROUND: Arterial stiffness is a natural consequence of aging, accelerated in certain chronic conditions, and predictive of cardiovascular events in adults. Emerging research suggests the importance of arterial stiffness in pediatric populations. METHODS: There are different indices of arterial stiffness. The present manuscript focuses on carotid-femoral pulse wave velocity and pulse wave analysis, although other methodologies are discussed. Also reviewed are specific measurement considerations for pediatric populations and the literature describing arterial stiffness in children with certain chronic conditions (primary hypertension, obesity, diabetes, chronic kidney disease, hypercholesterolemia, genetic syndromes involving vasculopathy, and solid organ transplant recipients). CONCLUSIONS: The measurement of arterial stiffness in children is feasible and, under controlled conditions, can give accurate information about the underlying state of the arteries. This potentially adds valuable information about the functionality of the cardiovascular system in children with a variety of chronic diseases well beyond that of the brachial artery blood pressure. PMID- 26587449 TI - Lifestyle Factors and Coronary Artery Calcification. AB - The effective prevention of cardiovascular disease (CVD) remains a global health challenge. Adopting a combined primary (prevention of the first episode of coronary heart disease or stroke) and primordial (prevention of the causal risk factors of CVD) prevention strategy is the best approach to prevent CVD. Most importantly, the primordial prevention strategy should in the first place be to promote cardiovascular health across individual and population levels by improving the underlying causal risk factors for CVD (i.e., unhealthy diets, physical inactivity, obesity, and cigarette smoking). Epidemiological evidence indicates that maintaining favorable underlying risk factors (lifestyle factors) is associated with a lower risk of incident CVD. Prevention of early atherosclerotic vascular disease is also an important strategy to prevent CVD. However, there has been limited research on the association between lifestyle factors and early atherosclerotic vascular disease (i.e., coronary or carotid atherosclerosis) across race and gender groups in population-based studies. This article briefly reviews whether lifestyle factors relate to subclinical atherosclerosis as assessed by coronary artery calcification in asymptomatic individuals. PMID- 26587451 TI - Hypertension Guidelines: Timely New Initiatives from East Asia. PMID- 26587450 TI - Lung Disease and Hypertension. AB - Chronic obstructive pulmonary disease (COPD) patients are at a high risk of developing cardiovascular diseases. Airflow limitation is a predictor of future risks of hypertension and cardiovascular events. COPD is now understood as a systemic inflammatory disease, with the focus on inflammation of the lungs. An association between inflammation and sympathetic overactivity has also been reported. In this article, we review the association between chronic lung disease and the risks of hypertension, cardiovascular morbidity, the underlying mechanisms, and the therapeutic approach to hypertension and cardiovascular diseases in patients with lung diseases. PMID- 26587452 TI - The Ten-Year History of the Asklepios Study: An Interview with Professor Ernst R. Rietzschel, Primary Investigator and Leader of the Asklepios Study. AB - The Asklepios study started 10 years ago when 2,500 subjects were screened between 2002 and 2004. And all of the 90+ publications we have for the moment are from those cross-sectional data. This is called round 1. Since 2011, in round 2, all of those patients have started to come back for a 10-year follow-up. At this moment, approximately 1,750 of those patients have been seen. The patients were followed by general practitioners (GP), and the GP again provided the information about what has happened with the medical status in the past 10 years including drug therapy: not only the drugs that they are taking at the moment were evaluated, but, because patients often use many drugs, the chronicles of drugs for major risk factors, for hypertension, lipids, contraceptives and more. Then, patients come to the study center where the same cluster of examinations are undertaken by one single doctor, Prof. Ernst R. Rietzschel and one study nurse, just like 10 years ago. Again, using a single observer at the two time frames has kept the methodology very strict. PMID- 26587453 TI - Chinese Hypertension Guidelines. AB - According to the 4th National Nutrition and Health Survey in 2002, the prevalence of hypertension in China was 18.8%. Although there are no recent updated nationwide data, it is believed that the prevalence of hypertension has increased substantially in the past decade up to more than 200 million hypertensive patients in the populous country of China. To fight against the growing risk of hypertension, three Chinese hypertension guidelines were compiled in the past two decades, in 1999, 2005, and 2011. The current guidance document for the management of hypertension was named '2010 Chinese hypertension guideline', but it was actually published in 2011. In this guideline, all five classes of antihypertensive drugs were recommended as possible initial and maintenance therapy. The goal of treatment was a systolic/diastolic blood pressure below 140/90 mm Hg in general, 130/80 mm Hg in various groups of high-risk patients, and 150/90 mm Hg in the elderly (>=65 years). With the recent publication of several national and international hypertension guidelines, the Chinese guideline is now under discussion for updating. PMID- 26587454 TI - The Korean Society of Hypertension Guidelines for the Management of Hypertension in 2013: Its Essentials and Key Points. AB - The Korean Society of Hypertension published new guidelines for the management of hypertension in 2013 which fully revised the first Korean hypertension treatment guideline published in 2004. Due to shortage of Korean data, the Committee decided to establish the guideline in the form of an 'adaptation' of the recently released guidelines. The prevalence of hypertension was 28.5% in the recent Korean National Health and Nutrition Examination Survey in 2011, and the awareness, treatment, and control rates are generally improving. However, the risks for cerebrovascular disease and coronary artery disease which are attributable to hypertension were the highest in Korea. The classification of hypertension is the same as in other guidelines. The remarkable difference is that prehypertension is further classified as stage 1 and 2 prehypertension because the cardiovascular risk is significantly different within the prehypertensive range. Although the decision-making was based on office blood pressure (BP) measured by the auscultation method using a stethoscope, the importance of home BP measurement and ambulatory BP monitoring is also stressed. The Korean guideline does not recommend a drug therapy in patients within the prehypertensive range, even in patients with prediabetes, diabetes mellitus, stroke, or coronary artery disease. In an elderly population over 65 years old, drug therapy can be initiated when the systolic BP (SBP) is >=160 mm Hg. The target BP is generally an SBP of <140 mm Hg and a diastolic BP (DBP) of <90 mm Hg regardless of previous cardiovascular events. However, in patients with hypertension and diabetes, the lower DBP control <85 mm Hg is recommended. Also, in patients with hypertension with prominent albuminuria, a more strict SBP control <130 mm Hg can be recommended. In lifestyle modification, sodium reduction is the most important factor in Korea. Five classes of antihypertensive drugs, including angiotensin-converting enzyme inhibitors, beta-blockers, calcium antagonists, and diuretics, are equally recommended as a first-line treatment, whereas a combination therapy chosen from renin-angiotensin system inhibitors, calcium antagonists, and diuretics is preferentially recommended. PMID- 26587455 TI - The Novelty of the 2015 Guidelines of the Taiwan Society of Cardiology and the Taiwan Hypertension Society for the Management of Hypertension. AB - The prevalence rate of hypertension in Asian countries grows faster than in other parts of the world, where stroke exceeds coronary heart disease in causing morbidities and mortalities. The optimal management of hypertension is therefore an especially important task in Asia. In a transparent and rigorous guideline development process, the most updated information available on the management of hypertension was summarized in the 2015 Taiwan Society of Cardiology (TSOC)/Taiwan Hypertension Society (TSH) hypertension guideline. In contradiction with the ESH/ESH joint hypertension guidelines and the 2014 Joint National Committee (JNC) report, this updated guideline suggests some different blood pressure (BP) targets. In brief, the BP target is 150/90 mm Hg for very elderly patients (>= 80 years), 130/80 mm Hg for patients with diabetes, coronary heart disease, proteinuric chronic kidney disease or those receiving antithrombotics for stroke prevention, and 140/90 mm Hg for all the other hypertension patients with or without the aforementioned comorbidities. To facilitate the adherence to the guideline, the following was proposed: mnemonics for lifestyle modifications: S-ABCDE (Sodium restriction, Alcohol limitation, Body weight reduction, Cigarette smoking cessation, Diet adaptation, and Exercise adoption), treatment algorithm: PROCEED (Previous experience, Risk factors, Organ damage, Contraindications or unfavorable conditions, Expert's or doctor's judgment, Expenses or cost, and Delivery and compliance issue), and medication adjustment algorithm: AT GOALs (Adherence, Timing of administration, Greater doses, Other classes of drugs, Alternative combination or single-pill combination, and Lifestyle modification + Laboratory tests). In particular, the effort of translating the concept of central BP into clinical practice may stand out from all other hypertension guidelines. In summary, our guidelines may deliver useful information and guidance to clinicians in managing hypertensive patients, including the approach to a more accurate diagnosis, treatment and adjustment algorithm, and evidence based recommendations. PMID- 26587456 TI - Key Points of the Japanese Society of Hypertension Guidelines for the Management of Hypertension in 2014. AB - The Japanese Society of Hypertension (JSH) published the new JSH guidelines for the management of hypertension in 2014, which is the revision of the JSH guidelines of 2009. The primary objective of the guideline is to provide physicians the standard treatment strategy of hypertension to prevent the hypertension-related target organ damage and cardiovascular events. The management of hypertension should be performed in hypertensive patients with a blood pressure of >=140/90 mm Hg. As Asians have a higher prevalence of stroke than of coronary artery disease and stroke is more steeply associated with the level of blood pressure, the target blood pressure should be lower than 130/80 mm Hg for high-risk patients such as those with diabetes or chronic kidney disease. Because of the increasing prevalence of obesity and the related metabolic syndrome, more salt intake and higher salt sensitivity in the population, lifestyle modifications are necessary in hypertensive patients and subjects with high normal blood pressure. This guideline provides evidence-based recommendations for the management of patients with hypertension with the characteristics of our society. PMID- 26587457 TI - Arterial Stiffening and Clinical Outcomes in Dialysis Patients. AB - Cardiovascular disease (CVD) is an important cause of morbidity and mortality in dialysis patients. Brachial-ankle pulse wave velocity (baPWV) is more efficient to handily assess arteriosclerosis than aortic PWV. The cardio-ankle vascular index (CAVI) is also a novel blood pressure-independent arterial stiffness parameter. In dialysis patients, both baPWV and CAVI are increased compared to general subjects. Several studies have demonstrated that increased baPWV is associated with carotid atherosclerosis and diastolic left ventricular dysfunction in hemodialysis (HD) patients. In addition, higher baPWV is related to all-cause and cardiovascular (CV) mortality. CAVI is similarly associated with CVD. However, baPWV is superior to CAVI as a predictor of CV outcomes in HD patients. Besides these outcomes, a close relationship exists between sarcopenia, abdominal visceral obesity and arterial stiffening. Reduction of thigh muscle mass is inversely correlated with baPWV and CAVI in males. Abdominal fatness is also associated with increased arterial stiffness in females. These observations provide further evidence of higher risk of CV events in HD patients with sarcopenic obesity. In addition, arterial stiffness is associated with cerebral small vessel disease and decreased cognitive function in the elderly. However, it is unknown whether arterial stiffness may be useful as an early indicator of cognitive decline in dialysis patients. Because dialysis patients are at risk of developing dementia, more studies are needed to elucidate the causal link between arterial stiffness and cognitive impairment. PMID- 26587458 TI - Prognostic Significance of Regional Arterial Stiffness for Stroke in Hypertension. AB - BACKGROUND: Hypertension is strongly associated with cardiovascular disease. It has been reported that arterial stiffness is related to cardiovascular mortality and morbidity in hypertensive patients and that the physiological evaluation of arterial stiffness may assist clinicians in the early detection of atherosclerosis. SUMMARY: It has been demonstrated that increased arterial stiffness is an independent predictor of cardiovascular disease, including stroke. Arterial stiffness is associated with structural changes in the brain. However, the stiffness responses of muscular arteries are different from those of elastic arteries, and so the impact of arterial stiffness and the conclusions to be drawn may be different depending on the region in which the measurement is taken. KEY MESSAGES: In this review, we summarize the current literature describing the association between arterial stiffness, including carotid-femoral and brachial-ankle pulse wave velocity and cardio-ankle vascular index, and cardiovascular disease, specifically stroke. We discuss the utility and prognostic significance of regional arterial stiffness measurements. PMID- 26587459 TI - Brachial-Ankle Pulse Wave Velocity: Myths, Misconceptions, and Realities. AB - A variety of techniques to evaluate central arterial stiffness have been developed and introduced. None of these techniques, however, have been implemented widely in regular clinical settings, except for brachial-ankle pulse wave velocity (baPWV). The most prominent procedural advantage of baPWV is its ease of use, since it only requires the wrapping of blood pressure cuffs on the 4 extremities. There is mounting evidence indicating the ability of baPWV to predict the risk of future cardiovascular events and total mortality. Additionally, the guidelines for the management of hypertension in Japan recommended the measurement of baPWV be included in the assessment of subclinical target organ damage. However, baPWV has not been fully accepted worldwide due to perceived theoretical and methodological issues. In this review, we address the most frequently mentioned questions and concerns regarding baPWV to shed some light on this simple and easy arterial stiffness measurement. PMID- 26587460 TI - Cardiopulmonary Exercise Test in Patients with Hypertension: Focused on Hypertensive Response to Exercise. AB - The cardiopulmonary exercise test (CPET) provides integrative exercise responses including the cardiovascular, pulmonary and skeletal muscle systems. It can be used for the identification of myocardial ischemia, evaluation of exercise capacity and tolerance, and the assessment of chronotropic competence or arrhythmias with the addition of ventilatory and gas exchange measurement information. Among them, hypertensive response to exercise (HRE) is known to be related with higher risk of future heart failure and cardiovascular events in patients with hypertension. Proposed underlying mechanisms of HRE can be found in ventricular-vascular uncoupling including decreased aortic distensibility, increased left ventricular mass, endothelial dysfunction, and diastolic dysfunction. The CPET might be useful in the identification of masked hypertension and the assessment of antihypertensive treatment efficacy in patients with hypertension. PMID- 26587461 TI - The Role of Monitoring Arterial Stiffness with Cardio-Ankle Vascular Index in the Control of Lifestyle-Related Diseases. AB - Arteriosclerosis is a major contributor to cardiovascular diseases. One of the difficulties in controlling those diseases is the lack of a suitable indicator of arteriosclerosis or arterial injury in routine clinical practice. Arterial stiffness was supposed to be one of the monitoring indexes of arteriosclerosis. Cardio-ankle vascular index (CAVI) is reflecting the stiffness of the arterial tree from the origin of the aorta to the ankle, and one of the features of CAVI is independency from blood pressure at a measuring time. When doxazosin, an alpha1-adrenergic blocker, was administered, CAVI decreased, indicating that arterial stiffness is composed of both organic stiffness and functional stiffness, which reflects the contraction of arterial smooth muscle. CAVI shows a high value with aging and in many arteriosclerotic diseases, and is also high in persons possessing main coronary risk factors such as diabetes mellitus, metabolic syndrome, hypertension and smoking. Furthermore, when the most of those risk factors were controlled by proper methods, CAVI improved. Furthermore, the co-relationship between CAVI and heart function was demonstrated during treatment of heart failure. This paper reviews the principle and rationale of CAVI, and discusses the meaning of monitoring CAVI in following up so-called lifestyle related diseases and cardiac dysfunction in routine clinical practice. PMID- 26587462 TI - Weight Loss, Dietary Intake and Pulse Wave Velocity. AB - We have recently conducted a meta-analysis to determine the effect of weight loss achieved by an energy-restricted diet with or without exercise, anti-obesity drugs or bariatric surgery on pulse wave velocity (PWV) measured at all arterial segments. Twenty studies, including 1,259 participants, showed that modest weight loss (8% of the initial body weight) caused a reduction in PWV measured at all arterial segments. However, due to the poor methodological design of the included studies, the results of this meta-analysis can only be regarded as hypothesis generating and highlight the need for further research in this area. In the future, well-designed randomised controlled trials are required to determine the effect of diet-induced weight loss on PWV and the mechanisms involved. In addition, there is observational evidence that dietary components such as fruit, vegetables, dairy foods, sodium, potassium and fatty acids may be associated with PWV, although evidence from well-designed intervention trials is lacking. In the future, the effect of concurrently improving dietary quality and achieving weight loss should be assessed in randomised controlled trials. PMID- 26587463 TI - Vasculopathy of Aging and the Revised Cardiovascular Continuum. AB - There have been attempts to explain the process of developments in overt cardiovascular disease, resulting in the presentation of the classic cardiovascular disease continuum and the aging cardiovascular continuum. Although the starting points of these two continua are different, they meet in the midstream of the cycle and reach a consensus at the end of the process. The announcement of the aging cardiovascular continuum made both continua complete, explaining the cardiovascular events in patients without atherosclerotic cardiovascular disease with aging. Impairment of the vascular structure by pulse wave and reflected wave is considered the cause of aortic damage, which influences the development of ischemic heart disease and the development of overt renal disease or cerebrovascular disease. The pathophysiology of vascular aging through pulse wave and its effect on other organs was discussed with Prof. Michael F. O'Rourke who devised the aging cardiovascular continuum. PMID- 26587464 TI - Lipoprotein(a) and Arterial Stiffness Parameters. AB - BACKGROUND: Circulating lipoprotein(a) [Lp(a)] and arterial stiffness are markers associated with the atherosclerotic processes. With regard to cardiovascular outcomes, the relationship between Lp(a) and arterial stiffness has not been sufficiently summarized. The present review focuses on the existing association between Lp(a) and arterial stiffness parameters. SUMMARY: This review included human clinical studies that were published between 1980 and 2015. The metrics of arterial stiffness parameters, 'pulse wave velocity' (PWV) and 'cardio-ankle vascular index' (CAVI), were used for this search, which yielded only 4 cross sectional studies on this topic. Of these 4 studies, 3 reports were based on the use of PWV, while 1 study was based on the use of CAVI. Three studies (including the study using CAVI) reported that high Lp(a) levels were positively associated with arterial stiffness. CONCLUSION: The present review indicates a positive association between Lp(a) and arterial stiffness, as assessed by PWV and CAVI. To definitively establish these findings, there is a need for further prospective outcome studies that simultaneously measure Lp(a) and the oxidative form of Lp(a) (as a pathological marker) as well as PWV and CAVI. PMID- 26587465 TI - Model for Predicting Cardiovascular Disease: Insights from a Korean Cardiovascular Risk Model. AB - The profile and prevalence of risk factors in cardiovascular disease (CVD) are different between Western and Asian populations. In the guidelines, tailored approaches following risk stratification based on CVD risk models are recommended for the primary prevention of CVD in asymptomatic subjects. However, current risk models for predicting CVD in Asian populations are limited. A recent study of a large cohort of asymptomatic Korean individuals developed a CVD risk model to predict global cardiovascular risk that showed good performance in predicting cardiovascular events. This model may be useful for the primary prevention of CVD in East Asian individuals as well as Koreans. PMID- 26587466 TI - Violence as a Threatening Factor to Public Health. PMID- 26587467 TI - Prevalence and Risk Factors of Gestational Diabetes in Iran: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Gestational Diabetes (GD) is one of the major public health issues. The purpose of the present study was to perform a systematic review and meta analysis to assess the risk factors and prevalence rate of this disorder in Iran. METHODS: This systematic review and meta- analysis article was prepared using the databases of Science Direct, Pub-Med, Scopus, Magiran, Iranmedex and SID, Google search engine, Gray Literature, reference lists check and hand searching using keywords such as "prevalence", "gestational diabetes mellitus", "GDM", "risk factor*", "Iran" and "Postpartum Diabetes". The selected papers were fully reviewed and the required information for the systematic review was extracted and summarized using extraction table in Microsoft Office Excel software. RESULTS: Twenty-four of 1011 papers were quite relevant to the objectives of the review so they were included. The mean age of the participants was 29.43+/-4.97 yr and the prevalence of GDM was 3.41% (the highest and the lowest prevalence rates were 18.6% and 1.3% respectively). Among the influential factors mentioned in the literature, potential causes of GDM are gestational age, history of gestational diabetes, family history of diabetes, body mass index, abortions and parity, and history of macrosomia. CONCLUSION: Considering the high prevalence of postpartum diabetes and its related factors in Iran, strategic planning for disease prevention and reduction is inevitable. PMID- 26587468 TI - Relationship between Type 2 Diabetes and Inflammation Diseases: Cohort Study in Chinese Adults. AB - BACKGROUND: This study aimed to investigate the association of seven common inflammatory diseases with Type 2 diabetes (T2D) in the Chinese Mainland population. METHODS: Participants were recruited from a great swathe of mainland from 2009 to 2013 for the cohort study. The demographic characteristics between patients with T2D or with inflammatory diseases, including age, sex, smoking status, hypertension etc. were analyzed using the chi(2) test. Cox proportional hazard regression models were used to determine the independent effects of diabetes on the risks of any types of inflammatory diseases in the model and age, sex, hypertension and gout adjusted were used after that. RESULTS: A total of 39367 participants were enrolled in the study and 1634 (4.2%) subjects with missing information on T2D and the inflammatory diseases were excluded. Compared to those without diabetes, after adjusting for age, sex, hypertension and gout, the incidences of asthma, chronic hepatitis, chronic bronchitis, chronic gastroenteritis, chronic gastritis or ulcer in diabetic patients were independently higher, with odd ratios of 0.235 (95% Confidence Interval [CI], 0.117-0.473), 0.845 (95% CI, 0.731-0.976), 0.585 (95% CI, 0.540-0.634), 0.875 (95% CI, 0.806-0.951), 0.843 (95% CI, 0.787-0.903) respectively. Only inflammatory hemorrhoid did not show any clinical significance. CONCLUSION: There was a decreased incidence of inflammatory diseases in the diabetic patients compared with non-diabetic subjects. Except for inflammatory hemorrhoid, asthma, chronic hepatitis, chronic bronchitis, chronic gastroenteritis, chronic gastritis and ulcer were associated with T2D of Chinese individuals, independently of hypertension and gout, and T2D might reduce the risk of these diseases. PMID- 26587469 TI - Association of Socioeconomic Factors and Sedentary Lifestyle in Belgrade's Suburb, Working Class Community. AB - BACKGROUND: Sedentary lifestyle represents a growing health problem and considering that there is already a range of unhealthy habits that are marked as health risk factors and the increasing prevalence of sedentary lifestyle worldwide, we aimed to investigate association of sedentary way of living in suburb, working class local community with socioeconomic determinants such as educational level, occupation and income status. METHODS: In this community-based cross-sectional study, 1126 independently functioning adults were enrolled into the study. The study protocol included a complete clinical and biochemical investigation revealing age, gender, lipid status, height, weight and blood pressure. Trained interviewers (nurses) collected information from patients about current state of chronic diseases (diabetes mellitus, arterial hypertension) smoking, medication and other socioeconomic data. Descriptive analysis, Chi square and logistic regression were performed as statistical calculations. RESULTS: Patients with elementary school were seven times more likely to be classified in category with sedentary lifestyle compared to patients with college or faculty degree. Being retired and reporting low income were significantly associated with higher odds of sedentary behavior when compared with students and patients with high-income status, respectively. CONCLUSIONS: The significance of this study lies in the fact that our results may help to easier identification of patients who may have a tendency towards a sedentary lifestyle. PMID- 26587471 TI - Using a Combined Platform of Swarm Intelligence Algorithms and GIS to Provide Land Suitability Maps for Locating Cardiac Rehabilitation Defibrillators. AB - BACKGROUND: Cardiac arrest is a condition in which the heart is completely stopped and is not pumping any blood. Although most cardiac arrest cases are reported from homes or hospitals, about 20% occur in public areas. Therefore, these areas need to be investigated in terms of cardiac arrest incidence so that places of high incidence can be identified and cardiac rehabilitation defibrillators installed there. METHODS: In order to investigate a study area in Petersburg, Pennsylvania State, and to determine appropriate places for installing defibrillators with 5-year period data, swarm intelligence algorithms were used. Moreover, the location of the defibrillators was determined based on the following five evaluation criteria: land use, altitude of the area, economic conditions, distance from hospitals and approximate areas of reported cases of cardiac arrest for public places that were created in geospatial information system (GIS). RESULTS: The A-P HADEL algorithm results were more precise about 27.36%. The validation results indicated a wider coverage of real values and the verification results confirmed the faster and more exact optimization of the cost function in the PSO method. CONCLUSION: The study findings emphasize the necessity of applying optimal optimization methods along with GIS and precise selection of criteria in the selection of optimal locations for installing medical facilities because the selected algorithm and criteria dramatically affect the final responses. Meanwhile, providing land suitability maps for installing facilities across hot and risky spots has the potential to save many lives. PMID- 26587470 TI - The Analysis of Gene Expression on Fertility Decline in Caenorhabditis elegans after the Treatment with 5-Fluorouracil. AB - BACKGROUND: 5-Fluorouracil could lead to a decline in fertility in Caenorhabditis elegans. The aim of this study was to describe the mechanisms underlying such an altered fertility phenotype and to illustrate the specific genes and pathways that are involved in the related phenotypic changes in C. elegans. METHODS: We isolated total RNA from the samples and used a new method called Digital Gene Expression (DGE), which can rapidly identify genes with altered transcript levels. The random genes were confirmed by real-time RT-PCR. RESULTS: We analyzed the results of two methods to draw conclusions based on a comparison between C. elegans and other harmful parasites. Compared with controls, 1147 genes were up regulated, and 1067 were down-regulated. Overall, 101 up-regulated genes had a log2 ratio higher than 8, whereas the log2 ratio of 141 down-regulated genes was higher than 8. After mapping to the reference database, 4 pathways were confirmed to be involved in this phenomenon, with statistically significant participation from 19 genes. CONCLUSION: For the first time, the transcript sequence of 5-Fu treated worms and controls was detected. We found that 4 possible pathways, i.e., ECM-receptor interaction pathway, TGF-beta signaling pathway, Focal adhesion and Hypertrophic cardiomyopathy, may be involved in the number decline in the embryos of C. elegans. Specifically, the ECM-receptor interaction pathway and Focal adhesion may be very important pathways that alter the reproduction of C. elegans. PMID- 26587472 TI - Effect of Air Pollution and Rural-Urban Difference on Mental Health of the Elderly in China. AB - BACKGROUND: China has become an aging society, and the mental health problem of the elderly is increasingly becoming prominent. This paper aimed to analyze the effect of air pollution and rural-urban difference on mental health of the elderly in China. METHODS: Using the data from the China Health and Retirement Longitudinal Survey (CHARLS, 2013), after controlling the social demography variable via Tobit and Probit, a regression analysis of the effect of air pollution and rural-urban difference on mental health and psychological disorder was conducted on 6,630 old people (?60 yr old) of China from February to April 2015. Mental health and psychological disorder of the elderly were measured by the CES-D score of respondents. Air pollution degree of counties and cities (n=123) were measured by SO2 emission. RESULTS: 27.8% of old people had psychological disorders. Air pollution significantly influenced the mental health of the elderly, showing a positive "U-shaped" curve (P<0.001). In China, the urban elderly had better psychological status than the rural elderly had. The female elderly had more serious mental health problems. Marriage, education, and social activities had positive effects on the mental health of the elderly. CONCLUSION: China's local governments should consider the influence of air pollution on the mental health of the elderly during economic development. This paper recommends paying attention to the difference in mental health between the urban and rural elderly when making public health policies. Governments could improve the mental health of the elderly by enriching social activities and increasing employment opportunities of the elderly. PMID- 26587473 TI - A Comparison between Accelerated Failure-time and Cox Proportional Hazard Models in Analyzing the Survival of Gastric Cancer Patients. AB - BACKGROUND: Gastric cancer is the one of the most prevalent reason of cancer related death in the world. Survival of patients after surgery involves identifying risk factors. There are various models to detect the effect of risk factors on patients' survival. The present study aims at evaluating these models. METHODS: Data from 330 gastric cancer patients diagnosed at the Iran cancer institute during 1995-99 and followed up the end of 2011 were analyzed. The survival status of these patients in 2011 was determined by reopening the files as well as phone calls and the effect of various factors such as demographic, clinical, treatment, and post-surgical on patients' survival was studied. To compare various models of survival, Akaike Information Criterion and Cox-Snell Residuals were used. STATA 11 was used for data analyses. RESULTS: Based on Cox Snell Residuals and Akaike Information Criterion, the exponential (AIC=969.14) and Gompertz (AIC=970.70) models were more efficient than other accelerated failure-time models. Results of Cox proportional hazard model as well as the analysis of accelerated failure-time models showed that variables such as age (at diagnosis), marital status, relapse, number of supplementary treatments, disease stage, and type of surgery were among factors affecting survival (P<0.05). CONCLUSION: Although most cancer researchers tend to use proportional hazard model, accelerated failure-time models in analogous conditions - as they do not require proportional hazards assumption and consider a parametric statistical distribution for survival time - will be credible alternatives to proportional hazard model. PMID- 26587474 TI - Iranian Households' Payments on Food and Health Out-of-Pocket Expenditures: Evidence of Inequality. AB - BACKGROUND: Inequality in households' payments on food and health expenditures presents the accessibility and utilization patterns between them. This study investigated the Iranian rural and urban households' inequality in payments on food and Out-of-Pocket health expenditures from 1998 to 2012. METHODS: This descriptive study was conducted through the analysis of Iranian Statistics Centre data on Iranian households' income and expenditures. The Gini Coefficients, Concentration and Kakwani indices have been calculated for Iranian rural and urban households' Out-of-Pocket health and food expenditures. RESULTS: The means of Iranian rural and urban total consumption expenditures inequality were 0.48 and 0.48, respectively. The means of concentration index of food expenditures for rural and urban regions were 0.35 and 0.34, respectively. The means of Out-of Pocket payments for health services for rural and urban regions were 0.51 and 0.5, respectively. Finally the means of Kakwani index of Out-of-Pocket health payments in rural and urban households were -0.005 and -0.018, respectively. CONCLUSION: There are relative high levels of inequality in Iranian households' payments on food and Out-of-Pocket health expenditures. PMID- 26587475 TI - Rocket and Two Dimensional Immunoelectrophoresis in Diagnosis of Caprine Brucellosis. AB - BACKGROUND: Brucellosis is a major bacterial zoonosis of global importance with the causative organisms of Gram-negative facultative intracellular pathogens. The aims of this study were to standardize two immunoelectrophoretic techniques, rocket and cross immunoelectrophoresis, and compare their results with other conventional serodiagnostic tests. METHODS: Sera from 15 sheep, without any history of brucellosis vaccination, infected with Brucella melitensis M16 subcutaneously, were employed in a comparison of culture, precipitating, and immunoelectrophoretic tests. A 125 days serologic follow-up was performed after the infection was started. As a reference, these tests also done in the five healthy sheep. RESULTS: The results obtained with the rocket immunoelectrophoresis test correlated very well with those of the cross immunoelectrophoresis, whereas results of other tests such as culture, Rose Bengal, standard tube agglutination and 2-mercaptoethanol seruagglutination tests were inferior. CONCLUSION: As agglutination test shows cross reaction and a prozone phenomenon, and in blood culture, the bacteria is not always detectable, so they are time consuming rocket and cross immunoelectrophoresis are recommended because their results can be obtained in a shorter time. PMID- 26587476 TI - Detection of Fungal Elements in Atherosclerotic Plaques Using Mycological, Pathological and Molecular Methods. AB - BACKGROUND: The aim of this study was to detect fungi in atherosclerotic plaques and investigate their possible role in atherosclerosis. METHODS: Coronary atherosclerotic plaques specimen were obtained from patients with atherosclerosis. Direct examination, culture, histopathology study, PCR and sequencing were performed to detect/identify the mycotic elements in the plaques. Age, sex, smoking, obesity, hypertension, hyperlipidemia, family history of heart diseases and diabetes were considered and data were analyzed using Chi Square test by SPSS version 15. RESULTS: A total of 41 specimens were analyzed. Direct examination for fungal elements was negative in all cases but in culture only one specimen grew as a mold colony. The presence of fungal elements were confirmed in 6 and 2 tissue sections stained by Gomori methenamine silver and Hematoxylin and Eosin methods, respectively. Using PCR, 11 cases were positive for fungi. The DNA sequence analysis of six positive specimens which were randomly selected revealed fungi as Candida albicans (n=3), Candida guilliermondii (n=2) and Monilia sp. (n=1). CONCLUSION: A significant association between the presence of fungi in atherosclerotic plaques and severity of atherogenesis and atherosclerotic disease was not found. This could be due to limited numbers of patients included in our study. However, the presence of fungal elements in 26.8% of our specimens is considerable and the results does not exclude the correlation between the presence of fungi with atherosclerosis and coronary artery disease. PMID- 26587477 TI - Fertility Desire in Iranian Women with HIV: A Qualitative Study. AB - BACKGROUND: Childbearing is a cause of concern for women living with HIV. To improve reproductive right of women with HIV and prevent the spread of HIV; it is needed to understand fertility experiences of infected women with HIV. The aim of this study was to explore fertility intentions and experiences of HIV-infected women in Iran. METHODS: Totally, 15 in-depth interviews were conducted with HIV- infected women who were at reproductive age and had referred to Imam Khomeini Hospital Consultation Center for Clients with Risky Behaviors in Tehran, Iran. Data were analyzed using the conventional content analysis method in MAXQDA 10. RESULTS: Analysis of the meaning units of interviews showed themes in describing of fertility desires of HIV women as follows: 1) Motherhood as a way for stability of life; 2) Uncertainties about the future; and 3) Unpleasant experience of pregnancy and delivery. This theme has three sub-themes as stigma, discrimination and weakness in health care system. CONCLUSION: Health care provider and community should respect the right of infected women and inform them on sexual and reproductive health. PMID- 26587478 TI - Acceptance of Cancer in Patients Diagnosed with Lung, Breast, Colorectal and Prostate Carcinoma. AB - BACKGROUND: The ability to accept illness is a major issue in the life of a person with cancer. Acceptance of disease is simultaneously conducted at two levels: the emotional and cognitive-behavioral one. It is consequential to cancer affecting numerous aspects of patient's life, i.e. the physical, mental, social and the spiritual area. The aim of the study was to verify the influence of socioeconomic factors on acceptance of illness in patients suffering from breast, lung, colorectal and prostate carcinoma. METHODS: The study included 902 patients treated on an outpatient basis at the Center of Oncology, the Maria Sklodowska Curie Institute in Warsaw, in the year 2013. The Paper and Pencil Interview (PAPI) technique was applied. The questionnaire comprised basic demographic questions (socioeconomic factors) and Acceptance of Illness Scale (AIS) test estimating the level of disease acceptance in patients. RESULTS: Prostate carcinoma patients scored highest (30, 39), whereas lung carcinoma patients scored lowest (23, 17) concerning illness acceptance according to the AIS scale. In all cases, linear dependence between the net income-per-household-member and the AIS score could be observed. Another diversification factor in the case of prostate carcinoma patients was the level of education. Yet one more dependence could be observed between the level of illness acceptance and chemotherapy over the course of past twelve months. CONCLUSION: The degree of disease acceptance is subject to a type of carcinoma. Patient income is an economic factor significantly affecting the acceptance of illness score. PMID- 26587479 TI - Recurrent Macroscopic Hematuria and Abdominal Pain: Questions and Answers. AB - A 6.5 yr old girl was admitted with a category of clinical signs and symptoms including recurrent gross hematuria, abdominal pain, and fever. After different examinations including genetic analysis, the disease was diagnosed as Familial Mediterranean fever (FMF). It is suggested to consider FMF as a rare cause of recurrent gross hematuria, which is responsive to colchicine treatment. PMID- 26587480 TI - Smoking-Suppressed Heart Rate Recovery in Young Male College Students Who Regularly Exercised. PMID- 26587481 TI - Comparison of One-Stage Managements in the Treatment of Obstructing Left-Sided Colorectal Cancer: Endolaparoscopic Approach vs. Emergency Open Surgery. PMID- 26587482 TI - Comparison between Real and Placebo Extracorporeal Shockwave Therapy for the Treatment of Chronic Plantar Fasciitis Pain in the Males. PMID- 26587483 TI - Halophytes as Possible Source of Antioxidant Compounds, in a Scenario Based On Threatened Agriculture and Food Crisis. PMID- 26587484 TI - Associations between Obesity and Diet-Related Compensatory Health Beliefs. PMID- 26587485 TI - Reformative Measures for Basic Health Units in Pakistan. PMID- 26587486 TI - Undesirable Cardiometabolic Outcomes of Fast-Food Patterns. PMID- 26587487 TI - First Visual Evidence of Leprosy in the Continental Shelf of Iran. PMID- 26587488 TI - Nausea and Vomiting Remedies in Iranian Traditional Medicine (ITM). PMID- 26587489 TI - Dietary and Medicinal Herbal Recommendation for Management of Primary Bile Reflux Gastritis in Traditional Persian Medicine. PMID- 26587490 TI - The Association between PTPN22 Genetic Polymorphism and Juvenile Idiopathic Arthritis (JIA) Susceptibility: An Updated Meta-Analysis. AB - BACKGROUND: Limited studies have focused on the association between the protein tyrosine phosphates non-receptor type 22 (PTPN22) genetic polymorphisms and Juvenile idiopathic arthritis (JIA) susceptibility in different populations, but the results were inconclusive. Therefore, this meta-analysis of PTPN22 polymorphism (1858 C>T) was performed to get a precise systematic estimation. The "rs" number of the PTPN22 polymorphism (1858 C>T) is 4. METHODS: A systematic literature search strategy was carried out using English databases (PubMed, Embase.) for the eligible studies. We ultimately identified 11 records from 10 articles involving the relationship between PTPN22 genetic polymorphisms and JIA risk from PubMed and Embase databases. Overall, 4552 cases and 10161 controls were investigated in this study to evaluate the association between PTPN22 (C allele vs. T allele) genotype and JIA susceptibility. RESULTS: Analysis using random effects model showed an increased risk of JIA with T allele of rs2476601 vs. A allele (P<0.001). Subgroup analysis suggested that the PTPN22 polymorphism (1858C>T) was significantly associated with JIA risk in America population (OR=1.52, 95% CI:1.30-1.78). Additionally, the subgroup analysis also showed that the associations were still significant in case number more than 500 (OR=1.38, 95% CI: 1.04-1.83), while in the case number less than 500 was OR=1.55, 95% CI: 1.39-1.72. CONCLUSIONS: SNPs of PTPN22 (1858C>T) showed an increased risk of developing JIA. PMID- 26587491 TI - Gender Differences in Elders' Participation in the National Cancer Screening Program: Evidence from the Korean National Health and Nutrition Examination Survey 2010-12. AB - BACKGROUND: Cancer-screening programs are effective in reducing cancer prevalence and mortality; however, cancer remains the leading cause of death in elderly people in Korea. The aim of this study was to identify the factors associated with elders' participation in the National Cancer Screening Program (NCSP) and differences in screening rates by gender. METHODS: Original data from the Korea National Health and Nutrition and Examination Survey were analyzed by logistic regression analysis. The sample consisted of 5,505 elderly individuals over age 60. Selected demographic variables, cancer screening participation, physical and psychological health status, and lifestyle were examined. RESULTS: The NCSP participation rates decreased in both men and women as age increased. Private medical insurance (OR 95% CI: 1.04-1.78), one or more chronic disease (OR 95% CI: 1.07-1.71), and current smoker (OR 95% CI: 0.52-0.94) had the strongest associations with cancer screening participation among men after multivariate adjustment. In contrast, cancer screening participation among women was significantly associated only with living place (OR 95% CI: 1.06-2.203) after multivariate adjustment. CONCLUSIONS: Effective health promoting interventions for elders require individualized programs that address gender-related factors associated with elders' participation in cancer screening programs. PMID- 26587492 TI - Isolation and Proteomic Analysis of Rhoptry-Enriched Fractions from Cryptosporidium parvum. AB - BACKGROUND: Rhoptries are unique secretory/excretory organelles that are found exclusively in the Apicomplexa, and their contents are discharged at the time of invasion and are critical in the establishment of productive infection. Several rhoptry proteins have been identified in Toxoplasma gondii, Plasmodium falciparum and Neospora caninum and have been linked not only with the parasites' adhesion and invasion processes but also with their intracellular pathways. To date, only one Cryptosporidium parvum rhoptry protein candidate related to TgRON1 of T. gondii and PfASP of P. falciparum has been reported. METHODS: Subcellular fractionation of sporozoites was performed to obtain highly purified organelles. One-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by liquid chromatography coupled with mass spectrometry was applied for fraction analysis, and 22 potential novel rhoptry proteins were detected by protein domain analysis using online softwares. RESULTS: Twenty-two potential novel rhoptry proteins were detected. A protein with T. gondii and N. caninum rhoptry protein homologs and some proteins with domains similar to that of T. gondii rhoptry proteins were identified. CONCLUSION: These novel candidate proteins may be considered targets for researching the invasion pathway of C. parvum and the pathogenic mechanisms of rhoptry proteins. The present work provides a starting point towards the elucidation of the repertoire and function of C. parvum rhoptry proteins. PMID- 26587493 TI - Lipid Variables Related to the Extent and Severity of Coronary Artery Disease in Non-Diabetic Turkish Cypriots. AB - BACKGROUND: We aimed to analyze the association between lipid variables and the extent and severity of coronary artery disease (CAD) in non-diabetic Turkish Cypriots. METHODS: Overall, 412 patients (mean (SD) age: 58.8 (10.5) yr, 50.1% male) who underwent diagnostic coronary angiography were included in this single center, cross-sectional study. The Friesinger index (FI) was used to assess the extent and severity of CAD. The lipid variables [total cholesterol, LDL-c, HDL-c, triglyceride (TG) levels and the TG/HDL-C ratio] were categorized into quartiles and evaluated regarding extensive/severe CAD. Potential risk factors in the Turkish Cypriot cohort were evaluated as predictors of CAD in univariate and multivariate logistic regression models. The population of this study are non diabetic Turkish Cypriots which are administrated North Cyprus. RESULTS: The mean (SD) Friesinger index was 6.9 (4.4), and 59.0% of the patients exhibited a Friesinger index category of >=5. In the univariate analysis, extensive/severe CAD was directly related to total triglycerides (P=0.01) and TG/HDL-c quartiiles (P=0.001) and inversely related to HDL-c quartiles (P=0.001). In the multivariate model, diabetes (OR: 4.9; 95% CI: 1.3 - 19.2; P=0.02), male gender (OR: 3.1; 95% CI: 0.95 - 10.3; P=0.06) and high TG/HDL-c ratio (OR: 2.2; 95% CI: 1.3 - 3.8; P=0.004 in the overall population and OR: 1.9; 95% CI: 1.4 - 2.3; P=0.003 except diabetics) were the significant predictors of CAD. CONCLUSION: We found a significant relationship between the lipid quartiles and the extent and severity of CAD based on the Friesinger index. Male gender, co-morbid diabetes and the TG/HDL-C ratio also played significant roles in predicting CAD risk in non diabetic Turkish Cypriots. PMID- 26587494 TI - Cataract Surgical Rate between 2006 and 2010 in Tehran Province. AB - BACKGROUND: Considering population aging in Iran and the importance of cataract surgery in the old age, this study was performed to show the cataract surgical rate (CSR) between 2006 and 2010 in Tehran Province. METHODS: Eighteen centers were randomly selected from cataract surgery centers in Tehran. In each center, one week in every season was randomly selected and the number of cataract surgeries in the week was calculated. In total, 20 weeks were selected in each center in five years. RESULTS: The CSR increased linearly from 8011 cases per 1,000,000 population in 2006 to 12465 cases per 1,000,000 population in 2010. As for patients below 40 years of age, the percentage of the male patients was more while after the age of 40 years, the percentage of the female patients was more in all age groups. At least 96.2% of the surgeries in each year were performed using the phacoemulsification method. From 2006 to 2010, the percentage of outpatient surgery increased from 48.7% to 72.5%. On the other hand, hospitalization for one night or more had a decreasing trend from 2006 to 2010. CONCLUSION: During 2006-2010, the CSR was acceptable in Tehran in comparison with other studies. However, attention should be paid to the increase in the population of the elderly people. Although more than 95% of the surgeries in the Province of Tehran are performed using the phacoemulsification method, the rate should increase to 100% in the eligible cases. PMID- 26587495 TI - Asthma Economic Costs in Adult Asthmatic Patients in Tehran, Iran. AB - BACKGROUND: High prevalence and increasing rate of asthmatic patients around the word witnesses the high burden of asthma. We have limited data on asthma burden and economic costs in Iran. This study aimed to find direct and indirect economic costs of asthma and their association with some background factors in one of the referral tertiary centers for adult patients with asthma. METHODS: We surveyed asthma related economic costs of 197 adult patients who referred to Milad Hospital, Tehran, Iran from Jun 2007 to January 2010. The patients were followed up for a period of one-year +/-1 month and asthma related costs and its control status were registered. RESULTS: Patients were consisted of 125 (64.1%) females and 70 (35.9%) males. Total cost of asthma was 590.22 +/-32.18 USD for one patient per one year, the cost of drug, paraclinic, doctor visit, hospitalization, emergency, transportation, and absent days were 327.02, 4.76, 35.44, 3.82, 0.26, 113.03, 105.89 USD respectively. Men showed a significant elevation in their total (P=0.009) and drug costs (P=0.028). In addition, we found significant differences between total asthma costs and asthma control status (P=0.002). CONCLUSIONS: According to the high proportion of asthma, related cost compare to Total Income of an Iranian family, the necessity of public coverage of health assurance is quite clear. We suggest that improving asthma management and accessibility to specialized treatment centers can result in decreasing asthma medication and transportation costs as major direct and indirect asthma related costs. PMID- 26587497 TI - The Economic Burden of Breast Cancer in Iran. AB - BACKGROUND: Although breast cancer imposes a considerable economic burden on high income countries, there is limited knowledge about its economic burden in low- and middle-income countries (LMCs), including Iran. In this study, we estimated the economic burden of breast cancer in Iran in 2010. METHODS: We used the prevalence-based approach and estimated the direct and indirect costs of all breast cancer cases in 2010. We used several data sources, including national cancer registry reports, hospital records, occupational data, and interviews with experts. RESULT: The economic burden of breast cancer was US$947,374,468. Most of the cost (77%) pertained to the productivity lost due to breast cancer deaths and the direct medical cost accounted for 18.56% of the estimated total cost. Out of the US$175,860,607 as the direct medical cost, the chemotherapy cost constituted the main part ($76,755,740), of which prescriptions of trastuzumab accounted for 41% ($31,529,280). CONCLUSION: The economic burden of breast cancer in Iran is substantial and is expected to increase significantly due to the increasing incidence rate. Strategies for the prevention and early detection of breast cancer should be prioritized in the national cancer control program. PMID- 26587496 TI - Seroepidemiology of Human Hydatidosis Using AgB-ELISA Test in Isfahan City and Suburb Areas, Isfahan Province, Central Iran. AB - BACKGROUND: The aim of this study was to conduct a sero-epidemiological survey in Isfahan City and suburb areas, central Iran to detect the rate of human hydatidosis using ELISA test. METHODS: Overall, 635 serum samples were collected from subjects referred to different health centers in urban and rural regions of the city. Sera were analyzed using Ag-B ELISA test. Ten MUg/ml antigens, serum dilutions of 1:500 and conjugate anti-human coombs with 1:10000 dilutions were utilized to perform the test. All subjects filled out a questionnaire and an informed consent. Data analysis was conducted using SPSS 18 software. Cut-off was calculated as X+3 SD. RESULTS: Cut-off value was calculated 0.19. Seven cases (1.1%) were seropositive for hydatidosis by ELISA test. The sero-prevalence of hydatidosis was 0.27% among females and 2.24% among males (P=0.019). Age group of 60-69 years old, with 2.59% as prevalence had the highest rate of positivity. There was no significant difference as regards age groups, job, residency, contact by dog and literacy. According to job, self-employed people had the highest rate of infection as 3.05%. The sero-prevalence of infection was 1.14% in diploma and 1.13% in illiterates. As regards residency, urban life (1.49%) showed no significant difference with rural life. CONCLUSION: The rate of prevalence in this region showed that necessary cautions should be taken into account to monitor the spread of human hydatidosis in this region. In comparison with other studies, the rate of infection was roughly less than other regions. PMID- 26587498 TI - Correlation between Self-Citation and Impact Factor in Iranian English Medical Journals in WoS and ISC: A Comparative Approach. AB - BACKGROUND: In this study, the impact of self-citation (Journal and Author) on impact factor of Iranian English Medical journals in two international citation databases, Web of Science (WoS) and Islamic world science citation center (ISC), were compared by citation analysis. METHODS: Twelve journals in WoS and 26 journals in ISC databases indexed between the years (2006-2009) were selected and compared. For comparison of self-citation rate in two databases, we used Wilcoxon and Mann-whitney tests. We used Pearson test for correlation of self-citation and IF in WoS, and the Spearman's correlation coefficient for the ISC database. Covariance analysis was used for comparison of two correlation tests. P. value was 0.05 in all of tests. RESULTS: There was no significant difference between self-citation rates in two databases (P>0.05). Findings also showed no significant difference between the correlation of Journal self-citation and impact factor in two databases (P=0.526) however, there was significant difference between the author's self-citation and impact factor in these databases (P<0.001). CONCLUSION: The impact of Author's self-citation in the Impact Factor of WoS was higher than the ISC. PMID- 26587499 TI - Child Labor and the Influencing Factors: Evidence from less Developed Provinces of Iran. AB - BACKGROUND: This study aimed to calculate the child labor rate and establish the factors affecting this phenomenon in the less developed provinces of Iran. METHODS: This study has used the secondary data of population and housing census gathered by Iranian Statistical Center in 2011. The data belonged to 14859 children between 10 and 14 of 9 less developed provinces of Iran. A multiple regression model was hypothesized drawing on related literature and accordingly using data; the logistic regression was estimated. Data cleaning process was also conducted prior to the analysis. RESULTS: The child labor force participation rate for all children between 10 and 14 years old was 1.7%, of which boys' child labor rate was higher than girls' (2.4% over 1%). As such, the mothers' fertility rate and education were of the strongest, yet converse, effect on child labor supply in the country. CONCLUSION: A little proportion of children in less developed regions of Iran was suffering from child labor. However, given the diminishing and rising effects of, respectively, variables such as mothers' literacy and working on the child labor; the authorities could restrict child labor attending more to such a group. The factors identified could also be of a high value for the policy-makers at both national and international level such as the Health and Welfare ministries, EMRO, ILO and UNICEF. PMID- 26587500 TI - Spatio-Temporal Pattern of Tuberculosis in the Regions Supervised by Shiraz University of Medical Sciences 2006-2012. AB - BACKGROUND: The present study aimed to identify the spatial distribution of tuberculosis and determine the TB control program parameters in the regions supervised by Shiraz University of Medical Sciences in 2006-2012. METHODS: The present ecological study was performed on 1797 TB patients in Shiraz University in 2006-2012 which were recorded by health centers using TB Register software. The study data were collected through over-counting and analyzed using the SPSS statistical software (ver. 19). Besides, the maps were drawn by ArcGIS, version 10. RESULTS: The incidence rate of TB was 4.8 in 100,000 at the end of 2012. Success in treatment was adequate only in 2012 (89.7%). However, recovery of pulmonary TB was not adequate in any of the study years. In our study, the majority of the patients belonged to the 25-34 years age group that constitutes the active faction of the society. Moreover, the maps provided by GIS showed a high incidence rate of extra pulmonary TB in Firozabad Township during 7 years (2.7 in 100000 populations). CONCLUSION: Incidence of TB in the regions supervised by Shiraz University of Medical Sciences follows a specific pattern, which requires exclusive studies for further evaluation of the incidence determinatives in various environmental and social conditions. PMID- 26587501 TI - Molecular Diversity of Candida albicans Isolated from Immunocompromised Patients, Based on MLST Method. AB - BACKGROUND: As regards multilocus sequence typing (MLST) method directly analyze the polymorphism within DNA sequences; we performed the first nationwide study on the genotypic relationships of Candida albicans strains obtained from oropharynx and bronchoalveolar lavage (BAL) samples from immunocompromised patients. METHODS: Fourteen epidemiologically unrelated clinical strains of C. albicans were obtained from three hospitals in Mazandaran Province, Iran (2006 to 2012) from seven patients with pulmonary infections and the rest with oropharyngeal samples of immunocompromised patients. Seven loci of housekeeping genes were sequenced for all fourteen isolates. RESULTS: MLST was applied to a subset of 14 unrelated isolates. Seventy-one (2.5%) nucleotide sites were found to be variable. Accordingly, 60 different alleles were identified in seven loci among the isolates, among which two new alleles were obtained. Furthermore, 12 independent diploid sequence types (DSTs) including five novel DSTs were identified. The fourteen unrelated isolates were placed in 10 clonal clusters (CC) while two isolates were singletons, by eBURST analysis. Most of the isolates belonged to CC461 of eBURST analysis from the clade 11 and two isolates assigned to CC172 from the clade 15. CONCLUSION: Pathogen distribution and relatedness for determining the epidemiology of nosocomial infections is highly recommended for pathogen control methods. PMID- 26587502 TI - Cardioprotective Effect of High Intensity Interval Training and Nitric Oxide Metabolites (NO2 (-), NO3 (-)). AB - BACKGROUND: The aim of this study was to investigate the effects of High Intensity Interval Training (HIIT) on nitric oxide metabolites (NO2(-), NO3(-)) and myocardial infarct size after Ischemia/Reperfusion (I/R) injury in healthy male rats. METHODS: A total of 44 Wistar rats were randomly divided into 4 groups including HIIT (n=8), HIIT + IR protocol (n=14), control (n=8), and control + IR (n=14). Each training session of HIIT consisted of 1 hour of exercise in three stages: 6-minute running at 50-60% VO2max for warm-up; 7 intervals of 7-minute running on treadmill with a slope of 5 degrees to 20 degrees (4 minutes with an intensity of 80-100% VO2max and 3 minutes at 50-60% VO2max); and 5-minute running at 50-60% VO2max for cool-down. The control group did not participate in any exercise program. Nitric Oxide (NO) and its metabolites were measured by using Griess reaction test. RESULTS: The results showed that eight weeks of exercise training exerted a significantly increasing effect on nitrite (8.55 MUmol per liter, equivalent to 34.79%), nitrate (62.02 MUmol per liter, equivalent to 149.48%), and NOx (66 MUmol per liter, equivalent to 98.11%) in the HIIT group compared with the control group. The results showed myocardial infract size (IS) was significantly smaller (23.2%, P<0.001) in the exercise training group compared with the control group. CONCLUSION: Incremental changes in NO-NO3 (-), NO2 (-) axis are one of mechanisms through which HIIT program can protect the heart from I/R injury and decrease myocardial infarction. PMID- 26587503 TI - Human Cystic Echinococcosis in Zanjan Area, Northwest Iran: A Retrospective Hospital Based Survey between 2007 and 2013. AB - BACKGROUND: Hydatidosis is the most important zoonotic disease that causes significant economic losses and public health problems worldwide. This study was conducted to evaluate retrospectively 136 patients diagnosed with hydatid cyst disease at two university medical centers between 2007 and 2013 in in Zanjan area, northwest Iran. METHODS: We surveyed medical records of infected patients with hydatid cyst who had been operated in two hospitals in Zanjan City, northwest, Iran. Several parameters were studied including age, sex, place of habitation, and the location of cysts. RESULTS: Of 136 cases, 54.4% were female with the mean age of 45 yr (4-86). The most affected age group was 21-40 yr old (36.02% of the cases). Cysts were localized in liver and lung in 64% and 23.5% of cases, respectively. Single organ involvement was seen in the majority of patients and 13 (9.5%) cases had multiple involvement. In 69.9% of cases, there was only one cyst, 8.1% had two cysts, 17.6% with three cysts, and 4.4% had four cysts or more. The distribution of residence of patients showed that 33 (24.3%) of them were urban residents. CONCLUSION: The prevalence of hydatidosis is high in this city and further studies are required to determine the prevalence, economic impact and risk factors of the disease in the area. PMID- 26587504 TI - Macroscopic Hydatiduria: An Uncommon Pathognomonic Presentation of Renal Hydatid Disease. AB - Isolated renal hydatid disease is a rare endemic infestation caused by larval form of Echinococcus granulosus. Hydatiduria is an uncommon presentation of renal hydatid disease. In 2012 a 34-year-old female referred to Razi Hospital, Rasht, Iran with complaints of right flank pain and grape-like material in urine. Diagnosis was made by ultrasonography and CT scan. The patient was treated surgically with nephrectomy in combination with perioperative chemotherapy with albendazol. PMID- 26587505 TI - The Effect of Smoking on Brain Wave Activity in Middle-Aged Men Measured by Electrocorticography. PMID- 26587506 TI - Determinants of Mortality in First-Ever Stroke Patients in the Suburban Malaysia: A Retrospective Hospital-Based Study, 2005-2011. PMID- 26587507 TI - Hepatitis C Infection in Egyptian Psoriatic Patients: Prevalence and Correlation with Severity of Disease. PMID- 26587508 TI - An Algorithm of Ethical Approach to The Orthodontic Patient. PMID- 26587509 TI - Risk Factors Associated with Low Birth Weight Infants Born in Elazig, Eastern of Turkey. PMID- 26587510 TI - Application of Social Marketing in Assisting Program Managers to Tackle Public Health Concerns. PMID- 26587511 TI - Community Assessment for Determining the Health Priority Problems and Community Diagnosis: A Case Study of Qala_Sayed Village, Kazeroun, Fars Province, Iran. PMID- 26587512 TI - The Burnt City and the Evolution of the Concept of "Probability" In the Human Brain. PMID- 26587513 TI - Resilience and Handicap in Deaf. PMID- 26587514 TI - Knowledge and Perception of Nigerian Men 40 years and above Regarding Prostate Cancer. AB - BACKGROUND: Carcinoma of the prostate is now the most commonly diagnosed male cancer worldwide. However, knowledge and perception of Nigerian men about the disease has not been fully investigated. AIM: To determine the level of awareness about prostate cancer among men 40 years and older in Ibadan, Southwestern Nigeria. METHOD: Four focus group discussions were used to obtain information from 29 randomly- selected Nigerian men, aged 40 years and above, about their knowledge of the common causes of morbidity and mortality among men of their age group as well as prostatic diseases and their perceived causes. In-depth interviews were then conducted among 656 participants using questionnaires. RESULTS: Generally, the respondents and discussants were unaware of the prostate gland and its diseases; whilst relatively few knew about carcinoma of the prostate and most were ignorant of the symptoms of the disease. Among discussants and respondents who knew about the gland, most thought that benign and malignant prostatic diseases were long-term complications of promiscuity and sexually transmitted infections. All the participants were interested in receiving information about all aspects of carcinoma of the prostate. CONCLUSION: . These results indicate that a large proportion of adult Nigerian men are ignorant of the prostate gland and its diseases in general, and carcinoma of the prostate in particular. There is therefore the need for community awareness programs on prostatic diseases in our locality. PMID- 26587515 TI - COMPARISON OF IOP READINGS USING REBOUND I CARE TONOMETER AND PERKINS APPLANATION TONOMETER IN AN AFRICAN POPULATION. AB - BACKGROUND: Accurate intra ocular pressure (IOP) measurement and monitoring using tonometry is a common clinical measurement in diagnosis and management of glaucoma, this is often a challenge in children. The ICare and Perkins tonometers are both handheld tonometers, Perkins uses applanation while ICare measures IOP with a rebound method. OBJECTIVES: The objectives of research were to study the IOP values from each tonometer, compare the value of IOP readings from both tonometers, determined the ease of their use in young children and document the various positions in which the tonometers were used successfully in children. METHOD: Intra ocular pressure readings were taken by two experienced examiners in upright position without sedation or anaesthesia. ICare tonometer was first used. Data were entered and analysed with SPSS 17 statistical package. The means were compared using paired sample T-test. RESULTS: A total of 480 eyes of 240 persons, aged between 2months and 90years with a mean of 46.2+/-22 years had their intra ocular pressure range between 3 and 44mmHg( Mean16.3+/-6) measured using ICare and Perkins tonometry. There was a high correlation, and no statistically significant differences in the mean IOP comparing ICare and Perkins tonometers. The mean difference in average IOP readings between ICare and Perkins was -0.08+/ 2.8 (95% CI: 0.45-0.30; r=0.87, p= 0.68) for right eye and -0.15+/-2.8mmHg (95% CI -0.53 to 0.23; r=0.86, p=0.44) in the left eye The difference in the average IOP reading from both tonometers was within 2mmHg 288(66.2%) eyes. Among the 147 (33.8%) eyes with a difference in IOP greater than 2mmHg, Perkins was responsible for the higher IOP reading in 76(51.7%) and ICare in 71(48.3%) p=0.56. Among 42 eyes of 21 children aged <=6years, IOP reading was successfully taken in 41(97.6%) and 21(50%) eyes with ICare and Perkins respectively without sedation or anaesthesia. CONCLUSION: The IOP readings using the ICare tonometer compares well with that of Perkins tonometer. The ICare was easier to use in young children (<=6year olds) without sedation or anaesthesia in this African population. PMID- 26587516 TI - ASSOCIATION OF EARLY CHILDHOOD CARIES WITH BREASTFEEDING AND BOTTLE FEEDING IN SOUTHWESTERN NIGERIAN CHILDREN OF PRESCHOOL AGE. AB - BACKGROUND: Early childhood caries constitute one of the most prevalent chronic diseases among children which have been found to be related to infant feeding practices. OBJECTIVE: to determine the association of early childhood caries with breastfeeding and bottle-feeding practices among children of preschool age. PATIENTS & METHODS: Information about oral health, infant feeding and other child and family characteristics were obtained through structured interviewer administered questionnaire from mothers of preschool children. Intra-oral examination of the children was done and dental caries status was recorded according to the World Health Organization (WHO) criteria. The data were analysed using Statistical Package for Social Sciences (SPSS) version 20.0. Statistical analyses of association of early childhood caries with various categorical variables were performed using chi-square. A logistic regression analysis was also performed with factors that were significant. P-value <= 0.05 was considered statistically significant. RESULTS: Of the 302 children in this study, 44% were solely breastfed, 2% were solely bottle-fed while 54% were both breastfed and bottle-fed. Statistical analysis showed that ECC significantly increased with night time bottle feeding (OR=4.5, p=0.001, CI=1.8-11.1), whereas it was significantly lower in children who were breastfed for 3 to 6 months (OR= 0.1, p<0.001, CI=0.03-0.18) as compared to those who were breastfed greater than 12 months duration. CONCLUSION: . This study has shown that breastfeeding for the first 3 - 6 months of life is associated with low incidence of dental caries while babies solely bottle-fed and night time bottle feeding are associated with high incidence of childhood dental caries. PMID- 26587518 TI - PEER-REVIEWED ABSTRACTS OF SCIENTIFIC PAPER PRESENTATION AT THE 54TH ANNUAL CONFERENCE OF THE WEST AFRICAN COLLEGE OF SURGEONS AT KUMASI, GHANA 24TH - 28TH FEBRUARY, 2014. PMID- 26587517 TI - ORAL HEALTH QUALITY OF LIFE IN A NIGERIAN UNIVERSITY UNDERGRADUATE POPULATION. AB - INTRODUCTION: Oral health related quality of life is utilized in health services research to examine trends in oral health and population-based needs assessment. OBJECTIVE: To assess both the generic and orthodontic specific aspects of the Oral health-related quality of life of a University undergraduate population. METHODOLOGY: This was a cross-sectional descriptive study carried out among 420 undergraduate students, aged 18-30years old, attending the University of Lagos, Nigeria. The data collection was carried out through oral interviews and self administered questionnaires. Two Oral health related quality of life instruments were used (1) A generic scale: the Shortened version of the Oral Health Impact Profile (OHIP-14) and (2) A condition specific scale: the Psychosocial impact of dental aesthetics questionnaire (PIDAQ). Data analysis was carried out using the Statistical Package for Social Sciences (SPSS). RESULTS: With respect to the Oral Health Impact Profile (OHIP-14) scale, the overall mean score recorded by the students was 10.43+7.85. The physical pain subscale recorded the highest impact with 93.3%, while the least impact was recorded in the handicap subscale, with 29.9%. The Psychosocial Impact of Dental Aesthetics Questionnaire (PIDAQ) scales revealed significant gender differences, with the subscales of 'social impact', 'psychological impact' and 'aesthetic concern' recording low mean subscale values. CONCLUSION: . The mean Oral Health Impact Profile (OHIP-14) score of the students (10.43 + 7.85) in this study reflects that the oral health status of most of the students did not significantly affect their Oral health-related quality of life. However, the physical pain domain was the most severely affected aspect of their Oral health-related quality of life. The Psychosocial Impact of Dental Aesthetics (PIDAQ) scale scores recorded significant gender differences. PMID- 26587519 TI - KNOWLEDGE AND PERCEPTION OF PROSTATE CANCER. PMID- 26587520 TI - VAGINAL BIRTH AFTER A PREVIOUS CAESAREAN SECTION: CURRENT TRENDS AND OUTLOOK IN GHANA. AB - BACKGROUND: The optimal mode of subsequent delivery of women with prior caesarean birth remains a subject of intense research and debate in contemporary obstetric practice especially in low resource settings like West Africa where there are obvious systemic and management-related challenges associated with trial of scar. However, there is evidence that vaginal birth after caesarean section (VBAC) is safe in appropriately selected women in addition to adequate intrapartum monitoring and ready access to theatre when emergency CS is indicated. AIM & OBJECTIVES: The primary objective of the study was to determine the current trends and performance of VBAC in Ghana after decades of practice of trial of labour after caesarean section (TOLAC) in the mist of inherent challenges in deciding the optimal mode of childbirth for women with a previous caesarean birth. The secondary objective was to relate evidence based practice of TOLAC to obstetric practice in low resource settings like Ghana and provide recommendations for improving maternal and newborn health among women with prior caesarean birth. PATIENTS & METHODS: This was a retrospective study of the records of patients who had had a prior caesarean delivery and who then proceeded to deliver the next babies at the Korle Bu Teaching Hospital (KBTH) between Jan 2010 and Dec 2014. The data on demography, antenatal care, labour and delivery and outcomes were collected from the Labour and Recovery wards and the Biostatistics unit of the Maternity unit of the Hospital. Excluded were women with a previous CS who had multiple pregnancies and those with incomplete notes as well as those whose delivery plans were not predetermined antenatally.. The data were analyzed using SPSS version 20. RESULTS: There were 53,581 deliveries during the study period. Vaginal delivery was obtained in 31,870 (59.5%) pregnancies and 21,711(40.5%) had CS. Also, 6261 (11.7%) had had a prior CS and 2472 (39.5%) of these were selected for TOLAC while 2119 (33.8) were scheduled for planned repeat CS. There was an inverse trend between the annual caesarean sections rates and the proportion of women with one previous CS scheduled for TOLAC. There was a statistically significant difference between women who had successful or failed VBAC regarding maternal age, parity, number of ANC visits, gestational age at delivery, birth weight, Apgar score at 1 min and Apgar score at 5 min. Birth weights of less than 1.5kg, and 3.5Kg or greater were associated significantly with higher incidence failed TOLAC and emergency repeat CS. However, birth weights ranging from 2.0 to 3.49kg were associated with significantly lower incidence of failed TOLAC and emergency repeat CS. Birth weight of 2.5-2.99kg was associated with the lowest incidence of failed TOLAC and repeat CS. CONCLUSION: . There is a significantly high vaginal birth after caesarian section (VBAC) success rate among carefully selected women undergoing trial of scar in Ghana although a decreasing trend towards trial of labor after caesarian section (TOLAC) and a rising CS rate were determined. TOLAC remains a viable option for child birth in low resource settings like West Africa even though there are specific clinical and management related challenges to overcome. Adequate patient education and counselling in addition to appropriate patient selection for TOLAC remains the cornerstone to achieving high VBAC success rate with minimal adverse outcomes in such settings. PMID- 26587521 TI - AN AUDIT OF MINOR OPHTHALMIC SURGICAL INTERVENTIONS IN A TERTIARY EYE CARE FACILITY IN NORTHERN NIGERIA. AB - BACKGROUND: An estimated 285 million persons are visually impaired globally, and 39 million of them are blind. Majority of the blind population reside in developing countries. Over 60% of blindness is attributable to surgical causes of blindness. A surgical audit reveals areas of performance that require improvement. AIM: To assess the output and pattern of minor ophthalmic surgeries over a seven year period. METHOD: The minor ophthalmic surgical records of Jos University Teaching Hospital, Jos, Nigeria were retrospectively reviewed to obtain information on the patients'demographics, diagnosis, indication, type of surgery, type of anaesthesia administered, outcome of management, histology report and the rank of surgeon. The data obtained were analyzed using Epi Info Statistical version 3.4, Atlanta, Georgia USA. RESULTS: A total of 536 patients had minor ophthalmic operations at the Jos University Teaching Hospital between January 2008 and December 2014. There were 281(52.4%) males and 255(47.6%) females (chi(2)=9.4, p>0.1) with a mean age of 37.2 years (SD:24). Furthermore, 41(7.6%) patients had surgery in both eyes. The main anatomical sites of ocular morbidity were eyelid/lashes, conjunctiva and anterior segment observed in 237 (41.1%), 166(28.8%) and 94(16.3%) eyes respectively. Posterior segment lesions as indication for minor surgery was observed in 11(1.9%) eyes in the year 2013 and increased to 38(6.6%) eyes in 2014. Most (75%) minor surgical procedures were performed by resident doctors under supervision (chi(2)=13.7, p<0.05). A total of 584 procedures were performed comprising over 33 different types of minor surgeries. The main surgical procedures included pterygium excision in 104(17.8%) cases, eyelid repair in 74(12.7%) cases and incision and curettage for chalazion in 65(11.1%) cases (chi2=23.9, p<0.001). A recurrence rate of 31.6% and 6.1% was observed in eyes that had pterygium excision and incision and curretage for chalazion respectively; 83.8% of eyelids repaired had no postoperative sequelae while notching of the eyelid margin was observed in 9.4% of eyelids repaired. CONCLUSION: Minor ophthalmic surgeries constitute an important aspect of comprehensive eye care delivery with significant impact on control of blindness programmes. Most minor ophthalmic surgeries are performed on the ocular adnexa, hence the need for strengthening of the orbito-oculoplastic sub-specialty in the hospital. PMID- 26587522 TI - ORAL HEALTH AWARENESS AND PRACTICES OF PRIMARY SCHOOL TEACHERS IN IBADAN, NIGERIA. AB - BACKGROUND: The school is an important avenue for promoting oral health most especially in developing countries with low resources. However, the success of any school based preventive oral health programme is dependent on the teachers about whom there is little information on their present state of oral health awareness and practices in Ibadan, South-western Nigeria. AIM & OBJECTIVES: To investigate the oral health awareness and practices of primary school teachers in Ibadan, Nigeria. MATERIALS & METHODS: A cross sectional study of randomly selected public primary school teachers in Ibadan was performed. Data were collected using structured self-administered questionnaire, which assessed their socio-demographic characteristics, oral health awareness, oral hygiene measures and utilization of dental services. Data were analysed using SPSS version 21. Chi square statistics was used to test for association between variables and p value set at < 0.05. RESULTS: A representative sample of 309 teachers participated in the study with a mean age of 48.7 (+/- 5.94) years. The majority, 284 (91.9%), were females. A few, 39 (12.6%), of the teachers knew what dental caries and its causes were, while 1 (0.3%) knew the cause of oral cancer. Only 149 (48.2%) knew that oral diseases could be prevented. If the teachers had problems with their teeth; 154 (49.8%) would go to the hospital, 115 (37.2%) would self-medicate, 20 (6.5%) would visit the drug shop (chemist), 1 (0.3%) would visit the traditional healer and 19 (6.2%) were not sure of what to do. About a third of participants, 99 (32.0%) have had previous consultations with the dentist, with many 72 (72.0%) doing so because of pain. Many of the teachers 183 (59.2%) cleaned their teeth twice or more daily before eating. Male teachers (84.0%) and those with less teaching experience (60.6%) were found spending longer time in cleaning their teeth (p = 0.035 and p = 0.002). CONCLUSION: Poor oral health awareness and practices still exists among the teachers. There is a need for urgent intervention to promote oral health amongst them. PMID- 26587523 TI - HYSTEROSALPINGOGRAPHY AND LAPAROSCOPY IN EVALUATING FALLOPIAN TUBES IN THE MANAGEMENT OF INFERTILITY IN COTONOU, BENIN REPUBLIC. AB - INTRODUCTION: Hysterosalpingography, along with laparoscoy, are the most requested examinations for tubal factor exploration for infertility, in developing countries. OBJECTIVE: To compare the results of hysperosalpingography and laparoscopy in patients assessed for infertility. PATIENTS & METHODS: This was a 5 years retrospective, descriptive study done at the Obstetrics and Gynecology Clinic of the HKM Centre, National University Hospital. All the patients admitted for infertility of tubal origin were included. These included 96 patients who had undergone hysterosalpingography followed by laparoscopy. The analysis was done with the SPSS version 12.0.1. RESULT: The mean age of the patients was 33.3 years. Infertility was primary in 66.3% of cases and secondary in 33.7% of cases and the average duration was 48.9 months. Hysterosalpingography diagnosed 9.37% of proximal tubal obstruction while laparoscopy diagnosed same in 17.71%. Besides pelvic adhesive bands seen in 33.33% of cases, laparoscopy was able to visualize patent tubes with some pathology in 11.46%, and pelvic endometriosis in 6.25% of cases. CONCLUSION: The results of HSG and those of laparoscopy are complementary in tubal infertility evaluation. While HSG seems to be reliable when the tubes are patent, laparoscopy helps to reveal false tubal obstructions observed with HSG, and also helps in the diagnosis of pelvic adhesive bands and endometriosis. PMID- 26587524 TI - OBSTRUCTED INGUINAL HERNIA IN CHILDREN: CASE-CONTROLLED APPROACH TO EVALUATE THE INFLUENCE OF SOCIO-DEMOGRAPHIC VARIABLES. AB - BACKGROUND: Obstructed inguinal hernia in children is associated with high morbidity in developing countries due to delay in accessing care. Attempts made to reduce waiting time to herniotomy are not backed by a predictive model of disease occurrence and modeling obstructed inguinal hernia implies knowledge of factors associated with this complication. AIM & OBJECTIVES: To determine the relationship between socio-demographic variables and obstructed inguinal hernia in children. DESIGN: Case controlled. SETTING: Paediatric surgery unit of a tertiary hospital. MATERIALS AND METHODS: The study was prospective - all children presenting with obstructed inguinal hernia at University College Hospital, Ibadan, Nigeria between May 2009 and April 2014 were studied. For each case, two children with non-obstructed inguinal hernia were recruited consecutively as controls. Their demographics, clinical features, management and outcomes were obtained including the socio-demographic attributes of the parents. The data obtained were computed using SPSS; the p-value for significance was set at < 0.05. RESULTS: A total of 81 consecutive patients (27 with obstructed inguinal hernia and 54 with non-obstructed inguinal hernia) were studied; they were aged between 2 weeks and 13 years with a mean of 25.9 +/- 3.8 months. There were no differences between cases and controls based on gender, parents' religion, tribe, social status and side affected (p > 0.05). The mean age at presentation was 13.7 +/- 5.6 months in the obstructed inguinal hernia vs. 32.0 +/- 4.8 months in the non-obstructed inguinal hernia groups (p = 0.016). The duration of groin swelling before presentation was not significantly different (30.0 +/- 7.7 vs. 28.3 +/- 6.4 months, p = 0.893). Infants were three times more likely than older children to develop obstruction (OR = 3.33, CI: 1.20, 9.09, p = 0.020). CONCLUSION: The age at presentation is the significant socio-demographic variable in this study that could predict obstruction in healthy children with inguinal hernia delivered at term. PMID- 26587525 TI - INITIAL EXPERIENCE WITH TRANSPUPILLARY DIODE LASER PHOTOCOAGULATION FOR RETINAL DISEASES. AB - BACKGROUND: Lasers are an invaluable treatment modality for the management of some retinovascular diseases. One of these lasers is the diode laser which is easy to procure and maintain. AIM: To review the outcomes of diode laser photocoagulation in patients with a variety of retinal conditions. PATIENTS & METHODS: A retrospective case series of all patients who had retinal laser photocoagulation between July 2012 and June 2014 with the semiconductor infrared diode laser was performed. Demographic and clinical data collected included age, sex, eye involved, visual acuity, diagnosis, associated systemic and ocular diseases, intra and post treatment findings, laser treatment parameters and follow up. RESULTS: A total of 22 eyes of 15 patients had diode laser treatment during the period under review comprising 8(53.3%) males and 7(46.7%) females with a mean age at presentation of 53.4+/-8.9 years. The indications for treatment were proliferative diabetic retinopathy in 18(81.8%) eyes of 11 patients, retinal vein occlusion in 2(9.1%) eyes of 2 patients and retinal breaks with lattice in 2(9.1%) eyes of 2 patients with fellow eye retinal detachment. Visual acuity in eyes with diabetic retinopathy improved in 9(50%) eyes, worsened in 3(16.7%) eyes and was unchanged/ stable in 6(33.3%) eyes. Regression of neovascularization was achieved in 2(100%) eyes with retinal vein occlusion. The retina of the 2(100%) eyes with breaks following retinopexy remained attached during the follow up period. The follow up period ranged from 2 days to 2 years with a mean duration of 13.5+/-15.8 months. CONCLUSION: The diode laser is an effective and beneficial treatment modality in the management of proliferative retinopathies and some retinal diseases. PMID- 26587526 TI - GIANT RECURRENT CYSTIC HYGROMA: A CASE REPORT. AB - Cystic hygroma is a benign lymphatic malformation most commonly occurring in the cervico-facial region. It arises from sequestered lymphatic sacs that fail to communicate with the lymphatico-venous system. Although commonly presenting in paediatric age, cystic hygroma can occur at any age. Recurrent cystic hygroma is a known entity and can result from inadequate excision or specific tumour characteristics. We report such a case of giant recurrent cystic hygroma in the neck in a 14 years old female the surgical management of which was challenging due to the large size, previous adhesions and proximity to vital structures. PMID- 26587528 TI - PEER-REVIEWED ABSTRACTS OF SCIENTIFIC PAPER PRESENTATION AT THE 54TH ANNUAL CONFERENCE OF THE WEST AFRICAN COLLEGE OF SURGEONS AT KUMASI, GHANA 24TH - 28TH FEBRUARY, 2014. PMID- 26587527 TI - MALIGNANT TRANSFORMATION OF CRANIAL NERVE SCHWANNOMA AFTER RADIOSURGERY - CASE REPORT. AB - We describe an unusual case of malignant transformation of benign cranial nerves schwannoma eleven months after surgery and five months post radiotherapy. There has been no evidence of recurrence after 5 years follow-up. This early malignant transformation of a schwannoma involved cranial nerves IX, X, XI. Due to the uncommon presentation and the uncertainty of the actual role of the radiation on the tumor behavior, the report of this case was considered clinically important. PMID- 26587529 TI - CURRENT TREND IN VAGINAL BIRTH AFTER CAESAREAN SECTION (VBAC) IN ACCRA. PMID- 26587530 TI - A Novel Mouse Model of Peritoneal Dialysis: Combination of Uraemia and Long-Term Exposure to PD Fluid. AB - Different animal models for peritoneal dialysis (PD) have been used in the past decades to develop PD fluids compatible with patient life and to identify markers of peritoneal fibrosis and inflammation. Only few of those studies have taken into account the importance of uraemia-induced alterations at both systemic and peritoneal levels. Moreover, some animal studies which have reported about PD in a uremic setting did not always entirely succeed in terms of uraemia establishment and animal survival. In the present study we induced uraemia in the recently established mouse PD exposure model in order to obtain a more clinically relevant mouse model for kidney patients. This new designed model reflected both the slight thickening of peritoneal membrane induced by uraemia and the significant extracellular matrix deposition due to daily PD fluid instillation. In addition the model offers the opportunity to perform long-term exposure to PD fluids, as it is observed in the clinical setting, and gives the advantage to knock out candidate markers for driving peritoneal inflammatory mechanisms. PMID- 26587531 TI - Intervention Mapping to Adapt Evidence-Based Interventions for Use in Practice: Increasing Mammography among African American Women. AB - This paper describes and demonstrates the use of the systematic planning process, Intervention Mapping, to adapt an evidence-based public health intervention (EBI). We used a simplified version of Intervention Mapping (IM Adapt) to increase an intervention's fit with a new setting and population. IM Adapt guides researchers and practitioners in selecting an EBI, making decisions about whether and what to adapt, and executing the adaptation while guarding the EBI's essential elements (those responsible for effectiveness). We present a case study of a project in which we used IM Adapt to find, adapt, implement, and evaluate an EBI to improve mammography adherence for African American women in a new practice setting in Houston, Texas. IM Adapt includes the following (1) assess needs and organizational capacity; (2) find EBIs; (3) plan adaptations based on fit assessments; (4) make adaptations; (5) plan for implementation; and (6) plan for evaluation of the adapted EBI. The case study shows an example of how public health researchers and practitioners can use the tool to make it easier to find and use EBIs, thus encouraging greater uptake. IM Adapt adds to existing dissemination and adaptation models by providing detailed guidance on how to decide on effective adaptation, while maintaining the essential elements of the EBI. PMID- 26587532 TI - Childhood Lead Exposure from Battery Recycling in Vietnam. AB - BACKGROUND: Battery recycling facilities in developing countries can cause community lead exposure. OBJECTIVE: To evaluate child lead exposure in a Vietnam battery recycling craft village after efforts to shift home-based recycling outside the village. METHODS: This cross-sectional study evaluated 109 children in Dong Mai village, using blood lead level (BLL) measurement, parent interview, and household observation. Blood samples were analyzed with a LeadCare II field instrument; highest BLLs (>=45 MUg/dL) were retested by laboratory analysis. Surface and soil lead were measured at 11 households and a school with X-ray fluorescence analyzer. RESULTS: All children had high BLLs; 28% had BLL >=45 MUg/dL. Younger age, family recycling, and outside brick surfaces were associated with higher BLL. Surface and soil lead levels were high at all tested homes, even with no recycling history. Laboratory BLLs were lower than LeadCare BLLs, in 24 retested children. DISCUSSION: In spite of improvements, lead exposure was still substantial and probably associated with continued home-based recycling, legacy contamination, and workplace take-home exposure pathways. There is a need for effective strategies to manage lead exposure from battery recycling in craft villages. These reported BLL values should be interpreted cautiously, although the observed field-laboratory discordance may reflect bias in laboratory results. PMID- 26587534 TI - Research Advances in Critical Care: Targeting Patients' Physiological and Psychological Outcomes. PMID- 26587533 TI - A New CT Method for Assessing 3D Movements in Lumbar Facet Joints and Vertebrae in Patients before and after TDR. AB - This study describes a 3D-CT method for analyzing facet joint motion and vertebral rotation in the lumbar spine after TDR. Ten patients were examined before and then three years after surgery, each time with two CT scans: provoked flexion and provoked extension. After 3D registration, the facet joint 3D translation and segmental vertebral 3D rotation were analyzed at the operated level (L5-S1) and adjacent level (L4-L5). Pain was evaluated using VAS. The median (+/-SD) 3D movement in the operated level for the left facet joint was 3.2 mm (+/-1.9 mm) before and 3.5 mm (+/-1.7 mm) after surgery and for the right facet joint was 3.0 mm (+/-1.0 mm) before and 3.6 mm (+/-1.4 mm) after surgery. The median vertebral rotation in the sagittal plane at the operated level was 5.4 degrees (+/-2.3 degrees ) before surgery and 6.8 degrees (+/-1.7 degrees ) after surgery and in the adjacent level was 7.7 degrees (+/-4.0 degrees ) before and 9.2 degrees (+/-2.7 degrees ) after surgery. The median VAS was reduced from 6 (range 5-8) to 3 (range 2-8) in extension and from 4 (range 2-6) to 2 (range 1 3) in flexion. PMID- 26587535 TI - Corrigendum to "Animal Models for the Study of Rodent-Borne Hemorrhagic Fever Viruses: Arenaviruses and Hantaviruses". PMID- 26587536 TI - Syncytiotrophoblast Functions and Fetal Growth Restriction during Placental Malaria: Updates and Implication for Future Interventions. AB - Syncytiotrophoblast lines the intervillous space of the placenta and plays important roles in fetus growth throughout gestation. However, perturbations at the maternal-fetal interface during placental malaria may possibly alter the physiological functions of syncytiotrophoblast and therefore growth and development of the embryo in utero. An understanding of the influence of placental malaria on syncytiotrophoblast function is paramount in developing novel interventions for the control of placental pathology associated with placental malaria. In this review, we discuss how malaria changes syncytiotrophoblast function as evidenced from human, animal, and in vitro studies and, further, how dysregulation of syncytiotrophoblast function may impact fetal growth in utero. We also formulate a hypothesis, stemming from epidemiological observations, that nutrition may override pathogenesis of placental malaria-associated-fetal growth restriction. We therefore recommend studies on nutrition-based-interventional approaches for high placental malaria risk women in endemic areas. More investigations on the role of nutrition on placental malaria pathogenesis are needed. PMID- 26587538 TI - ECG-Based Detection of Early Myocardial Ischemia in a Computational Model: Impact of Additional Electrodes, Optimal Placement, and a New Feature for ST Deviation. AB - In case of chest pain, immediate diagnosis of myocardial ischemia is required to respond with an appropriate treatment. The diagnostic capability of the electrocardiogram (ECG), however, is strongly limited for ischemic events that do not lead to ST elevation. This computational study investigates the potential of different electrode setups in detecting early ischemia at 10 minutes after onset: standard 3-channel and 12-lead ECG as well as body surface potential maps (BSPMs). Further, it was assessed if an additional ECG electrode with optimized position or the right-sided Wilson leads can improve sensitivity of the standard 12-lead ECG. To this end, a simulation study was performed for 765 different locations and sizes of ischemia in the left ventricle. Improvements by adding a single, subject specifically optimized electrode were similar to those of the BSPM: 2-11% increased detection rate depending on the desired specificity. Adding right-sided Wilson leads had negligible effect. Absence of ST deviation could not be related to specific locations of the ischemic region or its transmurality. As alternative to the ST time integral as a feature of ST deviation, the K point deviation was introduced: the baseline deviation at the minimum of the ST-segment envelope signal, which increased 12-lead detection rate by 7% for a reasonable threshold. PMID- 26587539 TI - T Lymphocyte Plasticity in Autoimmunity and Cancer. PMID- 26587537 TI - The Emerging Role of Extracellular Vesicle-Mediated Drug Resistance in Cancers: Implications in Advanced Prostate Cancer. AB - Emerging evidence has shown that the extracellular vesicles (EVs) regulate various biological processes and can control cell proliferation and survival, as well as being involved in normal cell development and diseases such as cancers. In cancer treatment, development of acquired drug resistance phenotype is a serious issue. Recently it has been shown that the presence of multidrug resistance proteins such as Pgp-1 and enrichment of the lipid ceramide in EVs could have a role in mediating drug resistance. EVs could also mediate multidrug resistance through uptake of drugs in vesicles and thus limit the bioavailability of drugs to treat cancer cells. In this review, we discussed the emerging evidence of the role EVs play in mediating drug resistance in cancers and in particular the role of EVs mediating drug resistance in advanced prostate cancer. The role of EV-associated multidrug resistance proteins, miRNA, mRNA, and lipid as well as the potential interaction(s) among these factors was probed. Lastly, we provide an overview of the current available treatments for advanced prostate cancer, considering where EVs may mediate the development of resistance against these drugs. PMID- 26587540 TI - Long-Term In Vitro Degradation of a High-Strength Brushite Cement in Water, PBS, and Serum Solution. AB - Bone loss and fractures may call for the use of bone substituting materials, such as calcium phosphate cements (CPCs). CPCs can be degradable, and, to determine their limitations in terms of applications, their mechanical as well as chemical properties need to be evaluated over longer periods of time, under physiological conditions. However, there is lack of data on how the in vitro degradation affects high-strength brushite CPCs over longer periods of time, that is, longer than it takes for a bone fracture to heal. This study aimed at evaluating the long-term in vitro degradation properties of a high-strength brushite CPC in three different solutions: water, phosphate buffered saline, and a serum solution. Microcomputed tomography was used to evaluate the degradation nondestructively, complemented with gravimetric analysis. The compressive strength, chemical composition, and microstructure were also evaluated. Major changes from 10 weeks onwards were seen, in terms of formation of a porous outer layer of octacalcium phosphate on the specimens with a concomitant change in phase composition, increased porosity, decrease in object volume, and mechanical properties. This study illustrates the importance of long-term evaluation of similar cement compositions to be able to predict the material's physical changes over a relevant time frame. PMID- 26587541 TI - Pathology of Tinnitus and Hyperacusis-Clinical Implications. PMID- 26587542 TI - JPPRED: Prediction of Types of J-Proteins from Imbalanced Data Using an Ensemble Learning Method. AB - Different types of J-proteins perform distinct functions in chaperone processes and diseases development. Accurate identification of types of J-proteins will provide significant clues to reveal the mechanism of J-proteins and contribute to developing drugs for diseases. In this study, an ensemble predictor called JPPRED for J-protein prediction is proposed with hybrid features, including split amino acid composition (SAAC), pseudo amino acid composition (PseAAC), and position specific scoring matrix (PSSM). To deal with the imbalanced benchmark dataset, the synthetic minority oversampling technique (SMOTE) and undersampling technique are applied. The average sensitivity of JPPRED based on above-mentioned individual feature spaces lies in the range of 0.744-0.851, indicating the discriminative power of these features. In addition, JPPRED yields the highest average sensitivity of 0.875 using the hybrid feature spaces of SAAC, PseAAC, and PSSM. Compared to individual base classifiers, JPPRED obtains more balanced and better performance for each type of J-proteins. To evaluate the prediction performance objectively, JPPRED is compared with previous study. Encouragingly, JPPRED obtains balanced performance for each type of J-proteins, which is significantly superior to that of the existing method. It is anticipated that JPPRED can be a potential candidate for J-protein prediction. PMID- 26587543 TI - Evaluation of MicroRNAs Regulating Anoikis Pathways and Its Therapeutic Potential. AB - Dysregulation of microRNAs (miRNAs) has been implicated in almost every known survival mechanisms utilized by cancer cells. One of such mechanisms, anoikis resistance, plays a pivotal role in enabling metastasis by allowing cancer cells to circumvent cell death induced by lack of attachment. Understanding how miRNAs regulate the various anoikis pathways has become the research question of increasing number of studies published in the past years. Through these studies, a growing list of miRNAs has been identified to be important players in promoting either anoikis or resistance to anoikis. In this review, we will be focusing on these miRNAs and how the findings from those studies can contribute to novel therapeutic strategies against cancer progression. We will be examining miRNAs that have been found to promote anoikis sensitivity in numerous cancer types followed by miRNAs that inhibit anoikis. In addition, we will also be taking a look at major signaling pathways involved in the action of the each of these miRNAs to gain a better understanding on how miRNAs regulate anoikis. PMID- 26587544 TI - Filament Dynamics during Simulated Ventricular Fibrillation in a High-Resolution Rabbit Heart. AB - The mechanisms underlying ventricular fibrillation (VF) are not well understood. The electrical activity on the heart surface during VF has been recorded extensively in the experimental setting and in some cases clinically; however, corresponding transmural activation patterns are prohibitively difficult to measure. In this paper, we use a high-resolution biventricular heart model to study three-dimensional electrical activity during fibrillation, focusing on the driving sources of VF: "filaments," the organising centres of unstable reentrant scroll waves. We show, for the first time, specific 3D filament dynamics during simulated VF in a whole heart geometry that includes fine-scale anatomical structures. Our results suggest that transmural activity is much more complex than what would be expected from surface observations alone. We present examples of complex intramural activity, including filament breakup and reattachment, anchoring to the thin right ventricular apex; rapid transitions among various filament shapes; and filament lengths much greater than wall thickness. We also present evidence for anatomy playing a major role in VF development and coronary vessels and trabeculae influencing filament dynamics. Overall, our results indicate that intramural activity during simulated VF is extraordinarily complex and suggest that further investigation of 3D filaments is necessary to fully comprehend recorded surface patterns. PMID- 26587545 TI - A Computer Simulation Study of Anatomy Induced Drift of Spiral Waves in the Human Atrium. AB - The interaction of spiral waves of excitation with atrial anatomy remains unclear. This simulation study isolates the role of atrial anatomical structures on spiral wave spontaneous drift in the human atrium. We implemented realistic and idealised 3D human atria models to investigate the functional impact of anatomical structures on the long-term (~40 s) behaviour of spiral waves. The drift of a spiral wave was quantified by tracing its tip trajectory, which was correlated to atrial anatomical features. The interaction of spiral waves with the following idealised geometries was investigated: (a) a wedge-like structure with a continuously varying atrial wall thickness; (b) a ridge-like structure with a sudden change in atrial wall thickness; (c) multiple bridge-like structures consisting of a bridge connected to the atrial wall. Spiral waves drifted from thicker to thinner regions and along ridge-like structures. Breakthrough patterns caused by pectinate muscles (PM) bridges were also observed, albeit infrequently. Apparent anchoring close to PM-atrial wall junctions was observed. These observations were similar in both the realistic and the idealised models. We conclude that spatially altering atrial wall thickness is a significant cause of drift of spiral waves. PM bridges cause breakthrough patterns and induce transient anchoring of spiral waves. PMID- 26587546 TI - Comment on "Second-Hand Smoking among Intermediate and Secondary School Students in Madinah, Saudi Arabia". PMID- 26587547 TI - Association between Genetic Variants and Diabetes Mellitus in Iranian Populations: A Systematic Review of Observational Studies. AB - INTRODUCTION: Diabetes mellitus as the most prevalent metabolic disease is a multifactorial disease which is influenced by environmental and genetic factors. In this systematic review, we assessed the association between genetic variants and diabetes/its complications in studies with Iranian populations. METHODS: Google Scholar, PubMed, Scopus, and Persian web databases were systematically searched up to January 2014. The search terms were "gene," "polymorphism," "diabetes," and "diabetic complications"; nephropathy, retinopathy, neuropathy, foot ulcer, and CAD (coronary artery diseases); and Persian equivalents. Animal studies, letters to editor, and in vitro studies were excluded. RESULTS: Out of overall 3029 eligible articles, 88 articles were included. We found significant association between CTLA-4, IL-18, VDR, TAP2, IL-12, and CD4 genes and T1DM, HNFalpha and MODY, haptoglobin, paraoxonase, leptin, TCF7L2, calreticulin, ERalpha, PPAR-gamma2, CXCL5, calpain-10, IRS-1 and 2, GSTM1, KCNJ11, eNOS, VDR, INSR, ACE, apoA-I, apo E, adiponectin, PTPN1, CETP, AT1R, resistin, MMP-3, BChE K, AT2R, SUMO4, IL-10, VEGF, MTHFR, and GSTM1 with T2DM or its complications. DISCUSSION: We found some controversial results due to heterogeneity in ethnicity and genetic background. We thought genome wide association studies on large number of samples will be helpful in identifying diabetes susceptible genes as an alternative to studying individual candidate genes in Iranian populations. PMID- 26587549 TI - Core samples for radiomics features that are insensitive to tumor segmentation: method and pilot study using CT images of hepatocellular carcinoma. AB - The purpose of this study is to investigate the utility of obtaining "core samples" of regions in CT volume scans for extraction of radiomic features. We asked four readers to outline tumors in three representative slices from each phase of multiphasic liver CT images taken from 29 patients (1128 segmentations) with hepatocellular carcinoma. Core samples were obtained by automatically tracing the maximal circle inscribed in the outlines. Image features describing the intensity, texture, shape, and margin were used to describe the segmented lesion. We calculated the intraclass correlation between the features extracted from the readers' segmentations and their core samples to characterize robustness to segmentation between readers, and between human-based segmentation and core sampling. We conclude that despite the high interreader variability in manually delineating the tumor (average overlap of 43% across all readers), certain features such as intensity and texture features are robust to segmentation. More importantly, this same subset of features can be obtained from the core samples, providing as much information as detailed segmentation while being simpler and faster to obtain. PMID- 26587550 TI - Quantitative performance characterization of image quality and radiation dose for a CS 9300 dental cone beam computed tomography machine. AB - This paper aims to characterize the radiation dose and image quality (IQ) performance of a dental cone beam computed tomography (CBCT) unit over a range of fields of view (FOV). IQ and dose were measured using a Carestream 9300 dental CBCT. Phantoms were positioned in the FOV to imitate clinical positioning. IQ was assessed by scanning a SEDENTEXCT IQ phantom, and images were analyzed in ImageJ. Dose index 1 was obtained using a thimble ionization chamber and SEDENTEXCT DI phantom. Mean gray values agreed within 93.5% to 99.7% across the images, with pixel-to-pixel fluctuations of 6% to 12.5%, with poorer uniformity and increased noise for child protocols. CNR was fairly constant across FOVs, with higher CNR for larger patient settings. The measured limiting spatial resolution agreed well with 10% MTF and bar pattern measurements. Dose was reduced for smaller patient settings within a given FOV; however, smaller FOVs obtained with different acquisition settings did not necessarily result in reduced dose. The use of patient-specific acquisition settings decreased the radiation dose for smaller patients, with minimal impact on the IQ. The full set of IQ and dose measurements is reported to allow dental professionals to compare the different FOV settings for clinical use. PMID- 26587548 TI - Cellular and Antibody Based Approaches for Pediatric Cancer Immunotherapy. AB - Progress in the use of traditional chemotherapy and radiation-based strategies for the treatment of pediatric malignancies has plateaued in the past decade, particularly for patients with relapsing or therapy refractory disease. As a result, cellular and humoral immunotherapy approaches have been investigated for several childhood cancers. Several monoclonal antibodies are now FDA approved and commercially available, some of which are currently considered standard of practice. There are also several new cellular immunotherapy approaches under investigation, including chimeric antigen receptor (CAR) modified T cells, cancer vaccines and adjuvants, and natural killer (NK) cell therapies. In this review, we will discuss previous studies on pediatric cancer immunotherapy and new approaches that are currently being investigated in clinical trials. PMID- 26587551 TI - Automatic segmentation of mandible in panoramic x-ray. AB - As the panoramic x-ray is the most common extraoral radiography in dentistry, segmentation of its anatomical structures facilitates diagnosis and registration of dental records. This study presents a fast and accurate method for automatic segmentation of mandible in panoramic x-rays. In the proposed four-step algorithm, a superior border is extracted through horizontal integral projections. A modified Canny edge detector accompanied by morphological operators extracts the inferior border of the mandible body. The exterior borders of ramuses are extracted through a contour tracing method based on the average model of mandible. The best-matched template is fetched from the atlas of mandibles to complete the contour of left and right processes. The algorithm was tested on a set of 95 panoramic x-rays. Evaluating the results against manual segmentations of three expert dentists showed that the method is robust. It achieved an average performance of [Formula: see text] in Dice similarity, specificity, and sensitivity. PMID- 26587552 TI - Matching methods evaluation framework for stereoscopic breast x-ray images. AB - Three-dimensional (3-D) imaging has been intensively studied in the past few decades. Depth information is an important added value of 3-D systems over two dimensional systems. Special focuses were devoted to the development of stereo matching methods for the generation of disparity maps (i.e., depth information within a 3-D scene). Dedicated frameworks were designed to evaluate and rank the performance of different stereo matching methods but never considering x-ray medical images. Yet, 3-D x-ray acquisition systems and 3-D medical displays have already been introduced into the diagnostic market. To access the depth information within x-ray stereoscopic images, computing accurate disparity maps is essential. We aimed at developing a framework dedicated to x-ray stereoscopic breast images used to evaluate and rank several stereo matching methods. A multiresolution pyramid optimization approach was integrated to the framework to increase the accuracy and the efficiency of the stereo matching techniques. Finally, a metric was designed to score the results of the stereo matching compared with the ground truth. Eight methods were evaluated and four of them [locally scaled sum of absolute differences (LSAD), zero mean sum of absolute differences, zero mean sum of squared differences, and locally scaled mean sum of squared differences] appeared to perform equally good with an average error score of 0.04 (0 is the perfect matching). LSAD was selected for generating the disparity maps. PMID- 26587553 TI - Myeloid cells as target of fingolimod action in multiple sclerosis. AB - OBJECTIVE: To track the effects of fingolimod, an approved drug for multiple sclerosis (MS), on the activation of myeloid cells from the periphery to the CNS. METHODS: In vitro and ex vivo immunologic studies coupled with flow cytometry were performed to evaluate the action of fingolimod on lipopolysaccharide (LPS) induced expression of activation markers in human monocytes from healthy participants, participants with untreated MS, and participants with fingolimod treated MS. In vivo administration of fingolimod during experimental autoimmune encephalomyelitis (EAE) was established to verify the activation state of splenic, CNS infiltrating, and CNS resident myeloid cells ex vivo at flow cytometer. RESULTS: We found that in vitro exposure of human monocytes to fingolimod inhibited LPS-induced CD25 and CD150 expression and tumor necrosis factor-alpha (TNF-alpha) secretion without altering immune cell survival. Further, EAE treatment with fingolimod led to reduced amounts of TNF-alpha produced by myeloid cells in vivo in the spleen and CNS. Finally, while displaying normal induction of CD25 and CD150 levels at high LPS concentration, monocytes from patients with fingolimod-treated MS showed significantly higher activation threshold at suboptimal LPS stimulation than controls. CONCLUSIONS: The inhibition of myeloid cell activation may be part of the immunosuppressive action of fingolimod and take place in the periphery and in the CNS. PMID- 26587554 TI - Intrathecal immunoglobulin A and G antibodies to synapsin in a patient with limbic encephalitis. AB - OBJECTIVE: To report on the identification of intrathecally synthesized immunoglobulin A (IgA) and immunoglobulin G (IgG) antibodies to synapsin, a synaptic vesicle-associated protein, in a patient with limbic encephalitis. METHODS: Methods included clinical characterization, indirect immunofluorescence, immunoprecipitation, mass spectrometry, immunoblots of wild-type and synapsin I/II/III knockout mice, and cell-based assays with synapsin Ia, Ib, IIa, and IIb plasmids. RESULTS: A 69-year-old man presented with confusion, disorientation, seizures, and left hippocampal hyperintensities on MRI. CSF examinations revealed an intrathecal IgA and IgG synthesis. Except for IgG antibodies to voltage-gated potassium channels in CSF, screening for known neuronal autoantibodies in serum and CSF was negative. However, indirect immunofluorescence using the patient's CSF showed binding of IgA to mouse hippocampus, amygdala, and cerebellum. Immunoprecipitation with CSF IgA followed by mass spectrometry identified synapsin as autoantigenic target. Knockout tissues and cell-based assays confirmed that IgA and IgG in the patient's CSF and serum reacted with synapsin Ia, Ib, and IIa. Calculation of antibody indices proved intrathecal synthesis of anti-synapsin IgA and IgG. The patient responded clinically to immunotherapy but developed left hippocampal atrophy. CSF IgA or IgG of the patient did not bind to live, unfixed, and nonpermeabilized mouse hippocampal neurons, compatible with synapsin being an intracellular antigen. CONCLUSIONS: This report identifies isoforms of the synaptic vesicle-associated protein synapsin as targets of intrathecally produced IgA and IgG antibodies in a patient with limbic encephalitis. Future studies should clarify the prevalence and pathogenic relevance of anti-synapsin antibodies in limbic encephalitis. PMID- 26587555 TI - Autoregulatory CD8 T cells depend on cognate antigen recognition and CD4/CD8 myelin determinants. AB - OBJECTIVE: To determine the antigenic determinants and specific molecular requirements for the generation of autoregulatory neuroantigen-specific CD8(+) T cells in models of multiple sclerosis (MS). METHODS: We have previously shown that MOG35-55-specific CD8(+) T cells suppress experimental autoimmune encephalomyelitis (EAE) in the C57BL/6 model. In this study, we utilized multiple models of EAE to assess the ability to generate autoregulatory CD8(+) T cells. RESULTS: We demonstrate that alternative myelin peptides (PLP178-191) and other susceptible mouse strains (SJL) generated myelin-specific CD8(+) T cells, which were fully capable of suppressing disease. The disease-ameliorating function of these cells was dependent on the specific cognate myelin antigen. Generation of these autoregulatory CD8(+) T cells was not affected by thymic selection, but was dependent on the presence of both CD4(+) and CD8(+) T-cell epitopes in the immunizing encephalitogenic antigen. CONCLUSIONS: These studies show that the generation of autoregulatory CD8(+) T cells is a more generalized, antigen specific phenomenon across multiple neuroantigens and mouse strains, with significant implications in understanding disease regulation. PMID- 26587557 TI - Specifications of ZnO growth for heterostructure solar cell and PC1D based simulations. AB - This data article is related to our recently published article (Hussain et al., in press [1]) where we have proposed a new solar cell model based on n-ZnO as front layer and p-Si as rear region. The ZnO layer will act as an active n-layer as well as antireflection (AR) coating saving considerable processing cost. There are several reports presenting use of ZnO as window/antireflection coating in solar cells (Mansoor et al., 2015; Haq et al., 2014; Hussain et al., 2014; Matsui et al., 2014; Ding et al., 2014 [2], [3], [4], [5], [6]) but, here, we provide data specifically related to simultaneous use of ZnO as n-layer and AR coating. Apart from the information we already published, we provide additional data related to growth of ZnO (with and without Ga incorporation) layers using MOCVD. The data related to PC1D based simulation of internal and external quantum efficiencies with and without antireflection effects of ZnO as well as the effects of doping level in p-Si on current-voltage characteristics have been provided. PMID- 26587556 TI - Fulminant demyelinating encephalomyelitis: Insights from antibody studies and neuropathology. AB - OBJECTIVES: Antibodies to myelin oligodendrocyte glycoprotein (MOG) are detectable in inflammatory demyelinating CNS diseases, and MOG antibody associated diseases seem to have a better prognosis despite occasionally severe presentations. METHODS: We report the case of a 71-year-old patient with acute visual and gait disturbance that dramatically worsened to bilateral amaurosis, tetraplegia, and respiratory insufficiency within a few days. RESULTS: MRI showed multiple progressive cerebral and spinal lesions with diffusion restriction (including both optic nerves) and marginal contrast enhancement. Routine blood and CSF measures including oligoclonal bands were normal. At disease onset, MOG immunoglobulin G was detected (serum titer 1:1,280, corresponding CSF titer was 1:20) and remained positive in patient serum. Aquaporin-4 antibodies were absent at disease onset but seroconverted to positive at week 9. In addition, CSF glial fibrillary acid protein and myelin basic protein levels were very high at onset but decreased during disease course. After 4 months, the patient died despite immunomodulatory treatment. Postmortem neuropathologic examination revealed an acute multiple sclerosis (MS) defined by multiple demyelinating lesions with a pronounced destructive component and loss of astrocytes. Lesion pattern of optic chiasm met MS pattern II characterized by antibody and complement-mediated demyelination. CONCLUSION: The case with the clinical presentation of an acute demyelinating encephalomyelitis with predominant optic and spinal involvement, absent oligoclonal bands, a histopathology of acute MS pattern II and development of aquaporin-4 antibodies extends the spectrum of MOG antibody-associated encephalomyelitis. Although, MOG antibodies are suspected to indicate a favorable prognosis, fulminant disease courses are possible and warrant an aggressive immunotherapy. PMID- 26587558 TI - Data characterizing compressive properties of Al/Al2O3 syntactic foam core metal matrix sandwich. AB - Microstructural observations and compressive property datasets of metal matrix syntactic foam core sandwich composite at quasi-static and high strain rate (HSR) conditions (525-845 s(-1)) are provided. The data supplied in this article includes sample preparation procedure prior to scanning electron and optical microscopy as well as the micrographs. The data used to construct the stress strain curves and the derived compressive properties of all specimens in both quasi-static and HSR regions are included. Videos of quasi-static compressive failure and that obtained by a high speed image acquisition system during deformation and failure of HSR specimen are also included. PMID- 26587559 TI - Data in support of substrate flexibility of a mutated acyltransferase domain and implications for polyketide biosynthesis. AB - Enzyme-directed mutasynthesis is an emerging strategy for the targeted derivatization of natural products. Here, data on the synthesis of malonic acid derivatives for feeding studies in Saccharopolyspora erythraea , the mutagenesis of DEBS and bioanalytical data on the experimental investigation of studies on the biosynthetic pathway towards erythromycin are presented. PMID- 26587560 TI - Diffusion coefficients and dissociation constants of enhanced green fluorescent protein binding to free standing membranes. AB - Recently, a new and versatile assay to determine the partitioning coefficient [Formula: see text] as a measure for the affinity of peripheral membrane proteins for lipid bilayers was presented in the research article entitled, "Introducing a fluorescence-based standard to quantify protein partitioning into membranes" [1]. Here, the well-characterized binding of hexahistidine-tag (His6) to NTA(Ni) was utilized. Complementarily, this data article reports the average diffusion coefficient [Formula: see text] of His6-tagged enhanced green fluorescent protein (eGFP-His6) and the fluorescent lipid analog ATTO-647N-DOPE in giant unilamellar vesicles (GUVs) containing different amounts of NTA(Ni) lipids. In addition, dissociation constants [Formula: see text] of the NTA(Ni)/eGFP-His6 system are reported. Further, a conversion between [Formula: see text] and [Formula: see text] is provided. PMID- 26587561 TI - TAILS N-terminomic and proteomic datasets of healthy human dental pulp. AB - The Data described here provide the in depth proteomic assessment of the human dental pulp proteome and N-terminome (Eckhard et al., 2015) [1]. A total of 9 human dental pulps were processed and analyzed by the positional proteomics technique TAILS (Terminal Amine Isotopic Labeling of Substrates) N-terminomics. 38 liquid chromatography tandem mass spectrometry (LC-MS/MS) datasets were collected and analyzed using four database search engines in combination with statistical downstream evaluation, to yield the by far largest proteomic and N terminomic dataset of any dental tissue to date. The raw mass spectrometry data and the corresponding metadata have been deposited in ProteomeXchange with the PXD identifier ; Supplementary Tables described in this article are available via Mendeley Data (10.17632/555j3kk4sw.1). PMID- 26587563 TI - Comment on "Dependence of Performance of Si Nanowire Solar Cells on Geometry of the Nanowires". PMID- 26587562 TI - Biological Evidence Management for DNA Analysis in Cases of Sexual Assault. AB - Biological evidence with forensic interest may be found in several cases of assault, being particularly relevant if sexually related. Sexual assault cases are characterized by low rates of disclosure, reporting, prosecution, and conviction. Biological evidence is sometimes the only way to prove the occurrence of sexual contact and to identify the perpetrator. The major focus of this review is to propose practical approaches and guidelines to help health, forensic, and law enforcement professionals to deal with biological evidence for DNA analysis. Attention should be devoted to avoiding contamination, degradation, and loss of biological evidence, as well as respecting specific measures to properly handle evidence (i.e., selection, collection, packing, sealing, labeling, storage, preservation, transport, and guarantee of the chain custody). Biological evidence must be carefully managed since the relevance of any finding in Forensic Genetics is determined, in the first instance, by the integrity and quantity of the samples submitted for analysis. PMID- 26587564 TI - Morphologic Response of the Pulmonary Vasculature to Endoscopic Lung Volume Reduction. AB - INTRODUCTION: Endoscopic Lung Volume Reduction has been used to reduce lung hyperinflation in selected patients with severe emphysema. Little is known about the effect of this procedure on the intraparenchymal pulmonary vasculature. In this study we used CT based vascular reconstruction to quantify the effect of the procedure on the pulmonary vasculature. METHODS: Intraparenchymal vasculature was reconstructed and quantified in 12 patients with CT scans at baseline and 12 weeks following bilateral introduction of sealants in the upper lobes. The volume of each lung and each lobe was measured, and the vascular volume profile was calculated for both lower lobes. The detected vasculature was further labeled manually as arterial or venous in the right lower lobe. RESULTS: There was an increase in the volume of the lower lobes (3.14L to 3.25L, p=0.0005). There was an increase in BV5, defined as the volume of blood vessels with cross sectional area of less than 5mm2, (53.2ml to 57.9ml, p=0.03). This was found to be correlated with the increase in lower lobe volumes (R=0.65, p=0.02). The changes appear to be symmetric for veins and arteries with a correlation coefficient of 0.87 and a slope of near identity. CONCLUSION: In the subjects studied, there was an increase, from baseline, in BV5 in the lower lobes that correlated with the change in the volume of the lower lobes. The change appeared to be symmetric for both arteries and veins. The study illustrates the use of intraparenchymal pulmonary vascular reconstruction to study morphologic changes in response to interventions. PMID- 26587565 TI - Isolated Large Cell Calcifying Sertoli Cell Tumor in a Young Boy, not Associated with Peutz-Jeghers Syndrome or Carney Complex. AB - BACKGROUND: Large cell calcifying sertoli cell tumor (LCCSCT) is an exceedingly rare lesion of the testicle. It is most often seen in patients with Carney complex (CNC) or Peutz-Jeghers syndrome (PJS). We now report the first pediatric patient with what appears to be bilateral LCCSCT and no other conditions or a genetic syndrome, such as PJS or CNC, have been associated with it. METHODS: A 10 year-old boy was found to have a right testicular mass during a routine pediatric examination; he underwent right orchiectomy. He was then evaluated clinically for PJS or CNC and underwent genetic testing. His tumor was studied by immunohistochemistry for the expression of calretinin, NY-ESO-1, inhibin, CD99, S100, PLAP, AE1/AE3, Bcl-2, p53, and Mib1. RESULTS: Patient did not have clinical features or genetic abnormalities of CNC and PJS. Microscopic features showed large, round or cubical intratubular and aggregated tumor cells with prominent nuclear atypia, large and prominent nucleoli and extensive calcification. In the Immunohistochemical studies, calretinin and inhibin alpha were up regulated in LCCSCT as compared to the adjacent benign Sertoli cells. Meanwhile, NY-ESO-1 and CD99 were down-regulated in LCCSCT. Focally and weakly positive S100 was found in the tumor tissue, but no S100 expression was present in the adjacent Sertoli cells. There was no expression of PLAP, P53, Bcl-2, Mib1 and AE1/AE3 in LCCSCT and adjacent Sertoli cells. Micro-calcifications were found in the other gonad by ultrasonography, suggesting LCCSCT. CONCLUSION: LCCSCT is a rare testicular neoplasm, and may present in isolated rather than in more typical association with syndromes such as CNC and PJS. PMID- 26587566 TI - Uniaxial magnetic anisotropy of square-planar chromium(II) complexes revealed by magnetic and HF-EPR studies. AB - Two mononuclear square-planar Cr(II) complexes are reported, exhibiting field induced slow magnetic relaxation. The axial zero-field splitting parameter was unambiguously determined by both a high-frequency/field electron paramagnetic resonance (HF-EPR) technique and magnetic measurements. This result represents the first observed single-molecule-magnet behavior in the square planar coordination geometry of any metal ions. PMID- 26587567 TI - Metal-organic framework derived hollow polyhedron metal oxide posited graphene oxide for energy storage applications. AB - A composite made from hollow polyhedron copper oxide and graphene oxide was synthesized by sintering a Cu-based metal-organic framework (Cu-MOF) embedded with exfoliated graphene oxide. As a proof-of-concept application, the obtained Cu(ox)-rGO materials were used in a lithium-ion battery and a sodium-ion battery as anode materials. Overall, the Cu(ox)-rGO composite delivers excellent electrochemical properties with stable cycling when compared to pure CuO-rGO and Cu-MOF. PMID- 26587569 TI - Chemo- and regioselective reductive transposition of allylic alcohol derivatives via iridium or rhodium catalysis. AB - We report highly chemo- and regioselective reductive transpositions of methyl carbonates to furnish olefin products with complementary regioselectivity to that of established Pd-catalysis. These Rh- and Ir-catalysed transformations proceed under mild conditions and enable selective deoxygenation in the presence of functional groups that are susceptible to reduction by metal hydrides. PMID- 26587568 TI - Influence of a curcumin derivative on hIAPP aggregation in the absence and presence of lipid membranes. AB - The deposition of aggregates of human islet amyloid polypeptide (hIAPP) has been correlated with the death of beta-cells in type II diabetes mellitus. The actual molecular mechanism of cell death remains largely unknown; however, it has been postulated that the process of aggregation from monomeric hIAPP is closely involved. A possible cause of cellular toxicity may be through the disruption of structural integrity of the cell membrane by IAPP. Herein, a water-soluble curcumin derivative, CurDAc, is used to investigate the mitigation of hIAPP aggregation in the absence and presence of lipid membrane. PMID- 26587570 TI - Mesoporous BaSnO3 layer based perovskite solar cells. AB - One of the limitations of TiO2 based perovskite solar cells is the poor electron mobility of TiO2. Here, perovskite oxide BaSnO3 is used as a replacement. It has a higher electron mobility and the same perovskite structure as the light harvesting materials. After optimization, devices based on BaSnO3 showed the best performance of 12.3% vs. 11.1% for TiO2. PMID- 26587571 TI - A novel multi-stimuli responsive gelator based on D-gluconic acetal and its potential applications. AB - We construct a simple-structured super gelator with multi-stimuli responsive properties, among which anion responsiveness follows the Hofmeister series in a non-aqueous system. Versatile applications such as being rheological and self healing agents, waste water treatment, spilled oil recovery and flexible optical device manufacture are integrated into a single organogelator, which was rarely reported. PMID- 26587572 TI - Phosphonium-containing diblock copolymers from living anionic polymerization of 4 diphenylphosphino styrene. AB - Living anionic polymerization of 4-diphenylphosphino styrene (DPPS) achieved well defined homopolymers, poly(DPPS-b-S) styrenic block copolymers, and poly(I-b DPPS) diene-based diblock copolymers with predictable molecular weights and narrow polydispersities. In situ FTIR spectroscopy monitored the anionic polymerization of DPPS and tracked monomer consumption for kinetic analysis. Post alkylation enabled controlled placement of phosphonium functionality in poly(I-b DPPS) diblock copolymers, producing well-defined phosphonium-containing block copolymers with low degrees of compositional heterogeneity. Incorporating phosphonium charge disrupted the lamellar bulk morphology of the neutral diblock precursor and provided morphologies with interdigitated packing of alkyl chains on the phosphonium cation. PMID- 26587573 TI - Design and synthesis of fluorescence-labeled nucleotide with a cleavable azo linker for DNA sequencing. AB - A cleavable azo linker was synthesized and reacted with 5-(6)-carboxytetramethyl rhodamine succinimidyl ester, followed by further reactions with di(N succinimidyl) carbonate and 5-(3-amino-1-propynyl)-2'-deoxyuridine 5' triphosphate [dUTP(AP3)] to obtain the terminal product dUTP-azo linker-TAMRA as a potential reversible terminator for DNA sequencing by synthesis with no need for 3'-OH blocking. PMID- 26587574 TI - Chondroitin sulfate coated gold nanoparticles: a new strategy to resolve multidrug resistance and thromboinflammation. AB - We have developed the first chondroitin sulfate polymer coated gold nanoparticles that can simultaneously overcome mulidrug resistance in cancer cells and suppress thromboinflammation triggered by the chemotherapeutic drug. PMID- 26587575 TI - Correction: Efficient singlet oxygen generation from sugar pendant C60 derivatives for photodynamic therapy. AB - Correction for 'Efficient singlet oxygen generation from sugar pendant C60 derivatives for photodynamic therapy' by Shigenobu Yano et al., Chem. Commun., 2015, DOI: 10.1039/c5cc07353g. PMID- 26587576 TI - Effects of thermodynamic inhibitors on the dissociation of methane hydrate: a molecular dynamics study. AB - We investigate the effects of methanol and NaCl, which are known as thermodynamic hydrate inhibitors, on the dissociation kinetics of methane hydrate in aqueous solutions by using molecular dynamics simulations. It is shown that the dissociation rate is not constant but changes with time. The dissociation rate in the initial stage is increased by methanol whereas it is decreased by NaCl. This difference arises from the opposite effects of the two thermodynamic inhibitors on the hydration free energy of methane. The dissociation rate of methane hydrate is increased by the formation of methane bubbles in the aqueous phase because the bubbles absorb surrounding methane molecules. It is found that both methanol and NaCl facilitate the bubble formation. However, their mechanisms are completely different from each other. The presence of ions enhances the hydrophobic interactions between methane molecules. In addition, the ions in the solution cause a highly non-uniform distribution of dissolved methane molecules. These two effects result in the easy formation of bubbles in the NaCl solution. In contrast, methanol assists the bubble formation because of its amphiphilic character. PMID- 26587577 TI - Fingolimod: a review of its mode of action in the context of its efficacy and safety profile in relapsing forms of multiple sclerosis. AB - Fingolimod is an orally administered, first-in-class therapy for the treatment of relapsing forms of multiple sclerosis. Data from pivotal clinical trials show that fingolimod has a robust, significant effect on annualized relapse rates and MRI outcomes. Fingolimod has a novel, well-characterized mechanism of action. It acts through a specific set of receptors, sphingosine 1-phosphate receptors, present on the surface of a wide range of human cells and tissues, including neural cells, neurons and lymphocytes. Here we review the current literature to describe the mechanism of action of fingolimod in the context of its well established clinical efficacy and safety profile. Understanding of the mechanisms behind any non-therapeutic effects of fingolimod facilitates their prediction and management in the clinical setting. PMID- 26587578 TI - Electron microscopic observation of the early stages of Cryptosporidium parvum asexual multiplication and development in in vitro axenic culture. AB - The stages of Cryptosporidium parvum asexual exogenous development were investigated at high ultra-structural resolution in cell-free culture using transmission electron microscopy (TEM). Early C. parvum trophozoites were ovoid in shape, 1.07 * 1.47 MUm(2) in size, and contained a large nucleus and adjacent Golgi complex. Dividing and mature meronts containing four to eight developing merozoites, 2.34 * 2.7 MUm(2) in size, were observed within the first 24h of cultivation. An obvious peculiarity was found within the merozoite pellicle, as it was composed of the outer plasma membrane with underlying middle and inner membrane complexes. Further novel findings were vacuolization of the meront's residuum and extension of its outer pellicle, as parasitophorous vacuole-like membranes were also evident. The asexual reproduction of C. parvum was consistent with the developmental pattern of both eimerian coccidia and Arthrogregarinida (formerly Neogregarinida). The unique cell-free development of C. parvum described here, along with the establishment of meronts and merozoite formation, is the first such evidence obtained from in vitro cell-free culture at the ultrastructural level. PMID- 26587580 TI - The relationship between hearing loss and vestibular dysfunction in patients with sudden sensorineural hearing loss. AB - OBJECTIVE: To investigate the relationship between hearing loss and vestibular dysfunction in patients with sudden sensorineural hearing loss (SSHL). METHODS: Clinical data including the symptom of vertigo of 149 SSHL patients were investigated retrospectively. Pure tone audiometry, ocular vestibular-evoked myogenic potential (oVEMP) and cervical vestibular-evoked myogenic potential (cVEMP) evoked by air-conducted sound (ACS), and caloric test were employed for cochlear and vestibular function assessment. The relationship between hearing level and vestibular dysfunction was analyzed. RESULTS: The pure tone averages (PTAs) (mean +/- SD) of SSHL patients with and without vertigo were 88.81 +/- 21.74 dB HL and 72.49 +/- 21.88 dB HL (Z = -4.411, p = 0.000), respectively. The PTAs of SSHL patients with abnormal and normal caloric test were 84.71 +/- 22.54 dB HL and 70.41 +/- 24.07 dB HL (t = -2.665, p = 0.009), respectively. Conversely, vertigo and abnormal caloric results also happened more frequently in patients with profound hearing loss. However, no consistent tendency could be found among vestibular evoked myogenic potentials (VEMPs) responses or hearing loss. CONCLUSIONS: SSHL patients with vertigo or abnormal caloric test displayed worse hearing loss; and vice versa, vertigo and abnormal caloric results happened more frequently in SSHL patients with profound hearing loss. PMID- 26587581 TI - Predictors of reoperation after sacral neuromodulation: A single institution evaluation of over 400 patients. AB - AIMS: To explore factors that may predispose patients to reoperation after sacral neuromodulation (SNM). METHODS: Patients enrolled in our longitudinal neuromodulation database were reviewed. Medical records data, and voiding diaries, Interstitial Cystitis Symptom-Problem Indices (ICSI-PI), and Overactive Bladder Questionnaires (OAB-q) at baseline and 3 months were analyzed with Pearson's chi2 , Fisher's Exact test, Wilcoxon rank tests, and multivariable logistic regression. RESULTS: Of 407 patients, 134 (33%) had at least one reoperation over median 28.9 months follow-up (range 1.6-121.7); 78/407 (19%) were revised, and 56/407 (14%) were explanted. The most common reason for reoperation was lack of efficacy/worsening symptoms (n = 87). The reoperations group had a higher proportion of women (P = 0.049), lower mean body mass index (BMI; P = 0.010), more reprogramming events (P < 0.0001), longer median follow-up (P = 0.0008), and higher proportions with interstitial cystitis (P = 0.013), using hormone replacement therapy (P = 0.0004), and complications (P < 0.0001). Both reoperations/no reoperations groups had similar improvements in ICSI-PI (P < 0.0001 for both), OAB-q severity (P < 0.0001 for both) and quality of life (P < 0.0001 for both). On multivariate analysis, only longer follow-up (P = 0.0011; OR 1.048; CI 1.019, 1.078) and having a complication (P < 0.0001; OR 23.2; CI 11.47, 46.75) were significant predictors of reoperations. In women only, using HRT at time of implant was also predictive of reoperation (P = 0.0027; OR 3.09; CI 1.48, 6.46). CONCLUSIONS: In this largest known series to date, one third of the patients required reoperation and the most common reason was lack of efficacy/worsening symptoms. Ongoing study is needed as the technology continues to evolve. Neurourol. Urodynam. 36:354-359, 2017. (c) 2015 Wiley Periodicals, Inc. PMID- 26587579 TI - Arsenic and Environmental Health: State of the Science and Future Research Opportunities. AB - BACKGROUND: Exposure to inorganic and organic arsenic compounds is a major public health problem that affects hundreds of millions of people worldwide. Exposure to arsenic is associated with cancer and noncancer effects in nearly every organ in the body, and evidence is mounting for health effects at lower levels of arsenic exposure than previously thought. Building from a tremendous knowledge base with > 1,000 scientific papers published annually with "arsenic" in the title, the question becomes, what questions would best drive future research directions? OBJECTIVES: The objective is to discuss emerging issues in arsenic research and identify data gaps across disciplines. METHODS: The National Institutes of Health's National Institute of Environmental Health Sciences Superfund Research Program convened a workshop to identify emerging issues and research needs to address the multi-faceted challenges related to arsenic and environmental health. This review summarizes information captured during the workshop. DISCUSSION: More information about aggregate exposure to arsenic is needed, including the amount and forms of arsenic found in foods. New strategies for mitigating arsenic exposures and related health effects range from engineered filtering systems to phytogenetics and nutritional interventions. Furthermore, integration of omics data with mechanistic and epidemiological data is a key step toward the goal of linking biomarkers of exposure and susceptibility to disease mechanisms and outcomes. CONCLUSIONS: Promising research strategies and technologies for arsenic exposure and adverse health effect mitigation are being pursued, and future research is moving toward deeper collaborations and integration of information across disciplines to address data gaps. CITATION: Carlin DJ, Naujokas MF, Bradham KD, Cowden J, Heacock M, Henry HF, Lee JS, Thomas DJ, Thompson C, Tokar EJ, Waalkes MP, Birnbaum LS, Suk WA. 2016. Arsenic and environmental health: state of the science and future research opportunities. Environ Health Perspect 124:890-899; http://dx.doi.org/10.1289/ehp.1510209. PMID- 26587582 TI - Eye Morphology and Retinal Topography in Hummingbirds (Trochilidae: Aves). AB - Hummingbirds are a group of small, highly specialized birds that display a range of adaptations to their nectarivorous lifestyle. Vision plays a key role in hummingbird feeding and hovering behaviours, yet very little is known about the visual systems of these birds. In this study, we measured eye morphology in 5 hummingbird species. For 2 of these species, we used stereology and retinal whole mounts to study the topographic distribution of neurons in the ganglion cell layer. Eye morphology (expressed as the ratio of corneal diameter to eye transverse diameter) was similar among all 5 species and was within the range previously documented for diurnal birds. Retinal topography was similar in Amazilia tzacatl and Calypte anna. Both species had 2 specialized retinal regions of high neuron density: a central region located slightly dorso-nasal to the superior pole of the pecten, where densities reached ~ 45,000 cells . mm(-2), and a temporal area with lower densities (38,000-39,000 cells . mm(-2)). A weak visual streak bridged the two high-density areas. A retina from Phaethornis superciliosus also had a central high-density area with a similar peak neuron density. Estimates of spatial resolving power for all 3 species were similar, at approximately 5-6 cycles . degree(-1). Retinal cross sections confirmed that the central high-density region in C. anna contains a fovea, but not the temporal area. We found no evidence of a second, less well-developed fovea located close to the temporal retina margin. The central and temporal areas of high neuron density allow for increased spatial resolution in the lateral and frontal visual fields, respectively. Increased resolution in the frontal field in particular may be important for mediating feeding behaviors such as aerial docking with flowers and catching small insects. PMID- 26587583 TI - Scope of Successive C-H Functionalizations of the Methyl Group in 3-Picolines: Intramolecular Carbonylation of Arenes to the Metal-Free Synthesis of 4 Azafluorenones. AB - A transition-metal-free, t-BuOOH mediated intramolecular carbonylation of arenes in 2-aryl-3-picolines via oxidative C-H functionalizations of the methyl group has been developed, providing an expedient synthesis of 4-azafluorenones. Distinct from the current literature wherein methylarenes have been used as acylating agents, 2-aryl-3-picolines in this study are transformed into aldehydes, which give 4-azafluorenones upon rapid intramolecular acylation. The study demonstrates the first example of intramolecular carbonylation of arenes utilizing a methyl group as latent carbonyl functionality. PMID- 26587584 TI - Enantioselective organocatalytic oxidation of ketimine. AB - C3-Symmetric chiral trisimidazolines with m-chloroperbenzoic acid promoted the organocatalytic oxidation of N-sulfonyl ketimine. The present imidazoline catalysis produced oxaziridines bearing a tetrasubstituted carbon stereogenic center in high yields with up to 87% ee. PMID- 26587585 TI - Dendritic Cell-Specific Deletion of beta-Catenin Results in Fewer Regulatory T Cells without Exacerbating Autoimmune Collagen-Induced Arthritis. AB - Dendritic cells (DCs) are professional antigen presenting cells that have the dual ability to stimulate immunity and maintain tolerance. However, the signalling pathways mediating tolerogenic DC function in vivo remain largely unknown. The beta-catenin pathway has been suggested to promote a regulatory DC phenotype. The aim of this study was to unravel the role of beta-catenin signalling to control DC function in the autoimmune collagen-induced arthritis model (CIA). Deletion of beta-catenin specifically in DCs was achieved by crossing conditional knockout mice with a CD11c-Cre transgenic mouse line. Bone marrow-derived DCs (BMDCs) were generated and used to study the maturation profile of these cells in response to a TLR2 or TLR4 ligand stimulation. CIA was induced by intra-dermal immunization with 100 MUg chicken type II collagen in complete Freund's adjuvant on days 0 and 21. CIA incidence and severity was monitored macroscopically and by histology. The T cell profile as well as their cytokine production were analysed by flow cytometry. Lack of beta-catenin specifically in DCs did not affect the spontaneous, TLR2- or TLR4-induced maturation and activation of BMDCs or their cytokine production. Moreover, no effect on the incidence and severity of CIA was observed in mice lacking beta catenin in CD11c+ cells. A decreased frequency of splenic CD3+CD8+ T cells and of regulatory T cells (Tregs) (CD4+CD25highFoxP3+), but no changes in the frequency of splenic Th17 (CCR6+CXCR3-CCR4+), Th2 (CCR6-CXCR3-CCR4+) and Th1 (CCR6 CXCR3+CCR4-) cells were observed in these mice under CIA condition. Furthermore, the expression of IL-17A, IL-17F, IL-22, IL-4 or IFNgamma was also not affected. Our data indicate that ablation of beta-catenin expression in DCs did not alter the course and severity of CIA. We conclude that although deletion of beta catenin resulted in a lower frequency of Tregs, this decrease was not sufficient to aggravate the onset and severity of CIA. PMID- 26587586 TI - Quality of Reporting and Adherence to ARRIVE Guidelines in Animal Studies for Chagas Disease Preclinical Drug Research: A Systematic Review. AB - Publication of accurate and detailed descriptions of methods in research articles involving animals is essential for health scientists to accurately interpret published data, evaluate results and replicate findings. Inadequate reporting of key aspects of experimental design may reduce the impact of studies and could act as a barrier to translation of research findings. Reporting of animal use must be as comprehensive as possible in order to take advantage of every study and every animal used. Animal models are essential to understanding and assessing new chemotherapy candidates for Chagas disease pathology, a widespread parasitic disease with few treatment options currently available. A systematic review was carried out to compare ARRIVE guidelines recommendations with information provided in publications of preclinical studies for new anti-Trypanosoma cruzi compounds. A total of 83 publications were reviewed. Before ARRIVE guidelines, 69% of publications failed to report any macroenvironment information, compared to 57% after ARRIVE publication. Similar proportions were observed when evaluating reporting of microenvironmental information (56% vs. 61%). Also, before ARRIVE guidelines publication, only 13% of papers described animal gender, only 18% specified microbiological status and 13% reported randomized treatment assignment, among other essential information missing or incomplete. Unfortunately, publication of ARRIVE guidelines did not seem to enhance reporting quality, compared to papers appeared before ARRIVE publication. Our results suggest that there is a strong need for the scientific community to improve animal use description, animal models employed, transparent reporting and experiment design to facilitate its transfer and application to the affected human population. Full compliance with ARRIVE guidelines, or similar animal research reporting guidelines, would be an excellent start in this direction. PMID- 26587587 TI - Reply to 'Comments on IgE responses to Ascaris and mite tropomyosins are risk factors for asthma'. PMID- 26587588 TI - Ambulatory Blood Pressure Monitoring (ABPM) as the reference standard for diagnosis of hypertension and assessment of vascular risk in adults. AB - New information has become available since the ISC, AAMCC, and SECAC released their first extensive guidedelines to improve the diagnosis and treatment of adult arterial hypertension. A critical assessment of evidence and a comparison of what international guidelines now propose are the basis for the following statements, which update the recommendations first issued in 2013. Office blood pressure (BP) measurements should no longer be considered to be the "gold standard" for the diagnosis of hypertension and assessment of cardiovascular risk. Relying on office BP, even when supplemented with at-home wake-time self measurements, to identify high-risk individuals, disregarding circadian BP patterning and asleep BP level, leads to potential misclassification of 50% of all evaluated persons. Accordingly, ambulatory BP monitoring is the recommended reference standard for the diagnosis of true hypertension and accurate assessment of cardiovascular risk in all adults >=18 yrs of age, regardless of whether office BP is normal or elevated. Asleep systolic BP mean is the most significant independent predictor of cardiovascular events. The sleep-time relative SBP decline adds prognostic value to the statistical model that already includes the asleep systolic BP mean and corrected for relevant confounding variables. Accordingly, the asleep systolic BP mean is the recommended protocol to diagnose hypertension, assess cardiovascular risk, and predict cardiovascular event-free interval. In men, and in the absence of compelling clinical conditions, reference thresholds for diagnosing hypertension are 120/70 mmHg for the asleep systolic/diastolic BP means derived from ambulatory BP monitoring. However, in women, in the absence of complicating co-morbidities, the same thresholds are lower by 10/5 mmHg, i.e., 110/65 mmHg for the asleep means. In high-risk patients, including those diagnosed with diabetes or chronic kidney disease, and/or those having experienced past cardiovascular events, the thresholds are even lower by 15/10 mmHg, i.e., 105/60 mmHg. Bedtime treatment with the full daily dose of >=1 hypertension medications is recommended as a cost-effective means to improve the management of hypertension and reduce hypertension associated risk. Bedtime treatment entailing the full daily dose of >=1 conventional hypertension medications must be the therapeutic regimen of choice for the elderly and those with diabetes, resistant and secondary hypertension, chronic kidney disease, obstructive sleep apnea, and medical history of past cardiovascular events, among others, given their documented high prevalence of sleep-time hypertension. PMID- 26587592 TI - Reaction Path Optimization without NEB Springs or Interpolation Algorithms. AB - This letter describes a chain-of-states method that optimizes reaction paths under the sole constraint of equally spaced structures. In contrast to NEB and string methods, it requires no spring forces, interpolation algorithms, or other heuristics to control structure distribution. Rigorous use of a quadratic PES allows calculation of an optimization step with a predefined distribution in Cartesian space. The method is a formal extension of single-structure quasi Newton methods. An initial guess can be evolved, as in the growing string method. PMID- 26587589 TI - Hunner-Type (Classic) Interstitial Cystitis: A Distinct Inflammatory Disorder Characterized by Pancystitis, with Frequent Expansion of Clonal B-Cells and Epithelial Denudation. AB - Interstitial cystitis (IC) is a chronic bladder disease with urinary frequency, bladder discomfort or bladder pain of unknown etiology. Based on cystoscopic findings, patients with IC are classified as either Hunner-type/classic IC (HIC), presenting with a specific Hunner lesion, or non-Hunner-type IC (NHIC), presenting with no Hunner lesion, but post-hydrodistension mucosal bleeding. Inflammatory cell infiltration, composed predominantly of lymphocytes, plasma cells and epithelial denudation, has in the past been documented as a major pathological IC finding. However, the significance of the pathological evaluation of IC, especially with regard to the difference between HIC and NHIC, has been downplayed in recent years. In this study, we performed immunohistochemical quantification of infiltrating T-lymphocytes, B-lymphocytes and plasma cells, and measured the amount of residual epithelium in urinary bladder biopsy specimens taken from patients with HIC and NHIC, and those with no IC, using image analysis software. In addition, in situ hybridization of the light chains was performed to examine clonal B-cell expansion. Lymphoplasmacytic infiltration was significantly more severe in HIC specimens than in NHIC specimens (P <0.0001). Substantial lymphoplasmacytic inflammation (>=200 cells/mm2) was observed in 93% of HIC specimens, whereas only 8% of NHIC specimens were inflamed. Plasmacytic infiltration was more prominent in HIC specimens compared with NHIC and non-IC cystitis specimens (P <0.005). Furthermore, expansion of light-chain-restricted B cells was observed in 31% of cases of HIC. The amount of residual epithelium was decreased in HIC specimens compared with NHIC specimens and non-IC cystitis specimens (P <0.0001). These results suggest that NHIC and HIC are distinct pathological entities, with the latter characterized by pancystitis, frequent clonal B-cell expansion and epithelial denudation. An abnormality in the B-cell population may be involved in the pathogenesis of HIC. PMID- 26587591 TI - Eosinophils from Murine Lamina Propria Induce Differentiation of Naive T Cells into Regulatory T Cells via TGF-beta1 and Retinoic Acid. AB - Treg cells play a crucial role in immune tolerance, but mechanisms that induce Treg cells are poorly understood. We here have described eosinophils in lamina propria (LP) that displayed high aldehyde dehydrogenase (ALDH) activity, a rate limiting step during all-trans retinoic acid (ATRA) synthesis, and expressed TGF beta1 mRNA and high levels of ATRA. Co-incubation assay confirmed that LP eosinophils induced the differentiation of naive T cells into Treg cells. Differentiation promoted by LP eosinophils were inhibited by blocked either TGF beta1 or ATRA. Peripheral blood (PB) eosinophils did not produce ATRA and could not induce Treg differentiation. These data identifies LP eosinophils as effective inducers of Treg cell differentiation through a mechanism dependent on TGF-beta1 and ATRA. PMID- 26587593 TI - Computational Alanine Scanning Mutagenesis: MM-PBSA vs TI. AB - Understanding protein-protein association and being able to determine the crucial residues responsible for their association (hot-spots) is a key issue with huge practical applications such as rational drug design and protein engineering. A variety of computational methods exist to detect hot-spots residues, but the development of a fast and accurate quantitative alanine scanning mutagenesis (ASM) continues to be crucial. Using four protein-protein complexes, we have compared a variation of the standard computational ASM protocol developed at our group, based on the Molecular Mechanics/Poisson-Boltzmann Surface Area (MM-PBSA) approach, against Thermodynamic Integration (TI), a well-known and accurate but computationally expensive method. To compare the efficiency and the accuracy of the two methods, we have calculated the protein-protein binding free energy differences upon alanine mutation of interfacial residues (DeltaDeltaGbind). In relation to the experimental DeltaDeltaGbind values, the average error obtained with TI was 1.53 kcal/mol, while the ASM protocol resulted in an average error of 1.18 kcal/mol. The results demonstrate that the much faster ASM protocol gives results at the same level of accuracy as the TI method but at a fraction of the computational time required to run TI. This ASM protocol is therefore a strong and efficient alternative to the systematic evaluation of protein-protein interfaces, involving hundreds of amino acid residues in search of hot-spots. PMID- 26587594 TI - Computational Analysis of a Zn-Bound Tris(imidazolyl) Calix[6]arene Aqua Complex: Toward Incorporating Second-Coordination Sphere Effects into Carbonic Anhydrase Biomimetics. AB - Molecular dynamics simulations and quantum-mechanical calculations were performed to characterize a supramolecular tris(imidazolyl) calix[6]arene Zn(2+) aqua complex, as a biomimetic model for the catalyzed hydration of carbon dioxide to bicarbonate, H2O + CO2 -> H(+) + HCO3(-). On the basis of potential-of-mean-force (PMF) calculations, stable conformations had distorted 3-fold symmetry and supported either one or zero encapsulated water molecules. The conformation with an encapsulated water molecule is calculated to be lower in free energy than the conformation with an empty cavity (DeltaG = 1.2 kcal/mol) and is the calculated free-energy minimum in solution. CO2 molecule partitioning into the cavity is shown to be very facile, proceeding with a barrier of 1.6 kcal/mol from a weak encounter complex which stabilizes the species by about 1.0 kcal/mol. The stabilization energy of CO2 is calculated to be larger than that of H2O (DeltaDeltaG = 1.4 kcal/mol), suggesting that the complex will preferentially encapsulate CO2 in solution. In contrast, the PMF for a bicarbonate anion entering the cavity is calculated to be repulsive in all nonbonding regions of the cavity, due to the diameter of the calix[6]arene walls. Geometry optimization of the Zn-bound hydroxide complex with an encapsulated CO2 molecule showed that multiple noncovalent interactions direct the reactants into optimal position for nucleophilic addition to occur. The calixarene complex is a structural mimic of the hydrophilic/hydrophobic divide in the enzyme, providing a functional effect for CO2 addition in the catalytic cycle. The results show that Zn-binding calix[6]arene scaffolds can be potential synthetic biomimetics for CO2 hydration catalysis, both in terms of preferentially encapsulating CO2 from solution and by spatially fixing the reactive species inside the cavity. PMID- 26587595 TI - Free Enthalpy Differences between alpha-, pi-, and 310-Helices of an Atomic Level Fine-Grained Alanine Deca-Peptide Solvated in Supramolecular Coarse-Grained Water. AB - Atomistic molecular dynamics simulations of peptides or proteins in aqueous solution are still limited to the multi-nanosecond time scale and multi-nanometer range by computational cost. Combining atomic solutes with a supramolecular solvent model in hybrid fine-grained/coarse-grained (FG/CG) simulations allows atomic detail in the region of interest while being computationally more efficient. We used enveloping distribution sampling (EDS) to calculate the free enthalpy differences between different helical conformations, i.e., alpha-, pi-, and 310-helices, of an atomic level FG alanine deca-peptide solvated in a supramolecular CG water solvent. The free enthalpy differences obtained show that by replacing the FG solvent by the CG solvent, the pi-helix is destabilized with respect to the alpha-helix by about 2.5 kJ mol(-1), and the 310-helix is stabilized with respect to the alpha-helix by about 9 kJ mol(-1). In addition, the dynamics of the peptide becomes faster. By introducing a FG water layer of 0.8 nm around the peptide, both thermodynamic and dynamic properties are recovered, while the hybrid FG/CG simulations are still four times more efficient than the atomistic simulations, even when the cutoff radius for the nonbonded interactions is increased from 1.4 to 2.0 nm. Hence, the hybrid FG/CG model, which yields an appropriate balance between reduced accuracy and enhanced computational speed, is very suitable for molecular dynamics simulation investigations of biomolecules. PMID- 26587596 TI - Efficient Combination of Environment Change and Alchemical Perturbation within the Enveloping Distribution Sampling (EDS) Scheme: Twin-System EDS and Application to the Determination of Octanol-Water Partition Coefficients. AB - The methodology of Enveloping Distribution Sampling (EDS) is extended to probe a single-simulation alternative to the thermodynamic cycle that is standardly used for measuring the effect of a modification of a chemical compound, e.g. from a given species to a chemical derivative for a ligand or solute molecule, on the free-enthalpy change associated with a change in environment, e.g. from the unbound state to the bound state for a protein-ligand system or from one solvent to another one for a solute molecule. This alternative approach relies on the coupled simulation of two systems (computational boxes) 1 and 2, and the method is therefore referred to as twin-system EDS. Systems 1 and 2 account for the two choices of environment. The end states of the alchemical perturbation for the twin-system associate the two alternative forms X and Y of the molecule to systems 1 and 2 or 2 and 1, respectively. In this way, the processes of transforming one molecule into the other are carried out simultaneously in opposite directions in the two environments, leading to a change in free enthalpy that is smaller than for the two individual processes and to an energy-difference distribution that is more symmetric. As an illustration, the method is applied to the calculation of octanol-water partition coefficients for C4 to C8 alkanes, 1 hexanol and 1,2-dimethoxyethane. It is shown in particular that the consideration of the residual hydration of octanol leads to calculated partition coefficients that are in better agreement with reported experimental numbers. PMID- 26587597 TI - Convergence of Sampling Kirkwood-Buff Integrals of Aqueous Solutions with Molecular Dynamics Simulations. AB - We discuss two methods for calculating Kirkwood-Buff integrals (KBIs) of aqueous cosolvent solutions from molecular simulations. The first method is based on computing running integrals over radial distribution functions obtained from NVT or NpT simulations. The second, more recent method, originally introduced by Schnell et al. (J. Phys. Chem. B2011, 115, 10911), obtains the KBIs from direct analysis of particle number fluctuations in small, open subvolumes embedded in a larger reservoir as provided by the NVT (NpT) simulation cell. The thermodynamic limit is taken in the first method by using the plateau-values of the running KBIs for large distances, while in the second method an analytical finite-size scaling relation is applied to the KBIs of subvolumes of variable size. We find that direct analysis of particle number fluctuations at small scales provides more precise estimates of KBIs for methanol-water and urea-water solutions. Converged KBIs could, however, not be obtained from nanosecond time scale molecular dynamics simulations with either of the two methods. Based on 0.1 MUs simulation trajectories of small and large system sizes time-converged KBIs were obtained with both methods. The running integral method suffers, however, from stronger finite-size artifacts than the sub-box method, also when empirical finite-size tail corrections are applied to the radial distribution functions. PMID- 26587598 TI - Quantum Thermochemistry: Multistructural Method with Torsional Anharmonicity Based on a Coupled Torsional Potential. AB - We present a new approximation for calculating partition functions and thermodynamic functions by the multistructural method with torsional anharmonicity (MS-T). The new approximation is based on a reference potential with torsional barriers obtained from a calculation that includes local torsional coupling. By comparing to a fully coupled classical rotational-torsional partition function evaluated as a numerical phase space integral, the method is shown to provide improved accuracy in the classical limit. Quantum effects, which are most important at low temperatures, are included based on the harmonic approximation (which can be upgraded to a quasiharmonic approximation, that is, harmonic formulas with effective frequencies). Calculations were performed for six molecules (ethanol, 1-butanol, hexane, isohexane, heptane, and isoheptane), one radical (1-pentyl radical), and the saddle point structures of a hydrogen abstraction reaction (hydroxyl plus ethanol) to illustrate the difference between the new coupled-potential MS-T approximation and the original uncoupled-potential MS-T approximation. The new method improves the agreement with experimental results of calcuated thermodynamic functions for 1-butanol, hexane, isohexane, and heptane. PMID- 26587599 TI - The Performance of Density Functionals for Sulfate-Water Clusters. AB - The performance of 24 density functionals, Hartree-Fock, and MP2 is assessed with respect to the CCSD(T)/CBS* energetics of 49 sulfate-water clusters with three to six water molecules. Included among the density functionals are GGA, meta-GGA, hybrid GGA, hybrid meta-GGA, and double hybrid density functionals, as well as the LDA. Three types of dispersion corrections (VV10, XDM, and -D) are tested in conjunction with these functionals. The 26 methods are compared using the relative and binding energies of the sulfate-water clusters as the main criteria. It was discovered that a majority of the tested density functionals are unable to simultaneously capture the physics necessary to describe both the relative and binding energies of the anionic solvation clusters. The three density functionals with the best overall performance are XYG3, omegaB97X-2, and XYGJ-OS. The only other density functional that performs comparably to these three double hybrids is M11. A majority of the density functionals that contain a fraction of exact exchange tend to perform well only for the relative energies, while functionals lacking exact exchange generally perform poorly with respect to both criteria. However, the meta-GGA functional, M11-L, stands out due to its superior performance for the relative energies. While dispersion correction functionals cannot replace the accuracy provided by MP2 correlation, it is shown that the proper combination of a hybrid GGA functional (LC-omegaPBE) with a dispersion correction functional (VV10) can lead to drastic improvements in the binding energies of the parent functional, while preserving its performance with respect to the relative energies. Ultimately, however, MP2 has the best overall performance out of the 26 benchmarked methods. PMID- 26587600 TI - Electrostatically Embedded Molecular Tailoring Approach and Validation for Peptides. AB - We add higher-order electronic polarization effects to the molecular tailoring approach (MTA) by embedding each fragment in background charges as in combined quantum mechanical and molecular mechanical (QM/MM) methods; the resulting method considered here is called electrostatically embedded MTA (EE-MTA). We compare EE MTA to MTA for a test peptide, Ace-(Ala)20-NMe, and we find that including background charges (embedding charges) greatly improves the performance. The fragmentation is performed on the basis of amino acids as monomers, and several sizes of fragment are tested. The fragments are capped with either hydrogen cap atoms or tuned fluorine cap atoms. The effective core potential of the tuned fluorine cap atom is optimized so as to reproduce the proton affinity for seven types of tetrapeptide, and the proton affinity calculated with the tuned cap atom shows a lower mean unsigned error than that obtained by using a hydrogen cap atom. In the application to the test peptide, these generically tuned cap atoms show better performance compared with the hydrogen cap atom for both the electronic energy and the energy difference between an alpha helix and a beta sheet (in the latter case, 1.0% vs 2.7% when averaged over three sizes of fragments and two locations for cut bonds). Also, we compared the accuracy of several charge redistribution schemes, and we find that the results are not particularly sensitive to these choices for the Ace-(Ala)20-NMe peptide. We also illustrate the dependence on the choice of charge model for the embedding charges, including both fixed embedding charges and embedding charges that depend on conformation. PMID- 26587601 TI - A New Mean-Field Method Suitable for Strongly Correlated Electrons: Computationally Facile Antisymmetric Products of Nonorthogonal Geminals. AB - We propose an approach to the electronic structure problem based on noninteracting electron pairs that has similar computational cost to conventional methods based on noninteracting electrons. In stark contrast to other approaches, the wave function is an antisymmetric product of nonorthogonal geminals, but the geminals are structured so the projected Schrodinger equation can be solved very efficiently. We focus on an approach where, in each geminal, only one of the orbitals in a reference Slater determinant is occupied. The resulting method gives good results for atoms and small molecules. It also performs well for a prototypical example of strongly correlated electronic systems, the hydrogen atom chain. PMID- 26587602 TI - Explicitly Correlated Methods within the ccCA Methodology. AB - The prediction of energetic properties within "chemical accuracy" (1 kcal mol(-1) from well-established experiment) can be a major challenge in computational quantum chemistry due to the computational requirements (computer time, memory, and disk space) needed to achieve this level of accuracy. Methodologies such as coupled cluster with single, double, and perturbative triple excitations (CCSD(T)) combined with very large basis sets are often required to reach this level of accuracy. Unfortunately, such calculations quickly become cost prohibitive as system size increases. Our group has developed an ab initio composite method, the correlation consistent Composite Approach (ccCA), which enables such accuracy to be possible, on average, but at reduced computational cost as compared with CCSD(T) in combination with a large basis set. While ccCA has proven quite useful, computational bottlenecks still occur. In this study, the means to reduce the computational cost of ccCA without compromising accuracy by utilizing explicitly correlated methods within ccCA have been considered, and an alternative formulation is described. PMID- 26587603 TI - Many-Body Expansion with Overlapping Fragments: Analysis of Two Approaches. AB - The traditional many-body expansion-in which a system's energy is expressed in terms of the energies of its constituent monomers, dimers, trimers, etc.-has recently been generalized to the case where the "monomers" (subsystems, or "fragments") overlap. Two such generalizations have been proposed, and here, we compare the two, both formally and numerically. We conclude that the two approaches are distinct, although in many cases they yield comparable and accurate results when truncated at the level of dimers. However, tests on fluoride-water clusters suggest that the approach that we have previously called the "generalized many-body expansion" (GMBE) [J. Chem. Phys.137, 064113 (2012)] is more robust, with respect to the choice of fragments, as compared to an alternative "many overlapping body expansion" [J. Chem. Theory Comput.8, 2669 (2012)]. A more detailed justification for the GMBE is also provided here. PMID- 26587604 TI - Density Matrix Embedding: A Strong-Coupling Quantum Embedding Theory. AB - We extend our density matrix embedding theory (DMET) [Phys. Rev. Lett.2012, 109, 186404] from lattice models to the full chemical Hamiltonian. DMET allows the many-body embedding of arbitrary fragments of a quantum system, even when such fragments are open systems and strongly coupled to their environment (e.g., by covalent bonds). In DMET, empirical approaches to strong coupling, such as link atoms or boundary regions, are replaced by a small, rigorous quantum bath designed to reproduce the entanglement between a fragment and its environment. We describe the theory and demonstrate its feasibility in strongly correlated hydrogen ring and grid models; these are not only beyond the scope of traditional embeddings but even challenge conventional quantum chemistry methods themselves. We find that DMET correctly describes the notoriously difficult symmetric dissociation of a 4 * 3 hydrogen atom grid, even when the treated fragments are as small as single hydrogen atoms. We expect that DMET will open up new ways of treating complex strongly coupled, strongly correlated systems in terms of their individual fragments. PMID- 26587605 TI - Conical Intersection Optimization Based on a Double Newton-Raphson Algorithm Using Composed Steps. AB - An algorithm for conical intersection optimization based on a double Newton Raphson step (DNR) has been implemented and tested in 11 cases using CASSCF as the electronic structure method. The optimization is carried out in redundant coordinates, and the steps are the sum of two independent Newton-Raphson steps. The first step is carried out to reach the energy degeneracy and uses the gradient of the energy difference between the crossing states and the so-called branching space Hessian. The second step minimizes the energy in the intersection space and uses the projected excited state gradient and the intersection space Hessian. The branching and intersection space Hessians are obtained with a Broyden-Fletcher-Goldfarb-Shanno update from the gradient difference and projected excited state gradients, respectively. In some cases, mixing of the quasi-degenerate states near the seam causes changes in the direction of the gradient difference vector and induces a loss of the degeneracy. This behavior is avoided switching to a composed step (CS) algorithm [Sicilia et al. J. Chem. Theory Comput.2008, 4, 27], i.e., a hybrid DNR-CS implementation. Compared to the composed gradient (CG) [Bearpark et al. Chem. Phys. Lett.1994, 223, 269] and hybrid CG-CS algorithms, the DNR-CS algorithm reaches the MECI in 30% and 15% less steps, respectively. The improvement occurs mostly because the approach to the seam is more efficient, and a degeneracy threshold of 0.001 hartree is reached at lower energies than in the CG and CG-CS cases. PMID- 26587606 TI - Evaluation of Approximate Exchange-Correlation Functionals in Predicting One-Bond (31)P-(1)H NMR Indirect Spin-Spin Coupling Constants. AB - This work benchmarks density functional theory, with several different exchange correlation functionals, for prediction of isotropic one-bond phosphorus-hydrogen NMR spin-spin coupling constants (SSCCs). Our test set consists of experimental SSCCs from 30 diverse molecules representing multiple phosphorus bonding environments. The results suggest the importance of a balance between the choice of correlation functional and the admixture of nonlocal exchange. Overall, standard DFT methods appear to suffice for usefully accurate predictions of (31)P (1)H SSCCs. PMID- 26587607 TI - Assessment of Orbital-Optimized Third-Order Moller-Plesset Perturbation Theory and Its Spin-Component and Spin-Opposite Scaled Variants for Thermochemistry and Kinetics. AB - An assessment of the OMP3 method and its spin-component and spin-scaled variants for thermochemistry and kinetics is presented. For reaction energies of closed shell systems, the CCSD, SCS-MP3, and SCS-OMP3 methods show better performances than other considered methods, and no significant improvement is observed due to orbital optimization. For barrier heights, OMP3 and SCS-OMP3 provide the lowest mean absolute deviations. The MP3 method yields considerably higher errors, and the spin scaling approaches do not help to improve upon MP3, but worsen it. For radical stabilization energies, the CCSD, OMP3, and SCS-OMP3 methods exhibit noticeably better performances than MP3 and its variants. Our results demonstrate that if the reference wave function suffers from a spin-contamination, then the MP3 methods dramatically fail. On the other hand, the OMP3 method and its variants can tolerate the spin-contamination in the reference wave function. For overall evaluation, we conclude that OMP3 is quite helpful, especially in electronically challenged systems, such as free radicals or transition states where spin contamination dramatically deteriorates the quality of the canonical MP3 and SCS-MP3 methods. Both OMP3 and CCSD methods scale as n(6), where n is the number of basis functions. However, the OMP3 method generally converges in much fewer iterations than CCSD. In practice, OMP3 is several times faster than CCSD in energy computations. Further, the stationary properties of OMP3 make it much more favorable than CCSD in the evaluation of analytic derivatives. For OMP3, the analytic gradient computations are much less expensive than CCSD. For the frequency computation, both methods require the evaluation of the perturbed amplitudes and orbitals. However, in the OMP3 case there is still a significant computational time savings due to simplifications in the analytic Hessian expression owing to the stationary property of OMP3. Hence, the OMP3 method emerges as a very useful tool for computational quantum chemistry. PMID- 26587608 TI - Spin-Crossing in an Organometallic Pt-Benzene Complex. AB - The interaction between the Pt atom and the benzene (Bz) molecule was investigated theoretically, using a symmetric Pt-Bz half-sandwich complex. Various levels of wave function theory (HF, MP2, CCSD(T), CASPT2, multistate (MS) MS-CASPT2) together with several functionals (PBE, PBE+D3, PBE+vdW, PBE/EE+vdW) of the density functional theory (DFT) were complemented by quantum Monte Carlo (QMC) calculations. Spin-orbit coupling (SOC) effects were also taken into account at the CASPT2 and DFT levels of theory. The inclusion of dynamic correlation energy was found to be essential to maintaining the stability of the complex. The dative type of bonding was identified to be responsible for the Pt Bz binding in the ground state. Single-reference CCSD(T) and MP2 as well as multireference CASPT2 and MS-CASPT2 methods reveal that the interaction curve has a single energy minimum (corresponding to the (1)S0 state) and a shoulder (arising from the crossing between the (1)S0 and (3)D3 states) at longer distances. The inclusion of SOC at the CASPT2 level leads to the appearance of another well-separated minimum, which corresponds to the triplet state (3)F4. The PBE/EE+vdW functional, which includes a fraction of exact-exchange (EE) and nonlocal electron correlation, shows the best qualitative agreement with respect to the CCSD(T) data among all DFT functionals used. Large-scale QMC calculations, based on DFT wave functions constructed using TPSSh and M11 functionals, were confronted with the CCSD(T) results. The QMC-TPSSh protocol favorably agrees with the CCSD(T) data, suggesting its possible use in other Pt-containing organometallic systems. All of the methods used (except for HF) show that the Pt benzene binding leads to the quenching of the Pt high-spin triplet ground state, and the low-spin closed-shell singlet state is found to be preferred in the ground-state of the complex. PMID- 26587609 TI - Analytic Molecular Hessian Calculations for CC2 and MP2 Combined with the Resolution of Identity Approximation. AB - An implementation of analytic second derivatives for the approximate coupled cluster singles and doubles model CC2 and for second-order Moller-Plesset perturbation theory (MP2) will be presented. The RI approximation for the two electron repulsion integrals is used to reduce memory demands, operation count, and I/O requirements. During the calculation, the storage of [Formula: see text] quantities (where [Formula: see text] is a measure for the system size) can completely be avoided. It is shown that with the MP2 method and an appropriate scaling of the harmonic frequencies, especially C-F stretch frequencies are reproduced much better in comparison to experiments than with the B3LYP density functional. Similar advantages are observed for molecules with strong, internal van der Waals interactions. Spin scaling offers additional improvements in these cases. The implementation has been tested for molecules with up to 81 atoms and 684 basis functions. PMID- 26587610 TI - Improved Predictor-Corrector Integrators For Evaluating Reaction Path Curvature. AB - The reaction path connects a chemical potential energy landscape and the conceptual descriptions of chemical mechanisms and reactivity. In recent years, a class of predictor-corrector integrators has been developed and shown to provide an excellent compromise between computational efficiency and numerical accuracy. Models based on projected frequencies along the reaction path and coupling matrix elements, such as Reaction Path Hamiltonian (RPH) and Unified Reaction Valley Approach (URVA), require highly accurate integration of the reaction path. In this report, the Euler Predictor-Corrector (EulerPC) and Hessian-based Predictor Corrector (HPC) methods are shown to be inadequate for studying reaction path curvature, which is a central component of the RPH and URVA models. The source of this apparent failure is explored, and a solution is developed. Importantly, the resulting enhanced EulerPC and HPC integrators do not require more intensive CPU or memory requirements than their predecessors. PMID- 26587611 TI - PowerBorn: A Barnes-Hut Tree Implementation for Accurate and Efficient Born Radii Computation. AB - Implicit solvent models are one of the standard tools in computational biophysics. While Poisson-Boltzmann methods offer highly accurate results within this framework, generalized Born models have been used due to their higher computational efficiency in many (bio)molecular simulations, where computational power is a limiting factor. In recent years, there have been remarkable advances to reduce some deficiencies in the generalized Born models. On the other hand, these advances come at an increased computational cost that contrasts the reasons for choosing generalized Born models over Poisson-Boltzmann methods. To address this performance issue, we present a new algorithm for Born radii computation, one performance critical part in the evaluation of generalized Born models, which is based on a Barnes-Hut tree code scheme. We show that an implementation of this algorithm provides accurate Born radii and polar solvation free energies in comparison to Poisson-Boltzmann computations, while delivering up to an order of magnitude better performance over existing, similarly accurate methods. The C++ implementation of this algorithm will be available at http://www.int.kit.edu/nanosim/ . PMID- 26587612 TI - Multipole-Based Force Fields from ab Initio Interaction Energies and the Need for Jointly Refitting All Intermolecular Parameters. AB - Distributed atomic multipole (MTP) moments promise significant improvements over point charges (PCs) in molecular force fields, as they (a) more realistically reproduce the ab initio electrostatic potential (ESP) and (b) allow to capture anisotropic atomic properties such as lone pairs, conjugated systems, and sigma holes. The present work focuses on the question of whether multipolar electrostatics instead of PCs in standard force fields leads to quantitative improvements over point charges in reproducing intermolecular interactions. To this end, the interaction energies of two model systems, benzonitrile (BZN) and formamide (FAM) homodimers, are characterized over a wide range of dimer conformations. It is found that although with MTPs the monomer ab initio ESP can be captured better by about an order of magnitude compared to point charges (PCs), this does not directly translate into better describing ab initio interaction energies compared to PCs. Neither ESP-fitted MTPs nor refitted Lennard-Jones (LJ) parameters alone demonstrate a clear superiority of atomic MTPs. We show that only if both electrostatic and LJ parameters are jointly optimized in standard, nonpolarizable force fields, atomic are MTPs clearly beneficial for reproducing ab initio dimerization energies. After an exhaustive exponent scan, we find that for both BZN and FAM, atomic MTPs and a 9-6 LJ potential can reproduce ab initio interaction energies with ~30% (RMSD 0.13 vs 0.18 kcal/mol) less error than point charges (PCs) and a 12-6 LJ potential. We also find that the improvement due to using MTPs with a 9-6 LJ potential is considerably more pronounced than with a 12-6 LJ potential (~ 10%; RMSD 0.19 versus 0.21 kcal/mol). PMID- 26587613 TI - MagiC: Software Package for Multiscale Modeling. AB - We present software package MagiC, which is designed to perform systematic structure-based coarse graining of molecular models. The effective pairwise potentials between coarse-grained sites of low-resolution molecular models are constructed to reproduce structural distribution functions obtained from the modeling of the system in a high resolution (atomistic) description. The software supports coarse-grained tabulated intramolecular bond and angle interactions, as well as tabulated nonbonded interactions between different site types in the coarse-grained system, with the treatment of long-range electrostatic forces by the Ewald summation. Two methods of effective potential refinement are implemented: iterative Boltzmann inversion and inverse Monte Carlo, the latter accounting for cross-correlations between pair interactions. MagiC uses its own Metropolis Monte Carlo sampling engine, allowing parallel simulation of many copies of the system with subsequent averaging of the properties, which provides fast convergence of the method with nearly linear scaling at parallel execution. PMID- 26587614 TI - Demonstrating the Transferability and the Descriptive Power of Sketch-Map. AB - Increasingly, it is recognized that new automated forms of analysis are required to understand the high-dimensional output obtained from atomistic simulations. Recently, we introduced a new dimensionality reduction algorithm, sketch-map, that was designed specifically to work with data from molecular dynamics trajectories. In what follows, we provide more details on how this algorithm works and on how to set its parameters. We also test it on two well-studied Lennard-Jones clusters and show that the coordinates we extract using this algorithm are extremely robust. In particular, we demonstrate that the coordinates constructed for one particular Lennard-Jones cluster can be used to describe the configurations adopted by a second, different cluster and even to tell apart different phases of bulk Lennard-Jonesium. PMID- 26587615 TI - Characterization of the Elusive Conformers of Glycine from State-of-the-Art Structural, Thermodynamic, and Spectroscopic Computations: Theory Complements Experiment. AB - A state-of-the-art computational strategy for the evaluation of accurate molecular structures as well as thermodynamic and spectroscopic properties along with the direct simulation of infrared (IR) and Raman spectra is established, validated (on the basis of the experimental data available for the Ip glycine conformer) and then used to provide a reliable and accurate characterization of the elusive IVn/gtt and IIIp/tct glycine conformers. The integrated theoretical model proposed is based on accurate post-Hartree-Fock computations (involving composite schemes) of energies, structures, properties, and harmonic force fields coupled to DFT corrections for the proper inclusion of vibrational effects at an anharmonic level (as provided by general second-order perturbative approach). It is shown that the approach presented here allows the evaluation of structural, thermodynamic, and spectroscopic properties with an overall accuracy of about, or better than, 0.001 A, 20 MHz, 1 kJ.mol(-1), and 10 cm(-1) for bond distances, rotational constants, conformational enthalpies, and vibrational frequencies, respectively. The high accuracy of the computational results allows one to support and complement experimental studies, thus providing (i) an unequivocal identification of several conformers concomitantly present in the experimental mixture and (ii) data not available or difficult to experimentally derive. PMID- 26587616 TI - Simultaneous Solvent and Counterion Effects on the Absorption Properties of a Model of the Rhodopsin Chromophore. AB - The ASEP/MD (averaged solvent electrostatic potential from molecular dynamics) method was employed in studying the environment effects (solvent and counterion) on the absorption spectrum of a model of the 11-cis-retinal protonated Schiff base. Experimental studies of the absorption spectra of the rhodopsin chromophore show anomalously large solvent shifts in apolar solvents. In order to clarify their origin, we study the role of the counterion and of the solute-solvent interactions. We compare the absorption spectra in the gas phase, cyclohexane, dichloromethane, and methanol. The counterion effect was described from both a classical and quantum point of view. In the latter case, the contribution of the chromophore-counterion charge transfer to the solvent shift could be analyzed. To the best of our knowledge, this is the first time that counterion and solvent effects on the absorption properties of the 11-cis-retinal chromophore have been simultaneously examined. We conclude that the counterion-solute ionic pair in the gas phase is not a good model to represent the solvent shift in nonpolar solvents, as it does not account for the effect that the thermal agitation of the solvent has on the geometry of the ionic pair. In contrast to nonpolar solvents, the experimental solvent shift values in methanol can be exclusively explained by the polarity of the medium. In dichloromethane, the presence of the counterion does not modify the solvent shift of the first absorption band, but it affects the position of the second excited state. In the three solvents considered, the first two excited states become almost degenerate. PMID- 26587617 TI - First Principles Studies of the Vibrationally Resolved Magnetic Circular Dichroism Spectra of Biphenylene. AB - We present density-functional response theory calculations of the one-photon absorption and magnetic circular dichroism spectral bandshapes of biphenylene. The effects from the surrounding solvent environment and molecular vibrations have been included. The solvent is described by the Polarizable Continuum Model (PCM), while the vibrational structures of the spectra have been computed including both Franck-Condon and Herzberg-Teller contributions in the vibronic model. This is the first study of vibronic effects on magnetic circular dichroism spectra including non-Franck-Condon contributions. A detailed comparison with experimental data has been performed, revealing that the B3LYP functional in combination with PCM gives the best agreement with experimental data. Our calculations indicate that nonadiabatic vibronic coupling may play a role, and even small computational inaccuracies might cause significant changes in the calculated HT term, which raises concerns about the inclusion of HT contributions in the calculations of vibronic MCD in systems that have close-lying excited states. PMID- 26587618 TI - Binding in Radical-Solvent Binary Complexes: Benchmark Energies and Performance of Approximate Methods. AB - In many situations, weak interactions between radicals and their environment potentially influence their properties and reactivity. We computed benchmark binding energies of 12 binary complexes involving radicals, using basis set extrapolated coupled cluster theory with up to CCSDT(Q) excitations plus corrections for core correlation and relativistic effects. The set was comprised of both electron-rich and electron-poor small radicals which were either neutral or positively charged. The radicals were complexed with the closed-shell polar (model) solvent molecules H2O and HF. On the basis of these accurate ab initio binding energies, we assess the performance of many modern DFT functionals for these radical-solvent molecule interactions. Radical hydrogen bonded complexes are well-described by most DFT methods, but two-center-three-electron interactions are at least slightly overbound by most functionals evaluated here, including range-separated functionals. No such systematic error was found for electron-rich metal-water complexes. None of the functionals tested yield chemical accuracy for all types of complexes. PMID- 26587619 TI - Benchmarking of London Dispersion-Accounting Density Functional Theory Methods on Very Large Molecular Complexes. AB - A new test set (S12L) containing 12 supramolecular noncovalently bound complexes is presented and used to evaluate seven different methods to account for dispersion in DFT (DFT-D3, DFT-D2, DFT-NL, XDM, dDsC, TS-vdW, M06-L) at different basis set levels against experimental, back-corrected reference energies. This allows conclusions about the performance of each method in an explorative research setting on "real-life" problems. Most DFT methods show satisfactory performance but, due to the largeness of the complexes, almost always require an explicit correction for the nonadditive Axilrod-Teller-Muto three-body dispersion interaction to get accurate results. The necessity of using a method capable of accounting for dispersion is clearly demonstrated in that the two-body dispersion contributions are on the order of 20-150% of the total interaction energy. MP2 and some variants thereof are shown to be insufficient for this while a few tested D3-corrected semiempirical MO methods perform reasonably well. Overall, we suggest the use of this benchmark set as a "sanity check" against overfitting to too small molecular cases. PMID- 26587620 TI - Toward Fully in Silico Melting Point Prediction Using Molecular Simulations. AB - Melting point is one of the most fundamental and practically important properties of a compound. Molecular simulation methods have been developed for the accurate computation of melting points. However, all of these methods need an experimental crystal structure as input, which means that such calculations are not really predictive since the melting point can be measured easily in experiments once a crystal structure is known. On the other hand, crystal structure prediction (CSP) has become an active field and significant progress has been made, although challenges still exist. One of the main challenges is the existence of many crystal structures (polymorphs) that are very close in energy. Thermal effects and kinetic factors make the situation even more complicated, such that it is still not trivial to predict experimental crystal structures. In this work, we exploit the fact that free energy differences are often small between crystal structures. We show that accurate melting point predictions can be made by using a reasonable crystal structure from CSP as a starting point for a free energy based melting point calculation. The key is that most crystal structures predicted by CSP have free energies that are close to that of the experimental structure. The proposed method was tested on two rigid molecules and the results suggest that a fully in silico melting point prediction method is possible. PMID- 26587621 TI - Nonequilibrium Molecular Simulations of New Ionic Lubricants at Metallic Surfaces: Prediction of the Friction. AB - We report nonequilibrium molecular dynamics of ionic liquids interacting with metallic surfaces. A specific set of interaction parameters for ionic liquids composed of alkylammonium cations and alkylsulfonate anions with an iron surface, which has been previously developed (J. Chem. Theory Comput.2012, 8, 3348) is used here. We develop a procedure for a quantitative prediction of the friction coefficient at different loads and shear rates. The simulated friction coefficient agrees very well with the available experimental ones. The dependence of friction on the load, shear velocity, surface topology, and length of alkyl side chains in the ionic liquid is also investigated. The changes in the frictional forces are explained in terms of the specific arrangements and orientations of groups forming the ionic liquid at the vicinity of the surface. PMID- 26587622 TI - Surface Tension of Organic Liquids Using the OPLS/AA Force Field. AB - Molecular dynamics simulations are performed to obtain the surface tension of 61 organic liquids using the OPLS/AA (all-atom optimized potential for liquid simulations). The force field parameters are the same as those recently used (Caleman et al. J. Chem. Theory Comput.2012, 8, 61) to determine several thermodynamic properties of 146 organic liquids. The correct evaluation of surface tension using slab simulations of liquids requires one to properly take into account the long-range interactions (Trukhymchuk and Alejandre J. Chem. Phys.1999, 111, 8510). In addition, the liquid density from slab simulations has to be the same as that obtained in liquid simulations at constant temperature and pressure. The new results of surface tensions from this work improve those reported by Caleman et al. The OPLS/AA force field gives good surface tensions compared with experimental data for most of the systems studied in this work, although it was developed to simulate liquids. PMID- 26587623 TI - GolP-CHARMM: First-Principles Based Force Fields for the Interaction of Proteins with Au(111) and Au(100). AB - Computational simulation of peptide adsorption at the aqueous gold interface is key to advancing the development of many applications based on gold nanoparticles, ranging from nanomedical devices to smart biomimetic materials. Here, we present a force field, GolP-CHARMM, designed to capture peptide adsorption at both the aqueous Au(111) and Au(100) interfaces. The force field, compatible with the bio-organic force field CHARMM, is parametrized using a combination of experimental and first-principles data. Like its predecessor, GolP (Iori, F.; et al. J. Comput. Chem.2009, 30, 1465), this force field contains terms to describe the dynamic polarization of gold atoms, chemisorbing species, and the interaction between sp(2) hybridized carbon atoms and gold. A systematic study of small molecule adsorption at both surfaces using the vdW-DF functional (Dion, M.; et al. Phys. Rev. Lett.2004, 92, 246401-1. Thonhauser, T.; et al. Phys. Rev. B2007, 76, 125112) is carried out to fit and test force field parameters and also, for the first time, gives unique insights into facet selectivity of gold binding in vacuo. Energetic and spatial trends observed in our DFT calculations are reproduced by the force field under the same conditions. Finally, we use the new force field to calculate adsorption energies, under aqueous conditions, for a representative set of amino acids. These data are found to agree with experimental findings. PMID- 26587624 TI - Establishing the Accuracy of Broadly Used Density Functionals in Describing Bulk Properties of Transition Metals. AB - The performance of various commonly used density functionals is established by comparing calculated values of atomic structure data, cohesive energies, and bulk moduli of all transition metals to available experimental data. The functionals explored are the Ceperley-Alder (CA), Vosko-Wilk-Nussair (VWN) implementation of the Local Density Approximation (LDA); the Perdew-Wang (PW91) and Perdew-Burke Ernzerhof (PBE) forms of the Generalized Gradient Approximation (GGA), and the RPBE and PBEsol modifications of PBE, aimed at better describing adsorption energies and bulk solid lattice properties, respectively. The present systematic study shows that PW91 and PBE consistently provide the smallest differences between the calculated and experimental values. Additional calculations of the (111) surface energy of several face centered cubic (fcc) transition metals reveal that LDA produces the most accurate results, while all other functionals significantly underestimate the experimental values. RPBE severely underestimates surface energy, which may be the origin for the reduced surface chemical activity and the better performance of RPBE describing adsorption energies. PMID- 26587625 TI - Toward Reproducing Sequence Trends in Phosphorus Chemical Shifts for Nucleic Acids by MD/DFT Calculations. AB - This work addresses the question of the ability of the molecular dynamics-density functional theory (MD/DFT) approach to reproduce sequence trend in (31)P chemical shifts (deltaP) in the backbone of nucleic acids. deltaP for [d(CGCGAATTCGCG)]2, a canonical B-DNA, have been computed using density functional theory calculations on model compounds with geometries cut out of snapshots of classical molecular dynamics (MD) simulations. The values of (31)P chemical shifts for two distinct B-DNA subfamilies BI and BII, deltaP/BI and deltaP/BII, have been determined as averages over the BI and BII subparts of the MD trajectory. This has been done for various samplings of MD trajectory and for two sizes of both the model and the solvent embedding. For all of the combinations of trajectory sampling, model size, and embedding size, sequence dependence of deltaP/BI in the order of 0.4-0.5 ppm has been obtained. Weighted averages for individual (31)P nuclei in the studied DNA double-helix have been calculated from deltaP/BI and deltaP/BII using BI and BII percentages from free MD simulations as well as from approaches employing NMR structural restraints. A good qualitative agreement is found between experimental sequence trends in deltaP and theoretical deltaP employing short (24 ns) MD run and BI, BII percentages determined by Hartmann et al. or via MD with the inclusion of NMR structural restraints. Theoretical deltaP exhibit a systematic offset of ca. 11 ppm and overestimation of trends by a factor of ca. 1.7. When scaled accordingly, theoretical deltaP/BI and deltaP/BII can be used to determine the expected percentage of BII to match the experimental value of deltaP. As evidenced by the calculations on snapshots from Car Parrinello molecular dynamics, the systematic offsets of the theoretical deltaP obtained by MD/DFT approach result primarily from the unrealistic bond lengths employed by classical MD. The findings made in this work provide structure-deltaP relationships for possible use as NMR restraints and suggest that NMR calculations on MD snapshots can be in the future employed for the validation of newly developed force fields. PMID- 26587626 TI - Atomistic Simulations of Wimley-White Pentapeptides: Sampling of Structure and Dynamics in Solution. AB - Wimley-White pentapeptides (Ac-WLXLL) can be used as a model system to study lipid-protein interactions as they bind to lipid/water interfaces, like many antimicrobial peptides, and thermodynamic experimental data on their interactions with lipids are available, making them useful for both force field and method testing and development. Here we present a detailed simulation study of Wimley White (WW) peptides in bulk water to investigate sampling, conformations, and differences due to the different X residue with an eye to future simulations at the lipid/water interface where sampling problems so far have hindered free energy calculations to reproduce the experimental thermodynamic data. We investigate the conformational preferences and slowest relaxation time of WW peptides in bulk water by building Markov State Models (MSM) from Molecular Dynamics (MD) simulation data. We show that clustering based on binning of backbone phi, psi dihedrals in combination with the community detection algorithm of Blondel et al. provides a quick way of building MSM from large data sets. Our results show that in some cases, implied times even in these small peptides range from 224 to 547 ns. The implications of these slow transitions on determining the potential of mean force profiles of peptide interactions with a lipid bilayer are discussed. PMID- 26587627 TI - Anisotropic Diffusion Effects on the Barnase-Barstar Encounter Kinetics. AB - We investigated effects of hydrodynamic anisotropy on the kinetics of a diffusional encounter of a bacterial ribonuclease, barnase, and its natural inhibitor barstar, using the rigid-body Brownian dynamics technique. We performed atomistically detailed Brownian dynamics simulations of barnase and barstar under periodic boundary conditions, taking into account excluded volume and electrostatic and hydrophobic interactions between the proteins. We studied their specific (i.e., orientationally restricted by their configuration in the X-ray complex) and nonspecific association, either taking into account hydrodynamic anisotropy of the proteins or treating them as hydrodynamically equivalent spheres. We found that even relatively small anisotropy of associating proteins may influence the rate of their encounter and this effect is quantitatively measurable in the simulations. The role of the anisotropic diffusion manifests itself only in case of specific encounters while the association toward nonspecific complexes is not influenced by anisotropic diffusion. Association rate constants obtained from Brownian dynamics simulations for the studied system are up to 20% larger when hydrodynamic anisotropies of barnase and barstar are taken into account. Moreover, the dissociation from the specific complex is also accelerated in case of anisotropic diffusion. PMID- 26587628 TI - Prediction of Hydrodynamic and Other Solution Properties of Partially Disordered Proteins with a Simple, Coarse-Grained Model. AB - The possibility of validating structures of intrinsically disordered proteins against solution properties is a goal that would be most helpful in the understanding of their function. We have devised a scheme for the prediction of solution properties of partially disordered proteins that comprise one or more ordered domains, along with flexible tails or linkers. A very simple, coarse grained, residue-level model, which is easily parametrized using available structural information, along with previously developed tools for the simulation of solution conformation and dynamics, allows the prediction of properties like sedimentation coefficients, relaxation times, and X-ray or neutron scattering. This is demonstrated for a variety of partially disordered proteins, for which well-characterized solution properties are very accurately evaluated, with predictions falling in most cases within experimental errors. PMID- 26587629 TI - Martini Force Field Parameters for Glycolipids. AB - We present an extension of the Martini coarse-grained force field to glycolipids. The glycolipids considered here are the glycoglycerolipids monogalactosyldiacylglycerol (MGDG), sulfoquinovosyldiacylglycerol (SQDG), digalactosyldiacylglycerol (DGDG), and phosphatidylinositol (PI) and its phosphorylated forms (PIP, PIP2), as well as the glycosphingolipids galactosylceramide (GCER) and monosialotetrahexosylganglioside (GM1). The parametrization follows the same philosophy as was used previously for lipids, proteins, and carbohydrates focusing on the reproduction of partitioning free energies of small compounds between polar and nonpolar solvents. Bonded parameters are optimized by comparison to lipid conformations sampled with an atomistic force field, in particular with respect to the representation of the most populated states around the glycosidic linkage. Simulations of coarse grained glycolipid model membranes show good agreement with atomistic simulations as well as experimental data available, especially concerning structural properties such as electron densities, area per lipid, and membrane thickness. Our coarse-grained model opens the way to large scale simulations of biological processes in which glycolipids are important, including recognition, sorting, and clustering of both external and membrane bound proteins. PMID- 26587630 TI - RNA/Peptide Binding Driven by Electrostatics-Insight from Bidirectional Pulling Simulations. AB - RNA/protein interactions play crucial roles in controlling gene expression. They are becoming important targets for pharmaceutical applications. Due to RNA flexibility and to the strength of electrostatic interactions, standard docking methods are insufficient. We here present a computational method which allows studying the binding of RNA molecules and charged peptides with atomistic, explicit-solvent molecular dynamics. In our method, a suitable estimate of the electrostatic interaction is used as an order parameter (collective variable) which is then accelerated using bidirectional pulling simulations. Since the electrostatic interaction is only used to enhance the sampling, the approximations used to compute it do not affect the final accuracy. The method is employed to characterize the binding of TAR RNA from HIV-1 and a small cyclic peptide. Our simulation protocol allows blindly predicting the binding pocket and pose as well as the binding affinity. The method is general and could be applied to study other electrostatics-driven binding events. PMID- 26587631 TI - How Does the Environment Affect the Absorption Spectrum of the Fluorescent Protein mKeima? AB - The absorption spectrum of a fluorescent protein is determined by its chromophore, but the residues that surround it also have a remarkable role, leading to noticeable spectral shifts. We have theoretically analyzed the monomeric protein Keima (mKeima), a red fluorescent protein most remarkable for an outstanding difference between the absorption and emission frequencies, and potentially suited for multicolor imaging applications. In the present work, we have performed excited state electronic calculations on the chromophore with an increasing number of atoms surrounding it, and we have compared these results with the excited states calculations on an ensemble of structures obtained from a molecular dynamics simulation of the complete protein. The importance of the inclusion of the effects of the whole protein in the electronic calculations has been proved, and it is concluded that only with the consideration of the thermal effects can the absorption spectra of the protein be properly characterized. PMID- 26587632 TI - Folding Kinetics and Unfolded State Dynamics of the GB1 Hairpin from Molecular Simulation. AB - The C-terminal beta-hairpin of protein G is a 16-residue peptide that folds in a two-state fashion akin to many larger proteins. However, with an experimental folding time of ~6 MUs, it remains a challenging system for all-atom, explicitly solvated, molecular dynamics simulations. Here, we use a large simulation data set (0.7 ms total) of the hairpin at 300 and 350 K to interpret its folding via a master equation approach. We find a separation of over an order of magnitude between the longest and second longest relaxation times, with the slowest relaxation corresponding to folding. However, in spite of this apparent two-state dynamics, the folding rate determined based on a first-passage time analysis depends on the initial conditions chosen, with a nonexponential distribution of first passage times being obtained in some cases. Using the master equation model, we are now able to account quantitatively for the observed distribution of first passage times. The deviation from the expected exponential distribution for a two-state system arises from slow dynamics in the unfolded state, associated with formation and melting of helical structures. Our results help to reconcile recent findings of slow dynamics in unfolded proteins with observed two-state folding kinetics. At the same time, they indicate that care is required in estimating folding kinetics from many short folding simulations. Last, we are able to use the master equation model to obtain details of the folding mechanism and folding transition state, which appear consistent with the "zipper" mechanism inferred from the experiment. PMID- 26587633 TI - A Comparative Molecular Dynamics, MM-PBSA and Thermodynamic Integration Study of Saquinavir Complexes with Wild-Type HIV-1 PR and L10I, G48V, L63P, A71V, G73S, V82A and I84V Single Mutants. AB - A great challenge toward Acquired Immunodeficiency Syndrome (AIDS) treatment is to combat the HIV-1 virus. The major problem of drug resistance has kept the virus one step ahead of the medical community, and the call for more effective drugs remains as urgent as ever. Saquinavir, the first inhibitor against HIV-1 protease, offers the most extensive clinical data regarding resistance mutations. In this work, we examine L10I, G48V, L63P, A71V, G73S, V82A, and I84V single mutant HIV-1 PR strains in complexes with saquinavir to elucidate drug-protease interactions and dynamics. A comparative analysis of these mutations at the molecular level may lead to a deeper understanding of saquinavir resistance. The G48V mutation induces structural changes to the protease that reflect upon the drug's binding affinity, as shown by MM-PBSA and thermodynamic integration (TI) calculations (DeltaDeltaGTI = 0.3 kcal/mol; DeltaDeltaGMM-PBSA = 1.2 kcal/mol). It was shown that mutations, which increase the flexibility of the flaps (G48V, L63P, L10I) diminish binding. The preservation of hydrogen bonds of saquinavir with both the active site and flap residues in the wild-type and certain single mutants (A71V, V82A) is also crucial for effective inhibition. It was shown that mutations conferring major resistance (G48V, L63P, I84V) did not present these interactions. Finally, it was indicated that a water-mediated hydrogen bond between saquinavir and Asp29 in the active site (wild-type, A71V, G73S) facilitates a proper placement of the drug into the binding cavity that favors binding. Mutants lacking this interaction (G48V, V82A, I84V) demonstrated reduced binding affinities. This systematic and comparative study is a contribution to the elucidation of the drug resistance mechanism in HIV-1 PR. PMID- 26587634 TI - Benchmark Study for the Cysteine-Histidine Proton Transfer Reaction in a Protein Environment: Gas Phase, COSMO, QM/MM Approaches. AB - Proton transfer reactions are of crucial interest for the investigation of proteins. We have investigated the accuracy of commonly used quantum chemical methods for the description of proton transfer reactions in different environments (gas phase, COSMO, QM/MM) using the proton transfer between the catalytic dyad residues cysteine 145 and histidine 41 of SARS coronavirus main protease as a case study. The test includes thermodynamic, kinetic, and structural properties. The study comprises computationally demanding ab initio approaches (HF, CC2, MP2, SCS-CC2, SCS-MP2, CCSD(T)), popular density functional theories (BLYP, B3LYP, M06-2X), and semiempirical methods (MNDO/d, AM1, RM1, PM3, PM6). The approximated coupled cluster approach LCCSD(T) is taken as a reference method. We find that the robustness of the tested methods with respect to the environment correlates well with the level of theory. As an example HF, CC2, MP2, and their SCS variants show similar errors for gas phase, COSMO, or QM/MM computations. In contrast for semiempirical methods, the errors strongly diversify if one goes from gas phase to COSMO or QM/MM. Particular problems are observed for the recent semiempirical methods PM6 and RM1, which show the best performance for gas phase calculations but possess larger errors in conjunction with COSMO. Finally, a combination of SCS-MP2 and B3LYP or M06-2X allows reliable estimates about remaining errors. PMID- 26587635 TI - A New Quantum Calibrated Force Field for Zinc-Protein Complex. AB - A quantum calibrated polarizable-charge transfer force field (QPCT) has been proposed to accurately describe the interaction dynamics of zinc-protein complexes. The parameters of the QPCT force field were calibrated by quantum chemistry calculation and capture the polarization and charge transfer effect. QPCTs are validated by molecular dynamic simulation of the hydration shell of the zinc ion, five proteins containing the most common zinc-binding sites (ZnCys2His2, ZnCys3His1, ZnCys4, Zn2Cys6), as well as protein-ligand binding energy in zinc protein MMP3. The calculated results show excellent agreement with the experimental measurement and with results from QM/MM simulation, demonstrating that QPCT is accurate enough to maintain the correct structural integrity of the zinc binding pocket and provide accurate interaction dynamics of the zinc-residue complex. The current approach can also be extended to the study of interaction dynamics of other metal-containing proteins by recalibrating the corresponding parameters to the specific complexes. PMID- 26587636 TI - Large Density-Functional and Basis-Set Effects for the DMSO Reductase Catalyzed Oxo-Transfer Reaction. AB - The oxygen-atom transfer reaction catalyzed by the mononuclear molybdenum enzyme dimethyl sulfoxide reductase (DMSOR) has attracted considerable attention through both experimental and theoretical studies. We show here that this reaction is more sensitive to details of quantum mechanical calculations than what has previously been appreciated. Basis sets of at least triple-zeta quality are needed to obtain qualitatively correct results. Dispersion has an appreciable effect on the reaction, in particular the binding of the substrate or the dissociation of the product (up to 34 kJ/mol). Polar and nonpolar solvation effects are also significant, especially if the enzyme can avoid cavitation effects by using a preformed active-site cavity. Relativistic effects are considerable (up to 22 kJ/mol), but they are reasonably well treated by a relativistic effective core potential. Various density-functional methods give widely different results for the activation and reaction energy (differences of over 100 kJ/mol), mainly reflecting the amount of exact exchange in the functional, owing to the oxidation of Mo from +IV to +VI. By calibration toward local CCSD(T0) calculations, we show that none of eight tested functionals (TPSS, BP86, BLYP, B97-D, TPSSH, B3LYP, PBE0, and BHLYP) give accurate energies for all states in the reaction. Instead, B3LYP gives the best activation barrier, whereas pure functionals give more accurate energies for the other states. Our best results indicate that the enzyme follows a two-step associative reaction mechanism with an overall activation enthalpy of 63 kJ/mol, which is in excellent agreement with the experimental results. PMID- 26587637 TI - Protein Effects on the Optical Spectrum of the Fenna-Matthews-Olson Complex from Fully Quantum Chemical Calculations. AB - We present a fully quantum-chemical study on the optical spectra of the Fenna Matthews-Olson (FMO) protein. We have investigated the structural and environmental effects on the site energies and excitonic couplings as well as on the UV/vis absorption spectra. Our largest model of the entire protein-pigment network contains more than 7000 atoms. Structures of all bacteriochlorophyll pigments have been optimized in their binding pockets, comprising more than 1000 atoms in some cases. We find that the site energies are quite sensitive to structural and environmental changes in the model setup, while excitonic couplings are more robust. It is shown that nonoptimized pigment structures lead to site energies closer to the ones for pigments optimized in their binding pocket than to those for conformations fully optimized in vacuum. The determination of reliable site energies is one of the key factors for an understanding of the excited-state properties of the FMO protein. PMID- 26587638 TI - Random Coordinate Descent with Spinor-matrices and Geometric Filters for Efficient Loop Closure. AB - Protein loop closure constitutes a critical step in loop and protein modeling whereby geometrically feasible loops must be found between two given anchor residues. Here, a new analytic/iterative algorithm denoted random coordinate descent (RCD) to perform protein loop closure is described. The algorithm solves loop closure through minimization as in cyclic coordinate descent but selects bonds for optimization randomly, updates loop conformations by spinor-matrices, performs loop closure in both chain directions, and uses a set of geometric filters to yield efficient conformational sampling. Geometric filters allow one to detect clashes and constrain dihedral angles on the fly. The RCD algorithm is at least comparable to state of the art loop closure algorithms due to an excellent balance between efficiency and intrinsic sampling capability. Furthermore, its efficiency allows one to improve conformational sampling by increasing the sampling number without much penalty. Overall, RCD turns out to be accurate, fast, robust, and applicable over a wide range of loop lengths. Because of the versatility of RCD, it is a solid alternative for integration with current loop modeling strategies. PMID- 26587639 TI - Validated Conformational Ensembles Are Key for the Successful Prediction of Protein Complexes. AB - Conformational fluctuations in proteins play key roles in their functions and interactions. In this work, validated conformational ensembles for ubiquitin have been used in docking trials. The ensembles were used in a systematic predictive study of known ubiquitin complexes by applying a cross-docking strategy against the bound structure of each partner. The global docking predictions obtained with the complete ubiquitin ensembles were significantly better than those obtained with the crystallographic structure of free ubiquitin. Importantly, in all cases we identified an individual ensemble member that performed equally well, or even better, than the bound structure of ubiquitin. These results unequivocally demonstrate that, for proteins that recognize binding partners by conformational selection, the availability of conformational ensembles can greatly improve the performance of automatic docking predictions. Our results highlight the need for docking methodologies to capitalize on validated ensemble representations of biomacromolecules. PMID- 26587640 TI - Stochastic Surface Walking Method for Structure Prediction and Pathway Searching. AB - We propose an unbiased general-purpose potential energy surface (PES) searching method for both the structure and the pathway prediction of a complex system. The method is based on the idea of bias-potential-driven dynamics and Metropolis Monte Carlo. A central feature of the method is able to perturb smoothly a structural configuration toward a new configuration and simultaneously has the ability to surmount the high barrier in the path. We apply the method for locating the global minimum (GM) of short-ranged Morse clusters up to 103 atoms starting from a random structure without using extra information from the system. In addition to GM searching, the method can identify the pathways for chemical reactions with large dimensionality, as demonstrated in a nanohelix transformation containing 222 degrees of freedoms. PMID- 26587641 TI - Surgical Strategies for Acutely Ruptured Arteriovenous Malformations. AB - Brain arteriovenous malformations (AVMs) are focal neurovascular lesions consisting of abnormal fistulous connections between the arterial and venous systems with no interposed capillaries. This arrangement creates a high-flow circulatory shunt with hemorrhagic risk and hemodynamic abnormalities. While most AVMs are asymptomatic, they may cause severe neurological complications and death. Each AVM carries an annual rupture risk of 2-4%. Intracranial hemorrhage due to AVM rupture is the most common initial manifestation (up to 70% of presentations), and it carries significant morbidity and mortality. This complication is particularly important in the young and otherwise healthy population, in whom AVMs cause up to one-third of all hemorrhagic strokes. A previous rupture is the single most important independent predictor of future hemorrhage. Current treatment modalities for AVM are microsurgery, endovascular embolization, and radiosurgery. In acutely ruptured AVMs, early microsurgical excision is usually avoided. The standard is to wait at least 4 weeks to allow for patient recovery, hematoma liquefaction, and inflammatory reactions to subside. Exceptions to this rule are small, superficial, low-grade AVMs with elucidated angioarchitecture, for which early simultaneous hematoma evacuation and AVM excision is feasible. Emergent hematoma evacuation with delayed AVM excision (unless, as mentioned, the AVM is low grade) is recommended in patients with a decreased level of consciousness due to intracranial hemorrhage, posterior fossa or temporal lobe hematoma of >30 ml, or hemispheric hematoma of >60 ml. The applicability of endovascular techniques for acutely ruptured AVMs is not clear, but feasible options, until a definitive treatment is determined, include occluding intranidal and distal flow-related aneurysms and 'sealing' any rupture site or focal angioarchitectural weakness when one can be clearly identified and safely accessed. Radiosurgery is not performed in acutely ruptured AVMs because its therapeutic effects occur in a delayed fashion. PMID- 26587642 TI - Cubosome Topologies at Various Particle Sizes and Crystallographic Symmetries. AB - The nanoparticles built of bicontinuos lyotropic phases of cubic symmetry are studied within the framework of the Landau-Brazovskii functional that correctly predicts the structure of soft monocrystals and thin films of bicontinuos lyotropic phases. A detailed description of the geometry and topology of cubosomes is presented. This level of description of the internal structure of cubosomes is not easily accessible by experimental techniques. I show that the internal structure of the cubosomes may be extremely rich. PMID- 26587643 TI - Prenatal diagnosis of single gene disorders using amniotic fluid as the starting material for PCR. AB - A rapid and inexpensive method for fetal genetic diagnosis using amniotic fluid (AF) as the starting material was demonstrated in this study. Raw AF was added directly to polymerase chain reaction (PCR) mixtures with HpH buffer (a high pH buffer), without any pre-treatment. Amplified products were detected by gel electrophoresis and then subjected to Sanger sequencing. The AF from four fetuses, each expressing a single gene disorder (achondroplasia, hypochondroplasia, thanatophoric dysplasia, or X-linked hypohidrotic ectodermal dysplasia), were analyzed. DNA fragments of different lengths were efficiently amplified from 8 MUl of AF, allowing each of these single gene disorders to be successfully diagnosed. Although the amplification efficiency of the AF-PCR method is comparable to that of the Chelex method, the amount of the AF sample required was considerably lower than that required for the Chelex method (10 ml). This proposed method of diagnosis is more efficient, simpler, and less expensive, and reduces the chance of cross-contamination relative to the Chelex method, which requires purified DNA or other pre-treatment processes. Our method offers a promising tool that can be used for the diagnosis of various gene disorders in fetuses. PMID- 26587644 TI - Significance of Toll-like Receptor 4 Signaling in Peripheral Blood Monocytes of Pre-eclamptic Patients. AB - OBJECTIVE: Preeclampsia (PE) is a serious condition affecting pregnant women and placing both the mother and fetus at risk. While little is known about the pathogenesis of PE, there is evidence for involvement from the maternal innate immune system, specifically, signaling arising from monocytes. The present study was to explore the role of Toll-like receptor (TLR) 4 on peripheral blood monocyte in the pathogenesis of PE. METHODS: This study included 22 patients with established preeclampsia and 23 healthy pregnant women (HP). All participants gave informed written consent for 4 mL of fresh venous blood to be collected into a tube containing heparin. The expression of TLR4 on monocytes was evaluated by flow cytometry (FCM). Monocytes were stimulated with LPS for 18 h and cytokine secretion (IL-6, IL-12P70, IL-10, and TNF-alpha) in supernatants was analyzed with Luminex platform (Luminex Corporation, Austin, TX). The expression of TLR4 and cytokine secretion (IL-6, IL-12P70, IL-10, and TNF-alpha) was compared between women with PE and healthy pregnant women. RESULTS: Compared with controls, the percentage of TLR4+ monocytes was significantly higher in PE patients. Collected monocytes stimulated with lipopolysaccharide (LPS) to induce inflammation had increased cytokine production, and monocytes from PE patients produced more IL-6 and TNF-alpha, and less IL-10 than cells from healthy participants. PE patients also showed a positive correlation between the percentage of TLR4+ monocytes and serum levels of IL-6 and TNFalpha. CONCLUSIONS: These results suggest that TLR4 signaling may play a role in the pathogenesis of preeclampsia. PMID- 26587645 TI - Surgical Site Infection Rates in Four Cities in Brazil: Findings of the International Nosocomial Infection Control Consortium. AB - BACKGROUND: There are no data on surgical site infection (SSI) rates stratified by surgical procedures (SPs) in Brazil, and our objective was to report such rates. METHODS: From January 2005 to December 2010 we conducted a surveillance study on SSIs in four hospital members of the International Nosocomial Infection Control Consortium (INICC) in four Brazilian cities. We applied the U.S. Centers for Disease Control and Prevention's National Healthcare Safety Network's (CDC NHSN's) surveillance methods. Surgical procedures were classified into following types following International Classification of Diseases (ICD-9) criteria. RESULTS: We recorded 349 SSIs, associated to 61,863 SPs (0.6%; [CI], 0.5-0.6). SSI rates per type of SP were compared with INICC and CDC-NHSN reports, respectively: 2.9% for cardiac surgery (vs. 5.6%, p = 0.001 vs. 1.3%, p = 0.001); 0.4% for cesarean section (vs. 0.7%, p = 0.001 vs. 1.8%, p = 0.001); 5.4% for craniotomy (vs. 4.4% p = 0.447 vs. 2.6% p = 0.005) and 1.1% for vaginal hysterectomy (vs. 2.0% p = 0.102 vs. 0.9% p = 0.499.) CONCLUSIONS: Our SSI rates were greater in two of the four analyzed types of SPs compared with CDC-NHSN, but similar to most INICC rates. These findings on the epidemiology of SSI in Brazil will enable us to introduce targeted interventions for infection control. PMID- 26587647 TI - Emergency Reversal Strategies for Anticoagulation and Platelet Disorders. AB - Bleeding is the most important adverse effect of antithrombotic treatment and may be a major cause of morbidity, longstanding debilitation, and even mortality. In the case of severe hemorrhage in a patient who uses anticoagulant agents, it may be crucial to reverse anticoagulant treatment. Conventional anticoagulants such as vitamin K antagonists can be neutralized by the administration of vitamin K or prothrombin complex concentrates, whereas heparin and heparin derivatives can be counteracted by protamine sulfate. The antihemostatic effect of aspirin and other antiplatelet strategies can be corrected by the administration of platelet concentrate and/or desmopressin. Recently, a new generation of anticoagulants with a greater specificity toward activated coagulation factors as well as new antiplatelet agents have been introduced, and these drugs show efficacy and safety profiles that are at least as good as those of conventional agents in clinical studies. A limitation of these new agents may be the lack of a specific strategy to reverse their effects if a bleeding event occurs, although experimental studies show encouraging results for some of these agents. PMID- 26587646 TI - Mechanistic Scrutiny Identifies a Kinetic Role for Cytochrome b5 Regulation of Human Cytochrome P450c17 (CYP17A1, P450 17A1). AB - Cytochrome P450c17 (P450 17A1, CYP17A1) is a critical enzyme in the synthesis of androgens and is now a target enzyme for the treatment of prostate cancer. Cytochrome P450c17 can exhibit either one or two physiological enzymatic activities differentially regulated by cytochrome b5. How this is achieved remains unknown. Here, comprehensive in silico, in vivo and in vitro analyses were undertaken. Fluorescence Resonance Energy Transfer analysis showed close interactions within living cells between cytochrome P450c17 and cytochrome b5. In silico modeling identified the sites of interaction and confirmed that E48 and E49 residues in cytochrome b5 are essential for activity. Quartz crystal microbalance studies identified specific protein-protein interactions in a lipid membrane. Voltammetric analysis revealed that the wild type cytochrome b5, but not a mutated, E48G/E49G cyt b5, altered the kinetics of electron transfer between the electrode and the P450c17. We conclude that cytochrome b5 can influence the electronic conductivity of cytochrome P450c17 via allosteric, protein-protein interactions. PMID- 26587648 TI - Adsorption of Organic Compounds to Diesel Soot: Frontal Analysis and Polyparameter Linear Free-Energy Relationship. AB - Black carbons (BCs) dominate the sorption of many hydrophobic organic compounds (HOCs) in soils and sediments, thereby reducing the HOCs' mobilities and bioavailabilities. However, we do not have data for diverse HOCs' sorption to BC because it is time-consuming and labor-intensive to obtain isotherms on soot and other BCs. In this study, we developed a frontal analysis chromatographic method to investigate the adsorption of 21 organic compounds with diverse functional groups to NIST diesel soot. This method was precise and time-efficient, typically taking only a few hours to obtain an isotherm. Based on 102 soot-carbon normalized sorption coefficients (KsootC) acquired at different sorbate concentrations, a sorbate-activity-dependent polyparameter linear free-energy relationship was established: logKsootC = (3.74 +/- 0.11)V + ((-0.35 +/- 0.02)log ai)E + (-0.62 +/- 0.10)A + (-3.35 +/- 0.11)B + (-1.45 +/- 0.09); (N = 102, R(2) = 0.96, SE = 0.18), where V, E, A, and B are the sorbate's McGowan's characteristic volume, excess molar refraction, and hydrogen acidity and basicity, respectively; and ai is the sorbate's aqueous activity reflecting the system's approach to saturation. The difference in dispersive interactions with the soot versus with the water was the dominant factor encouraging adsorption, and H-bonding interactions discouraged this process. Using this relationship, soot-water and sediment-water or soil-water adsorption coefficients of HOCs of interest (PAHs and PCBs) were estimated and compared with the results reported in the literature. PMID- 26587649 TI - Structural Insight into Archaic and Alternative Chaperone-Usher Pathways Reveals a Novel Mechanism of Pilus Biogenesis. AB - Gram-negative pathogens express fibrous adhesive organelles that mediate targeting to sites of infection. The major class of these organelles is assembled via the classical, alternative and archaic chaperone-usher pathways. Although non classical systems share a wider phylogenetic distribution and are associated with a range of diseases, little is known about their assembly mechanisms. Here we report atomic-resolution insight into the structure and biogenesis of Acinetobacter baumannii Csu and Escherichia coli ECP biofilm-mediating pili. We show that the two non-classical systems are structurally related, but their assembly mechanism is strikingly different from the classical assembly pathway. Non-classical chaperones, unlike their classical counterparts, maintain subunits in a substantially disordered conformational state, akin to a molten globule. This is achieved by a unique binding mechanism involving the register-shifted donor strand complementation and a different subunit carboxylate anchor. The subunit lacks the classical pre-folded initiation site for donor strand exchange, suggesting that recognition of its exposed hydrophobic core starts the assembly process and provides fresh inspiration for the design of inhibitors targeting chaperone-usher systems. PMID- 26587650 TI - Application of Cervical Collars - An Analysis of Practical Skills of Professional Emergency Medical Care Providers. AB - BACKGROUND/OBJECTIVE: The application of a cervical collar is a standard procedure in trauma patients in emergency medicine. It is often observed that cervical collars are applied incorrectly, resulting in reduced immobilization of the cervical spine. The objective of this study was to analyze the practical skills of trained professional rescue personnel concerning the application of cervical collars. MATERIAL AND METHODS: Within emergency medical conferences, n = 104 voluntary test subjects were asked to apply a cervical collar to a training doll, wherein each step that was performed received an evaluation. Furthermore, personal and occupational data of all study participants were collected using a questionnaire. RESULTS: The test subjects included professional rescue personnel (80.8%) and emergency physicians (12.5%). The average occupational experience of all study participants in pre-clinical emergency care was 11.1+/-8.9 years. Most study participants had already attended a certified training on trauma care (61%) and felt "very confident" in handling a cervical collar (84%). 11% applied the cervical collar to the training doll without errors. The most common error consisted of incorrect adjustment of the size of the cervical collar (66%). No association was found between the correct application of the cervical collar and the occupational group of the test subjects (trained rescue personnel vs. emergency physicians) or the participation in certified trauma courses. CONCLUSION: Despite pronounced subjective confidence regarding the application of cervical collars, this study allows the conclusion that there are general deficits in practical skills when cervical collars are applied. A critical assessment of the current training contents on the subject of trauma care must, therefore, be demanded. PMID- 26587651 TI - Multiple osteomas of the falx cerebri and anterior skull base: case report. AB - The authors describe a rare case of intracranial extraaxial parafalcine and anterior skull base osteomas in a 22-year-old woman presenting with bifrontal headaches. This case highlights the possible occurrence of such lesions along the anterior skull base and parafalcine region that, as such, should be considered as part of the differential diagnosis for extraaxial calcific lesions involving the anterior skull base. To the authors' knowledge, this is the first reported case of a patient who underwent complete successful resection of multiple extraaxial osteomas of the anterior skull base and parafalcine region. PMID- 26587652 TI - MRI-guided stereotactic radiofrequency thermocoagulation for 100 hypothalamic hamartomas. AB - OBJECT The aim of this study was to elucidate the invasiveness, effectiveness, and feasibility of MRI-guided stereotactic radiofrequency thermocoagulation (SRT) for hypothalamic hamartoma (HH). METHODS The authors examined the clinical records of 100 consecutive patients (66 male and 34 female) with intractable gelastic seizures (GS) caused by HH, who underwent SRT as a sole surgical treatment between 1997 and 2013. The median duration of follow-up was 3 years (range 1-17 years). Seventy cases involved pediatric patients. Ninety percent of patients also had other types of seizures (non-GS). The maximum diameter of the HHs ranged from 5 to 80 mm (median 15 mm), and 15 of the tumors were giant HHs with a diameter of 30 mm or more. Comorbidities included precocious puberty (33.0%), behavioral disorder (49.0%), and mental retardation (50.0%). RESULTS A total of 140 SRT procedures were performed. There was no adaptive restriction for the giant or the subtype of HH, regardless of any prior history of surgical treatment or comorbidities. Patients in this case series exhibited delayed precocious puberty (9.0%), pituitary dysfunction (2.0%), and weight gain (7.0%), besides the transient hypothalamic symptoms after SRT. Freedom from GS was achieved in 86.0% of patients, freedom from other types of seizures in 78.9%, and freedom from all seizures in 71.0%. Repeat surgeries were not effective for non GS. Seizure freedom led to disappearance of behavioral disorders and to intellectual improvement. CONCLUSIONS The present SRT procedure is a minimally invasive and highly effective surgical procedure without adaptive limitations. SRT involves only a single surgical procedure appropriate for all forms of epileptogenic HH and should be considered in patients with an early history of GS. PMID- 26587653 TI - Management of arteriovenous malformations in the elderly: a single-center case series and analysis of outcomes. AB - OBJECT Treatment of brain arteriovenous malformations (bAVMs) in the elderly remains a challenge for cerebrovascular surgeons. In this study the authors reviewed the patient characteristics, treatments, angiographic results, and clinical outcomes in 28 patients over 65 years of age who were treated at Henry Ford Hospital between 1990 and 2014. METHODS The bAVM database at the authors' institution was queried for records of elderly patients with bAVMs, and data regarding patient demographics, presenting symptoms, bAVM angioarchitecture, treatment modalities, angiographic results, clinical outcomes, and treatment complications were tabulated and analyzed. RESULTS There were 9 male (32%) and 19 female (68%) patients, with an average age ( +/- SD) of 73.0 +/- 6.95 years. The most common symptoms on presentation were hemorrhage (36%) and headaches (18%). The bAVMs were equally distributed between the supra- and infratentorial compartments. The most common Spetzler-Martin grade was II, observed in 57% of the patients. Eleven patients (39.3%) underwent resection, 4 patients (14.3%) received standalone radiation therapy, and 13 patients (46%) did not receive treatment or were managed expectantly. Four patients (14.3%) were lost to follow up. Complete bAVM obliteration was achieved in 87% of the treated patients. None of the patients who received any form of treatment died; the overall mortality rate was 3.6%. CONCLUSIONS Surgical management of bAVMs in the elderly can result in complete obliteration and acceptable clinical outcomes. PMID- 26587654 TI - Fiber tracts of the dorsal language stream in the human brain. AB - OBJECT The aim of this study was to examine the arcuate (AF) and superior longitudinal fasciculi (SLF), which together form the dorsal language stream, using fiber dissection and diffusion imaging techniques in the human brain. METHODS Twenty-five formalin-fixed brains (50 hemispheres) and 3 adult cadaveric heads, prepared according to the Klingler method, were examined by the fiber dissection technique. The authors' findings were supported with MR tractography provided by the Human Connectome Project, WU-Minn Consortium. The frequencies of gyral distributions were calculated in segments of the AF and SLF in the cadaveric specimens. RESULTS The AF has ventral and dorsal segments, and the SLF has 3 segments: SLF I (dorsal pathway), II (middle pathway), and III (ventral pathway). The AF ventral segment connects the middle (88%; all percentages represent the area of the named structure that is connected to the tract) and posterior (100%) parts of the superior temporal gyri and the middle part (92%) of the middle temporal gyrus to the posterior part of the inferior frontal gyrus (96% in pars opercularis, 40% in pars triangularis) and the ventral premotor cortex (84%) by passing deep to the lower part of the supramarginal gyrus (100%). The AF dorsal segment connects the posterior part of the middle (100%) and inferior temporal gyri (76%) to the posterior part of the inferior frontal gyrus (96% in pars opercularis), ventral premotor cortex (72%), and posterior part of the middle frontal gyrus (56%) by passing deep to the lower part of the angular gyrus (100%). CONCLUSIONS This study depicts the distinct subdivision of the AF and SLF, based on cadaveric fiber dissection and diffusion imaging techniques, to clarify the complicated language processing pathways. PMID- 26587655 TI - Dural arteriovenous fistula-induced thalamic dementia: report of 4 cases. AB - Nonhemorrhagic neurological deficits are underrecognized symptoms of intracranial dural arteriovenous fistulas (dAVFs) having cortical venous drainage. These symptoms are the consequence of cortical venous hypertension and portend a clinical course with increased risk of neurological morbidity and mortality. One rarely documented and easily misinterpreted type of nonhemorrhagic neurological deficit is progressive dementia, which can result from venous hypertension in the cortex or in bilateral thalami. The latter, which is due to dAVF drainage into the deep venous system, is the less common of these 2 dementia syndromes. Herein, the authors report 4 cases of dAVF with venous drainage into the vein of Galen causing bithalamic edema and rapidly progressive dementia. Two patients were treated successfully with endovascular embolization, and the other 2 patients were treated successfully with endovascular embolization followed by surgery. The radiographic abnormalities and presenting symptoms rapidly resolved after dAVF obliteration in all 4 cases. Detailed descriptions of these 4 cases are presented along with a critical review of 15 previously reported cases. In our analysis of these 19 published cases, the following were emphasized: 1) the clinical and radiographic differences between dAVF-induced thalamic versus cortical dementia syndromes; 2) the differential diagnosis and necessary radiographic workup for patients presenting with a rapidly progressive thalamic dementia syndrome; 3) the frequency at which delays in diagnosis occurred and potentially dangerous and avoidable diagnostic procedures were used; and 4) the rapidity and completeness of symptom resolution following dAVF treatment. PMID- 26587657 TI - Insufficient platelet inhibition and thromboembolic complications in patients with intracranial aneurysms after stent placement. AB - OBJECT Insufficient platelet inhibition has been associated with an increased incidence of thromboembolic complications in cardiology patients undergoing percutaneous coronary intervention. Data regarding the relationship between insufficient platelet inhibition and thromboembolic complications in patients undergoing neurovascular procedures remain controversial. The purpose of this study was to assess the relationship of insufficient platelet inhibition and thromboembolic complications in patients with intracranial aneurysm undergoing stent treatment. METHODS The authors prospectively recruited patients with intracranial aneurysms undergoing stent treatment and maintained the data in a database. MRI with diffusion-weighted sequences was performed within 24 hours of stent insertion to identify acute ischemic lesions. The authors used thromboelastography to assess the degree of platelet inhibition in response to clopidogrel and aspirin. Univariate and multivariate logistic regression analysis was used to identify potential risk factors of thromboembolic complications. RESULTS One hundred sixty-eight patients with 193 aneurysms were enrolled in this study. Ninety-one of 168 (54.2%) patients with acute cerebral ischemic lesions were identified by diffusion-weighted MRI. In 9 (5.4%) patients with ischemic lesions, transient ischemic attack or stroke was found at discharge, and these complications were found in 11 (6.5%) patients during the follow-up period. The incidence of periprocedural thromboembolic complications increased with resistance to antiplatelet agents, hypertension, hyperlipidemia, complete occlusion, and aneurysm of the anterior circulation. The multivariate regression analysis demonstrated that the anterior circulation and adenosine diphosphate (ADP) inhibition percentage were independent risk factors of perioperative thromboembolic complications. The maximum amplitude and ADP inhibition percentage were independent risk factors for thromboembolic complications during the follow up period. CONCLUSIONS The ADP inhibition percentage is related to thromboembolic complications after stent placement for intracranial aneurysms. The increase of the ADP inhibition may decrease the risk of thromboembolic complications. PMID- 26587656 TI - CYP2C19 and CES1 polymorphisms and efficacy of clopidogrel and aspirin dual antiplatelet therapy in patients with symptomatic intracranial atherosclerotic disease. AB - OBJECT Symptomatic intracranial atherosclerotic disease (ICAD) has a high risk of recurrent stroke. Genetic polymorphisms in CYP2C19 and CES1 are associated with adverse outcomes in cardiovascular patients, but have not been studied in ICAD. The authors studied CYP2C19 and CES1 single-nucleotide polymorphisms (SNPs) in symptomatic ICAD patients. METHODS Genotype testing for CYP2C19*2, (*)3, (*)8, (*)17 and CES1 G143E was performed on 188 adult symptomatic ICAD patients from 3 medical centers who were medically managed with clopidogrel and aspirin. Testing was performed prospectively at 1 center, and retrospectively from a DNA sample biorepository at 2 centers. Multiple logistic regression and Cox regression analysis were performed to assess the association of these SNPs with the primary endpoint, which was a composite of transient ischemic attack (TIA), stroke, myocardial infarction, or death within 12 months. RESULTS The primary endpoint occurred in 14.9% of the 188 cases. In multiple logistic regression analysis, the presence of the CYP2C19 loss of function (LOF) alleles *2, *3, and *8 in the medically managed patients was associated with lower odds of primary endpoint compared with wild-type homozygotes (odds ratio [OR] 0.13, 95% CI 0.03-0.62, p = 0.0101). Cox regression analysis demonstrated the CYP2C19 LOF carriers had a lower risk for the primary endpoint, with hazard ratio (HR) of 0.27 (95% CI 0.08 0.95), p = 0.041. A sensitivity analysis of a secondary composite endpoint of TIA, stroke, or death demonstrated a significant trend in multiple logistic regression analysis of CYP2C19 variants, with lower odds of secondary endpoint in patients carrying at least 1 LOF allele (*2, *3, *8) than in wild-type homozygotes (OR 0.27, 95% CI 0.06-1.16, p = 0.078). Cox regression analysis demonstrated that the carriers of CYP2C19 LOF alleles had a lower risk forthe secondary composite endpoint (HR 0.22, 95% CI 0.05-1.04, p = 0.056). CONCLUSIONS This is the first study examining genetic variants and their effects in symptomatic ICAD. Variant alleles of CYP2C19 (*2, *3, *8) were associated with lower odds of the primary and secondary composite endpoints. However, the direction of the association was opposite of what is expected based on this SNP. This may reflect an incomplete understanding of this genetic variation and its effect in symptomatic ICAD and warrants further investigations. PMID- 26587658 TI - Letter to the Editor: Radiosurgery for recurrent Grade 2 meningioma. PMID- 26587659 TI - Editorial: Hypothalamic hamartomas. PMID- 26587660 TI - Cost analysis of awake versus asleep deep brain stimulation: a single academic health center experience. AB - OBJECT The objective of this study was to compare the cost of deep brain stimulation (DBS) performed awake versus asleep at a single US academic health center and to compare costs across the University HealthSystem Consortium (UHC) Clinical Database. METHODS Inpatient and outpatient demographic and hospital financial data for patients receiving a neurostimulator lead implant (from the first quarter of 2009 to the second quarter of 2014) were collected and analyzed. Inpatient charges included those associated with International Classification of Diseases, Ninth Revision (ICD-9) procedure code 0293 (implantation or replacement of intracranial neurostimulator lead). Outpatient charges included all preoperative charges <= 30 days prior to implant and all postoperative charges <= 30 days after implant. The cost of care based on reported charges and a cost-to charge ratio was estimated. The UHC database was queried (January 2011 to March 2014) with the same ICD-9 code. Procedure cost data across like hospitals (27 UHC hospitals) conducting similar DBS procedures were compared. RESULTS Two hundred eleven DBS procedures (53 awake and 158 asleep) were performed at a single US academic health center during the study period. The average patient age ( +/- SD) was 65 +/- 9 years old and 39% of patients were female. The most common primary diagnosis was Parkinson's disease (61.1%) followed by essential and other forms of tremor (36%). Overall average DBS procedure cost was $39,152 +/- $5340. Asleep DBS cost $38,850 +/- $4830, which was not significantly different than the awake DBS cost of $40,052 +/- $6604. The standard deviation for asleep DBS was significantly lower (p <= 0.05). In 2013, the median cost for a neurostimulator implant lead was $34,052 at UHC-affiliated hospitals that performed at least 5 procedures a year. At Oregon Health & Science University, the median cost was $17,150 and the observed single academic health center cost for a neurostimulator lead implant was less than the expected cost (ratio 0.97). CONCLUSIONS In this single academic medical center cost analysis, DBS performed asleep was associated with a lower cost variation relative to the awake procedure. Furthermore, costs compared favorably to UHC-affiliated hospitals. While asleep DBS is not yet standard practice, this center exclusively performs asleep DBS at a lower cost than comparable institutions. PMID- 26587661 TI - Increased Contractile Response to Noradrenaline Induced By Factors Associated with the Metabolic Syndrome in Cultured Small Mesenteric Arteries. AB - This study investigated the effect of the metabolic syndrome associated risk factors hyperglycemia (glucose [Glc]), hyperinsulinemia (insulin [Ins]) and low grade inflammation (tumor necrosis factor alpha [TNFalpha]) on the vasomotor responses of resistance arteries. Isolated small mesenteric arteries from 3-month old Sprague-Dawley rats, were suspended for 21-23 h in tissue cultures containing either elevated Glc (30 mmol/l), Ins (100 nmol/l), TNFalpha (100 ng/ml) or combinations thereof. After incubation, the vascular response to noradrenaline (NA), phenylephrine, isoprenaline and NA in the presence of propranolol (10 umol/l) was measured by wire myography. RESULTS: Arteries exposed only to combinations of the risk factors showed a significant 1.6-fold increase in the contractile NA sensitivity, which suggests that complex combinations of metabolic risk factors might lead to changes in vascular tone. PMID- 26587662 TI - Dynamics of the Special Pair of Chlorophylls of Photosystem II. AB - Cholophylls are at the basis of the photosynthetic energy conversion mechanisms in algae, plants, and cyanobacteria. In photosystem II, the photoproduced electrons leave a special pair of chlorophylls (namely, P(D1) and P(D2)) that becomes cationic. This oxidizing pair [P(D1),P(D2)](+), in turn, triggers a cascade of oxidative events, eventually leading to water splitting and oxygen evolution. In the present work, using quantum mechanics/molecular mechanics calculations, we investigate the electronic structure and the dynamics of the P(D1)P(D2) special pair in both its oxidized and reduced states. In agreement with previously reported static calculations, the symmetry between the two chlorophylls was found to be broken, the positive charge being preferentially located on P(D1). Nevertheless, this study reveals for the first time that large charge fluctuations occur along dynamics, temporarily inverting the charge preference for the two branches. Finally, a vibrational analysis pinpointed that such charge fluctuations are strongly coupled to specific modes of the special pair. PMID- 26587663 TI - Impaired NFKBIE gene function decreases cellular uptake of methotrexate by down regulating SLC19A1 expression in a human rheumatoid arthritis cell line. AB - OBJECTIVE: A non-synonymous single nucleotide polymorphism (nsSNP, rs2233434, Val194Ala) in the NFKBIE (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, epsilon) gene is known to be a rheumatoid arthritis (RA) susceptibility polymorphism in the Japanese RA population and could be closely associated with nuclear factor kappaB (NF-kappaB) activity. Inflammation caused by RA is sometimes associated with changes in expression levels of MTX (methotrexate) pathway-related genes. It is of interest to examine whether the NFKBIE gene had any influences on the mode of MTX action. METHODS: Both knockdown of NFKBIE gene expression and overexpression of wild-type NFKBIE and Val194Ala mutation were performed. A transfected human RA synovial cell line was cultured and then gene expressions in the MTX pathway were measured. In addition, we measured the uptake and efflux of MTX derivatives under the NFKBIE knockdown condition. RESULTS: Knockdown of NFKBIE reduced the mRNA for SLC19A1, a main MTX membrane transporter, and the intracellular accumulations of MTX derivatives. Moreover, our experiments also confirmed that overexpression of Val194Ala mutant NFKBIE decreased the SLC19A1 mRNA when compared to that of wild-type NFKBIE. CONCLUSIONS: We suggest that the impairment of NFKBIE gene function can reduce the uptake of MTX into cells, suggesting that the gene is an important factor for the RA outcome. PMID- 26587664 TI - Parsimony, Exhaustivity and Balanced Detection in Neocortex. AB - The layout of sensory brain areas is thought to subtend perception. The principles shaping these architectures and their role in information processing are still poorly understood. We investigate mathematically and computationally the representation of orientation and spatial frequency in cat primary visual cortex. We prove that two natural principles, local exhaustivity and parsimony of representation, would constrain the orientation and spatial frequency maps to display a very specific pinwheel-dipole singularity. This is particularly interesting since recent experimental evidences show a dipolar structures of the spatial frequency map co-localized with pinwheels in cat. These structures have important properties on information processing capabilities. In particular, we show using a computational model of visual information processing that this architecture allows a trade-off in the local detection of orientation and spatial frequency, but this property occurs for spatial frequency selectivity sharper than reported in the literature. We validated this sharpening on high-resolution optical imaging experimental data. These results shed new light on the principles at play in the emergence of functional architecture of cortical maps, as well as their potential role in processing information. PMID- 26587665 TI - Epileptiform K-Complexes and Sleep Spindles: An Underreported Phenomenon in Genetic Generalized Epilepsy. AB - PURPOSE: To study the frequency of epileptiform K-complexes and sleep spindles as well as clinical variables influencing those abnormalities. METHODS: We prospectively performed 24-hour ambulatory EEGs in a cohort of patients with genetic generalized epilepsy diagnosed and classified according to the International League against Epilepsy criteria. Overlapping of epileptiform discharges with K-complexes and sleep spindles was defined as epileptiform K complexes and epileptiform sleep spindles. The presence of epileptiform K complexes and sleep spindles was tabulated for each patient, and frequencies were calculated. We performed multiple regression analysis to study the influence of clinical predictors on the occurrence of epileptiform K-complexes and sleep spindles. The predictor variables tested in the model were seizure-free duration, epilepsy duration, genetic generalized epilepsy syndrome, number of antiepileptic drugs, use of sodium valproate, and use of lamotrigine. RESULTS: A total of 107 patients (37 males and 70 females) were studied. The mean age was 28.5 +/- 10.7 years (range, 13-58). Juvenile absence epilepsy was the most common epilepsy syndrome in the cohort (31.8%), followed by generalized epilepsy with tonic clonic seizures only (26.2%), juvenile myoclonic epilepsy (26.2%), and childhood absence epilepsy (14%). Epileptiform K-complexes and sleep spindles were seen in 65.4% and 10.3% of patients, respectively. None of the clinical variables had any significant impact on the occurrence of epileptiform K-complexes and sleep spindles in our multivariable analysis. CONCLUSIONS: Epileptiform K-complexes are common in the sleep EEGs of patients diagnosed with genetic generalized epilepsy. This underreported phenomenon highlights the important association of arousals and epileptiform discharges in genetic generalized epilepsy. PMID- 26587666 TI - Decomposition of Pyruvic Acid on the Ground-State Potential Energy Surface. AB - A potential energy surface is reported for isomerization and decomposition of gas phase pyruvic acid (CH3C(O)C(O)OH) in its ground electronic state. Consistent with previous works, the lowest energy pathway for pyruvic acid decomposition is identified as decarboxylation to produce hydroxymethylcarbene (CH3COH), with overall barrier of 43 kcal mol(-1). This study discovers that pyruvic acid can also isomerize to the alpha-lactone form with a barrier of only 36 kcal mol(-1), from which CO elimination can occur at 49 kcal mol(-1) above pyruvic acid. An additional novel channel is identified for the tautomerisation of pyruvic acid to the enol form, via a double H-shift mechanism. The barrier for this process is 51 kcal mol(-1), which is around 20 kcal mol(-1) lower than the barrier for conventional keto-enol tautomerization via a 1,3-H shift transition state. Rate coefficients are calculated for pyruvic acid decomposition through RRKM theory/master equation simulations at 800-2000 K and 1 atm, showing good agreement with the available experimental data. The dissociation of vibrationally excited pyruvic acid produced through photoexcitation and subsequent internal conversion to the ground state is also modeled under tropospheric conditions and is seen to produce appreciable quantities of CO (~1-4%) in addition to CH3COH via the dominant CO2 loss channel. PMID- 26587667 TI - Label-Free Quantitative Proteomics Reveals Survival Mechanisms Developed by Hypertrophic Chondrocytes under ER Stress. AB - Emerging evidence implicates ER stress caused by unfolded mutant proteins in chondrocytes as the underlying pathology of chondrodysplasias. ER stress is triggered in hypertrophic chondrocytes (HCs) in a mouse model (13del) of metaphyseal chondrodysplasia type Schmid (MCDS) caused by misfolded mutant collagen X proteins, but the HCs do not undergo apoptosis; rather chondrocyte differentiation is altered, causing skeletal abnormality. How 13del HCs can escape from apoptosis and survive ER stress is not understood. Here we compared the proteomes of HCs isolated from 13del growth plates with normal HCs using a label-free quantitative mass spectrometry approach. Pathway enrichment analyses of differentially expressed proteins showed significant changes in glycolysis and ER-mitochondria pathways in 13del HCs as well as in ATDC5 cell lines expressing wt and 13del collagen X. In vivo, we showed expression of mitochondrial calcium channels was reduced while mitochondrial membrane polarity was maintained in 13del chondrocytes, while in vitro, glucose uptake was maintained. We propose 13del HCs survive by a mechanism whereby changes in ER-mitochondria communication reduce import of calcium coupled to maintenance of mitochondrial membrane polarity. These findings provide the initial insights into our understanding of growth plate changes caused by protein misfolding in the pathogenesis of chondrodysplasias. PMID- 26587669 TI - Osmolyte Induced Changes in Peptide Conformational Ensemble Correlate with Slower Amyloid Aggregation: A Coarse-Grained Simulation Study. AB - Stabilizing osmolytes are known to impact the process of amyloid aggregation, often altering aggregation kinetics. Recent evidence further suggests that osmolytes modify the peptide conformational dynamics, as well as change the physical characteristics of assembling amyloid fibrils. To resolve how these variations emerge on the molecular level, we simulated the initial aggregation steps of an amyloid-forming peptide in the presence and absence of the osmolyte sorbitol, a naturally occurring polyol. To this end, a coarse-grained force field was extended and implemented to access larger aggregate sizes and longer time scales. The force field optimization procedure placed emphasis on calibrating the solution thermodynamics of sorbitol, the aggregating peptide in its monomeric form, and the interaction of both of these components with each other and with water. Our simulations show a difference in aggregation kinetics and structural parameters in the presence of sorbitol compared to water, which qualitatively agree well with our experimentally resolved aggregation kinetics of the same peptide. The kinetic changes induced by sorbitol can be traced in our simulations to changes in monomer conformations resulting from osmolyte presence. These translate into changes in peptide conformations within the aggregated clusters and into differences in rates of monomer nucleation and of association to formed fibrils. We find that, compared to pure water as solvent, the presence of sorbitol induces formation of more aggregates each containing fewer peptides, with an increased tendency toward parallel interpeptide contacts. PMID- 26587668 TI - Mapping of Candidate Genes Involved in Bud Dormancy and Flowering Time in Sweet Cherry (Prunus avium). AB - The timing of flowering in perennial plants is crucial for their survival in temperate climates and is regulated by the duration of bud dormancy. Bud dormancy release and bud break depend on the perception of cumulative chilling during endodormancy and heat during the bud development. The objectives of this work were to identify candidate genes involved in dormancy and flowering processes in sweet cherry, their mapping in two mapping progenies 'Regina' * 'Garnet' and 'Regina' * 'Lapins', and to select those candidate genes which co-localized with quantitative trait loci (QTLs) associated with temperature requirements for bud dormancy release and flowering. Based on available data on flowering processes in various species, a list of 79 candidate genes was established. The peach and sweet cherry orthologs were identified and primers were designed to amplify sweet cherry candidate gene fragments. Based on the amplified sequences of the three parents of the mapping progenies, SNPs segregations in the progenies were identified. Thirty five candidate genes were genetically mapped in at least one of the two progenies and all were in silico mapped. Co-localization between candidate genes and QTLs associated with temperature requirements and flowering date were identified for the first time in sweet cherry. The allelic composition of the candidate genes located in the major QTL for heat requirements and flowering date located on linkage group 4 have a significant effect on these two traits indicating their potential use for breeding programs in sweet cherry to select new varieties adapted to putative future climatic conditions. PMID- 26587670 TI - Transcriptome Analysis of Syringa oblata Lindl. Inflorescence Identifies Genes Associated with Pigment Biosynthesis and Scent Metabolism. AB - Syringa oblata Lindl. is a woody ornamental plant with high economic value and characteristics that include early flowering, multiple flower colors, and strong fragrance. Despite a long history of cultivation, the genetics and molecular biology of S. oblata are poorly understood. Transcriptome and expression profiling data are needed to identify genes and to better understand the biological mechanisms of floral pigments and scents in this species. Nine cDNA libraries were obtained from three replicates of three developmental stages: inflorescence with enlarged flower buds not protruded, inflorescence with corolla lobes not displayed, and inflorescence with flowers fully opened and emitting strong fragrance. Using the Illumina RNA-Seq technique, 319,425,972 clean reads were obtained and were assembled into 104,691 final unigenes (average length of 853 bp), 41.75% of which were annotated in the NCBI non-redundant protein database. Among the annotated unigenes, 36,967 were assigned to gene ontology categories and 19,956 were assigned to eukaryoticorthologous groups. Using the Kyoto Encyclopedia of Genes and Genomes pathway database, 12,388 unigenes were sorted into 286 pathways. Based on these transcriptomic data, we obtained a large number of candidate genes that were differentially expressed at different flower stages and that were related to floral pigment biosynthesis and fragrance metabolism. This comprehensive transcriptomic analysis provides fundamental information on the genes and pathways involved in flower secondary metabolism and development in S. oblata, providing a useful database for further research on S. oblata and other plants of genus Syringa. PMID- 26587671 TI - Effects of Long-Term Odanacatib Treatment on Bone Gene Expression in Ovariectomized Adult Rhesus Monkeys: Differentiation From Alendronate. AB - Similar efficacy of the cathepsin K inhibitor odanacatib (ODN) and the bisphosphonate alendronate (ALN) in reducing bone turnover markers and increasing bone mineral density in spine and hip were previously demonstrated in ovariectomized (OVX)-monkeys treated for 20 months in prevention mode. Here, we profiled RNA from tibial metaphysis and diaphysis of the same study using Affymetrix microarrays, and selected 204 probe sets (p < 0.001, three-group ANOVA) that were differentially regulated by ODN or ALN versus vehicle. Both drugs produced strikingly different effects on known bone-related genes and pathways at the transcriptional level. Although ALN either reduced or had neutral effects on bone resorption-related genes, ODN significantly increased the expression of osteoclast genes (eg, APC5, TNFRSF11A, CTSK, ITGB3, and CALCR), consistent with previous findings on the effects of this agent in enhancing the number of nonresorbing osteoclasts. Conversely, ALN reduced the expression of known bone formation-related genes (eg, TGFBR1, SPP1, RUNX2, and PTH1R), whereas ODN either increased or had neutral effects on their expression. These differential effects of ODN versus ALN on bone resorption and formation were highly correlative to the changes in bone turnover markers, cathepsin K (Catk) target engagement marker serum C-terminal cross-linked telopeptide (1-CTP) and osteoclast marker tartrate resistant acid phosphatase isoform 5b (TRAP5b) in the same monkeys. Overall, the molecular profiling results are consistent with the known pharmacological actions of these agents on bone remodeling and clearly differentiate the molecular mechanisms of ODN from the bisphosphonates. PMID- 26587672 TI - [Caloric irrigation of the vestibular organ using near infrared: A device for use in clinical practice]. PMID- 26587673 TI - Gelsolin-Like Domain 3 Plays Vital Roles in Regulating the Activities of the Lily Villin/Gelsolin/Fragmin Superfamily. AB - The villin/gelsolin/fragmin superfamily is a major group of Ca2+-dependent actin binding proteins (ABPs) involved in various cellular processes. Members of this superfamily typically possess three or six tandem gelsolin-like (G) domains, and each domain plays a distinct role in actin filament dynamics. Although the activities of most G domains have been characterized, the biochemical function of the G3 domain remains poorly understood. In this study, we carefully compared the detailed biochemical activities of ABP29 (a new member of this family that contains the G1-G2 domains of lily ABP135) and ABP135G1-G3 (which contains the G1 G3 domains of lily ABP135). In the presence of high Ca2+ levels in vitro (200 and 10 MUM), ABP135G1-G3 exhibited greater actin severing and/or depolymerization and nucleating activities than ABP29, and these proteins had similar actin capping activities. However, in the presence of low levels of Ca2+ (41 nM), ABP135G1-G3 had a weaker capping activity than ABP29. In addition, ABP29 inhibited F-actin depolymerization, as shown by dilution-mediated depolymerization assay, differing from the typical superfamily proteins. In contrast, ABP135G1-G3 accelerated F actin depolymerization. All of these results demonstrate that the G3 domain plays specific roles in regulating the activities of the lily villin/gelsolin/fragmin superfamily proteins. PMID- 26587674 TI - Effects of Intrathecal kappa-Opioid Receptor Agonist on Morphine-Induced Itch and Antinociception in Mice. AB - The MU-opioid receptor (MOR) agonist-induced itch is a significant issue associated with analgesic therapies. Research suggested that systemically administered kappa-opioid receptor (KOR) agonists inhibit intrathecal morphine induced itch in primates. However, serious adverse effects induced by systemically administered KOR agonists may restrict their usefulness in humans. We investigated the effects of intrathecal KOR agonists on intrathecal morphine mediated itch and antinociception in mice.Mice received intrathecal injections of one of the following drugs: morphine (0.1-1.0 nmol), the selective KOR agonist TRK-820 100 pmol, the combination of morphine 0.3 nmol + TRK-820 (10-100 pmol), and 5 MUL of saline. One hour after intraperitoneal administration of the selective KOR antagonist nor-binaltorphimine 1.0 MUmol, the effect of TRK-820 100 pmol on intrathecal morphine 0.3 nmol-induced scratching was tested. Total numbers of scratches after intrathecal injection were analyzed. After observing scratching behavior, sedation level was evaluated subjectively. Nociceptive threshold was determined by tail immersion test with intrathecal injections of the following agents: morphine (0.1-1.0 nmol), TRK-820 (10-100 pmol), morphine 0.1 nmol + TRK-820 10 pmol, and 5 MUL of saline.Intrathecal TRK-820 dose dependently inhibited intrathecal morphine-induced scratching compared with that in the saline group. Intraperitoneal nor-binaltorphimine completely inhibited the antiscratching effect of intrathecal TRK-820 100 pmol. The combination of morphine 0.3 nmol and TRK-820 did not alter the sedation score compared with that in the morphine 0.3 nmol group. Morphine 0.1 nmol + TRK-820 10 pmol significantly produced greater thermal antinociceptive effects than morphine 0.1 nmol.We demonstrated that intrathecal KOR agonists exert antipruritic effects on intrathecal morphine-induced itch without affecting sedation. The combination of intrathecal morphine and intrathecal KOR agonists produces more potent antinociceptive effects against a thermal stimulus compared with morphine alone. PMID- 26587675 TI - Greater Cephalad Extent of Thoracic Epidural Sensory Anesthesia After Lidocaine and Epinephrine Test Dose Correlates With Analgesic Consumption and Pain Burden After Uterine Fibroid Artery Embolization. AB - BACKGROUND AND OBJECTIVES: Ischemic pain after uterine fibroid artery embolization (UFAE) is often severe. We evaluated the sensory anesthesia extent from thoracic epidural catheter test injection of lidocaine 75 mg with epinephrine 25 MUg as a predictor of analgesia effectiveness after UFAE. METHODS: One hundred patients were studied. Pinprick and cold insensitivity were assessed from L3 to T4 at 5-minute intervals for 30 minutes after the test dose. Thoracic epidural management was standardized. Total epidural infusate and numeric rating of pain (0-10) scores were recorded. RESULTS: Pinprick or cold insensitivity at T9 to T10 dermatome was present in 94% of patients. Forty-six subjects (45%) achieved a sensory level at or above the T6 dermatome at 30 minutes. Median analgesic consumption in the first hour and at catheter discontinuation was greater in subjects with a sensory level above T6 compared with those below T6: first hour difference, 7 mL (95% confidence interval [95% CI], 0-12 mL; P = 0.02); difference at discontinuation, 21 mL (95% CI, 4-35 mL; P = 0.02). The area under the pain score by time curve for the first 24 hours was greater in patients with sensory levels above T6: difference 32 score . hour (95% CI, 12 score . h - 60 score . h; P = 0.001). CONCLUSIONS: Sensory anesthesia spread above the T6 dermatome 30 minutes after a test dose of 1.5% lidocaine was an independent predictor of the analgesic consumption after UFAE. Pain burden and oral opioid consumption were also increased in subjects who demonstrated a high sensory spread after the test dose. PMID- 26587676 TI - Synthesis of Carbon Nanotube-Nanotubular Titania Composites by Catalyst-Free CVD Process: Insights into the Formation Mechanism and Photocatalytic Properties. AB - This work presents the synthesis of carbon nanotubes (CNTs) inside titania nanotube (TNTs) templates by a catalyst-free chemical vapor deposition (CVD) approach as composite platforms for photocatalytic applications. The nanotubular structure of TNTs prepared by electrochemical anodization provides a unique platform to grow CNTs with precisely controlled geometric features. The formation mechanism of carbon nanotubes inside nanotubular titania without using metal catalysts is explored and explained. The structural features, crystalline structures, and chemical composition of the resulting CNTs-TNTs composites were systematically characterized using scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), and Raman spectroscopy. The deposition time during CVD process was used to determine the formation mechanism of CNTs inside TNTs template. The photocatalytic properties of CNTs-TNTs composites were evaluated via the degradation of rhodamine B, an organic model molecule, in aqueous solution under mercury-xenon Hg (Xe) lamp irradiation monitored by UV visible spectroscopy. The obtained results reveal that CNTs induces a synergestic effect on the photocatalytic activity of TNTs for rhodamine B degradation, opening new opportunities to develop advanced photocatalysts for environmental and energy applications. PMID- 26587677 TI - DNA Damage in Bone Marrow Cells Induced by Femtosecond and Nanosecond Ultraviolet Laser Pulses. AB - OBJECTIVE: The purpose of this study was to investigate the possible genotoxic impact of new generation 205 nm femtosecond solid-state laser irradiation on the DNA of murine bone marrow cells in vitro, and to compare the DNA damage caused by both femtosecond and nanosecond UV laser pulses. BACKGROUND DATA: Recent experiments of corneal stromal ablation in vitro and in vivo applying femtosecond UV pulses showed results comparable with or superior to those obtained using nanosecond UV lasers. However, the possible genotoxic effect of ultrashort laser pulses was not investigated. METHODS: Mouse bone marrow cells were exposed to different doses of 205 nm femtosecond, 213 and 266 nm nanosecond lasers, and 254 nm UV lamp irradiation. The comet assay was used for the evaluation of DNA damage. RESULTS: All types of irradiation demonstrated intensity-dependent genotoxic impact. The DNA damage induced depended mainly upon wavelength rather than on other parameters such as pulse duration, repetition rate, or beam delivery to a target. CONCLUSIONS: Both 205 nm femtosecond and clinically applied 213 nm nanosecond lasers' pulses induced a comparable amount of DNA breakage in cells exposed to the same irradiation dose. To further evaluate the suitability of femtosecond UV laser sources for microsurgery, a separate investigation of the genotoxic and mutagenic effects on corneal cells in vitro and, particularly, in vivo is needed. PMID- 26587679 TI - Development and in vivo testing of a high frequency endoscopic Raman spectroscopy system for potential applications in the detection of early colonic neoplasia. AB - The objective of this study was to build and test an adjunct system to a colonoscope for in vivo measurement of Raman spectra from colon tissue for potentially improving the detection of early cancers. The novelty of this system was that low cost fibre optic probes were used, without the addition of expensive optical filters. Good quality in vivo Raman spectra were successfully obtained with a 1 s integration time in the high frequency (HF) range from normal tissue and polyps of patients during a colonoscopy. The polyps were subsequently removed, and their pathology determined. The acquired in vivo Raman spectra showed clear changes between tissue with normal and tubular adenoma pathology. Further clinical study with this low cost HF Raman probe is warranted to fully test its clinical utility. PMID- 26587678 TI - In Vitro Fermentation of caprine milk oligosaccharides by bifidobacteria isolated from breast-fed infants. AB - This study was conducted to investigate the catabolism and fermentation of caprine milk oligosaccharides (CMO) by selected bifidobacteria isolated from 4 breast-fed infants. Seventeen bifidobacterial isolates consisting of 3 different species (Bifidobacterium breve, Bifidobacterium longum subsp. longum and Bifidobacterium bifidum) were investigated. A CMO-enriched fraction (CMOF) (50% oligosaccharides, 10% galacto-oligosaccharides (GOS), 20% lactose, 10% glucose and 10% galactose) from caprine cheese whey was added to a growth medium as a sole source of fermentable carbohydrate. The inclusion of the CMOF was associated with increased bifidobacterial growth for all strains compared to glucose, lactose, GOS, inulin, oligofructose, 3'-sialyl-lactose and 6'-sialyl-lactose. Only one B. bifidum strain (AGR2166) was able to utilize the sialyl-CMO, 3' sialyl-lactose and 6'-sialyl-lactose, as carbohydrate sources. The inclusion of CMOF increased the production of acetic and lactic acid (P < 0.001) after 36 h of anaerobic fermentation at 37 degrees C, when compared to other fermentable substrates. Two B. bifidum strains (AGR2166 and AGR2168) utilised CMO, contained in the CMOF, to a greater extent than B. breve or B. longum subsp longum isolates, and this increased CMO utilization was associated with enhanced sialidase activity. CMOF stimulated bifidobacterial growth when compared to other tested fermentable carbohydrates and also increased the consumption of mono- and disaccharides, such as galactose and lactose present in the CMOF. These findings indicate that the dietary consumption of CMO may stimulate the growth and metabolism of intestinal Bifidobacteria spp. including B. bifidum typically found in the large intestine of breast-fed infants. PMID- 26587680 TI - Zinc(II)-Mediated Carbene Insertion into C-H Bonds in Alkanes. AB - The cationic zinc adduct {[HB(3,5-(CF3)2Pz)3]Zn(NCMe)2}ClO4 catalyzes the functionalization of tertiary, secondary, and primary C-H bonds of alkanes via carbene insertion. Ethyl diazoacetate serves as the :CHCO2Et carbene precursor. The counteranion, supporting ligand, and coordinating solvents affect the catalytic activity. An in situ generated {[HB(3,5-(CF3)2Pz)3]Zn}(+) species containing a bulkier {B[3,5-(CF3)2C6H3]4}(-) anion gives the best results among the zinc catalysts used. PMID- 26587682 TI - What Can Electronic Anesthesia Records Tell Us about Resident Competence? PMID- 26587681 TI - Lack of Association between Blood Pressure Management by Anesthesia Residents and Competence Committee Evaluations or In-training Exam Performance: A Cohort Analysis. AB - BACKGROUND: Prompt treatment of severe blood pressure instability requires both cognitive and technical skill. The ability to anticipate and respond to episodes of hemodynamic instability should improve with training. The authors tested the hypothesis that the duration of severe hypotension during anesthesia administered by residents correlates with concurrent adjusted overall performance evaluations by the Clinical Competence Committee and subsequent in-training exam scores. METHODS: The authors obtained data on 70 first- and second-year anesthesia residents at the Cleveland Clinic. Analysis was restricted to adults having noncardiac surgery with general anesthesia. Outcome variables were in-training exam scores and subjective evaluations of resident performance ranked in quintiles. The primary predictor was cumulative systolic arterial pressure less than 70 mmHg. Secondary predictors were administration of vasopressors, frequency of hypotension, average duration of hypotensive episodes, and blood pressure variability. RESULTS: The primary statistical approach was mixed-effects modeling, adjusted for potential confounders. The authors considered 15,216 anesthesia care episodes. A total of 1,807 hypotensive episodes were observed, lasting an average of 32 +/- 20 min (SD) per 100 h of anesthesia, with 68% being followed by vasopressor administration. The duration of severe hypotension (systolic pressure less than 70 mmHg) was associated with neither Competence Committee evaluations nor in-training exam scores. There was also no association between secondary blood pressure predictors and either Competence Committee evaluations or in-training exam results. CONCLUSIONS: There was no association between any of the five blood pressure management characteristics and either in training exam scores or clinical competence evaluations. However, it remains possible that the measures of physiologic control, as assessed from electronic anesthesia records, evaluate useful but different aspects of anesthesiologist performance. PMID- 26587683 TI - Perioperative Dextromethorphan as an Adjunct for Postoperative Pain: A Meta analysis of Randomized Controlled Trials. AB - BACKGROUND: N-methyl-D-aspartate receptor antagonists have been shown to reduce perioperative pain and opioid use. The authors performed a meta-analysis to determine whether the use of perioperative dextromethorphan lowers opioid consumption or pain scores. METHODS: PubMed, Web of Science, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Pubget, and EMBASE were searched. Studies were included if they were randomized, double blinded, placebo-controlled trials written in English, and performed on patients 12 yr or older. For comparison of opioid use, included studies tracked total consumption of IV or intramuscular opioids over 24 to 48 h. Pain score comparisons were performed at 1, 4 to 6, and 24 h postoperatively. Difference in means (MD) was used for effect size. RESULTS: Forty studies were identified and 21 were eligible for one or more comparisons. In 848 patients from 14 trials, opioid consumption favored dextromethorphan (MD, -10.51 mg IV morphine equivalents; 95% CI, -16.48 to -4.53 mg; P = 0.0006). In 884 patients from 13 trials, pain at 1 h favored dextromethorphan (MD, -1.60; 95% CI, -1.89 to -1.31; P < 0.00001). In 950 patients from 13 trials, pain at 4 to 6 h favored dextromethorphan (MD, -0.89; 95% CI, -1.11 to -0.66; P < 0.00001). In 797 patients from 12 trials, pain at 24 h favored dextromethorphan (MD, -0.92; 95% CI, -1.24 to -0.60; P < 0.00001). CONCLUSION: This meta-analysis suggests that dextromethorphan use perioperatively reduces the postoperative opioid consumption at 24 to 48 h and pain scores at 1, 4 to 6, and 24 h. PMID- 26587684 TI - Experimental Infections of Bluegill with the Trematode Ribeiroia ondatrae (Digenea: Cathaemasiidae): Histopathology and Hematological Response. AB - Infections by the digenetic trematode, Ribeiroia ondatrae, cause severe limb malformations in many North American amphibians. Ribeiroia ondatrae also infects fishes as second intermediate hosts, but less is known about the pathology and immune responses initiated in infected fish, even though reports of infected fish date back to early 1900s. To this end, we experimentally exposed juvenile Bluegills Lepomis macrochirus to three doses of R. ondatrae cercariae and monitored the pathology, parasite infection success, and humoral responses over 648 h. All exposed fish became infected with metacercariae, and the average infection load increased with exposure dose. Histologically, infection was associated with acute hemorrhages in the lateral line and local dermis at 36 h, followed by progressive granulomatous inflammation that led to the destruction of encysted metacercariae. Correspondingly, over the course of 648 h we observed an 85% decline in average infection load among hosts, reflecting the host's clearance of the parasite. Infection was not associated with changes in fish growth or survival, but did correlate with leukocytosis and neutrophilia in circulating host blood. Understanding the physiological responses of R. ondatrae in Bluegill will help to clarify the ecological effects of this parasite and provide a foundation for subsequent comparisons into its effects on behavior, individual health, and population dynamics of Bluegill. PMID- 26587685 TI - Bendamustine therapy associated resolution of anemia and splenomegaly in myelofibrosis. PMID- 26587686 TI - Accelerated adipogenic differentiation of hMSCs in a microfluidic shear stimulation platform. AB - The use of transplanted adipose tissue to repair crucial defects is clinically interesting for surgical reconstruction. Terminally differentiated adipocytes are utilized to promote the healthy regeneration of defective tissue. Use of differentiated mesenchymal stem cells, capable of differentiation into adipocytes, is advantageous because of their regenerative properties. Conventionally, the differentiation of hMSCs toward adipocytes occurs through chemical stimulation. We designed a microfluidic system, consisting of plastic tubing and a syringe pump, to create an environment of shear to accelerate this differentiation process. This system employed a flow rate equivalent to the accelerated flow rates found within the arterial system in order to promote and activate intracellular and extracellular proteins associated with the adipogenic lineage. Confirmation of sustained viability following shear exposure was obtained using a fluorescent live-dead assay. Visualization of intracellular lipid accumulation was achieved via Oil Red O staining. When placed into culture, shear stimulated hMSCs were further induced toward brown adipose tissue, as evidenced by a greater quantity of lipid triglycerides, relative to unstimulated hMSCs. qRT-PCR analysis validated the phenotypic changes observed when the hMSCs were later cultured in adipogenic differentiation media. Additionally, increased fold change for adipogenic markers such as LPL1, CFL1, and SSP1 were observed as a result of shear stimulation. The significance of this work lies in the demonstration that transient fluid shear exposure of hMSCs in suspension can influence differentiation into adipocytes. (c) 2015 American Institute of Chemical Engineers Biotechnol. Prog., 32:440-446, 2016. PMID- 26587687 TI - Multisensory teamwork: using a tactile or an auditory display to exchange gaze information improves performance in joint visual search. AB - In joint tasks, adjusting to the actions of others is critical for success. For joint visual search tasks, research has shown that when search partners visually receive information about each other's gaze, they use this information to adjust to each other's actions, resulting in faster search performance. The present study used a visual, a tactile and an auditory display, respectively, to provide search partners with information about each other's gaze. Results showed that search partners performed faster when the gaze information was received via a tactile or auditory display in comparison to receiving it via a visual display or receiving no gaze information. Findings demonstrate the effectiveness of tactile and auditory displays for receiving task-relevant information in joint tasks and are applicable to circumstances in which little or no visual information is available or the visual modality is already taxed with a demanding task such as air-traffic control. Practitioner Summary: The present study demonstrates that tactile and auditory displays are effective for receiving information about actions of others in joint tasks. Findings are either applicable to circumstances in which little or no visual information is available or when the visual modality is already taxed with a demanding task. PMID- 26587688 TI - The patient's perspective on the symptom and everyday life impact of AL amyloidosis. AB - INTRODUCTION: This study aimed to understand the symptomatic impact of amyloid light-chain (AL) amyloidosis from the patient's perspective. METHODS: Four data sources were included: a literature review, review of online patient blogs, expert clinician interviews and patient interviews. Patients were recruited through the Amyloidosis Foundation and physician referral. Phone interviews were conducted and included open-ended concept elicitation questions. Thematic analysis was performed to identify symptoms and impacts. Descriptive statistics were used to characterize the sample. A conceptual model was developed depicting the impact of disease and treatment. RESULTS: Two hundred seventy abstracts were identified; 10 articles were deemed relevant. No qualitative studies were identified, and only three studies included patient-reported measures. Ten patients completed interviews (mean age 61 [+/-8]; 7 male). Over 25 signs/symptoms were identified, including fatigue, weakness, dyspnea, neuropathy, edema, dizziness/lightheadedness, anorexia, diarrhea and constipation. Impacts included reduced physical and social functioning, and emotional impacts, including frustration, anxiety and depression. Findings from the blogs and expert interviews were consistent with patient reports. CONCLUSION: Symptoms can vary widely, but a core set of symptoms were common across patients. The conceptual model derived from this study can be used to ensure a patient-centered approach to drug development. PMID- 26587689 TI - Site-Specific Labeling of Protein Lysine Residues and N-Terminal Amino Groups with Indoles and Indole-Derivatives. AB - Indoles and indole-derivatives can be used to site-specifically label proteins on lysine and N-terminal amino groups under mild, nondenaturing reaction conditions. Hen egg white lysozyme (HEWL) and alpha-lactalbumin were labeled with indole, fluoroindole, or fluoroindole-2-carboxylate via electrophilic aromatic substitutions to lysine side chain Nepsilon- and N-terminal amino imines, formed in situ in the presence of formaldehyde. The reaction is highly site-selective, easily controlled by temperature, and does not eliminate the native charge of the protein, unlike many other common lysine-specific labeling strategies. (19)F NMR was used to monitor reaction progression, and in the case of HEWL, unique resonances for each labeled side chain could be resolved. We demonstrate that the indole tags are highly selective for primary amino groups. (19)F NMR demonstrates that each lysine exhibits a different rate of conjugation to indoles making it possible to employ these tags as a means of probing surface topology by NMR or mass spectrometry. Given the site-specificity of this tagging method, the mildness of the reaction conditions (aqueous, buffered, or unbuffered) and the low stoichiometry required for the reaction, indole-derivatives should serve as a valuable addition to the bioconjugation toolkit. We propose that labeling lysine side chains and N-terminal amino groups with indoles is a versatile and general strategy for bioconjugations with substituted indoles having broad implications for protein functionalization. PMID- 26587690 TI - Characterization of sorption sites and differential stress response of microalgae isolates against tannery effluents from ranipet industrial area-An application towards phycoremediation. AB - Phycoremediation ability of microalgae namely Oscillatoria acuminate and Phormidium irrigum were validated against the heavy metals from tannery effluent of Ranipet industrial area. The microalgae species were cultured in media containing tannery effluent in two different volumes and the parameters like specific growth rate, protein content and antioxidant enzyme activities were estimated. FTIR spectroscopy was carried out to know the sorption sites interaction. The antioxidant enzymes namely superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH) contents were increased in microalgae species indicating the free radical scavenging mechanism under heavy metal stress. SOD activity was 0.502 and 0.378 units/gram fresh weight, CAT activity was 1.36 and 0.256 units/gram fresh weight, GSH activity was 1.286 and 1.232 units/gram fresh weight respectively in the effluent treated microalgae species. Bio sorption efficiency for Oscillatoria acuminate and Phormidium irrigum was 90% and 80% respectively. FTIR analysis revealed the interaction of microalgae species with chemical groups present in the tannery effluent. From the results, the microalgae Oscillatoria acuminate possess high antioxidant activity and bio sorption efficiency when compared to Phormidium irrigum and hence considered useful in treating heavy metals contaminated effluents. PMID- 26587691 TI - An overview of new GLP-1 receptor agonists for type 2 diabetes. AB - INTRODUCTION: The increasing prevalence of type 2 diabetes mellitus (T2DM) and the eventual need for multiple medications in most patients stimulated the development of new drug classes to reduce plasma glucose levels. The GLP-1 receptor agonists (GLP-1RAs) are established as an option for treatment of T2DM after metformin. They are also effective in reducing body weight but current GLP 1RAs have to be given by subcutaneous injection daily or once weekly. AREAS COVERED: This review focuses on the new GLP-1RAs currently undergoing development, some of which require less frequent subcutaneous administration and others that are being developed in oral formulations that may favor patient adherence. EXPERT OPINION: The new GLP-1RAs may have the benefit of requiring less frequent subcutaneous dosing or being active by oral administration. However, cardiovascular outcome trials have shown that DPP4 inhibitors are neutral for cardiovascular events and the first cardiovascular outcome trial with lixisenatide reported similar results, whereas the trial with the SGLT2 inhibitor empagliflozin showed a reduction in cardiovascular events. These findings in patients with high cardiovascular risk may favor the use of SGLT2 inhibitors as a second line treatment after metformin but there should still be an important role for novel GLP-1RAs, especially when weight reduction is required. PMID- 26587692 TI - Haplosufficiency of PAX3 for melanoma development in Tyr: NRASQ61K; Cdkn2a-/- mice allows identification and sorting of melanoma cells using a Pax3GFP reporter allele. AB - The role of the Pax3 gene in embryonic development of pigment cells is well characterized. By contrast, the function of Pax3 in melanoma development is controversial. Indeed, data obtained from cultured cells suggest that PAX3 may contribute to melanomagenesis. PAX3 is found to be overexpressed in melanomas and also in nevi compared with normal skin samples. Pax3 homozygous loss of function is embryonic lethal. To assess the role of Pax3 in melanoma development in vivo, we analyzed Pax3 haploinsufficiency in a mouse model of melanoma predisposition. The Pax3(GFP/+) knock-in reporter system was combined with the Tyr::NRAS(Q61K); Cdkn2a(-/-) mouse melanoma model. Melanoma development was followed over 18 months. Histopathological, immunohistochemical, and molecular analyses of lesions at different stages of melanoma progression were carried out. Fluorescence activated cell sorting on GFP of cells from primary or metastatic melanoma was followed by ex-vivo transformation tests and in-vivo passaging. We report here that Tyr::NRAS(Q61K); Cdkn2a(-/-); Pax3(GFP/+) mice developed metastasizing melanoma as their Tyr::NRAS(Q61K); Cdkn2a(-/-); littermates. Histopathology showed no differences between the two genotypes, although Pax3 mRNA and PAX3 protein levels in Pax3(GFP/+) lesions were reduced by half. The Pax3(GFP) allele proved to be a convenient marker to identify and directly sort heterogeneous populations of melanoma cells within the tumor bulk at each stage of melanoma progression. This new mouse model represents an accurate and reproducible means for identifying melanoma cells in vivo to study the mechanisms of melanoma development. PMID- 26587693 TI - Seed fate and decision-making processes in scatter-hoarding rodents. AB - A mechanistic understanding of seed movement and survival is important both for the development of theoretical models of plant population dynamics, spatial spread, and community assembly, and for the conservation and management of plant communities under global change. While models of wind-borne seed dispersal have advanced rapidly over the past two decades, models for animal-mediated dispersal have failed to make similar progress due to their dependence on interspecific interactions and complex, context-dependent behaviours. In this review, we synthesize the literature on seed dispersal and consumption by scatter-hoarding, granivorous rodents and outline a strategy for development of a general mechanistic seed-fate model in these systems. Our review decomposes seed dispersal and survival into six distinct sub-processes (exposure, harvest, allocation, preparation, placement, and recovery), and identifies nine intermediate (latent) variables that link physical state variables (e.g. seed and animal traits, habitat structure) to decisions regarding seed allocation to hoarding or consumption, cache placement and management, and deployment of radicle-pruning or embryo excision behaviours. We also highlight specific areas where research on these intermediate relationships is needed to improve our mechanistic understanding of scatter-hoarder behaviour. Finally, we outline a strategy to combine detailed studies on individual functional relationships with seed-tracking experiments in an iterative, hierarchical Bayesian framework to construct, refine, and test mechanistic models for context-dependent, scatter hoarder-mediated seed fate. PMID- 26587694 TI - Pilot study on the detection of antiandrogen resistance using serial diffusion weighted imaging of bone metastases in prostate cancer. AB - PURPOSE: To evaluate serial apparent diffusion coefficient (ADC) measurements of bone metastases in prostate cancer to determine whether antiandrogen resistance can be detected and time to progression estimated. MATERIALS AND METHODS: Diffusion-weighted imaging (DWI) was performed at 1.5T in nine patients with treatment-naive metastatic prostate cancer (20 lesions) before antiandrogen treatment, after 1, 2, and 3 months of treatment, and thereafter every 4 months over 31 months or until antiandrogen resistance was detected. Tumor volumes were stable over time. Time courses of the ADCs when averaged over entire lesions and on functional diffusion maps (fDMs) were analyzed using marginal linear model (MLM) analysis. RESULTS: Starting at 1 month, MLM analysis revealed decreasing mean ADCs (P = 0.001) over time. Simultaneously, the percentage of voxels with significantly higher ADCs decreased (P = 0.004), whereas the percentage of voxels with significantly lower ADCs increased (P < 0.001) on fDMs. Both mean ADCs (P = 0.042) and percentages of voxels with significantly higher ADCs on fDMs (P = 0.039) decreased more rapidly over time in patients with a shorter progression free interval (PFI). Likewise, higher (P = 0.001) and more rapidly increasing (P = 0.002) percentages of voxels with significantly lower ADCs on fDMs were associated with a shorter PFI. CONCLUSION: The results of our pilot study suggest that the evolution of ADCs over time may permit early identification of antiandrogen resistance in bone metastases. J. Magn. Reson. Imaging 2016;43:1407 1416. PMID- 26587696 TI - Advanced Practice Nurses: Increasing Access to Opioid Treatment by Expanding the Pool of Qualified Buprenorphine Prescribers. PMID- 26587695 TI - Interventions for dissociated vertical deviation. AB - BACKGROUND: The term "strabismus" describes misalignment of the eyes. One or both eyes may deviate inward, outward, upward, or downward. Dissociated vertical deviation (DVD) is a well-recognized type of upward drifting of one or both eyes, which can occur in children or adults. DVD often develops in the context of infantile- or childhood-onset horizontal strabismus, either esotropia (inward turning) or exotropia (outward-turning). For some individuals, DVD remains controlled and can only be detected during clinical testing. For others, DVD becomes spontaneously "manifest" and the eye drifts up of its own accord. Spontaneously manifest DVD can be difficult to control and often causes psychosocial concerns. Traditionally, DVD has been thought to be asymptomatic, although some individuals have double vision. More recently it has been suggested that individuals with DVD may also suffer from eyestrain. Treatment for DVD may be sought either due to psychosocial concerns or because of these symptoms. The standard treatment for DVD is a surgical procedure; non-surgical treatments are offered less commonly. Although there are many studies evaluating different management options for the correction of DVD, a lack of clarity remains regarding which treatments are most effective. OBJECTIVES: The objective of this review was to determine the effectiveness and safety of various surgical and non-surgical interventions in randomized controlled trials of participants with DVD. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (2015, Issue 8), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to August 2015), EMBASE (January 1980 to August 2015), PubMed (1948 to August 2015), Latin American and Caribbean Health Sciences Literature Database (LILACS) (1982 to August 2015), the metaRegister of Controlled Trials (mRCT) (www.controlled trials.com) (last searched 3 February 2014), ClinicalTrials.gov (www.clinicaltrials.gov), and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 3 August 2015. SELECTION CRITERIA: We included randomized controlled trials (RCTs) of surgical and non-surgical interventions for the correction of DVD. DATA COLLECTION AND ANALYSIS: We used standard procedures expected by Cochrane. Two review authors independently completed eligibility screening, data abstraction, 'Risk of bias' assessment, and grading of the evidence. MAIN RESULTS: We found four RCTs eligible for inclusion in this review (248 eyes of 151 participants between the ages of 6 months to 22 years). All trials were assessed as having unclear risk of bias overall due to insufficient reporting of study methods. One trial was conducted in Canada and compared anteriorization of the inferior oblique muscle with resection versus anteriorization of the inferior oblique muscle alone; one in the USA compared superior rectus recession with posterior fixation suture versus superior rectus recession alone; and two in the Czech Republic compared anteriorization of the inferior oblique muscle versus myectomy of the inferior oblique muscle.Only one trial reported data that allowed analysis of the primary outcome for this review, the proportion of participants with treatment success. The difference between inferior oblique anteriorization plus resection versus inferior oblique anteriorization alone was uncertain when measured at least four months postoperatively (risk ratio 1.13, 95% confidence interval 0.60 to 2.11, 30 participants, very low-quality evidence). Three trials measured the magnitude of hyperdeviation, but did not provide sufficient data for analysis. All four trials reported a relatively low rate of adverse events; hypotropia, limited elevation, and need for repeat surgery were reported as adverse events associated with some of the surgical interventions. No trials reported any other secondary outcome specified for our review. AUTHORS' CONCLUSIONS: The four trials included in this review assessed the effectiveness of five different surgical procedures for the treatment of DVD. Nevertheless, insufficient reporting of study methods and data led to methodological concerns that undermine the conclusions of all studies. There is a pressing need for carefully executed RCTs of treatment for DVD in order to improve the evidence for the optimal management of this condition. PMID- 26587698 TI - The efficacy of adjuvant therapy for pancreatic invasive intraductal papillary mucinous neoplasm (IPMN). AB - BACKGROUND: The literature investigating pancreatic invasive intraductal papillary mucinous neoplasm (IPMN) has largely come from small institutional studies, preventing adequately powered comparisons of adjuvant therapy versus surgery alone (SA) within specific patient subgroups. METHODS: Patients with resected, stage I through IV, invasive IPMN and conventional pancreatic ductal adenocarcinoma (PDAC) were identified in the National Cancer Data Base (1998 2010). Cox modeling of patients with invasive IPMN was used to compare overall survival (OS) between patients who received adjuvant therapy and those who underwent SA. A second model was used to compare OS between patients with invasive IPMN and those with PDAC. RESULTS: For the 1220 patients with invasive IPMN, the median OS was 28.9 months; the 1-year and 5-year actuarial survival rates were 76% and 17%, respectively; and 47% received adjuvant therapy. Cox modeling associated SA with worse OS (hazard ratio, 1.36; 95% confidence interval, 1.17-1.58; P = .00005) as well as American Joint Committee on Cancer (AJCC) TNM stage III/IV disease, positive lymph node status, positive margins, and poor tumor differentiation (all P <= .05). In addition, Cox modeling stratified by the following characteristics demonstrated improved OS with adjuvant therapy: AJCC TNM stage II or III/IV, positive lymph node status, positive margins, and poorly differentiated tumors. There was no survival advantage from adjuvant therapy for patients who had AJCC TNM stage I or lymph node-negative disease. Patients who had invasive IPMN had improved risk-adjusted OS compared with those who had PDAC (hazard ratio, 0.73; 95% confidence interval, 0.68-0.78; P < .00001). CONCLUSIONS: Invasive IPMN appears to be more indolent than conventional PDAC. Adjuvant therapy is associated with improved OS compared with SA in patients with invasive IPMN, especially for those with higher stage disease, positive lymph nodes, positive margins, or poorly differentiated tumors. Conversely, this benefit does not extend to patients with stage I or lymph node negative disease. PMID- 26587700 TI - Greater cross-viewer similarity of semantic associations for representational than for abstract artworks. AB - It has been shown previously that liking and valence of associations in response to artworks show greater convergence across viewers for representational than for abstract artwork. The current research explored whether the same applies to the semantic content of the associations. We used data gained with an adapted unique corporate association valence measure, which invited 24 participants to give short verbal responses to 11 abstract and 11 representational artworks. We paired the responses randomly to responses given to the same artwork and computed semantic similarity scores using UMBC Ebiquity software. This showed significantly greater semantic similarity scores for representational than for abstract art. A control analysis in which responses were randomly paired with responses from the same category (abstract, representational) showed no significant results, ruling out a baseline effect. For both abstract and representational artworks, randomly paired responses resembled each other less than responses from the same artworks, but the effect was much larger for representational artworks. Our work shows that individuals share semantic associations with other viewers in response to artworks to a greater extent when the artwork is representational than when it is abstract. Our novel method shows potential utility for many areas of psychology that aim to understand the semantic convergence of people's verbal responses, not least aesthetic psychology. PMID- 26587699 TI - Knowing what the brain is seeing in three dimensions: A novel, noninvasive, sensitive, accurate, and low-noise technique for measuring ocular torsion. AB - Torsional eye movements are rotations of the eye around the line of sight. Measuring torsion is essential to understanding how the brain controls eye position and how it creates a veridical perception of object orientation in three dimensions. Torsion is also important for diagnosis of many vestibular, neurological, and ophthalmological disorders. Currently, there are multiple devices and methods that produce reliable measurements of horizontal and vertical eye movements. Measuring torsion, however, noninvasively and reliably has been a longstanding challenge, with previous methods lacking real-time capabilities or suffering from intrusive artifacts. We propose a novel method for measuring eye movements in three dimensions using modern computer vision software (OpenCV) and concepts of iris recognition. To measure torsion, we use template matching of the entire iris and automatically account for occlusion of the iris and pupil by the eyelids. The current setup operates binocularly at 100 Hz with noise <0.1 degrees and is accurate within 20 degrees of gaze to the left, to the right, and up and 10 degrees of gaze down. This new method can be widely applicable and fill a gap in many scientific and clinical disciplines. PMID- 26587701 TI - The Importance of Debriefing in Simulation-Based Learning: Comparison Between Debriefing and No Debriefing. AB - Debriefing is an essential component of simulation-based learning and is a constructive teaching strategy for teachers and an effective learning method to consolidate knowledge and skills for students. The purpose of this study was to verify the importance of debriefing in simulation-based learning for students in a nursing program. Participants in this study were 49 second-year nursing students who were enrolled at the Red Cross College of Nursing in Seoul, Korea. Collected data were analyzed using chi test, t test, and independent t test statistics. There were significant differences between students in the debriefing group and those in the no-debriefing group evaluated. The level of clinical performance competency, self-reflection, and satisfaction with simulation-based learning for debriefing group students was higher than that for no-debriefing group. Debriefing was an important factor in simulation-based learning to improve technical and nontechnical skills and facilitate self-reflection. These results suggest that debriefing by a trained instructor is essential for maximizing simulation-based learning success. In absence of a trained debriefing instructor, various alternative forms of debriefing should be considered. PMID- 26587702 TI - Do anti-viral neutrophil responses exacerbate lung inflammation in asthma? PMID- 26587703 TI - The role of chemistry in inventing a sustainable future. PMID- 26587704 TI - Interlocked molecules: Aqueous assembly. PMID- 26587705 TI - Photochemistry: A coherent picture of vision. PMID- 26587706 TI - 2015 Nobel Prize in Chemistry: Requiring repair. PMID- 26587707 TI - Biocatalysis: Chiral cascades. PMID- 26587708 TI - 2015 Nobel Prize in Physiology or Medicine: Punishing parasites. PMID- 26587709 TI - Domino reactions: More than just a game. PMID- 26587710 TI - Recent advances in the molecular design of synthetic vaccines. AB - Vaccines have typically been prepared using whole organisms. These are normally either attenuated bacteria or viruses that are live but have been altered to reduce their virulence, or pathogens that have been inactivated and effectively killed through exposure to heat or formaldehyde. However, using whole organisms to elicit an immune response introduces the potential for infections arising from a reversion to a virulent form in live pathogens, unproductive reactions to vaccine components or batch-to-batch variability. Synthetic vaccines, in which a molecular antigen is conjugated to a carrier protein, offer the opportunity to circumvent these problems. This Perspective will highlight the progress that has been achieved in developing synthetic vaccines using a variety of molecular antigens. In particular, the different approaches used to develop conjugate vaccines using peptide/proteins, carbohydrates and other small molecule haptens as antigens are compared. PMID- 26587711 TI - Monitoring one-electron photo-oxidation of guanine in DNA crystals using ultrafast infrared spectroscopy. AB - To understand the molecular origins of diseases caused by ultraviolet and visible light, and also to develop photodynamic therapy, it is important to resolve the mechanism of photoinduced DNA damage. Damage to DNA bound to a photosensitizer molecule frequently proceeds by one-electron photo-oxidation of guanine, but the precise dynamics of this process are sensitive to the location and the orientation of the photosensitizer, which are very difficult to define in solution. To overcome this, ultrafast time-resolved infrared (TRIR) spectroscopy was performed on photoexcited ruthenium polypyridyl-DNA crystals, the atomic structure of which was determined by X-ray crystallography. By combining the X ray and TRIR data we are able to define both the geometry of the reaction site and the rates of individual steps in a reversible photoinduced electron-transfer process. This allows us to propose an individual guanine as the reaction site and, intriguingly, reveals that the dynamics in the crystal state are quite similar to those observed in the solvent medium. PMID- 26587713 TI - Local vibrational coherences drive the primary photochemistry of vision. AB - The role of vibrational coherence-concerted vibrational motion on the excited state potential energy surface-in the isomerization of retinal in the protein rhodopsin remains elusive, despite considerable experimental and theoretical efforts. We revisited this problem with resonant ultrafast heterodyne-detected transient-grating spectroscopy. The enhanced sensitivity that this technique provides allows us to probe directly the primary photochemical reaction of vision with sufficient temporal and spectral resolution to resolve all the relevant nuclear dynamics of the retinal chromophore during isomerization. We observed coherent photoproduct formation on a sub-50 fs timescale, and recovered a host of vibrational modes of the retinal chromophore that modulate the transient-grating signal during the isomerization reaction. Through Fourier filtering and subsequent time-domain analysis of the transient vibrational dynamics, the excited-state nuclear motions that drive the isomerization reaction were identified, and comprise stretching, torsional and out-of-plane wagging motions about the local C11=C12 isomerization coordinate. PMID- 26587712 TI - Inhibition of human copper trafficking by a small molecule significantly attenuates cancer cell proliferation. AB - Copper is a transition metal that plays critical roles in many life processes. Controlling the cellular concentration and trafficking of copper offers a route to disrupt these processes. Here we report small molecules that inhibit the human copper-trafficking proteins Atox1 and CCS, and so provide a selective approach to disrupt cellular copper transport. The knockdown of Atox1 and CCS or their inhibition leads to a significantly reduced proliferation of cancer cells, but not of normal cells, as well as to attenuated tumour growth in mouse models. We show that blocking copper trafficking induces cellular oxidative stress and reduces levels of cellular ATP. The reduced level of ATP results in activation of the AMP-activated protein kinase that leads to reduced lipogenesis. Both effects contribute to the inhibition of cancer cell proliferation. Our results establish copper chaperones as new targets for future developments in anticancer therapies. PMID- 26587714 TI - A manganese catalyst for highly reactive yet chemoselective intramolecular C(sp(3))-H amination. AB - C-H bond oxidation reactions underscore the existing paradigm wherein high reactivity and high selectivity are inversely correlated. The development of catalysts capable of oxidizing strong aliphatic C(sp(3))-H bonds while displaying chemoselectivity (that is, tolerance of more oxidizable functionality) remains an unsolved problem. Here, we describe a catalyst, manganese tert butylphthalocyanine [Mn((t)BuPc)], that is an outlier to the reactivity selectivity paradigm. It is unique in its capacity to functionalize all types of C(sp(3))-H bond intramolecularly, while displaying excellent chemoselectivity in the presence of pi functionality. Mechanistic studies indicate that [Mn((t)BuPc)] transfers bound nitrenes to C(sp(3))-H bonds via a pathway that lies between concerted C-H insertion, observed with reactive noble metals such as rhodium, and stepwise radical C-H abstraction/rebound, as observed with chemoselective base metals such as iron. Rather than achieving a blending of effects, [Mn((t)BuPc)] aminates even 1 degrees aliphatic and propargylic C-H bonds, demonstrating reactivity and selectivity unusual for previously known catalysts. PMID- 26587715 TI - Reconstitution of [Fe]-hydrogenase using model complexes. AB - [Fe]-Hydrogenase catalyses the reversible hydrogenation of a methenyltetrahydromethanopterin substrate, which is an intermediate step during the methanogenesis from CO2 and H2. The active site contains an iron guanylylpyridinol cofactor, in which Fe(2+) is coordinated by two CO ligands, as well as an acyl carbon atom and a pyridinyl nitrogen atom from a 3,4,5,6 substituted 2-pyridinol ligand. However, the mechanism of H2 activation by [Fe] hydrogenase is unclear. Here we report the reconstitution of [Fe]-hydrogenase from an apoenzyme using two FeGP cofactor mimics to create semisynthetic enzymes. The small-molecule mimics reproduce the ligand environment of the active site, but are inactive towards H2 binding and activation on their own. We show that reconstituting the enzyme using a mimic that contains a 2-hydroxypyridine group restores activity, whereas an analogous enzyme with a 2-methoxypyridine complex was essentially inactive. These findings, together with density functional theory computations, support a mechanism in which the 2-hydroxy group is deprotonated before it serves as an internal base for heterolytic H2 cleavage. PMID- 26587716 TI - Quantitative self-assembly of a purely organic three-dimensional catenane in water. AB - Self-assembly by means of coordinative bond formation has opened up opportunities for the high-yield synthesis of molecules with complex topologies. However, the preparation of purely covalent molecular architectures in aqueous media has remained a challenging task. Here, we present the preparation of a three dimensional catenane through a self-assembly process that relies on the formation of dynamic hydrazone linkages in an acidic aqueous medium. The quantitative synthesis process and the mechanically interlocked structure of the resulting catenane were established by NMR spectroscopy, mass spectrometry, X-ray crystallography and HPLC studies. In addition, the labile hydrazone linkages of the individual [2]catenane components may be 'locked' by increasing the pH of the solution, yielding a relatively kinetically stable molecule. The present study thus details a simple approach to the creation and control of complex molecular architectures under reaction conditions that mimic biological milieux. PMID- 26587717 TI - A steric tethering approach enables palladium-catalysed C-H activation of primary amino alcohols. AB - Aliphatic primary amines are a class of chemical feedstock essential to the synthesis of higher-order nitrogen-containing molecules, commonly found in biologically active compounds and pharmaceutical agents. New methods for the construction of complex amines remain a continuous challenge to synthetic chemists. Here, we outline a general palladium-catalysed strategy for the functionalization of aliphatic C-H bonds within amino alcohols, an important class of small molecule. Central to this strategy is the temporary conversion of catalytically incompatible primary amino alcohols into hindered secondary amines that are capable of undergoing a sterically promoted palladium-catalysed C-H activation. Furthermore, a hydrogen bond between amine and catalyst intensifies interactions around the palladium and orients the aliphatic amine substituents in an ideal geometry for C-H activation. This catalytic method directly transforms simple, easily accessible amines into highly substituted, functionally concentrated and structurally diverse products, and can streamline the synthesis of biologically important amine-containing molecules. PMID- 26587718 TI - A labile hydride strategy for the synthesis of heavily nitridized BaTiO3. AB - Oxynitrides have been explored extensively in the past decade because of their interesting properties, such as visible-light absorption, photocatalytic activity and high dielectric permittivity. Their synthesis typically requires high temperature NH3 treatment (800-1,300 degrees C) of precursors, such as oxides, but the highly reducing conditions and the low mobility of N(3-) species in the lattice place significant constraints on the composition and structure-and hence the properties-of the resulting oxynitrides. Here we show a topochemical route that enables the preparation of an oxynitride at low temperatures (<500 degrees C), using a perovskite oxyhydride as a host. The lability of H(-) in BaTiO3-xHx (x <= 0.6) allows H(-)/N(3-) exchange to occur, and yields a room-temperature ferroelectric BaTiO3-xN2x/3. This anion exchange is accompanied by a metal-to insulator crossover via mixed O-H-N intermediates. These findings suggest that this 'labile hydride' strategy can be used to explore various oxynitrides, and perhaps other mixed anionic compounds. PMID- 26587719 TI - Diastereoselective addition of Grignard reagents to alpha-epoxy N-sulfonyl hydrazones. AB - The alpha-alkylation of ketones and their derivatives by the addition of their corresponding enolates to alkyl halides is a fundamental synthetic transformation, but its utility is limited because the key bond-forming step proceeds in a bimolecular nucleophilic substitution fashion. Here we describe how an umpolung strategy that involves the addition of Grignard reagents to alpha epoxy N-sulfonyl hydrazones-directed by the alkoxide of the 1-azo-3-alkoxy propenes formed in situ via base-induced ring opening of the epoxide-leads to the syn-selective production of alpha-alkyl-beta-hydroxy N-sulfonyl hydrazones with alpha-quaternary centres. This transformation is remarkable in its ability to incorporate an unprecedented range of carbon-based substituents, which include primary, secondary and tertiary alkyl, as well as alkenyl, aryl, allenyl and alkynyl groups. Subsequent hydrolysis of the beta-hydroxy N-sulfonyl hydrazone products produces the corresponding beta-hydroxy ketones. In addition to hydrolysis, the hydrazone products are poised to undergo numerous different known synthetic transformations via well-established chemistry, which would provide access to a wide array of useful structures. PMID- 26587720 TI - Efficient green methanol synthesis from glycerol. AB - The production of biodiesel from the transesterification of plant-derived triglycerides with methanol has been commercialized extensively. Impure glycerol is obtained as a by-product at roughly one-tenth the mass of the biodiesel. Utilization of this crude glycerol is important in improving the viability of the overall process. Here we show that crude glycerol can be reacted with water over very simple basic or redox oxide catalysts to produce methanol in high yields, together with other useful chemicals, in a one-step low-pressure process. Our discovery opens up the possibility of recycling the crude glycerol produced during biodiesel manufacture. Furthermore, we show that molecules containing at least two hydroxyl groups can be converted into methanol, which demonstrates some aspects of the generality of this new chemistry. PMID- 26587721 TI - Erratum: The essential role of charge-shift bonding in hypervalent prototype XeF2. PMID- 26587722 TI - Corrigendum: Organocatalytic removal of formaldehyde adducts from RNA and DNA bases. PMID- 26587723 TI - Correction. PMID- 26587724 TI - Rubidium round-the-clock. PMID- 26587726 TI - Alteration of myocardium glucose metabolism in atrial fibrillation: Cause or effect? PMID- 26587725 TI - Frequency, clinical and angiographic characteristics, and outcomes of high-risk non-ST-segment elevation acute coronary syndromes patients with left circumflex culprit lesions. AB - BACKGROUND: The relationship between culprit vessel, infarct size, and outcomes in non-ST-segment elevation acute coronary syndromes (NSTE ACS) is unclear. In some reports, the left circumflex artery (LCX) was more often the culprit at angiography than the right coronary artery (RCA) or left anterior descending artery (LAD), and infarcts were larger with LCX culprits. METHODS: We determined culprit vessel frequency and initial patency (TIMI flow grade), median fold elevation of peak troponin above the upper limit of normal, and outcomes (30-day death or myocardial infarction [MI] and 1-year mortality) by culprit vessel in high-risk NSTE ACS patients in the EARLY ACS trial. RESULTS: Of 9406 patients, 2066 (22.0%) had angiographic core laboratory data. We evaluated 1774 patients for whom the culprit artery was not the left main, a bypass graft, or branch vessel. The culprit was the LCX in 560 (31.6%), LAD in 653 (36.8%), and RCA in 561 (31.6%) patients. There were fewer women (24.1%) and more prior MI (25.5%) among patients with a culprit LCX compared with those with a culprit LAD or RCA. Patients with LCX (21.2%) and RCA (27.5%) culprits more often had an occluded artery (TIMI 0/1) than did those with LAD (11.3%). Peak troponin elevation was significantly higher for LCX than RCA or LAD culprits. LCX culprit vessels were not associated with worse 30-day or 1-year outcomes in adjusted models. CONCLUSIONS: Among patients with NSTE ACS, the frequencies of LCX, LAD, and RCA culprits were similar. Although LCX lesions were associated with higher peak troponin levels, there was no difference in short- or intermediate-term outcomes by culprit artery. PMID- 26587727 TI - Effects of light-intensity physical activity on red blood cell distribution width: Implications for a novel mechanism through which light-intensity physical activity may influence cardiovascular disease. PMID- 26587728 TI - Disappearing stent but persisting problems? Optical coherence tomography assessment of intra-scaffold restenosis. PMID- 26587729 TI - Decreased heart rate variability correlates to increased cardiovascular risk. PMID- 26587730 TI - The clover technique in endomyocardial biopsy-induced tricuspid regurgitation. PMID- 26587731 TI - Direct left atrial ICE imaging guided ablation for atrial fibrillation without employing contrast medium. AB - BACKGROUND: Preoperative and intraoperative use of a contrast medium is unavoidable in catheter ablation for atrial fibrillation, which can become a particularly significant issue for patients suffering from renal impairment. OBJECTIVE: The purpose of this study is to investigate the feasibility and safety of a technique for atrial fibrillation ablation without a contrast medium via intra-cardiac ultrasound imaging only. METHODS: We prepared the geometry of the pulmonary vein and left atrium via a SOUNDSTAR catheter from inside the left atrium, without preoperative and intraoperative investigations using contrast mediums, for computed tomography or magnetic resonance imaging and pulmonary venography. This was followed by retrospective investigation of the success rate and complications observed in 200 successive paroxysmal and persistent atrial fibrillation cases that underwent catheter ablation from January 2011 to November 2012. The outcomes were assessed after the one-year follow-up. RESULTS: Inserting a SOUNDSTAR catheter into the left atrium was successful in all cases, wherein rendering of all pulmonary veins and the left atrium was possible, and extensive encircling pulmonary vein isolation was successful in all cases. The sinus rhythm maintenance rate one year after the procedure was 90.4% for paroxysmal atrial fibrillation and 76.0% for persistent atrial fibrillation. The major complication rate was 0.5% (cardiac tamponade), with no cases presenting aggravation of renal function. CONCLUSION: Atrial fibrillation ablation using an intra-cardiac ultrasound from the left atrium without employing a contrast medium was safe, with no adverse effects on renal function. PMID- 26587732 TI - Use of calcium channel blockers in prostate cancer: Friends or foe? PMID- 26587733 TI - Sleep disruptions increase arterial stiffness. PMID- 26587734 TI - Effects of Trait Hostility, Mapping Interface, and Character Identification on Aggressive Thoughts and Overall Game Experience After Playing a Violent Video Game. AB - This study investigated the effects of trait-level hostility, interface types, and character identification on aggressive thoughts and overall game experience after playing a violent video game. Results showed that the mapping interface made participants with high trait-level hostility more readily accessible to aggressive contracts, yet it did not have any significant impact for participants with low trait-level hostility. Participants with low trait-level hostility reported more positive game experience in the mapping interface condition, while participants with high trait-level hostility in the same condition reported more negative game experience. Results also indicated that character identification has moderating effects on activating aggressive thoughts and mediating effects on overall game experience. Implications regarding possible ways of reducing potentially negative outcomes from violent games are discussed. PMID- 26587735 TI - The Rab GTPase Rab8 as a shared regulator of ciliogenesis and immune synapse assembly: From a conserved pathway to diverse cellular structures. AB - Rab GTPases, which form the largest branch of the Ras GTPase superfamily, regulate almost every step of vesicle-mediated trafficking. Among them, Rab8 is an essential participant in primary cilium formation. In a report recently published in the Journal of Cell Science, Finetti and colleagues identify Rab8 as a novel player in vesicular traffic in the non-ciliated T lymphocytes, which contributes to the assembly of the specialized signaling platform known as the immune synapse. By interacting with the v-SNARE VAMP-3, Rab8 is indeed responsible for the final docking/fusion step in T cell receptor (TCR) recycling to the immune synapse. A second important take-home message which comes to light from this work is that VAMP-3 also interacts with Rab8 at the base of the cilium in NIH-3T3 cells, where it regulates ciliary growth and targeting of Smoothened at the plasma membrane. Hence the data presented in this report, in addition to identifying Rab8 as a novel player in vesicular traffic to the immune synapse, reveal how both ciliated and non-ciliated cells take advantage of a conserved pathway to build highly specific cellular structures. PMID- 26587736 TI - Examining the role of particle size on ammonia-based bioprocessing of maize stover. AB - The role of particle size in carbohydrate fractionation upon pretreatment and glucan yields upon enzymatic hydrolysis was investigated at two different temperatures, to examine the possibility of pretreating under milder conditions smaller particles, in order to satisfy pilot-scale operational constraints. Maize stover was knife-milled through 1-mm and 0.5-mm screens and pretreated by soaking in aqueous ammonia pretreatment at 60 or 110 degrees C for 6 h. Pretreated solids were analyzed for composition and a material balance calculated for glucan, xylan, and lignin. At 60 degrees C, milling resulted in greater delignification compared to unmilled biomass. Delignification was more uniform at 110 degrees C. Pretreated solids were washed and cellulase hydrolysis carried out at 10% w/w solids loading, with low and high enzyme loadings. Liquid samples were drawn and concentration data developed through HPLC to calculate 48-h glucan and xylan hydrolytic yields. The differences in hydrolytic yield between milled and unmilled treatments were found to vary with pretreatment temperature and enzyme loading. The results show that while particle size impacts carbohydrate recovery and hydrolytic yield, it is less important in bioprocessing than pretreatment temperature and enzyme loading, possibly owing to the particles' morphology rather than the size. PMID- 26587738 TI - In reference to "medical management of patients on clozapine: A guide for internists". PMID- 26587739 TI - Effects of copper on growth, metamorphosis and endocrine disruption of Bufo gargarizans larvae. AB - Chinese toad (Bufo gargarizans) tadpoles were exposed to copper (1, 6.4, 32 and 64MUgL(-1) copper) from the beginning of larval period through completion of metamorphosis. We examined the effects of chronic copper exposure on mortality, growth, time to metamorphosis, tail resorption time, body size at the metamorphic climax (Gs 42) and completion of metamorphosis (Gs 46) and thyroid gland histology. In addition, type 2 and 3 iodothyronine deiodinase (Dio2 and Dio3), thyroid hormone receptors (TRalpha and TRbeta) mRNA levels were also measured to assess disruption of TH synthesis. Our result showed that 6.4-64MUgL(-1) copper concentration increased the mortality and inhibited the growth of B. gargarizans tadpoles. In addition, significant reduction in size at Gs 42 and a time delay to Gs 42 were observed at 6.4-64MUgL(-1) copper treatments. Moreover, histological examinations have clearly revealed that 64MUgL(-1) copper caused follicular cell hyperplasia in thyroid gland. According to real-time PCR results, exposure to 32 and 64MUgL(-1) copper significantly up-regulated mRNA expression of Dio3, but down-regulated mRNA expression of TRalpha and TRbeta mRNA level. We concluded that copper delayed amphibian metamorphosis through changing mRNA expression of Dio3, TRalpha and TRbeta, which suggests that copper might have the endocrine disrupting effect. PMID- 26587737 TI - Dopamine D1 receptor expression is bipolar cell type-specific in the mouse retina. AB - In the retina, dopamine is a key molecule for daytime vision. Dopamine is released by retinal dopaminergic amacrine cells and transmits signaling either by conventional synaptic or by volume transmission. By means of volume transmission, dopamine modulates all layers of retinal neurons; however, it is not well understood how dopamine modulates visual signaling pathways in bipolar cells. Here we analyzed Drd1a-tdTomato BAC transgenic mice and found that the dopamine D1 receptor (D1R) is expressed in retinal bipolar cells in a type-dependent manner. Strong tdTomato fluorescence was detected in the inner nuclear layer and localized to type 1, 3b, and 4 OFF bipolar cells and type 5-2, XBC, 6, and 7 ON bipolar cells. In contrast, type 2, 3a, 5-1, 9, and rod bipolar cells did not express Drd1a-tdTomato. Other interneurons were also found to express tdTomato including horizontal cells and a subset (25%) of AII amacrine cells. Diverse visual processing pathways, such as color or motion-coded pathways, are thought to be initiated in retinal bipolar cells. Our results indicate that dopamine sculpts bipolar cell performance in a type-dependent manner to facilitate daytime vision. J. Comp. Neurol. 524:2059-2079, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26587740 TI - Digital templating for THA: a simple computer-assisted application for complex hip arthritis cases. AB - INTRODUCTION: Total hip arthroplasty (THA) is the standard procedure for end stage arthritis of the hip. Its technical success relies on preoperative planning of the surgical procedure and virtual setup of the operative performance. Digital hip templating is one methodology of preoperative planning for THA which requires a digital preoperative radiograph and a computer with special software. PATIENTS AND METHODS: This is a prospective study involving 23 patients (25 hips) who were candidates for complex THA surgery (unilateral or bilateral). Digital templating is done by radiographic assessment using radiographic magnification correction, leg length discrepancy and correction measurements, acetabular component and femoral component templating as well as neck resection measurement. RESULTS: The overall accuracy for templating the stem implant's exact size is 81%. This percentage increased to 94% when considering sizing within 1 size. CONCLUSION: Digital templating has proven effective, reliable and essential technique for preoperative planning and accurate prediction of THA sizing and alignment. PMID- 26587741 TI - Diagnostic approach in children with unusual symptoms of acquired hypothyroidism. When to look for pituitary hyperplasia? AB - BACKGROUND: Pituitary hyperplasia secondary to primary longstanding hypothyroidism has been reported in the literature in adults and rarely in children. METHODS: Here we present the clinical presentation and diagnostic procedures in eight children with pituitary hyperplasia due to autoimmune thyroiditis, highlighting common findings, such as growth delay, fatigue or gaining weight, but also exceptional findings such as pericardial effusion, rhabdomyolysis, isolated hypertrichosis, and Van Wyk-Grumbach syndrome, which have rarely or never been described. RESULTS AND CONCLUSIONS: Surprisingly no thyroid enlargement was detected. We discuss the unusual presenting signs of autoimmune thyroiditis that should raise the suspicion of pituitary hyperplasia. We suggest that a more elaborate clinical assessment and even modification of the diagnostic approach to autoimmune thyroiditis is needed in order to avoid its serious complications. PMID- 26587742 TI - Pre-analytical phase in cryoglobulin (CRG) detection: an alternative method for sample transport. PMID- 26587743 TI - Performance of two commercially available BCR-ABL1 quantification assays that use an international reporting scale. AB - BACKGROUND: Quantifying the BCR-ABL1 rearrangement is important for monitoring chronic myelogenous leukemia (CML). To standardize BCR-ABL1 quantification, the World Health Organization (WHO) established the first international genetic reference panel. Here, we compared the BCR-ABL1 levels determined using international scale (IS)-based commercially available assays. METHODS: BCR-ABL1 transcripts were quantified using two IS-based assays. 10-1, 10-2, 10-3, 10-4, 10 5 and 10-6 dilutions of the b3a2 positive RNA were used for evaluating linearity, precision, and limit of detection. Correlation of the assay was evaluated by using DNA obtained from CML patients carrying the BCR-ABL1 b3a2 and b2a2 types. RESULTS: Both Ipsogen and Asuragen assays showed fine linearity with reasonable %CV. LOD of each assay was calculated as 0.003% for Ipsogen, and 0.005% for Asuragen. By comparing the results that were lower than 10% by either one of the assay, Ipsogen and Asuragen results showed an overall good linear correlation with a tendency for the Ipsogen assay to show slightly higher levels than the Asuragen assay for b3a2 transcript. For b2a2, the tendency was opposite, with Asuragen showing higher values than the Ipsogen. CONCLUSIONS: Two commercially available IS-based BCR-ABL1 assays showed an overall good quantitative correlation. It should be taken into consideration that each assay tended to produce higher values than the other, depending on the BCR-ABL1 subtypes, suggesting that a separate conversion factor for each subtype can be more helpful when BCR-ABL1 transcript levels are converted into IS. PMID- 26587744 TI - Investigation of sensitivity for coagulation factor deficiency in APTT and PT: how to perform it? PMID- 26587745 TI - Therapeutic drug monitoring of infliximab: performance evaluation of three commercial ELISA kits. AB - BACKGROUND: Therapeutic drug monitoring (TDM) of infliximab (IFX, Remicade(r)) can aid to optimize therapy efficacy. Many assays are available for this purpose. However, a reference standard is lacking. Therefore, we evaluated the analytical performance, agreement and clinically relevant differences of three commercially available IFX ELISA kits on an automated processing system. METHODS: The kits of Theradiag (Lisa Tracker Infliximab), Progenika (Promonitor IFX) and apDia (Infliximab ELISA) were implemented on an automated processing system. Imprecision was determined by triplicate measurements of patient samples on five days. Agreement was evaluated by analysis of 30 patient samples and four spiked samples by the selected ELISA kits and the in-house IFX ELISA of Sanquin Diagnostics (Amsterdam, The Netherlands). Therapeutic consequences were evaluated by dividing patients into four treatment groups using cut-off levels of 1, 3 and 7 MUg/mL and determining assay concordance. RESULTS: Within-run and between-run imprecision were acceptable (<=12% and <=17%, respectively) within the quantification range of the selected ELISA kits. The apDia assay had the best precision and agreement to target values. Statistically significant differences were found between all assays except between Sanquin Diagnostics and the Lisa Tracker assay. The Promonitor assay measured the lowest IFX concentrations, the apDia assay the highest. When patients were classified in four treatment categories, 70% concordance was achieved. CONCLUSIONS: Although all assays are suitable for TDM, significant differences were observed in both imprecision and agreement. Therapeutic consequences were acceptable when patients were divided in treatment categories, but this could be improved by assay standardization. PMID- 26587746 TI - Roles of leptin, adiponectin and resistin in the transcriptional regulation of steroidogenic genes contributing to decreased Leydig cells function in obesity. AB - The increase in obesity rate is a major public health issue associated with increased pathological conditions such as type 2 diabetes or cardiovascular diseases. Obesity also contributes to decreased testosterone levels in men. Indeed, the adipose tissue is an endocrine organ which produces hormones such as leptin, adiponectin and resistin. Obesity results in pathological accumulations of leptin and resistin, whereas adiponectin plasma levels are markedly reduced, all having a negative impact on testosterone synthesis. This review focuses on current knowledge related to transcriptional regulation of Leydig cells' steroidogenesis by leptin, adiponectin and resistin. We show that there are crosstalks between the regulatory mechanisms of these hormones and androgen production which may result in a dramatic negative influence on testosterone plasma levels. Indeed leptin, adiponectin and resistin can impact expression of different steroidogenic genes such as Star, Cyp11a1 or Sf1. Further investigations will be required to better define the implications of adipose derived hormones on regulation of steroidogenic genes expression within Leydig cells under physiological as well as pathological conditions. PMID- 26587748 TI - Direct Catalytic Asymmetric Synthesis of beta-Hydroxy Acids from Malonic Acid. AB - A nickel(II) catalyzed asymmetric synthesis of beta-hydroxy acids from malonic acid and ketones was developed, revealing for the first time the synthetic utility of malonic acid in the construction of chiral carboxyl acids; importantly, the synthetic potential of this strategy was further demonstrated by the rapid construction of cephalanthrin A, phaitanthrin B, cruciferane, and rice metabolites. PMID- 26587747 TI - DNA-Mediated Cellular Delivery of Functional Enzymes. AB - We report a strategy for creating a new class of protein transfection materials composed of a functional protein core chemically modified with a dense shell of oligonucleotides. These materials retain the native structure and catalytic ability of the hydrolytic enzyme beta-galactosidase, which serves as the protein core, despite the functionalization of its surface with ~25 DNA strands. The covalent attachment of a shell of oligonucleotides to the surface of beta galactosidase enhances its cellular uptake of by up to ~280-fold and allows for the use of working concentrations as low as 100 pM enzyme. DNA-functionalized beta-galactosidase retains its ability to catalyze the hydrolysis of beta glycosidic linkages once endocytosed, whereas equal concentrations of protein show little to no intracellular catalytic activity. PMID- 26587749 TI - Alkali- and Sulfur-Resistant Tungsten-Based Catalysts for NOx Emissions Control. AB - The development of catalysts with simultaneous resistance to alkalis and sulfur poisoning is of great importance for efficiently controlling NOx emissions using the selective catalytic reduction of NOx with NH3 (SCR), because the conventional V2O5/WO3-TiO2 catalysts often suffer severe deactivation by alkalis. Here, we support V2O5 on a hexagonal WO3 (HWO) to develop a V2O5/HWO catalyst, which has exceptional resistance to alkali and sulfur poisoning in the SCR reactions. A 350 MUmol g(-1) K(+) loading and the presence of 1,300 mg m(-3) SO2 do not almost influence the SCR activity of the V2O5/HWO catalyst, and under the same conditions, the conventional V2O5/WO3-TiO2 catalysts completely lost the SCR activity within 4 h. The strong resistance to alkali and sulfur poisoning of the V2O5/HWO catalysts mainly originates from the hexagonal structure of the HWO. The HWO allows the V2O5 to be highly dispersed on the external surfaces for catalyzing the SCR reactions and has the relatively smooth surfaces and the size suitable tunnels specifically for alkalis' diffusion and trapping. This work provides a useful strategy to develop SCR catalysts with exceptional resistance to alkali and sulfur poisoning for controlling NOx emissions from the stationary source and the mobile source. PMID- 26587750 TI - Daily rhythms in activity and mRNA abundance of enzymes involved in glucose and lipid metabolism in liver of rainbow trout, Oncorhynchus mykiss. Influence of light and food availability. AB - The present research aimed to investigate in a model of teleost fish (rainbow trout) the existence of daily changes in activity and mRNA abundance of several proteins involved in major pathways of carbohydrate and lipid metabolism in liver, and to test whether or not both the light-dark cycle and food availability might influence such rhythms. For this purpose, four cohorts of animals previously adapted to normal housing conditions (12L:12D; Lights on at ZT0; feeding time at ZT2) were subjected to: normal conditions (LD); 48-h constant darkness (DD); 96-h food deprivation (LD + Fasting); or constant darkness and food deprivation (DD + Fasting) respectively. After such time periods, fish were sacrificed and sampled every 4-h on the following 24-h period (ZT/CT0, 4, 8, 12, 16, 20 and 0'). Our results reveal that cortisol and all the analysed genes (gk, pepck, g6pase, pk, glut2, hoad and fas) exhibited well defined daily rhythms, which persisted even in the absence of light and/or food indicating the endogenous nature of such rhythms. Even when the variations of enzyme activities were not significant, their rhythms mostly paralleled those of the respective gene expression. The rhythms of mRNA abundance were apparently dependent on the presence of food, but the light/dark cycle also influenced such rhythms. Since cortisol does not appear to be mainly involved in generating such daily rhythms in liver, alternative mechanisms might be involved, such as a direct interaction between metabolism and the circadian system. PMID- 26587751 TI - Challenges for CTC-based liquid biopsies: low CTC frequency and diagnostic leukapheresis as a potential solution. AB - Circulating tumor cells (CTCs) are very attractive surrogate markers for systemic cancer. Currently, major efforts are being made to use these rare cells in the sense of a liquid biopsy to gain molecular information for rational therapeutic decision-making. The advancements in molecular analyses of CTCs down to the single-cell level have been significant in recent years and some applications are ready to be used in clinical studies. As discussed in this review, a major challenge for translating such molecular CTC-based assays into the clinic is the extremely low frequency of CTCs and the associated problems of their reliable detection and isolation. A potential solution to overcome the low CTC frequency is the recently introduced diagnostic leukapheresis that permits screening of liters of blood. Discussed here are the challenges as well as the current efforts implementing this method into clinical workflows to realize more reliable liquid biopsies. PMID- 26587752 TI - SUMO-mediated global and local control of recombination. PMID- 26587753 TI - Identification of roles for the SNARE-associated protein, SNAP29, in mouse platelets. AB - Platelets are critical for maintaining vascular hemostasis, but also play a major role in the formation of occlusive cardiovascular and cerebrovascular thrombi under disease conditions. Secretion of platelet alpha and dense granules is a requirement for efficient thrombus formation. Understanding and targeting the mechanisms of secretion is important to aid the development of effective antithrombotics. SNAP29 is a tSNARE found in platelets, but whose role has not been defined. Using a platelet-specific SNAP29 knockout mouse model, we assessed the role of SNAP29 in platelet secretion and function under standardized conditions and also in in vitro and in vivo thrombosis. The data showed no major defects in SNAP29-null platelets, but revealed a minor defect in alpha-granule secretion and a significant increase in embolization rate of thrombi in vivo. These data suggest that SNAP29 contributes to the regulation of platelet alpha granule secretion and thrombus stability, possibly partially masked by functional redundancy with other tSNAREs, such as SNAP23. PMID- 26587754 TI - A combination of pharmacophore modeling, atom-based 3D-QSAR, molecular docking and molecular dynamics simulation studies on PDE4 enzyme inhibitors. AB - Phosphodiesterases 4 enzyme is an attractive target for the design of anti inflammatory and bronchodilator agents. In the present study, pharmacophore and atom-based 3D-QSAR studies were carried out for pyrazolopyridine and quinoline derivatives using Schrodinger suite 2014-3. A four-point pharmacophore model was developed using 74 molecules having pIC50 ranging from 10.1 to 4.5. The best four feature model consists of one hydrogen bond acceptor, two aromatic rings, and one hydrophobic group. The pharmacophore hypothesis yielded a statistically significant 3D-QSAR model, with a high correlation coefficient (R(2 )= .9949), cross validation coefficient (Q(2 )= .7291), and Pearson-r (.9107) at six component partial least square factor. The external validation indicated that our QSAR model possessed high predictive power with R(2) value of .88. The generated model was further validated by enrichment studies using the decoy test. Molecular docking, free energy calculation, and molecular dynamics (MD) simulation studies have been performed to explore the putative binding modes of these ligands. A 10 ns MD simulation confirmed the docking results of both stability of the 1XMU ligand complex and the presumed active conformation. Outcomes of the present study provide insight in designing novel molecules with better PDE4 inhibitory activity. PMID- 26587756 TI - NMR-Based Metabolic Snapshot from Minibronchoalveolar Lavage Fluid: An Approach To Unfold Human Respiratory Metabolomics. AB - The utility of mini bronchoalveolar lavage (mBAL) and its applicability in metabolomics has not been explored in the field of human respiratory disease. mBAL, "an archetype" of the local lung environment, ensures a potent technique to get the snapshot of the epithelial lining fluid afflicted to human lung disorders. Characterization of the mBAL fluid has potential to help in elucidating the composition of the alveoli and airways in the diseased state, yielding diagnostic information on clinical applicability. In this study, one of the first attempts has been made to comprehensively assign and detect metabolites in mBAL fluid, extracted from human lungs, by the composite use of 800 MHz 1D and 2D NMR, J-resolved homonuclear spectroscopy, COSY, TOCSY, and heteronuclear HSQC correlation methods. A foremost all-inclusive sketch of the 50 metabolites has been corroborated and assigned, which can be a resourceful archive to further lung-directed metabolomics, prognosis, and diagnosis. Thus, NMR-based mBALF studies, as proposed in this article, will leverage many more prospective respiratory researches for routine clinical application and prove to be a viable approach to mirror the key predisposing factors contributing to the onset of lung disease. PMID- 26587755 TI - Safety and efficacy of upfront graded administration of trimethoprim sulfamethoxazole in systemic lupus erythematosus: A retrospective cohort study. AB - OBJECTIVES: Trimethoprim-sulfamethoxazole (TMP/SMX) is effective as prophylaxis against many infections in immunocompromised patients. However, it is not commonly prescribed for patients with systemic lupus erythematous (SLE) due to the risk of adverse reactions (ADRs). An upfront graded administration protocol for TMP/SMX was adopted, and its safety and efficacy were assessed. METHODS: Data from 59 patients with SLE patients who received prophylactic TMP/SMX were retrospectively analyzed. The incidence and risk factors for ADRs in patients who received TMP/SMX before and after the introduction of graded administration were assessed. RESULTS: The incidence of ADRs was 41.9% in the non-graded administration group, vs. 10.7% in the graded administration group (p = 0.009). The rate of high fever, liver function test (LFT) abnormality, shortness of breath, and hospitalization were reduced in upfront graded administration group. In addition, a higher rate of anti-Ro/SS-A positivity was found in patients experienced ADRs (46.2% in reactors vs. 5.6% in non-reactors; p = 0.012) in the non-graded administration group. CONCLUSIONS: Upfront graded administration of TMP/SMX reduces the incidence and severity of ADRs in SLE patients. The high incidence of TMP/SMX ADRs in SLE patients was also confirmed, especially when anti-Ro/SS-A antibody is present. PMID- 26587757 TI - Observing Vibrational Wavepackets during an Ultrafast Electron Transfer Reaction. AB - Recent work has proposed that coherent effects impact ultrafast electron transfer reactions. Here we report studies using broadband pump-probe and two-dimensional electronic spectroscopy of intramolecular nuclear motion on the time scale of the electron transfer between oxazine 1 (Ox1) and dimethylaniline (DMA). We performed time-frequency analysis on the time domain data to assign signal amplitude modulations to ground or excited electronic states in the reactive system (Ox1 in DMA) relative to the control system (Ox1 in chloronaphthalene). It was found that our ability to detect vibrational coherence via the excited electronic state of Ox1 diminishes on the time scale that population is lost by electron transfer. However, the vibrational wavepacket is not damped by the electron transfer process and has been observed previously by detecting the Ox1 radical transient absorption. The analysis presented here indicates that the "addition" of an electron to the photoexcited electron acceptor does not significantly perturb the vibrational coherence, suggesting its presence as a spectator, consistent with the Born-Oppenheimer separation of electronic and nuclear degrees of freedom. PMID- 26587758 TI - Automatized Parameterization of DFTB Using Particle Swarm Optimization. AB - We present a novel density-functional tight-binding (DFTB) parametrization toolkit developed to optimize the parameters of various DFTB models in a fully automatized fashion. The main features of the algorithm, based on the particle swarm optimization technique, are discussed, and a number of initial pilot applications of the developed methodology to molecular and solid systems are presented. PMID- 26587759 TI - Synthesis and Conformational Analysis of 3-Methyl-3-silatetrahydropyran by GED, FTIR, NMR, and Theoretical Calculations: Comparative Analysis of 1-Hetero-3 methyl-3-silacyclohexanes. AB - 3-Methyl-3-silatetrahydropyran 1 was synthesized and its molecular structure and conformational behavior was studied by gas-phase electron diffraction (GED), FTIR, low temperature (1)H and (13)C NMR spectroscopy, and by theoretical calculations (DFT, MP2). Two conformers, 1-ax and 1-eq, were located on the potential energy surface. In the gas phase, a slight predominance of the axial conformer was determined, with the ratio 1-ax:1-eq = 54(9):46(9) (from GED) or 53:47 or 61:39 (from IR). In solution, LT NMR spectroscopy at 103 K gives the ratio 1-ax:1-eq = 35:65 (-DeltaG degrees 103 = 0.13 kcal/mol). Simulation of solvent effects using the PCM continuum model or by calculation of the corresponding solvent-solute complexes allowed us to rationalize the experimentally observed opposite conformational predominance of the conformers of 3-methyl-3-silatetrahydropyran in the gas phase and in solution. Comparative analysis of the effect of heteroatom in 1-hetero-3-methyl-3-silacyclohexanes on the structure, stereoelectronic interactions, and relative energies of the conformers is done. PMID- 26587760 TI - Highly Sensitive, Uniform, and Reusable Surface-Enhanced Raman Scattering Substrate with TiO2 Interlayer between Ag Nanoparticles and Reduced Graphene Oxide. AB - TiO2 nanoparticles and Ag nanoparticles were successively deposited on reduced graphene oxide (rGO) by a two-step solvothermal process to develop a reusable surface-enhanced Raman scattering (SERS) substrate with high sensitivity and uniformity owing to the 2-dimensional planar structure of rGO, the photocatalytic activity of TiO2, and the SERS function of Ag nanoparticles. The presence of TiO2 interlayer efficiently diminished the interference from the Raman intensities of D-band and G-band of rGO and hence enhanced the sensitivity significantly. As compared to Ag/rGO nanocomposite, the detection limit of 4-aminothiophenol (4 ATP) for Ag/TiO2/rGO nanocomposite could be lowered from 10(-10) to 10(-14) M, and its enhancement factor could be raised from 1.27 * 10(10) to 3.46 * 10(12). Meanwhile, good uniformity remained, the relative standard deviation (RSD) value was about 10%. Furthermore, by UV irradiation in water, the photocatalytic property of TiO2 could eliminate the Raman signal of 4-ATP efficiently and made this substrate reusable. After being reused five times, its excellent SERS performance was still retained. Thus, the Ag/TiO2/rGO nanocomposite developed in this work was a promising SERS substrate with good reusability and high sensitivity and uniformity. PMID- 26587761 TI - Xp11.22 Microduplications Including HUWE1: Case Report and Literature Review. AB - Xp11.22 microduplications have been reported in different patients with X-linked intellectual disability. Comparing the duplicated segments, a minimum region of overlap has been identified. Within this region, only one gene, the HUWE1 gene, coding the E3 ubiquitin protein ligase, turned out to be duplicated in all previously described patients. We provide a review of the literature on this topic, making a comparison not only of genetic aspects, but also of clinical, neurophysiological, and neuroradiological findings. Furthermore, we describe the phenotypic and molecular characterization of a case of intellectual disability in a child carrying one of the smallest Xp11.22 microduplications reported, involving the whole sequence of HUWE1 gene. Unlike previously described cases, our patient's neuroimaging showed abnormal findings; he also experienced one seizure and showed interictal electroencephalogram (EEG) epileptiform abnormalities. Given the fact that HUWE1 duplications and mutations have previously been described in several patients with X-linked cognitive impairment, our findings support the hypothesis that HUWE1 gene might be implicate in the pathogenesis of intellectual disability. Nevertheless, further investigations and a more detailed examination of patients' clinical history are needed to clear up other eventual genotype-phenotype correlations, such as the presence of epilepsy/epileptiform EEG abnormalities. PMID- 26587762 TI - Neonatal Seizures: A Review of Outcomes and Outcome Predictors. AB - The majority of neonatal seizures are of acute symptomatic origin, and their occurrence is associated with higher mortality and morbidity compared with the general population, even if there is conflicting evidence of a detrimental effect per se. Etiology is considered the main determinant of outcome, but other factors, including gestational age, brain damage severity, neonatal neurological examination, and electroencephalographically (EEG) interictal and ictal characteristics are also related to neurodevelopmental outcome or death. Therefore, accuracy in early prognostication since the neonatal period can be improved by conveniently integrating different clinical and instrumental findings.The aim of this review is first to review the outcome of newborns with seizures (mortality, epilepsy, cerebral palsy, and intellectual disability), second to review the risk factors for adverse outcome after seizures in the newborn period, considering clinical, EEG/amplitude-integrated EEG, and neuroimaging findings associated with adverse outcome and lack of response to treatment, and finally to review published scoring systems for predicting neurologic outcome after neonatal seizures. PMID- 26587763 TI - Hydrogen-Substituted Superconductors SmFeAsO(1-x)Hx Misidentified As Oxygen Deficient SmFeAsO(1-x). AB - We investigated the preferred electron dopants at the oxygen sites of 1111-type SmFeAsO by changing the atmospheres around the precursor with the composition of Sm:Fe:As:O = 1:1:1:1 - x in high-pressure synthesis. Under H2O and H2 atmospheres, hydrogens derived from H2O or H2 molecules were introduced into the oxygen sites as a hydride ion, and SmFeAsO(1-x)Hx was obtained. However, when the H2O and H2 sources were removed from the synthetic process, nearly stoichiometric SmFeAsO was obtained and the maximum amount of oxygen vacancies introduced remained x = 0.05(4). Density functional theory calculations indicated that substitution of hydrogen in the form of H(-) is more stable than the formation of an oxygen vacancy at the oxygen site of SmFeAsO. These results strongly imply that oxygen-deficient SmFeAsO(1-x) reported previously is SmFeAsO(1-x)Hx with hydride ion incorporated unintentionally during high-pressure synthesis. PMID- 26587766 TI - Automated analysis of single cells using Laser Tweezers Raman Spectroscopy. AB - In recent years, significant progress has been made into the label-free detection and discrimination of individual cancer cells using Laser Tweezers Raman Spectroscopy (LTRS). However, the majority of examples reported have involved manual trapping of cells, which is time consuming and may lead to different cell lines being analysed in discrete batches. A simple, low-cost microfluidic flow chamber is introduced which allows single cells to be optically trapped and analysed in an automated fashion, greatly reducing the level of operator input required. Two implementations of the flow chamber are discussed here; a basic single-channel device in which the fluid velocity is controlled manually, and a dual-channel device which permits the automated capture and analysis of multiple cell lines with no operator input. Results are presented for the discrimination of live epithelial prostate cells and lymphocytes, together with a consideration of the consequences of traditional 'batch analysis' typically used for LTRS of live cells. PMID- 26587764 TI - Recommendations for pediatric tuberculosis vaccination in Italy. AB - Bacillus Calmette-Guerin (BCG) vaccine is still the only vaccine approved for the prevention of tuberculosis (TB), and is widely used in highly endemic countries, where all newborns receive a single intradermal dose immediately after birth; however, the recommendations concerning its use in Europe vary widely from country to country. This document describes the recommendations of a group of Italian scientific societies concerning its pediatric use in Italy, the persistence of the protection it provides, its safety, its interference with tuberculin skin test (TST) responses, and the children who should be vaccinated. The experts conclude that BCG vaccination provides a good level of protection against tuberculous meningitis and disseminated forms, and a fair level of protection against pulmonary disease; the protective effective lasts at least 10 years, and revaccination offers no advantages over a single administration. The vaccine is safe in immunocompetent subjects, and affects the response to a TST for at least 6 y On the basis of these observations, we recommend its use in Italy in all TST-negative immunocompetent newborns and breastfeeding infants aged <6 months, and all TST-negative children aged between 6 months and 5 y who come from highly epidemic areas, or whose parents come from highly endemic areas, or who have been in contact with a family member with active TB without contracting the disease themselves. PMID- 26587767 TI - Increased plant growth and copper uptake of host and non-host plants by metal resistant and plant growth-promoting endophytic bacteria. AB - The effects of inoculation with two metal-resistant and plant growth-promoting endophytic bacteria (Burkholderia sp. GL12 and Bacillus megaterium JL35) were evaluated on the plant growth and Cu uptake in their host Elsholtzia splendens and non-host Brassica napus plants grown in natural Cu-contaminated soil. The two strains showed a high level of ACC deaminase activities. In pot experiments, inoculation with strain GL12 significantly increased root and above-ground tissue dry weights of both plants, consequently increasing the total Cu uptake of E. splendens and Brassica napus by 132% and 48.2% respectively. Inoculation with strain JL35 was found to significantly increase not only the biomass of B. napus, consequently increasing the total Cu uptake of B. napus by 31.3%, but Cu concentration of E. splendens for above-ground tissues by 318% and roots by 69.7%, consequently increasing the total Cu uptake of E. splendens by 223%. The two strains could colonize the rhizosphere soils and root interiors of both plants. Notably, strain JL35 could colonize the shoot tissues and significantly increase the translocation factors and bioaccumulation factors of E. splendens. These results suggested that Burkholderia sp. GL12 and B. megaterium JL35 were valuable bacterial resource which had the potential in improving the efficiency of Cu phytoextraction by E. splendens and B. napus in a natural Cu-contaminated soil. PMID- 26587768 TI - Omecamtiv mecarbil: a new cardiac myosin activator for the treatment of heart failure. AB - INTRODUCTION: Current available inotropic agents increase cardiac contractility, but are associated with myocardial ischemia, arrhythmias, and mortality. A novel selective cardiac myosin activator, omecamtiv mecarbil (CK-1827452/ AMG-423) is a small molecule that activates the sarcomere proteins directly, resulting in prolonged systolic ejection time and increased cardiac contractility. AREAS COVERED: This paper discusses the chemistry, pharmacokinetics, clinical efficacy and safety of omecamtiv mecarbil. Omecamtiv mecarbil represents a novel therapeutic approach to directly improve cardiac function and is therefore proposed as a potential new treatment of patients with systolic heart failure. The authors review results of previous studies investigating the effect of omecamtiv mecarbil in heart failure animal models, healthy volunteers, and patients with acute and chronic systolic heart failure. EXPERT OPINION: Results of phase I and phase II studies demonstrate that omecamtiv mecarbil is safe and well tolerated both as an intravenous and oral formulation. In healthy volunteers and chronic systolic heart failure patients, administration of omecamtiv mecarbil resulted in a concentration-dependent increase of left ventricular ejection time, ejection fraction, fractional shortening, and stroke volume. The first results of a double-blind, randomized, placebo-controlled phase IIb dose-finding study with the oral formulation of omecamtiv mecarbil demonstrated beneficial effects on cardiac function and N-terminal pro-brain natriuretic peptide levels. This study will provide essential dosing information for the requisite phase III trials which will investigate whether the beneficial effects of omecamtiv mecarbil translate into improved clinical outcomes. PMID- 26587769 TI - Two brothers homozygous for the TTR V30M both presenting with a phenotype dominated by central nervous complications. PMID- 26587770 TI - Diversity and Karyotypic Evolution in the Genus Neacomys (Rodentia, Sigmodontinae). AB - Neacomys (Sigmodontinae) comprises 8 species mainly found in the Amazonian region. We describe 5 new karyotypes from Brazilian Amazonia: 2 cytotypes for N. paracou (2n = 56/FNa = 62-66), 1 for N. dubosti (2n = 64/FNa = 68), and 2 for Neacomys sp. (2n = 58/FNa = 64-70), with differences in the 18S rDNA. Telomeric probes did not show ITS. We provide a phylogeny using Cytb, and the analysis suggests that 2n = 56 with a high FNa is ancestral for the genus, as found in N. paracou, being retained by the ancestral forms of the other species, with an increase in 2n occurring independently in N. spinosus and N. dubosti. Alternatively, an increase in 2n may have occurred in the ancestral taxon of the other species, followed by independent 2n-reduction events in Neacomys sp. and in the ancestral species of N. tenuipes, N. guianae, N. musseri, and N. minutus. Finally, a drastic reduction event in the diploid number occurred in the ancestral species of N. musseri and N. minutus which exhibit the lowest 2n of the genus. The karyotypic variations found in both intra- and interspecific samples, associated with the molecular phylogeny, suggest a chromosomal evolution with amplification/deletion of constitutive heterochromatin and rearrangements including fusions, fissions, and pericentric inversions. PMID- 26587771 TI - Prognosis and Outcome of Intracerebral Haemorrhage. AB - Spontaneous intracerebral haemorrhage (ICH) accounts for approximately 15% of all strokes and is a leading cause of disability, with a one-month mortality rate of 40%. Whereas factors predicting short-term mortality are well known, data regarding long-term outcome are scarce and imprecise. The two main underlying vasculopathies responsible for ICH, i.e. deep perforating vasculopathy and cerebral amyloid angiopathy, might have an impact on the overall prognosis of ICH survivors. ICH survivors are at high risk of epileptic seizures, depression and cognitive impairment, which may influence their functional outcome. Lobar location of an ICH, frequently due to cerebral amyloid angiopathy, partly determines the long-term risk of recurrent haemorrhage. Because of common vascular risk factors, patients with ICH are also at considerable risk of serious ischaemic events. Risks of future ischaemic events may be as high as that of recurrent ICH, raising the relevance of antithrombotic treatment in ICH survivors. Future studies of long-term follow-up after ICH are needed to determine predictors of outcome, including biomarkers of the underlying vasculopathies, to tailor preventive strategies to survivors. PMID- 26587772 TI - Reperfusion-Related Intracerebral Hemorrhage. AB - The efficacy of intravenous thrombolysis (IVT) for acute ischemic stroke patients has been well established worldwide, with endovascular therapy performed in patients who have failed or are ineligible for IVT and who have major vessel occlusion. The most feared complication of acute stroke reperfusion therapy is intracerebral hemorrhage (ICH), as these patients have a poor clinical outcome and high mortality. The fundamental mechanisms responsible for reperfusion related ICH include increased permeability and disruption of the blood-brain barrier. Recombinant tissue plasminogen activator may exacerbate the blood-brain barrier disruption through its pharmacological action during IVT. Furthermore, interactions between the device and the vessel walls and contrast intoxication may also be related to ICH, which includes the occurrence of subarachnoid hemorrhage after endovascular therapy. Numerous factors have been reported to be associated with or to be able to predict ICH, and several scoring systems have been developed for predicting symptomatic ICH (sICH) after IVT. However, a scoring system with enough power to detect an unacceptably high risk of sICH or to provide information on when to withdraw IVT has yet to be definitively established. In current clinical practice, acute stroke patients without contraindications for IVT who have been identified by conventional computed tomography scans normally undergo IVT, irrespective of any clinical predictors of ICH after IVT. Strategies that have been suggested for preventing reperfusion related ICH in high-risk patients include intensive blood pressure control, tight glycemic control, and the avoidance of early aggressive antithrombotic therapy. If sICH, and especially massive parenchymal hematoma, does occur, hematoma expansion needs to be prevented through the use of tight blood pressure control and other methods. Although evidence of efficacy has yet to be established, surgical removal is performed not only for the purpose of saving lives but also for improving the functional outcome. In order to develop therapeutic strategies for reperfusion-related ICH that will lead to an improved stroke prognosis, further studies are warranted. PMID- 26587773 TI - Cytologic Features and Immunocytochemical Profiles of Malignant Effusions with Metastatic Papillary Thyroid Carcinoma: A Case Series from a Single Institution. AB - OBJECTIVE: Malignant effusions due to papillary thyroid carcinoma (PTC) are rare, but portend a poor prognosis. PTC metastases, although rare, most frequently occur in the lungs and bone. Therefore, differentiating thyroid etiology of malignant effusions from other sites becomes clinically significant in patient management. This study examines morphologic and immunocytochemical findings in 5 cases of malignant effusions with PTC involvement. STUDY DESIGN: The electronic database at the University of Michigan was searched from January 1, 1995 to December 31, 2014 for malignant pleural effusions with PTC involvement. Clinicopathologic data were obtained from electronic medical records. Cytologic slides were reviewed. RESULTS: Five cases of malignant effusions due to PTC were identified. Characteristic cytologic features of PTC, including ovoid nuclei, irregular nuclear contours, and psammomatous calcifications, were seen. However, the predominant cytologic feature observed was moderate amounts of delicate to vacuolated cytoplasm within the tumor cells. A review of immunocytochemistry demonstrated that all 5 cases showed patchy to diffuse TTF-1 positivity and diffuse positivity for Pax-8. Thyroglobulin only showed focal to patchy positivity in 3 of 5 cases. CONCLUSION: Given the morphologic features found in our case series, an immunocytochemical workup for the evaluation of involvement of an effusion by a thyroid primary is crucial for accurate diagnosis and appropriate clinical treatment. PMID- 26587774 TI - VIP: A New Promising Marker for AECOPD--A Fashionable Marker Soon Forgotten? PMID- 26587775 TI - Bilateral Through-and-Through Trajectory of a Low-Velocity Transcranial Penetrating Foreign Object in a Twelve-Month-Old. AB - A 12-month-old girl sustained a penetrating intracranial trauma of a thin aluminum rod traversing from the left frontal bone and exiting the right occipital bone. The rod entered the left anterior frontal lobe, traveled through the ventricular system, narrowly missed the right posterior cerebral artery by less than 1 mm and exited through the right cerebellum. The rod was surgically extracted, and the child remained neurologically intact. Pre- and postoperative vascular imaging, antibiotics, seizure prophylaxis and surgical planning are paramount to successful care of these delicate cases. PMID- 26587776 TI - Sodium polystyrene sulfonate for the treatment of acute hyperkalemia: a retrospective study. AB - BACKGROUND: Hyperkalemia is a common problem in hospitalized patients, especially those with underlying chronic kidney disease, but evidence-based guidelines for its treatment are lacking. Sodium polystyrene sulfonate (SPS), a cation exchange resin first approved by the FDA for the treatment of hyperkalemia in 1958, is frequently used alone or in conjunction with other medical therapies to lower serum potassium. Recently, the safety and efficacy of SPS have come into question based on multiple reported cases of bowel necrosis associated with SPS administration. OBJECTIVE: The primary objective of this study was to evaluate the use of SPS for the treatment of hyperkalemia, at a large tertiary community teaching hospital, to determine its effectiveness and the incidence of related adverse side effects. METHODS: A retrospective chart review was performed on all adult inpatients receiving single-dose SPS at a 466-bed tertiary community teaching hospital over a 3-year period. RESULTS: 501 patients received SPS for the treatment of hyperkalemia during their index hospital stay. Serum potassium levels decreased by 0.93 mEq/L on average at first recheck after SPS administration, with or without additional medical treatments. Our study identified 10 cases of hypernatremia (greater than 145 mEq/L), 31 cases of hypokalemia (less than 3.5 mEq/L), and 2 cases of bowel necrosis related to the administration of SPS. CONCLUSION: Our results suggest a serum potassium reduction of less than 1 mEq/L after administration of SPS for the treatment of acute hyperkalemia. Additionally, this study offers some evidence that the use of SPS may be associated with harm. We further note the need for standardized guidelines for the treatment of hyperkalemia at our institution. PMID- 26587777 TI - Acute bile nephropathy secondary to anabolic steroids. AB - Renal dysfunction in cholestatic liver disease is multifactorial. Acute kidney injury may develop secondary to renal vasoconstriction in the setting of peripheral vasodilation and relative hypovolemia, tubular obstruction by bile casts, and direct tubular toxicity from bile. Anabolic steroids are frequently used by athletes to boost endurance and increase muscle mass. These agents are a recently recognized cause of hepatotoxicity and jaundice and may lead to acute kidney injury. To increase awareness about this growing problem and to characterize the pathology of acute kidney injury in this setting, we report on a young male who developed acute kidney injury in the setting of severe cholestatic jaundice related to ingestion of anabolic steroids used for bodybuilding. Kidney biopsy showed bile casts within distal tubular lumina, filamentous bile inclusions within tubular cells, and signs of acute tubular injury. This report supports the recently re-emerged concept of bile nephropathy cholemic nephrosis. PMID- 26587778 TI - Diagnosis of low bone mass in CKD-5D patients. AB - BACKGROUND AND OBJECTIVES: Currently, there is no consensus whether dual-energy X ray absorptiometry (DXA) or quantitative computed tomography (QCT) can be used to screen for osteoporosis or osteopenia in CKD-5D patients. This study uses iliac bone histology, the "gold standard" for bone volume evaluation, to determine the utility of DXA and QCT for low bone mass screening in CKD-5D patients. PATIENTS AND METHODS: A cross-sectional study of patients with CKD-5D employing iliac crest bone biopsies to assess bone volume by histology and comparing results to bone mineral density (BMD) measurements of the hip and spine by DXA and QCT. Pearson's correlation, linear regression, and receiver operating characteristics curve analyses were performed. RESULTS: 46 patients (mean age 51 years, 52% women, median dialysis vintage 46 months) had bone biopsies, DXA, and QCT scans. 37 patients (80%) had low bone volume by histology. DXA and QCT BMD values (g/cm2) were very highly correlated at the femoral neck (rho = 0.97) and total hip (rho = 0.97), and to a lesser degree at the spine (rho = 0.65). DXA and QCT t scores were also highly correlated, but QCT t-scores were systematically greater than DXA t-scores (1.1 S.D. on average at the femoral neck) leading to less recognition of osteopenia and osteoporosis by QCT. A t-score below -1 by DXA at the femoral neck (i.e., osteopenic or osteoporotic) showed 83% sensitivity and 78% specificity relative to low bone volume by histology. A QCT t-score below -1 did not reach acceptable diagnostic levels of sensitivity and specificity. CONCLUSIONS: DXA and QCT provide nearly identical areal BMD measures at the hip. However, QCT t-scores are consistently higher than DXA t-scores resulting in less diagnosis of osteoporosis or osteopenia. DXA results showed acceptable diagnostic sensitivity and specificity for low bone volume by histology and can be used for diagnosis of osteopenia and osteoporosis in patients with CKD-5D. PMID- 26587779 TI - Glomerular expression of matrix metalloproteinases in AL-amyloidosis and association with renal function at the time of kidney biopsy. AB - BACKGROUND: Matrix metalloproteinases (MMPs) have been implicated in the pathophysiology of various renal diseases, however, there are limited data regarding their role in renal AL-amyloidosis. In the present study, we evaluated the glomerular expression of MMPs in renal-biopsy specimens containing AL-amyloid deposits. We also examined the association of MMPs with renal function at the time of diagnostic renal biopsy. METHODS: We performed immunohistochemistry with monoclonal antibodies against MMP-1, MMP-2, MMP-3, MMP-9, and TIMP-1 in 19 kidney biopsy specimens with AL-amyloidosis and 8 specimens from normal kidney tissue. We used clinical data of the patients at the time of kidney biopsy to evaluate the association between MMP expression and renal function. RESULTS: We found increased MMP-1 and MMP-3 expression within the amyloid deposits and adjacent tissues in > 50% of the amyloid-positive biopsies, whereas MMP-1 and MMP-3 were negative in control samples. In contrast, we found no significant glomerular MMP 2 and TIMP-1 expression in amyloid-containing or normal kidneys. MMP-9 expression was found in the glomerular basement membrane equally in AL-amyloidosis and control specimens. The presence of MMP-1 and MMP-3 in the glomeruli of patients with AL-amyloidosis correlated with worse renal function at the time of kidney biopsy. CONCLUSION: The findings of this study show increased glomerular expression of MMP-1 and MMP-3 in patients with AL-amyloidosis which is associated with worse renal function at the time of the kidney biopsy. Our results suggest an important role for MMP-1 and MMP-3 in the pathogenesis of renal damage in AL amyloidosis. PMID- 26587780 TI - Urodynamics findings in transverse myelitis patients with lower urinary tract symptoms: Results from a tertiary referral urodynamic center. AB - AIMS: To characterize urodynamic findings in patients referred with transverse myelitis (TM) and lower urinary tract symptoms (LUTS), as well as to identify any characteristics predictive of urodynamics findings. METHODS: This is a retrospective review of an IRB-approved neurogenic bladder database of patients followed by a single surgeon between 2001 and 2013. Patient characteristics, questionnaire data, radiologic studies, and urodynamic parameters were analyzed. RESULTS: Of the 836 patients in the neurogenic bladder database, 28 patients (17 females, 11 males) were referred with a principle diagnosis of TM (3%). Twenty one of twenty-eight patients (75%) underwent urodynamics testing. Bladder management at initial urologic evaluation was CIC or urethral catheter for 16/28 patients (57.1%). Median MCC was 303 ml (85-840 ml), detrusor overactivity (DO) was present in 16/21 (76%), detrusor sphincter dyssynergia (DSD) in 10/21 (48%), and decreased compliance in 7/21 (33%). For those voiding, mean Qmax was 12 +/- 10 ml/sec and pdet at Qmax was 41 +/- 17 cmH2 O. Longitudinally extensive TM (LETM) was the only patient characteristic associated with DO (P = 0.0276). No other patient characteristics were associated with urodynamics parameters. CONCLUSIONS: Significant urodynamic testing abnormalities are noted in the majority of TM patients undergoing urodynamics, with 95% having DO, DSD, altered compliance, or detrusor underactivity. Other than the association between LETM and DO, there were no patient characteristics predictive of urodynamics findings. Based on the severity of urodynamics findings in our series, patients with TM and LUTS should have thorough baseline urological evaluations including urodynamics and be offered ongoing surveillance. Neurourol. Urodynam. 36:360-363, 2017. (c) 2015 Wiley Periodicals, Inc. PMID- 26587781 TI - Cell death induced by endoplasmic reticulum stress. AB - The endoplasmic reticulum is an organelle with multiple functions. The synthesis of transmembrane proteins and proteins that are to be secreted occurs in this organelle. Many conditions that impose stress on cells, including hypoxia, starvation, infections and changes in secretory needs, challenge the folding capacity of the cell and promote endoplasmic reticulum stress. The cellular response involves the activation of sensors that transduce signaling cascades with the aim of restoring homeostasis. This is known as the unfolded protein response, which also intersects with the integrated stress response that reduces protein synthesis through inactivation of the initiation factor eIF2alpha. Central to the unfolded protein response are the sensors PERK, IRE1 and ATF6, as well as other signaling nodes such as c-Jun N-terminal kinase 1 (JNK) and the downstream transcription factors XBP1, ATF4 and CHOP. These proteins aim to restore homeostasis, but they can also induce cell death, which has been shown to occur by necroptosis and, more commonly, through the regulation of Bcl-2 family proteins (Bim, Noxa and Puma) that leads to mitochondrial apoptosis. In addition, endoplasmic reticulum stress and proteotoxic stress have been shown to induce TRAIL receptors and activation of caspase-8. Endoplasmic reticulum stress is a common feature in the pathology of numerous diseases because it plays a role in neurodegeneration, stroke, cancer, metabolic diseases and inflammation. Understanding how cells react to endoplasmic reticulum stress can accelerate discovery of drugs against these diseases. PMID- 26587782 TI - Enzalutamide Reduces the Bone Mass in the Axial But Not the Appendicular Skeleton in Male Mice. AB - Testosterone is a crucial regulator of the skeleton, but the role of the androgen receptor (AR) for the maintenance of the adult male skeleton is unclear. In the present study, the role of the AR for bone metabolism and skeletal growth after sexual maturation was evaluated by means of the drug enzalutamide, which is a new AR antagonist used in the treatment of prostate cancer patients. Nine-week-old male mice were treated with 10, 30, or 100 mg/kg.d of enzalutamide for 21 days or were surgically castrated and were compared with vehicle-treated gonadal intact mice. Although orchidectomy reduced the cortical bone thickness and trabecular bone volume fraction in the appendicular skeleton, these parameters were unaffected by enzalutamide. In contrast, both enzalutamide and orchidectomy reduced the bone mass in the axial skeleton as demonstrated by a reduced lumbar spine areal bone mineral density (P < .001) and trabecular bone volume fraction in L5 vertebrae (P < .001) compared with vehicle-treated gonadal intact mice. A compression test of the L5 vertebrae revealed that the mechanical strength in the axial skeleton was significantly reduced by enzalutamide (maximal load at failure -15.3% +/- 3.5%; P < .01). The effects of enzalutamide in the axial skeleton were associated with a high bone turnover. In conclusion, enzalutamide reduces the bone mass in the axial but not the appendicular skeleton in male mice after sexual maturation. We propose that the effect of testosterone on the axial skeleton in male mice is mainly mediated via the AR. PMID- 26587783 TI - Identification of the Long-Sought Leptin in Chicken and Duck: Expression Pattern of the Highly GC-Rich Avian leptin Fits an Autocrine/Paracrine Rather Than Endocrine Function. AB - More than 20 years after characterization of the key regulator of mammalian energy balance, leptin, we identified the leptin (LEP) genes of chicken (Gallus gallus) and duck (Anas platyrhynchos). The extreme guanine-cytosine content (~70%), the location in a genomic region with low-complexity repetitive and palindromic sequence elements, the relatively low sequence conservation, and low level of expression have hampered the identification of these genes until now. In vitro-expressed chicken and duck leptins specifically activated signaling through the chicken leptin receptor in cell culture. In situ hybridization demonstrated expression of LEP mRNA in granular and Purkinje cells of the cerebellum, anterior pituitary, and in embryonic limb buds, somites, and branchial arches, suggesting roles in adult brain control of energy balance and during embryonic development. The expression patterns of LEP and the leptin receptor (LEPR) were explored in chicken, duck, and quail (Coturnix japonica) using RNA-sequencing experiments available in the Short Read Archive and by quantitative RT-PCR. In adipose tissue, LEP and LEPR were scarcely transcribed, and the expression level was not correlated to adiposity. Our identification of the leptin genes in chicken and duck genomes resolves a long lasting controversy regarding the existence of leptin genes in these species. This identification was confirmed by sequence and structural similarity, conserved exon-intron boundaries, detection in numerous genomic, and transcriptomic datasets and characterization by PCR, quantitative RT PCR, in situ hybridization, and bioassays. Our results point to an autocrine/paracrine mode of action for bird leptin instead of being a circulating hormone as in mammals. PMID- 26587784 TI - Reducing Adiposity in a Critical Developmental Window Has Lasting Benefits in Mice. AB - Although most adults can lose weight by dieting, a well-characterized compensatory decrease in energy expenditure promotes weight regain more than 90% of the time. Using mice with impaired hypothalamic leptin signaling as a model of early-onset hyperphagia and obesity, we explored whether this unfavorable response to weight loss could be circumvented by early intervention. Early-onset obesity was associated with impairments in the structure and function of brown adipose tissue mitochondria, which were ameliorated by weight loss at any age. Although decreased sympathetic tone in weight-reduced adults resulted in net reductions in brown adipose tissue thermogenesis and energy expenditure that promoted rapid weight regain, this was not the case when dietary interventions were initiated at weaning. Enhanced energy expenditure persisted even after mice were allowed to resume overeating, leading to lasting reductions in adiposity. These findings reveal a time window when dietary interventions can produce metabolic improvements that are stably maintained. PMID- 26587786 TI - In silico prediction of ebolavirus RNA polymerase inhibition by specific combinations of approved nucleotide analogues. AB - BACKGROUND AND OBJECTIVE: The urgency of ebolavirus drug development is obvious in light of the current local epidemic in Western Africa with high morbidity and a risk of wider spread. We present an in silico study as a first step to identify inhibitors of ebolavirus polymerase activity based on approved antiviral nucleotide analogues. STUDY DESIGN: Since a structure model of the ebolavirus polymerase is lacking, we performed combined homology and ab initio modeling and report a similarity to known polymerases of human enterovirus, bovine diarrhea virus and foot-and-mouth disease virus. This facilitated the localization of a nucleotide binding domain in the ebolavirus polymerase. We next performed molecular docking studies with nucleotides (ATP, CTP, GTP and UTP) and nucleotide analogues, including a variety of approved antiviral drugs. RESULTS AND CONCLUSIONS: Specific combinations of nucleotide analogues significantly reduce the ligand-protein interaction energies of the ebolavirus polymerase for natural nucleotides. Any nucleotide analogue on its own did not reduce ligand-protein interaction energies. This prediction encourages specific drug testing efforts and guides future strategies to inhibit ebolavirus replication. PMID- 26587785 TI - Gene-by-Diet Interactions Affect Serum 1,25-Dihydroxyvitamin D Levels in Male BXD Recombinant Inbred Mice. AB - 1,25-Dihydroxyvitamin D (1,25[OH]2D) regulates calcium (Ca), phosphate, and bone metabolism. Serum 1,25(OH)2D levels are reduced by low vitamin D status and high fibroblast growth factor 23 (FGF23) levels and increased by low Ca intake and high PTH levels. Natural genetic variation controls serum 25-hydroxyvitamin D (25[OH]D) levels, but it is unclear how it controls serum 1,25(OH)2D or the response of serum 1,25(OH)2D levels to dietary Ca restriction (RCR). Male mice from 11 inbred lines and from 51 BXD recombinant inbred lines were fed diets with either 0.5% (basal) or 0.25% Ca from 4 to 12 weeks of age (n = 8 per line per diet). Significant variation among the lines was found in basal serum 1,25(OH)2D and in the RCR as well as basal serum 25(OH)D and FGF23 levels. 1,25(OH)2D was not correlated to 25(OH)D but was negatively correlated to FGF23 (r = -0.5). Narrow sense heritability of 1,25(OH)2D was 0.67 on the 0.5% Ca diet, 0.66 on the 0.25% Ca diet, and 0.59 for the RCR, indicating a strong genetic control of serum 1,25(OH)2D. Genetic mapping revealed many loci controlling 1,25(OH)2D (seven loci) and the RCR (three loci) as well as 25(OH)D (four loci) and FGF23 (two loci); a locus on chromosome 18 controlled both 1,25(OH)2D and FGF23. Candidate genes underlying loci include the following: Ets1 (1,25[OH]2D), Elac1 (FGF23 and 1,25[OH]2D), Tbc1d15 (RCR), Plekha8 and Lyplal1 (25[OH]D), and Trim35 (FGF23). This report is the first to reveal that serum 1,25(OH)2D levels are controlled by multiple genetic factors and that some of these genetic loci interact with the dietary environment. PMID- 26587787 TI - Identification of minority resistance mutations in the HIV-1 integrase coding region using next generation sequencing. AB - BACKGROUND: The current widely applied standard method to screen for HIV-1 genotypic resistance is based on Sanger population sequencing (Sseq), which does not allow for the identification of minority variants (MVs) below the limit of detection for the Sseq-method in patients receiving integrase strand-transfer inhibitors (INSTI). Next generation sequencing (NGS) has facilitated the detection of MVs at a much deeper level than Sseq. OBJECTIVES: Here, we compared Illumina MiSeq and Sseq approaches to evaluate the detection of MVs involved in resistance to the three commonly used INSTI: raltegravir (RAL), elvitegravir (EVG) and dolutegravir (DTG). STUDY DESIGN: NGS and Sseq were used to analyze RT PCR products of the HIV-1 integrase coding region from six patients and in serial samples from two patients. NGS sequences were assembled and analyzed using the low frequency variant detection (LFVDT) tool in CLC genomic workbench. RESULTS: Sseq detected INSTI resistance and accessory mutations in three of the patients (called INSTI Res+), while no resistance or accessory mutations were detected in the remaining three patients (called INSTI Res-). Additional INSTI resistance and/or accessory mutations were detected by NGS analysis of integrase sequences from all three INSTI Res+ and one INSTI Res- patient. CONCLUSION: Our observations suggested that NGS demonstrated a higher sensitivity than sSEQ in the identification of INSTI relevant MVs both in patients at treatment baseline and in patients receiving INSTI therapy. Thus NGS can be a valuable tool in monitoring of antiretroviral minority resistance in patients receiving INSTI therapy. PMID- 26587788 TI - Analysis of human cytomegalovirus strain populations in urine samples of newborns by ultra deep sequencing. AB - BACKGROUND: Different human cytomegalovirus (HCMV) strains may persistently coexist in the human host. In immunosuppressed patients infection with mixed HCMV populations was associated with a more severe course of infection. Congenital HCMV infection may lead to severe fetal disease and possibly mixed HCMV strain infections might have also impact on the clinical consequences for the newborn. Mixed HCMV strain populations were so far detected in saliva but only rarely in urine of congenitally infected newborns. OBJECTIVES: We have therefore analyzed the extent of mixed HCMV genotype populations in urine of congenitally infected newborns using a highly sensitive deep sequencing method. STUDY DESIGN: Twenty urine samples (17 initial and 3 follow-up samples) from 17 congenitally infected newborns with a median HCMV DNA load of 7.5log10 copies/ml were included. Deep sequencing was applied for gO (UL74) genotyping and quantitative real-time PCR assays were used for gB (UL55) and gH (UL75) genotyping. RESULTS: In none of the urine samples a gO genotype mixture was detected, although a mean of 10.000 sequence reads per amplicon was analyzed, which allows to explore gO genotypes down to less than 1% of the total gO sequences. Also only one gB genotype was detected in the patients' initial samples, while a gH genotype mixture was detected in one case using real time PCR with a sensitivity of 5% for minor populations. CONCLUSION: Mixed HCMV genotype populations are only rarely found in urine of congenitally infected newborns even when highly sensitive HCMV genotyping methods are applied. PMID- 26587789 TI - Dysregulated miR-98 Contributes to Extracellular Matrix Degradation by Targeting IL-6/STAT3 Signaling Pathway in Human Intervertebral Disc Degeneration. AB - Intervertebral disc degeneration (IDD) is associated with dysregulated expression of microRNAs (miRNAs). However, the precise molecular mechanisms underlying this disorder remain unclear. Therefore, we tested the hypothesis that miRNAs modulate IDD through effects on the IL-6/STAT3 signaling pathway, a potential regulator of IDD. The miRNA expression profile was determined in nucleus pulposus (NP) tissues from patients with IDD and controls, employing miRNA microarray and quantitative real-time PCR (RT-qPCR). Biological functions of differential expression miRNAs were further investigated using immunofluorescent staining. Luciferase reporter assays and Western blotting were performed to determine miRNA targets. We identified 41 miRNAs that were differentially expressed in patients compared with controls. Following RT-qPCR confirmation, miR-98 was significantly downregulated in degenerative NP tissues. Moreover, its level was inversely correlated with grade of disc degeneration. Through gain-of-function and loss-of-function studies, miR-98 was shown to significantly promote type II collagen expression in NP cells. Interleukin-6 (IL-6) was identified as a target of miR-98. Knockdown of IL-6 induced effects on NP cells similar to those induced by miR-98. In contrast, IL-6 treatment abrogated the effects induced by miR-98 upregulation. Moreover, miR-98 dramatically suppressed expression of STAT3 target gene, MMP2. IL-6 treatment antagonized this effect, whereas knockdown of IL-6 by IL-6 short hairpin RNA (shIL-6) induced inhibitory effects on the expression of p-STAT3 and its main target genes, similar to miR-98. The mRNA level of IL-6 was inversely correlated with that of miR-98 in degenerative NP tissues. These results suggest the downregulation of miR-98 could promote IDD through the IL-6/STAT3 signaling pathway. Our findings also highlight miR-98 as a novel hopeful therapeutic target for IDD. PMID- 26587790 TI - Recovery of nitrification in cadmium-inhibited activated sludge system by bio accelerators. AB - Cadmium (Cd) is toxic to nitrifying bacteria, but current studies on recovery process in Cd-inhibited activated sludge system are limited, especially on intensify-recovery processes with developing and optimizing nontoxic bio accelerators. In this study, bioactivity recovery effects were demonstrated with respect to effluent NH4(+)-N, NO2(-)-N, NO3(-)-N concentrations, specific oxygen uptake rates and cadmium distribution in five parallel SBRs. Results indicated that bioactivity of nitrifying bacteria was mainly inhibited by surface-bound Cd. Dosing biotin, l-aspartic acid and cytokinin simultaneously was the most effective. Linear chain, together with amide (NH) and carboxyl (COOH) groups, may be important factors in fast nitrification recovery process. In terms of dosage and dosing mode, six-multiple dosage of optimal mixture with dosing at each cycle evenly was the most effective and bioactivities of nitrifying bacteria could 100% recovered within 7days. The bio-accelerators and optimum usage can be potentially applied to cope with heavy metal shock-loading emergency situations. PMID- 26587791 TI - Integrating the selection of PHA storing biomass and nitrogen removal via nitrite in the main wastewater treatment line. AB - A novel scheme was developed for the treatment of municipal wastewater integrating nitritation/denitritation with the selection of polyhydroxyalkanoates (PHA) storing biomass under an aerobic/anoxic, feast/famine regime. The process took place in a sequencing batch reactor (SBR) and the subsequent PHA accumulation in a batch reactor. The carbon source added during the selection and accumulation steps consisted of fermentation liquid from the organic fraction of municipal solids waste (OFMSW FL) (Period I) and OFMSW and primary sludge fermentation liquid (Period II). Selection of PHA storing biomass was successful and denitritation was driven by internally stored PHA during the famine phase. Under optimum conditions of SBR operation ammonia removal was 93%, reaching a maximum nitrite removal of 98%. The treated effluent met the nitrogen limits, while PHA-storing biomass was successfully selected. The maximum accumulation of PHA was 10.6% (wt.) since the nutrients present in the carbon source promoted bacterial growth. PMID- 26587793 TI - Comment on IgE responses to Ascaris and mite tropomyosins are risk factors for asthma. PMID- 26587792 TI - DMSO Enhances TGF-beta Activity by Recruiting the Type II TGF-beta Receptor From Intracellular Vesicles to the Plasma Membrane. AB - Dimethyl sulfoxide (DMSO) is used to treat many diseases/symptoms. The molecular basis of the pharmacological actions of DMSO has been unclear. We hypothesized that DMSO exerts some of these actions by enhancing TGF-beta activity. Here we show that DMSO enhances TGF-beta activity by ~3-4-fold in Mv1Lu and NMuMG cells expressing Smad-dependent luciferase reporters. In Mv1Lu cells, DMSO enhances TGF beta-stimulated expression of P-Smad2 and PAI-1. It increases cell-surface expression of TGF-beta receptors (TbetaR-I and/or TbetaR-II) by ~3-4-fold without altering their cellular levels as determined by (125) I-labeled TGF-beta-cross linking/Western blot analysis, suggesting the presence of large intracellular pools in these cells. Sucrose density gradient ultracentrifugation/Western blot analysis reveals that DMSO induces recruitment of TbetaR-II (but not TbetaR-I) from its intracellular pool to plasma-membrane microdomains. It induces more recruitment of TbetaR-II to non-lipid raft microdomains than to lipid rafts/caveolae. Mv1Lu cells transiently transfected with TbetaR-II-HA plasmid were treated with DMSO and analyzed by indirect immunofluoresence staining using anti-HA antibody. In these cells, TbetaR-II-HA is present as a vesicle-like network in the cytoplasm as well as in the plasma membrane. DMSO causes depletion of TbetaR-II-HA-containing vesicles from the cytoplasm and co-localization of TbetaR-II-HA and cveolin-1 at the plasma membrane. These results suggest that DMSO, a fusogenic substance, enhances TGF-beta activity presumably by inducing fusion of cytoplasmic vesicles (containing TbetaR-II) and the plasma membrane, resulting in increased localization of TbetaR-II to non-lipid raft microdomains where canonical signaling occurs. Fusogenic activity of DMSO may play a pivotal role in its pharmacological actions involving membrane proteins with large cytoplasmic pools. J. Cell. Biochem. 117: 1568-1579, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26587794 TI - Detection and characterization of circulating tumor cells in lung cancer: Why and how? PMID- 26587795 TI - Retrospective cohort study on the incidence of acute kidney injury and death following hydroxyethyl starch (HES 10% 250/0.5/5:1) administration in dogs (2007 2010). AB - OBJECTIVE: To determine the incidence of in-hospital adverse outcomes including acute kidney injury (AKI) and death in a population of dogs admitted to the intensive care unit (ICU) receiving 10% hydroxyethyl starch (HES) [250/0.5/5:1] compared with the general ICU population, while controlling for illness severity. DESIGN: Cohort study conducted between January 2007 and March 2010. SETTING: Veterinary teaching hospital. ANIMALS: Consecutive sample of dogs receiving HES (n = 180) were compared with a randomly selected sample of dogs (n = 242) admitted to the ICU over the same period. INTERVENTIONS: None MEASUREMENTS AND MAIN RESULTS: AKI was defined as an at least 2-fold increase in baseline creatinine concentration or new onset of oliguria/anuria persisting for >=12 hours. The primary outcome was a composite of in-hospital death or AKI. Unadjusted and adjusted analysis controlling for illness severity using the acute patient physiologic and laboratory evaluation (APPLEfast ) score and other confounders was performed. HES was administered either as incremental boluses (median dose 8.2 mL/kg/day, interquartile range [IQR] 5.0-11.3 mL/kg/day) or as a continuous rate infusion (CRI; median dose 26mL/kg/day, IQR 24.0-48 mL/kg/day). In unadjusted analysis, HES administration was associated with increased risk of mortality (odds ratio [OR] = 2.33, 95% confidence interval [CI] = 1.51-3.58, P < 0.001) or AKI (OR = 3.87, 95% CI = 1.21-12.37, P = 0.02). In an adjusted analysis after controlling for illness severity, admission type, and concurrent administration of blood products, HES administration remained an independent risk factor for the composite adverse outcome (OR = 1.98, 95% CI = 1.22-3.22, P = 0.005), with a number needed to harm (NNH) = 6 (95% CI = 4-23). CONCLUSIONS: HES therapy is associated with increased risk of an adverse outcome including death or AKI in dogs. A randomized controlled trial investigating the safety of HES therapy in canine patients is warranted. PMID- 26587796 TI - Pharmacologic management of comorbid post-traumatic stress disorder and addictions. AB - BACKGROUND AND OBJECTIVES: Post-traumatic Stress Disorder (PTSD) and substance use disorders (SUD) frequently co-occur, and their combination can increase poor health outcomes as well as mortality. METHODS: Using PUBMED and the list of references from key publications, this review article covered the epidemiology, neurobiology and pharmacotherapy of PTSD with comorbid alcohol, opiate, and cannabis use disorders. These SUD represent two with and one without FDA approved pharmacotherapies. RESULTS: SUD is two to three times more likely among individuals with lifetime PTSD, and suicide, which is made more likely by both of these disorders, appears to be additively increased by having this comorbidity of SUD and PTSD. The shared neurobiological features of these two illnesses include amygdalar hyperactivity with hippocampal, medial prefrontal and anterior cingulate cortex dysfunction. Medications for comorbid PTSD and SUD include the PTSD treatment sertraline, often used in combination with anticonvulsants, antipsychotics, and adrenergic blockers. When PTSD is comorbid with alcohol use disorder (AUD), naltrexone, acamprosate or disulfiram may be combined with PTSD treatments. Disulfiram alone may treat both PTSD and AUD. For PTSD combined with opiate use disorder methadone or buprenorphine are most commonly used with sertraline. Marijuana use has been considered by some to be a treatment for PTSD, but no FDA treatment for this addiction is approved. Pregabalin and D-cycloserine are two innovations in pharmacotherapy for PTSD and SUD. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Comorbid PTSD and SUD amplifies their lethality and treatment complexity. Although they share important neurobiology, these patients uncommonly respond to a single pharmacotherapy such as sertraline or disulfiram and more typically require medication combinations and consideration of the specific type of SUD. PMID- 26587797 TI - Breast Imaging in the Era of Big Data: Structured Reporting and Data Mining. AB - OBJECTIVE: The purpose of this article is to describe structured reporting and the development of large databases for use in data mining in breast imaging. CONCLUSION: The results of millions of breast imaging examinations are reported with structured tools based on the BI-RADS lexicon. Much of these data are stored in accessible media. Robust computing power creates great opportunity for data scientists and breast imagers to collaborate to improve breast cancer detection and optimize screening algorithms. Data mining can create knowledge, but the questions asked and their complexity require extremely powerful and agile databases. New data technologies can facilitate outcomes research and precision medicine. PMID- 26587798 TI - Ischiofemoral Impingement in Children: Imaging With Clinical Correlation. AB - OBJECTIVE: The purpose of this study is to correlate the MRI finding of quadratus femoris edema in children with established measures of ischiofemoral impingement in adults and to determine their clinical significance. MATERIALS AND METHODS: A case-control retrospective review was performed of MR images of 12 hips of nine children (mean age, 10 years) that showed abnormal signal intensity in the quadratus femoris muscle. The findings were compared with those for 13 hips in 13 control subjects (mean age, 9.8 years). Two musculoskeletal radiologists independently measured the ischiofemoral space, quadratus femoris space, inclination angle, and hamstring tendon area. Quadratus femoris muscle edema, tears, or fatty replacement were assessed visually. Statistical analysis determined inter- and intraobserver variability and statistical differences between the two subject groups. RESULTS: Subjects with abnormal signal in the quadratus femoris muscle had a statistically significantly narrower ischiofemoral space (mean, 11.5 vs 20.7 mm; p < 0.05) and quadratus femoris space (mean, 7.2 vs 14.3 mm, p < 0.05) compared with control subjects. Inclination angles were statistically significantly larger in affected subjects (145.5 degrees vs 138.7 degrees ; p < 0.05). No statistically significant difference was found in hamstring tendon area. Four of 12 patient hips had no symptoms or symptoms unrelated to the abnormality. Inter- and intraobserver variability scores were strong for all continuous variables. CONCLUSION: Ischiofemoral impingement is a cause of hip pain in children and should be considered with the combination of quadratus femoris muscle edema and narrowing of ischiofemoral space and quadratus femoris space. Coxa valga may contribute to narrowing of these parameters and predispose to ischiofemoral impingement. The MRI features of ischiofemoral impingement, however, are nonspecific and may be seen in patients with pain localized to that hip or in patients with symptoms unrelated to the abnormality. PMID- 26587799 TI - Performance of DWI in the Nodal Characterization and Assessment of Lung Cancer: A Meta-Analysis. AB - OBJECTIVE: The purpose of this study is to assess the diagnostic performance of DWI in the N stage assessment of patients with lung cancer. MATERIALS AND METHODS: The PubMed, EMBASE, Cochrane Library, Web of Science, and EBSCO English language databases and two Chinese-language databases were searched for eligible studies. On the basis of the data extracted from included studies, we determined the pooled sensitivity and specificity, calculated the positive and negative likelihood ratios, and constructed summary ROC curves. In addition, we also performed threshold effect analysis, metaregression analysis, subgroup analysis, and publication bias analysis to explain the source of heterogeneity. RESULTS: A total of 18 articles involving 1116 patients met the inclusion criteria. On a per patient basis, the pooled sensitivity and specificity estimates of DWI were 0.68 (95% CI, 0.63-0.73) and 0.92 (95% CI, 0.90-0.94), respectively. On a per-lesion basis, the corresponding estimates were 0.72 (95% CI, 0.69-0.75) for sensitivity and 0.96 (95% CI, 0.95-0.96) for specificity. Only the analysis method (quantitative vs qualitative) affected the diagnostic accuracy on the basis of subgroup and metaregression analysis. CONCLUSION: Current evidence suggests that DWI is beneficial in the nodal assessment of patients with lung cancer, and it is necessary to conduct high-quality prospective studies regarding the use of DWI in detecting metastatic lymph nodes of lung cancer to determine its true value. PMID- 26587800 TI - Diagnosis of Usual Interstitial Pneumonitis in the Absence of Honeycombing: Evaluation of Specific CT Criteria With Clinical Follow-Up in 38 Patients. AB - OBJECTIVE: We sought to evaluate specific CT criteria for the diagnosis of usual interstitial pneumonitis (UIP) in the absence of honeycombing. These criteria included peripheral reticulation and lobular distortion; some upper lobe involvement, but a lower zone predominance; a heterogeneous appearance with areas of normal lung, minimal reticulation, and substantial distortion alternating throughout the study and often on an individual image; a nonsegmental distribution; and traction bronchiectasis. MATERIALS AND METHODS: We searched reports of CT studies performed between January 1, 2009, and January 1, 2012, to identify patients for whom UIP was a likely or probable diagnosis and reviewed the CT study for each case (n = 106). There were 38 patients who met all CT criteria and who also had a clinical diagnosis of idiopathic UIP (also known as idiopathic pulmonary fibrosis [IPF]) and follow-up of at least 6 months, as determined from the electronic medical record. We reviewed prior and subsequent CT examinations in this cohort. RESULTS: The median age of our patients was 80 years, and the duration of clinical follow-up was 6-104 months (mean, 38 months; median, 37 months). For all patients, a pulmonary medicine physician made a working diagnosis of IPF. Fifteen patients died from pulmonary complications, and 16 of the surviving patients had clinical or functional progression of disease. There were no instances in which the initial diagnosis was revised or reversed. CONCLUSION: Strict application of specific CT criteria may allow a specific diagnosis of UIP in the proper clinical setting in the absence of honeycombing. PMID- 26587802 TI - Dr. Menahem Hodara (1869-1926) and his contributions to dermatology. PMID- 26587801 TI - Decreased production of proinflammatory cytokines by monocytes from individuals presenting Candida-associated denture stomatitis. AB - Candida-associated denture stomatitis (DS) is the most frequent lesion among denture wearers, especially the elderly. DS is strongly associated with Candida albicans, as well as local and systemic factors, such as impaired immune response. Monocytes are important in the protective immune response against the fungus by the production of cytokines that recruit and activate leukocytes. There are functional changes in these cells with age, and individual alterations involving monocyte response may predispose the host to developing infections by Candida spp. In this study, our aim was to evaluate the production of TNF-alpha, IL-6, CXCL8, IL-1beta, MCP-1 and IL-10 by monocytes from elderly denture wearers with/without DS and elderly or young non-denture wearers. We detected that monocytes from elderly denture wearers with Candida-related denture stomatitis produced lower levels of CXCL-8, IL-6 and MCP-1. This imbalance in cytokine levels was observed in spontaneous or LPS-stimulated production. Therefore, our data suggested that inherent aspects of the host, such as changes in cytokine production by monocytes, might be associated with the development and the persistence of DS irrespective of aging. PMID- 26587803 TI - MicroRNA Regulation of Airway Inflammation and Airway Smooth Muscle Function: Relevance to Asthma. AB - Genetic and environmental factors contribute to the onset and severity of asthma. Molecular pathogenesis of asthma involves changes in gene expression by a variety of inflammatory mediators acting in autocrine and paracrine fashion on effector cells of the airways. Transcriptional regulation of gene expression in resident airway cells has been studied extensively. However, protein function in a target cell can be regulated at multiple levels starting from transcription followed by post-transcription, translation, and post-translation steps. In this context, small noncoding RNAs known as microRNAs (miRNAs) have evolved as one of the key regulators of gene expression post-transcriptionally. Most importantly, miRNA expression is dynamic in nature and can be regulated by a variety of external stimuli. Altered expression of individual or a group of miRNAs is thought to contribute to human diseases. Recent studies have implicated differential expression of miRNAs in the lungs during inflammation. Most importantly, advanced biochemical and molecular tools could be used to manipulate miRNA expression thereby effecting functional changes in target cells and organ systems. This review summarizes the current understanding of miRNA in the regulation of airway function in health and disease, and highlights the potential clinical utility of mRNAs as biomarkers of airway diseases and as potential therapeutic targets. PMID- 26587804 TI - C-kit(+) resident cardiac stem cells improve left ventricular fibrosis in pressure overload. AB - To investigate the effect of resident cardiac stem cells (RCSC) on myocardial remodeling, c-kit(+) RCSC were isolated from hearts of C57Bl/6-Tg (ACTb EGFP)1Osb/J mice expressing green fluorescent protein and expanded in vitro. C57/Bl6N wildtype mice were subjected to transverse aortic constriction (TAC, 360 MUm) or sham-operation. 5 * 10(5) c-kit(+) RCSC or c-kit(-) cardiac cells or cell buffer were infused intravenously 24 h post-surgery (n = 11-24 per group). Hypoxia-inducible factor-1alpha-mRNA in left ventricles of TAC mice was enhanced 24 h after transplantation. 35 days post-TAC, the density of c-kit(+) RCSC in the myocardium was increased by two-fold. Infusion of c-kit(+) resident cardiac stem cells post-TAC markedly reduced myocardial fibrosis and the expression of collagen Ialpha2 and connective tissue growth factor. Infusion of c-kit(-) cardiac cells did not ameliorate cardiac fibrosis. In parallel, expression of pro angiogenic mediators (FGFb, IL-4, IL-6, TGFbeta, leptin) and the density of CD31(+) and CD31(+) GFP(+) endothelial cells were increased. Transplantation reduced brain- and atrial natriuretic peptides and the cardiomyocyte cross sectional area. Infusion of c-kit(+) resident cardiac stem reduced the rate of apoptosis and oxidative stress in cardiomyocytes and in non-cardiomyocyte cells. PMID- 26587805 TI - Second Nordic Congress on Obesity in Gynecology and Obstetrics (NOCOGO). PMID- 26587806 TI - DNA fingerprinting approaches to trace Escherichia coli sharing between dogs and owners. AB - AIMS: To determine the prevalence of cross-species sharing of Escherichia coli between healthy dogs and humans living in the same household. METHODS AND RESULTS: Two faecal E. coli isolates from 25 healthy dog-owner pairs and 16 healthy control humans were tested using three fingerprinting methods. The prevalence of within-household sharing of E. coli was 4, 8 and 8% using pulsed field gel electrophoresis, randomly amplified polymorphic DNA and enterobacterial repetitive intergenic consensus-PCR analyses respectively. Within-household bacterial sharing was more prevalent than across-household sharing (P < 0.05). According to questionnaire analyses avoiding the dog-owner behaviours such as allowing a dog to kiss or lick the owner's face, sharing people food with dog and feeding it raw meat may decrease the chance of cross-species E. coli sharing. CONCLUSIONS: Direct contact between humans and dogs and environmental reservoirs may be important routes for cross-species sharing of bacteria. Good personal hygiene and appropriate veterinary care for pets can minimize this risk. SIGNIFICANCE AND IMPACT OF THE STUDY: Due to the importance of canine pathogenic E. coli reservoir hypothesis, close contacts between humans and dogs raises public health concerns. Determining the rate of cross-species bacterial sharing and confirm its accuracy by different fingerprinting techniques will help to find ways for reducing the economic impact of E. coli infections. This study support claims that public health concerns regarding the cross-species sharing of E. coli are warranted but this risk is minimal. PMID- 26587807 TI - EphA4 has distinct functionality from EphA7 in the corticothalamic system during mouse brain development. AB - Deciphering the molecular basis for guiding specific aspects of neocortical development remains a challenge because of the complexity of histogenic events and the vast array of protein interactions mediating these events. The Eph family of receptor tyrosine kinases is implicated in a number of neurodevelopmental activities. Eph receptors have been known to be capable of responding to several ephrin ligands within their subgroups, often eliciting similar downstream effects. However, several recent studies have indicated specificity between receptor-ligand pairs within each subfamily, the functional relevance of which is not defined. Here we show that a receptor of the EphA subfamily, EphA4, has effects distinct from those of its close relative, EphA7, in the developing brain. Both EphA4 and EphA7 interact similarly with corresponding ligands expressed in the developing neocortex. However, only EphA7 shows strong interaction with ligands in the somatosensory thalamic nuclei; EphA4 affects only cortical neuronal migration, with no visible effects on the guidance of corticothalamic (CT) axons, whereas EphA7 affects both cortical neuronal migration and CT axon guidance. Our data provide new evidence that Eph receptors in the same subfamily are not simply interchangeable but are functionally specified through selective interactions with distinct ligands in vivo. J. Comp. Neurol. 524:2080-2092, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26587808 TI - Slashing the timelines: Opting to generate high-titer clonal lines faster via viability-based single cell sorting. AB - Chinese hamster ovary (CHO) cell line development (CLD) is a long and laborious process, which requires up to 5 - 6 months in order to generate and bank CHO lines capable of stably expressing therapeutic molecules. Additionally, single cell cloning of these production lines is also necessary to confirm clonality of the production lines. Here we introduce the utilization of viability staining dye in combination with flow cytometer to isolate high titer clones from a pool of selected cells and single cell deposit them into the wells of culture plates. Our data suggests that a stringent selection procedure along with viability dye staining and flow cytometry-based sorting can be used to isolate high expressing clones with titers comparable to that of traditional CLD methods. This approach not only requires less labor and consumables, but it also shortens CLD timelines by at least 3 weeks. Furthermore, single cell deposition of selected cells by a flow sorter can be regarded as an additional clonality assurance factor that in combination with Day 0 imaging can ensure clonality of the production lines. PMID- 26587810 TI - A Mixed Bag: Childhood Obesity and Polio. PMID- 26587809 TI - Exploring Valleys without Climbing Every Peak: More Efficient and Forgiving Metabasin Metadynamics via Robust On-the-Fly Bias Domain Restriction. AB - Metadynamics is an enhanced sampling method designed to flatten free energy surfaces uniformly. However, the highest-energy regions are often irrelevant to study and dangerous to explore because systems often change irreversibly in unforeseen ways in response to driving forces in these regions, spoiling the sampling. Introducing an on-the-fly domain restriction allows metadynamics to flatten only up to a specified energy level and no further, improving efficiency and safety while decreasing the pressure on practitioners to design collective variables that are robust to otherwise irrelevant high energy driving. This paper describes a new method that achieves this using sequential on-the-fly estimation of energy wells and redefinition of the metadynamics hill shape, termed metabasin metadynamics. The energy level may be defined a priori or relative to unknown barrier energies estimated on-the-fly. Altering only the hill ensures that the method is compatible with many other advances in metadynamics methodology. The hill shape has a natural interpretation in terms of multiscale dynamics, and the computational overhead in simulation is minimal when studying systems of any reasonable size, for instance proteins or other macromolecules. Three example applications show that the formula is accurate and robust to complex dynamics, making metadynamics significantly more forgiving with respect to CV quality and thus more feasible to apply to the most challenging biomolecular systems. PMID- 26587811 TI - A 12-Year-Old Boy with Pars Planitis. PMID- 26587812 TI - Treating Teen Depression in Primary Care. AB - I recently had an adolescent patient who presented with a chief complaint of depression. He had classic symptoms of difficulty sleeping, dysthymia, and anhedonia (loss of interest in things that used to bring him joy). He was a very smart and self-aware 17-year-old, and was able to describe his symptoms easily. There were no concerns for manic episodes or psychosis, and he met diagnostic criteria for unipolar major depressive disorder. He denied suicidal ideation, and was already seeing a therapist weekly for the last several months. He had a strong family history of depression, with his father, aunts, and grandmother who also carried a diagnosis of depression. He presented with the support of his mother, asking about next steps, and specifically, pharmacotherapy. This patient is a perfect example of an adolescent who is a good candidate for initiation of antidepressant medication. Primary care pediatricians should feel comfortable with first-line agents for major depressive disorder in certain adolescents with depression, but many feel hesitant and rely on child and adolescent psychiatry colleagues for prescriptions. PMID- 26587813 TI - A 5-Year-Old Girl with Fatigue, Diffuse Edema, and Weakness. PMID- 26587814 TI - A 12-Month-Old Boy with a Soft Mass Over His Left 10th Rib. PMID- 26587815 TI - Early Childhood Exposures and Risk for Adult Disease. PMID- 26587816 TI - Common Neurocutaneous Syndromes. AB - Neurocutaneous syndromes are a diverse group of neurologic disorders with concurrent skin manifestations. Most neurocutaneous syndromes have a genetic basis and are believed to arise from a defect in the differentiation of the primitive ectoderm. In this regard, the skin can be a window into the central nervous system and can aid in the diagnosis of neurologic disease in children. The cutaneous signs may be subtle, which places great importance on the physical examination skills of clinicians providing primary care to children. Early recognition can help with proper diagnosis, formulating a treatment plan, anticipating potential complications, making appropriate referrals, and offering genetic counseling to families. PMID- 26587817 TI - The Perinatal Origins of Cardiovascular Disease. AB - In recent decades, with advances in neonatal intensive care, extremely premature infants are now surviving into adulthood. Epidemiologic data on the health of these ex-premature infants have begun to reveal a concerning motif-that is, prematurity, in and of itself, seems to be a risk factor for cardiovascular and metabolic disease in later adulthood. The mechanisms underlying this increased risk are unclear, but it is believed that both adverse fetal environment and postnatal exposures for a premature infant likely contribute to the developmental programming of disease by altering the normal trajectory of maturation and aging of multiple organ systems. This article specifically focuses on perinatal factors that may affect risk for cardiovascular disease. PMID- 26587818 TI - Neurodevelopmental Implications of Neonatal Pain and Morphine Exposure. AB - Neonatal pain management has evolved dramatically in the past few decades. Evidence is clear that neonates experience pain. Furthermore, we are increasingly aware of the detrimental effects of untreated neonatal pain during a critical period of neuronal maturation. Providing safe and effective pain relief is a primary goal of neonatal critical care specialists to ensure good outcomes. However, there are lingering concerns regarding the harmful effects of sedative analgesics on the developing brain. Thus, striking a fine balance between effective analgesia and avoiding serious short- and long-term adverse effects from pain medications remains a major challenge for caregivers. PMID- 26587819 TI - Early-Life Exposure to Antibiotics, Alterations in the Intestinal Microbiome, and Risk of Metabolic Disease in Children and Adults. AB - The intestinal microbiome is a complex ecosystem of microorganisms that colonize the human gastrointestinal tract. The microbiome evolves rapidly in early life with contributions from diet, genetics and immunomodulatory factors. Changes in composition of the microbiota due to antibiotics may lead to negative long-term effects including obesity and diabetes mellitus, as evidenced by both animal and large human studies. Inappropriate exposures to antibiotics occur frequently in early childhood. Therefore, an evidence-based system of antimicrobial use should be employed by all providers, especially those who care for pediatric patients. This article explores the natural evolution of the intestinal microbiome from the perinatal period into early childhood, the effect of antibiotics on the microbial ecology, and the implications for future health and disease. PMID- 26587820 TI - Childhood Exposures and Risk of Malignancy in Adulthood. AB - Pediatricians have significant roles in preventive health care, and understanding how various exposures during childhood can have long-lasting effects on cancer risk is critical in promoting future health. With the exception of rare genetic syndromes conferring increased cancer susceptibility, most cancers are considered idiopathic and may be influenced by modifiable exposures and risks. This review aims to serve as a brief overview of a subset of known exposures during childhood that have been associated with an increased risk of malignancy in adulthood, including the effects of radiation, chemotherapy, pesticides, nutrition, puberty, and infection. PMID- 26587821 TI - Benzoic acid and its derivatives as naturally occurring compounds in foods and as additives: Uses, exposure, and controversy. AB - Benzoic acid is an aromatic carboxylic acid naturally present in plant and animal tissues, which can also be produced by microorganisms. Benzoic acid and a wide range of derivatives and related benzenic compounds, such as salts, alkyl esters, parabens, benzyl alcohol, benzaldehyde, and benzoyl peroxide, are commonly used as antibacterial and antifungal preservatives and as flavoring agents in food, cosmetic, hygiene, and pharmaceutical products. As a result of their widespread occurrence, production, and uses, these compounds are largely distributed in the environment and found in water, soil, and air. Consequently, human exposure to them can be high, common, and lengthy. This review is mainly focused on the presence and use of benzoic acid in foods but it also covers the occurrence, uses, human exposure, metabolism, toxicology, analytical methods for detection, and legal limits for benzoic acid and its derivatives. Their controversial effects and potential public health concerns are discussed. PMID- 26587822 TI - The AJT Report. PMID- 26587824 TI - Water Safety: MMWR and FDA Reports. PMID- 26587825 TI - Surveillance for Waterborne Disease Outbreaks Associated With Drinking Water - United States, 2011-2012. PMID- 26587826 TI - 52-Year-Old Male With Upper Lobe Predominant Cystic Lung Disease Requiring Bilateral Lung Transplantation. PMID- 26587827 TI - Novel triazolium based 11(th) group NHCs: synthesis, characterization and cellular response mechanisms. AB - The novel NHC ligand precursor 1,4-bis(4-nitrobenzyl)-1H-1,2,4-triazol-4-ium bromide, [HTz((pNO2Bz)2)]Br, has been synthesized and used in the synthesis of the corresponding metal complexes M[Tz((pNO2Bz)2)]Br (M = Cu(I), Ag(I) or Au(I)). These compounds were characterized by several spectroscopic techniques including NMR and mass spectroscopy. The complete series of Au(I), Ag(I) and Cu(I) 1,2,4 triazole based NHC complexes has been synthesized aiming at a SAR study and at identifying the primary cellular targets accounting for their cytotoxic action. The cytotoxic properties of the NHC complexes have been assessed in various human cancer cell lines, including cisplatin sensitive and resistant cells, the most efficacious antiproliferative compound being Cu(I)-NHC, which was able to promote a growth inhibitory effect up to ten times higher than that promoted by cisplatin. A detailed analysis of molecular and cellular pharmacology allowed us to elucidate the role of the metallic core in determining the biological properties. In particular, gold(I) and silver(I) NHC complexes were found to be able to hamper mammalian thioredoxin reductase (TrxR) activity in human A431 cervical cancer cells, ultimately leading to a dramatic alteration of the cellular redox state and to the induction of cell death via apoptosis. Conversely, the copper NHC complex was found to be capable of inhibiting proteasome functionality thus determining the induction of a non-apoptotic cell death pathway. PMID- 26587828 TI - Metabolic reprogramming: a new relevant pathway in adult adrenocortical tumors. AB - Adrenocortical carcinomas (ACCs) are complex neoplasias that may present unexpected clinical behavior, being imperative to identify new biological markers that can predict patient prognosis and provide new therapeutic options. The main aim of the present study was to evaluate the prognostic value of metabolism related key proteins in adrenocortical carcinoma. The immunohistochemical expression of MCT1, MCT2, MCT4, CD147, CD44, GLUT1 and CAIX was evaluated in a series of 154 adult patients with adrenocortical neoplasia and associated with patients' clinicopathological parameters. A significant increase in was found for membranous expression of MCT4, GLUT1 and CAIX in carcinomas, when compared to adenomas. Importantly MCT1, GLUT1 and CAIX expressions were significantly associated with poor prognostic variables, including high nuclear grade, high mitotic index, advanced tumor staging, presence of metastasis, as well as shorter overall and disease free survival. In opposition, MCT2 membranous expression was associated with favorable prognostic parameters. Importantly, cytoplasmic expression of CD147 was identified as an independent predictor of longer overall survival and cytoplasmic expression of CAIX as an independent predictor of longer disease-free survival. We provide evidence for a metabolic reprogramming in adrenocortical malignant tumors towards the hyperglycolytic and acid-resistant phenotype, which was associated with poor prognosis. PMID- 26587829 TI - Infiltrating T cells promote renal cell carcinoma (RCC) progression via altering the estrogen receptor beta-DAB2IP signals. AB - Previous studies indicated the T cells, one of the most common types of immune cells existing in the microenvironment of renal cell carcinoma (RCC), may influence the progression of RCC. The potential linkage of T cells and the estrogen receptor beta (ERbeta), a key player to impact RCC progression, however, remains unclear. Our results demonstrate that RCC cells can recruit more T cells than non-malignant kidney cells. Using an in vitro matrigel invasion system, we found infiltrating T cells could promote RCC cells invasion via increasing ERbeta expression and transcriptional activity. Mechanism dissection suggested that co culturing T cells with RCC cells released more T cell attraction factors, including IFN-gamma, CCL3 and CCL5, suggesting a positive regulatory feed-back mechanism. Meanwhile, infiltrating T cells may also promote RCC cell invasion via increased ERbeta and decreased DAB2IP expressions, and knocking down DAB2IP can then reverse the T cells-promoted RCC cell invasion. Together, our results suggest that infiltrating T cells may promote RCC cell invasion via increasing the RCC cell ERbeta expression to inhibit the tumor suppressor DAB2IP signals. Further mechanism dissection showed that co-culturing T cells with RCC cells could produce more IGF-1 and FGF-7, which may enhance the ERbeta transcriptional activity. The newly identified relationship between infiltrating T cells/ERbeta/DAB2IP signals may provide a novel therapeutic target in the development of agents against RCC. PMID- 26587831 TI - Synthesis of Nanoparticulate Alloys of the Composition Cu2Zn(1-x)Fe(x)SnS4: Structural, Optical, and Magnetic Properties. AB - Nanoparticles of the semiconductor Cu2Zn(1-x)Fe(x)SnS4 with different mole fractions of iron (x(Fe)) were synthesized by the decomposition of molecular precursors in oleylamine. The composition, structure, optical, and magnetic properties of the nanoparticles are reported. The parent (Cu2ZnSnS4) zinc material is usually reported as kesteritic and the corresponding iron phase as stannitic; with different site occupancies and tetragonalities. In the small ca. 8-10 nm particles prepared, the smooth variation in lattice parameters and other measured properties suggest that the phase change, with composition, may be absent. SQUID magnetometry suggests that the iron containing samples are ferromagnetic at 5 K and paramagnetic at 300 K. PMID- 26587830 TI - Tumor invasion and metastasis regulated by microRNA-184 and microRNA-574-5p in small-cell lung cancer. AB - Small-cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor that has an extremely poor clinical prognosis. Metastasis is the key event in SCLC progression, but its mechanism has not been fully elucidated. MicroRNAs (miRNAs) have been proven to participate in cancer processes, but their function in SCLC has not been thoroughly studied either. Here, we performed microarray and quantitative real-time PCR (qRT-PCR) analyses to identify the miRNAs associated with metastasis and prognosis in SCLC as well as the correlation between serum and tissue. We also explored these miRNAs' promising molecular mechanisms by 3'UTR reporter assay and immunoblotting. We showed that miR-184 significantly attenuated the metastasis of SCLC, whereas miR-574-5p enhanced it. Both miRNAs were found to participate in beta-catenin signaling by suppressing protein tyrosine phosphatase receptor type U (PTPRU) or endothelial PAS domain protein 1 (EPAS1). Furthermore, miR-574-5p was verified as an independent prognostic risk factor for SCLC. Taken together, our findings provide a comprehensive analysis of the miRNA expression pattern in SCLC and indicate that miRNAs may serve as potential therapeutic and prognostic predictors in SCLC. PMID- 26587832 TI - Pooled Sequencing of Candidate Genes Implicates Rare Variants in the Development of Asthma Following Severe RSV Bronchiolitis in Infancy. AB - Severe infection with respiratory syncytial virus (RSV) during infancy is strongly associated with the development of asthma. To identify genetic variation that contributes to asthma following severe RSV bronchiolitis during infancy, we sequenced the coding exons of 131 asthma candidate genes in 182 European and African American children with severe RSV bronchiolitis in infancy using anonymous pools for variant discovery, and then directly genotyped a set of 190 nonsynonymous variants. Association testing was performed for physician-diagnosed asthma before the 7th birthday (asthma) using genotypes from 6,500 individuals from the Exome Sequencing Project (ESP) as controls to gain statistical power. In addition, among patients with severe RSV bronchiolitis during infancy, we examined genetic associations with asthma, active asthma, persistent wheeze, and bronchial hyperreactivity (methacholine PC20) at age 6 years. We identified four rare nonsynonymous variants that were significantly associated with asthma following severe RSV bronchiolitis, including single variants in ADRB2, FLG and NCAM1 in European Americans (p = 4.6x10-4, 1.9x10-13 and 5.0x10-5, respectively), and NOS1 in African Americans (p = 2.3x10-11). One of the variants was a highly functional nonsynonymous variant in ADRB2 (rs1800888), which was also nominally associated with asthma (p = 0.027) and active asthma (p = 0.013) among European Americans with severe RSV bronchiolitis without including the ESP. Our results suggest that rare nonsynonymous variants contribute to the development of asthma following severe RSV bronchiolitis in infancy, notably in ADRB2. Additional studies are required to explore the role of rare variants in the etiology of asthma and asthma-related traits following severe RSV bronchiolitis. PMID- 26587835 TI - Synthesis, Structure, and Complexation Properties of a C3-Symmetrical Triptycene Based Anion Receptor: Selectivity for Dihydrogen Phosphate. AB - A new anion binding motif based on triptycene core has been synthesized from 2,7,14-trinitrotriptycene. Its well-defined binding pocket allowed for the selective recognition and sensing of dihydrogen phosphate in DMSO-d(6) + 0.5% H(2)O. PMID- 26587834 TI - Developing Fast Fluorescent Protein Voltage Sensors by Optimizing FRET Interactions. AB - FRET (Forster Resonance Energy Transfer)-based protein voltage sensors can be useful for monitoring neuronal activity in vivo because the ratio of signals between the donor and acceptor pair reduces common sources of noise such as heart beat artifacts. We improved the performance of FRET based genetically encoded Fluorescent Protein (FP) voltage sensors by optimizing the location of donor and acceptor FPs flanking the voltage sensitive domain of the Ciona intestinalis voltage sensitive phosphatase. First, we created 39 different "Nabi1" constructs by positioning the donor FP, UKG, at 8 different locations downstream of the voltage-sensing domain and the acceptor FP, mKO, at 6 positions upstream. Several of these combinations resulted in large voltage dependent signals and relatively fast kinetics. Nabi1 probes responded with signal size up to 11% DeltaF/F for a 100 mV depolarization and fast response time constants both for signal activation (~2 ms) and signal decay (~3 ms). We improved expression in neuronal cells by replacing the mKO and UKG FRET pair with Clover (donor FP) and mRuby2 (acceptor FP) to create Nabi2 probes. Nabi2 probes also had large signals and relatively fast time constants in HEK293 cells. In primary neuronal culture, a Nabi2 probe was able to differentiate individual action potentials at 45 Hz. PMID- 26587833 TI - Competition between Heterochromatic Loci Allows the Abundance of the Silencing Protein, Sir4, to Regulate de novo Assembly of Heterochromatin. AB - Changes in the locations and boundaries of heterochromatin are critical during development, and de novo assembly of silent chromatin in budding yeast is a well studied model for how new sites of heterochromatin assemble. De novo assembly cannot occur in the G1 phase of the cell cycle and one to two divisions are needed for complete silent chromatin assembly and transcriptional repression. Mutation of DOT1, the histone H3 lysine 79 (K79) methyltransferase, and SET1, the histone H3 lysine 4 (K4) methyltransferase, speed de novo assembly. These observations have led to the model that regulated demethylation of histones may be a mechanism for how cells control the establishment of heterochromatin. We find that the abundance of Sir4, a protein required for the assembly of silent chromatin, decreases dramatically during a G1 arrest and therefore tested if changing the levels of Sir4 would also alter the speed of de novo establishment. Halving the level of Sir4 slows heterochromatin establishment, while increasing Sir4 speeds establishment. yku70Delta and ubp10Delta cells also speed de novo assembly, and like dot1Delta cells have defects in subtelomeric silencing, suggesting that these mutants may indirectly speed de novo establishment by liberating Sir4 from telomeres. Deleting RIF1 and RIF2, which suppresses the subtelomeric silencing defects in these mutants, rescues the advanced de novo establishment in yku70Delta and ubp10Delta cells, but not in dot1Delta cells, suggesting that YKU70 and UBP10 regulate Sir4 availability by modulating subtelomeric silencing, while DOT1 functions directly to regulate establishment. Our data support a model whereby the demethylation of histone H3 K79 and changes in Sir4 abundance and availability define two rate-limiting steps that regulate de novo assembly of heterochromatin. PMID- 26587837 TI - Comparative Susceptibility of Sheep of Different Origins, Breeds and PRNP Genotypes to Challenge with Bovine Spongiform Encephalopathy and Scrapie. AB - Sheep are natural hosts of the prion disease, scrapie. They are also susceptible to experimental challenge with various scrapie strains and with bovine spongiform encephalopathy (BSE), which affects cattle and has been accidentally transmitted to a range of other species, including man. Incidence and incubation period of clinical disease in sheep following inoculation is controlled by the PRNP gene, which has different alleles defined on the basis of polymorphisms, particularly at codons 136, 154 and 171, although other codons are associated with survival time, and the exact responses of the sheep may be influenced by other breed related differences. Here we report the results of a long term single study of experimental scrapie and BSE susceptibility of sheep of Cheviot, Poll Dorset and Suffolk breeds, originating from New Zealand and of a wide range of susceptible and resistant PRNP genotypes. Responses were compared with those of sheep from a closed Cheviot flock of UK origin (Roslin Cheviot flock). The unusually long observation period (6-8 years for most, but up to 12 years for others) allows us to draw robust conclusions about rates of survival of animals previously regarded as resistant to infection, particularly PRNP heterozygotes, and is the most comprehensive such study reported to date. BSE inoculation by an intracerebral route produced disease in all genotype groups with differing incubation periods, although M112T and L141F polymorphisms seemed to give some protection. Scrapie isolate SSBP/1, which has the shortest incubation period in sheep with at least one VRQ PRNP allele, also produced disease following sub-cutaneous inoculation in ARQ/ARQ animals of New Zealand origin, but ARQ/ARQ sheep from the Roslin flock survived the challenge. Our results demonstrate that the links between PRNP genotype and clinical prion disease in sheep are much less secure than previously thought, and may break down when, for example, a different breed of sheep is moved into a new flock. PMID- 26587836 TI - Hsp70 Isoforms Are Essential for the Formation of Kaposi's Sarcoma-Associated Herpesvirus Replication and Transcription Compartments. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic herpesvirus associated with various AIDS-related malignancies. Like other herpesviruses, multiple processes required for KSHV lytic replication, including viral transcription, viral DNA synthesis and capsid assembly occur in virus-induced intranuclear structures, termed replication and transcription compartments (RTCs). Here we utilised a novel methodology, combining subcellular fractionation and quantitative proteomics, to identify cellular proteins which are recruited to KSHV-induced RTCs and thus play a key role in KSHV lytic replication. We show that several isoforms of the HSP70 chaperone family, Hsc70 and iHsp70, are redistributed from the cytoplasm into the nucleus coinciding with the initial formation of KSHV-induced RTCs. We demonstrate that nuclear chaperone foci are dynamic, initially forming adjacent to newly formed KSHV RTCs, however during later time points the chaperones move within KSHV RTCs and completely co-localise with actively replicating viral DNA. The functional significance of Hsp70 isoforms recruitment into KSHV RTCs was also examined using the specific Hsp70 isoform small molecule inhibitor, VER-155008. Intriguingly, results highlight an essential role of Hsp70 isoforms in the KSHV replication cycle independent of protein stability and maturation. Notably, inhibition of Hsp70 isoforms precluded KSHV RTC formation and RNA polymerase II (RNAPII) relocalisation to the viral genome leading to the abolishment of global KSHV transcription and subsequent viral protein synthesis and DNA replication. These new findings have revealed novel mechanisms that regulate KSHV lytic replication and highlight the potential of HSP70 inhibitors as novel antiviral agents. PMID- 26587838 TI - Annotation of Differential Gene Expression in Small Yellow Follicles of a Broiler Type Strain of Taiwan Country Chickens in Response to Acute Heat Stress. AB - This study investigated global gene expression in the small yellow follicles (6-8 mm diameter) of broiler-type B strain Taiwan country chickens (TCCs) in response to acute heat stress. Twelve 30-wk-old TCC hens were divided into four groups: control hens maintained at 25 degrees C and hens subjected to 38 degrees C acute heat stress for 2 h without recovery (H2R0), with 2-h recovery (H2R2), and with 6 h recovery (H2R6). Small yellow follicles were collected for RNA isolation and microarray analysis at the end of each time point. Results showed that 69, 51, and 76 genes were upregulated and 58, 15, 56 genes were downregulated after heat treatment of H2R0, H2R2, and H2R6, respectively, using a cutoff value of two-fold or higher. Gene ontology analysis revealed that these differentially expressed genes are associated with the biological processes of cell communication, developmental process, protein metabolic process, immune system process, and response to stimuli. Upregulation of heat shock protein 25, interleukin 6, metallopeptidase 1, and metalloproteinase 13, and downregulation of type II alpha 1 collagen, discoidin domain receptor tyrosine kinase 2, and Kruppel-like factor 2 suggested that acute heat stress induces proteolytic disintegration of the structural matrix and inflamed damage and adaptive responses of gene expression in the follicle cells. These suggestions were validated through gene expression, using quantitative real-time polymerase chain reaction. Functional annotation clarified that interleukin 6-related pathways play a critical role in regulating acute heat stress responses in the small yellow follicles of TCC hens. PMID- 26587839 TI - Modeling and Validation of Environmental Suitability for Schistosomiasis Transmission Using Remote Sensing. AB - BACKGROUND: Schistosomiasis is the most widespread water-based disease in sub Saharan Africa. Transmission is governed by the spatial distribution of specific freshwater snails that act as intermediate hosts and human water contact patterns. Remote sensing data have been utilized for spatially explicit risk profiling of schistosomiasis. We investigated the potential of remote sensing to characterize habitat conditions of parasite and intermediate host snails and discuss the relevance for public health. METHODOLOGY: We employed high-resolution remote sensing data, environmental field measurements, and ecological data to model environmental suitability for schistosomiasis-related parasite and snail species. The model was developed for Burkina Faso using a habitat suitability index (HSI). The plausibility of remote sensing habitat variables was validated using field measurements. The established model was transferred to different ecological settings in Cote d'Ivoire and validated against readily available survey data from school-aged children. PRINCIPAL FINDINGS: Environmental suitability for schistosomiasis transmission was spatially delineated and quantified by seven habitat variables derived from remote sensing data. The strengths and weaknesses highlighted by the plausibility analysis showed that temporal dynamic water and vegetation measures were particularly useful to model parasite and snail habitat suitability, whereas the measurement of water surface temperature and topographic variables did not perform appropriately. The transferability of the model showed significant relations between the HSI and infection prevalence in study sites of Cote d'Ivoire. CONCLUSIONS/SIGNIFICANCE: A predictive map of environmental suitability for schistosomiasis transmission can support measures to gain and sustain control. This is particularly relevant as emphasis is shifting from morbidity control to interrupting transmission. Further validation of our mechanistic model needs to be complemented by field data of parasite- and snail-related fitness. Our model provides a useful tool to monitor the development of new hotspots of potential schistosomiasis transmission based on regularly updated remote sensing data. PMID- 26587840 TI - Multilocus Sequence Typing and Virulence Profiles in Uropathogenic Escherichia coli Isolated from Cats in the United States. AB - The population structure, virulence, and antimicrobial resistance of uropathogenic E. coli (UPEC) from cats are rarely characterized. The aim of this study was to compare and characterize the UPEC isolated from cats in four geographic regions of USA in terms of their multilocus sequence typing (MLST), virulence profiles, clinical signs, antimicrobial resistance and phylogenetic grouping. The results showed that a total of 74 E. coli isolates were typed to 40 sequence types with 10 being novel. The most frequent phylogenetic group was B2 (n = 57). The most frequent sequence types were ST73 (n = 12) and ST83 (n = 6), ST73 was represented by four multidrug resistant (MDR) and eight non-multidrug resistant (SDR) isolates, and ST83 were significantly more likely to exhibit no drug resistant (NDR) isolates carrying the highest number of virulence genes. Additionally, MDR isolates were more diverse, and followed by SDR and NDR isolates in regards to the distribution of the STs. afa/draBC was the most prevalent among the 29 virulence-associated genes. Linking virulence profile and antimicrobial resistance, the majority of virulence-associated genes tested were more prevalent in NDR isolates, and followed by SDR and MDR isolates. Twenty (50%) MLST types in this study have previously been associated with human isolates, suggesting that these STs are potentially zoonotic. Our data enhanced the understanding of E. coli population structure and virulence association from cats. The diverse and various combinations of virulence-associated genes implied that the infection control may be challenging. PMID- 26587841 TI - Candidate Gene Analysis of Mortality in Dialysis Patients. AB - BACKGROUND: Dialysis patients have high cardiovascular mortality risk. This study aimed to investigate the association between SNPs of genes involved in vascular processes and mortality in dialysis patients. METHODS: Forty two SNPs in 25 genes involved in endothelial function, vascular remodeling, cell proliferation, inflammation, coagulation and calcium/phosphate metabolism were genotyped in 1330 incident dialysis patients. The effect of SNPs on 5-years cardiovascular and non cardiovascular mortality was investigated. RESULTS: The mortality rate was 114/1000 person-years and 49.4% of total mortality was cardiovascular. After correction for multiple testing, VEGF rs699947 was associated with all-cause mortality (HR1.48, 95% CI 1.14-1.92). The other SNPs were not associated with mortality. CONCLUSIONS: This study provides further evidence that a SNP in the VEGF gene may contribute to the comorbid conditions of dialysis patients. Future studies should unravel the underlying mechanisms responsible for the increase in mortality in these patients. PMID- 26587842 TI - Investigating the Role of the Host Multidrug Resistance Associated Protein Transporter Family in Burkholderia cepacia Complex Pathogenicity Using a Caenorhabditis elegans Infection Model. AB - This study investigated the relationship between host efflux system of the non vertebrate nematode Caenorhabditis elegans and Burkholderia cepacia complex (Bcc) strain virulence. This is the first comprehensive effort to profile host transporters within the context of Bcc infection. With this aim, two different toxicity tests were performed: a slow killing assay that monitors mortality of the host by intestinal colonization and a fast killing assay that assesses production of toxins. A Virulence Ranking scheme was defined, that expressed the toxicity of the Bcc panel members, based on the percentage of surviving worms. According to this ranking the 18 Bcc strains were divided in 4 distinct groups. Only the Cystic Fibrosis isolated strains possessed profound nematode killing ability to accumulate in worms' intestines. For the transporter analysis a complete set of isogenic nematode single Multidrug Resistance associated Protein (MRP) efflux mutants and a number of efflux inhibitors were interrogated in the host toxicity assays. The Bcc pathogenicity profile of the 7 isogenic C. elegans MRP knock-out strains functionality was classified in two distinct groups. Disabling host transporters enhanced nematode mortality more than 50% in 5 out of 7 mutants when compared to wild type. In particular mrp-2 was the most susceptible phenotype with increased mortality for 13 out 18 Bcc strains, whereas mrp-3 and mrp-4 knock-outs had lower mortality rates, suggesting a different role in toxin-substrate recognition. The use of MRP efflux inhibitors in the assays resulted in substantially increased (>40% on average) mortality of wild-type worms. PMID- 26587843 TI - Maximizing Performance: Augmented Feedback, Focus of Attention, and/or Reward? AB - PURPOSE: Different approaches like providing augmented feedback (aF), applying an external focus of attention (EF), or rewarding participants with money (RE) have been shown to instantly enhance motor performance. So far, these approaches have been tested either in separate studies or directly against each other. However, there is no study that combined aF, EF, and/or RE to test whether this provokes additional benefits. The aim of the present study was therefore to identify the most powerful combination. METHODS: Eighteen participants performed maximal countermovement jumps in six different conditions: neutral (NE), aF, RE, aF + EF, aF + RE, and aF + EF + RE. RESULTS: Participants demonstrated the highest jump heights with aF + EF, followed by aF + EF + RE, aF + RE, aF, RE, and finally, NE. Activity of the M. rectus femoris differed significantly between conditions resulting in lower muscular activity in aF + EF and aF + EF + RE compared with NE. All other parameters, such as ground reaction forces and joint angles, were comparable across conditions. CONCLUSIONS: This is the first study showing superior performance when combining aF with EF. As reduced muscular activity was found only in conditions with EF, it is argued in line with the constrained action hypothesis that adopting an EF improves movement efficiency. In contrast, aF seems to rather enhance (intrinsic) motivation. However, monetary reward did not further amplify performance. PMID- 26587845 TI - Oxidative Stress and Fitness Changes in Cancer Patients after Exercise Training. AB - INTRODUCTION: The purpose of this study was to determine the effect of an exercise intervention (EX) on muscular strength, cardiorespiratory fitness (CRF), and oxidative stress in cancer survivors compared with a nonexercising cancer control group (CON). METHODS: Fifteen cancer patients and seven age-matched individuals with no history of cancer (NC) participated in this study. A blood draw and assessments of muscular strength and CRF were administered to cancer survivors within 6 wk of completing radiation or chemotherapy, and again 10 wk later. Eight cancer patients completed a 10-wk supervised exercise intervention, whereas seven continued standard care. Baseline oxidative stress was compared between cancer patients and the NC group. Changes in plasma protein carbonyls, 8 OHdG, and Trolox equivalent antioxidant capacity were compared between groups using repeated-measures ANOVA, and correlations between fitness and oxidative stress changes were evaluated. RESULTS: Baseline antioxidant capacity was significantly lower, and plasma protein carbonyls were significantly higher in cancer patients compared with NC (P = 0.001). EX had a significant increase in antioxidant capacity (P < 0.001) and decrease in protein carbonyls (P = 0.023), whereas CON did not. Improvements in composite arm (41%, P = 0.002) and leg strength (34%, P = 0.008), isometric handgrip strength (11%, P = 0.015), and VO2peak (16%, P = 0.018) were significant in EX but not in CON. 8-OHdG changes were significantly correlated with changes in VO2peak (r = -0.89, P < 0.001), arm strength (r = -0.67, P = 0.004), and leg strength (r = -0.56, P = 0.019). CONCLUSION: A whole-body exercise intervention for cancer survivors may be an effective method of concurrently increasing muscular strength, CRF, and antioxidant capacity while decreasing markers of oxidative stress. PMID- 26587844 TI - Older Runners Retain Youthful Running Economy despite Biomechanical Differences. AB - PURPOSE: Sixty-five years of age typically marks the onset of impaired walking economy. However, running economy has not been assessed beyond the age of 65 yr. Furthermore, a critical determinant of running economy is the spring-like storage and return of elastic energy from the leg during stance, which is related to leg stiffness. Therefore, we investigated whether runners older than 65 yr retain youthful running economy and/or leg stiffness across running speeds. METHODS: Fifteen young and 15 older runners ran on a force-instrumented treadmill at 2.01, 2.46, and 2.91 m.s(-1). We measured their rates of metabolic energy consumption (i.e., metabolic power), ground reaction forces, and stride kinematics. RESULTS: There were only small differences in running economy between young and older runners across the range of speeds. Statistically, the older runners consumed 2% to 9% less metabolic energy than the young runners across speeds (P = 0.012). Also, the leg stiffness of older runners was 10% to 20% lower than that of young runners across the range of speeds (P = 0.002), and in contrast to the younger runners, the leg stiffness of older runners decreased with speed (P < 0.001). CONCLUSIONS: Runners beyond 65 yr of age maintain youthful running economy despite biomechanical differences. It may be that vigorous exercise, such as running, prevents the age related deterioration of muscular efficiency and, therefore, may make everyday activities easier. PMID- 26587846 TI - Cardiorespiratory Fitness, Sedentary Time, and Cardiovascular Risk Factor Clustering. AB - PURPOSE: Prolonged sedentary time (ST) is associated with cardiovascular risk factors (CV-RF) independent of physical activity (PA). Whether a high level of cardiorespiratory fitness (CRF) can modify the deleterious health consequences related to high ST is not known. METHODS: We performed a cross-sectional study of 12,274 men and 14,209 women (>=20 yr) without known cardiovascular disease. Self reported ST measurements during a regular day were divided into three sex specific equally sized groups (<=4, 5 to <7, and >=7 h.d(-1)). CRF was estimated (eCRF) using a previously validated nonexercise model. Using logistic regression analyses, adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated for the association of ST with CV-RF clustering and for the potential modifying effect of eCRF. RESULTS: Each hour increase in ST was associated with 5% and 4% greater likelihood of having CV-RF clustering independent of PA in men and women, respectively. Among the participants with higher levels of eCRF, the adjusted OR values associated with >=7 h.d(-1) of ST were 0.92 (0.56-1.51) for men and 1.16 (0.49-2.74) for women, compared with men and women with low ST (<=4 h.d(-1)) and high eCRF levels. In combined analyses of eCRF, PA, and ST, compared with the reference group of participants meeting the recommendations, <=4 h.d(-1) of ST and high eCRF, the OR values were 0.63 (0.27-1.44) and 0.65 (0.14-3.07) in fit men and women with >=7 h.d(-1) of ST, which did not meet the recommendations. Men and women meeting the PA recommendations, but were unfit, had significantly increased odds of having CV-RF clustering across levels of ST. CONCLUSION: High levels of eCRF abolished the increased odds of having CV-RF clustering associated with high ST, even among those individuals who did not meet the current PA recommendations. PMID- 26587847 TI - Resistance Exercise Impacts Lean Muscle Mass in Women with Polycystic Ovary Syndrome. AB - PURPOSE: This study investigated the effects of progressive resistance training (PRT) on lean muscle mass (LMM) in women with or without polycystic ovary syndrome (PCOS) and its effects on metabolic factors and concentrations of related steroid hormones. DESIGN: This was a nonrandomized, therapeutic, open, single-arm study. PARTICIPANTS: All in all, 45 sedentary women with PCOS and 52 without (non-PCOS), 18-37 yr of age, with body mass indexes (BMI) of 18-39.9 kg.m(-2) of all races and social status, performed PRT three times a week for 4 months. Before and after PRT, the concentrations of hormones and metabolic factors and waist circumference were measured. LMM and total body fat percentage were determined using dual-energy x-ray absorptiometry. Clinical characteristics, LMM, and fasting glucose were adjusted for confounding covariables and compared using general linear mixed models. Each patient's menstrual history was taken before study enrollment and after PRT. RESULTS: PRT resulted in reduced plasma testosterone and fasting glucose levels. After PRT, the androstenedione concentration increased and the sex hormone-binding globulin concentration decreased in women with PCOS. The waist circumference was reduced (P < 0.01) and the muscle mass index, lean mass (LM)/height2, increased in women with PCOS (P = 0.04). Women with PCOS showed increased muscle mass indexes of appendicular LM/height2 (P = 0.03) and LM/height2 (P < 0.01) compared with the baseline. Total LM and trunk LM were elevated in women with PCOS (P = 0.01) at the baseline and after PRT. CONCLUSION: To our knowledge, this is the first report to show that resistance exercise alone can improve hyperandrogenism, reproductive function, and body composition by decreasing visceral fat and increasing LMM, but it has no metabolic impact on women with PCOS. PMID- 26587848 TI - Dynamic Proteomic Characteristics and Network Integration Revealing Key Proteins for Two Kernel Tissue Developments in Popcorn. AB - The formation and development of maize kernel is a complex dynamic physiological and biochemical process that involves the temporal and spatial expression of many proteins and the regulation of metabolic pathways. In this study, the protein profiles of the endosperm and pericarp at three important developmental stages were analyzed by isobaric tags for relative and absolute quantification (iTRAQ) labeling coupled with LC-MS/MS in popcorn inbred N04. Comparative quantitative proteomic analyses among developmental stages and between tissues were performed, and the protein networks were integrated. A total of 6,876 proteins were identified, of which 1,396 were nonredundant. Specific proteins and different expression patterns were observed across developmental stages and tissues. The functional annotation of the identified proteins revealed the importance of metabolic and cellular processes, and binding and catalytic activities for the development of the tissues. The whole, endosperm-specific and pericarp-specific protein networks integrated 125, 9 and 77 proteins, respectively, which were involved in 54 KEGG pathways and reflected their complex metabolic interactions. Confirmation for the iTRAQ endosperm proteins by two-dimensional gel electrophoresis showed that 44.44% proteins were commonly found. However, the concordance between mRNA level and the protein abundance varied across different proteins, stages, tissues and inbred lines, according to the gene cloning and expression analyses of four relevant proteins with important functions and different expression levels. But the result by western blot showed their same expression tendency for the four proteins as by iTRAQ. These results could provide new insights into the developmental mechanisms of endosperm and pericarp, and grain formation in maize. PMID- 26587849 TI - Quantitative Assessment of the Portal Pressure for the Liver Surgery Using Serological Tests. AB - OBJECTIVE: To establish a reliable equation to predict hepatic venous pressure gradient (HVPG) using serological tests for surgical patients with hepatocellular carcinoma (HCC). BACKGROUND: Accurate assessment of portal pressure for surgical patients with HCC is important for safe hepatic resection (HR). The HVPG is regarded as the most reliable method to detect portal hypertension. However, HVPG is not utilized in many medical centers due to invasiveness of procedure. METHODS: Between 2006 and 2008, 171 patients (Correlation cohort), who underwent liver surgery in a tertiary hospital, were enrolled. Preoperative measurements of the HVPG and serological tests were performed simultaneously. Correlation between the HVPG and serological tests were analyzed to establish an equation for calculated HVPG (cHVPG). Between 2008 and 2013, 510 surgical patients (Application cohort) were evaluated, and HR recommended when cHVPG < 10 mm Hg. The outcomes of HR were analyzed to evaluate reliability of the cHVPG for HR. RESULTS: In the correlation cohort, the equation for cHVPG was established using multivariate linear regression analysis; cHVPG (mm Hg) = 0.209 * [ICG-R15 (%)] - 1.646 * [albumin (g/dL)] - 0.01*[platelet count (10)] + 1.669 * [PT-INR] + 8.911. In the application cohort, 425 patients with cHVPG < 10 mm Hg underwent HR. Among them, 357 had favorable value of ICG-R15 < 20% (group A), and 68 had unfavorable value of ICG-R15 >= 20% (group B). There was no significant difference in patient demographics, tumor characteristics, operative outcome, and survival rates between group A and B. CONCLUSIONS: The equation for cHVPG of this study was established on statistical reliability. The cHVPG could be useful to predict portal pressure quantitatively for surgical patients with HCC using serological tests. PMID- 26587850 TI - Impact of Expanded Insurance Coverage on Racial Disparities in Vascular Disease: Insights From Massachusetts. AB - OBJECTIVE: To evaluate the impact of health insurance expansion on racial disparities in severity of peripheral arterial disease. BACKGROUND: Lack of insurance and non-white race are associated with increased severity, increased amputation rates, and decreased revascularization rates in patients with peripheral artery disease (PAD). Little is known about how expanded insurance coverage affects disparities in presentation with and management of PAD. The 2006 Massachusetts health reform expanded coverage to 98% of residents and provided the framework for the Affordable Care Act. METHODS: We conducted a retrospective cohort study of nonelderly, white and non-white patients admitted with PAD in Massachusetts (MA) and 4 control states. Risk-adjusted difference-in-differences models were used to evaluate changes in probability of presenting with severe disease. Multivariable linear regression models were used to evaluate disparities in disease severity before and after the 2006 health insurance expansion. RESULTS: Before the 2006 MA insurance expansion, non-white patients in both MA and control states had a 12 to 13 percentage-point higher probability of presenting with severe disease (P < 0.001) than white patients. After the expansion, measured disparities in disease severity by patient race were no longer statistically significant in Massachusetts (+3.0 percentage-point difference, P = 0.385) whereas disparities persisted in control states (+10.0 percentage-point difference, P < 0.001). Overall, non-white patients in MA had an 11.2 percentage-point decreased probability of severe PAD (P = 0.042) relative to concurrent trends in control states. CONCLUSIONS: The 2006 Massachusetts insurance expansion was associated with a decreased probability of patients presenting with severe PAD and resolution of measured racial disparities in severe PAD in MA. PMID- 26587851 TI - Does Anastomotic Leak Contribute to High Failure-to-rescue Rates? AB - OBJECTIVE: Our aim was to evaluate failure-to-rescue (FTR) after anastomotic leak (AL) in colectomy patients. BACKGROUND: In the era of pay for performance, it is imperative that we understand the quality measures under which we are scrutinized. FTR has been proposed as a marker of surgical quality. We investigated the role of complications in FTR rates in colectomy patients. METHODS: Patients who underwent nonemergent colectomy from 2012 to 2013 were identified from the The American College of Surgeons National Quality Improvement Program (ACS NSQIP database). Mortality after AL was assessed and stratified in relation to mortality after other postoperative complications. chi and logistic regression analysis were used to assess the effect of AL on mortality. RESULTS: We identified 30,101 patients who met inclusion criteria, 1127 suffered an AL (3.7%). FTR was increased in patients with AL compared with those without AL (6% vs 1%, P < 0.001). The mortality rate after leak was similar to mortality after other major complications. Independent risk factors for death after AL included older age (odds ratio [OR] 3.140; 95% confidence interval [CI], 1.744-5.651), cancer diagnosis (OR 2.032; 95% CI, 1.177-3.507), and open approach (OR 2.124; 95% CI, 1.194-3.776) while preoperative bowel preparation was protective (OR 0.563; 95% CI, 0.328-0.969). CONCLUSIONS: AL is a common complication after colectomy with a relatively high FTR rate. As hospitals are penalized for not reaching specific rates of FTR, we must better understand these complex relationships to improve quality and safety of patient care. PMID- 26587852 TI - Adherence to Anti-Tumor Necrosis Factor Therapy Administered Subcutaneously and Associated Factors in Patients With Rheumatoid Arthritis. AB - BACKGROUND: Adherence to biologic therapy is relatively poorly studied in rheumatoid arthritis (RA) because many of the studies have investigated the drug persistence, which represents only a surrogate of adherence. OBJECTIVES: The aims of this study were to determine the extent of adherence in RA patients with subcutaneously administered anti-tumor necrosis factor methotrexate agents and to identify the risk factors for nonadherence. METHODS: A cohort of RA patients who started a subcutaneous anti-tumor necrosis factor treatment were enrolled. After 12 months of treatment, all patients completed the 4-item Morisky Medication Adherence Scale questionnaire. Associations between beliefs and nonadherence and the influence of demographic, clinical, and radiographic features were assessed using logistic regression model. RESULTS: A total of 209 (80.4%) of the 260 patients were included in the analyses. Forty-three of 209 patients were considered nonadherent to their medication (20.6%) according to the 4-item Morisky Medication Adherence Scale. More than half (53.1%) of patients showed at least 1 form of nonadherent behavior.The logistic model showed that low disease activity (P = 0.003), higher patient-physician discordance ratings (P = 0.012), older age (P = 0.041), and a high number of comorbid conditions (P = 0.011) were significantly associated with increased likelihood of nonadherence. CONCLUSIONS: The overall nonadherence with subcutaneous biologic therapy is relatively high among RA patients and should be taken into account when a patient's response to treatment is unsatisfactory. PMID- 26587853 TI - IgG4-Related Disease: Treatment and Insight Into Pathophysiology: Video of the Lecture by John Stone MD, MPH. PMID- 26587854 TI - New Ultrasound Modalities in Rheumatology. AB - Over the years, ultrasound (US) has accumulated important evidence supporting its relevant role for the assessment of inflammatory processes of different rheumatologic diseases, as well as in the follow-up in assessing the response to different therapeutic approaches. This has been possible because of the increase in training, competency, and knowledge, as well as the rapid progress in the US technologies.Currently, some US machines can be equipped by sophisticated software modalities (i.e., 3-dimensional US, elastosonography, automated cardiovascular software, and fusion imaging) that can augment US traditional role as a safe, fast, and easy-to-perform modality and giving it new life and increased relevance in rheumatology. In this article, we evaluated the US developments, from conventional B-mode to more sophisticated technologies, and their potential clinical impact in the field of rheumatology.Three-dimensional US can improve the accuracy of the assessment of bone erosions and the quantification of power Doppler because of its multiplanar view including coronal, axial and sagital view. Elastosonography is still looking for its role in rheumatology. Preliminary works induce us to consider it as a promise tool for the assessment of tendon pathology and skin of patients with connective tissue disorders. The automated method for the measurement of carotid intima-media thickness permits a rapid and accurate assessment. The preliminary published data showed that it is reliable, and valid compared to the traditional method; they also support the future of rheumatologists as the direct operators in evaluating the cardiovascular risk in daily practice. Fusion imaging increases the diagnostic power of US, displaying simultaneously in the monitor, the US image, and the corresponding computed tomography/magnetic resonance imaging image. However, there are no sufficient data supporting its application in daily rheumatologic practice. PMID- 26587855 TI - Recurrent Fever, Anemia, Arthralgia, and Genu Varum as Late Manifestations of Congenital Syphilis. AB - We report an unusual case of recurrent fever, inflammatory knee pain, genu varum, persistent anemia, and high erythrocyte sedimentation rate in a 28-month-old boy as late manifestations of congenital syphilis (CS). Despite standard penicillin treatment at the end of the first month of life, it recurred later in life, more than once. In the first relapse, manifested by a likely gumma lesion, the prior penicillin treatment plus a negative venereal disease research laboratory result unduly led to exclusion of CS. A second treatment with penicillin led to complete clinical resolution. Although rare, bow legs, recurrent fever, anemia, and inflammatory arthralgias may be manifestations of late CS. Congenital syphilis should be considered throughout early childhood, especially if history of syphilis infection is present. A negative venereal disease research laboratory result does not exclude late syphilis, present in nearly 30% of these patients. The possibility of atypical symptoms of this "great masquerader" should always be borne in mind. PMID- 26587856 TI - Characteristic Splenic Calcifications in Systemic Lupus Erythematosus. PMID- 26587858 TI - First Diagnosis of Systemic Lupus Erythematosus in a Patient on Hemodialysis for Hereditary Polycystic Renal Disease. PMID- 26587859 TI - Successful Treatment of Intermittent Hydrarthrosis With Hydroxychloroquine. PMID- 26587860 TI - Primary Deforming and Reversible Arthropathy: A Variant of Jaccoud Arthropathy? PMID- 26587861 TI - A Patient With Rheumatoid Arthritis on Methotrexate and Etanercept Who Developed Pasteurella multocida Bacteremia. PMID- 26587862 TI - Severe Disability in a Patient With Rheumatoid Arthritis and Sickle Cell Anemia: An Underreported, But Yet a Potentially Treatable Combination of Diseases. PMID- 26587865 TI - Theoretical Considerations of the Prigogine-Defay Ratio with Regard to the Glass Forming Ability of Drugs from Undercooled Melts. AB - Drug behavior in undercooled melts is highly important for pharmaceutics with regard to amorphous solid dispersions, and therefore, categories were recently introduced that differentiate glass formers (GFs) from other drugs that are nonglass formers (nGFs). The present study is based on the assumption that molecular properties relevant for the so-called Prigogine-Defay (PD) ratio would be indicative of a drug's glass-forming ability. The PD ratio depends in theory on the entropy of fusion and molar volume. Experimental data were gathered from a broad set of pharmaceutical compounds (n = 54) using differential scanning calorimetry. The obtained entropy of fusion and molar volume were indeed found to significantly discriminate GFs from nGFs. In a next step, the entropy of fusion was predicted by different in silico methods. A first group contribution method provided rather unreliable estimates for the entropy of fusion, while an alternative in silico approach seemed more promising for drug categorization. Thus, a significant discrimination model employed molar volume, a so-called effective hydrogen bond number, and effective number of torsional bonds (or torsional units) to categorize GFs and nGFs (p <= 0.0000). The results led to new insights into drug vitrification and to practical rules of thumb. The latter may serve as guidance in pharmaceutical profiling and early formulation development with respect to amorphous drug formulations. PMID- 26587866 TI - Long-term assessment of clinical response to adalimumab therapy in refractory ulcerative colitis. AB - INTRODUCTION: The role of antitumour necrosis factor agents, in particular infliximab in ulcerative colitis (UC) has been well established. More recently adalimumab, a fully humanized antitumour necrosis factor alpha monoclonal antibody, was licensed for refractory moderately active UC in 2012. Available outcome data for adalimumab from routine clinical practice is limited. AIMS: To evaluate the clinical response and remission to adalimumab in a cohort of UC patients. METHODS: Patients with UC treated with adalimumab were identified from our inflammatory bowel disease database from 2007. A retrospective chart review was undertaken. Demographic and clinical data were recorded including a Mayo score and C-reactive protein (CRP) where available. All patients received standard induction subcutaneous therapy (160/80/40 mg) followed by a maintenance dose of 40 mg fortnightly. Clinical and biochemical response was assessed at 6 and 12 months. Clinical response was defined by a reduction in Mayo score more than or equal to 3, whereas clinical remission was defined by a total score of 2 or less. Dose adjustments and adverse events were also noted. RESULTS: In all, 52 patients were identified. Of these, 65% (n=34) were male and the mean age was 45 years (range 23-72 years). A total of 65% (n=34) had left sided disease, 31% (n=16) pancolitis and 4% (n=2) proctitis. The majority commenced adalimumab due to a loss of response to immunomodulator therapy (n=45, 87%), whereas the remaining 13% (n=7) had loss of response or been intolerant to infliximab. The mean disease duration was 8 years (1-29 years). At baseline 85% (n=44) had moderate disease and 15% (n=8) had mild disease. The baseline mean CRP was 13.5 mg/l (range 1-82 mg/l) and the mean Mayo score was 6 (range 4-10). The mean duration of treatment was 18.5 months (range 4-95 months). Follow-up data was available in 46 (88%) and 37 (71%) patients at 6 and 12 months. Overall there was a statistically significant improvement in mean partial Mayo score on follow-up; 6 months=2 [P=0.0001, 95% confidence interval (CI) 2.99-4.55], 12 months=2 (P=0.0001, 95% CI 2.74-4.46). While 65% (n=34) and 52% (n=27) had a clinical response at 6 and 12 months, respectively, 52% (n=27) and 42% (n=22) were in remission. Overall mean CRP normalized at 6 months (P=0.002, 95% CI 3.31-15.1). Of note 25% (n=13) required dose escalation during follow-up, while treatment was discontinued by seven patients, five (71%) due to a loss of response, the remaining two (29%) due to an adverse event. CONCLUSION: Our study shows adalimumab is an effective and safe long-term therapy for moderately active UC refractory to other treatments. While this data is encouraging, further work is required on patient selection and to determine the impact of treatment on both natural history and quality of life. PMID- 26587867 TI - Comparison of efficacy and renal safety of telbivudine and entecavir in treatment naive elderly patients with chronic hepatitis B. AB - BACKGROUND: Data comparing the clinical outcomes of telbivudine (LdT) and entecavir (ETV) in elderly patients with chronic hepatitis B are limited. GOALS: The aim of the present study was to compare the efficacy and renal safety of LdT and ETV in treatment-naive elderly (>= 60 years) patients with chronic hepatitis B. METHODS: A total of 33 patients treated with LdT were consecutively enrolled in the study. Each patient was matched on the basis of age, sex, and baseline hepatitis B virus (HBV) DNA levels with three to four randomly selected controls treated with ETV. RESULTS: Clinical characteristics were comparable between the two groups. Higher cumulative HBeAg-seroconversion rates were observed in the LdT group than in the ETV group after 2 years (50 vs. 20%) and 3 years (50 vs. 26.67%) of treatment (all P<0.0001). Virological response rate at week 24 was significantly lower in the LdT group than it was in the ETV group (54.55 vs. 70.87%, P<0.0001), but no significant difference was noted in long-term cumulative rates of undetectable HBV DNA levels between the two groups (P=0.562). Virological breakthrough occurred in six (18.18%) LdT patients, with no such cases reported in the ETV group (P<0.0001). Antiviral resistance was strongly associated with LdT use and the absence of undetectable HBV DNA at weeks 12 and 24 (P<0.0001). During the study, significant improvement was observed in the estimated glomerular filtration rate and model for end-stage liver disease score in LdT versus ETV group. CONCLUSION: LdT has a lower clinical efficacy for viral suppression and a higher risk of antiviral resistance than does ETV. However, LdT resulted in higher HBeAg-seroconversion rates and better renoprotective effects than did ETV. PMID- 26587868 TI - Kinetics of Chlorination of Benzophenone-3 in the Presence of Bromide and Ammonia. AB - The aim of this study was to assess the impact of chlorination on the degradation of one of the most commonly used UV filters (benzophenone-3 (BP-3)) and the effects of bromide and ammonia on the kinetics of BP-3 elimination. Bromide and ammonia are rapidly converted to bromine and chloramines during chlorination. At first, the rate constants of chlorine, bromine and monochloramine with BP-3 were determined at various pH levels. BP-3 was found to react rapidly with chlorine and bromine, with values of apparent second order rate constants equal to 1.25(+/ 0.14) * 10(3) M(-1).s(-1) and 4.04(+/-0.54) * 10(6) M(-1).s(-1) at pH 8.5 for kChlorine/BP-3 and kBromine/BP-3, respectively, whereas low monochloramine reactivity was observed (kNH2Cl/BP-3 = 0.112 M(-1).s(-1)). To assess the impact of the inorganic content of water on BP-3 degradation, chlorination experiments with different added concentrations of bromide and/or ammonia were conducted. Under these conditions, BP-3 degradation was found to be enhanced in the presence of bromide due to the formation of bromine, whereas it was inhibited in the presence of ammonia. However, the results obtained were pH dependent. Finally, a kinetic model considering 18 reactions was developed using Copasi to estimate BP 3 degradation during chlorination in the presence of bromide and ammonia. PMID- 26587869 TI - The Toxicology of New Psychoactive Substances: Synthetic Cathinones and Phenylethylamines. AB - BACKGROUND: New psychoactive substances (NPSs) are substitutes for classical drugs of abuse and there are now compounds available from all groups of classical drugs of abuse. During 2014, the number of synthetic cathinones increased dramatically and, together with phenylethylamines, they dominate the NPS markets in the European Union. In total, 31 cathinones and 9 phenylethylamines were encountered in 2014. The aim of this article was to summarize the existing knowledge about the basic pharmacology, metabolism, and human toxicology of relevant synthetic cathinones and phenylethylamines. Compared with existing reviews, we have also compiled the existing case reports from both fatal and nonfatal intoxications. METHODS: We performed a comprehensive literature search using bibliographic databases PubMed and Web of Science, complemented with Google Scholar. The focus of the literature search was on original articles, case reports, and previously published review articles published in 2014 or earlier. RESULTS: The rapid increase of NPSs is a growing concern and sets new challenges not only for societies in drug prevention and legislation but also in clinical and forensic toxicology. In vivo and in vitro studies have demonstrated that the pharmacodynamic profile of cathinones is similar to that of other psychomotor stimulants. Metabolism studies show that cathinones and phenylethylamines are extensively metabolized; however, the parent compound is usually detectable in human urine. In vitro studies have shown that many cathinones and phenylethylamines are metabolized by CYP2D6 enzymes. This indicates that these drugs may have many possible drug-drug interactions and that genetic polymorphism may influence their toxicity. However, the clinical and toxicological relevance of CYP2D6 in adverse effects of cathinones and phenylethylamines is questionable, because these compounds are metabolized by other enzymes as well. The toxidromes commonly encountered after ingestion of cathinones and phenylethylamines are mainly of sympathomimetic and hallucinogenic character with a risk of excited delirium and life-threatening cardiovascular effects. CONCLUSIONS: The acute and chronic toxicity of many NPSs is unknown or very sparsely investigated. There is a need for evidence-based-treatment recommendations for acute intoxications and a demand for new strategies to analyze these compounds in clinical and forensic cases. PMID- 26587870 TI - Population Pharmacokinetics of Hydroxychloroquine in Japanese Patients With Cutaneous or Systemic Lupus Erythematosus. AB - BACKGROUND: Hydroxychloroquine (HCQ) is an effective treatment for patients with cutaneous lupus erythematosus (CLE) or systemic lupus erythematosus (SLE) and has been used for these patients in more than 70 nations. However, in Japan, HCQ has not been approved for CLE or SLE. To establish an appropriate therapeutic regimen and to clarify the pharmacokinetics (PK) of HCQ in Japanese patients with CLE with or without SLE (CLE/SLE), a population pharmacokinetic (PopPK) analysis was performed. METHODS: In a clinical study of Japanese patients with a diagnosis of CLE irrespective of the presence of SLE, blood and plasma drug concentration-time data receiving multiple oral doses of HCQ sulfate (200-400 mg daily) were analyzed using nonlinear mixed-effects model software. The blood and plasma concentrations of HCQ were analyzed using a high-performance liquid chromatography tandem mass spectrometry method. Model evaluation and validation were performed using goodness-of-fit (GOF) plots, visual predictive check, and a bootstrap. RESULTS: The PopPKs of HCQ in the blood and plasma of 90 Japanese patients with CLE/SLE were well described by a 1-compartment model with first order absorption and absorption lag time. Body weight was a significant (P < 0.001) covariate of oral clearance of HCQ. The final model was assessed using GOF plots, a bootstrap, and visual predictive check, and this model was appropriate. Simulations based on the final model suggested that the recommended daily doses of HCQ sulfate (200-400 mg) based on the ideal body weight in Japanese patients with CLE/SLE were in the similar concentration ranges. CONCLUSIONS: The PopPK models derived from both blood and plasma HCQ concentrations of Japanese patients with CLE/SLE were developed and validated. Based on this study, the dosage regimens of HCQ sulfate for Japanese patients with CLE/SLE should be calculated using the individual ideal body weight. PMID- 26587871 TI - Methods for quantifying tongue shape and complexity using ultrasound imaging. AB - Quantification of tongue shape is potentially useful for indexing articulatory strategies arising from intervention, therapy and development. Tongue shape complexity is a parameter that can be used to reflect regional functional independence of the tongue musculature. This paper considers three different shape quantification methods - based on Procrustes analysis, curvature inflections and Fourier coefficients - and uses a linear discriminant analysis to test how well each method is able to classify tongue shapes from different phonemes. Test data are taken from six native speakers of American English producing 15 phoneme types. Results classify tongue shapes accurately when combined across quantification methods. These methods hold promise for extending the use of ultrasound in clinical assessments of speech deficits. PMID- 26587872 TI - Medical Student Training on Code Status Discussions: How Far Have We Come? AB - OBJECTIVES: It is unclear to what extent the recently increased focus on patient provider education and patient-centered care has affected education on communication at the undergraduate medical education (UME) level. This study aimed to investigate graduating students' exposure to and comfort with techniques surrounding the code status discussion, an important and ubiquitous component of patient-provider communication. METHODS: We surveyed fourth-year medical students who had recently matched to our internal medicine residency program on their medical school experiences with code status discussions, self-confidence with these conversations, and desire for further education. RESULTS: We obtained surveys from 56 students from 32 medical schools (89% response rate). Students had varying experience observing and conducting code status discussions, infrequently received guidance or feedback on these discussions, and did not know guidelines for best practices surrounding the conversations. Despite reporting moderate self-confidence with these conversations, most felt they required at least partial supervision conducting these discussions; all requested further formal instruction. CONCLUSIONS: Despite increased attention on the importance of physicians' communication with patients, including surrounding end-of-life care, students at many top medical schools continue to feel underprepared and underconfident to engage in code status discussions with their patients upon the start of residency. PMID- 26587873 TI - Could cancer drugs provide ammunition against aging? PMID- 26587874 TI - Stromal cell-derived factor-1 rs2297630 polymorphism associated with platelet production and treatment response in Chinese patients with chronic immune thrombocytopenia. AB - Stromal cell-derived factor-1 (SDF-1), signaling through CXCR4, is implicated in megakaryopoiesis and platelet production. SDF-1 rs2297630 is a functional polymorphism in linkage disequilibrium with other functional variants in SDF-1. This study aimed to investigate the role of SDF-1 rs2297630 in chronic ITP. The genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism and confirmed by direct sequencing. Immature platelet fraction (IPF) was performed using Sysmex XE-2100. Anti-platelet autoantibodies were assayed by enzyme-linked immunosorbent assay. The main characteristics at diagnosis and the outcome of chronic ITP in 201 Chinese patients were retrospectively reviewed. There was no significant difference in either genotype or allelic distribution between ITP patients and the controls (p = 0.114; p = 0.787). However, both heterozygote (GA) and homozygote minor allele (AA) patients had significantly increased megakaryocyte quantity compared to homozygote genotype (GG) patients at diagnosis (p = 0.011). The mean IPF values of GA and AA genotype patients were higher than those observed in the GG genotype patients when platelet counts <=50 * 10(9)/L at diagnosis (p = 0.007). Patients with GA and AA genotype showed a higher response rate to standard treatments than patients with GG genotype (p < 0.001). In particular, GA and AA genotype patients had a significantly increased chance of responding to steroids, intravenous immunoglobulin (IVIG), and thrombopoietin analogs (p = 0.007; p = 0.029; p = 0.034, respectively). No significant difference was found between anti-platelet antibodies and genotypes (p = 0.296). In summary, the SDF-1 rs2297630 was associated with platelet production and treatment response in Chinese patients with chronic ITP. PMID- 26587875 TI - Distribution and Organoleptic Impact of Ethyl 3-Hydroxybutanoate Enantiomers in Wine. AB - Enantiomers of ethyl 3-hydroxybutanoate were assayed in 87 commercial wines from various vintages and origins, using chiral gas chromatography (beta cyclodextrin). Generally, ethyl 3-hydroxybutanoate levels were higher in red than in white wines of the same age. The average S/R enantiomeric ratio of this compound in red wine was approximately 75:25 (+/- 13), with an average total concentration of ~ 450 (+/- 150) MUg/L. In red wines, R-form levels increased gradually during aging, but no variations were observed in S-form concentrations. To our knowledge, no previous research had determined the enantiomeric distribution of this compound in wine. The olfactory threshold of the S-form in dilute alcohol solution was 21 mg/L, one-third that of the R-form: 63 mg/L. The S and R-forms had different aromatic nuances. The olfactory threshold of their mixture (85:15, m/m) was 14 mg/L, indicating a simple additive effect in this binary mixture. Furthermore, the concentrations found in red wines were considerably below the olfactory threshold under the same experimental conditions. Sensory analysis revealed that ethyl 3-hydroxybutanoate (S/R, 85:15, m/m) had an enhancing effect on the perception of fruity aromas in the matrices studied. Sensory profiles highlighted the contribution of ethyl 3 hydroxybutanoate to red-berry and fresh-fruit descriptors, despite its subthreshold concentrations. PMID- 26587876 TI - Clinical predictors of silent but substantial liver fibrosis in primary Sjogren's syndrome. AB - OBJECTIVES: To investigate the prevalence and the predictors of silent but substantial liver fibrosis in patients with primary Sjogren's syndrome (pSS). METHODS: We enrolled 101 pSS patients with normal liver function and structures, and without significant liver diseases or other conditions affecting liver fibrosis. The European league against rheumatism (EULAR) SS patients reported index (ESSPRI) and the EULAR SS disease activity index (ESSDAI) were analyzed. Liver stiffness (LS) was measured using transient elastography and 7.4 kPa was determined as the cutoff value for significant liver fibrosis. RESULTS: The median age of patients (91women) was 53 years and the median LS value was 4.7 kPa. The median ESSPRI and ESSDAI showed no correlation with LS values. Twelve patients (11.9%) had significant liver fibrosis. In multivariate logistic regression, white blood cells count <=4000.0/mm(3) (Odds ratio [OR] 9.821), serum albumin <=3.8 mg/dL (OR 16.770) and aspartate aminotransferase (AST) >= 27.0 IU/L (OR 20.858) independently predicted silent but substantial liver fibrosis in pSS patients. CONCLUSIONS: The prevalence of silent but substantial liver fibrosis was 11.9% in pSS and its predictors were leukopenia, decreased serum albumin and increased AST levels. PMID- 26587877 TI - Self-Consistent Optimization of Excited States within Density-Functional Tight Binding. AB - We present an implementation of energies and gradients for the DeltaDFTB method, an analogue of Delta-self-consistent-field density functional theory (DeltaSCF) within density-functional tight-binding, for the lowest singlet excited state of closed-shell molecules. Benchmarks of DeltaDFTB excitation energies, optimized geometries, Stokes shifts, and vibrational frequencies reveal that DeltaDFTB provides a qualitatively correct description of changes in molecular geometries and vibrational frequencies due to excited-state relaxation. The accuracy of DeltaDFTB Stokes shifts is comparable to that of DeltaSCF-DFT, and DeltaDFTB performs similarly to DeltaSCF with the PBE functional for vertical excitation energies of larger chromophores where the need for efficient excited-state methods is most urgent. We provide some justification for the use of an excited state reference density in the DFTB expansion of the electronic energy and demonstrate that DeltaDFTB preserves many of the properties of its parent DeltaSCF approach. This implementation fills an important gap in the extended framework of DFTB, where access to excited states has been limited to the time dependent linear-response approach, and affords access to rapid exploration of a valuable class of excited-state potential energy surfaces. PMID- 26587878 TI - Base-Promoted Oxidative Cycloaddition Reaction of [60]Fullerene with Ethyl Acetoacetate for C60 Bis-2',3'-dihydrofuran Derivatives: Effect of Bulky Addends. AB - The base-promoted oxidative cycloaddition reaction of [60]fullerene with ethyl acetoacetate was investigated. The reaction resulted in C60 bis-2',3' dihydrofuran derivatives, but only with the trans-1, trans-2, trans-3, and e configurations rather than any cis or trans-4 structures, demonstrating a new regioselectivity resulting from steric influence on C60 bisaddition. In addition, distribution of the bisadducts was complicated by the unsymmetrical nature of the addends, where each individual configuration may consist of several regioisomers. PMID- 26587881 TI - [Functional Comparison of the Outcome after Midvastus and Medial Parapatellar Surgical Approach in Total Knee Arthroplasty]. AB - There are various approaches for total knee arthroplasty (TKA). On the basis of an analysis of the clinical results, it has been demonstrated that the midvastus approach (MV) is advantageous in the early postoperative period compared to the medial parapatellar surgical approach (MPP). The aim of this investigation was therefore to investigate whether the clinical advantage of MV is reflected in the functional outcome. This single blinded, prospective, randomised study was based on a power analysis. Selected randomised patients (MPP = 10, MV = 11) were examined using an instrumental gait analysis system (VICON) preoperatively, and 5 weeks (5 W) and 6 months (6 M) after implantation. The results were compared to a healthy control group (CG = 53). Besides clinical parameters, the primary objective of this study was to measure objective gait parameters; the secondary objective was to record self-assessment (Knee Society score, WOMAC). In both treatment groups, the measurements improved during the investigation period, although most parameters did not reach the CG levels. MV gave better values for the kinetic parameters sagittal knee moment (5 W) and knee power (5 W, 6 M), as well as self-assessment (WOMAC, 6 M). Other clinical parameters were similar in the two groups. In summary, in the early postoperative period, MV led to advantages in function and in subjective behaviour in daily life. From the biomechanical point of view, the MV approach is preferable. PMID- 26587880 TI - Rational Design of a Dephosphorylation-Resistant Reporter Enables Single-Cell Measurement of Tyrosine Kinase Activity. AB - Although peptide-based reporters of protein tyrosine kinase (PTK) activity have been used to study PTK enzymology in vitro, the application of these reporters to intracellular conditions is compromised by their dephosphorylation, preventing PTK activity measurements. Nonproteinogenic amino acids may be utilized to rationally design selective peptidic ligands by accessing greater chemical and structural diversity than is available using the native amino acids. We describe a peptidic reporter that, upon phosphorylation by the epidermal growth factor receptor (EGFR), is resistant to dephosphorylation both in vitro and in cellulo. The reporter contains a conformationally constrained phosphorylatable moiety (7 (S)-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) in the place of L tyrosine and is efficiently phosphorylated in A431 epidermoid carcinoma cells. Dephosphorylation of the reporter occurs 3 orders of magnitude more slowly compared with that of the conventional tyrosine-containing reporter. PMID- 26587882 TI - [Risk of Developing Clinical Symptomatically Postmeniscectomy Bone Marrow Edema]. AB - BACKGROUND: Bone marrow edema (BME) of the knee is often seen in MRI and has several different underlying pathologies. The correlation between disorders of the knee joint and a BME is not fully understood yet. Persistent or progressive postoperative pain and/or functional impairment after arthroscopic partial meniscectomy is still a common phenomenon in many patients. The aim of this prospective clinical trial was to find a correlation between the typical postoperative disorders and BME in MRI and to identify possible therapeutic consequences. PATIENTS, MATERIAL AND METHODS: 150 consecutive patients with preoperatively diagnosed meniscus defects and without any previous operation and no BME underwent arthroscopic partial meniscectomy. A two- to three-day resting period was established postoperatively. The patients then rapidly returned to full weight bearing. No crutches were used. As a standard analgetic, we used diclofenac 50 mg three times a day for three days. Clinical control and removal of the sutures was performed on day 8 postoperatively. The patients' pain status was controlled by using the IKDC score and the Visual Analogue Scale (VAS) before and six weeks after surgery. Six weeks after the surgical intervention, the patients underwent a standardized physical examination and, if there was ongoing functional impairment or discomfort of the knee, a new MRI was performed. However, if patients showed signs or severe discomfort prior to the end of the six-week observation period an MRI was scheduled earlier. RESULTS: Postoperatively 11 of the 150 patients (7,3 %) developed progressive discomfort with pain during stress and also by night. A postoperative BME in the MRI was seen in all 11 symptomatic patients (100 %). We saw a significant correlation to women older than 70 years (p < 0.05). The VAS score six weeks after arthroscopy was significant reduced in the group without any clinical symptoms (2.63 +/- 2.83 after arthroscopy and 4.27 +/- 2.36 MW +/- SEM before arthroscopy) compared to the group with proven BME (5.09 +/- 2.74 before arthroscopy and 5.27 +/- 2.57 MW +/- SEM after arthroscopy; p < 0.05). The IKDC score was significantly enhanced in the clinical asymptomatic group: 58.1 +/- 10.53 in comparison to the patients with proven BME, with 35.32 +/- 13.2 MW +/- SEM (p < 0.05). CONCLUSION: Patients with clinical symptomatic BME showed a significantly higher VAS score and a significantly lower IKDC score postoperatively. Therefore, in patients with postoperative discomfort, a prompt MRI should be performed and, if a BME is proven, further therapy should be modified. PMID- 26587879 TI - Evolutionary Conservation and Diversification of Puf RNA Binding Proteins and Their mRNA Targets. AB - Reprogramming of a gene's expression pattern by acquisition and loss of sequences recognized by specific regulatory RNA binding proteins may be a major mechanism in the evolution of biological regulatory programs. We identified that RNA targets of Puf3 orthologs have been conserved over 100-500 million years of evolution in five eukaryotic lineages. Focusing on Puf proteins and their targets across 80 fungi, we constructed a parsimonious model for their evolutionary history. This model entails extensive and coordinated changes in the Puf targets as well as changes in the number of Puf genes and alterations of RNA binding specificity including that: 1) Binding of Puf3 to more than 200 RNAs whose protein products are predominantly involved in the production and organization of mitochondrial complexes predates the origin of budding yeasts and filamentous fungi and was maintained for 500 million years, throughout the evolution of budding yeast. 2) In filamentous fungi, remarkably, more than 150 of the ancestral Puf3 targets were gained by Puf4, with one lineage maintaining both Puf3 and Puf4 as regulators and a sister lineage losing Puf3 as a regulator of these RNAs. The decrease in gene expression of these mRNAs upon deletion of Puf4 in filamentous fungi (N. crassa) in contrast to the increase upon Puf3 deletion in budding yeast (S. cerevisiae) suggests that the output of the RNA regulatory network is different with Puf4 in filamentous fungi than with Puf3 in budding yeast. 3) The coregulated Puf4 target set in filamentous fungi expanded to include mitochondrial genes involved in the tricarboxylic acid (TCA) cycle and other nuclear-encoded RNAs with mitochondrial function not bound by Puf3 in budding yeast, observations that provide additional evidence for substantial rewiring of post-transcriptional regulation. 4) Puf3 also expanded and diversified its targets in filamentous fungi, gaining interactions with the mRNAs encoding the mitochondrial electron transport chain (ETC) complex I as well as hundreds of other mRNAs with nonmitochondrial functions. The many concerted and conserved changes in the RNA targets of Puf proteins strongly support an extensive role of RNA binding proteins in coordinating gene expression, as originally proposed by Keene. Rewiring of Puf-coordinated mRNA targets and transcriptional control of the same genes occurred at different points in evolution, suggesting that there have been distinct adaptations via RNA binding proteins and transcription factors. The changes in Puf targets and in the Puf proteins indicate an integral involvement of RNA binding proteins and their RNA targets in the adaptation, reprogramming, and function of gene expression. PMID- 26587884 TI - Homo- and Heteropolynuclear Clusters of Phosphine Triphenolates. AB - The synthesis and structural characterization of a series of homo- and heteropolynuclear clusters constructed with a potentially tetradentate phosphine triphenolate ligand are presented. Treatment of tris(3,5-di-tert-butyl-2 hydroxyphenyl)phosphine (H3[O3P]) with 3 equiv of nBuLi in diethyl ether at -35 degrees C affords hexanuclear Li6[O3P]2(OEt2)2 (1) as colorless crystals. In situ lithiation of H3[O3P] with 3 equiv of nBuLi in THF at -35 degrees C followed by metathetical reactions with MnCl2 or NiCl2(DME) gives crystals of forest green pentanuclear MnLi4[O3P]2(THF)3 (2) or dark brown tetranuclear Ni2Li2[O3P]2(THF)2 (3), respectively. Alkane elimination of ZnR2 (R = Me, Et) with H3[O3P] in THF at 25 degrees C generates high yields of colorless crystalline trinuclear Zn3[O3P]2(THF)2 (4). The cluster structures of 1-4 were all determined by single crystal X-ray diffraction studies. These molecules represent the first examples of metal complexes supported by phosphine triphenolate derivatives. The cluster 2 contains a paramagnetic core of high spin Mn(II) (S = 5/2) as indicated by solution and solid state magnetic susceptibility measurements. PMID- 26587883 TI - [Quality in Revision Arthroplasty: A Comparison between Claims Data Analysis and External Quality Assurance]. AB - BACKGROUND: External quality assurance for revisions of total knee arthroplasty (TKA) and total hip arthroplasty (THA) are carried out through the AQUA institute in Germany. Data are collected by the providers and are analyzed based on predefined quality indicators from the hospital stay in which the revision was performed. The present study explores the possibility to add routine data analysis to the existing external quality assurance (EQS). Differences between methods are displayed. The study aims to quantify the benefit of an additional analysis that allows patients to be followed up beyond the hospitalization itself. MATERIAL AND METHODS: All persons insured in an AOK sickness fund formed the population for analysis. Revisions were identified using the same algorithm as the existing external quality assurance. Adverse events were defined according to the AQUA indicators for the years 2008 to 2011.The hospital stay in which the revision took place and a follow-up of 30 days were included. For re-operation and dislocation we also defined a 365 days interval for additional follow-up. The results were compared to the external quality control reports. RESULTS: Almost all indicators showed higher events in claims data analysis than in external quality control. Major differences are seen for dislocation (EQS SD: 1.87 vs. claims data [cd] SD: 2.06 %, cd+30 d: 2.91 %, cd+365 d: 7.27 %) and reoperation (hip revision: EQS SD: 5.88 % vs. claims data SD: 8.79 % cd+30 d: 9.82 %, cd+365 d: 15.0 %/knee revision: EQS SD: 3.21 % vs. claims data SD: 4.07 %, cd+30 d: 4.6 %, cd+365 d: 15.43 %). Claims data could show additional adverse events for all indicators after the initial hospital stay, rising to 77 % of all events. CONCLUSIONS: The number of adverse events differs between the existing external quality control and our claims data analysis. Claims data give the opportunity to complement existing methods of quality control though a longer follow-up, when many complications become evident. PMID- 26587885 TI - Reactive Oxygen Species-Manipulated Drug Release from a Smart Envelope-Type Mesoporous Titanium Nanovehicle for Tumor Sonodynamic-Chemotherapy. AB - Despite advances in drug delivery systems (DDSs), the stimuli-responsive controlled release DDSs with high spatial/temporal resolution are still the best choice. Herein, a novel type of envelope-type mesoporous titanium dioxide nanoparticle (MTN) was developed for one-demand drug delivery platform. Docetaxel (DTX) was loaded in the pores of MTN with a high drug loading efficiency (~26%). Then beta-cyclodextrin (beta-CD, a bulky gatekeeper) was attached to the outer surface of MTN via a reactive oxygen species (ROS) sensitive linker to block the pores (MTN@DTX-CD). MTN@DTX-CD could entrap the DTX in the pores and allow the rapid release until a focused ultrasound (US) emerged. A large number of ROS were generated by MTN under US radiation, leading to the cleavage of the ROS-sensitive linker; thus, DTX could be released rapidly since the gatekeepers (beta-CD) were detached. Besides, the generation of ROS could also be used for tumor-specific sonodynamic therapy (SDT). Studies have shown the feasibility of MTN@DTX-CD for US-triggered DTX release and sonodynamic-chemotherapy. In the in vitro and in vivo studies, by integrating SDT and chemotherapy into one system, MTN@DTX-CD showed excellent antitumor efficacy. More importantly, this novel DDS significantly decreased the side effects of DTX by avoiding the spleen and hematologic toxicity to tumor-bearing mice. PMID- 26587886 TI - Timing of HPV vaccine intervals among United States teens with consideration to the current ACIP schedule and the WHO 2-dose schedule. AB - The current recommendation for human papillomavirus (HPV) vaccination in the United States is for 3 doses to be administered over a 6 month period. In April 2014, the World Health Organization (WHO) recommended adoption of a 2-dose schedule, with doses spaced a minimum of 6 months apart, for teens who begin the series before age 15. We analyzed data from the 2013 National Immunization Survey Teen to examine the timing of second and third dose receipt among US adolescents. All analyses were restricted to adolescents age 13-17 y who had adequate provider data. The Wilcoxon-Mann-Whitney test measured differences in time to receive vaccine doses among demographic and socioeconomic groups. Logistic regression identified socioeconomic characteristics associated with receiving the second dose of HPV vaccine at least 6 months after the first dose. The median time for teens to receive the second dose of HPV vaccine was 2.6 months after the first dose, and the median time to receive the third dose was 4.9 months after the second dose. Minority teens and teens living below the poverty level took significantly longer to receive doses. Among teens that initiated the HPV vaccine series before age 15 y, 28.6% received the second dose at least 6 months after the first dose. If these teens, who met the WHO criteria for up-to-date HPV vaccination, were classified as having completed the vaccination series, overall coverage in the US would increase 3.9 percentage points, with African American and Hispanic teens having the greatest increases in coverage. PMID- 26587887 TI - Benign Conditions That Mimic Prostate Carcinoma: MR Imaging Features with Histopathologic Correlation. AB - Multiparametric magnetic resonance (MR) imaging combines anatomic and functional imaging techniques for evaluating the prostate and is increasingly being used in diagnosis and management of prostate cancer. A wide spectrum of anatomic and pathologic processes in the prostate may masquerade as prostate cancer, complicating the imaging interpretation. The histopathologic and imaging findings of these potential mimics are reviewed. These entities include the anterior fibromuscular stroma, surgical capsule, central zone, periprostatic vein, periprostatic lymph nodes, benign prostatic hyperplasia (BPH), atrophy, necrosis, calcification, hemorrhage, and prostatitis. An understanding of the prostate zonal anatomy is helpful in distinguishing the anatomic entities from prostate cancer. The anterior fibromuscular stroma, surgical capsule, and central zone are characteristic anatomic features of the prostate with associated low T2 signal intensity due to dense fibromuscular tissue or complex crowded glandular tissue. BPH, atrophy, necrosis, calcification, and hemorrhage all have characteristic features with one or more individual multiparametric MR imaging modalities. Prostatitis constitutes a heterogeneous group of infective and inflammatory conditions including acute and chronic bacterial prostatitis, infective and noninfective granulomatous prostatitis, and malacoplakia. These entities are associated with variable clinical manifestations and are characterized by the histologic hallmark of marked inflammatory cellular infiltration. In some cases, these entities are indistinguishable from prostate cancer at multiparametric MR imaging and may even exhibit extraprostatic extension and lymphadenopathy, mimicking locally advanced prostate cancer. It is important for the radiologists interpreting prostate MR images to be aware of these pitfalls for accurate interpretation. Online supplemental material is available for this article. PMID- 26587889 TI - MR Imaging with Metal-suppression Sequences for Evaluation of Total Joint Arthroplasty. AB - Metallic artifact at orthopedic magnetic resonance (MR) imaging continues to be an important problem, particularly in the realm of total joint arthroplasty. Complications often follow total joint arthroplasty and can be expected for a small percentage of all implanted devices. Postoperative complications involve not only osseous structures but also adjacent soft tissues-a highly problematic area at MR imaging because of artifacts from metallic prostheses. Without special considerations, susceptibility artifacts from ferromagnetic implants can unacceptably degrade image quality. Common artifacts include in-plane distortions (signal loss and signal pileup), poor or absent fat suppression, geometric distortion, and through-section distortion. Basic methods to reduce metallic artifacts include use of spin-echo or fast spin-echo sequences with long echo train lengths, short inversion time inversion-recovery (STIR) sequences for fat suppression, a high bandwidth, thin section selection, and an increased matrix. With care and attention to the alloy type (eg, titanium, cobalt-chromium, stainless steel), orientation of the implant, and magnetic field strength, as well as use of proprietary and nonproprietary metal-suppression techniques, previously nondiagnostic studies can yield key diagnostic information. Specifically, sequences such as the metal artifact reduction sequence (MARS), WARP (Siemens Healthcare, Munich, Germany), slice encoding for metal artifact correction (SEMAC), and multiacquisition with variable-resonance image combination (MAVRIC) can be optimized to reveal pathologic conditions previously hidden by periprosthetic artifacts. Complications of total joint arthroplasty that can be evaluated by using MR imaging with metal-suppression sequences include pseudotumoral conditions such as metallosis and particle disease, infection, aseptic prosthesis loosening, tendon injury, and muscle injury. PMID- 26587888 TI - Molecular Imaging of Prostate Cancer. AB - Prostate cancer is the most common noncutaneous malignancy among men in the Western world. The natural history and clinical course of prostate cancer are markedly diverse, ranging from small indolent intraprostatic lesions to highly aggressive disseminated disease. An understanding of this biologic heterogeneity is considered a necessary requisite in the quest for the adoption of precise and personalized management strategies. Molecular imaging offers the potential for noninvasive assessment of the biologic interactions underpinning prostate carcinogenesis. Currently, numerous molecular imaging probes are in clinical use or undergoing preclinical or clinical evaluation. These probes can be divided into those that image increased cell metabolism, those that target prostate cancer-specific membrane proteins and receptor molecules, and those that bind to the bone matrix adjacent to metastases to bone. The increased metabolism and vascular changes in prostate cancer cells can be evaluated with radiolabeled analogs of choline, acetate, glucose, amino acids, and nucleotides. The androgen receptor, prostate-specific membrane antigen, and gastrin-releasing peptide receptor (ie, bombesin) are overexpressed in prostate cancer and can be targeted by specific radiolabeled imaging probes. Because metastatic prostate cancer cells induce osteoblastic signaling pathways of adjacent bone tissue, bone-seeking radiotracers are sensitive tools for the detection of metastases to bone. Knowledge about the underlying biologic processes responsible for the phenotypes associated with the different stages of prostate cancer allows an appropriate choice of methods and helps avoid pitfalls. PMID- 26587890 TI - Internal Hernias in the Era of Multidetector CT: Correlation of Imaging and Surgical Findings. AB - Clinical diagnosis of internal hernias is challenging because of their nonspecific signs and symptoms. Many types of internal hernias have been defined: paraduodenal, small bowel mesentery-related, greater omentum-related, lesser sac, transverse mesocolon-related, pericecal, sigmoid mesocolon-related, falciform ligament, pelvic internal, and Roux-en-Y anastomosis-related. An internal hernia is a surgical emergency that can develop into intestinal strangulation and ischemia. Accurate preoperative diagnosis is crucial for appropriate management. Multidetector computed tomography (CT), with its thin-section axial images, high quality multiplanar reformations, and three-dimensional images, currently plays an essential role in preoperative diagnosis of internal hernias. The diagnostic approach to internal hernias at multidetector CT includes detecting an intestinal closed loop, identifying the hernia orifice, and analyzing abnormal displacement of surrounding structures and key vessels around the hernia orifice and hernia sac. At each step, multidetector CT can depict pathognomonic findings. A saclike appearance suggests an intestinal closed loop in several types of internal hernias. Convergence, engorgement, and twisting of mesenteric vessels in the hernia orifice can be seen clearly at multidetector CT, especially with use of multiplanar reformations. For definitive diagnosis of an internal hernia, analysis of displacement of anatomic landmarks around the hernia orifice is particularly important, and thin-section images provide the required information. Detailed knowledge of the anatomy, etiology, and imaging landmarks of the various hernia types is also necessary. Familiarity with the appearances of internal hernias at multidetector CT allows accurate and specific preoperative diagnosis. ((c))RSNA, 2015. PMID- 26587891 TI - Invited Commentary on "Molecular Imaging of Prostate Cancer". PMID- 26587892 TI - Screening of plants for phytoremediation of oil-contaminated soil. AB - Several species of ornamental flowering plants were evaluated regarding their phytoremediation ability for the cleanup of oil-contaminated soil in Japanese environmental conditions. Thirty-three species of plants were grown in oil contaminated soil, and Mimosa, Zinnia, Gazania, and cypress vine were selected for further assessment on the basis of their favorable initial growth. No significant difference was observed in the above-ground and under-ground dry matter weight of Gazania 180 days after sowing between contaminated and non contaminated plots. However, the other 3 species of plants died by the 180th day, indicating that Gazania has an especially strong tolerance for oil-contaminated soil. The total petroleum hydrocarbon concentration of the soils in which the 4 species of plants were grown decreased by 45-49% by the 180th day. Compared to an irrigated plot, the dehydrogenase activity of the contaminated soil also increased significantly, indicating a phytoremediation effect by the 4 tested plants. Mimosa, Zinnia, and cypress vine all died by the 180th day after seeding, but the roots themselves became a source of nutrients for the soil microorganisms, which led to a phytoremediation effect by increase in the oil degradation activity. It has been indicated that Gazania is most appropriate for phytoremediation of oil-contaminated soil. PMID- 26587894 TI - A Life That Mattered. AB - This article explores some of Hannelore Wass's many contributions to the field of death, dying, and bereavement as well as her distinctive teaching and mentoring gifts. It chronicles the highlights of a 30-year relationship that began as shared interests in death, dying and bereavement, expanded into sharing of classroom techniques and models and ultimately became a lasting and treasured friendship. PMID- 26587895 TI - Fluid Fat Injection for Volume Restoration and Skin Regeneration of the Periocular Aesthetic Unit. PMID- 26587896 TI - Mobilization of peripheral blood hematopoietic stem cells by granulocyte-colony stimulating factor and plerixafor in patients with cardiac AL amyloidosis. PMID- 26587897 TI - Micromotors Powered by Enzyme Catalysis. AB - Active biocompatible systems are of great current interest for their possible applications in drug or antidote delivery at specific locations. Herein, we report the synthesis and study of self-propelled microparticles powered by enzymatic reactions and their directed movement in substrate concentration gradient. Polystyrene microparticles were functionalized with the enzymes urease and catalase using a biotin-streptavidin linkage procedure. The motion of the enzyme-coated particles was studied in the presence of the respective substrates, using optical microscopy and dynamic light scattering analysis. The diffusion of the particles was found to increase in a substrate concentration dependent manner. The directed chemotactic movement of these enzyme-powered motors up the substrate gradient was studied using three-inlet microfluidic channel architecture. PMID- 26587898 TI - Vitamin D Status Is Related to Oxidative Stress But Not High-Sensitive C-Reactive Protein in Women with Pre-Eclampsia. AB - BACKGROUND/AIMS: Pre-eclampsia (PE) is associated with unfavorable metabolic profiles. Oxidative stress and inflammation have been increasingly postulated as major contributors to PE. Research suggests that vitamin D status is disturbed in women with PE. The aims of this study were to compare the serum levels of vitamin D and oxidative stress status in women with PE vs. women with normal pregnancies, and to evaluate the relationship between these 2 factors in women with PE. METHODS: In this case-control study, 40 women with PE and 40 healthy pregnant women were selected, and high-sensitivity C-reactive protein, malondialdehyde (MDA), total antioxidant capacity (TAC) and 25-hydroxyvitamin D (25(OH)D) levels were assessed. We compared the biochemical indicators between the 2 groups by analysing the data using the independent t test, Mann-Whitney U test, chi-square and logistic regression. RESULTS: Compared with the controls, the serum levels of MDA in women with PE were significantly higher (p = 0.001) and TAC and 25(OH)D levels were significantly lower (p < 0.05). TAC concentration was positively associated with 25(OH)D levels in cases of PE (beta = 0.428, p = 0.01). CONCLUSION: Our findings show lower levels of TAC and 25(OH)D in women with PE in comparison to controls, while having similar vitamin D intakes. In addition, our results suggest a positive relationship between TAC concentration and 25(OH)D levels in PE cases. PMID- 26587899 TI - Impact of Mechanical Bowel Preparation on Postoperative Outcomes after Liver Resection for Patients with Hepatocellular Carcinoma: A Single-Center Retrospective Cohort Study. AB - BACKGROUND: Despite the routine use of mechanical bowel preparation (MBP), the real impact of MBP for liver resection remains unclear. The aim of this study was to evaluate the postoperative outcomes of MBP after liver resection for hepatocellular carcinoma (HCC). METHODS: This was a retrospective cohort study of all patients undergoing liver resection for patients with HCC between from April 2008 to March 2015. MBP was defined as a preoperative medication of polyethylene glycol lavage. We compared perioperative outcomes in patients who did or did not receive MBP before liver resection. Open and laparoscopic hepatectomy were analyzed separately. RESULTS: A total of 227 patients underwent potentially curative liver resection for HCC during the study period. One hundred twenty eight patients received MBP while 99 did not. In the open hepatectomy group, overall and major (Clavien-Dindo >=3) complications were equivalent between the groups (31.9 vs. 25.8%, p = 0.840; 12.1 vs. 8.7%, p = 0.475). There were no meaningful differences in the incidence of liver failure (MBP: 22.4%, non-MBP: 13.0%, p = 0.116). Surgical-site infections occurred in 20 (17.2%) vs. 10 (14.5%) with no significant difference (p = 0.624). Similar results were obtained from the laparoscopic hepatectomy group. CONCLUSION: The use of MBP does not appear to impact the short outcomes after liver resection for patients with HCC. MBP might be omitted in liver surgery. PMID- 26587900 TI - Cerebral Microbleeds: Detection, Associations and Clinical Implications. AB - Vigorous investigations for cerebral microbleeds (CMBs) have been made since the late 1990s. CMBs on paramagnetic-sensitive magnetic resonance sequences correspond pathologically to clusters of hemosiderin-laden macrophages and have emerged as an important new imaging marker of cerebral small vessel disease, including intracerebral hemorrhage (ICH). The prevalence of CMBs varies according to the specific disease settings (stroke subtypes and dementing disorders) and is highest (60%) in ICH patients. The associations of CMBs with aging, hypertension and apolipoprotein E genotype are consistent with the two major underlying pathogeneses of CMBs: hypertensive arteriopathy and cerebral amyloid angiopathy (CAA). The distributional patterns of CMBs might help us to understand the predominant small vessel disease pathogenesis in the brain; the strictly lobar type of CMBs often reflects the presence of advanced CAA, while the other types of CMBs, such as 'deep or infratentorial CMBs', including the mixed type, are strongly associated with hypertension. CMBs might be associated with cognitive function (especially executive function), gait performance, and cerebrovascular events (spontaneous, antithrombotic drug-related or post-thrombolysis ICH). In the field of CAA, an understanding of CAA-related CMBs might help to guide decision making with regard to new therapeutic approaches, including the use of monoclonal antibodies against vascular amyloid. These concepts of CMBs might allow us to advance research on ICH as well as for dementia. PMID- 26587901 TI - Anomalous Posterior Arch of Atlas: A Rare Cause for Craniovertebral Junction Compression. AB - Congenital hypoplasia of the anterior and posterior arch of the atlas has been described in the literature. Currarino and associates classified this into various types based on the part of the arch that was hypoplastic. Gin and associates stated that posterior atlantal anomalies were more frequently encountered than anterior arch anomalies. Rarely do these anomalies present in the absence of genetic syndromes. Here, we describe our clinical experience of an anomalous posterior atlantal arch in a nonsyndromic patient. PMID- 26587902 TI - Lowered Levels of Carbonyl Proteins after Vitamin B Supplementation in Patients with Mild Cognitive Impairment and Alzheimer's Disease. AB - BACKGROUND: The critical role of neuro-inflammation and oxidative stress in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD) has become evident. OBJECTIVE: The aim of this study is to assess the influence of vitamin supplementation on parameters of oxidative stress, inflammation as well as on cognition in patients with AD and mild cognitive impairment. METHODS: In our study, patients with cognitive impairment and healthy controls were enrolled. All patients were intended to receive vitamin supplementation (vitamin B1, B6, B12 and folic acid) for 3 months. Mini Mental State Examination (MMSE) and laboratory markers [carbonyl proteins (CPs), malondialdehyde, tryptophan (Trp), kynurenine (Kyn), neopterin, folic acid, vitamin B12 level] were assessed for patients and controls at baseline and after 3 months. After half of the patients had been treated for 3 months, analyses were performed resulting in 3 subgroups: healthy controls without supplementation (15 subjects, 11 females), patients with vitamin supplementation (17 subjects, 10 females) and patients without vitamin supplementation (16 subjects, 9 females; baseline values prior to supplementation). RESULTS: Age was significantly higher for the supplemented group (76.4 +/- 6.7 years) compared to vitamin-naive patients (63.3 +/- 13.7 years; p < 0.01). The MMSE score was higher in the supplemented group (23.1 +/- 4.8 vs. 20.3 +/- 9.5) but did not reach significance. Levels of CPs were significantly higher in the vitamin-naive patients (p < 0.05). Levels of Kyn and the Kyn/Trp ratio were significantly lower in vitamin-naive patients compared to the supplemented group (p < 0.05). No significant difference was seen for the other markers. CONCLUSION: Vitamin supplementation leads to reduced levels of CPs in patients. Pearson's correlation coefficient shows a negative relation (r = 0.69) between CPs and MMSE. Future trials should assess whether CPs might be suitable markers for monitoring of demented patients. PMID- 26587903 TI - A Report of 134 Newly Diagnosed Multiple Myeloma Patients with Renal Impairment. AB - To analyze the effects of bortezomib on the prognosis of the newly diagnosed multiple myeloma patients with renal impairment, we assessed the outcomes of 134 multiple myeloma patients with renal impairment (serum creatinine >=178 MUmol/l) who were treated at Beijing Chaoyang Hospital. The patients were divided into two groups: bortezomib (n = 83) and nonbortezomib (n = 51). The overall response rate of the bortezomib group was higher than that of the nonbortezomib group. There was no significant difference in the time to restore renal function, but the complete renal response ratio was significantly higher in the bortezomib group. The 2-year overall survival (OS) rate of the bortezomib group was significantly greater than the nonbortezomib group, as was the 3-year OS rate. Kaplan-Meier analysis revealed significantly better survival for the bortezomib group. The main side effects in the bortezomib group were thrombocytopenia, peripheral neuropathy, infection, and herpes zoster, and there was a low incidence of grades 3 and 4 adverse events. Our findings indicate that bortezomib-based combination chemotherapy can improve the prognosis of the newly diagnosed multiple myeloma patients with renal impairment and should be considered as a first-line therapy. PMID- 26587904 TI - Ifosfamide and etoposide chemotherapy may interact with warfarin, enhancing the warfarin induced anticoagulant response. AB - PURPOSE: To report a case of warfarin-response enhancement during administration of ifosfamide and etoposide chemotherapy. CASE SUMMARY: A 15-yearold boy with rhabdomyosarcoma was treated with a regimen of alternating cycles of vincristine, doxorubicin, and cyclophosphamide (VDC) chemotherapy and ifosfamide and etoposide (IE) chemotherapy. During VDC chemotherapy, occlusion of the left middle cerebral artery occurred, and warfarin was started. On day 3 of IE chemotherapy, the patient's international normalized ratio (INR) transiently increased from baseline 2.61 to 5.45. The INR returned to normal within 3 days after warfarin discontinuation. An increase in INR was observed between days 1 and 3 of subsequent cycles of IE chemotherapy but not during VDC chemotherapy. This INR increase was also observed during concomitant use of aprepitant, an inducer of the CYP2C9. DISCUSSION: There are no reports describing the interaction between warfarin and IE chemotherapy because coadministration of warfarin and IE chemotherapy is unusual. The Drug Interaction Probability Scale score of this interaction was 7, and it is probable that the enhancement of the warfarin response was caused by an interaction with IE chemotherapy. Moreover, in the present case, the enhancement of warfarin response was observed during concomitant use of aprepitant, which has been reported to weaken the warfarin response. Therefore, this interaction may be quite powerful and may increase the risk of warfarin toxicity. CONCLUSION: A patient who was administered both warfarin and IE chemotherapy experienced a rapid increase in INR, suggesting that INR should be closely monitored in patients receiving warfarin with IE chemotherapy. PMID- 26587905 TI - Glass fragments from portable electronic devices: Implications for forensic examinations. AB - Personal electronic devices (PEDs) are now widespread in the community. Many such devices have glass display screens that, despite being a relatively strong and specialised material, are vulnerable to breakage. Unlike other glass objects that are usually thrown away when they break, PEDs can still function with a broken or cracked screen and it is not uncommon for their owners to keep using them in this condition. Broken PED screens, therefore, might represent a new and significant source of glass fragments that are present on the clothing and belongings of the general public and individuals suspected of offences involving the breaking of glass. The forensic implications of this new source of glass fragments in the community were investigated. PED glass is easily recognised using scanning electron microscopy-energy dispersive X-ray analysis and refractive index measurement and is easily distinguished from domestic and automotive soda-lime glass using these methods; as a consequence there should be no confusion of soda lime glass fragments and PED glass fragments in forensic glass casework. In cases where the objective is to compare recovered glass fragments to a putative PED source, comparison using refractive index measurement and elemental analysis achieves good discrimination between sources. PMID- 26587906 TI - Cultural adaptation of the female pelvic floor questionnaire (FPFQ) into French. AB - AIMS: The Female pelvic floor questionnaire (FPFQ) is a self-administered tool on pelvic floor function. Our aim was to carry out a cultural adaptation of the FPFQ into French and to assess its psychometric properties. METHODS: After cross cultural adaptation into French, acceptability and reliability of the questionnaire were assessed through a sample of 56 women in a test-retest. Discriminative construct validity was evaluated by comparing the results obtained by the FPFQ to those of other validated questionnaires. Longitudinal follow-up of the 282 pregnant women included in the PreNatal Pelvic floor Prevention trial (3PN) was used to analyze responsiveness. RESULTS: The proportion of missing data did not exceed 4% for questions about bladder function, bowel function, and pelvic organ prolapse; 10% for issues related to sexual function. Question 9 was considered difficult to understand by 14% of women. After rewriting, this issue was retested in a new sample of 52 women and presented no further problems. The intra-class correlation coefficient was greater than or equal to 0.7 for all domains during the test-retest. The FPFQ was strongly and significantly correlated (Spearman r > 0.5) with the other validated questionnaires. The French version of FPFQ recorded changes in urinary and sexual symptoms for the women involved in 3PN trial with a standardized response mean equal to 0.83 and 0.44, respectively. CONCLUSION: The French version of the FPFQ is self-administered, reliable, valid, and can detect a change in symptoms during follow-up. Neurourol. Urodynam. 36:253-258, 2017. (c) 2015 Wiley Periodicals, Inc. PMID- 26587907 TI - A non-catalytic N-terminal domain negatively influences the nucleotide exchange activity of translation elongation factor 1Balpha. AB - Eukaryotic translation elongation factor 1Balpha (eEF1Balpha) is a functional homolog of the bacterial factor EF-Ts, and is a component of the macromolecular eEF1B complex. eEF1Balpha functions as a catalyst of guanine nucleotide exchange on translation elongation factor 1A (eEF1A). The C-terminal domain of eEF1Balpha is necessary and sufficient for its catalytic activity, whereas the N-terminal domain interacts with eukaryotic translation elongation factor 1Bgamma (eEF1Bgamma) to form a tight complex. However, eEF1Bgamma has been shown to enhance the catalytic activity of eEF1Balpha attributed to the C-terminal domain of eEF1Balpha. This suggests that the N-terminal domain of eEF1Balpha may in some way influence the guanine nucleotide exchange process. We have shown that full length recombinant eEF1Balpha and its truncated forms are non-globular proteins with elongated shapes. Truncation of the N-terminal domain of eEF1Balpha, which is dispensable for catalytic activity, resulted in acceleration of the rate of guanine nucleotide exchange on eEF1A compared to full-length eEF1Balpha. A similar effect on the catalytic activity of eEF1Balpha was observed after its interaction with eEF1Bgamma. We suggest that the non-catalytic N-terminal domain of eEF1Balpha may interfere with eEF1A binding to the C-terminal catalytic domain, resulting in a decrease in the overall rate of the guanine nucleotide exchange reaction. Formation of a tight complex between the eEF1Bgamma and eEF1Balpha N-terminal domains abolishes this inhibitory effect. PMID- 26587908 TI - Patterns of axillary lymph node metastases and recurrent disease in grade 1 breast cancer in a New Zealand cohort: Does ethnicity matter? AB - BACKGROUND: In New Zealand, Maori and Pacific women are more likely than New Zealand/European women to present at a younger age with larger tumours and metastatic disease. Survival rates are also differential by ethnicity. Many factors are believed to be responsible for this including differences in comorbidities, delays to presentation and delays in treatment. It is unclear whether these differences exist amongst women with grade 1 cancer in New Zealand. Therefore, we examined patterns of axillary nodal involvement, recurrent disease and mortality in grade 1 breast cancer in New Zealand women, and whether ethnicity was an important predictor for any of these outcomes. METHOD: Data was retrieved from the Auckland Breast Cancer Registry (ABCR) and the Waikato Breast Cancer Registry (WBCR) which are prospective, population-based databases. All women newly diagnosed with grade 1 primary invasive breast cancer between 1 June 2000 and 31 May 2013 were identified from the two registries. RESULTS: There were 2857 grade 1 breast cancers diagnosed over this time period. Axillary lymph nodes were involved in 19.0% of women, and 5.1% developed recurrent disease (locoregional or distant). Pacific and Maori women were more likely than NZ European women to have larger tumours and lymphovascular invasion (LVI). Predictors for axillary node involvement were tumour size greater than 10mm, LVI and non-screen detected cancers. Tumour size greater than 10mm, lobular carcinoma and BCS without radiotherapy were predictive of recurrent and or metastatic disease. Ethnicity was not observed to be an independent predictor for axillary nodal involvement, recurrent and/or metastatic disease, or breast cancer specific mortality amongst New Zealand women with grade 1 breast cancer. CONCLUSION: Ethnicity was not a predictor of axillary node involvement, recurrent disease or mortality in grade 1 breast cancer in our population. PMID- 26587909 TI - S-Nitrosylation of NF-kappaB p65 Inhibits TSH-Induced Na(+)/I(-) Symporter Expression. AB - Nitric oxide (NO) is a ubiquitous signaling molecule involved in a wide variety of cellular physiological processes. In thyroid cells, NO-synthase III endogenously produced NO reduces TSH-stimulated thyroid-specific gene expression, suggesting a potential autocrine role of NO in modulating thyroid function. Further studies indicate that NO induces thyroid dedifferentiation, because NO donors repress TSH-stimulated iodide (I(-)) uptake. Here, we investigated the molecular mechanism underlying the NO-inhibited Na(+)/I(-) symporter (NIS) mediated I(-) uptake in thyroid cells. We showed that NO donors reduce I(-) uptake in a concentration-dependent manner, which correlates with decreased NIS protein expression. NO-reduced I(-) uptake results from transcriptional repression of NIS gene rather than posttranslational modifications reducing functional NIS expression at the plasma membrane. We observed that NO donors repress TSH-induced NIS gene expression by reducing the transcriptional activity of the nuclear factor-kappaB subunit p65. NO-promoted p65 S-nitrosylation reduces p65-mediated transactivation of the NIS promoter in response to TSH stimulation. Overall, our data are consistent with the notion that NO plays a role as an inhibitory signal to counterbalance TSH-stimulated nuclear factor-kappaB activation, thus modulating thyroid hormone biosynthesis. PMID- 26587912 TI - Bioaccumulation of human pharmaceuticals in fish across habitats of a tidally influenced urban bayou. AB - Though pharmaceuticals and other contaminants of emerging concern are increasingly observed in inland water bodies, the occurrence and bioaccumulation of pharmaceuticals in estuaries and coastal ecosystems are poorly understood. In the present study, bioaccumulation of select pharmaceuticals and other contaminants of emerging concern was examined in fish from Buffalo Bayou, a tidally influenced urban ecosystem that receives effluent from a major (~200 million gallons per day) municipal wastewater treatment plant in Houston, Texas, USA. Using isotope dilution liquid chromatography-tandem mass spectrometry, various target analytes were observed in effluent, surface water, and multiple fish species. The trophic position of each species was determined using stable isotope analysis. Fish tissue levels of diphenhydramine, which represented the only pharmaceutical detected in all fish species, did not significantly differ between freshwater and marine fish predominantly inhabiting benthic habitats; however, saltwater fish with pelagic habitat preferences significantly accumulated diphenhydramine to the highest levels observed in the present study. Consistent with previous observations from an effluent-dependent freshwater river, diphenhydramine did not display trophic magnification, which suggests site specific, pH-influenced inhalational uptake to a greater extent than dietary exposure in this tidally influenced urban ecosystem. The findings highlight the importance of understanding differential bioaccumulation and risks of ionizable contaminants of emerging concern in habitats of urbanizing coastal systems. PMID- 26587913 TI - "Detached concern" of medical students in a cadaver dissection course: A phenomenological study. AB - The cadaver dissection course remains a time-honored tradition in medical education, partly because of its importance in cultivating professional attitudes in students. This study aims to investigate students' attitudes-specifically characterized as "detached concern"-in a cadaver dissection course. An interpretative phenomenological analysis was performed with semi-structured, focus group interviews among 12 third-year medical students from a Taiwanese medical school to reveal their perceptions and learning experiences regarding human cadaver dissection. Based on these interviews, four relevant categories of perspectives were delineated: (1) initial emotional impact, (2) human referents, (3) coping strategies, and (4) ways of perceiving cadavers. Students were divided into two groups based on these categories. Students in Group 1 developed mechanisms described as "detachment" to cope with their initial emotional reactions to cadaveric dissection, which was noted to have disruptive effects on their learning. They considered human referents to be learning obstacles and avoided contact with or thinking about the human referents while performing dissections. Some of them faced a conflict between perceiving the cadaver as a learning tool versus as a human being. This impasse could be resolved if they latently adopted a "perspective switch" between the concept of a learning tool (rational aspect) and a human being (sensitive aspect). The students in Group 2 had no obvious initial emotional reaction. For them, the human referents functioned as learning supports, and the cadavers were consistently perceived as humans. These students held the notion that "cadaver dissection is an act of love"; therefore, they did not experience any need to detach themselves from their feelings during dissection. This alternative attitude revealed that detached concern alone is not sufficient to describe the entire range of medical students' attitudes toward cadaver dissection. Anat Sci Educ 9: 265-271. (c) 2015 American Association of Anatomists. PMID- 26587915 TI - Treatment of zinc toxicosis in a dog with chelation using d-penicillamine. AB - OBJECTIVE: To describe chelation therapy with d-penicillamine for treatment of zinc toxicosis in a dog. CASE SUMMARY: A 1.5-year-old intact female Maltese dog weighing 2.7 kg was presented with acute, progressive anorexia, lethargy, pigmenturia, and melena. The owner reported that the dog had ingested a hook from a dog leash made of a zinc-based alloy 9 days prior. A blood transfusion was administered and an abdominal radiograph revealed a metal-dense foreign body in the stomach. Laboratory findings revealed a serum zinc concentration of 1845.12 MUg/dL (reference interval, 70-200 MUg/dL) and a decreased hematocrit that remained low despite removal of the zinc foreign body. On day 3, another blood transfusion was performed and d-penicillamine therapy was instituted. After the administration of d-penicillamine, the clinical signs and hemogram progressively improved and the dog was discharged 2 days later. On day 9 after initial presentation, the hematocrit and platelet values were within normal limits and the serum zinc concentration was 280.16 MUg/dL. NEW OR UNIQUE INFORMATION PROVIDED: This case demonstrates the use of d-penicillamine in the treatment of zinc toxicosis. Serum zinc concentration appeared to decline more rapidly after administration of d-penicillamine than before chelation therapy. This is the first report to evaluate serial serum zinc concentrations before and during chelation therapy with d-penicillamine. PMID- 26587914 TI - The effects of acute cortical somatosensory deafferentation on grip force control. AB - Grip force control involves mechanisms to adjust to unpredictable and predictable changes in loads during manual manipulation. Somatosensory feedback is critical not just to reactive, feedback control but also to updating the internal representations needed for proactive, feedforward control. The role of primary somatosensory cortex (S1) in these control strategies is not well established. Here we investigated grip force control in a rare case of acute central deafferentation following resection of S1. The subject had complete loss of somatosensation in the right arm without any deficit in muscle strength or reflexes. In the first task, the subject was asked to maintain a constant grip force with and without visual feedback. The subject was able to attain the target force with visual feedback but not maintain that force for more than a few seconds after visual feedback was removed. In the second task, the subject was asked to grip and move an instrumented object. The induced acceleration-dependent loads were countered by adjustments in grip force. Both amplitude and timing of the grip force modulation were not affected by deafferentation. The dissociation of these effects demonstrates the differential contribution of S1 to the mechanisms of grip force control. PMID- 26587916 TI - Bupropion abuse resulting in hypomania in a geriatric amphetamine user: A case report. AB - BACKGROUND: Bupropion is a commonly prescribed antidepressant which acts on norepinephrine and dopamine neurotransmission. It is structurally similar to amphetamine. Several cases of recreational bupropion ingestion, insufflation, and injection have been reported in the literature. METHODS: Here we report a case of bupropion abuse in a 79-year-old gentleman with a history of alcohol and amphetamine use disorders, resulting in hypertension and hypomanic symptoms. RESULTS: To our knowledge, this is the first case of bupropion abuse documented in an older adult. The literature with respect to bupropion abuse is reviewed, and the matter of stimulant abuse in older adults is considered. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: This case emphasizes the need to consider bupropion's abuse potential when prescribing it to older adults with risk factors for substance abuse. PMID- 26587917 TI - Work-exposure to PM10 and aromatic volatile organic compounds, excretion of urinary biomarkers and effect on the pulmonary function and heme-metabolism: A study of petrol pump workers and traffic police personnel in Kolkata City, India. AB - This study focused work-exposure to particulate matter <= 10 um (PM10), volatile organic compounds (VOCs) and biological monitoring of major VOCs (BTEX) to observe the significant effects of traffic related pollutants on respiratory and hematological systems of workers engaged in two occupational settings, petrol pumps and traffic areas of Kolkata metropolitan city, India. PM10 was assessed by personal sampling and particle size distribution by 8-stage Cascade Impactor. VOCs were analysed by gas chromatography-flame ionization detector (GC-FID) and five urinary metabolites, trans trans- mercapturic acid (tt-MA), S-phenyl mercapturic acid (SPMA), hippuric acid (HA), mandelic acid (MA) and methyl hippuric acid (MHA) of VOCs, benzene, toluene, ethyl benzene and xylenes (BTEX) by reverse phase high performance liquid chromatography (HPLC). Pulmonary functions test (PFT) was measured Spirometrically. ?-aminoleavulinic acid (ALA) and porphobilinogen (PBG) in lymphocytes were measured spectrophometrically following column chromatographic separation. High exposure to PM10, having 50% of particles, <= 5.0 um in both the occupational settings. Exposure to toluene was highest in petrol pumps whereas benzene was highest (104.6 +/- 99.0 MUg m-3) for traffic police personnel. Workplace Benzene is found many fold higher than the National ambient standard. Air-benzene is correlated significantly with pre- and post-shift tt-MA (p < 0.001) and SPMA (p < 0.001) of exposed workers. Blood cell counts indicated benzene induced hematotoxicity. ALA and PBG accumulation in lymphocytes indicated alteration in heme-metabolism, especially among traffic police. Significant reduction of force exploratory volume in one second (FEV1) and forced vital capacity (FVC) of fuel fillers are observed with increased tt-MA and SPMA. Study revealed PFT impairments 11.11% (6.66% restrictive and 2.22% obstructive and combined restrictive and obstructive type, each) among petrol pumps and 8.3% obstructive type among traffic police. PMID- 26587918 TI - Section Editor's Notebook: Impact Factor--An Analog Metric in a Digital World. PMID- 26587919 TI - Opportunities for Targeted Education: Critical Neuroradiologic Findings Missed or Misinterpreted by Residents and Fellows. AB - OBJECTIVE: We reviewed neuroradiology cases in which a resident or fellow missed a significant finding, to identify potential areas of deficiency that could be strengthened through targeted education. MATERIALS AND METHODS: Included in the study were all neuroradiology reports from 2011 through 2013 that were marked with an electronic flag to indicate a significant modification between the preliminary and final versions. The reports were examined to determine whether a critical finding (CF) or a non-CF was missed, with the use of a hospital-approved list of 17 neuroradiology CFs. Results were analyzed for all trainees. RESULTS: A total of 978 modified reports were found among reports from 225,628 neuroradiology examinations. Of these modified reports, 891 (91.1%) contained an addendum that identified the discrepancy: 658 (73.8%) contained a CF,192 (21.7%) contained a non-CF, and 41 (4.6%) were changed from containing a CF to not containing a CF. A total of 725 missed CFs were found in the 658 modified reports. The CF miss rate for all trainees was 6.0% (95% CI, 5.6-6.4%), whereas that for residents was 8.6% and that for fellows was 4.8%. Residents missed hydrocephalus, intracranial pressure or edema, new hemorrhage, and new infarction more frequently than did fellows. The five most frequently missed CFs were congenital variation, infection, misplaced hardware, a new or enlarging mass, and vascular abnormality. CONCLUSION: Our trainees' overall CF miss rate was 6.0%. Five CFs had miss rates of approximately 10% or more, and residents missed four of the CFs more frequently than did fellows. With the use of these data, our curriculum could potentially be strengthened and our trainee error rates decreased, leading to improved patient care. PMID- 26587920 TI - Low-Grade and High-Grade Mucoepidermoid Carcinoma of the Lung: CT Findings and Clinical Features of 17 Cases. AB - OBJECTIVE: The objective of our study was to characterize the CT features and clinical findings of low-grade and high-grade mucoepidermoid carcinoma (MEC) of the lung. MATERIALS AND METHODS: The CT findings and clinical information of 17 consecutive patients with primary low-grade (n = 11) or high-grade (n = 6) MEC were analyzed retrospectively. We assessed tumor location, size, contour, margin, density, calcification, obstructive changes, presence of metastasis, and enhancement. RESULTS: In patients with low-grade MEC, tumor location was central in 10 and peripheral in one. In contrast, one and five tumors in patients with high-grade MEC were central and peripheral, respectively. There was a significant difference between central and peripheral locations among tumor grades (p = 0.005). In low-grade MECs, tumor contour was smoothly oval (n = 3) or spheric (n = 4); four were lobular. In five patients with low-grade MEC, tumors had well defined margins; margins in the other six were poorly defined. Tumor density was homogeneous and heterogeneous in eight and three low-grade tumors, respectively. All six high-grade tumors had heterogeneous density, lobular contours, and poorly defined margins. Enhancement in both low-grade and high-grade tumors was greater than that of chest wall muscles, and low-grade tumors showed greater enhancement (46.90 +/- 20.44 HU) than did high-grade tumors (22.50 +/- 8.38 HU) (p = 0.015). CONCLUSION: A markedly enhanced homogeneous central bronchial nodule or mass may suggest low-grade MEC. High-grade MEC tends to be peripheral, to have poorly defined margins, and to be lobular, heterogeneous nodules or masses with less enhancement. PMID- 26587921 TI - Longitudinal Changes in Liver Fat Content in Asymptomatic Adults: Hepatic Attenuation on Unenhanced CT as an Imaging Biomarker for Steatosis. AB - OBJECTIVE: The objective of this study was to evaluate changes in liver fat content over time in asymptomatic adults and to investigate the factors that may influence these changes. MATERIALS AND METHODS: Liver attenuation on unenhanced CT images of 1022 asymptomatic adults (556 women and 466 men; mean age at the time of the index CT examination, 56.7 years) was retrospectively measured on initial and surveillance CT colonography screening examinations (mean [+/- SD] interval, 5.5 +/- 0.8 years). Changes in liver attenuation (expressed as Hounsfield units) were assessed according to various factors, including body mass index (BMI), age, and sex. RESULTS: Mean liver attenuation was 60.3 HU on the index CT scan and 58.4 HU on the 5-year follow-up CT scan (p < 0.0001). Changes in liver attenuation greater than 10 HU, 5-10 HU, and less than 5 HU were observed in 187 (18%), 212 (21%), and 623 (61%) individuals, respectively. Changes in attenuation greater than 10 HU were negative (i.e., fattier liver) in 130 of 187 individuals (70%) and were more likely to be associated with an increase in BMI (83 of 130 individuals [64%] vs 19 of 57 individuals [33%]; p < 0.0001). For changes in attenuation of 5 HU or more, negative (steatotic) changes outnumbered positive changes, occurring in 258 of 1022 individuals (25%) versus 141 of 1022 individuals (14%) (p < 0.0001). Changes in BMI were negatively correlated with changes in attenuation (p = 0.015). There was no statistically significant correlation between changes in attenuation and either age or sex. An improved lipid profile and the use of a lipid-lowering medication regimen correlated with an interval decrease in liver attenuation. CONCLUSION: Changes in liver attenuation over time, reflecting temporal changes in fat content, were quite variable in this asymptomatic adult population and were only partially explained by the factors examined. These observations may provide early insight into the natural history of incidental hepatic steatosis in asymptomatic adults. PMID- 26587922 TI - Model-Based Iterative Reconstruction in CT Enterography. AB - OBJECTIVE: The purpose of this study was to analyze the performance of pure model based iterative reconstruction (MBIR) in low-dose CT enterography. SUBJECTS AND METHODS: Forty-four patients with Crohn disease referred for CT enterography were included. Low-dose modified-protocol and conventional-protocol CT datasets were contemporaneously acquired. Conventional-protocol image formation was performed with 40% adaptive statistical iterative reconstruction (ASIR). Modified-protocol data were reconstructed with 100% MBIR and 40% ASIR. Image quality was assessed subjectively and objectively at six levels. Independent clinical interpretations by two fully blinded radiologists were compared with reference standard consensus reviews by two nonblinded readers who had access to clinical information, previous imaging studies, and medical records. RESULTS: A 74.7% average radiation dose reduction was seen: low-dose modified-protocol effective dose, 1.61 +/- 1.18 mSv (size-specific-dose-estimate, 2.47 +/- 1.21 mGy); conventional-protocol effective dose, 6.05 +/- 2.84 mSv (size-specific-dose-estimate, 9.25 +/- 2.9 mGy). Image quality assessment yielded 9372 data points. Objective noise on modified-protocol MBIR images was superior (p < 0.05) to that with the conventional protocol at three of six levels and comparable at the other three levels. Modified-protocol images were superior to conventional-protocol ASIR images (p < 0.05 in all cases) for subjective noise, spatial resolution, contrast resolution, streak artifact, and diagnostic acceptability on coronal reconstructions. Axial diagnostic acceptability was superior for conventional protocol ASIR (p = 0.76). For both readers, modified-protocol MBIR clinical readings agreed more closely with reference standard readings than did conventional-protocol ASIR readings with regard to bowel wall disease assessment (kappa = 0.589 and 0.700 vs 0.583 and 0.564). Overall Crohn disease activity grade (kappa = 0.549 and 0.441 vs 0.315 and 0.596) and detection of acute complications (kappa = 1.0 and 0.689 vs 0.896 and 0.896) were comparable when evaluated on conventional-protocol ASIR and modified-protocol MBIR images. CONCLUSION: Low-dose CT enterography with MBIR yields images that are comparable to or superior to conventional images. PMID- 26587923 TI - Effective Treatment of Symptomatic Lower Esophageal (Schatzki) Rings With Acid Suppression Therapy: Confirmed on Barium Esophagography. AB - OBJECTIVE: Symptomatic lower esophageal (Schatzki) rings are one of the most common causes of dysphagia and esophageal food impaction. Although these rings are often diagnosed fluoroscopically, patients are typically referred for dilation procedures performed by a gastroenterologist. Because these procedures are invasive and carry risks, including esophageal perforation, an alternative treatment option is needed. Although recent research has shown the effectiveness of acid suppression medications used in addition to dilation procedures, our objective was to evaluate the effectiveness of treatment with acid suppression medication alone. MATERIALS AND METHODS: We retrospectively evaluated a cohort of nine patients who underwent barium esophagography at our institution to determine the ability to pass a 13-mm barium tablet and to identify a change in the lumen diameter of the lower esophageal rings after treatment with an oral proton pump inhibitor medication. RESULTS: The median ring diameter was 10 mm (range, 8-15 mm) before treatment and 15 mm (range, 13-25 mm) after treatment, a statistically significant difference (p = 0.008). The median tablet passage score was 2 before treatment (with tablet passage paused briefly) and 1 after treatment (with the tablet passing through the esophagus easily without stopping), which was also a statistically significant difference (p = 0.02). CONCLUSION: Significant improvements in both the ring lumen diameter and the ability to pass a tablet through the esophagus indicate that acid suppression medication is an effective alternative to the use of dilation procedures for the treatment of Schatzki rings. PMID- 26587924 TI - Multilocular Cystic Nephroma: A Systematic Literature Review of the Radiologic and Clinical Findings. AB - OBJECTIVE: The objective of our study was to systematically summarize the published evidence of demographic, clinical, diagnostic imaging, and therapeutic characteristics of patients with multilocular cystic nephroma (MLCN). CONCLUSION: Cross-sectional imaging evaluation is important for suggesting the diagnosis of MLCN but has several limitations. The number of radical nephrectomies reported for MLCN encourages discussion concerning the utility of percutaneous presurgical biopsy and frozen-section intraoperative biopsy as a more conservative diagnostic approach. PMID- 26587925 TI - Small (< 4 cm) Renal Masses: Differentiation of Angiomyolipoma Without Visible Fat From Renal Cell Carcinoma Using Unenhanced and Contrast-Enhanced CT. AB - OBJECTIVE: The purpose of this study was to evaluate if small (< 4 cm) angiomyolipoma without visible fat can be differentiated from renal cell carcinoma (RCC) using contrast-enhanced CT alone and using unenhanced and contrast-enhanced CT in combination. MATERIALS AND METHODS: Twenty-three patients with 24 angiomyolipomas without visible fat and 130 patients with 148 RCCs underwent unenhanced and contrast-enhanced CT. Demographic data and size, shape, CT attenuation, and heterogeneity (entropy and subjective score) of the renal mass on unenhanced CT and contrast-enhanced CT were recorded. Multivariate logistic regression models were constructed for parameters obtained by contrast enhanced CT alone and by both unenhanced and contrast-enhanced CT. Demographic data and size and shape of renal mass were used in each model. Sensitivity and specificity were calculated. RESULTS: Logistic regression model from contrast enhanced CT data included sex, percentage of exophytic growth, entropy, and CT attenuation on contrast-enhanced CT. Model from both unenhanced and contrast enhanced CT data included age, sex, short-axis diameter, percentage of exophytic growth, lesion-to-kidney CT attenuation difference on unenhanced CT, and CT attenuation on contrast-enhanced CT. The contrast-enhanced CT-based model and combined unenhanced and contrast-enhanced CT-based model differentiated angiomyolipoma from RCC with sensitivity and specificity of 42% and 98% versus 50% and 98%, respectively. CONCLUSION: Combinations of various CT and demographic findings allowed differentiation of angiomyolipoma from RCC. PMID- 26587926 TI - Characterization of Urinary Stone Composition by Use of Third-Generation Dual Source Dual-Energy CT With Increased Spectral Separation. AB - OBJECTIVE: The purpose of this phantom study was to determine the utility of a third-generation dual-source CT scanner with increased dual-energy spectral separation in differentiating urinary stone composition. MATERIALS AND METHODS: Eighty-seven urinary stones from humans were scanned in 35-, 40-, 45-, and 50-cm wide anthropomorphic phantoms with a third-generation dual-source scanner (system A) with a high-energy beam of 150 kV plus 0.6-mm tin filtration (Sn). The low energy data were acquired at 70, 80, 90, and 100 kV. A second-generation dual source scanner (system B) was used to acquire data at 140 kV plus 0.4-mm Sn for the high-energy and 80 or 100 kV for the low-energy images. Volume CT dose index was matched for a given phantom size. CT number ratios were calculated and used to differentiate uric acid from non-uric acid stones and oxalate from apatite stones in an ROC analysis. RESULTS: The area under the curve (AUC) of the ROC curve for uric acid versus non-uric acid stones increased for large phantoms. For example, for imaging of the 45-cm wide phantom with system A at the 100- and 150 kV Sn low- and high-energy combination, the AUC was 0.99, whereas for system B at the 100- and 140-kV Sn combination, the AUC was 0.86. At each phantom size and for all energy combinations, the AUC values for oxalate versus apatite stones were higher for system A than they were for any energy combination for system B. CONCLUSION: Compared with use of second-generation dual-source CT, use of third generation dual-source CT at the energy combination of 100 and 150 kV Sn improved classification of urinary stones across a wide range of phantom sizes and increased the ability to differentiate oxalate from apatite stones. PMID- 26587927 TI - Prostate Cancer: Utility of Whole-Lesion Apparent Diffusion Coefficient Metrics for Prediction of Biochemical Recurrence After Radical Prostatectomy. AB - OBJECTIVE: The purpose of this study was to investigate the additional value of whole-lesion histogram apparent diffusion coefficient (ADC) metrics, when combined with standard pathologic features, in prediction of biochemical recurrence (BCR) after radical prostatectomy for prostate cancer. MATERIALS AND METHODS: The study included 193 patients (mean age, 61 +/- 7 years) who underwent 3-T MRI with DWI (b values, 50 and 1000 s/mm(2)) before prostatectomy. Histogram metrics were derived from 3D volumes of interest encompassing the entire lesion on ADC maps. Pathologic features from radical prostatectomy and subsequent BCR were recorded for each patient. The Fisher exact test and Mann-Whitney test were used to compare ADC-based metrics and pathologic features between patients with and patients without BCR. Stepwise logistic regression analysis was used to construct multivariable models for prediction of BCR, which were assessed by ROC analysis. RESULTS: BCR occurred in 16.6% (32/193) of patients. Variables significantly associated with BCR included primary Gleason grade, Gleason score, extraprostatic extension, seminal vesicle invasion, positive surgical margin, preoperative prostate-specific antigen level, MRI tumor volume, mean whole-lesion ADC, entropy ADC, and mean ADC of the bottom 10th, 10-25th, and 25-50th percentiles (p <= 0.019). Significant independent predictors of BCR at multivariable analysis were primary Gleason grade, extraprostatic extension, mean of the bottom 10th percentile ADC, and entropy ADC (p = 0.002-0.037). The AUC of this multivariable model was 0.94 for prediction of BCR; the AUC of pathologic features alone was 0.89 (p = 0.001). CONCLUSION: A model integrating whole-lesion ADC metrics had significantly higher performance for prediction of BCR than did standard pathologic features alone and may help guide postoperative prognostic assessments and decisions regarding adjuvant therapy. PMID- 26587928 TI - Solid Renal Cell Carcinoma Measuring Water Attenuation (-10 to 20 HU) on Unenhanced CT. AB - OBJECTIVE: The objectives of this study were to evaluate the incidence of solid renal cell carcinoma (RCC) with attenuation similar to that of water (-10 to 20 HU) on unenhanced CT and to examine imaging features that can allow RCC to be differentiated from simple cysts. MATERIALS AND METHODS: We performed an enriched quantitative and qualitative retrospective analysis of consecutive patients who underwent unenhanced CT before resection of solid (noncystic and nonnecrotic) renal masses measuring < 5 cm from 2008 to 2013. In all, 93 patients with 96 tumors (55 clear cell, 27 papillary, and 14 chromophobe) were evaluated with unenhanced CT. Attenuation was measured at three standardized levels and compared using the Kruskal-Wallis test. Two radiologists independently assessed calcification, margin (smooth or irregular), and heterogeneity (homogeneous or heterogeneous). Results were compared using the chi-square test with Bonferroni correction. RESULTS: Mean +/- SD attenuation values were 31.8 +/- 9.6 HU (range, 11-63 HU) overall, 29.9 +/- 8.8 HU (range, 11.0-49.0 HU) for clear cell tumors, 34.6 +/- 10.3 HU (range, 20.3-63.0 HU) for papillary tumors, and 35.5 +/- 9.2 HU (range, 20.7-47 HU) for chromophobe tumors (p = 0.06). Eight clear cell RCCs had attenuation similar to that of water (15.7 +/- 2.4 HU; range, 11-18.7 HU). There was no significant difference in calcification or margin among different types of tumors (p = 0.91 and p = 0.55, respectively). Chromophobe tumors were more likely to be homogeneous (p < 0.001). Interobserver agreement was moderate to very good (kappa = 0.91 for calcification, kappa = 0.55 for margin, and kappa = 0.44 for heterogeneity). All eight clear cell RCCs with attenuation similar to that of water were considered heterogeneous by both readers. Irregular margins were identified in three of these eight tumors by reader 1 and four of eight tumors by reader 2. CONCLUSION: A minority of solid RCCs have attenuation similar to that of water on unenhanced CT. In this study, all such tumors were of the clear cell subtype and qualitatively heterogeneous, suggesting they can be distinguished from simple cysts on unenhanced CT. PMID- 26587929 TI - Acute Abdomen in the Emergency Department: Is CT a Time-Limiting Factor? AB - OBJECTIVE: The purpose of this study was to quantify and integrate key emergency department (ED) and radiology department workflow time intervals within the ED length of stay (LOS) for patients presenting with acute abdomen who require CT. MATERIALS AND METHODS: An 11-month retrospective review was performed of all patients presenting to the ED with an acute abdomen who required abdominal CT. Nine key time points associated with ED LOS and CT workflow were collected: triage, physician assessment, CT request, porter schedule, CT start, CT complete, provision of first CT report, ED disposition decision, and physical discharge. The median and 90th percentile times for each interval were reported. RESULTS: Ninety-six percent (2194/2292) of ED encounters during the study period met the inclusion criteria. The median ED LOS was 9.22 hours (90th percentile, 15.7 hours). Intervals associated with CT workflow accounted for 29% of the total LOS. Radiology turnaround time accounted for 32% of the entire CT workflow interval. Timeline analysis found three unique patterns of ED disposition: disposition after initial imaging report, disposition before report, and disposition before CT. CONCLUSION: To our knowledge, this study is the first to quantify the contribution of CT-related workflow time intervals within the context of ED LOS. We have shown that patients do not have identical ED transit pathways, and this may under- or overestimate time interval calculations. These results show the importance of site-specific ED LOS timeline analysis to identify potential targets for quality improvement and serve as baseline targets for measuring future quality improvement initiatives. PMID- 26587930 TI - JOURNAL CLUB: Radiology Report Addenda: A Self-Report Approach to Error Identification, Quantification, and Classification. AB - OBJECTIVE: The purpose of this study was to analyze report addenda to assess the self-reported error rate in radiologic study interpretation, the types of errors that occur, and the distribution of error by image modality. MATERIALS AND METHODS: Addenda to all diagnostic radiology reports were compiled over a 1-year period (n = 5568). The overall error rate was based on addenda frequency relative to the total number of studies performed. Addenda written over the most recent 2 month interval (n = 851) were classified into five major categories of predominant error type: underreading, overreading, poor communication, insufficient history, and poor technique. Each category was further divided into multiple subtypes. RESULTS: Diagnostic studies at our hospital had an error rate of 0.8%. Errors of poor communication occurred most frequently (44%), followed by underreading (7%), insufficient history (21%), overreading (8%), and poor technique (1%). Analyzed by imaging modality, most errors occurred in PET (19.45 per 1000 studies), followed by MRI (13.86 per 1000 studies) and CT (12.45 per 1000 studies). CONCLUSION: Through the use of report addenda to calculate error, discrepancy between individual radiologists is removed in a reproducible and widely applicable way. This approach to error typology eliminates sample bias and in a departure from previous analyses of difficult cases shows that errors of communication are most frequent, representing a clear area for targeted improvement. PMID- 26587931 TI - Current Concepts in Total Ankle Replacement for Radiologists: Complications. AB - OBJECTIVE: The purpose of this article is to review current concepts of total ankle replacement from an imaging perspective. The emphasis is on the reported complications and their imaging features in relation to current understanding of how and why these failures occur. CONCLUSION: Total ankle replacement has become mainstream surgical treatment of disabling ankle arthritis. With the many types of prostheses available for sale in the United States, rapid growth in the number of procedures can be expected with concomitant growth in the number of complications. Knowledge gained through experience with the more common hip and knee prostheses can generally be applied to ankle prostheses. Some complications are unique to the ankle, and some are unique to specific ankle prostheses. PMID- 26587932 TI - Femoral Trochlear Groove Morphometry Assessed on Oblique Coronal MR Images. AB - OBJECTIVE: The objective of our study as to assess several indexes relevant to patellofemoral instability (PFI) associated with femoral trochlear dysplasia as measured on oblique coronal MR images at three standardized reference levels. MATERIALS AND METHODS: A total of 30 knee MRI examinations were selected as the study group of PFI patients. Sixty knee MRI examinations were included as a control group. MRI protocols included sagittal T2-weighted, axial proton density weighted, and oblique coronal T2-weighted imaging. On a midline sagittal image, the following three levels of the femoral trochlear groove cartilage were determined: level 1 (one-fourth level of the trochlear groove in the midsagittal plane), level 2 (one-half level of the trochlear groove in the midsagittal plane), and level 3 (three-fourths level of the trochlear groove in the midsagittal plane). Three-level axial and oblique coronal images were selected using the sagittal image as a scout. Femoral trochlear indexes including the sulcus angle, sulcus depth, facet length, and trochlear groove area were measured on the axial and oblique coronal images. RESULTS: Most indexes showed significant differences between the PFI and control groups in the axial and oblique coronal planes at all three levels (p < 0.05). Almost all indexes measured on the oblique coronal plane images were significantly different from those measured on the axial plane images (p < 0.05). Oblique coronal images showed little variability in the sulcus angle among the three levels in contrast to a marked decrease in the angle from the proximal to distal level on axial images. CONCLUSION: Femoral trochlear indexes measured on oblique coronal knee MR images can be used to assess femoral trochlear dysplasia. Oblique coronal images showed less morphologic distortion of the distal femoral trochlear groove than axial images. PMID- 26587933 TI - Cerebral CT Venography Using a 320-MDCT Scanner With a Time-Density Curve Technique and Low Volume of Contrast Agent: Comparison With Fixed Time-Delay Technique. AB - OBJECTIVE: The purpose of this study was to compare a cerebral CT venography (CTV) technique performed on a 320-MDCT scanner with the use of a time-density curve (TDC) and a small volume of IV contrast medium (35 mL, with 15 mL used for the test bolus) with CTV performed using an established reference technique in which scanning is performed at a fixed time delay of 30 seconds with the use of a larger volume of contrast medium (100 mL). MATERIALS AND METHODS: The time of peak enhancement was determined from the TDC generated from a scan in which a test bolus dose was used. CTV was performed at the time of peak enhancement. The diagnostic quality of 31 CTV venograms acquired using this technique was compared retrospectively with the diagnostic quality of 29 CTV venograms obtained at a fixed time delay of 30 seconds. The densities in the major venous sinuses and the degree of arterial contamination on the scans acquired using the two techniques were compared using objective and semiobjective methods. The semiobjective assessments were made independently by two neuroradiologists. RESULTS: Attenuation was higher in the venous structures seen on CTV images acquired using the TDC technique. Of the scans obtained using the TDC technique, the proportion deemed to be of good quality, on the basis of a grading scale, was statistically significantly higher (p < 0.05). Also, the degree of arterial contamination was statistically significantly lower (p < 0.05). The interrater agreement for semiobjective assessments ranged from good to very good. CONCLUSION: We describe a CTV technique performed using a low volume of IV contrast medium and a TDC on a 320-MDCT scanner. This technique provides better venous opacification and lower arterial contamination compared with use of the fixed time-delay technique. PMID- 26587934 TI - Novel Application of Postmortem CT Angiography for Evaluation of the Intracranial Vascular Anatomy in Cadaver Heads. AB - OBJECTIVE: Postmortem CT angiography is a common procedure used to visualize the entire human vasculature. For visualization of a specific organ's vascular anatomy, casting is the preferred method. Because of the permanent and damaging nature of casting, the organ cannot be further used as an experimental model after angiography. Therefore, there is a need for a minimally traumatic method to visualize organ-specific vascular anatomy. The purpose of this study was to develop and evaluate a contrast enhancement technique that is capable of visualizing the intracranial vascular anatomy while preserving the anatomic integrity in cadaver heads. MATERIALS AND METHODS: Seven human heads were used in this study. Heads were prepared by cannulating the vertebral and internal carotid arteries. Contrast agent was injected as a mixture of tap water, polyethylene glycol 600, and an iodinated contrast agent. Postmortem imaging was executed on a 64-MDCT scanner. Primary image review and 3D reconstruction were performed on a CT workstation. RESULTS: Clear visualization of the major cerebral arteries and smaller intracranial branches was achieved. Adequate visualization was obtained for both the anterior and posterior intracranial circulation. The minimally traumatic angiography method preserved the vascular integrity of the cadaver heads. CONCLUSION: A novel application of postmortem CT angiography is presented here. The technique can be used for radiologic evaluation of the intracranial circulation in cadaver heads. After CT angiography, the specimen can be used for further experimental or laboratory testing and teaching purposes. PMID- 26587935 TI - Incidental Thyroid Nodules on CT or MRI: Discordance Between What We Report and What Receives Workup. AB - OBJECTIVE: The objective of this study was to determine the proportion of incidental thyroid nodules (ITNs) reported on CT or MRI that receive additional workup and the factors that influence workup. A secondary aim was to evaluate the effect of the American College of Radiology (ACR) white paper recommendations for reporting of ITNs. MATERIALS AND METHODS: We retrospectively reviewed patients with ITNs reported on CT or MRI studies over 12 months. We identified patients with ITNs that underwent workup and the factors associated with workup. The ACR white paper recommendations were retrospectively applied to estimate how their use would have changed the number of nodules reported in the impression section of radiology reports and the number of cancers diagnosed. The recommendations are based on suspicious imaging features, patient age, and nodule size. RESULTS: A total of 375 patients had ITNs reported. For 138 of these patients (37%), ITNs were reported by radiologists in the impression section of their reports; 26 patients (19%) received workup. Patients with ITNs reported in the impression section were 14 times more likely to undergo workup than were patients with ITNs reported only in the findings section of the radiology report. On multivariate analysis, the only factors associated with workup were younger patient age and larger nodule size (p <= 0.002). The ACR recommendations resulted in a 54% reduction in the number of ITNs reported in the impression section and one missed papillary cancer (TNM classification T1bN0M0). CONCLUSION: Only one in five patients with ITNs reported in the impression section of CT or MRI reports underwent additional workup, and this decision was influenced by younger patient age and larger nodule size. These factors are components of the ACR recommendations, which have the potential to reduce the number of reported ITNs and improve the standardization of radiology reporting. PMID- 26587936 TI - Visualization of the Oropharynx With Transcervical Ultrasound. AB - OBJECTIVE: The purposes of this article are to illustrate the sonographic appearance of the oropharynx and to discuss the potential role of ultrasound in evaluation of the oropharynx. CONCLUSION: Ultrasound is not currently used in the standard clinical evaluation of the oropharynx, but it is a promising imaging modality for evaluating the base of the tongue and the palatine tonsils. Ultrasound is comparable and complementary to CT and MRI, which have recognized limitations. PMID- 26587937 TI - Quantitative Comparison of Misregistration in Abdominal and Pelvic Organs Between PET/MRI and PET/CT: Effect of Mode of Acquisition and Type of Sequence on Different Organs. AB - OBJECTIVE: The objective of our study was to quantitatively compare misregistration in selected abdominopelvic organs between PET/CT acquisitions and simultaneous and sequential PET/MRI acquisitions. SUBJECTS AND METHODS: PET/MR images of 15 healthy volunteers and seven patients with bladder cancer were acquired. Ten clinical PET/CT studies acquired during the same time frame of body mass index-matched control subjects were chosen. PET/MRI and PET/CT registration of selected abdominopelvic organs was measured and compared. RESULTS: The overall mean misregistration with PET/MRI was significantly higher than that with PET/CT (p < 0.001). Sequential PET/MRI acquisition was significantly inferior to PET/CT (p = 0.02), whereas there was no significant difference between simultaneous PET/MRI acquisition and PET/CT (p = 0.38). Simultaneous PET/MRI acquisition was significantly better than sequential PET/MRI acquisition (p < 0.001). The mean misregistration for all organs with the T1-weighted volumetric interpolated breath-hold examination (VIBE) sequence (2.39 cm) was significantly inferior to PET/CT (p < 0.001). Although the T2-weighted HASTE breath-hold sequence was significantly inferior to PET/CT (p = 0.04), the T2 HASTE non-breath-hold sequence and T2 STIR sequence (0.18 cm) were significantly superior to both PET/CT and the T1 VIBE sequence (p < 0.001). Within the same sequence (T1 VIBE breath-hold sequence), the mean misregistrations with sequential and simultaneous PET/MRI acquisitions were both significantly greater than with PET/CT (p < 0.001), whereas simultaneous PET/MRI acquisition was superior to sequential PET/MRI acquisition (p < 0.001). CONCLUSION: In the abdominopelvic organs, sequentially obtained PET/MRI data have significantly higher misregistration than both PET/CT data and simultaneously acquired PET/MRI data. Simultaneously obtained PET/MRI data are statistically noninferior to PET/CT. Nonradial T1 VIBE has the highest misregistration, whereas T2 STIR and T2 HASTE non-breath-hold are significantly better than both PET/CT and T1 VIBE. PMID- 26587938 TI - Incidence and Spectrum of Renal Complications and Extrarenal Diseases and Syndromes in 380 Children and Young Adults With Horseshoe Kidney. AB - OBJECTIVE: The objective of our study was to evaluate the incidence and spectrum of renal complications and of extrarenal diseases and syndromes in children with horseshoe kidney (HSK). MATERIALS AND METHODS: The clinical data and imaging studies of 380 subjects (median age, 2.8 years) diagnosed with HSK over a 24-year period were reviewed: 366 children and young adults and 14 fetuses, one of whom died in utero. All renal complications and extrarenal diseases and syndromes were documented. Patient age, initial imaging modality, follow-up imaging modalities, and imaging modality at diagnosis were recorded. RESULTS: One hundred seventy five patients (46.1%) had renal complications. Pelvocaliectasis without an identifiable cause was the most common complication (n = 83, 21.8%) followed by vesicoureteral reflux (n = 37, 9.7%). Less common renal complications included duplex kidney, multicystic dysplastic kidney, renal stones, asymmetric renal size, ureteropelvic junction obstruction, ureteral stones, acute pyelonephritis, trauma, and renal rhabdomyosarcoma. One hundred ninety patients (50%) had extrarenal diseases or syndromes. Gastrointestinal tract (n = 62) and vertebral (n = 54) anomalies were the most common. Forty-nine patients had syndromes. Turner syndrome was the most common (n = 16) followed by caudal regression syndrome (n = 9). HSK was missed on initial imaging in 42 of 364 postnatal renal examinations and was diagnosed later. The patient groups with renal complications and with extrarenal diseases or syndromes and a missed diagnosis of HSK were significantly younger than the groups without them (p < 0.05, Wilcoxon rank sum test). CONCLUSION: Half of children with HSK have renal complications or extrarenal diseases or syndromes. The incidence is higher in younger children, and the spectrum of complications, diseases, and syndromes differs from those reported in previous studies of adults with HSK. Children with HSK, especially young children, therefore require follow-up renal examinations and extensive extrarenal workup. PMID- 26587939 TI - Pediatric Chest CT: Wide-Volume and Helical Scan Modes in 320-MDCT. AB - OBJECTIVE: The purpose of this study was to compare wide-volume and helical pediatric 320-MDCT of the chest with respect to radiation dose and image quality. MATERIALS AND METHODS: From November 2012 to September 2013, 59 wide-volume and 47 helical pediatric chest 320-MDCT images were obtained. The same tube potential and effective tube current-time product were applied in the two groups according to patient weight (group A, < 10 kg, n = 18; group B, 10-19.9 kg, n = 60; group C, 20-39.9 kg, n = 28). To compensate for overranging, adjusted CT dose index (CTDI) was calculated by dividing dose-length product (DLP) by the scan ranges imaged. Adjusted CTDI, DLP, overall image quality, motion artifact, noise, and scan ranges were compared by Mann-Whitney U test or t test. RESULTS: The adjusted CTDI was significantly lower in the group who underwent wide-volume CT than in the group who underwent helical CT (weight group A, p < 0.001; group B, p < 0.001; group C, p = 0.003). The DLP was lower in the wide-volume group than in the helical CT group in weight groups A (p < 0.001) and B (p < 0.001) but not in group C (p = 0.162). All CT scans were of diagnostic quality, and there was no significant difference between the wide-volume and helical CT groups (p = 0.318). The motion artifact score was significantly higher in the wide-volume group than in the helical CT group in groups B (p < 0.001) and C (p = 0.010) but not in group A (p = 0.931). The noise was significantly lower in the wide-volume group than in the helical CT group (p < 0.001). CONCLUSION: In pediatric chest CT, use of wide-volume CT can decrease radiation exposure while preserving image quality. It is associated with less noise than helical CT but may be subject to more motion artifact. PMID- 26587940 TI - Main Pulmonary Artery-to-Ascending Aorta Diameter Ratio in Healthy Children on MDCT. AB - OBJECTIVE: This study was performed to ascertain whether the adult ratio of 1:1 of the diameter of the main pulmonary artery (MPA) to the diameter of the ascending aorta (AA) (referred to hereafter as the MPA-to-AA ratio) on MDCT is applicable to children. MATERIALS AND METHODS: Our hypothesis, which is based on experiential observation, is that the MPA-to-AA ratio would be higher than 1 in healthy children. A retrospective analysis of vessel calibers in a population of children without pulmonary hypertension who had undergone MDCT was performed. RESULTS: The MPA-to-AA ratio was statistically significantly higher in children of all ages than in adults. We would, therefore, submit that the normal MPA-to-AA ratio in children on MDCT is greater than 1 and closer to 1.09. CONCLUSION: The demonstration of an MPA segment that is slightly larger than the AA in children undergoing MDCT should not suggest a diagnosis of pulmonary arterial hypertension. PMID- 26587941 TI - Thirty-Day Outcomes After Percutaneous Nephrostomy of Renal Transplant Kidneys: 19-Year Experience and Comparison With Existing Practice Parameters. AB - OBJECTIVE: The purpose of our study was to document the technical success rate, complications, and 30-day outcome after percutaneous nephrostomy catheter insertion into renal grafts. MATERIALS AND METHODS: Radiologic and clinical databases were used to identify all adult patients who underwent renal transplantation from January 1994 through December 2012. Patients who underwent transplant percutaneous nephrostomy catheter insertion for the immediate management of ureteric obstruction or leak were identified, and the 30-day outcomes were recorded. Complications were graded using the Society of Interventional Radiology and Clavien classification systems. RESULTS: Of 1476 consecutive kidney transplants, a total of 73 nephrostomy catheters were successfully inserted into 52 patients (male, 36; age range, 24-72 years), 45 with strictures and seven with strictures with leaks. The median serum creatinine level improved from 276 MUmol/L (95% CI, 229-342 MUmol/L) to 195 MUmol/L (95% CI, 170-223 MUmol/L) 7 days after intervention (p = 0.0001). Five complications were seen within 30 days and all were related to bleeding (Society of Interventional Radiology classification: grade A, n = 2; grade B, n = 2; grade D, n = 1; and Clavien classification system: grade I, n = 4; grade IIIa, n = 1). The overall complication rate was 6.8% (5/73), and the major complication rate was 1.4% (1/73). There were no cases of bowel injury or septicemia. The 30-day graft and mortality rates were 0%. CONCLUSION: Transplant percutaneous nephrostomy catheter insertion has a high technical and clinical success rate. The 30-day graft and mortality rates were 0%, the overall complication rate was 6.8%, and the major complication rate was 1.4%. PMID- 26587942 TI - Automated Tube Voltage Selection for Radiation Dose Reduction in CT Angiography Using Different Contrast Media Concentrations and a Constant Iodine Delivery Rate. AB - OBJECTIVE: The purpose of this study was to systematically investigate radiation dose reduction using automated tube voltage selection during CT angiography (CTA) and to evaluate the impact of contrast medium (CM) injection protocols on dose reduction. MATERIALS AND METHODS: A circulation phantom containing the thoracic and abdominal vasculature was used. Four different concentrations of CM (iopromide 300 and 370 mg I/mL and iomeprol 350 and 400 mg I/mL) were administered while maintaining an identical iodine delivery rate (1.8 g I/s) and total iodine load (20.0 g). Three different scanning protocols for CTA of the thoracoabdominal aorta were used: protocol A, no dose modulation; protocol B, automated tube current modulation (CARE Dose4D); and protocol C, automated tube voltage selection (CARE kV). The dose-length product was recorded to calculate the effective dose. Attenuation values (in Hounsfield units), image noise levels, and signal-to-noise ratios (SNRs) in six predefined intravascular sites (three thoracic and three abdominal) were measured by two readers. All values were analyzed using the Kruskal-Wallis test and two-way ANOVA. RESULTS: There was a significant reduction in the effective dose (in millisieverts) for protocols B (mean +/- SD, 2.03 +/- 0.1 mSv) and C (1.00 +/- 0.0 mSv) compared with protocol A (4.34 +/- 0.0 mSv). The dose was reduced by 53% for protocol B and by 77% for protocol C. No significant differences were found in the effective dose among the different CM injection protocols within the scanning protocols; all p values were > 0.05. The attenuation values and SNRs were comparable among all the different CM injection protocols; all p values were > 0.05. CONCLUSION: A large radiation dose reduction (77%) can be achieved using automated tube voltage selection independent of the CM injection protocol. PMID- 26587943 TI - Architectural Distortion on Mammography: Correlation With Pathologic Outcomes and Predictors of Malignancy. AB - OBJECTIVE: The objective of our study was to determine the risk of malignancy associated with architectural distortion and to evaluate the imaging and clinical features that may contribute to the prediction of malignancy in the setting of architectural distortion. MATERIALS AND METHODS: We performed a retrospective review of architectural distortion cases from January 1, 2004, to December 31, 2013. Imaging findings and pathology outcomes were reviewed. RESULTS: Over the 10 year study period, architectural distortion that was considered to be suspicious for or highly suggestive of malignancy was present in 435 of 231,051 (0.2%) mammographic examinations. Cases were excluded if the main finding described was a mass with an associated feature of architectural distortion (n = 62) or if no pathology results were available (n = 4). Two hundred seventy-five cases of invasive adenocarcinoma or ductal carcinoma in situ (DCIS) were identified; the positive predictive value (PPV) was therefore 74.5% (275/369). DCIS alone was identified in only 4.1% (15/369). The most common benign finding on pathology was a radial scar or complex sclerosing lesion (27/369, 7.3%). Architectural distortion was less likely to represent malignancy on screening mammography than on diagnostic mammography (67.0% vs 83.1%, respectively; p < 0.001). Architectural distortion without a sonographic correlate was less likely to represent malignancy than architectural distortion with a correlate (27.9% vs 82.9%, respectively; p < 0.001). There was no statistically significant difference in the malignancy rate between pure architectural distortion and architectural distortion with calcifications or asymmetries (73.0% vs 78.8%; p = 0.26). CONCLUSION: The PPV of architectural distortion for malignancy is 74.5%. Architectural distortion is less likely to represent malignancy if detected on screening mammography than on diagnostic mammography or if there is no sonographic correlate. PMID- 26587945 TI - Is Monitoring of Total Beam-On Time a Sufficient Measure of Patient Radiation Exposure in the Interventional Cardiology Laboratories? PMID- 26587944 TI - Imaging Features of Uncommon Gynecologic Cancers. AB - OBJECTIVE: The role of imaging in patients with suspected gynecologic malignancies is to provide an accurate diagnosis to achieve the best and most tailored treatment plan. Uncommon cancers pose a distinct challenge, because current knowledge of these diseases is still limited. Our purpose is to highlight the role of cross-sectional imaging techniques, including ultrasound, CT, MRI, and PET/CT, in the diagnosis and pretreatment stratification of patients with rare gynecologic cancers. CONCLUSION: This review shows the relevance of imaging findings for diagnosis, staging, and treatment planning in patients with uncommon uterine, cervical, vaginal, vulvar, and ovarian cancers. PMID- 26587946 TI - Fluid-Fluid Level and Pericardial Hyperdense Ring Appearance Findings on Unenhanced Postmortem CT Can Differentiate Between Postmortem and Antemortem Pericardial Hemorrhage. AB - OBJECTIVE: The objective of this study was to determine whether selected postmortem unenhanced CT findings can discriminate between antemortem and postmortem pericardial hemorrhage. MATERIALS AND METHODS: Thirty-one consecutive cases of postmortem CT followed by autopsy identifying at least 50 mL of hemorrhaged blood were reviewed. Seven cases were classified as postmortem pericardial hemorrhage secondary to chest compression (postmortem group), and 24 cases were classified as antemortem pericardial hemorrhage secondary to disease or trauma (antemortem group), on the basis of autopsy findings. Postmortem CT findings of pericardial hemorrhage were classified as stratification comprising upper low-density and lower high-density areas (i.e., fluid-fluid level) and a high-density concentric ring (i.e., pericardial hyperdense ring). Diagnostic values for detecting antemortem or postmortem pericardial hemorrhage using this classification system, along with attenuation (in Hounsfield units) of pericardial hemorrhage lesions and the presence or absence of flattened heart sign on postmortem CT, were measured. RESULTS: There were statistically significant differences in fluid-fluid level and pericardial hyperdense ring between the postmortem and antemortem groups (p < 0.001). The sensitivity, specificity, positive predictive value, and negative predictive value of fluid fluid level for detecting postmortem pericardial hemorrhage were 86%, 96%, 86%, and 100%, respectively. The mean attenuation of pericardial hemorrhage lesions differed statistically significantly between the groups (p = 0.004). The presentation of the flattened heart sign did not differ statistically significantly between the groups (p = 0.681). CONCLUSION: Fluid-fluid level and pericardial hyperdense ring on postmortem CT, combined with attenuation, are useful for differentiating between antemortem and postmortem pericardial hemorrhage secondary to chest compression. PMID- 26587947 TI - MDCT Diagnosis of Perineural Invasion Involving the Celiac Plexus in Intrahepatic Cholangiocarcinoma: Preliminary Observations and Clinical Implications. AB - OBJECTIVE: The purpose of this study was to test the hypothesis that soft-tissue infiltration along the celiac plexus and delayed enhancement exceeding two-thirds of the tumor area on preoperative MDCT correlate with histologic evidence of perineural invasion in resected intrahepatic cholangiocarcinomas. MATERIALS AND METHODS: Two experienced abdominal radiologists retrospectively reviewed preoperative multiphasic MDCT scans of 20 patients who underwent resection of intrahepatic cholangiocarcinoma, identifying soft-tissue infiltration along the celiac plexus, delayed enhancement exceeding two-thirds of the tumor area, and maximum tumor diameter. Consensus findings were compared with intratumoral perineural invasion in resected intrahepatic cholangiocarcinomas using the Fisher exact test. RESULTS: Six patients had histologic intratumoral perineural invasion, five of whom had soft-tissue infiltration along the celiac plexus on preoperative MDCT, with corresponding 83.3% sensitivity and 92.9% specificity for perineural invasion and significant association between these MDCT and histologic findings (p = 0.002). No patients with histologic perineural invasion had enhancement exceeding two-thirds of the tumor area on MDCT; sensitivity was 0.0% for this finding. Tumor diameter on MDCT was not significantly associated with perineural invasion at histopathology (p = 0.530). CONCLUSION: Soft-tissue infiltration along the celiac plexus on MDCT is an indicator of perineural invasion in patients with intrahepatic cholangiocarcinoma. The data did not confirm an association between delayed enhancement exceeding two-thirds of the tumor area and perineural invasion. Because perineural invasion from intrahepatic cholangiocarcinoma is associated with a very poor prognosis and is generally a contraindication to surgery, the MDCT diagnosis of celiac plexus perineural invasion in patients with intrahepatic cholangiocarcinoma may have important implications for prognosis and treatment planning. PMID- 26587948 TI - Ratio of Tumor to Normal Prostate Tissue Apparent Diffusion Coefficient as a Method for Quantifying DWI of the Prostate. AB - OBJECTIVE: The purpose of this study was to investigate the ability of the apparent diffusion coefficient (ADC) ratio of tumor to normal prostate tissue to overcome inherent variability based on choice of b values, with whole-mount histopathologic analysis as the reference standard for tumor identification. MATERIALS AND METHODS: Thirty-nine patients with prostate cancer underwent 3-T MRI, including DWI with b values of 0, 150, 750, and 1000 s/mm(2). ADC maps were derived from four b value combinations. Histologically derived ROIs were defined for prostate tumor and benign prostate tissue to generate a ratio. The concordance correlation coefficient was used to evaluate agreement and reproducibility at different b values. Bland-Altman plots were used to evaluate the pattern of relative measurement difference between b value combinations. The relationship between ADC values and Gleason score was tested by Spearman rank correlation. RESULTS: ADC values varied depending on the b value combination selected. The concordance correlation coefficient was higher for ADC ratios (0.883; 95% CI, 0.816-0.927) compared with absolute ADC values for normal tissue (0.873; 95% CI, 0.799-0.921) and tumor (0.792; 95% CI, 0.688-0.864). The ADC ratio concordance correlation coefficient for transition zone tumors was considerably higher than that for the peripheral zone in all cases. Bland-Altman analysis showed higher variation for ADC maps incorporating a b value of zero for both ratio and absolute values. There was a stronger inverse relationship to Gleason score for ADC ratios (rho, -0.354 to -0.456) compared with absolute ADC values (rho, -0.117 to -0.379). CONCLUSION: The use of a simple ratio of prostate tumor ADC to normal tissue ADC improved the concordance between different b value combinations and could provide a more robust means of assessing restricted diffusion in the prostate. PMID- 26587949 TI - Initial Performance of Radiologists and Radiology Residents in Interpreting Low Dose (2-mSv) Appendiceal CT. AB - OBJECTIVE: The objective of our study was to prospectively evaluate the initial diagnostic performance and learning curve of a community of radiologists and residents in interpreting 2-mSv appendiceal CT. SUBJECTS AND METHODS: We included 46 attending radiologists and 153 radiology residents from 22 hospitals who completed an online training course of 30 2-mSv CT cases. Appendicitis was confirmed in 14 cases. Most of the readers had limited (<= 10 cases, n = 32) or no (n = 118) prior experience with low-dose appendiceal CT. The order of cases was randomized for each reader. A multireader multicase ROC analysis was performed. Generalized estimating equations were used to model the learning curves in diagnostic performance. RESULTS: Diagnostic performance gradually improved with years of training. The average AUC was 0.94 (95% CI, 0.90-0.98), 0.92 (0.88-0.96), 0.90 (0.85-0.96), and 0.86 (0.80-0.92) for the attending radiologists, senior residents, 2nd-year residents, and 1st-year residents, respectively. We did not observe any notable intrareader learning curves over the training course of the 30 cases except a decrease in reading time. Diagnostic accuracy and sensitivity were significantly affected by the reader training level and prior overall experience with appendiceal CT but not by the prior specific experience with low-dose appendiceal CT. CONCLUSION: The learning curve is likely prolonged and forms gradually over years by overall radiology training and clinical experience in general rather than by experience with low-dose appendiceal CT specifically. PMID- 26587950 TI - A Different Type of Talocalcaneal Coalition With Os Sustentaculum: The Continued Necessity of Revision of Classification. AB - OBJECTIVE: The objective of our study was to retrospectively determine the prevalence and image findings of extraarticular talocalcaneal coalition with os sustentaculum, a type of talocalcaneal coalition that does not appear in current classification systems, in patients with an imaging diagnosis of foot coalition. MATERIALS AND METHODS: This study was performed using a database query of radiology reports of ankle and foot CT or MRI examinations performed from August 2001 to November 2013. Eighty-one patients were identified through a keyword search of the database for "talocalcaneal coalition," "tarsal coalition," "coalition," or "os sustentaculum." Imaging features of CT or MRI findings were evaluated. Chart review was used to identify demographic information. RESULTS: Extraarticular talocalcaneal coalition with os sustentaculum was diagnosed in 13 patients (nine men, four women), which represents a prevalence of 16.0% (13/81) in all foot coalitions and 24.1% (13/54) in all talocalcaneal coalitions. Four of 13 patients underwent surgical resection, and histology was obtained in three patients. Nine patients who had no history of trauma were symptomatic and all patients with bone marrow edema at the coalition sites on MRI (n = 5) were also symptomatic. Coexisting extraarticular talocalcaneal coalition with os sustentaculum and intraarticular talocalcaneal coalition were observed in 11 of 13 patients. CONCLUSION: The os sustentaculum is a component of extraarticular talocalcaneal coalitions and as such is usually related to the presence of symptoms. If a patient with an os sustentaculum has symptoms in the medial talocalcaneal joint area, an extraarticular talocalcaneal coalition related to the os sustentaculum should be considered. PMID- 26587951 TI - The Many Faces of Granulomatosis With Polyangiitis: A Review of the Head and Neck Imaging Manifestations. AB - OBJECTIVE: Wegener granulomatosis has recently been renamed as granulomatosis with polyangiitis (GPA). In this review, we examine the clinical criteria and pathologic and pathophysiologic mechanisms of GPA, with an emphasis on findings encountered in the realm of head and neck imaging. Particular attention is paid to generating an appropriate differential diagnosis, because many of the imaging features of GPA overlap with those of other diseases, most notably lymphoma and sarcoidosis. Recent therapeutic advancements have underscored the importance of the radiologist in suggesting the diagnosis early, resulting in earlier treatment and decreased patient morbidity. This is particularly true for the head and neck manifestations of GPA; although they are less common, they often herald a refractory disease course that requires aggressive immunosuppressive therapy. Knowledge of common and uncommon imaging findings enables the radiologist to diagnose GPA early enough to start treatment promptly and reduce patient morbidity. CONCLUSION: Although there are no reliable pathognomonic imaging features for GPA, the present article attempts to identify patterns of disease that are suggestive of the disease. The diagnosis ultimately relies on a constellation of radiographic findings, laboratory values, and accurate clinical history. PMID- 26587952 TI - The Breast Tumor Strain Ratio Is a Predictive Parameter for Axillary Lymph Node Metastasis in Patients With Invasive Breast Cancer. AB - OBJECTIVE: The purpose of this study was to evaluate the association between the breast tumor strain ratio and axillary lymph node metastasis in patients with invasive breast cancer. MATERIALS AND METHODS: The records of 284 patients with invasive breast cancer who underwent ultrasound elastography before surgery between March 2013 and May 2014 were reviewed retrospectively. For women with multifocal or bilateral cancer, the largest tumor was included. An experienced radiologist performed ultrasound elastography and measured the strain ratio, which is defined as the fat-to-lesion ratio and is indicative of the relative stiffness of the breast lesion, using dedicated software within the ultrasound equipment. The associations between axillary lymph node metastasis with the tumor strain ratio and clinical and biologic variables were evaluated using univariate and multivariate logistic regression analyses. RESULTS: Among 284 tumors, 85 (29.9%) showed axillary lymph node metastasis by surgical histopathologic analysis. The strain ratio was statistically significantly higher in tumors with axillary lymph node metastasis than in those without axillary lymph node metastasis (mean +/- SD, 5.19 +/- 1.28 vs 4.17 +/- 1.30, respectively; p < 0.001). On univariate analysis, a higher strain ratio (> 3.89), larger tumor size (> 2 cm), higher histologic grade (grade 3), presence of lymphovascular invasion, palpability, and higher expression of Ki-67 (>= 14%) were statistically significantly associated with axillary lymph node metastasis. On multivariate analysis, a higher strain ratio (> 3.89) (odds ratio [OR], 14.208; p < 0.001), presence of lymphovascular invasion (OR, 17.437; p < 0.001), and higher expression of Ki-67 (>= 14%) (OR, 3.744; p = 0.002) maintained independent significance for predicting axillary lymph node metastasis. CONCLUSION: The breast tumor strain ratio on ultrasound elastography is associated independently with axillary lymph node metastasis in patients with invasive breast cancer. PMID- 26587953 TI - Medicolegal--Malpractice and Ethical Issues in Radiology. In Response to Your Query About Temporary Loss of Mammography Accreditation. PMID- 26587954 TI - The Use of Lossy Compression of Digital Mammograms for Primary Interpretation and Image Retention. PMID- 26587955 TI - Reply to "The Use of Lossy Compression of Digital Mammograms for Primary Interpretation and Image Retention". PMID- 26587956 TI - Dual Pathology? Autoimmune Pancreatitis and Ductal Adenocarcinoma. PMID- 26587957 TI - Feedback control of one's own action: Self-other sensory attribution in motor control. AB - The sense of agency, the subjective experience of controlling one's own action, has an important function in motor control. When we move our own body or even external tools, we attribute that movement to ourselves and utilize that sensory information in order to correct "our own" movement in theory. The dynamic relationship between conscious self-other attribution and feedback control, however, is still unclear. Participants were required to make a sinusoidal reaching movement and received its visual feedback (i.e., cursor). When participants received a fake movement that was spatio-temporally close to their actual movement, illusory self-attribution of the fake movement was observed. In this situation, since participants tried to control the cursor but it was impossible to do so, the movement error was increased (Experiment 1). However, when the visual feedback was reduced to make self-other attribution difficult, there was no further increase in the movement error (Experiment 2). These results indicate that conscious self-other sensory attribution might coordinate sensory input and motor output. PMID- 26587958 TI - Body-scaled affordances in sensory substitution. AB - The research field on sensory substitution devices has strong implications for theoretical work on perceptual consciousness. One of these implications concerns the extent to which the devices allow distal attribution. The present study applies a classic empirical approach on the perception of affordances to the field of sensory substitution. The reported experiment considers the perception of the stair-climbing affordance. Participants judged the climbability of steps apprehended through a vibrotactile sensory substitution device. If measured with standard metric units, climbability judgments of tall and short participants differed, but if measured in units of leg length, judgments did not differ. These results are similar to paradigmatic results in regular visual perception. We conclude that our sensory substitution device allows the perception of affordances. More generally, we argue that the theory of affordances may enrich theoretical debates concerning sensory substitution to a larger extent than has hitherto been the case. PMID- 26587959 TI - Rab, Arf, and Arl-Regulated Membrane Traffic in Cortical Neuron Migration. AB - The migration of projection neurons from its birthplace in the subventricular zone to their final destination in the cortical plate is a complex process that requires a series of highly coordinated cellular events. Amongst the key factors involved in the processes are modulators of cytoskeletal dynamics, as well as cellular membrane traffic. Members of the small GTPases family responsible for the latter process, the Rabs and Arfs, have been recently implicated in cortical neuron migration. Rab5 and Rab11, which are key modulators of endocytosis and endocytic recycling respectively, ensure proper surface expression and distribution of N-cadherin, a key adhesion protein that tethers migrating neurons to the radial glia fiber tracts during pia-directed migration. Rab7, which is associated with lysosomal biogenesis and function, is important for the final step of terminal translocation when N-cadherin is downregulated by lysosomal degradation. Arf6 activity, which is known to be important in neuronal processes outgrowth, may negatively impact the multipolar-bipolar transition of cortical neurons undergoing radial migration, but the downstream effector of Arf6 in this regard is not yet known. In addition to the above, members of the Arl family which have been recently shown to be important in radial glia scaffold formation, would also be important for cortical neuron migration. In this short review, we discuss recent advances in our understanding of the importance of membrane traffic regulated by the Rab, Arf, and Arl family members in cortical neuron migration. PMID- 26587960 TI - Symptoms of thyrotoxicosis, bone metabolism and occult atrial fibrillation in older women with mild endogenous subclinical hyperthyroidism. AB - OBJECTIVE: The objective of this study was to evaluate symptoms of thyrotoxicosis, bone turnover, bone mineral density (BMD) and occult atrial fibrillation (AF) in women >=65 years with mild endogenous subclinical hyperthyroidism (SCH). DESIGN: Cross-sectional and case-control study. PATIENTS: Signs and symptoms of thyrotoxicosis, serum carboxyterminal telopeptide (CTx) and procollagen type I N-terminal propeptide (PINP), BMD, resting electrocardiogram (ECG) and 72-h ECG monitoring were evaluated in 180 women >=65 years, including 90 with mild SCH (TSH between 0.1 and 0.4 mIU/l) and 90 euthyroid controls matched for age and body mass index. RESULTS: Symptom Rating Scale scores did not differ between patients and controls. None of the patients with SCH scored 20 points, a score compatible with clinical thyrotoxicosis. Eighty patients with SCH (89%) obtained seven or fewer points, a score compatible with euthyroidism. No difference in serum CTx or PINP concentrations was observed between patients and controls. There was also no correlation between these markers and TSH, free T4 or total T3 levels. Finally, no difference in femoral neck or lumbar spine BMD was observed between patients with SCH and controls. Three patients with SCH (3.3%) and two euthyroid women (2.2%) had known AF or AF in the resting ECG. ECG monitoring for 72 h revealed episodes of occult AF in 1/87 patients with SCH and in 1/88 euthyroid women (1.1%). CONCLUSIONS: Mild endogenous SCH (TSH between 0.1 and 0.4 mIU/l) was not associated with symptoms of thyrotoxicosis, altered bone metabolism or a higher prevalence of occult AF in women >=65 years. PMID- 26587961 TI - Sensori-motor strategic variations and sequential effects in young and older adults performing a Fitts' task. AB - The present study aimed at investigating age-related changes in strategic variations and sequential effects in discrete Fitts' aiming task. Three sequential effects were investigated, namely trial sequential difficulty effects (TSDE), strategy sequential difficulty effects (SSDE), and strategy repetition effects (SRE). After generalizing previously observed aging effects on strategic variations, our results showed that movement times were longer when performed after harder ID level than when following easier ID level (TSDE). We also observed SSDE, such that is movement times were longer when participants executed a strategy of intermediate difficulty (i.e., the progressive-deceleration strategy) after having used a more difficult strategy (i.e., the undershoot strategy) on the previous trial than after an easier strategy (i.e., the one-shot strategy). These sequential difficulty effects related to both difficulty and strategy were similar in young and older adults. In addition, we found that across two successive trials, participants tended to repeat the one-shot strategy the most often and the undershoot strategy the least often, with repetition rates of the progressive-deceleration strategy being in-between (SRE). Finally, age related differences in strategy repetition effects varied with strategies (e.g., they were largest for the one-shot strategy). These findings have important implications for deciphering processes responsible for sequential effects in sensori-motor tasks as well as in cognitive tasks in general, and for our understanding of processes underlying sensori-motor performance in young and older adults. PMID- 26587962 TI - Atypical biological motion kinematics are represented by complementary lower level and top-down processes during imitation learning. AB - Learning a novel movement requires a new set of kinematics to be represented by the sensorimotor system. This is often accomplished through imitation learning where lower-level sensorimotor processes are suggested to represent the biological motion kinematics associated with an observed movement. Top-down factors have the potential to influence this process based on the social context, attention and salience, and the goal of the movement. In order to further examine the potential interaction between lower-level and top-down processes in imitation learning, the aim of this study was to systematically control the mediating effects during an imitation of biological motion protocol. In this protocol, we used non-human agent models that displayed different novel atypical biological motion kinematics, as well as a control model that displayed constant velocity. Importantly the three models had the same movement amplitude and movement time. Also, the motion kinematics were displayed in the presence, or absence, of end state-targets. Kinematic analyses showed atypical biological motion kinematics were imitated, and that this performance was different from the constant velocity control condition. Although the imitation of atypical biological motion kinematics was not modulated by the end-state-targets, movement time was more accurate in the absence, compared to the presence, of an end-state-target. The fact that end-state targets modulated movement time accuracy, but not biological motion kinematics, indicates imitation learning involves top-down attentional, and lower-level sensorimotor systems, which operate as complementary processes mediated by the environmental context. PMID- 26587963 TI - Approximate number and approximate time discrimination each correlate with school math abilities in young children. AB - What is the relationship between our intuitive sense of number (e.g., when estimating how many marbles are in a jar), and our intuitive sense of other quantities, including time (e.g., when estimating how long it has been since we last ate breakfast)? Recent work in cognitive, developmental, comparative psychology, and computational neuroscience has suggested that our representations of approximate number, time, and spatial extent are fundamentally linked and constitute a "generalized magnitude system". But, the shared behavioral and neural signatures between number, time, and space may alternatively be due to similar encoding and decision-making processes, rather than due to shared domain general representations. In this study, we investigate the relationship between approximate number and time in a large sample of 6-8 year-old children in Uruguay by examining how individual differences in the precision of number and time estimation correlate with school mathematics performance. Over four testing days, each child completed an approximate number discrimination task, an approximate time discrimination task, a digit span task, and a large battery of symbolic math tests. We replicate previous reports showing that symbolic math abilities correlate with approximate number precision and extend those findings by showing that math abilities also correlate with approximate time precision. But, contrary to approximate number and time sharing common representations, we find that each of these dimensions uniquely correlates with formal math: approximate number correlates more strongly with formal math compared to time and continues to correlate with math even when precision in time and individual differences in working memory are controlled for. These results suggest that there are important differences in the mental representations of approximate number and approximate time and further clarify the relationship between quantity representations and mathematics. PMID- 26587964 TI - Evaluation of the effect of post-translational modification toward protein structure: Chemical synthesis of glycosyl crambins having either a high mannose type or a complex-type oligosaccharide. AB - Glycoproteins are assembled and folded in the endoplasmic reticulum (ER) and transported to the Golgi for further processing of their oligosaccharides. During these processes, two types of oligosaccharides are used: that is, high mannose type oligosaccharide in the ER and complex-type oligosaccharide in the Golgi. We were interested to know how two different types of oligosaccharides could influence the folding pathway or the final three-dimensional structure of the glycoproteins. For this purpose, we synthesized a new glycosyl crambin having complex-type oligosaccharide and evaluated the folding process, the final protein structure analyzed by NMR, and compared the CD spectra with previously synthesized glycosyl crambin bearing high mannose-type oligosaccharides. From our analysis, we found that the two different oligosaccharides do not influence the folding pathway in vitro and the final structure of the small glycoproteins. (c) 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 446-452, 2016. PMID- 26587965 TI - The plant secondary metabolite citral alters water status and prevents seed formation in Arabidopsis thaliana. AB - Based on previous results, which showed that the secondary metabolite citral causes disturbances to plant water status, the present study is focused on demonstrating and detailing these effects on the water-related parameters of Arabidopsis thaliana adult plants, and their impact on plant fitness. Clear evidence of effects on water status and fitness were observed: plants treated with 1200 and 2400 MUm citral showed decreased RWC, reduced Psis , increased Psiw and reduced stomatal opening, even 7 days after the beginning of the experiment. Plant protection signals, such as leaf rolling or increased anthocyanin content, were also detected in these plants. In contrast, 14 days after beginning the treatment, treated plants showed signs of citral-related damage. Moreover, the reproductive success of treated plants was critically compromised, with prematurely withered flowers and no silique or seed development. This effect of citral on fitness of adult plants suggests a promising application of this natural compound in weed management by reducing the weed seed bank in the soil. PMID- 26587966 TI - Differential distribution of the sodium-activated potassium channels slick and slack in mouse brain. AB - The sodium-activated potassium channels Slick (Slo2.1, KCNT2) and Slack (Slo2.2, KCNT1) are high-conductance potassium channels of the Slo family. In neurons, Slick and Slack channels are involved in the generation of slow afterhyperpolarization, in the regulation of firing patterns, and in setting and stabilizing the resting membrane potential. The distribution and subcellular localization of Slick and Slack channels in the mouse brain have not yet been established in detail. The present study addresses this issue through in situ hybridization and immunohistochemistry. Both channels were widely distributed and exhibited distinct distribution patterns. However, in some brain regions, their expression overlapped. Intense Slick channel immunoreactivity was observed in processes, varicosities, and neuronal cell bodies of the olfactory bulb, granular zones of cortical regions, hippocampus, amygdala, lateral septal nuclei, certain hypothalamic and midbrain nuclei, and several regions of the brainstem. The Slack channel showed primarily a diffuse immunostaining pattern, and labeling of cell somata and processes was observed only occasionally. The highest Slack channel expression was detected in the olfactory bulb, lateral septal nuclei, basal ganglia, and distinct areas of the midbrain, brainstem, and cerebellar cortex. In addition, comparing our data obtained from mouse brain with a previously published study on rat brain revealed some differences in the expression and distribution of Slick and Slack channels in these species. J. Comp. Neurol. 524:2093-2116, 2016. (c) 2015 The Authors The Journal of Comparative Neurology Published by Wiley Periodicals, Inc. PMID- 26587967 TI - Effects of fermentation time and low temperature during the production process of Thai pickled fish (pla-som) on the viability and infectivity of Opisthorchis viverrini metacercariae. AB - Contamination of a popular fermented fish dish, pla-som, by Opisthorchis viverrini metacercariae (OVMC) is a possible cause of carcinogenic liver fluke infection in Thailand. Affected individuals are at risk of bile duct cancer, which is a major health problem for people in the Greater Mekong Subregion. In order to investigate concerns about food safety, we studied the effects of fermentation time and low temperature on the viability and infectivity of OVMC during the pla-som production process. Pla-som was prepared at room temperature for up to 1 week in duplicate experiments using cyprinid freshwater fish obtained from an O. viverrini-endemic area. OVMC were then isolated and identified under a stereomicroscope. Complete and viable OVMC were found on days 1-4 of fermentation, while their morphology was degenerated thereafter. After OVMC were fed to hamsters, the percentage of the worm recovery after 1 to 2 months of infection was 52%, 44.7%, 11.3% and 1% for days 1, 2, 3 and 4, respectively. In order to measure the effect of low temperature on OVMC, fish were kept in a refrigerator (4 degrees C) for up to five days and then subsequently fermented for three days. In fish stored in a refrigerator for 1 and 2 days, viable OVMC were clearly observed and were able to infect hamsters, a worm-recovery percentage of 3.3% and 12.7%, respectively. By contrast, in pla-som prepared from fish stored for 3 to 5 days, OVMC were degenerated and could not infect the host. In conclusion, pla-som fermentation for more than four days and refrigerating fish for three days before pla-som processing can prevent O. viverrini infection. This study may increase awareness of fermented-fish dish preparation to prevent liver fluke infection. PMID- 26587968 TI - Direct-Space Corrections Enable Fast and Accurate Lorentz-Berthelot Combination Rule Lennard-Jones Lattice Summation. AB - Long-range lattice summation techniques such as the particle-mesh Ewald (PME) algorithm for electrostatics have been revolutionary to the precision and accuracy of molecular simulations in general. Despite the performance penalty associated with lattice summation electrostatics, few biomolecular simulations today are performed without it. There are increasingly strong arguments for moving in the same direction for Lennard-Jones (LJ) interactions, and by using geometric approximations of the combination rules in reciprocal space, we have been able to make a very high-performance implementation available in GROMACS. Here, we present a new way to correct for these approximations to achieve exact treatment of Lorentz-Berthelot combination rules within the cutoff, and only a very small approximation error remains outside the cutoff (a part that would be completely ignored without LJ-PME). This not only improves accuracy by almost an order of magnitude but also achieves absolute biomolecular simulation performance that is an order of magnitude faster than any other available lattice summation technique for LJ interactions. The implementation includes both CPU and GPU acceleration, and its combination with improved scaling LJ-PME simulations now provides performance close to the truncated potential methods in GROMACS but with much higher accuracy. PMID- 26587969 TI - Quick generation of Raman spectroscopy based in-process glucose control to influence biopharmaceutical protein product quality during mammalian cell culture. AB - Mitigating risks to biotherapeutic protein production processes and products has driven the development of targeted process analytical technology (PAT); however implementing PAT during development without significantly increasing program timelines can be difficult. The development of a monoclonal antibody expressed in a Chinese hamster ovary (CHO) cell line via fed-batch processing presented an opportunity to demonstrate capabilities of altering percent glycated protein product. Glycation is caused by pseudo-first order, non-enzymatic reaction of a reducing sugar with an amino group. Glucose is the highest concentration reducing sugar in the chemically defined media (CDM), thus a strategy controlling glucose in the production bioreactor was developed utilizing Raman spectroscopy for feedback control. Raman regions for glucose were determined by spiking studies in water and CDM. Calibration spectra were collected during 8 bench scale batches designed to capture a wide glucose concentration space. Finally, a PLS model capable of translating Raman spectra to glucose concentration was built using the calibration spectra and spiking study regions. Bolus feeding in mammalian cell culture results in wide glucose concentration ranges. Here we describe the development of process automation enabling glucose setpoint control. Glucose-free nutrient feed was fed daily, however glucose stock solution was fed as needed according to online Raman measurements. Two feedback control conditions were executed where glucose was controlled at constant low concentration or decreased stepwise throughout. Glycation was reduced from ~9% to 4% using a low target concentration but was not reduced in the stepwise condition as compared to the historical bolus glucose feeding regimen. PMID- 26587970 TI - Cationic rhenium complexes ligated with N-heterocyclic carbenes - an overview. AB - This review provides an overview of the currently known cationic rhenium NHC complexes. Synthesis, structures and properties are described. The title compounds are potential candidates for both catalytic and medical applications. Besides the variety of ancillary ligands, which are in some cases easily substituted, functionalization can be carried out in the side chain or at the backbone of the carbene ligand as well as - in the case of biscarbene ligands - at the bridging moiety. Cationic Re NHC complexes are promising precursors for radiopharmaceuticals and diagnostics - not only because of the possibility to radiolabel the metal (steps in this direction have been made and described already) - but rather the opportunity to link the complexes to biomolecules via the different possibilities provided by the ligands. The development of OLEDs based on luminescent Re(i) carbene complexes renders another potential application. PMID- 26587971 TI - Efficacy and Safety of Sofosbuvir-Based Antiviral Therapy to Treat Hepatitis C Virus Infection After Kidney Transplantation. AB - There is no approved therapy for hepatitis C virus (HCV) infection after kidney transplantation, and no data regarding the use of new-generation direct antiviral agents (DAAs) have been published so far. The aims of this pilot study were to assess the efficacy and safety of an interferon-free sofosbuvir-based regimen to treat chronic HCV infection in kidney transplant recipients. Twenty-five kidney transplant recipients with chronic HCV infection were given, for 12 (n = 19) or 24 weeks (n = 6), sofosbuvir plus ribavirin (n = 3); sofosbuvir plus daclatasvir (n = 4); sofosbuvir plus simeprevir, with (n = 1) or without ribavirin (n = 6); sofosbuvir plus ledipasvir, with (n = 1) or without ribavirin (n = 9); and sofosbuvir plus pegylated-interferon plus ribavirin (n = 1). A rapid virological response, defined by undetectable viremia at week 4 after starting DAA therapy, was observed in 22 of the 25 patients (88%). At the end of therapy, HCV RNA was undetectable in all patients. At 4 and 12 weeks after completing DAA therapy, all had a sustained virological response. The tolerance to anti-HCV therapy was excellent and no adverse event was observed. A significant decrease in calcineurin inhibitor levels was observed after HCV clearance. New-generation oral DAAs are efficient and safe to treat HCV infection after kidney transplantation. PMID- 26587972 TI - The response of maize (Zea mays L.) plant assisted with bacterial consortium and fertilizer under oily sludge. AB - The objective of this study was to evaluate the role of PGPR consortium and fertilizer alone and in combination on the physiology of maize grown under oily sludge stress environment as well on the soil nutrient status. Consortium was prepared from Bacillus cereus (Acc KR232400), Bacillus altitudinis (Acc KF859970), Comamonas (Delftia) belonging to family Comamonadacea (Acc KF859971) and Stenotrophomonasmaltophilia (Acc KF859973). The experiment was conducted in pots with complete randomized design with four replicates and kept in field. Oily sludge was mixed in ml and Ammonium nitrate and Diammonium phosphate (DAP) were added at 70 ug/g and 7 ug/g at sowing. The plant was harvested at 21 d for estimation of protein, proline and antioxidant enzymes superoxide dismutase (SOD) and peroxidase (POD). To study the degradation, total petroleum hydrocarbon was extracted by soxhelt extraction and extract was analyzed by GC-FID at different period after incubation. Combined application of consortium and fertilizer enhanced the germination %, protein and, proline content by 90,130 and 99% higher than untreated maize plants. Bioavailability of macro and micro nutrient was also enhanced with consortium and fertilizer in oily sludge. The consortium and fertilizer in combined treatment decreased the superoxide dismutase (SOD), peroxidase dismutase (POD) of the maize leaves grown in oily sludge. Degradation of total petroleum hydrocarbon (TPHs) was 59% higher in combined application of consortium and fertilizer than untreated maize at 3 d. The bacterial consortium can enhanced the maize tolerance to oily sludge and enhanced degradation of total petroleum hydrocarbon (TPHs). The maize can be considered as tolerant plant species to remediate oily sludge contaminated soils. PMID- 26587973 TI - KIT over-expression by p55PIK-PI3K leads to Imatinib-resistance in patients with gastrointestinal stromal tumors. AB - Imatinib is the first-line drug for gastrointestinal stromal tumors (GISTs), as mutated KIT is closely associated with the occurrence of GIST. However, Imatinib resistance (IMA-resistance) occurs inevitably in most GIST patients. Although the over-expression of KIT in GIST is one of the major factors contributing to IMA resistance, the underlying mechanism is still unclear. In this study, we demonstrate that p55PIK, an isoform of phosphoinositide 3-kinase (PI3K), increases KIT expression, leading to IMA-resistance in GISTs by activating NF kappaB signaling pathway. Furthermore, down-regulation of p55PIK significantly decreases KIT expression and re-sensitizes IMA-resistance-GIST cells to Imatinib in vitro and in vivo. Interestingly, the expression of both p55PIK and KIT proteins is significantly increased in tumor samples from IMA-resistance-GIST patients, suggesting that p55PIK up-regulation may be important for IMA resistance in the clinical setting. Altogether, our data provide evidence that p55PIK-PI3K signaling can contribute to IMA-resistance in GIST by increasing KIT expression. Moreover, p55PIK may be a novel potential drug target for treating tumors that develop IMA-resistance. PMID- 26587974 TI - Mutant p53 induces EZH2 expression and promotes epithelial-mesenchymal transition by disrupting p68-Drosha complex assembly and attenuating miR-26a processing. AB - The tumor suppressor p53 and the transcriptional repressor Enhancer of Zeste Homolog 2 (EZH2) have both been implicated in the regulation of epithelial mesenchymal transition (EMT) and tumor metastasis via their impacts on microRNA expression. Here, we report that mutant p53 (mutp53) promotes EMT in endometrial carcinoma (EC) by disrupting p68-Drosha complex assembly. Overexpression of mutp53 has the opposite effect of wild-type p53 (WTp53), repressing miR-26a expression by reducing pri-miR-26a-1 processing in p53-null EC cells. Re expression of miR-26a in mutp53 EC cells decreases cell invasion and promotes mesenchymal-epithelial transition (MET). Rescuing miR-26a expression also inhibits EZH2, N-cadherin, Vimentin, and Snail expression and induces E-cadherin expression both in vitro and in vivo. Moreover, patients with higher serum miR 26a levels have a better survival rate. These results suggest that p53 gain-of function mutations accelerate EC tumor progression and metastasis by interfering with Drosha and p68 binding and pri-miR-26a-1 processing, resulting in reduced miR-26a expression and EZH2 overexpression. PMID- 26587975 TI - Novel histone deacetylase inhibitor MPT0G009 induces cell apoptosis and synergistic anticancer activity with tumor necrosis factor-related apoptosis inducing ligand against human hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is a frequent cause of cancer-related death; therefore, more effective anticancer therapies for the treatment of HCC are needed. Histone deacetylase (HDAC) inhibitors serve as promising anticancer drugs because they can induce cell growth arrest and apoptosis. We previously reported that 3-[1-(4-methoxybenzenesulfonyl)-2,3-dihydro-1H-indol-5-yl]-N hydroxyacrylamide (MPT0G009)-a novel 1-arylsulfonyl-5-(N hydroxyacrylamide)indolines compound-demonstrated potent pan-HDAC inhibition and anti-inflammatory effects. In this study, we evaluated the anti-HCC activity of MPT0G009 in vitro and in vivo. Growth inhibition, apoptosis, and inhibited HDAC activity induced by MPT0G009 were more potent than a marketed HDAC inhibitor SAHA (Vorinostat). Furthermore, MPT0G009-induced apoptosis of Hep3B cells was characterized by an increase in apoptotic (sub-G1) population, loss of mitochondrial membrane potential, activation of caspase cascade, increased levels of pro-apoptotic protein (Bim), and decreased levels of anti-apoptotic proteins (Bcl-2, Bcl-xL, and FLICE-inhibitory protein); the downregulation FLIP by MPT0G009 is mediated through proteasome-mediated degradation and transcriptional suppression. In addition, combinations of tumor necrosis factor-related apoptosis inducing ligand (TRAIL) with lower concentrations (0.1 MUM) of MPT0G009 were synergistic in cell growth inhibition and apoptosis in HCC cells. In the in vivo model, MPT0G009 markedly reduced Hep3B xenograft tumor volume, inhibited HDAC activities, and induced apoptosis in the Hep3B xenografts. Our results demonstrate that MPT0G009 is a potential new candidate drug for HCC therapy. PMID- 26587976 TI - Intraoperative Spectroscopy with Ultrahigh Sensitivity for Image-Guided Surgery of Malignant Brain Tumors. AB - Intraoperative cancer imaging and fluorescence-guided surgery have attracted considerable interest because fluorescence signals can provide real-time guidance to assist a surgeon in differentiating cancerous and normal tissues. Recent advances have led to the clinical use of a natural fluorophore called protoporphyrin IX (PpIX) for image-guided surgical resection of high-grade brain tumors (glioblastomas). However, traditional fluorescence imaging methods have only limited detection sensitivity and identification accuracy and are unable to detect low-grade or diffuse infiltrating gliomas (DIGs). Here we report a low cost hand-held spectroscopic device that is capable of ultrasensitive detection of protoporphyrin IX fluorescence in vivo, together with intraoperative spectroscopic data obtained from both animal xenografts and human brain tumor specimens. The results indicate that intraoperative spectroscopy is at least 3 orders of magnitude more sensitive than the current surgical microscopes, allowing ultrasensitive detection of as few as 1000 tumor cells. For detection specificity, intraoperative spectroscopy allows the differentiation of brain tumor cells from normal brain cells with a contrast signal ratio over 100. In vivo animal studies reveal that protoporphyrin IX fluorescence is strongly correlated with both MRI and histological staining, confirming that the fluorescence signals are highly specific to tumor cells. Furthermore, ex vivo spectroscopic studies of excised brain tissues demonstrate that the hand-held spectroscopic device is capable of detecting diffuse tumor margins with low fluorescence contrast that are not detectable with current systems in the operating room. These results open new opportunities for intraoperative detection and fluorescence-guided resection of microscopic and low-grade glioma brain tumors with invasive or diffusive margins. PMID- 26587977 TI - Nanofluidic Diodes with Dynamic Rectification Properties Stemming from Reversible Electrochemical Conversions in Conducting Polymers. AB - The use of solid state nanochannels as nanofluidic diodes is currently a topic of large interest in nanotechnology. Particularly, there is a focus in the development of nanochannels with surface functionalities that make them responsive to multiple environmental variables. Here, we present for the first time the construction of electrochemical potential- and pH-responsive nanofluidic diodes using a novel approach based on a controlled electrochemical polymerization of aniline on gold-coated polycarbonate asymmetric nanochannels. The polyaniline-modified nanochannels showed three different levels of reversible ionic rectification corresponding to the degrees of oxidation of the conducting polymer. Our results demonstrate that this strategy enables an accurate and reversible control of the rectification properties due to the well-defined and predictable electrochemical conversion of charged species generated on the pore walls. We envision that these results will create novel avenues to fabricate electrochemically modulated nanofluidic diodes using conducting polymers integrated into single conical nanopores. PMID- 26587978 TI - A Catalyst-Free Synthesis of Phosphinic Amides Using O-Benzoylhydroxylamines. AB - A practical approach for the synthesis of phosphinic amides via the coupling of secondary phosphine oxides (SPOs) with O-benzoylhydroxylamines has been reported. Simply heating the mixture of SPOs and O-benzoylhydroxylamines in the presence of K(2)CO(3) gave the phosphinic amides in moderate to excellent yields under an open air system. This method provides a practical and catalyst-free method for the synthesis of various synthetically valuable phosphinic amides. PMID- 26587979 TI - Conspicuous Coloration in Males of the Damselfly Nehalennia irene (Zygoptera: Coenagrionidae): Do Males Signal Their Unprofitability to Other Males? AB - In damselflies, sexual colour dimorphism is commonly explained as a consequence of selection on traits that increase male attractiveness to females. However, while many species in the damselfly family Coenagrionidae (Insecta: Odonata) are sexually dimorphic, the males do not engage in displays, and male competition for mates resembles a "scramble". An alternative explanation for the sexual differences in coloration within these species is that sexual dimorphism has evolved as a sex-related warning signal, with males signalling their uprofitability as mates to other males, thereby avoiding harassment from conspecifics. We evaluated an underlying assumption of the theory that male-male harassment rate is influenced by colour by comparing harassment of males of the species Nehalennia irene that had been painted to make them appear: (i) similar to an unaltered male (blue), (ii) different from a male (orange) and (iii) more similar to a female (black). When caged together we found that blue-painted males experienced significantly lower harassment than black-painted males. When unpainted males were caged with each type of painted male we found that blue painted males and the unpainted males housed in the same cages experienced lower rates of harassment than males housed in cages where some males were painted black, suggesting that a single, reliable signal of unprofitability may benefit the individuals that carry it. While our results do not in themselves demonstrate that sexual colour dimorphism originally evolved as an intra-specific warning signal, they do show that harassment is influenced by coloration, and that such selection could conceivably maintain male coloration as a warning signal. PMID- 26587980 TI - Curly Encodes Dual Oxidase, Which Acts with Heme Peroxidase Curly Su to Shape the Adult Drosophila Wing. AB - Curly, described almost a century ago, is one of the most frequently used markers in Drosophila genetics. Despite this the molecular identity of Curly has remained obscure. Here we show that Curly mutations arise in the gene dual oxidase (duox), which encodes a reactive oxygen species (ROS) generating NADPH oxidase. Using Curly mutations and RNA interference (RNAi), we demonstrate that Duox autonomously stabilizes the wing on the last day of pupal development. Through genetic suppression studies, we identify a novel heme peroxidase, Curly Su (Cysu) that acts with Duox to form the wing. Ultrastructural analysis suggests that Duox and Cysu are required in the wing to bond and adhere the dorsal and ventral cuticle surfaces during its maturation. In Drosophila, Duox is best known for its role in the killing of pathogens by generating bactericidal ROS. Our work adds to a growing number of studies suggesting that Duox's primary function is more structural, helping to form extracellular and cuticle structures in conjunction with peroxidases. PMID- 26587981 TI - The Effects of Renal Denervation on Renal Hemodynamics and Renal Vasculature in a Porcine Model. AB - RATIONALE: Recently, the efficacy of renal denervation (RDN) has been debated. It is discussed whether RDN is able to adequately target the renal nerves. OBJECTIVE: We aimed to investigate how effective RDN was by means of functional hemodynamic measurements and nerve damage on histology. METHODS AND RESULTS: We performed hemodynamic measurements in both renal arteries of healthy pigs using a Doppler flow and pressure wire. Subsequently unilateral denervation was performed, followed by repeated bilateral hemodynamic measurements. Pigs were terminated directly after RDN or were followed for 3 weeks or 3 months after the procedure. After termination, both treated and control arteries were prepared for histology to evaluate vascular damage and nerve damage. Directly after RDN, resting renal blood flow tended to increase by 29+/-67% (P = 0.01). In contrast, renal resistance reserve increased from 1.74 (1.28) to 1.88 (1.17) (P = 0.02) during follow-up. Vascular histopathology showed that most nerves around the treated arteries were located outside the lesion areas (8+/-7 out of 55+/-25 (14%) nerves per pig were observed within a lesion area). Subsequently, a correlation was noted between a more impaired adventitia and a reduction in renal resistance reserve (beta: -0.33; P = 0.05) at three weeks of follow-up. CONCLUSION: Only a small minority of renal nerves was targeted after RDN. Furthermore, more severe adventitial damage was related to a reduction in renal resistance in the treated arteries at follow-up. These hemodynamic and histological observations may indicate that RDN did not sufficiently target the renal nerves. Potentially, this may explain the significant spread in the response after RDN. PMID- 26587984 TI - Yttrium-90 radiation synovectomy revisited. PMID- 26587983 TI - Extended Anticoagulant and Aspirin Treatment for the Secondary Prevention of Thromboembolic Disease: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Patients who have had an unprovoked deep venous thrombosis (DVT) or pulmonary embolus (PE) are at a high risk for recurrent venous thromboembolism (VTE). Extended "life-long" anticoagulation has been recommended in these patients. However, the risk benefit ratio of this approach is controversial and the role of the direct oral anticoagulants (DOACs) and aspirin is unclear. Furthermore, in some patients with a "weak provoking factor" there is clinical equipoise regarding continuation or cessation of anticoagulant therapy after treatment of the acute VTE event. OBJECTIVE: A systematic review and meta analysis to determine the risks (major bleeding) and benefits (recurrent VTE and mortality) of extended anticoagulation with vitamin k antagonists (VKA), DOACs and aspirin in patients with an unprovoked VTE and in those patients with clinical equipoise regarding continuation or cessation of anticoagulant therapy. In addition, we sought to determine the risk of recurrent VTE events once extended anti-thrombotic therapy was discontinued. DATA SOURCES: MEDLINE, Cochrane Register of Controlled Trials, citation review of relevant primary and review articles. STUDY SELECTION: Randomized placebo-controlled trials (RCTs) that compared the risk of recurrent VTE in patients with an unprovoked DVT or PE who had been treated for at least 3 months with a VKA or a DOAC and were then randomized to receive an oral anti-thrombotic agent or placebo for at least 6 additional months. We included studies that included patients in whom clinical equipoise existed regarding the continuation or cessation of anticoagulant therapy. DATA EXTRACTION: Independent extraction of articles by both authors using predefined data fields, including study quality indicators. Data were abstracted on study size, study setting, initial event (DVT or PE), percentage of patients where the initial VTE event was unprovoked, the number of recurrent VTE events, major bleeds and mortality during the period of extended anticoagulation in the active treatment and placebo arms. In addition, we recorded the event rate once extended treatment was stopped. Meta-analytic techniques were used to summarize the data. Studies were grouped according to the type of anti-thrombotic agent. DATA SYNTHESIS: Seven studies which enrolled 6778 patients met our inclusion criteria; two studies evaluated the extended use of Coumadin, three studies evaluated a DOAC and two studies evaluated the use of aspirin. The duration of followup varied from 6 to 37 months. In the Coumadin and aspirin studies 100% of the randomized patients had an unprovoked VTE, while in the DOAC studies between 73.5% and 93.2% of the VTE events were unprovoked. In the control group recurrent VTE occurred in 9.7% of patients compared to 2.8% in the active treatment group (OR 0.21; 95% CI 0.11-0.42, p<0.0001). VKA, DOACs and aspirin significantly reduced the risk of recurrent VTE, with VKA and DOACs being significantly more effective than aspirin. Major bleeding events occurred in 12 patients in the control group (0.4%) and 25 of 3815 (0.6%) patients in the active treatment group (OR 1.64; 95% CI 0.69-3.90, NS). There were 39 (1.3%) deaths in control patients and 33 (0.9%) deaths in the anti-thrombotic group during the treatment period (OR 0.73; 95% CI 0.40-1.33, NS). Patients whose initial VTE event was a PE were more likely to have a recurrent PE than a DVT. The annualized event rate after discontinuation of extended antithrombotic therapy was 4.4% in the control group and 6.5% in the active treatment arm. CONCLUSIONS: VKA, DOACs and aspirin significantly reduced the risk of recurrent VTE, with DOACs and VKA being more effective than aspirin. The decision regarding life-long anticoagulation following an unprovoked DVT or PE should depend on the patients' risk for recurrent PE as well as the patients' values and preferences. PMID- 26587982 TI - Arenavirus Glycan Shield Promotes Neutralizing Antibody Evasion and Protracted Infection. AB - Arenaviruses such as Lassa virus (LASV) can cause severe hemorrhagic fever in humans. As a major impediment to vaccine development, delayed and weak neutralizing antibody (nAb) responses represent a unifying characteristic of both natural infection and all vaccine candidates tested to date. To investigate the mechanisms underlying arenavirus nAb evasion we engineered several arenavirus envelope-chimeric viruses and glycan-deficient variants thereof. We performed neutralization tests with sera from experimentally infected mice and from LASV convalescent human patients. NAb response kinetics in mice correlated inversely with the N-linked glycan density in the arenavirus envelope protein's globular head. Additionally and most intriguingly, infection with fully glycosylated viruses elicited antibodies, which neutralized predominantly their glycan deficient variants, both in mice and humans. Binding studies with monoclonal antibodies indicated that envelope glycans reduced nAb on-rate, occupancy and thereby counteracted virus neutralization. In infected mice, the envelope glycan shield promoted protracted viral infection by preventing its timely elimination by the ensuing antibody response. Thus, arenavirus envelope glycosylation impairs the protective efficacy rather than the induction of nAbs, and thereby prevents efficient antibody-mediated virus control. This immune evasion mechanism imposes limitations on antibody-based vaccination and convalescent serum therapy. PMID- 26587985 TI - 177Lu-DOTATATE versus 177Lu-EDTMP versus cocktail/sequential therapy in bone confined painful metastatic disease in medullary carcinoma of the thyroid and neuroendocrine tumour: can semiquantitative comparison of 68Ga-DOTATATE and 18F fluoride PET-CT aid in personalized treatment decision making in selecting the best therapeutic option? PMID- 26587987 TI - Combinations of Genetic Data Present in Bipolar Patients, but Absent in Control Persons. AB - The main objective of the study was to find combinations of genetic variants significantly associated with bipolar disorder. In a previous study of bipolar disorder, combinations of three single nucleotide polymorphism (SNP) genotypes taken from 803 SNPs were analyzed, and four clusters of combinations were found to be significantly associated with bipolar disorder. In the present study, combinations of four SNP genotypes taken from the same 803 SNPs were analyzed, and one cluster of combinations was found to be significantly associated with bipolar disorder. Combinations from the new cluster and from the four previous clusters were identified in the genomes of 209 of the 607 patients in the study whereas none of the 1355 control participants had any of these combinations in their genome. PMID- 26587988 TI - Plasmodium vivax Transmission in Africa. AB - Malaria in sub-Saharan Africa has historically been almost exclusively attributed to Plasmodium falciparum (Pf). Current diagnostic and surveillance systems in much of sub-Saharan Africa are not designed to identify or report non-Pf human malaria infections accurately, resulting in a dearth of routine epidemiological data about their significance. The high prevalence of Duffy negativity provided a rationale for excluding the possibility of Plasmodium vivax (Pv) transmission. However, review of varied evidence sources including traveller infections, community prevalence surveys, local clinical case reports, entomological and serological studies contradicts this viewpoint. Here, these data reports are weighted in a unified framework to reflect the strength of evidence of indigenous Pv transmission in terms of diagnostic specificity, size of individual reports and corroboration between evidence sources. Direct evidence was reported from 21 of the 47 malaria-endemic countries studied, while 42 countries were attributed with infections of visiting travellers. Overall, moderate to conclusive evidence of transmission was available from 18 countries, distributed across all parts of the continent. Approximately 86.6 million Duffy positive hosts were at risk of infection in Africa in 2015. Analysis of the mechanisms sustaining Pv transmission across this continent of low frequency of susceptible hosts found that reports of Pv prevalence were consistent with transmission being potentially limited to Duffy positive populations. Finally, reports of apparent Duffy independent transmission are discussed. While Pv is evidently not a major malaria parasite across most of sub-Saharan Africa, the evidence presented here highlights its widespread low-level endemicity. An increased awareness of Pv as a potential malaria parasite, coupled with policy shifts towards species-specific diagnostics and reporting, will allow a robust assessment of the public health significance of Pv, as well as the other neglected non-Pf parasites, which are currently invisible to most public health authorities in Africa, but which can cause severe clinical illness and require specific control interventions. PMID- 26587989 TI - The Possible Mechanism of Advanced Glycation End Products (AGEs) for Alzheimer's Disease. AB - Amyloid precursor protein (APP) has been modified by beta and gamma-secretase that cause amyloid deposits (plaques) in neuronal cells. Glyceraldhyde-derived AGEs has been identified as a major source of neurotoxicity in Alzheimer's disease (AD). In a previous study, we demonstrated that glyceraldehyde-derived AGEs increase APP and Abeta via ROS. Furthermore, the combination of AGEs and Abeta has been shown to enhance neurotoxicity. In mice, APP expression is increased by tail vein injection of AGEs. This evidence suggests a correlation between AGEs and the development of AD. However, the role played by AGEs in the pathogenesis of AD remains unclear. In this report, we demonstrate that AGEs up regulate APP processing protein (BACE and PS1) and Sirt1 expression via ROS, but do not affect the expression of downstream antioxidant genes HO-1 and NQO-1. Moreover, we found that AGEs increase GRP78 expression and enhance the cell death related pathway p53, bcl-2/bax ratio, caspase 3. These results indicate that AGEs impair the neuroprotective effects of Sirt1 and lead to neuronal cell death via ER stress. Our findings suggest that AGEs increase ROS production, which stimulates downstream pathways related to APP processing, Abeta production, Sirt1, and GRP78, resulting in the up-regulation of cell death related pathway. This in-turn enhances neuronal cell death, which leads to the development of AD. PMID- 26587990 TI - Pathology of Equine Influenza virus (H3N8) in Murine Model. AB - Equine influenza viruses (EIV)-H3N8 continue to circulate in equine population throughout the world. They evolve by the process of antigenic drift that leads to substantial change in the antigenicity of the virus, thereby necessitating substitution of virus strain in the vaccines. This requires frequent testing of the new vaccines in the in vivo system; however, lack of an appropriate laboratory animal challenge model for testing protective efficacy of equine influenza vaccine candidates hinders the screening of new vaccines and other therapeutic approaches. In the present investigation, BALB/c mouse were explored for suitability for conducting pathogenecity studies for EIV. The BALB/c mice were inoculated intranasally @ 2*106.24 EID50 with EIV (H3N8) belonging to Clade 2 of Florida sublineage and monitored for setting up of infection and associated parameters. All mice inoculated with EIV exhibited clinical signs viz. loss in body weights, lethargy, dyspnea, etc, between 3 and 5 days which commensurate with lesions observed in the respiratory tract including rhinitis, tracheitis, bronchitis, bronchiolitis, alveolitis and diffuse interstitial pneumonia. Transmission electron microscopy, immunohistochemistry, virus quantification through titration and qRT-PCR demonstrated active viral infection in the upper and lower respiratory tract. Serology revealed rise in serum lactate dehydrogenase levels along with sero-conversion. The pattern of disease progression, pathological lesions and virus recovery from nasal washings and lungs in the present investigations in mice were comparable to natural and experimental EIV infection in equines. The findings establish BALB/c mice as small animal model for studying EIV (H3N8) infection and will have immense potential for dissecting viral pathogenesis, vaccine efficacy studies, preliminary screening of vaccine candidates and antiviral therapeutics against EIV. PMID- 26587991 TI - The Mediating Role of Mental Adjustment in the Relationship between Perceived Stress and Depressive Symptoms in Hematological Cancer Patients: A Cross Sectional Study. AB - BACKGROUND: Depression is a particularly common psychological disorder that affects cancer patients. Diagnosed with hematological malignancies constitute a serious unpredictable and uncontrollable medical stress situation and patients are susceptible to suffer from depressive symptoms. The aims of the study were to explore the correlation between perceived stress and depressive symptoms in patients with hematological malignancies, and assess the mediating role of mental adjustment between these variables. METHODS: A single center, cross-sectional study was performed by convenience sampling between July 2013 and April 2014 in a hospital of China. The Center for Epidemiologic Studies Depression Scale, Perceived Stress Scale, and Mini-Mental Adjustment Scale, as well as questions about demographic and clinical factors was distributed to 300 hematological cancer patients. Completed questionnaires were received from 227 inpatients. RESULTS: The results showed that perceived stress was positively correlated with depressive symptoms. The mental adjustment significantly mediated the relationship between perceived stress and depressive symptoms. CONCLUSIONS: Among hematological cancer patients perceived stress may be a risk factor for depressive symptoms, whereas positive coping style might be protective against depressive symptoms. Results showed that medical managers could support the development of mental adjustment in the patients to alleviate psychological disorders. PMID- 26587993 TI - Safety and Tolerability of Acetazolamide in the Idiopathic Intracranial Hypertension Treatment Trial. AB - OBJECTIVE: To examine the tolerability and adverse events reported in the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT). METHODS: Randomized, double-masked, placebo-controlled clinical trial. Trial participants (n = 165) with mild visual loss concurrently receiving low-sodium weight reduction diet plus the maximally tolerated dosage of acetazolamide (up to 4 g/d) or placebo for 6 months. MAIN OUTCOMES MEASURES: adverse events (AEs), assessment of clinical and laboratory findings at study visits. RESULTS: Thirty-eight of 86 participants randomized to the acetazolamide group (44.1%) tolerated the maximum allowed dosage of 4 g/d. The average time to achieve maximum study dosage in the acetazolamide group was 13 weeks (median 12 weeks; range 10-24 weeks). A total of 676 AEs (acetazolamide, n = 480; placebo, n = 196) and 9 serious AEs (acetazolamide, n = 6; placebo, n = 3) were reported. Notably, the percentages of participants reporting at least 1 AE in the nervous, gastrointestinal, metabolic, and renal organ systems were significantly higher in the acetazolamide group (P < 0.05). The odds of paresthesia (OR 9.82; 95% CI 3.87-27.82), dysgeusia (OR infinity; 95% CI 3.99-infinity), vomiting and diarrhea (OR 4.11; 95% CI 1.04 23.41), nausea (OR 2.99; 95% CI 1.26-7.49) and fatigue (OR 16.48; 95% CI 2.39 702.40) were higher in the acetazolamide group than in the placebo group. CONCLUSION: Acetazolamide appears to have an acceptable safety profile at dosages up to 4 g/d in the treatment of idiopathic intracranial hypertension. The majority of participants in the Idiopathic Intracranial Hypertension Treatment Trial were able to tolerate acetazolamide above 1 g/d for 6 months. PMID- 26587992 TI - Intra-Tumoral Heterogeneity of HER2, FGFR2, cMET and ATM in Gastric Cancer: Optimizing Personalized Healthcare through Innovative Pathological and Statistical Analysis. AB - Current drug development efforts on gastric cancer are directed against several molecular targets driving the growth of this neoplasm. Intra-tumoral biomarker heterogeneity however, commonly observed in gastric cancer, could lead to biased selection of patients. MET, ATM, FGFR2, and HER2 were profiled on gastric cancer biopsy samples. An innovative pathological assessment was performed through scoring of individual biopsies against whole biopsies from a single patient to enable heterogeneity evaluation. Following this, false negative risks for each biomarker were estimated in silico. 166 gastric cancer cases with multiple biopsies from single patients were collected from Shanghai Renji Hospital. Following pre-set criteria, 56 ~ 78% cases showed low, 15 ~ 35% showed medium and 0 ~ 11% showed high heterogeneity within the biomarkers profiled. If 3 biopsies were collected from a single patient, the false negative risk for detection of the biomarkers was close to 5% (exception for FGFR2: 12.2%). When 6 biopsies were collected, the false negative risk approached 0%. Our study demonstrates the benefit of multiple biopsy sampling when considering personalized healthcare biomarker strategy, and provides an example to address the challenge of intra tumoral biomarker heterogeneity using alternative pathological assessment and statistical methods. PMID- 26587994 TI - Limited Efficiency of Drug Delivery to Specific Intracellular Organelles Using Subcellularly "Targeted" Drug Delivery Systems. AB - Many drugs have been designed to act on intracellular targets and to affect intracellular processes inside target cells. For the desired effects to be exerted, these drugs should permeate target cells and reach specific intracellular organelles. This subcellular drug targeting approach has been proposed for enhancement of accumulation of these drugs in target organelles and improved efficiency. This approach is based on drug encapsulation in drug delivery systems (DDSs) and/or their decoration with specific targeting moieties that are intended to enhance the drug/DDS accumulation in the intracellular organelle of interest. During recent years, there has been a constant increase in interest in DDSs targeted to specific intracellular organelles, and many different approaches have been proposed for attaining efficient drug delivery to specific organelles of interest. However, it appears that in many studies insufficient efforts have been devoted to quantitative analysis of the major formulation parameters of the DDSs disposition (efficiency of DDS endocytosis and endosomal escape, intracellular trafficking, and efficiency of DDS delivery to the target organelle) and of the resulting pharmacological effects. Thus, in many cases, claims regarding efficient delivery of drug/DDS to a specific organelle and efficient subcellular targeting appear to be exaggerated. On the basis of the available experimental data, it appears that drugs/DDS decoration with specific targeting residues can affect their intracellular fate and result in preferential drug accumulation within an organelle of interest. However, it is not clear whether these approaches will be efficient in in vivo settings and be translated into preclinical and clinical applications. Studies that quantitatively assess the mechanisms, barriers, and efficiencies of subcellular drug delivery and of the associated toxic effects are required to determine the therapeutic potential of subcellular DDS targeting. PMID- 26587995 TI - Immature platelet fraction in hypertensive pregnancy. AB - BACKGROUND: Imbalance in hemostatic mechanisms can occur during pregnancy with a tendency for hypercoagulability and increased thrombosis risk. Pregnant women with hypertensive disorder, especially preeclampsia, show alterations in platelet indexes. Immature platelet fraction (IPF) has been suggested as a sensitive index for monitoring changes in platelet production and destruction. OBJECTIVES: To evaluate the IPF in patients diagnosed with a gestational hypertensive disorder (GHD). PATIENTS AND METHODS: A cross-sectional study was conducted at an University Hospital to estimate maternal blood IPF index in 99 pregnant women, divided into three groups: normotensive pregnancy (NP), preeclampsia syndrome (PES), and non-proteinuric hypertensive pregnancy (nPHP). Following ethical approval and written informed consent, samples were collected from 33 NP, 34 PES, and 32 nPHP women. Platelet indexes were measured by fluorescent flow cytometry. RESULTS: IPF and mean platelet volume (MPV) counts in GHD were significantly higher than in NP (IPF: 3.8, 2.4-5.1%; 8.6, 5.8-10.6%; 7.3, 4.2-10.2%; p < 0.001 and MPV: 10.6 +/- 0.9 fL; 12.1 +/- 1.0 fL; 11.6 +/- 1.0 fL; p < 0.001 for NP, PES, and nPHP, respectively). No difference was detected between PES and nPHP groups. The distribution of patients with an IPF above 6.1%for NP, PES, and nPHP was 9%, 65%, and 43.8%, respectively (p < 0.001). IPF as a test to differentiate GHD from the controls achieved an area under the curve of 0.83 on a receiver operating characteristics curve. CONCLUSION: A distinct profile in platelet indexes was detected in hypertensive pregnancies. It suggests that these markers could be used in daily routine as an additional tool in the management of pregnant women. PMID- 26587996 TI - Clinical pharmacology review of safinamide for the treatment of Parkinson's disease. AB - Safinamide (XadagoTM) is an oral alpha-aminoamide derivative marketed for the treatment of Parkinson's disease (PD). The drug has both dopaminergic properties, namely highly selective and reversible inhibition of monoamine oxidase B, and nondopamimetic properties, namely selective sodium channel blockade and calcium channel modulation, with consequent inhibition of excessive glutamate release. In 2014, safinamide was approved in the European Economic Area, as "an add-on therapy to stable dose levodopa, alone or in combination with other PD therapies in mid- to late-stage-fluctuating PD patients." In addition, evidence has been provided for safinamide in the treatment of motor symptoms in early PD patients. This article summarizes the pharmacological properties, development program, clinical indications for PD treatment, stratified according to several disease's stages and the safety profile of safinamide. A meta-analysis of the most frequent adverse events among Phase III trials has been also performed. PMID- 26587997 TI - Organizational capacity for change in health care: Development and validation of a scale. AB - BACKGROUND: We do not have a strong understanding of a health care organization's capacity for attempting and completing multiple and sometimes competing change initiatives. Capacity for change implementation is a critical success factor as the health care industry is faced with ongoing demands for change and transformation because of technological advances, market forces, and regulatory environment. PURPOSE: The aim of this study was to develop and validate a tool to measure health care organizations' capacity to change by building upon previous conceptualizations of absorptive capacity and organizational readiness for change. METHODOLOGY/APPROACH: A multistep process was used to develop the organizational capacity for change survey. The survey was sent to two populations requesting answers to questions about the organization's leadership, culture, and technologies in use throughout the organization. Exploratory and confirmatory factor analyses were conducted to validate the survey as a measurement tool for organizational capacity for change in the health care setting. FINDINGS: The resulting organizational capacity for change measurement tool proves to be a valid and reliable method of evaluating a hospital's capacity for change through the measurement of the population's perceptions related to leadership, culture, and organizational technologies. PRACTICAL IMPLICATIONS: The organizational capacity for change measurement tool can help health care managers and leaders evaluate the capacity of employees, departments, and teams for change before large-scale implementation. PMID- 26587998 TI - Practice environments and job satisfaction and turnover intentions of nurse practitioners: Implications for primary care workforce capacity. AB - BACKGROUND: Health care professionals, organizations, and policy makers are calling for expansion of the nurse practitioner (NP) workforce in primary care to assure timely access and high-quality care. However, most efforts promoting NP practice have been focused on state level scope of practice regulations, with limited attention to the organizational structures. PURPOSE: We examined NP practice environments in primary care organizations and the extent to which they were associated with NP retention measures. METHODOLOGY: Data were collected through mail survey of NPs practicing in 163 primary care organizations in Massachusetts in 2012. NP practice environment was measured by the Nurse Practitioner Primary Care Organizational Climate Questionnaire, which has four subscales: Professional Visibility, NP-Administration Relations, NP-Physician Relations, and Independent Practice and Support. Two global items measured job satisfaction and NPs' intent to leave their job. We aggregated NP level data to organization level to attain measures of practice environments. Multilevel logistic regression models were used. FINDINGS: NPs rated the relationship between NPs and physicians favorably, contrary to the relationship between NPs and administrators. All subscales measuring NP practice environment had similar influence on the outcome variables. With every unit increase in each standardized subscale score, the odds of job satisfaction factors increased about 20% whereas the odds of intention of turnover decreased about 20%. NPs from organizations with higher mean scores on the NP-Administration subscale had higher satisfaction with their jobs (OR = 1.24, 95% CI [1.12, 1.39]) and had lower intent to leave (OR = 0.79, 95% CI [0.70, 0.90]). PRACTICE IMPLICATIONS: NPs were more likely to be satisfied with their jobs and less likely to report intent to leave if their organizations support NP practice, favorable relations with physicians and administration, and clear role visibility. Creating productive practice environments that can retain NPs is a potential strategy for increasing the primary care workforce capacity. PMID- 26587999 TI - The relationship between the external environment and physician e-mail communication: The mediating role of health information technology availability. AB - BACKGROUND: Physician e-mail communication, with patients and other providers, is one of the cornerstones of effective care coordination but varies significantly across physicians. A physician's external environment may contribute to such variations by enabling or constraining a physician's ability to adopt innovations such as health information technology (HIT) that can be used to support e-mail communication. PURPOSE: The aim of the study was to examine whether the relationship of the external environment and physician e-mail communication with patients and other providers is mediated by the practice's HIT availability. METHODOLOGY: The data were obtained from the Health Tracking Physician Survey (2008) and the Area Resource File (2008). Cross-sectional multivariable subgroup path analysis was used to investigate the mediating role of HIT availability across 2,850 U.S. physicians. FINDINGS: Solo physicians' perceptions about malpractice were associated with 0.97 lower odds (p < .05) of e-mail communication with patients and other providers, as compared to group and hospital practices, even when mediated by HIT availability. Subgroup analyses indicated that different types of practices are responsive to the different dimensions of the external environment. Specifically, solo practitioners were more responsive to the availability of resources in their environment, with per capita income associated with lower likelihood of physician e-mail communication (OR = 0.99, p < .01). In contrast, physicians working in the group practices were more responsive to the complexity of their environment, with a physician's perception of practicing in environments with higher malpractice risks associated with greater information technology availability, which in turn was associated with a greater likelihood of communicating via e-mail with patients (OR = 1.02, p < .05) and other physicians (OR = 1.03, p < .001). PRACTICAL APPLICATIONS: The association between physician e-mail communication and the external environment is mediated by the practice's HIT availability. Efforts to improve physician e mail communication and HIT adoption may need to reflect the varied perceptions of different types of practices. PMID- 26588000 TI - Quantifying Stochastic Noise in Cultured Circadian Reporter Cells. AB - Stochastic noise at the cellular level has been shown to play a fundamental role in circadian oscillations, influencing how groups of cells entrain to external cues and likely serving as the mechanism by which cell-autonomous rhythms are generated. Despite this importance, few studies have investigated how clock perturbations affect stochastic noise-even as increasing numbers of high throughput screens categorize how gene knockdowns or small molecules can change clock period and amplitude. This absence is likely due to the difficulty associated with measuring cell-autonomous stochastic noise directly, which currently requires the careful collection and processing of single-cell data. In this study, we show that the damping rate of population-level bioluminescence recordings can serve as an accurate measure of overall stochastic noise, and one that can be applied to future and existing high-throughput circadian screens. Using cell-autonomous fibroblast data, we first show directly that higher noise at the single-cell results in faster damping at the population level. Next, we show that the damping rate of cultured cells can be changed in a dose-dependent fashion by small molecule modulators, and confirm that such a change can be explained by single-cell noise using a mathematical model. We further demonstrate the insights that can be gained by applying our method to a genome-wide siRNA screen, revealing that stochastic noise is altered independently from period, amplitude, and phase. Finally, we hypothesize that the unperturbed clock is highly optimized for robust rhythms, as very few gene perturbations are capable of simultaneously increasing amplitude and lowering stochastic noise. Ultimately, this study demonstrates the importance of considering the effect of circadian perturbations on stochastic noise, particularly with regard to the development of small-molecule circadian therapeutics. PMID- 26588001 TI - Risk of bias in model-based economic evaluations: the ECOBIAS checklist. AB - Several biases can occur when performing economic evaluations (EE) and it is important for researchers to minimize these biases, as they can significantly affect economic outcomes. This review aims, firstly, to identify biases that can occur in model-based EE and to illustrate their impact on economic outcomes and, secondly, to present a checklist for assessing the overall risk of bias in EE. Eleven biases that can occur in model-based studies were identified through a scoping review, scrutiny of systematic reviews, the authors' own experiences and discussions with experts. By combining these biases that can occur in model-based studies with biases that were identified for trial-based studies in a previous article, a 22-item checklist was developed for assessing bias in EE - the ECOBIAS checklist. This study and the ECOBIAS checklist aim to help researchers reduce biases in future EE, particularly in model-based EE. Nevertheless, further validation of the checklist is needed. PMID- 26588002 TI - Earthworm Uptake Routes and Rates of Ionic Zn and ZnO Nanoparticles at Realistic Concentrations, Traced Using Stable Isotope Labeling. AB - The environmental behavior of ZnO nanoparticles (NPs), their availability to, uptake pathways by, and biokinetics in the earthworm Lumbricus rubellus were investigated using stable isotope labeling. Zinc isotopically enriched to 99.5% in (68)Zn ((68)Zn-E) was used to prepare (68)ZnO NPs and a dissolved phase of (68)Zn for comparison. These materials enabled tracing of environmentally relevant (below background) NP additions to soil of only 5 mg (68)Zn-E kg(-1). Uptake routes were isolated by introducing earthworms with sealed and unsealed mouthparts into test soils for up to 72 h. The Zn isotope compositions of the soils, pore waters and earthworms were then determined using multiple collector inductively coupled plasma mass spectrometry. Detection and quantification of (68)Zn-E in earthworm tissue was possible after only 4 h of dermal exposure, when the uptake of (68)Zn-E had increased the total Zn tissue concentration by 0.030/00. The results demonstrate that at these realistic exposure concentrations there is no distinguishable difference between the uptake of the two forms of Zn by the earthworm L. rubellus, with the dietary pathway accounting for ~95% of total uptake. This stands in contrast to comparable studies where high dosing levels were used and dermal uptake is dominant. PMID- 26588003 TI - Rb-mediated apoptosis or proliferation: It's up to JNK. PMID- 26588004 TI - Magnetic Interactions in a Series of Homodinuclear Lanthanide Complexes. AB - A series of seven isostructural homodinuclear lanthanide complexes are reported. The magnetic properties (ac and dc SQUID measurements) are discussed on the basis of the X-ray structural properties which show that the two lanthanide sites are structurally different. MCD spectroscopy of the dysprosium(III) and neodymium(III) complexes ([Dy(III)2(L)(OAc)4](+) and [Nd(III)2(L)(OAc)4](+)) allowed us to thoroughly analyze the ligand field, and high-frequency EPR spectroscopy of the gadolinium(III) species ([Gd(III)2(L)(OAc)4](+)) showed the importance of dipolar coupling in these systems. An extensive quantum-chemical analysis of the dysprosium(III) complex ([Dy(III)2(L)(OAc)4](+)), involving an ab initio (CASSCF) wave function, explicit spin-orbit coupling (RASSI-SO), and a ligand field analysis (Lines model and Stevens operators), is in full agreement with all experimental data (SQUID, HF-EPR, MCD) and specifically allowed us to accurately simulate the experimental chiT versus T data, which therefore allowed us to establish a qualitative model for all relaxation pathways. PMID- 26588005 TI - Recommendations on How to Improve Medication Adherence Studies in the Field of Transplantation. PMID- 26588006 TI - A Prospective Randomized Trial on the Effect of Using an Electronic Monitoring Drug Dispensing Device to Improve Adherence and Compliance. AB - BACKGROUND: Outcome after renal transplantation depends on patient compliance and adherence for early detection of complications and identification of intervention opportunities. Compliance describes the degree to which patients follow medical advice and take their medications. Adherence has been defined as the extent to which a patients' behavior coincides with clinical prescriptions. MATERIALS AND METHODS: Patients were randomized 7 to 14 days after transplantation into groups with (n = 40) and without (n = 40) an electronic medication dispenser (EMD). The EMD, which was used for the 1-year study period, recorded the date and time the patient took their medications and was monitored via a web-based application. Patients were monitored for 1 year regarding outpatient follow-up visits, emergency hospitalizations, renal biopsies, rejection episodes, renal function, and blood concentration of medications. RESULTS: Compliance in the intervention group was 97.8% (the control group was not assessed). Number of missed doses varied significantly by weekday (P = 0.033); patients were most likely to miss doses on Saturdays and Thursdays. Patients missed a total of 11 follow-up visits. During the study, 92 biopsies were performed on 55 patients (intervention group: 32 [17]; control group, 60 [38]). Biopsy-verified rejection was three times more common among controls (13 patients vs. 4; P = 0.054, not significant). Average P creatinine level was slightly lower in the intervention group than the control group (131 vs. 150 MUmol/L, not significant), whereas mean tacrolimus was similar (7.32 vs. 7.22 ng/mL, n.s.). CONCLUSIONS: The EMD is associated with high compliance, and there are also indications of a lower rejection rate. PMID- 26588007 TI - Canadian Forum on Combined Organ Transplantation. AB - The Canadian Society of Transplantation and Canadian Blood Services conducted a consensus forum on combined renal/nonrenal transplants, as they are not part of Canadian organ-specific allocation models at present. The purpose of this initiative was to make recommendations, develop eligibility criteria, and a decision-making model on listing and allocation. Forty-two participants with expertise in combined transplantation participated in the consensus forum. The United States and Canadian data were reviewed. The consensus forum made recommendations regarding the following: (1) investigation of etiology, severity, duration, and level of renal dysfunction; (2) documentation of degree of nonreversible kidney injury; (3) eligibility for combined (either simultaneous or staged) transplantation; (4) research. Key recommendations were: (1) patients with end-stage nonrenal disease with estimated glomerular filtration rate less than 30 mL/min per 1.73 m for longer than 1 month or on dialysis less than 3 months, who fulfill criteria for nonreversibility of renal dysfunction (by level and duration of renal dysfunction, imaging, and pathology findings), would be eligible for combined renal/nonrenal transplantation; (2) patients on dialysis longer than 3 months would be eligible for combined renal/nonrenal transplantation; (3) staged renal after nonrenal transplantation with subsequent prioritized allocation of renal transplant was endorsed in selected cases. The validation and impact of these recommendations on allocation will require further studies. PMID- 26588008 TI - Long-term Kidney Transplant Outcomes in Primary Glomerulonephritis: Analysis From the ERA-EDTA Registry. AB - BACKGROUND: We evaluated the 15-year kidney allograft survival in patients with primary glomerulonephritis and determined if the risk of graft loss varied with donor source within each glomerulonephritis group. METHODS: Using data from the European Renal Association-European Dialysis and Transplant Association Registry, Kaplan-Meier, competing risk, and Cox regression analyses were performed on adult, first kidney transplant recipients during 1991 to 2010 (n = 14 383). Follow-up was set to December 31, 2011. Adjustments for pretransplant dialysis duration, sex, country, and transplant era were made. "Death-adjusted graft survival" was assessed in patients with glomerulonephritis and compared with those with autosomal dominant polycystic kidney disease (ADPKD), in which the native kidney disease cannot recur. Additionally, death-adjusted graft survival was compared between living and deceased donor transplants within each glomerulonephritis group. RESULTS: All glomerulonephritides had a 15-year death adjusted graft survival probability above 55%. The 15-year risk of death-adjusted graft failure compared to ADPKD ranged from 1.17 (95% confidence interval [95% CI], 1.05-1.31) for immunoglobulin A nephropathy to 2.09 (95% CI, 1.56-2.78) for membranoproliferative glomerulonephritis type II. The expected survival benefits of living over deceased donor transplants were not present in membranoproliferative glomerulonephritis type I (adjusted hazard ratios [HRa], 1.08; 95% CI, 0.73-1.60) or type II (HRa, 0.90; 95% CI, 0.32-2.52) but present in immunoglobulin A nephropathy (HRa, 0.74; 95% CI, 0.59-0.92), membranous nephropathy (HRa, 0.47; 95% CI, 0.29-0.75), and focal segmental glomerulosclerosis (HRa, 0.69; 95% CI, 0.45-1.06). CONCLUSIONS: This large European study shows favorable long-term kidney graft survival in all primary glomerulonephritides, although this remains lower than graft survival in ADPKD, and confirms that the reluctance to use living donors in some primary glomerulonephritides remains unfounded. These data will further inform prospective renal transplant recipients and donors during pretransplant counselling. PMID- 26588009 TI - High Risk of Liver Allograft Failure During Late Adolescence and Young Adulthood. AB - BACKGROUND: Graft failure risk is highest during emerging adulthood (17-24 years) in kidney and heart transplant. It is unknown whether a similar association exists in liver transplant recipients. METHODS: We sought to estimate the relative hazards of graft failure at different current ages, compared with those aged 21 to 24 years. We evaluated 17 181 patients recorded in the Scientific Registry of Transplant Recipients who received a first isolated liver transplant at 40 years or younger (1988-2013) and had 6 months or longer of graft function. We used time-dependent Cox models to estimate the association between current age and failure risk, defined as retransplant or death after graft failure; observation was censored at death with graft function. RESULTS: There were 2540 failures. Absolute graft failure rates were highest in ages 25 to 29 years (3.0/100 person-years). Compared with individuals with the same time since transplantation, those aged 21 to 24 years had significantly higher failure rates than those younger than 17 years and older than 34 years; hazards did not differ for those aged 25 to 29 years (1.03 [0.86, 1.24]) and were lower, but not significantly, for those aged 17 to 20 years (hazards ratio, 0.83; 95% confidence interval, 0.68-1.01) and ages 30 to 34 years (hazards ratio, 0.84; 95% confidence interval, 0.70-1.01). CONCLUSIONS: Among young first isolated liver transplant recipients, graft failure risks are highest in the period from 21 to 29 years of age. PMID- 26588011 TI - [Correction: Successful Management of a Massive Bronchopleural Fistula with Endobronchial Valves in a Case of Perforated Central Lung Cancer: a Case Report]. PMID- 26588010 TI - Racial Differences in Survival of Incident Home Hemodialysis and Kidney Transplant Patients. AB - BACKGROUND: Previous studies have indicated that patients on maintenance hemodialysis have worse survival compared with kidney transplant (KTx) recipients. However, none of these studies have compared mortality of the US patients using alternative dialysis modalities such as home hemodialysis (HHD) with KTx recipients. METHODS: Comparing patients who started HHD with those who received kidney transplantation in the United States between 2007 and 2011, we created a 1:1 propensity score-matched cohort of 4000 patients and examined the association between treatment modality and all-cause mortality using Cox proportional hazard models. RESULTS: The mean +/- SD age of the propensity score matched HHD and KTx patients at baseline were 54 +/- 15 years and 54 +/- 14 years, 65% were men (both groups), 70% and 72% of patients were whites, and 19% were African American (both groups), respectively. Over 5 years of follow-up, HHD patients had 4 times higher mortality risk compared with KTx recipients in the entire patient population (hazard ratio [HR], 4.06; 95% confidence interval [95% CI], 3.27-5.04); total event number, 411), and similar difference was found across each race stratum. However, during the first year of therapy, although the white HHD patients had higher mortality risk (HR, 4.21; 95% CI, 3.10-5.73; total event number, 332) compared with their KTx counterparts, there was no significant difference in mortality risk between African American HHD and KTx patients (HR, 1.62; 95% CI, 0.77-3.39; total event number, 55). This result was consistent across different types of kidney donors. CONCLUSIONS: The HHD patients appear to have 4 times higher mortality compared with KTx recipients regardless of the type of kidney donor. Further studies are needed to understand the reasons underlying racial differenes during the first year of therapy. PMID- 26588012 TI - D-pi-A Compounds with Tunable Intramolecular Charge Transfer Achieved by Incorporation of Butenolide Nitriles as Acceptor Moieties. AB - Chromophores where a polyenic spacer separates a 4H-pyranylidene or benzothiazolylidene donor and three different butenolide nitriles have been synthesized and characterized. The role of 2(5H)-furanones as acceptor units on the polarization and the second-order nonlinear (NLO) properties has been studied. Thus, their incorporation gives rise to moderately polarized structures with NLO responses that compare favorably to those of related compounds featuring more efficient electron-withdrawing moieties. Derivatives of the proaromatic butenolide PhFu show the best nonlinearities. Benzothiazolylidene-containing chromophores present less alternated structures than their pyranylidene analogues, and, unlike most merocyanines, the degree of charge transfer does not decrease on lengthening the pi-bridge. PMID- 26588013 TI - Processing complex pseudo-words in mild cognitive impairment: The interaction of preserved morphological rule knowledge with compromised cognitive ability. AB - Mild cognitive impairment (MCI) affects the cognitive performance of elderly adults. However, the level of severity is not high enough to be diagnosed with dementia. Previous research reports subtle language impairments in individuals with MCI specifically in domains related to lexical meaning. The present study used both off-line (grammaticality judgment) and on-line (lexical decision) tasks to examine aspects of lexical processing and how they are affected by MCI. 21 healthy older adults and 23 individuals with MCI saw complex pseudo-words that violated various principles of word formation in Slovenian and decided if each letter string was an actual word of their language. The pseudo-words ranged in their degree of violability. A task effect was found, with MCI performance to be similar to that of healthy controls in the off-line task but different in the on line task. Overall, the MCI group responded slower than the elderly controls. No significant differences were observed in the off-line task, while the on-line task revealed a main effect of Violation type, a main effect of Group and a significant Violation * Group interaction reflecting a difficulty for the MCI group to process pseudo-words in real time. That is, while individuals with MCI seem to preserve morphological rule knowledge, they experience additional difficulties while processing complex pseudo-words. This was attributed to an executive dysfunction associated with MCI that delays the recognition of ungrammatical formations. PMID- 26588014 TI - Mechanical property and biological performance of electrospun silk fibroin polycaprolactone scaffolds with aligned fibers. AB - The mechanical strength, biocompatibility, and sterilizability of silk fibroin allow it to be a possible candidate as a natural bone regenerate material. To improve mechanical character and reinforce the cell movement induction, silk fibroin (SF)-polycaprolactone (PCL) alloy was fabricated by electrospinning techniques with a rotating collector to form aligned fibrous scaffolds and random oriented scaffolds. The scanning electron microscope image of the scaffold and the mechanical properties of the scaffold were investigated by tensile mechanical tests, which were compared to random-oriented scaffolds. Furthermore, mesenchymal stem cells were planted on these scaffolds to investigate the biocompatibility, elongation, and cell movement in situ. Scanning electron microscopy shows that 91% fibers on the aligned fibroin scaffold were distributed between the dominant direction +/-10 degrees . With an ideal support for stem cell proliferation in vitro, the aligned fibrous scaffold induces cell elongation at a length of 236.46 +/- 82 MUm and distribution along the dominant fiber direction with a cell alignment angle at 6.57 degrees +/- 4.45 degrees . Compared with random-oriented scaffolds made by artificial materials, aligned SF-PCL scaffolds could provide a moderate mesenchymal stem cell engraftment interface and speed up early stage cell movement toward the bone defect. PMID- 26588015 TI - Clinical Neurophysiological and Automated EEG-Based Diagnosis of the Alzheimer's Disease. AB - Alzheimer's disease (AD) is a progressive disorder affecting intellectual, behavioral and functional abilities. It is associated with age and pathological alterations leading to the formation of amyloid plaques and tangles. It is the most common source of dementia in the older population, which varies in its degrees of severity. We are yet to find efficient methods of diagnosis of AD, as its symptoms vary among individuals. This paper presents a review of recent research on the clinical neurophysiological and automated electroencephalography based diagnosis of the AD. Various therapeutic measures are also discussed briefly. PMID- 26588016 TI - Ultrasound surveillance for hepatocellular carcinoma: real-life performance in a hepatology outpatient clinic. AB - QUESTIONS: Regular surveillance of patients at risk for hepatocellular carcinoma (HCC) has been recommended by international guidelines and is practiced in many hepatology clinics. However, little is known about the effectiveness and the costs of 6 monthly ultrasound surveillance. METHODS: Clinical charts, ultrasound reports and reports of additional examinations (computed tomography, magnetic resonance imaging, liver biopsy) were systematically reviewed. The tumour stage of HCC detected in the surveillance programme was compared with stages of patients not surveyed. The number needed to survey to detect a HCC and the costs per detected HCC were calculated. RESULTS: In the 2-year period 2011-2012, 696 ultrasound examinations in 285 patients were performed in the hepatology outpatient clinic of the University Hospital Basel, Switzerland. Focal lesions were detected by ultrasound in 88 of the 285 patients. Nine of them had a newly diagnosed HCC. All of them were at early stage (Barcelona Clinic Liver Cancer staging 0 or A) and 8 of 9 fulfilled Milan Criteria. In this 2-year surveillance period, the number needed to screen was 32 patients. The calculated costs per detected HCC were 29 701 Swiss francs. CONCLUSIONS: In this retrospective analysis, HCC surveillance resulted in the detection of HCCs in an early stage. The number needed to screen and the costs of the surveillance are reasonably low. PMID- 26588017 TI - Effect of heating on the stability of amyloid A (AA) fibrils and the intra- and cross-species transmission of AA amyloidosis. AB - Amyloid A (AA) amyloidosis is a protein misfolding disease characterized by extracellular deposition of AA fibrils. AA fibrils are found in several tissues from food animals with AA amyloidosis. For hygienic purposes, heating is widely used to inactivate microbes in food, but it is uncertain whether heating is sufficient to inactivate AA fibrils and prevent intra- or cross-species transmission. We examined the effect of heating (at 60 degrees C or 100 degrees C) and autoclaving (at 121 degrees C or 135 degrees C) on murine and bovine AA fibrils using Western blot analysis, transmission electron microscopy (TEM), and mouse model transmission experiments. TEM revealed that a mixture of AA fibrils and amorphous aggregates appeared after heating at 100 degrees C, whereas autoclaving at 135 degrees C produced large amorphous aggregates. AA fibrils retained antigen specificity in Western blot analysis when heated at 100 degrees C or autoclaved at 121 degrees C, but not when autoclaved at 135 degrees C. Transmissible pathogenicity of murine and bovine AA fibrils subjected to heating (at 60 degrees C or 100 degrees C) was significantly stimulated and resulted in amyloid deposition in mice. Autoclaving of murine AA fibrils at 121 degrees C or 135 degrees C significantly decreased amyloid deposition. Moreover, amyloid deposition in mice injected with murine AA fibrils was more severe than that in mice injected with bovine AA fibrils. Bovine AA fibrils autoclaved at 121 degrees C or 135 degrees C did not induce amyloid deposition in mice. These results suggest that AA fibrils are relatively heat stable and that similar to prions, autoclaving at 135 degrees C is required to destroy the pathogenicity of AA fibrils. These findings may contribute to the prevention of AA fibril transmission through food materials to different animals and especially to humans. PMID- 26588018 TI - New Insights into Nonvitamin K Antagonist Oral Anticoagulants' Reversal of Intracerebral Hemorrhage. AB - The nonvitamin K antagonist oral anticoagulants (NOACs) dabigatran, rivaroxaban, apixaban, and edoxaban are associated with an equal or lower incidence of stroke and systemic embolism and a much lower incidence of intracranial hemorrhage and hemorrhagic stroke than warfarin is, without the need for routine laboratory monitoring. However, reversal strategies are not currently established in the case of NOAC-related hemorrhagic stroke. In emergency situations, well-defined management for NOAC-related hemorrhagic stroke may improve clinical outcomes. Thus, in this chapter, general measures initially required to prevent the expansion of intracerebral hematomas, charcoal administration to reduce NOAC absorption from the gastrointestinal tract, application of hemodialysis to remove dabigatran, and coagulation factor therapy including 4-factor prothrombin complex concentrate and recombinant activated factor VII are reviewed. The specific reversal agents idarucizumab, which is a monoclonal antibody against dabigatran; andexanet alfa, a recombinant human factor Xa decoy for Xa inhibitors; and PER977, a small synthetic molecule for reversal of both Xa and thrombin inhibitors, are currently under development. These agents will facilitate the clinical management of NOAC-associated hemorrhagic stroke and other severe bleeding. PMID- 26588019 TI - Portal Hypertension in Patients with Liver Cirrhosis: Diagnostic Accuracy of Spleen Stiffness. AB - PURPOSE: To evaluate the accuracy of spleen stiffness (SS) and liver stiffness (LS) measured by using acoustic radiation force impulse imaging in the diagnosis of portal hypertension in patients with liver cirrhosis, with the hepatic venous pressure gradient (HVPG) as a reference standard. MATERIALS AND METHODS: Institutional review board approval and informed consent were obtained for this prospective single-center study. From February 2012 to August 2013, 60 patients with liver cirrhosis (mean age, 70.8 years; age range, 34-88 years; 34 men, 26 women) with HVPG, LS, and SS measurements and gastrointestinal endoscopy and laboratory data were included if they met the following criteria: no recent episodes of gastrointestinal bleeding, no history of splenectomy, no history of partial splenic embolization, no history of beta-blocker therapy, and absence of portal thrombosis. The efficacy of the parameters for the evaluation of portal hypertension was analyzed by using the Spearman rank-order correlation coefficient and receiver operating characteristic (ROC) curve analysis. RESULTS: The correlation coefficient between SS and HVPG (r = 0.876) was significantly better than that between LS and HVPG (r = 0.609, P < .0001). The areas under the ROC curve of SS for the identification of clinically important portal hypertension (HVPG >= 10 mm Hg), severe portal hypertension (HVPG >= 12 mm Hg), esophageal varices (EVs), and high-risk EVs were significantly higher (0.943, 0.963, 0.937, and 0.955, respectively) than those of LS, spleen diameter, platelet count, and platelet count to spleen diameter ratio (P < .05 for all). SS could be used to accurately rule out the presence of clinically important portal hypertension, severe portal hypertension, EVs, and high-risk EVs (negative likelihood ratios, 0.051, 0.056, 0.054, and 0.074, respectively). CONCLUSION: SS is reliable and has better diagnostic performance than LS for identifying portal hypertension in liver cirrhosis. PMID- 26588020 TI - Is T1rho Mapping an Alternative to Delayed Gadolinium-enhanced MR Imaging of Cartilage in the Assessment of Sulphated Glycosaminoglycan Content in Human Osteoarthritic Knees? An in Vivo Validation Study. AB - PURPOSE: To determine if T1rho mapping can be used as an alternative to delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) in the quantification of cartilage biochemical composition in vivo in human knees with osteoarthritis. MATERIALS AND METHODS: This study was approved by the institutional review board. Written informed consent was obtained from all participants. Twelve patients with knee osteoarthritis underwent dGEMRIC and T1rho mapping at 3.0 T before undergoing total knee replacement. Outcomes of dGEMRIC and T1rho mapping were calculated in six cartilage regions of interest. Femoral and tibial cartilages were harvested during total knee replacement. Cartilage sulphated glycosaminoglycan (sGAG) and collagen content were assessed with dimethylmethylene blue and hydroxyproline assays, respectively. A four dimensional multivariate mixed-effects model was used to simultaneously assess the correlation between outcomes of dGEMRIC and T1rho mapping and the sGAG and collagen content of the articular cartilage. RESULTS: T1 relaxation times at dGEMRIC showed strong correlation with cartilage sGAG content (r = 0.73; 95% credibility interval [CI] = 0.60, 0.83) and weak correlation with cartilage collagen content (r = 0.40; 95% CI: 0.18, 0.58). T1rho relaxation times did not correlate with cartilage sGAG content (r = 0.04; 95% CI: -0.21, 0.28) or collagen content (r = -0.05; 95% CI = -0.31, 0.20). CONCLUSION: dGEMRIC can help accurately measure cartilage sGAG content in vivo in patients with knee osteoarthritis, whereas T1rho mapping does not appear suitable for this purpose. Although the technique is not completely sGAG specific and requires a contrast agent, dGEMRIC is a validated and robust method for quantifying cartilage sGAG content in human osteoarthritis subjects in clinical research. PMID- 26588021 TI - Chemical Exchange Saturation Transfer MR Imaging: Preliminary Results for Differentiation of Malignant and Benign Thoracic Lesions. AB - PURPOSE: To prospectively evaluate the capability of amide proton transfer weighted chemical exchange saturation transfer magnetic resonance (MR) imaging for characterization of thoracic lesions. MATERIALS AND METHODS: The institutional review board approved this study, and written informed consent was obtained from 21 patients (13 men and eight women; mean age, 72 years) prior to enrollment. Each patient underwent chemical exchange saturation transfer MR imaging by using respiratory-synchronized half-Fourier fast spin-echo imaging after a series of magnetization transfer pulses. Next, a magnetization transfer ratio asymmetry at 3.5 ppm map was computationally generated. Pathology examinations resulted in a diagnosis of 13 malignant and eight benign thoracic lesions. The malignant lesions were further diagnosed as being nine lung cancers, comprising six adenocarcinomas, three squamous cell carcinomas, and four other thoracic malignancies. The Student t test was used to evaluate the capability of magnetization transfer ratio asymmetry (at 3.5 ppm), as assessed by means of region of interest measurements, for differentiating benign and malignant lesions, lung cancers and other thoracic lesions, and adenocarcinomas and squamous cell carcinomas. RESULTS: Magnetization transfer ratio asymmetry (at 3.5 ppm) was significantly higher for malignant tumors (mean +/- standard deviation, 3.56% +/- 3.01) than for benign lesions (0.33% +/- 0.38, P = .008). It was also significantly higher for other thoracic malignancies (6.71% +/- 3.46) than for lung cancer (2.16% +/- 1.41, P = .005) and for adenocarcinoma (2.88% +/- 1.13) than for squamous cell carcinoma (0.71% +/- 0.17, P = .02). CONCLUSION: Amide proton transfer-weighted chemical exchange saturation transfer MR imaging allows characterization of thoracic lesions. PMID- 26588022 TI - Modeling of Spatially Correlated Energetic Disorder in Organic Semiconductors. AB - Mesoscale modeling of organic semiconductors relies on solving an appropriately parametrized master equation. Essential ingredients of the parametrization are site energies (driving forces), which enter the charge transfer rate between pairs of neighboring molecules. Site energies are often Gaussian-distributed and are spatially correlated. Here, we propose an algorithm that generates these energies with a given Gaussian distribution and spatial correlation function. The method is tested on an amorphous organic semiconductor, DPBIC, illustrating that the accurate description of correlations is essential for the quantitative modeling of charge transport in amorphous mesophases. PMID- 26588023 TI - Fabrication of Surface Protein-Imprinted Nanoparticles Using a Metal Chelating Monomer via Aqueous Precipitation Polymerization. AB - Molecular imprinting is a promising way for constructing artificial protein recognition materials, but it has been challenged by difficulties such as restricted biomacromolecule transfer in the cross-linked polymer networks, and reduced template-monomer interactions that are due to the required aqueous media. Herein, we propose a strategy for imprinting of histidine (His)-exposed proteins by combining previous approaches such as surface imprinting over nanostructures, utilization of metal coordination interactions, and adoption of aqueous precipitation polymerization capable of forming reversible physical crosslinks. With lysozyme as a model template bearing His residues, imprinted polymer nanoshells were grafted over vinyl-modified nanoparticles by aqueous precipitation copolymerization of a Cu(2+) chelating monomer with a temperature responsive monomer carried out at 37 degrees C, above the volume phase transition temperature (VPTT) of the final copolymer. The imprinted nanoshells showed significant temperature sensitivity and the template removal could be facilitated by swelling of the imprinted layers at 4 degrees C, below the VPTT. The resultant core-shell imprinted nanoparticles exhibited strikingly high rebinding selectivity against a variety of nontemplate proteins. An imprinting factor up to 22.7 was achieved, which is among the best values reported for protein imprinting, and a rather high specific binding capacity of 67.3 mg/g was obtained. Moreover, this approach was successfully extended to preliminary imprinting of hemoglobin, another protein with accessible His. Therefore, it may be a versatile method for fabrication of high-performance surface-imprinted nanoparticles toward His-exposed proteins. PMID- 26588024 TI - The Shreveport Myeloma Experience: Survival, Risk Factors and Other Malignancies in the Age of Stem Cell Transplantation. AB - BACKGROUND: The overall prognosis of multiple myeloma has improved significantly over the last 15 years. We wondered whether the overall improvement would also be seen in unselected patients in an academic center in Northwest Louisiana with a high proportion of minority patients, and if second malignant neoplasms are relevant for our patients. MATERIALS AND METHODS: Between 1998 and 2009, 215 patients were treated for multiple myeloma at our center and had complete follow up until May 2013. RESULTS: The mean survival of patients with multiple myeloma increased from 3.25 to 5.34 years, which is comparable to patients treated at larger centers. No prognostic difference was observed in the subgroups of myeloma patients. Among 215 patients followed for the development of secondary cancers, 16 already had a preexisting or concomitant malignancy (7.4%) and 10 developed secondary cancers. Our data indicate a significant background of histologically unrelated cancers and a cumulative incidence of new cancers of about 20% after 10 years of follow-up. Based on SEER data, preexisting or secondary cancers were not statistically increased in our population. CONCLUSIONS: The use of autologous transplantation and the introduction of new agents resulted in a significant improvement in the prognosis of multiple myeloma. Other cancers are not statistically increased before or after multiple myeloma is diagnosed and are not prognostically relevant. PMID- 26588025 TI - Use of Oral Misoprostol for Cervical Priming before Hysteroscopy: A Randomized Comparison of Two Dosages. AB - OBJECTIVE: The study aims to compare the safety and effectiveness of 200 and 400 ug of oral misoprostol for cervical priming before hysteroscopy. METHODS: A double-blinded randomized study included 70 patients scheduled for hysteroscopy in a Lebanese University Hospital. Two dosages of oral misoprostol (200 or 400 ug) were randomly distributed to these patients 1 h before surgery under general anesthesia. Subjective assessment of the ease of dilatation, size of the first used Hegar, cervical injuries, bleeding or uterine perforation, duration of the procedure and misoprostol adverse effect were all noted and compared. RESULTS: The difficulty of dilation until a Hegar 10 was similar for both treatment groups. Operative time was not reduced with a higher misoprostol dosage. We found 2 uterine perforations within the 200 ug group (6.7%), and none within the 400 ug group. Cervical lacerations and bleeding were similar (20%) for both treatment groups. A 2-fold increase in side effects (nausea, vomiting and cramps) is reported among the 400 ug group. CONCLUSIONS: Increasing the dose of misoprostol from 200 to 400 mg doubled the rate of side effects while no clinical benefit was noted. Larger trials are needed to assess rates of uterine perforation with the 200 ug dosage. PMID- 26588026 TI - Circulating microRNAs as biomarkers of muscle differentiation and atrophy in ALS. AB - AIMS: The identification of circulating biomarkers is needed to facilitate diagnosis and prognosis of amyotrophic lateral sclerosis (ALS) and to offer indicators of therapeutic response in clinical trials. We aimed to investigate the levels of muscle-specific microRNAs in serum of ALS patients subdivided according to bulbar or spinal onset. METHODS: In 14 ALS patients (10 spinal, 4 bulbar) we measured the serum levels of muscle-specific miR-206, miR-1, miR 133a/b, miR-27a, and the expression of myostatin and follistatin, which are negative regulators of muscle growth. Morphometric analysis of muscle fiber size was used to correlate muscle atrophy with biochemical-molecular parameters. RESULTS: In ALS patients the expression of miR-206 and miR-133 was significantly increased and that of miR-27a was significantly reduced as compared to controls, and also between spinal vs. bulbar ALS. Myostatin/follistatin ratio was significantly higher in ALS than in controls and in bulbar versus spinal ALS. Bulbar ALS patients present higher degree of muscle atrophy than spinal ALS, as documented by our muscle fiber morphometric analysis. CONCLUSIONS: Muscle mass regulators are particularly down-expressed in bulbar ALS, suggesting a more rapid and diffuse atrophic process. These biomarkers may be considered as useful biochemical and molecular indicators involved both in neuromuscular junction maintenance and reinnervation process. PMID- 26588027 TI - Evolving evidence on tumor and germline genetic classification of gliomas: implications for etiology and survival studies. AB - The Brain Tumor Epidemiology Consortium (BTEC) is an international consortium that has the mission of fostering the development of multi-center and inter disciplinary collaborations aiming to improve understanding of the etiology, outcomes, and prevention of brain tumors. Mayo Clinic faculty, Robert Jenkins, MD, PhD and Brian Patrick O'Neill, MD, hosted the 16th annual BTEC meeting on June 2-4, 2015, in Rochester, MN, USA. The meeting included presentations that emphasized the impact of new tumor classifications, methodological practices of population studies, as well as intra- and inter-tumoral molecular complexities on patient outcomes. The 2016 meeting will be held in Barcelona, Spain in June. PMID- 26588028 TI - Reiterated Targeting Peptides on the Nanoparticle Surface Significantly Promote Targeted Vascular Endothelial Growth Factor Gene Delivery to Stem Cells. AB - Nonviral gene delivery vectors hold great promise for gene therapy due to the safety concerns with viral vectors. However, the application of nonviral vectors is hindered by their low transfection efficiency. Herein, in order to tackle this challenge, we developed a nonviral vector integrating lipids, sleeping beauty transposon system and 8-mer stem cell targeting peptides for safe and efficient gene delivery to hard-to-transfect mesenchymal stem cells (MSCs). The 8-mer MSC targeting peptides, when synthetically reiterated in three folds and chemically presented on the surface, significantly promoted the resultant lipid-based nanoparticles (LBNs) to deliver VEGF gene into MSCs with a high transfection efficiency (~52%) and long-lasting gene expression (for longer than 170 h) when compared to nonreiterated peptides. However, the reiterated stem cell targeting peptides do not enable the highly efficient gene transfer to other control cells. This work suggests that the surface presentation of the reiterated stem cell targeting peptides on the nonviral vectors is a promising method for improving the efficiency of cell-specific nonviral gene transfection in stem cells. PMID- 26588029 TI - Effects of hydrotreated vegetable oil on emissions of aerosols and gases from light-duty and medium-duty older technology engines. AB - This study was conducted to assess the potential of hydrotreated vegetable oil renewable diesel (HVORD) as a control strategy to reduce exposure of workers to diesel aerosols and gases. The effects of HVORD on criteria aerosol and gaseous emissions were compared with those of ultralow sulfur diesel (ULSD). The results of comprehensive testing at four steady-state conditions and one transient cycle were used to characterize the aerosol and gaseous emissions from two older technology engines: (1) a naturally aspirated mechanically controlled and (2) a turbocharged electronically controlled engine. Both engines were equipped with diesel oxidation catalytic converters (DOCs). For all test conditions, both engines emitted measurably lower total mass concentrations of diesel aerosols, total carbon, and elemental carbon when HVORD was used in place of ULSD. For all test conditions, the reductions in total mass concentrations were more substantial for the naturally aspirated than for the turbocharged engine. In the case of the naturally aspirated engine, HVORD also favorably affected total surface area of aerosols deposited in the alveolar region of human lungs (TSAADAR) and the total number concentrations of aerosols. In the case of the turbocharged electronically controlled engine, for some of the test conditions HVORD adversely affected the TSAADAR and total number concentrations of aerosols. In the majority of the test cases involving the naturally aspirated mechanically controlled engine, HVORD favorably affected carbon dioxide (CO2), nitrogen oxides (NOX), and nitric oxide (NO) concentrations, but adversely affected NO2 and total hydrocarbon concentrations, while the effects of the fuels on carbon monoxide (CO) concentrations were masked by the effects of DOC. In the case of the turbocharged electronically controlled engine, the CO2, CO, NOX, NO, and total hydrocarbon concentrations were generally lower when HVORD was used in place of ULSD. The effects of the fuels on NO2 concentrations were masked by the more prominent effects of DOC. PMID- 26588030 TI - Perioperative Management of Multiple Noncardiac Implantable Electronic Devices. AB - The number of patients with noncardiac implantable electronic devices is increasing, and the absence of perioperative management standards, guidelines, practice parameters, or expert consensus statements presents clinical challenges. A 69-year-old woman presented for latissimus dorsi breast reconstruction. The patient had previously undergone implantation of a spinal cord stimulator, a gastric pacemaker, a sacral nerve stimulator, and an intrathecal morphine pump. After consultation with device manufacturers, the devices with patient programmability were switched off. Bipolar cautery was used intraoperatively. Postoperatively, all devices were interrogated to ensure appropriate functioning before home discharge. Perioperative goals include complete preoperative radiologic documentation of device component location, minimizing electromagnetic interference, and avoiding mechanical damage to implanted device components. PMID- 26588031 TI - Complete Neurological Recovery After Transesophageal Echocardiography-Guided Diagnosis and Management of Prolonged Cardiopulmonary Resuscitation. AB - A 70-year-old man was scheduled for open reduction and internal fixation of his right knee fracture. When the tourniquet was deflated after 150 minutes, his arterial blood pressure and heart rate decreased precipitously. The patient was deemed to exhibit pulseless electrical activity. Cardiopulmonary resuscitation was initiated. The bispectral index reading improved to 25 to 30, but his end tidal carbon dioxide was still very low (5 mm Hg). Transesophageal echocardiography showed a pulmonary embolism. Feedback from echo imaging improved the quality of chest compressions and motivated the resuscitation team to maintain the diastolic blood pressure>25 mm Hg. Although capnographic guidance was ineffective by itself, echocardiography monitoring was very helpful for showing the intracardiac events. PMID- 26588033 TI - Compartment Syndrome Resulting from Carbon Monoxide Poisoning. AB - Every year, especially in the cooler Fall and Winter months, hundreds of people die because of carbon monoxide poisoning. This occurs usually as an accident. It is a significant cause of poisoning worldwide. We present a case of compartment syndrome in both lower extremities with accompanying acute renal failure and systemic capillary leakage syndrome because of carbon monoxide poisoning. PMID- 26588032 TI - Electroencephalography of Seizure-Like Movements During General Anesthesia with Propofol: Seizures or Nonepileptic Events? AB - Seizure-like behavior is an uncommon yet worrisome phenomenon during anesthesia with propofol. The current case report describes a 23-year-old man admitted for elective surgery who experienced several seizure-like episodes after induction with propofol and during a desflurane-based general anesthetic that were so severe it was not possible to complete the procedure. A second surgery was rescheduled 2 days later with simultaneous scalp electroencephalographic (EEG) recording and general anesthesia with propofol and fentanyl. During the second operation, he again experienced numerous episodes of generalized shaking movements. Simultaneous intraoperative EEG recording showed a background of diffuse beta and alpha frequencies interspersed with periods of pseudoperiodic delta activity; electrographic seizures were not apparent. With this information, muscle relaxants were given and the procedure was performed without difficulty. This is the first report of apparent seizure-like activity during anesthesia with propofol of an otherwise relatively healthy adult, in which concurrent EEG recording demonstrates the nonepileptic nature. The current case demonstrates that, at least in some instances, these concerning movements are not seizure related. Concurrent EEG monitoring may be helpful to evaluate the nature of the episodes in select cases. PMID- 26588034 TI - Use of the Draeger Apollo to Deliver Bilevel Positive Pressure Ventilation During Awake Frontal Craniotomy for a Patient with Severe Chronic Obstructive Pulmonary Disease. AB - In this case report, we describe the use of the Draeger Apollo anesthesia machine to deliver bilevel positive airway pressure (BiPAP) to a patient with severe chronic obstructive pulmonary disease and a history of lung resection undergoing frontal craniotomy for the removal of a brain tumor under moderate to deep sedation. BiPAP in the perioperative period has been described for purposes of preoxygenation and postextubation recruitment. Although its utility as a mode of ventilation during moderate to deep sedation has been demonstrated, it has not come into widespread use. We describe the intraoperative use of pressure support mode on the anesthesia machine to deliver noninvasive positive pressure ventilation through a standard anesthesia mask. Given its ease of access and effectiveness, it is our belief that intraoperative BiPAP may reduce hypoxemia and/or hypercarbia in patients with chronic obstructive pulmonary disease and obstructive sleep apnea undergoing moderate to deep sedation. PMID- 26588035 TI - Cotton-Textile-Enabled, Flexible Lithium-Ion Batteries with Enhanced Capacity and Extended Lifespan. AB - Activated cotton textile (ACT) with porous tubular fibers embedded with NiS2 nanobowls and wrapped with conductive graphene sheets (ACT/NiS2-graphene) was fabricated by a simple two-step heat treatment method. When used as a binder-free electrode, the ACT/NiS2-graphene electrode exhibited an exceptional electrochemical performance including ultrahigh initial discharge capacity (~1710 mAh g(-1) at 0.01 C), magnificent rate performance (the discharge capacitance retained at ~645 mAh g(-1) at 1 C after 100 cycles) and excellent cyclic stability (the discharge capacitance recovered to ~1016 mAh g(-1) at 0.1 C after 400 cycles). PMID- 26588036 TI - Peanut-allergic patients in the MIRABEL survey: characteristics, allergists' dietary advice and lessons from real life. AB - BACKGROUND: The MIRABEL survey is an observational study on peanut allergy in France, Belgium and Luxemburg. The objectives are to provide data on a large population, to analyse the consumer behaviour, to study the presence of peanut traces in pre-packed foods with/without precautionary allergen labelling (PAL), and to combine these data to quantify allergic risk and produce a cost/benefit analysis. This paper reports a real-life observatory of 785 patients (< 16y: 86%): medical characteristics, eliciting doses (ED) in real life and in oral food challenges (OFC), factors associated with severe reactions, allergist dietary advice and patients' anxiety regarding their allergy. METHODS: Age and symptoms at diagnosis, route of exposure, comorbidities, allergy tests, ED (OFC/real life; mg peanut protein), dietary advice about PAL, and anxiety score were recorded. RESULTS: Median age was 3 years; 85% were declared allergic. Severe/potentially severe reactions were reported in 30% of the allergic patients: serious systemic reaction (15%), laryngeal angioedema (8%), shock (4%) and acute asthma (3%); 66% had atopic dermatitis, 58% asthma. Median ara h 2 sIgE level was 11.5 kUA/L. Of the 278 OFCs, 225 were positive (median ED: 67.3 mg). Real-life ED was < 100 mg in 44.3%. Severe reactions were significantly more frequent in teenagers and adults (P = 0.004), asthmatic patients (P = 0.033), and patients who reacted to inhalation (P < 0.001). No significant association was found for OFC ED or ara h 2 sIgE. Factors associated with strict avoidance advice including PAL were OFC ED < 100 mg (P < 0.001), but not severe reaction history (P = 0.051) or asthma (P = 0.34). Anxiety was significantly associated with strict avoidance (P < 0.001). CONCLUSION AND CLINICAL RELEVANCE: Severe/potentially severe reactions, allergic comorbidities, and low EDs in real life are frequent in peanut-allergic patients. Asthma, teenage/adulthood and reaction to inhalation are associated with severe symptoms. PAL and criteria guiding dietary advice need to be improved. PMID- 26588037 TI - Leishmania hijacking of the macrophage intracellular compartments. AB - Leishmania spp., transmitted to humans by the bite of the sandfly vector, are responsible for the three major forms of leishmaniasis, cutaneous, diffuse mucocutaneous and visceral. Leishmania spp. interact with membrane receptors of neutrophils and macrophages. In macrophages, the parasite is internalized within a parasitophorous vacuole and engages in a particular intracellular lifestyle in which the flagellated, motile Leishmania promastigote metacyclic form differentiates into non-motile, metacyclic amastigote form. This phenomenon is induced by Leishmania-triggered events leading to the fusion of the parasitophorous vacuole with vesicular members of the host cell endocytic pathway including recycling endosomes, late endosomes and the endoplasmic reticulum. Maturation of the parasitophorous vacuole leads to the intracellular proliferation of the Leishmania amastigote forms by acquisition of host cell nutrients while escaping host defense responses. PMID- 26588039 TI - Aerobic biodegradation potential of endocrine-disrupting chemicals in surface water sediment at Rocky Mountain National Park, USA. AB - Endocrine-disrupting chemicals (EDCs) in surface water and bed sediment threaten the structure and function of aquatic ecosystems. In natural, remote, and protected surface-water environments where contaminant releases are sporadic, contaminant biodegradation is a fundamental driver of exposure concentration, timing, duration, and, thus, EDC ecological risk. Anthropogenic contaminants, including known and suspected EDCs, were detected in surface water and sediment collected from 2 streams and 2 lakes in Rocky Mountain National Park (Colorado, USA). The potential for aerobic EDC biodegradation was assessed in collected sediments using 6 (14) C-radiolabeled model compounds. Aerobic microbial mineralization of natural (estrone and 17beta-estradiol) and synthetic (17alpha ethinylestradiol) estrogen was significant at all sites. Bed sediment microbial communities in Rocky Mountain National Park also effectively degraded the xenoestrogens bisphenol-A and 4-nonylphenol. The same sediment samples exhibited little potential for aerobic biodegradation of triclocarban, however, illustrating the need to assess a wider range of contaminant compounds. The present study's results support recent concerns over the widespread environmental occurrence of carbanalide antibacterials, like triclocarban and triclosan, and suggest that backcountry use of products containing these compounds should be discouraged. PMID- 26588038 TI - Aging, cytomegalovirus (CMV) and influenza vaccine responses. AB - Influenza vaccination is less effective in elderly as compared to young individuals. Several studies have identified immune biomarkers able to predict a protective humoral immune response to the vaccine. In this review, we summarize current knowledge on the effects of aging on influenza vaccine responses and on biomarkers so far identified, and we discuss the relevance of latent cytomegalovirus (CMV) infection on these vaccine responses. PMID- 26588040 TI - Total liver fat quantification using three-dimensional respiratory self-navigated MRI sequence. AB - PURPOSE: MRI can produce quantitative liver fat fraction (FF) maps noninvasively, which can help to improve diagnoses of fatty liver diseases. However, most sequences acquire several two-dimensional (2D) slices during one or more breath holds, which may be difficult for patients with limited breath-holding capacity. A whole-liver 3D FF map could also be obtained in a single acquisition by applying a reliable breathing-motion correction method. Several correction techniques are available for 3D imaging, but they use external devices, interrupt acquisition, or jeopardize the spatial resolution. To overcome these issues, a proof-of-concept study introducing a self-navigated 3D three-point Dixon sequence is presented here. METHODS: A respiratory self-gating strategy acquiring a center k-space profile was integrated into a three-point Dixon sequence. We obtained 3D FF maps from a water-fat emulsions phantom and fifteen volunteers. This sequence was compared with multi-2D breath-hold and 3D free-breathing approaches. RESULTS: Our 3D three-point Dixon self-navigated sequence could correct for respiratory motion artifacts and provided more precise FF measurements than breath-hold multi 2D and 3D free-breathing techniques. CONCLUSION: Our 3D respiratory self-gating fat quantification sequence could correct for respiratory motion artifacts and yield more-precise FF measurements. Magn Reson Med 76:1400-1409, 2016. (c) 2015 International Society for Magnetic Resonance in Medicine. PMID- 26588042 TI - FEA of Peri-Implant Stresses in Fixed Partial Denture Prostheses with Cantilevers. AB - PURPOSE: To compare stresses in the peri-implant bone produced by fixed partial prostheses with mesial and distal cantilevers, when cemented or screwed onto implants. MATERIALS AND METHODS: The experimental design consisted of four 3D models obtained by volumetric computerized tomography and analyzed using finite element analysis (FEA). Stresses were simulated in two stages. Stage 1 consisted of application of the preload. A 288 N load was applied to pillar screws of the cemented prosthesis, resulting in 389 MPa peak; 257 N was applied to the intermediate screw (multi-unit) resulting in 390 MPa peak; and 111 N was applied to the prosthesis infrastructure screw in the screwed prostheses, resulting in 390 MPa peak. In stage 2, the axial and oblique loads were applied. The axial load consisted of 50 N for molar implants and 30 N for premolar implants. The oblique load (on the buccal slope of the buccal cusp of each crown) consisted of 30 N for premolar implants and 50 N for molar implants, with a buccolingual vector at a 45 degrees angle with the occlusal plane. The response variables were the axial and oblique stresses on the peri-implant bone, according to the following groups: group 1-models of fixed partial prostheses cemented onto implants with mesial or distal cantilevers; group 2-models of fixed partial denture screwed onto implants with mesial or distal cantilevers. Data were recorded, evaluated, and compared. RESULTS: Oblique loads produced higher peak values than axial loads, and were located at the bone crest of the implant closest to the cantilever, regardless of the prosthesis type. In the cemented prosthesis models, oblique loads produced the highest peaks in the primary implant region when compared with the screwed prosthesis models. CONCLUSION: The screwed fixed prostheses caused less stress on peri-implant bone regardless of whether the cantilever was located mesially or distally. PMID- 26588041 TI - Nuclear Factor kappaB1/RelA Mediates Inflammation in Human Lung Epithelial Cells at Atmospheric Oxygen Levels. AB - Oxygen levels range from 2% to 9% in vivo. Atmospheric O2 levels (21%) are known to induce cell proliferation defects and cellular senescence in primary cell cultures. However, the mechanistic basis of the deleterious effects of higher O2 levels is not fully understood. On the other hand, immortalized cells including cancer cell lines, which evade cellular senescence are normally cultured at 21% O2 and the effects of higher O2 on these cells are understudied. Here, we addressed this problem by culturing immortalized human bronchial epithelial (BEAS 2B) cells at ambient atmospheric, 21% O2 and lower, 10% O2. Our results show increased inflammatory response at 21% O2 but not at 10% O2. We found higher RelA binding at the NF-kappaB1/RelA target gene promoters as well as upregulation of several pro-inflammatory cytokines in cells cultured at 21% O2. RelA knockdown prevented the upregulation of the pro-inflammatory cytokines at 21% O2, suggesting NF-kappaB1/RelA as a major mediator of inflammatory response in cells cultured at 21% O2. Interestingly, unlike the 21% O2 cultured cells, exposure of 10% O2 cultured cells to H2O2 did not elicit inflammatory response, suggesting increased ability to tolerate oxidative stress in cells cultured at lower O2 levels. PMID- 26588043 TI - What Is the Role of Developmental Disability in Patient Selection for Pediatric Solid Organ Transplantation? AB - The National Organ Transplant Act stipulates that deceased donor organs should be justly and wisely allocated based on sound medical criteria. Allocation schemes are consistent across the country, and specific policies are publicly vetted. Patient selection criteria are largely in the hands of individual organ transplant programs, and consistent standards are less evident. This has been particularly apparent for patients with developmental disabilities (DDs). In response to concerns regarding the fairness of transplant evaluations for patients with DDs, we developed a transplant centerwide policy using a multidisciplinary, community-based approach. This publication details the particular policy of our center. All patients should receive individualized assessments using consistent standards; disability should be neither a relative nor an absolute contraindication to transplantation. External review can increase trust in the selection process. Patients in persistent vegetative states should not be listed for transplantation. PMID- 26588044 TI - Particulate reactive oxygen species on total suspended particles - measurements in residences in Austin, Texas. AB - The biologically relevant characteristics of particulate matter (PM) in homes are important to assessing human health. The concentration of particulate reactive oxygen species (ROS) was assessed in eight homes and was found to be lower inside (mean +/- s.e. = 1.59 +/- 0.33 nmol/m3 ) than outside (2.35 +/- 0.57 nmol/m3 ). Indoor particulate ROS concentrations were substantial and a major fraction of indoor particulate ROS existed on PM2.5 (58 +/- 10%), which is important from a health perspective as PM2.5 can carry ROS deep into the lungs. No obvious relationships were evident between selected building characteristics and indoor particulate ROS concentrations, but this observation would need to be verified by larger, controlled studies. Controlled experiments conducted at a test house suggest that indoor ozone and terpene concentrations substantially influence indoor particulate ROS concentrations when outdoor ozone concentrations are low, but have a weaker influence on indoor particulate ROS concentrations when outdoor ozone concentrations are high. The combination of substantial indoor concentrations and the time spent indoors suggest that further work is warranted to assess the key parameters that drive indoor particulate ROS concentrations. PMID- 26588045 TI - Perspectives on the Two-Pore Domain Potassium Channel TREK-1 (TWIK-Related K(+) Channel 1). A Novel Therapeutic Target? AB - Potassium (K(+)) channels are membrane proteins expressed in most living cells that selectively control the flow of K(+) ions. More than 80 genes encode the K(+) channel subunits in the human genome. The TWIK-related K(+) channel (TREK-1) belongs to the two-pore domain K(+) channels (K2P) and displays various properties including sensitivity to physical (membrane stretch, acidosis, temperature) and chemical stimuli (signaling lipids, volatile anesthetics). The distribution of TREK-1 in the central nervous system, coupled with the physiological consequences of its opening and closing, leads to the emergence of this channel as an attractive therapeutic target. We review the TREK-1 channel, its structural and functional properties, and the pharmacological agents (agonists and antagonists) able to modulate its gating. PMID- 26588046 TI - Constant-pH MD Simulations of DMPA/DMPC Lipid Bilayers. AB - Current constant-pH molecular dynamics (CpHMD) simulations provide a proper treatment of pH effects on the structure and dynamics of soluble biomolecules like peptides and proteins. However, addressing such effects on lipid membrane assemblies has remained problematic until now, despite the important role played by lipid ionization at physiological pH in a plethora of biological processes. Modeling (de)protonation events in these systems requires a proper consideration of the physicochemical features of the membrane environment, including a sound treatment of solution ions. Here, we apply our recent CpHMD-L method to the study of pH effects on a 25% DMPA/DMPC bilayer membrane model, closely reproducing the correct lipid phases of this system, namely, gel-fluid coexistence at pH 4 and a fluid phase at pH 7. A significant transition is observed for the membrane ionization and mechanical properties at physiological pH, providing a molecular basis for the well-established role of phosphatidic acid (PA) as a key player in the regulation of many cellular events. Also, as reported experimentally, we observed pH-induced PA-PA lipid aggregation at acidic pH. By including the titration of anionic phospholipids, the current methodology makes possible to simulate lipid bilayers with increased realism. To the best of our knowledge, this is the first simulation study dealing with a continuous phospholipid bilayer with pH titration of all constituent lipids. PMID- 26588047 TI - Prevalence of depression in Parkinson's disease in a Lebanese tertiary clinic. AB - INTRODUCTION: Diagnosis of Parkinson's disease can be emotionally and psychologically challenging to patients. The aim of this study is to investigate the association between Parkinson's disease and depression and the impact of the disease stage and patients' age and gender on this association. METHOD: This is a cross-sectional retrospective study on 200 patients aged above 35 years old from 10 different nationalities. RESULTS: Depression was diagnosed in 46% of the patients enrolled. Most of these patients were treated with an antidepressant. Young age, female gender, and moderate Parkinson's disease stage were found to be significantly associated with depression (odds ratio of 1.19, 1.23, and 1.22, respectively, p < .05). CONCLUSION: This study, the first of its kind in Lebanon and the Middle East and North Africa region, highlights the importance of studying depression in Parkinson's disease and the need for identifying and treating depression symptoms when treating Parkinson's disease patients. PMID- 26588048 TI - Pyridazine N-Oxides as Precursors of Metallocarbenes: Rhodium-Catalyzed Transannulation with Pyrroles. AB - Pyridazine N-oxides are used for the first time as precursors of metallocarbenes. These nitrogen-rich heterocycles led to the discovery of a novel acceptor and donor-acceptor enalcarbenoids. The synthetic utility of these metallocarbenes was demonstrated in the rhodium-catalyzed denitrogenative transannulation of pyridazine N-oxides with pyrroles to the valuable alkyl, 7-aryl, and 7-styryl indoles. The transannulation strategy was applied to the synthesis of a potent anticancer agent. PMID- 26588049 TI - Simultaneous determination of thirteen major active compounds in Guanjiekang preparation by UHPLC-QQQ-MS/MS. AB - An ultra high performance liquid chromatography coupled to triple quadrupole mass spectrometry (UHPLC-QQQ-MS/MS) method has been developed to evaluate the quality of a pharmaceutical herbal preparation, Guanjiekang (GJK), through a simultaneous determination of 13 major active compounds with a huge difference in level of content. Chromatographic separation was achieved on a Waters Acquilty UPLC C18 column (2.1 * 100 mm, 1.7 MUm) with a mobile phase consisting of acetonitrile and buffer solution (10mM ammonium acetate containing 0.1% acetic acid) under a gradient elution manner. A triple quadrupole mass spectrometer was operated in positive ionization mode with multiple reaction monitoring for the detection of the 13 compounds. All calibration curves showed excellent linear regressions (R(2)>0.999) within the test range. The precision, repeatability and stability of the 13 compounds were below 5.0% in terms of RSD. The recoveries were 99.2-103.9% with RSD of 0.23-3.30% for GJK samples. The method was successfully used for the analysis of samples of GJK preparation and showed that the lowest level was in aconitine (0.582 +/- 0.143 ng/g) and the highest was in paeoniflorin (16.80 +/- 0.886 mg/g), with a 41800 folds of difference. In conclusion, a rapid, sensitive, precise, accurate, and reliable UHPLC-QQQ-MS/MS method has been developed for the simultaneous detection of 13 active compounds with massive difference in level of content in the pharmaceutical samples of GJK preparation, which can be applied for the quality control of GJK product. PMID- 26588050 TI - Effect of spacer length and type on the biological activity of peptide polysaccharide matrices. AB - Peptide-polysaccharide matrices can mimic extracellular matrix structure and function and are useful for tissue and cell engineering. The spacer between the peptide and the polysaccharide is important for both peptide conformation and the interaction between the peptide and receptors. Here, the effect of a spacer on the biological activity of peptide-polysaccharide matrices using various lengths of spacers consisting of glycine, beta-alanine, and epsilon-aminocaproic acid has been examined. Active laminin-derived peptides, including a syndecan-binding peptide (AG73: RKRLQVQLSIRT), an integrin alphavbeta3-binding peptide (A99a: ALRGDN), and an integrin alpha6beta1-binding peptide (A2G10: SYWYRIEASRTG), were used as the peptide ligands and chitosan was used as a polysaccharide matrix. The spacers did not influence the biological activity of the AG73-chitosan matrix. In contrast, the integrin-binding peptide-chitosan matrices showed spacer-dependent activity. Hydrophobic spacers enhanced the cell attachment activity of the A99a chitosan matrix. A four-glycine spacer showed the strongest effect for the biological activity of the A2G10-chitosan matrix. These results suggested that spacer-optimization for each peptide is important for designing effective peptide polysaccharide matrices. (c) 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 512-520, 2016. PMID- 26588051 TI - Mixed methods student evaluation of an online systemic human anatomy course with laboratory. AB - A fully online section of an existing face-to-face (F2F) systemic human anatomy course with a prosection laboratory was offered for the first time in 2012-2013. Lectures for F2F students (N = 365) were broadcast in both live and archived format to online students (N = 40) using virtual classroom software. Laboratories were delivered online by a teaching assistant who manipulated 3D computer models in the virtual classroom environment. An exploratory sequential mixed methods approach was undertaken to determine the most important deciding factors that drive students' preferences for a given format and then to generate theory on the strengths and weaknesses of the online format. Students (20 online; 310 F2F) volunteered to participate in a crossover period of one week to expose them to the course section in which they were not originally registered. Open ended interviews (20 online; 20 F2F) and quantitative surveys (270 F2F) were conducted following a crossover. Students valued pace control, schedule, and location flexibility of learning from archived materials and being assessed online. In the online laboratory they had difficulty using the 3D models and preferred the unique and hands-on experiences of cadaveric specimens. The F2F environment was conducive to learning in both lecture and laboratory because students felt more engaged by instructors in person and were less distracted by their surroundings. These results suggest the need to improve the online experience by increasing the quality of student-instructor communication and in turn student-content interaction with the 3D models. Anat Sci Educ 9: 272-285. (c) 2015 American Association of Anatomists. PMID- 26588052 TI - Number of citations 1 year after publication of trial results and their relation to medicines regulatory approval. PMID- 26588053 TI - The Role of Early HIV Status Disclosure in Retention in HIV Care. AB - The objective of this study was to evaluate whether nondisclosure or selective disclosure of HIV status to others is associated with retention in HIV care. This retrospective analysis evaluated the relationship of self-reported disclosure of HIV status as an indicator for poor retention in care (a gap in care >180 days) during the 12 months following initial entry into HIV care. Nondisclosure (disclosure to no one) and selective disclosure were compared to broad disclosure (referent). Univariate and multivariable (MV) logistic regression models were fit, including factors known to be associated with disclosure and retention in care. From 2007 to 2013, 508 HIV-infected patients presented to initiate care, of whom 63% were black, 54% had a CD4 + T lymphocyte count <350, and 82% were men (60% of whom were men who have sex with other men). Of these, 65 (13%) reported nondisclosure, 258 (49%) reported selective disclosure, and 185 (38%) reported broad disclosure. In MV analyses, nondisclosure was associated with poor retention in care (AOR 2.2; 95% CI 1.2, 4.2). Evaluating disclosure patterns among patients establishing HIV care may help predict and prevent inconsistent care. Further work is needed to understand the relationship between disclosure and retention in care in order to guide future interventions to improve HIV outcomes. PMID- 26588054 TI - Interaction of RECQ4 and MCM10 is important for efficient DNA replication origin firing in human cells. AB - DNA replication is a highly coordinated process that is initiated at multiple replication origins in eukaryotes. These origins are bound by the origin recognition complex (ORC), which subsequently recruits the Mcm2-7 replicative helicase in a Cdt1/Cdc6-dependent manner. In budding yeast, two essential replication factors, Sld2 and Mcm10, are then important for the activation of replication origins. In humans, the putative Sld2 homolog, RECQ4, interacts with MCM10. Here, we have identified two mutants of human RECQ4 that are deficient in binding to MCM10. We show that these RECQ4 variants are able to complement the lethality of an avian cell RECQ4 deletion mutant, indicating that the essential function of RECQ4 in vertebrates is unlikely to require binding to MCM10. Nevertheless, we show that the RECQ4-MCM10 interaction is important for efficient replication origin firing. PMID- 26588056 TI - Risk-reducing surgery in BRCA 1/2 mutation carries: a point of view. PMID- 26588057 TI - Sequencing rare T-cell populations. PMID- 26588055 TI - miR-671-5p inhibits epithelial-to-mesenchymal transition by downregulating FOXM1 expression in breast cancer. AB - MicroRNA (miRNA) dysfunction is associated with a variety of human diseases, including cancer. Our previous study showed that miR-671-5p was deregulated throughout breast cancer progression. Here, we report for the first time that miR 671-5p is a tumor-suppressor miRNA in breast tumorigenesis. We found that expression of miR-671-5p was decreased significantly in invasive ductal carcinoma (IDC) compared to normal in microdissected formalin-fixed, paraffin-embedded (FFPE) tissues. Forkhead Box M1 (FOXM1), an oncogenic transcription factor, was predicted as one of the direct targets of miR-671-5p, which was subsequently confirmed by luciferase assays. Forced expression of miR-671-5p in breast cancer cell lines downregulated FOXM1 expression, and attenuated the proliferation and invasion in breast cancer cell lines. Notably, overexpression of miR-671-5p resulted in a shift from epithelial-to-mesenchymal transition (EMT) to mesenchymal-to-epithelial transition (MET) phenotypes in MDA-MB-231 breast cancer cells and induced S-phase arrest. Moreover, miR-671-5p sensitized breast cancer cells to cisplatin, 5-fluorouracil (5-FU) and epirubicin exposure. Host cell reactivation (HCR) assays showed that miR-671-5p reduces DNA repair capability in post-drug exposed breast cancer cells. cDNA microarray data revealed that differentially expressed genes when miR-671-5p was transfected are associated with cell proliferation, invasion, cell cycle, and EMT. These data indicate that miR-671-5p functions as a tumor suppressor miRNA in breast cancer by directly targeting FOXM1. Hence, miR-671-5p may serve as a novel therapeutic target for breast cancer management. PMID- 26588058 TI - Prediction of systolic blood pressure using peripheral pulse palpation in cats. AB - OBJECTIVE: To evaluate the ability of peripheral pulse palpation to predict systolic blood pressure (SBP) in cats presenting as emergencies. DESIGN: Prospective observational study performed over an 8-month period. SETTING: University veterinary teaching hospital. ANIMALS: One hundred two cats presenting to the emergency service. Eligibility for inclusion in the study included a physical examination and a SBP via Doppler technique performed prior to treatment. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Femoral and metatarsal pulses were digitally palpated and the quality of the pulses was assessed as either strong, moderate, poor, or absent. A concurrent SBP was also recorded. The median SBP for all cats was 92.5 mm Hg (range, 30-240 mm Hg). Femoral pulse quality was found to strongly correlate with the admission SBP (P < 0.001, rho = 0.6755). The median SBP for each femoral pulse quality category (strong, moderate, poor, or absent) was significantly different (P < 0.05). For metatarsal pulses, the median SBP for cats with either absent or strong pulses was significantly different (P < 0.001). Cats with absent metatarsal and femoral pulses had a median SBP of 30 mm Hg (range, 30-105 mm Hg), whereas cats with strong metatarsal pulses had a median SBP of 135 mm Hg (range, 58-210 mm Hg). Absent metatarsal pulses correctly identified cats with a blood pressure of 75 mm Hg or less 84% the time (area under the curve: 0.89, confidence interval 0.81, 0.97). CONCLUSIONS: In cats, peripheral pulse quality assessment by emergency room veterinarians correlates with SBP. With progressive decreases in blood pressure, metatarsal pulses will disappear and it is only with severe hypotension that femoral pulses are absent. An assessment of both dorsal metatarsal pulse and femoral pulse quality during triage may be useful in identifying abnormalities in blood pressure. PMID- 26588059 TI - Microwave treated Salvadora oleoides as an eco-friendly biosorbent for the removal of toxic methyl violet dye from aqueous solution--A green approach. AB - In the present study, microwave treated Salvadora oleoides (MW-SO) has been investigated as a potential biosorbent for the removal of toxic methyl violet dye. A batch adsorption method was experimented for biosorptive removal of toxic methyl violet dye from the aqueous solution. The effect of various operating variables, viz., adsorbent dosage, pH, contact time and temperature on the removal of the dye was studied and it was found that nearly 99% removal of the dye was possible under optimum conditions. Kinetic study revealed that a pseudo second-order mechanism was predominant and the overall process of the dye adsorption involved more than one step. Hence, in order to investigate the rate determining step, intra-particle diffusion model was applied. Adsorption equilibrium study was made by analyzing Langmuir, Freundlich, and Dubinin Radushkevich (D-R) adsorption isotherm models and the biosorption data was found to be best represented by the Langmuir model. The biosorption efficiency of MW-SO was also compared with unmodified material, Salvadora oleoides (SO). It was found that the sorption capacity (qmax) increased from 58.5 mg/g to 219.7 mg/g on MW treatment. Determination of thermodynamic parameters such as free energy change (DeltaG degrees ), enthalpy change (DeltaH degrees ) and entropy change (DeltaS degrees ) confirmed the spontaneous, endothermic and feasible nature of the adsorption process. The preparation of MW-SO did not require any additional chemical treatment and a high percentage removal of methyl violet dye was obtained in much lesser time. Thus, it is in agreement with the principles of green chemistry. The results of the present research work suggest that MW-SO can be used as an environmentally friendly and economical alternative biosorbent for the removal of methyl violet dye from aqueous solutions. PMID- 26588060 TI - A high-throughput capillary isoelectric focusing immunoassay for fingerprinting protein sialylation. AB - The serum half-life, biological activity, and solubility of many recombinant glycoproteins depend on their sialylation. Monitoring glycoprotein sialylation during cell culture manufacturing is, therefore, critical to ensure product efficacy and safety. Here a high-throughput method for semi-quantitative fingerprinting of glycoprotein sialylation using capillary isoelectric focusing immunoassay on NanoPro (Protein Simple) platform was developed. The method was specific, sensitive, precise, and robust. It could analyze 2 MUL of crude cell culture samples without protein purification, and could automatically analyze from 8 samples in 4 h to 96 samples in 14 h without analyst supervision. Furthermore, its capability to detect various changes in sialylation fingerprints during cell culture manufacturing process was indispensable to ensure process robustness and consistency. Moreover, the changes in the sialylation fingerprints analyzed by this method showed strong correlations with intact mass analysis using liquid chromatography and mass spectrometry. PMID- 26588062 TI - Surface Enhanced Raman Spectroscopy at Electrochemically Fabricated Silver Nanowire Junctions. AB - Here we describe enhanced Raman scattering at Au electrode 1 (E1)/Ag nanowire (NW)/4-aminothiophenol (4-ATP)/Au electrode 2 (E2) nanojunctions fabricated by combining self-assembly and metal electrodeposition at microgap electrodes (E1 and E2). In this method we assemble the 4-ATP on electrode E2 and electrodeposit Ag on the opposite electrode E1 of an Au interdigitated array (IDA) electrode device. The electrodeposited Ag grows in the form of NWs on E1 and makes nanoscale contact to E2 to form the junctions. The presence of the Ag NW leads to strong Raman scattering of the 4-ATP molecules within the nanojunction leading to estimated enhancement factors ranging from 10(3) to 10(6). Scanning electron microscopy (SEM) images provide insight into the morphology of the junctions. The magnitude of the Raman enhancement depends on the extent of contact between the Ag NW and the 4-ATP self-assembled monolayer (SAM). With this approach we could detect 4-ATP molecules diluted by a factor of 1000 with hexanethiol molecules within the junctions. Our approach is simple and fast with the potential to correlate electronic measurements of molecules with Raman spectroscopy data of the same molecules in a nanoscale junction for molecular electronics or chemiresistive sensing applications. PMID- 26588061 TI - Salt tolerance of Beta macrocarpa is associated with efficient osmotic adjustment and increased apoplastic water content. AB - The chenopod Beta macrocarpa Guss (wild Swiss chard) is known for its salt tolerance, but the mechanisms involved are still debated. In order to elucidate the processes involved, we grew wild Swiss chard exposed to three salinity levels (0, 100 and 200 mm NaCl) for 45 days, and determined several physiological parameters at the end of this time. All plants survived despite reductions in growth, photosynthesis and stomatal conductance in plants exposed to salinity (100 and 200 mm NaCl). As expected, the negative effects of salinity were more pronounced at 200 mm than at 100 mm NaCl: (i) leaf apoplastic water content was maintained or increased despite a significant reduction in leaf water potential, revealing the halophytic character of B. macrocarpa; (ii) osmotic adjustment occurred, which presumably enhanced the driving force for water extraction from soil, and avoided toxic build up of Na(+) and Cl(-) in the mesophyll apoplast of leaves. Osmotic adjustment mainly occurred through accumulation of inorganic ions and to a lesser extent soluble sugars; proline was not implicated in osmotic adjustment. Overall, two important mechanisms of salt tolerance in B. macrocarpa were identified: osmotic and apoplastic water adjustment. PMID- 26588063 TI - Rational design of a highly sensitive and selective "turn-on" fluorescent sensor for PO4(3-) detection. AB - An efficient turn-on fluorescent sensor for PO4(3-) has been developed by rationally designing an in situ-generated iron(iii) complex with a 1,8 naphthalene-based Schiff base unit. The sensor exhibits high sensitivity and selectivity in both solution and solid-state film, even in the presence of other phosphate anions such as HPO4(2-) and H2PO4(-). PMID- 26588066 TI - Mechanical Stability of Polystyrene and Janus Particle Monolayers at the Air/Water Interface. AB - The compressional instability of particle-laden air/water interfaces is investigated with plain and surface-anisotropic (Janus) particles. We hypothesize that the amphiphilic nature of Janus particles leads to both anisotropic particle particle and particle-interface interactions that can yield particle films with unique collapse mechanisms. Analysis of Langmuir isotherms and microstructural characterization of the homogeneous polystyrene particle films during compression reveal an interfacial buckling instability followed by folding, which is in good agreement with predictions from classical elasticity theory. In contrast, Janus particle films exhibit a different behavior during compression, where the collapse mode occurs through the subduction of the Janus particle film. Our results suggest that particle-laden films comprised of surface-anisotropic particles can be engineered to evolve new material properties. PMID- 26588064 TI - New highly active antiplatelet agents with dual specificity for platelet P2Y1 and P2Y12 adenosine diphosphate receptors. AB - Currently approved platelet adenosine diphosphate (ADP) receptor antagonists target only the platelet P2Y12 receptor. Moreover, especially in patients with acute coronary syndromes, there is a strong need for rapidly acting and reversible antiplatelet agents in order to minimize the risk of thrombotic events and bleeding complications. In this study, a series of new P(1),P(4)-di(adenosine 5') tetraphosphate (Ap4A) derivatives with modifications in the base and in the tetraphosphate chain were synthesized and evaluated with respect to their effects on platelet aggregation and function of the platelet P2Y1, P2Y12, and P2X1 receptors. The resulting structure-activity relationships were used to design Ap4A analogs which inhibit human platelet aggregation by simultaneously antagonizing both P2Y1 and P2Y12 platelet receptors. Unlike Ap4A, the analogs do not activate platelet P2X1 receptors. Furthermore, the new compounds exhibit fast onset and offset of action and are significantly more stable than Ap4A to degradation in plasma, thus presenting a new promising class of antiplatelet agents. PMID- 26588065 TI - Synthesis, pharmacological assessment, molecular modeling and in silico studies of fused tricyclic coumarin derivatives as a new family of multifunctional anti Alzheimer agents. AB - A series of fused tricyclic coumarin derivatives bearing iminopyran ring connected to various amido moieties were developed as potential multifunctional anti-Alzheimer agents for their cholinesterase inhibitory and radical scavenging activities. In vitro studies revealed that most of these compounds exhibited high inhibitory activity on acetylcholinesterase (AChE), with IC50 values ranging from 0.003 to 0.357 MUM which is 2-220 folds more potent than the positive control, galantamine. Their inhibition selectivity against AChE over butyrylcholinesterase (BuChE) has increased about 194 fold compared with galantamine. The developed compounds also showed potent ABTS radical scavenging activity (IC50 7.98-15.99 MUM). Specifically, the most potent AChE inhibitor 6n (IC50 0.003 +/- 0.0007 MUM) has an excellent antioxidant profile as determined by the ABTS method (IC50 7.98 +/- 0.77 MUM). Moreover, cell viability studies in SK N SH cells showed that the compounds 6m-q have significant neuroprotective effects against H2O2-induced cell death, and are not neurotoxic at all concentrations except 6n and 6q. The kinetic analysis of compound 6n proved that it is a mixed-type inhibitor for EeAChE (Ki1 0.0103 MUM and Ki2 0.0193 MUM). Accordingly, the molecular modeling study demonstrated that 6m-q with substituted benzyl amido moiety possessed an optimal docking pose with interactions at catalytic active site (CAS) and peripheral anionic site (PAS) of AChE simultaneously and thereby they might prevent aggregation of Abeta induced by AChE. Furthermore, in silico ADMET prediction studies indicated that these compounds satisfied all the characteristics of CNS acting drugs. Most active inhibitor 6n is permeable to BBB as determined in the in vivo brain AChE activity. To sum up, the multipotent therapuetic profile of these novel tricyclic coumarins makes them promising leads for developing anti Alzheimer agents. PMID- 26588067 TI - Listeria monocytogenes: Strain Heterogeneity, Methods, and Challenges of Subtyping. AB - Listeria monocytogenes is a food-borne bacterial pathogen that is associated with 20% to 30% case fatality rate. L. monocytogenes is a genetically heterogeneous species, with a small fraction of strains (serotypes 1/2a, 1/2b, 4b) implicated in human listeriosis. Monitoring and source tracking of L. monocytogenes involve the use of subtyping methods, with the performance of genetic-based methods found to be superior to phenotypic-based ones. Various methods have been used to subtype L. monocytogenes isolates, with the pulsed-field gel electrophoresis (PFGE) being the gold standard. Although PFGE has had a massive impact on food safety through the establishment of the PulseNet, there is no doubt that whole genome sequence (WGS) typing is accurate, has a discriminatory power superior to any known method, and allows genome-wide differences between strains to be quantified through the comparison of nucleotide sequences. This review focuses on the different techniques that have been used to type L. monocytogenes strains, their performance challenges, and the tremendous impact WGS typing could have on the food safety landscape. PMID- 26588068 TI - The combination of 13N-ammonia and 18F-FDG whole-body PET/CT on the same day for diagnosis of advanced prostate cancer. AB - PURPOSE: The aim of the study was to evaluate the efficacy of 13N-ammonia and 18F fluorodeoxyglucose (18F-FDG) PET performed on the same day in the detection of advanced prostate cancer (PC) and its metastases. PATIENTS AND METHODS: Twenty six patients with high-risk PC [Gleason score 8-10 or prostate-specific antigen (PSA)> 20 ng/ml or clinical tumor extension >= T2c] were recruited into the study. 13N-Ammonia and 18F-FDG PET/CT were performed on the same day (18F-FDG followed ammonia, with an interval of a minimum of 2 h). Lesions were interpreted as positive, negative, or equivocal. Patient-based and field-based performance characteristics for both imaging techniques were reported. RESULTS: There was significant correlation between 13N-ammonia and 18F-FDG PET/CT in the detection of primary PC (kappa=0.425, P=0.001) and no significant difference in sensitivity (60.2 vs. 54.5%) and specificity (100 vs. 83.3%). The maximum standard uptake values and corresponding target-to-background ratio values of the concordantly positive lesions in prostate glands in the two studies did not differ significantly (P=0.124 and 0.075, respectively). The sensitivity and specificity of PET imaging using 13N-ammonia for lymph node metastases were 77.5 and 96.3%, respectively, whereas the values were 75 and 44.4% using 18F-FDG. The two modalities were highly correlated with respect to the detection of lymph nodes and bone metastases. CONCLUSION: The concordance between the two imaging modalities suggests a clinical impact of 13N-ammonia PET/CT in advanced PC patients as well as of 18F-FDG. 13N-Ammonia is a useful PET tracer and a complement to 18F-FDG for detecting primary focus and distant metastases in PC. The combination of these two tracers on the same day can accurately detect advanced PC. PMID- 26588069 TI - Applications of global quantitative 18F-FDG-PET analysis in temporal lobe epilepsy. AB - Temporal lobe epilepsy (TLE) is a prevalent neurodegenerative disease associated with various neuropsychiatric disorders and decreased quality of life. Much has been said about the use of fluorine-18 fluorodeoxyglucose positron emission tomography (18F-FDG-PET), magnetic resonance imaging (MRI), and computed tomography in the qualitative assessment of TLE. However, research into the applications of quantitative measurements to treat and diagnose TLE is severely lacking in the literature. Global quantitative analysis using 18F-FDG-PET is a powerful tool in the metabolic assessment of TLE, and can more accurately identify seizure lateralization and the potential effects of treatment as compared with visual assessments and traditional biopsy region-of-interest quantification. Therefore, there is a pressing need to introduce these novel methods to the treatment of TLE. Although 18F-FDG-PET is most commonly used for visual assessments, qualitative analysis is associated with high levels of interobserver and intraobserver variability. Semiquantitative analysis using standardized uptake value is a more consistently accurate measure of the hypometabolic patterns seen in TLE patients. Novel methods of global quantitative analysis developed in our laboratory have the potential to improve TLE assessment by limiting variability and correcting for the partial volume effect. It is of great importance to adopt these techniques into the mainstream diagnosis and treatment of TLE in order to improve patient care worldwide. PMID- 26588070 TI - Isolation, Biochemical and Molecular Identification, and In-Vitro Antimicrobial Resistance Patterns of Bacteria Isolated from Bubaline Subclinical Mastitis in South India. AB - Buffaloes are the second largest source of milk. Mastitis is a major impediment for milk production, but not much information is available about bubaline mastitis, especially subclinical mastitis. The aim of this study was to (a) investigate the application of various tests for the diagnosis of bubaline subclinical mastitis, (b) identify the major bacteria associated with it, and (c) evaluate the antibiotic resistance pattern of the bacteria. To this end, 190 quarter milk samples were collected from 57 domesticated dairy buffaloes from organized (64 samples) and unorganized (126 samples) sectors. Of these, 48.4%, 40.0%, 45.8%, 61.1%, and 61.6% were positive for subclinical mastitis by somatic cell count, electrical conductivity, California mastitis test, bromothymol blue test, and N-acetyl glucosaminidase test, respectively. As compared to the gold standard of somatic cell count, California mastitis test performed the best. However, a combination of the two methods was found to be the best option. Microbiological evaluation, both by biochemical methods as well as by monoplex and multiplex polymerase chain reaction, revealed that coagulase-negative staphylococci were the most predominant (64.8%) bacteria, followed by streptococci (18.1%), Escherichia coli (9.8%) and Staphylococcus aureus (7.3%). Most of the pathogens were resistant to multiple antibiotics, especially to beta lactam antibiotics. We propose that California mastitis test be combined with somatic cell count for diagnosis of subclinical mastitis in domestic dairy buffaloes. Further, our results reveal high resistance of the associated bacteria to the beta-lactam class of antibiotics, and a possible major role of coagulase negative staphylococci in causing the disease in India. PMID- 26588071 TI - Genome-Wide Association Study of Golden Retrievers Identifies Germ-Line Risk Factors Predisposing to Mast Cell Tumours. AB - Canine mast cell tumours (CMCT) are one of the most common skin tumours in dogs with a major impact on canine health. Certain breeds have a higher risk of developing mast cell tumours, suggesting that underlying predisposing germ-line genetic factors play a role in the development of this disease. The genetic risk factors are largely unknown, although somatic mutations in the oncogene C-KIT have been detected in a proportion of CMCT, making CMCT a comparative model for mastocytosis in humans where C-KIT mutations are frequent. We have performed a genome wide association study in golden retrievers from two continents and identified separate regions in the genome associated with risk of CMCT in the two populations. Sequence capture of associated regions and subsequent fine mapping in a larger cohort of dogs identified a SNP associated with development of CMCT in the GNAI2 gene (p = 2.2x10-16), introducing an alternative splice form of this gene resulting in a truncated protein. In addition, disease associated haplotypes harbouring the hyaluronidase genes HYAL1, HYAL2 and HYAL3 on cfa20 and HYAL4, SPAM1 and HYALP1 on cfa14 were identified as separate risk factors in European and US golden retrievers, respectively, suggesting that turnover of hyaluronan plays an important role in the development of CMCT. PMID- 26588072 TI - Cold Atmospheric Plasma: A Promising Complementary Therapy for Squamous Head and Neck Cancer. AB - Head and neck squamous cell cancer (HNSCC) is the 7th most common cancer worldwide. Despite the development of new therapeutic agents such as monoclonal antibodies, prognosis did not change for the last decades. Cold atmospheric plasma (CAP) presents the most promising new technology in cancer treatment. In this study the efficacy of a surface micro discharging (SMD) plasma device against two head and neck cancer cell lines was proved. Effects on the cell viability, DNA fragmentation and apoptosis induction were evaluated with the MTT assay, alkaline microgel electrophoresis (comet assay) and Annexin-V/PI staining. MTT assay revealed that the CAP treatment markedly decreases the cell viability for all tested treatment times (30, 60, 90, 120 and 180 s). IC 50 was reached within maximal 120 seconds of CAP treatment. Comet assay analysis showed a dose dependent high DNA fragmentation being one of the key players in anti-cancer activity of CAP. Annexin-V/PI staining revealed induction of apoptosis in CAP treated HNSCC cell lines but no significant dose dependency was seen. Thus, we confirmed that SMD Plasma technology is definitely a promising new approach on cancer treatment. PMID- 26588073 TI - The N-terminal Helical Region of the Hepatitis C Virus p7 Ion Channel Protein Is Critical for Infectious Virus Production. AB - The hepatitis C virus (HCV) p7 protein is required for infectious virus production via its role in assembly and ion channel activity. Although NMR structures of p7 have been reported, the location of secondary structural elements and orientation of the p7 transmembrane domains differ among models. Furthermore, the p7 structure-function relationship remains unclear. Here, extensive mutagenesis, coupled with infectious virus production phenotyping and molecular modeling, demonstrates that the N-terminal helical region plays a previously underappreciated yet critical functional role, especially with respect to E2/p7 cleavage efficiency. Interrogation of specific N-terminal helix residues identified as having p7-specific defects and predicted to point toward the channel pore, in a context of independent E2/p7 cleavage, further supports p7 as a structurally plastic, minimalist ion channel. Together, our findings indicate that the p7 N-terminal helical region is critical for E2/p7 processing, protein protein interactions, ion channel activity, and infectious HCV production. PMID- 26588074 TI - Direct Detection of Unnatural DNA Nucleotides dNaM and d5SICS using the MspA Nanopore. AB - Malyshev et al. showed that the four-letter genetic code within a living organism could be expanded to include the unnatural DNA bases dNaM and d5SICS. However, verification and detection of these unnatural bases in DNA requires new sequencing techniques. Here we provide proof of concept detection of dNaM and d5SICS in DNA oligomers via nanopore sequencing using the nanopore MspA. We find that both phi29 DNA polymerase and Hel308 helicase are capable of controlling the motion of DNA containing dNaM and d5SICS through the pore and that single reads are sufficient to detect the presence and location of dNaM and d5SICS within single molecules. PMID- 26588075 TI - Spatial Variation of the Gut Microbiota in Broiler Chickens as Affected by Dietary Available Phosphorus and Assessed by T-RFLP Analysis and 454 Pyrosequencing. AB - Molecular fingerprinting and sequencing based techniques have been widely used to characterize microbial communities. Terminal restriction fragment length polymorphism (T-RFLP) and 454-pyrosequencing were used to determine the microorganisms present in the different sections of the chicken gastrointestinal tract (GIT) (crop, jejunum, ileum and caeca). Broilers fed with diets differing in phosphorous (P) and calcium (Ca) as well as in phytase levels were used to study the microbiota of the upper and lower part of the GIT. A database with terminal restriction fragments (T-RF) of the most important organism present in the different gastrointestinal sections was constructed. The analysis revealed a distinct microbial assemblage on each section. Regardless of the diet, crop, jejunum and ileum were mainly colonized by Lactobacillaceae, and caeca were the most diverse site. The correlation between Lactobacillus crispatus and L. reuteri was positive in the crop, but negative in the jejunum. In crop samples, higher P and Ca levels led to a shift in the abundance of L. reuteri and L. crispatus to L. salivarius and L. taiwanensis whereas in the ileum supplementation of phytase favored L. salivarius and L. taiwanensis but resulted in decreased abundance of L. crispatus. Both methods were correlating significantly, being T-RFLP a reliable fingerprinting method to rapidly analyze large numbers of samples in a cost-effective and rapid manner. Results are easy to interpret with no need of deep bioinformatics knowledge and can be integrated with taxonomic information. PMID- 26588077 TI - The Role of Generalized Explicit and Implicit Guilt and Shame in Interpersonal Traumatization and Posttraumatic Stress Disorder. AB - Posttraumatic stress disorder (PTSD) and interpersonal traumatization are frequently associated with trauma-related guilt and shame. However, research on generalized guilt and shame in PTSD is lacking. The aim of this study was to investigate generalized explicit and implicit guilt and shame in interpersonal traumatization and PTSD. Interpersonally traumatized women either with PTSD (n = 28) or without PTSD (n = 32) and 32 nontraumatized women completed the Test of Self-Conscious Affect-3 and the Implicit Association Test to measure explicit and implicit guilt and shame. Explicit guilt and shame were significantly higher in women with PTSD than in traumatized women without PTSD. Traumatized women without PTSD showed significantly higher levels of explicit guilt and shame than nontraumatized women did. PTSD was associated with implicit guilt but not implicit shame. In addition to trauma-related guilt and shame, generalized explicit guilt and shame and implicit guilt seem to play a crucial role in PTSD. PMID- 26588076 TI - Deltamethrin Resistance Mechanisms in Aedes aegypti Populations from Three French Overseas Territories Worldwide. AB - BACKGROUND: Aedes aegypti is a cosmopolite mosquito, vector of arboviruses. The worldwide studies of its insecticide resistance have demonstrated a strong loss of susceptibility to pyrethroids, the major class of insecticide used for vector control. French overseas territories such as French Guiana (South America), Guadeloupe islands (Lesser Antilles) as well as New Caledonia (Pacific Ocean), have encountered such resistance. METHODOLOGY/PRINCIPAL FINDINGS: We initiated a research program on the pyrethroid resistance in French Guiana, Guadeloupe and New Caledonia. Aedes aegypti populations were tested for their deltamethrin resistance level then screened by an improved microarray developed to specifically study metabolic resistance mechanisms. Cytochrome P450 genes were implicated in conferring resistance. CYP6BB2, CYP6M11, CYP6N12, CYP9J9, CYP9J10 and CCE3 genes were upregulated in the resistant populations and were common to other populations at a regional scale. The implication of these genes in resistance phenomenon is therefore strongly suggested. Other genes from detoxification pathways were also differentially regulated. Screening for target site mutations on the voltage-gated sodium channel gene demonstrated the presence of I1016 and C1534. CONCLUSION /SIGNIFICANCE: This study highlighted the presence of a common set of differentially up-regulated detoxifying genes, mainly cytochrome P450 genes in all three populations. GUA and GUY populations shared a higher number of those genes compared to CAL. Two kdr mutations well known to be associated to pyrethroid resistance were also detected in those two populations but not in CAL. Different selective pressures and genetic backgrounds can explain such differences. These results are also compared with those obtained from other parts of the world and are discussed in the context of integrative research on vector competence. PMID- 26588078 TI - The Burden of Repeated Mood Episodes in Bipolar I Disorder: Results From the National Epidemiological Survey on Alcohol and Related Conditions. AB - The aim of this study was to examine the association between previous mood episodes and clinical course/functioning in a community sample (National Epidemiological Survey on Alcohol and Related Conditions [NESARC]). Subjects (n = 909) met Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, criteria for bipolar I disorder and provided data on number of previous episode recurrences. Number of previous mood episodes was used to predict outcomes at wave 1 and wave 2 of the NESARC. Previous mood episodes accounted for small but unique variance in outcomes. Recurrence was associated with poorer functioning, psychiatric and medical comorbidity, and increased odds of suicidality, disability, unemployment, and hospitalization at wave 1. Recurrences were associated with greater risk for new onset suicidality, psychiatric comorbidity, disability, unemployment, and poor functioning by wave 2. The course of bipolar disorder does worsen with progressive mood episodes but is attenuated in community, relative to clinical samples. Interventions to prevent future relapse may be particularly important to implement early in the course of illness. PMID- 26588079 TI - Posttraumatic Stress Disorder-Related Hospitalizations in the United States (2002 2011): Rates, Co-Occurring Illnesses, Suicidal Ideation/Self-Harm, and Hospital Charges. AB - The purpose of the present study was to evaluate posttraumatic stress disorder (PTSD)-related hospitalizations in the United States (2002-2011). Over this period, there were an estimated 1,477,944 hospitalizations (915,591 women) with either a primary (reason for hospitalization) or secondary PTSD diagnosis. Population-based hospitalization rates rose from 2002 to 2011; women in the age range of 20 to 44 years had the highest rates and the steepest rise. Most of the hospitalizations for men and women younger than 45 years had been assigned a primary diagnosis of mental illness (including PTSD). Mood and substance use disorders were among the most commonly co-occurring psychiatric diagnoses with PTSD. Suicidal ideation/suicide attempts declined with increasing age. The strongest predictor of this criterion was mood disorder, and its importance as a predictor increased as people aged. Total inflation-adjusted charges for all PTSD related hospitalizations were $34.9 billion, with 36% being for hospitalizations where a mental illness (including PTSD) was the primary diagnosis. PMID- 26588081 TI - Agoraphobia With and Without Panic Disorder: A 20-Year Follow-up of Integrated Exposure and Psychodynamic Therapy. AB - The aim of the current study was to compare the 20-year outcome in panic disorder with agoraphobia (PD with AG) and agoraphobia without panic disorder (AG without PD) patients after inpatient psychological treatment. Of 53 eligible patients having completed a medication-free integrated exposure and psychodynamic treatment, 38 (71.7%)-25 PD with AG and 13 AG without PD patients-attended 20 year follow-up. AG without PD patients improved less than PD with AG patients did on primary outcome measures. In the PD with AG group, there were large uncontrolled effect sizes (<-2.30). More of the AG without PD patients had avoidant personality disorder at pretreatment, but the presence of this disorder did not predict outcome. The follow-up results support that PD with AG and AG without PD are two different disorders. The results also suggest that the very long-term outcome in PD with AG patients is excellent for this integrated treatment. PMID- 26588080 TI - Reinforcement Learning Performance and Risk for Psychosis in Youth. AB - Early identification efforts for psychosis have thus far yielded many more individuals "at risk" than actually develop psychotic illness. Here, we test whether measures of reinforcement learning (RL), known to be impaired in chronic schizophrenia, are related to the severity of clinical risk symptoms. Because of the reliance of RL on dopamine-rich frontostriatal systems and evidence of dopamine system dysfunction in the psychosis prodrome, RL measures are of specific interest in this clinical population. The current study examines relationships between psychosis risk symptoms and RL task performance in a sample of adolescents and young adults (n = 70) receiving mental health services. We observed significant correlations between multiple measures of RL performance and measures of both positive and negative symptoms. These results suggest that RL measures may provide a psychosis risk signal in treatment-seeking youth. Further research is necessary to understand the potential predictive role of RL measures for conversion to psychosis. PMID- 26588082 TI - The First Step in Health Reform for Those With Serious Mental Illness: Integrating the Dis-Integrated Mental Health System. AB - Increasing attention is being directed toward meeting the psychiatric and medical needs of persons with persistent or recurrent mental illness through the integration of behavioral and medical healthcare. There are many models being considered or tested to achieve this objective. These models, however, generally ignore the challenge of integrating systems that are themselves dis-integrated. Also ignored is the fact that many persons with persistent or recurrent mental illness operate in the context of an array of entitlements; receive "services" from the criminal justice, as well as the health and behavioral health systems; and all these systems are both siloed and fail to meet the needs of this population. This article examines the current state of the cornucopia of services available to individuals with persistent or recurrent mental illness inclusive of federal statutes and policies to impact these services. Recommendations are made to move the dis-integrated system of mental health services toward an internally integrated system that would have the capacity to become integrated with a medical system of care and treatment to achieve a behavioral-medical integrated health delivery system. PMID- 26588083 TI - Clinicians' Judgments of the Clinical Utility of Personality Disorder Trait Descriptions. AB - Proposed for the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) was a five-domain, 25-dimensional trait model that would have constituted a significant part of the diagnostic criteria for each personality disorder. A primary concern with respect to the proposal was that clinicians might find such an approach to be unacceptable. This study provides results from three independent data collections that compared clinicians' clinical utility ratings for each iteration of the DSM-5 dimensional trait assignments, along with an alternative list of traits derived from the Five Factor Form (FFF). The clinicians considered the final trait assignments that were posted for the avoidant, narcissistic, obsessive-compulsive, and schizoid personality disorders to be significantly less acceptable than the original assignments. They also considered the FFF trait assignments to be preferable to the DSM-5 final postings with respect to the avoidant, narcissistic, obsessive-compulsive, dependent, and histrionic personality disorders. The implications of these results for future editions of the diagnostic manual are discussed. PMID- 26588084 TI - Platelets attenuate production of cytokines and nitric oxide by macrophages in response to bacterial endotoxin. AB - Considerable evidence has been accumulated concerning the roles of platelets in immune responses. In the present study, we examined the functional modulation of macrophages by platelets. When mouse bone marrow-derived macrophages (BMDMs) were co-cultured with platelets, BMDMs produced lower levels of nitric oxide (NO), tumor necrosis factor-alpha (TNF)-alpha, and interleukin (IL)-6 in response to a bacterial endotoxin (LPS) and zymosan. The attenuation in the macrophage susceptibility to LPS appeared to be mediated by soluble factors secreted from platelets. The mRNA levels of NOS2 (iNOS), TNF-alpha, and IL-6 in LPS-stimulated BMDMs that had been cultured with a conditioned medium of platelets were also decreased as analyzed by RT-qPCR. The ability of the platelet-conditioned medium to suppress macrophage NO production was recovered in a high-molecular-weight fraction (>670 kDa) after gel-filtration chromatography on a Superose 6 column. These results suggest that platelets control the susceptibility of macrophages to prevent excessive responses to LPS and provide mechanistic insight into a previous report that experimental thrombocytopenia aggravated organ failure in LPS-induced endotoxemia. PMID- 26588085 TI - Association of Erythropoietin-Stimulating Agent Responsiveness with Mortality in Hemodialysis and Peritoneal Dialysis Patients. AB - Erythropoiesis-stimulating agent (ESA) responsiveness has been reported to be associated with increased mortality in hemodialysis (HD) patients. ESA requirement to obtain the same hemoglobin (Hb) level is different between HD and peritoneal dialysis (PD) patients. In this study, we investigated the impact of ESA responsiveness on mortality between both HD and PD patients. Prevalent HD and PD patients were selected from the Clinical Research Center registry for end stage renal disease, a prospective cohort study in Korea. ESA responsiveness was estimated using an erythropoietin resistant index (ERI) (U/kg/week/g/dL). Patients were divided into three groups by tertiles of ERI. ESA responsiveness was also assessed based on a combination of ESA dosage and hemoglobin (Hb) levels. The primary outcome was all-cause mortality. A total of 1,594 HD and 876 PD patients were included. The median ESA dose and ERI were lower in PD patients compared with HD patients (ESA dose: 4000 U/week vs 6000 U/week, respectively. P<0.001, ERI: 7.0 vs 10.4 U/kg/week/g/dl, respectively. P<0.001). The median follow-up period was 40 months. In HD patients, the highest ERI tertile was significantly associated with higher risk for all-cause mortality (HR 1.96, 95% CI, 1.07 to 3.59, P = 0.029). HD patients with high-dose ESA and low Hb levels (ESA hypo-responsiveness) had a significantly higher risk of all-cause mortality (HR 2.24, 95% CI, 1.16 to 4.31, P = 0.016). In PD patients, there was no significant difference in all-cause mortality among the ERI groups (P = 0.247, log-rank test). ESA hypo-responsiveness was not associated with all-cause mortality (HR = 1.75, 95% CI, 0.58 to 5.28, P = 0.319). Our data showed that ESA hypo-responsiveness was associated with an increased risk of all-cause mortality in HD patients. However, in PD patients, ESA hypo-responsiveness was not related to all-cause mortality. These finding suggest the different prognostic value of ESA responsiveness between HD and PD patients. PMID- 26588086 TI - Pervasive Environmental Contamination with Human Feces Results in High Prevalence of Zoonotic Sarcocystis Infection in Pigs in the Punjab, India. AB - Three species of Sarcocystis-S. miescheriana, S. suihominis, and S. porcifelis have been recorded from pigs ( Sus scrofa ). Among these 3 species, the zoonotic species S. suihominis is of paramount importance and an important food safety issue. Previous studies indicate prevalence of porcine Sarcocystis species in India, but molecular evidence, among other evidence, is required for proper species differentiation. Myocardium from 250 stray and farm pigs destined for slaughter for human consumption were collected from slaughter shops located in urban slums in Punjab, northern India. Tissues were examined for Sarcocystis by using an intact cyst isolation method, pepsin acid digestion, Sarcocystis 18S ribosomal RNA polymerase chain reaction (PCR), and real-time quantitative PCR with melting curve analysis (qPCR-MCA). The combination of primers was used for 18S rRNA PCR amplification followed by sequencing. Ten representative samples were sequenced in both the directions from which 7 readable sequences were obtained for phylogenetic analysis. Sarcocystis cysts/zoites were recorded in 146 (58.4%), 169 (67.6%), 182 (72.8%), and 191 (76.4%) of samples by using intact cyst isolation, pepsin HCl digestion, conventional PCR, and qPCR-MCA, respectively. Molecularly, 1 S. miescheriana isolate and 6 isolates of the zoonotic species S. suihominis were recorded. This is the first study providing molecular identification for the presence of zoonotic species S. suihomonis in India. The prevalence of zoonotic S. suihominis in pork in India is worrisome and warrants intervention policies to stop the practice of rearing pigs under unhygienic conditions. PMID- 26588087 TI - High Prevalence of Antibodies against the Bacterium Treponema pallidum in Senegalese Guinea Baboons (Papio papio). AB - The bacterium Treponema pallidum is known to cause syphilis (ssp. pallidum), yaws (ssp. pertenue), and endemic syphilis (ssp. endemicum) in humans. Nonhuman primates have also been reported to be infected with the bacterium with equally versatile clinical manifestations, from severe skin ulcerations to asymptomatic. At present all simian strains are closely related to human yaws-causing strains, an important consideration for yaws eradication. We tested clinically healthy Guinea baboons (Papio papio) at Parc National Niokolo Koba in south eastern Senegal for the presence of anti-T. pallidum antibodies. Since T. pallidum infection in this species was identified 50 years ago, and there has been no attempt to treat non-human primates for infection, it was hypothesized that a large number of West African baboons are still infected with simian strains of the yaws-bacterium. All animals were without clinical signs of treponematoses, but 18 of 20 (90%) baboons tested positive for antibodies against T. pallidum based on treponemal tests. Yet, Guinea baboons seem to develop no clinical symptoms, though it must be assumed that infection is chronic or comparable to the latent stage in human yaws infection. The non-active character is supported by the low anti-T. pallidum serum titers in Guinea baboons (median = 1:2,560) versus serum titers that are found in genital-ulcerated olive baboons with active infection in Tanzania (range of medians among the groups of initial, moderate, and severe infected animals = 1:15,360 to 1:2.097e+7). Our findings provide evidence for simian infection with T. pallidum in wild Senegalese baboons. Potentially, Guinea baboons in West Africa serve as a natural reservoir for human infection, as the West African simian strain has been shown to cause sustainable yaws infection when inoculated into humans. The present study pinpoints an area where further research is needed to support the currently on-going second WHO led yaws eradication campaign with its goal to eradicate yaws by 2020. PMID- 26588088 TI - Impaired Ribosome Biogenesis and Skeletal Muscle Growth in a Murine Model of Inflammatory Bowel Disease. AB - BACKGROUND: Inflammation is a factor potentially underpinning skeletal muscle mass. Intestinal-derived inflammation in inflammatory bowel disease (IBD) results in loss of muscle mass; however, the underlying mechanism is unclear. The interleukin 10 gene-deficient (Il10-/-) mouse is a genetically modified animal model of IBD that can be used to study the effect of intestinal-derived inflammation on muscles. METHODS: Il10-/- and C57BL/6 wild-type (WT) mice were inoculated with intestinal bacteria to induce colon inflammation at the fifth week of age. Skeletal muscles were collected between 7 and 14 weeks of age for analysis of muscle weight, myofiber cross-sectional area (CSA), and molecular markers of inflammation and anabolism pathways, with a focus on ribosome biogenesis. RESULTS: Il10-/- animals that developed colon inflammation had a marked increase in muscle immunoglobulin G (IgG) compared with WT. Inflamed Il10 /- animals had impaired muscle mass gain and smaller myofiber CSA. Intramuscular IgG deposition negatively correlated with muscle mass. After the onset of muscle inflammation, Il10-/- mice had decreased levels of total and ribosomal RNAs (45S, 28S, 18S, and 5.8S rRNAs). Inflammation inversely correlated with muscle levels of total RNA and 28S rRNA which in turn positively correlated with muscle mass. The abundance of growth-related proteins (p70S6K and upstream binding factor, UBF) was decreased in Il10-/- mice. CONCLUSIONS: Muscle inflammation and associated decline of ribosome biogenesis lead to muscle growth impairment in Il10-/- mice. This may have implications for maintenance of muscle mass in conditions associated with chronic intestinal-derived inflammation. PMID- 26588090 TI - Gut Microbiota Dysbiosis as Risk and Premorbid Factors of IBD and IBS Along the Childhood-Adulthood Transition. AB - Gastrointestinal disorders, although clinically heterogeneous, share pathogenic mechanisms, including genetic susceptibility, impaired gut barrier function, altered microbiota, and environmental triggers (infections, social and behavioral factors, epigenetic control, and diet). Gut microbiota has been studied for inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) in either children or adults, while modifiable gut microbiota features, acting as risk and premorbid factors along the childhood-adulthood transition, have not been thoroughly investigated so far. Indeed, the relationship between variations of the entire host/microbiota/environmental scenario and clinical phenotypes is still not fully understood. In this respect, tracking gut dysbiosis grading may help deciphering host phenotype-genotype associations and microbiota shifts in an integrated top-down omics-based approach within large-scale pediatric and adult case-control cohorts. Large-scale gut microbiota signatures and host inflammation patterns may be integrated with dietary habits, under genetic and epigenetic constraints, providing gut dysbiosis profiles acting as risk predictors of IBD or IBS in preclinical cases. Tracking dysbiosis supports new personalized/stratified IBD and IBS prevention programmes, generating Decision Support System tools. They include (1) high risk or flare-up recurrence -omics-based dysbiosis profiles; (2) microbial and molecular biomarkers of health and disease; (3) -omics-based pipelines for laboratory medicine diagnostics; (4) health apps for self management of score-based dietary profiles, which can be shared with clinicians for nutritional habit and lifestyle amendment; (5) -omics profiling data warehousing and public repositories for IBD and IBS profile consultation. Dysbiosis-related indexes can represent novel laboratory and clinical medicine tools preventing or postponing the disease, finally interfering with its natural history. PMID- 26588089 TI - Reversibility of Stricturing Crohn's Disease-Fact or Fiction? AB - Intestinal fibrosis is a common feature of Crohn's disease and may appear as a stricture, stenosis, or intestinal obstruction. Fibrostenosing Crohn's disease leads to a significantly impaired quality of life in affected patients and constitutes a challenging treatment situation. In the absence of specific medical antifibrotic treatment options, endoscopic or surgical therapy approaches with their potential harmful side effects are frequently used. However, our understanding of mechanisms of fibrogenesis in general and specifically intestinal fibrosis has emerged. Progression of fibrosis in the liver, lung, or skin can be halted or even reversed, and possible treatment targets have been identified. In face of this observation and given the fact that fibrotic alterations in various organs of the human body share distinct core characteristics, this article aims to address whether reversibility of intestinal fibrosis may be conceivable and to highlight promising research avenues and therapies. PMID- 26588091 TI - Expression of AmGR10 of the Gustatory Receptor Family in Honey Bee Is Correlated with Nursing Behavior. AB - We investigated the association between the expression of a gene encoding gustatory receptor (G10) and division of labor in the honey bee, Apis mellifera. Among 10 GR genes encoding proteins 15% ~ 99% amino acid identity in the honey bee, we found that AmGR10 with 99% identity is involved in nursing or brood care. Expression of AmGR10 was restricted to organs of the hypopharyngeal gland, brain, and ovary in the nurse bee phase. Members of an extended nursing caste under natural conditions continued to express this gene. RNAi knockdown of AmGR10 accelerated the transition to foraging. Our findings demonstrate that this one gene has profound effects on the division of labor associated with the development and physiology of honeybee society. PMID- 26588093 TI - Longitudinal analysis of income-related health inequalities: methods, challenges and applications. AB - Socioeconomic inequalities in health are an important research area in health economics and public health. The concentration index has become a well established measure of income-related health inequalities, and a number of approaches to identify potential causes of health inequalities exist. With the increasing availability of suitable longitudinal data, more sophisticated approaches to monitor inequalities and to identify potential causal relationships between socioeconomic status and health evolved. We first review the concentration index and some more basic approaches to explain health inequalities. We then discuss advantages and potential shortcomings of "static" and "dynamic" health inequality measures. We review different concepts of health and socioeconomic mobility, as well as recent studies on the life course perspective and economic changes. Our aim is to provide an overview of the concepts and empirical methodologies in the current literature, and to guide interested researchers in their choice of an appropriate inequality measure. PMID- 26588092 TI - GWA Mapping of Anthocyanin Accumulation Reveals Balancing Selection of MYB90 in Arabidopsis thaliana. AB - Induction of anthocyanin accumulation by osmotic stress was assessed in 360 accessions of Arabidopsis thaliana. A wide range of natural variation, with phenotypes ranging from green to completely red/purple rosettes, was observed. A genome wide association (GWA) mapping approach revealed that sequence diversity in a small 15 kb region on chromosome 1 explained 40% of the variation observed. Sequence and expression analyses of alleles of the candidate gene MYB90 identified a causal polymorphism at amino acid (AA) position 210 of this transcription factor of the anthocyanin biosynthesis pathway. This amino acid discriminates the two most frequent alleles of MYB90. Both alleles are present in a substantial part of the population, suggesting balancing selection between these two alleles. Analysis of the geographical origin of the studied accessions suggests that the macro climate is not the driving force behind positive or negative selection for anthocyanin accumulation. An important role for local climatic conditions is, therefore, suggested. This study emphasizes that GWA mapping is a powerful approach to identify alleles that are under balancing selection pressure in nature. PMID- 26588094 TI - Patterns of Flexible Nanotubes Formed by Liquid-Ordered and Liquid-Disordered Membranes. AB - Biological membranes form both intra- and intercellular nanotubes that are used for molecular sorting within single cells and for long-distance connections between different cells. Such nanotubes can also develop from synthetic lipid bilayers in their fluid state. Each nanotube has a large area-to-volume ratio and stably encloses a water channel that is thereby shielded from its surroundings. The tubes are rather flexible and can easily change both their length and their conformation. Here, we study nanotubes formed by liquid-ordered (Lo) and liquid disordered (Ld) membranes with three lipid components exposed to aqueous mixtures of two polymers, polyethylene glycol (PEG) and dextran. Both types of membranes form striking patterns of nanotubes when we reduce the volume of giant vesicles by osmotic deflation, thereby exposing the two bilayer leaflets of the membranes to polymer solutions of different composition. With decreasing volume, three different patterns are observed corresponding to three distinct vesicle morphologies that reflect the interplay of spontaneous curvature and aqueous phase separation. We show that tube nucleation and growth is governed by two kinetic pathways and that the tubes undergo a novel shape transformation from necklace-like to cylindrical tubes at a certain critical tube length. We deduce the spontaneous curvature generated by the membrane-polymer interactions from the observed vesicle morphologies using three different and independent methods of image analysis. The spontaneous curvature of the Ld membranes is found to be 4.7 times larger than that of the Lo membranes. We also show that these curvatures are generated by weak PEG adsorption onto the membranes, with a binding affinity of about 1.6 kBT per chain. In this way, our study provides a direct connection between nanoscopic membrane shapes and molecular interactions. Our approach is rather general and can be applied to many other systems of interest such as polymersomes or membrane-bound proteins and peptides. PMID- 26588095 TI - Annexin A2: A new player in mitosis. PMID- 26588096 TI - Submicron-Scale Heterogeneities in Nickel Sorption of Various Cell-Mineral Aggregates Formed by Fe(II)-Oxidizing Bacteria. AB - Fe(II)-oxidizing bacteria form biogenic cell-mineral aggregates (CMAs) composed of microbial cells, extracellular organic compounds, and ferric iron minerals. CMAs are capable of immobilizing large quantities of heavy metals, such as nickel, via sorption processes. CMAs play an important role for the fate of heavy metals in the environment, particularly in systems characterized by elevated concentrations of dissolved metals, such as mine drainage or contaminated sediments. We applied scanning transmission (soft) X-ray microscopy (STXM) spectrotomography for detailed 3D chemical mapping of nickel sorbed to CMAs on the submicron scale. We analyzed different CMAs produced by phototrophic or nitrate-reducing microbial Fe(II) oxidation and, in addition, a twisted stalk structure obtained from an environmental biofilm. Nickel showed a heterogeneous distribution and was found to be preferentially sorbed to biogenically precipitated iron minerals such as Fe(III)-(oxyhydr)oxides and, to a minor extent, associated with organic compounds. Some distinct nickel accumulations were identified on the surfaces of CMAs. Additional information obtained from scatter plots and angular distance maps, showing variations in the nickel-iron and nickel-organic carbon ratios, also revealed a general correlation between nickel and iron. Although a high correlation between nickel and iron was observed in 2D maps, 3D maps revealed this to be partly due to projection artifacts. In summary, by combining different approaches for data analysis, we unambiguously showed the heterogeneous sorption behavior of nickel to CMAs. PMID- 26588098 TI - Computational Examination on the Active Site Structure of a (Peroxo)diiron(III) Intermediate in the Amine Oxygenase AurF. AB - In this work, we report the first computational investigation on the structure and properties of the (peroxo)diiron(III) intermediate of the AurF enzyme. Our calculations predict that, in the oxidized state of the AurF enzyme, the peroxo ligand is depicted in a MU-1,1-coordination mode with a protonated bridging ligand and is not in a MU-eta(2):eta(2) or MU-1,2 mode. Computed spectral data for the MU-1,1-coordination mode correlate well with experimental observations and unravel the potential of the energetics-spectroscopic approach adapted here. PMID- 26588099 TI - Beyond the Bifurcation: There Is More to Cerebrovascular Ultrasound Than Internal Carotid Artery Stenosis! AB - Carotid ultrasonography (US) is most commonly performed to identify potential areas of flow-limiting stenosis in the internal carotid artery. Identification of stenosis and unstable plaque is important because these entities are leading predictors of stroke, the fourth most common cause of death in the United States. However, US can detect other important but less common vascular pathologies if proper techniques and nuances of these entities are understood.In this article, we discuss the US appearance of abnormalities involving the carotid, vertebral, subclavian, and innominate arteries as well as the key clinical components of each diagnosis. These include congenital variants, dissection, stenosis, and vasculopathy. In addition, correlation of US findings with both magnetic resonance imaging and computed tomography more comprehensively demonstrates the complementary nature of these imaging modalities. PMID- 26588100 TI - Lymphatic Malformations: A Case-Based Overview. PMID- 26588097 TI - Stochastic Regulation of her1/7 Gene Expression Is the Source of Noise in the Zebrafish Somite Clock Counteracted by Notch Signalling. AB - The somite segmentation clock is a robust oscillator used to generate regularly sized segments during early vertebrate embryogenesis. It has been proposed that the clocks of neighbouring cells are synchronised via inter-cellular Notch signalling, in order to overcome the effects of noisy gene expression. When Notch dependent communication between cells fails, the clocks of individual cells operate erratically and lose synchrony over a period of about 5 to 8 segmentation clock cycles (2-3 hours in the zebrafish). Here, we quantitatively investigate the effects of stochasticity on cell synchrony, using mathematical modelling, to investigate the likely source of such noise. We find that variations in the transcription, translation and degradation rate of key Notch signalling regulators do not explain the in vivo kinetics of desynchronisation. Rather, the analysis predicts that clock desynchronisation, in the absence of Notch signalling, is due to the stochastic dissociation of Her1/7 repressor proteins from the oscillating her1/7 autorepressed target genes. Using in situ hybridisation to visualise sites of active her1 transcription, we measure an average delay of approximately three minutes between the times of activation of the two her1 alleles in a cell. Our model shows that such a delay is sufficient to explain the in vivo rate of clock desynchronisation in Notch pathway mutant embryos and also that Notch-mediated synchronisation is sufficient to overcome this stochastic variation. This suggests that the stochastic nature of repressor/DNA dissociation is the major source of noise in the segmentation clock. PMID- 26588101 TI - Testicular Adrenal Rests in Congenital Adrenal Hyperplasia: A Rare Presentation of Testicular Masses. PMID- 26588102 TI - Contrast-Enhanced Ultrasonography Diagnostic Evaluation of Esophageal Varices in Patients With Cirrhosis. AB - The purpose of this study was to clarify the usefulness of contrast-enhanced ultrasonography (CEUS) for the diagnosis of esophageal varices (EVs) in patients with cirrhosis. A total of 81 cases (56 patients with EVs and 25 control subjects without EV) were examined by CEUS and by esophagogastroduodenoscopy. According to the esophagogastroduodenoscopy results, we divided the subjects into 3 groups: G0, G1, and G2. The G0 group had 25 patients who exhibited no liver abnormality other than liver cyst or hemangioma without EVs, G1 comprised 9 patients with small EVs and 13 with medium EVs. G2 was composed of 34 cases of severe EVs. Under CEUS, the following parameters were measured: the thickness of double-layer mucosa and submucosa in the lower esophagus (Tm), the maximum anteroposterior diameter of the lower esophagus (De), and the ratio of Tm to De (Tm/De). Time intensity curves of the lower esophagus and aorta were drawn using QLAB software. One-factor analysis of variance was used to compare means between the 3 groups. The diagnostic value of CEUS was assessed by receiver operating characteristic curves. Bayes discriminant analysis was adopted for building discriminant equations. Tm, De, Tm/De, Tep, and Iep/Iap were greater in patients with EVs (G1 and G2) than in those without EVs (G0). The Tms for the G0, G1, and G2 groups were 4.16 +/- 0.59 mm, 7.06 +/- 0.89 mm, and 10.10 +/- 1.77 mm (P < 0.01), respectively, with 7.65 mm being the best cutoff value for diagnosing >= G2 (sensitivity 96.9%, specificity 90.0%). The area under the receiver operating characteristic curve was 0.987. Three discriminant equations were obtained by Bayes discriminant analysis: y0 = -6.2 + 2.5Tm, y1 = -15.1 + 4.1Tm and y2 = -31.7 + 6.0Tm, respectively. The equations correctly classified 91.7% of cases in the study, making an error rate of 8.3%. Tm attained from CEUS can be a new, convenient, noninvasive parameter for evaluating esophageal varices in patients with liver cirrhosis. PMID- 26588103 TI - Variability in Stiffness Assessment in a Thyroid Nodule Using Shear Wave Imaging. AB - PURPOSE: The aim of the study was to assess intrareader and interreader variability in placing a region of interest in the elastography color map in the thyroid nodule. METHOD AND MATERIALS: After institutional review board approval, elastograms were obtained by shear wave elastography from 38 individuals, with a total of 60 thyroid nodules. Two readers reviewed all images while blinded to the cytopathology or final histopathology results and to each other's measurements. For each image, readers first performed a qualitative assessment and recorded presence of stiff region(s) and number of stiff regions. Then, they placed a 3-mm circular region of interest on the stiffest region to quantify the mean and maximum stiffness in kilopascals. Intrareader and interreader agreement was summarized for categorical variables using Cohen kappa and for continuous variables using the concordance correlation coefficient (CCC) and coefficient of variation. RESULTS: There was good overall intrareader and interreader agreement for the presence of stiff regions and number of stiff regions after classifying them as 0, 1, and greater than 1 regions (kappa = 0.78-0.81 and 0.74-0.79, respectively). There was also good overall agreement for the the following quantitative measurements: mean kPa (CCC = 0.97 and 0.93) and max kPa (CCC = 0.97 and 0.93). The intrareader and interreader coefficient of variation was 13% and 21% for mean kPa and 14% and 21% for max kPa. CONCLUSIONS: There can be differences in measurement of stiffness by 2 different operators in softer nodules with shear wave imaging because of the lack of brighter areas on the color elastograms. A standardized technique is necessary to be able to compare results from 1 study to the next. PMID- 26588104 TI - ACR Appropriateness Criteria(r) Acute Pelvic Pain in the Reproductive Age Group. AB - Acute pelvic pain in premenopausal women frequently poses a diagnostic dilemma. These patients may exhibit nonspecific signs and symptoms such as nausea, vomiting and leukocytosis. The cause of pelvic pain includes a myriad of diagnostic possibilities such as obstetric, gynecologic, urologic, gastrointestinal, and vascular etiologies. The choice of the imaging modality is usually determined by a suspected clinical differential diagnosis. Thus the patient should undergo careful evaluation and the suspected differential diagnosis should be narrowed before an optimal imaging modality is chosen. Transvaginal and transabdominal pelvic sonography is the modality of choice, to assess for pelvic pain, when an obstetric or gynecologic etiology is suspected and computed tomography is often more useful when gastrointestinal or genitourinary pathology is thought to be more likely. Magnetic resonance imaging, when available in the acute setting, is favored over computed tomography for assessing pregnant patients for nongynecologic etiologies owing to its lack of ionizing radiation.The American College of Radiology Appropriateness Criteria(r) are evidence-based guidelines for specific clinical conditions that are reviewed every three years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. PMID- 26588105 TI - Production of pyruvate from mannitol by mannitol-assimilating pyruvate decarboxylase-negative Saccharomyces cerevisiae. AB - Mannitol is contained in brown macroalgae up to 33% (w/w, dry weight), and thus is a promising carbon source for white biotechnology. However, Saccharomyces cerevisiae, a key cell factory, is generally regarded to be unable to assimilate mannitol for growth. We have recently succeeded in producing S. cerevisiae that can assimilate mannitol through spontaneous mutations of Tup1-Cyc8, each of which constitutes a general corepressor complex. In this study, we demonstrate production of pyruvate from mannitol using this mannitol-assimilating S. cerevisiae through deletions of all 3 pyruvate decarboxylase genes. The resultant mannitol-assimilating pyruvate decarboxylase-negative strain produced 0.86 g/L pyruvate without use of acetate after cultivation for 4 days, with an overall yield of 0.77 g of pyruvate per g of mannitol (the theoretical yield was 79%). Although acetate was not needed for growth of this strain in mannitol-containing medium, addition of acetate had a significant beneficial effect on production of pyruvate. This is the first report of production of a valuable compound (other than ethanol) from mannitol using S. cerevisiae, and is an initial platform from which the productivity of pyruvate from mannitol can be improved. PMID- 26588106 TI - Permeability of Rubbery and Glassy Membranes of Ionic Liquid Filled Polymersome Nanoreactors in Water. AB - Nanoemulsion-like polymer vesicles (polymersomes) having ionic liquid interiors dispersed in water are attractive for nanoreactor applications. In a previous study, we demonstrated that small molecules could pass through rubbery polybutadiene membranes on a time scale of seconds, which is practical for chemical transformations. It is of interest to determine how sensitive the rate of transport is to temperature, particularly for membranes in the vicinity of the glass transition (Tg). In this work, the molecular exchange rate of 1 butylimidazole through glassy polystyrene (PS) bilayer membranes is investigated via pulsed field gradient nuclear magnetic resonance (PFG-NMR) over the temperature range from 25 to 70 degrees C. The vesicles were prepared by the cosolvent method in the ionic liquid 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl) imide ([EMIM][TFSI]), and four different polystyrene b-poly(ethylene oxide) (PS-PEO) diblock polymers with varying PS molecular weights were examined. The vesicles were transferred from the ionic liquid to water at room temperature to form nanoemulsion solutions of polymer vesicles in water. The exchange rate of 1-butylimidazole added to the aqueous solutions was observed under equilibrium conditions at each temperature. The exchange rate decreased as the membrane thickness increased, and the exchange rate through the glassy membranes was three to four times slower than through the rubbery polybutadiene membranes under the same experimental conditions. These results demonstrate that the permeability through nanosized membranes depends on both the dimension and chemistry of membrane-forming blocks. Furthermore, the exchange rate was investigated as a function of temperature in the vicinity of the Tg of PS-PEO membranes. The exchange rate, however, is not a strong function of the temperature in the vicinity of the membrane Tg, due to a combination of the nanoscopic dimension of the membrane, and some degree of solvent plasticization. PMID- 26588107 TI - High-Throughput, Algorithmic Determination of Nanoparticle Structure from Electron Microscopy Images. AB - Electron microscopy (EM) represents the most powerful tool to directly characterize the structure of individual nanoparticles. Accurate descriptions of nanoparticle populations with EM, however, are currently limited by the lack of tools to quantitatively analyze populations in a high-throughput manner. Herein, we report a computational method to algorithmically analyze EM images that allows for the first automated structural quantification of heterogeneous nanostructure populations, with species that differ in both size and shape. This allows one to accurately describe nanoscale structure at the bulk level, analogous to ensemble measurements with individual particle resolution. With our described EM protocol and our inclusion of freely available code for our algorithmic analysis, we aim to standardize EM characterization of nanostructure populations to increase reproducibility, objectivity, and throughput in measurements. We believe this work will have significant implications in diverse research areas involving nanomaterials, including, but not limited to, fundamental studies of structural control in nanoparticle synthesis, nanomaterial-based therapeutics and diagnostics, optoelectronics, and catalysis. PMID- 26588108 TI - Factors Influencing Graft Choice in Revision Anterior Cruciate Ligament Reconstruction in the MARS Group. AB - It has not been known what drives revision anterior cruciate ligament (ACL) reconstruction graft choice in the past. We undertook this study to utilize the Multicenter ACL Revision Study (MARS) group and propensity score statistical analysis to determine the drivers of revision ACL reconstruction graft choice. We hypothesized that propensity analysis would demonstrate that individual surgeons still have significant impact on revision ACL reconstruction. Twelve hundred patients were enrolled in this longitudinal revision cohort by 83 surgeons at 52 sites. The median age was 26 years and 505 (42%) were females. One thousand forty nine (87%) patients were undergoing their first ACL revision. Graft choice for revision ACL reconstruction for these patients was 48% autograft, 49% allograft, and 3% combination. The independent variables of this model included gender, age, ethnicity, body mass index, smoking status, sport, activity level, previous graft, revision number, surgeon, surgeon's opinion of failure, previous technical aspects, etc. Surgeons were defined as those who contributed more than 15 patients during the enrollment period. . We calculated a propensity score for graft type based on the predicted probability of receiving an allograft from a logistic regression model. Propensity scores demonstrated that surgeon, prior graft choice, and patient age each had significant influence on which graft type was chosen for the revision ACL reconstruction (p < 0.0001). The revising surgeon had the largest impact upon graft choice: ~ 5 times that of the second most important factor (prior graft). If the prior graft type was an autograft, then an allograft was 3.6 times more likely to be chosen for the revision. This current study demonstrates that the individual surgeon is ultimately the most important factor in revision ACL reconstruction graft choice. Additional statistically significant influences of graft choice included age, gender, previous graft choice, ACL revision number, concurrent medial collateral ligament/posteromedial repair, and opinion of the previous failure. This demonstrates that if graft choice is determined to impact outcome then surgeons have the ability to change and determine the graft utilized. Level of Evidence Level II (prospective comparative study). PMID- 26588109 TI - In Vitro Experimental Testing of the Human Knee: A Concise Review. AB - In vitro testing of the human knee provides valuable insight that contributes to further understanding knee biomechanics. Cadaveric testing correlates well with clinical trials because the tissue has similar properties to that of live subjects. In addition, in vitro testing allows studies to be performed that would otherwise be unethical to evaluate in vivo. Due to their many advantages, cadaveric testing has been utilized to evaluate many of medical devices and surgical techniques that have been developed in recent decades. This article aims to review the current technologies and methodologies utilized in experimental in vitro testing of the human knee. The article provides a summary of the different rigs and machines that are currently used to examine the biomechanics of the knee. It also highlights the variable experimental techniques and measurement systems that are used to collect the kinematics and kinetics of the knee joint. As technologies advance so do the measurement systems and equipment in the experimental biomechanics field. The influence of improvements to these testing equipment and measurement devices on in vitro testing of the knee will also be discussed in this review. PMID- 26588110 TI - Sexterrylenetetracarboxylic Bisimides: NIR Dyes. AB - Sexterrylenehexacarboxylic bisimides, extended peri-arylenes with the alignment of six peri-arranged naphthalene units, were prepared by Suzuki cross coupling and subsequent oxidative ring closure reactions of the perylene units and exhibit NIR absorption at 945 nm. Intermediates are strongly fluorescent with an increased Stokes shift because of dynamic processes. PMID- 26588111 TI - Efficacy of single-dose, extended-release naproxen sodium 660 mg in postsurgical dental pain: two double-blind, randomized, placebo-controlled trials. AB - OBJECTIVE: To evaluate the efficacy of a novel formulation of extended release/immediate-release (ER) naproxen sodium over 24 h in a dental pain model. RESEARCH DESIGN AND METHODS: Two randomized, double-blind, placebo-controlled trials in moderate to severe pain after extraction of one or two impacted third molars (at least one partial mandibular bony impaction). Treatment comprised oral ER naproxen sodium 660 mg (single dose), placebo (both studies) or immediate release (IR) naproxen sodium 220 mg tid (study 2). MAIN OUTCOME MEASURES: Primary efficacy endpoint: 24-h summed pain intensity difference (SPID). Secondary variables included total pain relief (TOTPAR), use of rescue medication. All treatment-emergent adverse events were recorded. CLINICAL TRIAL REGISTRATION: NCT00720057 (study 1), NCT01389284 (study 2). RESULTS: Primary efficacy analyses: pain intensity was significantly lower over 24 h with ER naproxen sodium vs. placebo (p < 0.001), with significant relief from 15 min (study 2). In study 2, ER naproxen sodium was non-inferior to IR naproxen sodium, reducing pain intensity to a comparable extent over 24 h. TOTPAR was significantly greater with ER and IR naproxen sodium vs. placebo at all time points, with generally comparable differences between active treatments. Significantly more placebo patients required rescue medication vs. ER and IR naproxen sodium from 2-24 h post-dose. Once daily ER naproxen sodium was generally safe and well tolerated, with a similar safety profile to IR naproxen sodium tid. LIMITATIONS: The studies were single dose, with limited ability to assess efficacy or safety of multiple doses over time. As the imputed pain score meant that estimated treatment differences may have been biased in favor of ER naproxen sodium, a post hoc analysis evaluated the robustness of the results for pain relief. CONCLUSIONS: A single dose of ER naproxen sodium 660 mg significantly reduced moderate to severe dental pain vs. placebo and was comparable to IR naproxen sodium 220 mg tid. Significant pain relief was experienced from 15 min and sustained over 24 h, resulting in a reduced need for rescue medication. ER naproxen sodium 660 mg once daily is a convenient and effective therapy providing 24 h relief of pain. PMID- 26588112 TI - Coexpression of CdSe and CdSe/CdS quantum dots in live cells using molecular hyperspectral imaging technology. AB - A direct spatial and spectral observation of CdSe and CdSe/CdS quantum dots (QDs) as probes in live cells is performed by using a custom molecular hyperspectral imaging (MHI) system. Water-soluble CdSe and CdSe/CdS QDs are synthesized in aqueous solution under the assistance of high-intensity ultrasonic irradiation and incubated with colon cancer cells for bioimaging. Unlike the traditional fluorescence microscopy methods, MHI technology can identify QD probes according to their spectral signatures and generate coexpression and stain titer maps by a clustering method. The experimental results show that the MHI method has potential to unmix biomarkers by their spectral information, which opens up a pathway of optical multiplexing with many different QD probes. PMID- 26588113 TI - The rewards of using a modelling approach in directing poultry research. AB - The purpose of this paper was to demonstrate the advantages of using a good theory as the basis for designing and conducting research, using personal experience of developing a simulation model to predict food intake in laying hens and broiler breeders. To develop such a model, research projects were designed to measure, among others, the effect of lighting programmes on age at sexual maturity, changes in internal cycle length, egg and body component weights over time, effects of temperature on performance, and to determine whether these birds would make use of body lipid reserves as an energy source. Most of the experiments described here were conceived and conducted only because they were seen as a means of collecting information required for the development of empirical and mechanistic models, both of which have contributed to a better understanding of the birds themselves, as well as to the basis for predicting food intake in broiler breeders and laying hens. For those researchers seeking ideas for further study, there is no better way of generating such ideas than by first developing a theory of the subject to be studied, the greatest benefit from this approach being that such targeted research is bound to be new, innovative and useful. PMID- 26588114 TI - Sickness certification in primary care: a survey on views and practices among Swiss physicians. AB - QUESTIONS UNDER STUDY: Studies from several countries (Scandinavia, United Kingdom) report that general practitioners (GPs) experience problems in sickness certification. Our study explored views of Swiss GPs towards sickness certification, their practice and experience, professional skills and problematic interactions with patients. METHODS: We conducted an online survey among GPs throughout Switzerland, exploring behaviour of physicians, patients and employers with regard to sickness certification; GPs' views about sickness certification; required competences for certifying sickness absence, and approaches to advance their competence. We piloted the questionnaire and disseminated it through the networks of the five Swiss academic institutes for primary care. RESULTS: We received 507 valid responses (response rate 50%). Only 43/507 GPs experienced sickness certification as problematic per se, yet 155/507 experienced problems in sickness certification at least once a week. The 507 GPs identified estimating a long-term prognosis about work capacity (64%), handling conflicts with patients (54%), and determining the reduction of work capacity (42%) as problematic. Over 75% would welcome special training opportunities, e.g., on sickness certifications during residency (93%), in insurance medicine (81%), and conflict management (80%). CONCLUSION: Sickness certification as such does not present a major problem to Swiss GPs, which contrasts with the experience in Scandinavian countries and in the UK. Swiss GPs did identify specific tasks of sickness certification as problematic. Training opportunities on sick-leave certification and insurance medicine in general were welcomed. PMID- 26588116 TI - Acceleration of Ab Initio QM/MM Calculations under Periodic Boundary Conditions by Multiscale and Multiple Time Step Approaches. AB - Development of multiscale ab initio quantum mechanical and molecular mechanical (AI-QM/MM) method for periodic boundary molecular dynamics (MD) simulations and their acceleration by multiple time step approach are described. The developed method achieves accuracy and efficiency by integrating the AI-QM/MM level of theory and the previously developed semiempirical (SE) QM/MM-Ewald sum method [J. Chem. Theory Comput. 2005, 1, 2] extended to the smooth particle-mesh Ewald (PME) summation method. In the developed methods, the total energy of the simulated system is evaluated at the SE-QM/MM-PME level of theory to include long-range QM/MM electrostatic interactions, which is then corrected on the fly using the AI QM/MM level of theory within the real space cutoff. The resulting energy expression enables decomposition of total forces applied to each atom into forces determined at the low-level SE-QM/MM method and correction forces at the AI-QM/MM level, to integrate the system using the reversible reference system propagator algorithm. The resulting method achieves a substantial speed-up of the entire calculation by minimizing the number of time-consuming energy and gradient evaluations at the AI-QM/MM level. Test calculations show that the developed multiple time step AI-QM/MM method yields MD trajectories and potential of mean force profiles comparable to single time step QM/MM results. The developed method, together with message passing interface (MPI) parallelization, accelerates the present AI-QM/MM MD simulations about 30-fold relative to the speed of single-core AI-QM/MM simulations for the molecular systems tested in the present work, making the method less than one order slower than the SE-QM/MM methods under periodic boundary conditions. PMID- 26588117 TI - Exploring the Reaction Coordinates for f-f Emission and Quenching of Lanthanide Complexes - Thermosensitivity of Terbium(III) Luminescence. AB - Lanthanide complexes with temperature dependent f-f emission intensities are commonly used as temperature sensors. The thermosensitivity can be controlled by the ligands, but their effects are difficult to predict. To clarify the origin of the differences in thermosensitivity, we propose a new theoretical strategy, the energy shift method, and use it to find crossing points between two states where intersystem crossing and excitation energy transfer take place. The different sensitivities of the three studied terbium(III) complexes are caused by the different rate-determining steps for emission or quenching. PMID- 26588115 TI - Leveraging strong social ties among young men in Dar es Salaam: A pilot intervention of microfinance and peer leadership for HIV and gender-based violence prevention. AB - Gender inequality is at the core of the HIV patterns that are evident in sub Saharan Africa. Gender-based violence (GBV) and lack of economic opportunity are important structural determinants of HIV risk. We piloted a microfinance and health promotion intervention among social networks of primarily young men in Dar es Salaam. Twenty-two individuals participated in the microfinance component and 30 peer leaders were recruited and trained in the peer health leadership component. We collected and analysed observational data from trainings, monitoring data on loan repayment, and reports of peer conversations to assess the feasibility and acceptability of the intervention. Eighteen of the loan recipients (82%) paid back their loans, and of these 15 (83%) received a second, larger loan. Among the loan defaulters, one died, one had chronic health problems, and two disappeared, one of whom was imprisoned for theft. The majority of conversations reported by peer health leaders focused on condoms, sexual partner selection, and HIV testing. Few peer leaders reported conversations about GBV. We demonstrated the feasibility and acceptability of this innovative HIV and GBV prevention intervention. The lessons learned from this pilot have informed the implementation of a cluster-randomised trial of the microfinance and peer health leadership intervention. PMID- 26588118 TI - Glucose-Promoted Localization Dynamics of Excess Electrons in Aqueous Glucose Solution Revealed by Ab Initio Molecular Dynamics Simulation. AB - Ab initio molecular dynamics simulations reveal that an excess electron (EE) can be more efficiently localized as a cavity-shaped state in aqueous glucose solution (AGS) than in water. Compared with that (~1.5 ps) in water, the localization time is shortened by ~0.7-1.2 ps in three AGSs (0.56, 1.12, and 2.87 M). Although the radii of gyration of the solvated EEs are all close to 2.6 A in the four solutions, the solvated EE cavities in the AGSs become more compact and can localize ~80% of an EE, which is considerably larger than that (~40-60% and occasionally ~80%) in water. These observations are attributed to a modification of the hydrogen-bonded network by the introduction of glucose molecules into water. The water acts as a promoter and stabilizer, by forming voids around glucose molecules and, in this fashion, favoring the localization of an EE with high efficiency. This study provides important information about EEs in physiological AGSs and suggests a new strategy to efficiently localize an EE in a stable cavity for further exploration of biological function. PMID- 26588119 TI - Stochastic Dynamics with Correct Sampling for Constrained Systems. AB - In this paper we discuss thermostatting using stochastic methods for molecular simulations where constraints are present. For so-called impulsive thermostats, like the Andersen thermostat, the equilibrium temperature will differ significantly from the imposed temperature when a limited number of particles are picked and constraints are applied. We analyze this problem and give two rigorous solutions for it. A correct general treatment of impulsive stochastic thermostatting, including pairwise dissipative particle dynamics and stochastic forcing in the presence of constraints, is given and it is shown that the constrained canonical distribution is sampled rigorously. We discuss implementation issues such as second order Trotter expansions. The method is shown to rigorously maintain the correct temperature for the case of extended simple point charge (SPC/E) water simulations. PMID- 26588120 TI - A Coupled Molecular Dynamics/Kinetic Monte Carlo Approach for Protonation Dynamics in Extended Systems. AB - We propose a multiscale simulation scheme that combines first-principles Molecular Dynamics (MD) and kinetic Monte Carlo (kMC) simulations to describe ion transport processes. On the one hand, the molecular dynamics trajectory provides an accurate atomistic structure and its temporal evolution, and on the other hand, the Monte Carlo part models the long-time motion of the acidic protons. Our hybrid approach defines a coupling scheme between the MD and kMC simulations that allows the kMC topology to adapt continuously to the propagating atomistic microstructure of the system. On the example of a fuel cell membrane material, we validate our model by comparing its results with those of the pure MD simulation. We show that the hybrid scheme with an evolving topology results in a better description of proton diffusion than a conventional approach with a static kMC transfer rate matrix. Furthermore, we show that our approach can incorporate additional dynamical features such as the coupling of the rotation of a side group in the molecular building blocks. In the present implementation, we focus on ion conduction, but it is straightforward to generalize our approach to other transport phenomena such as electronic conduction or spin diffusion. PMID- 26588121 TI - A Novel, Computationally Efficient Multipolar Model Employing Distributed Charges for Molecular Dynamics Simulations. AB - A truncated multipole expansion can be re-expressed exactly using an appropriate arrangement of point charges. This means that groups of point charges that are shifted away from nuclear coordinates can be used to achieve accurate electrostatics for molecular systems. We introduce a multipolar electrostatic model formulated in this way for use in computationally efficient multipolar molecular dynamics simulations with well-defined forces and energy conservation in NVE (constant number-volume-energy) simulations. A framework is introduced to distribute torques arising from multipole moments throughout a molecule, and a refined fitting approach is suggested to obtain atomic multipole moments that are optimized for accuracy and numerical stability in a force field context. The formulation of the charge model is outlined as it has been implemented into CHARMM, with application to test systems involving H2O and chlorobenzene. As well as ease of implementation and computational efficiency, the approach can be used to provide snapshots for multipolar QM/MM calculations in QM/MM-MD studies and easily combined with a standard point-charge force field to allow mixed multipolar/point charge simulations of large systems. PMID- 26588122 TI - Size-Consistent Multipartitioning QM/MM: A Stable and Efficient Adaptive QM/MM Method. AB - We propose a new adaptive QM/MM method, the size-consistent multipartitioning (SCMP) QM/MM scheme, which enables stable and computationally efficient QM/MM simulations. A number of partitionings with identical size of the QM and the MM regions are considered with a new adaptive scheme in order to (1) realize smooth QM/MM switching, (2) introduce a conserved quantity (total energy, Hamiltonian), (3) avoid spurious artificial forces on the QM/MM border, and (4) allow for an efficient parallel implementation. Benchmark simulations performed for "QM water in MM water" show that energy conservation can be significantly improved and the computational efficiency allows treating also larger QM regions, for which previous methods had to face an intractable increase in computer time. PMID- 26588123 TI - Quantifying the Lifetime of Triplet Energy Transfer Processes in Organic Chromophores: A Case Study of 4-(2-Naphthylmethyl)benzaldehyde. AB - We simulate the dynamics of triplet-triplet energy transfer in a donor-bridge acceptor system [4-(2-naphthylmethyl)benzaldehyde] with surface hopping, using electronic energies, gradients, and derivative couplings that are calculated on the fly. Using Boys localization to diabatize electronic states, we calculate energy transfer rates that agree favorably with experiment. The atomistic nature of our dynamical investigation produces several unique insights into this energy transfer reaction including an approximation of the decoherence time for the energy transfer process and the observation that the reaction pathway passes through a conical intersection. PMID- 26588124 TI - Nonequilibrium Candidate Monte Carlo Simulations with Configurational Freezing Schemes. AB - Nonequilibrium Candidate Monte Carlo simulation [Nilmeier et al., Proc. Natl. Acad. Sci. U.S.A. 2011, 108, E1009-E1018] is a tool devised to design Monte Carlo moves with high acceptance probabilities that connect uncorrelated configurations. Such moves are generated through nonequilibrium driven dynamics, producing candidate configurations accepted with a Monte Carlo-like criterion that preserves the equilibrium distribution. The probability of accepting a candidate configuration as the next sample in the Markov chain basically depends on the work performed on the system during the nonequilibrium trajectory and increases with decreasing such a work. It is thus strategically relevant to find ways of producing nonequilibrium moves with low work, namely moves where dissipation is as low as possible. This is the goal of our methodology, in which we combine Nonequilibrium Candidate Monte Carlo with Configurational Freezing schemes developed by Nicolini et al. (J. Chem. Theory Comput. 2011, 7, 582-593). The idea is to limit the configurational sampling to particles of a well established region of the simulation sample, namely the region where dissipation occurs, while leaving fixed the other particles. This allows to make the system relaxation faster around the region perturbed by the finite-time switching move and hence to reduce the dissipated work, eventually enhancing the probability of accepting the generated move. Our combined approach enhances significantly configurational sampling, as shown by the case of a bistable dimer immersed in a dense fluid. PMID- 26588125 TI - Spatial Averaging: Sampling Enhancement for Exploring Configurational Space of Atomic Clusters and Biomolecules. AB - Spatial averaging Monte Carlo (SA-MC) is an efficient algorithm dedicated to the study of rare-event problems. At the heart of this method is the realization that from the equilibrium density a related, modified probability density can be constructed through a suitable transformation. This new density is more highly connected than the original density, which increases the probability for transitions between neighboring states, which in turn speeds up the sampling. The first successful investigations included the diffusion of small molecules in condensed phase environments and characterization of the metastable states of the migration of the CO ligand in myoglobin. In the present work, a general and robust implementation including rotational and torsional moves in the CHARMM molecular modeling software is introduced. Also, a procedure to estimate unbiased properties is proposed in order to compute thermodynamic observables. These procedures are suitable to study a range of topical systems including Lennard Jones clusters of different sizes and the blocked alanine dipeptide (Ala)2 in implicit and explicit solvent. In all cases, SA-MC is found to outperform standard Metropolis simulations in sampling configurational space at little extra computational expense. The results for (Ala)2 in explicit solvent are in good agreement with previous umbrella sampling simulations. PMID- 26588126 TI - Range-Separated meta-GGA Functional Designed for Noncovalent Interactions. AB - The accuracy of applying density functional theory to noncovalent interactions is hindered by errors arising from low-density regions of interaction-induced change in the density gradient, error compensation between correlation and exchange functionals, and dispersion double counting. A new exchange-correlation functional designed for noncovalent interactions is proposed to address these problems. The functional consists of the range-separated PBEsol exchange considered in two variants, pure and hybrid, and the semilocal correlation functional of Modrzejewski et al. (J. Chem. Phys. 2012, 137, 204121) designed with the constraint satisfaction technique to smoothly connect with a dispersion term. Two variants of dispersion correction are appended to the correlation functional: the atom-atom pairwise additive DFT-D3 model and the density dependent many-body dispersion with self-consistent screening (MBD-rsSCS). From these building blocks, a set of four functionals is created to systematically examine the role of pure versus hybrid exchange and the underlying models for dispersion. The new functional is extensively tested on benchmark sets with diverse nature and size. Truly outstanding performance is demonstrated for water clusters of varying size, ionic hydrogen bonds, and thermochemistry of isodesmic n-alkane fragmentation reactions. The merits of each component of the new functional are discussed. PMID- 26588127 TI - Optimization of the Coupled Cluster Implementation in NWChem on Petascale Parallel Architectures. AB - The coupled cluster singles and doubles (CCSD) algorithm in the NWChem software package has been optimized to alleviate the communication bottleneck. This optimization provided a 2-fold to 5-fold speedup in the CCSD iteration time depending on the problem size and available memory, and improved the CCSD scaling to 20 000 nodes of the NCSA Blue Waters supercomputer. On 20 000 XE6 nodes of Blue Waters, a complete conventional CCSD(T) calculation of a system encountering 1042 basis functions and 103 occupied correlated orbitals obtained a performance of 0.32 petaflop/s and took 5 h and 24 min to complete. The reported time and performance included all stages of the calculation from initialization to termination for iterative single and double excitations as well as perturbative triples correction. In perturbative triples alone, the computation sustained a rate of 1.18 petaflop/s. The CCSD and (T) phases took approximately (3)/4 and (1)/4 of the total time to solution, respectively, showing that CCSD is the most time-consuming part at the large scale. The MP2, CCSD, and CCSD(T) computations in 6-311++G** basis set performed on guanine-cytosine deoxydinucleotide monophosphate probed the conformational energy difference between the A- and B conformations of single stranded DNA. Good agreement between MP2 and coupled cluster methods has been obtained, suggesting the utility of MP2 for conformational analysis in these systems. The study revealed a significant discrepancy between the quantum mechanical and classical force field predictions, suggesting a need to improve the dihedral parameters. PMID- 26588128 TI - Metropolis Evaluation of the Hartree-Fock Exchange Energy. AB - We examine the possibility of using a Metropolis algorithm for computing the exchange energy in a large molecular system. Following ideas set forth in a recent publication (Baer, Neuhauser, and Rabani, Phys. Rev. Lett. 111, 106402 (2013)) we focus on obtaining the exchange energy per particle (ExPE, as opposed to the total exchange energy) to a predefined statistical error and on determining the numerical scaling of the calculation achieving this. For this we assume that the occupied molecular orbitals (MOs) are known and given in terms of a standard Gaussian atomic basis set. The Metropolis random walk produces a sequence of pairs of three-dimensional points (x,x'), which are distributed in proportion to rho(x,x')(2), where rho(x,x') is the density matrix. The exchange energy per particle is then simply the average of the Coulomb repulsion energy upsilonC(|x-x'|) over these pairs. To reduce the statistical error we separate the exchange energy into a short-range term that can be calculated deterministically in a linear scaling fashion and a long-range term that is treated by the Metropolis method. We demonstrate the method on water clusters and silicon nanocrystals showing the magnitude of the ExPE standard deviation is independent of system size. In the water clusters a longer random walk was necessary to obtain full ergodicity as Metropolis walkers tended to get stuck for a while in localized regions. We developed a diagnostic tool that can alert a user when such a situation occurs. The calculation effort scales linearly with system size if one uses an atom screening procedure that can be made numerically exact. In systems where the MOs can be localized efficiently the ExPE can even be computed with "sublinear scaling" as the MOs themselves can be screened. PMID- 26588129 TI - A Parametrized Coupled-Pair Functional for Molecular Interactions: PCPF-MI. AB - We present a parametrized coupled-pair functional, optimized to describe molecular interactions (PCPF-MI). The method has the same computational cost as singles and doubles configuration interaction, is size extensive, and yields energies that are stationary with respect to variations in all of its excitation coefficients. This last property facilitates the construction of density matrices and the evaluation of one- and two-electron properties. For the S22, HSG, S66, and A24 databases of van der Waals dimers, PCPF-MI computations yield interaction energies with mean unsigned errors of 0.326, 0.149, 0.214, and 0.044 kcal mol( 1), respectively, relative to benchmark computations. PCPF-MI interaction energies consistently improve upon those obtained from several other coupled-pair methods, including the averaged coupled-pair functional (ACPF), the coupled electron-pair approximation [CEPA(n), n = 0,1,3], and averaged quadratic coupled cluster (AQCC). Optimal parameters for spin-component-scaled (SCS) variants of each of these methods are also presented. SCS-CEPA(0), SCS-CEPA(1), SCS-ACPF, and SCS-PCPF-MI all perform similarly, with average errors for the four databases of roughly 0.1 kcal mol(-1). The PCPF-MI method, without additional SCS parametrization, has an average error of 0.192 kcal mol(-1) over the four databases and, when compared to the SCS-parametrized coupled-pair methods, has the added benefit that the energy is stationary with respect to variations in all its excitation coefficients. PMID- 26588130 TI - Intergeminal Correction to the Antisymmetrized Product of Strongly Orthogonal Geminals Derived from the Extended Random Phase Approximation. AB - We present a correction to the antisymmetrized product of strongly orthogonalized geminals (APSG) approach accounting for intergeminal correlation energy that APSG lacks. The correction is based on the fluctuation dissipation theorem formulated for geminals with transition density matrices obtained from the recently formulated extended random phase approximation. We show that the proposed intergeminal correlation correction greatly improves upon APSG energies by accounting for short- and long-range dynamical correlation. For covalently bonded molecules the potential energy curves are in good agreement with the exact results in the entire range of bond breaking. Also the description of weakly interacting systems is superior to that of APSG. In particular, we show that the proposed intergeminal correlation energy reduces to the correct form of the dispersion energy and asymptotically yields exact interaction energy of the helium dimer. PMID- 26588131 TI - Prediction of Accurate Thermochemistry of Medium and Large Sized Radicals Using Connectivity-Based Hierarchy (CBH). AB - Accurate modeling of the chemical reactions in many diverse areas such as combustion, photochemistry, or atmospheric chemistry strongly depends on the availability of thermochemical information of the radicals involved. However, accurate thermochemical investigations of radical systems using state of the art composite methods have mostly been restricted to the study of hydrocarbon radicals of modest size. In an alternative approach, systematic error-canceling thermochemical hierarchy of reaction schemes can be applied to yield accurate results for such systems. In this work, we have extended our connectivity-based hierarchy (CBH) method to the investigation of radical systems. We have calibrated our method using a test set of 30 medium sized radicals to evaluate their heats of formation. The CBH-rad30 test set contains radicals containing diverse functional groups as well as cyclic systems. We demonstrate that the sophisticated error-canceling isoatomic scheme (CBH-2) with modest levels of theory is adequate to provide heats of formation accurate to ~1.5 kcal/mol. Finally, we predict heats of formation of 19 other large and medium sized radicals for which the accuracy of available heats of formation are less well known. PMID- 26588132 TI - Electrostatic Potential-Based Method of Balancing Charge Transfer Across ONIOM QM:QM Boundaries. AB - The inability to describe charge redistribution effects between different regions in a large molecule can be a source of error in an ONIOM hybrid calculation. We propose a new and an inexpensive method for describing such charge-transfer effects and for improving reaction energies obtained with the ONIOM method. Our method is based on matching the electrostatic potential (ESP) between the model system and the real system. The ESP difference arising due to charge redistribution is overcome by placing an optimum one electron potential at a defined buffer region. In our current implementation, the link atom nuclear charge is optimized iteratively to produce a model low ESP distribution equal to that in the real low calculation. These optimum charges are relatively small in magnitude and corroborate physical intuition. This new ESP-ONIOM-CT method is independent of any arbitrary definition of charges, is defined on the basis of a physical observable, and is less basis set dependent than previous approaches. The method is easily extended for studying reactions involving multiple link atoms. We present a thorough benchmark of this method on test sets consisting of one- and two-link atom reactions. Using reaction energies of four different test sets each with four different combinations of high:low levels of theory, the accuracy of ESP-ONIOM-CT improved by 40-60% over the ONIOM method. PMID- 26588133 TI - Numerical Methods for a Kohn-Sham Density Functional Model Based on Optimal Transport. AB - In this paper, we study numerical discretizations to solve density functional models in the "strictly correlated electrons" (SCE) framework. Unlike previous studies, our work is not restricted to radially symmetric densities. In the SCE framework, the exchange-correlation functional encodes the effects of the strong correlation regime by minimizing the pairwise Coulomb repulsion, resulting in an optimal transport problem. We give a mathematical derivation of the self consistent Kohn-Sham-SCE equations, construct an efficient numerical discretization for this type of problem for N = 2 electrons, and apply it to the H2 molecule in its dissociating limit. PMID- 26588134 TI - Mixed Ramp-Gaussian Basis Sets. AB - We discuss molecular orbital basis sets that contain both Gaussian and polynomial (ramp) functions. We show that, by modeling ramp-Gaussian products as sums of ramps, all of the required one- and two-electron integrals can be computed quickly and accurately. To illustrate our approach, we construct R-31+G, a mixed ramp-Gaussian basis in which the core basis functions of the 6-31+G basis are replaced by ramps. By performing self-consistent Hartree-Fock calculations, we show that the thermochemical predictions of R-31+G and 6-31+G are similar but the former has the potential to be significantly faster. PMID- 26588135 TI - Novel Effect Induced by Pseudo-Jahn-Teller Interactions: Broken Cylindrical Symmetry in Linear Molecules. AB - It is shown that in linear molecules the pseudo-Jahn-Teller (PJT) interaction of a Sigma or Pi term with a Delta term induces a bending instability that is angular dependent, reducing the symmetry of the adiabatic potential energy surface from expected Dinfinityh to D4h and Cinfinityv to C2v or C4v. This spontaneously broken cylindrical symmetry (BCS) emerges from the solution of the vibronic coupling equations of the PJT effect (PJTE) problems (Sigma+Delta)?w, (Pi+Delta)?w, (Pi+Sigma+Delta)?w, and (Delta+Delta)?w, where w includes linear, quadratic, and fourth order vibronic coupling terms, and it is confirmed by ab initio calculations for a series of triatomic molecules with ground or excited Delta terms. The BCS is due to the angular symmetry of the electronic wave functions of the Delta term, ~cos 2phi, and ~sin 2phi, split by the fourth order vibronic coupling, which in overlap with the other symmetry wave functions of the Sigma or Pi term provides for the periodical symmetry of the added covalency that facilitates the bending. The mechanism of this PJT-induced BCS effect is discussed in detail; the numerical values of the vibronic coupling parameters for the molecules under consideration were estimated by means of combining separate ab initio calculations of some of them with a procedure fitting the analytical expressions to ab initio calculated energy profiles. It is also shown that the bending of linear molecules in Delta states, similar to Pi states, is exclusively a PJT (not Renner-Teller) effect. The BCS revealed in this paper illustrates again the predicting power of the PJTE. PMID- 26588136 TI - Analytic Energy Gradients and Spin Multiplicities for Orbital-Optimized Second Order Perturbation Theory with Density-Fitting Approximation: An Efficient Implementation. AB - An efficient implementation of analytic energy gradients and spin multiplicities for the density-fitted orbital-optimized second-order perturbation theory (DF OMP2) [Bozkaya, U. J. Chem. Theory Comput. 2014, 10, 2371-2378] is presented. The DF-OMP2 method is applied to a set of alkanes, conjugated dienes, and noncovalent interaction complexes to compare the cost of single point analytic gradient computations with the orbital-optimized MP2 with the resolution of the identity approach (OO-RI-MP2) [Neese, F.; Schwabe, T.; Kossmann, S.; Schirmer, B.; Grimme, S. J. Chem. Theory Comput. 2009, 5, 3060-3073]. Our results demonstrate that the DF-OMP2 method provides substantially lower computational costs for analytic gradients than OO-RI-MP2. On average, the cost of DF-OMP2 analytic gradients is 9 11 times lower than that of OO-RI-MP2 for systems considered. We also consider aromatic bond dissociation energies, for which MP2 provides poor reaction energies. The DF-OMP2 method exhibits a substantially better performance than MP2, providing a mean absolute error of 2.5 kcal mol(-1), which is more than 9 times lower than that of MP2 (22.6 kcal mol(-1)). Overall, the DF-OMP2 method appears very helpful for electronically challenging chemical systems such as free radicals or other cases where standard MP2 proves unreliable. For such problematic systems, we recommend using DF-OMP2 instead of the canonical MP2 as a more robust method with the same computational scaling. PMID- 26588137 TI - Spin-Component-Scaled Double-Hybrid Density Functionals with Nonlocal van der Waals Correlations for Noncovalent Interactions. AB - Nonlocal (NL) van der Waals correlation has been incorporated into the spin component and spin-opposite scaled double-hybrid density functionals (DHDFs) for noncovalent interactions. The short-range attenuation parameters for the tested DHDFs with the NL correlations are optimized by minimizing the mean absolute deviations (MADs) against the S66 database. And consequently, the obtained DHDFs with the NL correlations are denoted as PWPB95-NL, DSD-BLYP-NL, DSD-PBEP86-NL, and DOD-PBEP86-NL. These four DHDFs with the NL correlations are further assessed with the S22B, NCCE31, and ADIM6 databases. On the basis of our benchmark computations, the cooperation of the NL correlation and the spin-component and spin-opposite scaled DHDFs is successful for noncovalent interactions. However, the performances of the four aforementioned DHDFs with the NL correlations on the charge transfer interactions are less than satisfactory. PMID- 26588138 TI - Hybrid Density Functionals for Clusters of Late Transition Metals: Assessing Energetic and Structural Properties. AB - We present the first application of hybrid density functional theory (DFT) methods to larger transition-metal clusters. To assess such functionals for this class of systems, we compare the performance of three modern hybrid DFT methods (PBE0, TPSSh, M06) and their semilocal counterparts (PBE, TPSS, M06L) regarding average bond distances and binding energies per atom for a series of octahedral model clusters Mn (M = Ni, Pd, Pt; n = 13, 38, 55, 79, 116). With application to large particles in mind, we extrapolated the results to their respective bulk limits and compared them to experimental values. In some cases, average nearest neighbor distances are notably overestimated by the PBE0 and M06 hybrid functionals. Results on energies allow a grouping of the tested functionals into sets of similar behavior for the three metals studied. Among the methods examined, the TPSSh hybrid density functional shows the best overall performance. PMID- 26588139 TI - Chemical Assignment of Symmetry-Adapted Perturbation Theory Interaction Energy Components: The Functional-Group SAPT Partition. AB - Recently, we introduced an effective atom-pairwise partition of the many-body symmetry-adapted perturbation theory (SAPT) interaction energy decomposition, producing a method known as atomic SAPT (A-SAPT) [Parrish, R. M.; Sherrill, C. D. J. Chem. Phys. 2014, 141, 044115]. A-SAPT provides ab initio atom-pair potentials for force field development and also automatic visualizations of the spatial contributions of noncovalent interactions, but often has difficulty producing chemically useful partitions of the electrostatic energy, due to the buildup of oscillating partial charges on adjacent functional groups. In this work, we substitute chemical functional groups in place of atoms as the relevant local quasiparticles in the partition, resulting in a functional-group-pairwise partition denoted as functional-group SAPT (F-SAPT). F-SAPT assigns integral sets of local occupied electronic orbitals and protons to chemical functional groups and linking sigma bonds. Link-bond contributions can be further assigned to chemical functional groups to simplify the analysis. This approach yields a SAPT partition between pairs of functional groups with integral charge (usually neutral), preventing oscillations in the electrostatic partition. F-SAPT qualitatively matches chemical intuition and the cut-and-cap fragmentation technique but additionally yields the quantitative many-body SAPT interaction energy. The conceptual simplicity, chemical utility, and computational efficiency of F-SAPT is demonstrated in the context of phenol dimer, proflavine(+)-DNA intercalation, and a cucurbituril host-guest inclusion complex. PMID- 26588140 TI - Physical Meaning of Virtual Kohn-Sham Orbitals and Orbital Energies: An Ideal Basis for the Description of Molecular Excitations. AB - In recent years, several benchmark studies on the performance of large sets of functionals in time-dependent density functional theory (TDDFT) calculations of excitation energies have been performed. The tested functionals do not approximate exact Kohn-Sham orbitals and orbital energies closely. We highlight the advantages of (close to) exact Kohn-Sham orbitals and orbital energies for a simple description, very often as just a single orbital-to-orbital transition, of molecular excitations. Benchmark calculations are performed for the statistical average of orbital potentials (SAOP) functional for the potential [J. Chem. Phys. 2000, 112, 1344; 2001, 114, 652], which approximates the true Kohn-Sham potential much better than LDA, GGA, mGGA, and hybrid potentials do. An accurate Kohn-Sham potential does not only perform satisfactorily for calculated vertical excitation energies of both valence and Rydberg transitions but also exhibits appealing properties of the KS orbitals including occupied orbital energies close to ionization energies, virtual-occupied orbital energy gaps very close to excitation energies, realistic shapes of virtual orbitals, leading to straightforward interpretation of most excitations as single orbital transitions. We stress that such advantages are completely lost in time-dependent Hartree-Fock and partly in hybrid approaches. Many excitations and excitation energies calculated with local density, generalized gradient, and hybrid functionals are spurious. There is, with an accurate KS, or even the LDA or GGA potentials, nothing problematic about the "band gap" in molecules: the HOMO-LUMO gap is close to the first excitation energy (the optical gap). PMID- 26588141 TI - The Right Computational Recipe for Olefin Metathesis with Ru-Based Catalysts: The Whole Mechanism of Ring-Closing Olefin Metathesis. AB - The initiation mechanism of ruthenium methylidene complexes was studied detailing mechanistic insights of all involved reaction steps within a classical olefin metathesis pathway. Computational studies reached a good agreement with the rarely available experimental data and even enabled to complement them. As a result, a highly accurate computational and rather cheap recipe is presented; M06/TZVP//BP86/SVP (PCM, P = 1354 atm). PMID- 26588142 TI - ls1 mardyn: The Massively Parallel Molecular Dynamics Code for Large Systems. AB - The molecular dynamics simulation code ls1 mardyn is presented. It is a highly scalable code, optimized for massively parallel execution on supercomputing architectures and currently holds the world record for the largest molecular simulation with over four trillion particles. It enables the application of pair potentials to length and time scales that were previously out of scope for molecular dynamics simulation. With an efficient dynamic load balancing scheme, it delivers high scalability even for challenging heterogeneous configurations. Presently, multicenter rigid potential models based on Lennard-Jones sites, point charges, and higher-order polarities are supported. Due to its modular design, ls1 mardyn can be extended to new physical models, methods, and algorithms, allowing future users to tailor it to suit their respective needs. Possible applications include scenarios with complex geometries, such as fluids at interfaces, as well as nonequilibrium molecular dynamics simulation of heat and mass transfer. PMID- 26588143 TI - Molecular Dynamics Simulations of the Ionic Liquid 1-n-Butyl-3-Methylimidazolium Chloride and Its Binary Mixtures with Ethanol. AB - Room temperature ionic liquids (ILs) of the imidazolium family have attracted much attention during the past decade for their capability to dissolve biomass. Besides experimental work, numerous compuational studies have been concerned with the physical properties of both neat ILs and their interactions with different solutes, in particular, carbohydrates. Many classical force fields designed specifically for ILs have been found to yield viscosities that are too high for the liquid state, which has been attributed to the fact that the effective charge densities are too high due to the lack of electronic polarizability. One solution to this problem has been uniform scaling of the partial charges by a scale factor in the range 0.6-0.9, depending on model. This procedure has been shown to improve the viscosity of the models, and also to positively affect other properties, such as diffusion constants and ionic conductivity. However, less attention has been paid to how this affects the overall thermodynamics of the system, and the problems it might create when the IL models are combined with other force fields (e.g., for solutes). In the present work, we employ three widely used IL force fields to simulate 1-n-butyl-3-methyl-imidazolium chloride in both the crystal and the liquid state, as well as its binary mixture with ethanol. Two approaches are used: one in which the ionic charge is retained at its full integer value and one in which the partial charges are uniformly reduced to 85%. We investigate and calculate crystal and liquid structures, molar heat capacities, heats of fusion, self-diffusion constants, ionic conductivity, and viscosity for the neat IL, and ethanol activity as a function of ethanol concentration for the binary mixture. We show that properties of the crystal are less affected by charge scaling compared to the liquid. In the liquid state, transport properties of the neat IL are generally improved by scaling, whereas values for the heat of fusion are unaffected, and results for the heat capacity are ambiguous. Neither full nor reduced charges could reproduce experimental ethanol activities for the whole range of compositions. PMID- 26588144 TI - Screened Electrostatic Interactions in Molecular Mechanics. AB - In a typical application of molecular mechanics (MM), the electrostatic interactions are calculated from parametrized partial atomic charges treated as point charges interacting by radial Coulomb potentials. This does not usually yield accurate electrostatic interactions at van der Waals distances, but this is compensated by additional parametrized terms, for example Lennard-Jones potentials. In the present work, we present a scheme involving radial screened Coulomb potentials that reproduces the accurate electrostatics much more accurately. The screening accounts for charge penetration of one subsystem's charge cloud into that of another subsystem, and it is incorporated into the interaction potential in a way similar to what we proposed in a previous article (J. Chem. Theory Comput. 2010, 6, 3330) for combined quantum mechanical and molecular mechanical (QM/MM) simulations, but the screening parameters are reoptimized for MM. The optimization is carried out with electrostatic-potential fitted partial atomic charges, but the optimized parameters should be useful with any realistic charge model. In the model we employ, the charge density of an atom is approximated as the sum of a point charge representing the nucleus and inner electrons and a smeared charge representing the outermost electrons; in particular, for all atoms except hydrogens, the smeared charge represents the two outermost electrons in the present model. We find that the charge penetration effect can cause very significant deviations from the popular point-charge model, and by comparison to electrostatic interactions calculated by symmetry-adapted perturbation theory, we find that the present results are considerably more accurate than point-charge electrostatic interactions. The mean unsigned error in electrostatics for a large and diverse data set (192 interaction energies) decreases from 9.2 to 3.3 kcal/mol, and the error in the electrostatics for 10 water dimers decreases from 1.7 to 0.5 kcal/mol. We could have decreased the average errors further, but at the cost of sometimes significantly overestimating the screening; instead we chose a more conservative (safer) parametrization that systematically underestimates the screening (which by definition means it improves over point charges) and only occasionally overestimates it. Despite this conservative choice, we find that the screened MM method is even more accurate for the electrostatics than unscreened QM/MM calculations. This new method is easy to implement in any MM program, and it can be used to develop more physical force fields for molecular simulations. PMID- 26588145 TI - Charge Anisotropy: Where Atomic Multipoles Matter Most. AB - Specific intermolecular interactions are largely guided by electrostatics. However, the most common model for electrostatic interactions-atomic point charges-fails to reproduce anisotropic charge distributions, such as lone pairs and sigma holes. Although this has long been known, point charges are still widely used in chemical modeling and reasoning. In this contribution, we analyze the deficiency of atomic point charges in reproducing the electrostatic potential (ESP) around molecules and find that multipole moments up to quadrupoles can, with a much lower error than point charges, reproduce the relevant ESP for all cases. Mapping the surface to the closest atom allows to compare ESP errors between atom types and to identify cases with the most urgent need for atomic multipoles. Our analysis shows that almost all heteroatoms require multipoles to correctly describe their charge distribution, with the most serious cases being nitrogen, sulfur, and halogens. Comparison with small molecule crystallography data studies supports our findings and emphasizes the need for incorporating anisotropic charge descriptions in chemical models. The scheme introduced here can be used to identify anisotropic binding preferences for atom types where there is too little coverage in crystal structure databases. PMID- 26588146 TI - A General Quantum Mechanically Derived Force Field (QMDFF) for Molecules and Condensed Phase Simulations. AB - A black-box type procedure is presented for the generation of molecule-specific, classical potential energy functions (force-field, FF) solely from quantum mechanically (QM) computed input data. The approach can treat covalently bound molecules and noncovalent complexes with almost arbitrary structure. The necessary QM information consists of the equilibrium structure and the corresponding Hessian matrix, atomic partial charges, and covalent bond orders. The FF fit is performed automatically without any further input and yields a specific (nontransferable) potential which very closely resembles the QM reference potential near the equilibrium. The resulting atomistic, fully flexible FF is anharmonic and allows smooth dissociation of covalent bonds into atoms. A newly proposed force-constant-bond-energy relation with little empiricism provides reasonably accurate (about 5-10% error) atomization energies for almost arbitrary diatomic and polyatomic molecules. Intra- and intermolecular noncovalent interactions are treated by using well established and accurate D3 dispersion coefficients, CM5 charges from small basis set QM calculations, and a new interatomic repulsion potential. Particular attention has been paid to the construction of the torsion potentials which are partially obtained from automatic QM-tight-binding calculations for model systems. Detailed benchmarks are presented for conformational energies, atomization energies, vibrational frequencies, gas phase structures of organic molecules, and transition metal complexes. Comparisons to results from standard FF or semiempirical methods reveal very good accuracy of the new potential. While further studies are necessary to validate the approach, the initial results suggest QMDFF as a routine tool for the computation of a wide range of properties and systems (e.g., for molecular dynamics of isolated molecules, explicit solvation, self-solvation (melting) or even for molecular crystals) in particular when standard parametrizations are unavailable. PMID- 26588147 TI - Solvatochromic Shift of Brooker's Merocyanine: Hartree-Fock Exchange in Time Dependent Density Functional Calculation and Hydrogen Bonding Effect. AB - The Brooker's merocyanine exhibits a large hypsochromic shift from an apolar aprotic solvent to a polar protic solvent. Quantum chemical calculations have been performed to study the solvatochromism, but there remained a discrepancy between the calculated and experimental solvatochromic shifts. In this paper we evaluate quantum mechanically the excitation energies of the Brooker's merocyanine in water, methanol, acetonitrile, and dichloromethane to investigate what are important factors to accurately model the solvatochromism of the dye by using TDDFT in combination with implicit and explicit solvation models including the PCM, PCMSMD, RISM-SCF-SEDD, and mean-field QM/MM. The results severely depend on the density functional, especially on the amount of Hartree-Fock exchange included in the functional. Furthermore, an explicit description of the solute solvent hydrogen bonds makes a non-negligible contribution to the shift. The experimental large solvatochromic shift can be accurately reproduced by the TDDFT/RISM-SCF-SEDD and mean-field QM/MM calculations with the LC-BOP functional, although the excitation energies in solutions are considerably overestimated. We also estimated the excitation energies and the solvatochromic shift at the SAC CI/RISM-SCF-SEDD and mean-field QM/MM level, which are in very good agreement with the experimental values. These results indicate that if an explicit solvent model is used, TDDFT calculations using such a long-range corrected functional can accurately model the solvatochromism. However, an ab initio quantum chemical method including sufficient electron correlation effects is required to reproduce not only the solvatochromism but also the excitation energies in solutions. PMID- 26588148 TI - Combining the Bethe-Salpeter Formalism with Time-Dependent DFT Excited-State Forces to Describe Optical Signatures: NBO Fluoroborates as Working Examples. AB - We propose to use a blend of methodologies to tackle a challenging case for quantum approaches: the simulation of the optical properties of asymmetric fluoroborate derivatives. Indeed, these dyes, which present a low-lying excited state exhibiting a cyanine-like nature, are treated not only with the Time Dependent Density Functional Theory (TD-DFT) method to determine both the structures and vibrational patterns but also with the Bethe-Salpeter approach to compute both the vertical absorption and emission energies. This combination allows us to obtain 0-0 energies with a significantly improved accuracy compared to the "raw" TD-DFT estimates. We also discuss the impact of various declinations of the Polarizable Continuum Model (linear-response, corrected linear-response, and state-specific models) on the obtained accuracy. PMID- 26588149 TI - Quantum Chemical Calculations of X-ray Emission Spectroscopy. AB - The calculation of X-ray emission spectroscopy with equation of motion coupled cluster theory (EOM-CCSD), time-dependent density functional theory (TDDFT), and resolution of the identity single excitation configuration interaction with second-order perturbation theory (RI-CIS(D)) is studied. These methods can be applied to calculate X-ray emission transitions by using a reference determinant with a core-hole, and they provide a convenient approach to compute the X-ray emission spectroscopy of large systems since all of the required states can be obtained within a single calculation, removing the need to perform a separate calculation for each state. For all of the methods, basis sets with the inclusion of additional basis functions to describe core orbitals are necessary, particularly when studying transitions involving the 1s orbitals of heavier nuclei. EOM-CCSD predicts accurate transition energies when compared with experiment; however, its application to larger systems is restricted by its computational cost and difficulty in converging the CCSD equations for a core hole reference determinant, which become increasing problematic as the size of the system studied increases. While RI-CIS(D) gives accurate transition energies for small molecules containing first row nuclei, its application to larger systems is limited by the CIS states providing a poor zeroth-order reference for perturbation theory which leads to very large errors in the computed transition energies for some states. TDDFT with standard exchange-correlation functionals predicts transition energies that are much larger than experiment. Optimization of a hybrid and short-range corrected functional to predict the X-ray emission transitions results in much closer agreement with EOM-CCSD. The most accurate exchange-correlation functional identified is a modified B3LYP hybrid functional with 66% Hartree-Fock exchange, denoted B(66)LYP, which predicts X-ray emission spectra for a range of molecules including fluorobenzene, nitrobenzene, acetone, dimethyl sulfoxide, and CF3Cl in good agreement with experiment. PMID- 26588150 TI - High-Accuracy Vibrational Computations for Transition-Metal Complexes Including Anharmonic Corrections: Ferrocene, Ruthenocene, and Osmocene as Test Cases. AB - Density functional theory calculations of infrared spectra at harmonic and anharmonic levels of theory have been carried out in order to define a reliable yet feasible strategy to perform accurate computations on metal complexes starting from metallocenes. We present different possibilities to compute with unprecedented accuracy either the ligand vibrations or vibrations where the metal atom is involved or even to obtain the entire spectrum without invoking any scaling factor. Anharmonic calculations employing second-order vibrational perturbation theory provide very good results when performed using the B3PW91 hybrid functional associated with an extended basis set and are able to reproduce quantitatively the entire spectrum of ferrocene, including the presence of overtones at ~1700 cm(-1). Furthermore, our results confirm that B3LYP is the best functional to reproduce ligand vibrations, but, unfortunately, it provides unreliable results for vibrations involving the metal atom. Conversely, the PBE0 functional gives accurate results for metal-ligand vibrational frequencies, but it is quite far from the experiment for intraligand ones. PMID- 26588151 TI - Improving the Accuracy of Excited-State Simulations of BODIPY and Aza-BODIPY Dyes with a Joint SOS-CIS(D) and TD-DFT Approach. AB - BODIPY and aza-BODIPY dyes constitute two key families of organic dyes with applications in both materials science and biology. Previous attempts aiming to obtain accurate theoretical estimates of their optical properties, and in particular of their 0-0 energies, have failed. Here, using time-dependent density functional theory (TD-DFT), configuration interaction singles with a double correction [CIS(D)], and its scaled-opposite-spin variant [SOS-CIS(D)], we have determined the 0-0 energies as well as the vibronic shapes of both the absorption and emission bands of a large set of fluoroborates. Indeed, we have selected 47 BODIPY and 4 aza-BODIPY dyes presenting diverse chemical structures. TD-DFT yields a rather large mean signed error between the experimental and theoretical 0-0 energies with a systematic overshooting of the transition energies (by ca. 0.4 eV). This error is reduced to ca. 0.2 [0.1] eV when the TD-DFT 0-0 energies are corrected with vertical CIS(D) [SOS-CIS(D)] energies. For BODIPY and aza BODIPY dyes, both CIS(D) and SOS-CIS(D) clearly outperform TD-DFT. The present computational protocol allows accurate data to be obtained for the most relevant properties, that is, 0-0 energies and optical band shapes. PMID- 26588152 TI - Calculating X-ray Absorption Spectra of Open-Shell Molecules with the Unrestricted Algebraic-Diagrammatic Construction Scheme for the Polarization Propagator. AB - X-ray absorption spectroscopy (XAS) is a powerful tool that provides information about the electronic structure of molecules via excitation of electrons from the K-shell core region to the unoccupied molecular levels. These high-lying electronic core-excited states can be accurately calculated using the algebraic diagrammatic construction scheme of second order ADC(2) by applying the core valence separation (CVS) approximation to the ADC(2) working equations. For the first time, an efficient implementation of an unrestricted CVS-ADC(2) variant CVS UADC(2) is presented for the calculation of open-shell molecules by treating alpha and beta spins separately from each other. The potential of the CVS-UADC(2) method is demonstrated with a set of small organic radicals by comparison with standard TD-DFT/B3LYP values and experimental data. It turns out that the extended variant CVS-UADC(2)-x, in particular, provides the most accurate results with errors of only 0.1% compared to experimental values. This remarkable agreement justifies the prediction of yet nonrecorded experimental XAS spectra like the one of the anthracene cation. The cation exhibits additional peaks due to the half-filled single-occupied molecular orbital, which may help to distinguish cation from the neutral species. PMID- 26588153 TI - Electronic Band Shapes Calculated with Optimally Tuned Range-Separated Hybrid Functionals. AB - Using a set of 20 organic molecules, we assess the accuracy of both the absorption and emission band shapes obtained by two optimally tuned range separated hybrid functionals possessing 0% (LC-PBE*) and 25% (LC-PBE0*) of short range exact exchange as well as by four other hybrid functionals including or not dispersion and long-range corrections (APF-D, PBE0-1/3, SOGGA11-X, and omegaB97X D). The band topologies are compared to experimental data and to previous time dependent density functional theory calculations. It turns out that both optimally tuned functionals vastly improve the vibronic band shapes obtained with the non-tuned LC-PBE approach but, statistically, do not yield more accurate topologies than standard hybrid functionals. In other words, optimal tuning allows to obtain more accurate excited-state energies without degrading the description of band shapes. In addition, the LC-PBE0* 0-0 energies have been determined for a set of 40 compounds, and it is shown that the results are, on average, less accurate than those obtained by LC-PBE* for the same panel of molecules. The correlation between the optimal range-separation parameters determined for LC-PBE* and LC-PBE0* is discussed as well. PMID- 26588154 TI - Improving Efficiency in SMD Simulations Through a Hybrid Differential Relaxation Algorithm. AB - The fundamental object for studying a (bio)chemical reaction obtained from simulations is the free energy profile, which can be directly related to experimentally determined properties. Although quite accurate hybrid quantum (DFT based)-classical methods are available, achieving statistically accurate and well converged results at a moderate computational cost is still an open challenge. Here, we present and thoroughly test a hybrid differential relaxation algorithm (HyDRA), which allows faster equilibration of the classical environment during the nonequilibrium steering of a (bio)chemical reaction. We show and discuss why (in the context of Jarzynski's Relationship) this method allows obtaining accurate free energy profiles with smaller number of independent trajectories and/or faster pulling speeds, thus reducing the overall computational cost. Moreover, due to the availability and straightforward implementation of the method, we expect that it will foster theoretical studies of key enzymatic processes. PMID- 26588155 TI - Charge Transport Properties of Durene Crystals from First-Principles. AB - We establish a rigorous computational scheme for constructing an effective Hamiltonian to be used for the determination of the charge carrier mobility of pure organic crystals at finite temperature, which accounts for van der Waals interactions, and it includes vibrational contributions from the entire phonon spectrum of the crystal. Such an approach is based on the ab initio framework provided by density functional theory and the construction of a tight-binding effective model via Wannier transformation. The final Hamiltonian includes coupling of the electrons to the crystals phonons, which are also calculated from density functional theory. We apply this methodology to the case of durene, a small pi-conjugated molecule, which forms a high-mobility herringbone-stacked crystal. We show that accounting correctly for dispersive forces is fundamental for obtaining a high-quality phonon spectrum, in agreement with experiments. Then, the mobility as a function of temperature is calculated along different crystallographic directions and the phonons most responsible for the scattering are identified. PMID- 26588156 TI - Ultrafast Estimation of Electronic Couplings for Electron Transfer between pi Conjugated Organic Molecules. AB - Simulation of charge transport in organic semiconducting materials requires the development of strategies for very fast yet accurate estimation of electronic coupling matrix elements for electron transfer between organic molecules (transfer integrals, Hab). A well-known relation that is often exploited for this purpose is the approximately linear dependence of electronic coupling with respect to the overlap of the corresponding diabatic state wave functions for a given donor-acceptor pair. Here we show that a single such relation can be established for a large number of different pi-conjugated organic molecules. In our computational scheme the overlap of the diabatic state wave function is simply estimated by the overlap of the highest singly occupied molecular orbital of donor and acceptor, projected on a minimum valence shell Slater-type orbital (STO) basis with optimized Slater decay coefficients. After calibration of the linear relation, the average error in Hab as obtained from the STO orbital overlap is a factor of 1.9 with respect to wave function-theory validated DFT calculations for a diverse set of pi-conjugated organic dimers including small arenes, arenes with S, N, and O heteroatoms, acenes, porphins, and buckyballs. The crucial advantage of the scheme is that the STO orbital overlap calculation is analytic. This leads to speedups of 6 orders of magnitude with respect to reference DFT calculations, with little loss of accuracy in the regime relevant to charge transport in organics. PMID- 26588157 TI - Free Energies of Quantum Particles: The Coupled-Perturbed Quantum Umbrella Sampling Method. AB - We introduce a new simulation method called Coupled-Perturbed Quantum Umbrella Sampling that extends the classical umbrella sampling approach to reaction coordinates involving quantum mechanical degrees of freedom. The central idea in our method is to solve coupled-perturbed equations to find the response of the quantum system's wave function along a reaction coordinate of interest. This allows for propagation of the system's dynamics under the influence of a quantum biasing umbrella potential and provides a method to rigorously undo the effects of the bias to compute equilibrium ensemble averages. In this way, one can drag electrons into regions of high free energy where they would otherwise not go, thus enabling chemistry by fiat. We demonstrate the applicability of our method for two condensed-phase systems of interest. First, we consider the interaction of a hydrated electron with an aqueous sodium cation, and we calculate a potential of mean force that shows that an e(-):Na(+) contact pair is the thermodynamically favored product starting from either a neutral sodium atom or the separate cation and electron species. Second, we present the first determination of a hydrated electron's free-energy profile relative to an air/water interface. For the particular model parameters used, we find that the hydrated electron is more thermodynamically stable in the bulk rather than at the interface. Our analysis suggests that the primary driving force keeping the electron away from the interface is the long-range electron-solvent polarization interaction rather than the short-range details of the chosen pseudopotential. PMID- 26588158 TI - Characterizing and Understanding Divalent Adsorbates on Carbon Nanotubes with Ab Initio and Classical Approaches: Size, Chirality, and Coverage Effects. AB - The study of oxygen chemisorption on single-walled carbon nanotubes generally relies on simple atomistic models and hence hampers the possibility to understand whether nanotube size or adduct concentration have a role in determining the surface-adsorbate interaction. Our large-scale DFT-based simulations show that structural and electronic properties as well as diffusion barriers strongly depend on both nanotube diameter and adsorbate concentration. Our atomistic models cover nanotube of different chirality with diameters from 0.6 to 1.5 nm and oxygen concentration from 0.1 to 1%. In particular, the tendency to cluster increases with concentration and stabilizes ether (ET) groups but affects hopping barriers only to a minor extent. Significant differences with graphene are found, also for 1.5 nm diameter nanotubes. Extension to species isoelectronic to oxygen reveals dissimilarities, and especially for sulfur that tends to form epoxides (EP), to diffuse more easily and to rapidly close the energy gap for increasing concentration. The relative ET-EP stability can be described in terms of the bare bond curvature, a concentration-dependent chemical descriptor here introduced. Comparison of these DFT calculations-using different exchange-correlation functionals-and our additional investigation with a reactive force-field (ReaxFF) clarifies several similarities but also discrepancies between the predictions of the two schemes. PMID- 26588159 TI - Direct Mixing of Atomistic Solutes and Coarse-Grained Water. AB - We present a new dual-resolution approach for coupling atomistic and coarse grained models in molecular dynamics simulations of hydrated systems. In particular, a coarse-grained point dipolar water model is used to solvate molecules represented with standard all-atom force fields. A unique characteristic of our methodology is that the mixing of resolutions is direct, meaning that no additional or ad hoc scaling factors, intermediate regions, or extra sites are required. To validate the methodology, we compute the hydration free energy of 14 atomistic small molecules (analogs of amino acid side chains) solvated by the coarse-grained water. Remarkably, our predictions reproduce the experimental data as accurately as the predictions from state-of-the-art fully atomistic simulations. We also show that the hydration free energy of the coarse grained water itself is in comparable or better agreement with the experimental value than the predictions from all but one of the most common multisite atomistic models. The coarse-grained water is then applied to solvate a typical atomistic protein containing both alpha-helix and beta-strand elements. Moreover, parallel tempering simulations are performed to investigate the folding free energy landscape of a representative alpha helical and a beta hairpin structure. For the simulations considered in this work, our dual-resolution method is found to be 3 to 6 times more computationally efficient than corresponding fully atomistic approaches. PMID- 26588160 TI - Evaluating AM1/d-CB1 for Chemical Glycobiology QM/MM Simulations. AB - The newly parametrized AM1/d-CB1 is evaluated for its performance in modeling monosaccharide structure, carbohydrate ring pucker, amino acid proton transfer, DNA base pair interactions, carbohydrate-aromatic pi interactions, and phosphates that are prominent in glycosyltransferases. The accuracy of the method in these computations is compared to a comprehensive range of NDDO methods commonly used to study glycan structure and reactivity in chemical biology. AM1/d-CB1 shows significant improvement over existing NDDO type methods in the computation of five and six membered carbohydrate ring pucker free energy surfaces. Moreover, the computation of carbohydrate amino acid interactions commonly present in catalytic domains and binding sites are improved over existing NDDO methods. AM1/d-CB1 shows slight improvement for carbohydrate-aromatic pi interactions compared to a commonly used NDDO method (AM1). The method is applied to a glycosyltransferase reaction, where it is the only NDDO method able to achieve an optimized reaction profile. Moreover, a comparison of the geometry optimized computations of the reaction scheme give a transition state energy barrier that best compares with DFT (MPW1K). Overall, AM1/d-CB1 is shown to significantly improve on existing NDDO methods in modeling chemical glycobiological events. PMID- 26588161 TI - Sampling Assessment for Molecular Simulations Using Conformational Entropy Calculations. AB - The extent and significance of conformational sampling is a major factor determining the reliability of long-scale molecular simulations of large and flexible biomolecules. Although several methods have been proposed to quantify the effective sample size of molecular simulations by transforming root mean squared distances between pairs of configurations into statistical/probabilistic quantities, there is still no standard technique for measuring the size of sampling. In this work, we study conformational entropy (Sconform) as a purely informational and probabilistic measure of sampling that does not require the adoption of any clustering protocol or distance metric between configurations. In addition Sconform, which is calculated from the probability mass functions associated with discretized dihedral angles, offers other potential advantages for sampling assessment (e.g., global character, thermodynamic significance, relationship with internal degrees of freedom, etc.). The utility of Sconform in sampling assessment is illustrated by carrying out test calculations on configurations produced by two extended molecular dynamics simulations, namely, a 2.0 MUs trajectory of a highly flexible 17-residue peptide and the trajectory data set of the 1.0 ms bovine pancreatic trypsin inhibitor simulation provided by the D. E. Shaw research group. PMID- 26588162 TI - Improved PEP-FOLD Approach for Peptide and Miniprotein Structure Prediction. AB - Peptides and mini proteins have many biological and biomedical implications, which motivates the development of accurate methods, suitable for large-scale experiments, to predict their experimental or native conformations solely from sequences. In this study, we report PEP-FOLD2, an improved coarse grained approach for peptide de novo structure prediction and compare it with PEP-FOLD1 and the state-of-the-art Rosetta program. Using a benchmark of 56 structurally diverse peptides with 25-52 amino acids and a total of 600 simulations for each system, PEP-FOLD2 generates higher quality models than PEP-FOLD1, and PEP-FOLD2 and Rosetta generate near-native or native models for 95% and 88% of the targets, respectively. In the situation where we do not have any experimental structures at hand, PEP-FOLD2 and Rosetta return a near-native or native conformation among the top five best scored models for 80% and 75% of the targets, respectively. While the PEP-FOLD2 prediction rate is better than the ROSETTA prediction rate by 5%, this improvement is non-negligible because PEP-FOLD2 explores a larger conformational space than ROSETTA and consists of a single coarse-grained phase. Our results indicate that if the coarse-grained PEP-FOLD2 method is approaching maturity, we are not at the end of the game of mini-protein structure prediction, but this opens new perspectives for large-scale in silico experiments. PMID- 26588163 TI - Erratum: Accurate Prediction of Noncovalent Interaction Energies with the Effective Fragment Potential Method: Comparison of Energy Components to Symmetry Adapted Perturbation Theory for the S22 Test Set. PMID- 26588164 TI - Epidemiology of Intracerebral Haemorrhage. AB - INTRODUCTION: Intracerebral haemorrhage (ICH) has an overall incidence of 24.6 per 100,000 person-years and is associated with a high case fatality. Understanding the risk factors for ICH occurrence informs primary prevention strategies. This article provides an update on the current global patterns of ICH incidence and the common and emerging risk factors associated with ICH. METHODS: We searched Ovid Medline (from 1980 to Oct 2014) for systematic reviews that addressed the epidemiology of ICH and for recent original studies that revealed new insights into the frequency of and the risk factors associated with ICH. RESULTS: The incidence of ICH has not changed over the last 30 years, and this consistency is thought to be due to changes in the risk factor profiles of ICH patients. It appears that ICH is more common in men and during the winter months. ICH affects Asian populations more frequently than other populations. In addition to the known risk factors of hypertension and increasing age, alcohol consumption, the presence of the apolipoprotein epsilon2 or epsilon4 allele, extremes of body mass index, diabetes, and ophthalmic conditions have been suggested to be associated with ICH. Factors associated with a reduced risk of ICH include hypercholesterolaemia and a diet high in fruits and vegetables. CONCLUSIONS: The overall incidence of ICH has remained unchanged, but its regional incidence varies by race, sex, season and geographical location. In high income countries, the beneficial effect of improving blood pressure control may be counterbalanced by the increased use of antithrombotic drugs. Emerging modifiable risk factors include alcohol consumption, body mass index, diabetes, and fruit and vegetable intake, all of which may be amenable to interventions for the primary prevention of ICH (as well as many other diseases). PMID- 26588165 TI - Improving outcomes of acute myocarditis in children. AB - Acute viral myocarditis may impair prognosis in children of all ages. Its true incidence is underestimated because of heterogeneity of presentation and outcome. Patients may either recover or progress to chronic cardiomyopathy or death. Improving short-term and long-term prognosis is challenging but can probably be achieved by new diagnostic techniques and novel targeted therapies. The objectives of this review are: (1) to detail the current state of knowledge of the pathophysiological mechanisms of acute myocarditis; (2) to provide an update on diagnostic tools such as magnetic resonance imaging and endomyocardial biopsy; and (3) to present new insights in therapeutic strategies, targeted therapies and management of fulminant cases. Options for improving outcomes in acute myocarditis in the pediatric population are discussed. PMID- 26588166 TI - Highly Stretchable and Transparent Microfluidic Strain Sensors for Monitoring Human Body Motions. AB - We report a new class of simple microfluidic strain sensors with high stretchability, transparency, sensitivity, and long-term stability with no considerable hysteresis and a fast response to various deformations by combining the merits of microfluidic techniques and ionic liquids. The high optical transparency of the strain sensors was achieved by introducing refractive-index matched ionic liquids into microfluidic networks or channels embedded in an elastomeric matrix. The microfluidic strain sensors offer the outstanding sensor performance under a variety of deformations induced by stretching, bending, pressing, and twisting of the microfluidic strain sensors. The principle of our microfluidic strain sensor is explained by a theoretical model based on the elastic channel deformation. In order to demonstrate its capability of practical usage, the simple-structured microfluidic strain sensors were performed onto a finger, wrist, and arm. The highly stretchable and transparent microfluidic strain sensors were successfully applied as potential platforms for distinctively monitoring a wide range of human body motions in real time. Our novel microfluidic strain sensors show great promise for making future stretchable electronic devices. PMID- 26588167 TI - Ultra-Early Hemostatic Therapy for Intracerebral Hemorrhage: Future Directions. AB - Hematoma expansion after initial bleeding is associated with many risk factors, such as anticoagulation, diagnosis by computed tomography (CT) shortly after symptom onset, liver disease, and a high initial blood pressure, among others, and with increased mortality and poor long-term functional outcomes. Contrast extravasation on CT angiogram, termed 'the spot sign', and on delayed-contrast CT scans (13-59%) may help to identify impending intracerebral hemorrhage growth and may open a window of opportunity for therapeutic interventions. The spot sign score, the prediction score for hematoma expansion, and the BRAIN score were developed to assess the probability of hematoma expansion at 24 h. Therapeutic interventions to promote hemostasis are currently limited to intensive blood pressure control and antagonization of the effect of antiplatelets and anticoagulation. Ultra-early hemostasis for ICH not associated with coagulopathy may include administration of recombinant factor VIIa and tranexamic acid to selected patients based on the presence of a spot sign on the CT angiogram is currently under investigation. PMID- 26588169 TI - A review of the use of fiducial markers for image-guided bladder radiotherapy. AB - BACKGROUND: Enhancing target visualization and reducing set-up errors in image guided radiotherapy (IGRT) are issues faced when trying to implement more conformal and partial bladder techniques. This review examines the evidence available pertaining to the clinical use of Lipiodol and gold fiducials for IGRT for bladder cancer. MATERIAL AND METHODS: Nine published articles relating to the feasibility of using Lipiodol injections or gold fiducial markers in IGRT for bladder patients were recruited from a database search strategy. Set-up errors were evaluated in addition to the stability and visibility of each on verification imaging. Adverse reactions from the insertion of each method were also assessed. RESULTS: Both Lipiodol and gold fiducials have the potential to remain stable and visible in the bladder, however, fading, washout and seed loss was also reported. Set-up errors can be reduced by using Lipiodol or fiducial registration when compared to other registration techniques. Adverse reactions reported were minimal for each. CONCLUSION: Current evidence suggests that Lipiodol injections and gold fiducial markers present as promising and highly accurate methods of overcoming interfraction bladder motion in IGRT. PMID- 26588168 TI - Endothelial Ca 2+ oscillations reflect VEGFR signaling-regulated angiogenic capacity in vivo. AB - Sprouting angiogenesis is a well-coordinated process controlled by multiple extracellular inputs, including vascular endothelial growth factor (VEGF). However, little is known about when and how individual endothelial cell (EC) responds to angiogenic inputs in vivo. Here, we visualized endothelial Ca(2+) dynamics in zebrafish and found that intracellular Ca(2+) oscillations occurred in ECs exhibiting angiogenic behavior. Ca(2+) oscillations depended upon VEGF receptor-2 (Vegfr2) and Vegfr3 in ECs budding from the dorsal aorta (DA) and posterior cardinal vein, respectively. Thus, visualizing Ca(2+) oscillations allowed us to monitor EC responses to angiogenic cues. Vegfr-dependent Ca(2+) oscillations occurred in migrating tip cells as well as stalk cells budding from the DA. We investigated how Dll4/Notch signaling regulates endothelial Ca(2+) oscillations and found that it was required for the selection of single stalk cell as well as tip cell. Thus, we captured spatio-temporal Ca(2+) dynamics during sprouting angiogenesis, as a result of cellular responses to angiogenic inputs. PMID- 26588170 TI - Patterns of Dialysis Initiation Affect Outcomes of Incident Hemodialysis Patients. AB - AIMS: There is a trend toward deferring the initiation of chronic dialysis until absolutely indicated. This strategy, however, might lead to increased uncertainties in the timing of dialysis access creation prior to dialysis onset for patients approaching end-stage renal disease (ESRD), and the impact of which on hard end points remains largely unclear. We hereby investigated the effect of varied patterns of dialysis initiation on outcomes of new-onset hemodialysis (HD) patients. METHODS: Four hundred sixty-two prospectively recruited patients were stratified into planned elective (n = 117, 25%), planned urgent (n = 65, 14%) or unplanned urgent (n = 280, 61%) starters based on the timing of access creation with respect to dialysis initiation. The outcome measures were all-cause mortality, hospitalization and access reconstruction over 2 years. RESULTS: The mean estimated glomerular filtration rate (eGFR) was higher in the planned elective than in the planned urgent or unplanned urgent starters at access creation (5.3 vs. 4.4 or 4.3 ml/min/1.73 m2), but not at dialysis initiation (4.2 vs. 3.9 or 4.3 ml/min/1.73 m2). During the follow-up, the planned elective population exhibited the lowest rates of overall mortality and hospitalization, but not access reconstruction. Multivariate Cox's regression analysis showed that the planned urgent and the unplanned urgent groups, comparing to the planned elective population, displayed a greater risk of early death (hazards ratio [HR] 3.324, 95% CI 1.409-7.840; HR 2.510, 95% CI 1.177-5.355, respectively) and early hospitalization (sub-hazards ratio [SubHR] 2.238, 95% CI 1.530-3.274; SubHR 1.529, 95% CI 1.096-2.133, respectively). CONCLUSION: Incident ESRD patients undergoing planned elective start of HD, compared to their planned or unplanned urgent counterparts, showed reduced risk of overall mortality and hospitalization in the first 2 years after commencing long-term dialysis at a mean eGFR <5 ml/min/1.73 m2. PMID- 26588171 TI - Switchable Polymerization Catalysts. PMID- 26588172 TI - Cadmium and lead in animal tissue (muscle, liver and kidney), cow milk and dairy products in Korea. AB - A survey of Cd and Pb in animal tissue, milk and dairy products was conducted. Muscle, liver and kidney of domestically produced cows, pigs, chickens and ducks were collected from eight regions in Korea. Raw cow milk was collected from 9 regions, and imported dairy products (butter, cheese, cream and powdered milk) were collected from 15 countries. Cd and Pb were analysed by inductively coupled plasma mass spectrometry (ICP-MS) after microwave digestion. Concentrations of Cd and Pb did not exceed the Korean legal maximum levels in any of the samples. Correlation coefficients were estimated between concentration of Cd or Pb and animal age and between muscle, liver and kidney. In cows, there were good correlations between age and Cd in kidney (r = 0.748) and between Cd in liver and in kidney (r = 0.878). Continuous monitoring will be an important role to safeguard consumers in the event of a food contamination incident. PMID- 26588173 TI - High-Risk, Advanced-Stage Hodgkin Lymphoma: The Impact of Combined Escalated BEACOPP and ABVD Treatment in Patients Who Rapidly Achieve Metabolic Complete Remission on Interim FDG-PET/CT Scan. AB - The escalated BEACOPP (escBEACOPP) regimen improves the outcome of patients with advanced-stage Hodgkin lymphoma (HL) but is associated with cumbersome toxicity. We analyzed the survival outcome of high-risk, advanced-stage HL patients treated with response-adapted therapy. escBEACOPP was administered for 2 cycles, and after complete remission (CR) or partial remission (PR) was observed on FDG PET/CT, treatment was de-escalated to 4 cycles of ABVD. Sixty-nine patients were evaluated, of them 45 participated in the multicenter, phase II prospective study between 2001 and 2007. Sixty patients had an international prognostic score >=3. At a median follow-up of 5.6 years, 4 patients had died, 2 of them due to advanced HL. After the initial 2 cycles of escBEACOPP, 52 (75%) patients were in CR and 17 (25%) had a PR. Progression-free survival and overall survival (OS) were 79 and 93%, respectively. OS was predicted from the results of early-interim FDG-PET/CT: 98% of the patients in CR and 79% of those with a PR (p = 0.015). Hematological toxicity was more frequent during the first 2 cycles of escBEACOPP than in the ABVD phase. In conclusion, this retrospective analysis indicates that combined escBEACOPP-ABVD therapy is well tolerated and efficacious in HL patients who achieve negative early-interim PET results, while a positive PET result partially identified those with a worse prognosis. PMID- 26588174 TI - The size of the expressed HIV reservoir predicts timing of viral rebound after treatment interruption. AB - OBJECTIVES: Therapies to achieve sustained antiretroviral therapy-free HIV remission will require validation in analytic treatment interruption (ATI) trials. Identifying biomarkers that predict time to viral rebound could accelerate the development of such therapeutics. DESIGN: A pooled analysis of participants from six AIDS Clinical Trials Group ATI studies to identify predictors of viral rebound. METHODS: Cell-associated DNA (CA-DNA) and CA-RNA were quantified in pre-ATI peripheral blood mononuclear cell samples, and residual plasma viremia was measured using the single-copy assay. RESULTS: Participants who initiated antiretroviral therapy (ART) during acute/early HIV infection and those on a non-nucleoside reverse transcriptase inhibitor containing regimen had significantly delayed viral rebound. Participants who initiated ART during acute/early infection had lower levels of pre-ATI CA-RNA (acute/early vs. chronic-treated: median <92 vs. 156 HIV-1 RNA copies/10 CD4 cells, P < 0.01). Higher pre-ATI CA-RNA levels were significantly associated with shorter time to viral rebound (<=4 vs. 5-8 vs. >8 weeks: median 182 vs. 107 vs. <92 HIV-1 RNA copies/10 CD4 cells, Kruskal-Wallis P < 0.01). The proportion of participants with detectable plasma residual viremia prior to ATI was significantly higher among those with shorter time to viral rebound. CONCLUSION: Higher levels of HIV expression while on ART are associated with shorter time to HIV rebound after treatment interruption. Quantification of the active HIV reservoir may provide a biomarker of efficacy for therapies that aim to achieve ART-free HIV remission. PMID- 26588175 TI - Validation of a screening tool to identify older children living with HIV in primary care facilities in high HIV prevalence settings. AB - OBJECTIVE: We previously proposed a simple tool consisting of five items to screen for risk of HIV infection in adolescents (10-19 years) in Zimbabwe. The objective of this study is to validate the performance of this screening tool in children aged 6-15 years attending primary healthcare facilities in Zimbabwe. METHODS: Children who had not been previously tested for HIV underwent testing with caregiver consent. The screening tool was modified to include four of the original five items to be appropriate for the younger age range, and was administered. A receiver operator characteristic analysis was conducted to determine a suitable cut-off score. The sensitivity, specificity and predictive value of the modified tool were assessed against the HIV test result. RESULTS: A total of 9568 children, median age 9 (interquartile, IQR: 7-11) years and 4971 (52%) men, underwent HIV testing. HIV prevalence was 4.7% (95% confidence interval, CI:4.2-5.1%) and increased from 1.4% among those scoring zero on the tool to 63.6% among those scoring four (P < 0.001). Using a score of not less than one as the cut-off for HIV testing, the tool had a sensitivity of 80.4% (95% CI:76.5-84.0%), specificity of 66.3% (95% CI:65.3-67.2%), positive predictive value of 10.4% and a negative predictive value of 98.6%. The number needed to screen to identify one child living with HIV would drop from 22 to 10 if this screening tool was used. CONCLUSION: The screening tool is a simple and sensitive method to identify children living with HIV in this setting. It can be used by lay healthcare workers and help prioritize limited resources. PMID- 26588176 TI - Access to Cyclic Amino Boronates via Rhodium-Catalyzed Functionalization of Alkyl MIDA Boronates. AB - Herein, we describe the rhodium-catalyzed C-H amination reaction of 1,2-boryl sulfamate esters derived from amphoteric alpha-boryl aldehydes. Depending on the substitution pattern of the boryl sulfamate ester, a diverse range of five- or six-membered ring heterocycles are accessible using this transformation. The highly chemoselective nature of the C-H functionalization reaction preserves the alkyl boronate functional group, which enables the synthesis of B-C-N and B-C-C-N motifs that are present in a number of hydrolase inhibitors. PMID- 26588177 TI - Dealing with uncertainty in landscape genetic resistance models: a case of three co-occurring marsupials. AB - Landscape genetics lacks explicit methods for dealing with the uncertainty in landscape resistance estimation, which is particularly problematic when sample sizes of individuals are small. Unless uncertainty can be quantified, valuable but small data sets may be rendered unusable for conservation purposes. We offer a method to quantify uncertainty in landscape resistance estimates using multimodel inference as an improvement over single model-based inference. We illustrate the approach empirically using co-occurring, woodland-preferring Australian marsupials within a common study area: two arboreal gliders (Petaurus breviceps, and Petaurus norfolcensis) and one ground-dwelling antechinus (Antechinus flavipes). First, we use maximum-likelihood and a bootstrap procedure to identify the best-supported isolation-by-resistance model out of 56 models defined by linear and non-linear resistance functions. We then quantify uncertainty in resistance estimates by examining parameter selection probabilities from the bootstrapped data. The selection probabilities provide estimates of uncertainty in the parameters that drive the relationships between landscape features and resistance. We then validate our method for quantifying uncertainty using simulated genetic and landscape data showing that for most parameter combinations it provides sensible estimates of uncertainty. We conclude that small data sets can be informative in landscape genetic analyses provided uncertainty can be explicitly quantified. Being explicit about uncertainty in landscape genetic models will make results more interpretable and useful for conservation decision-making, where dealing with uncertainty is critical. PMID- 26588178 TI - Design of amine-functionalized metal-organic frameworks for CO2 separation: the more amine, the better? AB - A total of 41,825 metal-organic frameworks (MOFs) were computationally screened toward the design of amine-functionalized MOFs for CO2 separation. Both the optimal species and number of amine functional groups were examined for eight MOFs with good performance in terms of CO2 uptake and selectivity. It was revealed that more amine functional groups grafted on the MOFs do not lead to a better CO2 separation capability, and the concept of saturation degree of functional groups was proposed. The ethylene-diamine-functionalized MOF-74 membrane was predicted to possess high CO2 permeation separation capability, which was confirmed by the parallel experimental test of gas permeation. PMID- 26588179 TI - Impact of 2-, 4- and 9-valent HPV vaccines on morbidity and mortality from cervical cancer. AB - Cervical cancer causes significant morbidity and mortality worldwide. Most cervical cancers are associated with oncogenic human papillomavirus (HPV), and vaccination with any of 3 available HPV vaccines is anticipated to greatly reduce the burden of cervical cancer. This review provides an overview of the burden of HPV, the efficacy and clinical effectiveness of the bivalent (HPV 16, 18), quadrivalent (HPV 6, 11, 16, 18) and 9vHPV (HPV 6, 11, 16, 1831, 33, 45, 52, 58) vaccines in order to assess the anticipated impact on cervical cancer. All three vaccines show high efficacy in prevention of vaccine-specific HPV-type infection and associated high-grade cervical dysplasia in HPV-naive women. Early clinical effectiveness data for the bivalent and quadrivalent vaccine demonstrate reduced rates of HPV 16 and 18 prevalence in vaccinated cohorts; data evaluating cervical dysplasia and cervical procedures as outcomes will shed further light on the clinical effectiveness of both vaccines. The bivalent vaccine has demonstrated cross-protection to non-vaccine HPV types, including the types in the 9vHPV vaccine. No clinical effectiveness data is yet available for the 9vHPV vaccine. While HPV vaccination has great promise to reduce cervical cancer morbidity and mortality, estimated benefits are largely theoretical at present. Large population-based clinical effectiveness studies will provide long-term immunogenicity and effectiveness, as well as assessment of cervical cancer as an endpoint, particularly as young vaccinated women enter the appropriate age range to initiate screening for cervical cancer. Strengthening screening and treatment programs will likely have the greatest impact in the short-term on cervical cancer morbidity and mortality. PMID- 26588180 TI - Effect of interleukin-2 receptor antagonists on new-onset diabetes after liver transplantation: A retrospective cohort study. AB - BACKGROUND: The aim of the present retrospective observational study was to examine the effect of interleukin-2 receptor antagonists (IL-2Ra) on new-onset diabetes after transplantation (NODAT) in liver transplant recipients. METHODS: Pre- and postoperative clinical data of 781 patients undergoing liver transplantation between April 2001 and December 2014 at Zhongshan Hospital, Fudan University, were analyzed. Patients were divided into two groups depending on the use of IL-2Ra (IL-2Ra and non-IL-2Ra). The cumulative incidence of NODAT was compared between the IL-2Ra and non-IL-2Ra groups and the effect of IL-2Ra on the incidence of NODAT in liver transplant recipients was evaluated. RESULTS: Of the 781 patients in the study, 451 received IL-2Ra. During follow-up, 138 (41.8%) and 137 (30.4%) patients in the non-IL-2Ra and IL-2Ra groups, respectively, developed NODAT (P = 0.001). The cumulative incidence of NODAT at 1, 3, 5, and 8 years after transplantation in the IL-2Ra group was 30%, 38%, 45%, and 54%, respectively; these values were substantially lower than corresponding values for the non-IL-2Ra group (P < 0.05). Cox regression analyses showed that IL-2Ra was a protective factor against NODAT development (odds ratio 0.685; 95% confidence interval 0.473-0.991; P = 0.044). This was independent of age, sex, donor type, hepatitis virus infection, body mass index, history of hypertension, preoperative liver function, preoperative fasting plasma glucose, total cholesterol, and total triglyceride levels, severity of liver cirrhosis, acute rejection, initial immunosuppressant regimen type, and postoperative immunosuppressant levels. CONCLUSION: In conclusion, IL-2Ra reduces the risk of NODAT in liver transplant recipients. PMID- 26588181 TI - Sorption of polycyclic aromatic hydrocarbons to polystyrene nanoplastic. AB - Microplastic has become an emerging contaminant of global concern. Bulk plastic can degrade to form smaller particles down to the nanoscale (<100 nm), which are referred to as nanoplastics. Because of their high surface area, nanoplastic may bind hydrophobic chemicals very effectively, increasing their hazard when such nanoplastics are taken up by biota. The present study reports distribution coefficients for sorption of polycyclic aromatic hydrocarbons (PAHs) to 70 nm polystyrene in freshwater, and PAH adsorption isotherms spanning environmentally realistic aqueous concentrations of 10(-5) MUg/L to 1 MUg/L. Nanopolystyrene aggregate state was assessed using dynamic light scattering. The adsorption isotherms were nonlinear, and the distribution coefficients at the lower ends of the isotherms were very high, with values up to 10(9) L/kg. The high and nonlinear sorption was explained from pi-pi interactions between the planar PAHs and the surface of the aromatic polymer polystyrene and was higher than for micrometer-sized polystyrene. Reduction of nanopolystyrene aggregate sizes had no significant effect on sorption, which suggests that the PAHs could reach the sorption sites on the pristine nanoparticles regardless of the aggregation state. Pre-extraction of the nanopolystyrene with C18 polydimethylsiloxane decreased sorption of PAHs, which could be explained by removal of the most hydrophobic fraction of the nanopolystyrene. Environ Toxicol Chem 2016;35:1650-1655. (c) 2015 SETAC. PMID- 26588182 TI - Beyond the mean: A systematic review on the correlates of daily intraindividual variability of sleep/wake patterns. AB - Features of an individual's sleep/wake patterns across multiple days are governed by two dimensions, the mean and the intraindividual variability (IIV). The existing literature focuses on the means, while the nature and correlates of sleep/wake IIV are not well understood. A systematic search of records in five major databases from inception to November 2014 identified 53 peer-reviewed empirical publications that examined correlates of sleep/wake IIV in adults. Overall, this literature appeared unsystematic and post hoc, with under-developed theoretical frameworks and inconsistent methodologies. Correlates most consistently associated with greater IIV in one or more aspects of sleep/wake patterns were: younger age, non-White race/ethnicity, living alone, physical health conditions, higher body mass index, weight gain, bipolar and unipolar depression symptomatology, stress, and evening chronotype; symptoms of insomnia and poor sleep were associated with higher sleep/wake IIV, which was reduced following sleep interventions. The effects of experimentally reduced sleep/wake IIV on daytime functioning were inconclusive. In extending current understanding of sleep/wake patterns beyond the mean values, IIV should be incorporated as an additional dimension when sleep is examined across multiple days. Theoretical and methodological shortcomings in the existing literature, and opportunities for future research are discussed. PMID- 26588183 TI - Safety profile of etifoxine: A French pharmacovigilance survey. AB - Etifoxine chlorhydrate is a benzoxazine derivative approved for the treatment of psychosomatic manifestations of anxiety since 1979. Previously labeled adverse drug reactions (ADRs) only include drowsiness, benign cutaneous reactions, and acute hypersensitivity reactions. The objectives were to examine recent data on etifoxine-related ADR by reviewing Individual Case Safety Reports (ICSRs) recorded in France especially unexpected ADRs. Etifoxine-related ICSRs were extracted from the French Pharmacovigilance database from 1 January 2000 to 30 April 2012 and data from the marketing authorization holder up to 31 December 2011 were also obtained. Of the 350 cases retained for analysis, 123 (35%) were considered serious. Dermatological or acute hypersensitivity reactions were the most frequent ADRs (59%) mainly isolated cutaneous eruptions. However, there were 24 cases of severe toxidermia (DRESS in 5, erythema multiforme in 10 and Stevens Johnson syndrome in 5) with etifoxine as the most suspected drug in 11 patients, and seven cases of vasculitis or serum sickness-like reaction. Liver disorders were reported in 34 patients of whom 25 developed acute hepatitis with a cytolytic biological pattern in 16. Other unexpected ADRs included 16 reversible cases of metrorrhagia with positive rechallenge in 5, and three cases of biopsy proven microscopic colitis of which one recurred after etifoxine re administration. Although etifoxine has been marketed for more than 30 years, this survey identified a number of unexpected and sometimes serious ADRs, in particularly severe toxidermia and acute cytolytic hepatitis. A recent update of the French etifoxine summary of the product characteristics (SPC) was based on these findings. PMID- 26588184 TI - Stretching Impacts Inflammation Resolution in Connective Tissue. AB - Acute inflammation is accompanied from its outset by the release of specialized pro-resolving mediators (SPMs), including resolvins, that orchestrate the resolution of local inflammation. We showed earlier that, in rats with subcutaneous inflammation of the back induced by carrageenan, stretching for 10 min twice daily reduced inflammation and improved pain, 2 weeks after carrageenan injection. In this study, we hypothesized that stretching of connective tissue activates local pro-resolving mechanisms within the tissue in the acute phase of inflammation. In rats injected with carrageenan and randomized to stretch versus no stretch for 48 h, stretching reduced inflammatory lesion thickness and neutrophil count, and increased resolvin (RvD1) concentrations within lesions. Furthermore, subcutaneous resolvin injection mimicked the effect of stretching. In ex vivo experiments, stretching of connective tissue reduced the migration of neutrophils and increased tissue RvD1 concentration. These results demonstrate a direct mechanical impact of stretching on inflammation-regulation mechanisms within connective tissue. PMID- 26588185 TI - Smoking impairs and circulating stem cells favour the protective effect of the T allele of the connexin37 gene in ischemic heart disease--A multinational study. AB - BACKGROUND: The connexin 37 (Cx37) gene is considered to be a candidate gene for ischemic heart disease (IHD). We analyzed the association between the C1019 > T (Pro319 > Ser) variant of the Cx37 gene and IHD in patients in the Czech Republic, Croatia, Hungary and Romania with regard to the presence/absence of selected cardiovascular risk factors (RF). In a complementary study, we analyzed the association between the Cx37 gene and circulating stem and endothelial progenitor cells in healthy women. METHODS: The study population comprised 2396 patients (663 women) with IHD. The control population comprised 2476 subjects (1, 337 women). Additionally, in 662 healthy women, the association between the Cx37 gene and circulating stem and endothelial progenitor cells was analyzed. RESULTS: The strongest protective effect of the Cx37 T allele was detected in non-smoking patients without diabetes mellitus and hypertension (OR 0.610, 95% CI 0.377 0.990); a similar effect was found in non-smoking men (OR 0.781, 95% CI 0.628 0.971); weaker effect was found in non-smoking women (OR 0.768, 95% CI 0.560 1.050). In non-smoking healthy women, stem cells were significantly higher in TT than in CT and CC carriers (p for trend 0.011). Additionally, non-smoking TT carriers had significantly higher number of stem cells than past and current smoking TT carriers (p for trend = 0.006); no such trend was found in CT and CC carriers. CONCLUSIONS: The protective effect of the T allele of the Cx37 gene might be strongly modified by smoking; in women, this effect could be mediated through stem cells. PMID- 26588187 TI - Design of selective TACE inhibitors using molecular docking studies: Synthesis and preliminary evaluation of anti-inflammatory and TACE inhibitory activity. AB - Tumor necrosis factor-alpha (TNF-alpha) converting enzyme (TACE) has been considered one of the principal therapeutic targets for the treatment of TNF dependent pathologies. Several TACE inhibitors have been reported, but none of them has been successfully passed to phase II clinical trials. In the present work, we attempted to design highly selective new non-hydroxamate sulfonamide TACE inhibitors. The docking study was performed on one of the crystal structures of TACE, selected based on its resolution and R value, to tackle the flexibility issue of the active site. The results allowed us to distinguish the analogues with a higher binding affinity toward the active site of TACE and to identify the substituent of analogues needed for binding with the surrounding site of the enzyme. Finally the analogues were docked on crystal structures of six different matrix metalloproteinases (MMPs) for a selectivity study of TACE over MMPs. Some of these analogues were synthesized and subjected to preliminary testing for in vivo anti-inflammatory activity and TACE inhibitory activity. PMID- 26588186 TI - Humanized Mouse Models for Transplant Immunology. AB - Our understanding of the molecular pathways that control immune responses, particularly immunomodulatory molecules that control the extent and duration of an immune response, have led to new approaches in the field of transplantation immunology to induce allograft survival. These molecular pathways are being defined precisely in murine models and translated into clinical practice; however, many of the newly available drugs are human-specific reagents. Furthermore, many species-specific differences exist between mouse and human immune systems. Recent advances in the development of humanized mice, namely, immunodeficient mice engrafted with functional human immune systems, have led to the availability of a small animal model for the study of human immune responses. Humanized mice represent an important preclinical model system for evaluation of new drugs and identification of the mechanisms underlying human allograft rejection without putting patients at risk. This review highlights recent advances in the development of humanized mice and their use as preclinical models for the study of human allograft responses. PMID- 26588188 TI - Prevalence of Bruxism in Hemifacial-Spasm Patients. AB - PURPOSE: A previous study reported an increased prevalence of bruxism (25%) in patients with cranio-cervical dystonia (CCD) compared to normal controls (13%). CCD can affect the muscles of the head and neck. Besides the CCD affecting these muscles, hemifacial spasm (HFS) is a form of peripheral myoclonus due to a neurovascular conflict affecting the muscles of the face. The fact that they affect the same muscle regions could lead to other links in clinical manifestations such as bruxism, which is more common in patients with CCD than in the normal population. The aim was to study the prevalence of bruxism in patients with HFS. MATERIALS AND METHODS: Patients with HFS were enrolled in the department of clinical neurophysiology (Bordeaux University Hospital) over a 6 month period. They were paired regarding age, the absence of neurological pathology or neuroleptics intake. To be included in the study, patients needed to have had unilateral involuntary facial muscle contractions affecting one hemiface. A hetero-questionnaire and a clinicial study were performed. The diagnostic criteria of bruxism included parafunction items such as grinding and clenching and at least one of the following clinical signs: abnormal tooth wear, temporomandibular joint (TMJ) pain, TMJ clicking, muscle hypertonia (masseter or temporal muscles). Additional epidemiological data were collected including age, sex, disease duration, stress, and sleep disorders. Stress symptoms inventory included symptoms like depression, strong heartbeat, dry mouth, anger, inability to concentrate, weakness, fatigability, insomnia, headache, and excessive sweating. The sleep disorder diagnosis included at least two of the symptoms described in the ICSD-3. All these criteria were recorded as either present (scored "1") or absent (scored "0"). RESULTS: The prevalence of bruxism in the two groups (normal and HFS) was not significantly different (p = 0.37). The rate was not significantly different between sleep and awake bruxism (p = 0.15) in both groups. Stress influenced the occurrence of bruxism in these two groups (p < 0.001). CONCLUSION: The results of this study indicated that clenching behaviors were higher in the HFS group, and that factors such as stress affected this group. The prevalence of bruxism was not higher in this population than in the normal control. PMID- 26588189 TI - Multiphosphine-Oxide Hosts for Ultralow-Voltage-Driven True-Blue Thermally Activated Delayed Fluorescence Diodes with External Quantum Efficiency beyond 20. AB - Highly efficient low-voltage-driven -true-blue thermally activated -delayed fluorescence diodes are realized through employing a tri-phosphine oxide host (2,2',4-tris(di(phenyl) -phosphoryl)-diphenylether (DPETPO)) with a record external quantum efficiency of 23.0% and the lowest onset voltage of 2.8 V to date. PMID- 26588191 TI - Simulating Valence-to-Core X-ray Emission Spectroscopy of Transition Metal Complexes with Time-Dependent Density Functional Theory. AB - Valence-to-core (VtC) X-ray emission spectroscopy (XES) has emerged as a powerful technique for the structural characterization of complex organometallic compounds in realistic environments. Since the spectrum represents electronic transitions from the ligand molecular orbitals to the core holes of the metal centers, the approach is more chemically sensitive to the metal-ligand bonding character compared with conventional X-ray absorption techniques. In this paper we study how linear-response time-dependent density functional theory (LR-TDDFT) can be harnessed to simulate K-edge VtC X-ray emission spectra reliably. LR-TDDFT allows one to go beyond the single-particle picture that has been extensively used to simulate VtC-XES. We consider seven low- and high-spin model complexes involving chromium, manganese, and iron transition metal centers. Our results are in good agreement with experiment. PMID- 26588190 TI - Structure-Activity Relationships of Novel Tryptamine-Based Inhibitors of Bacterial Transglycosylase. AB - Penicillin-binding proteins represent well-established, validated, and still very promising targets for the design and development of new antibacterial agents. The transglycosylase domain of penicillin-binding proteins is especially important, as it catalyzes polymerization of glycan chains, using the peptidoglycan precursor lipid II as a substrate. On the basis of the previous discovery of a noncovalent small-molecule inhibitor of transglycosylase activity, we systematically explored the structure-activity relationships of these tryptamine based inhibitors. The main aim was to reduce the nonspecific cytotoxic properties of the initial hit compound and concurrently to retain the mode of its inhibition. A focused library of tryptamine-based compounds was synthesized, characterized, and evaluated biochemically. The results presented here show the successful reduction of the nonspecific cytotoxicity, and the retention of the inhibition of transglycosylase enzymatic activity, as well as the ability of these compounds to bind to lipid II and to have antibacterial actions. PMID- 26588192 TI - Bisthiadiazole-Fused Tetraazapentacenequinone: An Air-Stable Solution-Processable n-Type Organic Semiconductor. AB - The synthesis and characterization of a tetraazapentacenequinone fused to two thiadiazoles is reported. This linear derivative constituting seven fused rings shows a very low LUMO level (-4.46 eV) and a low HOMO-LUMO gap (1.77 eV). Its high solubility, endowed by four triisopropylsilyl groups, allows the fabrication of air-stable field-effect transistors by liquid deposition methods that show electron mobilities up to 2.42 * 10(-3) cm(2) V(-1) s(-1) without any device optimization. PMID- 26588194 TI - A scoring framework for assessing anatomy competence of undergraduate preclinical students. AB - Recent higher education changes toward outcomes-based education emphasize competent learners, but a widely accepted definition of competence is still lacking. Although the importance of anatomy in health professions education is recognized, there is still uncertainty about what anatomical competence entails and how to assess it. This study aimed to provide a framework for assessing anatomical competence, using an anatomy competence score, for the anatomy course in the undergraduate medical learning program at the University of the Free State in South Africa. All assessments within the dissection program of two student groups (July 2012 to June 2014) were explored to determine the representation of the three competence domains: knowledge, skill and application in context. Student performance in the final objective structured practical examination (OSPE) was investigated for the three domains and the different body regions. Knowledge had +/-50% representation in assessments and the different body regions (in final OSPE) for both groups, and skill and application represented +/-25% each in both groups. The best average student performance was in the skill domain (64% and 67% for the respective groups). All domains showed good reliabilities (> 0.75) and student performance correlated well between the domains (P < 0.001). This study suggests a representation ratio of 2:1:1 between knowledge, skill and application (i.e., 50% knowledge and 25% skill and application respectively), for anatomical competence assessment. However, this ratio depends on the assessment type, the stage of the anatomy course and the institutional context. Nonetheless, it provides a guideline for ensuring that assessments address all competence domains. Anat Sci Educ 9: 319-329. (c) 2015 American Association of Anatomists. PMID- 26588193 TI - beta2 -microglobulin normalization within 6 months of ibrutinib-based treatment is associated with superior progression-free survival in patients with chronic lymphocytic leukemia. AB - BACKGROUND: A high pretreatment beta2 -microglobulin (B2M) level is associated with inferior survival outcomes in patients with chronic lymphocytic leukemia. However, to the authors' knowledge, the prognostic and predictive significance of changes in B2M during treatment have not been reported to date. METHODS: The authors analyzed 83 patients treated with ibrutinib-based regimens (66 with recurrent/refractory disease) and 198 treatment-naive patients who were treated with combined fludarabine, cyclophosphamide, and rituximab (FCR) to characterize changes in B2M and their relationship with clinical outcomes. RESULTS: B2M rapidly decreased during treatment with ibrutinib; on multivariable analysis, patients who received FCR (odds ratio, 0.40; 95% confidence interval [95% CI], 0.18-0.90 [P = .027]) were less likely to have normalized B2M at 6 months than patients treated with ibrutinib. On univariable analysis, normalization of B2M was associated with superior progression-free survival (PFS) from the 6-month landmark in patients treated with ibrutinib-based regimens and FCR. On multivariable analysis, failure to achieve normalized B2M at 6 months of treatment was associated with inferior PFS (hazard ratio, 16.9; 95% CI, 1.3-220.0 [P = .031]) for patients treated with ibrutinib, after adjusting for the effects of baseline B2M, stage of disease, fludarabine-refractory disease, and del(17p). In contrast, in patients treated with FCR, negative minimal residual disease status in the bone marrow was the only variable found to be significantly associated with superior PFS (hazard ratio, 0.28; 95% CI, 0.12-0.67 [P = .004]). CONCLUSIONS: Normalization of B2M at 6 months in patients treated with ibrutinib was found to be a useful predictor of subsequent PFS and may assist in clinical decision-making. PMID- 26588195 TI - Role of executive functions in prospective memory in multiple sclerosis: Impact of the strength of cue-action association. AB - OBJECTIVES: Patients diagnosed with multiple sclerosis (MS) often report prospective memory (PM) deficits. Although PM is important for daily functioning, it is not formally assessed in clinical practice. The aim of this study was to examine the role of executive functions in MS patients' PM revealed by the effect of strength of cue-action association on PM performance. METHOD: Thirty-nine MS patients were compared to 18 healthy controls matched for age, gender, and education on a PM task modulating the strength of association between the cue and the intended action. RESULTS: Deficits in MS patients affecting both prospective and retrospective components of PM were confirmed using 2 * 2 * 2 mixed analyses of variance (ANOVAs). Among patients, multiple regression analyses revealed that the impairment was modulated by the efficiency of executive functions, whereas retrospective memory seemed to have little impact on PM performance, contrary to expectation. More specifically, results of 2 * 2 * 2 mixed-model analyses of covariance (ANCOVAs) showed that low-executive patients had more difficulty detecting and, especially, retrieving the appropriate action when the cue and the action were unrelated, whereas high-executive patients' performance seemed to be virtually unaffected by the cue-action association. CONCLUSIONS: Using an objective measure, these findings confirm the presence of PM deficits in MS. They also suggest that such deficits depend on executive functioning and can be reduced when automatic PM processes are engaged through semantic cue-action association. They underscore the importance of assessing PM in clinical settings through a cognitive evaluation and offer an interesting avenue for rehabilitation. PMID- 26588196 TI - Paracetamol decreases steady-state exposure to lamotrigine by induction of glucuronidation in healthy subjects. AB - AIM: Patients receiving lamotrigine therapy frequently use paracetamol concomitantly. While one study suggests a possible, clinically relevant drug-drug interaction, practical recommendations of the concomitant use are inconsistent. We performed a systematic pharmacokinetic study in healthy volunteers to quantify the effect of 4 day treatment with paracetamol on the metabolism of steady-state lamotrigine. METHODS: Twelve healthy, male volunteers participated in an open label, sequential interaction study. Lamotrigine was titrated to steady-state (100 mg daily) over 36 days, and blood and urine sampling was performed in a non randomized order with and without paracetamol (1 g four times daily). The primary endpoint was change in steady-state area under the plasma concentration-time curve of lamotrigine. Secondary endpoints were changes in total apparent oral clearance, renal clearance, trough concentration of lamotrigine and formation clearance of lamotrigine glucuronide conjugates. RESULTS: Co-administration of lamotrigine and paracetamol decreased the steady-state area under the plasma concentration-time curve of lamotrigine by 20% (95% CI 10%, 25%; P < 0.001) from 166 to 127 MUmol l(-1) . Concomitant administration of paracetamol increased the formation clearance of lamotrigine glucuronide conjugates by 45% (95% CI 18%, 79%, P = 0.005) from 1.7 to 2.8 l h(-1) , while the trough value of lamotrigine was reduced by 25% (95% CI 12%, 36%, P = 0.003) from 5.3 to 3.9 MUmol l(-1) . CONCLUSION: Paracetamol statistically significantly induced steady-state lamotrigine glucuronidation, resulting in a 20% decrease in total systemic exposure and a 25% decrease in trough value of lamotrigine. This interaction may be of clinical relevance in some patients. PMID- 26588197 TI - Relationship Dynamics and Sexual Risk Reduction Strategies Among Heterosexual Young Adults: A Qualitative Study of Sexually Transmitted Infection Clinic Attendees at an Urban Chicago Health Center. AB - Few studies have examined risk-reduction alternatives to consistent condom use for HIV prevention among heterosexual young adults. We used qualitative methodology to explore risk reduction strategies and contextual factors influencing attempts to reduce risk in an urban, high morbidity sexually transmitted infection (STI) clinic. Focus groups were conducted October-December 2014 with heterosexually identified men (n = 13) and women (n = 20) aged 18-29 seeking STI screening at an urban clinic. Groups were audio recorded, transcribed verbatim, and analyzed for thematic content using Atlas.ti software. Quantitative information included sociodemographics, HIV/STI testing history, and 6-month sexual behaviors. Among 33 predominantly African-American participants with a median age of 22, risk-reduction strategies included monogamy agreements, selective condom use with casual and high-risk partners, and frequent HIV/STI testing, though testing was commonly used as a post-hoc reassurance after risk exposure. Many men and women used implicit risk assessment strategies due to mistrust or difficulty communicating. Concurrency was common but rarely discussed within partnerships. Despite attempts to reduce risk, monogamy agreements were often poorly adhered to and not openly discussed. Alcohol and substance use frequently interfered with safer sexual decisions. Participants were aware of HIV/STI risk and commonly practiced risk-reduction strategies, but acknowledged faulty assumptions and poor adherence. This work provides insights into risk reduction approaches that are already used and may be strengthened as part of effective HIV/STI prevention interventions. PMID- 26588199 TI - Phytoremediation of petroleum hydrocarbons by using a freshwater fern species Azolla filiculoides Lam. AB - In this study, the phytoremediation capacity of Azolla filiculoides Lam. for the water resources contaminated with petroleum hydrocarbons was investigated. The plants were grown in nitrogen-free Hoagland nutrient solution containing 0.005%, 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, and 0.5% crude oil under greenhouse conditions for 15 days. Although the growth rate of the plants were not negatively influenced by the presence of crude oil in the media for the concentration of 0.005% and 0.01% v/v, a gradual impeding effect of crude oil in the growth media has been observed at concentrations 0.05-0.1%. More than 0.1% crude oil in the growth medium ostensibly retarded the growth. For example, 0.2% oil in the media reduced growth approximately 50% relative to the control, and the presence of crude oil at concentrations 0.3% or more were lethal. The data about the percentage of plant growth, fresh weight increase and root growth clearly indicated that the tolerance level of A. filiculoides plants to crude oil ranges between 0.1% and 0.2%. In comparison to control samples, the biodegradation rate of total aliphatic and aromatic (phenathrene) hydrocarbons at 0.05-0.2% oil concentrations, was 94-73% and 81-77%, respectively. On the other hand, in case of further increases in oil concentration in media, i.e.; 0.3-0.5%, the biodegradation rate was still higher in the experimental samples, respectively 71-63% and 75-71%. The high biodegradation rates of petroleum hydrocarbons in the experimental samples suggested that A. filiculoides plants could be a promising candidate to be used for the phytoremediation of low crude oil contaminated precious freshwater resources. PMID- 26588198 TI - Characterization of a genetically engineered mouse model of hemophilia A with complete deletion of the F8 gene. AB - ESSENTIALS: Anti-factor VIII (FVIII) inhibitory antibody formation is a severe complication in hemophilia A therapy. We genetically engineered and characterized a mouse model with complete deletion of the F8 coding region. F8(TKO) mice exhibit severe hemophilia, express no detectable F8 mRNA, and produce FVIII inhibitors. The defined background and lack of FVIII in F8(TKO) mice will aid in studying FVIII inhibitor formation. BACKGROUND: The most important complication in hemophilia A treatment is the development of inhibitory anti-Factor VIII (FVIII) antibodies in patients after FVIII therapy. Patients with severe hemophilia who express no endogenous FVIII (i.e. cross-reacting material, CRM) have the greatest incidence of inhibitor formation. However, current mouse models of severe hemophilia A produce low levels of truncated FVIII. The lack of a corresponding mouse model hampers the study of inhibitor formation in the complete absence of FVIII protein. OBJECTIVES: We aimed to generate and characterize a novel mouse model of severe hemophilia A (designated the F8(TKO) strain) lacking the complete coding sequence of F8 and any FVIII CRM. METHODS: Mice were created on a C57BL/6 background using Cre-Lox recombination and characterized using in vivo bleeding assays, measurement of FVIII activity by coagulation and chromogenic assays, and anti-FVIII antibody production using ELISA. RESULTS: All F8 exonic coding regions were deleted from the genome and no F8 mRNA was detected in F8(TKO) mice. The bleeding phenotype of F8(TKO) mice was comparable to E16 mice by measurements of factor activity and tail snip assay. Similar levels of anti-FVIII antibody titers after recombinant FVIII injections were observed between F8(TKO) and E16 mice. CONCLUSIONS: We describe a new C57BL/6 mouse model for severe hemophilia A patients lacking CRM. These mice can be directly bred to the many C57BL/6 strains of genetically engineered mice, which is valuable for studying the impact of a wide variety of genes on FVIII inhibitor formation on a defined genetic background. PMID- 26588200 TI - Liberation of fermentable sugars from soybean hull biomass using ionic liquid 1 butyl-3-methylimidazolium acetate and their bioconversion to ethanol. AB - Optimized hydrolysis of lignocellulosic waste biomass is essential to achieve the liberation of sugars to be used in fermentation process. Ionic liquids (ILs), a new class of solvents, have been tested in the pretreatment of cellulosic materials to improve the subsequent enzymatic hydrolysis of the biomass. Optimized application of ILs on biomass is important to advance the use of this technology. In this research, we investigated the effects of using 1-butyl-3 methylimidazolium acetate ([bmim][Ac]) on the decomposition of soybean hull, an abundant cellulosic industrial waste. Reaction aspects of temperature, incubation time, IL concentration, and solid load were optimized before carrying out the enzymatic hydrolysis of this residue to liberate fermentable glucose. Optimal conditions were found to be 75 degrees C, 165 min incubation time, 57% (mass fraction) of [bmim][Ac], and 12.5% solid loading. Pretreated soybean hull lost its crystallinity, which eased enzymatic hydrolysis, confirmed by Fourier Transform Infrared analysis. The enzymatic hydrolysis of the biomass using an enzyme complex from Penicillium echinulatum liberated 92% of glucose from the cellulose matrix. The hydrolysate was free of any toxic compounds, such as hydroxymethylfurfural and furfural. The obtained hydrolysate was tested for fermentation using Candida shehatae HM 52.2, which was able to convert glucose to ethanol at yields of 0.31. These results suggest the possible use of ILs for the pretreatment of some lignocellulosic waste materials, avoiding the formation of toxic compounds, to be used in second-generation ethanol production and other fermentation processes. (c) 2015 American Institute of Chemical Engineers Biotechnol. Prog., 32:312-320, 2016. PMID- 26588201 TI - Single-port laparoscopic Hartmann reversal through the stoma site - a video vignette. PMID- 26588202 TI - Behaviour of radiocaesium in coastal rivers of the Fukushima Prefecture (Japan) during conditions of low flow and low turbidity--Insight on the possible role of small particles and detrital organic compounds. AB - To investigate riverine transfers from contaminated soils of the Fukushima Prefecture in Japan to the marine environment, suspended sediments, filtered water, sediments and detrital organic macro debris deposited onto river beds were collected in November 2013 within small coastal rivers during conditions of low flow rates and low turbidity. River waters were directly filtered on the field and high efficiency well-type Ge detectors were used to analyse radiocaesium concentrations in very small quantities of suspended particles and filtered water (a few mg to a few g). For such base-flow conditions, our results show that the watersheds studied present similar hydro-sedimentary behaviours at their outlets and that the exports of dissolved and particulate radiocaesium are comparable. Moreover, the contribution of these rivers to the instantaneous export of radiocaesium to the ocean is similar to that of the Abukuma River. Our preliminary results indicate that, in the estuaries, radiocaesium concentrations in suspended sediments would be reduced by more than 80%, while radiocaesium concentration in filtered waters would be maintained. Significant correlations between radiocaesium concentrations and radiocaesium inventories in the soils of the catchments indicate that there was at that time little intra and inter watershed variability in the transfer processes of radiocaesium from lands to rivers at this regional scale. The apparent liquid-solid partition coefficient (KD) values acquired for the lowest loads/finest particles complement the values acquired by using sediment traps and highlight the strong capacity of the smallest particles to transfer radiocaesium. Finally, but not least, our observations suggest that there could be a significant transfer of highly contaminated detrital biomass from forest litter to the downstream rivers in a rather conservative way. PMID- 26588203 TI - 3D cardiac MUtissues within a microfluidic device with real-time contractile stress readout. AB - We present the development of three-dimensional (3D) cardiac microtissues within a microfluidic device with the ability to quantify real-time contractile stress measurements in situ. Using a 3D patterning technology that allows for the precise spatial distribution of cells within the device, we created an array of 3D cardiac microtissues from neonatal mouse cardiomyocytes. We integrated the 3D micropatterning technology with microfluidics to achieve perfused cell-laden structures. The cells were encapsulated within a degradable gelatin methacrylate hydrogel, which was sandwiched between two polyacrylamide hydrogels. The polyacrylamide hydrogels were used as "stress sensors" to acquire the contractile stresses generated by the beating cardiac cells. The cardiac-specific response of the engineered 3D system was examined by exposing it to epinephrine, an adrenergic neurotransmitter known to increase the magnitude and frequency of cardiac contractions. In response to exogenous epinephrine the engineered cardiac tissues exhibited an increased beating frequency and stress magnitude. Such cost effective and easy-to-adapt 3D cardiac systems with real-time functional readout could be an attractive technological platform for drug discovery and development. PMID- 26588204 TI - A Manganese Alternative to Gadolinium for MRI Contrast. AB - Contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) are routinely used to diagnose soft tissue and vascular abnormalities. However, safety concerns limit the use of iodinated and gadolinium (Gd)-based CT and MRI contrast media in renally compromised patients. With an estimated 14% of the US population suffering from chronic kidney disease (CKD), contrast media compatible with renal impairment is sorely needed. We present the new manganese(II) complex [Mn(PyC3A)(H2O)](-) as a Gd alternative. [Mn(PyC3A)(H2O)](-) is among the most stable Mn(II) complexes at pH 7.4 (log KML = 11.40). In the presence of 25 mol equiv of Zn at pH 6.0, 37 degrees C, [Mn(PyC3A)(H2O)](-) is 20-fold more resistant to dissociation than [Gd(DTPA)(H2O)](2-). Relaxivity of [Mn(PyC3A)(H2O)](-) in blood plasma is comparable to commercial Gd contrast agents. Biodistribution analysis confirms that [Mn(PyC3A)(H2O)](-) clears via a mixed renal/hepatobiliary pathway with >99% elimination by 24 h. [Mn(PyC3A)(H2O)](-) was modified to form a bifunctional chelator and 4 chelates were conjugated to a fibrin-specific peptide to give Mn-FBP. Mn-FBP binds the soluble fibrin fragment DD(E) with Kd = 110 nM. Per Mn relaxivity of Mn-FBP is 4 fold greater than [Mn(PyC3A)(H2O)](-) and increases 60% in the presence of fibrin, consistent with binding. Mn-FBP provided equivalent thrombus enhancement to the state of the art Gd analogue, EP-2104R, in a rat model of arterial thrombosis. Mn metabolite analysis reveals no evidence of dechelation and the probe was >99% eliminated after 24 h. [Mn(PyC3A)(H2O)](-) is a lead development candidate for an imaging probe that is compatible with renally compromised patients. PMID- 26588205 TI - Secondary Orbital Reconstruction in Patients with Prior Orbital Fracture Repair. AB - PURPOSE: To evaluate clinical characteristics, preoperative imaging findings, pre and post-operative outcomes, and satisfaction of patients requiring secondary reconstruction after inadequate primary orbital fracture repair. METHODS: Retrospective review of 13 patients requiring secondary orbital reconstruction following unsatisfactory primary repair. Primary outcomes were postoperative changes in enophthalmos, hypo- or hyper-globus, superior sulcus deformity, and restrictive strabismus. Secondary outcomes included patient satisfaction. RESULTS: Of 13 patients, 9 patients had primary orbital implants, and 4 patients did not. Of the 9 with implants, 6 had inferior displacement posteriorly, 2 had superior displacement posteriorly, and 1 had good position but had entrapped orbital tissues beneath it. Findings from primary surgery included enophthalmos (12/13), hypoglobus (10/13), hyperglobus (1/13), superior sulcus deformity (9/13), restricted supraduction (12/13), and restricted infraduction (7/13). Mean preoperative enophthalmos and hypoglobus were 4.4 +/- 2.6 mm and 2.9 +/- 1.4 mm, respectively. Secondary reconstruction resulted in mean reduction of enophthalmos by 3.4 +/- 1.4 mm (p < 0.001), of hypoglobus by 2.9 +/- 1.5 mm (p < 0.001), and of hyperglobus by 1 mm (n = 1). All 9 patients had resolution of their superior sulcus deformity. Of 12 cases with restricted ocular motility, all had improvements in postoperative motility following secondary surgery. Mean improvement in supraduction and infraduction was 1.8 +/- 1.0 points (p < 0.001) and 1.4 +/- 1.3 points (p = 0.025), respectively. Twelve patients reported being very satisfied or satisfied with secondary surgery; 1 patient was neutral. CONCLUSIONS: This study demonstrates that secondary orbital reconstruction can achieve excellent functional and cosmetic results with high patient satisfaction and minimal complications. Secondary reconstruction of previously repaired orbital fractures should be considered when clinically indicated. PMID- 26588206 TI - Simultaneous Versus Staged Balanced Decompression for Thyroid-Related Compressive Optic Neuropathy. AB - PURPOSE: To compare the visual and exophthalmometry outcomes of simultaneous versus staged balanced decompression in patients with thyroid-related compressive optic neuropathy (CON). METHODS: All consecutive patients who underwent simultaneous or staged balanced decompressions for clinically diagnosed thyroid related CON performed by 4 surgeons at the Kellogg Eye Center of the University of Michigan between 1999 and 2014 were included in the study. Demographic, medical, and surgical covariates were collected. Orbits were stratified by decompression technique. Primary outcomes were improvement in CON score (which quantifies visual dysfunction using logarithm of the minimum angle of resolution, color vision, and Humphrey visual field mean deviation), and improvement in proptosis. The authors performed univariate and descriptive statistics to identify baseline differences and covariates associated with the outcomes of interest; multivariate mixed linear regression models (to adjust for interorbit correlation) were then constructed with inclusion of potential confounders with p value <=0.1. RESULTS: In total, 80 orbits of 53 patients were included in the study. Of the 80 orbits, 61% underwent simultaneous balanced decompression, and 39% underwent staged balanced decompression. Mean CON score reduction was 6.12 +/ 9.7 and mean proptosis reduction was 5.63 +/- 2.6 mm. Staged balanced decompression was significantly associated with greater CON score reduction (p = 0.038). However, staged (vs. simultaneous) decompression technique did not remain an independent predictor (p = 0.950) after multivariate analysis adjusted for confounders. For proptosis reduction, there were no statistically significant differences between simultaneous and staged balanced decompression on univariate (p = 0.122) or multivariate mixed linear regression models (p = 0.812). CONCLUSION: Simultaneous and staged balanced decompression are equally efficacious in treating visual dysfunction and exophthalmos due to thyroid eye disease in patients with clinically diagnosed CON. Patient choice should be the primary consideration and care should be individualized. Further studies validating the CON score used in the study and comparative studies individualizing surgical treatment of thyroid eye disease are warranted. PMID- 26588207 TI - A Case of a Bilateral Cicatricial Upper Eyelid Entropion After Hematopoietic Stem Cell Transplantation in Mucopolysaccharidosis Type I. AB - Minor eyelid abnormalities are commonly encountered in mucopolysaccharidosis, but only rarely leading to a clinically relevant situation. The authors report a clinical case of severe bilateral cicatricial entropion of the upper eyelids, leading to recurrent conjunctival infections, corneal erosion, persistent epiphora, and a major decline in life quality in a 7-year-old boy with mucopolysaccharidosis type I who underwent hematopoietic stem cell transplantation at 1.6 years old. A bilateral anterior lamellar repositioning including eyelid split and cryoepilation was performed to correct bilateral upper eyelid entropium and trichiasis. Three months after the surgical intervention, the patient showed a persistent regular eyelid position with only mild recurrent right-sided lateral upper eyelid entropion. A significant reduction in conjunctival infections and epiphora with complete discontinuation of topical therapy was achieved. Although mucopolysaccaridosis is associated with eyelid abnormalities, the authors conclude that the described case is most likely due to chronic graft versus host disease. PMID- 26588208 TI - Microbiology and Biofilm Trends of Silicone Lacrimal Implants: Comparing Infected Versus Routinely Removed Stents. AB - PURPOSE: To investigate the pathogens and biofilms responsible for clinically significant infection of silicone stents implanted within the lacrimal system. METHODS: Retrospective review of culture results and patient demographics for all silicone lacrimal stents removed early for clinically significant infection and sent to the Bascom Palmer Microbiology Laboratory through the end of year 2010. As a control, routinely removed, clinically noninfected stents from the same institution were prospectively sent for culture over a 6-month period. Four clinically infected and 6 clinically noninfected stents showing mucus within the lumen at removal were sent for scanning electron microscopy. Images were randomized and graded by a microbiologist for the presence of organisms, matrix deposits, organisms within matrix, and overall impression of significant biofilm formation. RESULTS: Nineteen stents were included in the study; 100% of clinically infected (n = 10) and noninfected (n = 9) stents were culture positive. Culture positivity for nontuberculous mycobacterium was found in 90% of infected stents and none of the noninfected stents (p < 0.001). Of infected stents, 50% grew Gram-positive organisms compared with 89% of noninfected stents (p = 0.07). Fifty percent of infected versus 67% of noninfected stents were culture positive for Gram-negative organisms (p = 0.46). Electron microscopy of stents revealed organisms consistent with culture results (size, shape) in planktonic and biofilm form. Masked observer image grading revealed a statistically significant higher amount of organism and biofilm on infected versus noninfected specimen. CONCLUSION: Nontuberculous mycobacteria comprise the primary pathogens responsible for clinically significant infection of silicone stents in the lacrimal system in South Florida. Robust biofilm production by this organism likely plays a role in pathogenesis. Further research into biofilm related lacrimal implant infection may aid in the development of useful prevention and treatment strategies. PMID- 26588209 TI - The Use of Multiplex PCR to Determine the Prevalence of Enterotoxigenic Staphylococcus aureus Isolated from Raw Milk, Feta Cheese, and Hand Swabs. AB - Staphylococcus aureus (S. aureus) can cause mastitis in cattle and, therefore, can be present in milk. This study was undertaken to determine the prevalence of coagulase positive S. aureus and its enterotoxin genes sea, seb, and sec in isolates recovered from raw milk, feta cheese, and human hand swabs of milk and cheese handlers in Beni-Suef province, Egypt. A total of 100 samples of raw milk and 50 samples of pasteurized-milk feta cheese were collected. In addition, 50 hand swabs from milk handlers and 25 hand swabs from cheese handlers were examined for the presence of coagulase positive S. aureus. The isolates were characterized by multiplex PCR for detection of sea, seb, and sec genes, and for resistance to 5 classes of commonly used antibiotics. Twelve (12/100), 12 (6/50), and 17% (13/75) of milk, cheese, and hand swab samples, respectively, were positive for coagulase positive S. aureus. One isolate was obtained from each positive sample (31 isolates), and none contained genes for SEA or SEC production. Twenty-five percent, 33%, and 31%, respectively, of the isolates contained the genes for SEB, resulting in 3%, 4%, and 5% of samples being positive for toxin producing coagulase positive S. aureus, respectively. At least one isolate was resistant to each of the antibiotics tested. Despite the low potential for SEB production shown, preventative measures, such as maintenance of the cold-chain and good hygienic practices should be implemented to further reduce the potential risk to public health from SEB, and to reduce the spread of antimicrobial resistance. PMID- 26588210 TI - Use of Cytokeratin-19 Concentration to Assess Early Recurrence and Prognosis of Hepatitis B Virus-Related Hepatocellular Carcinoma following Radical Resection in Patients with a Low Serum Alpha-Fetoprotein Concentration. AB - Cytokeratin 19 (CK-19) is a prognostic indicator of recurrence and metastasis of hepatocellular carcinoma (HCC) following radical resection. To investigate the role of CK-19 in assessment of early recurrence and prognosis in patients with hepatitis B virus (HBV)-related HCC following radical resection. In total, 235 patients with HBV-related HCC (age, 15-82 years; mean age, 54 +/- 10 years) undergoing radical resection were screened for inclusion from January 2005 to December 2010. Malignant tissues and adjacent non-malignant tissues were sampled during surgery, and CK-19 and Ki-67 expression was determined by tissue microarray and immunohistochemistry. CK-19 mRNA levels in 30 randomly selected frozen HCC specimens were examined by reverse transcription polymerase chain reaction from January 2011 to June 2011. Correlations of CK-19 and Ki-67 expression with tumor recurrence, metastasis, disease-free survival (DFS), and overall survival (OS) were analyzed. Elevated CK-19 expression was correlated with early recurrence (P = 0.001), shorter DFS (P = 0.001), and reduced OS (P = 0.010). CK-19 expression was correlated with the Ki-67 index (P = 0.037), histological differentiation (P = 0.016), focal number (P = 0.044), and blood vessel tumor embolism (P = 0.002). Patients with metastasis within 1 year exhibited stronger CK-19 expression than did patients without metastasis (P < 0.05). Furthermore, early recurrence was associated with elevated CK-19 mRNA levels (chi2 = 5.761, P = 0.016).When confirmed by a low alpha-fetoprotein concentration (<400 MUg/L), CK-19 expression in surgical biopsy specimens taken from patients with HCC during radical resection is an additional valuable indicator of early recurrence, distant metastasis, and poor prognosis in HBV positive patients. PMID- 26588212 TI - A lack of alpha1A-adrenergic receptor-mediated antidepressant-like effects of S (+)-niguldipine and B8805-033 in the forced swim test. AB - The alpha1-adrenergic receptors (alpha1-ARs), which belong to a G protein-coupled receptor family, consist of three highly homologous subtypes known as alpha1A ARs, alpha1B-ARs, and alpha1D-ARs. Our previous findings suggested that alpha1A ARs are an important target for imipramine and electroconvulsive therapy. The current study sought to evaluate whether S-(+)-niguldipine and B8805-033, two selective antagonists of alpha1A-ARs, can evoke antidepressant-like effects in the forced swim test in rats. Both compounds were administered at three time points (24, 5, and 1 h before testing), and the effects of three doses (2, 5, and 10 mg/kg) of each compound were investigated. S-(+)-Niguldipine produced no antidepressant-like effects other than a 14% reduction in immobility time at the highest dose. Although B8805-033 at a dose of 2 mg/kg did not influence the rats' behavior, higher B8805-033 doses (5 and 10 mg/kg) produced significant reductions in immobility time (approximately 42 and 44% vs. controls, respectively; P<0.01). However, this effect was abolished by the concomitant administration of WAY100135, a serotonin receptor antagonist, suggesting that the observed antidepressant-like effects of B8805-033 are unrelated to alpha1A-ARs. Nevertheless, given the current dearth of selective alpha1A-AR agonists, the question of whether this particular subtype could be involved in antidepressant therapy mechanisms remains unresolved. PMID- 26588211 TI - Conserved piRNA Expression from a Distinct Set of piRNA Cluster Loci in Eutherian Mammals. AB - The Piwi pathway is deeply conserved amongst animals because one of its essential functions is to repress transposons. However, many Piwi-interacting RNAs (piRNAs) do not base-pair to transposons and remain mysterious in their targeting function. The sheer number of piRNA cluster (piC) loci in animal genomes and infrequent piRNA sequence conservation also present challenges in determining which piC loci are most important for development. To address this question, we determined the piRNA expression patterns of piC loci across a wide phylogenetic spectrum of animals, and reveal that most genic and intergenic piC loci evolve rapidly in their capacity to generate piRNAs, regardless of known transposon silencing function. Surprisingly, we also uncovered a distinct set of piC loci with piRNA expression conserved deeply in Eutherian mammals. We name these loci Eutherian-Conserved piRNA cluster (ECpiC) loci. Supporting the hypothesis that conservation of piRNA expression across ~100 million years of Eutherian evolution implies function, we determined that one ECpiC locus generates abundant piRNAs antisense to the STOX1 transcript, a gene clinically associated with preeclampsia. Furthermore, we confirmed reduced piRNAs in existing mouse mutations at ECpiC-Asb1 and -Cbl, which also display spermatogenic defects. The Asb1 mutant testes with strongly reduced Asb1 piRNAs also exhibit up-regulated gene expression profiles. These data indicate ECpiC loci may be specially adapted to support Eutherian reproduction. PMID- 26588214 TI - The effect of daily small text message reminders for medicine compliance amongst young people connected with the outpatient department for child and adolescent psychiatry. A controlled and randomized investigation. AB - BACKGROUND: Many patients with psychiatric illnesses have difficulty maintaining medication over time. Many take their medicine irregularly and studies show that it is the most vulnerable patients who have the greatest problems adhering to treatment. Often only 50% are still under medical treatment after 6 months. AIM: In this study we investigated whether text message reminders could improve medicine compliance amongst vulnerable young people with psychiatric disorders who were being treated in the outpatient department for child and adolescent psychiatry and who either are under or were to commence medicinal treatment. METHODS: This study was conducted as a randomized controlled trial including all non-acute referrals to an outpatient department for adolescent psychiatry within a group aged 15-20 years starting medical treatment. The patients were followed until the end of their treatment, for a minimum of 3 months. To enhance medicine compliance, text messages were sent daily to one group. No message was sent to the other group. RESULTS: Compliance was not associated with text message intervention in any of the drug interventions. The effect size was calculated to 0.3013, which is low and therefore indicates a weak association between text message and compliance. The power in this study was calculated to 0.3539, which is also low and therefore the likelihood of finding significant association is low. CONCLUSION: This study does not show increased medicine compliance from the text message intervention group. The conclusion of this study is that it is essential that significant resources are spent preparing and testing a text message strategy. PMID- 26588213 TI - Pharmacological modulation of neuropathic pain-related depression of behavior: effects of morphine, ketoprofen, bupropion and [INCREMENT]9-tetrahydrocannabinol on formalin-induced depression of intracranial self-stimulation in rats. AB - Neuropathic pain is often associated with behavioral depression. Intraplantar formalin produces sustained, neuropathy-associated depression of intracranial self-stimulation (ICSS) in rats. This study evaluated pharmacological modulation of formalin-induced ICSS depression. Rats with intracranial electrodes targeting the medial forebrain bundle responded for electrical brain stimulation in an ICSS procedure. Bilateral intraplantar formalin administration depressed ICSS for 14 days. Morphine (0.32-3.2 mg/kg), ketoprofen (0.1-10 mg/kg), bupropion (3.2-32 mg/kg), and [INCREMENT]9-tetrahydrocannabinol (THC; 0.32-3.2 mg/kg) were evaluated for their effectiveness to reverse formalin-induced depression of ICSS. Drug effects on formalin-induced mechanical allodynia were evaluated for comparison. Morphine and bupropion reversed both formalin-induced ICSS depression and mechanical allodynia, and effects on ICSS were sustained during repeated treatment. Ketoprofen failed to reverse either formalin effect. THC blocked mechanical allodynia, but decreased ICSS in control rats and exacerbated formalin induced depression of ICSS. The failure of ketoprofen to alter formalin effects suggests that formalin effects result from neuropathy rather than inflammation. The effectiveness of morphine and bupropion to reverse formalin effects agrees with other evidence that these drugs block pain-depressed behavior in rats and relieve neuropathic pain in humans. The effects of THC suggest general behavioral suppression and do not support the use of THC to treat neuropathic pain. PMID- 26588215 TI - Stably Doped Conducting Polymer Nanoshells by Surface Initiated Polymerization. AB - Despite broad applications ranging from electronics to biomedical sensing and imaging, a long-standing problem of conducting polymers is the poor resistance to dedoping, which directly affects their signature electrical and optical properties. This problem is particularly significant for biomedical uses because of fast leaching of dopant ions in physiological environments. Here, we describe a new approach to engineer multimodal core-shell nanoparticles with a stably doped conductive polymer shell in biological environments. It was achieved by making a densely packed polymer brush rather than changing its molecular structure. Polyaniline (PANI) was used as a model compound due to its concentrated near-infrared (NIR) absorption. It was grafted onto a magnetic nanoparticle via a polydopamine intermediate layer. Remarkably, at pH 7 its conductivity is ca. 2000* higher than conventional PANI nanoshells. Similarly, its NIR absorption is enhanced by 2 orders of magnitude, ideal for photothermal imaging and therapy. Another surprising finding is its nonfouling property, even outperforming polyethylene glycol. This platform technology is also expected to open exciting opportunities in engineering stable conductive materials for electronics, imaging, and sensing. PMID- 26588216 TI - Global Analysis of the Fungal Microbiome in Cystic Fibrosis Patients Reveals Loss of Function of the Transcriptional Repressor Nrg1 as a Mechanism of Pathogen Adaptation. AB - The microbiome shapes diverse facets of human biology and disease, with the importance of fungi only beginning to be appreciated. Microbial communities infiltrate diverse anatomical sites as with the respiratory tract of healthy humans and those with diseases such as cystic fibrosis, where chronic colonization and infection lead to clinical decline. Although fungi are frequently recovered from cystic fibrosis patient sputum samples and have been associated with deterioration of lung function, understanding of species and population dynamics remains in its infancy. Here, we coupled high-throughput sequencing of the ribosomal RNA internal transcribed spacer 1 (ITS1) with phenotypic and genotypic analyses of fungi from 89 sputum samples from 28 cystic fibrosis patients. Fungal communities defined by sequencing were concordant with those defined by culture-based analyses of 1,603 isolates from the same samples. Different patients harbored distinct fungal communities. There were detectable trends, however, including colonization with Candida and Aspergillus species, which was not perturbed by clinical exacerbation or treatment. We identified considerable inter- and intra-species phenotypic variation in traits important for host adaptation, including antifungal drug resistance and morphogenesis. While variation in drug resistance was largely between species, striking variation in morphogenesis emerged within Candida species. Filamentation was uncoupled from inducing cues in 28 Candida isolates recovered from six patients. The filamentous isolates were resistant to the filamentation-repressive effects of Pseudomonas aeruginosa, implicating inter-kingdom interactions as the selective force. Genome sequencing revealed that all but one of the filamentous isolates harbored mutations in the transcriptional repressor NRG1; such mutations were necessary and sufficient for the filamentous phenotype. Six independent nrg1 mutations arose in Candida isolates from different patients, providing a poignant example of parallel evolution. Together, this combined clinical-genomic approach provides a high-resolution portrait of the fungal microbiome of cystic fibrosis patient lungs and identifies a genetic basis of pathogen adaptation. PMID- 26588220 TI - Journal of Forensic Nursing 2014 Articles of the Year. PMID- 26588218 TI - Volunteerism and Forensic Nurses. PMID- 26588217 TI - Ultrasound-Assisted Thoracic Paravertebral Block Reduces Intraoperative Opioid Requirement and Improves Analgesia after Breast Cancer Surgery: A Randomized, Controlled, Single-Center Trial. AB - OBJECTIVES: The contribution of ultrasound-assisted thoracic paravertebral block to postoperative analgesia remains unclear. We compared the effect of a combination of ultrasound assisted-thoracic paravertebral block and propofol general anesthesia with opioid and sevoflurane general anesthesia on volatile anesthetic, propofol and opioid consumption, and postoperative pain in patients having breast cancer surgery. METHODS: Patients undergoing breast cancer surgery were randomly assigned to ultrasound-assisted paravertebral block with propofol general anesthesia (PPA group, n = 121) or fentanyl with sevoflurane general anesthesia (GA group, n = 126). Volatile anesthetic, propofol and opioid consumption, and postoperative pain intensity were compared between the groups using noninferiority and superiority tests. RESULTS: Patients in the PPA group required less sevoflurane than those in the GA group (median [interquartile range] of 0 [0, 0] vs. 0.4 [0.3, 0.6] minimum alveolar concentration [MAC] hours), less intraoperative fentanyl requirements (100 [50, 100] vs. 250 [200, 300]MUg,), less intense postoperative pain (median visual analog scale score 2 [1, 3.5] vs. 3 [2, 4.5]), but more propofol (median 529 [424, 672] vs. 100 [100, 130] mg). Noninferiority was detected for all four outcomes; one-tailed superiority tests for each outcome were highly significant at P<0.001 in the expected directions. CONCLUSIONS: The combination of propofol anesthesia with ultrasound-assisted paravertebral block reduces intraoperative volatile anesthetic and opioid requirements, and results in less post operative pain in patients undergoing breast cancer surgery. TRIAL REGISTRATION: ClinicalTrial.gov NCT00418457. PMID- 26588221 TI - The Life Pattern of Incarcerated Women: The Complex and Interwoven Lives of Trauma, Mental Illness, and Substance Abuse. AB - PROBLEM: The fastest growing population in the U.S. prisons consists of women whose rate rose nearly twice that of men (Sipes, 2012). Incarcerated women are oftentimes victims of abuse and have high reported rates of mental illness and substance abuse, yet their life pattern is not well understood. PURPOSE: The purpose of the study was to develop the life pattern of incarcerated women to gain a better understanding of the life situations that have led to their incarceration and gain a better understanding of their needs during their imprisonment. METHOD: In-depth interviews were conducted with 18 incarcerated women. Margaret Newman's (1994) Theory of Health as Expanding Consciousness was used as the theoretical framework and research method to develop the community pattern. FINDINGS: The life pattern that evolved for the women was a complex and interwoven life filled with childhood trauma, mental illness, substance abuse, unhealthy relationships, and disorganized family situations that led to the women's incarceration. The women gained a better understanding of their pathway to prison. IMPLICATIONS: Correctional nurses are in a unique position to address the traumas women in prison have experienced and to assist them with the healing process. Addressing the traumas the women have endured could improve their health and better prepare them for release from prison. PMID- 26588222 TI - An Introspective Approach to Nursing Intimate Partner Violence Victims in Japan. AB - BACKGROUND AND AIMS: The number of intimate partner violence (IPV) cases has been increasing in Japan since the 1990s. Many victims tend to hide their victimization and conceal their clinic or hospital visits. In these cases, nurses face feelings of incongruity toward patients. We aimed to explore if the process of introspection can provide better care for patients who have experienced IPV and prevent burnout in nurses. We hypothesized that introspection training would have a positive effect on nursing interventions. METHODS: We interviewed Japanese nurses who handled IPV cases between 2006 and 2009 and analyzed responses on the Emotional Question Scale (EQS). We used a modified grounded theory approach to analyze narratives from 20 nurses. RESULTS: We found that nurses experienced difficulties in coping with their incongruence toward patients, did not always feel capable of IPV care, and lacked experience in caring for patients experiencing IPV. Introspection training did not lead to significant differences in EQS scores, although scores on the self-management, interpersonal management, and situation management subscales were correlated significantly. This indicated that utilizing the introspection process would result in EQS improvement. CONCLUSION: We concluded that the process of objectification of incongruity is effective in detecting hidden IPV and helpful in identifying negative feelings, thus preventing burnout in nurses. PMID- 26588223 TI - Engaging the Voice of Patients Affected by Gender-Based Violence: Informing Practice and Policy. AB - INTRODUCTION: Evidence regarding the benefits, opportunities, and risks associated with providing health care to patients experiencing gender-based violence (GBV) and, moreover, their satisfaction with health care services is sparse. METHOD: Using a patient- and trauma-informed relationship-based framework, survivors of GBV who were referred for follow-up care were asked to participate in a quality improvement (QI) initiative in an effort to understand their perspectives of receiving healthcare services. Patients were asked to answer three open-ended questions in regard to their healthcare experience. Individuals who were eligible for evidence collection after sexual assault (<5 days) were asked two additional questions. RESULTS: Of the 353 women and six men (359) referred to the C.A.R.E. (Coordinated Approach to Recovery and Empowerment) Clinic, 327 patients were contacted. Of the participants, 24% (86) had a mental health diagnosis; 41% (145) reported their incident to the police; 8% (28) had comorbidities of substance abuse, mental health, and/or homelessness; and 33% (118) of the incidents involved alcohol or drugs. Most of the patients stated that they were well cared for and felt safe during their visit. However, many reported "long waits," "disjointed," "chaotic," "too many" providers, "conflicting" and "miss-information," and "confusion" about what to do after their acute care visit. Over half (59%) did not report incident to the police. Some reported regrets with reporting to the police (16%) and regrets in having evidence collection (15%). Of the patients who did not have evidence collected (47), none expressed regret over choosing not to have evidence collected. Five patients with mental health problems were hospitalized within 5 days of their emergency department visit for suicidal thoughts. CONCLUSIONS: A number of opportunities to improve the healthcare response were identified. Patients affected by GBV require an improved coordinated and trauma-informed approach. Explicit consent related to evidence collection is needed. Not all patients who have been sexually assaulted should have evidence collected. More extensive research and program evaluation including outcomes research are warranted. PMID- 26588225 TI - Identification and Functional Analysis of the Nocardithiocin Gene Cluster in Nocardia pseudobrasiliensis. AB - Nocardithiocin is a thiopeptide compound isolated from the opportunistic pathogen Nocardia pseudobrasiliensis. It shows a strong activity against acid-fast bacteria and is also active against rifampicin-resistant Mycobacterium tuberculosis. Here, we report the identification of the nocardithiocin gene cluster in N. pseudobrasiliensis IFM 0761 based on conserved thiopeptide biosynthesis gene sequence and the whole genome sequence. The predicted gene cluster was confirmed by gene disruption and complementation. As expected, strains containing the disrupted gene did not produce nocardithiocin while gene complementation restored nocardithiocin production in these strains. The predicted cluster was further analyzed using RNA-seq which showed that the nocardithiocin gene cluster contains 12 genes within a 15.2-kb region. This finding will promote the improvement of nocardithiocin productivity and its derivatives production. PMID- 26588226 TI - Fast and unintentional evaluation of emotional sounds: evidence from brief segment ratings and the affective Simon task. AB - In the present study, we raised the question of whether valence information of natural emotional sounds can be extracted rapidly and unintentionally. In a first experiment, we collected explicit valence ratings of brief natural sound segments. Results showed that sound segments of 400 and 600 ms duration-and with some limitation even sound segments as short as 200 ms-are evaluated reliably. In a second experiment, we introduced an auditory version of the affective Simon task to assess automatic (i.e. unintentional and fast) evaluations of sound valence. The pattern of results indicates that affective information of natural emotional sounds can be extracted rapidly (i.e. after a few hundred ms long exposure) and in an unintentional fashion. PMID- 26588227 TI - Anti-inflammatory Effects of Poly-L-lysine in Intestinal Mucosal System Mediated by Calcium-Sensing Receptor Activation. AB - Calcium-sensing receptor (CaSR) is involved in maintaining cellular homeostasis and promoting recovery of damaged intestinal epithelial cells (IECs). Poly-L lysine (PL) is a basic polypeptide identified for its role in the activation of CaSR through allosteric binding. The primary goal of the current study was to identify the modulatory effect of PL on intestinal inflammation and to determine whether these effects were mediated by CaSR activation. We used human intestinal epithelial cell lines, Caco-2 and HT-29, to assess PL anti-inflammatory activities in vitro. We found that PL reduced the IL-8 secretion from tumor necrosis factor (TNF)-alpha-treated human intestinal epithelial cell lines. On the other hand, the gene expression of pro-inflammatory cytokines TNF-alpha, IL 6, and IL-1beta was inhibited by PL supplementation. We subsequently evaluated the anti-inflammatory activity of PL in vivo using a DSS-induced mouse colitis model. PL supplementation was shown to prevent dextran sulfate sodium salt (DSS) induced loss of weight, colitic symptoms, and shortening of colon length but maintained colonic morphology. The pro-inflammatory cytokine expression in the mouse colon, including TNF-alpha, IL-6, INF-gamma, IL-17, and IL-1beta, was significantly up-regulated by DSS treatment, but was inhibited upon PL administration. As shown by the results from both in vitro and in vivo studies, the reduction of inflammatory cytokine production caused by PL was reversed by NPS-2143 pretreatment. In the present study, we provide evidence that PL exerts anti-inflammatory effects on the gut system, which is primarily mediated by allosteric ligand activation of CaSR. PMID- 26588228 TI - MALDI-TOF Mass Spectrometry for Multilocus Sequence Typing of Escherichia coli Reveals Diversity among Isolates Carrying blaCMY-2-Like Genes. AB - Effective surveillance and management of pathogenic Escherichia coli relies on robust and reproducible typing methods such as multilocus sequence typing (MLST). Typing of E. coli by MLST enables tracking of pathogenic clones that are known to carry virulence factors or spread resistance, such as the globally-prevalent ST131 lineage. Standard MLST for E. coli requires sequencing of seven alleles, or a whole genome, and can take several days. Here, we have developed and validated a nucleic-acid-based MALDI-TOF mass spectrometry (MS) method for MLST as a rapid alternative to sequencing that requires minimal operator expertise. Identification of alleles was 99.6% concordant with sequencing. We employed MLST by MALDI-TOF MS to investigate diversity among 62 E. coli isolates from Sydney, Australia, carrying a blaCMY-2-like gene on an IncI1 plasmid to determine whether any dominant clonal lineages are associated with the spread of this globally disseminated resistance gene. Thirty-four known sequence types were identified, including lineages associated with human disease, animal and environmental sources. This suggests that the dissemination of blaCMY-2-like-genes is more complex than the simple spread of successful pathogenic clones. E. coli MLST by MALDI-TOF MS, employed here for the first time, can be utilised as an automated tool for large-scale population analyses or for targeted screening for known high risk clones in a diagnostic setting. PMID- 26588230 TI - Uterine Papillary Serous Carcinoma: A Single-Institution Review of 62 Cases. AB - OBJECTIVE: Uterine papillary serous carcinoma (UPSC) is a rare variant of endometrial carcinoma responsible for up to 40% of endometrial cancer deaths. Controversy remains regarding optimal adjuvant therapy for UPSC, with lack of randomized trials to date. The objective of this retrospective study was to evaluate clinicopathological factors and determine event-free survival and overall survival (OS) in patients with UPSC managed within a single institution. MATERIALS AND METHODS: Medical and pathological records between 1987 and 2004 were reviewed at the Royal Women's Hospital, Melbourne, Australia. Cox regression analysis was used to analyze effects of clinical and histopathological variables on patient survival and survival times following adjuvant therapy. Event-free survival and OS were analyzed using the Kaplan-Meier survival curve. RESULTS: Sixty-two patients were included; 96.8% were managed surgically and 56.5% were completely surgically staged. Myoinvasion was present in 72.6% (n = 45) of the patients.In patients with stage I disease, recurrence rate was 41.4% with a 5 year OS of 46%. In stage II, recurrence rate was 20% with a 5-year OS of 67%. In stage III, recurrence rate was 58.8% with a 5-year OS of 34%. In stage IV, recurrence rate was 71.4% with a 5-year OS of 29%.There was no significant difference in survival based on the presence of positive peritoneal cytology, positive lymphovascular space invasion or positive lymph nodes at diagnosis, and no significant difference in survival based on the type of adjuvant therapy administered. Depth of myometrial invasion was a significant determinant of poor prognosis (P = 0.027). CONCLUSIONS: Uterine papillary serous carcinoma is an aggressive variant of endometrial cancer associated with a high proportion of advanced-stage disease at diagnosis, high recurrence rates, and low OS. In our patients, prognosis was determined by myometrial invasion and International Federation of Gynecology and Obstetrics stage at diagnosis. Randomized trials in this area are required to clarify optimal adjuvant therapy for patients with UPSC. PMID- 26588229 TI - Shaking the Tree: Multi-locus Sequence Typing Usurps Current Onchocercid (Filarial Nematode) Phylogeny. AB - During the past twenty years, a number of molecular analyses have been performed to determine the evolutionary relationships of Onchocercidae, a family of filarial nematodes encompassing several species of medical or veterinary importance. However, opportunities for broad taxonomic sampling have been scarce, and analyses were based mainly on 12S rDNA and coxI gene sequences. While being suitable for species differentiation, these mitochondrial genes cannot be used to infer phylogenetic hypotheses at higher taxonomic levels. In the present study, 48 species, representing seven of eight subfamilies within the Onchocercidae, were sampled and sequences of seven gene loci (nuclear and mitochondrial) analysed, resulting in the hitherto largest molecular phylogenetic investigation into this family. Although our data support the current hypothesis that the Oswaldofilariinae, Waltonellinae and Icosiellinae subfamilies separated early from the remaining onchocercids, Setariinae was recovered as a well separated clade. Dirofilaria, Loxodontofilaria and Onchocerca constituted a strongly supported clade despite belonging to different subfamilies (Onchocercinae and Dirofilariinae). Finally, the separation between Splendidofilariinae, Dirofilariinae and Onchocercinae will have to be reconsidered. PMID- 26588232 TI - A Randomized Controlled Pilot Study Comparing the Impact of Aprepitant and Fosaprepitant on Chemotherapy Induced Nausea and Vomiting in Patients Treated for Gynecologic Cancer. AB - OBJECTIVE: The purpose of this pilot study was to compare the response rates and daily living activities of patients with newly diagnosed gynecologic cancer treated with fosaprepitant or aprepitant in the management of chemotherapy induced nausea and vomiting. METHODS AND MATERIALS: Eligible participants were randomized to either intravenous fosaprepitant (150 mg, day 1) or oral aprepitant (125 mg on day 1 and 80 mg on days 2-3) before undergoing weekly paclitaxel (80 mg/2)(2) and monthly carboplatin (AUC 6)-based chemotherapy. In addition, standard premedications (eg, ranitidine, dexamethasone, and diphenhydramine) were administered intravenously on day 1. Response evaluation and impact on daily life were measured throughout the acute phase (0-24 hours), delayed period (days 2-4), and overall phase (0-120 hours) of the patients' initial chemotherapy cycle via the Functional Living Index-Emesis. RESULTS: In the current investigation, 20 gynecologic cancer subjects were treated with either fosaprepitant (n = 10) or aprepitant (n = 10) before their first chemotherapy cycle. We observed 7 overall complete responses (70%, no emetic episodes or rescue medications) in the aprepitant group and 6 (60%) in the fosaprepitant cohort (P = 0.660). In addition, both treatment groups reported similarly, favorable rates of daily living activities throughout the acute (P = 0.626) and delayed (P = 0.648) phases of cycle 1 chemotherapy. CONCLUSIONS: The findings from the current analysis suggest that intravenous fosaprepitant and oral aprepitant confer beneficial antiemetic prevention. Moreover, the 2 medications theoretically afford a favorable impact on daily living, thereby potentially facilitating the completion of a patient's clinically prescribed chemotherapy regimen. PMID- 26588231 TI - Clinical Use of Cancer Biomarkers in Epithelial Ovarian Cancer: Updated Guidelines From the European Group on Tumor Markers. AB - OBJECTIVE: To present an update of the European Group on Tumor Markers guidelines for serum markers in epithelial ovarian cancer. METHODS: Systematic literature survey from 2008 to 2013. The articles were evaluated by level of evidence and strength of recommendation. RESULTS: Because of its low sensitivity (50-62% for early stage epithelial ovarian cancer) and limited specificity (94-98.5%), cancer antigen (CA) 125 (CA125) is not recommended as a screening test in asymptomatic women. The Risk of Malignancy Index, which includes CA125, transvaginal ultrasound, and menopausal status, is recommended for the differential diagnosis of a pelvic mass. Because human epididymis protein 4 has been reported to have superior specificity to CA125, especially in premenopausal women, it may be considered either alone or as part of the risk of ovarian malignancy algorithm, in the differential diagnosis of pelvic masses, especially in such women. CA125 should be used to monitor response to first-line chemotherapy using the previously published criteria of the Gynecological Cancer Intergroup, that is, at least a 50% reduction of a pretreatment sample of 70 kU/L or greater. The value of CA125 in posttherapy surveillance is less clear. Although a prospective randomized trial concluded that early administration of chemotherapy based on increasing CA125 levels had no effect on survival, European Group on Tumor Markers state that monitoring with CA125 in this situation should occur, especially if the patient is a candidate for secondary cytoreductive surgery. CONCLUSIONS: At present, CA125 remains the most important biomarker for epithelial ovarian cancer, excluding tumors of mucinous origin. PMID- 26588233 TI - Synchronous Primary Cancers of the Endometrium and Ovary With the Same Histopathologic Type Versus Endometrial Cancer With Ovarian Metastasis: A Single Institution Review of 72 Cases. AB - OBJECTIVE: The purpose of this study was to evaluate the clinicopathological characteristics and survival outcomes of women with simultaneous endometrial and ovarian carcinomas having the same histopathologic type. MATERIALS AND METHODS: A review of medical records from 1997 to 2015 identified 72 patients with simultaneous carcinomas of the endometrium and ovary with the same histopathologic type. Patients with synchronous primary cancers of endometrium and ovary (SCEOs) were compared with patients with primary endometrial cancer with ovarian metastasis (ECOM). Clinical and pathological data were obtained from the patients' medical records. Clinicopathological variables including categorical data were analyzed by chi(2) or Fisher exact test and continuous data by a Student t test. A Kaplan-Meier survival analysis was performed and compared by using the log-rank test. RESULTS: A univariate and multivariate analysis of 72 patients with SCEO with the same histopathologic type revealed that SCEO is an independent prognostic factor of 10-year overall survival. There were 31 patients in the SCEO group and 41 patients in the ECOM group. With a mean follow-up time of 68.2 months, the 10-year overall survival rates were 61.3% and 36.6% in SCEO and ECOM groups, respectively (P = 0.029). Age, menopausal status, stage of ovarian cancer, performing lymphadenectomy, grade of endometrial tumor, omental metastasis, and residual tumor were found to be significant risk factors for recurrence in the synchronous group. CONCLUSIONS: The differentiation between SCEO and ECOM is of great clinical importance while our results showed a better prognosis for patients with SCEO compared with patients with ECOM. More aggressive therapeutic approaches may be considered for patients with SCEO who are older, postmenopausal, and/or have advanced grade of endometrial tumor, omental metastasis, and residual tumor. Lymphadenectomy should be performed in every patient with SCEO. PMID- 26588234 TI - Endometrial Cancer Survivors' Perceptions of Provider Obesity Counseling and Attempted Behavior Change: Are We Seizing the Moment? AB - OBJECTIVE: To determine patients' perceptions of provider-based counseling and behavior changes made by endometrial cancer survivors. MATERIALS AND METHODS: Endometrial cancer survivors (diagnosed from 2011 to 2012) from a single institution were surveyed. Exclusion criteria included persistent or recurrent disease or those actively undergoing treatment. Information collected included demographics, weight assessments, health behaviors, and physician counseling. Statistical analysis was performed using descriptive statistics, Fisher exact test, McNemar test, and the kappa statistic as a measure of agreement. RESULTS: Of 233 surveys sent, 46% were returned. Median body mass index was 29.8 kg/m (range, 17.1-64.8 kg/m). Comparing primary care providers with gynecologic oncologists (GOs), 47% (n = 46) versus 25% (n = 23) provided dietary counseling and 62% (n = 60) versus 37% (n = 34) provided physical activity counseling (Fisher exact test, P = 0.001 and P < 0.001, respectively). Only 29% (n = 30) reported being told of the link between endometrial cancer and obesity. Fifty-two percent of responders attempted weight loss after their diagnosis. Fifty-nine percent of responders reported making changes in their diet. Fifty-six percent of patients made dietary changes within 3 months of diagnosis. Forty-eight percent of responders increased physical activity, with 62% implementing changes within 3 to 6 months of their diagnosis. The responders most likely to attempt weight loss were those who received counseling by a provider. All patients reporting attempted weight loss after their cancer diagnosis report being counseled by either a primary care provider or a GO to lose weight. Weight loss counseling was significantly associated with attempting weight loss (P < 0.001). CONCLUSIONS: One third of endometrial cancer survivors report counseling by their GO to lose weight. One half of endometrial cancer survivors reported attempted weight loss. All patients reporting weight loss counseling from their oncologist reported attempted weight loss. Most behavioral change occurred 3 to 6 months after a cancer diagnosis. Obesity in endometrial cancer survivors is not adequately addressed and represents a critical area for improvement. PMID- 26588235 TI - Use of Metformin in Obese Women With Type I Endometrial Cancer Is Associated With a Reduced Incidence of Cancer Recurrence. AB - OBJECTIVES: Recent evidence suggests that hyperinsulinemia associated with obesity may be a significant risk factor for the development of endometrial cancer. Metformin is used in type II diabetes to lower circulating insulin levels. We sought to examine our obese patients with endometrial cancer and examine those who were on metformin to determine any impact on their cancer course. METHODS: A retrospective review of all women with the diagnosis of endometrial cancer and a body mass index of 30 kg/m(2) or higher during a 6-year period (2005-2011) at our institution was conducted. Records were reviewed for standard demographic data, use of metformin, cancer characteristics, treatment, and cancer follow-up. RESULTS: A total of 351 women were identified who were obese and diagnosed as having endometrial cancer. Of these, 64 were on metformin (M+) at the time of diagnosis of endometrial cancer. The women on metformin had a significantly higher mean body mass index (44.6 vs 41.6, P < 0.05). Age, grade, stage, and adjuvant therapy did not differ between the 2 groups. Recurrence occurred in 15.3% of the M- women versus 7.8% of the M+ women (not significant). However, for those patients with type I endometrial cancer, only 1 patient (1.9%) who was on metformin recurred versus 10.3% who were not on the drug (P = 0.05). With a minimum of 24 months of follow-up, 89.1% of metformin users were alive and free of disease versus 83.9% of nonusers (not significant). CONCLUSIONS: Obese women who developed endometrial cancer while on metformin did not seem to have pathologic risk factors different from those not on metformin. However, the type I cancer patients on metformin were less likely to recur than those not on the drug. This suggests that a prospective trial of metformin at the time of diagnosis of endometrial cancer in the obese population may be warranted. PMID- 26588236 TI - Pazopanib Maintenance Therapy in East Asian Women With Advanced Epithelial Ovarian Cancer: Results From AGO-OVAR16 and an East Asian Study. AB - OBJECTIVE: The recent phase 3 trial AGO-OVAR16 demonstrated that pazopanib maintenance improved median progression-free survival in patients with ovarian cancer whose disease did not progress during first-line treatment. However, this improvement was not seen in the subset of East Asian patients. The current analysis evaluated the efficacy and safety of pazopanib maintenance in East Asian patients from AGO-OVAR16 and a separate East Asian study. MATERIALS AND METHODS: East Asian patients from AGO-OVAR16 (n = 209) and the East Asian study (N = 145) were randomized 1:1 to receive pazopanib 800 mg/d or placebo for up to 24 months. The primary end point for each study was progression-free survival by RECIST (Response Evaluation Criteria in Solid Tumors) based on investigator assessment. Clinical and genetics data were analyzed separately by study or pooled according to separate predetermined statistical plans. RESULTS: Pazopanib maintenance had a detrimental effect on median progression-free survival versus placebo in East Asian patients from the combined studies (n = 354; 17.9 vs 21.5 months; hazard ratio, 1.114; 95% confidence interval, 0.818-1.518; P = 0.4928). Pazopanib maintenance showed a disadvantage in overall survival in East Asian patients from AGO-OVAR16 versus placebo (hazard ratio, 1.706; 95% confidence interval, 1.010 2.883; P = 0.0465); overall survival analysis was not performed in the East Asian study because of insufficient event numbers. Pazopanib-treated patients had a significantly higher incidence of grade 3 or higher hypertension (27%) and neutropenia (13%) versus placebo. CONCLUSIONS: The treatment effect of maintenance pazopanib in East Asian patients seemed to differ from that in non Asian patients. In study-specific and pooled analyses, none of the potential factors analyzed could satisfactorily explain the different efficacy results of pazopanib in East Asian patients. PMID- 26588237 TI - Surgery for Recurrent Epithelial Ovarian Cancer in the Netherlands: A Population Based Cohort Study. AB - OBJECTIVE: The value of secondary cytoreductive surgery (SCS) in patients with recurrent epithelial ovarian cancer is controversial. The aim of this population based study was to investigate the role of SCS in the Netherlands. METHODS: Data of 408 patients who underwent SCS between 2000 and 2013 were retrospectively collected from 38 Dutch hospitals. Survival after complete and incomplete SCS was estimated by Kaplan-Meier curves. Factors associated with overall survival (OS) were explored with Cox regression. RESULTS: Median OS after SCS was 51 months (95% confidence interval [95% CI], 44.8-57.2). Complete SCS was achieved in 295 (72.3%) patients, with an OS of 57 months (95% CI, 49.0-65.0) compared with 28 months (95% CI, 20.8-35.2) in patients with incomplete SCS (log-rank test; P < 0.001). Nonserous histology (HR 0.65; 95% CI 0.45-0.95), a long progression free interval (hazard ratio [HR], 0.29; 95% CI, 0.07-1.18), a good performance status (HR, 0.68; 95% CI, 0.49-0.94), SCS without preoperative chemotherapy (HR, 0.72; 95% CI, 0.51-1.01), and complete SCS (HR, 0.46; 95% CI, 0.33-0.64) were prognostic factors for survival. CONCLUSIONS: This population-based retrospective study showed that there might be a role for SCS in recurrent epithelial ovarian cancer especially when complete SCS can be accomplished. However, before adopting SCS as a standard treatment modality for recurrent epithelial ovarian cancer, results of 3 ongoing prospectively randomized trials are needed. PMID- 26588238 TI - Surgical Techniques for Diaphragmatic Resection During Cytoreduction in Advanced or Recurrent Ovarian Carcinoma: A Systematic Review and Meta-analysis. AB - OBJECTIVE: Optimal cytoreduction is one the main factors improving survival outcomes in patients affected by ovarian cancer (OC). It is estimated that approximately 40% of OC patients have gross disease located on the diaphragm. However, no mature data evaluating outcomes of surgical techniques for the management of diaphragmatic carcinosis exist. In the present study, we aimed to estimate surgery-related morbidity of different surgical techniques for diaphragmatic cytoreduction in advanced or recurrent OC. METHODS: PubMed (MEDLINE), Web of Science, and Clincaltrials.gov databases were searched for records estimating outcomes of diaphragmatic peritoneal stripping (DPS) or diaphragmatic full-thickness resection (DFTR) for OC. The meta-analysis was performed using the Cochrane Review software. RESULTS: For the final analysis, 5 articles were available, including 272 patients. Diaphragmatic peritoneal stripping and DFTR were performed in 197 patients (72%) and 75 patients (28%), respectively. Pooled analysis suggested that the estimated pleural effusion rate was 43% and 51% after DPS and DFTR, respectively. The need for pleural punctures or chest tube placement was 4% and 9% after DPS and DFTR, respectively. The rate of postoperative pneumothorax (4% vs 9%; odds ratio, 0.31; 95% confidence interval, 0.05-2.08) and subdiaphragmatic abscess (3% vs 3%; odds ratio, 0.45; 95% confidence interval, 0.09-2.31) were similar after the execution of DPS and DFTR. CONCLUSIONS: Diaphragmatic surgery is a crucial step during cytoreduction for advanced or recurrent OC. Obviously, the choice to perform DPS or DFTR depends on the infiltration of the diaphragmatic muscle or not. Both the procedures are associated with a low pulmonary complication and chest tube placement rates. PMID- 26588239 TI - Evaluation of TOP2A as a Predictive Marker for Endometrial Cancer With Taxane Containing Adjuvant Chemotherapy. AB - OBJECTIVE: Paclitaxel plus carboplatin and doxorubicin plus cisplatin are usually selected as adjuvant chemotherapy for endometrial cancer. However, biomarkers that can determine the appropriate chemotherapy regimen are not known. In the present study, we performed a retrospective investigation of the association between TOP2A, HER2 overexpression, and disease-free and overall survival in patients with endometrial cancer receiving taxane and platinum. METHODS: Eligible patients had a diagnosis of endometrial cancer based on histology and treated with an adjuvant chemotherapy regimen comprising taxane-platinum after surgery, and the HER2 and TOP2A status of the endometrial cancer regions was determined. Overall survival and disease-free survival between HER2 status and TOP2A status were estimated by the Kaplan-Meier method and compared using the log-rank test. RESULTS: We identified 56 patients who fulfilled the previously described criteria. Median follow-up was 49 months (range, 18-110 months). HER2-positive tumors were detected in 11 patients (19.6%), and TOP2A-positive tumors were detected in 7 patients (12.5%). Overall survival was not significantly different between patients with HER2-positive tumors and those with HER2-negative tumors, although disease-free survival for patients with HER2-positive tumors was significantly lower than disease-free survival for patients with HER2-negative tumors (P = 0.049). In contrast, patients with TOP2A-positive tumors had significantly lower overall survival than did patients with TOP2A-negative tumors (P = 0.020), and disease-free survival for patients with TOP2A-positive tumors tended to be shorter than for those with TOP2A-negative tumors. CONCLUSIONS: Patients with TOP2A overexpression have a worse prognosis compared with those with TOP2A nonexpression, and TOP2A may be a useful biomarker in patients receiving adjuvant taxane-platinum regimens with moderate- to high-risk endometrial cancer. PMID- 26588240 TI - Clinical Presentation of Complete Hydatidiform Mole and Partial Hydatidiform Mole at a Regional Trophoblastic Disease Center in the United States Over the Past 2 Decades. AB - OBJECTIVE: The aim of this study was to compare the clinical presentation and incidence of postmolar gestational trophoblastic neoplasia (GTN) among cases of complete mole (CM) and partial mole (PM) from 1994 to 2013. METHODS: This study included all cases of patients with CM and PM from our trophoblastic disease center between 1994 and 2013. Their clinical and pathologic reports were reviewed. Gestational age at evacuation, features of clinical presentation, human chorionic gonadotropin levels, and the rate of progression to GTN were compared. RESULTS: The median gestational age at evacuation was 9 weeks for CM and 12 weeks for PM (P < 0.001). Patients with PM had lower pre-evacuation serum human chorionic gonadotropin levels (P < 0.001), and they were also less likely to present with vaginal bleeding (P < 0.001), biochemical hyperthyroidism (P < 0.001), anemia (P < 0.001), uterine size greater than dates (P < 0.001), and hyperemesis (P = 0.002). Consequently, patients with PM were less likely to have been clinically diagnosed as moles compared with CM prior to uterine evacuation (P < 0.001). The development of GTN occurred in 17.7% (33/186) and 4.1% (7/169) of patients with CM and PM, respectively (P < 0.001). CONCLUSIONS: This study indicates that, at our center over the past 20 years, both CM and PM were usually evacuated in the first trimester of pregnancy. Because CM more commonly presents with the signs and symptoms of molar disease than PM, CM is more commonly diagnosed prior to evacuation. PMID- 26588241 TI - Carbon Dioxide Emissions from Reservoirs in the Lower Jordan Watershed. AB - We have analyzed monthly hydrological, meteorological and water quality data from three irrigation and drinking water reservoirs in the lower Jordan River basin and estimated the atmospheric emission rates of CO2. The data were collected between 2006 and 2013 and show that the reservoirs, which differ in size and age, were net sources of CO2. The estimated surface fluxes were comparable in magnitude to those reported for hydroelectric reservoirs in the tropical and sub tropical zones. Highest emission rates were observed for a newly established reservoir, which was initially filled during the sampling period. In the two older reservoirs, CO2 partial pressures and fluxes were significantly decreasing during the observation period, which could be related to simultaneously occurring temporal trends in water residence time and chemical composition of the water. The results indicate a strong influence of water and reservoir management (e.g. water consumption) on CO2 emission rates, which is affected by the increasing anthropogenic pressure on the limited water resources in the study area. The low wind speed and relatively high pH favored chemical enhancement of the CO2 gas exchange at the reservoir surfaces, which caused on average a four-fold enhancement of the fluxes. A sensitivity analysis indicates that the uncertainty of the estimated fluxes is, besides pH, mainly affected by the poorly resolved wind speed and resulting uncertainty of the chemical enhancement factor. PMID- 26588242 TI - Safety and immunogenicity of a live attenuated Japanese encephalitis chimeric virus vaccine (IMOJEV(r)) in children. AB - JE-CV (IMOJEV(r), Sanofi Pasteur, France) is a live attenuated virus vaccine constructed by inserting coding sequences of the prM and E structural proteins of the Japanese encephalitis SA14-14-2 virus into the genome of yellow fever 17D virus. Primary immunization with JE-CV requires a single dose of the vaccine. This article reviews clinical trials of JE-CV in children aged up to 6 years conducted in countries across South-East Asia. Strong and persistent antibody responses were observed after single primary and booster doses, with 97% of children seroprotected up to five years after booster vaccination. Models of long term antibody persistence predict a median duration of protection of approximately 30 years after a booster dose. The safety and reactogenicity profiles of JE-CV primary and booster doses are comparable to other widely used childhood vaccines. PMID- 26588243 TI - Understanding the Role of Solvation Forces on the Preferential Attachment of Nanoparticles in Liquid. AB - Optimization of colloidal nanoparticle synthesis techniques requires an understanding of underlying particle growth mechanisms. Nonclassical growth mechanisms are particularly important as they affect nanoparticle size and shape distributions, which in turn influence functional properties. For example, preferential attachment of nanoparticles is known to lead to the formation of mesocrystals, although the formation mechanism is currently not well-understood. Here we employ in situ liquid cell scanning transmission electron microscopy and steered molecular dynamics (SMD) simulations to demonstrate that the experimentally observed preference for end-to-end attachment of silver nanorods is a result of weaker solvation forces occurring at rod ends. SMD reveals that when the side of a nanorod approaches another rod, perturbation in the surface bound water at the nanorod surface creates significant energy barriers to attachment. Additionally, rod morphology (i.e., facet shape) effects can explain the majority of the side attachment effects that are observed experimentally. PMID- 26588244 TI - Impact of China's Public Hospital Reform on Healthcare Expenditures and Utilization: A Case Study in ZJ Province. AB - BACKGROUND: High drug costs due to supplier-induced demand (SID) obstruct healthcare accessibility in China. Drug prescriptions can generate markup-related profits, and the low prices of other medical services can lead to labor-force underestimations; therefore, physicians are keen to prescribe drugs rather than services. Thus, in China, a public hospital reform has been instituted to cancel markups and increase service prices. METHODS: A retrospective pre/post-reform study was conducted in ZJ province to assess the impact of the reform on healthcare expenditures and utilization, ultimately to inform policy development and decision-making. The main indicators are healthcare expenditures and utilization. RESULTS: Post-reform, drug expenditures per visit decreased by 8.2% and 15.36% in outpatient and inpatient care, respectively; service expenditures per visit increased by 23.03% and 27.69% in outpatient and inpatient care, respectively. Drug utilization per visit increased by 5.58% in outpatient care and underwent no significant change in inpatient care. Both were lower than the theoretical drug-utilization level, which may move along the demand curve because of patient-initiated demand (PID); this indicates that SID-promoted drug utilization may decrease. Finally, service utilization per visit increased by 6% in outpatient care and by 13.10% in inpatient care; both were higher than the theoretical level moving along the demand curve, and this indicates that SID promoted service utilization may increase. CONCLUSION: The reform reduces drug prescription profits by eliminating drug markups; additionally, it compensates for service costs by increasing service prices. Post-reform, the SID of drug prescriptions decreased, which may reduce drug-resource waste. The SID of services increased, with potentially positive and negative effects: accessibility to services may be promoted when physicians provide more services, but the risk of resource waste may also increase. This warrants further research. It is recommended that comprehensive measures that control SID and promote physician enthusiasm be carried out concurrently. PMID- 26588245 TI - Activating pleiotropic receptors to kill cancer cells. PMID- 26588246 TI - Triclocarban Influences Antibiotic Resistance and Alters Anaerobic Digester Microbial Community Structure. AB - Triclocarban (TCC) is one of the most abundant organic micropollutants detected in biosolids. Lab-scale anaerobic digesters were amended with TCC at concentrations ranging from the background concentration of seed biosolids (30 mg/kg) to toxic concentrations of 850 mg/kg to determine the effect on methane production, relative abundance of antibiotic resistance genes, and microbial community structure. Additionally, the TCC addition rate was varied to determine the impacts of acclimation time. At environmentally relevant TCC concentrations (max detect = 440 mg/kg), digesters maintained function. Digesters receiving 450 mg/kg of TCC maintained function under gradual TCC addition, but volatile fatty acid concentrations increased, pH decreased, and methane production ceased when immediately fed this concentration. The concentrations of the mexB gene (encoding for a multidrug efflux pump) were higher with all concentrations of TCC compared to a control, but higher TCC concentrations did not correlate with increased mexB abundance. The relative abundance of the gene tet(L) was greater in the digesters that no longer produced methane, and no effect on the relative abundance of the class 1 integron integrase encoding gene (intI1) was observed. Illumina sequencing revealed substantial community shifts in digesters that functionally failed from increased levels of TCC. More subtle, yet significant, community shifts were observed in digesters amended with TCC levels that did not inhibit function. This research demonstrates that TCC can select for a multidrug resistance encoding gene in mixed community anaerobic environments, and this selection occurs at concentrations (30 mg/kg) that can be found in full-scale anaerobic digesters (U.S. median concentration = 22 mg/kg, mean = 39 mg/kg). PMID- 26588247 TI - Tlr4 Deficiency Protects against Cardiac Pressure Overload Induced Hyperinflammation. AB - Transverse aortic constriction provokes a pro-inflammatory reaction and results in cardiac hypertrophy. Endogenous ligands contribute to cardiac hypertrophy via toll-like receptor (TLR)-4 binding. A lack of TLR4 signaling diminishes hypertrophy and inflammation. Wild type mice undergoing aortic constriction respond to a lipopolysaccharide second-hit stimulus with hyperinflammation. The objective of this study was to assess whether other second-hit challenges utilizing TLR ligands provoke a comparable inflammatory reaction, and to find out whether this response is absent in TLR4 deficient mice. Assuming that cardiac stress alters the expression of pattern recognition receptors we analyzed the effects of transverse aortic constriction and second-hit virulence factor treatment on TLR expression, as well as cytokine regulation. Wild type and Tlr4-/ mice were subjected to three days of TAC and subsequently confronted with gram positive TLR2 ligand lipoteichoic acid (LTA, 15 mg/g bodyweight) or synthetic CpG oligodesoxynucleotide 1668 thioate (20 nmol/kg bodyweight, 30 min after D galactosamin desensitization) signaling via TLR9. Hemodynamic measurements and organ preservation were performed 6 h after stimulation. Indeed, the study revealed a robust enhancement of LTA induced pattern recognition receptor and cytokine mRNA expression and a LTA-dependent reduction of hemodynamic pressure in TAC wild type mice. Second-Hit treatment with CpG-ODNs led to similar results. However, second-hit effects were abolished in Tlr4-/- mice. In total, these data indicate for the first time that cardiac stress increases the inflammatory response towards both, gram-negative and gram-positive, TLR ligands as well as bacterial DNA. The decrease of the inflammatory response upon TLR2 and -9 ligand challenge in TAC Tlr4-/- mice demonstrates that a lack of TLR4 signaling does not only prevent left ventricular hypertrophy but also protects the mice from a cardiac stress induced hyperinflammatory reaction. PMID- 26588248 TI - Conditional Expression of E2A-HLF Induces B-Cell Precursor Death and Myeloproliferative-Like Disease in Knock-In Mice. AB - Chromosomal translocations are driver mutations of human cancers, particularly leukemias. They define disease subtypes and are used as prognostic markers, for minimal residual disease monitoring and therapeutic targets. Due to their low incidence, several translocations and their biological consequences remain poorly characterized. To address this, we engineered mouse strains that conditionally express E2A-HLF, a fusion oncogene from the translocation t(17;19) associated with 1% of pediatric B-cell precursor ALL. Conditional oncogene activation and expression were directed to the B-cell compartment by the Cre driver promoters CD19 or Mb1 (Igalpha, CD79a), or to the hematopoietic stem cell compartment by the Mx1 promoter. E2A-HLF expression in B-cell progenitors induced hyposplenia and lymphopenia, whereas expression in hematopoietic stem/progenitor cells was embryonic lethal. Increased cell death was detected in E2A-HLF expressing cells, suggesting the need for cooperating genetic events that suppress cell death for B cell oncogenic transformation. E2A-HLF/Mb1.Cre aged mice developed a fatal myeloproliferative-like disorder with low frequency characterized by leukocytosis, anemia, hepatosplenomegaly and organ-infiltration by mature myelocytes. In conclusion, we have developed conditional E2A-HLF knock-in mice, which provide an experimental platform to study cooperating genetic events and further elucidate translational biology in cross-species comparative studies. PMID- 26588249 TI - Association of TLR4 (896A/G and 1196C/T) Gene Polymorphisms with Asthma Risk: A Meta-Analysis. AB - BACKGROUND: Conflicting data have been reported on the association between Toll like receptor 4 (TLR4) +896A/G and +1196C/T polymorphisms and the risk of asthma. Therefore, we conducted this meta-analysis to clarify the effect of TLR4 +896A/G and +1196C/T polymorphisms on the risk of asthma. MATERIAL AND METHODS: An electronic literature search was performed using PubMed, Embase, Web of Science, Chinese National Knowledge Infrastructure (CNKI), and Wanfang Data to find relevant studies. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the associations. All statistical analyses were conducted using STATA software version 12.0. RESULTS: A total of 14 studies with 2873 asthma cases and 3110 controls were included. The pooled results indicated a significant association between TLR4 +1196C/T polymorphism and the risk of asthma (T vs. C: OR=0.79, 95%CI=0.63-0.99, P=0.04; TT+CT vs. CC: OR=0.76, 95%CI=0.59 0.96, P=0.03; CT vs. CC: OR=0.74, 95%CI=0.58-0.95, P=0.02). In subgroup analysis by ethnicity, TLR4 +1196C/T polymorphism was significantly associated with asthma risk in Asians (T vs. C: OR=0.73, 95%CI=0.54-0.98, P=0.04; TT+CT vs. CC: OR=0.70, 95%CI=0.51-0.96, P=0.03; CT vs. CC: OR=0.69, 95%CI=0.50-0.96, P=0.03), but not in whites. For TLR4 +896A/G polymorphism, no significant association was found between TLR4 +896A/G polymorphism and asthma risk under any genetic models. CONCLUSIONS: The results of this meta-analysis suggest that T allele of the TLR4 +1196C/T might act as a protective factor against the development of asthma. PMID- 26588250 TI - Cell suspension concentration monitoring by using a miniaturized serial high frequency SAWR sensor. AB - In this paper, a miniaturized cell suspension concentration monitoring method was investigated. The sensing unit was a carbon screen-printed electrode (CSPE) in serial with a 433MHz vacuum-packaged surface acoustic wave resonator (SAWR). SAWR provided a stable and high operating frequency, which helps to keep the stability and sensitivity of the monitoring system. Living cells suspensions in different concentrations were prepared and dropcast on CSPE. Frequency responses of the sensor were recorded. Cell quantity variation within the same culture media volume changed the dielectric properties of CSPE and finally affected the SAWR frequency. SAWR frequency declined with the decrease of cell concentration. The proposed sensor provided high sensitivity and remarkable stability for the cell suspensions. PMID- 26588251 TI - .OH Oxidation Toward S- and OH-Containing Amino Acids. AB - The hydroxyl radical is the most reactive oxygen species, and it is able to attack macromolecules such as proteins. Such oxidation processes are the cause of a number of diseases. Several oxidized products have been experimentally characterized, but the reaction pathways remain unclear. Herein, we present a theoretical study on the attack of hydroxyl radicals on hydroxyl- and sulfur containing amino acid side chains. Several reaction mechanisms, such as hydrogen abstraction, electron transfer, or .OH addition have been considered to investigate several reaction mechanisms. Two different dielectric values (4 and 80) have been used to model the effect of different protein environments. In addition, different alternative conformations of the amino acid backbone have been considered. Overall, the results indicate that the thermodynamics is the main factor driving the reaction pathway preference and, to a great extent, explains the formation of the experimental oxidized produts. Sulfur-containing amino acids would be oxidized more easily than OH-containing amino acids, which confirms the experimental evidence. This is determined by the stability of the sulfur radical intermediates. These results are not dramatically affected by either different dielectrics or backbone conformations. PMID- 26588253 TI - Hypertrophic Olivary Degeneration: A Neurosurgical Point of View. AB - Hypertrophic olivary degeneration (HOD) is a rare form of transsynaptic degeneration characterized by hypertrophy of the inferior olivary nucleus situated in the olivary body, part of the medulla oblongata, representing a major source of input to the cerebellum. HOD typically results from focal lesions interrupting connections from the inferior olive within the dentato-rubro-olivary pathway, a region also known as the triangle of Guillain-Mollaret (TGM) (red nucleus, inferior olivary nucleus, and contralateral dentate nucleus). Clinically, HOD presents classically as palatal tremor and can include dentatorubral tremor and/or ocular myoclonus. The pathologic changes associated with HOD feature radiologic changes with the inferior olivary nucleus appearing larger and increasing its T2-weighted signal intensity on magnetic resonance images. HOD is commonly managed with pharmacotherapy but may require surgical intervention in extreme cases. HOD has been found to develop as a consequence of any injury that disrupts the TGM pathways (e.g., pontine cavernoma).These findings highlight the critical importance of a thorough knowledge of TGM anatomy to avoid secondary HOD. We present a patient who developed HOD secondary to resection of a tectal plate cavernous malformation and review the literature with an emphasis on the current knowledge of this disorder. PMID- 26588252 TI - Finding New Order in Biological Functions from the Network Structure of Gene Annotations. AB - The Gene Ontology (GO) provides biologists with a controlled terminology that describes how genes are associated with functions and how functional terms are related to one another. These term-term relationships encode how scientists conceive the organization of biological functions, and they take the form of a directed acyclic graph (DAG). Here, we propose that the network structure of gene term annotations made using GO can be employed to establish an alternative approach for grouping functional terms that captures intrinsic functional relationships that are not evident in the hierarchical structure established in the GO DAG. Instead of relying on an externally defined organization for biological functions, our approach connects biological functions together if they are performed by the same genes, as indicated in a compendium of gene annotation data from numerous different sources. We show that grouping terms by this alternate scheme provides a new framework with which to describe and predict the functions of experimentally identified sets of genes. PMID- 26588254 TI - Telemetric Intracranial Pressure Measurement: A Graphical Approach to Data Analysis. AB - PURPOSE: In recent years, radiofrequency identification has been used for the continuous measurement of intracranial pressure (ICP) in patients with a cerebrospinal fluid (CSF) shunt for hydrocephalus . Unlike ICP monitoring in an inpatient setting, measurements in mobile patients outside the hospital provide ICP data that take into account the everyday activities of each individual patient. Common methods of ICP monitoring and analysis cannot be used for those patients. In addition, ICP measurements in mobile patients require considerably longer observation times than in-hospital monitoring. For this reason, ICP measurements over a period of 7 to 10 days must be analyzed effectively and efficiently. METHODS: A possible approach is to analyze ICP data graphically. Pathologic changes can be expected to be associated with specific patterns that can be detected graphically (e.g., Lundberg A waves). Patients without pathologic ICP values and without intracranial pathologies usually show an approximately normal distribution of ICP data. By contrast, patients with pathologic ICP values are likely to show major deviations from a normal distribution such as changes in minimum and maximum values and multimodal distributions. Against this background, we present a new graphical method for detecting pathologic conditions. This novel method is based on the distribution of ICP data that is assessed using GNU R, a free software package for statistical computing and graphics. RESULTS: A left skewed distribution indicates CSF shunt overdrainage and a right-skewed distribution suggests CSF shunt underdrainage. In addition, an additive analysis of the number of physiologic ICP values can be helpful in detecting possible causes of CSF shunt overdrainage or underdrainage. The approach presented here shows that patients with hydrocephalus objectively benefited from ICP-guided adjustments of the opening pressure of a shunt valve or the insertion of a valve. This objective improvement was confirmed by the patients' subjective perception of well-being. CONCLUSIONS: Further investigations should be performed to examine the influence of multimodal ICP distributions and to assess how data analysis is affected by a drift that can occur when a sensor has been in place for an extended period of time. PMID- 26588255 TI - Cost-effectiveness analysis of a multivariate index assay compared to modified American College of Obstetricians and Gynecologists criteria and CA-125 in the triage of women with adnexal masses. AB - OBJECTIVE: To evaluate the cost-effectiveness of the multivariate index assay (MIA) for use in triaging women with an adnexal mass relative to modified American College of Obstetricians and Gynecologists (mACOG) referral guidelines and CA-125 testing alone. METHODS: The MIA triage algorithm was based on qualitative serum testing of five biomarkers: transthyretin, apolipoprotein, A-1, 2-microglobulin, transferrin, and CA-125. An economic analysis was developed to evaluate the clinical and cost implications of adopting MIA in clinical practice versus the mACOG referral guidelines and CA-125 alone, over a lifetime horizon, from the perspective of the public payer. Clinical parameters used to characterize patients' disease status, quality of life, and treatment decisions were estimated using the results of published studies; costs were approximated using reimbursement rates from CMS fee schedules. Model endpoints included overall survival (OS), costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER). The cost-effectiveness threshold was set to $50,000 per QALY. One-way sensitivity analysis was performed to assess uncertainty of individual parameters included in the analysis. All costs were reported in 2014 US dollars. RESULTS: Use of MIA was cost-effective, resulting in fewer re-operations and pre-treatment CT scans. Overall MIA resulted in an ICER of $35,094/QALY gained. MIA was also cost-saving and QALY-increasing compared to use of CA-125 alone with an ICER of $12,189/QALY gained. One-way sensitivity analysis showed the ICER was most affected by the following parameters: (1) sensitivity of MIA; (2) sensitivity of mACOG; and (3) percentage of patients, not referred to a gynecologic oncologist, who were correctly diagnosed with advanced epithelial ovarian cancer (EOC). CONCLUSION: Use of MIA is a more cost-effective triage strategy than mACOG or CA-125. It is expected to increase the percentage of women with ovarian cancer that are referred to gynecologic oncologists, which is shown to improve clinical outcomes. Limitations include the use of assumptions when published data was unavailable, and the use of multiple sources for survival data. PMID- 26588257 TI - Author Response: Sufficient Evidence for Lymphatics in the Developing and Adult Human Choroid? PMID- 26588256 TI - Sufficient Evidence for Lymphatics in the Developing and Adult Human Choroid? PMID- 26588258 TI - Identification of the newly identified subtilase cytotoxin-encoding gene (subAB2 2) among clinical Shiga toxin-producing Escherichia coli isolates. AB - Subtilase cytotoxin (SubAB) is an important virulence factor of eae-negative Shiga toxin-producing Escherichia coli (STEC). Three variants of SubAB-encoding genes have been reported in the literature; however, the newly described subAB variant (subAB2-2) was found only in STEC strains from deer meat, sheep, and some wild animals. In this study, subAB variants were detected by PCR and DNA sequencing in 5 out of 12 (41.6%) eae-negative STEC strains isolated from patients. Most subAB-positive STEC strains (80%) harbored the subAB1 gene. The subAB2-2 gene was detected for the first time in the clinical STEC O128:H2 strain. Other virulence genes including stx1a, stx1c, stx2b, ehxA, and tia were also detected in this strain. The DNA sequence analyses of the subAB1 and subAB2 2 genes of the clinical STEC strains showed 99% and 100% identity to those of the reference strains 98NK2 and LM27558stx2, respectively. This is the first report on the detection of the subAB2-2 gene in a clinical STEC isolate. PMID- 26588259 TI - Rooming-in for Infants at Risk of Neonatal Abstinence Syndrome. AB - OBJECTIVE: To examine the impact of a rooming-in program for infants at risk of neonatal abstinence syndrome (NAS) on the need for pharmacologic treatment and length of hospitalization. STUDY DESIGN: Our hospital implemented a rooming-in program for newborns at risk of NAS in June 2013. Previously, standard care was to admit these infants to the neonatal intensive care unit. Charts were reviewed to abstract data on at-risk infants born in the 13-month periods prior and subsequent to implementation of rooming-in (n = 24 and n = 20, respectively) and the groups were compared with the outcomes of interest. RESULT: Rooming-in was associated with a reduced need for pharmacologic treatment and shorter length of stay. CONCLUSION: These findings add to an emerging body of evidence on the health care resource utilization benefits associated with rooming-in for infants at risk of NAS. Future studies should evaluate a broader range of outcomes for this model of care. PMID- 26588260 TI - Obesity Before, During, and After Pregnancy: A Review and Comparison of Five National Guidelines. AB - OBJECTIVE: This study aims to compare how national guidelines approach the management of obesity in reproductive age women. STUDY DESIGN: We conducted a search for national guidelines in the English language on the topic of obesity surrounding the time of a pregnancy. We identified six primary source documents and several secondary source documents from five countries. Each document was then reviewed to identify: (1) statements acknowledging increased health risks related to obesity and reproductive outcomes, (2) recommendations for the management of obesity before, during, or after pregnancy. RESULTS: All guidelines cited an increased risk for miscarriage, birth defects, gestational diabetes, hypertension, fetal growth abnormalities, cesarean sections, difficulty with anesthesia, postpartum hemorrhage, and obesity in offspring. Counseling on the risks of obesity and weight loss before pregnancy were universal recommendations. There were substantial differences in the recommendations pertaining to gestational weight gain goals, nutrient and vitamin supplements, screening for gestational diabetes, and thromboprophylaxis among the guidelines. CONCLUSION: Stronger evidence from randomized trials is needed to devise consistent recommendations for obese reproductive age women. This research may also assist clinicians in overcoming one of the many obstacles they encounter when providing care to obese women. PMID- 26588261 TI - Time of day affects heart rate recovery and variability after maximal exercise in pre-hypertensive men. AB - Heart rate (HR) recovery (HRR) and variability (HRV) after exercise are non invasive tools used to assess cardiac autonomic regulation and cardiovascular prognosis. Autonomic recovery is slower after evening than morning exercise in healthy individuals, but this influence is unknown in subjects with autonomic dysfunction, although it may affect prognostic evaluation. This study compared post-exercise HRR and HRV after maximal morning and evening exercise in pre hypertensive men. Ten volunteers randomly underwent two maximal exercise tests conducted in the morning (8-10 a.m.) and evening (6-8 p.m.). HRR60s (HR reduction at 60 s of recovery - prognostic index), T30 (short-term time-constant of HRR - parasympathetic reactivation marker), rMSSD30s (square root of the mean of the sum of the squares of differences between adjacent R-R intervals on subsequent 30 s segments - parasympathetic reactivation marker), and HRRtau (time constant of the first order exponential fitting of HRR - marker of sympathetic withdraw and parasympathetic reactivation) were measured. Paired t-test and two-way ANOVA were used. HRR60s and HRRtau were similar after exercise in the morning and evening (27 +/- 7 vs. 29 +/- 7 bpm, p = 0.111, and 79 +/- 14 vs. 96 +/- 29 s, p = 0.119, respectively). T30 was significantly greater after evening exercise (405 +/- 215 vs. 295 +/- 119 s, p = 0.002) and rMSSD30s was lower in the evening (main factor session, p = 0.009). In conclusion, in pre-hypertensive men, the prognostic index of HRR, HRR60s, is not affected by the time of day when exercise is conducted. However, post-exercise parasympathetic reactivation, evaluated by T30 and rMSSD30s, is blunted after evening exercise. PMID- 26588262 TI - Changes in coordination and its variability with an increase in running cadence. AB - Alterations in joint mechanics have been associated with common overuse injuries. An increase in running cadence in healthy runners has been shown to improve several parameters that have been tied to injury, but the reorganisation of motion that produces these changes has not been examined. The purpose of this study was to determine if runners change their segment coordination and coordination variability with an acute increase in cadence. Data were collected as ten uninjured runners ran overground at their preferred cadence as well as a cadence 10% higher than preferred. Segment coordination and coordination variability were calculated for select thigh-shank and shank-foot couples and selected knee mechanics were also calculated. Paired t-tests were used to examine differences between the preferred and increased cadence conditions. With increased cadence, there was a decrease in peak knee flexion and a later occurrence of peak knee flexion and internal rotation and shank internal rotation. Segment coordination was altered with most changes occurring in mid late stance. Coordination variability decreased with an increase in cadence across all couples and phases of gait. These results suggest examination of coordination and its variability could give insight into the risk of intervention induced injury. PMID- 26588263 TI - Development of Semiempirical Models for Proton Transfer Reactions in Water. AB - This letter presents a method for the parametrization of semiempirical models for proton transfer reactions in water clusters. Two new models are developed: AM1-W, which is a reparameterization of the classic AM1 model, and AM1PG-W, which is a modified AM1-like model including a pairwise correction to the core repulsion function. Both models show good performance on hydrogen-bonding energies and on proton transfer energy profiles, which are of great importance for proton transfer reactions in large water clusters and in proteins. The parametrization method introduced is general and can be used to develop any other system-specific semiempirical models. PMID- 26588264 TI - A Newfound Cancer-Activating Mutation Reshapes the Energy Landscape of Estrogen Binding Domain. AB - The ligand-binding domain (LBD) of an estrogen receptor undergoes a large conformational switching from an inactive to active state in response to hormone stimuli. Very recently, a novel D538G mutant has been identified to be active in advanced breast cancer tumors. Here, we ask if molecular simulations can provide insight on its mechanistic impact on the receptor's activation status. It has been challenging for ab initio modeling to identify two distinct conformations of a single amino acid sequence as large as that of the LBD. Using a coarse-grained (CG) model, we are able to correctly reproduce this LBD conformational switching. Furthermore, we found that the D538G mutation reshapes the energy landscape by stabilizing both active and inactive conformations, but preferring the active by 1.5 kcal/mol. This observation is consistent with the concept of a mutation shifting landscape and provides a structural explanation for the oncogenic D538G mutation at the detailed conformational level. PMID- 26588265 TI - The Right Answer for the Right Electrostatics: Force Field Methods Are Able to Describe Relative Energies of DNA Guanine Quadruplexes. AB - Different force fields and approximate density functional theory were applied in order to study the rotamer space of the telomeric G-quadruplex DNA. While some force fields show an erratic behavior when it comes to the reproduction of the higher-order DNA conformer space, OPLS and MMFF implementations are able to reproduce the experimentally known energy order. The stabilizing effect of the AA (anti-anti) versus SA (syn-anti) conformer is analyzed applying mechanical bond strength descriptors (compliance constants). The fact that we observe the correct energy order using appropriate force fields is in contrast with results previously reported, which suggested the general inappropriateness of force fields for the description of G-quadruplex structures. PMID- 26588266 TI - Development of a "First-Principles" Water Potential with Flexible Monomers. III. Liquid Phase Properties. AB - The MB-pol full-dimensional water potential introduced in the first two papers of this series [J. Chem. Theory Comput. 2013, 9, 5395 and J. Chem. Theory Comput. 2014, 10, 1599] is employed here in classical and quantum simulations of liquid water under ambient conditions. Comparisons with the available experimental data for several structural, thermodynamic, and dynamical properties indicate that MB pol provides a highly accurate description of the liquid phase. Combined with previous analyses of the dimer vibration-rotation tunneling spectrum, second and third virial coefficients, and cluster structures and energies, the present results demonstrate that MB-pol represents a major step toward the long-sought "universal model" capable of describing the properties of water from the gas to the condensed phases. PMID- 26588267 TI - Three-Dimensional Brownian Dynamics Simulator for the Study of Ion Permeation through Membrane Pores. AB - A three-dimensional numerical simulator based on Brownian dynamics (BD) for the study of ion transport through membrane pores is presented. Published BD implementations suffer from severe shortcomings in accuracy and efficiency. Such limitations arise largely from (i) the nonrigorous treatment of unphysical ion configurations; (ii) the assumption that ion motion occurs always in the high friction limit, (iii) the inefficient solution of the Poisson equation with dielectric interfaces, and (iv) the inaccurate treatment of boundary conditions for ion concentrations. Here, we introduce a new BD simulator in which these critical issues are addressed, implementing advanced techniques: (i) unphysical ion configurations are managed with a novel retracing technique; (ii) ion motion is evaluated integrating the Langevin equation with the algorithm of van Gunsteren and Berendsen (Mol. Phys. 1982, 45, 637-647); (iii) dielectric response in the Poisson equation is solved at run time with the Induced Charge Computation (ICC) method of Boda et al. (J. Chem. Phys. 2006, 125, 034901); and (iv) boundary conditions for ion concentrations are enforced by an accurate Grand Canonical Monte Carlo (GCMC) algorithm. Although some of these techniques have already been separately adopted for the simulation of membrane pores, our tool is the first BD implementation, to our knowledge, that fully retrace ions to avoid unphysical configurations and that computes dielectric interactions at each time step. Most other BD codes have been used on wide channels. Our BD simulator is specifically designed for narrow and crowded ion channels (e.g., L-type calcium channels) where all the aforementioned techniques are necessary for accurate results. In this paper, we introduce our tool, focusing on the implementation and testing of key features and we illustrate its capabilities through the analysis of test cases. The source code is available for download at www.phys.rush.edu/BROWNIES . PMID- 26588268 TI - State Representation Approach for Atomistic Time-Dependent Transport Calculations in Molecular Junctions. AB - We propose a new method for simulating electron dynamics in open quantum systems out of equilibrium, using a finite atomistic model. The proposed method is motivated by the intuitive and practical nature of the driven Liouville-von Neumann equation approach of Sanchez et al. [J. Chem. Phys. 2006, 124, 214708] and Subotnik et al. [J. Chem. Phys. 2009, 130, 144105]. A key ingredient of our approach is a transformation of the Hamiltonian matrix from an atomistic to a state representation of the molecular junction. This allows us to uniquely define the bias voltage across the system while maintaining a proper thermal electronic distribution within the finite lead models. Furthermore, it allows us to investigate complex molecular junctions, including multilead configurations. A heuristic derivation of our working equation leads to explicit expressions for the damping and driving terms, which serve as appropriate electron sources and sinks that effectively "open" the finite model system. Although the method does not forbid it, in practice we find neither violation of Pauli's exclusion principles nor deviation from density matrix positivity throughout our numerical simulations of various tight-binding model systems. We believe that the new approach offers a practical and physically sound route for performing atomistic time-dependent transport calculations in realistic molecular junction models. PMID- 26588269 TI - Reaction Path Following with Sparse Interpolation. AB - Computing the potential energy of an N-atom molecule is an expensive optimization process of 3N - 6 molecular coordinates, so following reaction pathways as a function of all 3N - 6 coordinates is unfeasible for large molecules. In this paper, we present a method that isolates d < 3N - 6 molecular coordinates and continuously follows reaction paths on d-dimensional potential energy surfaces approximated by a Smolyak's sparse grid interpolation algorithm.1 Compared to dense grids, sparse grids efficiently improve the ratio of invested storage and computing time to approximation accuracy and thus allow one to increase the number of coordinates d in molecular reaction path following simulations. Furthermore, evaluation of the interpolant is much less expensive than the evaluation of the actual energy function, so our technique offers a computationally efficient way to simulate reaction paths on ground and excited state potential energy surfaces. To demonstrate the capabilities of our method, we present simulation results for the isomerization of 2-butene with two, three, and six degrees of freedom. PMID- 26588270 TI - A Multiwavelet Treatment of the Quantum Subsystem in Quantum Wavepacket Ab Initio Molecular Dynamics through an Hierarchical Partitioning of Momentum Space. AB - We present an hierarchical scheme where the propagator in quantum dynamics is represented using a multiwavelet basis. The approach allows for a recursive refinement methodology, where the representation in momentum space can be adaptively improved through additional, decoupled layers of basis functions. The method is developed within the constructs of quantum-wavepacket ab initio molecular dynamics (QWAIMD), which is a quantum-classical method and involves the synergy between a time-dependent quantum wavepacket description and ab initio molecular dynamics. Specifically, the current development is embedded within an "on-the-fly" multireference electronic structural generalization of QWAIMD. The multiwavelet treatment is used to study the dynamics and spectroscopy in a small hydrogen bonded cluster. The results are in agreement with previous calculations and with experiment. The studies also allow an interpretation of the shared proton dynamics as one that can be modeled through the dynamics of dressed states. PMID- 26588271 TI - Free Energy Reconstruction from Metadynamics or Adiabatic Free Energy Dynamics Simulations. AB - In molecular dynamics simulations, most enhanced sampling methods are traditionally associated with one particular estimator to calculate the free energy surface (FES), such as the histogram, the mean force, or the bias potential. Here, we start from the realization that four enhanced sampling methods, metadynamics and well-tempered metadynamics (in their extended Lagrangian form), as well as driven adiabatic free energy dynamics (dAFED) and unified free energy dynamics (UFED), can be used in combination with any of the three above-mentioned FES estimators. We compare the convergence properties of these estimators on the alanine dipeptide and a sodium ion solvation shell. We find that the mean force estimator is superior in all cases. We also show that it can be marginally beneficial to combine information from the histogram and the force, provided that both are of comparable accuracy. PMID- 26588272 TI - Local Elevation Umbrella Sampling Applied to the Calculation of Alchemical Free Energy Changes via lambda-Dynamics: The lambda-LEUS Scheme. AB - When using molecular dynamics (MD) simulations for the calculation of alchemical free-energy changes, the extended-dynamics method called lambda-dynamics (lambdaD) in its currently available implementations does not compare very favorably with thermodynamic integration (TI) in terms of robustness, efficiency, and accuracy, although it is in principle easier to set up, postprocess, and automatize. In the present article, the main shortcomings of the lambdaD approach are carefully analyzed, and possible remedies are proposed. The resulting scheme, called lambda-LEUS, involves: (i) the use of a simple noninvertible coordinate transformation ensuring a finite sampling of the two physical end states; (ii) the application of the local elevation umbrella sampling (LEUS) memory-based biasing scheme to enforce homogeneous sampling and overcome barriers along the alchemical coordinate; (iii) recommendations concerning the choice of the mass parameter and of the temperature-coupling scheme for this coordinate; (iv) the use of a second-order splines basis set for the memory-based biasing functions. The lambda-LEUS scheme is described and tested considering the perturbation of hydroquinone to benzene in water. The results are compared to those of TI calculations and exhibit a superior accuracy-to-efficiency ratio, presumably because dynamic variations in the alchemical coordinate open up pathways to circumvent orthogonal barriers, these pathways being inaccessible when the coordinate is constrained. Therefore, lambda-LEUS combines the practical advantages of lambdaD with the robustness of TI, simultaneously affording a slightly enhanced computational efficiency. PMID- 26588273 TI - Efficient and Minimal Method to Bias Molecular Simulations with Experimental Data. AB - A primary goal in molecular simulations is to modify the potential energy of a system so that properties of the simulation match experimental data. This is traditionally done through iterative cycles of simulation and reparameterization. An alternative approach is to bias the potential energy so that the system matches experimental data. This can be done while minimally changing the underlying free energy of the molecular simulation. Current minimal biasing methods require replicas, which can lead to unphysical dynamics and introduces new complexity: the choice of replica number and their properties. Here, we describe a new method, called experiment directed simulation that does not require replicas, converges rapidly, can match many data simultaneously, and minimally modifies the potential. The experiment directed simulation method is demonstrated on model systems and a three-component electrolyte simulation. The theory used to derive the method also provides insight into how changing a molecular force-field impacts the expected value of observables in simulation. PMID- 26588274 TI - RM1 Model for the Prediction of Geometries of Complexes of the Trications of Eu, Gd, and Tb. AB - All versions of our previous Sparkle Model were very accurate in predicting lanthanide-lanthanide distances in complexes where the two lanthanide ions directly face each other, and mainly lanthanide-oxygen, and lanthanide-nitrogen distances, which are by far the most common ones in lanthanide complexes. In this article, we are advancing for the first time the RM1 model for lanthanides. Designed to be a much more general NDDO model, the RM1 model for lanthanides is capable of predicting geometries of lanthanide complexes for the cases when the central lanthanide trication is directly coordinated to any other atoms, not only oxygen or nitrogen. The RM1 model for lanthanides is defined by three important attributes: (a) the orbitals, the lanthanide ion has now three electrons and a NDDO basis set made of 5d, 6s, and 6p functions; (b) the parametrization, via cluster analysis and an adequate sampling; and (c), the statistical validation of the parameters to make sure the errors behave as random around a mean. All three aspects are described in detail in the article. Results indicate that the RM1 model does extend the accuracy of the previous Sparkle Models to types of coordinating bonds other than Ln-O and Ln-N; the most common ones for Eu, Gd, and Tb, being Ln-C, Ln-S, Ln-Cl, and Ln-Br. Overall, these other coordinating bonds are now predicted within 0.06 A of their correct values. Therefore, the RM1 model here presented is capable of predicting geometries of lanthanide complexes, materials, metal-organic frameworks, etc., with useful accuracy. PMID- 26588275 TI - Reaction Path Force Matching: A New Strategy of Fitting Specific Reaction Parameters for Semiempirical Methods in Combined QM/MM Simulations. AB - We present a general strategy of reparametrizing semiempirical (SE) methods against ab initio (AI) methods for combined quantum mechanical and molecular mechanical (QM/MM) simulations of specific chemical reactions in condensed phases. The resulting approach, designated Reaction Path Force Matching (RP-FM), features cycles of sampling configurations along a reaction path on an efficient SE/MM potential energy surface (PES) and adjusting specific reaction parameters (SRPs) in the SE method such that the atomic forces computed at the target AI/MM level are reproduced. Iterative applications of the RP-FM cycle make possible achieving the accuracy of AI/MM simulations without explicitly sampling the computationally expensive AI/MM PES. The bypassed sampling, nevertheless, is implicitly accomplished through the aid of the efficient SE-SRP/MM PES, on which the target-level reaction path is expected to be obtained upon convergence. We demonstrate the effectiveness of the RP-FM procedure for a symmetric proton transfer reaction in the gas phase and in solution. The remarkable agreements between the RP-FM optimized SE-SRP methods and the target AI method on various properties, including energy profiles, potential of mean force free energy profiles, atomic forces, charge populations, and solvation effects, suggest that RP-FM can be used as an efficient and reliable strategy for simulating condensed phase chemical reactions. PMID- 26588276 TI - New Approximation to the Third-Order Density. Application to the Calculation of Correlated Multicenter Indices. AB - In this work we present the formulas for the calculation of exact three-center electron sharing indices (3c-ESI) and introduce two new approximate expressions for correlated wave functions. The 3c-ESI uses the third-order density, the diagonal of the third-order reduced density matrix, but the approximations suggested in this work only involve natural orbitals and occupancies. In addition, the first calculations of 3c-ESI using Valdemoro's, Nakatsuji's and Mazziotti's approximation for the third-order reduced density matrix are also presented for comparison. Our results on a test set of molecules, including 32 3c ESI values, prove that the new approximation based on the cubic root of natural occupancies performs the best, yielding absolute errors below 0.07 and an average absolute error of 0.015. Furthemore, this approximation seems to be rather insensitive to the amount of electron correlation present in the system. This newly developed methodology provides a computational inexpensive method to calculate 3c-ESI from correlated wave functions and opens new avenues to approximate high-order reduced density matrices in other contexts, such as the contracted Schrodinger equation and the anti-Hermitian contracted Schrodinger equation. PMID- 26588277 TI - Ab Initio Quantum Mechanical Description of Noncovalent Interactions at Its Limits: Approaching the Experimental Dissociation Energy of the HF Dimer. AB - Hydrogen fluoride dimer is a perfect model system for studying hydrogen bonding. Its size makes it possible to apply the most advanced theoretical methods available, yet it is a full-featured complex of molecules with nontrivial electronic structure and dynamic properties. Moreover, the dissociation energy of the HF dimer has been measured experimentally with an unparalleled accuracy of +/ 1 cm(-1)(Bohac et al. J. Chem. Phys. 1992, 9, 6681). In this work, we attempt to reproduce it by purely ab initio means, using advanced quantum-mechanical computational methods free of any empiricism. The purpose of this study is to demonstrate the capabilities of today's computational chemistry and to point out its limitations by identifying the contributions that introduce the largest uncertainty into the result. The dissociation energy is calculated using a composite scheme including large basis set CCSD(T) calculations, contributions of higher excitations up to CCSDTQ, relativistic and diagonal Born-Oppenheimer corrections and anharmonic vibrational calculations. The error of the calculated dissociation energy is 0.07 kcal/mol (25 cm(-1), 2.5%) when compared to the experiment. The major part of this error can be attributed to the inaccuracy of the calculations of the zero-point vibrational energy. PMID- 26588278 TI - Shape of Multireference, Equation-of-Motion Coupled-Cluster, and Density Functional Theory Potential Energy Surfaces at a Conical Intersection. AB - We report and characterize ground-state and excited-state potential energy profiles using a variety of electronic structure methods along a loop lying on the branching plane associated with a conical intersection (CI) of a reduced retinal model, the penta-2,4-dieniminium cation (PSB3). Whereas the performance of the equation-of-motion coupled-cluster, density functional theory, and multireference methods had been tested along the excited- and ground-state paths of PSB3 in our earlier work, the ability of these methods to correctly describe the potential energy surface shape along a CI branching plane has not yet been investigated. This is the focus of the present contribution. We find, in agreement with earlier studies by others, that standard time-dependent DFT (TDDFT) does not yield the correct two-dimensional (i.e., conical) crossing along the branching plane but rather a one-dimensional (i.e., linear) crossing along the same plane. The same type of behavior is found for SS-CASPT2(IPEA=0), SS CASPT2(IPEA=0.25), spin-projected SF-TDDFT, EOM-SF-CCSD, and, finally, for the reference MRCISD+Q method. In contrast, we found that MRCISD, CASSCF, MS CASPT2(IPEA=0), MS-CASPT2(IPEA=0.25), XMCQDPT2, QD-NEVPT2, non-spin-projected SF TDDFT, and SI-SA-REKS yield the expected conical crossing. To assess the effect of the different crossing topologies (i.e., linear or conical) on the PSB3 photoisomerization efficiency, we discuss the results of 100 semiclassical trajectories computed by CASSCF and SS-CASPT2(IPEA=0.25) for a PSB3 derivative. We show that for the same initial conditions, the two methods yield similar dynamics leading to isomerization quantum yields that differ by only a few percent. PMID- 26588279 TI - Near Equivalence of Intrinsic Atomic Orbitals and Quasiatomic Orbitals. AB - A direct relationship between the Intrinsic Atomic Orbitals (IAO) method (Knizia, G. J. Chem. Theory Comp. 2013, 9, 4834-4843) and earlier work on the same topic, quasiatomic minimal basis set orbitals (QUAMBO) (Lu, W. C.; Wang, C. Z.; Schmidt, M. W.; Bytautas, L.; Ho, K. M.; Ruedenberg J. Chem. Phys. 2004, 2629) and later modifications (quasiatomic orbitals, QUAO) is investigated. It will be demonstrated mathematically that IAOs are almost identical to the original formulation of QUAMBOs and span the same space as a later QUAO modification. The construction of QUAOs involves minimization of a functional that requires matrix diagonalization, or singular matrix decomposition, while the IAO method provides a direct solution by projections. As a byproduct of this proof, it will be shown that (a) under mild conditions a simpler projection yields identical IAOs and (b) an alternative proof is obtained that IAOs span the full space of molecular orbitals if they are linearly independent. Utilization of QUAMBOs as the defining basis set results in rock-solid numerical stability of Pipek-Mezey localization and Mulliken or Lowdin population analysis in very large systems. The charges do not depend on the basis set used, as already shown by Knizia for smaller systems. In this paper, more difficult cases of large semiperiodic systems with strong linear dependency are tested, and it is shown that QUAMBOs perform extremely well. PMID- 26588280 TI - New Benchmark Set of Transition-Metal Coordination Reactions for the Assessment of Density Functionals. AB - We present the WCCR10 data set of 10 ligand dissociation energies of large cationic transition metal complexes for the assessment of approximate exchange correlation functionals. We analyze nine popular functionals, namely BP86, BP86 D3, B3LYP, B3LYP-D3, B97-D-D2, PBE, TPSS, PBE0, and TPSSh by mutual comparison and by comparison to experimental gas-phase data measured with well-known precision. The comparison of all calculated data reveals a large, system dependent scattering of results with nonnegligible consequences for computational chemistry studies on transition metal compounds. Considering further the comparison with experimental results, the nonempirical functionals PBE and TPSS turn out to be among the best functionals for our reference data set. The deviation can be lowered further by including Hartree-Fock exchange. Accordingly, PBE0 and TPSSh are the two most accurate functionals for our test set, but also these functionals exhibit deviations from experimental results by up to 50 kJ mol(-1) for individual reactions. As an important result, we found no functional to be reliable for all reactions. Furthermore, for some of the ligand dissociation energies studied in this work, invoking semiempirical dispersion corrections yields results which increase the deviation from experimental results. This deviation increases further if structure optimization including such dispersion corrections is performed, although the contrary should be the case, pointing to the need to develop the currently available dispersion corrections further. Finally, we compare our results to other benchmark studies and highlight that the performance assessed for different density functionals depends significantly on the reference molecule set chosen. PMID- 26588281 TI - Electronic Excitations in Push-Pull Oligomers and Their Complexes with Fullerene from Many-Body Green's Functions Theory with Polarizable Embedding. AB - We present a comparative study of excited states in push-pull oligomers of PCPDTBT and PSBTBT and prototypical complexes with a C60 acceptor using many-body Green's functions theory within the GW approximation and the Bethe-Salpeter equation. We analyze excitations in oligomers up to a length of 5 nm and find that for both materials the absorption energy practically saturates for structures larger than two repeat units due to the localized nature of the excitation. In the bimolecular complexes with C60, the transition from Frenkel to charge transfer excitons is generally exothermic and strongly influenced by the acceptor's position and orientation. The high CT binding energy of the order of 2 eV results from the lack of an explicit molecular environment. External polarization effects are then modeled in a GW-BSE based QM/MM approach by embedding the donor-acceptor complex into a polarizable lattice. The lowest charge transfer exciton is energetically stabilized by about 0.5 eV, while its binding energy is reduced to about 0.3 eV. We also identify a globally unbound charge transfer state with a more delocalized hole at higher energy while still within the absorption spectrum, which opens another potential pathway for charge separation. For both PCPDTBT and PSBTBT, the energetics are largely similar with respect to absorption and the driving force to form intermediate charge transfer excitations for free charge generation. These results support that the higher power conversion efficiency observed for solar cells using PSBTBT as donor material is a result of molecular packing rather than of the electronic structure of the polymer. PMID- 26588282 TI - New SCS- and SOS-MP2 Coefficients Fitted to Semi-Coulombic Systems. AB - Spin-component scaled second-order Moller-Plesset perturbation theory (SCS-MP2) energy calculations, which independently scale the opposite- and same-spin components of the MP2 correlation energy, are known to consistently provide improved interaction energies in comparison to conventional MP2. This has led to the development of a number of SCS-MP2 derivatives that target particular classes of molecules, interactions or properties. In this study, SCS-MP2 scaling coefficients targeted to interaction energies of single ion pair semi-Coulombic ionic liquid (IL) systems are presented in view of circumventing the need for counterpoise correction to eliminate basis set superposition error (BSSE). A set of 174 IL ion pairs consisting of imidazolium ([C(1-4)mim](+)) and pyrrolidinium ([C(1-4)mpyr](+)) cations and routinely used anions such as Br(-), Cl(-), [BF4]( ), [PF6](-), [DCA](-) (dicyanamide), [tos](-) (tosylate), [mes](-) (mesylate), and [NTf2](-) (bis(trifluoromethylsulfonyl)amide), each of which were arranged in multiple favorable conformations, were calculated at the MP2 level of theory with 17 popular basis sets ranging from double- to quadruple-zeta quality and at the CCSD(T)/CBS limit. For each basis set, the spin components of the IL set were scaled via least-squares multiple linear regression with respect to CCSD(T)/CBS benchmark interaction energies that were corrected for BSSE using the Boys and Bernardi approach. SCS-MP2 spin component coefficients of 1.05 and 0.68 are recommended for the opposite- and same-spin components, respectively, in conjunction with Dunning's cc-pVTZ basis set, which resulted in the most statistically reliable regression. Alternatively, a scaled opposite-spin MP2 (SOS MP2) scaling factors of 1.64 is recommended for the opposite-spin component and should be used where the omission of the same-spin component results in a calculation speed-up. These two scaling schemes are termed SCS-IL-MP2 and SOS-IL MP2, respectively. The SCS-IL-MP2 and SOS-IL-MP2 approaches show interaction energy errors on average less than 1.0 kJ mol(-1) with respect to CCSD(T)/CBS benchmark results and highlights the important consideration of basis set dependence when selecting spin-component coefficients. By calculating multiple conformations for each ion pair and scaling to reproduce BSSE corrected benchmark energies, it is suggested that improved energies may be obtained for larger IL clusters beyond ion pairs without performing costly counterpoise corrections. PMID- 26588283 TI - Proton Affinity Calculations with High Level Methods. AB - Proton affinities, stretching from small reference compounds, up to the methylbenzenes and naphthalene and anthracene, have been calculated with high accuracy computational methods, viz. W1BD, G4, G3B3, CBS-QB3, and M06-2X. Computed and the currently accepted reference proton affinities are generally in excellent accord, but there are deviations. The literature value for propene appears to be 6-7 kJ/mol too high. Reported proton affinities for the methylbenzenes seem 4-5 kJ/mol too high. G4 and G3 computations generally give results in good accord with the high level W1BD. Proton affinity values computed with the CBS-QB3 scheme are too low, and the error increases with increasing molecule size, reaching nearly 10 kJ/mol for the xylenes. The functional M06-2X fails markedly for some of the small reference compounds, in particular, for CO and ketene, but calculates methylbenzene proton affinities with high accuracy. PMID- 26588284 TI - Nitrogen and Sulfur Compounds in Atmospheric Aerosols: A New Parametrization of Polarized Molecular Orbital Model Chemistry and Its Validation against Converged CCSD(T) Calculations for Large Clusters. AB - The parametrization of the polarized molecular orbital (PMO) method, which is a neglect-of-diatomic-differential-overlap (NDDO) semiempirical method that includes polarization functions on hydrogens, is extended to include the constituents that dominate the nucleation of atmospheric aerosols, including ammonia, sulfuric acid, and water. The parametrization and validation are based mainly on CCSD(T)/CBS results for atmospheric clusters composed of sulfuric acid, dimethylamine, and ammonia and on M06-2X exchange-correlation functional calculations for other constituents of the atmospheric aerosols. The resulting model, called PMO2a, is parametrized for molecules containing any type of H, C, or O, amino or ammonium N, and S atoms bonded to O. The new method gives greatly improved electric polarization compared to any other member of the family of NDDO methods. In addition, PMO2a is shown to outperform previous NDDO methods for atomization energies and atmospheric aerosol reaction energies; therefore, its use can be recommended for realistic simulations. PMID- 26588285 TI - Basis Set Convergence of the Post-CCSD(T) Contribution to Noncovalent Interaction Energies. AB - We investigated the basis set convergence of high-order coupled-cluster interaction energy contributions for 21 small weakly bound complexes. By performing CCSDT(Q) calculations in at least the aug-cc-pVTZ basis set, and CCSDT calculations in at least aug-cc-pVQZ (aug-cc-pVTZ for one system), we found the convergence to be quite slow. In particular, the 6-31G*(0.25) and 6 31G**(0.25,0.15) bases advocated by Hobza et al. (J. Chem. Theory Comput. 2013, 9, 2151; ibid. 2013, 9, 3420) are unsuitable for the post-CCSD(T) effects, with average errors for the CCSDT(Q)-CCSD(T) interaction energy contribution of about 80% for 6-31G**(0.25,0.15) and 110% for 6-31G*(0.25). Upgrading the basis set to aug-cc-pVDZ reduces the average error to about 35% and extremely demanding CCSDT(Q)/aug-cc-pVTZ calculations are necessary for further improvement in accuracy. An error cancellation between basis set incompleteness effects at the CCSDT-CCSD(T) and CCSDT(Q)-CCSDT levels occurs for most (but not all) complexes, making it unproductive to carry out CCSDT calculations in a larger basis set than the more demanding CCSDT(Q) calculations. We also found that the frozen natural orbital approximation at the CCSDT and CCSDT(Q) levels works well only if the thresholds for discarding least occupied natural orbitals are very tight (significantly tighter than the thresholds recommended for molecular correlation energies in the original work of Rolik and Kallay, J. Chem. Phys. 2011, 134, 124111), making the performance gains quite limited. The interaction energy contributions through CCSDT(Q) are both a necessity and a bottleneck in the construction of top-accuracy interaction potentials and further improvements in the efficiency of high-order coupled-cluster calculations will be of great help. PMID- 26588286 TI - Wave Function and Density Functional Theory Studies of Dihydrogen Complexes. AB - We performed a benchmark study on a series of dihydrogen bond complexes and constructed a set of reference bond distances and interaction energies. The test set was employed to assess the performance of several wave function correlated and density functional theory methods. We found that second-order correlation methods describe relatively well the dihydrogen complexes. However, for high accuracy inclusion of triple contributions is important. On the other hand, none of the considered density functional methods can simultaneously yield accurate bond lengths and interaction energies. However, we found that improved results can be obtained by the inclusion of nonlocal exchange contributions. PMID- 26588287 TI - Extension of the FACTS Implicit Solvation Model to Membranes. AB - The generalized Born (GB) formalism can be used to model water as a dielectric continuum. Among the different implicit solvent models using the GB formalism, FACTS is one of the fastest. Here, we extend FACTS so that it can represent a membrane environment. This extension is accomplished by considering a position dependent dielectric constant and empirical surface tension parameter. For the calculation of the effective Born radii in different dielectric environments we present a parameter-free approximation to Kirkwood's equation, which uses the Born radii obtained with FACTS for the water environment as input. This approximation is tested for the calculation of self-free energies, pairwise interaction energies in solution and solvation free energies of complete protein conformations. The results compare well to those from the finite difference Poisson method. The new implicit membrane model is applied to estimate free energy insertion profiles of amino acid analogues and in molecular dynamics simulations of melittin, WALP23 and KALP23, glycophorin A, bacteriorhodopsin, and a Clc channel dimer. In all cases, the results agree qualitatively with experiments and explicit solvent simulations. Moreover, the implicit membrane model is only six times slower than a vacuum simulation. PMID- 26588288 TI - Base Pair Fraying in Molecular Dynamics Simulations of DNA and RNA. AB - Terminal base pairs of DNA and RNA molecules in solution are known to undergo frequent transient opening events (fraying). Accurate modeling of this process is important because of its involvement in nucleic acid end recognition and enzymatic catalysis. In this article, we describe fraying in molecular dynamics simulations with the ff99bsc0, ff99bsc0chiOL3, and ff99bsc0chiOL4 force fields, both for DNA and RNA molecules. Comparison with the experiment showed that while some features of fraying are consistent with the available data, others indicate potential problems with the force field description. In particular, multiple noncanonical structures are formed at the ends of the DNA and RNA duplexes. Among them are tWC/sugar edge pair, C-H edge/Watson-Crick pair, and stacked geometries, in which the terminal bases are stacked above each other. These structures usually appear within the first tens to hundreds of nanoseconds and substantially limit the usefulness of the remaining part of the simulation due to geometry distortions that are transferred to several neighboring base pairs ("end effects"). We show that stability of the noncanonical structures in ff99bsc0 may be partly linked to inaccurate glycosidic (chi) torsion potentials that overstabilize the syn region and allow for rapid anti to syn transitions. The RNA refined glycosidic torsion potential chiOL3 provides an improved description and substantially more stable MD simulations of RNA molecules. In the case of DNA, the chiOL4 correction gives only partial improvement. None of the tested force fields provide a satisfactory description of the terminal regions, indicating that further improvement is needed to achieve realistic modeling of fraying in DNA and RNA molecules. PMID- 26588289 TI - Finite Temperature Infrared Spectra from Polarizable Molecular Dynamics Simulations. AB - Infrared spectra of biomolecules are obtained from molecular dynamics simulations at finite temperature using the AMOEBA force field. Diverse examples are presented such as N-methylacetamide and its derivatives and a helical peptide. The computed spectra from polarizable molecular dynamics are compared in each case to experimental ones at various temperatures. The role of high-level electrostatic treatment and explicit polarization, including parameters improvements, is highlighted for obtaining spectral sensitivity to the environment including hydrogen bonds and water molecules and a better understanding of the observed experimental bands. PMID- 26588290 TI - Tailoring Pull-out Properties of Single-Walled Carbon Nanotube Bundles by Varying Binding Structures through Molecular Dynamics Simulation. AB - Single-walled carbon nanotubes (SWCNTs) have demonstrated a remarkable capacity for self-assembly into nanobundles through intermolecular van der Waals interactions, bestowing these agglomerates extraordinary mechanical, thermal, and electrical properties. However, how to improve the binding ability of SWCNT bundles to mitigate the delamination and sliding effects between individual nanotubes remains to be further investigated. By utilizing molecular dynamics simulation, here we present the construction of SWCNT bundles with discrete cylindrical and continuous helical binders by noncovalent coating of the bundle surface with sp(2)-hybridized carbon networks. Meanwhile, by modifying the binding potentials between the binder and SWCNT bundles to mimic the different binding types actually used, the bound SWCNT bundle presents a variety of distinct mechanical properties unmatched by unbound bundles. The pull-out tests with discrete binders portray an intriguing force-displacement curve which can help determine the number of discrete binders used in the system. SWCNT bundles with binders depict unique mechanical properties which can differentiate them from unbound SWCNT bundles. These findings provide compelling evidence that bound SWCNT bundles will open up novel avenues for a variety of applications, especially in nanocomposites. PMID- 26588291 TI - Leveraging Data Fusion Strategies in Multireceptor Lead Optimization MM/GBSA End Point Methods. AB - Accurate and efficient affinity calculations are critical to enhancing the contribution of in silico modeling during the lead optimization phase of a drug discovery campaign. Here, we present a large-scale study of the efficacy of data fusion strategies to leverage results from end-point MM/GBSA calculations in multiple receptors to identify potent inhibitors among an ensemble of congeneric ligands. The retrospective analysis of 13 congeneric ligand series curated from publicly available data across seven biological targets demonstrates that in 90% of the individual receptor structures MM/GBSA scores successfully identify subsets of inhibitors that are more potent than a random selection, and data fusion strategies that combine MM/GBSA scores from each of the receptors significantly increase the robustness of the predictions. Among nine different data fusion metrics based on consensus scores or receptor rankings, the SumZScore (i.e., converting MM/GBSA scores into standardized Z-Scores within a receptor and computing the sum of the Z-Scores for a given ligand across the ensemble of receptors) is found to be a robust and physically meaningful metric for combining results across multiple receptors. Perhaps most surprisingly, even with relatively low to modest overall correlations between SumZScore and experimental binding affinities, SumZScore tends to reliably prioritize subsets of inhibitors that are at least as potent as those that are prioritized from a "best" single receptor identified from known compounds within the congeneric series. PMID- 26588292 TI - Simulation of Liquid and Supercritical Hydrogen Sulfide and of Alkali Ions in the Pure and Aqueous Liquid. AB - A polarizable model for hydrogen sulfide (H2S) is optimized based on the experimental properties of the monomer and of the bulk liquid. The model is characterized by rigid SH bonds but flexible HSH angle and the polarizability is based on the Drude oscillator model. Bonded parameters and atomic charges are based on the experimental properties of the gaseous monomer. Atomic Lennard-Jones (LJ) parameters are adjusted based on the density of H2S around the critical point (in the temperature range 363-393 K and pressure range 8.023-10.013 MPa). The model gives binding energies for H2S dimers, trimers, and tetramers in good agreement with ab initio MP2(full)/6-311++G(d,p) results. It shows a liquid structure in very good agreement with neutron diffraction data. The model also gives density, self-diffusion coefficient, heat of vaporization, and dielectric constant of liquid hydrogen sulfide at the normal boiling point in good agreement with experimental data. In addition, the model is transferable to high temperature and pressure conditions, as evidenced from simulations up to 542.2 K and 40 MPa. The model is used in combination with the SWM4-NDP water model, with LJ parameters between the S and O atoms adjusted to reproduce the experimental hydration free energy of H2S. Simulations suggest that, in its first solvation shell, a single H2O molecule is solvated by 10 H2S molecules while a single H2S molecule is solvated by 20.5 H2O molecules. Pair-specific LJ parameters between alkali ions (Li(+), Na(+), K(+), Rb(+), Cs(+)) and the S atom are adjusted to reproduce ab initio binding energies of the ion-H2S pairs at the CCSD(T) level. Simulations based on these parameters show that alkali ions have higher coordination numbers and lower solvation free energies in liquid H2S than in liquid water or liquid ammonia. The model is also used to investigate the preferential solvation of the ions in aqueous solutions with a 10% H2S mole fraction. Results show that the ions are preferentially solvated by water in their first solvation shell but have no significant selectivity to either ligands in their second shells. PMID- 26588293 TI - pyProCT: Automated Cluster Analysis for Structural Bioinformatics. AB - Cluster analysis is becoming a relevant tool in structural bioinformatics. It allows analyzing large conformational ensembles in order to extract features or diminish redundancy, or just as a first step for other methods. Unfortunately, the successfulness of this analysis strongly depends on the data set traits, the chosen algorithm, and its parameters, which can lead to poor or even erroneous results not easily detected. In order to overcome this problem, we have developed pyProCT, a Python open source cluster analysis toolkit specially designed to be used with ensembles of biomolecule conformations. pyProCT implements an automated protocol to choose the clustering algorithm and parameters that produce the best results for a particular data set. It offers different levels of customization according to users' expertise. Moreover, pyProCT has been designed as a collection of interchangeable libraries, making it easier to reuse it as part of other programs. PMID- 26588294 TI - Including the Dispersion Attraction into Structure-Adapted Fast Multipole Expansions for MD Simulations. PMID- 26588295 TI - Two-Photon Absorption in Fluorescent Protein Chromophores: TDDFT and CC2 Results. AB - Two-photon spectroscopy of fluorescent proteins is a powerful bioimaging tool. Considerable effort has been made to measure absolute two-photon absorption (TPA) for the available fluorescent proteins. Being a technically involved procedure, there is significant variation in the published experimental measurements even for the same protein. In this work, we present a time-dependent density functional theory (TDDFT) study on isolated chromophores comparing the ability of four functionals (PBE0, B3LYP, CAM-B3LYP, and LC-BLYP) combined with the 6 31+G(d,p) basis set to reproduce averaged experimental TPA energies and cross sections. The TDDFT energies and TPA cross sections are also compared to corresponding CC2/6-31+G(d,p) results for excitation to S1 for the five smallest chromophores. In general, the computed TPA energies are less functional dependent than the TPA cross sections. The variation between functionals is more pronounced when higher-energy transitions are studied. Changes to the conformation of a chromophore are shown to change the TPA cross-section considerably. This adds to the difficulty of comparing an isolated chromophore to the one embedded in the protein environment. All functionals considered give moderate agreement with the corresponding CC2 results; in general, the TPA cross sections determined by TDDFT are 1.5-10 times smaller than the corresponding CC2 values for excitation to S1. LC-BLYP and CAM-B3LYP give erroneously large TPA cross sections in the higher energy regions. On the other hand, B3LYP and PBE0 yield values that are of the same order of magnitude and in some cases very close to the averaged experimental data. Thus, based on the results reported here, B3LYP and PBE0 are the preferred functionals for screening chromphores for TPA. However, at best, TDDFT can be used to semiquantitatively scan chromophores for potential TPA probes and highlight spectroscopic peaks that could be present in the mature protein. PMID- 26588296 TI - Calculating CD Spectra of Flexible Peptides: An Assessment of TD-DFT Functionals. AB - Calculations of CD spectra can provide important structural information for peptide systems. Although TD-DFT is an attractive method for these calculations, recent studies have pointed to problems with modeling charge transfer excitations. Motivated by these problems, we benchmarked the performances of CAM B3LYP, omegaB97X-D, M06-2X, B3LYP, and PBE0 against high level ab initio RICC2 calculations for selected peptide structures. Furthermore, we compared the performance of the functionals with the experimentally available data. Our results show that long-range corrected functionals (CAM-B3LYP and omegaB97X-D) correlate relatively well with RICC2 calculations, as does the meta-hybrid M06 2X, while the global hybrid functionals (B3LYP and PBE0) exhibit the aforementioned charge-transfer artifacts. On the other hand, PBE0 and even more so M06-2X and B3LYP produce spectra in better agreement with the experimental data. We have clarified this apparent discrepancy by finding that the surplus charge-transfer excitations, exhibited by B3LYP and PBE0, seem to have a negligible contribution to the final spectra, once appropriate structural averaging is performed. PMID- 26588297 TI - Comparison of LC-TDDFT and ADC(2) Methods in Computations of Bright and Charge Transfer States in Stacked Oligothiophenes. AB - Long-range corrected time-dependent density functional theory (LC-TDDFT) has been applied to compute singlet vertical electronic excitations of oligothiophene molecules and their dimers and compared with the algebraic diagrammatic construction method to second order [ADC(2)], a wave function-based polarization propagator method. The excitation energies obtained from both methods agree to each other excellently. In particular, energetics of charge transfer states is concertedly reproduced. The linear response (LR) and the state specific (SS) approaches have been evaluated to appraise solvent effect on excited states. Benchmarked by the reference wave function method, the necessity of the SS treatment is justified in the prediction of charge transfer (CT) states under the TDDFT framework. PMID- 26588298 TI - Ab Initio Optoelectronic Properties of Silicon Nanoparticles: Excitation Energies, Sum Rules, and Tamm-Dancoff Approximation. AB - We present an ab initio study of the excited state properties of silicon nanoparticles (NPs) with diameters of 1.2 and 1.6 nm. Quasiparticle corrections were computed within the G0W0 approximation. The absorption spectra were computed by time-dependent density functional theory (TDDFT) using the adiabatic PBE approximation, and by solving the Bethe-Salpeter equation (BSE). In our calculations, we used recently developed methods that avoid the explicit inversion of the dielectric matrix and summations over empty electronic states. We found that a scissor operator reliably describes quasiparticle corrections for states in the low energy part of the spectra. Our results also showed good agreement between the positions of the absorption peaks obtained using TDDFT and the BSE in the low part of the spectra, although the peak intensities differ. We discuss the effect of the Tamm-Dancoff approximation on the optical properties of the NPs and present a quantitative analysis in terms of sum rules. In the case of the BSE we found that, even in the absence of the Tamm-Dancoff approximation, the f-sum rule is not fully satisfied due to an inconsistency between the approximations used for the BSE kernel and for the quasiparticle Hamiltonian. PMID- 26588299 TI - Applications of Time Dependent and Time Independent Density Functional Theory to the First pi to pi* Transition in Cyanine Dyes. AB - The first pi -> pi* transition in a number of cyanine dyes was studied using both time dependent and time independent density functional methods using a coupled cluster (CC2) method as the benchmark scheme. On the basis of 10 different functionals, it was concluded that adiabatic time dependent density functional theory (ATDDFT) almost independently of the functional gives rise to a singlet triplet separation that is too large by up to 1 eV, leading to too high singlet energies and too low triplet energies. This trend is even clearer when the Tamm Dancoff (TD) approximation is introduced and can in ATDDFT/TD be traced back to the representation of the singlet-triplet separation by a HF-type exchange integral between pi and pi*. The time independent DFT methods (DeltaSCF and RSCF CV-DFT) afford triplet energies that are functional independent and close to those obtained by ATDDFT. However, both the singlet energies and the singlet triplet separations increases with the fraction alpha of HF exchange. This trend can readily be explained in terms of the modest magnitude of a KS-exchange integral between pi and pi* in comparison to the much larger HF-exchange integral. It was shown that a fraction alpha of 0.5 affords good estimates of both the singlet energies and the singlet-triplet separations in comparison to several ab initio benchmarks. PMID- 26588301 TI - Theoretical Study on the UVR8 Photoreceptor: Sensing Ultraviolet-B by Tryptophan and Dissociation of Homodimer. AB - By the irradiation of ultraviolet-B (UV-B) light, UVR8 photoreceptor can undergo dissociation of the protein homodimer and regulate gene expression in plants. We have carried out high-level quantum mechanics (QM) and ONIOM(QM:MM) calculations and molecular dynamics (MD) simulations to study spectra of key tryptophan residues in UVR8 homodimer and to clarify the key role of important charged residues and their salt bridges as well as the feasible dissociation mechanism. First, benchmark calculations on the absorption and emission of 3-methylindole in the gas phase have been performed by different QM methods (TD-DFT, CASSCF, MS CASPT2, and SAC-CI). Twenty different DFT functionals, including double hybrid and Minnesota functionals, were tested, but all these functionals failed to give satisfactory description of two key transitions. In comparison, SAC-CI and CASPT2 methods can give reliable transition energies and a correct order of (1)La and (1)Lb excited states. Furthermore, the vertical absorption and emission energies of tryptophan in UVR8 have been investigated by the ONIOM method. The present results suggest that W285 is the major chromophore of UVR8, while W233 can also sense the UV-B light and may be responsible for exciton coupling. Geometrical effects as well as electrostatic and polarization interactions with the protein matrix were found to influence optical properties of these tryptophan residues in UVR8. At the homodimeric interface, R286-D107 and R338-D44 salt bridges are suggested to play a crucial role for the UVR8 monomerization. In addition, the UV B induced dissociation mechanism of the UVR8 homodimer has been proposed. The electrostatic repulsion between the partially negatively charged benzene ring of W285 in the (1)La excited state and the negatively charged D44/D107, along with electron and/or proton transfers among W285, R286 (or R338), W233 and D129, was suggested to result in the breakage of the key salt bridges, and destabilization as well as dissociation of the UVR8 dimer. The proposed mechanism also accounts for the fluorescence quenching in UVR8, and the stability and the enhanced red shifted fluorescence in the W285F mutant. PMID- 26588300 TI - Benchmarking DFT and TD-DFT Functionals for the Ground and Excited States of Hydrogen-Rich Peptide Radicals. AB - We assess the pros and cons of a large panel of DFT exchange-correlation functionals for the prediction of the electronic structure of hydrogen-rich peptide radicals formed after electron attachment on a protonated peptide. Indeed, despite its importance in the understanding of the chemical changes associated with the reduction step, the question of the attachment site of an electron and, more generally, of the reduced species formed in the gas phase through electron-induced dissociation (ExD) processes in mass spectrometry is still a matter of debate. For hydrogen-rich peptide radicals in which several positive groups and low-lying pi* orbitals can capture the incoming electron in ExD, inclusion of full Hartree-Fock exchange at long-range interelectronic distance is a prerequisite for an accurate description of the electronic states, thereby excluding several popular exchange-correlation functionals, e.g., B3LYP, M06-2X, or CAM-B3LYP. However, we show that this condition is not sufficient by comparing the results obtained with asymptotically correct range-separated hybrids (M11, LC-BLYP, LC-BPW91, omegaB97, omegaB97X, and omegaB97X-D) and with reference CASSCF-MRCI and EOM-CCSD calculations. The attenuation parameter omega significantly tunes the spin density distribution and the excited states vertical energies. The investigated model structures, ranging from methylammonium to hexapeptide, allow us to obtain a description of the nature and energy of the electronic states, depending on (i) the presence of hydrogen bond(s) around the cationic site(s), (ii) the presence of pi* molecular orbitals (MOs), and (iii) the selected DFT approach. It turns out that, in the present framework, LC-BLYP and omegaB97 yields the most accurate results. PMID- 26588302 TI - Binding Free Energy Calculations for Lead Optimization: Assessment of Their Accuracy in an Industrial Drug Design Context. AB - Correctly ranking compounds according to their computed relative binding affinities will be of great value for decision making in the lead optimization phase of industrial drug discovery. However, the performance of existing computationally demanding binding free energy calculation methods in this context is largely unknown. We analyzed the performance of the molecular mechanics continuum solvent, the linear interaction energy (LIE), and the thermodynamic integration (TI) approach for three sets of compounds from industrial lead optimization projects. The data sets pose challenges typical for this early stage of drug discovery. None of the methods was sufficiently predictive when applied out of the box without considering these challenges. Detailed investigations of failures revealed critical points that are essential for good binding free energy predictions. When data set-specific features were considered accordingly, predictions valuable for lead optimization could be obtained for all approaches but LIE. Our findings lead to clear recommendations for when to use which of the above approaches. Our findings also stress the important role of expert knowledge in this process, not least for estimating the accuracy of prediction results by TI, using indicators such as the size and chemical structure of exchanged groups and the statistical error in the predictions. Such knowledge will be invaluable when it comes to the question which of the TI results can be trusted for decision making. PMID- 26588303 TI - The Development of a Classical Force Field To Determine the Selectivity of an Aqueous Fe(3+)-EDA Complex for TcO4(-) and SO4(2.). AB - A classical force field has been developed in order to investigate the selective exchange of oxyanions (TcO4(-) vs SO4(2-)) with other ligands (H2O, Cl(-)) to an aqueous Fe(3+)-ethylenediamine (EDA) complex. Potentials of mean force for a range of exchange reactions were generated using umbrella sampling and classical molecular dynamics simulations in order to calculate the affinity of each oxyanion for the Fe(3+)-EDA complex in aqueous solution. In order to accurately introduce a degree of specificity for the interaction of Fe(3+) with each ligand type, force field parameters were tuned to match the results of density functional theory calculations. Preferential exchange of H2O, Cl(-), and SO4(2-) for TcO4(-) via an interchange mechanism is observed, in agreement with experimental observations. Both the relative solvation entropies and enthalpies of the anions were found to be critically important factors governing the magnitude of the observed selectivities. These results have important implications for the design and modeling of functionalized materials for the remediation of land contaminated with radioactive (99)Tc. PMID- 26588304 TI - Hybrid Quantum Mechanics/Molecular Mechanics Solvation Scheme for Computing Free Energies of Reactions at Metal-Water Interfaces. AB - We report the development of a quantum mechanics/molecular mechanics free energy perturbation (QM/MM-FEP) method for modeling chemical reactions at metal-water interfaces. This novel solvation scheme combines planewave density function theory (DFT), periodic electrostatic embedded cluster method (PEECM) calculations using Gaussian-type orbitals, and classical molecular dynamics (MD) simulations to obtain a free energy description of a complex metal-water system. We derive a potential of mean force (PMF) of the reaction system within the QM/MM framework. A fixed-size, finite ensemble of MM conformations is used to permit precise evaluation of the PMF of QM coordinates and its gradient defined within this ensemble. Local conformations of adsorbed reaction moieties are optimized using sequential MD-sampling and QM-optimization steps. An approximate reaction coordinate is constructed using a number of interpolated states and the free energy difference between adjacent states is calculated using the QM/MM-FEP method. By avoiding on-the-fly QM calculations and by circumventing the challenges associated with statistical averaging during MD sampling, a computational speedup of multiple orders of magnitude is realized. The method is systematically validated against the results of ab initio QM calculations and demonstrated for C-C cleavage in double-dehydrogenated ethylene glycol on a Pt (111) model surface. PMID- 26588305 TI - Dual Approach to Vibrational Spectra in Solution: Microscopic Influence of Hydrogen Bonding to the State of Motion of Glycine in Water. AB - We have proposed a new theoretical methodology to clarify the microscopic nature of the vibrational properties in solution, which consists of a combination of the vibrational frequency analyses (VFAs) with two kinds of Hessian matrices, that is, the effective Hessian on the free energy surface (free energy Hessian: "FE Hessian") and the instantaneous one (instantaneous normal mode Hessian: "INM Hessian") within QM/MM framework. In these VFAs, the Hessians were obtained by the analytical approach, having the advantages from the aspect of both the computational efficiency and accuracy in comparison to those obtained by the numerical one. In the present study, we have applied them to the glycine aqueous solution. First, by using the VFA with the FE-Hessian (VFA-FEH), we estimated the vibrational frequency shifts induced by solvent water molecules. The calculated values were quantitatively in agreement with experimental ones. It was clearly demonstrated that such vibrational shifts are attributed to not only the structural relaxation but also the explicit solute-solvent interactions (i.e., interatomic interactions). Second, by using the VFA with the INM-Hessian (VFA INMH), the vibrational spectra in solution were investigated through the vibrational INM densities of states (DOS). By the comparison between the spectroscopic features and the microscopic solvation structure around glycine molecule, it was found that the frequency shifts and bandwidths in IR spectra are closely correlated with the hydrogen bonding (HB) network formations. In particular, the instantaneous changes of vibrational states of the hydroxyl group and carbonyl one, showing apparently inverse tendency on the strength of the HB interaction, can be explained very well on the basis of two different mechanisms, that is, the direct change of electron density in the bonding orbitals and the indirect one due to hyperconjugation between the lone electron pair and the antibonding orbitals, respectively. In conclusion, the present dual VFA approach is a quite useful strategy to interpret the microscopic origin of the experimental vibrational spectra. PMID- 26588306 TI - Progress in Visualizing Atomic Size Effects with DFT-Chemical Pressure Analysis: From Isolated Atoms to Trends in AB5 Intermetallics. AB - The notion of atomic size poses an important challenge to chemical theory: empirical evidence has long established that atoms have spatial requirements, which are summarized in tables of covalent, ionic, metallic, and van der Waals radii. Considerations based on these radii play a central role in the design and interpretation of experiments, but few methods are available to directly support arguments based on atomic size using electronic structure methods. Recently, we described an approach to elucidating atomic size effects using theoretical calculations: the DFT-Chemical Pressure analysis, which visualizes the local pressures arising in crystal structures from the interactions of atomic size and electronic effects. Using this approach, a variety of structural phenomena in intermetallic phases have already been understood in terms that provide guidance to new synthetic experiments. However, the applicability of the DFT-CP method to the broad range of the structures encountered in the solid state is limited by two issues: (1) the difficulty of interpreting the intense pressure features that appear in atomic core regions and (2) the need to divide space among pairs of interacting atoms in a meaningful way. In this article, we describe general solutions to these issues. In addressing the first issue, we explore the CP analysis of a test case in which no core pressures would be expected to arise: isolated atoms in large boxes. Our calculations reveal that intense core pressures do indeed arise in these virtually pressure-less model systems and allow us to trace the issue to the shifts in the voxel positions relative to atomic centers upon expanding and contracting the unit cell. A compensatory grid unwarping procedure is introduced to remedy this artifact. The second issue revolves around the difficulty of interpreting the pressure map in terms of interatomic interactions in a way that respects the size differences of the atoms and avoids artificial geometrical constraints. In approaching this challenge, we have developed a scheme for allocating the grid pressures to contacts inspired by the Hirshfeld charge analysis. Here, each voxel is allocated to the contact between the two atoms whose free atom electron densities show the largest values at that position. In this way, the differing sizes of atoms are naturally included in the division of space without resorting to empirical radii. The use of the improved DFT-CP method is illustrated through analyses of the applicability of radius ratio arguments to Laves phase structures and the structural preferences of AB5 intermetallics between the CaCu5 and AuBe5 structure types. PMID- 26588307 TI - Single Molecule Rectification Induced by the Asymmetry of a Single Frontier Orbital. AB - A mechanism for electronic rectification under low bias potentials is elucidated for the prototype molecule HS-phenyl-amide-phenyl-SH. We apply density functional theory (DFT) combined with the nonequilibrium Green's function formalism (NEGF), as implemented in the TranSIESTA computational code to calculate transport properties. We find that a single frontier orbital, the closest to the Fermi level, provides the dominant contribution to the overall transmission and determines the current. The asymmetric distribution of electron density in that orbital leads to rectification in charge transport due to its asymmetric response, shifting toward (or away from) the Fermi level under forward (or reverse) applied bias voltage. These findings provide a simple design principle to suppress recombination in molecular assemblies of dye-sensitized solar cells (DSSCs) where interfacial electron transfer is mediated by frontier orbitals with asymmetric character. PMID- 26588308 TI - First-Principles Prediction of Liquid/Liquid Interfacial Tension. AB - The interfacial tension between two liquids is the free energy per unit surface area required to create that interface. Interfacial tension is a determining factor for two-phase liquid behavior in a wide variety of systems ranging from water flooding in oil recovery processes and remediation of groundwater aquifers contaminated by chlorinated solvents to drug delivery and a host of industrial processes. Here, we present a model for predicting interfacial tension from first principles using density functional theory calculations. Our model requires no experimental input and is applicable to liquid/liquid systems of arbitrary compositions. The consistency of the predictions with experimental data is significant for binary, ternary, and multicomponent water/organic compound systems, which offers confidence in using the model to predict behavior where no data exists. The method is fast and can be used as a screening technique as well as to extend experimental data into conditions where measurements are technically too difficult, time consuming, or impossible. PMID- 26588309 TI - An Infinite Order Discrete Variable Representation of an Effective Mass Hamiltonian: Application to Exciton Wave Functions in Quantum Confined Nanostructures. AB - We describe an extension of the conventional Fourier grid discrete variable representation (DVR) to the bound state problem of a particle with a position dependent mass. An infinite order DVR, derived for a variable mass kinetic energy operator, coupled with an efficient grid contraction scheme yields essentially exact eigenvalues for a chosen grid spacing. Implementation of the method is shown to be very practical due to the fact that in a DVR no integral evaluation is necessary and that the resultant kinetic energy matrix is sparse. Numerical calculations are presented for exciton states of spherical, cylindrical, and toric Type I (CdSe/ZnS) core-shell quantum dots. In these examples, electron-hole interaction is treated explicitly by solving a self-consistent Schrodinger Poisson equation on a contracted DVR grid. Prospective applications of the developed approach to calculating electron transfer rates between adsorbed molecular acceptors and quantum confined nanocrystals of generic shape, dimensionality, and composition are also discussed. PMID- 26588310 TI - Application of Diffusion Monte Carlo to Materials Dominated by van der Waals Interactions. AB - van der Waals forces are notoriously difficult to account for from first principles. We have performed extensive calculations to assess the usefulness and validity of diffusion quantum Monte Carlo when predicting van der Waals forces. We present converged results for noble gas solids and clusters, archetypical van der Waals dominated systems, as well as the highly relevant pi-pi stacking supramolecular complex: DNA + intercalating anticancer drug ellipticine. Analysis of the calculated binding energies underscores the existence of significant interatomic many-body contributions. PMID- 26588311 TI - Benchmarking Calculated Lattice Parameters and Energies of Molecular Crystals Using van der Waals Density Functionals. AB - The development of new functionals and methods to accurately describe van der Waals forces in density functional theory (DFT) has become popular in recent years, with the vast majority of studies assessing the accuracy of the energetics of collections of molecules, and to a lesser extent molecular crystalline systems. As the energies are a function of the atom positions, we assess the accuracy of DFT calculations from both a geometric and energetics point of view for the C21 reference data set of Otero-de-la-Roza and Johnson for molecular crystals, and a set of monosaccharide molecular crystals. In particular, we examine the performance of exchange-correlation functionals designed to handle van der Waals forces, including the vdW-DF, vdW-DF2, and XDM methods. We also assess the effect of using small and large basis sets, the choice of basis functions (local atomic orbitals using the SIESTA code versus planewaves using the Quantum ESPRESSO code), and the effect of corrections for basis set superposition errors. Finally, we examine the geometries and energies of the S22 reference set of molecular complexes. Overall, the most accurate geometries for both choices of basis functions are obtained with the vdW-DF2 functional, while the most accurate lattice energies are obtained using vdW-DF2 with local atomic orbitals and XDM with planewaves with mean absolute errors of less than 4 kJ/mol. PMID- 26588312 TI - Simulating Large-Scale Conformational Changes of Proteins by Accelerating Collective Motions Obtained from Principal Component Analysis. AB - Enhanced sampling methods remain of continuing interest over the past decades because they are able to explore conformational space of proteins much more extensively than conventional molecular dynamics (MD) simulations. In this paper, we report a new sampling method that utilizes a few collective modes obtained from principal component analysis (PCA) to guide the MD simulations. Two multidomain proteins, bacteriophage T4 lysozyme and human vinculin, are studied to test the method. By updating the PCA modes with a proper frequency, our method can sample large-amplitude conformational changes of the proteins much more efficiently than standard MD. Since those PCA modes are calculated from structural ensembles generated by all-atom simulations, the method may overcome an inherent limitation called "tip effect" that would possibly appear in those sampling techniques based on coarse-grained elastic network models. The algorithm proposed here is potentially very useful in developing tools for flexible fitting of protein structures integrating cryo-electron microscope or small-angle X-ray scattering data. PMID- 26588313 TI - Probabilistic Determination of Native State Ensembles of Proteins. AB - The motions of biological macromolecules are tightly coupled to their functions. However, while the study of fast motions has become increasingly feasible in recent years, the study of slower, biologically important motions remains difficult. Here, we present a method to construct native state ensembles of proteins by the combination of physical force fields and experimental data through modern statistical methodology. As an example, we use NMR residual dipolar couplings to determine a native state ensemble of the extensively studied third immunoglobulin binding domain of protein G (GB3). The ensemble accurately describes both local and nonlocal backbone fluctuations as judged by its reproduction of complementary experimental data. While it is difficult to assess precise time-scales of the observed motions, our results suggest that it is possible to construct realistic conformational ensembles of biomolecules very efficiently. The approach may allow for a dramatic reduction in the computational as well as experimental resources needed to obtain accurate conformational ensembles of biological macromolecules in a statistically sound manner. PMID- 26588314 TI - Studies of pH-Sensitive Optical Properties of the deGFP1 Green Fluorescent Protein Using a Unique Polarizable Force Field. AB - The aim of this study is to identify the responsible molecular forms for the pH dependent optical properties of the deGFP1 green fluorescent protein mutant. We have carried out static and dynamic type calculations for all four protonation states of the chromophore to unravel the contributions due to finite temperature and the flexible protein backbone on the pH dependent optical properties. In particular, we have used a combined molecular dynamics and density functional molecular mechanics linear response approach by means of which the optical property calculations were carried out for the chromophore in the explicitly treated solvent and bioenvironment. Two different models were used to describe the environment-electronic embedding and polarizable electronic embedding accounting for the polarization of the chromophore and the mutual polarization between the chromophore and the environment, respectively. For this purpose a polarizable force field was derived quantum mechanically for the protein environment by use of analytical response theory. While the gas-phase calculations for the chromophore predict that the induced red shift going from low to high pH is attributed to the change of molecular forms from neutral to zwitterionic, the two more advanced models that explicitly account for the protein backbone attribute the pH shift to a neutral to anionic conversion. Some ramifications of the results for the use of GFPs as pH sensors are discussed. PMID- 26588315 TI - Energetics of Hydrophilic Protein-Protein Association and the Role of Water. AB - Hydrophilic protein-protein interfaces constitute a major part of all protein protein interfaces and are thus of great importance. However, the quantitative characterization of their association is still an ongoing challenge and the driving force behind their association remains poorly characterized. Here, we have addressed the association of hydrophilic proteins and the role of water by means of extensive molecular dynamics simulations in explicit water using three well studied protein complexes; Barnase-Barstar, cytochrome c-cytochrome c peroxidase, and the N-terminal domain of enzyme I-histidine-containing phosphocarrier. The one-dimensional free energy profiles obtained from umbrella sampling simulations are downhill or, in other words, barrierless. Using these one-dimensional free energy profiles, the computed standard free energies of binding are -12.7 +/- 1.1 kcal/mol, -9.4 +/- 0.7 kcal/mol, and -8.4 +/- 1.9 kcal/mol that are in reasonable to very good agreement with the experimental values of -19.6 kcal/mol, -8.8 kcal/mol, and -7.8 kcal/mol. As expected, analysis of the confined water between the hydrophilic complex partners shows that the density and the orientational order parameter deviate noticeably from the bulk values, especially at close separations of the confining proteins. PMID- 26588316 TI - The Pathway for O2 Diffusion inside CotA Laccase and Possible Implications on the Multicopper Oxidases Family. AB - Laccases and multicopper oxidases (MCOs) oxidize a wide range of organic compounds while reducing O2 to water, enabling numerous biotechnological applications. It is still unknown how O2 reaches the internalized catalytic center of MCOs where it gets reduced, despite a proposed channel inferred from X ray crystallography structures. Herein, an alternative new pathway is found through the use of a combination of free energy calculations (implicit ligand sampling), landscape analysis, and Markov modeling. The reported pathway is shown to be the one mostly contributing to O2 reaching the catalytic center. This pathway is considered in light of the whole MCO family, and a relation to the protonation state of a structurally conserved acidic residue right above the center is advanced. PMID- 26588317 TI - Elucidating the Relation between Internal Motions and Dihedral Angles in an RNA Hairpin Using Molecular Dynamics. AB - Molecular dynamics simulations were performed to characterize the internal motions of the ribonucleic acid apical stem loop of human hepatitis B virus. The NMR relaxation rates calculated directly from the trajectory are in good agreement with the experiment. Calculated order parameters follow the experimental pattern. Order parameters lower than 0.8 are observed for nucleotides that are weakly hydrogen bonded to their base pair partner, unpaired, or part of the loop. These residues show slow decay of the internal correlation functions of their base and sugar C-H vectors. Concerted motions around backbone dihedral angles influence the amplitude of motion of the sugar and base C-H vectors. The order parameters for base C-H vectors are also affected by the fluctuation of the glycosidic dihedral angle. PMID- 26588318 TI - A Solvent-Mediated Coarse-Grained Model of DNA Derived with the Systematic Newton Inversion Method. AB - We present a new class of coarse-grained (CG) force fields (FFs) for B-DNA with explicit ions suited for large-scale mesoscale simulations at microsecond micrometer scale using a wide spectrum of particle simulation methods from molecular dynamics to dissipative particle dynamics. The effective solvent mediated pairwise interactions making up the FFs are obtained by inverting radial distribution functions and other particle-particle distributions obtained from all-atom simulations of numbers of octadecamer DNA fragments from the Ascona B DNA library. The inverse Monte Carlo (IMC) method, later known as Newton inversion (NI) (Lyubartsev, A. P.; Laaksonen, A. Phys. Rev. E, 1995, 52, 3730 3737), was used together with the iterative Boltzmann inversion (IBI) scheme to compute the effective CG potentials. We show that this systematic structure-based approach is capable of providing converged potentials that accurately reproduce the structural features of the underlying atomistic system within a few percents of relative difference. We also show that a simple one-site-per-nucleotide model with 10 intramolecular pair interaction potentials is able to reproduce key features of DNA, for example, the persistence length and its dependence on the ionic concentration, experimentally determined around 50 nm at physiological salt concentration. PMID- 26588319 TI - Prediction of Ligand Binding Affinity by the Combination of Replica-Exchange Method and Double-Decoupling Method. AB - A prediction method for ligand binding affinities to proteins is proposed. We first predict the structures of protein-ligand complex by the replica-exchange umbrella sampling or its extension. We then calculate ligand binding affinities based on these predicted ligand-protein bound structures by the double-decoupling method. As a test of the effectiveness of the proposed method, we applied it to the system of the oncoprotein MDM2 and a ligand. The value of the predicted binding affinity turned out to be in good agreement with that from experiments. PMID- 26588320 TI - Prediction of Solvation Free Energies with Thermodynamic Integration Using the General Amber Force Field. AB - Computer-aided drug design (CADD) techniques can be very effective in reducing costs and speeding up drug discovery. The determination of binding and solvation free energies is pivotal for this process and is, therefore, the subject of many studies. In this work, the solvation free energy change (DeltaDeltaGsolv) for a total of 92 transformations in small molecules was predicted using Thermodynamic Integration (TI). It was our aim to compare experimental and calculated solvation free energies for typical and prime additions considered in drug optimizations, analyzing trends, and optimizing a TI protocol. The results showed a good agreement between experimental and predicted values, with an overestimation of the predicted values for CH3, halogens, and NH2, as well as an underestimation for CONH2, but all fall within +/-1 kcal/mol. NO2 addition showed a larger and systematic underestimation of the predicted DeltaDeltaGsolv, indicating the need for special attention in these cases. For small molecules, if no experimental data is available, using TI as a theoretical strategy thus appears to be a suitable choice in CADD. It provides a good compromise between time and accuracy. PMID- 26588321 TI - Molecular Recognition of Platinated DNA from Chromosomal HMGB1. AB - Cisplatin cures testicular and ovarian cancers with unprecedented potency. It induces its beneficial activity by covalently binding to DNA. Repair enzymes, which remove the platinated lesions from DNA, cause drug resistance. Chromosomal High Mobility Group Box proteins (HMGB) may interfere with this process by binding to platinated DNA. Using 8 MUs multiple-walker well-tempered metadynamics simulations, here, we investigated the structural and the energetic determinants of one of the HMGB proteins (HMGB1A) in complex with the platinated oligonucleotide [Pt(NH3)2](2+)-d(CCUCTCTG*G*ACCTTCC)-d(GGAGAGACCTGGAAGG) (*G are platinated guanines), for which experimental structural information is available. The calculated affinity is in good agreement with experiment. The process is predicted to be enthalpy-driven, as found for other protein/DNA complexes. The Lys7 residue, whose side-chain was not resolved in the X-ray structure, is found to interact with the C4 5'-phosphate and this interaction emerges as a key facet for the molecular recognition process. In addition, our calculations provide a molecular basis for the experimentally measured decreased affinity of HMGB1A for platinated DNA, as a consequence of Cys22-Cys44 S-S bridge formation (such an oxidation cannot take place in some members of this protein family present in the testis, where the drug is particularly effective). This decrease is likely to be caused by a small yet significant rearrangement of helices H1 and H2 with consequent alteration of the Phe37 juxtaposition. PMID- 26588322 TI - Erratum: Development of a "First-Principles" Water Potential with Flexible Monomers: Dimer Potential Energy Surface, VRT Spectrum, and Second Virial Coefficient. PMID- 26588323 TI - Erratum: Harmonic Models in Cartesian and Internal Coordinates to Simulate the Absorption Spectra of Carotenoids at Finite Temperatures. PMID- 26588324 TI - Poly(3,4-ethylenedioxythiophene) Bearing Phosphorylcholine Groups for Metal-Free, Antibody-Free, and Low-Impedance Biosensors Specific for C-Reactive Protein. AB - Conducting polymers possessing biorecognition elements are essential for developing electrical biosensors sensitive and specific to clinically relevant biomolecules. We developed a new 3,4-ethylenedioxythiophene (EDOT) derivative bearing a zwitterionic phosphorylcholine group via a facile synthesis through the Michael-type addition thiol-ene "click" reaction for the detection of an acute phase biomarker human C-reactive protein (CRP). The phosphorylcholine group, a major headgroup in phospholipid, which is the main constituent of plasma membrane, was also expected to resist nonspecific adsorption of other proteins at the electrode/solution interface. The biomimetic EDOT derivative was randomly copolymerized with EDOT, via an electropolymerization technique with a dopant sodium perchlorate, onto a glassy carbon electrode to make the synthesized polymer film both conductive and target-responsive. The conducting copolymer films were characterized by cyclic voltammetry, scanning electron microscopy, attenuated total reflection Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, and electrochemical impedance spectroscopy. The specific interaction of CRP with phosphorylcholine in a calcium-containing buffer solution was determined by differential pulse voltammetry, which measures the altered redox reaction between the indicators ferricyanide/ferrocyanide as a result of the binding event. The conducting polymer-based protein sensor achieved a limit of detection of 37 nM with a dynamic range of 10-160 nM, covering the dynamically changing CRP levels in circulation during the acute phase. The results will enable the development of metal-free, antibody-free, and low impedance electrochemical biosensors for the screening of nonspecific biomarkers of inflammation and infection. PMID- 26588325 TI - Strategies to accelerate immune recovery after allogeneic hematopoietic stem cell transplantation. AB - The interplay existing between immune reconstitution and patient outcome has been extensively demonstrated in allogeneic hematopoietic stem cell transplantation. One of the leading causes of infection-related mortality is the slow recovery of T-cell immunity due to the conditioning regimen and/or age-related thymus damage, poor naive T-cell output, and restricted T-cell receptor (TCR) repertoires. With the aim of improving posttransplantation immune reconstitution, several immunotherapy approaches have been explored. Donor leukocyte infusions are widely used to accelerate immune recovery, but they carry the risk of provoking graft versus-host disease. This review will focus on sophisticated strategies of thymus function-recovery, adoptive infusion of donor-derived, allodepleted T cells, T cell lines/clones specific for life-threatening pathogens, regulatory T cells, and of T cells transduced with suicide genes. PMID- 26588326 TI - The effects of vascular endothelial growth factor (VEGF) on human orbital preadipocyte. AB - PURPOSE: To investigate the presence of the Vascular Endothelial Growth Factor (VEGF) and its receptor (VEGFR) in human orbital preadipocytes, and to evaluate the effect of VEGF on human orbital preadipocyte differentiation and adipogenesis in vitro. RESULTS: Four isoforms of VEGF (VEGF121, 155, 189, and 206), VEGFR-1, VEGF-2, and neuropilin-1 were expressed in human orbital preadipocytes. Treatment with 100 ng/ml VEGF induced higher expressions of C/EBPalpha and LPL than the non treated control (p = 0.03 and p = 0.01) or treatment with 50ng/ml (p = 0.04 for both). At both concentrations VEGF enhanced the accumulation of intra-cytoplasmic lipid versus the control, and treatment with 100 ng/ml VEGF induced more lipid accumulation than treatment with 50 ng/ml VEGF (p = 0.03). CONCLUSIONS: VEGF and VEGFR were observed in human orbital preadipocytes, and exogenous VEGF enhanced adipogenesis in these cells. These results suggest that VEGF plays a role as an autocrine or paracrine growth factor during human orbital preadipocyte differentiation. PMID- 26588327 TI - Emergency Imaging of Intracerebral Haemorrhage. AB - Spontaneous intracerebral haemorrhage (ICH) is a devastating condition with high mortality and morbidity despite advances in neurocritical care. Early deterioration is common in the first few hours after ICH onset, secondary to rapid haematoma expansion and growth. Rapid diagnosis and aggressive early management of these patients are therefore crucial. Imaging plays a key role in establishing the diagnosis and the underlying aetiology of ICH, identifying complications and predicting patients who are at high risk for haematoma expansion. In this chapter, we present an evidence-based imaging framework for the management of spontaneous ICH in the acute setting. Non-enhanced computed tomography is long established as the gold standard for ICH diagnosis but has limitations in demonstrating the underlying aetiology in cases of secondary ICH. There is now growing evidence for the ability of non-invasive angiography to establish the underlying aetiology and to predict further haematoma expansion. The presence of small enhancing foci within the haematoma on computed tomography angiography (CTA), the CTA Spot Sign, has been prospectively validated as a predictor of haematoma expansion. Early identification of patients at risk of haematoma expansion allows for the appropriate escalation of care to a neurosurgical team, admission to a neurocritical care unit, appropriate supportive therapy and targeted novel medical and surgical interventions. Catheter angiography, which remains the gold standard for identifying underlying secondary vascular lesions, should be used in selected cases. However, non invasive vascular imaging should be considered as an important step in the diagnosis and early management of secondary ICH patients. Previous concerns related to the radiation dose, contrast-induced nephropathy and cost are addressed in this chapter. Recently, animal models have enabled the qualitative assessment of haematoma expansion, and our increased understanding of ICH may inform future trials of targeted medical and surgical therapies. PMID- 26588328 TI - Toxicology Strategies for Drug Discovery: Present and Future. AB - Attrition due to nonclinical safety represents a major issue for the productivity of pharmaceutical research and development (R&D) organizations, especially during the compound optimization stages of drug discovery and the early stages of clinical development. Focusing on decreasing nonclinical safety-related attrition is not a new concept, and various approaches have been experimented with over the last two decades. Front-loading testing funnels in Discovery with in vitro toxicity assays designed to rapidly identify unfavorable molecules was the approach adopted by most pharmaceutical R&D organizations a few years ago. However, this approach has also a non-negligible opportunity cost. Hence, significant refinements to the "fail early, fail often" paradigm have been proposed recently to reflect the complexity of accurately categorizing compounds with early data points without taking into account other important contextual aspects, in particular efficacious systemic and tissue exposures. This review provides an overview of toxicology approaches and models that can be used in pharmaceutical Discovery at the series/lead identification and lead optimization stages to guide and inform chemistry efforts, as well as a personal view on how to best use them to meet nonclinical safety-related attrition objectives consistent with a sustainable pharmaceutical R&D model. The scope of this review is limited to small molecules, as large molecules are associated with challenges that are quite different. Finally, a perspective on how several emerging technologies may impact toxicity evaluation is also provided. PMID- 26588329 TI - Ventriculostomy and Lytic Therapy for Intracerebral Hemorrhage. AB - Intraventricular hemorrhage (IVH) frequently complicates intracranial hemorrhage (ICH) and is a significant independent contributor to morbidity and mortality, yet therapy directed at ameliorating intraventricular clotting has been limited and until recently, has not been subject to systematic evaluation. Thrombolytic therapy with placement of an external ventricular drain for management of severe IVH secondary to ICH has been investigated in multiple observational studies, small randomized controlled trials and several meta-analyses, soon to culminate with the completion of the 500 patient CLEAR IVH randomized controlled trial. We review conventional and lytic therapeutic approaches to severe IVH in the setting of small ICH, articulating the scope of the problem, management issues, and relevant questions for future research. PMID- 26588331 TI - Gaucher Disease: Clinical, Biological and Therapeutic Aspects. AB - We present a brief review of Gaucher disease (GD), the most common lysosomal storage disease. GD is a rare autosomal recessive disorder characterized by the defective function of the catabolic enzyme beta-glucocerebrosidase (GBA), leading to an accumulation of its substrate, glucocerebroside. Clinical signs and symptoms include neurological dysfunctions, bone infarcts and malformations, hepatosplenomegaly and hypersplenism leading to anemia, neutropenia and thrombocytopenia. Enzyme replacement therapy with recombinant GBA is the mainstay of treatment for GD, which became the first successfully managed lipid storage disease. Future treatments may include oral enzyme replacement and/or gene therapy interventions. PMID- 26588332 TI - Histopathologic Distinguishing Features Between Lupus and Lichenoid Keratosis on the Face. AB - BACKGROUND: The occurrence of lichenoid keratosis (LK) on the face is not well characterized, and the histopathologic distinction between LK and lupus erythematosus (LE) occurring on the face is often indeterminate. The authors aimed to describe differences between LE and LK occurring on the face by hematoxylin and eosin alone. METHODS: Cases of LK and LE were obtained using computer-driven queries. Clinical correlation was obtained for each lupus case. Other diagnoses were excluded for the LK cases. Hematoxylin and eosin-stained sections were reviewed. RESULTS: Forty-five cases of LK and 30 cases of LE occurring on the face were identified. Shared features included follicular involvement, epidermal atrophy, pigment incontinence, paucity of eosinophils, and basket-weave orthokeratosis. Major differences between LK and LE, respectively, included perivascular inflammation (11%, 90%), high Civatte bodies (44%, 7%), solar elastosis (84%, 33%), a predominate pattern of cell-poor vacuolar interface dermatitis (7%, 73%), compact follicular plugging (11%, 50%), hemorrhage (22%, 70%), mucin (0%, 77%), hypergranulosis (44%, 17%), and edema (7%, 60%). A predominate pattern of band-like lichenoid interface was seen more commonly in LK as compared with LE (93% vs. 27%). CONCLUSIONS: The authors established the occurrence of LK on the face and identified features to help distinguish LK from LE. Follicular involvement, basket-weave orthokeratosis, pigment incontinence, paucity of eosinophils, and epidermal atrophy were not reliable distinguishing features. Perivascular inflammation, cell-poor vacuolar interface, compact follicular plugging, mucin, hemorrhage, and edema favored LE. High Civatte bodies, band-like lichenoid interface, and solar elastosis favored LK. PMID- 26588333 TI - MAP Kinase Pathways: Molecular Roads to Primary Acral Lentiginous Melanoma. AB - The etiology and pathogenesis of lentiginous acral melanomas are poorly understood. Recent studies have postulated that DNA repair mechanisms and cell growth pathways are involved in the development of melanoma, particularly changes in the MAPK pathways (RAS, BRAF, MEK 1/2, and ERK 1/2). The aim of this study is to assess the status of the MAP kinase pathways in the pathogenesis of acral melanomas. The authors examined the components of the RAS-RAF-MEK-ERK cascades by immunohistochemistry in a series of 16 primary acral melanomas by tissue microarray. The expression of MAP kinase cascade proteins changed in most cases. The authors observed that 57.14% of cases were BRAF positive and that 61.53%, 71.42%, and 71.42% of cases were positive for MEK2, ERK1, and ERK2, respectively; RAS was not expressed in 92.31%, and all cases were negative for MEK1. The absence of RAS and positivity for MEK2, ERK1, and ERK2 were most seen in invasive cases with high thickness. These aspects of the MAPK pathway require further examination in acral melanomas between different populations. Nevertheless, the results highlight significant alterations in the MAP kinase cascades that are related to histological indicators of prognosis in primary acral melanomas. PMID- 26588334 TI - A Rare Case of a Pilar Cyst With Ductal Differentiation. AB - Pilar cysts are common squamous-lined cysts that typically occur on the scalp. They are believed to arise from the isthmus of anagen hairs or from the sac surrounding catagen and telogen hairs. The authors describe a rare case of a pilar cyst with prominent ductal differentiation, presumably of eccrine derivation. Sweat duct differentiation has been described in a myriad of cutaneous neoplasms and rarely within epidermoid cysts. The authors could only find one other case in the literature describing a pilar cyst with sebaceous and apocrine differentiation. The clinicopathologic findings are described here. PMID- 26588335 TI - Unique Cyst in a 22-Year-Old Man. Molluscum contagiosum in an epidermoid cyst. PMID- 26588336 TI - Blastic Plasmacytoid Dendritic Cell Neoplasm in the Pediatric Population: A Case Series and Review of the Literature. AB - Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare aggressive hematologic malignancy primarily found in adults, often carrying a poor prognosis. There are only 33 reported pediatric cases of BPDCN in the literature. Although standard treatment is not yet established for children, current literature recommends the use of high-risk acute lymphoblastic leukemia (ALL) type chemotherapy. Recent studies, however, have explored the benefits of combining chemotherapy with stem-cell transplantation. Here, the authors present 2 cases of pediatric BPDCN treated with different modalities. The first case is a 13-year-old girl who presented with a 3-month history of an initially asymptomatic firm nodule on her left shin. The second case is a 15-year-old boy who presented with a 4-month history of an enlarging subcutaneous nodule on the lower leg. Immunohistochemical staining of both patients was positive for markers consistent with BPDCN. The latter patient received ALL-type therapy alone, whereas the former received ALL-type chemotherapy and stem-cell transplantation. Since initial treatment, both patients remain disease-free. These cases contribute to the limited number of pediatric BPDCN cases, thus helping to advance our knowledge toward an optimal treatment protocol for clinical remission. PMID- 26588337 TI - Cornoid Lamella-Like Structures in HIV-Associated Epidermodysplasia Verruciformis: A Unique Histopathologic Finding. AB - Epidermodysplasia verruciformis (EV) is an uncommon inherited skin condition with increased vulnerability to widespread infection by certain human papillomavirus types, resulting in extensive verruca plana-like papules coalescing to large confluent plaques. Since the AIDS epidemic starting in the 1980s, an acquired type of EV has been described in patients infected with human immunodeficiency virus. The histopathologic features of EV consist of papillated epidermal hyperplasia with hypergranulosis and a distinct bluish-gray color in the large human papillomavirus-infected keratinocytes in the stratum granulosum. The authors present a case of HIV-associated EV with a unique histopathologic finding of multiple cornoid lamella-like structures. To the authors' knowledge, this finding has not been previously described in the literature. PMID- 26588338 TI - Zoledronic Acid-Induced Interface Dermatitis. AB - Zoledronic acid (ZA) is a bisphosphonate given intravenously, most commonly for the treatment of postmenopausal osteoporosis. Increase in usage of ZA because it was FDA-approved has resulted in increasing reports of side effects. For the most part, these are systemic. Cutaneous side effects associated with ZA are infrequent and limited to 2 reports of dermatomyositis to date. In both, patients presented with clinical and laboratory stigmata of dermatomyositis soon after initiation of therapy. In this report, we describe a 62-year-old woman who presented with diffuse, erythematous scaly plaques over the right thigh after 12 hours of infusion of ZA. Histopathologic examination of a skin biopsy from the right thigh revealed patchy scale crust containing neutrophils and inspissated serum, interface change with scattered individually necrotic keratinocytes, and a mild, superficial perivascular lymphocytic infiltrate with scattered eosinophils and pigment incontinence-findings consistent with an interface dermatitis. Given that the patient had no other systemic manifestations or laboratory abnormalities, to the best of our knowledge, ours is the first report of interface dermatitis secondary to ZA with the caveat that longer follow-up is required to definitively exclude the development of drug-induced connective tissue disease. PMID- 26588339 TI - Combined Cutaneous Rosai-Dorfman Disease and Localized Cutaneous Langerhans Cell Histiocytosis Within a Single Subcutaneous Nodule. AB - Rosai-Dorfman disease (RDD) is a reactive multisystem histiocytosis that typically presents with cervical lymphadenopathy and systemic symptoms. Cutaneous involvement occurs in approximately 10% of cases, and 3% of cases are limited to the skin without nodal or other extranodal involvement. Langerhans cell histiocytosis (LCH) is a clonal histiocytosis with a wide spectrum of presentations ranging from isolated skin or bone disease to multisystem involvement. Rare case reports have identified concomitant presentation of RDD and LCH; however, most of these reports have involved LCH and RDD occurring concurrently but at separate sites. We present a rare case of concurrent RDD and LCH presenting within a single skin nodule. The patient did not have any evidence of systemic involvement and has remained stable without additional treatment. We also review the literature on this unusual co-presentation and suggest possible underlying mechanisms. Finally, we recommend baseline laboratory and imaging studies and discuss treatment options based on the available evidence. PMID- 26588340 TI - "Melanocytic Nests Arising in Lichenoid Inflammation": Reappraisal of the Terminology "Melanocytic Pseudonests". AB - Pseudonests or pseudomelanocytic nests represent aggregates of cells and cell fragments, including keratinocytes, macrophages, lymphocytes, and occasional melanocytes. Pseudomelanocytic nests in the setting of lichenoid inflammation can mimic atypical melanocytic proliferations. Several reports documented nonspecific staining of pseudonests with melanoma antigen recognized by T cells-1/Melan-A, which can be detected in the cytoplasm of nonmelanocytic cells. In contrast, nuclear stains, such as MITF and SOX10, avoid this nonmelanocyte cytoplasmic staining. The authors have previously proposed the term melanocytic pseudonests to describe junctional nests with numerous (>2) true melanoma antigen recognized by T cells-1/Melan-A, SOX10, and MITF in a nonmelanocytic lesion with lichenoid inflammation (unilateral lichen planus pigmentosus/erythema dyschromicum perstans). In this study, the authors report another case of this phenomenon arising in a different lichenoid inflammatory dermatitis (lichen planus). The immunophenotype and number of clustered true melanocytes indicate that these dermoepidermal aggregates represent true melanocytic nests and not pseudonests of any type. Therefore, the authors propose the revised terminology of "melanocytic nests arising in lichenoid inflammation" to describe this novel pattern of benign melanocytic reorganization or proliferation in a subset of lichenoid dermatitides. Because this phenomenon can mimic atypical melanocytic proliferations, clinicopathologic correlation is essential for the correct diagnosis. PMID- 26588341 TI - Infective Dermatitis in an Adult Patient With HTLV-1. AB - Infective dermatitis is a chronic exudative eczematous eruption presenting in human T-lymphotropic virus type 1 (HTLV-1)-infected people. It presents with relapsing erythematous, scaly, and crusted lesions affecting simultaneously the scalp, external ear, retroauricular area, eyelid, paranasal skin, neck axilla, and groin. Superimposed Staphylococcus and Streptococcus infection are common. It mainly affects children and exceptionally adults, and there are only a few published cases. The authors present the first reported case in Paraguay of an adult patient who had symptoms of human T-lymphotropic virus type 1-associated progressive tropical spastic paraparesis, and 6 years after the onset of the neurological symptoms, the patient developed infective dermatitis lesions on the skin, with frequent exacerbations since then. PMID- 26588343 TI - Spontaneous Involution of Congenital Melanocytic Nevus With Halo Phenomenon. AB - Congenital melanocytic nevus (CMN) is a neural crest-derived hamartoma, which appear at or soon after birth. CMN has a dynamic course and may show variable changes over time, including spontaneous involution. Spontaneous involution of CMN is a rare phenomenon and is often reported in association with halo phenomenon or vitiligo. The mechanism of halo phenomenon is yet to be investigated but is suggested to be a destruction of melanocytes by immune responses of cytotoxic T cells or IgM autoantibodies. Here, the authors report an interesting case of spontaneously regressed medium-sized CMN with halo phenomenon and without vitiligo, which provides evidence that cytotoxic T cells account for the halo formation and pigmentary regression of CMN. PMID- 26588344 TI - Folliculosebaceous Cystic Hamartoma With Spindle Cell Lipoma-Like Stromal Features. AB - Folliculosebaceous cystic hamartoma is a distinctive cutaneous hamartoma composed of follicular, sebaceous, and mesenchymal components. The lesions are most commonly found on the face and scalp of young adults, with approximately 30% occurring in the nasal or paranasal regions of the face. The clinical differential diagnoses are extensive and include epidermoid cyst, dermal nevus, soft fibroma, and adnexal tumors including sebaceous neoplasms. Here, the authors present a case of a 24-year-old man who presented for evaluation of an asymptomatic growth on the nose, which had slowly enlarged over 9 years. On examination, there was a 0.6 cm dome-shaped flesh-colored papule on the nasal bridge. The clinical differential included dermatofibroma versus intradermal nevus. A shave biopsy was performed, and histological examination of the sections showed a proliferation of multiple enlarged and irregular-appearing sebaceous glands attached to a cystic follicular structure. The associated dermal mesenchymal component consisted of numerous mature-appearing adipocytes associated with a fibromyxoid stroma, prominent collections of mucin, and bundles of ropey collagen resembling a spindle cell lipoma. This combination of a folliculosebaceous cystic hamartoma with a spindle cell lipoma-like mesenchymal proliferation is unusual and has not been previously reported. PMID- 26588345 TI - Grape Cells (Multinucleated Keratinocytes) in Noninfectious Dermatoses: Case Series and Review of the Literature. AB - Multinucleated keratinocytes (also known as multinucleated epidermal giant cells) are a frequently overlooked histological finding in noninfectious inflammatory dermatoses. They are sometimes found in conditions characterized by chronic rubbing and pruritus, such as lichen simplex chronicus or prurigo nodularis, and may be a helpful clue in making the clinical diagnosis. This finding must be differentiated from other conditions characterized by multinucleated keratinocytes on histopathology, specifically herpes simplex, varicella zoster, or measles viral infections. The authors present a case series of 2 patients with unique clinical noninfectious diagnoses but similar histopathologic findings on biopsy. The histopathologic findings on both cases demonstrated multinucleated keratinocytes, which were related to manipulation of the epidermis. PMID- 26588346 TI - Preorganization in a Cleft-Type Anion Receptor Featuring Iodo-1,2,3-Triazoles As Halogen Bond Donors. AB - Preorganization via intramolecular hydrogen bonds was applied in a cleft-type receptor by exploiting the excellent halogen bond donor ability as well as hydrogen bond acceptor function of iodo-1,2,3-triazoles. As investigated by isothermal calorimetric titrations, the restriction of conformational freedom causes an enhanced entropic contribution resulting in a strongly increased binding affinity. This efficient way to improve the binding strength of 5-halo 1,2,3-triazoles paves the way for applications of new charge-neutral halogen bond donors in solution. PMID- 26588347 TI - Melanocortin-4 Receptor Gene Variation Is Associated with Eating Behavior in Chilean Adults. AB - BACKGROUND/AIMS: To evaluate the association between allelic variants of melanocortin receptors -3 and -4 (MC3R and MC4R, respectively) and leptin receptor (LEPR) genes with body mass index (BMI) and eating behavior. METHODS: We selected 344 Chilean adults (57.8% women; age 39.1 +/- 6.6 years) with a wide variation in BMI (30.3 +/- 6.3 kg/m2). The Three-Factor Eating Questionnaire-R18 that measures uncontrolled eating (UE), emotional eating (EE) and cognitive restraint scores was adapted, validated and assessed for association with BMI. Genotypes were determined by polymerase chain reaction followed by restriction fragment length polymorphism techniques and Taqman assays. RESULTS: Higher EE scores were found in obese vs. non-obese in both men (p = 0.01) and women (p < 0.001). UE scores were significantly associated with BMI only in women (p = 0.002). No significant differences in eating behavior scores or BMI were found by LEPR (rs1137101, rs8179183 and rs1137100 polymorphisms) or MC3R (rs3746619 and rs3827103). Carriers of the C allele for MC4R rs17782313 showed significantly higher scores of UE compared to non-carriers (2.3 +/- 0.8 vs. 2.0 +/- 0.7; p = 0.02). Additionally, we also report a monogenic case of obesity carrying the pathogenic mutation 449C>T (Thr150Ile) in MC4R gene with no apparent alterations in eating behavior scores. CONCLUSIONS: UE scores were higher in C-allele carriers of MC4R-rs17782313 compared to non-carriers. PMID- 26588348 TI - Sex-specific fitness effects of unpredictable early life conditions are associated with DNA methylation in the avian glucocorticoid receptor. AB - Organisms can adapt to variable environments by using environmental cues to modulate developmental gene expression. In principle, maternal influences can adaptively adjust offspring phenotype when early life and adult environments match, but they may be maladaptive when future environments are not predictable. One of the best-studied 'maternal effects' is through modification of the offspring's hypothalamic-pituitary-adrenal (HPA) axis, the neuroendocrine system that controls responses to stress. In addition to the direct transfer of glucocorticoids from mother to offspring, offspring HPA function and other phenotypes can also be affected by epigenetic modifications like DNA methylation of the glucocorticoid receptor promoter. Here we examine how among-year variation in rainfall is related to DNA methylation during development and fitness in adulthood in the superb starling (Lamprotornis superbus), which lives in a climatically unpredictable environment where early life and adult environments are unlikely to match. We found that DNA methylation in the putative promoter of the glucocorticoid receptor gene is reduced in chicks - particularly in males - born following drier prebreeding periods. Additionally, DNA methylation is lower in males that become breeders than those that never breed. However, there is no relationship in females between DNA methylation and the likelihood of dispersing from the natal group to breed elsewhere. These results suggest that early life conditions may positively affect fitness in a sex-specific manner through chemical modification of an HPA-associated gene. This study is the first to show that epigenetic modifications during early life may influence the fitness of free living organisms adapted to unpredictable environments. PMID- 26588349 TI - Near infrared light-responsive and injectable supramolecular hydrogels for on demand drug delivery. AB - A near infrared (NIR) light-responsive supramolecular hydrogel consisting of alpha-cyclodextrin and poly(ethylene glycol)-modified dendrimer-encapsulated platinum nanoparticles was developed. Upon NIR irradiation, this hydrogel underwent a photothermo-sensitive degradation to release the entrapped therapeutic agents in an on-demand and dose-tunable fashion. PMID- 26588351 TI - Metabolic Syndrome: Bridging the Gap from Childhood to Adulthood. AB - Childhood and adolescence are particularly vulnerable periods of life to the effects of cardiometabolic risk and later development of atherosclerosis, hypertension, and diabetes mellitus. Developing countries with limited resources suffer most heavily from the consequences of cardiometabolic risk in children and its future implications to the global health burden. A better understanding of mechanisms leading to cardiometabolic risk in early life may lead to more effective prevention and intervention strategies to reduce metabolic stress in children and later disease. Longitudinal "tracking" studies of cardiometabolic risk in children provide a tremendous global resource to direct prevention strategies for cardiovascular disease. In this review, we will summarize the pathophysiology, existing definitions for cardiometabolic risk components in children. Screening and identifying children and adolescents of high cardiometabolic risk and encouraging them and their families through healthy lifestyle changes should be implemented to as a global public health strategy. PMID- 26588350 TI - From hacking the human genome to editing organs. AB - In the recent decades, human genome engineering has been one of the major interesting research subjects, essentially because it raises new possibilities for personalized medicine and biotechnologies. With the development of engineered nucleases such as the Zinc Finger Nucleases (ZFNs), the Transcription activator like effector nucleases (TALENs) and more recently the Clustered Regularly Interspaced short Palindromic Repeats (CRISPR), the field of human genome edition has evolved very rapidly. Every new genetic tool is broadening the scope of applications on human tissues, even before we can completely master each of these tools. In this review, we will present the recent advances regarding human genome edition tools, we will discuss the numerous implications they have in research and medicine, and we will mention the limits and concerns about such technologies. PMID- 26588352 TI - Role of [(11)C] methionine positron emission tomography in the diagnosis and prediction of survival in brain tumours. AB - OBJECTIVE: [(11)C] methionine (MET) positron-emission tomography (PET) is a useful diagnostic and therapeutic tool in neuro-oncology. The aim of this study was to evaluate the relationship between MET uptake and the histopathological grade in both primary brain tumours and brain metastases. A secondary goal was to assess the relationship between MET uptake and patients' survival after surgery. METHODS: We reviewed a consecutive series of 43 PET studies performed at our institution. Out of the 43 patients studied, 35 harboured primary brain tumours (3 grade I, 12 grade II, 7 grade III and 13 grade IV) and 8 patients had brain metastases. We measured the tumour/cortex ratio (T/C ratio) on each PET study and we investigated the correlations among the tracer uptake, tumour grade, tumour type, MRI parameters and outcome. RESULTS: The mean T/C ratio was 1.8 +/- 0.9 for benign lesions and low grade gliomas (grade I and II) and 2.7 +/- 1 for high grade gliomas (grade III and IV). In brain metastases it was 2.5 +/- 0.7, with a significant difference in MET uptake between low and high grades gliomas (P=0.03). There was no statistically significant difference among all different histologic types. We found that both contrast enhancement and perfusion studies correlate with MET uptake in brain tumours. Moreover, in Kaplan-Meier curves, the T/C ratio adversely affects long term survival in patients with brain tumours (P=0.01). CONCLUSIONS: MET PET appears to be useful in diagnosis and evaluation of potential malignancy in brain tumours. MET uptake is also related with the overall survival in patients with brain tumours. Nevertheless, further studies are needed in order to define its possible clinical implications in identifying patients at high risk of tumour progression or resistance to therapy. PMID- 26588353 TI - A High Amount of Local Adipose Tissue Is Associated With High Cortical Porosity and Low Bone Material Strength in Older Women. AB - Obesity is associated with increased risk of fractures, especially at skeletal sites with a large proportion of cortical bone, such as the humerus and ankle. Obesity increases fracture risk independently of BMD, indicating that increased adipose tissue could have negative effects on bone quality. Microindentation assesses bone material strength index (BMSi) in vivo in humans. The aim of this study was to investigate if different depots of adipose tissue were associated with BMSi and cortical bone microstructure in a population based group of 202 women, 78.2 +/- 1.1 (mean +/- SD) years old. Bone parameters and subcutaneous (s.c.) fat were measured at the tibia with an XtremeCT device. BMSi was assessed using the OsteoProbe device, and based on at least 11 valid reference point indentations at the mid-tibia. Body composition was measured with dual X-ray absorptiometry. BMSi was inversely correlated to body mass index (BMI) (r = 0.17, p = 0.01), whole body fat mass (r = -0.16,p = 0.02), and, in particular, to tibia s.c. fat (r = -0.33, p < 0.001). Tibia s.c. fat was also correlated to cortical porosity (Ct.Po; r = 0.19, p = 0.01) and cortical volumetric BMD (Ct.vBMD; r = -0.23, p = 0.001). Using linear regression analyses, tibia s.c. fat was found to be independent of covariates (age, height, log weight, bisphosphonates or glucocorticoid use, smoking, calcium intake, walking speed, and BMSi operator) and associated with BMSi (beta = -0.34,p < 0.001), Ct.Po (beta = 0.18, p = 0.01), and Ct.vBMD (beta = -0.32, p < 0.001). BMSi was independent of covariates associated with cortical porosity (beta = -0.14, p = 0.04) and cortical volumetric BMD (beta = 0.21, p = 0.02) at the distal tibia, but these bone parameters could only explain 3.3% and 5.1% of the variation in BMSi, respectively. In conclusion, fat mass was independently and inversely associated with BMSi and Ct.vBMD, but positively associated with Ct.Po, indicating a possible adverse effect of adipose tissue on bone quality and bone microstructure. Local s.c. fat in tibia was most strongly associated with these bone traits, suggesting a local or paracrine, rather than systemic, negative effect of fat on bone. PMID- 26588354 TI - Organization of the sleep-related neural systems in the brain of the harbour porpoise (Phocoena phocoena). AB - The present study provides the first systematic immunohistochemical neuroanatomical investigation of the systems involved in the control and regulation of sleep in an odontocete cetacean, the harbor porpoise (Phocoena phocoena). The odontocete cetaceans show an unusual form of mammalian sleep, with unihemispheric slow waves, suppressed REM sleep, and continuous bodily movement. All the neural elements involved in sleep regulation and control found in bihemispheric sleeping mammals were present in the harbor porpoise, with no specific nuclei being absent, and no novel nuclei being present. This qualitative similarity of nuclear organization relates to the cholinergic, noradrenergic, serotonergic, and orexinergic systems and is extended to the gamma-aminobutyric acid (GABA)ergic elements involved with these nuclei. Quantitative analysis of the cholinergic and noradrenergic nuclei of the pontine region revealed that in comparison with other mammals, the numbers of pontine cholinergic (126,776) and noradrenergic (122,878) neurons are markedly higher than in other large-brained bihemispheric sleeping mammals. The diminutive telencephalic commissures (anterior commissure, corpus callosum, and hippocampal commissure) along with an enlarged posterior commissure and supernumerary pontine cholinergic and noradrenergic neurons indicate that the control of unihemispheric slow-wave sleep is likely to be a function of interpontine competition, facilitated through the posterior commissure, in response to unilateral telencephalic input related to the drive for sleep. In addition, an expanded peripheral division of the dorsal raphe nuclear complex appears likely to play a role in the suppression of REM sleep in odontocete cetaceans. Thus, the current study provides several clues to the understanding of the neural control of the unusual sleep phenomenology present in odontocete cetaceans. J. Comp. Neurol. 524:1999-2017, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26588355 TI - Lack of Association Between Polymorphisms in AGT and ATR1 and IgA Nephropathy in a Chinese Population. AB - OBJECTIVE: The mechanism of immunoglobulin A nephropathy (IgAN) remains unclear. Genetic factors may be associated with the risk of IgAN. This study aims to identify the possible association of M268T (rs699) in the Angiotensinogen (AGT) gene and A1166C (rs5186) in the Angiotensin II receptor type 1 (ATR1) gene with IgAN risk. METHODS: Study subjects included 351 patients with IgAN and 310 controls from the Chinese population. The tag SNPs (tSNPs) were genotyped by Sequenom MassARRAY RS1000. Statistical analysis of the association between tSNPs and IgAN was performed using the chi(2) test and SNPStats software. RESULTS: The AGT (M268T) genotypes were distributed in IgAN as CC 61.9%, CT 34.8%, and TT 3.2%, while in controls CC 64.1%, CT 31.3%, and TT 4.6%. Distribution of ATR1 (A1166C) was AA 87.7%, CA 12.3%, and CC 0%, while in controls AA 87.2%, CA 12%, and CC 0.8%. We further analyzed tSNPs under different inheritance models and found that there were no significant differences in the genotypes and allele frequencies of rs699 and rs5186 between two groups (p > 0.05). We also analyzed tSNPs based on the rate of pressure, proteinuria and Lee's classification, and no significant differences were found in the models (p > 0.05). CONCLUSION: rs699 in the AGT gene and rs5186 in the ATR1 gene were not associated with the risk and clinical outcomes of IgAN. PMID- 26588356 TI - Late Failing Heart Allografts: Pathology of Cardiac Allograft Vasculopathy and Association With Antibody-Mediated Rejection. AB - In heart transplantation, there is a lack of robust evidence of the specific causes of late allograft failure. We hypothesized that a substantial fraction of failing heart allografts may be associated with antibody-mediated injury and immune-mediated coronary arteriosclerosis. We included all patients undergoing a retransplantation for late terminal heart allograft failure in three referral centers. We performed an integrative strategy of heart allograft phenotyping by assessing the heart vascular tree including histopathology and immunohistochemistry together with circulating donor-specific antibodies. The main analysis included 40 explanted heart allografts patients and 402 endomyocardial biopsies performed before allograft loss. Overall, antibody mediated rejection was observed in 19 (47.5%) failing heart allografts including 16 patients (40%) in whom unrecognized previous episodes of subclinical antibody mediated rejection occurred 4.5 +/- 3.5 years before allograft loss. Explanted allografts with evidence of antibody-mediated rejection demonstrated higher endothelitis and microvascular inflammation scores (0.89 +/- 0.26 and 2.25 +/- 0.28, respectively) compared with explanted allografts without antibody-mediated rejection (0.42 +/- 0.11 and 0.36 +/- 0.09, p = 0.046 and p < 0.0001, respectively). Antibody-mediated injury was observed in 62.1% of failing allografts with pure coronary arteriosclerosis and mixed (arteriosclerosis and atherosclerosis) pattern, while it was not observed in patients with pure coronary atherosclerosis (p = 0.0076). We demonstrate that antibody-mediated rejection is operating in a substantial fraction of failing heart allografts and is associated with severe coronary arteriosclerosis. Unrecognized subclinical antibody-mediated rejection episodes may be observed years before allograft failure. PMID- 26588357 TI - Comparison of Rehabilitating Missing Mandibular First Molars with Implant- or Tooth-Supported Prostheses Using Masticatory Efficiency and Patient Satisfaction Outcomes. AB - PURPOSE: To determine whether a fixed partial denture (FPD) or an implant replacement of a single missing tooth leads to better masticatory efficiency and patient satisfaction. MATERIALS AND METHODS: One-hundred and twenty participants with missing mandibular right first molars were selected on the basis of predefined inclusion and exclusion criteria. After obtaining informed consent, 60 participants were randomized to the teeth-supported (FPD) group and 60 to the implant placement group (IMP). The study was divided into the following parts: (i) Completion of a Likert scale satisfaction questionnaire (postrehabilitation) by the participants. (ii) Evaluation of masticatory efficiency and performance 3 months after rehabilitation. Data were evaluated by applying t-test and z-test using statistical analysis (alpha ? 0.05). RESULTS: Masticatory efficiency of participants in the IMP and FPD groups was 74.95 +/- 0.90% and 74.41 +/- 3.35%, respectively (p = 0.607). Total satisfaction questionnaire scores for the two groups were also not significantly different; however, the mean scores of overall satisfaction and function categories in this questionnaire were significantly higher for the IMP group, while the mean score for the duration of treatment question was higher for the FPD group (p < 0.05). CONCLUSION: The results of this study suggested that although masticatory performance and efficiency were not statistically different for single teeth replaced with implants or FPDs, patients perceived higher satisfaction with implant restorations; they also preferred the shorter treatment times for rehabilitation in the FPD group. PMID- 26588358 TI - Memory cueing during sleep modifies the interpretation of ambiguous scenes in adolescents and adults. AB - The individual tendency to interpret ambiguous situations negatively is associated with mental disorders. Interpretation biases are already evident during adolescence and due to the greater plasticity of the developing brain it may be easier to change biases during this time. We investigated in healthy adolescents and adults whether stabilizing memories of positive or negative scenes modulates the later interpretation of similar scenes. In the evening, participants learnt associations between ambiguous pictures and words that disambiguate the valence of the pictures in a positive or negative direction. Half of the words were acoustically presented (i.e. cued) during post-learning sleep which is known to benefit memory consolidation by inducing reactivation of learned information. Cued compared to un-cued stimuli were remembered better the next morning. Importantly, cueing positively disambiguated pictures resulted in more positive interpretations whereas cueing negatively disambiguated pictures led to less positive interpretations of new ambiguous pictures with similar contents the next morning. These effects were not modulated by participants' age indicating that memory cueing was as efficient in adolescents as in adults. Our findings suggest that memory cueing during sleep can modify interpretation biases by benefitting memory stabilization and generalization. Implications for clinical settings are discussed. PMID- 26588359 TI - CoNi@SiO2 @TiO2 and CoNi@Air@TiO2 Microspheres with Strong Wideband Microwave Absorption. AB - The synthesis of CoNi@SiO2 @TiO2 core-shell and CoNi@Air@TiO2 yolk-shell microspheres is reported for the first time. Owing to the magnetic-dielectric synergistic effect, the obtained CoNi@SiO2 @TiO2 microspheres exhibit outstanding microwave absorption performance with a maximum reflection loss of -58.2 dB and wide bandwidth of 8.1 GHz (8.0-16.1 GHz, < -10 dB). PMID- 26588361 TI - FAST Conformational Searches by Balancing Exploration/Exploitation Trade-Offs. AB - Molecular dynamics simulations are a powerful means of understanding conformational changes. However, it is still difficult to simulate biologically relevant time scales without the use of specialized supercomputers. Here, we introduce a goal-oriented sampling method, called fluctuation amplification of specific traits (FAST), for extending the capabilities of commodity hardware. This algorithm rapidly searches conformational space for structures with desired properties by balancing trade-offs between focused searches around promising solutions (exploitation) and trying novel solutions (exploration). FAST was inspired by the hypothesis that many physical properties have an overall gradient in conformational space, akin to the energetic gradients that are known to guide proteins to their folded states. For example, we expect that transitioning from a conformation with a small solvent-accessible surface area to one with a large surface area will require passing through a series of conformations with steadily increasing surface areas. We demonstrate that such gradients are common through retrospective analysis of existing Markov state models (MSMs). Then we design the FAST algorithm to exploit these gradients to find structures with desired properties by (1) recognizing and amplifying structural fluctuations along gradients that optimize a selected physical property whenever possible, (2) overcoming barriers that interrupt these overall gradients, and (3) rerouting to discover alternative paths when faced with insurmountable barriers. To test FAST, we compare its performance to other methods for three common types of problems: (1) identifying unexpected binding pockets, (2) discovering the preferred paths between specific structures, and (3) folding proteins. Our conservative estimate is that FAST outperforms conventional simulations and an adaptive sampling algorithm by at least an order of magnitude. Furthermore, FAST yields both the proper thermodynamics and kinetics, allowing for a direct connection with kinetic experiments that is impossible with many other advanced sampling algorithms because they provide only thermodynamic information. Therefore, we expect FAST to be of great utility for a wide range of applications. PMID- 26588362 TI - Dynamical Detection of Topological Phase Transitions in Short-Lived Atomic Systems. AB - We demonstrate that dynamical probes provide direct means of detecting the topological phase transition (TPT) between conventional and topological phases, which would otherwise be difficult to access because of loss or heating processes. We propose to avoid such heating by rapidly quenching in and out of the short-lived topological phase across the transition that supports gapless excitations. Following the quench, the distribution of excitations in the final conventional phase carries signatures of the TPT. We apply this strategy to study the TPT into a Majorana-carrying topological phase predicted in one-dimensional spin-orbit-coupled Fermi gases with attractive interactions. The resulting spin resolved momentum distribution, computed by self-consistently solving the time dependent Bogoliubov-de Gennes equations, exhibits Kibble-Zurek scaling and Stuckelberg oscillations characteristic of the TPT. We discuss parameter regimes where the TPT is experimentally accessible. PMID- 26588360 TI - N'-3-(Trifluoromethyl)phenyl Derivatives of N-Aryl-N'-methylguanidines as Prospective PET Radioligands for the Open Channel of the N-Methyl-d-aspartate (NMDA) Receptor: Synthesis and Structure-Affinity Relationships. AB - N-Methyl-d-aspartate (NMDA) receptor dysfunction has been linked to several neuropsychiatric disorders, including Alzheimer's disease, epilepsy, drug addiction, and schizophrenia. A radioligand that could be used with PET to image and quantify human brain NMDA receptors in the activated "open channel" state would be useful for research on such disorders and for the development of novel therapies. To date, no radioligands have shown well-validated efficacy for imaging NMDA receptors in human subjects. In order to discover improved radioligands for PET imaging, we explored structure-affinity relationships in N' 3-(trifluoromethyl)phenyl derivatives of N-aryl-N'-methylguanidines, seeking high affinity and moderate lipophilicity, plus necessary amenability for labeling with a positron-emitter, either carbon-11 or fluorine-18. Among a diverse set of 80 prepared N'-3-(trifluoromethyl)phenyl derivatives, four of these compounds (13, 19, 20, and 36) displayed desirable low nanomolar affinity for inhibition of [(3)H](+)-MK801 at the PCP binding site and are of interest for candidate PET radioligand development. PMID- 26588363 TI - Spontaneous Increase of Magnetic Flux and Chiral-Current Reversal in Bosonic Ladders: Swimming against the Tide. AB - The interplay between spontaneous symmetry breaking in many-body systems, the wavelike nature of quantum particles and lattice effects produces an extraordinary behavior of the chiral current of bosonic particles in the presence of a uniform magnetic flux defined on a two-leg ladder. While noninteracting as well as strongly interacting particles, stirred by the magnetic field, circulate along the system's boundary in the counterclockwise direction in the ground state, interactions stabilize vortex lattices. These states break translational symmetry, which can lead to a reversal of the circulation direction. Our predictions could readily be accessed in quantum gas experiments with existing setups or in arrays of Josephson junctions. PMID- 26588364 TI - Postquantum Steering. AB - The discovery of postquantum nonlocality, i.e., the existence of nonlocal correlations that are stronger than any quantum correlations but nevertheless consistent with the no-signaling principle, has deepened our understanding of the foundations of quantum theory. In this work, we investigate whether the phenomenon of Einstein-Podolsky-Rosen steering, a different form of quantum nonlocality, can also be generalized beyond quantum theory. While post-quantum steering does not exist in the bipartite case, we prove its existence in the case of three observers. Importantly, we show that postquantum steering is a genuinely new phenomenon, fundamentally different from postquantum nonlocality. Our results provide new insight into the nonlocal correlations of multipartite quantum systems. PMID- 26588365 TI - Nonhydrodynamic Transport in Trapped Unitary Fermi Gases. AB - Many strongly coupled fluids are known to share similar hydrodynamic transport properties. In this work we argue that this similarity could extend beyond hydrodynamics to transient dynamics through the presence of nonhydrodynamic modes. We review nonhydrodynamic modes in kinetic theory and gauge-gravity duality and discuss their signatures in trapped Fermi gases close to unitarity. Reanalyzing previously published experimental data we find hints of nonhydrodynamic modes in cold Fermi gases in two and three dimensions. PMID- 26588366 TI - Entangling the Whole by Beam Splitting a Part. AB - A beam splitter is a basic linear optical element appearing in many optics experiments and is frequently used as a continuous-variable entangler transforming a pair of input modes from a separable Gaussian state into an entangled state. However, a beam splitter is a passive operation that can create entanglement from Gaussian states only under certain conditions. One such condition is that the input light is suitably squeezed. We demonstrate, experimentally, that a beam splitter can create entanglement even from modes which do not possess such a squeezing provided that they are correlated to, but not entangled with, a third mode. Specifically, we show that a beam splitter can create three-mode entanglement by acting on two modes of a three-mode fully separable Gaussian state without entangling the two modes themselves. This beam splitter property is a key mechanism behind the performance of the protocol for entanglement distribution by separable states. Moreover, the property also finds application in collaborative quantum dense coding in which decoding of transmitted information is assisted by interference with a mode of the collaborating party. PMID- 26588367 TI - Irreversibility and the Arrow of Time in a Quenched Quantum System. AB - Irreversibility is one of the most intriguing concepts in physics. While microscopic physical laws are perfectly reversible, macroscopic average behavior has a preferred direction of time. According to the second law of thermodynamics, this arrow of time is associated with a positive mean entropy production. Using a nuclear magnetic resonance setup, we measure the nonequilibrium entropy produced in an isolated spin-1/2 system following fast quenches of an external magnetic field. We experimentally demonstrate that it is equal to the entropic distance, expressed by the Kullback-Leibler divergence, between a microscopic process and its time reversal. Our result addresses the concept of irreversibility from a microscopic quantum standpoint. PMID- 26588368 TI - Towards an Optimal Flow: Density-of-States-Informed Replica-Exchange Simulations. AB - Replica exchange (RE) is one of the most popular enhanced-sampling simulations technique in use today. Despite widespread successes, RE simulations can sometimes fail to converge in practical amounts of time, e.g., when sampling around phase transitions, or when a few hard-to-find configurations dominate the statistical averages. We introduce a generalized RE scheme, density-of-states informed RE, that addresses some of these challenges. The key feature of our approach is to inform the simulation with readily available, but commonly unused, information on the density of states of the system as the RE simulation proceeds. This enables two improvements, namely, the introduction of resampling moves that actively move the system towards equilibrium and the continual adaptation of the optimal temperature set. As a consequence of these two innovations, we show that the configuration flow in temperature space is optimized and that the overall convergence of RE simulations can be dramatically accelerated. PMID- 26588369 TI - Smooth Optimal Quantum Control for Robust Solid-State Spin Magnetometry. AB - We experimentally demonstrate a simple yet versatile optimal quantum control technique that achieves tailored robustness against qubit inhomogeneities and control errors while requiring minimal bandwidth. We apply the technique to nitrogen-vacancy (NV) centers in diamond and verify its performance using quantum process tomography. In a wide-field NV center magnetometry scenario, we achieve a homogeneous sensitivity across a 33% drop in control amplitude, and we improve the sensitivity by up to 2 orders of magnitude for a normalized detuning as large as 40%, achieving a value of 20 nT Hz(-1/2) MUm(3/2) in sensitivity times square root volume. PMID- 26588370 TI - Evidence of the Missing Baryons from the Kinematic Sunyaev-Zeldovich Effect in Planck Data. AB - We estimate the amount of the missing baryons detected by the Planck measurements of the cosmic microwave background in the direction of central galaxies (CGs) identified in the Sloan galaxy survey. The peculiar motion of the gas inside and around the CGs unveils values of the Thomson optical depth tau(T) in the range 0.2-2*10(-4), indicating that the regions probed around CGs contain roughly half of the total amount of baryons in the Universe at the epoch where the CGs are found. If baryons follow dark matter, the measured tau(T)'s are compatible with the detection of all of the baryons existing inside and around the CGs. PMID- 26588371 TI - Higgs Decay to Two Photons at One Loop in the Standard Model Effective Field Theory. AB - We present the calculation of the CP conserving contributions to Gamma(h >gammagamma), from dimension six operators at one-loop order, in the linear standard model effective field theory. We discuss the impact of these corrections on interpreting current and future experimental bounds on this decay. PMID- 26588372 TI - Next-to-Next-to-Next-to-Leading Order QCD Prediction for the Top Antitop S-Wave Pair Production Cross Section Near Threshold in e(+)e(-) Annihilation. AB - We present the third-order QCD prediction for the production of top antitop quark pairs in electron-positron collisions close to the threshold in the dominant S wave state. We observe a significant reduction of the theoretical uncertainty and discuss the sensitivity to the top quark mass and width. PMID- 26588373 TI - Matching Pion-Nucleon Roy-Steiner Equations to Chiral Perturbation Theory. AB - We match the results for the subthreshold parameters of pion-nucleon scattering obtained from a solution of Roy-Steiner equations to chiral perturbation theory up to next-to-next-to-next-to-leading order, to extract the pertinent low-energy constants including a comprehensive analysis of systematic uncertainties and correlations. We study the convergence of the chiral series by investigating the chiral expansion of threshold parameters up to the same order and discuss the role of the Delta(1232) resonance in this context. Results for the low-energy constants are also presented in the counting scheme usually applied in chiral nuclear effective field theory, where they serve as crucial input to determine the long-range part of the nucleon-nucleon potential as well as three-nucleon forces. PMID- 26588375 TI - Nonadiabatic Electron Dynamics in Orthogonal Two-Color Laser Fields with Comparable Intensities. AB - We theoretically investigate the nonadiabatic subcycle electron dynamics in orthogonally polarized two-color laser fields with comparable intensities. The photoelectron dynamics is simulated by exact solution to the 3D time-dependent Schrodinger equation, and also by two other semiclassical methods, i.e., the quantum trajectory Monte Carlo simulation and the Coulomb-corrected strong field approximation. Through these methods, we identify the underlying mechanisms of the subcycle electron dynamics and find that both the nonadiabatic effects and the Coulomb potential play very important roles. The contribution of the nonadiabatic effects manifest in two aspects, i.e., the nonadiabatic ionization rate and the nonzero initial velocities at the tunneling exit. The Coulomb potential has a different impact on the electrons' trajectories for different relative phases between the two pulses. PMID- 26588376 TI - Inducing Resonant Interactions in Ultracold Atoms with a Modulated Magnetic Field. AB - In systems of ultracold atoms, pairwise interactions can be resonantly enhanced by a new mechanism that does not rely upon a magnetic Feshbach resonance. In this mechanism, interactions are controlled by tuning the frequency of an oscillating parallel component of the magnetic field close to the transition frequency between the scattering atoms and a two-atom bound state. The real part of the resulting s-wave scattering length a is resonantly enhanced when the oscillation frequency is close to the transition frequency. The resonance parameters can be controlled by varying the amplitude of the oscillating field. The amplitude also controls the imaginary part of a, which arises because the oscillating field converts atom pairs into molecules. The real part of a can be made much larger than the background scattering length without introducing catastrophic atom losses from the imaginary part. For the case of a shallow bound state in the scattering channel, the dimensionless resonance parameters are universal functions of the dimensionless oscillation amplitude. PMID- 26588374 TI - Extension of the N=40 Island of Inversion towards N=50: Spectroscopy of (66)Cr, (70,72)Fe. AB - We report on the measurement of the first 2(+) and 4(+) states of (66)Cr and (70,72)Fe via in-beam gamma-ray spectroscopy. The nuclei of interest were produced by (p,2p) reactions at incident energies of 260 MeV/nucleon. The experiment was performed at the Radioactive Isotope Beam Factory, RIKEN, using the DALI 2gamma-ray detector array and the novel MINOS device, a thick liquid hydrogen target combined with a vertex tracker. A low-energy plateau of 2(1)(+) and 4(1)(+) energies as a function of the neutron number was observed for N>=38 and N>=40 for even-even Cr and Fe isotopes, respectively. State-of-the-art shell model calculations with a modified Lenzi-Nowacki-Poves-Sieja (LNPS) interaction in the pfg(9/2)d(5/2) valence space reproduce the observations. Interpretation within the shell model shows an extension of the island of inversion at N=40 for more neutron-rich isotopes towards N=50. PMID- 26588377 TI - Catching Conical Intersections in the Act: Monitoring Transient Electronic Coherences by Attosecond Stimulated X-Ray Raman Signals. AB - Conical intersections (CIs) dominate the pathways and outcomes of virtually all photophysical and photochemical molecular processes. Despite extensive experimental and theoretical effort, CIs have not been directly observed yet and the experimental evidence is being inferred from fast reaction rates and some vibrational signatures. We show that short x-ray (rather than optical) pulses can directly detect the passage through a CI with the adequate temporal and spectral sensitivity. The technique is based on a coherent Raman process that employs a composite femtosecond or attosecond x-ray pulse to detect the electronic coherences (rather than populations) that are generated as the system passes through the CI. PMID- 26588378 TI - Ultracold Long-Range Rydberg Molecules with Complex Multichannel Spectra. AB - A generalized class of ultralong-range Rydberg molecules is predicted which consist of a multichannel Rydberg atom whose outermost electron creates a chemical bond with a distant ground state atom. Such multichannel Rydberg molecules exhibit favorable properties for laser excitation, because states exist where the quantum defect varies strongly with the principal quantum number. The resulting occurrence of near degeneracies with states of high orbital angular momentum promotes the admixture of low l into the high l deeply bound "trilobite" molecule states, thereby circumventing the usual difficulty posed by electric dipole selection rules. Such states also can exhibit multiscale binding possibilities that could present novel options for quantum manipulation. PMID- 26588379 TI - Shaping the Biphoton Temporal Waveform with Spatial Light Modulation. AB - We demonstrate a technique for shaping the temporal wave function of biphotons generated from spatially modulated spontaneous four-wave mixing in cold atoms. We show that the spatial profile of the pump field can be mapped onto the biphoton temporal wave function in the group delay regime. The spatial profile of the pump laser beam is shaped by using a spatial light modulator. This spatial-to-temporal mapping enables the generation of narrow-band biphotons with controllable temporal waveforms. PMID- 26588380 TI - Measurement and Shaping of Biphoton Spectral Wave Functions. AB - In this work we present a simple method to reconstruct the complex spectral wave function of a biphoton, and hence gain complete information about the spectral and temporal properties of a photon pair. The technique, which relies on quantum interference, is applicable to biphoton states produced with a monochromatic pump when a shift of the pump frequency produces a shift in the relative frequencies contributing to the biphoton. We demonstrate an example of such a situation in type-II parametric down conversion allowing arbitrary paraxial spatial pump and detection modes. Moreover, our test cases demonstrate the possibility to shape the spectral wave function. This is achieved by choosing the spatial mode of the pump and of the detection modes, and takes advantage of spatiotemporal correlations. PMID- 26588381 TI - All-Optical Reconstruction of Crystal Band Structure. AB - The band structure of matter determines its properties. In solids, it is typically mapped with angle-resolved photoemission spectroscopy, in which the momentum and the energy of incoherent electrons are independently measured. Sometimes, however, photoelectrons are difficult or impossible to detect. Here we demonstrate an all-optical technique to reconstruct momentum-dependent band gaps by exploiting the coherent motion of electron-hole pairs driven by intense midinfrared femtosecond laser pulses. Applying the method to experimental data for a semiconductor ZnO crystal, we identify the split-off valence band as making the greatest contribution to tunneling to the conduction band. Our new band structure measurement technique is intrinsically bulk sensitive, does not require a vacuum, and has high temporal resolution, making it suitable to study reactions at ambient conditions, matter under extreme pressures, and ultrafast transient modifications to band structures. PMID- 26588382 TI - Quantum-Spillover-Enhanced Surface-Plasmonic Absorption at the Interface of Silver and High-Index Dielectrics. AB - We demonstrate an unexpectedly strong surface-plasmonic absorption at the interface of silver and high-index dielectrics based on electron and photon spectroscopy. The measured bandwidth and intensity of absorption deviate significantly from the classical theory. Our density-functional calculation well predicts the occurrence of this phenomenon. It reveals that due to the low metal to-dielectric work function at such interfaces, conduction electrons can display a drastic quantum spillover, causing the interfacial electron-hole pair production to dominate the decay of surface plasmons. This finding can be of fundamental importance in understanding and designing quantum nanoplasmonic devices that utilize noble metals and high-index dielectrics. PMID- 26588383 TI - Topological States in Partially-PT-Symmetric Azimuthal Potentials. AB - We introduce partially-parity-time (pPT)-symmetric azimuthal potentials composed from individual PT-symmetric cells located on a ring, where two azimuthal directions are nonequivalent in a sense that in such potential excitations carrying topological dislocations exhibit different dynamics for different directions of energy circulation in the initial field distribution. Such nonconservative ratchetlike structures support rich families of stable vortex solitons in cubic nonlinear media, whose properties depend on the sign of the topological charge due to the nonequivalence of azimuthal directions. In contrast, oppositely charged vortex solitons remain equivalent in similar fully PT-symmetric potentials. The vortex solitons in the pPT- and PT-symmetric potentials are shown to feature qualitatively different internal current distributions, which are described by different discrete rotation symmetries of the intensity profiles. PMID- 26588384 TI - Noncollinear Polarization Gating of Attosecond Pulse Trains in the Relativistic Regime. AB - High order harmonics generated at relativistic intensities have long been recognized as a route to the most powerful extreme ultraviolet pulses. Reliably generating isolated attosecond pulses requires gating to only a single dominant optical cycle, but techniques developed for lower power lasers have not been readily transferable. We present a novel method to temporally gate attosecond pulse trains by combining noncollinear and polarization gating. This scheme uses a split beam configuration which allows pulse gating to be implemented at the high beam fluence typical of multi-TW to PW class laser systems. Scalings for the gate width demonstrate that isolated attosecond pulses are possible even for modest pulse durations achievable for existing and planned future ultrashort high power laser systems. Experimental results demonstrating the spectral effects of temporal gating on harmonic spectra generated by a relativistic laser plasma interaction are shown. PMID- 26588385 TI - Nonlinear Cavity and Frequency Comb Radiations Induced by Negative Frequency Field Effects. AB - Optical Kerr frequency combs (KFCs) are an increasingly important optical metrology tool with applications ranging from ultraprecise spectroscopy to time keeping. KFCs may be generated in compact resonators with extremely high quality factors. Here, we show that the same features that lead to high quality frequency combs in these resonators also lead to an enhancement of nonlinear emissions that may be identified as originating from the presence of a negative frequency (NF) component in the optical spectrum. While the negative frequency component of the spectrum is naturally always present in the real-valued optical field, it is not included in the principal theoretical model used to model nonlinear cavities, i.e., the Lugiato-Lefever equation. We therefore extend these equations in order to include the contribution of NF components and show that the predicted emissions may be studied analytically, in excellent agreement with full numerical simulations. These results are of importance for a variety of fields, such as Bose-Einstein condensates, mode-locked lasers, nonlinear plasmonics, and polaritonics. PMID- 26588386 TI - Synchronization of Heterogeneous Oscillators by Noninvasive Time-Delayed Cross Coupling. AB - We demonstrate that nonidentical systems, in particular, nonlinear oscillators with different time scales, can be synchronized if a mutual coupling via time delayed control signals is implemented. Each oscillator settles on an unstable state, say a fixed point or an unstable periodic orbit, with a coupling force which vanishes in the long time limit. We present the underlying theoretical considerations and numerical simulations, and, moreover, demonstrate the concept experimentally in nonlinear electronic oscillators. PMID- 26588387 TI - Turbulence Locality and Granularlike Fluid Shear Viscosity in Collisional Suspensions. AB - We reanalyze previous experimental measurements of solid volume fraction, mean velocity, and velocity fluctuations in collisional suspensions of plastic cylinders and water flowing over inclined, erodible beds. We show that the particle pressure scales with the granular temperature, as predicted by kinetic theory of granular gases. The assumption that the particle shear stress is also well predicted by kinetic theory permits us to determine the fluid shear stress and the effective fluid viscosity from the experiments. The fluid viscosity can be decomposed into turbulent and granularlike components: the turbulent viscosity can be modeled using a mixing length, which is a decreasing function of the local volume fraction and does not depend upon the distance from the bed; the granularlike viscosity, associated with the transfer of momentum due to the conjugate motion of the fluid mass added to the particles, can be modeled by replacing the particle density with the density of the added fluid mass in the viscosity of kinetic theory. PMID- 26588388 TI - Experimental Evidence of Helical Flow in Porous Media. AB - Helical flow leads to deformation of solute plumes and enhances transverse mixing in porous media. We present experiments in which macroscopic helical flow is created by arranging different materials to obtain an anisotropic macroscopic permeability tensor with spatially variable orientation. The resulting helical flow entails twisting streamlines which cause a significant increase in lateral mass exchange and thus a large enhancement of plume dilution (up to 235%) compared to transport in homogenous media. The setup may be used to effectively mix solutes in parallel streams similarly to static mixers, but in porous media. PMID- 26588389 TI - Relativistic Electron Vortex Beams in a Laser Field. AB - The orbital angular momentum Hall effect and the spin Hall effect of electron vortex beams (EVBs) have been studied for the EVBs interacting with a laser field. In the scenario of a paraxial beam, the cumulative effect of the orbit orbit interaction of EVBs and laser fields drives the orbital Hall effect, which in turn produces a shift of the center of the beam from that of the field-free case towards the polarization axis of the photons. In addition, for nonparaxial beams one can also perceive a similar shift of the center of the beam owing to the spin Hall effect involving spin-orbit interaction. Our analysis suggests that the shift in the paraxial beams will always be larger than that in the nonparaxial beams. PMID- 26588390 TI - Multi-MeV Electron Acceleration by Subterawatt Laser Pulses. AB - We demonstrate laser-plasma acceleration of high charge electron beams to the ~10 MeV scale using ultrashort laser pulses with as little energy as 10 mJ. This result is made possible by an extremely dense and thin hydrogen gas jet. Total charge up to ~0.5 nC is measured for energies >1 MeV. Acceleration is correlated to the presence of a relativistically self-focused laser filament accompanied by an intense coherent broadband light flash, associated with wave breaking, which can radiate more than ~3% of the laser energy in a ~1 fs bandwidth consistent with half-cycle optical emission. Our results enable truly portable applications of laser-driven acceleration, such as low dose radiography, ultrafast probing of matter, and isotope production. PMID- 26588391 TI - Positron Acceleration by Plasma Wakefields Driven by a Hollow Electron Beam. AB - A scheme for positron plasma wakefield acceleration using hollow or donut-shaped electron driver beams is studied. An annular-shaped, electron-free region forms around the hollow driver beam, creating a favorable region (longitudinal field is accelerating and transverse field is focusing) for positron acceleration. For Facility for Advanced Accelerator Experimental Tests (FACET)-like parameters, the hollow beam driver produces accelerating gradients on the order of 10 GV/m. The accelerating gradient increases linearly with the total charge in the driver beam. Simulations show acceleration of a 23-GeV positron beam to 35.4 GeV with a maximum energy spread of 0.4% and very small emittance over a plasma length of 140 cm is possible. PMID- 26588392 TI - Statistical Transmutation in Floquet Driven Optical Lattices. AB - We show that interacting bosons in a periodically driven two dimensional (2D) optical lattice may effectively exhibit fermionic statistics. The phenomenon is similar to the celebrated Tonks-Girardeau regime in 1D. The Floquet band of a driven lattice develops the moat shape, i.e., a minimum along a closed contour in the Brillouin zone. Such degeneracy of the kinetic energy favors fermionic quasiparticles. The statistical transmutation is achieved by the Chern-Simons flux attachment similar to the fractional quantum Hall case. We show that the velocity distribution of the released bosons is a sensitive probe of the fermionic nature of their stationary Floquet state. PMID- 26588393 TI - Symmetry-Protected Topological Phase in a One-Dimensional Correlated Bosonic Model with a Synthetic Spin-Orbit Coupling. AB - By performing large-scale density-matrix renormalization group simulations, we investigate a one-dimensional correlated bosonic lattice model with a synthetic spin-orbit coupling realized in recent experiments. In the insulating regime, this model exhibits a symmetry-protected topological phase. This symmetry protected topological phase is stabilized by time-reversal symmetry and it is identified as a Haldane phase. We confirm our conclusions further by analyzing the entanglement spectrum. In addition, we find four conventional phases: a Mott insulating phase with no long range order, a ferromagnetic superfluid phase, a ferromagnetic insulating phase, and a density-wave phase. PMID- 26588394 TI - Four-Dimensional Quantum Hall Effect with Ultracold Atoms. AB - We propose a realistic scheme to detect the 4D quantum Hall effect using ultracold atoms. Based on contemporary technology, motion along a synthetic fourth dimension can be accomplished through controlled transitions between internal states of atoms arranged in a 3D optical lattice. From a semiclassical analysis, we identify the linear and nonlinear quantized current responses of our 4D model, relating these to the topology of the Bloch bands. We then propose experimental protocols, based on current or center-of-mass-drift measurements, to extract the topological second Chern number. Our proposal sets the stage for the exploration of novel topological phases in higher dimensions. PMID- 26588395 TI - Bending Rules in Graphene Kirigami. AB - The three-dimensional shapes of graphene sheets produced by nanoscale cut-and join kirigami are studied by combining large-scale atomistic simulations with continuum elastic modeling. Lattice segments are selectively removed from a graphene sheet, and the structure is allowed to close by relaxing in the third dimension. The surface relaxation is limited by a nonzero bending modulus which produces a smoothly modulated landscape instead of the ridge-and-plateau motif found in macroscopic lattice kirigami. The resulting surface shapes and their interactions are well described by a new set of microscopic kirigami rules that resolve the competition between bending and stretching energies. PMID- 26588396 TI - Second Harmonic Generation of Nanoscale Phonon Wave Packets. AB - Phonons are often regarded as delocalized quasiparticles with certain energy and momentum. The anharmonic interaction of phonons determines macroscopic properties of the solid, such as thermal expansion or thermal conductivity, and a detailed understanding becomes increasingly important for functional nanostructures. Although phonon-phonon scattering processes depicted in simple wave-vector diagrams are the basis of theories describing these macroscopic phenomena, experiments directly accessing these coupling channels are scarce. We synthesize monochromatic acoustic phonon wave packets with only a few cycles to introduce nonlinear phononics as the acoustic counterpart to nonlinear optics. Control of the wave vector, bandwidth, and consequently spatial extent of the phonon wave packets allows us to observe nonlinear phonon interaction, in particular, second harmonic generation, in real time by wave-vector-sensitive Brillouin scattering with x-rays and optical photons. PMID- 26588397 TI - Temperature-Dependent Transformation Thermotics: From Switchable Thermal Cloaks to Macroscopic Thermal Diodes. AB - The macroscopic control of ubiquitous heat flow remains poorly explored due to the lack of a fundamental theoretical method. Here, by establishing temperature dependent transformation thermotics for treating materials whose conductivity depends on temperature, we show analytical and simulation evidence for switchable thermal cloaking and a macroscopic thermal diode based on the cloaking. The latter allows heat flow in one direction but prohibits the flow in the opposite direction, which is also confirmed by our experiments. Our results suggest that the temperature-dependent transformation thermotics could be a fundamental theoretical method for achieving macroscopic heat rectification, and it could provide guidance both for the macroscopic control of heat flow and for the design of the counterparts of switchable thermal cloaks or macroscopic thermal diodes in other fields like seismology, acoustics, electromagnetics, and matter waves. PMID- 26588398 TI - Perfect Lensing by a Single Interface: Defying Loss and Bandwidth Limitations of Metamaterials. AB - Loss is known to be detrimental for achieving perfect focusing with the passive perfect lens designs suggested thus far, and it is believed to pose a fundamental barrier. We show that perfect lensing can be achieved with actual lossy left handed metamaterials, without a need for gain or nonlinearity. The proposed loss immune perfect lens is composed of a single interface between a conventional dielectric material on the source side and a lossy left-handed material on the image side. Its immunity to material loss was derived analytically using three complementary methodologies, confirming perfect lensing with point-to-point accuracy and shedding light on the underlying focusing mechanism. This result provides a new road map for practical realization of a near-field camera based on the single-interface lens design. PMID- 26588399 TI - Enhancement of Water Evaporation on Solid Surfaces with Nanoscale Hydrophobic Hydrophilic Patterns. AB - Using molecular dynamics simulations, we show that the evaporation of nanoscale water on hydrophobic-hydrophilic patterned surfaces is unexpectedly faster than that on any surfaces with uniform wettability. The key to this phenomenon is that, on the patterned surface, the evaporation rate from the hydrophilic region only slightly decreases due to the correspondingly increased water thickness; meanwhile, a considerable number of water molecules evaporate from the hydrophobic region despite the lack of water film. Most of the evaporated water from the hydrophobic region originates from the hydrophilic region by diffusing across the contact lines. Further analysis shows that the evaporation rate from the hydrophobic region is approximately proportional to the total length of the contact lines. PMID- 26588400 TI - Field Effect and Strongly Localized Carriers in the Metal-Insulator Transition Material VO(2). AB - The intrinsic field effect, the change in surface conductance with an applied transverse electric field, of prototypal strongly correlated VO(2) has remained elusive. Here we report its measurement enabled by epitaxial VO(2) and atomic layer deposited high-kappa dielectrics. Oxygen migration, joule heating, and the linked field-induced phase transition are precluded. The field effect can be understood in terms of field-induced carriers with densities up to ~5*10(13) cm( 2) which are trongly localized, as shown by their low, thermally activated mobility (~1*10(-3) cm(2)/V s at 300 K). These carriers show behavior consistent with that of Holstein polarons and strongly impact the (opto)electronics of VO(2). PMID- 26588401 TI - Exciting Polaritons with Quantum Light. AB - We discuss the excitation of polaritons-strongly coupled states of light and matter-by quantum light, instead of the usual laser or thermal excitation. As one illustration of the new horizons thus opened, we introduce "Mollow spectroscopy" a theoretical concept for a spectroscopic technique that consists of scanning the output of resonance fluorescence onto an optical target-from which weak nonlinearities can be read with high precision even in strongly dissipative environments. PMID- 26588402 TI - Exact Double Counting in Combining the Dynamical Mean Field Theory and the Density Functional Theory. AB - We propose a continuum representation of the dynamical mean field theory, in which we were able to derive an exact overlap between the dynamical mean field theory and band structure methods, such as the density functional theory; double counting. The implementation of this exact double counting shows improved agreement between the theory and experiment in several correlated solids, such as the transition metal oxides and lanthanides. Previously introduced nominal double counting is in much better agreement with the exact double counting than the most widely used fully localized limit formula. PMID- 26588403 TI - Resonant Scattering by Magnetic Impurities as a Model for Spin Relaxation in Bilayer Graphene. AB - We propose that the observed spin relaxation in bilayer graphene is due to resonant scattering by magnetic impurities. We analyze a resonant scattering model due to adatoms on both dimer and nondimer sites, finding that only the former give narrow resonances at the charge neutrality point. Opposite to single layer graphene, the measured spin-relaxation rate in the graphene bilayer increases with carrier density. Although it has been commonly argued that a different mechanism must be at play for the two structures, our model explains this behavior rather naturally in terms of different broadening scales for the same underlying resonant processes. Not only do our results-using robust and first-principles inspired parameters-agree with experiment, they also predict an experimentally testable sharp decrease of the spin-relaxation rate at high carrier densities. PMID- 26588404 TI - Strong Suppression of the Spin Hall Effect in the Spin Glass State. AB - We have measured spin Hall effects in spin glass metals, CuMnBi alloys, with the spin absorption method in the lateral spin valve structure. Far above the spin glass temperature T(g) where the magnetic moments of Mn impurities are randomly frozen, the spin Hall angle of a CuMnBi ternary alloy is as large as that of a CuBi binary alloy. Surprisingly, however, it starts to decrease at about 4T(g) and becomes as little as 7 times smaller at 0.5T(g). A similar tendency was also observed in anomalous Hall effects in the ternary alloys. We propose an explanation in terms of a simple model considering the relative dynamics between the localized moment and the conduction electron spin. PMID- 26588405 TI - Coulomb Blockade in a Two-Dimensional Conductive Polymer Monolayer. AB - Electronic transport was investigated in poly(3-hexylthiophene-2,5-diyl) monolayers. At low temperatures, nonlinear behavior was observed in the current voltage characteristics, and a nonzero threshold voltage appeared that increased with decreasing temperature. The current-voltage characteristics could be best fitted using a power law. These results suggest that the nonlinear conductivity can be explained using a Coulomb blockade (CB) mechanism. A model is proposed in which an isotropic extended charge state exists, as predicted by quantum calculations, and percolative charge transport occurs within an array of small conductive islands. Using quantitatively evaluated capacitance values for the islands, this model was found to be capable of explaining the observed experimental data. It is, therefore, suggested that percolative charge transport based on the CB effect is a significant factor giving rise to nonlinear conductivity in organic materials. PMID- 26588406 TI - Unpaired Majorana Modes in Josephson-Junction Arrays with Gapless Bulk Excitations. AB - The search for Majorana bound states in solid-state physics has been limited to materials that display a gap in their bulk spectrum. We show that such unpaired states appear in certain quasi-one-dimensional Josephson-junction arrays with gapless bulk excitations. The bulk modes mediate a coupling between Majorana bound states via the Ruderman-Kittel-Yosida-Kasuya mechanism. As a consequence, the lowest energy doublet acquires a finite energy difference. For a realistic set of parameters this energy splitting remains much smaller than the energy of the bulk eigenstates even for short chains of length L~10. PMID- 26588407 TI - Nematic Crossover in BaFe(2)As(2) under Uniaxial Stress. AB - Raman scattering can detect spontaneous point-group symmetry breaking without resorting to single-domain samples. Here, we use this technique to study BaFe(2)As(2), the parent compound of the "122" Fe-based superconductors. We show that an applied compression along the Fe-Fe direction, which is commonly used to produce untwinned orthorhombic samples, changes the structural phase transition at temperature T(s) into a crossover that spans a considerable temperature range above T(s). Even in crystals that are not subject to any applied force, a distribution of substantial residual stress remains, which may explain phenomena that are seemingly indicative of symmetry breaking above T(s). Our results are consistent with an onset of spontaneous nematicity only below T(s). PMID- 26588408 TI - Laser-Induced Spatiotemporal Dynamics of Magnetic Films. AB - We present a theory for the coherent magnetization dynamics induced by a focused ultrafast laser beam in magnetic films, taking into account nonthermal (inverse Faraday effect) and thermal (heating) actuation. The dynamic conversion between spin waves and phonons is induced by the magnetoelastic coupling that allows efficient propagation of angular momentum. The anisotropy of the magnetoelastic coupling renders characteristic angle dependences of the magnetization propagation that are strikingly different for thermal and nonthermal actuation. PMID- 26588409 TI - Fluctuations and All-In-All-Out Ordering in Dipole-Octupole Nd(2)Zr(2)O(7). AB - By means of neutron scattering and magnetization measurements down to 90 mK, we determine the magnetic ground state of the spin-ice candidate Nd(2)Zr(2)O(7). We show that, despite ferromagnetic interactions, Nd(2)Zr(2)O(7) undergoes a transition around 285 mK towards an all-in-all-out antiferromagnetic state, with a strongly reduced ordered magnetic moment. We establish the (H,T) phase diagram in the three directions of the applied field and reveal a metamagnetic transition around 0.1 T, associated with an unexpected shape of the magnetization curves. We propose that this behavior results from the peculiar nature of the Nd^{3+} doublet, a dipolar-octupolar doublet, different from the standard Kramers doublet studied to date, thus revealing the importance of multipolar correlations in the properties of pyrochlore oxides. PMID- 26588410 TI - What is the Valence of Mn in Ga(1-x)Mn(x)N? AB - We investigate the current debate on the Mn valence in Ga(1-x)Mn(x)N, a diluted magnetic semiconductor (DMS) with a potentially high Curie temperature. From a first-principles Wannier-function analysis, we unambiguously find the Mn valence to be close to 2+ (d(5)), but in a mixed spin configuration with average magnetic moments of 4MU(B). By integrating out high-energy degrees of freedom differently, we further derive for the first time from first-principles two low-energy pictures that reflect the intrinsic dual nature of the doped holes in the DMS: (1) an effective d(4) picture ideal for local physics, and (2) an effective d(5) picture suitable for extended properties. In the latter, our results further reveal a few novel physical effects, and pave the way for future realistic studies of magnetism. Our study not only resolves one of the outstanding key controversies of the field, but also exemplifies the general need for multiple effective descriptions to account for the rich low-energy physics in many-body systems in general. PMID- 26588411 TI - End States and Subgap Structure in Proximity-Coupled Chains of Magnetic Adatoms. AB - A recent experiment [Nadj-Perge et al., Science 346, 602 (2014)] provides evidence for Majorana zero modes in iron (Fe) chains on the superconducting Pb(110) surface. Here, we study this system by scanning tunneling microscopy using superconducting tips. This high-resolution technique resolves a rich subgap structure, including zero-energy excitations in some chains. We compare the symmetry properties of the data under voltage reversal against theoretical expectations and provide evidence that the putative Majorana signature overlaps with a previously unresolved low-energy resonance. Interpreting the data within a Majorana framework suggests that the topological gap is smaller than previously extracted from experiment. Aided by model calculations, we also analyze higher energy features of the subgap spectrum and their relation to high-bias peaks which we associate with the Fe d bands. PMID- 26588412 TI - Piezomagnetoelectric Effect of Spin Origin in Dysprosium Orthoferrite. AB - The piezomagnetoelectric effect, namely, the simultaneous induction of both the ferromagnetic moment and electric polarization by an application of uniaxial stress, was demonstrated in the nonferroelectric antiferromagnetic ground state of DyFeO(3). The induced electric polarization and ferromagnetic moment are coupled with each other, and monotonically increase with increasing uniaxial stress. The present work provides a new guiding principle for designing multiferroics where its magnetic symmetry is broken by external uniaxial stress. PMID- 26588413 TI - Delocalization of Nonlinear Optical Responses in Plasmonic Nanoantennas. AB - Remote excitation and emission of two-photon luminescence and second-harmonic generation are observed in micrometer long gold rod optical antennas upon local illumination with a tightly focused near-infrared femtosecond laser beam. We show that these nonlinear radiations are emitted from the entire antenna and the measured far-field angular patterns bear the information regarding the nature and origins of the respective nonlinear processes. We demonstrate that the nonlinear responses are locally induced by a propagating surface plasmon at the excitation frequency, enabling thereby a polariton-mediated spatial tailoring and design of coherent and incoherent nonlinear responses. PMID- 26588414 TI - Spin-Selective Electron Quantum Transport in Nonmagnetic MgZnO/ZnO Heterostructures. AB - We report magnetotransport measurements on a high-mobility two-dimensional electron system at the nonmagnetic MgZnO/ZnO heterointerface showing distinct behavior for electrons with spin-up and spin-down orientations. The low-field Shubnikov-de Haas oscillations manifest alternating resistance peak heights which can be attributed to distinct scattering rates for different spin orientations. The tilt-field measurements at a half-integer filling factor reveal that the majority spins show usual diffusive behavior, i.e., peaks with the magnitude proportional to the index of the Landau level at the Fermi energy. By contrast, the minority spins develop "plateaus" with the magnitude of dissipative resistivity that is fairly independent of the Landau level index and is of the order of the zero-field resistivity. PMID- 26588415 TI - Exciton Lifetime Paradoxically Enhanced by Dissipation and Decoherence: Toward Efficient Energy Conversion of a Solar Cell. AB - Energy dissipation and decoherence are at first glance harmful to acquiring the long exciton lifetime desired for efficient photovoltaics. In the presence of both optically forbidden (namely, dark) and allowed (bright) excitons, however, they can be instrumental, as suggested in photosynthesis. By simulating the quantum dynamics of exciton relaxations, we show that the optimized decoherence that imposes a quantum-to-classical crossover with the dissipation realizes a dramatically longer lifetime. In an example of a carbon nanotube, the exciton lifetime increases by nearly 2 orders of magnitude when the crossover triggers a stable high population in the dark excitons. PMID- 26588416 TI - Chiral Ordering in Supercooled Liquid Water and Amorphous Ice. AB - The emergence of homochiral domains in supercooled liquid water is presented using molecular dynamics simulations. An individual water molecule possesses neither a chiral center nor a twisted conformation that can cause spontaneous chiral resolution. However, an aggregation of water molecules will naturally give rise to a collective chirality. Such homochiral domains possess obvious topological and geometrical orders and are energetically more stable than the average. However, homochiral domains cannot grow into macroscopic homogeneous structures due to geometrical frustrations arising from their icosahedral local order. Homochiral domains are the major constituent of supercooled liquid water and the origin of heterogeneity in that substance, and are expected to be enhanced in low-density amorphous ice at lower temperatures. PMID- 26588417 TI - Mobility Measurements Probe Conformational Changes in Membrane Proteins due to Tension. AB - The function of membrane-embedded proteins such as ion channels depends crucially on their conformation. We demonstrate how conformational changes in asymmetric membrane proteins may be inferred from measurements of their diffusion. Such proteins cause local deformations in the membrane, which induce an extra hydrodynamic drag on the protein. Using membrane tension to control the magnitude of the deformations, and hence the drag, measurements of diffusivity can be used to infer-via an elastic model of the protein-how conformation is changed by tension. Motivated by recent experimental results [Quemeneur et al., Proc. Natl. Acad. Sci. U.S.A. 111, 5083 (2014)], we focus on KvAP, a voltage-gated potassium channel from Aeropyrum pernix. The conformation of KvAP is found to change considerably due to tension, with its "walls," where the protein meets the membrane, undergoing significant angular strains. The torsional stiffness is determined to be 26.8k(B)T per radian at room temperature. This has implications for both the structure and the function of such proteins in the environment of a tension-bearing membrane. PMID- 26588418 TI - Confinement-Induced Glassy Dynamics in a Model for Chromosome Organization. AB - Recent experiments showing scaling of the intrachromosomal contact probability, P(s)~s(-1) with the genomic distance s, are interpreted to mean a self-similar fractal-like chromosome organization. However, scaling of P(s) varies across organisms, requiring an explanation. We illustrate dynamical arrest in a highly confined space as a discriminating marker for genome organization, by modeling chromosomes inside a nucleus as a homopolymer confined to a sphere of varying sizes. Brownian dynamics simulations show that the chain dynamics slows down as the polymer volume fraction (phi) inside the confinement approaches a critical value phi(c). The universal value of phi(c)(infinity)~0.44 for a sufficiently long polymer (N?1) allows us to discuss genome dynamics using phi as the sole parameter. Our study shows that the onset of glassy dynamics is the reason for the segregated chromosome organization in humans (N~3*10(9), phi?phi(c)(infinity)), whereas chromosomes of budding yeast (N~10(8), phi 6 cm above the supraclavicular fossa (SCF), and their outcomes resembled the outcomes of those with low extension. Replacing SCF with the lower neck (extension below the caudal border of the cricoid cartilage) did not affect the hazard distinction between different N categories. With the proposed T and N categories, there were no significant differences in outcome between T4N0-2 and T1-4N3 disease. CONCLUSIONS: After a review by AJCC/UICC preparatory committees, the changes recommended for the 8th edition include changing MP/LP involvement from T4 to T2, adding prevertebral muscle involvement as T2, replacing SCF with the lower neck and merging this with a maximum nodal diameter > 6 cm as N3, and merging T4 and N3 as stage IVA criteria. These changes will lead not only to a better distinction of hazards between adjacent stages/categories but also to optimal balance in clinical practicability and global applicability. PMID- 26588427 TI - Age and education adjusted normative data and discriminative validity for Rey's Auditory Verbal Learning Test in the elderly Greek population. AB - Rey's Auditory Verbal Learning Test (RAVLT) is a widely used neuropsychological test to assess episodic memory. In the present study we sought to establish normative and discriminative validity data for the RAVLT in the elderly population using previously adapted learning lists for the Greek adult population. We administered the test to 258 cognitively healthy elderly participants, aged 60-89 years, and two patient groups (192 with amnestic mild cognitive impairment, aMCI, and 65 with Alzheimer's disease, AD). From the statistical analyses, we found that age and education contributed significantly to most trials of the RAVLT, whereas the influence of gender was not significant. Younger elderly participants with higher education outperformed the older elderly with lower education levels. Moreover, both clinical groups performed significantly worse on most RAVLT trials and composite measures than matched cognitively healthy controls. Furthermore, the AD group performed more poorly than the aMCI group on most RAVLT variables. Receiver operating characteristic (ROC) analysis was used to examine the utility of the RAVLT trials to discriminate cognitively healthy controls from aMCI and AD patients. Area under the curve (AUC), an index of effect size, showed that most of the RAVLT measures (individual and composite) included in this study adequately differentiated between the performance of healthy elders and aMCI/AD patients. We also provide cutoff scores in discriminating cognitively healthy controls from aMCI and AD patients, based on the sensitivity and specificity of the prescribed scores. Moreover, we present age- and education-specific normative data for individual and composite scores for the Greek adapted RAVLT in elderly subjects aged between 60 and 89 years for use in clinical and research settings. PMID- 26588428 TI - Immunohistochemical detection of the BRAF V600E mutant protein in colorectal cancers in Taiwan is highly concordant with the molecular test. AB - AIMS: The aims of this study were to investigate the incidence of BRAF mutations in colorectal cancers (CRCs) in Taiwan and the sensitivity and specificity of VE1 immunohistochemistry in detecting the BRAF(V) (600E) mutation. METHODS AND RESULTS: A total of 425 resected colorectal adenocarcinoma specimens were recruited into this study. Direct Sanger sequencing of exon 15 of the BRAF gene was performed for all cases. The incidence of BRAF mutation was 5.4% (23 of 425). Tissue microarrays were constructed for VE1 immunohistochemistry, and the staining intensity was scored as negative (0), weak (1+), moderate (2+) and strong (3+). In BRAF-mutated cases, two (8.7%) scored as 0, three (13.0%) as 1+, 13 (56.5%) as 2+ and five (21.7%) as 3+. Among 402 BRAF wild-type cases, five (1.2%) were scored as 1+, while the others were negative. The sensitivity and specificity of VE1 expression in detecting the BRAF mutation was 91.3% and 98.8%, respectively. CONCLUSIONS: Immunohistochemistry for VE1 antibody is a sensitive and specific marker for detection of BRAF mutations in CRCs. Incorporation of VE1 immunohistochemistry into Lynch syndrome screening protocol may be a reliable and cost-effective method. PMID- 26588430 TI - Hospitalists caring for patients with advanced cancer: An experience-based guide. AB - Every year, nearly 5 million adults with cancer are hospitalized. Limited evidence suggests that hospitalization of the cancer patient is associated with adverse morbidity and mortality. Hospitalization of the patient with advanced cancer allows for an intense examination of health status in the face of terminal illness and an opportunity for defining goals of care. This experience-based guide reports what is currently known about the topic and outlines a systematic approach to maximizing opportunities, improving quality, and enhancing the well being of the hospitalized patient with advanced cancer. PMID- 26588429 TI - Attitudes, Knowledge, and Correlates of Self-Efficacy for the Provision of Safer Conception Counseling Among Ugandan HIV Providers. AB - High rates of childbearing desires (59%) and serodiscordant partnerships (50%) among people living with HIV (PHLA) in Uganda highlight the need for safer conception counseling (SCC). Provider attitudes about counseling PLHA on the use of safer conception methods (SCM) have been explored in qualitative studies, but published quantitative investigations are scarce. Data from 57 Ugandan providers were collected to examine providers' attitudes about childbearing among PLHA and engagement in discussions about childbearing, as well as their knowledge, interest, self-efficacy, and intentions to provide SCC. Correlates of self efficacy for the provision of SCC were explored to inform the development of training programs. Providers reported a general awareness of most SCM, especially timed unprotected intercourse (TUI); but just over half felt they knew enough to counsel clients in the future and all wanted more training. Childbearing was discussed with less than a third of reproductive aged patients and was mostly initiated by patients. Most providers saw value in providing SCC and believed that most aspects of SCM would be acceptable to their clients, but numerous barriers were endorsed. Self-efficacy was greatest among providers who had had more childbearing conversations, greater SCM awareness, perceived fewer barriers and greater intentions to counsel on TUI. Providers evidence fewer stigmatizing attitudes than in the past. However, those who endorsed more stigmatizing attitudes evidenced a trend for reporting lower self-efficacy for providing SCC. Training will need to simultaneously focus on increasing providers' SCC knowledge and skills while instilling a more realistic appraisal of the risks of assisting couples to employ SCM versus doing nothing. PMID- 26588431 TI - Enhanced accumulation of Cd in castor (Ricinus communis L) by soil-applied chelators. AB - Phytoextraction has been identified as one of the most propitious methods of phytoremediation. This pot experiment were treated with varying amounts of (ethylenediamine triacetic acid) EDTA 3-15, (Nitriloacetic acid) NTA 3-10, (Ammonium citrate) NH4 citrate 10 - 25 mmol and one mg kg(-1)Cd, filled with 5 kg soil. The addition of chelators significantly increased Cd concentration in soil and plant. The results showed that maximum Cd uptake was noted under root, shoot and leaf of castor plant tissue (2.26, 1.54, and 0.72 mg kg(-1)) under EDTA 15, NTA 10, and NH4 citrate 25 mmol treatments respectively, and in soil 1.08, 1.06 and 0.52 mg kg(-1) pot(-1) under NH4 citrate 25, NTA 10 and EDTA 15 mmol treatments respectively, as against to control (p < 0.05). Additions of chelators reduction biomass under the EDTA 15 mmol as compared to other treatments, However, Bioconcentration factor (BCF), translocation factor (TF) and remediation factor (RF) were significantly increased under EDTA 15 and NH4 citrate 25 mmol as against control. Our results demonstrated that castor plant proved satisfactory for phytoextraction on contaminated soil, and EDTA 15 and NH4 citrate 25 mmol had the affirmative effect on the Cd uptake in the artificial Cd-contaminated soil. PMID- 26588432 TI - Production of rhamnolipids and diesel oil degradation by bacteria isolated from soil contaminated by petroleum. AB - Biosurfactants are microbial secondary metabolites. The most studied are rhamnolipids, which decrease the surface tension and have emulsifying capacity. In this study, the production of biosurfactants, with emphasis on rhamnolipids, and diesel oil degradation by 18 strains of bacteria isolated from waste landfill soil contaminated by petroleum was analyzed. Among the studied bacteria, gram positive endospore forming rods (39%), gram positive rods without endospores (17%), and gram-negative rods (44%) were found. The following methods were used to test for biosurfactant production: oil spreading, emulsification, and hemolytic activity. All strains showed the ability to disperse the diesel oil, while 77% and 44% of the strains showed hemolysis and emulsification of diesel oil, respectively. Rhamnolipids production was observed in four strains that were classified on the basis of the 16S rRNA sequences as Pseudomonas aeruginosa. Only those strains showed the rhlAB gene involved in rhamnolipids synthesis, and antibacterial activity against Escherichia coli, P. aeruginosa, Staphylococcus aureus, Bacillus cereus, Erwinia carotovora, and Ralstonia solanacearum. The highest production of rhamnolipids was 565.7 mg/L observed in mineral medium containing olive oil (pH 8). With regard to the capacity to degrade diesel oil, it was observed that 7 strains were positive in reduction of the dye 2,6 dichlorophenolindophenol (2,6-DCPIP) while 16 had the gene alkane mono-oxygenase (alkB), and the producers of rhamnolipids were positive in both tests. Several bacterial strains have shown high potential to be explored further for bioremediation purposes due to their simultaneous ability to emulsify, disperse, and degrade diesel oil. (c) 2015 American Institute of Chemical Engineers Biotechnol. Prog., 32:262-270, 2016. PMID- 26588433 TI - BODIPY-Coumarin Conjugate as an Endoplasmic Reticulum Membrane Fluidity Sensor and Its Application to ER Stress Models. AB - An endoplasmic reticulum (ER) membrane-selective chemosensor composed of BODIPY and coumarin moieties and a long alkyl chain (n-C18) was synthesized. The emission ratio of BODIPY to coumarin depends on the solution viscosity. The probe is localized to the ER membrane and was applied to reveal the reduced ER membrane fluidity under ER stress conditions. PMID- 26588436 TI - Persistent colitis after emergency laparoscopic subtotal colectomy for ulcerative colitis: a cautionary note. PMID- 26588434 TI - Socioeconomic conditions across life related to multiple measures of the endocrine system in older adults: Longitudinal findings from a British birth cohort study. AB - BACKGROUND: Little is known about how socioeconomic position (SEP) across life impacts on different axes of the endocrine system which are thought to underlie the ageing process and its adverse consequences. We examined how indicators of SEP across life related to multiple markers of the endocrine system in late midlife, and hypothesized that lower SEP across life would be associated with an adverse hormone profile across multiple axes. METHODS: Data were from a British cohort study of 875 men and 905 women followed since their birth in March 1946 with circulating free testosterone and insulin-like growth factor-I (IGF-I) measured at both 53 and 60-64 years, and evening cortisol at 60-64 years. Indicators of SEP were ascertained prospectively across life-paternal occupational class at 4, highest educational attainment at 26, household occupational class at 53, and household income at 60-64 years. Associations between SEP and hormones were investigated using multiple regression and logistic regression models. RESULTS: Lower SEP was associated with lower free testosterone among men, higher free testosterone among women, and lower IGF-I and higher evening cortisol in both sexes. For example, the mean standardised difference in IGF-I comparing the lowest with the highest educational attainment at 26 years (slope index of inequality) was -0.4 in men (95% CI -0.7 to -0.2) and -0.4 in women (-0.6 to -0.2). Associations with each hormone differed by SEP indicator used and sex, and were particularly pronounced when using a composite adverse hormone score. For example, the odds of having 1 additional adverse hormone concentration in the lowest compared with highest education level were 3.7 (95% CI: 2.1, 6.3) among men, and 1.6 (1.0, 2.7) among women (P (sex interaction) = 0.02). We found no evidence that SEP was related to apparent age-related declines in free testosterone or IGF-I. CONCLUSIONS: Lower SEP was associated with an adverse hormone profile across multiple endocrine axes. SEP differences in endocrine function may partly underlie inequalities in health and function in later life, and may reflect variations in biological rates of ageing. Further studies are required to assess the likely functional relevance of these associations. PMID- 26588435 TI - Internalized gay ageism, mattering, and depressive symptoms among midlife and older gay-identified men. AB - OBJECTIVE: In this paper we introduce the construct of "internalized gay ageism," or the sense that one feels denigrated or depreciated because of aging in the context of a gay male identity, which we identify as an unexplored aspect of sexual minority stress specific to midlife and older gay-identified men. METHODS: Using a social stress process framework, we examine the association between internalized gay ageism and depressive symptoms, and whether one's sense of mattering mediates or moderates this association, controlling for three decades of depressive symptom histories. The sample is 312 gay-identified men (average age = 60.7 years, range = 48-78, 61% HIV-negative) participating in the Multicenter AIDS Cohort Study (MACS) since 1984/85, one of the largest and longest running studies of the natural history of HIV/AIDS in the U.S., who provided contemporary (2012/13) reports of stress experiences. RESULTS: We find that internalized gay ageism can reliably be measured among these men, is positively associated with depressive symptoms net of an array of other factors that may also influence symptomatology (including depressive symptom histories), and mattering partially mediates but does not moderate its effect on depressive symptoms. CONCLUSION: Midlife and older gay men have traversed unparalleled historical changes across their adult lives and have paved the way for younger generations of sexual minorities to live in a time of less institutionalized discrimination. Still, they are at distinct risk for feeling socially invisible and devalued in their later years. PMID- 26588437 TI - Atomic force microscopy identification of Al-sites on ultrathin aluminum oxide film on NiAl(110). AB - Ultrathin alumina film formed by oxidation of NiAl(110) was studied by non contact atomic force microscopy in an ultra high vacuum at room temperature with the quest to provide the ultimate understanding of structure and bonding of this complicated interface. Using a very stiff Si cantilever with significantly improved resolution, we have obtained images of this system with unprecedented resolution, surpassing all the previous results. In particular, we were able to unambiguously resolve all the differently coordinated aluminum atoms. This is of importance as the previous images provide very different image patterns, which cannot easily be reconciled with the existing structural models. Experiments are supported by extensive density functional theory modeling. We find that the system is strongly ionic and the atomic force microscopy images can reliably be understood from the electrostatic potential which provides an image model in excellent agreement with the experiments. However, in order to resolve the finer contrast features we have proposed a more sophisticated model based on more realistic approximants to the incommensurable alumina interface. PMID- 26588438 TI - Variation in the reporting of outcomes among pregnant women with epilepsy: a systematic review. AB - Studies on pregnant women with epilepsy should evaluate both neurological and pregnancy outcomes. We undertook a systematic review of the literature of studies on pregnant women with epilepsy to collate the outcomes reported, and the quality of outcomes report in these studies. We searched major electronic databases (from 1999 until January 2015). Two independent reviewers selected studies and extracted data on study design, the risk of bias of the studies, journal impact factor and the quality of reported outcomes. We assessed the quality outcomes report using a six items standardised tool (score range 0-6). There were 70 different outcomes reported in 232 studies (maternal neurological (13/70, 19%), fetal and neonatal (28/70, 40%), and obstetric outcomes (29/70, 41%)). Most studies reported on major congenital fetal abnormalities (103/232, 44%), followed by live birth (60/232, 26%). Quality of the reported outcomes was poor (mean 1.54, SD 1.36). It was associated with journal impact factor (p=0.007), but not with study design (p=0.60), or risk of bias (p=0.17). The outcomes reported in studies on pregnant women with epilepsy varied widely, and the quality of the outcomes report was poor. There is a need to identify a set of core outcome to harmonise reporting in future clinical studies. PMID- 26588439 TI - Corticotropin releasing hormone and Urocortin 2 activate inflammatory pathways in cultured trophoblast cell lines. AB - OBJECTIVE: Embryo implantation and parturition are recognized as inflammatory events involving endocrine and immune system. NF-kB and MAPK are two transcription factor families involved in inflammation. A possible role of neuroendocrine mechanism in early pregnancy and delivery was proposed for the neuropeptides related to corticotropin releasing hormones (CRH), named Urocortins (Ucns). Experimental and clinical studies support a role for CRH, Ucn, Ucn2 and Ucn3 in the endocrine/immune modulation of inflammation in human trophoblast; however the intracellular mechanisms are not yet recognized. The aim of the present study was to evaluate which of these neuropeptides modulate NF-kB or MAPKs pathways. STUDY DESIGN: In Jeg-3 placental cell line the effect of CRH, Ucn, Ucn2 or Ucn3 on NF-kB and MAPKs pathways were evaluated using Western blot analysis. RESULTS: CRH induced the phosphorylation of MAPK subunits; Ucn2 was able to induce the phosphorylation of both NF-kB and MAPK subunits. Ucn and Ucn3 had no effects on these pathways. CONCLUSIONS: These data provide novel information on inflammatory process in trophoblast cells: Ucn2 is a potent pro inflammatory neuropeptide via NF-kB and MAPK pathways and CRH via MAPK, and CRH and Ucn2 network participates in the inflammatory mechanisms of pregnancy and parturition. PMID- 26588440 TI - Identification of key active constituents of Buchang Naoxintong capsules with therapeutic effects against ischemic stroke by using an integrative pharmacology based approach. AB - Integrative pharmacology has been used to identify the key active constituents (KACs) of Buchang Naoxintong capsules (BNCs), a traditional Chinese medical preparation; this approach involves the evaluation of the content profiles and drug-like properties of the BNC constituents and development of an ingredient target network. In this study, we used a sensitive analytical method to simultaneously identify and quantify 16 constituents of BNCs. Metabolism of these constituents by gut microbiota and human oral bioavailability were predicted using an in silico approach, followed by construction of networks to analyze the interactions between BNC constituents, their molecular targets, and proteins known to be the molecular targets for Food and Drug Administration-approved colitis medication. Finally, an animal model of ischemic stroke was used to verify the therapeutic effects of the KACs of BNCs. Amygdalin and paeoniflorin were identified as the KACs because they were the 2 most abundant BNC constituents, having appropriate drug-like properties, and produced therapeutic effects against cerebral ischemia. Amygdalin produced an anti-cerebral ischemia effect, likely by interacting with the glucocorticoid receptor (NR3C1) and serpin peptidase inhibitor, clade C (antithrombin), member 1 (SERPINC1). These results form the basis for conducting studies to identify KACs in traditional medicinal preparations; such studies might improve quality control and allow the in vivo evaluation of synergistic interactions between the complex mixtures of compounds. PMID- 26588441 TI - Aqueous-Phase Preparation of Model HDS Catalysts on Planar Alumina Substrates: Support Effect on Mo Adsorption and Sulfidation. AB - The role of the oxide support on the structure of the MoS2 active phase (size, morphology, orientation, sulfidation ratio, etc.) remains an open question in hydrotreating catalysis and biomass processing with important industrial implications for the design of improved catalytic formulations. The present work builds on an aqueous-phase surface-science approach using four well-defined alpha alumina single crystal surfaces (C (0001), A (1120), M (1010), and R (1102) planes) as surrogates for gamma-alumina (the industrial support) in order to discriminate the specific role of individual support facets. The reactivity of the various surface orientations toward molybdenum adsorption is controlled by the speciation of surface hydroxyls that determines the surface charge at the oxide/water interface. The C (0001) plane is inert, and the R (1102) plane has a limited Mo adsorption capacity while the A (1120) and M (1010) surfaces are highly reactive. Sulfidation of model catalysts reveals the highest sulfidation degree for the A (1120) and M (1010) planes suggesting weak metal/support interactions. Conversely, a low sulfidation rate and shorter MoS2 slabs are found for the R (1102) plane implying stronger Mo-O-Al bonds. These limiting cases are reminiscent of type I/type II MoS2 nanostructures. Structural analogies between alpha- and gamma- alumina surfaces allow us to bridge the material gap with real Al2O3-supported catalysts. Hence, it can be proposed that Mo distribution and sulfidation rate are heterogeneous and surface-dependent on industrial gamma Al2O3-supported high-surface-area catalysts. These results demonstrate that a proper control of the gamma-alumina morphology is a strategic lever for a molecular-scale design of hydrotreating catalysts. PMID- 26588442 TI - Contribution of Monomeric Anthocyanins to the Color of Young Red Wine: Statistical and Experimental Approaches. AB - Monomeric anthocyanin contributions to young red wine color were investigated using partial least square regression (PLSR) and aqueous alcohol solutions in this study. Results showed that the correlation between the anthocyanin concentration and the solution color fitted in a quadratic regression rather than linear or cubic regression. Malvidin-3-O-glucoside was estimated to show the highest contribution to young red wine color according to its concentration in wine, whereas peonidin-3-O-glucoside in its concentration contributed the least. The PLSR suggested that delphinidin-3-O-glucoside and peonidin-3-O-glucoside under the same concentration resulted in a stronger color of young red wine compared with malvidin-3-O-glucoside. These estimates were further confirmed by their color in aqueous alcohol solutions. These results suggested that delphinidin-3-O-glucoside and peonidin-3-O-glucoside were primary anthocyanins to enhance young red wine color by increasing their concentrations. This study could provide an alternative approach to improve young red wine color by adjusting anthocyanin composition and concentration. PMID- 26588443 TI - Oral Human Papillomavirus Infection in Children. AB - Oral human papillomavirus infection is rare in children, but the presence of a villous lesion with slow but continuous growth concerns parents, who need information and therapeutic solutions from the physician. All these aspects are discussed based on a case report of a 9-year-old child with an oral human papillomavirus infection. PMID- 26588444 TI - Essential roles for platelets during neutrophil-dependent or lymphocyte-mediated defense against bacterial pathogens. AB - Emerging evidence from animal models suggests that platelets may participate in a wide variety of processes including the immune response against infection. More than 200 whole blood samples from patients and healthy controls were run in the System XE-5000 analyzer, and plasma fractions were separated for the following tests by ELISA, Luminex and light scattering. We describe two mechanisms by which platelets may contribute to immune function against various bacterial pathogens based on increased mean platelet volume in gram-positive bacterial infections and increased platelet counts in gram-negative bacterial infections. Gram-negative bacteria activate platelets to recruit neutrophils, which participate in the immune response against infection. During this process, fractalkine, macrophage inflammatory protein-1beta, interleukin-17A, tumor necrosis factor-alpha and platelet-activating factor were higher in patients infected with Escherichia coli; additionally, giant platelets were observed under the microscope. Meanwhile, we found that platelets played a different role in gram-positive bacterial infections. Specifically, they could actively adhere to gram-positive bacteria in circulation and transfer them to immune sites to promote antibacterial lymphocyte expansion. During this process, complement C3 and factor XI were more highly expressed in patients infected with Staphylococcus aureus; additionally, we detected more small platelets under the microscope. Platelets participate in the immune response against both gram-negative and gram-positive bacteria, although the mechanisms differ. These results will help us understand the complex roles of platelets during infections, and direct our use of antibiotics based on clinical platelet data. PMID- 26588445 TI - Guidelines for laboratory diagnosis of factor XIII deficiency. AB - Factor XIII (FXIII) deficiency is an extremely rare hemorrhagic disorder with an approximate worldwide incidence of one per two million. With current tests, diagnosis of this disease can be made more precisely. However, factors such as the number of patients with FXIII deficiency (FXIIID), available diagnostic coagulation tests and the number of molecular studies have affected the diagnosis of FXIIID in different parts of the world. Various laboratory approaches can be used, including screening and diagnosis of the disorder in countries with a relatively high rate of FXIIID and recurrent mutation(s) with a simple polymerase chain reaction-restriction fragment length polymorphism analysis or polymerase chain reaction-sequencing for detection of one or a few specific mutations. In other countries, two different laboratory approaches can be used, depending on available coagulation tests. In less-equipped coagulation laboratories, the clot solubility test remains the only diagnostic test for FXIIID. Even in these countries, at least one referral laboratory should perform FXIII activity and, if possible, confirmation of FXIIID by molecular analysis. In countries with well equipped coagulation laboratories, FXIII activity should be used to screen suspected FXIIID patients; more specific tests such as molecular analysis should be used for confirmation. This study suggests a simple, reliable and flexible algorithm for early diagnosis of FXIIID, and may, with one-time diagnosis of FXIIID, reduce the rate of morbidity and mortality in patients with the disorder. PMID- 26588446 TI - Inherited antithrombin deficiency and anabolic steroids: a risky combination. AB - A 20-year-old male with asymptomatic inherited type 1 antithrombin deficiency and a family history of thrombosis started injecting himself with testosterone 250 mg intramuscularly twice weekly for 5 weeks. He presented to the hospital with progressive dyspnea on exertion, chest pain and hemoptysis. Workup revealed bilateral submassive pulmonary embolism and proximal right lower extremity deep vein thrombosis. He was treated with intravenous (IV) unfractionated heparin and underwent catheter-directed thrombolysis with alteplase to the main pulmonary arteries. Postprocedure, he remained on IV alteplase infusion for 24 h and unfractionated heparin in the intensive care unit. Concomitantly he received plasma-derived antithrombin concentrate. He was transitioned to subcutaneous enoxaparin twice daily and discharged from the hospital on oral rivaroxaban 15 mg twice a day. This case highlights the heightened thrombogenic effect of anabolic steroids in the setting of underlying thrombophilia especially in younger subjects. PMID- 26588447 TI - Acquired coagulation factor XIII deficiency: a case report. AB - The main objective of the study is to summarize the clinical characteristics of acquired factor XIII (FXIII) deficiency caused by a spontaneous FXIII inhibitor. Here we report a new case of acquired FXIII deficiency caused by FXIII inhibitor and review the medical literature regarding the characteristics and treatment of this disorder. FXIII deficiency caused by FXIII inhibitors is rare and of uncertain pathogenesis. Experience with therapeutic measures is limited to data from case reports. Immunosuppressive drugs may reduce autoantibodies or inhibit the cell clone generating the antibodies and may have been of benefit in our patient. The impact of such therapy on patient prognosis is incompletely known. PMID- 26588448 TI - FIBTEM provides prediction of massive bleeding in total hip replacement arthroplasty. AB - This retrospective study evaluated the association between maximum clot firmness of FIBTEM (MCFFIB) and blood loss, and determined a cutoff value of MCFFIB that may predict massive bleeding in total hip replacement arthroplasty (THRA). Seventy-two adult patients undergoing THRA for avascular necrosis of the femoral head or degenerative arthritis of the hip were included. Patients' medical records were reviewed to collect pre and postoperative laboratory data, as well as the amount of intra and postoperative blood loss (IBL and PBL). Each pre and postoperative fibrinogen level had a significant correlation with the pre and postoperative MCFFIB, respectively (rho = 0.289, P = 0.014 and rho = 0.286, P = 0.015). IBL had significant correlations with pre and postoperative MCFFIB (rho = -0.305, P = 0.010 and rho = -0.297, P = 0.013, respectively), and PBL also showed significant correlations with the pre and postoperative MCFFIB (rho = -0.471, P < 0.001 and rho = -0.475, P < 0.001, respectively). A respective pre or postoperative MCFFI cutoff value of 16 mm or less or 10 mm or less showed the highest sensitivity and specificity for predicting IBL 1000 ml or above or PBL 400 ml or above. Postoperative transfusion was performed more frequently in patients showing postoperative MCFFIB 10 mm or less (31 vs. 3.3%, P = 0.005). MCFFIB correlated well with the amount of IBL or PBL. In addition, a particular value of pre or postoperative MCFFIB could offer the predictive standard for massive bleeding in THRA. PMID- 26588450 TI - Central Diabetes Insipidus in Infancy With or Without Hypothalamic Adipsic Hypernatremia Syndrome: Early Identification and Outcome. AB - CONTEXT: Neonatal central diabetes insipidus (CDI) with or without adipsia is a very rare complication of various complex hypothalamic disorders. It is associated with greater morbidity and a high risk of developing both hypernatremia and hyponatremia, due to the condition itself or secondary to treatment with vasopressin analogs or fluid administration. Its outcomes have yet to be evaluated. OBJECTIVE: To investigate the clinical outcomes of patients with neonatal-onset CDI or adipsic CDI with hypernatremia. DESIGN, SETTING, AND PARTICIPANTS: All patients diagnosed with neonatal CDI in a university hospital based observational study and followed between 2005 and 2015 were included and analyzed retrospectively. MAIN OUTCOME MEASURES: The various causes of CDI were grouped. Clinical outcome and comorbidities were analyzed. RESULTS: Ten of the 12 patients had an underlying condition with brain malformations: optic nerve hypoplasia (n = 3), septo-optic dysplasia (n = 2), semilobar holoprosencephaly (n = 1), ectopic neurohypophysis (n = 3), and unilateral absence of the internal carotid artery (n = 1). The other two were idiopathic cases. During the median follow-up period of 7.8 (4.9-16.8) years, all but one patient displayed anterior pituitary deficiency. Transient CDI was found in three (25%) patients for whom a posterior pituitary hyperintense signal was observed with (n = 2) and without (n = 1) structural hypothalamic pituitary abnormalities, and with no other underlying cerebral malformations. Patients with permanent CDI with persistent adipsia (n = 4) and without adipsia (n = 5) required adequate fluid intake and various doses of desamino-D-arginine-8-vasopressin. Those with adipsia were more likely to develop hypernatremia (45 vs 33%), hyponatremia (16 vs 4%) (P < .0001), and severe neurodevelopmental delay (P < .05) than those without adipsia. Comorbidities were common. The underlying cause remains unknown at the age of 23 years for one patient with CDI and normal thirst. CONCLUSION: Neonatal CDI may be transient or permanent. These vulnerable patients have high rates of comorbidity and require careful monitoring. PMID- 26588449 TI - Adiposity in Children Born Small for Gestational Age Is Associated With beta-Cell Function, Genetic Variants for Insulin Resistance, and Response to Growth Hormone Treatment. AB - BACKGROUND: Genetic susceptibility to insulin resistance is associated with lower adiposity in adults. Insulin resistance, and therefore adiposity, may alter sensitivity to GH. We aimed to determine the relationship between adiposity, genetic susceptibility to insulin resistance or insulin secretion, and response to GH treatment in short children born small for gestational age (SGA). METHODS: In 89 short prepubertal SGA children (age, 6.2 +/- 1.6 y; 55 boys) treated with GH for 1 year in a multicenter study, body fat percentage was estimated at baseline and 1 year using dual-energy x-ray absorptiometry. The main outcome measures were treatment-related changes in height, IGF-1 standard deviation score, insulin sensitivity, insulin secretion, and disposition index. Combined multiallele gene scores based on single nucleotide polymorphisms with known associations with lower insulin sensitivity (gene scores for insulin resistance [GS-InRes]) and insulin secretion (gene scores for insulin secretion [GS-InSec]) were analyzed for their relationships with adiposity. RESULTS: Mean percentage body fat at baseline was low compared to normative data (P = .045) and decreased even further on GH treatment (baseline vs 1-year z-scores, -0.26 +/- 1.2 vs -1.23 +/- 1.54; P < .0001). Baseline percentage body fat was positively associated with IGF-1 responses (p-trends = .042), first-year height gains (B [95% confidence interval], 0.61 cm/y [0.28,0.95]; P < .0001), insulin secretion at baseline (p trends = .020) and 1 year (p-trends = .004), and disposition index at 1 year (p trends = .024). GS-InRes was inversely associated with body mass index (-0.13 SD score per allele [-0.26, -0.01]; P = .040), body fat (-0.49% per allele [-0.97, 0.007]; P = .047), and limb fat (-0.81% per allele [-1.62, 0.00]; P = .049) at baseline. During GH treatment, GS-InRes was related to a lesser decline in trunk fat (0.38% per allele [0.16, 0.59]; P = .001) and a higher trunk-limb fat ratio at 1 year (0.04 per allele [0.01, 0.08]; P = .008). GS-InSec was positively associated with truncal fat (0.36% per allele [0.09, 0.63]; P = .009). CONCLUSIONS: Adiposity in SGA children has favorable effects on GH sensitivity and glucose metabolism. The associations with multiallele scores support a causal role of insulin resistance in linking lesser body fat to reduced sensitivity to exogenous GH. PMID- 26588451 TI - Polymer-coated micro-optofluidic ring resonator detector for a comprehensive two dimensional gas chromatographic microsystem: MUGC *MUGC-MUOFRR. AB - We describe first results from a micro-analytical subsystem that integrates a detector comprising a polymer-coated micro-optofluidic ring resonator (MUOFRR) chip with a microfabricated separation module capable of performing thermally modulated comprehensive two-dimensional gas chromatographic separations (MUGC *MUGC) of volatile organic compound (VOC) mixtures. The 2 * 2 cm MUOFRR chip consists of a hollow, contoured SiO(x) cylinder (250 MUm i.d.; 1.2 MUm wall thickness) grown from a Si substrate, and integrated optical and fluidic interconnection features. By coupling to a 1550 nm tunable laser and photodetector via an optical fiber taper, whispering gallery mode (WGM) resonances were generated within the MUOFRR wall, and shifts in the WGM wavelength caused by transient sorption of eluting vapors into the PDMS film lining the MUOFRR cylinder were monitored. Isothermal separations of a simple alkane mixture using a PDMS coated 1st-dimension ((1)D) MUcolumn and an OV-215 coated 2nd-dimension ((2)D) MUcolumn confirmed that efficient MUGC *MUGC-MUOFRR analyses could be performed and that responses were dominated by film-swelling. Subsequent tests with more diverse VOC mixtures demonstrated that the modulated peak width and the VOC sensitivity were inversely proportional to the vapor pressure of the analyte. Modulated peaks as narrow as 120 ms and limits of detection in the low-ng range were achieved. Structured contour plots generated with the MUOFRR and a reference FID were comparable. PMID- 26588452 TI - Exploring the Relationship Between Illness Perceptions and Negative Emotions in Relatives of People With Schizophrenia Within the Context of an Affiliate Stigma Model. AB - BACKGROUND: Stigma affects patients with schizophrenia and may influence perceptions of the illness, which may affect how family members interact with and care for these patients. PURPOSE: The aims of this study were to (a) explore the relationship between perceptions of schizophrenia and the negative emotions of family members within the context of an affiliate stigma model, and (b) validate the proposed affiliate stigma model. METHODS: A cross-sectional design was used. Eligibility for participation was limited to the relatives of patients with schizophrenia. The participants were recruited from two regional psychiatric hospitals in central Taiwan. The study was approved by an Institutional Review Board, and all potential participants signed informed consent before enrollment. Sixty-two participants completed the set of self-administered questionnaires, including (a) a demographic questionnaire, (b) Affiliate Stigma Scale, and (c) the Illness Perception Questionnaire for Schizophrenia-Relatives version. Canonical correlations and structural equation modeling in STATISTICA 6.0 were used to validate the model of illness perceptions and negative emotions. RESULTS: (a) There were three domains of perception regarding schizophrenia for the relatives of patients: disease chronicity, disease in control, and disease treatability. The correlation between these dimensions and negative emotion was r = .42. (b) The adjusted goodness of fit for the proposed affiliate stigma model was .79. CONCLUSIONS: The results of this study suggest that the affiliate stigma model is an appropriate resource for developing practical disease management strategies for the relatives of patients with schizophrenia. PMID- 26588453 TI - Effects of a Home-Based Resistance Training Program on Recovery From Total Hip Replacement Surgery: Feasibility and Pilot Testing. AB - BACKGROUND: Postoperative exercise rehabilitation helps patients recover normal joint functions after total hip arthroplasty (total hip replacement surgery or THR) by strengthening the muscles that surround the replaced hip joint. However, the high cost of professionally supervised exercise rehabilitation programs limits access to program participation and, thus, to optimal recovery of normal joint functions. Therefore, the development of an effective home-based, self monitored exercise rehabilitation program is critical to promote the optimal recovery of THR patients. PURPOSE: This study tests the efficacy of a home-based resistance-band exercise program on mobility, functional exercise capacity, and health-related quality of life in THR patients. METHODS: This study uses a preexperimental repeated measures design. A convenience sample of 30 patients who underwent total hip replacement for osteoarthritis was recruited. All patients participated in a 12-week home-based resistance training program. Data were collected at baseline and at 2, 6, and 12 weeks postoperation on the following dimensions: up-and-go time, timed walking distance, and quality of life. In addition, intervention-related adverse events and the exercise adherence rate were monitored. Generalized estimation equations were used to analyze changes in the outcome variables across time. RESULTS: The study included 21 women and nine men. The mean age of the participants was 67.9 years (SD = 8.1 years, range = 55 86 years). Results of the generalized estimation equations showed a statistically significant time effect for up-and-go time, 6-minute walking distance, and health related quality of life. After 12 weeks of training, the participants' up-and-go time decreased 40.33% from the baseline measurements, with a mean change of 6.38 seconds (p < .001). The 6-minute walking distance increased 41.34%, with a mean change of 117.12 meters (p < .001). The score for health-related quality of life decreased 78.94%, with a mean change of 39.10 (p < .001). The average exercise adherence rate was 72.63%. The average score for the feasibility of the intervention was 8.8 (range = 6-10). CONCLUSIONS/IMPLICATIONS FOR PRACTICE: The results of this study support the hypothesis that a home-based resistance training program is safe, feasible, and effective for improving the mobility, functional exercise capacity, and health-related quality of life of THR patients. Considering the low cost and convenience of a home-based resistance training program, health professionals should consider this and similar exercise programs when providing guidance to THR patients. PMID- 26588454 TI - Parkinson's Protein alpha-Synuclein Binds Efficiently and with a Novel Conformation to Two Natural Membrane Mimics. AB - Binding of human alpha-Synuclein, a protein associated with Parkinson's disease, to natural membranes is thought to be crucial in relation to its pathological and physiological function. Here the binding of alphaS to small unilamellar vesicles mimicking the inner mitochondrial and the neuronal plasma membrane is studied in situ by continuous wave and pulsed electron paramagnetic resonance. Local binding information of alphaS spin labeled by MTSL at positions 56 and 69 respectively shows that also helix 2 (residues 50-100) binds firmly to both membranes. By double electron-electron resonance (DEER) on the mutant spin labeled at positions 27 and 56 (alphaS 27/56) a new conformation on the membrane is found with a distance of 3.6 nm/ 3.7 nm between residues 27 and 56. In view of the low negative charge density of these membranes, the strong interaction is surprising, emphasizing that function and pathology of alphaS could involve synaptic vesicles and mitochondria. PMID- 26588455 TI - Onyx embolization of an intraosseous pseudoaneurysm of the middle meningeal artery in a patient with meningiomatosis, McCune-Albright syndrome, and gray platelet syndrome. AB - A 13-year-old boy with meningiomatosis, McCune-Albright syndrome, and gray platelet syndrome presented with an enlarging "lump" on his right forehead. A head CT scan revealed a polyostotic fibrous dysplasia involving the entire skull. A 3.4-cm right frontal osseous cavity and an overlying right forehead subcutaneous soft-tissue mass were seen, measuring 5.2 cm in diameter and 1.6 cm thick. Ultrasound of the cavity and overlying mass showed swirling of blood and an arterialized waveform. MRI revealed an en plaque meningioma underlying the cavity. An intraosseous pseudoaneurysm fed by 3 distal anterior division branches of the right middle meningeal artery (MMA) with contrast extravasation was found on angiography. Two MMA feeders were embolized with Onyx, with anterograde filling of the intraosseous cavity with Onyx. A small pocket of residual intracavity contrast filling postembolization from a smaller third MMA feeder eventually thrombosed and the forehead lump regressed. PMID- 26588456 TI - Short-term mortality following surgical procedures for the diagnosis of pediatric brain tumors: outcome analysis in 5533 children from SEER, 2004-2011. AB - OBJECT Thirty-day mortality is increasingly a reference metric regarding surgical outcomes. Recent data estimate a 30-day mortality rate of 1.4-2.7% after craniotomy for tumors in children. No detailed analysis of short-term mortality following a diagnostic neurosurgical procedure (e.g., resection or tissue biopsy) for tumor in the US pediatric population has been conducted. METHODS The Surveillance, Epidemiology and End Results (SEER) data sets identified patients <= 21 years who underwent a diagnostic neurosurgical procedure for primary intracranial tumor from 2004 to 2011. One- and two-month mortality was estimated. Standard statistical methods estimated associations between independent variables and mortality. RESULTS A total of 5533 patients met criteria for inclusion. Death occurred within the calendar month of surgery in 64 patients (1.16%) and by the conclusion of the calendar month following surgery in 95 patients (1.72%). Within the first calendar month, patients < 1 year of age (n = 318) had a risk of death of 5.66%, while those from 1 to 21 years (n = 5215) had a risk of 0.88% (p < 0.0001). By the end of the calendar month following surgery, patients < 1 year (n = 318) had a risk of death of 7.23%, while those from 1 to 21 years (n = 5215) had a risk of 1.38% (p < 0.0001). Children < 1 year at diagnosis were more likely to harbor a high-grade lesion than older children (OR 1.9, 95% CI 1.5-2.4). CONCLUSIONS In the SEER data sets, the risk of death within 30 days of a diagnostic neurosurgical procedure for a primary pediatric brain tumor is between 1.16% and 1.72%, consistent with contemporary data from European populations. The risk of mortality in infants is considerably higher, between 5.66% and 7.23%, and they harbor more aggressive lesions. PMID- 26588457 TI - Long-term follow-up for lumbar intrathecal baclofen catheters placed using the paraspinal subfascial technique. AB - OBJECT Intrathecal baclofen (ITB) is a valuable therapeutic option for patients with spasticity and dystonia. The techniques that place an ITB pump catheter into the subcutaneous fat of a lumbar incision are well described. Because patients who require ITB often have low body fat content, they may be predisposed to catheter-related complications. The senior author used a novel technique to place the catheter in a paraspinal subfascial fashion, and the short-term results were previously published. That study demonstrated no development of hardware erosions, catheter migrations, or CSF leaks within an average follow-up of 5 months. This study followed up on those initial findings by looking at the long term outcomes since this technique was introduced. METHODS Using the institutional review board-approved protocol, the electronic medical records were reviewed retrospectively for all patients who underwent paraspinal subfascial catheter placement by the senior author. Patients received follow-up with the surgeon at 2 weeks postoperatively and were followed routinely by their physiatrist thereafter. RESULTS Of the 43 patients identified as having undergone surgery by the senior author using the paraspinal subfascial technique between July 2010 and February 2014, 12 patients (27.9%) required reoperation. There were 5 patients (11.6%) who had complications related to the catheter or lumbar incision. No hardware erosions or CSF leaks were identified. These patients received a median follow-up of 3.0 years, with 30 of 43 patients receiving follow up over 2.0 years. CONCLUSION This follow-up study suggests that the technique of paraspinal subfascial catheter placement translates to long-term decreases in CSF leakage and complications from erosion, infection, and also catheter malfunctions. It does not seem to affect the overall rate of complications. PMID- 26588458 TI - Successful treatment of primary intracranial sarcoma with the ICE chemotherapy regimen and focal radiation in children. AB - OBJECT Primary CNS sarcomas are very rare pediatric tumors with no defined standard of care. METHODS This study was a retrospective review of children diagnosed with a primary CNS sarcoma and treated at 2 Canadian tertiary care centers between 1995 and 2012. This report focuses on patients with cerebral hemispheric tumor location due to their specific clinical presentation. RESULTS Fourteen patients with nonmetastatic primary CNS sarcoma were identified; in 9 patients, tumors were located in the cerebral hemisphere and 7 of these patients presented with intratumoral hemorrhage. One infant who died of progressive disease postoperatively before receiving any adjuvant therapy was not included in this study. The final cohort therefore included 8 patients (4 males). Median patient age at diagnosis was 11.8 years (range 5.8-17 years). All tumors were located in the right hemisphere. Duration of symptoms prior to diagnosis was very short with a median of 2 days (range 3-7 days), except for 1 patient. Three (37.5%) patients had an underlying diagnosis of neurofibromatosis Type 1 (NF1). Gross-total resection was achieved in 5 patients. The dose of focal radiation therapy (RT) ranged between 54 Gy and 60 Gy. Concomitant etoposide was administered during RT. ICE (ifosfamide, carboplatin, etoposide) chemotherapy was administered prior to and after RT for a total of 6-8 cycles. Seven of the 8 patients were alive at a median time of 4.9 years (range 1.9-17.9 years) after treatment. CONCLUSIONS In this retrospective series, patients with primary CNS sarcomas located in the cerebral hemisphere most commonly presented with symptomatic acute intratumoral hemorrhage. Patients with NF1 were overrepresented. The combination of adjuvant ICE chemotherapy and focal RT provided encouraging outcomes. PMID- 26588459 TI - Natural and surgical history of Chiari malformation Type I in the pediatric population. AB - OBJECT The natural and surgical history of Chiari malformation Type I (CM-I) in pediatric patients is currently not well described. In this study the authors discuss the clinical and radiological presentation and outcomes in a large cohort of pediatric CM-I patients treated with either conservative or surgical management. METHODS The authors retrospectively reviewed 95 cases involving pediatric patients with CM-I who presented between 2004 and 2013. The patients ranged in age from 9 months to 18 years (mean 8 years) at presentation. The cohort was evenly split between the sexes. Twenty-five patients underwent posterior fossa decompression (PFD) with either dural splitting or duraplasty. Seventy patients were managed without surgery. Patients were followed radiologically (mean 44.8 months, range 1.2-196.6 months) and clinically (mean 66.3 months, range 1.2-106.5 months). RESULTS Seventy patients were treated conservatively and followed with serial outpatient neurological and radiological examinations, whereas 25 patients were treated with PFD. Of these 25 surgical patients, 11 were treated with duraplasty (complete dural opening) and 14 were treated with a dura-splitting technique (incomplete dural opening). Surgical intervention was associated with better clinical resolution of symptoms and radiological resolution of tonsillar ectopia and syringomyelia (p = 0.0392). Over the course of follow-up, 20 (41.7%) of 48 nonsurgical patients who were symptomatic at presentation experienced improvement in symptoms and 18 (75%) of 24 symptomatic surgical patients showed clinical improvement (p = 0.0117). There was no statistically significant difference in resolution of symptoms between duraplasty and dura-splitting techniques (p = 0.3572) or between patients who underwent tonsillectomy and tonsillopexy (p = 0.1667). Neither of the 2 patients in the conservative group with syrinx at presentation showed radiological evidence of resolution of the syrinx, whereas 14 (87.5%) of 16 patients treated with surgery showed improvement or complete resolution of syringomyelia (p = 0.0392). In the nonsurgical cohort, 3 patients (4.3%) developed new or increased syrinx. CONCLUSIONS The overwhelming majority of CM-I patients (92.9%) managed conservatively do not experience clinical or radiological progression, and a sizeable minority (41.7%) of those who present with symptoms improve. However, appropriately selected symptomatic patients (sleep apnea and dysphagia) and those presenting with syringomyelia should be considered surgical candidates because of the high rates of clinical (75%) and radiological improvement (87.5%). PMID- 26588460 TI - Cranial juvenile psammomatoid ossifying fibroma: case report. AB - Juvenile psammomatoid ossifying fibroma (JPOF) is a fibroosseous tumor that arises in the craniofacial bones in young people. This lesion usually originates in the jaw, orbit, and ethmoid complex but can also be associated with the skull base and calvaria. Diagnosis must be made based on observing typical radiological and histopathological features. Although JPOF is a rare pathological entity, neurosurgeons must consider this odontogenic lesion in the differential diagnosis of skull masses given the lesion's aggressive behavior and locally invasive growth. Treatment must be gross-total resection. In the following article, the authors present a case of cranial JPOF and discuss various aspects of this entity. PMID- 26588461 TI - Characterization of complications associated with open and endoscopic craniosynostosis surgery at a single institution. AB - OBJECT The authors present a retrospective cohort study examining complications in patients undergoing surgery for craniosynostosis using both minimally invasive endoscopic and open approaches. METHODS Over the past 10 years, 295 nonsyndromic patients (140 undergoing endoscopic procedures and 155 undergoing open procedures) and 33 syndromic patients (endoscopic procedures in 10 and open procedures in 23) met the authors' criteria. Variables analyzed included age at surgery, presence of a preexisting CSF shunt, skin incision method, estimated blood loss, transfusions of packed red blood cells, use of intravenous steroids or tranexamic acid, intraoperative durotomies, procedure length, and length of hospital stay. Complications were classified as either surgically or medically related. RESULTS In the nonsyndromic endoscopic group, the authors experienced 3 (2.1%) surgical and 5 (3.6%) medical complications. In the nonsyndromic open group, there were 2 (1.3%) surgical and 7 (4.5%) medical complications. Intraoperative durotomies occurred in 5 (3.6%) endoscopic and 12 (7.8%) open cases, were repaired primarily, and did not result in reoperations for CSF leakage. Similar complication rates were seen in syndromic cases. There was no death or permanent morbidity. Additionally, endoscopic procedures were associated with significantly decreased estimated blood loss, transfusions, procedure length, and length of hospital stay compared with open procedures. CONCLUSIONS Rates of intraoperative durotomies and surgical and medical complications were comparable between endoscopic and open techniques. This is the largest direct comparison to date between endoscopic and open interventions for synostosis, and the results are in agreement with previous series that endoscopic surgery confers distinct advantages over open surgery in appropriate patient populations. PMID- 26588463 TI - Gadolinium Deposition in Humans: When Did We Learn That Gadolinium Was Deposited In Vivo? AB - Recently, there have been numerous major peer-reviewed publications reporting deposition of gadolinium in the dentate nucleus and globus pallidus in subjects with normal renal function. This review takes a retrospective look back through the development of gadolinium-based contrast agents to describe the historical evidence of gadolinium deposition in vivo and shows that deposition in the basal ganglia should come as no surprise. Evidence for gadolinium deposition in both animal models and human patients is described. Stability differences among gadolinium contrast agents have long been recognized in vitro, and deposition of gadolinium in tissues has been described in animal models since at least 1984. The first major study that showed deposition in humans appeared in 1998 regarding patients with renal failure and in 2004 in patients with normal renal function. The historical literature indicates that gadolinium retention in healthy patients is occurring, although the clinical consequences of deposition remain unknown. PMID- 26588462 TI - A Cytosine Methyltransferase Modulates the Cell Envelope Stress Response in the Cholera Pathogen [corrected]. AB - DNA methylation is a key epigenetic regulator in all domains of life, yet the effects of most bacterial DNA methyltransferases on cellular processes are largely undefined. Here, we used diverse techniques, including bisulfite sequencing, transcriptomics, and transposon insertion site sequencing to extensively characterize a 5-methylcytosine (5mC) methyltransferase, VchM, in the cholera pathogen, Vibrio cholerae. We have comprehensively defined VchM's DNA targets, its genetic interactions and the gene networks that it regulates. Although VchM is a relatively new component of the V. cholerae genome, it is required for optimal V. cholerae growth in vitro and during infection. Unexpectedly, the usually essential sigmaE cell envelope stress pathway is dispensable in ?vchM V. cholerae, likely due to its lower activation in this mutant and the capacity for VchM methylation to limit expression of some cell envelope modifying genes. Our work illuminates how an acquired DNA methyltransferase can become integrated within complex cell circuits to control critical housekeeping processes. PMID- 26588464 TI - The Chromatin Regulator CHD8 Is a Context-Dependent Mediator of Cell Survival in Murine Hematopoietic Malignancies. AB - Aberrant chromatin regulation is a frequent driver of leukemogenesis. Mutations in chromatin regulators often result in more stem-like cells that seed a bulk leukemic population. Inhibitors targeting these proteins represent an emerging class of therapeutics, and identifying further chromatin regulators that promote disease progression may result in additional drug targets. We identified the chromatin-modifying protein CHD8 as necessary for cell survival in a mouse model of BCR-Abl+ B-cell acute lymphoblastic leukemia. This disease has a poor prognosis despite treatment with kinase inhibitors targeting BCR-Abl. Although implicated as a risk factor in autism spectrum disorder and a tumor suppressor in prostate and lung cancer, the mechanism of CHD8's activity is still unclear and has never been studied in the context of hematopoietic malignancies. Here we demonstrate that depletion of CHD8 in B-ALL cells leads to cell death. While multiple B cell malignancies were dependent on CHD8 expression for survival, T cell malignancies displayed milder phenotypes upon CHD8 knockdown. In addition, ectopic expression of the Notch1 intracellular domain in a T cell malignancy partially alleviated the detrimental effect of CHD8 depletion. Our results demonstrate that CHD8 has a context-dependent role in cell survival, and its inhibition may be an effective treatment for B lymphoid malignancies. PMID- 26588465 TI - Genomic and Post-Translational Modification Analysis of Leucine-Rich-Repeat Receptor-Like Kinases in Brassica rapa. AB - Among several receptor-like kinases (RLKs), leucine-rich-repeat receptor-like kinases (LRR-RLKs) are a major group of genes that play crucial roles in growth, development and stress responses in plant systems. Given that they have several functional roles, it is important to investigate their roles in Brassica rapa. In the present study, 303 LRR-RLKs were identified in the genome of B. rapa and comparative phylogenetic analysis of 1213 combined LRR-RLKs of B. rapa, Arabidopsis thaliana, Oryza sativa and Populus trichocarpa helped us to categorize the gene family into 15 subfamilies based on their sequence and structural similarities. The chromosome localizations of 293 genes allowed the prediction of duplicates, and motif conservation and intron/exon patterns showed differences among the B. rapa LRR-RLK (BrLRR-RLK) genes. Additionally, computational function annotation and expression analysis was used to predict their possible functional roles in the plant system. Biochemical results for 11 selected genes showed variations in phosphorylation activity. Interestingly, BrBAK1 showed strong auto-phosphorylation and trans-phosphorylation on its tyrosine and threonine residues compared with AtBAK1 in previous studies. The AtBAK1 receptor kinase is involved in plant growth and development, plant innate immunity, and programmed cell death, and our results suggest that BrBAK1 might also be involved in the same functions. Another interesting result was that BrBAK1, BrBRI1, BrPEPR1 and BrPEPR2 showed activity with both anti phosphotyrosine and anti-phosphothreonine antibodies, indicating that they might have dual-specificity kinase activity. This study provides comprehensive results for the BrLRR-RLKs, revealing expansion of the gene family through gene duplications, structural similarities and variations among the genes, and potential functional roles according to gene ontology, transcriptome profiling and biochemical analysis. PMID- 26588466 TI - T cell epitope redundancy: cross-conservation of the TCR face between pathogens and self and its implications for vaccines and autoimmunity. AB - T cells are extensively trained on 'self' in the thymus and then move to the periphery, where they seek out and destroy infections and regulate immune response to self-antigens. T cell receptors (TCRs) on T cells' surface recognize T cell epitopes, short linear strings of amino acids presented by antigen presenting cells. Some of these epitopes activate T effectors, while others activate regulatory T cells. It was recently discovered that T cell epitopes that are highly conserved on their TCR face with human genome sequences are often associated with T cells that regulate immune response. These TCR-cross-conserved or 'redundant epitopes' are more common in proteins found in pathogens that have co-evolved with humans than in other non-commensal pathogens. Epitope redundancy might be the link between pathogens and autoimmune disease. This article reviews recently published data and addresses epitope redundancy, the "elephant in the room" for vaccine developers and T cell immunologists. PMID- 26588467 TI - Unusually Large Number of Mutations in Asexually Reproducing Clonal Planarian Dugesia japonica. AB - We established a laboratory clonal strain of freshwater planarian (Dugesia japonica) that was derived from a single individual and that continued to undergo autotomous asexual reproduction for more than 20 years, and we performed large scale genome sequencing and transcriptome analysis on it. Despite the fact that a completely clonal strain of the planarian was used, an unusually large number of mutations were detected. To enable quantitative genetic analysis of such a unique organism, we developed a new model called the Reference Gene Model, and used it to conduct large-scale transcriptome analysis. The results revealed large numbers of mutations not only outside but also inside gene-coding regions. Non-synonymous SNPs were detected in 74% of the genes for which valid ORFs were predicted. Interestingly, the high-mutation genes, such as metabolism- and defense-related genes, were correlated with genes that were previously identified as diverse genes among different planarian species. Although a large number of amino acid substitutions were apparently accumulated during asexual reproduction over this long period of time, the planarian maintained normal body-shape, behaviors, and physiological functions. The results of the present study reveal a unique aspect of asexual reproduction. PMID- 26588468 TI - Prevalence of and Factors Associated with Human Cysticercosis in 60 Villages in Three Provinces of Burkina Faso. AB - BACKGROUND: Taenia solium, a zoonotic infection transmitted between humans and pigs, is considered an emerging infection in Sub-Saharan Africa, yet individual and community-level factors associated with the human infection with the larval stages (cysticercosis) are not well understood. This study aims to estimate the magnitude of association of individual-level and village-level factors with current human cysticercosis in 60 villages located in three Provinces of Burkina Faso. METHODOLOGY/PRINCIPAL FINDINGS: Baseline cross-sectional data collected between February 2011 and January 2012 from a large community randomized-control trial were used. A total of 3609 individuals provided serum samples to assess current infection with cysticercosis. The association between individual and village-level factors and the prevalence of current infection with cysticercosis was estimated using Bayesian hierarchical logistic models. Diffuse priors were used for all regression coefficients. The prevalence of current cysticercosis varied across provinces and villages ranging from 0% to 11.5%. The results obtained suggest that increased age, being male and consuming pork as well as a larger proportion of roaming pigs and percentage of sand in the soil measured at the village level were associated with higher prevalences of infection. Furthermore, consuming pork at another village market had the highest increased prevalence odds of current infection. Having access to a latrine, living in a household with higher wealth quintiles and a higher soil pH measured at the village level decreased the prevalence odds of cysticercosis. CONCLUSIONS/SIGNIFICANCE: This is the first large-scale study to examine the association between variables measured at the individual-, household-, and village-level and the prevalence odds of cysticercosis in humans. Factors linked to people, pigs, and the environment were of importance, which further supports the need for a One Health approach to control cysticercosis infection. PMID- 26588469 TI - Complex Magnetic Exchange Coupling between Co Nanostructures and Ni(111) across Epitaxial Graphene. AB - We report on the magnetic coupling between isolated Co atoms as well as small Co islands and Ni(111) mediated by an epitaxial graphene layer. X-ray magnetic circular dichroism and scanning tunneling microscopy combined with density functional theory calculations reveal that Co atoms occupy two distinct adsorption sites, with different magnetic coupling to the underlying Ni(111) surface. We further report a transition from an antiferromagnetic to a ferromagnetic coupling with increasing Co cluster size. Our results highlight the extreme sensitivity of the exchange interaction mediated by graphene to the adsorption site and to the in-plane coordination of the magnetic atoms. PMID- 26588470 TI - NFkappaB drives TERT promoter reactivation in cancer. PMID- 26588472 TI - Mechanical Properties of a Calcium Dietary Supplement, Calcium Fumarate Trihydrate. AB - The mechanical properties of calcium fumarate trihydrate, a 1D coordination polymer considered for use as a calcium source for food and beverage enrichment, have been determined via nanoindentation and high-pressure X-ray diffraction with single crystals. The nanoindentation studies reveal that the elastic modulus (16.7-33.4 GPa, depending on crystallographic orientation), hardness (1.05-1.36 GPa), yield stress (0.70-0.90 GPa), and creep behavior (0.8-5.8 nm/s) can be rationalized in view of the anisotropic crystal structure; factors include the directionality of the inorganic Ca-O-Ca chain and hydrogen bonding, as well as the orientation of the fumarate ligands. High-pressure single-crystal X-ray diffraction studies show a bulk modulus of ~ 20 GPa, which is indicative of elastic recovery intermediate between small molecule drug crystals and inorganic pharmaceutical ingredients. The combined use of nanoindentation and high-pressure X-ray diffraction techniques provides a complementary experimental approach for probing the critical mechanical properties related to tableting of these dietary supplements. PMID- 26588471 TI - Early Gelatinase Activity Is Not a Determinant of Long-Term Recovery after Traumatic Brain Injury in the Immature Mouse. AB - The gelatinases, matrix metalloproteinases (MMP)-2 and MMP-9, are thought to be key mediators of secondary damage in adult animal models of brain injury. Moreover, an acute increase in these proteases in plasma and brain extracellular fluid of adult patients with moderate-to-severe traumatic brain injuries (TBIs) is associated with poorer clinical outcomes and mortality. Nonetheless, their involvement after TBI in the pediatric brain remains understudied. Using a murine model of TBI at postnatal day 21 (p21), approximating a toddler-aged child, we saw upregulation of active and pro-MMP-9 and MMP-2 by gelatin zymography at 48 h post-injury. We therefore investigated the role of gelatinases on long-term structural and behavioral outcomes after injury after acute inhibition with a selective gelatinase inhibitor, p-OH SB-3CT. After systemic administration, p-OH SB-3CT crossed the blood-brain barrier at therapeutically-relevant concentrations. TBI at p21 induced hyperactivity, deficits in spatial learning and memory, and reduced sociability when mice were assessed at adulthood, alongside pronounced tissue loss in key neuroanatomical regions. Acute and short term post-injury treatment with p-OH SB-3CT did not ameliorate these long-term behavioral, cognitive, or neuropathological deficits as compared to vehicle treated controls, suggesting that these deficits were independent of MMP-9 and MMP-2 upregulation. These findings emphasize the vulnerability of the immature brain to the consequences of traumatic injuries. However, early upregulation of gelatinases do not appear to be key determinants of long-term recovery after an early-life injury. PMID- 26588474 TI - Farewell to Giorgio Gambale. PMID- 26588473 TI - Lacrimal Cytokines Assessment in Subjects Exposed to Different Levels of Ambient Air Pollution in a Large Metropolitan Area. AB - BACKGROUND: Air pollution is one of the most environmental health concerns in the world and has serious impact on human health, particularly in the mucous membranes of the respiratory tract and eyes. However, ocular hazardous effects to air pollutants are scarcely found in the literature. DESIGN: Panel study to evaluate the effect of different levels of ambient air pollution on lacrimal film cytokine levels of outdoor workers from a large metropolitan area. METHODS: Thirty healthy male workers, among them nineteen professionals who work on streets (taxi drivers and traffic controllers, high pollutants exposure, Group 1) and eleven workers of a Forest Institute (Group 2, lower pollutants exposure compared to group 1) were evaluated twice, 15 days apart. Exposure to ambient PM2.5 (particulate matter equal or smaller than 2.5 MUm) was 24 hour individually collected and the collection of tears was performed to measure interleukins (IL) 2, 4, 5 and 10 and interferon gamma (IFN-gamma) levels. Data from both groups were compared using Student's t test or Mann- Whitney test for cytokines. Individual PM2.5 levels were categorized in tertiles (lower, middle and upper) and compared using one-way ANOVA. Relationship between PM2.5 and cytokine levels was evaluated using generalized estimating equations (GEE). RESULTS: PM2.5 levels in the three categories differed significantly (lower: <=22 MUg/m3; middle: 23 37.5 MUg/m3; upper: >37.5 MUg/m3; p<0.001). The subjects from the two groups were distributed unevenly in the lower category (Group 1 = 8%; Group 2 = 92%), the middle category (Group 1 = 89%; Group 2 = 11%) and the upper category (Group 1 = 100%). A significant relationship was found between IL-5 and IL-10 and PM2.5 levels of the group 1, with an average decrease of 1.65 pg/mL of IL-5 level and of 0.78 pg/mL of IL-10 level in tear samples for each increment of 50 MUg/m3 of PM2.5 (p = 0.01 and p = 0.003, respectively). CONCLUSION: High levels of PM2.5 exposure is associated with decrease of IL-5 and IL-10 levels suggesting a possible modulatory action of ambient air pollution on ocular surface immune response. PMID- 26588475 TI - Genetic engineering of Ganoderma lucidum for the efficient production of ganoderic acids. AB - Ganoderma lucidum is a well-known traditional medicinal mushroom that produces ganoderic acids with numerous interesting bioactivities. Genetic engineering is an efficient approach to improve ganoderic acid biosynthesis. However, reliable genetic transformation methods and appropriate genetic manipulation strategies remain underdeveloped and thus should be enhanced. We previously established a homologous genetic transformation method for G. lucidum; we also applied the established method to perform the deregulated overexpression of a homologous 3 hydroxy-3-methyl-glutaryl coenzyme A reductase gene in G. lucidum. Engineered strains accumulated more ganoderic acids than wild-type strains. In this report, the genetic transformation systems of G. lucidum are described; current trends are also presented to improve ganoderic acid production through the genetic manipulation of G. lucidum. PMID- 26588477 TI - Self-Assembly Strategy for Fabricating Connected Graphene Nanoribbons. AB - We use self-assembly to fabricate and to connect precise graphene nanoribbons end to end. Combining scanning tunneling microscopy, Raman spectroscopy, and density functional theory, we characterize the chemical and electronic aspects of the interconnections between ribbons. We demonstrate how the substrate effects of our self-assembly can be exploited to fabricate graphene structures connected to desired electrodes. PMID- 26588476 TI - Characterization of FGF23-Dependent Egr-1 Cistrome in the Mouse Renal Proximal Tubule. AB - Fibroblast growth factor 23 (FGF23) is a potent regulator of phosphate (Pi) and vitamin D homeostasis. The transcription factor, early growth response 1 (egr-1), is a biomarker for FGF23-induced activation of the ERK1/2 signaling pathway. We have shown that ERK1/2 signaling blockade suppresses renal egr-1 gene expression and prevents FGF23-induced hypophosphatemia and 1,25-dihydroxyvitamin D (1,25(OH)2D) suppression in mice. To test whether egr-1 itself mediates these renal actions of FGF23, we administered FGF23 to egr-1-/- and wild-type (WT) mice. In WT mice, FGF23 induced hypophosphatemia and suppressed expression of the renal Na/Pi cotransporters, Npt2a and Npt2c. In FGF23-treated egr-1-/- mice, hypophosphatemic response was greatly blunted and Na/Pi cotransporter expression was not suppressed. In contrast, FGF23 induced equivalent suppression of serum 1,25(OH)2D concentrations by suppressing renal cyp27b1 and stimulating cyp24a1 mRNA expression in both groups of mice. Thus, downstream of receptor binding and ERK1/2 signaling, we can distinguish the effector pathway that mediates FGF23 dependent inhibition of Pi transport from the pathway that mediates inhibition of 1,25(OH)2D synthesis in the kidney. Furthermore, we demonstrate that the hypophosphatemic effect of FGF23 is significantly blunted in Hyp/egr-1-/- mice; specifically, serum Pi concentrations and renal Npt2a and Npt2c mRNA expression are significantly higher in Hyp/egr-1-/- mice than in Hyp mice. We then characterized the egr-1 cistrome in the kidney using ChIP-sequencing and demonstrate recruitment of egr-1 to regulatory DNA elements in proximity to several genes involved in Pi transport. Thus, our data demonstrate that the effect of FGF23 on Pi homeostasis is mediated, at least in part, by activation of egr-1. PMID- 26588478 TI - A pilot study on pharmacokinetic/pharmacodynamic target attainment in critically ill patients receiving piperacillin/tazobactam. AB - BACKGROUND: In critically ill patients, multi-trauma and intensive therapy can influence the pharmacokinetics (PK) and pharmacodynamics (PD) of antibiotics with time-dependent bacterial killing. Consequently, PK/PD targets (%fT>MIC) - crucial for antimicrobial effects -may not be attained. METHODS: Two patients admitted to the surgical ICU of the University Hospital in Hradec Kralove for multiple-trauma were given piperacillin/tazobactam by 1-hour IV infusion 4/0.5 g every 8h. PK variables: total and renal clearance (CLtot, CLR), volume of distribution (Vd), and elimination half-life (T1/2) were calculated, followed by glomerular filtration rate (MDRD) and cumulative fluid balance (CFB-total fluid volume based on 24-h registered fluid intake minus output). The PK/PD target attainment (100%fT>MIC) was defined as free (f) piperacillin plasma concentrations that remain, during the entire dosing interval (T), above the minimum inhibitory concentration (100%fT>MIC) within days 4-8 (when CFB culminates and disappears). Piperacillin concentrations were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and corrected for unbound fraction (22%). RESULTS: CFB culminated over days 2-5 reaching 15-30 L and was associated with a large Vd (29 42 L). While MDRD in patient 1 was low (0.3-0.4 mL s-1 1.7 m-2), that of patient 2 was increasing (> 3.1 mL s-1 1.7 m-2), which was associated with augmented CLR. In patient 2, the fT reached only 62, 52, and 44% on days 4, 6, and 8, respectively. In patient 1, the %fT was much higher, attaining values four to fivefold greater than that targeted. CONCLUSIONS: Critically ill patients are at risk of drug under- or overdosing without dose up-titration with regard to covariate effects and individual drug pharmacokinetics. PMID- 26588479 TI - Incidence and prognosis of intra-abdominal hypertension and abdominal compartment syndrome in severely burned patients: Pilot study and review of the literature. AB - BACKGROUND: Burn patients are at high risk for secondary intra-abdominal hypertension (IAH) and abdominal compartment syndrome (ACS) due to capillary leak and large volume fluid resuscitation. Our objective was to examine the incidence the incidence of IAH and ACS and their relation to outcome in mechanically ventilated (MV) burn patients. METHODS: This observational study included all MV burn patients admitted between April 2007 and December 2009. Various physiological parameters, intra-abdominal pressure (IAP) measurements and severity scoring indices were recorded on admission and/or each day in ICU. Transpulmonary thermodilution parameters were also obtained in 23 patients. The mean and maximum IAP during admission was calculated. The primary endpoint was ICU (burn unit) mortality. RESULTS: Fifty-six patients were included. The average Simplified Acute Physiology Score (SAPS II) and Sequential Organ Failure Assessment (SOFA) scores were 43.4 (+/- 15.1) and 6.4 (+/- 3.4), respectively. The average total body surface area (TBSA) affected by burns was 24.9% (+/- 24.9), with 33 patients suffering inhalational injuries. Forty-four (78.6%) patients developed IAH and 16 (28.6%) suffered ACS. Patients with ACS had higher TBSAs burned (35.8 +/- 30 vs. 20.6 +/- 21.4%, P = 0.04) and higher cumulative fluid balances after 48 hours (13.6 +/- 16L vs. 7.6 +/- 4.1 L, P = 0.03). The TBSA burned correlated well with the mean IAP (R = 0.34, P = 0.01). Mortality was notably high (26.8%) and significantly higher in patients with IAH (34.1%, P = 0.014) and ACS (62.5%, P < 0.0001). Most patients received more fluids than calculated by the Parkland Consensus Formula while, interestingly, non-survivors received less. However, when patients with pure inhalation injury were excluded there were no differences. Non-surgical interventions (n = 24) were successful in removing body fluids and were related to a significant decrease in IAP, central venous pressure (CVP) and an improvement in oxygenation and urine output. Non resolution of IAH was associated with a significantly worse outcome (P < 0.0001). CONCLUSION: Based on our preliminary results we conclude that IAH and ACS have a relatively high incidence in MV burn patients compared to other groups of critically ill patients. The percentage of TBSA burned correlates with the mean IAP. The combination of high CLI, positive (daily and cumulative) fluid balance, high IAP, high EVLWI and low APP suggest a poor outcome. Non-surgical interventions appear to improve end-organ function. Non-resolution of IAH is related to a worse outcome. PMID- 26588480 TI - From cardiac output to blood flow auto-regulation in shock. AB - Shock is defined as a state in which the circulation is unable to deliver sufficient oxygen to meet the demands of the tissues, resulting in cellular dysoxia and organ failure. In this process, the factors that govern the circulation at a haemodynamic level and oxygen delivery at a microcirculatory level play a major role. This manuscript aims to review the blood flow regulation from macro- and micro-haemodynamic point of view and to discuss new potential therapeutic approaches for cardiovascular instability in patients in cardiovascular shock. Despite the recent advances in haemodynamics, the mechanisms that control the vascular resistance and the venous return are not fully understood in critically ill patients. The physical properties of the vascular wall, as well as the role of the mean systemic filling pressure are topics that require further research. However, the haemodynamics do not totally explain the physiopathology of cellular dysoxia, and several factors such as inflammatory changes at the microcirculatory level can modify vascular resistance and tissue perfusion. Cellular vasoactive mediators and endothelial and glucocalix damage are also involved in microcirculatory impairment. All the levels of the circulatory system must be taken into account. Evaluation of microcirculation may help one to detect under-diagnosed shock, and together with classic haemodynamics, guide one towards the appropriate therapy. Restoration of classic haemodynamic parameters is essential but not sufficient to detect and treat patients in cardiovascular shock. PMID- 26588481 TI - Methodological background and strategy for the 2012-2013 updated consensus definitions and clinical practice guidelines from the abdominal compartment society. AB - The Abdominal Compartment Society (www.wsacs.org) previously created highly cited Consensus Definitions/Management Guidelines related to intra-abdominal hypertension (IAH) and abdominal compartment syndrome (ACS). Implicit in this previous work, was a commitment to regularly reassess and update in relation to evolving research. Two years preceding the Fifth World Congress on Abdominal Compartment Syndrome, an International Guidelines committee began preparation. An oversight/steering committee formulated key clinical questions regarding IAH/ /ACS based on polling of the Executive to redundancy, structured according to the Patient, Intervention, Comparator, and Outcome (PICO) format. Scientific consultations were obtained from Methodological GRADE experts and a series of educational teleconferences were conducted to educate scientific review teams from among the wscacs. org membership. Each team conducted systematic or structured reviews to identify relevant studies and prepared evidence summaries and draft Grades of Recommendation Assessment, Development and Evaluation (GRADE) recommendations. The evidence and draft recommendations were presented and debated in person over four days. Updated consensus definitions and management statements were derived using a modified Delphi method. A writingcommittee subsequently compiled the results utilizing frequent Internet discussion and Delphi voting methods to compile a robust online Master Report and a concise peer reviewed summarizing publication. A dedicated Paediatric Guidelines Subcommittee reviewed all recommendations and either accepted or revised them for appropriateness in children. Of the original 12 IAH/ACS definitions proposed in 2006, three (25%) were accepted unanimously, with four (33%) accepted by > 80%, and four (33%) accepted by > 50%, but required discussion to produce revised definitions. One (8%) was rejected by > 50%. In addition to previous 2006 definitions, the panel also defined the open abdomen, lateralization of the abdominal musculature, polycompartment syndrome, abdominal compliance, and suggested a refined open abdomen classification system. Recommendations were possible regarding intra-abdominal pressure (IAP) measurement, approach to sustained IAH, philosophy of protocolized IAP management and same-hospital-stay fascial closure, use of decompressive laparotomy, and negative pressure wound therapy. Consensus suggestions included use of non-invasive therapies for treating IAH/ACS, considering body position and IAP, damage control resuscitation, prophylactic open abdomen usage, and prudence in early biological mesh usage. No recommendations were made for the use of diuretics, albumin, renal replacement therapies, and utilizing abdominal perfusion pressure as a resuscitation-endpoint. Collaborating Methodological Guideline Development and Clinical Experts produced Consensus Definitions/Clinical Management statements encompassing the most contemporary evidence. Data summaries now exist for clinically relevant IAH/ACS questions, which will facilitate future scientific reanalysis. PMID- 26588482 TI - Speckle-Tracking analysis of left ventricular systolic function in the intensive care unit. AB - Speckle-tracking analysis is a new available tool in order to assess left ventricular function in cardiology. Its novelty relies on the technological ability to track natural acoustic markers (known as speckle) within the myocardium during the cardiac cycle. This technology allows the evaluation of myocardium strain during systole and diastole. To date, global longitudinal strain (GLS) has been extensively studied in cardiology. It is now well established that GLS is more sensitive than left ventricular ejection fraction with 2D echocardiography in detecting systolic function impairment. It is also superior to left ventricular ejection fraction in the prediction of major cardio vascular events. In the intensive care unit (ICU) setting, data are scarce. In experimental model and human studies in septic shock, speckle-tracking analysis suggests that GSL is impaired along with preserved left ventricular ejection fraction. Recent data also suggest that GLS impairment could predict in-ICU mortality in septic shock. In severe subarachnoid haemorrhage patients, speckle tracking analysis could be more sensitive in detecting stress cardiomyopathy. However, there are many gaps to fill in the critically ill patient. For instance, the influence of mechanical ventilation on GLS is not fully elucidated, and there are, to date, too few data to exactly assess potential GLS alterations on the patient's outcome. Nonetheless, this new tool provides objective and sensitive data with acceptable intra and inter-observer variability and may be of primary interest in the evaluation of left-ventricular systolic function in the ICU. PMID- 26588483 TI - Intravenous balanced solutions: from physiology to clinical evidence. AB - "Balanced" solutions are commonly defined as intravenous fluids having an electrolyte composition close to that of plasma. As such, they should minimally affect acid-base equilibrium, as compared to the commonly reported 0.9% NaCl related hyperchloremic metabolic acidosis. Recently, the term "balanced" solution has been also employed to indicate intravenous fluids with low chloride content, being the concentration of this electrolyte the most altered and supra physiologic in 0.9% NaCl as compared to plasma, and based upon a suggested detrimental effect on renal function associated with hyperchloremia. Despite efforts for its identification, the ideal balanced solution, with minimal effects on acid-base status, low chloride content, and adequate tonicity, is not yet available. After the accumulation of pre-clinical and clinical physiologic data, in the last three years, several clinical trials, mostly observational and retrospective, have addressed the question of whether the use of balanced solutions has beneficial effects as compared to the standard of care, sometimes even suggesting an improvement in survival. Nonetheless, the first large randomized controlled trial comparing the effects of a balanced vs. unbalanced solution on renal function in critically-ill patients (SPLIT trial, the 0.9% Saline vs Plasma-Lyte 148 for Intensive Cate Unit Fluid Therapy), just recently published, showed identical equipoise between the two treatments. In the present review, we offer a comprehensive and updated summary on this issue, firstly, by providing a full physiological background of balanced solutions, secondly, by summarizing their potential pathophysiologic effects, and lastly, by presenting the clinical evidence available to support, at the moment, their use. PMID- 26588484 TI - Cardiac Ultrasonography in the critical care setting: a practical approach to asses cardiac function and preload for the "non-cardiologist". AB - Cardiac ultrasonography has become an indispensible tool in the management of hemodynamically unstable critically ill patients. Some consider it as the modern stethoscope. Echocardiography is non-invasive and safe while the modern portable devices allow to be used at the bedside in order to provide fast, specific and vital information regarding the hemodynamic status, as well as the function, structure and anatomy of the heart. In this review, we will give an overview of cardiac function in general followed by an assessment of left ventricular function using echocardiography with calculation of cardiac output, left ventricular ejection fraction (EF), fractional shortening, fractional area contraction, M mode EF, 2D planimetry and 3D volumetry. We will briefly discuss mitral annulus post systolic excursion (MAPSE), calculation of dP/dt, speckle tracking or eyeballing to estimate EF for the experienced user. In a following section, we will discuss how to assess cardiac preload and diastolic function in 4 simple steps. The first step is the assessment of systolic function. The next step assesses the left atrium. The third step evaluates the diastolic flow patterns and E/e' ratio. The final step integrates the information of the previous steps. Echocardiography is also the perfect tool to evaluate right ventricular function with tricuspid annular plane systolic excursion (TAPSE), tissue Doppler imaging, together with inferior vena cava dimensions and systolic pulmonary artery pressure and right ventricular systolic pressure measurement. Finally, methods to assess fluid responsiveness with echocardiography are discussed with the inferior vena cava collapsibility index and the variation on left ventricle outflow tract peak velocity and velocity time integral. Cardiac ultrasonography is an indispensible tool for the critical care physician to assess cardiac preload, afterload and contractile function in hemodynamically unstable patients in order to fine-tune treatment with fluids, inotropes and/or vasopressors. PMID- 26588486 TI - Fragility fracture risk and skeletal muscle function. AB - Low-intensity fractures are closely related with age-related musculoskeletal disorders, including osteoporosis, muscle dysfunction and sarcopenia, age-related chronic diseases, and pharmacological treatments. During the last years, a huge amount of information and recommendations has been released in relation to bone metabolism and mineral content. Muscle dysfunction and sarcopenia are highly prevalent during the second half of life, especially in older subjects. The development of sarcopenia may be slowed through healthy lifestyle changes, which include adequate dietary protein, vitamin D and mineral intakes, and regular physical activity. Prevention of falls should be integral, including correction in major involved factors in order to reduce fragility fracture, improve quality of life and appropriately focus clinical and economic resources. Therefore, to obtain better results a global approach is needed to prevent age-related fractures in frail patients that is not only centered on bone metabolism and antiresorptive drugs. PMID- 26588485 TI - Evolutionary Loss of Activity in De-Ubiquitylating Enzymes of the OTU Family. AB - Understanding function and specificity of de-ubiquitylating enzymes (DUBs) is a major goal of current research, since DUBs are key regulators of ubiquitylation events and have been shown to be mutated in human diseases. Most DUBs are cysteine proteases, relying on a catalytic triad of cysteine, histidine and aspartate to cleave the isopeptide bond between two ubiquitin units in a poly ubiquitin chain. We have discovered that the two Drosophila melanogaster homologues of human OTUD4, CG3251 and Otu, contain a serine instead of a cysteine in the catalytic OTU (ovarian tumor) domain. DUBs that are serine proteases instead of cysteine- or metallo-proteases have not been described. In line with this, neither CG3251 nor Otu protein were active to cleave ubiquitin chains. Re introduction of a cysteine in the catalytic center did not render the enzymes active, indicating that further critical features for ubiquitin binding or cleavage have been lost in these proteins. Sequence analysis of OTUD4 homologues from various other species showed that within this OTU subfamily, loss of the catalytic cysteine has occurred frequently in presumably independent events, as well as gene duplications or triplications, suggesting DUB-independent functions of OTUD4 proteins. Using an in vivo RNAi approach, we show that CG3251 might function in the regulation of Inhibitor of Apoptosis (IAP)-antagonist-induced apoptosis, presumably in a DUB-independent manner. PMID- 26588487 TI - A combined upflow anaerobic sludge bed and trickling biofilter process for the treatment of swine wastewater. AB - A combined upflow anaerobic sludge blanket (UASB)-trickling biofilter (TBF) process was constructed to treat swine wastewater, a typical high-strength organic wastewater with low carbon/nitrogen ratio and ammonia toxicity. The results showed that the UASB-TBF system can remarkably enhance the removal of pollutants in the swine wastewater. At an organic loading rate of 2.29 kg/m(3) d and hydraulic retention time of 48 h in the UASB, the chemical oxygen demand (COD), Suspended Solids and Total Kjeldahl Nitrogen removals of the combined process reached 83.6%, 84.1% and 41.2%, respectively. In the combined system the UASB served as a pretreatment process for COD removal while nitrification and denitrification occurred only in the TBF process. The TBF performed reasonably well at a surface hydraulic load as high as 0.12 m(3)/m(2) d. Since the ratio of influent COD to total mineral nitrogen was less than 3.23, it is reasonable to suggest that the wood chips in TBF can serve as a new carbon source for denitrification. PMID- 26588488 TI - A Dual Model for Prioritizing Cancer Mutations in the Non-coding Genome Based on Germline and Somatic Events. AB - We address here the issue of prioritizing non-coding mutations in the tumoral genome. To this aim, we created two independent computational models. The first (germline) model estimates purifying selection based on population SNP data. The second (somatic) model estimates tumor mutation density based on whole genome tumor sequencing. We show that each model reflects a different set of constraints acting either on the normal or tumor genome, and we identify the specific genome features that most contribute to these constraints. Importantly, we show that the somatic mutation model carries independent functional information that can be used to narrow down the non-coding regions that may be relevant to cancer progression. On this basis, we identify positions in non-coding RNAs and the non coding parts of mRNAs that are both under purifying selection in the germline and protected from mutation in tumors, thus introducing a new strategy for future detection of cancer driver elements in the expressed non-coding genome. PMID- 26588489 TI - Arterial stiffness evaluated by cardio-ankle vascular index (CAVI) in adolescent hypertension. AB - Elevated blood pressure (BP) is a major risk factor for atherosclerosis. As the studies concerning vascular alterations in pediatric patients are rare, we aimed to study the relationship between hypertension and arterial stiffness in adolescence by novel method independent from BP during examination. Twenty nonobese adolescent boys (16.5 +/- 0.4 years) with newly diagnosed essential hypertension, 20 adolescent boys (16.7 +/- 0.4 years) with newly diagnosed white coat hypertension, and 20 healthy controls matched to age and body mass index were examined. Cardio-ankle vascular index (CAVI), brachial-ankle pulse wave velocity (baPWV), pre-ejection period (PEP), and ejection time (ET) were evaluated. CAVI was significantly increased in essential hypertension patients compared with controls (p < 0.05) with no significant difference in white-coat hypertension patients. Significantly higher baPWV was found in essential and white-coat hypertension patients compared with controls (both p < 0.001). White coat hypertension patients showed significantly shortened PEP and ET compared with controls (p < 0.01 and p < 0.001, respectively) and essential hypertension patients (both p < 0.05). For the first time, the arterial stiffness in adolescents with newly diagnosed essential and white-coat hypertension was studied using BP-independent index CAVI combined with conventional baPWV. Our study revealed significantly increased CAVI in adolescents with newly diagnosed essential hypertension compared with controls. Our findings could help to understand hypertension-atherosclerosis interaction. PMID- 26588490 TI - Subcutaneous Adipose Tissue Type II Deiodinase Gene Expression Reduced in Obese Individuals with Metabolic Syndrome. AB - The present study aimed to evaluate the role of subcutaneous adipose tissue (SAT) type II deiodinase enzyme gene (DIO2) expression in developing metabolic syndrome (MetS). A total of 51 obese patients with MetS and without MetS and 13 healthy subjects enrolled in the study. Body mass index (BMI), waist circumference (WC), waist-to-hip circumference ratio (WHR), hip circumference, and systolic (SBP) and diastolic blood pressures (DBP) of all subjects were recorded. Fasting plasma glucose (FPG), fasting plasma insulin, high density lipoprotein- cholesterol (HDL C), low density lipoprotein-cholesterol (LDL-C), total cholesterol (TC) and triglyceride (TG) of all subjects were analyzed. Expression of the DIO2 gene in adipose tissue was determined by reverse transcription polymerase chain reaction (qRT-PCR). BMI, WC and WHR were not significantly difference between obese with and without MetS. SBP, DBP, FPG and TG were significantly higher in obese with MetS group than obese without MetS group. While the free triiodothyronine (T3) level was in the normal range in all group, it was significantly lower in the obese with MetS than both obese without MetS and control group. DIO2 expression was significantly lower in the obese with MetS group compared to the control. In correlation analysis, DIO2 expression was negatively correlated with DBP, TG and homeostasis model assessment of insulin resistance (HOMA-IR) levels and positively correlated with free T3. In conclusion, the reduction of SAT DIO2 expression is negatively correlated with DBP and TG levels that are associated with the MetS. This might have an effect on developing MetS. We believe that DIO2 gene may be an important molecular target for future studies in developing targeted treatment options for obese people with MetS. PMID- 26588491 TI - Serum Irisin Level is Higher and Related with Insulin in Acanthosis Nigricans related Obesity. AB - OBJECTIVE: Acanthosis nigricans (AN) is proved to be a skin phenotype of hyperinsulinemia especially in obese patients. Irisin is a new myokine which plays an important role in metabolic disorders, such as obesity, insulin resistance, and type 2 diabetes. The role of irisin in the development of AN related obesity is not yet understood. In this study, we aimed to investigate the relationship between irisin and AN-related obesity. Patients & Measurements: 30 obese patients without AN (OB group), 30 obese patients with AN (AN group), and 20 age-matched healthy volunteers (control group, CON) were included in this study. Weight, BMI, lipid profile, FFA, UA, and CRP were measured in all participants. Oral Glucose Tolerance tests (OGTT) were performed and serum glucose and plasma insulin were measured at 0, 30, 60,120 and 180 min. The AUC (area under curve) of glucose and insulin was calculated. Serum irisin was measured by ELISA. RESULTS: Hyperinsulinemia is found in both AN and OB groups. The AN group had higher levels of insulin but better blood glucose tolerance and insulin response. The difference in irisin levels between the 3 groups was statistically significant, with the AN group showing the highest serum level of irisin. Serum irisin levels were positively correlated with BMI, and fasting insulin. CONCLUSION: AN is a state of hyperinsulinmia and has better insulin response and glucose tolerance compared to obese patients without AN. Serum irisin may be a protective factor against impaired beta cell function in obesity with AN. PMID- 26588492 TI - Analysis of Factors Affecting the Length of Hospital Stay for Patients with Diabetes. AB - OBJECTIVE: The sharp rise in health expenditure of diabetes has become a huge financial and medical burden. A retrospective study was conducted to investigate the length of hospitalization for patients with diabetes and the control methods of the length of hospitalization, so as to improve the social and economic benefits of the hospital. METHODS: Data of patients with diabetes who were admitted in the Guangdong Shantou Central Hospital from 2011 to 2013 were collected. Descriptive statistics and logistic regression analysis were used to explore the factors influencing the length of hospitalization for patients with diabetes such as sociological factors, disease factors, and clinical factors. RESULTS: Univariate analysis results indicated that there were factors influencing the length of hospitalization for patients with diabetes, which were as follows: sociological factors including age (P<0.001), occupation (P=0.001), payment method (P<0.001), and the number of hospitalizations (P<0.001); disease factors including comorbidity (P<0.001) and initial glycated hemoglobin levels (P<0.001); and clinical factors including hospital-acquired infection (P<0.001), surgery (P<0.001), diagnoses within 3 days (P<0.001), department transfers (P=0.007), and treatment efficacy (P=0.003). In logistic regression analysis, 7 factors including surgery, hospital-acquired infections, comorbidities, age, payment methods, number of hospitalizations, and treatment efficacy had significant impacts on the length hospitalization for patients with diabetes. CONCLUSION: The results of this study will be provided as a reference for a reasonable length of hospitalization of patients with diabetes. PMID- 26588493 TI - Differentiation Potential of Mouse Embryonic Stem Cells into Insulin Producing Cells in Pancreatic Islet Microenvironment. AB - BACKGROUND: The differentiation capacity of embryonic stem cells (ESCs) has great promise for type-1 diabetes for cellular treatment. Therefore, different strategies have been reported so far for derivation of insulin producing cells (IPCs) from ESCs. Providing similar microenvironmental conditions as in vivo, functional differentiation of stem cells into desired cell types could be obtained in vitro. The aim of the present research was to utilize differentiation potential of ESCs to IPCs by co-culture with mouse pancreatic islets (mPIs) for the first time. METHODS: We present an in-direct differentiation protocol which compared with a conventional differentiation protocol. Novel in-direct co-culture differentiation protocol in which mPIs induced differentiation of ESCs into IPCs was used. This technique was compared with the chemical differentiation protocol that involved supplementing the differentiation media with specific growth factors. We analyzed differentiated cells in both groups by immune labelling, gene expression and protein secretion. RESULTS: IPCs were obtained with in-direct co-culture within 30 days. Differentiated ESCs were found to be positive for IPC specific markers, Pdx1, Insulin, C-peptide, Glut2 and MafA. The results of immunocytochemical and gene expression analysis showed higher differentiation efficiency in co-culture group than chemical differentiation group. These results were confirmed by the response assay to high glucose levels with ELISA for insulin. DISCUSSION: Our findings illustrate the significant effect of co-culture in different stages of differentiation and maturation of ESCs in vitro. We have developed an efficient and easy way to differentiate ESCs into IPCs, which possess similar characters of mature insulin positive cells. PMID- 26588494 TI - The Emerging Role of Sirtuin 1 in Cellular Metabolism, Diabetes Mellitus, Diabetic Kidney Disease and Hypertension. AB - Despite diagnostic and therapeutic approaches, diabetic kidney disease (DKD) is the most common cause of end-stage renal disease worldwide. Sirtuins, a group of nicotinamid adenine dinucleotide (NAD) dependent enzymes, can deacetylase target enzymes that regulate a wide variety of cellular processes regarding protein, carbohydrate and lipid metabolism, mitochondrial homeostasis and programmed cell death mechanisms including autophagy and apoptosis. Among sirtuins, sirtuin 1 (SIRT1) has been the most studied one in the pathogenesis and progression of DKD. In recent years, the relation between SIRT1 and hypertension was also evaluated.In the present review, we aimed to represent the mechanisms of SIRT1 in glucose and lipid metabolism and in the pathogenesis of diabetes mellitus. We also sought to highlight the emerging role of SIRT1 in the pathogenesis and treatment of DKD and hypertension. PMID- 26588495 TI - "Chrono-functional milk": The difference between melatonin concentrations in night-milk versus day-milk under different night illumination conditions. AB - Pineal melatonin (MLT) is produced at highest levels during the night, under dark conditions. We evaluated differences in MLT-concentration by comparing daytime versus night time milk samples, from two dairy farms with different night illumination conditions: (1) natural dark (Dark-Night); (2) short wavelength Artificial Light at Night (ALAN, Night-Illuminated). Samples were collected from 14 Israeli Holstein cows from each commercial dairy farm at 04:30 h ("Night milk") 12:30 h ("Day-milk") and analyzed for MLT-concentration. In order to study the effects of night illumination conditions on cows circadian rhythms, Heart Rate (HR) daily rhythms were recorded. MLT-concentrations of Night-milk samples from the dark-night group were significantly (p < 0.001) higher than those of Night-illuminated conditions (30.70 +/- 1.79 and 17.81 +/- 0.33 pg/ml, respectively). Interestingly, night illumination conditions also affected melatonin concentrations at daytime where under Dark-Night conditions values are significantly (p < 0.001) higher than Night-Illuminated conditions, (5.36 +/- 0.33 and 3.30 +/- 0.18 pg/ml, respectively). There were no significant differences between the two treatments in the milk yield and milk composition except somatic cell count (SCC), which was significantly lower (p = 0.02) in the Dark-Night group compared with the Night-Illuminated group. Cows in both groups presented a significant (p < 0.01) HR daily rhythm, therefore we assume that in the night illuminated cows feeding and milking time are the "time keeper", while in the Dark-night cows, HR rhythms were entrained by the light/dark cycle. The higher MLT-concentration in Dark-night cows with the lower SCC values calls upon farmers to avoid exposure of cows to ALAN. Therefore, under Dark-night conditions milk quality will improve by lowering SCC values where separation between night and day of such milk can produce chrono-functional milk, naturally rich with MLT. PMID- 26588496 TI - Reversible coma and Duret hemorrhage after intracranial hypotension from remote lumbar spine surgery: case report. AB - Intracranial hypotension is a rare condition caused by spontaneous or iatrogenic CSF leaks that alter normal CSF dynamics. Symptoms range from mild headaches to transtentorial herniation, coma, and death. Duret hemorrhages have been reported to occur in some patients with this condition and are traditionally believed to be associated with a poor neurological outcome. A 73-year-old man with a remote history of spinal fusion presented with syncope and was found to have small subdural hematomas on head CT studies. He was managed nonoperatively and discharged with a Glasgow Coma Scale score of 15, only to return 3 days later with obtundation, fixed downward gaze, anisocoria, and absent cranial nerve reflexes. A CT scan showed Duret hemorrhages and subtle enlargement of the subdural hematomas, though the hematomas remained too small to account for his poor clinical condition. Magnetic resonance imaging of the spine revealed a large lumbar pseudomeningocele in the area of prior fusion. His condition dramatically improved when he was placed in the Trendelenburg position and underwent repair of the pseudomeningocele. He was kept flat for 7 days and was ultimately discharged in good condition. On long-term follow-up, his only identifiable deficit was diplopia due to an internuclear ophthalmoplegia. Intracranial hypotension is a rare condition that can cause profound morbidity, including tonsillar herniation and brainstem hemorrhage. With proper identification and treatment of the CSF leak, patients can make functional recoveries. PMID- 26588497 TI - Thoracolumbar kyphoscoliosis with unilateral subluxation of the spine and postoperative lumbar spondylolisthesis in Hunter syndrome. AB - Surgical correction for kyphoscoliosis is increasingly being performed for patients with mucopolysaccharidosis (MPS). Reported case series have predominantly included patients with Type I (Hurler) and Type IV (Morquio) MPS. To their knowledge, the authors describe the first case report of surgical management of thoracolumbar kyphoscoliosis in Hunter syndrome (MPS Type II) and the rare occurrence of lumbar spondylolisthesis following surgical stabilization. A 12-year-old boy with Hunter syndrome presented with severe thoracolumbar kyphoscoliosis and no associated symptoms. Spinal radiographs demonstrated kyphosis of 48 degrees (T11-L3) and scoliosis of 22 degrees (T11-L3) with an anteriorly hypoplastic L-1 vertebra. The deformity progressed to kyphosis of 60 degrees and scoliosis of 42 degrees prior to surgical intervention. Spinal CT scans identified left T12-L1 facet subluxation, causing anterior rotatory displacement of the spine proximal to L-1 and bilateral L-5 isthmic spondylolysis with no spondylolisthesis. A combined single-stage anterior and posterior instrumented spinal arthrodesis from T-9 to L-4 was performed. Kyphosis and scoliosis were corrected to 4 degrees and 0 degrees , respectively. Prolonged ventilator support and nasogastric feedings were required for 3 months postoperatively. At 2.5 years following surgery, the patient was asymptomatic, mobilizing independently, and had achieved a solid spinal fusion. However, he had also developed a Grade II spondylolisthesis at L4-5; this was managed nonoperatively in the absence of symptoms or further deterioration of the spondylolisthesis to the 3.5-year postoperative follow-up visit. Satisfactory correction of thoracolumbar kyphoscoliosis in Hunter syndrome can be achieved by combined anterior/posterior instrumented arthrodesis. The risk of developing deformity or instability in motion segments adjacent to an instrumented fusion may be greater in patients with MPS related to the underlying connective tissue disorder. PMID- 26588498 TI - Vertebral hemangioma coincident with metastasis of colon adenocarcinoma. AB - The authors report on colon cancer metastasis to the L-3 vertebra, which had been previously found to be involved by an asymptomatic hemangioma. A 61-year-old female patient was admitted after onset of lumbar axial pain and weakness of the right quadriceps muscle. Her medical history included colon cancer that had been diagnosed 3 years earlier and was treated via a right hemicolectomy followed by chemotherapy. Presurgical imaging revealed an asymptomatic hemangioma in the L-3 vertebral body. Computed tomography and MRI of the spine were performed after admission and revealed a hemangioma in the L-3 vertebral body as well as a soft tissue mass protruding from the L-3 vertebral body to the spinal canal. Treatment consisted of vertebroplasty of the hemangioma, left L-3 hemilaminectomy, and removal of the pathological mass from the spinal canal and the L-3 vertebral body. Histopathological examination revealed the presence of colon cancer metastasis and a hemangioma in the same vertebra. PMID- 26588499 TI - Hemothorax caused by the trocar tip of the rod inserter after minimally invasive transforaminal lumbar interbody fusion: case report. AB - Minimally invasive surgery (MIS) for transforaminal lumbar interbody fusion (MIS TLIF) is widely used for lumbar degenerative diseases. In the paper the authors report a unique case of a hemothorax caused by the trocar tip of the rod inserter after MIS-TLIF. A 61-year-old woman presented with thigh pain and gait disturbance due to weakness in her lower right extremity. She was diagnosed with a lumbar disc herniation at L1-2 and the MIS-TLIF procedure was performed. Immediately after surgery, the patient's thigh pain resolved and she remained stable with normal vital signs. The next day after surgery, she developed severe anemia and her hemoglobin level decreased to 7.6 g/dl, which required blood transfusions. A chest radiograph revealed a hemothorax. A CT scan confirmed a hematoma of the left paravertebral muscle. A chest tube was placed to treat the hemothorax. After 3 days of drainage, there was no active bleeding. The patient was discharged 14 days after surgery without leg pain or any respiratory problems. This complication may have occurred due to injury of the intercostal artery by the trocar tip of the rod inserter. A hemothorax after spine surgery is a rare complication, especially in the posterior approach. The rod should be caudally inserted in the setting of the thoracolumbar spine. PMID- 26588500 TI - Intraspinal hemorrhage in spontaneous intracranial hypotension: link to superficial siderosis? Report of 2 cases. AB - Spontaneous intracranial hypotension due to a spinal CSF leak has become a well recognized cause of headaches, but such spinal CSF leaks also are found in approximately half of patients with superficial siderosis of the CNS. It has been hypothesized that friable vessels at the site of the spinal CSF leak are the likely source of chronic bleeding in these patients, but such an intraspinal hemorrhage has never been visualized. The authors report on 2 patients with spontaneous intracranial hypotension and intraspinal hemorrhage, offering support for this hypothesis. A 33-year-old man and a 62-year-old woman with spontaneous intracranial hypotension were found to have a hemorrhage within the ventral spinal CSF collection and within the thecal sac, respectively. Treatment consisted of microsurgical repair of a ventral dural tear in the first patient and epidural blood patching in the second patient. The authors suggest that spontaneous intracranial hypotension should be included in the differential diagnosis of spontaneous intraspinal hemorrhage, and that the intraspinal hemorrhage can account for the finding of superficial siderosis when the CSF leak remains untreated. PMID- 26588501 TI - Posterior osteosynthesis of a spontaneous bilateral pedicle fracture of the lumbar spine. AB - Spontaneous bilateral pedicle fractures of the lumbar spine are rare, and an optimal surgical treatment has not been suggested. The authors report the case of a 50-year-old woman who presented with low-back pain and right leg radiating pain of 1 year's duration. Radiological studies revealed a spontaneous bilateral pedicle fracture of L-5. All efforts at conservative treatment failed, and the patient underwent surgery for osteosynthesis of the fractured pedicle using bilateral pedicle screws connected with a bent rod. Her low-back and right leg pain were relieved postoperatively. A CT scan performed 3 months postoperatively revealed the disappearance of the pedicle fracture gap and presence of newly formed bony trabeculation. In rare cases of spontaneous bilateral pedicle fracture of the lumbar spine, osteosynthesis of the fractured pedicle using bilateral pedicle screws and a bent rod is a motion-preserving technique that may be an effective option when conservative management has failed. PMID- 26588502 TI - Nitrogen-Rich Mesoporous Carbon as Anode Material for High-Performance Sodium-Ion Batteries. AB - Nitrogen-rich carbon with interconnected mesoporous structure has been simply prepared via a nano-CaCO3 template method, using polyaniline as carbon and nitrogen precursors. The preparation process includes in situ polymerization of aniline in a nano-CaCO3 aqueous solution, carbonization of the composites and removal of the template with diluted hydrochloric acid. Nitrogen sorption shows the carbon-enriched mesopores with a specific surface area of 113 m(2) g(-1). The X-ray photoelectron spectroscopy (XPS) analysis indicates that the carbon has a high nitrogen content of 7.78 at. %, in the forms of pyridinic and pyrrolic, as well as graphitic nitrogen. The nitrogen-rich mesoporous carbon shows a high reversible capacity of 338 mAh g(-1) at a current density of 30 mA g(-1), and good rate performance as well as ultralong cycling durability (110.7 mAh g(-1) at a current density of 500 mA g(-1) over 800 cycles). The excellent sodium storage performance of the nitrogen-rich mesoporous carbon is attributed to its disordered structure with large interlayer distance, interconnected porosity, and the enriched nitrogen heteroatoms. PMID- 26588503 TI - Exploring the Unfolding Pathway of Maltose Binding Proteins: An Integrated Computational Approach. AB - Recent single-molecule force spectroscopy experiments on the Maltose Binding Proteins (MBPs) identified four stable structural units, termed unfoldons, that resist mechanical stress and determine the intermediates of the unfolding pathway. In this work, we analyze the topological origin and the dynamical role of the unfoldons using an integrated approach which combines a graph-theoretical analysis of the interaction network of the MBP native-state with steered molecular dynamics simulations. The topological analysis of the native state, while revealing the structural nature of the unfoldons, provides a framework to interpret the MBP mechanical unfolding pathway. Indeed, the experimental pathway can be effectively predicted by means of molecular dynamics simulations with a simple topology-based and low-resolution model of the MBP. The results obtained from the coarse-grained approach are confirmed and further refined by all-atom molecular dynamics. PMID- 26588504 TI - Global Flux Surface Hopping Approach for Mixed Quantum-Classical Dynamics. AB - A novel global flux surface hopping (GFSH) approach is proposed. In this method, the surface hopping probabilities rely on the gross population flow between states, rather than the state-to-state flux as in the standard fewest switches surface hopping (FSSH). GFSH captures the superexchange mechanism of population transfer, while FSSH lacks this capability. In other aspects, including minimization of the number of hops, internal consistency, velocity rescaling, and detailed balance, the GFSH algorithm is similar to FSSH. The advantages of GFSH are demonstrated with a model 3-level system and an Auger process in a semiconductor quantum dot. Current studies indicate that GFSH can replace FSSH, but further tests are needed. PMID- 26588505 TI - On Extracting Subfemtosecond Data from Femtosecond Quantum Dynamics Calculations: The Methane Cation. PMID- 26588506 TI - Estimating Translational and Orientational Entropies Using the k-Nearest Neighbors Algorithm. AB - Inhomogeneous fluid solvation theory (IFST) and free energy perturbation (FEP) calculations were performed for a set of 20 solutes to compute the hydration free energies. We identify the weakness of histogram methods in computing the IFST hydration entropy by showing that previously employed histogram methods overestimate the translational and orientational entropies and thus underestimate their contribution to the free energy by a significant amount. Conversely, we demonstrate the accuracy of the k-nearest neighbors (KNN) algorithm in computing these translational and orientational entropies. Implementing the KNN algorithm within the IFST framework produces a powerful method that can be used to calculate free-energy changes for large perturbations. We introduce a new KNN approach to compute the total solute-water entropy with six degrees of freedom, as well as the translational and orientational contributions. However, results suggest that both the solute-water and water-water entropy terms are significant and must be included. When they are combined, the IFST and FEP hydration free energies are highly correlated, with an R(2) of 0.999 and a mean unsigned difference of 0.9 kcal/mol. IFST predictions are also highly correlated with experimental hydration free energies, with an R(2) of 0.997 and a mean unsigned error of 1.2 kcal/mol. In summary, the KNN algorithm is shown to yield accurate estimates of the combined translational-orientational entropy and the novel approach of combining distance metrics that is developed here could be extended to provide a powerful method for entropy estimation in numerous contexts. PMID- 26588507 TI - Transition-Tempered Metadynamics: Robust, Convergent Metadynamics via On-the-Fly Transition Barrier Estimation. AB - Well-tempered metadynamics has proven to be a practical and efficient adaptive enhanced sampling method for the computational study of biomolecular and materials systems. However, choosing its tunable parameter can be challenging and requires balancing a trade-off between fast escape from local metastable states and fast convergence of an overall free energy estimate. In this article, we present a new smoothly convergent variant of metadynamics, transition-tempered metadynamics, that removes that trade-off and is more robust to changes in its own single tunable parameter, resulting in substantial speed and accuracy improvements. The new method is specifically designed to study state-to-state transitions in which the states of greatest interest are known ahead of time, but transition mechanisms are not. The design is guided by a picture of adaptive enhanced sampling as a means to increase dynamical connectivity of a model's state space until percolation between all points of interest is reached, and it uses the degree of dynamical percolation to automatically tune the convergence rate. We apply the new method to Brownian dynamics on 48 random 1D surfaces, blocked alanine dipeptide in vacuo, and aqueous myoglobin, finding that transition-tempered metadynamics substantially and reproducibly improves upon well-tempered metadynamics in terms of first barrier crossing rate, convergence rate, and robustness to the choice of tuning parameter. Moreover, the trade-off between first barrier crossing rate and convergence rate is eliminated: the new method drives escape from an initial metastable state as fast as metadynamics without tempering, regardless of tuning. PMID- 26588508 TI - Path Integral Coarse-Graining Replica Exchange Method for Enhanced Sampling. AB - An enhanced conformational space sampling method is developed that utilizes replica exchange molecular dynamics between a set of imaginary time Feynman path integral replicas, each having an increasing degree of contraction (or coarse graining) of the quasi-particle or "polymer beads" in the evaluation of the isomorphic ring-polymer potential energy terms. However, there is no contraction of beads in the effectively harmonic kinetic energy terms. The final replica in this procedure is the fully contracted one in which the potential energy is evaluated only at the centroid of the beads-and hence it is the classical distribution in the centroid variable-while the initial replica has the full degree (or even a heightened degree, if desired) of quantum delocalization and tunneling in the physical potential by the polymer necklace beads. The exchange between the different ring-polymer ensembles is governed by the Metropolis criteria to guarantee detailed balance. The method is applied successfully to several model systems, ranging from one-dimensional prototype rough energy landscape models having analytical solutions to the more realistic alanine dipeptide. A detailed comparison with the classical temperature-based replica exchange method shows an improved efficiency of this new method in the classical conformational space sampling due to coupling with the fictitious path integral (quantum) replicas. PMID- 26588509 TI - Strong Correlations in Density-Functional Theory: A Model of Spin-Charge and Spin Orbital Separations. AB - It is known that the separation of electrons into spinons and chargons, the spin charge separation, plays a decisive role when describing one-dimensional (1D) strongly correlated systems [ Phys. Rev. B 2012 , 86 , 075132 ]. In this paper, within the density-functional theory (DFT) formalism, we extend the investigation by considering a model for the third electron fractionalization: the separation into spinons, chargons and orbitons, the last associated with the electronic orbital degree of freedom. Specifically, we deal with two exact constraints of exchange-correlation (XC) density-functionals: (i) the constancy of the highest occupied (HO) Kohn-Sham (KS) eigenvalues upon fractional electron numbers and (ii) their discontinuities at integers. By means of 1D discrete Hubbard chains and 1D H2 molecules in the continuum, we find that spin-charge separation yields almost constant HO KS eigenvalues, whereas the spin-orbital counterpart can be decisive when describing derivative discontinuities of XC potentials at strong correlations. PMID- 26588510 TI - Benchmark Torsional Potentials of Building Blocks for Conjugated Materials: Bifuran, Bithiophene, and Biselenophene. AB - The utility of pi-conjugated oligomers and polymers continues to grow, and oligofurans, oligothiophenes, and oligoselenophenes have shown great promise in the context of organic electronic materials. Vital to the performance of these materials is the maintenance of planarity along the conjugated backbone. Consequently, there has been a great deal of work modeling the torsional behavior of these prototypical components of conjugated organic materials both in the gas and condensed phases. Such simulations generally rely on classical molecular mechanics force fields or density functional theory (DFT) potentials. Unfortunately, there is a lack of benchmark quality, converged ab initio torsional potentials for bifuran, bithiophene, and biselenophene against which these lower level theoretical methods can be calibrated. To remedy this absence, we present highly accurate torsional potentials for these three molecules based on focal point analyses. These potentials will enable the benchmarking and parametrization of DFT functionals and classical molecular mechanics force fields. Here, we provide an initial assessment of the performance of common DFT functional and basis set combinations, to identify methods that provide robust descriptions of the torsional behavior of these prototypical building blocks for conjugated systems. PMID- 26588511 TI - Intermediate Hamiltonian Fock Space Multireference Coupled Cluster Approach to Core Excitation Spectra. AB - The Fock space multireference coupled cluster (FSMRCC) method provides an efficient approach for the direct calculation of excitation energies. In intermediate Hamiltonian (IH-FSMRCC) formulation, the method is free from intruder state problems and associated convergence difficulties, even with a large model space. In this paper, we demonstrate that the IH-FSMRCC method with suitably chosen model space can be used for the accurate description of core excitation spectra of molecules, and our results are in excellent agreement with the experimental values. We have investigated the effect of choice of model space on the computed results. Unlike the equation-of-motion (EOM)-based method, the IH FSMRCC does not require any special technique for convergence and in singles and doubles approximation gives a performance comparable to that of the standard EOMEE-CCSD method, even better in some of the cases. PMID- 26588512 TI - Multiconfiguration Pair-Density Functional Theory. AB - We present a new theoretical framework, called Multiconfiguration Pair-Density Functional Theory (MC-PDFT), which combines multiconfigurational wave functions with a generalization of density functional theory (DFT). A multiconfigurational self-consistent-field (MCSCF) wave function with correct spin and space symmetry is used to compute the total electronic density, its gradient, the on-top pair density, and the kinetic and Coulomb contributions to the total electronic energy. We then use a functional of the total density, its gradient, and the on top pair density to calculate the remaining part of the energy, which we call the on-top-density-functional energy in contrast to the exchange-correlation energy of Kohn-Sham DFT. Because the on-top pair density is an element of the two particle density matrix, this goes beyond the Hohenberg-Kohn theorem that refers only to the one-particle density. To illustrate the theory, we obtain first approximations to the required new type of density functionals by translating conventional density functionals of the spin densities using a simple prescription, and we perform post-SCF density functional calculations using the total density, density gradient, and on-top pair density from the MCSCF calculations. Double counting of dynamic correlation or exchange does not occur because the MCSCF energy is not used. The theory is illustrated by applications to the bond energies and potential energy curves of H2, N2, F2, CaO, Cr2, and NiCl and the electronic excitation energies of Be, C, N, N(+), O, O(+), Sc(+), Mn, Co, Mo, Ru, N2, HCHO, C4H6, c-C5H6, and pyrazine. The method presented has a computational cost and scaling similar to MCSCF, but a quantitative accuracy, even with the present first approximations to the new types of density functionals, that is comparable to much more expensive multireference perturbation theory methods. PMID- 26588513 TI - Theoretical Study of the Dissociation Energy of First-Row Metallocenium Ions. AB - The bond dissociation energy of a series of metallocenium ions, i.e., the energy difference of the reaction MCp2(+) -> MCp(+) + Cp. (with M = Ti, V, Cr, Mn, Fe, Co, and Ni), was studied by means of multiconfigurational perturbation theory (CASPT2, RASPT2, NEVPT2) and restricted coupled cluster theory (CCSD(T)). From a comparison between the results obtained from these different methods, and a detailed analysis of their treatment of electron correlation effects, a set of MCp(+)-Cp binding energies are proposed with an accuracy of 5 kcal/mol. The computed results are in good agreement with the experimental data measured by threshold photoelectron photoion coincidence (TPEPICO) spectroscopy but disagree with the more recent threshold collision-induced dissociation (TCID) experiments. PMID- 26588514 TI - Simulations of Raman Spectra Using the Fragment Molecular Orbital Method. AB - We developed an approach to calculate normal Raman activities based on the fragment molecular orbital method. For this purpose, we derived the FMO gradient and coupled-perturbed Hartree-Fock equations in the presence of the static electric field. The accuracy is evaluated in comparison with full ab initio calculations for a set of closed-shell and radical systems. We applied the method to calculate Raman and IR spectra of a polystyrene oligomer and crambin (PDB: 1CRN ) and performed an assignment of peaks based on localized normal modes. The computational timings demonstrate the efficiency of the method. PMID- 26588515 TI - Trouble with the Many-Body Expansion. AB - Longstanding conventional wisdom dictates that the widely used Many-Body Expansion (MBE) converges rapidly by the four-body term when applied to large chemical systems. We have found, however, that this is not true for calculations using many common, moderate-sized basis sets such as 6-311++G** and aug-cc-pVDZ. Energy calculations performed on water clusters using these basis sets showed a deceptively small error when the MBE was truncated at the three-body level, while inclusion of four- and five-body contributions drastically increased the error. Moreover, the error per monomer increases with system size, showing that the MBE is unsuitable to apply to large chemical systems when using these basis sets. Through a systematic study, we identified the cause of the poor MBE convergence to be a many-body basis set superposition effect exacerbated by diffuse functions. This was verified by analysis of MO coefficients and the behavior of the MBE with increasing monomer-monomer separation. We also found poor convergence of the MBE when applied to valence-bonded systems, which has implications for molecular fragmentation methods. The findings in this work suggest that calculations involving the MBE must be performed using the full cluster basis set, using basis sets without diffuse functions, or using a basis set of at least aug-cc-pVTZ quality. PMID- 26588516 TI - Prediction of Intramolecular Polarization of Aromatic Amino Acids Using Kriging Machine Learning. AB - Present computing power enables novel ways of modeling polarization. Here we show that the machine learning method kriging accurately captures the way the electron density of a topological atom responds to a change in the positions of the surrounding atoms. The success of this method is demonstrated on the four aromatic amino acids histidine, phenylalanine, tryptophan, and tyrosine. A new technique of varying training set sizes to vastly reduce training times while maintaining accuracy is described and applied to each amino acid. Each amino acid has its geometry distorted via normal modes of vibration over all local energy minima in the Ramachandran map. These geometries are then used to train the kriging models. Total electrostatic energies predicted by the kriging models for previously unseen geometries are compared to the true energies, yielding mean absolute errors of 2.9, 5.1, 4.2, and 2.8 kJ mol(-1) for histidine, phenylalanine, tryptophan, and tyrosine, respectively. PMID- 26588517 TI - Ab Initio Treatment of Disorder Effects in Amorphous Organic Materials: Toward Parameter Free Materials Simulation. AB - Disordered organic materials have a wide range of interesting applications, such as organic light emitting diodes, organic photovoltaics, and thin film electronics. To model electronic transport through such materials it is essential to describe the energy distribution of the available electronic states of the carriers in the material. Here, we present a self-consistent, linear-scaling first-principles approach to model environmental effects on the electronic properties of disordered molecular systems. We apply our parameter free approach to calculate the energy disorder distribution of localized charge states in a full polaron model for two widely used benchmark-systems (tris(8 hydroxyquinolinato)aluminum (Alq3) and N,N'-bis(1-naphthyl)-N,N'-diphenyl-1,1' biphenyl-4,4'-diamine (alpha-NPD)) and accurately reproduce the experimental charge carrier mobility over a range of 4 orders of magnitude. The method can be generalized to determine electronic and optical properties of more complex systems, e.g. guest-host morphologies, organic-organic interfaces, and thus offers the potential to significantly contribute to de novo materials design. PMID- 26588518 TI - On The Nature of the Halogen Bond. AB - The wide-ranging applications of the halogen bond (X-bond), notably in self assembling materials and medicinal chemistry, have placed this weak intermolecular interaction in a center of great deal of attention. There is a need to elucidate the physical nature of the halogen bond for better understanding of its similarity and differences vis-a-vis other weak intermolecular interactions, for example, hydrogen bond, as well as for developing improved force-fields to simulate nano- and biomaterials involving X bonds. This understanding is the focus of the present study that combines the insights of a bottom-up approach based on ab initio valence bond (VB) theory and the block-localized wave function (BLW) theory that uses monomers to reconstruct the wave function of a complex. To this end and with an aim of unification, we studied the nature of X-bonds in 55 complexes using the combination of VB and BLW theories. Our conclusion is clear-cut; most of the X-bonds are held by charge transfer interactions (i.e., intermolecular hyperconjugation) as envisioned more than 60 years ago by Mulliken. This is consistent with the experimental and computational findings that X-bonds are more directional than H-bonds. Furthermore, the good linear correlation between charge transfer energies and total interaction energies partially accounts for the success of simple force fields in the simulation of large systems involving X-bonds. PMID- 26588519 TI - Quasi-diabatic States from Active Space Decomposition. AB - We present ab initio theory and efficient algorithms for computing model Hamiltonians of excited-state dynamics in the quasi-diabatic representation. The method is based on a recently developed multiconfiguration electronic structure method, called the active space decomposition method (ASD), in which quasi diabatic basis states are constructed from physical fragment states. An efficient tree-based algorithm is presented for computing and reusing intermediate tensors appearing in the ASD model. Parallel scalability and wall times are reported to attest the efficiency of our program. Applications to electron, hole, and triplet energy transfers in molecular dimers are presented, demonstrating its versatility. PMID- 26588520 TI - Benchmarking Coupled Cluster Methods on Valence Singlet Excited States. AB - In this paper, benchmark results are presented on Coupled Cluster calculation of singlet excitation energies and the corresponding oscillator strength. The test set of Thiel et al. (Schreiber, M.; Silva, M. R. J.; Sauer, S. P. A.; Thiel, W. J. Chem. Phys. 2008, 128, 134110) has been used, and the earlier results have been extended by CC3 oscillator strength for the whole set, CC3 excitation energies for larger molecules, and CCSDT results for some small molecules. Accuracy of the members of the hierarchy CC2-CCSD-CC3-CCSDT has been analyzed. The results show that both CC2 and CCSD are quite accurate and the difference to CC3 excitations energies is typically not larger than 0.2-0.3 eV. While the mean deviation of the CC2 results is close to zero, CCSD systematically overshoots the CC3 results by about 0.2 eV. The standard deviation is, however, somewhat smaller for CCSD, that is, the latter method provides more systematic results. Still, only a few cases could be identified were the absolute value of the error is over 0.3 eV in case of CC2. The results are even better for CCSD, with the exception of uracil, where surprisingly large error of the excitation energies have been found for two of the four lowest n-pi* transitions. Both LR (Linear Response) and EOM (Equation of Motion) style oscillator strengths have been calculated. The former is more accurate at both CC2 and CCSD levels, but the difference between them is only 1-2% in case of CCSD. The error of the CC2 oscillator strength are substantially larger than that of CCSD but qualitatively still correct. PMID- 26588521 TI - Full Parallel Implementation of an All-Electron Four-Component Dirac-Kohn-Sham Program. AB - A full distributed-memory implementation of the Dirac-Kohn-Sham (DKS) module of the program BERTHA (Belpassi et al., Phys. Chem. Chem. Phys. 2011, 13, 12368 12394) is presented, where the self-consistent field (SCF) procedure is replicated on all the parallel processes, each process working on subsets of the global matrices. The key feature of the implementation is an efficient procedure for switching between two matrix distribution schemes, one (integral-driven) optimal for the parallel computation of the matrix elements and another (block cyclic) optimal for the parallel linear algebra operations. This approach, making both CPU-time and memory scalable with the number of processors used, virtually overcomes at once both time and memory barriers associated with DKS calculations. Performance, portability, and numerical stability of the code are illustrated on the basis of test calculations on three gold clusters of increasing size, an organometallic compound, and a perovskite model. The calculations are performed on a Beowulf and a BlueGene/Q system. PMID- 26588522 TI - Performance of Density Functional Theory Procedures for the Calculation of Proton Exchange Barriers: Unusual Behavior of M06-Type Functionals. AB - We have examined the performance of a variety of density functional theory procedures for the calculation of complexation energies and proton-exchange barriers, with a focus on the Minnesota-class of functionals that are generally highly robust and generally show good accuracy. A curious observation is that M05 type and M06-type methods show an atypical decrease in calculated barriers with increasing proportion of Hartree-Fock exchange. To obtain a clearer picture of the performance of the underlying components of M05-type and M06-type functionals, we have investigated the combination of MPW-type and PBE-type exchange and B95-type and PBE-type correlation procedures. We find that, for the extensive E3 test set, the general performance of the various hybrid-DFT procedures improves in the following order: PBE1-B95 -> PBE1-PBE -> MPW1-PBE -> PW6-B95. As M05-type and M06-type procedures are related to PBE1-B95, it would be of interest to formulate and examine the general performance of an alternative Minnesota DFT method related to PW6-B95. PMID- 26588523 TI - Exact and Optimal Quantum Mechanics/Molecular Mechanics Boundaries. AB - Motivated by recent work in density matrix embedding theory, we define exact link orbitals that capture all quantum mechanical (QM) effects across arbitrary quantum mechanics/molecular mechanics (QM/MM) boundaries. Exact link orbitals are rigorously defined from the full QM solution, and their number is equal to the number of orbitals in the primary QM region. Truncating the exact set yields a smaller set of link orbitals optimal with respect to reproducing the primary region density matrix. We use the optimal link orbitals to obtain insight into the limits of QM/MM boundary treatments. We further analyze the popular general hybrid orbital (GHO) QM/MM boundary across a test suite of molecules. We find that GHOs are often good proxies for the most important optimal link orbital, although there is little detailed correlation between the detailed GHO composition and optimal link orbital valence weights. The optimal theory shows that anions and cations cannot be described by a single link orbital. However, expanding to include the second most important optimal link orbital in the boundary recovers an accurate description. The second optimal link orbital takes the chemically intuitive form of a donor or acceptor orbital for charge redistribution, suggesting that optimal link orbitals can be used as interpretative tools for electron transfer. We further find that two optimal link orbitals are also sufficient for boundaries that cut across double bonds. Finally, we suggest how to construct "approximately" optimal link orbitals for practical QM/MM calculations. PMID- 26588524 TI - Some Observations on Counterpoise Corrections for Explicitly Correlated Calculations on Noncovalent Interactions. AB - The basis set convergence of explicitly correlated ab initio methods, when applied to noncovalent interactions, has been considered in the presence (and absence) of Boys-Bernardi counterpoise corrections, as well as using "half counterpoise" (the average of raw and counterpoise-corrected values) as recently advocated in this journal [Burns, L. A.; Marshall, M. S.; Sherrill, C. D. J. Chem. Theory Comput. 2014, 10, 49-57]. Reference results were obtained using basis sets so large that BSSE (basis set superposition error) can be shown to be negligible. For the HF+CABS component, full counterpoise unequivocally exhibits the fastest basis set convergence. However, at the MP2-F12 and CCSD(T*)-F12b levels, surprisingly good uncorrected results can be obtained with small basis sets like cc-pVDZ-F12, owing to error compensation between basis set superposition error (which overbinds) and intrinsic basis set insufficiency (which underbinds). For intermediate sets like cc-pVTZ-F12, "half-half" averages work best, while for large basis sets like cc-pVQZ-F12, full counterpoise may be preferred but BSSE in uncorrected values is tolerably small for most purposes. A composite scheme in which CCSD(T)-MP2 "high level corrections" obtained at the CCSD(T*)-F12b/cc-pVDZ-F12 level are combined with "half-counterpoise" MP2-F12/cc pVTZ-F12 interaction energies yields surprisingly good performance for standard benchmark sets like S22 and S66. PMID- 26588525 TI - Relativistic Prolapse-Free Gaussian Basis Set of Quadruple-zeta Quality: (aug )RPF-4Z. I. The s- and p-Block Elements. AB - This study reports a new relativistic prolapse-free Gaussian basis set series of quadruple-zeta quality, RPF-4Z, and an augmented version that includes extra diffuse functions, aug-RPF-4Z, for all the s- and p-block elements. The relativistic adapted Gaussian basis sets (RAGBSs), which are free of variational prolapse, were used as the starting primitive sets. Exponents of correlating/polarization functions were taken from a polynomial version of the generator coordinate Dirac-Fock (p-GCDF) method, in which the previously optimized RAGBS parameters are applied. By using such procedure we aimed to reduce the computational demand of these sets in comparison with fully optimized ones. The effect of these basis set increments on the correlation energy was evaluated by atomic multireference configuration interaction calculations with single and double excitations out of the valence shell. Finally, atomic and molecular calculations of fundamental properties (bond lengths, vibrational frequencies, dipole moments and electron affinities) corroborate the quadruple zeta quality of these new sets that are also about half-time-consuming than the correspondent Dyall's v4z sets. The read-to use format of these (aug-)RPF-4Fz sets are available as Supporting Information files and can also be found at http://basis-sets.iqsc.usp.br/ . PMID- 26588526 TI - Correlated Ab Initio and Density Functional Studies on H2 Activation by FeO(.). AB - The reaction FeO(+) + H2 -> Fe(+) + H2O is a simple model for hydrogen abstraction processes in biologically important heme systems. The geometries of all relevant stationary points on the lowest sextet and quartet surfaces were optimized using several density functionals as well as the CASSCF method. The corresponding energy profiles were computed at the following levels: density functional theory using gradient-corrected, hybrid, meta, hybrid-meta, and perturbatively corrected double hybrid functionals; single-reference coupled cluster theory including up to single, double, triple, and perturbative quadruple excitations [CCSDT(Q)]; correlated multireference ab initio methods (MRCI, MRAQCC, SORCI, SORCP, MRMP2, NEVPT2, and CASPT2). The calculated energies were corrected for scalar relativistic effects, zero-point vibrational energies, and core-valence correlation effects. MRCI and SORCI energies were corrected for size consistency errors using an a posteriori Davidson correction (+Q) leading to MRCI+Q and SORCI+Q. Comparison with the available experimental data shows that CCSDT(Q) is most accurate and can thus serve as benchmark method for this electronically challenging reaction. Among the density functionals, B3LYP performs best. In the correlated ab initio calculations with a full-valence active space, SORCI+Q yields the lowest deviations from the CCSDT(Q) reference results, with qualitatively similar energy profiles being obtained from MRCI+Q and MRAQCC. SORCI+Q benefits from the quality of the approximate average natural orbitals used in the final step of the SORCI procedure. Many of the tested methods show surprisingly large errors. The present results validate the common use of B3LYP in computational studies of heme systems and offer guidance on which correlated ab initio methods are most suitable for such studies. PMID- 26588527 TI - Optimum Exchange for Calculation of Excitation Energies and Hyperpolarizabilities of Organic Electro-optic Chromophores. AB - Organic electro-optic (OEO) materials integrated into silicon-organic hybrid devices afford significant improvements in size, weight, power, and bandwidth performance of integrated electronic/photonic systems critical for current and next generation telecommunication, computer, sensor, transportation, and defense technologies. Improvement in molecular first hyperpolarizability (beta), and in turn electro-optic activity, is crucial to optimizing device performance. Common hybrid density functional theory (DFT) methods, while attractive due to their computational scaling, often perform poorly for optical properties in systems with substantial intramolecular charge-transfer character, such as OEO chromophores. This study evaluates the utility of the long-range corrected (LC) DFT methods for computation of the molecular second-order nonlinear optical response. We compare calculated results for a 14-molecule benchmark set of OEO chromophores with the corresponding experimentally measured beta and one-photon absorption energy, lambdamax. We analyze the distance dependence of the fraction of exact exchange in LC-DFT methods for accurately computing these properties for OEO chromophores. We also examine systematic tuning of the range-separation parameter to enforce Koopmans'/ionization potential theorem. This tuning method improves prediction of excitation energies but is not reliable for predicting the hyperpolarizabilities of larger chromophores since the tuning parameter value can be too small, leading to instabilities in the computation of betaHRS. Additionally, we find that the size dependence of the optimal tuning parameter for the ionization potential has the opposite size dependence of optimal tuning parameter for best agreement with the experimental lambdamax, suggesting the tuning for the ionization potential is unreliable for extended conjugated systems. PMID- 26588528 TI - Bulk Properties of Transition Metals: A Challenge for the Design of Universal Density Functionals. AB - Systematic evaluation of the accuracy of exchange-correlation functionals is essential to guide scientists in their choice of an optimal method for a given problem when using density functional theory. In this work, accuracy of one Generalized Gradient Approximation (GGA) functional, three meta-GGA functionals, one Nonseparable Gradient Approximation (NGA) functional, one meta-NGA, and three hybrid GGA functionals was evaluated for calculations of the closest interatomic distances, cohesive energies, and bulk moduli of all 3d, 4d, and 5d bulk transition metals that have face centered cubic (fcc), hexagonal closed packed (hcp), or body centered cubic (bcc) structures (a total of 27 cases). Our results show that including the extra elements of kinetic energy density and Hartree-Fock exchange energy density into gradient approximation density functionals does not usually improve them. Nevertheless, the accuracies of the Tao-Perdew-Staroverov Scuseria (TPSS) and M06-L meta-GGAs and the MN12-L meta-NGA approach the accuracy of the Perdew-Burke-Ernzerhof (PBE) GGA, so usage of these functionals may be advisable for systems containing both solid-state transition metals and molecular species. The N12 NGA functional is also shown to be almost as accurate as PBE for bulk transition metals, and thus it could be a good choice for studies of catalysis given its proven good performance for molecular species. PMID- 26588529 TI - Electrostatic Forces: Formulas for the First Derivatives of a Polarizable, Anisotropic Electrostatic Potential Energy Function Based on Machine Learning. AB - Explicit formulas are derived analytically for the first derivatives of a (i) polarizable, (ii) high-rank multipolar electrostatic potential energy function for (iii) flexible molecules. The potential energy function uses a machine learning method called Kriging to predict the local-frame multipole moments of atoms defined via the Quantum Chemical Topology (QCT) approach. These atomic multipole moments then interact via an interaction tensor based on spherical harmonics. Atom-centered local coordinate frames are used, constructed from the internal geometry of the molecular system. The forces involve derivatives of both this geometric dependence and of the trained kriging models. In the near future, these analytical forces will enable molecular dynamics and geometry optimization calculations as part of the QCT force field. PMID- 26588530 TI - Filling the Gap between Pseudopotential and All-Electron Schemes: Frozen-Core Calculations with Efficient Use of Density-Fitting. AB - Pseudopotentials simulate the interaction of the valence-electron system with frozen atomic cores using radially nodeless pseudo-orbitals. This leads to computational simplifications absent in frozen-core all-electron calculations. It is argued here that applying density fitting allows for using essentially the same (reduced) auxiliary basis sets for the valence interaction in both pseudopotential and all-electron calculations. We furthermore show that reduced auxiliary basis sets may also be made use of for fitting core Coulomb and exchange operators beyond on-site matrix elements. This leads to efficient substitutes for pseudopotentials in frozen-core all-electron calculations. At some pilot examples (Aun, HfO, RnF6), we demonstrate the possibility to systematically improve the accuracy of standard pseudopotential calculations with limited additional computational effort. PMID- 26588531 TI - Origin of Reactivity Trends of Noble Gas Endohedral Fullerenes Ng2@C60 (Ng = He to Xe). AB - We have computationally studied the factors governing the enhanced Diels-Alder reactivity of noble gas endohedral fullerenes Ng2@C60 when Ng = Ar, Kr, and Xe as compared to Ng = none, He, and Ne. To this end, we have employed the activation strain model of reactivity in combination with the energy decomposition analysis (EDA) method in DFT calculations on the Diels-Alder cycloaddition reaction between Ng2@C60 and 1,3-butadiene. Our results indicate that when heavier noble gas dimers are introduced inside the C60 cage, dramatic effects on both the geometrical and electronic structure of the fullerenic cage occur leading to a remarkable enhanced interaction between the deformed reactants along the entire reaction coordinate. PMID- 26588532 TI - Minimalist Model for the Dynamics of Helical Polypeptides: A Statistic-Based Parametrization. AB - Low-resolution models are often used to address macroscopic time and size scales in molecular dynamics simulations of biomolecular systems. Coarse graining is often coupled to knowledge-based parametrization to obtain empirical potentials able to reproduce the system thermodynamic behavior. Here, a minimalist coarse grained (GC) model for the helical structures of proteins is reported. A knowledge-based parametrization strategy is coupled to the explicit inclusion of hydrogen-bonding-related terms, resulting in an accurate reproduction of the structure and dynamics of each single helical type, as well as the internal conformational variables correlation. The proposed strategy of basing the force field terms on real physicochemical interactions is transferable to different secondary structures. Thus, this work, though conclusive for helices, is to be considered the first of a series devoted to the application of the knowledge based, physicochemical model to extended secondary structures and unstructured proteins. PMID- 26588533 TI - Toward a Quantitative Assessment of Electronic Transitions' Charge-Transfer Character. AB - We hereby report studies devoted to a topological descriptor of photoinduced electronic charge density variation. Our novel index, symbolized as phiS, consists in the detachment and attachment densities overlap, where the detachment density physically depicts the electron density removed from the ground state of a molecule during the transition while the attachment density consists in the rearranged density in the excited state. Our method provides a simple and efficient way to quantitatively evaluate how easy the charge-separation is made upon the chromophore's light absorption. Furthermore, this model can be applied for instance to address a comment on new push-pull dyes charge-transfer ability in order to assess their potentiality as candidates for light absorption-based devices. Moreover, the phiS assessment allows us to perform some methodological diagnostic tests concerning the use of long-range corrected exchange-correlation functional in a time-dependent density functional theory (TDDFT) framework. This paper relates the phiS descriptor's mathematical foundations from various perspectives (detachment/attachment densities or natural transition orbitals), together with its application to several types of chromophores. Connections and divergences with a formerly proposed index are finally evidenced. PMID- 26588534 TI - New Insight into the Topology of Excited States through Detachment/Attachment Density Matrices-Based Centroids of Charge. AB - In parallel with the derivation of a novel descriptor (phiS) related to chromophores' electronic excited states topology, the present article emphasizes some congruence of significance between our phiS index and formerly developed centroid-related indices. We especially point out the possibility to formally adapt a barycenter (centroid) approach to the use of detachment/attachment densities. While the reciprocity of the two approaches can be mathematically evidenced, we will show that some difficulties brought by the use of ground and excited states electron densities in direct space can be overcome by undertaking some operations on the Hilbert space-related detachment/attachment matrices. We further wish to point out the crucial case of some chromophores holding two electron-withdrawing groups symmetrically disposed in a rod-like structure. Finally, we will qualitatively highlight the quadratic-like relationship between the amount of displaced charge induced by light absorption and the phiS index. PMID- 26588535 TI - Relaxation Mechanisms of 5-Azacytosine. AB - The photophysics and deactivation pathways of the noncanonical 5-azacytosine nucleobase were studied using the CASPT2//CASSCF protocol. One of the most significant differences with respect to the parent molecule cytosine is the presence of a dark (1)(nNpi*) excited state placed energetically below the bright excited state (1)(pipi*) at the Franck-Condon region. The main photoresponse of the system is a presumably efficient radiationless decay back to the original ground state, mediated by two accessible conical intersections involving a population transfer from the (1)(pipi*) and the (1)(nNpi*) states to the ground state. Therefore, a minor contribution of the triplet states in the photophysics of the system is expected, despite the presence of a deactivation path leading to the lowest (3)(pipi*) triplet state. The global scenario on the photophysics and photochemistry of the 5-azacytosine system gathered on theoretical grounds is consistent with the available experimental data, taking especially into account the low values of the singlet-triplet intersystem crossing and fluorescence quantum yields observed. PMID- 26588536 TI - Excited State Geometries and Vertical Emission Energies of Solvated Dyes for DSSC: A PCM/TD-DFT Benchmark Study. AB - The ability of Time-Dependent Density Functional Theory (TD-DFT) to provide excited state geometries and reproduce emission energies of organic D-pi-A dyes designed for DSSC applications is evaluated. The performance of six functionals (CAM-B3LYP, MPW1K, omegaB97X-D, LC-BLYP, LC-omegaPBE, and M06-HF) in combination with three basis sets (cc-pVDZ, 6-31+G(d,p), and 6-311+G(2d,p)) has been analyzed. Solvent effects have been taken into account by means of a Polarizable Continuum Model in both LR and SS formalisms. Our LR-PCM/TD-DFT results show that accurate emission energies are obtained only when solvent effects are included in the computation of excited state geometries and when a range separated hybrid functional is used. Vertical emission energies are reproduced with a mean absolute error of at most 0.2 eV. The accuracy is further improved using the SS PCM formalism. PMID- 26588537 TI - Benchmark Many-Body GW and Bethe-Salpeter Calculations for Small Transition Metal Molecules. AB - We study the electronic and optical properties of 39 small molecules containing transition metal atoms and 7 others related to quantum-dots for photovoltaics. We explore in particular the merits of the many-body GW formalism, as compared to the DeltaSCF approach within density functional theory, in the description of the ionization energy and electronic affinity. Mean average errors of 0.2-0.3 eV with respect to experiment are found when using the PBE0 functional for DeltaSCF and as a starting point for GW. The effect of partial self-consistency at the GW level is explored. Further, for optical excitations, the Bethe-Salpeter formalism is found to offer similar accuracy as time-dependent DFT-based methods with the hybrid PBE0 functional, with mean average discrepancies of about 0.3 and 0.2 eV, respectively, as compared to available experimental data. Our calculations validate the accuracy of the parameter-free GW and Bethe-Salpeter formalisms for this class of systems, opening the way to the study of large clusters containing transition metal atoms of interest for photovoltaic applications. PMID- 26588538 TI - Optical Properties of Diarylethenes with TD-DFT: 0-0 Energies, Fluorescence, Stokes Shifts, and Vibronic Shapes. AB - This contribution is an investigation of both the structures and optical properties of a set of 14 diverse, recently synthesized diarylethenes using Time Dependent Density Functional Theory (TD-DFT) at the omegaB97X-D/6-31G(d) level of theory. The linear response (LR) and state-specific (SS) versions of the Polarizable Continuum Model (PCM) have been adopted to account for the bulk solvation effects and their relative performances were critically accessed. It is shown, for the first time in the case of nontrivial diarylethenes, that TD-DFT provides good agreement between the experimental absorption-fluorescence crossing points (AFCPs) and their theoretical counterparts when a robust model accounting for both geometrical relaxation and vibrational corrections is used instead of the vertical approximation. On the other hand, the theoretical estimates for the Stokes shifts based on the vertical transition energies were found to be in disagreement with respect to experiment, prompting us to simulate the absorption/emission vibronic band shapes. It is proved that difficulties associated with the breakdown of the harmonic approximation in Cartesian coordinates exist for the investigated system, and we show how they can be at least partially overcome by means of a vertical approach including Duschinsky effects. Our results provide a valuable basis to rationalize the experimental vibronic structure of both emission and absorption bands and are expected to be a significant asset to the understanding of the optical properties of diarylethene derivatives. PMID- 26588539 TI - Role of Protonation State and Solvation on the pH Dependent Optical Properties of Bromocresol Green. AB - pH sensors play a key role in many industrial and diagnostic applications. Mostly their usage is based on experience, and in many cases the working mechanisms of these sensors are not known in detail, thereby hindering a systematic improvement of such sensors for specific applications. In this report, we present results from combined quantum chemical and molecular mechanics calculations of molecular structures and optical absorption properties of bromocresol green (BRG) in aqueous solution with varying pH value. In the acidic pH range, this chromophore has an intense band with absorption maximum at 444 nm and in the basic pH regime the absorption spectra show a redshift toward 613 nm. In order to identify the molecular structures responsible for this pH dependent optical behavior the closed and open forms of BRG are studied using static approaches considering in each case the three possible protonated states namely, neutral, anionic, and dianionic. For the most significant forms, i.e. the open forms of BRG, extensive modeling based on the integrated approach has been carried out, where the structure and dynamics were studied using hybrid QM/MM molecular dynamics, while the excitation energy calculations were carried out using time dependent density functional theory wherein the surrounding solvent was described as polarizable continuum, semicontinuum, or via a molecular mechanics force-field. The anionic and dianionic forms of BRG have been recognized as molecular forms responsible for its acidic and basic pH behavior, respectively. In contrast to the case of solvatochromic probes, the different protonation states determine the optical behavior in different pH values for pH probes. Hence, the level of solvent description appears to be of minor importance. Independent of the level of theory used to describe the solvent, all models reproduce the spectral features of BRG in different pH and also the pH induced redshift in good agreement with experiment. PMID- 26588540 TI - Benchmark Study on the Triplet Excited-State Geometries and Phosphorescence Energies of Heterocyclic Compounds: Comparison Between TD-PBE0 and SAC-CI. AB - In this work, we investigated the properties of the triplet excited states of heterocyclic compounds including their geometries, electronic properties, and phosphorescence energies by using both the direct symmetry-adapted cluster configuration interaction (SAC-CI) method and the TD-DFT approach with the PBE0 exchange-correlation functional (TD-PBE0). The target states are the pipi* and npi* triplet states of furan, pyrrole, pyridine, p-benzoquinone, uracil, adenine, 9,10-anthraquinone, coumarin, and 1,8-naphthalimide as well as the Rydberg states. The present benchmark demonstrates that these two methods provide reasonably accurate geometries for the excited states of these heterocyclic compounds. The calculated Stokes shifts, which reflect geometry changes, were consistent for both these methods. The trends of agreement with experimental or reference values obtained for a panel of exchange-correlation functionals used to compute the absolute emission energies from the triplet states, differ from those found for the singlet excited states. Some of the low-lying triplet excited states were examined in detail for the first time, including vibrational analysis. PMID- 26588541 TI - Derivation of the RPA (Random Phase Approximation) Equation of ATDDFT (Adiabatic Time Dependent Density Functional Ground State Response Theory) from an Excited State Variational Approach Based on the Ground State Functional. AB - The random phase approximation (RPA) equation of adiabatic time dependent density functional ground state response theory (ATDDFT) has been used extensively in studies of excited states. It extracts information about excited states from frequency dependent ground state response properties and avoids, thus, in an elegant way, direct Kohn-Sham calculations on excited states in accordance with the status of DFT as a ground state theory. Thus, excitation energies can be found as resonance poles of frequency dependent ground state polarizability from the eigenvalues of the RPA equation. ATDDFT is approximate in that it makes use of a frequency independent energy kernel derived from the ground state functional. It is shown in this study that one can derive the RPA equation of ATDDFT from a purely variational approach in which stationary states above the ground state are located using our constricted variational DFT (CV-DFT) method and the ground state functional. Thus, locating stationary states above the ground state due to one-electron excitations with a ground state functional is completely equivalent to solving the RPA equation of TDDFT employing the same functional. The present study is an extension of a previous work in which we demonstrated the equivalence between ATDDFT and CV-DFT within the Tamm-Dancoff approximation. PMID- 26588542 TI - Toward the Understanding of the Photophysics and Photochemistry of 1 Nitronaphthalene under Solar Radiation: The First Theoretical Evidence of a Photodegradation Intramolecular Rearrangement Mechanism Involving the Triplet States. AB - 1-Nitronaphthalene belongs to the class of nitrated polycyclic aromatic hydrocarbons, and constitutes an atmospheric pollutant commonly found in urban environments due to its production during incomplete combustions. On the basis of CASPT2//CASSCF quantum chemical calculations, the photophysics and photochemistry of the system under solar exposure have for the first time been studied. According to the characteristics of the incident radiation (either UVA or UVB, both present in the portion of the solar spectrum reaching the earth), a different excited state will be mainly populated. In both cases, the main decay path undertaken by the corresponding bright state leads to an efficient intersystem crossing process toward the (3)(piOpi*) triplet excited state. The population of the triplet manifold is then identified as the primary photoinduced process in the title molecule, not only after UVA interaction but also under UVB exposure. From the (3)(piOpi*) state, the system can either decay in a radiationless manner to the original ground state minimum, or undergo a photodegradation process mediated by the presence of an accessible singlet triplet crossing region characterized by the formation of a oxaziridine ring. The determination of such a photodegradation path constitutes the first theoretical evidence supporting the hypothesis formulated almost 50 years ago in the seminal work of Chapman et al. (J. Am. Chem. Soc. 1966, 88, 5550), according to which the photolysis undertaken by nitrated polycyclic aromatic hydrocarbons proceeds through an intramolecular rearrangement mechanism, here characterized on the triplet manifold. PMID- 26588543 TI - Charge Transfer, Luminescence, and Phonon Bottleneck in TiO2 Nanowires Computed by Eigenvectors of Liouville Superoperator. AB - A nonadiabatic excited state dynamics study of ?001? anatase TiO2 nanowire is obtained by combining density matrix in Liouville-Redfield formalism and ab initio electronic structure calculations. The properties of eigenvectors of Liouville-Redfield superoperator are investigated. The time evolutions of Kohn Sham orbital populations are obtained for different electronic excitations. The numerical solutions of the population changes over time are in agreement with the analytical results. The analytical and numerical results on the electron and hole relaxation rates are compared. The electron nonradiative relaxation to the bottom of conduction band involves Ti 3d orbitals, whereas the hole nonradiative relaxation to the top of valence band is mainly localized in surface O 2p orbitals. The rate of relaxation in nanowire is slower than in bulk TiO2 demonstrating phonon-bottleneck effect. Calculated emission spectrum has vanishing contribution from lowest energy excitation, which indicates charge transfer. PMID- 26588544 TI - Theoretical Determination of Electronic Spectra and Intersystem Spin-Orbit Coupling: The Case of Isoindole-BODIPY Dyes. AB - Density functional theory and its time-dependent extension (DFT, TDDFT) has been herein employed to elucidate the structural and electronic properties for a series of isoindole-boron dipyrromethene (isoindole-BODIPY) derivatives. The role played by both the nature and the positions of the substituents on intersystem spin-crossing has been investigated computing the spin-orbit matrix elements between singlet and triplet excited state wave functions weighted by the TDDFT transition coefficients. Their potential therapeutic use as photosensitizers in photodynamic therapy (PDT) is proposed on the basis of their strong absorbance in the red part of the visible spectrum, vertical triplet energies resulting higher than 0.98 eV, and the spin-orbit matrix elements that result to be comparable with different drugs already used in PDT. PMID- 26588545 TI - Density Relaxation in Time-Dependent Density Functional Theory: Combining Relaxed Density Natural Orbitals and Multireference Perturbation Theories for an Improved Description of Excited States. AB - Making use of the recently developed excited state charge displacement analysis [E. Ronca et al., J. Chem. Phys. 140, 054110 (2014)], suited to quantitatively characterize the charge fluxes coming along an electronic excitation, we investigate the role of the density relaxation effects in the overall description of electronically excited states of different nature, namely, valence, ionic, and charge transfer (CT), considering a large set of prototypical small and medium sized molecular systems. By comparing the response densities provided by time dependent density functional theory (TDDFT) and the corresponding relaxed densities obtained by applying the Z-vector postlinear-response approach [N. C. Handy and H. F. Schaefer, J. Chem. Phys. 81, 5031 (1984)] with those obtained by highly correlated state-of-the-art wave function calculations, we show that the inclusion of the relaxation effects is imperative to get an accurate description of the considered excited states. We also examine what happens at the quality of the response function when an increasing amount of Hartree-Fock (HF) exchange is included in the functional, showing that the usually improved excitation energies in the case of CT states are not always the consequence of an improved description of their overall properties. Remarkably, we find that the relaxation of the response densities is always able to reproduce, independently of the extent of HF exchange in the functional, the benchmark wave function densities. Finally, we propose a novel and computationally convenient strategy, based on the use of the natural orbitals derived from the relaxed TDDFT density to build zero order wave function for multireference perturbation theory calculations. For a significant set of different excited states, the proposed approach provided accurate excitation energies, comparable to those obtained by computationally demanding ab initio calculations. PMID- 26588546 TI - Quantum Dynamics Simulations Reveal Vibronic Effects on the Optical Properties of [n]Cycloparaphenylenes. AB - The size-dependent ultraviolet/visible photophysical property trends of [n]cycloparaphenylenes ([n]CPPs, n = 6, 8, and 10) are theoretically investigated using quantum dynamics simulations. For geometry optimizations on the ground- and excited-state Born-Oppenheimer potential energy surfaces (PESs), we employ density functional theory (DFT) and time-dependent DFT calculations. Harmonic normal-mode analyses are carried out for the electronic ground state at Franck Condon geometries. A diabatic Hamiltonian, comprising four low-lying singlet excited electronic states and 26 vibrational degrees of freedom of CPP, is constructed within the linear vibronic coupling (VC) model to elucidate the absorption spectral features in the range of 300-500 nm. Quantum nuclear dynamics is simulated within the multiconfiguration time-dependent Hartree approach to calculate the vibronic structure of the excited electronic states. The symmetry forbidden S0 -> S1 transition appears in the longer wavelength region of the spectrum with weak intensity due to VC. It is found that the Jahn-Teller and pseudo-Jahn-Teller effects in the doubly degenerate S2 and S3 electronic states are essential in the quantitative interpretation of the experimental observation of a broad absorption peak around 340 nm. The vibronic mixing of the S1 state with higher electronic states is responsible for the efficient photoluminescence from the S1 state. The fluorescence properties are characterized on the basis of the stationary points of the excited-state PESs. The findings reveal that vibronic effects become important in determining the photophysical properties of CPPs with increased ring size. PMID- 26588547 TI - Elucidating the Electronic Structures of the Ground States of the VO2(-/0) Clusters: Synergism between Computation and Experiment. AB - Electronic structures of VO2 and its anion were investigated with density functional theory (DFT), complete active space second-order perturbation theory (CASPT2), and restricted coupled-cluster with single, double, and perturbative triple excitations (RCCSD(T)) computational quantum chemical methods. The results show that there is a near-degeneracy of the lowest (3)B1, (3)A1, and (1)A1 states of the anion. Therefore, the 532 and 193 nm photoelectron spectra of VO2(-) are interpreted by exploring these states as possible initial states. The anionic ground state was identified at the highest computational level, that is, RCCSD(T), as (3)B1 allowing the X band to be assigned to the (3)B1 -> (2)B1 transition, while the lower intensity and lower binding energy X' and X" features are ascribed to the (1)A1 -> (2)A1 and (3)A1 -> (2)A1 ionizations, respectively. The latter assignment is different from the recently proposed assignment of the corresponding slow electron velocity-map imaging (SEVI) spectra. Further, the A band is suggested to be mainly the result of an ionization from (3)B1 to 2(2)A1. For all these ionizations an electron is removed from a predominant metal orbital. The higher energy bands B and C on the contrary can be ascribed as electron detachments out of molecular orbitals largely located on the oxygen centers. More precisely, the B band is attributed to the ionizations from (3)B1 to (4)A2 and (2)A2, while the C band is proposed to originate from the (3)B1 -> (4)B1 and (3)B1 -> 2(2)B1 ionizations. The proposed novel assignment is further corroborated by calculating the Franck-Condon factors, which largely agree with the experimental vibrational progressions of the SEVI spectra. PMID- 26588548 TI - Scalable High-Performance Algorithm for the Simulation of Exciton Dynamics. Application to the Light-Harvesting Complex II in the Presence of Resonant Vibrational Modes. AB - The accurate simulation of excitonic energy transfer in molecular complexes with coupled electronic and vibrational degrees of freedom is essential for comparing excitonic system parameters obtained from ab initio methods with measured time resolved spectra. Several exact methods for computing the exciton dynamics within a density-matrix formalism are known but are restricted to small systems with less than 10 sites due to their computational complexity. To study the excitonic energy transfer in larger systems, we adapt and extend the exact hierarchical equation of motion (HEOM) method to various high-performance many-core platforms using the Open Compute Language (OpenCL). For the light-harvesting complex II (LHC II) found in spinach, the HEOM results deviate from predictions of approximate theories and clarify the time scale of the transfer process. We investigate the impact of resonantly coupled vibrations on the relaxation and show that the transfer does not rely on a fine-tuning of specific modes. PMID- 26588549 TI - Evaluation of Host-Guest Binding Thermodynamics of Model Cavities with Grid Cell Theory. AB - A previously developed cell theory model of liquid water was used to evaluate the excess thermodynamic properties of confined clusters of water molecules. The results are in good agreement with reference thermodynamic integration calculations, suggesting that the model is adequate to probe the thermodynamic properties of water at interfaces or in cavities. Next, the grid cell theory (GCT) method was applied to elucidate the thermodynamic signature of nonpolar association for a range of idealized host-guest systems. Polarity and geometry of the host cavities were systematically varied, and enthalpic and entropic solvent components were spatially resolved for detailed graphical analyses. Perturbations in the thermodynamic properties of water molecules upon guest binding are restricted to the immediate vicinity of the guest in solvent-exposed cavities, whereas longer-ranged perturbations are observed in buried cavities. Depending on the polarity and geometry of the host, water displacement by a nonpolar guest makes a small or large enthalpic or entropic contribution to the free energy of binding. Thus, no assumptions about the thermodynamic signature of the hydrophobic effect can be made in general. Overall the results warrant further applications of GCT to more complex systems such as protein-ligand complexes. PMID- 26588550 TI - Free Energy Surface Reconstruction from Umbrella Samples Using Gaussian Process Regression. AB - We demonstrate how the Gaussian process regression approach can be used to efficiently reconstruct free energy surfaces from umbrella sampling simulations. By making a prior assumption of smoothness and taking account of the sampling noise in a consistent fashion, we achieve a significant improvement in accuracy over the state of the art in two or more dimensions or, equivalently, a significant cost reduction to obtain the free energy surface within a prescribed tolerance in both regimes of spatially sparse data and short sampling trajectories. Stemming from its Bayesian interpretation the method provides meaningful error bars without significant additional computation. A software implementation is made available on www.libatoms.org . PMID- 26588551 TI - Optical Absorption Spectra Calculated from a First-Principles Wave Function Theory for Solids: Transcorrelated Method Combined with Configuration Interaction Singles. AB - We present a new ab initio method for excited-state calculations based on wave function theory: transcorrelated (TC) method combined with configuration interaction singles (CIS). Conventional CIS with the Hartree-Fock wave function, while a popular method for excited-state calculations of molecular systems, cannot describe electron correlation effects, such as the screening effect in solids, resulting in inaccurate results such as overestimation of the band gap and exciton binding energy. Here, we adopt the TC method, which takes electron correlations into account through a similarity transformation of the Hamiltonian using the Jastrow factor, and combine it with the CIS approximation. We calculate the optical absorption spectra of solid LiF and GaAs as a test, and verify that the present method reproduces the spectra more accurately than the conventional HF-CIS. The excitonic effect is well described with our method. PMID- 26588552 TI - Coarse-Graining of TIP4P/2005, TIP4P-Ew, SPC/E, and TIP3P to Monatomic Anisotropic Water Models Using Relative Entropy Minimization. AB - Coarse-grained models are becoming a competitive alternative for modeling processes that occur over time and length scales beyond the reach of fully atomistic molecular simulations. Ideally, coarse-grained models should not only achieve high computational efficiency but also provide accurate predictions and fundamental insight into the role of molecular interactions, the characteristic behavior, and properties of the system they model. In this work we derive a series of monatomic coarse-grained water models mX(REM) from the most popular atomistic water models X = TIP3P, SPC/E, TIP4P-Ew, and TIP4P/2005, using the relative entropy minimization (REM) method. Each coarse-grained water molecule is represented by a single particle that interacts through short-ranged anisotropic interactions that encourage the formation of "hydrogen-bonded" structures. We systematically investigate the features of the coarse-grained models in reproducing over 20 structural, dynamic, and thermodynamic properties of the reference atomistic water models-including the existence and locus of the characteristic density anomaly. The mX(REM) coarse-grained models reproduce quite faithfully the radial and angular distribution function of water, produce a temperature of maximum density (TMD), and stabilize the ice I crystal. Moreover, the ratio between the TMD and the melting temperature of the crystal in the mX(REM) models and liquid-ice equilibrium properties show reasonable agreement with the results of the corresponding atomistic models. The mX(REM) models, however, severely underestimate the cohesive energy of the condensed water phases. We investigate which specific limitations of the coarse-grained models arise from the REM methodology, from the monatomic nature of the models, and from the Stillinger-Weber interaction potential form. Our analysis indicates that a small compromise in the accuracy of structural properties can result in a significant increase of the overall accuracy and representability of the coarse grained water models. We evaluate the accuracy of the atomistic and the monatomic anisotropic coarse-grained water models, including the mW water model, in reproducing experimental water properties. We find that mW and mTIP4P/2005(REM) score closer to experiment than widely used atomistic water models. We conclude that monatomic models of water with short-range, anisotropic "hydrogen-bonding" three-body interactions can be competitive in accuracy with fully atomistic models for the study of a wide range of properties and phenomena at less than 1/100th of the computational cost. PMID- 26588553 TI - CHARMM Force-Fields with Modified Polyphosphate Parameters Allow Stable Simulation of the ATP-Bound Structure of Ca(2+)-ATPase. AB - Adenosine triphosphate (ATP) is an indispensable energy source in cells. In a wide variety of biological phenomena like glycolysis, muscle contraction/relaxation, and active ion transport, chemical energy released from ATP hydrolysis is converted to mechanical forces to bring about large-scale conformational changes in proteins. Investigation of structure-function relationships in these proteins by molecular dynamics (MD) simulations requires modeling of ATP in solution and ATP bound to proteins with accurate force-field parameters. In this study, we derived new force-field parameters for the triphosphate moiety of ATP based on the high-precision quantum calculations of methyl triphosphate. We tested our new parameters on membrane-embedded sarcoplasmic reticulum Ca(2+)-ATPase and four soluble proteins. The ATP-bound structure of Ca(2+)-ATPase remains stable during MD simulations, contrary to the outcome in shorter simulations using original parameters. Similar results were obtained with the four ATP-bound soluble proteins. The new force-field parameters were also tested by investigating the range of conformations sampled during replica-exchange MD simulations of ATP in explicit water. Modified parameters allowed a much wider range of conformational sampling compared with the bias toward extended forms with original parameters. A diverse range of structures agrees with the broad distribution of ATP conformations in proteins deposited in the Protein Data Bank. These simulations suggest that the modified parameters will be useful in studies of ATP in solution and of the many ATP-utilizing proteins. PMID- 26588554 TI - Benchmarking of Force Fields for Molecule-Membrane Interactions. AB - Studies of drug-membrane interactions witness an ever-growing interest, as penetration, accumulation, and positioning of drugs play a crucial role in drug delivery and metabolism in human body. Molecular dynamics simulations complement nicely experimental measurements and provide us with new insight into drug membrane interactions; however, the quality of the theoretical data dramatically depends on the quality of the force field used. We calculated the free energy profiles of 11 molecules through a model dimyristoylphosphatidylcholine (DMPC) membrane bilayer using five force fields, namely Berger, Slipids, CHARMM36, GAFFlipids, and GROMOS 43A1-S3. For the sake of comparison, we also employed the semicontinuous tool COSMOmic. High correlation was observed between theoretical and experimental partition coefficients (log K). Partition coefficients calculated by all-atomic force fields (Slipids, CHARMM36, and GAFFlipids) and COSMOmic differed by less than 0.75 log units from the experiment and Slipids emerged as the best performing force field. This work provides the following recommendations (i) for a global, systematic and high throughput thermodynamic evaluations (e.g., log K) of drugs COSMOmic is a tool of choice due to low computational costs; (ii) for studies of the hydrophilic molecules CHARMM36 should be considered; and (iii) for studies of more complex systems, taking into account all pros and cons, Slipids is the force field of choice. PMID- 26588555 TI - Conformational Changes and Free Energies in a Proline Isomerase. AB - Proteins are dynamic molecules and their ability to adopt alternative conformations is central to their biological function. The structural and biophysical properties of transiently and sparsely populated states are, however, difficult to study and an atomic-level description of those states is challenging. We have used enhanced-sampling all-atom, explicit-solvent molecular simulations, guided by structural information from X-ray crystallography and NMR, to describe quantitatively the transition between the major and a minor state of Cyclophilin A, thus providing new insight into how dynamics can affect enzyme function. We calculate the conformational free energy between the two states, and comparison with experiments demonstrates a surprisingly high accuracy for both the wild type protein and a mutant that traps the protein in its alternative conformation. Our results demonstrate how the combination of state-of-the-art force fields and enhanced sampling methods can provide a detailed and quantitative description of the conformational changes in proteins such as those observed in Cyclophilin A. PMID- 26588556 TI - IgE-mediated mechanisms in bullous pemphigoid and other autoimmune bullous diseases. AB - Autoimmune bullous diseases (AIBDs) are characterized by autoantibodies against structural proteins of the dermal-epidermal junction (in pemphigoid diseases) and the epidermal/ epithelial desmosomes (in pemphigus diseases). By far, the most common AIBD is bullous pemphigoid, which is immunopathologically characterized by autoantibodies against BP180 (type XVII collagen) and BP230. IgG and, to a lesser extent, IgA autoantibodies are the major autoantibody isotypes in these disorders. IgE autoantibodies are increasingly reported in particular in bullous pemphigoid. The development of specific and sensitive anti-BP180 IgE ELISA systems, the report of two experimental murine models employing IgE autoantibodies against BP180, and the successful treatment of bullous pemphigoid with the anti-IgE antibody omalizumab have raised interest in the role of IgE autoantibodies and the modulation of their production in AIBDs. Here, the relevance of IgE autoantibodies in the diagnosis, pathophysiology, and treatment decisions of AIBDs, with a focus on bullous pemphigoid, is reviewed. PMID- 26588557 TI - Cell Mechanics: Combining Speed with Precision. PMID- 26588558 TI - Nucleation: The Birth of a New Protein Phase. PMID- 26588559 TI - Nanopore Sequencing: Forcing Improved Resolution. PMID- 26588560 TI - Mechanistic Insights into the Modulation of Voltage-Gated Ion Channels by Inhalational Anesthetics. AB - General anesthesia is a relatively safe medical procedure, which for nearly 170 years has allowed life saving surgical interventions in animals and people. However, the molecular mechanism of general anesthesia continues to be a matter of importance and debate. A favored hypothesis proposes that general anesthesia results from direct multisite interactions with multiple and diverse ion channels in the brain. Neurotransmitter-gated ion channels and two-pore K+ channels are key players in the mechanism of anesthesia; however, new studies have also implicated voltage-gated ion channels. Recent biophysical and structural studies of Na+ and K+ channels strongly suggest that halogenated inhalational general anesthetics interact with gates and pore regions of these ion channels to modulate function. Here, we review these studies and provide a perspective to stimulate further advances. PMID- 26588561 TI - CHARMM-GUI HMMM Builder for Membrane Simulations with the Highly Mobile Membrane Mimetic Model. AB - Slow diffusion of the lipids in conventional all-atom simulations of membrane systems makes it difficult to sample large rearrangements of lipids and protein lipid interactions. Recently, Tajkhorshid and co-workers developed the highly mobile membrane-mimetic (HMMM) model with accelerated lipid motion by replacing the lipid tails with small organic molecules. The HMMM model provides accelerated lipid diffusion by one to two orders of magnitude, and is particularly useful in studying membrane-protein associations. However, building an HMMM simulation system is not easy, as it requires sophisticated treatment of the lipid tails. In this study, we have developed CHARMM-GUI HMMM Builder (http://www.charmm gui.org/input/hmmm) to provide users with ready-to-go input files for simulating HMMM membrane systems with/without proteins. Various lipid-only and protein-lipid systems are simulated to validate the qualities of the systems generated by HMMM Builder with focus on the basic properties and advantages of the HMMM model. HMMM Builder supports all lipid types available in CHARMM-GUI and also provides a module to convert back and forth between an HMMM membrane and a full-length membrane. We expect HMMM Builder to be a useful tool in studying membrane systems with enhanced lipid diffusion. PMID- 26588562 TI - Extracting Cell Stiffness from Real-Time Deformability Cytometry: Theory and Experiment. AB - Cell stiffness is a sensitive indicator of physiological and pathological changes in cells, with many potential applications in biology and medicine. A new method, real-time deformability cytometry, probes cell stiffness at high throughput by exposing cells to a shear flow in a microfluidic channel, allowing for mechanical phenotyping based on single-cell deformability. However, observed deformations of cells in the channel not only are determined by cell stiffness, but also depend on cell size relative to channel size. Here, we disentangle mutual contributions of cell size and cell stiffness to cell deformation by a theoretical analysis in terms of hydrodynamics and linear elasticity theory. Performing real-time deformability cytometry experiments on both model spheres of known elasticity and biological cells, we demonstrate that our analytical model not only predicts deformed shapes inside the channel but also allows for quantification of cell mechanical parameters. Thereby, fast and quantitative mechanical sampling of large cell populations becomes feasible. PMID- 26588563 TI - Modeling Local X-ROS and Calcium Signaling in the Heart. AB - Stretching single ventricular cardiac myocytes has been shown experimentally to activate transmembrane nicotinamide adenine dinucleotide phosphate oxidase type 2 to produce reactive oxygen species (ROS) and increase the Ca2+ spark rate in a process called X-ROS signaling. The increase in Ca2+ spark rate is thought to be due to an increase in ryanodine receptor type 2 (RyR2) open probability by direct oxidation of the RyR2 protein complex. In this article, a computational model is used to examine the regulation of ROS and calcium homeostasis by local, subcellular X-ROS signaling and its role in cardiac excitation-contraction coupling. To this end, a four-state RyR2 model was developed that includes an X ROS-dependent RyR2 mode switch. When activated, [Ca2+]i-sensitive RyR2 open probability increases, and the Ca2+ spark rate changes in a manner consistent with experimental observations. This, to our knowledge, new model is used to study the transient effects of diastolic stretching and subsequent ROS production on RyR2 open probability, Ca2+ sparks, and the myoplasmic calcium concentration ([Ca2+]i) during excitation-contraction coupling. The model yields several predictions: 1) [ROS] is produced locally near the RyR2 complex during X-ROS signaling and increases by an order of magnitude more than the global ROS signal during myocyte stretching; 2) X-ROS activation just before the action potential, corresponding to ventricular filling during diastole, increases the magnitude of the Ca2+ transient; 3) during prolonged stretching, the X-ROS-induced increase in Ca2+ spark rate is transient, so that long-sustained stretching does not significantly increase sarcoplasmic reticulum Ca2+ leak; and 4) when the chemical reducing capacity of the cell is decreased, activation of X-ROS signaling increases sarcoplasmic reticulum Ca2+ leak and contributes to global oxidative stress, thereby increases the possibility of arrhythmia. The model provides quantitative information not currently obtainable through experimental means and thus provides a framework for future X-ROS signaling experiments. PMID- 26588564 TI - Kymographic Imaging of the Elastic Modulus of Epithelial Cells during the Onset of Migration. AB - Epithelial cell migration during wound repair involves a complex interplay of intracellular processes that enable motility while preserving contact among the cells. Recent evidence suggests that fluctuations of the intracellular biophysical state of cells generate traction forces at the basal side of the cells that are necessary for the cells to migrate. However, less is known about the biophysical and structural changes throughout the cells that accompany these fluctuations. Here, we utilized, to our knowledge, a novel kymographic nanoindentation method to obtain spatiotemporal measurements of the elastic moduli of living cells during migration after wounding. At the onset of migration, the elastic modulus increased near the migration front. In addition, the intensity of fluctuations in the elastic modulus changed at the migration front, and these changes were dependent upon f-actin, one of the major components of the cytoskeleton. These results demonstrate the unique biophysical changes that occur at the onset of migration as cells transition from a stationary to a migratory state. PMID- 26588565 TI - Ellipsoid Localization Microscopy Infers the Size and Order of Protein Layers in Bacillus Spore Coats. AB - Multilayered protein coats are crucial to the dormancy, robustness, and germination of bacterial spores. In Bacillus subtilis spores, the coat contains over 70 distinct proteins. Identifying which proteins reside in each layer may provide insight into their distinct functions. We present image analysis methods that determine the order and geometry of concentric protein layers by fitting a model description for a spheroidal fluorescent shell image to optical micrographs of spores incorporating fluorescent fusion proteins. The radius of a spherical protein shell can be determined with <10 nm error by fitting an equation to widefield fluorescence micrographs. Ellipsoidal shell axes can be fitted with comparable precision. The layer orders inferred for B. subtilis and B. megaterium are consistent with measurements in the literature. The aspect ratio of elongated spores and the tendency of some proteins to localize near their poles can be quantified, enabling measurement of structural anisotropy. PMID- 26588566 TI - The Molecular Mechanism Underlying Recruitment and Insertion of Lipid-Anchored LC3 Protein into Membranes. AB - Lipid modification of cytoplasmic proteins initiates membrane engagement that triggers diverse cellular processes. Despite the abundance of lipidated proteins in the human proteome, the key determinants underlying membrane recognition and insertion are poorly understood. Here, we define the course of spontaneous membrane insertion of LC3 protein modified with phosphatidylethanolamine using multiple coarse-grain simulations. The partitioning of the lipid anchor chains proceeds through a concerted process, with its two acyl chains inserting one after the other. Concurrently, a conformational rearrangement involving the alpha helix III of LC3, especially in the three basic residues Lys65, Arg68, and Arg69, ensures stable insertion of the phosphatidylethanolamine anchor into membranes. Mutational studies validate the crucial role of these residues, and further live cell imaging analysis shows a substantial reduction in the formation of autophagic vesicles for the mutant proteins. Our study captures the process of water-favored LC3 protein recruitment to the membrane and thus opens, to our knowledge, new avenues to explore the cellular dynamics underlying vesicular trafficking. PMID- 26588567 TI - Vesicle Leakage Reflects the Target Selectivity of Antimicrobial Lipopeptides from Bacillus subtilis. AB - Cyclic lipopeptides act against a variety of plant pathogens and are thus highly efficient crop-protection agents. Some pesticides contain Bacillus subtilis strains that produce lipopeptide families, such as surfactins (SF), iturins (IT), and fengycins (FE). The antimicrobial activity of these peptides is mainly mediated by permeabilizing cellular membranes. We used a fluorescence-lifetime based leakage assay to examine the effect of individual lipid components in model membranes on lipopeptide activity. Leakage induction by FE was strongly inhibited by cholesterol (CHOL) as well as by phosphatidylethanolamine (PE) and -glycerol (PG) lipids. Already moderate amounts of CHOL increased the tolerable FE content in membranes by an order of magnitude to 0.5 FE per PC + CHOL. This indicates reduced FE-lipid demixing and aggregation, which is known to be required for membrane permeabilization and explains the strong inhibition by CHOL. Ergosterol (ERG) had a weak antagonistic effect. This confirms results of microbiological tests and agrees with the fungicidal activity and selectivity of FE. SF is known to be much less selective in its antimicrobial action. In line with this, liposome leakage by SF was little affected by sterols and PE. Interestingly, PG increased SF activity and changed its leakage mechanism toward all-or-none, suggesting more specific, larger, and/or longer-lived defect structures. This may be because of the reduced energetic cost of locally accumulating anionic SF in an anionic lipid matrix. IT was found largely inactive in our assays. B. subtilis QST713 produces the lipopeptides in a ratio of 6 mol SF: 37 mol FE: 57 mol IT. Leakage induced by this native mixture was inhibited by CHOL and PE, but unaffected by ERG and by PG in the absence of PE. Note that fungi contain anionic lipids, but little PE. Hence, our data explain the strong, fungicidal activity and selectivity of B. subtilis QST713 lipopeptides. PMID- 26588568 TI - Insight into Early-Stage Unfolding of GPI-Anchored Human Prion Protein. AB - Prion diseases are fatal neurodegenerative disorders, which are characterized by the accumulation of misfolded prion protein (PrPSc) converted from a normal host cellular prion protein (PrPC). Experimental studies suggest that PrPC is enriched with alpha-helical structure, whereas PrPSc contains a high proportion of beta sheet. In this study, we report the impact of N-glycosylation and the membrane on the secondary structure stability utilizing extensive microsecond molecular dynamics simulations. Our results reveal that the HB (residues 173 to 194) C terminal fragment undergoes conformational changes and helix unfolding in the absence of membrane environments because of the competition between protein backbone intramolecular and protein-water intermolecular hydrogen bonds as well as its intrinsic instability originated from the amino acid sequence. This initiation of the unfolding process of PrPC leads to a subsequent increase in the length of the HB-HC loop (residues 195 to 199) that may trigger larger rigid body motions or further unfolding around this region. Continuous interactions between prion protein and the membrane not only constrain the protein conformation but also decrease the solvent accessibility of the backbone atoms, thereby stabilizing the secondary structure, which is enhanced by N-glycosylation via additional interactions between the N-glycans and the membrane surface. PMID- 26588569 TI - Contributions of Ca2+-Independent Thin Filament Activation to Cardiac Muscle Function. AB - Although Ca2+ is the principal regulator of contraction in striated muscle, in vitro evidence suggests that some actin-myosin interaction is still possible even in its absence. Whether this Ca2+-independent activation (CIA) occurs under physiological conditions remains unclear, as does its potential impact on the function of intact cardiac muscle. The purpose of this study was to investigate CIA using computational analysis. We added a structurally motivated representation of this phenomenon to an existing myofilament model, which allowed predictions of CIA-dependent muscle behavior. We found that a certain amount of CIA was essential for the model to reproduce reported effects of nonfunctional troponin C on myofilament force generation. Consequently, those data enabled estimation of DeltaGCIA, the energy barrier for activating a thin filament regulatory unit in the absence of Ca2+. Using this estimate of DeltaGCIA as a point of reference (~7 kJ mol(-1)), we examined its impact on various aspects of muscle function through additional simulations. CIA decreased the Hill coefficient of steady-state force while increasing myofilament Ca2+ sensitivity. At the same time, CIA had minimal effect on the rate of force redevelopment after slack/restretch. Simulations of twitch tension show that the presence of CIA increases peak tension while profoundly delaying relaxation. We tested the model's ability to represent perturbations to the Ca2+ regulatory mechanism by analyzing twitch records measured in transgenic mice expressing a cardiac troponin I mutation (R145G). The effects of the mutation on twitch dynamics were fully reproduced by a single parameter change, namely lowering DeltaGCIA by 2.3 kJ mol(-1) relative to its wild-type value. Our analyses suggest that CIA is present in cardiac muscle under normal conditions and that its modulation by gene mutations or other factors can alter both systolic and diastolic function. PMID- 26588570 TI - High Spatiotemporal-Resolution Magnetic Tweezers: Calibration and Applications for DNA Dynamics. AB - The observation of biological processes at the molecular scale in real time requires high spatial and temporal resolution. Magnetic tweezers are straightforward to implement, free of radiation or photodamage, and provide ample multiplexing capability, but their spatiotemporal resolution has lagged behind that of other single-molecule manipulation techniques, notably optical tweezers and AFM. Here, we present, to our knowledge, a new high-resolution magnetic tweezers apparatus. We systematically characterize the achievable spatiotemporal resolution for both incoherent and coherent light sources, different types and sizes of beads, and different types and lengths of tethered molecules. Using a bright coherent laser source for illumination and tracking at 6 kHz, we resolve 3 A steps with a 1 s period for surface-melted beads and 5 A steps with a 0.5 s period for double-stranded-dsDNA-tethered beads, in good agreement with a model of stochastic bead motion in the magnetic tweezers. We demonstrate how this instrument can be used to monitor the opening and closing of a DNA hairpin on millisecond timescales in real time, together with attendant changes in the hairpin dynamics upon the addition of deoxythymidine triphosphate. Our approach opens up the possibility of observing biological events at submillisecond timescales with subnanometer resolution using camera-based detection. PMID- 26588571 TI - Protein Polymerization into Fibrils from the Viewpoint of Nucleation Theory. AB - The assembly of various proteins into fibrillar aggregates is an important phenomenon with wide implications ranging from human disease to nanoscience. Using general kinetic results of nucleation theory, we analyze the polymerization of protein into linear or helical fibrils in the framework of the Oosawa-Kasai (OK) model. We show that while within the original OK model of linear polymerization the process does not involve nucleation, within a modified OK model it is nucleation-mediated. Expressions are derived for the size of the fibril nucleus, the work for fibril formation, the nucleation barrier, the equilibrium and stationary fibril size distributions, and the stationary fibril nucleation rate. Under otherwise equal conditions, this rate decreases considerably when the short (subnucleus) fibrils lose monomers much more frequently than the long (supernucleus) fibrils, a feature that should be born in mind when designing a strategy for stymying or stimulating fibril nucleation. The obtained dependence of the nucleation rate on the concentration of monomeric protein is convenient for experimental verification and for use in rate equations accounting for nucleation-mediated fibril formation. The analysis and the results obtained for linear fibrils are fully applicable to helical fibrils whose formation is describable by a simplified OK model. PMID- 26588572 TI - Bacterial Motility Reveals Unknown Molecular Organization. AB - The water solubility of lyotropic liquid crystals (LCs) makes them very attractive to study the behavior of biological microorganisms in an environment where local symmetry is broken (as often encountered in nature). Several recent studies have shown a dramatic change in the behavior of flagellated bacteria when swimming in solutions of the lyotropic LC disodium cromoglycate (DSCG). In this study, the movements of Escherichia coli bacteria in DSCG-water solutions of different concentrations are observed to improve our understanding of this phenomenon. In addition, the viscosity of DSCG aqueous solutions is measured as a function of concentration at room temperature. We also experimentally identify a previously undescribed isotropic pretransition zone where bacteria start sticking to each other and to surfaces. Simple estimations show that the unbalanced osmotic pressure induced depletion force might be responsible for this sticking phenomenon. An estimate of the bacteria propulsive force and the DSCG aggregates length (versus concentration) are calculated from the measured viscosity of the medium. All these quantities are found to undergo a strong increase in the pretransition zone, starting at a threshold concentration of 6+/-1 wt % DSCG that is well below the known isotropic-LC transition (~10 wt %). This study also shines light on the motility of flagellated bacteria in realistic environments, and it opens new avenues for interesting applications such as the use of motile microorganisms to probe the physical properties of their host or smart bandages that could guide bacteria out of wounds. PMID- 26588573 TI - Interpreting Heterogeneity in Response of Cells Expressing a Fluorescent Hydrogen Peroxide Biosensor. AB - Fluorescent, genetically encoded sensors of hydrogen peroxide have enabled visualization of perturbations to the intracellular level of this signaling molecule with subcellular and temporal resolution. Ratiometric sensors hold the additional promise of meaningful quantification of intracellular hydrogen peroxide levels as a function of time, a longstanding goal in the field of redox signaling. To date, studies that have connected the magnitudes of observed ratios with peroxide concentrations have either examined suspensions of cells or small numbers of adherent cells (~10). In this work, we examined the response of all cells in several microscopic fields of view to an identical perturbation and observed a striking degree of heterogeneity of fluorescence ratios from individual cells. The expression level of the probe and phase within the cell cycle were each examined as potential contributors to the observed heterogeneity. Higher ratiometric responses correlated with greater expression levels of the probe and phase in the cell cycle were also shown to influence the magnitude of response. To aid in the interpretation of experimental observations, we incorporated the reaction of the reduced probe with peroxide and the reactions of the oxidized probe with glutathione and glutaredoxin into a larger kinetic model of peroxide metabolism. The predictions of the kinetic model suggest possible explanations for the experimental observations. This work highlights the importance of a systems-level approach to understanding the output of genetically encoded sensors that function via redox reactions involving thiol and disulfide groups. PMID- 26588574 TI - Coupling Controls the Synchrony of Clock Cells in Development and Knockouts. AB - In mammals, a network of coupled neurons within the hypothalamus coordinates physiological rhythms with daily changes in the environment. In each neuron, delayed negative transcriptional feedbacks generate oscillations, albeit noisy and unreliable ones. Coupling mediated by diffusible neuropeptides lends precision and robustness to circadian rhythms. The double knockout of Cryptochrome Cry turns adult mice arrhythmic. But, remarkably, double knockout neonates continue to show robust oscillation much like wild-type neonates and appear to lose rhythmicity with development. We study quantitatively dispersed neurons and brain slices from wild-type and Cry double knockout mice to understand the links between single cell rhythmicity and intercellular coupling. We quantify oscillator properties of dispersed cells using nonlinear regression and study bifurcations diagrams of network models. We find that varying just three parameters-oscillator strength, strength of coupling, and timing of coupling-can reproduce experimentally observed features. In particular, modeling reveals that minor changes in timing of coupling can destroy synchronization as observed in adult slices from knockout mice. PMID- 26588575 TI - Diffusion Regulation in the Vitreous Humor. AB - The efficient treatment of many ocular diseases depends on the rapid diffusive distribution of solutes such as drugs or drug delivery vehicles through the vitreous humor. However, this multicomponent hydrogel possesses selective permeability properties, which allow for the diffusion of certain molecules and particles, whereas others are immobilized. In this study, we perform an interspecies comparison showing that the selective permeability properties of the vitreous are conserved across several mammalian species. We identify the polyanionic glycosaminoglycans hyaluronic acid and heparan sulfate as two key macromolecules that establish this selective permeability. We show that electrostatic interactions between the polyanionic macromolecules and diffusing solutes can be weakened by charge screening or enzymatic glycosaminoglycan digestion. Furthermore, molecule penetration into the vitreous is also charge dependent and only efficient as long as the net charge of the molecule does not exceed a certain threshold. PMID- 26588576 TI - Colocalization and Sequential Enzyme Activity in Aqueous Biphasic Systems: Experiments and Modeling. AB - Subcellular compartmentalization of biomolecules and their reactions is common in biology and provides a general strategy for improving and/or controlling kinetics in metabolic pathways that contain multiple sequential enzymes. Enzymes can be colocalized in multiprotein complexes, on scaffolds or inside subcellular organelles. Liquid organelles formed by intracellular phase coexistence could provide an additional means of sequential enzyme colocalization. Here we use experiment and computation to explore the kinetic consequences of sequential enzyme compartmentalization into model liquid organelles in a crowded polymer solution. Two proteins of the de novo purine biosynthesis pathway, ASL (adenylosuccinate lyase, Step 8) and ATIC (5-aminoimidazole-4-carboxamide ribonucleotide transformylase/inosine monophosphate cyclohydrolase, Steps 9 and 10), were studied in a polyethylene glycol/dextran aqueous two-phase system. Dextran-rich phase droplets served as model liquid compartments for enzyme colocalization. In this system, which lacks any specific binding interactions between the phase-forming polymers and the enzymes, we did not observe significant rate enhancements from colocalization for the overall reaction under our experimental conditions. The experimental results were used to adapt a mathematical model to quantitatively describe the kinetics. The mathematical model was then used to explore additional, experimentally inaccessible conditions to predict when increased local concentrations of enzymes and substrates can (or cannot) be expected to yield increased rates of product formation. Our findings indicate that colocalization within these simplified model liquid organelles can lead to enhanced metabolic rates under some conditions, but that very strong partitioning into the phase that serves as the compartment is necessary. In vivo, this could be provided by specific binding affinities between components of the liquid compartment and the molecules to be localized within it. PMID- 26588577 TI - Bacillus subtilis Bacteria Generate an Internal Mechanical Force within a Biofilm. AB - A key issue in understanding why biofilms are the most prevalent mode of bacterial life is the origin of the degree of resistance and protection that bacteria gain from self-organizing into biofilm communities. Our experiments suggest that their mechanical properties are a key factor. Experiments on pellicles, or floating biofilms, of Bacillus subtilis showed that while they are multiplying and secreting extracellular substances, bacteria create an internal force (associated with a -80+/-25 Pa stress) within the biofilms, similar to the forces that self-equilibrate and strengthen plants, organs, and some engineered buildings. Here, we found that this force, or stress, is associated with growth induced pressure. Our observations indicate that due to such forces, biofilms spread after any cut or ablation by up to 15-20% of their initial size. The force relaxes over very short timescales (tens of milliseconds). We conclude that this force helps bacteria to shape the biofilm, improve its mechanical resistance, and facilitate its invasion and self-repair. PMID- 26588578 TI - Model of Growth Cone Membrane Polarization via Microtubule Length Regulation. AB - We present a mathematical model of membrane polarization in growth cones. We proceed by coupling an active transport model of cytosolic proteins along a two dimensional microtubule (MT) network with a modified Dogterom-Leibler model of MT growth. In particular, we consider a Rac1-stathmin-MT pathway in which the growth and catastrophe rates of MTs are regulated by cytosolic stathmin, while the stathmin is regulated by Rac1 at the membrane. We use regular perturbation theory and numerical simulations to determine the steady-state stathmin concentration, the mean MT length distribution, and the resulting distribution of membrane-bound proteins. We thus show how a nonuniform Rac1 distribution on the membrane generates a polarized distribution of membrane proteins. The mean MT length distribution and hence the degree of membrane polarization are sensitive to the precise form of the Rac1 distribution and parameters such as the catastrophe promoting constant and tubulin association rate. This is a consequence of the fact that the lateral diffusion of stathmin tends to weaken the effects of Rac1 on the distribution of mean MT lengths. PMID- 26588579 TI - A correlation analysis between HDAC1 over-expression and clinical features of laryngeal squamous cell carcinoma. AB - CONCLUSION: HDAC1 may be a prognostic biomarker for LSCC malignant potency and a potent factor resulting in decreased sensitivity of LSCC in radiotherapy. OBJECTIVE: The aim of this study was to evaluate the correlation between histone deacetylase 1 (HDAC1) over-expression and clinical features in laryngeal squamous cell carcinoma (LSCC). METHODS: This study assessed the HDAC1 expressions in 90 formalin-fixed paraffin-embedded LSCC samples, 30 adjacent non-neoplastic tissues, and 30 laryngeal polyp tissues by immunohistochemistry (IHC). In addition, another 40 LSCC samples were collected that were divided into two groups after 3-month radiotherapy: the high radio-sensitive group (HRS) and low radio-sensitive group (LRS). Overall survival curves of all the LSCC patients were constructed by Kaplan-Meier method and long-rank test. RESULTS: All ninety samples were positively immunostained for HDAC1. The expression of HDAC1 was up regulated and significantly associated with T classification, lymph node metastases, tumor location and clinical stage. HDAC1 was mainly labeled in the epithelial cells of laryngeal polyp tissues and adjacent non-neoplastic tissues. In addition, the expression of HDAC1 was significantly higher in LRS than that in HRS. The positive rates for stage III-IV tumor were significantly higher than those for stage II. LSCC patients with HDAC1 over-expression and LRS presented a shorter 5-year overall survival rate. PMID- 26588580 TI - Editorial Comment: New Guidelines for Post-Cardiac Arrest Targeted Temperature Management. PMID- 26588581 TI - Evidence-Based Critical Care of Intracerebral Hemorrhage: An Overview. AB - Outcome of intracerebral hemorrhage (ICH) is still poor and siginificantly influenced by complications during the acute phase, so optimized neurocritical care is crucial. Vital parameters, neurological status and laboratory values of ICH-patient should be monitored very closely with special attention on blood pressure and intracranial pressure. Systolic blood pressure should be kept <140 mm Hg and intracranial pressure <20 mm Hg. Administration of hemostatic agents in spontaneous ICH without intake of anticoagulants is actually not recommended out of clinical trials. Neurosurgical treatment of ICH is still an individual decision. Patients with a higher level of consciousness may profit from an early operation. PMID- 26588582 TI - Surgical Craniotomy for Intracerebral Haemorrhage. AB - Craniotomy is probably indicated for patients with superficial spontaneous lobar supratentorial intracerebral haemorrhage (ICH) when the level of consciousness drops below 13 within the first 8 h of the onset of the haemorrhage. Once the level drops below 9, it is probably too late to consider craniotomy for these patients, so clinical vigilance is paramount. While this statement is only backed up by evidence that is moderately strong, meta-analysis of available data suggests that it is true in the rather limited number of patients with ICH. Meta analyses like this can often predict the results of future prospective randomised controlled trials a decade or more before the trials are completed and published. Countless such examples exist in the literature, as is the case for thrombolysis in patients with myocardial infarction in the last millennium: meta-analysis determined the efficacy more than a decade BEFORE the last trial (ISIS-2) confirmed the benefit of thrombolysis for myocardial infarction. Careful examination of the meta-analysis' Forest plots in this chapter will demonstrate why this statement is made at the outset. Other meta-analyses of surgery for ICH have also indicated that minimal interventional techniques using topical thrombolysis or endoscopy via burrholes or even twist drill aspiration may be particularly successful for the treatment of supratentorial ICH, especially when the clot is deep seated. Ongoing clinical trials (CLEAR III and MISTIE III) should confirm this in the fullness of time. There are 2 exceptions to these generalisations. First, based on trial evidence, aneurysmal ICH is best treated with surgery. Second, cerebellar ICH represents a special case because of the development of hydrocephalus, which may require expeditious drainage as the intracranial pressure rises. The cerebellar clot will then require evacuation, usually via posterior fossa craniectomy, rather than craniotomy. Technical advances suggest that image-guided surgery may improve the completeness of surgical evacuation and outcomes, regardless of which surgical technique is employed. PMID- 26588583 TI - Effects of Evodiamine on the Pharmacokinetics of Dapoxetine and Its Metabolite Desmethyl Dapoxetine in Rats. AB - The objective of this work was to investigate the effect of orally administered evodiamine on the pharmacokinetics of dapoxetine and its active metabolite desmethyl dapoxetine in rats. Twelve healthy male Sprague-Dawley rats were randomly divided into 2 groups: the control group (received oral 10 mg/kg dapoxetine alone) and the combination group (10 mg/kg dapoxetine orally co administered with 100 mg/kg evodiamine). The plasma concentration of dapoxetine and desmethyl dapoxetine were estimated by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), and different pharmacokinetic parameters were calculated using the Drug and Statistics 2.0 software. Compared to the control group, the pharmacokinetic parameter of t1/2, AUC(0-infinity) and Tmax of dapoxetine in combination group was significantly increased by 63.3% (p < 0.01), 44.8% (p < 0.01) and 50.4% (p < 0.01), respectively. Moreover, evodiamine had significantly decreased the pharmacokinetic parameter of t1/2 and AUC(0-infinity) of desmethyl dapoxetine. This study demonstrated that evodiamine inhibits the metabolism of dapoxetine. Henceforth, the pharmacodynamic influence of this interaction should be taken into consideration while prescribing dapoxetine to the patients already taking evodiamine. PMID- 26588584 TI - Caffeine Impact on Metabolic Syndrome Components Is Modulated by a CYP1A2 Variant. AB - Cultural, dietary, and lifestyle factors are the main modulators of type 2 diabetes mellitus (T2DM) disease risk. Coffee is one of the most popular worldwide beverages, and recent epidemiological studies have showed that coffee consumption is associated with a lower risk of T2DM. This study investigates the impact of coffee intake on T2DM risk and assesses the effect of CYP variants with caffeine exposures on T2DM. Data from 7,607 study subjects were analyzed by logistic regression models, among whom 3,290 GWAS data were available for CYP variants association studies using Plink analysis. These data suggest a protective relationship for women, but not for men; however, the results were not statistically significant in this dataset and there is a significant interaction in favor of women regarding heavy coffee consumption. The interaction between male gender and heavy coffee consumption becomes significant, thereby tending to cancel the protective effect of coffee for males. CYP rs2470890 allele 'C' increases the odds of T2DM by a factor of around 1.2 but decreases the odds of caffeine boosting T2DM of 1.7 by a factor of 0.77. rs2470890 showed an association with T2DM only when the interaction with coffee was considered, thereby setting an example of genetic activation by dietary changes associating with metabolic syndrome. PMID- 26588585 TI - Synthesis of Denosomin-Vitamin D3 Hybrids and Evaluation of Their Anti Alzheimer's Disease Activities. AB - As an extension of previously conducted studies on developing an anti-Alzheimer's disease agent, denosomin (1-deoxy-24-norsominone, an artificial inducer of neurite elongation), derivatives were designed and synthesized based on the hypothesis that our denosomin would exhibit axonal extension activity via a 1,25D(3)-membrane-associated, rapid response steroid-binding protein (1,25D(3) MARRS) pathway. The biological assay revealed that the hybridization of characteristic delta-lactone in denosomin and the triene moiety in VD(3) was effective to enhance the nerve re-extension activity in amyloid beta (Abeta) damaged neurons. PMID- 26588586 TI - Efficacy of Calcium Channel Blockers Versus Other Classes of Antihypertensive Medication in the Treatment of Hypertensive Patients With Previous Stroke and/or Coronary Artery Disease: A Systematic Review and Meta-Analysis. AB - Hypertensive patients, such as those with established coronary artery disease (CAD) or those who have suffered a stroke, are at increased risk of morbidity and mortality. This systematic literature review and meta-analysis assesses the long term effects of calcium channel blockers (CCBs) compared with other classes of antihypertensive medications on major cardiovascular (CV) outcomes in these high risk subgroups of hypertensive patients. Randomized, active controlled parallel group trials were included if they compared CCBs with alpha-blockers, beta blockers, angiotensin II receptor blockers, angiotensin-converting enzyme inhibitors, or diuretics, had a follow-up of >=6 months, and had assessments of blood pressure (BP) and CV events [all-cause death, CV death, major CV events (myocardial infarction, MI; congestive heart failure, CHF; stroke; and CV death), MI, stroke, or CHF] in patients with baseline systolic/diastolic BP >=140/>=90 mm Hg with either concomitant previous stroke and/or CAD. The final dataset included 19 publications reporting on 7 unique trials. In hypertensive patients with previous stroke, there was no difference between CCBs and comparators for any CV outcome. In those with CAD, there was no difference for all-cause death, CV death, major CV events, and MI for CCBs relative to comparators; however, a reduction in the risk of stroke and an increase in the risk of CHF were seen. For BP lowering, CCBs were at least as efficacious as comparators. The findings of our systematic review and analysis add to the body of evidence for the use of CCBs for the long-term treatment of hypertension in difficult-to-treat high CV risk populations. PMID- 26588587 TI - Prevalence of pediatric epilepsy in low-income rural Midwestern counties. AB - Epilepsy is one of the most common disabling neurological disorders, but significant gaps exist in our knowledge about childhood epilepsy in rural populations. The present study assessed the prevalence of pediatric epilepsy in nine low-income rural counties in the Midwestern United States overall and by gender, age, etiology, seizure type, and syndrome. Multiple sources of case identification were used, including medical records, schools, community agencies, and family interviews. The prevalence of active epilepsy was 5.0/1000. Prevalence was 5.1/1000 in males and 5.0/1000 in females. Differences by age group and gender were not statistically significant. Future research should focus on methods of increasing study participation in rural communities, particularly those in which research studies are rare. PMID- 26588588 TI - A prospective study of the modified Atkins diet for adults with idiopathic generalized epilepsy. AB - For children with pharmacoresistant epilepsy, the ketogenic diet is an established treatment option worldwide. However, for adults, this treatment is less frequently offered, and its efficacy less well-documented. The aim of this study was to examine efficacy and tolerability of such a diet as an adjuvant therapy to antiepileptic drugs for adult patients with pharmacoresistant generalized epilepsy. Thirteen patients (12 women) aged 16-57 years were included prospectively. They were treated with a modified Atkins diet for 12 weeks. Nine of the 13 participants had juvenile myoclonic epilepsy (JME), two had childhood absence epilepsy, one had Jeavons syndrome, and one had generalized epilepsy of unknown type. Six participants, all with JME, completed the 12-week study period. Among these six, four had >50% seizure reduction. Their seizure severity, using the revised Liverpool Seizure Severity Scale, was reduced by 1, 5, 57.5, and 70 points, respectively (scale: 1-100 points). In three of these four responders, quality of life, assessed by QOLIE-89, increased more than 20 points (scale: 0 100 points). Mean reduction of body weight after 12 weeks on diet was 6.5 (range: 4.3-8.1) kg. Lack of motivation, poor compliance, and seizure aggravation were the main reasons for premature termination of the diet. Apart from one patient who developed gallstones when ending the treatment after 10 months, no adverse effects were noted. In conclusion, using a modified Atkins diet for 12 weeks led to a clinically relevant reduction of seizure frequency in four of thirteen adult patients with pharmacoresistant generalized epilepsy. All responders were diagnosed with JME. In three of the four, the benefits of diet were so considerable that they chose to continue the treatment. PMID- 26588589 TI - Electrical conductance and structure of copper atomic junctions in the presence of water molecules. AB - We have investigated Cu atomic contacts in the presence of H2O both experimentally and theoretically. The conductance measurements showed the formation of H2O/Cu junctions with a fixed conductance value of around 0.1 G0 (G0 = 2e(2)/h). These structures were found to be stable and could be stretched over 0.5 nm, indicating the formation of an atomic or molecular chain. In agreement with the experimental findings, theoretical calculations revealed that the conductance of H2O/Cu junctions decreases in stages as the junction is stretched, with the formation of a H2O/Cu atomic chain with a conductance of ca. 0.1 G0 prior to junction rupture. Conversely, in the absence of H2O, the conductance of the Cu junction remains close to 1 G0 prior to the junction rupture and abrupt conductance drop. PMID- 26588590 TI - Incidence and Characteristics of Atypical Femoral Fractures: Clinical and Geometrical Data. AB - Despite the multitude of studies published on atypical femoral fractures (AFFs), a profile for patients at risk does not exist. This study aimed first at estimating AFF incidence over a 19-month-period in Quebec City using the ASBMR Task force criteria to define AFF. The medical records of patients hospitalized for hip or femoral fracture between June 1, 2009, and December 31, 2010, were reviewed. Thirty-six cases of atypical fractures were identified during the 19 month period, representing an AFF incidence of 7.0 (range, 4.7 to 9.3) cases per 100,000 person-years. In the second part of the study, data regarding the characteristics suspected of increasing the risks of AFF were collected from medical and pharmacological records, proximal femur radiographs, and patient interviews. The data regarding each patient with an AFF during years 2008-2011 were compared to two controls with a hip or femoral fragility fracture or a traumatic fracture, paired for age and sex. Twenty patients with AFF were added to the 36 patients with AFF selected in the first part, thereby 56 patients with AFF were investigated. The association between the occurrence of AFF and bisphosphonates (BPs) use was proven statistically significant in multivariate analysis, odds ratio (OR) = 10.39 (95% CI, 2.22 to 48.58; p = 0.0029). Compared to controls, patients with AFF had excessive femoral offset (43.1 mm versus 38.3 mm, p = 0.0007), proximal femoral neck angle in varus (128.9 degrees versus 134.0 degrees, p < 0.0001), and had greater proximal cortical thickness. This retrospective study confirms the low incidence of AFF, confirms its significant association with exposure to BPs, and reveals the possible contribution of proximal femoral geometry in AFF occurrence. PMID- 26588591 TI - The effect of time to release of an obstructing synthetic mid-urethral sling on repeat surgery for stress urinary incontinence. AB - AIMS: The primary objectives were to describe the rate of repeat surgery for stress urinary incontinence (SUI) after release of an obstructing synthetic mid urethral sling (MUS) and to evaluate the effect of time from sling placement to sling release on repeat surgery rates. The secondary objective was to assess rates of recurrent and persistent SUI. METHODS: This is a retrospective review of women who underwent synthetic MUS release (incision or excision of segment of sling) from 2005-2013. SUI rates and repeat surgery were ascertained by patient report and urinary distress inventory (UDI-6) questionnaire responses. Data analysis included descriptive statistics and multivariable logistic regression analysis. RESULTS: 107 patients were included. Median time to sling release was 22 months (IQR 5-49 months). 43.2% were transobturator slings. 15/107 patients (14%) underwent repeat surgery for SUI. On multivariable analysis, women were significantly less likely to undergo repeat surgery for SUI when sling release was performed >24 months after initial sling surgery (OR 0.12, 95% CI 0.02-0.85, P = 0.03) compared to release within 3 months. 49% and 77% reported recurrent and persistent SUI after sling release, of which 83% were significantly bothered. CONCLUSION: The repeat surgery rate for SUI was 14%. The rate of recurrent SUI was 49%. Most of these women were significantly bothered. On multivariate analysis, longer interval to sling release was associated with decreased likelihood of repeat surgery for SUI. The reason for a low repeat surgery rate for SUI despite a high rate of bothersome SUI should be explored in future studies. Neurourol. Urodynam. 36:349-353, 2017. (c) 2015 Wiley Periodicals, Inc. PMID- 26588592 TI - Benefits and Risks of Sharing Genomic Information. PMID- 26588593 TI - The design-by-treatment interaction model: a unifying framework for modelling loop inconsistency in network meta-analysis. AB - In this note, we clarify and prove the claim made Higgins et al. () that the design-by-treatment interaction model contains all possible loop inconsistency models. This claim provides a strong argument for using the design-by-treatment interaction model to describe loop inconsistencies in network meta-analysis. (c) 2015 The Authors. Research Synthesis Methods published by John Wiley & Sons, Ltd. PMID- 26588594 TI - Relationships between Lead Halide Perovskite Thin-Film Fabrication, Morphology, and Performance in Solar Cells. AB - Solution-processed lead halide perovskite thin-film solar cells have achieved power conversion efficiencies comparable to those obtained with several commercial photovoltaic technologies in a remarkably short period of time. This rapid rise in device efficiency is largely the result of the development of fabrication protocols capable of producing continuous, smooth perovskite films with micrometer-sized grains. Further developments in film fabrication and morphological control are necessary, however, in order for perovskite solar cells to reliably and reproducibly approach their thermodynamic efficiency limit. This Perspective discusses the fabrication of lead halide perovskite thin films, while highlighting the processing-property-performance relationships that have emerged from the literature, and from this knowledge, suggests future research directions. PMID- 26588596 TI - Late Cardiac Allograft Failure, Cardiac Allograft Vasculopathy, and Antibody Mediated Rejection: Untangling Some Knots? PMID- 26588595 TI - Cell Therapy Strategies to Combat Immunosenescence. AB - Declining function of the immune system, termed "immunosenescence," leads to a higher incidence of infection, cancer, and autoimmune disease related mortalities in the elderly population. (1) Increasing interest in the field of immunosenescence is well-timed, as 20% of the United States population is expected to surpass the age of 65 by the year 2030. (2) Our current understanding of immunosenescence involves a shift in function of both adaptive and innate immune cells, leading to a reduced capacity to recognize new antigens and widespread chronic inflammation. The present review focuses on changes that occur in haematopoietic stem cells, macrophages, and T-cells using knowledge gained from both rodent and human studies. The review will discuss emerging strategies to combat immunosenescence, focusing on cellular and genetic therapies, including bone marrow transplantation and genetic reprogramming. A better understanding of the mechanisms and implications of immunosenescence will be necessary to combat age-related mortalities in the future. PMID- 26588597 TI - Classification and toxicity mechanisms of novel flame retardants (NFRs) based on whole genome expression profiling. AB - Recently some novel alternative flame retardants (NFRs), which have been widely applied to meet demands for mandated flame retardation of products, have been detected in various matrices of the environment. However, knowledge on toxic effects and associated molecular mechanisms of these chemicals was limited. Here, toxic mechanisms of action of six NFRs, bis (2-ethylhexyl) phosphate (BEHP), chlorendic acid (Het acid), 2,2-bis (bromomethyl)-1,3-propanediol (BMP), tris (2 butoxyethyl) phosphate (TBEP), triethyl phosphate (TEP), tributyl phosphate (TBP) were investigated by use of a library containing ~1820 modified green fluorescent protein (GFP) expressing promoter reporter vectors constructed from Escherichia coli K12(E.coli). BEHP, Het acid, BMP, TBEP, TEP, TBP inhibited growth of E. coli with 4 h 10%-inhibition concentrations of 53.0-3102.3 MUM. A total of 119, 44, 26, 131, 62, 103 genes out of 336 genes selected during preliminary screening were significantly altered with fold-changes greater than 1.5 by BEHP, Het acid, BMP, TBEP, TEP and TBP, respectively. GO analyses of responsive genes suggested that RNA and primary metabolism process were involved in molecular mechanisms of toxicity. Chemical clustering based on expression of 62 multi-responsive genes showed that BEHP, TBP and TBEP were grouped together, which is consistent with similarity of their chemical structures, especially for BEHP and TBP. Clustering by molecular descriptors and molecular activity by use of the multivariate classification system ToxCast was consistent with that by profiles of multi responsive genes. The results of this study demonstrated the utility of the E. coli, whole-cell assay for determining mechanisms of toxic action of chemicals. PMID- 26588598 TI - Does a Healing Procedure Referring to Theta Rhythms Also Generate Theta Rhythms in the Brain? AB - BACKGROUND/OBJECTIVES: ThetaHealing(r) (Vianna Stibal, Kalispell, MT) is a spiritual healing method in which the practitioner and client engage in joint meditations during several healing sessions. It is claimed that these meditation periods are characterized by a "theta state" in which the presence of theta-waves in the electroencephalograph (EEG) frequency spectrum of both the healer and the client is supposed. This study sought to test this hypothesis as well as the presence of synchronicities in the two EEGs. METHODS: Measurements were obtained with a dual EEG system with 2 * 32 channels, allowing for simultaneous EEG measurements of healer and client. Ten healers and 10 clients performed 10 ThetaHealing sessions while the EEG was measured. RESULTS: Theta frequency band did not increase in healers or in clients. Rather, the contrary was found, with a significant decrease in theta-2 band during healing in healers. Small correlations were seen between the Fourier amplitudes of healer and client in the theta-2 band, as well as small phase synchronicities in theta frequencies. CONCLUSION: The hypothesis that ThetaHealing is associated with an enhanced generation of theta frequencies in the brain could not be confirmed. This finding makes no claim about whether ThetaHealing is beneficial from a clinical perspective. PMID- 26588599 TI - Three-Year Outcome of Fixed Partial Rehabilitations Supported by Implants Inserted with Flap or Flapless Surgical Techniques. AB - PURPOSE: The aim of this prospective clinical study was to evaluate the 3-year outcome of fixed partial prostheses supported by implants with immediate provisionalization without occlusal contacts inserted in predominantly soft bone with flap and flapless protocols. MATERIALS AND METHODS: Forty-one patients partially rehabilitated with 72 NobelSpeedy implants (51 maxillary; 21 mandibular) were consecutively included and treated with a flapless surgical protocol (n = 20 patients; 32 implants) and flapped surgical protocol (n = 21 patients; 40 implants). Primary outcome measure was implant survival; secondary outcome measures were marginal bone resorption (comparing the bone levels at 1 and 3 years with baseline) and the incidence of biological, mechanical, and esthetic complications. Survival was computed through life tables; descriptive statistics were applied to the remaining variables of interest. RESULTS: Eight patients with eight implants dropped out of the study. One implant failed in one patient (flapless group) giving an overall cumulative survival rate (CSR) of 98.6%. No failures were noted with the flapped protocol (CSR 100%), while for the implants placed with the flapless surgical technique, a 96.9% CSR was registered. The overall average marginal bone resorption at 3 years was 1.37 mm (SD = 0.94 mm), with 1.14 mm (SD = 0.49 mm) and 1.60 mm (SD = 1.22 mm) for the flap and flapless groups, respectively. Mechanical complications occurred in nine patients (n = 5 patients in the flapless group; n = 4 patients in the flap group). Implant infection was registered in three implants and three patients (flapless group), who exhibited inadequate oral hygiene levels. CONCLUSIONS: Partial edentulism rehabilitation through immediate provisionalization fixed prosthesis supported by dental implants inserted through flap or flapless surgical techniques in areas of predominantly soft bone was viable at 3 years of follow-up. The limitations and risks of the "free-hand" method in flapless surgery should be considered when planning implant-supported fixed prosthetic reconstructions. PMID- 26588600 TI - Organization of the sleep-related neural systems in the brain of the river hippopotamus (Hippopotamus amphibius): A most unusual cetartiodactyl species. AB - This study provides the first systematic analysis of the nuclear organization of the neural systems related to sleep and wake in the basal forebrain, diencephalon, midbrain, and pons of the river hippopotamus, one of the closest extant terrestrial relatives of the cetaceans. All nuclei involved in sleep regulation and control found in other mammals, including cetaceans, were present in the river hippopotamus, with no specific nuclei being absent, but novel features of the cholinergic system, including novel nuclei, were present. This qualitative similarity relates to the cholinergic, noradrenergic, serotonergic, and orexinergic systems and is extended to the gamma-aminobutyric acid (GABA)ergic elements of these nuclei. Quantitative analysis reveals that the numbers of pontine cholinergic (259,578) and noradrenergic (127,752) neurons, and hypothalamic orexinergic neurons (68,398) are markedly higher than in other large brained mammals. These features, along with novel cholinergic nuclei in the intralaminar nuclei of the dorsal thalamus and the ventral tegmental area of the midbrain, as well as a major expansion of the hypothalamic cholinergic nuclei and a large laterodorsal tegmental nucleus of the pons that has both parvocellular and magnocellular cholinergic neurons, indicates an unusual sleep phenomenology for the hippopotamus. Our observations indicate that the hippopotamus is likely to be a bihemispheric sleeper that expresses REM sleep. The novel features of the cholinergic system suggest the presence of an undescribed sleep state in the hippopotamus, as well as the possibility that this animal could, more rapidly than other mammals, switch cortical electroencephalographic activity from one state to another. J. Comp. Neurol. 524:2036-2058, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26588601 TI - Refinement of the Sugar-Phosphate Backbone Torsion Beta for AMBER Force Fields Improves the Description of Z- and B-DNA. AB - Z-DNA duplexes are a particularly complicated test case for current force fields. We performed a set of explicit solvent molecular dynamics (MD) simulations with various AMBER force field parametrizations including our recent refinements of the epsilon/zeta and glycosidic torsions. None of these force fields described the ZI/ZII and other backbone substates correctly, and all of them underpredicted the population of the important ZI substate. We show that this underprediction can be attributed to an inaccurate potential for the sugar-phosphate backbone torsion angle beta. We suggest a refinement of this potential, beta(OL1), which was derived using our recently introduced methodology that includes conformation dependent solvation effects. The new potential significantly increases the stability of the dominant ZI backbone substate and improves the overall description of the Z-DNA backbone. It also has a positive (albeit small) impact on another important DNA form, the antiparallel guanine quadruplex (G-DNA), and improves the description of the canonical B-DNA backbone by increasing the population of BII backbone substates, providing a better agreement with experiment. We recommend using beta(OL1) in combination with our previously introduced corrections, epsilonzeta(OL1) and chi(OL4), (the combination being named OL15) as a possible alternative to the current beta torsion potential for more accurate modeling of nucleic acids. PMID- 26588602 TI - Disturbance of time orientation, attention, and verbal memory in amnesic patients with confabulation. AB - Confabulation is often observed in amnesic patients after brain damage. However, evidence regarding the relationship between confabulation and other neuropsychological functions is scarce. In addition, previous studies have proposed two possibilities of the relationship between confabulation and false memory, in which patients with confabulation are likely to retrieve false memories, or confabulations are relatively independent of false memories. The present study investigated how confabulation is related to various cognitive functions, including orientation, attention, frontal lobe function, memory, and mental status, and to false memories, as assessed by the Deese-Roediger-Mcdermott (DRM) paradigm. Patients with organic amnesia participated, and confabulations were evaluated using the Confabulation Battery. Amnestic patients were classified into two groups: confabulating (CP) and nonconfabulating patients (NCP). The CP group was significantly impaired in time orientation, attention, and verbal memory, compared to the NCP group and age-matched healthy controls (HC). Results of the DRM paradigm revealed no significant difference in false memory retrieval induced by critical lures across CP, NCP, and HC groups. Confabulating responses in organic amnesia could be in part induced by disturbance of time consciousness and attention control in severe impairment of verbal memories, and confabulation and false memory could be modulated by different cognitive systems. PMID- 26588603 TI - Can Small Chemical Modifications of Natural Pan-inhibitors Modulate the Biological Selectivity? The Case of Curcumin Prenylated Derivatives Acting as HDAC or mPGES-1 Inhibitors. AB - Curcumin, or diferuloylmethane, a polyphenolic molecule isolated from the rhizome of Curcuma longa, is reported to modulate multiple molecular targets involved in cancer and inflammatory processes. On the basis of its pan-inhibitory characteristics, here we show that simple chemical modifications of the curcumin scaffold can regulate its biological selectivity. In particular, the curcumin scaffold was modified with three types of substituents at positions C-1, C-8, and/or C-8' [C5 (isopentenyl, 5-8), C10 (geranyl, 9-12), and C15 (farnesyl, 13, 14)] in order to make these molecules more selective than the parent compound toward two specific targets: histone deacetylase (HDAC) and microsomal prostaglandin E2 synthase-1 (mPGES-1). From combined in silico and in vitro analyses, three selective inhibitors by proper substitution at position 8 were revealed. Compound 13 has improved HDAC inhibitory activity and selectivity with respect to the parent compound, while 5 and 9 block the mPGES-1 enzyme. We hypothesize about the covalent interaction of curcumin, 5, and 9 with the mPGES-1 binding site. PMID- 26588604 TI - Process development in the QbD paradigm: Role of process integration in process optimization for production of biotherapeutics. AB - Biotherapeutics have become the focus of the pharmaceutical industry due to their proven effectiveness in managing complex diseases. Downstream processes of these molecules consist of several orthogonal, high resolution unit operations designed so as to be able to separate variants having very similar physicochemical properties. Typical process development involves optimization of the individual unit operations based on Quality by Design principles in order to define the design space within which the process can deliver product that meets the predefined specifications. However, limited efforts are dedicated to understanding the interactions between the unit operations. This paper aims to showcase the importance of understanding these interactions and thereby arrive at operating conditions that are optimal for the overall process. It is demonstrated that these are not necessarily same as those obtained from optimization of the individual unit operations. Purification of Granulocyte Colony Stimulating Factor (G-CSF), a biotherapeutic expressed in E. coli., has been used as a case study. It is evident that the suggested approach results in not only higher yield (91.5 vs. 86.4) but also improved product quality (% RP-HPLC purity of 98.3 vs. 97.5) and process robustness. We think that this paper is very relevant to the present times when the biotech industry is in the midst of implementing Quality by Design towards process development. (c) 2015 American Institute of Chemical Engineers Biotechnol. Prog., 32:355-362, 2016. PMID- 26588605 TI - Influence of soil texture on nutrients and potentially hazardous elements in Eremanthus erythropappus. AB - Understanding the factors that control uptake rates and allocation of chemical elements among plant organs is a fundamental prerequisite to improve phytostabilization techniques of hazardous elements in contaminated areas. The present study shows evidence that different substrate textures (coarse and fine laterite) do not significantly change the partitioning of root and shoot dry biomass and with few exceptions, do not significantly affect the final average concentration of elements in Eremanthus erythropappus, but change the root:shoot allocation of both essential nutrients and elements potentially toxic to biota. Growth on coarse laterite resulted in significant higher K (30%), Mg (34%), P (25%), S (32%), Cu (58%), and Na (43%) concentrations in roots and lower Cd concentration (29%). In shoots, coarse laterite led to reduction in K, Fe, Al, and Cr and increase in Na and Sr concentrations. Changes in element allocation could be, in part, a result of differences in the water availability of substrates. Matric potential in coarse laterite was significantly lower in at least 47% of the days analyzed throughout the year. Changes in element phytoextraction or phytostabilization potential could influence the efficiency of rehabilitation projects in areas degraded by mining activities. PMID- 26588607 TI - The Cover Page. PMID- 26588606 TI - Changes in the expression profiles of claudins during gonocyte differentiation and in seminomas. AB - Testicular germ cell tumors (TGCTs) are the most common type of cancer in young men and their incidence has been steadily increasing for the past decades. TGCTs and their precursor carcinoma in situ (CIS) are thought to arise from the deficient differentiation of gonocytes, precursors of spermatogonial stem cells. However, the mechanisms relating failed gonocyte differentiation to CIS formation remain unknown. The goal of this study was to uncover genes regulated during gonocyte development that would show abnormal patterns of expression in testicular tumors, as prospective links between failed gonocyte development and TGCT. To identify common gene and protein signatures between gonocytes and seminomas, we first performed gene expression analyses of transitional rat gonocytes, spermatogonia, human normal testicular, and TGCT specimens. Gene expression arrays, pathway analysis, and quantitative real-time PCR analysis identified cell adhesion molecules as a functional gene category including genes downregulated during gonocyte differentiation and highly expressed in seminomas. In particular, the mRNA and protein expressions of claudins 6 and 7 were found to decrease during gonocyte transition to spermatogonia, and to be abnormally elevated in seminomas. The dynamic changes in these genes suggest that they may play important physiological roles during gonocyte development. Moreover, our findings support the idea that TGCTs arise from a disruption of gonocyte differentiation, and position claudins as interesting genes to further study in relation to testicular cancer. PMID- 26588608 TI - Is Clinical Neurology Dead? PMID- 26588609 TI - Cheaper may be safer in migraine. PMID- 26588610 TI - Multiple sclerosis-Indian perspective. PMID- 26588611 TI - Unruptured intracranial aneurysms. PMID- 26588612 TI - Endoscopic keyhole technique for anterior circulation aneurysms: Present status. PMID- 26588613 TI - Dural venous sinus thrombosis after head injury. PMID- 26588614 TI - Trigeminal neuralgia: Centuries of pain and the era of minimally invasive pain relief. PMID- 26588615 TI - Trigeminal neuralgia: Therapeutic options. PMID- 26588616 TI - Stereotactic radiosurgery for intracranial arteriovenous malformations: A review. AB - Stereotactic radiosurgery (SRS) has proven to be an effective strategy in the management of intracranial arteriovenous malformations (AVMs) in children and adults over the past three decades. Its application has resulted in lowering the morbidity and mortality associated with treatment of deep-seated AVMs. SRS has been used as a primary modality of therapy as well as in conjunction with embolization and microsurgery in the management of AVMs. The obliteration rate after SRS has been reported to range from 35% to 92%. Smaller AVMs receiving higher marginal doses have obliteration rates of 70% and more. The median follow up reported in most series is approximately 36-40 months. The median time to obliteration has been reported to be approximately 24-36 months in most series. Radiation-induced neurological complications have been reported in less than 10% of patients, with a 1.5%-6% risk of developing a new permanent neurological deficit. The bleeding rate during the latency to obliteration has been reported to be approximately 5%. This review describes the experience reported in literature with respect to the indications, dosage, factors affecting obliteration rate of AVMs, and complications after SRS. PMID- 26588617 TI - Treatment of unruptured intracranial aneurysms-Current perspective. AB - Unruptured intracranial aneurysms (UIAs) present a unique challenge due to the lack of a clear understanding of their natural history and outcome. As the treatment of UIAs is aimed at preventing the possibility of rupture, the immediate risk of treatment must be weighed against the risk of rupture in the future. As such, no specific guidelines exist for a large proportion of UIAs, and treatment is currently individualized. It is also of paramount importance that the physicians be aware of the recent advances in the therapy of UIAs. The present article focuses on the recent advances in the understanding of UIAs. PMID- 26588618 TI - The effect of zolmitriptan on cardiac autonomic modulation in patients with migraine: A double-blind, placebo-controlled, crossover study. AB - BACKGROUND: Triptans, which activate 5-hydroxytryptamine (5-HT)-1B/1D receptors in cerebral arteries, are very effective in aborting attacks of migraine. Although activation of 5-HT-1B/1D receptors diminishes the secretion of noradrenaline from cardiac sympathetic nerves, some studies report that they may cause chest discomfort, myocardial infarction and arrhythmias due to coronary vasospasm. The effect of zolmitriptan on cardiac autonomic modulation has not been evaluated in migraineurs. SUBJECTS AND METHODS: Ten patients with migraine (nine women, mean age 33 +/- 4 years) were crossover randomized to 2.5 mg zolmitriptan or identical placebo at least 5 days apart. Both time domain parameters (the mean R-R interval, the standard deviation of RR interval [SDNN], and the root mean square of successive R-R interval differences) and frequency domain parameters (low frequency [LF], high frequency [HF], and LF/HF ratio) of heart rate variability (HRV) were obtained during supine position, controlled respiration and handgrip exercise before and 2 h after zolmitriptan or placebo administration. RESULTS: Baseline HRV parameters were similar for each occasion. Single dose zolmitriptan administration did not affect both time and frequency domain HRV parameters compared with the placebo. CONCLUSIONS: A single dose, 2.5 mg oral zolmitriptan administration did not change sympathetic and parasympathetic reactivity and sympathovagal balance in migraineurs. PMID- 26588619 TI - Natural history of multiple sclerosis from the Indian perspective: Experience from a tertiary care hospital. AB - CONTEXT: Multiple sclerosis (MS) has a spectrum of heterogeneity, as seen in western and eastern hemispheres, in the clinical features, topography of involvement and differences in natural history. AIM: To study the clinical spectrum, imaging, and electrophysiological as well as cerebrospinal fluid (CSF) characteristics and correlate them with outcome. SETTINGS AND DESIGN: Retrospective analysis of MS patients during a period of 20 years. SUBJECTS AND METHODS: Cases were selected according to recent McDonald's criteria (2010), They were managed in the Department of Neurology, Christian Medical College, Vellore. STATISTICAL ANALYSIS USED: Chi-square and Fisher's exact tests were used for categorical variables. Multiple binary logistic regressions were done to assess significance. Kaplan-Meier curves were drawn to estimate the time to irreversible disability. RESULTS: A total of 157 patients with female preponderance (55%) were included. The inter quartile range duration of follow-up was 9.1 (8.2, 11) years for 114 patients, who were included for final outcome analysis. Relapsing remitting MS (RRMS) (54.1%) was the most common type of MS seen. RRMS had a significantly better outcome (odds ratio: 0.12, 95% confidence interval: 0.02 0.57, P = 0.008) compared to progressive form of MS (primary progressive, secondary progressive). The Expanded Disability Status Scale score of patients at presentation and at final follow-up was 4.4 +/- 1.31 and 4.1 +/- 2.31, respectively. During the first presentation, polysymptomatic manifestations like motor and sphincteric involvement, incomplete recovery from the first attack; and, during the disease course, bowel, bladder, cerebellar and pyramidal affliction, predicted a worse outcome. CONCLUSION: A high incidence of optico spinal presentation, predominance of RRMS and a low yield on cerebrospinal fluid (CSF) studies are the major findings of our study. A notable feature was the analysis of prognostic markers of disability. PMID- 26588620 TI - Endoscopic controlled clipping of anterior circulation aneurysms via keyhole approach: Our initial experience. AB - INTRODUCTION: Surgical clipping is the most definite treatment for intracranial aneurysms. Its aim is to achieve complete aneurysmal occlusion without compromising the lumen of a parent vessel or perforators, and with minimal brain tissue trauma. OBJECTIVE: To evaluate the role of endoscopic controlled keyhole approach in clipping of anterior circulation aneurysms. MATERIALS AND METHODS: In this retrospective study, all consecutive patients undergoing endoscopic controlled clipping via the keyhole approach by the senior author during the last 1 year were included. The cases in which a microscope was used at any stage of surgery were excluded. RESULTS: Fourteen patients with anterior circulation aneurysms underwent clipping via the endoscopic keyhole approach (supraorbital and mini-pterional). Seven patients had anterior communicating (ACom) artery aneurysms, four had middle cerebral artery (MCA) bifurcation aneurysms, two had internal carotid artery bifurcation aneurysms, and one had a posterior communicating artery aneurysm. Ten patients presented with subarachnoid hemorrhage (Hunt and Hess grade I in 6 and grade II in 4 patients), whereas the remaining four were incidentally detected. The pre-clipping dissection as well as the clipping were successfully performed endoscopically in all patients. The post clipping inspection revealed inclusion of a perforator within the clip blades in 2 patients (ACom and MCA bifurcation) that required clip readjustment. There was no residual neck/incompletely clipped aneurysm detected on post-clipping inspection. There was no morbidity directly attributable to the use of keyhole approach or the endoscope. CONCLUSION: Endoscopic keyhole approach for intracranial aneurysms combines the advantages of both keyhole approach and endoscopy. Endoscopic visualization can help to reduce chances of an incompletely clipped aneurysms/residual neck and the risk of parent vessel/perforator occlusion. However, the use of an endoscope in narrow corridors with space constraints has a learning curve that can be overcome by practicing on cadavers and initially performing several simple endoscopic procedures. PMID- 26588621 TI - Risk factors and early diagnosis of cerebral venous sinus occlusion secondary to traumatic brain injury. AB - OBJECTIVE: This study was designed to investigate the risk factors of, and the strategy for early diagnosis of cerebral venous sinus occlusion (CVSO) secondary to traumatic brain injury. MATERIALS AND METHODS: The clinical data of 240 consecutive patients were analyzed retrospectively. The clinical symptoms were observed and imaging was carried out. The risk factors of CVSO were evaluated with logistic regression analysis. Early diagnosis of CVSO was established based on the clinical and imaging features. RESULTS: Forty patients were diagnosed to be having CVSO according to the findings of computerized tomographic venogram (CTV) and magnetic resonance venogram (MRV). They were classified into three sub types (thrombosis occlusion type, compression type, and mixed type). A skull fracture crossing the sinus (odds ratio [OR] =8.026; 95% confidence interval [CI]: 3.107-20.734) and an epidural hematoma crossing the sinus (OR = 3.062; 95% CI: 1.355-6.921) were risk factors associated with CVSO, and the former played a more significant role. The female gender (OR = 0.306; 95% CI: 1.715-61.943) was the risk factor for the thrombosis occlusion type of CVSO. An epidural hematoma crossing the sinus (OR = 5.653; 95% CI: 1.767-18.084) was the risk factor of the compression type of CVSO. The past medical history of deep vein thrombosis (DVT) (OR = 11.276; 95% CI: 1.315-96.664) combined with a skull fracture and epidural hematoma crossing the sinus were risk factors for the mixed type of CVSO. CONCLUSIONS: Paying close attention to the past medical history of DVT, skull fracture, and the imaging finding of an epidural hematoma that crosses the sinus are necessary for the early diagnosis of CVSO. CTV and MRV help in making an early diagnosis of CVSO. PMID- 26588622 TI - Percutaneous retrogasserian glycerol rhizotomy for trigeminal neuralgia: A simple, safe, cost-effective procedure. AB - OBJECTIVE: Trigeminal neuralgia (TN) is a condition that has been studied over decades and whose pathogenesis has still not been well defined. Various open and minimally invasive procedures are in vogue for the treatment of intractable TN. All these procedures have their complications and recurrence rates. Percutaneous retrogasserian glycerol rhizotomy (PRGR) is one of the minimally invasive procedures that have been popular for quite a long time. MATERIAL AND METHODS: This paper is a prospective study analyzing the results of 93 patients with refractory TN who were treated with PRGR. RESULTS: There was an immediate pain relief in 96.8% of patients and long-term pain relief in 89.4% of patients, with a mean follow-up duration of 18.8 months. Recurrence of pain was seen in 10.4% of patients. CONCLUSIONS: The PRGR is a simple, safe, cost-effective procedure without any need for expensive equipment and with a good outcome that is compared to the other relatively more expensive open and minimally invasive procedures. PMID- 26588623 TI - Four-quadrant osteoplastic decompressive craniotomy: A novel technique for refractory intracranial hypertension - A pilot study. AB - BACKGROUND: Decompressive craniectomy (DC) with duroplasty is the gold standard for refractory intracranial hypertension despite paucity of randomized controlled trials. There are several morbidities associated with DC of which the persistence of bony defect is of paramount importance. Studies have shown that many of the morbidities associated with DC get reversed following replacement of the bone flap. AIM: To design a novel technique for control of refractory intracranial pressure (ICP), as well as to study its safety and efficacy compared to the conventional DC technique. MATERIAL AND METHODS: We conducted a prospective, comparative, observational pilot study comparing four-quadrant osteoplastic decompressive craniotomy (FoQOsD) with conventional DC. The demographic features, postoperative variables such as operating time, number of days of intensive care unit (ICU) stay and survival, as well as radiographic variables such as change in the midline shift (MLS) and expansion of the compressed brain were analyzed using relevant statistical tests. RESULTS: Twenty patients were selected and grouped into two groups of 10 patients each. The male: female ratio in the two groups were 8:2 and 7:3, respectively, and the mean age at presentation was 42.7 +/- 1.45 years in the FoQOsD group and 43.6 +/- 1.32 years in the DC group. Both the groups were comparable in relation to the duration of surgery, duration of ICU stay, and survival (P > 0.05). There was significant brain expansion and reversal of MLS (P < 0.001) in the FoQOsD group, factors which were comparable to that in the DC group. CONCLUSIONS: FoQOsD may be as effective as conventional DC in managing intracranial hypertension. This procedure mainly avoids a revision cranioplasty. A prospective randomized controlled trial with a large sample size may be initiated for obtaining more accurate data. PMID- 26588624 TI - Surface electromyography activity in the upper limbs of patients following surgery for compressive cervical myelopathy. AB - BACKGROUND: Surface electromyography (EMG) is a noninvasive, accurate method to measure electrical activity produced in muscles. AIM: To assess the improvement of spasticity after decompressive surgery for compressive myelopathy using surface EMG. SETTING AND DESIGN: Neurophysiology laboratory of a tertiary care center. Before-after trial. Both EMG and Modified Modified Ashworth Scale (MMAS) were utilized. MATERIALS AND METHODS: Thirty-one nonconsecutive patients (28 males; age 25-72 years) with compressive cervical myelopathy and spasticity (MMAS score >=1) were recruited. Patients with lower motor neuron findings, Nurick grade 5, and those with joint deformities, contractures, or thrombophlebitis of the upper limbs were excluded. EMG activity was measured from the pronator teres and biceps brachii for 31 age-related controls (25 males) as well as for the patients both pre- and post-operatively. STATISTICAL ANALYSIS: Student's t-test for comparison of continuous variables and Pearson correlation co-efficient for assessing the significance of associations. RESULTS: EMG recording done 1-week postoperatively showed a reduction in baseline activity in the pronators and supinators by 21% and 36%, respectively. There was a decrease in co-activation of the pronators during active supination by almost 62% and of the supinators during active pronation by around 33% (P < 0.05). On passive movement, there was a decrease in co-activation of the pronators during supination by approximately 23%, and the supinators during pronation by 35% (P < 0.05). EMG activity was significantly reduced in the pronators during supination in all patients, including those in whom the MMAS scores remained the same postoperatively. CONCLUSION: Surface EMG is an objective tool to detect improvement in spasticity following decompressive surgery for compressive cervical myelopathy even in those patients who showed no improvement on the MMAS. PMID- 26588625 TI - Bilateral pallidal deep brain stimulation in idiopathic dystonic camptocormia. AB - INTRODUCTION: Camptocormia is seen with Parkinson's disease (PD), segmental or generalized dystonia, extensor myopathies, anterior horn cell disorders, and muscle disorders. In severe selected cases of PD with camptocormia and dystonic camptocormia, deep brain stimulation (DBS) has been tried with variable success. In this paper, the first case report of its kind from India, we report a case of dystonic camptocormia who underwent DBS and review the available literature. METHODS: A 42-year-old male, presented with dystonia of 5-year duration, that initially started with cervical dystonia and later progressed to severe disturbance of posture causing involuntary truncal flexion induced by standing or sitting. The camptocormia was completely relieved when sitting on a chair or lying down on the bed. Routine blood testing was normal. The workup for secondary dystonia including slit lamp examination for Kayser-Fleischer ring and serum copper studies did not reveal any abnormality. Magnetic resonance imaging of the brain was unremarkable. The electromyogram of the lumbar and thoracic paraspinal muscles was also normal. RESULTS: The patient was initially treated with multiple drugs and Botulinum A toxin which were ineffective. He underwent bilateral globus pallidus interna (GPi) DBS Over a period of 2 weeks; there was a mild reduction in the dystonia of the trunk and neck. The maximum improvement in dystonia, approximately 30% over baseline, was noted at 2 weeks postsurgery and over a further long-term follow-up, the improvement was 50% as determined by the sub item (trunk) assessment of the Burke-Fahn-Marsden (BFM) dystonia score. Cervical dystonia improved by >90% in sub-item (neck) assessment of BFM scale. CONCLUSIONS: In this report, we have shown the efficacy of GPi DBS in the treatment of drug refractory dystonia associated camptocormia. Although only reported for PD associated camptocormia, evaluation for truncal extensor myopathy is mandatory in these cases also to achieve a good outcome. PMID- 26588626 TI - Neurocognitive impairment in Susac syndrome: Magnetic resonance imaging and Tc 99m hexamethylpropyleneamine oxime single photon emission computed tomography correlation. AB - Susac syndrome is a clinical triad of branch retinal artery occlusions, sensorineural hearing loss, and encephalopathy. The characteristic central corpus callosum involvement in Susac syndrome is readily recognizable on conventional magnetic resonance imaging (MRI); however, the neurocognitive effect of these lesions is not well-understood. We present a case of Susac syndrome with typical MRI findings of central callosal lesions at diagnosis. The patient had a protracted clinical course and did not respond well to immunosuppression therapy. Follow-up brain single photon emission computed tomography with Tc-99m hexamethylpropyleneamine oxime revealed marked unilateral frontoparietal and temporal lobe hypoperfusion. Our case highlights the utility of functional neuroimaging to uncover the possible underlying white matter dysfunction, which is not otherwise detectable with conventional MRI techniques. PMID- 26588627 TI - Management of brachial plexus injuries in adults: Clinical evaluation and diagnosis. AB - Brachial plexus injuries are devastating injuries that usually affect the younger population. The usual modes of injuries are roadside accidents, falls, and assaults. The affected individuals are crippled and may suffer from excruciating peripheral or central deafferentation pain for rest of their lives. The loss of functional capacity accounts for a significant number of man-hours lost at the workplace and consequent financial burden on the family. The results of brachial plexus reconstructive surgery have generally been unsatisfactory in the past. However, in recent decades, the efficacy of surgery has been proven beyond doubt, and there have been various published series in literature that have reported a good outcome after surgical management of these injuries. This has been made possible by the use of operating microscopes, better microsuture techniques for nerve graft and nerve or tendon transfer repair, and advanced perioperative electrophysiological techniques. The key to successful management lies in the proper clinical evaluation, supplemented with electrophysiology, preoperative imaging studies, and planning of surgical strategy. The partial injuries have a better outcome as compared with global palsies, and early referral should be emphasized. Selective combinations of nerve graft and transfers provide a moderate shoulder and elbow control. However, a multispecialty approach involving hand surgeons, plastic surgeons, and physiotherapists is required. PMID- 26588628 TI - Vascular complications of tuberculous meningitis: An autopsy study. AB - AIMS: Vascular complications have the most serious consequences in patients with tuberculous meningitis (TBM). Although stroke is seen in approximately 20% of patients with TBM, the underlying vascular damage and infarction are much more extensive. This study has been undertaken to study the pathology at different levels of cerebral vessels and their resultant complications in TBM. MATERIALS AND METHODS: Fifty-one postmortem TBM brains were examined over a period of 16 years (1997-2012). The vascular pathology was studied in detail. Changes in middle cerebral artery (MCA) and basilar artery (BA) and their branches at different levels were analyzed in all cases. RESULTS: The age of the patients ranged from 3 months to 72 years. Infarcts were found in 37 cases, among which they were grossly visible in 27 cases. Macroscopic infarcts were more common in MCA territory whereas microscopic infarction was more in BA distribution brainstem and cerebellum. Vascular involvement was almost universal, with smaller branches of both MCA (94%) and BA (100%) carrying the brunt of the disease, whereas the larger branches were variably involved. Infiltrative lesions were most common at all levels; necrotizing lesions were more common in smaller branches, whereas proliferative changes were seen more in larger branches. CONCLUSION: This study showed extensive damage of cerebral vessels in TBM, which was responsible for the presence of widespread infarctions. Microscopic infarctions in the brainstem and cerebellum were much more common than reported by radiological studies. Thus, more aggressive management of TBM is required to combat its vascular complications. PMID- 26588629 TI - Drug treatment of vertigo in neurological disorders. AB - Vertigo is a common symptom in everyday clinical practice. The treatment depends on the specific etiology. Vertigo may be secondary to inner ear pathology, or any existing brainstem or cerebellar lesion but may also be psychogenic. Central vertigo is a consequence of a central nervous system lesion. It is often associated with a focal neurological deficit. Peripheral vertigo is secondary to dysfunction of the peripheral vestibular system and is usually characterized by an acute vertigo with loss of balance, sensation of spinning in the space or around self, and is exaggerated with changes of the head and body position; no other neurological deficit is present. Some medications may also cause vertigo. Depending on the cause of the vertigo, drugs with different mechanisms of action, physical therapy, psychotherapy, as well as surgery may be used to combat this disabling malady. Symptomatic treatment has a particularly important role, regardless of the etiology of vertigo. We reviewed the current medications recommended for patients with vertigo, their mechanisms of action and their most frequent side effects. PMID- 26588630 TI - The Madras Institute of Neurology, Madras Medical College, Chennai. AB - The Madras Medical College and its affiliated Government General Hospital, Chennai, are among the oldest medical institutions in India. The Madras Institute of Neurology (MIN) was the second neurosciences department to be started in India. The MIN has trained several batches of illustrious neurologists and neurosurgeons. This article briefly traces the history of the MIN, its important milestones, and its current developments. PMID- 26588631 TI - A summary of some of the recently published seminal papers in Neuroscience. PMID- 26588632 TI - Migrated autologous fat graft presenting as a ring enhancing lesion of brain: A novel complication of endoscopic transnasal duroplasty for posttraumatic cerebrospinal fluid rhinorrhoea. PMID- 26588633 TI - Intraoperative fluorescence reveals diffuse subpial spread in glioblastoma. PMID- 26588634 TI - Malignant phyllodes tumor of the breast with isolated intracranial metastases: A report. PMID- 26588635 TI - Dialysis-related amyloidosis: An unusual etiology for pathological odontoid fracture. PMID- 26588636 TI - Hemorrhage within a syrinx: An unusual presentation of Chiari malformation type I. PMID- 26588638 TI - Familial idiopathic basal ganglia calcification (Fahr's disease) and diabetes mellitus: A review of literature. PMID- 26588637 TI - Vanishing infarct on CT-Fogging phenomenon: Perplexing scenario for the beginners. PMID- 26588639 TI - Ipsilateral hemisensory syndrome in a patient with lateral medullary infarction: A new sensory pattern. PMID- 26588640 TI - Neuro-ophthalmological manifestations in three cases of Miller Fisher syndrome and a brief review of literature. PMID- 26588641 TI - Rapid improvement of the confusional state and electroencephalography after spinal tap in a patient with headache and neurologic deficits with cerebrospinal fluid lymphocytosis (HaNDL) syndrome. PMID- 26588642 TI - Sturge-Weber syndrome with bilateral cerebral calcifications but without a facial nevus. PMID- 26588643 TI - Hypertrophic olivary degeneration due to the presence of pontine cavernomas. PMID- 26588644 TI - Foix-Chavany-Marie syndrome after an isolated pontine infarct: A 7-year follow up. PMID- 26588645 TI - RYR1-associated core myopathy. PMID- 26588646 TI - Transverse myelitis in a patient with primary antiphospholipid syndrome. PMID- 26588647 TI - Unilateral hearing loss: An unusual presentation of an undiagnosed giant vertebrobasilar artery aneurysm. PMID- 26588648 TI - Achalasia cardia causing dysphagia in amyotrophic lateral sclerosis. PMID- 26588649 TI - Shunt entrapment: Unusual placement of the distal end inside the falciform ligament. PMID- 26588650 TI - Retrievable stent for migrated coil removal: Literature review. PMID- 26588651 TI - The owl and the monkey - The varied faces of pons in central pontine myelinolysis. PMID- 26588652 TI - MR imaging and MR diffusion tensor imaging in mega corpus callosum. PMID- 26588653 TI - Brain magnetic resonance image changes following acute ethylene glycol poisoning. PMID- 26588654 TI - Primary pituitary abscess. PMID- 26588655 TI - Large unilateral brain stone in TORCH infection. PMID- 26588656 TI - Neurosurgical teaching in the present context. PMID- 26588657 TI - Age and sex matching in case control studies. PMID- 26588658 TI - Limitations of cross-sectional studies. PMID- 26588659 TI - Complete intracranial migration of a ventriculoperitoneal shunt: Rare complication of a common procedure. PMID- 26588660 TI - Anomalous vertebral artery is not a deterrent to C1-2 joint dissection and manipulation for congenital atlantoaxial dislocation. PMID- 26588661 TI - Programmed death ligand 1 expression in triple-negative breast cancer is associated with tumour-infiltrating lymphocytes and improved outcome. AB - AIMS: Triple-negative breast cancer (TNBC) patients generally have a poor outcome; there is a pressing need to identify more effective therapeutic strategies. Clinical trials targeting programmed death 1/programmed death ligand 1 (PD1/PDL1) in melanoma and non-small-cell lung cancer have reported high response rates, and tumoral PDL1 expression has been suggested as a potential biomarker to enrich for patient response to these treatments. There are only very limited data to date reporting the expression of PDL1 in TNBC. METHODS AND RESULTS: PDL1 immunohistochemistry was performed on 161 primary TNBCs and assessed in the tumour as well as immune cells in the stromal compartment. PDL1 expression was very common in TNBC, expressed in the tumour cell membrane (64%), cytoplasm (80%) and stromal (93%) cellular compartments. Cytoplasmic tumoral expression of PDL1 was associated with a lower risk of breast cancer-specific death [hazard ratio (HR) 0.45, P = 0.035] while stromal PDL1 expression was associated with a lower rate of deaths from all causes (HR 0.305, P = 0.0042). Membranous expression of PDL1 was not associated with outcome. While both PDL1 expression and tumour-infiltrating lymphocytes were associated with a better outcome, only lymphovascular invasion and high tumour-infiltrating lymphocytes were independently prognostic for breast cancer-specific death. CONCLUSION: While PDL1 expression is frequent in TNBC, it was not independently prognostic. There were differences in outcome depending on the cellular compartment of PDL1 expression. These data provide further impetus for investigating the utility of immune checkpoint therapies in TNBC, given the clinical significance of tumour infiltrating lymphocytes (TILs) and PDL1 expression in this cohort. PMID- 26588662 TI - Phase 1 dose escalation trial of the safety and pharmacokinetics of cabozantinib concurrent with temozolomide and radiotherapy or temozolomide after radiotherapy in newly diagnosed patients with high-grade gliomas. AB - BACKGROUND: Cabozantinib inhibits mesenchymal-epithelial transition factor (MET) and vascular endothelial growth factor receptor 2 (VEGFR2) and has demonstrated activity in patients with recurrent glioblastoma, warranting evaluation of the addition of cabozantinib to radiotherapy (RT) and temozolomide (TMZ) for patients with newly diagnosed high-grade glioma. METHODS: Cabozantinib doses of 40 mg and 60 mg were explored. Patients on the concurrent treatment arm received cabozantinib daily with standard TMZ and after RT continued cabozantinib daily with adjuvant TMZ. In the maintenance arm, patients who completed RT and >=1 adjuvant cycle of TMZ continued adjuvant TMZ with added cabozantinib (3 schedules: days 1-28, days 1-14, or days 8-21). RESULTS: A total of 26 patients (25 with recurrent glioblastoma and 1 patient with anaplastic astrocytoma) aged 30 to 72 years were enrolled (10 to the concurrent arm and 16 to the maintenance arm). The median number of post-RT TMZ cycles was 4.5 (range, 0-14 cycles) in the concurrent arm and 5.5 (range, 1-12 cycles) in the maintenance arm. Cabozantinib at a dose of 60 mg daily was the maximum administered dose and a dose of 40 mg daily was determined to be the maximum tolerated dose for both treatment arms (schedule of days 1-28). The most frequent grade 3/4 adverse events were thrombocytopenia (31% of patients), leukopenia (27% of patients, including 5 patients with neutropenia), and deep vein thrombosis and/or pulmonary embolism (23% of patients) (adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 3.0]). CONCLUSIONS: Cabozantinib at a dose of 40 mg daily with RT plus TMZ and post-RT TMZ for patients with newly diagnosed high-grade glioma was generally well tolerated, and demonstrated no pharmacokinetic interactions with concurrent TMZ. Given the strong theoretical rationale for combining anti-VEGF and anti-MET activity with standard therapy, cabozantinib at a dose of 40 mg daily warrants evaluation in combination with standard therapy for patients with newly diagnosed glioblastoma. PMID- 26588664 TI - A case of lung volume reduction surgery with decortication for a septic patient in respiratory failure. AB - INTRODUCTION: Decortication and lung volume reduction surgery are both major operations and each has its independent risk of morbidity and mortality. CASE REPORT: We present the case of a 41 year old gentleman with left sided empyema and giant bullae of the upper lobe with an active air leak that was transferred to our tertiary referral centre for further management. We performed emergency left thoracotomy, decorticated the left lower lobe with extensive lung volume reduction surgery of the upper lobe. Patient's respiratory status significantly improved along with excellent radiological results. CONCLUSION: Our case demonstrates that a combination of complex procedures is feasible with excellent outcomes. PMID- 26588663 TI - Risk Factors for HIV Transmission and Barriers to HIV Disclosure: Metropolitan Atlanta Youth Perspectives. AB - Youth carry the highest incidence of HIV infection in the United States. Understanding adolescent and young adult (AYA) perspectives on HIV transmission risk is important for targeted HIV prevention. We conducted a mixed methods study with HIV-infected and uninfected youth, ages 18-24 years, from Atlanta, GA. We provided self-administered surveys to HIV-infected and HIV-uninfected AYAs to identify risk factors for HIV acquisition. By means of computer-assisted thematic analyses, we examined transcribed focus group responses on HIV education, contributors to HIV transmission, and pre-sex HIV status disclosure. The 68 participants had the following characteristics: mean age 21.5 years (standard deviation: 1.8 years), 85% male, 90% black, 68% HIV-infected. HIV risk behaviors included the perception of condomless sex (Likert scale mean: 8.0) and transactional sex (88% of participants); no differences were noted by HIV status. Qualitative analyses revealed two main themes: (1) HIV risk factors among AYAs, and (2) barriers to discussing HIV status before sex. Participants felt the use of social media, need for immediate gratification, and lack of concern about HIV disease were risk factors for AYAs. Discussing HIV status with sex partners was uncommon. Key reasons included: fear of rejection, lack of confidentiality, discussion was unnecessary in temporary relationships, and disclosure negatively affecting the mood. HIV prevention strategies for AYAs should include improving condom use frequency and HIV disclosure skills, responsible utilization of social media, and education addressing HIV prevention including the risks of transactional sex. PMID- 26588665 TI - Perovskite Solar Cells Employing Dopant-Free Organic Hole Transport Materials with Tunable Energy Levels. AB - Conjugated small-molecule hole-transport materials (HTMs) with tunable energy levels are designed and synthesized for efficient perovskite solar cells. A champion device with efficiency of 16.2% is demonstrated using a dopant-free DERDTS-TBDT HTM, while the DORDTS-DFBT-HTM-based device shows an inferior performance of 6.2% due to its low hole mobility and unmatched HOMO level with the valence band of perovskite film. PMID- 26588666 TI - Direct admission to the hospital: An alternative approach to hospitalization. AB - Appropriate use of emergency departments (EDs) is a focus of national healthcare reform efforts, and patients requiring hospital admission account for a substantial proportion of ED utilization. Despite this, little attention has been paid to evaluating direct admission to the hospital as an alternative to hospital admissions beginning in the ED. In this Perspective, we discuss the role of hospital medicine in the changing epidemiology of hospital admissions, the potential risks and benefits of direct admission to the hospital, and the need for research to evaluate the safety and effectiveness of this admission approach. We propose that transitions of care research and quality improvement, historically focused on hospital-to-home transitions, be expanded to address transitions into the hospital. PMID- 26588667 TI - Reconstruction and analysis of a genome-scale metabolic model for Eriocheir sinensis eyestalks. AB - The eyestalk of Eriocheir sinensis has significant biological functions with many nerve peptide hormones expressed in the X-organ which exists in the eyestalk. A metabolic network model is an effective tool for the systematic study of E. sinensis eyestalks. In this work, we reconstructed a metabolic network model for E. sinensis eyestalks based on transcriptome sequencing. The model contains 1304 reactions, 1381 unigenes and 1243 metabolites distributing in 98 pathways. The reconstructed metabolic network model was used for the functional module and block metabolite analysis of eyestalks, which reveals that the function of the eyestalk network agrees with its function as the centre of the E. sinensis endocrine system. The difference expression analysis of reactions in the model indicates that the eyestalk mainly functions in the regulation of amino acids, carbohydrate and nucleotide metabolism. PMID- 26588668 TI - Efficient Preparation of Site-Specific Antibody-Drug Conjugates Using Phosphopantetheinyl Transferases. AB - Post-translational modification catalyzed by phosphopantetheinyl transferases (PPTases) has previously been used to site-specifically label proteins with structurally diverse molecules. PPTase catalysis results in covalent modification of a serine residue in acyl/peptidyl carrier proteins and their surrogate substrates which are typically fused to the N- or C-terminus. To test the utility of PPTases for preparing antibody-drug conjugates (ADCs), we inserted 11 and 12 mer PPTase substrate sequences at 110 constant region loop positions of trastuzumab. Using Sfp-PPTase, 63 sites could be efficiently labeled with an auristatin toxin, resulting in 95 homogeneous ADCs. ADCs labeled in the CH1 domain displayed in general excellent pharmacokinetic profiles and negligible drug loss. A subset of CH2 domain conjugates underwent rapid clearance in mouse pharmacokinetic studies. Rapid clearance correlated with lower thermal stability of the particular antibodies. Independent of conjugation site, almost all ADCs exhibited subnanomolar in vitro cytotoxicity against HER2-positive cell lines. One selected ADC was shown to induce tumor regression in a xenograft model at a single dose of 3 mg/kg, demonstrating that PPTase-mediated conjugation is suitable for the production of highly efficacious and homogeneous ADCs. PMID- 26588669 TI - External validation of models predicting the individual risk of metachronous peritoneal carcinomatosis from colon and rectal cancer. AB - AIM: To externally validate previously published predictive models of the risk of developing metachronous peritoneal carcinomatosis (PC) after resection of nonmetastatic colon or rectal cancer and to update the predictive model for colon cancer by adding new prognostic predictors. METHOD: Data from all patients with Stage I-III colorectal cancer identified from a population-based database in Stockholm between 2008 and 2010 were used. We assessed the concordance between the predicted and observed probabilities of PC and utilized proportional-hazard regression to update the predictive model for colon cancer. RESULTS: When applied to the new validation dataset (n = 2011), the colon and rectal cancer risk-score models predicted metachronous PC with a concordance index of 79% and 67%, respectively. After adding the subclasses of pT3 and pT4 stage and mucinous tumour to the colon cancer model, the concordance index increased to 82%. CONCLUSION: In validation of external and recent cohorts, the predictive accuracy was strong in colon cancer and moderate in rectal cancer patients. The model can be used to identify high-risk patients for planned second-look laparoscopy/laparotomy for possible subsequent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. PMID- 26588670 TI - Orthogonal Cysteine-Penicillamine Disulfide Pairing for Directing the Oxidative Folding of Peptides. AB - Precise disulfide pairing in synthetic peptides usually is achieved using orthogonal protecting group strategies or relies on primary sequence manipulation. Orthogonal disulfide pairing technology should be promising for directing the rational folding of multicyclic peptides from the fully reduced peptides. Here, we report a discovery on the orthogonality between heterodisulfide pairing of cysteine (Cys) and penicillamine (Pen) and formation of Cys-Cys/Pen-Pen homodisulfides. The orthogonal Cys-Pen disulfide pairing can be exploited for highly selective production of certain (multi)cyclic structures (or even a sole structure without isomers) through direct oxidation in air or thiol-disulfide exchanges in redox media. This strategy makes rational folding of multicyclic peptides without protecting groups, sequence manipulation, and complex synthetic reactions a reality, thus providing invaluable assets to peptide communities, and should greatly benefit the development of multicyclic peptide therapeutics and ligands. PMID- 26588671 TI - A novel method for identifying the order of interference using phase-shifting digital holography. AB - In this paper, we introduced a mathematical method for measuring the optical path length differences (OPDs), which is suitable for large OPD values where the fringes connections are difficult to detect. The proposed method is based on varying the width of the fringes, without changing the wavelength of the used coherent source. Also, in this work, we discussed the need for such method in off axis phase-shifting digital holography. Low-resolution off-axis holograms failed to detect the correct interference order. In general, off-axis phase-shifting digital holography is limited by the resolution of the captured holograms. The results obtained using our proposed technique were compared to the results obtained using off-axis phase-shifting digital holograms and conventional two beam interferometry. Holograms were given for illustration. PMID- 26588672 TI - Rv3369 Induces Cytokine Interleukin-1beta Production and Enhances Mycobacterium smegmatis Intracellular Survival. AB - The pathogenesis of tuberculosis, caused by Mycobacterium tuberculosis, is largely because of the pathogen's successful entry and survival within macrophages. We predicted that rv3369, a gene encoding a conserved protein, might play a role in the interactions with host cells. To test this, rv3369 gene was heterologously expressed in a nonpathogenic fast-growing Mycobacterium smegmatis strain. The recombinant strain survives better than the control within macrophages, accompanied by more host cell death and a marked higher secretion of interleukin-1beta (IL-1beta). Furthermore, pharmacological inhibition experiments showed that the NF-kappaB and ERK pathways were involved in the Rv3369-triggered IL-1beta changes. These results provided evidence for the engagement of Rv3369 in the interaction between mycobacteria and host. PMID- 26588673 TI - Direct-growth carbon nanotubes on 3D structural microelectrodes for electrophysiological recording. AB - A novel 3D carbon nanotube (CNT) microelectrode was developed through direct growth of CNTs on a gold pin-shaped 3D microelectrode at a low temperature (400 degrees C) for applications in neural and cardiac recording. With an electroplated Ni catalyst layer covering the entire surface of the pin-shaped structure, CNTs were synthesized on a 3D microelectrode by catalytic thermal chemical vapor deposition (CVD). According to the analyses by electrochemical impedance spectroscopy, the impedance of 3D microelectrodes after CNT growth and UV/O3 treatment decreased from 9.3 Omega mm(-2) to 1.2 Omega mm(-2) and the capacitance increased largely from 2.2 mF cm(-2) to 73.3 mF cm(-2). The existence of UVO3-treated CNT led to a large improvement of interfacial capacitance, contributing to the decrease of impedance. The electrophysiological detection capability of this 3D CNT microelectrode was demonstrated by the distinguished P waves, QRS complex and T waves in the electrocardiogram of the zebrafish heart and the action potential recorded from individual rat hippocampal neurons. The compatibility of integration with ICs, high resolution in space, electrophysiological signals, and non-invasive long-term recording suggest that the 3D CNT microelectrode exhibits promising potential for applications in electrophysiological research and clinical trials. PMID- 26588674 TI - Special Review: Caught in the Crosshairs: Targeted Drugs and Personalized Medicine. AB - All drugs have molecular targets; however, this does not mean that they are targeted therapeutics. Only by the interaction with a disease-specific molecule can the drug be classified as a targeted therapeutic. This is often not clearly defined and might refer to several different therapeutic modalities such as genomically targeted therapy, immune checkpoint therapy, or pharmacokinetic targeting. To develop a precise concept of targeted therapy, it is crucial to understand how drugs were discovered and how our rapidly expanding knowledge concerning disease mechanism is driving a fundamental conceptual change in modern drug discovery and development. In combination with the increasingly detailed analysis of disease at an individual patient level, we believe that it is very timely to consider the past and current approaches involved in the development of new medicines and to discuss the paradigm shift in and basic concepts associated with targeted therapies and personalized medicine. PMID- 26588675 TI - From the Guest Editor: Adoptive Cell Therapy: Fulfilling Its Promise. PMID- 26588676 TI - Tumor-Infiltrating Lymphocyte Therapy: Addressing Prevailing Questions. AB - Autologous adoptive T-cell therapies have made tremendous strides over the last few years with excitement currently being generated by technologies that can reprogram T-cell specificities toward any desired antigen including chimeric antigen receptors and recombinant T-cell receptors. Time will tell whether these new genetically engineered T-cell technologies will be effective as advertised, especially in solid tumors, considering the limited availability of specific antigens and the difficulty in managing the unpredictable on-target, off-tissue toxicities. However, a form of T-cell therapy that has been utilized in patients more than any other and has left a lasting mark in the field is tumor infiltrating lymphocytes (TILs). Tumor-infiltrating lymphocyte therapy has consistently yielded durable clinical responses in selected patients with metastatic melanoma and is now being increasingly applied to treat other solid tumors, including head and neck squamous cell carcinoma, cervical cancer, breast cancer, and lung cancer. Despite its long history in the clinic and key developments over the last few decades that have augmented response rates and have made TIL manufacturing more streamlined, a number of key outstanding conceptual questions remain to be answered in the TIL therapy field. In this review, we address critical questions, including the mechanism of action of TILs and active T-cell subsets, the current need for lymphoablative preconditioning, predictive biomarkers, the role of combination therapy such as checkpoint blockade, new excitement over the recognition of mutated antigens (the "mutanome") by TILs, and issues in developing TILs for nonmelanoma indications. In each case, we will critically discuss the main issues and concerns and how they can affect the eventual positioning of TIL therapy in the mainstream of cancer care. PMID- 26588677 TI - Tumor-Infiltrating Lymphocytes: Clinical Experience. AB - Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TILs) in combination with lymphodepletion and high-dose interleukin 2 has shown reproducible objective response rates of approximately 50% in patients with highly advanced, refractory metastatic melanoma. As confirmed by different clinical centers, TIL ACT can yield durable responses especially in patients with complete regression, who are mostly disease-free many years after treatment, suggesting the possibility of cure. Most TIL ACT trials have been conducted as salvage therapy for patients with multiple metastases, frequently in visceral organs and even brain, and who failed numerous treatments, including checkpoint inhibitors, which underlines the value of the treatment. Recent developments in the identification and selection of tumor-specific T-cell populations have facilitated the implementation of TIL ACT also in nonmelanoma malignancies. We summarize the clinical experience of TIL ACT in melanoma, briefly discuss new directions for further improvement of this promising therapy, and present the latest clinical results in nonmelanoma cancers. PMID- 26588678 TI - CD19-Targeted T Cells for Hematologic Malignancies: Clinical Experience to Date. AB - Recently, immunotherapy for cancer has begun to garner traction with encouraging results in a number of malignancies. Included within this arena has been the genetic engineering of autologous T cells with chimeric antigen receptors (CARs) against tumor target. The majority of this experience has included the use of CAR T cells directed against CD19 for B-cell hematologic malignancies. The most striking efficacy to date with CAR T cells directed against CD19 has been in relapsed and refractory B-cell acute lymphoblastic leukemia, with the overwhelming majority of patients experiencing complete remissions. In addition, single-center and largely early-phase studies have demonstrated responses in patients with varying histologic findings of relapsed and refractory B-cell non Hodgkin lymphoma. The favorable response rates seen with this technology have been tempered by the high risk of toxicity, particularly in the form of cytokine release syndrome and neurotoxicity. Agents such as tocilizumab and corticosteroids have been used to treat these toxicities. The current state of the science includes strategies to circumvent and treat toxicity, manufacturing, and study of later-generation CAR constructs with the intention of improving efficacy and development of CARs against other tumor targets for both hematologic and solid tumor malignancies. The observation of an early efficacy ensures further integration and development of this modality into future immunotherapeutic strategies for various cancers. PMID- 26588679 TI - Chimeric Antigen Receptor T-Cells: New Approaches to Improve Their Efficacy and Reduce Toxicity. AB - The durable remission of B-cell leukemia and lymphoma following chimeric antigen receptor (CAR) T-cell therapy has brought this new form of adoptive immunotherapy to center stage with the expectation that CAR T-cell therapy may provide similar efficacy in other hematologic and solid cancers. Herein, we review recent advances in the areas of CAR design that improve CAR T-cell proliferation, engraftment, and efficacy, as well as clinical application strategies that are designed to improve clinical efficacy while reducing the risk of toxicity and broaden patient access to this promising form of cancer immunotherapy. PMID- 26588680 TI - T-Cell Receptor-Transduced T Cells: Clinical Experience. AB - The large number of T-cell epitopes that have been found to be processed and presented on human tumors, now numbering in the hundreds, provides a rich source of targets for therapeutic interventions aimed at inducing durable tumor regression. Vaccination strategies aimed at inducing responses to these antigens have been largely ineffective, and it has been challenging to generate large numbers of T cells with the functional capacity to mediate durable tumor regressions in adoptive immunotherapy strategies in patients who have common epithelial malignancies. The ability to generate T-cell receptors that recognize shared as well as unique antigens expressed in a wide variety of common tumor types that include lung, breast, ovarian, gastrointestinal, urothelial, and genitourinary cancers provides an opportunity to develop widely applicable therapies based on the adoptive transfer of autologous T cells transduced with those receptors. PMID- 26588682 TI - Endogenous T-Cell Therapy: Clinical Experience. AB - Adoptive cellular therapy represents a robust means of augmenting the tumor reactive effector population in patients with cancer by adoptive transfer of ex vivo expanded T cells. Three approaches have been developed to achieve this goal: the use of tumor-infiltrating lymphocytes or tumor-infiltrating lymphocytess extracted from patient biopsy material; the redirected engineering of lymphocytes using vectors expressing a chimeric antigen receptor and T-cell receptor; and third, the isolation and expansion of often low-frequency endogenous T cells (ETCs) reactive to tumor antigens from the peripheral blood of patients. This last form of adoptive transfer of T cells, known as ETC therapy, requires specialized methods to isolate and expand from peripheral blood the very low frequency tumor-reactive T cells, methods that have been developed over the last 2 decades, to the point where such an approach may be broadly applicable not only for the treatment of melanoma but also for that of other solid tumor malignancies. One compelling feature of ETC is the ability to rapidly deploy clinical trials following identification of a tumor-associated target epitope, a feature that may be exploited to develop personalized antigen-specific T-cell therapy for patients with almost any solid tumor. With a well-validated antigen discovery pipeline in place, clinical studies combining ETC with agents that modulate the immune microenvironment can be developed that will transform ETC into a feasible treatment modality. PMID- 26588681 TI - Natural Killer Cell Adoptive Transfer Therapy: Exploiting the First Line of Defense Against Cancer. AB - Natural killer (NK) cells constitute an important component of the initial immunological response against transformed cells. However, chronic exposure to the tumor microenvironment can fundamentally alter the ability of NK cells to sufficiently control tumor progression. Thus, the adoptive transfer of healthy, functional NK cells as an interventional therapy has been an area of great interest for improving patient outcomes. Recent developments in the field have provided a better understanding of what makes the NK compartment effective against malignant cells. Moreover, there are now multiple potential sources of NK cell products for infusion as well as techniques to manipulate these cells to enhance their antitumor functions. This review explores the advantages and disadvantages of various sources of NK cells as well as prospective therapeutic enhancements to adoptively transferred NK cells. PMID- 26588683 TI - Marrow Infiltrating Lymphocytes: Their Role in Adoptive Immunotherapy. AB - The clinical results achieved with immunotherapy in the past few years have now firmly established it within the cancer armamentarium. Our group has explored a novel approach to adoptive T-cell therapy utilizing marrow-infiltrating lymphocytes (MILs) initially developed with the concept of utilizing a population of T cells with a higher endogenous tumor specificity. Marrow-infiltrating lymphocytes are antigen-experienced T cells that home to and remain in the bone marrow (BM) because of the unique biology of the BM microenvironment. Marrow infiltrating lymphocytes can easily be obtained from the BM and can be expanded to demonstrate enhanced antigen specificity. Current clinical trials utilize MILs for patients with myeloma as well as patients with relapsed disease following an allogeneic transplant. Ongoing preclinical work is currently evaluating MILs for use in solid cancers as well as pediatric cancers. The examination of a MIL as a source cell for chimeric antigen receptor T or transgenic cell receptor is also in the preclinical stages. Until now, for both chimeric antigen receptor T-cell therapy and transgenic cell receptor T-cell therapy, the target cell of choice has included peripheral blood. The unique antigen-experienced properties of MILs may make them the ideal source of cell for gene modification strategies. Therefore, MILs are a distinctive set of T cells that have been shaped by the unique BM microenvironment and may play a future role as a novel immunotherapy for hematologic malignancies. PMID- 26588684 TI - Toxicities Associated With Adoptive T-Cell Transfer for Cancer. AB - This review describes the toxicities associated with the therapeutic administration of cultured immune cells for the treatment of cancer by review of the literature. The toxicities seen are of 4 types: infection associated with preparative host immunosuppression with chemotherapy prior to cell administration, acute cytokine release by the infused cells, autoimmune complications from attacking "self-antigens" also expressed by some normal tissues, and off-target toxicities where antigens, other than the intended, are attacked. Complications from immunosuppression and cytokine release are often short-lived and currently best addressed by supportive care. Autoimmunity, either "on target, off tumor" or "off target," is the result of the selection of imperfect target antigens. In some cases, this can be tolerated because the benefits outweigh the costs. In other cases, alternative target antigens must be found. New strategies targeting viral antigens for virally induced cancers and antigens encoded by tumor-specific mutations seem to have promise as safe and potentially effective targets for adoptive cell transfer. PMID- 26588685 TI - Evaluation of the Leptospira interrogans Outer Membrane Protein OmpL37 as a Vaccine Candidate. AB - The identification of potential vaccine candidates against leptospirosis remains a challenge. However, one such candidate is OmpL37, a potentially surface-exposed antigen that has the highest elastin-binding ability described to date, suggesting that it plays an important role in host colonization. In order to evaluate OmpL37's ability to induce a protective immune response, prime-boost, DNA and subunit vaccine strategies were tested in the hamster model of lethal leptospirosis. The humoral immune response was evaluated using an indirect ELISA test, and the cytokine profile in whole blood was determined by quantitative real time PCR. Unlike the DNA vaccine, the administration of recombinant OmpL37 induced a strong IgG antibody response. When individually administrated, both formulations stimulated a TNF-alpha mediated inflammatory response. However, none of the OmpL37 formulations or vaccination strategies induced protective immunity. Further studies are required towards the identification of new vaccine targets against leptospirosis. PMID- 26588687 TI - Association between Maternal and Child Nutritional Status in Hula, Rural Southern Ethiopia: A Cross Sectional Study. AB - BACKGROUND: Maternal and child under nutrition is highly prevalent in low-income and middle-income countries, resulting in substantial increases in mortality and overall disease burden. The aim of this baseline survey was to determine the association between selected maternal characteristics, maternal nutritional status and children's nutritional status. METHODS AND FINDINGS: A survey with a cross sectional design was conducted between September and October 2012 in Hula, Ethiopia. The study subjects were 197 mothers of children between the ages of 6 and 23 months. Weight and height (mothers) or recumbent length (children) were measured using calibrated, standardized techniques. Seven percent of children were below -2 weight for height Z score (WHZ), 11.5% were below -2 height for age Z score (HAZ) and 9.9% were below -2 weight for age Z score (WAZ). Maternal anthropometrics were associated with child nutritional status in the bivariate analysis. Maternal BMI (r = 0.16 P = 0.02) and educational status (r = 0.25 P = 0.001) were correlated with WHZ of children while maternal height (r = 0.2 P = 0.007) was correlated with HAZ of children. After multivariate analysis, children whose mothers had salary from employment had a better WHZ score (P = 0.001) and WAZ score (P<0.001). Both maternal BMI and maternal height were associated with WHZ (P = 0.04) and HAZ (P = 0.01) score of children. CONCLUSION: Having a mother with better nutritional status and salaried employment is a benefit for the nutritional status of the child. The interrelationship between maternal and child nutritional status stresses the value of improving maternal nutritional status as this should improve both maternal and child health outcomes. Therefore strategies to improve nutritional status of children should also include improving the nutritional status of the mother and empowering her financially. PMID- 26588686 TI - Bromoenol Lactone Attenuates Nicotine-Induced Breast Cancer Cell Proliferation and Migration. AB - OBJECTIVES: Calcium independent group VIA phospholipase A2 (iPLA2beta) and Matrix Metalloproteinase-9 (MMP-9) are upregulated in many disease states; their involvement with cancer cell migration has been a recent subject for study. Further, the molecular mechanisms mediating nicotine-induced breast cancer cell progression have not been fully investigated. This study aims to investigate whether iPLA2beta mediates nicotine-induced breast cancer cell proliferation and migration through both in-vitro and in-vivo techniques. Subsequently, the ability of Bromoenol Lactone (BEL) to attenuate the severity of nicotine-induced breast cancer was examined. METHOD AND RESULTS: We found that BEL significantly attenuated both basal and nicotine-induced 4T1 breast cancer cell proliferation, via an MTT proliferation assay. Breast cancer cell migration was examined by both a scratch and transwell assay, in which, BEL was found to significantly decrease both basal and nicotine-induced migration. Additionally, nicotine-induced MMP-9 expression was found to be mediated in an iPLA2beta dependent manner. These results suggest that iPLA2beta plays a critical role in mediating both basal and nicotine-induced breast cancer cell proliferation and migration in-vitro. In an in-vivo mouse breast cancer model, BEL treatment was found to significantly reduce both basal (p<0.05) and nicotine-induced tumor growth (p<0.01). Immunohistochemical analysis showed BEL decreased nicotine-induced MMP-9, HIF 1alpha, and CD31 tumor tissue expression. Subsequently, BEL was observed to reduce nicotine-induced lung metastasis. CONCLUSION: The present study indicates that nicotine-induced migration is mediated by MMP-9 production in an iPLA2beta dependent manner. Our data suggests that BEL is a possible chemotherapeutic agent as it was found to reduce both nicotine-induced breast cancer tumor growth and lung metastasis. PMID- 26588688 TI - Er:YAG Laser Versus Cold Knife Excision in the Treatment of Nondysplastic Oral Lesions: A Randomized Comparative Study for the Postoperative Period. AB - OBJECTIVE: The aim of this prospective study was to estimate the effects of Erbium substituted: Yttrium Aluminium Garnet (Er:YAG) laser, compared with traditional scalpel, on the early postoperative sequelae of nondysplastic oral lesion removal. BACKGROUND DATA: There is limited evidence that laser surgery could exhibit advantages over scalpel in oral mucosal surgery. METHODS: The investigators studied a cohort of 344 patients; 394 lesions were randomized and treated. Outcome statistically evaluated variables were: age, gender, the site and size of investigated lesions, visual analogue score (VAS) of pain, the Oral Health Impact Profile questionnaire (OHIP-14) and the Quality of Life test (QOL), and number of analgesics taken in the 1st week after surgery. RESULTS: Significant differences were found if considering the surgical time, VAS, and QOL and OHIP-14 questionnaires; regarding those data, the Er:YAG laser appeared to be faster and less painful than traditional scalpel (p < 0.05). For bigger lesions, patients statistically took more painkillers if they had undergone traditional surgery. Considering the site of the treated lesions, Er:YAG laser was less painful, especially in the gingiva and palate (p < 0.05). CONCLUSIONS: This is the first randomized controlled surgical trial reported for the management of nondysplastic oral lesions with the use of an Er:YAG laser. With many limitations, the present report identifies significant difference in the immediate postoperative surgical period between the two treatments, meaning that the Er:YAG laser seemed to be less painful, and better accepted by patients, than traditional scalpel. PMID- 26588689 TI - Markov chain evaluation of acute postoperative pain transition states. AB - Previous investigations on acute postoperative pain dynamicity have focused on daily pain assessments, and so were unable to examine intraday variations in acute pain intensity. We analyzed 476,108 postoperative acute pain intensity ratings, which were clinically documented on postoperative days 1 to 7 from 8346 surgical patients using Markov chain modeling to describe how patients are likely to transition from one pain state to another in a probabilistic fashion. The Markov chain was found to be irreducible and positive recurrent, with no absorbing states. Transition probabilities ranged from 0.0031, for the transition from state 10 to state 1, to 0.69 for the transition from state 0 to state 0. The greatest density of transitions was noted in the diagonal region of the transition matrix, suggesting that patients were generally most likely to transition to the same pain state as their current state. There were also slightly increased probability densities in transitioning to a state of asleep or 0 from the current state. An examination of the number of steps required to traverse from a particular first pain score to a target state suggested that overall, fewer steps were required to reach a state of 0 (range 6.1-8.8 steps) or asleep (range 9.1-11) than were required to reach a mild pain intensity state. Our results suggest that using Markov chains is a feasible method for describing probabilistic postoperative pain trajectories, pointing toward the possibility of using Markov decision processes to model sequential interactions between pain intensity ratings, and postoperative analgesic interventions. PMID- 26588690 TI - Early-onset treadmill training reduces mechanical allodynia and modulates calcitonin gene-related peptide fiber density in lamina III/IV in a mouse model of spinal cord contusion injury. AB - Below-level central neuropathic pain (CNP) affects a large proportion of spinal cord injured individuals. To better define the dynamic changes of the spinal cord neural network contributing to the development of CNP after spinal cord injury (SCI), we characterized the morphological and behavioral correlates of CNP in female C57BL/6 mice after a moderate T11 contusion SCI (50 kdyn) and the influence of moderate physical activity. Compared with sham-operated animals, injured mice developed mechanical allodynia 2 weeks post injury when tested with small-diameter von Frey hair filaments (0.16 g and 0.4 g filament), but presented hyporesponsiveness to noxious mechanical stimuli (1.4 g filament). The mechano sensory alterations lasted up to 35 days post injury, the longest time point examined. The response latency to heat stimuli already decreased significantly 10 days post injury reaching a plateau 2 weeks later. In contrast, injured mice developed remarkable hyposensitivity to cold stimuli. Animals that underwent moderate treadmill training (2 * 15 minutes; 5 d/wk) showed a significant reduction in the response rate to light mechanical stimuli as early as 6 days after training. Calcitonin gene-related peptide (CGRP) labeling in lamina III-IV of the dorsal horn revealed significant increases in CGRP-labeling density in injured animals compared with sham control animals. Importantly, treadmill training reduced CGRP-labeling density by about 50% (P < 0.01), partially reducing the injury-induced increases. Analysis of IB4-labeled nonpeptidergic sensory fibers revealed no differences between experimental groups. Abnormalities in temperature sensation were not influenced by physical activity. Thus, treadmill training partially resolves signs of below-level CNP after SCI and modulates the density of CGRP-labeled fibers. PMID- 26588691 TI - Are multidisciplinary interventions multicultural? A topical review of the pain literature as it relates to culturally diverse patient groups. PMID- 26588692 TI - The effect of bodily illusions on clinical pain: a systematic review and meta analysis. AB - This systematic review and meta-analysis critically examined the evidence for bodily illusions to modulate pain. Six databases were searched; 2 independent reviewers completed study inclusion, risk of bias assessment, and data extraction. Included studies evaluated the effect of a bodily illusion on pain, comparing results with a control group/condition. Of the 2213 studies identified, 20 studies (21 experiments) were included. Risk of bias was high due to selection bias and lack of blinding. Consistent evidence of pain decrease was found for illusions of the existence of a body part (myoelectric/Sauerbruch prosthesis vs cosmetic/no prosthesis; standardized mean differences = -1.84, 95% CI = -2.67 to 1.00) and 4 to 6 weeks of mirror therapy (standardized mean differences = -1.11, 95% CI = -1.66 to -0.56). Bodily resizing illusions had consistent evidence of pain modulation (in the direction hypothesized). Pooled data found no effect on pain for 1 session of mirror therapy or for incongruent movement illusions (except for comparisons with congruent mirrored movements: incongruent movement illusion significantly increased the odds of experiencing pain). Conflicting results were found for virtual walking illusions (both active and inactive control comparisons). Single studies suggest no effect of resizing illusions on pain evoked by noxious stimuli, no effect of embodiment illusions, but a significant pain decrease with synchronous mirrored stroking in nonresponders to traditional mirror therapy. There is limited evidence to suggest that bodily illusions can alter pain, but some illusions, namely mirror therapy, bodily resizing, and use of functional prostheses show therapeutic promise. PMID- 26588693 TI - Prescription trajectories and effect of total hip arthroplasty on the use of analgesics, hypnotics, antidepressants, and anxiolytics: results from a population of total hip arthroplasty patients. AB - Total hip arthroplasty (THA) has been shown to reduce pain and improve function. In addition, it is suggested that THA improves sleep and alleviates symptoms of anxiety and depression. Patients with chronic pain are frequent users of analgesic and psychotropic drugs and thereby risk adverse drug events. The impact of THA on such drug use has not been thoroughly investigated. Based on merged data from the Norwegian Prescription Database and the Norwegian Arthroplasty Register, this study sought to investigate redeemed medications in a complete population (N = 39,688) undergoing THA in 2005 to 2011. User rates and redeemed drug volume of analgesics (nonsteroid anti-inflammatory drugs (NSAIDs), opioids, and nonopioids) and psychotropics (hypnotics, anxiolytics, and antidepressants) were calculated for 4 quarters before and 4 quarters after surgery. We analysed preoperative prescription trends (Q1 vs Q4), postoperative prescription (Q4 vs Q5), and long-term effect of surgery (Q4 vs Q8). Before surgery, use of all drug groups increased from Q1 to Q4. Use of opioids, nonopioids, and hypnotics dramatically increased from Q4 to Q5. Long-term (Q4 vs Q8) surgery reduced prescriptions of analgesics, hypnotics, and anxiolytics, but not antidepressants. Overall, the present results extend the positive effects of THA to include reduced reliance on medication to alleviate symptoms. PMID- 26588694 TI - Pelvic pain after childbirth: a longitudinal population study. AB - In this longitudinal population study, the aims were to study associations of mode of delivery with new onset of pelvic pain and changes in pelvic pain scores up to 7 to 18 months after childbirth. We included 20,248 participants enrolled in the Norwegian Mother and Child Cohort Study (1999-2008) without preexisting pelvic pain in pregnancy. Data were obtained by 4 self-administered questionnaires and linked to the Medical Birth Registry of Norway. A total of 4.5% of the women reported new onset of pelvic pain 0 to 3 months postpartum. Compared to unassisted vaginal delivery, operative vaginal delivery was associated with increased odds of pelvic pain (adjusted odds ratio [OR]: 1.30; 95% confidence interval [CI]: 1.06-1.59). Planned and emergency cesarean deliveries were associated with reduced odds of pelvic pain (adjusted OR: 0.48; 95% CI: 0.31-0.74 and adjusted OR: 0.65; 95% CI: 0.49-0.87, respectively). Planned cesarean delivery, young maternal age, and low Symptom Checklist-8 scores were associated with low pelvic pain scores after childbirth. A history of pain was the only factor associated with increased pelvic pain scores over time (P = 0.047). We conclude that new onset of pelvic pain after childbirth was not commonly reported, particularly following cesarean delivery. Overall, pelvic pain scores were rather low at all time points and women with a history of pain reported increased pelvic pain scores over time. Hence, clinicians should follow up women with pelvic pain after a difficult childbirth experience, particularly if they have a history of pain. PMID- 26588696 TI - Widespread pain sensitization after partial infraorbital nerve transection in MRL/MPJ mice. AB - Clinical studies show that chronic pain can spread to adjacent or even distant body regions in some patients. However, little is known about how this happens. In this study, we found that partial infraorbital nerve transection (p-IONX) in MRL/MPJ mice induced not only marked and long-lasting orofacial thermal hyperalgesia but also thermal hyperalgesia from day 3 postoperatively (PO) and tactile allodynia from day 7 PO in bilateral hind paws. Pain sensitization in the hind paw was negatively correlated with facial thermal hyperalgesia at early but not late stage after p-IONX. After a rapid activation of c-Fos, excitability and excitatory synaptic neurotransmission in lumbar dorsal horn neurons were elevated from day 3 and day 7 PO, respectively. In addition, microglial activation after p IONX transmitted caudally from the Vc in the medulla to lumber dorsal horn in a time-dependent manner. Inhibition of microglial activation by minocycline at early but not late stage after p-IONX postponed and attenuated pain sensitization in the hind paw. These results indicate that neuropathic pain after p-IONX in MRL/MPJ mice spreads from the orofacial region to distant somatic regions and that a rostral-caudal transmission of central sensitization in the spinal cord is involved in the spreading process of pain hypersensitivity. PMID- 26588695 TI - Adenosine-A1 receptor agonist induced hyperalgesic priming type II. AB - We have recently shown that repeated exposure of the peripheral terminal of the primary afferent nociceptor to the mu-opioid receptor (MOR) agonist DAMGO ([D Ala, N-Me-Phe, Gly-ol]-enkephalin acetate salt) induces a model of transition to chronic pain that we have termed type II hyperalgesic priming. Similar to type I hyperalgesic priming, there is a markedly prolonged response to subsequent administration of proalgesic cytokines, prototypically prostaglandin E2 (PGE2). However, type II hyperalgesic priming differs from type I in being rapidly induced, protein kinase A (PKA), rather than PKCepsilon dependent, not reversed by a protein translation inhibitor, occurring in female as well as in male rats, and isolectin B4-negative neuron dependent. We report that, as with the repeated injection of a MOR agonist, the repeated administration of an agonist at the A1 adenosine receptor, also a Gi-protein coupled receptor, N-cyclopentyladenosine (CPA), also produces priming similar to DAMGO-induced type II hyperalgesic priming. In this study, we demonstrate that priming induced by repeated exposure to this A1-adenosine receptor agonist shares the same mechanisms, as MOR-agonist induced priming. However, the prolongation of PGE2 hyperalgesia induced by repeated administration of CPA depends on G-protein alphai subunit activation, differently from DAMGO-induced type II priming, in which it depends on the beta/gamma subunit. These data implicate a novel form of Gi-protein signaling pathway in the type II hyperalgesic priming induced by repeated administration of an agonist at A1-adenosine receptor to the peripheral terminal of the nociceptor. PMID- 26588697 TI - A longitudinal study of pain, personality, and brain plasticity following peripheral nerve injury. AB - We do not know precisely why pain develops and becomes chronic after peripheral nerve injury (PNI), but it is likely due to biological and psychological factors. Here, we tested the hypotheses that (1) high Pain Catastrophizing Scale (PCS) scores at the time of injury and repair are associated with pain and cold sensitivity after 1-year recovery and (2) insula gray matter changes reflect the course of injury and improvements over time. Ten patients with complete median and/or ulnar nerve transections and surgical repair were tested ~3 weeks after surgical nerve repair (time 1) and ~1 year later for 6 of the 10 patients (time 2). Patients and 10 age-/sex-matched healthy controls completed questionnaires that assessed pain (patients) and personality and underwent quantitative sensory testing and 3T MRI to assess cortical thickness. In patients, pain intensity and neuropathic pain correlated with pain catastrophizing. Time 1 pain catastrophizing trended toward predicting cold pain thresholds at time 2, and at time 1 cortical thickness of the right insula was reduced. At time 2, chronic pain was related to the time 1 pain-PCS relationship and cold sensitivity, pain catastrophizing correlated with cold pain threshold, and insula thickness reversed to control levels. This study highlights the interplay between personality, sensory function, and pain in patients following PNI and repair. The PCS-pain association suggests that a focus on affective or negative components of pain could render patients vulnerable to chronic pain. Cold sensitivity and structural insula changes may reflect altered thermosensory or sensorimotor awareness representations. PMID- 26588698 TI - Meta-analysis of placebo responses in central neuropathic pain: impact of subject, study, and pain characteristics. AB - The placebo response is a complex construct related to psychobiological effects, as well as natural history and regression to the mean. Moreover, patient and study design characteristics have also been proposed as significantly affecting placebo responses. The aim of the current investigation was to identify factors that contribute to variable placebo responses in clinical trials involving individuals with central neuropathic pain. To this end, we performed a systematic review and meta-analysis of placebo-controlled trials examining pharmacological and noninvasive brain stimulation interventions for central neuropathic pain. Study design, subject characteristics, and pain ratings for the placebo group were extracted from each trial. Pooling of results and identification of moderating factors were carried out using random effects meta-analysis and meta regression techniques. A total of 39 published trials met the inclusion criteria (spinal cord injury, n = 26; stroke, n = 6; multiple sclerosis, n = 7). No significant publication bias was detected. Overall, there was a significant effect for placebo to reduce central pain (-0.64, CI: -0.83 to -0.45). Smaller placebo responses were associated with crossover-design studies, longer pain duration, and greater between-subject baseline pain variability. There were no significant effects for neurological condition (stroke vs multiple sclerosis vs spinal cord injury) or the type of intervention (eg, pharmacological vs noninvasive brain stimulation). In a planned subanalysis, the severity of damage in the spinal cord also had no significant effect on the placebo response. Further study is warranted to identify factors that may explain the impact of pain duration on the placebo response at the individual subject level. PMID- 26588699 TI - Water Desalination through Zeolitic Imidazolate Framework Membranes: Significant Role of Functional Groups. AB - A molecular simulation study is reported for water desalination through five zeolitic imidazolate framework (ZIF) membranes, namely ZIF-25, -71, -93, -96, and -97. The five ZIFs possess identical rho-topology but differ in functional groups. The rejection of salt (NaCl) is found to be around 97% in ZIF-25, and 100% in the other four ZIFs. The permeance ranges from 27 to 710 kg/(m(2).h.bar), about one~two orders of magnitude higher compared with commercial reverse osmosis membranes. Due to a larger aperture size da, ZIF-25, -71, and -96 exhibit a much higher water flux than ZIF-93 and -97; however, the flux in ZIF-25, -71, and -96 is governed by the polarity of functional group rather than da. With the hydrophobic CH3 group, ZIF-25 has the highest flux despite the smallest da among ZIF-25, -71, and -96. The lifetime of hydrogen bonding in ZIF-25 is shorter than that in ZIF-71 and -96. Furthermore, water molecules undergo a fast flushing motion in ZIF-25, but frequent jumping in ZIF-96 and particularly in ZIF-97. An Arrhenius-type relationship is found between water flux in ZIF-25 and temperature, and the activation energy is predicted to be 6.5 kJ/mol. This simulation study provides a microscopic insight into water desalination in a series of ZIFs, reveals the key factors (aperture size and polarity of functional group) governing water flux, and suggests that ZIF-25 might be an interesting reverse osmosis membrane for high-performance water desalination. PMID- 26588700 TI - Anti-Obesity Effect of the CB2 Receptor Agonist JWH-015 in Diet-Induced Obese Mice. AB - The cannabinoid receptor 2 (CB2) is well known for its immune modulatory role. However, recent localisation of CB2 receptors in metabolically active tissue suggests that the CB2 receptor plays a significant role in energy homeostasis. This study was designed to investigate the impact of chronic CB2 receptor stimulation on food intake, body weight and mood. Lean male C57BL/6 mice were injected i.p. with the selective CB2 receptor agonist, JWH-015 (0.0, 1.0, 5.0 and 10.0 mg kg-1) to establish dose response parameters. Mice made obese following exposure to a diet consisting of 19.4 MJ/kg (4641 Kcal/kg) of energy (19.0% protein, 21.0% total fat, 4.7% crude fiber, and 4.7% AD fiber were given either vehicle or 10 mg/kg JWH-015. Impact on mood, food intake, body weight, plasma metabolites, expression of key metabolic proteins in the brown adipose tissue (BAT) and white adipose tissue (WAT), and markers of inflammation were measured. High dose (10 mg/kg) JWH-015 reduced food intake after 1, 2, 4, and 24 h in lean mice. When given to diet induced obese (DIO) mice, a 10 mg/kg dose of JWH-015 significantly reduced body weight compared to vehicle. This dose led to a shift in markers of lipid metabolism and inflammation in WAT consistent with lipolysis and improved immune response. Furthermore, JWH-015 (10 mg/kg) produced a transient reduction in food intake and significant reduction in fat mass and adipocyte cell size. Importantly, JWH-015 produced an anxiolytic response in the elevated plus maze while having no effect on immobility time in the forced swim test. It should be noted that though the 10 mg/kg dose produced positive effects on the obese state, the possibility that these effects are mediated via non-CB2 receptor mechanisms cannot be ruled out. These results demonstrate a role for CB2 receptors in modulating energy homeostasis and obesity associated metabolic pathologies in the absence of any adverse impact on mood. PMID- 26588701 TI - SOX18 Is a Novel Target Gene of Hedgehog Signaling in Cervical Carcinoma Cell Lines. AB - Although there is much evidence showing functional relationship between Hedgehog pathway, in particular Sonic hedgehog, and SOX transcription factors during embryonic development, scarce data are available regarding their crosstalk in cancer cells. SOX18 protein plays an important role in promoting tumor angiogenesis and therefore emerged as a promising potential target in antiangiogenic tumor therapy. Recently it became evident that expression of SOX18 gene in tumors is not restricted to endothelium of accompanying blood and lymphatic vessels, but in tumor cells as well.In this paper we have identified human SOX18 gene as a novel target gene of Hedgehog signaling in cervical carcinoma cell lines. We have presented data showing that expression of SOX18 gene is regulated by GLI1 and GLI2 transcription factors, final effectors of Hedgehog signaling, and that modulation of Hedgehog signaling activity in considerably influence SOX18 expression. We consider important that Hedgehog pathway inhibitors reduced SOX18 expression, thus showing, for the first time, possibility for manipulationwith SOX18 gene expression. In addition, we analyzed the role of SOX18 in malignant potential of cervical carcinoma cell line, and showed that its overexpression has no influence on cells proliferation and viability, but substantially promotes migration and invasion of cells in vitro. Pro-migratory effect of SOX18 suggests its role in promoting malignant spreading, possibly in response to Hedgehog activation. PMID- 26588703 TI - Serum Thiol/Disulphide Homeostasis in Preeclampsia. AB - OBJECTIVE: To determine the serum thiol/disulphide homeostasis in preeclampsia and to investigate the association with clinical parameters. METHODS: Forty-three pregnant women with preeclampsia and 43 healthy, uncomplicated pregnancies were included in the study. Native thiol, disulphide, and total thiol concentrations were measured by a novel automated method. RESULTS: The serum native and total thiol levels were significantly lower in preeclampsia when compared with the healthy group (p < 0.001). There were significant correlations among the homeostatic parameters and preeclampsia. CONCLUSION: Serum thiol/disulphide homeostasis may have a role in the pathogenesis and can be evaluated with the clinical and laboratory findings of preeclampsia. PMID- 26588702 TI - A Tandem Duplicate of Anti-Mullerian Hormone with a Missense SNP on the Y Chromosome Is Essential for Male Sex Determination in Nile Tilapia, Oreochromis niloticus. AB - Variation in the TGF-beta signaling pathway is emerging as an important mechanism by which gonadal sex determination is controlled in teleosts. Here we show that amhy, a Y-specific duplicate of the anti-Mullerian hormone (amh) gene, induces male sex determination in Nile tilapia. amhy is a tandem duplicate located immediately downstream of amhDelta-y on the Y chromosome. The coding sequence of amhy was identical to the X-linked amh (amh) except a missense SNP (C/T) which changes an amino acid (Ser/Leu92) in the N-terminal region. amhy lacks 5608 bp of promoter sequence that is found in the X-linked amh homolog. The amhDelta-y contains several insertions and deletions in the promoter region, and even a 5 bp insertion in exonVI that results in a premature stop codon and thus a truncated protein product lacking the TGF-beta binding domain. Both amhy and amhDelta-y expression is restricted to XY gonads from 5 days after hatching (dah) onwards. CRISPR/Cas9 knockout of amhy in XY fish resulted in male to female sex reversal, while mutation of amhDelta-y alone could not. In contrast, overexpression of Amhy in XX fish, using a fosmid transgene that carries the amhy/amhDelta-y haplotype or a vector containing amhy ORF under the control of CMV promoter, resulted in female to male sex reversal, while overexpression of AmhDelta-y alone in XX fish could not. Knockout of the anti-Mullerian hormone receptor type II (amhrII) in XY fish also resulted in 100% complete male to female sex reversal. Taken together, these results strongly suggest that the duplicated amhy with a missense SNP is the candidate sex determining gene and amhy/amhrII signal is essential for male sex determination in Nile tilapia. These findings highlight the conserved roles of TGF-beta signaling pathway in fish sex determination. PMID- 26588705 TI - Brief Report: Enhanced Allogeneic Cellular Responses to Mismatched HLA-B Antigens Results in More Efficient Killing of HIV Infected Cells. AB - Epidemiologic studies have demonstrated that HIV-1 discordant couples who share HLA-B alleles were more likely to transmit HIV-1. These data lead us to hypothesize that individuals who match at both HLA-B alleles should have a reduced allogeneic response than those who are not matched. We observed diminished killing of CD4 target cells only when HLA-B alleles were matched. We propose that for cell-associated HIV-1 transmission, the ability of the recipient to eliminate infected cells from a donor partner may be enhanced when HLA-B alleles are different between partners. These findings suggest a novel mechanism for protection against HIV infection. PMID- 26588704 TI - Genomic Analysis of Detoxification Supergene Families in the Mosquito Anopheles sinensis. AB - Anopheles sinensis is an important malaria vector in China and other Southeast Asian countries, and the emergence of insecticide resistance in this mosquito poses a serious threat to the efficacy of malaria control programs. The recently published An. sinensis genome and transcriptome provide an opportunity to understand the molecular mechanisms of insecticide resistance. Analysis of the An. sinensis genome revealed 174 detoxification genes, including 93 cytochrome P450s (P450s), 31 glutathione-S-transferases (GSTs), and 50 choline/carboxylesterases (CCEs). The gene number was similar to that in An. gambiae, but represented a decrease of 29% and 42% compared with Aedes aegypti and Culex quinquefasciatus, respectively. The considerable contraction in gene number in Anopheles mosquitoes mainly occurred in two detoxification supergene families, P450s and CCEs. The available An. sinensis transcriptome was also re analyzed to further identify key resistance-associated detoxification genes. Among 174 detoxification genes, 124 (71%) were detected. Several candidate genes overexpressed in a deltamethrin-resistant strain (DR-strain) were identified as belonging to the CYP4 or CYP6 family of P450s and the Delta GST class. These generated data provide a basis for identifying the resistance-associated genes of An. sinensis at the molecular level. PMID- 26588707 TI - Chromium Environment within Cr-Doped BaAl2O4: Correlation of X-ray Diffraction and X-ray Absorption Spectroscopy Investigations. AB - Powder BaAl2O4 samples doped with 0 and 1.76 atom % Cr in relation to Al were hydrothermally prepared. Both samples were characterized by X-ray diffraction and synchrotron based X-ray absorption spectroscopy at the Cr K- and the Ba L3-edge. Diffraction patterns indicated that samples were nanocrystalline with a hexagonal crystal structure, space group P63. Chromium doping of barium aluminate caused an increase of the unit-cell volume and diffraction line broadening. The doped sample contained a small amount of an impurity phase, namely, BaCrO4. Analyzed Cr K-edge X-ray absorption near edge structure for the doped sample showed the presence of chromium in 6+ and 3+ oxidation states: Cr(6+) was characteristic for chromium in the impurity phase BaCrO4, while Cr(3+) participated in the formation of the doped phase BaAl2O4:Cr. Extended X-ray absorption fine structure suggested an unusual tetrahedral coordination of Cr(3+) ions within the BaAl2O4 host phase. The structure of samples was refined by the Rietveld method, simultaneously with the analysis of diffraction line broadening. Rietveld structure refinement showed that in doping the Cr(3+) ions likely substituted for Al(3+) ions on Al1 tetrahedral sites of barium aluminate crystal lattice. Crystallite sizes in the samples decreased with chromium doping, from 32 nm for pure BaAl2O4 to 24 nm for Cr-doped BaAl2O4. The dopant Cr(3+) cations acted as defects in the barium aluminate structure that increased lattice strain from 0.02% for pure BaAl2O4 to 0.14% for doped BaAl2O4 and disturbed the crystallites to grow. PMID- 26588706 TI - Effects of Low-Dose Diethylstilbestrol Exposure on DNA Methylation in Mouse Spermatocytes. AB - Evidence from previous studies suggests that the male reproductive system can be disrupted by fetal or neonatal exposure to diethylstilbestrol (DES). However, the molecular basis for this effect remains unclear. To evaluate the effects of DES on mouse spermatocytes and to explore its potential mechanism of action, the levels of DNA methyltransferases (DNMTs) and DNA methylation induced by DES were detected. The results showed that low doses of DES inhibited cell proliferation and cell cycle progression and induced apoptosis in GC-2 cells, an immortalized mouse pachytene spermatocyte-derived cell line, which reproduces primary cells responses to E2. Furthermore, global DNA methylation levels were increased and the expression levels of DNMTs were altered in DES-treated GC-2 cells. A total of 141 differentially methylated DNA sites were detected by microarray analysis. Rxra, an important component of the retinoic acid signaling pathway, and mybph, a RhoA pathway-related protein, were found to be hypermethylated, and Prkcd, an apoptosis-related protein, was hypomethylated. These results showed that low-dose DES was toxic to spermatocytes and that DNMT expression and DNA methylation were altered in DES-exposed cells. Taken together, these data demonstrate that DNA methylation likely plays an important role in mediating DES-induced spermatocyte toxicity in vitro. PMID- 26588708 TI - A novel role for atypical MAPK kinase ERK3 in regulating breast cancer cell morphology and migration. AB - ERK3 is an atypical Mitogen-activated protein kinase (MAPK6). Despite the fact that the Erk3 gene was originally identified in 1991, its function is still unknown. MK5 (MAP kinase- activated protein kinase 5) also called PRAK is the only known substrate for ERK3. Recently, it was found that group I p21 protein activated kinases (PAKs) are critical effectors of ERK3. PAKs link Rho family of GTPases to actin cytoskeletal dynamics and are known to be involved in the regulation of cell adhesion and migration. In this study we demonstrate that ERK3 protein levels are elevated as MDA-MB-231 breast cancer cells adhere to collagen I which is concomitant with changes in cellular morphology where cells become less well spread following nascent adhesion formation. During this early cellular adhesion event we observe that the cells retain protrusive activity while reducing overall cellular area. Interestingly exogenous expression of ERK3 delivers a comparable reduction in cell spread area, while depletion of ERK3 expression increases cell spread area. Importantly, we have detected a novel specific endogenous ERK3 localization at the cell periphery. Furthermore we find that ERK3 overexpressing cells exhibit a rounded morphology and increased cell migration speed. Surprisingly, exogenous expression of a kinase inactive mutant of ERK3 phenocopies ERK3 overexpression, suggesting a novel kinase independent function for ERK3. Taken together our data suggest that as cells initiate adhesion to matrix increasing levels of ERK3 at the cell periphery are required to orchestrate cell morphology changes which can then drive migratory behavior. PMID- 26588710 TI - Clarithromycin ion pair in a liposomal membrane to improve its stability and reduce its irritation caused by intravenous administration. AB - OBJECTIVE: The aim of this study was to improve the drug loading (DL) and stability of clarithromycin (CLA)-loaded liposomes, and reduce the irritation caused by intravenous administration of CLA. METHODS: A CLA-cholesteryl hemisuccinate (CHEMS) ion pair (CIP) was prepared by the solvent evaporation method and confirmed by fourier transform infrared spectroscopy, (1)H-nuclear magnetic resonance, differential scanning calorimetry and X-ray powder diffraction. Subsequently, CIP liposomes (CIP-Lip) were prepared by the thin-film dispersion method and evaluated in terms of their size, zeta-potential, in vitro release, stability, in vitro antimicrobial activity and irritation. RESULTS: The CIP-Lip exhibited a homogeneous round shape, and their size, zeta-potential, encapsulation efficiency (EE) and DL were 71.89 +/- 2.6 nm, -9.91 +/- 0.82 mV, 95.1 +/- 1.5% and 7.8 +/- 0.3%, respectively. The physical appearance and drug content of CIP-Lip over a three-month storage remained almost unchanged. The release of CLA in CIP-Lip was pH-dependent, with a more rapid release at pH 6.0 than at pH 7.4. Although the in vitro antimicrobial activity of CIP-Lip was comparable with free CLA, the irritation produced by CIP-Lip was significantly reduced compared with CLA solution. CONCLUSIONS: These findings suggest that CIP Lip is a promising intravenous drug delivery system, especially on account of its high DL and reduced irritation. PMID- 26588709 TI - Co-expression of fibulin-5 and VEGF165 increases long-term patency of synthetic vascular grafts seeded with autologous endothelial cells. AB - Small caliber synthetic vascular grafts are commonly used for bypass surgery and dialysis access sites but have high failure rates because of neointima formation and thrombosis. Seeding synthetic grafts with endothelial cells (ECs) provides a biocompatible surface that may prevent graft failure. However, EC detachment following exposure to blood flow still remains a major obstacle in the development of biosynthetic grafts. We tested the hypothesis that induced expression by the seeded EC, of vascular endothelial growth factor165 (VEGF165) and of fibulin-5, an extracellular matrix glycoprotein that has a crucial role in elastin fiber organization and increase EC adherence to surfaces, may improve long-term graft patency. Autologous ECs were isolated from venous segments, and were transduced with retroviral vectors expressing fibulin-5 and VEGF165. The modified cells were seeded on expanded polytetrafluoroethylene (ePTFE) grafts and implanted in a large animal model. Three months after transplantation, all grafts seeded with modified EC were patent on a selective angiography, whereas only a third of the control grafts were patent. Similar results were shown at 6 months. Thus, seeding ePTFE vascular grafts with genetically modified EC improved long term small caliber graft patency. The biosynthetic grafts may provide a novel therapeutic modality for patients with peripheral vascular disease and patients requiring vascular access for hemodialysis. PMID- 26588711 TI - Treatment for superficial infusion thrombophlebitis of the upper extremity. AB - BACKGROUND: Although superficial thrombophlebitis of the upper extremity represents a frequent complication of intravenous catheters inserted into the peripheral veins of the forearm or hand, no consensus exists on the optimal management of this condition in clinical practice. OBJECTIVES: To summarise the evidence from randomised clinical trials (RCTs) concerning the efficacy and safety of (topical, oral or parenteral) medical therapy of superficial thrombophlebitis of the upper extremity. SEARCH METHODS: The Cochrane Vascular Group Trials Search Co-ordinator searched the Specialised Register (last searched April 2015) and the Cochrane Register of Studies (2015, Issue 3). Clinical trials registries were searched up to April 2015. SELECTION CRITERIA: RCTs comparing any (topical, oral or parenteral) medical treatment to no intervention or placebo, or comparing two different medical interventions (e.g. a different variant scheme or regimen of the same intervention or a different pharmacological type of treatment). DATA COLLECTION AND ANALYSIS: We extracted data on methodological quality, patient characteristics, interventions and outcomes, including improvement of signs and symptoms as the primary effectiveness outcome, and number of participants experiencing side effects of the study treatments as the primary safety outcome. MAIN RESULTS: We identified 13 studies (917 participants). The evaluated treatment modalities consisted of a topical treatment (11 studies), an oral treatment (2 studies) and a parenteral treatment (2 studies). Seven studies used a placebo or no intervention control group, whereas all others also or solely compared active treatment groups. No study evaluated the effects of ice or the application of cold or hot bandages. Overall, the risk of bias in individual trials was moderate to high, although poor reporting hampered a full appreciation of the risk in most studies. The overall quality of the evidence for each of the outcomes varied from low to moderate mainly due to risk of bias and imprecision, with only single trials contributing to most comparisons. Data on primary outcomes improvement of signs and symptoms and side effects attributed to the study treatment could not be statistically pooled because of the between-study differences in comparisons, outcomes and type of instruments to measure outcomes.An array of topical treatments, such as heparinoid or diclofenac gels, improved pain compared to placebo or no intervention. Compared to placebo, oral non-steroidal anti-inflammatory drugs reduced signs and symptoms intensity. Safety issues were reported sparsely and were not available for some interventions, such as notoginseny creams, parenteral low-molecular-weight heparin or defibrotide. Although several trials reported on adverse events with topical heparinoid creams, Essaven gel or phlebolan versus control, the trials were underpowered to adequately measure any differences between treatment modalities. Where reported, adverse events with topical treatments consisted mainly of local allergic reactions. Only one study of 15 participants assessed thrombus extension and symptomatic venous thromboembolism with either oral non-steroidal anti-inflammatory drugs or low-molecular-weight heparin, and it reported no cases of either. No study reported on the development of suppurative phlebitis, catheter-related bloodstream infections or quality of life. AUTHORS' CONCLUSIONS: The evidence about the treatment of acute infusion superficial thrombophlebitis is limited and of low quality. Data appear too preliminary to assess the effectiveness and safety of topical treatments, systemic anticoagulation or oral non-steroidal anti-inflammatory drugs. PMID- 26588712 TI - High Temperature Chemistry of Chlorinated Acenaphthylene. 3C Bay Acetylene Additions and Annealing by Five-Membered Ring Shifts. AB - Experimental and theoretical results concerning the growth and isomerization of chlorinated acenaphthylene, C12H8, during the pyrolysis of chlorohydrocarbons are presented here. A fullerene subunit, C12H8, is a useful system to investigate regarding C60 formation. However, direct experimental observation of isomerization and annealing processes in particular are difficult to confirm due to the high symmetry of the parent molecule. Chlorination lowers the symmetry, essentially labeling carbon atoms, allowing growth and isomerization to be followed directly. Pyrolysis of dichloro- and trichloroethylene, and their copyrolyses with trichlorobenzenes, provides an efficient and general source of chlorinated acenaphthylenes in a range of degrees of chlorination and over a number of unique congeners. Analysis of congener yields as a function of reagents employed, guided by DFT/B3LYP/6-311G(d,p) level calculations, strongly suggests that C2 addition across three-carbon bays in naphthalene is a major driver of growth. Additionally, extremely facile five-membered ring shifts are operative, with chlorine promoting isomerization. Theoretical study of C16H10- and C18H10 based congeners indicate that this is a general phenomenon, and with chlorine also favoring internal cyclopentafused rings in addition to increased isomerization rates, this suggests halogen moieties may be an important feature for efficient fullerene growth. PMID- 26588713 TI - RabGEF1/Rabex-5 Regulates TrkA-Mediated Neurite Outgrowth and NMDA-Induced Signaling Activation in NGF-Differentiated PC12 Cells. AB - Nerve growth factor (NGF) binds to its cognate receptor TrkA and induces neuronal differentiation by activating distinct downstream signal transduction events. RabGEF1 (also known as Rabex-5) is a guanine nucleotide exchange factor for Rab5, which regulates early endosome fusion and vesicular trafficking in endocytic pathways. Here, we used the antisense (AS) expression approach to induce an NGF dependent sustained knockdown of RabGEF1 protein expression in stable PC12 transfectants. We show that RabGEF1 is a negative regulator of NGF-induced neurite outgrowth and modulates other cellular and signaling processes that are activated by the interaction of NGF with TrkA receptors, such as cell cycle progression, cessation of proliferation, and activation of NGF-mediated downstream signaling responses. Moreover, RabGEF1 can bind to Rac1, and the activation of Rac1 upon NGF treatment is significantly enhanced in AS transfectants, suggesting that RabGEF1 is a negative regulator of NGF-induced Rac1 activation in PC12 cells. Furthermore, we show that RabGEF1 can also interact with NMDA receptors by binding to the NR2B subunit and its associated binding partner SynGAP, and negatively regulates activation of nitric oxide synthase activity induced by NMDA receptor stimulation in NGF-differentiated PC12 cells. Our data suggest that RabGEF1 is a negative regulator of TrkA-dependent neuronal differentiation and of NMDA receptor-mediated signaling activation in NGF-differentiated PC12 cells. PMID- 26588716 TI - [Posttraumatic Stress Disorder - an Interdisciplinary Problem for Psychiatrists and Neurologists]. PMID- 26588715 TI - The Relationship Between Sexual Content on Mass Media and Social Media: A Longitudinal Study. AB - The goal of this study was to investigate whether exposure to sexual reality television content and Internet pornography (IP) is related to sexual self presentation on social media. Based on a two-wave panel survey among 1,765 adolescents aged 13-17 years, we found that watching sexual reality television content stimulated adolescents to produce and distribute sexual images of themselves on social media. In turn, sexual self-presentation on social media led adolescents to watch sexual reality television content more frequently. These relationships were similar among boys and girls. No reciprocal relationship between exposure to IP and boys' and girls' sexual self-presentation on social media was found. The results suggest that sexual content in mainstream mass media may predict adolescents' sexually oriented behavior on social media and vice versa. Moreover, adolescents seem to differentiate between types of sexual content (i.e., mainstream versus more explicit sexual content) when incorporating sexual media content in their sexual behavior online. PMID- 26588714 TI - Upper Airway Changes after Orthodontic Extraction Treatment in Adults: A Preliminary Study using Cone Beam Computed Tomography. AB - OBJECTIVE: Whether the orthodontic treatment with premolar extraction and maximum anchorage in adults will lead to a narrowed upper airway remains under debated. The study aims to investigate the airway changes after orthodontic extraction treatment in adult patients with Class II and hyperdivergent skeletal malocclusion. MATERIALS AND METHODS: This retrospective study enrolled 18 adults with Class II and hyperdivergent skeletal malocclusion (5 males and 13 females, 24.1 +/- 3.8 years of age, BMI 20.33 +/- 1.77 kg/m2). And 18 untreated controls were matched 1:1 with the treated patients for age, sex, BMI, and skeletal pattern. CBCT images before and after treatment were obtained. DOLPHIN 11.7 software was used to reconstruct and measure the airway size, hyoid position, and craniofacial structures. Changes in the airway and craniofacial parameters from pre to post treatment were assessed by Wilcoxon signed rank test. Mann-Whitney U test was used in comparisons of the airway parameters between the treated patients and the untreated controls. Significant level was set at 0.05. RESULTS: The upper and lower incisors retracted 7.87 mm and 6.10 mm based on the measurement of U1-VRL and L1-VRL (P < 0.01), while the positions of the upper and lower molars (U6-VRL, and L6-VRL) remained stable. Volume, height, and cross sectional area of the airway were not significantly changed after treatment, while the sagittal dimensions of SPP-SPPW, U-MPW, PAS, and V-LPW were significantly decreased (P < 0.05), and the morphology of the cross sections passing through SPP-SPPW, U-MPW, PAS, and V-LPW became anteroposteriorly compressed (P <0.001). No significant differences in the airway volume, height, and cross-sectional area were found between the treated patients and untreated controls. CONCLUSIONS: The airway changes after orthodontic treatment with premolar extraction and maximum anchorage in adults are mainly morphological changes with anteroposterior dimension compressed in airway cross sections, rather than a decrease in size. PMID- 26588717 TI - [A Systematic Review of Personality Disorders and Addiction: Epidemiology, Course and Treatment]. AB - AIM: This paper provides a systematic overview of the comorbidity of personality and addictive disorders including behavioural addictions. METHOD: Systematic review. RESULTS: Personality disorders and substance-related addictions show high comorbidity rates. This is equally true of behavioural addictions. Most empirical research is on comorbidity with borderline personality disorder. For treatment of individuals with dual diagnoses, three psychotherapies have been demonstrated to be effective. Pharmacotherapeutic approaches have hardly been investigated. CONCLUSION: METHODologically integrative treatment represents therapy of choice for patients with dual diagnoses. Comorbidity of personality disorders and behavioural addictions needs further investigation. PMID- 26588718 TI - [Characteristics of Hospitalized Mentally ill Spanish Migrants in Germany - Results of a Statistical Reanalysis]. AB - OBJECTIVE: To draft a clinical profile of mentally ill first-generation Spanish immigrants in Germany treated in a special setting in their native language and to identify possible correlations between time of onset of a mental disorder and migration and also between degree of utilization and clinical as well as care variables. METHOD: Statistical reanalysis of individual data (n = 100) of a previously published descriptive study with aggregated data corresponding to 15 variables. Correlations are calculated using chi-square as well as Fisher's exact test. Multivariate regression and logistic models were conducted. In addition to the explained variance of the models (R(2)), analyses of residuals as well as post-hoc power analyses (1-beta) were performed. RESULTS: A quarter of the sample (26 %) was mentally ill before migration; most of the patients received treatment very late (about 10 years after onset) and became chronically ill. Half of the sample shows a relevant somatic comorbidity and large average lengths of inpatient stays (54 days). In 16 % of treated cases, repatriation had to be organized. The degree of chronicity correlates with mental illness prior to migration. Severe mood disorders and psychoses occur late after having migrated, addictions and neurotic disorders are equally distributed over time. DISCUSSION: Migration can not be set in a causal relationship with the development of mental disorders, although there is a positive correlation between affective disorders and the duration of the migration status. Chronicity is related to an outbreak of the disease before migration. The sample is relatively homogeneous (one nationality, first generation), but loses epidemiological representativeness (not related to a catchment area). PMID- 26588719 TI - [Differences in Attitudes of Patients with Mild Cognitive Impairment Towards Early Diagnosis at a University Clinic and a Specialist Physician's Office]. AB - AIM: To examine the attitude of patients with mild cognitive impairment to diagnostics under different healthcare settings. METHODOLOGY: A comparative survey was carried out of 38 patients at a university outpatient clinic and 91 patients at a specialist practice with regard to their attitudes towards early diagnosis of dementia and willingness to undergo CSF analysis. RESULTS: Willingness to undergo CSF analysis was higher among the patients at the university outpatient unit than those at the specialist practice (p = 0.040), and willingness to undergo early diagnosis was comparable high in both groups. CONCLUSION: Different attitudes of patients with mild cognitive impairment should be reflected in different healthcare settings. PMID- 26588720 TI - [On the Differential Diagnosis of Intractable Psychogenic Chronic Cough: Neuropathic Larynx Irritable - Gabapentin's Antitussive Action]. AB - We present the case of a 76 year old female inpatient who suffered from a chronic intractable cough which arose simultaneously to a severe major depression and was secondary to an exorbitant psychological distress. Chronic cough had never been experienced before and was initially considered to have a mere psychogenic origin since a comprehensive and guideline-based diagnostic screening did not reveal any underlying somatic cause. However, several factors cast doubt on the solitary psychic genesis of the chronic cough: i) occurrence immediately after a penetrant cold, ii) embedding in other complaints of laryngeal hyperreagibility (larynx irritable), such as persistent globus pharyngeus sensation, throat clearing and episodic dysphonia, iii) first occurrence on old life, iv) erupting from sleep as well, v) persistence despite remission of the major depression, and v) no sustaining benefit from specific psychotherapy and speech therapy. Therefore, diagnostics were extended to apparative tools for objective evaluation of swallowing by using fiberoptic videoendoscopic (FEES) and videofluoroscopic (VFS) techniques, which revealed signs of laryngeal neuropathy but without evidence of penetration or aspiration. A co-existing small goiter and an impaired glucose tolerance along with a putative intracellular vitamin B12 or folate deficiency (as indirectly derived from an apparent hyperhomocysteinemia) were assumed to be responsible for the neuropathy and underwent specific treatments. The impaired glucose tolerance and putative vitamin deficit were compatible with a distal symmetric sensorimotoric, even subclinical polyneuropathy of the lower extremities. The larynx irritable improved under gabapentin being confirmed by drug removals several times, and finally calmed down almost completely under gabapentin, which was in line with the scant literature of this topic. Re examination of the larynx per FEES nine months later showed no deficits any more under the well-tolerated treatment (gabapentin, levothyroxine, vitamin B12 and folic acid substitution, weight reduction and physical training). All in all, the larynx irritable as well as the chronic cough were most probably induced by a laryngeal neuropathy and were not solely of psychic origin. Due to good treatment options a larynx irritable should be regularly taken into consideration of the investigation of intractable chronic cough. Therefore, an apparative evaluation of deglutition is recommended in the diagnostic toolbox of chronic cough - even if embedded in a psychiatric disorder or distress - before diagnosing a sole psychic origin. An hypothetical scheme of the development of a larynx irritable caused by neuropathic and non-neuropathic ("nociceptive") conditions is proposed. PMID- 26588721 TI - [Assessment of Trauma-Related Disorders]. AB - The assessment of trauma-related disorders is increasingly important in forensic psychiatric expert opinion. The most important diagnosis in this context is posttraumatic stress disorder. Diagnostic criteria of this disorder are outlined. Differential diagnostic considerations with regard to less specific symptom complexes, such as the complex posttraumatic stress disorder are discussed. Furthermore the significance of symptom validity tests is critically discussed. Test results have to be considered carefully in the medicolegal context and require thorough clinical assessment. PMID- 26588722 TI - [Not Available]. PMID- 26588723 TI - [Not Available]. PMID- 26588724 TI - Circadian rhythm mediates the relationship between physical activity and quality of life in younger and older cancer survivors. AB - Increasing evidence suggests that physical activity (PA) improves the quality of life (QoL) of cancer survivors. However, the biological mechanisms underlying the relationship between PA and QoL are unclear. The purpose of this study was to determine whether the relationship between PA and QoL differs in younger and older cancer survivors and whether circadian rhythm (CR) mediates this relationship. We also explored the effect of the CR on QoL. The participants were 235 cancer survivors, comprising 143 younger and 92 older patients. Data were collected using the Taiwanese versions of the Physical Activity Scale for the Elderly and Short Form-36. The robustness and stability of the CR were measured using an actigraph. Mediation was tested using multiple mediation analyses. The CR mediated the relationship between PA and the physical domain of QoL in younger and older cancer survivors (23% and 59% mediating effects, respectively). The CR partially mediated the effect of PA on the mental dimension of QoL in older cancer survivors (36% mediating effect), but not in younger cancer survivors. Cancer survivors with a more robust CR had a significantly higher QoL, particularly in the physical functioning domain (d = 0.43, p < 0.001). The results provided evidence that the CR mediated the relationship between PA and QoL. Moreover, this mediating effect differed in younger and older cancer survivors. These results can serve as a reference for designing individualized PA programs for cancer survivors. PMID- 26588725 TI - Adherence to Surgical Antibiotic Prophylaxis Guidelines in New South Wales, Australia: Identifying Deficiencies and Regression Analysis of Contributing Factors. AB - BACKGROUND: Surgical antibiotic prophylaxis is frequently reported in the literature to be suboptimal, a finding having both clinical and public health implications. This study aimed to calculate rates and patterns of adherence to guidelines at two sites and identify extrinsic contributing factors. METHODS: A retrospective analysis was conducted over two 12-mo periods during 2013-2014 at the metropolitan Blacktown Hospital and regional Lismore Base Hospital, New South Wales, Australia. A group of 400 patients undergoing abdominal general surgery was selected via simple random sampling (n = 200 per site). Medical records were reviewed, and prophylactic antibiotic regimens were compared with the Australian guideline, Therapeutic Guidelines: Antibiotic (v. 14) with respect to drug choice, dosage, timing of administration, and duration of administration. RESULTS: The overall rate of adherence to the guidelines was 16.5% at Blacktown Hospital and 19.5% at Lismore Base Hospital. At each site, prophylaxis was administered to more than 95% of patients and was inappropriately withheld in 4%. Drug choice was the most frequent error type, specifically involving inappropriate omission of metronidazole and use of newer-generation cephalosporins. Errors in the timing of administration also were frequent, with prophylaxis typically occurring excessively early. Logistic regression identified emergency surgery as independently associated with prophylactic errors in both the Blacktown Hospital (p < 0.001) and the Lismore Base Hospital cohorts (p = 0.020). CONCLUSIONS: Adherence to antibiotic prophylactic guidelines was poor at both the metropolitan and regional sites. Choice of antibiotic and timing of administration were identified as major error types. Consideration should be given to multidisciplinary involvement of anesthetists, implementation of focused interventions with an emphasis on emergency settings, and further research correlating antibiotic use with clinical significance. PMID- 26588726 TI - Significantly Enhanced Dielectric Performance of Poly(vinylidene fluoride-co hexafluoropylene)-based Composites Filled with Hierarchical Flower-like TiO2 Particles. AB - In this study, we report a feasible strategy for fabricating high-dielectric constant polymer composites for applications in energy storage devices and embedded capacitors. Hierarchical flower-like TiO2 particles were prepared via a facile solvothermal process and incorporated into the P(VDF-HFP) matrix. The temperature and frequency dependent dielectric properties of flower-like TiO2/P(VDF-HFP) composites as well as commercial TiO2/P(VDF-HFP) composites were investigated. The results reveal that the flower-like TiO2 particles are more effective in increasing the dielectric constant of P(VDF-HFP) when compared with commercial TiO2. Typically, the dielectric constant of the P(VDF-HFP) composite filled with 20 vol % flower-like TiO2 reaches 83.1 at 100 Hz, in contrast to 43.4 for the composite filled with 20 vol % commercial TiO2 and 11.3 for pristine P(VDF-HFP). Also, the flower-like TiO2-filled composites exhibit similar characteristic breakdown strengths to their commercial TiO2-filled counterparts. The significant improvement in the dielectric constant could be attributed to the enhancement of Maxwell-Wagner-Sillars polarization, which originates from the sophisticated morphology of flower-like TiO2 particles. PMID- 26588728 TI - Molecular Simulations Highlight the Role of Metals in Catalysis and Inhibition of Type II Topoisomerase. AB - Type II topoisomerase (topoII) is a metalloenzyme targeted by clinical antibiotics and anticancer agents. Here, we integrate existing structural data with molecular simulation and propose a model for the yet uncharacterized structure of the reactant state of topoII. This model describes a canonical two metal-ion mechanism and suggests how the metals could rearrange at the catalytic pocket during enzymatic turnover, explaining also experimental evidence for topoII inhibition. These results call for further experimental validation. PMID- 26588729 TI - Resolutions of the Coulomb Operator: VII. Evaluation of Long-Range Coulomb and Exchange Matrices. AB - Use of the resolution of Ewald operator method for computing long-range Coulomb and exchange interactions is presented. We show that the accuracy of this method can be controlled by a single parameter in a manner similar to that used by conventional algorithms that compute two-electron integrals. Significant performance advantages over conventional algorithms are observed, particularly for high quality basis sets and globular systems. The approach is directly applicable to hybrid density functional theory. PMID- 26588730 TI - Quantifying Changes in Intrinsic Molecular Motion Using Support Vector Machines. AB - The ensemble of three-dimensional (3-D) configurations exhibited by a molecule, that is, its intrinsic motion, can be altered by several environmental factors, and also by the binding of other molecules. Quantification of such induced changes in intrinsic motion is important because it provides a basis for relating thermodynamic changes to changes in molecular motion. This task is, however, challenging because it requires comparing two high-dimensional data sets. Traditionally, when analyzing molecular simulations, this problem is circumvented by first reducing the dimensions of the two ensembles separately, and then comparing summary statistics from the two ensembles against each other. However, since dimensionality reduction is carried out prior to ensemble comparison, such strategies are susceptible to artifactual biases from information loss. Here, we introduce a method based on support vector machines that yields a normalized quantitative estimate for the difference between two ensembles after comparing them directly against one another. While this method can be applied to any molecular system, including nonbiological molecules and crystals, here, we show how it can be applied to identify the specific regions of a paramyxovirus G protein that are affected by the binding of its preferred human receptor, Ephrin B2. This protein-protein interaction initiates the fusion of the virus with the host cell. Specifically, for every residue in the G protein, we obtain separately a quantitative difference between the ensemble of configurations they sample in the presence and in the absence of Ephrin B2. These ensembles were generated using molecular dynamics simulations. Rank-ordering and then mapping the residues that undergo the greatest change in motion onto the 3-D structure of the G protein reveals that they are clustered primarily on a single contiguous facet of the protein and include the set that is known experimentally to play a vital role in regulating viral fusion. PMID- 26588727 TI - Computational Model of MicroRNA Control of HIF-VEGF Pathway: Insights into the Pathophysiology of Ischemic Vascular Disease and Cancer. AB - HRMs (hypoxia-responsive miRNAs) are a specific group of microRNAs that are regulated by hypoxia. Recent studies revealed that several HRMs including let-7 family miRNAs were highly induced in response to HIF (hypoxia-inducible factor) stabilization in hypoxia, and they potently participated in angiogenesis by targeting AGO1 (argonaute 1) and upregulating VEGF (vascular endothelial growth factor). Here we constructed a novel computational model of microRNA control of HIF-VEGF pathway in endothelial cells to quantitatively investigate the role of HRMs in modulating the cellular adaptation to hypoxia. The model parameters were optimized and the simulations based on these parameters were validated against several published in vitro experimental data. To advance the mechanistic understanding of oxygen sensing in hypoxia, we demonstrated that the rate of HIF 1alpha nuclear import substantially influences its stabilization and the formation of HIF-1 transcription factor complex. We described the biological feedback loops involving let-7 and AGO1 in which the impact of external perturbations were minimized; as a pair of master regulators when low oxygen tension was sensed, they coordinated the critical process of VEGF desuppression in a controlled manner. Prompted by the model-motivated discoveries, we proposed and assessed novel pathway-specific therapeutics that modulate angiogenesis by adjusting VEGF synthesis in tumor and ischemic cardiovascular disease. Through simulations that capture the complex interactions between miRNAs and miRNA processing molecules, this model explores an innovative perspective about the distinctive yet integrated roles of different miRNAs in angiogenesis, and it will help future research to elucidate the dysregulated miRNA profiles found in cancer and various cardiovascular diseases. PMID- 26588731 TI - Calculating Position-Dependent Diffusivity in Biased Molecular Dynamics Simulations. AB - Calculating transition rates and other kinetic quantities from molecular simulations requires knowledge not only of the free energy along the relevant coordinate but also the diffusivity as a function of that coordinate. A variety of methods are currently used to map the free-energy landscape in molecular simulations; however, simultaneous calculation of position-dependent diffusivity is complicated by biasing forces applied with many of these methods. Here, we describe a method to calculate position-dependent diffusivities in simulations including known time-dependent biasing forces, which relies on a previously proposed Bayesian inference scheme. We first apply the method to an explicitly diffusive model, and then to an equilibrium molecular dynamics simulation of liquid water including a position-dependent thermostat, comparing the results to those of an established method. Finally, we test the method on a system of liquid water, where oscillations of the free energy along the coordinate of interest preclude sufficient sampling in an equilibrium simulation. The adaptive biasing force method permits roughly uniform sampling along this coordinate, while the method presented here gives a consistent result for the position-dependent diffusivity, even in a short simulation where the adaptive biasing force is only partially converged. PMID- 26588732 TI - Protein-Ligand Binding from Distancefield Distances and Hamiltonian Replica Exchange Simulations. AB - The calculation of protein-ligand binding free energies is an important goal in the field of computational chemistry. Applying path-sampling methods for this purpose involves calculating the associated potential of mean force (PMF) and gives insight into the binding free energy along the binding process. Without a priori knowledge about the binding path, sampling reversible binding can be difficult to achieve. To alleviate this problem, we introduce the distancefield (DF) as a reaction coordinate for such calculations. DF is a grid-based method in which the shortest distance between the binding site and a ligand is determined avoiding routes that pass through the protein. Combining this reaction coordinate with Hamiltonian replica exchange molecular dynamics (HREMD) allows for the reversible binding of the ligand to the protein. A comparison is made between umbrella sampling using regular distance restraints and HREMD with DF restraints to study aspirin binding to the protein phospholipase A2. Although the free energies of binding are similar for both methods, the increased sampling with HREMD has a significant influence on the shape of the PMF. A remarkable agreement between the calculated binding free energies from the PMF and the experimental estimate is obtained. PMID- 26588733 TI - Quasiclassical Trajectory Studies of the Photodissociation Dynamics of NO3 from the D0 and D1 Potential Energy Surfaces. AB - We report new global potential energy surfaces (PESs) for the D0 and D1 states of NO3. The PESs are permutationally invariant fits to roughly 90 000 electronic energies (MS-CAS(17e,13o)PT2/aug-cc-pVTZ). Hundreds of thousands of quasiclassical trajectories are run from the D0 global minimum and one previously identified "roaming saddle point" as well as a roaming saddle point on D1, identified previously [Xiao, H.; Maeda, S.; Morokuma, K. J. Chem. Theory Comput. 2012, 8, 2600]. The calculations are done at a total energy of relevance to recent experiments where, together with theoretical analysis [Grubb, M. P.; Warter, M. L.; Xiao, H.; Maeda, S.; Morokuma, K.; North, S. W. Science 2012, 335, 1075], point to roaming pathways to the O2+NO products on both D1 and D0. Detailed comparisons with experiment are made for the distributions of O2 vibrational and rotational states, the relative translational energy and the NO rotational states, and the NO v-j vector correlation. PMID- 26588734 TI - Zero-point Energy is Needed in Molecular Dynamics Calculations to Access the Saddle Point for H+HCN->H2CN* and cis/trans-HCNH* on a New Potential Energy Surface. AB - We calculate the probabilities for the association reactions H+HCN->H2CN* and cis/trans-HCNH*, using quasiclassical trajectory (QCT) and classical trajectory (CT) calculations, on a new global ab initio potential energy surface (PES) for H2CN including the reaction channels. The surface is a linear least-squares fit of roughly 60 000 CCSD(T)-F12b/aug-cc-pVDZ electronic energies, using a permutationally invariant basis with Morse-type variables. The reaction probabilities are obtained at a variety of collision energies and impact parameters. Large differences in the threshold energies in the two types of dynamics calculations are traced to the absence of zero-point energy in the CT calculations. We argue that the QCT threshold energy is the realistic one. In addition, trajectories find a direct pathway to trans-HCNH, even though there is no obvious transition state (TS) for this pathway. Instead the saddle point (SP) for the addition to cis-HCNH is evidently also the TS for direct formation of trans-HCNH. PMID- 26588735 TI - Simple Quantitative Tests to Validate Sampling from Thermodynamic Ensembles. AB - It is often difficult to quantitatively determine if a new molecular simulation algorithm or software properly implements sampling of the desired thermodynamic ensemble. We present some simple statistical analysis procedures to allow sensitive determination of whether the desired thermodynamic ensemble is properly sampled. These procedures use paired simulations to cancel out system dependent densities of state and directly test the extent to which the Boltzmann distribution associated with the ensemble (usually canonical, isobaric isothermal, or grand canonical) is satisfied. We demonstrate the utility of these tests for model systems and for molecular dynamics simulations in a range of situations and describe an implementation of the tests designed for end users. PMID- 26588736 TI - Governing Parameters of Long-Range Intramolecular S-to-N Acyl Transfers within (S)-Acyl Isopeptides. AB - The governing parameters for the long-range intramolecular S-to-N acyl transfer in (S)-acyl isopeptides are shown by computational and statistical methods (principal component analysis and cluster analysis) to be driven by enthalpic and geometric effects over the range n = 5-20. The results emphasize the dependency of DeltaG(?) on the geometrical parameters governing the approach of the reactive termini and the importance of stabilizing intramolecular hydrogen bonds in the transition states (TSs), rather than the effects of TS ring-size. The competition between the intra- (uni-) and inter- (bi)molecular acyl transfers were studied for representative examples. PMID- 26588737 TI - Pairwise Alternatives to Ewald Summation for Calculating Long-Range Electrostatics in Ionic Liquids. AB - Room temperature ionic liquid calculations require extensive sampling due to the large degree of localized structuring in the liquid phase relative to conventional solutions. Consequently, a large amount of computer time is required for the convergence of solvent properties, much of which is spent evaluating long range electrostatics via Ewald summations. The damped Coulomb potential and cutoff-neutralized method of Wolf et al. (J. Chem. Phys.1999, 110, 8254) provides the framework for an accurate, linear-scaling alternative to Ewald in the ionic liquid simulations. The method has been the subject of multiple modifications for improved accuracy, including the damped Coulombic potential of Zahn et al. (J. Phys. Chem. B2002, 106, 10725), the damped shifted force method of Fennell and Gezelter (J. Chem. Phys.2006, 124, 234104), and the shifted force gradient of Kale and Herzfeld (J. Chem. Theory Comput.2011, 7, 3620). These pairwise electrostatic interaction alternatives along with the CHARMM shifted force potential and a new method proposed herein, the shifted force third derivative (SF3), have been examined on 59 unique ionic liquid combinations of 1-alkyl-3 methylimidazolium [RMIM] (R = M (methyl), E (ethyl), B (butyl), H (hexyl), and O (octyl)) and N-alkylpyridinium [RPyr] cations, along with Cl(-), PF6(-), BF4(-), NO3(-), AlCl4(-), Al2Cl7(-), and TfO(-) anions. Monte Carlo simulations utilizing our custom OPLS-AA ionic liquid force field and employing the pairwise alternatives with multiple cutoff distances and electrostatic damping values are compared to the energetics from full Ewald sums. PMID- 26588738 TI - Anharmonic Vibrational Frequency Calculations Are Not Worthwhile for Small Basis Sets. AB - Anharmonic calculations using vibrational perturbation theory are known to provide near-spectroscopic accuracy when combined with high-level ab initio potential energy functions. However, performance with economical, popular electronic structure methods is less well characterized. We compare the accuracy of harmonic and anharmonic predictions from Hartree-Fock, second-order perturbation, and density functional theories combined with 6-31G(d) and 6 31+G(d,p) basis sets. As expected, anharmonic frequencies are closer than harmonic frequencies to experimental fundamentals. However, common practice is to correct harmonic predictions using multiplicative scaling. The surprising conclusion is that scaled anharmonic calculations are no more accurate than scaled harmonic calculations for the basis sets we used. The data used are from the Computational Chemistry Comparison and Benchmark Database (CCCBDB), maintained by the National Institute of Standards and Technology, which includes more than 3939 independent vibrations for 358 molecules. PMID- 26588739 TI - Intricacies of Describing Weak Interactions Involving Halogen Atoms within Density Functional Theory. AB - In this work we assess the performance of different dispersion-corrected density functional theory (DFT) approaches (M06, M06-2X, DFT-D3, and DCACP) in reproducing high-level wave function based benchmark calculations on the weakly bound halogen dimers X2...X2 and X2...Ar (for X = F, Cl, Br, and I), as well as the prototype halogen bonded complexes H3CX...OCH2 (X = Cl, Br, I). In spite of the generally good performance of all tested methods for weakly bound systems, their performance for halogen-containing compounds varies largely. We find maximum errors in the energies with respect to the CCSD(T) reference values of 0.13 kcal/mol for DCACP, 0.22 kcal/mol for M06-2X, 0.47 kcal/mol for BLYP-D3, and 0.77 kcal/mol for M06. The root-mean-square deviations are 0.13 kcal/mol for DCACP and M06-2X, 0.44 kcal/mol for M06, and 0.51 kcal/mol for BLYP-D3. PMID- 26588740 TI - Acceleration of Electron Repulsion Integral Evaluation on Graphics Processing Units via Use of Recurrence Relations. AB - Electron repulsion integral (ERI) calculation on graphical processing units (GPUs) can significantly accelerate quantum chemical calculations. Herein, the ab initio self-consistent-field (SCF) calculation is implemented on GPUs using recurrence relations, which is one of the fastest ERI evaluation algorithms currently available. A direct-SCF scheme to assemble the Fock matrix efficiently is presented, wherein ERIs are evaluated on-the-fly to avoid CPU-GPU data transfer, a well-known architectural bottleneck in GPU specific computation. Realized speedups on GPUs reach 10-100 times relative to traditional CPU nodes, with accuracies of better than 1 * 10(-7) for systems with more than 4000 basis functions. PMID- 26588741 TI - Solvent Effects on Electronically Excited States Using the Conductor-Like Screening Model and the Second-Order Correlated Method ADC(2). AB - The conductor-like screening model (COSMO) is used to treat solvent effects on excited states within a correlated method based on the algebraic-diagrammatic construction through second-order ADC(2). The origin of solvent effects is revisited, and it is pointed out that two types of contributions have to be considered. One effect is due to the change of the solute's charge distribution after excitation, which triggers a reorganization of the solvent. Initially, only the electronic degrees of freedom adapt to the new charge distribution (nonequilibrium case); for sufficiently long-lived states, the reorientation of the solvent molecules contributes, as well (equilibrium case). The second effect is the coupling of the transition densities to the fast (purely electronic) response of the solvent molecules, which can be viewed as excitonic coupling between solute and solvent molecules. This interaction is also responsible for the screening of excitonic couplings between spatially separated chromophores. While most previous implementations of comparable continuum solvation models only include either of both effects, we argue that both contributions should be taken into account. Both effects can significantly influence the excitation energy and excited state properties of the solute, as exemplified for the pi-pi* and n-pi* excitations of acrolein, and no a priori reason exists to neglect either. The implementation is also tested for the excitonic coupling of the ethene dimer where linear response contributions are indispensable for recovering the screening effects due to the solvent. Example applications to larger cases are provided, too. We discuss the excitonic coupling in a linked dyad consisting of two perylene-tetracarboxy-diimide chromophores, and the solvent effects on an intramolecular charge-transfer state of 4-(N,N-dimethylamino)benzonitrile. PMID- 26588742 TI - Assessing the Accuracy of Density Functional and Semiempirical Wave Function Methods for Water Nanoparticles: Comparing Binding and Relative Energies of (H2O)16 and (H2O)17 to CCSD(T) Results. AB - The binding energies and relative conformational energies of five configurations of the water 16-mer are computed using 61 levels of density functional (DF) theory, 12 methods combining DF theory with molecular mechanics damped dispersion (DF-MM), seven semiempirical-wave function (SWF) methods, and five methods combining SWF theory with molecular mechanics damped dispersion (SWF-MM). The accuracies of the computed energies are assessed by comparing them to recent high level ab initio results; this assessment is more relevant to bulk water than previous tests on small clusters because a 16-mer is large enough to have water molecules that participate in more than three hydrogen bonds. We find that for water 16-mer binding energies the best DF, DF-MM, SWF, and SWF-MM methods (and their mean unsigned errors in kcal/mol) are respectively M06-2X (1.6), omegaB97X D (2.3), SCC-DFTB-gamma(h) (35.2), and PM3-D (3.2). We also mention the good performance of CAM-B3LYP (1.8), M05-2X (1.9), and TPSSLYP (3.0). In contrast, for relative energies of various water nanoparticle 16-mer structures, the best methods (and mean unsigned errors in kcal/mol), in the same order of classes of methods, are SOGGA11-X (0.3), omegaB97X-D (0.2), PM6 (0.4), and PMOv1 (0.6). We also mention the good performance of LC-omegaPBE-D3 (0.3) and omegaB97X (0.4). When both relative and binding energies are taken into consideration, the best methods overall (out of the 85 tested) are M05-2X without molecular mechanics and omegaB97X-D when molecular mechanics corrections are included; with considerably higher average errors and considerably lower cost, the best SWF or SWF-MM method is PMOv1. We use six of the best methods for binding energies of the water 16 mers to calculate the binding energies of water hexamers and water 17-mers to test whether these methods are also reliable for binding energy calculations on other types of water clusters. PMID- 26588743 TI - Evaluating and Interpreting the Chemical Relevance of the Linear Response Kernel for Atoms. AB - Although a lot of work has been done on the chemical relevance of the atom condensed linear response kernel chiAB regarding inductive, mesomeric, and hyperconjugative effects as well as (anti)aromaticity of molecules, the same cannot be said about its not condensed form chi(r,r'). Using a single Slater determinant KS type ansatz involving second order perturbation theory, we set out to investigate the linear response kernel for a number of judiciously chosen closed (sub)shell atoms throughout the periodic table and its relevance, e.g., in relation to the shell structure and polarizability. The numerical results are to the best of our knowledge the first systematic study on this noncondensed linear response function, the results for He and Be being in line with earlier work by Savin. Different graphical representations of the kernel are presented and discussed. Moreover, a frontier orbital approach has been tested illustrating the sensitivity of the nonintegrated kernel to the nodal structure of the orbitals. As a test of our method, a numerical integration of the linear response kernel was performed, yielding an accuracy of 10(-4). We also compare calculated values of the polarizability tensor and their evolution throughout the periodic table to high-level values found in the literature. PMID- 26588744 TI - Exploring Relative Thermodynamic Stabilities of Formic Acid and Formamide Dimers Role of Low-Frequency Hydrogen-Bond Vibrations. AB - The low-frequency fundamentals together with the high-frequency modes, responsible for hydrogen bonding (OH/NH stretching modes), were analyzed to correlate the intensities with the hydrogen-bond strengths/binding energies of the formic acid and formamide dimers using Moller-Plesset second-order perturbation (MP2) and coupled cluster computations with explicit anharmonicity corrections. Linear correlations were observed for both the formic acid and formamide dimers, and as consequence of such correlation an additive properties of binding energies with respect to the local hydrogen-bond energies of fragments involved (for these dimers) has been proposed. It has been further observed that (i) the nature of their six low-frequency fundamentals are very similar, and (ii) the in-plane bending and stretch-bend fundamentals of different dimers of these two species (depending on the dimer structure), in this low-frequency region, modulate their strength of hydrogen-bond/binding hence their relative stability order. These results were further verified against the results from Gaussian-G4 MP2 (G4MP2), Gaussian-G2-MP2 (G2MP2), and complete basis set (CBS-QB3) methods of high accuracy energy calculations. PMID- 26588745 TI - Defined-Sector Explicit Solvent in Continuum Cluster Model for Computational Prediction of pKa: Consideration of Secondary Functionality and Higher Degree of Solvation. AB - Benchmark accuracy for prediction of first and second dissociation constants (pKa1 and pKa2 values) is realized with the recently developed Defined-Sector Explicit Solvent in Continuum Cluster Model. The model provides a systematic basis for inclusion of explicit solvation, essential for accurate prediction of dissociation constants using computational continuum model approaches. The DSES CC model is demonstrated by considering the structure-to-chemical affinity relationship of the carboxyl functional group and is shown to provide predictability with mean absolute error of 0.5 pK units across a wide array of carboxylic acid functionality. PMID- 26588746 TI - Tuned and Balanced Redistributed Charge Scheme for Combined Quantum Mechanical and Molecular Mechanical (QM/MM) Methods and Fragment Methods: Tuning Based on the CM5 Charge Model. AB - Tuned and balanced redistributed charge schemes have been developed for modeling the electrostatic fields of bonds that are cut by a quantum mechanical-molecular mechanical boundary in combined quantum mechanical and molecular mechanical (QM/MM) methods. First, the charge is balanced by adjusting the charge on the MM boundary atom to conserve the total charge of the entire QM/MM system. In the balanced smeared redistributed charge (BSRC) scheme, the adjusted MM boundary charge is smeared with a smearing width of 1.0 A and is distributed in equal portions to the midpoints of the bonds between the MM boundary atom and the MM atoms bonded to it; in the balanced redistributed charge-2 (BRC2) scheme, the adjusted MM boundary charge is distributed as point charges in equal portions to the MM atoms that are bonded to the MM boundary atom. The QM subsystem is capped by a fluorine atom that is tuned to reproduce the sum of partial atomic charges of the uncapped portion of the QM subsystem. The new aspect of the present study is a new way to carry out the tuning process; in particular, the CM5 charge model, rather than the Mulliken population analysis applied in previous studies, is used for tuning the capping atom that terminates the dangling bond of the QM region. The mean unsigned error (MUE) of the QM/MM deprotonation energy for a 15 system test suite of deprotonation reactions is 2.3 kcal/mol for the tuned BSRC scheme (TBSRC) and 2.4 kcal/mol for the tuned BRC2 scheme (TBRC2). As was the case for the original tuning method based on Mulliken charges, the new tuning method performs much better than using conventional hydrogen link atoms, which have an MUE on this test set of about 7 kcal/mol. However, the new scheme eliminates the need to use small basis sets, which can be problematic, and it allows one to be more consistent by tuning the parameters with whatever basis set is appropriate for applications. (Alternatively, since the tuning parameters and partial charges obtained by the new method do not depend strongly on basis set, one can continue to use available CM5-tuned parameters even when one changes the basis set.) Furthermore, we found that, as compared to Mulliken charges, the CM5 charges describe the charge distributions in test molecules better, and they reproduce the dipole moments of full quantum mechanical calculations better; therefore the new tuning procedure is more physical and should be more reliable and robust. PMID- 26588747 TI - Sparse Projected-Gradient Method As a Linear-Scaling Low-Memory Alternative to Diagonalization in Self-Consistent Field Electronic Structure Calculations. AB - Large-scale electronic structure calculations usually involve huge nonlinear eigenvalue problems. A method for solving these problems without employing expensive eigenvalue decompositions of the Fock matrix is presented in this work. The sparsity of the input and output matrices is preserved at every iteration, and the memory required by the algorithm scales linearly with the number of atoms of the system. The algorithm is based on a projected gradient iteration applied to the constraint fulfillment problem. The computer time required by the algorithm also scales approximately linearly with the number of atoms (or non null elements of the matrices), and the algorithm is faster than standard implementations of modern eigenvalue decomposition methods for sparse matrices containing more than 50 000 non-null elements. The new method reproduces the sequence of semiempirical SCF iterations obtained by standard eigenvalue decomposition algorithms to good precision. PMID- 26588748 TI - Variational versus Perturbational Treatment of Spin-Orbit Coupling in Relativistic Density Functional Calculations of Electronic g Factors: Effects from Spin-Polarization and Exact Exchange. AB - Different approaches are compared for relativistic calculations of electronic g factors of molecules with light atoms, transition metal complexes, and selected complexes with actinides, using density functional theory (DFT) and Hartree-Fock (HF) theory. The comparison includes functionals with range-separated exchange. Within the variationally stable zeroth-order regular approximation (ZORA) relativistic framework, g factors are obtained with a linear response (LR) method where spin-orbit (SO) coupling is treated as a linear perturbation, a spin polarized approach based on magnetic anisotropy (MA) that includes SO coupling variationally, and a quasi-restricted variational SO method previously devised by van Lenthe, van der Avoird, and Wormer (LWA). The MA and LWA approaches were implemented in the open-source NWChem quantum chemistry package. We address the importance of electron correlation (DFT vs HF), the importance of including spin polarization in the g tensor methodology, the question of whether the use of nonrelativistic spin density functionals is adequate for such calculations, and the importance of treating spin-orbit coupling beyond first-order. For selected systems, the extent of the DFT delocalization error is explicitly investigated via calculations of the energy as a function of fractional electron numbers. For a test set of small molecules with light main group atoms, all levels of calculation perform adequately as long as there is no energetic near-degeneracy among occupied and unoccupied orbitals. The interplay between different factors determining the accuracy of calculated g factors becomes more complex for systems with heavy elements such as third row transition metals and actinides. The MA approach is shown to perform acceptably well for a wide range of scenarios. PMID- 26588749 TI - A Density Functional Theory View of Quantum Phase Transitions. AB - It is shown that there is a one-to-one map between the ground state wave function and the control parameter. Wu et al. [Phys. Rev. A2006, 74, 052335] introduced an analogue of the Density Functional Theory (DFT) density and showed that the "density" determines the "control parameter" (corresponding to the DFT "external potential"). We prove that any strictly monotonous function can be used to obtain a new density with a different control parameter (or DFT "external potential"), and the new density determines the new control parameter. Moreover, there is also a one-to-one map between the Renyi entropy of a given order and the control parameter. Therefore, the Renyi entropy can be used as a control parameter. PMID- 26588750 TI - First-Principles Study on Structural and Chemical Asymmetry of a Biomimetic Water Splitting Dimanganese Complex. AB - Density-functional theory calculations are carried out for a biomimetic dimanganese complex, [H2O(terpy)Mn(III)(MU-O)2Mn(IV)(terpy)OH2](3+)(1, terpy = 2,2':6',2"-terpyridine), which is a structural model for the oxygen evolving center of photosystem II. Theoretical investigations aim at elucidating the asymmetry features in the geometric and electronic structures of complex 1, as well as their influences on the chemical functions of the two manganese centers, in the presence of water solvent. With the insight gained from the first principles calculations, we study the oxidation state of complex 1 in the acetate buffer solution. Both the thermodynamic and kinetic aspects are explored in detail, and the structural and chemical asymmetry of the two manganese centers is fully considered. It is found that the larger steric repulsion associated with the Mn(IV) center plays a decisive role, which leads to the predominant acetate coordination at the Mn(III) ion. This thus resolves the existing controversy on the preferential acetate binding to complex 1. PMID- 26588751 TI - The Importance of Electron Correlation on Stacking Interaction of Adenine-Thymine Base-Pair Step in B-DNA: A Quantum Monte Carlo Study. AB - We report fixed-node diffusion Monte Carlo (DMC) calculations of stacking interaction energy between two adenine(A)-thymine(T) base pairs in B-DNA (AA:TT), for which reference data are available, obtained from a complete basis set estimate of CCSD(T) (coupled-cluster with singles, doubles, and perturbative triples). We consider four sets of nodal surfaces obtained from self-consistent field calculations and examine how the different nodal surfaces affect the DMC potential energy curves of the AA:TT molecule and the resulting stacking energies. We find that the DMC potential energy curves using the different nodes look similar to each other as a whole. We also benchmark the performance of various quantum chemistry methods, including Hartree-Fock (HF) theory, second order Moller-Plesset perturbation theory (MP2), and density functional theory (DFT). The DMC and recently developed DFT results of the stacking energy reasonably agree with the reference, while the HF, MP2, and conventional DFT methods give unsatisfactory results. PMID- 26588752 TI - Strong Spin-Orbit Coupling Facilitates C-H Activation in the Reactions of Os(+) with CH3F: Theoretical Investigations. AB - The relativistic effects are essential for a complete understanding of the reactions involving heavy transition metal cations with hydrocarbons. Despite this, spin-orbit coupling (SOC) along the reaction pathway is rarely considered. In this work, we demonstrate an unusual SOC on the chemical reactivity of a reaction of Os(+) with methyl fluoride (CH3F) using density functional theory (DFT), high-level ab initio, and spin-orbit multiconfigurational ab initio methods. With the inclusion of the SO effect in the relevant potential energy surfaces (PESs), C-H bond activation by an Os(+) cation occurs readily via almost barrierless (about 2 kcal/mol) PESs of the SO coupled ground state. In contrast, a substantial reaction barrier was observed for C-F bond activation. The calculated results are in line with recent systematic experimental findings for reactions of transition metal cations with CH3F. These results show that the SO effect can facilitate specific bond activation in chemical reactions associated with catalytic transition metal cations. PMID- 26588753 TI - Alchemical FEP Calculations of Ligand Conformer Focusing in Explicit Solvent. AB - Slow rotational degrees of freedom in ligands can make alchemical FEP simulations unreliable due to inadequate sampling. We addressed this problem by introducing a FEP-based protocol of ligand conformer focusing in explicit solvent. Our method involves FEP transformations between conformers using equilibrium dihedral angle as a reaction coordinate and provides the cost of "focusing" on one specific conformational state that binds to a protein. The calculated conformer focusing term made a considerable difference of 5-10 kJ/mol in computed relative binding free energies of studied Syk inhibitors and significantly improved the resulting accuracy of predictions. PMID- 26588754 TI - A Critical Assessment of Two-Body and Three-Body Interactions in Water. AB - The microscopic behavior of water under different conditions and in different environments remains the subject of intense debate. A great number of the controversies arise due to the contradictory predictions obtained within different theoretical models. Relative to conclusions derived from force fields or density functional theory, there is comparably less room to dispute highly correlated electronic structure calculations. Unfortunately, such ab initio calculations are severely limited by system size. In this study, a detailed analysis of the two- and three-body water interactions evaluated at the CCSD(T) level is carried out to quantitatively assess the accuracy of several force fields, DFT models, and ab initio based interaction potentials that are commonly used in molecular simulations. On the basis of this analysis, a new model, HBB2 pol, is introduced which is capable of accurately mapping CCSD(T) results for water dimers and trimers into an efficient analytical function. The accuracy of HBB2-pol is further established through comparison with the experimentally determined second and third virial coefficients. PMID- 26588755 TI - Solvated Charge Transfer States of Functionalized Anthracene and Tetracyanoethylene Dimers: A Computational Study Based on a Range Separated Hybrid Functional and Charge Constrained Self-Consistent Field with Switching Gaussian Polarized Continuum Models. AB - We benchmark several protocols for evaluating the energies of excited charge transfer (CT) states of organic molecules dissolved in polar liquids. The protocols combine time-dependent density functional theory using range-separated hybrid functionals, constrained density functional theory, dispersion corrected functional, and a dielectric continuum model for representing the solvent. We compare the different protocols against well-established experimental measured charge transfer state energies in solvated dimers of functionalized anthracene and tetracyanoethylene. We find that using the range-separated hybrid functional for the charge-transfer state energies and the combination of constrained density functional theory with the recently improved switching Gaussian polarizable continuum model (PCM) provide good agreement with the experimental values of the solvated CT states. We also find that using dispersion corrected solvated geometries for the weakly coupled donor-acceptor dimers considered here leads to improved agreement with experimental measured values. PMID- 26588756 TI - Correlation Function Formalism for Triplet Excited State Decay: Combined Spin Orbit and Nonadiabatic Couplings. AB - Based on the second-order perturbation combining spin-orbit and nonadiabatic couplings, we derived an analytical formula for nonradiative decay rate between the triplet and singlet states by using the thermal vibration correlation function (TVCF) approach. Origin displacement, distortion, and Duschinsky rotation of the potential energy surfaces are taken into accounts within the multiple harmonic oscillator model. When coupled with first-principles calculation for the anthracene, the theoretical phosphorescence spectrum is in good agreement with the experiment. Furthermore, we found that the intersystem crossing from the first excited singlet state (S1) to the triplet states S1(Bu) >T2(Ag) is forbidden by direct spin-orbit coupling at the first-order perturbation but becomes allowed through combined spin-orbit and the nonadiabatic couplings at the second-order perturbation, and the rate is calculated to be 0.26 * 10(8) s(-1), in good agreement with the experiment. Such formalism is also applied to describe the phosphorescence quantum efficiency and the temperature dependent optical emission spectrum for fac-tris(2-phenylpyridine) iridium. We predict that the radiative decay rate is 6.36 * 10(5) s(-1), the nonradiative decay rate is 5.04 * 10(4) s(-1), and the phosphorescence quantum efficiency is found to be 92.7% from T1 to S0, which reproduce well the corresponding experimental measurements. PMID- 26588757 TI - Role of Geometric Distortion and Polarization in Localizing Electronic Excitations in Conjugated Polymers. AB - Five different Density Functional Theory (DFT) models (ranging from pure GGA to long-range-corrected hybrid functionals) were used to study computationally the nature of the self-trapped electronic states in oligophenylene vinylenes. The electronic excitations in question include the lowest singlet (S1) and triplet (T1(?)) excitons (calculated using Time Dependent DFT (TD-DFT) method), positive (P(+)) and negative (P(-)) polarons, and the lowest triplet (T1) states (computed with the Self-Consistent Field (SCF) scheme). The polaron formation (spatial localization of excitations) is observed only with the use of range-corrected hybrid DFT models including long-range electronic exchange interactions. The extent of localization for all studied excitations is found to be invariant with respect to the size of the oligomer chain in their corresponding optimal geometries. We have analyzed the interdependence between the extent of the geometrical distortion and the localization of the orbital and spin density, and have observed that the localization of the P(+) and P(-) charged species is quite sensitive to solvent polarization effects and the character of the DFT functional used, rather than the structural deformations. In contrast, the localization of neutral states, S1 and T1(?), is found to follow the structural distortions. Notably, T1 excitation obtained with the mean field SCF approach is always strongly localized in range-corrected hybrid DFT models. The molecular orbital energetics of these excitations was further investigated to identify the relationship between state localization and the corresponding orbital structure. A characteristic stabilization (destabilization) of occupied (virtual) orbitals is observed in hybrid DFT models, compared to tight-binding model-like orbital filling in semilocal GGA functionals. The molecular and natural orbital representation allows visualization of the spatial extent of the underlying electronic states. In terms of stabilization energies, neutral excitons have higher binding energies compared to charged excitations. In contrast, the polaronic species exhibit the highest solvation energies among all electronic states studied. PMID- 26588758 TI - Exploring the Conical Intersection Seam: The Seam Space Nudged Elastic Band Method. AB - Conical intersections (CIs) play a fundamental role in photoreactions. Although it is widely known that CIs are not isolated points but rather multidimensional seams, there is a dearth of techniques to explore and characterize these seams beyond the immediate vicinity of minimum energy points within the intersection space (minimum energy conical intersections or MECIs). Here, we develop a method that connects these MECIs by minimal energy paths within the space of geometries that maintain the electronic degeneracy (the "seam space") in order to obtain a more general picture of a CI seam. This method, the seam space nudged elastic band (SS-NEB) method, combines the nudged elastic band method with gradient projected MECI optimization. It provides a very efficient way of finding minimum energy seam paths in the conical intersection seam. The method is demonstrated by application to two molecules: ethylene and the green fluorescent protein (GFP) chromophore. The results show that previously known MECIs for these molecules are connected within a single seam, adding further support to previous conjectures that all MECIs are topologically connected in the seam space. Analysis of the nonadiabatic dynamics further suggests that a broad range of seam geometries, not only the vicinity of MECIs, is involved in the nonadiabatic transition events. The current method provides a tool to characterize CI seams in different environments and to explore the importance of the seam in the dynamics. PMID- 26588759 TI - Calculation of Molecular Entropies Using Temperature Integration. AB - There are two fundamental definitions of entropy, Clausius's thermodynamic definition and the Boltzmann-Gibbs statistical mechanical definition. The Clausius definition, applied here to the calculation of molecular entropies, requires an integration over temperature. Analytical and numerical error analysis shows that this quadrature can be done accurately using a small number of large temperature steps involving the calculation of one average system property, the mean internal energy. This makes the method computationally practical for systems with many degrees of freedom, such as biological molecules. The Clausius definition provides a simple and physically insightful way to decompose a total entropy change into components and is useful for benchmarking statistical mechanical based methods for entropy calculation. A temperature quenching protocol is described whereby the Clausius method can be used with existing force fields to evaluate entropy changes in anharmonic and diffusive systems. PMID- 26588760 TI - Solvation Energies of the Proton in Methanol. AB - pKa's, proton affinities, and proton dissociation free energies characterize numerous properties of drugs and the antioxidant activity of some chemical compounds. Even with a higher computational level of theory, the uncertainty in the proton solvation free energy limits the accuracy of these parameters. We investigated the thermochemistry of the solvation of the proton in methanol within the cluster-continuum model. The scheme used involves up to nine explicit methanol molecules, using the IEF-PCM and the strategy based on thermodynamic cycles. All computations were performed at B3LYP/6-31++G(dp) and M062X/6 31++G(dp) levels of theory. It comes out from our calculations that the functional M062X is better than B3LYP, on the evaluation of gas phase clustering energies of protonated methanol clusters, per methanol stabilization of neutral methanol clusters and solvation energies of the proton in methanol. The solvation free energy and enthalpy of the proton in methanol were obtained after converging the partial solvation free energy of the proton in methanol and the clustering free energy of protonated methanol clusters, as the cluster size increases. Finally, the recommended values for the solvation free energy and enthalpy of the proton in methanol are -257 and -252 kcal/mol, respectively. PMID- 26588761 TI - Hybrid QM/QM Simulations of Excited-State Intramolecular Proton Transfer in the Molecular Crystal 7-(2-Pyridyl)-indole. AB - A subtractive implementation of the QM/QM hybrid method for the description of photochemical reactions occurring in molecular crystals is presented and tested by applying it in a simulation study of the ultrafast intramolecular excited state proton transfer reaction in the crystal form of 7-(2-pyridyl)-indole, an organic compound featuring an intramolecular hydrogen bond within a six-membered ring. By propagating molecular dynamics on the excited-state potential energy surface, a mean proton transfer time was calculated as 80 fs. The reaction mechanism is discussed in terms of three-dimensional reaction coordinate diagrams. Proton transfer was found to be barrierless and to be strongly coupled to vibrational modes of the photoexcited molecule that modulate the proton donor acceptor distance. Some 300 fs after the initial photoexcitation, the excited state molecule reached an S1/S0 conical intersection through the mutual twist of the pyridyl and indolyl moieties. PMID- 26588762 TI - Polarizable Site Charge Model at Liquid/Solid Interfaces for Describing Surface Polarity: Application to Structure and Molecular Dynamics of Water/Rutile TiO2(110) Interface. AB - We present a novel scheme to construct a polarizable force field for liquid/solid interfaces, which takes into account the effect of the surface polarity induced by liquid-solid interactions explicitly. We extend the charge response kernel (CRK) method for molecules to solid surfaces by introducing the surface CRK. The CRK parameters are systematically determined by the first-principles calculations in the slab model with the dipole-correction method. Our methodology is applied to the water/clean rutile TiO2(110) interface. Structures and induced charges of a single water molecule attached to the TiO2 surface optimized by our polarizable force field show good agreement with those predicted by the first-principles calculations. Further, we carried out MD simulations for the liquid water/TiO2 interface and found three stable structures of water attached to the TiO2 surface. Two of them are predicted by both the polarizable and the nonpolarizable force fields, while the polarizable force field model predicts a structure of water with the hydrogen and oxygen atoms interacting with the oxygen atom of the surface TiO2 and the hydrogen atom of the other water molecule, respectively, which was reported by the previous first-principles MD simulation. This indicates that the dipole moments of water and TiO2 induced by the water-TiO2 interactions have significant impact on molecular conformations of the water/TiO2 interface. PMID- 26588763 TI - Wagging the Tail: Essential Role of Substrate Flexibility in FAAH Catalysis. AB - The serine hydrolase, fatty acid amide hydrolase (FAAH), is responsible for the intracellular degradation of anandamide and other bioactive fatty acid ethanolamides involved in the regulation of pain, inflammation, and other pathophysiological processes. The catalytic site of FAAH is composed of multiple cavities with mixed hydrophobic and hydrophilic properties, the role of which remains incompletely understood. Anandamide is thought to enter the active site through a "membrane-access" (MA) channel and position its flexible fatty acyl chain in a highly hydrophobic "acyl chain-binding" (AB) cavity to allow for hydrolysis to occur. Using microsecond molecular dynamics (MD) simulations of FAAH embedded in a realistic membrane/water environment, we show now that anandamide may not lock itself into the AB cavity but may rather assume catalytically significant conformations required for hydrolysis by moving its flexible arachidonoyl tail between the MA and AB cavities. This process is regulated by a phenylalanine residue (Phe432) located at the boundary between the two cavities, which may act as a "dynamic paddle." The results identify structural flexibility as a key determinant by which FAAH recognizes its primary lipid substrate. PMID- 26588764 TI - Ribose 2'-Hydroxyl Groups Stabilize RNA Hairpin Structures Containing GCUAA Pentaloop. AB - The chemical structure of RNA and DNA is very similar; however, the three dimensional conformation of these two nucleic acids is very different. Whereas the DNA adopts a repetitive structure of a double-stranded helix, RNA is primarily single stranded with a complex three-dimensional structure in which the hairpin is the most common secondary structure. Apart from the difference between uracil and thymine, the difference in the chemical structure between RNA and DNA is the presence of a hydroxyl group at position 2' of the sugar (ribose) instead of a hydrogen (deoxyribose). In this paper, we present molecular dynamics simulations addressing the contribution of 2'-hydroxyls to the stability of a GCUAA pentaloop motif. The results indicate that the 2'-hydroxyls stabilize the hairpin conformation of the GCUAA pentaloop relative to an analogous oligonucleotide in which the ribose sugars in the loop region were substituted with deoxyriboses. The magnitude of the stabilization was found to be 23.8 +/- 4.1 kJ/mol using an alchemical mutations free energy method and 4.2 +/- 6.5 kJ/mol using potential of mean force calculations. The latter indicates that in addition to its larger thermodynamic stability the RNA hairpin is also kinetically more stable. We find that the excess stability is a result of intrahairpin hydrogen bonds in the loop region between the 2'-hydroxyls and sugars, bases, and phosphates. The hydrogen bonds with the sugars and phosphates involve predominantly interactions with adjacent nucleotides. However, the hydrogen bonds with the bases involve also interactions between groups on opposite sides of the loop or with the middle base of the loop and are therefore likely to contribute significantly to the stability of the loop. Of these hydrogen bonds, the most frequent is observed between the 2'-hydroxyl at the first position of the pentaloop with N6/N7 of adenine at the forth position, as well as between the 2'-hydroxyl at position -1 with N6 of adenine at the fifth position. Our results contribute to the notion that one of the important roles of the ribose sugars in RNA is to facilitate hairpin formation. PMID- 26588765 TI - Efficient Relaxation of Protein-Protein Interfaces by Discrete Molecular Dynamics Simulations. AB - Protein-protein interactions are responsible for the transfer of information inside the cell and represent one of the most interesting research fields in structural biology. Unfortunately, after decades of intense research, experimental approaches still have difficulties in providing 3D structures for the hundreds of thousands of interactions formed between the different proteins in a living organism. The use of theoretical approaches like docking aims to complement experimental efforts to represent the structure of the protein interactome. However, we cannot ignore that current methods have limitations due to problems of sampling of the protein-protein conformational space and the lack of accuracy of available force fields. Cases that are especially difficult for prediction are those in which complex formation implies a non-negligible change in the conformation of the interacting proteins, i.e., those cases where protein flexibility plays a key role in protein-protein docking. In this work, we present a new approach to treat flexibility in docking by global structural relaxation based on ultrafast discrete molecular dynamics. On a standard benchmark of protein complexes, the method provides a general improvement over the results obtained by rigid docking. The method is especially efficient in cases with large conformational changes upon binding, in which structure relaxation with discrete molecular dynamics leads to a predictive success rate double that obtained with state-of-the-art rigid-body docking. PMID- 26588766 TI - "Adapted Linear Interaction Energy": A Structure-Based LIE Parametrization for Fast Prediction of Protein-Ligand Affinities. AB - We present a structure-based parametrization of the Linear Interaction Energy (LIE) method and show that it allows for the prediction of absolute protein ligand binding energies. We call the new model "Adapted" LIE (ALIE) because the alpha and beta coefficients are defined by system-dependent descriptors and do therefore not require any empirical gamma term. The best formulation attains a mean average deviation of 1.8 kcal/mol for a diverse test set and depends on only one fitted parameter. It is robust with respect to additional fitting and cross validation. We compare this new approach with standard LIE by Aqvist and co workers and the LIE + gammaSASA model (initially suggested by Jorgensen and co workers) against in-house and external data sets and discuss their applicabilities. PMID- 26588767 TI - A Candidate Ion-Retaining State in the Inward-Facing Conformation of Sodium/Galactose Symporter: Clues from Atomistic Simulations. AB - The recent Vibrio parahaemolyticus sodium/galactose (vSGLT) symporter crystal structure captures the protein in an inward-facing substrate-bound conformation, with the sodium ion placed, by structural alignment, in a site equivalent to the Na2 site of the leucine transporter (LeuT). A recent study, based on molecular dynamics simulations, showed that the sodium ion spontaneously leaves its initial position diffusing outside vSGLT, toward the intracellular space. This suggested that the crystal structure corresponds to an ion-releasing state of the transporter. Here, using metadynamics, we identified a more stable Na(+) binding site corresponding to a putative ion-retaining state of the transporter. In addition, our simulations, consistently with mutagenesis studies, highlight the importance of D189 that, without being one of the Na(+)-coordinating residues, regulates its binding/release. PMID- 26588768 TI - Free Energy Calculations Reveal the Origin of Binding Preference for Aminoadamantane Blockers of Influenza A/M2TM Pore. AB - Aminoadamantane derivatives, such as amantadine and rimantadine, have been reported to block the M2 membrane protein of influenza A virus (A/M2TM), but their use has been discontinued due to reported resistance in humans. Understanding the mechanism of action of amantadine derivatives could assist the development of novel potent inhibitors that overcome A/M2TM resistance. Here, we use Free Energy Perturbation calculations coupled with Molecular Dynamics simulations (FEP/MD) to rationalize the thermodynamic origin of binding preference of several aminoadamantane derivatives inside the A/M2TM pore. Our results demonstrate that apart from crucial protein-ligand intermolecular interactions, the flexibility of the protein, the water network around the ligand, and the desolvation free energy penalty to transfer the ligand from the aqueous environment to the transmembrane region are key elements for the binding preference of these compounds and thus for lead optimization. The high correlation of the FEP/MD results with available experimental data (R(2) = 0.85) demonstrates that this methodology holds predictive value and can be used to guide the optimization of drug candidates binding to membrane proteins. PMID- 26588769 TI - Modeling Local Structural Rearrangements Using FEP/REST: Application to Relative Binding Affinity Predictions of CDK2 Inhibitors. AB - Accurate and reliable calculation of protein-ligand binding affinities remains a hotbed of computer-aided drug design research. Despite the potentially large impact FEP (free energy perturbation) may have in drug design projects, practical applications of FEP in industrial contexts have been limited. In this work, we use a recently developed method, FEP/REST (free energy perturbation/replica exchange with solute tempering), to calculate the relative binding affinities for a set of congeneric ligands binding to the CDK2 receptor. We compare the FEP/REST results with traditional FEP/MD (molecular dynamics) results and MM/GBSA (molecular mechanics/Generalized Born Surface Area model) results and examine why FEP/REST performed notably better than these other methods, as well as why certain ligand mutations lead to large increases of the binding affinity while others do not. We also introduce a mathematical framework for assessing the consistency and reliability of the calculations using cycle closures in FEP mutation paths. PMID- 26588770 TI - Tacrolimus for the prevention and treatment of rejection of solid organ transplants. AB - Since its introduction to the antirejection armamentarium in 1994, tacrolimus has become the workhorse of transplant professionals for avoidance of solid organ transplant rejection. Not only does tacrolimus have potent immunosuppressive qualities that prevent rejection, but dosing is straight forward and it is generally well tolerated. However, in the long term, conditions such as calcineurin inhibitor nephrotoxicity can become a problem. A discussion of the compound, the pharmacokinetics, history, and current approved uses for tacrolimus is described. Indeed, tacrolimus is the most important drug for preventing transplant rejection. However, the increased appreciation for significant side effects, particularly in the long term, has led to building interest in new agents with different mechanisms of action and different metabolism. PMID- 26588771 TI - Parapharyngeal space tumors: Fifty-one cases managed in a single tertiary care center. AB - CONCLUSIONS: Pre-operative planning for parapharyngeal tumors must include meticulous analysis. Factors such as tumor size, distance to cranial base, and relation to neurovascular structures must guide the selection of a surgical approach. OBJECTIVE: To summarize experience in diagnosis and surgical management of parapharyngeal tumors, analyzing the frequencies of various tumoral types, clinical presentation, choice of surgical approach and outcomes. This study also compares the results with the most relevant case series in the literature. METHODS: A retrospective review was performed of the records of 51 patients treated by the team, from 1984-2012. Only primary tumors were included, excluding invasion from adjacent spaces and metastatic disease. All patients underwent imaging studies and surgical resection of the neoplasm. Cytological analysis and arteriography were used on an individualized basis. Surgical excision was performed via different approaches, predominantly through a cervicoparotid route. RESULTS: Benign neoplasms were predominant (80%), and the most frequent tumor was pleomorphic adenoma. FNAC had a 100% accuracy to differentiate benign vs malignant tumors. The most common post-operative sequel was compromise of a cranial nerve, and three patients presented local complications after surgery. After follow-up, only three of 41 patients with benign tumors had recurring disease. PMID- 26588772 TI - Notch Signaling: Piercing a Harness of Simplicity. AB - The Notch pathway is an attractive therapeutic target for treatment of cancer and T cell-mediated pathology, but Notch inhibition leads to many side effects. Pinnell et al. (2015) demonstrate that oncogenic functions can be separated biochemically from other functions of Notch, opening new options for more selective targeting of this pathway. PMID- 26588773 TI - Not-So-Negative Selection. AB - It once seemed clear that negative selection of self-specific T cells in the thymus was the major mechanism of central tolerance. But recent studies, including Legoux et al. (2015) in this issue of Immunity, show that this is not always the case. PMID- 26588774 TI - Pyroptosis: Caspase-11 Unlocks the Gates of Death. AB - How inflammatory caspases trigger pyroptotic cell death is mostly unexplained. In this issue of Immunity, Nunez and colleagues report that caspase-11 cleaves the transmembrane channel pannexin-1, causing an efflux of cellular ATP that promotes a P2X7 receptor-dependent pyroptosis. PMID- 26588775 TI - Common Characteristics of HIV-Neutralizing Antibodies with a Fondness for Sugars. AB - Broadly neutralizing antibodies targeting quaternary epitopes on the apex of the HIV-1 envelope spike are an attractive vaccine target, yet engineering immunogens that recapitulate such epitopes has proven difficult. In this issue of Immunity, Andrabi and colleagues (2015) identify an exciting new candidate immunogen that could initiate the production of these types of antibodies through vaccination. PMID- 26588776 TI - Worming Their Way into the Picture: Microbiota Help Helminths Modulate Host Immunity. AB - Parasitic helminths are potent regulators of host immunity, including inhibition of allergic inflammation. In this issue of Immunity, Zaiss et al. (2015) reveal that microbiota compositional shifts during helminth infection contribute to the multifaceted ways that helminths modulate host immunity. PMID- 26588777 TI - "Bringing Up Baby" to Tolerate Germs. AB - How immune tolerance is maintained in the skin remains unclear. In this issue of Immunity, Rosenblum and colleagues demonstrate that tolerance to commensal bacteria is established during the neonatal period via regulatory T cells. Defining the crucial window during which commensal-specific tolerance is achieved has strategic implications for the induction of tolerance in allergic diseases. PMID- 26588778 TI - Immune Interactions with Pathogenic and Commensal Fungi: A Two-Way Street. AB - We are exposed to a wide spectrum of fungi including innocuous environmental organisms, opportunistic pathogens, commensal organisms, and fungi that can actively and explicitly cause disease. Much less is understood about effective host immunity to fungi than is generally known about immunity to bacterial and viral pathogens. Innate and adaptive arms of the immune system are required for effective host defense against Candida, Aspergillus, Cryptococcus, and others, with specific elements of the host response regulating specific types of fungal infections (e.g., mucocutaneous versus systemic). Here we will review themes and controversies that are currently shaping investigation of antifungal immunity (primarily to Candida and Aspergillus) and will also examine the emerging field of the role of fungi in the gut microbiome. PMID- 26588779 TI - Isoforms of RNA-Editing Enzyme ADAR1 Independently Control Nucleic Acid Sensor MDA5-Driven Autoimmunity and Multi-organ Development. AB - Mutations in ADAR, which encodes the ADAR1 RNA-editing enzyme, cause Aicardi Goutieres syndrome (AGS), a severe autoimmune disease associated with an aberrant type I interferon response. How ADAR1 prevents autoimmunity remains incompletely defined. Here, we demonstrate that ADAR1 is a specific and essential negative regulator of the MDA5-MAVS RNA sensing pathway. Moreover, we uncovered a MDA5 MAVS-independent function for ADAR1 in the development of multiple organs. We showed that the p150 isoform of ADAR1 uniquely regulated the MDA5 pathway, whereas both the p150 and p110 isoforms contributed to development. Abrupt deletion of ADAR1 in adult mice revealed that both of these functions were required throughout life. Our findings delineate genetically separable roles for both ADAR1 isoforms in vivo, with implications for the human diseases caused by ADAR mutations. PMID- 26588780 TI - Pulmonary Epithelial Cell-Derived Cytokine TGF-beta1 Is a Critical Cofactor for Enhanced Innate Lymphoid Cell Function. AB - Epithelial cells orchestrate pulmonary homeostasis and pathogen defense and play a crucial role in the initiation of allergic immune responses. Maintaining the balance between homeostasis and inappropriate immune activation and associated pathology is particularly complex at mucosal sites that are exposed to billions of potentially antigenic particles daily. We demonstrated that epithelial cell derived cytokine TGF-beta had a central role in the generation of the pulmonary immune response. Mice that specifically lacked epithelial cell-derived TGF-beta1 displayed a reduction in type 2 innate lymphoid cells (ILCs), resulting in suppression of interleukin-13 and hallmark features of the allergic response including airway hyperreactivity. ILCs in the airway lumen were primed to respond to TGF-beta by expressing the receptor TGF-betaRII and ILC chemoactivity was enhanced by TGF-beta. These data demonstrate that resident epithelial cells instruct immune cells, highlighting the central role of the local environmental niche in defining the nature and magnitude of immune reactions. PMID- 26588781 TI - Identification of Common Features in Prototype Broadly Neutralizing Antibodies to HIV Envelope V2 Apex to Facilitate Vaccine Design. AB - Broadly neutralizing antibodies (bnAbs) directed to the V2 apex of the HIV envelope (Env) trimer isolated from individual HIV-infected donors potently neutralize diverse HIV strains, but strategies for designing immunogens to elicit bnAbs have not been identified. Here, we compared four prototypes (PG9, CH01, PGT145, and CAP256.VRC26.09) of V2 apex bnAbs and showed that all recognized a core epitope of basic V2 residues and the glycan-N160. Two prototype bnAbs were derived from VH-germlines that were 99% identical and used a common germline D gene encoded YYD-motif to interact with the V2-epitope. We identified isolates that were neutralized by inferred germline (iGL) versions of three of the prototype bnAbs. Soluble Env derived from one of these isolates was shown to form a well-ordered Env trimer that could serve as an immunogen to initiate a V2-apex bnAb response. These studies illustrate a strategy to transition from panels of bnAbs to vaccine candidates. PMID- 26588784 TI - Foreword. PMID- 26588782 TI - Superoxide Dismutase 1 Protects Hepatocytes from Type I Interferon-Driven Oxidative Damage. AB - Tissue damage caused by viral hepatitis is a major cause of morbidity and mortality worldwide. Using a mouse model of viral hepatitis, we identified virus induced early transcriptional changes in the redox pathways in the liver, including downregulation of superoxide dismutase 1 (Sod1). Sod1(-/-) mice exhibited increased inflammation and aggravated liver damage upon viral infection, which was independent of T and NK cells and could be ameliorated by antioxidant treatment. Type I interferon (IFN-I) led to a downregulation of Sod1 and caused oxidative liver damage in Sod1(-/-) and wild-type mice. Genetic and pharmacological ablation of the IFN-I signaling pathway protected against virus induced liver damage. These results delineate IFN-I mediated oxidative stress as a key mediator of virus-induced liver damage and describe a mechanism of innate immunity-driven pathology, linking IFN-I signaling with antioxidant host defense and infection-associated tissue damage. VIDEO ABSTRACT. PMID- 26588785 TI - Corrigendum. PMID- 26588783 TI - A Wave of Regulatory T Cells into Neonatal Skin Mediates Tolerance to Commensal Microbes. AB - The skin is a site of constant dialog between the immune system and commensal bacteria. However, the molecular mechanisms that allow us to tolerate the presence of skin commensals without eliciting destructive inflammation are unknown. Using a model system to study the antigen-specific response to S. epidermidis, we demonstrated that skin colonization during a defined period of neonatal life was required for establishing immune tolerance to commensal microbes. This crucial window was characterized by an abrupt influx of highly activated regulatory T (Treg) cells into neonatal skin. Selective inhibition of this Treg cell wave completely abrogated tolerance. Thus, the host-commensal relationship in the skin relied on a unique Treg cell population that mediated tolerance to bacterial antigens during a defined developmental window. This suggests that the cutaneous microbiome composition in neonatal life is crucial in shaping adaptive immune responses to commensals, and disrupting these interactions might have enduring health implications. PMID- 26588787 TI - New Insights into Blood Pressure Control for Intracerebral Haemorrhage. AB - Although blood pressure (BP) levels may rise in the weeks preceding intracerebral haemorrhage (ICH), in contrast to findings in the ischaemic stroke population, the initial post-ICH BP is often much higher than the last pre-morbid level. Elevated BP is therefore common in acute ICH, often with markedly elevated levels, and is associated with poor outcomes, though the exact pathophysiological mechanisms remain unclear. The Antihypertensive Treatment of Acute Cerebral Haemorrhage (ATACH) trial and the INTEnsive blood pressure Reduction in Acute Cerebral haemorrhage Trial (INTERACT) demonstrated that early and intensive lowering of elevated BP in the acute ICH period is feasible and safe. Importantly, recent CT perfusion studies have shown that early, intense BP reduction does not reduce cerebral blood flow or promote cerebral ischaemia. The recent, large INTERACT2 trial confirmed the safety of early BP lowering in ICH and suggested that intensive target-driven BP reduction may improve outcomes, with a non-significant trend towards reduced death and major disability and a significant favourable shift of scores on the modified Rankin scale compared with guideline-based treatment. BP lowering in acute ICH may reduce haematoma growth, particularly when target levels are achieved early and are sustained, though the evidence is partly conflicting. Other aspects of BP may also be important following acute ICH, with maximum systolic BP and systolic BP variability being independent predictors of poor outcomes in a recent study. This chapter gives an overview of the current evidence regarding BP in ICH and covers the following topics: the incidence of elevated BP in acute ICH and the patterns of BP observed before and after the event; the effect of elevated BP on outcomes in ICH and the potential underlying pathophysiological mechanisms; the safety and feasibility of BP lowering; the effects of BP lowering on clinical and radiological outcomes; other important aspects of BP in ICH; and the choice of antihypertensive agent. PMID- 26588788 TI - Lewis Acid Catalyzed Synthesis of alpha-Trifluoromethyl Esters and Lactones by Electrophilic Trifluoromethylation. AB - An electrophilic trifluoromethylation of ketene silyl acetals (KSAs) by hypervalent iodine reagents 1 and 2 has been developed. The reaction proceeds under very mild conditions in the presence of a catalytic amount of trimethylsilyl bis(trifluoromethanesulfonyl)imide (up to 2.5 mol %) as a Lewis acid providing a direct access to a variety of secondary, tertiary, and quaternary alpha-trifluoromethyl esters and lactones in high yield (up to 98%). PMID- 26588789 TI - New Insights in Minimally Invasive Surgery for Intracerebral Hemorrhage. AB - The poor clinical outcome of acute intracerebral hemorrhage (ICH) relates closely to the bleeding amount per unit of time and the hematoma position in the brain. Removal of an intracerebral hematoma in time can effectively improve clinical prognosis. Minimally invasive surgery (MIS) for the treatment of ICH is the main clinical method that is currently used, despite the lack of large-scale, clinical, multi-center, randomized controlled trials. This article comprehensively reviews the history and development of MIS for ICH and analyzes various roles of MIS in ICH treatment. General CT image-guided surgery with the local use of thrombolysis techniques is a major MIS method used in current ICH treatment. PMID- 26588790 TI - Compliance with the Mediterranean Diet Quality Index (KIDMED) among Balearic Islands' Adolescents and Its Association with Socioeconomic, Anthropometric and Lifestyle Factors. AB - BACKGROUND AND AIMS: To assess the compliance levels of adolescents in the Balearic Islands with the Mediterranean Diet Quality Index (KIDMED Index) and to assess its associations with socioeconomic, anthropometric and lifestyle characteristics. METHODS: A cross-sectional survey (n = 1,231; 12-17 years) carried out in 2007-2008. The degree of adherence to the Mediterranean diet (MedDiet) was evaluated using the KIDMED Index. Body composition, body image, socioeconomic factors, and physical activity were also assessed. RESULTS: Around 30% of adolescents showed high adherence to MedDiet and 15.7% showed poor adherence. More boys (32.0%) than girls (25.2%) showed high adherence to MedDiet. However, the proportion of adolescents who were reported to skip breakfast was higher among girls than boys (30.0 vs. 19.2%, respectively). The OR for poor adherence to MedDiet was higher in adolescents who usually attend mass media during mealtime, in boys eating <=3 occasions/day, and in physically inactive girls. In boys, poor adherence to MedDiet was associated with lower OR in the age range 12-13 and in those who wished to have a thin body shape. In girls, high parental educational level, time spent on media <2 h/day and eating breakfast regularly were also associated with lower OR for poor adherence to MedDiet. CONCLUSIONS: A high percentage of adolescents in Balearic Islands showed poor adherence to MedDiet. PMID- 26588791 TI - Structural instability and mechanical properties of MoS2 toroidal nanostructures. AB - Molybdenum disulfide (MoS2) nanostructures have received considerable research attention due to their outstanding physical and chemical properties. Recently, a form of MoS2 ring structure exhibiting unique transport properties has been experimentally identified. Herein, we present the first report describing direct molecular dynamics (MD) simulations of structural instability and mechanical properties of hypothetical MoS2 nanotube (NT) toroidal nanostructures. Nanorings with small diameter MoS2 NTs retain their circular shape because of the higher bending stability of NTs, while for those with large diameter MoS2 NTs buckling/kinking and displacive phase transformations appear to effectively reduce bending stress as a mechanism for stabilizing the nanorings. However, the nanorings which have to polygonize maintain a circular shape as thick multi walled inner nanorings are presented. Furthermore, mechanical responses of various nanoweaves (nanochains, nanomailles, and nanochainmailles) by linking nanorings together are also studied. The results show that Young's modulus, stretchability and tensile strength of such nanoweaves depend not only on the helicity of MoS2 NTs but also on the woven pattern. For example, nanostructures with 4-in-1 weaves of nanorings exhibit much higher tensile strength and stiffness but lower extensibility than those with 2-in-1 weaves. The finding suggests that MoS2 NT nanorings and their woven hierarchical structures may be used in the development of new flexible, light-weight electromechanical and optoelectronic nanodevices. PMID- 26588792 TI - Food Protein-Induced Non-Immunoglobulin E-Mediated Allergic Colitis in Infants and Older Children: What Cytokines Are Involved? AB - BACKGROUND: Food protein-induced allergic proctocolitis (FPIAP) is mostly a non immunoglobulin E-mediated disease where a T-cell-mediated reaction to cow's milk protein has been suggested. We determined the expression of transforming growth factor (TGF)-beta, TGF-beta receptor-1, tumor necrosis factor (TNF)-alpha, CD86, and CD23 on the colon mucosa to investigate their roles in the pathogenesis of the two subtypes of FPIAP, i.e. infantile FPIAP and FPIAP in older children. METHODS: Group 1 comprised children with infantile FPIAP (age <6 months, n = 21), group 2 referred to FPIAP in older children (age >1.5 years, n = 7), and group 3 included children with juvenile hyperplastic polyps (n = 22). Immunohistochemical staining of colonic biopsy specimens was performed. RESULTS: The expression of TNF-alpha was significantly higher in groups 1 and 2 compared to group 3. Group 2 patients had a significantly lower TGF-beta expression compared to the other groups. The expression of CD86 was higher in group 1 than in group 3 (p = 0.012). Eosinophil counts per high-power field in the lamina propria were significantly correlated with CD86 expression (p = 0.026, r = 0.388). CONCLUSION: Our results suggest that TNF-alpha is implicated in the pathogenesis of both types of FPIAP. The decreased activity of TGF-beta receptor-1 accompanied by the increased expression of CD86 in infants and the decreased activity of TGF-beta in older children appear to play a role in the development of FPIAP. PMID- 26588793 TI - Diffusional kurtosis imaging for differentiating between high-grade glioma and primary central nervous system lymphoma. AB - BACKGROUND: The aim of this study was to assess the diagnostic accuracy of diffusion kurtosis magnetic resonance imaging parameters for differentiating high grade gliomas (HGGs) from primary central nervous system lymphomas (PCNSLs). METHODS: Diffusion parameters, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (lambda// ), radial diffusivity (lambda? ); and kurtosis parameters, including mean kurtosis (MK), axial kurtosis (K// ), and radial kurtosis (K? ), were normalized to contralateral normal-appearing white matter (NAWMc) to decrease inter-individual and inter-regional changes across the entire brain, and then compared with the solid parts of 20 HGGs and 11 PCNSLs [median 95% confidence interval (CI), P < 0.004; 0.05/14], significance level, Kolmogorov-Smirnov test, Bonferroni correction]. RESULTS: FA, MD, lambda// , and lambda? values were higher in HGGs than in PCNSLs, but not significantly [HGGs: 0.209 (95% CI, 0.134-0.338), 1.385 (95% CI, 1.05-1.710), 1.655 (95% CI, 1.30 2.060), 1.228 (95% CI, 0.932-1.480), respectively; PCNSLs: 0.143 (95% CI, 0.110 0.317), 1.070 (95% CI, 0.842-1.470), 1.260 (95% CI, 0.960-1.930), 1.010 (95% CI, 0.782-1.240)], respectively; P = 0.120, 0.010, 0.004, and 0.004, respectively). However, MK and K// were significantly higher in PCNSLs compared with HGGs [PCNSLs: 0.765 (95% CI, 0.697-0.890), 0.787 (95% CI, 0.615-1.030), respectively; HGGs: 0.531 (95% CI, 0.402-0.766), 0.532 (95% CI, 0.432-0.680], respectively; P = 0.001, 0.000, respectively); but not K? [0.774 (95% CI, 0.681-0.899) for PCNSLs; 0.554 (95% CI, 0.389-0.954) for HGGs; P = 0.024]. CONCLUSION: There were significant differences in kurtosis parameters (MK and K// ) between HGGs and PCNSLs, while differences in diffusion parameters between them did not reach significance; hence, better separation was achieved with these parameters than with conventional diffusion imaging parameters. J. Magn. Reson. Imaging 2016;44:30-40. PMID- 26588794 TI - Determinants of Transitional Zone Area and Porosity of the Proximal Femur Quantified In Vivo in Postmenopausal Women. AB - Bone architecture as well as size and shape is important for bone strength and risk of fracture. Most bone loss is cortical and occurs by trabecularization of the inner part of the cortex. We therefore wanted to identify determinants of the bone architecture, especially the area and porosity of the transitional zone, an inner cortical region with a large surface/matrix volume available for intracortical remodeling. In 211 postmenopausal women aged 54 to 94 years with nonvertebral fractures and 232 controls from the Tromso Study, Norway, we quantified femoral subtrochanteric architecture in CT images using StrAx1.0 software, and serum levels of bone turnover markers (BTM, procollagen type I N terminal propeptide and C-terminal cross-linking telopeptide of type I collagen). Multivariable linear and logistic regression analyses were used to quantify associations of age, weight, height, and bone size with bone architecture and BTM, and odds ratio (OR) for fracture. Increasing age, height, and larger total cross-sectional area (TCSA) were associated with larger transitional zone CSA and transitional zone CSA/TCSA (standardized coefficients [STB] = 0.11 to 0.80, p <= 0.05). Increasing weight was associated with larger TCSA, but smaller transitional zone CSA/TCSA and thicker cortices (STB = 0.15 to 0.22, p < 0.01). Increasing height and TCSA were associated with higher porosity of the transitional zone (STB = 0.12 to 0.46, p < 0.05). Increasing BTM were associated with larger TCSA, larger transitional zone CSA/TCSA, and higher porosity of each of the cortical compartments (p < 0.01). Fracture cases exhibited larger transitional zone CSA and higher porosity than controls (p < 0.001). Per SD increasing CSA and porosity of the transitional zone, OR for fracture was 1.71 (95% CI, 1.37 to 2.14) and 1.51 (95% CI, 1.23 to 1.85), respectively. Cortical bone architecture is determined mainly by bone size as built during growth and is modified by lifestyle factors throughout life through bone turnover. Fracture cases exhibited larger transitional zone area and porosity, highlighting the importance of cortical bone architecture for fracture propensity. PMID- 26588796 TI - Management of LUTS in patients with dementia and associated disorders . AB - AIMS: To systematically review the management of lower urinary tract symptoms (LUTS) in patients with dementia and associated disorders. METHODS: This systematic review was performed according to the PRISMA statement. Studies were identified by electronic search of Embase and Medline databases (last search August 2015) and by screening of reference lists and reviews. RESULTS: Of 1,426 abstracts that were screened, 102 full-text articles were identified and assessed for eligibility. Seventy-six articles were then included in the quantitative synthesis. Urinary incontinence (UI) prevalence rates in dementia patients have varied considerably, ranging from 11 to 93%. In Alzheimer's disease patients, UI usually correlates with disease progression (late-stage dementia). In contrast, LUTS usually precede severe mental failure in Lewy body disease and in vascular dementia. Behavioral therapy, including toilet training and prompted voiding, may be especially useful in patients with unawareness UI. High-quality data to guide the choice of treatment strategies in this population are lacking. Current evidence suggests that antimuscarinics, especially oxybutynin, can be associated with cognitive worsening, due to the blockade of M1 receptors. Thus, the use of antimuscarinics that do not easily cross the blood-brain barrier or are more M2/M3 selective should be considered. No data are available for beta-3 agonists so far. CONCLUSION: Different types of dementia cause different LUTS at varying time points during the disease process and need singular therapeutic approaches. Treatment of LUTS should be tailored to individual patient needs and disease status, considering factors like mobility, cognitive function, and general medical condition. Neurourol. Urodynam. 36:245-252, 2017. (c) 2015 Wiley Periodicals, Inc. PMID- 26588795 TI - Selective binding of C-6 OH sulfated hyaluronic acid to the angiogenic isoform of VEGF(165). AB - Vascular endothelial growth factor 165 (VEGF165) is an important extracellular protein involved in pathological angiogenesis in diseases such as cancer, wet age related macular degeneration (wet-AMD) and retinitis pigmentosa. VEGF165 exists in two different isoforms: the angiogenic VEGF165a, and the anti-angiogenic VEGF165b. In some angiogenic diseases the proportion of VEGF165b may be equal to or higher than that of VEGF165a. Therefore, developing therapeutics that inhibit VEGF165a and not VEGF165b may result in greater anti-angiogenic activity and therapeutic benefit. To this end, we report the selective binding properties of sulfated hyaluronic acid (s-HA). Selective biopolymers offer several advantages over antibodies or aptamers including cost effective and simple synthesis, and the ability to make nanoparticles or hydrogels for drug delivery applications or VEGF165a sequestration. Limiting sulfation to the C-6 hydroxyl (C-6 OH) in the N acetyl-glucosamine repeat unit of hyaluronic acid (HA) resulted in a polymer with strong affinity for VEGF165a but not VEGF165b. Increased sulfation beyond the C-6 OH (i.e. greater than 1 sulfate group per HA repeat unit) resulted in s-HA polymers that bound both VEGF165a and VEGF165b. The C-6 OH sulfated HA (Mw 150 kDa) showed strong binding properties to VEGF165a with a fast association rate constant (Ka; 2.8 * 10(6) M(-1) s(-1)), slow dissociation rate constant (Kd; 2.8 * 10(-3) s(-1)) and strong equilibrium binding constant (KD; ~1.0 nM)), which is comparable to the non-selective VEGF165 binding properties of the commercialized therapeutic anti-VEGF antibody (Avastin((r))). The C-6 OH sulfated HA also inhibited human umbilical vein endothelial cell (HUVEC) survival and proliferation and human dermal microvascular endothelial cell (HMVEC) tube formation. These results demonstrate that the semi-synthetic natural polymer, C-6 OH sulfated HA, may be a promising biomaterial for the treatment of angiogenesis related disease. PMID- 26588797 TI - Sanctuary Sites: What Lies Behind Ebola Eye Infections, Sexual Transmission, and Relapses. PMID- 26588799 TI - Apoptosis Evaluation by Electrochemical Techniques. AB - Apoptosis has close relevance to pathology, pharmacology, and toxicology. Accurate and convenient detection of apoptosis would be beneficial for biological study, clinical diagnosis, and drug development. Based on distinct features of apoptotic cells, a diversity of analytical techniques have been exploited for sensitive analysis of apoptosis, such as surface plasmon resonance, electrochemical methods, flow cytometry, and some imaging assays. Among them, the features of simplicity, easy operation, low cost, and high sensitivity make electrochemical techniques powerful tools to investigate electron-transfer processes of in vitro biological systems. In this contribution, a general overview of current knowledge on various technical approaches for apoptosis evaluation is provided. Furthermore, recently developed electrochemical biosensors for detecting apoptotic cells and their advantages over traditional methods are summarized. One of the main considerations focuses on designing the recognition elements based on various biochemical events during apoptosis. PMID- 26588798 TI - The stress-related, rhizobial small RNA RcsR1 destabilizes the autoinducer synthase encoding mRNA sinI in Sinorhizobium meliloti. AB - Quorum sensing is a cell density-dependent communication system of bacteria relying on autoinducer molecules. During the analysis of the post-transcriptional regulation of quorum sensing in the nitrogen fixing plant symbiont Sinorhizobium meliloti, we predicted and verified a direct interaction between the 5'-UTR of sinI mRNA encoding the autoinducer synthase and a small RNA (sRNA), which we named RcsR1. In vitro, RcsR1 prevented cleavage in the 5'-UTR of sinI by RNase E and impaired sinI translation. In line with low ribosomal occupancy and transcript destabilization upon binding of RcsR1 to sinI, overproduction of RcsR1 in S. meliloti resulted in lower level and shorter half-life of sinI mRNA, and in decreased autoinducer amount. Although RcsR1 can influence quorum sensing via sinI, its level did not vary at different cell densities, but decreased under salt stress and increased at low temperature. We found that RcsR1 and its stress related expression pattern, but not the interaction with sinI homologs, are conserved in Sinorhizobium, Rhizobium and Agrobacterium. Consistently, overproduction of RcsR1 in S. meliloti and Agrobacterium tumefaciens inhibited growth at high salinity. We identified conserved targets of RcsR1 and showed that most conserved interactions and the effect on growth under salt stress are mediated by the first stem-loop of RcsR1, while its central part is responsible for the species-specific interaction with sinI. We conclude that RcsR1 is an ancient, stress-related riboregulator in rhizobia and propose that it links stress responses to quorum sensing in S. meliloti. PMID- 26588801 TI - Magnetic properties, microstructure and mineralogical phases of technogenic magnetic particles (TMPs) in urban soils: Their source identification and environmental implications. AB - Magnetic measurement is an effective method to determine spatial distribution and the degree of heavy metal pollution and to identify various anthropogenic sources of heavy metals. The objectives of this investigation are to characterize the magnetic properties, microstructure and mineralogical phases of technogenic magnetic particles (TMPs) in urban soils and to discuss their potential environmental implications. The TMPs are separated from the urban topsoils of Luoyang city, China. The magnetic properties, morphology, and mineral phase of TMPs are studied using mineral magnetic measurement, scanning electron microscopy equipped with energy-dispersive X-ray spectroscopy (SEM/EDS), X-ray diffraction, and synchrotron-radiation-based microprobe. The content of TMPs in urban topsoils ranges from 0.05 to 1.95% (on average 0.32%). The magnetic susceptibility of TMPs ranges from 4559*10(-8) to 23,661*10(-8) m(3) kg(-1) (on average 13,637*10(-8) m(3) kg(-1)). Thermomagnetic and bulk X-ray diffraction analyses indicate that main magnetic minerals of TMPs are magnetite (Fe3O4) and hematite (alpha-Fe2O3). The morphology of TMPs observed by SEM includes three shape types: spherule, irregular-shaped, and aggregate particles. The size of spherical TMPs ranges from 30 to about 200 MUm, with the largest percentage of 30-50 MUm. Synchrotron radiation-based microprobe (MU-XRF and MU-XRD) indicates that TMPs are enriched with heavy metals Pb, Cd, Zn, Cu, and Cr, which are incorporated into lattice or adsorbed on the surface of magnetite/hematite. The content of TMPs significantly relates with the Tomlinson Pollution Load Index (PLI) (R(2)=0.467), suggesting that it can be used as proxy indicator of degree of heavy metal contamination in urban soils. The magnetic properties, microstructure and mineralogical phases of TMPs can serve as the identification of pollution sources in urban soils. PMID- 26588800 TI - Organization of the sleep-related neural systems in the brain of the minke whale (Balaenoptera acutorostrata). AB - The current study analyzed the nuclear organization of the neural systems related to the control and regulation of sleep and wake in the basal forebrain, diencephalon, midbrain, and pons of the minke whale, a mysticete cetacean. While odontocete cetaceans sleep in an unusual manner, with unihemispheric slow wave sleep (USWS) and suppressed REM sleep, it is unclear whether the mysticete whales show a similar sleep pattern. Previously, we detailed a range of features in the odontocete brain that appear to be related to odontocete-type sleep, and here present our analysis of these features in the minke whale brain. All neural elements involved in sleep regulation and control found in bihemispheric sleeping mammals and the harbor porpoise were present in the minke whale, with no specific nuclei being absent, and no novel nuclei being present. This qualitative similarity relates to the cholinergic, noradrenergic, serotonergic and orexinergic systems, and the GABAergic elements of these nuclei. Quantitative analysis revealed that the numbers of pontine cholinergic (274,242) and noradrenergic (203,686) neurons, and hypothalamic orexinergic neurons (277,604), are markedly higher than other large-brained bihemispheric sleeping mammals. Small telencephalic commissures (anterior, corpus callosum, and hippocampal), an enlarged posterior commissure, supernumerary pontine cholinergic and noradrenergic cells, and an enlarged peripheral division of the dorsal raphe nuclear complex of the minke whale, all indicate that the suite of neural characteristics thought to be involved in the control of USWS and the suppression of REM in the odontocete cetaceans are present in the minke whale. J. Comp. Neurol. 524:2018-2035, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26588803 TI - QM/MM Protocol for Direct Molecular Dynamics of Chemical Reactions in Solution: The Water-Accelerated Diels-Alder Reaction. AB - We describe a solvent-perturbed transition state (SPTS) sampling scheme for simulating chemical reaction dynamics in condensed phase. The method, adapted from Truhlar and Gao's ensemble-averaged variational transition state theory, includes the effect of instantaneous solvent configuration on the potential energy surface of the reacting system (RS) and allows initial conditions for the RS to be sampled quasiclassically by TS normal mode sampling. We use a QM/MM model with direct dynamics, in which QM forces of the RS are computed at each trajectory point. The SPTS scheme is applied to the acceleration of the Diels Alder reaction of cyclopentadiene (CP) + methyl vinyl ketone (MVK) in water. We explored the effect of the number of SPTS and of solvent box size on the distribution of bond lengths in the TS. Statistical sampling of the sampling was achieved when distribution of forming bond lengths converged. We describe the region enclosing the partial bond lengths as the transition zone. Transition zones in the gas phase, SMD implicit solvent, QM/MM, and QM/MM+QM (3 water molecules treated by QM) vary according to the ability of the medium to stabilize zwitterionic structures. Mean time gaps between formation of C-C bonds vary from 11 fs for gas phase to 25 fs for QM/MM+QM. Mean H-bond lengths to O(carbonyl) in QM/MM+QM are 0.14 A smaller at the TS than in MVK reactant, and the mean O(carbonyl)-H(water)-O(water) angle of H-bonds at the TS is 10 degrees larger than in MVK reactant. PMID- 26588802 TI - Increased levels of etheno-DNA adducts and genotoxicity biomarkers of long-term exposure to pure diesel engine exhaust. AB - Etheno-DNA adducts are biomarkers for assessing oxidative stress. In this study, the aim was to detect the level of etheno-DNA adducts and explore the relationship between the etheno-DNA adducts and genotoxicity biomarkers of the diesel engine exhaust (DEE)-exposed workers. We recruited 86 diesel engine testing workers with long-term exposure to DEE and 99 non-DEE-exposed workers. The urinary mono-hydroxylated polycyclic aromatic hydrocarbons (OH-PAHs) and etheno-DNA adducts (epsilondA and epsilondC) were detected by HPLC-MS/MS and UPLC MS/MS, respectively. Genotoxicity biomarkers were also evaluated by comet assay and cytokinesis-block micronucleus assay. The results showed that urinary epsilondA was significantly higher in the DEE-exposed workers (p<0.001), exhibited 2.1-fold increase compared with the non-DEE-exposed workers. The levels of urinary OH-PAHs were positively correlated with the level of epsilondA among all the study subjects (p<0.001). Moreover, we found that the increasing level of epsilondA was significantly associated with the increased olive tail moment, percentage of tail DNA, or frequency of micronucleus in the study subjects (p<0.01). No significant association was observed between the epsilondC level and any measured genotoxicity biomarkers. In summary, epsilondA could serve as an indicator for DEE exposure in the human population. PMID- 26588804 TI - The effect of premorbid attention-deficit/hyperactivity disorder on neuropsychological functioning in individuals with acute mild traumatic brain injuries. AB - INTRODUCTION: Mild traumatic brain injury (mTBI) is a frequent, yet undertreated condition that typically manifests with transient neurological and cognitive symptoms that resolve over the course of several weeks. In contrast, attention deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that presents initially in childhood but often persists into adulthood. mTBI and ADHD include overlapping symptomatology, making it difficult for clinicians to disentangle the sequelae of each condition when they co-occur in the same individual. We hypothesized that neuropsychological tests would be sensitive to preexisting ADHD in inpatients with acute mTBIs. METHOD: We retrospectively examined the medical charts of 100 inpatients, aged 18-40 years (96% Caucasian; 77% male) with mTBIs in an acute care setting, half of whom had self-reported the presence of premorbid ADHD, and half of whom were matched controls. We analyzed group differences across neuropsychological tests of attention, processing speed, and executive functions, examined the profile ratings of independent, blinded, board-certified neuropsychologists, and correlated cognitive performance with time from traumatic injury to testing. RESULTS: Individuals with premorbid ADHD (a) performed significantly worse than their matched counterparts on several tests of attention, processing speed, and working memory, and (b) were significantly more likely to produce profiles later rated as impaired by independent, board-certified clinical neuropsychologists. In addition, time from traumatic injury to testing was found to be negatively correlated with neurocognitive performance. CONCLUSIONS: These findings (a) argue for the utility of a brief assessment of premorbid ADHD in the acute care of individuals with mTBIs and (b) provide clinicians with a barometer for gauging the relative contributions of premorbid ADHD to neuropsychological impairments in the neurocognitive profiles of individuals with mTBIs. Reported effect sizes will assist clinicians in accurately weighing the impact of premorbid ADHD when interpreting such profiles. PMID- 26588805 TI - Charge Saturation and Intrinsic Doping in Electrolyte-Gated Organic Semiconductors. AB - Electrolyte gating enables low voltage operation of organic thin film transistors, but little is known about the nature of the electrolyte/organic interface. Here we apply charge-modulation Fourier transform infrared spectroscopy, in conjunction with electrical measurements, on a model electrolyte gated organic semiconductor interface: single crystal rubrene/ion-gel. We provide spectroscopic signature for free-hole like carriers in the organic semiconductor and unambiguously show the presence of a high density of intrinsic doping of the free holes upon formation of the rubrene/ion-gel interface, without gate bias (Vg = 0 V). We explain this intrinsic doping as resulting from a thermodynamic driving force for the stabilization of free holes in the organic semiconductor by anions in the ion-gel. Spectroscopy also reveals the saturation of free-hole like carrier density at the rubrene/ion-gel interface at Vg < -0.5 V, which is commensurate with the negative transconductance seen in transistor measurements. PMID- 26588806 TI - Simulation of the dynamic packing behavior of preparative chromatography columns via discrete particle modeling. AB - Preparative packed-bed chromatography using polymer-based, compressible, porous resins is a powerful method for purification of macromolecular bioproducts. During operation, a complex, hysteretic, thus, history-dependent packed bed behavior is often observed but theoretical understanding of the causes is limited. Therefore, a rigorous modeling approach of the chromatography column on the particle scale has been made which takes into account interparticle micromechanics and fluid-particle interactions for the first time. A three dimensional deterministic model was created by applying Computational Fluid Dynamics (CFD) coupled with the Discrete Element Method (DEM). The column packing behavior during either flow or mechanical compression was investigated in-silico and in laboratory experiments. A pronounced axial compression-relaxation profile was identified that differed for both compression strategies. Void spaces were clearly visible in the packed bed after compression. It was assumed that the observed bed inhomogeneity was because of a force-chain network at the particle scale. The simulation satisfactorily reproduced the measured behavior regarding packing compression as well as pressure-flow dependency. Furthermore, the particle Young's modulus and particle-wall friction as well as interparticle friction were identified as crucial parameters affecting packing dynamics. It was concluded that compaction of the chromatographic bed is rather because of particle rearrangement than particle deformation. (c) 2015 American Institute of Chemical Engineers Biotechnol. Prog., 32:363-371, 2016. PMID- 26588807 TI - Exercise test using dry air in random adolescents: Temporal profile and predictors of bronchoconstriction. AB - BACKGROUND AND OBJECTIVE: Guidelines recommend exercise tests using dry air to diagnose exercise-induced bronchoconstriction (EIB). Lung function changes subsequent to these tests have not been investigated in a general adolescent population, and it remains unknown whether signs of airway inflammation, measured using exhaled nitric oxide (FeNO), can predict a positive response. The aim of this study was to investigate the temporal aspect of decline in forced expiratory volume in 1 s (FEV1 ) after an exercise test using dry air, and to investigate predictors of EIB. METHODS: From a cross-sectional study on adolescents aged 13 15 years (n = 3838), a random subsample of 146 adolescents (99 with and 47 without self-reported exercise-induced dyspnoea) underwent standardized treadmill exercise tests for EIB while breathing dry air. RESULTS: Of the adolescents, 34% had a positive EIB test (decline of >=10% in FEV1 from baseline) within 30 min. Of the subjects with EIB, 53% showed the greatest decline in FEV1 at 5 to 10 min (mean decline 18.5%), and the remaining 47% of the subjects showed the greatest decline at 15 to 30 min (mean decline 18.9%) after exercise. Increased FeNO (>20 ppb), female gender and self-reported exercise-induced dyspnoea were independently associated with a positive EIB test. CONCLUSION: When assessing general adolescents for EIB with exercise test using dry air, there is a temporal variation in the greatest FEV1 decline after exercise. Therefore, lung function should be measured for at least 30 min after the exercise. Increased FeNO, female gender and self-reported exercise-induced dyspnoea can be predictors of a positive EIB test. PMID- 26588808 TI - Current variations in childhood cancer supportive care in the Netherlands. AB - BACKGROUND: Current treatment strategies in pediatric oncology are intensive and lead to high survival rates but also to treatment-related complications. Therefore, supportive care plays an increasingly important role. This study was designed to evaluate variations in supportive care practice in children with cancer in the Netherlands and adherence to selected existing international guidelines through an in-depth review of local guidelines and protocols at all 6 Dutch pediatric cancer centers. METHODS: Based on shared expert opinion, a questionnaire regarding current supportive care practice was compiled. For each center, the required information was extracted from local supportive care guidelines, and the list was sent to a pediatric oncologist of that center to verify its correspondence with local daily practice. Subsequently, it was determined whether clinical practice was concordant (same in >= 5 of 6 centers), partly concordant (highly overlapping in >= 5 of 6 centers), or discordant (same in < 5 of 6 centers). Local practices were compared with strong recommendations from high-quality, evidence-based guidelines. RESULTS: The questionnaire comprised 67 questions regarding supportive care practice. Concordance was observed for 11 of 67 practice items (16%), partial concordance was observed for 6 of 67 practice items (9%), and discordance was observed for 50 of 67 practice items (75%). Adherence to strong recommendations of 4 high-quality, evidence based guidelines varied but was generally low. CONCLUSIONS: Large variations exist in pediatric oncology supportive care practice, and this could negatively influence care. Adherence to existing evidence-based guidelines and the development and implementation of new clinical practice guidelines have the potential of standardizing supportive care practice and thereby improving outcomes for children with cancer. PMID- 26588809 TI - Effects of aromatase inhibition vs. testosterone in older men with low testosterone: randomized-controlled trial. AB - Aging in men is associated with loss of bone mass, impaired physical function and altered body composition. The objective of this proof-of-concept randomized, double-blind, placebo-controlled, parallel-group, single-center trial was to determine the relative effects of testosterone (T) and estradiol (E(2)) on bone mineral density, body composition, and physical performance in older men. The primary outcome was lumbar spine bone mineral density (BMD), and secondary outcomes were body composition, muscle strength, gait speed, and sex hormone concentrations. Forty three men (age range, 65-82 years; mean age 71 years) with low total T levels <350 ng/dL were randomized to one of three groups: 5 g transdermal testosterone gel (TT) (N = 16), anastrozole (AI) 1 mg (N = 14) or placebo daily (N = 13) for 12 months. Outcomes were assessed at baseline, 3, 6, and 12 months. Both TT and AI increased serum TT levels (>500 ng/dL, p < 0.05) compared to baseline; T values remained stable throughout the duration of the trial. At 12 months, TT improved the primary outcome of lumbar spine BMD (p < 0.01).Both interventions improved knee strength at 12 months compared to baseline (p < 0.05) while lean body mass significantly increased only in the AI group at 6 and 12 months (1.49 +/- 0.38 kg, p < 0.01; 1.24 +/- 0.39 kg, p < 0.05, respectively) compared to baseline. Interestingly, TT improved fast gait speed at 3 and 12 months (p < 0.01, p < 0.05, respectively). In summary, this proof-of concept study confirms that aromatization of T is required for maintaining BMD in older men with low-T levels. The trial also uncovered the novel finding that aromatization of T is required for improvement in fast gait speed, an observation that needs to be verified in future studies. PMID- 26588811 TI - Chronic myeloid leukemia: Second-line drugs of choice. AB - The efficacy of second-line treatment for chronic myeloid leukemia (CML) plays an important role in allowing CML patients to enjoy a normal life expectancy. Four tyrosine kinase inhibitors (TKIs) are presently available: bosutinib, dasatinib, nilotinib, ponatinib. Each one has different safety and activity profiles, which are reviewed here. No controlled studies are available to guide treatment decision, which must be based on the characterization of leukemic cells, especially in cases of resistance to TKI, coupled with the safety profile of each TKI. Patient comorbidities also play an important role in the treatment decision, which can achieve a new durable response in over 50% of treated patients. PMID- 26588810 TI - Successful Application of Closed-Loop Artificial Pancreas Therapy After Islet Autotransplantation. AB - Total pancreatectomy with islet autotransplantation (TPIAT) may relieve the pain of chronic pancreatitis while avoiding postsurgical diabetes. Minimizing hyperglycemia after TPIAT limits beta cell apoptosis during islet engraftment. Closed-loop (CL) therapy combining an insulin pump with a continuous glucose monitor (CGM) has not been investigated previously in islet transplant recipients. Our objective was to determine the feasibility and efficacy of CL therapy to maintain glucose profiles close to normoglycemia following TPIAT. Fourteen adult subjects (36% male; aged 35.9 +/- 11.4 years) were randomized to subcutaneous insulin via CL pump (n = 7) or multiple daily injections with blinded CGM (n = 7) for 72 h at transition from intravenous to subcutaneous insulin. Mean serum glucose values were significantly lower in the CL pump group than in the control group (111 +/- 4 vs. 130 +/- 13 mg/dL; p = 0.003) without increased risk of hypoglycemia (percentage of time <70 mg/dL: CL pump 1.9%, control 4.8%; p = 0.46). Results from this pilot study suggest that CL therapy is superior to conventional therapy in maintaining euglycemia without increased hypoglycemia. This technology shows significant promise to safely maintain euglycemic targets during the period of islet engraftment following islet transplantation. PMID- 26588812 TI - Possibilities of mercury removal in the dry flue gas cleaning lines of solid waste incineration units. AB - Dry methods of the flue gas cleaning (for HCl and SO2 removal) are useful particularly in smaller solid waste incineration units. The amount and forms of mercury emissions depend on waste (fuel) composition, content of mercury and chlorine and on the entire process of the flue gas cleaning. In the case of high HCl/total Hg molar ratio in the flue gas, the majority (usually 70-90%) of mercury is present in the form of HgCl2 and a smaller amount in the form of mercury vapors at higher temperatures. Removal of both main forms of mercury from the flue gas is dependent on chemical reactions and sorption processes at the temperatures below approx. 340 degrees C. Significant part of HgCl2 and a small part of elemental Hg vapors can be adsorbed on fly ash and solid particle in the air pollution control (APC) processes, which are removed in dust filters. Injection of non-impregnated active carbon (AC) or activated lignite coke particles is able to remove mainly the oxidized Hg(2+) compounds. Vapors of metallic Hg(o) are adsorbed relatively weakly. Much better chemisorption of Hg(o) together with higher sorbent capacity is achieved by AC-based sorbents impregnated with sulfur, alkali poly-sulfides, ferric chloride, etc. Inorganic sorbents with the same or similar chemical impregnation are also applicable for deeper Hg(o) removal (over 85%). SCR catalysts convert part of Hg(o) into oxidized compounds (HgO, HgCl2, etc.) contributing to more efficient Hg removal, but excess of NH3 has a negative effect. Both forms, elemental Hg(o) and HgCl2, can be converted into HgS particles by reacting with droplets/aerosol of poly sulfides solutions/solids in flue gas. Mercury captured in the form of water insoluble HgS is more advantageous in the disposal of solid waste from APC processes. Four selected options of the dry flue gas cleaning with mercury removal are analyzed, assessed and compared (in terms of efficiency of Hg emission reduction and costs) with wet methods and retrofits for more efficient Hg-removal. Overall mercury removal efficiencies from flue gas can attain 80-95%, depending on sorbent type/impregnation, sorbent surplus and operating conditions. PMID- 26588814 TI - Adaptation and detoxification mechanisms of Vetiver grass (Chrysopogon zizanioides) growing on gold mine tailings. AB - Vetiver grass (Chrysopogon zizanioides) was investigated for its potential use in the rehabilitation of gold mine tailings, its ability to extract and accumulate toxic metals from the tailings and its metal tolerant strategies. Vetiver grass was grown on gold mine tailings soil, in a hothouse, and monitored for sixteen weeks. The mine tailings were highly acidic and had high electrical conductivity. Vetiver grass was able to grow and adapt well on gold mine tailings. The results showed that Vetiver grass accumulated large amounts of metals in the roots and restricted their translocation to the shoots. This was confirmed by the bioconcentration factor of Zn, Cu, and Ni of >1 and the translocation factor of <1 for all the metals. This study revealed the defense mechanisms employed by Vetiver grass against metal stress that include: chelation of toxic metals by phenolics, glutathione S-tranferase, and low molecular weight thiols; sequestration and accumulation of metals within the cell wall that was revealed by the scanning electron microscopy that showed closure of stomata and thickened cell wall and was confirmed by high content of cell wall bound phenolics. Metal induced reactive oxygen species are reduced or eliminated by catalase, superoxide dismutase and peroxidase dismutase. PMID- 26588813 TI - Inorganic Arsenic-Related Changes in the Stromal Tumor Microenvironment in a Prostate Cancer Cell-Conditioned Media Model. AB - BACKGROUND: The tumor microenvironment plays an important role in the progression of cancer by mediating stromal-epithelial paracrine signaling, which can aberrantly modulate cellular proliferation and tumorigenesis. Exposure to environmental toxicants, such as inorganic arsenic (iAs), has also been implicated in the progression of prostate cancer. OBJECTIVE: The role of iAs exposure in stromal signaling in the tumor microenvironment has been largely unexplored. Our objective was to elucidate molecular mechanisms of iAs-induced changes to stromal signaling by an enriched prostate tumor microenvironment cell population, adipose-derived mesenchymal stem/stromal cells (ASCs). RESULTS: ASC conditioned media (CM) collected after 1 week of iAs exposure increased prostate cancer cell viability, whereas CM from ASCs that received no iAs exposure decreased cell viability. Cytokine array analysis suggested changes to cytokine signaling associated with iAs exposure. Subsequent proteomic analysis suggested a concentration-dependent alteration to the HMOX1/THBS1/TGFbeta signaling pathway by iAs. These results were validated by quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and Western blotting, confirming a concentration-dependent increase in HMOX1 and a decrease in THBS1 expression in ASC following iAs exposure. Subsequently, we used a TGFbeta pathway reporter construct to confirm a decrease in stromal TGFbeta signaling in ASC following iAs exposure. CONCLUSIONS: Our results suggest a concentration-dependent alteration of stromal signaling: specifically, attenuation of stromal-mediated TGFbeta signaling following exposure to iAs. Our results indicate iAs may enhance prostate cancer cell viability through a previously unreported stromal-based mechanism. These findings indicate that the stroma may mediate the effects of iAs in tumor progression, which may have future therapeutic implications. CITATION: Shearer JJ, Wold EA, Umbaugh CS, Lichti CF, Nilsson CL, Figueiredo ML. 2016. Inorganic arsenic-related changes in the stromal tumor microenvironment in a prostate cancer cell-conditioned media model. Environ Health Perspect 124:1009 1015; http://dx.doi.org/10.1289/ehp.1510090. PMID- 26588815 TI - Proteome basis for intramuscular variation in color stability of beef semimembranosus. AB - The objective of the present study was to characterize the proteome basis for intramuscular color stability variations in beef semimembranosus. Semimembranosus muscles from eight carcasses (n=8) were fabricated into 2.54-cm thick color labile inside (ISM) and color-stable outside (OSM) steaks. One steak for sarcoplasmic proteome analysis was immediately frozen, whereas other steaks were allotted to retail display under aerobic packaging. Color attributes were evaluated instrumentally and biochemically on 0, 2, and 4days. Sarcoplasmic proteome was analyzed using two-dimensional electrophoresis and tandem mass spectrometry. ISM steaks demonstrated greater (P<0.01) abundance of glycolytic enzymes (fructose-bisphosphate aldolase A, phosphoglycerate mutase 2, and beta enolase) and phosphatidylethanolamine-binding protein 1 than their OSM counterparts. Possible rapid post-mortem glycolysis in ISM, insinuated by over abundance of glycolytic enzymes, could lead to rapid pH decline during early post mortem, which in turn could potentially compromise its color stability. These results indicated that differential abundance of sarcoplasmic proteome contributes to intramuscular variations in beef color stability. PMID- 26588816 TI - Respiratory syncytial virus shedding by children hospitalized with lower respiratory tract infection. AB - Children with respiratory syncytial virus (RSV) infection shed virus for variable periods. The aim of this study was to quantify the viral load in nasopharyngeal aspirates of children with RSV throughout their hospitalization. This study included 37 children who were admitted with a diagnosis of RSV infection based on a positive rapid diagnostic test. Nasopharyngeal aspirates were collected from patients every day, from admission to discharge. Viral detection and quantification were performed using quantitative real-time PCR. Of the 37 patients, RSV-A was detected in 29 and RSV-B in 6. Two patients were PCR-negative for any type of RSV. RSV-A was detected in 12 of 16 patients (75%) 6 days after admission. These patients shed detectable virus from days 1 to 12, and for a significantly longer period (mean 5.7 days) than RSV-B (mean 3.8 days) patients. Half of the RSV-A patients were also positive on day 14 following onset. RSV-A was detected in patients <12 months of age for significantly longer periods after onset than in patients >=12 months of age. RSV-A viral load was negatively correlated with days from admission and days from onset. Because RSV shedding was frequently prolonged, the hospitalized children may have contracted RSV as a nosocomial infection. To prevent nosocomial RSV infections in hospital wards, healthcare workers must take appropriate infection control measures and provide adequate guidance on hand washing to the family of the patient. PMID- 26588817 TI - Bradykinin B2 receptor expression in the bronchial mucosa of allergic asthmatics: the role of NF-kB. AB - BACKGROUND: Bradykinin (BK) mediates acute allergic asthma and airway remodelling. Nuclear factor-kappa B (NF-kB) is potentially involved in BK B2 receptor (B2R) regulation. OBJECTIVE: In this observational cross-sectional study, B2R and NF-kB expression was evaluated in bronchial biopsies from mild asthmatics (after diluent/allergen challenge) and healthy controls, examining the role of NF-kB in B2R expression in primary human fibroblasts from normal and asthmatic subjects (HNBFb and HABFb). METHODS: B2R and NF-kB (total and nuclear) expression was analysed by immunohistochemistry in biopsies from 10 mild intermittent asthmatics (48 h after diluent/allergen challenge) and 10 controls undergoing bronchoscopy. B2R co-localization in 5B5(+) and alphaSMA(+) mesenchymal cells was studied by immunofluorescence/confocal microscopy, and B2R expression in HABFb/HNBFb incubated with interleukin (IL)-4/IL-13 with/without BK, and after NF-kB inhibitor, by Western blotting. RESULTS: Bronchial mucosa B2R and nuclear NF-kB expression was higher in asthmatics after diluent (B2R only) and allergen challenge than in controls (P < 0.05), while B2R and NF-kB (total and nuclear) increased after allergen compared with after diluent (P < 0.05). Allergen exposure increased B2R expression in 5B5(+) and alphaSMA(+) cells. Constitutive B2R protein expression was higher in HABFb than in HNBFb (P < 0.05) and increased in both cell types after IL-13 or IL-4/IL-13 and BK treatment. This increase was suppressed by a NF-kB inhibitor (P < 0.05). CONCLUSIONS & CLINICAL RELEVANCE: Bronchial B2R expression is constitutively elevated in allergic asthma and is further increased after allergen exposure together with NF-kB expression. NF-kB inhibitor blocked IL-4/IL-13-induced increase in B2R expression in cultured fibroblasts, suggesting a role as potential anti-asthma drug. PMID- 26588818 TI - The origin of the animals and a 'Savannah' hypothesis for early bilaterian evolution. AB - The earliest evolution of the animals remains a taxing biological problem, as all extant clades are highly derived and the fossil record is not usually considered to be helpful. The rise of the bilaterian animals recorded in the fossil record, commonly known as the 'Cambrian explosion', is one of the most significant moments in evolutionary history, and was an event that transformed first marine and then terrestrial environments. We review the phylogeny of early animals and other opisthokonts, and the affinities of the earliest large complex fossils, the so-called 'Ediacaran' taxa. We conclude, based on a variety of lines of evidence, that their affinities most likely lie in various stem groups to large metazoan groupings; a new grouping, the Apoikozoa, is erected to encompass Metazoa and Choanoflagellata. The earliest reasonable fossil evidence for total-group bilaterians comes from undisputed complex trace fossils that are younger than about 560 Ma, and these diversify greatly as the Ediacaran-Cambrian boundary is crossed a few million years later. It is generally considered that as the bilaterians diversified after this time, their burrowing behaviour destroyed the cyanobacterial mat-dominated substrates that the enigmatic Ediacaran taxa were associated with, the so-called 'Cambrian substrate revolution', leading to the loss of almost all Ediacara-aspect diversity in the Cambrian. Why, though, did the energetically expensive and functionally complex burrowing mode of life so typical of later bilaterians arise? Here we propose a much more positive relationship between late-Ediacaran ecologies and the rise of the bilaterians, with the largely static Ediacaran taxa acting as points of concentration of organic matter both above and below the sediment surface. The breaking of the uniformity of organic carbon availability would have signalled a decisive shift away from the essentially static and monotonous earlier Ediacaran world into the dynamic and burrowing world of the Cambrian. The Ediacaran biota thus played an enabling role in bilaterian evolution similar to that proposed for the Savannah environment for human evolution and bipedality. Rather than being obliterated by the rise of the bilaterians, the subtle remnants of Ediacara-style taxa within the Cambrian suggest that they remained significant components of Phanerozoic communities, even though at some point their enabling role for bilaterian evolution was presumably taken over by bilaterians or other metazoans. Bilaterian evolution was thus an essentially benthic event that only later impacted the planktonic environment and the style of organic export to the sea floor. PMID- 26588820 TI - Comparative proteomic profiling of Hodgkin lymphoma cell lines. AB - Classical Hodgkin lymphoma (cHL) is a malignancy with complex pathogenesis. The hallmark of the disease is the presence of large mononucleated Hodgkin and bi- or multinucleated Reed/Sternberg (H/RS) cells. The origin of HRS cells in cHL is controversial as these cells show the coexpression of markers of several lineages. Using a proteomic approach, we compared the protein expression profile of cHL models of T- and B-cell derivation to find proteins differentially expressed in these cell lines. A total of 67 proteins were found differentially expressed between the two cell lines including metabolic proteins and proteins involved in the regulation of the cytoskeleton and/or cell migration, which were further validated by western blotting. Additionally, the expression of selected B and T-cell antigens was also assessed by flow cytometry to reveal significant differences in the expression of different surface markers. Bioinformatics analysis was then applied to our dataset to find enriched pathways and networks, and to identify possible key regulators. In the present study, a proteomic approach was used to compare the protein expression profiles of two cHL cell lines. The identified proteins and/or networks, many of which not previously related to cHL, may be important to better define the pathogenesis of the disease, to identify novel diagnostic markers, and to design new therapeutic strategies. PMID- 26588821 TI - Health Anxiety and Its Relationship to Disability and Service Use: Findings From a Large Epidemiological Survey. AB - OBJECTIVE: To explore the contribution of health anxiety to disability and use of mental health and medical services, independently of co-occurring mental and physical conditions. METHODS: Data from the Australian National Survey of Mental Health and Wellbeing 2007 were analyzed (n = 8841). Participants were aged 16 to 85 years (mean [standard deviation] = 46.3 [19.0] years) and 54% were women. RESULTS: Health anxiety accounted independently for high disability and service use. People with health anxiety were more likely to use both mental health (for psychiatrists: odds ratio [OR] = 2.1, 95% confidence interval [CI] = 1.2-3.5; for psychologists: OR = 1.9, 95% CI = 1.2-3.3) and specialist medical services (OR = 1.7, 95% CI = 1.2-2.3) than people without health anxiety. However, they were not high-frequency attenders to specialist mental health services (OR = 1.6 [95% CI = 0.9-3.0] and OR = 1.3 [95% CI = 0.6-2.9]) compared with people with other mental disorders (OR = 11.7 [95% CI = 4.3-31.8] and OR = 29.5 [95% CI = 13.5-64.6] for psychiatrists and psychologists, respectively). People with health anxiety were likely to be high-frequency attenders to general practice (OR = 2.0, 95% CI = 1.4 2.8) and specialist medical services (OR = 2.4, 95% CI = 1.7-3.6). CONCLUSIONS: It is important to recognize and treat health anxiety, even when coexisting with other conditions, to prevent high disability burden and excessive service use. The cross-sectional design and self-reported outcomes may have resulted in overestimation of the associations. Future work is needed on actual service use using reviews of medical records. PMID- 26588822 TI - Sources of Placebo-Induced Relief From Nausea: The Role of Instruction and Conditioning. AB - OBJECTIVES: It is well documented that expectancies alter the nauseous response. However, the lack of integration in research examining sources of expectancy has limited our understanding of how expectancies are formed and, consequently, our ability to intervene. The present study explored the role of both instructions and conditioning in placebo-induced relief from nausea. METHODS: The study used a 2 * 2 between-subjects design with instruction and conditioning as factors with 56 healthy volunteers. The instruction manipulation involved randomizing participants to receive information that a sham treatment (a peppermint essence vapor) would reduce nausea or no such instructions. The conditioning manipulation involved further randomizing participants to have the first administration of this sham treatment paired with a surreptitious reduction in galvanic vestibular stimulation (GVS) intensity or no prior pairing. Nausea was induced through GVS. On test, all groups received the same level of GVS with the sham treatment present. RESULTS: On test, participants who received instruction had significantly lower nauseous response scores than those who did not (F(1,46) = 6.71, p = .013), and those who received conditioning also reported less nausea than those who did not (F(1,46) = 5.20, p = .027), with the interaction between the two not reaching statistical significance (F(1,46) = 2.33, p = .13). CONCLUSIONS: These findings indicate that placebo responding in nausea can be induced both through positive instructions and as little as one pairing of a treatment with a reduction in nausea, as well as their combination. This suggests that using placebo effects to complement antiemetic therapy may offer an important method of further reducing nausea in the clinic. PMID- 26588824 TI - Isolation and enrichment of circulating biomarkers for cancer screening, detection, and diagnostics. AB - Much research has been performed over the past several decades in an attempt to conquer cancer. Tissue biopsy is the conventional method for gathering biological materials to analyze cancer and has contributed greatly to the understanding of cancer. However, this method is limited because it is time-consuming (requires tissue sectioning, staining, and pathological analysis), costly, provides scarce starting materials for multiple tests, and is painful. A liquid biopsy, which analyzes cancer-derived materials from various body fluids using a minimally invasive procedure, is more practical for real-time monitoring of disease progression than tissue biopsy. Biomarkers analyzable through liquid biopsy include circulating tumor cells (CTCs), exosomes, circulating cell-free DNA (cfDNA), miRNA, and proteins. Research on CTCs has been actively conducted because CTCs provide information on the whole cell, unlike the other biomarkers mentioned above. However, owing to the rarity and heterogeneity of CTCs, CTC research faces many critical concerns. Although exosomes and cfDNA have some technical challenges, they are being highlighted as new target materials. That is because they also have genetic information on cancers. Even though the number of exosomes and cfDNA from early stage cancer patients are similar to healthy individuals, they are present in high concentrations after metastasis. In this article, we review several technologies for material analyses of cancer, discuss the critical concerns based on hands-on experience, and describe future directions for cancer screening, detection, and diagnostics. PMID- 26588823 TI - Association of Epidemiologic Factors and Genetic Variants Influencing Hypothalamic-Pituitary-Adrenocortical Axis Function With Postconcussive Symptoms After Minor Motor Vehicle Collision. AB - OBJECTIVES: To determine the influence of epidemiologic factors and the influence of genetic variants affecting FKBP5, a protein known to modulate hypothalamic pituitary-adrenocortical axis function, on the severity of somatic symptoms commonly termed "postconcussive" 6 and 12 months after motor vehicle collision (MVC). METHODS: European Americans 18 to 65 years of age who presented to one of eight emergency departments (EDs) after MVC were enrolled. Exclusion criteria included hospital admission. Blood samples were collected in the ED for genotyping. Participants completed evaluations including an adapted Rivermead Post-Concussive Symptoms Questionnaire in the ED and at 6 weeks, 6 months, and 1 year. Repeated-measures analysis of covariance was used to evaluate the association between epidemiologic factors (sociodemographic, pre-MVC health, collision characteristics, head injury, peritraumatic pain, and stress), FKBP5 genetic variants, and postconcussive symptom severity. RESULTS: Among 943 patients recruited in the ED, follow-up was completed on 835 (88%) at 6 months and 857 (90%) at 1 year. Self-reported head impact during collision was not associated with chronic postconcussive symptom severity. After correction for multiple testing, three FKBP5 single-nucleotide polymorphisms (rs3800373, rs7753746, and rs9380526) predicted chronic postconcussive symptom severity, with an average symptom severity of 1.10 (95% confidence interval = 0.96-1.24), 1.36 (1.21-1.51), and 1.55 (1.23-1.88) for one, two, or three copies of minor allele at rs3800373 (p = .001). Similar effect sizes were observed for the minor alleles of rs7753746 and rs9380526. CONCLUSIONS: Postconcussive symptoms after minor MVC are not generally related to the severity of mild brain injury. This study shows that neurobiologic stress systems may play a role in the pathogenesis of postconcussive symptoms. PMID- 26588825 TI - Interhospital transfer patients discharged by academic hospitalists and general internists: Characteristics and outcomes. AB - BACKGROUND: Prior work suggests interhospital transfer (IHT) may be a risky event. Outcomes for patients transferred from another acute care institution and discharged by hospitalists and general internists at academic health systems are not well described. OBJECTIVE: Investigate the characteristics and outcomes of IHT patients compared with patients admitted from the emergency department (ED) to academic health systems. DESIGN: Retrospective cohort study. SETTING/PATIENTS: A total of 885,392 adult inpatients discharged by hospitalists or general internal medicine physicians from 158 academic medical centers and affiliated hospitals participating in the University HealthSystem Consortium Clinical Database and Resource Manager from April 1, 2011 to March 31, 2012. METHODS: Patient cohorts were defined by admission source: those from another acute care institution were IHTs, and those coming through the ED whose source of origination was not another hospital or ambulatory surgery site were ED admissions. In-hospital mortality was our primary outcome. We analyzed our data using descriptive statistics, t tests, chi(2) tests, and logistic regression. RESULTS: Compared with ED admissions, IHT patients had a longer average length of stay, higher proportion of time spent in the intensive care unit, higher costs per hospital day, lower frequency of discharges home, and higher inpatient mortality (4.1% vs 1.8%, P < 0.01). After adjusting for patient characteristics and risk of mortality measures, IHT patients had a higher risk of in-hospital death (odds ratio: 1.36, 95% confidence interval: 1.29-1.43). CONCLUSIONS: In this large national sample, IHT status is independently associated with inpatient mortality. PMID- 26588826 TI - Monodispersed Hollow SO3H-Functionalized Carbon/Silica as Efficient Solid Acid Catalyst for Esterification of Oleic Acid. AB - SO3H-functionalized monodispersed hollow carbon/silica spheres (HS/C-SO3H) with primary mesopores were prepared with polystyrene as a template and p toluenesulfonic acid (TsOH) as a carbon precursor and -SO3H source simultaneously. The physical and chemical properties of HS/C-SO3H were characterized by N2 adsorption, TEM, SEM, XPS, XRD, Raman spectrum, NH3-TPD, element analysis and acid-base titration techniques. As a solid acid catalyst, HS/C-SO3H shows excellent performance in the esterification of oleic acid with methanol, which is a crucial reaction in biodiesel production. The well-defined hollow architecture and enhanced active sites accessibility of HS/C-SO3H guarantee the highest catalytic performance compared with the catalysts prepared by activation of TsOH deposited on the ordered mesoporous silicas SBA-15 and MCM 41. At the optimized conditions, high conversion (96.9%) was achieved and no distinct activity drop was observed after 5 recycles. This synthesis strategy will provide a highly effective solid acid catalyst for green chemical processes. PMID- 26588827 TI - ICU Attending Handoff Practices: Results From a National Survey of Academic Intensivists. AB - OBJECTIVES: To characterize intensivist handoff practices and expectations and to explore perceptions of the patient safety implications of attending handoffs. DESIGN: Cross-sectional electronic survey administered in 2014. SETTING: One hundred sixty-nine U.S. hospitals with critical care training programs accredited by the Accreditation Council for Graduate Medical Education. SUBJECTS: Academic intensivists were recruited via e-mail invitation from a database of 1,712 eligible academic intensivists. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Six hundred sixty-one intensivists completed the survey (completion rate, 38.6%). Responses were received from at least one individual at 147 of 169 unique hospitals (87.0%) represented in the study database. Five hundred seventy three (87%) respondents reported participating in handoffs at the end of each ICU rotation. A variety of communication methods were used for end-of-rotation handoffs, including in-person discussion (92.9%), telephone calls (83.9%), e-mail messages (69.0%), computer-generated documents (64.6%), and text messages (23.6%). Mean satisfaction with current handoff process was rated as 68.4 on a scale from 0 to 100 (SD, 22.6). Respondents (55.4%) said that attending handoffs should be standardized, but only 13.3% (76/572) of those participating in end-of rotation handoffs reported using a standardized process. Specific handoff topics, including active clinical issues and resuscitation status, were reportedly discussed less frequently than would be ideal (p < 0.001 for the difference between reported frequency and ideal frequency). In free-text comments, 76 respondents (11.5%) expressed skepticism that attending handoffs were necessary given the presence of residents and fellows and given a lack of agreement about necessary content. Two hundred respondents (30.8%) reported knowing of an adverse event (inappropriate treatment, cardiac arrest, and death) attributable to inadequate attending handoffs. CONCLUSIONS: ICU attending handoffs in the United States exhibit marked heterogeneity, and intensivists do not agree about the value of attending handoffs. In addition, some intensivists perceive a link between suboptimal attending handoffs, inappropriate treatment, and serious adverse events that warrants further study. PMID- 26588828 TI - Circulating Histone Concentrations Differentially Affect the Predominance of Left or Right Ventricular Dysfunction in Critical Illness. AB - OBJECTIVES: Cardiac complications are common in critical illness and associated with grave consequences. In this setting, elevated circulating histone levels have been linked to cardiac injury and dysfunction in experimental models and patients with sepsis. The mechanisms underlying histone-induced cardiotoxicity and the functional consequences on left ventricle and right ventricle remain unclear. This study aims to examine dose-dependent effects of circulating histones on left ventricle and right ventricle function at clinically relevant concentrations. DESIGN: Prospective laboratory study with in vitro and in vivo investigations. SETTING: University research laboratory. SUBJECTS: Twelve-week old male C57BL/6N mice. INTERVENTIONS: Cultured cardiomyocytes were incubated with clinically relevant histone concentrations, and a histone infusion mouse model was also used with hemodynamic changes characterized by echocardiography and left ventricle/right ventricle catheter-derived variables. Circulating histones and cardiac troponin levels were obtained from serial blood samples. MEASUREMENTS AND MAIN RESULTS: IV histone infusion caused time-dependent cardiac troponin elevation to indicate cardiac injury. At moderate sublethal histone doses (30 mg/kg), left ventricular contractile dysfunction was the prominent abnormality with reduced ejection fraction and prolonged relaxation time. At high doses (>= 60 mg/kg), pulmonary vascular obstruction induced right ventricular pressure increase and dilatation, but left ventricular end-diastolic volume improved because of reduced blood return from the lungs. Mechanistically, histones induced profound calcium influx and overload in cultured cardiomyocytes with dose-dependent detrimental effects on intracellular calcium transient amplitude, contractility, and rhythm, suggesting that histones directly affect cardiomyocyte function adversely. However, increasing histone-induced neutrophil congestion, neutrophil extracellular trap formation, and thrombosis in the pulmonary microvasculature culminated in right ventricular dysfunction. Antihistone antibody treatment abrogated histone cardiotoxicity. CONCLUSIONS: Circulating histones significantly compromise left ventricular and right ventricular function through different mechanisms that are dependent on histone concentrations. This provides a translational basis to explain and target the spectral manifestations of cardiac dysfunction in critical illness. PMID- 26588829 TI - Effects of Hyperoxia and Mild Therapeutic Hypothermia During Resuscitation From Porcine Hemorrhagic Shock. AB - OBJECTIVE: Hemorrhagic shock-induced tissue hypoxia induces hyperinflammation, ultimately causing multiple organ failure. Hyperoxia and hypothermia can attenuate tissue hypoxia due to increased oxygen supply and decreased demand, respectively. Therefore, we tested the hypothesis whether mild therapeutic hypothermia and hyperoxia would attenuate postshock hyperinflammation and thereby organ dysfunction. DESIGN: Prospective, controlled, randomized study. SETTING: University animal research laboratory. SUBJECTS: Thirty-six Bretoncelles-Meishan Willebrand pigs of either gender. INTERVENTIONS: After 4 hours of hemorrhagic shock (removal of 30% of the blood volume, subsequent titration of mean arterial pressure at 35 mm Hg), anesthetized and instrumented pigs were randomly assigned to "control" (standard resuscitation: retransfusion of shed blood, fluid resuscitation, norepinephrine titrated to maintain mean arterial pressure at preshock values, mechanical ventilation titrated to maintain arterial oxygen saturation > 90%), "hyperoxia" (standard resuscitation, but FIO2, 1.0), "hypothermia" (standard resuscitation, but core temperature 34 degrees C), or "combi" (hyperoxia plus hypothermia) (n = 9 each). MEASUREMENTS AND MAIN RESULTS: Before, immediately at the end of and 12 and 22 hours after hemorrhagic shock, we measured hemodynamics, blood gases, acid-base status, metabolism, organ function, cytokine production, and coagulation. Postmortem kidney specimen were taken for histological evaluation, immunohistochemistry (nitrotyrosine, cystathionine gamma lyase, activated caspase-3, and extravascular albumin), and immunoblotting (nuclear factor-kappaB, hypoxia-inducible factor-1alpha, heme oxygenase-1, inducible nitric oxide synthase, B-cell lymphoma-extra large, and protein expression of the endogenous nuclear factor-kappaB inhibitor). Although hyperoxia alone attenuated the postshock hyperinflammation and thereby tended to improve visceral organ function, hypothermia and combi treatment had no beneficial effect. CONCLUSIONS: During resuscitation from near-lethal hemorrhagic shock, hyperoxia attenuated hyperinflammation, and thereby showed a favorable trend toward improved organ function. The lacking efficacy of hypothermia was most likely due to more pronounced barrier dysfunction with vascular leakage-induced circulatory failure. PMID- 26588830 TI - Sympathetic Vasoconstrictor Responsiveness of the Leg Vasculature During Experimental Endotoxemia and Hypoxia in Humans. AB - OBJECTIVE: Sympathetic vasoconstriction regulates peripheral circulation and controls blood pressure, but sepsis is associated with hypotension. We evaluated whether apparent loss of sympathetic vasoconstrictor responsiveness relates to distended smooth muscles or to endotoxemia and/or hypoxia. DESIGN: Prospective descriptive study. SETTING: Hospital research laboratory. SUBJECTS: Ten healthy young men (age [mean +/- SD], 31 +/- 8 yr; body weight, 83 +/- 10 kg) participated in the study. INTERVENTIONS: Leg blood flow and mean arterial pressure were determined, whereas leg vascular conductance was calculated during 1) adenosine infusion (vasodilator control), 2) hypoxia (FIO2 = 10%), 3) endotoxemia, and 4) endotoxemia + hypoxia. Leg sympathetic vasoconstrictor responsiveness (reduction in leg vascular conductance) was evaluated by femoral artery tyramine infusion. MEASUREMENTS AND MAIN RESULTS: Endotoxemia increased body temperature from 36.9 +/- 0.4 degrees C to 38.6 +/- 0.5 degrees C (p < 0.01) and plasma tumor necrosis factor-alpha from 6 pg/mL (3-8 pg/mL) to 391 pg/mL (128 2258 pg/mL) (p < 0.01; median [range]). Mean arterial pressure decreased similarly during endotoxemia (-11% +/- 16%) and endotoxemia + hypoxia (-10% +/- 15%; both p < 0.05). Leg blood flow and leg vascular conductance were not affected by endotoxemia, whereas both were elevated by adenosine infusion (leg blood flow, +94% +/- 61%; leg vascular conductance, +97% +/- 57%), hypoxia (leg blood flow: +93% +/- 58%; leg vascular conductance, +100% +/- 115%), and endotoxemia + hypoxia (leg blood flow, +67% +/- 120%; leg vascular conductance, +65% +/- 57%; p < 0.05). Endotoxemia lessened the tyramine-induced reduction in leg vascular conductance (-28% +/- 13%) compared with the reduction during adenosine infusion (-47% +/- 5%; p < 0.05). Also, endotoxemia + hypoxia (-17% +/- 21%) attenuated the tyramine-induced reduction in leg vascular conductance compared with both adenosine infusion and hypoxia (-45% +/- 13%; p < 0.05). CONCLUSIONS: Both endotoxemia and combined hypoxia and endotoxemia blunted sympathetic vasoconstrictor responsiveness. Furthermore, tyramine normalized the doubled leg vascular conductance during administration of adenosine, suggesting that distension of vascular smooth muscles does not explain blunted sympathetic vasoconstrictor responsiveness during endotoxemia. PMID- 26588831 TI - Glucose Meters: Here Today, Gone Tomorrow? AB - OBJECTIVE: This special article will review the history of blood glucose meter hospital use and current issues surrounding their use in this patient population. STUDY SELECTION: Secondary to accuracy concerns that have been known, but likely underappreciated for many years, the U.S. Food and Drug Administration and Centers for Medicare and Medicaid Services are moving toward eliminating current blood glucose meters for use with critically ill patients. DATA SOURCES: Recent guidance from the U.S. Food and Drug Administration and Centers for Medicare and Medicaid Services along with several recent publications will be used as the primary data sources. DATA EXTRACTION: U.S. Food and Drug Administration, Centers for Medicare and Medicaid Services communications combined with recent interpretation of this guidance were used to provide this overview. DATA SYNTHESIS: Centers for Medicare and Medicaid Services have issued a temporary moratorium on the prohibition of the use of blood glucose meters in the critically ill. They have not given a deadline for the moratorium or solicited comments. CONCLUSIONS: Physicians who care for critically ill patients need to be cognizant of the accuracy and interference limitations of blood glucose meters and aware of the current regulatory situation. PMID- 26588832 TI - Efficient Reconstruction of Heterogeneous Networks from Time Series via Compressed Sensing. AB - Recent years have witnessed a rapid development of network reconstruction approaches, especially for a series of methods based on compressed sensing. Although compressed-sensing based methods require much less data than conventional approaches, the compressed sensing for reconstructing heterogeneous networks has not been fully exploited because of hubs. Hub neighbors require much more data to be inferred than small-degree nodes, inducing a cask effect for the reconstruction of heterogeneous networks. Here, a conflict-based method is proposed to overcome the cast effect to considerably reduce data amounts for achieving accurate reconstruction. Moreover, an element elimination method is presented to use the partially available structural information to reduce data requirements. The integration of both methods can further improve the reconstruction performance than separately using each technique. These methods are validated by exploring two evolutionary games taking place in scale-free networks, where individual information is accessible and an attempt to decode the network structure from measurable data is made. The results demonstrate that for all of the cases, much data are saved compared to that in the absence of these two methods. Due to the prevalence of heterogeneous networks in nature and society and the high cost of data acquisition in large-scale networks, these approaches have wide applications in many fields and are valuable for understanding and controlling the collective dynamics of a variety of heterogeneous networked systems. PMID- 26588833 TI - The necessity of fixation in Gartland type 2 supracondylar fracture of the distal humerus in children (modified Gartland type 2A and 2B). AB - In type 2 supracondylar fracture, closed pinning has been recommended in most patients. However, a stable, mildly displaced fracture can be treated with nonsurgical means. If stable, mildly displaced fractures are categorized as Gartland type 2A and unstable fractures as type 2B, orthopedic surgeons will be greatly benefited while selecting the most appropriate treatment. This study was conducted to evaluate the results of pinning versus conservative treatment in these two groups of patients. Patients with Gartland type 2 supracondylar fractures were categorized into two groups: the first group (type 2A) consisted of patients with Baumann angle (BA) differing from the uninjured side by less than 5 degrees ; the second group (type 2B) consisted of patients with BA difference greater than or equal to 5 degrees . Statistical analysis was performed between the two groups. In type 2A, we also analyzed the data on loss alignment in patients who had undergone closed reduction without fixation to clarify the necessity of fixation. Type 2A fractures had a median BA difference from the uninjured side of 3 degrees , a median lateral capitellohumeral angle (LCHA) difference from the uninjured side of 19.5 degrees , and a shaft condylar angle (SCA) difference from the uninjured side of 18 degrees . Type 2B fractures had a median BA difference of 8 degrees , an LCHA difference of 27 degrees , and an SCA difference of 28 degrees . The BA, LCHA, and SCA differences were statistically significant (P<0.001, P=0.019, and 0.002 between the two types, respectively). Type 2A patients who were treated without fixation had improved SCA of 6 degrees and improved LHCA of 11 degrees from postreduced radiographs, with statistical significance (P=0.018 and P<0.001, respectively). The ROC curve in type 2A patients show that if the LCHA difference or the SCA difference from the uninjured side is less than 18 degrees , it is stable enough to maintain reduction without fixation. Classification into modified type 2A and 2B is very helpful for orthopedic surgeons in determining the most suitable treatment strategy. In type 2A patients with LCHA difference or SCA difference from the uninjured side less than 18 degrees , Kirschner-wire fixation is deemed inessential. In the case of type 2B fractures, fixation was recommended in all patients because of the unstable reduction from loss of BA, LCHA, and SCA. PMID- 26588834 TI - Prophylactic pinning for slipped capital femoral epiphysis: does it affect proximal femoral morphology? AB - This study was designed to determine whether prophylactic pinning of the unaffected hip in unilateral slipped capital femoral epiphysis affects the proximal femoral morphology. Twenty-four hips prophylactically pinned were compared with 26 cases observed. The articulotrochanteric distance (ATD) and the trochanteric-trochanteric distance (TTD) were measured. Postoperative radiographs were compared with final follow-up radiographs. The final TTD : ATD ratio was higher (P=0.048) in the pinned group, suggesting relative coxa vara/breva. There was a smaller difference between the two hips in the prophylactically pinned group (0.7) as opposed to those observed (1.47). Prophylactic pinning does not cause growth to stop immediately but alters the proximal femoral morphology. PMID- 26588835 TI - Satisfaction and pain levels after proximal femoral valgus osteotomy according to Schanz in patients with cerebral palsy and hip dislocation. AB - Outcome after Schanz osteotomy in the treatment of chronic hip dislocation in children with cerebral palsy was evaluated. Medical charts and questionnaires were used to assess pain, functional outcome and satisfaction. A total of 24 children, with a mean age of 13.8 years (+/- 8.9), were included in the study, out of which 11 were classified with Gross Motor Function Classification System (GMFCS) level IV and 13 with GMFCS level V. Current pain was comparable to patients without chronic hip dislocation, and satisfaction was intermediate. Functional outcome improved in several domains. Longer postoperative time was associated with improved pain and satisfaction. The Schanz osteotomy allowed improvement in pain levels; however, it did not completely meet caregiver's expectation and has high reoperation rates. PMID- 26588836 TI - Pedobarographic changes in Ponseti-treated clubfeet with and without anterior tibialis tendon transfer: changes due to growth and surgical intervention. AB - The aim of this study was to identify significant changes in pedobarographic parameters attributed to growth versus growth and surgical intervention for uninvolved feet, clubfeet (CF) subjected to anterior tibialis tendon transfer surgery, and unilateral nonsurgical CF. Participants underwent foot-pressure analysis preoperatively and 3 years postoperatively. Six parameters related to the lateral midfoot showed increases for uninvolved and nonsurgical CF, whereas CF subjected to surgery decreased. Transferring the anterior tibialis tendon resulted in improvements beyond typical growth and in a more balanced foot postoperatively. These changes are not simply changes in the peak pressure, but changes in force/pressure over time in the lateral foot. PMID- 26588837 TI - Surgical treatment of upper extremity contractures in Emery-Dreifuss muscular dystrophy. AB - Emery-Dreifuss muscular dystrophy is a rare form of muscular dystrophy. In the present study we present two patients with Emery-Dreifuss muscular dystrophy and severe upper extremity contractures treated successfully with contracture release and musculotendinous lengthenings. For each of these patients a chart review was carried out and surgical technique reviewed. Patient 1 demonstrated elbow flexion contractures of 65 degrees (right) and 60 degrees (left) preoperatively and ~45 degrees (right) and 20 degrees (left) postoperatively. Patient 2 demonstrated flexion contractures of 75 degrees bilaterally preoperatively and 45 degrees bilaterally postoperatively. For more severe elbow contractures, surgical treatment resulted in improved range of motion without a significant sacrifice of strength, allowing these patients to remain independent. PMID- 26588838 TI - The 'trampoline ankle': severe medial malleolar physeal injuries in children and adolescents secondary to multioccupant use of trampolines. AB - The purpose of this study was to describe a series of patients presenting with medial malleolus Salter-Harris types III and IV fractures (MacFarland fractures) related to trampoline use. In total, 11 patients were reviewed retrospectively (mean age: 11.8 years; four boys and seven girls). Salter-Harris type III fractures were more commonly seen (n=7). Undisplaced fractures were more prevalent (n=6). Six children underwent surgical treatment. Average follow-up time was 17.8 months. A medial physeal bar with subsequent growth arrest and ankle deformity was observed in two patients. More than one user was present on the trampoline at the time of the injury in nine of the reported cases. Medial malleolus growth-plate injuries can be seen after trampoline injuries where multiple users were involved. Potential complications including growth arrest can occur. PMID- 26588839 TI - Congenital talipes equinovarus associated with hereditary congenital common peroneal nerve neuropathy: a literature review. AB - We present a unique case of a congenital hereditary common peroneal nerve neuropathy with congenital idiopathic congenital talipes equinovarus that had been treated with the Ponseti method with satisfactory outcome at 5-year follow up, along with a literature review. PMID- 26588840 TI - Hydrodynamic and Sediment Responses of Open Channels to Exposed Pipe Encasements. AB - The effects of exposed pipe encasements on the local variation of hydrodynamic and sediment conditions in a river channel are examined. Laboratory experiments are performed to assess the response of water level, flow regime and bed deformation to several representative types of concrete encasements. The experimental conditions considered are: three types of exposed pipe encasements exposed on the bed, including trapezoidal shape, circular-arc shape and polygonal shape, and three sets of discharges, including annual discharge, once-in-3-year flood, and once-in-50-year flood. Our experiments show that: (1) the amount of backwater definitely depends on the encasement geometric shape and the background discharge; (2) smaller discharges generally tend to induce local scour of river bed downstream of the encasement, and the order of sensitivity of bed deformation to the encasement geometric shape is trapezoidal > circular-arc > polygonal; (3) comparatively speaking, the polygonal encasement may be considered as a suitable protective structure for pipelines across alluvial rivers, with relatively modest effects on the local hydrodynamic conditions and bed stabilization. PMID- 26588841 TI - Application of a Patient Derived Xenograft Model for Predicative Study of Uterine Fibroid Disease. AB - Human uterine fibroids, benign tumors derived from the smooth muscle layers of the uterus, impose a major health burden to up to 50% of premenopausal women in their daily life. To improve our understanding of this disease, we developed and characterized a patient-derived xenograft model by subcutaneous transplantation of pieces of human uterine fibroid tissue into three different strains of severe combined immunodeficient mice. Engrafted uterine fibroid tissue preserved the classical morphology with interwoven bundles of smooth muscle cells and an abundant deposition of collagenous matrix, similar to uterine fibroids in situ. The grafts expressed both estrogen receptor 1 and progesterone receptor. Additionally, both receptors were up-regulated by estrogen treatment. Growth of the fibroid grafts was dependent on 17beta-estradiol and progesterone supplementation at levels similar to women with the disease and was studied for up to 60 days at maximum. Co-treatment with the antiprogestin mifepristone reduced graft growth (four independent donors, p<0.0001 two-sided t-test), as did treatment with the mTOR inhibitor rapamycin (three independent donors, p<0.0001 two-sided t-test). This in vivo animal model preserves the main histological and functional characteristics of human uterine fibroids, is amenable to intervention by pharmacological treatment, and can thus serve as an adequate model for the development of novel therapies. PMID- 26588842 TI - Implementation of Departmental Quality Strategies Is Positively Associated with Clinical Practice: Results of a Multicenter Study in 73 Hospitals in 7 European Countries. AB - BACKGROUND: Given the amount of time and resources invested in implementing quality programs in hospitals, few studies have investigated their clinical impact and what strategies could be recommended to enhance its effectiveness. OBJECTIVE: To assess variations in clinical practice and explore associations with hospital- and department-level quality management systems. DESIGN: Multicenter, multilevel cross-sectional study. SETTING AND PARTICIPANTS: Seventy three acute care hospitals with 276 departments managing acute myocardial infarction, deliveries, hip fracture, and stroke in seven countries. INTERVENTION: None. MEASURES: Predictor variables included 3 hospital- and 4 department-level quality measures. Six measures were collected through direct observation by an external surveyor and one was assessed through a questionnaire completed by hospital quality managers. Dependent variables included 24 clinical practice indicators based on case note reviews covering the 4 conditions (acute myocardial infarction, deliveries, hip fracture and stroke). A directed acyclic graph was used to encode relationships between predictors, outcomes, and covariates and to guide the choice of covariates to control for confounding. RESULTS AND LIMITATIONS: Data were provided on 9021 clinical records by 276 departments in 73 hospitals. There were substantial variations in compliance with the 24 clinical practice indicators. Weak associations were observed between hospital quality systems and 4 of the 24 indicators, but on analyzing department level quality systems, strong associations were observed for 8 of the 11 indicators for acute myocardial infarction and stroke. Clinical indicators supported by higher levels of evidence were more frequently associated with quality systems and activities. CONCLUSIONS: There are significant gaps between recommended standards of care and clinical practice in a large sample of hospitals. Implementation of department-level quality strategies was significantly associated with good clinical practice. Further research should aim to develop clinically relevant quality standards for hospital departments, which appear to be more effective than generic hospital-wide quality systems. PMID- 26588843 TI - Activation of Type I and III Interferon Response by Mitochondrial and Peroxisomal MAVS and Inhibition by Hepatitis C Virus. AB - Sensing viruses by pattern recognition receptors (PRR) triggers the innate immune system of the host cell and activates immune signaling cascades such as the RIG I/IRF3 pathway. Mitochondrial antiviral-signaling protein (MAVS, also known as IPS-1, Cardif, and VISA) is the crucial adaptor protein of this pathway localized on mitochondria, peroxisomes and mitochondria-associated membranes of the endoplasmic reticulum. Activation of MAVS leads to the production of type I and type III interferons (IFN) as well as IFN stimulated genes (ISGs). To refine the role of MAVS subcellular localization for the induction of type I and III IFN responses in hepatocytes and its counteraction by the hepatitis C virus (HCV), we generated various functional and genetic knock-out cell systems that were reconstituted to express mitochondrial (mito) or peroxisomal (pex) MAVS, exclusively. Upon infection with diverse RNA viruses we found that cells exclusively expressing pexMAVS mounted sustained expression of type I and III IFNs to levels comparable to cells exclusively expressing mitoMAVS. To determine whether viral counteraction of MAVS is affected by its subcellular localization we employed infection of cells with HCV, a major causative agent of chronic liver disease with a high propensity to establish persistence. This virus efficiently cleaves MAVS via a viral protease residing in its nonstructural protein 3 (NS3) and this strategy is thought to contribute to the high persistence of this virus. We found that both mito- and pexMAVS were efficiently cleaved by NS3 and this cleavage was required to suppress activation of the IFN response. Taken together, our findings indicate comparable activation of the IFN response by pex- and mitoMAVS in hepatocytes and efficient counteraction of both MAVS species by the HCV NS3 protease. PMID- 26588844 TI - The lncRNA RZE1 Controls Cryptococcal Morphological Transition. AB - In the fungal pathogen Cryptococcus neoformans, the switch from yeast to hypha is an important morphological process preceding the meiotic events during sexual development. Morphotype is also known to be associated with cryptococcal virulence potential. Previous studies identified the regulator Znf2 as a key decision maker for hypha formation and as an anti-virulence factor. By a forward genetic screen, we discovered that a long non-coding RNA (lncRNA) RZE1 functions upstream of ZNF2 in regulating yeast-to-hypha transition. We demonstrate that RZE1 functions primarily in cis and less effectively in trans. Interestingly, RZE1's function is restricted to its native nucleus. Accordingly, RZE1 does not appear to directly affect Znf2 translation or the subcellular localization of Znf2 protein. Transcriptome analysis indicates that the loss of RZE1 reduces the transcript level of ZNF2 and Znf2's prominent downstream targets. In addition, microscopic examination using single molecule fluorescent in situ hybridization (smFISH) indicates that the loss of RZE1 increases the ratio of ZNF2 transcripts in the nucleus versus those in the cytoplasm. Taken together, this lncRNA controls Cryptococcus yeast-to-hypha transition through regulating the key morphogenesis regulator Znf2. This is the first functional characterization of a lncRNA in a human fungal pathogen. Given the potential large number of lncRNAs in the genomes of Cryptococcus and other fungal pathogens, the findings implicate lncRNAs as an additional layer of genetic regulation during fungal development that may well contribute to the complexity in these "simple" eukaryotes. PMID- 26588846 TI - International Statement Recommending Against the Use of Terminology That Can Stigmatize People. PMID- 26588845 TI - Continuous Exposure to Low-Dose-Rate Gamma Irradiation Reduces Airway Inflammation in Ovalbumin-Induced Asthma. AB - Although safe doses of radiation have been determined, concerns about the harmful effects of low-dose radiation persist. In particular, to date, few studies have investigated the correlation between low-dose radiation and disease development. Asthma is a common chronic inflammatory airway disease that is recognized as a major public health problem. In this study, we evaluated the effects of low-dose rate chronic irradiation on allergic asthma in a murine model. Mice were sensitized and airway-challenged with ovalbumin (OVA) and were exposed to continuous low-dose-rate irradiation (0.554 or 1.818 mGy/h) for 24 days after initial sensitization. The effects of chronic radiation on proinflammatory cytokines and the activity of matrix metalloproteinase-9 (MMP-9) were investigated. Exposure to low-dose-rate chronic irradiation significantly decreased the number of inflammatory cells, methylcholine responsiveness (PenH value), and the levels of OVA-specific immunoglobulin E, interleukin (IL)-4, and IL-5. Furthermore, airway inflammation and the mucus production in lung tissue were attenuated and elevated MMP-9 expression and activity induced by OVA challenge were significantly suppressed. These results indicate that low-dose rate chronic irradiation suppresses allergic asthma induced by OVA challenge and does not exert any adverse effects on asthma development. Our findings can potentially provide toxicological guidance for the safe use of radiation and relieve the general anxiety about exposure to low-dose radiation. PMID- 26588847 TI - Benefits for Voice Learning Caused by Concurrent Faces Develop over Time. AB - Recognition of personally familiar voices benefits from the concurrent presentation of the corresponding speakers' faces. This effect of audiovisual integration is most pronounced for voices combined with dynamic articulating faces. However, it is unclear if learning unfamiliar voices also benefits from audiovisual face-voice integration or, alternatively, is hampered by attentional capture of faces, i.e., "face-overshadowing". In six study-test cycles we compared the recognition of newly-learned voices following unimodal voice learning vs. bimodal face-voice learning with either static (Exp. 1) or dynamic articulating faces (Exp. 2). Voice recognition accuracies significantly increased for bimodal learning across study-test cycles while remaining stable for unimodal learning, as reflected in numerical costs of bimodal relative to unimodal voice learning in the first two study-test cycles and benefits in the last two cycles. This was independent of whether faces were static images (Exp. 1) or dynamic videos (Exp. 2). In both experiments, slower reaction times to voices previously studied with faces compared to voices only may result from visual search for faces during memory retrieval. A general decrease of reaction times across study test cycles suggests facilitated recognition with more speaker repetitions. Overall, our data suggest two simultaneous and opposing mechanisms during bimodal face-voice learning: while attentional capture of faces may initially impede voice learning, audiovisual integration may facilitate it thereafter. PMID- 26588848 TI - Primary Aldosteronism: New Answers, New Questions. AB - There have been 2, and possibly 3, major questions for primary aldosteronism (PA) answered at least in principle over the past 5 years. The first is that of somatic mutations underlying the majority of aldosterone producing adenomas. The second is the extension of our knowledge of the genetics of familial hypertension, and the third the role of renal intercalated cells in sodium homeostasis. New questions for the next 5 years include a single accepted confirmatory/exclusion test; standardisation of assays and cut-offs; alternatives to universal adrenal venous sampling; reclassification of 'low renin hypertension'; recognition of the extent of 'occult' PA; inclusion of low-dose mineralocorticoid receptor antagonist in first-line therapy for hypertension; and finally, possible resolution of the aldosterone/inappropriate sodium status enigma at the heart of the cardiovascular damage in PA. PMID- 26588849 TI - Does the Biosocial Model Explain the Emergence of Status Differences in Conversations among Unacquainted Men? AB - Fifteen triads of unacquainted men conversed for ten minutes while stress was measured in real time by pulse rate and thumb blood volume (TBV). Salivary measures of testosterone (T), cortisol (C), and the stress-related enzyme alpha amylase (AA) were measured at the beginning and end of the session. Fully or partially transitive status hierarchies formed in 14 triads. (Highest ranked man was scored 1, lowest 3, with ties allowed.) Ten of the triads participated in Study 1, where nothing was at stake in the casual conversation. Five additional triads were run in Study 2, intended to introduce competition by offering a $20 reward to the man afterward chosen as having led the conversation. Most results from the two studies are similar, suggesting that the $20 reward had little effect. Combining studies, pulse and TBV show that conversation is more stressful than watching a video beforehand. Within the conversation, speaking turns are more stressful than listening turns, especially among the lowest ranked men, less so among those higher in rank. This supports a stress-based mechanism for status allocation among humans. Apparently, human speech is a form of status signaling, homologous with nonlinguistic status signals used by other primates, as posited by the "biosocial model." The biosocial model also posits that a physiological substrate (T, C, and AA) is related to dominance or status. Predicted effects are not replicated here, except for an inverse relationship between the stress enzyme AA and status. The mostly null results, obtained from conversations where there was little or nothing at stake, suggest that T and C (and their interaction) are not relevant to emergent status in the absence of serious competition. PMID- 26588851 TI - Correction: Microbial Forensics: Predicting Phenotypic Characteristics and Environmental Conditions from Large-Scale Gene Expression Profiles. PMID- 26588850 TI - Preeclampsia and Retinopathy of Prematurity in Very-Low-Birth-Weight Infants: A Population-Based Study. AB - Preeclampsia and retinopathy of prematurity (ROP) are associated with impaired angiogenesis. Previous studies on the relationship between preeclampsia and ROP have produced conflicting results. The goal of this study was to evaluate the association between maternal preeclampsia and ROP using a large population-based cohort of very-low-birth-weight (VLBW) infants from 21 neonatal departments registered in the database of the Premature Baby Foundation of Taiwan. Multivariable logistic regression analysis was used to estimate the adjusted odds ratios (OR) and 95% confidence intervals (CI) for preeclampsia with reference to ROP and severe ROP. A total of 5,718 VLBW infants (844 cases with maternal preeclampsia) were included for analysis. The overall incidences of mild and severe ROP were 36.0% and 12.2%, respectively. Univariable analysis showed lower GA and lower birth weight, vaginal delivery, non-SGA, RDS, PDA, sepsis, transfusion, and absence of maternal preeclampsia to be associated with mild and severe ROP development. However, OR (95% CI) adjusted for the variables that were significant according to univariable analysis showed the risks of developing any stage ROP and severe ROP for maternal preeclampsia to be 1.00 (0.84-1.20) and 0.89 (0.63-1.25), respectively. The results remained unchanged in stratified analyses according to SGA status. Our data showed that maternal preeclampsia was not associated with the subsequent development of any stage or severe ROP in VLBW infants. PMID- 26588852 TI - [The importance of postoperative circulatory alterations in hepatic surgery]. AB - There are two afferent (hepatic artery, portal vein) and one efferent (hepatic veins) systems responsible for the unique circulation of the liver. Given this special form of vasculature, acute, isolated (i.e. involving selectively one particular vessel) vascular occlusions may lead to different, however still life threatening conditions. Hence, it is essential to recognize these anomalies in order to preserve the healthy state of both the liver and the patient's lives. Acute circulatory failures are dominantly associated with liver surgery. Adequate therapy can only be provided promptly, if the clinician is well aware of the peculiarities of these conditions. The aim of this study is to overview the etiology and symptoms of these clinical conditions; furthermore to offer technical proposals for the required diagnostic and therapeutical steps via case reports. Furthermore, hepatic injury, caused by ischemia-reperfusion secondary to total vascular occlusion (Pringle maneuver) used in hepatic surgery is outlined. PMID- 26588853 TI - [Adaptive clinical study methodologies in drug development]. AB - The evolution of drug development in human, clinical phase studies triggers the overview of those technologies and procedures which are labelled as adaptive clinical trials. The most relevant procedural and operational aspects will be discussed in this overview from points of view of clinico-methodological aspect. PMID- 26588854 TI - [Can urinary neutrophil gelatinase-associated lipocalin predict acute rejection following deceased donor kidney transplantation?]. AB - INTRODUCTION: Delayed graft function and acute rejection have negative impact on graft survival. AIM: To asses the predictive value of urinary neutrophil gelatinase-associated lipocalin, which has been found to be a promising biomarker for the diagnosis of acute kidney injury. METHOD: In this prospective study urinary neutrophil gelatinase-associated lipocalin levels of 27 kidney recipients were measured. RESULTS: Patients were grouped as follows: group 1, no complication; group 2, rejection; group 3, delayed graft function requiring dialysis; group 4, rejection plus delayed graft function. There were no significant differences between groups 1 and 2, and between groups 3 and 4. Patients in groups 3 and 4 had significantly higher urinary neutrophil gelatinase associated lipocalin levels as compared to those in groups 3 and 4. There was a paralIel change in urinary neutrophil gelatinase-associated lipocalin levels in groups 1 and 2. CONCLUSIONS: In these patients urinary neutrophil gelatinase associated lipocalin levels failed to provide useful information in both cases of normal and impaired function. PMID- 26588855 TI - [Importance of nerve-sparing surgical technique in the treatment of deep infiltrating endometriosis]. AB - INTRODUCTION: Traditional surgeries performed in cases of deep infiltrating endometriosis lead to impaired quality of life. AIM: To summarize the postoperative outcome and to compare the rate of postoperative complications after different therapeutic approaches applied in deep infiltrating endometriosis. METHOD: The authors analized the articles published between March 31, 2004 and March 31, 2015, in the database http://www.pubmed.org using the following keywords: endometriosis, deep infiltrating, nerve sparing, surgery. RESULTS: Non-nerve sparing surgery resulted in temporary urinary dysfunction in 19.1-38.5% of patients, while it occurred in 0.61-33.3% of patients after nerve sparing surgery. Non-nerve sparing surgical technique resulted in an average of 121 days of need for self-catheretisation. When nerve-sparing surgeries were performed the duration of self-catheterisation varied between 7 to 39.8 days. After nerve sparing surgeries, permanent bladder dysfunction was not detected in any case. CONCLUSIONS: Because of the successful treatment of the patients symptoms and the lower postoperative complication rate, nerve-sparing surgical technique leads to a significant improvement of the quality of life. PMID- 26588856 TI - [The history of urology in Hungary from Balassa until the recent past]. PMID- 26588857 TI - Cost-effectiveness of denosumab as a bone protective agent for patients with castration resistant prostate cancer. AB - Fortunately, novel agents are nowadays available for the management of patients with castration-resistant prostate cancer (CRPC). Denosumab is a new bone protective agent, approved for the prevention and management of skeletal-related events. Studies have demonstrated that denosumab has better efficacy and similar rate of adverse effects in comparison with zoledronic acid, which was the standard bone-protective agent. In the present review we study the cost effectiveness of denosumab in patients with CRPC. PMID- 26588858 TI - Ionic Strength-Controlled Mn (Hydr)oxide Nanoparticle Nucleation on Quartz: Effect of Aqueous Mn(OH)2. AB - The early formation of manganese (hydr)oxide nanoparticles at mineral-water interfaces is crucial in understanding how Mn oxides control the fate and transport of heavy metals and the cycling of nutrients. Using atomic force microscopy, we investigated the heterogeneous nucleation and growth of Mn (hydr)oxide under varied ionic strengths (IS; 1-100 mM NaNO3). Experimental conditions (i.e., 0.1 mM Mn(2+) (aq) concentration and pH 10.1) were chosen to be relevant to Mn remediation sites. We found that IS controls Mn(OH)2 (aq) formation, and that the controlled Mn(OH)2 (aq) formation can affect the system's saturation and subsequent Mn(OH)2 (s) and further Mn3O4 (s) nanoparticle formation. In 100 mM IS system, nucleated Mn (hydr)oxide particles had more coverage on the quartz substrate than those in 1 mM and 10 mM IS systems. This high IS also resulted in low supersaturation ratio and thus favor heterogeneous nucleation, having better structural matching between nucleating Mn (hydr)oxides and quartz. The unique information obtained in this work improves our understanding of Mn (hydr)oxide formation in natural as well as engineered aqueous environments, such as groundwater contaminated by natural leachate and acid mine drainage remediation. PMID- 26588859 TI - Development of a Child Abuse Level Management (CALM) Guide for Research with Young Children. AB - Reporting child abuse or neglect is an ethical expectation and a legislated mandate of behavioral and health care professionals in the United States. In particular, researchers who investigate parent-child dyads are responsible for submitting procedures and informed consent documents to institutional review boards that provide for the protection of children. The challenge for researchers is to recognize failing quality of parent-child interaction, prior to any event of maltreatment and to intercede in a deteriorating dynamic. The obligation to report any suspicions of child maltreatment supersedes the responsibility to provide for confidentiality of research data. The purpose of this paper is to describe the rationale for the development of a research protocol guide, Child Abuse Level Management (CALM), and address protection of children in research. The CALM is a brief, flexible guide designed for use by researchers to help identify and respond to negative trends in the parent-child interaction during data collection. Suggested intervention scripts are provided that can be modified for specific culture-focused samples. The CALM guide can be used for training of data collectors using simulations prior to initiating any study involving higher risk dyads. PMID- 26588860 TI - Resuscitation versus end-of-life care: Exploring the obstacles and supportive behaviors to providing end-of-life care as perceived by emergency nurses after implementing the end-of-life care pathway. AB - AIM: To evaluate the obstacles and supportive behaviors to providing end-of-life care as perceived by emergency nurses after implementing the end-of-life care pathway. BACKGROUND: The end-of-life care pathway was implemented in an emergency department. However, the life-saving mission of emergency nurses and the chaotic and fast-paced emergency setting induced some difficulties to providing end-of life care. METHODS: A cross-sectional descriptive survey of 42 emergency nurses was conducted to measure the perceived magnitude scores of 28 obstacles and 23 supportive behaviors, reflecting their intensity and frequency when providing end of-life care. RESULTS: Six of the 10 obstacles with the highest scores were related to family issues. Moreover, five of the 10 supportive behaviors with the highest scores were associated with the provision of favorable environment. CONCLUSION: Though emergency nurses in different parts of the world face similar obstacles and supportive behaviors, discrepancies exist because of differing care pathways, emergency department design, and nursing education. PMID- 26588861 TI - 3-(2-Oxo-2-phenylethylidene)-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinolin 4(11bH)-one (compound 1), a novel potent Nrf2/ARE inducer, protects against DSS induced colitis via inhibiting NLRP3 inflammasome. AB - NLRP3 inflammasome is a key component of the inflammatory process and its dysregulation contributes to IBD for its ability to induce IL-1beta release. Previously, we reported that a novel small molecular activator of Nrf2, 3-(2-oxo 2-phenylethylidene)-2,3,6,7-tetrahydro-1H-pyrazino-[2,1-a]isoquinolin-4(11bH)-one (compound 1) can prevent the development of colorectal adenomas in AOM-DSS models. Here we further investigated the anti-inflammatory effect of compound 1 in DSS-induced colitis in C57BL/6 and NLRP3(-/-) mice, and revealed the possible modulation by compound 1 of NLRP3 inflammasome-mediated IL-1beta release from macrophages. In C57BL/6 mice, oral administration of compound 1 significantly attenuated DSS-induced colonic pathological damage, remarkably inhibited inflammatory cells infiltration and decreased myeloperoxidase (MPO) and IL-1beta secretion in colons. In contrast, mice deficient for NLRP3 were less sensitive to DSS-induced acute colitis, and compound 1 treatment exerted no protective effect on DSS-induced intestinal inflammation in NLRP3(-/-) mice. The protective effect of compound 1 may be attributed to its inhibition of NLRP3 inflammasome and Nrf2 activation in colons. Furthermore, compound 1, as a small molecular activator of Nrf2, significantly inhibited NLRP3 inflammasome activation in both THP-1 derived macrophages and bone-marrow derived macrophages, as indicated by reduced expression of NLRP3 and cleaved caspase-1, and lowered IL-1beta secretion. Finally, compound 1-induced NLRP3 inflammasome inhibition is through blocking NLRP3 priming step and dependent on Nrf2 activation. Taken together, our findings demonstrate that compound 1 might be a potential agent for the treatment of IBD by targeting Nrf2 and NLRP3 inflammasome. PMID- 26588862 TI - An integrated genomic analysis of Tudor domain-containing proteins identifies PHD finger protein 20-like 1 (PHF20L1) as a candidate oncogene in breast cancer. AB - Tudor domain-containing proteins (TDRDs), which recognize and bind to methyl lysine/arginine residues on histones and non-histone proteins, play critical roles in regulating chromatin architecture, transcription, genomic stability, and RNA metabolism. Dysregulation of several TDRDs have been observed in various types of cancer. However, neither the genomic landscape nor clinical significance of TDRDs in breast cancer has been explored comprehensively. Here, we performed an integrated genomic and transcriptomic analysis of 41 TDRD genes in breast cancer (TCGA and METABRIC datasets) and identified associations among recurrent copy number alterations, gene expressions, clinicopathological features, and survival of patients. Among seven TDRDs that had the highest frequency (>10%) of gene amplification, the plant homeodomain finger protein 20-like 1 (PHF20L1) was the most commonly amplified (17.62%) TDRD gene in TCGA breast cancers. Different subtypes of breast cancer had different patterns of copy number and expression for each TDRD. Notably, amplification and overexpression of PHF20L1 were more prevalent in aggressive basal-like and Luminal B subtypes and were significantly associated with shorter survival of breast cancer patients. Furthermore, knockdown of PHF20L1 inhibited cell proliferation in PHF20L1-amplified breast cancer cell lines. PHF20L1 protein contains N-terminal Tudor and C-terminal plant homeodomain domains. Detailed characterization of PHF20L1 in breast cancer revealed that the Tudor domain likely plays a critical role in promoting cancer. Mechanistically, PHF20L1 might participate in regulating DNA methylation by stabilizing DNA methyltransferase 1 (DNMT1) protein in breast cancer. Thus, our results demonstrated the oncogenic potential of PHF20L1 and its association with poor prognostic parameters in breast cancer. PMID- 26588863 TI - Individual estimates of age at detectable amyloid onset for risk factor assessment. AB - INTRODUCTION: Individualized estimates of age at detectable amyloid-beta (Abeta) accumulation, distinct from amyloid positivity, allow for analysis of onset age of Abeta accumulation as an outcome measure to understand risk factors. METHODS: Using longitudinal Pittsburgh compound B (PiB) positron emission tomography data from Baltimore Longitudinal Study of Aging, we estimated the age at which each PiB+ individual began accumulating Abeta. We used survival analysis methods to quantify risk of accumulating Abeta and differences in onset age of Abeta accumulation in relation to APOE epsilon4 status and sex among 36 APOE epsilon4 carriers and 83 noncarriers. RESULTS: Age at onset of Abeta accumulation for the APOE epsilon4- and epsilon4+ groups was 73.1 and 60.7, respectively. APOE epsilon4 positivity conferred a threefold risk of accumulating Abeta after adjusting for sex and education. DISCUSSION: Estimation of onset age of amyloid accumulation may help gauge treatment efficacy in interventions to delay symptom onset in Alzheimer's disease. PMID- 26588864 TI - Left Subclavian Arterial Coverage and Stroke During Thoracic Aortic Endografting: A Systematic Review. AB - Stroke is a devastating complication of thoracic endovascular aortic repair (TEVAR). Whether left subclavian artery (LSA) coverage and LSA revascularization affect stroke rate is debated. Whether patients with aneurysms or dissections undergoing TEVAR have higher stroke rates is also debated. We report a systematic review of 63 studies comprising more than 3,000 patients. We conclude that stroke risk after TEVAR is increased by LSA coverage, and that LSA revascularization reduces stroke risk. LSA revascularization may lower the rate of posterior stroke. TEVAR for aneurysm is associated with increased stroke risk compared to TEVAR for dissection. PMID- 26588865 TI - Spasm in Arterial Grafts in Coronary Artery Bypass Grafting Surgery. AB - Spasm of arterial grafts in coronary artery bypass grafting surgery is still a clinical problem, and refractory spasm can occasionally be lethal. Perioperative spasm in bypass grafts and coronary arteries has been reported in 0.43% of all coronary artery bypass grafting surgery, but this may be an underestimate. Spasm can develop not only in the internal mammary artery but more frequently in the right gastroepiploic and radial artery. The mechanism of spasm can involve many pathways, particularly those involving regulation of the intracellular calcium concentration. Endothelial dysfunction also plays a role in spasm. Depending on the clinical scenario, the possibility of spasm during and after coronary artery bypass grafting should be confirmed by angiography. If present, immediate intraluminal injection of vasodilators is often effective, although other procedures such as an intraaortic balloon pump or extracorporeal membrane oxygenation may also become necessary to salvage the patient. Prevention of spasm involves many considerations, and the principles are discussed in this review article. PMID- 26588866 TI - Assessment of the Association of Bilateral Internal Thoracic Artery Skeletonization and Sternal Wound Infection After Coronary Artery Bypass Grafting. AB - BACKGROUND: Skeletonization is a technique of bilateral internal thoracic artery (BITA) harvest that preserves sternal blood flow. We sought to identify the relationship of skeletonization and sternal wound infection in a population undergoing BITA harvest. METHODS: Demographics and outcomes were recorded from patients undergoing coronary artery bypass graft surgery with BITA using either skeletonized (n = 531) or nonskeletonized (n = 970) techniques. The primary outcome was total infection. Propensity scores analysis as well as univariable and multivariable analysis was performed to determine the effect of skeletonization in the total cohort and in each sex. RESULTS: Although patients undergoing skeletonized BITA had a lower body mass index, they were significantly older, with a higher proportion of women, diabetes mellitus, urgent or emergent surgery, renal failure, vascular and lung disease, and lower preoperative hemoglobin. There was a significant effect of skeletonization in decreasing total infection incidence (odds ratio [OR] 0.606, 95% confidence interval [CI]: 0.383 to 0.959, p = 0.032). The effect of skeletonization on total infection in men was more prominent (OR 0.466, 95% CI: 0.290 to 0.870), whereas there was no effect in women (OR 0.887, 95% CI: 0.441 to 1.786). Multivariable analysis confirmed that skeletonization was protective (OR 0.606, 95% CI: 0.383 to 0.957, p = 0.032). Other factors associated included being female (OR 3.327, 95% CI: 2.080 to 5.322, p < 0.001), insulin-dependent diabetes mellitus (OR 2.638, 95% CI: 1.506 to 4.624, p = 0.001), peripheral vascular disease (OR 2.101, 95% CI: 1.247 to 3.539, p = 0.005), increased body mass index (OR 1.100, 95% CI: 1.054 to 1.149, p < 0.001), and decreased preoperative hemoglobin (OR 0.984, 95% CI: 0.972 to 0.997, p = 0.013). CONCLUSIONS: Skeletonization is associated with a significant protective effect with regard to sternal infection after coronary artery bypass graft surgery with BITA. Being female is a major risk factor for infection, and the risk is not modified significantly with a strategy of skeletonization in women. PMID- 26588867 TI - National Trends in Utilization, Mortality, Complications, and Cost of Care After Left Ventricular Assist Device Implantation From 2005 to 2011. AB - BACKGROUND: Left ventricular assist devices (LVADs) have shown survival benefit in end-stage heart failure patients. LVAD technology has evolved considerably with the development of continuous-flow devices. METHODS: The Nationwide Inpatient Sample was queried from 2005 to 2011 using International Classification of Diseases, 9th Edition procedure code 37.66, Insertion of Implantable Heart System, in any procedure field. Patients with primary diagnosis of orthotopic heart transplant or use of temporary mechanical circulatory support devices were excluded. Procedural complications were identified using International Classification of Diseases, 9th Edition codes and patient safety indicators. Cochran-Armitage and Cuzick tests for trend were used to identify time trends for categorical and continuous variables, respectively. RESULTS: There were 2,038 LVAD implantations from 2005 to 2011. LVAD use increased from 127 procedures in 2005 to 506 procedures in 2011, and in-hospital mortality declined from 47.2% to 12.7% (p < 0.001), with sharp inflection points in the year 2008. Average length of stay decreased from 44 days in the pulsatile-flow era (2005 to 2007) to 36 days in the continuous-flow era (2008 to 2011). Cost of hospitalization increased from $194,380 in 2005 to $234,808 in 2011 but remained constant from 2008 to 2011. There was a trend of increased incidence of major bleeding and thromboembolism and decreased incidence of infectious and iatrogenic cardiac complications in the continuous-flow era. CONCLUSIONS: LVAD use has increased and in-hospital mortality and LOS after LVAD implantation have declined. These changes coincide with United States Food and Drug Administration (FDA) approval of continuous-flow devices in 2008. PMID- 26588868 TI - Adipose Tissue: Sanctuary for HIV/SIV Persistence and Replication. AB - This commentary highlights new findings from a recent study identifying adipose tissue as a potential HIV reservoir and a major site of inflammation during chronic human/simian immunodeficiency virus (HIV/SIV) infection. A concise discussion about upcoming challenges and new research avenues for reducing chronic adipose inflammation during HIV/SIV infection is presented. PMID- 26588869 TI - Epidemiological factors associated to spread of porcine epidemic diarrhea in Japan. AB - Porcine epidemic diarrhea (PED) is an emerging disease of pigs that has recently led to large numbers of piglet deaths in a number of countries of Eastern Asia and The Americas. The objective of the present study was to identify and compare risk factors associated with PED infection in locally and non-locally PED-exposed farms in Japan. A questionnaire was administered to a convenience selection of pig farms located throughout Japan. Questionnaires were administered between November 2013 (when the first case was reported in Japan) and August 2014. PED positive farms (cases, n=124) were asked to provide information on their status (positive or negative) and select herd management practices for the two weeks prior to onset of PED clinical signs. Negative farms (controls, n=128) were given the same questionnaire and asked herd management practices for the two weeks prior to a given reference date. This date was assigned based on the date of PED occurrence in the town/prefecture in which the farm was located. Case and control farms were categorized as "locally exposed" if they were located within a 5km radius from a PED-infected farm and "non-locally exposed", otherwise. Logistic regression analysis was used to identify factors associated with PED infection. Two separate regressions were done for locally exposed and non-locally exposed farms using PED status (positive/negative) as the dependent variable. PED in locally-exposed farms was associated (P<0.05) with increased farm size (in 100 pig increments), shorter distances to the closest PED-positive farm (less than1,001m), and a disinfectant contact time of less than 20min. In non-locally exposed farms, PED was associated (P<0.05) with increased feed truck visits to the farm, no visit of the veterinarian, and again a disinfectant contact time of less than 20min. These findings suggest that the mechanisms of PED spread in Japan were different for farms closer to case-farms compared to farms that were further away from PED cases. These results will contribute to understanding the epidemiology of the disease in Japan and will ultimately aid in designing and implementing effective prevention and control strategies in Japan and other regions epidemically infected by the PED virus. PMID- 26588870 TI - Foot abscess in sheep: Evaluation of risk factors and management options. AB - Foot abscess of sheep is a painful, suppurative and necrotic infection of the phalanges and interphalangeal joints. Sheep affected by foot abscess may be acutely lame and pregnant ewes may die with secondary pregnancy toxemia when they fail to maintain their required level of nutrition. We conducted a cross sectional observational study to identify and quantify possible risk factors for foot abscess. A questionnaire was designed and used to conduct telephone interviews with 115 sheep farmers in the Central Tablelands of NSW in November 2012. They were asked to provide information on their farm, the animals, and management-related information for the lambing period of a selected cohort of ewes. Multivariable logistic regression analyses were conducted using two outcome variables: (a) the presence of foot abscess, and (b) low (<1%), medium (between 1% and 5%) or high (>5%) levels of foot abscess. High levels of clover in the paddocks grazed by sheep was associated with increased odds of foot abscess in both the models (binary model odds ratio [OR]: 3.18; 95% confidence interval [CI]: 1.22, 8.77 and ordinal model OR: 2.92; 95% CI: 1.35, 6.54). High risk was also associated with the farmer's observation that it had been a wet season (ordinal model OR: 7.89, 95% CI: 2.72, 24.43) and moving sheep during lambing (binary model OR: 14.15, 95% CI: 2.30, 296.61). Similarly, farms with shale/slate type soils had lower odds of the disease compared to farms with basalt-derived soils. Farmers who used foot-baths (binary model OR: 4.05, 95% CI: 1.15, 19.34) and antibiotics (ordinal model OR: 3.16, 95% CI: 1.38, 7.66) had higher odds of foot abscess, as might be expected as they adopted these measures to deal with an increased prevalence of foot abscess. The findings from this study can be used to provide extension advice to farmers and for designing further confirmatory studies. PMID- 26588871 TI - Diarachidonoylphosphoethanolamine induces apoptosis of malignant pleural mesothelioma cells through a Trx/ASK1/p38 MAPK pathway. AB - 1,2-Diarachidonoyl-sn-glycero-3-phosphoethanolamine (DAPE) induces both necrosis/necroptosis and apoptosis of NCI-H28 malignant pleural mesothelioma (MPM) cells. The present study was conducted to understand the mechanism for DAPE induced apoptosis of NCI-H28 cells. DAPE induced caspase-independent apoptosis of NCI-H28 malignant pleural mesothelioma (MPM) cells, and the effect of DAPE was prevented by antioxidants or an inhibitor of NADPH oxidase (NOX). DAPE generated reactive oxygen species (ROS) and inhibited activity of thioredoxin (Trx) reductase (TrxR). DAPE decreased an association of apoptosis signal-regulating kinase 1 (ASK1) with thioredoxin (Trx), thereby releasing ASK1. DAPE activated p38 mitogen-activated protein kinase (MAPK), which was inhibited by an antioxidant or knocking-down ASK1. In addition, DAPE-induced NCI-H28 cell death was also prevented by knocking-down ASK1. Taken together, the results of the present study indicate that DAPE stimulates NOX-mediated ROS production and suppresses TrxR activity, resulting in the decrease of reduced Trx and the dissociation of ASK1 from a complex with Trx, allowing sequential activation of ASK1 and p38 MAPK, to induce apoptosis of NCI-H28 MPM cells. PMID- 26588872 TI - Role of the lysophosphatidylinositol/GPR55 axis in cancer. AB - Lysophosphatidylinositol (LPI) is a well-known bioactive lipid that is able to activate signalling cascades relevant to cell proliferation, migration, survival and tumourigenesis. It is well-established that the G protein-coupled receptor 55 (GPR55) is the specific receptor for LPI. Several investigations have demonstrated that the signalling pathways activated by LPI through its receptor GPR55 play a pivotal role in different cancer type. This review focuses on the role of the LPI/GPR55 axis, in particular with regards to its pharmacological potential therapeutic exploitation. PMID- 26588873 TI - Roles of phosphoinositide-specific phospholipase Cgamma1 in brain development. AB - Over the past decade, converging evidence suggests that PLCgamma1 signaling has key roles in controlling neural development steps. PLCgamma1 functions as a signal transducer that converts an extracellular stimulus into intracellular signals by generating second messengers such as DAG and IP3. DAG functions as an activator of either PKC or transient receptor potential cation channels (TRPCs), while IP3 induces the calcium release from intracellular calcium stores. These second messengers regulate the morphological change of neuron, such as neurite outgrowth, migration, axon pathfinding, and synapse formation. These morphological changes depend on finely tuned calcium signaling following receptor tyrosine kinase-mediated PLCgamma1 signaling. Thus, deregulation of PLCgamma1 signaling causes various abnormalities of neuronal development and it may be associated with diverse neurological disorders. Herein, we discuss the current understanding of the PLCgamma1 signaling pathway in neural development and provide recent advances of how PLCgamma1 signaling is involved in the formation of neuronal processes for functionally faithful brain development. PMID- 26588874 TI - Dark shadows of rumination: Finnish young adults' identity profiles, personal goals and concerns. AB - Young adults actively construct their identity by exploring and committing to opportunities through the setting of personal goals. Typically personal goal contents are related to young adults' developmental tasks but sometimes goals are self-focused. This longitudinal study explored personal goal and concern contents in relation to identity profiles among young Finns (N = 577) followed from age 23 to 25. Applying the Dimensions of Identity Development Scale, identity formation was measured at age 23. Latent Profile Analysis yielded five profiles: moderate achievement, moderate diffusion, achievement, diffused diffusion, and reconsidering achievement. Two "dark side" identity profiles, characterized by low commitment and high ruminative exploration, were identified: moderate diffusion and diffused diffusion. The moderate diffusion profile seemed to have developmental task-related personal goals and concerns. In the diffused diffusion profile, self-focused personal goals and concerns were typical and personal goals and concerns towards relationships atypical. These findings persisted over the two-year follow-up. PMID- 26588875 TI - Molecular complexation of curcumin with pH sensitive cationic copolymer enhances the aqueous solubility, stability and bioavailability of curcumin. AB - Curcumin is a natural dietary compound with demonstrated potential in preventing/treating several chronic diseases in animal models. However, this success is yet to be translated to humans mainly because of its poor oral bioavailability caused by extremely low water solubility. This manuscript demonstrates that water insoluble curcumin (~1MUg/ml) forms highly aqueous soluble complexes (>2mg/ml) with a safe pH sensitive polymer, poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl-methacrylate) when precipitated together in water. The complexation process was optimized to enhance curcumin loading by varying several formulation factors. Acetone as a solvent and polyvinyl alcohol as a stabilizer with 1:2 ratio of drug to polymer yielded complexes with relatively high loading (~280MUg/ml) and enhanced solubility (>2mg/ml). The complexes were amorphous in solid and were soluble only in buffers with pHs less than 5.0. Hydrogen bond formation and hydrophobic interactions between curcumin and the polymer were recorded by infrared spectroscopy and nuclear magnetic resonance spectroscopy, respectively. Molecular complexes of curcumin were more stable at various pHs compared to unformulated curcumin. In mice, these complexes increased peak plasma concentration of curcumin by 6 times and oral bioavailability by ~20 times. This is a simple, economic and safer strategy of enhancing the oral bioavailability of curcumin. PMID- 26588876 TI - Antimicrobial resistance of Aeromonas hydrophila isolated from different food sources: A mini-review. AB - Aeromonas hydrophila is a Gram-negative, oxidase-positive, facultative, anaerobic, opportunistic aquatic pathogen. A. hydrophila produces virulence factors, such as hemolysins, aerolysins, adhesins, enterotoxins, phospholipase and lipase. In addition to isolation from aquatic sources, A. hydrophila has been isolated from meat and meat products, milk and dairy products, and vegetables. However, various studies showed that this opportunistic pathogen is resistant to commercial antibiotics. This is attributed to factors such as the indiscriminate use of antibiotics in aquaculture, plasmids or horizontal gene transfer. In this report, we highlight the occurrence, prevalence and antimicrobial resistance of A. hydrophila isolated from different food samples. The presence of antimicrobial resistant A. hydrophila in food poses threats to public and aquatic animal health. PMID- 26588877 TI - Simultaneous quantification of hyperin, reynoutrin and guaijaverin in mice plasma by LC-MS/MS: application to a pharmacokinetic study. AB - A specific and sensitive LC-MS/MS assay was developed to simultaneously quantify three structurally similar flavonoid glycosides - hyperin, reynoutrin and guaijaverin - in mouse plasma. Biosamples were prepared by solid-phase extraction. Isocratic chromatographic separation was performed on an AichromBond AQ C18 column (250 * 2.1 mm, 5 MUm) with methanol-acetonitrile-water-formic acid (20:25:55:0.1) as the mobile phase. Detection of hyperin, reynoutrin, guaijaverin and internal standard [luteolin-7-O-beta-d-apiofuranosyl-(1 -> 6)-beta-d glucopyranoside] was achieved by ESI-MS/MS in the negative ion mode using m/z 463 -> m/z 300, m/z 433 -> m/z 300, m/z 433 -> m/z 300 and m/z 579 -> m/z 285 transitions, respectively. Linear concentration ranges of calibration curves were 4.0-800.0 ng/mL for hyperin and reynoutrin and 8.0-1600.0 ng/mL for guaijaverin when 100 MUL of plasma was analyzed. We used this validated method to study the pharmacokinetics of hyperin, reynoutrin and guaijaverin in mice following oral and intravenous administration. All three quercetin-3-O-glycosides showed poor oral absorption in mice, and the absolute bioavailability of hyperin after oral administration of 100 mg/kg was 1.2%. Pretreatment with verapamil increased the peak concentration and area under the concentration-time curve of hyperin, which were significantly higher than the control values. The half-life of hyperin with verapamil was significantly prolonged compared with that of the control. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26588878 TI - Cancer therapy targeting the fibrinolytic system. AB - The tumor microenvironment is recognized as a key factor in the multiple stages of cancer progression, mediating local resistance, immune-escape and metastasis. Cancer growth and progression require remodeling of the tumor stromal microenvironment, such as the development of tumor-associated blood vessels, recruitment of bone marrow-derived cells and cytokine processing. Extracellular matrix breakdown achieved by proteases like the fibrinolytic factor plasmin and matrix metalloproteases is necessary for cell migration crucial for cancer invasion and metastasis. Key components of the fibrinolytic system are expressed in cells of the tumor microenvironment. Plasmin can control growth factor bioavailability, or the regulation of other proteases leading to angiogenesis, and inflammation. In this review, we will focus on the role of the fibrinolytic system in the tumor microenvironment summarizing our current understanding of the role of the fibrinolytic factors for the modulation of the local chemokine/cytokine milieu, resulting in myeloid cell recruitment, which can promote neoangiogenesis. PMID- 26588879 TI - The wheat TaGBF1 gene is involved in the blue-light response and salt tolerance. AB - Light and abiotic stress both strongly modulate plant growth and development. However, the effect of light-responsive factors on growth and abiotic stress responses in wheat (Triticum aestivum) is unknown. G-box binding factors (GBFs) are blue light-specific components, but their function in abiotic stress responses has not been studied. Here we identified a wheat GBF1 gene that mediated both the blue light- and abiotic stress-responsive signaling pathways. TaGBF1 was inducible by blue light, salt and exposure to abscisic acid (ABA). TaGBF1 interacted with a G-box light-responsive element in vitro and promoted a blue-light response in wheat and Aradidopsis thaliana. Both TaGBF1 over expression in wheat and its heterologous expression in A. thaliana heighten sensitivity to salinity and ABA, but its knockdown in wheat conferred resistance to high salinity and ABA. The expression of AtABI5, a key component of the ABA signaling pathway in A. thaliana, and its homolog Wabi5 in wheat was increased by transgenic expression of TaGBF1. The hypersensitivity to salt and ABA caused by TaGBF1 was not observed in the abi5 mutant background, showing that ABI5 is the mediator in TaGBF1-induced abiotic stress responses. However, the hypersensitivity to salt conferred by TaGBF1 is not dependent on light. This suggests that TaGBF1 is a common component of blue light- and abiotic stress responsive signaling pathways. PMID- 26588880 TI - TCF-1 at the Tfh and Th1 Divergence. AB - Three recent studies provide new insight into the mechanisms that promote the differentiation of antigen-primed T cells into the follicular helper T (Tfh) lineage, revealing a key role for the transcription factor TCF-1 in the regulation of the Bcl6-Blimp-1 axis that mediates the divergence between the Tfh and the Th1 lineages. PMID- 26588881 TI - A simple bedside approach to therapeutic goals achievement during the management of deceased organ donors--An adapted version of the "VIP" approach. AB - The disproportion between the supply and demand of transplant organs could be alleviated by improving the quality of clinical management of deceased potential donors. As a large number of donor losses by cardiac arrest occur due to hemodynamic instability, without instituting all essential maintenance measures, it is likely that the application of simplified potential donor maintenance protocols will help to decrease potential donor losses and increase the supply of organs for transplantation. The Ventilation, Infusion and Pumping (VIP) strategy is a mnemonic method that brings together key aspects of the restoration of oxygen delivery to tissues during hemodynamic instability: adequate mechanical Ventilation, volume Infusion and evaluation of heart Pump effectiveness. The inclusion of the additional initials, "P" and "S," refers to Pharmacological treatment and Specificities involved in the etiology of shock. The use of simplified care standards can assist in adhering to essential potential donor management measures. Therefore, using a simplified method as the adapted VIP approach can contribute to improving management standards of potential organ donors and increasing the supply of organs for transplantation. PMID- 26588882 TI - mTOR inhibition by rapamycin protects against deltamethrin-induced apoptosis in PC12 Cells. AB - The autophagy pathway can be induced and upregulated in response to intracellular reactive oxygen species (ROS). In this study, we explored a novel pharmacotherapeutic approach involving the regulation of autophagy to prevent deltamethrin (DLM) neurotoxicity. We found that DLM-induced apoptosis in PC12 cells, as demonstrated by the activation of caspase-3 and -9 and by nuclear condensation. DLM treatment significantly decreased dopamine (DA) levels in PC12 cells. In addition, we observed that cells treated with DLM underwent autophagic cell death, by monitoring the expression of LC3-II, p62, and Beclin-1. Exposure of PC12 cells to DLM led to the production of ROS. Treatment with N-acetyl cysteine (NAC) effectively blocked both apoptosis and autophagy. In addition, mitogen-activated protein kinase (MAPK) inhibitors attenuated apoptosis as well as autophagic cell death. We also investigated the modulation of DLM-induced apoptosis in response to autophagy regulation. Pretreatment with the autophagy inducer, rapamycin, significantly enhanced the viability of DLM-exposed cells, and this enhancement of cell viability was partially due to alleviation of DLM induced apoptosis via a decrease in levels of cleaved caspase-3. However, pretreatment of cells with the autophagy inhibitor, 3-methyladenine (3MA), significantly increased DLM toxicity in these cells. Our results suggest that DLM induced cytotoxicity is modified by autophagy regulation and that rapamycin protects against DLM-induced apoptosis by enhancing autophagy. Pharmacologic induction of autophagy by rapamycin may be a useful treatment strategy in neurodegenerative disorders. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 32: 109-121, 2017. PMID- 26588883 TI - Moderate alcohol drinking in pregnancy increases risk for children's persistent conduct problems: causal effects in a Mendelian randomisation study. AB - BACKGROUND: Heavy alcohol use during pregnancy can cause considerable developmental problems for children, but effects of light-moderate drinking are uncertain. This study examined possible effects of moderate drinking in pregnancy on children's conduct problems using a Mendelian randomisation design to improve causal inference. METHODS: A prospective cohort study (ALSPAC) followed children from their mother's pregnancy to age 13 years. Analyses were based on 3,544 children whose mothers self-reported either not drinking alcohol during pregnancy or drinking up to six units per week without binge drinking. Children's conduct problem trajectories were classified as low risk, childhood-limited, adolescence onset or early-onset-persistent, using six repeated measures of the Strengths and Difficulties Questionnaire between ages 4-13 years. Variants of alcohol metabolising genes in children were used to create an instrumental variable for Mendelian randomisation analysis. RESULTS: Children's genotype scores were associated with early-onset-persistent conduct problems (OR = 1.29, 95% CI = 1.04 1.60, p = .020) if mothers drank moderately in pregnancy, but not if mothers abstained from drinking (OR = 0.94, CI = 0.72-1.25, p = .688). Children's genotype scores did not predict childhood-limited or adolescence-onset conduct problems. CONCLUSIONS: This quasi-experimental study suggests that moderate alcohol drinking in pregnancy contributes to increased risk for children's early onset-persistent conduct problems, but not childhood-limited or adolescence-onset conduct problems. PMID- 26588884 TI - Complexity and variability of the center of pressure time series during quiet standing in patients with knee osteoarthritis. AB - BACKGROUND: While several studies have investigated the traditional linear measures in patients with knee osteoarthritis, no study has yet reported the non linear structure of postural sway in these patients. METHODS: We used two non linear methods, recurrence quantification analysis (percent of determinism-%DET) and central tendency measure, to respectively investigate differences in the complexity and variability of sway dynamics between two groups of knee osteoarthritis patients (n=27) and healthy controls (n=27) under different conditions of postural and cognitive tasks. The experimental conditions included standing on (1) rigid surface with open eyes; (2) rigid surface with closed eyes; (3) foam surface with open eyes; and (4) foam surface with closed eyes. All these conditions were performed isolated (single-task) and while performing concurrent cognitive task (dual-task). FINDINGS: The results showed greater %DET and lesser central tendency measure (both in mediolateral direction) in patients compared with healthy subjects. Moreover, in both groups, the %DET increased and central tendency measure decreased with increasing postural difficulty while %DET decreased and central tendency measure increased when moving from single- to dual task conditions. INTERPRETATIONS: The complexity loss was observed in patients compared with healthy controls. The observed increase in the variability coupled with a decrease in the complexity could be explained by the exploratory behavior of postural control system to gather information during difficult postural conditions relative to the easy ones. Moreover, the observed increase in the complexity coupled with the decrease in the amount of variability may enhance the flow of information to facilitate the perceptual control of standing balance during dual-task conditions. PMID- 26588886 TI - 25 years of the Scandinavian Journal of Medicine and Science in Sports. PMID- 26588885 TI - Acquired midfoot deformity and function in individuals with diabetes and peripheral neuropathy. AB - BACKGROUND: Diabetes mellitus related medial column foot deformity is a major contributor to ulceration and amputation. However, little is known about the relationship between medial column alignment and function and the integrity of the soft tissues that support and move the medial column. The purposes of this study were to determine the predictors of medial column alignment and function in people with diabetes and peripheral neuropathy. METHODS: 23 participants with diabetes and neuropathy had radiographs, heel rise kinematics, magnetic resonance imaging and isokinetic muscle testing to measure: 1) medial column alignment (Meary's angle--the angle between the 1st metatarsal longitudinal axis and the talar head and neck), 2) medial column function (forefoot relative to hindfoot plantarflexion during heel rise), 3) intrinsic foot muscle and fat volume, ratio of posterior tibialis to flexor digitorum tendon volume, 4) plantar fascia function (Meary's angle change from toes flat to extended) and 5) plantarflexor peak torque. Predictors of medial column alignment and function were determined using simultaneous entry multiple regression. FINDINGS: Posterior tibialis to flexor digitorum tendon volume ratio and intrinsic foot muscle volume were significant predictors of medial column alignment (P<.05), accounting for 44% of the variance. Intrinsic foot fat volume and plantarflexor peak torque were significant predictors of medial column function (P<.05), accounting for 37% of the variance. INTERPRETATION: Deterioration of medial column supporting structures predicted alignment and function. Prospective research is required to monitor alignment, structure, and function over time to inform early intervention strategies to prevent deformity, ulceration, and amputation. PMID- 26588887 TI - CHADS2 scores as a predictor of ischemic stroke after radical prostatectomy. AB - Patients with prostate cancer have an increased risk of stroke, but their absolute rate of stroke depends on age and comorbid conditions. The Charlson Comorbidity Index Score (CCIS) is a widely accepted measure for risk adjustment in administrative claims data sets. This study assesses the predictive value of CHADS2 scores and CCIS for stroke among patients with prostate cancer. The study was conducted based on data taken from Taiwan's National Health Insurance Research Database (NHIRD). We identified a total of 5414 participants with nonatrial fibrillation (AF) prostate cancer diagnoses who underwent radical prostatectomy between 1997 and 2011. CHADS2 scores and CCIS were used to stratify the 5-year ischemic stroke risk. All participants were followed from the date of enrollment until ischemic stroke, death, or the end of the 5-year follow-up period. The 5-year risk of ischemic stroke in the present study was 1.7%. Ischemic stroke has a better correlation with CHADS2 (CHADS2 score = 0 to 1: 0.02%, CHADS2 score = 2 to 3: 13.9%, CHADS2 score >= 4: 44.4%; AUC = 0.978) than CCIS (CCIS = 0 to 1: 1.6%, CCIS = 2 to 3: 1.7%, CCIS >= 4: 3.8%; AUC = 0.520). Our results show that patients with prostate cancer who underwent radical prostatectomy show significantly higher risk of ischemic stroke in high CHADS2 score patients, and the CHADS2 score could be applied for ischemic stroke prediction. Cardiovascular risks evaluation and management are suggested for prostate cancer patients with higher CHADS2 score. PMID- 26588888 TI - Novel picornavirus in domestic rabbits (Oryctolagus cuniculus var. domestica). AB - Picornaviruses (family Picornaviridae) are small, non-enveloped viruses with positive sense, single-stranded RNA genomes. The numbers of the novel picornavirus species and genera are continuously increasing. Picornaviruses infect numerous vertebrate species from fish to mammals, but have not been identified in a member of the Lagomorpha order (pikas, hares and rabbits). In this study, a novel picornavirus was identified in 16 (28.6%) out of 56 faecal samples collected from clinically healthy rabbits (Oryctolagus cuniculus var. domestica) in two (one commercial and one family farms) of four rabbit farms in Hungary. The 8364 nucleotide (2486 amino acid) long complete genome sequence of strain Rabbit01/2013/HUN (KT325852) has typical picornavirus genome organization with type-V IRES at the 5'UTR, encodes a leader (L) and a single 2A(H-box/NC) proteins, contains a hepatitis-A-virus-like cis-acting replication element (CRE) in the 2A, but it does not contain the sequence forming a "barbell-like" secondary structure in the 3'UTR. Rabbit01/2013/HUN has 52.9%, 52% and 57.2% amino acid identity to corresponding proteins of species Aichivirus A (genus Kobuvirus): to murine Kobuvirus (JF755427) in P1, to canine Kobuvirus (JN387133) in P2 and to feline Kobuvirus (KF831027) in P3, respectively. The sequence and phylogenetic analysis indicated that Rabbit01/2013/HUN represents a novel picornavirus species possibly in genus Kobuvirus. This is the first report of detection of picornavirus in rabbit. Further study is needed to clarify whether this novel picornavirus plays a part in any diseases in domestic or wild rabbits. PMID- 26588889 TI - Fertilizability of oocytes derived from Holstein cows having different antral follicle counts in ovaries. AB - In this study, to clarify the relationship between ovarian reserve and oocyte quality, cumulus-oocyte complexes (COCs) were collected repeatedly by ovum pick up (OPU) from cows with high and low antral follicle counts (AFCs) at short (3-4 days) and long (7 days) intervals, and COC morphologies and oocyte fertilizability were examined. The relationship between AFC and follicular growth after OPU was also investigated. Cows showing AFC of >=30 in at least one OPU session were grouped into the high-AFC group. At a short interval, follicular sizes and COC morphologies were similar between the different AFC groups. However, the normal fertilization rate was higher in the high-AFC group than in the low one, although total penetration rates were similar. At a long interval, the percentage of COCs with poor morphology in the high-AFC group was higher and the normal fertilization rate was lower than in the low one. In the low-AFC group, normal fertilization rates at short and long intervals were similar, and mean follicular size became larger at a long than at a short interval. However, mean follicular sizes at short- and long-interval OPU were similar in the high AFC group. In conclusion, it is suggested that oocytes derived from cows with high AFC had higher fertilizability than those from cows with low AFC when OPUs were performed at a short (3-4 days) interval. However, oocyte quality in high AFC cows was impaired by long-interval (7 days) OPU, possibly due to the degradation of follicles. PMID- 26588890 TI - Effect of semen extenders on frozen-thawed boar sperm characteristics and distribution in the female genital tract after deep intrauterine insemination in sows. AB - We compared the effects of extenders of frozen-thawed semen on post-thaw sperm characteristics and the distribution of frozen-thawed spermatozoa in the female genital tract after fixed-timed deep intrauterine insemination (DIUI) in sows. Frozen semen samples were thawed and diluted in either modified Modena solution (mMS) or porcine fertilization medium (PFM) containing theophylline, adenosine and cysteine. Sperm quality, assessed in vitro based on motility using a computer assisted sperm analyzer and the integrity of the plasma and acrosomal membranes using flow cytometry, was evaluated at 0.5, 1.5, 3 and 6h after thawing. Progressive motility and the percentage of spermatozoa with damaged acrosomal membranes in PFM were significantly better than in mMS throughout the 6h. Sows with estrus synchronized using prostaglandin F2 alpha, equine chorionic gonadotropin and human chorionic gonadotropin (hCG) were inseminated once with mMS- or PFM-diluted 5 * 10(8) frozen-thawed spermatozoa by DIUI at 34 h after the hCG injection. At 4h after DIUI, reproductive tracts were recovered from 30 sows. There were significantly fewer polymorphonuclear leukocytes (PMNs) and more spermatozoa outside PMNs in the uterine horn after PFM treatment than with mMS. When 22 sows were administered DIUI with 10 * 10(8) frozen-thawed spermatozoa at 36 h after hCG, the pregnancy rates did not differ significantly between the mMS- (36%) and PFM- (64%) treated groups. Thus, PFM enhanced progressive sperm motility but increased sperm membrane damage compared with mMS; it also suppressed the migration of PMNs into the uterine lumen. PMID- 26588891 TI - Cutaneous plasmacytosis associated with autoimmune hemolytic anemia. PMID- 26588892 TI - Assessment of potential public health impact of a quadrivalent inactivated influenza vaccine in Thailand. AB - BACKGROUND: Each year, an influenza B strain representing only one influenza B lineage is included in the trivalent inactivated influenza vaccine (IIV3); a mismatch between the selected lineage and circulating viruses can result in suboptimal vaccine effectiveness. We modeled the added potential public health impact of a quadrivalent inactivated influenza vaccine (IIV4) that includes strains from both influenza B lineages compared to IIV3 on influenza-associated morbidity and mortality in Thailand. METHODS: Using data on the incidence of influenza-associated hospitalizations and deaths, vaccine effectiveness, and vaccine coverage from the 2007-2012 influenza seasons in Thailand, we estimated rates of influenza-associated outcomes that might be averted using IIV4 instead of IIV3. We then applied these rates to national population estimates to calculate averted illnesses, hospitalizations, and deaths for each season. We assumed that the influenza B lineage included in IIV3 would provide a relative vaccine effectiveness of 75% against the other B lineage. RESULTS: Compared to use of IIV3, use of IIV4 might have led to an additional reduction ranging from 0.4 to 14.3 influenza-associated illnesses per 100 000 population/year, <0.1 to 0.5 hospitalizations per 100 000/year, and <0.1 to 0.4 deaths per 1000/year. Based on extrapolation to national population estimates, replacement of IIV3 with IIV4 might have averted an additional 267-9784 influenza-associated illnesses, 9 320 hospitalizations, and 0-3 deaths. CONCLUSION: Compared to use of IIV3, IIV4 has the potential to further reduce the burden of influenza-associated morbidity and mortality in Thailand. PMID- 26588893 TI - Mammographic Appearance of Intra-Nipple Hyaluronic Acid Injection. PMID- 26588894 TI - Evolutionary comparison of prenylation pathway in kinetoplastid Leishmania and its sister Leptomonas. AB - BACKGROUND: Leptomonas is monogenetic kinetoplastid parasite of insects and is primitive in comparison to Leishmania. Comparative studies of these two kinetoplastid may share light on the evolutionary transition to dixenous parasitism in Leishmania. In order to adapt and survive within two hosts, Leishmania species must have acquired virulence factors in addition to mechanisms that mediate susceptibility/resistance to infection in the pathology associated with disease. Rab proteins are key mediators of vesicle transport and contribute greatly to the evolution of complexity of membrane transport system. In this study we used our whole genome sequence data of these two divergent kinetoplastids to analyze the orthologues/paralogues of Rab proteins. RESULTS: During change of lifestyle from monogenetic (Leptomonas) to digenetic (Leishmania), we found that the prenyl machinery remained unchanged. Geranylgeranyl transferase-I (GGTase-I) was absent in both Leishmania and its sister Leptomonas. Farnesyltransferase (FTase) and geranylgeranyl transferase-II (GGTase-II) were identified for protein prenylation. We predict that activity of the missing alpha-subunit (alpha-subunit) of GGTase-II in Leptomonas was probably contributed by the alpha-subunit of FTase, while beta-subunit (beta-subunit) of GGTase-II was conserved and indicated functional conservation in the evolution of these two kinetoplastids. Therefore the beta-subunit emerges as an excellent target for compounds inhibiting parasite activity in clinical cases of co infections. We also confirmed that during the evolution to digenetic life style in Leishmania, the parasite acquired capabilities to evade drug action and maintain parasite virulence in the host with the incorporation of short-chain dehydrogenase/reductase (SDR/MDR) superfamily in Rab genes. CONCLUSION: Our study based on whole genome sequences is the first to build comparative evolutionary analysis and identification of prenylation proteins in Leishmania and its sister Leptomonas. The information presented in our present work has importance for drug design targeted to kill L. donovani in humans but not affect the human form of the prenylation enzymes. PMID- 26588895 TI - Factors affecting willingness to receive a kidney transplant among minority patients at an urban safety-net hospital: a cross-sectional survey. AB - BACKGROUND: In the US, African Americans (AAs) are four times more likely to develop end stage renal disease (ESRD) but half as likely to receive a kidney transplant as whites. Patient interest in kidney transplantation is a fundamental step in the kidney transplant referral process. Our aim was to determine the factors associated with the willingness to receive a kidney transplant among chronic kidney disease (CKD) patients in a predominantly minority population. METHODS: CKD patients from an outpatient nephrology clinic at a safety-net hospital (n = 213) participated in a cross-sectional survey from April to June, 2013 to examine the factors associated with willingness to receive a kidney transplant among a predominantly minority population. The study questionnaire was developed from previously published literature. Multivariable logistic regression analysis was used to determine factors associated with willingness to undergo a kidney transplant. RESULTS: Respondents were primarily AAs (91.0%), mostly female (57.6%) and middle aged (51.6%). Overall, 53.9% of participants were willing to undergo a kidney transplant. Willingness to undergo a kidney transplant was associated with a positive perception towards living kidney donation (OR 7.31, 95% CI: 1.31-40.88), willingness to attend a class about kidney transplant (OR = 7.15, CI: 1.76-29.05), perception that a kidney transplant will improve quality of life compared to dialysis (OR = 5.40, 95% CI: 1.97-14.81), and obtaining information on kidney transplant from other sources vs. participant's physician (OR =3.30, 95% CI: 1.13-9.67), when compared with their reference groups. CONCLUSION: It is essential that the quality of life benefits of kidney transplantation be known to individuals with CKD to increase their willingness to undergo kidney transplantation. Availability of multiple sources of information and classes on kidney transplantation may also contribute to willingness to undergo kidney transplantation, especially among AAs. PMID- 26588896 TI - Clinical efficacy of stereotactic ablative radiotherapy for lung metastases arising from colorectal cancer. AB - BACKGROUND: Limited data describe the prognosis after stereotactic ablative radiotherapy for lung metastases arising from colorectal cancer. Thus, we evaluated treatment outcomes of stereotactic ablative radiotherapy for those patients. METHODS: The study involved patients received stereotactic ablative radiotherapy for one to three lung metastases arising from colorectal cancer at a single institution. A total dose of 40-60 Gy (median, 48 Gy) in three or four fractions was prescribed. RESULTS: A total of 79 metastatic lung lesions from 50 patients who underwent curative resection for their primary colorectal cancer or salvage treatment at a recurrent site were included. The one- and three-year local control rates were 88.7 % and 70.6 %, respectively. The three-year overall survival and progression-free survival rates were 64.0 % and 24.0 %, respectively. Patients with tumor volume <=1.5 mL had a significantly better overall survival rate than those with tumor volume >1.5 mL (68.0 % vs. 60.0 % at three-year, p = 0.02). Local control was associated with a trend towards better survival (p = 0.06). No pulmonary complications greater than grade 2 were observed. CONCLUSION: Stereotactic ablative radiotherapy is a competitive treatment modality for the management of lung metastases arising from colorectal cancer. PMID- 26588897 TI - Matrix-derived inflammatory mediator N-acetyl proline-glycine-proline is neurotoxic and upregulated in brain after ischemic stroke. AB - BACKGROUND: N-acetyl proline-glycine-proline (ac-PGP) is a matrix-derived chemokine produced through the proteolytic destruction of collagen by matrix metalloproteinases (MMPs). While upregulation and activation of MMPs and concomitant degradation of the extracellular matrix are known to be associated with neurological injury in ischemic stroke, the production of ac-PGP in stroke brain and its effects on neurons have not been investigated. FINDINGS: We examined the effects of ac-PGP on primary cortical neurons and found that it binds neuronal CXCR2 receptors, activates extracellular signal-regulated kinase 1/2 (ERK1/2), and induces apoptosis associated with caspase-3 cleavage in a dose dependent manner. After transient ischemic stroke in rats, ac-PGP was significantly upregulated in infarcted brain tissue. CONCLUSIONS: The production of ac-PGP in brain in ischemia/reperfusion injury and its propensity to induce apoptosis in neurons may link MMP-mediated destruction of the extracellular matrix and opening of the blood-brain barrier to progressive neurodegeneration associated with the initiation and propagation of inflammation. Ac-PGP may be a novel neurotoxic inflammatory mediator involved in sustained inflammation and neurodegeneration in stroke and other neurological disorders associated with activation of MMPs. PMID- 26588899 TI - Dasatinib blocks transcriptional and promigratory responses to transforming growth factor-beta in pancreatic adenocarcinoma cells through inhibition of Smad signalling: implications for in vivo mode of action. AB - BACKGROUND: We have previously shown in pancreatic ductal adenocarcinoma (PDAC) cells that the SRC inhibitors PP2 and PP1 effectively inhibited TGF-beta1 mediated cellular responses by blocking the kinase function of the TGF-beta type I receptor ALK5 rather than SRC. Here, we investigated the ability of the clinically utilised SRC/ABL inhibitor dasatinib to mimic the PP2/PP1 effect. METHODS: The effect of dasatinib on TGF-beta1-dependent Smad2/3 phosphorylation, general transcriptional activity, gene expression, cell motility, and the generation of tumour stem cells was measured in Panc-1 and Colo-357 cells using immunoblotting, reporter gene assays, RT-PCR, impedance-based real-time measurement of cell migration, and colony formation assays, respectively. RESULTS: In both PDAC cell lines, dasatinib effectively blocked TGF-beta1-induced Smad phosphorylation, activity of 3TPlux and pCAGA(12)-luc reporter genes, cell migration, and expression of individual TGF-beta1 target genes associated with epithelial-mesenchymal transition and invasion. Moreover, dasatinib strongly interfered with the TGF-beta1-induced generation of tumour stem cells as demonstrated by gene expression analysis and single cell colony formation. Dasatinib also inhibited the high constitutive migratory activity conferred on Panc-1 cells by ectopic expression of kinase-active ALK5. CONCLUSIONS: Our data suggest that the clinical efficiency of dasatinib may in part be due to cross inhibition of tumour-promoting TGF-beta signalling. Dasatinib may be useful as a dual TGF-beta/SRC inhibitor in experimental and clinical therapeutics to prevent metastatic spread in late-stage PDAC and other tumours. PMID- 26588900 TI - Seasonal variations in onset and exacerbation of inflammatory bowel diseases in children. AB - BACKGROUND: Studies have suggested that inflammatory bowel diseases (IBD) follow a seasonal pattern with regard to their onset and exacerbations. The aim of this study is to determine if there is any seasonal pattern to the onset and exacerbation of IBD in the pediatric population and if the birth of children diagnosed with IBD follows a seasonal pattern. METHODS: Patients between the ages of 1 and 21 years and with a diagnosis of IBD established between July 1992 and July 2012 were included. Their onset and exacerbations of IBD (year and season) were recorded. The birth dates of the patients were aggregated to determine whether a seasonal birth pattern existed amongst them. RESULTS: A total of 170 children were included in this study; 34% of patients had their onset in the fall and 19% of them had their onset in the summer. The total number of documented exacerbations was 358 and the median number of exacerbations was two, with a range of 1-11. IBD exacerbations were generally uniformly distributed throughout the year. We did not observe any specific season where children with IBD tended to be born. CONCLUSIONS: Our data suggests that the onset of symptoms of IBD tends to have a seasonal trend with the highest incidence in the fall. However, we did not observe any association between seasonality and exacerbations in the pediatric population. Moreover, there was no specific season in which children with IBD tended to be born in greater numbers. PMID- 26588901 TI - Normal values for pancreatic stone protein in different age groups. AB - BACKGROUND: Pancreatic stone protein (PSP) has been identified as a promising sepsis marker in adults, children and neonates. However, data on population-based reference values are lacking. This study aimed to establish age-specific reference values for PSP. METHODS: PSP was determined using a specific ELISA. PSP serum concentrations were determined in 372 healthy subjects including 217 neonates, 94 infants and children up to 16 years, and 61 adults. The adjacent categories method was used to determine which age categories had significantly different PSP concentrations. RESULTS: PSP circulating levels were not gender dependent and ranged from 1.0 to 99.4 ng/ml with a median of 9.2 ng/ml. PSP increased significantly between the age categories, from a median of 2.6 ng/ml in very preterm newborns, to 6.3 ng/ml in term newborns, to 16.1 ng/ml in older children (p < 0.001). PSP levels were higher on postnatal day three compared to levels measured immediately post delivery (p < 0.001). Paired umbilical artery and umbilical vein samples were strongly correlated (p < 0.001). Simultaneously obtained capillary heel-prick versus venous samples showed a good level of agreement for PSP (Rho 0.89, bias 19 %). CONCLUSIONS: This study provides age specific normal values that may be used to define cut-offs for future trials on PSP. We demonstrate an age-dependent increase of PSP from birth to childhood. PMID- 26588903 TI - Erratum to: An ecological study of sand flies (Diptera: Psychodidae) in the vicinity of Lencois Maranhenses National Park, Maranhao, Brazil. PMID- 26588898 TI - HIV-1 functional cure: will the dream come true? AB - The reservoir of human immunodeficiency virus type 1 (HIV-1), a long-lived pool of latently infected cells harboring replication-competent viruses, is the major obstacle to curing acquired immune deficiency syndrome (AIDS). Although the combination antiretroviral therapy (cART) can successfully suppress HIV-1 viremia and significantly delay the progression of the disease, it cannot eliminate the viral reservoir and the patient must continue to take anti-viral medicines for life. Currently, the appearance of the 'Berlin patient', the 'Boston patients', and the 'Mississippi baby' have inspired many therapeutic strategies for HIV-1 aimed at curing efforts. However, the specific eradication of viral latency and the recovery and optimization of the HIV-1-specific immune surveillance are major challenges to achieving such a cure. Here, we summarize recent studies addressing the mechanisms underlying the viral latency and define two categories of viral reservoir: 'shallow' and 'deep'. We also present the current strategies and recent advances in the development of a functional cure for HIV-1, focusing on full/partial replacement of the immune system, 'shock and kill', and 'permanent silencing' approaches. PMID- 26588904 TI - Dynamic changes of histone H3 lysine 9 following trimethylation in bovine oocytes and pre-implantation embryos. AB - OBJECTIVES: We have examined dynamic changes of histone H3 lysine 9 following trimethylation (H3K9me3), the mRNA expression levels of SUV39H1 and SUV39H2 in bovine oocytes and the role in the development of in vitro fertilization (IVF) pre-implantation embryos. RESULTS: There were strong H3K9me3 signals in germinal vesicle (GV) oocytes but no signals in MII oocytes. H3K9me3 signals were maintained during IVF pre-implantation embryo development. SUV39H1 and SUV39H2 showed significantly higher mRNA expression levels in GV oocytes than MII oocytes (P < 0.01). SUV39H1 showed high mRNA expression level in two-cell embryos, however, SUV39H2 showed high mRNA expression level in four-cell embryos. In other development stage, SUV39H1 and SUV39H2 showed low expression levels. CONCLUSION: Bovine IVF pre-implantation embryos maintain strong H3K9me3 signals and SUV39H1 and SUV39H2 are highly expressed at the early development stage of pre implantation embryos. PMID- 26588902 TI - Strengthening HIV surveillance in the antiretroviral therapy era: rationale and design of a longitudinal study to monitor HIV prevalence and incidence in the uMgungundlovu District, KwaZulu-Natal, South Africa. AB - BACKGROUND: South Africa has over 6,000,000 HIV infected individuals and the province of KwaZulu-Natal (KZN) is the most severely affected. As public health initiatives to better control the HIV epidemic are implemented, timely, detailed and robust surveillance data are needed to monitor, evaluate and inform the programmatic interventions and policies over time. We describe the rationale and design of the HIV Incidence Provincial Surveillance System (HIPSS) to monitor HIV prevalence and incidence. METHODS/DESIGN: The household-based survey will include a sample of men and women from two sub-districts of the uMgungundlovu municipality (Vulindlela and the Greater Edendale) of KZN, South Africa. The study is designed as two sequential cross-sectional surveys of 10,000 randomly selected individuals aged 15-49 years to be conducted one year apart. From the cross sectional surveys, two sequential cohorts of HIV negative individuals aged 15-35 years will be followed-up one year later to measure the primary outcome of HIV incidence. Secondary outcomes include the laboratory measurements for pulmonary tuberculosis, sexually transmitted infections and evaluating tests for estimating population-level HIV incidence. Antiretroviral therapy (ART) access, HIV-1 RNA viral load, and CD4 cell counts in HIV positive individuals will assess the effectiveness of the HIV treatment cascade. Household and individual-level socio-demographic characteristics, exposure to HIV programmatic interventions and risk behaviours will be assessed as predictors of HIV incidence. The incidence rate ratio of the two cohorts will be calculated to quantify the change in HIV incidence between consecutive samples. In anticipation of better availability of population-level HIV prevention and treatment programmes leading to decreases in HIV incidence, the sample size provides 84% power to detect a reduction of 30% in the HIV incidence rate between surveys. DISCUSSION: The results from HIPSS will provide critical data regarding HIV prevalence and incidence in this community and will establish whether HIV prevention and treatment efforts in a "real world", non-trial setting have an impact on HIV incidence at a population level. Importantly, the study design and methods will inform future methods for HIV surveillance. PMID- 26588906 TI - Implementation of Certified EHR, Patient Portal, and "Direct" Messaging Technology in a Radiology Environment Enhances Communication of Radiology Results to Both Referring Physicians and Patients. AB - Since 2009, the Federal government distributed over $29 billion to providers who were adopting compliant electronic health record (EHR) technology. With a focus on radiology, we explore how EHR technology impacts interoperability with referring clinicians' EHRs and patient engagement. We also discuss the high-level details of contributing supporting frameworks, specifically Direct messaging and health information service provider (HISP) technology. We characterized Direct messaging, a secure e-mail-like protocol built to allow exchange of encrypted health information online, and the new supporting HISP infrastructure. Statistics related to both the testing and active use of this framework were obtained from DirectTrust.org, an organization whose framework supports Direct messaging use by healthcare organizations. To evaluate patient engagement, we obtained usage data from a radiology-centric patient portal between 2014 and 2015, which in some cases included access to radiology reports. Statistics from 2013 to 2015 showed a rise in issued secure Direct addresses from 8724 to 752,496; a rise in the number of participating healthcare organizations from 667 to 39,751; and a rise in the secure messages sent from 122,842 to 27,316,438. Regarding patient engagement, an average of 234,679 patients per month were provided portal access, with 86,400 patients per month given access to radiology reports. Availability of radiology reports online was strongly associated with increased system usage, with a likelihood ratio of 2.63. The use of certified EHR technology and Direct messaging in the practice of radiology allows for the communication of patient information and radiology results with referring clinicians and increases patient use of patient portal technology, supporting bidirectional radiologist-patient communication. PMID- 26588907 TI - Dementia is a major risk factor for hip fractures in patients with chronic kidney disease. AB - Chronic kidney disease increases the risk of hip fractures which can be promoted by dementia. We here showed that dementia increased the risk of hip fractures in dialysis patients, but in a similar manner than without dialysis. Attention should be paid to dementia to prevent hip fractures. INTRODUCTION: Hip fractures (HF) are associated with significant morbidity and is further increased in patients with chronic kidney disease (CKD). Dementia, frequent in CKD, might be a risk factor for HF. We here aimed to assess if dementia increased the risk of hip fracture in CKD. METHODS: The study was derived from the French National Database of Hospitalization. Data were obtained over the period 2011-2013. Three populations of subjects >60 years were extracted. Hip fractures, dialysis, and dementia were the main studied factors. The three populations were crossed to estimate the fracture risk based on dementia or dialysis, adjusted for age and gender. The fracture risk was calculated using a multiple logistic regression model. RESULTS: Over this period, 213,180 patients experienced a HF, 660,434 patients were diagnosed for dementia, and 47,430 patients were on dialysis. There was an effect of age and gender on the incidence of HF and dementia. In CKD patients, the risk of HF was significantly higher in demented patients compared to those without dementia: OR 2.0 [95 % CI 1.7-2.4], this being the same for men (OR 2.4 [1.8-3.1]) and women (OR 2.6 [2.0-3.3]) and at any age. However, the adjusted risk for HF in demented patients on dialysis therapy is not different than in demented patients without CKD (OR 1.3 [1.0-1.6]). CONCLUSIONS: Dementia significantly increases the risk of HF in patients on dialysis, but this risk in demented patients is equally high whether receiving dialysis therapy or not. These results highlight dementia as a major risk factor for HF in dialysis and indicate that reduction of fracture risk should include dementia as a risk factor. PMID- 26588908 TI - No causal effect of serum urate on bone-related outcomes among a population of postmenopausal women and elderly men of Chinese Han ethnicity--a Mendelian randomization study. AB - SUMMARY: We conducted a Mendelian randomization analysis to assess the effect of serum uric acid on bone-related outcomes using a weighted urate transporter genetic risk score as the instrumental variable. The results showed no significance. Our study identified no evidence of a causal role between uric acid and bone-related outcomes. INTRODUCTION: Observational studies have associated elevated levels of serum uric acid (SUA) with increasing bone mineral density (BMD) and a lowered prevalence of osteoporotic fractures (OFs) in postmenopausal women and elderly men. However, due to unmeasured confounding variables, these observational studies have not provided insight into the causal relationship between SUA and bone-related outcomes. Our aim was to evaluate the effect of SUA on bone-related outcomes using Mendelian randomization. METHODS: We recruited 1322 Chinese Han individuals (214 elderly men and 1108 postmenopausal women) from the Shanghai area in China. Mendelian randomization using a two-stage least squares regression method was conducted with SUA as the exposure variable, a weighted urate transporter genetic risk score as the instrumental variable, and all-site BMD, bone turnover markers, and levels of 25-hydroxyvitamin D3 [25(OH)D], serum calcium (Ca), serum phosphorus (P), and parathyroid hormone (PTH) as outcome variables. RESULTS: Strong associations between SUA and bone related outcomes were observed in an ordinary observational analysis (lumbar spine: beta = 0.122, p < 0.0001; hip: beta = 0.104, p < 0.0001; femoral neck: beta = 0.108, p < 0.0001). However, the Mendelian randomization analysis showed no evidence for a causal association of SUA with BMD (lumbar spine: beta = 0.385, p = 0.257; hip: beta = 0.191, p = 0.499; femoral neck: beta = 0.194, p = 0.533). Similar results were found between SUA and other bone-related phenotypes. CONCLUSIONS: Our study identified no evidence of a causal role between SUA and bone-related outcomes, although strong associations in an observational analysis were observed in a population of postmenopausal women and elderly men. PMID- 26588909 TI - Higher levels of s-RANKL and osteoprotegerin in children and adolescents with type 1 diabetes mellitus may indicate increased osteoclast signaling and predisposition to lower bone mass: a multivariate cross-sectional analysis. AB - Simultaneous lower bone mineral density, metabolic bone markers, parathyroid hormone (PTH), magnesium, insulin-like growth factor 1 (IGF1), and higher levels of total soluble receptor activator of nuclear factor-kappa B ligand (s-RANKL), osteoprotegerin (OPG), and alkaline phosphatase (ALP) are indicative of lower osteoblast and increased osteoclast signaling in children and adolescents with type 1 diabetes mellitus, predisposing to adult osteopenia and osteoporosis. INTRODUCTION: Type 1 diabetes mellitus (T1DM) is a risk factor for reduced bone mass, disrupting several bone metabolic pathways. We aimed at identifying association patterns between bone metabolic markers, particularly OPG, s-RANKL, and bone mineral density (BMD) in T1DM children and adolescents, in order to study possible underlying pathophysiologic mechanisms of bone loss. METHODS: We evaluated 40 children and adolescents with T1DM (mean +/- SD age 13.04 +/- 3.53 years, T1DM duration 5.15 +/- 3.33 years) and 40 healthy age- and gender-matched controls (aged12.99 +/- 3.3 years). OPG, s-RANKL, osteocalcin, C-telopeptide cross-links (CTX), IGF1, electrolytes, PTH, and total 25(OH)D were measured, and total body along with lumbar spine BMD were evaluated with dual energy X-ray absorptiometry (DXA). Multivariate regression and factor analysis were performed after classic inference. RESULTS: Patients had significantly lower BMD, with lower bone turnover markers, PTH, magnesium, and IGF1 than controls, indicating lower osteoblast signaling. Higher levels of total s-RANKL, OPG, and total ALP were observed in patients, with log(s-RANKL) and OPG correlation found only in controls, possibly indicating increased osteoclast signaling in patients. Coupling of bone resorption and formation was observed in both groups. Multivariate regression confirmed simultaneous lower bone turnover, IGF1, magnesium, and higher total s-RANKL, OPG, and ALP in patients, while factor analysis indicated possible activation of RANK/RANKL/OPG system in patients and its association with magnesium and IGF1. Patients with longer disease duration or worse metabolic control had lower BMD. CONCLUSIONS: T1DM children and adolescents have impaired bone metabolism which seems to be multifactorial. Reduced osteoblast and increased osteoclast signaling, resulting from multiple simultaneous disturbances, could lead to reduced peak bone accrual in early adulthood, predisposing to adult osteopenia and osteoporosis. PMID- 26588910 TI - Receptor-mediated inhibitory mechanisms and the regulation of platelet function. PMID- 26588911 TI - NK cells play a significant role in immunosurveillance at the early stage of MLL AF9 acute myeloid leukemia via CD226/CD155 interactions. AB - Acute myeloid leukemia (AML) is an aggressive hematological malignancy, and the mechanism underlying immune system involvement in leukemia development is unclear. In the present study, we utilized a myeloid/lymphoid or mixed-lineage leukemia; translocated to, 3 (MLLT3/MLL-AF9)-induced AML mouse model with or without exposure to irradiation. We found that the leukemia cells could survive and expand in hosts with intact immune systems, whereas leukemia progression was accelerated in mice with impaired immune systems. Moreover, the leukemia cells escaped from host immunosurveillance via editing their immunogenicity, including the up-regulation of an inhibitory antigen (i.e., CD47) and the down-regulation of active antigens (i.e., CD86, CD54, retinoic acid early transcript (RAE), histocompatibility 2, D region locus b (H2-Db) and H2-Dd). Natural killer (NK) cells were activated in the early phase of AML progression, whereas T cells were stimulated in the late phase. Furthermore, NK cell depletion showed that NK cells were necessary for the elimination of leukemia cells in our AML mouse model. Notably, CD155/CD226 primarily mediated the interaction between NK cells and leukemia cells and contributed to the antitumor effects of NK cells during the early phase of AML. Clinical data from patients with diverse hematological malignancies showed that CD155 expression was decreased in hematological malignancies. Taken together, our results demonstrate that NK cells play a pivotal role in immunosurveillance against leukemia cells during the early stage of AML primarily through the CD226/CD155 interaction; however, NK cells are not sufficient to eliminate leukemia cells. PMID- 26588912 TI - NK cell-based cancer immunotherapy: from basic biology to clinical application. AB - Natural killer (NK) cells, which recognize and kill target cells independent of antigen specificity and major histocompatibility complex (MHC) matching, play pivotal roles in immune defence against tumors. However, tumor cells often acquire the ability to escape NK cell-mediated immune surveillance. Thus, understanding mechanisms underlying regulation of NK cell phenotype and function within the tumor environment is instrumental for designing new approaches to improve the current cell-based immunotherapy. In this review, we elaborate the main biological features and molecular mechanisms of NK cells that pertain to regulation of NK cell-mediated anti-tumor activity. We further overview current clinical approaches regarding NK cell-based cancer therapy, including cytokine infusion, adoptive transfer of autologous or allogeneic NK cells, applications of chimeric antigen receptor (CAR)-expressing NK cells and adoptive transfer of memory-like NK cells. With these promising clinical outcomes and fuller understanding the basic questions raised in this review, we foresee that NK cell based approaches may hold great potential for future cancer immunotherapy. PMID- 26588913 TI - Novel methods for studying normal and disordered erythropoiesis. AB - Erythropoiesis is a process during which multipotential hematopoietic stem cells proliferate, differentiate and eventually form mature erythrocytes. Interestingly, unlike most cell types, an important feature of erythropoiesis is that following each mitosis the daughter cells are morphologically and functionally different from the parent cell from which they are derived, demonstrating the need to study erythropoiesis in a stage-specific manner. This has been impossible until recently due to lack of methods for isolating erythroid cells at each distinct developmental stage. This review summarizes recent advances in the development of methods for isolating both murine and human erythroid cells and their applications. These methods provide powerful means for studying normal and impaired erythropoiesis associated with hematological disorders. PMID- 26588914 TI - The priming induction regimen of HAG as a low dose chemotherapy strategy in AML clonal evolution. PMID- 26588915 TI - Transplantation of kidneys with tumors. AB - The shortage of donors in the face of the increasing number of patients wait listed for renal transplantation has prompted several strategies including the use of kidneys with a tumor, whether found by chance on harvesting from a deceased donor or intentionally removed from a living donor and transplanted after excision of the lesion. Current evidence suggests that a solitary well differentiated renal cell carcinoma, Fuhrman nuclear grade I-II, less than 1 cm in diameter and resected before grafting may be considered at minimal risk of recurrence in the recipient who, however, should be informed of the possible risk and consent to receive such a graft. PMID- 26588917 TI - Novel techniques for increasing the size of the radial artery during ultrasound guided cannulation. PMID- 26588916 TI - Cadmium overkill: autophagy, apoptosis and necrosis signalling in endothelial cells exposed to cadmium. AB - Apoptosis, necrosis, or autophagy-it is the mode of cell demise that defines the response of surrounding cells and organs. In case of one of the most toxic substances known to date, cadmium (Cd), and despite a large number of studies, the mode of cell death induced is still unclear. As there exists conflicting data as to which cell death mode is induced by Cd both across various cell types and within a single one, we chose to analyse Cd-induced cell death in primary human endothelial cells by investigating all possibilities that a cell faces in undergoing cell death. Our results indicate that Cd-induced death signalling starts with the causation of DNA damage and a cytosolic calcium flux. These two events lead to an apoptosis signalling-related mitochondrial membrane depolarisation and a classical DNA damage response. Simultaneously, autophagy signalling such as ER stress and phagosome formation is initiated. Importantly, we also observed lysosomal membrane permeabilization. It is the integration of all signals that results in DNA degradation and a disruption of the plasma membrane. Our data thus suggest that Cd causes the activation of multiple death signals in parallel. The genotype (for example, p53 positive or negative) as well as other factors may determine the initiation and rate of individual death signals. Differences in the signal mix and speed may explain the differing results recorded as to the Cd-induced mode of cell death thus far. In human endothelial cells it is the sum of most if not all of these signals that determine the mode of Cd-induced cell death: programmed necrosis. PMID- 26588918 TI - Domain-specific versus generalized cognitive screening in acute stroke. AB - Cognitive assessments after stroke are typically short form tests developed for dementia that generates pass/fail classifications (e.g. the MoCA). The Oxford Cognitive Screen (OCS) provides a domain-specific cognitive profile designed for stroke survivors. This study compared the use of the MoCA and the OCS in acute stroke with respect to symptom specificity and aspects of clinical utility. A cross-sectional study with a consecutive sample of 200 stroke patients within 3 weeks of stroke completing MoCA and OCS. Demographic data, lesion side and Barthel scores were recorded. Inclusivity was assessed in terms of completion rates and reasons for non-completion were evaluated. The incidence of cognitive impairments on both the MoCA and OCS sub-domains was calculated and differences in stroke specificity, cognitive profiles and independence of the measures were addressed. The incidence of acute cognitive impairment was high: 76% of patients were impaired on MoCA, and 86% demonstrated at least one impairment on the cognitive domains assessed in the OCS. OCS was more sensitive than MoCA overall (87 vs 78% sensitivity) and OCS alone provided domain-specific information on prevalent post-stroke cognitive impairments (neglect, apraxia and reading/writing ability). Unlike the MOCA, the OCS was not dominated by left hemisphere impairments but gave differentiated profiles across the contrasting domains. The OCS detects important cognitive deficits after stroke not assessed in the MoCA, it is inclusive for patients with aphasia and neglect and it is less confounded by co-occurring difficulties in these domains. PMID- 26588919 TI - Pseudobulbar affect (PBA) in an incident ALS cohort: results from the Apulia registry (SLAP). AB - The aim of this study is to investigate the frequency and the clinical correlations of pseudobulbar affect (PBA) in a population-based incident cohort of ALS patients. Incident ALS cases, diagnosed in 2011 and 2012, according to El Escorial criteria were enrolled from a prospective population-based registry in Apulia, Southern Italy. Neurological status was assessed using a standard neurological examination and the revised ALS Functional Rating Scale (ALSFRSr). The Center for Neurologic Study-Lability Scale (CNS-LS), a self-administered questionnaire, was used to evaluate the presence and severity of PBA. Total scores range from 7 to 35. A score >=13 was used to identify the presence of PBA. One-hundred thirty-two sporadic incident ALS cases were enrolled. Median disease duration was 20 months (range 2-143), median onset-diagnosis interval (ODI) 12 months (range 2-131), median ALSFRSr at baseline 36/48 (range 2-47) and median ALSFRSr bulbar sub-score 10/12 (range 0-12). Neurological examination revealed presence of PBA in 34/132 patients (26%). Pathological CNS-LS score was found in 45/132 patients (34%). Median total CNS-LS score was 9/35 (range 7-29). The subgroup with pathological CNS-LS was characterized by a short disease duration from symptom onset, ODI, time to diffusion to a second region, time to generalization and ALSFRSr bulbar sub-score, bulbar onset, "definite" diagnostic category, bulbar upper motor-neuron involvement and presence of PBA at neurological examination. In population-based setting, one-third of ALS patients present PBA at diagnosis. The presence of PBA is associated with bulbar UMN involvement and markers of a more severe phenotype. PMID- 26588920 TI - Emergence of a novel equine-like G3P[8] inter-genogroup reassortant rotavirus strain associated with gastroenteritis in Australian children. AB - During 2013, a novel equine-like G3P[8] rotavirus emerged as the dominant strain in Australian children with severe rotavirus gastroenteritis. Full genome analysis demonstrated that the strain was an inter-genogroup reassortant, containing an equine-like G3 VP7, a P[8] VP4 and a genogroup 2 backbone I2-R2-C2 M2-A2-N2-T2-E2-H2. The genome constellation of the equine-like G3P[8] was distinct to Australian and global G3P[8] strains. Phylogenetic analysis demonstrated a genetic relationship to multiple gene segments of Japanese strains RVA/JPN/S13-30/2013/G3P[4] and RVA/Human-wt/JPN/HC12016/2012/G1P[8]. The Australian equine-like G3P[8] strain displayed a distinct VP7 antigenic profile when compared with the previously circulating Australian G3P[8] strains. Identification of similar genes in strains from several geographical regions suggested the equine-like G3P[8] strain was derived by multiple reassortment events between globally co-circulating strains from both human and animal sources. This study reinforces the dynamic nature of rotavirus strains and illustrates the potential for novel human/animal reassortant strains to emerge within the human population. PMID- 26588921 TI - Plasma Functionalized Multiwalled Carbon Nanotubes for Immobilization of Candida antarctica Lipase B: Production of Biodiesel from Methanolysis of Rapeseed Oil. AB - Surface modification of multiwalled carbon nanotubes (MWCNTs) through functionalization could improve the characteristics of these nanomaterials as support for enzymes. Carboxylation of MWCNTs (MWCNT-COOH) has been carried out in this study using the dielectric barrier discharge (DBD) plasma reactor through humidified air. The chemical method was also used for further functionalization of the MWCNT-COOH through which the amidation of the surfaces with either butylamine (MWCNT-BA) or octadecylamine (MWCNT-OA) was performed. By immobilization of Candida antarctica B lipase (CALB) on these nanoparticles, performance of the immobilized enzyme in catalyzing methanolysis of rapeseed oil was evaluated. The CALB loading on the MWCNT-BA and MWCNT-COOH was 20 mg protein/g, while the value for MWCNT-OA was 11 mg protein/g. The yield of biodiesel was determined as percentage of mass of fatty acid methyl ester (FAME) produced per initial mass of the oil, and the yield value for the two of these three supports namely, MWCNT-COOH and MWCNT-BA used for the CALB immobilization was similar at about 92 %, while 86 % was the yield for the reaction catalyzed by the lipase immobilized on MWCNT-OA. Thermal stability of the immobilized CALB and the catalytic ability of the enzyme in the repeated batch experiments have also been determined. PMID- 26588922 TI - DNA Methylation and Methylation Polymorphism in Genetically Stable In vitro Regenerates of Jatropha curcas L. Using Methylation-Sensitive AFLP Markers. AB - The present investigation aimed to evaluate the degree and pattern of DNA methylation using methylation-sensitive AFLP (MS-AFLP) markers in genetically stable in vitro regenerates of Jatropha curcas L.. The genetically stable in vitro regenerates were raised through direct organogenesis via enhanced axillary shoot bud proliferation (Protocol-1) and in vitro-derived leaf regeneration (Protocol-2). Ten selective combinations of MS-AFLP primers produced 462 and 477 MS-AFLP bands in Protocol-1 (P-1) and Protocol-2 (P-2) regenerates, respectively. In P-1 regenerates, 15.8-31.17 % DNA was found methylated with an average of 25.24 %. In P-2 regenerates, 15.93-32.7 % DNA was found methylated with an average of 24.11 %. Using MS-AFLP in P-1 and P-2 regenerates, 11.52-25.53 % and 13.33-25.47 % polymorphism in methylated DNA was reported, respectively. Compared to the mother plant, P-1 regenerates showed hyper-methylation while P-2 showed hypo-methylation. The results clearly indicated alternation in degree and pattern of DNA methylation; hence, epigenetic instability in the genetically stable in vitro regenerates of J. curcas, developed so far using two different regeneration systems and explants of two different origins. The homologous nucleotide fragments in genomes of P-1 and P-2 regenerates showing methylation re-patterning might be involved in immediate adaptive responses and developmental processes through differential regulation of transcriptome under in vitro conditions. PMID- 26588923 TI - First Case of Trichoderma longibrachiatum CIED (Cardiac Implantable Electronic Device)-Associated Endocarditis in a Non-immunocompromised Host: Biofilm Removal and Diagnostic Problems in the Light of the Current Literature. AB - BACKGROUND: Trichoderma species are saprophytic filamentous fungi producing localized and invasive infections that are cause of morbidity and mortality, especially in immunocompromised patients, causing up to 53% mortality. Non immunocompromised patients, undergoing continuous ambulatory peritoneal dialysis, are other targets of this fungus. Current molecular diagnostic tools, based on the barcode marker ITS, fail to discriminate these fungi at the species level, further increasing the difficulty associated with these infections and their generally poor prognosis. CASE REPORT: We report on the first case of endocarditis infection caused by Trichoderma longibrachiatum in a 30-year-old man. This patient underwent the implantation of an implantable cardioverter defibrillator in 2006, replaced in 2012. Two years later, the patient developed fever, treated successfully with amoxicillin followed by ciprofloxacin, but an echocardiogram showed large vegetation onto the ventricular lead. After CIED extraction, the patient had high-grade fever. The culturing of the catheter tip was positive only in samples deriving from sonication according to the 2014 ESCMID guidelines, whereas the simple washing failed to remove the biofilm cells from the plastic surface. Subsequent molecular (ITS sequencing) and microbiological (macromorphology) analyses showed that the vegetation was due to T. longibrachiatum. CONCLUSIONS: This report showed that T. longibrachiatum is an effective threat and that sonication is necessary for the culturing of vegetations from plastic surfaces. Limitations of the current barcode marker ITS, and the long procedures required by a multistep approach, call for the development of rapid monophasic tests. PMID- 26588924 TI - Safety and tolerability of ibrutinib monotherapy in Japanese patients with relapsed/refractory B cell malignancies. AB - In this phase I dose-escalation study we evaluated the safety, tolerability, pharmacokinetics, and antitumor activity of ibrutinib, an oral covalent inhibitor of Bruton's tyrosine kinase (BTK, in Japanese patients with relapsed/refractory B cell malignancies (RRBCM). Fifteen patients aged 42-78 years were enrolled to one of three cohorts. Cohort 1 (n = 3) consisted of two phases, a single-dose (140 and 280 mg) phase and a multiple-dose (420 mg) phase of ibrutinib; cohort 2 (n = 6) included multiple doses of ibrutinib 560 mg; and cohort 3 (n = 6) included only patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) dosed at ibrutinib 420 mg. One patient (CLL/SLL cohort) experienced grade 3 pneumonia and sepsis, which were considered dose-limiting toxicities. No deaths were reported. The most common (>= 20% patients) adverse events were neutropenia, anemia, nasopharyngitis, increased bilirubin, and rash. Dose dependent increase in maximum plasma concentration and area under the concentration from 0 to the last quantifiable time was observed, while time to reach maximum plasma concentration and elimination half-life was similar between doses. The overall response rate was 73.3% (11/15) for all cohorts combined. Overall, ibrutinib (420 and 560 mg) was tolerable with acceptable safety profiles and effective for Japanese patients with RRBCM including CLL/SLL. CLINICAL TRIAL REGISTRATION: NCT01704963. PMID- 26588925 TI - Phase 1 study of bortezomib in combination with melphalan and dexamethasone in Japanese patients with relapsed AL amyloidosis. AB - We performed a phase 1 study to evaluate the safety and feasibility of bortezomib (BOR) with melphalan and dexamethasone (BMD) in patients with light chain amyloidosis (AL) without severe cardiac failure. Patients received BOR on a twice weekly schedule (days 1, 4, 8, and 11 of 28-day treatment cycles) at planned doses of 1.0 (dose level 1) and 1.3 (dose level 2) mg/m(2) in combination with melphalan 8 mg/m(2) on days 1-4 and dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12. Dose-limiting toxicity (DLT) was evaluated at the end of cycle one, and treatment was continued for four cycles. Six patients were enrolled at dose level 1, and one showed DLT (grade 3: herpes zoster). Further 3 patients were enrolled at dose level 2, and none experienced DLT. Thus, the maximum tolerated dose was defined as BOR doses of 1.3 mg/m(2) for the twice-weekly schedule. A total of 32 cycles of BMD therapy were given, and the most common hematologic toxicity was thrombocytopenia (47%). Peripheral neuropathy was the most common non-hematologic toxicity (16%). We demonstrated that BMD is safe and tolerable for Japanese AL patients without severe cardiac damage. CLINICAL TRIAL REGISTRATION: UMIN000006604. PMID- 26588926 TI - Clinical efficacy and tolerability of vincristine in splenectomized patients with refractory or relapsed immune thrombocytopenia: a retrospective single-center study. AB - Therapeutic options for immune thrombocytopenia (ITP) patients after splenectomy failure are limited. In the present study, we evaluated the role of vincristine in patients who relapsed after or were refractory to splenectomy for ITP. Sixty two ITP patients treated with vincristine after splenectomy were retrospectively analyzed. Vincristine was administered in doses of 1.5 or 2 mg by 2-h intravenous infusion every 7 days for 4 weeks. Twenty-six (41.9 %) and 36 (58.1 %) patients were in the persistent and chronic phases of ITP, respectively. Most patients (67.7 %) received four doses of vincristine. Two months after starting vincristine, 47 (75.8 %) patients had achieved an overall response, at a median time to response of 9 days after the first dose. There was no difference in the response rate for different ITP phases, vincristine dose received, or response to splenectomy. Thirty-two (68 %) and 24 (51.1 %) of the responders maintained the response for 6 months and 1 year, respectively. Relapse occurred mostly within 6 months, with a median relapse-free survival of 12.5 months; thereafter, a durable response was observed. The administration of vincristine was well tolerated in all patients, with grade 1 peripheral neuropathy being the most common adverse event. Our study suggests that vincristine may be an effective therapeutic option, with acceptable toxicity, for salvage treatment of ITP after splenectomy. PMID- 26588927 TI - Scripts for TRUMP data analyses. Part II (HLA-related data): statistical analyses specific for hematopoietic stem cell transplantation. AB - The Transplant Registry Unified Management Program (TRUMP) made it possible for members of the Japan Society for Hematopoietic Cell Transplantation (JSHCT) to analyze large sets of national registry data on autologous and allogeneic hematopoietic stem cell transplantation. However, as the processes used to collect transplantation information are complex and differed over time, the background of these processes should be understood when using TRUMP data. Previously, information on the HLA locus of patients and donors had been collected using a questionnaire-based free-description method, resulting in some input errors. To correct minor but significant errors and provide accurate HLA matching data, the use of a Stata or EZR/R script offered by the JSHCT is strongly recommended when analyzing HLA data in the TRUMP dataset. The HLA mismatch direction, mismatch counting method, and different impacts of HLA mismatches by stem cell source are other important factors in the analysis of HLA data. Additionally, researchers should understand the statistical analyses specific for hematopoietic stem cell transplantation, such as competing risk, landmark analysis, and time-dependent analysis, to correctly analyze transplant data. The data center of the JSHCT can be contacted if statistical assistance is required. PMID- 26588928 TI - SF3B1 and IGHV gene mutation status predict poor prognosis in Japanese CLL patients. AB - The incidence of chronic lymphocytic leukemia (CLL) is low in Japan. The clinical course ranges from very indolent to rapidly progressive. Recently, several reports have indicated that mutation of the splicing factor 3b, subunit 1 (SF3B1) gene in CLL is predictive of a poor prognosis. Here, we investigated the SF3B1 mutational status of Japanese CLL patients and clarified the association between SF3B1 mutational status and prognostic factors. One hundred and two patients that were referred to our institutions between 1999 and 2013 were enrolled. Mutation analysis of SF3B1 (n = 87) and of the immunoglobulin heavy chain gene (IGHV) (n = 102) was performed at diagnosis. FISH analysis of del(11)(q22) was performed for 17 patients. Seven patients have SF3B1 mutation (8.0 %: K700E, 5/7; G742D, 1/7 and Y623C, 1/7). The median survival times for patients with mutated and non mutated SF3B1 were 53 and 130 months, respectively. Overall survival of the mutated SF3B1 group was significantly lower than that of the non-mutated group (p = 0.0187). No relationship was observed between IGHV mutational status and SF3B1 mutation. There was no patient with SF3B1 mutation in the IGHV1-69 population (0/2). In conclusion, mutation of SF3B1 at diagnosis in Japanese CLL patients is predictive of a poor prognosis. PMID- 26588929 TI - Present and future of anticoagulant therapy using antithrombin and thrombomodulin for sepsis-associated disseminated intravascular coagulation: a perspective from Japan. AB - In sepsis, the coagulation system is often systemically activated in combination with the simultaneous impairment of fibrinolysis and anticoagulant systems. Since this hypercoagulable state often leads to disseminated intravascular coagulation (DIC), an independent predictor of mortality in critically ill patients, the appropriate management of DIC itself is a crucial part of treatment strategies for severe sepsis. In this context, the Japanese Association of Acute Medicine (JAAM) scoring system for DIC has been proposed as a valid test for diagnosing DIC; this system is also expected to aid in devising specifically tailored management strategies. Anticoagulant therapy is commonly given to septic patients with DIC as part of the standard care in Japan. More recently, antithrombin concentrate and recombinant thrombomodulin have become the two major anticoagulant agents of choice. In relation to the use of antithrombin, recent studies have indicated that the recovery of antithrombin activity to within the normal range (>70%) is necessary if supplementation therapy is to provide a favorable outcome. Recombinant thrombomodulin is slightly more controversial, with favorable results being greater among severe cases of DIC. In the present review, we summarize recent clinical advances in anticoagulant therapy for sepsis associated DIC. PMID- 26588931 TI - A non-local model for cancer stem cells and the tumour growth paradox. AB - The tumour growth paradox refers to the observation that incomplete treatment of cancers can enhance their growth. As shown here and elsewhere, the existence of cancer stem cells (CSCs) can explain this effect. CSC are less sensitive to treatments, hence any stress applied to the tumour selects for CSC, thereby increasing the fitness of the tumour. In this paper, we use a mathematical model to understand the role of CSC in the progression of cancer. Our model is a rather general system of integro-differential equations for tumour growth and tumour spread. Such a model has never been analysed, and we prove results on local and global existence of solutions, their uniqueness and their boundedness. We show numerically that this model exhibits the tumour growth paradox for all parameters tested. This effect becomes more relevant for small renewal rate of the CSC. PMID- 26588932 TI - Erratum to: Investigating the effect of gallium curcumin and gallium diacetylcurcumin complexes on the structure, function and oxidative stability of the peroxidase enzyme and their anticancer and antibacterial activities. PMID- 26588930 TI - Protoporphyrin IX: the Good, the Bad, and the Ugly. AB - Protoporphyrin IX (PPIX) is ubiquitously present in all living cells in small amounts as a precursor of heme. PPIX has some biologic functions of its own, and PPIX-based strategies have been used for cancer diagnosis and treatment (the good). PPIX serves as the substrate for ferrochelatase, the final enzyme in heme biosynthesis, and its homeostasis is tightly regulated during heme synthesis. Accumulation of PPIX in human porphyrias can cause skin photosensitivity, biliary stones, hepatobiliary damage, and even liver failure (the bad and the ugly). In this work, we review the mechanisms that are associated with the broad aspects of PPIX. Because PPIX is a hydrophobic molecule, its disposition is by hepatic rather than renal excretion. Large amounts of PPIX are toxic to the liver and can cause cholestatic liver injury. Application of PPIX in cancer diagnosis and treatment is based on its photodynamic effects. PMID- 26588933 TI - Oxidation of 5'-dGMP, 5'-dGDP, and 5'-dGTP by a platinum(IV) complex. AB - We previously reported that a Pt(IV) complex, [Pt(IV)(dach)Cl4] [trans-d,l-1,2 diaminocyclohexanetetrachloroplatinum(IV)] binds to the N7 of 5'-dGMP (deoxyguanosine-5'-monophosphate) at a relatively fast rate and oxidizes it to 8 oxo-5'-dGMP. Here, we further studied the kinetics of the oxidation of 5'-dGMP by the Pt(IV) complex. The electron transfer rate constants between 5'-dGMP and Pt(IV) in [H8-5'-dGMP-Pt(IV)] and [D8-5'-dGMP-Pt(IV)] were similar, giving a small value of the kinetic isotope effect (KIE: 1.2 +/- 0.2). This small KIE indicates that the deprotonation of H8 in [H8-5'-dGMP-Pt(IV)] is not involved in the rate-determining step in the electron transfer between guanine (G) and Pt(IV). We also studied the reaction of 5'-dGDP (deoxyguanosine-5'-diphosphate) and 5'-dGTP (deoxyguanosine-5'-triphosphate) with the Pt(IV) complex. Our results showed that [Pt(IV)(dach)Cl4] oxidized 5'-dGDP and 5'-dGTP to 8-oxo-5'-dGDP and 8 oxo-5'-dGTP, respectively, by the same mechanism and kinetics as for 5'-dGMP. The Pt(IV) complex binds to N7 followed by a two-electron inner sphere electron transfer from G to Pt(IV). The reaction was catalyzed by Pt(II) and occurred faster at higher pH. The electron transfer was initiated by either an intramolecular nucleophilic attack by any of the phosphate groups or an intermolecular nucleophilic attack by free OH(-) in the solution. The rates of reactions for the three nucleotides followed the order: 5'-dGMP > 5'-dGDP > 5' dGTP, indicating that the bulkier the phosphate groups are, the slower the reaction is, due to the larger steric hindrance and rotational barrier of the phosphate groups. PMID- 26588935 TI - Clinical importance cannot be ruled out using mean difference alone. PMID- 26588934 TI - Oxygen stress: impact on innate immune system, antioxidant defence system and expression of HIF-1alpha and ATPase 6 genes in Catla catla. AB - Catla catla catla (2.28 +/- 0.1 g) were exposed to six different levels of dissolved oxygen: 1 (DO-1), 3 (DO-3), 5 (DO-5), 7 (DO-7), 9 (DO-9) and 11 (DO-11) mg/L. DO-5 served as control. In DO-1 and DO-3, the number of red blood cells (RBC), lysozyme, respiratory burst activity and nitric oxide synthase were significantly (p < 0.05) lower compared to the control one. In DO-7 and DO-9, RBC and lysozyme were significantly (p < 0.05) higher compared to the control one. Thiobarbituric acid reactive substances was significantly (p < 0.05) higher in catla exposed at low (1 and 3 mg/L) and high (9 and 11 mg/L) dissolved oxygen compared to others. In muscles and hepatopancreas, reduced glutathione was significantly (p < 0.05) higher in DO-5 and DO-7 and in gills of DO-5 compared to others after 1 h. In muscles, glutathione S-transferase (GST) was significantly (p < 0.05) lower in DO-5 and DO-7 compared to others. In hepatopancreas, GST and glutathione peroxidise (GPx) were significantly (p < 0.05) higher in DO-1 and DO 3 compared to others. In gills, GPx was higher in DO-9 and DO-11 after 48 h. In brain, hypoxia-inducible factor (HIF)-1alpha mRNA level was induced in DO-1 and DO-3 compared to others after 1 h of exposure. In gills and hepatopancreas, HIF 1alpha mRNA level was significantly (p < 0.05) higher in DO-1 compared to others after 1 h. The ATPase 6 mRNA level was significantly (p < 0.05) higher in brain and hepatopancreas of DO-1 after 1 h and in gills and hepatopancreas of DO-3 and DO-9, respectively, after 48 h compared to others. PMID- 26588936 TI - Ease of Retrieval Effects on Relationship Commitment: The Role of Future Plans. AB - How do perceptions of future romantic plans affect close relationships? In three studies, we examined the effects of ease of retrieval of future plans on romantic relationship commitment. We hypothesized that greater ease of retrieval would be associated with greater relationship commitment among those who were high in need for cognition. Study 1 participants listed either two or 10 future plans and completed a measure assessing need for cognition. Results showed that high need for cognition individuals asked to list two instead of 10 future plans reported greater commitment, but those low in need for cognition showed the opposite pattern. Study 2 replicated this effect while controlling for plan substitutability. Study 3 examined the mediational role of commitment doubt. Those high in need for cognition listing more plans had more doubts and reported lower commitment. These findings suggest that perceptions of future plans can influence relationship commitment under specific conditions. PMID- 26588938 TI - China has raised the tax on cigarettes: what's next? AB - The Chinese government raised tobacco tax on 10th May 2015, 10 years after the ratification of the WHO Framework Convention on tobacco control. The increase in the resulting tax rate as a percentage of the retail price from 49% to 56% is still relatively low compared to the WHO-recommended benchmark, which is about 70% of the retail price. Therefore, ample room remains for the Chinese government to further increase the tax on cigarettes. PMID- 26588937 TI - National Trends in Frequency and Amount of Nondaily Smoking, and Relation to Quit Attempts, 2000-2012. AB - INTRODUCTION: To understand changes occurring in nondaily smoking, we assessed differences in demographics and trends in nondaily smoking, by smoking frequency and amount. METHODS: Participants were 13 966 adult nondaily cigarette smokers (NDS) age 18 years and older responding to the 2000-2012 US National Health Interview Survey, an annual, nationally-representative, cross-sectional, household interview survey. We created a nine-level smoking frequency-amount variable using tertile cut points from the number of days smoked in the past 30 (1-7, 8-14, 15-29 days) and number of cigarettes smoked per day (cpd; 1-2, 3-5, >=6). We computed weighted frequencies by low-, moderate-, high-frequency use, by low-, moderate-, high-cpd amount, and by demographics. We estimated temporal trends using weighted least squares regression, and the association between groups and past-year quit attempts using logistic regression. RESULTS: Overall prevalence of nondaily smoking among adults remained stable between 2000 to 2012 (P = .62). The most prevalent nondaily smoking frequency-amount groups were: smoking 15-29 days (in the past 30), 3-5 cpd (20.2%); 1-7 days, 1-2 cpd (19.7%); 15-29 days, 1-2 cpd (14.9%); and 15-29 days, >=6 cpd (12.1%). From 2000 to 2012, low-cpd NDS (1-2 cpd) across moderate (8-14 days) and high (15-29 days) frequency groups increased (P < .01), while moderate frequency-moderate cpd (8-14 days, 3-5 cpd; P < .05) and high frequency-high cpd (15-29 days, >=6 cpd; P < .01) NDS declined. Adjusting for demographics and year, the lowest frequency-amount groups had the lowest odds of past-year quit attempts. CONCLUSION: Changes occurred in NDS frequency and amount from 2000 to 2012, suggesting that more granular classifications may be important for monitoring NDS patterns. IMPLICATIONS: From 2000 to 2012, low-cpd NDS (1-2 cpd) across moderate- (8-14 days) and high frequency (15-29 days) groups increased in the United States, while moderate frequency-moderate cpd (8-14 days, 3-5 cpd) and high frequency-high cpd (15-29 days, >=6 cpd) NDS declined. Demographic differences were found across NDS frequency-amount groups. Adjusting for demographics and year, the lowest frequency-amount groups had the lowest odds of past-year quit attempts. These data can be used to further understand evolving patterns of NDS behavior, and to provide possible targeted groups-both by demographics and smoking frequency/amount-for future research and intervention. PMID- 26588939 TI - What is a good educator? A qualitative study on the perspective of individuals with coronary heart disease. AB - BACKGROUND: Patient views are especially important in patient education, as patient involvement is essential. However, no empirical research clarifies what knowledge, skills and competencies are needed for health professionals to competently serve as a good educator according to the patients themselves. AIM: To explore what qualities patients with coronary heart disease perceive in a good educator. METHODS: A qualitative research method, with semi-structured individual interviews, was used in this study. Purposeful sampling was used to recruit participants from a general hospital in Iceland and in Norway. The data were analysed using systematic text condensation. RESULTS: The participants included 17 patients who had been through a percutaneous coronary intervention and participated in formal patient education after discharge from hospital. The patients saw a good educator as one who they feel is trustworthy and who individualizes the education to patients' needs and context and translates general information to their personal situation in lay language. Building trust was dependent on the patients' perceiving the educator to be knowledgeable and good at connecting with the individual patient, so that the patients feel they are being treated as a whole person with equality and respect. CONCLUSIONS: The patients perceived the capability of building trust and tailoring the education to the individual as the most prominent characteristics of a good educator. Training skills that facilitate patients' trust, being observant of the patient and his learning needs and adjusting the patient education to individual needs and situations should be key objectives in health professionals' training in patient education. PMID- 26588940 TI - The Efficacy of Adapted MBCT on Core Symptoms and Executive Functioning in Adults With ADHD: A Preliminary Randomized Controlled Trial. AB - OBJECTIVE: The aim of this study was to examine the effectiveness of mindfulness as a treatment for adults diagnosed with ADHD. A 12-week-adapted mindfulness based cognitive therapy (MBCT) program is compared with a waiting list (WL) group. METHOD: Adults with ADHD were randomly allocated to MBCT (n = 55) or waitlist (n = 48). Outcome measures included investigator-rated ADHD symptoms (primary), self-reported ADHD symptoms, executive functioning, depressive and anxiety symptoms, patient functioning, and mindfulness skills. RESULTS: MBCT resulted in a significant reduction of ADHD symptoms, both investigator-rated and self-reported, based on per-protocol and intention-to-treat analyses. Significant improvements in executive functioning and mindfulness skills were found. Additional analyses suggested that the efficacy of MBCT in reducing ADHD symptoms and improving executive functioning is partially mediated by an increase in the mindfulness skill "Act With Awareness." No improvements were observed for depressive and anxiety symptoms, and patient functioning. CONCLUSION: This study provides preliminary support for the effectiveness of MBCT for adults with ADHD. PMID- 26588941 TI - Partnership: The Missing Link in the Process of De-Institutionalization of Mental Health Care. AB - This study discusses the main barriers to partnership between family and health services in the context of schizophrenia and de-institutionalization (reduction of the length of hospitalization whenever possible and returning the patient to the community) addressed to deal with the increasing costs and demand for health care services. Thus, in de-institutionalization the burden of care is not resolved but shared with the family, under the assumption that the patient has someone-a family caregiver-who can take up the responsibility of care at home. Despite the high burden of care faced by the family caregiver in mental illness, the necessary systematic partnership between the medical team and the family caregiver is missing. Subjects were 47 family caregivers of persons living with schizophrenia. Data were collected using in-depth interviews, structured questionnaires and attitudinal scales. Data analysis included factor analysis and odds ratios. Two types of barriers to partnership are identified in the literature: health services barriers and barriers attributed to the family. The findings confirm the health services barriers but reject the assumed family barriers. PMID- 26588942 TI - Half-Managed Care: A Preliminary Assessment of a Capitation Program in a Health Care System Without Gatekeepers. AB - In 2011, a novel capitation program was launched in Taiwan under its universal health insurance plan. This study aimed to assess the short-term impact of the program. Two hospitals in the greater Taipei area, one participating in the "loyal patient" model (13,319 enrollees) and one in the "regional resident" model (13,768 enrollees), were analyzed. Two comparison groups were selected by propensity score matching. Generalized estimating equation models with differences-in-differences analysis were used to examine the net effects of the capitation program on health care utilization, expenses, and outcomes. Enrollees in the loyal patient model had fewer physician visits in the host hospital, but more physician visits outside that hospital during the program year than they had the year before. Compared with non-enrollees, the loyal patient model enrollees incurred fewer physician visits (beta = -0.042, p < .001), fewer emergency department visits, (beta = -0.140, p < .001), and similar total expenses and outcome. For the regional resident model, no differences were found in the number of physician visits, expenses, or outcomes between enrollees and non-enrollees. The novel capitation models in Taiwan had minimal impact on health care utilization after 1 year of implementation and the health care outcome was not compromised. PMID- 26588943 TI - "Life's Simple 7" and Long-Term Mortality After Stroke. AB - BACKGROUND: The American Heart Association developed criteria dubbed "Life's Simple 7" defining ideal cardiovascular health: not smoking, regular physical activity, healthy diet, maintaining normal weight, and controlling cholesterol, blood pressure, and blood glucose levels. The impact of achieving these metrics on survival after stroke is unknown. We aimed to determine cardiovascular health scores among stroke survivors in the United States and to assess the link between cardiovascular health score and all-cause mortality after stroke. METHODS AND RESULTS: We assessed cardiovascular health metrics among a nationally representative sample of US adults with stroke (n=420) who participated in the National Health and Nutrition Examination Surveys in 1988-1994 (with mortality assessment through 2006). We determined cumulative all-cause mortality by cardiovascular health score under the Cox proportional hazards model after adjusting for sociodemographic characteristics and comorbidities. No stroke survivors met all 7 ideal health metrics. Over a median duration of 98 months (range, 53-159), there was an inverse dose-dependent relationship between number of ideal lifestyle metrics met and 10-year adjusted mortality: 0 to 1: 57%; 2: 48%; 3: 43%; 4: 36%; and >=5: 30%. Those who met >=4 health metrics had lower all cause mortality than those who met 0 to 1 (hazard ratio, 0.51; 95% confidence interval, 0.28-0.92). After adjusting for sociodemographics, higher health score was associated with lower all-cause mortality (trend P-value, 0.022). CONCLUSIONS: Achieving a greater number of ideal cardiovascular health metrics is associated with lower long-term risk of dying after stroke. Specifically targeting "Life's Simple 7" goals might have a profound impact, extending survival after stroke. PMID- 26588944 TI - Residual Cardiovascular Risk in Individuals on Blood Pressure-Lowering Treatment. AB - BACKGROUND: Hypertensive individuals on blood pressure (BP)-lowering treatment with BP in the normal or high-normal range have higher cardiovascular risk than untreated persons with usual BP in the same range. This residual risk (relative and absolute) is not well quantified and may be attributable in part to the higher burden of subclinical disease in treated individuals. METHODS AND RESULTS: We assigned 3024 Framingham Offspring Cohort participants to 5 categories based on systolic BP (SBP) and diastolic BP (DBP) and use of BP-lowering treatment: (1) untreated SBP/DBP <120/80 mm Hg; (2) untreated SBP/DB >=120/80 to <140/90 mm Hg; (3) treated SBP/DBP <140/90 mm Hg; (4) untreated SBP/DBP >=140/90 mm Hg; and (5) treated SBP/DBP >=140/90 mm Hg. A composite subclinical disease score was constructed, including information on left ventricular hypertrophy, systolic dysfunction, carotid ultrasound abnormality, peripheral artery disease, and microalbuminuria. The prevalence of subclinical disease rose across BP groups, as did the event rates for incident cardiovascular disease (449 events, median follow-up of 11 years; group 1, 0.65 event per 100 person-years; group 5, 3.20 events per 100 person-years; P<0.0001 for trend). On multivariable adjustment, treated hypertensives in groups 3 and 5 had 50% (95% CI 13% to 99%) and 28% (95% CI -6% to 73%) higher hazards, respectively, of developing cardiovascular disease compared with their untreated counterparts with similar levels of BP (groups 1 and 2 and group 4, respectively). The increased risk of cardiovascular disease in treated hypertensives was attributable in part to greater subclinical disease burden. CONCLUSIONS: Treated hypertensives have higher subclinical cardiovascular disease burden, which partly explains their higher cardiovascular disease risk compared with untreated persons with similar BP levels. PMID- 26588945 TI - Social support, psychological vulnerability, and HIV risk among African American men who have sex with men. AB - Previous research has suggested a need to understand the social-psychological factors contributing to HIV risk among African American men who have sex with men (MSM). We conducted individual in-depth interviews with 34 adult African American MSM to examine their personal experiences about: (i) sources of social support, (ii) psychological responses to the presence or absence of social support and (iii) influences of social support on sexual behaviours. The majority of participants described limited positive encouragement and lack of emotional support from family, as well as few meaningful personal relationships. Feelings of isolation and mistrust about personal relationships led many participants to avoid emotional intimacy and seek physical intimacy through sexual encounters. Findings highlight a need for multilevel interventions that enhance social support networks and address the social-psychological, emotional and interpersonal factors that contribute to HIV risk among African American MSM. PMID- 26588947 TI - Combining 2d-Periodic Quantum Chemistry with Molecular Force Fields: A Novel QM/MM Procedure for the Treatment of Solid-State Surfaces and Interfaces. AB - The feasibility of a novel approach for the hybrid quantum mechanical/molecular mechanical (QM/MM) treatment of solid-state surfaces without the requirement of artificially keeping atoms at fixed positions is explored. In order to avoid potential artifacts of the QM/MM transition near the surface, a 2d-periodic QM treatment of the system is employed. Thus, the only QM/MM interface between atoms of the solid is along the non-periodic z-dimension. It is shown for the metal oxide and metal systems MgO(100) and Be(0001) that a properly adjusted embedding potential supplemented by adequate non-Coulombic potentials (if required) enables the application of the QM/MM framework in all-atom structure optimization and molecular dynamics (MD) simulation. The commonly employed constraint to keep at least some of the embedding atoms at fixed position is not required. Two exemplary applications of H2O on MgO(100) and H2 on Be(0001) demonstrate the applicability of the framework in exemplary MD simulation studies. PMID- 26588946 TI - Oral ixazomib maintenance therapy in multiple myeloma. AB - Continuous therapy has proven to be an effective therapeutic strategy to improve the outcome of both young and elderly multiple myeloma patients. Remarkably, lenalidomide and bortezomib showed to play a crucial role in this setting due to their safety profile allowing long-term exposure. Ixazomib, the first oral proteasome inhibitor to be evaluated in multiple myeloma, exerts substantial anti myeloma activity as a single agent and particularly in combination with immunomodulatory drugs and it may be an attractive option for maintenance therapy. Here we address the issue of maintenance therapy as part of a therapeutic approach of multiple myeloma patients focusing on the potential role of ixazomib. PMID- 26588949 TI - Multideterminant Wave Functions in Quantum Monte Carlo. AB - Quantum Monte Carlo (QMC) methods have received considerable attention over past decades due to their great promise for providing a direct solution to the many body Schrodinger equation in electronic systems. Thanks to their low scaling with the number of particles, QMC methods present a compelling competitive alternative for the accurate study of large molecular systems and solid state calculations. In spite of such promise, the method has not permeated the quantum chemistry community broadly, mainly because of the fixed-node error, which can be large and whose control is difficult. In this Perspective, we present a systematic application of large scale multideterminant expansions in QMC and report on its impressive performance with first row dimers and the 55 molecules of the G1 test set. We demonstrate the potential of this strategy for systematically reducing the fixed-node error in the wave function and for achieving chemical accuracy in energy predictions. When compared to traditional quantum chemistry methods like MP2, CCSD(T), and various DFT approximations, the QMC results show a marked improvement over all of them. In fact, only the explicitly correlated CCSD(T) method with a large basis set produces more accurate results. Further developments in trial wave functions and algorithmic improvements appear promising for rendering QMC as the benchmark standard in large electronic systems. PMID- 26588948 TI - Pembrolizumab for the treatment of PD-L1 positive advanced or metastatic non small cell lung cancer. AB - The emergence of immune checkpoint inhibitors marked an important advancement in the development of cancer therapeutics. Pembrolizumab is a selective humanized IgG4 kappa monoclonal antibody that inhibits the programmed death-1 (PD-1) receptor, an integral component of immune checkpoint regulation in the tumor microenvironment. The drug is currently approved by the Food and Drug Administration for the treatment of advanced melanoma and metastatic squamous and nonsquamous non-small cell lung cancer (NSCLC). Several published studies demonstrate that single-agent pembrolizumab is safe and has efficacy in patients with NSCLC. Many ongoing protocols are investigating the role of pembrolizumab in combination with other agents in lung cancer and various other cancer types. We review the available data on pembrolizumab in NSCLC and examine the role of potential predictive biomarkers of response to therapy. PMID- 26588950 TI - Efficient Simulation of Explicitly Solvated Proteins in the Well-Tempered Ensemble. AB - Herein, we report significant reduction in the cost of combined parallel tempering and metadynamics simulations (PTMetaD). The efficiency boost is achieved using the recently proposed well-tempered ensemble (WTE) algorithm. We studied the convergence of PTMetaD-WTE conformational sampling and free energy reconstruction of an explicitly solvated 20-residue tryptophan-cage protein (trp cage). A set of PTMetaD-WTE simulations was compared to a corresponding standard PTMetaD simulation. The properties of PTMetaD-WTE and the convergence of the calculations were compared. The roles of the number of replicas, total simulation time, and adjustable WTE parameter gamma were studied. PMID- 26588951 TI - A New Approach to Noncollinear Spin Density Functional Theory beyond the Local Density Approximation. AB - The application of density functional theory to heavy elements and magnetic materials requires the generalization of existing functionals to the case of noncollinear spins. This letter describes a new idea to achieve such a generalization which, unlike previous efforts in this direction, (i) affords a nonvanishing local magnetic torque, (ii) is invariant with respect to spin rotations, (iii) is free from numerical instabilities in regions of small magnetization, and (iv) reduces to the proper collinear limit. PMID- 26588952 TI - Hybrid QM/MM Molecular Dynamics Study of Benzocaine in a Membrane Environment: How Does a Quantum Mechanical Treatment of Both Anesthetic and Lipids Affect Their Interaction. AB - Biomolecular dynamics studies using a QM/MM approach have been largely used especially to study enzymatic reactions. However, to the best of our knowledge, the very same approach has not been used to study the water/membrane interface using a quantum mechanical treatment for the lipids. Since a plethora of biochemical processes take place in this region, we believe that it is of primary importance to understand, at the level of molecular orbitals, the behavior of a drug in such an odd environment. In this work, we take advantage of an integration of the CPMD and the GROMACS code, using the Car-Parrinello method, to treat the benzocaine local anesthetic as well as two of the membrane lipids and the GROMOS force field to treat the remaining lipids and the water molecules. PMID- 26588953 TI - Application of Drug-Perturbed Essential Dynamics/Molecular Dynamics (ED/MD) to Virtual Screening and Rational Drug Design. AB - We present here the first application of a new algorithm, essential dynamics/molecular dynamics (ED/MD), to the field of small molecule docking. The method uses a previously existing molecular dynamics (MD) ensemble of a protein or protein-drug complex to generate, with a very small computational cost, perturbed ensembles which represent ligand-induced binding site flexibility in a more accurate way than the original trajectory. The use of these perturbed ensembles in a standard docking program leads to superior performance than the same docking procedure using the crystal structure or ensembles obtained from conventional MD simulations as templates. The simplicity and accuracy of the method opens up the possibility of introducing protein flexibility in high throughput docking experiments. PMID- 26588954 TI - Constrained Broyden Dimer Method with Bias Potential for Exploring Potential Energy Surface of Multistep Reaction Process. AB - To predict the chemical activity of new matter is an ultimate goal in chemistry. The identification of reaction pathways using modern quantum mechanics calculations, however, often requires a high demand in computational power and good chemical intuition on the reaction. Here, a new reaction path searching method is developed by combining our recently developed transition state (TS) location method, namely, the constrained Broyden dimer method, with a basin filling method via bias potentials, which allows the system to walk out from the energy traps at a given reaction direction. In the new method, the reaction path searching starts from an initial state without the need for preguessing the TS like or final state structure and can proceed iteratively to the final state by locating all related TSs and intermediates. In each elementary reaction step, a reaction direction, such as a bond breaking, needs to be specified, the information of which is refined and preserved as a normal mode through biased dimer rotation. The method is tested successfully on the Baker reaction system (50 elementary reactions) with good efficiency and stability and is also applied to the potential energy surface exploration of multistep reaction processes in the gas phase and on the surface. The new method can be applied for the computational screening of new catalytic materials with a minimum requirement of chemical intuition. PMID- 26588955 TI - EMMA: A Software Package for Markov Model Building and Analysis. AB - The study of folding and conformational changes of macromolecules by molecular dynamics simulations often requires the generation of large amounts of simulation data that are difficult to analyze. Markov (state) models (MSMs) address this challenge by providing a systematic way to decompose the state space of the molecular system into substates and to estimate a transition matrix containing the transition probabilities between these substates. This transition matrix can be analyzed to reveal the metastable, i.e., long-living, states of the system, its slowest relaxation time scales, and transition pathways and rates, e.g., from unfolded to folded, or from dissociated to bound states. Markov models can also be used to calculate spectroscopic data and thus serve as a way to reconcile experimental and simulation data. To reduce the technical burden of constructing, validating, and analyzing such MSMs, we provide the software framework EMMA that is freely available at https://simtk.org/home/emma . PMID- 26588956 TI - Elucidating the Molecular Origin of Hydrolysis Energy of Pyrophosphate in Water. AB - The molecular origin of the energy produced by the ATP hydrolysis has been one of the long-standing fundamental issues. A classical view is that the negative hydrolysis free energy of ATP originates from intramolecular effects connected with the backbone P-O bond, so called "high-energy bond". On the other hand, it has also been recognized that solvation effects are essential in determining the hydrolysis free energy. Here, using the 3D-RISM-SCF (three-dimensional reference interaction site model self-consistent field) theory that integrates the ab initio quantum chemistry method and the statistical mechanical theory of liquids, we investigate the molecular origin of hydrolysis free energy of pyrophosphate, an ATP analogue, in water. We demonstrate that our theory quantitatively reproduces the experimental results without the use of empirical parameters. We clarify the crucial role of water in converting the hydrolysis free energy in the gas phase determined solely by intramolecular effects, which ranges from endothermic, thermoneutral, to highly exothermic depending on the charged state of pyrophosphate, into moderately exothermic in the aqueous phase irrespective of the charged state as observed in experimental data. We elucidate that this is brought about by different natures of solute-water interactions depending on the charged state of solute species: the hydration free energy of low-charged state is mainly subjected to short-range hydrogen-bonds, while that of high-charged state is dominated by long-range electrostatic interactions. We thus provide unambiguous evidence on the critical role of water in determining the ATP hydrolysis free energy. PMID- 26588957 TI - Metadynamics with Adaptive Gaussians. AB - Metadynamics is an established sampling method aimed at reconstructing the free energy surface relative to a set of appropriately chosen collective variables. In standard metadynamics, the free-energy surface is filled by the addition of Gaussian potentials of preassigned and typically diagonal covariance. Asymptotically the free-energy surface is proportional to the bias deposited. Here, we consider the possibility of using Gaussians whose variance is adjusted on the fly to the local properties of the free-energy surface. We suggest two different prescriptions: one is based on the local diffusivity and the other on the local geometrical properties. We further examine the problem of extracting the free-energy surface when using adaptive Gaussians. We show that the standard relation between the bias and the free energy does not hold. In the limit of narrow Gaussians an explicit correction can be evaluated. In the general case, we propose to use instead a relation between bias and free energy borrowed from umbrella sampling. This relation holds for all kinds of incrementally deposited bias. We illustrate on the case of alanine dipeptide the advantage of using adaptive Gaussians in conjunction with the new free-energy estimator both in terms of accuracy and speed of convergence. PMID- 26588958 TI - How Important is Orbital Choice in Single-Determinant Diffusion Quantum Monte Carlo Calculations? AB - The accuracy of total electronic energies obtained using the fixed-node diffusion quantum Monte Carlo (FN-DMC) method is determined by the choice of the many-body nodal surface. Here, we perform a systematic comparison of the quality of FN-DMC energies for a selection of atoms and diatomic molecules using nodal surfaces defined by single determinants of Hartree-Fock, B3LYP, and LDA orbitals. Through comparison with experimental results, we show that the use of Kohn-Sham orbitals results in significantly improved FN-DMC atomization energies over those obtained using Hartree-Fock orbitals. We also discuss the effect of spin contamination in the orbitals. PMID- 26588959 TI - Convergence of Electronic Structure with the Size of the QM Region: Example of QM/MM NMR Shieldings. AB - The influence of the chemical environment on NMR shifts of a central molecular region is studied for several biomolecular and supramolecular systems. To investigate the long-range effects, we systematically increase the QM region until the changes of the NMR shielding tensor are negligible for the considered nuclei; that is, convergence with the selected QM size is reached. To reach size convergence, QM regions with up to about 1500 atoms and 15 000 basis functions are treated by our density matrix-based linear-scaling coupled perturbed self consistent field methods. The results also provide insights into the locality and convergence of the electronic structure. Furthermore, we demonstrate to what extent the inclusion of the chemical environment as partial point charges within a hybrid QM/MM approach improves the convergence behavior. In addition, some benchmark data on NMR accuracies are provided using various ab initio methods. PMID- 26588960 TI - Semiempirical Quantum Chemical Calculations Accelerated on a Hybrid Multicore CPU GPU Computing Platform. AB - In this work, we demonstrate that semiempirical quantum chemical calculations can be accelerated significantly by leveraging the graphics processing unit (GPU) as a coprocessor on a hybrid multicore CPU-GPU computing platform. Semiempirical calculations using the MNDO, AM1, PM3, OM1, OM2, and OM3 model Hamiltonians were systematically profiled for three types of test systems (fullerenes, water clusters, and solvated crambin) to identify the most time-consuming sections of the code. The corresponding routines were ported to the GPU and optimized employing both existing library functions and a GPU kernel that carries out a sequence of noniterative Jacobi transformations during pseudodiagonalization. The overall computation times for single-point energy calculations and geometry optimizations of large molecules were reduced by one order of magnitude for all methods, as compared to runs on a single CPU core. PMID- 26588961 TI - Accuracy of Several Wave Function and Density Functional Theory Methods for Description of Noncovalent Interaction of Saturated and Unsaturated Hydrocarbon Dimers. AB - The proper description of noncovalent complexes is a notoriously difficult problem, especially for complexes dominated by the dispersion energy. Accurate and reliable results can be obtained using computationally demanding methods such as the coupled clusters with iterative treatment of single and double excitations and perturbative triples correction (CCSD(T)), close to the complete basis set (CBS) limit. The sizes of the noncovalent complexes of interest, however, often exceed the computational capability of available computer facilities and software. Computationally efficient yet accurate and reliable theoretical methods are highly desired. In this work, we assembled a small test set of noncovalent complexes of un/saturated a/cyclic hydrocarbon (HC) dimers in order to inspect the accuracy and reliability of several routinely used low-order scaling wave function (WFT) and density functional theory (DFT) methods. The test set comprises dispersion dominated complexes of two different monomer types, saturated and unsaturated. The unsaturated systems are relatively well populated in one of the most popular training data sets for noncovalent complexes, the S22 set of Jurecka et al. The opposite is true for saturated systems, for which rather poor performance of "approximate" methods has been observed. From the results shown is this work, it is clear that unsaturated, e.g., pi...pi stacked, covalent complexes are described more accurately on average. With the exception of a few "balanced methods", such as MP2C, MP2.5, SCS-/SCS(MI)-CCSD, or DFT-D3 with the TPSS and PBE functionals, a simultaneous description of saturated and unsaturated HCs introduces serious errors (i.e., more than 1 kcal/mol). PMID- 26588962 TI - Modulating the Strength of Hydrogen Bonds through Beryllium Bonds. AB - The mutual influence between beryllium bonds and inter- or intramolecular hydrogen bonds (HBs) has been investigated at the B3LYP/6-311++G(3df,2p) level of theory, using the complexes between imidazole dimer and malonaldehyde with BeH2 and BeF2 as suitable model systems. Imidazole and its dimer form very strong beryllium bonds with both BeH2 and BeF2, accompanied by a significant geometry distortion of the Lewis acid. More importantly, we have found a clear cooperativity between these two noncovalent interactions, since the intermolecular HB between the two imidazole molecules in the dimer-BeX2 complex becomes much stronger than in the isolated dimer, whereas the beryllium bond becomes also stronger in the dimer-BeX2 complex, with respect to that found in the imidazole-BeX2 complex. The effects of beryllium bonds are also dramatic on the strength of intramolecular HBs. Depending on to which center the BeX2 is attached, the intramolecular HB becomes much stronger or much weaker. The first situation is found when the beryllium derivative is attached to the HB donor, whereas the second occurs if it is attached to the HB acceptor. The first effect can be so strong as to produce a spontaneous proton transfer, as it is actually the case of the malonaldehyde-BeF2 complex. PMID- 26588963 TI - van der Waals Interaction Energies of Small Fragments of P, As, Sb, S, Se, and Te: Comparison of Complete Basis Set Limit CCSD(T) and DFT with Approximate Dispersion. AB - Interaction energies of small model van der Waals fragments of group VA (P, As, Sb) and group VIA (S, Se, Te) are calculated using the complete basis set CCSD(T) method and compared to density functional results with approximate treatment of dispersion interaction using vdW-DF- and DFT-D-types of theories. These simple systems show surprising diversity of electronic properties ranging from more "metallic" to more "insulator" like, a property which needs to be captured in the approximate methods. While none of the standard approximate DFT theories provides an entirely satisfactory description of all the systems, we identify the most reliable approaches of each type. In addition, we show that results can be further tuned to chemical accuracy. In vdW-DF theory, guided by physical insights and the availability of quasi-exact CCSD(T) results, we supply the missing parts of correlation by matching an appropriate hybrid/semilocal exchange-correlation functional to describe short-/medium-range correlations accurately. In the DFT-D type of theories, we reparametrize the empirical dispersion term. Since for such an accurate treatment benchmark calculations are needed, which typically is feasible only for a finite cluster, we argue that the cluster based model of the exchange-correlation hole is transferrable also to extended systems with vdW dispersion interactions. PMID- 26588964 TI - Exchange-Correlation Functional with Good Accuracy for Both Structural and Energetic Properties while Depending Only on the Density and Its Gradient. AB - The generalized gradient approximation (GGA) has been a workhorse exchange correlation functional for electronic structure studies of extended systems (liquid-phase reactions, solids, heterogeneous and enzymatic catalysis, biopolymers) because its dependence on only the spin-labeled electron densities and their reduced gradients makes it the most affordable choice that produces realistic results for thermochemistry. However, much recent research has focused on its poor performance for solid-state lattice constants; the results for lattice constants can be improved but only at the cost of making the energetic predictions worse. In the present article, we propose a new density functional, called N12, which may be thought of as a generalization of range-separated functionals. The N12 functional depends only on the spin-labeled electron densities and their reduced gradients, but with a new kind of nonseparable term that gives it much greater flexibility. The N12 functional is the first exchange correlation functional depending only on the spin-labeled electron densities and their reduced gradients that simultaneously provides good accuracy for the four key energetic and structural properties of solids and molecules, namely, solid state cohesive energies and lattice constants and molecular atomization energies and bond lengths. PMID- 26588965 TI - Influence of Hydrogen Bonds on the P...P Pnicogen Bond. AB - Ab initio MP2/aug'-cc-pVTZ calculations have been carried out to investigate the influence of F-H...F hydrogen bonds on the P...P pnicogen bond in complexes nFH:(PH2F)2 for n = 1-3. The formation of F-H...F hydrogen bonds leads to a shortening of the P-P distance, a lengthening of the P-F distance involved in the hydrogen bond, a strengthening of the P...P interaction, and changes in atomic populations, NMR (31)P chemical shieldings, and (1p)J(P-P) coupling constants. The magnitude of these changes depends on the number of FH molecules and their positions in the complex and are relatively modest except for complexes 2FH:(PH2F)2 and 3FH:(PH2F)2 that have all FH molecules hydrogen bonded to the same F-atom. For these two complexes, (1p)J(P-P) decreases as the P-P distance decreases and approaches the value of (1)J(P-P) for P2H4. The dramatic changes in these two complexes reflect the changing nature of the hydrogen bonds and the pnicogen bond. Thus, the complex 3FH:(PH2F)2 acquires ion-pair character represented as [3(FH)F(-):(H2P-PH2F)(+)], and the P...P pnicogen bond acquires significant covalent character. These changes are observed to a lesser extent in 2FH:(PH2F)2. PMID- 26588966 TI - Efficient Monte Carlo Simulations of Gas Molecules Inside Porous Materials. AB - Monte Carlo (MC) simulations are commonly used to obtain adsorption properties of gas molecules inside porous materials. In this work, we discuss various optimization strategies that lead to faster MC simulations with CO2 gas molecules inside host zeolite structures used as a test system. The reciprocal space contribution of the gas-gas Ewald summation and both the direct and the reciprocal gas-host potential energy interactions are stored inside energy grids to reduce the wall time in the MC simulations. Additional speedup can be obtained by selectively calling the routine that computes the gas-gas Ewald summation, which does not impact the accuracy of the zeolite's adsorption characteristics. We utilize two-level density-biased sampling technique in the grand canonical Monte Carlo (GCMC) algorithm to restrict CO2 insertion moves into low-energy regions within the zeolite materials to accelerate convergence. Finally, we make use of the graphics processing units (GPUs) hardware to conduct multiple MC simulations in parallel via judiciously mapping the GPU threads to available workload. As a result, we can obtain a CO2 adsorption isotherm curve with 14 pressure values (up to 10 atm) for a zeolite structure within a minute of total compute wall time. PMID- 26588967 TI - How Do Heavier Halide Ligands Affect the Signs and Magnitudes of the Zero-Field Splittings in Halogenonickel(II) Scorpionate Complexes? A Theoretical Investigation Coupled to Ligand-Field Analysis. AB - This work presents a detailed analysis of the physical origin of the zero-field splittings (ZFSs) in a series of high-spin (S = 1) nickel(II) scorpionate complexes Tp*NiX (Tp* = hydrotris(3,5-dimethylpyrazole)borate, X = Cl, Br, I) using quantum chemical approaches. High-frequency and -field electron paramagnetic resonance studies have shown that the complexes with heavier halide ligands (Br, I) have greater magnitudes but opposite signs of the ZFSs compared with the chloro congener (Desrochers, P. J.; Telser, J.; Zvyagin, S. A.; Ozarowski, A.; Krzystek, J.; Vicic, D. A. Inorg. Chem.2006, 45, 8930-8941). To rationalize the experimental findings, quantum chemical calculations of the ZFSs in this Ni(II) halide series have been conducted. The computed ZFS using wave function-based ab initio methods (state-averaged CASSCF, NEVPT2, and SORCI) are in good agreement with the experiment. For comparison, density functional theory was only marginally successful. The ligand-field analysis demonstrates that the signs and magnitudes of the ZFSs are subtly determined by the trade-off between the negative contributions from the (1,3)A1(1e->2e) transitions relative to the positive contributions from the remaining d-d excited states. The term from (1,3)A1(1e->2e) stems from the structural feature that the metal center displaces out of the equatorial plane, and gains the importance when heavier halide ligand is involved. PMID- 26588968 TI - Cooperating Dinitrogen and Phenyl Rotations in trans-Azobenzene Photoisomerization. AB - Semiempirical OM2/MRCI surface-hopping simulations have been performed to study the trans-to-cis photoisomerization of azobenzene upon excitation to the S1 state. The decay dynamics to the ground state shows an oscillatory pattern that can be attributed to an out-of-plane rotation of the N2 moiety. The reaction is thus initially driven by N2 rotation which triggers phenyl rotations around the C N bonds. The cis isomer is produced most effectively when the phenyl rings rotate in phase. Mode-specific excitations cause variations in the computed decay times and product yields. PMID- 26588969 TI - TD-DFT Assessment of Functionals for Optical 0-0 Transitions in Solvated Dyes. AB - Using TD-DFT, we performed simulations of the adiabatic energies of 40 fluorescent molecules for which the experimental 0-0 energies in condensed phase are available. We used six hybrid functionals (B3LYP, PBE0, M06, M06-2X, CAM B3LYP, and LC-PBE) that have been shown to provide accurate transition energies in previous TD-DFT assessments, selected two diffuse-containing basis sets, and applied the most recent models for estimating bulk solvation effects. In each case, the correction arising from the difference of zero-point vibrational energies between the ground and the excited states has been consistently determined. Basis set effects have also been carefully studied. It turned out that PBE0 and M06 are the most effective functionals in terms of average deviation (mean absolute error of 0.22-0.23 eV). However, both the M06-2X global hybrid that contains more exact exchange and the CAM-B3LYP range-separated hybrid significantly improve the consistency of the prediction for a relatively negligible degradation of the average error. In addition, we assessed (1) the cross-structure/spectra relationships, (2) the importance of solvent effects, and (3) the differences between adiabatic and vertical energies. PMID- 26588970 TI - New Soft-Core Potential Function for Molecular Dynamics Based Alchemical Free Energy Calculations. AB - The fields of rational drug design and protein engineering benefit from accurate free energy calculations based on molecular dynamics simulations. A thermodynamic integration scheme is often used to calculate changes in the free energy of a system by integrating the change of the system's Hamiltonian with respect to a coupling parameter. These methods exploit nonphysical pathways over thermodynamic cycles involving particle introduction and annihilation. Such alchemical transitions require the modification of the classical nonbonded potential energy terms by applying soft-core potential functions to avoid singularity points. In this work, we propose a novel formulation for a soft-core potential to be applied in nonequilibrium free energy calculations that alleviates singularities, numerical instabilities, and additional minima in the potential energy for all combinations of nonbonded interactions at all intermediate alchemical states. The method was validated by application to (a) the free energy calculations of a closed thermodynamic cycle, (b) the mutation influence on protein thermostability, (c) calculations of small ligand solvation free energies, and (d) the estimation of binding free energies of trypsin inhibitors. The results show that the novel soft-core function provides a robust and accurate general purpose solution to alchemical free energy calculations. PMID- 26588971 TI - Ice Ih-Water Interfacial Free Energy of Simple Water Models with Full Electrostatic Interactions. AB - We employ the cleaving approach to calculate directly the ice Ih-water interfacial free energy for the simple models of water, TIP4P, TIP4P-Ew, and TIP5P-E, with full electrostatic interactions evaluated via the Ewald sums. The results are in good agreement with experimental values, but lower than previously obtained for TIP4P-Ew and TIP5P-E by indirect methods. We calculate the interfacial free energies for basal, prism, and {1120} interfaces and find that the anisotropy of the TIP5P-E model is different from that of the TIP4P models. The effect of including full electrostatic interactions is determined to be smaller than 10% compared to the water models with damped Coulomb interactions, which indicates that the value of the ice-water interfacial free energy is determined predominantly by the short-range packing interaction between water molecules. We also observe a strong linear correlation between the interfacial free energy and the melting temperature of different water models. PMID- 26588972 TI - Efficient Computation of the Total Solvation Energy of Small Molecules via the R6 Generalized Born Model. AB - Efficient and accurate methodologies to compute solvation free energies of small molecules are relevant for many biological and industrial research areas including rational drug design. In this work we test the performance of a recently developed generalized Born method, GB_NSR6 (Aguilar et al. J. Chem. Theory Comput. 2010, 6, 3613-3639) on a common benchmark set of 504 small molecules. The computed solvation energies are compared with those obtained previously by explicit solvent models and experiment. The dominant polar component of the solvation energy is computed by GB_NSR6 with no adjustable parameters, producing a root mean square deviation (RMSD) of 0.89 kcal/mol with respect to explicit solvent (TIP3P). The relatively small nonpolar contribution is estimated using the Gallicchio et al. (J. Comput. Chem. 2005, 25, 479-499) approach. Our results show that GB_NSR6 offers a reasonable balance between efficiency and accuracy: the RMSD from the experiment of computed solvation energies is 1.2 kcal/mol, which is essentially the same as the accuracy of the much more computationally expensive explicit solvent treatment. The average computational time needed to compute the total solvation energy per molecule via GB_NSR6 is only tens of milliseconds on a commodity PC for a typical molecule of about 20 atoms. All of the software developed in this work is freely available from http://people.cs.vt.edu/onufriev/software.php . PMID- 26588973 TI - Performance of the SCC-DFTB Model for Description of Five-Membered Ring Carbohydrate Conformations: Comparison to Force Fields, High-Level Electronic Structure Methods, and Experiment. AB - The solution conformations of biologically important mono- and di-alpha-d arabinofuranosides were investigated using the dispersion-corrected self consistent charge density functional tight binding (SCC-DFTB) and the AMBER/GLYCAM models. Simulations were performed using both long dynamics and umbrella sampling simulations. Angular distributions about the exocyclic C-C bonds and puckering distributions of the rings obtained from the SCC-DFTB model were quite different from those obtained with the AMBER/GLYCAM approach. The joint probability distribution of rotamer and ring puckering parameters reveals further discrepancies, while both methods predict weak correlation between exocyclic torsions and ring puckering. To assess the reliability of the simulations, ensemble-averaged vicinal proton-proton coupling constants ((3)JH,H) were calculated and compared directly to experimental NMR coupling constants. It is found that the (3)JH,H values obtained from the AMBER/GLYCAM simulations agree with experiment, while those obtained from the SCC-DFTB method, in most cases, differ from experimental (3)JH,H values. Potential energy surfaces (PES) along the exocyclic torsion obtained from ab initio and DFT calculations differ significantly from those obtained with the SCC-DFTB method. This study establishes that a high-quality all-atom force field would be more suitable than one of the superior semiempirical methods, SCC-DFTB, for investigation of rotamer populations and ring puckering in floppy ring systems such as furanosides. PMID- 26588974 TI - Can We Accurately Describe the Structure of Adenine Tracts in B-DNA? Reference Quantum-Chemical Computations Reveal Overstabilization of Stacking by Molecular Mechanics. AB - Sequence-dependent local variations of helical parameters, structure, and flexibility are crucial for molecular recognition processes involving B-DNA. A tracts, i.e., stretches of several consecutive adenines in one strand that are in phase with the DNA helical repeat, mediate significant DNA bending. During the past few decades, there have been intense efforts to understand the sequence dependence of helical parameters in DNA. Molecular dynamics (MD) simulations can provide valuable insights into the molecular mechanism behind the relationship between sequence and structure. However, although recent improvements in empirical force fields have helped to capture many sequence-dependent B-DNA properties, several problems remain, such as underestimation of the helical twist and suspected underestimation of the propeller twist in A-tracts. Here, we employ reference quantum mechanical (QM) calculations, explicit solvent MD, and bioinformatics to analyze the underestimation of propeller twisting of A-tracts in simulations. Although we did not identify a straightforward explanation, we discovered two imbalances in the empirical force fields. The first was overestimation of stacking interactions accompanied by underestimation of base pairing energy, which we attribute to anisotropic polarizabilities that are not reflected by the isotropic force fields. This may lead to overstacking with potentially important consequences for MD simulations of nucleic acids. The second observed imbalance was steric clash between A(N1) and T(N3) nitrogens of AT base pairs in force-field descriptions, resulting in overestimation of the AT pair stretch in MD simulations. We also substantially extend the available set of benchmark estimated CCSD(T)/CBS data for B-DNA base stacking and provide a code that allows the generation of diverse base-stacking geometries suitable for QM computations with predefined intra- and interbase pair parameters. PMID- 26588975 TI - Scalable Anisotropic Shape and Electrostatic Models for Biological Bromine Halogen Bonds. AB - Halogens are important substituents of many drugs and secondary metabolites, but the structural and thermodynamic properties of their interactions are not properly treated by current molecular modeling and docking methods that assign simple isotropic point charges to atoms. Halogen bonds, for example, are becoming widely recognized as important for conferring specificity in protein-ligand complexes but, to this point, are most accurately described quantum mechanically. Thus, there is a need to develop methods to both accurately and efficiently model the energies and geometries of halogen interactions in biomolecular complexes. We present here a set of potential energy functions that, based on fundamental physical properties of halogens, properly model the anisotropic structure-energy relationships observed for halogen interactions from crystallographic and calorimetric data, and from ab initio calculations for bromine halogen bonds in a biological context. These energy functions indicate that electrostatics alone cannot account for the very short-range distances of bromine halogen bonds but require a flattening of the effective van der Waals radius that can be modeled through an angular dependence of the steric repulsion term of the standard Lennard-Jones type potential. This same function that describes the aspherical shape of the bromine is subsequently applied to model the charge distribution across the surface of the halogen, resulting in a force field that uniquely treats both the shape and electrostatic charge parameters of halogens anisotropically. Finally, the electrostatic potential was shown to have a distance dependence that is consistent with a charge-dipole rather than a simple Coulombic type interaction. The resulting force field for biological halogen bonds (ffBXB) is shown to accurately model the geometry-energy relationships of bromine interactions to both anionic and neutral oxygen acceptors and is shown to be tunable by simply scaling the electrostatic component to account for effects of varying electron-withdrawing substituents (as reflected in their Hammett constants) on the degree of polarization of the bromine. This approach has broad applications to modeling the structure-energy relationships of halogen interactions, including the rational design of inhibitors against therapeutic targets. PMID- 26588976 TI - Screening for the Location of RNA using the Chloride Ion Distribution in Simulations of Virus Capsids. AB - The complete structure of the genomic material inside a virus capsid remains elusive, although a limited amount of symmetric nucleic acid can be resolved in the crystal structure of 17 icosahedral viruses. The negatively charged sugar phosphate backbone of RNA and DNA as well as the large positive charge of the interior surface of the virus capsids suggest that electrostatic complementarity is an important factor in the packaging of the genomes in these viruses. To test how much packing information is encoded by the electrostatic and steric envelope of the capsid interior, we performed extensive all-atom molecular dynamics (MD) simulations of virus capsids with explicit water molecules and solvent ions. The model systems were two small plant viruses in which significant amounts of RNA has been observed by X-ray crystallography: satellite tobacco mosaic virus (STMV, 62% RNA visible) and satellite tobacco necrosis virus (STNV, 34% RNA visible). Simulations of half-capsids of these viruses with no RNA present revealed that the binding sites of RNA correlated well with regions populated by chloride ions, suggesting that it is possible to screen for the binding sites of nucleic acids by determining the equilibrium distribution of negative ions. By including the crystallographically resolved RNA in addition to ions, we predicted the localization of the unresolved RNA in the viruses. Both viruses showed a hot-spot for RNA binding at the 5-fold symmetry axis. The MD simulations were compared to predictions of the chloride density based on nonlinear Poisson-Boltzmann equation (PBE) calculations with mobile ions. Although the predictions are superficially similar, the PBE calculations overestimate the ion concentration close to the capsid surface and underestimate it far away, mainly because protein dynamics is not taken into account. Density maps from chloride screening can be used to aid in building atomic models of packaged virus genomes. Knowledge of the principles of genome packaging might be exploited for both antiviral therapy and technological applications. PMID- 26588977 TI - Collective Reaction Coordinate for Hybrid Quantum and Molecular Mechanics Simulations: A Case Study of the Hydride Transfer in Dihydrofolate Reductase. AB - The optimal description of the reaction coordinate in chemical systems is of great importance in simulating condensed phase reactions. In the current work, we present a collective reaction coordinate which is composed of several geometric coordinates which represent structural progress during the course of a hydride transfer reaction: the antisymmetric reactive stretch coordinate, the donor acceptor distance (DAD) coordinate, and an orbital rehybridization coordinate. In this approach, the former coordinate serves as a distinguished reaction coordinate, while the latter two serve as environmental, Marcus-type inner-sphere reorganization coordinates. The classical free energy surface is obtained from multidimensional quantum mechanics-molecular mechanics (QM/MM) potential of mean force (PMF) simulations in conjunction with a general and efficient multidimensional weighted histogram method implementation. The minimum free energy path, or the collective reaction coordinate, connecting the dividing hypersurface to reactants and products, is obtained using an iterative scheme. In this approach, the string method is used to find the minimum free energy path. This path guides the multidimensional sampling, while the path is adaptively refined until convergence is achieved. As a model system, we choose the hydride transfer reaction in Escherichia coli dihydrofolate reductase (ecDHFR) using a recently developed accurate semiempirical potential energy surface. To estimate the advantages of the collective reaction coordinate, we perform activated dynamics simulations to obtain the reaction transmission coefficient. The results show that the combination of a distinguished reaction coordinate and an inner sphere reorganization coordinate considerably reduces the dividing surface recrossing. PMID- 26588978 TI - Dynamic and Thermodynamic Signatures of Native and Non-Native Protein States with Application to the Improvement of Protein Structures. AB - Accurate knowledge of the 3D structural ensemble of proteins is important for understanding of their biological function. We report here the application of microsecond all-atom molecular dynamics (MD) simulations in explicit solvent for the improvement of the quality of low-resolution structures obtained by protein structure prediction (decoys). Seventy MD simulations of ~1 MUs average duration were performed on 13 different protein systems starting from X-ray crystal structures and decoys. Their behavior can be divided into three groups: 22 trajectories converged toward the native state, 27 trajectories displayed a quasi equilibrium by populating mainly a single non-native free energy basin, and 21 trajectories drifted away from their initial decoy structure transiently visiting multiple free energy minima. To determine whether the native structure can be identified among non-native ensembles, the free energy was determined for each basin by the MM/GBSA method together with the von Mises entropy estimator in dihedral angle space. For the proteins studied here, it is found that the ensembles belonging to free energy basins with the lowest free energies and the longest residence times are most native-like. The results demonstrate that explicit solvent microsecond MD simulations using the latest generation of protein force fields and free energy metrics are sufficiently accurate to permit positive identification of native state ensembles against low-resolution structural models and decoys. The approach can be applied to the direct refinement of predicted or experimental low-resolution protein structures. PMID- 26588979 TI - Serial Generalized Ensemble Simulations of Biomolecules with Self-Consistent Determination of Weights. PMID- 26588980 TI - Sustained favourable haemodynamics 1 year after TAVI: improvement in NYHA functional class related to improvement of left ventricular diastolic function. AB - AIMS: Despite expected improvement in left ventricular (LV) systolic and diastolic function after transcatheter aortic valve implantation (TAVI), the complex relationship between pre-existent LV systolic and diastolic function and changes in LV haemodynamics and clinical symptoms have been scarcely investigated. This study investigated the presence of pre-operative LV diastolic dysfunction and its improvement over time after TAVI alongside improvement in New York Heart Association (NYHA) class in high-risk patients with severe aortic stenosis. METHODS AND RESULTS: The study population (n = 358) was divided into two groups according to baseline LV ejection fraction (LVEF): LVEF < 50% (n = 96) and LVEF >= 50% (n = 262). We compared clinical and echocardiographic parameters between groups before TAVI, at 6 and 12 months follow-up. Grade III LV diastolic dysfunction was more frequent in patients with LVEF < 50% compared with patients with LVEF >= 50% (50.0 vs. 16.3%, P < 0.001). Systolic and diastolic echocardiographic parameters improved after TAVI together with improvement in NYHA class both in patients with LVEF < 50% (diastolic dysfunction grade >=2: baseline 100% of patients; 12 months 58.8%, P < 0.001; NYHA III/IV: baseline, 93.8%; 12 months, 9.7%, P < 0.001) and with LVEF >= 50% (diastolic dysfunction grade >=2: baseline, 87.1%; 12 months, 61.2%; NYHA III/IV: baseline, 74.5%; 12 months, 2.6%, P < 0.001). All-cause mortality was comparable between groups. CONCLUSION: TAVI exerts favourable effects on LV systolic and diastolic function with a remarkable improvement in LV diastolic function associated with improvement in NYHA functional class at follow-up. Prognosis at 1 year after TAVI was not influenced by baseline LV diastolic dysfunction both in patients with and without LV systolic dysfunction. PMID- 26588981 TI - Cardiac resynchronization therapy in low-flow low-gradient aortic stenosis. PMID- 26588982 TI - 3D-ECHO for TAVI: two arrows, just in case. PMID- 26588983 TI - Prognostic significance of (123)I-mIBG SPECT myocardial imaging in heart failure: differences between patients with ischaemic and non-ischaemic heart failure. AB - AIMS: The purpose of this study was to examine the prognostic significance of uptake patterns on quantitative myocardial (123)I-mIBG and (99m)Tc-tetrofosmin SPECT imaging in heart failure (HF) subjects and to assess the differences between patients with ischaemic and non-ischaemic HF. METHODS AND RESULTS: Results of quantitative analyses of (123)I-mIBG myocardial SPECT, alone and in combination with (99m)Tc tetrofosmin SPECT, were studied in 619 ischaemic (I) and 319 non-ischaemic (NI) HF subjects from the ADMIRE-HF trial. Cardiac and all cause mortality data for 2-year follow-up were collected in the extension study (ADMIRE-HFX) and were examined in relation to extent and severity of voxel-based defects, the number of myocardial segments with significant dysinnervation (derived score >=2), and (123)I-mIBG/(99m)Tc tetrofosmin mismatch quantitation. Cox proportional hazards and survival analyses were used to identify higher and lower risk groups and to define thresholds for optimal discrimination between the two. Two-year all-cause and cardiac mortality were not significantly different between IHF and NIHF subjects. Mortality was higher in patients with dysinnervation involving >50% of the myocardium. Highest cardiac mortality risk for IHF subjects was seen with perfusion defects involving 20-40% of the myocardium. By comparison, NIHF subjects with smaller perfusion abnormalities (<20% of myocardium), but with a large discrepancy between (123)I-mIBG and (99m)Tc tetrofosmin defect sizes, were at highest risk of cardiac death. CONCLUSIONS: Prognostic significance of patterns of (123)I-mIBG and MPI uptake differ between IHF and NIHF subjects. SPECT imaging may provide new insights into underlying disease processes in HF, including the degree of dysinnervation in areas with preserved myocardial perfusion in non-ischaemic HF patients. PMID- 26588984 TI - Relationship of visually assessed apical rocking and septal flash to response and long-term survival following cardiac resynchronization therapy (PREDICT-CRT). AB - AIMS: Apical rocking (ApRock) and septal flash (SF) are often observed phenomena in asynchronously contracting ventricles. We investigated the relationship of visually assessed ApRock and SF, reverse remodelling, and long-term survival in cardiac resynchronization therapy (CRT) candidates. METHODS AND RESULTS: A total of 1060 patients eligible for CRT underwent echocardiographic examinations before and 12 +/- 6 months after device implantation. Three blinded physicians were asked to visually assess the presence of ApRock and SF before device implantation and also their correction by CRT 12 +/- 6 months post-implantation. Patients with a left ventricular (LV) end-systolic volume decrease of >=15% during the first year of follow-up were regarded as responders. Patients were followed for a median period of 46 months (interquartile range: 27-65 months) for the occurrence of death of any cause. If corrected by CRT, visually assessed ApRock and SF were associated with reverse remodelling with a sensitivity of 84 and 79%, specificity of 79 and 74%, and accuracy of 82 and 77%, respectively. ApRock (hazard ratio [HR] 0.40, 95% confidence interval [CI] 0.30-0.53, P < 0.0001) and SF (HR 0.45 [CI 0.34-0.61], P < 0.001) were independently associated with lower all-cause mortality after CRT and had an incremental value over clinical variables and QRS width for identifying CRT responders. Both the absence of ApRock/SF and unsuccessful correction of ApRock/SF despite CRT were associated with a high risk for non-response and an unfavourable long-term survival. CONCLUSION: A specific LV mechanical dyssynchrony pattern, characterized by ApRock and SF, is associated with a more favourable long-term survival after CRT. Both parameters are also indicators of an effective therapy. PMID- 26588985 TI - Quantitative assessment of right ventricular glucose metabolism in idiopathic pulmonary arterial hypertension patients: a longitudinal study. AB - AIMS: Right ventricular (RV) glucose metabolism disorder in pulmonary arterial hypertension (PAH) has been studied using (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging with inconsistent results. We aimed to quantitatively assess RV glucose metabolism and further identify its role of monitoring RV function in idiopathic PAH (IPAH) patients in a longitudinal study. METHODS AND RESULTS: Twenty-seven treatment-naive IPAH patients and 21 healthy control subjects performed FDG-PET dynamic scan for quantification of the rate of myocardium glucose utilization (rMGU) and echocardiography for assessment of cardiac function. Right heart catheterization was conducted for IPAH patients for haemodynamic measurement. A subgroup of 14 patients repeated FDG-PET and echocardiography after 6-month treatment. RV rMGU was significantly increased compared with controls; while the rMGU in left ventricle showed no difference. RV rMGU was significantly correlated with pulmonary artery pressure, pulmonary vascular resistance, RV Tei index, and right atrial area, and negatively correlated with RV ejection fraction (RVEF) and tricuspid annular plane systolic excursion. Six of 14 patients with increased RV rMGU after 6-month treatment showed no change in RVEF, 6-min walk distance (6MWD), and RV Tei index; however, the other 8 patients with decreased RV rMGU demonstrated significantly increased RVEF and 6MWD and decreased RV Tei index. Notably, the change in RV rMGU of 14 patients was significantly correlated with the change in 6MWD and RV Tei index. CONCLUSION: Increased RV rMGU of IPAH correlates with RV dysfunction and RV pressure overload. The change in RV glucose metabolism may help monitor RV function after treatment. PMID- 26588986 TI - Clinical value of cardiovascular magnetic resonance in patients with MR conditional pacemakers. AB - AIMS: Magnetic resonance (MR) conditional pacemakers are increasingly implanted into patients who may need cardiovascular MR (CMR) subsequent to device implantation. We assessed the added value of CMR for diagnosis and management in this population. METHODS AND RESULTS: CMR and pacing data from consecutive patients with MR conditional pacemakers were retrospectively reviewed. Images were acquired at 1.5 T (Siemens Magnetom Avanto). The indication for CMR and any resulting change in management was recorded. The quality of CMR was rated by an observer blinded to clinical details, and data on pacemaker and lead parameters were collected pre- and post-CMR. Seventy-two CMR scans on 69 patients performed between 2011 and 2015 were assessed. All scans were completed successfully with no significant change in lead thresholds or pacing parameters. Steady-state free precession (SSFP) cine imaging resulted in a greater frequency of non-diagnostic imaging (22 vs. 1%, P < 0.01) compared with gradient echo sequences (GRE). Right sided pacemakers were associated with less artefact than left-sided pacemakers. Late gadolinium enhancement imaging was performed in 59 scans with only 2% of segments rated of non-diagnostic quality. The CMR data resulted in a new diagnosis in 27 (38%) of examinations; clinical management was changed in a further 18 (25%). CONCLUSIONS: CMR in patients with MR conditional pacemakers provided diagnostic or management-changing information in the majority (63%) of our cohort. The use of gradient echo cine sequences can reduce rates of non diagnostic imaging. Right-sided device implantation may be considered in patients likely to require CMR examination. PMID- 26588987 TI - Myocardial oedema in acute myocarditis detected by echocardiographic 2D myocardial deformation analysis. AB - AIMS: The clinical diagnosis of acute myocarditis is based on symptoms, electrocardiography, elevated myocardial necrosis biomarkers, and echocardiography. Often, conventional echocardiography reveals no obvious changes in global cardiac function and therefore has limited diagnostic value. Myocardial deformation imaging by echocardiography is an evolving method used to characterize quantitatively longitudinal systolic function, which may be affected in acute myocarditis. The aim of our study was to assess the utility of echocardiographic deformation imaging of the left ventricle in patients with diagnosed acute myocarditis in whom cardiovascular magnetic resonance (CMR) evaluation was performed. METHODS AND RESULTS: We included 28 consecutive patients (mean age 32 +/- 13 years) with CMR-verified diagnosis of acute myocarditis according to the Lake Louise criteria. Cardiac function was evaluated by a comprehensive assessment of left ventricular (LV) function, including 2D speckle-tracking echocardiography. We found no significant correlation between the peak values of cardiac enzymes and the amount of myocardial oedema assessed by CMR (troponin: r= 0.3; P = 0.05 and CK-MB: r = 0.1; P = 0.3). We found a larger amount of myocardial oedema in the basal part of the left ventricle [American Heart Association (AHA) segments 1-6] in inferolateral and inferior segments, compared with the anterior, anterolateral, anteroseptal, and inferoseptal segments. In the mid LV segments (AHA segments 7-12), this was more pronounced in the anterior, anterolateral, and inferolateral segments. Among conventional echocardiographic parameters, LV function was not found to correlate with the amount of myocardial oedema of the left ventricle. In contrast, we found the wall motion score index to be significantly correlated with the amount of myocardial oedema, but this correlation was only present in patients with an extensive amount of oedema (>11% of the total left ventricle). Global longitudinal systolic myocardial strain correlated significantly with the amount of oedema (r = 0.65; P < 0.001). We found that both the epicardial longitudinal and the endocardial longitudinal systolic strains were significantly correlated with oedema (r = 0.55; P = 0.003 and r = 0.54; P < 0.001). CONCLUSION: In patients with acute myocarditis, 2D speckle-tracking echocardiography was a useful tool in the diagnostic process of acute myocarditis. Global longitudinal strain adds important information that can support clinical and conventional echocardiographic evaluation, especially in patients with preserved LV ejection fraction in relation to the diagnosis and degree of myocardial dysfunction. PMID- 26588988 TI - Down-regulation of LATS kinases alters p53 to promote cell migration. AB - p53 is a pivotal tumor suppressor and a major barrier against cancer. We now report that silencing of the Hippo pathway tumor suppressors LATS1 and LATS2 in nontransformed mammary epithelial cells reduces p53 phosphorylation and increases its association with the p52 NF-kappaB subunit. Moreover, it partly shifts p53's conformation and transcriptional output toward a state resembling cancer associated p53 mutants and endows p53 with the ability to promote cell migration. Notably, LATS1 and LATS2 are frequently down-regulated in breast cancer; we propose that such down-regulation might benefit cancer by converting p53 from a tumor suppressor into a tumor facilitator. PMID- 26588989 TI - NLK phosphorylates Raptor to mediate stress-induced mTORC1 inhibition. AB - The mechanistic target of rapamycin (mTOR) is a central cell growth controller and forms two distinct complexes: mTORC1 and mTORC2. mTORC1 integrates a wide range of upstream signals, both positive and negative, to regulate cell growth. Although mTORC1 activation by positive signals, such as growth factors and nutrients, has been extensively investigated, the mechanism of mTORC1 regulation by stress signals is less understood. In this study, we identified the Nemo-like kinase (NLK) as an mTORC1 regulator in mediating the osmotic and oxidative stress signals. NLK inhibits mTORC1 lysosomal localization and thereby suppresses mTORC1 activation. Mechanistically, NLK phosphorylates Raptor on S863 to disrupt its interaction with the Rag GTPase, which is important for mTORC1 lysosomal recruitment. Cells with Nlk deletion or knock-in of the Raptor S863 phosphorylation mutants are defective in the rapid mTORC1 inhibition upon osmotic stress. Our study reveals a function of NLK in stress-induced mTORC1 modulation and the underlying biochemical mechanism of NLK in mTORC1 inhibition in stress response. PMID- 26588990 TI - Context-dependent modulation of Pol II CTD phosphatase SSUP-72 regulates alternative polyadenylation in neuronal development. AB - Alternative polyadenylation (APA) is widespread in neuronal development and activity-mediated neural plasticity. However, the underlying molecular mechanisms are largely unknown. We used systematic genetic studies and genome-wide surveys of the transcriptional landscape to identify a context-dependent regulatory pathway controlling APA in the Caenorhabditis elegans nervous system. Loss of function in ssup-72, a Ser5 phosphatase for the RNA polymerase II (Pol II) C terminal domain (CTD), dampens transcription termination at a strong intronic polyadenylation site (PAS) in unc-44/ankyrin yet promotes termination at the weak intronic PAS of the MAP kinase dlk-1. A nuclear protein, SYDN-1, which regulates neuronal development, antagonizes the function of SSUP-72 and several nuclear polyadenylation factors. This regulatory pathway allows the production of a neuron-specific isoform of unc-44 and an inhibitory isoform of dlk-1. Dysregulation of the unc-44 and dlk-1 mRNA isoforms in sydn-1 mutants impairs neuronal development. Deleting the intronic PAS of unc-44 results in increased pre-mRNA processing of neuronal ankyrin and suppresses sydn-1 mutants. These results reveal a mechanism by which regulation of CTD phosphorylation controls coding region APA in the nervous system. PMID- 26588992 TI - Curative therapies for hepatocellular carcinoma: an update and perspectives. AB - Curative treatments, including liver transplantation, surgical resection and percutaneous treatments, are the recommended therapies in BCLC-0 (Barcelona Clinic of Liver Cancer) or BCLC-A hepatocellular carcinoma (HCC). This review provides an overview of some issues of clinical importance concerning curative treatments in HCC. PMID- 26588993 TI - Vedolizumab for the treatment of ulcerative colitis. AB - A substantial proportion of patients with ulcerative colitis (UC) have failed conventional therapies such as steroids, immunosuppressants or TNF-antibodies, or have experienced side effects. This article reviews the pharmacological properties of vedolizumab (VDZ), its efficacy and side effects in UC. By its relatively specific gut-selective mode of action, VDZ's safety profile appears more favorable than that of anti-TNF therapies. VDZ is more effective than placebo for the induction and maintenance of remission in moderate-to-severe UC in both naive patients and patients who have failed anti-TNF treatment. However, in some patients, VDZ has a slower onset of action. But, to place VDZ as a first line therapy, it must go head-to-head with azathioprine and anti-TNF antibodies in future studies. PMID- 26588991 TI - Alternate wiring of a KNOXI genetic network underlies differences in leaf development of A. thaliana and C. hirsuta. AB - Two interrelated problems in biology are understanding the regulatory logic and predictability of morphological evolution. Here, we studied these problems by comparing Arabidopsis thaliana, which has simple leaves, and its relative, Cardamine hirsuta, which has dissected leaves comprising leaflets. By transferring genes between the two species, we provide evidence for an inverse relationship between the pleiotropy of SHOOTMERISTEMLESS (STM) and BREVIPEDICELLUS (BP) homeobox genes and their ability to modify leaf form. We further show that cis-regulatory divergence of BP results in two alternative configurations of the genetic networks controlling leaf development. In C. hirsuta, ChBP is repressed by the microRNA164A (MIR164A)/ChCUP-SHAPED COTYLEDON (ChCUC) module and ChASYMMETRIC LEAVES1 (ChAS1), thus creating cross-talk between MIR164A/CUC and AS1 that does not occur in A. thaliana. These different genetic architectures lead to divergent interactions of network components and growth regulation in each species. We suggest that certain regulatory genes with low pleiotropy are predisposed to readily integrate into or disengage from conserved genetic networks influencing organ geometry, thus rapidly altering their properties and contributing to morphological divergence. PMID- 26588994 TI - Early Post-operative Mortality After Major Lower Limb Amputation: A Systematic Review of Population and Regional Based Studies. AB - OBJECTIVE: Lower limb amputation is often associated with a high risk of early post-operative mortality. Mortality rates are also increasingly being put forward as a possible benchmark for surgical performance. The primary aim of this systematic review is to investigate early post-operative mortality following a major lower limb amputation in population/regional based studies, and reported factors that might influence these mortality outcomes. METHODS: Embase, PubMed, Cinahl and Psycinfo were searched for publications in any language on 30 day or in hospital mortality after major lower limb amputation in population/regional based studies. PRISMA guidelines were followed. A self developed checklist was used to assess quality and susceptibility to bias. Summary data were extracted for the percentage of the population who died; pooling of quantitative results was not possible because of methodological differences between studies. RESULTS: Of the 9,082 publications identified, results were included from 21. The percentage of the population undergoing amputation who died within 30 days ranged from 7% to 22%, the in hospital equivalent was 4-20%. Transfemoral amputation and older age were found to have a higher proportion of early post-operative mortality, compared with transtibial and younger age, respectively. Other patient factors or surgical treatment choices related to increased early post-operative mortality varied between studies. CONCLUSIONS: Early post-operative mortality rates vary from 4% to 22%. There are very limited data presented for patient related factors (age, comorbidities) that influence mortality. Even less is known about factors related to surgical treatment choices, being limited to amputation level. More information is needed to allow comparison across studies or for any benchmarking of acceptable mortality rates. Agreement is needed on key factors to be reported. PMID- 26588995 TI - The many pros and the few cons of noninvasive ventilation in ordinary wards. PMID- 26588996 TI - [What means pulmonary rehabilitation in 2015?]. PMID- 26588997 TI - Intrathyroidal parathyroid carcinoma. A case report and review of literature. PMID- 26588998 TI - Towards a better understanding of the clinical association of anti-DFS70 autoantibodies. AB - Anti-DFS70 antibodies and their clinical associations remain an immunological paradox. Unlike other antinuclear antibodies (ANA), especially when present at high titres, anti-DFS70 antibodies are not prevalent in ANA associated rheumatic diseases. Despite significant interest and progress in understanding the clinical association of anti-DFS70 antibodies, no specific clinical associations have been confirmed. In reality, several studies reporting clinical association of these antibodies (i.e. atopic dermatitis, thrombosis, autoimmune thyroiditis) have added confusion instead of bringing significant insight. In addition, several groups have consistently reported on the occurrence of anti-DFS70 antibodies in a relevant fraction of apparently healthy individuals. This review aims to analyse the current knowledge and to provide future guidance to analyse potential clinical associations of anti-DFS70 antibodies by summarizing and interpreting recent findings. PMID- 26588999 TI - The effect of health insurance coverage on medical care utilization and health outcomes: Evidence from Medicaid adult vision benefits. AB - Increasing the proportion of adults that have regular, comprehensive eye exams and reducing visual impairment due to uncorrected refractive error and other common eye health problems are federal health objectives. We examine the effect of vision insurance on eye care utilization and vision health outcomes by taking advantage of quasi-experimental variation in Medicaid coverage of adult vision care. Using a difference-in-difference-in-difference approach, we find that Medicaid beneficiaries with vision coverage are 4.4 percentage points (p<0.01) more likely to have seen an eye doctor in the past year, 5.3 percentage points (p<0.01) less likely to report needing but not purchasing eyeglasses or contacts due to cost, 2.0 percentage points (p<0.05) less likely to report difficulty seeing with usual vision correction, and 1.2 percentage points (p<0.01) less likely to have a functional limitation due to vision. PMID- 26589000 TI - Association of chitotriosidase enzyme activity and genotype with the risk of nephropathy in type 2 diabetes. AB - OBJECTIVE: The immune-inflammatory system has been implicated in the pathogenesis of diabetic nephropathy; however, many of the mechanisms involved remain unclear. Chitotriosidase enzyme is an active human chitinase and a major protein product of activated macrophages. Although playing an important role in innate and acquired immunity, chitotriosidase involvement in the development of diabetic nephropathy is unknown. DESIGN AND METHODS: Chitotriosidase enzyme activity and the presence of the functional 24-bp duplication mutation of the chitotriosidase gene (CHIT1) were assessed in 262 Egyptian type 2 diabetic patients with and without nephropathy and 90 non-diabetic controls. In diabetic patients, multiple linear regression models were adapted to assess the association of chitotriosidase activity with two important measures of renal disease progression: urinary albumin/creatinine ratio and eGFR, while the association of the CHIT1 genotype with the incidence of nephropathy was evaluated by multiple logistic regression. RESULTS: In diabetic patients, chitotriosidase enzyme activity showed a statistically significant elevation as compared to controls and correlated positively with the progression of nephropathy. A significant association of chitotriosidase activity with both urinary albumin/creatinine ratio and eGFR was detected after adjusting for age, gender, duration of diabetes, body mass index, hypertension status, total cholesterol, triglycerides and HbA1c levels, P<0.001. We also identified a protective association between the CHIT1 mutated genotype and diabetic nephropathy after adjusting for the same confounders (odds ratio: 0.517, 95% CI: 0.289-0.924, P=0.026). CONCLUSIONS: This study demonstrates for the first time that the immunomodulatory effects of chitotriosidase enzyme could be implicated in the development of nephropathy in type 2 diabetes. PMID- 26589001 TI - Factors influencing naproxen metabolite interference in total bilirubin assays. AB - BACKGROUND: The factors influencing naproxen metabolite O-desmethylnaproxen (ODMN) positive interference in diazo-based Jendrassik and Grof (JG) total bilirubin (Tbil) assays and lack of interference in direct bilirubin (Dbil) assays have not been resolved. The objective of this study was to understand the conditions causing this interference pattern. METHODS: Pooled normal and ultra filtered plasma samples spiked with ODMN and naproxen were measured on the Beckman Coulter DxC and AU instruments. Absorbance spectra were obtained for ODMN mixed with Dbil reagent at original and adjusted pH. Absorbance spectra were also obtained for ODMN and bilirubin samples mixed with Tbil assay reagents. RESULTS: ODMN produces a positive interference in the DxC JG Tbil assays, but not the AU Tbil or Dbil assays or the DxC Dbil assay. Neutralizing the acidic pH of AU and DxC Dbil reagents allows ODMN to react with diazo salts. ODMN samples mixed with DxC and AU Tbil reagents produce broad peaks from 450 to 560nm and 400 to 540nm, respectively. The DxC JG Tbil assay monitors a change in absorbance at 520nm close to peak absorbance wavelength of diazo-reacted ODMN, whereas the AU Tbil assay monitors a change in absorbance at 570/660nm, beyond the peak absorbance wavelengths of diazo-reacted ODMN. CONCLUSION: The acidic pH of diazo-based Dbil assay reagents inhibits the reaction of ODMN with diazo salts. The AU JG Tbil assay is a reliable method to measure Tbil in the setting of naproxen overdose. PMID- 26589002 TI - Frataxin expression in reticulocytes of non-splenectomized and splenectomized patients with HbE-beta-thalassaemia. AB - OBJECTIVES: A previous report revealed that thalassaemic patients with transfusional iron overload developed oxidative stress. The aims of this study were to investigate the FXN mRNA levels in the reticulocytes of patients with HbE beta-thalassaemia who were treated with regular transfusions, to compare the results with those from normal controls and to evaluate the relationships of the levels of FXN mRNA with malondialdehyde (MDA) and iron parameters in these patients. DESIGN AND METHODS: The levels of FXN mRNA in the reticulocytes of patients (30 non-splenectomized and 30 splenectomized) and 30 normal individuals were assessed by RT-PCR. The levels of MDA and the transferrin saturations (TSs) were analysed with thiobarbituric acid-reactive substance assay and spectrometry, respectively. The level of ferritin was determined by ELISA. RESULTS: The levels of FXN mRNA, MDA, ferritin, and TS in the patients were significantly higher than those in the controls. The levels of FXN mRNA, MDA, and ferritin in the non splenectomized and splenectomized patients were significantly different, but the levels of TS in these two patient groups were comparable. The relative FXN expression in the patients was found to be correlated with the levels of MDA and ferritin but not correlated with TS. CONCLUSIONS: The elevation of FXN expression in the reticulocytes of these patients seems to be linked to oxidative stress and iron status. PMID- 26589004 TI - Smartphone-based tactile cueing improves motor performance in Parkinson's disease. AB - INTRODUCTION: Visual and auditory cueing improve functional performance in Parkinson's disease (PD) patients. However, audiovisual processing shares many cognitive resources used for attention-dependent tasks such as communication, spatial orientation, and balance. Conversely, tactile cues (TC) may be processed faster, with minimal attentional demand, and may be more efficient means for modulating motor-cognitive performance. In this study we aimed to investigate the efficacy and limitations of TC for modulating simple (heel tapping) and more complex (walking) motor tasks (1) over a range of cueing intervals, (2) with/without a secondary motor task (holding tray with cups of water). METHODS: Ten PD patients (71 +/- 9 years) and 10 healthy controls (69 +/- 7 years) participated in the study. TCs was delivered through a smart phone attached to subjects' dominant arm and were controlled by a custom-developed Android application. RESULTS: PD patients and healthy controls were able to use TC to modulate heel tapping (F(3.8,1866.1) = 1008.1, p < 0.001), and partially modulate walking (F(3.5,1448.7) = 187.5, p < 0.001) tasks. In the walking task, PD patients modulated performance over a narrower range of cueing intervals (R(2) = 0.56) than healthy controls (R(2) = 0.84; group difference F(3.5,1448.7) = 8.6, p < 0.001). TC diminished synchronization error associated with performance of secondary motor task during walking in PD patients and healthy controls (main effect of Task (F(1,494) = 0.4; p = 0.527), Task X Group interaction (F(1,494) = 0.5; p = 0.493)). CONCLUSION: This study expands modalities of TC usage for movement modulation and motor-cognitive integration in PD patients. The smartphone TC application was validated as a user-friendly movement modulation aid. PMID- 26589003 TI - Genome-wide estimate of the heritability of Multiple System Atrophy. AB - INTRODUCTION: Multiple System Atrophy (MSA) is a neurodegenerative disease which presents heterogeneously with symptoms and signs of parkinsonism, ataxia and autonomic dysfunction. Although MSA typically occurs sporadically, rare pathology proven MSA families following either autosomal recessive or autosomal dominant patterns have been described, indicating a heritable contribution to the pathogenesis. METHODS: We used Genome-Wide Complex Trait Analysis (GCTA) to estimate the heritable component of MSA due to common coding variability in imputed genotype data of 907 MSA cases and 3866 population-matched controls. GCTA only assesses the effect of putative causal variants in linkage disequilibrium (LD) with all common SNPs on the genotyping platform. RESULTS: We estimate the heritability among common variants of MSA in pooled cases at 2.09-6.65%, with a wider range of values in geographic and diagnostic subgroups. Meta-analysis of our geographic cohorts reveals high between-group heterogeneity. Contributions of single chromosomes are generally negligible. We suggest that all calculated MSA heritability among common variants could be explained by the presence of misdiagnosed cases in the clinical subgroup based on a Bayesian estimate using literature-derived rates of misdiagnosis. DISCUSSION: MSA is a challenging disease to study due to high rates of misdiagnosis and low prevalence. Given our low estimates of heritability, common genetic variation appears to play a less prominent role in risk for MSA than in other complex neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and Amyotrophic Lateral Sclerosis. The success of future gene discovery efforts rests on large pathologically-confirmed case series and an interrogation of both common and rare genetic variants. PMID- 26589006 TI - Inversion of the Electric Field at the Electrified Liquid-Liquid Interface. AB - The thermodynamics of the general system of two immiscible electrolytes in the presence of an electric field depends strongly on the distribution of ions near the liquid interface. Here, we calculate the corresponding electrostatic potential difference, excess surface tension, and differential capacity via Monte Carlo simulations, which include ion correlations and polarization effects, and via a modified nonlinear Poisson-Boltzmann theory. Macroscopically, we find good agreement between our results and experimental data without needing any fitting parameter. At higher salt concentrations, charge overcompensation in the lower permittivity region is observed, which results in a local inversion of the electric field accompanied by charge inversion near the interface. We find that these interesting phenomena are mainly driven by the excluded-volume effects associated with large organic ions in the oil phase, although polarization effects and between-layer ion correlations have a significant impact in the adsorption of ions close to the liquid interface. In addition, our Monte Carlo simulations predict that the differential capacity is maximal at the point of zero charge, in contrast with the classical Poisson-Boltzmann theory results. PMID- 26589005 TI - Calcifying nested stromal-epithelial tumor (CNSET) of the liver: a newly recognized entity to be considered in the radiologist's differential diagnosis. AB - Calcifying nested stromal-epithelial tumor (CNSET), an extremely rare tumor found in the liver, was first described in 2001 by Ishak et al. The characteristic imaging features include large size, well-circumscribed, enhancing mass with calcification. To our knowledge, since 2001, there have been 29 reported. Typically arising from the right hepatic lobe, it is primarily found in children and shows clear predilection for females. Emphasizing imaging, we report a 14 year-old female with Beckwith-Wiedemann syndrome who presented with CNSET. PMID- 26589007 TI - Expeditious Stochastic Approach for MP2 Energies in Large Electronic Systems. AB - A fast stochastic method for calculating the second order Moller-Plesset (MP2) correction to the correlation energy of large systems of electrons is presented. The approach is based on reducing the exact summation over occupied and unoccupied states to a time-dependent trace formula amenable to stochastic sampling. We demonstrate the abilities of the method to treat systems with thousands of electrons using hydrogen passivated silicon spherical nanocrystals represented on a real space grid, much beyond the capabilities of present day MP2 implementations. PMID- 26589008 TI - The Fate of a Zwitterion in Water from ab Initio Molecular Dynamics: Monoethanolamine (MEA)-CO2. AB - Understanding the fundamental reactions accompanying the capture of carbon dioxide in amine solutions is critical for the design of high-performance solvents and requires an accurate modeling of the solute-solvent interaction. As a first step toward this goal, using ab initio molecular dynamics (Car Parrinello) simulations, we investigate a zwitterionic carbamate, a species long proposed as intermediate in the formation of a stable carbamate, in a dilute aqueous solution. CO2 release and deprotonation are competitive routes for its dissociation and are both characterized by free-energy barriers of 6-8 kcal/mol. Water molecules play a crucial role in both pathways, resulting in large entropic effects. This is especially true in the case of CO2 release, which is accompanied by a strong reorganization of the solvent beyond the first coordination shell, leading to the formation of a water cage entrapping the solute (hydrophobic effect). Our results contrast with the assumptions of implicit solvent models. PMID- 26589009 TI - Evaluating the Accuracy of Hessian Approximations for Direct Dynamics Simulations. AB - Direct dynamics simulations are a very useful and general approach for studying the atomistic properties of complex chemical systems, since an electronic structure theory representation of a system's potential energy surface is possible without the need for fitting an analytic potential energy function. In this paper, recently introduced compact finite difference (CFD) schemes for approximating the Hessian [J. Chem. Phys.2010, 133, 074101] are tested by employing the monodromy matrix equations of motion. Several systems, including carbon dioxide and benzene, are simulated, using both analytic potential energy surfaces and on-the-fly direct dynamics. The results show, depending on the molecular system, that electronic structure theory Hessian direct dynamics can be accelerated up to 2 orders of magnitude. The CFD approximation is found to be robust enough to deal with chaotic motion, concomitant with floppy and stiff mode dynamics, Fermi resonances, and other kinds of molecular couplings. Finally, the CFD approximations allow parametrical tuning of different CFD parameters to attain the best possible accuracy for different molecular systems. Thus, a direct dynamics simulation requiring the Hessian at every integration step may be replaced with an approximate Hessian updating by tuning the appropriate accuracy. PMID- 26589010 TI - Ab Initio Molecular Dynamics Study of the Very Short O-H...O Hydrogen Bonds in the Condensed Phases. AB - In this paper are presented the results of theoretical studies of the structure and proton motion in very short O...O intramolecular hydrogen bonds in two molecular crystals. A comparison was conducted between 3-cyano-2,4-pentanedione (I) and 4-cyano-2,2,6,6-tetramethyl-3,5-heptanedione (II) in the solid state. The dynamics of proton motion in the O-H...O hydrogen bond were investigated in he NVT ensemble at 298 and 50 K, respectively, for crystals I and II using Car Parrinello and path integral molecular dynamics. Very large delocalization of the bridging proton was noted especially in the path integral simulation where quantum effects are taken into account. The infrared spectrum was calculated, and a comparative vibrational analysis was performed. CPMD vibrational results appear to be in qualitative agreement with the experimental ones. PMID- 26589011 TI - A Case Study of Truncated Electrostatics for Simulation of Polyelectrolyte Brushes on GPU Accelerators. AB - Numerous issues have disrupted the trend for increasing computational performance with faster CPU clock frequencies. In order to exploit the potential performance of new computers, it is becoming increasingly desirable to re-evaluate computational physics methods and models with an eye toward approaches that allow for increased concurrency and data locality. The evaluation of long-range Coulombic interactions is a common bottleneck for molecular dynamics simulations. Enhanced truncation approaches have been proposed as an alternative method and are particularly well-suited for many-core architectures and GPUs due to the inherent fine-grain parallelism that can be exploited. In this paper, we compare efficient truncation-based approximations to evaluation of electrostatic forces with the more traditional particle-particle particle-mesh (P(3)M) method for the molecular dynamics simulation of polyelectrolyte brush layers. We show that with the use of GPU accelerators, large parallel simulations using P(3)M can be greater than 3 times faster due to a reduction in the mesh-size required. Alternatively, using a truncation-based scheme can improve performance even further. This approach can be up to 3.9 times faster than GPU-accelerated P(3)M for many polymer systems and results in accurate calculation of shear velocities and disjoining pressures for brush layers. For configurations with highly nonuniform charge distributions, however, we find that it is more efficient to use P(3)M; for these systems, computationally efficient parametrizations of the truncation-based approach do not produce accurate counterion density profiles or brush morphologies. PMID- 26589012 TI - Exploring the Dynamic Functional Landscape of Adenylate Kinase Modulated by Substrates. AB - Adenylate kinase (ADK) has been explored widely, through both experimental and theoretical studies. However, still less is known about how the functional dynamics of ADK is modulated explicitly by its natural substrates. Here, we report a quantitative study of the dynamic energy landscape for ADK responding to the substrate binding by integrating both experimental investigations and theoretical modeling. We make theoretical predictions which are in remarkable agreement with the single molecule experiments on the substrate-bound complex. With our combined models of ADK in its apo form, in the presence of AMP or ATP, and in complex with both substrates, we specifically address the following key questions: (1) Are there intermediate state(s) during their catalytic cycle and if so how many? (2) How many pathways are there along the open-to-closed transitions and what are their corresponding weights? (3) How do substrates influence the pathway weights and the stability of the intermediates? (4) Which lid's motion is rate-limiting along the turnover cycle, the NMP or the LID domain? Our models predict two major parallel stepwise pathways and two on pathway intermediates which are denoted as IN (NMP domain open while LID domain closed) and IL (LID domain open and NMP domain closed), respectively. Further investigation of temperature effects suggests that the IN pathway is dominant at room temperature, but the IL pathway is dominant at the optimal temperature. This leads us to propose that the IL pathway is more dominant by entropy and IN pathway by enthalpy. Remarkably, our results show that even with maximum concentrations of natural substrates, ADK still fluctuates between multiple functional states, reflecting an intrinsic capability of large-scale conformational fluctuations which may be essential to its biological function. The results based on the dual-ligands model provide the theoretical validation of random bisubstrate biproducts (Bi-Bi) mechanism for the enzymatic reaction of ADK. Additionally, the pathway flux analysis strongly suggests that the motion of the NMP domain is the rate-determining step for the conformational cycle (opening and closing). PMID- 26589013 TI - Conformational Dynamics of the FMN-Binding Reductase Domain of Monooxygenase P450BM-3. AB - In the cytochrome P450BM-3, the flavin mononucleotide (FMN) binding domain is an intermediate electron donor between the flavin adenine dinucleotide (FAD) binding domain and the HEME domain. Experimental evidence has shown that different redox states of FMN cofactor were found to induce conformational changes in the FMN domain. Herein, molecular dynamics (MD) simulation is used to gain insight into the latter phenomenon at the atomistic level. We have studied the effect of FMN cofactor and its redox states (oxidized and reduced) on the structure and dynamics of the FMN domain. The results of our study show significant differences in the atomic fluctuation amplitude of the FMN domain in both holo- and apoprotein. The change in the protonation state of FMN cofactor mostly affects its binding in holo-protein. In particular, the loops involved in the binding of the isoalloxazine ring (Lbeta4) and ribityl side chain (Lbeta1) adopt different conformations in both reduced and oxidized states. In addition, the reduced FMN cofactor mainly induces a conformational change in Trp574 residue (Lbeta4) that is essential for controlling electron transfer (ET) within P450BM-3 domains. The structure of the apoprotein in solution remains mostly unchanged with respect to the crystal structure of the holo-protein. However, FMN binding loops were more flexible in apoprotein that might favor the rebinding of FMN cofactor. In the holo-protein simulation, the largest conformational changes in FMN cofactor are caused by the ribityl side chain. The isoalloxazine ring of FMN cofactor remains almost planar (~177 degrees ) in the oxidized state and bends along the N5-N10 axis at an angle of ~160 degrees in the reduced state. The collective modes of the isoalloxazine ring were identical in both protonation states of FMN cofactor except the first eigenvector. In the reduced state, the isoalloxazine ring attains the butterfly motion as a dominant collective motion in the first eigenvector due to the bending along the N5-N10 axis. PMID- 26589014 TI - Liquid Methanol from DFT and DFT/MM Molecular Dynamics Simulations. AB - We present a comparative study of computational protocols for the description of liquid methanol from ab initio molecular dynamics simulations, in view of further applications directed at the modeling of chemical reactivity of organic and organometallic molecules in (explicit) methanol solution. We tested density functional theory molecular dynamics (DFT-MD) in its Car-Parrinello Molecular Dynamics (CPMD) and Quickstep/Born-Oppenheimer MD (CP2K) implementations, employing six popular density functionals with and without corrections for dispersion interactions (namely BLYP, BLYP-D2, BLYP-D3, BP86, BP86-D2, and B97 D2). Selected functionals were also tested within the two QM/MM frameworks implemented in CPMD and CP2K, considering one DFT molecule in a MM environment (described by the OPLS model of methanol). The accuracy of each of these methods at describing the bulk liquid phase under ambient conditions was evaluated by analyzing their ability to reproduce (i) the average structure of the liquid, (ii) the mean squared displacement of methanol molecules, (iii) the average molecular dipole moments, and (iv) the gas-to-liquid red-shift observed in their infrared spectra. We show that it is difficult to find a DFT functional that describes these four properties equally well within full DFT-MD simulations, despite a good overall performance of B97-D2. On the other hand, DFT/MM-MD provides a satisfactory description of the solvent-solute polarization effects with all functionals and thus represents a good alternative for the modeling of methanol solutions in the context of chemical reactivity in an explicit environment. PMID- 26589015 TI - Consistent View of Protein Fluctuations from All-Atom Molecular Dynamics and Coarse-Grained Dynamics with Knowledge-Based Force-Field. AB - It is widely recognized that atomistic Molecular Dynamics (MD), a classical simulation method, captures the essential physics of protein dynamics. That idea is supported by a theoretical study showing that various MD force-fields provide a consensus picture of protein fluctuations in aqueous solution [Rueda, M. et al. Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 796-801]. However, atomistic MD cannot be applied to most biologically relevant processes due to its limitation to relatively short time scales. Much longer time scales can be accessed by properly designed coarse-grained models. We demonstrate that the aforementioned consensus view of protein dynamics from short (nanosecond) time scale MD simulations is fairly consistent with the dynamics of the coarse-grained protein model - the CABS model. The CABS model employs stochastic dynamics (a Monte Carlo method) and a knowledge-based force-field, which is not biased toward the native structure of a simulated protein. Since CABS-based dynamics allows for the simulation of entire folding (or multiple folding events) in a single run, integration of the CABS approach with all-atom MD promises a convenient (and computationally feasible) means for the long-time multiscale molecular modeling of protein systems with atomistic resolution. PMID- 26589016 TI - Combination of Enveloping Distribution Sampling (EDS) of a Soft-Core Reference State Hamiltonian with One-Step Perturbation to Predict the Effect of Side Chain Substitution on the Relative Stability of Right- and Left-Helical Folds of beta Peptides. AB - Folding free enthalpies of many not too different polypeptides can be efficiently and accurately predicted with the one-step perturbation (OSP) method using only one or a few molecular dynamics (MD) simulations. In this article, we introduce a combination of enveloping distribution sampling (EDS) and the OSP method (EDS OSP) and apply it to predict the free enthalpy differences between a right-handed 2.710/12-helix and a left-handed 314-helix for 16 beta-peptides with slightly different side-chain substitution patterns. An EDS simulation of a designed soft core reference-state peptide was carried out in which both helices were sampled. Then, the soft-core atoms were perturbed into physical atoms. Thus, free enthalpy differences between the two helices for the 16 beta-peptides can be predicted from only one simulation. The results predicted by EDS-OSP and a previous OSP study are very similar, i.e., the deviations between the results of the 16 peptides are mostly within the order of kBT, and the average absolute deviation is 1.2 kJ mol(-1). Together with the EDS parameter update simulation, about 128 ns of MD simulations needed to be carried out using the EDS-OSP method, while 700 ns of MD simulations were required in the previous OSP study where two separate reference-state simulations and an additional long time MD simulation of one of the 16 beta-peptides were carried out. Thus, the computational effort was significantly reduced, i.e., by more than a factor of 5, using the EDS-OSP method. Hence, we consider this method an efficient tool to predict conformational free enthalpy differences from MD simulations. PMID- 26589017 TI - On Reaction Coordinate Optimality. AB - The following question is addressed: how to establish that a constructed reaction coordinate is optimal, i.e., that it provides an accurate description of dynamics. It is shown that the reaction coordinate is optimal if its cut free energy profile, determined using length-weighted transitions, is constant, i.e., it is position and sampling interval independent. The observation leads to a number of interesting results. In particular, the equilibrium flux between two boundary states can be computed exactly as diffusion on a free energy profile associated with the coordinate. The mean square displacement, for the trajectory projected onto the coordinate, grows linear with time. That for the same trajectory projected onto a suboptimal coordinate grows slower than linear with time. The results are illustrated on a number of model systems, Sierpinski gasket, FIP35 protein, and beta3s peptide. PMID- 26589018 TI - Accounting for Finite-Number Effects on Cluster Size Distributions in Simulations of Equilibrium Aggregation. AB - An approach is given to analyze aggregate size distributions obtained from simulations of a fixed number N of monomers undergoing reversible self-assembly. Equilibrium distributions are derived from size-dependent equilibrium association constants by appropriately weighted sums over all partitions of N monomers into aggregates. Conversely, equilibrium association constants can be obtained from an iterative fit to a finite-N equilibrium distribution. Model data for a micelle forming system are used to show how results from simulations containing few micelles can yield infinite-N limiting distributions. A strategy is also suggested to exploit small-N effects on aggregate size distributions to enhance sampling of critical clusters in determination of nucleation free energy functions. PMID- 26589019 TI - Density of States Partitioning Method for Calculating the Free Energy of Solids. AB - We propose a new simulation method, which combines a cage model and a density of states partitioning technique, to compute the free energy of an arbitrary solid. The excess free energy is separated into two contributions, noninteracting and interacting. The excess free energy of the noninteracting solid is computed by partitioning its geometrical configuration space with respect to the ideal gas. This quantity depends on the lattice type and the number of molecules. The excess free energy of the interacting solid, with respect to the noninteracting solid, is calculated using density of states partitioning and a cage model. The cage model is better than the cell model in that it has a smaller configuration space and better represents the equilibrium distribution of solid configurations. Since the partition function (and hence free energy) is obtained from the density of states, which is independent of the temperature, equilibrium thermodynamic properties at any condition can be obtained by varying the density. We illustrate our method in the context of the free energy of dry ice. PMID- 26589020 TI - Solvent Free Ionic Solution Models from Multiscale Coarse-Graining. AB - Solvent free models for aqueous ionic solutions are derived using the multiscale coarse-graining (MS-CG) method to obtain many-body potentials of mean force and generalized Langevin equations to propagate the model in time. The resulting models are compared to other implicit solvent models for aqueous NaCl in terms of both sampling efficiency and accuracy. First, the equilibrium structural properties of the models are compared, and then the temperature dependence of the interion potentials of mean force are determined to obtain the pairwise entropy associated with the effective ionic interactions. After validating the equilibrium behavior of the new models, the dynamical properties are investigated using generalized Langevin equation dynamics simulations. The dynamical properties can be put into better agreement with the original atomistic models by introducing an exponential memory kernel to account for the strong coupling between the ions and their water solvation shells. PMID- 26589021 TI - Self-Assembly of Triblock Janus Nanoparticle in Nanotube. AB - We have performed molecular simulations to investigate morphologies and the phase diagram of the self-assembled triblock Janus nanoparticle confined to nanotubes. The triblock Janus nanoparticle is decorated with two hydrophobic caps at the north and south poles with a tunable area, separated by an electrically charged middle band. On the basis of the observed pressure- and tube-radius-dependent morphologies, we derive semiquantitative phase diagrams of the axial pressure versus the ratio of the radius of the nanoparticle to the radius of the nanotube. Three distinct walls of the nanotube, namely, hydrophobic, hydrophilic, and hydroneutral, are considered. We find that the three phase diagrams corresponding to three chemically different walls of the nanotube show some universal features. These features can be illustrated through a schematic assembly map and a roadmap on the variation of coordination number of the nanoparticles. In particular, we find that highly ordered morphologies tend to form when the coordination number of Janus particles is a multiple of 2. The orientation ordering and self-assembly behavior of the Janus nanoparticles can be qualitatively predicted when the chemical nature of the nanotube wall is known. PMID- 26589022 TI - Accurate and Efficient Treatment of Continuous Solute Charge Density in the Mean Field QM/MM Free Energy Calculation. AB - QM/MM free energy calculation is computationally demanding because of the need for an excessive number of electronic structure calculations. A practical approach for reducing the computational cost is that based on mean field approximation, which calculates the QM wave function in the presence of a partially or totally averaged potential of the MM environment. For obtaining the latter potential, it is common to first represent the QM molecule in terms of point charges and then perform statistical sampling of MM molecules. However, the point charge approximation has the drawback that it tends to overestimate electrostatic (ES) interactions at short-range, which may give rise to a divergence problem in the self-consistent iterations. In this paper, we thus consider a more accurate and robust implementation of mean-field QM/MM method based on continuous QM charge density, here utilizing the following combination: (i) grid-based treatment of ES potential generated by the QM molecule, which allows for an efficient sampling of MM molecules in the presence of QM charge density, and (ii) adaptation of the QM/MM-Ewald method to the mean-field framework for eliminating cutoff errors in the long-range ES interactions. As a numerical test, we apply the obtained method to several benchmark reactions in aqueous solution, and show that the density-based method essentially eliminates the divergence problem while providing the free energy profile consistent with experiment. In addition, we test the utility of a recently proposed screened charge model for the QM charge density and show that the latter also performs well for the free energy calculation. These results suggest that explicit inclusion of charge penetration effects is beneficial for improving the accuracy and stability of the mean-field QM/MM calculation. PMID- 26589023 TI - Analytical Gradients of Hartree-Fock Exchange with Density Fitting Approximations. AB - We extend the local exchange (LK) algorithm [Aquilante, F.; Pedersen, T. B.; Lindh, R. J. Chem. Phys.2007, 126, 194106] to the calculation of analytical gradients with density fitting. We discuss the features of the screening procedure and demonstrate the possible advantages of using this formulation, which is easily interfaced to a standard integral-direct gradient code. With auxiliary basis sets obtained from Cholesky decomposition of atomic or molecular integral blocks with a decomposition threshold of 10(-4)Eh, typical errors due to the density fitting in bond lengths, bond angles, and dihedral angles are 0.1 pm, 0.1 degrees , and 0.5 degrees , respectively. The overall speedup of geometry optimizations is about 1 order of magnitude for atomic natural-orbital-type basis sets but much less pronounced for correlation-consistent basis sets. PMID- 26589024 TI - Generating Efficient Quantum Chemistry Codes for Novel Architectures. AB - We describe an extension of our graphics processing unit (GPU) electronic structure program TeraChem to include atom-centered Gaussian basis sets with d angular momentum functions. This was made possible by a "meta-programming" strategy that leverages computer algebra systems for the derivation of equations and their transformation to correct code. We generate a multitude of code fragments that are formally mathematically equivalent, but differ in their memory and floating-point operation footprints. We then select between different code fragments using empirical testing to find the highest performing code variant. This leads to an optimal balance of floating-point operations and memory bandwidth for a given target architecture without laborious manual tuning. We show that this approach is capable of similar performance compared to our hand tuned GPU kernels for basis sets with s and p angular momenta. We also demonstrate that mixed precision schemes (using both single and double precision) remain stable and accurate for molecules with d functions. We provide benchmarks of the execution time of entire self-consistent field (SCF) calculations using our GPU code and compare to mature CPU based codes, showing the benefits of the GPU architecture for electronic structure theory with appropriately redesigned algorithms. We suggest that the meta-programming and empirical performance optimization approach may be important in future computational chemistry applications, especially in the face of quickly evolving computer architectures. PMID- 26589025 TI - Design and Implementation of Scientific Software Components to Enable Multiscale Modeling: The Effective Fragment Potential (QM/EFP) Method. AB - The design and development of scientific software components to provide an interface to the effective fragment potential (EFP) methods are reported. Multiscale modeling of physical and chemical phenomena demands the merging of software packages developed by research groups in significantly different fields. Componentization offers an efficient way to realize new high performance scientific methods by combining the best models available in different software packages without a need for package readaptation after the initial componentization is complete. The EFP method is an efficient electronic structure theory based model potential that is suitable for predictive modeling of intermolecular interactions in large molecular systems, such as liquids, proteins, atmospheric aerosols, and nanoparticles, with an accuracy that is comparable to that of correlated ab initio methods. The developed components make the EFP functionality accessible for any scientific component-aware software package. The performance of the component is demonstrated on a protein interaction model, and its accuracy is compared with results obtained with coupled cluster methods. PMID- 26589026 TI - The GW-Method for Quantum Chemistry Applications: Theory and Implementation. AB - The GW-technology corrects the Kohn-Sham (KS) single particle energies and single particle states for artifacts of the exchange-correlation (XC) functional of the underlying density functional theory (DFT) calculation. We present the formalism and implementation of GW adapted for standard quantum chemistry packages. Our implementation is tested using a typical set of molecules. We find that already after the first iteration of the self-consistency cycle, G0W0, the deviations of quasi-particle energies from experimental ionization potentials and electron affinities can be reduced by an order of magnitude against those of KS-DFT using GGA or hybrid functionals. Also, we confirm that even on this level of approximation there is a considerably diminished dependency of the G0W0-results on the XC-functional of the underlying DFT. PMID- 26589027 TI - Structure, Energy, and Vibrational Frequencies of Oxygen Allotropes On (n <= 6) in the Covalently Bound and van der Waals Forms: Ab Initio Study at the CCSD(T) Level. AB - Recent experiments on the UV and electron beam irradiation of solid O2 reveals a series of IR features near the valence antisymmetric vibration band of O3 which are frequently interpreted as the formation of unusual On allotropes in the forms of weak complexes or covalently bound molecules. In order to elucidate the question of the nature of the irradiation products, the structure, relative energies, and vibrational frequencies of various forms of On (n = 1-6) in the singlet, triplet, and, in some cases, quintet states were studied using the CCSD(T) method up to the CCSD(T,full)/cc-pCVTZ and CCSD(T,FC)/aug-cc-pVTZ levels. The results of calculations demonstrate the existence of stable highly symmetric structures O4 (D3h), O4 (D2d), and O6 (D3d) as well as the intermolecular complexes O2.O2, O2.O3, and O3.O3 in different conformations. The calculations show that the local minimum corresponding to the O3...O complex is quite shallow and cannot explain the nu3 band features close to 1040 cm(-1), as was proposed previously. For the ozone dimer, a new conformer was found which is more stable than the structure known to date. The effect of the ozone dimer on the registered IR spectra is discussed. PMID- 26589028 TI - Long-Range Corrected Hybrid Density Functionals with Improved Dispersion Corrections. AB - By incorporating the improved empirical atom-atom dispersion corrections from DFT D3 [Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H. J. Chem. Phys.2010, 132, 154104], two long-range corrected (LC) hybrid density functionals are proposed. Our resulting LC hybrid functionals, omegaM06-D3 and omegaB97X-D3, are shown to be accurate for a very wide range of applications, such as thermochemistry, kinetics, noncovalent interactions, frontier orbital energies, fundamental gaps, and long-range charge-transfer excitations, when compared with common global and LC hybrid functionals. Relative to omegaB97X-D [Chai, J.-D.; Head-Gordon, M. Phys. Chem. Chem. Phys.2008, 10, 6615], omegaB97X-D3 (reoptimization of omegaB97X D with improved dispersion corrections) is shown to be superior for nonbonded interactions, and similar in performance for bonded interactions, while omegaM06 D3 is shown to be superior for general applications. PMID- 26589029 TI - Assessment of a Nonlocal Correction Scheme to Semilocal Density Functional Theory Methods. AB - A nonlocal correction method to (semi)local density-functional theory (DFT) methods is derived that is based on a partitioning of the correlation-energy density into atom-atom contributions. Nonlocal interaction contributions, which are absent in standard DFT methods, are introduced in this method by using atomic weight functions that do not vanish exponentially as the atomic densities but with the inverse sixth power of the atomic distances. The parameters contained in these weight functions were fitted to reproduce intermolecular interaction energies for a range a small dimer systems. The new functional has then been tested both for intermolecular interactions, using the S22, S66 * 8, and IonHB databases from Hobza et al., and for other thermodynamical properties using a subset of 14 databases of the GMTKN30 database of Grimme et al. It is found that for intermolecular interactions the accuracy of the method is often higher than with standard DFT+D methods while for other properties, such as reaction energies or relative conformation energies of medium sized organic molecules, the accuracy is similar to hybrid-DFT+D methods. The nonlocal correction method has been tested also to predict the interaction energy of the water-graphene system yielding an estimated interaction energy of -2.87 kcal/mol, which is in line with previous theoretical investigations. PMID- 26589030 TI - Conical Intersection and Potential Energy Surface Features of a Model Retinal Chromophore: Comparison of EOM-CC and Multireference Methods. AB - This work investigates the performance of equation-of-motion coupled-cluster (EOM CC) methods for describing the changes in the potential energy surfaces of the penta-2,4-dieniminium cation, a reduced model of the retinal chromophore of visual pigments, due to dynamical electron correlation effects. The ground-state wave function of this model includes charge-transfer and diradical configurations whose weights vary along different displacements and are rapidly changing at the conical intersection between the ground and the first excited states, making the shape of the potential energy surface sensitive to a balanced description of nondynamical and dynamical correlation. Recently, variational (MRCISD) and perturbative (MRPT2) approaches for including dynamical correlation in CASSCF based calculations were tested along three representative ground state paths. Here, we use the same three paths to compare the performance of single-reference EOM-CC methods against MRCISD and MRCISD+Q. We find that the spin-flip variant of EOM-CCSD with perturbative inclusion of triple excitations (dT or fT) produces potential energy profiles of the two lowest electronic states in quantitative agreement with MRCISD+Q (our highest-quality reference method). The nonparallelity errors and differences in vertical energy differences of the two surfaces along these scans are less than 1.4 kcal/mol (EOM-SF-CCSD(dT) versus MRCISD+Q). For comparison, the largest error of MRCISD versus MRCISD+Q is 1.7 kcal/mol. Our results show that the EOM-CC methods provide an alternative to multireference approaches and may be used to study photochemical systems like the one used in this work. PMID- 26589031 TI - Accurate Noncovalent Interaction Energies Using Truncated Basis Sets Based on Frozen Natural Orbitals. AB - We assess the accuracy of basis set truncations based on natural orbitals determined by second-order perturbation theory for computing noncovalent interaction energies with coupled cluster through perturbative triples [CCSD(T)]. We consider two methods for truncation: (i) the usual frozen natural orbital approach (FNO) in which the basis set truncation occurs before the iterative CCSD computation [FNO CCSD(T)] and (ii) an approach in which the truncation occurs only for the perturbative triples contribution [CCSD+FNO(T)]. The errors incurred are comparable for both methods and are small enough for the methods to be used for benchmark-quality studies of noncovalent interactions. For the FNO CCSD(T) method with a modest natural orbital occupation tolerance of 10(-5), the mean absolute error in the interaction energies for the S22 data set in an aug-cc-pVDZ basis set is only 0.012 kcal mol(-1) versus canonical CCSD(T) values. The same method exhibits a mean absolute error of 0.020 kcal mol(-1) for the S11 data set in the aug-cc-pVTZ basis set versus canonical CCSD(T) values. PMID- 26589032 TI - Structure-Properties Relationships in Triplet Ground State Organic Diradicals: A Computational Study. AB - A fast and efficient computational protocol, devised for the accurate calculation of singlet-triplet magnetic splittings in organic diradicals, is here applied to several promising organic magnets, recently considered in the literature. The very good agreement with the measured values, obtained for all investigated compounds, suggests that the present approach could successfully flank the experiment in the design of novel magnetic materials. Indeed, some structure magnetic properties relationships were rationalized thanks to the theoretical soundness of the adopted multireference approach. In particular the different effects of N. and NO. magnetic moieties, as well as the role of lateral aliphatic chains and phenyl pendant substituents, are discussed in detail. PMID- 26589033 TI - Performance of Non-Local and Atom-Pairwise Dispersion Corrections to DFT for Structural Parameters of Molecules with Noncovalent Interactions. AB - The nonlocal, electron density dependent dispersion correction of Vydrov and Van Voorhis (Vydrov, O. A.; Van Voorhis, T. J. Chem. Phys.2010, 133, 244103), termed VV10 or DFT-NL, has been implemented for structural optimizations of molecules. It is tested in combination with the four (hybrid)GGA density functionals TPSS, TPSS0, B3LYP, and revPBE38 for inter- and intramolecular noncovalent interactions (NCI) and compared to results from atom-pairwise dispersion corrected DFT-D3. The methods are applied to a wide range of different problems, namely the S22 and S66 test sets, large transition metal complexes, water hexamer clusters, hexahelicene, and four other difficult cases of intramolecular NCI. Critical interatomic distances are computed remarkably accurately by both dispersion corrections compared to theoretical or experimental reference data and inter- and intramolecular interactions are treated on equal footing. The methods can be recommended as reliable and robust tools for geometry optimizations of large systems in which long-range dispersion forces are crucial. PMID- 26589035 TI - Benchmarking the Starting Points of the GW Approximation for Molecules. AB - The GW approximation is nowadays being used to obtain accurate quasiparticle energies of atoms and molecules. In practice, the GW approximation is generally evaluated perturbatively, based on a prior self-consistent calculation within a simpler approximation. The final result thus depends on the choice of the self consistent mean-field chosen as a starting point. Using a recently developed GW code based on Gaussian basis functions, we benchmark a wide range of starting points for perturbative GW, including Hartree-Fock, LDA, PBE, PBE0, B3LYP, HSE06, BH&HLYP, CAM-B3LYP, and tuned CAM-B3LYP. In the evaluation of the ionization energy, the hybrid functionals are clearly superior results starting points when compared to Hartree-Fock, to LDA, or to the semilocal approximations. Furthermore, among the hybrid functionals, the ones with the highest proportion of exact-exchange usually perform best. Finally, the reliability of the frozen core approximation, that allows for a considerable speed-up of the calculations, is demonstrated. PMID- 26589034 TI - CCSDTQ Optimized Geometry of Water Dimer. AB - The equilibrium geometry of the lowest energy structure of water dimer [(H2O)2] has been investigated using coupled cluster theory. A hierarchy of conventional coupled cluster methods is utilized up to singles doubles triples and quadruples excitations (CCSDTQ). The geometry of (H2O)2 is also optimized using the explicitly correlated coupled cluster singles doubles and perturbative triples [CCSD(T)-F12b] method. Overall, we find that the effect of including excitations beyond CCSD(T) is smaller than inclusion of core-valence correlation and comparable to scalar-relativistic and adiabatic effects. PMID- 26589036 TI - Basis Set Dependence of Interaction Energies Computed Using Composite Post-MP2 Methods. AB - We report the performance of composite post-MP2 ab initio methods with small basis sets for description of noncovalent interactions, using the S66 data set as a benchmark. For three representative complexes, it is shown that explicitly correlated coupled cluster (CCSD-F12a) methods yield interaction energies ca. 0.1 kcal/mol from the complete basis set limit with aug-cc-pVDZ. Triple excitations are not explicitly correlated in this approach, but we show that scaling the perturbative triples via the (T*) approximation improves agreement with benchmark values. Across the entire S66 data set, this approach results in a root-mean square error (RMSE) of 0.13 kcal/mol or 3%, with well-balanced description of all classes of complex. The basis set dependence of traditional CCSD(T) interaction energies is examined, and the small 6-31G*(0.25) basis set is found to give particularly accurate results (RMSE = 0.15 kcal/mol, or 4%). We also employ spin component scaling (SCS) of CCSD-F12a data, which gives slightly better accuracy than CCSD(T*)-F12a if contributions from same- and opposite-spin pairs are optimized for this data set (RMSE = 0.08 kcal/mol, or 2%). Interpolation of local MP2 and MP3 is also shown to accurately reproduce benchmark data with both aug-cc pVDZ (RMSE = 0.18 kcal/mol or 5%) and 6-31G*(0.25) (RMSE = 0.13 kcal/mol or 4%). PMID- 26589037 TI - Parametrization and Benchmark of DFTB3 for Organic Molecules. AB - DFTB3 is a recent extension of the self-consistent-charge density-functional tight-binding method (SCC-DFTB) and derived from a third order expansion of the density functional theory (DFT) total energy around a given reference density. Being applied in combination with the parametrization of its predecessor (MIO), DFTB3 improves for hydrogen binding energies, proton affinities, and hydrogen transfer barriers. In the present study, parameters especially designed for DFTB3 are presented, and its performance is evaluated for small organic molecules focusing on thermochemistry, geometries, and vibrational frequencies from our own and several databases from literature. The new parameters remove significant overbinding errors, reduce errors for geometries of noncovalent interactions, and improve the overall performance. PMID- 26589038 TI - Performance of meta-GGA Functionals on General Main Group Thermochemistry, Kinetics, and Noncovalent Interactions. AB - Among the computationally efficient semilocal density functionals for the exchange-correlation energy, meta-generalized-gradient approximations (meta-GGAs) are potentially the most accurate. Here, we assess the performance of three new meta-GGAs (revised Tao-Perdew-Staroverov-Scuseria or revTPSS, regularized revTPSS or regTPSS, and meta-GGA made simple or MGGA_MS), within and beyond their "comfort zones," on Grimme's big test set of main-group molecular energetics (thermochemistry, kinetics, and noncovalent interactions). We compare them against the standard Perdew-Burke-Ernzerhof (PBE) GGA, TPSS, and Minnesota M06L meta-GGAs, and Becke-3-Lee-Yang-Parr (B3LYP) hybrid of GGA with exact exchange. The overall performance of these three new meta-GGA functionals is similar. However, dramatic differences occur for different test sets. For example, M06L and MGGA_MS perform best for the test sets that contain noncovalent interactions. For the 14 Diels-Alder reaction energies in the "difficult" DARC subset, the mean absolute error ranges from 3 kcal mol(-1) (MGGA_MS) to 15 kcal mol(-1) (B3LYP), while for some other reaction subsets the order of accuracy is reversed; more generally, the tested new semilocal functionals outperform the standard B3LYP for ring reactions. Some overall improvement is found from long-range dispersion corrections for revTPSS and regTPSS but not for MGGA_MS. Formal and universality criteria for the functionals are also discussed. PMID- 26589039 TI - CCSD[T] Describes Noncovalent Interactions Better than the CCSD(T), CCSD(TQ), and CCSDT Methods. AB - The CCSD(T) method is often called the "gold standard" of computational chemistry, because it is one of the most accurate methods applicable to reasonably large molecules. It is particularly useful for the description of noncovalent interactions where the inclusion of triple excitations is necessary for achieving a satisfactory accuracy. While it is widely used as a benchmark, the accuracy of CCSD(T) interaction energies has not been reliably quantified yet against more accurate calculations. In this work, we compare the CCSD[T], CCSD(T), and CCSD(TQ) noniterative methods with full CCSDTQ and CCSDT(Q) calculations. We investigate various types of noncovalent complexes [hydrogen bonded (water dimer, ammonia dimer, water ... ammonia), dispersion-bound (methane dimer, methane ... ammonia), and pi-pi stacked (ethene dimer)] using various coupled-clusters schemes up to CCSDTQ in 6-31G*(0.25), 6-31G**(0.25, 0.15), and aug-cc-pVDZ basis sets. We show that CCSDT(Q) reproduces the CCSDTQ results almost exactly and can thus serve as a benchmark in the cases where CCSDTQ calculations are not feasible. Surprisingly, the CCSD[T] method provides better agreement with the benchmark values than the other noniterative analogs, CCSD(T) and CCSD(TQ), and even than the much more expensive iterative CCSDT scheme. The CCSD[T] interaction energies differ from the benchmark data by less than 5 cal/mol on average (for all complexes and all basis sets), whereas the error of CCSD(T) is 9 cal/mol. In larger systems, the difference between these two methods can grow by as much as 0.15 kcal/mol. While this effect can be explained only as an error compensation, the CCSD[T] method certainly deserves more attention in accurate calculations of noncovalent interactions. PMID- 26589040 TI - Interactions between Methane and Polycyclic Aromatic Hydrocarbons: A High Accuracy Benchmark Study. AB - Minimum energy structures and interaction energies are obtained for a series of polycyclic aromatic hydrocarbons (PAHs) interacting with a methane molecule. The PAHs include benzene, naphthalene, anthracene, phenanthrene, tetracene, pyrene, and coronene. Interaction energies are calculated using the highest level of theory and basis set available, that is, complete-basis-set extrapolated MP2 plus a conventional or explicitly correlated CCSD(T) correction in moderately sized basis sets. The results show that the singly coordinated minimum configuration observed earlier for benzene-methane is no longer the global minimum one for naphthalene and larger PAHs. Instead, triply coordinated geometries are lower in energy. The global minimum structures for methane interacting with extended systems like graphene sheets and carbon nanotubes are likely to be triply coordinated as well. A variety of novel dispersion-including DFT approaches are compared against the wave-function-based benchmark potential energy curves. The top performer, the B3LYP functional combined with the -D3 dispersion correction, is then employed to calculate interaction energies for methane interacting with hexabenzocoronene and circumcoronene in order to estimate the methane adsorption energy on graphite. The delicate balance between dispersion and exchange in PAH methane interactions is elucidated using symmetry-adapted perturbation theory with a DFT description of monomers. The present study provides an important benchmark for the design and tuning of more approximate methods for an accurate description of hydrocarbon physisorption on carbon nanostructures. PMID- 26589041 TI - Quantum Monte Carlo Study of pi-Bonded Transition Metal Organometallics: Neutral and Cationic Vanadium-Benzene and Cobalt-Benzene Half Sandwiches. AB - We present accurate quantum Monte Carlo (QMC) calculations that enabled us to determine the structure, spin multiplicity, ionization energy, dissociation energy, and spin-dependent electronic gaps of neutral and positively charged vanadium-benzene and cobalt-benzene systems. From total/ionization energy, we deduce a sextet (quintet) state of neutral (cationic) vanadium-benzene systems and quartet (triplet) state of the neutral (cationic) cobalt-benzene systems. Vastly different energy gaps for the two spin channels are predicted for the vanadium-benzene system and broadly similar energy gaps for the cobalt-benzene system. For this purpose, we have used a multistage combination of techniques with consecutive elimination of systematic biases except for the fixed-node approximation in QMC. Our results significantly differ from the established picture based on previous less accurate calculations and point out the importance of high-level many-body methods for predictive calculations of similar transition metal-based organometallic systems. PMID- 26589042 TI - More pi Electrons Make a Difference: Emergence of Many Radicals on Graphene Nanoribbons Studied by Ab Initio DMRG Theory. AB - Graphene nanoribbons (GNRs), also seen as rectangular polycyclic aromatic hydrocarbons, have been intensively studied to explore their potential applicability as superior organic semiconductors with high mobility. The difficulty arises in the synthesis or isolation of GNRs with increased conjugate length, GNRs being known to have radical electrons on their zigzag edges. Here, we use a most advanced ab initio theory based on density matrix renormalization group (DMRG) theory to show the emerging process of how GNRs develop electronic states from nonradical to radical characters with increasing ribbon length. We show the mesoscopic size effect that comes into play in quantum many-body interactions of pi electrons, which is responsible for the polyradical nature. An analytic form is presented to model the size dependence of the number of radicals for arbitrary-length GNRs. These results and associated insights deepen the understanding of carbon-based chemistry and offer useful information for the synthesis and design of stable and functional GNRs. PMID- 26589043 TI - Incremental CCSD(T)(F12)|MP2-F12-A Method to Obtain Highly Accurate CCSD(T) Energies for Large Molecules. AB - In this work, we apply the recently proposed MP2 correction to incremental energies within the domain-specific basis set approach to incrementally expanded CCSD(T)(F12) energies. The approach is tested for a set of 27 molecules with different electronic structures including water clusters, aqua complexes, aliphatic hydrocarbons, alkenes, alkynes, aromatic systems, and amino acids. The root mean squared deviation of the absolute energies with respect to the standard calculation is 1.7 kJ/mol, the mean absolute deviation is 1.2 kJ/mol, and the range is 4.7 kJ/mol. The wall time of the computations is reduced due to the application of a doubly parallel strategy-the independent coupled cluster calculations are performed on up to 70 nodes in parallel, and in addition the computations on one node are performed with the SMP-parallelized coupled cluster code in TURBOMOLE. Using this strategy, we can perform computations in minutes or hours, instead of days or months. Applying the proposed scheme enables us to routinely treat systems with 50 atoms at the CCSD(T)(F12) level in combination with appropriate basis sets to obtain nearly CBS accuracy. Also, larger systems are still feasible on a standard cluster as demonstrated for H3O(+)(H2O)25Cl(-) with 80 atoms. PMID- 26589044 TI - Which Ab Initio Wave Function Methods Are Adequate for Quantitative Calculations of the Energies of Biradicals? The Performance of Coupled-Cluster and Multi Reference Methods Along a Single-Bond Dissociation Coordinate. AB - We examine the accuracy of single-reference and multireference correlated wave function methods for predicting accurate energies and potential energy curves of biradicals. The biradicals considered are intermediate species along the bond dissociation coordinates for breaking the F-F bond in F2, the O-O bond in H2O2, and the C-C bond in CH3CH3. We apply a host of single-reference and multireference approximations in a consistent way to the same cases to provide a better assessment of their relative accuracies than was previously possible. The most accurate method studied is coupled cluster theory with all connected excitations through quadruples, CCSDTQ. Without explicit quadruple excitations, the most accurate potential energy curves are obtained by the single-reference RCCSDt method, followed, in order of decreasing accuracy, by UCCSDT, RCCSDT, UCCSDt, seven multireference methods, including perturbation theory, configuration interaction, and coupled-cluster methods (with MRCI+Q being the best and Mk-MR-CCSD the least accurate), four CCSD(T) methods, and then CCSD. PMID- 26589045 TI - Coarse-Grained Potentials for Local Interactions in Unfolded Proteins. AB - Recent studies have revealed the key role of natively unfolded proteins in many important biological processes. In order to study the conformational changes of these proteins, a one-bead-per-amino-acid coarse grained (CG) model is developed, and a method is proposed to extract the potential functions for the local interactions between CG beads. Experimentally obtained Ramachandran data for the coil regions of proteins are converted into distributions of pseudo-bond and pseudo-dihedral angles between neighboring alpha-carbons in the polypeptide chain. These are then used to derive bending and torsion potentials, which are residue and sequence specific. The validity of the developed model is testified by studying the radius of gyration as well as the hydrodynamic properties of chemically denatured proteins. PMID- 26589046 TI - Critical Assessment of Current Force Fields. Short Peptide Test Case. AB - The applicability of molecular dynamics simulations for studies of protein folding or intrinsically disordered proteins critically depends on quality of energetic functions-force fields. The four popular force fields for biomolecular simulations, CHARMM22/CMAP, AMBER FF03, AMBER FF99SB, and OPLS-AA/L, were compared in prediction of conformational propensities of all common proteinogenic amino acids. The minimalistic model of terminally block amino acids (dipeptides) was chosen for assessment of side chain effects on backbone propensities. The precise metadynamics simulations revealed striking inconsistency of trends in conformational preferences as manifested by investigated force fields for both backbone and side chains. To trace this disapproval between force fields, the two related AMBER force fields were studied more closely. In the cases of FF99SB and FF03, we uncovered that the distinct tends were driven by different charge models. Additionally, the effects of recent correction for side chain torsion (FF99SB-ILDN) were examined on affected amino acids and exposed significant coupling between free energy profiles and propensities of backbone and side chain conformers. These findings have important consequences for further force field development. PMID- 26589047 TI - Systematic Parametrization of Polarizable Force Fields from Quantum Chemistry Data. AB - We introduce ForceBalance, a method and free software package for systematic force field optimization with the ability to parametrize a wide variety of functional forms using flexible combinations of reference data. We outline several important challenges in force field development and how they are addressed in ForceBalance, and present an example calculation where these methods are applied to develop a highly accurate polarizable water model. ForceBalance is available for free download at https://simtk.org/home/forcebalance. PMID- 26589048 TI - Mechanisms for Solvatochromic Shifts of Free-Base Porphine Studied with Polarizable Continuum Models and Explicit Solute-Solvent Interactions. AB - Solvatochromic shifts of free-base porphine in the Q-band and B-band were studied using the polarizable continuum model (PCM) and explicit solvent molecules employing time-dependent density functional theory (TDDFT) and the symmetry adapted cluster-configuration interaction (SAC-CI) method. The state-specific (SS) and linear-response (LR) methods were examined in the PCM calculations. These models involve different types of solute-solvent interactions. The LR PCM and explicit solvation models reproduced the experimentally observed trends of the solvatochromic shifts, while the SS PCM failed to reproduce the experimental findings. The origin of the solvatochromic shifts of free-base porphine was dispersive interactions between the solute and solvent. Specific solute-solvent interactions would be important for a decrease of the splitting width between Q bands. Based on the Casimir-Polder formula and a decomposition analysis, it was found that the dominant part of the solute-solvent interactions can be considered using independent particle approximations. PMID- 26589049 TI - Proton/Hydrogen Transfer Mechanisms in the Guanine-Cytosine Base Pair: Photostability and Tautomerism. AB - Proton/hydrogen-transfer processes have been broadly studied in the past 50 years to explain the photostability and the spontaneous tautomerism in the DNA base pairs. In the present study, the CASSCF/CASPT2 methodology is used to map the two dimensional potential energy surfaces along the stretched NH reaction coordinates of the guanine-cytosine (GC) base pair. Concerted and stepwise pathways are explored initially in vacuo, and three mechanisms are studied: the stepwise double proton transfer, the stepwise double hydrogen transfer, and the concerted double proton transfer. The results are consistent with previous findings related to the photostability of the GC base pair, and a new contribution to tautomerism is provided. The C-based imino-oxo and imino-enol GC tautomers, which can be generated during the UV irradiation of the Watson-Crick base pair, have analogous radiationless energy-decay channels to those of the canonical base pair. In addition, the C-based imino-enol GC tautomer is thermally less stable. A study of the GC base pair is carried out subsequently taking into account the DNA surroundings in the biological environment. The most important stationary points are computed using the quantum mechanics/molecular mechanics (QM/MM) approach, suggesting a similar scenario for the proton/hydrogen-transfer phenomena in vacuo and in DNA. Finally, the static model is complemented by ab initio dynamic simulations, which show that vibrations at the hydrogen bonds can indeed originate hydrogen-transfer processes in the GC base pair. The relevance of the present findings for the rationalization of the preservation of the genetic code and mutagenesis is discussed. PMID- 26589050 TI - Spectral "Fine" Tuning in Fluorescent Proteins: The Case of the GFP-Like Chromophore in the Anionic Protonation State. AB - Fluorescent proteins (FPs), featuring the same chromophore but different chromophore-protein interactions, display remarkable spectral variations even when the same chromophore protonation state, i.e. the anionic state, is involved. We examine the mechanisms behind this tuning by means of structural analysis, molecular dynamics simulations, and vertical excitation energy calculations using QM/MM Time-Dependent Density Functional Theory (TD-DFT), CASPT2/CASSCF, and SAC CI. The proteins under investigation include the structurally similar, though spectrally distinct, Dronpa and mTFP0.7, with absorption peaks at 453 and 503 nm, respectively. We extend our analysis to two Green Fluorescent Protein variants, GFP-S65T (absorption peak at 484 nm), for comparison with previous computational studies, and GFP-S65G/V68L/S72A/T203Y, a yellow fluorescent protein (514 nm), in order to include one of the most red-shifted FPs containing a GFP-like chromophore. We compare different choices of the QM system, and we discuss how molecular dynamics simulations affect the calculation of excitation energies, with respect to X-ray structures. We are able to partially reproduce the spectral tuning of the FPs and correlate it to the chromophore bond-length variations, as determined by specific interactions with the chromophore environment. PMID- 26589051 TI - A Full Dimensionality Approach to Evaluate the Nonlinear Optical Properties of Molecules with Large Amplitude Anharmonic Tunneling Motions. AB - Previously, a reduced dimensionality approach was used to determine the vibrational contribution to nonlinear optical properties for molecules with large amplitude anharmonic modes that takes into account tunneling between potential wells (Luis, J. M.; Reis, H.; Papadopoulos, M. G.; Kirtman, B. J. Chem. Phys.2009, 131, 034116). Here, the treatment is extended, again using ammonia as an example, to include the remaining modes at several approximate levels. It is shown that this extension is essential to obtaining the correct results. Our new approach fully accounts for tunneling and avoids possible convergence problems associated with the normal coordinate expansion of the potential energy surface in a single-well treatment. For accurate numerical values, a good treatment of electron correlation is required along with a flexible basis set including diffuse functions. PMID- 26589052 TI - Interfacial States in Donor-Acceptor Organic Heterojunctions: Computational Insights into Thiophene-Oligomer/Fullerene Junctions. AB - Donor-acceptor heterojunctions composed of thiophene oligomers and C60 fullerene were investigated with computational methods. Benchmark calculations were performed with time-dependent density functional theory. The effects of varying the density functional, the number of oligomers, the intermolecular distance, the medium polarization, and the chemical functionalization of the monomers were analyzed. The results are presented in terms of diagrams where the electronic states are classified as locally excited states, charge-transfer states, and delocalized states. The effects of each option for computational simulations of realistic heterojunctions employed in photovoltaic devices are evaluated and discussed. PMID- 26589053 TI - An Assessment of RASSCF and TDDFT Energies and Gradients on an Organic Donor Acceptor Dye Assisted by Resonance Raman Spectroscopy. AB - The excitation energies and gradients in the ground and the first excited state of a novel donor-(pi-bridge)-acceptor 4-methoxy-1,3-thiazole-based chromophore were investigated by means of MS-RASPT2/RASSCF and TDDFT in solution. Within both methods, the excitation energies strongly depend on the employed equilibrium structures, whose differences can be rationalized in terms of bond length alternation indexes. It is shown that functionals with an increased amount of exact exchange provide the best estimation of the ground and excited state properties. While B3LYP fails to predict the excitation energies due to its intrinsic problems in describing charge transfer (CT) states, the long-range corrected CAM-B3LYP and M06-2X functionals deliver good agreement with the experimental UV/vis absorption spectrum. The calculation of resonance Raman intensity patterns is used to discern which ground and excited state gradients are best. The results clearly evidence that both CAM-B3LYP and RASSCF excited state gradients and energies in combination with CAM-B3LYP ground state gradients are appropriate to describe the CT state of this push-pull chromophore. PMID- 26589054 TI - Cluster-Continuum Calculations of Hydration Free Energies of Anions and Group 12 Divalent Cations. AB - Understanding aqueous phase processes involving group 12 metal cations is relevant to both environmental and biological sciences. Here, quantum chemical methods and polarizable continuum models are used to compute the hydration free energies of a series of divalent group 12 metal cations (Zn(2+), Cd(2+), and Hg(2+)) together with Cu(2+) and the anions OH(-), SH(-), Cl(-), and F(-). A cluster-continuum method is employed, in which gas-phase clusters of the ion and explicit solvent molecules are immersed in a dielectric continuum. Two approaches to define the size of the solute-water cluster are compared, in which the number of explicit waters used is either held constant or determined variationally as that of the most favorable hydration free energy. Results obtained with various polarizable continuum models are also presented. Each leg of the relevant thermodynamic cycle is analyzed in detail to determine how different terms contribute to the observed mean signed error (MSE) and the standard deviation of the error (STDEV) between theory and experiment. The use of a constant number of water molecules for each set of ions is found to lead to predicted relative trends that benefit from error cancellation. Overall, the best results are obtained with MP2 and the Solvent Model D polarizable continuum model (SMD), with eight explicit water molecules for anions and 10 for the metal cations, yielding a STDEV of 2.3 kcal mol(-1) and MSE of 0.9 kcal mol(-1) between theoretical and experimental hydration free energies, which range from -72.4 kcal mol(-1) for SH( ) to -505.9 kcal mol(-1) for Cu(2+). Using B3PW91 with DFT-D3 dispersion corrections (B3PW91-D) and SMD yields a STDEV of 3.3 kcal mol(-1) and MSE of 1.6 kcal mol(-1), to which adding MP2 corrections from smaller divalent metal cation water molecule clusters yields very good agreement with the full MP2 results. Using B3PW91-D and SMD, with two explicit water molecules for anions and six for divalent metal cations, also yields reasonable agreement with experimental values, due in part to fortuitous error cancellation associated with the metal cations. Overall, the results indicate that the careful application of quantum chemical cluster-continuum methods provides valuable insight into aqueous ionic processes that depend on both local and long-range electrostatic interactions with the solvent. PMID- 26589055 TI - Replica-Permutation Method with the Suwa-Todo Algorithm beyond the Replica Exchange Method. AB - We propose a new method for molecular dynamics and Monte Carlo simulations, which is referred to as the replica-permutation method (RPM), to realize more efficient sampling than the replica-exchange method (REM). In RPM, not only exchanges between two replicas but also permutations among more than two replicas are performed. Furthermore, instead of the Metropolis algorithm, the Suwa-Todo algorithm is employed for replica-permutation trials to minimize its rejection ratio. We applied RPM to particles in a double-well potential energy, Met enkephalin in a vacuum, and a C-peptide analog of ribonuclease A in explicit water. For comparison purposes, replica-exchange molecular dynamics simulations were also performed. As a result, RPM sampled not only the temperature space but also the conformational space more efficiently than REM for all systems. From our simulations of C-peptide, we obtained the alpha-helix structure with salt bridges between Gly2 and Arg10, which is known in experiments. Calculating its free energy landscape, the folding pathway was revealed from an extended structure to the alpha-helix structure with the salt bridges. We found that the folding pathway consists of the two steps: The first step is the "salt-bridge formation step," and the second step is the "alpha-helix formation step." PMID- 26589056 TI - Efficient Computation of Hartree-Fock Exchange Using Recursive Subspace Bisection. AB - We use a recursive subspace bisection approach introduced in Phys. Rev. Lett.2009, 102, 166406 to accelerate the computation of the Hartree-Fock exchange operator in plane-wave pseudopotential electronic structure calculations. Recursive subspace bisection allows for an unbiased localization of orbitals in domains of varying size and a truncation of orbitals that preserves accuracy in a controlled manner. This representation is used to accelerate the computation of the Hartree-Fock exchange operator, which in turn makes first-principles molecular dynamics simulations based on hybrid density functionals feasible for larger systems than previously possible. We describe a parallel implementation of the method and a load balancing algorithm. The efficiency and accuracy of this approach are demonstrated in electronic structure calculations of a chloride ion solvated in liquid water and calculations of the vacancy formation energy in a 512-atom silicon crystal using the PBE0 hybrid exchange-correlation functional. PMID- 26589057 TI - Efficient Two-Step Procedures for Locating Transition States of Surface Reactions. AB - Using various two-step strategies, we examined how to accurately locate transition states (TS) of reactions using the example of eight reactions at metal surfaces with 14-33 moving atoms. These procedures combined four path-finding methods for locating approximate TS structures (nudged elastic band, standard string, climbing image string, and searching string, using a conjugate gradient or a modified steepest-descent method for optimization and two types of coordinate systems) with subsequent local refinement by two dimer methods. The dimer-Lanczos variant designed for this study required on average 20% fewer gradient calls than the standard dimer method. During the path finding phase, using mixed instead of Cartesian coordinates reduced the numbers of gradient calls on average by an additional 21%, while using a modified steepest-descent method improved that key efficiency criterion on average by 13%. For problematic cases we suggest strategies especially adapted to the problem at hand. PMID- 26589058 TI - Free Energy Approaches for Modeling Atomic Force Microscopy in Liquids. AB - High resolution atomic force microscopy (AFM) in liquids offers atomic scale insight into the structure at water/solid interfaces and is perhaps the only tool capable of resolving the nature of formed hydration layers. However, convolution between the imaging signal and the tip/surface interactions and hydration layers means that interpretation is far from straightforward. Modeling the complex imaging mechanism of atomic force microscopy in liquids requires calculation of the free energy profile as a function of the distance between AFM tip and surface. Its derivative is the best approximation for the force acting on the AFM tip, including entropic contributions from interactions with water molecules in hydration layers over the surface and around the tip apex. In order to establish a reliable approach for these simulations, we compare two methods of calculating free energy profiles from atomistic molecular dynamics simulations, umbrella sampling and free energy perturbation, on two model surfaces, calcium fluoride and calcium carbonate. Our results demonstrate that both methods effectively provide equivalent free energy profiles but offer different possibilities in terms of efficiency, constraints, and analysis of the free energy components. PMID- 26589059 TI - Generalized Born Solvation Model SM12. AB - We present a new self-consistent reaction-field implicit solvation model that employs the generalized Born approximation for the bulk electrostatic contribution to the free energy of solvation. The new solvation model (SM) is called SM12 (where "12" stands for 2012), and it is available with two sets of parameters, SM12CM5 and SM12ESP. The SM12CM5 parametrization is based on CM5 partial atomic charges, and the SM12ESP parametrization is based on charges derived from a quantum-mechanically calculated electrostatic potential (ESP) (in particular, we consider ChElPG and Merz-Kollman-Singh charges). The model was parametrized over 10 combinations of theoretical levels including the 6-31G(d) and MG3S basis sets and the B3LYP, mPW1PW, M06-L, M06, and M06-2X density functionals against 2979 reference experimental data. The reference data include 2503 solvation free energies and 144 transfer free energies of neutral solutes composed of H, C, N, O, F, Si, P, S, Cl, Br, and I in water and in 90 organic solvents as well as 332 solvation free energies of singly charged anions and cations in acetonitrile, dimethyl sulfoxide, methanol, and water. The advantages of the new solvation model over our previous generalized Born model (SM8) and all other previous generalized Born solvation models are (i) like the SMD model based on electron density distributions, it may be applied with a single set of parameters with arbitrary extended basis sets, whereas the SM8 model involves CM4 or CM4M charges that become unstable for extended basis sets, (ii) it is parametrized against a more diverse training sets than any previous solvation model, and (iii) it is defined for the entire periodic table. PMID- 26589060 TI - Ions and RNAs: Free Energies of Counterion-Mediated RNA Fold Stabilities. AB - We present an implicit ion model fo the calculation of the electrostatic free energies of RNA conformations in the presence of divalent counterions such as Mg(2+). The model was applied to the native and several non-native structures of the hammerhead ribozyme and the group I intron in Tetrahymena to study the stability of candidate unfolding intermediates. Based on a rigorous statistical mechanical treatment of the counterions that are closely associated with the RNA while handling the rest of the ions in the solution via a mean field theory in the Grand Canonical ensemble, the implicit ion model accurately reproduces the ordering of their free energies, correctly identifying the native fold as the most stable structure out of the other alternatives. For RNA concentrations in the range below 0.1 MUM, divalent concentrations of ~0.5 mM or above, and over a wide range of solvent dielectric constants, the equilibrium number of divalent ions associated with the RNA remains close to what is needed to exactly neutralize the phosphate negative charges, but the stability of compact RNA folds can be reversed when the divalent ion concentration is lower than ~0.1 mM, causing the number of associated ions to underneutralize the RNA. In addition to calculating counterion-mediated free energies, the model is also able to identify potential high-affinity electronegative ion binding pockets on the RNA. The model can be easily integrated into an all-atom Monte Carlo RNA simulation as an implicit counterion model. PMID- 26589061 TI - Accurate Reaction Energies in Proteins Obtained by Combining QM/MM and Large QM Calculations. AB - We here suggest and test a new method to obtain stable energies in proteins for charge-neutral reactions by running large quantum mechanical (QM) calculations on structures obtained by combined QM and molecular mechanics (QM/MM) geometry optimization on several snapshots from molecular dynamics simulations. As a test case, we use a proton transfer between a metal-bound cysteine residue and a second-sphere histidine residue in the active site of [Ni,Fe] hydrogenase, which has been shown to be very sensitive to the surroundings. We include in the QM calculations all residues within 4.5 A of the active site, two capped residues on each side of the active-site residues, and all charged groups that are buried inside the protein, which for this enzyme includes three iron-sulfur clusters, in total, 930 atoms. These calculations are performed at the BP86/def2-SV(P) level, but the energies are then extrapolated to the B3LYP/def2-TZVP level with a smaller QM system, and zero-point energy, entropy, and thermal effects are added. We test three approaches to model the remaining atoms of the protein solvent, viz., by standard QM/MM approaches using either mechanical or electrostatic embedding or by using a continuum solvation model for the large QM systems. Quite encouragingly, the three approaches give the same results within 14 kJ/mol, and variations in the size of the QM system do not change the energies by more than 8 kJ/mol, provided that the QM/MM junctions are not moved closer to the QM system. The statistical precision for the average over 10 snapshots is 1-3 kJ/mol. PMID- 26589062 TI - Molecular Dynamics Simulations Provide Atomistic Insight into Hydrogen Exchange Mass Spectrometry Experiments. AB - It is now clear that proteins are flexible entities that in solution switch between conformations to achieve their function. Hydrogen/Deuterium Exchange Mass Spectrometry (HX/MS) is an invaluable tool to understand dynamic changes in proteins modulated by cofactor binding, post-transductional modifications, or protein-protein interactions. ERK2MAPK, a protein involved in highly conserved signal transduction pathways of paramount importance for normal cellular function, has been extensively studied by HX/MS. Experiments of the ERK2MAPK in the inactive and active states (in the presence or absence of bound ATP) have provided valuable information on the plasticity of the MAPK domain. However, interpretation of the HX/MS data is difficult, and changes are mostly explained in relation to available X-ray structures, precluding a complete atomic picture of protein dynamics. In the present work, we have used all atom Molecular Dynamics simulations (MD) to provide a theoretical framework for the interpretation of HX/MS data. Our results show that detailed analysis of protein solvent interaction along the MD simulations allows (i) prediction of the number of protons exchanged for each peptide in the HX/MS experiments, (ii) rationalization of the experimentally observed changes in exchange rates in different protein conditions at the residue level, and (iii) that at least for ERK2MAPK, most of the functionally observed differences in protein dynamics are related to what can be considered the native state conformational ensemble. In summary, the combination of HX/MS experiments with all atom MD simulations emerges as a powerful approach to study protein native state dynamics with atomic resolution. PMID- 26589063 TI - Cardiolipin Models for Molecular Simulations of Bacterial and Mitochondrial Membranes. AB - Present in bacterial and mitochondrial membranes, cardiolipins have a unique dimeric structure, which carries up to two charges (i.e., one per phosphate group) and, under physiological conditions, can be unprotonated or singly protonated. Exhaustive models and characterization of cardiolipins are to date scarce; therefore we propose an ab initio parametrization of cardiolipin species for molecular simulation consistent with commonly used force fields. Molecular dynamics simulations using these models indicate a protonation dependent lipid packing. A peculiar interaction with solvating mono- and divalent cations is also observed. The proposed models will contribute to the study of the assembly of more realistic bacterial and mitochondrial membranes and the investigation of the role of cardiolipins for the biophysical and biochemical properties of membranes and membrane-embedded proteins. PMID- 26589064 TI - Free Energies by Thermodynamic Integration Relative to an Exact Solution, Used to Find the Handedness-Switching Salt Concentration for DNA. AB - Sets of free energy differences are useful for finding the equilibria of chemical reactions, while absolute free energies have little physical meaning. However finding the relative free energy between two macrostates by subtraction of their absolute free energies is a valuable strategy in certain important cases. We present calculations of absolute free energies of biomolecules, using a combination of the well-known Einstein molecule method (for treating the solute) with a conceptually related method of recent genesis for computing free energies of liquids (to treat the solvent and counterions). The approach is based on thermodynamic integration from a detailed atomistic model to one which is simplified but analytically solvable, thereby giving the absolute free energy as that of the tractable model plus a correction term found numerically. An example calculation giving the free energy with respect to salt concentration for the B- and Z-isomers of all-atom duplex DNA in explicit solvent and counterions is presented. The coexistence salt concentration is found with unprecedented accuracy. PMID- 26589065 TI - Improved Parameters for the Martini Coarse-Grained Protein Force Field. AB - The Martini coarse-grained force field has been successfully used for simulating a wide range of (bio)molecular systems. Recent progress in our ability to test the model against fully atomistic force fields, however, has revealed some shortcomings. Most notable, phenylalanine and proline were too hydrophobic, and dimers formed by polar residues in apolar solvents did not bind strongly enough. Here, we reparametrize these residues either through reassignment of particle types or by introducing embedded charges. The new parameters are tested with respect to partitioning across a lipid bilayer, membrane binding of Wimley-White peptides, and dimerization free energy in solvents of different polarity. In addition, we improve some of the bonded terms in the Martini protein force field that lead to a more realistic length of alpha-helices and to improved numerical stability for polyalanine and glycine repeats. The new parameter set is denoted Martini version 2.2. PMID- 26589066 TI - Free Energy Profile and Kinetics Studies of Paclitaxel Internalization from the Outer to the Inner Wall of Microtubules. AB - Several pieces of experimental evidence led us to hypothesize that the mechanism of action of paclitaxel (Taxol) could involve a two-steps binding process, with paclitaxel first binding within the outer wall of microtubules and then moving into the inner binding site. In this work, we first used multiply targeted molecular dynamics (MTMD) for steering paclitaxel from the outer toward the inner binding site. This rough trajectory was then submitted to a refinement procedure in the path collective variables space. Paclitaxel binding energy was monitored along the refined pathway, highlighting the relevance of residues belonging to the H6-H7 and the M- loops. Computational results were supported by kinetics studies performed on fluorescent paclitaxel derivatives. PMID- 26589067 TI - Force Biased Molecular Dynamics Simulation Study of Effect of Dendrimer Generation on Interaction with DNA. AB - We have studied the effect of dendrimer generation on the interaction between dsDNA and the PAMAM dendrimer using force biased simulation of dsDNA with three generations of dendrimer: G3, G4, and G5. Our results for the potential of mean force (PMF) and the dendrimer asphericity along the binding pathway, combined with visualization of the simulations, demonstrate that dendrimer generation has a pronounced impact on the interaction. The PMF increases linearly with increasing generation of the dendrimer. While, in agreement with previous results, we see an increase in the extent to which the dendrimer bends the dsDNA with increasing dendrimer generation, we also see that the deformation of the dendrimer is greater with smaller generation of the dendrimer. The larger dendrimer forces the dsDNA to conform to its structure, while the smaller dendrimer is forced to conform to the structure of the dsDNA. Monitoring the number of bound cations at different values of force bias distance shows the expected effect of ions being expelled when the dendrimer binds dsDNA. PMID- 26589068 TI - The Role of the Flexible L43-S54 Protein Loop in the CcrA Metallo-beta-lactamase in Binding Structurally Dissimilar beta-Lactam Antibiotics. AB - The CcrA di-Zn beta-lactamase is a bacterial enzyme capable of efficiently hydrolyzing and thus disabling a diverse set of beta-lactam antibiotics. Understanding the factors that contribute to the efficiency of CcrA is essential for the design of new CcrA-resistant antibiotics and enzyme inhibitors. The efficacy of CcrA has been speculated to be partially attributable to the flexible protein loop located above the active site (L43-S54), which would mold around structurally different substrates, for snag binding. Confirmation of this hypothesis about the role of the loop has been a challenge, from both an experimental and a theoretical point of view. We employed our newly developed method that combines extensive sampling of the protein structure via discrete molecular dynamics (DMD) and quantum mechanical (QM) treatment of the active site, QM/DMD, to investigate the structural role of the L43-S54 loop in binding three different beta-lactam antibiotics: imipenem, ampicillin, and cephalorodine. QM/DMD sampling was followed by high level ab initio calculations for the assessment of the energy contributions to loop-substrate interactions. We show that upon binding of all three antibiotic molecules, the loop comes in direct contact with the substrates and adopts distinctly different conformations depending on the bound substrate. The loop contributes to the binding affinity of CcrA to antibiotics. The primary component of the loop-substrate interaction is hydrophobic, and nonspecific, except for cephalorodine that is capable of pi stacking with W49 via one of the two competing modes. PMID- 26589069 TI - Localizing the Charged Side Chains of Ion Channels within the Crowded Charge Models. AB - The simplified coarse grained models of selectivity of Nonner and co-workers predict ion selectivity for a variety of different ion channels. The model includes the charged atoms of the channel's charged residues and permeant ions. However its MC implementation does not take advantage of the increasingly large body of structural information available. Here, we introduce the location of the channel's charged residues into the model's Hamiltonian. In the DEKA Na(+) channel, this allows us to correlate the lysine's topological location directly with the predicted selectivity. In the NanC channel, from Escherichia coli , the dramatic variation in the resulting ion population predicts novel selectivity regions and binding sites that can be directly correlated with structural information. These results have well-defined thermodynamic properties that are significantly modified by structural detail allowing new insights with molecular detail. PMID- 26589070 TI - Another Piece of the Membrane Puzzle: Extending Slipids Further. AB - To be able to model complex biological membranes in a more realistic manner, the force field Slipids (Stockholm lipids) has been extended to include parameters for sphingomyelin (SM), phosphatidylglycerol (PG), phosphatidylserine (PS) lipids, and cholesterol. Since the parametrization scheme was faithful to the scheme used in previous editions of Slipids, all parameters are consistent and fully compatible. The results of careful validation of a number of key structural properties for one and two component lipid bilayers are in excellent agreement with experiments. Potentials of mean force for transferring water across binary mixtures of lipids and cholesterol were also computed in order to compare water permeability rates to experiments. In agreement with experimental and simulation studies, it was found that the permeability and partitioning of water is affected by cholesterol in lipid bilayers made of saturated lipids to the largest extent. With the extensions of Slipids presented here, it is now possible to study complex systems containing many different lipids and proteins in a fully atomistic resolution in the isothermic-isobaric (NPT) ensemble, which is the proper ensemble for membrane simulations. PMID- 26589071 TI - PaLaCe: A Coarse-Grain Protein Model for Studying Mechanical Properties. AB - We present a coarse-grain protein model PaLaCe (Pasi-Lavery-Ceres) that has been developed principally to allow fast computational studies of protein mechanics and to clarify the links between mechanics and function. PaLaCe uses a two-tier protein representation with one to three pseudoatoms representing each amino acid for the main nonbonded interactions, combined with atomic-scale peptide groups and some side chain atoms to allow the explicit representation of backbone hydrogen bonds and to simplify the treatment of bonded interactions. The PaLaCe force field is composed of physics-based terms, parametrized using Boltzmann inversion of conformational probability distributions derived from a protein structure data set, and iteratively refined to reproduce the experimental distributions. PaLaCe has been implemented in the MMTK simulation package and can be used for energy minimization, normal mode calculations, and molecular or stochastic dynamics. We present simulations with PaLaCe that test its ability to maintain stable structures for folded proteins, reproduce their dynamic fluctuations, and correctly model large-scale, force-induced conformational changes. PMID- 26589072 TI - Modeling Protein-Protein Recognition in Solution Using the Coarse-Grained Force Field SCORPION. AB - We present here the SCORPION-Solvated COaRse-grained Protein interactION-force field, a physics-based simplified coarse-grained (CG) force field. It combines our previous CG protein model and a novel particle-based water model which makes it suitable for Molecular Dynamics (MD) simulations of protein association processes. The protein model in SCORPION represents each amino acid with one to three beads, for which electrostatic and van der Waals effective interactions are fitted separately to reproduce those of the all-atom AMBER force field. The protein internal flexibility is accounted for by an elastic network model (ENM). We now include in SCORPION a new Polarizable Coarse-Grained Solvent (PCGS) model, which is computationally efficient, consistent with the protein CG representation, and yields accurate electrostatic free energies of proteins. SCORPION is used here for the first time to perform hundreds-of-nanoseconds-long MD simulations of protein/protein recognition in water, here the case of the barnase/barstar complex. These MD simulations showed that, for five of a total of seven simulations starting from several initial conformations, and after a time going from 1 to 500 ns, the proteins bind in a conformation very close to the native bound structure and remain stable in this conformation for the rest of the simulation. An energetic analysis of these MD show that this recognition is driven both by van der Waals and electrostatic interactions between proteins. SCORPION appears therefore as a useful tool to study protein-protein recognition in a solvated environment. PMID- 26589073 TI - A New Tabu-Search-Based Algorithm for Solvation of Proteins. AB - The proper description of explicit water shells is of enormous importance for all atom calculations. We propose a new approach for the setup of water shells around proteins based on Tabu-Search global optimization and compare its efficiency with standard molecular dynamics protocols using the chignolin protein as a test case. Both algorithms generate reasonable water shells, but the new approach provides solvated systems with an increased water-enzyme interaction and offers further advantages. It enables a stepwise buildup of the solvent shell, so that the more important inner part can be prepared more carefully. It also allows the generation of solute structures which can be biased either toward the (experimental) starting structure or the underlying theoretical model, i.e., the employed force field. PMID- 26589074 TI - Implicit Solvent Models and Stabilizing Effects of Mutations and Ligands on the Unfolding of the Amyloid beta-Peptide Central Helix. AB - We have systematically evaluated the ability of molecular dynamics simulation with implicit solvation models (EEF1.1, SASA, ASPENR, SCPISM, RUSH, ACE2, GBORN, GBSW, GBMV II, FACTS) to characterize the unfolding of the amyloid beta (Abeta) peptide and the stabilizing effects of mutations and ligands. The 13-26 region of Abeta (Abeta13-26) unfolds and leads to the formation of amyloid fibrils, the causative agent of Alzheimer's disease. Stabilization of Abeta13-26 decreases Abeta polymerization as well as the formation of intermediate structures, which may also be toxic. The unfolding behavior of wild-type Abeta13-26 with an increase in temperature led us to select GBORN, GBMV II, and SCPISM for further investigation considering their ability to reproduce the stabilizing effect on the Abeta13-26 helical conformation due to mutations (V18A/F19A/F20A and V18L/F19L/F20L) and ligands (Dec-DETA and Pep1b) designed to stabilize Abeta13 26. Structural parameters (RMSD, helicity) of the peptide were used to assess the performance of the implicit solvent models with reference to previous explicit solvent simulations. PMID- 26589075 TI - Aromatic Excimers: Ab Initio and TD-DFT Study. AB - Excited dimers (excimers) formed by aromatic molecules are important in biological systems as well as in chemical sensing. The structure of many biological systems is governed by excimer formation. Since theoretical studies of such systems provide important information about mutual arrangement of aromatic molecules in structural biology, we carried out extensive calculations on the benzene excimer using EOM-CCSD, RI-CC2, CASPT2, and TD-DFT approaches. For the benzene excimer, we evaluate the reliability of the TD-DFT method based on the B3LYP, PBE, PBE0, and omegaPBEh functionals. We extended the calculations to naphthalene, anthracene, and pyrene excimers. We find that nearly parallel stacked forms are the minimum energy structure. On the basis of the benzene to pyrene excimers, we might roughly estimate the equilibrium layer-to-layer distance for bilayer-long arenes in the first singlet excited state, which is predicted to be bound. PMID- 26589076 TI - Pseudoadenoid dysplasia in proliferative verrucous leukoplakia. PMID- 26589077 TI - The Ponseti Method in Low and Middle Income Countries: Challenges and Lessons Learned. AB - Diffusing a health care innovation like the Ponseti method in low and middle income countries requires more than the application of the traditional continuing medical education approach of providing lectures on the topic. Challenges include limited personnel, competing priorities, inadequate medical supplies, and limited resources. Experience has indicated that the best chances of success in establishing such a program include identifying and advising in-country "champions" to provide the leadership, energy, and direction to build the program. PMID- 26589078 TI - Treatment of Idiopathic Clubfoot in the Ponseti Era and Beyond. AB - The initial treatment of idiopathic clubfoot was mostly surgical for the 1980s/1990s. In the latter half of the 1990s, there was a surge of interest in the Ponseti method of casting after the publication of Dr. Ponseti's 30-year results. Many authors have since shown correction rates in the high 90th percentile, rendering posteromedial release surgery almost obsolete. The success of the Ponseti method has been brought internationally and extrapolated to more and more difficult cases, such as idiopathic or syndromic, primary or recurrence. This new trend will create a different subset of complications. PMID- 26589079 TI - Treatment of Severe Recurrent Clubfoot. AB - Understanding the pathoanatomy of severe recurrent clubfoot and its implication on treatment options is important for the successful treatment. A comprehensive clinical evaluation of the different components helps in selecting procedures. Individual needs and social and psychological factors influencing treatment and the impact of treatment on the child have to be considered. With increasing dissemination and improved understanding of the Ponseti method, a further decrease in the frequency of severe recurrent clubfoot can be hoped for and expected. PMID- 26589080 TI - Evaluation and Surgical Management of the Overcorrected Clubfoot Deformity in the Adult Patient. AB - Adult patients presenting with an overcorrected clubfoot often have had a posteromedial release. They present later in life and have compensated quite well despite the development of deformity. Minor trauma may lead to the onset of acute symptoms. A spectrum of deformity exists. Key features include a dorsally subluxated navicular, a dorsal bunion from overpull of the tibialis anterior tendon, valgus of the ankle or hindfoot or both, and a flattop talus. This article details the diagnostic approach to the overcorrected clubfoot patient and options for management of the various components of the deformity. PMID- 26589081 TI - Tendon Transfers Around the Foot: When and Where. AB - Tendon transfers are invaluable in the treatment of severe children's foot deformities. They are often preferable to simple releases, lengthening, or fusion in surgical treatment because they provide an active motor function for deformity correction and, when properly selected, the procedures stabilize the foot against progressive deformity. The authors describe 4 commonly used tendon transfer procedures that are useful in children's foot deformity surgeries. PMID- 26589082 TI - Syndromic Feet: Arthrogryposis and Myelomeningocele. AB - Treatment of myelomeningocele and arthrogrypotic foot deformities has been controversial; many different procedures have been advocated for each type of deformity. In most cases, outcomes have had variable success rates, and many complications can occur. Treatment strategies should highlight care that avoids the development of a stiffened foot and allows for a variety of options to regain correction when a relapse occurs. This is particularly true in myelomeningocele, whereby a stiff foot runs a high risk for skin ulceration, leading to osteomyelitis. Discussion includes appropriate circumstances for the use of presented procedures and the author's preferred treatment for each deformity. PMID- 26589083 TI - Cavus Foot. AB - Cavus foot is usually related to neurologic abnormalities and then requires complete clinical and imaging evaluation. It is important to identify whether the deformity is flexible or rigid, and combine different soft tissue and bony techniques to accomplish the best lasting results. On rigid feet, it is crucial to determine the apex of the deformity to guide the bony procedures indicated for each specific case. Tarsectomies are preferred to arthrodesis in these rigid feet with the aim of achieve a plantigrade foot. PMID- 26589084 TI - Neuromuscular Foot: Spastic Cerebral Palsy. AB - Foot and ankle deformities in cerebral palsy can be effectively treated with surgery. Surgery should be considered in patients with significant deformity and those who have pain or difficulty with orthotic and shoe wear. Equinus contracture of both gastrocnemius and soleus can be treated with open tendoachilles lengthening; ankle valgus with medial epiphysiodesis. Equinovarus is more commonly seen in hemiplegic patients and this deformity can usually be treated with tendon transfers. Triple arthrodesis is an option in children with severe degenerative changes. It is important to address all aspects of the child's pathology at the time of surgical correction. PMID- 26589085 TI - Tarsal Coalitions--Calcaneonavicular Coalitions. AB - Calcaneonavicular coalitions are an important cause of adolescent foot pain and deformity. The congenital condition is characterized by an aberrant osseous, cartilaginous, or fibrinous union of the calcaneal and navicular bones. Calcaneonavicular coalitions are the most common form of tarsal coalitions identified within epidemiologic studies. A thorough understanding of this clinically significant entity is important for restoring joint motion and preventing long-term disability. PMID- 26589086 TI - Talocalcaneal Coalitions. AB - Talocalcaneal coalitions present with complaints of flatfeet, foot or ankle pain after minor injury, or recurrent ankle sprains. Physical examination findings include limited subtalar motion and prominence inferior to the medial malleolus. Use of computed topography (CT) scan is recommended for preoperative planning. Confirmation of resection with intraoperative CT. Resection of talocalcaneal coalitions with fat-graft interposition has superior results to primary arthrodesis. Improved outcomes have been reported after resection, with foot scores averaging 90/100 (AOFAS). PMID- 26589087 TI - Painful Flexible Flatfoot. AB - Flatfoot is commonly encountered by pediatric orthopedic surgeons and pediatricians. A paucity of literature exists on how to define a flatfoot. The absence of the medial arch with a valgus hindfoot is the hallmark of this pathology. Flatfoot can be flexible or rigid. This review focuses on the diagnosis and treatment of the flexible flatfoot. Most flatfeet are flexible and clinically asymptomatic, and warrant little intervention. If feet are symptomatic, treatment is needed. Most patients who require treatment improve with foot orthotics and exercises. Only feet resistant to conservative modalities are deemed surgical candidates. The presence of a tight heel cord is often found in patients who fail conservative management. PMID- 26589089 TI - Managing Pediatric Foot and Ankle Deformity. PMID- 26589088 TI - Pediatric Ankle Fractures: Concepts and Treatment Principles. AB - Current clinical concepts are reviewed regarding the epidemiology, anatomy, evaluation, and treatment of pediatric ankle fractures. Correct diagnosis and management relies on appropriate examination, imaging, and knowledge of fracture patterns specific to children. Treatment is guided by patient history, physical examination, plain film radiographs and, in some instances, computed tomography. Treatment goals are to restore acceptable limb alignment, physeal anatomy, and joint congruency. For high-risk physeal fractures, patients should be monitored for growth disturbance as needed until skeletal maturity. PMID- 26589090 TI - Metastatic chromophobe renal cell carcinoma to the brain. AB - Metastases represent the most common tumors of the central nervous system, with clear cell renal cell carcinomas showing a particular predilection to involve the brain. This report documents an unusual case of a patient with a chromophobe renal cell carcinoma presenting with a brain metastasis. A 58-year-old man presented with stroke-like symptomatology, including expressive aphasia, right side facial weakness, headaches and vomiting. CT imaging demonstrated a 4.7 cm left frontal lobe hemorrhagic mass. He underwent surgery with excision of the mass, which was marked by sheets of large cells with lightly eosinophilic to clear cytoplasm. PAX8 staining was positive and a diagnosis of clear cell carcinoma of probably renal origin was rendered. Subsequently, CT imaging of the abdomen revealed a 12.9 cm left renal mass. The patient underwent a left nephrectomy and a diagnosis of chromophobe renal cell carcinoma was made. The tumor was noted to extend into the perirenal fat and to have involved a paraaortic lymph node. Re-review of the frontal lobe lesion confirmed the tumor was the same. Chromophobe renal cell carcinomas are far less common than clear cell tumors, are less likely to metastasize, and generally have a more favorable overall prognosis. When they metastasize, they most commonly involve the liver, lung and lymph nodes, in contrast to the more common clear cell carcinomas that typically spread to the lungs, bone and brain. PMID- 26589091 TI - The solution structure of the soluble form of the lipid-modified azurin from Neisseria gonorrhoeae, the electron donor of cytochrome c peroxidase. AB - Neisseria gonorrhoeae colonizes the genitourinary track, and in these environments, especially in the female host, the bacteria are subjected to low levels of oxygen, and reactive oxygen and nitrosyl species. Here, the biochemical characterization of N. gonorrhoeae Laz is presented, as well as, the solution structure of its soluble domain determined by NMR. N. gonorrhoeae Laz is a type 1 copper protein of the azurin-family based on its spectroscopic properties and structure, with a redox potential of 277+/-5 mV, at pH7.0, that behaves as a monomer in solution. The globular Laz soluble domain adopts the Greek-key motif, with the copper center located at one end of the beta-barrel coordinated by Gly48, His49, Cys113, His118 and Met122, in a distorted trigonal geometry. The edge of the His118 imidazole ring is water exposed, in a surface that is proposed to be involved in the interaction with its redox partners. The heterologously expressed Laz was shown to be a competent electron donor to N. gonorrhoeae cytochrome c peroxidase. This is an evidence for its involvement in the mechanism of protection against hydrogen peroxide generated by neighboring lactobacilli in the host environment. PMID- 26589092 TI - Dietary nitrogen and calcium modulate bone metabolism in young goats. AB - Ruminants, possessing the rumino-hepatic circulation, are thought to cope easily with reduced dietary nitrogen (N) supply which is of economic and environmental interest to diminish N output. Nevertheless, feeding an N reduced diet to young goats resulted in a decrease in calcitriol and calcium (Ca) plasma concentrations. Although a dietary Ca reduction alone stimulated calcitriol synthesis and plasma Ca concentrations were restored, in combination with a reduced N supply this stimulating effect was abolished. Based on the important role bone tissue plays in maintaining Ca homeostasis, aim of the present study was to determine effects of an N reduced diet with or without a concomitant Ca reduction on bone metabolism in young goats. A dietary N reduction alone resulted in a significant rise in plasma concentrations of bone resorption marker C terminal telopeptide of type I collagen (CTX) and bone formation marker osteocalcin (OC), while reduced intake of Ca as well as the combination of both dietary interventions increased bone markers only slightly. Bone mineral content and bone mineral density of metatarsi were decreased by reduced N intake, while Ca and phosphorus (P) content of dried bones remained unaffected. In contrast, a dietary Ca reduction alone led to decreased Ca and P content of dried bones. From these data it can be concluded that a dietary N reduction alone or in combination with a reduced dietary Ca supply modulated bone metabolism in young goats. PMID- 26589093 TI - Neurosteroids in hepatic encephalopathy: Novel insights and new therapeutic opportunities. AB - Hepatic encephalopathy (HE) is a serious neuropsychiatric disorder resulting from liver failure. Symptoms of HE include mild cognitive impairment, stupor and coma. Morphological changes to neuroglia (both astrocytes and microglia) occur in HE consisting of cytotoxic brain edema (astrocyte swelling) in acute liver failure and Alzheimer type-2 astrocytosis in cirrhosis. Visual-evoked responses in animals with liver failure and HE manifest striking similarities to those in animals treated with agonists of the GABA-A receptor complex. Neurosteroids are synthesized in brain following activation of translocator protein (TSPO), a mitochondrial neuroglial cholesterol-transporter protein. TSPO sites are activated in both animal models of HE as well as in autopsied brain tissue from HE patients. Activation of TSPO sites results in increased cholesterol transport into the mitochondrion followed by stimulation of a metabolic pathway culminating in the synthesis of allopregnanolone (ALLO) and tetrahydrodeoxycorticosterone (THDOC), neurosteroids with potent positive allosteric modulatory action on the GABA-A receptor complex. Concentrations of ALLO and THDOC in brain tissue from mice with HE resulting from toxic liver injury are sufficient to induce sedation in animals of the same species and significant increases in concentrations of ALLO have been reported in autopsied brain tissue from cirrhotic patients with HE leading to the proposal that "increased GABAergic tone" in HE results from that increased brain concentrations of this neurosteroid. Agents with the potential to decrease neurosteroid synthesis and/or prevent their modulatory actions on the GABA-A receptor complex may provide novel approaches to the management and treatment of HE. Such agents include indomethacin, benzodiazepine receptor inverse agonists and a novel series of compounds known as GABA-A receptor modulating steroid antagonists (GAMSA). PMID- 26589094 TI - Determining the quality of life of depressed patients in Singapore through a multiple mediation framework. AB - Quality of Life (QOL) is reported to be lower for patients with depression than the general population. This study aims to investigate the mediational effects of protective resource factors (PSFs), such as depressive symptom management ability, self-efficacy, social support and problem-focused coping act, in the relationship between dysfunctional attitudes and QOL. It is hypothesized that these PSFs have different mediating strengths. Self-report questionnaires which aimed to determine the influences of these PSFs through a multiple mediation framework were completed by 80 depressed adult outpatients from the National University Hospital of Singapore. PSFs have different influence on mental and physical QOL. Depressive symptom management ability is the most important PSF mediating both domains and better problem-focused coping abilities demonstrate improvement in the physical domain of QOL. Self-efficacy and social support are shown to be non-significant mediators. The results suggest for future effective interventions to focus primarily on improving depression patients' symptom management ability and problem-focused coping skills to raise their life quality. Furthermore, findings from this study have implications on the future investigation of QOL as a unitary construct. PMID- 26589095 TI - Restricted temporal access to food and anorexia in mice: Microstructure of eating within feeding opportunities. AB - Intake and body weight were recorded in a closed economy as male and female C57BL/6 mice progressed through either fixed interval (FI) or fixed unit price (FUP) schedules of cost for 20-mg food pellets. Access to food was constrained to four 40 min food opportunities (FOs) per day, spaced 4-h apart through the dark phase. Nose poke responses and pellet deliveries were collected at 10-s resolution to allow pellet-by-pellet analysis. In the FI protocol, mice maintained adequate food intake and body weight through the study, even though at the highest FI (50-s) they spent the entire 40-min FOs engaged in eating at or near the maximum rate allowed by the schedule. In the FUP protocol, mice greatly reduced their intake and lost weight at the highest FUP (50 responses/pellet). The analysis of response and pellet distributions showed these mice were not filling the FOs with responding and ate less at dusk (FO #1) and dawn (FO #4) than at FOs #2 and 3 in the middle of the night. The principal, and unexpected, sex difference was that females tended to eat more than males despite lower body weight, but behavioral changes as a function of feeding cost or schedule were qualitatively similar in both sexes. These results show that slow eating as imposed by an FI is not sufficient to produce hypophagia and, in the FUP protocol, hypophagia cannot be explained by slowed eating due to response requirements. We discuss the role of effort or time in FUP-induced anorexia, and suggest this murine model may emulate some aspects of human anorexia nervosa better than current activity-based protocols. PMID- 26589096 TI - What are the risks and knowledge deficits for prescribing and administering opioids in the ward environment? A quality project on assessing and improving knowledge. AB - Investigations into Medical Emergency Team (MET) calls and related clinical incident reviews at a large district teaching hospital provided evidence that over sedation can be a significant issue post opioid administration and that safe and effective pain management requires accurate opioid knowledge and patient assessment skills. The aim of the study was to develop education that was directed at identified knowledge deficits, and to evaluate the impact of this tailored education program on knowledge of safe prescribing and administration of opioids. Knowledge levels were explored using a structured questionnaire in a pre and post-test design. A convenience sample of 34 nurses and 5 junior medical officers across three surgical wards in a tertiary referral hospital had their knowledge assessed. Results showed significant improvement when repeat questionnaires were given two weeks post-delivery of education. Mean scores were 68% at baseline and 89% two weeks post completion of the education program. The greatest improvement in scores was recorded for drug knowledge including dose, half-life and administration. The findings from this study suggest that the opioid education program is effective in improving the knowledge of safe prescribing and administration of opioids, however further studies are required. PMID- 26589097 TI - Efficacy of lifestyle interventions on clinical and neuroimaging outcomes in elderly. AB - The prevalence of Alzheimer's disease (AD) is constantly growing worldwide in absence of any effective treatment. Methodology and technique advancements facilitated the early diagnosis of AD leading to a shift toward preclinical AD stages investigation in order to delay the disease onset in individuals at risk for AD. Recent evidence demonstrating the aging related multifactorial nature of AD supported the hypothesis that modifiable environmental factors can accelerate or delay the disease onset. In particular, healthy dietary habits, constant physical and cognitive activities are associated with reduced brain atrophy, amyloid load and incidence of AD cases. Due to these promising results, an emerging field of studies is currently investigating the efficacy of interventions addressing different lifestyle habits in cognitive intact elderly individuals as a potential preventive strategy against AD onset. We provide a critical overview of the current evidence on nonpharmacologic treatments in elderly individuals, discussing their efficacy on clinical and neuroimaging outcomes and identifying current methodological issues. Future perspectives, relevant for the scientific community and the worldwide public health institutes will be further discussed. PMID- 26589098 TI - The effects of composting approaches on the emissions of anthropogenic volatile organic compounds: A comparison between vermicomposting and general aerobic composting. AB - Emission patterns of 13 VOCs were investigated in three types of vermicomposting systems (Eisenia fetida, Metaphire posthuma, and Lampito mauritii) in reference to a traditional aerobic composting system by feeding the systems with mixtures of three materials (coal ash (CA), municipal solid waste (MSW), and cow dung (CD)). On an average, the emission rates of aromatic VOCs (benzene, toluene, xylenes, and styrene) were two to three times higher than all other groups (aldehyde, ketones, esters, and alcohols) from all three types of feeding mixtures. However, the emission rates of aromatic VOCs were generally reduced over time in both aerobic composting and vermicomposting systems. Such reduction in the emission rates was most prominent from Eisenia-treated CD + MSW (1:1), Lampito-treated CD + CA (1:1), and Metaphire-treated CD. The results clearly indicated that the increase in humified organic C fractions (humic acid and fulvic acid) and the microbial biomass present during the biocomposting processes greatly reduced the emissions of VOCs. Hence, the study recommends that vermicomposting of coal ash and municipal solid waste in combination with cow dung in 1:1 ratio is an environmentally gainful proposition. PMID- 26589100 TI - The impact of sediment bioturbation by secondary organisms on metal bioavailability, bioaccumulation and toxicity to target organisms in benthic bioassays: Implications for sediment quality assessment. AB - Bioturbation alters the properties of sediments and modifies contaminant bioavailability to benthic organisms. These naturally occurring disturbances are seldom considered during the assessment of sediment quality. We investigated how the presence (High bioturbation) and absence (Low bioturbation) of a strongly bioturbating amphipod within three different sediments influenced metal bioavailability, survival and bioaccumulation of metals to the bivalve Tellina deltoidalis. The concentrations of dissolved copper decreased and manganese increased with increased bioturbation. For copper a strong correlation was observed between increased bivalve survival (53-100%) and dissolved concentrations in the overlying water. Increased bioturbation intensity resulted in greater tissue concentrations for chromium and zinc in some test sediments. Overall, the results highlight the strong influence that the natural bioturbation activities from one organism may have on the risk contaminants pose to other organisms within the local environment. The characterisation of field-based exposure conditions concerning the biotic or abiotic resuspension of sediments and the rate of attenuation of released contaminants through dilution or readsorption may enable laboratory-based bioassay designs to be adapted to better match those of the assessed environment. PMID- 26589099 TI - Metal measurement in aquatic environments by passive sampling methods: Lessons learning from an in situ intercomparison exercise. AB - Passive sampling devices (PS) are widely used for pollutant monitoring in water, but estimation of measurement uncertainties by PS has seldom been undertaken. The aim of this work was to identify key parameters governing PS measurements of metals and their dispersion. We report the results of an in situ intercomparison exercise on diffusive gradient in thin films (DGT) in surface waters. Interlaboratory uncertainties of time-weighted average (TWA) concentrations were satisfactory (from 28% to 112%) given the number of participating laboratories (10) and ultra-trace metal concentrations involved. Data dispersion of TWA concentrations was mainly explained by uncertainties generated during DGT handling and analytical procedure steps. We highlight that DGT handling is critical for metals such as Cd, Cr and Zn, implying that DGT assembly/dismantling should be performed in very clean conditions. Using a unique dataset, we demonstrated that DGT markedly lowered the LOQ in comparison to spot sampling and stressed the need for accurate data calculation. PMID- 26589101 TI - [Pulse oximetry versus electrocardiogram for heart rate assessment during resuscitation of the preterm infant]. AB - BACKGROUND: Heart rate (HR) assessment is essential during neonatal resuscitation, and it is usually done by auscultation or pulse oximetry (PO). The aim of the present study was to determine whether HR assessment with ECG is as fast and reliable as PO during preterm resuscitation. MATERIAL AND METHODS: Thirty-nine preterm (<32 weeks of gestational age and/or<1.500g of birth weight) newborn resuscitations were video-recorded. Simultaneous determinations of HR using ECG and PO were registered every 5s for the first 10min after birth. Time needed to place both devices and to obtain reliable readings, as well as total time of signal loss was registered. The proportion of reliable HR readings available at the beginning of different resuscitation manoeuvres was also determined. RESULTS: Time needed to connect the ECG was shorter compared with the PO (26.64+/-3.01 vs. 17.10+/-1.28 s, for PO and ECG, respectively, P<.05). Similarly, time to obtain reliable readings was shorter for the ECG (87.28+/ 12.11 vs. 26.38+/-3.41 s, for PO and ECG, respectively, P<.05). Availability of reliable HR readings at initiation of different resuscitation manoeuvres was lower with the PO (PO vs. ECG for positive pressure ventilation: 10.52 vs. 57.89% P<.05; intubation: 33.33 vs. 91.66%, P<.05). PO displayed lower HR values during the first 6min after birth (P<.05, between 150 and 300s). CONCLUSIONS: Reliable HR is obtained later with the PO than with the ECG during preterm resuscitation. PO underestimates HR in the first minutes of resuscitation. PMID- 26589102 TI - [Five years after the Spanish neonatal resuscitation survey. Are we improving?]. AB - INTRODUCTION: An analysis is presented of delivery room (DR) neonatal resuscitation practices in Spanish hospitals. METHODS: A questionnaire was sent by e-mail to all hospitals attending deliveries in Spain. RESULTS: A total of 180 questionnaires were sent, of which 155 were fully completed (86%). Less than half (71, 46%) were level i or ii hospitals, while 84 were level iii hospital (54%). In almost three-quarters (74.2%) of the centres, parents and medical staff were involved in the decision on whether to start resuscitation or withdraw it. A qualified resuscitation team (at least two members) was available in 80% of the participant centres (63.9% level i-ii, and 94.0% level iii, P<.001). Neonatal resuscitation courses were held in 90.3% of the centres. The availability of gas blenders, pulse oximeters, manual ventilators, and plastic wraps was higher in level iii hospitals. Plastic wraps for pre-term hypothermia prevention were used in 63.9% of the centres (40.8% level i-iiand 83.3% level iii, P<.001). Term newborn resuscitation was started on room air in 89.7% of the centres. A manual ventilator (T-piece) was the device used in most cases when ventilation was required (42.3% level i-iiand 78.6% level iii, P<.001). Early CPAP in preterm infants was applied in 91.7% of the tertiary hospitals. In last 5 years some practices have improved, such neonatal resuscitation training, pulse oximeter use, or early CPAP support. CONCLUSIONS: There is an improvement in some practices of neonatal resuscitation. Significant differences have been found as regards the equipment or practices in the DR, when comparing hospitals of different levels of care. PMID- 26589103 TI - Regenerating gene (REG) product and its potential clinical usage. AB - INTRODUCTION: The regenerating gene (Reg) was identified in regenerating islets and its related genes were revealed to constitute the Reg gene family. Reg family proteins act as growth factors for several cells. Recently, autoimmunity against the Reg family proteins has been reported in several diseases. In addition, the Reg family genes were found to be expressed in a large number of cancers and to influence prognosis. AREAS COVERED: The historical background and current view of the structure, function, and expression of Reg family genes/proteins and their physiological/pathological significance in several diseases are described. Based on the findings, the diagnostic/therapeutic potential of Reg family genes/proteins is also discussed. EXPERT OPINION: Autoimmunity against Reg family proteins may be a new diagnostic marker and/or therapeutic target for immune mediated diseases. Treatment aimed at the expansion of the beta-cell mass by the Reg genes/proteins, combined with the abrogation of autoimmunity, constitutes a potential approach for the treatment of diabetes. Conversely, some cancer cells have gained the ability to overexpress the Reg genes/proteins, thereby enhancing their proliferative capacities, resulting in these cells having a considerable growth advantage. Thus, the Reg genes/proteins are expected to be a new prognostic marker in cancer and/or a future therapeutic target. PMID- 26589104 TI - Markers of bone turnover in patients with epilepsy and their relationship to management of bone diseases induced by antiepileptic drugs. AB - Data from cross-sectional and prospective studies revealed that patients with epilepsy and on long-term treatment with antiepileptic drugs (AEDs) are at increased risk for metabolic bone diseases. Bone diseases were reported in about 50% of patients on AEDs. Low bone mineral density, osteopenia/osteoporosis, osteomalacia, rickets, altered concentration of bone turnover markers and fractures were reported with phenobarbital, phenytoin, carbamazepine, valproate, oxcarbazepine and lamotrigine. The mechanisms for AEDs-induced bone diseases are heterogeneous and include hypovitaminosis D, hypocalcemia and direct acceleration of bone loss and/or reduction of bone formation. This article reviews the evidence, predictors and mechanisms of AEDs-induced bone abnormalities and its clinical implications. For patients on AEDs, regular monitoring of bone health is recommended. Prophylactic administration of calcium and vitamin D is recommended for all patients. Treatment doses of calcium and vitamin D and even anti resorptive drug therapy are reserved for patients at high risk of pathological fracture. PMID- 26589105 TI - Immunogenicity associated with metreleptin treatment in patients with obesity or lipodystrophy. AB - OBJECTIVE: Recombinant human leptin (metreleptin) improves glycaemia and hypertriglyceridaemia in patients with generalized lipodystrophy; antibody development with in vitro neutralizing activity has been reported. We aimed to characterize antimetreleptin antibody development, including in vitro neutralizing activity. DESIGN: Two randomized controlled studies in patients with obesity (twice-daily metreleptin +/- pramlintide for 20-52 weeks; 2006-2009); two long-term, open-label studies in patients with lipodystrophy (once-daily or twice daily metreleptin for 2 months to 12.3 years; 2000-2014). PATIENTS: A total of 579 metreleptin-treated patients with obesity and 134 metreleptin-treated patients with lipodystrophy (antibody/neutralizing activity data: n = 105). MEASUREMENTS: Antimetreleptin antibodies, in vitro neutralizing activity. RESULTS: Antimetreleptin antibodies developed in most patients (obese: 96-100%; lipodystrophy: 86-92%). Peak antibody titers (approximately 1:125 to 1:3125) generally occurred within 4-6 months and decreased with continued therapy (lipodystrophy). Antibody development did not adversely impact efficacy or safety (patients with obesity), except for inflammatory injection site reactions, but was associated with elevated leptin concentrations. Three patients with obesity developed in vitro neutralizing activity coincident with weight gain. Weight later returned to baseline in one patient despite persistent neutralizing activity. Four patients with generalized lipodystrophy developed in vitro neutralizing activity concurrent with worsened metabolic control; two with confounding comorbidities had sepsis. One patient with lipodystrophy had resolution of neutralizing activity on metreleptin. CONCLUSIONS: Development of in vitro neutralizing activity could be associated with loss of efficacy but has not been consistently associated with adverse clinical consequences. Whether neutralization of endogenous leptin with clinical consequences occurs remains unclear. PMID- 26589106 TI - The role of marine reserves in the replenishment of a locally impacted population of anemonefish on the Great Barrier Reef. AB - The development of parentage analysis to track the dispersal of juvenile offspring has given us unprecedented insight into the population dynamics of coral reef fishes. These tools now have the potential to inform fisheries management and species conservation, particularly for small fragmented populations under threat from exploitation and disturbance. In this study, we resolve patterns of larval dispersal for a population of the anemonefish Amphiprion melanopus in the Keppel Islands (southern Great Barrier Reef). Habitat loss and fishing appear to have impacted this population and a network of no-take marine reserves currently protects 75% of the potential breeders. Using parentage analysis, we estimate that 21% of recruitment in the island group was generated locally and that breeding adults living in reserves were responsible for 79% (31 of 39) of these of locally produced juveniles. Overall, the network of reserves was fully connected via larval dispersal; however, one reserve was identified as a critical source of larvae for the island group. The population in the Keppel Islands also appears to be well-connected to other source populations at least 60 km away, given that 79% (145 of 184) of the juveniles sampled remained unassigned in the parentage analysis. We estimated the effective size of the A. melanopus metapopulation to be 745 (582-993 95% CI) and recommend continued monitoring of its genetic status. Maintaining connectivity with populations beyond the Keppel Islands and recovery of local recruitment habitat, potentially through active restoration of host anemone populations, will be important for its long-term persistence. PMID- 26589107 TI - The effects of polymer carrier, hot melt extrusion process and downstream processing parameters on the moisture sorption properties of amorphous solid dispersions. AB - OBJECTIVE: The aim of this study was to evaluate the effect of polymer carrier, hot melt extrusion and downstream processing parameters on the water uptake properties of amorphous solid dispersions. METHODS: Three polymers and a model drug were used to prepare amorphous solid dispersions utilizing the hot melt extrusion technology. The sorption-desorption isotherms of solid dispersions and their physical mixtures were measured by the dynamic vapour sorption system, and the effects of polymer hydrophobicity, hygroscopicity, molecular weight and the hot melt extrusion process were investigated. Fourier transform infrared (FTIR) imaging was performed to understand the phase separation driven by the moisture. KEY FINDINGS: Solid dispersions with polymeric carriers with lower hydrophilicity, hygroscopicity and higher molecular weight could sorb less moisture under the high relative humidity (RH) conditions. The water uptake ability of polymer-drug solid dispersion systems were decreased compared with the physical mixture after hot melt extrusion, which might be due to the decreased surface area and porosity. The FTIR imaging indicated that the homogeneity of the drug molecularly dispersed within the polymer matrix was changed after exposure to high RH. CONCLUSION: Understanding the effect of formulation and processing on the moisture sorption properties of solid dispersions is essential for the development of drug products with desired physical and chemical stability. PMID- 26589108 TI - Reliability of endoscopic ultrasound in predicting the number and size of common bile duct stones before endoscopic retrograde cholangiopancreatography. AB - BACKGROUND: Endoscopic ultrasound (EUS) is accurate for the diagnosis of choledocholithiasis; however, data are lacking regarding the prediction of stone number and size. AIMS: To evaluate the concordance between EUS and endoscopic retrograde cholangiopancreatography (ERCP) in stone number and size assessment. METHODS: We performed a retrospective analysis of consecutive patients undergoing ERCP due to detection of choledocholithiasis by EUS. Concordance between EUS and ERCP was defined as difference in stone diameter <30% and perfect match in stone number. RESULTS: Among 116 patients, 25% had sludge, 37.9% had single and 37.1% had multiple stones. Overall concordance was 62.9%. Sludge was correctly assessed in 85.7%, single stone in 81.3% and multiple stones in 45.1% (P=0.0001). EUS was accurate in 78.8% of patients who underwent both procedures in the same session, but only in 61.9% in those who underwent ERCP within 1 week. Multivariate analysis identified the single-session approach (odds ratio 2.894; P=0.035) and multiple stones (odds ratio 0.244; P=0.001) as independent predictors of concordance. CONCLUSIONS: Concordance between EUS and ERCP was correlated to the single session approach and inversely correlated to the presence of multiple stones. EUS may predict potentially difficult ERCP allowing to plan the best treatment strategy. PMID- 26589109 TI - Targeting hypoxia-mediated mucin 2 production as a therapeutic strategy for mucinous tumors. AB - Excessive accumulation of mucin 2 (MUC2; a gel-forming secreted mucin) protein in the peritoneal cavity is the major cause of morbidity and mortality in pseudomyxoma peritonei (PMP). Hypoxia (hypoxia-inducible factor-1alpha; HIF 1alpha) has been shown to regulate the expression of similar mucins (eg, MUC5AC). We hypothesized that hypoxia (HIF-1alpha) drives MUC2 expression in PMP and is therefore a novel target to reduce mucinous tumor growth. The regulation of MUC2 by 2% hypoxia (HIF-1alpha) was evaluated in MUC2-secreting LS174T cells. The effect of BAY 87-2243, an inhibitor of HIF-1alpha, on MUC2 expression and mucinous tumor growth was evaluated in LS174T cells, PMP explant tissue, and in a unique intraperitoneal murine xenograft model of PMP. In vitro exposure of LS174T cells to hypoxia increased MUC2 messenger RNA (mRNA) and protein expression and increased HIF-1alpha binding to the MUC2 promoter. Hypoxia-mediated MUC2 protein overexpression was downregulated by transfected HIF-1alpha small interfering RNA (siRNA) compared with scrambled siRNA in LS174T cells. BAY 87-2243 inhibited hypoxia-induced MUC2 mRNA and protein expression in LS174T cells and PMP explant tissue. In a murine xenograft model of PMP, chronic oral therapy with BAY 87-2243 inhibited mucinous tumor growth and MUC2, HIF-1alpha expression in the tumor tissue. Our data suggest that hypoxia (HIF-1alpha) induces MUC2 promoter activity to increase MUC2 expression. HIF-1alpha inhibition decreases MUC2 production and mucinous tumor growth, providing a preclinical rationale for the use of HIF 1alpha inhibitors to treat patients with PMP. PMID- 26589110 TI - Cellular and molecular hypoxic response in common carp (Cyprinus carpio) exposed to linear alkylbenzene sulfonate at sublethal concentrations. AB - Linear alkylbenzene sulfonate (LAS) is an anionic surfactant commonly used in cleaning agents such as laundry detergents. Trace amounts of LAS are released into environmental waters after processing in wastewater treatment plants after the use of this chemical. Acute toxicity of LAS has been well-studied using various organisms, and its effects are particularly well known in fish. LAS damages fish gill morphology and induces mucous excretion from these organs. LAS also causes hematological changes. These observations suggest that LAS might induce hypoxic conditions in fish. However, the connections between hypoxia and hematological changes at the cellular and molecular levels remain unknown. Common carp were exposed to LAS at concentrations of 625, 1250, and 2500 MUg/L for 96 h. A total of 9-10 fish were sampled at the end of the exposure period for each concentration. For hematological analysis, carp blood was sampled from the caudal vein. Gill tissue was used for real-time PCR analysis to evaluate transcriptional changes of hypoxia-induced genes. The number of normal red blood cells and the number of immature red blood cells were significantly decreased and increased, respectively, in fish exposed to 2500 ug/L LAS. The hypoxic marker genes hypoxia inducible factor 1alpha, myoglobin 1, and erythropoietin 2 were upregulated in these fish. Our results suggest that LAS decreases erythrocyte numbers and induces hypoxic conditions. In addition, LAS-exposed fish increase production of immature erythrocytes and upregulate myoglobin expression in gills to improve oxygen transport and absorption. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 32: 122-130, 2017. PMID- 26589111 TI - Editorial. PMID- 26589112 TI - Along paths converging to Bengt Saltin's early contributions in exercise physiology. AB - A fascinating chain of events led in 1941 to the formation of the Department of Physiology at the Royal Gymnastic Central Institute (GCI) in Stockholm, Sweden. Erik Hohwu Christensen, from the scientifically advanced Lindhard School in Copenhagen became its first professor. A central research question for him concerned determining the limiting factors for maximal physical performance in man. This was the academic setting where the sports interested medical student Bengt Saltin was introduced to exercise physiology. In the summer of 1959, he became involved in a study on intermittent vs continuous running. A doctoral project, with Per-Olof Astrand as his tutor, resulted in 1964 as the thesis "Aerobic work capacity and circulation at exercise in man. With special reference to the effect of prolonged exercise and/or heat exposure". In the decade that followed, Saltin continued along that path. However, he also added a vital research line involving pioneering studies on skeletal muscles in the exercising man, a series of novel studies on the physiological demands in various sports, and studies of the effects of physical training within the general population. PMID- 26589113 TI - The Copenhagen Muscle Research Centre (CMRC) 1994-2004. AB - This paper presents an impressionistic summary of the formation, activities, accomplishments, and impact of the Copenhagen Muscle Research Centre (CMRC) from 1994 to 2004. The history of the CMRC is viewed in the context of the goals of the original program, the tradition of excellence in exercise physiology in Copenhagen since the time of August Krogh, and the structure of the center. The key role of Professor Bengt Saltin as a visionary, flexible, and inclusive leader is highlighted. PMID- 26589114 TI - Exercise, muscle, and CHO metabolism. AB - Carbohydrates (CHO) are a key source of energy for contracting skeletal muscle during strenuous exercise and fatigue during such exercise often coincides with CHO depletion. Our current understanding of the importance of CHO for exercise metabolism has its foundations in classic studies in the early 20th century by Scandinavian physiologists and Bengt Saltin contributed significantly to that tradition. This brief review summarizes our contemporary understanding of key aspects of muscle glycogen and glucose metabolism during exercise, through the lens of seminal studies by Bengt Saltin. PMID- 26589115 TI - Muscle glycogen and cell function--Location, location, location. AB - The importance of glycogen, as a fuel during exercise, is a fundamental concept in exercise physiology. The use of electron microscopy has revealed that glycogen is not evenly distributed in skeletal muscle fibers, but rather localized in distinct pools. In this review, we present the available evidence regarding the subcellular localization of glycogen in skeletal muscle and discuss this from the perspective of skeletal muscle fiber function. The distribution of glycogen in the defined pools within the skeletal muscle varies depending on exercise intensity, fiber phenotype, training status, and immobilization. Furthermore, these defined pools may serve specific functions in the cell. Specifically, reduced levels of these pools of glycogen are associated with reduced SR Ca(2+) release, muscle relaxation rate, and membrane excitability. Collectively, the available literature strongly demonstrates that the subcellular localization of glycogen has to be considered to fully understand the role of glycogen metabolism and signaling in skeletal muscle function. Here, we propose that the effect of low muscle glycogen on excitation-contraction coupling may serve as a built-in mechanism, which links the energetic state of the muscle fiber to energy utilization. PMID- 26589116 TI - Mitochondrial specialization revealed by single muscle fiber proteomics: focus on the Krebs cycle. AB - We have developed a highly sensitive mass spectrometry-based proteomic workflow to examine the proteome of single muscle fibers. This study revealed significant differences in the mitochondrial proteome of the four major fiber types present in mouse skeletal muscle. Here, we focus on Krebs cycle enzymes and in particular on the differential distribution of the two mitochondrial isocitrate dehydrogenases, IDH2 and IDH3. Type 1/slow fibers contain high levels of IDH2 and relatively low levels of IDH3, whereas fast 2X and 2B fibers show an opposite expression pattern. The findings suggest that in skeletal muscle, IDH2 functions in the forward direction of the Krebs cycle and that substrate flux along the cycle occurs predominantly via IDH2 in type 1 fibers and via IDH3 in 2X and 2B fibers. IDH2-mediated conversion of isocitrate to alpha-ketoglutarate leads to the generation of NADPH, which is critical to buffering the H2O2 produced by the respiratory chain. Nicotinamide nucleotide transhydrogenase (NNT), the other major mitochondrial enzyme involved in NADPH generation, is also more abundant in type 1 fibers. We suggest that the continuously active type 1 fibers are endowed with a more efficient H2O2 scavenging capacity to cope with the higher levels of reactive oxygen species production. PMID- 26589117 TI - Muscle adaptation to exercise: New Saltin's paradigms. AB - The title assigned for my lecture at the Saltin Symposium was "Muscle adaptation to exercise: new paradigms." The title's topic made me remember that some of Saltin's paradigms for his development of a novel exercise model were either originated by him or modified by him from existing information. Therefore, I deemed it would be instructive for future generations to consider one facet of his 54-year career--human exercise models. I arbitrarily selected to share five examples of new paradigm models initiated by Saltin. They are: bed rest; arms vs legs; one leg vs the other leg; myokine communication from skeletal muscle to other organs/tissues; and 42-day cross-country skiing expedition. I arbitrarily selected the above as examples of novel approaches that he used to the study humans during maximal endurance exercise. Noteworthy though is that Saltin's lifetime demeanor, itself, is a model for other scientists. In final analysis, the world is richer due to his passion to study humans to advance medical science by uncovering mechanisms as to how the human body is constructed to perform endurance types of exercise at maximal intensities and durations. PMID- 26589118 TI - Regulation of cardiac output in hypoxia. AB - This brief review addresses the regulation of cardiac output (Q) at rest and during submaximal exercise in acute and chronic hypoxia. To preserve systemic O2 delivery in acute hypoxia Q is increased by an acceleration of heart rate, whereas stroke volume (SV) remains unchanged. Tachycardia is governed by activation of carotid and aortic chemoreceptors and a concomitant reduction in arterial baroreflex activation, all balancing sympathovagal activity toward sympathetic dominance. As hypoxia extends over several days a combination of different adaptive processes restores arterial O2 content to or beyond sea level values and hence Q normalizes. The latter however occurs as a consequence of a decrease in SV whereas tachycardia persists. The diminished SV reflects a lower left ventricular end-diastolic volume which is primarily related to hypoxia generated reduction in plasma volume. Hypoxic pulmonary vasoconstriction may contribute by increasing right ventricular afterload and thus decreasing its ejection fraction. In summary, the Q response to hypoxia is the result of a complex interplay between several physiological mechanisms. Future studies are encouraged to establish the individual contributions of the different components from an integrative perspective. PMID- 26589119 TI - Vascular function in health, hypertension, and diabetes: effect of physical activity on skeletal muscle microcirculation. AB - Regulation of skeletal muscle blood flow is a complex process, which involves an integration of multiple mechanisms and a number of vasoactive compounds. Overall, muscle blood flow is regulated through a balance between vasoconstrictor and vasodilator signals. In a healthy cardiovascular system, the increase in muscle blood flow required for oxygen supply during exercise is achieved through a substantial increase in vasodilators locally formed in the active muscle tissue that overcome the vasoconstrictor signals. Most of the vasodilator signals are mediated via endothelial cells, which lead to the formation of vasodilators such as nitric oxide (NO) and prostacyclin. In essential hypertension and type II diabetes, the endothelial function and regulation of vascular tone is impaired with consequent increases in peripheral vascular resistance and inadequate regulation of oxygen supply to the skeletal muscle, which can affect muscle function. Central aspects in the vascular impairments are alterations in the formation of prostacyclin, the bioavailability of NO and an increased formation of vasoconstrictors and reactive oxygen species (ROS). Regular physical activity effectively improves vascular function by enhancing vasodilator formation and reducing the levels of vasoconstrictors and ROS. PMID- 26589120 TI - Reflex control of the circulation during exercise. AB - Appropriate cardiovascular and hemodynamic adjustments are necessary to meet the metabolic demands of working skeletal muscle during exercise. Alterations in the sympathetic and parasympathetic branches of the autonomic nervous system are fundamental in ensuring these adjustments are adequately made. Several neural mechanisms are responsible for the changes in autonomic activity with exercise and through complex interactions, contribute to the cardiovascular and hemodynamic changes in an intensity-dependent manner. This short review is from a presentation made at the Saltin Symposium June 2-4, 2015 in Copenhagen, Denmark. As such, the focus will be on reflex control of the circulation with an emphasis on the work of the late Dr. Bengt Saltin. Moreover, a concerted effort is made to highlight the novel and insightful concepts put forth by Dr. Saltin in his last published review article on the regulation of skeletal muscle blood flow in humans. Thus, the multiple roles played by adenosine triphosphate (ATP) including its ability to induce vasodilatation, override sympathetic vasoconstriction and stimulate skeletal muscle afferents (exercise pressor reflex) are discussed and a conceptual framework is set suggesting a major role of ATP in blood flow regulation during exercise. PMID- 26589121 TI - A re-analysis of the 1968 Saltin et al. "Bedrest" paper. AB - In 1968, Saltin et al. published a landmark paper describing the alterations in VO2max resulting from two sequential interventions--20 days of bed rest and almost 8 weeks of training. They concluded that bed rest reduced VO2max through reductions in maximal cardiac output, while training enhanced VO2max by an equal combination of increased maximal cardiac output and increased arterio-venous [O2] difference (A-V Delta [O2]). At the time, A-V Delta [O2] was taken as an index of peripheral (skeletal muscle) adaptation. A key interpretive element that was not featured was consideration of how alterations in cardiac output affect the O2 extraction process secondary to changes in red cell transit time through the muscle microcirculation, even in the absence of adaptive changes in the skeletal muscles per se. For the 2015 Saltin Symposium, it was therefore thought appropriate to re-examine the 1968 O2 transport data and re-evaluate the roles central cardiovascular and peripheral muscle changes after bed rest and training allowing for their interaction. The analysis supports the conclusion that bed rest reduced VO2max mainly through reduction in cardiac output, but after training, it is proposed that the 1968 conclusions should be modified: the majority of the increase in VO2max from the control state can be attributed to an improvement in diffusive unloading of O2 from the muscle microcirculation, with a much smaller role for enhanced blood flow. PMID- 26589122 TI - Performance in sports--With specific emphasis on the effect of intensified training. AB - Performance in most sports is determined by the athlete's technical, tactical, physiological and psychological/social characteristics. In the present article, the physical aspect will be evaluated with a focus on what limits performance, and how training can be conducted to improve performance. Specifically how intensified training, i.e., increasing the amount of aerobic high-intensity and speed endurance training, affects physiological adaptations and performance of trained subjects. Periods of speed endurance training do improve performance in events lasting 30 s-4 min, and when combined with aerobic high-intensity sessions, also performance during longer events. Athletes in team sports involving intense exercise actions and endurance aspects, such as soccer and basketball, can also benefit from intensified training. Speed endurance training does reduce energy expenditure and increase expression of muscle Na(+), K(+) pump alpha subunits, which may preserve muscle cell excitability and delay fatigue development during intense exercise. When various types of training are conducted in the same period (concurrent training), as done in a number of sports, one type of training may blunt the effect of other types of training. It is not, however, clear how various training modalities are affecting each other, and this issue should be addressed in future studies. PMID- 26589123 TI - The elite cross-country skier provides unique insights into human exercise physiology. AB - Successful cross-country skiing, one of the most demanding of endurance sports, involves considerable physiological challenges posed by the combined upper- and lower-body effort of varying intensity and duration, on hilly terrain, often at moderate altitude and in a cold environment. Over the years, this unique sport has helped physiologists gain novel insights into the limits of human performance and regulatory capacity. There is a long-standing tradition of researchers in this field working together with coaches and athletes to improve training routines, monitor progress, and refine skiing techniques. This review summarizes research on elite cross-country skiers, with special emphasis on the studies initiated by Professor Bengt Saltin. He often employed exercise as a means to learn more about the human body, successfully engaging elite endurance athletes to improve our understanding of the demands, characteristics, and specific effects associated with different types of exercise. PMID- 26589124 TI - The Kenyan runners. AB - Today the Kenyan dominance in middle- and long-distance running is so profound that it has no equivalence to any other sport in the world. Critical physiological factors for performance in running include maximal oxygen consumption (VO2max), fractional VO2max utilization and running economy (energetic cost of running). Kenyan and non-Kenyan elite runners seem to be able to reach very high, but similar maximal oxygen uptake levels just as there is some indication that untrained Kenyans and non-Kenyans have a similar VO2max. In addition, the fractional utilization of VO2max seems to be very high but similar in Kenyan and European runners. Similarly, no differences in the proportion of slow muscle fibers have been observed when comparing Kenyan elite runners with their Caucasian counterparts. In contrast, the oxygen cost of running at a given running velocity has been found to be lower in Kenyan elite runners relative to other elite runners and there is some indication that this is due to differences in body dimensions. Pulmonary system limitations have been observed in Kenyan runners in the form of exercise-induced arterial hypoxemia, expiratory flow limitation, and high levels of respiratory muscle work. It appears that Kenyan runners do not possess a pulmonary system that confers a physiological advantage. Additional studies on truly elite Kenyan runners are necessary to understand the underlying physiology which permits extraordinary running performances. PMID- 26589125 TI - The "Saltin-Grimby Physical Activity Level Scale" and its application to health research. AB - The use of a four-level questionnaire to assess leisure time physical activity (PA) and its validation is reviewed in this paper. This questionnaire was first published in 1968 and has then been used by more than 600,000 subjects, especially in different population studies in the Nordic countries. A number of modifications to the questionnaire have been published. These are mostly minor changes, such as adding practical examples of activities to illustrate the levels of PA. Some authors have also added duration requirements that were not included for all levels of PA in the original version. The concurrent validity, with respect to aerobic capacity and movement analysis using objective measurements has been shown to be good, as has the predictive validity with respect to various risk factors for health conditions and for morbidity and mortality. PMID- 26589126 TI - Mitochondrial coupling and capacity of oxidative phosphorylation in skeletal muscle of Inuit and Caucasians in the arctic winter. AB - During evolution, mitochondrial DNA haplogroups of arctic populations may have been selected for lower coupling of mitochondrial respiration to ATP production in favor of higher heat production. We show that mitochondrial coupling in skeletal muscle of traditional and westernized Inuit habituating northern Greenland is identical to Danes of western Europe haplogroups. Biochemical coupling efficiency was preserved across variations in diet, muscle fiber type, and uncoupling protein-3 content. Mitochondrial phenotype displayed plasticity in relation to lifestyle and environment. Untrained Inuit and Danes had identical capacities to oxidize fat substrate in arm muscle, which increased in Danes during the 42 days of acclimation to exercise, approaching the higher level of the Inuit hunters. A common pattern emerges of mitochondrial acclimatization and evolutionary adaptation in humans at high latitude and high altitude where economy of locomotion may be optimized by preservation of biochemical coupling efficiency at modest mitochondrial density, when submaximum performance is uncoupled from VO2max and maximum capacities of oxidative phosphorylation. PMID- 26589127 TI - Maintained peak leg and pulmonary VO2 despite substantial reduction in muscle mitochondrial capacity. AB - We recently reported the circulatory and muscle oxidative capacities of the arm after prolonged low-intensity skiing in the arctic (Boushel et al., 2014). In the present study, leg VO2 was measured by the Fick method during leg cycling while muscle mitochondrial capacity was examined on a biopsy of the vastus lateralis in healthy volunteers (7 male, 2 female) before and after 42 days of skiing at 60% HR max. Peak pulmonary VO2 (3.52 +/- 0.18 L.min(-1) pre vs 3.52 +/- 0.19 post) and VO2 across the leg (2.8 +/- 0.4L.min(-1) pre vs 3.0 +/- 0.2 post) were unchanged after the ski journey. Peak leg O2 delivery (3.6 +/- 0.2 L.min(-1) pre vs 3.8 +/- 0.4 post), O2 extraction (82 +/- 1% pre vs 83 +/- 1 post), and muscle capillaries per mm(2) (576 +/- 17 pre vs 612 +/- 28 post) were also unchanged; however, leg muscle mitochondrial OXPHOS capacity was reduced (90 +/- 3 pmol.sec( 1) .mg(-1) pre vs 70 +/- 2 post, P < 0.05) as was citrate synthase activity (40 +/- 3 MUmol.min(-1) .g(-1) pre vs 34 +/- 3 vs P < 0.05). These findings indicate that peak muscle VO2 can be sustained with a substantial reduction in mitochondrial OXPHOS capacity. This is achieved at a similar O2 delivery and a higher relative ADP-stimulated mitochondrial respiration at a higher mitochondrial p50. These findings support the concept that muscle mitochondrial respiration is submaximal at VO2max , and that mitochondrial volume can be downregulated by chronic energy demand. PMID- 26589128 TI - Central and peripheral hemodynamics in exercising humans: leg vs arm exercise. AB - In humans, arm exercise is known to elicit larger increases in arterial blood pressure (BP) than leg exercise. However, the precise regulation of regional vascular conductances (VC) for the distribution of cardiac output with exercise intensity remains unknown. Hemodynamic responses were assessed during incremental upright arm cranking (AC) and leg pedalling (LP) to exhaustion (Wmax) in nine males. Systemic VC, peak cardiac output (Qpeak) (indocyanine green) and stroke volume (SV) were 18%, 23%, and 20% lower during AC than LP. The mean BP, the rate pressure product and the associated myocardial oxygen demand were 22%, 12%, and 14% higher, respectively, during maximal AC than LP. Trunk VC was reduced to similar values at Wmax. At Wmax, muscle mass-normalized VC and fractional O2 extraction were lower in the arm than the leg muscles. However, this was compensated for during AC by raising perfusion pressure to increase O2 delivery, allowing a similar peak VO2 per kg of muscle mass in both extremities. In summary, despite a lower Qpeak during arm cranking the cardiovascular strain is much higher than during leg pedalling. The adjustments of regional conductances during incremental exercise to exhaustion depend mostly on the relative intensity of exercise and are limb-specific. PMID- 26589129 TI - Neurotoxicity induced by the recommended acyclovir dosing in a dialysis patient with herpes zoster: A case letter. PMID- 26589130 TI - Mammary "Swiss Cheese Disease" in a 26-Year-Old Woman with Cowden Syndrome. PMID- 26589131 TI - Induction chemotherapy followed by concurrent radio-chemotherapy versus concurrent radio-chemotherapy alone as treatment of locally advanced squamous cell carcinoma of the head and neck (HNSCC): A meta-analysis of randomized trials. AB - BACKGROUND: Induction chemotherapy with docetaxel, cisplatin and 5 FU (TPF) before radiotherapy (RT) or radio-chemotherapy (RT-CHX) has been shown to improve overall survival (OS) compared to induction chemotherapy with cisplatin and 5 FU in locally advanced squamous cell carcinoma of the head and neck (HNSCC). Whether TPF induction before RT-CHX improves clinical outcome in comparison with RT-CHX alone is still a matter of debate. Recently, the results of 5 randomized trials addressing this question have become available. METHODS: In the 5 trials of interest, in total 1022 patients with locally advanced HNSCC were randomly assigned to receive either TPF induction CHX followed by concurrent RT-CHX or concurrent RT-CHX alone. Platin or taxane based CHX was used during RT. 51.3% of the patients had oropharyngeal, 7.3% hypoharyngeal, 18.7% laryngeal, 19.4% oral cavity and 3.5% had other HNSCC. Published hazard ratios and hazard ratios extracted from available survival curves for OS and progression free survival (PFS) were basis of the meta-analysis. Meta-analysis of the effect sizes on OS and PFS was performed using a random effects model based on parameter estimates of log hazard ratios in Cox models and their standard errors. RESULTS: Additional induction CHX with TPF before RT-CHX did neither result in a significant improvement of OS (Hazard Ratio: 1.010, 95% confidence limits (CL) 0.84-1.21, p=0.92), nor in a statistically significant benefit of PFS (Hazard Ratio: 0.91, 95% CL 0.75-1.1, p=0.32). CONCLUSION: Additional induction CHX with TPF before RT CHX does not improve OS and PFS in locally advanced HNSCC compared to definite RT CHX. PMID- 26589132 TI - Improving the representativeness of influenza viruses shared within the WHO Global Influenza Surveillance and Response System. AB - BACKGROUND: Sharing influenza viruses within the WHO Global Influenza Surveillance and Response System is crucial for monitoring evolution of influenza viruses. OBJECTIVES: Analysis of timeliness and geographic representativeness of viruses shared by National Influenza Centres (NICs) in the WHO European Region with the London WHO Collaborating Centre for Reference and Research on Influenza for the Northern Hemisphere's 2010-2011 and 2011-2012 influenza seasons. MATERIALS AND METHODS: Data from NICs on influenza-positive specimens shared with WHO CC London for the above-mentioned influenza seasons were analyzed for timeliness of sharing with respect to the February deadline (31 January) for inclusion in the WHO consultations on the composition of influenza virus vaccines for the Northern Hemisphere and geographic representativeness. RESULTS: The 2010 2011 and 2011-2012 seasons were different in terms of the seasonal pattern, the timing of the epidemic, and the dominant virus. Consistent patterns of virus sharing across the seasons were observed. Approximately half the viruses collected before the deadline were not shared within the deadline; the average delay between date of specimen collection and shipment receipt was 3 and 1.5 months for the first and second season, respectively. CONCLUSION: A baseline was provided for future work on enhancement of specimen sharing in the WHO European Region and improving the vaccine virus selection process. Greater insight into virus selection criteria applied by countries and the causes of delays in shipment are needed to understand the representativeness of viruses shared and to assess the importance of this for vaccine strain selection. PMID- 26589133 TI - Trends and outcomes in right vs. left living donor nephrectomy: an analysis of the OPTN/UNOS database of donor and recipient outcomes--should we be doing more right-sided nephrectomies? AB - BACKGROUND: Discussion continues about right vs. left donor nephrectomy (LDN). Left side is preferred due to longer renal vein while right side has been associated with renal vein thrombosis and shorter vessels. METHODS: A retrospective analysis of UNOS database for adult living donor transplants between 1 January 2000 and 31 December 2009. RESULTS: We identified 58 599 living donor transplants, of which 86.1% were LDN. There were no significant differences between the recipients or donors demographics. There were higher rates of delayed graft function in right donor nephrectomy (RDN) recipients with a hazard risk of 1.38 (95% CI 1.24-1.53; p < 0.0001). Primary failure rates were similar. In the RDN group, graft thrombosis as cause of graft failure was statistically higher with a hazard ratio of 1.48 (95% CI 1.18-1.86, p = 0.0004), and graft survival was significantly inferior (p = 0.006 log-rank test). For living donors outcomes, the conversion from laparoscopic to open was higher in the RDN group with an odds ratio of 2.02 (95% CI 1.61-2.52; p < 0.00001). There was no significant difference in vascular complications or re-operation required due to bleeding. Re operations and re-admissions were higher in the LDN group. CONCLUSION: There are statistical differences between left and right kidney donor nephrectomies on recipient outcomes, but the difference is extremely small. The choice and laterality should be based on center and surgeon preference and experience. PMID- 26589135 TI - Applied anatomy of the anterior cranial fossa: what can fracture patterns tell us? AB - The skull base is uniquely placed to absorb anteriorly directed forces imparted either via the midfacial skeleton or cranial vault. A variety of skull base fracture classifications exist. Less well understood, however, is fracture extension beyond the anterior cranial fossa (ACF) into the middle and posterior cranial fossae. The cases of 81 patients from two UK major trauma centres were studied to examine the distribution of fractures across the skull base and any relationship between the vector of force and extent of skull base injury. It was found that predominantly lateral force to the craniofacial skeleton produced a fracture that propagated beyond the ACF into the middle cranial fossa in 77.4% of cases, significantly more (P<0.001) than for predominantly anterior force (12.0%). Fractures were significantly more likely to propagate into the posterior fossa with a lateral vector of impact compared to an anterior vector (P=0.049). This difference in energy transfer across the skull base may, in part, be explained by the local anatomy. The more delicate central ACF acts as a 'crumple zone' in order to absorb force. Conversely, no collapsible interface exists in the lateral aspect of the ACF, thus the lateral ACF behaves like a 'buttress', resulting in increased energy transfer. PMID- 26589134 TI - Genetic determinants of fibro-osseous lesions in aged inbred mice. AB - Fibro-osseous lesions in mice are progressive aging changes in which the bone marrow is replaced to various degrees by fibrovascular stroma and bony trabeculae in a wide variety of bones. The frequency and severity varied greatly among 28 different inbred mouse stains, predominantly affecting females, ranging from 0% for 10 strains to 100% for KK/HlJ and NZW/LacJ female mice. Few lesions were observed in male mice and for 23 of the strains, no lesions were observed in males for any of the cohorts. There were no significant correlations between strain-specific severities of fibro-osseous lesions and ovarian (r=0.11; P=0.57) or endometrial (r=0.03; P=0.89) cyst formation frequency or abnormalities in parathyroid glands. Frequency of fibro-osseous lesions was most strongly associated (P<10(-6)) with genome variations on chromosome (Chr) 8 at 90.6 and 90.8Mb (rs33108071, rs33500669; P=5.0.10(-10), 1.3.10(-6)), Chr 15 at 23.6 and 23.8Mb (rs32087871, rs45770368; P=7.3.10(-7), 2.7.10(-6)), and Chr 19 at 33.2, 33.4, and 33.6Mb (rs311004232, rs30524929, rs30448815; P=2.8.10(-6), 2.8.10(-6), 2.8.10(-6)) in genome-wide association studies (GWAS). The relatively large number of candidate genes identified in the GWAS analyses suggests that this may be an extremely complex polygenic disease. These results indicate that fibro osseous lesions are surprisingly common in many inbred strains of laboratory mice as they age. While this presents little problem in most studies that utilize young animals, it may complicate aging studies, particularly those focused on bone. PMID- 26589136 TI - Vibrations inside buildings due to subway railway traffic. Experimental validation of a comprehensive prediction model. AB - The present paper focuses on the experimental validation of a numerical approach previously proposed by the authors for the prediction of vibrations inside buildings due to railway traffic in tunnels. The numerical model is based on the concept of dynamic substructuring and is composed by three autonomous models to simulate the following main parts of the problem: i) generation of vibrations (train-track interaction); ii) propagation of vibrations (track-tunnel-ground system); iii) reception of vibrations (building coupled to the ground). The experimental validation consists in the comparison between the results predicted by the proposed numerical model and the measurements performed inside a building due to the railway traffic in a shallow tunnel located in Madrid. Apart from the brief description of the numerical model and of the case study, the main options and simplifications adopted on the numerical modeling strategy are discussed. The balance adopted between accuracy and simplicity of the numerical approach proved to be a path to follow in order to transfer knowledge to engineering practice. Finally, the comparison between numerical and experimental results allowed finding a good agreement between both, fact that ensures the ability of the proposed modeling strategy to deal with real engineering practical problems. PMID- 26589137 TI - Challenges of river basin management: Current status of, and prospects for, the River Danube from a river engineering perspective. AB - In the Danube River Basin multiple pressures affect the river system as a consequence of river engineering works, altering both the river hydrodynamics and morphodynamics. The main objective of this paper is to identify the effects of hydropower development, flood protection and engineering works for navigation on the Danube and to examine specific impacts of these developments on sediment transport and river morphology. Whereas impoundments are characterised by deposition and an excess of sediment with remobilisation of fine sediments during severe floods, the remaining five free flowing sections of the Danube are experiencing river bed erosion of the order of several centimetres per year. Besides the effect of interruption of the sediment continuum, river bed degradation is caused by an increase in the sediment transport capacity following an increase in slope, a reduction of river bed width due to canalisation, prohibition of bank erosion by riprap or regressive erosion following base level lowering by flood protection measures and sediment dredging. As a consequence, the groundwater table is lowered, side-arms are disconnected, instream structures are lost and habitat quality deteriorates affecting the ecological status of valuable floodplains. The lack of sediments, together with cutting off meanders, leads also to erosion of the bed of main arms in the Danube Delta and coastal erosion. This paper details the causes and effects of river engineering measures and hydromorphological changes for the Danube. It highlights the importance of adopting a basin-wide holistic approach to river management and demonstrates that past management in the basin has been characterised by a lack of integration. To date insufficient attention has been paid to the wide-ranging impacts of river engineering works throughout the basin: from the basin headwaters to the Danube Delta, on the Black Sea coast. This highlights the importance of new initiatives that seek to advance knowledge exchange and knowledge transfer within the basin to reach the goal of integrated basin management. PMID- 26589138 TI - Tracking the association between metro-railway construction works and PM levels in an urban Mediterranean environment. AB - Metro-railways are considered to be a sustainable means of public transportation, as they contribute substantially to the reduction of air pollutant emissions through the decrease in the number of cars and heavy vehicles circulating in the road network. However, the works related to their construction may pose an extra burden in air quality status and consequently in public health. In the present study, we studied the possible effects of the metro-railway construction works in Thessaloniki, Greece, on public health through 2 well-established air quality indices, namely the PI and DAQI. The analysis suggested that there were excess high levels of PM10 measured in the close vicinity of the construction-sites during the period studied (2008-2014). These concentrations are likely to have originated from local construction sources rather than transport or continental secondary dust sources and might have an adverse health impact, as according to the PI index, the majority of days in the construction sites were grouped as "low pollution" or "moderate pollution", while a small percentage of days (1.84%) were suggested to be unhealthy for the most vulnerable groups of the population. Similarly, the DAQI index revealed that the vast majority of days were grouped as "poor" air quality, while 5.50% of the days reflected the most oppressive conditions for public health, as they were characterized as "very poor" air quality. Given the need of reaching a compromise between future transportation sustainability and public health during the construction works, the feasibility of appropriate measures in the area should be examined. PMID- 26589139 TI - Genome-wide association and genomic prediction of breeding values for fatty acid composition in subcutaneous adipose and longissimus lumborum muscle of beef cattle. AB - BACKGROUND: Identification of genetic variants that are associated with fatty acid composition in beef will enhance our understanding of host genetic influence on the trait and also allow for more effective improvement of beef fatty acid profiles through genomic selection and marker-assisted diet management. In this study, 81 and 83 fatty acid traits were measured in subcutaneous adipose (SQ) and longissimus lumborum muscle (LL), respectively, from 1366 purebred and crossbred beef steers and heifers that were genotyped on the Illumina BovineSNP50 Beadchip. The objective was to conduct genome-wide association studies (GWAS) for the fatty acid traits and to evaluate the accuracy of genomic prediction for fatty acid composition using genomic best linear unbiased prediction (GBLUP) and Bayesian methods. RESULTS: In total, 302 and 360 significant SNPs spanning all autosomal chromosomes were identified to be associated with fatty acid composition in SQ and LL tissues, respectively. Proportions of total genetic variance explained by individual significant SNPs ranged from 0.03 to 11.06% in SQ, and from 0.005 to 24.28% in the LL muscle. Markers with relatively large effects were located near fatty acid synthase (FASN), stearoyl-CoA desaturase (SCD), and thyroid hormone responsive (THRSP) genes. For the majority of the fatty acid traits studied, the accuracy of genomic prediction was relatively low (<0.40). Relatively high accuracies (> = 0.50) were achieved for 10:0, 12:0, 14:0, 15:0, 16:0, 9c-14:1, 12c-16:1, 13c-18:1, and health index (HI) in LL, and for 12:0, 14:0, 15:0, 10 t,12c-18:2, and 11 t,13c + 11c,13 t-18:2 in SQ. The Bayesian method performed similarly as GBLUP for most of the traits but substantially better for traits that were affected by SNPs of large effects as identified by GWAS. CONCLUSIONS: Fatty acid composition in beef is influenced by a few host genes with major effects and many genes of smaller effects. With the current training population size and marker density, genomic prediction has the potential to predict the breeding values of fatty acid composition in beef cattle at a moderate to relatively high accuracy for fatty acids that have moderate to high heritability. PMID- 26589140 TI - Reliability of focused cardiac ultrasound by novice sonographer in preoperative anaesthetic assessment: an observational study. AB - BACKGROUND: Use of preoperative echocardiography may help to identify patients with increased cardiac risk, who may benefit from modification of perioperative plan. The objective of our study was to evaluate the reliability of preoperative focused cardiac ultrasound (FoCUS) performed by an anaesthetist with basic ultrasound training and its impact on patient's management. METHODS: The prospective observational study was conducted in 159 adult patients, scheduled for elective operations. Cardiac ultrasound was performed by one anaesthetist with a limited experience of FoCUS. A simple, mnemonic scheme was used for the final reporting of each study. The same scheme was used by a cardiologist who produced an independent report based on digital video loops stored in the machine memory. Anaesthetists in-charge made final perioperative plan. Comparative analysis of anaesthetist and cardiologist performed ultrasound report was made. The incidence of modification of initial perioperative plan resulting from FoCUS report was analyzed. RESULTS: The average time required to complete the examination was 182 s 95% CI [173-190]. Images of quality adequate to answer all questions from the scheme were obtained in 97.5% (155/159) of patients. There was strong agreement between the anaesthetist and the cardiologist in 97.8% (2274/2325) of the examined categories. In two categories (global and regional left ventricle contractility impairment) statistically significant discrepancies between both diagnosticians were confirmed (p McNemar <0.04). When compared with the cardiologist's assessment the agreement of the anesthetist's diagnosis had sensitivity of 0.84, specificity 0.99, positive predictive value 0.78 and negative predictive value 0.99. Kappa statistics showed good agreement between both examining doctors (kappa = 0.797). Based on ultrasound findings, the preliminary anaesthetic plan was changed in relation to 20.8% (33/159) of patients. CONCLUSIONS: An anaesthetist with limited training in FoCUS can perform a reliable preoperative examination which alters the perioperative management. PMID- 26589141 TI - Transcriptional response to interferon beta-1a treatment in patients with secondary progressive multiple sclerosis. AB - BACKGROUND: Interferon (IFN) beta-1a is an approved treatment for relapsing remitting multiple sclerosis (RRMS) and has been examined for use in secondary progressive multiple sclerosis (SPMS). However, no information regarding blood transcriptional changes induced by IFN treatment in SPMS patients is available. Our aim was to identify a subgroup of SPMS patients presenting a gene expression signature similar to that of RRMS patients who are clinical responders to IFN treatment. METHODS: SPMS patients (n = 50, 20 IFN treated and 30 untreated) were classified using unsupervised hierarchical clustering according to IFN inducible gene expression profile identified in RRMS clinical responders to treatment. IFN inducible gene expression profile was determined by finding differentially expressed genes (DEGs) between IFN treated (n = 10) and untreated (n = 25) RRMS patients. Validation was performed on an additional independent group of 27 SPMS IFN treated patients by qRT-PCR. RESULTS: One hundred and four DEGs, enriched by IFN signaling pathway (p = 7.4E-08), were identified in IFN treated RRMS patients. Classification of SPMS patients based on these DEGs yielded two patient groups: (1) IFN transcriptional responders (n = 12, 60% of SPMS treated patients) showing gene-expression profile similar to IFN treated RRMS patients; (2) IFN transcriptional non-responders (n = 8) showing expression profile similar to untreated patients. IFN transcriptional responders were characterized by a more active disease, as defined by higher EDSS progression and annual relapse rate. CONCLUSION: Within the IFN treated SPMS population, 60% of patients have a transcriptional response to IFN which is similar to that of RRMS patients who are IFN responders to treatment. PMID- 26589142 TI - Pre-warming the Streamlined Liner of the Pharynx Airway (SLIPA) improves fitting to the laryngeal structure: a randomized, double-blind study. AB - BACKGROUND: The Streamlined Liner of the Pharynx Airway (SLIPA), a type of supraglottic airway, has a non-inflatable cuff that softens at body temperature to fit the laryngeal structure. We investigated whether pre-warming of SLIPA to body temperature may improve insertion parameters. METHODS: Ninety adult patients were assigned equally randomized to either Group W or Group R. Anesthesia was induced using propofol, fentanyl, and rocuronium. In Group W, the SLIPA was warmed to 37 degrees C before insertion, whereas in Group R, it was inserted at room temperature. The insertion time, oropharyngeal leak pressure, postoperative throat pain, blood staining, regurgitation, number of attempts at insertion, and difficulty of insertion were compared between the two groups. RESULTS: The insertion time was shorter in Group W than in Group R (3.60 [3.15-4.06] s vs. 6.00 [4.45-7.50] s; P < 0.001). Oropharyngeal leak pressure from the time of insertion until 3 min after insertion was significantly higher in Group W than in Group R (P < 0.05). Postoperative throat pain, measured using the visual analog scale, was lower in Group W than in Group R (0.00 [0.00-2.50] vs. 2.00 [0.00 4.50]; P = 0.006). The difficulty of insertion was lower in Group W than in Group R (P < 0.004). There were no significant differences in terms of blood staining, regurgitation, and number of attempts. CONCLUSIONS: Pre-warming the SLIPA to body temperature has significant benefits compared to maintaining the device at room temperature. Specifically, insertion was easier, both insertion and fitting to the laryngeal structure could be performed more quickly, and the incidence of sore throat was reduced. TRIAL REGISTRATION: Clinical Research Information Identifier NCT01209000. PMID- 26589143 TI - Single center experience with wrapping of the dilated ascending aorta. AB - BACKGROUND: External wrapping is a surgical technique performed in patients with a dilated ascending aorta. The aim of this study is to present the mid-term results of wrapping of the dilated ascending aorta. METHODS: 34 patients (mean age: 64.4 +/- 10.8 years, 21 males) with a dilated ascending aorta were operated on at a single cardiac surgery center using a wrapping technique. The aortas were wrapped with 32-36 mm straight Dacron vascular prostheses. The aortic wall was not excised in any of the patients. Wrapping was performed concomitant to other cardiac surgery procedures in 30 patients (88 %), which involved surgery on the aortic valve in 28 patients (82 %). RESULTS: The mean follow-up time was 19.5 +/- 8.3 months (median: 18 months, range: 12-36 months). None of the patients died or had aortic complications during the hospital stay and the follow-up period. A rethoracotomy had to be performed due to excessive postoperative bleeding in two patients. One patient was diagnosed with a transient ischemic attack on the 4th postoperative day, while another had respiratory failure requiring prolonged intubation. No redilatation of the ascending aorta or dislocation of the wrap was noticed in any of the patients. CONCLUSIONS: According to our study, external wrapping of the ascending aorta has good short-term results and may be regarded as a safe surgical option for patients with a moderately dilated ascending aorta. PMID- 26589144 TI - A global sensitivity analysis approach for morphogenesis models. AB - BACKGROUND: Morphogenesis is a developmental process in which cells organize into shapes and patterns. Complex, non-linear and multi-factorial models with images as output are commonly used to study morphogenesis. It is difficult to understand the relation between the uncertainty in the input and the output of such 'black box' models, giving rise to the need for sensitivity analysis tools. In this paper, we introduce a workflow for a global sensitivity analysis approach to study the impact of single parameters and the interactions between them on the output of morphogenesis models. RESULTS: To demonstrate the workflow, we used a published, well-studied model of vascular morphogenesis. The parameters of this cellular Potts model (CPM) represent cell properties and behaviors that drive the mechanisms of angiogenic sprouting. The global sensitivity analysis correctly identified the dominant parameters in the model, consistent with previous studies. Additionally, the analysis provided information on the relative impact of single parameters and of interactions between them. This is very relevant because interactions of parameters impede the experimental verification of the predicted effect of single parameters. The parameter interactions, although of low impact, provided also new insights in the mechanisms of in silico sprouting. Finally, the analysis indicated that the model could be reduced by one parameter. CONCLUSIONS: We propose global sensitivity analysis as an alternative approach to study the mechanisms of morphogenesis. Comparison of the ranking of the impact of the model parameters to knowledge derived from experimental data and from manipulation experiments can help to falsify models and to find the operand mechanisms in morphogenesis. The workflow is applicable to all 'black-box' models, including high-throughput in vitro models in which output measures are affected by a set of experimental perturbations. PMID- 26589147 TI - Quantum Monte Carlo Methods Describe Noncovalent Interactions with Subchemical Accuracy. AB - An accurate description of noncovalent interaction energies is one of the most challenging tasks in computational chemistry. To date, nonempirical CCSD(T)/CBS has been used as a benchmark reference. However, its practical use is limited due to the rapid growth of its computational cost with the system complexity. Here, we show that the fixed-node diffusion Monte Carlo (FN-DMC) method with a more favorable scaling is capable of reaching the CCSD(T)/CBS within subchemical accuracy (<0.1 kcal/mol) on a testing set of six small noncovalent complexes including the water dimer. In benzene/water, benzene/methane, and the T-shape benzene dimer, FN-DMC provides interaction energies that agree within 0.25 kcal/mol with the best available CCSD(T)/CBS estimates. The demonstrated predictive power of FN-DMC therefore provides new opportunities for studies of the vast and important class of medium/large noncovalent complexes. PMID- 26589145 TI - Live attenuated African swine fever viruses as ideal tools to dissect the mechanisms involved in viral pathogenesis and immune protection. AB - African swine fever virus (ASFV) is the causal agent of African swine fever, a hemorrhagic and often lethal porcine disease causing enormous economical losses in affected countries. Endemic for decades in most of the sub-Saharan countries and Sardinia, the risk of ASFV-endemicity in Europe has increased since its last introduction into Europe in 2007. Live attenuated viruses have been demonstrated to induce very efficient protective immune responses, albeit most of the time protection was circumscribed to homologous ASFV challenges. However, their use in the field is still far from a reality, mainly due to safety concerns. In this study we compared the course of the in vivo infection caused by two homologous ASFV strains: the virulent E75 and the cell cultured adapted strain E75CV1, obtained from adapting E75 to grow in the CV1 cell-line. Interestingly, the kinetics of both viruses not only differed on the clinical signs that they caused and in the virus loads found, but also in the immunological pathways activated throughout the infections. Furthermore, E75CV1 confirmed its protective potential against the homologous E75 virus challenge and allowed the demonstration of poor cross-protection against BA71, thus defining it as heterologous. The in vitro specificity of the CD8(+) T-cells present at the time of lethal challenge showed a clear activation against the homologous virus (E75) but not against BA71. These findings will be of utility for a better understanding of ASFV pathogenesis and for the rational designing of safe and efficient vaccines against this virus. PMID- 26589146 TI - Does deterioration in mental health after smoking cessation predict relapse to smoking? AB - BACKGROUND: It is possible that some people who quit smoking experience improved mental health after cessation and therefore remain abstinent, whereas other people who quit may experience worse mental health after cessation and therefore be more likely to relapse to smoking. Thus, in this study we aimed to examine the association between an enduring change in mental health following the cessation period and future risk of relapse. METHODS: A secondary analysis of prospective data pooled from five placebo-controlled randomised trials for smoking reduction conducted in Europe, USA and Australia. Change in mental health (SF-36, scored 0 100) was measured from baseline to four months for those who were biologically validated as point-prevalence abstainers at four month follow-up. Thereafter we assessed whether relapse to smoking by 12 months was more likely in those whose mental health had worsened between baseline and four months compared with those who saw no change or an improvement. RESULTS: After adjustment for baseline mental health and other major covariates, there was no greater tendency to relapse at 12 months for those whose mental health worsened after cessation compared with those who had no change or an improvement. The odds ratio and 95% confidence interval was 1.01 (0.97 to 1.05). CONCLUSIONS: People whose mental health worsens after smoking cessation are at no greater risk of subsequent relapse to smoking than those whose mental health stays the same or improves. PMID- 26589148 TI - Improved Density Dependent Correction for the Description of London Dispersion Forces. AB - The Tkatchenko-Scheffler method for calculating dispersion correction to standard density-functional theory, which uses fixed neutral atoms as a reference to estimate the effective volumes of atoms-in-molecule and to calibrate their polarizabilities and dispersion coefficients, fails to describe the structure and the energetics of ionic solids. Here, we propose a more appropriate partitioning, based on the iterative Hirshfeld scheme, where the fractionally charged atomic reference state is determined self-consistently. We show that our new method extends the applicability of the original method in particular to study ionic systems and adsorption phenomena on surfaces of ionic solids. PMID- 26589149 TI - Analytical Nuclear Gradients of Density-Fitted Dirac-Fock Theory with a 2-Spinor Basis. AB - An efficient algorithm is presented for evaluating the analytical nuclear gradients of density-fitted four-component relativistic Dirac-Fock theory as an initial step toward realizing large-scale geometry optimization of heavy-element complexes. Our algorithm employs kinetically balanced 2-spinor basis functions for the small components. The computational cost of nuclear gradient evaluation is found to be smaller than that of a Dirac-Fock self-consistent iteration. Timing data are presented for Ir(ppy)3 (61 atoms) using a double-zeta basis set. PMID- 26589150 TI - Simulations of Adiabatic Electrochemical Reduction of the CF3I Molecule Assessment of Different Models. AB - The kinetics and mechanism of electrochemical reduction of the CF3I molecule are studied using molecular dynamics simulations. The potential energy surface used in the simulations is based on the Newns-Anderson-Schmickler Hamiltonian and on the analytical potentials fitted to points obtained from quantum calculations for the CF3I neutral molecule and anion. Two different sets of points were used for fitting: the first obtained in vacuo1 and the second in dimethyl sulfoxide,2 which yields two models, named respectively "VAC" and "SOLV." Additionally, each model was tested with two different values of the solvent reorganization energies: lambda = 0.624 eV and lambda = 1 eV. The results show that both models provide results which are qualitatively similar but differ quantitatively, mainly due to a shift in the overpotential eta. The electron transfer coefficient is found to vary linearly at a certain range of overpotentials, but this relation changes for larger eta, where it takes a parabolic-like form. The transfer coefficient is very sensitive to the lambda value: at T = 298 K and eta = 0.9 V, we report values alpha = 0.204 obtained for lambda = 0.624 eV and alpha = 0.28 for lambda = 1 eV. PMID- 26589151 TI - Performance of the EOMIP-CCSD(2) Method for Determining the Structure and Properties of Doublet Radicals: A Benchmark Investigation. AB - We present a benchmark study on the performance of the EOMIP-CCSD(2) method for computation of structure and properties of doublet radicals. The EOMIP-CCSD(2) method is a second-order approximation to the standard EOMIP-CCSD method. By retaining the black box nature of the standard EOMIP-CCSD method and adding favorable N(5) scaling, the EOMIP-CCSD(2) method can become the method of choice for predicting the structure and spectroscopic properties of large doublet radicals. The EOMIP-CCSD(2) method overcomes the typical problems associated with the standard single reference ab initio treatment of doublet radicals. We compare our results for geometries and harmonic vibrational frequencies with those obtained using the standard EOMIP-CCSD method, as well as unrestricted Hartree Fock (UHF)- and restricted open-shell Hartree-Fock (ROHF)-based single-reference coupled-cluster and second order many-body perturbation theory (MBPT(2)) methods. The effect of the basis set on the quality of the results has been studied using a hierarchy of Dunning's correlation-consistent aug-cc-pVXZ (X = D, T, Q) basis sets. Numerical results show that the EOMIP-CCSD(2) method, despite its N(5) scaling, gives better agreement with experimental results, compared to the UHF- and ROHF-based MBPT(2), as well as the single-reference coupled-cluster methods. PMID- 26589152 TI - Effect of Dot Size on Exciton Binding Energy and Electron-Hole Recombination Probability in CdSe Quantum Dots. PMID- 26589153 TI - Real-Space Density Functional Theory on Graphical Processing Units: Computational Approach and Comparison to Gaussian Basis Set Methods. AB - We discuss the application of graphical processing units (GPUs) to accelerate real-space density functional theory (DFT) calculations. To make our implementation efficient, we have developed a scheme to expose the data parallelism available in the DFT approach; this is applied to the different procedures required for a real-space DFT calculation. We present results for current-generation GPUs from AMD and Nvidia, which show that our scheme, implemented in the free code Octopus, can reach a sustained performance of up to 90 GFlops for a single GPU, representing a significant speed-up when compared to the CPU version of the code. Moreover, for some systems, our implementation can outperform a GPU Gaussian basis set code, showing that the real-space approach is a competitive alternative for DFT simulations on GPUs. PMID- 26589154 TI - Discovery of Most Stable Structures of Neutral and Anionic Phenylalanine through Automated Scanning of Tautomeric and Conformational Spaces. AB - We have developed a software tool for combinatorial generation of tautomers and conformers of small molecules. We have demonstrated it by performing a systematic search for the most stable structures of neutral and anionic phenylalanine (Phe) using electronic structure methods. For the neutral canonical tautomer we found out that the conformers with and without the intramolecular (O)H...NH2 hydrogen bond are similarly stable, within the error bars of our method. A unique IR signature of the conformer without the hydrogen bond has been identified. We also considered anions of Phe, both valence type and dipole-bound. We have found out that tautomers resulting from proton transfer from the carboxylic OH to the phenyl ring do support valence anions that are vertically strongly bound, with electron vertical detachment energies (VDE) in a range of 3.2-3.5 eV. The most stable conformer of these valence anions remains adiabatically unbound with respect to the canonical neutral by only 2.17 kcal/mol at the CCSD(T)/aug-cc-pVDZ level. On the basis of our past experience with valence anions of nucleic acid bases, we suggest that the valence anions of Phe identified in this report can be observed experimentally. The most stable conformer of canonical Phe is characterized by an adiabatic electron affinity of 53 meV (a dipole-bound state). PMID- 26589155 TI - On the Short-Range Behavior of Correlated Pair Functions from the Adiabatic Connection Fluctuation-Dissipation Theorem of Density-Functional Theory. AB - The short-range behavior of correlated pair functions from the adiabatic connection fluctuation-dissipation theorem (ACFD) of density functional theory (DFT) employing local exchange-correlation kernels has been analyzed. It has been found that for large basis sets the pair function exhibits unphysical humps for small interelectronic distances if the adiabatic local density approximation kernel is used in the ACFD scheme (this method is termed ACFD/ALDA in this work). However, up to basis set sizes of quadruple-zeta type quality, the correlated pair function of ACFD/ALDA behaves physically correct and the method yields reasonable results for atomization energies, ionization potentials, and intermolecular interaction energies. In order to correct the deficiencies of the pair function of ACFD/ALDA for large basis sets, a short-range correction scheme has been devised on the basis of a combination of the ACFD/ALDA pair function for the large distance regime with a proper physically correctly behaving pair function at smaller distances. While this approach, termed as ACFD/ALDAcorr, practically yields results close to those of the ACFD/ALDA method for finite basis sets, it enables basis set extrapolation techniques and thus can take dynamic correlation effects fully into account in contrast to the ACFD/ALDA approach. This work also presents an efficient density-fitting algorithm to compute the ACFD correlation energies that enables the calculation of correlation energies of extended molecular systems. PMID- 26589156 TI - Convergence Acceleration of Parallel Monte Carlo Second-Order Many-Body Perturbation Calculations Using Redundant Walkers. AB - A Monte Carlo (MC) integration of the second-order many-body perturbation (MP2) corrections to energies and self-energies eliminates the usual computational bottleneck of the MP2 algorithm (i.e., the basis transformation of two-electron integrals), thereby achieving near-linear size dependence of its operation cost, a negligible core and disk memory cost, and a naturally parallel computational kernel. In this method, the correlation correction expressions are recast into high-dimensional integrals, which are approximated as the sums of integrands evaluated at coordinates of four electron random walkers guided by a Metropolis algorithm for importance sampling. The gravest drawback of this method, however, is the inevitable statistical uncertainties in its results, which decay slowly as the inverse square-root of the number of MC steps. We propose an algorithm that can increase the number of MC sampling points in each MC step by many orders of magnitude by having 2m electron walkers (m > 2) and then using m(m - 1)/2 permutations of their coordinates in evaluating the integrands. Hence, this algorithm brings an O(m(2))-fold increase in the number of MC sampling points at a mere O(m) additional cost of propagating redundant walkers, which is a net O(m) fold enhancement in sampling efficiency. We have demonstrated a large performance increase in the Monte Carlo MP2 calculations for the correlation energies of benzene and benzene dimer as well as for the correlation corrections to the energy, ionization potential, and electron affinity of C60. The calculation for C60 has been performed with a parallel implementation of this method running on up to 400 processors of a supercomputer, yielding an accurate prediction of its large electron affinity, which makes its derivative useful as an electron acceptor in bulk heterojunction organic solar cells. PMID- 26589157 TI - Assessment of Coupled Cluster Theory and more Approximate Methods for Hydrogen Bonded Systems. AB - To assess the accuracy of post-Hartree-Fock methods like CCSD(T), MP3, MP2.5, MP2, SCS-MP2, SOS-MP2, and DFT-SAPT, we evaluated several effects going beyond valence-correlated CCSD(T). For 16 small hydrogen bonded systems, CCSD(T) achieves an RMS error of 0.17 kJ/mol in the dissociation energy compared to our best estimate, which is a composite method akin to W4 theory. The error of CCSD(T) is thus much lower than for atomization energies. MP2 is surprisingly accurate for these systems with an RMS error of 1.3 kJ/mol. MP2.5 yields a clear improvement over MP2 (RMS of 0.5 kJ/mol) but still has an error about 3 times as large as CCSD(T) for the absolute RMS and almost 10 times as large for the relative RMS error. Neither SCS-MP2, SOS-MP2, nor DFT-SAPT yield lower errors than MP2. With a DeltaCCSD(T) correction to MP2, the basis set limit is readily achieved when employing diffuse functions-without these, the convergence is rather slow. PMID- 26589158 TI - Assessment of Tuning Methods for Enforcing Approximate Energy Linearity in Range Separated Hybrid Functionals. AB - A range of tuning methods, for enforcing approximate energy linearity through a system-by-system optimization of a range-separated hybrid functional, are assessed. For a series of atoms, the accuracy of the frontier orbital energies, ionization potentials, electron affinities, and orbital energy gaps is quantified, and particular attention is paid to the extent to which approximate energy linearity is actually achieved. The tuning methods can yield significantly improved orbital energies and orbital energy gaps, compared to those from conventional functionals. For systems with integer M electrons, optimal results are obtained using a tuning norm based on the highest occupied orbital energy of the M and M + 1 electron systems, with deviations of just 0.1-0.2 eV in these quantities, compared to exact values. However, detailed examination for the carbon atom illustrates a subtle cancellation between errors arising from nonlinearity and errors in the computed ionization potentials and electron affinities used in the tuning. PMID- 26589159 TI - Efficient Linear-Scaling Density Functional Theory for Molecular Systems. AB - Despite recent progress in linear scaling (LS) density function theory (DFT), the computational cost of the existing LS methods remains too high for a widespread adoption at present. In this work, we exploit nonorthogonal localized molecular orbitals to develop a series of LS methods for molecular systems with a low computational overhead. High efficiency of the proposed methods is achieved with a new robust two-stage variational procedure or by replacing the optimization altogether with an accurate nonself-consistent approach. We demonstrate that, even for challenging condensed-phase systems, the implemented LS methods are capable of extending the range of accurate DFT simulations to molecular systems that are an order of magnitude larger than those previously treated. PMID- 26589160 TI - Electron Transfer in Electrophilic Aromatic Nitration and Nitrosation: Computational Evidence for the Marcus Inverted Region. AB - Electrophilic aromatic nitrosation and nitration are among the most important electron transfer (ET) reactions. According to the electron transfer theory, an ET process can be described with two electron-localized diabatic states, and the electronic coupling between these two states, together with the organization energy and reaction energy, determine the ET efficiency. A proper definition of the strictly electron-localized states thus is the key. Here we used the valence bond theory to derive the diabatic states and probe the interactions of NO(+) and NO2(+) with benzene and identify the origin of their significant difference in reactivity. Results show that the high deformation cost for NO2(+) overshadows the fact that it has much high charge transfer interaction in [C6H6,NO2](+). While NO(+) uses pi orbitals to bind benzene and the orbital switch results in a high barrier from pi- to sigma-complex, NO2(+) uses a vacant sigma(Nsp(2)) orbital, making the transition nearly barrierless. Significantly, we found that the post-ET state [C6H6(+)-NO] is more stable than the prior-ET state [C6H6,NO(+)]. Energy profiles with respect to the distance between the electrophile and the benzene confirm that the ET reaction of benzene and NO(+) falls in the Marcus inverted region, and the outer-sphere ET occurs at ~2.6 A with the electronic coupling energy of 1.06 eV, compared with the experimental estimate 1.4 +/- 0.5 eV. PMID- 26589161 TI - Free Cyclooctatetraene Dianion: Planarity, Aromaticity, and Theoretical Challenges. PMID- 26589162 TI - Bonding in Sulfur-Oxygen Compounds-HSO/SOH and SOO/OSO: An Example of Recoupled Pair pi Bonding. AB - The ground states (X(2)A") of HSO and SOH are extremely close in energy, yet their molecular structures differ dramatically, e.g., re(SO) is 1.485 A in HSO and 1.632 A in SOH. The SO bond is also much stronger in HSO than in SOH: 100.3 kcal/mol versus 78.8 kcal/mol [RCCSD(T)-F12/AVTZ]. Similar differences are found in the SO2 isomers, SOO and OSO, depending on whether the second oxygen atom binds to oxygen or sulfur. We report generalized valence bond and RCCSD(T)-F12 calculations on HSO/SOH and OSO/SOO and analyze the bonding in all four species. We find that HSO has a shorter and stronger SO bond than SOH due to the presence of a recoupled pair bond in the pi(a") system of HSO. Similarly, the bonding in SOO and OSO differs greatly. SOO is like ozone and has substantial diradical character, while OSO has two recoupled pair pi bonds and negligible diradical character. The ability of the sulfur atom to form recoupled pair bonds provides a natural explanation for the dramatic variation in the bonding in these and many other sulfur-oxygen compounds. PMID- 26589163 TI - Characterizing and Understanding the Remarkably Slow Basis Set Convergence of Several Minnesota Density Functionals for Intermolecular Interaction Energies. AB - For a set of eight equilibrium intermolecular complexes, it is discovered that the basis set limit (BSL) cannot be reached by aug-cc-pV5Z for three of the Minnesota density functionals: M06-L, M06-HF, and M11-L. In addition, the M06 and M11 functionals exhibit substantial, but less severe, difficulties in reaching the BSL. By using successively finer grids, it is demonstrated that this issue is not related to the numerical integration of the exchange-correlation functional. In addition, it is shown that the difficulty in reaching the BSL is not a direct consequence of the structure of the augmented functions in Dunning's basis sets, since modified augmentation yields similar results. By using a very large custom basis set, the BSL appears to be reached for the HF dimer for all of the functionals. As a result, it is concluded that the difficulties faced by several of the Minnesota density functionals are related to an interplay between the form of these functionals and the structure of standard basis sets. It is speculated that the difficulty in reaching the basis set limit is related to the magnitude of the inhomogeneity correction factor (ICF) of the exchange functional. A simple modification of the M06-L exchange functional that systematically reduces the basis set superposition error (BSSE) for the HF dimer in the aug-cc-pVQZ basis set is presented, further supporting the speculation that the difficulty in reaching the BSL is caused by the magnitude of the exchange functional ICF. Finally, the BSSE is plotted with respect to the internuclear distance of the neon dimer for two of the examined functionals. PMID- 26589164 TI - Multireference Ab Initio Density Matrix Renormalization Group (DMRG)-CASSCF and DMRG-CASPT2 Study on the Photochromic Ring Opening of Spiropyran. AB - The photochromic ring-opening reaction of spiropyran has been revisited at the multireference CASSCF and CASPT2 level with a CAS(22e,20o) active space, in combination with density matrix renormalization group (DMRG) methods. The accuracy of the DMRG-CASSCF and DMRG-CASPT2 calculations, with respect to the number of renormalized states, the number of roots in state-averaged wave functions, and the number basis functions, was examined. For the current system, chemically accurate results can be obtained with a relatively small number of renormalized states. The nature and vertical excitation energies of the excited (S1 and S2) states are consistent with conventional CAS(or RAS)PT2 with medium active spaces. The capability of the DMRG-CASSCF method in the optimization of molecular geometry is demonstrated for the first time. The computation costs (several hours per optimization cycle) are comparable with that of the conventional CASSCF geometry optimization with small active space. Finally, the DMRG-PT2 computed S1-MEP for the C-O and C-N bond-cleavage processes show good agreement with our previous calculations with a CAS(12e,10o) active space [Liu, F.; Morokuma, K. J. Am. Chem. Soc. 2013, 135, 10693-10702]. Especially, the role of the HOOP valleys in the S1 -> S0 nonadiabatic decay has been confirmed. PMID- 26589165 TI - AM1 Specific Reaction Parameters for Reactions of Hydroxide Ion with Halomethanes in Complex Environments: Development and Testing. AB - A specific reaction parameters (SRP) approach is used to reparameterize the semiempirical AM1 method to represent two SN2 reactions of OH(-) with halomethanes (CH3F and CH3Cl). The objective is to develop SRP models that are able to accurately reproduce ab initio potential energy surfaces but with a reduction of several orders of magnitude in computational cost. The developed models, labeled AM1-SRP, have been tested in gas and aqueous phases. The results show that the AM1-SRP models are able to predict a minimum reaction path in close agreement with high level ab initio calculations in gas phase. A QM/MM simulation method with the solutes represented by the AM1-SRP models is used to compute the free energy profiles of the reactions in aqueous phase. The AM1-SRP models predict reaction free energies and free energy barriers in good agreement with experimental values. The current study indicates that semiempirical models may be improved to accurately reproduce an ab initio minimum reaction path at a considerably lower cost. The SRP approach is expected to be useful in long time scale molecular dynamics simulations where it is very expensive to use ab initio methods, specially in condensed phases. PMID- 26589166 TI - Solvent Effects on the Absorption Spectra of the para-Coumaric Acid Chromophore in Its Different Protonation Forms. AB - The effects of the solvent and protonation state on the electronic absorption spectrum of the para-coumaric acid (pCA), a model of the photoactive yellow protein (PYP), have been studied using the ASEP/MD (averaged solvent electrostatic potential from molecular dynamics) method. Even though, in the protein, the chromophore is assumed to be in its phenolate monoanionic form, when it is found in water solution pH control can favor neutral, monoanionic, and dianionic species. As the pCA has two hydrogens susceptible of deprotonation, both carboxylate and phenolate monoanions are possible. Their relative stabilities are strongly dependent on the medium. In gas phase, the most stable isomer is the phenolate while in aqueous solution it is the carboxylate, although the population of the phenolate form is not negligible. The s-cis, s-trans, syn, and anti conformers have also been included in the study. Electronic excited states of the chromophore have been characterized by SA-CAS(14,12)-PT2/cc-pVDZ level of theory. The bright state corresponds, in all the cases, to a pi -> pi* transition involving a charge displacement in the system. The magnitude and direction of this displacement depends on the protonation state and on the environment (gas phase or solution). In the same way, the calculated solvatochromic shift of the absorption maximum depends on the studied form, being a red shift for the neutral, carboxylate monoanion, and dianionic chromophores and a blue shift for the phenolate monoanion. Finally, the contribution that the solvent electronic polarizability has on the solvent shift was analyzed. It represents a very important part of the total solvent shift in the neutral form, but its contribution is completly negligible in the mono- and dianionic forms. PMID- 26589167 TI - Mapping the Excited State Potential Energy Surface of a Retinal Chromophore Model with Multireference and Equation-of-Motion Coupled-Cluster Methods. AB - The photoisomerization of the retinal chromophore of visual pigments proceeds along a complex reaction coordinate on a multidimensional surface that comprises a hydrogen-out-of-plane (HOOP) coordinate, a bond length alternation (BLA) coordinate, a single bond torsion and, finally, the reactive double bond torsion. These degrees of freedom are coupled with changes in the electronic structure of the chromophore and, therefore, the computational investigation of the photochemistry of such systems requires the use of a methodology capable of describing electronic structure changes along all those coordinates. Here, we employ the penta-2,4-dieniminium (PSB3) cation as a minimal model of the retinal chromophore of visual pigments and compare its excited state isomerization paths at the CASSCF and CASPT2 levels of theory. These paths connect the cis isomer and the trans isomer of PSB3 with two structurally and energetically distinct conical intersections (CIs) that belong to the same intersection space. MRCISD+Q energy profiles along these paths provide benchmark values against which other ab initio methods are validated. Accordingly, we compare the energy profiles of MRPT2 methods (CASPT2, QD-NEVPT2, and XMCQDPT2) and EOM-SF-CC methods (EOM-SF-CCSD and EOM-SF-CCSD(dT)) to the MRCISD+Q reference profiles. We find that the paths produced with CASSCF and CASPT2 are topologically and energetically different, partially due to the existence of a "locally excited" region on the CASPT2 excited state near the Franck-Condon point that is absent in CASSCF and that involves a single bond, rather than double bond, torsion. We also find that MRPT2 methods as well as EOM-SF-CCSD(dT) are capable of quantitatively describing the processes involved in the photoisomerization of systems like PSB3. PMID- 26589168 TI - Is the Tamm-Dancoff Approximation Reliable for the Calculation of Absorption and Fluorescence Band Shapes? AB - The reliability of the Tamm-Dancoff approximation (TDA) for predicting vibrationally resolved absorption and emission spectra of several prototypical conjugated molecules has been addressed by performing a series of extensive theoretical calculations. To this end, we have systematically compared the TDA results with the full Time-Dependent Density Functional Theory (TDDFT), the Random Phase Approximation (RPA), as well as the Configuration Interaction Singles (CIS) methods that are routinely employed for the prediction of optical spectra of large molecules. Comparisons have been made with experimental results for both the band shapes and 0-0 energies. They revealed that TDA is generally able to reproduce the experimental band shapes along with the positions of the absorption and emission peaks. With respect to TDDFT, TDA leads to an underestimation of the relative intensities for most cases but does not alter any other feature of the spectra. For the case of 0-0 energies, it leads to a better agreement between theory and experiment compared to TDDFT for the majority of the molecules studied, at least when combined with the popular B3LYP functional. PMID- 26589169 TI - Quantification of Solvent Contribution to the Stability of Noncovalent Complexes. AB - We introduce an indirect approach to estimate the solvation contributions to the thermodynamics of noncovalent complex formation through molecular dynamics simulation. This estimation is demonstrated by potential of mean force and entropy calculations on the binding process between beta-cyclodextrin (host) and four drug molecules puerarin, daidzin, daidzein, and nabumetone (guest) in explicit water, followed by a stepwise extraction of individual enthalpy (DeltaH) and entropy (DeltaS) terms from the total free energy. Detailed analysis on the energetics of the host-guest complexation demonstrates that flexibility of the binding partners and solvation-related DeltaH and DeltaS need to be included explicitly for accurate estimation of the binding thermodynamics. From this, and our previous work on the solvent dependency of binding energies (Zhang et al. J. Phys. Chem. B 2012, 116, 12684-12693), it follows that calculations neglecting host or guest flexibility, or those employing implicit solvent, will not be able to systematically predict binding free energies. The approach presented here can be readily adopted for obtaining a deeper understanding of the mechanisms governing noncovalent associations in solution. PMID- 26589170 TI - Interaction of Nucleic Acid Bases with the Au(111) Surface. AB - The fate of an individual DNA molecule when it is deposited on a hard inorganic surface in a "dry" environment is unknown, while it is a crucial determinant for nanotechnology applications of nucleic acids. In the absence of experimental approaches that are able to unravel the three-dimensional atomic structure of the target system, here we tackle the first step toward a computational solution of the problem. By using first-principles quantum mechanical calculations of the four nucleobases on the Au(111) surface, we present results for the geometries, energetics, and electronic structure, in view of developing a force field that will enable classical simulations of DNA on Au(111) to investigate the structural modifications of the duplex in these non-native conditions. We fully characterize each system at the individual level. We find that van der Waals interactions are crucial for a correct description of the geometry and energetics. However, the mechanism of adsorption is well beyond pure dispersion interactions. Indeed, we find charge sharing between the substrate and the adsorbate, the formation of hybrid orbitals, and even bonding orbitals. Yet, this molecule-surface association is qualitatively distinct from the thiol adsorption mechanism: we discuss such differences and also the relation to the adsorption mechanism of pure aromatic molecules. PMID- 26589171 TI - Hydration of Cisplatin Studied by an Effective Ab Initio Pair Potential Including Solute-Solvent Polarization. AB - The hydration of cis-[PtCl2(NH3)2] (cisplatin) has been studied by means of classical molecular dynamics simulations using a new interaction potential obtained by fitting about 4000 ab initio interaction energies calculated at the MP2 level. The functional form included several r(-n) terms (n = 4, 6, 8, 12) to achieve an accurate description of the interactions in the different regions around the cisplatin. Bulk solvent effects on the cisplatin-water molecule interactions have been included by means of a continuum model. Radial Distribution Function (RDF) analysis does not provide a clear enough description of the hydration pattern due to the intricate solvent arrangement around the solute. Angle-solved RDFs and spatial distribution functions have been used to provide more detailed pictures of the local hydration structure around the two ligands, chloride and ammine groups, and the axial region. Based on this information, it is shown a more convenient way to compute the running coordination number for the first hydration shell by simultaneously considering angle-solved RDFs centered on the ligand representative atoms of the complex: ammino N, Cl, and Pt atoms. This way, the hydration number is obtained by integrating over an interlocking-sphere volume built by the spheres centered on the cation and the main atoms of each ligand. Compared to previous works dealing with cisplatin hydration, the global hydration number for the first coordination shell is now higher and involves about 27 water molecules. The importance of the structural sampling, the computational level, as well as the functional form adopted for the interaction potential are thoroughly discussed with respect to the previous proposed intermolecular potential. PMID- 26589172 TI - What Is the Dielectric Constant of a Protein When Its Backbone Is Fixed? AB - Monte Carlo (MC) simulations with a fixed protein backbone but mobile sidechains are common for acid/base constants and protein design. To characterize the fluctuations in these models, estimating the Frohlich-Kirkwood dielectric constant can give physical insight and allow comparison both with models that are more rigorous (fully flexible) and ones that are simpler (Poisson-Boltmann without any explicit protein flexibility). MC simulations of two small proteins yield protein dielectric constants of 12 and 14, about 70% of the result from MD (16 and 22). Thus, the consistency between the fully explicit MD and partly explicit MC is only fair. PMID- 26589173 TI - Absolute Free Energy of Binding and Entropy of the FKBP12-FK506 Complex: Effects of the Force Field. AB - The hypothetical scanning molecular dynamics (HSMD) method combined with thermodynamic integration (HSMD-TI) has been extended recently for calculating DeltaA(0)-the absolute free energy of binding of a ligand to a protein. With HSMD TI, DeltaA(0) is obtained in a new way as a sum of several components, among them is DeltaSligand-the change in the conformational entropy as the ligand is transferred from the bulk solvent to the active site-this entropy is obtained by a specific reconstruction procedure. This unique aspect of HSMD (which is useful in rational drug design) is in particular important for treating large ligands, where DeltaSligand might be significant. Technically, one should verify that the results for DeltaSligand converge-a property that might become more difficult for large ligands; therefore, studying ligands of increasing size would define the range of applicability of HSMD-TI for binding. In this paper, we check the performance of HSMD-TI by applying it to the relatively large ligand FK506 (126 atoms) complexed with the protein FKBP12, where DeltaA(0) = -12.8 kcal/mol is known experimentally as well as the crystal structure of the complex. This structure was initially equilibrated by carrying out a 100 ns molecular dynamics trajectory, where the system is modeled by the AMBER force field, TIP3P water, and Particle Mesh Ewald. HSMD-TI calculations were carried out in three conformational regions defined by the intervals [0.2,2], [2,5], and [5,100] ns along the trajectory, where local equilibration of the total energy has been observed; we obtained DeltaA(0) = -13.6 +/- 1.1, -16.6 +/- 1.4, and -16.7 +/- 1.4 kcal/mol, respectively indicating the following: (1) The second and third regions belong to the same conformational subspace of the complex, which is different from the [0.2,2] ns subspace. (2) The unsatisfactory result for DeltaA(0) obtained in the well equilibrated (hence theoretically preferred) latter regions reflects the nonperfect modeling used, which however (3) has led to the experimental DeltaA(0) in the [0.2,2] ns region close to the crystal structure. Keeping the complex near its crystal structure has been a successful approach in the literature. To check this avenue further, we applied harmonic restraints on backbone atoms and obtained unsatisfactory results for DeltaA(0), suggesting that implementation of this approach is not straightforward. Converging results for DeltaSligand were obtained in all regions, where the result DeltaSligand([0.2,2]) = 7.1 +/- 1.2 kcal/mol is less region dependent than DeltaA(0) and is relatively large probably due to the large ligand. PMID- 26589174 TI - Challenges in Computing Electron-Transfer Energies of DNA Repair Using Hybrid QM/MM Models. AB - The influence of the molecular environment on chemical activity is an important factor in biomolecular mechanisms. We studied the effects of ionic groups, that is, a protonated histidine side chain and deprotonated phosphates of DNA, on electron transfer in light-induced DNA repair. On the basis of the X-ray crystal structure, we prepared a hybrid QM/MM model of the macromolecular complex formed between the (6-4) photolyase enzyme and the DNA substrate containing the thymine thymine (6-4) photoproduct. At the optimized geometries, we computed with the CASSCF and CASPT2 methods the excited states of the electron donor and electron acceptor complex, consisting of the reduced flavin and the (6-4) photoproduct. The donor-acceptor complex interacts with its environment comprised of the protein, the double-stranded DNA substrate with its counterions, and the solvating water molecules, which we modeled using the AMBER94 force field. The excited states of our interest include two locally excited (LE) states of the flavin chromophore and intermolecular electron-transfer (ET) states. We identify only minor changes of the LE excitation energies by interactions with the environment, but in drastic contrast to that, we found significant changes of the ET excitation energies. In the presence of the positively charged His365H(+), the ET excitation energies decrease, indicating facilitated electron transfer. In addition, the excitation energy of the second LE state, explaining the flavin's absorption at 380 nm, undergoes a 0.2 eV downshift. In contrast to the active site protonation, reduced screening of the DNA phosphates increases the ET excitation energies but not the LE excitation energies. Accordingly, the electron affinities of the (6-4) photoproduct are significantly reduced, which should hinder electron transfer from the excited flavin. We also show that dynamic electron correlation accounted by the second order perturbation theory CASPT2 does not alter the energy trends obtained with the CASSCF method. Including the histidine side chain in the QM part enhances the effect of the histidine protonation on the ET energies. We also note that protonated His365H(+) can serve as an electron acceptor. PMID- 26589175 TI - Quantum Mechanical Study of Vicinal J Spin-Spin Coupling Constants for the Protein Backbone. AB - We have performed densisty functional theory (DFT) calculations of vicinal J coupling constants involving the backbone torsional angle for the protein GB3 using our recently developed automatic fragmentation quantum mechanics/molecular mechanics (AF-QM/MM) approach (Xiao He et al. J. Phys. Chem. B 2009, 113, 10380 10388). Interestingly, the calculated values based on an NMR structure are more accurate than those based on a high-resolution X-ray strucure because the NMR structure was refined using a large number of residual dipolar couplings (RDCs) whereas the hydrogen atoms were added into the X-ray structure in idealized positions, confirming that the postioning of the hydrogen atoms relative to the backbone atoms is important to the accuracy of J coupling constant prediction. By comparing three Karplus equations, our results have demonstrated that hydrogen bonding, substituent and electrostatic effects could have significant impacts on vicinal J couplings even though they depend mostly on the intervening dihedral angles. The root-mean-square deviations (RMSDs) of the calculated (3)J(H(N),H(alpha)), (3)J(H(N),C(beta)), (3)J(H(N),C') values based on the NMR structure are 0.52, 0.25, and 0.35 Hz, respectively, after taking the dynamic effect into consideration. The excellent accuracy demonstrates that our AF-QM/MM approach is a useful tool to study the relationship between J coupling constants and the structure and dynamics of proteins. PMID- 26589176 TI - Prediction of Protein-Ligand Binding Structures by Replica-Exchange Umbrella Sampling Simulations: Application to Kinase Systems. AB - We have applied our prediction method, which is based on the replica-exchange umbrella sampling for protein-ligand binding structures, to two kinase systems (p38 and JNK3) with two different ligand molecules for each kinase. Starting from configurations in which the protein and the ligand are far away from each other, our method predicted the ligand binding structures in excellent agreement with the experimental data from PDB in all four cases, which suggests the general applicability of our method to kinase systems. In addition, the protein flexibility was shown to be essential to predict the correct binding structure for one of the systems, where dihydroquinolinone was bound to p38 alpha kinase (PDB ID: 1OVE ). PMID- 26589177 TI - Identification of global regulators of T-helper cell lineage specification. AB - BACKGROUND: Activation and differentiation of T-helper (Th) cells into Th1 and Th2 types is a complex process orchestrated by distinct gene activation programs engaging a number of genes. This process is crucial for a robust immune response and an imbalance might lead to disease states such as autoimmune diseases or allergy. Therefore, identification of genes involved in this process is paramount to further understand the pathogenesis of, and design interventions for, immune mediated diseases. METHODS: We aimed at identifying protein-coding genes and long non-coding RNAs (lncRNAs) involved in early differentiation of T-helper cells by transcriptome analysis of cord blood-derived naive precursor, primary and polarized cells. RESULTS: Here, we identified lineage-specific genes involved in early differentiation of Th1 and Th2 subsets by integrating transcriptional profiling data from multiple platforms. We have obtained a high confidence list of genes as well as a list of novel genes by employing more than one profiling platform. We show that the density of lineage-specific epigenetic marks is higher around lineage-specific genes than anywhere else in the genome. Based on next generation sequencing data we identified lineage-specific lncRNAs involved in early Th1 and Th2 differentiation and predicted their expected functions through Gene Ontology analysis. We show that there is a positive trend in the expression of the closest lineage-specific lncRNA and gene pairs. We also found out that there is an enrichment of disease SNPs around a number of lncRNAs identified, suggesting that these lncRNAs might play a role in the etiology of autoimmune diseases. CONCLUSION: The results presented here show the involvement of several new actors in the early differentiation of T-helper cells and will be a valuable resource for better understanding of autoimmune processes. PMID- 26589179 TI - Incidence of peri-implantitis and oral quality of life in patients rehabilitated with implants with different neck designs: A 10-year retrospective study. AB - OBJECTIVES: To evaluate peri-implant bone loss, the presence of peri-implantitis, aesthetic satisfaction, and quality of life in patients with implant-based prosthetic restorations using implants with or without smooth necks, placed in different bone positions. MATERIALS AND METHODS: 400 patients received 1,244 implants: 515 with smooth neck monitored over an average of 6.44 +/- 2.55 years and 729 without smooth neck monitored over 5.61 +/- 2.52 years. Radiographic bone loss, presence of periimplantitis, implant loss, quality of life (OHIP-14), and patient satisfaction with prosthetic esthetics were evaluated, comparing groups. RESULTS: 120 implants developed peri-implantitis, 15 with a 2.5 mm smooth neck and 105 without smooth neck. Patients without smooth-necked implants showed a worse quality of life with statistically significant difference (p < 0.001). Patient satisfaction with prostheses was higher among the group without smooth neck. CONCLUSIONS: Implants with smooth polished necks would appear to suffer less bone loss and peri-implantitis, and lead to better patient quality of life. However, implants without smooth necks placed crestally led to higher patient satisfaction with aesthetics. PMID- 26589178 TI - Reducing Exacerbations in the Inner City: Lessons from the Inner-City Asthma Consortium (ICAC). AB - Asthma exacerbations are important components of asthma morbidity. The Inner-City Asthma Consortium was established in the early 1990s to identify risk factors for and to evaluate treatments to reduce asthma symptoms and exacerbations. Early studies identified atopy and inadequate treatment as important drivers of asthma morbidity. Later studies demonstrated that good adherence to guidelines-based asthma care could virtually eliminate symptoms and reduce but not eliminate exacerbations. Looking at exacerbations by season, risk factors were found to vary across the different seasons. Of the 7 factors identified, allergic status and pulmonary functions were found to be important for exacerbations in all seasons, but allergy had its strongest effect in the fall season. Therefore, additional therapy directed at reducing the role of allergy was evaluated and found to significantly reduce exacerbations even in participants with good symptom control when receiving guidelines-based therapy. Despite this year around aggressive therapy, exacerbations remain albeit at a lower level and with less seasonal variation. Another strategy, the short term use of therapy aimed at reducing the role of allergy begun before the fall season and focused on individuals at high risk for exacerbations, was found to be an effective approach to minimize exacerbations and to limit the amount of therapy necessary. PMID- 26589180 TI - Oral brush biopsy and melanoma-associated antigens A (MAGE-A) staining in clinically suspicious lesions. AB - PURPOSE: In oral cancer and in other tumor entities, melanoma-associated antigens are present. These antigens contribute to tumor progression and poor prognosis, and reduce the cytotoxicity of antineoplastic drugs. The aim of this study was to investigate the diagnostic potential of these antigens in combination with oral brush biopsies. MATERIAL AND METHODS: We analyzed 72 oral brush biopsy specimens for melanoma-associated antigens A (MAGE-A) expression by immunocytologic staining with the MAGE-A 57B antibody. A total of 24 healthy specimens, 15 lichen ruber cases, 18 leukoplakia cases, and 15 invasive carcinomas were studied. Incisional biopsy served as the gold standard. RESULTS: In total, 66 of 72 specimens (91.6%) could be assessed. Twelve of 15 (80%) carcinomas stained positive for MAGE-A. MAGE-A staining was detected in four of 51 nonmalignant specimens, resulting in a false-positive rate of 7.8%. However, MAGE-A positive staining was significantly correlated with oral squamous cell carcinoma (p < 0.0005). Sensitivity and specificity for MAGE-A staining and carcinoma were 80% and 92.2%, respectively. The diagnostic accuracy was 89.4%. CONCLUSION: Our results indicate that oral brush biopsy with MAGE-A staining serves as an additional tool for use in oral cancer diagnosis. These findings might help to facilitate an easier and more representative surveillance of the mucosa, particularly for large areas of altered mucosa. PMID- 26589181 TI - Image analysis of the inferior rectus muscle in orbital floor fracture using cine mode magnetic resonance imaging. AB - PURPOSE: The main cause of diplopia induced by orbital floor fracture is strangulation or damage of the extraocular muscles, and the outcome varies depending on the severity of trauma. In this study, we evaluated the dynamics of the eyeball and inferior rectus muscle based on cine magnetic resonance (MR) images acquired before surgery. The preoperative images and outcomes were retrospectively investigated. MATERIAL AND METHODS: The subjects were 20 patients with orbital floor fracture. The patients repeated upgaze and downgaze, and images of these were acquired using cine mode magnetic resonance imaging (MRI). Image series were obtained in the sagittal direction including the eyeball and long axis of the optic nerve. The eyeball rotation angle, strangulation, and morphology of the inferior rectus muscle were evaluated in each phase. RESULTS: On cine mode MRI, the outcome was poor in cases with a maximal inferior rectus muscle thickness of 5 mm or greater on extension (two or more times thicker than on the healthy side). CONCLUSIONS: Our results suggest that the development of sequelae can be predicted by preoperative image analysis using cine MRI, which may be beneficial to help surgeons understand the mechanism of contracture. PMID- 26589182 TI - Direct structural evidence of protein redox regulation obtained by in-cell NMR. AB - The redox properties of cellular environments are critical to many functional processes, and are strictly controlled in all living organisms. The glutathione glutathione disulfide (GSH-GSSG) couple is the most abundant intracellular redox couple. A GSH redox potential can be calculated for each cellular compartment, which reflects the redox properties of that environment. This redox potential is often used to predict the redox state of a disulfide-containing protein, based on thermodynamic considerations. However, thiol-disulfide exchange reactions are often catalyzed by specific partners, and the distribution of the redox states of a protein may not correspond to the thermodynamic equilibrium with the GSH pool. Ideally, the protein redox state should be measured directly, bypassing the need to extrapolate from the GSH. Here, by in-cell NMR, we directly observe the redox state of three human proteins, Cox17, Mia40 and SOD1, in the cytoplasm of human and bacterial cells. We compare the observed distributions of redox states with those predicted by the GSH redox potential, and our results partially agree with the predictions. Discrepancies likely arise from the fact that the redox state of SOD1 is controlled by a specific partner, its copper chaperone (CCS), in a pathway which is not linked to the GSH redox potential. In principle, in-cell NMR allows determining whether redox proteins are at the equilibrium with GSH, or they are kinetically regulated. Such approach does not need assumptions on the redox potential of the environment, and provides a way to characterize each redox regulating pathway separately. PMID- 26589183 TI - Assessment of liposome disruption to quantify drug delivery in vitro. AB - Efficient liposome disruption inside the cells is a key for success with any type of drug delivery system. The efficacy of drug delivery is currently evaluated by direct visualization of labeled liposomes internalized by cells, not addressing objectively the release and distribution of the drug. Here, we propose a novel method to easily assess liposome disruption and drug release into the cytoplasm. We propose the encapsulation of the cationic dye Hoechst 34580 to detect an increase in blue fluorescence due to its specific binding to negatively charged DNA. For that, the dye needs to be released inside the cell and translocated to the nucleus. The present approach correlates the intensity of detected fluorescent dye with liposome disruption and consequently assesses drug delivery within the cells. PMID- 26589184 TI - Development of neuropeptide Y-mediated heart innervation in rats. AB - Neuropeptide Y (NPY) plays a trophic role in the nervous and vascular systems and in cardiac hypertrophy. However, there is no report concerning the expression of NPY and its receptors in the heart during postnatal development. In the current study, immunohistochemistry and Western blot analysis was used to label NPY, and Y1R, Y2R, and Y5R receptors in the heart tissue and intramural cardiac ganglia from rats of different ages (newborn, 10 days old, 20 days old, 30 days old, 60 days old, 1 year old, and 2 years old).The obtained data suggest age-dependent changes of NPY-mediated heart innervation. The density of NPY-immunoreactive (IR) fibers was the least in newborn animals and increased in the first 20 days of life. In the atria of newborn and 10-day-old rats, NPY-IR fibers were more abundant compared with the ventricles. The vast majority of NPY-IR fibers also contained tyrosine hydroxylase, a key enzyme in catecholamine synthesis.The expression of Y1R increased between 10 and 20 days of life. Faint Y2R immunoreactivity was observed in the atria and ventricles of 20-day-old and older rats. In contrast, the highest level of the expression of Y5R was found in newborn pups comparing with more adult rats. All intramural ganglionic neurons were also Y1R-IR and Y5R-IR and Y2R-negative in all studied animals.Thus, the increasing of density of NPY-containing nerve fibers accompanies changes in relation of different subtypes of NPY receptors in the heart during development. PMID- 26589185 TI - Impact of the surgeon of the week system in an academic pediatric surgery practice. AB - BACKGROUND: A pilot rounding surgeon of the week (SOW) program was implemented in our institution on July 2013 to improve patient care through focused attending rounds. The purpose of this study was to assess the impact of the SOW. METHODS: We performed a descriptive retrospective study from a single, large-volume academic center. Data were collected from July to December 2013 (post-SOW) and compared to July to December 2012 (pre-SOW). Outcomes included patient safety (safety reports) and team productivity (billing data). We also evaluated nursing satisfaction through a 10-point Likert scale survey. RESULTS: The total number of patient safety complaints decreased after the SOW (37 pre-SOW versus 27 post SOW). Work relative value units (wRVUs) increased by 8% while nonoperative billing increased by 15%. Twenty of the daytime nursing staff completed the survey and overall satisfaction with the SOW was 8.3. Twelve were employed prior to the SOW and, when analyzed independently, the proportion of employees satisfied with nursing to physician communication was higher after the SOW (55% pre-SOW vs. 83% post-SOW, p=0.13) as was perception of parental satisfaction (33% vs. 75%, p=0.04). CONCLUSIONS: The SOW program appears to improve patient safety as evidenced by a decrease in patient safety events. Additionally, the SOW program led to higher ancillary staffing satisfaction and perceived parental satisfaction without decreasing revenue. This study suggests that the SOW may be a beneficial program that could be considered at other large-volume institutions. PMID- 26589186 TI - A prospective study comparing laparoscopic and conventional Kasai portoenterostomy in children with biliary atresia. AB - OBJECTIVE: The objective of the study is to evaluate the outcome of laparoscopic Kasai portoenterostomy for type III biliary atresia in children. METHODS: A total of 95 type III biliary atresia patients were treated at the Capital Institute of Pediatrics between September 2009 and August 2011. The patients were randomized into 2 groups preoperatively: the laparoscopic group (LP group, n=48) and the open group (OP group, n=47). In the LP group, 4 patients were converted to open operations, whereas the remaining 44 patients in the LP group and 47 patients in the OP group were included in the study. RESULTS: The gender distribution and age of the LP group did not differ from those of the OP group (LP group F/M 21/23, median age 61.5days, OP group F/M 24/23, median age 67days, P=0.75 and 0.11). The operation time in the LP group was significantly longer than that in the OP group (median 169.5min vs 146min, P<0.01). Intraoperative blood loss in the LP group was significantly lower than in the OP group (median 10ml vs 15ml, P<0.01). The resumption oral intake was significantly faster in the LP group than in the OP group (median 3days vs 3days, P<0.01). There were no significant differences between the postoperative hospital stay in the two groups (median 12.5days vs 13days, P=0.21). The median follow-up period was 16months in the LP group and 17months in the OP group. There was no statistically significant difference in the jaundice clearance rate at the end of the third postoperative month or in the incidence of cholangitis, native liver survival rate, and liver function recovery between the 2 groups. CONCLUSIONS: The short-term and mid-term results are comparable between the laparoscopic and open Kasai portoenterostomy groups. The laparoscopic Kasai procedure does not improve the prognosis of biliary atresia. PMID- 26589187 TI - Major neonatal surgery: psychosocial consequence of the patient and mothers. AB - PURPOSE: Our previous studies of long-term QOL after major neonatal surgery revealed an unexpectedly high incidence of mental retardation as well as emotional and psychosocial problems, and the patients' QOL correlated with maternal QOL and post-traumatic stress disorder (PTSD). The main purpose of this study was to clarify the risk factors affecting long-standing maternal PTSD. MATERIALS AND METHODS: Sixty-eight patients, aged between 6 and 17years, and their mothers were enrolled in this study. The underlying diseases included congenital diaphragmatic hernia in 21, anorectal anomalies in 25 and esophageal atresia in 22. Psychoanalysts carried out intelligence tests, the Child Behavior Checklist and QOL evaluation in the patients. QOL was evaluated with WHOQOL26 and PTSD with IES-R questionnaires in their mothers. The mothers were divided into two groups; low- and high-risk groups according to PTSD score. RESULTS: Patient QOL scores correlated positively with maternal QOL (p<0.05) and negatively with maternal PTSD scores (p<0.05). There were significant differences in total number of hospital admissions (p<0.05), feeling of economic burden (p<0.05), and satisfaction with husband's help (p<0.01) between the two groups. CONCLUSION: Risk factors for maternal PTSD include repeated hospitalization, a feeling of economic burden, and lack of satisfaction with husband's help. PMID- 26589188 TI - How to measure the affinity of aptamers for membrane proteins expressed on the surface of living adherent cells. AB - Recently, an increasing number of aptamers have been selected against biomarkers that are expressed at the surface of cells. This class of targets, mostly membrane proteins, is in close contact with the intra- and extra-cellular matrixes and their three-dimensional structures are inextricably linked to their inclusion in lipid bilayers. Therefore, although binding studies can be performed on the isolated form of these proteins, it remains crucial to measure the affinity of these aptamers in a more physiological environment, i.e., directly on living cells. Here, we describe a procedure for radioactive binding assays that can be adapted for measuring the affinity of aptamers against different cell lines. This method has been semi-automated using a liquid handling robot in order to reproducibly measure the apparent dissociation constant Kd and the apparent number of targets per cell. Relevant issues are discussed including the labeling of aptamers, the cells preparation, the incubation, the washings, the use of non specific competitors, the data analysis and finally the reporting. PMID- 26589189 TI - Ghrelin has both indirect and direct inhibiting effect on GnRH neurons: Reply for letter to editor "Ghrelin directly affects GnRH neurons". PMID- 26589190 TI - Commentary on "No effect of basic bladder advice in enuresis: A randomized controlled trial". PMID- 26589191 TI - Small diameter metal-on-metal total hip arthroplasty at 13 years - a follow-up study. AB - INTRODUCTION: Theoretically, the properties of second-generation metal-on-metal (MoM) bearings are better for wear, osteolysis and longevity. However, follow-up studies of more than 10 years are rare, in particular with hybrid fixation (cemented stainless steel stems and cementless cup), therefore we evaluated the results of this combination after a mean follow-up of 12.8 years: (1) to analyze the survival rate, (2) to compare it with the survival rate in the same series after 6.4 years (95.8% cup, 94.8% stem), (3) to evaluate clinical and radiographic outcome and (4) to analyze these failures. HYPOTHESIS: The number of revisions would increase after 10 years. MATERIALS AND METHODS: We evaluated 106 total hip arthroplasties (THA) (CediorTM press-fit cup with cemented AcoraTM (n=50) and ExafitTM (n=56) stems and 28mm MetasulTM bearings performed between January 1999 and December 2002. The survival rate was calculated by the Kaplan Meier method. The clinical assessment included the Postel Merle d'Aubigne (PMA) and Oxford scores. The radiographic assessment evaluated radiolucencies and osteolysis on standard X-rays. A histological analysis was only performed during revision THA. RESULTS: After a mean 12.8 years of follow-up (10-16), 53 THA were reviewed in 48 patients. Thirteen THA revisions (14%) were performed including 11 aseptic revisions (5 stem fractures, 2 cases of impingement and 3 loosenings [1 bipolar and 3 cups] and one case of osteolysis). Overall survival, taking into account revision for aseptic loosening, was 87.6% (CI 95%=77.3 to 99.3%). The mean PMA and Oxford scores at the final follow-up were 17.6+/-0.8 points (16-18) and 16.5+/-5.2 points (12-38) respectively. The radiological follow-up mainly identified radiolucencies around the stem in Gruen zones 1 and 7 (17 and 21% respectively). DISCUSSION: The survival rate of hybrid MoM THA in this series decreased after 10 years and is lower than studies evaluating cementless THA with the 28-mm MetasulTM bearings (90.9 to 100% survival). Although the clinical results are satisfactory, survival is lower. However, the role of MoM bearings is relative in these failures, in particular because trunnionoses (stainless steel stem with 28-mm head), impingement and especially 5-stem fractures were the main causes of failure. LEVEL OF EVIDENCE: IV: retrospective study. PMID- 26589192 TI - Inefficacy of Kinesio-Taping((r)) on early postoperative pain after ACL reconstruction: Prospective comparative study. AB - INTRODUCTION: Kinesio-Taping((r)) (K-Tape) is used in sports traumatology with the aim of reducing pain and improving blood and lymph circulation. The main objective of the present study was to assess the efficacy of K-Tape on early postoperative pain after anterior cruciate ligament (ACL) reconstruction. The study hypothesis was that K-Tape significantly decreases pain. METHOD: A prospective non-randomized comparative study was conducted in 2013-2014 and included all patients who underwent primary ACL reconstruction by hamstring graft. Analgesia was standardized. Two groups, "K-Tape" and "controls", were formed according to the days on which the study physiotherapist was present. The K-Tape compression/decompression assembly was applied immediately postoperatively and maintained for 3days. Patients filled out online questionnaires. The main assessment criterion was mean postoperative pain (D0-D3) on a 0-to-10 scale. Secondary criteria were analgesia intake on the three WHO levels, awakening during the night of D0 due to pain, signs of postoperative discomfort, and patient satisfaction. RESULTS: Sixty patients (30 per group) were included, 57 of whom could be assessed: 28 K-Tape, 29 controls; 44 male, 13 female; mean age, 30.9+/-8.9 years. At inclusion, the two groups were comparable. There was no significant difference in mean (D0-D3) knee pain intensity: 3.8+/-2.2 for K-Tape, and 3.9+/-2 for controls (P=0.93). Analysis of variance (ANOVA) found no significant intergroup difference in evolution of pain (P=0.34). There were no other significant differences on the other assessment criteria. CONCLUSION: K Tape showed no efficacy on early postoperative pain following ACL reconstruction. LEVEL OF EVIDENCE: III; prospective non-randomized comparative study. PMID- 26589193 TI - Does primary total knee arthroplasty for acute knee joint fracture maintain autonomy in the elderly? A retrospective study of 21 cases. AB - INTRODUCTION: Due to poor results and failure encountered in osteosynthesis of peri-articular fracture of the knee, arthroplasty may be suggested to osteopenic elderly subjects. All osteosynthesis techniques entail loss of independence and are associated with elevated mortality. No studies definitively establish better management of such fractures. HYPOTHESIS: Total arthroplasty provides better autonomy after peri-articular fracture of the knee. MATERIAL AND METHOD: Seventy nine patients aged over 65years were operated on for peri-articular fracture of the knee between April 2008 and March 2013. In 21 cases, treated by a single surgeon, total knee arthroplasty was performed in view of osteopenia or osteoarthritis. Mean age was 79years (range, 68-96years). There were 10 distal femoral and 11 proximal tibial fractures. Mean follow-up was 31months (range, 9 68months). Cases of pathologic fracture, failed osteosynthesis and non-operative management were excluded. All patients showed severe osteopenia on radiology and half already had advanced osteoarthritis. RESULTS: One-year mortality was 14%. At last follow-up, the revision rate was 9.5%. Fifteen patients were followed up. Mean Parker score fell from 7.2 (range, 2-9) preoperatively to 4.6 (range, 0-9) at last follow-up, indicating loss of independence. At follow-up, mean IKS score was 116.6 (range, 0-192) with mean IKS knee score of 78.4 (range, 0-100) and IKS function score of 38.2 (range, 0-100). Mean Oxford score was 36/60 (range, 18 53). Global IKS and IKS function scores were significantly better in case of ASA 2 than ASA-3 (P<0.05). There was no difference between femoral and tibial fractures in terms of IKS or Oxford score or loss of independence. DISCUSSION: Total knee arthroplasty can be considered for peri-articular fracture of the knee in osteopenic geriatric patients. Although surgical revision was less frequent than after osteosynthesis and resumption of weight-bearing was immediate, autonomy was still impaired. Mortality was comparable to other reports. LEVEL OF EVIDENCE: IV, retrospective study. PMID- 26589194 TI - Multiple sclerosis and fatigue: A review on the contribution of inflammation and immune-mediated neurodegeneration. AB - Multiple sclerosis (MS) is an immune mediated disease of the central nervous system (CNS) and the leading cause of non-traumatic disability among young and middle-aged adults in the western world. One of its most prevalent and debilitating symptoms is fatigue. Despite the general acceptance of the idea of an immune pathogenesis of MS itself, the role of autoimmunity in the course of MS fatigue is a matter of debate. Both immune-related processes (acute inflammation, chronic inflammation, immune-mediated neurodegeneration, immune-mediated alterations of endocrine functions related to fatigue) and presumably non-immune mediated disturbances and factors (sleep disturbances, depression, cognitive alterations, chronic infections, adverse effects of medications) contribute to the clinical picture. Data from in vitro and animal experiments has provided evidence for a role of cytokines as IL-1 and TNF-alpha. This association could not be verified directly in blood samples from humans whereas whole blood stimulation protocols gave some indirect evidence for a role of cytokines in MS fatigue. MRI being able to detect acute and chronic immune mediated damage to the CNS could depict that global atrophy of gray or white matter does not correlate with fatigue. Rather, distinctive clusters of lesions and atrophy at different locations, mostly bifrontal or in subcortical structures, correlate specifically with fatigue. Regardless of the difficulties in pinpointing the immunogenesis of MS-fatigue, an important role of autoimmunity is strongly supported by an indirect route: A growing amount of data shows that the highly effective immunotherapeutics which have been introduced to MS-treatment over the last years effectively and sustainably stabilize and ameliorate fatigue in parallel to their dampening effects on the neuroinflammatory process. This review summarizes the existing data on the relation between inflammation, patterns of CNS-lesions and the effects of immunotherapeutics on MS-fatigue. PMID- 26589195 TI - Is there an association between the Expanded Disability Status Scale and inflammatory markers in multiple sclerosis? AB - BACKGROUND: Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease characterized by inflammation of white matter in the central nervous system. It has been indicated that this inflammation causes increased levels of proinflammatory cytokines. Therefore, we aimed to evaluate if there is a possible association between inflammatory markers and the Expanded Disability Status Scale (EDSS) score in patients with MS. METHODS: We reviewed the data of 127 patients (91 women and 36 men) who were retrospectively diagnosed as MS according to the revised Mc Donald's criteria who were seen at our facility between January 2007 and December 2012. Patients were divided into two groups according to EDSS score: Group 1, EDSS < 5; and Group 2, EDSS >= 5. The risk factors that were evaluated included age and sex of the patients, duration of MS, drugs, thyroid function tests, vitamin B12 levels, homocysteine levels, immunoglobulins (Ig) A, G, and M, rheumatoid factor, complement 3 and 4, antistreptolysin O, C reactive protein (CRP), white blood cell count, and neutrophile-lymphocyte ratio (NLR). RESULTS: There was a statistically significant difference between the groups in terms of age, duration of the disease, drug received, Ig M, free T3, serum homocysteine levels, CRP, and NLR (p < 0.05). Pearson's correlation analysis showed a significant correlation between age, duration of MS, IgM, serum homocysteine levels, CRP, and NLR. According to the receiver operating characteristic curve analysis, IgM and NLR were discriminative factors in patients in Group 2. CONCLUSION: According to this study, inflammation may have a role in the pathogenesis of MS and in patients with EDSS > 5. Additionally, NLR and CRP levels may be discriminative factors of adverse clinical outcomes. PMID- 26589196 TI - Increased flow resistance and decreased flow rate in patients with acute respiratory distress syndrome: The role of autonomic nervous modulation. AB - BACKGROUND: The aim of this study was to investigate the flow resistance and flow rate in patients with acute respiratory distress syndrome (ARDS) in the surgical intensive care unit and their relation with autonomic nervous modulation. METHODS: Postoperative patients of lung or esophageal cancer surgery without ARDS were included as the control group (n = 11). Patients who developed ARDS after lung or esophageal cancer surgery were included as the ARDS group (n = 21). The ARDS patients were further divided into survivor and nonsurvivor subgroups according to their outcomes. All patients required intubation and mechanical ventilation. RESULTS: The flow rate was significantly decreased, while the flow resistance was significantly increased, in ARDS patients. The flow rate correlated significantly and negatively with positive end-expiratory pressure (PEEP), while the flow resistance correlated significantly and positively with PEEP in ARDS patients. Furthermore, the flow rate correlated significantly and negatively with the tidal volume-corrected normalized high-frequency power but correlated significantly and positively with the tidal volume-corrected low-/high frequency power ratio. In contrast, the flow resistance correlated significantly and negatively with normalized very low-frequency power and tidal volume corrected low-/high-frequency power ratio, but correlated significantly and positively with tidal volume-corrected normalized high-frequency power. CONCLUSION: The flow rate is decreased and the flow resistance increased in patients with ARDS. PEEP is one of the causes of increased flow resistance and decreased flow rate in patients with ARDS. Another cause of decreased flow rate and increased flow resistance in ARDS patients is the increased vagal activity and decreased sympathetic activity. The monitoring of flow rate and flow resistance during mechanical ventilation might be useful for the proper management of ARDS patients. PMID- 26589197 TI - Defined Medium Conditions for the Induction and Expansion of Human Pluripotent Stem Cell-Derived Retinal Pigment Epithelium. AB - We demonstrate that a combination of Noggin, Dickkopf-1, Insulin Growth Factor 1 and basic Fibroblast Growth Factor, promotes the differentiation of human pluripotent stem cells into retinal pigment epithelium (RPE) cells. We describe an efficient one-step approach that allows the generation of RPE cells from both human embryonic stem cells and human induced pluripotent stem cells within 40-60 days without the need for manual excision, floating aggregates or imbedded cysts. Compared to methods that rely on spontaneous differentiation, our protocol results in faster differentiation into RPE cells. This pro-retinal culture medium promotes the growth of functional RPE cells that exhibit key characteristics of the RPE including pigmentation, polygonal morphology, expression of mature RPE markers, electrophysiological membrane potential and the ability to phagocytose photoreceptor outer segments. This protocol can be adapted for feeder, feeder free and serum-free conditions. This method thereby provides a rapid and simplified production of RPE cells for downstream applications such as disease modelling and drug screening. PMID- 26589199 TI - Mother-induced hypertension in familial dysautonomia. AB - Here we report the case of a patient with familial dysautonomia (a genetic form of afferent baroreflex failure), who had severe hypertension (230/149 mmHg) induced by the stress of his mother taking his blood pressure. His hypertension subsided when he learnt to measure his blood pressure without his mother's involvement. The case highlights how the reaction to maternal stress becomes amplified when catecholamine release is no longer under baroreflex control. PMID- 26589198 TI - Erase and Rewind: Epigenetic Conversion of Cell Fate. AB - The potential of cell therapy in regenerative medicine has greatly expanded thanks to the availability of sources of pluripotent cells. In particular, induced pluripotent stem cells (iPS) have dominated the scenario in the last years for their ability to proliferate and differentiate into specific cell types. Nevertheless, the concerns inherent to the cell reprogramming process, limit iPS use in therapy and pose questions on the long-term behavior of these cells. In particular, despite the development of virus-free methods for their obtainment, a major and persisting drawback, is related to the acquisition of a stable pluripotent state, that is un-physiological and may lead to cell instability. The increased understanding of epigenetic mechanisms has paved the way to the use of "small molecules" and "epigenetic modifiers" that allow the fine tuning of cell genotype and phenotype. In particular, it was demonstrated that an adult mature cell could be directly converted into a different cell type with the use of these chemicals, obtaining a new patient-specific cell, suitable for cell therapy. This approach is simple and direct and may represent a very promising tool for the regenerative medicine of several and diverse degenerative diseases. PMID- 26589200 TI - Methodological quality assessment of paper-based systematic reviews published in oral health. AB - OBJECTIVES: This study aimed to conduct a methodological assessment of paper based systematic reviews (SR) published in oral health using a validated checklist. A secondary objective was to explore temporal trends on methodological quality. MATERIAL AND METHODS: Two electronic databases (OVID Medline and OVID EMBASE) were searched for paper-based SR of interventions published in oral health from inception to October 2014. Manual searches of the reference lists of paper-based SR were also conducted. Methodological quality of included paper based SR was assessed using an 11-item questionnaire, Assessment of Multiple Systematic Reviews (AMSTAR) checklist. Methodological quality was summarized using the median and inter-quartile range (IQR) of the AMSTAR score over different categories and time periods. RESULTS: A total of 643 paper-based SR were included. The overall median AMSTAR score was 4 (IQR 2-6). The highest median score (5) was found in the pain dentistry and periodontology fields, while the lowest median score (3) was found in implant dentistry, restorative dentistry, oral medicine, and prosthodontics. The number of paper-based SR per year and the median AMSTAR score increased over time (median score in 1990s was 2 (IQR 2-3), 2000s was 4 (IQR 2-5), and 2010 onwards was 5 (IQR 3-6)). CONCLUSION: Although the methodological quality of paper-based SR published in oral health has improved in the last few years, there is still scope for improving quality in most evaluated dental specialties. CLINICAL RELEVANCE: Large-scale assessment of methodological quality of dental SR highlights areas of methodological strengths and weaknesses that can be targeted in future publications to encourage better quality review methodology. PMID- 26589201 TI - [Multiparametric imaging with simultaneous MRI/PET: Methodological aspects and possible clinical applications]. AB - BACKGROUND: Combined MRI/PET enables the acquisition of a variety of imaging parameters during one examination, including anatomical and functional information such as perfusion, diffusion, and metabolism. OBJECTIVE: The present article summarizes these methods and their applications in multiparametric imaging via MRI/PET. RESULTS: Numerous studies have shown that the combination of these parameters can improve diagnostic accuracy for many applications, including the imaging of oncological, neurological, and inflammatory conditions. Because of the amount and the complexity of the acquired multiparametric data, there is a need for advanced analysis tools, such as methods of parameter selection and data classification. DISCUSSION: Currently, the clinical application of this process still has limitations. On the one hand, software for the fast calculation and standardized evaluation of the imaging data acquired is still lacking. On the other hand, there are deficiencies when comparing the results because of a lack of standardization of the assessment and diagnostic procedure. PMID- 26589202 TI - [Originators and eponyms of dermatomyositis : Ernst Leberecht Wagner (1821-1888) and Heinrich Unverricht (1853-1912)]. AB - Dermatomyositis is a rare muscle disease that was first described by Ernst Leberecht Wagner and Heinrich Unverricht.After providing a survey on both scientists' life works, this contribution describes the most significant subsequent works on the diagnostics and classification of clinical symptoms and the progress of the disease that the author has been observing for more than three decades.Polymyositis/dermatomyositis (also known as Unverricht-Wagner or Wagner-Unverricht syndrome) was described in two publications by Ernst Leberecht Wagner in 1863 and 1887. Wagner was - probably uniquely in Germany - consecutively professor of pathology and also, as a successor to K. A. Wunderlich, of internal medicine at the University of Leipzig. The most frequently used designation for polymyositis/dermatomyositis today was originated by Heinrich Unverricht in 1891. After his education in his home town of Breslau, Unverricht was first employed as head of the clinic for internal medicine in Jena. From 1886 he was a professor in Dorpat, but he left this university when the language of teaching was changed to Russian in 1892. Unverricht then became the first director of the newly founded Sudenburg Hospital in Magdeburg (Medical Academy from 1954 to 1991).During the subsequent decades, further medical scientists have studied the disease and brought about today's precise classification criteria for diagnostics - based on Wagner's and Unverricht's findings. PMID- 26589203 TI - [Primary central nervous system vasculitis]. AB - Primary angiitis of the central nervous system (PACNS) is a rare disorder. However, it is often considered in the differential diagnosis of vascular or inflammatory CNS diseases. Diagnosis is challenging, as specific biomarkers are lacking and the clinical presentation can be variable. A definitive diagnosis can only be established by biopsy of the inflammatory changes in the vascular wall. Alternatively, the diagnosis of PACNS can also be based on the synopsis of clinical, radiological, and laboratory findings. Different subtypes of PACNS have been described in recent years, depending on the size of the affected vessels or histopathological patterns. Based on selective literature research in the database PubMed on the subject of CNS vasculitis, this article reviews the diagnostic characteristics and differential diagnosis of the condition. We suggest a diagnostic algorithm customized to the size of the affected vessels. Lastly, therapeutic options and the outcome of PACNS are briefly outlined. PMID- 26589204 TI - Effect of teaching and checklist implementation on accuracy of medication history recording at hospital admission. AB - BACKGROUND: Medication discrepancies at hospital admission is an extensive problem and knowledge is limited regarding improvement strategies. OBJECTIVE: To investigate the effect of teaching and checklist implementation on accuracy of medication history recording during hospitalization. METHOD: Patients admitted to an internal medicine ward were prospectively included in two consecutive periods. Between the periods, non-mandatory teaching lessons were provided and a checklist assisting medication history recording implemented. Discrepancies between the recorded medications at admission and the patient's actual drug use, as revealed by pharmacist-conducted medication reconciliation, were compared between the periods. The primary endpoint was difference between the periods in proportion of patients with minimum one discrepancy. Difference in median number of discrepancies was included as a secondary endpoint. RESULTS: 56 and 119 patients were included in period 1 (P1) and period 2 (P2), respectively. There was no significant difference in proportion of patients with minimum one discrepancy in P2 (68.9 %) versus P1 (76.8 %, p = 0.36), but a tendency of lower median number of discrepancies was observed in P2 than P1, i.e. 1 and 2, respectively (p = 0.087). CONCLUSION: More powerful strategies than non-mandatory teaching activities and checklist implementation are required to achieve sufficient improvements in medication history recording during hospitalization. PMID- 26589206 TI - German Curriculum in Interventional Neuroradiology--How Many Interventionalists are Necessary? Did We Need Support from Other Societies for Stroke Treatment? PMID- 26589205 TI - Evaluation of Cardiovascular Changes in Children with BAVs. AB - The objectives of this study were to investigate left ventricular (LV) function, aortic dilation, and atherosclerosis in children with mildly deteriorated isolated bicuspid aortic valve (BAV) function using echocardiographic studies and biochemical markers of atherosclerosis and to correlate results with normal children. Biochemical analyses indicating cardiovascular risk of atherosclerosis and vascular changes in the aorta in relation to BAV were performed in 41 children aged 5-15 years old with isolated BAV and in 25 children with tricuspid aortic valves. Evaluations of aortic valve structures and functions; examinations of the LV M-mode and ascending aorta Doppler; and measurements of the LV Tei index (MPI), propagation velocity, ascending aorta at four levels, and carotid intima-media thickness (CIMT) were performed. There were no statistically significant differences in CIMTs, plasma matrix metalloproteinase-9, tissue metalloproteinase inhibitor-1 levels, or other biochemical parameters indicating cardiovascular risk or atherosclerosis between study and control groups. Deterioration of LV function, which could not be seen with M-mode echocardiography, was evident by MPI. MPI values in the study versus control groups were 0.46 +/- 0.080 versus 0.40 +/- 0.086 (p < 0.05). Diameters of the aorta in the study and control groups were 19.7 +/- 4.7 and 17.2 +/- 2.8 mm (p < 0.05) at the sinotubular junction level and 20.6 (14.4-40.5) and 18.3 (12.4-24) mm at the ascending aorta level (p < 0.05). Increased aortic valve insufficiency was related to increased aortic diameter. No sign of atherosclerosis was detected in children with BAV. Deterioration of LV function was seen using MPI, and aortic dilation was related to the severity of aortic valve insufficiency. PMID- 26589207 TI - Physics, Techniques and Review of Neuroradiological Applications of Diffusion Kurtosis Imaging (DKI). AB - In recent years many papers about diagnostic applications of diffusion tensor imaging (DTI) have been published. This is because DTI allows to evaluate in vivo and in a non-invasive way the process of diffusion of water molecules in biological tissues. However, the simplified description of the diffusion process assumed in DTI does not permit to completely map the complex underlying cellular components and structures, which hinder and restrict the diffusion of water molecules. These limitations can be partially overcome by means of diffusion kurtosis imaging (DKI). The aim of this paper is the description of the theory of DKI, a new topic of growing interest in radiology. DKI is a higher order diffusion model that is a straightforward extension of the DTI model. Here, we analyze the physics underlying this method, we report our MRI acquisition protocol with the preprocessing pipeline used and the DKI parametric maps obtained on a 1.5 T scanner, and we review the most relevant clinical applications of this technique in various neurological diseases. PMID- 26589208 TI - [Not Available]. AB - There is an ongoing discussion about reimbursement of stent-angioplasty for the treatment of intracranial stenoses in Germany. The discussion was initiated by the statutory health insurance companies after publication of the SAMMPRIS study results, which were in favor for medical management compared to stent-angioplasty with the Wingspan(r) stent system. A report (Rapid report N14-01) mainly based on SAMMPRIS was written by the German Institute for Quality and Efficiency in Health Care (IQWiG) and serves as a basis for the decision-making process. This report was previously commented by the medical societies involved. Limitations of the SAMMPRIS trial and vital indications for intracranial stenting were outlined in this comment (acute vessel occlusion, hemodynamic impairment, recurrent symptoms under medical treatment). Currently also emergency stent procedures are a matter of debate. In this context a second IQWiG report was commissioned (GA 15 - 02) addressing the results of the VISSIT trial, the transferability of the results of the first report to emergency treatments and the practice of emergency intracranial stent treatment in Germany. Regarding transferability of results the main conclusion was that there was no evidence that the results of the studies analyzed for the first report (mainly SAMMPRIS) could not be transferred to emergency treatments. From a medical professional and scientific standpoint it is inacceptable to compare outcomes of a secondary prophylactic treatment with emergency procedures. The analysis of emergency treatments in Germany based on retrospective case series with a cumulative number of 31 patients. Since most emergency procedures are performed in a clinical context and are not necessarily subject to scientific evaluation, this does not reflect current practice in Germany. The first part of this statement briefly outlines the design of SAMMPRIS and VISSIT and the interpretation of the trial results from a professional perspective. The current state of discussion regarding reimbursement of intracranial stenting is summarized. The second section contains a detailed comment on the current IQWiG report GA15-02 "Stents for the treatment of intracranial artery stenosis: VISSIT study and acute treatment in Germany". PMID- 26589210 TI - Energy dependence measurement of small-type optically stimulated luminescence (OSL) dosimeter by means of characteristic X-rays induced with general diagnostic X-ray equipment. AB - For X-ray inspections by way of general X-ray equipment, it is important to measure an entrance-skin dose. Recently, a small optically stimulated luminescence (OSL) dosimeter was made commercially available by Landauer, Inc. The dosimeter does not interfere with the medical images; therefore, it is expected to be a convenient detector for measuring personal exposure doses. In an actual clinical situation, it is assumed that X-rays of different energies will be detected by a dosimeter. For evaluation of the exposure dose measured by a dosimeter, it is necessary to know the energy dependence of the dosimeter. Our aim in this study was to measure the energy dependence of the OSL dosimeter experimentally in the diagnostic X-ray region. Metal samples weighing several grams were irradiated and, in this way, characteristic X-rays having energies ranging from 8 to 85 keV were generated. Using these mono-energetic X-rays, the dosimeter was irradiated. Simultaneously, the fluence of the X-rays was determined with a CdTe detector. The energy-dependent efficiency of the dosimeter was derived from the measured value of the dosimeter and the fluence. Moreover, the energy-dependent efficiency was calculated by Monte-Carlo simulation. The efficiency obtained in the experiment was in good agreement with that of the simulation. In conclusion, our proposed method, in which characteristic X-rays are used, is valuable for measurement of the energy dependence of a small OSL dosimeter in the diagnostic X-ray region. PMID- 26589211 TI - Phylogenetic analysis of PR genes in some pome fruit species with the emphasis on transcriptional analysis and ROS response under Erwinia amylovora inoculation in apple. AB - Attempts were made to identify eight pathogenesis related (PR) genes (i.e., PR 1a, PR3-ch1, PR3-Ch2, PR3-Ch3, PR3-Ch4, PR3-Ch5, PR-5 and PR-8) from 27 genotypes of apple, quince and pear, which are induced in response to inoculation with the pathogen Erwinia amylovora, the causal agent of fire blight. Totally, 32 PR genes of different families were obtained, excepting PR3-Ch2 (amplified only in apple) and PR3-Ch4 (amplified only in apple and pear), the others were successfully amplified in all the genotypes of apple, quince and pear. Evolutionary, the genes of each family exhibited significant homology with each other, as the corresponded phylogenetic neighbor-joining-based dendrograms were taken into consideration. Meanwhile, according to the expression assay, it was deduced that the pathogen activity can significantly affect the expression levels of some selected PR genes of PR3-Ch2, PR3-Ch4, PR3-Ch5 and particularly Cat I in both resistant (MM-111) and semi-susceptible (MM-106) apple rootstocks. Lastly, it was concluded that the pathogen E. amylovora is able to stimulate ROS response, particularly using generation of hydrogen peroxide (H2O2) in both aforementioned apple rootstock. PMID- 26589213 TI - New Trends and Perspectives in the Evolution of Neurotransmitters in Microbial, Plant, and Animal Cells. AB - The evolutionary perspective on the universal roles of compounds known as neurotransmitters may help in the analysis of relations between all organisms in biocenosis-from microorganisms to plant and animals. This phenomenon, significant for chemosignaling and cellular endocrinology, has been important in human health and the ability to cause disease or immunity, because the "living environment" influences every organism in a biocenosis relationship (microorganism microorganism, microorganism-plant, microorganism-animal, plant-animal, plant plant and animal-animal). Non-nervous functions of neurotransmitters (rather "biomediators" on a cellular level) are considered in this review and ample consideration is given to similarities and differences that unite, as well as distinguish, taxonomical kingdoms. PMID- 26589212 TI - Microbial Endocrinology: An Ongoing Personal Journey. AB - The development of microbial endocrinology is covered from a decidedly personal perspective. Specific focus is given to the role of microbial endocrinology in the evolutionary symbiosis between man and microbe as it relates to both health and disease. Since the first edition of this book series 5 years ago, the role of microbial endocrinology in the microbiota-gut-brain axis is additionally discussed. Future avenues of research are suggested. PMID- 26589214 TI - Catecholamine-Directed Epithelial Cell Interactions with Bacteria in the Intestinal Mucosa. AB - The catecholamines epinephrine, norepinephrine and dopamine are present in or have access to mucous membranes in the digestive, respiratory and genitourinary tracts, which represent the first sites of microbial colonization and infection within the body. Epithelial cells at mucosal surfaces establish and maintain symbiotic microbial communities and serve as the initial cellular point of contact for pathogens with the animal host. These cells express receptors that are capable of detecting and responding to microbe-associated molecular patterns and in most host species express G protein-coupled receptors for catecholamines. Although it is increasingly recognized that substances produced and released from nerves and endocrine cells can exert immuno-modulatory actions at mucosal sites, there have been few investigations focused specifically on the catecholaminergic modulation of interactions between the mucosal epithelium and bacteria or other mucosa-associated microorganisms. The potential biomedical importance of this phenomenon cannot be understated. For example, psychological stress or other conditions that activate the sympathetic nervous system to release epinephrine and norepinephrine may act to produce short-term changes in luminal and mucosal microbial communities or alter the course of a bacterial infection. This chapter will briefly review this developing and important research area of mucosa-microbe interactions with a focus on intestinal host defense. PMID- 26589215 TI - Dietary Catechols and their Relationship to Microbial Endocrinology. AB - This chapter examines the evidence that the ability of neuroendocrine hormones, notably norepinephrine and epinephrine, to stimulate bacterial growth in iron restricted media is not limited to molecules with a catecholamine structure but is also possessed by a variety of other catechols, many of which are of plant origin and are common in the diet. Catechols derived from the diet, such as the tea flavanols, can be present in the plasma at submicromolar and micromolar concentrations, comparable with the concentrations of catecholamines that have been shown to be effective in promoting bacterial growth under conditions of iron restriction, although many dietary catechols, notably quercetin derivatives, are present in the plasma and tissues largely as conjugates, from which the catechol function has been lost. Finally, although bacterial growth promotion through relief of iron restriction appears to be exhibited by a wide range of catechols, the gene-activation effects of catecholamines demonstrated to occur in some bacteria may be much more specific, although the definitive experiments to establish structure-function relationships have yet to be reported. PMID- 26589216 TI - Interactions Between Bacteria and the Gut Mucosa: Do Enteric Neurotransmitters Acting on the Mucosal Epithelium Influence Intestinal Colonization or Infection? AB - The intestinal epithelium is a critical barrier between the internal and external milieux of the mammalian host. Epithelial interactions between these two host environments have been shown to be modulated by several different, cross communicating cell types residing in the gut mucosa. These include enteric neurons, whose activity is influenced by bacterial pathogens, and their secreted products. Neurotransmitters appear to influence epithelial associations with bacteria in the intestinal lumen. For example, internalization of Salmonella enterica and Escherichia coli O157:H7 into the Peyer's patch mucosa of the small intestine is altered after the inhibition of neural activity with saxitoxin, a neuronal sodium channel blocker. Catecholamine neurotransmitters, such as dopamine and norepinephrine, also alter bacterial internalization in Peyer's patches. In the large intestine, norepinephrine increases the mucosal adherence of E. coli. These neurotransmitter actions are mediated by well-defined catecholamine receptors situated on the basolateral membranes of epithelial cells rather than through direct interactions with luminal bacteria. Investigations of the involvement of neuroepithelial communication in the regulation of interactions between the intestinal mucosa and luminal bacteria will provide novel insights into the mechanisms underlying bacterial colonization and pathogenesis at mucosal surfaces. PMID- 26589217 TI - Modulation of the Interaction of Enteric Bacteria with Intestinal Mucosa by Stress-Related Catecholamines. AB - Stress associated with parturition, transport or mixing has long been correlated with enhanced faecal excretion of diarrhoeal zoonotic pathogens in animals such as Salmonella enterica and Escherichia coli. It may also predispose humans to infection and/or be associated with more severe outcomes. One possible explanation for this phenomenon is the ability of enteric bacterial pathogens to sense and respond to host stress-related catecholamines. This article reviews evidence of the ability of catecholamine hormones to modulate interactions between Gram-negative diarrhoeal pathogens and intestinal mucosa, as well as the molecular mechanisms that may be at work. PMID- 26589218 TI - Molecular Profiling: Catecholamine Modulation of Gene Expression in Escherichia coli O157:H7 and Salmonella enterica Serovar Typhimurium. AB - Investigations of Escherichia coli O157:H7 and Salmonella enterica serovar Typhimurium have demonstrated that these bacterial pathogens can respond to the presence of catecholamines including norepinephrine and/or epinephrine in their environment by modulating gene expression and exhibiting various phenotypes. For example, one of the most intensively investigated phenotypes following exposure of E. coli and S. Typhimurium to norepinephrine is enhanced bacterial growth in a serum-based medium. Host-pathogen investigations have demonstrated that the mammalian host utilizes nutritional immunity to sequester iron and prevent extraintestinal growth by bacterial pathogens. However, Salmonella and certain E. coli strains have a genetic arsenal designed for subversion and subterfuge of the host. Norepinephrine enhances bacterial growth due, in part, to increased iron availability, and transcriptional profiling indicates differential expression of genes encoding iron acquisition and transport proteins. Bacterial motility of E. coli and S. Typhimurium is also enhanced in the presence of catecholamines and increased flagellar gene expression has been described. Furthermore, epinephrine and norepinephrine are chemoattractants for E. coli O157:H7. In S. Typhimurium, norepinephrine enhances horizontal gene transfer and increases expression of genes involved in plasmid transfer. Exposure of E. coli O157:H7 to norepinephrine increases expression of the genes encoding Shiga toxin and operons within the locus of enterocyte effacement (LEE). Alterations in the transcriptional response of enteric bacteria to catecholamine exposure in vivo are predicted to enhance bacterial colonization and pathogen virulence. This chapter will review the current literature on the transcriptional response of E. coli and S. Typhimurium to catecholamines. PMID- 26589219 TI - Staphylococci, Catecholamine Inotropes and Hospital-Acquired Infections. AB - Patients in hospital intensive care units have long been recognized as being at high risk for developing infections from bacteria, fungi, and viruses from within the hospital locality. Risk factors for development of nosocomial infections have usually focussed on the patient's physical condition and the number and type of invasive medical procedures administered. Using the staphylococci as its focus, this chapter presents recent evidence that some of the medications routinely used in the treatment of acutely ill patients may also be a risk factor for the development of nosocomial infections. PMID- 26589220 TI - Interkingdom Chemical Signaling in Enterohemorrhagic Escherichia coli O157:H7. AB - Escherichia coli is one of the most-studied species of bacteria due to its frequent incidence in diverse environments and hosts, as well as its use as a tool in molecular biology. Most E. coli strains are commensal, in that they colonize the host without causing disease; however, some strains of E. coli are pathogens and are able to cause diverse illnesses, including urinary tract infections, sepsis/meningitis, as well as intestinal disease that result in diarrhea (Kaper et al. 2004). Six categories of diarrheagenic E. coli are recognized, and these are classified in part based on how they interact with epithelial cells (Kaper et al. 2004). Of these, enterohemorrhagic E. coli O157:H7 (EHEC) is one of the most important pathogenic E. coli strains. EHEC causes major outbreaks of bloody diarrhea that can result in the development of fatal hemorrhagic colitis and hemolytic uremic syndrome (Karmali et al. 1983). EHEC colonizes the colon, where it forms attaching and effacing (AE) lesions on the intestinal epithelial cell. AE lesions are characterized by intimate attachment of EHEC to epithelial cells, effacement of the microvilli and rearrangement of the underlying cytoskeleton, which results in formation of a pedestal-like structure beneath the bacterium (Jerse et al. 1990; Jarvis et al. 1995; Kenny et al. 1997). Most of the genes involved in the formation of AE lesions are encoded within a chromosomal pathogenicity island termed the locus of enterocyte effacement (LEE) (McDaniel et al. 1995). The LEE contains 41 genes that are organized in five major operons (LEE1, LEE2, LEE3, LEE5, and LEE4) (Elliott et al. 1998, 1999; Mellies et al. 1999). The LEE encodes a type three secretion system (T3SS) (Jarvis et al. 1995), an adhesin (intimin) (Jerse et al. 1990) and its receptor (Tir) (Kenny et al. 1997), as well as effector proteins (Kenny et al. 1996; Abe et al. 1997; McNamara and Donnenberg 1998; Elliott et al. 2001; Tu et al. 2003; Kanack et al. 2005). EHEC also encodes an arsenal of effector proteins located outside of the LEE that are important in EHEC virulence (Campellone et al. 2004; Deng et al. 2004; Garmendia et al. 2004, 2005; Gruenheid et al. 2004; Tobe et al. 2006). PMID- 26589221 TI - Mechanisms of Stress-Mediated Modulation of Upper and Lower Respiratory Tract Infections. AB - Stress is an external factor known to be a potent exacerbator of respiratory infections. Most explanations of how stress affects susceptibility to airway infections focus on the immune system. However, evidence is increasing that respiratory pathogens are equally responsive to the hormonal output of stress. This chapter considers the bacterial and mucosal determinants of respiratory tract infections and their interrelationship during stressful conditions. PMID- 26589222 TI - Psychological Stress, Immunity, and the Effects on Indigenous Microflora. AB - Psychological stress is an intrinsic part of life that affects all organs of the body through direct nervous system innervation and the release of neuroendocrine hormones. The field of PsychoNeuroImmunology (PNI) has clearly demonstrated that the physiological response to psychological stressors can dramatically impact the functioning of the immune system, thus identifying one way in which susceptibility to or severity of diseases are exacerbated during stressful periods. This chapter describes research at the interface between the fields of PNI and Microbial Endocrinology to demonstrate that natural barrier defenses, such as those provided by the commensal microflora, can be disrupted by exposure to psychological stressors. These stress effects are evident in the development of the intestinal microflora in animals born from stressful pregnancy conditions, and in older animals with fully developed microbial populations. Moreover, data are presented demonstrating that exposure to different types of stressors results in the translocation of microflora from cutaneous and mucosal surfaces into regional lymph nodes. When considered together, a scenario emerges in which psychological stressors induce a neuroendocrine response that has the potential to directly or indirectly affect commensal microflora populations, the integrity of barrier defenses, and the internalization of microbes. Finally, a hypothesis is put forth in which stressor-induced alterations of the microflora contribute to the observed stressor-induced increases in inflammatory markers in the absence of overt infection. PMID- 26589223 TI - The Epinephrine/Norepinephrine/Autoinducer-3 Interkingdom Signaling System in Escherichia coli O157:H7. AB - Epinephrine/norepinephrine/AI-3 signaling is used as an interkingdom chemical signaling system between microbes and their hosts. This system is also exploited by pathogens to regulate virulence traits. In enterohemorrhagic E. coli (EHEC) O157:H7, it is essential for pathogenesis and flagella motility. These three signals activate expression of a pathogenicity island named locus of enterocyte effacement (LEE), Shiga toxin, and the flagella regulon. These signals are sensed by the two-component system QseBC, whereas the bacterial membrane receptor QseC autophosphorylates and phosphorylates the QseB response regulator initiating a complex phosphorelay signaling cascade that activates the expression of a second two-component system, QseEF. The QseEF two-component system is also involved in the expression of the virulence genes, and it senses epinephrine, phosphate, and sulfate. This complex signaling cascade still needs to be completely elucidated. PMID- 26589224 TI - The Role of the Microbiome in the Relationship of Asthma and Affective Disorders. AB - The effect of stress, anxiety and other affective states on inflammatory conditions such as asthma is well documented. Although several immune pathway mechanisms have been proposed and studied, they cannot fully explain the relationship. In this chapter we present a new perspective on asthma development and exacerbation that integrates findings on the role of psychological factors in asthma with the microbiome and the hygiene hypothesis in asthma development. PMID- 26589225 TI - Effects of Stress on Commensal Microbes and Immune System Activity. AB - The body harbors a vast array of microbes that are collectively known as the microbiota. Increasing attention is being paid to the role of the gut microbiota in the health of the host. Gut microbial communities are relatively resistant to change, though alterations in homeostasis can also significantly change gut microbial community structure. An important factor that has been demonstrated to alter the composition of the gut microbiota is exposure to psychological stressors. And, evidence indicates that the commensal microbiota are involved in stressor-induced immunomodulation. This chapter will discuss the impact of psychosocial stress on immunity, and present evidence that stressor-induced alterations in the composition of gut microbial communities contributes to stressor-induced immunomodulation and neurobiological sequelae. Finally, the role of the microbiota in the perinatal time period will be explored, and an integrative hypothesis of the role of the microbiome in health and stress response will be proposed. PMID- 26589226 TI - Microbiome to Brain: Unravelling the Multidirectional Axes of Communication. AB - The gut microbiome plays a crucial role in host physiology. Disruption of its community structure and function can have wide-ranging effects making it critical to understand exactly how the interactive dialogue between the host and its microbiota is regulated to maintain homeostasis. An array of multidirectional signalling molecules is clearly involved in the host-microbiome communication. This interactive signalling not only impacts the gastrointestinal tract, where the majority of microbiota resides, but also extends to affect other host systems including the brain and liver as well as the microbiome itself. Understanding the mechanistic principles of this inter-kingdom signalling is fundamental to unravelling how our supraorganism function to maintain wellbeing, subsequently opening up new avenues for microbiome manipulation to favour desirable mental health outcome. PMID- 26589227 TI - Mycologic Endocrinology. AB - The interactions of fungi and chemical messenger molecules, hormones or pheromones, are addressed in this chapter. These interactions include mammalian fungal pathogens, also plant pathogens, or non-pathogenic fungi, which can result in functional responses in receptor- or non-receptor-mediated fashions. Endogenous ligands in the fungi have been demonstrated to be important for mating in a number of systems. Mammalian hormones have been demonstrated to have stimulatory or inhibitory effects on growth for organisms such as Candida albicans, Paracoccidioides brasiliensis, Saccharomyces cerevisiae, Rhizopus nigricans, Aspergillus fumigatus, Coccidioides, and dermatophytic fungi. A number of fungi have been shown to have specific binding proteins for corticosteroid, estrogen and progesterone that are stereo-specific and high affinity. In some instances, the interactions of a mammalian hormone with the organism, in vivo, affects pathogenesis. Genome expression profiles of C. albicans in the presence of estradiol or progesterone, and S. cerevisiae with progesterone, indicate major up-regulation of various drug resistance pumps, like CDR1, and CDR2, can affect antifungal susceptibility. Azole antifungal interactions occur with fungal hormone binding proteins. Azoles also can block mammalian steroidogenesis. The finding of interactions of mammalian hormones with fungi and subsequent functional responses by the fungi, suggest that hormonal interactions with fungal systems has been conserved throughout evolution and have an important role in fungal pathogenesis, as well as in the overall biology of the organisms. PMID- 26589228 TI - PicoMolar level detection of protein biomarkers based on electronic sizing of bead aggregates: theoretical and experimental considerations. AB - We demonstrate a novel method for electronically detecting and quantifying protein biomarkers using microfluidic impedance cytometry. Our biosensor, which consists of gold electrodes micro-fabricated in a microchannel, detects the differences between bead aggregates of varying sizes in a micro-pore sandwiched between two micro channels. We perform a sandwich immunoassay, where the complementary antibody pairs are immobilized on two different bead types, and the presence of antigen results in bead aggregation, the amount of which depends on antigen quantity. When single beads or bead aggregates pass through the impedance sensor, differences in impedance change are detected. In this manuscript, we perform a comprehensive theoretical study on the limits imposed on sensitivity of this technique due to electronic noise and also mass transfer and reaction limits. We also experimentally characterize the performance of this technique by validating the technique on an IgG detection assay. A detection limit at the picoMolar level is demonstrated, thus comparable in sensitivity to a sandwich ELISA. PMID- 26589230 TI - Role of non-hepatotropic viruses in acute sporadic viral hepatitis and acute-on chronic liver failure in adults. AB - BACKGROUND: Acute viral hepatitis (AVH) is mostly caused by hepatitis E (HEV) and hepatitis A (HAV) viruses in India. This study was undertaken to find out the incidence of various hepatotropic and non-hepatotropic viruses in AVH and acute on-chronic liver failure (ACLF) patients. METHODS: Six-hundred and seventy-three adult patients of AVH and ACLF were screened for acute serological markers of hepatotropic (A, B, C, D, and E) and the non-hepatotropic cytomegalovirus (CMV) and Epstein-Barr virus (EBV). RESULTS: Viral etiology profile in 295 samples with confirmed etiology were HEV in 155 (52.5 %); HAV in 43 (14.5 %); HBV in 35 (11.8 %); HCV in 1 (0.3 %); mixed viral etiology in 30 (10.1 %); and non-hepatotropic viruses, cytomegalovirus, and Epstein-Barr virus in 31 (10.5 %). Two-hundred and six patients (69.8 %) were AVH and 89 (30.1 %) ACLF. HEV was the commonest cause of infection in both the groups AVH (n = 95, 46.1 %) and ACLF (n = 60, 67.4 %). Twenty-nine (9.8 %) patients died on follow up; mortality was higher in ACLF (25/89, 28 %) than AVH group (4/206, 1.94 %; p < 0.001). The mortality was higher when HEV was the cause of acute event (20/29, 68.9 %). In AVH, mixed infection was more common as compared to ACLF (27 vs. 3, p < 0.001). Non-hepatotropic viruses contributed significantly higher infections in AVH as compared to ACLF (29 vs. 2, p = 0.002) patients. CONCLUSIONS: HEV was an important cause of symptomatic hepatitis in both AVH and ACLF patients. Non-hepatotropic viruses like CMV and EBV were identified in a significant number of patients with AVH and much less frequently in ACLF. PMID- 26589229 TI - Fecal calprotectin and its correlation with inflammatory markers and endoscopy in patients from India with inflammatory bowel disease. AB - INTRODUCTION: In clinical practice, endoscopic findings are often used for assessing disease activity in inflammatory bowel disease (IBD). In recent years, blood and stool markers are being increasingly used for this purpose. Among them, the fecal calprotectin (FC) level is probably the most favored. Data on the reliability of FC are lacking from countries like India, where gut infections are common. OBJECTIVE: The aims of this study were to compare the FC level with the erythrocyte sedimentation rate (ESR) and the C-reactive protein (CRP) as non invasive markers of IBD and, in patients with ulcerative colitis (UC), and to study its correlation with disease extent, clinical activity, and endoscopic severity. METHODS: Records of patients with IBD who had tests for FC, ESR and CRP and colonoscopy done within a 2-week period, between 2012 and 2014, were retrieved. Sixty-three patients (UC 32, Crohn's disease [CD] 31) were included for analysis. ESR, CRP and FC were compared to endoscopy to assess inflammation. RESULTS: Patients with UC had higher levels of FC than those with ileocolonic CD (median FC 800 mcg/g vs. 619 mcg/g, respectively; p = 0.04). FC levels correlated with CRP (r = 0.4, p < 0.001) but not with ESR (r = 0.21, p = 0.09). In patients with UC with endoscopic evidence of inflammation, more (86.9 %) had FC > 200 mcg/g (cut-off for disease activity in our laboratory) than had ESR >20 mm in the first hour (60.6 %) or positive CRP (65.6 %) (< 0.01); FC levels increased with increasing endoscopic Mayo score (p = 0.001) and Truelove-Witt's clinical severity score (p = 0.006), but did not correlate with disease extent (p = 0.7). The best FC cut-off level to identify 'active UC' (Mayo grade 2 or more) was 800 mcg/g. CONCLUSION: Fecal calprotectin level correlates with CRP but not with ESR. In patients with UC with inflammation, FC > 200 mcg/g is more often positive than raised ESR or CRP; it also correlates with clinical and endoscopic activity but not with disease extent. FC level > 800 mcg/g can be used to differentiate active from inactive UC. PMID- 26589232 TI - Recurrence of macular edema in eyes with branch retinal vein occlusion changes the diameter of unaffected retinal vessels. PMID- 26589231 TI - Small-incision lenticule extraction (SMILE): outcomes of 722 eyes treated for myopia and myopic astigmatism. AB - PURPOSE: To study the outcomes of small-incision lenticule extraction (SMILE) for treatment of myopia and myopic astigmatism. METHODS: Retrospective study of patients treated for myopia or myopic astigmatism with SMILE, using a VisuMax((r)) femtosecond laser (Carl Zeiss Meditec, Jena, Germany), at the Department of Ophthalmology, Odense University Hospital, Odense, Denmark. Inclusion criteria were corrected distance visual acuity (CDVA) of 20/25 or better before surgery and no ocular conditions other than myopia up to -10.00 diopters (D) with astigmatism up to 3.00 D. RESULTS: Of the 729 treatments, 722 were included. The spherical equivalent (SE) refraction averaged -6.82 +/- 1.66 diopters (D) before surgery. After 3 months, 88 % of eyes were within +/-0.50 D of the intended refraction, whilst 98 % were within +/-1.00 D. The mean difference between attempted and achieved SE refraction at 3 months after surgery was -0.06 +/- 0.01 D (range: -1.25 to 1.25 D). In eyes with emmetropia as target refraction (n = 362), 63 % had uncorrected distance visual acuity (UDVA) of 20/25 or better 1 day after surgery, rising to 83 % at 3 months after surgery. The average gain in CDVA from before surgery to 3 months after surgery was 0.07 +/- 0.03 (logMAR). However, 12 eyes (1.6 %) lost 2 or more lines of CDVA from before surgery to 3 months postoperatively. Simultaneous treatment of up to 3.00 D of astigmatism was not associated with less predictable refractive outcomes. CONCLUSIONS: In the short term, SMILE seemed predictable, efficient, and safe for treatment of myopia and myopic astigmatism. PMID- 26589233 TI - Occult hypertensive choroidopathy: novel finding of suprachoroidal fluid. PMID- 26589234 TI - Evidence for Epigenetic Regulation of Pro-Inflammatory Cytokines, Interleukin-12 and Interferon Gamma, in Peripheral Blood Mononuclear Cells from PTSD Patients. AB - While Post Traumatic Stress Disorder (PTSD) is associated with immune dysfunction, the underlying mechanisms remain unclear. Studies suggest a role for involvement of epigenetic mechanisms and microRNAs (miRNAs). Here, we examined genome-wide histone and DNA methylation in the peripheral blood mononuclear cells (PBMCs) in PTSD. We noted significant differences in histone H3 trimethylation at K4, K9, K27 and K36 sites in PTSD when compared to control. While overall DNA methylation level did not differ significantly between control and PTSD, the promoters of several individual genes (e.g., Interferon gamma (IFNG) and Interleukin (IL)-12B) were differentially methylated. ChIP-seq data revealed that the promoter of IFNG and TBX-21 was associated with the activation marker H3K4me3 in PTSD. The transcript levels of both IFNG and TBX-21 were higher in PTSD correlating well with the altered methylation patterns. Furthermore, PTSD patients showed increased expression of IL-12 in their PBMCs. Analysis of both histone and DNA methylation markers suggested that the expression of IL-12 was also possibly activated through epigenetic modification. Knockdown of lysine (K) specific demethylase 5B (KDM5B), or inhibition of DNA (Cytosine-5-) methyltransferase 1 (DNMT1) caused up-regulation of IL-12. Furthermore, the expression of these cytokines was also regulated by miRNAs. Our miRNA microarray identified many downregulated miRNAs in PTSD that are predicted to target IFNG and IL-12. Consequently, we showed that up-regulation of hsa-miR-193a-5p could decrease the expression of IL-12. Overall, the current study demonstrated that the elevated expression of pro-inflammatory cytokines in PTSD patients might be regulated by multiple epigenetic mechanisms and miRNAs. PMID- 26589236 TI - Stand up: comparison of two electrical screed levelling machines to reduce the work demands for the knees and low back among floor layers. AB - Electrical screed levelling machines are developed to reduce kneeling and trunk flexion of sand-cement-bound screed floor layers. An observational intervention study among 10 floor layers was performed to assess the differences between a self-propelled and a manually moved machine. The outcome measures were work demands, production time, perceived load, discomfort and applicability. Compared to the self-propelled machine, the duration of kneeling (?13 min; p = 0.003) and trunk flexion (?12 min; p < 0.001) was shorter using the manually moved machine, and the duration of pushing and pulling increased (?39 min; p < 0.001). No significant or relevant differences were found for production time, perceived load and discomfort. Nine out of ten floor layers found the manually moved machine applicable and three out of ten found the self-propelled machine applicable. When compared with the traditional manner of floor laying, both electrical machines reduced the exposure towards kneeling and trunk flexion. Practitioner Summary: Electrical machines may help to reduce high physical work demands on floor layers. A manually moved machine is better applicable for the installation of screed floors in residences with smaller floor areas. A self propelled machine is better applicable on large floor areas with a minimum width of 4 m. PMID- 26589235 TI - Safety and Clinical Outcomes of Rituximab Treatment in Patients with Multiple Sclerosis and Neuromyelitis Optica: Experience from a National Online Registry (GRAID). AB - INTRODUCTION: Multiple sclerosis (MS) is an immune-mediated disease. Over the last decades therapeutic options have broadened tremendously. Nevertheless, various therapeutic agents, e.g., rituximab, are currently used in the treatment of MS off label. Disease or health registries are useful methods to collect information about off-label treatments. The German registry for autoimmune disease (GRAID) is a multicenter, retrospective, non-interventional database of patients with various autoimmune diseases. AIM/METHODS: The aim of this observational analysis is to present safety data of rituximab in the treatment of MS and neuromyelitis optica (NMO) in a real life clinical setting based on the available registry data. RESULTS: Data were collected nationwide in patients who received rituximab. 56 patients were treated with rituximab for MS or NMO. Average observation period was 9.6 months (SD 7.6, ranging from 6 to 29.7 months). Interval between treatments cycles differed tremendously (ranging from 0 to 21 months, median 10 months). Number of infusions ranged from 1 up to more than 8. The analysis provides experience on almost 50 patient years. Infusion related reactions were most common and reported in four patients; infections were seen in three patients (two of them were hospitalized for urinary tract infection and urosepsis). All patients recovered from infection. Full treatment response was attested in a quarter of the patients; two thirds benefited partially from treatment. DISCUSSION: Safety data of almost 50 patient years of treatment with rituximab show that rituximab is tolerated well in MS/NMO patients. Infections and infusion reactions are the most common adverse events. Our data may help the individual physician to balance efficacy of rituximab against the risk. * Data on rituximab in MS and NMO are provided for almost 50 patientyears * Rituximab was tolerated well * No unexpected side effects were seen * Almost 80% of the patients benefited at least partially from treatment. PMID- 26589237 TI - Factors affecting parathyroid hormone levels in different types of primary aldosteronism. AB - BACKGROUND: Recent studies have found that mild secondary hyperparathyroidism might be another clinical feature of patients with primary aldosteronims (PA), but whether serum parathyroid hormone level (PTH) is correlated with subtypes of PA and what contributes to the elevated PTH level remains unclear. OBJECTIVE: To illustrate the changes of PTH in PA and to partly explain the mechanism of how the effects of aldosterone regulating the secretion of PTH in PA. METHODS: We enrolled a total of 120 patients with primary hypertension (PH) and 242 patients with PA, which included 89 APAs (aldosterone-producing adenoma), 119 IHAs (idiopathic hyperaldosteronism) and 34 UAHs (unilateral adrenal hyperplasia). The plasma levels of aldosterone, renin activity, parathyroid hormone and markers associated with calcium metabolism were measured. RESULTS: We found serum PTH level was significantly elevated in patients with PA compared with primary hypertension [9.0 (6.6, 11.7) vs 5.7 (4.4, 7.0)] pmol/l, P < 0.001]. However, no difference was found between the three PA subtypes (P > 0.05). Stepwise multiple regression analysis showed that in patients with PA, serum levels of K(+) and Ca(2+) were independently associated with serum PTH level. More importantly, elevated PTH level could be corrected either by unilateral adrenalectomy [9.9 (7.5, 12.8) vs 5.2 (4.4, 7.0) pmol/l, P < 0.001] or mineralocorticoid receptor (MR) antagonists treatment [11.7 (9.1, 13.4) vs 6.3 (5.1, 7.8) pmol/l, P < 0.001]. CONCLUSIONS: PTH level is elevated in PA patients and irrelevant with subtypes of PA. Serum K(+) and serum Ca(2+) level are main factors influence the plasma PTH level in PA patients. After medical or surgical treatment, PTH levels return to normal. PMID- 26589238 TI - Combination therapy of sodium-glucose co-transporter-2 inhibitors and dipeptidyl peptidase-4 inhibitors in type 2 diabetes: rationale and evidences. AB - No single antidiabetic agent can correct all the pathophysiologic defects manifested in type 2 diabetes mellitus (T2DM) and, therefore, multiple agents are often required to achieve optimal glycemic control. Combination therapies, having different mechanisms of action, not only have the potential to complement their action, but may possess the properties to counter the undesired compensatory response. Recent finding suggests that sodium-glucose co-transporter-2 inhibitors (SGLT2i) increase endogenous glucose production (EGP) from liver, due to the increase in glucagon which may offset its glucose-lowering potential. In contrast, dipeptidyl peptidase-4 inhibitors (DPP4i) decrease glucagon and EGP. Especially in the light of this finding, combination therapies with SGLT2i and DPP4i are particularly appealing, and are expected to produce an additive effect. Indeed, studies find no drug-drug interaction between SGLT2i and DPP4i. Moreover, significant reduction in glycated hemoglobin has also been observed. This article aims to review the efficacy and safety of combination therapy of SGLT2i and DPP4i in T2DM. PMID- 26589239 TI - Evaluating the performance of selection scans to detect selective sweeps in domestic dogs. AB - Selective breeding of dogs has resulted in repeated artificial selection on breed specific morphological phenotypes. A number of quantitative trait loci associated with these phenotypes have been identified in genetic mapping studies. We analysed the population genomic signatures observed around the causal mutations for 12 of these loci in 25 dog breeds, for which we genotyped 25 individuals in each breed. By measuring the population frequencies of the causal mutations in each breed, we identified those breeds in which specific mutations most likely experienced positive selection. These instances were then used as positive controls for assessing the performance of popular statistics to detect selection from population genomic data. We found that artificial selection during dog domestication has left characteristic signatures in the haplotype and nucleotide polymorphism patterns around selected loci that can be detected in the genotype data from a single population sample. However, the sensitivity and accuracy at which such signatures were detected varied widely between loci, the particular statistic used and the choice of analysis parameters. We observed examples of both hard and soft selective sweeps and detected strong selective events that removed genetic diversity almost entirely over regions >10 Mbp. Our study demonstrates the power and limitations of selection scans in populations with high levels of linkage disequilibrium due to severe founder effects and recent population bottlenecks. PMID- 26589240 TI - Uricosuric agents decrease the plasma urate level in rats by concomitant treatment with topiroxostat, a novel xanthine oxidoreductase inhibitor. AB - OBJECTIVES: The aim of this study was to establish the rat model for evaluating hypouricemic effects by some uricosuric agents. METHODS: Rats were made hyperuricemic by subcutaneous administration of potassium oxonate, a uricase inhibitor, or made hypouricemic by oral administration of topiroxostat, a xanthine oxidoreductase inhibitor. Furthermore, rats were co-treated with topiroxostat and inosine, a urate precursor. In each condition, hypouricemic effects by uricosuric agents were examined. KEY FINDINGS: In potassium oxonate treated rats, treatment with uricosuric agents such as FYU-981, F12859 and probenecid showed no hypouricemic effect. On the other hand, in topiroxostat treated rats, uricosuric agents remarkably lowered plasma urate level compared with topiroxostat treatment alone, with a dose dependency of 30 and 100 mg/kg for FYU-981 and F12859 each. The decrease in the plasma urate level observed in the topiroxostat-treated rats disappeared by further co-treatment with inosine. CONCLUSIONS: Effects of uricosuric agents on the plasma urate level in rats were sensitive to the rate of urate formation. Induction of slower urate formation by topiroxostat provides valuable model for evaluation of hypouricemic effects by uricosuric agents in rats. PMID- 26589241 TI - Brain MRI Volume Findings in Diabetic Adults With Albuminuria: The ACCORD-MIND Study. AB - BACKGROUND: Albuminuria is associated with cognitive impairment in people with type 2 diabetes mellitus (T2DM). The brain volume correlates of albuminuria in people with T2DM have not been well investigated. METHODS: We examined 502 individuals with T2DM (9-12 years duration; mean age ~62 years) who had a brain MRI at baseline and at 40 months. Baseline MRI findings were examined by the presence or absence of albuminuria (>=30mg/g creatinine). Changes in MRI findings were examined by whether albuminuria was persistent, intermittent, or absent during follow-up. RESULTS: At baseline, participants with albuminuria (28.7% of the cohort) had more abnormal white matter volume (AWMV) than participants without albuminuria on unadjusted analysis. This difference was attenuated with adjustment for systolic blood pressure, which was higher in participants with albuminuria than in those without albuminuria. During ~3.5 years of follow-up, participants with persistent albuminuria (15.8%) had a greater increase in new AWMV than participants without albuminuria (59.8%) or those with intermittent albuminuria on unadjusted analysis. This difference was attenuated with adjustment for age and systolic blood pressure. There were no significant differences in gray matter volume and total brain volume between participants with or without albuminuria at baseline or during follow-up. There was no significant effect modification of these findings by estimated glomerular filtration rate (eGFR) at baseline or change in eGFR during follow-up. CONCLUSIONS: In this diabetic cohort, baseline albuminuria and persistent albuminuria were not independently associated with any significant differences in brain volume measurements compared with participants without albuminuria. PMID- 26589242 TI - Print-Speech Convergence Predicts Future Reading Outcomes in Early Readers. AB - Becoming a skilled reader requires building a functional neurocircuitry for printed-language processing that integrates with spoken-language-processing networks. In this longitudinal study, functional MRI (fMRI) was used to examine convergent activation for printed and spoken language (print-speech coactivation) in selected regions implicated in printed-language processing (the reading network). We found that print-speech coactivation across the left-hemisphere reading network in beginning readers predicted reading achievement 2 years later beyond the effects of brain activity for either modality alone; moreover, coactivation effects accounted for variance in later reading after controlling for initial reading performance. Within the reading network, effects of coactivation were significant in bilateral inferior frontal gyrus (IFG) and left inferior parietal cortex and fusiform gyrus. The contribution of left and right IFG differed, with more coactivation in left IFG predicting better achievement but more coactivation in right IFG predicting poorer achievement. Findings point to the centrality of print-speech convergence in building an efficient reading circuitry in children. PMID- 26589243 TI - Effects of lisdexamfetamine in a rat model of binge-eating. AB - Binge-eating disorder is a common psychiatric disorder affecting ~2% of adults. Binge-eating was initiated in freely-fed, lean, adult, female rats by giving unpredictable, intermittent access to ground, milk chocolate over four weeks. The rats avidly consumed chocolate during 2 hr binge sessions, with compensatory reductions of normal chow intake in these sessions and the days thereafter. Bodyweights of binge-eating rats were normal. The model's predictive validity was explored using nalmefene (0.1-1.0mg/kg), R-baclofen (1.0-10mg/kg) and SB-334867 (3.0-30 mg/kg) (orexin-1 antagonist), which all selectively decreased chocolate bingeing without reducing chow intake. Sibutramine (0.3-5.0mg/kg) non-selectively reduced chocolate and chow consumption. Olanzapine (0.3-3.0mg/kg) was without effect and rolipram (1.0-10mg/kg) abolished all ingestive behaviour. The pro drug, lisdexamfetamine (LDX; 0.1-1.5mg/kg), dose-dependently reduced chocolate bingeing by ? 71% without significantly decreasing normal chow intake. Its metabolite, D-amphetamine (0.1-1.0mg/kg), dose-dependently and preferentially decreased chocolate bingeing ? 56%. Using selective antagonists to characterize LDX's actions revealed the reduction of chocolate bingeing was partially blocked by prazosin (alpha1-adrenoceptor; 0.3 and 1.0mg/kg) and possibly by SCH-23390 (D1; 0.1mg/kg). RX821002 (alpha2-adrenoceptor; 0.1 and 0.3mg/kg) and raclopride (D2; 0.3 and 0.5mg/kg) were without effect. The results indicate that LDX, via its metabolite, d-amphetamine, reduces chocolate bingeing, partly by indirect activation of alpha1-adrenoceptors and perhaps D1 receptors. PMID- 26589244 TI - From BILAG to BILAG-based combined lupus assessment-30 years on. AB - Disease activity in SLE can be difficult to measure and there is no biomarker that uniformly reflects disease activity. There are various disease activity scores, but there is no gold standard assessment tool. This is a review of the development of the BILAG index from the classic BILAG disease activity index to the BILAG-2004 disease activity index and composite response criteria. The original classic BILAG index was revised and distinguished nine organs/systems. Features that indicated damage, such as avascular necrosis, were excluded. There was improvement in the glossary, scoring system and software. The BILAG-2004 index has been shown to be reliable, valid and sensitive to change. The BILAG 2004 index has been modified for pregnancy and has also been used in paediatrics. The SLE Responder Index (SRI) and the BILAG-based combined lupus assessment (BICLA) are composite responder indices incorporating the BILAG index. Since the initial development of the BILAG index in 1984, major improvements have been made in the measurement of disease activity in lupus. However, the BILAG-2004 index is the only transitional index that grades clinical features as being new, the same, worse or improving and incorporates severity in the scoring. PMID- 26589245 TI - Doctors can withdraw feeding from patient in minimally conscious state, judge rules. PMID- 26589248 TI - Methods related to molecular virology. PMID- 26589246 TI - Risk factors for transmission of Ebola or Marburg virus disease: a systematic review and meta-analysis. AB - BACKGROUND: The Ebola virus disease outbreak that started in Western Africa in 2013 was unprecedented because it spread within densely populated urban environments and affected many thousands of people. As a result, previous advice and guidelines need to be critically reviewed, especially with regard to transmission risks in different contexts. METHODS: Scientific and grey literature were searched for articles about any African filovirus. Articles were screened for information about transmission (prevalence or odds ratios especially). Data were extracted from eligible articles and summarized narratively with partial meta-analysis. Study quality was also evaluated. RESULTS: A total of 31 reports were selected from 6552 found in the initial search. Eight papers gave numerical odds for contracting filovirus illness; 23 further articles provided supporting anecdotal observations about how transmission probably occurred for individuals. Many forms of contact (conversation, sharing a meal, sharing a bed, direct or indirect touching) were unlikely to result in disease transmission during incubation or early illness. Among household contacts who reported directly touching a case, the attack rate was 32% [95% confidence interval (CI) 26-38%]. Risk of disease transmission between household members without direct contact was low (1%; 95% CI 0-5%). Caring for a case in the community, especially until death, and participation in traditional funeral rites were strongly associated with acquiring disease, probably due to a high degree of direct physical contact with case or cadaver. CONCLUSIONS: Transmission of filovirus is unlikely except through close contact, especially during the most severe stages of acute illness. More data are needed about the context, intimacy and timing of contact required to raise the odds of disease transmission. Risk factors specific to urban settings may need to be determined. PMID- 26589249 TI - Ibuprofen intake increases exercise time to exhaustion: A possible role for preventing exercise-induced fatigue. AB - Although the intake of nonsteroidal anti-inflammatory drugs (NSAIDs) intake by athletes prevents soreness, little is known concerning their role in exercise performance. This study assessed the effects of ibuprofen intake on an exhaustive protocol test after 6 weeks of swimming training in rats. Animals were divided into sedentary and training groups. After training, animals were subdivided into two subsets: saline or ibuprofen. Afterwards, three repeated swimming bouts were performed by the groups. Ibuprofen (15 mg/kg) was administered once a day. Pain measurements were performed and inflammatory and oxidative stress parameters were assayed in cerebral cortex and gastrocnemius muscle. Training, ibuprofen administration, or both combined (P < 0.05; 211 +/- 18s, 200 +/- 31s, and 279 +/- 23s) increased exercise time to exhaustion. Training decreased the acetylcholinesterase (AChE) activity (P < 0.05; 149 +/- 11) in cerebral cortex. Ibuprofen intake decreased the AChE activity after exhaustive protocol test in trained and sedentary rats (P < 0.05; 270 +/- 60; 171 +/- 38; and 273 +/- 29). It also prevented neuronal tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL 1beta) increase. Fatigue elicited by this exhaustive protocol may involve disturbances of the central nervous system. Additive anti-inflammatory effects of exercise and ibuprofen intake support the hypothesis that this combination may constitute a more effective approach. In addition, ergogenic aids may be a useful means to prevent exercise-induced fatigue. PMID- 26589247 TI - Cholesterol-loaded nanoparticles ameliorate synaptic and cognitive function in Huntington's disease mice. AB - Brain cholesterol biosynthesis and cholesterol levels are reduced in mouse models of Huntington's disease (HD), suggesting that locally synthesized, newly formed cholesterol is less available to neurons. This may be detrimental for neuronal function, especially given that locally synthesized cholesterol is implicated in synapse integrity and remodeling. Here, we used biodegradable and biocompatible polymeric nanoparticles (NPs) modified with glycopeptides (g7) and loaded with cholesterol (g7-NPs-Chol), which per se is not blood-brain barrier (BBB) permeable, to obtain high-rate cholesterol delivery into the brain after intraperitoneal injection in HD mice. We report that g7-NPs, in contrast to unmodified NPs, efficiently crossed the BBB and localized in glial and neuronal cells in different brain regions. We also found that repeated systemic delivery of g7-NPs-Chol rescued synaptic and cognitive dysfunction and partially improved global activity in HD mice. These results demonstrate that cholesterol supplementation to the HD brain reverses functional alterations associated with HD and highlight the potential of this new drug-administration route to the diseased brain. PMID- 26589250 TI - Adverse reproductive effects of maternal low-dose melamine exposure during pregnancy in rats. AB - Melamine is a heterocyclic, aromatic amine and nitrogen-enriched environmental toxicant, found in not only adulterated foodstuffs but also industrial household tableware and paints. Previous studies demonstrated adverse effects of high-dose melamine on human infants and pregnant animals, but effects of low-dose melamine on pregnancy have not been reported. In this study, reproductive effects of low dose melamine were investigated in pregnant rats. Melamine in the range of 12.5 50 mg/kg was administered to pregnant rats at different gestational stages. Maternal weight gain was not significantly affected, and other maternal morbidity was not observed. Low-dose melamine exposure during pregnancy increased fetal size but reduced somite number in gastrulation (GD8.5-GD10.5) and organogenesis (GD10.5-GD16.5) periods, and increased incidence of stillbirth in whole gestational period (GD0.5 to delivery). Embryotoxicity of melamine was further confirmed by whole embryo culture in vitro that melamine retarded embryonic growth, impaired development of brain and heart, and induced open neural tube and atrioventricular defects with increased apoptosis. In conclusion, adverse reproductive effects of low-dose melamine during pregnancy were identified in the developing rat embryos and the perinatal effects of melamine were gestational and developmental stage dependent. Detailed hazard and risk assessment of melamine in reproduction system are warrant. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 32: 131-138, 2017. PMID- 26589251 TI - CASH algorithm versus 3-point checklist and its modified version in evaluation of melanocytic pigmented skin lesions: The 4-point checklist. AB - Dermoscopy, in expert hands, increases accuracy, sensitivity and specificity in diagnosis of pigmented skin lesions of a single operator, compared with clinical examination. Simplified algorithmic methods have been developed to help less expert dermoscopists in diagnosis of melanocytic lesions. This study included 125 melanocytic skin lesions divided into melanocytic nevi, dysplastic nevi and thin melanomas (<1 mm). We compared the 3-point checklist and CASH algorithm to analyze different pigmented skin lesions. Based on preliminary results, we proposed a new modified algorithm, called the 4-point checklist, whose accuracy is similar to the CASH algorithm and whose simplicity is similar to the 3-point checklist. PMID- 26589252 TI - Bradford Hill's criteria, emerging zoonoses, and One Health. AB - Zoonoses constitute more than 60% of infectious diseases and 75% of emerging infectious diseases. Inappropriate overemphasis of specialization of disciplines has ignored public health. Identifying the causes of disease and determining how exposures are related to outcomes in "emerging zoonoses" affecting multiple species are considered to be the hallmarks of public health research and practice that compels the adoption of "One Health". The interactions within and among populations of vertebrates in the causation and transmissions of emerging zoonotic diseases are inherently dynamic, interdependent, and systems based. Disease causality theories have moved from one or several agents causing disease in a single species, to one infectious agent causing disease in multiple species emerging zoonoses. Identification of the causative pathogen components or structures, elucidating the mechanisms of species specificity, and understanding the natural conditions of emergence would facilitate better derivation of the causal mechanism. Good quality evidence on causation in emerging zoonoses affecting multiple species makes a strong recommendation under the One Health approach for disease prevention and control from diagnostic tests, treatment, antimicrobial resistance, preventive vaccines, and evidence informed health policies. In the tenets of One Health, alliances work best when the legitimate interests of the different partners combine to prevent and control emerging zoonoses. PMID- 26589253 TI - Efficacy and safety of dapagliflozin in Asian patients with type 2 diabetes after metformin failure: A randomized controlled trial. AB - BACKGROUND: Dapagliflozin, a highly selective sodium-glucose cotransporter 2 inhibitor, reduces hyperglycemia, body weight, and blood pressure in patients with type 2 diabetes (T2D). METHODS: This randomized double-blind placebo controlled parallel-group 24-week study assessed the efficacy, safety, and tolerability of dapagliflozin added to metformin in Asian patients with inadequately controlled T2D (HbA1c 7.5%-10.5%). Patients were randomized to receive placebo (n = 145) or dapagliflozin 5 (n = 147) or 10 mg (n = 152). RESULTS: Most participants were Chinese (86.0%), with a mean age of 53.8 years and mean T2D duration of 4.9 years; 92.1% completed the study. Adjusted mean HbA1c changes from baseline at Week 24 (primary endpoint) were -0.23%, -0.82%, and -0.85% in the placebo, dapagliflozin 5 and 10 mg groups, respectively, resulting in dapagliflozin 5 and 10 mg versus placebo differences of -0.59% and 0.62%, respectively (both P < 0.0001). Dapagliflozin 5 and 10 mg differences versus placebo were, respectively: -1.2 and -1.5 mmol/L for fasting plasma glucose; -1.1 and -1.8 kg for weight; and -2.3 and -2.7 mmol/L for 2-h postprandial glucose (all P <0.0001). In the placebo, dapagliflozin 5 and 10 mg groups, respectively: adverse events (AEs) occurred in 52.4%, 52.4%, and 55.3% of patients; serious AEs occurred in 4.1%, 2.0%, and 2.0%; urinary tract infections occurred in 4.8%, 4.1%, and 6.6%; and genital infections occurred in 0%, 2.0%, and 1.3%. No AEs of pyelonephritis or renal failure occurred. CONCLUSIONS: Dapagliflozin 5 or 10 mg as add-on to metformin was well tolerated in Asian patients with T2D and significantly improved glycemic control with the additional benefit of weight reduction. PMID- 26589254 TI - Bilateral, Synchronous Breast Carcinoma in Monozygotic Male Twins with Multi system Developmental Anomalies: Proposition of a Congenital Etiology. PMID- 26589255 TI - How to quantify exposure to traumatic stress? Reliability and predictive validity of measures for cumulative trauma exposure in a post-conflict population. AB - BACKGROUND: While studies with survivors of single traumatic experiences highlight individual response variation following trauma, research from conflict regions shows that almost everyone develops posttraumatic stress disorder (PTSD) if trauma exposure reaches extreme levels. Therefore, evaluating the effects of cumulative trauma exposure is of utmost importance in studies investigating risk factors for PTSD. Yet, little research has been devoted to evaluate how this important environmental risk factor can be best quantified. METHODS: We investigated the retest reliability and predictive validity of different trauma measures in a sample of 227 Ugandan rebel war survivors. Trauma exposure was modeled as the number of traumatic event types experienced or as a score considering traumatic event frequencies. In addition, we investigated whether age at trauma exposure can be reliably measured and improves PTSD risk prediction. RESULTS: All trauma measures showed good reliability. While prediction of lifetime PTSD was most accurate from the number of different traumatic event types experienced, inclusion of event frequencies slightly improved the prediction of current PTSD. CONCLUSIONS: As assessing the number of traumatic events experienced is the least stressful and time-consuming assessment and leads to the best prediction of lifetime PTSD, we recommend this measure for research on PTSD etiology. PMID- 26589256 TI - Trauma-related mental health problems among national humanitarian staff: a systematic review of the literature. AB - BACKGROUND: Working in humanitarian crisis situations is dangerous. National humanitarian staff in particular face the risk of primary and secondary trauma exposure which can lead to mental health problems. Despite this, research on the mental health of national staff is scarce, and a systematic analysis of up-to date findings has not been undertaken yet. OBJECTIVE: This article reviews the available literature on trauma-related mental health problems among national humanitarian staff. It focuses on the prevalence of selected mental health problems in relation to reference groups; sex and/or gender as predictive factors of mental health problems; and the influence of organization types on mental health problems. METHOD: Three databases were systematically searched for relevant studies published in the English language in peer-reviewed journals. RESULTS: Fourteen articles matched the inclusion criteria. Findings suggest that national staff experience mental health problems and the prevalence of posttraumatic stress disorder, depression, and anxiety among this occupation group is mostly similar to or higher than among reference groups. Research on both substance use disorder and suicidal behavior among national staff is particularly scarce. The relation between sex and/or gender and mental health problems among national staff appears to be complex, and organizational staff support seems to be an important determinant for mental health. CONCLUSION: All findings call for increased attention from the humanitarian community and further research on the topic. PMID- 26589257 TI - Neglect and perceived stigmatization impact psychological distress of orphans in Tanzania. AB - BACKGROUND: Research has shown that orphans in sub-Saharan Africa are at increased risk for mental health problems. Exposure to maltreatment and HIV/AIDS related stigmatization are related to orphans' psychological distress. Yet, researchers stress the need for more research in low-income countries to identify which factors of being an orphan may lead to psychological distress. OBJECTIVES: The present study aims to systematically investigate orphans' experiences of maltreatment and stigmatization to identify factors that relate to their psychological distress. METHODS: In total, 89 Tanzanian children who had lost at least one parent were compared to 89 matched non-orphans (mean age: 11 years; 51% boys). We measured exposure to maltreatment and perceived stigmatization as an orphan. Mental health was assessed using the Strengths and Difficulties Questionnaire, the Children's Depression Inventory, the UCLA PTSD Index for Children, and the Reactive-Proactive Questionnaire. RESULTS: Orphans reported significantly more experiences of neglect, but not of abuse. A group comparison revealed more depressive symptoms, posttraumatic stress symptoms, and aggressive behavior among orphans. Neglect, abuse, and stigmatization correlated with orphans' internalizing and externalizing problems, yet only neglect and stigmatization were related to orphans' depression severity. Perceived stigmatization moderated the relationship between neglect and depression. CONCLUSIONS: Our findings suggest that orphans in Tanzania are at increased risk of experiencing neglect. Maltreatment and perceived stigmatization may play a role in orphans' psychological distress. Culturally appropriate and evidence based interventions may help to prevent maltreatment and stigmatization of orphans. PMID- 26589258 TI - The "treatment gap" in global mental health reconsidered: sociotherapy for collective trauma in Rwanda. AB - BACKGROUND: The "treatment gap" (TG) for mental disorders refers to the difference that exists between the number of people who need care and those who receive care. The concept is strongly promoted by the World Health Organization and widely used in the context of low- and middle-income countries. Although accepting the many demonstrable benefits that flow from this approach, it is important to critically reflect on the limitations of the concept of the TG and its implications for building capacity for mental health services in Rwanda. OBJECTIVE: The article highlights concerns that the evidence base for mental health interventions is not globally valid, and problematizes the preponderance of psychiatric approaches in international guidelines for mental health. Specifically, the risk of medicalization of social problems and the limited way in which "community" has been conceptualized in global mental health discourses are addressed. Rather than being used as a method for increasing economic efficiency (i.e., reducing healthcare costs), "community" should be promoted as a means of harnessing collective strengths and resources to help promote mental well-being. This may be particularly beneficial for contexts, like Rwanda, where community life has been disrupted by collective violence, and the resulting social isolation constitutes an important determinant of mental distress. CONCLUSIONS: Moving forward there is a need to consider alternative paradigms where individual distress is understood as a symptom of social distress, which extends beyond the more individually oriented TG paradigm. Sociotherapy, an intervention used in Rwanda over the past 10 years, is presented as an example of how communities of support can be built to promote mental health and psychosocial well-being. PMID- 26589259 TI - Global mental health and trauma exposure: the current evidence for the relationship between traumatic experiences and spirit possession. AB - BACKGROUND: We present a literature review on trauma exposure and spirit possession in low- and middle-income countries (LMICs). Despite the World Health Organization's objective of culturally appropriate mental health care in the Mental Health Action Plan 2013-2020, and the recommendations of the Inter-Agency Standing Committee to consider local idioms of distress and to collaborate with local resources, this topic still receives very little attention. Pathological spirit possession is commonly defined as involuntary, uncontrollable, and occurring outside of ritual settings. It is often associated with stigmatization, suffering, and dysfunctional behavior. While spirit possession has been discussed as an idiom of distress in anthropological literature, recent quantitative studies have presented support for a strong relationship between traumatic experiences and pathological possession states. OBJECTIVE: The aim of this review was to investigate this relationship systematically in LMICs, in view of the debate on how to address the mental health gap in LMICs. METHODS: Twenty-one articles, published in peer-reviewed English-language journals between 1994 and 2013, were identified and analyzed with regard to prevalence of possessive trance disorders, patients' sociodemographic characteristics, and its relation to traumatic experiences. RESULTS: The review and analysis of 917 patients with symptoms of possessive trance disorders from 14 LMICs indicated that it is a phenomenon occurring worldwide and with global relevance. This literature review suggests a strong relationship between trauma exposure and spirit possession with high prevalence rates found especially in postwar areas in African countries. CONCLUSIONS: More attention for possessive trance disorders in mental health and psychosocial intervention programs in humanitarian emergency settings as well as in societies in transition in LMICs is needed and justified by the results of this systematic literature review. PMID- 26589260 TI - Global mental health and trauma: the current evidence and the long road ahead. PMID- 26589261 TI - Feasibility of whole-body vibration as an early inpatient rehabilitation tool after lung transplantation--a pilot study. AB - OBJECTIVE: Optimal rehabilitation programs are essential in the early phase after lung transplantation (LTx). Whole-body vibration (WBV) may be a novel approach in rehabilitation that has not yet been investigated in these patients. PATIENTS AND METHODS: Ten patients in the early postoperative phase after LTx after discharge from the intensive care unit (ICU) were included in the study. WBV training was performed until transfer to a rehabilitation center. Six-minute walk distance (6 MWD), pulmonary function, maximal workload, and quality of life (SF-36) were assessed at the beginning and after completion of the training program. RESULTS: Patients revealed a significant improvement of the 6-MWD, the vital capacity (VC), the maximal workload, and in quality of life. Peak cough flow (PCF), forced expiratory volume (FEV1), and parts of the quality of life questionnaire showed no significant changes. No adverse events occurred in these patients. CONCLUSION: WBV in lung transplant recipients after discharge from ICU is safe and feasible. WBV may effectively support rehabilitation programs improving pulmonary function and quality of life. PMID- 26589263 TI - Potential stem cell labeling ability of poly-L-lysine complexed to ultrasmall iron oxide contrast agent: An optimization and relaxometry study. AB - For non-invasive stem cells tracking through MRI, it is important to understand the efficiency of in vitro labeling of stem cells with iron oxide with regard to its relaxation behavior. In this study, we have carried out a pilot study of labeling mice mesenchymal stem cells (mMSCs) with ultrasmall superparamagnetic iron oxide (USPIO) entrapped with poly-L-lysine (PLL) in different ratios and incubated with different times. Our results demonstrated that 50:1.5 ug/ml of iron oxide and PLL at an incubation time of 6h with 10% serum concentration are sufficient enough for effective labeling. Optimized labeling showed that >98% of viability and <3% toxicity were observed at a total iron content of 11.8 pg/cell. In vitro relaxometry study showed that almost a 6.6 fold reduction in transverse relaxation time (T2) was observed after labeling as compared to unlabeled. IO-PLL complex was more effective than iron oxide alone in labeling and a detectable lower limit found to be hundred with optimized concentration. Significant increase in Oct-4 expression on day-3 after labeling was observed, whereas CD146 expression remains unchanged in real time RT-PCR. This optimized labeling method of MSCs may be very useful for cellular MRI and stem cells tracking studies. PMID- 26589262 TI - cAMP effects in neuroendocrine tumors: The role of Epac and PKA in cell proliferation and adhesion. AB - cAMP effects have been initially attributed to protein kinase A (PKA) activation. Subsequently, two exchange proteins directly activated by cAMP (Epac1/2) have been identified as cAMP targets. Aim of this study was to investigate cAMP effects in pancreatic-NET (P-NET) and bronchial carcinoids and in corresponding cell lines (QGP-1 and H727) on cell proliferation and adhesion and to determine PKA and Epac role in mediating these effects. We found that cAMP increased cyclin D1 expression in P-NET and QGP-1 cells, whereas it had opposite effects on bronchial carcinoids and H727 cells and it promoted cell adhesion in QGP-1 and H727 cells. These effects are mimicked by Epac and PKA specific analogs, activating the small GTPase Rap1. In conclusion, we demonstrated that cAMP exerted divergent effects on proliferation and promoted cell adhesion of different neuroendocrine cell types, these effects being mediated by both Epac and PKA and involving the same effector GTPase Rap1. PMID- 26589264 TI - XL413, a cell division cycle 7 kinase inhibitor enhanced the anti-fibrotic effect of pirfenidone on TGF-beta1-stimulated C3H10T1/2 cells via Smad2/4. AB - Pirfenidone is an orally bioavailable synthetic compound with therapeutic potential for idiopathic pulmonary fibrosis. It is thought to act through antioxidant and anti-fibrotic pathways. Pirfenidone inhibits proliferation and/or myofibroblast differentiation of a wide range of cell types, however, little studies have analyzed the effect of pirfenidone on the mesenchymal stem cells, which play an important role on the origin of myofibroblasts. We recently found that pirfenidone had anti-proliferative activity via G1 phase arrest and cell division cycle 7 (Cdc7) kinase expression decrease in transforming growth factor beta1 (TGF-beta1)-stimulated murine mesenchymal stem C3H10T1/2 cells. Pirfenidone also had inhibiting effect on the migration and alpha-SMA expression. Moreover, in this study we showed for the first time that Cdc7 inhibitor XL413 enhanced the anti-fibrotic activity of pirfenidone via depressed the expression of Smad2/4 proteins, and also prevented the nuclear accumulation and translocation of Smad2 protein. In conclusion, we demonstrated that pirfenidone inhibited proliferation, migration and differentiation of TGF-beta1-stimulated C3H10T1/2 cells, which could be enhanced by Cdc7 inhibitor XL413, via Smad2/4. Combination with pirfenidone and XL413 might provide a potential candidate for the treatment of TGF-beta1 associated fibrosis. It needs in vivo studies to further validate its therapeutic function and safety in the future. PMID- 26589267 TI - Profiling and Characterization of Small RNAs in the Liverwort, Marchantia polymorpha, Belonging to the First Diverged Land Plants. AB - MicroRNAs (miRNAs) have important roles in gene regulation during plant development. Previous studies revealed that some miRNAs are highly shared by most land plants. Recently, the liverwort, Marchantia polymorpha, has been studied by molecular genetic approaches, and sequencing of its genome is currently underway. The expression pattern and the detailed functions of miRNAs during Marchantia development are unknown. Here, we profiled the small RNAs expressed in thalli, antheridiophores and archegoniophores of M. polymorpha using high-throughput RNA sequencing. We revealed that a limited number of miRNAs are shared between M. polymorpha and the moss, Physcomitrella patens, and that a number of miRNAs are M. polymorpha specific. Like other land plants, cognate target genes corresponding to conserved miRNAs could be found in the genome database and were experimentally confirmed to guide cleavage of target mRNAs. The results suggested that two genes in the SPL (SQUAMOSA PROMOTER BINDING-LIKE) transcription factor family, which are regulated by miR156 in most land plants, were instead targeted by two distinct miRNAs in M. polymorpha. In order to demonstrate the physiological roles of miRNAs in M. polymorpha, we constructed an miRNA ectopic expression system to establish overexpression transformants for conserved miRNAs, miR166 and miR319. Ectopic expression of these miRNAs induced abnormal development of the thallus and gemma cups, suggesting that balanced expression of miRNA/target mRNAs has a crucial role in developmental regulation in M. polymorpha. Profiling data on miRNA together with the ectopic expression system would provide new information on the liverwort small RNA world and evolutionary divergence/conservation of small RNA function among land plants. PMID- 26589268 TI - Deep Sequencing of the Fruit Transcriptome and Lipid Accumulation in a Non-Seed Tissue of Chinese Tallow, a Potential Biofuel Crop. AB - Chinese tallow (Triadica sebifera) is a valuable oilseed-producing tree that can grow in a variety of conditions without competing for food production, and is a promising biofuel feedstock candidate. The fruits are unique in that they contain both saturated and unsaturated fat present in the tallow and seed layer, respectively. The tallow layer is poorly studied and is considered only as an external fatty deposition secreted from the seed. In this study we show that tallow is in fact a non-seed cellular tissue capable of triglyceride synthesis. Knowledge of lipid synthesis and storage mechanisms in tissues other than seed is limited but essential to generate oil-rich biomass crops. Here, we describe the annotated transcriptome assembly generated from the fruit coat, tallow and seed tissues of Chinese tallow. The final assembly was functionally annotated, allowing for the identification of candidate genes and reconstruction of lipid pathways. A tallow tissue-specific paralog for the transcription factor gene WRINKLED1 (WRI1) and lipid droplet-associated protein genes, distinct from those expressed in seed tissue, were found to be active in tallow, underpinning the mode of oil synthesis and packaging in this tissue. Our data have established an excellent knowledge base that can provide genetic and biochemical insights for engineering non-seed tissues to accumulate large amounts of oil. In addition to the large data set of annotated transcripts, the study also provides gene-based simple sequence repeat and single nucleotide polymorphism markers. PMID- 26589269 TI - Is atrial fibrillation a risk factor for contrast-induced nephropathy in patients with ST-elevation myocardial infarction? AB - BACKGROUND: Contrast-induced nephropathy (CIN) is an iatrogenic problem in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). Atrial fibrillation (AF) may also contribute to impaired kidney function. Several factors may contribute to the development of CIN. In patients with STEMI, concomitant AF is associated with higher in-hospital/follow-up mortality and morbidity. Therefore, we aimed to investigate the relationship between AF and CIN developments. METHODS: In this study, 650 consecutive STEMI patients treated with PPCI were enrolled. Patients with AF at admission who did not achieve a sinus rhythm during 48h after hospitalization were defined as AF patients. CIN was defined by an increase in serum creatinine by >25% or 0.5mg/dL within 72h following contrast media exposure. RESULTS: Our patients were divided into two groups based on whether they had AF, and although warfarin usage was different, the other parameters were similar between the groups. When our patients were grouped according to CIN development [group 1: CIN (+), group 2: CIN (-)], creatinine levels prior to PPCI (p=0.020), estimated glomerular filtration rate (eGFR) prior to PPCI (p<0.001), left ventricular ejection fraction (LVEF) (p=0.011), AF (p<0.001), and warfarin usage (p=0.016) were different between the two groups. We also performed multivariate logistic regression analyses and found that AF [odds ratio (OR), 6.945; 95% confidence interval (CI), 2.789-17.293; p<0.001], eGFR (OR, 0.973; 95% CI, 0.957-0.989; p=0.001), and LVEF (OR, 0.963; 95% CI, 0.935-0.991; p=0.010) independently predicted CIN development in patients with STEMI. CONCLUSIONS: The risk factors for CIN are multifactorial and identifying high-risk patients is the most important step for prevention. In addition to traditional risk factors, AF can contribute to CIN development in patients with STEMI. PMID- 26589270 TI - Clot structure and fibrinolytic potential in patients with post thrombotic syndrome. AB - INTRODUCTION: Post-thrombotic syndrome (PTS) is a chronic sequel of deep vein thrombosis (DVT). The clot structure and fibrinolytic potential in PTS is currently unknown. OBJECTIVE: To assess the fibrinolytic potential and clot structure in patients with PTS. MATERIALS AND METHODS: Patients with a history of DVT were included in a case-control study: patients with PTS (cases n=30) and without PTS (controls n=30), and 30 apparently healthy individuals (HI) without venous thromboembolism (VTE) or venous insufficiency were enrolled. Fibrinolysis and clot structure were assessed by turbidimetric assays, permeation, and confocal microscopy. Fibrinogen was measured by Clauss and fibrinogen gamma' by ELISA. RESULTS: We observed a significant trend of decreasing maximum turbidity from HI (median 0.52 [IQR 0.46-0.62]), to controls (0.49 [IQR 0.41-0.55]), to cases (0.46 [IQR 0.39-0.49]) p=0.020. Fibrinogen was lower in patients (cases and controls) (3.69g/L [IQR 3.31-4.26]) compared to HI (4.17 [IQR 3.69-4.65]) p=0.041. Patients with recurrent VTE had lower maximum turbidity and lower permeation than patients with one episode of VTE; (0.31 [IQR 0.25-0.39] versus 0.38 [IQR 0.34-0.44] p=0.008) and (6.0*10(-9)/cm(2) [IQR 5.1-7.9] versus 7.7*10( 9)/cm(2) [IQR 6.0-10.0] p=0.047) respectively, at equal fibrinogen levels. There were no differences in lysis time, confocal microscopy, or fibrinogen gamma'. CONCLUSIONS: Lower maximum turbidity, indicating a tendency towards thinner fibres and denser clots, was found in patients with PTS as well as in patients with recurrent VTE. Fibrinogen levels did not explain these differences in clot structure. The abnormal clot structure may contribute to the increased thrombotic risk profile in patients with PTS. PMID- 26589271 TI - AccessFold: predicting RNA-RNA interactions with consideration for competing self structure. AB - MOTIVATION: There are numerous examples of RNA-RNA complexes, including microRNA mRNA and small RNA-mRNA duplexes for regulation of translation, guide RNA interactions with target RNA for post-transcriptional modification and small nuclear RNA duplexes for splicing. Predicting the base pairs formed between two interacting sequences remains difficult, at least in part because of the competition between unimolecular and bimolecular structure. RESULTS: Two algorithms were developed for improved prediction of bimolecular RNA structure that consider the competition between self-structure and bimolecular structure. These algorithms utilize two novel approaches to evaluate accessibility: free energy density minimization and pseudo-energy minimization. Free energy density minimization minimizes the folding free energy change per nucleotide involved in an intermolecular secondary structure. Pseudo-energy minimization (called AccessFold) minimizes the sum of free energy change and a pseudo-free energy penalty for bimolecular pairing of nucleotides that are unlikely to be accessible for bimolecular structure. The pseudo-free energy, derived from unimolecular pairing probabilities, is applied per nucleotide in bimolecular pairs, and this approach is able to predict binding sites that are split by unimolecular structures. A benchmark set of 17 bimolecular RNA structures was assembled to assess structure prediction. Pseudo-energy minimization provides a statistically significant improvement in sensitivity over the method that was found in a benchmark to be the most accurate previously available method, with an improvement from 36.8% to 57.8% in mean sensitivity for base pair prediction. AVAILABILITY AND IMPLEMENTATION: Pseudo-energy minimization is available for download as AccessFold, under an open-source license and as part of the RNAstructure package, at: http://rna.urmc.rochester.edu/RNAstructure.html CONTACT: david_mathews@urmc.rochester.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26589272 TI - iPQF: a new peptide-to-protein summarization method using peptide spectra characteristics to improve protein quantification. AB - MOTIVATION: Isobaric labelling techniques such as iTRAQ and TMT are popular methods for relative protein abundance estimation in proteomic studies. However, measurements are assessed at the peptide spectrum level and exhibit substantial heterogeneity per protein. Hence, clever summarization strategies are required to infer protein ratios. So far, current methods rely exclusively on quantitative values, while additional information on peptides is available, yet it is not considered in these methods. METHODS: We present iPQF ( I: sobaric P: rotein Q: uantification based on F: eatures) as a novel peptide-to-protein summarization method, which integrates peptide spectra characteristics as well as quantitative values for protein ratio estimation. We investigate diverse features characterizing spectra reliability and reveal significant correlations to ratio accuracy in spectra. As a result, we developed a feature-based weighting of peptide spectra. RESULTS: A performance evaluation of iPQF in comparison to nine different protein ratio inference methods is conducted on five published MS2 and MS3 datasets with predefined ground truth. We demonstrate the benefit of using peptide feature information to improve protein ratio estimation. Compared to purely quantitative approaches, our proposed strategy achieves increased accuracy by addressing peptide spectra reliability. AVAILABILITY AND IMPLEMENTATION: The iPQF algorithm is available within the established R/Bioconductor package MSnbase (version >= 1.17.8). CONTACT: renardB@rki.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26589273 TI - CellTracker (not only) for dummies. AB - MOTIVATION: Time-lapse experiments play a key role in studying the dynamic behavior of cells. Single-cell tracking is one of the fundamental tools for such analyses. The vast majority of the recently introduced cell tracking methods are limited to fluorescently labeled cells. An equally important limitation is that most software cannot be effectively used by biologists without reasonable expertise in image processing. Here we present CellTracker, a user-friendly open source software tool for tracking cells imaged with various imaging modalities, including fluorescent, phase contrast and differential interference contrast (DIC) techniques. AVAILABILITY AND IMPLEMENTATION: CellTracker is written in MATLAB (The MathWorks, Inc., USA). It works with Windows, Macintosh and UNIX based systems. Source code and graphical user interface (GUI) are freely available at: http://celltracker.website/ CONTACT: horvath.peter@brc.mta.hu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26589274 TI - LocusExplorer: a user-friendly tool for integrated visualization of human genetic association data and biological annotations. AB - : In this article, we present LocusExplorer, a data visualization and exploration tool for genetic association data. LocusExplorer is written in R using the Shiny library, providing access to powerful R-based functions through a simple user interface. LocusExplorer allows users to simultaneously display genetic, statistical and biological data for humans in a single image and allows dynamic zooming and customization of the plot features. Publication quality plots may then be produced in a variety of file formats. AVAILABILITY AND IMPLEMENTATION: LocusExplorer is open source and runs through R and a web browser. It is available at www.oncogenetics.icr.ac.uk/LocusExplorer/ or can be installed locally and the source code accessed from https://github.com/oncogenetics/LocusExplorer CONTACT: tokhir.dadaev@icr.ac.uk. PMID- 26589275 TI - FoCuS-point: software for STED fluorescence correlation and time-gated single photon counting. AB - MOTIVATION: Fluorescence Correlation Spectroscopy (FCS) is a popular tool for measuring molecular mobility and how mobility relates to molecular interaction dynamics and bioactivity in living cells. The FCS technique has been significantly advanced by its combination with super-resolution STED microscopy (STED-FCS). Specifically, the use of gated detection has shown great potential for enhancing STED-FCS, but has also created a demand for software which is efficient and also implements the latest algorithms. Prior to this study, no open software has been available which would allow practical time-gating and correlation of point data derived from STED-FCS experiments. RESULTS: The product of this study is a piece of stand-alone software called FoCuS-point. FoCuS-point utilizes advanced time-correlated single-photon counting (TCSPC) correlation algorithms along with time-gated filtering and innovative data visualization. The software has been designed to be highly user-friendly and is tailored to handle batches of data with tools designed to process files in bulk. FoCuS-point also includes advanced fitting algorithms which allow the parameters of the correlation curves and thus the kinetics of diffusion to be established quickly and efficiently. AVAILABILITY AND IMPLEMENTATION: FoCuS-point is written in python and is available through the github repository: https://github.com/dwaithe/FCS_point_correlator Furthermore, compiled versions of the code are available as executables which can be run directly in Linux, Windows and Mac OSX operating systems. CONTACT: dominic.waithe@imm.ox.ac.uk. PMID- 26589276 TI - ParTIES: a toolbox for Paramecium interspersed DNA elimination studies. AB - MOTIVATION: Developmental DNA elimination occurs in a wide variety of multicellular organisms, but ciliates are the only single-celled eukaryotes in which this phenomenon has been reported. Despite considerable interest in ciliates as models for DNA elimination, no standard methods for identification and characterization of the eliminated sequences are currently available. RESULTS: We present the Paramecium Toolbox for Interspersed DNA Elimination Studies (ParTIES), designed for Paramecium species, that (i) identifies eliminated sequences, (ii) measures their presence in a sequencing sample and (iii) detects rare elimination polymorphisms. AVAILABILITY AND IMPLEMENTATION: ParTIES is multi-threaded Perl software available at https://github.com/oarnaiz/ParTIES. ParTIES is distributed under the GNU General Public Licence v3. PMID- 26589277 TI - SomVarIUS: somatic variant identification from unpaired tissue samples. AB - MOTIVATION: Somatic variant calling typically requires paired tumor-normal tissue samples. Yet, paired normal tissues are not always available in clinical settings or for archival samples. RESULTS: We present SomVarIUS, a computational method for detecting somatic variants using high throughput sequencing data from unpaired tissue samples. We evaluate the performance of the method using genomic data from synthetic and real tumor samples. SomVarIUS identifies somatic variants in exome-seq data of ~150 * coverage with at least 67.7% precision and 64.6% recall rates, when compared with paired-tissue somatic variant calls in real tumor samples. We demonstrate the utility of SomVarIUS by identifying somatic mutations in formalin-fixed samples, and tracking clonal dynamics of oncogenic mutations in targeted deep sequencing data from pre- and post-treatment leukemia samples. AVAILABILITY AND IMPLEMENTATION: SomVarIUS is written in Python 2.7 and available at http://www.sjdlab.org/resources/ CONTACT: subhajyoti.de@ucdenver.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26589278 TI - Reliable ABC model choice via random forests. AB - MOTIVATION: Approximate Bayesian computation (ABC) methods provide an elaborate approach to Bayesian inference on complex models, including model choice. Both theoretical arguments and simulation experiments indicate, however, that model posterior probabilities may be poorly evaluated by standard ABC techniques. RESULTS: We propose a novel approach based on a machine learning tool named random forests (RF) to conduct selection among the highly complex models covered by ABC algorithms. We thus modify the way Bayesian model selection is both understood and operated, in that we rephrase the inferential goal as a classification problem, first predicting the model that best fits the data with RF and postponing the approximation of the posterior probability of the selected model for a second stage also relying on RF. Compared with earlier implementations of ABC model choice, the ABC RF approach offers several potential improvements: (i) it often has a larger discriminative power among the competing models, (ii) it is more robust against the number and choice of statistics summarizing the data, (iii) the computing effort is drastically reduced (with a gain in computation efficiency of at least 50) and (iv) it includes an approximation of the posterior probability of the selected model. The call to RF will undoubtedly extend the range of size of datasets and complexity of models that ABC can handle. We illustrate the power of this novel methodology by analyzing controlled experiments as well as genuine population genetics datasets. AVAILABILITY AND IMPLEMENTATION: The proposed methodology is implemented in the R package abcrf available on the CRAN. CONTACT: jean-michel.marin@umontpellier.fr SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26589279 TI - CDSfold: an algorithm for designing a protein-coding sequence with the most stable secondary structure. AB - MOTIVATION: An important problem in synthetic biology is to design a nucleotide sequence of an mRNA that confers a desirable expression level of a target protein. The secondary structure of protein-coding sequences (CDSs) is one potential factor that could have both positive and negative effects on protein production. To elucidate the role of secondary structure in CDSs, algorithms for manipulating secondary structure should be developed. RESULTS: We developed an algorithm for designing a CDS with the most stable secondary structure among all possible ones translated into the same protein, and implemented it as the program CDSfold. The algorithm runs the Zuker algorithm under the constraint of a given amino acid sequence. The time and space complexity is O(L(3)) and O(L(2)), respectively, where L is the length of the CDS to be designed. Although our algorithm is slower than the original Zuker algorithm, it could design a relatively long (2.7-kb) CDS in approximately 1 h. AVAILABILITY AND IMPLEMENTATION: The CDSfold program is freely available for non-commercial users as stand-alone and web-based software from http://cdsfold.trahed.jp/cdsfold/ CONTACTS: terai-goro@aist.go.jp or asai@k.u-tokyo.ac.jp SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26589280 TI - hybridSPAdes: an algorithm for hybrid assembly of short and long reads. AB - MOTIVATION: Recent advances in single molecule real-time (SMRT) and nanopore sequencing technologies have enabled high-quality assemblies from long and inaccurate reads. However, these approaches require high coverage by long reads and remain expensive. On the other hand, the inexpensive short reads technologies produce accurate but fragmented assemblies. Thus, a hybrid approach that assembles long reads (with low coverage) and short reads has a potential to generate high-quality assemblies at reduced cost. RESULTS: We describe hybridSPAdes algorithm for assembling short and long reads and benchmark it on a variety of bacterial assembly projects. Our results demonstrate that hybridSPAdes generates accurate assemblies (even in projects with relatively low coverage by long reads) thus reducing the overall cost of genome sequencing. We further present the first complete assembly of a genome from single cells using SMRT reads. AVAILABILITY AND IMPLEMENTATION: hybridSPAdes is implemented in C++ as a part of SPAdes genome assembler and is publicly available at http://bioinf.spbau.ru/en/spades CONTACT: d.antipov@spbu.ru SUPPLEMENTARY INFORMATION: supplementary data are available at Bioinformatics online. PMID- 26589281 TI - Large-scale machine learning for metagenomics sequence classification. AB - MOTIVATION: Metagenomics characterizes the taxonomic diversity of microbial communities by sequencing DNA directly from an environmental sample. One of the main challenges in metagenomics data analysis is the binning step, where each sequenced read is assigned to a taxonomic clade. Because of the large volume of metagenomics datasets, binning methods need fast and accurate algorithms that can operate with reasonable computing requirements. While standard alignment-based methods provide state-of-the-art performance, compositional approaches that assign a taxonomic class to a DNA read based on the k-mers it contains have the potential to provide faster solutions. RESULTS: We propose a new rank-flexible machine learning-based compositional approach for taxonomic assignment of metagenomics reads and show that it benefits from increasing the number of fragments sampled from reference genome to tune its parameters, up to a coverage of about 10, and from increasing the k-mer size to about 12. Tuning the method involves training machine learning models on about 10(8) samples in 10(7) dimensions, which is out of reach of standard softwares but can be done efficiently with modern implementations for large-scale machine learning. The resulting method is competitive in terms of accuracy with well-established alignment and composition-based tools for problems involving a small to moderate number of candidate species and for reasonable amounts of sequencing errors. We show, however, that machine learning-based compositional approaches are still limited in their ability to deal with problems involving a greater number of species and more sensitive to sequencing errors. We finally show that the new method outperforms the state-of-the-art in its ability to classify reads from species of lineage absent from the reference database and confirm that compositional approaches achieve faster prediction times, with a gain of 2-17 times with respect to the BWA-MEM short read mapper, depending on the number of candidate species and the level of sequencing noise. AVAILABILITY AND IMPLEMENTATION: Data and codes are available at http://cbio.ensmp.fr/largescalemetagenomics CONTACT: pierre.mahe@biomerieux.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26589283 TI - Gold nanoparticles as multimodality imaging agents for brain gliomas. AB - BACKGROUND: Nanoparticles can be used for targeted drug delivery, in particular for brain cancer therapy. However, this requires a detailed analysis of nanoparticles from the associated microvasculature to the tumor, not easy because of the required high spatial resolution. The objective of this study is to demonstrate an experimental solution of this problem, based in vivo and post mortem whole organ imaging plus nanoscale 3-dimensional (3D) X-ray microscopy. RESULTS: The use of gold nanoparticles (AuNPs) as contrast agents paved the way to a detailed high-resolution three dimensional (3D) X-ray and fluorescence imaging analysis of the relation between xenografted glioma cells and the tumor induced angiogenic microvasculature. The images of the angiogenic microvessels revealed nanoparticle leakage. Complementary tests showed that after endocytotic internalization fluorescent AuNPs allow the visible-light detection of cells. CONCLUSIONS: AuNP-loading of cells could be extended from the case presented here to other imaging techniques. In our study, they enabled us to (1) identify primary glioma cells at inoculation sites in mice brains; (2) follow the subsequent development of gliomas. (3) Detect the full details of the tumor related microvasculature; (4) Finding leakage of AuNPs from the tumor-related vasculature, in contrast to no leakage from normal vasculature. PMID- 26589285 TI - A Family of Routes to Substituted Phenols, Including Meta-Substituted Phenols. AB - A new family of routes to substituted phenols has been developed. 2-Bromo-3 methoxycyclohex-2-en-1-ones are readily deprotonated at C-6, and the resulting anions react smoothly with a variety of electrophiles; treatment with DBU in PhMe at room temperature then results in efficient aromatization to benzene derivatives of a regiochemically defined substitution pattern. This sequence affords phenolic azides (ArN3), sulfides (ArSR, ArSAr'), selenides (ArSePh), alcohols [ArCH(OH)R], amino derivatives [ArCH(NHSO2Ar')R), and 1,2-benzenediols. A complementary set of substitution patterns is obtained by DIBAL-H reduction or reaction with a Grignard reagent before aromatization; the latter process gives compounds in which the newly introduced substituent is meta to the phenolic hydroxyl. PMID- 26589282 TI - Transcriptomic profiling of host-parasite interactions in the microsporidian Trachipleistophora hominis. AB - BACKGROUND: Trachipleistophora hominis was isolated from an HIV/AIDS patient and is a member of a highly successful group of obligate intracellular parasites. METHODS: Here we have investigated the evolution of the parasite and the interplay between host and parasite gene expression using transcriptomics of T. hominis-infected rabbit kidney cells. RESULTS: T. hominis has about 30% more genes than small-genome microsporidians. Highly expressed genes include those involved in growth, replication, defence against oxidative stress, and a large fraction of uncharacterised genes. Chaperones are also highly expressed and may buffer the deleterious effects of the large number of non-synonymous mutations observed in essential T. hominis genes. Host expression suggests a general cellular shutdown upon infection, but ATP, amino sugar and nucleotide sugar production appear enhanced, potentially providing the parasite with substrates it cannot make itself. Expression divergence of duplicated genes, including transporters used to acquire host metabolites, demonstrates ongoing functional diversification during microsporidian evolution. We identified overlapping transcription at more than 100 loci in the sparse T. hominis genome, demonstrating that this feature is not caused by genome compaction. The detection of additional transposons of insect origin strongly suggests that the natural host for T. hominis is an insect. CONCLUSIONS: Our results reveal that the evolution of contemporary microsporidian genomes is highly dynamic and innovative. Moreover, highly expressed T. hominis genes of unknown function include a cohort that are shared among all microsporidians, indicating that some strongly conserved features of the biology of these enormously successful parasites remain uncharacterised. PMID- 26589284 TI - May clinical neurophysiology help to predict the recovery of neurological early rehabilitation patients? AB - BACKGROUND: So far, the role of clinical neurophysiology in the prediction of outcome from neurological and neurosurgical early rehabilitation is unclear. METHODS: Clinical and neurophysiological data of a large sample of 803 early rehabilitation cases of the BDH-Clinic Hessisch Oldendorf in Northern Germany have been carefully reviewed. Most patients (43.5%) were transferred to rehabilitation after stroke, mean age was 66.6 (15.5) years. Median somatosensory (SEP), auditory (AEP) and visual evoked potentials (VEP) along with EEG recordings took place within the first two weeks after admission. Length of stay (LOS) in early rehabilitation was 38.3 (37.2) days. RESULTS: Absence of SEP on one or both sides was associated with poor outcome, chi2 = 12.98 (p = 0.005); only 12.5% had a good outcome (defined as Barthel index, BI >=50) when SEP were missing on both sides. In AEP, significantly longer bilateral latencies III were observed in the poor outcome group (p < 0.05). Flash VEP showed that patients in the poor outcome group had a significantly longer latency III on both sides (p < 0.05). The longer latency III, the smaller BI changes (BI discharge minus admission) were observed (latency III right r = -0.145, p < 0.01; left r = 0.206, p < 0.001). While about half of the patients with alpha EEG activity belonged to the good outcome group (80/159, 50.3%), only 39/125 (31.2%) with theta and 5/41 (12.2%) with delta rhythm had a favourable outcome, chi2 = 24.2, p < 0.001. CONCLUSIONS: Results from this study suggest that loss of median SEP, prolongation of wave III in AEP and flash-VEP as well as theta or delta rhythms in EEG are associated with poor outcome from neurological early rehabilitation. Further studies on this topic are strongly encouraged. PMID- 26589286 TI - St. Jude Medical Trifecta aortic valve: results from a prospective regional multicentre registry. AB - BACKGROUND: The Trifecta aortic bioprosthesis (St. Jude Medical, Inc., St. Paul, MN, USA) is a stented pericardial heart valve with excellent preliminary results. Aim of the study was to evaluate its early clinical and hemodynamic performances in a multicenter regional registry. METHODS: Between January 2011 and June 2012, 178 consecutive patients undergoing aortic valve replacement with the Trifecta bioprosthesis were prospectively enrolled at 9 Italian centers. Clinical and echocardiographic data were collectedat discharge, 6-months and at 1-year postoperatively. RESULTS: The average age was 75.4 +/- 7.7 years,and 95 (53 %) were men. Indication for valve replacement included stenosis in 123 patients (69 %), mixed lesions in 25 (14 %), and regurgitation in 30 (17 %). Ninety-three (52 %) patients were in NYHA functional class III/ IV. Hospital mortality accounted for 5 (2.8 %) patients. No valve-related perioperative complications were encountered. Median follow-up was 20.5 months (range: 1-34). Early (<=6 months) complications included one thromboembolic event, one major bleeding, and 3 endocarditis (2 explants). Two late (>6 months) thromboembolic events and two endocarditis (1 explant) were registered. No valve thrombosis or structural deterioration were observed after discharge. At 30-months, freedom from all-cause mortality was 87 %, freedom from valve-related mortality 99.4 %, freedom from endocarditis 97.5 %, and freedom from valve explants 98 %. At 1-year, mean gradients ranged from 8 to 16 mmHg, and effective orifice area indexes from 1.0 to 1.2 cm(2)/m(2) for valve sizes from 19 to 27 mm, respectively. No patients had severe prosthesis-patient mismatch. CONCLUSIONS: Trifecta bioprosthesis provided favourable clinical and hemodynamic results over time. PMID- 26589287 TI - Pathobiochemical signatures of cholestatic liver disease in bile duct ligated mice. AB - BACKGROUND: Disrupted bile secretion leads to liver damage characterized by inflammation, fibrosis, eventually cirrhosis, and hepatocellular cancer. As obstructive cholestasis often progresses insidiously, markers for the diagnosis and staging of the disease are urgently needed. To this end, we compiled a comprehensive data set of serum markers, histological parameters and transcript profiles at 8 time points of disease progression after bile duct ligation (BDL) in mice, aiming at identifying a set of parameters that could be used as robust biomarkers for transition of different disease progression phases. RESULTS: Statistical analysis of the more than 6,000 data points revealed distinct temporal phases of disease. Time course correlation analysis of biochemical, histochemical and mRNA transcript parameters (=factors) defined 6 clusters for different phases of disease progression. The number of CTGF-positive cells provided the most reliable overall measure for disease progression at histological level, bilirubin at biochemical level, and metalloproteinase inhibitor 1 (Timp1) at transcript level. Prominent molecular events exhibited by strong transcript peaks are found for the transcriptional regulator Nr0b2 (Shp) and 1,25-dihydroxyvitamin D(3) 24-hydroxylase (Cyp24a1) at 6 h. Based on these clusters, we constructed a decision tree of factor combinations potentially useful as markers for different time intervals of disease progression. Best prediction for onset of disease is achieved by fibronectin (Fn1), for early disease phase by Cytochrome P450 1A2 (Cyp1a2), passage to perpetuation phase by collagen1alpha-1 (Col1a1), and transition to the progression phase by interleukin 17-a (Il17a), with early and late progression separated by Col1a1. Notably, these predictions remained stable even for randomly chosen small sub-sets of factors selected from the clusters. CONCLUSION: Our detailed time-resolved explorative study of liver homogenates following BDL revealed a well-coordinated response, resulting in disease phase dependent parameter modulations at morphological, biochemical, metabolic and gene expression levels. Interestingly, a small set of selected parameters can be used as diagnostic markers to predict disease stages in mice with cholestatic liver disease. PMID- 26589288 TI - MiR-155 Knockout in Fibroblasts Improves Cardiac Remodeling by Targeting Tumor Protein p53-Inducible Nuclear Protein 1. AB - Cardiac remodeling caused by acute myocardial infarction (AMI) represents a major challenge for heart failure research. MiR-155 has been identified as a key mediator of cardiac inflammation and hypertrophy. In this study, we investigate the role of miR-155 in cardiac remodeling induced by AMI. We demonstrate that miR 155 expressed in cardiac fibroblasts is a potent contributor to cardiac remodeling. We reveal that in vivo, miR-155 knockout improves left ventricular function, reduces infarct size, and attenuates collagen deposition, whereas overexpression of miR-155 produces the opposite effects. MiR-155 knockout also inhibits cardiac fibroblast proliferation and differentiation into myofibroblasts. In addition, downregulation of tumor protein p53-inducible nuclear protein 1 (TP53INP1) by small interfering RNA reverses the effects of miR 155 knockout on cardiac fibroblasts. Our data reveal that knockout of miR-155 in cardiac fibroblasts improves cardiac remodeling by targeting TP53INP1, which may be a novel treatment strategy for cardiac remodeling. PMID- 26589289 TI - Effect of Elevated Reperfusion Pressure on "No Reflow" Area and Infarct Size in a Porcine Model of Ischemia-Reperfusion. AB - BACKGROUND: The "no reflow" phenomenon (microvascular obstruction despite restoration of epicardial blood flow) develops postreperfusion in acute myocardial infarction and is associated with poor prognosis. We hypothesized that increased reperfusion pressure may attenuate the no reflow phenomenon, as it could provide adequate flow to overcome the high resistance of the microvasculature within the no reflow zone. Thus, we investigated the effect of modestly elevated blood pressure during reperfusion on the extent of no reflow area and infarct size in a porcine model of ischemia-reperfusion. METHODS: Eighteen farm pigs underwent acute myocardial infarction by occlusion of the anterior descending coronary artery for 1 hour, followed by 2 hours of reperfusion. Just prior to reperfusion, animals were randomized into 2 groups: in group 1 (control group, n = 9), no intervention was performed. In group 2 (n = 9), aortic pressure was increased by ~20% (compared to ischemia) by partial clamping of the ascending aorta during reperfusion. Following 2 hours of reperfusion, animals were euthanized to measure area at risk, infarct size, and area of no reflow. RESULTS: Partial clamping of the ascending aorta resulted in modest elevation of blood pressure during reperfusion. The area at risk did not differ between the 2 groups. The no reflow area was significantly increased in group 2 compared to control animals (50% +/- 13% vs 37% +/- 9% of the area at risk; P = .04). The infarcted area was significantly increased in group 2 compared to control animals (75% +/- 17% vs 52% +/- 23% of the area at risk; P = .03). Significant positive correlations were observed between systolic aortic pressure and no reflow area, between systolic aortic pressure and infarcted area and between infarcted area and no reflow area during reperfusion. CONCLUSIONS: Modestly elevated blood pressure during reperfusion is associated with an increase in no reflow area and in infarct size in a clinically relevant porcine model of ischemia-reperfusion. PMID- 26589290 TI - Relaxin' the Heart: A Novel Therapeutic Modality. AB - The peptide hormone relaxin has traditionally been linked to the maternal adaptation of the cardiovascular system during the first trimester of pregnancy. By promoting nitric oxide formation through different molecular signaling events, relaxin has been proposed as a pleiotropic and cardioprotective hormone in the setting of many cardiovascular diseases. In fact, preclinical studies were able to demonstrate that relaxin promotes vasodilatation and angiogenesis, ameliorates ischemia/reperfusion injury, and regulates extracellular matrix turnover and remodeling. In the RELAX-AHF phase 3 clinical trial, serelaxin (recombinant human relaxin) was shown to be safe, and it exerted survival benefits in patients with acute heart failure. RELAX-AHF-2 is currently ongoing, and it aims to address a larger population and evaluate harder clinical outcomes. Besides heart failure, acute myocardial infarction, peripheral arterial disease, and stable coronary disease could be target diseases for treatment with serelaxin in future clinical trials. PMID- 26589291 TI - Prevalence of dyslipidemia and associated factors among the hypertensive population from rural Northeast China. AB - BACKGROUND: Our latest study reported the grim status of hypertension in rural China with the prevalence of hypertension reached 51.1%. However, we lack the latest data about the prevalence and epidemiological features of dyslipidemia among hypertensive residents in rural China. METHODS: A cross-sectional survey was conducted from July 2012 to August 2013 through a cluster multistage sampling to a resident group of 4048 individuals (2152 men, 2896 women) with hypertension, age >= 35 years, in the rural Northeast China. Serum lipids level were proposed by National Cholesterol Education Program Adult Treatment Panel III. RESULTS: Of the hypertension residents without antihypertension treatment, 34.5% had borderline high total cholesterol, 19.2% had high total cholesterol, 11.4% had low high-density lipoprotein cholesterol and 37.4% had high non HDL-C. The population with borderline high, high, and very high low-density lipoprotein cholesterol was 20.9, 6.7 and 2.3%, respectively. In addition, 14.3% had borderline high triglycerides, 17.4% had high TG and 2.4% had very high TG. The awareness rate of dyslipidemia among the study population was 5.9%. After adjusting for independent variables, fasting plasma glucose, body mass index, Han nationality, current drinking and smoking, higher annual income and classification of blood pressure were risk factors for dyslipidemia while moderate physical activity was protective factor for dyslipidemia. On the contrary, gender and current drinking decrease the risk of HDL-C. CONCLUSION: The prevalence of dyslipidemia was dramatically high and dyslipidemia screening was in-need in all diagnosed hypertensive individuals. PMID- 26589292 TI - Experimental infection of a US spike-insertion deletion porcine epidemic diarrhea virus in conventional nursing piglets and cross-protection to the original US PEDV infection. AB - Although the original US porcine epidemic diarrhea virus (PEDV) was confirmed as highly virulent by multiple studies, the virulence of spike-insertion deletion (S INDEL) PEDV strains is undefined. In this study, 3-4 day-old conventional suckling piglets were inoculated with S-INDEL PEDV Iowa106 (4 pig litters) to study its virulence. Two litters of age-matched piglets were inoculated with either the original US PEDV PC21A or mock as positive and negative controls, respectively. Subsequently, all pigs were challenged with the original US PEDV PC21A on 21-29 days post-inoculation (dpi) to assess cross-protection. All S INDEL Iowa106- and the original US PC21A-inoculated piglets developed diarrhea. However, the severity of clinical signs, mortality (0-75%) and fecal PEDV RNA shedding titers varied among the four S-INDEL Iowa106-inoculated litters. Compared with the original PC21A, piglets euthanized/died acutely from S-INDEL Iowa106 infection had relatively milder villous atrophy, lower antigen scores and more limited intestinal infection. Two of four S-INDEL Iowa106-infected sows and the original PC21A-infected sow showed anorexia and watery diarrhea for 1-4 days. After the original PC21A challenge, a subset (13/16) of S-INDEL Iowa106 inoculated piglets developed diarrhea, whereas all (5/5) and no (0/4) pigs in the mock and original PC21A-inoculated pigs had diarrhea, respectively. Our results suggest that the virulence of S-INDEL PEDV Iowa106 was less than the original US PEDV PC21A in suckling pigs, with 100% morbidity and 18% (6/33) overall (0-75%) mortality in suckling pigs depending on factors such as the sow's health and lactation and the piglets' birth weight. Prior infection by S-INDEL Iowa106 provided partial cross-protection to piglets against the original PC21A challenge at 21-29 dpi. PMID- 26589293 TI - TCLP: an online cancer cell line catalogue integrating HLA type, predicted neo epitopes, virus and gene expression. AB - Human cancer cell lines are an important resource for research and drug development. However, the available annotations of cell lines are sparse, incomplete, and distributed in multiple repositories. Re-analyzing publicly available raw RNA-Seq data, we determined the human leukocyte antigen (HLA) type and abundance, identified expressed viruses and calculated gene expression of 1,082 cancer cell lines. Using the determined HLA types, public databases of cell line mutations, and existing HLA binding prediction algorithms, we predicted antigenic mutations in each cell line. We integrated the results into a comprehensive knowledgebase. Using the Django web framework, we provide an interactive user interface with advanced search capabilities to find and explore cell lines and an application programming interface to extract cell line information. The portal is available at http://celllines.tron-mainz.de. PMID- 26589294 TI - Comparison of four decontamination treatments on porcine renal decellularized extracellular matrix structure, composition, and support of human renal cortical tubular epithelium cells. AB - Engineering whole organs from porcine decellularized extracellular matrix and human cells may lead to a plentiful source of implantable organs. Decontaminating the porcine decellularized extracellular matrix scaffolds is an essential step prior to introducing human cells. However, decontamination of whole porcine kidneys is a major challenge because the decontamination agent or irradiation needs to diffuse deep into the structure to eliminate all microbial contamination while minimizing damage to the structure and composition of the decellularized extracellular matrix. In this study, we compared four decontamination treatments that could be applicable to whole porcine kidneys: 70% ethanol, 0.2% peracetic acid in 1 M NaCl, 0.2% peracetic acid in 4% ethanol, and gamma (gamma) irradiation. Porcine kidneys were decellularized by perfusion of 0.5% (w/v) aqueous solution of sodium dodecyl sulfate and the four decontamination treatments were optimized using segments (n = 60) of renal tissue to ensure a consistent comparison. Although all four methods were successful in decontamination, gamma-irradiation was very damaging to collagen fibers and glycosaminoglycans, leading to less proliferation of human renal cortical tubular epithelium cells within the porcine decellularized extracellular matrix. The effectiveness of the other three optimized solution treatments were then all confirmed using whole decellularized porcine kidneys (n = 3). An aqueous solution of 0.2% peracetic acid in 1 M NaCl was determined to be the best method for decontamination of porcine decellularized extracellular matrix. PMID- 26589295 TI - Evaluation of the biocompatibility of regenerated cellulose hydrogels with high strength and transparency for ocular applications. AB - Prompt emergency treatment for ocular injury, particularly in a battlefield setting, is essential to preserve vision, reduce pain, and prevent secondary infection. A bandage contact lens that could be applied in the field, at the time of injury, would protect the injured ocular surface until hospital treatment is available. Cellulose, a natural polymer, is widely used in biomedical applications including bandage materials. Hydrogels synthesized from different cellulose sources, such as plants, cotton, and bacteria, can have the optical transparency and mechanical strength of contact lenses, by tailoring synthesis parameters. Thus, we optimized the fabrication of cellulose-based hydrogels and evaluated their in vivo biocompatibility and related physical properties. Our data demonstrate that along with tailorable physical properties, our novel cellulose-based hydrogels could be made with contact lens geometry, exhibit no significant signs of material toxicity after 22 days of in vivo testing, and show significant promise for use as a corneal bandage immediately following ocular trauma. PMID- 26589296 TI - Three-dimensional plotted hydroxyapatite scaffolds with predefined architecture: comparison of stabilization by alginate cross-linking versus sintering. AB - Scaffolds for bone tissue engineering are essentially characterized by porous three-dimensional structures with interconnected pores to facilitate the exchange of nutrients and removal of waste products from cells, thereby promoting cell proliferation in such engineered scaffolds. Although hydroxyapatite is widely being considered for bone tissue engineering applications due to its occurrence in the natural extracellular matrix of this tissue, limited reports are available on additive manufacturing of hydroxyapatite-based materials. In this perspective, hydroxyapatite-based three-dimensional porous scaffolds with two different binders (maltodextrin and sodium alginate) were fabricated using the extrusion method of three-dimensional plotting and the results were compared in reference to the structural properties of scaffolds processed via chemical stabilization and sintering routes, respectively. With the optimal processing conditions regarding to pH and viscosity of binder-loaded hydroxyapatite pastes, scaffolds with parallelepiped porous architecture having up to 74% porosity were fabricated. Interestingly, sintering of the as-plotted hydroxyapatite-sodium alginate (cross-linked with CaCl2 solution) scaffolds led to the formation of chlorapatite (Ca9.54P5.98O23.8Cl1.60(OH)2.74). Both the sintered scaffolds displayed progressive deformation and delayed fracture under compressive loading, with hydroxyapatite-alginate scaffolds exhibiting a higher compressive strength (9.5 +/- 0.5 MPa) than hydroxyapatite-maltodextrin scaffolds (7.0 +/- 0.6 MPa). The difference in properties is explained in terms of the phase assemblage and microstructure. PMID- 26589298 TI - Airway management in a child with Treacher Collins syndrome using C-MAC videolaryngoscope. PMID- 26589297 TI - Fibroblast-loaded cholecyst-derived scaffold induces faster healing of full thickness burn wound in rabbit. AB - Graft-assisted healing is often proposed for clinical management of large-sized third-degree cutaneous burn wounds. Skin-graft substitutes prepared by loading appropriate cell types on suitable scaffolds have been found successful. We have previously shown that cholecyst-derived scaffold prepared by a non detergent/enzymatic method can be used as skin-graft substitute for promoting healing of full thickness excision wounds in rabbit. This article examines the use of this scaffold for preparing bio-artificial grafts by loading homologous fibroblasts. The healing potential was evaluated in a rabbit model of full thickness skin-burn wound. The healing process was evaluated by gross morphology evaluation and histomorphology evaluation at 7, 14 and 28 days of healing. Ex vivo imaging of the wounded tissue was performed and it was found that the loaded fibroblasts remained viable at least for 14 days in the healing wound. By the first week, re-epithelialisation was evident in all animals treated with the cell loaded graft. Histomorphological wound healing parameters such as the quickness of re-epithelialisation, the nature of collagen deposition and the extent of neo vascularisation indicated that cell-loaded grafts promoted faster healing of the wounds. Results of immunohistochemistry indicated a parallel change in the number of proliferating cells and myofibroblast in the healing tissue. Although the pathophysiology of the healing reaction was not established, the observations suggested that homologus fibroblast-loaded cholecyst-derived scaffold promoted faster healing of third-degree wounds in rabbit model by modulating myofibroblast response. It was concluded that cholecyst-derived scaffold prepared by the non detergent/enzymatic method is a potential scaffold for fabricating bioartificial skin grafts. PMID- 26589299 TI - Internal hernia after laparoscopic gastrectomy with Roux-en-Y reconstruction for gastric cancer. AB - BACKGROUND/OBJECTIVE: Laparoscopic gastrectomy (LG) is increasingly used to treat gastric cancer. Simultaneously, internal hernia (IH) has been reported after LG with Roux-en-Y reconstruction (RY). The aim of this study was to investigate IH after LG with RY for gastric cancer. METHODS: This study included 15 patients with IH from a database of 355 consecutive patients who underwent LG with RY for gastric cancers. We retrospectively analyzed IH incidence and clinical characteristics by operative procedures. RESULTS: The total incidence of IH was 4.2%. The incidence of IH at Petersen's defect tended to decrease with modifications to the reconstruction methods, but not significantly so. The incidence of IH at jejunojejunostomy mesenteric defect significantly decreased with closure of this defect (p = 0.01). The incidence of IH at transverse mesocolic defect was 1.3% in patients who underwent retrocolic RY; emergent small bowel resection was only required in two cases of herniation through this defect after laparoscopic total gastrectomy. CONCLUSION: Retrocolic RY with appropriate closure of defects can reduce IH incidence at Petersen's defect and at jejunojejunostomy mesenteric defect. Although the IH incidence at the transverse mesocolic defect is not particularly high, the possibility of herniation through this defect should be kept in mind. PMID- 26589300 TI - Early family regularity protects against later disruptive behavior. AB - Infants' temperamental anger or frustration reactions are highly stable, but are also influenced by maturation and experience. It is yet unclear why some infants high in anger or frustration reactions develop disruptive behavior problems whereas others do not. We examined family regularity, conceptualized as the consistency of mealtime and bedtime routines, as a protective factor against the development of oppositional and aggressive behavior. This study used prospectively collected data from 3136 families participating in the Generation R Study. Infant anger or frustration reactions and family regularity were reported by mothers when children were ages 6 months and 2-4 years, respectively. Multiple informants (parents, teachers, and children) and methods (questionnaire and interview) were used in the assessment of children's oppositional and aggressive behavior at age 6. Higher levels of family regularity were associated with lower levels of child aggression independent of temperamental anger or frustration reactions (beta = -0.05, p = 0.003). The association between child oppositional behavior and temperamental anger or frustration reactions was moderated by family regularity and child gender (beta = 0.11, p = 0.046): family regularity reduced the risk for oppositional behavior among those boys who showed anger or frustration reactions in infancy. In conclusion, family regularity reduced the risk for child aggression and showed a gender-specific protective effect against child oppositional behavior associated with anger or frustration reactions. Families that ensured regularity of mealtime and bedtime routines buffered their infant sons high in anger or frustration reactions from developing oppositional behavior. PMID- 26589301 TI - Zinc enhances the number of regulatory T cells in allergen-stimulated cells from atopic subjects. AB - PURPOSE: The trace element zinc is essential for immune function and its regulation. Since zinc deficiency and allergic hyperresponsive reactions are often accompanied, the influence of zinc on allergen-induced cell growth, CD4+ regulatory T (Treg) cell numbers and cytokine expression during allergic immune reactions was investigated. METHODS: Peripheral blood mononuclear cells (PBMCs) from non-atopic and atopic subjects were treated with timothy grass allergen pre incubated with or without zinc. Proliferation was determined by analyzing the incorporation of 3H-thymidine. Intracellular zinc and Foxp3 levels and cell surface antigens were measured by FACS, cytokine expression by ELISA and real time PCR. RESULTS: Incubation with 50 MUM zinc sulfate (Zn50) enhances cytosolic zinc concentrations in CD3+ T cells. The data also reveal that the combination of Zn50 plus allergen significantly reduces PBMC proliferation of atopic subjects. Additionally, Zn50 plus allergen enhances Th1 cytokine responses shown by increased interferon (IFN)-gamma/interleukin (IL)-10 ratios as well as enhanced tumor necrosis factor-alpha release. In response to allergen, zinc increases Treg cells and upregulates the mRNA expression of cytotoxic T-lymphocyte antigen-4 in atopic subjects. Interestingly, Zn50 alone leads to an increase of CD4+CD25high(hi)+ cells in atopic and non-atopic subjects. CONCLUSIONS: Zinc may regulate unwanted hyperresponsive immune reactions by suppressing proliferation through a significant shift from IL-10 to the Th1 cytokine IFN-gamma, and enhanced regulatory T cell numbers. Therefore, zinc supplementation may be a promising tool for the therapy of allergies, without negatively affecting the immune system. PMID- 26589302 TI - Intakes of whole grain in an Italian sample of children, adolescents and adults. AB - PURPOSE: There is wide evidence that regular consumption of whole grain foods may reduce the risk of chronic diseases. The aim of this work was to quantify the intake of whole grains and identify main dietary sources in the Italian population. METHODS: Whole grain intakes were calculated in a sample of 2830 adults/older adults and of 440 children/adolescents from the last national survey INRAN-SCAI 2005-06. Food consumption was assessed from a 3-day food record. The whole grain content of foods was estimated mainly from quantitative ingredient declarations on labels. RESULTS: Mean whole grain intakes were 3.7 g/day in adults/older adults and 2.1 g/day in children/adolescents. Overall, 23 % of the sample reported consumption of whole grain foods during the survey, among which mean whole grain intakes ranged from 6.0 g/day in female children to 19.1 g/day in female older adults. The main sources of whole grains were breakfast cereals in children/adolescents (32 %) and bread in adults/older adults (46 %). Consumption of whole grain among adults was associated with significantly higher daily intakes and adequacy of dietary fibre, several vitamins (thiamine, riboflavin, vitamin B6) and minerals (iron, calcium, potassium, phosphorus, zinc, magnesium) compared to non-consumption. Among children, whole grain intake was associated with significantly higher intakes of iron and magnesium. CONCLUSIONS: The study reveals very low whole grain intakes across all age groups of the Italian population. Considering the positive association in consumers between whole grain intakes and fibre and micro-nutrient intakes, public health strategies to increase whole grain consumption should be considered. PMID- 26589303 TI - Development of a screening MRI for infants at risk for abusive head trauma. AB - BACKGROUND: Abusive head trauma (AHT) is an important cause of morbidity in infants. Identifying which well-appearing infants are at risk for AHT and need neuroimaging is challenging, and concern about radiation exposure limits the use of head CT. Availability of an MRI protocol that is highly sensitive for intracranial hemorrhage would allow for AHT screening of well-appearing infants without exposing them to radiation. OBJECTIVE: To develop a screening MRI protocol to identify intracranial hemorrhage in well-appearing infants at risk for AHT. MATERIALS AND METHODS: Infants enrolled in a parent study of well appearing infants at increased risk for AHT were eligible for the current study if they underwent both head CT and conventional brain MRI. A derivation cohort of nine infants with AHT was used to identify sequences that provided the highest sensitivity for intracranial hemorrhage. A validation cohort of 78 infants including both controls with normal neuroimaging and cases with AHT was used to evaluate the accuracy of the selected sequences. RESULTS: Three pulse sequences - axial T2, axial gradient recalled echo (GRE) and coronal T1-W inversion recovery were 100% sensitive for intracranial hemorrhage in the derivation cohort. The same sequences were 100% sensitive (25/25) and 83% specific (44/53) for intracranial hemorrhage in the validation cohort. CONCLUSION: A screening MRI protocol including axial T2, axial GRE and coronal T1-W inversion recovery sequences is highly sensitive for intracranial hemorrhage and may be useful as a screening tool to differentiate well-appearing infants at risk for AHT who should undergo head CT from those who can safely be discharged without head CT. Additional research is needed to evaluate the feasibility of this approach in clinical practice. PMID- 26589304 TI - Fetal suprarenal masses--assessing the complementary role of magnetic resonance and ultrasound for diagnosis. AB - OBJECTIVE: To assess the value and complementary roles of fetal MRI and US for characterization and diagnosis of suprarenal masses. MATERIALS AND METHODS: We conducted a multi-institutional retrospective database search for prenatally diagnosed suprarenal masses between 1999 and 2012 and evaluated the roles of prenatal US and fetal MRI for characterization and diagnosis, using postnatal diagnosis or surgical pathology as the reference standard. Prenatal US and fetal MRI were assessed for unique findings of each modality. RESULTS: The database yielded 25 fetuses (gestational age 20-37 weeks) with suprarenal masses. Twenty one fetuses had prenatal US, 22 had MRI, 17 had both. Postnatal diagnoses included nine subdiaphragmatic extralobar sequestrations, seven adrenal hemorrhages, five neuroblastomas (four metastatic), two lymphatic malformations, one duplex kidney with upper pole cystic dysplasia, and one adrenal hyperplasia. Ultrasound was concordant with MRI for diagnoses in 12/17 (70.6%) cases. Discordant diagnoses between US and MRI included three neuroblastomas and two adrenal hemorrhages. In the three neuroblastomas US was equivocal and MRI was definitive for neuroblastoma, demonstrating heterogeneous, intermediate-signal solid masses and liver metastases. In the two cases of adrenal hemorrhage US was equivocal and MRI was definitive with signal characteristics of hemorrhage. In 2/4 neuroblastomas, Doppler US demonstrated a systemic artery suggesting extralobar sequestration; however MRI signal characteristics correctly diagnosed neuroblastoma. All cases of extralobar sequestration were correctly diagnosed by US and MRI. CONCLUSION: US and MRI both accurately detect suprarenal masses. MRI complements US in equivocal diagnoses and detects additional findings such as liver metastases in neuroblastoma. PMID- 26589305 TI - Factors influencing the diagnostic yield and accuracy of image-guided percutaneous needle biopsy of pediatric tumors: single-center audit of a 26-year experience. AB - BACKGROUND: Image-guided percutaneous core needle biopsy is a common procedure for diagnosis of both solid tumors and hematological malignancies in children. Despite recent improvements, a certain rate of non-diagnostic biopsies persists. OBJECTIVE: To assess the factors influencing the diagnostic yield and accuracy of percutaneous core needle biopsies of pediatric tumors. MATERIALS AND METHODS: We conducted a single-center retrospective study of a 26-year experience with image guided biopsies in children and young adults. Using uni- and multivariate analysis, we evaluated the association of diagnostic yield and accuracy with technical factors (image-guided procedure, pathological technique) and clinical factors (complication rate, histological type and anatomical location). RESULTS: We retrieved data relating to 396 biopsies were performed in 363 children and young adults (mean age: 7.4 years). Overall, percutaneous core needle biopsy showed a diagnostic yield of 89.4% (95% confidence interval [CI] 85.9-92.2) and an accuracy of 90.9% (CI 87.6-93.6) with a complication rate of 2.5% (CI 1.2 4.6).The diagnostic yield increased with the use of advanced tissue assessment techniques (95.7% with immunohistochemistry versus 82.3% without immunohistochemistry; P < 0.0001) and an increased number of passes (mean: 3.96 for diagnostic biopsies versus 3.62 for non-diagnostic biopsies; P = 0.044). CONCLUSION: The use of advanced pathological techniques and an increased number of passes are the two main factors influencing the diagnostic success of biopsies in pediatric tumors. PMID- 26589306 TI - [Torsional osteotomy : Operative treatment of patellofemoral maltracking]. AB - BACKGROUND: Patellofemoral maltracking may congenitally be caused by excessive internal maltorsion of the femur and/or excessive external maltorsion of the tibia. OBJECTIVE: Pain relief, femoropatellar stability, well-balanced charge of femoral and patellar cartilage. INDICATIONS: Anterior knee pain, patellar instability, associated with "inwardly pointing knee" syndrome. CONTRAINDICATIONS: Open physes, > 50 years, chronic/fixed patella luxation, congenital connective tissue and bone healing disorders. SURGICAL TECHNIQUE: Analysis of leg geometry and patellofemoral anatomy. Knee arthroscopy. Supracondylar external torsional osteotomy of the femur: medial approach, ventral shift of vastus medialis muscle. Definition of osteotomy plane. Torsion control. Complete transversal osteotomy. Acute external torsional correction. Fixation with internal plate. Supratuberositary internal torsional osteotomy of the tibia: exposure of lateral tibial head, detachment of the tibialis anterior muscle. Partial chisel osteotomy of the proximal tibial tuberosity. Definition of supratuberositary osteotomy plane. Torsion control with Schanz screws. Bending of a DC plate (DCP). Complete transversal osteotomy. Acute internal torsional correction and fixation with prebent DCP. With internal torsional correction > 10 degrees , decompression of the peroneal nerve and proximal tibialis anterior fasciotomy. POSTOPERATIVE MANAGEMENT: Neurovascular and muscle function follow up. On postsurgery day 1, drainage removal, x-ray control, mobilization. Partial weight bearing (20 kg) for 4 weeks with stepwise load increments. Active/passive exercises. Thromboprophylaxis. RESULTS: In 25 patients, 30 external torsional osteotomies of the supracondylar femur with 13.8 degrees (5-26 degrees ); in 45 patients, 53 internal torsional osteotomies of the supratuberositary tibial head with an average 10.8 degrees (5-18 degrees ). No persisting compartment syndrome or infection. One non-union healed after revision. One dysfunction of the peroneal nerve resolved with time. No subluxation or redislocation of the patella. Anterior knee pain decreased significantly in both groups. PMID- 26589307 TI - Antihypertensive Medications, Loop Diuretics, and Risk of Hip Fracture in the Elderly: A Population-Based Cohort Study of 81,617 Italian Patients Newly Treated Between 2005 and 2009. AB - OBJECTIVE: Our objective was to assess the relationship between antihypertensive drugs, loop diuretics, and the risk of hospitalization for hip fracture (HF). DESIGN: We conducted a population-based study in a cohort of 81,617 patients from Lombardy (Italy) aged 70-90 years who were newly treated with antihypertensive agents or loop diuretics between 2005 and 2009. Cases were the 2153 patients who experienced the outcome (hospitalization for HF before 31 December 2012). For each case, up to three controls were randomly selected from the cohort to be matched for sex, age at cohort entry, and date of initial prescription. The case control and case-crossover designs and the logistic regression for matched sets were used to measure the strength of the association between current use of an antihypertensive drug (within 30 days before the HF hospitalization) and the risk of outcome. RESULTS: Case-control and case-crossover odds ratios (ORs) for current use of loop diuretics were 1.67 (95% confidence interval [CI] 1.28-2.18) and 1.49 (95% CI 1.05-2.10), respectively. Among patients aged 81-90 years, case control and case-crossover ORs were 1.52 (95% CI 1.04-2.21) and 1.82 (95% CI 1.10 3.00) for current use of loop diuretics and 1.86 (95% CI 1.03-3.35) and 1.88 (95% CI 1.01-3.48) for alpha-blockers. No other agent was associated with the outcome. CONCLUSIONS: Evidence that loop diuretics and alpha-blockers are associated with a higher risk of HF was consistent in the two observational approaches. Clinicians should carefully consider the risk of falls in their selection of drugs for hypertension and in the clinical use of loop diuretics. PMID- 26589308 TI - BDDCS Predictions, Self-Correcting Aspects of BDDCS Assignments, BDDCS Assignment Corrections, and Classification for more than 175 Additional Drugs. AB - The biopharmaceutics drug disposition classification system was developed in 2005 by Wu and Benet as a tool to predict metabolizing enzyme and drug transporter effects on drug disposition. The system was modified from the biopharmaceutics classification system and classifies drugs according to their extent of metabolism and their water solubility. By 2010, Benet et al. had classified over 900 drugs. In this paper, we incorporate more than 175 drugs into the system and amend the classification of 13 drugs. We discuss current and additional applications of BDDCS, which include predicting drug-drug and endogenous substrate interactions, pharmacogenomic effects, food effects, elimination routes, central nervous system exposure, toxicity, and environmental impacts of drugs. When predictions and classes are not aligned, the system detects an error and is able to self-correct, generally indicating a problem with initial class assignment and/or measurements determining such assignments. PMID- 26589309 TI - Novel Injectable Pentablock Copolymer Based Thermoresponsive Hydrogels for Sustained Release Vaccines. AB - The need for multiple vaccinations to enhance the immunogenicity of subunit vaccines may be reduced by delivering the vaccine over an extended period of time. Here, we report two novel injectable pentablock copolymer based thermoresponsive hydrogels made of polyethyleneglycol-polycaprolactone polylactide-polycaprolactone-polyethyleneglycol (PEG-PCL-PLA-PCL-PEG) with varying ratios of polycaprolactone (PCL) and polylactide (PLA), as single shot sustained release vaccines. Pentablock copolymer hydrogels were loaded with vaccine-encapsulated poly lactic-co-glycolic acid nanoparticles (PLGA-NP) or with the soluble vaccine components. Incorporation of PLGA-NP into the thermoresponsive hydrogels increased the complex viscosity of the gels, lowered the gelation temperature, and minimized the burst release of antigen and adjuvants. The two pentablock hydrogels stimulated both cellular and humoral responses. The addition of PLGA-NP to the hydrogels sustained immune responses for up to 49 days. The polymer with a higher ratio of PCL to PLA formed a more rigid gel, induced stronger immune responses, and stimulated effective anti-tumor responses in a prophylactic melanoma tumor model. PMID- 26589310 TI - Heterologous Expression in Yeast of Human Ornithine Carriers ORNT1 and ORNT2 and of ORNT1 Alleles Implicated in HHH Syndrome in Humans. AB - Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is an autosomal recessive metabolic disorder usually presenting in the neonatal period with intermittent episodes of hyperammonemia, psychomotor delay, and progressive encephalopathy. Adult cases usually evolve into frank spastic paraparesis. The syndrome is caused by mutations in SLC25A15/ORNT1 encoding the mitochondrial ornithine transporter; a second ornithine transporter, ORNT2 of unknown function, is also present in most placental mammals. ORNT2 is believed to originate from an ancient retro-transposition event. In yeast Saccharomyces cerevisiae the major function of the transporter (encoded by Arg11) is to shuttle ornithine from the mitochondrial matrix to the cytosol. Its inactivation abolishes growth in the absence of arginine.In this work, we used functional complementation in S. cerevisiae to characterize the function of human ORNT2 and to test the pathogenicity of ORNT1 mutations found in HHH patients. Notably, we found that human ORNT1 but not ORNT2 complements the deletion of the yeast gene, despite their high level of homology. However, we identified some key residues in ORNT2, which may recover its functional competence when replaced with the corresponding residues of ORNT1, suggesting that roles of the two transporters are different. Moreover, we used this system to test a series of missense mutations of ORNT1 identified in patients with HHH syndrome. All mutations had a detrimental effect on the functionality of the human gene, without however clear genotype-phenotype correlations. Our data support yeast as a simple and effective model to validate missense mutations occurring in patients with HHH. PMID- 26589311 TI - Inborn Errors of Metabolism in the United Arab Emirates: Disorders Detected by Newborn Screening (2011-2014). AB - This study reports on the inborn errors of metabolism (IEM) detected by our national newborn screening between 2011 and 2014. One hundred fourteen patients (55 UAE citizens and 59 residents) were diagnosed during this period. The program was most comprehensive (tested 29 IEM) and universally applied in 2013, giving an incidence of 1 in 1,787 citizens. This relatively high prevalence resulted from the frequent consanguineous marriages (81.5%) among affected families. The following eight disorders accounted for 80% of the entities: biotinidase deficiency (14 of 55), phenylketonuria (11 of 55), 3-methylcrotonyl glycinuria (9 of 55), medium-chain acyl-CoA dehydrogenase deficiency (4 of 55), argininosuccinic aciduria, glutaric aciduria type 1, glutaric aciduria type 2, and methylmalonyl-CoA mutase deficiency (2 of 55 each). Mutation analysis was performed in 48 (87%) of the 55 patients, and 33 distinct mutations were identified. Twenty-nine (88%) mutations were clinically significant and, thus, could be included in our premarital screening. Most mutations were homozygous, except for the biotinidase deficiency. The BTD mutations c.1207T>G (found in citizens) and c.424C>A (found in Somalians) were associated with undetectable biotinidase activity. Thus, the high prevalence of IEM in our region is amenable to newborn and premarital screening, which is expected to halt most of these diseases. PMID- 26589312 TI - Novel Report of Phosphoserine Phosphatase Deficiency in an Adult with Myeloneuropathy and Limb Contractures. AB - Serine is a nonessential amino acid that plays a vital role in proper development and functioning of the central nervous system (CNS). Serine deficiency leads to microcephaly, intellectual disability, seizures, and psychomotor retardation in children and severe axonal neuropathy in adults. Serine deficiency syndrome is due to a deficiency of one of three enzymes in the endogenous serine biosynthesis pathway: phosphoglycerate dehydrogenase, phosphoserine transaminase, or, most rarely, phosphoserine phosphatase. Of critical importance to clinical care, serine deficiency syndrome is treatable. Herein, we describe the novel presentation of phosphoserine phosphatase deficiency in an adult. The patient had intrauterine growth restriction, lifelong intellectual disability, childhood onset epilepsy, and borderline microcephaly. In adulthood, she developed progressively severe lower extremity hypertonia, axonal neuropathy, and hand contractures. Neuropathy was complicated by non-healing wounds. Fasting plasma amino acids showed low serine and glycine. Molecular analysis revealed compound heterozygous mutations in phosphoserine phosphatase (PSPH). Treatment with oral serine resulted in improvement of plasma serine levels, decreased neuropathic pain, and subjective improvement in energy level. Although the first case of phosphoserine phosphatase deficiency was described nearly 20 years ago, only eight cases have been reported, all in children. This is the first report of phosphoserine phosphatase deficiency in an adult. PMID- 26589314 TI - SNPs and breast cancer risk prediction for African American and Hispanic women. AB - For African American or Hispanic women, the extent to which clinical breast cancer risk prediction models are improved by including information on susceptibility single nucleotide polymorphisms (SNPs) is unknown, even though these women comprise increasing proportions of the US population and represent a large proportion of the world's population. We studied 7539 African American and 3363 Hispanic women from the Women's Health Initiative. The age-adjusted 5-year risks from the BCRAT and IBIS risk prediction models were measured and combined with a risk score based on >70 independent susceptibility SNPs. Logistic regression, adjusting for age group, was used to estimate risk associations with log-transformed age-adjusted 5-year risks. Discrimination was measured by the odds ratio (OR) per standard deviation (SD) and the area under the receiver operator curve (AUC). When considered alone, the ORs for African American women were 1.28 for BCRAT, and 1.04 for IBIS. When combined with the SNP risk score (OR 1.23), the corresponding ORs were 1.39 and 1.22. For Hispanic women the corresponding ORs were 1.25 for BCRAT, and 1.15 for IBIS. When combined with the SNP risk score (OR 1.39), the corresponding ORs were 1.48 and 1.42. There was no evidence that any of the combined models were not well calibrated. Including information on known breast cancer susceptibility loci provides approximately 10 and 19% improvement in risk prediction using BCRAT for African Americans and Hispanics, respectively. The corresponding figures for IBIS are approximately 18 and 26%, respectively. PMID- 26589315 TI - Breast cancer-related lymphoedema and venepuncture: a review and evidence-based recommendations. AB - Lymphoedema is a recognised complication of axillary surgery in women with early breast cancer. Such women are widely advised to avoid venepuncture on the ipsilateral side lest this cause complications including lymphoedema. This can lead to multiple failed venepuncture attempts causing distress to both patient and healthcare professional. We reviewed current guidelines and critically appraised the evidence relating the development of lymphoedema to venepuncture to educate healthcare professionals and develop evidence-based guidelines. A systematic search of bibliographic databases was performed and an Internet search undertaken to identify patient information leaflets from societies and support groups. Seven published articles were identified together with 15 published patient information leaflets. Only one small prospective study was identified (level of evidence 2), the remainder being case-control studies (level 3) or retrospective reviews (level 4). There is no good evidence that venepuncture can precipitate lymphoedema. New, patient-centred, evidence-based recommendations for venepuncture in women with breast cancer are proposed. Whenever possible, venepuncture should be performed on the contralateral arm. If this is not readily achieved, in the absence of lymphoedema it is preferable to consider venepuncture in the ipsilateral arm or insertion of a central venous device than to make further attempts in the contralateral arm or resort to sites such as veins in the foot. In the absence of lymphoedema, venesection in the ipsilateral arm carries little, if any, risk of additional complications. We offer evidence-based, patient-centred guidelines for venepuncture in patients with breast cancer following an axillary intervention. PMID- 26589313 TI - The evolution of an integrated ultrasound curriculum (iUSC) for medical students: 9-year experience. AB - Interest in ultrasound education in medical schools has increased dramatically in recent years as reflected in a marked increase in publications on the topic and growing attendance at international meetings on ultrasound education. In 2006, the University of South Carolina School of Medicine introduced an integrated ultrasound curriculum (iUSC) across all years of medical school. That curriculum has evolved significantly over the 9 years. A review of the curriculum is presented, including curricular content, methods of delivery of the content, student assessment, and program assessment. Lessons learned in implementing and expanding an integrated ultrasound curriculum are also presented as are thoughts on future directions of undergraduate ultrasound education. Ultrasound has proven to be a valuable active learning tool that can serve as a platform for integrating the medical student curriculum across many disciplines and clinical settings. It is also well-suited for a competency-based model of medical education. Students learn ultrasound well and have embraced it as an important component of their education and future practice of medicine. An international consensus conference on ultrasound education is recommended to help define the essential elements of ultrasound education globally to ensure ultrasound is taught and ultimately practiced to its full potential. Ultrasound has the potential to fundamentally change how we teach and practice medicine to the benefit of learners and patients across the globe. PMID- 26589316 TI - Surgical biopsy is still necessary for BI-RADS 4 calcifications found on digital mammography that are technically too faint for stereotactic core biopsy. AB - The purpose of this study was to evaluate the outcome of faint BI-RADS 4 calcifications detected with digital mammography that were not amenable to stereotactic core biopsy due to suboptimal visualization. Following Institutional Review Board approval, a HIPAA compliant retrospective search identified 665 wire localized surgical excisions of calcifications in 606 patients between 2007 and 2010. We included all patients that had surgical excision for initial diagnostic biopsy due to poor calcification visualization, whose current imaging was entirely digital and performed at our institution and who did not have a diagnosis of breast cancer within the prior 2 years. The final study population consisted of 20 wire-localized surgical biopsies in 19 patients performed instead of stereotactic core biopsy due to poor visibility of faint calcifications. Of the 20 biopsies, 4 (20% confidence intervals 2, 38%) were malignant, 5 (25%) showed atypia and 11 (55%) were benign. Of the malignant cases, two were invasive ductal carcinoma (2 and 1.5 mm), one was intermediate grade DCIS and one was low grade DCIS. Malignant calcifications ranged from 3 to 12 mm. The breast density was scattered in 6/19 (32%), heterogeneously dense in 11/19 (58%) and extremely dense in 2/19 (10%). Digital mammography-detected faint calcifications that were not amenable to stereotactic biopsy due to suboptimal visualization had a risk of malignancy of 20%. While infrequent, these calcifications should continue to be considered suspicious and surgical biopsy recommended. PMID- 26589317 TI - The RS685012 Polymorphism of ACCN2, the Human Ortholog of Murine Acid-Sensing Ion Channel (ASIC1) Gene, is Highly Represented in Patients with Panic Disorder. AB - Panic disorder (PD) is a disabling anxiety disorder that is characterized by unexpected, recurrent panic attacks, associated with fear of dying and worrying about possible future attacks or other behavioral changes as a consequence of the attacks. The acid-sensing ion channels (ASICs) are a family of proton-sensing channels expressed throughout the nervous system. Their activity is linked to a variety of behaviors including fear, anxiety, pain, depression, learning, and memory. The human analog of ASIC1a is the amiloride-sensitive cation channel 2 (ACCN2). Adenosine A2A receptors are suggested to play an important role in different brain circuits and pathways involved in anxiety reactions. In this work we aimed to evaluate the distribution of ACCN2 rs685012 and ADORA2A rs2298383 polymorphisms in PD patients compared with healthy subjects. We found no association between ADORA2A polymorphism and PD. Instead, the C mutated allele for ACCN2 rs685012 polymorphism was significantly more frequent in patients than in controls. On the contrary, the TT homozygous wild-type genotype and also the ACCN2 TT/ADORA2A CT diplotype were significantly more represented in controls. These results are suggestive for a role of ACCN2 rs685012 polymorphism in PD development in Caucasian people. PMID- 26589318 TI - A quantitative study of nanoparticle skin penetration with interactive segmentation. AB - In the last decade, the application of nanotechnology techniques has expanded within diverse areas such as pharmacology, medicine, and optical science. Despite such wide-ranging possibilities for implementation into practice, the mechanisms behind nanoparticle skin absorption remain unknown. Moreover, the main mode of investigation has been qualitative analysis. Using interactive segmentation, this study suggests a method of objectively and quantitatively analyzing the mechanisms underlying the skin absorption of nanoparticles. Silica nanoparticles (SNPs) were assessed using transmission electron microscopy and applied to the human skin equivalent model. Captured fluorescence images of this model were used to evaluate degrees of skin penetration. These images underwent interactive segmentation and image processing in addition to statistical quantitative analyses of calculated image parameters including the mean, integrated density, skewness, kurtosis, and area fraction. In images from both groups, the distribution area and intensity of fluorescent silica gradually increased in proportion to time. Since statistical significance was achieved after 2 days in the negative charge group and after 4 days in the positive charge group, there is a periodic difference. Furthermore, the quantity of silica per unit area showed a dramatic change after 6 days in the negative charge group. Although this quantitative result is identical to results obtained by qualitative assessment, it is meaningful in that it was proven by statistical analysis with quantitation by using image processing. The present study suggests that the surface charge of SNPs could play an important role in the percutaneous absorption of NPs. These findings can help achieve a better understanding of the percutaneous transport of NPs. In addition, these results provide important guidance for the design of NPs for biomedical applications. PMID- 26589319 TI - Modelling of the toe trajectory during normal gait using circle-fit approximation. AB - This work aimed to validate the approach of using a circle to fit the toe trajectory relative to the hip and to investigate linear regression models for describing such toe trajectories from normal gait. Twenty-four subjects walked at seven speeds. Best-fit circle algorithms were developed to approximate the relative toe trajectory using a circle. It was detected that the mean approximation error between the toe trajectory and its best-fit circle was less than 4 %. Regarding the best-fit circles for the toe trajectories from all subjects, the normalised radius was constant, while the normalised centre offset reduced when the walking cadence increased; the curve range generally had a positive linear relationship with the walking cadence. The regression functions of the circle radius, the centre offset and the curve range with leg length and walking cadence were definitively defined. This study demonstrated that circle fit approximation of the relative toe trajectories is generally applicable in normal gait. The functions provided a quantitative description of the relative toe trajectories. These results have potential application for design of gait rehabilitation technologies. PMID- 26589320 TI - Using exposure windows to explore an elusive biomarker: blood manganese. AB - PURPOSE: We sought to understand the time course between exposure to manganese (Mn) and uptake into the blood, to allow a more meaningful interpretation of exposure biomarker data, and to determine the utility of blood as a biomarker of Mn exposure. METHODS: Welder trainees were monitored over the course of a five quarter training program. Each quarter, trainees gave eight blood samples and had personal air monitoring four times. A mixed model was fit to obtain estimates of airborne exposure by welding type (fixed effect), adjusted for subject (random effect). Considering weekends and days absent as zero exposure, estimated exposures were summed over various exposure windows and related to measured blood manganese (MnB) using a mixed model. RESULTS: A relationship consistent with zero was found between MnB and modeled 1 or 7 days of exposure. After 30 days of preceding exposure, a 1 mg-days/m(3) increase in air Mn is associated with a 0.57 ng/mL increase in MnB (95% CI -0.04, 1.19). Considering a 90-day exposure window and a cumulative exposure window, a 1 mg-days/m(3) increase in air Mn is associated with a 0.26 (95% CI 0.005, 0.51) and 0.09 (95% CI 0.006, 0.17) ng/mL increase in MnB, respectively. CONCLUSIONS: From this analysis, MnB may begin to act as a biomarker of Mn exposure over longer time periods, or at higher levels of exposure. This novel study design allowed investigation of how MnB relates to different time windows of exposure, representing the most robust Mn exposure assessment in the biomarker literature. PMID- 26589321 TI - High light exposure on seed coat increases lipid accumulation in seeds of castor bean (Ricinus communis L.), a nongreen oilseed crop. AB - Little was known on how sunlight affects the seed metabolism in nongreen seeds. Castor bean (Ricinus communis L.) is a typical nongreen oilseed crop and its seed oil is an important feedstock in industry. In this study, photosynthetic activity of seed coat tissues of castor bean in natural conditions was evaluated in comparison to shaded conditions. Our results indicate that exposure to high light enhances photosynthetic activity in seed coats and consequently increases oil accumulation. Consistent results were also reached using cultured seeds. High throughput RNA-Seq analyses further revealed that genes involved in photosynthesis and carbon conversion in both the Calvin-Benson cycle and malate transport were differentially expressed between seeds cultured under light and dark conditions, implying several venues potentially contributing to light enhanced lipid accumulation such as increased reducing power and CO2 refixation which underlie the overall lipid biosynthesis. This study demonstrated the effects of light exposure on oil accumulation in nongreen oilseeds and greatly expands our understanding of the physiological roles that light may play during seed development in nongreen oilseeds. Essentially, our studies suggest that potential exists to enhance castor oil yield through increasing exposure of the inflorescences to sunlight either by genetically changing the plant architecture (smart canopy) or its growing environment. PMID- 26589322 TI - Native FMO-reaction center supercomplex in green sulfur bacteria: an electron microscopy study. AB - Chlorobaculum tepidum is a representative of green sulfur bacteria, a group of anoxygenic photoautotrophs that employ chlorosomes as the main light-harvesting structures. Chlorosomes are coupled to a ferredoxin-reducing reaction center by means of the Fenna-Matthews-Olson (FMO) protein. While the biochemical properties and physical functioning of all the individual components of this photosynthetic machinery are quite well understood, the native architecture of the photosynthetic supercomplexes is not. Here we report observations of membrane bound FMO and the analysis of the respective FMO-reaction center complex. We propose the existence of a supercomplex formed by two reaction centers and four FMO trimers based on the single-particle analysis of the complexes attached to native membrane. Moreover, the structure of the photosynthetic unit comprising the chlorosome with the associated pool of RC-FMO supercomplexes is proposed. PMID- 26589323 TI - Diabetes-induced changes in the morphology and nociceptinergic innervation of the rat uterus. AB - The prevalence of diabetes mellitus (DM) is about 6% across the globe. This prevalence has been reported to increase in the near future. This means that the number of women with DM who would like to get pregnant and have children will also increase. The present study is aimed at investigating the morphological changes observed in the uterus after the onset of DM. The study also examined the pattern of distribution of nociceptin (NC), a neuropeptide involved in the regulation of pain, a major physiological factor during parturition. The study shows a severe atrophy of uteri as early as 15 days post DM and continued until the termination of the eight-week study. This atrophy was confirmed by light microscopy. Electron microscopy study showed atrophy of the columnar cells of the endometrium, reduced myofibril number and destruction of smooth muscle cells in the myometrium of diabetic rats compared to control. Immunofluorescence and immunoelectron microscopy studies clearly demonstrated the presence of NC in the endometrium, myometrium and on the myofibrils of the smooth muscles of both control and diabetic rat uteri. In addition, NC-positive neurons and varicose fibres were observed in the myometrium of both normal and diabetic rats. However, the expression of NC decreased after the onset of DM. Morphometric analysis showed that the number of NC-labeled cells was significantly (p < 0.05) lower in diabetic rat uteri compared to those of control. In conclusion, DM-induced uterine atrophy is associated with a decrease in the expression of NC in cells, neurons and myofibrils of the rat uterus. PMID- 26589325 TI - Myocardial Po2 does not limit aerobic metabolism in the postischemic heart. AB - Reperfused hypertrophic hearts are prone to develop reflow abnormalities, which are likely to impair O2 return to the myocardium. Yet, reflow deficit may not be the only factor determining postischemic oxygenation in the hypertrophic heart. Altered O2 demand may also contribute to hypoxia. In addition, the extent to which myocardial Po2 dictates energy and functional recovery in the reperfused heart remains uncertain. In the present study, moderately hypertrophied hearts from spontaneously hypertensive rats were subjected to ischemia-reperfusion, and the recovery time courses of pH and high-energy phosphates were followed by (31)P NMR. (1)H NMR measurement of intracellular myoglobin assessed tissue O2 levels. The present study found that the exacerbation of hypoxia in the postischemic spontaneously hypertensive rat heart arises mostly from impaired microvascular supply of O2. However, postischemic myocardial Po2, at least when it exceeds ~18% of the preischemic level, does not limit mitochondrial respiration and high energy phosphate resynthesis. It only passively reflects changes in the O2 supply demand balance. PMID- 26589324 TI - A comparison of the enzymatic properties of three recombinant isoforms of thrombolytic and antibacterial protein--Destabilase-Lysozyme from medicinal leech. AB - BACKGROUND: Destabilase-Lysozyme (mlDL) is a multifunctional i-type enzyme that has been found in the secretions from the salivary glands of medicinal leeches. mlDL has been shown to exhibit isopeptidase, muramidase and antibacterial activity. This enzyme attracts interest because it expresses thrombolytic activity through isopeptidolysis of the epsilon-(gamma-Glu)-Lys bonds that cross link polypeptide chains in stabilised fibrin. To date, three isoforms of mlDL have been identified. The enzymatic properties of pure mlDL isoforms have not yet been described because only destabilase complexes containing other proteins could be isolated from the salivary gland secretion and because low product yield from the generation of recombinant proteins has made comprehensive testing difficult. RESULTS: In the present study, we optimised the procedures related to the expression, isolation and purification of active mlDL isoforms (mlDL-Ds1, mlDL Ds2, mlDL-Ds3) using an Escherichia coli expression system, and we detected and compared their muramidase, lytic, isopeptidase and antimicrobial activities. After optimisation, the product yield was 30 mg per litre of culture. The data obtained in our study led to the suggestion that the recombinant mlDL isoforms isolated from inclusion bodies form stable oligomeric complexes. Analyses of the tested activities revealed that all isoforms exhibited almost identical patterns of pH and ionic strength effects on the activities. We determined that mlDL-Ds1, 2, 3 possessed non-enzymatic antibacterial activity independent of their muramidase activity. For the first time, we demonstrated the fibrinolytic activity of the recombinant mlDL and showed that only intact proteins possessed this activity, suggesting their enzymatic nature. CONCLUSIONS: The recombinant Destabilase-Lysozyme isoforms obtained in our study may be considered potential thrombolytic agents that act through a mechanism different from that of common thrombolytics. PMID- 26589326 TI - Sphingosine 1-phosphate signaling contributes to cardiac inflammation, dysfunction, and remodeling following myocardial infarction. AB - Sphingosine 1-phosphate (S1P) mediates multiple pathophysiological effects in the cardiovascular system. However, the role of S1P signaling in pathological cardiac remodeling following myocardial infarction (MI) remains controversial. In this study, we found that cardiac S1P greatly increased post-MI, accompanied with a significant upregulation of cardiac sphingosine kinase-1 (SphK1) and S1P receptor 1 (S1PR1) expression. In MI-operated mice, inhibition of S1P production by using PF543 (the SphK1 inhibitor) ameliorated cardiac remodeling and dysfunction. Conversely, interruption of S1P degradation by inhibiting S1P lyase augmented cardiac S1P accumulation and exacerbated cardiac remodeling and dysfunction. In the cardiomyocyte, S1P directly activated proinflammatory responses via a S1PR1 dependent manner. Furthermore, activation of SphK1/S1P/S1PR1 signaling attributed to beta1-adrenergic receptor stimulation-induced proinflammatory responses in the cardiomyocyte. Administration of FTY720, a functional S1PR1 antagonist, obviously blocked cardiac SphK1/S1P/S1PR1 signaling, ameliorated chronic cardiac inflammation, and then improved cardiac remodeling and dysfunction in vivo post MI. In conclusion, our results demonstrate that cardiac SphK1/S1P/S1PR1 signaling plays an important role in the regulation of proinflammatory responses in the cardiomyocyte and targeting cardiac S1P signaling is a novel therapeutic strategy to improve post-MI cardiac remodeling and dysfunction. PMID- 26589327 TI - Muscle heat: a window into the thermodynamics of a molecular machine. AB - The contraction of muscle is characterized by the development of force and movement (mechanics) together with the generation of heat (metabolism). Heat represents that component of the enthalpy of ATP hydrolysis that is not captured by the microscopic machinery of the cell for the performance of work. It arises from two conceptually and temporally distinct sources: initial metabolism and recovery metabolism. Initial metabolism comprises the hydrolysis of ATP and its rapid regeneration by hydrolysis of phosphocreatine (PCr) in the processes underlying excitation-contraction coupling and subsequent cross-bridge cycling and sliding of the contractile filaments. Recovery metabolism describes those process, both aerobic (mitochondrial) and anaerobic (cytoplasmic), that produce ATP, thereby allowing the regeneration of PCr from its hydrolysis products. An equivalent partitioning of muscle heat production is often invoked by muscle physiologists. In this formulation, total enthalpy expenditure is separated into external mechanical work (W) and heat (Q). Heat is again partitioned into three conceptually distinct components: basal, activation, and force dependent. In the following mini-review, we trace the development of these ideas in parallel with the development of measurement techniques for separating the various thermal components. PMID- 26589328 TI - Baroreflex failure increases the risk of pulmonary edema in conscious rats with normal left ventricular function. AB - In heart failure with preserved ejection fraction (HFpEF), the complex pathogenesis hinders development of effective therapies. Since HFpEF and arteriosclerosis share common risk factors, it is conceivable that stiffened arterial wall in HFpEF impairs baroreflex function. Previous investigations have indicated that the baroreflex regulates intravascular stressed volume and arterial resistance in addition to cardiac contractility and heart rate. We hypothesized that baroreflex dysfunction impairs regulation of left atrial pressure (LAP) and increases the risk of pulmonary edema in freely moving rats. In 15-wk Sprague-Dawley male rats, we conducted sinoaortic denervation (SAD, n = 6) or sham surgery (Sham, n = 9), and telemetrically monitored ambulatory arterial pressure (AP) and LAP. We compared the mean and SD (lability) of AP and LAP between SAD and Sham under normal-salt diet (NS) or high-salt diet (HS). SAD did not increase mean AP but significantly increased AP lability under both NS (P = 0.001) and HS (P = 0.001). SAD did not change mean LAP but significantly increased LAP lability under both NS (SAD: 2.57 +/- 0.43 vs. Sham: 1.73 +/- 0.30 mmHg, P = 0.01) and HS (4.13 +/- 1.18 vs. 2.45 +/- 0.33 mmHg, P = 0.02). SAD markedly increased the frequency of high LAP, and SAD with HS prolonged the duration of LAP > 18 mmHg by nearly 20-fold compared with Sham (SAD + HS: 2,831 +/- 2,366 vs. Sham + HS: 148 +/- 248 s, P = 0.01). We conclude that baroreflex failure impairs volume tolerance and together with salt loading increases the risk of pulmonary edema even in the absence of left ventricular dysfunction. Baroreflex failure may contribute in part to the pathogenesis of HFpEF. PMID- 26589329 TI - Fractal regional myocardial blood flows pattern according to metabolism, not vascular anatomy. AB - Regional myocardial blood flows are markedly heterogeneous. Fractal analysis shows strong near-neighbor correlation. In experiments to distinguish control by vascular anatomy vs. local vasomotion, coronary flows were increased in open chest dogs by stimulating myocardial metabolism (catecholamines + atropine) with and without adenosine. During control states mean left ventricular (LV) myocardial blood flows (microspheres) were 0.5-1 ml.g(-1).min(-1) and increased to 2-3 ml.g(-1).min(-1) with catecholamine infusion and to ~4 ml.g(-1).min(-1) with adenosine (Ado). Flow heterogeneity was similar in all states: relative dispersion (RD = SD/mean) was ~25%, using LV pieces 0.1-0.2% of total. During catecholamine infusion local flows increased in proportion to the mean flows in 45% of the LV, "tracking" closely (increased proportionately to mean flow), while ~40% trended toward the mean. Near-neighbor regional flows remained strongly spatially correlated, with fractal dimension D near 1.2 (Hurst coefficient 0.8). The spatial patterns remain similar at varied levels of metabolic stimulation inferring metabolic dominance. In contrast, adenosine vasodilation increased flows eightfold times control while destroying correlation with the control state. The Ado-induced spatial patterns differed from control but were self consistent, inferring that with full vasodilation the relaxed arterial anatomy dominates the distribution. We conclude that vascular anatomy governs flow distributions during adenosine vasodilation but that metabolic vasoregulation dominates in normal physiological states. PMID- 26589331 TI - Organ perfusion during voluntary pulmonary hyperinflation; a magnetic resonance imaging study. AB - Pulmonary hyperinflation is used by competitive breath-hold divers and is accomplished by glossopharyngeal insufflation (GPI), which is known to compress the heart and pulmonary vessels, increasing sympathetic activity and lowering cardiac output (CO) without known consequence for organ perfusion. Myocardial, pulmonary, skeletal muscle, kidney, and liver perfusion were evaluated by magnetic resonance imaging in 10 elite breath-hold divers at rest and during moderate GPI. Cardiac chamber volumes, stroke volume, and thus CO were determined from cardiac short-axis cine images. Organ volumes were assessed from gradient echo sequences, and organ perfusion was evaluated from first-pass images after gadolinium injection. During GPI, lung volume increased by 5.2 +/- 1.5 liters (mean +/- SD; P < 0.001), while spleen and liver volume decreased by 46 +/- 39 and 210 +/- 160 ml, respectively (P < 0.05), and inferior caval vein diameter by 4 +/- 3 mm (P < 0.05). Heart rate tended to increase (67 +/- 10 to 86 +/- 20 beats/min; P = 0.052) as right and left ventricular volumes were reduced (P < 0.05). Stroke volume (107 +/- 21 to 53 +/- 15 ml) and CO (7.2 +/- 1.6 to 4.2 +/- 0.8 l/min) decreased as assessed after 1 min of GPI (P < 0.01). Left ventricular myocardial perfusion maximum upslope and its perfusion index decreased by 1.52 +/ 0.15 s(-1) (P < 0.001) and 0.02 +/- 0.01 s(-1) (P < 0.05), respectively, without transmural differences. Pulmonary tissue, spleen, kidney, and pectoral-muscle perfusion also decreased (P < 0.05), and yet liver perfusion was maintained. Thus, during pulmonary hyperinflation by GPI, CO and organ perfusion, including the myocardium, as well as perfusion of skeletal muscles, are reduced, and yet perfusion of the liver is maintained. Liver perfusion seems to be prioritized when CO decreases during GPI. PMID- 26589330 TI - Impact of age on the vasodilatory function of human skeletal muscle feed arteries. AB - Although advancing age is often associated with attenuated skeletal muscle blood flow and skeletal muscle feed arteries (SMFAs) have been recognized to play a regulatory role in the vasculature, little is known about the impact of age on the vasodilatory capacity of human SMFAs. Therefore, endothelium-dependent and independent vasodilation were assessed in SMFAs (diameter: 544 +/- 63 MUm) obtained from 24 (equally represented) young (33 +/- 2 yr) and old (71 +/- 2 yr) subjects in response to three stimuli: 1) flow-induced shear stress, 2) ACh, and 3) sodium nitropusside (SNP). Both assessments of endothelium-dependent vasodilation, flow (young subjects: 68 +/- 1% and old subjects: 32 +/- 7%) and ACh (young subjects: 92 +/- 3% and old subjects: 73 +/- 4%), were significantly blunted (P < 0.05) in SMFAs of old compared with young subjects, with no such age related differences in endothelium-independent vasodilation (SNP). In response to an increase in flow-induced shear stress, vasodilation kinetics (time constant to reach 63% of the amplitude of the response: 55 +/- 1 s in young subjects and 92 +/- 7 s in old subjects) and endothelial nitric oxide synthase (eNOS) activation (phospho-eNOS(s1177)/total eNOS: 1.0 +/- 0.1 in young subjects and 0.2 +/- 0.1 in old subjects) were also significantly attenuated in old compared with young subjects (P < 0.05). Furthermore, the vessel superoxide concentration was greater in old subjects (old subjects: 3.9 +/- 1.0 area under curve/mg and young subjects: 1.7 +/- 0.1 area under the curve/mg, P < 0.05). These findings reveal that the endothelium-dependent vasodilatory capacity, including vasodilation kinetics but not smooth muscle function, of human SMFAs is blunted with age and may be due to free radicals. Given the potential regulatory role of SMFAs in skeletal muscle blood flow, these findings may explain, at least in part, the often observed attenuated perfusion of skeletal muscle with advancing age that may contribute to exercise intolerance in the elderly. PMID- 26589332 TI - Activity-induced manganese-dependent MRI (AIM-MRI) and functional MRI in awake rabbits during somatosensory stimulation. AB - Activity-induced manganese-dependent MRI (AIM-MRI) is a powerful tool to track system-wide neural activity using high resolution, quantitative T1-weighted MRI in animal models and has significant advantages for investigating neural activity over other modalities including BOLD fMRI. With AIM-MRI, Mn(2+) ions enter neurons via voltage-gated calcium channels preferentially active during the time of experimental exposure. A broad range of AIM-MRI studies using different species studying different phenomena have been performed, but few of these studies provide a systematic evaluation of the factors influencing the detection of Mn(2+) such as dosage and the temporal characteristics of Mn(2+) uptake. We identified an optimal dose of Mn(2+) (25 mg/kg, s.c.) in order to characterize the time-course of Mn(2+) accumulation in active neural regions in the rabbit. T1 weighted MRI and functional MRI were collected 0-3, 6-9, and 24-27 h post-Mn(2+) injection while the vibrissae on the right side were vibrated. Significant BOLD activation in the left somatosensory (SS) cortex and left ventral posteromedial (VPM) thalamic nucleus was detected during whisker vibration. T1-weighted signal intensities were extracted from these regions, their corresponding contralateral regions and the visual cortex (to serve as controls). A significant elevation in T1-weighted signal intensity in the left SS cortex (relative to right) was evident 6-9 and 24-27 h post-Mn(2+) injection while the left VPM thalamus showed a significant enhancement (relative to the right) only during the 24-27 h session. Visual cortex showed no hemispheric difference at any timepoint. Our results suggest that studies employing AIM-MRI would benefit by conducting experimental manipulations 6-24 h after subcutaneous MnCl2 injections to optimize the concentration of contrast agent in the regions active during the exposure. PMID- 26589334 TI - Localizing Pain Matrix and Theory of Mind networks with both verbal and non verbal stimuli. AB - Functional localizer tasks allow researchers to identify brain regions in each individual's brain, using a combination of anatomical and functional constraints. In this study, we compare three social cognitive localizer tasks, designed to efficiently identify regions in the "Pain Matrix," recruited in response to a person's physical pain, and the "Theory of Mind network," recruited in response to a person's mental states (i.e. beliefs and emotions). Participants performed three tasks: first, the verbal false-belief stories task; second, a verbal task including stories describing physical pain versus emotional suffering; and third, passively viewing a non-verbal animated movie, which included segments depicting physical pain and beliefs and emotions. All three localizers were efficient in identifying replicable, stable networks in individual subjects. The consistency across tasks makes all three tasks viable localizers. Nevertheless, there were small reliable differences in the location of the regions and the pattern of activity within regions, hinting at more specific representations. The new localizers go beyond those currently available: first, they simultaneously identify two functional networks with no additional scan time, and second, the non-verbal task extends the populations in whom functional localizers can be applied. These localizers will be made publicly available. PMID- 26589335 TI - Neuroplasticity for spontaneous functional recovery after neonatal hypoxic ischemic brain injury in rats observed by functional MRI and diffusion tensor imaging. AB - For infants and children, an incredible resilience from injury is often observed. There is growing evidence that functional recovery after brain injury might well be a consequence of the reorganization of the neural network as a process of neuroplasticity. We demonstrate the presence of neuroplasticity at work in spontaneous recovery after neonatal hypoxic ischemic (HI) injury, by elucidating a precise picture in which such reorganization takes place using functional MRI techniques. For all 12 siblings, 6 rats were subjected to severe HI brain injury and 6 rats underwent sham operation only. Severe HI brain injury was induced to postnatal day 7 (p7) Sprague-Dawley rats according to the Rice-Vannucci model (right carotid artery occlusion followed by 150min of hypoxia with 8% O2 and 92% of N2). Brain activation maps along with anatomical and functional connectivity maps related to the sensory motor function were obtained at adult (p63) using blood oxygen level dependent (BOLD)-functional MRI (fMRI), resting state functional MRI (rs-fMRI) and diffusion tensor imaging (DTI); each of these MRI data was related to sensory motor functional outcome. In-depth investigation of the functional MRI data revealed: 1) intra-hemispheric expansion of BOLD signal activation in the contralesional undamaged hemisphere for ipsilesional forepaw stimuli to include the M2 and Cg1 in addition to the S1 and M1 wide spreading in the anterior and posterior directions, 2) inter-hemispheric transfer of BOLD signal activation for contralesional forepaw stimuli, normally routed to the injured hemisphere, to analogous sites in the contralesional undamaged hemisphere, localized newly to the M1 and M2 with a reduced portion of the S1, 3) inter-hemispheric axonal disconnection and axonal rewiring within the undamaged hemisphere as shown through DTI, and 4) increased functional interactions within the cingulate gyrus in the HI injured rats as shown through rs-fMRI. The BOLD signal amplitudes as well as DTI and rs-fMRI data well correlate with behavioral tests (tape to remove). We found that function normally utilizing what would be the injured hemisphere is transferred to the uninjured hemisphere, and functionality of the uninjured hemisphere remains not untouched but is also rewired in an expansion corresponding to the newly formed sensorimotor function from both the contralesional and the ipsilesional sides. The conclusion drawn from the data in our current study is that enhanced motor function in the contralesional hemisphere governs both the normal and damaged sides, indicating that active plasticity with brain laterality was spontaneously generated to overcome functional loss and established autonomously through normal experience via modification of neural circuitry for neonatal HI injured brain. PMID- 26589336 TI - Determination of head conductivity frequency response in vivo with optimized EIT EEG. AB - Electroencephalography (EEG) benefits from accurate head models. Dipole source modelling errors can be reduced from over 1cm to a few millimetres by replacing generic head geometry and conductivity with tailored ones. When adequate head geometry is available, electrical impedance tomography (EIT) can be used to infer the conductivities of head tissues. In this study, the boundary element method (BEM) is applied with three-compartment (scalp, skull and brain) subject-specific head models. The optimal injection of small currents to the head with a modular EIT current injector, and voltage measurement by an EEG amplifier is first sought by simulations. The measurement with a 64-electrode EEG layout is studied with respect to three noise sources affecting EIT: background EEG, deviations from the fitting assumption of equal scalp and brain conductivities, and smooth model geometry deviations from the true head geometry. The noise source effects were investigated depending on the positioning of the injection and extraction electrode and the number of their combinations used sequentially. The deviation from equal scalp and brain conductivities produces rather deterministic errors in the three conductivities irrespective of the current injection locations. With a realistic measurement of around 2 min and around 8 distant distinct current injection pairs, the error from the other noise sources is reduced to around 10% or less in the skull conductivity. The analysis of subsequent real measurements, however, suggests that there could be subject-specific local thinnings in the skull, which could amplify the conductivity fitting errors. With proper analysis of multiplexed sinusoidal EIT current injections, the measurements on average yielded conductivities of 340 mS/m (scalp and brain) and 6.6 mS/m (skull) at 2 Hz. From 11 to 127 Hz, the conductivities increased by 1.6% (scalp and brain) and 6.7% (skull) on the average. The proper analysis was ensured by using recombination of the current injections into virtual ones, avoiding problems in location-specific skull morphology variations. The observed large intersubject variations support the need for in vivo measurement of skull conductivity, resulting in calibrated subject-specific head models. PMID- 26589337 TI - Addressing Underrepresentation in Sex Work Research: Reflections on Designing a Purposeful Sampling Strategy. AB - Men, transgender people, and those working in off-street locales have historically been underrepresented in sex work health research. Failure to include all sections of sex worker populations precludes comprehensive understandings about a range of population health issues, including potential variations in the manifestation of such issues within and between population subgroups, which in turn can impede the development of effective services and interventions. In this article, we describe our attempts to define, determine, and recruit a purposeful sample for a qualitative study examining the interrelationships between sex workers' health and the working conditions in the Vancouver off-street sex industry. Detailed is our application of ethnographic mapping approaches to generate information about population diversity and work settings within distinct geographical boundaries. Bearing in mind the challenges and the overwhelming discrimination sex workers experience, we scope recommendations for safe and effective purposeful sampling inclusive of sex workers' heterogeneity. PMID- 26589333 TI - Running rewires the neuronal network of adult-born dentate granule cells. AB - Exercise improves cognition in humans and animals. Running increases neurogenesis in the dentate gyrus of the hippocampus, a brain area important for learning and memory. It is unclear how running modifies the circuitry of new dentate gyrus neurons to support their role in memory function. Here we combine retroviral labeling with rabies virus mediated trans-synaptic retrograde tracing to define and quantify new neuron afferent inputs in young adult male C57Bl/6 mice, housed with or without a running wheel for one month. Exercise resulted in a shift in new neuron networks that may promote sparse encoding and pattern separation. Neurogenesis increased in the dorsal, but not the ventral, dentate gyrus by three fold, whereas afferent traced cell labeling doubled in number. Regional analysis indicated that running differentially affected specific inputs. Within the hippocampus the ratio of innervation from inhibitory interneurons and glutamatergic mossy cells to new neurons was reduced. Distal traced cells were located in sub-cortical and cortical regions, including perirhinal, entorhinal and sensory cortices. Innervation from entorhinal cortex (EC) was augmented, in proportion to the running-induced enhancement of adult neurogenesis. Within EC afferent input and short-term synaptic plasticity from lateral entorhinal cortex, considered to convey contextual information to the hippocampus was increased. Furthermore, running upregulated innervation from regions important for spatial memory and theta rhythm generation, including caudo-medial entorhinal cortex and subcortical medial septum, supra- and medial mammillary nuclei. Altogether, running may facilitate contextual, spatial and temporal information encoding by increasing adult hippocampal neurogenesis and by reorganization of new neuron circuitry. PMID- 26589338 TI - Can geodata be used to determine the distribution of fast food outlets in relation to the prevalence and severity of asthma? A novel methodology. AB - RESEARCH QUESTION: Can the distribution of fast food outlets be obtained and effectively used to identify if there is a relationship between the placement of these and the prevalence and severity of asthma, rhinoconjunctivitis and eczema (ARE) in children and adolescents? METHOD: Fast food restaurant location data was obtained for seven countries. Data from the International Study of Asthma and Allergies in Childhood (ISAAC) was used from 53 centres in the same seven countries. Each ISAAC centre provided a detailed map of the study area. The location of restaurants and ISAAC centres were overlaid using the ArcMap software, and the number of restaurants within each ISAAC centre counted. Bivariate regression analysis was used to compare outlet density with ARE prevalence and severity. RESULTS: The results from the analyses showed a positive (non-significant) trend on a regression plot between outlet density and ARE severity. This project has shown that it is practical to systematically obtain and map fast food outlets and compare their distribution worldwide with the prevalence and severity of diseases, in this case ARE. The devised methodology has proven to be an efficient way to obtain restaurant distribution data in a form that is manageable and suitable to compare with area based disease prevalences. This project has shown that a larger scale investigation is both feasible and warranted. PMID- 26589339 TI - Exhaled nitric oxide in relation to asthma control: A real-life survey. AB - BACKGROUND: Asthma is characterised by chronic airway inflammation, a complex cascade of events, mostly sustained by eosinophil recruitment and activation. Fractional exhaled nitric oxide (FeNO) is a surrogate marker of airway inflammation closely associated with bronchial eosinophilia. FeNO is used to define asthma phenotype, to assess eosinophilic inflammatory severity and to predict corticosteroid responsiveness. OBJECTIVE: The aim of this study was to investigate whether FeNO may be associated with some clinical and functional factors in asthmatics evaluated in a real life setting. METHODS: Globally 363 patients (150 males, mean age 46.3 years) with asthma were consecutively evaluated. The following parameters were assessed: history, including comorbidities, physical examination, body mass index (BMI), lung function, asthma control grade, asthma control test (ACT), and FeNO. RESULTS: FeNO values were significantly higher in patients with poorly controlled asthma (p<0.01), asthma symptoms (p=0.015), wheezing (p<0.001), rhinitis diagnosis, (p=0.049) and rhinitis symptoms (p=0.019), but lower in patients with GERD (p=0.024) and pneumonia history (p=0.048). FeNO values increased in patients with the lowest corticosteroid dose (p=0.031). FeNO values>25ppb were associated with poorly controlled asthma (OR 3.71), asthma signs (OR 3.5) and symptoms (OR 1.79). A FeNO value cut-off of 29.9ppb was fairly predictive of (AUC 0.7) poorly controlled asthma. CONCLUSIONS: FeNO assessment in clinical practice may be a useful tool for monitoring asthmatics as it is associated with several clinical factors, including asthma control. PMID- 26589340 TI - Prevalence of and risk factors for atopic dermatitis: A birth cohort study of infants in southeast Turkey. AB - BACKGROUND: Atopic dermatitis (AD) is most common in the first year of life. The aim of this study was to determine the prevalence of and risk factors for AD in a birth cohort of infants from southeast Turkey. METHODS: Adana Paediatric Allergy Research (ADAPAR) birth cohort study was derived from 1377 infants who were born in Cukurova University, Medical Hospital, Adana, Turkey between February 2010 and February 2011. At birth, a physical examination was performed, cord blood samples were taken, and the mother completed a baseline questionnaire that provided data on gestational conditions, family history of allergic diseases and environmental exposures. Follow-up visits scheduled at 3, 6, and 12 months included an infant physical examination and an extended questionnaire. Skin prick test was performed and food-specific IgE levels were measured at 6 and 12 months. Atopic dermatitis was diagnosed based on confirmatory examination by a physician. RESULTS: Of the 1377 infants enrolled, 59 (4.3%) were diagnosed with AD as of 12 months. Maternal allergic disease (ORs 6.28, 95% CI 1.03-38.30; p=0.046), maternal infection during gestation (ORs 3.73, 95% CI 1.25-11.09; p=0.018), and presence of food allergy (ORs 13.7, 95% CI 3.07-61.0; p=0.001) were identified as risk factors for AD. Breastfeeding and cord blood IgE levels were not identified as risk factors. CONCLUSIONS: In this cohort we found prevalence of AD as 4.3% during the first year of life. Positive family history of atopic diseases, prenatal infections and presence of food allergy are the risk factors for early presentation of AD. PMID- 26589341 TI - College Students Must Overcome Barriers to Use Calorie Labels in Fast-Food Restaurants. AB - OBJECTIVE: To explore predictors of intention of college students to use calorie labels on fast-food menus and differences in calories ordered after viewing calorie information. DESIGN: Quasi-experimental design. Participants selected a meal from a menu without calorie labels, selected a meal from the same menu with calorie labels, and completed a survey that assessed demographics, dietary habits, Theory of Planned Behavior constructs, and potential barriers to use of calorie labeling. SETTING: A southern university. PARTICIPANTS: Undergraduate university students (n = 97). MAIN OUTCOME MEASURES: Predictors of intention to use calorie labels and whether calories selected from the nonlabeled menu differed from the labeled menu. ANALYSIS: Confirmatory factor analysis, exploratory factor analysis, multiple regression, and paired t tests. RESULTS: Participants ordered significantly fewer calories (P = .02) when selecting from the labeled menu vs the menu without labels. Attitudes (P = .006), subjective norms (P < .001), and perceived behavioral control (P = .01) predicted intention to use calorie information but did not predict a difference in the calories ordered. Hunger (P = .03) and cost (P = .04) were barriers to using the calorie information. CONCLUSIONS AND IMPLICATIONS: If students can overcome barriers, calorie labeling could provide information that college students need to select lower-calorie items at fast-food restaurants. PMID- 26589342 TI - An analysis of closed medical litigations against the obstetrics departments in Taiwan from 2003 to 2012?. AB - OBJECTIVE: To examine the epidemiologic data of closed medical claims from Taiwanese civil courts against obstetric departments and identify high-risk diseases. DESIGN: A retrospective descriptive study. SETTING/STUDY PARTICIPANTS: The verdicts from the national database of the Taiwan judicial system that pertained to obstetric departments were reviewed. Between 2003 and 2012, a total of 79 closed medical claims were included. MAIN OUTCOME MEASURES: The epidemiologic data of litigations including the results of adjudication and the disease and outcome of the alleged injury. RESULTS: A majority of the disputes (65.9%) were fetus-related. Four disease categories accounted for 78.5% of all claims including (i) perinatal maternal complications (25.3%); (ii) errors in antenatal screening or ultrasound diagnoses (21.5%); (iii) fetal hypoxemic ischemia encephalopathy (16.5%); and (iv) brachial plexus injury (15.2%). Six cases (7.6%) resulted in an indemnity payment with a mean amount of $109 205. Fifty-one cases (64.6%) were closed in the district court. The mean incident-to litigation closure time was 52.9 +/- 29.3 months. All cases with indemnity payments were deemed negligent or were at least determined to be controversial by a medical appraisal, while all defendants whose care was judged as appropriate by a medical appraisal won their lawsuits. CONCLUSIONS: Almost 93% of clinicians win their cases but spend 4.5 years waiting for final adjudication. The court ruled against the clinician only if there was no appropriate response during a complication or if there was no follow-up or further testing for potential critical diseases. PMID- 26589344 TI - Thyroid Functions in Healthy Infants during the First Year of Life. AB - OBJECTIVE: To study the pattern of thyroid function testing in healthy newborns during the first year of life. STUDY DESIGN: We used the computerized database of a health management organization. Among the 18,507 infants insured by the Clalit Health Services born in the Sheba Medical Center between 2002 and 2007, 652 full term healthy newborns with birth weight >2 kg and no significant perinatal morbidity underwent thyrotropin (TSH) determination as outpatients in their first year of life. The Clalit Health Services database provided demographic data, laboratory results, and dispensed medications for the newborns and their mothers. RESULTS: Initial serum TSH levels were within normal range (0.35-5.5 mIU/L) in 91.1%, elevated (> 5.5-<= 10 mIU/L) in 8.3%, and highly elevated (>10 mIU/L) in 0.6% of the studied cohort. The 97.5 and 2.5 percentile values were 7.4 and 0.74 mIU/L, respectively. TSH measurements were repeated in 34.2%, 72.2%, and 100% of children with normal, elevated, and highly elevated initial levels, respectively; results were normal in 96%, 74%, and 50% of patients with initial normal, elevated, and highly elevated TSH, respectively; repeated TSH levels were > 97.5 percentile in 35% of patients with initial TSH > 97.5 percentile compared with 1% with first results < 97.5 percentile (P = .005). Only 4 (0.6%) of the 652 newborns included in the study received thyroxin treatment. CONCLUSION: The normal TSH levels found in most healthy infants with normal thyroid screening and the spontaneous normalization of TSH values below 7.4 mIU/liter, substantiate the reliability of the screening, reduce unnecessary work-up and unnecessary thyroxin treatment of neonates meeting these criteria. PMID- 26589343 TI - Celiac Disease Does Not Influence Fracture Risk in Young Patients with Type 1 Diabetes. AB - OBJECTIVES: To examine the risk of any fractures in patients with both type 1 diabetes (T1D) and celiac disease (CD) vs patients with T1D only. STUDY DESIGN: We performed a population-based cohort study. We defined T1D as individuals aged <=30 years who had a diagnosis of diabetes recorded in the Swedish National Patient Register between 1964 and 2009. Individuals with CD were identified through biopsy report data between 1969 and 2008 from any of Sweden's 28 pathology departments. Some 958 individuals had both T1D and CD and were matched for sex, age, and calendar period with 4598 reference individuals with T1D only. We then used a stratified Cox regression analysis, where CD was modeled as a time dependent covariate, to estimate the risk of any fractures and osteoporotic fractures (hip, distal forearm, thoracic and lumbar spine, and proximal humerus) in patients with both T1D and CD compared with that in patients with T1D only. RESULTS: During follow-up, 12 patients with T1D and CD had a fracture (1 osteoporotic fracture). CD did not influence the risk of any fracture (adjusted hazard ratio = 0.77; 95% CI = 0.42-1.41) or osteoporotic fractures (adjusted hazard ratio = 0.46; 95% CI = 0.06-3.51) in patients with T1D. Stratification for time since CD diagnosis did not affect risk estimates. CONCLUSION: Having a diagnosis of CD does not seem to influence fracture risk in young patients with T1D. Follow-up in this study was, however, too short to ascertain osteoporotic fractures which traditionally occur in old age. PMID- 26589345 TI - Management and Outcomes of Patients with Occlusive Thrombosis after Pediatric Cardiac Surgery. AB - OBJECTIVES: To evaluate management and outcomes of thrombosis after pediatric cardiac surgery and stratify thrombi according to risk of short- and long-term complications to better guide therapeutic choices. STUDY DESIGN: Retrospective review was performed of 513 thrombi (400 occlusive) diagnosed after 213 pediatric cardiac operations. Long-term outcomes over time were assessed with the use of parametric hazard regression models. RESULTS: Serious complications and/or high intensity treatment occurred with 17%-24% of thrombi depending on location, most commonly in thrombi affecting the cardiac and cerebral circulation. Bleeding complications affected 13% of patients; associated factors included thrombolytics (OR 8.7, P < .001), greater daily dose of unfractionated heparin (OR 1.25 per 5 U/kg/day, P = .03), and extracorporeal support (OR 4.5, P = .007). Radiologic thrombus persistence was identified in 30% +/- 3% at 12 months; associated factors included extracorporeal support (hazard ratio [HR] 1.9, P = .003), venous (HR 1.7, P = .003), and occlusive thrombi at presentation (HR 1.8, P = .001); greater oxygen saturation before surgery (HR 1.13/10%, P = .05) and thrombi in femoral veins (HR 1.9, P = .001) were associated with increased hazard of resolution. Freedom from postthrombotic syndrome was 83% +/- 4% at 6 years, greater number of persistent vessel segment occlusions (HR 1.8/vessel, P = .001) and greater fibrinogen at diagnosis (HR 1.1 per g/L, P = .02) were associated with increased hazard. CONCLUSIONS: Thrombosis outcomes after pediatric cardiac surgery remain suboptimal. Given that more intensive treatment would likely increase the risk of bleeding, the focus should be on both thrombosis-prevention strategies, as well as in tailoring therapy according to a thrombosis outcome risk stratification approach. PMID- 26589346 TI - Noninvasive Treatment of Pyogenic Granulomas in Young Children with Topical Timolol and Trichloroacetic Acid. PMID- 26589347 TI - Review of the pathophysiological aspects involved in urological disease associated with metabolic syndrome. AB - INTRODUCTION: Metabolic syndrome is a constellation of disorders that includes insulin resistance, central obesity, arterial hypertension and hyperlipidaemia. These disorders can have implications for the genitourinary apparatus. OBJECTIVES: To conduct a review on the pathophysiological aspects that explain the relationship between metabolic syndrome and sexual dysfunction, lower urinary tract syndrome, prostate cancer and stone disease. METHODS: We performed a qualitative, narrative literature review through a literature search on PubMed of articles published between 1997 and 2015, using the terms pathophysiology, metabolic syndrome, endothelial dysfunction, lipotoxicity, mitochondrial dysfunction, kidney stones, hypogonadism, erectile dysfunction, lower urinary tract syndrome and prostate cancer. SYNTHESIS OF THE EVIDENCE: Metabolic syndrome constitutes an established complex of symptoms, defined as the presence of insulin resistance, central obesity, hypertension and hyperlipidaemia. Endothelial dysfunction secondary to lipotoxicity generates an inflammatory state, which involves renal cell metabolism, vascularisation of the pelvis and androgen production. These facts explain the relationship between metabolic syndrome, nephrolithiasis, lower urinary tract syndrome, hypogonadism and erectile dysfunction in men. CONCLUSIONS: Strategies such as proper diet, regular exercise, insulin treatment, testosterone-replacement therapy, therapy with antioxidants and free-radical inhibitors and urological treatments classically used for lower urinary tract syndrome have shown promising results in this syndrome. PMID- 26589348 TI - Childhood Adversity and Men's Relationships in Adulthood: Life Course Processes and Racial Disadvantage. AB - OBJECTIVES: Prior U.S. population studies have found that childhood adversity influences the quality of relationships in adulthood, with emerging research suggesting that this association might be especially strong for black men. We theorize psychosocial and behavioral coping responses to early life adversity and how these responses may link early life adversity to strain in men's relationships with their indeterminate partners and children across the life course, with attention to possible racial variation in these experiences and implications for later life well-being. METHOD: We analyze in-depth interviews with 15 black men and 15 white men. We use qualitative analysis techniques to connect childhood experiences to psychosocial processes in childhood and behavioral coping strategies associated with relationship experiences throughout adulthood. RESULTS: Black men describe much stronger and more persistent childhood adversity than do white men. Findings further suggest that childhood adversity contributes to psychosocial processes (e.g., diminished sense of mastery) that may lead to ways of coping with adversity (e.g., self-medication) that are likely to contribute to relationship difficulties throughout the life span. DISCUSSION: A life course perspective directs attention to the early life origins of cumulative patterns of social disadvantage, patterns that extend to later life. Our findings suggest psychosocial and behavioral pathways through which early life adversity may constrain and strain men's relationships, possibly contributing to racial inequality in family relationships across the life span. PMID- 26589349 TI - THE APPLICATION OF DIAGNOSTIC REFERENCE LEVELS FOR OPTIMISATION OF X-RAY IMAGING IN THE UK. AB - The concept of diagnostic reference levels (DRLs) has been introduced to provide standard doses against which hospital patient dose measurements can be compared to evaluate practices. DRLs are defined in terms of measured dose quantities. National DRLs can be derived from surveys of patient doses for common types of examinations in 20-30 large hospitals. The International Commission on Radiological Protection proposes that median doses for each type of examination at every hospital be collated and DRLs based on the third quartile value of the distribution. Once DRLs have been set, periodic audits of patient dose should be undertaken for examinations that reflect the clinical workload. Median doses from these distributions should be compared with relevant DRLs to identify procedures for which further optimisation is required and appropriate corrective action taken. This paper discusses factors that should be considered in the optimisation process and gives examples of experiences in application of DRLs in Scotland. PMID- 26589350 TI - Transcranial direct current stimulation in the neuromodulation of pain in fibromyalgia: A case study. PMID- 26589351 TI - Volition and low back pain: When patients talk. AB - OBJECTIVE: Our objective was to explore, describe and understand volition of chronic low back pain (LBP) patients, highlighting barriers and facilitators to practicing regular physical activity in order to develop a questionnaire assessing those volitional competencies. METHODS: A content analysis of semi structured interviews with 30 chronic LBP patients was performed. Participants were asked about their pain, motivation, physical abilities, barriers and facilitators to regular exercises and finally strategies implemented to achieve the exercise program. RESULTS: Patients often reported that they were motivated and that exercises had no negative effects on LBP. Many patients recognized having difficulties performing all their exercises regularly. The main barriers were: lack of time, fatigue, lack of visible results, pain and other daily priorities. The main facilitators were: group exercise, help from the therapist, strategic planning, favorable environment, pleasure associated with exercises, fear of pain recurrence and pain itself. CONCLUSION: Content analysis showed that sharing stories allowed patients to express their experience of LBP in their own words. It provides a solid ground to develop a questionnaire assessing volitional competencies in chronic LBP patients in order to identify patients who will not realize their exercises and help them be (more) active and avoid chronicity. PMID- 26589352 TI - Dead end1 is an essential partner of NANOS2 for selective binding of target RNAs in male germ cell development. AB - RNA-binding proteins (RBPs) play important roles for generating various cell types in many developmental processes, including eggs and sperms. Nanos is widely known as an evolutionarily conserved RNA-binding protein implicated in germ cell development. Mouse NANOS2 interacts directly with the CCR4-NOT (CNOT) deadenylase complex, resulting in the suppression of specific RNAs. However, the mechanisms involved in target specificity remain elusive. We show that another RBP, Dead end1 (DND1), directly interacts with NANOS2 to load unique RNAs into the CNOT complex. This interaction is mediated by the zinc finger domain of NANOS2, which is essential for its association with target RNAs. In addition, the conditional deletion of DND1 causes the disruption of male germ cell differentiation similar to that observed in Nanos2-KO mice. Thus, DND1 is an essential partner for NANOS2 that leads to the degradation of specific RNAs. We also present the first evidence that the zinc finger domain of Nanos acts as a protein-interacting domain for another RBP, providing a novel insight into Nanos-mediated germ cell development. PMID- 26589353 TI - Synaptotagmin-11 inhibits clathrin-mediated and bulk endocytosis. AB - Precise and efficient endocytosis is essential for vesicle recycling during a sustained neurotransmission. The regulation of endocytosis has been extensively studied, but inhibitors have rarely been found. Here, we show that synaptotagmin 11 (Syt11), a non-Ca(2+)-binding Syt implicated in schizophrenia and Parkinson's disease, inhibits clathrin-mediated endocytosis (CME) and bulk endocytosis in dorsal root ganglion neurons. The frequency of both types of endocytic event increases in Syt11 knockdown neurons, while the sizes of endocytosed vesicles and the kinetics of individual bulk endocytotic events remain unaffected. Specifically, clathrin-coated pits and bulk endocytosis-like structures increase on the plasma membrane in Syt11-knockdown neurons. Structural-functional analysis reveals distinct domain requirements for Syt11 function in CME and bulk endocytosis. Importantly, Syt11 also inhibits endocytosis in hippocampal neurons, implying a general role of Syt11 in neurons. Taken together, we propose that Syt11 functions to ensure precision in vesicle retrieval, mainly by limiting the sites of membrane invagination at the early stage of endocytosis. PMID- 26589355 TI - The Limited English Proficiency Patient Family Advocate Role: Fostering Respectful and Effective Care Across Language and Culture in a Pediatric Oncology Setting. AB - Patients and families with limited English proficiency (LEP) face a multitude of barriers both inside and outside the hospital walls. These barriers can contribute to difficulty accessing care and understanding/adhering to treatment recommendations, ultimately placing them at higher risk for poorer outcomes than their English-speaking counterparts. The LEP Patient Family Advocate role was created with the aim of improving access, promoting effective communication, and equalizing care for children with cancer from families with LEP. The goal of this mixed methods study was to describe the level of satisfaction and experiences of parents and health care providers who used the LEP Patient Family Advocate while receiving or providing care. Twelve parents and 15 health care providers completed quantitative surveys and an open-ended question about their experiences. High levels of satisfaction were reported. Themes about the role from qualitative responses included its positive effect on communication, trust, and connectedness between parents and staff. Continuity of care and safety were improved, and parents thought the role helped decrease their stress. The LEP Patient Family Advocate has a positive influence on family-centered cultural care. PMID- 26589354 TI - A computational analysis of S-(2-succino)cysteine sites in proteins. AB - The adduction of fumaric acid to the sulfhydryl group of certain cysteine (Cys) residues in proteins via a Michael-like reaction leads to the formation of S-(2 succino)cysteine (2SC) sites. Although its role remains to be fully understood, this post-translational Cys modification (protein succination) has been implicated in the pathogenesis of diabetes/obesity and fumarate hydratase-related diseases. In this study, theoretical approaches to address sequence- and 3D structure-based features possibly underlying the specificity of protein succination have been applied to perform the first analysis of the available data on the succinate proteome. A total of 182 succinated proteins, 205 modifiable, and 1750 non-modifiable sites have been examined. The rate of 2SC sites per protein ranged from 1 to 3, and the overall relative abundance of modifiable sites was 10.8%. Modifiable and non-modifiable sites were not distinguishable when the hydrophobicity of the Cys-flaking peptides, the acid dissociation constant value of the sulfhydryl groups, and the secondary structure of the Cys containing segments were compared. By contrast, significant differences were determined when the accessibility of the sulphur atoms and the amino acid composition of the Cys-flaking peptides were analysed. Based on these findings, a sequence-based score function has been evaluated as a descriptor for Cys residues. In conclusion, our results indicate that modifiable and non-modifiable sites form heterogeneous subsets when features often discussed to describe Cys reactivity are examined. However, they also suggest that some differences exist, which may constitute the baseline for further investigations aimed at the development of predictive methods for 2SC sites in proteins. PMID- 26589356 TI - Animal-Assisted Activities: Results From a Survey of Top-Ranked Pediatric Oncology Hospitals. AB - Animal-assisted activities (AAA) are increasingly common, yet little is known about practices in pediatric oncology. To address this gap, we surveyed the top 20 pediatric oncology hospitals in the United States in May and June of 2014. Questionnaires were sent via e-mail and generally returned by e-mail or postal mail. Among the 19 responding hospitals, the 18 that offered AAA to pediatric patients formed the basis of our analysis. All sites had written AAA policies. Most programs were restricted to dogs. At 11 hospitals, children with cancer could participate in AAA activities. Outpatient waiting rooms and individual inpatient rooms were the most common locations for AAA with pediatric oncology patients. Safety precautions varied by hospital, but all required hand sanitation after visits and that animals receive an annual health examination, be on a leash or in a carrier, be >=1 year old, and not be directly from a shelter. Our findings reveal consistencies and variations in practice that may help other hospitals develop their own programs and researchers identify areas of future study. PMID- 26589357 TI - Reconsidering Physical Activity Restrictions for Mononephric Survivors of Childhood Cancer: A Report From the Children's Oncology Group. AB - Although traditional recommendations for mononephric childhood cancer survivors are to avoid contact sports in order to protect the remaining kidney, review of available evidence suggests that the majority of renal loss is caused by accidents not involving sports. An interdisciplinary team performed a review of the English literature published from 1999 to 2012 within the PubMed, Cochrane, Google Scholar, and National Guidelines Clearinghouse databases. The level of evidence and proposed recommendations were graded according to an established rubric and GRADE criteria. Our review found that kidney loss is most commonly caused by nonsports activities such as motor vehicle accidents and falls, implying that restrictions on sports-related activity in mononephric pediatric survivors are not well supported. This favors encouraging ordinary sports and related activities without restriction in mononephric childhood cancer survivors because the known benefits of exercise outweigh the exceedingly low risk of renal loss. Accordingly, activity recommendations for mononephric patients have been revised in the most current version of the Children's Oncology Group Long-term Follow-Up Guidelines for Survivors of Childhood, Adolescent and Young Adult Cancers. This has important implications for this and similar populations who may now undertake individual and organized sports without undue regard for their mononephric status. PMID- 26589358 TI - Visualization and detection of live and apoptotic cells with fluorescent carbon nanoparticles. AB - Apoptosis is a genetically encoded cell death program that involves different processes occurring on molecular and sub-cellular levels. Here we report on its new features--the increased accumulation of fluorescent carbon nanoparticles (CDots) in cells and their changed distribution within cell interior, which can witness on altered mechanisms of their translocation through the membrane. The comparative studies of living (intact) and apoptotic cells were provided with two cell lines (HeLa, Vero) using two types of fluorescent nanoparticles ("violet" and "blue" CDots). In all studied cases the images of living and apoptotic cells were different; the apoptotic cells incorporated larger number of CDots resulting in their much brighter images. These nanoparticles are distributed in cell cytoplasm, however, when the cells are fixed and treated with detergent, their nucleus is also labeled. Flow cytometry allows distinguishing the sub-populations of living and apoptotic cells in their cultures and suggests a very cheap and easy way to characterize them. PMID- 26589359 TI - Information processing becomes slower and predominantly serial in aging: Characterization of response-related brain potentials in an auditory-visual distraction-attention task. AB - The aim of this study was to evaluate the effects of aging and attentional capture provoked by novel auditory stimuli on behavior (reaction time [RT], hits) and on response-related brain potentials (preRFP, CRN, postRFP, parietalRP) to target visual stimuli. Twenty-two young, 27 middle-aged, and 24 old adults performed an auditory-visual distraction-attention task. The RTs and latencies of preRFP, postRFP and parietalRT were longer in old and middle-aged than in young participants, reflecting the well-established age-related slowing of processing and performance. The inter-peak latencies (P3b-preRFP, preRFP-parietalRP, parietalRP-postRFP) were also longer in old and middle-aged than in young participants, further indicating an age-related tendency to increased predominance of serial (rather than parallel) processing of information, and that preRFP, CRN, postRFP, and parietalRP represent different cognitive processes from those indexed by the stimulus-related P3b. Finally, a distraction effect in performance (all three groups) and in postRFP latency (only middle-aged group) was also observed. PMID- 26589360 TI - Hemolytic disease of the fetus and newborn in the molecular era. AB - Maternal-fetal red cell antigen incompatibility can lead to alloimmunization, maternal immunoglobulin transplacental transfer, and hemolytic disease of the fetus and newborn (HDFN). The use of routine antenatal anti-D prophylaxis (RAADP) has sharply decreased the incidence of and mortality from HDFN due to RhD allosensitization. The ability to identify pregnancies/fetuses at risk of HDFN has significantly improved due to paternal molecular RHD zygosity testing, and non-invasive fetal molecular diagnostics for detecting putative antigen(s) (notably RhD) in fetuses utilizing cff-DNA in maternal plasma. Fetal RHD genotyping using cff-DNA has become increasingly accurate for fetal RHD detection, prompting some countries to implement targeted RAADP through mass screening programs of RhD-negative pregnant women. Along with middle cerebral artery Doppler ultrasonography for predicting fetal anemia, non-invasive fetal molecular diagnostics have greatly decreased the need for invasive diagnostic procedures in pregnancies at risk for severe HDFN. This review highlights these molecular advancements in HDFN-related prenatal diagnostics. PMID- 26589361 TI - Patterns of gene expression and DNA methylation in human fetal and adult liver. AB - BACKGROUND: DNA methylation is an important epigenetic control mechanism that has been shown to be associated with gene silencing through the course of development, maturation and aging. However, only limited data are available regarding the relationship between methylation and gene expression in human development. RESULTS: We analyzed the methylome and transcriptome of three human fetal liver samples (gestational age 20-22 weeks) and three adult human liver samples. Genes whose expression differed between fetal and adult numbered 7,673. Adult overexpression was associated with metabolic pathways and, in particular, cytochrome P450 enzymes while fetal overexpression reflected enrichment for DNA replication and repair. Analysis for DNA methylation using the Illumina Infinium 450 K HumanMethylation BeadChip showed that 42% of the quality filtered 426,154 methylation sites differed significantly between adult and fetal tissue (q <= 0.05). Differences were small; 69% of the significant sites differed in their mean methylation beta value by <=0.2. There was a trend among all sites toward higher methylation in the adult samples with the most frequent difference in beta being 0.1. Characterization of the relationship between methylation and expression revealed a clear difference between fetus and adult. Methylation of genes overexpressed in fetal liver showed the same pattern as seen for genes that were similarly expressed in fetal and adult liver. In contrast, adult overexpressed genes showed fetal hypermethylation that differed from the similarly expressed genes. An examination of gene region-specific methylation showed that sites proximal to the transcription start site or within the first exon with a significant fetal-adult difference in beta (>0.2) showed an inverse relationship with gene expression. CONCLUSIONS: Nearly half of the CpGs in human liver show a significant difference in methylation comparing fetal and adult samples. Sites proximal to the transcription start site or within the first exon that show a transition from hypermethylation in the fetus to hypomethylation or intermediate methylation in the adult are associated with inverse changes in gene expression. In contrast, increases in methylation going from fetal to adult are not associated with fetal-to-adult decreased expression. These findings indicate fundamentally different roles for and/or regulation of DNA methylation in human fetal and adult liver. PMID- 26589362 TI - Defining 'reasonable medical certainty' in court: What does it mean to medical experts in child abuse cases? AB - Physicians and others who provide expert testimony in court cases involving alleged child abuse may be instructed to state their conclusions within a 'reasonable medical certainty' (RMC). However, neither judges nor jurors knows what degree of probability constitutes RMC for a given expert, nor whether different experts use different standards to formulate their opinions. We sought to better understand how experts define RMC in the context of court cases. An email survey was sent to members of six list-serves, representing four specialties, whose members testify in child abuse cases. Respondents were asked to define how RMC corresponded to (1) the numerical probability that abuse occurred, (2) the ordinal probability, and (3) how their determinations relate to common legal standards ('preponderance of the evidence', 'clear and convincing', and 'beyond a reasonable doubt'). Participants were also asked how comfortable they were in defining RMC; whether their definition changed according to the charges or type of proceeding; and how they would apply RMC to several hypothetical cases. The 294 list-serve participants who responded included child abuse pediatricians (46%), forensic pathologists (21%), pediatric neurosurgeons (15%), pediatric ophthalmologists (12%), and others (6%). Though 95% of respondents had testified in court, only 45% had received training in the definition of RMC. Only 37% were comfortable defining RMC. Although many responses were highly clustered and paired comparisons showed that 95% of participants' responses were internally consistent, there was variability in respondents' definitions of RMC. There is some variability in how child abuse expert witnesses define and use the term RMC; we provide suggestions about how to more accurately and transparently define RMC to ensure justice in these cases. PMID- 26589363 TI - The need for research addressing alcohol use disorder and diabetes. PMID- 26589364 TI - Exposure to the mixture of organophosphorus pesticides is embryotoxic and teratogenic on gestational rats during the sensitive period. AB - Mixture of organophosphorus pesticides (MOPs) has been used worldwide to increase food production. The MOPs are harmful, and the exposure to them is both agricultural and nonagricultural through contaminated food. The neurotoxicity of MOPs has received more consideration recently due to the increased cases of malformed fetuses suspected to be caused by the MOPs exposure during gestation; however, relevant studies in animal model are rare. In this study, we performed a comprehensive analysis and demonstrated potential perinatal embryotoxicity and teratogenicity of MOPs exposure. As results, we found that MOPs decreased in utero fetal growth and alter the ratio of organs to whole body weight of the pregnant rats. MOPs also had been shown to disturb the balance of sex hormones and affect the reproduction of rats. Furthermore, we found various significantly elevated deformities in MOPs exposed embryos, confirming the embryotoxic and teratogenic effects of maternal exposure to MOPs. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 32: 139-146, 2017. PMID- 26589365 TI - Mixed primary squamous cell carcinoma, follicular carcinoma, and micropapillary carcinoma of the thyroid gland: A case report. AB - Primary squamous cell carcinoma of the thyroid gland is rare, and mixed squamous cell and follicular carcinoma is even rarer still, with only a few cases reported in the literature. The simultaneous presentation of three primary cancers of the thyroid has not been reported previously. Here we report a case of primary squamous cell carcinoma of the thyroid, follicular thyroid carcinoma, and micropapillary thyroid carcinoma. A 62-year-old female patient presented with complaints of pain and a 2-month history of progressively increased swelling in the anterior region of the neck. Fine-needle-aspiration cytology of both lobes indicated the possibility of the presence of a follicular neoplasm. Total thyroidectomy with left-sided modified radical neck dissection was performed. Postoperative pathological examination confirmed the diagnosis of thyroid follicular carcinoma with squamous cell carcinoma and micropapillary carcinoma of the thyroid. Thyroid-stimulating hormone suppressive therapy with l-thyroxine was administered. Radioiodine and radiotherapy also were recommended, but the patient did not complete treatment as scheduled. The patient remained alive more than 9 months after operation. The present case report provides an example of the coexistence of multiple distinct malignancies in the thyroid. PMID- 26589366 TI - Unilateral generalized linear porokeratosis with nail dystrophy. PMID- 26589367 TI - The effects of adiponectin and inflammatory cytokines on diabetic vascular complications in obese and non-obese patients with type 2 diabetes mellitus. AB - AIMS: To evaluate the associations between inflammatory cytokines and adiponectin and various vascular complications in type 2 diabetes mellitus (T2DM). METHODS: A total of 761 patients with T2DM were divided into a non-obese group and an obese group to enable the effects of obesity and T2DM on vascular complications to be differentiated. The serum levels of circulating inflammatory cytokines, that is, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-6, total adiponectin, and high molecular weight (HMW) adiponectin were measured, and carotid intima media thickness (IMT), the presence of carotid plaque, and the severities of retinopathy and nephropathy, were assessed. RESULTS: The obese group had significantly lower serum total and HMW adiponectin levels than the non-obese group. In the obese group, serum levels of total and HMW adiponectin, and TNF alpha were significantly higher in patients with proliferative retinopathy than in those without retinopathy after adjusting for covariates. In the non-obese group, only IL-6 levels were significantly higher in patients with proliferative retinopathy than in those without. Serum levels of total and HMW adiponectin were significantly higher in patients with macroalbuminuria than in those with normoalbuminuria. No significant difference of three cytokines levels were observed depending on the carotid IMT or the presence of plaque. Logistic regression analysis revealed that serum total adiponectin (OR=1.209, P=0.038), diabetes duration (OR=1.230, P=0.014), and HbA1c (OR=2.359, P=0.006) were significantly associated with proliferative retinopathy in the obese group. CONCLUSION: The study shows total adiponectin may influence proliferative retinopathy in obese patient with T2DM. PMID- 26589368 TI - Switching from atorvastatin to rosuvastatin lowers small, dense low-density lipoprotein cholesterol levels in Japanese hypercholesterolemic patients with type 2 diabetes mellitus. AB - AIMS: This open-label, randomized, parallel-group comparative study compared the efficacy of rosuvastatin (5mg/day) and atorvastatin (10mg/day) for reduction of small dense low-density lipoprotein cholesterol (sd LDL-C) levels in Japanese patients with type 2 diabetes mellitus (T2DM). METHODS: Patients with T2DM and hypercholesterolemia with detectable sd LDL-C after receiving 10mg/day atorvastatin for >= 24 weeks were randomly assigned to receive rosuvastatin (5mg/day; switched treatment) or atorvastatin (10mg/day; continued treatment) for 12 weeks. The primary endpoints were changes in sd LDL-C levels and sd LDL C/total LDL-C ratio evaluated using the LipoPhor AS((r)) system. RESULTS: There were no significant percent changes from baseline for LDL-C levels between the switched (n=55) and the continued treatment group (n=56). However, the former group exhibited a statistically significant reduction from baseline of sd LDL-C levels, sd LDL-C/total LDL-C ratio compared with the latter group (-3.8 mg/dL vs. -1.4 mg/dL, p=0.014; -2.3% vs. -0.6%, p=0.004, respectively). Multiple regression analysis among all subjects revealed that independent factors contributing to the reduction in sd LDL-C levels were a change in LDL-C (p=0.003) and triglyceride (TG) levels (p=0.006), treatment group (the switched group=1, the continued group=0; standard coefficient=-1.2, p=0.034) and baseline glycated hemoglobin A1c (HbA1c) (p=0.045), respectively. CONCLUSION: Switching from 10mg atorvastatin to 5mg rosuvastatin may be a useful therapeutic option to reduce sd LDL-C levels in Japanese hypercholesterolemic patients with T2DM. PMID- 26589370 TI - Liver function may play an uneven role in haemorrhagic transformation for stroke subtypes after acute ischaemic stroke. AB - BACKGROUND AND PURPOSE: Haemorrhagic transformation (HT) is common after acute ischaemic stroke. Whether liver function plays a role in HT remains an open question. METHODS: Acute ischaemic stroke patients within 7 days from stroke onset were included. Baseline data including liver function tests were collected. An independent association between liver function and HT was identified by multivariate regression analysis for stroke overall and stroke subtypes. RESULTS: A total of 2788 patients were included. HT occurred in 277 patients (9.9%), with 32 patients (1.1%) with symptomatic HT and 245 patients (8.8%) with asymptomatic HT. On multivariate regression analysis, aspartate aminotransferase (AST) and bilirubin (BILI) were independently associated with HT for stroke overall. In different stroke subtypes, AST was independently associated with HT for cardioembolic stroke, BILI for stroke of undetermined aetiology, and no liver function indicators for stroke of large-artery atherosclerosis and small-artery occlusion. CONCLUSIONS: Liver function played an uneven role in HT for different stroke subtypes. Indicators of liver function independently associated with HT were AST for cardioembolic stroke, BILI for stroke of undetermined aetiology and none for stroke of large-artery atherosclerosis and small-artery occlusion. PMID- 26589369 TI - Clinical significance of subclinical varicocelectomy in male infertility: systematic review and meta-analysis. AB - Recent meta-analysis by the Cochrane collaboration concluded that treatment of varicocele may improve an infertile couple's chance of pregnancy. However, there has been no consensus on the management of subclinical varicocele. Therefore, we determine the impact of varicocele treatment on semen parameters and pregnancy rate in men with subclinical varicocele. The randomised controlled trials that assessed the presence and/or treatment of subclinical varicocele were included for systematic review and meta-analysis. Random effect model was used to calculate the weighted mean difference of semen parameters and odds ratio of pregnancy rates. Seven trials with 548 participants, 276 in subclinical varicocelectomy and 272 in no-treatment or clomiphene citrate subjects, were included. Although there was also no statistically significant difference in pregnancy rate (OR 1.29, 95% CI 0.99-1.67), surgical treatment resulted in statistically significant improvements on forward progressive sperm motility (MD 3.94, 95% CI 1.24-6.65). However, the evidence is not enough to allow final conclusions because the quality of included studies is very low and further research is needed. PMID- 26589371 TI - Essential phospholipids as a supportive adjunct in the management of patients with NAFLD. AB - BACKGROUND AND STUDY AIMS: Treatment of nonalcoholic fatty liver (NAFLD) is important because NAFLD patients have a 1.7-fold increase in standardised age and gender matched mortality. Currently treatment is based on life style modification and managing comorbid associating disease. Other medications remain experimental. Essential phospholipid (EPL) is a nutrient for the liver, helping to maintain vitality of cell membranes where the vast majority of liver activities are regulated. We performed a randomised open label study to evaluate EPL as an adjuvant nutrient to the treatment of primary NAFLD or NAFLD with comorbid disease. PATIENTS AND METHOD: Three groups of NAFLD patients were recruited: lone (n=113), diabetes mellitus type 2 (n=107) and mixed hyperlipidaemia (n=104). Diagnosis was established by excluding other chronic liver diseases. A standard diet and physical activity plan were advised to all patients. 1800mg of EPL a day was given for 24weeks, followed by 900mg for 48weeks. RESULTS: Essential phospholipid EPL led to a significant improvement of symptoms and a mean reduction of ALT of 50.8IU and AST of 46.1IU per patient (p<0.01). Abdominal ultrasonography indicated normalisation in 4.6% and a shift from grade II to grade I in 24% of patients. Liver stiffness measurement indicated an improvement in 21.1%, with a mean reduction in the LSM of 3.1K Pascal/patient. Reducing the dosage after six months led to a limited relapse in 43.8-63.2% of patients, for lone and NAFLD with co-morbid conditions. CONCLUSION: Essential phospholipid (EPL) as a nutritional supplement resulted in a significant improvement in clinical parameters and transaminases for all NAFLD patients. Ultrasound and LSM revealed modest improvement. There is a need for uninterrupted maintenance to avoid relapse. PMID- 26589372 TI - Critical points related to the complications after endoscopic sphincterotomy in liver transplant recipients. PMID- 26589373 TI - Developments in surgical revascularization to achieve improved morbidity and mortality. AB - Coronary artery bypass graft surgery remains the main treatment modality for multivessel coronary artery disease and has consistently been demonstrated to have significantly lower rates of major adverse cardiac and cerebrovascular events in comparison to percutaneous coronary intervention. In this article we will explore the advances over time and the recent refinements in the techniques of surgical revascularization and how these contribute to the superior outcome profile associated with coronary artery bypass graft surgery. These include the current outcome status of coronary artery bypass grafting; the major landmark trials, registries and meta-analyses comparing coronary artery bypass grafting and percutaneous coronary intervention; the developments in coronary artery disease lesion classification; the techniques for the physiological assessment of coronary artery lesions; bypass grafting using arterial conduits; the role of off pump coronary artery surgery; the outcomes of reoperative surgery; hybrid techniques for coronary revascularization; minimally invasive coronary artery surgery and finally robotic surgery. PMID- 26589374 TI - Glycomapping the fine specificity of monoclonal and polyclonal Lewis antibodies with type-specific Lewis kodecytes and function-spacer-lipid constructs printed on paper. AB - BACKGROUND: Lewis serologic reagents frequently give inaccurate phenotyping results. Furthermore these serologic reagents are often used in nonserologic assays such as inhibition and immunohistochemistry. In both scenarios knowledge of the fine specificity and cross-reactivity of these reagents will improve the quality of results obtained. STUDY DESIGN AND METHODS: A range of contemporary and historical workshop and developmental Lewis reagents including mouse monoclonal (MoAb) and human and goat polyclonal (PoAb) reagents were evaluated. All were evaluated both against Lewis kodecytes expressing only single Le(a) , Le(b) , ALe(b) , BLe(b) , Le(x) , Le(y) , ALe(y) , or BLe(y) antigens and against the same antigens inkjet printed on a paper-based microplate and analyzed by enzyme immunoassay. Nine clinical samples were also evaluated. A kodecyte antigen dilution sensitivity assay was used to establish the ratio of Le(b) antigen between group A1 /A2 and O RBCs. RESULTS: A continuum of cross-reactivity from Le(x) through to H was observed with MoAbs. All PoAb and few MoAb anti-Le(a) samples and reagents cross-reacted to some degree with Le(b) antigen. Some PoAb and MoAb anti-Le(b) did not cross-react with Le(a) . All polyclonal goat anti Le(b) reagents showed substantial activity against ALe(b) and BLe(b) , while no MoAb reagent had this activity. A1 RBCs had less than half the Le(b) antigen of A2 /O RBCs. CONCLUSIONS: Substantial cross-reactivity of both MoAbs and PoAbs with related antigens highlights the risks of using serologic reagents in nonserologic assays or against synthetic antigens. The lack of ALe(b) activity in anti-Le(b) MoAbs explains their poor performance against blood group A1 Le(a-b+) phenotypes. PMID- 26589375 TI - Role of Pleiotropic Properties of Peroxisome Proliferator-Activated Receptors in the Heart: Focus on the Nonmetabolic Effects in Cardiac Protection. AB - Peroxisome proliferator-activated receptors, PPARalpha, PPARbeta/delta, and PPARgamma, are a group of nuclear receptors that function as transcriptional regulators of lipid metabolism, energy homeostasis, and inflammation. Given the role of metabolism imbalance under pathological states of the heart, PPARs have emerged as important therapeutic targets, and accumulating evidence highlights their protective role in the improvement of cardiac function under diverse pathological settings. Although the role of PPARs in the regulation of cardiac substrate utilization preference and energy homeostasis is well documented, their effects related to the regulation of cellular inflammatory and redox responses in the heart are less studied. In this review, we provide an overview on recent progress with respect to understanding the role of the nonmetabolic effects of PPARs in cardiac dysfunction, namely during ischemia/reperfusion injury, hypertrophy, and cardiac failure, and highlight the mechanisms underlying the protective effects against inflammation, oxidative stress, and cell death. The role of receptor-independent, nongenomic effects of PPAR agonists is also discussed. PMID- 26589376 TI - Reasons for, and outcomes of patients who were referred for a ventricular assist device but were declined: the recent era forgotten ones. AB - BACKGROUND: Ventricular assist devices (VADs) have a proven survival benefit in select patients with advanced heart failure, yet many patients considered for implantation are declined for various reasons. The outcome of these patients is obscure owing to their exclusion from recent VAD studies. We aim to compare the outcomes of patients who received a VAD to those who did not. METHODS: For this study, the Artificial Heart Program's database at Intermountain Medical Center was queried from 2006 to 2012 for patients referred for a VAD. Kaplan-Meier survival analysis was performed with log-rank test determining significance. RESULTS: Of 232 patients included, 118 patients received a VAD and 114 patients did not. The prevailing reason for VAD decline in eligible and willing patients was due to pre-existing illness (39%). Mortality was higher in non-VAD vs. VAD patients (58.8% vs. 35.6%, p < 0.001) with a median time-to-death of 67 (IQR:12 314) and 301 (IQR:136-694) d, respectively (p = 0.007). CONCLUSIONS: In the current era of non-pulsatile VADs, mortality of patients who are considered but not implanted remains high. Additionally, mortality of these patients occurred much sooner. Educational efforts ensuring timely referral for VAD therapy are important to maximize the number of patients who may benefit. PMID- 26589377 TI - Stress-related growth following sport injury: Examining the applicability of the organismic valuing theory. AB - This study explored the applicability of organismic valuing theory (OVT) to stress-related growth (SRG) following sport injury. Specifically, the direct and indirect relationships between need satisfaction (i.e., autonomy, competence, and relatedness), SRG, and subjective well-being (i.e., positive affect) were examined. Previously injured athletes (n = 520), ranging from 18 to 59 years of age (Mage = 23.3 years; standard deviation = 6.5), completed three measures: needs satisfaction scale, stress-related growth scale, and positive affect scale. Structural equation modeling with maximum likelihood estimation revealed a significant positive relationship between competence and relatedness and SRG, and between SRG and positive affect. In line with OVT, SRG was also found to mediate the relationship between need satisfaction (competence and relatedness) and subjective well-being. The findings offer preliminary support for the applicability of OVT in aiding our understanding of the antecedents and consequences of SRG. Future avenues of research are discussed, together with recommended methodologies to further extend and refine knowledge and understanding of the phenomenon of SRG following sport injury. PMID- 26589378 TI - Entomological studies of phlebotomine sand flies (Diptera: Psychodidae) in relation to cutaneous leishmaniasis transmission in Al Rabta, North West of Libya. AB - Al Rabta in the North-West of Libya is a rural area where cutaneous leishmaniasis (CL) is endemic for long time. Few reports are available on sand flies in this area which is an important focus of CL. Therefore, this study aimed at updating the species composition, and monthly fluctuation of sand flies in this area. Sand flies were biweekly collected by CDC light traps from June to November 2012 and April to November 2013 in two villages, Al Rabta East (RE) and Al Rabta West (RW). Nine species (6 Phlebotomus and 3 Sergentomyia) were reported in the two villages. A total of 5605 and 5446 flies were collected of which Phlebotomus represented 59.30 and 56.63% in RE and RW, respectively. Sergentomyia minuta and Phlebotomus papatasi were the abundant species. Generally, more males were collected than females for all species. The overall ratios (males: females) for most of species were not deviated from the expected 1:1 ratio (Chi-squared, P>0.05). Sand fly abundance (fly/trap) is directly related to the temperature and RH (P<0. 01) while it inversely related to wind velocity (P>0.05). Flies were active from April to November with increased activity from June to October. Prominent peaks were in September and June. The abundance of P. papatasi and Phlebotomus sergenti, vectors of CL (August-October) coincided with the reported higher numbers of CL cases (August- November). The obtained results could be important for the successful planning and implementation of leishmaniasis control programs. PMID- 26589381 TI - Bronsted Acid-Catalyzed Reactions of Trifluoroborate Salts with Benzhydryl Alcohols. AB - Bronsted acid-catalyzed carbon-carbon bond forming methodology using potassium alkynyl- and alkenyltrifluoroborate salts has been developed. Organotrifluoroborates react with benzhydryl alcohols to afford a broad range of alkynes and alkenes in good to excellent yields. This protocol features good atom economy because organotrifluoroborate salts and alcohols react in a 1:1 ratio. Furthermore, a variety of unprotected functional groups were tolerated under the developed conditions, including amide, aldehyde, free hydroxyl, and carboxylic acid. PMID- 26589380 TI - Understanding the impact of survival and human papillomavirus tumor status on timing of recurrence in oropharyngeal squamous cell carcinoma. AB - OBJECTIVES: Human papillomavirus (HPV)-positive tumor status is associated with improved prognosis after disease recurrence in oropharyngeal squamous cell carcinoma (OPSCC). In this study the potential role of survival bias in the relationship between HPV tumor status and the timing of recurrence was evaluated, given conflicting evidence in the literature. MATERIALS & METHODS: A secondary analysis was performed on a previously published retrospective two institution study of recurrent OPSCC with known HPV tumor status. Patients were categorized as "early" (surviving <24 months) or "late" survivors (?24 months). Timing of first recurrence and overall survival were analyzed using Kaplan-Meier and cox proportional hazard methods. Two-sided p-values <0.05 were considered significant. RESULTS: In total 101 patients met criteria including 81 late and 20 early survivors. HPV-positive tumor status was associated with longer time to recurrence in late survivors (median 21.8 vs. 13.8 months, p=0.028). Late survivors had later recurrences in HPV-positive (p<0.001) and HPV-negative patients (p=0.0096), as well as in both locoregional (p<0.0001) and distant metastatic recurrence (p<0.0001). In multivariate analysis, both HPV-positive tumor status (adjusted HR [aHR] 0.48, p=0.006) and survival beyond 24 months (aHR 0.21, p<0.001) were associated with later recurrence. When stratified, HPV tumor status was only associated with later recurrence in late survivors (aHR 0.47, p=0.015). CONCLUSIONS: Late survivorship was associated with late recurrence for both HPV-positive and HPV-negative patients. Stratification by survival illustrates how survival bias links late survivorship with late recurrences and contributes to our understanding of the impact of HPV tumor status on the timing of recurrence. PMID- 26589379 TI - Increasing women's sexual desire: The comparative effectiveness of estrogens and androgens. AB - Both estradiol and testosterone have been implicated as the steroid critical for modulating women's sexual desire. By contrast, in all other female mammals only estradiol has been shown to be critical for female sexual motivation and behavior. Pharmaceutical companies have invested heavily in the development of androgen therapies for female sexual desire disorders, but today there are still no FDA approved androgen therapies for women. Nonetheless, testosterone is currently, and frequently, prescribed off-label for the treatment of low sexual desire in women, and the idea of testosterone as a possible cure-all for female sexual dysfunction remains popular. This paper places the ongoing debate concerning the hormonal modulation of women's sexual desire within a historical context, and reviews controlled trials of estrogen and/or androgen therapies for low sexual desire in postmenopausal women. These studies demonstrate that estrogen-only therapies that produce periovulatory levels of circulating estradiol increase sexual desire in postmenopausal women. Testosterone at supraphysiological, but not at physiological, levels enhances the effectiveness of low-dose estrogen therapies at increasing women's sexual desire; however, the mechanism by which supraphysiological testosterone increases women's sexual desire in combination with an estrogen remains unknown. Because effective therapies require supraphysiological amounts of testosterone, it remains unclear whether endogenous testosterone contributes to the modulation of women's sexual desire. The likelihood that an androgen-only clinical treatment will meaningfully increase women's sexual desire is minimal, and the focus of pharmaceutical companies on the development of androgen therapies for the treatment of female sexual desire disorders is likely misplaced. PMID- 26589382 TI - Autobiographical age awareness disturbance syndrome in autoimmune limbic encephalitis: two case reports. AB - BACKGROUND: Autobiographical memory is a form of episodic memory characterized by a sense of time and consciousness that enables an individual to subjectively re experience his or her past. As part of this mental re-enactment, the past is recognized relative to the present. Dysfunction of this memory system may lead to confusion regarding the present perception of time. CASE PRESENTATION: Two Japanese women (42 and 55 years old) temporarily believed they were living in their past during a course of autoimmune limbic encephalitis. Their autobiographical memories and behaviour reflected their self-estimated age, and they could not recall memories experienced beyond that age. More surprisingly, their subjective age estimations and autobiographical memories were transiently corrected when they were made aware of their true age. Disorientation, anterograde amnesia, and retrograde amnesia were common additional symptoms. Neuroimaging suggested disturbances in medial temporal and orbitofrontal brain regions in both cases. CONCLUSIONS: This syndrome is characterized by three elements: 1) failure to subjectively recognize the present; 2) inability to suppress irrelevant past memories; and 3) transient restitution of awareness of the present through realization of the individual's true age. We defined this syndrome as 'autobiographical age awareness disturbance', and focused our investigation on the role of age self-awareness. If recall of relevant and suppression of irrelevant past memories are both necessary to subjectively recognize the present relative to the past, dysfunction of medial temporal and orbitofrontal brain regions is predicted to lead to abnormal subjective placement in time. However, the subjective experience of age tends to be an important informational component for retrieving remote autobiographical memories. This suggests that correct age awareness is essential for the proper recognition of the remote past in relation to the present. This is the first report to focus on the relationship between subjective temporal orientation and age self-awareness. While the role of age awareness in this process is still unclear, investigating autobiographical age awareness disturbance as a part of subjective temporal awareness dysfunction can be useful in understanding the processes underlying human time recognition. PMID- 26589383 TI - Single-prolonged stress induce different change in the cell organelle of the hippocampal cells: A study of ultrastructure. AB - MRI studies have revealed structural and functional changes in the hippocampus of post-traumatic stress disorder (PTSD) patients. Previous studies conducted by us in a PTSD animal model found that single prolonged stress (SPS) induced abnormal morphological changes in hippocampal cells. The effects of SPS on cellular organelles of the hippocampal neurons remain unknown; however, these changes have been involved in SPS-induced abnormal hippocampal function. The aim of the present study is to examine ultrastructural changes in cellular organelles, including the lysosomes, mitochondria (Mit), Golgi apparatus, and endoplasmic reticulum (ER), following SPS exposure using transmission electron microscopy, enzyme histochemistry, and enzyme cytochemistry. First, morphological changes of the hippocampal cells and ultrastructural changes in cellular organelles, including lysosomes, ER, and Mit-induced by SPS were observed. Results from histo and cytochemistry demonstrated that the Mit marker enzyme, cytochrome c oxidase (COX), and the lysosomal enzyme acid phosphatase, (ACP), increased following exposure to SPS. SPS induced COX release from Mit and led to a wider distribution of ACP in round lysosomes, NLY, and the Golgi. In addition, we found that SPS increased the presence of autophagosomes and induced changes in the autophagy related protein, Beclin. These results indicated the differential effects of SPS on cellular organelles, that is, a positive effect on lysosomes as well as a negative effect on the Mit and ER. Increased lysosomal function may serve as protection against SPS-induced cell damage. Structural changes in the Mit and ER may be involved in SPS-induced disorders of energy metabolism and protein synthesis and export. PMID- 26589384 TI - Expression patterns of taste receptor type 1 subunit 3 and alpha-gustducin in the mouse testis during development. AB - Taste receptor type 1 subunit 3 (T1R3) and its associated heterotrimeric G protein alpha-gustducin (Galpha) are involved in sweet and umami sensing in taste cells. They are also strongly expressed in the testis and sperm, but their expression patterns and potential roles involved were previously unknown. In present study, we investigated the expression patterns of T1R3 and Galpha in the mouse testis at critical stages of postnatal life, and throughout the spermatogenic cycle. Our results indicated that T1R3 and Galpha exhibited a stage dependent expression pattern during mouse development, and a cell-specific pattern during the spermatogenic cycle. Their expressions have been increased significantly from prepubertal to pubertal periods (P<005), and decreased significantly in aged mice (P<005). The changes were mainly attributed to the differential expression of T1R3 or Galpha in elongated spermatids and Leydig cells at different stages of the spermatogenic cycle. In addition, the expression of T1R3 and Galpha were first observed in residual bodies of spermatozoa and endothelial cells of blood vessels at post-pubertal mice, while Galpha was located in apoptotic spermatogonia of postnatal mice. These novel expression patterns suggest a role of T1R3 and Galpha in the onset of spermatogenesis, pace of spermatogenic cycle, and aging of the testis. PMID- 26589385 TI - Patterns of tear progression for asymptomatic degenerative rotator cuff tears. AB - BACKGROUND: The purpose of this study was to examine patterns of rotator cuff tear size progression in degenerative rotator cuff tears and to compare tear progression risks for tears with and without anterior supraspinatus tendon disruption. METHODS: Asymptomatic full-thickness rotator cuff tears with minimum 2-year follow-up were examined with annual shoulder ultrasound examinations. Integrity of the anterior 3 mm of the supraspinatus tendon determined classification of cable-intact vs. cable-disrupted tears. Tear enlargement was defined as an increase of 5 mm or more in width. Tear propagation direction was calculated from measured changes in tear width in reference to the biceps tendon on serial ultrasound examinations. RESULTS: The cohort included 139 full thickness tears with a mean subject age of 63.3 years and follow-up duration of 6.0 years. Ninety-six (69.1%) of the tears were considered cable intact. Cable disrupted tears were larger at baseline (median, 19.0 mm vs. 10.0 mm; P < .0001) than cable-intact tears. There was no difference in the risk of enlargement (52.1% vs. 67.4%; P = .09) or time to enlargement (3.2 vs. 2.2 years; P = .37) for cable-intact compared with cable-disrupted tears. There was no difference in the magnitude of enlargement for cable-intact and cable-disrupted tears (median, 7.0 mm vs.9.0 mm; P = .18). Cable-intact tears propagated a median of 5 mm anteriorly and 4 mm posteriorly, whereas cable-disrupted tears propagated posteriorly. CONCLUSIONS: The majority of degenerative rotator cuff tears spare the anterior supraspinatus tendon. Although tears classified as cable disrupted are larger at baseline than cable-intact tears, tear enlargement risks are similar for each tear type. PMID- 26589386 TI - Tip cell overtaking occurs as a side effect of sprouting in computational models of angiogenesis. AB - BACKGROUND: During angiogenesis, the formation of new blood vessels from existing ones, endothelial cells differentiate into tip and stalk cells, after which one tip cell leads the sprout. More recently, this picture has changed. It has become clear that endothelial cells compete for the tip position during angiogenesis: a phenomenon named tip cell overtaking. The biological function of tip cell overtaking is not yet known. From experimental observations, it is unclear to what extent tip cell overtaking is a side effect of sprouting or to what extent it is regulated through a VEGF-Dll4-Notch signaling network and thus might have a biological function. To address this question, we studied tip cell overtaking in computational models of angiogenic sprouting in absence and in presence of VEGF Dll4-Notch signaling. RESULTS: We looked for tip cell overtaking in two existing Cellular Potts models of angiogenesis. In these simulation models angiogenic sprouting-like behavior emerges from a small set of plausible cell behaviors. In the first model, cells aggregate through contact-inhibited chemotaxis. In the second model the endothelial cells assume an elongated shape and aggregate through (non-inhibited) chemotaxis. In both these sprouting models the endothelial cells spontaneously migrate forwards and backwards within sprouts, suggesting that tip cell overtaking might occur as a side effect of sprouting. In accordance with other experimental observations, in our simulations the cells' tendency to occupy the tip position can be regulated when two cell lines with different levels of Vegfr2 expression are contributing to sprouting (mosaic sprouting assay), where cell behavior is regulated by a simple VEGF-Dll4-Notch signaling network. CONCLUSIONS: Our modeling results suggest that tip cell overtaking can occur spontaneously due to the stochastic motion of cells during sprouting. Thus, tip cell overtaking and sprouting dynamics may be interdependent and should be studied and interpreted in combination. VEGF-Dll4-Notch can regulate the ability of cells to occupy the tip cell position in our simulations. We propose that the function of VEGF-Dll4-Notch signaling might not be to regulate which cell ends up at the tip, but to assure that the cell that randomly ends up at the tip position acquires the tip cell phenotype. PMID- 26589387 TI - Sleep inertia associated with a 10-min nap before the commute home following a night shift: A laboratory simulation study. AB - Night shift workers are at risk of road accidents due to sleepiness on the commute home. A brief nap at the end of the night shift, before the commute, may serve as a sleepiness countermeasure. However, there is potential for sleep inertia, i.e. transient impairment immediately after awakening from the nap. We investigated whether sleep inertia diminishes the effectiveness of napping as a sleepiness countermeasure before a simulated commute after a simulated night shift. N=21 healthy subjects (aged 21-35 y; 12 females) participated in a 3-day laboratory study. After a baseline night, subjects were kept awake for 27h for a simulated night shift. They were randomised to either receive a 10-min nap ending at 04:00 plus a 10-min pre-drive nap ending at 07:10 (10-NAP) or total sleep deprivation (NO-NAP). A 40-min York highway driving task was performed at 07:15 to simulate the commute. A 3-min psychomotor vigilance test (PVT-B) and the Samn Perelli Fatigue Scale (SP-Fatigue) were administered at 06:30 (pre-nap), 07:12 (post-nap), and 07:55 (post-drive). In the 10-NAP condition, total pre-drive nap sleep time was 9.1+/-1.2min (mean+/-SD), with 1.3+/-1.9min spent in slow wave sleep, as determined polysomnographically. There was no difference between conditions in PVT-B performance at 06:30 (before the nap). In the 10-NAP condition, PVT-B performance was worse after the nap (07:12) compared to before the nap (06:30); no change across time was found in the NO-NAP condition. There was no significant difference between conditions in PVT-B performance after the drive. SP-Fatigue and driving performance did not differ significantly between conditions. In conclusion, the pre-drive nap showed objective, but not subjective, evidence of sleep inertia immediately after awakening. The 10-min nap did not affect driving performance during the simulated commute home, and was not effective as a sleepiness countermeasure. PMID- 26589389 TI - Diet, exercise and the metabolic syndrome in schizophrenia: A cross-sectional study. PMID- 26589390 TI - Patterns of premorbid functioning in individuals at clinical high risk of psychosis. AB - In schizophrenia, four typical patterns of premorbid functioning have been observed: stable-good, stable-intermediate, poor-deteriorating and deteriorating. However, it is unknown whether similar patterns exist in those who are at clinical high risk (CHR) of psychosis. The aim of this study was to examine patterns of premorbid functioning in a large sample of individuals at CHR of psychosis and its association with symptoms, functioning, and conversion to psychosis. One-hundred sixty people at CHR of psychosis were assessed on premorbid functioning using the Premorbid Adjustment Scale. Poorer premorbid functioning was significantly correlated with worse negative symptom severity and lower social functioning. Cluster analysis was used to identify patterns of premorbid functioning. Results indicated three patterns of premorbid functioning in our CHR sample: stable-intermediate, stable-good, and deteriorating. The deteriorating group had more severe disorganization, worse negative symptoms, and poorer social functioning than the other groups. Participants who made the conversion to psychosis had significantly poorer premorbid functioning during adolescence compared to those who did not convert. These results suggest that those at a clinical high risk for psychosis display similar patterns in premorbid functioning as have been observed in those with a psychotic illness and that poor premorbid functioning may be a predictor of psychosis. PMID- 26589388 TI - Akathisia: prevalence and risk factors in a community-dwelling sample of patients with schizophrenia. Results from the FACE-SZ dataset. AB - The main objective of this study was to determine the prevalence of akathisia in a community-dwelling sample of patients with schizophrenia, and to determine the effects of treatments and the clinical variables associated with akathisia. 372 patients with schizophrenia or schizoaffective disorder were systematically included in the network of FondaMental Expert Center for Schizophrenia and assessed with validated scales. Akathisia was measured with the Barnes Akathisia Scale (BAS). Ongoing psychotropic treatment was recorded. The global prevalence of akathisia (as defined by a score of 2 or more on the global akathisia subscale of the BAS) in our sample was 18.5%. Patients who received antipsychotic polytherapy were at higher risk of akathisia and this result remained significant (adjusted odd ratio=2.04, p=.025) after controlling the influence of age, gender, level of education, level of psychotic symptoms, substance use comorbidities, current administration of antidepressant, anticholinergic drugs, benzodiazepines, and daily-administered antipsychotic dose. The combination of second-generation antipsychotics was associated with a 3-fold risk of akathisia compared to second generation antipsychotics used in monotherapy. Our results indicate that antipsychotic polytherapy should be at best avoided and suggest that monotherapy should be recommended in cases of akathisia. Long-term administration of benzodiazepines or anticholinergic drugs does not seem to be advisable in cases of akathisia, given the potential side effects of these medications. PMID- 26589391 TI - Implications for reactive oxygen species in schizophrenia pathogenesis. AB - Oxidative stress is a well-recognized participant in the pathophysiology of multiple brain disorders, particularly neurodegenerative conditions such as Alzheimer's and Parkinson's diseases. While not a dementia, a wide body of evidence has also been accumulating for aberrant reactive oxygen species and inflammation in schizophrenia. Here we highlight roles for oxidative stress as a common mechanism by which varied genetic and epidemiologic risk factors impact upon neurodevelopmental processes that underlie the schizophrenia syndrome. While there is longstanding evidence that schizophrenia may not have a single causative lesion, a common pathway involving oxidative stress opens the possibility for intervention at susceptible phases. PMID- 26589392 TI - Early insulin resistance predicts weight gain and waist circumference increase in first-episode psychosis--A one year follow-up study. AB - First-episode psychosis (FEP) is associated with weight gain during the first year of treatment, and risk of abdominal obesity is particularly increased. To identify early risk markers of weight gain and abdominal obesity, we investigated baseline metabolic differences in 60 FEP patients and 27 controls, and longitudinal changes during the first year of treatment in patients. Compared to controls at baseline, patients had higher low-density lipoprotein, triglyceride and apolipoprotein B levels, and lower levels of high-density lipoprotein and apolipoprotein A-I but no difference in body mass index or waist circumference. At 12-month follow-up, 60.6% of patients were overweight or obese and 58.8% had abdominal obesity. No significant increase during follow-up was seen in markers of glucose and lipid metabolism or blood pressure, but increase in C-reactive protein between baseline and 12-month follow-up was statistically significant. Weight increase was predicted by baseline insulin resistance and olanzapine use, while increase in waist circumference was predicted by baseline insulin resistance only. In conclusion, insulin resistance may be an early marker of increased vulnerability to weight gain and abdominal obesity in young adults with FEP. Olanzapine should be avoided as a first-line treatment in FEP due to the substantial weight increase it causes. In addition, the increase in the prevalence of overweight and abdominal obesity was accompanied by the emergence of low-grade systemic inflammation. PMID- 26589394 TI - Myocardial histology and outcome after cardiopulmonary bypass of neonatal piglets. AB - BACKGROUND: Early after neonatal cardiac surgery hemodynamic dysfunction may be evident. However, still is not clear if dysfunction and outcome is related to visible myocardial alterations. The aim of the present study was the histological analysis of myocardial tissue of neonatal piglets after cardiopulmonary bypass (CPB) and cardioplegic arrest. METHODS: Neonatal piglets (younger than 7 days) were connected to CPB for 180 min, including 90 min of cardioplegic heart arrest at 32 degrees C. After termination of CPB the piglets were observed up to 6 h. During this observational period animals did not receive any inotropic support. Some piglets died within this period and formed the non-survivors group (CPB-NS group) and the remaining animals formed the CPB-6 h group. Myocardial biopsies (stained with H&E) were scored from 0 to 3 regarding histological alterations. Then, the histological data were evaluated and compared to the probes of animals handled comparable to previous piglets but without CPB (non-CPB group; n = 3) and to sibling piglets without specific treatment (control; n = 5). RESULTS: In the first hours after CPB six piglets out of 10 died (median 3.3 h). The animals of CPB-6 h group (n = 4) were sacrificed at the end of experiments (6 h after CPB). Although the myocardial histological score of CPB-6 h group and CPB-NS group were higher than non-CPB group (2.0 +/- 0.8, 1.5 +/- 0.9, and 0.8 +/- 0.3 respectively), these differences were statistically not significant. But compared to control animals (score 0.3 +/- 0.5) the scores of CPB-6 h and CPB-NS groups were significantly higher (p < 0.05). Between the left and the right ventricular tissue there were no significant differences. CONCLUSIONS: Myocardial tissue alterations in newborn piglets are related to the surgical trauma and potentiated by cardiopulmonary bypass and ischemia. However, outcome is not related to the degree of tissue alteration. PMID- 26589393 TI - Relationship of serum levels of TNF-alpha, IL-6 and IL-18 and schizophrenia-like symptoms in chronic ketamine abusers. AB - OBJECTIVE: Exposing to NMDAR receptor antagonists, such as ketamine, produces schizophrenia-like symptoms in humans and deteriorates symptoms in schizophrenia patients. Meanwhile, schizophrenia is associated with alterations of cytokines in the immune system. This study aims to examine the serum TNF-alpha, IL-6 and IL-18 levels in chronic human ketamine users as compared to healthy subjects. The correlations between the serum cytokines levels with the demographic, ketamine use characteristics and psychiatric symptoms were also assessed. METHODS: 155 subjects who fulfilled the criteria of ketamine dependence and 80 healthy control subjects were recruited. Serum TNF-alpha, IL-6 and IL-18 levels were measured using an enzyme-linked immunosorbent assay (ELISA). The psychiatric symptoms of the ketamine abusers were assessed using the Positive and Negative Syndrome Scale (PANSS). RESULTS: Serum IL-6 and IL-18 levels were significantly higher, while serum TNF-alpha level was significantly lower among ketamine users than among healthy controls (p<0.05). Serum TNF-alpha levels showed a significant negative association with PANSS total score (r=-0.210, p<0.01) and negative subscore (r= 0.300, p<0.01). No significant association was found between PANSS score and serum levels of IL-6 and IL-18. CONCLUSIONS: Serum levels of TNF-alpha, IL-6 and IL-18 were altered in chronic ketamine abusers which may play a role in schizophrenia-like symptoms in chronic ketamine abusers. PMID- 26589396 TI - Erratum to: Do personalised e-mail invitations increase the response rates of breast cancer survivors invited to participate in a web-based behaviour change intervention? A quasi-randomised 2-arm controlled trial. PMID- 26589395 TI - Seasonal variation in affective and other clinical symptoms among high-risk families for bipolar disorders in an Arctic population. AB - BACKGROUND: In bipolar disorder (BD), seasonality of symptoms is common and disturbances in circadian rhythms have been reported. OBJECTIVES: We identified high-penetrance families in a geographically restricted area in Northern Fennoscandia and studied the seasonal variation of clinical symptoms among BD subjects and their healthy relatives. DESIGN: We explored the clinical characteristics of subjects living in Northern Fennoscandia, with extreme annual variation in daylight. Among known indigenous high-risk families for BD, we compared the affected ones (N=16) with their healthy relatives (N=15), and also included 18 healthy non-related controls from the same geographical area. Seasonal fluctuation in clinical measures was followed up at the 4 most demarcated photoperiodic time points of the annual cycle: around the summer solstice and autumn equinox in 2013, the winter solstice in 2013/2014, and the spring equinox in 2014. In the baseline, lifetime manic symptoms [Mood Disorder Questionnaire (MDQ)] and morningness-eveningness questionnaire type (MEQ) were registered, whereas in the follow-up, depressive [Beck Depression Inventory (BDI)] and distress [General Health Questionnaire (GHQ-12)] symptoms and alcohol consumption and sleep were recorded. RESULTS: Possibly indicative or statistically significant differences in symptoms between the affected subjects and their healthy relatives were the BDI winter (13.3 vs. 2.6, t=-2.51, p=0.022) and spring scores (12.6 vs. 3.2, t=-1.97, p=0.063) and GHQ winter (4.2 vs. 0.82, t=-2.08, p=0.052) and spring scores (3.8 vs. 0.82, t=-1.97, p=0.063). Scores were higher among the affected subjects, exceeding a possibly diagnostic threshold (10 and 3) at all the time points, and without the notable seasonality which was observed among the healthy relatives. In the overall population, MDQ and MEQ scores had an inverse correlation (-0.384, significant at 0.016), indicating increased lifetime manic behaviour among "the night owl" chronotype subjects. CONCLUSIONS: In an Arctic population sample, we found different seasonal fluctuation in mood and distress symptoms and sleep duration scores between subjects with bipolar spectrum disorders and their healthy relatives. Despite the relatively small sample size, the results indicate that the symptoms and signs of BD relate to a disturbance in seasonal variation. Seasonal variation can be considered as an interesting endophenotype for BD and a promising target for further genetic studies. PMID- 26589398 TI - Novel therapeutic targets in advanced urothelial carcinoma. AB - Bladder cancer remains one of the most common and lethal diseases that cause approximately 150,000 deaths per year worldwide. Over the past two decades, the options currently available to patients with invasive disease remained essentially unchanged and no effective drugs have been approved in that time. Cisplatin-based combination chemotherapy remains the standard of care for first line systemic treatment of metastatic urothelial carcinoma. However, the major advances in understanding the genetic background of urothelial tumors open up a new therapeutic area. Here, we summarize the current state of development of targeted agents in urothelial cancer; with an emphasis on immune checkpoints inhibitors and FGFR targeted therapies that represent the most promising therapeutic approaches for invasive bladder cancer. PMID- 26589397 TI - Centrosome amplification and clonal evolution in multiple myeloma: Short review. AB - Multiple myeloma (MM) is composed of an array of multiple clones, each potentially associated with different clinical behavior. Previous studies focused on clinical implication of centrosome amplification (CA) in MM show contradictory results. It seems that the role of CA as well as CA formation in MM differ from other malignancies. This has brought about a question about the role of CA positive clone which is--is it going to be a more aggressive clone evolutionally arising under pressure of negative conditions or can CA serve as a marker of cell abnormality and lead to cell death and further elimination of this damaged subpopulation? This current review is devoted to the discussion of the existence of MM subclones with centrosome amplification (CA), its evolutionary behaviour within intraclonal heterogeneity as well as its potential impact on the disease progression and MM treatment. PMID- 26589399 TI - Do open youth unemployment and youth programs leave the same mental health scars? -Evidence from a Swedish 27-year cohort study. AB - BACKGROUND: Recent findings suggest that the mental health costs of unemployment are related to both short- and long-term mental health scars. The main policy tools for dealing with young people at risk of labor market exclusion are Active Labor Market Policy programs for youths (youth programs). There has been little research on the potential effects of participation in youth programs on mental health and even less on whether participation in such programs alleviates the long-term mental health scarring caused by unemployment. This study compares exposure to open youth unemployment and exposure to youth program participation between ages 18 and 21 in relation to adult internalized mental health immediately after the end of the exposure period at age 21 and two decades later at age 43. METHODS: The study uses a five wave Swedish 27-year prospective cohort study consisting of all graduates from compulsory school in an industrial town in Sweden initiated in 1981. Of the original 1083 participants 94.3% of those alive were still participating at the 27-year follow up. Exposure to open unemployment and youth programs were measured between ages 18-21. Mental health, indicated through an ordinal level three item composite index of internalized mental health symptoms (IMHS), was measured pre-exposure at age 16 and post exposure at ages 21 and 42. Ordinal regressions of internalized mental health at ages 21 and 43 were performed using the Polytomous Universal Model (PLUM). Models were controlled for pre-exposure internalized mental health as well as other available confounders. RESULTS: Results show strong and significant relationships between exposure to open youth unemployment and IMHS at age 21 (OR = 2.48, CI = 1.57-3.60) as well as at age 43 (OR = 1.71, CI = 1.20-2.43). No such significant relationship is observed for exposure to youth programs at age 21 (OR = 0.95, CI = 0.72-1.26) or at age 43 (OR = 1.23, CI = 0.93-1.63). CONCLUSIONS: A considered and consistent active labor market policy directed at youths could potentially reduce the short- and long-term mental health costs of youth unemployment. PMID- 26589400 TI - Transcriptomic analysis of the host response to an iridovirus infection in Chinese giant salamander, Andrias davidianus. AB - The emergence of an infectious viral disease caused by the Chinese giant salamander iridovirus (GSIV) has led to substantial economic losses. However, no more molecular information is available for the understanding of the mechanisms associated with virus-host interaction. In this study, de novo sequencing was used to obtain abundant high-quality ESTs and investigate differentially expressed genes in the spleen of Chinese giant salamanders that were either infected or mock infected with GSIV. Comparative expression analysis indicated that 293 genes were down-regulated and 220 genes were up-regulated. Further enrichment analysis showed that the most enriched pathway is "complement and coagulation cascades", and significantly enriched diseases include "inherited thrombophilia", "immune system diseases", "primary immunodeficiency", "complement regulatory protein defects", and "disorders of nucleotide excision repair". Additionally, 30 678 simple sequence repeats (SSRs) from all spleen samples, 26 355 single nucleotide polymorphisms (SNPs) from the spleens of uninfected animals and 36 070 SNPs from the spleens of infected animals were detected. The large amount of variation was specific for the Chinese giant salamanders that were infected with GSIV. The results reported herein provided significant and new EST information that could contribute greatly in investigations into the molecular functions of immune genes in the Chinese giant salamander. PMID- 26589401 TI - Effectiveness of facial exercise therapy for facial nerve dysfunction after superficial parotidectomy: a randomized controlled trial. AB - OBJECTIVES: To compare the effectiveness of a daily home-based facial exercise therapy with a supervised rehabilitation technique for the treatment of postoperative facial dysfunction in patients undergoing conventional superficial parotidectomy. DESIGN: Prospective, randomized trial, controlled. SETTING: Surgery and Rehabilitation Units, university hospital. SUBJECTS: Consecutive patients ( n=79, mean age 48 years) who underwent superficial parotidectomy with facial nerve dissection were randomly divided into two groups. INTERVENTION: Control group (CG) were given a daily homework manual to perform ordinary postoperative facial mimic exercises autonomously in front of the mirror at home. Experimental group (EG) patients with moderate-severe paresis received supervised rehabilitation therapy that consisted in weekly sessions with facial exercises and massages and performed daily facial exercises at home. EG patients with slight paresis were instructed to undertake self-massage and mirror exercises. MAIN OUTCOME MEASURES: Postoperative dysfunction of facial nerve and branches was quantified measuring the prevalence, magnitude and duration of paresis by the House-Brackmann Facial Nerve Grading System up to 12th months. RESULTS: Facial paresis incidence at 1st week was 77.2%, being the marginal-mandibular nerve the most affected (64.5%). No statistically significant differences were found at any time of the study when comparing the frequency, magnitude and duration of paresis between EG and CG and among patients who had presented moderate-severe paresis. In the absence of intraoperative nerve injury, complete recovery of facial mobility was observed within 12 months, regardless of treatment group. CONCLUSION: Rehabilitation therapy and mirror facial exercises performed autonomously at home were equally effective for postoperative functional recovery. PMID- 26589403 TI - Patterns of Exposure of Iberian Wolves (Canis lupus) to Canine Viruses in Human Dominated Landscapes. AB - Wildlife inhabiting human-dominated landscapes is at risk of pathogen spill-over from domestic species. With the aim of gaining knowledge in the dynamics of viral infections in Iberian wolves (Canis lupus) living in anthropized landscapes of northern Spain, we analysed between 2010 and 2013 the samples of 54 wolves by serology and polymerase chain reaction (PCR) for exposure to four pathogenic canine viruses: canine distemper virus (CDV), canine parvovirus-2 (CPV), canine adenovirus 1 and 2 (CAV-1 and CAV-2) and canine herpesvirus. Overall, 76% of the studied wolves presented evidence of exposure to CPV (96% by HI, 66% by PCR) and 75% to CAV (75% by virus neutralization (VN), 76% by PCR, of which 70% CAV-1 and 6% CAV-2). This represents the first detection of CAV-2 infection in a wild carnivore. CPV/CAV-1 co-infection occurred in 51% of the wolves. The probability of wolf exposure to CPV was positively and significantly correlated with farm density in a buffer zone around the place where the wolf was found, indicating that rural dogs might be the origin of CPV infecting wolves. CPV and CAV-1 appear to be enzootic in the Iberian wolf population, which is supported by the absence of seasonal and inter-annual variations in the proportion of positive samples detected. However, while CPV may depend on periodical introductions by dogs, CAV 1 may be maintained within the wolf population. All wolves were negative for exposure to CDV (by VN and PCR) and CHV (by PCR). The absence of acquired immunity against CDV in this population may predispose it to an elevated rate of mortality in the event of a distemper spill-over via dogs. PMID- 26589404 TI - Molecular mechanism of positive allosteric modulation of the metabotropic glutamate receptor 2 by JNJ-46281222. AB - BACKGROUND AND PURPOSE: Allosteric modulation of the mGlu2 receptor is a potential strategy for treatment of various neurological and psychiatric disorders. Here, we describe the in vitro characterization of the mGlu2 positive allosteric modulator (PAM) JNJ-46281222 and its radiolabelled counterpart [(3) H] JNJ-46281222. Using this novel tool, we also describe the allosteric effect of orthosteric glutamate binding and the presence of a bound G protein on PAM binding and use computational approaches to further investigate the binding mode. EXPERIMENTAL APPROACH: We have used radioligand binding studies, functional assays, site-directed mutagenesis, homology modelling and molecular dynamics to study the binding of JNJ-46281222. KEY RESULTS: JNJ-46281222 is an mGlu2 selective, highly potent PAM with nanomolar affinity (KD = 1.7 nM). Binding of [(3) H]-JNJ-46281222 was increased by the presence of glutamate and greatly reduced by the presence of GTP, indicating the preference for a G protein bound state of the receptor for PAM binding. Its allosteric binding site was visualized and analysed by a computational docking and molecular dynamics study. The simulations revealed amino acid movements in regions expected to be important for activation. The binding mode was supported by [(3) H]-JNJ-46281222 binding experiments on mutant receptors. CONCLUSION AND IMPLICATIONS: Our results obtained with JNJ-46281222 in unlabelled and tritiated form further contribute to our understanding of mGlu2 allosteric modulation. The computational simulations and mutagenesis provide a plausible binding mode with indications of how the ligand permits allosteric activation. This study is therefore of interest for mGlu2 and class C receptor drug discovery. PMID- 26589405 TI - [Percutaneous lead extraction. Complications and their management]. AB - BACKGROUND: Percutaneous lead extraction represents one of the most difficult and challenging interventions in the therapy with cardiac implantable electronic devices (CIEDs). Despite the progress in outcome and safety of these procedures in the last decade, the first published results of the ELECTRa registry point out that the risk of life-threatening complications should not be underestimated. Therefore, pre-operative screening for indications, present infections, pacemaker dependency, age and type of implanted leads, previous cardiac surgery and presence of anatomic variations are prerequisite to assess the individual operation risk. RESULTS: Apart from the decision for any particular operative approach, the risk-adjusted settings should be selected in order to enable intraoperative escalation of extraction methods, if needed. A good theoretical knowledge of potential perioperative problems and complications as well as the intraoperative use of TEE enables early detection and management of complications. Furthermore, preoperative arrangements with other professionals and a team approach in emergency management enable fast and structured action when needed, thus, reducing mortality in case of life-threatening complications. PMID- 26589402 TI - Practical guidelines for B-cell receptor repertoire sequencing analysis. AB - High-throughput sequencing of B-cell immunoglobulin repertoires is increasingly being applied to gain insights into the adaptive immune response in healthy individuals and in those with a wide range of diseases. Recent applications include the study of autoimmunity, infection, allergy, cancer and aging. As sequencing technologies continue to improve, these repertoire sequencing experiments are producing ever larger datasets, with tens- to hundreds-of millions of sequences. These data require specialized bioinformatics pipelines to be analyzed effectively. Numerous methods and tools have been developed to handle different steps of the analysis, and integrated software suites have recently been made available. However, the field has yet to converge on a standard pipeline for data processing and analysis. Common file formats for data sharing are also lacking. Here we provide a set of practical guidelines for B-cell receptor repertoire sequencing analysis, starting from raw sequencing reads and proceeding through pre-processing, determination of population structure, and analysis of repertoire properties. These include methods for unique molecular identifiers and sequencing error correction, V(D)J assignment and detection of novel alleles, clonal assignment, lineage tree construction, somatic hypermutation modeling, selection analysis, and analysis of stereotyped or convergent responses. The guidelines presented here highlight the major steps involved in the analysis of B-cell repertoire sequencing data, along with recommendations on how to avoid common pitfalls. PMID- 26589406 TI - Photophysical properties of copper(I) complexes containing pyrazine-fused phenanthroline ligands: a joint experimental and theoretical investigation. AB - Two copper(I) complexes [Cu(Pyz-Phen)2]PF6 (1) and [Cu(POP)(Pyz-Phen)]PF6 (2) (Pyz-Phen = pyrazino[2,3-f] [1, 10]phenanthroline, POP = bis[2-diphenylphosphino] phenyl]ether) have been synthesized and characterized. The photophysical properties of these complexes in solution have been studied. The electronic absorption spectrum of complexes 1 exhibit the lowest-lying MLCT absorption band at 459 nm and high-energy ligand-based transitions at 275 nm, while that of complex 2 exhibits the MLCT/LLCT band at 400 nm and ligand pi-pi* band at 262 nm. In addition, both 1 and 2 show similar phosphorescence (3)MLCT/(3)LLCT emissions with maximum emission wavelengths of 569 and 572 nm, respectively. Density functional theory (DFT) and time-dependent density functional theory (TDDFT) were employed to rationalize the photophysical properties of the complexes studied. The theoretical data confirm the assignment of the experimental absorption spectra and the nature of the emitting states. Graphical Abstract Photophysical properties of copper(I) complexes containing pyrazine-fused phenanthroline ligands. PMID- 26589407 TI - Ensembling and filtering: an effective and rapid in silico multitarget drug design strategy to identify RIPK1 and RIPK3 inhibitors. AB - Necroptosis, a programmed necrosis pathway, is witnessed in diverse human diseases and is primarily regulated by receptor-interacting serine/threonine protein kinase 1 (RIPK1) and RIPK3. Ablation or inhibition of these individual proteins, or both, has been shown to be protective in various in vitro and in vivo disease models involving necroptosis. In this study, we propose an effective and rapid virtual screening strategy to identify multitarget inhibitors of both RIPK1 and RIPK3. It involves ensemble pharmacophore-based screening (EPS) of a compound database, post-EPS filtration (PEPSF) of the ligand hits, and multiple dockings. Structurally diverse inhibitors were identified through ensemble pharmacophore features, and the speed of this process was enhanced by filtering out the compounds containing cross-features. The stability of these inhibitors with both of the proteins was verified by means of molecular dynamics (MD) simulation. Graphical Abstract A generalized workflow employed in this study. Subsequent utilization of EPS and PEPSF might lead to reduced computational time and load. PMID- 26589408 TI - Theoretical investigation of the aromaticity and electronic properties of protonated and unprotonated molecules in the series hexaphyrin(1.0.0.1.0.0) to hexaphyrin(1.1.1.1.1.1). AB - A series of hexaphyrins with different meso-carbon atoms and their protonated structures were investigated using density functional theory (DFT) and time dependent DFT. Frontier molecular orbitals (FMOs), aromaticity, and electronic spectra were investigated systematically before and after protonation. The FMO energy gaps before and after protonation were different for the antiaromatic molecules, while they were only slightly different for the aromatic molecules. By analyzing the electronic spectra of the aromatic molecules, the absorption peaks in the Q-like and B-like bands were not significantly different before and after protonation. However, the absorption peaks of the antiaromatic molecules were clearly different before and after protonation in both the Q-like and B-like bands. [24]Hexaphyrin (1.0.1.0.1.0) has 24 pi-electrons and is Huckel antiaromatic. However, the absorption spectrum of protonated [24]hexaphyrin (1.0.1.0.1.0) showed aromaticity. In addition, these conclusions were generally consistent with the FMOs, nucleus-independent chemical shifts, harmonic oscillator model of aromaticity, and absorption spectra. Although protonated [24]hexaphyrin (1.0.1.0.1.0) has 24 pi-electrons and is Huckel antiaromatic, it has Mobius aromaticity because of the single-sided Mobius topological structure. This explains why [24]hexaphyrin (1.0.1.0.1.0) has diatropic ring currents in solvent. To the best of our knowledge, this system is the smallest Mobius aromatic molecule among the many uncoordinated extended porphyrins. PMID- 26589409 TI - Biomarkers related to immunosenescence: relationships with therapy and survival in lung cancer patients. AB - PURPOSE: There are well-known alterations occurring within the immune system with aging. Collectively, these changes are known as immunosenescence. The incidence of malignancies also increases with age. The aim of this study was to determine the presence of immunosenescence biomarkers in non-small cell lung cancer (NSCLC) patients and to evaluate some of them as predictive biomarkers of CIMAvax-EGF cancer vaccine efficacy. METHODS: Sixty-six NSCLC patients, vaccinated or not with CIMAvax-EGF cancer vaccine, and 37 age-matched controls were enrolled. Peripheral blood samples were studied for CD19+, CD4+, CD8+, CD28-, CD57+ and CD45RA+ subpopulations by flow cytometry. RESULTS: Absolute count of CD19+ and the CD4/CD8 ratio were significantly lower in NSCLC patients than in age-paired controls, while highly differentiated T cells increased in NSCLC patients treated with platinum-based chemotherapy. Using Cox regression, we were able to dichotomize the patient population according to biomarkers. Vaccinated patients with frequency <24 % of CD8 + CD28- T cells, >40 % of CD4 T cells and CD4/CD8 ratio higher than two at the beginning of immunotherapy achieved a 20-month increase in median survival regarding control patients. CONCLUSIONS: Distribution of lymphocyte subsets was influenced by cancer and chemotherapy in NSCLC patients. CD19 + B cells decrease by cancer disease and not by chemotherapy, and CD28- subpopulations increase by chemotherapy and not by cancer. The proportion of CD8 + CD28- T cells, CD4+ T cells and CD4/CD8 ratio can be used as predictive biomarkers of CIMAvax-EGF efficacy in NSCLC patients and thereby could, be a useful tool for a personalized treatment. PMID- 26589410 TI - A Novel Method for Preparing Surface-Modified Fluocinolone Acetonide Loaded PLGA Nanoparticles for Ocular Use: In Vitro and In Vivo Evaluations. AB - Our objective was to prepare nanoparticulate system using a simple yet attractive innovated method as an ophthalmic delivery system for fluocinolone acetonide to improve its ocular bioavailability. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles were prepared by adopting thin film hydration method using PLGA/poloxamer 407 in weight ratios of 1:5 and 1:10. PLGA was used in 75/25 and 50/50 copolymer molar ratio of DL-lactide/glycolide. Results revealed that using PLGA with lower glycolic acid monomer ratio exhibited high particle size (PS), zeta potential (ZP) and drug encapsulation efficiency (EE) values with slow drug release pattern. Also, doubling the drug concentration during nanoparticles preparation ameliorated its EE to reach almost 100%. Furthermore, studies for separating the un-entrapped drug in nanoparticles using centrifugation method at 20,000 rpm for 30 min showed that the separated clear supernatant contained nanoparticles encapsulating an important drug amount. Therefore, separation of un entrapped drug was carried out by filtrating the preparation using 20-25 MUm pore size filter paper to avoid drug loss. Aiming to increase the PLGA nanoparticles mucoadhesion ability, surface modification of selected formulation was done using different amount of stearylamine and chitosan HCl. Nanoparticles coated with 0.1% w/v chitosan HCl attained most suitable results of PS, ZP and EE values as well as high drug release properties. Transmission electron microphotographs illustrated the deposition of chitosan molecules on the nanoparticles surfaces. Pharmacokinetic studies on Albino rabbit's eyes using HPLC indicated that the prepared novel chitosan-coated PLGA nanoparticles subjected to separation by filtration showed rapid and extended drug delivery to the eye. PMID- 26589411 TI - Are Efficient Designs Used in Discrete Choice Experiments Too Difficult for Some Respondents? A Case Study Eliciting Preferences for End-of-Life Care. AB - BACKGROUND: Although efficient designs have sample size advantages for discrete choice experiments (DCEs), it has been hypothesised that they may result in biased estimates owing to some respondents using simplistic heuristics. OBJECTIVES: The main objective was to provide a case study documenting that many respondents choose on the basis of a single attribute when exposed to highly efficient DCE designs but switch to a conventional multi-attribute decision rule when the design efficiency was lowered (resulting in less need to trade across all attributes). Additional objectives included comparisons of the sizes of the estimated coefficients and characterisation of heterogeneity, thus providing evidence of the magnitude of bias likely present in highly efficient designs. METHODS: Five hundred and twenty-five respondents participating in a wider end-of life survey each answered two DCEs that varied in their design efficiency. The first was a Street and Burgess 100% efficient Orthogonal Main Effects Plan design (2(7) in 8), using the top and bottom levels of all attributes. The second DCE comprised one eighth of the full Orthogonal Main Effects Plan in 32 pairs, (a 2 * 4(6)). Linear probability models estimated every respondent's complete utility function in DCE1. The number of respondents answering on the basis of one attribute level was noted, as was the proportion of these who then violated this rule in DCE2, the less efficient DCE. Latent class analyses were used to identify heterogeneity. RESULTS: Sixty per cent of respondents answered all eight tasks comprising DCE1 using a single attribute; most used the rule "choose cheapest end of-life care plan". However, when answering the four less efficient tasks in DCE2, one third of these (20% overall) then traded across attributes at least once. Among those whose decision rule could not be described qualitatively, latent class models identified two classes; compared to class one, class two was more concerned with quality rather than cost of care and wished to die in an institution rather than at home. Higher efficiency was also associated with smaller regression coefficients, suggesting either weaker preferences or lower choice consistency (larger errors). CONCLUSION: This is the first within-subject study to investigate the association between DCE design efficiency and utility estimates. It found that a majority of people did not trade across attributes in the more efficient design but that one third of these then did trade in the less efficient design. More within-subject studies are required to establish how common this is. It may be that future DCEs should attempt to maximise some joint function of statistical and cognitive efficiency to maximise overall efficiency and minimise bias. PMID- 26589413 TI - Antibody Drug Conjugates for Cancer Therapy. AB - Antibody drug conjugates (ADCs) constitute a family of cancer therapeutics designed to preferentially direct a cytotoxic drug to cells expressing a cell surface antigen recognized by an antibody. The antibody and drug are linked through chemistries that enable release of the cytotoxic drug or drug adduct upon internalization and digestion of the ADC by the cell. Over 40 distinct ADCs, targeting an array of antigens and utilizing a variety of drugs and linkers, are undergoing clinical evaluation. This review primarily covers ADCs that have advanced to clinical investigation with a particular emphasis on how the individual targets, linker chemistries, and appended drugs influence their behavior. PMID- 26589414 TI - Mitochondrial Quality Control as a Therapeutic Target. AB - In addition to oxidative phosphorylation (OXPHOS), mitochondria perform other functions such as heme biosynthesis and oxygen sensing and mediate calcium homeostasis, cell growth, and cell death. They participate in cell communication and regulation of inflammation and are important considerations in aging, drug toxicity, and pathogenesis. The cell's capacity to maintain its mitochondria involves intramitochondrial processes, such as heme and protein turnover, and those involving entire organelles, such as fusion, fission, selective mitochondrial macroautophagy (mitophagy), and mitochondrial biogenesis. The integration of these processes exemplifies mitochondrial quality control (QC), which is also important in cellular disorders ranging from primary mitochondrial genetic diseases to those that involve mitochondria secondarily, such as neurodegenerative, cardiovascular, inflammatory, and metabolic syndromes. Consequently, mitochondrial biology represents a potentially useful, but relatively unexploited area of therapeutic innovation. In patients with genetic OXPHOS disorders, the largest group of inborn errors of metabolism, effective therapies, apart from symptomatic and nutritional measures, are largely lacking. Moreover, the genetic and biochemical heterogeneity of these states is remarkably similar to those of certain acquired diseases characterized by metabolic and oxidative stress and displaying wide variability. This biologic variability reflects cell-specific and repair processes that complicate rational pharmacological approaches to both primary and secondary mitochondrial disorders. However, emerging concepts of mitochondrial turnover and dynamics along with new mitochondrial disease models are providing opportunities to develop and evaluate mitochondrial QC-based therapies. The goals of such therapies extend beyond amelioration of energy insufficiency and tissue loss and entail cell repair, cell replacement, and the prevention of fibrosis. This review summarizes current concepts of mitochondria as disease elements and outlines novel strategies to address mitochondrial dysfunction through the stimulation of mitochondrial biogenesis and quality control. PMID- 26589415 TI - Serum androgens and prostate cancer risk: results from the placebo arm of the Prostate Cancer Prevention Trial. AB - BACKGROUND: Compelling and long-standing data suggest that androgens play an important role in the development of both normal prostate epithelium and prostate cancer. Although testosterone administration can induce prostate cancer (PCA) in laboratory animals, serum-based epidemiologic studies examining androgens in humans have not consistently supported a role for androgens in prostate carcinogenesis. We examined whether pre-diagnostic serum androgens were associated with PCA risk in the placebo arm of the Prostate Cancer Prevention Trial. METHODS: In this nested case-control study, cases (n = 1,032) were primarily local-stage, biopsy-detected cancers, and controls (n = 1,025) were biopsy-confirmed to be PCA-free. Pre-diagnostic serum androgens (total testosterone, 3alpha-androstanediol glucuronide, free testosterone), estrogen-to testosterone ratio, and sex hormone-binding globulin (SHBG) concentrations were measured in pooled (baseline and year 3) blood samples. RESULTS: We found no significant associations between serum androgens, estrogen-to-testosterone ratios, or SHBG and risk of total, low (Gleason <7) or high-grade (Gleason 7-10) PCA. CONCLUSION: Much remains to be learned about the role of androgens in prostate carcinogenesis. Further research is needed to evaluate the role of androgens, timing of exposure, genetic modulators of androgen metabolism, or environmental exposures that may affect androgen influence on prostate carcinogenesis. PMID- 26589416 TI - Understanding rural-urban differences in risk factors for breast cancer in an Indian population. AB - PURPOSE: Although cancer registry data indicate that there are large differences in breast cancer (BC) rates between rural and urban regions of India, the reasons for these differences are not well understood. METHODS: We conducted a hospital based case-control study (1,637 breast cancer cases; 1,515 visitor controls) in Mumbai, India, during the years 2009-2013. Extensive questionnaire data, anthropometry measurement and blood samples were collected on all participants. Using logistic regression models, we estimated risk based on odds ratio (OR) and 95 % confidence intervals (CI) for various reproductive and anthropometric measures, stratified by rural-urban status depending upon residence in first 20 years of life. RESULTS: Waist-to-hip ratio of >=0.95 compared to ratio <=0.84 was strongly associated with risk of BC in both rural and urban populations (ORurban = 4.10, 95 % CI 3.03-5.56; ORrural = 3.01, 95 % CI 1.85-4.90). First full-term pregnancy after the age of 25 compared to first full-term pregnancy below 20 years of age was associated with risk of BC in both urban and rural women (ORurban = 1.78, 95 % CI 1.32-2.41; ORrural = 2.24, 95 % CI 1.13-4.43). The prevalence of age at first full-term pregnancy was significantly lower in rural (mean age at first full-term pregnancy = 19.39 years) versus urban women (mean age at first full-term pregnancy = 22.62 years), whereas mean waist circumference was much higher in urban women (82.13 cm) compared to rural women (79.26 cm). We did not observe any association between breast feeding and risk of BC. CONCLUSIONS: Differences in the prevalence of central adiposity and age at first full-term pregnancy between rural and urban women from India may explain some differences in breast cancer rates between these two populations. PMID- 26589417 TI - Overexpression of microRNA-30a-5p inhibits liver cancer cell proliferation and induces apoptosis by targeting MTDH/PTEN/AKT pathway. AB - Increasing results suggest microRNAs (miRNAs) could function important roles in malignant tumor progression. miR-30a-5p is downregulated in variety of cancers and acts as a cancer suppressing gene. The functions and molecular mechanisms of miRNA-30a-5p in hepatocellular carcinoma (HCC) remain unclear. In the present study, quantitative real-time PCR (qRT-PCR) was used to detect miR-30a-5p expression in 16 pairs of HCC and their adjacent non-cancerous tissues and HCC cell lines. By overexpression of miRNA-30a-5p, CCK-8 and colon formation assay were used to evaluate cell growth and flow cytometry to evaluate cell apoptosis. Western blot was used to test protein expression. And potential mechanisms were analyzed with luciferase activity assay. In vivo HepG2 tumor growth was observed with nude mice. Our results showed that miR-30a-5p expression in HCC tissues was significantly lower compared to adjacent non-cancerous liver tissues, and lower miR-30a-5p expression was also observed in HCC cell lines compared to normal liver cell. Luciferase assay showed that metadherin (MTDH) mRNA was a direct target of miR-30a-5p. A significant reverse correlation between miR-30a-5p and MTDH in liver cancer tissues was observed. miR-30a-5p overexpression in HCC cells significantly inhibited cell proliferation, colon formation, and induced apoptosis while MTDH overexpression reversed growth inhibition and apoptosis induction of miRNA-30a-5p in HCC cells. miRNA-30a-5p upregulated phosphatase and tensin homolog (PTEN) protein expression and thus inhibited AKT activating by targeting MTDH. miRNA-30a-5p also significantly inhibited HepG2 tumor growth in vivo. Our results suggest that underexpression of miR-30a-5p might function as a tumor suppressing miRNA by directly targeting MTDH in HCC and is therefore a potential candidate biomarker for HCC targeting therapy. PMID- 26589418 TI - Effectiveness of a diet with low advanced glycation end products, in improving glycoxidation and lipid peroxidation: a long-term investigation in patients with chronic renal failure. PMID- 26589419 TI - Genome-wide identification and phylogenetic analysis of plant RNA binding proteins comprising both RNA recognition motifs and contiguous glycine residues. AB - This study focused on the identification and phylogenetic analysis of glycine rich RNA binding proteins that contain an RNA recognition motif (RRM)-type RNA binding domain in addition to a region with contiguous glycine residues in representative plant species. In higher plants, glycine-rich proteins with an RRM have met considerable interest as they are responsive to environmental cues and play a role in cold tolerance, pathogen defense, flowering time control, and circadian timekeeping. To identify such RRM containing proteins in plant genomes we developed an RRM profile based on the known glycine-rich RRM containing proteins in the reference plant Arabidopsis thaliana. The application of this remodeled RRM profile that omitted sequences from non-plant species reduced the noise when searching plant genomes for RRM proteins compared to a search performed with the known RRM_1 profile. Furthermore, we developed an island scoring function to identify regions with contiguous glycine residues, using a sliding window approach. This approach tags regions in a protein sequence with a high content of the same amino acid, and repetitive structures score higher. This definition of repetitive structures in a fixed sequence length provided a new glance for characterizing patterns which cannot be easily described as regular expressions. By combining the profile-based domain search for well-conserved regions (the RRM) with a scoring technique for regions with repetitive residues we identified groups of proteins related to the A. thaliana glycine-rich RNA binding proteins in eight plant species. PMID- 26589420 TI - Molecular cytogenetic analysis and genomic organization of major DNA repeats in castor bean (Ricinus communis L.). AB - This article addresses the bioinformatic, molecular genetic, and cytogenetic study of castor bean (Ricinus communis, 2n = 20), which belongs to the monotypic Ricinus genus within the Euphorbiaceae family. Because castor bean chromosomes are small, karyotypic studies are difficult. However, the use of DNA repeats has yielded new prospects for karyotypic research and genome characterization. In the present study, major DNA repeat sequences were identified, characterized and localized on mitotic metaphase and meiotic pachytene chromosomes. Analyses of the nucleotide composition, curvature models, and FISH localization of the rcsat39 repeat suggest that this repeat plays a key role in building heterochromatic arrays in castor bean. Additionally, the rcsat390 sequences were determined to be chromosome-specific repeats located in the pericentromeric region of mitotic chromosome A (pachytene chromosome 1). The localization of rcsat39, rcsat390, 45S and 5S rDNA genes allowed for the development of cytogenetic landmarks for chromosome identification. General questions linked to heterochromatin formation, DNA repeat distribution, and the evolutionary emergence of the genome are discussed. The article may be of interest to biologists studying small genome organization and short monomer DNA repeats. PMID- 26589421 TI - Regulation signature of miR-143 and miR-26 in porcine Salmonella infection identified by binding site enrichment analysis. AB - Salmonella infects many vertebrate species, and pigs colonized with Salmonella are typically Salmonella carriers. Transcriptomic analysis of the response to Salmonella infection in whole blood has been reported for the pig. The objective of this study is to identify the important miRNAs involved in Salmonella infection using binding site enrichment analysis. We predicted porcine microRNA (miRNA) binding sites in the 3' UTR of protein-coding genes for all miRNA families. Based on those predictions, we analyzed miRNA-binding sites for mRNAs expressed in peripheral blood to investigate the functional importance of miRNAs in Salmonella infection in pig. Enrichment analysis revealed that binding sites of five miRNAs (including miR-143, -9839, -26, -2483, and -4335) were significantly over represented for the differentially expressed gene sets. Real time PCR results indicated that selected members of this miRNA group (miR-143, 26, and -4335) were differentially expressed in whole blood after Salmonella inoculation. The luciferase reporter assay showed that ATP6V1A and IL13RA1 were targets of miR-143 and that miR-26 regulates BINP3L and ARL6IP6. The results strongly suggest that miR-143 and miR-26 play important regulatory roles in the development of Salmonella infection in pig. PMID- 26589422 TI - The radiology of diffuse interstitial pulmonary disease in children: pearls, pitfalls and new kids on the block in 2015. AB - Diffuse interstitial lung disease in children differs markedly from interstitial lung disease in adults and is a distinct entity. The childhood interstitial lung disease (ChILD) classification, devised in 2010 separates conditions into those occurring in infancy, and those not specific to infants, the later group containing many conditions related to systemic diseases (including connective tissue diseases and depositional/storage disorders), and conditions occurring in immunocompromised children. In this article, we briefly review normal lung growth and development. We discuss our preferred technique for imaging the lungs with computed tomography in children, and review the recent literature regarding the radiological appearance of various ChILD. We illustrate this with cases from our institution and emphasize the more recently recognised conditions including pleuroparenchymal fibroelastosis and filamin A deficiency-related lung disease. PMID- 26589423 TI - Dysfunction of Self-Regulation and Self-Control in Facebook Addiction. AB - Nowadays, Facebook has become one of the most popular communication tools. With its increasing popularity, a new phenomenon connected with extensive use has appeared: namely, Facebook intrusion. The answer to the question of who is prone to become addicted still remains open. This study aimed to explore whether insufficient self-control and self-regulation resources in Facebook users are related to Facebook addiction. The participants in the study were 284 people. The Facebook Intrusion Questionnaire, the Brief Self-Control Scale, the Self Regulation Scale, Action Control Scale, and the Multitasking Scale were used. We found that dysfunctional self-control system can be related to Facebook addiction. An insufficient self-control and low level of failure-related action orientation are those psychological characteristics that put Facebook users "at risk" of Facebook addiction. The study reveals a picture showing that those Facebook users who are able to resist an impulse or temptation, are more self disciplined, and do not focus on negative emotions are less likely to develop Facebook addiction. The obtained findings may serve as a basis for prevention programs for people at risk of Facebook addiction. PMID- 26589424 TI - Gender Differentiation of Relationships Between Manifestations of Indirect Self Destructiveness and Dimensions of Emotional Intelligence. AB - The aim of this study has been to explore the gender differentiation of relationships between individual manifestations of indirect self-destructiveness and particular dimensions of emotional intelligence. A population of 260 individuals (130 women and 130 men) aged 20-30 (mean age of 24.5) was studied by using the Polish version of the Chronic Self-Destructiveness Scale (CS-DS) and INTE, i.e. the Polish version of the Assessing Emotions Scale (AES). Manifestations of indirect self-destructiveness showed significant correlations with INTE variables, and those correlations were mainly negative. Relationships between specific dimensions of emotional intelligence and specific manifestations of self-destructiveness differed between women and men. One of the most important differences was the relationship between transgression and ability to recognize emotions. The knowledge of the differentiation of the above relationships may allow to orient prophylactic and therapeutic actions, and adjust them to the specific gender. PMID- 26589426 TI - Disparities in road crash mortality among pedestrians using wheelchairs in the USA: results of a capture-recapture analysis. AB - OBJECTIVE: This study aims to quantify and describe the burden of fatal pedestrian crashes among persons using wheelchairs in the USA from 2006 to 2012. DESIGN: The occurrence of fatal pedestrian crashes among pedestrians using wheelchairs was assessed using two-source capture-recapture. Descriptive analysis of fatal crashes was conducted using customary approaches. SETTING: Two registries were constructed, both of which likely undercounted fatalities among pedestrians who use wheelchairs. The first used data from the Fatality Analysis Reporting System, and the second used a LexisNexis news search. OUTCOME MEASURES: Mortality rate (per 100 000 person-years) and crash-level, driver-level and pedestrian-level characteristics of fatal crashes. RESULTS: This study found that, from 2006 to 2012, the mortality rate for pedestrians using wheelchairs was 2.07/100 000 person-years (95% CI 1.60 to 2.54), which was 36% higher than the overall population pedestrian mortality rate (p=0.02). Men's risk was over fivefold higher than women's risk (p<0.001). Compared to the overall population, persons aged 50-64 using wheelchairs had a 38% increased risk (p=0.04), and men who use wheelchairs aged 50-64 had a 75% increased risk over men of the same age in the overall population (p=0.006). Almost half (47.6%; 95% CI 42.8 to 52.5) of fatal crashes occurred in intersections and 38.7% (95% CI 32.0 to 45.0) of intersection crashes occurred at locations without traffic control devices. Among intersection crashes, 47.5% (95% CI 40.6 to 54.5) involved wheelchair users in a crosswalk; no crosswalk was available for 18.3% (95% CI 13.5 to 24.4). Driver failure to yield right-of-way was noted in 21.4% (95% CI 17.7 to 25.7) of crashes, and no crash avoidance manoeuvers were detected in 76.4% (95% CI 71.0 to 81.2). CONCLUSIONS: Persons who use wheelchairs experience substantial pedestrian mortality disparities calling for behavioural and built environment interventions. PMID- 26589425 TI - Epidemiology of haemodialysis catheter complications: a survey of 865 dialysis patients from 14 haemodialysis centres in Henan province in China. AB - OBJECTIVES: To investigate the incidence rates and risk factors for catheter related complications in different districts and populations in Henan Province in China. DESIGN: Cross-sectional. SETTING: Fourteen hospitals in Henan Province. PARTICIPANTS: 865 patients with renal dysfunction undergoing dialysis using catheters between October 2013 and October 2014. MAIN OUTCOME MEASURES: The main outcome measures were complications, risk factors and patient characteristics. Catheter-related complications included catheter-related infection (catheter exit site infection, catheter tunnel infection and catheter-related bloodstream infection), catheter dysfunction (thrombosis, catheter malposition or kinking, and fibrin shell formation) and central vein stenosis. RESULTS: The overall incidence rate was 7.74/1000 catheter-days, affecting 38.61% of all patients, for catheter infections, 10.58/1000 catheter-days, affecting 56.65% of all patients, for catheter dysfunction, and 0.68/1000 catheter-days, affecting 8.79% of all patients, for central vein stenosis. Multivariate analysis showed that increased age, diabetes, primary educational level or below, rural residence, lack of a nephropathy visit before dialysis and pre-established permanent vascular access, not taking oral drugs to prevent catheter thrombus, lower serum albumin levels and higher ferritin levels were independently associated with catheter infections. Rural residence, not taking oral drugs to prevent thrombus, lack of an imaging examination after catheter insertion, non-tunnel catheter type, lack of medical insurance, lack of nephropathy visit before dialysis and pre established permanent vascular access, left-sided catheter position, access via the femoral vein and lower haemoglobin level were independently associated with catheter dysfunction. Diabetes, lack of nephropathy visit before dialysis and pre established permanent vascular access, lack of oral drugs to prevent catheter thrombus, left-sided catheter location and higher number of catheter insertions, were independently associated with central vein stenosis. CONCLUSIONS: The rate of catheter-related complications was high in patients with end-stage renal disease in Henan Province. Our finding suggest that strategies should be implemented to decrease complication rates. PMID- 26589427 TI - Social determinants of HIV infection, hotspot areas and subpopulation groups in Ethiopia: evidence from the National Demographic and Health Survey in 2011. AB - OBJECTIVE: This study identifies social determinants of HIV infection, hotspot areas and subpopulation groups in Ethiopia. DESIGN: The study used data from the 2011 Ethiopian Demographic and Health Survey (EDHS). Sample blood tests from the finger pricks collected on filter paper cards were labelled with a barcode unique to each respondent. Spatial scan statistics and geographic information system tools were used to map hotspot areas of HIV prevalence. Bivariate and multivariable logistic regression models were used to identify social determinants of HIV infection. POPULATION: A total of 30,625 adults (16,515 women and 14,110 men) were included from 11 administrative states of Ethiopia. MAIN OUTCOME MEASURES: Laboratory-confirmed HIV serostatus is the main outcome variable. RESULTS: HIV prevalence reached 10-21% in the central, eastern and western geographic clusters of Ethiopia. Multivariable analysis showed that individuals who were in the middle, richer and richest wealth quintiles had increased odds of having HIV over those in the poorest quintile. Adults who had primary, secondary and higher educational levels had higher odds of being HIV positive than non-educated individuals. The odds of having HIV were higher among adults who had multiple lifetime sexual partners than those with a single partner. An increasing odds of HIV infection were observed among adults in the age groups of 25-29, 30-34, 35-39 and 40-45 years compared with adults in the age group of 45-49 years. Merchants had higher odds of being HIV positive than those who were not employed. The odds of having HIV were higher among urban residents and females than among rural residents and males, respectively. CONCLUSIONS: This study found statistically significant HIV concentrations in administrative zones of central, eastern and western Ethiopia. Geospatial monitoring and targeting of prevention strategies for specific population groups is recommended. PMID- 26589428 TI - Cross-sectional study of depression and help-seeking in Uttarakhand, North India. AB - OBJECTIVES: This study sought to use a population-based cross-sectional survey to describe depression prevalence, healthcare seeking and associations with socioeconomic determinants in a district in North India. SETTING: This study was conducted in Sahaspur and Raipur, administrative blocks of Dehradun district, Uttarakhand, in July 2014. PARTICIPANTS: A population-based sample of 960 people over the age of 18 years was selected in 30 randomised clusters after being stratified by rural:urban census ratios. PRIMARY OUTCOME MEASURES: The survey used a validated screening tool, Patient Health Questionnaire, to identify people with depression, and collected information regarding socioeconomic variables and help-seeking behaviours. Depression prevalence and health seeking behaviours were calculated, and multivariable logistic regression was used to assess associations between risk factors and depression. RESULTS: Prevalence of depression was 6% (58/960), with a further 3.9% (37/960) describing a depressive episode of over 2 weeks in the past 12 months. Statistically significant adjusted OR for depression of more than 2 were found for people who were illiterate, classified as Scheduled Caste/Tribe or Other Backward Castes, living in temporary material housing and who had recently taken a loan. While over three quarters of people with depression (79%) had attended a private or government general medical practitioner in the past 3 months, none had received talking therapy (100% treatment gap) and two people (3.3%) had been prescribed antidepressants. CONCLUSIONS: There are clear associations between social, educational and economic disadvantage and depression in this population. Strategies that address the social determinants of depression, such as education, social exclusion, financial protection and affordable housing for all are indicated. To address the large treatment gap in Uttarakhand, we must ensure access to primary and secondary mental health providers who can recognise and appropriately manage depression. PMID- 26589429 TI - Memory for gist and detail information in patients with Parkinson's disease. AB - OBJECTIVE: Memory formation is proposed to be a dual process that involves the simultaneous memorisation of both detailed information (item-specific memory) and gist information (gist memory). Memory deficits have been reported in patients with Parkinson's disease (PD); however, few studies have explicitly addressed the nature of these deficits. To obtain a detailed understanding of memory dysfunction in patients with PD, it is of crucial importance to establish whether item-specific memory and gist memory performance are impaired. The aim of this study is to explore whether gist memory and item-specific memory performance are still intact in patients with PD, as well as to determine which psychological mechanisms are responsible for memory formation. SETTING: Two hospitals in northern Taiwan. PARTICIPANTS: Thirty-nine patients with PD and 28 normal controls were recruited. Each participant received a gist-based recognition test following the Deese-Roediger-McDermott paradigm, as well as neuropsychological tests and measures of clinical characteristics. RESULTS: Gist memory was impaired in patients with advanced-stage disease (Hoehn and Yahr (H&Y) stage: III) (F2,64=3.58, p=0.033), whereas item-specific memory was preserved throughout all disease stages. Correlation analysis showed that item-specific memory was related to executive functions in normal controls and early-stage patients with PD (H&Y stage: I-II); however, item-specific memory was related to episodic memory, rather than to executive functions, in advanced-stage patients with PD. Moreover, gist memory was related to episodic memory, but only in early-stage patients with PD. CONCLUSIONS: We discovered that impaired gist memory is found in advanced stage, but not in early-stage, patients with PD. Our findings suggest that the techniques used to take advantage of the relatively preserved gist memory in early-stage patients with PD, as well as the preserved item-specific memory in patients with PD of all stages, could be useful for memory rehabilitation programmes. PMID- 26589430 TI - Modeling long-term diabetes and related complications in rats. AB - INTRODUCTION: Accurate preclinical modeling of diabetic complications such as retinopathy, nephropathy and neuropathy is crucial to enable the development of novel preventative therapies. The aims of this study were to establish a model of long-term diabetes with sustained medium scale hyperglycemia and characterize the pathological changes detectable after 4months, with particular respect to dependence on the degree of hyperglycemia. METHODS: Streptozotocin-induced diabetic CFY rats were subjected to four different insulin substitution protocols to achieve different levels of glycemic control (Diabetic 1-4 groups). Eyes were investigated by ophthalmoscopy, kidney function by urine analysis, and neuropathy by functional tests. Retinal and renal morphological evaluations were performed by histology, immuno-histochemistry and electron microscopy. RESULTS: Rats of the Diabetic 3 group showed massive hyperglycemia-dependent anterior segment neovascularization, enhanced total retinal score and retinal apoptotic cell number, degeneration of dopaminergic amacrine cells, increased glomerular PAS positivity, altered excreted total protein/creatinine ratio and cold allodynia, parallel with medium scale hyperglycemia (blood glucose level between 22 and 25mmol/L) and satisfying state of health. DISCUSSION: We established a treatment protocol in rats enabling complex investigation of diabetic retinopathy, nephropathy and neuropathy on a long-term period. Clearly hyperglycemic dependent parameters of these complications serve as good outcome measures for preclinical trials. Our results provide a useful basis for designing studies for testing preventative treatments as well as other translational medical research in this field. PMID- 26589431 TI - Robustness of arterial blood gas analysis for assessment of respiratory safety pharmacology in rats. AB - Whole body plethysmography using unrestrained animals is a common technique for assessing the respiratory risk of new drugs in safety pharmacology studies in rats. However, wide variations in experimental technique make cross laboratory comparison of data difficult and raise concerns that non-appropriate conditions may mask the deleterious effects of test compounds - in particular with suspected respiratory depressants. Therefore, the objective of this study was to evaluate the robustness of arterial blood gas analysis as an alternative to plethysmography in rats. We sought to do this by assessing the effect of different vehicles and times post-surgical catheterization on blood gas measurements, in addition to determining sensitivity to multiple opioids. Furthermore, we determined intra-lab variability from multiple datasets utilizing morphine and generated within a single lab and lastly, inter-lab variability was measured by comparing datasets generated in two separate labs. Overall, our data show that arterial blood gas analysis is a measure that is both flexible in terms of experimental conditions and highly sensitive to respiratory depressants, two key limitations when using plethysmography. As such, our data strongly advocate the adoption of arterial blood gas analysis as an investigative approach to reliably examine the respiratory depressant effects of opioids. PMID- 26589433 TI - Pericytes Promote Malignant Ovarian Cancer Progression in Mice and Predict Poor Prognosis in Serous Ovarian Cancer Patients. AB - PURPOSE: The aim of this study was to investigate the role of pericytes in regulating malignant ovarian cancer progression. EXPERIMENTAL DESIGN: The pericyte mRNA signature was used to interrogate ovarian cancer patient datasets to determine its prognostic value for recurrence and mortality. Xenograft models of ovarian cancer were used to determine if co-injection with pericytes affected tumor growth rate and metastasis, whereas co-culture models were utilized to investigate the direct effect of pericytes on ovarian cancer cells. Pericyte markers were used to stain patient tissue samples to ascertain their use in prognosis. RESULTS: Interrogation of two serous ovarian cancer patient datasets [the Australian Ovarian Cancer Study, n= 215; and the NCI TCGA (The Cancer Genome Atlas), n= 408] showed that a high pericyte score is highly predictive for poor patient prognosis. Co-injection of ovarian cancer (OVCAR-5 & -8) cells with pericytes in a xenograft model resulted in accelerated ovarian tumor growth, and aggressive metastases, without altering tumor vasculature. Pericyte co-culture in vitro promoted ovarian cancer cell proliferation and invasion. High alphaSMA protein levels in patient tissue microarrays were correlated with more aggressive disease and earlier recurrence. CONCLUSIONS: High pericyte score provides the best means to date of identifying patients with ovarian cancer at high risk of rapid relapse and mortality (mean progression-free survival time < 9 months). The stroma contains rare yet extremely potent locally resident mesenchymal stem cells a subset of "cancer-associated fibroblasts" that promote aggressive tumor growth and metastatic dissemination, underlying the prognostic capacity of a high pericyte score to strongly predict earlier relapse and mortality. PMID- 26589432 TI - Taselisib (GDC-0032), a Potent beta-Sparing Small Molecule Inhibitor of PI3K, Radiosensitizes Head and Neck Squamous Carcinomas Containing Activating PIK3CA Alterations. AB - PURPOSE: ActivatingPIK3CAgenomic alterations are frequent in head and neck squamous cell carcinoma (HNSCC), and there is an association between phosphoinositide 3-kinase (PI3K) signaling and radioresistance. Hence, we investigated the therapeutic efficacy of inhibiting PI3K with GDC-0032, a PI3K inhibitor with potent activity against p110alpha, in combination with radiation in HNSCC. EXPERIMENTAL DESIGN: The efficacy of GDC-0032 was assessedin vitroin 26 HNSCC cell lines with crystal violet proliferation assays, and changes in PI3K signaling were measured by Western blot analysis. Cytotoxicity and radiosensitization were assessed with Annexin V staining via flow cytometry and clonogenic survival assays, respectively. DNA damage repair was assessed with immunofluorescence for gammaH2AX foci, and cell cycle analysis was performed with flow cytometry.In vivoefficacy of GDC-0032 and radiation was assessed in xenografts implanted into nude mice. RESULTS: GDC-0032 inhibited potently PI3K signaling and displayed greater antiproliferative activity in HNSCC cell lines withPIK3CAmutations or amplification, whereas cell lines withPTENalterations were relatively resistant to its effects. Pretreatment with GDC-0032 radiosensitizedPIK3CA-mutant HNSCC cells, enhanced radiation-induced apoptosis, impaired DNA damage repair, and prolonged G2-M arrest following irradiation. Furthermore, combined GDC-0032 and radiation was more effective than either treatment alonein vivoin subcutaneous xenograft models. CONCLUSIONS: GDC-0032 has increased potency in HNSCC cell lines harboringPIK3CA-activating aberrations. Further, combined GDC-0032 and radiotherapy was more efficacious than either treatment alone inPIK3CA-altered HNSCCin vitroandin vivo This strategy warrants further clinical investigation. PMID- 26589434 TI - Balancing Efficacy and Safety of an Anti-DLL4 Antibody through Pharmacokinetic Modulation. AB - PURPOSE: Although agents targeting Delta-like ligand 4 (DLL4) have shown great promise for angiogenesis-based cancer therapy, findings in recent studies have raised serious safety concerns. To further evaluate the potential for therapeutic targeting of the DLL4 pathway, we pursued a novel strategy to reduce toxicities related to DLL4 inhibition by modulating the pharmacokinetic (PK) properties of an anti-DLL4 antibody. EXPERIMENTAL DESIGN: The F(ab')2 fragment of anti-DLL4 antibody (anti-DLL4 F(ab')2) was generated and assessed in efficacy and toxicity studies. RESULTS: Anti-DLL4 F(ab')2 enables greater control over the extent and duration of DLL4 inhibition, such that intermittent dosing of anti-DLL4 F(ab')2 can maintain significant antitumor activity while markedly mitigating known toxicities associated with continuous pathway inhibition. CONCLUSIONS: PK modulation has potentially broad implications for development of antibody-based therapeutics. Our safety studies with anti-DLL4 F(ab')2 also provide new evidence reinforcing the notion that the DLL4 pathway is extremely sensitive to pharmacologic perturbation, further underscoring the importance of exercising caution to safely harness this potent pathway in humans. PMID- 26589435 TI - ImmunoPET with Anti-Mesothelin Antibody in Patients with Pancreatic and Ovarian Cancer before Anti-Mesothelin Antibody-Drug Conjugate Treatment. AB - PURPOSE: Mesothelin (MSLN) is frequently overexpressed in pancreatic and ovarian cancers, making it a potential drug target. We performed an (89)Zr-PET imaging study with MMOT0530A, a MSLN antibody, in conjunction with a phase I study with the antibody-drug conjugate DMOT4039A, containing MMOT0530A bound to MMAE. The aim was to study antibody tumor uptake, whole-body distribution, and relation between uptake, response to treatment, and MSLN expression. EXPERIMENTAL DESIGN: Before DMOT4039A treatment, patients received 37 MBq (89)Zr-MMOT0530A followed by PET/CT imaging 2, 4, and 7 days postinjection. Tracer uptake was expressed as standardized uptake value (SUV). MSLN expression was determined with immunohistochemistry (IHC) on archival tumor tissue. RESULTS: Eleven patients were included, 7 with pancreatic and 4 with ovarian cancer. IHC MSLN expression varied from absent to strong. Suitable tracer antibody dose was 10 mg MMOT0530A and optimal imaging time was 4 and 7 days postinjection. Tumor tracer uptake occurred in 37 lesions with mean SUVmax of 13.1 (+/-7.5) on PET 4 days postinjection, with 11.5 (+/-7.5) in (N= 17) pancreatic and 14.5 (+/-8.7) in (N= 20) ovarian cancer lesions. Within patients, a mean 2.4-fold (+/-1.10) difference in uptake between tumor lesions existed. Uptake in blood, liver, kidneys, spleen, and intestine reflected normal antibody distribution. Tracer tumor uptake was correlated to IHC. Best response to DMOT4039A was partial response in one patient. CONCLUSIONS: With (89)Zr-MMOT0530A-PET, pancreatic and ovarian cancer lesions as well as antibody biodistribution could be visualized. This technique can potentially guide individualized antibody-based treatment. PMID- 26589436 TI - AGS16F Is a Novel Antibody Drug Conjugate Directed against ENPP3 for the Treatment of Renal Cell Carcinoma. AB - PURPOSE: New cancer-specific antigens are required for the design of novel antibody-drug conjugates (ADC) that deliver tumor-specific and highly potent cytotoxic therapy. EXPERIMENTAL DESIGN: Suppression subtractive hybridization identified ectonucleotide pyrophosphatase/phosphodiesterase 3 (ENPP3 or CD203c) as a potential human cancer-specific antigen. Antibodies targeting the extracellular domain of human ENPP3 were produced and selected for specific binding to ENPP3. Expression of ENPP3 in normal and cancer tissue specimens was evaluated by immunohistochemistry (IHC). ADCs comprising anti-ENPP3 Ab conjugated with maleimidocaproyl monomethyl auristatin F via a noncleavable linker (mcMMAF) were selected for therapeutic potential using binding and internalization assays, cytotoxicity assays, and tumor growth inhibition in mouse xenograft models. Pharmacodynamic markers were evaluated by IHC in tissues and ELISA in blood. RESULTS: ENPP3 was highly expressed in clear cell renal cell carcinoma: 92.3% of samples were positive and 83.9% showed high expression. By contrast, expression was negligible in normal tissues examined, with the exception of the kidney. High expression was less frequent in papillary renal cell carcinoma and hepatocellular carcinoma samples. AGS16F, an anti-ENPP3 antibody-mcMMAF conjugate, inhibited tumor growth in three different renal cell carcinoma (RCC) xenograft models. AGS16F localized to tumors, formed the active metabolite Cys-mcMMAF, induced cell cycle arrest and apoptosis, and increased blood levels of caspase-cleaved cytokeratin-18, a marker of epithelial cell death. CONCLUSIONS: AGS16F is a promising new therapeutic option for patients with RCC and is currently being evaluated in a phase I clinical trial. PMID- 26589437 TI - Changes in Socio-Emotional and Behavioral Functioning After Attending a Camp for Children with Tourette Syndrome: A Preliminary Investigation. AB - Children and adolescents with Tourette syndrome are at risk for social, emotional, and behavioral difficulties that may negatively influence feelings of self-competence and attitudes toward having this diagnosis. Attending a camp for children with Tourette syndrome may facilitate improvements in overall socio emotional and behavioral functioning and self-perception. The current study obtained data from 37 campers (76 % male, 24 % female) and 47 caregivers of campers to investigate changes in children's emotional and behavioral functioning, self-perception (i.e., social and general), attitudes towards having Tourette syndrome, and how different they felt from peers after attending a 1 week summer camp for youth with Tourette syndrome using a pre-post design. Results indicated that campers endorsed a significantly improved sense of social self-competence and more favorable attitudes toward having Tourette syndrome post camp. Campers also tended to endorse feeling less different than peers at camp versus peers in general. Caregivers endorsed significantly less severe symptoms associated with Tourette syndrome for campers after attending camp. No pre-to post-camp changes were observed for campers' levels of anxiety or obsessive compulsive symptoms. These preliminary findings suggest that attending camp or having other opportunities to interact with similar peers may promote better perceptions of social self-competence, more favorable attitudes toward having Tourette syndrome, and a stronger sense of affiliation with peers for children with Tourette syndrome. PMID- 26589439 TI - Staging classification for cancer of the ovary and the fallopian tube should include in situ carcinoma. PMID- 26589438 TI - FoCo: a simple and robust quantification algorithm of nuclear foci. AB - BACKGROUND: The number of gammaH2AX foci per nucleus is an accepted measure of the number of DNA double-strand breaks in single cells. One of the experimental techniques for gammaH2AX detection in cultured cells is immunofluorescent labelling of gammaH2AX and nuclei followed by microscopy imaging and analysis. RESULTS: In this study, we present the algorithm FoCo for reliable and robust automatic nuclear foci counting in single cell images. FoCo has the following advantages with respect to other software packages: i) the ability to reliably quantify even densely distributed foci, e.g., on images of cells subjected to radiation doses up to 10 Gy, ii) robustness of foci quantification in the sense of suppressing out-of-focus background signal, and iii) its simplicity. FoCo requires only 5 parameters that have to be adjusted by the user. CONCLUSIONS: FoCo is an open-source user-friendly software with GUI for individual foci counting, which is able to produce reliable and robust foci quantifications even for low signal/noise ratios and densely distributed foci. PMID- 26589440 TI - Comorbidity Assessment Using Charlson Comorbidity Index and Simplified Comorbidity Score and Its Association With Clinical Outcomes During First-Line Chemotherapy for Lung Cancer. AB - BACKGROUND: Limited data is available on comorbidity assessment in patients with lung cancer. The present prospective study assessed the prevalence and association of the Charlson comorbidity index (CCI) and simplified comorbidity score (SCS) with clinical outcomes in patients with newly diagnosed lung cancer undergoing chemotherapy. PATIENTS AND METHODS: All patients received histology guided platinum doublets. The outcomes assessed were overall survival (OS), radiologic responses using Response Evaluation Criteria in Solid Tumors and toxicity using the Common Toxicity Criteria, version 3.0. The groups analyzed were SCS <= 9 (n = 173) and > 9 (n = 65) and CCI = 0 (n = 88), 1 (n = 97), and >= 2 (n = 53). Correlations of the CCI and SCS were assessed using Spearman's (rho) method. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated for the factors affecting OS using Cox proportional hazard (CPH) modeling. RESULTS: Most patients had advanced disease (stage IIIB in 33.6%, stage IV in 42.4%). The median SCS was 7 (interquartile range, 7-11), and the median CCI was 1 (interquartile range, 0-1). The correlation between the CCI and SCS was moderate (rho = 0.474; P < .001). Age correlated weakly with both SCS (rho = 0.293; P < .001) and CCI (rho = 0.205; P < .001). The SCS > 9 group (vs. SCS <= 9) had a significantly older mean age, patients aged >= 70 years, men, smokers, and squamous cell histologic type. The mean age in the CCI groups was 55.2 years for a CCI of 0, 59.6 years for a CCI of 1, and 60.3 years for a CCI of 2, with a statistically significant difference (P = .002). The radiologic responses and toxicity profiles were similar between the SCS and CCI groups. The median OS was 287 days (95% CI, 232-342 days) and did not differ between the SCS and CCI groups. On multivariate CPH analyses, worse OS was independently associated with stage IV disease (adjusted HR, 2.0; 95% CI, 1.4-2.7) and poor performance status (Eastern Cooperative Oncology Group score >= 2; adjusted HR, 1.8; 95% CI, 1.1 2.8) but not with comorbidity, histologic type, or age. CONCLUSION: The SCS and CCI scores correlated moderately with each other and weakly with age. The presence of comorbidities did not adversely influence clinical outcomes in this Indian cohort of lung cancer patients undergoing first-line chemotherapy. PMID- 26589441 TI - Evaluation of cement-retained versus screw-retained implant-supported restorations for marginal bone loss: A systematic review and meta-analysis. AB - STATEMENT OF PROBLEM: No consensus has been reached on which retention system, cement- or screw-retained, is best to avoid bone loss around the implant of a fixed implant-supported restoration. PURPOSE: The purpose of this systematic review and meta-analysis was to compare cement- and screw-retained retention systems in fixed implant-supported restorations in terms of marginal bone loss, implant survival, and prosthetic complications. MATERIAL AND METHODS: A comprehensive search of studies published from January 1995 to March 2015 and listed in the PubMed/MEDLINE, Embase, Scopus and the Cochrane Library databases was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The meta-analysis was based on the Mantel-Haenszel and inverse variance methods. Marginal bone loss was the continuous outcome measure evaluated by mean difference (MD), and implant survival and prosthetic complications were the dichotomous outcome measures evaluated by risk ratio (RR), both with corresponding 95% confidence intervals (CI). RESULTS: The 20 studies selected for review evaluated 2139 participants, whose mean age was 47.14 years and who had received 8989 dental implants. The mean follow-up was 65.4 months (range: 12-180 months). Results of the MD for marginal bone loss showed statistically significant differences in favor of the cement-retained prosthesis (P =.04; MD: -0.19; CI: -0.37 to -0.01). The implant survival rate was higher for the cement-retained prosthesis (P =.01; RR: 0.49; CI: 0.28 to 0.85), and the prosthetic complication rate was higher for the screw retained prosthesis (P =.04; RR: 0.52; CI: 0.28 to 0.98). Additional analysis of the mean plaque index did not show differences between retention systems (P=.58; MD: 0.13; CI: -0.32 to 0.57). CONCLUSIONS: The current meta-analysis indicated that cement-retained, fixed implant-supported restorations showed less marginal bone loss than screw-retained, fixed implant-supported restorations during the follow-up period, which ranged from 12 to 180 months. However, the small difference between the mean values may not show clinical significance. The rates of prosthetic complication and implant survival also compared favorably with cement-retained prostheses. PMID- 26589442 TI - Effect of toothbrushing on shade and surface roughness of extrinsically stained pressable ceramics. AB - STATEMENT OF PROBLEM: The effect of toothbrushing on extrinsically stained pressable ceramic materials is unknown. PURPOSE: The purpose of this in vitro study was to investigate the effects of toothbrushing on the shade and surface roughness of extrinsically stained, pressable ceramics. MATERIAL AND METHODS: Two materials, leucite-based (IPS Empress Esthetic [EE]; Ivoclar Vivadent AG) and lithium disilicate-based ceramic (IPS e.max Press [EP]; Ivoclar Vivadent AG), were studied. For each material, 24 disk-shaped specimens, 10 mm (diameter)*3 mm (height) were fabricated. Three different methods (n=8) of applying extrinsic stains were performed on each material: glazed only (G, control group); stained then glazed (SG); and stained and glazed together (T). The specimens were brushed with a multistation brushing machine under a load of 1.96 N at a rate of 90 strokes per minute with a soft and straight toothbrush (Oral-B #35) and a 1:1 toothpaste and distilled water slurry. Shade and roughness were measured at baseline and at 72, 144, 216, and 288 hours, which is equivalent to 3, 6, 9, and 12 years of simulated toothbrushing for 2 minutes twice a day. A repeated measures ANOVA with staining technique as a fixed factor was used to evaluate shade and roughness (alpha=.05). RESULTS: For EE groups, no significant change was found after 12 years of simulated toothbrushing regarding shade and surface roughness, irrespective of staining techniques (P>.05). However, EP groups demonstrated a significant shade change and an increase in surface roughness after 12 years of simulated toothbrushing. Shade change was found to depend on the method of applying stain. For the EP-SG technique, a significant shade change was observed only at the 9- to 12-year interval (P=.047). However, the EP-T technique demonstrated a significant difference in shade between baseline and 3 years (P=.005) and in the 6- to 9-year interval (P=.005). Surface roughness was only significantly affected at baseline and 3 years for the EP-T group (P=.005). CONCLUSIONS: For the shade and surface roughness of the EE groups, no statistically significant difference was found after 12 years of toothbrushing, irrespective of the staining technique. The shade and surface roughness of the EP groups were significantly statistically affected by toothbrushing time; only shade changes were found to depend on technique. PMID- 26589443 TI - Loculated pleural effusion. PMID- 26589444 TI - The Revised Screening Scale for Pedophilic Interests (SSPI-2): Development and Criterion-Related Validation. AB - The Screening Scale for Pedophilic Interests (SSPI) is a structured rating scale of four child victim characteristics: number, age, gender, and relationship of victims. Sexual offenders against children who score higher on the SSPI are more likely to be identified as having pedophilic sexual arousal and are more likely to sexually reoffend. Recent research suggests that child pornography offending is a valid and perhaps independent indicator of pedophilia. In this study, we examined whether child pornography offending would add to the criterion-related validity of the SSPI. In the construction sample of 950 offenders with child victims, the SSPI with a fifth item of child pornography (Screening Scale for Pedophilic Interests-2 [SSPI-2]) was significantly associated with phallometrically assessed sexual arousal to children. In a validation sample of 950 offenders with child victims, the SSPI-2 was again related to phallometrically assessed sexual arousal to children, outperforming the original SSPI. We recommend clinicians and researchers use the SSPI-2 as a structured method of assessing pedophilic sexual interests based on offending behavior. PMID- 26589445 TI - Orthopaedic patient education practice. AB - AIM: The aim of this study was to explore orthopaedic nurses' perceptions of patient education practice; the educational skills of a nurse, the content, structure and educational approaches to patient education and its changes during nine years at a university hospital in Finland. METHODS: The subjects of this survey were orthopaedic nurses at one university hospital - 56 nurses in 2001 and 51 nurses in 2010. RESULTS: On the whole, no statistically significant change had taken place in the nurses' patient education skills in the two periods compared. In 2001, the nurses discussed more often the learning objectives with patients compared to 2010. In both years, individual education sessions and written material were often used. In both years, the bio-physiological area of patient education was found to be dealt with most adequately, while the social area received less attention in 2010 than in 2001. CONCLUSIONS: According to our results, no change in a positive direction in nurses' patient education skills and the implementation of patient education can be seen over the past decade. The results of the study indicate clear development needs in patient education practice. PMID- 26589446 TI - Contralateral ulnar neuropathy following total hip replacement and intraoperative positioning. AB - Peripheral neuropathy is a rare but important complication of total hip arthroplasty (THA) and has previously been reported in the ipsilateral arm and associated with inflammatory arthritis. The results of 7004 primary hip arthroplasties performed between January 1993 and February 2009 were retrospectively reviewed to identify patients who reported ulnar neuropathy symptoms, with ten patients identified at mean follow-up of 57 months (range = 3 195 months). Eight patients experienced unilateral ulnar nerve symptoms in the contralateral upper limb post-surgery, one patient experienced symptoms in the ipsilateral upper limb and one patient experienced symptoms in both upper limbs. The incidence of post-THA ulnar neuropathy was 0.14%. All patients had a pre operative diagnosis of osteoarthritis and none had diabetes, a previous history of neuropathy or inflammatory arthritis. All operations were primary arthroplasties and were performed under the care of a single surgeon in a single centre. Two of the ten patients (20%) had a general anaesthetic. The pattern of symptoms reported, i.e. mainly unilateral affecting the contralateral side with variable resolution, contrasts with previous studies and suggests that intraoperative patient positioning may be an important factor influencing ulnar neuropathy following THA. Attention to support and positioning of the contralateral arm may help reduce the incidence of this complication. PMID- 26589447 TI - A Xyloglucan Backbone 6-O-Acetyltransferase from Brachypodium distachyon Modulates Xyloglucan Xylosylation. PMID- 26589448 TI - Programmatic access to logical models in the Cell Collective modeling environment via a REST API. AB - Cell Collective (www.cellcollective.org) is a web-based interactive environment for constructing, simulating and analyzing logical models of biological systems. Herein, we present a Web service to access models, annotations, and simulation data in the Cell Collective platform through the Representational State Transfer (REST) Application Programming Interface (API). The REST API provides a convenient method for obtaining Cell Collective data through almost any programming language. To ensure easy processing of the retrieved data, the request output from the API is available in a standard JSON format. AVAILABILITY AND IMPLEMENTATION: The Cell Collective REST API is freely available at http://thecellcollective.org/tccapi. All public models in Cell Collective are available through the REST API. For users interested in creating and accessing their own models through the REST API first need to create an account in Cell Collective (http://thecellcollective.org). CONTACT: thelikar2@unl.edu. SUPPLEMENTARY INFORMATION: Technical user documentation: https://goo.gl/U52GWo. PMID- 26589449 TI - Communication: First results of cases series of one-stage repair of gastroschisis using human acellular dermal matrix in 7 neonates. PMID- 26589450 TI - Aging in Taiwan: Building a Society for Active Aging and Aging in Place. AB - Taiwan's accelerated rate of aging is more than twice that of European countries and United States. Although demographic aging was not a major concern in Taiwan until 1993, when it became an aging society, aging issues now have become an imperative topic both in policy and in practice in the country. As this article demonstrates, in response to the challenge of the rapidly growing older population and the inspiration of cultural values of filial obligation and respect to elders, the concepts of active aging and aging in place are leading the policies and practices of gerontology to meet the diverse needs of the aging population in Taiwan. However, challenges remain, including the question of how to promote systematic endeavors, both in policies or research on aging, and how to encourage greater involvement of nongovernment organizations in the aging issue. In addition, some emerging issues about aging are addressed in this article including inadequate resources for older rural adults, building an age friendly environment, and the increasing number of people with dementia. PMID- 26589451 TI - Emotion-induced loss aversion and striatal-amygdala coupling in low-anxious individuals. AB - Adapting behavior to changes in the environment is a crucial ability for survival but such adaptation varies widely across individuals. Here, we asked how humans alter their economic decision-making in response to emotional cues, and whether this is related to trait anxiety. Developing an emotional decision-making task for functional magnetic resonance imaging, in which gambling decisions were preceded by emotional and non-emotional primes, we assessed emotional influences on loss aversion, the tendency to overweigh potential monetary losses relative to gains. Our behavioral results revealed that only low-anxious individuals exhibited increased loss aversion under emotional conditions. This emotional modulation of decision-making was accompanied by a corresponding emotion-elicited increase in amygdala-striatal functional connectivity, which correlated with the behavioral effect across participants. Consistent with prior reports of 'neural loss aversion', both amygdala and ventral striatum tracked losses more strongly than gains, and amygdala loss aversion signals were exaggerated by emotion, suggesting a potential role for this structure in integrating value and emotion cues. Increased loss aversion and striatal-amygdala coupling induced by emotional cues may reflect the engagement of adaptive harm-avoidance mechanisms in low anxious individuals, possibly promoting resilience to psychopathology. PMID- 26589453 TI - Recent findings on vertebrate developmental immunity using the zebrafish model. AB - To grant survival against sterile or microbe induced inflammation, all animals rely on correct immune system functioning. The development of immunity occurs in vertebrates during embryogenesis in a process called hematopoiesis, which is characterized by the formation of blood cellular components such as embryonic erythrocytes and primitive macrophages. These cells are formed in a sterile environment from a rare subset of pluripotent hematopoietic stem cells (HSC) during a brief period of the primitive hematopoietic wave. Diverse signals, like Notch, are indispensable in HSC emergence and differentiation. However, to successfully replicate the process in vitro using pluripotent precursors, the full set of required signals is still a matter of debate. Among the latest findings, proinflammatory signals produced by transient primitive myelocites in zebrafish have been seen to act as essential mediators in establishing the HSC program of the adult vertebrate hematopoietic system. In this regard, the zebrafish immune model has emerged as a feasible live vertebrate model for examining developmental immunity and related host-microbe interactions, both at the molecular and cellular level. Thus, using the zebrafish embryo, this review summarizes recent findings, on the signals required for immune development and further maturation of the system, in a context where no adaptive immune response has yet been developed. PMID- 26589452 TI - First-trimester diagnosis and management of Cesarean scar pregnancies after in vitro fertilization-embryo transfer: a retrospective clinical analysis of 12 cases. AB - BACKGROUND: Although Caesarean scar pregnancy (CSP) is rare, it can cause life threatening complications. The increasing rate of Cesarean delivery plus rapid development of in vitro fertilization-embryo transfer (IVF-ET) may increase the occurrence of CSP as well as the ratio of heterotopic CSP (HCSP)/CSP. Therefore, early diagnosis and management of CSP are necessary to avoid serious complications. And the purpose of this article is to evaluate the importance and feasibility of the first-trimester diagnosis and management of CSP after IVF-ET. METHODS: All the 12 cases were secondary infertility patients who had a history of Cesarean section and underwent IVF-ET in our reproductive center. All cases with CSP were diagnosed using transvaginal color Doppler sonography (TVS). Medical, surgical and expectant managements were implemented, and the management results were traced. RESULTS: Patients with CSP (n = 12) were diagnosed from January 2011 to April 2015, 6 (50 %) of which were HCSP. The prevalence of CSP was 1:1688 pregnancies. The gestational age ranged from 5 + 3 to 7 + 4 weeks in all CSP, and from 5 + 6 to 7 + 4 weeks in HCSP at diagnosis. Five patients received successful surgical treatment. The success rate of medical and expectant management was 50 % (1/2) and 100 % (5/5), respectively. One patient with failed medical management needed an emergency laparotomy to evacuate CSP. The uterus was preserved in all 12 patients. CONCLUSIONS: The Caesarean section and IVF-ET may increase the ratio of HCSP/CSP. TVS is a noninvasive and effective tool for use in diagnosing CSP. CSP should be carefully excluded in patients who have had a history of Caesarean section. Early diagnosis of CSP in the first trimester may contribute towards the preservation of uterus as well as intrauterine pregnancy (IUP) in HCSP. PMID- 26589454 TI - Immunogenicity and protective efficacy of a recombinant adenoviral based vaccine expressing heat-stable enterotoxin (STa) and K99 adhesion antigen of enterotoxigenic Escherichia coli in mice. AB - The diarrheal disease of domestic animals or in humans caused by enterotoxigenic Escherichia coli (ETEC) infections remains a major issue for public health in developing countries. Unfortunately, there is no effective vaccine available for preventing from an ETEC infection. Therefore, the development of a safe and effective vaccine against ETEC is urgently needed. In the present study, A recombinant adenoviral vector Ad5-STa-K99 that capable of expressing a fusion protein of heat-stable enterotoxin (STa) and K99 adhesion antigen of ETEC was generated and its immunogenicity was evaluated in a murine model. The intestinal mucosal secretory IgA(sIgA), serum anti-STa-K99 antibody responses, antigen specific CD4(+) and CD8(+) T cells frequencies, as well as T-cell proliferation of mice immunized with the viral vector were determined as immunological indexes. The results demonstrated that Ad5-STa-K99 was able to enhance humoral responses with a dramatically augmented antigen-specific serum IgG antibody, and an elevated production of intestinal sIgA in immunized mice, suggesting the elicitation of both of humoral and mucosal immune responses. In addition, this adenoviral vector could significantly promote splenic T cell proliferation and increase the frequencies of CD4(+) and CD8(+) T cell populations in mice, indicative of a capacity to activate T cell responses. More importantly, vaccination of the Ad5-STa-K99 showed a potential to evoke a protective effect from ETEC challenge in mice. These data indicate that the Ad5-STa-K99 is a highly immunogenic vector able to induce a broad range of antigen-specific immune responses in vivo, and evoke a protective immune response against ETEC infections, implying that it may be a novel vaccine candidate warranted for further investigation. PMID- 26589455 TI - Toll-like receptor 4 signaling promotes invasion of hepatocellular carcinoma cells through MKK4/JNK pathway. AB - Toll-like receptor (TLR) 4-mediated signaling has been shown to be important to cell survival, invasion and metastasis in a variety of cancers. The present study aimed to explore the role and downstream pathways of TLR4 signaling in the invasion of hepatocellular carcinoma (HCC) cell lines. We found that LPS, the agonist of TLR4, notably enhanced the invasiveness of HCC cells and the expression of MMP2 and MMP9, as well as the production of IL-6 and TNFalpha. LPS treatment dramatically increased the TLR4 expression on HCC cells surface and MKK4/JNK activation, while knockdown of TLR4 inhibited the LPS-induced invasion and the phosphorylation of MKK4 and JNK. Furthermore, silencing of MKK4 or inhibition of JNK activity led to impaired invasiveness of HCCs, low expression level of MMPs and TLR4, as well as limited production of cytokines. However, LPS stimulation only triggered moderate activation of NF-kB. Silencing of NF-kB or NF kB inhibitor had no obvious effect on the invasive ability of HCCs and TLR4 expression, but suppressed IL-6 and TNFalpha production. These findings suggested that LPS-TLR4 signaling enhanced the invasiveness of HCCs mainly through MKK4/JNK pathway. PMID- 26589456 TI - Response to Bird et al.: The importance of post-release engagement in treatment in estimating impacts on post-release deaths. PMID- 26589457 TI - Methamidophos induces cytotoxicity and oxidative stress in human peripheral blood mononuclear cells. AB - Previous studies have shown that organophosphate pesticide (OP) exposure is associated with oxidative stress. Methamidophos (MET) is an OP widely used in agriculture, which is regarded as a highly toxic pesticide and it is a potent inhibitor of acetylcholinesterase. The aim of this study was to evaluate whether MET can induce oxidative stress at low concentrations in primary cultures of human peripheral blood mononuclear cells (PBMCs). PBMCs from healthy individuals were exposed to MET (0-80 mg/L) for 0-72 h. We performed the MTT and neutral-red assays to assess the cytotoxicity. As indicators of oxidative stress, the levels of reactive oxygen species (ROS) were assessed using flow cytometry, and the malondialdehyde (MDA) and reduced glutathione (GSH) levels were determined. MET decreased the viability of PBMCs in a dose-dependent manner. At concentrations of 3, 10, or 20 mg/L for 24 h, MET increased the ROS production significantly compared with the vehicle control. Similarly, MET increased the levels of MDA at the same concentrations that increased ROS (10 and 20 mg/L); however, no changes in GSH levels were observed. These results suggest that MET increased the generation of oxidative stress in PBMCs. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 32: 147-155, 2017. PMID- 26589458 TI - Evaluation and Diagnosis of Back Pain in Children and Adolescents. AB - Although traditionally it has been accepted that back pain in young children and adolescents most often has an organic etiology, nonorganic back pain in this population is becoming more common. The most common identifiable clinical entities responsible for such pain are spondylolysis, spondylolisthesis, Scheuermann kyphosis, overuse syndromes, disk herniation, apophyseal ring fracture, spondylodiscitis, vertebral osteomyelitis, and neoplasm. Appropriate clinical workup leads to earlier diagnosis and management of back pain and avoids unnecessary cost. Knowledge of the most common diagnoses associated with back pain in children and adolescents and the use of a systematic method to select the appropriate diagnostic tests can help the clinician to minimize costs and maximize the likelihood of making the correct diagnosis and providing appropriate treatment. PMID- 26589459 TI - Role of Fresh Osteochondral Allografts for Large Talar Osteochondral Lesions. AB - Osteochondral lesions of the talus, large or small, present a challenge to the treating orthopaedic surgeon. These cartilage and bony defects can cause substantial pain and functional disability. Surgical treatment of small lesions of the talus has been thoroughly explored and includes retrograde drilling, arthroscopic debridement and marrow stimulation, osteochondral autografting from cartilage/bone unit harvested from the ipsilateral knee (mosaicplasty), and autologous chondrocyte implantation. Although each of these reparative, replacement, or regenerative techniques has various degrees of success, they may be insufficient for the treatment of large osteochondral lesions of the talus. Large-volume osteochondral lesions of the talus (>1.5 cm in diameter or area >150 mm) often involve sizable portions of the weight-bearing section of the talar dome, medially or laterally. To properly treat these osteochondral lesions of the talus, a fresh structural osteochondral allograft is a viable treatment option. PMID- 26589461 TI - Molecular cloning and functional characterization of a novel i-type lysozyme in the freshwater mussel Cristaria plicata. AB - The freshwater bivalve Cristaria plicata, which is widely distributed in Eastern Asia, is a key species in the pearl culture industry. In this study, a novel invertebrate-type lysozyme, designated as CpLYZ2, was cloned from hemocytes of C. plicata. This lysozyme shares high sequence identity and is homologous to a previously identified lysozyme CpLYZ1 isolated from C. plicata and with HcLyso3 isolated from Hyriopsis cumingii. The full-length cDNA of CpLYZ2 is 913 bp long, which includes an open reading frame (ORF) of 486 bp, a 3' untranslated region (UTR) of 389 bp and a 5' UTR of 38 bp. The ORF encodes a putative polypeptide of 161 amino acids with a predicted molecular mass of 18.2 kDa and a theoretical isoelectric point of 6.56. CpLYZ2 mRNA transcripts can be detected in hemocytes, hepatopancreas, muscle, gills and mantle tissues, the greatest expression being observed in the gills. CpLYZ2 expression in hemocytes, hepatopancreas and gills increased significantly after the mussel was challenged with Aeromonas hydrophila. Furthermore, the optimal pH and temperature for enzyme activity of the recombinant CpLYZ2 were 5.5 and 50 degrees C, respectively. The recombinant lysozyme protein exhibited bacteriolytic activity against Escherichia coli, A. hydrophila, Staphylococcus aureus, Bacillus subtilis, Streptococcus sp. and Staphylococcus epidermidis. The findings of this study help to elucidate immune responses in molluscs and will thus expedite disease management of these key freshwater species, in turn boosting pearl culture in eastern Asia. PMID- 26589462 TI - Effect of a backboard on compression depth during cardiac arrest in the ED: a simulation study. AB - RESEARCH PURPOSE: We evaluated the impact of a backboard on chest compression depth during cardiac arrest practice sessions conducted using a high-fidelity mannequin on a standard emergency department stretcher. METHODS: Forty-three health care trainees completed cardiac resuscitation simulations requiring 2 minutes of uninterrupted chest compressions. Twenty-one were randomly allocated to the intervention group in which a backboard was concealed by placement between the stretcher mattress and a top sheet and, 22 were allocated to the control group in which no backboard was placed. The mannequin software automatically recorded mean chest compression depth in 10-second intervals for the 2 minutes of compressions. RESULTS: The backboard group achieved a mean compression depth of 41.2 mm (95% confidence interval, 37.8-44.6). The no-backboard group's mean compression depth was 41.4 mm (95% confidence interval, 38.7-44.2). Most subjects in both groups did not achieve the 50-mm compression depth threshold recommended by the American Heart Association. CONCLUSIONS: Use of a backboard as an adjunct during cardiopulmonary resuscitation of a simulated patient lying on a standard emergency department stretcher did not improve the mean chest compression depth achieved by advanced life support rescuers. Most rescuers did not achieve the minimum compression depth of 50 mm recommended by the American Heart Association. PMID- 26589460 TI - Quantitative analysis of chromatin interaction changes upon a 4.3 Mb deletion at mouse 4E2. AB - BACKGROUND: Circular chromosome conformation capture (4C) has provided important insights into three dimensional (3D) genome organization and its critical impact on the regulation of gene expression. We developed a new quantitative framework based on polymer physics for the analysis of paired-end sequencing 4C (PE-4Cseq) data. We applied this strategy to the study of chromatin interaction changes upon a 4.3 Mb DNA deletion in mouse region 4E2. RESULTS: A significant number of differentially interacting regions (DIRs) and chromatin compaction changes were detected in the deletion chromosome compared to a wild-type (WT) control. Selected DIRs were validated by 3D DNA FISH experiments, demonstrating the robustness of our pipeline. Interestingly, significant overlaps of DIRs with CTCF/Smc1 binding sites and differentially expressed genes were observed. CONCLUSIONS: Altogether, our PE-4Cseq analysis pipeline provides a comprehensive characterization of DNA deletion effects on chromatin structure and function. PMID- 26589463 TI - Persistent hiccups followed by acute respiratory failure. PMID- 26589464 TI - Emergency physician sonographers can identify and inject the regions of the trigeminal nerve foramina in a human cadaveric model. PMID- 26589465 TI - Homelessness and ED use: myths and facts- the author's reply. PMID- 26589466 TI - Evaluation of hidden HIV infections in an urban ED with a rapid HIV screening program. AB - BACKGROUND: To investigate the prevalence of undiagnosed HIV infections in an emergency department (ED) with an established screening program. METHODS: Evaluation of the prevalence and risk factors for HIV from an 8-week (June 24, 2007-August 18, 2007) identity-unlinked HIV serosurvey, conducted at the same time as an ongoing opt-in rapid oral-fluid HIV screening program. Testing facilitators offering 24/7 bedside rapid testing to patients aged 18 to 64 years, with concordant collection of excess sera collected as part of routine clinical procedures. Known HIV positivity was determined by (1) medical record review or self-report from the screening program and/or (2) presence of antiretrovirals in serum specimens. RESULTS: Among 3207 patients, 1165 (36.3%) patients were offered an HIV test. Among those offered, 567 (48.7%) consented to testing. Concordance identity-unlinked study revealed that the prevalence of undiagnosed infections was as follows: 2.3% in all patients, 1.0% in those offered testing vs 3.0% in those not offered testing (P < .001); and 1.3% in those who declined testing compared with 0.4% in those who were tested (P = .077). Higher median viral loads were observed in those not offered testing (14255 copies/mL; interquartile range, 1147-64354) vs those offered testing (1865 copies/mL; interquartile range, undetectable-21786), but the difference was not statistically significant. CONCLUSIONS: High undiagnosed HIV prevalence was observed in ED patients who were not offered HIV testing and those who declined testing, compared with those who were tested. This indicates that even with an intensive facilitator-based rapid HIV screening model, significant missed opportunities remain with regard to identifying undiagnosed infections in the ED. PMID- 26589467 TI - Quadratic blind linear unmixing: A graphical user interface for tissue characterization. AB - Spectral unmixing is the process of breaking down data from a sample into its basic components and their abundances. Previous work has been focused on blind unmixing of multi-spectral fluorescence lifetime imaging microscopy (m-FLIM) datasets under a linear mixture model and quadratic approximations. This method provides a fast linear decomposition and can work without a limitation in the maximum number of components or end-members. Hence this work presents an interactive software which implements our blind end-member and abundance extraction (BEAE) and quadratic blind linear unmixing (QBLU) algorithms in Matlab. The options and capabilities of our proposed software are described in detail. When the number of components is known, our software can estimate the constitutive end-members and their abundances. When no prior knowledge is available, the software can provide a completely blind solution to estimate the number of components, the end-members and their abundances. The characterization of three case studies validates the performance of the new software: ex-vivo human coronary arteries, human breast cancer cell samples, and in-vivo hamster oral mucosa. The software is freely available in a hosted webpage by one of the developing institutions, and allows the user a quick, easy-to-use and efficient tool for multi/hyper-spectral data decomposition. PMID- 26589468 TI - ISRUC-Sleep: A comprehensive public dataset for sleep researchers. AB - To facilitate the performance comparison of new methods for sleep patterns analysis, datasets with quality content, publicly-available, are very important and useful. We introduce an open-access comprehensive sleep dataset, called ISRUC Sleep. The data were obtained from human adults, including healthy subjects, subjects with sleep disorders, and subjects under the effect of sleep medication. Each recording was randomly selected between PSG recordings that were acquired by the Sleep Medicine Centre of the Hospital of Coimbra University (CHUC). The dataset comprises three groups of data: (1) data concerning 100 subjects, with one recording session per subject; (2) data gathered from 8 subjects; two recording sessions were performed per subject, and (3) data collected from one recording session related to 10 healthy subjects. The polysomnography (PSG) recordings, associated with each subject, were visually scored by two human experts. Comparing the existing sleep-related public datasets, ISRUC-Sleep provides data of a reasonable number of subjects with different characteristics such as: data useful for studies involving changes in the PSG signals over time; and data of healthy subjects useful for studies involving comparison of healthy subjects with the patients, suffering from sleep disorders. This dataset was created aiming to complement existing datasets by providing easy-to-apply data collection with some characteristics not covered yet. ISRUC-Sleep can be useful for analysis of new contributions: (i) in biomedical signal processing; (ii) in development of ASSC methods; and (iii) on sleep physiology studies. To evaluate and compare new contributions, which use this dataset as a benchmark, results of applying a subject-independent automatic sleep stage classification (ASSC) method on ISRUC-Sleep dataset are presented. PMID- 26589469 TI - Protective effects of udenafil citrate, piracetam and dexmedetomidine treatment on testicular torsion/detorsion-induced ischaemia/reperfusion injury in rats. AB - The aim of this study was to investigate the antioxidant properties of udenafil citrate (1.4 mg kg(-1) -2.8 mg kg(-1) ), dexmedetomidine 25 MUg kg(-1) and piracetam 200 mg kg(-1) administered on ipsilateral/contralateral testes after ischaemia in a rat model of testicular torsion/detorsion (T/D) and define its protective effect histologically. Fifty-six Wistar albino rats were included and randomly assigned into 6 groups. No intervention was performed in control group (Group 1, n = 8) and in torsion/detorsion group, (Group 2, n = 8). Udenafil 1.4 mg kg(-1) was given to torsion/detorsion group (Group 3, n = 10), udenafil 2.8 mg kg(-1) was given to torsion/detorsion group (Group 4, n = 10), piracetam 200 mg kg(-1) was given to torsion/detorsion group (Group 5, n = 10) and dexmedetomidine 25 MUg kg(-1) was given to torsion/detorsion group (Group 6, n = 10) intraperitoneally after 60 mins of testicular torsion. Biochemical and histopathological testicular injury were evaluated. When the tissue was examined by TOS values, Group 3, Group 4 and Group 5 were significantly lower than Group 2. In contrary Group 6 values were significantly higher than Group 2. The increasing doses of udenafil demonstrated antioxidant properties on the testis tissue and histopathological that protects the testicles. PMID- 26589470 TI - Minimum mycophenolic acid levels are associated with donor-specific antibody formation. AB - Although de novo DSA are associated with inferior graft survival, there are no effective strategies to prevent their formation. Underexposure to MPA (prodrug: MMF) also contributes to rejection rates early after transplantation, but the effect of this phenomenon on the formation of DSA long-term post-transplantation is unknown. Data are expressed as mean (standard deviation). All available data from 32 renal transplant recipients (age at transplantation 7.5 [4.5] yr) on tacrolimus and MPA immunosuppression with an average follow-up of 9.4 (s.d. 4.6) yr were analyzed. DSA were measured using the Luminex assay (>500 MFI was considered DSA-positive). Tacrolimus and MPA levels were measured with the Abbot Tacro II and EMIT assay, respectively. Among 1964 MPA and 3462 tacrolimus trough levels, the average MPA trough level was 3.2 (1.5) mg/L and the average tacrolimus level was 6.7 (2.8) ng/mL. At last follow-up, only 5/32 patients had undetectable DSA, with 5/32 having no class I antibodies and 6/32 having no class II antibodies. DSA formation was associated with a lower minimum MPA trough level (0.27 [0.23] vs. 0.47 [0.18] mg) and cystatin C eGFR (48 [21] vs. 70 [23] mL/min/1.73 m(2)) for class I DSA formers. The average eGFR of patients without class I DSA was 70 (23) mL/min/1.73 m(2), whereas the average eGFR of patients with class I DSA was 48 (21) mL/min/1.73 m(2) (p = 0.0071). MPA trough levels <1.3 mg/L long-term post-transplantation are associated with the formation of DSA. The association between the formation of DSA and minimum MPA exposure may support a strategy for preventing the formation of DSA. PMID- 26589472 TI - Critical Review and Update on the Treatment of Acute and Chronic Pulmonary Embolism. AB - Pulmonary embolism (PE), can be life-threatening without rapid appropriate therapy and often leads to chronic disease and disability. The ambiguity of symptoms makes PE difficult to diagnose, and available imaging strategies have their limitations. Treatment options for acute PE include fibrinolytics, surgical embolectomy, catheter-directed treatment, or vena cava filter placement as well as traditional parenteral anticoagulants, used alone or as a bridge to a vitamin K antagonist (VKA). The direct oral anticoagulants (DOACs) rivaroxaban and apixaban allow for single drug therapy, eliminating the need for initial parenteral anticoagulation, while dabigatran and edoxaban are initiated after a short course of parenteral therapy. The DOACs serve as a viable alternative to warfarin for chronic management for PE. Pulmonary embolism provoked from transient risk factors often requires a short-term course of anticoagulation (3 months). Unprovoked events, and those that occur in the presence of continuing risk factors such as cancer, or clinical markers such as residual vein thrombosis and elevated d-dimers can predict a higher risk of recurrent events and warrant extended anticoagulation. This review evaluates current recommendations for the treatment of PE, including dosing strategies, duration of therapy, and special populations such as renal impairment, malignancy, and obesity. PMID- 26589471 TI - Clopidogrel Response Variability: Review of the Literature and Practical Considerations. AB - Dual antiplatelet therapy with aspirin and a P2Y12 inhibitor is standard therapy following acute coronary syndrome and percutaneous coronary intervention. Despite the use of potent antiplatelet agents, vascular events continue to occur. Lack of response to clopidogrel therapy has been widely investigated using various methods of platelet function testing. These studies have consistently found an association between poor clopidogrel response and an increased risk of vascular events. Strategies to overcome this problem include higher clopidogrel doses or the use of an alternative P2Y12 agent. To date, the majority of studies investigating tailored antiplatelet therapy have failed to show any reduction in clinical events likely due to the low-risk population studied. Despite this lack of benefit from altering therapy, platelet function testing may be done in certain patient populations. Patients at high risk of deleterious outcomes from stent thrombosis may be an appropriate patient population for platelet function testing to ensure adequate response to therapy. In addition, emerging data suggests a potential role for platelet function testing to assess for bleeding risk. The purpose of this article is to review the key studies demonstrating response variability to clopidogrel therapy, strategies to overcome variability, and practical considerations for the clinician. PMID- 26589473 TI - [Immunisation schedule of the Spanish Association of Paediatrics: 2016 recommendations]. AB - The Advisory Committee on Vaccines of the Spanish Association of Paediatrics (CAV AEP) annually publishes the immunisation schedule which, in our opinion, estimates optimal for children resident in Spain, considering available evidence on current vaccines. We acknowledge the effort of the Ministry of Health during the last year in order to optimize the funded unified Spanish vaccination schedule, with the recent inclusion of pneumococcal and varicella vaccination in early infancy. Regarding the funded vaccines included in the official unified immunization schedule, taking into account available data, CAV-AEP recommends 2+1 strategy (2, 4 and 12 months) with hexavalent (DTPa-IPV-Hib-HB) vaccines and 13 valent pneumococcal conjugate vaccine. Administration of Tdap and poliomyelitis booster dose at the age of 6 is recommended, as well as Tdap vaccine for adolescents and pregnant women, between 27-36 weeks gestation. The two-dose scheme should be used for MMR (12 months and 2-4 years) and varicella (15 months and 2-4 years). Coverage of human papillomavirus vaccination in girls aged 11-12 with a two dose scheme (0, 6 months) should be improved. Information for male adolescents about potential beneficial effects of this immunisation should be provided as well. Regarding recommended unfunded immunisations, CAV-AEP recommends the administration of meningococcal B vaccine, due to the current availability in Spanish communitary pharmacies, with a 3+1 scheme (3, 5, 7 and 13 15 months). CAV-AEP requests the incorporation of this vaccine in the funded unified schedule. Vaccination against rotavirus is recommended in all infants. Annual influenza immunisation and vaccination against hepatitis A are indicated in population groups considered at risk. PMID- 26589474 TI - [Mitral valve replacement in infants less than 6 months-old]. PMID- 26589475 TI - [Serum S100beta protein reference values in a paediatric population]. AB - INTRODUCTION: S100beta protein has been proposed as a potential biomarker for both chronic and acute neurological disorders. Reference values of this protein are well defined in adults but not in children, in whom serum levels appear to vary with age. Reference values for serum S100beta in children from 0 to 14 years are presented. MATERIALS AND METHODS: A prospective study was conducted on 257 healthy children, who were divided into three age groups (under 12 months, 12 to 24 months and over 24 months). RESULTS: The study included179 boys and 78 girls, with a mean age of 5.5 (3.75) years. The mean serum concentration of protein S100beta was 0.156 (0.140-0.172) MUg/l. In children under 12 months, serum S100beta concentration was 0.350 (0.280-0.421) MUg/l; 0.165 (0.139-0.190) MUg/l in the group between 12 and 24 months and 0.121 (0.109-0.133) MUg/l in children older than 24 months. An inverse relationship was observed between age and serum S100beta, which declines as age increases. No differences were observed between sexes. CONCLUSIONS: The concentration of S100beta remains stable after two years of age, being possible to establish a baseline of S100beta for over two years. During the first two years of life, S100beta serum concentration is higher, the lower the age of the child. No differences in serum S100beta levels between sexes are observed. PMID- 26589476 TI - Management considerations for childhood-onset systemic lupus erythematosus patients and implications on therapy. AB - Childhood-onset systemic lupus erythematosus (cSLE) is a chronic inflammatory and autoimmune disease that may involve various organs and systems. This narrative review focuses on the recent evidence relating to cSLE management. The general management considerations of cSLE patients require the use of validated classification criteria, disease and health-related quality of life tools evaluation, as well as assessments of lupus nephritis biomarkers and cSLE quality indicators. The drug treatment for cSLE patients includes general supportive care and immunosuppressive therapy. Important implications on cSLE therapy are also updated such as infection, vaccination, infertility, pregnancy, contraception, dyslipidemia, physical activity, cancer, bone health, drug pharmacokinetics, adherence, academic outcomes, transition to adult care and cumulative organ damage. PMID- 26589477 TI - TLR3 activation increases chemokine expression in human fetal airway smooth muscle cells. AB - Viral infections, such as respiratory syncytial virus and rhinovirus, adversely affect neonatal and pediatric populations, resulting in significant lung morbidity, including acute asthma exacerbation. Studies in adults have demonstrated that human airway smooth muscle (ASM) cells modulate inflammation through their ability to secrete inflammatory cytokines and chemokines. The role of ASM in the developing airway during infection remains undefined. In our study, we used human fetal ASM cells as an in vitro model to examine the effect of Toll like receptor (TLR) agonists on chemokine secretion. We found that fetal ASM express multiple TLRs, including TLR3 and TLR4, which are implicated in the pathogenesis of respiratory syncytial virus and rhinovirus infection. Cells were treated with TLR agonists, polyinosinic-polycytidylic acid [poly(I:C)] (TLR3 agonist), lipopolysaccharide (TLR4 agonist), or R848 (TLR7/8 agonist), and IL-8 and chemokine (C-C motif) ligand 5 (CCL5) secretion were evaluated. Interestingly, poly(I:C), but neither lipopolysaccharide nor R848, increased IL-8 and chemokine (C-C motif) ligand 5 secretion. Examination of signaling pathways suggested that the poly(I:C) effects in fetal ASM involve TLR and ERK signaling, in addition to another major inflammatory pathway, NF-kappaB. Moreover, there are variations between fetal and adult ASM with respect to poly(I:C) effects on signaling pathways. Pharmacological inhibition suggested that ERK pathways mediate poly(I:C) effects. Overall, our data show that poly(I:C) initiates activation of proinflammatory pathways in developing ASM, which may contribute to immune responses to infection and exacerbation of asthma. PMID- 26589478 TI - MicroRNA-155 regulates host immune response to postviral bacterial pneumonia via IL-23/IL-17 pathway. AB - Postinfluenza bacterial pneumonia is associated with significant mortality and morbidity. MicroRNAs (miRNAs) are small, noncoding RNAs that regulate gene expression posttranscriptionally. miR-155 has recently emerged as a crucial regulator of innate immunity and inflammatory responses and is induced in macrophages during infection. We hypothesized upregulation of miR-155 inhibits IL 17 and increases susceptibility to secondary bacterial pneumonia. Mice were challenged with 100 plaque-forming units H1N1 intranasally and were infected with 10(7) colony-forming units of MRSA intratracheally at day 5 postviral challenge. Lungs were harvested 24 h later, and expression of miR-155, IL-17, and IL-23 was measured by real-time RT-PCR. Induction of miR-155 was 3.6-fold higher in dual infected lungs compared with single infection. miR-155(-/-) mice were protected with significantly lower (4-fold) bacterial burden and no differences in viral load, associated with robust induction of IL-23 and IL-17 (2.2- and 4.8-fold, respectively) postsequential challenge with virus and bacteria, compared with WT mice. Treatment with miR-155 antagomir improved lung bacterial clearance by 4.2 fold compared with control antagomir postsequential infection with virus and bacteria. Moreover, lung macrophages collected from patients with postviral bacterial pneumonia also had upregulation of miR-155 expression compared with healthy controls, consistent with observations in our murine model. This is the first demonstration that cellular miRNAs regulate postinfluenza immune response to subsequent bacterial challenge by suppressing the IL-17 pathway in the lung. Our findings suggest that antagonizing certain microRNA might serve as a potential therapeutic strategy against secondary bacterial infection. PMID- 26589479 TI - Raf/ERK drives the proliferative and invasive phenotype of BMPR2-silenced pulmonary artery endothelial cells. AB - A proliferative endothelial cell phenotype, inflammation, and pulmonary vascular remodeling are prominent features of pulmonary arterial hypertension (PAH). Bone morphogenetic protein type II receptor (BMPR2) loss-of-function is the most common cause of heritable PAH and has been closely linked to the formation of pathological plexiform lesions. Although some BMPR2 mutations leave ligand dependent responses intact, the disruption of ligand-independent, noncanonical functions are universal among PAH-associated BMPR2 genotypes, but incompletely understood. This study examined the noncanonical signaling consequences of BMPR2 silencing in human pulmonary artery endothelial cells to identify potential therapeutic targets. BMPR2 siRNA silencing resulted in a proliferative, promigratory pulmonary artery endothelial cell phenotype and disruption of cytoskeletal architecture. Expression profiling closely reflected these phenotypic changes. Gene set enrichment and promoter analyses, as well as the differential expression of pathway components identified Ras/Raf/ERK signaling as an important consequence of BMPR2 silencing. Raf family members and ERK1/2 were constitutively activated after BMPR2 knockdown. Two Raf inhibitors, sorafenib and AZ628, and low-dose nintedanib, a triple receptor tyrosine kinase inhibitor upstream from Ras, reversed the abnormal proliferation and hypermotility of BMPR2 deficiency. Inhibition of dysregulated Ras/Raf/ERK signaling may be useful in reversing vascular remodeling in PAH. PMID- 26589481 TI - Thromboembolic outcomes after use of a four-factor prothrombin complex concentrate for vitamin K antagonist reversal in a real-world setting. AB - BACKGROUND: A four-factor prothrombin complex concentrate (4F-PCC) was recently licensed in the United States for urgent vitamin K antagonist (VKA) reversal based on two randomized clinical trials. These studies excluded patients at high risk of thrombosis; therefore, the risk of thrombotic complications in unselected patients remains a concern. STUDY DESIGN AND METHODS: This study retrospectively evaluated the incidence of thromboembolic events (TEEs) and death in patients who received 4F-PCC for VKA reversal. The study included 113 consecutive patients who were 18 years of age and older and were administered 4F-PCC for VKA reversal. The incidence of TEE and deaths was evaluated for up to 60 days after PCC administration or until the end of hospitalization, whichever came later. RESULTS: Seven (6.2%) patients developed TEEs and 17 (15%) patients died. PCC administration was probably related to TEE and subsequent death in two (1.8%) patients. Multivariate analysis revealed that a diagnosis of Factor V Leiden or antiphospholipid syndrome was predictive of TEE, and active malignancy was predictive of death. CONCLUSION: This study supports the safety of 4F-PCC for urgent VKA reversal even in unselected patients. The underlying type of hypercoagulable state and the dose of PCC may influence the incidence of TEE. PMID- 26589480 TI - Pulmonary instillation of MWCNT increases lung permeability, decreases gp130 expression in the lungs, and initiates cardiovascular IL-6 transsignaling. AB - Pulmonary instillation of multiwalled carbon nanotubes (MWCNT) has the potential to promote cardiovascular derangements, but the mechanisms responsible are currently unclear. We hypothesized that exposure to MWCNT would result in increased epithelial barrier permeability by 24 h postexposure and initiate a signaling process involving IL-6/gp130 transsignaling in peripheral vascular tissue. To test this hypothesis we assessed the impact of 1 and 10 MUg/cm(2) MWCNT on transepithelial electrical resistance (TEER) and expression of barrier proteins and cell activation in vitro using normal human bronchial epithelial primary cells. Parallel studies using male Sprague-Dawley rats instilled with 100 MUg MWCNT measured bronchoalveolar lavage (BAL) differential cell counts, BAL fluid total protein, and lung water-to-tissue weight ratios 24 h postexposure and quantified serum concentrations of IL-6, soluble IL-6r, and soluble gp130. Aortic sections were examined immunohistochemically for gp130 expression, and gp130 mRNA/protein expression was evaluated in rat lung, heart, and aortic tissue homogenates. Our in vitro findings indicate that 10 MUg/cm(2) MWCNT decreased the development of TEER and zonula occludens-1 expression relative to the vehicle. In rats MWCNT instillation increased BAL protein, lung water, and induced pulmonary eosinophilia. Serum concentrations of soluble gp130 decreased, aortic endothelial expression of gp130 increased, and expression of gp130 in the lung was downregulated in the MWCNT-exposed group. We propose that pulmonary exposure to MWCNT can manifest as a reduced epithelial barrier and activator of vascular gp130-associated transsignaling that may promote susceptibility to cardiovascular derangements. PMID- 26589482 TI - Treatment of cytomegalovirus infection and disease pre- and post-quantitative nucleic acid test standardization: does use of a more sensitive assay lead to longer treatment duration? AB - Quantitative cytomegalovirus (CMV) nucleic acid testing (NAT) has been standardized using the World Health Organization (WHO) international calibration standard. A new FDA-approved WHO-calibrated assay (CA) was found to be more sensitive than a laboratory-developed test (LDT). We hypothesized that monitoring therapeutic response using a more sensitive assay may lead to longer antiviral therapy in solid organ and hematopoietic stem cell transplant patients with CMV infection. We reviewed transplant patients with CMV disease retrospectively, and divided them into two groups: those diagnosed and managed based on LDT and those managed using WHO-CA. Compared to patients monitored by LDT, the time to reach an undetectable viral load was significantly longer in the group monitored by the WHO-CA. However, a trend toward shorter duration of antiviral treatment was observed (median, 34 vs. 41 d; p = 0.058), with earlier discontinuation of induction antiviral therapy upon reaching undetectable viral load using WHO-CA (11 vs. 18 d; p = 002). We concluded that despite using a more sensitive CMV NAT, the total duration of antiviral treatment was not significantly prolonged in transplant patients with CMV infection and disease. Relapse rates did not differ between the two groups. PMID- 26589483 TI - Large eccentric strength increase using the Copenhagen Adduction exercise in football: A randomized controlled trial. AB - Hip adductor injuries are frequent in football, and players with low adductor strength appear to be at increased risk of injury. High adductor muscle activity has been shown in the Copenhagen Adduction exercise (CA); however, an associated strength gain has not been investigated. This study aims to examine the eccentric hip adduction strength (EHAD) gain using the CA in-season. Two U-19 sub-elite football teams, including 24 football players, were randomized to either an 8 week supervised progressive training program in addition to the usual training (intervention) or to continue training as usual (control). EHAD, eccentric hip abduction strength (EHAB), and side-bridge endurance were measured using reliable test procedures at baseline and follow-up by a blinded tester. There was a significant interaction between group and time on EHAD, EHAB, and EHAD/EHAB ratio (P < 0.025). The intervention group demonstrated a 35.7% increase in EHAD (P < 0.001); a 20.3% increase in EHAB (P = 0.003), and 12.3% increase in EHAD/EHAB ratio (P = 0.019). No significant within-group differences were found in the control group (P > 0.335). Compliance was 91.25%, and median muscle soreness ranged from 0 to 2. The CA implemented in-season with an 8-week progressive training program elicited a large significant increase in EHAD, EHAB, and EHAD/EHAB ratio. PMID- 26589484 TI - Effect of Allopurinol on Cardiovascular Outcomes in Hyperuricemic Patients: A Cohort Study. AB - BACKGROUND: Hyperuricemia and gout have been associated with increased cardiovascular risk. Allopurinol is an effective urate-lowering drug. Whether lowering of urate by allopurinol improves the cardiovascular risk in hyperuricemic patients remains to be established. OBJECTIVE: Our objective was to investigate the effect of allopurinol on cardiovascular outcomes in hyperuricemic patients in an observational setting. METHODS: We had access to a study population consisting of all patients from Funen County, Denmark with high urate levels (>=6 mg/dL) from 1992 to 2010. We linked 4 registries; all blood samples, all in- and outpatient contacts in hospitals, all reimbursed prescriptions and causes of death. We identified all incident allopurinol users and matched them 1:1 to nonusers of urate-lowering therapy, with similar urate levels, by using propensity scores. Hazard ratios were calculated using competing risk regression model, with respect to Antiplatelet Trialists' Collaboration composite outcome (myocardial infarction, stroke, or cardiovascular death) and all-cause mortality. RESULTS: Among 65,971 patients with hyperuricemia, we found 7127 patients on allopurinol treatment. In the propensity score-matched cohort we found a hazard ratio of 0.89 (95% confidence interval, 0.81-0.97) for the main outcome among allopurinol treated compared with nonusers of allopurinol. The corresponding hazard ratio for all-cause mortality was 0.68 (95% confidence interval, 0.62 0.74). CONCLUSION: Allopurinol treatment is associated with a decreased cardiovascular risk among hyperuricemic patients. PMID- 26589485 TI - Histone deacetylase inhibitor trichostatin A resensitizes gemcitabine resistant urothelial carcinoma cells via suppression of TG-interacting factor. AB - Gemcitabine and cisplatin (GC) has been widely used for advanced and metastatic urothelial carcinoma (UC). However, resistance to this remedy has been noticed. We have demonstrated that increase of TG-interacting factor (TGIF) in specimens is associated with worse prognosis of upper tract UC (UTUC) patients. The roles of TGIF in the gemcitabine resistance of UC were explored. Specimens of 23 locally advanced/advanced stage UTUC patients who received GC systemic chemotherapy after radical nephroureterectomy were collected to evaluate the alterations of TGIF in the resistance to the remedy by using immunohistochemistry. In vitro characterizations of mechanisms mediating TGIF in gemcitabine resistance were conducted by analyzing NTUB1 cells and their gemcitabine-resistant subline, NGR cells. Our results show that increased TGIF is significantly associated with chemo-resistance, poor progression-free survival, and higher cancer-related deaths of UTUC patients. Higher increases of TGIF, p AKT(Ser473) and invasive ability were demonstrated in NGR cells. Overexpression of TGIF in NTUB1 cells upregulated p-AKT(Ser473) activation, enhanced migration ability, and attenuated cellular sensitivity to gemcitabine. Knockdown of TGIF in NGR cells downregulated p-AKT(Ser473) activation, declined migration ability, and enhanced cellular sensitivity to gemcitabine. In addition, histone deacetylases inhibitor trichostatin A (TSA) inhibited TGIF, p-AKT(Ser473) expression and migration ability. Synergistic effects of gemcitabine and TSA on NGR cells were also demonstrated. Collectively, TGIF contributes to the gemcitabine resistance of UC via AKT activation. Combined treatment with gemcitabine and TSA might be a promising therapeutic remedy to improve the gemcitabine resistance of UC. PMID- 26589486 TI - Can altruism be unified? AB - There is clearly a plurality of forms of altruism. Classically, biological altruism is distinguished from psychological altruism. Recent discussions of altruism have attempted to distinguish even more forms of altruism. I will focus on three altruism concepts, biological altruism, psychological altruism, and helping altruism. The questions I am concerned with here are, first, how should we understand these concepts? and second, what relationship do these concepts bear to one another? In particular, is there an essence to altruism that unifies these concepts? I suggest that while there is no essence to altruism, this does not mean that the array of altruism concepts is completely disunified. Instead, I propose we place all the concepts into a common framework-an altruism space-that could lead to new questions about how this space can be filled. PMID- 26589487 TI - Proposal for staging of inflammatory lesions in the frontal region. AB - Frontal swelling can be due to multiple etiologies, including: mucocele, Pott's puffy tumor, fibro osseous lesions, benign and malignant neoplasms of the nose and paranasal sinuses, intracranial lesions, and metastasis. The objective of this study was to describe the clinical protocol used for the diagnosis of patients presented with frontal swelling and the proposal for staging of inflammatory lesions. We performed an observational retrospective analysis. We found 7 cases of patients with frontal swelling: 4 cases secondary to inflammatory pathology (3 Potts puffy tumors and one frontal mucocele), and 3 cases secondary to neoplasms (one benign and 2 malignant neoplasms). It's very important to consider the wide differential diagnosis that can present as frontal swelling, from inflammatory pathologies secondary to possible advanced infections of the paranasal sinuses to invasive malignant neoplasms. We propose a system of staging of frontal inflammatory lesions. PMID- 26589488 TI - In vitro activity of 'old antibiotics' against highly resistant Gram-negative bacteria. PMID- 26589489 TI - Two sides of the same coin--an interview study of Swedish obstetricians' experiences using ultrasound in pregnancy management. AB - BACKGROUND: The extended use of ultrasound that is seen in maternity care in most Western countries has not only affected obstetric care but also impacted on the conception of the fetus in relation to the pregnant woman. This situation has also raised concerns regarding the pregnant woman's reproductive freedom. The purpose of this study was to explore Swedish obstetricians' experiences and views on the role of obstetric ultrasound particularly in relation to clinical management of complicated pregnancy, and in relation to situations where the interests of maternal and fetal health conflict. METHODS: A qualitative study design was applied, and data were collected in 2013 through interviews with 11 obstetricians recruited from five different obstetric clinics in Sweden. Data were analysed using qualitative content analysis. RESULTS: The theme that emerged in the analysis 'Two sides of the same coin' depicts the view of obstetric ultrasound as a very important tool in obstetric care while it also was experienced as having given rise to new and challenging issues in the management of pregnancy. This theme was built on three categories: I. Ultrasound is essential and also demanding; II. A woman's health interest is prioritised in theory, but not always in practice; and III. Ultrasound is rewarding but may also cause unwarranted anxiety. CONCLUSIONS: The widespread use of ultrasound in obstetric care has entailed new challenges for clinicians due to enhanced possibilities to diagnose and treat fetal conditions, which in turn might conflict with the health interests of the pregnant woman. There is a need for further ethical discussions regarding the obstetrician's position in management of situations where maternal and fetal health interests conflict. The continuing advances in the potential of ultrasound to impact on pregnancy management will also increase the need for adequate and appropriate information and counselling. Together with other health care professionals, obstetricians therefore need to develop improved ways of enabling pregnant women and their partners to make informed decisions regarding pregnancy management. PMID- 26589490 TI - Capturing Individual Differences: Challenges in Animal Models of Posttraumatic Stress Disorder and Drug Abuse. PMID- 26589491 TI - Harnessing Reconsolidation to Treat Mental Disorders. PMID- 26589492 TI - Spatiotemporal Neural Dynamics of Enhanced Attention to Danger Cues in Posttraumatic Stress Disorder. PMID- 26589493 TI - Reprogramming away from the exhausted T cell state. AB - Induced pluripotent stem cells (iPSCs) describe somatic cells that have been reprogrammed to the pluripotent state from which they can then be differentiated into any cell type of the body. This ability has tremendous implications on a wide number of medical sciences and applications, including cancer treatments. In many cancer patients, tumor infiltrating lymphocytes (TILs) have reached an exhausted state and are unable to exert effector function despite detecting and localizing at the tumor. Although the isolation, ex vivo expansion and transplantation of TILs is effective in a significant group of patients, too many patients do not respond positively to this treatment, in part because the expanded TIL population does not include a sufficient number of cells with the naive or memory phenotype. Cell reprogramming using iPSC technologies aims to overcome this problem by returning TILs to the pluripotent state from which they can be differentiated into a heterogeneous population of T cells that are best suited to combat the tumor. PMID- 26589494 TI - Reconstruction of gene networks using prior knowledge. AB - BACKGROUND: Reconstructing gene regulatory networks (GRNs) from expression data is a challenging task that has become essential to the understanding of complex regulatory mechanisms in cells. The major issues are the usually very high ratio of number of genes to sample size, and the noise in the available data. Integrating biological prior knowledge to the learning process is a natural and promising way to partially compensate for the lack of reliable expression data and to increase the accuracy of network reconstruction algorithms. RESULTS: In this manuscript, we present PriorPC, a new algorithm based on the PC algorithm. PC algorithm is one of the most popular methods for Bayesian network reconstruction. The result of PC is known to depend on the order in which conditional independence tests are processed, especially for large networks. PriorPC uses prior knowledge to exclude unlikely edges from network estimation and introduces a particular ordering for the conditional independence tests. We show on synthetic data that the structural accuracy of networks obtained with PriorPC is greatly improved compared to PC. CONCLUSION: PriorPC improves structural accuracy of inferred gene networks by using soft priors which assign to edges a probability of existence. It is robust to false prior which is not avoidable in the context of biological data. PriorPC is also fast and scales well for large networks which is important for its applicability to real data. PMID- 26589495 TI - ABT-199 (venetoclax) and BCL-2 inhibitors in clinical development. AB - With the advent of new agents targeting CD20, Bruton's tyrosine kinase, and phosphoinositol-3 kinase for chronic lymphoid leukemia (CLL), more treatment options exist than ever before. B-cell lymphoma-2 (BCL-2) plays a major role in cellular apoptosis and is a druggable target. Small molecule inhibitors of BCL-2 are in active clinical studies. ABT-199 (venetoclax, RG7601, GDC-0199) has been granted breakthrough designation by FDA for relapsed or refractory CLL with 17p deletion. In this review, we summarized the latest clinical development of ABT 199/venetoclax and other novel agents targeting the BCL-2 proteins. PMID- 26589496 TI - Development methods of guidelines and documents with recommendations on physical restraint reduction in nursing homes: a systematic review. AB - BACKGROUND: Physical restraint, e.g. bedrails or belts in beds or chairs, are commonly used in nursing homes. However, there have been reports of pronounced differences in the prevalence between different facilities. Guidelines or other documents with recommendations for clinical practice are one approach to overcome centre variation and improve the quality of care. Rigorous development methods are deemed to ensure the validity, clarity and clinical applicability of practice recommendations. This study aims at describing the development methods of documents offering recommendations on physical restraint reduction in geriatric long-term care. METHODS: We performed a systematic search (February 2014) in electronic databases (PubMed, CINAHL, Gerolit, Carelit), the World Wide Web (via google.de) and on the homepages of 34 international scientific or healthcare organisations, using various terms related to documents offering guidance for clinical practice and physical restraints. All German and English language documents with recommendations for clinical practice aimed at reducing physical restraints' in nursing homes were included. Documents targeting mental health or acute care settings were excluded. Two reviewers independently selected the documents and extracted data, using a self-developed and piloted data extraction form. RESULTS: We identified 28 documents from Germany, USA, Australia, Switzerland, Canada and UK, published between 2002 and 2014. The documents were developed or published by governmental organisations, nursing or healthcare organisations, non-profit organisation, research institutions and private organisations. Two documents were developed mono-disciplinary (nursing) and eight documents interdisciplinary (including different healthcare professionals, lawyers or other stakeholders). In 18 documents the composition of the development group was not described. Two documents described the methods used for developing the recommendations. In both documents, the recommendations were based on a systematic literature search, critical appraisal of the evidence and developed in a consensus process. Materials or tools supporting the implementation were mentioned in 18 documents. CONCLUSIONS: This review shows that most of the identified documents with recommendations to reduce physical restraints in nursing homes did not adhere to rigorous scientific development methods. Only two documents comprised a systematic literature search and critical appraisal. Guidance aimed to inform clinical practice should rely on transparent and evidence-based methodologically with sound developed recommendations. PMID- 26589498 TI - Erratum to: What value is the CINAHL database when searching for systematic reviews of qualitative studies? PMID- 26589497 TI - A functional genomic model for predicting prognosis in idiopathic pulmonary fibrosis. AB - BACKGROUND: The course of disease for patients with idiopathic pulmonary fibrosis (IPF) is highly heterogeneous. Prognostic models rely on demographic and clinical characteristics and are not reproducible. Integrating data from genomic analyses may identify novel prognostic models and provide mechanistic insights into IPF. METHODS: Total RNA of peripheral blood mononuclear cells was subjected to microarray profiling in a training (45 IPF individuals) and two independent validation cohorts (21 IPF/10 controls, and 75 IPF individuals, respectively). To identify a gene set predictive of IPF prognosis, we incorporated genomic, clinical, and outcome data from the training cohort. Predictor genes were selected if all the following criteria were met: 1) Present in a gene co expression module from Weighted Gene Co-expression Network Analysis (WGCNA) that correlated with pulmonary function (p < 0.05); 2) Differentially expressed between observed "good" vs. "poor" prognosis with fold change (FC) >1.5 and false discovery rate (FDR) < 2%; and 3) Predictive of mortality (p < 0.05) in univariate Cox regression analysis. "Survival risk group prediction" was adopted to construct a functional genomic model that used the IPF prognostic predictor gene set to derive a prognostic index (PI) for each patient into either high or low risk for survival outcomes. Prediction accuracy was assessed with a repeated 10-fold cross-validation algorithm and independently assessed in two validation cohorts through multivariate Cox regression survival analysis. RESULTS: A set of 118 IPF prognostic predictor genes was used to derive the functional genomic model and PI. In the training cohort, high-risk IPF patients predicted by PI had significantly shorter survival compared to those labeled as low-risk patients (log rank p < 0.001). The prediction accuracy was further validated in two independent cohorts (log rank p < 0.001 and 0.002). Functional pathway analysis revealed that the canonical pathways enriched with the IPF prognostic predictor gene set were involved in T-cell biology, including iCOS, T-cell receptor, and CD28 signaling. CONCLUSIONS: Using supervised and unsupervised analyses, we identified a set of IPF prognostic predictor genes and derived a functional genomic model that predicted high and low-risk IPF patients with high accuracy. This genomic model may complement current prognostic tools to deliver more personalized care for IPF patients. PMID- 26589499 TI - The high frequency relationship: implications for torsadogenic hERG blockers. AB - BACKGROUND AND PURPOSE: Ventricular arrhythmias induced by human ether-a-go-go related gene (hERG; Kv 11.1 channel) blockers are a consequence of alterations in ventricular repolarisation in association with high-frequency (HF) oscillations, which act as a primary trigger; the autonomic nervous system plays a modulatory role. In the present study, we investigated the role of beta1 -adrenoceptors in the HF relationship between magnitude of heart rate and QT interval changes within discrete 10 s intervals (sorted into 5 bpm heart rate increments) and its implications for torsadogenic hERG blockers. EXPERIMENTAL APPROACH: The HF relationship was studied under conditions of autonomic blockade with atenolol (beta1 -adrenoceptor blocker) in the absence or presence of five hERG blockers in beagle dogs. In total, the effects of 14 hERG blockers on the HF relationship were investigated. KEY RESULTS: All the torsadogenic hERG blockers tested caused a vertical shift in the HF relationship, while hERG blockers associated with a low risk of Torsades de Pointes did not cause any vertical shift. Atenolol completely prevented the effects four torsadogenic agents (quinidine, thioridazine, risperidone and terfenadine) on the HF relationship, but only partially reduced those of dofetilide, leading to the characterization of two types of torsadogenic agent. CONCLUSIONS AND IMPLICATIONS: Analysis of the vertical shift in the HF relationship demonstrated that signs of transient sympathetic activation during HF oscillations in the presence of torsadogenic hERG blockers are mediated by beta1 -adrenoceptors. We suggest the HF relationship as a new biomarker for assessing Torsades de pointes liability, with potential implications in both preclinical studies and the clinic. PMID- 26589501 TI - Effect of High-Grade Disease on Outcomes of Surgically Treated Colon Cancer. AB - INTRODUCTION: Tumor grade is one of the cardinal pathological characteristics of colon cancer. Despite a large body of evidence on disease grade in general, the exact impact of high-grade disease in the context of the simplified high/low grade dichotomy that is based on glandular formation rate has yet to be quantified. METHODS: Patients with sporadic colon cancer treated surgically at our center (2004-2011) were included in an institutional review board-approved database. We measured the rates of distant and nodal disease spread in baseline pathology and the multivariable hazard radio (mHR) of recurrence and overall- and disease-specific mortality. RESULTS: Among 922 patients with specified tumor grade in baseline surgical pathology, 175 (19.0 %) had high-grade disease. These patients were at far higher risk of lymph node metastasis (63.8 vs. 39.6 %; P < 0.001) and metastatic presentation (31.4 vs. 15.8 %; P < 0.001). These baseline differences also led to significantly worse outcomes, including disease recurrence (17.1 vs. 10.6 %; mHR = 1.83; P = 0.026), overall mortality (57.7 vs. 33.3 %; mHR = 1.65; P < 0.001), and colon cancer-specific mortality (39.4 vs. 16.9 %; mHR = 1.57; P = 0.004). Most significantly, in stage II patients (n = 294), those with high-grade disease (16.0 %) had an mHR of 2.84 (P < 0.001) for mortality. CONCLUSIONS: High-grade disease on baseline surgical pathology is associated with a considerably higher rate of nodal and distant metastasis in colon cancer. As a result, the colon cancer-related mortality doubles for patients with high-grade disease. These findings were independent of baseline staging and confirm that the high-/low-grade tumor dichotomy is an important prognostic factor greatly influencing colon cancer outcomes across stages. PMID- 26589500 TI - Immunoinformatics and epitope prediction in the age of genomic medicine. AB - Immunoinformatics involves the application of computational methods to immunological problems. Prediction of B- and T-cell epitopes has long been the focus of immunoinformatics, given the potential translational implications, and many tools have been developed. With the advent of next-generation sequencing (NGS) methods, an unprecedented wealth of information has become available that requires more-advanced immunoinformatics tools. Based on information from whole genome sequencing, exome sequencing and RNA sequencing, it is possible to characterize with high accuracy an individual's human leukocyte antigen (HLA) allotype (i.e., the individual set of HLA alleles of the patient), as well as changes arising in the HLA ligandome (the collection of peptides presented by the HLA) owing to genomic variation. This has allowed new opportunities for translational applications of epitope prediction, such as epitope-based design of prophylactic and therapeutic vaccines, and personalized cancer immunotherapies. Here, we review a wide range of immunoinformatics tools, with a focus on B- and T cell epitope prediction. We also highlight fundamental differences in the underlying algorithms and discuss the various metrics employed to assess prediction quality, comparing their strengths and weaknesses. Finally, we discuss the new challenges and opportunities presented by high-throughput data-sets for the field of epitope prediction. PMID- 26589502 TI - Percutaneous Computed Tomography-Guided Thermal Ablation of Pulmonary Osteosarcoma Metastases in Children. AB - INTRODUCTION: The role of percutaneous thermal ablation as a minimally-invasive treatment has not been evaluated in children under 18 years of age with pulmonary osteosarcoma metastases. METHODS: This was a retrospective review of children treated with percutaneous thermal ablation for pulmonary osteosarcoma metastasis after prior surgical metastasectomy and chemotherapy. Selection criteria included number of pulmonary nodules <5 and nodule size smaller than 2 cm. Indications were discussed at multidisciplinary meetings. The goal was to achieve complete remission using percutaneous thermal ablation, thereby avoiding additional thoracotomies. RESULTS: A total of 26 pulmonary nodules (mean size 6.7 mm, range 2-16 mm) were successfully treated by percutaneous computed tomography (CT) guided thermal ablation in 11 children with osteosarcoma between the ages of 7 and 17 years (median 12.5). Patients denied post-procedure pain. Complications were limited to three pneumothoraxes (two minor, one major), and median hospitalization duration was 2.0 days. One patient died of rapidly progressive lumbar metastasis discovered 20 days post-ablation. Of the remaining 10 patients, local control at the ablation site was achieved, with median follow up of 16.7 months (range 4.1-41.8). Five patients remained in complete remission after median follow-up of 37.5 months, and five patients developed new metastases (one osseous, four pulmonary), of which two are in remission after subsequent treatment. CONCLUSION: Percutaneous thermal ablation is a safe and effective minimally-invasive curative local treatment alternative for children with oligometastatic pulmonary osteosarcoma in whom surgical intervention is clinically contraindicated or unappealing. PMID- 26589503 TI - The Unmet Needs of Paediatric Therapeutics in Poor Countries. PMID- 26589504 TI - Luminescent Silica Nanoparticles Featuring Collective Processes for Optical Imaging. AB - The field of nanoparticles has successfully merged with imaging to optimize contrast agents for many detection techniques. This combination has yielded highly positive results, especially in optical and magnetic imaging, leading to diagnostic methods that are now close to clinical use. Biological sciences have been taking advantage of luminescent labels for many years and the development of luminescent nanoprobes has helped definitively in making the crucial step forward in in vivo applications. To this end, suitable probes should present excitation and emission within the NIR region where tissues have minimal absorbance. Among several nanomaterials engineered with this aim, including noble metal, lanthanide, and carbon nanoparticles and quantum dots, we have focused our attention here on luminescent silica nanoparticles. Many interesting results have already been obtained with nanoparticles containing only one kind of photophysically active moiety. However, the presence of different emitting species in a single nanoparticle can lead to diverse properties including cooperative behaviours. We present here the state of the art in the field of silica luminescent nanoparticles exploiting collective processes to obtain ultra bright units suitable as contrast agents in optical imaging and optical sensing and for other high sensitivity applications. PMID- 26589505 TI - Self-Assembling Nanoparticles of Amphiphilic Polymers for In Vitro and In Vivo FRET Imaging. AB - Self-assembling nanoparticles of amphiphilic polymers are viable delivery vehicles for transporting hydrophobic molecules across hydrophilic media. Noncovalent contacts between the hydrophobic domains of their macromolecular components are responsible for their formation and for providing a nonpolar environment for the encapsulated guests. However, such interactions are reversible and, as a result, these supramolecular hosts can dissociate into their constituents amphiphiles to release the encapsulated cargo. Operating principles to probe the integrity of the nanocarriers and the dynamic exchange of their components are, therefore, essential to monitor the fate of these supramolecular assemblies in biological media. The co-encapsulation of complementary chromophores within their nonpolar interior offers the opportunity to assess their stability on the basis of energy transfer and fluorescence measurements. Indeed, the exchange of excitation energy between the entrapped chromophores can only occur if the nanoparticles retain their integrity to maintain donors and acceptors in close proximity. In fact, energy-transfer schemes are becoming invaluable protocols to elucidate the transport properties of these fascinating supramolecular constructs in a diversity of biological preparations and can facilitate the identification of strategies to deliver contrast agents and/or drugs to target locations in living organisms for potential diagnostic and/or therapeutic applications. PMID- 26589506 TI - Polymeric Nanoparticles for Cancer Photodynamic Therapy. AB - In chemotherapy a fine balance between therapeutic and toxic effects needs to be found for each patient, adapting standard combination protocols each time. Nanotherapeutics has been introduced into clinical practice for treating tumors with the aim of improving the therapeutic outcome of conventional therapies and of alleviating their toxicity and overcoming multidrug resistance. Photodynamic therapy (PDT) is a clinically approved, minimally invasive procedure emerging in cancer treatment. It involves the administration of a photosensitizer (PS) which, under light irradiation and in the presence of molecular oxygen, produces cytotoxic species. Unfortunately, most PSs lack specificity for tumor cells and are poorly soluble in aqueous media, where they can form aggregates with low photoactivity. Nanotechnological approaches in PDT (nanoPDT) can offer a valid option to deliver PSs in the body and to solve at least some of these issues. Currently, polymeric nanoparticles (NPs) are emerging as nanoPDT system because their features (size, surface properties, and release rate) can be readily manipulated by selecting appropriate materials in a vast range of possible candidates commercially available and by synthesizing novel tailor-made materials. Delivery of PSs through NPs offers a great opportunity to overcome PDT drawbacks based on the concept that a nanocarrier can drive therapeutic concentrations of PS to the tumor cells without generating any harmful effect in non-target tissues. Furthermore, carriers for nanoPDT can surmount solubility issues and the tendency of PS to aggregate, which can severely affect photophysical, chemical, and biological properties. Finally, multimodal NPs carrying different drugs/bioactive species with complementary mechanisms of cancer cell killing and incorporating an imaging agent can be developed. In the following, we describe the principles of PDT use in cancer and the pillars of rational design of nanoPDT carriers dictated by tumor and PS features. Then we illustrate the main nanoPDT systems demonstrating potential in preclinical models together with emerging concepts for their advanced design. PMID- 26589507 TI - Inorganic Nanoparticles for Photodynamic Therapy. AB - Photodynamic therapy (PDT) is a well-established technique employed to treat aged macular degeneration and certain types of cancer, or to kill microbes by using a photoactivatable molecule (a photosensitizer, PS) combined with light of an appropriate wavelength and oxygen. Many PSs are used against cancer but none of them are highly specific. Moreover, most are hydrophobic, so are poorly soluble in aqueous media. To improve both the transportation of the compounds and the selectivity of the treatment, nanoparticles (NPs) have been designed. Thanks to their small size, these can accumulate in a tumor because of the well-known enhanced permeability effect. By changing the composition of the nanoparticles it is also possible to achieve other goals, such as (1) targeting receptors that are over-expressed on tumoral cells or neovessels, (2) making them able to absorb two photons (upconversion or biphoton), and (3) improving singlet oxygen generation by the surface plasmon resonance effect (gold nanoparticles). In this chapter we describe recent developments with inorganic NPs in the PDT domain. Pertinent examples selected from the literature are used to illustrate advances in the field. We do not consider either polymeric nanoparticles or quantum dots, as these are developed in other chapters. PMID- 26589508 TI - Photoactivatable Nanostructured Surfaces for Biomedical Applications. AB - This review aims to summarize the current status of photoactivatable nanostructured film and polymeric nanofiber surfaces used in biomedical applications with emphasis on their photoantimicrobial activity, oxygen-sensing in biological media, light-triggered release of drugs, and physical or structural transformations. Many light-responsive functions have been considered as novel ways to alter surfaces, i.e., in terms of their reactivities and structures. We describe the design of surfaces, nano/micro-fabrication, the properties affected by light, and the application principles. Additionally, we compare the various approaches reported in the literature. PMID- 26589509 TI - Gold-Based Nanomaterials for Applications in Nanomedicine. AB - In this review, an overview of the current state-of-the-art of gold-based nanomaterials (Au NPs) in medical applications is given. The unique properties of Au NPs, such as their tunable size, shape, and surface characteristics, optical properties, biocompatibility, low cytotoxicity, high stability, and multifunctionality potential, among others, make them highly attractive in many aspects of medicine. First, the preparation methods for various Au NPs including functionalization strategies for selective targeting are summarized. Second, recent progresses on their applications, ranging from the diagnostics to therapeutics are highlighted. Finally, the rapidly growing and promising field of gold-based theranostic nano-platforms is discussed. Considering the great body of existing information and the high speed of its renewal, we chose in this review to generalize the data that have been accumulated during the past few years for the most promising directions in the use of Au NPs in current medical research. PMID- 26589510 TI - Diagnostic and Therapeutic Applications of Quantum Dots in Nanomedicine. AB - The interest in Quantum Dots as a class of nanomaterials has grown considerably since their discovery by Ekimov and Efros in the early 1980s. Although this early work focussed primarily on CdSe-based nanocrystals, the field has now expanded to include various classes of nanoparticles with different types of core, shell or passivation chemistry. Such differences can have a profound effect on the optical properties and potential biocompatibility of the resulting constructs. Although QDs have predominantly been used for imaging and sensing applications, more examples of their use as therapeutics are beginning to emerge. In this chapter we discuss the progress made over the past decade in developing QDs for imaging and therapeutic applications. PMID- 26589511 TI - Phototherapeutic Release of Nitric Oxide with Engineered Nanoconstructs. AB - The multiple role nitric oxide (NO) plays in a number of physiological and pathophysiological processes has, over the last few years, stimulated a massive interest in the development of new strategies and methods for generating NO in a controlled way, with the exciting prospect of tackling important diseases. Photochemical precursors of NO are particularly suited to this end because light triggering permits an exquisite control of location and timing of NO delivery. Integration of NO photodonors within the structure of appropriate materials represents a key step in the fabrication of functional devices for phototherapeutic applications. It also offers the advantage of concentrating a large number of chromophores in a restricted area with the result of significantly increasing the NO reservoir and the light harvesting properties. We present here an overview of the most significant advances made in the last 5 years in the fabrication of engineered nanoconstructs able to delivery NO under the exclusive control of light inputs, highlighting the logical design and their potential applications in battling cancer and bacterial infections. PMID- 26589512 TI - Prognostic Factors for Breast Cancer: an Immunomorphological Update. AB - The prognostic variability recorded within homogeneous groups of patients for anatomo-clinical disease stages has led to a more detailed biological characterization of breast cancer. Recently, the attention of the scientific community has focused on the role of tumor-infiltrating lymphocytes (TILs). Therefore, the need of an in-depth immunomorphological characterization of TILs has been emerged. The presence of TILs has been retrospectively investigated in 113 female cases of ductal carcinoma. An immunohistochemical investigation with CD3, CD4, CD8, CD20, CD56, granulysin, perforin-1, granzyme-B and TIA-1 was performed according to the standard procedures on all 17 cases with TILs evidence. TILs consisted of T and B lymphocytes: the prevalent population showed a T immunoprofile with a CD8-immunopositive killer subpopulation (Tk), close linked to carcinomatous cells, and a CD4-immunopositive helper subpopulation (Th), inside the tumor. A time sequence (firstly T, then B) has been disclosed. Granulysin, perforin, granzyme-B and TIA-1 were expressed by Tk cells. The activated Tk cells secrete these mediators as a result of the binding to the tumor target cell, causing its lytic planned death. The cytotoxicity supported by Tk cells appears an important favorable prognostic factor. Therefore, a graduation system for TILs in breast cancer has been here proposed (absent, non brisk, brisk). PMID- 26589513 TI - The Clinicopathologic Significance of BAF250a (ARID1A) Expression in Hepatocellular Carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most common and lethal human cancers. Recently, exome sequencing has revealed that mutation of ARID1A is frequent in HCC. Herein, we determined the clinicopathologic significance of ARID1A expression in HCC. We detected the level of mRNA and protein expression of ARID1A in 12 paired HCC tumors and adjacent non-cancerous tissues by quantitative real-time PCR and immunohistochemistry (IHC). In addition, we determined the expression of BAF250a on 121 HCC tumors by IHC and assessed the association between BAF250a expression and clinicopathologic and prognostic features. The levels of ARID1A mRNA were significantly elevated in 10 of 12 HCC tumors compared with adjacent non-cancerous tissues. The level of BAF250a protein expression was higher in 10 of 12 HCC tumors compared with adjacent liver tissues. IHC indicated that 12.17 % of HCC tumors (14/115) were BAF250a-negative. Loss of BAF250a was significantly associated with larger tumor size, but not associated with other clinicopathologic features. There was no significant difference in disease-free or overall survival between BAF250a-positive and BAF250a-negative patients. Most HCCs had an increased level of ARID1A mRNA and BAF250a expression. Loss of BAF250a was significantly more frequent in larger HCC tumors, but had no prognostic significance. PMID- 26589514 TI - [Molecular diagnosis of melanocytic tumors]. AB - Melanoma therapy has undergone a paradigm shift. Classic chemotherapies with poor treatment responses have been replaced by modern immune checkpoint blockades and targeted therapies with excellent responses. The latter require precise diagnosis of mutations in the melanoma genome as molecular targets for the small molecules. The diagnosis of melanomas has also been supplemented by molecular techniques. Differential diagnosis of melanoma and melanoma simulators such as atypical Spitz nevi can be supported by fluorescence in situ hybridization (FISH) and comparative genomic hybridization (CGH). Here we review the indications and methods for molecular diagnosis of melanocytic tumors. PMID- 26589515 TI - The Role of Trunk Muscle Strength for Physical Fitness and Athletic Performance in Trained Individuals: A Systematic Review and Meta-Analysis. AB - BACKGROUND: The importance of trunk muscle strength (TMS) for physical fitness and athletic performance has been demonstrated by studies reporting significant correlations between those capacities. However, evidence-based knowledge regarding the magnitude of correlations between TMS and proxies of physical fitness and athletic performance as well as potential effects of core strength training (CST) on TMS, physical fitness and athletic performance variables is currently lacking for trained individuals. OBJECTIVE: The aims of this systematic review and meta-analysis were to quantify associations between variables of TMS, physical fitness and athletic performance and effects of CST on these measures in healthy trained individuals. DATA SOURCES: PubMed, Web of Science, and SPORTDiscus were systematically screened from January 1984 to March 2015. STUDY ELIGIBILITY CRITERIA: Studies were included that investigated healthy trained individuals aged 16-44 years and tested at least one measure of TMS, muscle strength, muscle power, balance, and/or athletic performance. STUDY APPRAISAL AND SYNTHESIS METHODS: Z-transformed Pearson's correlation coefficients between measures of TMS and physical performance were aggregated and back-transformed to r values. Further, to quantify the effects of CST, weighted standardized mean differences (SMDs) of TMS and physical performance were calculated using random effects models. The methodological quality of CST studies was assessed by the Physiotherapy Evidence Database (PEDro) scale. RESULTS: Small-sized relationships of TMS with physical performance measures (-0.05 <= r <= 0.18) were found in 15 correlation studies. Sixteen intervention studies revealed large effects of CST on measures of TMS (SMD = 1.07) but small-to-medium-sized effects on proxies of physical performance (0 <= SMD <= 0.71) compared with no training or regular training only. The methodological quality of CST studies was low (median PEDro score = 4). CONCLUSIONS: Our findings indicate that TMS plays only a minor role for physical fitness and athletic performance in trained individuals. In fact, CST appears to be an effective means to increase TMS and was associated with only limited gains in physical fitness and athletic performance measures when compared with no or only regular training. PMID- 26589516 TI - Relationship of basal-septal fibrosis with LV outflow tract obstruction in hypertrophic cardiomyopathy: insights from cardiac magnetic resonance analysis. AB - Myocardial fibrosis is frequently observed and may be associated with the prognosis in patients with hypertrophic cardiomyopathy (HCM); however, the clinical pathophysiological features, particularly in terms of fibrosis, of hypertrophic obstructive cardiomyopathy (HOCM) remain unclear. This study aimed to determine a role of local fibrosis in HOCM using cardiac magnetic resonance (CMR). 108 consecutive HCM patients underwent CMR. HOCM was defined as a left ventricular outflow tract (LVOT) pressure gradient >=30 mmHg at rest. Myocardial mass and fibrosis mass by late gadolinium-enhancement CMR (LGE-CMR) were calculated and the distribution/pattern was analyzed using the AHA 17-segment model. LV ejection fraction (LVEF) was significantly higher in patients with HOCM (n = 19) than in those with nonobstructive HCM (n = 89) (P < 0.05). Both total myocardial and fibrosis masses in LV were similar in the two groups (P = 0.385 and P = 0.859, respectively). However, fibrosis in the basal septum was significantly less frequent in the HOCM group than in the nonobstructive HCM group (P < 0.01). The LVOT pressure gradient was significantly higher in the basal-septal non-fibrosis group than in the fibrosis group (23.6 +/- 37.3 vs. 4.8 +/- 11.4 mmHg, P < 0.01). Multivariate analysis revealed that basal-septal fibrosis was an independent negative predictor of LVOT obstruction in addition to the local wall thickness and LVEF as positive predictors in HCM patients. In conclusion, a significant association was observed between LVOT obstruction and basal septal fibrosis by LGE-CMR in HCM patients. In addition to negative impact of basal-septal fibrosis, basal-septal hypertrophy and preserved global LV contractility may be associated with the pathophysiological features of LVOT obstruction. PMID- 26589517 TI - Coarctation of the aorta diagnosed by cardiac computed tomography angiography in a 49-year-old man presenting with acute myocardial infarction. AB - Aortic coarctation in patients with acute myocardial infarction is an uncommon finding, We report the case of a 49-year-old man with acute myocardial infarction and diagnosis of severe aortic coarctation in concomitance with a three dimensional computed tomography scan. PMID- 26589518 TI - A measles outbreak in a middle school with high vaccination coverage and evidence of prior immunity among cases, Beijing, P.R. China. AB - BACKGROUND: Age-appropriate receipt of >= 2 measles-containing vaccine (MCV) doses has been considered evidence of immunity against measles. Transmission of measles is rarely reported among such persons. METHODS: We report a measles outbreak in a middle school in Beijing that has high coverage with >= 2 documented MCV doses. History of previous measles and documentation of MCV receipt were collected for all individuals. Cases were identified by active surveillance and confirmed by laboratory tests. Measles immunoglobulin G (IgG) titers and clinical presentations were obtained for each case. RESULTS: Of 1331 individuals without a prior history of measles, 1172 (88.1% [95%CI:86.4-91.5%]) and 1078 (81.0% [95%CI:78.9-83.1%]) had age-appropriate receipt of >= 2 MCV doses by domestic and U.S. CDC/ACIP criteria, respectively. Thirteen measles cases occurred in the outbreak. The index case and 3 secondary cases were students. The 9 tertiary cases included 2 teachers and 7 students. All 11 student cases received >= 2 age-appropriate MCV doses by Chinese domestic criteria; 8 were age appropriately vaccinated by U.S. CDC/ACIP criteria. Measles IgG was detected during the acute phase of measles for all but 2 cases -the first case and 1 tertiary case. Among students with age-appropriate receipt of >= 2 MCV doses, the length of time since the last MCV was significantly associated with risk of measles: for the 1172 students, the risk was 4.6 [OR5.6;95%CI:1.4-22.9] and 5.5 [OR6.5;95%CI:1.4-29.8] times higher when the last MCV dose was 5-9 years and >= 10 years prior, respectively, compared with <5 years prior; for the 1078 students, the risk was 4.1 [OR5.1;95%CI:1.3-20.7] times higher when the last MCV dose was 5-9 years prior compared with <5 years prior. CONCLUSIONS: This is the first report from China showing measles transmission among persons with prior evidence of immunity. Secondary vaccine failure may have played an important role in measles transmission. Further laboratory surveillance is needed to assess the persistence of vaccine-induced immunity of domestically-produced MCV in China. PMID- 26589519 TI - Effectiveness of live attenuated influenza vaccine and inactivated influenza vaccine in children 2-17 years of age in 2013-2014 in the United States. AB - BACKGROUND: A postmarketing observational study was initiated to evaluate quadrivalent live attenuated influenza vaccine (LAIV) effectiveness in children aged 2-17 years in the United States. METHODS: Children and adolescents aged 2-17 years seeking outpatient care for febrile acute respiratory illness <5 days duration were enrolled at 4 geographically diverse sites during the 2013-2014 influenza season. Nasal swabs were tested for influenza using reverse transcription polymerase chain reaction. Vaccination status was documented from medical records or immunization registries. Children who received >=1 dose of influenza vaccine >=14 days before study visit were considered vaccinated. Vaccine effectiveness (VE) was estimated as 100*(1-adjusted odds ratio), where the odds of interest are the odds of vaccine exposure among influenza cases and test-negative controls. RESULTS: In total, 1033 children and adolescents were included in the analysis. Influenza was detected in 14% (145/1033) of all children, with 74% (108/145) of the influenza cases due to A/H1N1pdm09 strains, 21% (31) to influenza B, and 4% (6) to influenza H3N2. LAIV did not show significant effectiveness against A/H1N1pdm09 (VE 13% [95% CI: -55 to 51]) but was effective against B/Yamagata strains (82% [95% CI: 12-96]). Inactivated influenza vaccine was effective against A/H1N1pdm09 (74% [95% CI: 50-86]) and B/Yamagata (70% [95% CI: 18-89]). CONCLUSIONS: LAIV provided significant protection against B/Yamagata influenza but not against A/H1N1pdm09 in children aged 2-17 years in 2013-2014, resulting in a proposed change of the 2015-2016 formulation with a new and more heat-stable A/H1N1pdm09 LAIV strain. PMID- 26589520 TI - Age-related forgetting in locomotor adaptation. AB - The healthy aging process affects the ability to learn and remember new facts and tasks. Prior work has shown that motor learning can be adversely affected by non motor deficits, such as time. Here we investigated how age, and a dual task influence the learning and forgetting of a new walking pattern. We studied healthy younger (<30 yo) and older adults (>50 yo) as they alternated between 5 min bouts of split-belt treadmill walking and resting. Older subjects learned a new walking pattern at the same rate as younger subjects, but forgot some of the new pattern during the rest breaks. We tested if forgetting was due to reliance on a cognitive strategy that was not fully engaged after rest breaks. When older subjects performed a dual cognitive task to reduce strategic control of split belt walking, their adaptation rate slowed, but they still forgot much of the new pattern during the rest breaks. Our results demonstrate that the healthy aging process is one component that weakens motor memories during rest breaks and that this phenomenon cannot be explained solely by reliance on a conscious strategy in older adults. PMID- 26589521 TI - Cost-Effectiveness Analysis of Insulin Detemir Compared to Neutral Protamine Hagedorn (NPH) in Patients with Type 1 and Type 2 Diabetes Mellitus in Spain. AB - INTRODUCTION: An Excel(r) (Microsoft Corporation) model was adapted to estimate the short-term (1-year) cost effectiveness of insulin detemir (IDet) versus neutral protamine Hagedorn (NPH) insulin in patients initiating insulin treatment with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) in Spain. METHODS: Clinical benefits included the non-severe hypoglycemia rate for T1DM and T2DM, and weight change for T2DM. Three scenarios were included with different hypoglycemia rates estimated on the basis of clinical trials and observational studies. Costs, estimated from perspective of the Spanish Public Healthcare System (Euros 2014), included insulin treatment and non-severe hypoglycemia management costs. Non-severe hypoglycemia, defined as a self-managed event, implied the use of extra glucose testing strips and a general practitioner visit during the week following the event for 25% of patients. An average disutility value was associated to non-severe hypoglycemia events and, for T2DM, to one body mass index unit gain to calculate quality-adjusted life years (QALYs). RESULTS: For the three scenarios a range of 0.025-0.076 QALYs for T1DM and 0.014-0.051 QALYs for T2DM were gained for IDet versus NPH due to non-severe hypoglycemia and weight gain avoidance, in return of an incremental cost of ?145 192 for T1DM and ?128-206 for T2DM. This resulted in the IDet versus NPH incremental cost-effectiveness ratio (ICER) ranging between ?1910/QALY and ?7682/QALY for T1DM and ?2522/QALY and ?15,009/QALY for T2DM. CONCLUSION: IDet was a cost-effective alternative to NPH insulin in the first year of treatment of patients with T1DM and patients with T2DM in Spain, with ICERs under the threshold value commonly accepted in Spain (?30,000/QALY). FUNDING: Novo Nordisk. PMID- 26589522 TI - Stoichiometric implications of a biphasic life cycle. AB - Animals mediate flows of elements and energy in ecosystems through processes such as nutrient sequestration in body tissues, and mineralization through excretion. For taxa with biphasic life cycles, the dramatic shifts in anatomy and physiology that occur during ontogeny are expected to be accompanied by changes in body and excreta stoichiometry, but remain little-explored, especially in vertebrates. Here we tested stoichiometric hypotheses related to the bodies and excreta of the wood frog (Lithobates sylvaticus) across life stages and during larval development. Per-capita rates of nitrogen (N) and phosphorus (P) excretion varied widely during larval ontogeny, followed unimodal patterns, and peaked midway through development (Taylor-Kollros stages XV and XII, respectively). Larval mass did not increase steadily during development but peaked at stage XVII and declined until the termination of the experiment at stage XXII. Mass-specific N and P excretion rates of the larvae decreased exponentially during development. When coupled with population-biomass estimates, population-level excretion rates were greatest at stages VIII-X. Percent carbon (C), N, and C:N of body tissue showed weak trends across major life stages; body P and C:P, however, increased sixfold during development from egg to adult. Our results demonstrate that intraspecific ontogenic changes in nutrient contents of excretion and body tissues can be significant, and that N and P are not always excreted proportionally throughout life cycles. These results highlight the dynamic roles that species play in ecosystems, and how the morphological and physiological changes that accompany ontogeny can influence ecosystem-level processes. PMID- 26589523 TI - The Resource Identification Initiative: A Cultural Shift in Publishing. AB - A central tenet in support of research reproducibility is the ability to uniquely identify research resources, i.e., reagents, tools, and materials that are used to perform experiments. However, current reporting practices for research resources are insufficient to identify the exact resources that are reported or to answer basic questions such as "How did other studies use resource X?" To address this issue, the Resource Identification Initiative was launched as a pilot project to improve the reporting standards for research resources in the methods sections of papers and thereby improve identifiability and scientific reproducibility. The pilot engaged over 25 biomedical journal editors from most major publishers, as well as scientists and funding officials. Authors were asked to include Research Resource Identifiers (RRIDs) in their manuscripts prior to publication for three resource types: antibodies, model organisms, and tools (i.e., software and databases). RRIDs are assigned by an authoritative database, for example a model organism database, for each type of resource. To make it easier for authors to obtain RRIDs, resources were aggregated from the appropriate databases and their RRIDs made available in a central web portal ( http://scicrunch.org/resources ). RRIDs meet three key criteria: they are machine readable, free to generate and access, and are consistent across publishers and journals. The pilot was launched in February of 2014 and over 300 papers have appeared that report RRIDs. The number of journals participating has expanded from the original 25 to more than 40 with RRIDs appearing in 62 different journals to date. Here, we present an overview of the pilot project and its outcomes to date. We show that authors are able to identify resources and are supportive of the goals of the project. Identifiability of the resources post pilot showed a dramatic improvement for all three resource types, suggesting that the project has had a significant impact on identifiability of research resources. PMID- 26589524 TI - Expected and Unexpected Consequences of the Affordable Care Act: The Impact on Patients and Surgeons-Pro and Con Arguments. AB - The Patient Protection and Affordable Care Act (PPACA), called the Affordable Care Act (ACA) or "ObamaCare" for short, was enacted in 2010. The Public Policy and Advocacy Committee of the Society for Surgery of the Alimentary Tract (SSAT) hosted a debate with an expert panel to discuss the ACA and its impact on surgical care after the first year of patient enrollment. The purpose of this debate was to focus on the impact of ACA on the public and surgeons. At the core of the ACA are insurance industry reforms and expanded coverage, with a goal of improved clinical outcomes and reduced costs of care. We have observed supportive and opposing views on ACA. Nonetheless, we will witness major shifts in health care delivery as well as restructuring of our relationship with payers, institutions, and patients. With the rapidly changing health care landscape, surgeons will become key members of health systems and will likely need to lead transition from solo-practice to integrated care systems. The full effects of the ACA remain unrealized, but its implementation has begun to change the map of the American health care system and will surely impact the practice of surgery. Herein, we provide a synopsis of the "pro" and "con" arguments for the expected and unexpected consequences of the ACA on society and surgeons. PMID- 26589525 TI - Repeated Surgical or Endoscopic Myotomy for Recurrent Dysphagia in Patients After Previous Myotomy for Achalasia. AB - AIM: Surgical myotomy of the lower esophageal sphincter has a 5-year success rate of approximately 91 %. Peroral endoscopic myotomy can provide similar results for controlling dysphagia. Some patients experience either persistent or recurrent dysphagia after myotomy. We present here a retrospective analysis of our experience with redo myotomy for recurrent dysphagia in patients with achalasia. METHODS: From March 1996 to February 2015, 234 myotomies for primary or recurrent achalasia were performed in our center. Fifteen patients (6.4 %) had had a previous myotomy and were undergoing surgical redo myotomy (n = 9) or endoscopic redo myotomy (n = 6) for recurrent symptoms. RESULTS: Patients presented at a median of 10.4 months after previous myotomy. Median preoperative Eckardt score was 6. Among the nine patients undergoing surgical myotomy, three esophageal perforations occurred intraoperatively (all repaired immediately). Surgery lasted 111 and 62 min on average (median) in the surgical and peroral endoscopic myotomy (POEM) groups, respectively. No postoperative complications occurred in either group. Median postoperative stay was 3 and 2.5 days in the surgical and POEM groups, respectively. In the surgical group, Eckardt score was <3 for seven out of nine patients after a mean follow-up of 19 months; it was <3 for all six patients in the POEM group after a mean follow-up of 5 months. CONCLUSIONS: A redo myotomy should be considered in patients who underwent myotomy for achalasia and presenting with recurrent dysphagia. Preliminary results using POEM indicate that the technique can be safely used in patients who have undergone previous surgical myotomy. PMID- 26589526 TI - Hiatal Herniation After Transhiatal Esophagectomy: an Underreported Complication. AB - INTRODUCTION: The incidence and presentation of hiatal hernias after esophagectomy (HHAE) are not well characterized, and may be changing with increased survival from esophageal cancer. The aims of this study were to define the incidence and presentation of HHAE in our population of patients undergoing transhiatal esophagectomy (THE), as it may have implications for management. METHODS: A retrospective cohort study (2004-2013) was performed of esophageal cancer patients who underwent THE. To determine the presence or absence of HHAE independent of the original radiology report, a radiologist sub-specializing in body imaging independently reviewed post-operative computed tomography images. A time-to-event competing risk analysis was performed to estimate the cumulative incidence of HHAE. RESULTS: Among 192 patients, the two-year cumulative incidence of HHAE was 14 % (95 % confidence interval 7.5-21 %). Of the 22 patients determined to have HHAE by independent expert radiologist review, only 11 (50 %) were identified by the original interpreting radiologist. Seven patients were symptomatic, and each underwent hiatal hernia repair (4 via laparotomy, 3 via laparoscopy). CONCLUSION: HHAE is not rare and is often unrecognized. As more patients with esophageal cancer survive, the number of patients becoming symptomatic and requiring repair may also rise. Therefore, it is important to consider this diagnosis when following patients long-term after esophagectomy. PMID- 26589527 TI - The impact of taste and smell alterations on quality of life in head and neck cancer patients. AB - PURPOSE: Taste and smell alterations (TSAs) are among the most frequent and troublesome symptoms reported by head and neck cancer (HNC) patients after treatment. Little is known about the relationship between TSAs and quality of life (QoL) among HNC patients. The aim of this study was to determine the effect of TSAs on overall QoL among tube-fed and orally fed HNC patients before treatment, at end of treatment and at 2.5-month follow-up. METHODS: Data were collected in a longitudinal study prior to treatment (n = 126), at end of treatment (n = 100) and at 2.5-month follow-up (n = 85). Chemosensory Complaint Score (CCS) and the University of Washington Quality of Life Questionnaire version 3 were used to assess TSAs and QoL, respectively. Generalized estimated equation modeling was used to estimate the effect of CCS on QoL. RESULTS: At end of treatment, QoL and CCS had declined for both tube-fed and orally fed patients and thereafter improved, but not to pre-treatment levels. Neither QoL nor CCS mean scores were different between the two groups at any time point. CCS was a significant predictor of overall QoL (beta = -1.82, p < 0.0001), social-emotional (beta = -1.76, p < 0.0001), physical (beta = -1.12, p < 0.0001) and overall functions (beta = -1.15, p < 0.0001) at a multivariate level. Taste was reported as an important symptom for both tube-fed and orally fed groups at end of treatment and follow-up. CONCLUSIONS: TSAs are an important symptom and an independent predictor of QoL for both tube-fed and orally fed HNC patients. HNC patients need support to manage TSAs, regardless of the method of nutritional intake. PMID- 26589528 TI - Validation of a new patient-reported outcome instrument of health-related quality of life specific to patients with alcohol use disorder: the Alcohol Quality of Life Scale (AQoLS). AB - PURPOSE: The Alcohol Quality of Life Scale (AQoLS) is a new patient-reported outcome 34-item questionnaire measuring health-related quality of life (HRQOL), specific to patients with an alcohol use disorder, developed from the patients' perspective. This is the first report establishing evidence in support of measurement reliability and validity of the AQoLS. METHODS: A total of 285 randomly selected patients receiving interventions for alcohol use disorder in addiction specialised care settings in France were included in the study (response rate 80.1 %). Exploratory factor analysis was conducted to evaluate the hypothesised-during-development-stage dimensional structure of the AQoLS. Internal consistency of the total score and the dimensions subscores were assessed through Cronbach's alpha coefficients. Construct validity was tested through correlations with the Short-Form 36 Health Survey (SF-36) and EuroQol 5 dimensions (EQ-5D). RESULTS: Exploratory analysis indicated seven observed dimensions which differed slightly from the 7 dimensions defined a priori in the framework hypothesised during the scale development: activities, relationships, living conditions, negative emotions, self-esteem, control and sleep. A major common factor allows the summing of the 34 items to obtain a total score. All the 34 items were acceptable. Cronbach's alpha for the AQoLS total score was 0.96 and ranged from 0.8 to 0.9 for the dimensions subscores. Negative correlations between AQoLS and all dimensions of the SF-36, but general health and positive correlations between AQoLS and all items of the EQ-5D were shown. As expected, the correlations were mostly moderate in magnitude, low with scores referring to physical areas and the highest with the SF-36 MSC. CONCLUSION: This study provides evidence of the measure's psychometric properties in terms of construct validity and internal consistency. The "control" and "self-esteem" dimensions are of particular interest as these concepts are not captured in existing HRQOL. Further longitudinal validation of the scale is necessary to assess sensitivity to change. PMID- 26589529 TI - Response shift and disease activity in inflammatory bowel disease. AB - PURPOSE: Response shift (RS) may mask true change in health-related quality of life in longitudinal studies. People with chronic conditions may experience RS as they adapt to their disease, but it is unknown whether fluctuations in disease activity will influence the presence of RS. The study purpose was to test for RS in individuals with inflammatory bowel disease (IBD), a condition characterized by periods of symptom flares and remission. METHODS: Data were from the Manitoba IBD Cohort Study (N = 388). Multi-group confirmatory factor analysis (MG-CFA) and a RS detection method based on structural equation modeling were used to test for reconceptualization, reprioritization, and recalibration RS in participants with consistent active, consistent inactive, and inconsistent disease activity over a 6-month period on the SF-36. RESULTS: The MG-CFA revealed that a weak invariance model with equal factor loadings across groups was the best fit to the baseline SF-36 data. Reconceptualization, uniform recalibration, and non-uniform recalibration RS was detected in the consistent active group, but effect sizes were small. For the consistent inactive group, recalibration RS was observed and effect sizes were small to moderate. For the inconsistent disease activity group, small-to-moderate recalibration RS effects were observed. There was no evidence of reprioritization. CONCLUSIONS: Individuals with a chronic disease may exhibit RS even if they are not actively experiencing symptoms on a consistent basis. Heterogeneity in the type and magnitude of RS effects may be observed in chronic disease patients who experience changes in disease symptoms. PMID- 26589530 TI - Toward 3-D Echocardiographic Determination of Regional Myofiber Structure. AB - As a step toward the goal of relating changes in underlying myocardial structure to observed altered cardiac function in the hearts of individual patients, this study addresses the feasibility of creating echocardiography-derived maps of regional myocardial fiber structure for entire, intact, excised sheep hearts. Backscatter data were obtained from apical echocardiographic images acquired with a clinical ultrasonic imaging system and used to determine local fiber orientations in each of seven hearts. Systematic acquisition across the entire heart volume provided information sufficient to give a complete map for each heart. Results from the echocardiography-derived fiber maps compare favorably with corresponding results derived from diffusion tensor magnetic resonance imaging. The results of this study provide evidence of the feasibility of using echocardiographic methods to generate individualized whole heart fiber maps for patients. PMID- 26589531 TI - Sonographic Detection of Abnormal Plaque Motion of the Carotid Artery: Its Usefulness in Diagnosing High-Risk Lesions Ranging from Plaque Rupture to Ulcer Formation. AB - We investigated the feasibility of using sonography of abnormal plaque motion to diagnose high-risk carotid lesions ranging from plaque rupture to ulcer formation. Fifty consecutive carotid arteries of 49 patients (71 +/- 7 y, 37 males) who underwent carotid endarterectomy were investigated by carotid sonography to find a plaque concavity (sonographic ulcer [SU]), fine trembling motion inside the plaque (FTMI) and systolic retractive motion of the plaque surface (SRMS). Plaque rupture or ulcer, necrotic core and intra-plaque hemorrhage were determined at carotid endarterectomy. Twenty-two SUs, 41 cases of FTMI and 20 cases of SRMS were detected by carotid sonography. The sensitivity and specificity of SU in diagnosing plaque rupture or ulcer at carotid endarterectomy were 48% and 90%, and those of FTMI were 93% and 60%. Plaques with SRMS more frequently had both a necrotic core and intra-plaque hemorrhage than those without SRMS (80% vs. 30%, p = 0.0005). Abnormal plaque motion detected by carotid sonography is useful in detecting a ruptured or ulcerated plaque with a necrotic core and/or hemorrhage. PMID- 26589532 TI - A Systematic Review of Montessori-Based Activities for Persons With Dementia. AB - OBJECTIVES: Montessori-based activities are becoming a popular approach for the care of older adults living with dementia. The aim of this study was to systematically assess the quality of the research examining the benefits of Montessori-based activities for persons with dementia. METHODS: Six peer-reviewed databases were systematically searched for all relevant articles published until April 2015. Included articles were peer-reviewed studies published in English that employed Montessori-based activities with persons with dementia. Methodological quality was assessed by 2 independent raters using the Physiotherapy Evidence Database Scale or the Downs and Black evaluation tool. Levels of evidence were assigned to the study design using a modified Sackett scale. RESULTS: One hundred fifty articles were identified, and 14 were selected for inclusion. Level-2 evidence examining the impact of Montessori-based activities on eating behaviors suggested that difficulties with eating could be reduced with Montessori training. There was limited level-4 evidence for the benefits of Montessori-based activities on cognition, wherein benefits appeared to be specific to lower-level cognitive abilities including memory and attention. Finally, there is level-1 (n = 1), level-2 (n = 3), and level-4 (n = 6) evidence for the benefits of Montessori-based activities on engagement and affect, whereby constructive engagement and positive affect were heightened. DISCUSSION: Overall, there is a strong level of evidence for the benefits of Montessori-based activities on eating behaviors and weak evidence for the benefits on cognition. Evidence for the benefits of Montessori-based activities on engagement and affect are mixed. Future research is needed to examine the long-term benefits of Montessori-based activities. PMID- 26589534 TI - Is it possible to live well with dementia? PMID- 26589535 TI - Structural equation model linking dementia cognitive functioning, caregiver mental health, burden, and quality of informal care in Argentina. AB - The purpose of this study was to create a path model linking cognitive functioning in individuals with dementia, caregiver burden and mental health, and quality of care provided for the individual with dementia in Argentina. One hundred and two dementia caregivers from San Lucas, Argentina completed questionnaires assessing these constructs. Regressions found that caregiver burden, depression, anxiety, and satisfaction with life explained 18.8% of the variance in quality of care-respect and 14.7% of the variance in quality of care provide. A structural equation model with generally adequate fit indices uncovered that cognitive functioning in individuals with dementia was inversely associated with caregiver burden, caregiver burden was inversely associated with mental health, and mental health was positively associated with quality of care. Further, patient cognitive functioning yielded a significant indirect effect on caregiver mental health through caregiver burden, as did burden on quality of care through mental health. Despite this negative cascade, these relationships may also be reversed with the development and use of dementia caregiver interventions that improve caregiver burden and mental health and as a result, the quality of care for individuals with dementia in Latin America. PMID- 26589536 TI - Supporting the Spectrum Hypothesis: Self-Reported Temperament in Children and Adolescents with High Functioning Autism. AB - This study tested the spectrum hypothesis, which posits that children and adolescents with high functioning autism (HFA) differ quantitatively but not qualitatively from typically developing peers on self-reported temperament. Temperament refers to early-appearing, relatively stable behavioral and emotional tendencies, which relate to maladaptive behaviors across clinical populations. Quantitatively, participants with HFA (N = 104, aged 10-16) self-reported less surgency and more negative affect but did not differ from comparison participants (N = 94, aged 10-16) on effortful control or affiliation. Qualitatively, groups demonstrated comparable reliability of self-reported temperament and associations between temperament and parent-reported behavior problems. These findings support the spectrum hypothesis, highlighting the utility of self-report temperament measures for understanding individual differences in comorbid behavior problems among children and adolescents with HFA. PMID- 26589537 TI - Preoperative carotid ultrasound through the looking glass: Curiouser and curiouser! PMID- 26589538 TI - Poor correlation between acute phase reactants and intestinal involvement in patients with onset of Crohn's disease under treatment with an interleukin-6 inhibitor due to seronegative arthropathy. PMID- 26589539 TI - [Chronic hepatitis caused by hepatitis E virus and treated with ribavirin]. PMID- 26589540 TI - [Is there a role for pentoxifylline in the treatment of alcoholic hepatitis?]. AB - Despite better knowledge of the pathogenesis of severe alcoholic hepatitis (AH), corticosteroids are still the treatment recommended by clinical guidelines, pentoxifylline being the second-line option for non-responders to corticosteriods and for patients with contraindications. Pentoxifylline is a phosphodiesterase inhibitor with an anti-TNF effect and has been reported to reduce mortality and the incidence of hepatorenal syndrome in severe AH. After the first report, several studies, of distinct quality, have tested the efficacy of pentoxifylline in different scenarios. The conclusions of these studies are that pentoxifylline seems to improve survival in comparison to placebo but has lower efficacy than corticosteroids, with no improvement in survival when added to corticosteroids or in non-responders to steroid therapy. The role of pentoxifylline in severe alcoholic hepatitis is even more doubtful after the results of a very recent controlled study that showed no beneficial effect on survival at 1, 3 and 12 months of follow up, although a very recent network meta-analysis reported a beneficial effect of pentoxifylline alone or with corticosteroids on short-term survival. In conclusion, pentoxifylline has no clear beneficial effects in severe AH but could perhaps be used in patients with a contraindication to corticosteroids. However, the recommendations of clinical guidelines should be reconsidered and it is essential to search for new therapeutic targets for this disease. PMID- 26589541 TI - Introduction to the special issue: Substance use and the adolescent brain: Developmental impacts, interventions, and longitudinal outcomes. AB - Adolescent substance abuse is a major public health problem, particularly given the negative brain and behavioral consequences that often occur during and following acute intoxication. Negative outcomes appear to be especially pronounced when substance use is initiated in the early adolescent years, perhaps due to neural adaptations that increase risk for substance use disorders into adulthood. Recent models to explain these epidemiological trends have focused on brain-based vulnerabilities to use as well as neurodevelopmental aberrations associated with initiation of use in substance naive samples or through the description of case-control differences between heavy users and controls. Within this research, adolescent alcohol and marijuana users have shown relative decreases in regional gray matter volumes, substance-specific alterations in white matter volumes, deviations in microstructural integrity in white matter tracts that regulate communication between subcortical areas and higher level regulatory control regions, and deficits in functional connectivity. How these brain anomalies map onto other types of youth risk behavior and later vulnerabilities represent major questions for continued research. This special issue addresses these compelling and timely questions by introducing new methodologies, empirical relationships, and perspectives from major leaders in this field. PMID- 26589542 TI - The developmental basis of mesenchymal stem/stromal cells (MSCs). AB - BACKGROUND: Mesenchymal Stem/Stromal Cells (MSCs) define a population of progenitor cells capable of giving rises to at least three mesodermal lineages in vitro, the chondrocytes, osteoblasts and adipocytes. The validity of MSCs in vivo has been questioned because their existence, either as a homogeneous progenitor cell population or as a stem cell lineage, has been difficult to prove. The wide use of primary MSCs in regenerative and therapeutic applications raises ethical and regulatory concerns in many countries. In contrast to hematopoietic stem cells, a parallel concept which carries an embryological emphasis from its outset, MSCs have attracted little interest among developmental biologists and the embryological basis for their existence, or lack thereof, has not been carefully evaluated. METHODS: This article provides a brief, embryological overview of these three mesoderm cell lineages and offers a framework of ontological rationales for the potential existence of MSCs in vivo. RESULTS: Emphasis is given to the common somatic lateral plate mesoderm origin of the majority of body's adipose and skeletal tissues and of the major sources used for MSC derivation clinically. Support for the MSC hypothesis also comes from a large body of molecular and lineage analysis data in vivo. CONCLUSIONS: It is concluded that despite the lack of a definitive proof, the MSC concept has a firm embryological basis and that advances in MSC research can be facilitated by achieving a better integration with developmental biology. PMID- 26589543 TI - Incidence of Urinary Tract Infection Among Siblings of Children With Vesicoureteral Reflux. AB - BACKGROUND: Siblings of children with vesicoureteral reflux (VUR) are at elevated risk of VUR. Screening siblings may identify VUR before a clinical illness such as a urinary tract infection (UTI), but the benefit of screening has not been demonstrated. We sought to determine the incidence of UTI among siblings, and we hypothesized that the sibling UTI rate is similar between screened and unscreened siblings. METHODS: We performed a retrospective cohort analysis using insurance claims data (January 1, 2000, to December 31, 2009). Within each family, we identified the index VUR patient and siblings; we included siblings who were enrolled in the insurance plan from birth for at least 1 year. We identified siblings who were screened for VUR and/or had UTI. We investigated the association of screening and UTI, controlling for patient characteristics and clustering within families. RESULTS: Among 617 siblings (associated with 497 index patients), 317 (51%) were girls. Median insurance enrollment time was 53.0 months, with 424 enrolled >=3 years. Among those with 1 or 3 years of enrollment, the proportions of siblings who experienced UTI was 8.4% (52 of 617) and 10.4% (44 of 424), respectively. Median age at initial UTI was 32.7 months. A total of 223 siblings (36.0%) underwent sibling screening. There was no significant difference in UTI between screened and unscreened siblings (odds ratio 1.57, 95% confidence interval 0.87-2.85; P = .14). In multivariate analysis, screening was not associated with sibling UTI incidence (odds ratio 1.33, 95% confidence interval 0.68-2.60; P = .40). CONCLUSIONS: Although UTI is relatively common among siblings of VUR patients, there was no statistically significant difference in UTI incidence between screened and unscreened siblings. PMID- 26589544 TI - Accessing characters in spoken Chinese disyllables: An ERP study on the resolution of auditory ambiguity. AB - Chinese differs from most Indo-European languages in its phonological, lexical, and syntactic structures. One of its unique properties is the abundance of homophones at the monosyllabic/morphemic level, with the consequence that monosyllabic homophones are all ambiguous in speech perception. Two-morpheme Chinese words can be composed of two high homophone-density morphemes (HH words), two low homophone-density morphemes (LL words), or one high and one low homophone density morphemes (LH or HL words). The assumption of a simple inhibitory homophone effect is called into question in the case of disyllabic spoken word recognition, in which the recognition of one morpheme is affected by semantic information given by the other. Event-related brain potentials (ERPs) were used to trace on-line competitions among morphemic homophones in accessing Chinese disyllables. Results showing significant differences in ERP amplitude when comparing LL and LH words, but not when comparing LL and HL words, suggested that the first morpheme cannot be accessed without feedback from the second morpheme. Most importantly, analyses of N400 amplitude among different densities showed a converse homophone effect in which LL words, rather than LH or HL words, triggered larger N400. These findings provide strong evidence of a dynamic integration system at work during spoken Chinese disyllable recognition. PMID- 26589545 TI - Morphological analysis of the vestibular system of guinea pigs poisoned by organophosphate. AB - INTRODUCTION: The vestibular system is responsible for body balance. There are substances that damage it, causing dizziness; these are termed vestibulotoxic substances. Agrochemicals have been investigated for ototoxicity because of studies that identified dizziness as a recurrent symptom among rural workers' complaints. OBJECTIVE: To histopathologically evaluate the vestibular system in guinea pigs exposed to an organophosphate, and to identify the drug's effects on this system. METHODS: Experimental clinical study. Eighteen guinea pigs were used; six of them poisoned with the organophosphate chlorpyrifos at doses of 0.5mg/kg/day and seven of them at 1mg/kg/day; and a control group of five guinea pigs was exposed to distilled water, all for 10 consecutive days. Later, ciliary tufts of saccule and utricle maculae were counted by scanning electron microscopy. RESULTS: Comparing the groups, a one-way ANOVA test for the variable "saccule" (p=0.0569) and a Kruskal-Wallis test for the variable "utricle" (p=0.8958) were performed, revealing no difference among groups in both variables. CONCLUSION: The histopathologic analysis of the vestibular system of guinea pigs exposed to an organophosphate showed no difference in the amount of ciliary tufts of saccule and utricle maculae at the doses tested, although the result for the variable "saccule" was considered borderline, showing a trend for significance. PMID- 26589546 TI - Wellbeing or welfare benefits--what are the drivers for migration? PMID- 26589547 TI - Automatic Processing of Chromatograms in a High-Throughput Environment. AB - BACKGROUND: A major challenge in high-throughput clinical and toxicology laboratories is the reliable processing of chromatographic data. In particular, the identification, location, and quantification of analyte peaks needs to be accomplished with minimal human supervision. Data processing should have a large degree of self-optimization to reduce or eliminate the need for manual adjustment of processing parameters. Ultimately, the algorithms should be able to provide a simple quality metric to the batch reviewer concerning confidence about analyte peak parameters. CONTENT: In this review we cover the basic conceptual and mathematical underpinnings of peak detection necessary to understand published algorithms suitable for a high-throughput environment. We do not discuss every approach appearing in the literature. Instead, we focus on the most common approaches, with sufficient detail that the reader will be able to understand alternative methods better suited to their own laboratory environment. In particular it will emphasize robust algorithms that perform well in the presence of substantial noise and nonlinear baselines. SUMMARY: The advent of fast computers with 64-bit architecture and powerful, free statistical software has made practical the use of advanced numeric methods. Proper choice of modern data processing methodology also facilitates development of algorithms that can provide users with sufficient information to support QC strategies including review by exception. PMID- 26589548 TI - An Empirical Approach to Signature Peptide Choice for Selected Reaction Monitoring: Quantification of Uromodulin in Urine. AB - BACKGROUND: Many avenues have been proposed for a seamless transition between biomarker discovery data and selected reaction monitoring (SRM) assays for biomarker validation. Unfortunately, studies with the abundant urinary protein uromodulin have shown that these methods do not converge on a consistent set of surrogate peptides for targeted mass spectrometry. As an alternative, we present an empirical peptide selection work flow for robust protein quantification. METHODS: We compared the relative SRM signal intensity of 12 uromodulin-derived peptides between tryptic digests of 9 urine samples. Pairwise CVs between the 12 peptides were 0.19-0.99. We used a correlation matrix to identify peptides that reproducibly tracked the amount of uromodulin protein and selected 4 peptides with robust and highly correlated SRM signals. Absolute quantification was performed with stable isotope-labeled versions of these peptides as internal standards and a standard curve prepared from a tryptic digest of purified uromodulin. RESULTS: Absolute quantification of uromodulin in 40 clinical urine samples yielded interpeptide correlations of >=0.984 and correlations of >=0.912 with ELISA data. The SRM assays were linear over >3 orders of magnitude and had typical interdigest CVs of <10%, interinjection CVs of <7%, and intertransition CVs of <7%. CONCLUSIONS: Comparing the apparent abundance of a plurality of peptides derived from the same target protein makes it possible to select signature peptides that are unaffected by the unpredictable confounding factors inevitably present in biological samples. PMID- 26589549 TI - Unsolicited Patient Complaints in Ophthalmology: An Empirical Analysis from a Large National Database. AB - PURPOSE: The number of unsolicited patient complaints about a physician has been shown to correlate with increased malpractice risk. Using a large national patient complaint database, we evaluated the number and content of unsolicited patient complaints about ophthalmologists to identify significant risk factors for receiving a complaint. DESIGN: Retrospective cohort study. PARTICIPANTS: Ophthalmologists, nonophthalmic surgeons, nonophthalmic nonsurgeons. METHODS: We analyzed 2087 unsolicited or spontaneous complaints reported about 815 ophthalmologists practicing in 24 academic and nonacademic organizations using the Patient Advocacy Reporting System (PARS). Complaints against 5273 nonophthalmic surgeons and 19487 nonophthalmic nonsurgeons during the same period were used for comparison. Complaint type profiles were assigned using a previously validated standardized coding system. We (1) described the distribution of complaints against ophthalmologists; (2) compared the distribution and rates of patient complaints about ophthalmologists with those of nonophthalmic surgeons and nonophthalmic nonsurgeons in the database; (3) analyzed differences in complaint type profiles and quantity of complaints by ophthalmic subspecialty, practice setting, physician gender, medical school type, and graduation date; and (4) identified significant risk factors for high numbers of unsolicited patient complaints after adjusting for other covariates. MAIN OUTCOME MEASURES: Unsolicited patient complaints. RESULTS: Ophthalmologists had significantly fewer complaints per physician than other nonophthalmic surgeons and nonsurgeons. Sixty-three percent of ophthalmologists had 0 complaints, whereas 10% of ophthalmologists accounted for 61% of all complaints. Ophthalmologists from academic centers, female ophthalmologists, and younger ophthalmologists had significantly more complaints (P < 0.01), and general ophthalmologists had significantly fewer complaints than subspecialists (P < 0.05). After adjusting for covariates using multivariable analysis, working at an academic center was a statistically significant risk factor (adjusted relative risk, 1.82; 95% confidence interval, 1.36-2.43; P < 0.001). CONCLUSIONS: Ophthalmologists had significantly fewer complaints than nonophthalmic surgeons and nonophthalmic nonsurgeons, and by implication may have a lower malpractice risk as a group. Nevertheless, a small number of ophthalmologists generated a disproportionate number of complaints. Working at an academic center was a significant independent risk factor for having more patient complaints. Further research is needed to clarify the underlying reasons for this association and to identify interventions that may decrease this risk. PMID- 26589550 TI - A TGN/EE-Localized V-ATPase Contributes to Vacuolar Acidification. PMID- 26589551 TI - The ASYMMETRIC LEAVES Complex Employs Multiple Modes of Regulation to Affect Adaxial-Abaxial Patterning and Leaf Complexity. AB - Flattened leaf architecture is not a default state but depends on positional information to precisely coordinate patterns of cell division in the growing primordium. This information is provided, in part, by the boundary between the adaxial (top) and abaxial (bottom) domains of the leaf, which are specified via an intricate gene regulatory network whose precise circuitry remains poorly defined. Here, we examined the contribution of the ASYMMETRIC LEAVES (AS) pathway to adaxial-abaxial patterning in Arabidopsis thaliana and demonstrate that AS1 AS2 affects this process via multiple, distinct regulatory mechanisms. AS1-AS2 uses Polycomb-dependent and -independent mechanisms to directly repress the abaxial determinants MIR166A, YABBY5, and AUXIN RESPONSE FACTOR3 (ARF3), as well as a nonrepressive mechanism in the regulation of the adaxial determinant TAS3A. These regulatory interactions, together with data from prior studies, lead to a model in which the sequential polarization of determinants, including AS1-AS2, explains the establishment and maintenance of adaxial-abaxial leaf polarity. Moreover, our analyses show that the shared repression of ARF3 by the AS and trans-acting small interfering RNA (ta-siRNA) pathways intersects with additional AS1-AS2 targets to affect multiple nodes in leaf development, impacting polarity as well as leaf complexity. These data illustrate the surprisingly multifaceted contribution of AS1-AS2 to leaf development showing that, in conjunction with the ta-siRNA pathway, AS1-AS2 keeps the Arabidopsis leaf both flat and simple. PMID- 26589553 TI - Comparative Analysis of Midtrimester Amniotic Fluid Cytokine Levels to Predict Spontaneous Very Pre-term Birth in Patients with Cervical Insufficiency. AB - PROBLEM: Few studies have investigated the roles of cytokines and chemokines in women with cervical insufficiency, and those that have done so evaluated only a limited number of cytokines in amniotic fluid. METHOD OF STUDY: A retrospective cohort study enrolled 71 patients undergoing physical examination-indicated cerclage to determine whether expanded amniotic fluid cytokine levels predict spontaneous very pre-term birth (<=32 weeks of gestation) in patients with cervical insufficiency. Analysis of multiple cytokines and chemokines was performed with the multiplex immunoassay. RESULTS: Sixty-seven amniotic fluid samples were available for analysis and assayed for 15 cytokines. Thirty-eight (56.7%) patients delivered pre-term. Of these, 26 (38.8%) were spontaneous very pre-term births. Most cytokine levels were significantly increased in the amniotic fluid from the study group when compared with those from controls. The levels of interleukin-1beta (IL-1beta), IL- 6, IL- 7, IL-15, IL-17alpha, tumour necrosis factor-alpha (TNF-alpha), MIP-1alpha, and MIP-1beta were higher in patients with a very pre-term delivery than in those with a late pre-term delivery. IL-1beta, IL-6, IL-7, IL-17alpha, TNF-alpha, and cervical dilation were independently associated with a very pre-term birth. CONCLUSION: Intra-amniotic inflammation may contribute to cervical insufficiency, and the severity of inflammation is associated with a very pre-term birth in women with cervical insufficiency. PMID- 26589552 TI - Job Sharing in the Endomembrane System: Vacuolar Acidification Requires the Combined Activity of V-ATPase and V-PPase. AB - The presence of a large central vacuole is one of the hallmarks of a prototypical plant cell, and the multiple functions of this compartment require massive fluxes of molecules across its limiting membrane, the tonoplast. Transport is assumed to be energized by the membrane potential and the proton gradient established by the combined activity of two proton pumps, the vacuolar H(+)-pyrophosphatase (V PPase) and the vacuolar H(+)-ATPase (V-ATPase). Exactly how labor is divided between these two enzymes has remained elusive. Here, we provide evidence using gain- and loss-of-function approaches that lack of the V-ATPase cannot be compensated for by increased V-PPase activity. Moreover, we show that increased V ATPase activity during cold acclimation requires the presence of the V-PPase. Most importantly, we demonstrate that a mutant lacking both of these proton pumps is conditionally viable and retains significant vacuolar acidification, pointing to a so far undetected contribution of the trans-Golgi network/early endosome localized V-ATPase to vacuolar pH. PMID- 26589554 TI - The relationships of irisin with bone mineral density and body composition in PCOS patients. AB - OBJECTIVE: Our study aims to assay the irisin level and investigate the relationships of irisin level with body mass index (BMI), body composition and bone metabolism in the polycystic ovary syndrome (PCOS) and control women. METHODS: Fifty two PCOS and 39 control women were recruited. Serum sex hormone, fasting insulin and C-peptide were tested. Fasting serum irisin and adiponectin were measured with enzyme-linked immunosorbent assay. Body composition and bone mineral density were assayed by dual energy X-ray absorptiometry. RESULTS: Polycystic ovary syndrome women showed different body compositions compared with controls. Serum irisin level of PCOS did not show significant difference compared with controls although it was decreased. The level of adiponectin in PCOS patients was significantly reduced. BMI had no correlation with irisin level. It indicated a positive correlation between serum irisin levels and bone mineral density in the control group and a negative correlation in the PCOS group after BMI and age adjusted. Furthermore, total lean mass has a significant effect on irisin concentration in the PCOS group. There are no correlations between adiponection and body compositions and bone mineral density in both groups. CONCLUSIONS: The abnormal body composition in PCOS may contribute to the circulation irisin. The crosstalk of irisin in different organs was found and may be related to disease development in PCOS. PMID- 26589555 TI - Males with low serum levels of vitamin D have lower pregnancy rates when ovulation induction and timed intercourse are used as a treatment for infertile couples: results from a pilot study. AB - BACKGROUND: Vitamin D (Vit D) is important for the regulation of reproductive physiology. In humans, maternal Vit D deficiency has been implicated in several reproductive- and pregnancy-related disorders. Very few data are available regarding the Vit D status in male partners of couples attempting pregnancy. This observational study (IRB Prot. N. 078/13) aimed to evaluate whether low Vit D serum levels in males might decrease the rate of successful conception in couples attempting pregnancy. METHODS: Male and female partners of infertile couples (n = 102) were classified into 2 GROUPS according to normal (>=30 ng/ml) or low (below 30 ng/ml) serum Vit D levels in male partners. Semen analysis was performed in each male participant based on the WHO reference criteria. The female partners of both groups were subjected to 3 consecutive cycles of gonadotropin-induced mono ovulation. The main outcome measures included the clinical pregnancy rate, delivery per patient and per cycle, and miscarriage rate between the 2 groups evaluated at the end of the three-month period of the study. RESULTS: In male partners of both groups, standard semen analysis did not highlight substantial differences in sperm concentration, sperm progressive motility, or typical form. The pregnancy rates per patient and per cycle and delivery rates per patient and per cycle were all significantly higher (p< 0.05) in couples with normal Vit D levels. CONCLUSIONS: These results suggest the existence of a relationship between male Vit D serum levels and semen ability to begin a pregnancy during cycles of timed vaginal intercourse. PMID- 26589556 TI - Consumption of probiotic Lactobacillus rhamnosus (MTCC: 5897) containing fermented milk plays a key role in development of the immune system in newborn mice during the suckling-weaning transition. AB - Early infancy, the period when offspring rely not only on their own immunity to combat food-borne antigens but also acquire immunity through maternal sources (via transplacental routes and breast milk), is critical for immune system development Hence the present study was designed to evaluate the effect on offspring of administration of probiotic-containing fermented milk (PFM) either to mothers during the suckling period or to their offspring after weaning either separately or sequentially. PFM-fed mice showed enhanced leukocyte functionality in offspring as evidenced by significantly (P < 0.05) increased release of lysosomal enzymes (beta-galactosidase, beta-glucuronidase) in peritoneal fluid and nitric oxide production in culture supernatants of activated macrophages. Further, remarkably reduced levels (P < 0.01) of inflammatory markers (TNF-alpha, monocyte chemotactic protein-1) and allergic antibodies (total and milk specific IgE) were observed in offspring where PFM was fed either to them or to their mothers. However, considerably increased levels (P < 0.05) of SIgA were found in the guts of control and experimental groups animals irrespective of their exposure to PFM. Restoration of Th1/Th2 homeostasis further confirmed the useful effects of PFM supplementation by shifting the cytokine profile (IL-4, IFN-gamma and IL-10) with increased IFN-gamma/IL-4 and reduced IgE/Ig2Ga ratios. Hence, it is logical to conclude that administration of Lactobacillus rhamnosus-containing (MTCC:5897) fermented milk to mothers during the suckling period and to their offspring after weaning has beneficial effects on the development of newborns immune systems; this effect appears to be more pronounced when mothers are fed with it. PMID- 26589557 TI - Stress Cardiomyopathy Caused by Diving: Case Report and Review of the Literature. AB - BACKGROUND: Stress cardiomyopathy is characterized by transient myocardial dysfunction that mimics a myocardial infarction in the absence of obstructive coronary artery disease. The onset is frequently triggered by an acute illness or intense physical or emotional stress. CASE REPORT: We describe the case of a 47 year-old woman who was brought to the emergency department with acute onset shortness of breath while scuba diving. She was found to have acute pulmonary edema radiographically. Her troponins were noted to be positive. Initial echocardiogram showed basal hypokinesis with hyperkinesis of apex. She was treated with noninvasive ventilation and intravenous diuretic therapy and her symptoms significantly improved. She subsequently underwent cardiac catheterization which revealed nonobstructive coronary artery disease. An exercise stress echocardiogram was performed 2 days later that revealed resolution of the wall motion abnormality and no ischemia at high levels of exercise. A diagnosis of reverse stress (Takotsubo) cardiomyopathy was made based on Mayo Clinic Diagnostic criteria. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: This case brings to light the risk of stress cardiomyopathy in divers. The diagnosis should be considered in patients presenting with acute pulmonary edema during diving. PMID- 26589558 TI - Ultrasound-guided Greater Auricular Nerve Block for Emergency Department Ear Laceration and Ear Abscess Drainage. AB - BACKGROUND: Adequate emergency department (ED) anesthesia for painful ear conditions, such as ear lacerations or ear abscesses, can be challenging. Much of the sensory innervation of the ear is supplied from the anterior and posterior branches of the greater auricular nerve (GAN). The GAN is a branch of the superficial cervical plexus, which arises from the C2/C3 spinal roots. The GAN innervation includes most of the helix, antihelix, the lobule, and the skin over the mastoid process and parotid gland. Anesthesia of the GAN is commonly performed in emergency medicine as part of a landmark-based ear "ring" block. Recently, a selective ultrasound-guided GAN block has been described. CASE REPORT: We report the first cases of ultrasound-guided greater auricular nerve block (UGANB) successfully performed in the ED as the sole procedural anesthesia for both an ear laceration and abscess drainage. In addition, we review the relevant anatomy and technical details of the procedure. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Our cases suggest that UGANB is a potentially effective nerve block for ED management of acute ear pain related to procedures involving the tail of the helix and the lobule, such as ear lacerations or ear abscess incision and drainage. Advantages include real-time visualization of the GAN that may increase block success and the decreased volume of local anesthetic required for a block. PMID- 26589559 TI - John Caffey: Shaken Infant Syndrome. PMID- 26589560 TI - A Menacing Maculopapular Rash. PMID- 26589561 TI - Acute Concussion Management with Remove-Reduce/Educate/Adjust-Accommodate/Pace (REAP). AB - BACKGROUND: With increased concussion awareness and significantly increased numbers of emergency department (ED) visits for pediatric concussion, a seamless process of managing a patient with a concussion can begin in the ED. CASE REPORT: This article demonstrates the effectiveness of the Remove-Reduce/Educate/Adjust Accommodate/Pace (REAP) concussion management program in the evaluation, management, and return to play of an acutely concussed pediatric patient. The REAP program was developed in Colorado and promotes a multidisciplinary team approach to concussion management. The team consists of parents, teachers, athletic personnel, and clinicians. The patient described in this case report had concussion management initiated in the ED. He was able to successfully return to sports, having recovered from his concussion with the guidance of the Center for Concussion (Centennial, Colorado) staff utilizing the REAP model of care and the currently recommended graduated return-to-play process. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Busy EDs are often the initial point of contact for school-aged patients with concussion. We present a program that we believe represents a good model of patient care with concussion management implemented in the ED and carried through to clearance of the patient. PMID- 26589562 TI - Case Series: Pneumorrhachis Secondary to Spontaneous Pneumomediastinum. AB - BACKGROUND: Pneumorrhachis (PR) describes the clinical finding of air within the spinal canal and rarely has been associated with spontaneous pneumomediastinum. There is little medical literature addressing the evaluation and management of these patients in the emergency department. CASE REPORT: We present a series of patients with PR secondary to a spontaneous pneumomediastinum and briefly review the available literature on the topic to discuss reasonable management strategies for patients presenting with this rare finding. In both cases, the patients had excellent outcomes with expectant management despite the worrisome finding of air in the spinal canal. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Emergency physicians must be able to promptly recognize and appropriately assess even uncommon pathology. As with other rare conditions, there are no published guidelines for the ED management of PR, necessitating the use of case presentations to educate providers as to the complications and plan of care of this diagnosis. PMID- 26589563 TI - Abdominal Pain in a Young Man with Oral Pigmentations. PMID- 26589564 TI - Respiratory Distress in an Infant: An Uncommon Cause for a Common Complaint. AB - BACKGROUND: Respiratory distress and tachycardia are common presenting complaints in infants and young children, and evaluation typically focuses on respiratory infections. Tachydysrhythmias causing heart failure are rare and can be difficult to diagnose in young children, but are reversible if recognized and treated early. CASE REPORT: We discuss a 7-week-old female infant who presented with respiratory distress and persistent tachycardia. Evaluation revealed severe cardiac dysfunction with an underlying atrial flutter discovered on electrocardiography after adenosine administration. Rate control by synchronized electrocardioversion resulted in resolution of symptoms and restoration of cardiac function, confirming the diagnosis of atrial flutter-induced cardiomyopathy. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Persistent or inappropriate tachycardia in a young child should not be dismissed and underlying dysrhythmia should be considered. PMID- 26589565 TI - The Dangerous Claim of "Being First". PMID- 26589566 TI - In Response to "The Dangerous Claim of 'Being First'". PMID- 26589567 TI - Acetylfentanyl: An Emerging Drug of Abuse. AB - BACKGROUND: Opioid analgesics are widely used in health care, yet have significant potential for abuse. High doses are associated with potentially fatal respiratory depression, which caused 21,314 deaths in the United States in 2011. Acetylfentanyl, a synthetic opioid agonist closely related to fentanyl, recently emerged as a drug of abuse linked to numerous deaths in North America. CASE REPORT: A 36-year-old male developed the habit of using a propylene glycol electronic cigarette filled with acetylfentanyl to aid relaxation. He purchased the drug online in a manner that appeared legal to him, which compromised his insight about the danger of the substance. He had been using the e-cigarette with increasing frequency while on medical leave, and his wife reported finding him weakly responsive on more than one occasion. At approximately 3 am, the family activated 911 for altered mental status. His presentation included respiratory depression, pinpoint pupils, hypoxemia, and a Glasgow Coma Scale score of 6. He responded to serial doses of intravenous naloxone with improvement in his mental status and respiratory condition. Due to the need for repeated dosing, he was placed on a naloxone infusion and recovered uneventfully in intensive care. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Complications from emerging drugs of abuse, like acetylfentanyl, frequently present first to emergency departments. Prompt recognition and treatment can help avoid morbidity and mortality. Acetylfentanyl can be managed effectively with naloxone, although higher than conventional dosing may be required to achieve therapeutic effect. PMID- 26589568 TI - The Effect of Noise Distraction on Emergency Medicine Resident Performance During Intubation of a Patient Simulator. AB - BACKGROUND: The environment in the Emergency Department (ED) is chaotic, and physicians are expected to perform procedures amongst distractions. OBJECTIVES: Our aim was to prospectively determine the effects of various levels of noise distraction on the success and time to successful intubation of a simulator. METHODS: Forty-five Emergency Medicine, Emergency Medicine/Internal Medicine, and Emergency Medicine/Family Medicine Residents were studied in background noise environments of <50 decibels (noise level 1), 60-70 decibels (noise level 2), and of >70 decibels (noise level 3). Residents attempted three intubations on a simulator in succession, with three randomized noise levels. Time, in seconds, to intubation was measured in each of the successful intubations. Generalized linear models were employed to examine associations between noise level and time to intubation by attempt. RESULTS: Time to intubation decreased with each attempt (median = 25.9, 17.9, 14.4 for attempt numbers 1, 2, and 3, respectively). Decibel noise level was not associated with time to intubation (p > 0.6) or success rate (p > 0.1). Attempt number did not modify the association between noise and time to intubation (p-for-interaction = 0.16). CONCLUSION: Noise level did not have an effect on time to intubation or intubation success rate, suggesting that noise levels in the ED do not affect provider ability to perform procedures. However, knowing that increased noise levels increase stress and impair the ability to communicate with team members, further study needs to be done to definitively conclude that noise does not affect provider performance in the ED setting. PMID- 26589569 TI - The Pivotal Roles of Risk Factors for Acute Respiratory Distress Syndrome. PMID- 26589570 TI - Lower levels of placental growth hormone in early pregnancy in women with type 1 diabetes and large for gestational age infants. AB - OBJECTIVE: To evaluate whether levels of placental growth hormone (GH) and Insulin-like Growth Factor-I (IGF-I) are associated with development of LGA infants in pregnant women with type 1 diabetes. DESIGN: Observational study of 103 consecutive pregnant women with long-term type 1 diabetes and median HbA1c 6.6% (range 4.9-10.5) (49 mmol/mol (30-91)) in early pregnancy. At 8, 14, 21, 27 and 33 weeks weight was recorded and blood was sampled for measurements of placental GH, IGF-I and HbA1c. LGA was defined as birth weight >90th percentile after adjustment for gender and gestational age. RESULTS: Throughout pregnancy placental GH levels were similar in 51 (50%) women delivering LGA infants compared with the remaining women except at 8 weeks where placental GH levels were lower in women with LGA infants (1.1 ng/ml (0.1-4.3) vs. 1.7 (0.3-11.7), p = 0.04). IGF-I levels were similar in women with and without LGA infants (p=0.97). Gestational age at first blood sampling was similar in women with and without LGA infants (60 days (37-89) vs. 61.5 (42-94), p = 0.42). Placental GH levels at 14 weeks correlated negatively with weight gain in early pregnancy (r=-0.32, p=0.002). As predictors of LGA infants,multivariate logistic regression analysis identified placental GH levels at 8 weeks (OR 0.4 (95% CI: 0.2-0.9), p = 0.02), HbA1c at 33 weeks (3.6 (1.3-9.9), p = 0.01) and parity >=1 (3.1 (1.3-7.5), p = 0.01) after adjustment for pre-pregnancy BMI. CONCLUSIONS: Women delivering LGA infants had lower placental GH levels in early pregnancy. Growth factors and maternal weight gain in early pregnancy may be important for healthy fetal growth. PMID- 26589571 TI - Gene expression profiling in non-human primate jejunum, ileum and colon after total-body irradiation: a comparative study of segment-specific molecular and cellular responses. AB - BACKGROUND: Although extensive studies have investigated radiation-induced injuries in particular gastrointestinal (GI) segments, a systematic comparison among the different segments on the basis of mode, magnitude and mechanism has not been reported. Here, a comparative study of segment-specific molecular and cellular responses was performed on jejunum, ileum and colon obtained at three time points (4, 7 and 12 days after irradiation) from non-human primate (Rhesus macaque) models exposed to 6.7 Gy or 7.4 Gy total body irradiation (TBI). RESULTS: Pathway analysis on the gene expression profiles identified radiation induced time-, dose- and segment-dependent activation of tumor necrosis factor alpha (TNFalpha) cascade, tight junction, apoptosis, cell cycle control/DNA damage repair and coagulation system signaling. Activation of these signaling pathways suggests that colon sustained the severest mucosal barrier disruption and inflammation, and jejunum the greatest DNA damage, apoptosis and endothelial dysfunction. These more pronounced alterations correlate with the high incidence of macroscopic pathologies that are observed in the colon after TBI. Compared to colon and jejunum, ileum was resistant to radiation injury. In addition to the identification a marked increase of TNFalpha cascade, this study also identified radiation induced strikingly up-regulated tight junction gene CLDN2 (196-fold after 7.4-Gy TBI), matrix degradation genes such as MMP7 (increased 11- and 41 fold after 6.7-Gy and 7.4-Gy TBI), and anoikis mediated gene EDA2R that mediate mucosal shedding and barrier disruption. CONCLUSIONS: This is the first systematic comparative study of the molecular and cellular responses to radiation injury in jejunum, ileum and colon. The strongest activation of TNFalpha cascades and the striking up-regulation of its down-stream matrix-dissociated genes suggest that TNFalpha modulation could be a target for mitigating radiation induced mucosal barrier disruption. PMID- 26589573 TI - Long-term outcomes of locally or radically resected T1 colorectal cancer. AB - AIM: Little is known about the long-term outcome of T1 colorectal cancer (CRC) following curative resection. The present study addressed the long-term outcome of locally or radically resected T1 CRCs. METHOD: A total of 430 patients with T1 CRC who underwent local or radical resection were considered. Unfavourable histological factors were defined as positive resection margin, deep submucosal invasion, vascular invasion, Grade 3 and budding. The patients were classified as low-risk (unfavourable histological factor negative, n = 65) or high-risk (unfavourable histological factor positive, n = 365). RESULTS: Over a median follow-up of 78.4 months, disease recurred in 16 (3.7%) patients in the high-risk group, and no recurrence in the low-risk group. Resection type and vascular invasion were significantly associated with recurrence. In the vascular invasion (+) high-risk group, both 5-year disease-free survival rate and 5-year overall survival rate were significantly associated with resection type (radical 94.6%, local 43.8%, P < 0.001, and radical 99.1%, local 66.7%, P < 0.001). In the vascular invasion (-) high-risk group, 5-year disease-free survival rate was also significantly associated with resection type (radical 98.9%, local 84.7%, P = 0.001). However, 5-year overall survival rate was not associated with resection type (radical 98.9%, local 95.2%, P = 0.816). CONCLUSION: Local resection may be effective and oncologically safe in low-risk T1 CRC. Although additional surgery should be recommended for the locally resected high-risk T1 CRC cases, intensive surveillance without additional surgery and timely salvage operation may offer another treatment option, if vascular invasion is negative. PMID- 26589572 TI - Pharmacological management of anticholinergic delirium - theory, evidence and practice. AB - The spectrum of anticholinergic delirium is a common complication following drug overdose. Patients with severe toxicity can have significant distress and behavioural problems that often require pharmacological management. Cholinesterase inhibitors, such as physostigmine, are effective but widespread use has been limited by concerns about safety, optimal dosing and variable supply. Case series support efficacy in reversal of anticholinergic delirium. However doses vary widely and higher doses commonly lead to cholinergic toxicity. Seizures are reported in up to 2.5% of patients and occasional cardiotoxic effects are also recorded. This article reviews the serendipitous path whereby physostigmine evolved into the preferred anticholinesterase antidote largely without any research to indicate the optimal dosing strategy. Adverse events observed in case series should be considered in the context of pharmacokinetic/pharmacodynamic studies of physostigmine which suggest a much longer latency before the maximal increase in brain acetylcholine than had been previously assumed. This would favour protocols that use lower doses and longer re-dosing intervals. We propose based on the evidence reviewed that the use of cholinesterase inhibitors should be considered in anticholinergic delirium that has not responded to non-pharmacological delirium management. The optimal risk/benefit would be with a titrated dose of 0.5 to 1 mg physostigmine (0.01 0.02 mg kg(-1) in children) with a minimum delay of 10-15 min before re-dosing. Slower onset and longer acting agents such as rivastigmine would also be logical but more research is needed to guide the appropriate dose in this setting. PMID- 26589574 TI - Probing sialoglycans on fetal bovine fetuin with azido-sugars using glycosyltransferases. AB - Sialic acids are negatively charged sugar residues commonly found on the terminal positions of most glycoproteins. They play important roles in the stability and solubility of these proteins. Due to their unique positioning, they also frequently act as receptors for various ligands, and therefore are involved in numerous cell-cell and cell-pathogen interactions. Here, using in vitro incorporation of clickable monosaccharides with various glycosyltransferases, we probed the sialoglycans on fetal bovine fetuin. The incorporated monosaccharides were detected with chemiluminescence via click chemistry in a format of western blotting. The results indicate that the non-reducing end Gal residues on both N- and O-glycans are fully sialylated, but the peptide-linked GalNAc residues in O glycans are not. The presence of sialyl core-1 glycan was repeatedly confirmed by probing with alpha-2,3-sialyltransferases, N-acetylgalactosaminide alpha-2,6 sialyltransferases and a beta-1,6-N-acetylglucosaminyltransferase that is specific for core-1 glycan. The results also suggest the presence of a minute amount of sialyl Tn antigen on the protein. PMID- 26589575 TI - The clinical potential of Enhanced-ice-COLD-PCR. AB - Enhanced-ice-COLD-PCR (E-ice-COLD-PCR) is a novel assay format that allows for the efficient enrichment and sensitive detection of all mutations in a region of interest using a chemically modified blocking oligonucleotide, which impedes the amplification of wild-type sequences. The assay is compatible with DNA extracted from tissue and cell-free circulating DNA. The main features of E-ice-COLD-PCR are the simplicity of the setup and the optimization of the assay, the use of standard laboratory equipment and the very short time to results (~4 h including DNA extraction, enrichment and sequence-based identification of mutations). E-ice COLD-PCR is therefore a highly promising technology for a number of basic research as well as clinical applications including detection of clinically relevant mutated subclones and monitoring of treatment response or disease recurrence. PMID- 26589576 TI - Restorative treatment for initial, cavitated and gross coronal carious lesions. AB - BACKGROUND: Treatment patterns for caries have been shown to reflect high rates of restorative services. The objective of this study was to investigate types of restorative treatment provided to patients with a main diagnosis of coronal caries in relation to the severity of the caries lesion. METHODS: A random sample of Australian dentists was surveyed by mailed questionnaires in 2009-2010 (response rate 67%). Data on types of restorative treatment, patient characteristics and main diagnosis were collected from a service log. RESULTS: Models of service rates adjusted for age, gender, insurance status and reason for visit showed that compared to the reference category of initial caries lesions, there were lower rates [Rate Ratio, 95% CI] of adhesive anterior restorative services [0.57, 0.34-0.95] and lower rates of adhesive posterior restorations [0.56, 0.40-0.79] for gross lesions. CONCLUSIONS: Treatment of coronal caries was characterized by high rates of adhesive posterior restorative services, but gross lesions had lower rates of both anterior and posterior adhesive restorations. Types of restorative treatment for coronal caries were similar between initial and cavitated lesions. This could indicate scope for the adoption of more minimum intervention approaches to the management of initial carious lesions. PMID- 26589577 TI - Nanoparticle dosage-a nontrivial task of utmost importance for quantitative nanosafety research. AB - For a detailed and correct understanding of effects of colloidal nanoparticles exposed to organisms, a correlation of such effects to the physicochemical properties of the nanoparticles is a necessity. Such correlation is complex by the fact that many physicochemical parameters such as size, shape, surface charge, and colloidal stability are interlinked, and nontrivial to experimentally determine. This review aims to give an overview regarding such correlations. Particular focus will be given on the role of determining nanoparticle concentrations, which is the basis for most quantitative toxicity evaluations. A comparison of mass versus particle number concentrations is given, and their respective differences are highlighted. WIREs Nanomed Nanobiotechnol 2016, 8:479 492. doi: 10.1002/wnan.1378 For further resources related to this article, please visit the WIREs website. PMID- 26589578 TI - Validation of the Japanese version of the Systemic Lupus Activity Questionnaire that includes physician-based assessments in a large observational cohort. AB - The Systemic Lupus Activity Questionnaire (SLAQ) is a patient-reported outcome for systemic lupus erythematosus (SLE). We aimed to translate it into Japanese and further investigate its validity and reliability. The English version of the SLAQ was translated into Japanese and administered to Japanese SLE patients at our university clinic. Physicians assessed disease activity using the SLE Disease Activity Index 2000 (SLEDAI-2K). The patients were prospectively followed for repeat assessment a year later. Ultimately, 255 patients participated. The patients' 10-point ratings of disease activity and SLAQ scores were significantly correlated (Spearman's rho = 0.53). The SLAQ score was weakly correlated with the SLE Disease Activity Index 2000 (SLEDAI-2K)-nolab (omitting laboratory items; rho = 0.18) but not with the SLEDAI-2K (rho = 0.02). These results suggested its convergent and discriminant validity. The SLAQ demonstrated acceptable internal consistency (Cronbach's alpha = 0.80), and good test-retest reliability (intraclass correlation coefficient = 0.85). The effect sizes and the standardized response means of the SLAQ were as follows: clinical worsening, 0.26 and 0.31, and improvement, -0.39 and -0.41, respectively, which indicated a small but significant responsiveness. The Japanese version of the SLAQ demonstrated acceptable reliability and validity; its performance was comparable to that of the original version. PMID- 26589579 TI - Peak oxygen uptake and self-reported physical health are strong predictors of long-term survival after heart transplantation. AB - BACKGROUND: Peak oxygen uptake (VO2peak ) is known as the gold standard measure of cardiopulmonary fitness. We therefore hypothesized that measures of physical health would predict long-term survival in heart transplant recipients (HTx). METHODS: This retrospective study investigated survival in two HTx populations; the cardiopulmonary exercise test (CPET) cohort comprised 178 HTx patients who completed a VO2peak test during their annual follow-up (1990-2003), and the SF-36 cohort comprised 133 patients who completed a quality of life questionnaire, SF 36v1 (1998-2000). RESULTS: Mean (SD) age in the CPET cohort was 52 (12) yr and 54 (11) yr in the SF-36 cohort. Mean observation time was, respectively, 11 and 10 yr. Mean (SD) VO2peak was 19.6 (5.3) mL/kg/min, and median (IR) physical function (PF) score was 90 (30). VO2peak and PF scores were both significant predictors in univariate Cox regression. Multiple Cox regression analyses adjusted for other potential predictors showed that VO2peak , age, and cardiac allograft vasculopathy (CAV) were the most important predictors in the CPET cohort, whereas age, PF score, smoking, and CAV were the most important predictors in the SF-36 cohort. In Kaplan-Meier analysis, VO2peak and PF scores above the median value were related to significant longer survival time. CONCLUSION: Peak oxygen uptake and self-reported physical health are strong predictors for long-term survival in HTx recipients. VO2peak is a crucial measurement and should be more frequently used after HTx. PMID- 26589580 TI - Evaluation of methods for calculating maximum allowable standing height in amputees competing in Paralympic athletics. AB - The International Paralympic Committee has a maximum allowable standing height (MASH) rule that limits stature to a pre-trauma estimation. The MASH rule reduces the probability that bilateral lower limb amputees use disproportionately long prostheses in competition. Although there are several methods for estimating stature, the validity of these methods has not been compared. To identify the most appropriate method for the MASH rule, this study aimed to compare the criterion validity of estimations resulting from the current method, the Contini method, and four Canda methods (Canda-1, Canda-2, Canda-3, and Canda-4). Stature, ulna length, demispan, sitting height, thigh length, upper arm length, and forearm length measurements in 31 males and 30 females were used to calculate the respective estimation for each method. Results showed that Canda-1 (based on four anthropometric variables) produced the smallest error and best fitted the data in males and females. The current method was associated with the largest error of those tests because it increasingly overestimated height in people with smaller stature. The results suggest that the set of Canda equations provide a more valid MASH estimation in people with a range of upper limb and bilateral lower limb amputations compared with the current method. PMID- 26589581 TI - Staphylococcus aureus develops increased resistance to antibiotics by forming dynamic small colony variants during chronic osteomyelitis. AB - OBJECTIVES: Staphylococcus aureus osteomyelitis often develops to chronicity despite antimicrobial treatments that have been found to be susceptible in in vitro tests. The complex infection strategies of S. aureus, including host cell invasion and intracellular persistence via the formation of dynamic small colony variant (SCV) phenotypes, could be responsible for therapy-refractory infection courses. METHODS: To analyse the efficacy of antibiotics in the acute and chronic stage of bone infections, we established long-term in vitro and in vivo osteomyelitis models. Antibiotics that were tested include beta-lactams, fluoroquinolones, vancomycin, linezolid, daptomycin, fosfomycin, gentamicin, rifampicin and clindamycin. RESULTS: Cell culture infection experiments revealed that all tested antibiotics reduced bacterial numbers within infected osteoblasts when treatment was started immediately, whereas some antibiotics lost their activity against intracellular persisting bacteria. Only rifampicin almost cleared infected osteoblasts in the acute and chronic stages. Furthermore, we detected that low concentrations of gentamicin, moxifloxacin and clindamycin enhanced the formation of SCVs, and these could promote chronic infections. Next, we treated a murine osteomyelitis model in the acute and chronic stages. Only rifampicin significantly reduced the bacterial load of bones in the acute phase, whereas cefuroxime and gentamicin were less effective and gentamicin strongly induced SCV formation. During chronicity none of the antimicrobial compounds tested showed a beneficial effect on bone deformation or reduced the numbers of persisting bacteria. CONCLUSIONS: In all infection models rifampicin was most effective at reducing bacterial loads. In the chronic stage, particularly in the in vivo model, many tested compounds lost activity against persisting bacteria and some antibiotics even induced SCV formation. PMID- 26589582 TI - Structure, physical property and antioxidant activity of catechin grafted Tremella fuciformis polysaccharide. AB - In this study, structural characterization, physical property and antioxidant activity of catechin grafted Tremella fuciformis polysaccharide (catechin-g-TPS) were investigated. Crude polysaccharides were isolated from the fruit bodies of T. fuciformis and further purified on DEAE-52 and Sepharose CL-4B chromatography to afford a main purified fraction (named TPS). The molecular weight of TPS was determined as 5.82 * 10(5)Da by HPLC. Then, the free radical mediated grafting of catechin onto TPS was achieved by using a redox system. As compared with the unmodified TPS, catechin-g-TPS showed new bands within the range of 1300-1600 cm( 1) in FT-IR spectrum, and exhibited new signals at around delta 6.00 and 6.80 ppm in (1)H NMR spectrum. Thermogravimetric analysis indicated the thermal stability of catechin-g-TPS was higher than TPS. X-ray diffraction spectrum of catechin-g TPS exhibited two sharp narrow diffraction peaks at 14.2 and 32.1 degrees , corresponding to the crystalline peaks of catechin. Scanning electron microscopy observation revealed the surface of TPS was smooth, whereas the surface of catechin-g-TPS was much rough. These results all confirmed the successful grafting of catechin onto TPS. Moreover, catechin-g-TPS had higher 2,2-diphenyl-1 picrylhydrazyl radical scavenging activity and reducing power as compared to TPS. PMID- 26589583 TI - An Analysis of Factors Influencing Quality of Vision After Big-Bubble Deep Anterior Lamellar Keratoplasty in Keratoconus. AB - PURPOSE: To identify causes of reduced visual acuity and contrast sensitivity after big-bubble deep anterior lamellar keratoplasty (DALK) in keratoconus. DESIGN: Prospective interventional case series. METHODS: This study included 36 eyes in 36 patients with keratoconus who underwent DALK using the big-bubble technique. A bare Descemet membrane was achieved in all cases. Univariate analyses and multiple linear regression were used to investigate recipient-, donor-, and postoperative-related variables capable of influencing the postoperative quality of vision, including best spectacle-corrected visual acuity (BSCVA) and contrast sensitivity. RESULTS: The mean patient age was 27.7 +/- 6.9 years, and the patients were followed for 24.6 +/- 15.1 months postoperatively. The mean postoperative BSCVA was 0.17 +/- 0.09 logMAR. Postoperative BSCVA >=20/25 was achieved in 14 eyes (38.9%), whereas a BSCVA of 20/30, 20/40, or 20/50 was observed in 15 eyes (41.7%), 6 eyes (16.6%), and 1 eye (2.8%), respectively. Preoperative vitreous length was significantly associated with postoperative BSCVA (beta = 0.02, P = .03). Donor-recipient interface reflectivity significantly influenced scotopic (beta = -0.002, P = .04) and photopic (beta = -0.003, P = .02) contrast sensitivity. The root mean square of tetrafoil was significantly negatively associated with scotopic (beta = -0.25, P = .01) and photopic (beta = -0.23, P = .04) contrast sensitivity. Recipient age, keratoconus severity, donor-related variables, recipient trephination size, and graft and recipient bed thickness were not significantly associated with postoperative visual acuity or contrast sensitivity. CONCLUSION: Large vitreous length, higher-order aberrations, and surgical interface haze may contribute to poor visual outcomes after big-bubble DALK in keratoconus. PMID- 26589584 TI - Primary HPV DNA based cervical cancer screening at 25 years: Views of young Australian women aged 16-28 years. AB - BACKGROUND: Revised Australian guidelines have been announced under the Renew((r)) program to commence screening at 25 years of age with HPV testing in 5 yearly intervals, in 2017. We conducted a study of young Victorian women to assess attitudes towards a change in cervical screening practice. METHODS: An online survey was conducted of young women aged 16-28 years enrolled in the Young Female Health Initiative (YFHI) study at the Royal Women's Hospital, Melbourne, to assess attitudes towards delaying the age of cervical screening, widening screening intervals and screening with HPV DNA testing, prior to the announcement of the renewal. RESULTS: Of 149 respondents (response rate 75%), mean age was 23.2 (range 16-27) years. Most (85/131, 65%) were concerned about delaying the age of cervical screening until 25 years. The majority (79% (106/135) were willing to undertake primary screening with HPV testing, whilst 66% (88/133) were willing to undertake HPV testing from 25 years, only 34% (45/132) were willing to undertake such screening every five years. Those willing to change screening practice were more likely to perceive that people important to them would expect them to do so; to have been vaccinated; and to value the importance of national guidelines (p<=0.05). While 69% (95/136) of participants indicated that a positive HPV test would be a source of worry, 76% (103/136) reported they would not feel ashamed about it. CONCLUSION: Targeted health campaigns are needed to address the concerns of young women prior to the introduction of new cervical screening guidelines in 2017. PMID- 26589585 TI - Protective Effects of Tinospora cordifolia on Hepatic and Gastrointestinal Toxicity Induced by Chronic and Moderate Alcoholism. AB - AIMS: Heavy alcohol intake depletes the plasma vitamins due to hepatotoxicity and decreased intestinal absorption. However, moderate alcohol intake is often thought to be healthy. Therefore, effects of chronic moderate alcohol intake on liver and intestine were studied using urinary vitamin levels. Furthermore, effects of Tinospora cordifolia water extract (TCE) (hepatoprotective) on vitamin excretion and intestinal absorption were also studied. METHODS: In the study, asymptomatic moderate alcoholics (n = 12) without chronic liver disease and healthy volunteers (n = 14) of mean age 39 +/- 2.2 (mean +/- SD) were selected and divided into three groups. TCE treatment was performed for 14 days. The blood and urine samples were collected on Day 0 and 14 after treatment with TCE and analyzed. RESULTS: In alcoholics samples, a significant increase in the levels of gamma-glutamyl transferase, aspartate transaminase, alanine transaminase, Triglyceride, Cholesterol, HDL and LDL (P < 0.05) was observed but their level get downregulated after TCE intervention. Multivariate analysis of metabolites without missing values showed an increased excretion of 7-dehydrocholesterol, orotic acid, pyridoxine, lipoamide and niacin and TCE intervention depleted their levels (P < 0.05). In contrast, excretion of biotin, xanthine, vitamin D2 and 2-O p-coumaroyltartronic acid (CA, an internal marker of intestinal absorption) were observed to be decreased in alcoholic samples; however, TCE intervention restored the CA and biotin levels. Vitamin metabolism biomarkers, i.e. homocysteine and xanthurenic acid, were also normalized after TCE intervention. CONCLUSION: Overall data depict that moderate alcohol intake is also hepatotoxic and decreases intestinal absorption. However, TCE treatment effectively increased the intestinal absorption and retaining power of liver that regulated alcohol-induced multivitamin deficiency. PMID- 26589587 TI - Reply. PMID- 26589586 TI - Lack of autophagy induces steroid-resistant airway inflammation. AB - BACKGROUND: Neutrophilic corticosteroid-resistant asthma accounts for a significant proportion of asthma; however, little is known about the mechanisms that underlie the pathogenesis of the disease. OBJECTIVE: We sought to address the role of autophagy in lung inflammation and the pathogenesis of corticosteroid resistant neutrophilic asthma. METHODS: We developed CD11c-specific autophagy related gene 5 (Atg5)(-/-) mice and used several murine models to investigate the role of autophagy in asthmatic patients. RESULTS: For the first time, we found that deletion of the Atg5 gene specifically in CD11c(+) cells, which leads to impairment of the autophagy pathway, causes unprovoked spontaneous airway hyperreactivity and severe neutrophilic lung inflammation in mice. We found that severe lung inflammation impairs the autophagy pathway, particularly in pulmonary CD11c(+) cells in wild-type mice. We further found that adoptive transfer of Atg5(-/-), but not wild-type, bone marrow-derived dendritic cells augments lung inflammation with increased IL-17A levels in the lungs. Our data indicate that neutrophilic asthma in Atg5(-/-) mice is glucocorticoid resistant and IL-17A dependent. CONCLUSION: Our results suggest that lack of autophagy in pulmonary CD11c(+) cells induces neutrophilic airway inflammation and hyperreactivity. PMID- 26589588 TI - Evaluating protocols for normalizing forearm electromyograms during power grip. AB - Many studies use a reference task of an isometric maximum voluntary power grip task in a mid-pronated forearm posture to normalize their forearm electromyographic (EMG) signal amplitude. Currently there are no recommended protocols to do this. In order to provide guidance on the topic, we examined the EMG amplitude of six forearm muscles (three flexors and three extensors) during twenty different maximal voluntary efforts that included various gripping postures, force and moment exertions and compared them to a frequently used normalization task of exerting a maximum grip force, termed the reference task. 16 participants (8 male and 8 female, aged 18-26) were recruited for this study. Overall, maximal muscle activity was produced during the resisted moment tasks. When contrasted with the reference task, the resisted moment tasks produced EMG activity that was up to 2.8 times higher (p<0.05). Although there was no one task that produced greater EMG values than the reference task for all forearm muscles, the resisted flexor and extensor moment tasks produced similar, if not higher EMG activity than the reference task for the three flexors and three extensor muscles, respectively. This suggests that researchers wishing to normalize forearm EMG activity during power gripping prehensile tasks should use resisted flexor and extensor moment tasks to obtain better estimates of the forearm muscles' maximum electrical activation magnitudes. PMID- 26589589 TI - Integrating heterogeneous genomic data to accurately identify disease subtypes. AB - BACKGROUND: High-throughput biotechnologies have been widely used to characterize clinical samples from various perspectives e.g., epigenomics, genomics and transcriptomics. However, because of the heterogeneity of these technologies and their outputs, individual analysis of the various types of data is hard to create a comprehensive view of disease subtypes. Integrative methods are of pressing need. METHODS: In this study, we evaluated the possible issues that hamper integrative analysis of the heterogeneous disease data types, and proposed iBFE, an effective and efficient computational method to subvert those issues from a feature extraction perspective. RESULTS: Strict experiments on both simulated and real datasets demonstrated that iBFE can easily overcome issues caused by scale conflicts, noise conflicts, incompleteness of patient relationships, and conflicts between patient relationships, and that iBFE can effectively combine the merits of DNA methylation, mRNA expression and microRNA (miRNA) expression datasets to accurately identify disease subtypes of significantly different prognosis. CONCLUSIONS: iBFE is an effective and efficient method for integrative analysis of heterogeneous genomic data to accurately identify disease subtypes. The Matlab code of iBFE is freely available from http://zhangroup.aporc.org/iBFE. PMID- 26589590 TI - Clinical implication of the serum galectin-1 expression in epithelial ovarian cancer patients. AB - BACKGROUND: galectin-1 has been implicated in tumor invasion and metastasis and is frequently over-expressed in epithelial ovarian cancer (EOC), but its potential as a biomarker remains unclear. In this novel study, we have explored the possible use of galectin-1 as a biomarker for EOC. METHODS: galectin-1 in sera was evaluated by ELISA in a pilot panel of EOC patients, healthy volunteers, patients with benign gynecologic tumors or other gynecologic malignancies. We examined galectin-1 expression in EOC tumor samples by Western Blot, qRT-PCR and immunohistochemistry. In vitro experiments were conducted to elucidate the biologic role of galectin-1 in EOC progression using over-expression of galectin 1 in OVCAR-3 cells. We also looked for the association of galectin-1 expression with clinic pathological variables and survival outcomes in EOC. RESULTS: A significant difference was detected in serum galectin-1 between EOC patients with non-metastatic and those with metastatic disease, but not between EOC patients and healthy volunteers. It increased in recurrent cases and decreased after debulking surgery. Both of galectin-1 mRNA and protein levels were increased in 90 % of the examined EOC tissue samples, compared with a wedge resection of a normal ovary. High galectin-1 in peritumor stroma was primarily detected in advanced stages of EOC. Over expression of galectin-1 significantly increased the ability of OVCAR-3 cells' migration and invasion. CONCLUSIONS: Our results suggest that galectin-1 might play a role in tumor progression and be associated with poor outcome in EOC. It could be a novel prognostic and progression biomarker in EOC patients. PMID- 26589591 TI - Metagenomic cross-talk: the regulatory interplay between immunogenomics and the microbiome. AB - The human microbiome, often referred to as the 'second genome', encompasses up to 100-fold more genes than the host genome. In contrast to the human genome, the microbial genome is flexible and amenable to change during the host's lifetime. As the composition of the microbial metagenome has been associated with the development of human disease, the mechanisms controlling the composition and function of the metagenome are of considerable interest and therapeutic potential. In the past few years, studies have revealed how the host immune system is involved in determining the microbial metagenome, and, in turn, how the microbiota regulates gene expression in the immune system. This species-specific bidirectional interaction is required for homeostatic health, whereas aberrations in the tightly controlled regulatory circuits that link the host immunogenome and the microbial metagenome drive susceptibility to common human diseases. Here, we summarize some of the major principles orchestrating this cross-talk between microbial and host genomes, with a special focus on the interaction between the intestinal immune system and the gut microbiome. Understanding the reciprocal genetic and epigenetic control between host and microbiota will be an important step towards the development of novel therapies against microbiome-driven diseases. PMID- 26589593 TI - Posthepatectomy Liver Failure Affects Long-Term Function After Resection for Hepatocellular Carcinoma. AB - BACKGROUND: This study examined whether the severity of posthepatectomy liver failure (PLF) affected the long-term postoperative liver recovery of patients with hepatocellular carcinoma (HCC). METHODS: We performed a retrospective cohort study of 395 HCC patients who underwent hepatectomy from 2004 to 2012 at the Kyoto University Hospital. The severity of PLF between postoperative days 5 and 10 was categorized according to the International Study Group of Liver Surgery criteria. We compared the Child-Pugh (C-P) score, platelet count (PLT), and the ratio of future remnant liver volume (FRLV) to the total liver volume (%RLV) at 3, 6, and 12 months after hepatectomy in the non-PLF, grade A, and grade B groups. RESULTS: The non-PLF, grade A, and grade B groups contained 272, 63, and 56 patients, respectively. The C-P score in the grade A group recovered from 5.37 points before hepatectomy to 5.38 points at 12 months after hepatectomy. The C-P score in the grade B group increased from 5.51 to 6.81 points at 3 months and was significantly higher (6.00 points) at 12 months than in the non-PLF group (5.47 points). The PLT significantly decreased at 12 months in the grade B group compared with the non-PLF group. The %RLV at 12 months in the non-PLF, grade A, and grade B groups were 84, 83, and 78 %, respectively. The remnant liver hypertrophy in the grade B group was significantly slower than that in the non PLF group. CONCLUSIONS: PLF severity affects long-term liver function recovery and remnant liver hypertrophy after hepatectomy. PMID- 26589594 TI - Original Scientific Reports: Clinicopathological Findings of Remnant Pancreatic Cancers in Survivors Following Curative Resections of Pancreatic Cancers. AB - BACKGROUND: This retrospective study aimed to evaluate clinicopathological findings of remnant pancreatic cancers in survivors of invasive ductal adenocarcinomas of the pancreas (PDAC). METHODS: A group of 23 patients out of 826 who had curative resections for PDAC between 1980 and 2011 was identified and treated for metachronous pancreatic cancer. RESULTS: The following tubular adenocarcinomas were found at the first surgery: 3 well differentiated, 17 moderately differentiated, 1 papillary, and 1 poorly differentiated. Treatments for the remnant pancreas consisted of remnant pancreatectomy in 12 patients, chemotherapy in 6, and the best supportive care in 5. The mean time to treatment was 74.2 months. The 12 patients who received remnant resections had 10 PDACs and 2 intraductal papillary mucinous carcinomas. The median survival time was 31.6 months, and 8 patients are still alive. CONCLUSIONS: Long-term survivors after curative resection for pancreatic cancer should receive follow-up for remnant pancreatic cancer, and aggressive resection should be considered for more favorable prognosis of PDAC. PMID- 26589592 TI - SNTF immunostaining reveals previously undetected axonal pathology in traumatic brain injury. AB - Diffuse axonal injury (DAI) is a common feature of severe traumatic brain injury (TBI) and may also be a predominant pathology in mild TBI or "concussion". The rapid deformation of white matter at the instant of trauma can lead to mechanical failure and calcium-dependent proteolysis of the axonal cytoskeleton in association with axonal transport interruption. Recently, a proteolytic fragment of alpha-II spectrin, "SNTF", was detected in serum acutely following mild TBI in patients and was prognostic for poor clinical outcome. However, direct evidence that this fragment is a marker of DAI has yet to be demonstrated in either humans following TBI or in models of mild TBI. Here, we used immunohistochemistry (IHC) to examine for SNTF in brain tissue following both severe and mild TBI. Human severe TBI cases (survival <7d; n = 18) were compared to age-matched controls (n = 16) from the Glasgow TBI archive. We also examined brains from an established model of mild TBI at 6, 48 and 72 h post-injury versus shams. IHC specific for SNTF was compared to that of amyloid precursor protein (APP), the current standard for DAI diagnosis, and other known markers of axonal pathology including non-phosphorylated neurofilament-H (SMI-32), neurofilament-68 (NF-68) and compacted neurofilament-medium (RMO-14) using double and triple immunofluorescent labeling. Supporting its use as a biomarker of DAI, SNTF immunoreactive axons were observed at all time points following both human severe TBI and in the model of mild TBI. Interestingly, SNTF revealed a subpopulation of degenerating axons, undetected by the gold-standard marker of transport interruption, APP. While there was greater axonal co-localization between SNTF and APP after severe TBI in humans, a subset of SNTF positive axons displayed no APP accumulation. Notably, some co-localization was observed between SNTF and the less abundant neurofilament subtype markers. Other SNTF positive axons, however, did not co localize with any other markers. Similarly, RMO-14 and NF-68 positive axonal pathology existed independent of SNTF and APP. These data demonstrate that multiple pathological axonal phenotypes exist post-TBI and provide insight into a more comprehensive approach to the neuropathological assessment of DAI. PMID- 26589595 TI - Pharmacological interventions in traumatic brain injury: Can we rely on systematic reviews for evidence? AB - INTRODUCTION: Providing current, reliable and evidence based information for clinicians and researchers in a synthesised and summarised way can be challenging particularly in the area of traumatic brain injury where a vast number of reviews exists. These reviews vary in their methodological quality and are scattered across varying sources. In this paper, we present an overview of systematic reviews that evaluate the pharmacological interventions in traumatic brain injury (TBI). By doing this, we aim to evaluate the existing evidence for improved outcomes in TBI with pharmacological interventions, and to identify gaps in the literature to inform future research. METHODS: We searched the Neurotrauma Evidence Map on systematic reviews relating to pharmacological interventions for managing TBI in acute phase. Two reviewers independently screened search results and appraised each systematic review using the validated AMSTAR tool and extracted data from the review. RESULTS: A total of 288 systematic reviews relating to TBI were available on the Neurotrauma Evidence Map at the time of this study. We identified 19 systematic reviews on pharmacological management for acute TBI with publications dates ranging from 1998 to 2014. The studies were of varying methodological quality, with a mean AMSTAR score of 7.78 (range 2-11]. CONCLUSION: The evidence from high quality systematic reviews show that there is currently insufficient evidence for the use of magnesium, monoaminergic and dopamine agonists, progesterone, aminosteroids, excitatory amino acid inhibitors, haemostatic and antifibrinolytic drugs in TBI. Anti-convulsants are only effective in reducing early seizures with no significant difference between phenytoin and leviteracetam. There is no difference between propofol and midazolam for sedation in TBI patients and ketamine may not cause increased ICP. Overviews of systematic review provide informative and powerful summaries of evidence based research. PMID- 26589596 TI - Silver ion doped ceramic nano-powder coated nails prevent infection in open fractures: In vivo study. AB - BACKGROUND: Despite improvement in operative techniques and antibiotic therapy, septic complications still occur in open fractures. We developed silver ion containing ceramic nano powder for implant coating to provide not only biocompatibility but also antibacterial activity to the orthopaedic implants. QUESTIONS/PURPOSES: We hypothesised silver ion doped calcium phosphate based ceramic nano-powder coated titanium nails may prevents bacterial colonisation and infection in open fractures as compared with uncoated nails. METHODS: 33 rabbits divided into three groups. In the first group uncoated, in the second group hydroxyapatite coated, and in the third group silver doped hydroxyapatite coated titanium nails were inserted left femurs of animals from knee regions with retrograde fashion. Before implantation of nails 50 MUl solution containing 10(6)CFU/ml methicillin resistance Staphylococcus aureus (MRSA) injected intramedullary canal. Rabbits were monitored for 10 weeks. Blood was taken from rabbits before surgery and on 2nd, 6th and 10th weeks. Blood was analysed for biochemical parameters, blood count, C-reactive protein and silver levels. At the end of the 10 weeks animals were sacrificed and rods were extracted in a sterile fashion. Swab cultures were taken from intramedullary canal. Bacteria on titanium rods were counted. Liver, heart, spleen, kidney and central nervous tissues samples were taken for determining silver levels. Histopathological evaluation of bone surrounding implants was also performed. RESULTS: No significant difference was detected between the groups from hematologic, biochemical, and toxicological aspect. Microbiological results showed that less bacterial growth was detected with the use of silver doped ceramic coated implants compared to the other two groups (p=0.003). Accumulation of silver was not detected. No cellular inflammation was observed around the silver coated prostheses. No toxic effect of silver on bone cells was seen. CONCLUSION: Silver ion doped calcium phosphate based ceramic nano powder coating to orthopaedic implants may prevents bacterial colonisation and infection in open fractures compared with those for implants without any coating. PMID- 26589597 TI - Multiplexed Fluid Flow Device to Study Cellular Response to Tunable Shear Stress Gradients. AB - Endothelial cells (ECs) line the interior of blood and lymphatic vessels and experience spatially varying wall shear stress (WSS) as an intrinsic part of their physiological function. How ECs, and mammalian cells generally, sense spatially varying WSS remains poorly understood, due in part to a lack of convenient tools for exposing cells to spatially varying flow patterns. We built a multiplexed device, termed a 6-well impinging flow chamber, that imparts controlled WSS gradients to a six-well tissue culture plate. Using this device, we investigated the migratory response of lymphatic microvascular ECs, umbilical vein ECs, primary fibroblasts, and epithelial cells to WSS gradients on hours to days timescales. We observed that lymphatic microvascular ECs migrate upstream, against the direction of flow, a response that was unique among all the cells types investigated here. Time-lapse, live cell imaging revealed that the microtubule organizing center relocated to the upstream side of the nucleus in response to the applied WSS gradient. To further demonstrate the utility of our device, we screened for the involvement of canonical signaling pathways in mediating this upstream migratory response. These data highlight the importance of WSS magnitude and WSS spatial gradients in dictating the cellular response to fluid flow. PMID- 26589598 TI - On Studying the Interaction Between Different Stent Models and Rabbit Tracheal Tissue: Numerical, Endoscopic and Histological Comparison. AB - Stenting technique is employed worldwide for treating atherosclerotic vessel and tracheal stenosis. Both diseases can be treated by means of metallic stents which present advantages but are affected by the main problem of restenosis of the stented area. In this study we have built a rabbit trachea numerical model and we have analyzed it before and after insertion and opening of two types of commercial stent: a Zilver((r)) FlexTM Stent and a WallStentTM. In experimental parallel work, two types of stent were implanted in 30 New Zealand rabbits divided in two groups of 10 animals corresponding to each stent type and a third group made up of 10 animals without stent. The tracheal wall response was assessed by means of computerized tomography by endoscopy, macroscopic findings and histopathological study 90 days after stent deployment. Three idealized trachea models, one model for each group, were created in order to perform the computational study. The animal model was used to validate the numerical findings and to attempt to find qualitative correlations between numerical and experimental results. Experimental findings such as inflammation, granuloma and abnormal tissue growth, assessed from histomorphometric analyses were compared with derived numerical parameters such as wall shear stress (WSS) and maximum principal stress. The direct comparison of these parameters and the biological response supports the hypothesis that WSS and tensile stresses may lead to a greater tracheal epithelium response within the stented region, with the latter seeming to have the dominant role. This study may be helpful for improving stent design and demonstrates the feasibility offered by in-silico investigated tracheal structural and fluid dynamics. PMID- 26589600 TI - [Computer Assisted Surgery around the Head (CASH): Interdisciplinary symposium and hands-on workshop, Ulm, 25-26 September 2015]. PMID- 26589601 TI - Genetic Factors Influencing B-type Natriuretic Peptide-Mediated Production of Cyclic Guanosine Monophosphate and Blood Pressure Effects in Heart Failure Patients. AB - Natriuretic peptides (NPs) represent a critical pathway in heart failure (HF). We explored genetic determinants of pharmacodynamic effects of B-type NP (BNP) and changes in plasma cyclic guanosine monophosphate (cGMP) and blood pressure (BP). HF patients (n = 135) received recombinant human BNP (nesiritide) at standard doses, and plasma cGMP levels were measured at baseline and during infusion. We tested the association of 119 single nucleotide polymorphisms (SNPs) in 4 candidate genes (NPR1, NPR2, NPR3, and membrane metallo-endopeptidase (MME)) with the change in cGMP and BP. Gene-based testing for association of genetic variation with endpoints was significant only for MME. Upon individual SNP testing, two loci in MME were associated with DeltacGMP; another (rs16824656) showed association with BP change. In summary, the pharmacodynamic effects of BNP vary substantially in HF patients and are associated with genetic variation in MME. MME genetic variation may be an important determinant of NP-mediated effects in humans. PMID- 26589602 TI - Oligometastatic non-small cell lung cancer (NSCLC): adrenal metastases. Experience in a single institution. AB - Though the actual incidence of an adrenal oligometastasis is between 1.5 and 3.5 %, secondary adrenal neoplasms occur in less than 10 % patients with non-small cell lung cancer (NSCLC). According to 7 degrees ed. TNM staging system, the presence of an adrenal metastasis (M1b disease) configures stage IV, which is usually associated with poor prognosis. We evaluated if metastasectomy in selected patients with oligometastatic disease improves overall survival. A 15 year retrospective study concerning patients with NSCLC was performed and an oligometastatic disease was found in 1.61 % of the patients. 18 adrenalectomies were performed. Clustering the population according to different therapeutic strategies, a benefit in terms of survival was found in patients who underwent adrenalectomy. A statistical relevance was found, indeed, between adrenalectomy (p < 0.01), metachronous disease (p < 0.01), the presence of a homolateral disease (p < 0.05) and overall survival. Adrenalectomy should be offered in selected patients with oligometastatic disease. PMID- 26589605 TI - A stepwise approach based on a rational use of components separation and double mesh prosthesis for incisional hernia repair. AB - PURPOSE: We aimed to evaluate the results of a protocol for a tension-free reconstruction of the abdominal wall in midline incisional hernia repair, based on the rational association of components separation and prosthesis, independently of the hernia size. METHODS: A total of 100 consecutive patients with midline incisional hernias were prospectively included in the study. Three groups according to the transverse diameter of the defect [group A (<4 cm, N = 18), group B (4-10 cm, N = 59), and group C (>10 cm, N = 23)] were identified. RESULTS: Components separation was necessary in 54% of the patients: 16.7% (3/18) in group A, 59.3% (35/59) in group B, and 69.6% (16/23) in group C. Complete tension-free reconstruction was achieved in 87% of the patients: 94.4% (17/18) in group A, 91.5% (54/59) in group B, and 69.6% (16/23) in group C. Overall morbidity rate was 21% (21/100) [group A 16.7% (3/18), group B 22% (13/59), and group C 21.7% (5/23)]. Hospital length of stay was 3.7 +/- 3.3 days (group A 1.83 +/- 1.43 days, group B 3.05 +/- 2.11 days, and group C 6.91 +/- 4.45 days). Median follow-up was 25 months (interquartile range 12.25-55.25) with overall recurrence of 2%. CONCLUSION: A tension-free abdominal wall reconstruction can be achieved in most cases of small and large midline incisional hernia repair, by a stepwise approach based on a rational association of components separation and double mesh prosthesis, with a low morbidity and recurrence rates. PMID- 26589603 TI - New advances in ovarian autotransplantation to restore fertility in cancer patients. AB - Human ovary autotransplantation is a promising option for fertility preservation of young women and girls undergoing gonadotoxic treatments for cancer or some autoimmune diseases. Although experimental, it resulted in at least 42 healthy babies worldwide. According to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic literature review was performed for all relevant full-text articles published in English from 1 January 2000 to 01 October 2015 in PubMed to explore the latest clinical and research advances of human ovary autotransplantation. Human ovary autotransplantation involves ovarian tissue extraction, freezing/thawing, and transplantation back into the same patient. Three major forms of human ovary autotransplantation exist including (a) transplantation of cortical ovarian tissue, (b) transplantation of whole ovary, and (c) transplantation of ovarian follicles (artificial ovary). According to the recent guidelines, human ovary autotransplantation is still considered experimental; however, it has unique advantages in comparison to other options of female fertility preservation. Human ovary autotransplantation (i) does not need prior ovarian stimulation, (ii) allows immediate initiation of cancer therapy, (iii) can restore both endocrine and reproductive ovarian functions, and (iv) may be the only fertility preservation option suitable for prepubertal girls or for young women with estrogen-sensitive malignancies. As any other fertility preservation option, human ovary autotransplantation has both advantages and disadvantages and may not be feasible for all cases. The major challenges facing this option are how to avoid the risk of reintroducing malignant cells and how to prolong the lifespan of ovarian transplant as well as how to improve artificial ovary results. PMID- 26589606 TI - EGFR mutations are associated with higher incidence of distant metastases and smaller tumor size in patients with non-small-cell lung cancer based on PET/CT scan. AB - The study aimed to explore the correlation of epidermal growth factor receptor (EGFR) mutation with tumor node metastasis (TNM) stage in patients with non-small cell lung cancer (NSCLC) who underwent positron emission tomography/computed tomography (PET/CT) scan. Patients diagnosed with NSCLC who underwent EGFR mutation status testing and PET/CT or PET/CT plus brain magnetic resonance imaging scan at initial diagnosis in Nanfang Hospital between July 2010 and June 2014 were consecutively enrolled. The correlation of EGFR mutation status with TNM stage and distant metastasis organs including brain, bone, liver, pleural, adrenals and contralateral lobe of lung were analyzed. A total of 401 patients were enrolled. Tumor size in EGFR mutation group was significantly smaller than the wild-type group (P < 0.001). Further, patients with EGFR mutations were demonstrated significantly more frequent in patients with distant metastasis than non-metastasis (45.7 vs 32.2 %, P = 0.007). The rates of bone (32.2 vs 22.8 %, P = 0.007) and brain (16.3 vs 9.4 %, P = 0.008) metastasis were significantly higher in EGFR mutation group than the wild-type group. In the subgroup of 199 metastatic NSCLC patients, patients with EGFR mutation were significantly associated with a smaller tumor size (P = 0.013) and earlier N stage (P = 0.033). Of note, compared with the EGFR wild-type group, patients had a higher likelihood of developing brain plus bone metastases at initial diagnosis of EGFR mutation group (20.9 vs 7.5 %, P = 0.018). Taken together, we identify that EGFR mutations might associate with more aggressive tumor progression than the wild types in NSCLC. In addition, patients with tumor having EGFR mutation had a smaller tumor size than without mutation. PMID- 26589607 TI - Icariin protects SH-SY5Y cells from formaldehyde-induced injury through suppression of Tau phosphorylation. AB - OBJECTIVE: To investigate the neuroprotective effects of icariin on formaldehyde (FA)-treated human neuroblastoma SH-SY5Y cells and the possible mechanisms involved. METHODS: SH-SY5Y cells were divided into FA treatment group, FA treatment group with icariin, and the control group. Cell viability, apoptosis, and morphological changes were determined by cell counting kit-8 (CCK 8), flow cytometry, and confocal microscopy, respectively. The phosphorylation of Tau protein was examined by western blotting. RESULTS: FA showed a half lethal dose (LD50) of 0.3 mmol/L in SH-SY5Y cells under the experimental conditions. Icariin (1-10 umol/L) prevented FA-induced cell death in SH-SY5Y cells in a dose dependent manner, with the optimal effect observed at 5 umol/L. After FA treatment, the absorbance in FA group was 1.31+/-0.05, while in the group of icariin (5 umol/L) was 1.63+/-0.05. Examination of cell morphology by confocal microscopy demonstrated that 5 umol/L icariin significantly attenuated FA-induced cell injury (P <0.05). Additionally, Icariin inhibited FA-induced cell apoptosis in SH-SY5Y cells. Results from western blotting showed that icariin suppressed FA induced phosphorylation at Thr 181 and Ser 396 of Tau protein, while having no effect on the expression of the total Tau protein level. Furthermore, FA activated Tau kinase glycogen synthase kinase 3 beta (GSK-3beta) by enhancement of Y216 phosphorylation, but icariin reduced Y216 phosphorylation and increased Ser 9 phosphorylation. CONCLUSION: Icariin protects SH-SY5Y cells from FA-induced injury pobetasibly through the inhibition of GSK-3beta-mediated Tau phosphorylation. PMID- 26589608 TI - Aqueous extracts of Tribulus terrestris protects against oxidized low-density lipoprotein-induced endothelial dysfunction. AB - OBJECTIVE: To investigate the role of aqueous extracts of Tribulus terrestris (TT) against oxidized low-density lipoprotein (ox-LDL)-induced human umbilical vein endothelial cells (HUVECs) dysfunction in vitro. METHODS: HUVECs were pre incubated for 60 min with TT (30 and 3 MUg/mL respectively) or 10(-5) mol/L valsartan (as positive controls) and then the injured endothelium model was established by applying 100 MUg/mL ox-LDL for 24 h. Cell viability of HUVECs was observed by real-time cell electronic sensing assay and apoptosis rate by Annexin V/PI staining. The cell migration assay was performed with a transwell insert system. Cytoskeleton remodeling was observed by immunofluorescence assay. The content of endothelial nitric oxide synthase (eNOS) was measured by enzyme-linked immunosorbent assay. Intracellular reactive oxygen species (ROS) generation was assessed by immunofluorescence and flow cytometer. Key genes associated with the metabolism of ox-LDL were chosen for quantitative real-time polymerase chain reaction to explore the possible mechanism of TT against oxidized LDL-induced endothelial dysfunction. RESULTS: TT suppressed ox-LDL-induced HUVEC proliferation and apoptosis rates significantly (41.1% and 43.5% after treatment for 3 and 38 h, respectively; P<0.05). It also prolonged the HUVEC survival time and postponed the cell's decaying stage (from the 69th h to over 100 h). According to the immunofluorescence and transwell insert system assay, TT improved the endothelial cytoskeletal network, and vinculin expression and increased cell migration. Additionally, TT regulated of the synthesis of endothelial nitric oxide synthase and generation of intracellular reactive oxygen species (P<0.05). Both 30 and 3 MUg/mL TT demonstrated similar efficacy to valsartan. TT normalized the increased mRNA expression of PI3Kalpha and Socs3. It also decreased mRNA expression of Akt1, AMPKalpha1, JAK2, LepR and STAT3 induced by ox-LDL. The most notable changes were JAK2, LepR, PI3Kalpha, Socs3 and STAT3. CONCLUSIONS: TT demonstrated potential lowering lipid benefits, anti-hypertension and endothelial protective effects. It also suggested that the JAK2/STAT3 and/or PI3K/AKT pathway might be a very important pathway which was involved in the pharmacological mechanism of TT as the vascular protective agent. PMID- 26589609 TI - A metallo-keratinase from a newly isolated Acinetobacter sp. R-1 with low collagenase activity and its biotechnological application potential in leather industry. AB - Microbial keratinase is a well-recognized enzyme that can specifically degrade insoluble keratins. A keratinase-producing bacterium was isolated from a duck ranch soil and identified as Acinetobacter sp. R-1 based on the biochemical characteristics and 16S rDNA gene sequencing. It showed high keratinase activity and low collagenase activity. The keratinase was purified to electrophoretic homogeneity with 6.69% recovery, 2.68-fold purification and an estimated molecular weight of 25 kDa. Additionally, the keratinase showed optimal activity at 50 degrees C and pH11. Keratinase activity of Acinetobacter sp. significantly increased in the presence of Li(+), Na(+), and Ca(2+), while it was completely inhibited by EDTA, indicating it was a metallo-keratinase. Moreover, the crude keratinase from Acinetobacter sp. R-1 could thoroughly depilate goat skin and simultaneously modify the wool surface, which indicated its applicable potential in leather and textile industries. PMID- 26589611 TI - Magnesium handling in peritoneal dialysis patients with preserved residual diuresis. PMID- 26589610 TI - Does chromophobe renal cell carcinoma have better survival than clear cell renal cell carcinoma? A clinical-based cohort study and meta-analysis. AB - BACKGROUND: It is controversial whether chromophobe renal cell carcinoma (chRCC) or clear cell renal cell carcinoma (ccRCC) is associated with better survival. We conducted a clinical-based cohort study and meta-analysis to evaluate the prognostic role of histology between chRCC and ccRCC. METHODS: A cohort of 1540 patients (166 with chRCC and 1374 with ccRCC) were selected from Sun Yat-sen University and The Cancer Genome Atlas databases. The clinicopathological parameters and overall survival (OS) were compared between patients with chRCC and those with ccRCC. For the meta-analysis, we searched the PubMed, Cochrane Library, and Ovid databases for studies comparing OS or cancer-specific survival (CSS) between chRCC and ccRCC. RESULTS: The cohort study revealed that patients with chRCC were younger (median 52 vs. 55 years, P < 0.001), were more commonly female (47.0 vs. 33.0%, P < 0.001), and had a larger tumor size (mean 7.1 vs. 5.9 cm, P < 0.001), and they had a lower stage compared with those with ccRCC. Five year OS rates for chRCC and ccRCC were 90.3 and 75.3%, respectively (P < 0.001). We found significantly better survival for chRCC in stratification analysis by age, sex, tumor size, and stage. Similar results were observed on both univariate [hazard ratio (HR), 0.30; 95% confidence interval (CI) 0.16-0.55, P < 0.001] and multivariate analyses (HR 0.42; 95% CI 0.23-0.79, P = 0.006). Ten studies were included in our meta-analysis. Eight of them provided data on univariate analysis. The pooled HR was statistically significant for OS (pooled HR 0.49; 95% CI 0.30-0.79, P = 0.004) and CSS (pooled HR 0.49; 95% CI 0.37-0.64, P < 0.001). Seven studies reported the HR on multivariate analysis. The pooled HR was also statistically significant for OS (pooled HR 0.63; 95% CI 0.51-0.77, P < 0.001) and CSS (pooled HR 0.72; 95 % CI 0.57-0.90, P = 0.003). These data indicate that patients with chRCC had better outcomes than those with ccRCC. CONCLUSIONS: Our large cohort study and meta-analysis confirmed that chRCC had better survival than ccRCC. PMID- 26589612 TI - A rare case of nutcracker phenomenon with nephrotic syndrome. PMID- 26589613 TI - Spontaneous ureteral rupture in a patient with polyarteritis nodosa. PMID- 26589614 TI - Cartilage matrix changes in contralateral mobile knees in a rabbit model of osteoarthritis induced by immobilization. AB - BACKGROUND: Many researches have investigated the changes associated with immobilization-induced osteoarthritis (OA). However, there are only few studies focusing on the effect of unilateral knee immobilization on cartilage matrix changes in the contralateral mobile knee. The aim of the present study was to investigate the influence of immobilization on the cartilage matrix in the contralateral mobile knees in a rabbit model of OA induced by immobilization. METHODS: Right knees (experimental knees) of eighteen mature female rabbits were immobilized at an extension of 180 degrees with orthopedic casting tape for 2, 4, or 8 weeks. Left knees (contralateral knees) of the immobilized rabbits were not subjected to immobilization. The knees of six non-immobilized rabbits were designated as control knees. Following immobilization, cartilage specimens from the medial femoral condyle underwent macroscopic, histological, immunohistochemical, and biochemical evaluations. RESULTS: Roughness of cartilage surface was detected in the experimental knees at 2 weeks, and cartilage degeneration was further developed. In the contralateral knee, cartilage showed degenerative changes after 4 weeks. Safranin-O staining and glycosaminoglycan (GAG) contents were reduced in the experimental knees following immobilization and in the contralateral intact knees after 4 and 8 weeks. Type II collagen staining was gradually reduced, type I collagen accumulation was obviously detected in the upper and middle layers of cartilage in experimental knees after 8 weeks, and the collagen orientation was gradually disorganized in both knees at 4 and 8 weeks. For both experimental and contralateral knees, collagen contents were significantly decreased at 8 weeks, and Mankin and Osteoarthritis Research Society International (OARSI) scores increased over time. CONCLUSION: OA developed in the contralateral intact knee with the progress of OA in the immobilized knee in a rabbit model of immobilization-induced OA. PMID- 26589616 TI - Large Studies Expand Genomic View of CLL. AB - The largest genomic studies on chronic lymphocytic leukemia to date confirm the genetic heterogeneity of the disease, reveal dozens of putative new driver mutations, and trace the evolution of tumors during treatment and relapse. PMID- 26589615 TI - Molecular recognition of thiaclopride by Aplysia californica AChBP: new insights from a computational investigation. AB - The binding of thiaclopride (THI), a neonicotinoid insecticide, with Aplysia californica acetylcholine binding protein (Ac-AChBP), the surrogate of the extracellular domain of insects nicotinic acetylcholine receptors, has been studied with a QM/QM' hybrid methodology using the ONIOM approach (M06-2X/6 311G(d):PM6). The contributions of Ac-AChBP key residues for THI binding are accurately quantified from a structural and energetic point of view. The importance of water mediated hydrogen-bond (H-bond) interactions involving two water molecules and Tyr55 and Ser189 residues in the vicinity of the THI nitrile group, is specially highlighted. A larger stabilization energy is obtained with the THI-Ac-AChBP complex compared to imidacloprid (IMI), the forerunner of neonicotinoid insecticides. Pairwise interaction energy calculations rationalize this result with, in particular, a significantly more important contribution of the pivotal aromatic residues Trp147 and Tyr188 with THI through CH...pi/CH...O and pi-pi stacking interactions, respectively. These trends are confirmed through a complementary non-covalent interaction (NCI) analysis of selected THI-Ac-AChBP amino acid pairs. PMID- 26589617 TI - Correlating mechanical work with energy consumption during gait throughout pregnancy. AB - BACKGROUND: Measures of mechanical work may be useful in evaluating efficiency of walking during pregnancy. Various adaptations in the body during pregnancy lead to altered gait, consequently contributing to the total energy cost of walking. Measures of metabolic energy expenditure may not be reliable for measuring energetic cost of gait during pregnancy as pregnancy results in numerous metabolic changes resulting from foetal development. Therefore, the aim of this study is to determine if mechanical work prediction equations correlate with the metabolic energy cost of gait during pregnancy. METHODS: Thirty-five (35) women (27.5 +/- 6.1 years) gave informed consent for participation in the study at different weeks of gestation pregnancy. Gas exchange and gait data were recorded while walking at a fixed self-selected walking speed. External (Wext) work was estimated assuming no energy transfer between segments, while internal work (Wint) assumed energy transfer between segments. Hence total energy of the body (Wtot) was calculated based on the segmental changes relative to the surrounding, and relative to the centre of mass of the whole body. Equations for mechanical work were correlated with net and gross O2 rate, and O2 cost. RESULTS: External, internal and total mechanical energy showed significant positive relationship with gross O2 rate (r = 0.48, r = 0.35; and r = 0.49 respectively), and gross O2 cost (r = 0.42; r = 0.70, and r = 0.62, respectively). In contrast, external, internal and total mechanical energy had no significant relationship with net O2 rate (r = 0.19, r = 0.24, and r = 0.24, respectively). Net O2 cost was significant related Wext (r = 0.49) Wint (r = 0.66) and Wtot (r = 0.62). Energy recovery improved with increase in gait speed. CONCLUSIONS: Measures of mechanical work, when adjusted for resting energy expenditure, and walking speed may be useful in comparing metabolic energy consumption between women during pregnancy, or assessment or gait changes of the same individual throughout pregnancy. PMID- 26589618 TI - Elusive ditrysian phylogeny: an account of combining systematized morphology with molecular data (Lepidoptera). AB - BACKGROUND: Ditrysia comprise close to 99 % of all butterflies and moths. The evolutionary relationships among the ditrysian superfamilies have received considerable attention in phylogenetic studies based on DNA and transcriptomic data, but the deepest divergences remain for large parts unresolved or contradictory. To obtain complementary insight into the evolutionary history of the clade, and to test previous hypotheses on the subdivision of Ditrysia based on morphology, we examine the morphology of larvae, pupae and adult males and females of 318 taxa representing nearly all ditrysian superfamilies and families. We present the most comprehensive morphological dataset on Ditrysia to date, consisting of over 500 morphological characters. The data are analyzed alone and combined with sequence data (one mitochondrial and seven nuclear protein-coding gene regions, sequenced from 422 taxa). The full dataset consists of 473 exemplar species. Analyses are performed using maximum likelihood methods, and parsimony methods for the morphological dataset. We explore whether combining morphological data and DNA-data can stabilize taxa that are unstable in phylogenetic studies based on genetic data only. RESULTS: Morphological characters are found phylogenetically informative in resolving apical nodes (superfamilies and families), but characters serving as evidence of relatedness of larger assemblages are few. Results include the recovery of a monophyletic Tineoidea, Sesioidea and Cossoidea, and a stable position for some unstable taxa (e.g. Epipyropidae, Cyclotornidae, Urodoidea + Schreckensteinioidea). Several such taxa, however, remain unstable even though morphological characters indicate a position in the tree (e.g. Immidae). Evidence supporting affinities between clades are suggested, e.g. a novel larval synapomorphy for Tineidae. We also propose the synonymy of Tineodidae with Alucitidae, syn. nov. CONCLUSIONS: The large morphological dataset provides information on the diversity and distribution of morphological traits in Ditrysia, and can be used in future research on the evolution of these traits, in identification keys and in identification of fossil Lepidoptera. The "backbone" of the phylogeny for Ditrysia remains largely unresolved. As previously proposed as an explanation for the scarcity of molecular signal in resolving the deeper nodes, this may be due to the rapid radiation of Ditrysia in the Cretaceous. PMID- 26589619 TI - The role of high-dose myeloablative chemotherapy with haematopoietic stem cell transplantation (HSCT) in children with central nervous system (CNS) tumours: protocol for a systematic review and meta-analysis. AB - OBJECTIVES: The objective of the study is to conduct a systematic review to compare the effects of high-dose chemotherapy (HDCT) with autologous haematopoietic stem cell transplantation (HSCT) versus standard-dose chemotherapy (SDCT) in children with malignant central nervous system (CNS) tumours. METHODS: Standard systematic review methods aimed at minimising bias will be employed for study identification, selection and data extraction. Ten electronic databases will be searched, along with citation searching and reference checking. Studies assessing the effects of HDCT with HSCT in children with CNS tumours will be included. The outcomes are survival (overall, progression-free, event-free, disease-free), response rates, short- and long-term adverse events and health related quality of life (HRQoL). Two reviewers will independently screen and select randomised and non-randomised controlled trials and controlled and uncontrolled observational studies for inclusion. Quality assessment will be tailored to the different study designs. Where possible data will be summarised using combined estimates of effect for the hazard ratio for survival outcomes and the risk ratio for response rates. A fixed effect model will be used; sub-group analyses and meta-regression will be used to explore potential sources of heterogeneity between studies. DISCUSSION: Given the poor prognosis of malignant brain tumours in children in terms of survival and quality of life, this review will help guide clinical practice by summarising the current evidence on the use of high-dose myeloblative chemotherapy with stem cell support in children with CNS tumours. PMID- 26589621 TI - Managing combat laparostomy: Author's Reply. PMID- 26589622 TI - Perimitral atrial flutter ablation by transaortic radiofrequency application. PMID- 26589623 TI - Safety, efficacy, and clinical applicability of pulmonary vein isolation with circular multi-electrode ablation systems: PVAC(r) vs. nMARQTM for atrial fibrillation ablation. AB - AIMS: We compare our experience with available circular multi-electrode catheters for atrial fibrillation (AF) ablation: PVAC((r)), a phased radiofrequency system, and nMARQTM, an irrigated tip-CARTO-based technology. METHODS AND RESULTS: Prospective observational study of 175 consecutive patients with follow-up duration of at least 5 months who underwent pulmonary vein isolation (PVI) for symptomatic AF using PVAC((r)) (n = 93, age 61.4 +/- 9.8 years; 60% male, 13% persistent AF) vs. nMARQTM (n = 82, age 63.2 +/- 10.6 years; 67% male, 24% persistent AF). Procedure and radiation times were 94 +/- 27 and 33 +/- 13 min for PVAC((r)) and 81 +/- 18 and 30 +/- 8.5 for nMARQTM (P = 0.0008 and P = 0.18), respectively. The number of applications and the total burning time (min) were 20 +/- 7 and 19 +/- 6.7 for PVAC((r)) and 16 +/- 5.6 and 11 +/- 4 for nMARQTM (P < 0.0001 for both), respectively. In two nMARQTM patients with small atria and pulmonary veins (PVs) and in two PVAC((r)) patients with large PVs, the procedure failed; switching to the alternative technology was successful. Acute success rate was 97% for PVAC((r)) and 95% for nMARQTM. There was one tamponade in nMARQTM group and non-significant different minor complications for both techniques. One-year freedom from AF was 79 and 80.7% with PVAC((r)) vs. nMARQTM, after one PVI, and 88 vs. 87.7% after two PVIs. CONCLUSION: Both technologies have short procedure and fluoroscopy times, comparable complication rates, and comparable acute and 1-year success rates. The number of applications and total procedure and burning times were shorter with nMARQTM. nMARQTM was more suitable for larger atria and PVs. Thus, a patient-based pre-ablation anatomy definition is probably warranted for appropriate selection of technology type. PMID- 26589624 TI - The value of the 12-lead electrocardiogram in localizing the scar in non ischaemic cardiomyopathy. AB - AIMS: Patients with non-ischaemic cardiomyopathy (NICM) and ventricular tachycardia can be categorized as anteroseptal (AS) or inferolateral (IL) scar sub-types based on imaging and voltage mapping studies. The aim of this study was to correlate the baseline electrocardiogram (ECG) with endo-epicardial voltage maps created during ablation procedures and identify the ECG characteristics that may help to distinguish the scar as AS or IL. METHODS AND RESULTS: We assessed 108 baseline ECGs; 72 patients fulfilled criteria for dilated cardiomyopathy whereas 36 showed minimal structural abnormalities. Based on the unipolar low voltage distribution, the scar pattern was classified as predominantly AS (n = 59) or IL (n = 49). Three ECG criteria (PR interval < 170 ms or QRS voltage in inferior leads <0.6 mV or a lateral q wave) resulted in 92% sensitivity and 90% specificity for predicting an IL pattern in patients with preserved ejection fraction (EF). The four-step algorithm for dilated cardiomyopathy included a paced ventricular rhythm or PR > 230 ms or QRS > 170 ms or an r <= 0.3 mV in V3 having 92 and 81% of sensitivity and specificity, respectively, in predicting AS scar pattern. A significant negative correlation was found between the extension of the endocardial unipolar low voltage area and left ventricular EF (rs = 0.719, P < 0.001). The extent of endocardial AS unipolar low voltage was correlated with PR interval and QRS duration (rs = 0.583 and rs = 0.680, P < 0.001, respectively) and the IL epicardial unipolar low voltage with the mean voltage of the limb leads (rs = -0.639, P < 0.001). CONCLUSION: Baseline ECG features are well correlated with the distribution of unipolar voltage abnormalities in NICM and may help to predict the location of scar in this population. PMID- 26589625 TI - Peripheral arterial disease is associated with an increased risk of atrial fibrillation in the elderly. AB - AIMS: To examine the relationship between peripheral arterial disease (PAD) and atrial fibrillation (AF) in a population-based cohort study of older adults. METHODS AND RESULTS: We examined the relationship between PAD and AF in 5143 participants (85% white, 43% male) in the Cardiovascular Health Study (CHS), a longitudinal, observational study of adults aged 65 years and older. Peripheral arterial disease was defined by abnormal ankle-brachial index (ABI) values (<1.0 or >1.4). Incident AF events were ascertained by self-reported history, study electrocardiograms, and hospitalization discharge records. Cox regression was used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between PAD and AF. Over a median follow-up of 11.7 years, a total of 1521 participants developed AF. The incidence rate (per 1000 person-years) of AF was higher in those with PAD (incidence rate = 32.9, 95% CI = 29.5, 36.7) than those without PAD (incidence rate = 23.3, 95% CI = 22.0, 24.6). In a multivariate Cox regression analysis, PAD was associated with an increased risk for AF (HR = 1.52, 95% CI = 1.34, 1.72). Each 0.1 decrease in the ABI was associated with a 6% increase in the risk for AF (HR = 1.06, 95% CI = 1.02, 1.10). The associations of high (>1.4) and low (<1.0) ABI values with AF were examined separately and were in the same direction as the main result for PAD (ABI < 1.0: HR = 1.24, 95% CI = 1.08, 1.42; ABI > 1.4: HR = 1.33, 95% CI = 0.95, 1.86). CONCLUSION: The presence of PAD should alert practitioners to the increased risk of AF. Elderly patients with PAD possibly will benefit from routine electrocardiographic screening to identify AF events. PMID- 26589626 TI - The elusive rotor electrogram footprint. PMID- 26589627 TI - Evaluation of a new very low dose imaging protocol: feasibility and impact on X ray dose levels in electrophysiology procedures. AB - AIMS: This study presents and evaluates the impact of a new lowest-dose fluoroscopy protocol (Siemens AG), especially designed for electrophysiology (EP) procedures, on X-ray dose levels. METHODS AND RESULTS: From October 2014 to March 2015, 140 patients underwent an EP study on an Artis zee angiography system. The standard low-dose protocol was operated at 23 nGy (fluoroscopy) and at 120 nGy (cine-loop), the new lowest-dose protocol was operated at 8 nGy (fluoroscopy) and at 36 nGy (cine-loop). Procedural data, X-ray times, and doses were analysed in 100 complex left atrial and in 40 standard EP procedures. The resulting dose-area products were 877.9 +/- 624.7 uGym2 (n = 50 complex procedures, standard low dose), 199 +/- 159.6 uGym2 (n = 50 complex procedures, lowest dose), 387.7 +/- 36.0 uGym2 (n = 20 standard procedures, standard low dose), and 90.7 +/- 62.3 uGym2 (n = 20 standard procedures, lowest dose), P < 0.01. In the low-dose and lowest-dose groups, procedure times were 132.6 +/- 35.7 vs. 126.7 +/- 34.7 min (P = 0.40, complex procedures) and 72.3 +/- 20.9 vs. 85.2 +/- 44.1 min (P = 0.24, standard procedures), radiofrequency (RF) times were 53.8 +/- 26.1 vs. 50.4 +/- 29.4 min (P = 0.54, complex procedures) and 10.1 +/- 9.9 vs. 12.2 +/- 14.7 min (P = 0.60, standard procedures). One complication occurred in the standard low-dose and lowest-dose groups (P = 1.0). CONCLUSION: The new lowest-dose imaging protocol reduces X-ray dose levels by 77% compared with the currently available standard low-dose protocol. From an operator standpoint, lowest X-ray dose levels create a different, reduced image quality. The new image quality did not significantly affect procedure or RF times and did not result in higher complication rates. Regarding radiological protection, operating at lowest-dose settings should become standard in EP procedures. PMID- 26589628 TI - Artificial Pancreas Device Systems for the Closed-Loop Control of Type 1 Diabetes: What Systems Are in Development? AB - BACKGROUND: Closed-loop artificial pancreas device (APD) systems are externally worn medical devices that are being developed to enable people with type 1 diabetes to regulate their blood glucose levels in a more automated way. The innovative concept of this emerging technology is that hands-free, continuous, glycemic control can be achieved by using digital communication technology and advanced computer algorithms. METHODS: A horizon scanning review of this field was conducted using online sources of intelligence to identify systems in development. The systems were classified into subtypes according to their level of automation, the hormonal and glycemic control approaches used, and their research setting. RESULTS: Eighteen closed-loop APD systems were identified. All were being tested in clinical trials prior to potential commercialization. Six were being studied in the home setting, 5 in outpatient settings, and 7 in inpatient settings. It is estimated that 2 systems may become commercially available in the EU by the end of 2016, 1 during 2017, and 2 more in 2018. CONCLUSIONS: There are around 18 closed-loop APD systems progressing through early stages of clinical development. Only a few of these are currently in phase 3 trials and in settings that replicate real life. PMID- 26589629 TI - Testing for latent tuberculosis infection using interferon gamma release assays in commercial sex workers at an outreach clinic in Birmingham. AB - This report demonstrates that using interferon gamma release assays to screen for latent tuberculosis infection in female commercial sex workers in an outreach sexual health clinic is feasible and acceptable. Routine interferon gamma release assay use successfully identified high numbers of latent tuberculosis infection. Innovative approaches to treatment and follow up were required to improve treatment adherence in this group. Direct observation of therapy within the sexual health clinic was also feasible. Successful follow up was dependent on the support of outreach workers, interpreters and tuberculosis nurses. PMID- 26589630 TI - Establishment of reference intervals for aldosterone and renin in a Caucasian population using the newly developed Immunodiagnostic Systems specialty immunoassay automated system. AB - BACKGROUND: Measurement of aldosterone and/or renin is essential to aid the differential diagnosis of secondary hypertension, guide strategy for therapeutic management of hypertension and assess adequacy of mineralocorticoid replacement. AIM: The objective was to establish normative data for aldosterone and renin using the Immunodiagnostic Systems specialty immunoassay system platform in a Caucasian population. METHODS: Following informed consent, 365 subjects were recruited to this study. Subjects were ambulatory and attended clinic for blood pressure measurement and phlebotomy between the hours of 7:00 and 11:00. Blood pressure was measured according to the 2013 European Society of Hypertension/Cardiology guidelines. The inclusion criteria: age >=18 years, BMI <30 kg/m(2), non-pregnant, blood pressure <140/90, normal electrolytes and kidney function and not taking prescribed/over the counter medications. Ninety-four subjects were excluded based on these criteria. A total of 271 volunteers (females n = 145), aged 18-65 years formed the reference cohort. Blood for aldosterone/renin was collected into ethylenediaminetetraacetic acid specimen tubes. Samples were kept at room temperature and transported within 30 min of blood draw to the laboratory for immediate processing (centrifugation, separation and freezing of plasma). Plasma was stored at -20C prior to analysis on the Immunodiagnostic Systems specialty immunoassay system instrument. RESULTS: The established reference intervals in an Irish Caucasian population for renin: females: 6.1-62.7 mIU/L, males: 9.0-103 mIU/L, for aldosterone: females: <138 1179 pmol/L, males: <138-670 pmol/L, respectively. CONCLUSION: This study demonstrates that reference intervals for aldosterone and renin should be gender specific. These automated immunoassays offer rapid stratification of patients with refractory hypertension and will better facilitate the optimization of therapeutic management. PMID- 26589631 TI - A direct assay for the routine measurement of testosterone, androstenedione, dihydrotestosterone and dehydroepiandrosterone by liquid chromatography tandem mass spectrometry. AB - BACKGROUND: The measurement of androgens in many laboratories is often limited to testosterone. To more accurately determine the androgen status in both sexes, the measurement of other androgens such as dihydrotestosterone, the more potent metabolite of testosterone, and androstenendione and dehydroepiandrosterone, the most abundant circulating androgens in women would be informative. We report a combined liquid chromatography tandem mass spectrometry method for the measurement of these androgens. METHODS: Internal standards in methanol (10 uL) were added to 100 uL serum followed by the addition of zinc sulphate (100 uL). After mixing, 100 uL of acetonitrile was added and was further mixed. The samples were centrifuged and the steroids extracted using an automated online solid phase extraction on a C18 cartridge by a Waters Acquity with online sample manager coupled to a TQS mass spectrometer. RESULTS: Separation of the androgens was achieved by liquid chromatography. The run time was 6.5 min per sample. The lower limit of quantitation was 0.1 nmol/L for testosterone, androstenedione and dihydrotestosterone and 1 nmol/L for dehydroepiandrosterone. The coefficient of variation of the assay in serum for testosterone was <6%, androstenedione <8% and dihydrotestosterone and dehydroepiandrosterone <10%. DISCUSSION: We have developed a rapid assay for the liquid chromatography tandem mass spectrometry measurement of testosterone, androstenedione, dihydrotestosterone and dehydroepiandrosterone in a routine clinical laboratory. The assay requires a small volume of serum, and all analytes are measured simultaneously. The assay is rapid and simple to execute offering the potential for routine clinical application. PMID- 26589633 TI - Injection frequency of botulinum toxin A for spastic equinus: a randomized clinical trial. AB - AIM: We compared two botulinum toxin A (BoNT-A) injection frequency regimens, 12 monthly versus 4-monthly, for spastic equinus in a randomized clinical trial. The primary outcome measure was passive ankle dorsiflexion. METHOD: Forty-two ambulant children with spastic equinus, secondary to cerebral palsy (23 males and 19 females; mean age 3y 6mo, SD 13mo; GMFCS levels I [n=20], II [n=19], III [n=3]) were randomized to receive either 12-monthly or 4-monthly BoNT-A injections to the calf, over a 26-month period. Twenty-one children had spastic hemiplegia, 21 children had spastic diplegia. A fixed 6U/kg dose of Botox was injected into the gastrocnemius muscle of both limbs in children with diplegia and the gastrocsoleus of the affected limb in children with hemiplegia, under mask anaesthesia. RESULTS: Forty-two children entered the trial with 21 participants randomized to each group. There were three withdrawals and two children received serial casting midway through the trial. There was no significant difference in passive dorsiflexion between 12-monthly and 4-monthly regimens (p=0.41). There were also no significant between group differences on secondary outcome measures. There were no serious adverse events - the rate was 1.2 adverse events per child per year in the 12-monthly group and 2.2 adverse events per child per year in the 4-monthly group. Subgroup analysis revealed a significant difference in passive dorsiflexion between children with hemiplegia and diplegia (p=0.01). INTERPRETATION: There was no significant difference between 12-monthly and 4-monthly injection regimens on passive dorsiflexion or secondary outcome measures. BoNT-A injections for spastic equinus may be recommended on a 12-monthly basis. PMID- 26589634 TI - Cloning, expression and characterization of Ostrinia furnacalis serpin1, a regulator of the prophenoloxidase activation system. AB - Serine protease inhibitors of the serpin superfamily are regulators of proteases involved in a variety of physiological processes including immune responses. In this study, we have isolated a full-length serpin cDNA from Ostrinia furnacalis. The 1188 bp open reading frame encodes a 395-residue protein with a theoretical molecular mass of 43.3 kDa and an isoelectric point of 4.92. Ofserpin1 contains a putative signal peptide followed by a conserved domain including a reactive center loop (RCL) with a hinge region (E(344) to S(353)) and a predicted P1-P1' cleavage site (Leu(360)-Ser(361)). Ofserpin1 mRNA and protein were detected in all the tested tissues, particularly in hemocytes and integument. The recombinant protein inhibited chymotrypsin and trypsin in a dose-dependent manner, and were significantly cleaved by the enzyme trypsin and chymotrypsin. Ofserpin1 impeded the prophenoloxidase activation cascade by 45.6% at 16.5 MUg, and affected activity of prophenoloxidase activating protease. Levels of Ofserpin1 transcripts in the integument were higher than those in hemocytes, fat body and midgut. After an immune challenge with Staphylococcus aureus and Escherichia coli, the relative mRNA levels of Ofserpin1 decreased in 2-10h post-infection (hpi) in integument and hemocytes compared to the untreated control. Our results suggested that Ofserpin1 has serine protease inhibitory activity and is likely involved in the regulation of prophenoloxidase activation system in O. furnacalis. PMID- 26589632 TI - Short linear motifs - ex nihilo evolution of protein regulation. AB - Short sequence motifs are ubiquitous across the three major types of biomolecules: hundreds of classes and thousands of instances of DNA regulatory elements, RNA motifs and protein short linear motifs (SLiMs) have been characterised. The increase in complexity of transcriptional, post transcriptional and post-translational regulation in higher Eukaryotes has coincided with a significant expansion of motif use. But how did the eukaryotic cell acquire such a vast repertoire of motifs? In this review, we curate the available literature on protein motif evolution and discuss the evidence that suggests SLiMs can be acquired by mutations, insertions and deletions in disordered regions. We propose a mechanism of ex nihilo SLiM evolution - the evolution of a novel SLiM from "nothing" - adding a functional module to a previously non-functional region of protein sequence. In our model, hundreds of motif-binding domains in higher eukaryotic proteins connect simple motif specificities with useful functions to create a large functional motif space. Accessible peptides that match the specificity of these motif-binding domains are continuously created and destroyed by mutations in rapidly evolving disordered regions, creating a dynamic supply of new interactions that may have advantageous phenotypic novelty. This provides a reservoir of diversity to modify existing interaction networks. Evolutionary pressures will act on these motifs to retain beneficial instances. However, most will be lost on an evolutionary timescale as negative selection and genetic drift act on deleterious and neutral motifs respectively. In light of the parallels between the presented model and the evolution of motifs in the regulatory segments of genes and (pre-)mRNAs, we suggest our understanding of regulatory networks would benefit from the creation of a shared model describing the evolution of transcriptional, post transcriptional and post-translational regulation. PMID- 26589635 TI - Brassica database (BRAD) version 2.0: integrating and mining Brassicaceae species genomic resources. AB - The Brassica database (BRAD) was built initially to assist users apply Brassica rapa and Arabidopsis thaliana genomic data efficiently to their research. However, many Brassicaceae genomes have been sequenced and released after its construction. These genomes are rich resources for comparative genomics, gene annotation and functional evolutionary studies of Brassica crops. Therefore, we have updated BRAD to version 2.0 (V2.0). In BRAD V2.0, 11 more Brassicaceae genomes have been integrated into the database, namely those of Arabidopsis lyrata, Aethionema arabicum, Brassica oleracea, Brassica napus, Camelina sativa, Capsella rubella, Leavenworthia alabamica, Sisymbrium irio and three extremophiles Schrenkiella parvula, Thellungiella halophila and Thellungiella salsuginea. BRAD V2.0 provides plots of syntenic genomic fragments between pairs of Brassicaceae species, from the level of chromosomes to genomic blocks. The Generic Synteny Browser (GBrowse_syn), a module of the Genome Browser (GBrowse), is used to show syntenic relationships between multiple genomes. Search functions for retrieving syntenic and non-syntenic orthologs, as well as their annotation and sequences are also provided. Furthermore, genome and annotation information have been imported into GBrowse so that all functional elements can be visualized in one frame. We plan to continually update BRAD by integrating more Brassicaceae genomes into the database. Database URL: http://brassicadb.org/brad/. PMID- 26589637 TI - Percutaneous coronary intervention with the TandemHeartTM percutaneous left ventricular assist device support: Six years of experience and outcomes. AB - OBJECTIVES: Our study was designed to evaluate the outcomes of TandemHeartTM assistance during percutaneous coronary intervention, specifically in relationship to pre-procedural clinical and hemodynamic risk factors in patients ineligible for surgical revascularization. BACKGROUND: We have used the TandemHeartTM percutaneous left ventricular assist device during percutaneous coronary intervention (PCI) in patients for whom conventional PCI and aorto coronary bypass would pose substantial risk owing to comorbidities and/or clinical presentations. METHODS: We retrospectively analyzed data from 626 consecutive PCIs at the Texas Heart Institute from 2005 to 2011. Among these, 74 interventions were performed with TandemHeartTM support. Mortality and morbidity were analyzed in relationship to presentation status (elective, urgent, emergent, or emergent salvage), and then we recorded outcomes and survival rates over the course of six years. RESULTS: At 30 days after PCI, survival rates were 94%, 88%, 79%, and 55% in the elective, urgent, emergent, and emergent salvage groups, respectively. Survival rates at one year were at 75% in the elective, 64% in the urgent, 52% in the emergent, and 45% in the emergent salvage groups. Survival rates at 6 years were 68% in the elective, 53% in the urgent, 31% in the emergent, and 41% in the emergent salvage groups, respectively. In elective and urgent groups, successful weaning from mechanical support was possible in all patients. In the emergent and emergent salvage groups, successful weaning from mechanical support was possible in 84% and 55% of patients, respectively. CONCLUSIONS: TandemHeartTM assisted PCI is a viable option for revascularization in cases of profound cardiogenic shock or extremely risky intervention due to complex anatomy. (c) 2015 Wiley Periodicals, Inc. PMID- 26589636 TI - The effect of heterogeneous Transcription Start Sites (TSS) on the translatome: implications for the mammalian cellular phenotype. AB - BACKGROUND: The genetic program, as manifested as the cellular phenotype, is in large part dictated by the cell's protein composition. Since characterisation of the proteome remains technically laborious it is attractive to define the genetic expression profile using the transcriptome. However, the transcriptional landscape is complex and it is unclear as to what extent it reflects the ribosome associated mRNA population (the translatome). This is particularly pertinent for genes using multiple transcriptional start sites (TSS) generating mRNAs with heterogeneous 5' transcript leaders (5'TL). Furthermore, the relative abundance of the TSS gene variants is frequently cell-type specific. Indeed, promoter switches have been reported in pathologies such as cancer. The consequences of this 5'TL heterogeneity within the transcriptome for the translatome remain unresolved. This is not a moot point because the 5'TL plays a key role in regulating mRNA recruitment onto polysomes. RESULTS: In this article, we have characterised both the transcriptome and translatome of the MCF7 (tumoural) and MCF10A (non-tumoural) cell lines. We identified ~550 genes exhibiting differential translation efficiency (TE). In itself, this is maybe not surprising. However, by focusing on genes exhibiting TSS heterogeneity we observed distinct differential promoter usage patterns in both the transcriptome and translatome. Only a minor fraction of these genes belonged to those exhibiting differential TE. Nonetheless, reporter assays demonstrated that the TSS variants impacted on the translational readout both quantitatively (the overall amount of protein expressed) and qualitatively (the nature of the proteins expressed). CONCLUSIONS: The results point to considerable and distinct cell-specific 5'TL heterogeneity within both the transcriptome and translatome of the two cell lines analysed. This observation is in-line with the ribosome filter hypothesis which posits that the ribosomal machine can selectively filter information from within the transcriptome. As such it cautions against the simple extrapolation transcriptome -> proteome. Furthermore, polysomal occupancy of specific gene 5'TL variants may also serve as novel disease biomarkers. PMID- 26589638 TI - Measuring Use of Health-Related Support on the Internet: Development of the Health Online Support Questionnaire (HOSQ). AB - BACKGROUND: Social support plays an important role for the perceived health in people with health problems and chronic diseases. Provision of different kinds of support during the disease trajectory is crucial for many people. Online support is ubiquitous and represents a promising modality for people with chronic diseases. There are no existing instruments that measure various aspects of online support. OBJECTIVE: The objective of this study was to create a generic questionnaire regarding health-related support online that can be applied to people with various health problems and illnesses. Additionally, we wanted to test the questionnaire in a cancer population to assess its adequacy in the context of severe disease. METHODS: Initial items for the Health Online Support Questionnaire (HOSQ) were inspired by sociologist James House regarding social support. An exploratory factor analysis was conducted in healthy persons or with minor health problems (n=243) on 31 initial items. The scale was reduced to 18 items and the internal consistency and reliability of the scale was examined along with content validity. Further validation was conducted by a confirmatory analysis on the 18-item scale in a cancer population (n=215). In addition, data on demographics, health problems experienced, and Internet use were collected. RESULTS: The exploratory factor analysis on the final 18-item scale resulted in 2 factors. After scrutinizing the content, these factors were labeled "reading" and "interacting" and they demonstrated good internal consistency (Cronbach alphas .88 and .77, respectively). The factors were confirmed in the cancer population. The response pattern revealed expected differences both between the interaction and reading scales and according to age, gender, education, and health problems thereby supporting the validity of the HOSQ. CONCLUSIONS: The HOSQ may be a reliable and valid instrument for measuring the use of online support for people with health problems, but the results ought to be replicated in more studies to confirm the results for different diagnoses. If the results of this study are corroborated by future studies, the HOSQ may be used as a basis for the development of different forms of support on the Internet. PMID- 26589639 TI - Towards adaptive management of the natural capital: Disentangling trade-offs among marine activities and seagrass meadows. AB - This paper investigates the ecological, social and institutional dimensions of the synergies and trade-offs between seagrasses and human activities operating in the Natura 2000 protected site of San Simon Bay (Galicia, NW Spain). By means of a multidisciplinary approach that brings together the development of a biological inventory combined with participatory mapping processes we get key spatial and contextual understanding regarding how, where and why marine users interact with seagrasses and how seagrasses are considered in policy making. The results highlight the fisheries' reliance on seagrass meadows and the controversial links with shellfisheries. The study also reveals unresolved conflicts among those management plans that promote the protection of natural values and those responsible for the exploitation of marine resources. We conclude that the adoption of pre-planning bottom-up participatory processes is crucial for the design of realistic strategies where both seagrasses and human activities were considered as a couple system. PMID- 26589640 TI - Heavy metals in red crabs, Chaceon quinquedens, from the Gulf of Mexico. AB - The red crab, Chaceon quinquedens, is distributed in deep waters of the Gulf of Mexico (GOM) and is most abundant in an area associated with sediment deposition from the Mississippi River. Sediment geochemistry and biological and ecological traits of red crabs favor accumulation of contaminants. Red crabs, sediment, and bottom water samples were taken from three distinct geographic locations representing areas with differing exposure to contaminant laden effluents from the Mississippi River. Inductively coupled plasma spectrophotometry and atomic absorption spectrophotometry were employed to determine levels of heavy metals in red crab muscle tissue. Ion site partitioning was used to determine metal speciation in sediments. Red crabs showed evidence of heavy metal bioaccumulation in all sample areas with high variability in contaminant levels in individual crabs for some metals. Bioavailability of metals in sediment did not always result in accumulation in muscle tissue. PMID- 26589641 TI - Efficient dispersion of crude oil by blends of food-grade surfactants: Toward greener oil-spill treatments. AB - Effectiveness of oil spill dispersants containing lecithin/Tween 80 (L/T) blends in ethanol was measured as a function of L:T ratio, surfactant:solvent ratio, solvent composition, and dispersant:oil ratio (DOR) using baffled flask dispersion effectiveness tests. Optimal L:T ratios are between 60:40 and 80:20 (w/w); at higher L:T ratios, effectiveness is limited by high interfacial tension, while at lower L:T ratios, insufficient lecithin is present to form a well-packed monolayer at an oil-water interface. These optimal L:T ratios retain high effectiveness at low DOR: 80:20 (w/w) L:T dispersant is 89% effective at 1:25 DOR (v/v) and 77% effective at 1:100 DOR (v/v). Increasing surfactant:solvent ratio increases dispersant effectiveness even when DOR is proportionally reduced to keep total surfactant concentration dosed into the oil constant. Replacing some of the ethanol with octane or octanol also increases dispersant effectiveness, suggesting that ethanol's hydrophilicity lowers dispersant-oil miscibility, and that more hydrophobic solvents would increase effectiveness. PMID- 26589643 TI - In vivo assessment of tumour angiogenesis in colorectal cancer: the role of confocal laser endomicroscopy. AB - AIM: Tumour neoangiogenesis is a key factor in tumour progression and metastatic spread and the possibility to assess tumour angiogenesis might provide prognostic information. The aim of this study was to establish the role of probe-based confocal laser endomicroscopy (p-CLE) in the identification of vascular architecture and specific morphological patterns in normal colorectal mucosa and malignant lesions during routine endoscopy. METHOD: Fourteen consecutive patients with colorectal cancer were included. The following features were identified and then compared between normal and neoplastic mucosa on p-CLE images: vessel shape (straight vs irregular) vessel diameter the 'branching patterns' vessel permeability (fluorescein leakage) and blood flow (normal vs defective flux). Immunohistochemistry was used to confirm the presence and to study the morphology of vascular structures (CD-34 staining) and 'neo-vessels' (WT-1 staining) on tumour and normal mucosal sections. RESULTS: Tumour vessels appeared as irregular, ectatic and with a highly variable calibre and branching patterns on p CLE images. The mean diameter of tumour vessels was significantly larger than those in normal mucosa (weighted mean difference 3.38, 95% CI 2.65-4.11, P = 0.01). Similarly, 'vessel branching' (OR 2.74, 95% CI 1.23-6.14, P = 0.01), fluorescent dye 'extravasation' (OR 3.46, 95% CI 1.39-8.57, P = 0.01) were significantly more frequent in colorectal cancer than in normal colorectal mucosa. Immunohistochemistry corroborated the p-CLE findings, showing higher vascularity in tumour sections due to neoformed vessels, presenting irregular patterns. CONCLUSION: Probe-based confocal laser endomicroscopy provides a noninvasive characterization of the microvascular architecture of colonic mucosa. Different morphological patterns have been described, discriminating normal and malignant microvascular networks in colorectal mucosa. PMID- 26589644 TI - Diagnostic Performance of the Extensor Carpi Ulnaris (ECU) Synergy Test to Detect Sonographic ECU Abnormalities in Chronic Dorsal Ulnar-Sided Wrist Pain. AB - OBJECTIVES: The extensor carpi ulnaris (ECU) tendon synergy test is a simple and unique diagnostic maneuver for evaluation of chronic dorsal ulnar-sided wrist pain, which applies isolated tension to the ECU without greatly stressing other structures. This study aimed to investigate the diagnostic performance of the ECU synergy test to detect ECU abnormalities on sonography. METHODS: Forty affected wrists from 39 consecutive patients with chronic dorsal ulnar-sided wrist pain that continued for greater than 1 month were examined with the ECU synergy test and sonography. The sensitivity, specificity, positive predictive value, and negative predictive value of the ECU synergy test to detect ECU abnormalities were evaluated. We compared the results of the ECU synergy test between groups with and without ECU abnormalities and also compared the ages, sexes, and symptomatic durations of the patients between groups with positive and negative ECU synergy test results and between the groups with and without ECU abnormalities. RESULTS: The sensitivity, specificity, positive predictive value, and negative predictive value were 73.7%, 85.7%, 82.4%, and 78.3%, respectively. There was significant difference in the ECU synergy test results between the groups with and without ECU abnormalities (P < .01). There was no significant difference in age, sex, or symptomatic duration between any of the groups. CONCLUSIONS: The results of this prospective study support the hypothesis that the ECU synergy test could be a useful provocative maneuver to detect ECU abnormalities in patients with chronic dorsal ulnar-sided wrist pain. PMID- 26589642 TI - Targeting glutamate homeostasis for potential treatment of nicotine dependence. AB - Several studies demonstrated that impairment in glutamatergic neurotransmission is linked to drug dependence and drug-seeking behavior. Increased extracellular glutamate concentration in mesocorticolimbic regions has been observed in animals developing nicotine dependence. Changes in glutamate release might be associated with stimulatory effect of nicotinic acetylcholine receptors (nAChRs) via nicotine exposure. We and others have shown increased extracellular glutamate concentration, which was associated with down regulation of the major glutamate transporter, glutamate transporter 1 (GLT-1), in brain reward regions of animals exposed to drug abuse, including nicotine and ethanol. Importantly, studies from our laboratory and others showed that upregulation of GLT-1 expression in the mesocorticolimbic brain regions may have potential therapeutic effects in drug dependence. In this review article, we discussed the effect of antagonizing presynaptic nAChRs in glutamate release, the upregulatory effect in GLT-1 expression and the role of glutamate receptors antagonists in the treatment of nicotine dependence. PMID- 26589645 TI - Effect of Carpal Tunnel Syndrome on the Ulnar Nerve at the Wrist: Sonographic and Electrophysiologic Studies. AB - OBJECTIVES: The aim of this study was to compare the ulnar nerve at the wrist by sonographic and electrophysiologic studies between patients with carpal tunnel syndrome and control participants and to verify the effect of carpal tunnel syndrome of the ulnar nerve at the wrist. METHODS: Forty-two hands of patients with carpal tunnel syndrome and 37 hands of control participants were examined. Electrophysiologic studies of the ulnar nerve were done in all participants. The cross-sectional areas of the median and ulnar nerves at the wrist were evaluated by sonography. Fifteen hands of patients with carpal tunnel syndrome who underwent carpal tunnel release were also evaluated by sonography after the operation. RESULTS: The ulnar nerve cross-sectional area of the patients with carpal tunnel syndrome (mean +/- SD, 5.16 +/- 1.04 mm(2)) was significantly larger than that of the controls (3.56 +/- 0.52 mm(2); P < .0001). After release of the transverse carpal ligament, the cross-sectional area of the ulnar nerve was significantly smaller than the size measured prior to surgery (P < .0001). The cross-sectional area of the median nerve was significantly correlated with that of the ulnar nerve (P < .05). However, no statistically significant difference was found between the patients with carpal tunnel syndrome and controls in ulnar nerve conduction. There were no statistically significant differences in nerve conduction study results or cross-sectional area of the ulnar nerve between patients with carpal tunnel syndrome with and without extramedian symptoms. CONCLUSIONS: The cross-sectional areas of the ulnar and median nerves at the wrist are increased in patients with carpal tunnel syndrome. Also, the cross-sectional area of the ulnar nerve is decreased after carpal tunnel release. PMID- 26589646 TI - ACES: Accurate Cervical Evaluation With Sonography. AB - OBJECTIVES: Transvaginal sonographic cervical length screening is an important tool for the evaluation of preterm labor. However, a structured curriculum is lacking in obstetrics and gynecology residency programs. The Accurate Cervical Evaluation with Sonography (ACES) program was developed to address this deficiency and combines an online didactic course with a standardized performance assessment of live scans. We sought to evaluate the effectiveness of the ACES program to teach residents sonographic cervical length assessment. METHODS: All obstetrics and gynecology residents at our institution were invited to participate from 2012 to 2013. The program consisted of an initial supervised transvaginal cervical evaluation, an online didactic course and written examination, and 5 subsequent supervised scans. The instructor performed an independent cervical length measurement at each encounter. The primary outcome was the difference in cervical length measurement between the resident and instructor. We hypothesized that this difference would decrease over time. At each visit, a 10-item checklist was used for skill assessment. Comparisons of checklist scores over time were also performed. RESULTS: Seventeen of 20 residents completed at least some of the training, and 10 completed the entire program. The median difference in cervical length measurement between residents and instructors at posttests 3, 4, and 5 improved significantly compared to the pretest scan (all P <= .02). Similarly, the checklist scores improved over time (all P <= .0008). CONCLUSIONS: Transvaginal cervical sonography is an important tool in the evaluation of preterm labor. The ACES program provides residents a structured curriculum for cervical evaluation and supervisors a standardized means of evaluating trainees' skills. PMID- 26589648 TI - Countdown to a Silver Jubilee for Heart, Lung and Circulation Journal in 2016 - Looking Back in Order to Move Forward. PMID- 26589647 TI - Substantia Nigra Hyperechogenicity: Validation of Transcranial Sonography for Parkinson Disease Diagnosis in a Large Estonian Cohort. AB - OBJECTIVES: Substantia nigra hyperechogenicity is a promising biomarker for Parkinson disease (PD). Substantia nigra hyperechogenicity has previously been established as a useful diagnostic criterion in several European and Asian patient cohorts. However, diagnostic cutoff values for substantia nigra hyperechogenicity remain unknown for most patient populations. This study validated the diagnostic accuracy of substantia nigra hyperechogenicity in a large cohort of patients with PD in Estonia. METHODS: The study included 300 patients with PD from Estonia, representing 10% of the national PD patient population, and 200 healthy control participants. To define the optimal cutoff value in the PD cohort, data from a single assessment versus repetitive assessments by transcranial sonography were compared. With the use of 3 repetitive assessments, the diagnostic accuracy of the data was measured. In addition, calculations for percentile values were used to define substantia nigra hyperechogenicity among controls. RESULTS: Our data showed that the multiassessment approach yielded higher diagnostic accuracy than a single assessment (P = .021). The highest diagnostic accuracy was achieved by using the measurement mean to define substantia nigra hyperechogenicity, which was 0.23 cm(2) (sensitivity, 88.7%; specificity, 92.2%), whereas single measurements detected PD with higher sensitivity (sensitivity, 93.2%; specificity, 85.1%). No significant difference was found between mean and median measurements (P= .18). CONCLUSIONS: This study indicates the diagnostic merit of transcranial sonography in PD diagnosis in an additional population and demonstrates that transcranial sonography of the substantia nigra is a relevant and useful diagnostic tool for patients with PD. PMID- 26589649 TI - Reversible posterior leukoencephalopathy syndrome: A recurrent and atypical case in hemodialysis. PMID- 26589650 TI - The Role of Protein Modelling in Predicting the Disease Severity of Cystinuria. PMID- 26589651 TI - End user bag-mask ability and perceptions of two infant resuscitation mannequins. AB - AIM: To examine user ability and preference in performing bag-mask ventilation (BMV) with four different configurations of infant mannequins. METHODS: Participants provided a 30-second period of BMV to a Resusci Baby mannequin (RB), NeoNatalie mannequin (NN), NN filled with air (NNA), NN filled with water (NNW) and NN filled with 50% air and 50% water mix (NNAW). Participants rated the fidelity of each configuration. RESULTS: Of the 20 participants, 65% rated NNW as having a high level of fidelity (HLF) 'to hold' (50% for NNAW, 10% for RB and 0% for NNA) (p < 0.001). Half rated NNAW as having a HLF in 'tone' (40% for NNW, 20% for RB and 5% for NNA) (p = 0.008). About 45% of participants rated NNAW as having a HLF in 'appearance' (45% for the RB, 20% for NNA and 15% for NNW) (p = 0.035). About 35% of participants rated NNAW as having a HLF in how it 'felt to touch' (30% for NNW, 15% for RB and 10% for NNA) (p = 0.008). Half of participants rated NNAW as having a HLF in terms of 'weight' (45% for NNW, 40% for RB and 0% for NNA) (p = 0.003). Participants delivered the greatest number of effective ventilations to the NNW mannequin. CONCLUSION: The NNW and NNAW configurations had the highest fidelity and had the highest percentage of effective ventilations delivered. PMID- 26589652 TI - Differential Spatiotemporal Patterns of Galectin Expression are a Hallmark of Endotheliochorial Placentation. AB - PROBLEM: Galectins influence the progress of pregnancy by regulating key processes associated with embryo-maternal cross talk, including angiogenesis and placentation. Galectin family members exert multiple roles in the context of hemochorial and epitheliochorial placentation; however, the galectin prolife in endotheliochorial placenta remains to be investigated. METHOD OF STUDY: Here, we used immunohistochemistry to analyze galectin (gal)-1, gal-3 and gal-9 expression during early and late endotheliochorial placentation in two different species (dogs and cats). RESULTS: We found that during early feline gestation, all three galectin members were more strongly expressed on trophoblast and maternal vessels compared to the decidua. This was accompanied by an overall decrease of gal-1, gal-3 and gal-9 expressions in late feline gestation. In canine early pregnancy, we observed that gal-1 and gal-9 were expressed strongly in cytotrophoblast (CTB) cells compared to gal-3, and no galectin expression was observed in syncytiotrophoblast (STB) cells. Progression of canine gestation was accompanied by increased gal-1 and gal-3 expressions on STB cells, whereas gal-9 expression remained similar in CTB and STB. CONCLUSION: These data suggest that both the maternal and fetal compartments are characterized by a spatiotemporal regulation of galectin expression during endotheliochorial placentation. This strongly suggests the involvement of the galectin family in important developmental processes during gestation including immunemodulation, trophoblast invasion and angiogenesis. A conserved functional role for galectins during mammalian placental development emerges from these studies. PMID- 26589653 TI - Do infants perceive the social robot Keepon as a communicative partner? AB - This study investigates if infants perceive an unfamiliar agent, such as the robot Keepon, as a social agent after observing an interaction between the robot and a human adult. 23 infants, aged 9-17 month, were exposed, in a first phase, to either a contingent interaction between the active robot and an active human adult, or to an interaction between an active human adult and the non-active robot, followed by a second phase, in which infants were offered the opportunity to initiate a turn-taking interaction with Keepon. The measured variables were: (1) the number of social initiations the infant directed toward the robot, and (2) the number of anticipatory orientations of attention to the agent that follows in the conversation. The results indicate a significant higher level of initiations in the interactive robot condition compared to the non-active robot condition, while the difference between the frequencies of anticipations of turn taking behaviors was not significant. PMID- 26589654 TI - Costs of non-small cell lung cancer in the Netherlands. AB - OBJECTIVES: Real-world resource use and cost data on non-small cell lung cancer (NSCLC) are scarce. This data is needed to inform health-economic modelling to assess the impact of new diagnostic and/or treatment technologies. This study provides detailed insight into real-world medical resource use and costs of stage I-IV NSCLC in the Netherlands. MATERIALS AND METHODS: A random sample of patients newly diagnosed with NSCLC (2009-2011) was selected from four Dutch hospitals. Data was retrospectively collected from patient charts. This data included patient characteristics, tumour characteristics, treatment details, adverse events, survival and resource use. Resource use was multiplied by Dutch unit costs expressed in EUR 2012. Total mean costs were corrected for censoring using the Bang and Tsiatis weighted complete-case estimator. Furthermore, costs of adverse events, costs per phase of NSCLC management and costs of second opinions are presented. RESULTS: Data was collected on 1067 patients. Total mean costs for NSCLC diagnosis, treatment and follow-up are ?28,468 during the study period and ?33,143 when corrected for censoring. Adverse events were recorded in the patient charts for 369 patients (41%) and 82 patients (9%) experienced an adverse event of grade III or higher. For these patients, adverse event-related hospital admissions cost on average ?2,091. Mean total costs are ?1,725 for the diagnostic period, ?17,296 for first treatment line, and ?13,236 for each later treatment line. Costs of providing a second opinion are ?2,580 per patient. CONCLUSIONS: Total mean hospital costs per NSCLC patient are ?33,143 for the total duration of the disease. Ignoring censoring in our data underestimates these costs by 14%. Main limitations of the study relate to the short follow-up time, staging difficulties and missing data. Its main strength is that it provides highly detailed, real-world data on the costs of NSCLC. PMID- 26589655 TI - Communicating efficacy information based on composite scores in direct-to consumer prescription drug advertising. AB - OBJECTIVE: Drug efficacy can be measured by composite scores, which consist of two or more symptoms or other clinical components of a disease. We evaluated how individuals interpret composite scores in direct-to-consumer (DTC) prescription drug advertising. METHODS: We conducted an experimental study of seasonal allergy sufferers (n=1967) who viewed a fictitious print DTC ad that varied by the type of information featured (general indication, list of symptoms, or definition of composite scores) and the presence or absence of an educational intervention about composite scores. We measured composite score recognition and comprehension, and perceived drug efficacy and risk. RESULTS: Ads that featured either (1) the composite score definition alone or (2) the list of symptoms or general indication information along with the educational intervention improved composite score comprehension. Ads that included the composite score definition or the educational intervention led to lower confidence in the drug's benefits. The composite score definition improved composite score recognition and lowered drug risk perceptions. CONCLUSION: Adding composite score information to DTC print ads may improve individuals' comprehension of composite scores and affect their perceptions of the drug. PRACTICE IMPLICATIONS: Providing composite score information may lead to more informed patient-provider prescription drug decisions. PMID- 26589656 TI - Psychological distance modulates the performance of the embodiment effect: Evidence from behavioral and ERP studies. AB - Research on embodied cognition suggests the ubiquity of embodiment effects during interaction with the environment. However, construal level theory (CLT) holds that these effects could be moderated by the psychological distance between self and objects and are attenuated by higher-level mental construal. The current research explored the "action-evaluation" embodiment effect in the evaluation of words located at different spatial distances. Results showed that for "short distance" words, the response model conflicted with this embodiment effect slower reaction time and induced a larger P2 component than the opposite response model. However, evaluation of "long-distance" words was not significantly influenced by the response model. The results are consistent with CLT and suggest that the action-evaluation embodiment effect influences the coding and execution of evaluating actions, but only for stimuli at close psychological distance locations. PMID- 26589657 TI - Is the Saudi public aware of Middle East respiratory syndrome? AB - To limit the spread of Middle East respiratory syndrome coronavirus (MERS-CoV) in Saudi Arabia, the Ministry of Health tried to raise public awareness using different public campaigns. We aimed to measure public awareness of MERS in Saudi Arabia. A cross-sectional study was conducted between May and June 2014 using a newly designed Arabic questionnaire that was distributed and completed online. We analyzed the response of 1149 respondents across Saudi Arabia. We found that 97% of the participants were aware of MERS. In addition, 72% realized that coughing and sneezing could spread the infection. Furthermore, 83% thought that some patients with MERS could be cured. Moreover, 62% knew that no vaccine can prevent the disease. However, only 36% realized that taking antibiotics will not stop the infection, and only 41% recognized that no medication has yet been manufactured to treat it. Regarding protection measures, 74% used hand sanitizers, 43% avoided crowded places, and 11% wore masks in public places. Moreover, only 47% knew that bats and camels are the primary source of the virus. As anticipated, this level of awareness varied between the different categories of the studied population. Female, married, older, and more educated participants were significantly more knowledgeable about the disease. Public awareness of MERS is generally sufficient. However, some false beliefs about treatment were fairly common. In addition, almost half of the population remains unaware that bats and camels are the most likely sources of the virus. PMID- 26589658 TI - A cross-sectional study assessing the residual bio-efficacy and durability of field-distributed long-lasting insecticidal nets in malaria endemic ethnic communities of Assam, Northeast India. AB - Long-lasting insecticidal nets (LLINs) are being promoted for malaria vector control in the northeastern Indian state of Assam. A cross-sectional study was conducted to assess the current residual bio-efficacy and durability of both the Olyset((r)) and PermaNet((r))2.0 LLINs that were distributed earlier in 2009, 2011 and 2013 to help formulate informed policy regarding net procurement, supplies and replacement. The study was undertaken in three different malaria endemic blocks of Assam during the period of June to October of 2014. The residual bio-efficacies were ascertained using the WHO cone-bioassay method for mosquito mortality post-exposure and corroborated with the ring-net assay for the median knockdown times of both types of LLINs in use by these communities. Cross sectional community surveys were distributed to assess net ownership, utilization, community practices and the physical conditions of the nets in terms of being torn and the numbers of holes per position. Both the Olyset((r)) and PermaNet((r))2.0 LLINs that were distributed in 2009 (i.e., nearly after five years of community usage) were completely torn, worn out and obsolete. However, the LLINs distributed in 2011 (i.e., three years of community usage) retained their residual bio-efficacies in susceptibility ranges that varied from 57% to 79%. However, for the LLINs that were distributed in 2013, the observed residual efficacy was adequate and resulted in a mosquito mortality rate >80 percent. Of the two types of LLINs inspected, the Olyset((r))nets were more durable and robust in terms of being torn less frequently (37.1%, 39/105) compared with the PermaNet((r))2.0 nets (51.8%, 204/394). Regarding the LLINs that were distributed in 2013, all were physically intact and in good condition. The majority of the distributed LLINs (99.2%, 639/644) were still in the possession of the householders of the surveyed populations. This study revealed that the serviceable life of the nets was slightly less than three years in terms of waning residual bio-efficacy and durability that warranted replacement. The communities were aware of the benefits of the use of mosquito net for personal protection and regularly used the nets; thus, LLIN-based interventions for sustained vector control should be scaled up. PMID- 26589659 TI - Profile of the MP Diagnostics HTLV Blot 2.4 test: a supplemental assay for the confirmation and differentiation of antibodies to HTLV-1 and HTLV-2. AB - As the first US FDA-approved assay for supplemental HTLV testing, the MP Diagnostics HTLV Blot 2.4 is an effective and efficient method for confirming and differentiating HTLV type infection in repeatedly reactive samples. Novel and patented antigens added increased sensitivity in identifying specimens from infected individuals while differentiating those from uninfected individuals with false reactivity. PMID- 26589660 TI - The static electrocardiogram in clinically healthy, anesthetized, zoo-kept black tailed prairie dogs (Cynomys ludovicianus). AB - OBJECTIVES: The goal of this study was to evaluate the static electrocardiograms of clinically healthy black-tailed prairie dogs (Cynomys ludovicianus), and suggest normal values. ANIMALS: Thirteen clinically healthy black-tailed prairie dogs were included in the study. They were anesthetized for physical examination, and complete laboratory data including troponin I concentration, thoracic radiographs, echocardiograms, and static ECG were recorded. MATERIAL AND METHODS: Static electrocardiograms were recorded using standard, six-limb leads from each of the 13 apparently healthy prairie dogs. Each prairie dog was anesthetized with isoflurane via facemask. Electrocardiograms were recorded in right lateral recumbency. The data were retrospectively analyzed. Lead II was used for waveform analysis. RESULTS: The median heart rate was 250 bpm (range 147-320). Median P wave amplitude was 0.05 mV (range 0.01-0.06) and P-wave duration was 0.03 s (range 0.02-0.03). The PR interval was 0.06 s (range 0.04-0.06). The R-wave amplitude was 0.5 mV (range 0.1-1.15) and the QRS duration was 0.02 s (range 0.02 0.03). The QT interval was 0.12 s (range 0.1-0.14). Sixty-two percent of the QRS complexes were of Rs configuration. CONCLUSIONS: Static electrocardiograms can be performed and evaluated in anesthetized prairie dogs. This report provided normal values in clinically healthy black-tailed prairie dogs. PMID- 26589661 TI - [Intramedullary spinal cord metastasis from gastric adenocarcinoma: Case report and review of literature]. AB - Intramedullary spinal cord metastases are very rare and usually associated with lung or breast cancer, with gastric origin being exceptional. Their clinical onset tends to be faster than that of primary intramedullary tumours. The most common early symptoms of intramedullary spinal cord metastasis are motor deficit in one or more limbs, pain, sensory loss, and sphincter disturbances. The appearance of a rapidly progressive Brown-Sequard syndrome in an oncology patient should orientate the diagnosis of this condition. The prognosis is very poor, with a median survival of 4 months. However, recent research has shown that surgery could offer a slight benefit in survival and functionality. The case is reported of a 61-year-old man with an intramedullary spinal cord metastasis from a gastric carcinoma, as well as a literature review of this topic. It has been found that this case is the fourth one reported in the literature. PMID- 26589662 TI - [Traumatic intracranial aneurysm secondary to a bullet wound. Clinical case and a review of the literature]. AB - Traumatic intracranial aneurysms (AICT) are rare and are associated with high morbidity and mortality. AICT are the result of head injuries caused by accidents, explosions, and gunfire. The case is reported here of a 28 year old man who was admitted to our hospital after suffering a penetrating head injury caused by a bullet. Radiographic studies showed interhemispheric subarachnoid haemorrhage and a likely AICT image that initially went unnoticed. One week later he underwent a cerebral angiography which showed a bilateral vasospasm of the terminal portion of the internal carotid and the appearance of a 2mm fusiform AICT at the orbit-frontal branch of the anterior cerebral artery. This was surgically treated after an aneurismal growth of 3.4mm and failure of the endovascular treatment. The patient showed a favourable outcome after surgery. PMID- 26589663 TI - [Bilateral chronic subdural haematoma: Analysis of a series of 190 patients]. AB - OBJECTIVE: The aim of this study is to analyse the clinical findings and surgical results in a series of patients with bilateral chronic subdural haematoma (BCSDH), and compare the results with a series of patients treated for unilateral chronic subdural haematoma (UCSDH). PATIENTS AND METHODS: A retrospective study was performed on 1523 patients diagnosed and surgically treated for chronic subdural haematoma over a period of 30 years. Patients were divided into 2 groups: The study group consisting of 190 patients operated on for a BCSDH and the control group consisting of patients operated on for an UCSDH (1333 cases). RESULTS: The patient series included 126 males (66.3%) and 64 females (33.7%), with a mean age at diagnosis of 74.8+/-10.2. The control group consisted of 870 males (65.2%) and 463 women (34.8%), with a mean age of 73.2+/-12.1. The most common presenting symptoms was cognitive impairment in 63 patients (33.2%) with BCSDH and 416 (29.5%) with UCSDH. Recurrence rates were 9.4% (18 patients) and 5.7% (77 patients) in unilateral and bilateral haematomas, respectively. The mortality was 10 patients (5.2%) with BCSDH and 55(4%) with UCSDH. Factors significantly related to recurrence in the univariate analysis were being male (P=.040), anticoagulant/antiplatelet therapy (P=.032), and poor neurological status at admission (P=.039). CONCLUSIONS: This study indicates that BCSDH is more frequent in males, and the most common presentation is headache. The most important factors influencing recurrences are being male, intake of anticoagulant antiaggregant drugs, and worse clinical status at admission. PMID- 26589664 TI - [The complications of brain biopsies]. PMID- 26589665 TI - [Brain biopsy is not minor surgery]. PMID- 26589666 TI - Danionella dracula, an escape from the cypriniform Bauplan via developmental truncation? AB - We provide a detailed account of the osteology of the miniature Asian freshwater cyprinid fish Danionella dracula. The skeleton of D. dracula shows a high degree of developmental truncation when compared to most other cyprinids, including its close relative the zebrafish Danio rerio. Sixty-one bones, parts thereof or cartilages present in most other cyprinids are missing in D. dracula. This impressive organism-wide case of progenesis renders it one of the most developmentally truncated bony fishes or even vertebrates. Danionella dracula lacks six of the eight unique synapomorphies that define the order Cypriniformes and has, thus, departed from the cypriniform Bauplan more dramatically than any other member of this group. This escape from one of the most successful Bauplane among bony fishes may have been facilitated by the organism-wide progenesis encountered in D. dracula. By returning in its skeletal structure to the early developmental condition of other cypriniforms, D. dracula may have managed to overcome the evolutionary constraints associated with this Bauplan and opened up new evolutionary avenues that enabled it to evolve a number of striking morphological novelties, including its tooth-like odontoid processes and a complex drumming apparatus. PMID- 26589667 TI - The Special Topics Section of Alzheimer's & Dementia. PMID- 26589668 TI - Dense motion field estimation from myocardial boundary displacements. AB - Minimally invasive cardiovascular interventions guided by multiple imaging modalities are rapidly gaining clinical acceptance for the treatment of several cardiovascular diseases. These images are typically fused with richly detailed pre-operative scans through registration techniques, enhancing the intra operative clinical data and easing the image-guided procedures. Nonetheless, rigid models have been used to align the different modalities, not taking into account the anatomical variations of the cardiac muscle throughout the cardiac cycle. In the current study, we present a novel strategy to compensate the beat to-beat physiological adaptation of the myocardium. Hereto, we intend to prove that a complete myocardial motion field can be quickly recovered from the displacement field at the myocardial boundaries, therefore being an efficient strategy to locally deform the cardiac muscle. We address this hypothesis by comparing three different strategies to recover a dense myocardial motion field from a sparse one, namely, a diffusion-based approach, thin-plate splines, and multiquadric radial basis functions. Two experimental setups were used to validate the proposed strategy. First, an in silico validation was carried out on synthetic motion fields obtained from two realistic simulated ultrasound sequences. Then, 45 mid-ventricular 2D sequences of cine magnetic resonance imaging were processed to further evaluate the different approaches. The results showed that accurate boundary tracking combined with dense myocardial recovery via interpolation/diffusion is a potentially viable solution to speed up dense myocardial motion field estimation and, consequently, to deform/compensate the myocardial wall throughout the cardiac cycle. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26589669 TI - Characterization of thrombopoietin kinetics within 60 days after allogeneic hematopoietic stem cell transplantation and its correlation with megakaryocyte ploidy distribution. AB - Thrombopoietin (TPO) has been identified as a key cytokine for both megakaryogenesis and thrombopoiesis. We attempt to characterize the kinetics of TPO and its correlation with megakaryocytes (MKs) ploidy distribution pattern within 60 d after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Forty-six consecutive patients undergoing allo-HSCT from October 2008 to December 2008 were included. TPO levels and ploidy distribution patterns of MKs were measured using ELISA and flow cytometric analysis, respectively. The results indicated that TPO levels and the platelet count followed opposite trends after allo-HSCT. The preconditioning TPO levels and the number of transplanted CD34(+) cells were significant predisposing factors for rapid platelet engraftment (p = 0.010 and 0.007, respectively) by multivariate analysis. There was a reduction of ploidy and an increase in immature MKs in patients with higher endogenous TPO levels (>250 pg/mL) on day 60 after allo-HSCT. Moreover, lower TPO levels (<=250 pg/mL) on day 60 after allo-HSCT were associated with significantly improved five yr overall survival (p = 0.021) and reduced transplant-related mortality (p = 0.033). In conclusion, endogenous TPO levels may be associated with platelet recovery and have prognostic significance during allo-HSCT. PMID- 26589671 TI - Factors associated with playing football after anterior cruciate ligament reconstruction in female football players. AB - This study investigated whether player-related factors (demographic, personality, or psychological factors) or the characteristics of the anterior cruciate ligament (ACL) injury were associated with the return to playing football in females after ACL reconstruction (ACLR). We also compared current knee function, knee related quality of life and readiness to return to sport between females who returned to football and those who had not returned. Females who sustained a primary ACL rupture while playing football and underwent ACLR 6-36 months ago were eligible. Of the 460 contacted, 274 (60%) completed a battery of questionnaires, and 182 were included a median of 18 months (IQR 13) after ACLR. Of these, 94 (52%) returned to football and were currently playing, and 88 (48%) had not returned. Multiple logistic regression analysis identified two factors associated with returning to football: short time between injury and ACLR (0-3 months, OR 5.6; 3-12 months OR 4.7 vs reference group > 12 months) and high motivation. Current players showed higher ratings for current knee function, knee related quality of life, and psychological readiness to return to sport (P < 0.001). Undergoing ACLR sooner after injury and high motivation to return to sports may impact a player's return to football after ACLR. PMID- 26589670 TI - HVR1-mediated antibody evasion of highly infectious in vivo adapted HCV in humanised mice. AB - OBJECTIVE: HCV is a major cause of chronic liver disease worldwide, but the role of neutralising antibodies (nAbs) in its natural history remains poorly defined. We analysed the in vivo role of hypervariable region 1 (HVR1) for HCV virion properties, including nAb susceptibility. DESIGN: Analysis of HCV from human liver chimeric mice infected with cell-culture-derived prototype genotype 2a recombinant J6/JFH1 or HVR1-deleted variant J6/JFH1DeltaHVR1 identified adaptive mutations, which were analysed by reverse genetics in Huh7.5 and CD81-deficient S29 cells. The increased in vivo genomic stability of the adapted viruses facilitated ex vivo density analysis by ultracentrifugation and in vivo neutralisation experiments addressing the role of HVR1. RESULTS: In vivo, J6/JFH1 and J6/JFH1DeltaHVR1 depended on single substitutions within amino acids 867-876 in non-structural protein, NS2. The identified A876P-substitution resulted in a 4.7-fold increase in genomic stability. In vitro, NS2 substitutions enhanced infectivity 5-10-fold by increasing virus assembly. Mouse-derived mJ6/JFH1A876P and mJ6/JFH1DeltaHVR1/A876P viruses displayed similar heterogeneous densities of 1.02-1.1 g/mL. Human liver chimeric mice loaded with heterologous patient H (genotype 1a) immunoglobulin had partial protection against mJ6/JFH1A876P and complete protection against mJ6/JFH1DeltaHVR1/A876P. Interestingly, we identified a putative escape mutation, D476G, in mJ6/JFH1A876P. This mutation in hypervariable region 2 conferred 6.6-fold resistance against H06 IgG in vitro. CONCLUSIONS: The A876P-substitution bridges in vitro and in vivo studies using J6/JFH1-based recombinants. We provide the first in vivo evidence that HVR1 protects cross-genotype conserved HCV neutralisation epitopes, which advocates the possibility of using HVR1-deleted viruses as vaccine antigens to boost broadly reactive protective nAb responses. PMID- 26589672 TI - The Arabidopsis ABHD11 Mutant Accumulates Polar Lipids in Leaves as a Consequence of Absent Acylhydrolase Activity. AB - Alpha/beta hydrolase domain (ABHD)-containing proteins are structurally related with diverse catalytic activities. In various species, some ABHD proteins have been characterized and shown to play roles in lipid homeostasis. However, little is known about ABHD proteins in plants. Here, we characterized AT4G10030 (AtABHD11), an Arabidopsis (Arabidopsis thaliana) homolog of a human ABHD11 gene. In silico analyses of AtABHD11 revealed homology with other plant species with a conserved GXSXG lipid motif. Interestingly, Arabidopsis abhd11 mutant plants exhibited an enhanced growth rate compared with wild-type plants. Quantitative analyses of the total lipids showed that the mutant abhd11 has a high amount of phospholipid and galactolipid in Arabidopsis leaves. The overexpression of AtABHD11 in Escherichia coli led to a reduction in phospholipid levels. The bacterially expressed recombinant AtABHD11 hydrolyzed lyso(phospho)lipid and monoacylglycerol. Furthermore, using whole-genome microarray and real-time PCR analyses of abhd11 and wild-type plants, we noted the up-regulation of MGD1, -2, and -3 and DGD1. Together, these findings suggested that AtABHD11 is a lyso(phospho)lipase. The disruption of AtABHD11 caused the accumulation of the polar lipids in leaves, which in turn promoted a higher growth rate compared with wild-type plants. PMID- 26589674 TI - Getting to Zero: Goal Commitment to Reduce Blood Stream Infections. AB - While preventing health care-associated infections (HAIs) can save lives and reduce health care costs, efforts designed to eliminate HAIs have had mixed results. Variability in contextual factors such as work culture and management practices has been suggested as a potential explanation for inconsistent results across organizations and interventions. We examine goal-setting as a factor contributing to program outcomes in eight hospitals focused on preventing central line-associated bloodstream infections (CLABSIs). We conducted qualitative case studies to compare higher- and lower-performing hospitals, and explored differences in contextual factors that might contribute to performance variation. We present a goal commitment framework that characterizes factors associated with successful CLABSI program outcomes. Across 194 key informant interviews, internal and external moderators and characteristics of the goal itself differentiated actors' goal commitment at higher- versus lower-performing hospitals. Our findings have implications for organizations struggling to prevent HAIs, as well as informing the broader goal commitment literature. PMID- 26589673 TI - The bHLH Transcription Factors TSAR1 and TSAR2 Regulate Triterpene Saponin Biosynthesis in Medicago truncatula. AB - Plants respond to stresses by producing a broad spectrum of bioactive specialized metabolites. Hormonal elicitors, such as jasmonates, trigger a complex signaling circuit leading to the concerted activation of specific metabolic pathways. However, for many specialized metabolic pathways, the transcription factors involved remain unknown. Here, we report on two homologous jasmonate-inducible transcription factors of the basic helix-loop-helix family, TRITERPENE SAPONIN BIOSYNTHESIS ACTIVATING REGULATOR1 (TSAR1) and TSAR2, which direct triterpene saponin biosynthesis in Medicago truncatula. TSAR1 and TSAR2 are coregulated with and transactivate the genes encoding 3-HYDROXY-3-METHYLGLUTARYL-COENZYME A REDUCTASE1 (HMGR1) and MAKIBISHI1, the rate-limiting enzyme for triterpene biosynthesis and an E3 ubiquitin ligase that controls HMGR1 levels, respectively. Transactivation is mediated by direct binding of TSARs to the N-box in the promoter of HMGR1. In transient expression assays in tobacco (Nicotiana tabacum) protoplasts, TSAR1 and TSAR2 exhibit different patterns of transactivation of downstream triterpene saponin biosynthetic genes, hinting at distinct functionalities within the regulation of the pathway. Correspondingly, overexpression of TSAR1 or TSAR2 in M. truncatula hairy roots resulted in elevated transcript levels of known triterpene saponin biosynthetic genes and strongly increased the accumulation of triterpene saponins. TSAR2 overexpression specifically boosted hemolytic saponin biosynthesis, whereas TSAR1 overexpression primarily stimulated nonhemolytic soyasaponin biosynthesis. Both TSARs also activated all genes of the precursor mevalonate pathway but did not affect sterol biosynthetic genes, pointing to their specific role as regulators of specialized triterpene metabolism in M. truncatula. PMID- 26589675 TI - Do Veterans Health Administration Enrollees Generalize to Other Populations? AB - The Veterans Health Administration (VHA) has historically served a disproportionately male patient population with lower income and greater rates of mental illness than non-VHA populations. The generalizability of research based on VHA enrollees is unknown because the overlap between VHA and non-VHA populations has never been empirically examined. This study used 2013 National Health Interview Survey data to examine the extent to which VHA enrollees had similar demographic and health characteristics as individuals with Medicaid, Medicare, or private insurance coverage, based on propensity score models. A majority of male VHA enrollees were similar to Medicare beneficiaries suggesting greater generalizability of VHA studies than commonly hypothesized. Overlap declined when comparing with Medicaid enrollees or privately insured individuals, suggesting more limited generalizability of VHA studies to these populations. PMID- 26589677 TI - The Libyan civil conflict: selected case series of orthopaedic trauma managed in Malta in 2014. AB - AIM: The purpose of this series of cases was to analyse our management of orthopaedic trauma casualties in the Libyan civil war crisis in the European summer of 2014. We looked at both damage control orthopaedics and for case variety of war trauma at a civilian hospital. Due to our geographical proximity to Libya, Malta was the closest European tertiary referral centre. Having only one Level 1 trauma care hospital in our country, our Trauma and Orthopaedics department played a pivotal role in the management of Libyan battlefield injuries. Our aims were to assess acute outcomes and short term mortality of surgery within the perspective of a damage control orthopaedic strategy whereby aggressive wound management, early fixation using relative stability principles, antibiotic cover with adequate soft tissue cover are paramount. We also aim to describe the variety of war injuries we came across, with a goal for future improvement in regards to service providing. METHODS: Prospective collection of six interesting cases with severe limb and spinal injuries sustained in Libya during the Libyan civil war between June and November 2014. CONCLUSIONS: We applied current trends in the treatment of war injuries, specifically in damage control orthopaedic strategy and converting to definitive treatment where permissible. The majority of our cases were classified as most severe (Type IIIB/C) according to the Gustilo-Anderson classification of open fractures. The injuries treated reflected the type of standard and improved weaponry available in modern warfare affecting both militants and civilians alike with increasing severity and extent of damage. Due to this fact, multidisciplinary team approach to patient centred care was utilised with an ultimate aim of swift recovery and early mobilisation. It also highlighted the difficulties and complex issues required on a hospital management level as a neighbouring country to war zone countries in transforming care of civil trauma to military trauma. PMID- 26589676 TI - Metabolic engineering of Escherichia coli for poly(3-hydroxybutyrate) production via threonine bypass. AB - BACKGROUND: Poly(3-hydroxybutyrate) (PHB), have been considered to be good candidates for completely biodegradable polymers due to their similar mechanical properties to petroleum-derived polymers and complete biodegradability. Escherichia coli has been used to simulate the distribution of metabolic fluxes in recombinant E. coli producing poly(3-hydroxybutyrate) (PHB). Genome-scale metabolic network analysis can reveal unexpected metabolic engineering strategies to improve the production of biochemicals and biofuels. RESULTS: In this study, we reported the discovery of a new pathway called threonine bypass by flux balance analysis of the genome-scale metabolic model of E. coli. This pathway, mainly containing the reactions for threonine synthesis and degradation, can potentially increase the yield of PHB and other acetyl-CoA derived products by reutilizing the CO2 released at the pyruvate dehydrogenase step. To implement the threonine bypass for PHB production in E. coli, we deregulated the threonine and serine degradation pathway and enhanced the threonine synthesis, resulting in 2.23-fold improvement of PHB titer. Then, we overexpressed glyA to enhance the conversion of glycine to serine and activated transhydrogenase to generate NADPH required in the threonine bypass. CONCLUSIONS: The result strain TB17 (pBHR68) produced 6.82 g/L PHB with the yield of 0.36 g/g glucose in the shake flask fermentation and 35.92 g/L PHB with the yield of 0.23 g/g glucose in the fed batch fermentation, which was almost 3.3-fold higher than the parent strain. The work outlined here shows that genome-scale metabolic network analysis can reveal novel metabolic engineering strategies for developing efficient microbial cell factories. PMID- 26589679 TI - Trends in Physical Medicine and Rehabilitation Publications Over the Past 16 Years. AB - OBJECTIVES: To test the hypothesis that the number of publications in the field of physical medicine and rehabilitation (PMR) has increased over the last 16 years in a linear fashion, and to compare the trends in publication between the pediatric and adult literature. DESIGN: We evaluated all MEDLINE articles from January 1, 1998, to December 31, 2013, using Medical Subject Headings categories of rehabilitation. An age filter separated adult and pediatric articles. We divided articles into those with a low level of scientific evidence such as letters and editorials, and those with a high level of evidence such as controlled trials and meta-analyses. We used regression analysis to evaluate the effect of the year of publication on the number of publications of each type. SETTING: Not applicable. PARTICIPANTS: Not applicable. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Not applicable. RESULTS: MEDLINE reported a total of 98,501 adult publications and 30,895 pediatric publications during the evaluated period. There was a significant linear increase in the total number of publications in adult and pediatric rehabilitation publications with multiplication factors of 3.3 and 2.9, respectively. Importantly, publications with a high level of evidence showed larger multiplication factors compared with those with a low level of evidence (5.5 and 5.1 vs 2.1 and 2.0) for the adult and pediatric literature. CONCLUSIONS: The number of publications in the PMR field, especially those with a high level of scientific evidence, has increased linearly over the years, reflecting the rapid evolution of both adult and pediatric PMR. PMID- 26589678 TI - Electroencephalography during general anaesthesia differs between term-born and premature-born children. AB - OBJECTIVES: Premature birth is associated with a wide range of complications in later life, including structural and functional neurological abnormalities and altered pain sensitivity. We investigated whether during anaesthesia premature born children display different patterns of background EEG activity and exhibit increased responses to nociceptive stimuli. METHODS: We examined background EEG and time-locked responses to clinical cannulation in 45 children (mean age (+/ SD) at study: 4.9(+/-3.0)years) under sevoflurane monoanaesthesia maintained at a steady-state end-tidal concentration of 2.5%. 15 were born prematurely (mean gestational age at birth: 29.2 +/- 3.9 weeks) and 30 were age-matched term-born children. RESULTS: Background levels of alpha and beta power were significantly lower in the premature-born children compared to term-born controls (p=0.048). Clinical cannulation evoked a significant increase in delta activity (p=0.032), which was not significantly different between the two groups (p=0.44). CONCLUSIONS: The results indicate that whilst under anaesthesia premature-born children display different patterns of background brain activity compared to term born children. SIGNIFICANCE: As electrophysiological techniques are increasingly used by anaesthetists to gauge anaesthetic depth, differences in background levels of electrophysiological brain activity between premature and term-born children may be relevant when considering titration of anaesthetic dose. PMID- 26589680 TI - Experimental determination of the elbow's center of rotation using the VICONTM optoelectronic motion capture system. AB - PURPOSE: Knowledge of elbow kinematics is essential to better understand this joint. There is currently no reliable dynamic method to accurately study the elbow joint in a non-invasive manner. The goal of this study was to implement an accurate protocol to study in vivo elbow kinematics using a VICONTM optoelectronic motion analysis system. MeTHODS: The elbow's centers of rotation (CR) were calculated for 10 anatomical specimens. The effect of skin movement was determined by comparing measurements taken using skin surface markers and bone fixed markers. The validated protocol was then used in 30 healthy subjects who underwent passive elbow joint movements. RESULTS: The elbow's CR was found to be distal (7 +/- 14 mm), lateral (4 +/- 9 mm) and anterior (4 +/- 10 mm) to the medial epicondyle in vitro. Mean CR values for anatomical specimens did not differ whether calculated using the skin-based or bone-fixed markers. CONCLUSION: This study has validated a dynamic, non-invasive, and accurate method for locating the elbow's center of rotation. This preliminary study thus found a different center of rotation of the one in the middle of the trochlea previously thought. This could lead us to reflect on the designs of our prostheses to reduce the mechanical stresses and the risk of loosening. PMID- 26589681 TI - Surgical treatment of syphilitic superficial femoral artery aneurysm: a rare case report. AB - BACKGROUND: Arterial aneurysm is a known complication of syphilis, but the occurrence of femoral artery aneurysm secondary to the syphilitic disease has never been reported. CASE PRESENTATION: The present study described a 60-year-old Chinese male who presented with two aneurysms in the middle and lower segment of the right superficial femoral artery causing the symptoms of pain, coldness and numbness in the right lower limb. This case was diagnosed with syphilitic superficial femoral aneurysm because of positive syphilitic testing and the inflammatory cell infiltration around the adventitial vasa vasorum under the pathological examination. Anti-syphilis treatment, stent graft implantation and open surgery were attempted to eliminate the syphilis and aneurysm, which was ultimately successful, with no symptoms after a follow-up of 3 months. CONCLUSION: Combined open and endovascular repair may be effective and safe for treatment of syphilitic femoral artery aneurysms. PMID- 26589682 TI - Paenibacillus chinensis sp. nov., isolated from maize (Zea mays L.) seeds. AB - Four Gram-stain positive bacterial strains, designated as 4R1(T), 4R9, 4L13 and 4L18, isolated from seeds of hybrid maize (Zea mays L., Jingke 968), were investigated using a polyphasic taxonomic approach. The cells were found to be facultatively aerobic, motile, spore-forming and rod-shaped. Phylogenetic analysis based on 16S rRNA gene sequences showed that the isolates should be recognised as a species of the genus Paenibacillus, with two close neighbours being Paenibacillus nicotianae YIM h-19(T) (98.41 % similarity) and Paenibacillus hordei RH-N24(T) (98.37 %). The DNA G+C content of strain 4R1(T) was determined to be 51.6 mol %. Its polar lipid profile was found to consist of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine and an unidentified lipid. The predominant respiratory quinone was identified as MK-7 and the major fatty acids were found to be anteiso-C15:0, anteiso-C12:0, anteiso C13:0 and anteiso-C11:0. Strains 4R1(T), 4R9, 4L13 and 4L18 were clearly distinguished from the reference type strains using phylogenetic analysis, DNA DNA hybridization and a range of physiological and biochemical characteristics. It is evident from the genotypic and phenotypic data that strains 4R1(T), 4R9, 4L13 and 4L18 represent a novel species of the genus Paenibacillus, for which the name Paenibacillus chinensis sp. nov. is proposed. The type strain is 4R1(T) (=KCTC 33672(T) = CICC 23864(T)). PMID- 26589683 TI - Microbispora camponoti sp. nov., a novel actinomycete isolated from the cuticle of Camponotus japonicus Mayr. AB - A novel actinomycete, designated strain 2C-HV3(T), was isolated from the cuticle of Camponotus japonicus Mayr collected from Harbin, Heilongjiang province, north China and characterised using a polyphasic approach. The 16S rRNA gene sequence of strain 2C-HV3(T) showed that it has high sequence similarities with Microbispora bryophytorum NEAU-TX2-2(T) (99.9 %), Microbispora amethystogenes JCM 3021(T) (98.9 %) and Microbispora rosea subsp. rosea JCM 3006(T) (98.6 %). Phylogenetic analysis based on 16S rRNA and gyrB gene sequences demonstrated that strain 2C-HV3(T) clusters with M. bryophytorum NEAU-TX2-2(T) using two tree making algorithms. Moreover, key morphological and chemotaxonomic properties also confirmed the affiliation of strain 2C-HV3(T) to the genus Microbispora. Longitudinal paired spores were observed to be born on short sporophores branching from the aerial hyphae. The cell wall was found to contain meso diaminopimelic acid as the diagnostic diamino acid; madurose was found in the whole cell hydrolysate. The polar lipid profile was found to consist of diphosphatidylglycerol, phosphatidylmonomethylethanolamine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylinositolmannoside, ninhydrin-positive glycophospholipids, an unidentified phospholipid and an unidentified glycolipid. The predominant menaquinones were identified as MK-9(H2) and MK-9(H4). The major fatty acids were identified as 10-methyl C17:0 and iso C16:0. However, a combination of DNA-DNA hybridization results and some phenotypic characteristics demonstrated that strain 2C-HV3(T) can be distinguished from its closely related relatives. Consequently, it is proposed that strain 2C-HV3(T) represents a new species of the genus Microbispora, for which the name Microbispora camponoti sp. nov. is proposed. The type strain is 2C HV3(T) (=CGMCC 4.7281(T) = DSM 100527(T)). PMID- 26589685 TI - Correlation of IL36RN mutation with different clinical features of pustular psoriasis in Chinese patients. AB - Different studies have reported various values for the percentage of patients with IL36RN mutations, and it has also been reported that the sites of these mutations differ among different ethnicities. The current study was a cross sectional study conducted to investigate the risk factors predicting IL36RN mutation in Chinese patients with different clinical features of pustular psoriasis. 57 Han Chinese patients, including 32 with generalized pustular psoriasis, 14 with palmoplantar pustulosis, 9 with plaque-type psoriasis with pustules, and 2 with erythrodermic psoriasis, were enrolled between March 2013 and July 2014. Blood samples were collected, genomic DNA was extracted from leukocytes, and polymerase chain reaction (PCR)-based Sanger sequencing was used to analyze the coding exons and flanking introns of the IL36RN gene. The patients with generalized pustular psoriasis exhibited the highest IL36RN mutation rate (75 %) among the aforementioned patient types, with the subgroup consisting of those patients who had features of acrodermatitis continua of Hallopeau exhibiting the highest c.115+6T>C mutation rate (93.8 %). In addition, early onset, ever generalized pustular psoriasis (more than two attacks), ever acrodermatitis continua of Hallopeau, inverse psoriasis, and a family history of pustular psoriasis were associated with IL36RN mutation. The c.115+6T>C mutation was the most common and the most important variant in all subtypes of pustular psoriasis with IL36RN mutations among our sample of Chinese patients. PMID- 26589684 TI - Serum leptin and serum leptin/serum leptin receptor ratio imbalance in obese rheumatoid arthritis patients positive for anti-cyclic citrullinated peptide antibodies. AB - INTRODUCTION: Leptin has a prominent role in the development and maintenance of acute and chronic inflammatory states such as rheumatoid arthritis (RA) and obesity. Nevertheless, the association of serum leptin (sLep) and soluble leptin receptor (sLepR) in RA pathogenesis has not been clarified. The purpose of this study was to evaluate the association of sLep, sLepR and leptin production indexes such as sLep/fat mass ratio with clinical activity and biomarkers and anti-cyclic citrullinated peptide (anti-CCP) antibodies in RA compared with body mass index (BMI) matched control subjects. METHODS: We included 64 RA patients and 66 controls matched for age, gender and BMI. Subjects were evaluated for BMI, fat mass distribution, sLep, sLepR, sLep/fat mass ratio and sLepR/fat mass ratio. Patients were evaluated for clinical activity and anti-CCP antibodies. RESULTS: We found two or three fold increased sLep levels, sLep/sLepR ratio and sLep/fat mass ratio in obese anti-CCP positive RA patients vs. CONTROLS: Partial correlations showed that anti-CCP antibodies were correlated with sLep/fat mass ratio (partial r = 0.347, P = 0.033) after adjustment for age, subcutaneous adipose tissue and fat mass. CONCLUSIONS: In preobese and obese RA patients there is and increased production of sLep according to anti-CCP positivity. This phenomenon suggests there is an additive effect of chronic inflammation resulting from RA and obesity in which leptin favors the humoral response against citrullinated proteins. In summary, the data observed in our study suggests sLep could be a surrogate marker of chronicity and humoral immunity in RA in the presence of obesity. PMID- 26589686 TI - Random plasma glucose in early pregnancy is a better predictor of gestational diabetes diagnosis than maternal obesity. AB - AIMS/HYPOTHESIS: Asymptomatic pregnant women are screened for gestational diabetes (GDM) at 24-28 weeks' gestation. Recent guidelines also recommend screening early in gestation to identify undiagnosed pre-existing overt diabetes. We assessed the performance of random plasma glucose (RPG) testing at antenatal booking in predicting GDM diagnosis later in pregnancy. METHODS: Data from 25,543 consecutive singleton pregnancies at the Rosie Hospital in Cambridge (UK) were obtained from hospital electronic records as a service evaluation. All women were invited for an antenatal RPG (12-16 weeks) and a 50 g glucose challenge test (GCT; 24-28 weeks) with a 75 g OGTT if GCT >7.7 mmol/l (139 mg/dl). RESULTS: At booking, 17,736 women had an RPG that was able to predict GDM (receiver operating characteristic AUC 0.8) according to various diagnostic criteria in common use. A cut-off point of >=7.5 mmol/l (135 mg/dl) gave a sensitivity of 0.70 and a specificity of 0.90 for GDM diagnosis. Theoretically, using this screening policy, 13.2% of women would have been categorised at high risk (26.3% had GDM) and 86.8% of women at low risk (1.7% had GDM). RPG performed better than maternal age (AUC 0.60) or BMI (AUC 0.65) at predicting GDM diagnosis. CONCLUSIONS/INTERPRETATION: RPG at booking has reasonable performance as a screening test and is better than maternal age or BMI for identifying women at high risk of GDM. RPG cannot replace OGTT for diagnosis but it may be useful to exclude women who do not need further investigation for GDM and to identify women who could be prioritised for early diagnosis or lifestyle interventions. PMID- 26589687 TI - Automatic artifacts and arousals detection in whole-night sleep EEG recordings. AB - BACKGROUND: In sleep electroencephalographic (EEG) signals, artifacts and arousals marking are usually part of the processing. This visual inspection by a human expert has two main drawbacks: it is very time consuming and subjective. NEW METHOD: To detect artifacts and arousals in a reliable, systematic and reproducible automatic way, we developed an automatic detection based on time and frequency analysis with adapted thresholds derived from data themselves. RESULTS: The automatic detection performance is assessed using 5 statistic parameters, on 60 whole night sleep recordings coming from 35 healthy volunteers (male and female) aged between 19 and 26. The proposed approach proves its robustness against inter- and intra-, subjects and raters' scorings, variability. The agreement with human raters is rated overall from substantial to excellent and provides a significantly more reliable method than between human raters. COMPARISON: Existing methods detect only specific artifacts or only arousals, and/or these methods are validated on short episodes of sleep recordings, making it difficult to compare with our whole night results. CONCLUSION: The method works on a whole night recording and is fully automatic, reproducible, and reliable. Furthermore the implementation of the method will be made available online as open source code. PMID- 26589688 TI - A rapid and sensitive method to determine tacrolimus in rat whole blood using liquid-liquid extraction with mild temperature ultrasonication and LC-MS/MS. AB - Tacrolimus (TAC) is an immunosuppressant widely used in organ transplantation, but its extremely low aqueous solubility causes poor intestinal absorption. There have been efforts to develop an alternative TAC formulation with an improved dissolution rate and oral bioavailability (BA), and the development of a rapid and sensitive analytical method for its in vivo pharmacokinetic study is an essential prerequisite. Thus, here, we develop a novel method to determine TAC in rat whole blood based on liquid chromatography and tandem mass spectrometry, and liquid-liquid extraction (LLE) with mild temperature ultrasonication. For rapid and efficient separation of TAC from other hydrophobic compounds, a C8 column was chosen with isocratic mobile phase elution. With the help of the high specificity and the high sensitivity of multiple reaction monitoring in positive ion mode, the present method showed good performance including specificity, linearity (r(2) >= 0.996 within 1-200 ng/mL), sensitivity (the lower limit of quantitation at 1 ng/mL), intra- and inter-day accuracy (88.7-104.5 %) and precision (<=10.3 %), and recovery (94.7-102.6 %). Also, the stability of TAC and ascomycin, the internal standard, in rat whole blood was confirmed before and after the sample preparation. The validated method was satisfactorily applied to a pharmacokinetic study to determine TAC in rat whole blood following oral administration of the marketed product (Prograf((r)), Astellas Pharma). In the present study, LLE with mild temperature ultrasonication was successfully expanded to the determination of a drug from whole blood or plasma for the first time. Therefore, the present method can contribute to the rapid in vivo evaluation of novel TAC formulations, and will be able to contribute to the development of TAC formulations with a higher dissolution rate and a higher BA. PMID- 26589689 TI - Preventive effect of Vaccinium uliginosum L. extract and its fractions on age related macular degeneration and its action mechanisms. AB - Age-related macular degeneration (AMD) is the leading cause of vision loss and blindness among the elderly. Although the pathogenesis of this disease remains still obscure, several researchers have report that death of retinal pigmented epithelium (RPE) caused by excessive accumulation of A2E is crucial determinants of AMD. In this study, the preventive effect of Vaccinium uliginosum L. (V.U) extract and its fractions on AMD was investigated in blue light-irradiated human RPE cell (ARPE-19 cells). Blue light-induced RPE cell death was significantly inhibited by the treatment of V.U extract or its fraction. To identify the mechanism, FAB-MS analysis revealed that V.U inhibits the photooxidation of N retinyl-N-retinylidene ethanolamine (A2E) induced by blue light in cell free system. Moreover, monitoring by quantitative HPLC also revealed that V.U extract and its fractions reduced intracellular accumulation of A2E, suggesting that V.U extract and its fractions inhibit not only blue light-induced photooxidation, but also intracellular accumulation of A2E, resulting in RPE cell survival after blue light exposure. A2E-laden cell exposed to blue light induced apoptosis by increasing the cleaved form of caspase-3, Bax/Bcl-2. Additionally, V.U inhibited by the treatment of V.U extract or quercetin-3-O-arabinofuranoside. These results suggest that V.U extract and its fractions have preventive effect on blue light induced damage in RPE cells and AMD. PMID- 26589690 TI - Nuclear Dynamics at Molecule-Metal Interfaces: A Pseudoparticle Perspective. AB - We discuss nuclear dynamics at molecule-metal interfaces including nonequilibrium molecular junctions. Starting from the many-body states (pseudoparticle) formulation of the molecule-metal system in the molecular vibronic basis, we introduce gradient expansion to reduce the adiabatic nuclear dynamics (that is, nuclear dynamics on a single molecular potential surface) into its semiclassical form while maintaining the effect of the nonadiabatic electronic transitions between different molecular charge states. This yields a set of equations for the nuclear dynamics in the presence of these nonadiabatic transitions, which reproduce the surface-hopping formulation in the limit of small metal-molecule coupling (where broadening of the molecular energy levels can be disregarded) and Ehrenfest dynamics (motion on the potential of mean force) when information on the different charging states is traced out. PMID- 26589691 TI - Erratum to: Effects of Renal Sympathetic Denervation on Arterial Stiffness and Blood Pressure Control in Resistant Hypertensive Patients: A Single Centre Prospective Study. PMID- 26589692 TI - Letter From the Guest Editor: Imaging of the Jaw. PMID- 26589693 TI - Embryology and Anatomy of the Jaw and Dentition. AB - Radiologists should possess working knowledge of the embryological development and anatomy of the jaw and dentition in order to aid in the diagnosis of both simple and complex disorders that affect them. Here, we review the elaborate process of odontogenesis, as well as describe in detail the anatomy of a tooth and its surrounding structures. PMID- 26589694 TI - Imaging of the jaws. PMID- 26589695 TI - Dental Implants. AB - Dental implants restore function to near normal in partially or completely edentulous patients. A root-form implant is the most frequently used type of dental implant today. The basis for dental implants is osseointegration, in which osteoblasts grow and directly integrate with the surface of titanium posts surgically embedded into the jaw. Radiologic assessment is critical in the preoperative evaluation of the dental implant patient, as the exact height, width, and contour of the alveolar ridge must be determined. Moreover, the precise locations of the maxillary sinuses and mandibular canals, as well as their relationships to the site of implant surgery must be ascertained. As such, radiologists must be familiar with implant design and surgical placement, as well as augmentation procedures utilized in those patients with insufficient bone in the maxilla and mandible to support dental implants. PMID- 26589696 TI - Dental Implant Complications. AB - Dental implants have increased in the last few decades thus increasing the number of complications. Since many of these complications are easily diagnosed on postsurgical images, it is important for radiologists to be familiar with them and to be able to recognize and diagnose them. Radiologists should also have a basic understanding of their treatment. In a pictorial fashion, this article will present the basic complications of dental implants which we have divided into three general categories: biomechanical overload, infection or inflammation, and other causes. Examples of implant fracture, loosening, infection, inflammation from subgingival cement, failure of bone and soft tissue preservation, injury to surround structures, and other complications will be discussed as well as their common imaging appearances and treatment. Lastly, we will review pertinent dental anatomy and important structures that are vital for radiologists to evaluate in postoperative oral cavity imaging. PMID- 26589697 TI - Inflammatory Diseases of the Teeth and Jaws. AB - The teeth are unique in that they provide a direct pathway for spread of infection into surrounding osseous and soft tissue structures. Periodontal disease is the most common cause of tooth loss worldwide, referring to infection of the supporting structures of the tooth, principally the gingiva, periodontal ligament, cementum, and alveolar bone. Periapical disease refers to an infectious or inflammatory process centered at the root apex of the tooth, usually occurring when deep caries infect the pulp chamber and root canals. We review the pathogenesis, clinical features, and radiographic findings (emphasis on computed tomography) in periodontal and periapical disease. PMID- 26589698 TI - Lesions of the Jaw. AB - Imaging of lesions within the maxilla and mandible is often fraught with difficulty owing to the similarity in the imaging appearance of a diverse array of pathological processes. Principally, lesions arise from either odontogenic sources or from primary bone lesions. The response of the cancellous and cortical bone to pathologic insult can be expressed either through an osteolytic or an osteoblastic response; thus the majority of lesions within the jaws can be classified as cystic or lytic appearing, sclerotic, or a mixture of the two. This article will review the imaging features of the most common cysts, fibro-osseous lesions, benign and malignant neoplasms, and highlight those features key to the differential diagnosis. PMID- 26589700 TI - Ultrasonographic reproductive tract measures and pelvis measures as predictors of pregnancy failure and anestrus in restricted bred beef heifers. AB - Previous reports have shown that reproductive tract score (RTS) can predict reproduction outcomes in seasonally bred beef heifers, although the accuracy can vary. Some ultrasonographic measures of the female reproductive tract and pelvis area have also been associated with reproductive outcome in young heifers. The objectives of this study were to determine which transrectal ultrasound or pelvis measures taken at a single examination are independent predictors of reproductive failure and whether the RTS system can be optimized with this information. In this observational study, year-old beef heifers (n = 488) in 2 birth cohorts were followed from just before the first breeding until confirmation of pregnancy. A single pre-breeding examination included body condition score, RTS, ultrasound measures of the reproductive tract (length and diameter of the left and right ovaries, presence and diameter of a CL, largest follicle diameter and left uterus horn diameter) and transverse and vertical diameters of the pelvis. Additional farm records including dam parity, sire, birth weight and birth date, weaning weight, weaning date, prebreeding body weight, AI dates, and semen used were available. Breeding consisted of 50 days of AI, followed 5 to 7 days later by a 42-day bull breeding period. Pregnancy failure was defined as the failure to become pregnant after the AI and bull breeding periods, while anestrus was defined as the failure to be detected in estrus during the 50-day AI period. From the prebreeding data and farm records, independent predictors of pregnancy failure and anestrus were identified using stepwise reduction in multiple logistic regression models. Age at the onset of breeding was the only consistent independent predictor of pregnancy failure and anestrus in both cohorts of this study (P < 0.05). Body condition score, uterus horn diameter, absence of a CL, largest follicle of less than 13 mm, and pelvis area (PA) were the prebreeding examination variables that remained in prognostic models (P < 0.1). Combining either the model based on the 3 remaining ultrasound measures or RTS with PA provided more accurate prognostic models for pregnancy failure and anestrus than using RTS alone (P < 0.05). It is concluded that ultrasound measures have prognostic value for pregnancy failure in restricted bred yearling heifers as a result of their association with anestrus, and that smaller PA has additional prognostic value for poorly performing heifers. PMID- 26589701 TI - A novel epigenetic mechanism regulating hyaluronan production in pancreatic cancer cells. AB - Pancreatic ductal adenocarcinoma (PDAC) is characterized by an abundant stroma enriched with hyaluronan (HA), a major component of extracellular matrix known to play a critical role in tumor progression. The mechanisms that regulate HA synthesis in PDAC are poorly understood. To investigate whether DNA methylation and HA production from PDAC cells are associated, we studied the effect of 5-aza 2'-deoxycitidine (5-aza-dC), an inhibitor of DNA methylation, or DNA methyltransferase 1 (DNMT1) knockdown by small interfering RNA, on the HA production from PDAC cells. HA production into the conditioned medium was evaluated in PDAC cells treated with 5-aza-dC or DNMT1 knockdown. mRNA expression of HA synthase (HAS) genes was investigated by real-time RT-PCR. Treatment of PDAC cells with 5-aza-dC led to a significant increase in the HA production (up to 2.5-fold increase) in all 4 cell lines tested. This enhanced HA production by 5-aza-dC treatment was accompanied by increased mRNA expression of HAS2 and HAS3. Furthermore, increased HA production and HAS2/HAS3 mRNA expression was also observed in PDAC cells by knockdown of DNMT1. These findings provide evidence, for the first time, that epigenetic mechanism is involved in the regulation of HA synthesis in PDAC cells. PMID- 26589699 TI - Enhanced Dissociation of Intact Proteins with High Capacity Electron Transfer Dissociation. AB - Electron transfer dissociation (ETD) is a valuable tool for protein sequence analysis, especially for the fragmentation of intact proteins. However, low product ion signal-to-noise often requires some degree of signal averaging to achieve high quality MS/MS spectra of intact proteins. Here we describe a new implementation of ETD on the newest generation of quadrupole-Orbitrap-linear ion trap Tribrid, the Orbitrap Fusion Lumos, for improved product ion signal-to-noise via ETD reactions on larger precursor populations. In this new high precursor capacity ETD implementation, precursor cations are accumulated in the center section of the high pressure cell in the dual pressure linear ion trap prior to charge-sign independent trapping, rather than precursor ion sequestration in only the back section as is done for standard ETD. This new scheme increases the charge capacity of the precursor accumulation event, enabling storage of approximately 3-fold more precursor charges. High capacity ETD boosts the number of matching fragments identified in a single MS/MS event, reducing the need for spectral averaging. These improvements in intra-scan dynamic range via reaction of larger precursor populations, which have been previously demonstrated through custom modified hardware, are now available on a commercial platform, offering considerable benefits for intact protein analysis and top down proteomics. In this work, we characterize the advantages of high precursor capacity ETD through studies with myoglobin and carbonic anhydrase. PMID- 26589703 TI - Rockefeller Foundation-Lancet Commission report: A call to action for human health. PMID- 26589702 TI - The use of genetic markers in the molecular epidemiology of histoplasmosis: a systematic review. AB - Histoplasmosis is a systemic mycosis caused by Histoplasma capsulatum, a dimorphic fungal pathogen that can infect both humans and animals. This disease has worldwide distribution and affects mainly immunocompromised individuals. In the environment, H. capsulatum grows as mold but undergoes a morphologic transition to the yeast morphotype under special conditions. Molecular techniques are important tools to conduct epidemiologic investigations for fungal detection, identification of infection sources, and determination of different fungal genotypes associated to a particular disease symptom. In this study, we performed a systematic review in the PubMed database to improve the understanding about the molecular epidemiology of histoplasmosis. This search was restricted to English and Spanish articles. We included a combination of specific keywords: molecular typing [OR] genetic diversity [OR] polymorphism [AND] H. capsulatum; molecular epidemiology [AND] histoplasmosis; and molecular epidemiology [AND] Histoplasma. In addition, we used the specific terms: histoplasmosis [AND] outbreaks. Non English or non-Spanish articles, dead links, and duplicate results were excluded from the review. The results reached show that the main methods used for molecular typing of H. capsulatum were: restriction fragment length polymorphism, random amplified polymorphic DNA, microsatellites polymorphism, sequencing of internal transcribed spacers region, and multilocus sequence typing. Different genetic profiles were identified among H. capsulatum isolates, which can be grouped according to their source, geographical origin, and clinical manifestations. PMID- 26589704 TI - Surface modification strategies on mesoporous silica nanoparticles for anti biofouling zwitterionic film grafting. AB - In the past decade, zwitterionic-based anti-biofouling layers had gained much focus as a serious alternative to traditional polyhydrophilic films such as PEG. In the area of assembling silica nanoparticles with stealth properties, the incorporation of zwitterionic surface film remains fairly new but considering that silica nanoparticles had been widely demonstrated as useful biointerfacing nanodevice, zwitterionic film grafting on silica nanoparticle holds much potential in the future. This review will discuss on the conceivable functional chemistry approaches, some of which are potentially suitable for the assembly of such stealth systems. PMID- 26589705 TI - Transient Expression of Functional Glucocerebrosidase for Treatment of Gaucher's Disease in the Goat Mammary Gland. AB - Gaucher disease (GD) is an orphan disease characterized by the lack or incapacity of glucocerebrosidase (hGCase) to properly process glucosylceramide, resulting in its accumulation in vital structures of the human body. Enzyme replacement therapy supplies hGCase to GD patients with a high-cost recombinant enzyme produced in vitro in mammalian or plant cell culture. In this study, we produced hGCase through the direct injection of recombinant adenovirus in the mammary gland of a non-transgenic goat. The enzyme was secreted in the milk during six days at a level up to 111.1 +/- 8.1 mg/L, as identified by mass spectrometry, showing high in vitro activity. The milk-produced hGCase presented a mass correspondent to the intermediary high-mannose glycosylated protein, which could facilitate its delivery to macrophages through the macrophage mannose receptor. Further studies are underway to determine the in vivo delivery capacity of milk hGCase, but results from this study paves the way toward the generation of transgenic goats constitutively expressing hGCase in the milk. PMID- 26589706 TI - Low-Cost Method to Monitor Patient Adherence to HIV Antiretroviral Therapy Using Multiplex Cathepsin Zymography. AB - Monitoring patient adherence to HIV antiretroviral therapy (ART) by patient survey is inherently error prone, justifying a need for objective, biological measures affordable in low-resource settings where HIV/AIDS epidemic is highest. In preliminary studies conducted in Ethiopia and South Africa, we observed loss of cysteine cathepsin activity in peripheral blood mononuclear cells of HIV positive patients on ART. We optimized a rapid protocol for multiplex cathepsin zymography to quantify cysteine cathepsins, and prospectively enrolled 350 HIV positive, ART-naive adults attending the Themba Lethu Clinic, Johannesburg, South Africa, to test if suppressed cathepsin activity could be a biomarker of ART adherence (103 patients were included in final analysis). Poor adherence was defined as detectable viral load (>400 copies/ml) or simplified medication adherence questionnaire, 4-6 months after ART initiation. 86 % of patients with undetectable viral loads after 6 months were cathepsin negative, and cathepsin positive patients were twice as likely to have detectable viral loads (RR 2.32 95 % CI 1.26-4.29). Together, this demonstrates proof of concept that multiplex cathepsin zymography may be an inexpensive, objective method to monitor patient adherence to ART. Low cost of this electrophoresis-based assay makes it a prime candidate for implementation in resource-limited settings. PMID- 26589708 TI - The Impact of Sparse Follow-up on Marginal Structural Models for Time-to-Event Data. AB - The impact of risk factors on the amount of time taken to reach an endpoint is a common parameter of interest. Hazard ratios are often estimated using a discrete time approximation, which works well when the by-interval event rate is low. However, if the intervals are made more frequent than the observation times, missing values will arise. We investigated common analytical approaches, including available-case (AC) analysis, last observation carried forward (LOCF), and multiple imputation (MI), in a setting where time-dependent covariates also act as mediators. We generated complete data to obtain monthly information for all individuals, and from the complete data, we selected "observed" data by assuming that follow-up visits occurred every 6 months. MI proved superior to LOCF and AC analyses when only data on confounding variables were missing; AC analysis also performed well when data for additional variables were missing completely at random. We applied the 3 approaches to data from the Canadian HIV Hepatitis C Co-infection Cohort Study (2003-2014) to estimate the association of alcohol abuse with liver fibrosis. The AC and LOCF estimates were larger but less precise than those obtained from the analysis that employed MI. PMID- 26589707 TI - Parental, In Utero, and Early-Life Exposure to Benzene and the Risk of Childhood Leukemia: A Meta-Analysis. AB - Benzene is an established cause of adult leukemia, but whether it is associated with childhood leukemia remains unclear. We conducted a meta-analysis in which we reviewed the epidemiologic literature on this topic and explored causal inference, bias, and heterogeneity. The exposure metrics that we evaluated included occupational and household use of benzenes and solvents, traffic density, and traffic-related air pollution. For studies of occupational and household product exposure published from 1987 to 2014, the summary relative risk for childhood leukemia was 1.96 (95% confidence interval (CI): 1.53, 2.52; n = 20). In these studies, the summary relative risk was higher for acute myeloid leukemia (summary relative risk (sRR) = 2.34, 95% CI: 1.72, 3.18; n = 6) than for acute lymphoblastic leukemia (sRR = 1.57; 95% CI: 1.21, 2.05; n = 14). The summary relative risk was higher for maternal versus paternal exposure, in studies that assessed benzene versus all solvents, and in studies of gestational exposure. In studies of traffic density or traffic-related air pollution published from 1999 to 2014, the summary relative risk was 1.48 (95% CI: 1.10, 1.99; n = 12); it was higher for acute myeloid leukemia (sRR = 2.07; 95% CI: 1.34, 3.20) than for acute lymphoblastic leukemia (sRR = 1.49; 95% CI: 1.07, 2.08) and in studies that involved detailed models of traffic pollution (sRR = 1.70; 95% CI: 1.16, 2.49). Overall, we identified evidence of associations between childhood leukemia and several different potential metrics of benzene exposure. PMID- 26589709 TI - Toward Rigorous Data Harmonization in Cancer Epidemiology Research: One Approach. AB - Cancer epidemiologists have a long history of combining data sets in pooled analyses, often harmonizing heterogeneous data from multiple studies into 1 large data set. Although there are useful websites on data harmonization with recommendations and support, there is little research on best practices in data harmonization; each project conducts harmonization according to its own internal standards. The field would be greatly served by charting the process of data harmonization to enhance the quality of the harmonized data. Here, we describe the data harmonization process utilized at the Fred Hutchinson Cancer Research Center (Seattle, Washington) by the coordinating centers of several research projects. We describe a 6-step harmonization process, including: 1) identification of questions the harmonized data set is required to answer; 2) identification of high-level data concepts to answer those questions; 3) assessment of data availability for data concepts; 4) development of common data elements for each data concept; 5) mapping and transformation of individual data points to common data elements; and 6) quality-control procedures. Our aim here is not to claim a "correct" way of doing data harmonization but to encourage others to describe their processes in order that we can begin to create rigorous approaches. We also propose a research agenda around this issue. PMID- 26589710 TI - Cerebral changes and cognitive impairment after an ischemic heart disease: a multimodal MRI study. AB - Three to 6 months after an acute coronary syndrome (ACS), cognitive impairment is observed in more than 30 % of the patients, mainly in executive functioning. The aim of this study was to investigate, using multimodal MRI, cerebral anatomo functional substratum of executive dysfunction. Thirty-three patients were recruited 4 +/- 1 months after a first ACS. Executive functions were evaluated with the Trail-Making-Test-B (TMTB) at baseline (ie 4 +/- 1 months after ACS) and 6 months later (ie 10 +/- 1 months after ACS). Using both time-points, we identified 3 groups of patients according to normative data based on age, gender and education level: 15 'cognitively normal' patients without impairment at each follow-up, 10 'transient impaired' patients with an impairment only at baseline and 8 'impairing' patients with an impairment only at follow-up. We explored, in the whole-brain, the structural integrity using Voxel-Based Morphometry and Tract Based Spatial Statistics and the resting-state functional connectivity using Network-Based Statistics. No structural difference was observed between impaired and cognitively normal patients. At the functional level, compared to the 'cognitively normal' group, the 'transient impaired' patients presented an increased functional connectivity in a network centered on middle-orbito-frontal regions, whereas the 'impairing' patients presented only a non-significant decrease of functional connectivity. Executive dysfunction in ACS patients is associated to functional but no structural characteristics, particularly to an increased functional connectivity in cognitive networks in transient impaired patients. Further studies with larger sample size are needed to confirm these results and to determine if these patients could be at higher risk for developing permanent cognitive disorders. PMID- 26589712 TI - [What is the point of this study?]. PMID- 26589711 TI - Topical ambroxol for the treatment of neuropathic pain. An initial clinical observation. AB - BACKGROUND: Neuropathic pain is difficult to treat, and the available options are often inadequate. The expectorant ambroxol also acts as a strong local anaesthetic and blocks sodium channels about 40 times more potently than lidocaine. It preferentially inhibits the channel subtype Nav 1.8, which is expressed especially in nociceptive C-fibres. In view of the low toxicity of ambroxol, it seemed reasonable to try using it for the treatment of neuropathic pain that failed to respond to other standard options. MATERIAL AND METHODS: The medical records of seven patients with severe neuropathic pain and pain reduction following topical ambroxol treatment are reported retrospectively. As standard therapies had not proved sufficient, a topical ambroxol 20% cream was repeatedly applied by the patients in the area of neuropathic pain. RESULTS: The reasons for neuropathic pain were postherpetic neuralgia (2 *), mononeuropathy multiplex, phantom pain, deafferentation pain, postoperative neuralgia and foot neuropathy of unknown origin. The individual mean pain intensity reported was between 4 and 6/10 (NRS), maximum pain at 6-10/10 (NRS). The pain reduction achieved individually following ambroxol cream was 2-8 points (NRS) within 5-30 min and lasted for 3-8 h. Pain attacks were reduced in all five patients presenting with this problem. Four patients with no improvement after lidocaine 5% and one patient with no response to capsaicin 8% nevertheless experienced a pain reduction with topical ambroxol. No patient reported any side effects or skin changes during a treatment that has since been continued for up to 4 years. CONCLUSION: Ambroxol acts as a strong local anaesthetic and preferentially inhibits the nociceptively relevant sodium channel subtype Nav 1.8. For the first time, we report below on a relevant pain relief following topical ambroxol 20% cream in patients with neuropathic pain. In view of the positive side effect profile, the clinical benefit in patients with pain should be investigated further. PMID- 26589713 TI - [Study on epidural steroid injection]. PMID- 26589714 TI - [Diagnostic comparison of thermal parameters of quantitative sensory testing and laser stimulation in postherpetic neuralgia]. PMID- 26589716 TI - Musculoskeletal pain in people with and without type 2 diabetes in Taiwan: a population-based, retrospective cohort study. AB - BACKGROUND: Musculoskeletal pain in people with type 2 diabetes is a common issue even to this day. The study aimed to explore the 10-year cumulative incidence of musculoskeletal pain, the mean number of doctor visits for musculoskeletal pain, and the mean number of doctor visits for musculoskeletal pain by location in people with type 2 diabetes, compared with respective values for people without diabetes. METHODS: The study utilized a population-based retrospective cohort study design. The subjects were randomly obtained from the Taiwan National Health Insurance Research Database. The diabetic group included 6586 people with type 2 diabetes aged 18-50 years, while the non-diabetic group consisted of 32,930 age- and sex-matched people. Based on the medical records of individuals with musculoskeletal pain in the two groups from 2001 to 2010, the 10-year cumulative incidence of musculoskeletal pain, the mean number of doctor visits for musculoskeletal pain, and the mean number of doctor visits for musculoskeletal pain by location were calculated and compared, with the aim of identifying differences between the two groups. RESULTS: Showed that people in the diabetic group had a higher 10-year cumulative incidence of and a higher mean number of doctor visits for musculoskeletal pain than the non-diabetic group (p < 0.05). The relative risk (RR) of the 10-year cumulative incidence of musculoskeletal pain in the two groups was the highest (RR = 1.39) for people between 30 and 39 years of age. The mean number of doctor visits for musculoskeletal pain by location was significantly different between the two groups. However, the mean number of doctor visits for limb pain registered the largest difference between the two groups. CONCLUSION: People with type 2 diabetes aged 18-50 years had a higher 10-year cumulative incidence of and a higher mean number of doctor visits for musculoskeletal pain than the non-diabetic group. Musculoskeletal pain might directly or indirectly interfere with or decrease the physical activity levels of people with diabetes. Therefore, it is important to detect and treat musculoskeletal pain early in order to promote physical activity and optimize blood sugar control. PMID- 26589717 TI - Drug-induced torsades de pointes in an underserved urban population. Methadone: is there therapeutic equipoise? AB - BACKGROUND: Although it has been well established that methadone use can result in prolonged QTc/torsades de pointes (TdP) and has been labeled as one of the main drugs that cause TdP, it is still prescribed indiscriminately, and several cases of methadone-associated TdP have been seen in our community. METHODS: Our objective was to determine the associated factors for prolonged QTc and the development of torsades de pointes (TdP) in our underserved patient population. We found 12,550 ECGs with prolonged QTc between 2002 and 2013. Medical records were reviewed in order to identify precipitating factors for prolonged QTc and to detect incidence of TdP. RESULTS: We identified 2735 patients with prolonged QTc who met the inclusion criteria. Of these, 89 (3%) experienced TdP. There was a greater prevalence of HIV infection in the TdP group (11.2 vs. 3.7%, p < 0.001). Furosemide, hydrochlorothiazide, selective serotonin reuptake inhibitors (SSRIs), amiodarone, ciprofloxacin, methadone, haloperidol, and azithromycin were the drugs most often associated with prolonged QTc (31, 8.2, 7.6, 7.1, 3.9, 3.4 and 3.3%, respectively). However, the agents most commonly associated with TdP were furosemide (39.3%), methadone (27%), SSRIs (19.1%), amiodarone (18%), and dofetilide (9%). The medications with statistical significance in the multivariate analysis for TdP development in descending order were as follows: ranolazine (odds ratios [OR] = 53.61, 95% confidence interval [CI] 5.4-524, p < 0.001), dofetilide (OR = 25, CI 6.47-103.16, p < 0.001), voriconazole (OR = 21.40, CI 3.24-124.25, p < 0.001), verapamil (OR = 10.98, CI 2.62-44.96, p < 0.001), sotalol (OR = 12.72, 1.95-82.81, p = 0.008), methadone (OR = 9.89, CI 4.05-24.15, p < 0.001), and SSRI (OR = 2.26, CI 1.10-5.96, p < 0.001). This multivariate analysis revealed that amiodarone and HIV infection were not implicated in TdP. CONCLUSION: Methadone was by far the leading medication implicated in the development of TdP and an independent predictor in both univariate and multivariate analyses despite the fact that it was not the most common QT-prolonging medication in our population. PMID- 26589718 TI - CoCStom trial: study protocol for a randomised trial comparing completeness of adjuvant chemotherapy after early versus late diverting stoma closure in low anterior resection for rectal cancer. AB - BACKGROUND: Current evidence supports a diverting stoma in patients undergoing low anterior resection with total mesorectal excision for rectal cancer as it reduces clinical severity of anastomotic leakage. However, relevant stoma morbidity after rectal cancer surgery exists and has a significant impact on quality of life. Moreover, a diverting stoma has an influence on completeness of chemotherapy but it remains unclear in which way. There is no evidence regarding optimal timing for stoma closure in relation to adjuvant chemotherapy. Two randomised controlled trials have studied early stoma closure after low anterior resection in patients with rectal cancer, one of them showing that early closure around day 8 after resection is possible without increasing morbidity. METHODS/DESIGN: CoCStom is a randomised multicentre trial comparing completeness of adjuvant chemotherapy as primary endpoint after early (8-10 days after resection, before starting adjuvant therapy) versus late (~26 weeks after resection and completion of adjuvant therapy) stoma closure in patients with locally advanced rectal cancer undergoing low anterior resection after neoadjuvant therapy. After exclusion of post-operative anastomotic leakage 257 patients from 30 German hospitals are planned to be included in order to assure a power of 80% for the confirmatory analysis of at least 214 evaluable cases. An absolute increase of 20% for the rate of completely administered adjuvant chemotherapy is regarded as a clinically meaningful step forward and serves as basis for sample size calculation. Quality of life, stoma-related complications, individual completeness of chemotherapy rate, percentage of patients stopping adjuvant therapy or undergoing dose modifications or delay, oncological outcomes, cumulative days of hospitalisation and number of readmissions, rate of symptomatic anastomotic leaks after stoma closure, mortality, post-operative complications and toxicity of adjuvant chemotherapy are secondary endpoints. DISCUSSION: The CoCStom trial aims to clarify optimal timing of stoma closure in the context of adjuvant chemotherapy. Depending on the results of the trial, patients could benefit either from early or late stoma closure in regard to long term oncological survival due to a higher rate of completeness of adjuvant chemotherapy treatment and thus better effectiveness. TRIAL REGISTRATION: German Clinical Trials Register, DRKS00005113. Registered 28 August 2013. PMID- 26589720 TI - Trientine induced colitis during therapy for Wilson disease: a case report and review of the literature. AB - BACKGROUND: Wilson disease (WD) is an autosomal recessive disorder of human copper metabolism characterized by copper accumulation in the liver due to impaired excretion of copper into the bile. Brain accumulation of copper may cause neuropsychiatric symptoms. Trientine (triethylenetetramine dihydrochloride) is a copper-chelating agent used to treat patients with WD. Trientine has been considered an option for initial treatment and maintentance therapy of WD due to its safety profile. CASE PRESENTATION: A 40 year old female with a recent diagnosis of WD was started on treatment with trientine for her WD. Within one month she developed profound bloody diarrhea unresponsive to medical treatment. Trientine was discontinued and a colonoscopy with biopsy showed moderately active ileitis and moderate to severe pancolitis, consistent with a drug induced mucosal injury. The colitis improved immediately upon withdrawal of trientine, and recurred when medication was rechallenged because of worsened WD symptoms. After second compulsory discontinuation of trientine, she remained on zinc therapy for her WD and her colitis resolved by time. CONCLUSION: Drug induced colitis is a very rare side effect of trientine. Although trientine therapy is well tolerated and less side effects are reported with this medication than penicillamine, colitis can occur during trientine treatment. Zinc therapy may be an effective alternative for treatment of WD in patients experiencing side effects from chelation therapy. PMID- 26589719 TI - A comparison of human and mouse gene co-expression networks reveals conservation and divergence at the tissue, pathway and disease levels. AB - BACKGROUND: A deeper understanding of differences and similarities in transcriptional regulation between species can uncover important information about gene functions and the role of genes in disease. Deciphering such patterns between mice and humans is especially important since mice play an essential role in biomedical research. RESULTS: Here, in order to characterize evolutionary changes between humans and mice, we compared gene co-expression maps to evaluate the conservation of co-expression. We show that the conservation of co-expression connectivity of homologous genes is negatively correlated with molecular evolution rates, as expected. Then we investigated evolutionary aspects of gene sets related to functions, tissues, pathways and diseases. Genes expressed in the testis, eye and skin, and those associated with regulation of transcription, olfaction, PI3K signalling, response to virus and bacteria were more divergent between mice and humans in terms of co-expression connectivity. Surprisingly, a deeper investigation of the PI3K signalling cascade revealed that its divergence is caused by the most crucial genes of this pathway, such as mTOR and AKT2. On the other hand, our analysis revealed that genes expressed in the brain and in the bone, and those associated with cell adhesion, cell cycle, DNA replication and DNA repair are most strongly conserved in terms of co-expression network connectivity as well as having a lower rate of duplication events. Genes involved in lipid metabolism and genes specific to blood showed a signature of increased co-expression connectivity in the mouse. In terms of diseases, co-expression connectivity of genes related to metabolic disorders is the most strongly conserved between mice and humans and tumor-related genes the most divergent. CONCLUSIONS: This work contributes to discerning evolutionary patterns between mice and humans in terms of gene interactions. Conservation of co-expression is a powerful approach to identify gene targets and processes with potential similarity and divergence between mice and humans, which has implications for drug testing and other studies employing the mouse as a model organism. PMID- 26589721 TI - Laryngeal motility alteration: A missing link between sleep apnea and vagus nerve stimulation for epilepsy. AB - This study aimed to evaluate the prevalence and the relationship of sleep breathing disorders (SBDs) and laryngeal motility alterations in patients with drug-resistant epilepsy after vagus nerve stimulator (VNS) implantation. Twenty three consecutive patients with medically refractory epilepsy underwent out-of center sleep testing before and after VNS implantation. Eighteen eligible subjects underwent endoscopic laryngeal examination post-VNS implantation. Statistical analysis was carried out to assess an association between laryngeal motility alterations and the onset/worsening of SBDs. After VNS implantation, 11 patients showed a new-onset mild/moderate SBD. Half of the patients already affected by obstructive sleep apnea (OSA) showed worsening of SBD. All of the patients with a new-onset OSA had a laryngeal pattern with left vocal cord adduction (LVCA) during VNS stimulation. The association between VNS-induced LVCA and SBD was statistically significant. This study suggests an association between VNS and SBD, hinting to a pivotal role of laryngeal motility alterations. The relationship between SBD and VNS-induced LVCA supports the need to routinely investigate sleep respiratory and laryngeal motility patterns before and after VNS implantation. PMID- 26589722 TI - Autophagic lysosomal reformation depends on mTOR reactivation in H2O2-induced autophagy. AB - Autophagic lysosomal reformation, a key cellular process for maintaining lysosome homeostasis in elevated autophagy, so far has only been reported for cells under certain forms of starvation. For this reason, it is controversial that whether this phenomenon is starvation-specific and its importance in lysosomal regeneration at the late stage of autophagy is often challenged. Here we show that exogenous hydrogen peroxide (H2O2) induced lysosome depletion and recovery characteristic of autophagic lysosomal reformation, and we confirmed the occurrence of autophagic lysosomal reformation after H2O2 treatment by demonstrating Rab7 dissociation from autolysosomes, recruitment of Phosphatidylinositol 4-phosphate (PI4P) and clathrin to the surface of autolysosomes, and the existence of tubular "pro-lysosome" structures extending from autolysosomes. Similar to starvation, H2O2 caused an initial deactivation and a subsequent reactivation for mTOR, and mTOR reactivation was essential for ALR. Our results provided a first non-starvation example of autophagic lysosomal reformation and provide evidence for its importance for some autophagic processes other than that of starvation. PMID- 26589723 TI - Challenging the anticoagulant paradigm? PMID- 26589725 TI - How Should Alcohol Problems Be Conceptualized? Causal Indicators Within the Rutgers Alcohol Problem Index. AB - Alcohol-related problems have traditionally been conceptualized and measured by an effect indicator model. That is, it is generally assumed that observed indicators of alcohol problems are caused by a latent variable. However, there are reasons to think that this construct is more accurately conceptualized as including at least some causal indicators, in which observed indicators cause the latent variable. The present study examined the measurement model of a well-known alcohol consequences questionnaire, the Rutgers Alcohol Problem Index. Participants were 703 students from a large public university in the Northeast mandated to an alcohol intervention. We conducted a zero tetrad test to examine a measurement model consisting solely of effect indicators and a model with both causal and effect indicators. Overall, the results suggested the hybrid model fit the data better than a model with only effect indicators. These findings have implications regarding the theoretical underpinnings of alcohol-related consequences. PMID- 26589724 TI - Vps34 and PLD1 take center stage in nutrient signaling: their dual roles in regulating autophagy. AB - Autophagy is a critical pathway leading to lysosomal degradation of cellular components in response to changes in nutrient availability. Autophagy includes the biogenesis of autophagosomes and their sequential maturation through fusion with endo-lysosomes. The class III PI3 kinase Vps34 and its product phosphatidylinositol-3-phosphate (PI(3)P) play a critical role in this process, and enable the amino acid-mediated activation of mammalian target of rapamycin (mTOR), a suppressor of autophagy. Recent studies have shown that phospholipase PLD1, a downstream regulator of Vps34, is also closely involved in both mTOR activation and autophagy. This mini review summarizes recent findings in the regulation of Vps34 and PLD1 and highlights the role of these lipid-metabolizing enzymes in both mTOR activation and autophagy. PMID- 26589726 TI - Emerging Role of MRI for Radiation Treatment Planning in Lung Cancer. AB - Magnetic resonance imaging (MRI) provides excellent soft-tissue contrast and allows for specific scanning sequences to optimize differentiation between various tissue types and properties. Moreover, it offers the potential for real time motion imaging. This makes magnetic resonance imaging an ideal candidate imaging modality for radiation treatment planning in lung cancer. Although the number of clinical research protocols for the application of magnetic resonance imaging for lung cancer treatment is increasing (www.clinicaltrials.gov) and the magnetic resonance imaging sequences are becoming faster, there are still some technical challenges. This review describes the opportunities and challenges of magnetic resonance imaging for radiation treatment planning in lung cancer. PMID- 26589727 TI - Early aspirin desensitization in unstable patients with acute coronary syndrome: Short and long-term efficacy and safety. AB - BACKGROUND: Aspirin hypersensitivity is not a rare condition among patients with acute coronary syndrome. However, despite the publication of several successful desensitization protocols, the procedure is not as widespread as expected. We present a cohort of patients with acute coronary syndrome undergoing aspirin desensitization to evaluate its short- and long-term efficacy and safety and to reinforce data from previous studies. METHODS: Of 1306 patients admitted to our Coronary Care Unit between February 2011 and February 2013, 24 (1.8%) had a history of aspirin hypersensitivity. All 24 patients underwent an eight-dose aspirin desensitization protocol (0.1, 0.3, 1, 3, 10, 25, 50 and 100 mg of aspirin given by mouth every 15 minutes) after premedication with antihistamines and corticosteroids or antileucotrienes. Previously prescribed beta blockers and angiotensin-converting enzyme inhibitors were not discontinued. All patients were desensitized within 72 hours of admission. Those requiring urgent catheterization (five patients with ST segment elevation myocardial infarction) were desensitized within 12 hours of catheterization and the remainder before catheterization. RESULTS: All patients were successfully desensitized and only one presented with an urticarial reaction. The five patients with ST segment elevation myocardial infarction were treated with abciximab until desensitization was complete. All but one patient underwent catheterization and 20 underwent percutaneous coronary intervention, most (66%) with the implantation of a bare metal stent. At follow up (a minimum of 6-24 months), only two patients had discontinued aspirin, both due to gastrointestinal bleeding, and no hypersensitivy reaction had occurred. CONCLUSIONS: Aspirin desensitization is effective and safe in unstable patients with acute coronary syndrome in both the short and long term. PMID- 26589728 TI - Digital Interventions to Promote Self-Management in Adults With Hypertension: Protocol for Systematic Review and Meta-Analysis. AB - BACKGROUND: Digital interventions, defined as any intervention accessed and taking input from patients in the form of a computer/Web-based program or mobile phoned-based app, can potentially help empower patients to self-manage long-term conditions such as hypertension. Importantly, digital interventions have the potential to provide patients with personalized information and support for active involvement in treatment as well as cost saving. OBJECTIVE: The purpose of this systematic review is to synthesize the evidence for using digital interventions to support patient self-management of hypertension, and determine their impact on control and reduction of blood pressure, other clinical outcomes, quality of life, medication adherence, health service utilization, and economic benefits. METHODS: A systematic search of bibliographic databases including Medline, Embase, CINAHL, and PsycINFO will be undertaken. Abstracts and citations will be independently screened by 2 researchers against predetermined inclusion criteria. Any disagreements will be resolved by discussion and further consideration of the inclusion criteria. Only randomized controlled trials which have been published in peer peer-reviewed journals with a diagnosis of hypertension will be considered. Inclusion criteria will be (1) adults (age >= 18 years) with hypertension (as defined by the primary authors); (2) an interactive digital intervention compared with usual care; and (3) outcomes of objectively measured change in blood pressure. Data extraction from identified articles will be undertaken by 2 independent reviewers using a uniform template. The main outcomes are systolic blood pressure (SBP) and diastolic blood pressure (DBP), and quality of life indicators. Secondary outcomes include cost- effectiveness, medication adherence, emotional well-being, and physical activity. Risk of bias of included studies will be assessed using the Cochrane tool. RESULTS: Our research is currently ongoing. Data will be summarized narratively, and if possible, meta-analyses will be performed to assess the impact of the interventions on outcomes. CONCLUSIONS: By summarizing and synthesizing available data, this review will help inform policy on the use of digital interventions for self-management of hypertension and will clarify areas for further research. TRIAL REGISTRATION: Prospero 2014: CRD42014010268; http://www.crd.york.ac.uk/PROSPERO/display_record.asp? ID=CRD42014010268 (Archived by WebCite at http://www.webcitation.org/6c5alQQJL). PMID- 26589729 TI - Cisplatin- Versus Non-Cisplatin-based First-Line Chemotherapy for Advanced Urothelial Carcinoma Previously Treated With Perioperative Cisplatin. AB - INTRODUCTION: The optimal choice of first-line chemotherapy for patients with relapse of urothelial carcinoma (UC) after perioperative cisplatin-based chemotherapy (PCBC) is unclear. We investigated the outcomes with cisplatin rechallenge versus a non-cisplatin regimen in patients with recurrent metastatic UC after PCBC in a multicenter retrospective study. PATIENTS AND METHODS: Individual patient-level data were collected for patients who had received various first-line chemotherapy regimens for advanced UC after previous PCBC. Cox proportional hazards models were used to investigate the prognostic ability of the type of perioperative and first-line chemotherapy to independently affect overall survival (OS) and progression-free survival (PFS) after accounting for known prognostic factors. RESULTS: Data were available for 145 patients (12 centers). The mean age was 62 years; the Eastern Cooperative Oncology Group (ECOG) performance status (PS) was > 0 for 42.0% of the patients. Of the 145 patients, 63% had received cisplatin-based first-line chemotherapy. The median time from previous chemotherapy (TFPC) was 6.2 months (range, 1-154 months). The median OS was 22 months (95% confidence interval [CI], 18-27 months), and the median PFS was 6 months (95% CI, 5-7 months). A better ECOG PS and a longer TFPC (> 12 months vs. <= 12 months; hazard ratio [HR], 0.32; 95% CI, 0.20-0.52; P < .001) was prognostic for OS and PFS. Cisplatin-based chemotherapy was associated with poor OS (HR, 1.86; 95% CI, 1.13-3.06; P = .015), which appeared to be pronounced in those patients with a TFPC of <= 12 months. Retreatment with cisplatin in the first-line setting was associated with worse OS (HR, 3.38; P < .001). CONCLUSION: The results of the present retrospective analysis suggest that for patients who have undergone previous PCBC for UC, rechallenging with cisplatin might confer a poorer OS, especially for those with progression within < 1 year. PMID- 26589730 TI - Intrahepatic bile duct mixed adenoneuroendocrine carcinoma: a case report and review of the literature. AB - BACKGROUND: Mixed adeno-neuroendocrine carcinoma (MANEC) of the biliary tract is rare with only a few reported cases. Consequently, knowledge about their pathogenesis, histopathological characteristics and outcomes is sparce. CASE PRESENTATION: A 53-year old man presented with epigastric pain on a background of excessive alcohol consumption. Contrast-enhanced computed tomography imaging of the liver revealed a central enhancing mass located at the bifurcation of right anterior and posterior portal veins. Magnetic resonance imaging demonstrated intrahepatic biliary duct dilatation distal to the mass. The patient underwent a right lobe hepatectomy and excision of the extrahepatic biliary tree with formation of a hepaticojejunostomy. Histopathological finding of the specimen revealed an intraductal tumour with predominant neuroendocrine immunohistochemical phenotype and infiltration into nearby tissue. An element of glandular differentiation on immunohistochemistry confirmed the lesion as MANEC. CONCLUSIONS: We present the first reported histopathological case of a MANEC arising from the intrahepatic bile ducts. This report aims to review what is known about primary neuroendocrine and mixed adeno-neuroendocrine carcinoma of the bile ducts, particularly in comparison to other types of biliary and hepatic tumours. PMID- 26589731 TI - Comparative transcriptome analysis of lufenuron-resistant and susceptible strains of Spodoptera frugiperda (Lepidoptera: Noctuidae). AB - BACKGROUND: The evolution of insecticide resistance in Spodoptera frugiperda (Lepidoptera: Noctuidae) has resulted in large economic losses and disturbances to the environment and agroecosystems. Resistance to lufenuron, a chitin biosynthesis inhibitor insecticide, was recently documented in Brazilian populations of S. frugiperda. Thus, we utilized large-scale cDNA sequencing (RNA Seq analysis) to compare the pattern of gene expression between lufenuron resistant (LUF-R) and susceptible (LUF-S) S. larvae in an attempt to identify the molecular basis behind the resistance mechanism(s) of S. frugiperda to this insecticide. RESULTS: A transcriptome was assembled using approximately 19.6 million 100 bp-long single-end reads, which generated 18,506 transcripts with a N50 of 996 bp. A search against the NCBI non-redundant database generated 51.1% (9,457) functionally annotated transcripts. A large portion of the alignments were homologous to insects, with the majority (45%) being similar to sequences of Bombyx mori (Lepidoptera: Bombycidae). Moreover, 10% of the alignments were similar to sequences of various species of Spodoptera (Lepidoptera: Noctuidae), with 3% of them being similar to sequences of S. frugiperda. A comparative analysis of the gene expression between LUF-R and LUF-S S. frugiperda larvae identified 940 differentially expressed transcripts (p <= 0.05, t-test; fold change >= 4). Six of them were associated with cuticle metabolism. Of those, four were overexpressed in LUF-R larvae. The machinery involved with the detoxification process was represented by 35 differentially expressed transcripts; 24 of them belonging to P450 monooxygenases, four to glutathione-S transferases, six to carboxylases and one to sulfotransferases. RNA-Seq analysis was validated for a number of selected candidate transcripts by using quantitative real time PCR (qPCR). CONCLUSIONS: The gene expression profile of LUF-R larvae of S. frugiperda differs from LUF-S larvae. In general, gene expression is much higher in resistant larvae when compared to the susceptible ones, particularly for those genes involved with pathways for xenobiotic detoxification, mainly represented by P450 monooxygenases transcripts. Our data indicate that enzymes involved with the detoxification process, and mostly the P450, are one of the resistance mechanisms employed by the LUF-R S. frugiperda larvae against lufenuron. PMID- 26589732 TI - [Hyperparathyroidism in multiple endocrine neoplasia type 2A syndrome. Surgical and genetic implications]. PMID- 26589733 TI - [Shared decision making]. PMID- 26589734 TI - [Cutaneous involvement of amyloidosis associated with multiple myeloma]. PMID- 26589735 TI - [Unna-Thost syndrome]. PMID- 26589736 TI - [The Middle East respiratory syndrome coronavirus]. PMID- 26589737 TI - [Hashimoto's encephalopaty associated with primary biliary cirrhosis and vitiligo]. PMID- 26589738 TI - [Vipera latastei (Hocicuda viper) bite]. PMID- 26589739 TI - Influence of magnetic field on zebrafish activity and orientation in a plus maze. AB - We describe an impact of the geomagnetic field (GMF) and its modification on zebrafish's orientation and locomotor activity in a plus maze with four arms oriented to the north, east, south and west. Zebrafish's directional preferences were bimodal in GMF: they visited two arms oriented in opposed directions (east west) most frequently. This bimodal preference remained stable for same individuals across experiments divided by several days. When the horizontal GMF component was turned 90 degrees clockwise, the preference accordingly shifted by 90 degrees to arms oriented to the north and south. Other modifications of GMF (reversal of both vertical and horizontal GMF components; reversal of vertical component only; and reversal of horizontal component only) did not exert any discernible effect on the orientation of zebrafish. The 90 degrees turn of horizontal component also resulted in a significant increase of fish's locomotor activity in comparison with the natural GMF. This increase became even more pronounced when the horizontal component was repeatedly turned by 90 degrees and back with 1min interval between turns. Our results show that GMF and its variations should be taken into account when interpreting zebrafish's directional preferences and locomotor activity in mazes and other experimental devices. PMID- 26589740 TI - Editorial overview: Viral immunology: Early events in viral infection. PMID- 26589741 TI - Extreme obesity does not predict poor cancer outcomes after surgery for renal cell cancer. AB - OBJECTIVE: To assess whether extreme obesity (body mass index [BMI] >= 40 kg/m(2) ) is associated with peri-operative outcomes, overall survival (OS), cancer specific survival (CSS), or recurrence-free survival (RFS) after surgical treatment for renal cell carcinoma (RCC). PATIENTS AND METHODS: After institutional review board approval, we used an institutional database to identify patients treated surgically between January 2000 and December 2014 with a pathological diagnosis of RCC. Comprehensive clinical and pathological data were reviewed. Kaplan-Meier analyses were used to estimate OS, RFS and CSS. Univariate and multivariate Cox proportional hazards analysis was used to evaluate associations with OS, CSS and RFS in patients with extreme obesity, among other known predictive variables. RESULTS: In all, 100 patients (11.9%) with a BMI >= 40 kg/m(2) and 743 patients (88.1%) with a BMI < 40 kg/m(2) who were treated surgically for RCC were identified. Morbid obesity was not associated with an increased risk of blood transfusion (odds ratio [OR] 1, 95% confidence interval [CI] 0.587-1.70; P = 1.0). The median (interquartile range) length of hospital stay (LOS) was 4 (3-6) days. Morbid obesity was not associated with longer LOS (P = 0.26) or 30-day hospital readmission rates (P = 1.0). Major complications (Clavien >= 3a) were recorded in 67 patients (7.95%). BMI >= 40 kg/m(2) was not a predictor of major complications (OR 0.58, 95% CI 0.227-1.47; P = 0.251) or 90-day mortality (P = 0.4067). BMI >= 40 kg/m(2) was not associated with worse OS (P = 0.7), CSS (P = 0.2) or RFS (P = 0.5). BMI >= 35 kg/m(2) was also not associated with worse OS, CSS or RFS (P = 0.3, 0.1, 0.5, respectively). The 5-year OS rate was 68.9% for the entire cohort, including 69 and 70% for patients with BMI < 40 kg/m(2) and BMI >= 40 kg/m(2) , respectively (P = 0.69). The 5-year CSS was 79.5% for the entire cohort, including 78.4 and 87.9% (P = 0.16) for patients with BMI < 40 kg/m(2) and BMI >= 40 kg/m(2) , respectively. The 5-year RFS rates for BMI < 40 kg/m(2) and BMI >= 40 kg/m(2) were 84.1 and 90.6%, respectively (P = 0.48). CONCLUSIONS: Extreme obesity is not associated with worse peri-operative or cancer outcomes after surgery for RCC. Surgery should remain a standard treatment option in well selected morbidly obese patients. PMID- 26589742 TI - Using Autoimmunity To Inform Tumor Immunity. PMID- 26589743 TI - Comment on "The B Cell-Stimulatory Cytokines BLyS and APRIL Are Elevated in Human Periodontitis and Are Required for B Cell-Dependent Bone Loss in Experimental Murine Periodontitis.". PMID- 26589744 TI - Response to Comment on "The B Cell-Stimulatory Cytokines BLyS and APRIL Are Elevated in Human Periodontitis and Are Required for B Cell-Dependent Bone Loss in Experimental Murine Periodontitis". PMID- 26589745 TI - Comment on "mTOR Inhibition Per Se Induces Nuclear Localization of FOXP3 and Conversion of Invariant NKT (iNKT) Cells into Immunosuppressive Regulatory iNKT Cells". PMID- 26589746 TI - Response to Comment on "mTOR Inhibition Per Se Induces Nuclear Localization of FOXP3 and Conversion of Invariant NKT (iNKT) Cells into Immunosuppressive Regulatory iNKT Cells". PMID- 26589747 TI - Beyond Hypothesis: Direct Evidence That V(D)J Recombination Is Regulated by the Accessibility of Chromatin Substrates. PMID- 26589748 TI - Pillars Article: Cell Type-Specific Chromatin Structure Determines the Targeting of V(D)J Recombinase Activity In Vitro. Cell. 1996. 85: 887-897. PMID- 26589749 TI - Landscape of Tumor Antigens in T Cell Immunotherapy. AB - Cancer immunotherapy is a rapidly evolving field that exploits T cell responses to tumor-associated Ags to induce tumor rejection. Molecular identification of tumor rejection Ags has helped define several classes of Ags, including tissue differentiation and tumor germline Ags. The ability to genetically engineer Ag specific receptors into T cells provides an opportunity to translate these findings into therapies. New immunotherapy agents, notably checkpoint inhibitors, have demonstrated unprecedented efficacy in certain cancers. However, the nature of the Ags driving those beneficial immune responses remains unclear. New evidence suggests that tumors express immunogenic, tumor-specific epitopes generated from the same mutations that drive cancer development. Correlations between cancer types responding to immunotherapies and the frequency of somatic mutations may clarify what drives natural antitumor immune responses. This fusion of tumor immunology and genetics is leading to new ways to target this class of ideal tumor-specific Ags and could allow the application of immunotherapy to many cancers. PMID- 26589750 TI - Positioning a Scientific Community on Unproven Cellular Therapies: The 2015 International Society for Cellular Therapy Perspective. PMID- 26589751 TI - Challenges in the harmonization of immune monitoring studies and trial design for cell-based therapies in the context of hematopoietic cell transplantation for pediatric cancer patients. AB - Clinical trials aimed at improving results of hematopoietic cell transplantation (HCT) by adjuvant cell-based interventions in children have been limited by small numbers and pediatric-specific features. The need for a larger number of pediatric HCT centers to participate in trials has resulted in a demand for harmonization of disease-specific clinical trials and immune-monitoring. Thus far, most phase I/II trials select different end points evaluated at disparate time points, making inter-study comparisons difficult and, sometimes, impossible. In this review, we discuss the various aspects that are important to consider for harmonizing clinical trial design as well as the critical elements for standardized (immune)-monitoring protocols in cell-based intervention trials in the context of HCT. Comparison data from trials applying harmonized trial design will lead to optimized immunotherapeutic treatment protocols to maximize clinical efficacy while minimizing toxicity. PMID- 26589752 TI - Intravenous infusion of allogeneic mesenchymal stromal cells in refractory or relapsed aplastic anemia. AB - BACKGROUND AIMS: For patients with aplastic anemia (AA) who are refractory to anti-thymocyte globulin (ATG) and cyclosporine, a second course of immunosuppression is successful in only one-fourth to one-third of cases. METHODS: We conducted a phase 1/2 study to evaluate the addition of two to five weekly intravenous infusions of allogeneic unrelated non-human leukocyte antigen matched bone marrow-derived mesenchymal stromal cells (MSCs) (median, 2.7 * 10(6) cells/kg/infusion; range, 1.3-4.5) to standard rabbit ATG and cyclosporine in nine patients with refractory or relapsed AA. RESULTS: After a median follow-up of 20 months, no infusion-related adverse event was observed, but four deaths occurred as the result of heart failure and bacterial or invasive fungal infections; only two patients achieved partial hematologic responses at 6 months. We failed to demonstrate by fluorescence in situ hybridization or variable number tandem repeat any MSC engraftment in patient marrow 30, 90 or 180 days after infusions. CONCLUSIONS: Infusion of allogeneic MSCs in AA is safe but does not improve clinical hematologic response or engraft in recipient bone marrow. This study was registered at clinicaltrials.gov, identifier: NCT01297972. PMID- 26589753 TI - The effect of fibroblast growth factor on distinct differentiation potential of cord blood-derived unrestricted somatic stem cells and Wharton's jelly-derived mesenchymal stem/stromal cells. AB - BACKGROUND AIMS: Perinatal tissues are considered an attractive source of mesenchymal stem/stromal cells (MSCs) and have unique characteristics depending on their origin. In this study, we compared the basic characteristics of unrestricted somatic stem cells isolated from cord blood (CB-USSCs) and MSCs isolated from Wharton's jelly of umbilical cords (WJ-MSCs). We also evaluated the effect of basic fibroblast growth factor (bFGF) supplementation on the growth and differentiation of these cells. METHODS: CB-USSCs and WJ-MSCs were isolated from the same individual (n = 6), and their morphology, cell surface antigens, proliferation, expression of stemness markers and adipogenic, osteogenic and chondrogenic differentiation potentials were evaluated. Their morphology, proliferation and differentiation potentials were then also compared in the presence of bFGF supplementation (10 ng/mL). RESULTS: Overall, CB-USSCs expressed DLK-1 and negative for all the HOX gene markers. The expression of cell surface antigen CD90, growth capacity and adipogenic differential potential of CB-USSCs were lower than those of WJ-MSCs. WJ-MSCs showed higher growth capacity, but the expression of CD73 and CD105 and their osteogenic differentiation potential were lower than those of CB-USSCs. The spindle morphology of both CB-USSCs and WJ-MSCs and the growth and adipogenic differentiation of CB-USSCs were improved by bFGF supplementation. However, the bFGF supplement did not have any positive effect on the tri-lineage differentiation potentials of WJ-MSCs. CONCLUSIONS: CB-USSCs and WJ-MSCs each had distinct characteristics including different growth capacity, distinguishable cell surface markers and distinct adipogenic and osteogenic potentials. bFGF supplementation improved the growth capacity and adipogenic differentiation of CB-USSCs. PMID- 26589754 TI - Combined platelet and plasma derivatives enhance proliferation of stem/progenitor cells maintaining their differentiation potential. AB - BACKGROUND AIMS: Platelet derivatives have been proposed as alternatives to animal sera given that for cell therapy applications, the use of fetal bovine/calf serum (FBS/FCS) is subjected to severe limitations for safety and ethical concerns. We developed a cell culture medium additive obtained by the combination of two blood-derived standardized components. METHODS: A platelet lysate (PL) and a platelet-poor plasma (PPP) were produced in a lyophilized form. Each component was characterized for its growth factor content (platelet-derived growth factor-BB/vascular endothelial growth factor). PL and PPP were used as single components or in combination in different ratio at cumulative 5% final concentration in the culture medium. RESULTS: The single components were less effective than the component combination. In primary cell cultures (bone marrow stromal cells, adipose derived adult stem cells, osteoblasts, chondrocytes, umbilical cord-derived mesenchymal stromal cells, lymphocytes), the PL/PPP supplement promoted an increased cell proliferation in respect to the standard FCS culture in a dose-dependent manner, maintaining the cell functionality, clonogenicity, phenotype and differentiative properties throughout the culture. At a different component ratio, the supplement was also used to support proliferation of a cell line (U-937). CONCLUSIONS: The PL/PPP supplement is an efficient cell culture medium additive that can replace FCS to promote cell proliferation. It can outdo FCS, especially when adopted in primary cultures from tissue biopsies. Moreover, the dual component nature of the supplement allows the researcher to determine the more appropriate ratio of the two components for the nutritional and functional requirements of the cell type of interest. PMID- 26589755 TI - [Survey of methicillin-resistant Staphylococcus aureus control measures in hospitals participating in the VINCat program]. AB - INTRODUCTION: VINCat is a nosocomial infection surveillance program in hospitals in Catalonia. The aim of the study was to determine the surveillance and control measures of methicillin-resistant Staphylococcus aureus (MRSA) in these centres. METHODS: An e-mail survey was carried out from January to March 2013 with questions related to the characteristics of the hospitals and their control measures for MRSA. RESULTS: A response was received from 53 hospitals (>500 beds: 7; 200-500 beds: 14;<200 beds: 32; had ICU: 29). Computer alert of readmissions was available in 63%. There was active surveillance of patients admitted from another hospital (46.2%) or a long-term-care centre (55.8%), both being significantly more common measures in hospitals with a rate of MRSA<=22% (global median). Compliance with hand hygiene was observed in 77.4% of the centres, and was greater than 50% in 69.7% of them. All hospitals had contact precautions, although 62.3% did not have exclusive frequently used clinical material in bedrooms. The room cleaning was performed more frequently in 54.7% of hospitals, and 67.9% of them had programs for the appropriate use of antibiotics. CONCLUSIONS: This study provides information on the implementation of measures to prevent MRSA in hospitals participating in the VINCat program. Most of the centres have an MRSA protocol, however compliance with it should be improved, especially in areas such as active detection on admission in patients at risk, hand hygiene adherence, cleaning frequency and optimising the use of antibiotics. PMID- 26589757 TI - Culturally and linguistically diverse healthcare students can find integration into clinical placements. PMID- 26589756 TI - Phenotypic and genotypic characterization of vancomycin-resistant Enterococcus faecium clinical isolates from two hospitals in Mexico: First detection of VanB phenotype-vanA genotype. AB - INTRODUCTION: Enterococcus faecium has emerged as a multidrug-resistant nosocomial pathogen involved in outbreaks worldwide. Our aim was to determine the antimicrobial susceptibility, biofilm production, and clonal relatedness of vancomycin-resistant E. faecium (VREF) clinical isolates from two hospitals in Mexico. METHODS: Consecutive clinical isolates (n=56) were collected in two tertiary care hospitals in Mexico from 2011 to 2014. VREF isolates were characterized by phenotypic and molecular methods including pulsed-field gel electrophoresis (PFGE). RESULTS: VREF isolates were highly resistant to vancomycin, erythromycin, norfloxacin, high-level streptomycin, and teicoplanin, and showed lower resistance to tetracycline, nitrofurantoin and quinupristin dalfopristin. None of the isolates were resistant to linezolid. The vanA gene was detected in all isolates. Two VanB phenotype-vanA genotype isolates, highly resistant to vancomycin and susceptible to teicoplanin, were detected. Furthermore, 17.9% of the isolates were classified as biofilm producers, and the espfm gene was found in 98.2% of the isolates. A total of 37 distinct PFGE patterns and 6 clones (25% of the isolates as clone A, 5.4% as clone B, and 3.6% each as clone C, D, E, and F) were detected. Clone A was detected in 5 different wards of the same hospital during 14 months of surveillance. CONCLUSION: The high resistance to most antimicrobial agents and the moderate cross-transmission of VREF detected accentuates the need for continuous surveillance of E. faecium in the hospital setting. This is also the first reported incidence of the E. faecium VanB phenotype-vanA genotype in the Americas. PMID- 26589758 TI - Provision of preoperative and postoperative information increases the likelihood a person will be fully prepared for home recovery. PMID- 26589759 TI - Quantification of damage due to low-dose radiation exposure in mice: construction and application of a biodosimetric model using mRNA indicators in circulating white blood cells. AB - Biodosimetry, the measurement of radiation damage in a biologic sample, is a reliable tool for increasing the accuracy of dose estimation. Although established chromosome analyses are suitable for estimating the absorbed dose after high-dose irradiation, biodosimetric methodology to measure damage following low-dose exposure is underdeveloped. RNA analysis of circulating blood containing radiation-sensitive cells is a candidate biodosimetry method. Here we quantified RNA from a small amount of blood isolated from mice following low-dose body irradiation (<0.5 Gy) aimed at developing biodosimetric tools for situations that are difficult to study in humans. By focusing on radiation-sensitive undifferentiated cells in the blood based on Myc RNA expression, we quantified the relative levels of RNA for DNA damage-induced (DDI) genes, such as Bax, Bbc3 and Cdkn1a. The RNA ratios of DDI genes/Myc in the blood increased in a dose dependent manner 4 h after whole-body irradiation at doses ranging from 0.1 to 0.5 Gy (air-kerma) of X-rays, regardless of whether the mice were in an active or resting state. The RNA ratios were significantly increased after 0.014 Gy (air kerma) of single X-ray irradiation. The RNA ratios were directly proportional to the absorbed doses in water ranging from 0.1 to 0.5 Gy, based on gamma irradiation from (137)Cs. Four hours after continuous irradiation with gamma-rays or by internal contamination with a beta-emitter, the increased RNA ratios resembled those following single irradiation. These findings indicate that the RNA status can be utilized as a biodosimetric tool to estimate low-dose radiation when focusing on undifferentiated cells in blood. PMID- 26589760 TI - Predictive biomarkers in PD-1/PD-L1 checkpoint blockade immunotherapy. AB - Checkpoint blockades turn on a new paradigm shift in immunotherapy for cancer. Remarkable clinical efficacy, durable response and low toxicity of programmed death 1 (PD-1)/programmed death ligand-1 (PD-L1) checkpoint blockades have been observed in various malignancies. However, a lot of cancer patients failed to respond to the PD-1/PD-L1 checkpoint blockades. It is crucial to identify a biomarker to predict the response to checkpoint blockades. The overexpression of PD-L1 is an important and widely-explored predictive biomarker for the response to PD-1/PD-L1 antibodies. However PD-L1 staining cannot be used to accurately select patients for PD-1/PD-L1 pathway blockade due to the low prediction accuracy and dynamic changes. Tumor-infiltrating immune cells and molecules in the tumor microenvironment, or along with PD-L1 expression, may be important in predicting clinical benefits of PD-1/PD-L1 checkpoint blockades. Gene analysis has proven to be new approach for judging the potential clinical benefit of immune checkpoint inhibitors, such as mutational landscape and mismatch-repair deficiency. Further preclinical and clinical studies are necessary to carry out before its application in clinical practice. Challenges should be overcome to identify patients accurately who will benefit from PD-1/PD-L1 checkpoint blockades. In this review, we focus on the predictive biomarkers for checkpoint blockades of PD-1/PD-L1 pathway. PMID- 26589761 TI - The development of a non-invasive model to predict the presence of non-alcoholic steatohepatitis in patients with non-alcoholic fatty liver disease. AB - BACKGROUND: Non-alcoholic steatohepatitis (NASH) is an advanced and aggressive form of non-alcoholic fatty liver disease (NAFLD), which remains difficult to diagnose without a liver biopsy. Hyperferritinemia has increasingly been associated with the presence of NASH. Hence, we sought to explore the relationship between ferritin and NASH and to develop a composite model based on ferritin to predict the presence of NASH. METHODS: A total of 405 patients with biopsy-proven NAFLD were enrolled in the study. Comparison was explored to assess differences between patients with and without NASH, upon which a scoring model was established using variables found to be independent predictors of NASH. RESULTS: Among all patients with NAFLD, 291 (72%) had biopsy-proven NASH, and 114 (28%) had non-NASH. Mean age was 48 +/- 12 years, and 56% were female. Ferritin was significantly higher in NASH compared with non-NASH patients (184 vs 126, respectively; P < 0.001) but lacked diagnostic accuracy for predicting NASH alone (area under the curve [AUC 0.62]). The addition of other significant variables such as aspartate aminotransferase, body mass index, platelet count, diabetes, and hypertension to ferritin improved the prediction of NASH with an AUC 0.81 (95% confidence interval: 0.76-0.86). Internal validation of the model using imputed data sets demonstrated that AUC did not change materially. CONCLUSIONS: While higher ferritin was significantly associated with NASH, ferritin alone lacked diagnostic accuracy to predict NASH. However, incorporating several easily obtainable variables with ferritin allowed the construction of a novel scoring system that can be easily applied in the clinical setting to guide management of NAFLD. PMID- 26589762 TI - Recurrent Pregnancy Loss in Women with Killer Cell Immunoglobulin-Like Receptor KIR2DS1 is Associated with an Increased HLA-C2 Allelic Frequency. AB - PROBLEM: During human pregnancy, the uterine lining is highly populated with killer-immunoglobulin-like receptor (KIR)-expressing NK cells that recognize HLA C molecules on trophoblast cells. The goal of this study was to analyze the KIR gene contents and frequencies in a N. American cohort of women with RPL of unknown etiology to evaluate whether there is a genetic susceptibility to RPL based on a woman's KIR repertoire and her HLA-C group, as well as the HLA-C group of the partner. METHOD OF STUDY: The frequencies of KIR and HLA-C1 and HLA-C2 genes were evaluated in 139 Caucasian women with RPL; HLA-C1, and HLA-C2 group genes were analyzed in their partners (n = 42). The gene frequencies were compared with data reported from corresponding populations. RESULTS: Overall, the frequencies of HLA-C groups and KIR genes and genotypes in RPL cohort resembled the frequencies for US Caucasians. The HLA-C1 and HLA-C2 group distribution was significantly different between women with or without KIR2DS1. Women positive for KIR2DS1 (45.3% of the study cohort) had an increased frequency of its ligand, HLA C2 (0.5159 versus 0.3684 in KIR2DS1 negative women, P = 0.014). CONCLUSION: Our results indicate that among KIR2DS1 pos women, the co-expression of HLA-C2 is associated with RPL. PMID- 26589763 TI - Relapse of ileus in patients with psychiatric disorders: A 2-year chart review. AB - OBJECTIVE: To explore risk factors for relapse of paralytic ileus in a psychiatric population. METHOD: We conducted a systematic chart-review to examine two-year relapse rates in psychiatric patients who received treatment for ileus from 2008 to 2012. Binary logistic regression analyses were performed to evaluate associations between sociodemographic and clinical characteristics and relapse of ileus. RESULTS: Sixty-three subjects (38 women; age, 66.0 +/- 11.3 years) were included; 62 subjects recovered from ileus. During the subsequent 2 years, 26 (41.3%) subjects experienced relapse. In the entire sample, relapse of ileus was associated with history of abdominal surgery (P=.03, odds ratio=4.34, 95% CI=1.15 16.42) and duration of psychiatric disorders (P=.02, odds ratio=1.00, 95% CI=1.00 1.00). In a subgroup of 43 subjects with schizophrenia, history of abdominal surgery (P=.01, odds ratio=12.09, 95% CI=1.78-82.15) and age (P=.02, odds ratio=1.12, 95% CI=1.02-1.23) predicted relapse of ileus. CONCLUSIONS: Since relapse of ileus is common and can be serious in psychiatric patients, special attention is warranted to those who are old, have a history of abdominal surgery or a longer duration of psychiatric disorders to prevent relapse of ileus. PMID- 26589764 TI - Electroconvulsive therapy in the intensive care unit for the treatment of catatonia: a case series and review of the literature. AB - OBJECTIVE: Catatonia is an underdiagnosed syndrome that may occur in severely ill patients. The malignant subtype, consisting of motor symptoms, autonomic instability and fever, is associated with high mortality rates, though exact current mortality rates are unknown. This subtype requires a fast detection and treatment with high doses of a benzodiazepine or electroconvulsive therapy (ECT), preferably in an intensive care unit (ICU) setting. METHOD: Case series and qualitative literature review. RESULTS: This paper presents four patients admitted to the ICU of an academic hospital diagnosed with malignant catatonia. All patients received ECT after an ineffective trial of high-dose intravenous benzodiazepine treatment. The duration of ECT ranged from 6 to 23 treatments after which the catatonic features partially or fully remitted. In addition, we have reviewed the diagnostic challenges, neurobiology, possible causes, differential diagnosis and treatment options of catatonia, focusing on the treatment with ECT and the importance of detection and multidisciplinary collaboration. CONCLUSION: Malignant catatonia is an underdiagnosed, potentially life-threatening syndrome that requires fast recognition and prompt treatment, preferably in an ICU setting. PMID- 26589765 TI - Using PTSD Coach in primary care with and without clinician support: a pilot randomized controlled trial. AB - OBJECTIVE: This study aims to evaluate the feasibility and potential effectiveness of two approaches to using the PTSD Coach mobile application in primary care: Self-Managed PTSD Coach and Clinician-Supported PTSD Coach. This study also aims to gather preliminary data to investigate if clinician support improves the benefits of using PTSD Coach on posttraumatic stress disorder (PTSD) severity and specialty mental healthcare utilization. METHOD: Twenty primary care veterans with PTSD symptoms were randomized to either Self-Managed PTSD Coach consisting of one 10-min session providing instructions for application use or Clinician-Supported PTSD Coach consisting of four 20-min sessions focused on setting symptom reduction goals and helping veterans fully engage with application content. RESULTS: Research procedures and intervention conditions appear feasible as indicated by high rates of assessment and intervention retention and high clinician fidelity and satisfaction. Both treatments resulted in reductions in PTSD symptoms, with 7 Clinician-Supported PTSD Coach and 3 Self Managed PTSD Coach participants reporting clinically significant improvements. Clinician-Supported PTSD Coach resulted in more specialty PTSD care use postintervention and possibly greater reductions in PTSD symptoms. CONCLUSIONS: Both PTSD Coach interventions are feasible and potentially helpful. The addition of clinician support appears to increase the effectiveness of self-management alone. A larger-scale randomized controlled trial is warranted to confirm these encouraging preliminary findings. PMID- 26589766 TI - Retuning of Mouse NK Cells after Interference with MHC Class I Sensing Adjusts Self-Tolerance but Preserves Anticancer Response. AB - Natural killer (NK) cells are most efficient if their targets do not express self MHC class I, because NK cells carry inhibitory receptors that interfere with activating their cytotoxic pathway. Clinicians have taken advantage of this by adoptively transferring haploidentical NK cells into patients to mediate an effective graft-versus-leukemia response. With a similar rationale, antibody blockade of MHC class I-specific inhibitory NK cell receptors is currently being tested in clinical trials. Both approaches are challenged by the emerging concept that NK cells may constantly adapt or "tune" their responsiveness according to the amount of self MHC class I that they sense on surrounding cells. Hence, these therapeutic attempts would initially result in increased killing of tumor cells, but a parallel adaptation process might ultimately lead to impaired antitumor efficacy. We have investigated this question in two mouse models: inhibitory receptor blockade in vivo and adoptive transfer to MHC class I-disparate hosts. We show that changed self-perception via inhibitory receptors in mature NK cells reprograms the reactivity such that tolerance to healthy cells is always preserved. However, reactivity against cancer cells lacking critical MHC class I molecules (missing self-reactivity) still remains or may even be increased. This dissociation between activity against healthy cells and tumor cells may provide an answer as to why NK cells mediate graft-versus-leukemia effects without causing graft-versus-host disease and may also be utilized to improve immunotherapy. PMID- 26589767 TI - Identification of Anti-CA125 Antibody Responses in Ovarian Cancer Patients by a Novel Deep Sequence-Coupled Biopanning Platform. AB - High-grade epithelial ovarian cancer kills more women than any other gynecologic cancer and is rarely diagnosed at an early stage. We sought to identify tumor associated antigens (TAA) as candidate diagnostic and/or immunotherapeutic targets by taking advantage of tumor autoantibody responses in individuals with ovarian cancer. Plasma-derived IgG from a pool of five patients with advanced ovarian cancer was subjected to iterative biopanning using a library of bacteriophage MS2 virus-like particles (MS2-VLPs) displaying diverse short random peptides. After two rounds of biopanning, we analyzed the selectant population of MS2-VLPs by Ion Torrent deep sequencing. One of the top 25 most abundant peptides identified (DISGTNTSRA) had sequence similarity to cancer antigen 125 (CA125/MUC16), a well-known ovarian cancer-associated antigen. Mice immunized with MS2-DISGTNTSRA generated antibodies that cross-reacted with purified soluble CA125 from ovarian cancer cells but not membrane-bound CA125, indicating that the DISGTNTSRA peptide was a CA125/MUC16 peptide mimic of soluble CA125. Preoperative ovarian cancer patient plasma (n = 100) was assessed for anti-DISGTNTSRA, anti CA125, and CA125. Patients with normal CA125 (<35 IU/mL) at the time of diagnosis had significantly more antibodies to DISGTNTSRA and to CA125 than those patients who had high CA125 (>35 IU/mL). A statistically significant survival advantage was observed for patients who had either normal CA125 and/or higher concentrations of antibodies to CA125 at the time of diagnosis. These data show the feasibility of using deep sequence-coupled biopanning to identify TAA autoantibody responses from cancer patient plasma and suggest a possible antibody mediated mechanism for low CA125 plasma concentrations in some ovarian cancer patients. PMID- 26589768 TI - Radiologic Heterogeneity in Responses to Anti-PD-1/PD-L1 Therapy in Metastatic Renal Cell Carcinoma. AB - Radiologic assessment of tumor response remains a challenge in patients treated with immune checkpoint inhibitors. In metastatic melanoma, for example, a spectrum of imaging patterns in response to immunotherapies have been recognized and associated with clinical benefit. In metastatic renal cell carcinoma (mRCC), less than half of patients treated with immune checkpoint inhibitors achieve objective responses, but some of the responses have been durable. In this series, five different imaging patterns of response and progression are described in mRCC patients treated with anti-PD-1/PD-L1 agents: (i) early and complete response, (ii) pseudoprogression, (iii) disease stability before ultimate response, (iv) mixed response with new lesions, and (v) early progression/primary refractory disease. The implications of the different imaging patterns of patient responses on disease prognosis are discussed and highlight the need for individualized patient assessment when using these novel immune-targeted agents. PMID- 26589769 TI - Proteomic analysis of SRF associated transcription complexes identified TFII-I as modulator of SRF function in neurons. AB - The serum response factor (SRF) is a neuronal activity regulated transcription factor (TF) mediating an immediate early (IEGs, e.g. cFos, Egr1) and actin cytoskeletal gene response. SRF activity is adjusted by two competing cofactor families, ternary complex factors (TCF; e.g. Elk-1) and myocardin related transcription factors (MRTF). We investigated mechanisms of SRF activation upon seizure associated neuronal activity in mice. SRF serine 103 phosphorylation or promoter binding was not obviously changed upon neuronal activation. In contrast, a SRF directed proteomic analysis uncovered established and potentially novel components of SRF associated protein complexes whose abundance was modified by neuronal activity. This included the general transcription factor TFII-I for which we provide a first functional analysis in neurons. TFII-I modulated neuronal SRF target gene expression, enhanced nerve fiber growth and modulated the shape of neuronal growth cones. Interestingly, TFII-I modulated two SRF cofactors, Elk-1 and MRTF-A, in opposite directions. TFII-I and Elk-1 co expression enhanced SRF target gene abundance, SRF promoter binding and neurite growth, whereas TFII-I and MRTF-A resulted in opposite outcomes. In summary, we provide a first proteome wide analysis of SRF associated proteins. We characterized TFII-I as modulator of SRF activity by imposing differential impact on two SRF cofactors. PMID- 26589770 TI - Branched DNA-based Alu quantitative assay for cell-free plasma DNA levels in patients with sepsis or systemic inflammatory response syndrome. AB - Cell-free circulating DNA (cf-DNA) can be detected by various of laboratory techniques. We described a branched DNA-based Alu assay for measuring cf-DNA in septic patients. Compared to healthy controls and systemic inflammatory response syndrome (SIRS) patients, serum cf-DNA levels were significantly higher in septic patients (1426.54 +/- 863.79 vs 692.02 +/- 703.06 and 69.66 +/- 24.66 ng/mL). The areas under the receiver operating characteristic curve of cf-DNA for normal vs sepsis and SIRS vs sepsis were 0.955 (0.884-1.025), and 0.856 (0.749-0.929), respectively. There was a positive correlation between cf-DNA and interleukin 6 or procalcitonin or Acute Physiology and Chronic Health Evaluation II. The cf-DNA concentration was higher in intensive care unit nonsurviving patients compared to surviving patients (2183.33 +/- 615.26 vs 972.46 +/- 648.36 ng/mL; P < .05). Branched DNA-based Alu assays are feasible and useful to quantify serum cf-DNA levels. Increased cf-DNA levels in septic patients might complement C-reactive protein and procalcitonin in a multiple marker format. Cell-free circulating DNA might be a new marker in discrimination of sepsis and SIRS. PMID- 26589771 TI - Criteria for initiation of invasive ventilation in septic shock: An international survey. AB - PURPOSE: The objective of this study is to record intensivists' beliefs on indications and modalities of ventilatory support in critically ill patients with septic shock. METHODS: The instrument is a 23-items questionnaire, sent to all members of the Systemic Inflammation and Sepsis section of the European Society of Intensive Care Medicine. RESULTS: A total of 186 intensivists from 30 countries completed the survey. For 95% of respondents, intubation should be performed in patients with neurologic or respiratory failure. There was much less consensus about cardiovascular failure as a reason for initiation of invasive mechanical ventilation. Among the 7 hemodynamic criteria proposed, none achieved strong agreement. Among respiratory criteria, hypoxemia, signs of respiratory distress, and cyanosis were the most strongly associated with the will to intubate. Among neurologic criteria, a Glasgow score lower than 8 was strongly associated with the will to intubate. Strikingly, 51% of respondents believed that invasive mechanical ventilation would worsen patients with septic shock, mainly through hemodynamic deterioration (70.4%). CONCLUSIONS: This survey highlights the general belief that invasive mechanical ventilation may worsen hemodynamic status in patients with septic shock. There was general agreement with the mandatory need to initiate mechanical ventilation in patients with respiratory failure and coma, but with little respect to hemodynamic criteria. PMID- 26589772 TI - Interaction of threat and verbal working memory in adolescents. AB - Threat induces a state of sustained anxiety that can disrupt cognitive processing, and, reciprocally, cognitive processing can modulate an anxiety response to threat. These effects depend on the level of cognitive engagement, which itself varies as a function of task difficulty. In adults, we recently showed that induced anxiety impaired working memory accuracy at low and medium but not high load. Conversely, increasing the task load reduced the physiological correlates of anxiety (anxiety-potentiated startle). The present work examines such threat-cognition interactions as a function of age. We expected threat to more strongly impact working memory in younger individuals by virtue of putatively restricted cognitive resources and weaker emotion regulation. This was tested by examining the influence of age on the interaction of anxiety and working memory in 25 adolescents (10 to 17 years) and 25 adults (22 to 46 years). Working memory load was manipulated using a verbal n-back task. Anxiety was induced using the threat of an aversive loud scream and measured via eyeblink startle. Findings revealed that, in both age groups, accuracy was lower during threat than safe conditions at low and medium but not high load, and reaction times were faster during threat than safe conditions at high load but did not differ at other loads. Additionally, anxiety-potentiated startle was greater during low and medium than high load. Thus, the interactions of anxiety with working memory appear similar in adolescents and adults. Whether these similarities reflect common neural mechanisms would need to be assessed using functional neuroimaging. PMID- 26589773 TI - Cost-effectiveness of treatments for high-risk myelodysplastic syndromes after failure of first-line hypomethylating agent therapy. AB - PURPOSE: To evaluate optimal salvage therapy in high-risk myelodysplastic syndromes patients who have failed a first-line hypomethylating agent (HMA) therapy, given that treatment choice is challenging. METHODS: Using published literature and expert opinion, we developed a Markov model to evaluate the cost effectiveness of current treatments for patients who failed first-line HMA therapy. The model predicted costs, life years, quality-adjusted life years and incremental cost-effectiveness ratios. Sensitivity analyses were conducted to assess the impact of uncertainty in model inputs. RESULTS: Supportive care was the least expensive option ($65,704/patient) with the shortest survival (0.48 years). Low- and high-intensity chemotherapies and hematopoietic cell transplantation increased survival and costs with incremental cost-effectiveness ratios of $108,808, 306,103 and 318,163/life year, respectively. Switching HMA was more costly and less efficacious than another treatment option, namely low intensity chemotherapy. CONCLUSIONS: Subsequent treatments in myelodysplastic syndrome patients who failed first-line HMA significantly increase costs, while only providing marginal clinical benefit and substantially increasing treatment related morbidities. Additional treatment options would benefit resource allocation, clinical decision-making and patient outcomes. PMID- 26589774 TI - European Code against Cancer 4th Edition: Infections and Cancer. AB - Of the 2,635,000 new cancer cases (excluding non-melanoma skin cancers) occurring in the European Union (EU) in 2012, it is estimated that approximately 185,000 are related to infection with human papillomaviruses (HPVs), hepatitis B and C viruses (HBV and HCV), and Helicobacter pylori (H. pylori). Chronic infection with these agents can lead to cancers of the cervix uteri, liver, and stomach, respectively. Chronic infection with HCV can also lead to B-cell non-Hodgkin lymphoma. Human immunodeficiency virus (HIV) infection continues to be of major public health importance in several EU countries and increases cancer risk via HIV-induced immunosuppression. The fourth edition of the European Code Against Cancer presents recommendations on effective and safe preventive interventions in order to reduce the risk of infection-related cancers in EU citizens. Based on current available evidence, the fourth edition recommends that parents ensure the participation of their children in vaccination programs against HBV (for newborns) and HPV (for girls). In the 'Questions and Answers' (Q&As) section about vaccination and infections in the website for the European Code Against Cancer, individuals who are at risk of chronic HBV or HCV are advised to seek medical advice about testing and obtaining treatment when appropriate. Individuals most at risk of HIV are advised to consult their doctor or healthcare provider to access counselling and, if needed, testing and treatment without delay. Information about H. pylori testing and treatment is also provided as testing might currently be offered in some high-risk areas in Europe. The rationale and supporting evidence for the recommendations on vaccination in the European Code Against Cancer, and for the main recommendations on vaccination and infection in the Q&As, are explained in the present review. PMID- 26589775 TI - [Pain management nursing in hospitalized patients with non-oncological diseases]. AB - AIM: To assess pain management in patients hospitalized with a non-oncological disease and evaluate factors involved in pain assessment. METHODS: A descriptive, cross-sectional study. We reviewed pain episodes documented in the medical records of 105 patients aged>18 years admitted to the medical units of a regional hospital between September and December 2014. Reports of pain episodes were evaluated by assessing 22 variables related to pain management quality criteria. RESULTS: A total of 184 reports were reviewed. Pain was measured using the visual analogue scale (VAS) in 70.1% of patients (n=129); pain was reassessed in 44.3% (n=54) of patients. Pain reassessment was significantly more frequent in patients aged<70 years, as compared to older patients (53.1 vs. 26.8%, respectively; p=0.01). Pain was more frequently considered to be unrelated to the cause of admission in women as compared to men (50 vs. 25.7% p=0.027). Pain was identified in the patient care plan as a collaborative problem by the nurse for 21.1% of the patients. CONCLUSIONS: Some aspects of pain management should be improved, especially those regarding pain description and reassessment. The age and sex of patients significantly influence the approach of pain. PMID- 26589776 TI - Correlation of serum chromium, zinc, magnesium and SOD levels with HbA1c in type 2 diabetes: A cross sectional analysis. AB - The loss of dynamic integrity between homoeostasis of free radicals and antioxidants causes the development of complications like retinopathy, nephropathy, neuropathy, atherosclerosis and cardiovascular diseases in T2DM. AIMS AND OBJECTIVES: To assess the concentrations of serum chromium, zinc, magnesium and SOD in subjects of T2DM and control and to investigate the effect of these variables versus HbA1c. RESULTS: Insignificant difference (P=0.493) was reported in age (50+/-4.7 year compared with 50+/-7.2 year), while body mass Index (23+/-2kg/m(2) compared with 26+/-4.5kg/m(2)) between the T2DM subjects and control subject showed significant difference (<0.0001). Inverse Pearson correlation coefficient, r (-0.376), (-0.689), (-0.05), (-0.05), (-0.40), ( 0.14), (-0.342) and (-0.548) were established when HbA1c of control and T2DM patients were compared with control and T2DM patients of serum Cr, Zn, Mg and SOD variables in that order. The overall "p"-value demonstrated highly significant result at p<0.0001 between the T2DM subjects and controls. CONCLUSION: Strong association between serum chromium and SOD in relation to HbA1c in this study gives a strong point that these variables could be used as markers of cell injury with the intention in further part of life en route to progressive complications in T2DM. PMID- 26589777 TI - Discordance between lipid markers used for predicting cardiovascular risk in patients with type 2 diabetes. AB - AIMS: Non-high density lipoprotein cholesterol (non-HDL-C) is gaining importance over low density lipoprotein cholesterol (LDL-C) as cardiovascular risk marker in patients with type 2 diabetes. It represents the overall lipid burden and is a surrogate marker for the apolipoprotein B. We studied the discordance between the old (LDL-C) and the new (non-HDL-C) lipid markers in a large group of diabetes patients. METHODS: The lipid profile data of all diabetes (T2DM, aged 18-75, using oral or injectable anti diabetic agents) patients was analyzed in this study. We excluded patients with type1 diabetes, secondary forms of diabetes and gestational diabetes. Elevated lipid parameters (LDL>100mg/dL and non HDL C>130mg/dL) were defined as per the guidelines of Adult Treatment Panel III. RESULTS: The study participants (409 M:360 F) had a mean age of 47.3+/-12.4 years, BMI of 28.4+/-5.6kg/m(2) and an A1c of 8.8+/-2.2%. Elevated LDL-C was observed in 383 patients (49.8%) and elevated non HDL-C in 418 (54.4%) patients. Of the 383 patients with elevated LDL-C, 346 (90.3%) had corresponding elevated levels of non-HDL-C and out of 418 patients with elevated non HDL-C, 346 (83%) had elevated LDL-C. Discordance between the elevated LDL-C and non-HDL-C values were greater among patients with low triglyceride levels when compared with those with high triglycerides (Pearson's chi(2) test=67.7; P<0.001). CONCLUSION: Our data suggest a significant discordance between the LDL-C and non-HDL-C in patients with diabetes. This discordance leads to the residual cardiovascular risk in diabetes patients. PMID- 26589778 TI - Epidemiological study of soft-tissue sarcomas in Ireland. AB - Soft-tissue sarcomas (STS) account for 1% of adult and 7% of pediatric malignancies. Histopathology and classification of these rare tumors requires further refinements. The aim of this paper is to describe the current incidence and survival of STS from 1994 to 2012 in Ireland and compare these with comparably coded international published reports. This is a retrospective, population study based on the data from the National Cancer Registry of Ireland (NCRI). Incidence and relative survival rates for STS in Ireland were generated. Incidence of STS based on gender, age and anatomical location was examined. Annual mean incidence rate (European Age Standardized) in Ireland between 1994 and 2012 was 4.48 +/- 0.15 per 100,000 person-years. The overall relative 5-year survival rate of STS for the period 1994-2011 in Ireland was 56%, which was similar to that reported in the U.K. but lower than in most of Europe and U.S.A. Survival rate fluctuated over the period examined, declining slightly in females but showing an increase in males. STS incidence trends in Ireland were comparable to international reports. Survival trends of STS were significantly different between Ireland and other European countries, requiring further study to understand causation. PMID- 26589779 TI - Salvage therapy with pegylated liposomial doxorubicin-based regimen in relapsed/refractory multiple myeloma: comments to the article by Romano et al. PMID- 26589780 TI - Structure of the lepidopteran proboscis in relation to feeding guild. AB - Most butterflies and moths (Lepidoptera) use modified mouthparts, the proboscis, to acquire fluids. We quantified the proboscis architecture of five butterfly species in three families to test the hypothesis that proboscis structure relates to feeding guild. We used scanning electron microscopy to elucidate the fine structure of the proboscis of both sexes and to quantify dimensions, cuticular patterns, and the shapes and sizes of sensilla and dorsal legulae. Sexual dimorphism was not detected in the proboscis structure of any species. A hierarchical clustering analysis of overall proboscis architecture reflected lepidopteran phylogeny, but did not produce a distinct group of flower visitors or of puddle visitors within the flower visitors. Specific characters of the proboscis, nonetheless, can indicate flower and nonflower visitors, such as the configuration of sensilla styloconica, width of the lower branches of dorsal legulae, presence or absence of dorsal legulae at the extreme apex, and degree of proboscis tapering. We suggest that the overall proboscis architecture of Lepidoptera reflects a universal structural organization that promotes fluid uptake from droplets and films. On top of this fundamental structural organization, we suggest that the diversity of floral structure has selected for structural adaptations that facilitate entry of the proboscis into floral tubes. PMID- 26589782 TI - Purification and characterization of a thermophilic 1,3-1,4-beta-glucanase from Bacillus methylotrophicus S2 isolated from booklice. AB - An extracellular 1,3-1,4-beta-glucanase-producing strain S2 was isolated from booklice and identified as Bacillus methylotrophicus. Furthermore, a homogeneous extracellular 1,3-1,4-beta-glucanase GCS2 was purified by ammonium sulfate precipitation and cation-exchange chromatography. The gene for the 1,3-1,4-beta glucanase was cloned, and the nucleotide sequence was determined. Characterization of the purified enzyme revealed the molecular mass of 26 kDa and the optimum activity at pH 7.5, 55 degrees C. The purified enzyme can highly hydrolyze carboxymethylcellulose including oat gum, barley beta-glucan, CMC and lichenan, while low activity on avicel, cellobiose, filter paper, p-nitrophenyl beta-d-cellobioside, and p-nitrophenyl beta-d-glucoside, but no activity against microcrystalline cellulose or salicin. The enzyme was stable at wide range of pHs 5-10 and still maintained above 60% activity at 70 degrees C. The enzyme activity was stimulated by Trixon X-100. The property of the enzyme GCS2 makes this enzyme a broad prospect in brewing and commercial detergent industry. To our knowledge, this is the first report of a 1,3-1,4-beta-glucanase from microbes associated with booklice. PMID- 26589781 TI - Rat-to-Chinese tree shrew heart transplantation is a novel small animal model to study non-Gal-mediated discordant xenograft humoral rejection. AB - Since alpha-1,3-galactosyltransferase knockout (GalT-KO) pigs became available, there has been an increasing interest in non-Gal natural antibody (nAb)-mediated xenograft rejection. To better understand mechanisms of non-Gal nAb-mediated rejection, a simple small animal model without gene manipulation would be extremely valuable. Here, we tested whether the Chinese tree shrew (CTS), which is a small-sized mammal that is phylogenetically close to primates, could serve as a model for discordant xenograft rejection. METHODS: Study 1: Expression of alpha-Gal antigens in hearts and kidneys of CTSs and rats was assessed by IB4 lectin binding. Presence of anti-Gal and anti-non-Gal IgM and IgG nAb in CTS sera was tested by FACS using Gal+ and GalTKO PBMC as well as BSA-ELISA. Study 2: Rat hearts were transplanted into CTS recipients (group 1, n = 7), and CTS hearts were transplanted in rats [n = 10; seven received no immunosuppression (group 2) and three received FK506 + leflunomide (group 3)]. RESULTS: Study 1: Both CTSs and rats had alpha-Gal expression in hearts and kidneys. ELISA showed CTSs do not have anti-Gal nAb, and flow cytometry indicated CTSs have anti-non-Gal IgM and IgG nAb in serum. Study 2: Rat hearts in CTSs were uniformly rejected within 35 mins, while CTS hearts in rats continued beating until day 5 without immunosuppression, and up to day 8 with immunosuppression. CONCLUSION: Rat-to-CTS heart transplantation is a discordant xenotransplant model, CTS-to-Rat heart transplantation is a concordant xenotransplant model. CTSs are valuable small animals to study mechanisms and strategies to avoid non-Gal nAb-mediated xenograft rejection. PMID- 26589783 TI - New tyrosinase inhibitory decapeptide: Molecular insights into the role of tyrosine residues. AB - Tyrosinase, a rate-limiting enzyme in melanin biosynthesis, catalyzes the hydroxylation of l-tyrosine to 3,4-dihydroxy-l-phenylalanine (l-dopa) (monophenolase reaction) and the subsequent oxidation of l-dopa to l-dopaquinone (diphenolase reaction). Thus, tyrosinase inhibitors have been proposed as skin lightening agents; however, many of the existing inhibitors cannot be widely used in the cosmetic industry due to their high cytotoxicity and instability. On the other hand, some tyrosinase inhibitory peptides have been reported as safe. In this study, we found that the peptide TH10, which has a similar sequence to the characterized inhibitory peptide P4, strongly inhibits the monophenolase reaction with a half-maximal inhibitory concentration of 102 MUM. Seven of the ten amino acid residues in TH10 were identical to P4; however, TH10 possesses one N terminal tyrosine, whereas P4 contains three tyrosine residues located at its N terminus, center, and C-terminus. Subsequent analysis using sequence-shuffled variants indicated that the tyrosine residues located at the N-terminus and center of P4 have little to no contribution to its inhibitory activity. Furthermore, docking simulation analysis of these peptides with mushroom tyrosinase demonstrated that the active tyrosine residue was positioned close to copper ions, suggesting that TH10 and P4 bind to tyrosinase as a substrate analogue. PMID- 26589784 TI - NP24 induces apoptosis dependent on caspase-like activity in Saccharomyces cerevisiae. AB - Tomato NP24 is a homolog of osmotin, a PR-5 protein from tobacco that can initiate apoptosis in yeast via PHO36 in the plasma membrane. We cloned and sequenced NP24 from tomato cv. Momotaro. Based on phylogenetic analysis, NP24 from Momotaro belonged to the Solanaceae clade. The amino acid sequence was identical to that of cv. Ailsa Craig including signal peptide, but the residues predicted to interact with the adiponectin receptor, ADIPOR, were slightly different from osmotin. Recombinant NP24 (rNP24) was expressed in a reductase deficient mutant of Escherichia coli as host cell, and purified from cell extract by affinity chromatography. Purified rNP24 significantly inhibited growth of Saccharomyces cerevisiae wild-type spheroplasts. In contrast, growth of PHO36 deletion mutant (DeltaIzh2) spheroplasts was not inhibited. Moreover, rNP24 induced significant activity of reactive oxygen species, caspase-like activity, and also nuclear fragmentation in wild-type spheroplast cells. These results demonstrated that rNP24 from Momotaro greatly influenced cell viability due to triggering apoptosis through PHO36. Notably, apoptosis induced by NP24 was caspase-like protease dependent. PMID- 26589785 TI - ATP synthase from Escherichia coli: Mechanism of rotational catalysis, and inhibition with the epsilon subunit and phytopolyphenols. AB - ATP synthases (FoF1) are found ubiquitously in energy-transducing membranes of bacteria, mitochondria, and chloroplasts. These enzymes couple proton transport and ATP synthesis or hydrolysis through subunit rotation, which has been studied mainly by observing single molecules. In this review, we discuss the mechanism of rotational catalysis of ATP synthases, mainly that from Escherichia coli, emphasizing the high-speed and stochastic rotation including variable rates and an inhibited state. Single molecule studies combined with structural information of the bovine mitochondrial enzyme and mutational analysis have been informative as to an understanding of the catalytic site and the interaction between rotor and stator subunits. We discuss the similarity and difference in structure and inhibitory regulation of F1 from bovine and E. coli. Unlike the crystal structure of bovine F1 (alpha3beta3gamma), that of E. coli contains a epsilon subunit, which is a known inhibitor of bacterial and chloroplast F1 ATPases. The carboxyl terminal domain of E. coli epsilon (epsilonCTD) interacts with the catalytic and rotor subunits (beta and gamma, respectively), and then inhibits rotation. The effects of phytopolyphenols on F1-ATPase are also discussed: one of them, piceatannol, lowered the rotational speed by affecting rotor/stator interactions. PMID- 26589786 TI - Gains attained in malaria control coverage within settings earmarked for pre elimination: malaria indicator and prevalence surveys 2012, Eritrea. AB - BACKGROUND: Eritrea, like most countries in sub-Saharan Africa, has expended much effort towards malaria control with the view of transitioning from reduction of the disease burden to elimination. This paper reports on the level of achievement as highlighted by the follow-on, malaria-endemic area representative, survey that aimed to provide data and to assess progress on malaria indicators and parasite prevalence at household level across the country. METHODS: In 2012, data were collected using a two-stage stratified cluster random sample of 1887 households in 96 clusters (villages in rural areas and census enumeration areas in urban centers) during a malaria indicator and prevalence survey in Eritrea. The survey determined parasite prevalence in vulnerable population groups and evaluated coverage, use and access to malaria control services. Standardized Roll-Back Malaria Monitoring and Evaluation Reference Group household and women's questionnaires were adapted to the local situation and used for collection of data that were analysed and summarized using descriptive statistics. RESULTS: The results of the survey showed that 90% (95% CI 89-91) of households owned at least one mosquito net. The proportion of the population with access to an insecticide treated net (ITN) in their household was 55% (95% CI 54-56). The utilization of ITNs was 67% (95% CI 65-70) for children under 5 years and 60% (95% CI 58-63) for pregnant women (OR: 0. 73(95% CI 0.62-0.85); P = 0.52). Only 28% (95% CI 26-30) of households were covered by indoor residual spraying (IRS) the previous year with significant heterogeneity by zoba (Debub 50 % (95% CI 45-54) vs Gash Barka 32 % (95% CI 28-36); OR = 0. 47 (95% CI 0.36-0.61), P = 0.05). Malaria parasite prevalence was low; 1.1% (95% CI 0.9-1.3) in the general population and 1.4% (95% CI 1.0-2.0) in children under five and 0.7% (95% CI 0.4-1.1) among women aged 15 49 years. Only 19% (95% CI 15-26) of children under five had fever in the 2 weeks preceding the survey, with 61% (95% CI 54.1-67.1) seeking treatment from a health facility. Data on knowledge levels show that 92% reported that malaria is transmitted by mosquitoes, 92% mentioned that the use of mosquito nets could prevent malaria, 47% knew malaria prevention medication, 83% cited fever as a sign and symptom of malaria, and 35% had heard or seen malaria awareness messages. CONCLUSION: Notwithstanding confounders, the observed low malaria parasite prevalence could be associated with malaria intervention coverage, access and utilization as well as high and equitable knowledge levels in the population. This indicates that Eritrea is on the right track towards pre elimination. However, technical and infrastructure capacity should be strengthened to facilitate implementation, surveillance, monitoring, and evaluation. PMID- 26589789 TI - The ability of mannitol to decrease cisplatin-induced nephrotoxicity in children: real or not? AB - PURPOSE: Platinum compounds are very effective drugs for the treatment of childhood malignancies, and their use has contributed to an increase in the long term survival of children with cancer. Unfortunately, the risk of severe disabling effects such as nephrotoxicity is well known among children receiving cisplatin-based chemotherapy. METHODS: The main pharmacodynamics and clinical characteristics of cisplatin nephrotoxicity are described in order to explore the real ability of mannitol to prevent cisplatin-related nephrotoxicity. RESULTS: Currently, the choice of hydration alone or hydration plus mannitol to prevent nephrotoxicity is controversial. No guidelines are available to provide recommendations on this issue either in adults or in children. CONCLUSIONS: Appropriate hydration remains the main fundamental strategy for reducing the risk of cisplatin-induced nephrotoxicity. In conventional treatment regimens employing doses of cisplatin of less than 100 mg/m(2) in patients with normal renal function, pre- and post-hydration (3 l/m(2) at least 12 h pre-cisplatin and 24 h post-cisplatin) alone should be routinely used. In higher doses, pre- and post hydration plus mannitol should be considered in order to ensure a valid diuresis. PMID- 26589787 TI - The burden of bacteremia and invasive diseases in children aged less than five years with fever in Italy. AB - BACKGROUND: Invasive diseases (ID) caused by Streptococcus pneumoniae (S. pneumoniae), Haemophilus influenzae (H. influenzae), and Neisseria meningitidis are a major public health problem worldwide. Comprehensive data on the burden of bacteremia and ID in Italy, including data based on molecular techniques, are needed. METHODS: We conducted a prospective, multi-centre, hospital-based study (GSK study identifier: 111334) to assess the burden of bacteremia and ID among children less than five years old with a fever of 39 degrees C or greater. Study participation involved a single medical examination, collection of blood for polymerase chain reaction (PCR) and blood culture, and collection of an oropharyngeal swab for colonization analysis by PCR. RESULTS: Between May 2008 and June 2009, 4536 patients were screened, 944 were selected and 920 were enrolled in the study. There were 225 clinical diagnoses of ID, 9.8 % (22) of which were bacteremic. A diagnosis of sepsis was made for 38 cases, 5.3 % (2) of which were bacteremic. Among the 629 non-ID diagnoses, 1.6 % (10) were bacteremic. Among the 34 bacteremic cases, the most common diagnoses were community-acquired pneumonia (15/34), pleural effusion (4/34) and meningitis (4/34). S. pneumoniae was the most frequently detected bacteria among bacteremic cases (29/34) followed by H. influenzae (3/34). Ninety percent (27/30) of bacteremic patients with oropharyngeal swab results were colonized with the studied bacterial pathogens compared to 46.1 % (402/872) of non-bacteremic cases (p < 0.001). PCV7 (7-valent pneumococcal conjugate vaccine) vaccination was reported for 55.9 % (19/34) of bacteremic cases. S. pneumoniae serotypes were non vaccine serotypes in children who had been vaccinated. Mean duration of hospitalization was longer for bacteremic cases versus non-bacteremic cases (13.6 versus 5.8 days). CONCLUSIONS: These results confirm that S. pneumoniae is one of the pathogens frequently responsible for invasive disease. PMID- 26589788 TI - Interval cancers using a quantitative faecal immunochemical test (FIT) for haemoglobin when colonoscopy capacity is limited. AB - OBJECTIVES: Quantitative faecal immunochemical tests (FIT) for faecal haemoglobin (f-Hb) in colorectal cancer (CRC) screening pose challenges when colonoscopy is limited. For low positivity rates, high f-Hb concentration cut-offs are required, but little is known about interval cancer (IC) proportions using FIT. We assessed IC proportions using an 80 ug Hb/g cut-off. METHODS: In two NHS Boards in the Scottish Bowel Screening Programme, f-Hb was estimated for 30,893 participants aged 50-75, of whom 753 participants with f-Hb >= 80 ug Hb/g were referred for colonoscopy. ICs, defined as CRC within two years of a negative result, were identified from the Scottish Cancer Registry. RESULTS: There were 31 ICs and 30 screen-detected (SD) CRCs, an IC proportion of 50.8% (48.4% for men, 53.3% for women). CRC site distribution was similar between ICs and SD, but ICs were later stage (46.7% and 33.3%, Dukes' stages C and D, respectively). Of 31 ICs, 23 had f Hb < 10 ug Hb/g, including six with undetectable f-Hb. A f-Hb cut-off of 10 ug Hb/g would have raised the positivity rate from 2.4% to 9.4%, increased colonoscopy requirement from 753 to 2147, and reduced the IC proportion to 38.3%. CONCLUSIONS: The IC proportion was similar to that seen with guaiac-based FOBT. The later stage distribution of ICs highlights the benefits of lower f-Hb cut offs, but with 19.4% of ICs having undetectable f-Hb, some cancers would have been missed, even with drastic reduction in the f-Hb cut-off. PMID- 26589790 TI - A phase II trial of modified FOLFOX6 as first-line therapy for adenocarcinoma of an unknown primary site. AB - PURPOSE: The aim of the study was to assess the clinical activity and toxicity of oxaliplatin and leucovorin in combination with bolus and continuous infusional 5 fluorouracil administered every 2 weeks (modified FOLFOX-6 regimen) to patients with adenocarcinoma of an unknown primary site (ACUP). METHODS: Previously untreated ACUP patients were treated with oxaliplatin (100 mg/m(2)) and leucovorin (200 mg/m(2)) as a 2-h infusion followed by bolus administration of 5 fluorouracil (400 mg/m(2)) and continuous infusion of 5-fluorouracil (2400 mg/m(2)) every 2 weeks. RESULTS: A total of 23 patients were enrolled and treated with a modified FOLFOX-6 regimen between May 2009 and November 2014. This trial was terminated before the scheduled enrollment due to poor accrual. A total of 134 cycles of mFOLFOX-6 were administered to 23 patients. The median number of cycles of mFOLFOX-6 was 5 (range 1-12). Among 20 patients whose tumor responses were evaluable, seven patients showed a partial response (no complete response), with an objective response rate of 35.0%. The median duration of response was 3.9 months (range 3.0-19.8). The median progression-free survival and overall survival were 3.0 and 9.5 months, respectively (95% confidence interval 1.4-6.7 months and 4.8-26.4 months, respectively). Treatment-related toxicity was manageable. CONCLUSIONS: mFOLFOX-6 showed modest activity in treatment-naive patients with ACUP. A future, prospective large-scale study incorporating a parallel molecular prediction marker study is warranted. PMID- 26589791 TI - Erratum to: Phase 1 study of oral TAS-102 in patients with refractory metastatic colorectal cancer. PMID- 26589792 TI - Treatment regimens of classical and newer taxanes. AB - The classical taxanes (paclitaxel, docetaxel), the newer taxane cabazitaxel and the nanoparticle-bound nab-paclitaxel are among the most widely used anticancer drugs. The taxanes share the characteristics of extensive hepatic metabolism and biliary excretion, the need for dose adaptation in patients with liver dysfunction, and a substantial pharmacokinetic variability even after taking into account known covariates. Data from clinical studies suggest that optimal scheduling of the taxanes is dependent not only on the specific taxane compound, but also on the tumor type and line of treatment. Still, the optimal dosing regimen (weekly vs 3 weekly) and optimal dose of the taxanes are controversial, as is the value of pharmacological personalization of taxane dosing. In this article, an overview is given on the pharmacological properties of the taxanes, including metabolism, pharmacokinetics-pharmacodynamics and aspects in the clinical use of taxanes. The latter includes the ongoing debate on the most active and safe regimen, the recommended initial dose and the issue of therapeutic drug dosing. PMID- 26589793 TI - Oxaliplatin in the era of personalized medicine: from mechanistic studies to clinical efficacy. AB - Oxaliplatin is a third-generation platinum compound approved for clinical use relatively recently as compared to other drugs of the same class. Its main cellular target is DNA, where similarly to cisplatin and carboplatin it forms cross-links. However, due to a unique indication for colorectal cancer, synergistic interaction with fluoropyrimidines and peculiar toxicity profile, oxaliplatin is different from those compounds. Multiple lines of evidence indicate differences in transport and metabolism, consequences of DNA platination, as well as DNA repair and transduction of DNA damage. Here, we explore the preclinical features that may explain the unique properties of oxaliplatin in the clinics. Among them, the capability to accumulate in tumor cells via organic cation transporters, to kill KRAS mutant cells and to activate immunogenic cell death appears helpful to explain in part its clinical behavior. The continuous investigation of the molecular pharmacology of oxaliplatin is expected to provide clues to the definitions of predictors of drug activity and toxicity to translate to the clinical setting. PMID- 26589794 TI - Cancer Cell Invasion in Three-dimensional Collagen Is Regulated Differentially by Galpha13 Protein and Discoidin Domain Receptor 1-Par3 Protein Signaling. AB - Cancer cells can invade in three-dimensional collagen as single cells or as a cohesive group of cells that require coordination of cell-cell junctions and the actin cytoskeleton. To examine the role of Galpha13, a G12 family heterotrimeric G protein, in regulating cellular invasion in three-dimensional collagen, we established a novel method to track cell invasion by membrane type 1 matrix metalloproteinase-expressing cancer cells. We show that knockdown of Galpha13 decreased membrane type 1 matrix metalloproteinase-driven proteolytic invasion in three-dimensional collagen and enhanced E-cadherin-mediated cell-cell adhesion. E cadherin knockdown reversed Galpha13 siRNA-induced cell-cell adhesion but failed to reverse the effect of Galpha13 siRNA on proteolytic invasion. Instead, concurrent knockdown of E-cadherin and Galpha13 led to an increased number of single cells rather than groups of cells. Significantly, knockdown of discoidin domain receptor 1 (DDR1), a collagen-binding protein that also co-localizes to cell-cell junctions, reversed the effects of Galpha13 knockdown on cell-cell adhesion and proteolytic invasion in three-dimensional collagen. Knockdown of the polarity protein Par3, which can function downstream of DDR1, also reversed the effects of Galpha13 knockdown on cell-cell adhesion and proteolytic invasion in three-dimensional collagen. Overall, we show that Galpha13 and DDR1-Par3 differentially regulate cell-cell junctions and the actin cytoskeleton to mediate invasion in three-dimensional collagen. PMID- 26589795 TI - Increasing the Receptor Tyrosine Kinase EphB2 Prevents Amyloid-beta-induced Depletion of Cell Surface Glutamate Receptors by a Mechanism That Requires the PDZ-binding Motif of EphB2 and Neuronal Activity. AB - Diverse lines of evidence suggest that amyloid-beta (Abeta) peptides causally contribute to the pathogenesis of Alzheimer disease (AD), the most frequent neurodegenerative disorder. However, the mechanisms by which Abeta impairs neuronal functions remain to be fully elucidated. Previous studies showed that soluble Abeta oligomers interfere with synaptic functions by depleting NMDA-type glutamate receptors (NMDARs) from the neuronal surface and that overexpression of the receptor tyrosine kinase EphB2 can counteract this process. Through pharmacological treatments and biochemical analyses of primary neuronal cultures expressing wild-type or mutant forms of EphB2, we demonstrate that this protective effect of EphB2 depends on its PDZ-binding motif and the presence of neuronal activity but not on its kinase activity. We further present evidence that the protective effect of EphB2 may be mediated by the AMPA-type glutamate receptor subunit GluA2, which can become associated with the PDZ-binding motif of EphB2 through PDZ domain-containing proteins and can promote the retention of NMDARs in the membrane. In addition, we show that the Abeta-induced depletion of surface NMDARs does not depend on several factors that have been implicated in the pathogenesis of Abeta-induced neuronal dysfunction, including aberrant neuronal activity, tau, prion protein (PrP(C)), and EphB2 itself. Thus, although EphB2 does not appear to be directly involved in the Abeta-induced depletion of NMDARs, increasing its expression may counteract this pathogenic process through a neuronal activity- and PDZ-dependent regulation of AMPA-type glutamate receptors. PMID- 26589796 TI - Lipoprotein LprI of Mycobacterium tuberculosis Acts as a Lysozyme Inhibitor. AB - Mycobacterium tuberculosis executes numerous defense strategies for the successful establishment of infection under a diverse array of challenges inside the host. One such strategy that has been delineated in this study is the abrogation of lytic activity of lysozyme by a novel glycosylated and surface localized lipoprotein, LprI, which is exclusively present in M. tuberculosis complex. The lprI gene co-transcribes with the glbN gene (encoding hemoglobin (HbN)) and both are synchronously up-regulated in M. tuberculosis during macrophage infection. Recombinant LprI, expressed in Escherichia coli, exhibited strong binding (Kd <= 2 nm) with lysozyme and abrogated its lytic activity completely, thereby conferring protection to fluorescein-labeled Micrococcus lysodeikticus from lysozyme-mediated hydrolysis. Expression of the lprI gene in Mycobacterium smegmatis (8-10-fold) protected its growth from lysozyme inhibition in vitro and enhanced its phagocytosis and survival during intracellular infection of peritoneal and monocyte-derived macrophages, known to secrete lysozyme, and in the presence of exogenously added lysozyme in secondary cell lines where lysozyme levels are low. In contrast, the presence of HbN enhanced phagocytosis and intracellular survival of M. smegmatis only in the absence of lysozyme but not under lysozyme stress. Interestingly, co-expression of the glbN lprI gene pair elevated the invasion and survival of M. smegmatis 2-3-fold in secondary cell lines in the presence of lysozyme in comparison with isogenic cells expressing these genes individually. Thus, specific advantage against macrophage-generated lysozyme, conferred by the combination of LprI-HbN during invasion of M. tuberculosis, may have vital implications on the pathogenesis of tuberculosis. PMID- 26589797 TI - Trichomonas vaginalis Lipophosphoglycan Exploits Binding to Galectin-1 and -3 to Modulate Epithelial Immunity. AB - Trichomoniasis is the most common non-viral sexually transmitted infection caused by the vaginotropic extracellular protozoan parasite Trichomonas vaginalis. The infection is recurrent, with no lasting immunity, often asymptomatic, and linked to pregnancy complications and risk of viral infection. The molecular mechanisms of immune evasion by the parasite are poorly understood. We demonstrate that galectin-1 and -3 are expressed by the human cervical and vaginal epithelial cells and act as pathogen-recognition receptors for the ceramide phosphoinositol glycan core (CPI-GC) of the dominant surface protozoan lipophosphoglycan (LPG). We used an in vitro model with siRNA galectin knockdown epithelial clones, recombinant galectins, clinical Trichomonas isolates, and mutant protozoan derivatives to dissect the function of galectin-1 and -3 in the context of Trichomonas infection. Galectin-1 suppressed chemokines that facilitate recruitment of phagocytes, which can eliminate extracellular protozoa (IL-8) or bridge innate to adaptive immunity (MIP-3alpha and RANTES (regulated on activation normal T cell expressed and secreted)). Silencing galectin-1 increased and adding exogenous galectin-1 suppressed chemokine responses to Trichomonas or CPI-GC/LPG. In contrast, silencing galectin-3 reduced IL-8 response to LPG. Live Trichomonas depleted the extracellular levels of galectin-3. Clinical isolates and mutant Trichomonas CPI-GC that had reduced affinity to galectin-3 but maintained affinity to galectin-1 suppressed chemokine expression. Thus via CPI GC binding, Trichomonas is capable of regulating galectin bioavailability and function to the benefit of its parasitic survival. These findings suggest novel approaches to control trichomoniasis and warrant further studies of galectin binding diversity among clinical isolates as a possible source for symptom disparity in parasitic infections. PMID- 26589798 TI - The Structure of a Type 3 Secretion System (T3SS) Ruler Protein Suggests a Molecular Mechanism for Needle Length Sensing. AB - The type 3 secretion system (T3SS) and the bacterial flagellum are related pathogenicity-associated appendages found at the surface of many disease-causing bacteria. These appendages consist of long tubular structures that protrude away from the bacterial surface to interact with the host cell and/or promote motility. A proposed "ruler" protein tightly regulates the length of both the T3SS and the flagellum, but the molecular basis for this length control has remained poorly characterized and controversial. Using the Pseudomonas aeruginosa T3SS as a model system, we report the first structure of a T3SS ruler protein, revealing a "ball-and-chain" architecture, with a globular C-terminal domain (the ball) preceded by a long intrinsically disordered N-terminal polypeptide chain. The dimensions and stability of the globular domain do not support its potential passage through the inner lumen of the T3SS needle. We further demonstrate that a conserved motif at the N terminus of the ruler protein interacts with the T3SS autoprotease in the cytosolic side. Collectively, these data suggest a potential mechanism for needle length sensing by ruler proteins, whereby upon T3SS needle assembly, the ruler protein's N-terminal end is anchored on the cytosolic side, with the globular domain located on the extracellular end of the growing needle. Sequence analysis of T3SS and flagellar ruler proteins shows that this mechanism is probably conserved across systems. PMID- 26589799 TI - MicroRNA-424 Predicts a Role for beta-1,4 Branched Glycosylation in Cell Cycle Progression. AB - MicroRNA regulation of protein expression plays an important role in mediating many cellular processes, from cell proliferation to cell death. The human microRNA miR-424 is up-regulated in response to anti-proliferative cytokines, such as transforming growth factor beta (TGFbeta), and directly represses cell cycle progression. Our laboratory recently established that microRNA can be used as a proxy to identify biological roles of glycosylation enzymes (glycogenes). Herein we identify MGAT4A, OGT, and GALNT13 as targets of miR-424. We demonstrate that MGAT4A, an N-acetylglucosaminyltransferase that installs the beta-1,4 branch of N-glycans, is directly regulated by miR-424 in multiple mammary epithelial cell lines and observe the loss of MGAT4A in response to TGFbeta, an inducer of miR-424. Knockdown of MGAT4A induces cell cycle arrest through decreasing CCND1 levels. MGAT4A does not affect levels of beta-1,6 branched N-glycans, arguing that this effect is specific to beta-1,4 branching and not due to gross changes in overall N-linked glycosylation. This work provides insight into the regulation of cell cycle progression by specific N-glycan branching patterns. PMID- 26589800 TI - Optimal Neutralization of Centruroides noxius Venom Is Understood through a Structural Complex between Two Antibody Fragments and the Cn2 Toxin. AB - The current trend of using recombinant antibody fragments in research to develop novel antidotes against scorpion stings has achieved excellent results. The polyclonal character of commercial antivenoms, obtained through the immunization of animals and which contain several neutralizing antibodies that recognize different epitopes on the toxins, guarantees the neutralization of the venoms. To avoid the use of animals, we aimed to develop an equivalent recombinant antivenom composed of a few neutralizing single chain antibody fragments (scFvs) that bind to two different epitopes on the scorpion toxins. In this study, we obtained scFv RU1 derived from scFv C1. RU1 showed a good capacity to neutralize the Cn2 toxin and whole venom of the scorpion Centruroides noxius. Previously, we had produced scFv LR, obtained from a different parental fragment (scFv 3F). LR also showed a similar neutralizing capacity. The simultaneous administration of both scFvs resulted in improved protection, which was translated as a rapid recovery of previously poisoned animals. The crystallographic structure of the ternary complex scFv LR-Cn2-scFv RU1 allowed us to identify the areas of interaction of both scFvs with the toxin, which correspond to non-overlapping sites. The epitope recognized by scFv RU1 seems to be related to a greater efficiency in the neutralization of the whole venom. In addition, the structural analysis of the complex helped us to explain the cross-reactivity of these scFvs and how they neutralize the venom. PMID- 26589802 TI - An investigation into the effects of antenatal stressors on the postpartum neuroimmune profile and depressive-like behaviors. AB - Postpartum depression is a specific type of depression that affects approximately 10-15% of mothers [28]. While many have attributed the etiology of postpartum depression to the dramatic change in hormone levels that occurs immediately postpartum, the exact causes are not well-understood. It is well-known, however, that pregnancy induces a number of dramatic changes in the peripheral immune system that foster the development of the growing fetus. It is also well-known that changes in immune function, specifically within the brain, have been linked to several neuropsychiatric disorders including depression. Thus, we sought to determine whether pregnancy induces significant neuroimmune changes postpartum and whether stress or immune activation during pregnancy induce a unique neuroimmune profile that may be associated with depressive-like behaviors postpartum. We used late-gestation sub-chronic stress and late-gestation acute immune activation to examine the postpartum expression of depressive-like behaviors, microglial activation markers, and inflammatory cytokines within the medial prefrontal cortex (mPFC) and the hippocampus (HP). The expression of many immune molecules was significantly altered in the brain postpartum, and postpartum females also showed significant anhedonia, both independently of stress. Following late-gestation immune activation, we found a unique set of changes in neuroimmune gene expression immediately postpartum. Thus, our data indicate that even in the absence of additional stressors, postpartum females exhibit significant changes in the expression of cytokines within the brain that are associated with depressive-like behavior. Additionally, different forms of antenatal stress produce varying profiles of postpartum neuroimmune gene expression and associated depressive-like behaviors. PMID- 26589803 TI - Plastic changes to dendritic spines on layer V pyramidal neurons are involved in the rectifying role of the prefrontal cortex during the fast period of motor learning. AB - The prefrontal cortex participates in the rectification of information related to motor activity that favors motor learning. Dendritic spine plasticity is involved in the modifications of motor patterns that underlie both motor activity and motor learning. To study this association in more detail, adult male rats were trained over six days in an acrobatic motor learning paradigm and they were subjected to a behavioral evaluation on each day of training. Also, a Golgi-based morphological study was carried out to determine the spine density and the proportion of the different spine types. In the learning paradigm, the number of errors diminished as motor training progressed. Concomitantly, spine density increased on days 1 and 3 of training, particularly reflecting an increase in the proportion of thin (day 1), stubby (day 1) and branched (days 1, 2 and 5) spines. Conversely, mushroom spines were less prevalent than in the control rats on days 5 and 6, as were stubby spines on day 6, together suggesting that this plasticity might enhance motor learning. The increase in stubby spines on day 1 suggests a regulation of excitability related to the changes in synaptic input to the prefrontal cortex. The plasticity to thin spines observed during the first 3 days of training could be related to the active rectification induced by the information relayed to the prefrontal cortex -as the behavioral findings indeed showed-, which in turn could be linked to the lower proportion of mushroom and stubby spines seen in the last days of training. PMID- 26589801 TI - Arabidopsis Rab Geranylgeranyltransferases Demonstrate Redundancy and Broad Substrate Specificity in Vitro. AB - Posttranslational lipid modifications mediate the membrane attachment of Rab GTPases, facilitating their function in regulating intracellular vesicular trafficking. In Arabidopsis, most Rab GTPases have two C-terminal cysteines and potentially can be double-geranylgeranylated by heterodimeric Rab geranylgeranyltransferases (Rab-GGTs). Genes encoding two putative alpha subunits and two putative beta subunits of Rab-GGTs have been annotated in the Arabidopsis thaliana genome, but little is known about Rab-GGT activity in Arabidopsis. In this study, we demonstrate that four different heterodimers can be formed between putative Arabidopsis Rab-GGT alpha subunits RGTA1/RGTA2 and beta subunits RGTB1/RGTB2, but only RGTA1.RGTB1 and RGTA1.RGTB2 exhibit bona fide Rab-GGT activity, and they are biochemically redundant in vitro. We hypothesize that RGTA2 function might be disrupted by a 12-amino acid insertion in a conserved motif. We present evidence that Arabidopsis Rab-GGTs may have preference for prenylation of C-terminal cysteines in particular positions. We also demonstrate that Arabidopsis Rab-GGTs can not only prenylate a great variety of Rab GTPases in the presence of Rab escort protein but, unlike Rab-GGT in yeast and mammals, can also prenylate certain non-Rab GTPases independently of Rab escort protein. Our findings may help to explain some of the phenotypes of Arabidopsis protein prenyltransferase mutants. PMID- 26589804 TI - Don't watch where you're going: The neural correlates of decoupling eye and arm movements. AB - "Standard" visually-guided reaching movements consist of a saccade and an arm movement to the same target location. In the current study, functional magnetic resonance imaging was used to contrast brain activity during standard visually guided reaches with activity during a "non-standard" visuomotor mapping where the targets of the saccade and arm movement were spatially decoupled. Multi-voxel pattern analysis approaches showed discrimination of standard versus non-standard visuomotor mapping in the cuneus and medial premotor regions without accompanying task-related differences in MRI signal amplitude in these areas. Contrasts of signal amplitude did reveal greater activity associated with the non-standard task relative to the standard task in the right inferior parietal lobule and a portion of the left superior posterior cerebellum. The findings of this study shed light on brain regions involved in overcoming our default tendency to spatially couple eye and arm movements during visually-guided reaching. Further, the results suggest that the regions reported here may be important in neurological disorders such as optic ataxia, Alzheimer's disease, and mild cognitive impairment, which are associated with deficits in producing non standard visuomotor mappings while leaving standard visuomotor mapping relatively intact. PMID- 26589805 TI - Enterohemorrhagic Escherichia coli outbreaks related to childcare facilities in Japan, 2010-2013. AB - BACKGROUND: Enterohemorrhagic Escherichia coli (EHEC) is an important cause of gastroenteritis in Japan. Although non-O157 EHEC infections have been increasingly reported worldwide, their impact on children has not been well described. METHODS: We collected national surveillance data of EHEC infections reported between 2010 and 2013 in Japan and characterized outbreaks that occurred in childcare facilities. Per Japanese outbreak investigation protocol, faecal samples from contacts of EHEC cases were collected regardless of symptomatic status. Cases and outbreaks were described by demographics, dates of diagnosis and onset, clinical manifestations, laboratory data, and relation to specific outbreaks in childcare facilities. RESULTS: During 2010-2013, a total of 68 EHEC outbreaks comprised of 1035 cases were related to childcare facilities. Among the 66 outbreaks caused by a single serogroup, 29 were serogroup O26 and 22 were O157; 35 outbreaks were caused by stx1-producing strains. Since 2010, the number of reported outbreaks steadily increased, with a rise in cases and outbreaks caused by stx1-producing O26. Of 7069 EHEC cases reported nationally in 2010 2011, the majority were caused by O157 (n = 4938), relative to O26 (n = 1353) and O111 (n = 195). However, relative to 69 cases of O157 (2%) associated with childcare facility EHEC outbreaks, there were 131 (10%) such cases of O26, and this trend intensified in 2012-2013 (O157, 3%; O26, 24%; O111, 48%). Among family members of childcare facility cases, the proportion of cases that were symptomatic declined with age; 10/16 cases (63%) aged 6 years or younger, 16/53 cases (30%) 6-19 years old, 23/120 cases (19%) 20-49 years old and 2/28 cases (7%) 50 years or older were symptomatic. Thirty one of the 68 outbreaks (46%) were classified as foodborne-related. CONCLUSIONS: Childcare facility EHEC outbreaks due to non-O157 serogroups, particularly O26 and O111, increased during 2010-2013. These facilities should pay extra attention to health conditions in children. As older family members of childcare facility cases appear to be less symptomatic, they should be vigilant about hand-washing to prevent further transmission. PMID- 26589806 TI - Ticks and tick-borne novel bunyavirus collected from the natural environment and domestic animals in Jinan city, East China. AB - Since 2011, 73 cases of the severe fever with thrombocytopenia syndrome, a novel tick-borne disease, have been reported in Jinan city through information system for disease control and prevention. Therefore, this study aimed to investigate the species, distribution, host animals of ticks and tick-borne pathogens. A total of 722 ticks were collected from two types of natural environment and six kinds of domestic animal in Jinan city. All the sampled ticks belonged to the same species, namely Haemaphysalis longicornis, and 94.7% of them were adult. The density of free-living ticks in grassland was nearly six times that in shrub. The prevalence of the goat (53.3%) was highest among the domestic animals. The host body region most frequently parasitized by H. longicornis was the head (77.8%), especially ears and periocular region. Novel bunyavirus was detected on the free ranging goats in Jinan city. Acaricide treatment with a higher concentration on the ears, periocular region and the groin of domestic animals should be recommended to control the ticks effectively. PMID- 26589809 TI - Entropy-Suppressed Ferroelectricity in Hybrid Lead-Iodide Perovskites. AB - The actual nature of the electric polarization in hybrid lead-iodide perovskites is unveiled on the basis of ab initio and model results. A finite, albeit small electric polarization of few MUC/cm(2) is found to be pervasive in this system, due to the polar-uncompensated alignment of methylammonium dimers, at least for temperature lower than the activation energy of dimer rotations; however, the presence of a large number of structural local minima corresponding to differently oriented polarization directions counteracts the stabilization of an ordered ferroelectric phase at the macroscale. According to our estimate, only for temperatures lower than 40-50 K a clear ferroelectric behavior is displayed. At higher temperature the polarization is progressively suppressed and the ferroelectric ordering hindered by the large configurational entropy, giving rise to a superparaelectric-like behavior at the macroscale. PMID- 26589807 TI - Peripheral blood natural killer cell percentages in granulomatosis with polyangiitis correlate with disease inactivity and stage. AB - INTRODUCTION: The role of CD3-CD56+ natural killer (NK) cells in granulomatosis with polyangiitis (GPA) is poorly understood. Recently, it has been shown that peripheral blood NK cells can kill renal microvascular endothelial cells, suggesting a pathogenic role of NK cells in this disease. So far, subset distribution, phenotype, and function of peripheral blood NK cells in relation to GPA disease activity have not been elucidated. Moreover, it is not known whether NK cells infiltrate GPA tissue lesions. METHODS: Paraffin sections of GPA granulomas and controls were stained with anti-CD56 and anti-CD3 antibodies. Peripheral blood lymphocyte subsets were analyzed by flow cytometry. NK cell degranulation was analyzed using cocultures of patient PBMCs with target cells and surface expression of CD107a. Clinical data were extracted from medical records. Statistical analysis was performed in an exploratory way. RESULTS: CD56+ cells were not detectable in active granulomatous GPA lesions but were found frequently in granulomas from tuberculosis and sarcoidosis patients. In GPA, the proportion of NK cells among peripheral blood lymphocytes correlated negatively with the Birmingham Vasculitis Activity Score (BVAS) (n = 28). Accordingly, NK cell percentages correlated positively with the duration of remission (n = 28) and were significantly higher in inactive GPA (BVAS = 0, n = 17) than in active GPA, healthy controls (n = 29), and inactive control diseases (n = 12). The highest NK cell percentages were found in patients with long-term remission and tapered immunosuppressive therapy. NK cell percentages >18.5% of peripheral blood lymphocytes (n = 12/28) determined GPA inactivity with a specificity of 100%. The differentiation into CD56(dim) and CD56(bright) NK cell subsets was unchanged in GPA (n = 28), irrespective of disease activity. Similar surface expression of the activating NK cell-receptors (NKp30, NKp46, and NKG2D) was determined. Like in healthy controls, GPA NK cells degranulated in the presence of NK cell receptor ligand bearing epithelial and lymphatic target cells. CONCLUSIONS: NK cells were not detectable in GPA granulomas. Peripheral blood NK cell percentages positively correlate with the suppression of GPA activity and could serve as a biomarker for GPA activity. Peripheral blood NK cells in GPA patients are mature NK cells with preserved immune recognition. PMID- 26589810 TI - Volumetric Differences in Cerebellar Lobes in Individuals from Multiplex Alcohol Dependence Families and Controls: Their Relationship to Externalizing and Internalizing Disorders and Working Memory. AB - Offspring from families with multiple cases of alcohol dependence have a greater likelihood of developing alcohol dependence and related substance use disorders. Greater susceptibility for these disorders may be related to cerebellar morphology. Because posterior regions of the cerebellum are associated with cognitive abilities, we investigated whether high-risk offspring would display regionally specific differences in cerebellar morphology and whether these would be related to working memory performance. The relationship to externalizing and internalizing psychopathology was of interest because cerebellar morphology has previously been associated with a cognitive affective syndrome. A total of 131 participants underwent magnetic resonance imaging (MRI) with volumes of the cerebellar lobes obtained with manual tracing. These individuals were from high risk (HR) for alcohol dependence families (N = 72) or from low-risk (LR) control families (N = 59). All were enrolled in a longitudinal follow-up that included repeated clinical assessments during childhood and young-adulthood prior to the scan that provided information on Axis I psychopathology. The Working Memory Index of the Wechsler Memory Scale was given at the time of the scan. Larger volumes of the corpus medullare and inferior posterior lobes and poorer working memory performance were found for the HR offspring relative to LR controls. Across all subjects, a significant positive association between working memory and total volume of corpus of the cerebellum was seen, controlling for familial risk. Presence of an internalizing or externalizing disorder interacting with familial risk was also associated with volume of the corpus medullare. PMID- 26589811 TI - Characterization of the Protective Role of Regulatory T Cells in Experimental Periapical Lesion Development and Their Chemoattraction Manipulation as a Therapeutic Tool. AB - INTRODUCTION: The pathogenesis of periapical lesions is determined by the balance between host proinflammatory immune response and counteracting anti-inflammatory and reparative responses, which include regulatory T cells (Tregs) as potential immunoregulatory agents. In this study, we investigated (in a cause-and-effect manner) the involvement of CCL22-CCR4 axis in Treg migration to the periapical area and the role of Tregs in the determination of outcomes in periapical lesions. METHODS: Periapical lesions were induced in C57Bl/6 (wild-type) and CCR4KO mice (pulp exposure and bacterial inoculation) and treated with anti glucocorticoid-induced TNF receptor family regulated gene to inhibit Treg function or alternatively with CCL22-releasing, polylactic-glycolic acid particles to induce site-specific migration of Tregs. After treatment, lesions were analyzed for Treg influx and phenotype, overall periapical bone loss, and inflammatory/immunologic and wound healing marker expression (analyzed by real time polymerase chain reaction array). RESULTS: Treg inhibition by anti glucocorticoid-induced TNF receptor family regulated gene or CCR4 depletion results in a significant increase in periapical lesion severity, associated with upregulation of proinflammatory, T-helper 1, T-helper 17, and tissue destruction markers in parallel with decreased Treg and healing marker expression. The local release of CCL22 in the root canal system resulted in the promotion of Treg migration in a CCR4-dependent manner, leading to the arrest of periapical lesion progression, associated with downregulation of proinflammatory, T-helper 1, T helper 17, and tissue destruction markers in parallel with increased Treg and healing marker expression. CONCLUSIONS: Because the natural and CCL22-induced Treg migration switches active lesion into inactivity phenotype, Treg chemoattractant may be a promising strategy for the clinical management of periapical lesions. PMID- 26589812 TI - Modified mRNA as a new therapeutic option for pediatric respiratory diseases and hemoglobinopathies. AB - BACKGROUND: The immunogenicity and limited stability of conventional messenger RNA (mRNA) has traditionally restricted its potential therapeutic use. In 1992, the first clinical application of mRNA was reported as a potential protein replacement therapy; however, subsequent investigations have not been made for almost two decades. Recent developments, including increased stability, controlling immunogenicity, as well as utilization of mRNA encoding zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and CRISPR-Cas9, have implicated modified mRNA as a very promising option for cancer immunotherapy, vaccines, protein expression replacement, and genome editing. This review aims to offer a summary of our present understanding of and improvements in mRNA-based drug technologies, along with a focus on the role in therapeutic options for pediatric respiratory diseases and hemoglobinopathies. CONCLUSIONS: This mini review summarizes the recent advances in modified mRNA-based therapy and its potential therapeutic effect in treating major pediatric diseases. PMID- 26589813 TI - Laser refrigeration of hydrothermal nanocrystals in physiological media. AB - Coherent laser radiation has enabled many scientific and technological breakthroughs including Bose-Einstein condensates, ultrafast spectroscopy, superresolution optical microscopy, photothermal therapy, and long-distance telecommunications. However, it has remained a challenge to refrigerate liquid media (including physiological buffers) during laser illumination due to significant background solvent absorption and the rapid (~ ps) nonradiative vibrational relaxation of molecular electronic excited states. Here we demonstrate that single-beam laser trapping can be used to induce and quantify the local refrigeration of physiological media by >10 degrees C following the emission of photoluminescence from upconverting yttrium lithium fluoride (YLF) nanocrystals. A simple, low-cost hydrothermal approach is used to synthesize polycrystalline particles with sizes ranging from <200 nm to >1 MUm. A tunable, near-infrared continuous-wave laser is used to optically trap individual YLF crystals with an irradiance on the order of 1 MW/cm(2). Heat is transported out of the crystal lattice (across the solid-liquid interface) by anti-Stokes (blue shifted) photons following upconversion of Yb(3+) electronic excited states mediated by the absorption of optical phonons. Temperatures are quantified through analysis of the cold Brownian dynamics of individual nanocrystals in an inhomogeneous temperature field via forward light scattering in the back focal plane. The cold Brownian motion (CBM) analysis of individual YLF crystals indicates local cooling by >21 degrees C below ambient conditions in D2O, suggesting a range of potential future applications including single-molecule biophysics and integrated photonic, electronic, and microfluidic devices. PMID- 26589815 TI - Erratum to: Benzylammonium Thermometer Ions: Internal Energies of Ions Formed by Low Temperature Plasma and Atmospheric Pressure Chemical Ionization. PMID- 26589816 TI - Severe Lactic Acidosis in a Parenteral Nutrition-Dependent Teenager with Ulcerative Colitis. PMID- 26589814 TI - Synthetic CRISPR RNA-Cas9-guided genome editing in human cells. AB - Genome editing with the clustered, regularly interspaced, short palindromic repeats (CRISPR)-Cas9 nuclease system is a powerful technology for manipulating genomes, including introduction of gene disruptions or corrections. Here we develop a chemically modified, 29-nucleotide synthetic CRISPR RNA (scrRNA), which in combination with unmodified transactivating crRNA (tracrRNA) is shown to functionally replace the natural guide RNA in the CRISPR-Cas9 nuclease system and to mediate efficient genome editing in human cells. Incorporation of rational chemical modifications known to protect against nuclease digestion and stabilize RNA-RNA interactions in the tracrRNA hybridization region of CRISPR RNA (crRNA) yields a scrRNA with enhanced activity compared with the unmodified crRNA and comparable gene disruption activity to the previously published single guide RNA. Taken together, these findings provide a platform for therapeutic applications, especially for nervous system disease, using successive application of cell permeable, synthetic CRISPR RNAs to activate and then silence Cas9 nuclease activity. PMID- 26589817 TI - Comparison of Outcomes and Complications of Endoscopic Common Bile Duct Stone Removal Between Asymptomatic and Symptomatic Patients. AB - INTRODUCTION: Endoscopic retrograde cholangiopancreatography (ERCP) is generally recommended for removal of CBD stones. There were no studies focusing on the role of symptoms related to CBD stone in performing endoscopic stone removal. The aim of our study was to compare outcomes and complications of ERCP between asymptomatic and symptomatic CBD stones. METHODS: The medical records of 568 patients with naive papilla who underwent ERCP for treatment of CBD stone from Jan 2009 to Aug 2014 were reviewed and analyzed retrospectively. Patients were divided as asymptomatic group (n = 32) and symptomatic group (n = 536). RESULTS: Age and gender were not significantly different between the two groups (p > 0.005). Mean sizes of CBD and CBD stones were not significantly different between asymptomatic and symptomatic group (p > 0.05). No differences in performance of needle knife fistulotomy, endoscopic sphincterotomy, and endoscopic papillary balloon dilatation were observed between the two groups (p > 0.05). Unintentional injection into the pancreatic duct was not significantly different between the two groups (p > 0.05). The overall complete stone removal rate was 96.9 % in the asymptomatic group and 94.4 % in the symptomatic group (p = 0.295). Requirement of mechanical lithotripsy was not significantly different between asymptomatic and symptomatic group (18.8 vs 8.4 %, p = 0.057). Significantly higher incidence of post-ERCP pancreatitis was observed in the asymptomatic group than in the symptomatic group (12.5 vs 3.9 %, p = 0.045). CONCLUSION: The overall success rates of CBD stone removal were comparable between asymptomatic and symptomatic patients. However, risk of post-ERCP pancreatitis appears to be increased in patients with asymptomatic CBD stones. PMID- 26589818 TI - Percutaneous Closure of Perimembranous Ventricular Septal Defects Using the Second-Generation Amplatzer Vascular Occluders. AB - Earlier attempts at percutaneous closure of perimembranous ventricular septal defects (Pm VSDs) were abandoned because of incidence of heart block likely as a result of device rigidity and/or oversizing. This is retrospective review and data reporting of patients who underwent percutaneous closure using the softer second-generation Amplatzer vascular occluders; namely the Amplatzer vascular plug, second generation, (AVP II) and the Amplatzer duct occluder, second generation (ADO II) in our institution. A total of 20 patients were identified; AVP II was used in 9 patients and ADO II in 11 patients. Median weight was 13.45 kg (range 6.5 to 76); age 28.5 months (range 11 to 352). After procedure, 4 were noted to have aortic insufficiency; trivial in 3 and mild in 1 (unrelated to the device). Mild tricuspid regurgitation possibly device or procedure related was seen in 4. Residual flow through the device was common after procedure and disappeared in all but 3, graded as trivial in 1, small in 2. Average follow-up period was 7.54 months +/- 7.5 (1 day to 25 months). There was no incidence of heart block, bacterial endocarditis, hemolysis, device embolization, or fracture. The aortic insufficiency resolved in 1 patient and was estimated to be trivial in the remaining 3 patients. In conclusion, percutaneous closure of Pm VSDs using the softer new generation devices as the AVP II and the ADO II is feasible and safe. Longer follow-up and larger series are needed. PMID- 26589820 TI - Validation of the Framingham Heart Study and CHARGE-AF Risk Scores for Atrial Fibrillation in Hispanics, African-Americans, and Non-Hispanic Whites. AB - A risk score for atrial fibrillation (AF) has been developed by the Framingham Heart Study and Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE)-AF consortium. However, validation of these risk scores in an inner-city population is uncertain. Thus, a validation model was built using the Framingham Risk Score for AF and CHARGE-AF covariates. An in and outpatient electrocardiographic database was interrogated from 2000 to 2013 for the development of AF. Patients were included if their age was >45 and <95 years, had <10-year follow-up, if their initial electrocardiogram was without AF, had >= 2 electrocardiograms, and declared a race and/or ethnicity as non-Hispanic white, African-American, or Hispanic. For the Framingham Heart Study, 49,599 patients met inclusion criteria, of which 4,860 developed AF. Discrimination analysis using area under the curve (AUC) for original risk equations: non-Hispanic white AUC = 0.712 (95% confidence interval [CI] 0.694 to 0.731), African-American AUC = 0.733 (95% CI 0.716 to 0.751), and Hispanic AUC = 0.740 (95% CI 0.723 to 0.757). For the CHARGE-AF, 45,571 patients met inclusion criteria, of which 4,512 developed AF. Non-Hispanic white AUC = 0.673 (95% CI 0.652 to 0.694), African American AUC = 0.706 (95% CI 0.685 to 0.727), and Hispanic AUC = 0.711 (95% CI 0.691 to 0.732). Calibration analysis showed qualitative similarities between cohorts. In conclusion, this is the first study to validate both the Framingham Heart Study and CHARGE-AF risk scores in both a Hispanic and African-American cohort. All models predicted AF well across all race and ethnic cohorts. PMID- 26589819 TI - Should Antihypertensive Treatment Recommendations Differ in Patients With and Without Coronary Heart Disease? (from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial [ALLHAT]). AB - Thiazide-type diuretics have been recommended for initial treatment of hypertension in most patients, but should this recommendation differ for patients with and without coronary heart disease (CHD)? The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was a randomized, double-blind hypertension treatment trial in 42,418 participants with high risk of combined cardiovascular disease (CVD) (25% with preexisting CHD). This post hoc analysis compares long-term major clinical outcomes in those assigned amlodipine (n = 9048) or lisinopril (n = 9,054) with those assigned chlorthalidone (n = 15,255), stratified by CHD status. After 4 to 8 years, randomized treatment was discontinued. Total follow-up (active treatment + passive surveillance using national databases for deaths and hospitalizations) was 8 to 13 years. For most CVD outcomes, end-stage renal disease, and total mortality, there were no differences across randomized treatment arms regardless of baseline CHD status. In-trial rates of CVD were significantly higher for lisinopril compared with chlorthalidone, and rates of heart failure were significantly higher for amlodipine compared with chlorthalidone in those with and without CHD (overall hazard ratios [HRs] 1.10, p <0.001, and 1.38, p <0.001, respectively). During extended follow-up, significant outcomes according to CHD status interactions (p = 0.012) were noted in amlodipine versus chlorthalidone comparison for CVD and CHD mortality (HR 0.88, p = 0.04, and 0.84, p = 0.04, respectively) in those with CHD at baseline (HR 1.06, p = 0.15, and 1.08, p = 0.17) and in those without. The results of the overall increased stroke mortality in lisinopril compared with chlorthalidone (HR 1.2; p = 0.03) and hospitalized heart failure in amlodipine compared with chlorthalidone (HR 1.12; p = 0.01) during extended follow-up did not differ by baseline CHD status. In conclusion, these results provide no reason to alter our previous recommendation to include a properly dosed diuretic (such as chlorthalidone 12.5 to 25 mg/day) in the initial antihypertensive regimen for most hypertensive patients. PMID- 26589821 TI - Comparison of Adherence to Guideline-Based Cholesterol Treatment Goals in Men Versus Women. AB - Studies show women do not receive aggressive cardiovascular interventions and may not be given guideline-based treatment to reduce cardiac events. We describe cholesterol treatment in an academic practice of family and internal medicine physicians to understand factors associated with achievement of guideline-based treatment goals in women compared with men. Primary care patients aged 40 to 75 years were included if they were prescribed a statin, had a Framingham risk score of >= 10%, had diabetes, or had atherosclerotic cardiovascular disease. Patients were classified into Adult Treatment Panel III categories and assessed to whether they were in compliance with Adult Treatment Panel III guidelines. Odds ratios of goal adherence between women and men were calculated, and a multivariate model for goal achievement was created. In 2,747 patients, women were less likely to achieve cholesterol goals (odds ratio [OR] 0.82; 95% confidence interval [CI] 0.70 to 0.95) despite having more prescriptions for statins (48% vs 39%, p <0.001). More women than men failed to reach low-density lipoprotein goals because they were not prescribed a statin (OR 0.69; 95% CI 0.56 to 0.85) and women on high-intensity statins were less likely than men to achieve goals (OR 0.51; 95% CI 0.27 to 0.96). In all patients, diabetes was associated with nonattainment of cholesterol goals, but in high-risk women, the presence of diabetes improved goal achievement. In conclusion, women achieved guideline-based cholesterol recommendations at a lower rate than men, even when individual goals are considered. PMID- 26589822 TI - Erratum to: Non-surgical periodontal treatment of peri-implant diseases with the adjunctive use of diode laser: preliminary clinical study. PMID- 26589823 TI - The free energy method and the Wright-Fisher model with 2 alleles. AB - We systematically investigate the Wright-Fisher model of population genetics with the free energy functional formalism of statistical mechanics and in the light of recent mathematical work on the connection between Fokker-Planck equations and free energy functionals. In statistical physics, entropy increases, or equivalently, free energy decreases, and the asymptotic state is given by a Gibbs type distribution. This also works for the Wright-Fisher model when rewritten in divergence to identify the correct free energy functional. We not only recover the known results about the stationary distribution, that is, the asymptotic equilibrium state of the model, in the presence of positive mutation rates and possibly also selection, but can also provide detailed formulae for the rate of convergence towards that stationary distribution. In the present paper, the method is illustrated for the simplest case only, that of two alleles. PMID- 26589824 TI - Hypoxia-Targeting Fluorescent Nanobodies for Optical Molecular Imaging of Pre Invasive Breast Cancer. AB - PURPOSE: The aim of this work was to develop a CAIX-specific nanobody conjugated to IRDye800CW for molecular imaging of pre-invasive breast cancer. PROCEDURES: CAIX-specific nanobodies were selected using a modified phage display technology, conjugated site-specifically to IRDye800CW and evaluated in a xenograft breast cancer mouse model using ductal carcinoma in situ cells (DCIS). RESULTS: Specific anti-CAIX nanobodies were obtained. Administration of a CAIX-specific nanobody into mice with DCIS xenografts overexpressing CAIX showed after 2 h a mean tumor to-normal tissue ratio (TNR) of 4.3 +/- 0.6, compared to a TNR of 1.4 +/- 0.2 in mice injected with the negative control nanobody R2-IR. In DCIS mice, a TNR of 1.8 +/- 0.1 was obtained. Biodistribution studies demonstrated an uptake of 14.0 +/- 1.1 %I.D./g in DCIS + CAIX tumors, 4.6 +/- 0.8 %I.D./g in DCIS tumors, while 2.0 +/- 0.2 %I.D./g was obtained with R2-IR. CONCLUSIONS: These results demonstrate the successful generation of a CAIX-specific nanobody-IRDye800CW conjugate that can be used for rapid imaging of (pre-)invasive breast cancer. PMID- 26589826 TI - Growing degree hours - a simple, accurate, and precise protocol to approximate growing heat summation for grapevines. AB - Despite its low accuracy and consistency, growing degree days (GDD) has been widely used to approximate growing heat summation (GHS) for regional classification and phenological prediction. GDD is usually calculated from the mean of daily minimum and maximum temperatures (GDDmm) above a growing base temperature (T gb). To determine approximation errors and accuracy, daily and cumulative GDDmm was compared to GDD based on daily average temperature (GDDavg), growing degree hours (GDH) based on hourly temperatures, and growing degree minutes (GDM) based on minute-by-minute temperatures. Finite error, due to the difference between measured and true temperatures above T gb is large in GDDmm but is negligible in GDDavg, GDH, and GDM, depending only upon the number of measured temperatures used for daily approximation. Hidden negative error, due to the temperatures below T gb when being averaged for approximation intervals larger than measuring interval, is large in GDDmm and GDDavg but is negligible in GDH and GDM. Both GDH and GDM improve GHS approximation accuracy over GDDmm or GDDavg by summation of multiple integration rectangles to reduce both finite and hidden negative errors. GDH is proposed as the standardized GHS approximation protocol, providing adequate accuracy and high precision independent upon T gb while requiring simple data recording and processing. PMID- 26589825 TI - Assessing changes in quality of life using the Oral Health Impact Profile (OHIP) in patients with different classifications of malocclusion during comprehensive orthodontic treatment. AB - BACKGROUND: The objectives of this study were to investigated changes in OHRQoL among patients with different classifications of malocclusion during comprehensive orthodontic treatment. METHODS: Clinical data were collected from 81 patients (aged 15 to 24) who had undergone comprehensive orthodontic treatment. Participants were classified 3 groups: Class I (n = 35), II (n = 32) and III (n = 14) by Angle classification. OHRQoL was assessed using the Oral Health Impact Profile (OHIP-14). All subjects were examined and interviewed at baseline (T0), after alignment and leveling (T1), after correction of molar relationship and space closure (T2), after finishing (T3). Friedman 2-way analysis of variance (ANOVA) and Wilcoxon signed rank tests were used to compare the relative changes of OHRQoL among the different time points. A Bonferroni correction with P < 0.005 was used to declare significance. RESULTS: Significant reductions were observed in all seven OHIP-14 domains of three groups except for social disability (P > 0.005) in class I and class II, Handicap in class II and class III (P > 0.005). Class I patients showed significant changes for psychological disability and psychological discomfort domain at T1, functional limitation, physical pain at T2. Class III patients showed a significant benefit in all domains except physical pain and functional limitation. Class II patients showed significant changes in the physical pain, functional disability, and physical disability domains at T1. CONCLUSIONS: The impact of comprehensive orthodontic treatment on patients' OHRQoL do not follow the same pattern among patients with different malocclusion. Class II patients benefits the most from the stage of space closure, while class I patients benefits the first stage (alignment and leveling) of treatment in psychological disability and psychological discomfort domains. PMID- 26589827 TI - Growth, immune, antioxidant, and bone responses of heat stress-exposed broilers fed diets supplemented with tomato pomace. AB - A study was conducted to investigate the effects of supplementation of dried tomato pomace (DTP) on growth performance, relative weights of viscera, serum biological parameters, antioxidant status, immune response, and bone composition of broilers exposed to a high ambient temperature. A total of 352 one-day-old male broiler chickens were randomly divided into four groups consisting of four replicates with 22 birds each. One group was reared under the thermoneutral zone and fed a corn-soybean meal basal diet. The other three groups were subjected to a cyclic heat stress from 29 to 42 days of age (34 +/- 1 degrees C, 55 % RH, 5 h/day). These birds were fed corn-soybean meal basal diet or the same diet supplemented with 3 % DTP (420 mg lycopene/kg diet) or 5 % (708 mg lycopene/kg diet) of DTP. Blood samples were collected on days 28 and 42, and the birds were slaughtered at the same times. Supplementation of 5 % of DTP increased body weight and production index and decreased feed conversion ratio during 1-28 days of age. On day 28, the broilers supplemented with 5 % DTP had lower serum triglycerides and higher high-density lipoprotein (HDL) cholesterol concentration than those on the other dietary treatments. The activities of glutathione peroxidase (GPx) and superoxide dismutase (SOD) were higher and the concentration of malondialdehyde (MDA) was lower in the broilers fed 5 % TP than those of the broilers fed other diets at 28 days of age. The effects of heat stress (HS) were impaired body weight, enhanced serum activities of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, lipase, and MDA concentration while reducing the activities of GPx and SOD. Dried tomato pomace supplementation did not influence growth performance under HS but ameliorated the negative effects of HS on the serum enzyme activities, GPx activity, and lipid peroxidation. Heat stress did not change the relative weights of the lymphoid organs but reduced the total and IgG titers for secondary antibody response to sheep red blood cells and titer against Newcastle disease virus and increased the heterophil/lymphocyte ratio. The supplementation with 5 % of DTP completely alleviated the negative effects of HS on immune responses. The ash, Ca, and P contents of the tibia bone were decreased under HS. The ash and Ca contents of the tibia were not significantly different between thermoneutral and heat stressed broilers supplemented with 5 % DTP. In conclusion, dietary supplementation of DTP, particularly 5 % DTP, to broiler diet attenuated the detrimental effects of HS on the activities of serum enzymes, oxidative status, immune response, and bone composition. PMID- 26589828 TI - Optimal weighted combinatorial forecasting model of QT dispersion of ECGs in Chinese adults. AB - This study aims to provide a scientific basis for unifying the reference value standard of QT dispersion of ECGs in Chinese adults. Three predictive models including regression model, principal component model, and artificial neural network model are combined to establish the optimal weighted combination model. The optimal weighted combination model and single model are verified and compared. Optimal weighted combinatorial model can reduce predicting risk of single model and improve the predicting precision. The reference value of geographical distribution of Chinese adults' QT dispersion was precisely made by using kriging methods. When geographical factors of a particular area are obtained, the reference value of QT dispersion of Chinese adults in this area can be estimated by using optimal weighted combinatorial model and reference value of the QT dispersion of Chinese adults anywhere in China can be obtained by using geographical distribution figure as well. PMID- 26589829 TI - Contributions of cultivar shift, management practice and climate change to maize yield in North China Plain in 1981-2009. AB - The impact of climate change on crop yield is compounded by cultivar shifts and agronomic management practices. To determine the relative contributions of climate change, cultivar shift, and management practice to changes in maize (Zea mays L.) yield in the past three decades, detailed field data for 1981-2009 from four representative experimental stations in North China Plain (NCP) were analyzed via model simulation. The four representative experimental stations are geographically and climatologically different, represent the typical cropping system in the study area, and have more complete weather/crop records for the period of 1981-2009. The results showed that while the shift from traditional to modern cultivar increased yield by 23.9-40.3 %, new fertilizer management increased yield by 3.3-8.6 %. However, the trends in climate variables for 1981 2009 reduced maize yield by 15-30 % in the study area. Among the main climate variables, solar radiation had the largest effect on maize yield, followed by temperature and then precipitation. While a significant decline in solar radiation in 1981-2009 (maybe due to air pollution) reduced yield by 12-24 %, a significant increase in temperature reduced yield by 3-9 %. In contrast, a non significant increase in precipitation during the maize growth period increased yield by 0.9-3 % at three of the four investigated stations. However, a decline in precipitation reduced yield by 3 % in the remaining station. The study revealed that although the shift from traditional to modern cultivars and agronomic management practices contributed most to the increase in maize yield, the negative impact of climate change was large enough to offset 46-67 % of the trend in the observed yields in the past three decades in NCP. The reduction in solar radiation, especially in the most critical period of maize growth, limited the process of photosynthesis and thereby further reduced maize yield. PMID- 26589831 TI - Gastric cancer progression associated with local humoral immune responses. AB - BACKGROUND: Although the association between H. pylori and gastric cancer has been well described, the alterations studies are scarce in the humoral immune response in specific anatomical areas of stomach and during the stages of gastric cancer. The aim in this study was to determine the influence of humoral immune responses against H. pylori infection on gastric carcinoma. METHODS: We selected 16 gastric cancer cases and approximately one matched control per case at the National Institute of Medical Sciences and Nutrition Salvador Zubiran (INCMNSZ); all the cases met the inclusion criteria for the study. We obtained three biopsies from each patient and from each of the predetermined regions of the stomach: antrum, angular portion, corpus, and fundus. From the patients with gastric cancer, additional biopsy specimens were obtained from tumor mid-lesion and tumor margin, and additional specimens were collected at least 2 and 5 cm from the tumor margin. We compared IgA levels against H. pylori in each area of stomach between cases and controls as well as between early and advanced stages of gastric cancer. RESULTS: IgA values were strikingly elevated in cancer cases compared with control subjects; a value that was even higher in the distant periphery of tumor but was remarkably decreased toward the carcinoma lesion. The advanced stages of gastric cancer demonstrated the relapse of the humoral immune response in the mid-lesion region of the tumor compared with the tumor margins and adjacent non-tumor tissue. CONCLUSIONS: Gastric cancer is characterized by progressive accumulation of a concentrated, specific IgA response against H. pylori, beginning with an abnormal increase in the entire stomach but particularly in the adjacent non-tumor tissue. Thus, it is possible that this strong immune response also participates in some degree in the damage and in the development of gastric cancer to some extent. PMID- 26589832 TI - Kynurenine-3-monooxygenase: a review of structure, mechanism, and inhibitors. AB - Kynurenine monooxygenase (KMO) is an enzyme of the kynurenine (Kyn) pathway (KP), which is the major catabolic route of tryptophan. Kyn represents a branch point of the KP, being converted into the neurotoxin 3-hydroxykynurenine via KMO, neuroprotectant kynurenic acid, and anthranilic acid. As a result of this branch point, KMO is an attractive drug target for several neurodegenerative and/or neuroinflammatory diseases, especially Huntington's (HD), Alzheimer's (AD), and Parkinson's (PD) diseases. Although a neurological target, administration of KMO inhibitors in the periphery has demonstrated promising pharmacological results. In light of a recent crystal structure release and reports of preclinical candidates, here we provide a concise yet comprehensive update on the current state of research into the enzymology of KMO and related drug discovery efforts, highlighting areas where further work is required. PMID- 26589833 TI - Mapping lifecycle management activities for blockbuster drugs in Japan based on drug approvals and patent term extensions. AB - Drug lifecycle management (LCM), which entails acquiring drug approvals and patent protections, contributes to maximizing drug discovery investment returns. In a previous survey, a comparative analysis between Japan and the USA indicated that a unique patent term extension system has an important role in Japanese drug LCM. Therefore, in this survey, we focused on drug approvals and patent term extensions, and found that the LCM for blockbuster drugs in Japan can be categorized into three types (drug approval-oriented LCM, patent term extension oriented LCM, and inactive-type LCM), of which the first two have been implemented recently. Here, we suggest a strategy for selecting a suitable LCM approach among these three types based on the prospects for drug improvements. PMID- 26589834 TI - Host infection history modifies co-infection success of multiple parasite genotypes. AB - Co-infections by multiple parasite genotypes are common and have important implications for host-parasite ecology and evolution through within-host interactions. Typically, these infections take place sequentially, and therefore, the outcome of co-infection may be shaped by host immune responses triggered by previous infections. For example, in vertebrates, specific immune responses play a central role in protection against disease over the course of life, but co infection research has mostly focused on previously uninfected individuals. Here, we investigated whether sequential exposure and activation of host resistance in rainbow trout Oncorhynchus mykiss affects infection success and interactions between co-infecting parasite genotypes of the trematode eye-fluke Diplostomum pseudospathaceum. In accordance with earlier results, we show that a simultaneous attack of two parasite genotypes facilitates parasite establishment in previously uninfected hosts. However, we find for the first time that this facilitation in co-infection is lost in hosts with prior infection. We conclude that vertebrate host infection history can affect the direction of within-host-parasite interactions. Our results may have significant implications for the evolution of co-infections and parasite transmission strategies. PMID- 26589835 TI - Prognostic significance of (18)FDG PET/CT in colorectal cancer patients with liver metastases: a meta-analysis. AB - BACKGROUND: The role of 18-fluorodeoxyglucose positron emission tomography CT ((18)FDG PET/CT), as a prognostic factor for survival in colorectal cancer patients with liver metastases, is still controversial. We sought to perform a meta-analysis of the literature to address this issue. METHODS: A systematic literature search was performed to identify the studies that associated (18)FDG PET/CT to clinical survival outcomes of patients with liver metastases. Methodological qualities of the included studies were also assessed. The summarized hazard ratio (HR) was estimated by using fixed- or random-effect model according to heterogeneity between trails. RESULTS: By analyzing a total of 867 patients from 15 studies, we found that PET/CT for metabolic response to the therapy was capable of predicting event-free survival (EFS) and overall survival (OS) with statistical significance, and the HR was 0.45 (95% confidence interval [CI], 0.26-0.78) and 0.36 (95% CI, 0.18-0.71), respectively. Furthermore, pre treatment (18)FDG PET/CT with high standardized uptake value (SUV) was also significantly associated with poorer OS HR, 1.24; (95% CI, 1.06-1.45). However, we did not find a statistically significant effect of post-treatment SUV for predicting OS HR, 1.68; (95% CI, 0.63-4.52). CONCLUSIONS: The present meta analysis confirms that (18)FDG PET/CT is a useful tool to help predict survival outcomes in patients with liver metastases. PMID- 26589836 TI - ADAMTS-13 and von Willebrand factor predict venous thromboembolism in patients with cancer. AB - ESSENTIALS: Cancer patients are at high risk of venous thromboembolism (VTE). In this study, cases and controls were cancer patients who did or did not develop VTE. von Willebrand factor (VWF) levels were higher if compared with controls and correlated with cancer stage. VWF and ADAMTS-13 are associated with the occurrence of VTE in cancer. BACKGROUND: Patients with cancer are at high risk of venous thromboembolism (VTE). ADAMTS-13 regulates von Willebrand factor (VWF) activity, which plays a role in the development of cancer and in VTE. OBJECTIVES: The aim of this study was to search for an association between the levels of VWF and ADAMTS-13 and VTE in patients with cancer and to compare current scoring systems for prediction of VTE before and after addition of these parameters. PATIENTS/METHODS: In a case-control study, in which patients with recently diagnosed cancer were followed-up for 6 months, we compared 20 patients who developed VTE (cases) and 140 patients with cancer without VTE (controls), matched for sex, age, and type and stage of cancer. We measured VWF, ADAMTS-13 (activity and antigen), P-selectin, D-dimer and F1 + 2 levels at baseline, and calculated both the Khorana score and the Khorana score expanded after addition of P-selectin and D-dimer levels. RESULTS: VWF levels were significantly higher in cases when compared with controls (326 +/- 185% vs. 242 +/- 158%) and correlated with advanced stage of cancer: localized, 185 [142; 222]; locally advanced, 240 [146; 257]; metastatic, 267 [153; 324] (mean [interquartile range]). The addition of two biomarkers, ADAMTS-13 activity and F1 + 2 levels, to the Khorana score improved receiver operating curves. CONCLUSIONS: von Willebrand factor and ADAMTS-13 are associated with the occurrence of VTE in patients with cancer. Moreover, addition of ADAMTS-13 and F1 + 2 levels to the Khorana score considerably increases the predictive value for VTE. PMID- 26589837 TI - Radiographic Identification of Arthroscopically Relevant Acetabular Structures. AB - BACKGROUND: The anatomy of the acetabulum has been described extensively in the literature, but radiographic acetabular guidelines have not been well established. This study provides a radiographic map of acetabular landmarks in the hip. PURPOSE/HYPOTHESIS: The purpose of this study was to quantify the precise radiographic location of arthroscopic landmarks around the acetabulum. The hypothesis was that their locations were reproducible despite variability in the anatomy and positioning of pelvic specimens. STUDY DESIGN: Descriptive laboratory study. METHODS: Ten fresh-frozen cadaveric specimens were dissected, and radio-opaque hardware was placed for each landmark of interest. Anteroposterior (AP) and false-profile radiographs were obtained, and measurements were taken using a digital picture archiving and communication system. RESULTS: On AP radiographs, the direct and indirect heads of the rectus femoris were a mean 48.2 +/- 4.6 mm and 44.7 +/- 4.3 mm proximal to the teardrop line, respectively. The mean radiographic distance between their insertions was 5.0 +/- 3.4 mm. Moreover, the anterior inferior iliac spine was a mean 11.5 +/- 3.8 mm from the acetabular rim. On false-profile radiographs, the mean distance between the direct and indirect heads of the rectus femoris was 31.4 +/- 6.2 mm. The mean distance between the superior margin of the anterior labral sulcus (the psoas-u) and the midpoint of the transverse acetabular ligament was 41.0 +/- 5.7 mm. Additionally, the direct and indirect heads of the rectus femoris corresponded to the 2:30 and 1:30 locations on the acetabular clockface, respectively. The midpoint of the transverse acetabular ligament was located at 7 o'clock on the clockface. CONCLUSION: The most important finding of this study, determined by quantitative measurements, was that the described surgical landmarks had reliable locations on radiographs. Distances between landmarks as well as distances between landmarks and reference lines were reproducible in both AP and false-profile views. CLINICAL RELEVANCE: An understanding of how acetabular structures present on radiographs could lead to more accurate portal and hardware placement intraoperatively during arthroscopic surgery as well as better preoperative and postoperative assessments. PMID- 26589838 TI - The Mechanical Functionality of the EXO-L Ankle Brace: Assessment With a 3 Dimensional Computed Tomography Stress Test. AB - BACKGROUND: A new type of ankle brace (EXO-L) has recently been introduced. It is designed to limit the motion of most sprains without limiting other motions and to overcome problems such as skin irritation associated with taping or poor fit in the sports shoe. PURPOSE: To evaluate the claimed functionality of the new ankle brace in limiting only the motion of combined inversion and plantar flexion. STUDY DESIGN: Controlled laboratory study. METHODS: In 12 patients who received and used the new ankle brace, the mobility of the joints was measured with a highly accurate and objective in vivo 3-dimensional computed tomography (3D CT) stress test. Primary outcomes were the ranges of motion as expressed by helical axis rotations without and with the ankle brace between the following extreme positions: dorsiflexion to plantar flexion, and combined eversion and dorsiflexion to combined inversion and plantar flexion. Rotations were acquired for both talocrural and subtalar joints. A paired Student t test was performed to test the significance of the differences between the 2 conditions (P <= .05). RESULTS: The use of the ankle brace significantly restricted the rotation of motion from combined eversion and dorsiflexion to combined inversion and plantar flexion in both the talocrural (P = .004) and subtalar joints (P < .001). No significant differences were found in both joints for the motion from dorsiflexion to plantar flexion. CONCLUSION: The 3D CT stress test confirmed that under static and passive testing conditions, the new ankle brace limits the inversion-plantar flexion motion that is responsible for most ankle sprains without limiting plantar flexion or dorsiflexion. CLINICAL RELEVANCE: This test demonstrated its use in the objective evaluation of braces. PMID- 26589841 TI - The existential cancer journey: Travelling through the intersubjective structure of homeworld/alienworld. AB - In the past couple of decades, there has been significant interest in the research literature and patient narratives that focus on describing the cancer journey as involving existential and spiritual transformative experiences. The purpose of this article is to contribute with a new and deepened understanding of the existing literature by offering a philosophical informed analytic conceptualization that highlights the 'liminal', transformative and 'generative' dimension of the cancer journey. For that purpose, qualitative data drawn from a qualitative study investigating existential experiences of a group of Danish patients in rehabilitation were analysed employing the American phenomenologist Anthony J. Steinbock's interpretation of the Husserlian concepts homeworld/alienworld ( Heimwelt/Fremdwelt). Data used in this article derived from qualitative interviews (11 individual interviews and 9 focus group interviews) with cancer patients participating in rehabilitation week courses at a Danish rehabilitation centre. The analysis led to the development of three themes: 'The heavy break with the homeworld', 'Realizing a new homefellowship' and 'Transformation of the homeworld'. Findings suggest that journeying with cancer involves a 'liminal' experiencing of having to navigate in a borderless and unfamiliar territory between a homeworld and an alienworld before ultimately arriving at a sense of transformation in which meaning is derived from both lifeworlds. It is argued that such an understanding of the intersubjectivity between lifeworlds highlights the need for health care professionals communicating with patients throughout their cancer journey about whether and how the illness experiences have been integrated into their lifeworld and whether help is needed in order to achieve existential rehabilitation. PMID- 26589840 TI - The therapeutic potential of microbial proteasome inhibitors. AB - The proteasome influences cellular homeostasis through the degradation of regulatory proteins, many of which are also involved in disease pathogenesis. In particular, numerous regulatory proteins associated with tumor growth, such as cyclins, cyclin-dependent kinase inhibitors, tumor suppressors, and NF-kappaB inhibitors are degraded by the proteasome. Proteasome inhibitors can stabilize these regulatory proteins, resulting in the suppression of tumor development and the regulation of immune responses. Thus, proteasome inhibitors are promising candidate antitumor agents and immune-regulatory agents. Bortezomib is the first in-class proteasome inhibitor approved for the treatment of multiple myeloma. Despite its high efficiency, however, a large proportion of patients do not attain sufficient clinical response due to toxicity and drug resistance. Therefore, the development of new proteasome inhibitors with improved pharmacological properties is needed. Natural products produced by microorganisms are a promising source of such compounds. This review provides an overview of proteasome inhibitors produced by microorganisms, with special focus on inhibitors isolated from actinomycetes. PMID- 26589842 TI - Disability Management Education: Does the Instructional Delivery Modality Make a Difference? AB - Each year, thousands of professionals and practitioners opt to learn more about disability management practices by attending conferences, self-study, and registering for advanced educational courses. Their motivation is to enhance their competencies, advance their careers, and attain or maintain professional certification. However, for their efforts, are they accessing the most effective mode of disability management instruction? This clinical research indicated that the "online delivery" of disability management instruction nets a 5% higher score on the outcome measure than the "in-class delivery" modality. PMID- 26589843 TI - Investigation of ossification in the posterior longitudinal ligament using micro focus X-ray CT scanning and histological examination. AB - BACKGROUND: Ossification in the posterior longitudinal ligament (PLL) correlates with changes of enthesis during the early stages of development, but this issue remains controversial, as little is known regarding the details of this process. The aim of the present study was to elucidate part of the ossification mechanism. Thus, in the present study, we observed and evaluated minute ossifications in the PLL that did not exhibit symptoms of ossification of the posterior longitudinal ligament (OPLL). METHODS: The subjects in the present study were derived from serial autopsy cases from January 2009 to December 2013 at Toho University Omori Medical Center, Japan. Minute ossifications in the PLL from autopsy subjects without any history of OPLL were screened as high-density areas using micro-focus X-ray CT, and the foci were histologically examined. Subsequently, we conducted both micro-focus X-ray CT image analysis and histological examination, and evaluated the correlation between these findings and putative predictive factors reported in previous studies. RESULTS: A total of 103 individuals among the 267 subjects involved in the present study were analyzed within the study period. There were no cases involving OPLL identification prior to death, and no subjects presented with neurological symptoms of myelopathy. The incidence of cases involving high-density areas greater than 0.1 mm(2) in the PLL was 46.6 %, half of which revealed mature bone structures inside this area. Thus, the high-density areas comprised three types: a continuous posterior-annular fibrosus type (23 cases), an isolated posterior-annular fibrosus type (11 cases), and a posterior vertebral type (29 cases). However, a positive correlation was observed between the proportion of high-density areas, age (Pearson r = 0.265, p < 0.01), and HbA1c (Pearson r = 0.294, p < 0.01). Histological examination confirmed that these high-density areas involved calcification with or without mature bone formation. CONCLUSIONS: We evaluated minute foci of calcification with and without ossification in the PLL from 103 cadavers, generating the following observations: 1. Minute calcification foci greater than 0.1 mm(2) were observed in the PLL of 48 cases (46.6 %), half of which revealed mature bone structures inside this area (23.3 %). 2. The proportion of minute calcification foci observed in the present study was correlated with age and glucose tolerance, suggesting changes in the OPLL in the early stage. 3. Three different mechanisms of ossification were suggested: The two structures developed behind the disc might reflect the elongation of enthesis or rupture of annular fibrosus, while the remaining structure developed behind the vertebral body might reflect a dystrophic calcification-based bony metaplasia sequence. PMID- 26589844 TI - A fixed movable resin-bonded fixed dental prosthesis--A 16 years clinical report. AB - PATIENTS: This report describes the case of a 48-year-old female patient who initially received a 4-unit fixed-fixed (FF) resin-bonded fixed dental prosthesis (RBFDP) for replacement of mandibular left second premolar and first molar. Twenty-one months later, debond of the RBFDP was found at one of retainers. A new fixed-movable RBFDPs with a modified non-rigid connector as well as increased resistance form features was placed and successfully retained at the 16-year clinical review. DISCUSSION: RBFDPs are a conservative tooth replacement option that requires minimum tooth preparation and retention by a resin cement to etched enamel. However debonding is the most frequently seen complication and has been attributed to the relative movement between abutment teeth during function that stress the bonding interface. This case report highlights the use of modified non rigid connector which allows relative movement between abutment teeth and therefore a reduced stress on the bonding interface. CONCLUSION: It is proposed that the use of modified non-rigid connectors that allow independent movement between the abutment teeth during function was responsible for the long term clinical success of fixed-movable RBFDPs. PMID- 26589839 TI - Review of Journal of Cardiovascular Magnetic Resonance 2014. AB - There were 102 articles published in the Journal of Cardiovascular Magnetic Resonance (JCMR) in 2014, which is a 6% decrease on the 109 articles published in 2013. The quality of the submissions continues to increase. The 2013 JCMR Impact Factor (which is published in June 2014) fell to 4.72 from 5.11 for 2012 (as published in June 2013). The 2013 impact factor means that the JCMR papers that were published in 2011 and 2012 were cited on average 4.72 times in 2013. The impact factor undergoes natural variation according to citation rates of papers in the 2 years following publication, and is significantly influenced by highly cited papers such as official reports. However, the progress of the journal's impact over the last 5 years has been impressive. Our acceptance rate is <25% and has been falling because the number of articles being submitted has been increasing. In accordance with Open-Access publishing, the JCMR articles go on line as they are accepted with no collating of the articles into sections or special thematic issues. For this reason, the Editors have felt that it is useful once per calendar year to summarize the papers for the readership into broad areas of interest or theme, so that areas of interest can be reviewed in a single article in relation to each other and other recent JCMR articles. The papers are presented in broad themes and set in context with related literature and previously published JCMR papers to guide continuity of thought in the journal. We hope that you find the open-access system increases wider reading and citation of your papers, and that you will continue to send your quality papers to JCMR for publication. PMID- 26589845 TI - Effect of short glass fiber/filler particle proportion on flexural and diametral tensile strength of a novel fiber-reinforced composite. AB - PURPOSE: To evaluate the effect of glass fiber/filler particles proportion on flexural strength and diametral tensile strength of an experimental fiber reinforced composite. METHODS: Four experimental groups (N=10) were created using an experimental short fiber-reinforced composite, having as a factor under study the glass fiber (F) and filler particle (P) proportion: F22.5/P55 with 22.5 wt% of fiber and 55 wt% of filler particles; F25/P52.5 with 25 wt% of fiber and 52.5 wt% of filler particles; F27.5/P50 with 27.5 wt% of fiber and 50 wt% of filler particles; F30/P47.5 with 30 wt% of fiber and 47.5 wt% of filler particles. The experimental composite was made up by a methacrylate-based resin (50% Bis-GMA and 50% TEGDMA). Specimens were prepared for Flexural Strength (FS) (25 mm * 2 mm * 2 mm) and for Diametral Tensile Strength (DTS) (3*6 O mm) and tested at 0.5 mm/min in a universal testing machine. RESULTS: The results (in MPa) showed significance (different superscript letters mean statistical significant difference) for FS (p<0.009) and DTS (p<0.001)--FS results: F22.5/P55: 217.24+/-20.64(B); F25/P52.5: 245.77+/-26.80(AB); F27.5/P50: 246.88+/-32.28(AB); F30/P47.5: 259.91+/-26.01(A). DTS results: F22.5/P55: 21.82+/-4.42(B); F25/P52.5: 22.00+/-7.40(B); F27.5/P50: 18.63+/-4.41(B); F30/P47.5: 31.05+/-2.97(A). In SEM analysis, areas without fiber reinforcement demonstrated to be more prone to the presence of bubbles and crack development. The group F30/P47.5 showed areas with a great quantity of fibers without empty spaces for crack propagation. CONCLUSION: Increasing fiber content results in higher flexural and diametral tensile strength of an experimental composite reinforced with glass fibers. PMID- 26589846 TI - MiR-181a suppresses autophagy and sensitizes gastric cancer cells to cisplatin. AB - A number of chemotherapy drugs can induce autophagy. This inducible autophagy is a pro-survival mechanism and contributes to the development of acquired drug resistance. Emerging evidence indicates that miRNA regulates autophagy via targeting autophagy related genes and is involved in drug resistance. We previously demonstrated that miR-181a plays an important role in gastric cancer. The present study aimed to explore the effect of miR-181a on autophagy regulation and cisplatin resistance. We revealed that miR-181a is a novel negative regulator of autophagy in cisplatin-resistant cells SGC7901/CDDP. Then we indicated that ATG5 was a potential target of miR-181a. Furthermore, overexpression of miR-181a significantly enhanced the sensitivity of SGC7901/CDDP cells to cisplatin in vitro and reduced the volumes of gastric tumor xenografts in nude mice. Our finding provides evidence that miR-181a functions as a primary autophagy-related modulator and reverses cisplatin-resistance in GC cells. PMID- 26589848 TI - BJOG Editors-in-Chief since 1902: Editor-in-Chief number 5: John Shields Fairbairn (1909-1914). PMID- 26589850 TI - Recurrent pre-eclampsia in women with metabolic syndrome and low plasma volume: a retrospective cohort study. AB - OBJECTIVE: To determine the prevalence of recurrent pre-eclampsia in women with a history of pre-eclampsia with both metabolic syndrome and low plasma volume postpartum, as compared with women without either entity. DESIGN: Retrospective cohort study. SETTING: Three tertiary referral hospitals in the Netherlands. POPULATION: Women with a history of pre-eclampsia. METHODS: In 196 women with a history of pre-eclampsia we determined the presence or absence of metabolic syndrome using the World Health Organization criteria and measured plasma volume with the (125) I-human serum albumin indicator dilution technique. We compared the prevalence of recurrent pre-eclampsia in four groups, classified according to presence or absence of metabolic syndrome and low or normal plasma volume, calculating odds ratios (OR), adjusted for confounders. MAIN OUTCOME MEASURE: Recurrence of pre-eclampsia in the subsequent pregnancy. RESULTS: The prevalence of recurrent pre-eclampsia was 12% (12/99) in women without metabolic syndrome with normal plasma volume, versus 47% (8/17) in women with both metabolic syndrome and low plasma volume: OR 6.44 (95% CI 2.09-19.90), adjusted OR 7.90 (95% CI 2.30-27.16). Recurrent pre-eclampsia was present in 44% (10/23) and 25% (14/57) of women with isolated metabolic syndrome and low plasma volume, respectively. CONCLUSIONS: In the concomitant presence of metabolic syndrome and low plasma volume, the prevalence of recurrent pre-eclampsia was nearly 50%, which is four times as high as the prevalence in women without either entity. TWEETABLE ABSTRACT: Metabolic syndrome and low plasma volume raise the risk of recurrent pre-eclampsia to nearly 50%. PMID- 26589851 TI - Endometrial ablation and steam vaporisation: the true first generation ablative technique. PMID- 26589852 TI - Vaginal sub-total hysterectomy--an early minimally invasive procedure. PMID- 26589853 TI - Re: Factors associated with maternal death from direct pregnancy complications: a UK national case-control study. PMID- 26589854 TI - Authors' reply re: Factors associated with maternal death from direct pregnancy complications: a UK national case-control study. PMID- 26589855 TI - Re: Transverse uterine fundal incision for placenta praevia with accreta, involving the entire anterior uterine wall: a case series: How to reduce overuse of the new method for dealing with placenta praevia suggested by Kotsuji et al. PMID- 26589856 TI - Authors' reply re: Transverse uterine fundal incision for placenta praevia with accreta, involving the entire anterior uterine wall: a case series. PMID- 26589857 TI - Author's reply re: Previous caesarean delivery and the risk of unexplained stillbirth: retrospective cohort study and meta-analysis. PMID- 26589858 TI - Re: Previous caesarean delivery and the risk of unexplained stillbirth: retrospective cohort study and meta-analysis. PMID- 26589859 TI - Re: The prevention and treatment of postpartum haemorrhage: what do we know, and where do we go to next?: The treatment of postpartum haemorrhage: holding the intrauterine balloon 'there'. PMID- 26589860 TI - Re: Transvaginal prolapse repair with or without the addition of a midurethral sling in women with genital prolapse and stress urinary incontinence: a randomised trial. PMID- 26589861 TI - Authors' reply re: Transvaginal prolapse repair with or without the addition of a midurethral sling in women with genital prolapse and stress urinary incontinence: a randomised trial. PMID- 26589862 TI - Authors' reply re: Teens and young adults should be started on longacting reversible contraceptives before sexual activity commences. PMID- 26589863 TI - Re: Teens and young adults should be started on longacting reversible contraceptives before sexual activity commences. An opt-out programme to avoid teen pregnancy. PMID- 26589865 TI - Re: The Montgomery ruling extends patient autonomy. PMID- 26589866 TI - Re: Differential effect of intrauterine growth restriction on childhood neurodevelopment: a systematic review. PMID- 26589867 TI - Author's reply re: The Montgomery ruling extends patient autonomy. PMID- 26589868 TI - Assessment of marine debris in beaches or seawaters around the China Seas and coastal provinces. AB - Compared with United States of America (USA), Brazil, Chile, Australia, limited attention has been paid to marine debris research in China and few studies have attempted to quantify the abundance and mass of marine debris. In this study, firstly the general status and sources of marine debris in China were assessed in the time period between 2007 and 2014, and secondly marine debris situation was evaluated in three China Sea Areas (the North China Sea, the East China Sea and the South China Sea) from 2009 to 2013, and finally marine debris conditions and sources were analyzed in beaches or seawaters around some coastal provinces of China during 2007-2013. Based on above analysis, the primary conclusions were as follows: (1) The mean number and weight densities of beached marine debris (BMD) and submerged marine debris (SMD) were 4.30, 0.13items/100m(2) and 133.80, 22.60g/100m(2) in China from 2007 to 2014, respectively. The average number density of the large size FMD (LOSFMD) was 0.0024items/100m(2) and that of the small and medium size FMD (SMSFMD) was 0.30items/100m(2), and the mean weight density of the SMSFMD was 1.40g/100m(2) from 2008 to 2014. The SMD and FMD densities were at the low level and the BMD density was at the high level in China. (2) The marine debris primarily was comprised of plastic, Styrofoam, wood, glass, rubber, fabric/fiber and metal, which included almost all major categories of marine debris. (3) Sources of BMD and FMD were as follows: the first source was coastal/recreational activities, followed by other disposal sources, navigation/fishing activities and the activities related smoking, and the least source being those associated with medical/sanitary activities, while the source of SMD remained unknown. (4) The mean number and weight densities of BMD were the biggest in the North China Sea, while those of FMD and SMD were the highest in the northern South China Sea. The results of this study were beneficial to the establishment of management measures for dealing with ecological and environmental problems that were generated by the high speed socio-economic development in China. PMID- 26589869 TI - Compostability assessment of nano-reinforced poly(lactic acid) films. AB - Nanomaterials can provide plastics with great advantages on mechanical and active properties (i.e. release and capture of specific substances). Therefore, packaging is expected to become one of the leading applications for these substances by 2020. There are some applications already in the market. Nevertheless, there is still some areas under development. A key issue to be analyzed is the end-of-life of these materials once they become waste, and specifically when nanomaterials are used in biodegradable products. The present study evaluated the disintegration, biodegradability, and ecotoxicity of poly(lactic acid) films reinforced with the three following nanomaterials: (1) montmorillonite modified with an ammonium quaternary salt, (2) calcium carbonate and (3) silicon dioxide. Results on disintegration showed that films completely disintegrated into visually indistinguishable residues after 6-7weeks of incubation in composting environment. Moreover, no differences were observed in the evolution of the bioresidue with respect to color, aspect, and odor in comparison with the control. It was also observed that nanomaterials did not significantly reduce the level of biodegradability of PLA (p>0.05). In fact, biodegradation was higher, without finding significant differences (p>0.05), in all the nano-reinforced samples with respect to PLA after 130days in composting (9.4% in PLA+Nano-SiO2; 34.0% in PLA+Clay1; 48.0% in PLA+Nano-CaCO3). Finally, no significant differences (p>0.05) in ecotoxicity in plants were observed as a result of the incorporation of nanoparticles in the PLA matrix. PMID- 26589870 TI - Identification of a Golgi-localized UDP-N-acetylglucosamine transporter in Trypanosoma cruzi. AB - BACKGROUND: Nucleotide sugar transporters (NSTs) play an essential role in translocating nucleotide sugars into the lumen of the endoplasmic reticulum and Golgi apparatus to be used as substrates in glycosylation reactions. This intracellular transport is an essential step in the biosynthesis of glycoconjugates. RESULTS: We have identified a family of 11 putative NSTs in Trypanosoma cruzi, the etiological agent of Chagas' disease. A UDP-N acetylglucosamine transporter, TcNST1, was identified by a yeast complementation approach. Based on a phylogenetic analysis four candidate genes were selected and used for complementation assays in a Kluyveromyces lactis mutant strain. The transporter is likely expressed in all stages of the parasite life cycle and during differentiation of epimastigotes to infective metacyclics. Immunofluorescence analyses of a GFP-TcNST1 fusion protein indicate that the transporter is localized to the Golgi apparatus. As many NSTs are multisubstrate transporters, we also tested the capacity of TcNST1 to transport GDP-Man. CONCLUSIONS: We have identified a UDP-N-acetylglucosamine transporter in T. cruzi, which is specifically localized to the Golgi apparatus and seems to be expressed, at the mRNA level, throughout the parasite life cycle. Functional studies of TcNST1 will be important to unravel the role of NSTs and specific glycoconjugates in T. cruzi survival and infectivity. PMID- 26589871 TI - [To improve cardiovascular health: we are forced for not loosing impulse]. PMID- 26589872 TI - Histological tumor typing in the age of molecular profiling. AB - Clinical oncology and pathological diagnostics regard cancer as an organ- and tissue-specific disease. Comprehensive mutational profiling information from next generation sequencing projects may be used to study to what extent the anatomic tumor classifications relate to the observed molecular profiles. Here, we review data that show substantial genetic similarities across major anatomic cancer types and that propose novel tumor classifications based on mutational profiling. Although these studies provide important insight into molecular tumor properties and some even propose novel tumor classification systems, current clinical evidence is lacking that genetic tumor profiling is sufficient to replace histological tumor typing. Recent studies rather show that targeted treatments efficaceous in one tumor type are not necessarily successful in another despite the presence of the same (actionable) mutations. We discuss the implications of the observed complex mutational tumor profiles for targeted therapy selection and future trial design in precision oncology. PMID- 26589873 TI - The Role of Psychosocial Care in Adapting to Health Care Reform. PMID- 26589874 TI - Developmental Biology of Zeugodacus cucurbitae (Diptera: Tephritidae) in Three Cucurbitaceous Hosts at Different Temperature Regimes. AB - Fruit flies are key pests of cucurbits in many parts of the world, including Tanzania. Developmental biology of Zeugodacus cucurbitae (Coquillett) has been determined across temperature regimes in some cucurbitaceous hosts, in limited geographies. This study was conducted to determine duration and survival rates of immature stages of Z. cucurbitae in three cucurbitaceous hosts, at different temperature regimes. It was hypothesized that temperature and cucurbitaceous hosts influence duration and survival of immature stages of Z. cucurbitae. We conducted experiments in the environmental chamber set at 75 +/- 10% RH and a photoperiod of 12:12 (L:D) h, at temperatures of 20, 25, and 30 degrees . Our results showed that duration and survival of immature stages of Z. cucurbitae differed significantly among the temperature regimes but not among the hosts. Egg incubation period as well as larval and pupal stages were significantly longer (P < 0.0001) at low temperature in all three hosts Likewise, survival rate of all immature stages were significantly higher (P < 0.0001) at higher than lower temperatures. The three hosts, cucumber (Cucumis sativus), watermelon (Citrullus lanatus (Thunb.) Matsum. and Nakai), and pumpkin (Cucurbita pepo) did not significantly affect duration or survival rates of immature stages of Z. cucurbitae. The low developmental thresholds were estimated at 15.88, 13.44, and 12.62 for egg, larva and pupa, respectively. These results further confirm that Z. cucurbitae is well adapted to warm climate, which dominates many areas of Tanzania. PMID- 26589875 TI - Additive impact of pre-liver transplant metabolic factors on survival post-liver transplant. AB - BACKGROUND AND AIM: Diabetes at time of liver transplantation is associated with reduced post-transplant survival. We aimed to assess whether additional metabolic conditions such as obesity or hypertension had additive prognostic impact on post transplantation survival. METHODS: A multi-center cohort study of 617 adult subjects undergoing liver transplantation between 2003 and 2009 has been used. Dry body mass index was calculated following adjustment for ascites. RESULTS: After a median follow-up of 5.8 years (range 0-10.5), 112 (18.2%) patients died. Diabetes was associated with reduced post-transplant survival (hazard ratio 1.89, 95% confidence interval [CI] 1.25-2.86, P = 0.003), whereas obesity, hypertension, dyslipidemia, and the metabolic syndrome itself were not (P > 0.3 for all). Patients with concomitant diabetes and obesity had lower survival (adjusted Hazard Ratio [aHR] 2.40, 95%CI 1.32-4.38, P = 0.004), whereas obese non diabetic patients or diabetic non-obese patients had similar survival compared with non-diabetic, non-obese individuals. The presence of hypertension or dyslipidemia did not impact on survival in patients with diabetes (P > 0.1 for both). Obese diabetic patients had longer intensive care and hospital stays than non-obese diabetic or obese, non-diabetic patients (P < 0.05). The impact of concomitant obesity and diabetes on survival was greater in subjects aged 50+ years (52.6% 5-year survival, aHR 3.04, 95% CI 1.54-5.98) or those transplanted with hepatocellular carcinoma (34.1% 5-year survival, aHR 3.35, 95% CI 1.31 5.57). Diabetes without obesity was not associated with an increased mortality rate in these sub-groups. CONCLUSIONS: Concomitant diabetes and obesity but not each condition in the absence of the other is associated with reduced post-liver transplant survival. The impact of diabetes and obesity is greater in older patients and those with hepatocellular carcinoma. PMID- 26589876 TI - Oxidative Stress: Placenta Function and Dysfunction. AB - During pregnancy, the placenta is a site of active oxygen metabolism that continuously generates oxidative stress (OS). Overproduction of reactive oxygen species and reactive nitrogen species can destroy normal placental functions. Therefore, the feto-placental unit generates abundant antioxidants to keep OS under control. Properly controlled oxidative species have been proven to serve as indispensable cellular signal messengers by regulating gene expression and downstream cellular activities. OS also plays an important immunoregulatory role during pregnancy. Oxidative disorder and immune disturbances are associated with adverse pregnancy outcomes such as spontaneous abortion, preeclampsia and intrauterine growth restriction. In this review, we introduce recent studies revealing basal functions and regulatory roles of placental OS in metabolism and immunity. The relationships between OS- and pregnancy-related disorders are also discussed. PMID- 26589877 TI - Orthovoltage radiotherapy for nonmelanoma skin cancer (NMSC): Comparison between 2 different schedules. AB - BACKGROUND: Radiotherapy is an established treatment for some types of patients with nonmelanoma skin cancer. A hypofractionated schedule has been proposed as a valuable option for elderly disabled patients to minimize the number of hospital visits. OBJECTIVE: We sought to compare a weekly hypofractionated orthovoltage radiotherapy regimen with a standard daily one for the treatment of nonmelanoma skin cancer. METHODS: A retrospective cohort study was performed on 436 tumors. Overall survival, disease-free survival, and cosmetic outcome were measured. Life table analysis, Kaplan-Meier survival analysis, and multivariate Cox regression model were performed. RESULTS: The hypofractionated regimen was not associated with increased recurrence rates and mortality, or with a poorer cosmetic outcome, when compared with the daily schedule. LIMITATIONS: Absence of complete information about acute treatment toxicity and a shorter follow-up time for patients receiving the weekly schedule are limitations of this study. CONCLUSIONS: A weekly hypofractionated regimen of orthovoltage radiotherapy seems to be the most appropriate approach in elderly disabled patients with nonmelanoma skin cancers. PMID- 26589878 TI - Category attribution as a device for diagnosis: fitting children to the autism spectrum. AB - The practice of medicine involves applying abstract diagnostic classifications to individual patients. Patients present with diverse histories and symptoms, and clinicians are tasked with fitting them into generic categories. They must also persuade patients, or family members, that the diagnosis is appropriate and elicit compliance with prescribed treatments. This can be especially challenging with psychiatric disorders such as autism, for which there are no clear biomarkers. In this paper, we explicate a discursive procedure, which we term category attribution. The procedure juxtaposes a narrative about the child with a claim about members of a clinically relevant category, in this case, either children with autism or typically/normally developing children. The attribution procedure carries the implication that the child does or does not belong to that category. We show that category attributions are organised in a recurrent interactional sequence. Further, we argue that category attributions encode normative expectations about child development, such that the child is rendered typical or atypical relative to clinical and social norms. Accordingly, such categorisation devices have a moral dimension as well as a clinical one. PMID- 26589879 TI - Outcomes of In-Hospital Cardiopulmonary Resuscitation Among Patients With Cancer. AB - OBJECTIVE: To review all episodes where an emergency code was called in a cancer specialized hospital in Pakistan and to assess survival to discharge among patients who received a cardiopulmonary resuscitation (CPR). METHODS: We reviewed demographic and clinical data related to all "code blue" calls over 3 years. Multivariate logistic regression analyses were used to test the association of clinical characteristics with the primary outcome of survival to discharge. RESULTS: A total of 646 code blue calls were included in the analysis. The CPR was performed in 388 (60%) of these calls. For every 20 episodes of CPR among patients with cancer of all ages, only 1 resulted in a patient's survival to discharge, even though in 52.2% episodes there was a return of spontaneous circulation. No association was found between the type of rhythm at initiation of CPR and likelihood of survival to discharge. CONCLUSIONS: The proportion of patients with advanced cancer surviving to discharge after in-hospital CPR in a low-income country was in line with the reported international experience. Most patients with cancer who received in-hospital CPR did not survive to discharge and did not appear to benefit from resuscitation. Advance directives by patients with cancer limiting aggressive interventions at end of life and proper documentation of these directives will help in provision of care that is humane and consonant with patients' wishes for a dignified death. Patients' early appreciation of the limited benefits of CPR in advanced cancer is likely to help them formulate such advance directives. PMID- 26589880 TI - Aripiprazole. AB - Delirium is a palliative care emergency where patients experience changes in perception, awareness, and behavior. Common features include changes in the sleep wake cycle, emotional lability, delusional thinking, and language and thought disorders. Delirium results from neurotransmitter imbalances involving several neurotransmitters such as dopamine, glutamate, norepinephrine, acetylcholine, gamma-aminobutyric acid, and serotonin. Untreated delirium causes significant morbidity and mortality. Nonpharmacologic and pharmacologic approaches treat delirium. Current pharmacologic management of delirium involves using agents such as haloperidol or second-generation antipsychotics. Third-generation atypical antipsychotic drugs have emerged as a potential choice for delirium management. Aripiprazole is a third-generation antipsychotic with a dopamine receptor-binding profile distinct from other second-generation antipsychotics. Aripiprazole acts as partial agonist at dopamine D2 and 5-hydroxytryptamine (5-HT)1A receptors, stabilizing the dopamine receptor leading to improvement in symptoms. The article reviews the pharmacology, pharmacodynamics, metabolism, and evidence of clinical efficacy for this new antipsychotic agent. This article explores possible roles in palliative care. PMID- 26589881 TI - Validation of 2 Prognostic Models in Hospitalized Patients With Advanced Hematological Malignancies in Japan. AB - Patients with advanced hematological malignancies are less likely to be referred to specialist palliative care services compared with patients having solid tumors. It has been reported that one of the most important reasons for the lack of referral is difficulties in the prognostication of terminally ill patients with hematologic malignancies. The study objective was to evaluate the predictive accuracy of the Palliative Prognostic Index (PPI) and the prognostic model developed by Kripp et al in hospitalized patients under the care of a hematologist. Using clinical charts, we retrospectively calculated the above scores. We reviewed the records of 114 patients admitted to the hematology ward. The inclusion criterion was patient with disease considered incurable using standard treatments. The prognostic models were assessed according to the original reports. Using PPI cutoff points of 2 and 4, we divided the patients into 3 groups of significantly different survival times ( P < .01). Moreover, we confirmed the usefulness of predicting survival <3 and <6 weeks using PPI scores of 6 and 4 as cutoff points, respectively. When we classified patients according to the prognostic model of Kripp et al, the high-risk group survived significantly shorter times than the intermediate- and low-risk groups ( P < .001). However, there was no significant difference in survival between the intermediate- and low-risk groups. Use of these models might enable physicians to provide more appropriate end-of-life care and to refer patients to palliative care earlier. PMID- 26589883 TI - Heart Failure, Nonvalvular Atrial Fibrillation and Anticoagulation Control With Vitamin K Antagonists. PMID- 26589882 TI - Elucidation and Pharmacological Targeting of Novel Molecular Drivers of Follicular Lymphoma Progression. AB - Follicular lymphoma, the most common indolent subtype of non-Hodgkin lymphoma, is associated with a relatively long overall survival rate ranging from 6 to 10 years from the time of diagnosis. However, in 20% to 60% of follicular lymphoma patients, transformation to aggressive diffuse large B-cell lymphoma (DLBCL) reduces median survival to only 1.2 years. The specific functional and genetic determinants of follicular lymphoma transformation remain elusive, and genomic alterations underlying disease advancement have only been identified for a subset of cases. Therefore, to identify candidate drivers of follicular lymphoma transformation, we performed systematic analysis of a B-cell-specific regulatory model exhibiting follicular lymphoma transformation signatures using the Master Regulator Inference algorithm (MARINa). This analysis revealed FOXM1, TFDP1, ATF5, HMGA1, and NFYB to be candidate master regulators (MR) contributing to disease progression. Accordingly, validation was achieved through synthetic lethality assays in which RNAi-mediated silencing of MRs individually or in combination reduced the viability of (14;18)-positive DLBCL (t-DLBCL) cells. Furthermore, specific combinations of small-molecule compounds targeting synergistic MR pairs induced loss of viability in t-DLBCL cells. Collectively, our findings indicate that MR analysis is a valuable method for identifying bona fide contributors to follicular lymphoma transformation and may therefore guide the selection of compounds to be used in combinatorial treatment strategies. PMID- 26589884 TI - Interaction of natural killer cells with neutrophils exerts a significant antitumor immunity in hematopoietic stem cell transplantation recipients. AB - Autologous hematopoietic stem cell transplantation (HSCT) can induce a strong antitumor immunity by homeostatic proliferation (HP) of T cells and suppression of regulatory T cells following preconditioning-induced lymphopenia. However, the role of innate immunity including natural killer (NK) cells is still not understood. Here, first, we examined whether NK cells exert an antitumor effect after syngeneic HSCT in a murine colon cancer model. Flow cytometry showed that NK cells as well as T cells rapidly proliferated after HSCT, and the frequency of mature NK cells was increased in tumor during HP. Furthermore, NK cells undergoing HP were highly activated, which contributed to substantial tumor suppression. Then, we found that a large number of neutrophils accumulated in tumor early after syngeneic HSCT. It was recently reported that neutrophil derived mediators modulate NK cell effector functions, and so we examined whether the neutrophils infiltrated in tumor are associated with NK cell-mediated antitumor effect. The depletion of neutrophils significantly impaired an activation of NK cells in tumor and increased the fraction of proliferative NK cells accompanied by a decrease in NK cell survival. The results suggested that neutrophils in tumor prevent NK cells from activation-induced cell death during HP, thus leading to a significant antitumor effect by NK cells. This study revealed a novel aspect of antitumor immunity induced by HSCT and may contribute to the development of an effective therapeutic strategy for cancer using HSCT. PMID- 26589885 TI - Colorectal mucus non-invasively collected from patients with inflammatory bowel disease and its suitability for diagnostic cytology. AB - Colorectal mucus is a key component of the protective gut barrier which is altered in inflammatory bowel disease (IBD). We aimed to cytologically characterize colorectal mucus non-invasively collected from IBD patients using our new sampling technique. Colorectal mucus was self-collected by 58 IBD patients comprising 31 ulcerative colitis (UC) and 27 Crohn's disease (CD) cases. The samples were examined cytologically, and immunocytochemically. Large numbers of well-preserved granulocytes were typically detected (neutrophils undergoing degradation were observed as well). Plasma cells and erythrophagocytosis were present in 18.2% and 29.1% of cases, respectively, predominantly in patients with UC and distal CD. Immunocytochemical visualization of calprotectin in neutrophils, eosinophil-derived neurotoxin in eosinophils and tumour necrosis factor-alpha in macrophages was also achieved. Correct cytological diagnosis was made in 61.8% of analysed IBD cases. Our new method of colorectal mucus sampling provides highly informative material for cytology. Findings of the presence of plasmocytes and erythrophagocytosis in colorectal mucus are unique and may reflect previously unknown mechanisms of IBD pathogenesis. Immunocytochemical detection of inflammation biomarkers demonstrates the suitability of this material for biomarker quantification. These promising results suggest a potential role for colorectal mucus cytology in the non-invasive diagnosis of IBD. PMID- 26589886 TI - [What would you do with an adult patient who complains of a neck mass?]. AB - Family physicians frequently encounter patients with neck mass. There are multiple causes that range from no clinical importance to malignant tumours. The critical challenge for the primary care physician is to identify which cases are secondary to malignancies or other serious conditions. With a good knowledge of the complex anatomy of the neck and a careful clinical history, including a complete physical examination, the different causes can be narrowed down, as well as to differentiate between significant and non-significant neck masses and select the appropriate studies. Lymphoma commonly presents as a painless enlarged lump in the neck, as in the case of the patient presented. An algorithm is provided to help practioners. PMID- 26589887 TI - [Cataplexy and drowsiness or Gelineau syndrome in Primary Care emergencies]. PMID- 26589888 TI - Pigment cell mechanism of postembryonic stripe pattern formation in the Japanese four-lined snake. AB - Postembryonic changes in the dermal and epidermal pigment cell architecture of the striped and nonstriped morph of the Japanese four-lined snake Elaphe quadrivirgata were examined to reveal stripe pattern formation after hatching. The striped and nonstriped morphs were distinguishable at the hatching, suggesting that the basis of stripe pattern was formed during embryonic development. In the striped morph, the color of stripes changed from red-brown in juveniles to vivid dark-brown in adults, and density of dermal melanophore increased much more in the stripe than background dorsal scales with growth. This increase in density of dermal melanophore was accompanied not only by the increased epidermal melanophore density but also by the change in vertical structures of dermal melanophore. By contrast, the density of epidermal and dermal melanophore evenly increased over the dorsal scales in the nonstriped morph. Thus, the increased vividness of the stripe pattern after hatching is achieved through localized increase of melanophore density particularly in the stripe region but not over the whole dorsal scales. PMID- 26589889 TI - A Japanese case of lymphocytic esophagitis. AB - We report the case of a 68-year-old Japanese man diagnosed with lymphocytic esophagitis (LE), a rare disease associated with refractory dysphagia. He has had severe dysphagia and heartburn since 2007. Findings of esophagogastroduodenoscopy (EGD) carried out by a local physician in 2010 showed pale mucosa with white exudate and lateral furrows in the esophagus. He was referred to Tohoku University Hospital in 2012, because the symptoms did not improve, despite regular use of a proton pump inhibitor (PPI). At that time, EGD revealed the coexistence of a slight stricture in the upper esophagus, the histopathological findings of which included a predominantly peri-papillary distribution of abundant, infiltrating CD3+ /CD4+ /CD8+ /CD20- lymphocytes without any granulocytes (CD4+ : CD8+ = 3.3:1). These were consistent with a diagnostic criteria of LE. Thereafter, severe dysphagia with food impaction occurred twice a month, despite the long-term use of a PPI, and EGD showed worsened strictures, where endoscopic ultrasonography findings showed marked circumferential thickness of the mucosal and submucosal layers. Then, one session of endoscopic balloon dilatation dramatically improved the dysphagia. Accordingly, LE should be considered an important differential diagnosis of refractory dysphagia based on the characteristic features of endoscopic and pathological findings. PMID- 26589890 TI - Somatostatin expression in the pancreatic cells of smoking and non-smoking chronic pancreatitis patients with or without diabetes. AB - OBJECTIVES: The aim of the analysis is to determine the location and degree of the hormone immunoreactivity in tissues of patients with chronic pancreatitis and diabetes. METHODS: The study was performed on 11 non-smoking and 12 smoking patients with chronic pancreatitis (CP) with/without diabetes. The hormone was located in the pancreatic tissues by means of the immunohistochemical method using somatostatin antibodies. The histopathological evaluation of the hormone expression intensity in tissue sections was carried out using the semi quantitative method and was calculated by means of a digital image analysis. RESULTS: The hormone's strong immunohistochemical reaction and the modified D cell location may be a result of the pancreatic tissue fibrosis process prevention in patients with CP. Changes in the intensity of SS immunoreactivity and the D-cell distribution in the pancreas of patients with CP and diabetes may possibly result from the additional hormone compensatory effect in the excessive glucagon secretion inhibition. Smoking patients with diabetes showed significantly higher hormone immunostaining in the pancreas compared to non smoking patients without diabetes and healthy persons. CONCLUSIONS: The severity of histopathological changes in smoking CP patients indicates that the cigarette smoke components may further exacerbate the inflammatory reactions. Patients with CP were found to have a strong immunohistochemical reaction to SS and changes in the distribution of D cells when compared to healthy patients. The strongest immunohistochemical SS reaction has been identified in the pancreatic tissue from smoking patients with diabetes. PMID- 26589891 TI - The emergence of insecticide resistance in the major malaria vector Anopheles funestus (Diptera: Culicidae) from sentinel sites in Mutare and Mutasa Districts, Zimbabwe. AB - BACKGROUND: Insecticide resistance in major malaria vectors poses severe challenges for stakeholders responsible for controlling the disease. During the 2013/14 season, malaria vector sentinel sites in Mutare and Mutasa Districts, Zimbabwe, experienced high presence of gravid malaria vector mosquitoes resting indoors in recently pyrethroid-sprayed structures. Subsequently, an evaluation of insecticide resistance in Anopheles funestus populations, the major malaria vector, was conducted to better inform the Zimbabwe National Malaria Control Programme. METHODS: Indoor-resting mosquitoes were collected in randomly selected pyrethroid-sprayed houses around Burma Valley and Zindi sentinel sites in Mutare and Mutasa Districts, respectively, using prokopac aspirator in February 2014. A. funestus mosquitoes were identified in the field using morphological keys and divided into two cohorts. One cohort was used immediately for WHO susceptibility tests and the other batch was transferred to the National Institute of Health Research insectary in Harare for oviposition. Susceptibility and intensity resistance assays were carried out on polymerase chain reaction-assayed, 3-5 days old, A. funestus s.s. F1 progeny females. RESULTS: Eight-hundred and thirty-six A. funestus and seven Anopheles gambiae complex mosquitoes were collected resting inside living structures. Wild caught females showed resistance to lambda cyhalothrin (3.3% mortality), deltamethrin (12.9% mortality), etofenprox (9.2% mortality), and bendiocarb (11.7% mortality). F1 A. funestus female progeny indicated resistance to deltamethrin (14.5% mortality), lambda-cyhalothrin (6.9% mortality), etofenprox (8.3% mortality), and bendiocarb (16.8% mortality). Wild caught and female progeny were susceptible to DDT and pirimiphos-methyl (100% mortality). Intensity resistance assay to bendiocarb was 100% mortality, while deltamethrin, lambda-cyhalothrin, and etofenprox had increased knockdown times with mortalities ranging between 66.7 and 92.7% after 24-h exposures. CONCLUSION: This study is the first report of pyrethroid and carbamate resistance in A. funestus populations from Burma Valley and Zindi areas and indicates a major threat to the gains made in malaria vector control in Zimbabwe. In view of the current extension and intensity of such resistance, there is urgent need to set up a periodic and systematic insecticide resistance-monitoring programme which will form the basis for guiding the selection of insecticides for indoor residual spraying and distribution of pyrethroid-treated mosquito nets. PMID- 26589892 TI - Timing of antibiotics, volume and vasoactive infusions in children with sepsis: it is all in the timing. PMID- 26589893 TI - The oxygen reduction pathway and heat shock stress response are both required for Entamoeba histolytica pathogenicity. AB - Several species belonging to the genus Entamoeba can colonize the mouth or the human gut; however, only Entamoeba histolytica is pathogenic to the host, causing the disease amoebiasis. This illness is responsible for one hundred thousand human deaths per year worldwide, affecting mainly underdeveloped countries. Throughout its entire life cycle and invasion of human tissues, the parasite is constantly subjected to stress conditions. Under in vitro culture, this microaerophilic parasite can tolerate up to 5 % oxygen concentrations; however, during tissue invasion the parasite has to cope with the higher oxygen content found in well-perfused tissues (4-14 %) and with reactive oxygen and nitrogen species derived from both host and parasite. In this work, the role of the amoebic oxygen reduction pathway (ORP) and heat shock response (HSP) are analyzed in relation to E. histolytica pathogenicity. The data suggest that in contrast with non-pathogenic E. dispar, the higher level of ORP and HSPs displayed by E. histolytica enables its survival in tissues by diminishing and detoxifying intracellular oxidants and repairing damaged proteins to allow metabolic fluxes, replication and immune evasion. PMID- 26589894 TI - Neurogenic lower urinary tract dysfunction in the early disease phase of paediatric multiple sclerosis. AB - Neurogenic lower urinary tract dysfunction (LUTD) in multiple sclerosis (MS) is highly prevalent in adults, but has not previously been described in paediatric MS. A total of 24 consecutive children with newly diagnosed MS were prospectively assessed for bladder and bowel problems early after diagnosis. Five of 24 children (21%) showed LUTD during assessment. One of these patients did not report voiding complaints. This high prevalence of LUTD indicates that all recently diagnosed patients with paediatric MS should be evaluated early in their disease and treated for urinary problems in order to prevent potential damage to the upper urinary tract. PMID- 26589895 TI - Report of the 2015 British Society for Protist Biology Spring Meeting. PMID- 26589896 TI - CIN III lesions and regression: retrospective analysis of 635 cases. AB - BACKGROUND: The rate of spontaneous regression in CIN III lesions is controversial. Whereas some studies have reported high regression rates of up to 38% after prolonged biopsy-conus intervals, others have shown rates between 0 and 4% without considering time intervals. Identification of young patients with potentially regressing CIN III could offer the chance to avoid conisation, thus lowering the risk of preterm labour. METHODS: To further clarify the facts, we retrospectively compared 635 biopsies showing CIN III with the diagnosis of the conisation. Either regression (CIN I or less) or non-regression (CIN II and higher) was recorded. Diagnoses were made by light microscopy and p16 immunostaining. RESULTS: Conisation was performed between 2 and 463 days after biopsy (median 8.9 weeks). Six hundred twenty one (98%) were HPV-HR positive. In 345 cases, HPV subtyping was available, showing HPV16 infection in 57%. Routine processing of the conisation tissue showed no corresponding CIN lesion (< CIN II) in 40 cases (6.3%). Additional step sectioning of the tissue revealed small CIN II+ lesions in 80%. Finally, eight cases (1.3%) fulfilled the criteria of regression. No regression was seen in HPV16 positive cases. Twelve invasive carcinomas were detected by routine processing of the conisation tissue. CONCLUSION: These results are in contrast with some prior reports that might have overestimated spontaneous regression of CIN III. Study size and an accurate discrimination between CIN II and CIN III lesions by histopathology seem to be the most likely factors to explain the diverging results published. Complete step sectioning of the whole tissue is also mandatory in questionable cases. Although theories exist that the initial biopsy might stimulate the immune system, thus triggering regression within weeks, our data do not substantially support such a mechanism. Overall, the chance of a CIN III lesion to regress rapidly within weeks or months after diagnosis seems to be small. We found more previously undetected invasive cancer than we observed regression. Therefore, a change in the current policy to treat CIN III lesions is unwarranted. PMID- 26589897 TI - Probability and heritability estimates on primary osteoarthritis of the hip leading to total hip arthroplasty: a nationwide population based follow-up study in Danish twins. AB - INTRODUCTION: Primary hip osteoarthritis, radiographic as well as symptomatic, is highly associated with increasing age in both genders. However, little is known about the mechanisms behind this, in particular if this increase is caused by genetic factors. This study examined the risk and heritability of primary osteoarthritis of the hip leading to a total hip arthroplasty, and if this heritability increased with increasing age. METHODS: In a nationwide population based follow-up study 118,788 twins from the Danish Twin Register and 90,007 individuals from the Danish Hip Arthroplasty Register for the period 1995 to 2010 were examined. Our main outcomes were the cumulative incidence, proband-wise concordance and heritability on age, within-pair correlations in monozygotic and dizygotic twin pairs, and the genetic and environmental influence estimated in models taking into account that individuals may not have had a total hip arthroplasty at the time of follow-up. RESULTS: There were 94,063 twins eligible for analyses, comprising 835 cases of 36 concordant and 763 discordant twin pairs. The probability increased particularly from 50 years of age. After sex and age adjustment a significant additive genetic component of 47% (12:79), a shared environmental component of 21% (2:76) and a unique environment component of 32% (21:41) accounted for the variation in population liability to total hip arthroplasty. The sex-adjusted proband-wise concordance and heritability on age indicated an increasing age-associated genetic influence onwards from 60 years of age. CONCLUSION: The cumulative incidence in primary hip osteoarthritis leading to total hip arthroplasty increases in particular after the age of 50 years in both genders. Family factors of genes and shared environment are highly significant and account for 68% of the variation in the population liability to total hip arthroplasty; however, the genetic influence increases significantly from 60 years of age onwards. PMID- 26589898 TI - Quantification of lymph nodes in the central compartment of the neck: a cadaveric study. AB - Differentiated thyroid cancer (DTC) accounts for over 90 % of thyroid malignancies, and is frequently associated with central neck compartment nodal metastasis that requires a therapeutic central compartment neck dissection (CCND) for clinically evident nodes. Current knowledge on the expected lymph node yield from a CCND is limited, compared with data on the lateral neck. The aim of our study was to accurately quantify nodal yield from the cadaveric central neck compartment. Twenty-eight cadaveric necks were dissected and the central neck compartment was subdivided into four regions: pre-laryngeal (delphian), pre tracheal, right and left para-tracheal regions. Each cadaver had a thyroid gland, which was also removed, and the CCND tissue in each compartment was processed and examined by a consultant histopathologist. Only lymphoid tissue with a defined microscopic fibrous capsule and subcapsular sinus was included in the node count. The median total lymph node count per cadaver was four (range 1-16), with a median of one node detectable in each para-tracheal region (range 0-7) and the pre-tracheal region (range 0-8). The median pre-laryngeal node count was 0 (range 0- 2). The average lymph node size across all compartments was 2.9 mm. This is the first European study to assess cadaveric central neck lymph nodes and establish baseline counts for nodal yield. If a prophylactic or therapeutic CCND is required during thyroid surgery, those involved in DTC management must recognise that there is a wide range, and low median yield of central neck compartment lymph nodes. PMID- 26589899 TI - Some unpublished documents and unusual portraits of Anton von Troltsch (1828 1890), one of the founders of this journal. AB - Anton Friedrich Baron von Troltsch (1829-1890) was a very famous German otologist in Wurzburg in the second part of the 19th century. The aim of this study is to present some unpublished documents related to his biography: a 4-page autobiographical unsigned text probably written for his habilitation in 1861, a 4 page autobiographical letter sent by von Troltsch to the editors of the Brockhaus Conversations-Lexikon in 1872, a unique album of portraits of the main otologists of the second part of the 19th century, collected for his 1886 Privat Docent jubilee anniversary, and a portrait of unknown origin. They are discussed with other unusual portraits. These new documents demonstrate at least two major points. One, von Troltsch was aware of his qualities and the importance of his work in otology but he was not boastful. Two, he was really loved and respected by its colleagues, nearly 150 of them came just for a one-day ovation in Wurzburg for his 25th Privat Docent Jubilee and his retirement from his otological practice. Von Troltsch was and remains an example for all otologists. PMID- 26589900 TI - Evaluation of Biochemical, Genetic and Hematological Biomarkers in a Commercial Catfish Rhamdia quelen Exposed to Diclofenac. AB - Juveniles Rhamdia quelen fish species were exposed to diclofenac for 96 h at concentrations of 0.2, 2, and 20 MUg/L. Biochemical, genetic, and hematological biomarkers were assessed in the liver, kidney, and blood in order to evaluate the toxic effects. No oxidative stress was observed in liver. In kidney the superoxide dismutase activity increased in all concentrations, suggesting an alteration in the hydrogen peroxide production, but DNA damage and lipid peroxidation were not detected. Diclofenac exposure increased the red blood cells number at concentrations of 0.2 and 2 MUg/L, and monocytes and neutrophils at 2 and 20 MUg/L, respectively. These results suggest that acute exposure to diclofenac, even at low concentrations, caused hematologic and renal enzymatic alterations in R. quelen. PMID- 26589901 TI - [Challenges on off label medicine use]. PMID- 26589902 TI - A case of inflammatory hepatocellular adenoma displaying an unusual histological pattern. AB - Hepatocellular adenoma (HCA) is a rare type of liver tumor. Here, we report a variant case of HCA in a 56-year-old Japanese man which displayed unusual histological features. The patient had undergone surgery for esophageal and gastric cancer 2 years prior. A computed tomography scan performed in the follow up period detected a single lesion (diameter 1.4 cm) in the right posterior lobe of the liver, leading to a partial hepatectomy. Histologically, the lesion was composed of two different types of cells. The larger cells, which accounted for most of the cells in the tumor, exhibited granular and eosinophilic cytoplasm, large nuclei and apparent nucleoli. These cells, which were designated the common cells, were typical of the HCA. The other cells, which were designated the pyknotic cells, were smaller, possessed an eosinophilic, homogeneous cytoplasm and pyknotic small nuclei, but did not contain nucleoli. Immunohistochemically, the common cells reacted strongly positive for C-reactive protein and serum amyloid A, which is compatible with a diagnosis of inflammatory HCA; in contrast, the pyknotic cells tested negative for these molecules. Since the pyknotic cells tested positive for several markers of apoptosis, they were considered to be apoptotic. In addition, as the common cells demonstrated a higher ki-67 labeling index, the lesion was considered to display upregulated cell kinetics, i.e. increases in both cell growth and death. Although HCA is a rare type of tumor, there have been several reports on HCA variants. The case reported here is that of a new type of HCA variant that demonstrated an unusual histological pattern and upregulated cell kinetics. PMID- 26589903 TI - Magnetic field interaction between a left ventricular assist device controller and a cardiac resynchronization therapy-defibrillator. PMID- 26589904 TI - EHRA research network surveys: 6 years of EP wires activity. AB - Clinical practice should follow guidelines and recommendations mainly based on the results of controlled trials, which are often conducted in selected populations and special conditions, whereas clinical practice may be influenced by factors different from controlled scientific studies. Hence, the real-world setting is better assessed by the observational registries enrolling patients for longer periods of time. However, this may be difficult, expensive, and time consuming. In 2009, the Scientific Initiatives Committee of the European Heart Rhythm Association (EHRA) has instigated a series of surveys covering the controversial issues in clinical electrophysiology (EP). With this in mind, an EHRA EP research network has been created, which included EP centres in Europe among which the surveys on 'hot topic' were circulated. This review summarizes the overall experience conducting EP wires over the past 6 years, categorizing and assessing the topics regarding clinical EP, and evaluating the acceptance and feedback from the responding centres, in order to improve participation in the surveys and better address the research needs and aspirations of the European EP community. PMID- 26589905 TI - Dysphagia in the elderly: focus on rehabilitation strategies. AB - Prevalence of oropharyngeal dysphagia among the elderly is high, but underestimated and underdiagnosed. It may give raise to relevant complications impacting on morbidity, hospital length of stay and health care costs. Dysphagia evaluation and management is a multidisciplinary task; it includes a detailed history taking, clinical and instrumental exams, and identification of the risk of aspiration. Long-standing individual abilities and impairments determine the goals of an ad hoc rehabilitation program. Currently there are no standard algorithmic approaches for the management of dysphagia in the elderly. Education of health professionals on early diagnosis and improvement of therapeutic strategies are mainstays to allow maximal recovery potential in this population. This narrative review summarizes the current rehabilitation approaches for dysphagia in the elderly. The aim is to inform the treating health care professionals, whether caring physician, physical medicine doctor, speech/swallowing therapist or nurse, on the state-of-the-art and stimulate discussion in the scientific community. PMID- 26589906 TI - Internet, home-based cognitive and strategy training with older adults: a study to assess gains to daily life. AB - Computerised training has been shown to benefit cognitive function in older adults but rarely, if ever, enhances performance in everyday life. This study examines how an entirely internet-based cognitive programme can generalise to daily functioning. This is an exploratory study (n = 25) of computer and video based strategy training with older adults that was conducted over the internet to facilitate generalisation. Results found no evidence of gains to measures in daily functioning. The only training benefits were on tasks that had been trained. The results suggest that not all training procedures produce benefits and a lack of transfer to daily life was evident here. Caution should be taken in interpretation due to the small sample under investigation. This research may be useful for the design and conduct of future rehabilitation studies. PMID- 26589907 TI - Elevated transpulmonary gradient and cardiac magnetic resonance-derived right ventricular remodeling predict poor outcomes in sickle cell disease. PMID- 26589908 TI - Combined CXCR3/CXCR4 measurements are of high prognostic value in chronic lymphocytic leukemia due to negative co-operativity of the receptors. PMID- 26589909 TI - Monosomal karyotype as an adverse prognostic factor in patients with acute myeloid leukemia treated with allogeneic hematopoietic stem-cell transplantation in first complete remission: a retrospective survey on behalf of the ALWP of the EBMT. AB - Despite the overall benefit from allogeneic hematopoietic stem cell transplantation observed in patients with poor cytogenetic risk acute myeloid leukemia in first complete remission, the precise effect of this procedure for different poor-risk subtypes has not been fully analyzed. This retrospective analysis was performed to investigate whether allogeneic hematopoietic stem cell transplantation performed in first complete remission in patients with monosomal karyotype can overcome the adverse prognosis associated with these patients. Of the 4635 patients included in the study, 189 (4%) harbored a monosomal karyotype. The presence of a monosomal karyotype was associated with a worse outcome, with an inferior leukemia-free survival and overall survival (5-year leukemia-free survival and overall survival: 24 +/- 3% and 26 +/- 3% vs. 53 +/- 1% and 57 +/- 1% in monosomal-karyotype and non-monosomal-karyotype, respectively; P<0.0001) and higher relapse risk after transplantation (cumulative incidence of relapse at 5 years: 56 +/- 4% in monosomal-karyotype vs. 28 +/- 1% in non-monosomal karyotype; P<0.0001). The adverse negative impact of monosomal karyotype cytogenetics was confirmed in the entire cohort in a multivariate analysis [Hazard Ratio (HR): 1.88, 95% Confidence Interval (CI):1.29-2.73, P=0.001 for relapse incidence; HR:1.71, 95%CI:1.27-2.32, P<0.0001 for leukemia-free survival; HR:1.81, 95%CI:1.32-2.48, P=0.0002 for overall survival], and was independent of the presence of other poor-risk cytogenetic subtypes. In summary, monosomal karyotype arises as a strong negative prognostic feature in acute myeloid leukemia also in patients who undergo allogeneic hematopoietic stem cell transplantation in first complete remission, stressing the need to develop additional pre- and post-transplantation strategies aimed at improving overall results. Nonetheless, allogeneic hematopoietic stem cell transplantation in early phase is currently the best therapy for this very poor-risk acute myeloid leukemia subtype. PMID- 26589910 TI - Expression and function of ABC-transporter protein ABCB1 correlates with inhibitory capacity of Ruxolitinib in vitro and in vivo. PMID- 26589911 TI - UGT2B17 expression: a novel prognostic marker within IGHV-mutated chronic lymphocytic leukemia? PMID- 26589912 TI - Mathematical modeling reveals differential effects of erythropoietin on proliferation and lineage commitment of human hematopoietic progenitors in early erythroid culture. AB - Erythropoietin is essential for the production of mature erythroid cells, promoting both proliferation and survival. Whether erythropoietin and other cytokines can influence lineage commitment of hematopoietic stem and progenitor cells is of significant interest. To study lineage restriction of the common myeloid progenitor to the megakaryocyte/erythroid progenitor of peripheral blood CD34(+) cells, we have shown that the cell surface protein CD36 identifies the earliest lineage restricted megakaryocyte/erythroid progenitor. Using this marker and carboxyfluorescein succinimidyl ester to track cell divisions in vitro, we have developed a mathematical model that accurately predicts population dynamics of erythroid culture. Parameters derived from the modeling of cultures without added erythropoietin indicate that the rate of lineage restriction is not affected by erythropoietin. By contrast, megakaryocyte/erythroid progenitor proliferation is sensitive to erythropoietin from the time that CD36 first appears at the cell surface. These results shed new light on the role of erythropoietin in erythropoiesis and provide a powerful tool for further study of hematopoietic progenitor lineage restriction and erythropoiesis. PMID- 26589913 TI - PPARgamma antagonist attenuates mouse immune-mediated bone marrow failure by inhibition of T cell function. AB - Acquired aplastic anemia is an immune-mediated disease, in which T cells target hematopoietic cells; at presentation, the bone marrow is replaced by fat. It was reported that bone marrow adipocytes were negative regulators of hematopoietic microenvironment. To examine the role of adipocytes in bone marrow failure, we investigated peroxisomal proliferator-activated receptor gamma, a key transcription factor in adipogenesis, utilizing an antagonist of this factor called bisphenol-A-diglycidyl-ether. While bisphenol-A-diglycidyl-ether inhibited adipogenesis as expected, it also suppressed T cell infiltration of bone marrow, reduced plasma inflammatory cytokines, decreased expression of multiple inflammasome genes, and ameliorated marrow failure. In vitro, bisphenol-A diglycidyl-ether suppressed activation and proliferation, and reduced phospholipase C gamma 1 and nuclear factor of activated T-cells 1 expression, as well as inhibiting calcium flux in T cells. The in vivo effect of bisphenol-A diglycidyl-ether on T cells was confirmed in a second immune-mediated bone marrow failure model, using different strains and non-major histocompatibility antigen mismatched: bisphenol-A-diglycidyl-ether ameliorated marrow failure by inhibition of T cell infiltration of bone marrow. Our data indicate that peroxisomal proliferator-activated receptor gamma antagonists may attenuate murine immune mediated bone marrow failure, at least in part, by suppression of T cell activation, which might hold implications in the application of peroxisomal proliferator-activated receptor gamma antagonists in immune-mediated pathophysiologies, both in the laboratory and in the clinic. Genetically "fatless" mice developed bone marrow failure with accumulation of marrow adipocytes in our model, even in the absence of body fat, suggesting different mechanisms of systematic and marrow adipogenesis and physiologic versus pathophysiologic fat accumulation. PMID- 26589914 TI - Spleen tyrosine kinase inhibitors reduce CD40L-induced proliferation of chronic lymphocytic leukemia cells but not normal B cells. PMID- 26589915 TI - FGFR1OP2-FGFR1 induced myeloid leukemia and T-cell lymphoma in a mouse model. PMID- 26589916 TI - Jak2V617F driven myeloproliferative neoplasm occurs independently of interleukin 3 receptor beta common signaling. PMID- 26589917 TI - Functional status and failed rotator cuff repair predict outcomes after arthroscopic-assisted latissimus dorsi transfer for irreparable massive rotator cuff tears. AB - BACKGROUND: Arthroscopic-assisted latissimus dorsi tendon transfer (LDTT) has been recently introduced for treatment of irreparable, posterosuperior massive rotator cuff tears. We sought to evaluate the functional outcomes of this technique and to check for possible outcome predictors. METHODS: The study reviewed 86 patients (aged 59.8 +/- 5.9 years) who underwent an arthroscopic assisted latissimus dorsi tendon transfer after 36.4 +/- 9 months of follow-up. Of these, 14 patients (16.3%) sustained an irreparable massive rotator cuff tear after a failed arthroscopic rotator cuff repair. The Constant and Murley score (CMS) was used to assess patients' functionality preoperatively and at follow-up. RESULTS: As a group, the CMS improved with surgery from 35.5 +/- 6.1 to 69.5 +/- 12.3 (P < .001). A lower preoperative CMS and a previous failed rotator cuff repair resulted in lower postoperative range of motion (P = .044 and P = .007, respectively) and CMS (P = .042 and P = .018, respectively). A previous rotator cuff repair resulted in lower satisfaction with surgery (P = .009). Gender and age did not affect the clinical outcomes. CONCLUSIONS: Our results support the effectiveness of arthroscopic-assisted LDTT in the treatment of patients with an irreparable, posterosuperior massive rotator cuff tears in pain relief, functional recovery, and postoperative satisfaction. Patients with lower preoperative CMS and a history of failed rotator cuff repair have a greater likelihood of having a lower clinical result. However, the favorable values of summary postoperative scores do not exclude these patients as candidates for arthroscopic-assisted LDTT. PMID- 26589918 TI - Shoulder arthroplasty for post-traumatic osteonecrosis of the humeral head. AB - BACKGROUND: Osteonecrosis (ON) of the humeral head is a known complication of proximal humeral trauma. Prosthetic replacement may be the last option to treat the associated pain. Depending on the condition of the glenoid, hemiarthroplasty (HA) or total shoulder arthroplasty (TSA) can be considered. To date, the peer reviewed literature offers limited direction on the better treatment for this population. METHODS: Between 1973 and 2010, 93 arthroplasties were performed for post-traumatic ON of the humeral head after conservative treatments failed. Of these, 37 HAs and 46 TSAs were monitored for a minimum of 2 years (mean, 8.9 years) or until reoperation. RESULTS: The HA and TSA groups showed improvements in pain (P < .001), elevation (P < .01), and external rotation (P < .01). The TSA group had less pain at follow-up than the HA group (2.1 vs 3.0, P = .001). TSA led to better satisfaction (70% vs 56%) and more excellent/satisfactory Neer ratings (57% vs 41%) compared with HA. Nine HA patients and 5 TSA patients underwent reoperation. The most common causes for reoperation were painful glenoid arthrosis (n = 8) in HA and rotator cuff failure (n = 4) in TSA. The estimated 15-year survivorship was 79.5% for HA and 83% for TSA. DISCUSSION: In patients with post-traumatic ON of the humeral head, shoulder arthroplasty provides improvements in range of motion. However, TSA provides superior pain relief, with better patient-reported satisfaction. TSA should be strongly considered in patients with post-traumatic ON of the humeral head with damage to the glenoid cartilage. PMID- 26589919 TI - Craniofacial Muscle Development. AB - The developmental mechanisms that control head muscle formation are distinct from those that operate in the trunk. Head and neck muscles derive from various mesoderm populations in the embryo and are regulated by distinct transcription factors and signaling molecules. Throughout the last decade, developmental, and lineage studies in vertebrates and invertebrates have revealed the peculiar nature of the pharyngeal mesoderm that forms certain head muscles and parts of the heart. Studies in chordates, the ancestors of vertebrates, revealed an evolutionarily conserved cardiopharyngeal field that progressively facilitates the development of both heart and craniofacial structures during vertebrate evolution. This ancient regulatory circuitry preceded and facilitated the emergence of myogenic cell types and hierarchies that exist in vertebrates. This chapter summarizes studies related to the origins, signaling circuits, genetics, and evolution of the head musculature, highlighting its heterogeneous characteristics in all these aspects, with a special focus on the FGF-ERK pathway. Additionally, we address the processes of head muscle regeneration, and the development of stem cell-based therapies for treatment of muscle disorders. PMID- 26589920 TI - Mandible and Tongue Development. AB - The tongue and mandible have common origins. They arise simultaneously from the mandibular arch and are coordinated in their development and growth, which is evident from several clinical conditions such as Pierre Robin sequence. Here, we review in detail the molecular networks controlling both mandible and tongue development. We also discuss their mechanical relationship and evolution as well as the potential for stem cell-based therapies for disorders affecting these organs. PMID- 26589922 TI - Genetic Influences on Temporomandibular Joint Development and Growth. AB - The temporomandibular joint (TMJ) is a small synovial joint at which the mandible articulates with the skull during movements involved in speaking and mastication. However, the secondary cartilage lining its joint surfaces is indicative of a very different developmental history than limb cartilages. This review summarizes our current knowledge of genes that regulate the formation of primary components of the TMJ, as well as genes that regulate postnatal growth of the TMJ. Although the TMJ is regulated by some of the same genes that are important in limb joints, others appear unique to the TMJ or have different actions. Runx2, Sox9, and members of the TGF-beta/BMP family are critical drivers of chondrogenesis during condylar cartilage morphogenesis, and Indian hedgehog (Ihh) is important for formation of the articular disc and cavitation. Osterix (Osx) is a critical regulator of endochondral bone formation during postnatal TMJ growth. PMID- 26589923 TI - Regulatory Mechanisms Driving Salivary Gland Organogenesis. AB - Salivary glands develop as highly branched structures designed to produce and secrete saliva. Advances in mouse genetics, stem cell biology, and regenerative medicine are having a tremendous impact on our understanding of salivary gland organogenesis. Understanding how submandibular gland (SMG) initiation, branching morphogenesis, and cell differentiation occur, as well as defining the progenitor/stem cells and cell and tissue interactions that drive SMG development will help guide regenerative approaches for patients suffering from loss of salivary gland function. This review focuses on recent literature from the past 5 years investigating the regulatory mechanisms driving SMG organogenesis. PMID- 26589921 TI - Cellular and Molecular Mechanisms of Palatogenesis. AB - Palatogenesis involves the initiation, growth, morphogenesis, and fusion of the primary and secondary palatal shelves from initially separate facial prominences during embryogenesis to form the intact palate separating the oral cavity from the nostrils. The palatal shelves consist mainly of cranial neural crest-derived mesenchymal cells covered by a simple embryonic epithelium. The growth and patterning of the palatal shelves are controlled by reciprocal epithelial mesenchymal interactions regulated by multiple signaling pathways and transcription factors. During palatal shelf outgrowth, the embryonic epithelium develops a "teflon" coat consisting of a single, continuous layer of periderm cells that prevents the facial prominences and palatal shelves from forming aberrant interepithelial adhesions. Palatal fusion involves not only spatiotemporally regulated disruption of the periderm but also dynamic cellular and molecular processes that result in adhesion and intercalation of the palatal medial edge epithelia to form an intershelf epithelial seam, and subsequent dissolution of the epithelial seam to form the intact roof of the oral cavity. The complexity of regulation of these morphogenetic processes is reflected by the common occurrence of cleft palate in humans. This review will summarize major recent advances and discuss major remaining gaps in the understanding of cellular and molecular mechanisms controlling palatogenesis. PMID- 26589924 TI - The Development of the Calvarial Bones and Sutures and the Pathophysiology of Craniosynostosis. AB - The skull vault is a complex, exquisitely patterned structure that plays a variety of key roles in vertebrate life, ranging from the acquisition of food to the support of the sense organs for hearing, smell, sight, and taste. During its development, it must meet the dual challenges of protecting the brain and accommodating its growth. The bones and sutures of the skull vault are derived from cranial neural crest and head mesoderm. The frontal and parietal bones develop from osteogenic rudiments in the supraorbital ridge. The coronal suture develops from a group of Shh-responsive cells in the head mesoderm that are collocated, with the osteogenic precursors, in the supraorbital ridge. The osteogenic rudiments and the prospective coronal suture expand apically by cell migration. A number of congenital disorders affect the skull vault. Prominent among these is craniosynostosis, the fusion of the bones at the sutures. Analysis of the pathophysiology underling craniosynostosis has identified a variety of cellular mechanisms, mediated by a range of signaling pathways and effector transcription factors. These cellular mechanisms include loss of boundary integrity, altered sutural cell specification in embryos, and loss of a suture stem cell population in adults. Future work making use of genome-wide transcriptomic approaches will address the deep structure of regulatory interactions and cellular processes that unify these seemingly diverse mechanisms. PMID- 26589925 TI - Tissue Interactions Regulating Tooth Development and Renewal. AB - Reciprocal interactions between epithelial and mesenchymal tissues play a fundamental role in the morphogenesis of teeth and regulate all aspects of tooth development. Extensive studies on mouse tooth development over the past 25 years have uncovered the molecular details of the signaling networks mediating these interactions (reviewed by Jussila & Thesleff, 2012; Lan, Jia, & Jiang, 2014). Five conserved signaling pathways, namely, the Wnt, BMP, FGF, Shh, and Eda, are involved in the mediation of the successive reciprocal epithelial-mesenchymal cross talk which follows the general principle of morphogenetic interactions (Davidson, 1993). The pathways regulate the expression of transcription factors which confer the identity of dental epithelium and mesenchyme. The signals and transcription factors are integrated in complex signaling networks whose fine tuning allows the generation of the variation in tooth morphologies. In this review, we describe the principles and molecular mechanisms of the epithelial mesenchymal interactions regulating successive stages of tooth formation: (i) the initiation of tooth development, with special reference to the shift of tooth forming potential from epithelium to mesenchyme; (ii) the morphogenesis of the tooth crown, focusing on the roles of epithelial signaling centers; (iii) the differentiation of odontoblasts and ameloblasts, which produce dentin and enamel, respectively; and (iv) the maintenance of dental stem cells, which support the continuous growth of teeth. PMID- 26589926 TI - Stem Cells in Tooth Development, Growth, Repair, and Regeneration. AB - Human teeth contain stem cells in all their mesenchymal-derived tissues, which include the pulp, periodontal ligament, and developing roots, in addition to the support tissues such as the alveolar bone. The precise roles of these cells remain poorly understood and most likely involve tissue repair mechanisms but their relative ease of harvesting makes teeth a valuable potential source of mesenchymal stem cells (MSCs) for therapeutic use. These dental MSC populations all appear to have the same developmental origins, being derived from cranial neural crest cells, a population of embryonic stem cells with multipotential properties. In rodents, the incisor teeth grow continuously throughout life, a feature that requires populations of continuously active mesenchymal and epithelial stem cells. The discrete locations of these stem cells in the incisor have rendered them amenable for study and much is being learnt about the general properties of these stem cells for the incisor as a model system. The incisor MSCs appear to be a heterogeneous population consisting of cells from different neural crest-derived tissues. The epithelial stem cells can be traced directly back in development to a Sox10(+) population present at the time of tooth initiation. In this review, we describe the basic biology of dental stem cells, their functions, and potential clinical uses. PMID- 26589927 TI - Development and Integration of the Ear. AB - The perception of our environment via sensory organs plays a crucial role in survival and evolution. Hearing, one of our most developed senses, depends on the proper function of the auditory system and plays a key role in social communication, integration, and learning ability. The ear is a composite structure, comprised of the external, middle, and inner ear. During development, the ear is formed from the integration of a number of tissues of different embryonic origin, which initiate in distinct areas of the embryo at different time points. Functional connections between the components of the hearing apparatus have to be established and maintained during development and adulthood to allow proper sound submission from the outer to the middle and inner ear. This highly organized and intimate connectivity depends on intricate spatiotemporal signaling between the various tissues that give rise to the structures of the ear. Any alterations in this chain of events can lead to the loss of integration, which can subsequently lead to conductive hearing loss, in case of outer and middle ear defects or sensorineural hearing loss, if inner ear structures are defective. This chapter aims to review the current knowledge concerning the development of the three ear compartments as well as mechanisms and signaling pathways that have been implicated in the coordination and integration process of the ear. PMID- 26589929 TI - Regulation of Jaw Length During Development, Disease, and Evolution. AB - Molecular and cellular mechanisms that control jaw length are becoming better understood. This is significant since the jaws are not only critical for species specific adaptation and survival, but they are often affected by a variety of size-related anomalies including mandibular hypoplasia, retrognathia, asymmetry, and clefting. This chapter overviews how jaw length is established during the allocation, proliferation, differentiation, and growth of jaw precursor cells, which originate from neural crest mesenchyme (NCM). The focus is mainly on results from experiments transplanting NCM between quail and duck embryos. Quail have short jaws whereas those of duck are relatively long. Quail-duck chimeras reveal that the determinants of jaw length are NCM mediated throughout development and include species-specific differences in jaw progenitor number, differential regulation of various signaling pathways, and the autonomous activation of programs for skeletal matrix deposition and resorption. Such insights help make the goal of devising new therapies for birth defects, diseases, and injuries to the jaw skeleton seem ever more likely. PMID- 26589930 TI - Facial Morphogenesis: Physical and Molecular Interactions Between the Brain and the Face. AB - Morphogenesis of the brain and face is intrinsically linked by a number of factors. These include: origins of tissues, adjacency allowing their physical interactions, and molecular cross talk controlling growth. Neural crest cells that form the facial primordia originate on the dorsal neural tube. In the caudal pharyngeal arches, a Homeobox code regulates arch identity. In anterior regions, positional information is acquired locally. Second, the brain is a structural platform that influences positioning of the facial primordia, and brain growth influences the timing of primordia fusion. Third, the brain helps induce a signaling center, the frontonasal ectodermal zone, in the ectoderm, which participates in patterned growth of the upper jaw. Similarly, signals from neural crest cells regulate expression of fibroblast growth factor 8 in the anterior neural ridge, which controls growth of the anterior forebrain. Disruptions to these interactions have significant consequences for normal development of the craniofacial complex, leading to structural malformations and birth defects. PMID- 26589928 TI - Zebrafish Craniofacial Development: A Window into Early Patterning. AB - The formation of the face and skull involves a complex series of developmental events mediated by cells derived from the neural crest, endoderm, mesoderm, and ectoderm. Although vertebrates boast an enormous diversity of adult facial morphologies, the fundamental signaling pathways and cellular events that sculpt the nascent craniofacial skeleton in the embryo have proven to be highly conserved from fish to man. The zebrafish Danio rerio, a small freshwater cyprinid fish from eastern India, has served as a popular model of craniofacial development since the 1990s. Unique strengths of the zebrafish model include a simplified skeleton during larval stages, access to rapidly developing embryos for live imaging, and amenability to transgenesis and complex genetics. In this chapter, we describe the anatomy of the zebrafish craniofacial skeleton; its applications as models for the mammalian jaw, middle ear, palate, and cranial sutures; the superior imaging technology available in fish that has provided unprecedented insights into the dynamics of facial morphogenesis; the use of the zebrafish to decipher the genetic underpinnings of craniofacial biology; and finally a glimpse into the most promising future applications of zebrafish craniofacial research. PMID- 26589931 TI - Developmental Plasticity of Patterned and Regenerating Oral Organs. AB - In many aquatic vertebrates, including bony and cartilaginous fishes, teeth and taste buds colocalize on jaw elements. In these animals, taste buds are renewed continuously throughout life, whereas teeth undergo cycled whole-organ replacement by various means. Recently, studies of cichlid fishes have yielded new insights into the development and regeneration of these dental and sensory oral organs. Tooth and taste bud densities covary positively across species with different feeding strategies, controlled by common regions of the genome and integrated molecular signals. Developing teeth and taste buds share a bipotent epithelium during early patterning stages, from which dental and taste fields are specified. Moreover, these organs share a common epithelial ribbon that supports label-retaining cells during later stages of regeneration. During both patterning and regeneration stages, dental organs can be converted to taste bud fate by manipulation of BMP signaling. These observations highlight a surprising long term plasticity between dental and sensory organ types. Here, we review these findings and discuss the implications of developmental plasticity that spans the continuum of craniofacial organ patterning and regeneration. PMID- 26589932 TI - Regulating Craniofacial Development at the 3' End: MicroRNAs and Their Function in Facial Morphogenesis. AB - Defects in craniofacial development represent a majority of observed human birth defects, occurring at a rate as high as 1:800 live births. These defects often occur due to changes in neural crest cell (NCC) patterning and development and can affect non-NCC-derived structures due to interactions between NCCs and the surrounding cell types. Proper craniofacial development requires an intricate array of gene expression networks that are tightly controlled spatiotemporally by a number of regulatory mechanisms. One of these mechanisms involves the action of microRNAs (miRNAs), a class of noncoding RNAs that repress gene expression by binding to miRNA recognition sequences typically located in the 3' UTR of target mRNAs. Recent evidence illustrates that miRNAs are crucial for vertebrate facial morphogenesis, with changes in miRNA expression leading to facial birth defects, including some in complex human syndromes such as 22q11 (DiGeorge Syndrome). In this review, we highlight the current understanding of miRNA biogenesis, the roles of miRNAs in overall craniofacial development, the impact that loss of miRNAs has on normal development and the requirement for miRNAs in the development of specific craniofacial structures, including teeth. From these studies, it is clear that miRNAs are essential for normal facial development and morphogenesis, and a potential key in establishing new paradigms for repair and regeneration of facial defects. PMID- 26589933 TI - Transcription Factors in Craniofacial Development: From Receptor Signaling to Transcriptional and Epigenetic Regulation. AB - Craniofacial morphogenesis is driven by spatial-temporal terrains of gene expression, which give rise to stereotypical pattern formation. Transcription factors are key cellular components that control these gene expressions. They are information hubs that integrate inputs from extracellular factors and environmental cues, direct epigenetic modifications, and define transcriptional status. These activities allow transcription factors to confer specificity and potency to transcription regulation during development. PMID- 26589934 TI - Mouse Models of Rare Craniofacial Disorders. AB - A rare disease is defined as a condition that affects less than 1 in 2000 individuals. Currently more than 7000 rare diseases have been documented, and most are thought to be of genetic origin. Rare diseases primarily affect children, and congenital craniofacial syndromes and disorders constitute a significant proportion of rare diseases, with over 700 having been described to date. Modeling craniofacial disorders in animal models has been instrumental in uncovering the etiology and pathogenesis of numerous conditions and in some cases has even led to potential therapeutic avenues for their prevention. In this chapter, we focus primarily on two general classes of rare disorders, ribosomopathies and ciliopathies, and the surprising finding that the disruption of fundamental, global processes can result in tissue-specific craniofacial defects. In addition, we discuss recent advances in understanding the pathogenesis of an extremely rare and specific craniofacial condition known as syngnathia, based on the first mouse models for this condition. Approximately 1% of all babies are born with a minor or major developmental anomaly, and individuals suffering from rare diseases deserve the same quality of treatment and care and attention to their disease as other patients. PMID- 26589935 TI - From Bench to Bedside and Back: Improving Diagnosis and Treatment of Craniofacial Malformations Utilizing Animal Models. AB - Craniofacial anomalies are among the most common birth defects and are associated with increased mortality and, in many cases, the need for lifelong treatment. Over the past few decades, dramatic advances in the surgical and medical care of these patients have led to marked improvements in patient outcomes. However, none of the treatments currently in clinical use address the underlying molecular causes of these disorders. Fortunately, the field of craniofacial developmental biology provides a strong foundation for improved diagnosis and for therapies that target the genetic causes of birth defects. In this chapter, we discuss recent advances in our understanding of the embryology of craniofacial conditions, and we focus on the use of animal models to guide rational therapies anchored in genetics and biochemistry. PMID- 26589936 TI - Signaling Pathways in Craniofacial Development: Insights from Rare Skeletal Disorders. AB - In the developing embryo, signaling pathways define how the mesenchymal precursors of bone form individual skeletal elements with the proper size, shape, orientation, and integration. Disruptions to these signaling processes lead to a large variety of congenital conditions categorized as skeletal dysplasias. While individually these skeletal disorders are rare, collectively they represent a significant cause of disability in the United States. Here, we discuss how the study of these rare events in human development reveal novel and unexpected insights into signaling mechanisms that regulate normal skeletal development and, in the process, advance novel molecular-based therapies for treatment of rare and common bone diseases alike. PMID- 26589937 TI - Clinical and Genomic Approaches for the Diagnosis of Craniofacial Disorders. AB - With the rapid development of readily accessible molecular diagnostic tools, a growing number of patients and families with craniofacial anomalies will have access to a confirmed molecular diagnosis. This chapter provides an overview to current clinical and molecular resources and approaches used by diagnostician today. Clarifying the underlying cause of a congenital defect is necessary to provide proper counseling, identify carrier/risk status of family members, inform prognosis and direct appropriate management, treatments, and surveillance recommendations. The use of molecular testing has evolved to confirm a suspected clinical diagnosis, establish a diagnosis in an unclear condition and end a diagnostic odyssey for many children with underlying syndromes, but the use of these techniques to understand common nonsyndromic malformations like clefts and craniosynostosis is still an active area of research that will contribute to clinical care in the future. PMID- 26589939 TI - Imaging the Cell and Molecular Dynamics of Craniofacial Development: Challenges and New Opportunities in Imaging Developmental Tissue Patterning. AB - The development of the vertebrate head requires cell-cell and tissue-tissue interactions between derivatives of the three germ layers to coordinate morphogenetic movements in four dimensions (4D: x, y, z, t). The high spatial and temporal resolution offered by optical microscopy has made it the main imaging modularity for capturing the molecular and cellular dynamics of developmental processes. In this chapter, we highlight the challenges and new opportunities provided by emerging technologies that enable dynamic, high-information-content imaging of craniofacial development. We discuss the challenges of varying spatial and temporal scales encountered from the biological and technological perspectives. We identify molecular and fluorescence imaging technology that can provide solutions to some of the challenges. Application of the techniques described within this chapter combined with considerations of the biological and technical challenges will aid in formulating the best image-based studies to extend our understanding of the genetic and environmental influences underlying craniofacial anomalies. PMID- 26589938 TI - Morphometrics, 3D Imaging, and Craniofacial Development. AB - Recent studies have shown how volumetric imaging and morphometrics can add significantly to our understanding of morphogenesis, the developmental basis for variation, and the etiology of structural birth defects. On the other hand, the complex questions and diverse imaging data in developmental biology present morphometrics with more complex challenges than applications in virtually any other field. Meeting these challenges is necessary in order to understand the mechanistic basis for variation in complex morphologies. This chapter reviews the methods and theory that enable the application of modern landmark-based morphometrics to developmental biology and craniofacial development, in particular. We discuss the theoretical foundations of morphometrics as applied to development and review the basic approaches to the quantification of morphology. Focusing on geometric morphometrics, we discuss the principal statistical methods for quantifying and comparing morphological variation and covariation structure within and among groups. Finally, we discuss the future directions for morphometrics in developmental biology that will be required for approaches that enable quantitative integration across the genotype-phenotype map. PMID- 26589940 TI - Preface. PMID- 26589942 TI - PDCD2 and NCoR1 as putative tumor suppressors in gastric gastrointestinal stromal tumors. AB - PURPOSE: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the gastrointestinal tract. Previously, PDCD2 (programmed cell death protein 2) has been identified as a putative tumor suppressor in gastric cancer. As yet, however, no reports on PDCD2 expression and its physical interactor NCoR1 (nuclear receptor co-repressor), and their effects in GIST have been reported. METHODS: The expression of PDCD2 and NCoR1 was assessed in 43 primary gastric GIST and normal gastric tissue samples using Western blotting and quantitative real-time PCR. Next, associations between PDCD2 and NCoR1 expression and various clinicopathological features, including survival, were determined. To assess the effects of PDCD2 and NCoR1 expression in vitro, two GIST-derived cell lines (GIST T1 and GIST882) were (co-)transfected with the expression vectors pEGFP-N1-PDCD2 and pcDNA3.1-NCoR1, after which the cells were subjected to CCK-8, PI staining and Annexin V-FITC/PI double staining assays, respectively. Finally, the mechanisms of action of PDCD2 and NCoR1 in GIST-derived cells were determined using immunoprecipitation and Western blotting assays. RESULTS: We found that the PDCD2 and NCoR1 protein levels were lower in gastric GIST tissues than in normal gastric tissues. The PDCD2 and NCoR1 expression levels were found to be significantly associated with the survival of the patients. Through exogenous expression analyses, we found that PDCD2 and NCoR1 can decrease proliferation, and increase apoptosis and G1 cell cycle arrest, in GIST-derived cells. Furthermore, we found that PDCD2 and NCoR1 can activate Smad2 and Smad3. CONCLUSIONS: Our data indicate that both PDCD2 and NCoR1 may act as tumor suppressors in GIST cells through the Smad signaling pathway. PMID- 26589943 TI - Quantitation of repaglinide and metabolites in mouse whole-body thin tissue sections using droplet-based liquid microjunction surface sampling-high performance liquid chromatography-electrospray ionization tandem mass spectrometry. AB - Herein, quantitation aspects of a fully automated autosampler/HPLC-MS/MS system applied for unattended droplet-based surface sampling of repaglinide dosed thin tissue sections with subsequent HPLC separation and mass spectrometric analysis of parent drug and various drug metabolites were studied. Major organs (brain, lung, liver, kidney and muscle) from whole-body thin tissue sections and corresponding organ homogenates prepared from repaglinide dosed mice were sampled by surface sampling and by bulk extraction, respectively, and analyzed by HPLC MS/MS. A semi-quantitative agreement between data obtained by surface sampling and that by employing organ homogenate extraction was observed. Drug concentrations obtained by the two methods followed the same patterns for post dose time points (0.25, 0.5, 1 and 2 h). Drug amounts determined in the specific tissues was typically higher when analyzing extracts from the organ homogenates. In addition, relative comparison of the levels of individual metabolites between the two analytical methods also revealed good semi-quantitative agreement. PMID- 26589944 TI - Aminoglutethimide-imprinted xerogels in bulk and spherical formats, based on a multifunctional organo-alkoxysilane precursor. AB - The multifunctional alkoxysilane precursor, 2,6-bis(propyl trimethoxysilylurelene)pyridine (DPS) was designed and synthesized, envisaging a multiple hydrogen-bond interaction in the molecular imprinting of the drug aminoglutethimide (AGT). Imprinted xerogels were obtained in bulk and spherical formats. The spherical format was achieved by pore-filling onto spherical mesoporous silica, as a straightforward technique to generate the spherical format. The bulk gels presented better selectivity for the template against its glutarimide (GLU) analogue (selectivity factor: bulk 13.4; spherical 4.6), and good capacity (bulk 5521MUmol/L; spherical 2679MUmol/L) and imprinting factor parameters (bulk 11.3; spherical 1.4). On the other hand, the microspherical format exhibited better dynamic properties associated to chromatographic efficiency (theoretical plates: bulk 6.8; spherical 75) and mass transfer, due mainly to the existence of a mesoporous network, lacking in the bulk material. The performance of the imprinted xerogels was not as remarkable as that of their acrylic counterparts, previously described. Overall it was demonstrated that the use of designed new "breeds" of organo-alkoxysilanes may be a strategy to achieve satisfactory imprints by the sol-gel processes. DPS may in principle be applied even more effectively to other templates bearing better-matching spatially compatible acceptor-donor-acceptor arrays. PMID- 26589945 TI - Rapid and automated analysis of aflatoxin M1 in milk and dairy products by online solid phase extraction coupled to ultra-high-pressure-liquid-chromatography tandem mass spectrometry. AB - This study reports a fast and automated analytical procedure for the analysis of aflatoxin M1 (AFM1) in milk and dairy products. The method is based on the simultaneous protein precipitation and AFM1 extraction, by salt-induced liquid liquid extraction (SI-LLE), followed by an online solid-phase extraction (online SPE) coupled to ultra-high-pressure-liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) analysis to the automatic pre-concentration, clean up and sensitive and selective determination of AFM1. The main parameters affecting the extraction efficiency and accuracy of the analytical method were studied in detail. In the optimal conditions, acetonitrile and NaCl were used as extraction/denaturant solvent and salting-out agent in SI-LLE, respectively. After centrifugation, the organic phase (acetonitrile) was diluted with water (1:9 v/v) and purified (1mL) by online C18 cartridge coupled with an UHPLC column. Finally, selected reaction monitoring (SRM) acquisition mode was applied to the detection of AFM1. Validation studies were carried out on different dairy products (whole and skimmed cow milk, yogurt, goat milk, and powder infant formula), providing method quantification limits about 25 times lower than AFM1 maximum levels permitted by EU regulation 1881/2006 in milk and dairy products for direct human consumption. Recoveries (86-102%) and repeatability (RSD<3, n=6) meet the performance criteria required by EU regulation N. 401/2006 for the determination of the levels of mycotoxins in foodstuffs. Moreover, no matrix effects were observed in the different milk and dairy products studied. The proposed method improves the performance of AFM1 analysis in milk samples as AFM1 determination is performed with a degree of accuracy higher than the conventional methods. Other advantages are the reduction of sample preparation procedure, time and cost of the analysis, enabling high sample throughput that meet the current concerns of food safety and the public health protection. PMID- 26589946 TI - UV-filter benzophenone-3 inhibits agonistic behavior in male Siamese fighting fish (Betta splendens). AB - Benzophenone-3 (BP-3) is a widely used organic UV-filter compound. Despite the frequent occurrence of BP-3 in aquatic environments, little is known about its effect on fish behavior. The aim of this study was to investigate the endocrine disrupting effects of BP-3 in male fighting fish (Betta splendens) with a focus on agonistic behavior. Male fighting fish were exposed to 10, 100, and 1000 MUg/L BP-3, as well as a solvent control (0.1% ethanol) and a positive control (100 ng/L 17alpha-ethynylestradiol, EE2), for 28 days. At the beginning and the end of exposure, standard length and body mass of the fish were measured for calculating the condition factor (CF). In addition, spontaneous swimming activity (total distance moved) and agonistic behavior (maximum velocity and duration of opercular display in front of a mirror) were also quantified. At the end of exposure, the fish gonads were sampled for gonadosomatic index (GSI) measurement and histology. After the exposure, CF was significantly decreased in the 1000 MUg/L BP-3 groups. Spontaneous swimming activity was not affected. However, maximum velocity was significantly reduced in the EE2 and 1000 MUg/L BP-3 treatments; duration of opercular display was significantly decreased in the EE2 and 10 and 1000 MUg/L BP-3 treatments. GSI was not significantly different between groups. There was a slight but statistically significant decrease of relative proportion of mature spermatozoa in testicular tissue in the 100 MUg/L BP-3 treatment. Collectively, our results demonstrate that BP-3 can disrupt agonistic behavior of male fighting fish, indicating the endocrine disrupting activity of this compound. PMID- 26589947 TI - Genome sequencing reveals mechanisms for heavy metal resistance and polycyclic aromatic hydrocarbon degradation in Delftia lacustris strain LZ-C. AB - Strain LZ-C, isolated from a petrochemical wastewater discharge site, was found to be resistant to heavy metals and to degrade various aromatic compounds, including naphenol, naphthalene, 2-methylnaphthalene and toluene. Data obtained from 16S rRNA gene sequencing showed that this strain was closely related to Delftia lacustris. The 5,889,360 bp genome of strain LZ-C was assembled into 239 contigs and 197 scaffolds containing 5855 predicted open reading frames (ORFs). Among these predicted ORFs, 464 were different from the type strain of Delftia. The minimal inhibitory concentrations were 4 mM, 30 uM, 2 mM and 1 mM for Cr(VI), Hg(II), Cd(II) and Pb(II), respectively. Both genome sequencing and quantitative real-time PCR data revealed that genes related to Chr, Czc and Mer family genes play important roles in heavy metal resistance in strain LZ-C. In addition, the Na(+)/H(+) antiporter NhaA is important for adaptation to high salinity resistance (2.5 M NaCl). The complete pathways of benzene and benzoate degradation were identified through KEGG analysis. Interestingly, strain LZ-C also degrades naphthalene but lacks the key naphthalene degradation gene NahA. Thus, we propose that strain LZ-C exhibits a novel protein with a function similar to NahA. This study is the first to reveal the mechanisms of heavy metal resistance and salinity tolerance in D. lacustris and to identify a potential 2 methylnaphthalene degradation protein in this strain. Through whole-genome sequencing analysis, strain LZ-C might be a good candidate for the bioremediation of heavy metals and polycyclic aromatic hydrocarbons. PMID- 26589948 TI - In vivo micronucleus test in the assessment of cytogenotoxicity of landfill leachates in three animal models from various ecological habitats. AB - The in vivo micronucleus (MN) test, a standard test for the genotoxicity screening of xenobiotics, was used to evaluate the cytotoxic and genotoxic activities of landfill leachates in Clarias gariepinus, Coturnix coturnix japonica and Rattus norvegicus. These organisms were exposed to various sub lethal concentrations (1-50%) of Olusosun and Aba Eku landfill leachates. At post exposure, peripheral erythrocytes from catfish and quail, and bone marrow cells of quail and rat were subjected to MN analysis following standard protocols. The leachates induced significant increase in MN formation and total nuclear abnormalities (NAs) in the peripheral erythrocytes of catfish and quail. NAs occurred in the order; BN > BL > LB > NT in the catfish and BN > BudN > TLN > TN in quail. There was significant increase in MN formation in the bone marrow cells of quail, and micronucleated polychromatic erythrocytes and micronucleated normochromatic erythrocytes formation in the bone marrow of rats. The concentration dependent significant (p < 0.05) decrease in the PCE/NCE ratio in the bone marrow of the leachate treated rats suggest alterations in the bone marrow cell proliferation, leading to the suppression of immature erythrocytes (PCE). MN induction showed positive corrections with leachate concentrations in the test organisms; and it increased with exposure duration in the catfish. Indiscriminate disposal of solid waste generates leachates containing multiple xenobiotics that are capable of increasing genomic instability among vertebrates inhabiting various ecological habitats. PMID- 26589950 TI - New-onset rectoanal intussusception may not result in symptomatic improvement after laparoscopic ventral rectopexy for external rectal prolapse. AB - BACKGROUND: This study was designed to assess defecatory function in patients who underwent laparoscopic ventral rectopexy (LVR) for external rectal prolapse (ERP). METHODS: Thirty-one patients who underwent evacuation proctography 6 months postoperatively were assessed. Preoperative proctography had been performed in 21 patients of these patients. Defecatory function was evaluated using the constipation scoring system (CSS) and fecal incontinence severity index (FISI). RESULTS: The findings of postoperative proctography revealed no full thickness ERP in any patient, although in 10 patients the ERP was replaced by rectoanal intussusception (RAI). Of the 31 patients, 30 presented with fecal incontinence preoperatively. Ten of 30 had new-onset RAI. Six months postoperatively, a reduction of at least 50 % in the FISI score of the patients with new-onset RAI tended to be significantly smaller than in the patients without RAI (6/10 vs. 18/20, p = 0.141). Seventeen patients presented with obstructed defecation preoperatively. Seven of them had new-onset RAI. Six months postoperatively, a reduction of at least 50 % in their CSS score in the patients with new-onset RAI was significantly smaller than in patients without RAI (0/7 vs. 8/10, p = 0.002). CONCLUSIONS: Evacuation proctography showed new-onset RAI in some patients with ERP who underwent LVR, which was associated with a lack of symptomatic improvement. PMID- 26589951 TI - Influence of variceal bleeding on natural history of ACLF and management options. AB - Patients with diagnosed and undiagnosed chronic liver diseases experience one or more acute assaults of a hepatic nature and develop a downhill course of liver diseases, a condition regarded as acute-on-chronic liver failure (ACLF). It is a medical emergency, the prognosis of ACLF is extremely bad and considerable numbers of patients with ACLF die even after diagnosis and receiving conservative treatment. ACLF is characterized by jaundice, coagulopathy, ascites and encephalopathy. ACLF patients are very sick and associated with different hemodynamic profiles and have very high 3-month mortality. As these groups of patients have high baseline hepatic venous pressure gradients, the chances of variceal bleed are also high, and the impact is also greater in comparison to stable cirrhosis; however, evidence is lacking to substantiate such effects. The aim of this review is to discuss the natural course of variceal bleeding in ACLF patients and to develop insights into the management of variceal bleeding in ACLF. PMID- 26589952 TI - Resection of pulmonary endometriosis using video-assisted thoracoscopic surgery under preoperative CT-guided marking. AB - Pulmonary endometriosis is a gynecological disorder in which endometrial tissue grows outside of the uterine cavity. Usually, the ectopic implants are located in the pelvis and manifest as dysmenorrhea, chronic pelvic pain, or infertility. Pulmonary endometriosis sometimes occurs in the pleurae and can result in catamenial pneumothorax; however, true pulmonary endometriosis, tissue growing in the lung itself, is rare. We report a 22-year-old patient with pulmonary endometriosis and catamenial hemoptysis. Pulmonary endometriosis was proved histologically and treated successfully by wedge resection using video-assisted thoracoscopic surgery. PMID- 26589953 TI - Progression of obstructive sleep apnoea syndrome in Japanese patients. AB - PURPOSE: The aggravation of obstructive sleep apnoea syndrome (OSAS) is reportedly associated with weight gain. The present study investigated the factors associated with worsening of respiratory functional parameters in Japanese OSAS patients who showed no body weight change during the follow-up period. METHODS: A follow-up polysomnography (PSG) was performed in 82 patients with a mean of 7.5 years after the diagnostic PSG, and the apnoea-hypopnoea index (AHI), respiratory event duration, minimum percutaneous oxygen saturation (SpO2), baseline SpO2, and 3 % oxygen desaturation index (ODI) during sleep were compared between the two PSGs. Furthermore, factors associated with worsened AHI, respiratory event duration, and minimum SpO2 were investigated using logistic regression analysis. RESULTS: No significant differences were observed in AHI, baseline SpO2, and 3 % ODI between the two PSGs. However, there was a significantly increased respiratory event duration and decreased minimum SpO2 observed. In addition, 17 patients had a >=25 % AHI increase, and the age of 40 60 years and initial OSAS severity (mild and moderate) were the significantly associated factors. Age of >=60 years and a baseline body mass index (BMI) of >=25 kg/m(2) were significantly associated with prolonged respiratory event duration. The age of 40-60 years was significantly associated with decreased minimum SpO2. CONCLUSIONS: Untreated middle-aged patients may be at a high risk for worsened AHI and SpO2 even without weight gain. PMID- 26589954 TI - Enrichment of Circulating and Mucosal Cytotoxic CD8+ T Cells Is Associated with Postoperative Endoscopic Recurrence in Patients with Crohn's Disease. AB - BACKGROUND AND AIMS: Evidence from mouse colitis models indicates that cytotoxic CD8+ T cells [CTL] play a key role in the initiation of gut lesions. We investigated whether changes in CD8+ CTL in blood or lamina propria [LP] of the neoterminal ileum were associated with postoperative endoscopic recurrence of Crohn's disease [CD]. METHODS: A total of 37 CD patients with ileocolonic resection were endoscopically followed up at 6 and 12 months post-surgery. CD8+ T cells were analysed by flow cytometry in blood and ileal LP. RESULTS: Granzyme B- and perforin-producing CD8+ T cells were significantly increased at 6 months in blood and in ileum LP in patients with endoscopic recurrence, as compared with those in remission. At a cutoff point of 45% of CD8+ CTL, the overall accuracies of the frequency of blood granzyme B+ or perforin+ CD8+ T cells to identify patients with postoperative endoscopic recurrence were 77% and 83%, respectively. Interestingly, patients with endoscopic recurrence at 12 months were those showing the highest mucosal CD8+ CTL frequency at 6 months, while still in remission. CONCLUSIONS: Enrichment of cytotoxic CD8+ T cells in blood and ileal mucosa coincides with CD postoperative endoscopic recurrence. This underscores that CD8 CTL may play a pathophysiological role in the initiation of gut lesions during CD. PMID- 26589955 TI - Lamina Propria CD4+LAP+ Regulatory T Cells Are Increased in Active Ulcerative Colitis but Show Increased IL-17 Expression and Reduced Suppressor Activity. AB - BACKGROUND: A CD4+CD25- regulatory T cell population expressing the surface TGF beta in its latent form LAP+ [latency associated peptide] cells was proved to be protective in experimental colitis and to be suppressive of human peripheral blood [PB] T proliferation. We investigated the frequency and function of lamina propria [LP] CD4+LAP+ T cells in inflammatory bowel disease [IBD] patients. METHODS: Specimens from patients undergoing colonoscopy or bowel resection for IBD and colonic cancer were used as source of lamina propria mononuclear cells [LPMC]. The ulcerative colitis [UC] group was divided according to endoscopic activity evaluated with modified Baron Score. IL-17, IFN-gamma, IL-10, LAP, and Foxp3 expression in CD3+CD8- [CD4] or CD3+/CD4+ gated cell population was assessed by immunofluorescence. The ability of FACS-sorted LP CD3+CD8-[CD4] LAP+CD25- to inhibit stimulated autologous PB CD3+CD8-[CD4] LAP- CD25- cells proliferation was assessed. RESULTS: LP CD4LAP+ cells were significantly increased, when compared with controls, in active UC patients and not in Crohn's disease patients. The majority of LP CD4+LAP+ cells were Foxp3-. The percentage of IL-17+ cells in LP CD3+CD8-[CD4] LAP+ cells was significantly higher in active UC patients when compared with controls. LP CD3+CD8-[CD4]LAP+CD25- isolated from UC patients showed reduced or no ability to inhibit autologous PB CD3+CD8 [CD4]LAP-CD25- cell proliferation when compared with controls. Removal of IL-17+ cells from LP CD3+CD8-[CD4] LAP+ cells increases their suppressive ability. CONCLUSIONS: The percentage of LP CD4LAP+ cells is increased in active UC, showing reduced suppressor activity due to their increased proportion of intracellular IL-17 expression. PMID- 26589956 TI - Diagnostic Delay in Romanian Patients with Inflammatory Bowel Disease: Risk Factors and Impact on the Disease Course and Need for Surgery. AB - BACKGROUND: The epidemiology of inflammatory bowel disease [IBD] in Eastern Europe is poorly understood, particularly with regard to diagnostic delay. Here we investigated the factors leading to delayed diagnosis and the effect of the delay on several disease progression and outcome measures. METHODS: A total of 1196 IBD cases [682 ulcerative colitis [UC], 478 Crohn's disease [CD], 36 indeterminate colitis] from the Romanian national registry IBDPROSPECT were reviewed. Standard clinical and demographic factors were evaluated as predictors of a long diagnostic delay in both CD and UC. Diagnostic delay was subsequently evaluated as a potential risk factor for bowel stenoses, bowel fistulas, perianal fistulas, perianal surgery, and intestinal surgery in CD patients. RESULTS: The median diagnostic delay was significantly longer in CD [5 months] than in UC [1 month] patients [p < 0.001]. Compared with 5 months for UC patients, 75% of CD patients were diagnosed within 18 months of symptom onset. In CD patients, extra ileal location was a protective factor (odds ratio [OR], 0.5; p = 0.03), whereas being an active smoker [OR, 2.09; p = 0.01] and symptom onset during summer [OR, 3.35; p < 0.001] were independent risk factors for a long diagnostic delay [> 18 months]. In UC patients, an age > 40 years was a protective factor [OR, 0.68; p = 0.04] for a long delay. Regarding outcomes, a long diagnostic delay in CD patients positively correlated with bowel stenoses [OR, 3.38; p < 0.01] and any IBD-related surgery [OR, 1.95; p = 0.03] and had a positive trend for intestinal fistulas [OR, 2.64; p = 0.08] and perianal fistulas [OR, 2.9; p = 0.07]. Disease duration since diagnosis positively correlated with bowel stenoses [OR, 1.04; p = 0.04], any IBD-related surgery [OR, 1.04; p = 0.02], and intestinal surgery [OR, 1.07; p < 0.01]. CONCLUSIONS: A long diagnostic delay in IBD correlates with an increased frequency of bowel stenoses and need for IBD-related surgery. PMID- 26589958 TI - Sexual activity as a trigger for intracranial hemorrhage. AB - BACKGROUND: Intracranial hemorrhage (ICH) has been reported in association with sexual activity. A case-series of patients with ICH following sexual activity is presented to further elucidate the role of the physiologic sexual response as a trigger of ICH. METHOD: A retrospective review of the medical record was performed, identifying patients presenting with ICH temporally related to sexual activity. Clinical and radiographic data were collected and reported. RESULTS: Sixteen patients presented with non-traumatic ICH temporally related to sexual activity. Eight (50 %) patients presented with aneurysmal subarachnoid hemorrhage, four (25 %) with angiogram-negative subarachnoid hemorrhage, two (12.5 %) with a ruptured arteriovenous malformation, and two (12.5 %) with an intracerebral basal ganglia hemorrhage. Overall average age was 49.9 (range, 28 74) years. Sexual activity involved male-female intercourse in 14 (87.5 %) patients and masturbation in 2 (12.5 %) patients. CONCLUSIONS: Sexual-activity related ICH is rare and includes various etiologies. The human sexual response in associated with dramatic increases in arterial blood pressure, which likely underlies the association. PMID- 26589957 TI - Pragmatic cluster randomised controlled trial of facilitated family case conferencing compared with usual care for improving end of life care and outcomes in nursing home residents with advanced dementia and their families: the IDEAL study protocol. AB - BACKGROUND: Care for people with advanced dementia requires a palliative approach targeted to the illness trajectory and tailored to individual needs. However, care in nursing homes is often compromised by poor communication and limited staff expertise. This paper reports the protocol for the IDEAL Project, which aims to: 1) compare the efficacy of a facilitated approach to family case conferencing with usual care; 2) provide insights into nursing home- and staff related processes influencing the implementation and sustainability of case conferencing; and 3) evaluate cost-effectiveness. DESIGN/METHODS: A pragmatic parallel cluster randomised controlled trial design will be used. Twenty Australian nursing homes will be randomised to receive either facilitated family case conferencing or usual care. In the intervention arm, we will train registered nurses at each nursing home to work as Palliative Care Planning Coordinators (PCPCs) 16 h per week over 18 months. The PCPCs' role will be to: 1) use evidence-based 'triggers' to identify optimal time-points for case conferencing; 2) organise, facilitate and document case conferences with optimal involvement from family, multi-disciplinary nursing home staff and community health professionals; 3) develop and oversee implementation of palliative care plans; and 4) train other staff in person-centred palliative care. The primary endpoint will be symptom management, comfort and satisfaction with care at the end of life as rated by bereaved family members on the End of Life in Dementia (EOLD) Scales. Secondary outcomes will include resident quality of life (Quality of Life in Late-stage Dementia [QUALID]), whether a palliative approach is taken (e.g. hospitalisations, non-palliative medical treatments), staff attitudes and knowledge (Palliative Care for Advanced Dementia [qPAD]), and cost effectiveness. Processes and factors influencing implementation, outcomes and sustainability will be explored statistically via analysis of intervention 'dose' and qualitatively via semi-structured interviews. The pragmatic design and complex nature of the intervention will limit blinding and internal validity but support external validity. DISCUSSION: The IDEAL Project will make an important contribution to the evidence base for dementia-specific case conferencing in nursing homes by considering processes and contextual factors as well as overall efficacy. Its strengths and weaknesses will both lie in its pragmatic design. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12612001164886. Registered 02/11/2012. PMID- 26589959 TI - Etiologies of conjugated hyperbilirubinemia in infancy: a systematic review of 1692 subjects. AB - BACKGROUND: The etiologies of conjugated hyperbilirubinemia in infancy are diverse. OBJECTIVE: Determine the prevalence rates of the specific etiologies of conjugated hyperbilirubinemia in infancy. DATA SOURCES: EMBASE and Pubmed were searched electronically and the bibliographies of selected studies were search manually. The search was conducted independently by two authors. STUDY SELECTION: (1) prospective or retrospective case series or cohort study with 10 or more subjects; (2) consecutive infants who presented with conjugated hyperbilirubinemia; (3) subjects underwent appropriate diagnostic work-up for conjugated hyperbilirubinemia; (4) no specific diagnoses were excluded in the studied cohort. DATA EXTRACTION: Patient number, age range, country of origin, and categorical and specific etiologies. RESULTS: From 237 studies identified, 17 studies encompassing 1692 infants were selected. Idiopathic neonatal hepatitis (INH) occurred in 26.0% of cases; the most common specific etiologies were extrahepatic biliary atresia (EHBA) (25.89%), infection (11.47%), TPN- associated cholestasis (6.44%), metabolic disease (4.37%), alpha-1 anti-trypsin deficiency (4.14%), and perinatal hypoxia/ischemia (3.66%). CMV was the most common infection identified (31.51%) and galactosemia (36.49%) was the most common metabolic disease identified. LIMITATIONS: Major limitations are: (1) inconsistencies in the diagnostic evaluations among the different studies and (2) variations among the sample populations. CONCLUSIONS: INH is the most common diagnosis for conjugated hyperbilirubinemia in infancy while EHBA and infection are the most commonly identified etiologies. The present review is intended to be a guide to the differential diagnosis and evaluation of the infant presenting with conjugated hyperbilirubinemia. PMID- 26589960 TI - Reduced expression of MyHC slow isoform in rat soleus during unloading is accompanied by alterations of endogenous inhibitors of calcineurin/NFAT signaling pathway. AB - Under muscle disuse conditions decrease of expression of MyHC of slow type, and sometimes of type IIa, as well as upregulation of expression of IIb and IId/x isoforms were observed. Through dephosphorylation and entry of NFAT molecules to the nucleus calcineurin/NFATc1 signaling pathway promotes upregulation of the slow MyHC expression. We supposed that downregulation of calcineurin pathway took place during unloading. The study was aimed to analyze the states of the myonuclear NFAT inhibitors calsarcin I (CSI) and calsarcin II (CSII) (also referred to as myozenin II and I) and GSK3beta in rat soleus during hindlimb suspension (HS). Male Wistar rats were subjected to 3, 7 and 14 day of HS. We found that after 3 days of HS the content of CSII mRNA twofold increased in soleus as compared to the controls. This level was increased by more than fivefold (as compared to control) after 2 weeks of HS. The increase of CSII mRNA expression may be explained as the mechanism of stabilization of fast phenotype. We found that from the 3 day till 14 day of HS the content of MuRF-1 and MuRF-2 in the nuclear fraction fourfold to fivefold increased in HS soleus. We supposed that nuclear import of the MuRFs allows to promote CSII expression during unloading. We also observed the decline of the phosphorylated GSK3beta content in the nuclear extract of the soleus tissue. Thus decline of slow MyHC expression characteristic for the unloading conditions is accompanied with the increased expression and activation of the factors known to prevent NFAT accumulation in the myonuclei. PMID- 26589961 TI - Age- and strain-dependent differences in the outcome of experimental infections of domestic pigs with wild boar pseudorabies virus isolates. AB - Although pseudorabies virus (PRV) has been eradicated in domestic swine in many countries, its presence in wild boars remains a threat for a reintroduction into the currently unprotected swine population. To assess the possible impact of such a reintroduction in a naive herd, an in vivo infection study using two genetically characterized wild boar PRV isolates (BEL24043 and BEL20075) representative for wild boar strains circulating in south-western and central Europe and the virulent NIA3 reference strain was performed in 2- and 15-week-old domestic pigs. Our study revealed an attenuated nature of both wild boar strains in 15-week-old pigs. In contrast, it showed the capacity of strain BEL24043 to induce severe clinical symptoms and mortality in young piglets, thereby confirming that the known age dependency of disease outcome after PRV infection also holds for wild boar isolates. Despite the absence of clinical disease in 15 week-old sows, both wild boar PRV strains were able to induce seroconversion, but to a different extent. Importantly, differences in infection and transmission capacity of both strains were observed in 15-week-old sows. Strain BEL24043 induced a more prolonged and disseminated infection than strain BEL20075 and was able to spread efficiently to contact animals, indicative of its capacity to induce a sustained infection. In conclusion, it was shown that a reintroduction of a wild boar isolate into the domestic swine population could have serious economic consequences due to the induction of clinical symptoms in piglets and by jeopardizing the PRV-negative status. PMID- 26589962 TI - Climate and habitat interact to shape the thermal reaction norms of breeding phenology across lizard populations. AB - Substantial plastic variation in phenology in response to environmental heterogeneity through time in the same population has been uncovered in many species. However, our understanding of differences in reaction norms of phenology among populations from a given species remains limited. As the plasticity of phenological traits is often influenced by local thermal conditions, we expect local temperature to generate variation in the reaction norms between populations. Here, we explored temporal variation in parturition date across 11 populations of the common lizard (Zootoca vivipara) from four mountain chains as a function of air temperatures during mid-gestation. We characterized among population variation to assess how local weather conditions (mean and variance of ambient temperatures during mid-gestation) and habitat openness (an index of anthropogenic disturbance) influence the thermal reaction norms of the parturition date. Our results provide evidence of interactive effects of anthropogenic disturbance and thermal conditions, with earlier parturition dates in warmer years on average especially in closed habitats. Variation in the reaction norms for parturition date was correlated with mean local thermal conditions at a broad geographical scale. However, populations exposed to variable thermal conditions had flatter thermal reaction norms. Assessing whether environmental heterogeneity drives differentiation among reaction norms is crucial to estimate the capacity of different populations to contend with projected climatic and anthropogenic challenges. PMID- 26589963 TI - Gene-expression analysis of adult-onset Still's disease and systemic juvenile idiopathic arthritis is consistent with a continuum of a single disease entity. AB - BACKGROUND: Adult-onset Still's disease (AOSD), a rare autoinflammatory disorder, resembles systemic juvenile idiopathic arthritis (SJIA). The superimposable systemic clinical features of AOSD and SJIA suggest both clinical phenotypes represent the same disease continuum with different ages of onset. To further characterize the similarity between AOSD and SJIA at the molecular level, 2 previously identified response gene sets in SJIA were used to investigate how genes that respond to interleukin (IL)-1beta inhibition with canakinumab in SJIA patients behave in AOSD patients with active disease prior to IL-1beta targeting therapy, relative to healthy subjects. FINDINGS: All genes downregulated in SJIA patients following canakinumab treatment were upregulated in most patients with active AOSD prior to canakinumab treatment, relative to healthy subjects. A few patients with milder AOSD had expectedly gene-expression patterns that resembled those in healthy subjects. Comparison of the gene-expression patterns with neutrophil counts showed a correlation between elevated neutrophil numbers and upregulation of canakinumab-responsive genes. Correspondingly, most genes upregulated following canakinumab treatment in patients with SJIA patients were downregulated in the majority of AOSD patients. CONCLUSIONS: These results further support the concept of a Still's disease continuum that includes both a pediatric/juvenile onset (SJIA) and adult onset (AOSD) form. PMID- 26589964 TI - A re-appraisal of publication rates of scientific papers presented at the Otorhinolaryngology Research Society meetings. AB - OBJECTIVES: To review the rate of publication of papers in peer-reviewed journals after oral presentations at the Otorhinolaryngology Research Society meetings between 1996 and 2013 and to compare trends with the previous review (1979-1995). DESIGN: Literature review. SETTING: Merseyside ENT Research Collaborative. PARTICIPANTS: The abstracts of presentations at Otorhinolaryngology Research Society meetings are published in Clinical Otolaryngology. A structured search of PubMed was undertaken to identify published Otorhinolaryngology Research Society presentations. MAIN OUTCOME MEASURES: Publication rates. RESULTS: A total of 460 abstracts were identified. The interobserver reliability among reviewers was 98%. Of the total, 259 (56.3%) abstracts were published in peer-reviewed journals. The average time from Otorhinolaryngology Research Society presentation to publication was 27.7 months (median 23), which was not significantly different from the previous review. Publication by subspeciality was as follows: head and neck (45.6%), otology (30.5%), rhinology (22%) and others (1.9%). Most published Otorhinolaryngology Research Society presentations were published in Clinical Otolaryngology (22.4%), followed by the Journal of Laryngology and Otology (8.1%) and the Laryngoscope (7.3%). Clinical research was the most common category of abstracts being presented at Otorhinolaryngology Research Society meetings, followed by laboratory-based research. Over half (56.5%) of laboratory research presented were head and neck themed, while otology and rhinology predominated clinical research presentations. Over half (52.1%) of Otorhinolaryngology Research Society abstracts originated from units in the North of England. Bristol presented the most abstracts (30.1%), followed by Newcastle (25.1%). CONCLUSIONS: The publication rate of Otorhinolaryngology Research Society presentations remains high and many are subsequently published in high-impact factor otolaryngology journals. More Otorhinolaryngology Research Society presentations are now published in American and European journals. PMID- 26589965 TI - Glycogen synthase kinase-3-mediated phosphorylation of serine 73 targets sterol response element binding protein-1c (SREBP-1c) for proteasomal degradation. AB - Sterol regulatory element binding protein-1c (SREBP-1c) is a key transcription factor that regulates genes involved in the de novo lipid synthesis and glycolysis pathways. The structure, turnover and transactivation potential of SREBP-1c are regulated by macronutrients and hormones via a cascade of signalling kinases. Using MS, we have identified serine 73 as a novel glycogen synthase kinase-3 (GSK-3) phosphorylation site in the rat SREBP-1c purified from McA RH7777 hepatoma cells. Our site-specific mutagenesis strategy revealed that the turnover of SREBP-1c, containing wild type, phospho-null (serine to alanine) or phospho-mimetic (serine to aspartic acid) substitutions, was differentially regulated. We show that the S73D mutant of pSREBP-1c, that mimicked a state of constitutive phosphorylation, dissociated from the SREBP-1c-SCAP complex more readily and underwent GSK-3-dependent proteasomal degradation via SCF(Fbw7) ubiquitin ligase pathway. Pharmacologic inhibition of GSK-3 or knockdown of GSK-3 by siRNA prevented accelerated degradation of SREBP-1c. As demonstrated by MS, SREBP-1c was phosphorylated in vitro by GSK-3beta at serine 73. Phosphorylation of serine 73 also occurs in the intact liver. We propose that GSK-3-mediated phosphorylation of serine 73 in the rat SREBP-1c and its concomitant destabilization represents a novel mechanism involved in the inhibition of de novo lipid synthesis in the liver. PMID- 26589966 TI - Mitochondrial dysfunction in fatty acid oxidation disorders: insights from human and animal studies. AB - Mitochondrial fatty acid oxidation (FAO) plays a pivotal role in maintaining body energy homoeostasis mainly during catabolic states. Oxidation of fatty acids requires approximately 25 proteins. Inherited defects of FAO have been identified in the majority of these proteins and constitute an important group of inborn errors of metabolism. Affected patients usually present with severe hepatopathy, cardiomyopathy and skeletal myopathy, whereas some patients may suffer acute and/or progressive encephalopathy whose pathogenesis is poorly known. In recent years growing evidence has emerged indicating that energy deficiency/disruption of mitochondrial homoeostasis is involved in the pathophysiology of some fatty acid oxidation defects (FAOD), although the exact underlying mechanisms are not yet established. Characteristic fatty acids and carnitine derivatives are found at high concentrations in these patients and more markedly during episodes of metabolic decompensation that are associated with worsening of clinical symptoms. Therefore, it is conceivable that these compounds may be toxic. We will briefly summarize the current knowledge obtained from patients and genetic mouse models with these disorders indicating that disruption of mitochondrial energy, redox and calcium homoeostasis is involved in the pathophysiology of the tissue damage in the more common FAOD, including medium-chain acyl-CoA dehydrogenase (MCAD), long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) and very long-chain acyl-CoA dehydrogenase (VLCAD) deficiencies. We will also provide evidence that the fatty acids and derivatives that accumulate in these diseases disrupt mitochondrial homoeostasis. The elucidation of the toxic mechanisms of these compounds may offer new perspectives for potential novel adjuvant therapeutic strategies in selected disorders of this group. PMID- 26589969 TI - Pain management in photoepilation. AB - The hair follicle is a complex, hormonally active structure with permanent and cyclically renewed parts which are highly innervated by myelinated and unmyelinated afferent fibers. Hair removal, a very ancient practice, affects this sensory network and causes both acute and diffuse pain associated with inflammatory reaction. Optic permanent hair removal is becoming a popular alternative to traditional methods such as shaving, waxing, among other methods. These optical removal devices thermally destroy the target chromophore, that is, melanin, without damaging the surrounding skin. The increase in the skin surface temperature causes mild-to-severe pain, and optical hair removal has to be combined with pain relieving devices. Pain management relies on topical anesthetic agents, cooling devices, or non-noxious cutaneous stimulation whose mechanisms of action and efficiency are discussed in this article. PMID- 26589970 TI - Double staining of beta-galactosidase with fibrosis and cancer markers reveals the chronological appearance of senescence in liver carcinogenesis induced by diethylnitrosamine. AB - Cellular senescence is characterized by irreversible cell arrest and is associated with the development of chronic diseases, including cancer. Here, we investigated the induction of cellular senescence during liver carcinogenesis. Liver cancer was induced in Fischer 344 rats with a weekly intraperitoneal injection of diethylnitrosamine (50mg/kg body weight) for 16 weeks. Double detection of beta-galactosidase with Ki67 for cell proliferation; a-SMA and Pdgfrb for cell specificity; p53, p21, p16, and cyclin D1, CDK2, and CDK4 for senescence-associated molecular pathways and gamma-glutamyltranspeptidase (GGT) for hepatocarcinogenesis was assessed to determine the association of these markers with cellular senescence. DNA damage was measured through senescence associated heterochromatin foci (SAHF) detection. Progressive cellular senescence was observed in both fibrotic septa and hepatocytes from week 10 to 18. The maximum peak of positive senescent and fibrotic cells was observed at week 16 and decreased at week 18, but cell proliferation remained high. Whereas the increased p16 expression and SAHF were concomitant with that of beta-galactosidase, those of p53 and p21 were barely detected. Furthermore, beta-galactosidase positive myofibroblast-like cells were mainly surrounding GGT-positive tumors. Our findings showed that in hepatocarcinogenesis by diethylnitrosamine, cellular senescence is associated with p16 pathway activation and is mainly localized in myofibroblast-like cells. PMID- 26589968 TI - Evolution of unusual morphologies in Lentibulariaceae (bladderworts and allies) and Podostemaceae (river-weeds): a pictorial report at the interface of developmental biology and morphological diversification. AB - BACKGROUND: Various groups of flowering plants reveal profound ('saltational') changes of their bauplans (architectural rules) as compared with related taxa. These plants are known as morphological misfits that appear as rather large morphological deviations from the norm. Some of them emerged as morphological key innovations (perhaps 'hopeful monsters') that gave rise to new evolutionary lines of organisms, based on (major) genetic changes. SCOPE: This pictorial report places emphasis on released bauplans as typical for bladderworts (Utricularia, approx. 230 secies, Lentibulariaceae) and river-weeds (Podostemaceae, three subfamilies, approx. 54 genera, approx. 310 species). Bladderworts (Utricularia) are carnivorous, possessing sucking traps. They live as submerged aquatics (except for their flowers), as humid terrestrials or as epiphytes. Most Podostemaceae are restricted to rocks in tropical river-rapids and waterfalls. They survive as submerged haptophytes in these extreme habitats during the rainy season, emerging with their flowers afterwards. The recent scientific progress in developmental biology and evolutionary history of both Lentibulariaceae and Podostemaceae is summarized. CONCLUSIONS: Lentibulariaceae and Podostemaceae follow structural rules that are different from but related to those of more typical flowering plants. The roots, stems and leaves - as still distinguishable in related flowering plants - are blurred ('fuzzy'). However, both families have stable floral bauplans. The developmental switches to unusual vegetative morphologies facilitated rather than prevented the evolution of species diversity in both families. The lack of one-to-one correspondence between structural categories and gene expression may have arisen from the re-use of existing genetic resources in novel contexts. Understanding what developmental patterns are followed in Lentibulariaceae and Podostemaceae is a necessary prerequisite to discover the genetic alterations that led to the evolution of these atypical plants. Future molecular genetic work on morphological misfits such as bladderworts and river-weeds will provide insight into developmental and evolutionary aspects of more typical vascular plants. PMID- 26589971 TI - Health Assimilation among Hispanic Immigrants in the United States: The Impact of Ignoring Arrival-cohort Effects. AB - A large literature has documented that Hispanic immigrants have a health advantage over their U.S.-born counterparts upon arrival in the United States. Few studies, however, have disentangled the effects of immigrants' arrival cohort from their tenure of U.S. residence, an omission that could produce imprecise estimates of the degree of health decline experienced by Hispanic immigrants as their U.S. tenure increases. Using data from the 1996-to-2014 waves of the March Current Population Survey, we show that the health (i.e., self-rated health) of Hispanic immigrants varies by both arrival cohort and U.S. tenure for immigrants hailing from most of the primary sending countries/regions of Hispanic immigrants. We also find evidence that acculturation plays an important role in determining the health trajectories of Hispanic immigrants. With respect to self rated health, however, our findings demonstrate that omitting arrival-cohort measures from health assimilation models may result in overestimates of the degree of downward health assimilation experienced by Hispanic immigrants. PMID- 26589967 TI - Nucleotide-binding mechanisms in pseudokinases. AB - Pseudokinases are classified by the lack of one or several of the highly conserved motifs involved in nucleotide (nt) binding or catalytic activity of protein kinases (PKs). Pseudokinases represent ~10% of the human kinome and they are found in all evolutionary classes of kinases. It has become evident that pseudokinases, which were initially considered somewhat peculiar dead kinases, are important components in several signalling cascades. Furthermore, several pseudokinases have been linked to human diseases, particularly cancer, which is raising interest for therapeutic approaches towards these proteins. The ATP binding pocket is a well-established drug target and elucidation of the mechanism and properties of nt binding in pseudokinases is of significant interest and importance. Recent studies have demonstrated that members of the pseudokinase family are very diverse in structure as well as in their ability and mechanism to bind nts or perform phosphoryl transfer reactions. This diversity also precludes prediction of pseudokinase function, or the importance of nt binding for said function, based on primary sequence alone. Currently available data indicate that ~40% of pseudokinases are able to bind nts, whereas only few are able to catalyse occasional phosphoryl transfer. Pseudokinases employ diverse mechanisms to bind nts, which usually occurs at low, but physiological, affinity. ATP binding serves often a structural role but in most cases the functional roles are not precisely known. In the present review, we discuss the various mechanisms that pseudokinases employ for nt binding and how this often low-affinity binding can be accurately analysed. PMID- 26589972 TI - Exploring the function and effectiveness of knowledge brokers as facilitators of knowledge translation in health-related settings: a systematic review and thematic analysis. AB - BACKGROUND: Knowledge brokers (KBs) work collaboratively with key stakeholders to facilitate the transfer and exchange of information in a given context. Currently, there is a perceived lack of evidence about the effectiveness of knowledge brokering and the factors that influence its success as a knowledge translation (KT) mechanism. Thus, the goal of this review was to systematically gather evidence regarding the nature of knowledge brokering in health-related settings and determine if KBs effectively contributed to KT in these settings. METHODS: A systematic review was conducted using a search strategy designed by a health research librarian. Eight electronic databases (MEDLINE, Embase, PsycINFO, CINAHL, ERIC, Scopus, SocINDEX, and Health Business Elite) and relevant grey literature sources were searched using English language restrictions. Two reviewers independently screened the abstracts, reviewed full-text articles, extracted data, and performed quality assessments. Analysis included a confirmatory thematic approach. To be included, studies must have occurred in a health-related setting, reported on an actual application of knowledge brokering, and be available in English. RESULTS: In total, 7935 records were located. Following removal of duplicates, 6936 abstracts were screened and 240 full-text articles were reviewed. Ultimately, 29 articles, representing 22 unique studies, were included in the thematic analysis. Qualitative (n = 18), quantitative (n = 1), and mixed methods (n = 6) designs were represented in addition to grey literature sources (n = 4). Findings indicated that KBs performed a diverse range of tasks across multiple health-related settings; results supported the KB role as a 'knowledge manager', 'linkage agent', and 'capacity builder'. Our systematic review explored outcome data from a subset of studies (n = 8) for evidence of changes in knowledge, skills, and policies or practices related to knowledge brokering. Two studies met standards for acceptable methodological rigour; thus, findings were inconclusive regarding KB effectiveness. CONCLUSIONS: As knowledge managers, linkage agents, and capacity builders, KBs performed many and varied tasks to transfer and exchange information across health-related stakeholders, settings, and sectors. How effectively they fulfilled their role in facilitating KT processes is unclear; further rigourous research is required to answer this question and discern the potential impact of KBs on education, practice, and policy. PMID- 26589973 TI - Increasing time trends of thin melanomas in The Netherlands: What are the explanations of recent accelerations? AB - BACKGROUND: A disproportional increase in in situ or thin melanomas may point at underlying causes such as increased melanoma awareness, as well as 'overdiagnosis' of melanoma in diagnostically equivocal small lesions. OBJECTIVES: The purposes of this study were to estimate trends in melanoma incidence by sex, Breslow thickness (thin melanomas subdivided into four subgroups: <0.25 mm, 0.25-0.49 mm, 0.50-0.74 mm, and 0.75-1.0 mm), age and location, and to compare these with trends in subgroups of thicker melanomas. METHODS: Data on all histologically confirmed in situ and invasive melanomas diagnosed between 1994 and 2010 were retrieved from the Netherlands Cancer Registry. Trends in European standardised rates (ESRs) were assessed using joinpoint analysis, and expressed as estimated annual percentage change (EAPC). RESULTS: Between 1994 and 2010, 34,156 persons were diagnosed with an in situ or thin melanoma. The ESR of in situ melanomas doubled for males and females with a recent steeper rise in incidence (EAPC 12% (95% confidence interval [CI]: 8.1-16) and 13% (95% CI: 5.9-20), respectively). ESR for thin melanomas amongst males approximately doubled with a steep, but non-significant acceleration compared to other thickness categories since 2006 for <0.25 mm melanomas (EAPC 26% (95% CI: 2.1-35)). For female patients with thin melanomas the ESRs increased almost two fold, except for <0.25 mm melanomas. CONCLUSIONS: The incidence rates of in situ, thin and thick melanomas increased similarly between 1994 and 2010. Recently steep increases were found for in situ melanomas and thin melanomas in men. Explanations are 'overdiagnosis' in conjunction with increased ultraviolet exposure (natural and artificial) and therefore a 'true' increase, increased awareness, early detection, diagnostic drift and changed market forces in the Dutch health care system. PMID- 26589975 TI - Validation of a point-of-care instrument for bedside glutamine screening in the intensive care unit. AB - BACKGROUND: A point-of-care instrument developed for measuring glutamine levels in cell cultures was validated for bedside use in the ICU setting and compared with a standard HPLC technique to measure plasma glutamine. The aim was to evaluate the instrument for absolute measurements and for screening purposes. METHODS: Consecutive blood samples were obtained from one hundred adult ICU patients 3-5 days apart during their ICU stay. Each sample was divided into 3 aliquots, out of which two were used for analyses of plasma and whole blood glutamine by the point-of-care instrument, and one was used for analysis of plasma glutamine concentration by the gold standard HPLC technique. Comparisons were performed by Bland-Altman analyses. RESULTS: Comparison of the initial plasma sample of each subject (n = 100), between the point of care instrument and HPLC analysis revealed a systematic bias of -221 MUmol/L. Comparisons between plasma and whole blood on the point-of-care instrument revealed comparable results. After pragmatic adjustments for the measured bias and hematocrit, whole blood analyses during ICU stay (n = 316) compared with HPLC plasma analyses showed a line of identity of -34 MUmol/L and limits of agreement between 288 and 355 MUmol/L. CONCLUSION: When compared to the HPLC gold standard in particular, the lines of agreement indicate that the point-of-care instrument is not suitable for quantitative plasma or whole blood glutamine concentration measurements. For screening purposes the instrument may be useful in order to identify patients with hypoglutaminemia and hyperglutaminemia and the tested accuracy was high enough for safe supplementation of glutamine to patients with low plasma values measured with the device. The point-of-care instrument may also serve as a screening tool for scientific studies. PMID- 26589976 TI - Segmental hair analysis to assess effectiveness of single-session motivational intervention to stop ethanol use during pregnancy. AB - BACKGROUND: This study aimed to test the effectiveness of single-session motivational intervention to stop ethanol use during pregnancy using segmental hair analysis of ethyl glucuronide to objectively verify drinking behavior before and after intervention. METHODS: 168 pregnant women attending Hospital del Mar (Barcelona, Spain) for antenatal visit were included in the study and randomly assigned to one of two conditions: single-session motivational intervention (MI; N=83) or single-session educational control condition (ECC; N=85). Ethyl glucuronide was measured in maternal hair divided into three segments of 3 cm each corresponding to the three different gestation trimesters by a validated liquid chromatography tandem mass spectrometry method. Concentrations of EtG<7 pg/mg, between 7 and 30 pg/mg and >=30 pg/mg in each segment were used to assess total abstinence, repetitive moderate drinking and chronic excessive consumption in the previous three months. RESULTS: About a third of pregnant women self reporting no ethanol consumption during gestation showed hair EtG values corresponding to ethanol drinking. Single-session MI helped in decreasing alcohol consumption during pregnancy as assessed by lower hair EtG concentrations in 2nd and 3rd trimesters. However, it did not significantly increase complete abstinence in pregnant women who previously showed hair EtG compatible with ethanol consumption. CONCLUSIONS: Pregnant women did not correctly self reported ethanol consumption during gestation, while hair EtG was essential to correctly identify drinking patterns. Single-session MI was not enough to stop ethanol use during pregnancy. Interventions at any visit during pregnancy are strongly recommended. PMID- 26589974 TI - Landscape of dietary factors associated with risk of gastric cancer: A systematic review and dose-response meta-analysis of prospective cohort studies. AB - BACKGROUND: The associations between dietary factors and gastric cancer risk have been analysed by many studies, but with inconclusive results. We conducted a meta analysis of prospective studies to systematically investigate the associations. METHODS: Relevant studies were identified through searching Medline, Embase, and Web of Science up to June 30, 2015. We included prospective cohort studies of intake of dietary factors with risk estimates and 95% confidence intervals for gastric cancer. RESULTS: Seventy-six prospective cohort studies were eligible and included in the analysis. We ascertained 32,758 gastric cancer cases out of 6,316,385 participants in relations to intake of 67 dietary factors, covering a wide ranging of vegetables, fruit, meat, fish, salt, alcohol, tea, coffee, and nutrients, during 3.3 to 30 years of follow-up. Evidence from this study indicates that consumption of total fruit and white vegetables, but not total vegetables, was inversely associated with gastric cancer risk. Both fruit and white vegetables are rich sources of vitamin C, which showed significant protective effect against gastric cancer by our analysis too. Furthermore, we found concordant positive associations between high-salt foods and gastric cancer risk. In addition, a strong effect of alcohol consumption, particularly beer and liquor but not wine, on gastric cancer risk was observed compared with nondrinkers. Dose-response analysis indicated that risk of gastric cancer was increased by 12% per 5 g/day increment of dietary salt intake or 5% per 10 g/day increment of alcohol consumption, and that a 100 g/day increment of fruit consumption was inversely associated with 5% reduction of risk. CONCLUSION: This study provides comprehensive and strong evidence that there are a number of protective and risk factors for gastric cancer in diet. Our findings may have significant public health implications with regard to prevention of gastric cancer and provide insights into future cohort studies and the design of related clinical trials. PMID- 26589978 TI - 'A profession in charge of its future'--a vision for 2030. PMID- 26589977 TI - Adverse metabolic phenotype of adolescent girls with non-alcoholic fatty liver disease plus polycystic ovary syndrome compared with other girls and boys. AB - BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) and polycystic ovary syndrome (PCOS) share risk associations of adiposity and insulin resistance. We examined the impact of a PCOS diagnosis on the metabolic phenotype of adolescent girls with NAFLD and compared this to girls without PCOS or NAFLD and to age-matched boys. METHODS: Community-based adolescents from the Raine Cohort participated in assessments for NAFLD (572 girls and 592 boys) and PCOS (244 girls). One hundred and ninety-nine girls attended both assessments. RESULTS: Amongst the 199 girls, PCOS was diagnosed in 16.1% and NAFLD in 18.6%. NAFLD was diagnosed in 10.1% of the boys. NAFLD was more prevalent in girls with PCOS than girls without PCOS (37.5% vs 15.1%, P = 0.003). Girls with NAFLD plus PCOS had greater adiposity (waist circumference, body mass index, suprailiac skinfold thickness [SST], serum androgens, high-sensitivity C-reactive protein, ferritin, homeostasis model assessment for insulin resistance (HOMA-IR), and lower serum sex hormone binding globulin levels than girls with NAFLD without a PCOS diagnosis (all P < 0.05). Girls with NAFLD plus PCOS had similar adiposity, HOMA-IR, and adiponectin levels to boys with NAFLD, but more adiposity, serum leptin and HOMA-IR than both girls and boys without NAFLD. PCOS (odds ratios 2.99, 95% confidence intervals 1.01-8.82, P = 0.048) and SST (odds ratios 1.14, 95% confidence intervals 1.08-1.20, P < 0.001) independently predicted NAFLD in adolescent girls, however, serum androgens and HOMA-IR levels did not. CONCLUSIONS: Adolescent girls with NAFLD plus PCOS have a similar metabolic phenotype to boys with NAFLD. Increasing SST and pre-existing PCOS independently predict NAFLD in adolescent girls. PMID- 26589979 TI - Minister launches bovine TB biosecurity campaign. PMID- 26589980 TI - BVA president highlights the value of working in partnership. PMID- 26589981 TI - Staying sound in mind and body. PMID- 26589982 TI - Antimicrobial resistance: 'too important for uncoordinated approaches'. PMID- 26589983 TI - Working together on the responsible use of medicines. PMID- 26589984 TI - The future of wearable healthcare in the veterinary profession. PMID- 26589985 TI - Veterinary bake off to help beat rabies. PMID- 26589986 TI - Bracken poisoning in cattle. PMID- 26589987 TI - Control of liver fluke: an emerging issue in terms of veterinary residues. PMID- 26589988 TI - Use of antibiotics in people and animals. PMID- 26589989 TI - Flock health. PMID- 26589990 TI - Shortage of experienced vets. PMID- 26589991 TI - A life in veterinary public health. PMID- 26589992 TI - Hindbrain regional growth in preterm newborns and its impairment in relation to brain injury. AB - Premature birth globally affects about 11.1% of all newborns and is a risk factor for neurodevelopmental disability in surviving infants. Histology has suggested that hindbrain subdivisions grow differentially, especially in the third trimester. Prematurity-related brain injuries occurring in this period may selectively affect more rapidly developing areas of hindbrain, thus accompanying region-specific impairments in growth and ultimately neurodevelopmental deficits. The current study aimed to quantify regional growth of the cerebellum and the brainstem in preterm neonates (n = 65 with individually multiple scans). We probed associations of the regional volumes with severity of brain injury. In neonates with no imaging evidence of injury, our analysis using a mixed-effect linear model showed faster growth in the pons and the lateral convexity of anterior/posterior cerebellar lobes. Different patterns of growth impairment were found in relation to early cerebral intraventricular hemorrhage and cerebellar hemorrhage (P < 0.05), likely explaining different mechanisms through which neurogenesis is disrupted. The pattern of cerebellar growth identified in our study agreed excellently with details of cerebellar morphogenesis in perinatal development, which has only been observed in histological data. Our proposed analytic framework may provide predictive imaging biomarkers for neurodevelopmental outcome, enabling early identification and treatment of high risk patients. Hum Brain Mapp 37:678-688, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26589993 TI - Mycobacterium tuberculosis causing tuberculous lymphadenitis in Maputo, Mozambique. AB - BACKGROUND: The zoonosis bovine tuberculosis (TB) is known to be responsible for a considerable proportion of extrapulmonary TB. In Mozambique, bovine TB is a recognised problem in cattle, but little has been done to evaluate how Mycobacterium bovis has contributed to human TB. We here explore the public health risk for bovine TB in Maputo, by characterizing the isolates from tuberculous lymphadenitis (TBLN) cases, a common manifestation of bovine TB in humans, in the Pathology Service of Maputo Central Hospital, in Mozambique, during one year. RESULTS: Among 110 patients suspected of having TBLN, 49 had a positive culture result. Of those, 48 (98%) were positive for Mycobacterium tuberculosis complex and one for nontuberculous mycobacteria. Of the 45 isolates analysed by spoligotyping and Mycobacterial Interspersed Repetitive Unit-Variable Number Tandem Repeat (MIRU-VNTR), all were M. tuberculosis. No M. bovis was found. Cervical TBLN, corresponding to 39 (86.7%) cases, was the main cause of TBLN and 66.7% of those where from HIV positive patients. We found that TBLN in Maputo was caused by a variety of M. tuberculosis strains. The most prevalent lineage was the EAI (n = 19; 43.2%). Particular common spoligotypes were SIT 48 (EAI1_SOM sublineage), SIT 42 (LAM 9), SIT 1 (Beijing) and SIT53 (T1), similar to findings among pulmonary cases. CONCLUSIONS: M. tuberculosis was the main etiological agent of TBLN in Maputo. M. tuberculosis genotypes were similar to the ones causing pulmonary TB, suggesting that in Maputo, cases of TBLN arise from the same source as pulmonary TB, rather than from an external zoonotic source. Further research is needed on other forms of extrapulmonary TB and in rural areas where there is high prevalence of bovine TB in cattle, to evaluate the risk of transmission of M. bovis from cattle to humans. PMID- 26589994 TI - Are Human Translated Pseudogenes Functional? AB - By definition, pseudogenes are relics of former genes that no longer possess biological functions. Operationally, they are identified based on disruptions of open reading frames (ORFs) or presumed losses of promoter activities. Intriguingly, a recent human proteomic study reported peptides encoded by 107 pseudogenes. These peptides may play currently unrecognized physiological roles. Alternatively, they may have resulted from accidental translations of pseudogene transcripts and possess no function. Comparing between human and macaque orthologs, we show that the nonsynonymous to synonymous substitution rate ratio (omega) is significantly smaller for translated pseudogenes than other pseudogenes. In particular, five of 34 translated pseudogenes amenable to evolutionary analysis have omega values significantly lower than 1, indicative of the action of purifying selection. This and other findings demonstrate that some but not all translated pseudogenes have selected functions at the protein level. Hence, neither ORF disruption nor presence of protein product disproves or proves gene functionality at the protein level. PMID- 26589995 TI - The Impact of Missing Data on Species Tree Estimation. AB - Phylogeneticists are increasingly assembling genome-scale data sets that include hundreds of genes to resolve their focal clades. Although these data sets commonly include a moderate to high amount of missing data, there remains no consensus on their impact to species tree estimation. Here, using several simulated and empirical data sets, we assess the effects of missing data on species tree estimation under varying degrees of incomplete lineage sorting (ILS) and gene rate heterogeneity. We demonstrate that concatenation (RAxML), gene-tree based coalescent (ASTRAL, MP-EST, and STAR), and supertree (matrix representation with parsimony [MRP]) methods perform reliably, so long as missing data are randomly distributed (by gene and/or by species) and that a sufficiently large number of genes are sampled. When data sets are indecisive sensu Sanderson et al. (2010. Phylogenomics with incomplete taxon coverage: the limits to inference. BMC Evol Biol. 10:155) and/or ILS is high, however, high amounts of missing data that are randomly distributed require exhaustive levels of gene sampling, likely exceeding most empirical studies to date. Moreover, missing data become especially problematic when they are nonrandomly distributed. We demonstrate that STAR produces inconsistent results when the amount of nonrandom missing data is high, regardless of the degree of ILS and gene rate heterogeneity. Similarly, concatenation methods using maximum likelihood can be misled by nonrandom missing data in the presence of gene rate heterogeneity, which becomes further exacerbated when combined with high ILS. In contrast, ASTRAL, MP-EST, and MRP are more robust under all of these scenarios. These results underscore the importance of understanding the influence of missing data in the phylogenomics era. PMID- 26589996 TI - A Dominant Evolutionary Theme Emerges to Better Predict Clinical Outcomes for Cancer. PMID- 26589997 TI - Epistatic Interactions in the Arabinose Cis-Regulatory Element. AB - Changes in gene expression are an important mode of evolution; however, the proximate mechanism of these changes is poorly understood. In particular, little is known about the effects of mutations within cis binding sites for transcription factors, or the nature of epistatic interactions between these mutations. Here, we tested the effects of single and double mutants in two cis binding sites involved in the transcriptional regulation of the Escherichia coli araBAD operon, a component of arabinose metabolism, using a synthetic system. This system decouples transcriptional control from any posttranslational effects on fitness, allowing a precise estimate of the effect of single and double mutations, and hence epistasis, on gene expression. We found that epistatic interactions between mutations in the araBAD cis-regulatory element are common, and that the predominant form of epistasis is negative. The magnitude of the interactions depended on whether the mutations are located in the same or in different operator sites. Importantly, these epistatic interactions were dependent on the presence of arabinose, a native inducer of the araBAD operon in vivo, with some interactions changing in sign (e.g., from negative to positive) in its presence. This study thus reveals that mutations in even relatively simple cis-regulatory elements interact in complex ways such that selection on the level of gene expression in one environment might perturb regulation in the other environment in an unpredictable and uncorrelated manner. PMID- 26589998 TI - Efficacy of commercially available wipes for disinfection of pulse oximeter sensors. AB - BACKGROUND: This study examined the effectiveness of commercially available disinfecting wipes and cosmetic wipes in disinfecting pulse oximeter sensors contaminated with pathogenic bacterial surrogates. METHODS: Surrogates of potential biological warfare agents and bacterial pathogens associated with hospital-acquired infections (HAIs) were spotted on test surfaces, with and without an artificial test soil (sebum), allowed to dry, and then cleaned with different commercially available cleaning and disinfecting wipes or sterile gauze soaked in water, bleach (diluted 1:10), or 70% isopropanol. The percentage of microbial survival and an analytical estimation of remaining test soil on devices were determined. RESULTS: Wipes containing sodium hypochlorite as the active ingredient and gauze soaked in bleach (1:10) were the most effective in removing both vegetative bacteria and spores. In the presence of selective disinfectants, sebum had a protective effect on vegetative bacteria, but not on spores. CONCLUSIONS: The presence of sebum reduces the cleaning efficiency of some commercially available wipes for some select microbes. Various commercial wipes performed significantly better than the designated cleaning agent (70% isopropanol) in disinfecting the oximetry sensor. Cosmetic wipes were not more effective than the disinfecting wipes in removing sebum. PMID- 26589999 TI - Outbreak in newborns of methicillin-resistant Staphylococcus aureus related to the sequence type 5 Geraldine clone. AB - We describe the first nosocomial outbreak of a toxic shock syndrome-positive methicillin-resistant Staphylococcus aureus (MRSA) sequence type 5 Geraldine clone. Infection control interventions that are usually successful were implemented to control the outbreak. Spread of this virulent MRSA strain highlights the need to be vigilant to MRSA antibiotic susceptibilities. PMID- 26590000 TI - Cleaning, resistant bacteria, and antibiotic prescribing in residential aged care facilities. AB - Residents of residential aged care facilities (RACFs) are at risk of colonization and infection with multidrug-resistant bacteria, and antibiotic prescribing is often inappropriate and not based on culture-proven infection. We describe low levels of resident colonization and environmental contamination with resistant gram-negative bacteria in RACFs, but high levels of empirical antibiotic use not guided by microbiologic culture. This research highlights the importance of antimicrobial stewardship and environmental cleaning in aged care facilities. PMID- 26590001 TI - A novel predictive marker for the viscosity of otitis media with effusion. AB - OBJECTIVES: To evaluate the significance of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio for the prediction of the viscosity of otitis media with effusion. METHODS: This retrospective study was performed on 81 patients who were admitted to the otolaryngology clinic.The patients were divided into two groups according to their effusion type, as serous or mucoid, which was defined intraoperatively after myringotomy. The NLR and PLR were calculated as a simple ratio between the absolute neutrophil/platelet and absolute lymphocyte counts.Tympanostomy tube insertion was performed for all cases.Under direct visualization, the effusion was aspirated and classified as serous or mucous. RESULTS: We postulated that an NLR value of less than 1.38 may show mucoid effusion and if the PLR value is less than 97.96, the effusion is mucoid. CONCLUSIONS: We speculate that a useful predictor of viscosity for a middle ear effusion could prevent unnecessary surgeries and additional costs in the treatment of EMO. Additional studies are needed to confirm our results. PMID- 26590002 TI - Cochlear sensitivity in children with chronic kidney disease and end-stage renal disease undergoing hemodialysis. AB - OBJECTIVES: Auditory system abnormalities commonly occur in patients with chronic renal disease and end-stage renal disease undergoing hemodialysis. The aim of this study was to determine the relationship between cochlear sensitivity and hemodialysis in dialytic and non-dialytic chronic kidney disease patients. METHODS: The study included children aged 6-18 years that were divided into 3 groups: 36 non-dialytic patients with chronic kidney disease, 16 end-stage renal disease patients undergoing hemodialysis, and 30 healthy controls. Blood urea nitrogen, serum cystatin C levels, duration of chronic kidney disease, and the duration of hemodialysis were compared between the chronic kidney disease patients and end-stage renal disease patients undergoing hemodialysis. Hearing health was measured via tympanometry, pure-tone audiometry and distortion product otoacoustic emissions testing. RESULTS: Distortion product otoacoustic emission amplitudes and signal-to-noise ratios were significantly lower at all frequencies tested in the non-dialytic and dialytic groups than in the control group (p<0.05). Patients with normal hearing had significantly lower distortion product otoacoustic emission amplitudes and signal-to-noise ratios than the healthy controls (p<0.05). The duration of CKD, the cystatin C level, and the blood urea level were not associated with hearing loss. The present findings suggest that there was a significant association between the duration of HD and hearing loss. CONCLUSION: The present findings show that there was impaired cochlear function in the dialytic and non-dialytic patient groups, regardless of hearing loss, as compared to the control group. Patients with chronic renal disease-both dialytic and non-dialytic-should be monitored to prevent any further deterioration by avoiding potential ototoxic agents, even if their hearing thresholds are within normal limits. PMID- 26590003 TI - Fetal distress and circulatory disturbance in monochorionic twins: Possible risk factors for sialadenitis? AB - Neonatal sialadenitis is a rare condition. The vast majority of cases are caused by Staphylococcus aureus with predominant involvement of the parotid gland and need for long-term antimicrobial therapy. We reviewed three distinct cases of submandibular sialadenitis in preterm infants from monochorionic pregnancies. The association with neonatal sialadenitis is unproven. We speculate about the role of fetal distress and circulatory compromise in monochorionic twins as a risk factor in the development of this serious condition. PMID- 26590004 TI - Oral morphine for pain management in paediatric patients after tonsillectomy and adenotonsillectomy. AB - OBJECTIVES: The withdrawal of codeine for use in children following tonsillectomy enforced a change in our practice of providing regular paracetamol and ibuprofen, with codeine for breakthrough pain relief. Our objectives were to; examine the effectiveness of paracetamol and ibuprofen; examine the effectiveness of the addition of rescue (PRN) morphine to regular paracetamol and ibuprofen. METHODS: A 2 cycle prospective audit was conducted on our unit. Telephone consultations were conducted with parents of 74 children undergoing tonsillectomy and adenotonsillectomy. Cycle 1 (C1, without morphine) contained 24 consecutive patients and cycle 2 (C2, with morphine) contained 50 consecutive patients. Postoperative health service contact and outcome was recorded: worst pain scores on days 4 and 7 were obtained using validated pain assessment tools scoring 0-10. Cycle 2 results underwent subgroup analysis by method of surgery i.e. coblation (C2C) and cold steel dissection (C2D) groups. RESULTS: More than half of parents felt simple analgesia was not effective enough in both cycles, this number was significantly higher in both 2nd cycle groups (C1=54%, C2C=74%, p=0.003, C2D=84%, p=0.0001). Mean worst pain reported at day 4 was similar for all groups, but the morphine groups reported higher pain at day 7 (C1 1.6, C2C 3.59, p=0.017, C2D 3.90, p=0.002). Antibiotic prescribing for children contacting a GP after surgery was significantly lower in the morphine groups (C1 24%, C2C 7%, p=0.0014, C2D 5%, p=0.0002). There was no difference in measured outcomes between the 2nd cycle groups. CONCLUSION: This service evaluation found that postoperative morphine on an as-required basis, in addition to regular paracetamol and ibuprofen, did not significantly alter initial pain profile, worst pain scores or rate of health service contact when compared to regular paracetamol and ibuprofen alone. The majority of children in this study felt additional analgesia required. Children in the morphine groups experienced significantly less pharmacological intervention when contacting the GP after surgery. PMID- 26590005 TI - Intracranial venous sinus thrombosis as a complication of otitis media in children: Critical review of diagnosis and management. AB - OBJECTIVES: Otogenic lateral sinus thrombosis (LST) is a rare intracranial complication of acute otitis media (AOM), which can lead to severe neurological sequelae and death. The aim of this study was to analyze the clinical presentation, management and outcome of LST in children, investigating a possible correlation between clinical aspects, radiological findings and anatomical variations. METHODS: At a tertiary Italian hospital, a retrospective review was conducted on the medical records of eight patients diagnosed with otogenic LST over a 3-year period. Four children were males and mean age was 4.7 years. RESULTS: All patients had a history of otitis media at diagnosis and 4/8 presented also with more than one neurological sign or symptom. Mastoiditis signs were detected in 5/8 patients. Thrombosis was diagnosed by computed tomography, enhanced magnetic resonance and magnetic resonance venography. Treatment was medical, alone or combined with surgery. Medical treatment consisted in anticoagulants eventually combined with anti-edema medication on clinical basis. Mastoidectomy and/or myringotomy+/-trans-tympanic drainage placement were performed in 7/8 patients. Complete vessel recanalization was obtained in 6/8 children after a median follow-up time of 4.8 months. No complications, neither clinical sequelae occurred. In our series, neurological signs and symptoms were significantly associated with the presence of hypoplasia of the contralateral venous sinus (p=0.029). CONCLUSION: LST is a severe condition occurring even in absence of otological signs, and despite adequate antibiotic therapy for AOM, which should be ruled out and promptly treated. A dominant neurological presentation is associated in our series with anatomical variations of cerebral sinus venous drainage patterns. This should be carefully evaluated and considered in diagnosis, treatment planning and prognosis. PMID- 26590006 TI - Combined endonasal and neurosurgical resection of a congenital teratoma with pharyngeal, intracranial and orbital extension: Case report, surgical technique and review of the literature. AB - OBJECTIVES: This study reports a patient with a large teratoma involving the oropharynx, the nasopharynx and the left orbit, with intracranial extension. This case represents one of the first reported instances of such an association. A literature review reporting head and neck teratomas with intracranial involvement is also presented. CASE REPORT: The authors describe a case of a neonate presenting with a huge teratoma causing respiratory distress due to upper airway obstruction. The child was operated on at 3 months of age with a combined neurosurgical and endonasal endoscopic-assisted approach. After more than 1-year follow-up, the child has no recurrence and no complications of surgery. DISCUSSION: This type of teratoma is very rare and surgical morbidity is common. The diagnosis may be apparent before birth, which will facilitate the planning of respiratory management. The combined neurosurgical and otolaryngologic approach for a neonatal teratoma has not previously been described. Using an endoscopic assisted approach for intranasal tumors removal in neonates and infants is a very rare surgical challenge. CONCLUSION: Large nasopharyngeal teratomas of infancy with sinonasal and intracranial extension may be managed using a combined endoscopic-assisted endonasal and neurosurgical procedure. PMID- 26590007 TI - Possible interaction of quinolone antibiotics with peptide transporter 1 in oral absorption of peptide-mimetic drugs. AB - The study investigated whether quinolone antibiotics inhibit the PEPT1-mediated uptake of its substrates. Among the quinolones examined, lomefloxacin, moxifloxacin (MFLX) and purlifloxacin significantly inhibited the uptake of PEPT1 substrate phenylalanine-Psi(CN-S)-alanine (Phe-Psi-Ala) in HeLa/PEPT1 cells to 31.6 +/- 1.3%, 27.6 +/- 2.9%, 36.8 +/- 2.2% and 32.6 +/- 1.4%, respectively. Further examination showed that MFLX was an uncompetitive inhibitor, with an IC50 value of 4.29 +/- 1.29 mm. In addition, MFLX significantly decreased the cephalexin and valacyclovir uptake in HeLa/PEPT1 cells. In an in vivo study in rats, the maximum plasma concentration (C(max)) of orally administered Phe-Psi Ala was significantly decreased in the presence of MFLX (171 +/- 1 ng/ml) compared with that in its absence (244 +/- 9 ng/ml). The area under the concentration-time curve (AUC) of orally administered Phe-Psi-Ala in the presence of MFLX (338 +/- 50 ng/ml . h) tended to decrease compared with that in its absence (399 +/- 75 ng/ml . h). The oral bioavailability of Phe-Psi-Ala in the presence and absence of MFLX was 41.7 +/- 6.2% and 49.2 +/- 9.2%, respectively. The results indicate that administration of quinolone antibiotics concomitantly with PEPT1 substrate drugs may potentially result in drug-drug interaction. PMID- 26590008 TI - Nine-Year-Old Girl With Blank Stares and Recent-Onset Diabetes. PMID- 26590009 TI - Reliability of power profiles measured on NIMO TR1504 (Lambda-X) and effects of lens decentration for single vision, bifocal and multifocal contact lenses. AB - PURPOSE: To evaluate the repeatability of power profiles measured on NIMO TR1504 (Lambda-X, Belgium) and investigate the effects of lens decentration on the power profiles for single vision (SV), bifocal (BF) and multifocal (MF) contact lenses. METHODS: Accuracy of the sphere power was evaluated using single vision BK-7 calibration glass lenses of six minus and six plus powers. Three SV and four BF/MF contact lenses - three lenses each, were measured five times to calculate the coefficients of repeatability (COR) of the instrument. The COR was computed for each chord position, lens design, prescription power and operator. One lens from each type was measured with a deliberate decentration up to +/-0.5mm in 0.1mm steps. RESULTS: For all lenses, the COR varied across different regions of the half-chord position. In general, SV lenses showed lower COR compared to the BF/MF group lenses. There were no noticeable trends of COR between prescription powers for SV and BF/MF lenses. The shape of the power profiles was not affected when lenses were deliberately decentered for all SV and PureVision MF lenses. However, for Acuvue BF lenses, the peak to trough amplitude of the power profiles flattened up to 1.00D. CONCLUSION: The COR across the half-chord of the optic zone diameter was mostly within clinical relevance except for the central 0.5mm half-chord position. COR were dependent on the lens type, whereby BF/MF group produced higher COR than SV lenses. The effects of deliberate decentration on the shape of power profiles were pronounced for lenses where the profiles had sharp transitions of power. PMID- 26590010 TI - Racial disparities of pancreatic cancer in Georgia: a county-wide comparison of incidence and mortality across the state, 2000-2011. AB - Understanding the geographic distribution of pancreatic cancer is important in assessing disease burden and identifying high-risk populations. This study examined the geographic trends of pancreatic cancer incidence, mortality, and mortality-to-incidence ratios (MIRs) in Georgia, with a special focus on racial disparities of disease. Directly age-adjusted pancreatic cancer incidence and mortality rates for Georgia counties (N = 159) were obtained for 2000-2011. Maps of county age-adjusted disease rates and MIRs were generated separately for African Americans and Caucasians. Cluster analyses were conducted to identify unusual geographic aggregations of cancer cases or deaths. Pearson correlation coefficients were calculated to examine associations between county health factors (e.g., health behaviors, clinical care, and physical environment) and pancreatic cancer incidence or mortality rates. African Americans displayed a significantly higher age-adjusted incidence (14.6/100,000) and mortality rate (13.3/100,000), compared to Caucasians. Cluster analyses identified five significant incidence clusters and four significant mortality clusters among Caucasians; one significant incidence cluster and two significant mortality clusters were identified among African Americans. Weak but significant correlations were noted between physical environment and pancreatic cancer incidence (rho = 0.16, P = 0.04) and mortality (rho = 0.18, P = 0.02) among African Americans. A disproportion burden of pancreatic cancer incidence and mortality was exhibited among African Americans in Georgia. Disease intervention efforts should be implemented in high-risk areas, such as the southwest and central region of the state. Future studies should assess health behaviors and physical environment in relationship with the spatial distribution of pancreatic cancer. PMID- 26590011 TI - ProExTM C is a useful ancillary study for grading anal intraepithelial neoplasia alone and in combination with other biomarkers. AB - Anal intraepithelial neoplasia (AIN) is a precursor to invasive anal squamous cell carcinoma. Histologic evaluation is hampered by intra- and interobserver variability. Various biomarkers have been investigated to improve the accuracy and reproducibility of diagnosis and grading, but interpretation can be challenging. ProExTM C is an antibody cocktail for proteins upregulated in cervical intraepithelial neoplasia. This study investigated ProExTM C's role alone and with p16 and Ki-67 in the diagnosis and grading of AIN. Sixty-seven anal tissue samples (22 AIN I, 25 AIN II/III, and 20 non-dysplastic) were stained for ProExTM C, Ki-67, and p16. Staining patterns were recorded and correlated with morphologic diagnoses. Considering AIN II/III vs I, full-thickness ProExTM C staining was more frequent in AIN II/III (p = 0.0373), and showed the highest sensitivity of the biomarkers. In combination with Ki-67, sensitivity was lower, but specificity for AIN II/III rose to 83%. For differentiating non-dysplasia from AIN I, negative ProExTM C staining correlated with non-dysplasia (p < 0.0001) and had the highest sensitivity (90%). In combination with Ki-67, sensitivity dropped to 80%, but specificity was high (96%). ProExTM C is useful for diagnosing and grading AIN, performing as well or better than other markers at identifying AIN II/III and non-dysplastic epithelium. PMID- 26590012 TI - Skin eruption elicited by magnesium oxide (Maglax((r)) ). PMID- 26590013 TI - Prevalence and predictive factors of depression and anxiety in patients with pancreatic cancer: a longitudinal study. AB - OBJECTIVE: It is known that depression and anxiety occur more frequently in pancreatic cancer patients than in those with other malignancies. However, few studies have assessed depression and anxiety using reliable psychiatric diagnostic tools. The purpose of this study was to determine the prevalence of depression and anxiety among pancreatic cancer patients before and 1 month after the start of anticancer treatment using reliable psychiatric diagnostic tools, and to identify factors that predict their occurrence. METHODS: Pancreatic cancer patients were consecutively recruited. Structured clinical interviews were used to determine the presence of affective disorders, anxiety disorders and adjustment disorders. Baseline interviews were performed prior to initiation of anticancer treatment, while follow-up interviews were performed 1 month after treatment was started. Medical, demographic and psychosocial backgrounds were also assessed as predictive factors. RESULTS: One hundred and ten patients participated in the baseline interview and 91 in the follow-up interview. Depression and anxiety were observed in 15 patients (13.6%) at the baseline, and 15 patients (16.5%) at the follow-up. Lack of confidants was associated with depression and anxiety at the baseline. At the baseline, sadness, lower Karnofsky Performance Status and prior experience with the death of a family member due to cancer predicted newly diagnosed depression and anxiety at the follow-up. CONCLUSION: A considerable percentage of pancreatic cancer patients experienced depression and anxiety. Multidimensional psychosocial predictive factors were found and optimal psychological care should incorporate early detection of sadness. PMID- 26590014 TI - Predictive factors for survival and correlation to toxicity in advanced Stage III non-small cell lung cancer patients with concurrent chemoradiation. AB - OBJECTIVE: Concurrent chemoradiotherapy is the standard treatment for locally advanced Stage III non-small cell lung cancer in patients with a good performance status and minimal weight loss. This study aimed to define subgroups with different survival outcomes and identify correlations with the radiation-related toxicities. METHODS: We retrospectively reviewed 381 locally advanced Stage III non-small cell lung cancer patients with a good performance status or weight loss of <10% who received concurrent chemoradiotherapy between 2004 and 2011. Three dimensional conformal radiotherapy was administered once daily, combined with weekly chemotherapy. The Kaplan-Meier method was used for survival comparison and Cox regression for multivariate analysis. Multivariate analysis was performed using all variables with P values <0.1 from the univariate analysis. RESULTS: Median survival of all patients was 24 months. Age > 75 years, the diffusion lung capacity for carbon monoxide <=80%, gross tumor volume >=100 cm(3) and subcarinal nodal involvement were the statistically significant predictive factors for poor overall survival both in univariate and multivariate analyses. Patients were classified into four groups according to these four predictive factors. The median survival times were 36, 29, 18 and 14 months in Groups I, II, III and IV, respectively (P < 0.001). Rates of esophageal or lung toxicity >=Grade 3 were 5.9, 14.1, 12.5 and 22.2%, respectively. The radiotherapy interruption rate differed significantly between the prognostic subgroups; 8.8, 15.4, 22.7 and 30.6%, respectively (P = 0.017). CONCLUSION: Severe toxicity and interruption of radiotherapy were more frequent in patients with multiple adverse predictive factors. To maintain the survival benefit in patients with concurrent chemoradiotherapy, strategies to reduce treatment-related toxicities need to be deeply considered. PMID- 26590015 TI - Development of two major resources for pea genomics: the GenoPea 13.2K SNP Array and a high-density, high-resolution consensus genetic map. AB - Single nucleotide polymorphism (SNP) arrays represent important genotyping tools for innovative strategies in both basic research and applied breeding. Pea is an important food, feed and sustainable crop with a large (about 4.45 Gbp) but not yet available genome sequence. In the present study, 12 pea recombinant inbred line populations were genotyped using the newly developed GenoPea 13.2K SNP Array. Individual and consensus genetic maps were built providing insights into the structure and organization of the pea genome. Largely collinear genetic maps of 3918-8503 SNPs were obtained from all mapping populations, and only two of these exhibited putative chromosomal rearrangement signatures. Similar distortion patterns in different populations were noted. A total of 12 802 transcript derived SNP markers placed on a 15 079-marker high-density, high-resolution consensus map allowed the identification of ohnologue-rich regions within the pea genome and the localization of local duplicates. Dense syntenic networks with sequenced legume genomes were further established, paving the way for the identification of the molecular bases of important agronomic traits segregating in the mapping populations. The information gained on the structure and organization of the genome from this research will undoubtedly contribute to the understanding of the evolution of the pea genome and to its assembly. The GenoPea 13.2K SNP Array and individual and consensus genetic maps are valuable genomic tools for plant scientists to strengthen pea as a model for genetics and physiology and enhance breeding. PMID- 26590016 TI - Effects of joint effusion on quadriceps muscles in patients with knee osteoarthritis. AB - OBJECTIVES: To evaluate the effect of knee effusion on the quadriceps muscle in patients with knee osteoarthritis (OA). DESIGN: Single-blind, randomized, controlled clinical trial. SETTING: Single medical center. PARTICIPANTS: Forty subjects with knee OA were assigned to a experimental (n = 20) or control (n = 20) group. MAIN OUTCOME MEASURES: Quadriceps torque and root mean square (RMS) values of surface electromyography (EMG) of the vastus medialis and vastus lateralis muscles were measured during a maximal isometric contraction at 60 degrees knee flexion. Thereafter, 20 mL of normal saline was injected into the knee joint of the experimental group. Quadriceps torque and RMS values were again measured. RESULTS: Five subjects did not complete the study. No significant difference in quadriceps peak torque or RMS of EMG activity was observed at baseline, pre-effusion, or post-effusion measures in either group. The experimental group showed no significant change in quadriceps peak torque or RMS of EMG activity in any period compared with the control group. CONCLUSIONS: These results demonstrate that a 20 ml joint effusion did not affect peak torque or RMS values of the quadriceps muscle in patients with knee OA. PMID- 26590017 TI - Suppression of OsKu80 results in defects in developmental growth and increased telomere length in rice (Oryza sativa L.). AB - The Ku70-Ku80 heterodimer plays a critical role in the maintenance of genomic stability in humans and yeasts. In this report, we identified and characterized OsKu80 in rice, a model monocot crop. OsKu80 forms a heterodimer with OsKu70 in yeast and plant cells, as demonstrated by yeast two-hybrid, in vivo co immunoprecipitation, and bimolecular fluorescence complementation assays. RNAi mediated knock-down T3 transgenic rice plants (Ubi:RNAi-OsKu80) displayed a retarded growth phenotype at the post-germination stage. In addition, the Ubi:RNAi-OsKu80 knock-down progeny exhibited noticeably increased telomere length as compared to wild-type rice. These results are discussed with the idea that OsKu80 plays a role in developmental growth and telomere length regulation in rice plants. PMID- 26590018 TI - A transcriptome resource for common carp after growth hormone stimulation. AB - Growth is one of the most important phenotypes for aquaculture and is thus a subject of great interest for researchers. Growth hormone (GH) is a key peptide controlling the growth of various fish species. To understand transcriptome changes induced by GH, common carp was injected with 2 MUg/g GH and tissue isolated after 6h. RNA-Seq was performed to estimate the effects of GH on gene expression in hepatic tissues. The results revealed that GH regulated the expression of multiple genes, including those related to cell growth, sexual development and immune system processes. These data show that GH affects various physiological activities by regulating gene expression, and provides a useful resource for studying common carp. PMID- 26590019 TI - De-novo assembly and characterization of Chlorella minutissima UTEX2341 transcriptome by paired-end sequencing and the identification of genes related to the biosynthesis of lipids for biodiesel. AB - Chlorella minutissima is considered to be one of the promising feedstocks for biofuels in the future. In this study, the transcriptome from the oil-rich strain UTEX2341 of C. minutissima was generated based on Illumina paired-end sequencing. Through de-novo assembly, a total of 14,905 isogenes were obtained and compacted into 6216 unigenes. A total of 80% of the unigenes were assigned with GO terms and were further subdivided into 55 sub-categories. KEGG analysis demonstrated that 37.2% of the unigenes could be accessed and mapped into 278 pathways. Interestingly, the genes that encoded key enzymes that are involved in the biosynthesis, elongation, and metabolism of fatty acids were identified, including malonyl-CoA-ACP transacylase, 3-ketoacyl-ACP synthase, 3-ketoacyl-ACP reductase, and others. Moreover, the genes that are involved in triacylglycerol (TAG) biosynthesis and metabolism were also observed. Therefore, the transcriptome analysis of C. minutissima UTEX2341 not only supplies comprehensive insight into the molecular pathway that is involved in the biosynthesis of biofuel precursors but also provides substantial valuable genomic resources to accelerate the further development and utilization of biofuels. PMID- 26590020 TI - Bringing stakeholders together for urban health equity: hallmarks of a compromised process. AB - There is a global trend towards the use of ad hoc participation processes that seek to engage grassroots stakeholders in decisions related to municipal infrastructure, land use and services. We present the results of a scholarly literature review examining 14 articles detailing specific cases of these processes to contribute to the discussion regarding their utility in advancing health equity. We explore hallmarks of compromised processes, potential harms to grassroots stakeholders, and potential mitigating factors. We conclude that participation processes often cut off participation following the planning phase at the point of implementation, limiting convener accountability to grassroots stakeholders, and, further, that where participation processes yield gains, these are often due to independent grassroots action. Given the emphasis on participation in health equity discourse, this study seeks to provide a real world exploration of the pitfalls and potential harms of participation processes that is relevant to health equity theory and practice. PMID- 26590021 TI - The tumor-targeting core-shell structured DTX-loaded PLGA@Au nanoparticles for chemo-photothermal therapy and X-ray imaging. AB - In this study, an organic-inorganic hybrid nanocomposite was synthesized by deposition of Au onto the surface of docetaxel (DTX)-loaded poly (lactide-co glycolide) (PLGA) nanoparticle cores to form the core-shell structured DTX-loaded PLGA@Au nanoparticles. The tumor targeting peptide, angiopep-2, was then introduced onto the gold nanoshell through Au-S bond, achieving drug delivery with active targeting capability. This novel system allowed combined chemotherapy and thermal therapy for cancer, resulting from DTX and gold nanoshell. The formation of tumor-targeting gold nanoshell surrounding PLGA nanocore, designated as ANG/GS/PLGA/DTX NPs, was confirmed by its surface plasmon resonance (SPR) band in the UV-Vis spectrum and by a transmission electron microscope (TEM). The release profiles of DTX from this system showed strong dependence on near infrared (NIR) laser. Compared with DTX alone, the ANG/GS/PLGA/DTX NPs afforded much higher anti-tumor efficiency without obvious toxic effects. Besides, it also showed potential X-ray imaging ability. These results demonstrated that the tumor targeting core-shell structured DTX-loaded PLGA@Au nanoparticles could be used as a multifunctional nanomaterial system with NIR-triggered drug-releasing properties for tumor-targeted chemo-photothermal therapy and theranostics. PMID- 26590022 TI - Mortality associated with anxiolytic and hypnotic drugs-A systematic review and meta-analysis. AB - BACKGROUND: Use of hypnotics or anxiolytic drugs is common and various studies have reported increased mortality with hypnotics or anxiolytic use. OBJECTIVE: To consolidate the evidence on mortality risk associated with hypnotics or anxiolytic use METHODS: Major databases were searched through April 2014 for studies reporting mortality risk associated with hypnotics or anxiolytics use. A pooled hazard ratio with 95% confidence interval was estimated using random effects model. RESULTS: After screening 2188 articles, 25 studies (24 cohort, 1 case-control) enrolling 2,350,093 patients with 59% females (age 18-102 years) were included in the meta-analysis. Hypnotics or anxiolytic users had 43% higher risk of mortality than non-users (hazard ratio, 1.43; 95% confidence interval, [1.12, 1.84]). Eight studies reported risk estimates for each gender category and pooled results from these studies showed increased risk of mortality among men (hazard ratio = 1.60, 95% confidence interval = [1.29,1.99]) and women (hazard ratio = 1.68, 95% confidence interval = [1.38, 2.04]). Pooled results from 10 studies showed higher mortality among benzodiazepine users compared to non-users (hazard ratio = 1.60, 95% confidence interval = [1.03, 2.49]), while pooled results from five studies showed an increased risk of mortality with Z-drugs use although the effect could not reach statistical significance (hazard ratio = 1.73, 95% confidence interval = [0.95, 3.16]). Significant heterogeneity was observed in the analyses and the quality of included studies was good. CONCLUSION: This meta-analysis suggests that hypnotics or anxiolytics drugs use is associated with increased mortality and hence should be used with caution. Future studies focused on underlying mechanism of increased mortality with hypnotics or anxiolytics use are required. PMID- 26590023 TI - Medical burden, body mass index and the outcome of psychosocial interventions for bipolar depression. AB - OBJECTIVE: Individuals with bipolar disorder experience a disproportionately high incidence of medical co-morbidity and obesity. These health-related problems are a barrier to recovery from mood episodes and have been linked with unfavorable responses to pharmacological treatment. However, little is known about whether and how these characteristics affect responses to adjunctive psychotherapy. METHOD: Embedded in the Systematic Treatment Enhancement Program for Bipolar Disorder was a randomized controlled trial of psychotherapy for bipolar depression comparing the efficacy of intensive psychotherapy plus pharmacotherapy with collaborative care (a three-session psycho-educational intervention) plus pharmacotherapy. We conducted a post-hoc analysis to evaluate whether medical burden and body mass index predicted and/or moderated the likelihood of recovery and time until recovery from a depressive episode among patients in the two treatments. RESULTS: Participants who had medical co-morbidity and body mass index data constituted 199 of the 293 patients in the original Systematic Treatment Enhancement Program for Bipolar Disorder trial. Higher medical burden predicted a lower likelihood of recovery from depression in both treatment conditions (odds ratio = 0.89), but did not moderate responses to intensive psychotherapy vs collaborative care. Intensive psychotherapy yielded superior recovery rates for individuals of normal body mass index (odds ratio= 2.39) compared with collaborative care, but not among individuals who were overweight or obese. CONCLUSION: Medical co-morbidity and body weight impacts symptom improvement and attention to this co-morbidity may inform the development of more personalized treatments for bipolar disorder. PMID- 26590024 TI - Diagnostic features of prematurely fused cranial sutures on plain skull X-rays. PMID- 26590025 TI - Assessment of endoscopic treatment for quadrigeminal cistern arachnoid cysts: A 7 year experience with 28 cases. AB - BACKGROUND: Quadrigeminal cistern arachnoid cysts (QACs) are difficult to treat because of their deep location and the presence of nervous and vascular structures of the pineal-quadrigeminal region. There are several surgical procedures available for QACs, including craniotomy and cyst excision or fenestration, ventriculoperitoneal or cystoperitoneal shunting, and endoscopic fenestration. There is a debate about which method is the best. OBJECTIVE: The aim of this study is to evaluate the effectiveness and safety of endoscopic ventriculocystostomy (VC) and third ventriculostomy (ETV) for treatment of arachnoid cysts of the quadrigeminal cistern. METHODS: Twenty-eight patients with QACs who had undergone endoscopic treatment in our department between August 2007 and June 2014 were studied retrospectively. Patient age at the time of endoscopic treatment ranged from 5 months to 42 years, including 25 children (14 males and 11 females) and 3 adults (one male and two females). All patients presented with hydrocephalus and did not undergo shunting prior to neuroendoscopic surgery. The first endoscopic procedures included lateral ventricle cystostomy (LVC) together with ETV in 18 cases, third ventricle cystostomy (3rd VC) together with ETV in 3 cases, and double VC (3rd VC and LVC) together with ETV in 7 cases. Data were obtained on clinical and neuroradiological presentation, indications to treat, surgical technique, complications, and the results of clinical and neuroradiological follow-up. RESULTS: Complete success was achieved in 25 (89.3 %) of 28 cases. During the follow-up period, one case underwent endoscopic reoperation with success. Shunts were implanted in 2 patients due to progression of symptoms and increase in hydrocephalus after the first endoscopic operation. Shunt independency was achieved in 26 (92.9 %) of 28 cases. The cyst was reduced in size in 22 cases (78.6 %). Postoperative images showed a reduction in the size of the ventricles in 23 cases (82.1 %). There was no surgical mortality. Subdural collection developed in 4 cases (14.3 %) and required a transient subduroperitoneal shunt in 2 cases, whereas the other 2 patients were asymptomatic and did not require any surgical treatment. CONCLUSIONS: VC together with ETV through precoronal approach is an effective treatment for symptomatic QACs and should be the initial surgical procedure. The surgical indications should include signs of elevated ICP (including increased head circumference), Parinaud syndrome, gait ataxia, and nystagmus. Also, surgery is indicated by progressive enlargement of the cyst and young children with large cysts even if the patients are asymptomatic. Contraindications to surgery include the absence of symptoms (older children and adult) and isolated developmental delay. The main criterion for successful surgery should be improvement of clinical symptoms instead of reduced cyst volume and/or ventricular size. Repeated endoscopic procedures may be considered only for the patients whose symptoms improved after first endoscopic operation. PMID- 26590026 TI - Excellent response to levetiracetam in epilepsy with Wolf-Hirschhorn syndrome. PMID- 26590027 TI - Viability of D283 medulloblastoma cells treated with a histone deacetylase inhibitor combined with bombesin receptor antagonists. AB - PURPOSE: Medulloblastoma (MB) comprises four distinct molecular subgroups, and survival remains particularly poor in patients with Group 3 tumors. Mutations and copy number variations result in altered epigenetic regulation of gene expression in Group 3 MB. Histone deacetylase inhibitors (HDACi) reduce proliferation, promote cell death and neuronal differentiation, and increase sensitivity to radiation and chemotherapy in experimental MB. Bombesin receptor antagonists potentiate the antiproliferative effects of HDACi in lung cancer cells and show promise as experimental therapies for several human cancers. Here, we examined the viability of D283 cells, which belong to Group 3 MB, treated with an HDACi alone or combined with bombesin receptor antagonists. METHODS: D283 MB cells were treated with different doses of the HDACi sodium butyrate (NaB), the neuromedin B receptor (NMBR) antagonist BIM-23127, the gastrin releasing peptide receptor (GRPR) antagonist RC-3095, or combinations of NaB with each receptor antagonist. Cell viability was examined by cell counting. RESULTS: NaB alone or combined with receptor antagonists reduced cell viability at all doses tested. BIM-23127 alone did not affect cell viability, whereas RC-3095 at an intermediate dose significantly increased cell number. CONCLUSION: Although HDACi are promising agents to inhibit MB growth, the present results provide preliminary evidence that combining HDACi with bombesin receptor antagonists is not an effective strategy to improve the effects of HDACi against MB cells. PMID- 26590028 TI - Low prevalence of hepatitis C co-infection in recently HIV-infected minority men who have sex with men in Los Angeles: a cross-sectional study. AB - BACKGROUND: Geographic and sociodemographic characterization of hepatitis C virus (HCV) transmission amongst men who have sex with men (MSM) has been limited. Our aim was to characterize HCV prevalence, risk factors for HCV co-infection, and patterns of HIV and HCV co-transmission and transmitted drug resistance mutations (DRMs) in newly HIV-diagnosed Los Angeles MSM. METHODS: Viral RNA was extracted from stored plasma samples from a Los Angeles cohort of newly diagnosed HIV infected MSM with well-characterized substance use and sexual behavioral characteristics via computer-assisted self-interviewing surveys. Samples were screened for HCV by qPCR. HCV E1, E2, core, NS3 protease and NS5B polymerase and HIV-1 protease and reverse transcriptase regions were amplified and sequenced. Phylogenetic analysis was used to determine relatedness of HCV and HIV-1 isolates within the cohort and viral sequences were examined for DRMs. RESULTS: Of 185 newly HIV-diagnosed MSM, the majority (65%) were of minority race/ethnicity and recently infected (57.8%), with median age of 28.3 years. A minority (6.6%) reported injection drug use (IDU), whereas 96 (52.8%) reported recent substance use, primarily cannabis or stimulant use. High risk sexual behaviors included 132 (74.6%) with unprotected receptive anal intercourse, 60 (33.3%) with group sex, and 10 (5.7%) with fisting. Forty-five (24.3%) had acute gonorrhea or chlamydia infection. Only 3 (1.6%) subjects had detectable HCV RNA. Amongst these subjects, HIV and HCV isolates were unrelated by phylogenetic analysis and none possessed clinically relevant NS3 or NS5B HCV DRMs. CONCLUSIONS: Prevalence of HCV co infection was low and there was no evidence of HIV-HCV co-transmission in this cohort of relatively young, predominantly minority, newly HIV-diagnosed MSM, most with early HIV infection, with high rates of high risk sexual behaviors, STI, and non-IDU. The low HCV prevalence in a group with high-risk behaviors for non-IDU HCV acquisition suggests an opportune time for targeted HCV prevention measures. PMID- 26590029 TI - Biofilm formation affects surface properties of novel bioactive glass-containing composites. AB - OBJECTIVES: This study investigated the effects of bacterial biofilm on the surface properties of novel bioactive glass (BAG)-containing composites of different initial surface roughness. METHODS: BAG (65 mol% Si; 4% P; 31% Ca) and BAG-F (61% Si; 31% Ca; 4% P; 3% F; 1% B) were synthesized by the sol-gel method and micronized (size ~0.1-10 MUm). Composites with 72wt% total filler load were prepared by replacing 15% of the silanized Sr glass with BAG, BAG-F, or silanized silica. Specimens (n=10/group) were light-cured and divided into 4 subgroups of different surface roughness by wet polishing with 600 and then up to 1200, 2400, or 4000 grit SiC. Surface roughness (SR), gloss, and Knoop microhardness were measured before and after incubating in media with or without a Streptococcus mutans (UA 159) biofilm for 2 weeks. Results were analyzed with ANOVA/Tukey's test (alpha=0.05). RESULTS: The SR of the BAG-containing composites with the smoothest surfaces (2400/4000 grit) increased in media or bacteria; the SR of the roughest composites (600 grit) decreased. The gloss of the smoothest BAG containing composites decreased in bacteria and media-only, but more in media alone. The microhardness of all of the composites decreased with exposure to media or bacteria, with BAG-containing composites affected more than the control. SIGNIFICANCE: Exposure to bacterial biofilm and its media produced enhanced roughness and reduced gloss and surface microhardness of highly polished dental composites containing a bioactive glass additive, which could affect further biofilm formation, as well as the esthetics, of restorations made from such a material. PMID- 26590030 TI - In vitro evaluation of adhesive characteristics of 4-META/MMA-TBB resin with organic filler. AB - OBJECTIVES: A commercial restorative material, BondfillSB (BF), is a modification of 4-META/MMA-TBB resin cement. BF uses a self-etching primer and added pre polymerized organic fillers. We compared BF with another self-etching system, EasyBond (EB), in shear bond strength, bonded interface characteristics to human dentin and contraction gap when used in bulk-filling. METHODS: Shear bond strength of BF and EB + Z100 (Z), bonded by different experience-level operators, was evaluated. Bonded interfaces were characterized by SEM, AFM, and AFM based nano-indentation. Contraction gaps (CG) at 0h and 24h after polymerization were evaluated for BF or EB bulk filled class I cavities. To meet the clinical recommendation, BF's powder was replaced by experimental radioopaque powder (BFO) for the CG study. EB was used with Z (EBZ) or with a resin marketed for bulk-fill base (SureFil-SDR-flow (EBSF)). RESULTS: Shear bond strengths (Mean +/- Standard Deviation (S.D.)) of BF (37.4 +/- 2.6 MPa; n=36) were higher and less variable than EBZ (18.2 +/- 7.6 MPa; n=36) (p<0.0001, One-way ANOVA). Weibull characteristic strength (eta) differed significantly between materials (p<0.0001) but not between operators (p=0.90). EBZ often had non-uniform interfaces and a wider band of reduced elastic modulus (E) of greater than 20 MUm across the interface. BF had uniform interfaces and a smaller width of affected dentin under the interface (~1 MUm). There was a difference in dentin-E between EBZ and BF up to 9 MUm from the interface (mixed-effects model; P=0.03). A stratified linear regression model used for CG. EBSF and BFO showed significantly smaller CG than EBZ at time 0. None of three combinations showed any significant change between 0h-CG and 24h-CG. SIGNIFICANCE: BF possessed bonding characteristics required to serve as a restorative. PMID- 26590031 TI - Low rate of cetuximab hypersensitivity reactions in Northeast Tennessee: An Appalachian effect? AB - PURPOSE: Cetuximab is a monoclonal antibody with a known risk of hypersensitivity reactions. Early studies showed hypersensitivity reaction rates of 3%, but there appears to be a higher incidence in the southeastern United States. To confirm the findings from nearby institutions that cetuximab-associated hypersensitivity reactions occur in approximately 20% of patients in the southeastern United States. METHODS: A retrospective chart review was conducted at Johnson City Medical Center in Johnson City, Tennessee. Each patient's first infusion was analyzed for hypersensitivity reaction, as well as for demographic information such as allergy and smoking history, pre-medications, and malignancy type. RESULTS: Data from the first infusion of cetuximab were collected for a total of 71 patients with various malignancies. The overall rate of grade 3 or higher hypersensitivity reaction was 1.4%, and total rate of hypersensitivity reaction was 8.5%. These findings more closely correlate to the early clinical trials and package insert. Both severe (p = 0.001) and any-grade (p = 0.002) hypersensitivity reaction occurred less frequently in one Southeastern Appalachian medical center compared to academic medical centers directly to the east and west. CONCLUSIONS: Patients in southern Appalachia may be less likely to develop cetuximab hypersensitivity reactions compared to surrounding areas in the Southeastern U.S. These results lend support to the theory that exposure to lonestar ticks (Amblyomma americanum) may be responsible for the development of IgE antibodies to cetuximab that cause hypersensitivity reactions. The development of quick and reliable bedside predictors of cetuximab hypersensitivity reactions may aid clinicians considering the use of cetuximab. PMID- 26590032 TI - Interleukin-6-dependent influence of nociceptive sensory neurons on antigen induced arthritis. AB - INTRODUCTION: Interleukin-6 (IL-6) is an important mediator of inflammation. In addition to cells involved in inflammation, sensory nociceptive neurons express the IL-6 signal-transducer glycoprotein 130 (gp130). These neurons are not only involved in pain generation but also produce neurogenic inflammation by release of neuropeptides such as calcitonin gene-related peptide (CGRP). Whether IL-6 activation of sensory neurons contributes to the induction of inflammation is unknown. This study explored whether the action of IL-6 on sensory neurons plays a role in the generation of neurogenic inflammation and arthritis induction. METHODS: In SNS-gp130(-/-) mice lacking gp130 selectively in sensory neurons and appropriate control littermates (SNS-gp130(flox/flox)), we induced antigen induced arthritis (AIA), and assessed swelling, histopathological arthritis scores, pain scores, expression of CGRP in sensory neurons, serum concentrations of CGRP and cytokines, and the cytokine release from single cell suspensions from lymph nodes and spleens. In wild-type mice CGRP release was determined during development of AIA and, in cultured sensory neurons, upon IL-6 stimulation. RESULTS: Compared to SNS-gp130(flox/flox) mice SNS-gp130(-/-) mice showed significantly weaker initial swelling, reduced serum concentrations of CGRP, IL 6, and IL-2, no inflammation-evoked upregulation of CGRP in sensory neurons, but similar histopathological arthritis scores during AIA. During the initial swelling phase of AIA, CGRP was significantly increased in the serum, knee and spleen. In vitro, IL-6 augmented the release of CGRP from cultured sensory neurons. Upon antigen-specific restimulation lymphocytes from SNS-gp130(-/-) mice released more interleukin-17 and interferon-gamma than lymphocytes from SNS gp130(flox/flox) mice. In naive lymphocytes from SNS-gp130(flox/flox) and SNS gp130(-/-) mice CGRP reduced the release of IL-2 (a cytokine which inhibits the release of interleukin-17 and interferon-gamma). CONCLUSIONS: IL-6 signaling in sensory neurons plays a role in the expression of arthritis. Selective deletion of gp130 signaling in sensory neurons reduces the swelling of the joint (most likely by reducing neurogenic inflammation) but increases some proinflammatory systemic cellular responses such as the release of interleukin-17 and interferon gamma from lymphocytes upon antigen-specific restimulation. Thus IL-6 signaling in sensory neurons is not only involved in pain generation but also in the coordination of the inflammatory response. PMID- 26590033 TI - Modeling cell response to low doses of photon irradiation--Part 1: on the origin of fluctuations. AB - Intra- and inter-individual variability is a well-known aspect of biological responses of cells observed at low doses of radiation, whichever the phenomenon considered (adaptive response, bystander effects, genomic instability, etc.). There is growing evidence that low-dose phenomena are related to cell mechanisms other than DNA damage and misrepair, meaning that other cellular structures may play a crucial role. Therefore, in this study, a series of calculations at low doses was carried out to study the distribution of specific energies from different irradiation doses (3, 10 and 30 cGy) in targets of different sizes (0.1, 1 and 10 MUm) corresponding to the dimensions of different cell structures. The results obtained show a strong dependence of the probability distributions of specific energies on the target size: targets with dimensions comparable to those of the cell show a Gaussian-like distribution, whereas very small targets are very likely to not be hit. A statistical analysis showed that the level of fluctuations in the fraction of aberrant cells is only related to the fraction of aberrant cells and the number of irradiated cells, regardless of, for instance, the heterogeneity in cell response. PMID- 26590034 TI - Speckle tracking in patients with atypical Takotsubo syndrome: seek, and ye shall find! PMID- 26590035 TI - Editorial Comment. PMID- 26590036 TI - Reply. PMID- 26590037 TI - Editorial Comment. PMID- 26590038 TI - Editorial Comment. PMID- 26590039 TI - Editorial Comment. PMID- 26590040 TI - Editorial Comment. PMID- 26590041 TI - Reply. PMID- 26590042 TI - Where Do Sexual Dysfunctions Fit into the Meta-Structure of Psychopathology? A Factor Mixture Analysis. AB - Sexual dysfunctions have not been included in research on the broad structure of psychopathology to date, despite their high prevalence and impact on quality of life. Preliminary research has shown that they may fit well in an internalizing spectrum, alongside depressive and anxiety disorders. This study compared dimensional and categorical models of the relationships between depression, anxiety, and sexual problems with "hybrid" models (i.e., factor mixture analyses), which combine dimensional and categorical components simultaneously. Participants (n = 1000) were selectively recruited to include a range of symptom levels, and completed a series of self-report measures online. A hybrid model that combined dimensional and categorical components fit best for men and women. Taken together, the results are consistent with a nosology that explicitly recognizes the relationships between the diagnostic chapters of depressive and anxiety disorders and sexual dysfunctions, but still maintains discrete diagnoses, which is compatible with the structure of the DSM-5 and upcoming ICD 11. PMID- 26590043 TI - The effect of video review of resident laparoscopic surgical skills measured by self- and external assessment. AB - BACKGROUND: Video review of surgical skills is an educational modality that allows trainees to reflect on self-performance. The purpose of this study was to determine whether resident and attending assessments of a resident's laparoscopic performance differ and whether video review changes assessments. METHODS: Third year surgery residents were invited to participate. Elective laparoscopic procedures were video recorded. The Global Operative Assessment of Laparoscopic Skills evaluation was completed immediately after the procedure and again 7 to 10 days later by both resident and attending. Scores were compared using t tests. RESULTS: Nine residents participated and 76 video reviews were completed. Residents scored themselves significantly lower than the faculty scores both before and after video review. Resident scores did not change significantly after video review. CONCLUSIONS: Attending and resident self-assessment of laparoscopic skills differs and subsequent video review does not significantly affect Global Operative Assessment of Laparoscopic Skills scores. Further studies should evaluate the impact of video review combined with verbal feedback on skill acquisition and assessment. PMID- 26590044 TI - A hierarchical task analysis of cricothyroidotomy procedure for a virtual airway skills trainer simulator. AB - BACKGROUND: Despite the critical importance of cricothyroidotomy (CCT) for patient in extremis, clinical experience with CCT is infrequent, and current training tools are inadequate. The long-term goal is to develop a virtual airway skills trainer that requires a thorough task analysis to determine the critical procedural steps, learning metrics, and parameters for assessment. METHODS: Hierarchical task analysis is performed to describe major tasks and subtasks for CCT. A rubric for performance scoring for each task was derived, and possible operative errors were identified. RESULTS: Time series analyses for 7 CCT videos were performed with 3 different observers. According to Pearson's correlation tests, 3 of the 7 major tasks had a strong correlation between their task times and performance scores. CONCLUSIONS: The task analysis forms the core of a proposed virtual CCT simulator, and highlights links between performance time and accuracy when teaching individual surgical steps of the procedure. PMID- 26590045 TI - Successful resolution of stromal keratitis and uveitis using canakinumab in a patient with chronic infantile neurologic, cutaneous, and articular syndrome: a case study. AB - BACKGROUND: Cryopyrin-associated periodic syndrome (CAPS) is a group of rare autoinflammatory diseases, and of these, chronic infantile neurologic, cutaneous, and articular/neonatal-onset multisystem inflammatory disease (CINCA/NOMID) syndrome has the most severe phenotype. Canakinumab, a monoclonal antibody that targets interleukin-1beta, has been shown to be an effective treatment for resolving systemic inflammation. However, its efficacy for treating ophthalmic symptoms of this disorder remains unclear. FINDINGS: A 64-year-old female reported episodes of nonpruritic urticaria, fever, aseptic meningitis, and bilateral sensorineural deafness. Her son had experienced similar symptoms. She was initially referred for ophthalmologic treatment for an infectious corneal ulcer. Examination of her right eye by slit lamp biomicroscopy showed diffuse conjunctival injection, corneal infiltrates, a corneal ulcer, and hypopyon. She was therefore treated aggressively with topical and systemic antibiotics in addition to antifungal medications. However, this was ineffective. Genetic analysis detected the heterozygous germline p.Asp303Asn mutation in the NLRP3 gene in both our patient and her son. She was therefore diagnosed with CINCA/NOMID syndrome based on her clinical manifestations. All of the patient's physical and ophthalmic symptoms were resolved within a few days after the initiation of canakinumab treatment. During an 18-month follow-up period, no adverse events or severe infections were observed. CONCLUSIONS: Our case report indicates that canakinumab is effective not only for the treatment of systemic inflammation but also for treating ophthalmic involvement, such as recurrent stromal keratitis and anterior uveitis. PMID- 26590046 TI - Uveitic band keratopathy: child and adult. AB - BACKGROUND: Calcified band keratopathy is a chronic degenerative disease characterized by the deposition of gray to white opacity in superficial layers of the cornea that typically develops over months or years. It is associated with a variety of conditions, including chronic uveitis. PURPOSE: The objective of this study is to assess visual acuity and corneal changes in patients with band keratopathy secondary to uveitis who underwent phototherapeutic keratectomy (PTK). SETTING: The place where this study was performed was in the Department of Ophthalmology and Visual Sciences, Federal University of Sao Paulo. DESIGN: This is a retrospective study. METHODS: Patients with uveitic band keratopathy were submitted to PTK. The PTK was performed using Allegreto Wave EX500, with the ablation area of 6 mm. RESULTS: Twelve patients (13 eyes) diagnosed with band keratopathy secondary to chronic uveitis were analyzed. Of the 12 patients, 8 patients were female (66 %), aged 22 years (7-53 years). From the 12 patients (13 eyes) evaluated in this study, only one patient (one eye) did not have visual improvement, due to epithelial deposits 2 weeks after PTK, and all the others benefited with the procedure. In the children group, all eyes had visual improvement, and quantitatively speaking, the children had a more significant improvement than adults. CONCLUSIONS: PTK is a safe and effective procedure even for children. However, the improvement in visual acuity was restricted due to other ocular changes secondary to uveitis, such as cataract and retinal changes, or even the corneal irregularity. PMID- 26590047 TI - Impairment of Interleukin-17A Expression in Canine Visceral Leishmaniosis is Correlated with Reduced Interferon-gamma and Inducible Nitric Oxide Synthase Expression. AB - Dogs are the primary urban reservoir of Leishmania infantum and play a crucial role in the transmission of this parasite to man via sandflies. The spleen and liver are the main target organs of L. infantum infection, but few studies have evaluated the immune response to this infection in the canine liver. To identify the immunological mediators involved in resistance and/or susceptibility to canine visceral leishmaniosis (CVL), we selected 21 dogs naturally infected by L. infantum and classified as asymptomatic or symptomatic. Immunological parameters were analysed and correlations with clinical signs were determined. Symptomatic dogs showed higher numbers of parasites and less leucocyte infiltration in the liver compared with asymptomatic dogs. The progression of this disease was characterized not only by the down regulation of T helper (Th) 1-related cytokines, such as interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha, but also by the down regulation of genes encoding interleukin (IL)-17A, inducible nitric oxide synthase (iNOS) and IL-10 in the spleen and liver in symptomatic dogs compared with asymptomatic dogs. Importantly, IL-17A gene transcription level was positively correlated with mRNA expression for iNOS and IFN-gamma. Th1- and Th17-related cytokines therefore appear to play a role in restricting parasite growth via iNOS activation and decrease susceptibility of dogs to CVL. PMID- 26590048 TI - A qualitative study to assess the potential of the human papillomavirus vaccination programme to encourage under-screened mothers to attend for cervical screening. AB - BACKGROUND: Coverage of the UK National Health Service Cervical Screening Programme is declining. Under-screened women whose daughters participate in the human papillomavirus (HPV) vaccination programme could be stimulated to attend. We investigated whether factors associated with the vaccination programme changed mothers' intentions for future screening. METHODS: Questionnaires were sent to mothers of girls aged 12-13 years across two North West primary care trusts (n=2387) to assess the effect of the HPV vaccination programme on screening intentions. This identified mothers whose intentions had changed. Consent was sought to contact them for a semi-structured interview to discuss their screening intentions. Key themes were identified using framework analysis. RESULTS: 97/606 women responding to the questionnaire had changed their views about cervical screening. 23 women were interviewed, 10 of whom expressed a positive change and 13 no change. Most had discussed the vaccine information, including cervical screening, with their daughters. Mothers who made a positive change decision recognised their daughters' risk of cervical cancer, the need for future screening, and the importance of their own example. In this way daughters became 'significant others' in reinforcing their mothers' cervical screening motivation. CONCLUSIONS: A daughter's invitation for HPV vaccination instigates a reassessment of cervical screening intention in some under-screened mothers. PMID- 26590049 TI - Spatial negative priming: In touch, it's all about location. AB - Spatial negative priming (SNP) refers to the finding that responses to stimuli that are presented from previously ignored locations are slowed relative to responses to stimuli presented from previously unstimulated locations. To date, this effect has been demonstrated in vision, audition, and touch. Importantly, however, the cognitive processes involved differ between vision and audition. Although SNP is attributable to feature mismatch in the auditory modality, it is primarily caused by response inhibition in vision. To date, the locus of SNP in touch has not been established, though recently it has been shown that tactile SNP is not modulated by feature mismatch. Here, we demonstrate that in touch, as compared to vision and audition, SNP is more sensitive to the location features and not solely to the response and stimulus features. Thus, in stark contrast to identity-based negative priming, in which responses to previously ignored stimuli (based on the stimulus identity) can be explained by the same mechanisms in all three sensory modalities, SNP would appear to be caused by different processes in each sensory modality, thus suggesting that the processing of the spatial properties of distractors is modality-specific. PMID- 26590051 TI - Risk factors associated with relapse or infectious complications in Japanese patients with microscopic polyangiitis. AB - BACKGROUND: The prevention of relapse and infection complications during remission maintenance therapy is required to improve the prognosis of patients with microscopic polyangiitis (MPA) showing rapidly progressive glomerulonephritis (RPGN). The clinicopathological characteristics of patients with ANCA-positive MPA were examined to determine the risk factors for relapse or infectious complications after remission induction therapy. PATIENTS AND METHODS: The study population consisted of 52 patients diagnosed as ANCA-positive MPA showing RPGN from 2002 to 2012, after publication of the Japanese guideline for RPGN. The clinicopathological findings were examined between the presence and absence of relapse or infectious complications. RESULTS: The value of vasculitis damage index (VDI) was high for the relapse group and VDI value was identified as the leading factor associated with relapse [hazard ratio (HR) 3.36, 95 % confidence interval (CI) 1.58-7.12, P < 0.01]. On the other hand, the values of Birmingham Vasculitis Activity Score, clinical grade category of RPGN at diagnosis, and VDI at remission were high in the infectious group. Furthermore, clinical grade category of RPGN was the leading factor associated with infectious complications (HR 5.30, 95 % CI 1.41-19.9, P = 0.01). CONCLUSION: The disease activity at diagnosis and severity of organ damage at remission were associated with relapse and infectious complications during remission maintenance therapy and infectious complication affected kidney survival and all-cause mortality in patients with ANCA-positive MPA exhibiting RPGN. PMID- 26590050 TI - Auditory distance perception in humans: a review of cues, development, neuronal bases, and effects of sensory loss. AB - Auditory distance perception plays a major role in spatial awareness, enabling location of objects and avoidance of obstacles in the environment. However, it remains under-researched relative to studies of the directional aspect of sound localization. This review focuses on the following four aspects of auditory distance perception: cue processing, development, consequences of visual and auditory loss, and neurological bases. The several auditory distance cues vary in their effective ranges in peripersonal and extrapersonal space. The primary cues are sound level, reverberation, and frequency. Nonperceptual factors, including the importance of the auditory event to the listener, also can affect perceived distance. Basic internal representations of auditory distance emerge at approximately 6 months of age in humans. Although visual information plays an important role in calibrating auditory space, sensorimotor contingencies can be used for calibration when vision is unavailable. Blind individuals often manifest supranormal abilities to judge relative distance but show a deficit in absolute distance judgments. Following hearing loss, the use of auditory level as a distance cue remains robust, while the reverberation cue becomes less effective. Previous studies have not found evidence that hearing-aid processing affects perceived auditory distance. Studies investigating the brain areas involved in processing different acoustic distance cues are described. Finally, suggestions are given for further research on auditory distance perception, including broader investigation of how background noise and multiple sound sources affect perceived auditory distance for those with sensory loss. PMID- 26590052 TI - Effects of cyclophosphamide on the prognosis of Japanese patients with renal vasculitis associated with anti-neutrophil cytoplasmic antibody-positive microscopic polyangiitis. AB - BACKGROUND: The aim of this study was to determine the efficacy of cyclophosphamide (CY) on anti-neutrophil cytoplasmic antibody (ANCA)-positive microscopic polyangiitis (MPA) with renal involvement in Japanese patients. METHODS: Eighty-two patients with newly diagnosed ANCA-positive MPA were enrolled in this retrospective study. Patients were divided into two groups based on whether they received combination therapy with a corticosteroid (CS) plus CY (CY group) or CS alone or with other therapies (non-CY group). The primary outcome was defined as the combination of death and end-stage renal disease (ESRD). RESULTS: The CY and non-CY groups included 29 and 53 patients, respectively. In the non-CY group, 31 patients were treated with CS alone, and 22 with a combination of CS and other therapeutics. The percentage of males and mean Birmingham vasculitis activity scores were higher in the CY group than those in the non-CY group, but other factors such as age, serum creatinine, serum albumin, or CRP at baseline were equivalent in the two groups. No differences were observed in remission rates using induction therapy for the two groups. However, the survival rate 5 years after induction therapy was lower in the CY group than in the non-CY group (0.50 vs. 0.73; P = 0.041), although the hazard ratio of CY for the primary outcome adjusted for all confounding factors was 1.321 [95 % confidence interval (CI), 0.662-2.637; P = 0.171]. CONCLUSIONS: CY may not have an additive effect on induction therapy with CS for Japanese patients with renal vasculitis associated with ANCA-positive MPA. PMID- 26590054 TI - Erratum to: Visceral obesity stimulates anaphase bridge formation and spindle assembly checkpoint dysregulation in radioresistant oesophageal adenocarcinoma. PMID- 26590053 TI - Emergency peripartum hysterectomy: our experience. AB - PURPOSE: To investigate the incidence of and reasons for emergency peripartum hysterectomy (EPH) between 2009 and 2013 in our hospital, one of the three hospitals with the highest rates of delivery in Turkey. METHODS: A retrospective study. Seventy-six peripartum hysterectomies were evaluated. We compared the modes of delivery and examined whether bilateral internal iliac artery ligation was performed. RESULTS: The incidence of EPH was 0.77 in 1000. The majority of cases involved multiparity, uterine rupture, placenta praevia, or placental invasion abnormalities. The most frequent reason for EPH was uterine atony (64.5 %). There was no statistically significant relationship with mode of delivery; however, the complication rate and requirement for fresh frozen plasma were significantly (p < 0.01) related to whether bilateral internal iliac artery ligation was performed. CONCLUSION: Uterine atony was the most common indication for EPH. The most important step to avoid performing EPH is to calculate patients' risks for postpartum bleeding. Postpartum haemorrhage may not be preventable, but when it happens, obstetricians must be prepared to perform EPH, and in high-risk patients, to perform internal iliac artery ligation. PMID- 26590055 TI - Dynamics of difenoconazole and propiconazole residues on pomegranate over 2 years under field conditions. AB - Residue dynamics of difenoconazole and propiconazole on pomegranate was studied after application at the recommended and double doses of 125 and 250 g active ingredient (a.i.) ha(-1) during August-October 2012. The study was repeated during the same period in 2013. QuEChERS method, in conjunction with gas chromatography (GC), was used for analysis of the fungicides after carrying out the method validation. The recoveries of the fungicides from pomegranate and soil were between 80.3 and 96.2 %; the limit of detection (LOD) and limit of quantification (LOQ) were 0.016 and 0.05 mg kg(-1), respectively. The uncertainties of measurement were between 9.7 and 16.3 %. The initial residue deposits of difenoconazole were 0.875 and 1.205 mg kg(-1) from treatment at the recommended dose and 1.54 and 1.672 mg kg(-1) from treatment at the double dose from the first- and second-year studies. Propiconazole residues were 0.663 and 0.864 mg kg(-1) from recommended dose treatments and 1.474 and 2.045 mg kg(-1) from double dose treatments from the first- and second-year studies. The half lives of degradation of difenoconazole were 6.4-8.4 days and propiconazole 7.9 8.5 days over the 2 years. Residues of difenoconazole and propiconazole remained on the pomegranate fruit surface and did not move to the edible part (aril). The pre-harvest intervals (PHIs), the time required for the residues to reduce below their respective EU maximum residue limits (MRLs), were 25.4 and 30.8 days for difenoconazole and 33.3 and 43.8 days for propiconazole from treatments at the recommended and double doses, respectively. Keeping in view consumer safety, the longer PHI from the two studies has been selected. PMID- 26590056 TI - Relevance of the Parana River hydrology on the fluvial water quality of the Delta Biosphere Reserve. AB - The increasing frequency of extreme events in large rivers may affect not only their flow, but also their water quality. In the present study, spatial and temporal changes in fluvial physico-chemical variables were analyzed in a mega river delta during two extreme hydrological years (La Nina-El Nino) and related to potential explanatory factors. Basic water variables were evaluated in situ at 13 points (distant 2-35 km from each other) in watercourses of the Delta Biosphere Reserve (890 km(2)) in the Lower Parana River (Argentina) in nine surveys (October 2008-July 2010) without meteorological tides. Samples for laboratory analyses were collected from each main river. Multivariate tests by permutations were applied. The period studied was influenced by a drought, within a long period dominated by low flows combined with dry weather and wildfires, and a large (10 years of recurrence) and prolonged (7 months) flood. The hydrological phase, followed by the season and the hydrological year (according to the ENSO event) were the principal explanatory factors of the main water quality changes, whereas the drainage sub-basin and the fluvial environment (river or stream) were secondary explanatory factors. During the drought period, conductivity, turbidity, and associated variables (e.g., major ions, silicon, and iron concentrations) were maximal, whereas real color was minimal. In the overbanking flood phase, pH and dissolved oxygen concentration were minimal, whereas real color was maximal. Dissolved oxygen saturation was also low in the receding flood phase and total major ion load doubled after the arrival of the overbanking stage. The water quality of these watercourses may be affected by the combination of several influences, such as the Parana River flow, the pulses with sediments and solutes from the Bermejo River, the export of the Delta floodplain properties mainly by the flood, the season, and the saline tributaries to the Lower Parana River. The high influence of the hydrology of this large river on the Delta fluvial water quality emphasizes the relevance of changes in its flow regime in recent decades, such as the seasonality attenuation. Considering that the effects of extreme events differ among and within fluvial systems, specific ecohydrological evaluations and powerful appropriate statistics are key tools to gain knowledge on these systems and to provide bases for suitable management measures in a scenario of climate change and increasing human alterations and demands. PMID- 26590057 TI - Soil microbial response to tetracycline in two different soils amended with cow manure. AB - High amounts of antibiotics are introduced in the soil environment by manure amendment, which is the most important spreading route in soil, with a potential ecotoxicological impact on the environment. The objectives of this study were (a) to assess the tetracycline (Tc) bioavailability in a clay and in a sandy soil, and (b) to evaluate the effects of the Tc and cow manure on the structure and function of soil microbial communities. Clay and sandy soils were spiked with Tc at the concentrations of 100 and 500 mg Tc kg(-1) soil, and were amended or not with cow manure. The clay soil showed greater Tc sorption capacity and bioavailable Tc was between 0.157 and 4.602 mg kg(-1) soil. Tc dose and time dependent effects on soil microbial communities were investigated by fluorescein diacetate activity, phospholipid fatty acids analysis, as well as by Biolog community level physiological profile and microbial counts at 2, 7 and 60 days after Tc and/or manure addition. The added Tc caused detrimental effect on the microbial activity and structure, particularly in the short term at the highest concentrations. However, the Tc effect was transient' it decreased after 7 days and totally disappeared within 60 days. Cow manure shifted the bacterial structure in both soils, increased the microbial activity in clay soil and contributed to recover the microbial structure in Tc-spiked manure treatments. PMID- 26590058 TI - Measurements of nitrous acid (HONO) in urban area of Shanghai, China. AB - Nitrous acid (HONO), as a precursor of the hydroxyl radical (OH), plays an important role in the photochemistry of the troposphere, especially in the polluted urban atmosphere. A field campaign was conducted to measure atmospheric HONO concentration and that of other pollutants (such as NO2 and particle mass concentration) in the autumn of 2009 at Shanghai urban areas. HONO mixing ratios were simultaneously measured by three different techniques: long path absorption photometer (LOPAP), differential optical absorption spectroscopy (DOAS) and chemical ionization mass spectrometer (CIMS). The measurements showed that the mixing ratios of HONO were highly variable and depended strongly on meteorological parameters. The HONO levels ranged from 0.5 to 7 ppb with maximum values during early morning and minimum levels during late afternoon. The three instruments reproduced consistent diurnal pattern of HONO concentrations with higher concentration during the night compared to the daylight hours. Comparison of HONOLOPAP/HONOCIMS ratios during daytime and nighttime periods exhibited a non systematic disagreement of 0.93 and 1.16, respectively. This would indicate different chemical compositions of sampled air for the LOPAP and the CIMS instruments during daytime and nighttime periods, which have possibly affected measurements. Mean HONO concentration reported by LOPAP was 33 % higher than by DOAS on the whole period with no significant difference between daytime and nighttime periods. This revealed a systematic deviation from both instruments. The present data provides complementary information of HONO ambient levels in the atmosphere of Shanghai urban areas. PMID- 26590059 TI - Surfactants in aquatic and terrestrial environment: occurrence, behavior, and treatment processes. AB - Surfactants belong to a group of chemicals that are well known for their cleaning properties. Their excessive use as ingredients in care products (e.g., shampoos, body wash) and in household cleaning products (e.g., dishwashing detergents, laundry detergents, hard-surface cleaners) has led to the discharge of highly contaminated wastewaters in aquatic and terrestrial environment. Once reached in the different environmental compartments (rivers, lakes, soils, and sediments), surfactants can undergo aerobic or anaerobic degradation. The most studied surfactants so far are linear alkylbenzene sulfonate (LAS), quaternary ammonium compounds (QACs), alkylphenol ethoxylate (APEOs), and alcohol ethoxylate (AEOs). Concentrations of surfactants in wastewaters can range between few micrograms to hundreds of milligrams in some cases, while it reaches several grams in sludge used for soil amendments in agricultural areas. Above the legislation standards, surfactants can be toxic to aquatic and terrestrial organisms which make treatment processes necessary before their discharge into the environment. Given this fact, biological and chemical processes should be considered for better surfactants removal. In this review, we investigate several issues with regard to: (1) the toxicity of surfactants in the environment, (2) their behavior in different ecological systems, (3) and the different treatment processes used in wastewater treatment plants in order to reduce the effects of surfactants on living organisms. PMID- 26590060 TI - Side effects of Bacillus thuringiensis var. kurstaki on the hymenopterous parasitic wasp Trichogramma chilonis. AB - Most of the detrimental effects of using conventional insecticides to control crop pests are now well identified and are nowadays major arguments for replacing such compounds by the use of biological control agents. In this respect, the bacterium Bacillus thuringiensis var. kurstaki and Trichogramma (Hymenoptera: Trichogrammatidae) parasitic wasp species are both effective against lepidopterous pests and can actually be used concomitantly. In this work, we studied the potential side effects of B. thuringiensis var. kurstaki on Trichogramma chilonis females. We first evidenced an acute toxicity of B. thuringiensis on T. chilonis. Then, after ingestion of B. thuringiensis at sublethal doses, we focused on life history traits of T. chilonis such as longevity, reproductive success and the time spent on host eggs patches. The reproductive success of T. chilonis was not modified by B. thuringiensis while a significant effect was observed on longevity and the time spent on host eggs patches. The physiological and ecological meanings of the results obtained are discussed. PMID- 26590061 TI - Inhibition of the growth of cyanobacteria during the recruitment stage in Lake Taihu. AB - Microcystis is the dominant algal bloom genus in Lake Taihu. Thus, controlling the recruitment and growth of Microcystis is the most crucial aspect of solving the problem of algal blooms. Different concentrations (0.025, 0.05, and 0.1 g L( 1)) of tea extract were used to treat barrels of lake water at the recruitment stage of cyanobacteria. There was an inhibitory effect on algal growth in all treatment groups. The inhibitory effect on cyanobacteria was stronger than on other algae. The metabolic activity of cells in the treatment groups was significantly enhanced compared to the control, as an adaptation to the stress caused by tea polyphenols. The photosynthetic activity diminished in the treatment groups and was barely detected in the 0.05 and 0.1 g L(-1) treatments. The levels of reactive oxygen species increased substantially in treated cells with the algal cells experiencing oxidative damage. The effect of tea on zooplankton was also studied. The number of Bosmina fatalis individuals did not change significantly in the 0.025 and 0.05 g L(-1) treatments. These results suggested that the application of tea extracts, during the recruitment stage of blue-green algae, suppressed the recruitment and growth of cyanobacteria, thus offering the potential to prevent cyanobacterial blooms. PMID- 26590062 TI - Chlordecone disappearance in tissues of growing goats after a one month decontamination period--effect of body fatness on chlordecone retention. AB - Chlordecone (CLD) is an organochlorine pesticide whose extended use led to the contamination of at least 20% of agricultural soils from the French West Indies. Livestock reared on polluted areas are involuntary contaminated by CLD and their level of contamination may exceed the threshold values set by the European Union. Thus, characterizing the CLD behaviour in farm animals appear as a real issue in terms of food safety for local populations. The aim of this experiment was (i) to characterize the CLD disappearance in various tissues after exposure cessation and (ii) to evaluate the potential effect of body fatness on this process. Two groups of eight growing goats were submitted to either a basal diet or a high energy diet for 50 days before being intravenously contaminated with 1 mg CLD kg( 1) body weight. Two days after CLD contamination, half of the kids of each experimental group were slaughtered in order to determine pollutant levels in the serum, liver, adipose tissues, and empty carcass. The remaining animals were submitted to a 30-day decontamination period before slaughtering and measurements as described above. The implemented nutritional plan resulted in both groups of kids with significant differences in terms of body fatness. CLD was mainly concentrated in the liver of animals as described in the literature. It was found also in kids' empty carcass and adipose tissues; however its levels in the empty carcass (muscles and bones) were unexpected since they were higher than in fat. These results indicate that the lipophilic pollutant CLD is found mainly in liver but also in muscles and fat. Concerning the animals' depuration, a 30-d decontamination period was sufficient to observe a decrease of CLD levels by more than 75% in both experimental groups and neither CLD concentrations nor CLD amounts were significantly affected by kids' body fatness. PMID- 26590063 TI - Removal of elemental mercury by TiO2doped with WO3 and V2O5 for their photo- and thermo-catalytic removal mechanisms. AB - The catalytic removal of Hg(0) was investigated to ascertain whether the catalysts could simultaneously possess both thermo- and photo-catalytic reactivity. The immobilized V2O5/TiO2 and WO3/TiO2 catalysts were synthesized by sol-gel method and then coated on the surface of glass beads for catalytic removal of Hg(0). They were also characterized by SEM, BET, XRD, UV-visible, and XPS analysis, and their catalytic reactivity was tested under 100-160 degrees C under the near-UV irradiation. The results indicated that V2O5/TiO2 solely possessed the thermo-catalytic reactivity while WO3/TiO2 only had photo-catalytic reactivity. Although the synthesis catalytic reactivity has not been found for these catalysts up to date, but compared with TiO2, the removal efficiencies of Hg(0) at 140 and 160 degrees C were enhanced; particularly, the efficiency was improved from 20 % at 160 degrees C by TiO2 to nearly 90 % by WO3/TiO2 under the same operating conditions. The effects of doping amount of V2O5 and WO3 were also investigated, and the results showed that 10 % V2O5 and 5 % WO3/TiO2 were the best immobilized catalysts for thermo- and photo-catalytic reactivity, respectively. The effect of different influent concentrations of Hg(0) was demonstrated that the highest concentration of Hg(0) led to the best removal efficiencies for V2O5/TiO2 and WO3/TiO2 at 140 and 160 degrees C, because high Hg(0) concentration increased the mass transfer rate of Hg(0) toward the surface of catalysts and drove the reaction to proceed. At last, the effect of single gas component on the removal of Hg(0) was also investigated. PMID- 26590064 TI - Global gene expression profiling using heterologous DNA microarrays to analyze alterations in the transcriptome of Mus spretus mice living in a heavily polluted environment. AB - Microarray platforms are a good approach for assessing biological responses to pollution as they enable the simultaneous analyses of changes in the expression of thousands of genes. As an omic and non-targeted methodology, this technique is open to unforeseen responses under particular environmental conditions. In this study, we successfully apply a commercial oligonucleotide microarray containing Mus musculus whole-genome probes to compare and assess the biological effects of living in a heavily polluted settlement, the Domingo Rubio stream (DRS), at the Huelva Estuary (SW Spain), on inhabitant free-living Mus spretus mice. Our microarray results show that mice living in DRS suffer dramatic changes in gene and protein expression compared with reference specimens. DRS mice showed alteration in the oxidative status of hepatocytes, with activation of both the innate and the acquired immune responses and the induction of chronic inflammation, accompanied by metabolic alterations that imply the accumulation of lipids in the liver (hepatic steatosis). The identified deregulated genes may be useful as biomarkers of environmental pollution. PMID- 26590065 TI - Changing climate cues differentially alter zooplankton dormancy dynamics across latitudes. AB - In seasonal climates, dormancy is a common strategy that structures biodiversity and is necessary for the persistence of many species. Climate change will likely alter dormancy dynamics in zooplankton, the basis of aquatic food webs, by altering two important hatching cues: mean temperatures during the ice-free season, and mean day length when lakes become ice free. Theory suggests that these changes could alter diversity, hatchling abundances and phenology within lakes, and that these responses may diverge across latitudes due to differences in optimal hatching cues and strategies. To examine the role of temperature and day length on hatching dynamics, we collected sediment from 25 lakes across a 1800 km latitudinal gradient and exposed sediment samples to a factorial combination of two photoperiods (12 and 16 h) and two temperatures (8 and 12 degrees C) representative of historical southern (short photoperiod, warm) and northern (long photoperiod, cool) lake conditions. We tested whether sensitivity to these hatching cues varies by latitudinal origin and differs among taxa. Higher temperatures advanced phenology for all taxa, and these advances were greatest for cladocerans followed by copepods and rotifers. Although phenology differed among taxa, the effect of temperature did not vary with latitude. The latitudinal origin of the egg bank influenced egg abundance and hatchling abundance and diversity, with these latter effects varying with taxa, temperature and photoperiod. Copepod hatchling abundances peaked at mid-latitudes in the high temperature and long photoperiod treatments, whereas hatchling abundances of other zooplankton were greatest at low latitudes and high temperature. The overall diversity of crustacean zooplankton (copepods and cladocerans) also reflected distinct responses of each taxa to our treatments, with the greatest diversity occurring at mid-latitudes (~56 degrees N) in the shorter photoperiod treatment. Our results demonstrate that hatching cues differ for broad taxonomic groups that vary in developmental and life-history strategies. These differences are predicted to drive latitude-specific shifts in zooplankton emergence with climate change and could alter the base of aquatic food webs. PMID- 26590068 TI - Could an experimental dengue virus infection fail to induce solid immunity against homologous viral challenge in non-human primates? AB - There are several dengue vaccine candidates at advanced stages of development, but none of them are licensed. Despite the reactogenicity and immunogenicity profile in humans of the tetravalent ChimeriVaxTM dengue vaccine candidate, in efficacy trials, it has failed to confer complete protection against dengue virus (DENV)-1 and DENV-2. However, full protection against the four serotypes had been observed previously in monkeys immunized with this vaccine candidate. Some authors have tried to explain this contradiction by hypothesizing that protection rates in non-human primates (NHPs) are associated with a lack of post-challenge anamnestic immune responses. Here, we studied the protection and anamnestic response patterns after homologous challenge in NHPs previously infected with DENV-2. Two immunization schemes were used, varying the viral doses and the intervals between them. Animals developed immunity against DENV-2 that provided full protection against reinfection with a homologous virus. However, all monkeys showed a significant increase in antiviral and neutralizing antibody titers after challenge. Our results suggest that sterilizing immunity could not be induced by infection with the virus despite the lack of detectable viremia in some animals in which an increase in antibody titer was observed. For this reason, we propose that the lack of an anamnestic neutralizing antibody response after challenge, as suggested by some authors, should be carefully reviewed as a criterion for evaluating the functionality of vaccine candidates. PMID- 26590066 TI - Development and process evaluation of an educational intervention for overdose prevention and naloxone distribution by general practice trainees. AB - BACKGROUND: Overdose is the most common cause of fatalities among opioid users. Naloxone is a life-saving medication for reversing opioid overdose. In Ireland, it is currently available to ambulance and emergency care services, but General Practitioners (GP) are in regular contact with opioid users and their families. This positions them to provide naloxone themselves or to instruct patients how to use it. The new Clinical Practice Guidelines of the Pre-hospital Emergency Care Council of Ireland allows trained bystanders to administer intranasal naloxone. We describe the development and process evaluation of an educational intervention, designed to help GP trainees identify and manage opioid overdose with intranasal naloxone. METHODS: Participants (N = 23) from one postgraduate training scheme in Ireland participated in a one-hour training session. The repeated-measures design, using the validated Opioid Overdose Knowledge (OOKS) and Attitudes (OOAS) Scales, examined changes immediately after training. Acceptability and satisfaction with training were measured with a self administered questionnaire. RESULTS: Knowledge of the risks of overdose and appropriate actions to be taken increased significantly post-training [OOKS mean difference, 3.52 (standard deviation 4.45); P < 0.001]; attitudes improved too [OOAS mean difference, 11.13 (SD 6.38); P < 0.001]. The most and least useful delivery methods were simulation and video, respectively. CONCLUSION: Appropriate training is a key requirement for the distribution of naloxone through general practice. In future studies, the knowledge from this pilot will be used to inform a train-the-trainer model, whereby healthcare professionals and other front-line service providers will be trained to instruct opioid users and their families in overdose prevention and naloxone use. PMID- 26590067 TI - Traditional Versus Simulation Resident Surgical Laparoscopic Salpingectomy Training: A Randomized Controlled Trial. AB - STUDY OBJECTIVES: To evaluate the effectiveness of the porcine training model for obstetrics-gynecology (OB/GYN) residents in laparoscopic salpingectomy. DESIGN: Randomized, controlled single-blinded trial. CLASSIFICATION: Canadian Task Force Classification I. SETTING: A large community-based teaching hospital. PARTICIPANTS: All postgraduate year 1 through year 4 OB/GYN residents were enrolled (n = 22). INTERVENTION: All participants underwent a preintervention objective skills assessment test (OSAT), in which the participant performed live human laparoscopic salpingectomy. Residents were randomly assigned (using a computer-generated randomization table, in blocks of 2, stratified by ranked baseline OSAT scores) to the intervention or control group. The intervention group consisted of 1 educational session with presession assigned reading, a 40 min didactic lecture, viewing of a procedural video, and simulation and practice of laparoscopic salpingectomy on a porcine cadaver. The control group received traditional training per routine residency rotations. MEASUREMENTS AND MAIN RESULTS: Laparoscopic salpingectomy was performed on live patients by study participants pre- and postintervention. These procedures were video recorded, and then scored by a single blinded evaluator of the OSATs. Nine pre- and postintervention OSAT indicators, reflecting provider knowledge and skill, were the primary outcome measures. Secondary outcomes were the changes in 10 subjective measures of comfort, assessed by a pre- and postintervention survey. The outcomes were assessed using 5-point Likert scales (for OSATs 1 = lowest score; for the subjective survey 1 = highest score). The control group OSAT scores did not change (pre: 26.6 +/- 10.8, post: 26.2 +/- 10.1; p = .65). There were significant improvements in 2-handed surgery (pre: 2.8 +/- 1.6, post: 3.5 +/ 1.3; p = .004) and use of energy (pre: 2.9 +/- 1.3, post: 3.6 +/- 1.0; p = .01) in the intervention group, contributing to an overall score change (pre: 26.7 +/- 10.6, post: 29.9 +/- 9.8; p <= .001). The control group had no change in comfort levels. The intervention group experienced both increases (anatomy, steps of surgery, 2-handed surgery, and use of energy) and decreases (reading and learning in operating room) in reported comfort levels. CONCLUSION: This study demonstrates that simulation can improve surgical technique OSATs. However, of 45 possible points, both groups' average scores were <70% of the optimum. Thus, the improvement, although statistically significant, was relatively small and indicates that further supplementation in training is needed to substantially increase the residents' surgical skills. PMID- 26590069 TI - Surveillance for severe acute respiratory infections in Southern Arizona, 2010 2014. AB - BACKGROUND: The Binational Border Infectious Disease Surveillance program began surveillance for severe acute respiratory infections (SARI) on the US-Mexico border in 2009. Here, we describe patients in Southern Arizona. METHODS: Patients admitted to five acute care hospitals that met the SARI case definition (temperature >=37.8 degrees C or reported fever or chills with history of cough, sore throat, or shortness of breath in a hospitalized person) were enrolled. Staff completed a standard form and collected a nasopharyngeal swab which was tested for selected respiratory viruses by reverse transcription polymerase chain reaction. RESULTS: From October 2010-September 2014, we enrolled 332 SARI patients. Fifty-two percent were male and 48% were white non-Hispanic. The median age was 63 years (47% >=65 years and 5.2% <5 years). During hospitalization, 51 of 230 (22%) patients required intubation, 120 of 297 (40%) were admitted to intensive care unit, and 28 of 278 (10%) died. Influenza vaccination was 56%. Of 309 cases tested, 49 (16%) were positive for influenza viruses, 25 (8.1%) for human metapneumovirus, 20 (6.5%) for parainfluenza viruses, 16 (5.2%) for coronavirus, 11 (3.6%) for respiratory syncytial virus, 10 (3.2%) for rhinovirus, 4 (1.3%) for rhinovirus/enterovirus, 3 (1.0%) for enteroviruses, and 3 (1.0%) for adenovirus. Among the 49 influenza-positive specimens, 76% were influenza A (19 H3N2, 17 H1N1pdm09, and 1 not subtyped), and 24% were influenza B. CONCLUSION: Influenza viruses were a frequent cause of SARI in hospitalized patients in Southern Arizona. Monitoring respiratory illness in border populations will help better understand the etiologies. Improving influenza vaccination coverage may help prevent some SARI cases. PMID- 26590070 TI - Parental anxiety related to referral of childhood heart murmur; an observational/interventional study. AB - BACKGROUND: Detection of a heart murmur in healthy children is common, but may generate anxiety among parents. Many parents believe a heart murmur is a sign of heart disease, although the majority of heart murmurs are innocent. The purpose of this study was to assess anxiety and concerns in parents of children referred for evaluation of a heart murmur and to evaluate the effect of receiving a fact sheet about heart murmurs before the cardiologic consultation. METHODS: Parents of children referred for evaluation of a heart murmur responded to questionnaires assessing family and patient characteristics, parental concerns and anxiety. Anxiety was measured using the State Trait Anxiety Index (STAI) before and two weeks after the consultation. One third of the parents received a fact sheet before the consultation. RESULTS: Two hundred fifty-eight parents of 178 children participated. About 60 % of the parents had an increased level of anxiety before the consultation. The majority of the parents (71 %) had at least one major concern about heart murmurs in children, and having a concern was related to higher anxiety levels (p = 0.02). Anxious personality and lower education predicted an increased anxiety level. Before the consultation, parents who received a fact sheet presented a lower mean STAI state anxiety level (33.2) than those who did not (35.3), but the difference was not significant (p = 0.09). Fewer parents in the intervention group believed their child would have increased risk of heart disease later in life (p = 0.04) or that heart murmurs in children represents valvular-or congenital heart disease (p = 0.02). After the consultation, parental anxiety decreased from a mean STAI state of 34.9 to 30.6 (p < 0.01), and the mean STAI state scores were similar for the control and intervention group. CONCLUSION: Parents with a child referred for a heart murmur presented a higher mean anxiety level than pre-school parents, and having an anxious personality, a major concern or low education predicted an increased anxiety level. After the consultation, parental anxiety decreased. Receiving a fact sheet about heart murmurs did not significantly reduce parental anxiety levels, but had a modest effect on concerns for the consequences of a heart murmur. PMID- 26590071 TI - Introduction to the Special Issue: A Tribute to Ralph M. Reitan. PMID- 26590072 TI - Ralph M. Reitan: The Pioneer of Clinical Neuropsychology. PMID- 26590073 TI - Ralph Reitan and Biological Intelligence. PMID- 26590074 TI - Ralph M. Reitan: Evidenced Based Before Evidence Based Was Cool. PMID- 26590075 TI - Ralph M. Reitan: A Singular Career. PMID- 26590076 TI - Contributions to Neuropsychology of Reitan and Associates: Neuropsychology Laboratory, Indiana University Medical Center, 1960s. PMID- 26590077 TI - A Personal Tribute to Ralph M. Reitan. PMID- 26590078 TI - Ralph M. Reitan: A Founding Father of Neuropsychology. PMID- 26590079 TI - A Remembrance: My Advisor, Ralph M. Reitan. PMID- 26590080 TI - A Personal Perspective from an Appreciative Student. PMID- 26590081 TI - Happy Trails. PMID- 26590082 TI - The Influence of Ralph Reitan on the Development of the Luria-Nebraska Neuropsychological Battery. PMID- 26590083 TI - Ralph Reitan: A Scientist in Neuropsychology. PMID- 26590084 TI - Ralph M. Reitan's bibliography. PMID- 26590085 TI - Effects of ageing on expression of the muscle-specific E3 ubiquitin ligases and Akt-dependent regulation of Foxo transcription factors in skeletal muscle. AB - Controversy exists as to whether the muscle-specific E3 ubiquitin ligases MAFbx and MuRF1 are transcriptionally upregulated in the process of sarcopenia. In the present study, we investigated the effects of ageing on mRNA/protein expression of muscle-specific E3 ubiquitin ligases and Akt/Foxo signalling in gastrocnemius muscles of female mice. Old mice exhibited a typical sarcopenic phenotype, characterized by loss of muscle mass and strength, decreased amount of myofibrillar proteins, incidence of aberrant muscle fibres, and genetic signature to sarcopenia. Activation levels of Akt were lower in adult and old mice than in young mice. Consequently, Akt-mediated phosphorylation levels of Foxo1 and Foxo3 proteins were decreased. Nuclear levels of Foxo1 and Foxo3 proteins showed an overall increasing trend in old mice. MAFbx mRNA expression was decreased in old mice relative to adult mice, whereas MuRF1 mRNA expression was less affected by ageing. At the protein level, MAFbx was less affected by ageing, whereas MuRF1 was increased in old mice relative to adult mice, with ubiquitin-protein conjugates being increased with ageing. In conclusion, we provided evidence for no mRNA upregulation of muscle-specific E3 ubiquitin ligases and disconnection between their expression and Akt/Foxo signalling in sarcopenic mice. Their different responsiveness to ageing may reflect different roles in sarcopenia. PMID- 26590086 TI - Significance of twist and iNOS expression in human breast carcinoma. AB - Twist is a basic helix-loop-helix transcription factor family normally expressed during embryonic development and apparently activated in variety of tumours. Overexpression of twist is correlated with uncontrolled cell proliferation, differentiation, invasion and metastasis. Twist expression is associated with oestrogen receptor (ER); however, the molecular mechanism behind involvement of twist in progression of breast cancer is still unclear. Nitric oxide synthases (NOSs) which cause damage to the cellular DNA are also shown to be involved in cancer progression. The present study involves total number of n = 85 breast biopsies, which include 19 non-cancer and 66 cancerous lesions. We analysed twist, iNOS and ER expression pattern in human breast carcinomas by RT-PCR and also analysed twist cellular localisation by immunohistochemical analysis. iNOS expression pattern was correlated with different stages of breast carcinoma. Twist expression was significantly increased in cancer lesions when compared to the non-cancer. The breast cancer lesions positive to ER showed positivity to twist (72%) as well. The higher stages of cancer lesions showed a significant expression of twist localised in cytoplasm of the cancer cells. Collectively these data indicate that up-regulation of twist is correlated with the ER presenting breast cancer, and iNOS expression was positively correlated with tumour-node metastasis (TNM) staging of breast cancer. These findings suggest that expression of twist and iNOS may have a functional role in cancer progression. PMID- 26590087 TI - Sox6 suppression induces RA-dependent apoptosis mediated by BMP-4 expression during neuronal differentiation in P19 cells. AB - Sox6 is a transcription factor that induces neuronal differentiation in P19 cells; its suppression not only inhibits neuronal differentiation but also induces retinoic acid (RA)-dependent apoptosis of P19 cells. In the present study, we found that Sox6 suppression-induced apoptosis was mediated by activation of caspase 9 and 3. Moreover, we noted a weak leakage of cytochrome c into the cytoplasm from the mitochondria, indicating that apoptosis occurs through a mitochondrial pathway in Sox6-suppressed P19 (P19[anti-Sox6]) cells. Sox6 suppression in the presence of RA also induced the expression and secretion of bone morphogenetic protein 4 (BMP-4). Addition of an anti-BMP-4 antibody for neutralization increased cell viability and led to RA-dependent death of P19[anti Sox6] cells. Our results indicate that Sox6 suppression induces RA-dependent cell death of P19 cells, mediated by BMP-4 expression and secretion. Normally, high Sox6 expression leads to RA-mediated neuronal differentiation in P19 cells; however, Sox6 deficiency induces production and secretion of BMP-4, which mediates selective cell death. Our findings suggest that Sox6 contributes to cell survival by suppressing BMP-4 transcription during neuronal differentiation. PMID- 26590089 TI - Pseudorabies virus isolates from domestic pigs and wild boars show no apparent in vitro differences in replication kinetics and sensitivity to interferon-induced antiviral status. AB - Pseudorabies virus is the causative agent of Aujeszky's disease. Domestic pigs and wild boars are its natural hosts, and strains circulating within both populations differ in their capacity to induce clinical disease. Cell biological and molecular explanations for the observed differences in virulence are, however, lacking. Different virulence determinants that can be assessed in vitro were determined for five domestic swine strains, four wild boar strains and the NIA3 reference strain. Replication kinetics and plaque formation capacity in continuous swine testicular cells and different primary porcine cell lines were highly similar for isolates from both populations. Treatment of these cell lines with IFNalpha, IFNgamma or a combination of both provoked similar plaque-reducing effects for all strains. In conclusion, our results indicate that isolates from domestic swine and wild boar differ neither in intrinsic replication and dissemination capacity nor in sensitivity to antiviral effects of IFNs. PMID- 26590088 TI - Ascorbic acid prevents VEGF-induced increases in endothelial barrier permeability. AB - Vascular endothelial growth factor (VEGF) increases endothelial barrier permeability, an effect that may contribute to macular edema in diabetic retinopathy. Since vitamin C, or ascorbic acid, can tighten the endothelial permeability barrier, we examined whether it could prevent the increase in permeability due to VEGF in human umbilical vein endothelial cells (HUVECs). As previously observed, VEGF increased HUVEC permeability to radiolabeled inulin within 60 min in a concentration-dependent manner. Loading the cells with increasing concentrations of ascorbate progressively prevented the leakage caused by 100 ng/ml VEGF, with a significant inhibition at 13 uM and complete inhibition at 50 uM. Loading cells with 100 uM ascorbate also decreased the basal generation of reactive oxygen species and prevented the increase caused by both 100 ng/ml VEGF. VEGF treatment decreased intracellular ascorbate by 25%, thus linking ascorbate oxidation to its prevention of VEGF-induced barrier leakage. The latter was blocked by treating the cells with 60 uM L-NAME (but not D-NAME) as well as by 30 uM sepiapterin, a precursor of tetrahydrobiopterin that is required for proper function of endothelial nitric oxide synthase (eNOS). These findings suggest that VEGF-induced barrier leakage uncouples eNOS. Ascorbate inhibition of the VEGF effect could thus be due either to scavenging superoxide or to peroxynitrite generated by the uncoupled eNOS, or more likely to its ability to recycle tetrahydrobiopterin, thus avoiding enzyme uncoupling in the first place. Ascorbate prevention of VEGF-induced increases in endothelial permeability opens the possibility that its repletion could benefit diabetic macular edema. PMID- 26590092 TI - Ebola Virus Disease. AB - Nurses are the largest group of health care providers and, therefore, are often at the forefront of epidemics: responding, treating, educating, and coordinating care as needed. But what happens when nurses are afraid of contracting an illness and decide to leave the workplace? The fear due to Ebola was in part caused by conflicting information around the proper use of personal protective equipment and need for quarantine. The nursing response to as well as the role occupational health nurses can play in diffusing the fear of contracting contemporary infectious diseases are discussed. PMID- 26590090 TI - Differential expression of miRNAs in pancreatobiliary type of periampullary adenocarcinoma and its associated stroma. AB - Periampullary adenocarcinomas can be of two histological subtypes, intestinal or pancreatobiliary. The latter is more frequent and aggressive, and characterized by a prominent desmoplastic stroma, which is tightly related to the biology of the cancer, including its poor response to chemotherapy. Whereas miRNAs are known to regulate various cellular processes and interactions between cells, their exact role in periampullary carcinoma remains to be characterized, especially with respect to the prominent stromal component of pancreatobiliary type cancers. The present study aimed at elucidating this role by miRNA expression profiling of the carcinomatous and stromal component in twenty periampullary adenocarcinomas of pancreatobiliary type. miRNA expression profiles were compared between carcinoma cells, stromal cells and normal tissue samples. A total of 43 miRNAs were found to be differentially expressed between carcinoma and stroma of which 11 belong to three miRNA families (miR-17, miR-15 and miR-515). The levels of expression of miRNAs miR-17, miR-20a, miR-20b, miR-223, miR-10b, miR-2964a and miR-342 were observed to be higher and miR-519e to be lower in the stromal component compared to the carcinomatous and normal components. They follow a trend where expression in stroma is highest followed by carcinoma and then normal tissue. Pathway analysis revealed that pathways regulating tumor-stroma interactions such as ECM interaction remodeling, epithelial-mesenchymal transition, focal adhesion pathway, TGF-beta, MAPK signaling, axon guidance and endocytosis were differently regulated. The miRNA-mRNA mediated interactions between carcinoma and stromal cells add new knowledge regarding tumor-stroma interactions. PMID- 26590094 TI - The Changing Risk of Japanese Encephalitis for Business Travelers. AB - Japanese Encephalitis is an often fatal and vaccine preventable disease. New vaccine recommendations are needed due to changes in travel and disease patterns. PMID- 26590091 TI - Primary complement and antibody deficiencies in autoimmune rheumatologic diseases with juvenile onset: a prospective study at two centers. AB - BACKGROUND: Our aim was to investigate the prevalence and clinical relevance of inherited complement and antibody deficiency states in a large series of patients with various autoimmune rheumatologic diseases (ARD) with juvenile onset. METHODS: A total number of 117 consecutive patients from 2 tertiary referral hospitals were included in the study. All patients underwent genetic screening for type I C2 deficiency and C4 allotyping. Serum levels of immunoglobulin classes measured systematically throughout their regular medical care were recorded retrospectively. RESULTS: Our cohort of patients included 84 with juvenile idiopathic arthritis (JIA), 21 with systemic lupus erythematosus (SLE), 6 with systemic vasculitis, 2 with juvenile scleroderma, 2 with idiopathic uveitis, 1 with mixed connective tissue disease and 1 with SLE/scleroderma overlap syndrome. We have found 16 patients with evidence of primary immunodeficiency in our series (13.7%), including 7 with C4 deficiency, 5 with selective IgA deficiency, 3 with C2 deficiency and 2 with unclassified hypogammaglobulinemia (one also presented C4D). Of the 84 patients with JIA, 4 (4.8%) had a complement deficiency, which was less prevalent than in the SLE cohort (23.8%), but all of them have exhibited an aggressive disease. Most of our patients with primary antibody deficiencies showed a more complicated and severe disease course and even the co-occurrence of two associated autoimmune diseases (SLE/scleroderma overlap syndrome and SLE/autoimmune hepatitis type 1 overlap). CONCLUSIONS: Our findings among others demonstrate that complement and immunoglobulin immunodeficiencies need careful consideration in patients with ARD, as they are common and might contribute to a more severe clinical course of the disease. PMID- 26590095 TI - Monitoring predictors of mortality: A necessary action to reach TB elimination. PMID- 26590096 TI - Is the 2-cm size cutoff relevant for small nonfunctioning pancreatic neuroendocrine tumors: A French multicenter study. AB - BACKGROUND: Nonfunctioning pancreatic neuroendocrine tumors (NF-PNETs) are often discovered at a small size. No clear consensus exists on the management of NF PNETs <= 2 cm. The aim of our study was to determine the prognostic value of indicators of malignancy in sporadic NF-PNETs <= 2 cm. METHODS: Eighty patients were evaluated retrospectively in 7 French University Hospital Centers. Patients were managed by operative resection (operative group [OG]) or observational follow-up (non-OG [NOG]). Pathologic characteristics and outcomes were analyzed. RESULTS: Sixty-six patients (58% women) were in the OG (mean age, 59 years; 95% CI, 56.0-62.3; mean tumor size, 1.6 cm; 95% CI, 1.5-1.7); 14 (72% women, n = 10) were in the NOG (mean age, 63 years; 95% CI, 56-70; mean tumor size, 1.4 cm; 95% CI, 1.0-1.7). All PNETs were ranked using the European Neuroendocrine Tumor Society grading system. Fifteen patients (19%) had malignant tumors defined by node or liver metastasis (synchronous or metachronous). The median disease-free survival was different between malignant and nonmalignant PNETs, respectively: 16 (range, 4-72) versus 30 months (range, 1-156; P = .03). On a receiver operating characteristic (ROC) curve, tumor size had a significant impact on malignancy (area under the curve [AUC], 0.75; P = .03), but not Ki-67 (AUC, 0.59; P = .31). A tumor size cutoff was found on the ROC curve at 1.7 cm (odd ratio, 10.8; 95% CI; 2.2-53.2; P = .003) with a sensitivity of 92% and a specificity of 75% to predict malignancy. CONCLUSION: Based on our retrospective study, the cutoff of 2 cm of malignancy used for small NF-PNETs could be decreased to 1.7 cm to select patients more accurately. PMID- 26590097 TI - Global metabolic profiling for the study of Rhizoma Paridis saponins-induced hepatotoxicity in rats. AB - Rhizoma Paridis saponins (RPS) is a traditional Chinese medicine (TCM) from the plant Paris polyphylla var. yunnanensis (Fr.) Hand.-Mazz. Despite its potentially clinical utility such as anticancer and anti-inflammation, it has slight side effects and toxicity as previous report. In this work, 90-day administration of RPS induced liver injury. 1 H-NMR- and GC/MS-based metabonomic analyses in conjunction with histopathological examinations, blood biochemistry and hepatic phase I and II enzymes assays were performed to evaluate the toxic mechanisms of RPS induced in rats. As a result, oral administration of RPS possessed certain liver toxicity in SD rats. 1 H-NMR and GC/MS data indicated that RPS inhibited the oxidation of fatty acids, glycolysis, and TCA cycle pathway, and disturbed glycine, serine, and threonine metabolism. Low expression of TG, T-CHO, and LDL-C and high levels of ALT and AST indicated that chronic exposure to RPS caused hepatocyte damage, synthesis dysfunction, and transportation failure of lipoproteins. In addition, RPS downregulated the mRNA levels of CYP1A2, CYP2E1, and UGTs. In conclusion, we used metabonomics approach to study the toxicity of RPS for the first time. This research demonstrated that metabonomics method was a promising tool to study and diagnose TCM-induced toxicity. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 32: 99-108, 2017. PMID- 26590098 TI - Comparative analysis of web search trends between experts and public for medicinal herbs in Korea. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The information and knowledge about ethno medicinal herbs are getting stronger interest in Global and Korea after the agreement of the Nagoya Protocol. However, it is known that there is a serious asymmetry of ethno-medicinal information between experts and public, thus this study aimed to analyze the similarities and differences in interest between experts and public for medicinal herbs in Korea through big data analysis. MATERIALS AND METHODS: The medicinal herbs selected in this study were the top 10 herbs in terms of the amounts purchased by TKM centers. And two representative web search engines were selected to collect the web search logs, i.e. big data, of experts and public for medicinal herbs in Korea. Comparative analysis was accomplished through descriptive statistical analysis, Pearson's correlation coefficient, and time-series graph analysis. RESULTS: The web search traffic logs were collected for the past three years (2012-2014) from OASIS and NAVER, which are the representative web search engines of experts and public respectively in Korea. First, regarding OASIS, the most searched medicinal herb was Angelicae Gigantis Radix while the least searched was Alismatis Rhizoma; for NAVER, the most searched medicinal herb was Paeoniae Radix, unlike OASIS, and the least searched was Alismatis Rhizoma, as with OASIS. The coefficient between rank of herbs and OASIS was -0.401, and that between rank of herbs and NAVER was -0.387, and the correlational coefficient for web search trends of OASIS and NAVER during the past three years was 0.438. Also the correlation of interest between experts and public for each herb on monthly web trends basis was similar with regard to Glycyrrhizae Radix et Rhizoma and Angelicae Gigantis Radix, but different with regard to the other 8 medicinal herbs. Finally, significant outcomes or suggestions were figured out through time-series graph analysis. CONCLUSION: This study presents meaningful results concerning the similarities and differences in interest between experts and public for popular medicinal herbs in Korea. Contrary to the common assumption that there exists big different interest between experts and public, this study revealed that there is apparent similar interest between experts and public on popular medicinal herbs in Korea. PMID- 26590100 TI - Discovery of benzamides as potent human beta3 adrenergic receptor agonists. AB - The paper will describe the synthesis and SAR studies that led to the discovery of benzamide (reverse amide) as potent and selective human beta3-adrenergic receptor agonist. Based on conformationally restricted pyrrolidine scaffold we discovered earlier, pyrrolidine benzoic acid intermediate 22 was synthesized. From library synthesis and further optimization efforts, several structurally diverse reverse amides such as 24c and 24i were found to have excellent human beta3-adrenergic potency and good selectivity over the beta1 and beta2 receptors. In addition to human beta1, beta2, beta3 and hERG data, PK of selected compounds will be described. PMID- 26590101 TI - Discovery of bisindolyl-substituted cycloalkane-anellated indoles as novel class of antibacterial agents against S. aureus and MRSA. AB - Antibiotic resistance is an ongoing problem in the treatment of bacterial diseases. Among the various antibacterial infections Staphylococcus aureus infections remain critical due to the increasing resistances, especially against the methicillin-resistant S. aureus (MRSA). We discovered novel antibacterial compounds with activities against both S. aureus and MRSA types. Structure activity relationships (SAR) are discussed and show that the activity depends on the ring size of the anellated cycloalkane. Moreover, first substituent effects have been investigated for both the cycloalkane and the indole residues. PMID- 26590099 TI - Qishenyiqi Dropping Pill attenuates myocardial fibrosis in rats by inhibiting RAAS-mediated arachidonic acid inflammation. AB - ETHNOPHARMACOLOGICAL SIGNIFICANCE: In China, Qishenyiqi Dropping Pill (QSDP), a Chinese medicine formula containing Astragalus membranaceus (Fisch.) Bunge, Salvia miltiorrhiza Bunge, Panax notoginseng (Burkill) F.H.Chen and Dalbergia odorifera T.C.Chen, has been used frequently in traditional folk medicine for treatment of coronary heart diseases (CHD) and heart failure (HF). AIM OF STUDY: Previous study has shown that QSDP has definite therapeutic effects on promoting the heart function on CHD patients. The present study was designed to study the anti-fibrosis effects of QSDP on HF rats and to explore the underlying molecular mechanisms. MATERIALS AND METHODS: HF rat model was induced by left anterior descending (LAD) coronary artery ligation. Two-dimensional (2D) echocardiography was adopted to evaluate heart functions. Immunohistochemical (IHC) method and Western-blot were used to detect expression of critical proteins in renin angiotensin-aldosterone system (RAAS) or arachidonic acid (AA) metabolic pathway. RESULTS: Heart functions were seriously injured in the model group. Expressions of fibrotic markers, such as collagen I, collagen III, matrix metallopeptidase 2 (MMP2) and MMP9 were elevated in the model group. RAAS pathway was activated. Interestingly, AA pathway was also up-regulated in the model group and it was down-regulated by angiotensin converting enzyme inhibitors (ACEIs) drug Captopril. Expressions of the important signal-transuding proteins, including NF kappaB, JAK1/STAT3 and Akt, all increased remarkably in the model group. Treatment with QSDP could attenuate myocardial fibrosis by inhibiting RAAS activated pathway, as indicated by decreased angiotensin type 1 receptor (AT1) and increased AT2 expression. Expressions of phospholipase A2 (PLA2), cyclooxygenase 1 (COX1) and COX2 were also down-regulated in the QSDP-treated group. In addition, "therapeutic" QSDP administration seemed to down-regulate expressions of NF-kappaB, JAK1/ STAT3 and Akt which may play important roles in myocardial fibrosis. CONCLUSION: QSDP can exert anti-fibrosis effect by down regulating RAAS pathway, and subsequently inhibiting expressions of proteins in AA pathway. PMID- 26590102 TI - An efficient green synthesis of 2-arylbenzothiazole analogues as potent antibacterial and anticancer agents. AB - We have demonstrated a novel and green approach for the synthesis of 2 substituted benzothiazole analogues. A number of 2-aryl and heteroaryl benzothiazole scaffolds were synthesized using Amberlite IR-120 resin under microwave irradiation. The catalytic role and reusability of the resin was well established here. 2-Substituted benzothiazole analogues (3a-l) were also tested against several bacterial strains (Staphylococcus aureus, Escherichia coli, Bacillus subtilis, Salmonella) and cancer cell lines (MCF-7 and HeLa). The stability of compound 2-phenyl benzothiazole (3a) and 2-pyridin-2-yl benzothiazole (3k) in GSH (0.01mM dissolved in DMSO) was measured by UV-Vis spectroscopy. Compound 3k also shows remarkable fluorescence in MeOH. PMID- 26590103 TI - Optimization of carbon ion and proton treatment plans using the raster-scanning technique for patients with unresectable pancreatic cancer. AB - BACKGROUND: The aim of the thesis is to improve radiation plans of patients with locally advanced, unresectable pancreatic cancer by using carbon ion and proton beams. PATIENTS AND METHODS: Using the treatment planning system Syngo RT Planning (Siemens, Erlangen, Germany) a total of 50 treatment plans have been created for five patients with the dose schedule 15 * 3 Gy(RBE). With reference to the anatomy, five field configurations were considered to be relevant. The plans were analyzed with respect to dose distribution and individual anatomy, and compared using a customized index. RESULTS: Within the index the three-field configurations yielded the best results, though with a high variety of score points (field setup 5, carbon ion: median 74 (range 48-101)). The maximum dose in the myelon is low (e.g. case 3, carbon ion: 21.5 Gy(RBE)). A single posterior field generally spares the organs at risk, but the maximum dose in the myelon is high (e.g. case 3, carbon ion: 32.9 Gy(RBE)). Two oblique posterior fields resulted in acceptable maximum doses in the myelon (e.g. case 3, carbon ion: 26.9 Gy(RBE)). The single-field configuration and the two oblique posterior fields had a small score dispersion (carbon ion: median 66 and 58 (range 62-72 and 40-69)). In cases with topographic proximity of the organs at risk to the target volume, the single-field configuration scored as well as the three-field configurations. CONCLUSION: In summary, the three-field configurations showed the best dose distributions. A single posterior field seems to be robust and beneficial in case of difficult topographical conditions and topographical proximity of organs at risk to the target volume. A setup with two oblique posterior fields is a reasonable compromise between three-field and single-field configurations. PMID- 26590104 TI - Intra-tumoral IFN-gamma-producing Th22 cells correlate with TNM staging and the worst outcomes in pancreatic cancer. AB - PDAC (pancreatic ductal adenocarcinoma) is the fifth leading cause of cancer related death. The causes of this cancer remain unknown, but increasing evidence indicates a key role of the host immune response and cytokines in human carcinogenesis. Intra-tumoral IL (interleukin)-22 levels have been shown to be elevated in PDAC patients. However, little is known regarding the expression and clinical relevance of Th22 cells in human PDAC and, furthermore, which TILs (tumour-infiltrating lymphocytes) are the main producers of IL-22 is unknown. In the present study, we characterized the functional proprieties of the different subsets of IL-22-producing TILs and analysed their relationship with the TNM staging system and patient survival. We have demonstrated for the first time that, in PDAC patients, the T-cells co-producing IFN-gamma (interferon gamma) and exerting perforin-mediated cytotoxicity are the major intra-tumoral source of IL 22. In addition, isolated Th22 cells were able to induce apoptosis, which was antagonized by IL-22. Finally, we observed that the IL-22-producing T-cells were significantly increased in tumour tissue and that this increase was positively correlated with TNM staging of PDAC and poorer patient survival. These novel findings support the dual role of the anti-tumour immune system and that IL-22 producing cells may participate in PDAC pathogenesis. Therefore monitoring Th22 levels could be a good diagnostic parameter, and blocking IL-22 signalling may represent a viable method for anti-PDAC therapies. PMID- 26590106 TI - A Case of Myelodysplastic Syndrome with Intestinal Behcet's Disease-Like Symptoms Treated by Prednisolone and Azacitidine. AB - BACKGROUND Intestinal Behcet's disease-like symptoms are rare complications of myelodysplastic syndrome and are often refractory to immunosuppressive therapies. We described a case of myelodysplastic syndrome complicated by Behcet's disease like symptoms treated with prednisolone and azacitidine. CASE REPORT A 68-year old Japanese woman was admitted to our hospital because of persistent high fever and lower abdominal pain. Oral ulcerations developed after admission, and multiple ulcers were found in her terminal ileum by endoscopic examination. She was diagnosed with myelodysplastic syndrome with trisomy 8 by bone marrow examination. Her symptoms diminished after administration of prednisolone, but relapsed afterwards. She began azacitidine therapy and her symptoms have been controlled for at least 10 months. CONCLUSIONS This case might suggest the possibility of azacitidine as a treatment option for myelodysplastic syndrome complicated by Behcet's disease-like symptoms. PMID- 26590105 TI - MAIT cells are activated and accumulated in the inflamed mucosa of ulcerative colitis. AB - BACKGROUND AND AIM: Ulcerative colitis (UC) is a chronic, relapsing and remitting, inflammatory disorder of the large intestine. Mucosal associated invariant T (MAIT) cells are a member of innate-like lymphocytes found abundantly in the mucosal tissue. The contribution of MAIT cells in the pathogenesis of UC is still unclear; therefore, this study aimed at investigating the role of these cells in patients with UC. METHODS: The frequency of MAIT cells, as well as the production of cytokines and expression levels of activation markers by these cells in the peripheral blood of UC patients and healthy controls, was analyzed by flow cytometry. MAIT cells were also quantified in colon biopsies of UC patients using a confocal microscope. RESULTS: There was a significant reduction in MAIT cell frequency in the peripheral blood of UC patients compared with healthy controls (P < 0.0001). MAIT cells from UC patients secreted more interleukin (IL)-17 than healthy controls (P < 0.05). The expression levels of CD69 on these cells were correlated with disease activity and endoscopic scores and plasma levels of IL-18. Furthermore, MAIT cells increased in the inflamed mucosa, and their frequency was correlated with clinical and endoscopic disease activity in UC patients. CONCLUSIONS: The findings from this study indicate that MAIT cells could be associated with UC and may serve as potential biomarkers or therapeutic targets in UC. PMID- 26590107 TI - Milk Fistula: Diagnosis, Prevention, and Treatment. AB - Milk fistula is an uncommon condition which occurs when there is an abnormal connection that forms between the skin surface and the duct in the breast of a lactating woman, resulting in spontaneous and often constant drainage of milk from this path of least resistance. A milk fistula is usually a complication that results from a needle biopsy or surgical intervention in a lactating patient. Here, the authors present an unusual case of a spontaneous milk fistula which developed from an abscess in the breast of a lactating woman. The patient initially presented to the office with a large open wound on her breast, formed from skin breakdown, within which milk was pooling. She was treated with local wound care and cessation of breastfeeding, with appropriate healing of the wound and closure of the fistula with 6 weeks. Diagnosis, prevention, and treatment of milk fistula were reviewed. PMID- 26590108 TI - Endothelial progenitor cell therapy: From bench to bedside. PMID- 26590109 TI - Priming status-legitimizing beliefs: Examining the impact on perceived anti-White bias, zero-sum beliefs, and support for Affirmative Action among White people. AB - The current research examines how status-legitimizing beliefs (SLBs) influence White people's perceptions of anti-White bias, endorsement of zero-sum beliefs, and support for Affirmative Action. We suggest that SLBs perpetuate inequality by increasing White people's perceptions of zero-sum beliefs and anti-White bias, which in turn lead to decreased support for Affirmative Action. White individuals primed with SLBs perceived greater anti-White bias, endorsed greater zero-sum beliefs, and indicated less support for Affirmative Action than individuals primed with neutral content. Mediation analysis revealed that the SLB prime decreased support for Affirmative Action by increasing perceptions of anti-White bias. This research offers experimental evidence that SLBs contribute to White people's perceptions of anti-White bias and to decreased support for Affirmative Action. PMID- 26590110 TI - Treatment of Type IIIb Endoleaks After EVAR Using the Nellix EndoVascular Aneurysm Sealing System. AB - PURPOSE: To describe the successful endovascular treatment of 2 patients with type IIIb endoleak using the Nellix EndoVascular Aneurysm Sealing (EVAS) System. CASE REPORT: Two men aged 75 and 83 years presented with type IIIb endoleak several years (8 and 3, respectively) after initial endovascular aneurysm repair. Dual Nellix endoprosthesis were deployed in the stent-grafts, and the endobags were filled with polymer to seal the defect and eliminate the endoleak. The perioperative periods were uneventful. At up to 6-month follow-up, no endoleaks were detected, aneurysm diameters were unchanged, and the endografts were patent. One patient died 7 months after revision due to a metastatic malignancy. CONCLUSION: The Nellix EVAS System may prove useful for the treatment of type IIIb endoleak. PMID- 26590111 TI - Estimating the location and size of retinal injections from orthogonal images of an intact retina. AB - BACKGROUND: To study the mapping from the retina to the brain, typically a small region of the retina is injected with a dye, which then propagates to the retina's target structures. To determine the location of the injection, usually the retina is dissected out of the eye, flattened and then imaged, causing tears and stretching of the retina. The location of the injection is then estimated from the image of the flattened retina. Here we propose a new method that avoids dissection of the retina. RESULTS: We have developed IntactEye, a software package that uses two orthogonal images of the intact retina to locate focal injections of a dye. The two images are taken while the retina is still inside the eye. This bypasses the dissection step, avoiding unnecessary damage to the retina, and speeds up data acquisition. By using the native spherical coordinates of the eye, we avoid distortions caused by interpreting a curved structure in a flat coordinate system. Our method compares well to the projection method and to the Retistruct package, which both use the flattened retina as a starting point. We have tested the method also on synthetic data, where the injection location is known. Our method has been designed for analysing mouse retinas, where there are no visible landmarks for discerning retinal orientation, but can also be applied to retinas from other species. CONCLUSIONS: IntactEye allows the user to precisely specify the location and size of a retinal injection from two orthogonal images taken of the eye. We are solving the abstract problem of locating a point on a spherical object from two orthogonal images, which might have applications outside the field of neuroscience. PMID- 26590112 TI - Therapeutic targeting of BET protein BRD4 delays murine lupus. AB - BRD4 is a member of the BET (bromodomain and extraterminal domain) family proteins that can bind acetylated histones and influence transcription, which are considered as potential therapeutic targets in many distinct diseases. And the BET inhibitor JQ1 has been proven to be effective in suppressing multiple inflammatory and autoimmune diseases. This study aimed to examine the therapeutic potential of JQ1 on a lupus model, MRL-lpr mice. Ten-week-old MRL-lpr mice were treated with JQ1 (oral administration of 200mg/kg) or vehicle for 8weeks. The proteinuria, nephritic damage, serum biochemistry, autoantibodies and cytokines were examined. Splenocytes of MRL-lpr mice were isolated for in vitro experiments. Treatment with JQ1 significantly attenuated the progression of proteinuria and nephritis. The serum concentrations of anti-dsDNA antibody as well as B-cell activating factor (BAFF), interleukin (IL)-1beta, IL-6, IL-17 and INF-gamma were inhibited, and IL-10 augmented by JQ1. Importantly, JQ1 improved the survival of lupus mice. In vitro, BAFF, IL-1beta, IL-6, IL-17 and INF-gamma were inhibited, and IL-10 augmented by JQ1 (500nM) in the cultures of splenocytes from diseased MRL-lpr mice, which was further supported by a significant reduction in immune complex-mediated activation of human monocytes in vitro by JQ1. Taken together, JQ1 effectively alleviates lupus in MRL-lpr mice by suppressing BAFF, pro-inflammatory cytokines and autoimmunity, supporting the therapeutic value of JQ1 in lupus disease. PMID- 26590113 TI - Antinociceptive and anti-inflammatory effects of essential oil extracted from Chamaecyparis obtusa in mice. AB - Essential oil extracted from Chamaecyparis obtusa (EOCO) consists of several monoterpenes with anti-inflammatory effects. Monoterpenes are expected to have an analgesic effect through inhibition of pro-inflammatory mediators. The present study investigated the anti-nociceptive and anti-inflammatory effects of EOCO in animal models of pain. Intraperitoneal injection with EOCO (5 or 10mg/kg), aspirin (positive control, 300mg/kg), or DMSO (negative control) was performed 1h before the nociception tests: acetic acid-induced writhing response, formalin test, and hot plate test in mice, and acidic saline-induced allodynia in rats. The expression of pro-inflammatory cytokines and pro-inflammatory enzymes in formalin-injected paws was determined by ELISA and western blotting, respectively. Treatment with EOCO significantly reduced acetic acid-induced writhing and paw-licking time in late response of the formalin tests. The anti nociceptive effect was comparable with aspirin. However, EOCO did not affect the reaction time of licking of the hind paws or jumping in hot plate test and the mechanical withdrawal thresholds in acidic saline-induced allodynia model. Formalin-injected paws of mice treated with EOCO revealed the down-regulated expression of tumor necrosis factor-alpha, interleukin-1beta, inducible nitric oxide synthase, and cyclooxygenase-2, as compared with those of control mice. These data showed the anti-nociceptive and anti-inflammatory effects of EOCO. The pain-relieving effect might be attributed to inhibition of peripheral pain in association with inflammatory response. EOCO could be a useful therapeutic strategy to manage pain and inflammatory diseases. PMID- 26590114 TI - Fisetin inhibits TNF-alpha-induced inflammatory action and hydrogen peroxide induced oxidative damage in human keratinocyte HaCaT cells through PI3K/AKT/Nrf-2 mediated heme oxygenase-1 expression. AB - Oxidative skin damage and skin inflammation play key roles in the pathogenesis of skin-related diseases. Fisetin is a naturally occurring flavonoid abundantly found in several vegetables and fruits. Fisetin has been shown to exert various positive biological effects, such as anti-cancer, anti-proliferative, neuroprotective and anti-oxidative effects. In this study, we investigate the skin protective effects and anti-inflammatory properties of fisetin in hydrogen peroxide- and TNF-alpha-challenged human keratinocyte HaCaT cells. When HaCaT cells were treated with non-cytotoxic concentrations of fisetin (1-20MUM), heme oxygenase (HO)-1 mRNA and protein expression increased in a dose-dependent manner. Furthermore, fisetin dose-dependently increased cell viability and reduced ROS production in hydrogen peroxide-treated HaCaT cells. Fisetin also inhibited the production of NO, PGE2 IL-1beta, IL-6, expression of iNOS and COX 2, and activation of NF-kappaB in HaCaT cells treated with TNF-alpha. Fisetin induced Nrf2 translocation to the nuclei. HO-1 siRNA transient transfection reversed the effects of fisetin on cytoprotection, ROS reduction, NO, PGE2, IL 1beta, IL-6, and TNF-alpha production, and NF-kappaB DNA-binding activity. Moreover, fisetin increased Akt phosphorylation and a PI3K pathway inhibitor (LY294002) abolished fisetin-induced cytoprotection and NO inhibition. Taken together, these results provide evidence for a beneficial role of fisetin in skin therapy. PMID- 26590115 TI - Anti-tumor and immunomodulatory activity of iron hepta-tungsten phosphate oxygen clusters complex. AB - Polyoxometalates (POMs) have attracted a considerable attention due to their unique structural characteristics, physicochemical properties and biological activities. In this study, iron hepta-tungsten phosphate oxygen clusters complex Na12H[Fe(HPW7O28)2].44H2O (IHTPO) was synthesized and evaluated for in vitro cytotoxic activities on human hepatoma HepG2, leukemia K562, lung carcinoma A549, and large cell lung cancer NCI-H460 cells, therapeutic efficacies on mice transplantable tumor, and immunomodulatory potentials on the immune response in tumor-bearing mice. IHTPO exhibited lower in vitro cytotoxic activities against four human tumor cell lines, with the IC50 values being higher than 62.5MUM (ca. 300MUg/ml). IHTPO, however, significantly inhibited the growth of S180 sarcoma transplanted in mice. It was further showed that IHTPO could not only significantly promote splenocytes proliferation, NK cell and CTL activity from splenocytes, but remarkably enhance serum antigen-specific IgG, IgG2a and IgG2b antibody levels in S180-bearing mice. IHTPO also significantly promoted Th1 cytokines IFN-gamma and IL-2 production, and up-regulated the mRNA expression levels of IFN-gamma, IL-2 and Th1 transcription factors T-bet and STAT-4 in splenocytes from the S180-bearing mice. These results suggested that IHTPO significantly inhibited the growth of mice transplantable tumor, and that its in vivo antitumor activity might be achieved by improving Th1 protective cell mediated immunity. IHTPO could act as antitumor agent with immunomodulatory activity. PMID- 26590116 TI - The anti-malaria drug artesunate inhibits cigarette smoke and ovalbumin concurrent exposure-induced airway inflammation and might reverse glucocorticoid insensitivity. AB - BACKGROUND: The anti-malaria drug artesunate has been shown to attenuate experimental allergic asthma via inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. This study was to further determine the effects of artesunate on cigarette smoke and ovalbumin (OVA) concurrent exposure-induced airway inflammation, the related mechanism, and glucocorticoid insensitivity. METHODS AND RESULTS: In vivo: Female BALB/c mice concurrently exposed to cigarette smoke and OVA developed mixed eosinophilic and neutrophilic airway inflammation. Airway hyper-responsiveness, total and differential cell counts, and pro-inflammatory cytokine levels (interleukin (IL)-4, IL-8, IL-13 and tumor necrosis factor (TNF) alpha) in bronchoalveolar lavage fluid (BALF) were measured. Lung tissue sections were stained for histological analysis, and proteins were extracted for Western blotting. Artesunate reduced methacholine-induced airway hyper-responsiveness, suppressed pulmonary inflammation cell recruitment and IL-4, IL-8, IL-13 and TNF alpha levels, selectively inhibited PI3Kdelta/Akt pathway, and restored HDAC2 activity. In vitro: BEAS-2B cells were exposed to cigarette smoke extract (CSE) for 6h and then stimulated with TNF-alpha overnight. Glucocorticoid sensitivity was evaluated by the inhibition of TNF-alpha-induced IL-8 production by dexamethasone. CSE reduced the effects of dexamethasone on TNF-alpha-induced IL-8 production in BEAS-2B cells, while artesunate reversed CSE-induced glucocorticoid insensitivity and restored HDAC2 deactivation induced by CSE. CONCLUSION: Artesunate ameliorated cigarette smoke and OVA concurrent exposure-induced airway inflammation, inhibited the PI3Kdelta/Akt pathway, restored HDAC2 activity, and reversed CSE-induced glucocorticoid insensitivity in BEAS-2B cells. These findings indicate that artesunate might play a protective role in asthma induced by cigarette smoke and glucocorticoid insensitivity. PMID- 26590117 TI - Protective effects of melatonin on lipopolysaccharide-induced mastitis in mice. AB - Melatonin, a secretory product of the pineal gland, has been reported to have antioxidant and anti-inflammatory effects. However, the protective effects of melatonin on lipopolysaccharide (LPS)-induced mastitis have not been reported. The purpose of this study was to investigate the anti-inflammatory effects and the underlying mechanisms of melatonin on LPS-induced mastitis both in vivo and in vitro. In vivo, our results showed that melatonin attenuated LPS-induced mammary histopathologic changes and myeloperoxidase (MPO) activity. Melatonin also inhibited LPS-induced inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) production in mammary tissues. In vitro, melatonin was found to inhibit LPS-induced TNF-alpha and IL-6 production in mouse mammary epithelial cells. Melatonin also suppressed LPS-induced Toll-like receptor 4 (TLR4) expression and nuclear factor-kappaB (NF kappaB) activation in a dose-dependent manner. In addition, melatonin was found to up-regulate the expression of PPAR-gamma. Inhibition of PPAR-gamma by GW9662 reduced the anti-inflammatory effects of melatonin. In conclusion, we found that melatonin, for the first time, had protective effects on LPS-induced mastitis in mice. The anti-inflammatory mechanism of melatonin was through activating PPAR gamma which subsequently inhibited LPS-induced inflammatory responses. PMID- 26590118 TI - Mechanisms of growth inhibition of primary prostate epithelial cells following gamma irradiation or photodynamic therapy include senescence, necrosis, and autophagy, but not apoptosis. AB - In comparison to more differentiated cells, prostate cancer stem-like cells are radioresistant, which could explain radio-recurrent prostate cancer. Improvement of radiotherapeutic efficacy may therefore require combination therapy. We have investigated the consequences of treating primary prostate epithelial cells with gamma irradiation and photodynamic therapy (PDT), both of which act through production of reactive oxygen species (ROS). Primary prostate epithelial cells were cultured from patient samples of benign prostatic hyperplasia and prostate cancer prior to treatment with PDT or gamma irradiation. Cell viability was measured using MTT and alamar blue assay, and cell recovery by colony-forming assays. Immunofluorescence of gamma-H2AX foci was used to quantify DNA damage, and autophagy and apoptosis were assessed using Western blots. Necrosis and senescence were measured by propidium iodide staining and beta-galactosidase staining, respectively. Both PDT and gamma irradiation reduced the colony-forming ability of primary prostate epithelial cells. PDT reduced the viability of all types of cells in the cultures, including stem-like cells and more differentiated cells. PDT induced necrosis and autophagy, whereas gamma irradiation induced senescence, but neither treatment induced apoptosis. PDT and gamma irradiation therefore inhibit cell growth by different mechanisms. We suggest these treatments would be suitable for use in combination as sequential treatments against prostate cancer. PMID- 26590119 TI - Comparison of predictive value of activity limitation staging systems based on dichotomous versus trichotomous responses in the Medicare Current Beneficiary Survey. AB - BACKGROUND: Traditional ways of measuring disability include summary indices, binary expressions, or counts of limitations. However, counts of activity of daily living (ADL) or instrumental activity of daily living (IADL) limitations do not specify which activities are limited. Activity limitation staging systems within the ADL and IADL domains depict both the severity and types of limitations experienced and specify clinically meaningful patterns of increasing difficulty with self-care. OBJECTIVE: To compare the predictive value and utility of ADL and IADL stages based on dichotomous versus trichotomous responses to ADL and IADL questions based on "difficulty" and "receive help" responses. METHODS: Data were analyzed from the 2005, 2006, and 2007 Medicare Current Beneficiary Survey (MCBS) entry panels on 11,706 beneficiaries. This was a prospective cohort study that examined time to inpatient admission, all-cause mortality, skilled nursing facility (SNF) admission, and long-term care (LTC) facility admission based on dichotomous versus trichotomous stages. RESULTS: For both ADLs and IADLs, Akaike information criteria for most outcomes were lower (indicating better-performing models) for the trichotomous staging systems than the dichotomous staging systems. The hazard ratios (HRs) and 95% confidence intervals (CIs) of the dichotomous ADL staging system increased as disability increased, whereas the HRs of the other staging systems fluctuated. CONCLUSIONS: Both staging systems have strong associations with each outcome. The dichotomous staging system is more clinically relevant while the trichotomous staging system may provide utility for clinicians, health care organizations, and policy makers seeking to predict death or admission to a hospital, SNF, or LTC facility. PMID- 26590120 TI - Response to "Measures of aging with disability in NHATS". PMID- 26590121 TI - HOXB13 as an immunohistochemical marker of prostatic origin in metastatic tumors. AB - HOBX13 is a transcription factor expressed in the normal prostatic glands and overexpressed in prostate cancer. Recent studies suggested that HOXB13 represents a prostate-specific marker in the differential diagnosis between prostatic and urothelial carcinoma. The aim of this study was to analyze and compare the diagnostic value of HOXB13 and prostate-specific antigen (PSA) immunoexpression for the detection of prostatic origin in metastatic tumours. PSA and HOXB13 immunohistochemical expression was assessed in 50 metastatic tumors, including 15 metastases from prostatic adenocarcinoma, 11 from lung adenocarcinoma, 12 from urinary bladder urothelial carcinoma, 11 from colorectal carcinoma, and in 1 from hepatocellular carcinoma. Strong staining for HOXB13 was observed in >75% of neoplastic cells in 15/15 (100%) metastases from prostate cancer. Weak staining in <25% of cells was found in 2/12 (17%) metastases from urothelial carcinoma. PSA immunostaining was detected only in 8 (53%) cases of prostatic origin. The sensitivity and specificity for metastatic prostate cancer were 100% and 94% for HOXB13 and 53% and 100% for PSA. Due to its high sensitivity and specificity, HOXB13 may be included in the pool of prostate-specific markers in metastases showing absent or weak staining for PSA before excluding prostatic derivation. PMID- 26590122 TI - Spindle cell squamous cell carcinoma arising from chronic osteomyelitis. PMID- 26590123 TI - Effects of Chronic Endurance Exercise on Doxorubicin-Induced Thymic Damage. AB - The use of prior exercise training has shown promise in minimizing doxorubicin (DOX)-induced physical impairments. The purpose of this study was to compare changes in thymus mass, thymocyte (T-cell) number, and tissue peroxidation following chronic endurance exercise and DOX treatment in the rat. The thymus mass, number of viable T-cells, and levels of malondialdehyde and 4 hydroxyalkenals (MDA+4-HAE) were compared 3 days post-injection between rats assigned to the following treatment conditions: (a) 10 weeks of endurance training, followed by a saline injection 24 hours after the last training session (TM+SAL); (b) treadmill training as above, followed by a single, bolus 10-mg/kg injection of DOX (TM+10); (c) treadmill training with 12.5 mg/kg of DOX (TM+12.5); (d) sedentary (without exercise) and a saline injection (SED+SAL); (e) sedentary with 10 mg/kg of DOX (SED+10); and (f) sedentary with 12.5 mg/kg (SED+12.5). Thymic mass and T-cell numbers significantly decreased following DOX injections. TM rats exhibited significantly less lipid peroxidation compared with paired-dose SED groups. TM+10 did not significantly differ from SED+SAL in thymic levels of lipid peroxidation. We conclude that chronic endurance exercise decreases levels of lipid peroxidation in the thymus seen with acute DOX treatment. PMID- 26590124 TI - Jian Pi Li Qi Decoction Alleviated Postembolization Syndrome Following Transcatheter Arterial Chemoembolization for Hepatocellular Carcinoma: A Randomized, Double-Blind, Placebo-Controlled Trial. AB - OBJECTIVE: To evaluate the effectiveness of Jian Pi Li Qi (JPLQ) decoction in improving quality of life of patients with hepatocellular carcinoma (HCC) following transcatheter arterial chemoembolization (TACE). METHODS: A randomized, double-blind, placebo-controlled trial was conducted. A total of 150 patients with HCC were randomly assigned into 3 groups. Groups were designed as follows: neither herbal medicine nor placebo administration (group A), placebo treatment (group B), and JPLQ decoction treatment (group C). The measurement methods of the observed outcomes include MD Anderson Symptom Inventory-Gastrointestinal module, armpit temperature, and laboratory tests. RESULTS: Among the 140 patients studied, the 12 symptoms rated as most severe, which characterize postembolization syndrome (PES), were fever, pain, fatigue, nausea, disturbed sleep, distress, lack of appetite, drowsiness, dry mouth, vomiting, constipation, and feeling bloated. All these increased significantly (all P < .05) after TACE; 7 symptoms, including fever, pain, fatigue, lack of appetite, drowsiness, dry mouth, and constipation (all P < .05), were found to be relieved significantly by JPLQ. JPLQ also improved the liver function damage caused by TACE. CONCLUSION: JPLQ decoction may be an effective modality to relieve PES and protect liver function in patients with HCC after TACE. PMID- 26590125 TI - Yoga Intervention for Patients With Prostate Cancer Undergoing External Beam Radiation Therapy: A Pilot Feasibility Study. AB - PURPOSE: Studies have demonstrated beneficial health effects from yoga interventions in cancer patients, but predominantly in breast cancer. Research on its role in alleviating prostate cancer (PC) patients' side effects has been lacking. Our primary goal was to determine the feasibility of recruiting PC patients on a clinical trial of yoga while they underwent external beam radiation therapy (RT). METHODS: Twice-weekly yoga interventions were offered throughout the RT course (6-9 weeks). Baseline demographic information was collected. Feasibility was declared if 15 of the first 75 eligible PC patients approached (20%) were successfully accrued and completed the intervention. Additional end points included standardized assessments of fatigue, erectile dysfunction (ED), urinary incontinence (UI), and quality of life (QOL) at time points before, during, and after RT. RESULTS: Between May 2013 and June 2014, 68 eligible PC patients were identified. 23 patients (34%) declined, and 45 (56%) consented to the study. 18 (40%) were voluntarily withdrawn due to treatment conflicts. Of the remaining 27, 12 (30%) participated in >=50% of classes, and 15 (59%) were evaluable. Severity of fatigue scores demonstrated significant variability, with fatigue increasing by week 4, but then improving over the course of treatment (P = .008). ED, UI, and general QOL scores demonstrated reassuringly stable, albeit not significant trends. CONCLUSIONS: A structured yoga intervention of twice weekly classes is feasible for PC patients during a 6- to 9-week course of outpatient radiotherapy. Preliminary results are promising, showing stable measurements in fatigue, sexual health, UI, and general QOL. PMID- 26590126 TI - Flux balance analysis of primary metabolism in the diatom Phaeodactylum tricornutum. AB - Diatoms (Bacillarophyceae) are photosynthetic unicellular microalgae that have risen to ecological prominence in oceans over the past 30 million years. They are of interest as potential feedstocks for sustainable biofuels. Maximizing production of these feedstocks will require genetic modifications and an understanding of algal metabolism. These processes may benefit from genome-scale models, which predict intracellular fluxes and theoretical yields, as well as the viability of knockout and knock-in transformants. Here we present a genome-scale metabolic model of a fully sequenced and transformable diatom: Phaeodactylum tricornutum. The metabolic network was constructed using the P. tricornutum genome, biochemical literature, and online bioinformatic databases. Intracellular fluxes in P. tricornutum were calculated for autotrophic, mixotrophic and heterotrophic growth conditions, as well as knockout conditions that explore the in silico role of glycolytic enzymes in the mitochondrion. The flux distribution for lower glycolysis in the mitochondrion depended on which transporters for TCA cycle metabolites were included in the model. The growth rate predictions were validated against experimental data obtained using chemostats. Two published studies on this organism were used to validate model predictions for cyclic electron flow under autotrophic conditions, and fluxes through the phosphoketolase, glycine and serine synthesis pathways under mixotrophic conditions. Several gaps in annotation were also identified. The model also explored unusual features of diatom metabolism, such as the presence of lower glycolysis pathways in the mitochondrion, as well as differences between P. tricornutum and other photosynthetic organisms. PMID- 26590127 TI - Association between perfluoroalkyl acids and kidney function in a cross-sectional study of adolescents. AB - BACKGROUND: Perfluoroalkyl acids are synthetic compounds widely used in industrial and commercial applications. Laboratory studies suggest that these persistent and bioaccumulative chemicals produce oxidant stress and damage glomerular endothelial cells, raising concern regarding the impact of these compounds on renal function. METHODS: We performed cross-sectional analyses of data 1960 participants aged 12-19 years of the 2003-2010 National Health and Nutrition Examination Surveys. PFAA exposure was assessed using levels of perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid, and perfluorohexane sulfonic acid. Primary study outcomes were estimated glomerular filtration rate (eGFR) and serum uric acid. RESULTS: While adjusting for demographics, cotinine, prehypertension, insulin resistance, body mass index, and hypercholesterolemia, adolescents in the highest PFOA and PFOS quartile had a lower eGFR, 6.84 mL/min/1.73 m(2) (95% CI: 2.19 to 11.48) and 9.69 mL/min/1.73 m(2) (95 % CI: -4.59 to 14.78), respectively, compared to the lowest quartile. Highest PFOA and PFOS quartiles were also associated with 0.21 mg/dL (95% CI: 0.056 to 0.37) and 0.19 mg/dL (95% CI: 0.032 to 0.34) increases in uric acid, respectively. CONCLUSIONS: PFAAs are associated with a reduction in kidney function and increased uric acid levels in otherwise healthy adolescents. Reverse causation and residual confounding could explain the results. Our study results confirm and amplify previous findings, though longitudinal studies examining prenatal and childhood biomarkers in relationship with robust measures of childhood renal function are needed. PMID- 26590128 TI - A randomized pilot study on the effect of niacin on pulmonary arterial pressure. AB - BACKGROUND: Niacin induces the release of vasodilating prostaglandins, for which receptors are present within the pulmonary arterial circulation. We hypothesized that immediate-release niacin would reduce right ventricular systolic pressure in patients with pulmonary hypertension in a randomized, double-blinded, single-dose provocation study. METHODS: We recruited inpatient subjects with a Doppler echocardiogram showing a peak tricuspid regurgitation (TR) jet velocity of 2.7 m/s or greater, and who were free of known pulmonary vascular disease. Subjects were randomized in a 1:2:2 ratio to receive a single dose of either placebo, niacin 100 mg or niacin 500 mg, respectively. TR jet velocities were measured immediately before, and 1 hour post dose, corresponding to peak niacin absorption and prostaglandin release. The primary endpoint was the change in mean TR jet velocity measured over ten successive cardiac cycles. RESULTS: The baseline mean estimated right ventricular systolic pressure (RVSP) for all 49 subjects (25 male) was 51.9 +/- 12.1 mm Hg. The primary endpoint of mean change in TR jet velocity was 0.016 +/- 0.065 m/s in the placebo group, compared to -0.017 +/- 0.065 m/s with niacin 100 mg, and -0.063 +/- 0.038 m/s with niacin 500 mg (P = 0.63). The change in maximum estimated RVSP across the three drug groups was 0.2 +/- 1.6 mm Hg, -1.3 +/- 1.8 mm Hg and -2.2 +/- 1.2 mm Hg (P = 0.62). In exploratory pairwise analysis in the high-dose niacin group (500 mg), the reduction in mean RVSP was from 50.9 +/- 9.4 mm Hg to 48.7 +/- 10.0 mm Hg (P = 0.09). CONCLUSIONS: A single dose of immediate-release niacin (100 mg or 500 mg) had no significant effect on RVSP 1 hour post administration. A nonsignificant dose-dependent trend for a modest reduction in RVSP, most notable in the 500 mg group, was noted. (ISRCTN number 12353191, registered April 23, 2015). PMID- 26590129 TI - Analysis of surgically excised breast masses in 119 pediatric patients. AB - PURPOSE: Breast masses in children and adolescents are uncommon and the vast majority are benign. There are currently limited analyses of breast masses in this population and clinical management is highly variable between institutions and providers. The purpose of our study is to analyze the demographics, pathology and management of 119 pediatric patients with breast masses; one of the largest studies to date. METHODS: We performed a retrospective review of patients who underwent excision of a breast mass at a single pediatric center from June 2009 to November 2013. Demographics, imaging, pathology and management were reviewed. RESULTS: Average patient age was 15.3 years, average mass size was 3.15 cm and 20.3 % had a family history of breast cancer. 68 % of patients had pre-operative ultrasound, and 31.9 % underwent a period of observation. The most common indication for resection was patient and family anxiety. All masses were benign, with fibroadenoma being the most common histopathology (75.2 %). CONCLUSIONS: In our cohort there were no cases of malignancy. Only 31.9 % of patients underwent some form of observation and patient or family anxiety was the most common indication for proceeding with surgery. This suggests that patient anxiety may result in unnecessary operation. Our data may help reassure patients, families and providers that the risk of malignancy is low and could help develop more optimal management strategies. PMID- 26590130 TI - Effects of Qigong Exercise on Biomarkers and Mental and Physical Health in Adults With at Least One Risk Factor for Coronary Artery Disease. AB - Current medical technology permits the early detection of risk factors for coronary artery disease (CAD) in adults, and interventions are available to prevent CAD-related morbidity and mortality. The goal of this study was to determine the effectiveness of a Qigong exercise intervention in improving biomarker levels and mental and physical health outcomes in community-dwelling adults diagnosed with CAD risk factors, in a southern Taiwanese city. Participants were randomly assigned to an experimental (n= 84) group that participated in a 60-min Qigong group session 3 times per week for 3 months or a control (n= 61) group that did not receive the intervention. Self-perceived mental and physical health assessed with the Chinese Health Questionnaire-12, and body fat percentage were measured at baseline and 6, 12, and 16 weeks. Blood samples were collected at baseline and 12 weeks for analysis of lipid profiles, high-sensitivity C-reactive protein (hs-CRP), glycated hemoglobin (HbA1c), and fasting plasma sugar. Linear mixed model analyses revealed that experimental participants had significantly improved perceived mental and physical health and body fat percentage compared to the control group at 6 and 12 weeks but not 16 weeks. The lipid profiles were significantly more improved in the Qigong group than in the control group at 12 weeks. Qigong exercise, however, had no significant effects on hs-CRP, HbA1c, or fasting plasma sugar. Findings suggest that Qigong exercise improves a limited number of CAD risk factors in community dwelling adults aged 40 years and over. PMID- 26590131 TI - Frequency of the moyamoya-related RNF213 p.Arg4810Lys variant in 1,516 Korean individuals. AB - BACKGROUND: Moyamoya disease (MMD) is a progressive steno-occlusive vasculopathy that involves large intracranial arteries accompanied by abnormal collateral vessels. Recently, RNF213 was identified as a susceptibility gene for MMD and p.Arg4810Lys (rs112735431) is the most common variant in East Asian MMD patients. Interestingly, many studies have reported that a certain proportion of the general population in Japan, Korea, and China also has this variant. In this study, we investigated the frequency of this variant and estimated an odds ratio of MMD using two different Korean populations. METHODS: A total of 1,516 anonymous DNA samples, 799 from an umbilical cord blood bank and 717 from routine health-checked adults, were genotyped using targeted Sanger sequencing. RESULTS: The p.Arg4810Lys variant was detected at genotype frequencies of 2.25% (18/799; 95% confidence interval (CI), 1.43-3.53%) in cord blood samples and 2.65% (19/717; 95% CI, 1.70-4.10%) in adult samples, respectively. This variant showed a strong association with MMD (P < 0.001), giving an odds ratio of 162.7 (95% CI, 65.5-403.9) and 137.8 (95% CI, 55.8-339.9) based on the cord blood and adults samples, respectively. CONCLUSIONS: These results confirm that the RNF213 p.Arg4810Lys variant is not uncommon in the general Korean population and provide reference data for the association of this variant and MMD. PMID- 26590132 TI - Meta-analytic approaches to determine gender differences for delayed healing in venous leg ulcers. AB - Objective The aim of this analysis was to perform a meta-analysis evaluating gender difference of delayed healing risk in patients with venous leg ulcers. Methods We searched the PubMed and Web of Knowledge from their inception to 4 July 2015. The meta-analysis of pooled odds ratio and 95% confidence interval for venous leg ulcers healing risk were calculated. Results Twelve studies with 4453 patients were included in the meta-analysis. The pooled odds ratio for healing rate stratified by gender was 1.055 (95% CI 0.955-1.165; Z = 1.05, p = 0.292) by fix-effects model. The Begg's test (z = 2.67, p = 0.007), the Egger's test (t = 4.00, p = 0.003), and asymmetric funnel plot suggested there was significant publication bias. Subgroup analysis showed the pooled odds ratios were 1.048 (95% CI 0.945-1.162; Z = 0.88, p = 0.376) in prospective studies and 1.439 (95% CI 0.757-2.736; Z = 1.11, p = 0.266) in retrospective studies. Sensitivity analyses by only pooled adjusted odds ratios showed the pooled odds ratio was 1.049 (95% CI 0.946-1.163; Z = 0.91, p = 0.365), which indicated the results of meta analysis were robust. Meta-regression analysis showed the healing rate odds ratio stratified by gender was not related with healing rate (t = 0.73, p = 0.484). Conclusion Our meta-analysis indicates that no gender difference existed for delayed healing in venous leg ulcers. Our results may be also useful in developing a risk score for failure of venous leg ulcers to heal. PMID- 26590134 TI - Kinship analysis: assessment of related vs unrelated based on defined pedigrees. AB - The study aimed at evaluating whether the adoption of enlarged batteries of STR markers in kinship analysis may provide LR values suitable for discrimination of relatives from non-relatives, in comparison to conventionally used STR panels. The presence of LD among some loci and its effects on LR values were also assessed. Three hundred pairs of related and unrelated individuals, each separated from 1-3 generations and residing in North Italy were genotyped with the Investigator HDplex STR kit (Qiagen), AmpFlSTR Identifiler (Applied Biosystems), and PowerPlex Fusion System (Promega). Loci and alleles shared between each pair and within groups of relatives were compared. Also, combined LR values with and without loci in LD, sensitivity and specificity were calculated for each commercial kit and their combinations. Full siblings displayed the largest number of shared loci and alleles, with a proportion of LR >= 10 results significantly higher than other degrees of relatedness and, consequently, with the lowest percentage of inconclusive and false negative results. Only minor differences were detected in the combined LR distributions, after including or omitting loci in LD. However, these became only appreciable when analyzing more distant relative pairs.The implementation of additional STRs into the LR calculation allowed a complete and robust discrimination between relatives and non-relatives only for full siblings, by removing the typical uncertainty of the "grey zone", while this was not achieved among other degrees of relatedness. Furthermore, the presence of loci in LD seems to not significantly affect LR distributions within each generation. PMID- 26590135 TI - Genes, Culture and Conservatism-A Psychometric-Genetic Approach. AB - The Wilson-Patterson conservatism scale was psychometrically evaluated using homogeneity analysis and item response theory models. Results showed that this scale actually measures two different aspects in people: on the one hand people vary in their agreement with either conservative or liberal catch-phrases and on the other hand people vary in their use of the "?" response category of the scale. A 9-item subscale was constructed, consisting of items that seemed to measure liberalism, and this subscale was subsequently used in a biometric analysis including genotype-environment interaction, correcting for non homogeneous measurement error. Biometric results showed significant genetic and shared environmental influences, and significant genotype-environment interaction effects, suggesting that individuals with a genetic predisposition for conservatism show more non-shared variance but less shared variance than individuals with a genetic predisposition for liberalism. PMID- 26590133 TI - A before and after cross-sectional analysis of a public health campaign to increase kidney health awareness in a Canadian province. AB - BACKGROUND: Chronic kidney disease (CKD) has a major impact on patient health and health system resources. The prevalence of kidney disease is increasing, with Manitoba being one of the provinces in Canada with the highest per capita rate of CKD and end stage renal disease (Anonymous, Canadian organ replacement register annual report: treatment of end-stage organ failure in Canada, 2001-2010, 2011). In 2011, a public health campaign to promote kidney health, by increasing awareness of CKD and its risk factors, was created to target high-risk individuals such as First Nations and those with hypertension and diabetes in urban and rural/remote Manitoba. In this study, we aimed to determine the effectiveness of this public health campaign on increasing the awareness of CKD. METHODS: Our public health campaign ran in March 2011, and employed a multifaceted approach with radio, television, internet, and print advertisements. Campaign awareness and understanding of the public health message were assessed with a telephone omnibus survey of randomly selected individuals with a Manitoba area code during February and April 2011. A before and after cross-sectional analysis was utilized to measure the effect of exposure to the campaign in telephone respondents. RESULTS: 1606 individuals participated in the survey (804 pre and 802 post). Overall awareness of the campaign messaging increased from 7% pre campaign to 25% in the post campaign period. Approximately two-thirds of respondents correctly identified a main theme message of the campaign. Awareness improved across most subgroups surveyed aside from those with lower education and income. CONCLUSIONS: Our study demonstrates the effective reach of our campaign and its relative effectiveness at raising awareness of chronic kidney disease and its risk factors. PMID- 26590136 TI - A first reported case of clear cell carcinoma associated with delayed extrusion of midurethral tape. AB - We present the first reported case of clear cell carcinoma associated with a midurethral tape (MUT), the possible hypotheses and the management pitfalls we encountered. We report a 58-year-old woman who presented with symptoms of urinary tract infection and acute retention of urine associated with vaginal tape exposure 10 years after placement of an inside-out transobturator tape. She subsequently had a partial transobturator tape excision and a diagnostic cystoscopy, which revealed inflammatory changes within the urethra. Postoperatively, her symptoms persisted and the vaginal epithelium healed poorly. A biopsy of the friable tissue reported clear cell carcinoma. Imaging showed a locally invasive periurethral mass and bony and lymphatic metastases. This was treated with palliative radiation therapy. She was still receiving palliative care 5 months after the initial surgery. PMID- 26590137 TI - A systematic review and meta-analysis on the efficacy of intravesical therapy for bladder pain syndrome/interstitial cystitis. AB - Bladder pain syndrome/interstitial cystitis (BPS/IC) is a chronic disease characterised by persistent irritating micturition symptoms and pain. The objective was to compare the clinical efficacy of currently available products for intravesical therapy of BPS/IC and to assess their pharmacoeconomic impact. A Pubmed/Medline database search was performed for articles on intravesical therapy for BPS/IC. A total of 345 publications were identified, from which 326 were excluded. Statistical evaluation was performed with effect size (ES) assessment of symptom reduction and response rates. The final set of 19 articles on intravesical BPS/IC therapy included 5 prospective controlled trials (CTs), the remaining were classified as uncontrolled clinical studies. The total number of patients included was 801, 228 of whom had been evaluated in a CT. For CTs, the largest ES for symptom reduction as well as response rate was observed for high molecular weight hyaluronic acid (HMW-HA), with similar findings in two uncontrolled studies with HMW-HA. The number needed to treat to achieve a response to intravesical therapy was 2.67 for intravesical pentosan polysulphate and 1.31 for HMW-HA which were superior to all other instillates. HMW-HA was significantly superior in cost effectiveness and cost efficacy to all other instillation regimes. The present meta-analysis combined medical and pharmacoeconomic aspects and demonstrated an advantage of HMW-HA over other instillation agents; however, direct comparisons between the different products have not been performed to date in properly designed controlled studies. PMID- 26590139 TI - Do Flexible Goal Adjustment and Acceptance Help Preserve Quality of Life in Patients with Multiple Sclerosis? AB - BACKGROUND: Goal regulation strategies such as flexible goal adjustment and acceptance are believed to be protective factors in persons with chronic illness, but research on their relative contributions to quality of life in multiple sclerosis (MS) is lacking. PURPOSE: We aimed to test the idea that acceptance and flexible goal adjustment (in contrast to tenacious goal pursuit) may help preserve the quality of life in persons with MS. METHOD: A sample of 117 patients with MS was recruited. They completed questionnaires measuring quality of life (physical functioning, psychological distress), acceptance, flexible goal adjustment, and tenacious goal pursuit. RESULTS: Acceptance significantly accounted for variance in all three indexes of quality of life, beyond the effects of demographic and illness characteristics. The role of goal regulation style was less clear. Flexible goal adjustment significantly accounted for psychological well-being only. Surprisingly, tenacious goal pursuit predicted better psychological functioning and less psychological distress. No support was found for the hypothesis that acceptance and flexible goal adjustment would moderate the relation between illness severity and quality of life. CONCLUSION: The findings suggest the potential importance of acceptance in understanding MS patients' quality of life, although its hypothesized protective function could not be confirmed. Further conceptual work on acceptance and goal regulation style is needed, as well as prospective work investigating their causal status. PMID- 26590140 TI - Clinical Characteristics and Referral Patterns of Outpatients Visiting a Japanese Psychosomatic Medicine Clinic. AB - BACKGROUND: The definition of psychosomatic medicine is not consistent across countries. PURPOSE: The study purpose was to clarify the applicability of the definition of psychosomatic illness issued by the Japanese Society of Psychosomatic Medicine to different types of referral in a university hospital. METHODS: The sample consisted of 1067 outpatients visiting a psychosomatic clinic. Participants completed questionnaires to assess degrees of somatization, depression, anxiety, and psychosocial stress after completing clinical interviews based on the Diagnostic and Statistical Manual, Fourth Edition, Text Revision. All subjects were classified into psychosomatic and non-psychosomatic groups, and the non-psychosomatic group was further divided into three additional groups: depression, anxiety, and other. RESULTS: In total, 398 (37 %) of the subjects were placed in the psychosomatic group. The percentage of the psychosomatic group was 46 % in those referred within the hospital, 37 % in those referred outside the hospital, and 28 % in those without referral from physicians. Concerning the non-psychosomatic group, 269 (25 %) were placed in the depression group, 229 (22 %) in the anxiety group, and 171 (16 %) in the other group. Membership in the psychosomatic group was positively associated with age and the severity of somatosensory amplification (both p < 0.05), but negatively associated with the severity of depression and anxiety as well as the classification of non-referral (all p < 0.05). CONCLUSIONS: Although patients with psychiatric disorders, including depressive and anxiety disorders, are frequently seen in the Japanese psychosomatic clinic, patients who are diagnosed with psychosomatic illnesses tend to have been referred by physicians within the hospital. The concept of psychosomatic medicine needs to be further developed to assist both clinical practitioners and patients. PMID- 26590141 TI - Academic Psychiatry Elective: Mentored Academic Leadership Development for Medical Students. PMID- 26590138 TI - Understanding Pain and Depression in Back Pain: the Role of Catastrophizing, Help /Hopelessness, and Thought Suppression as Potential Mediators. AB - PURPOSE: The cognitive mediation hypothesis describes the influence of psychological factors on the relationship between pain and depression such as cognitions of catastrophizing and help-/hopelessness. More recent research also emphasizes the role of suppression of negative thoughts and experiences such as pain. However, there is little research investigating direct and indirect effects of these contrasting cognitions. METHOD: A total of 164 acute and sub-acute non specific back pain patients participated in this study. Pain intensity, depression, and pain-related cognitions were measured using questionnaires, such as the Beck Depression Inventory and the Kiel Pain Inventory. Data were analyzed using structural equation modeling. RESULTS: The results of the path analysis support the hypothesis that cognitive coping strategies have a mediating effect on pain and depression. Consistent with previous research, we found that pain had no direct relation with depression. Help-/hopelessness had a direct path to depression, whereas catastrophizing had an indirect effect via increased help /hopelessness. The current results also indicate that thought suppression mediated the relationship between pain and depression via both direct and indirect effects. CONCLUSION: Cognitive mediators, such as help-/hopelessness, catastrophizing, and thought suppression, have a significant impact on depression in patients with acute and sub-acute back pain. The current results may aid in the optimization of treatments for these patients by focusing attention toward the modification of dysfunctional cognitive pain-coping strategies. PMID- 26590142 TI - Population Dynamics of the Swallowtail Butterfly Battus polystictus polystictus (Butler) (Lepidoptera: Papilionidae) with Notes on Its Natural History. AB - Battus polystictus (Butler) is a butterfly from the Neotropical region, occurring in the Atlantic Forest and Pampa biomes. It is commonly found in forest fragments surrounded by meadow formations, subjected to marked seasonal changes. Here, we report the population dynamics of B. polystictus at a high latitude environment and provide notes on its natural history. Population parameters were estimated on a 12-month mark-recapture program and the seasonality of resources investigated by exhaustive mapping of host-plants and flowers. The number of butterflies per day was not stable during the year, ranging from zero (winter) to 22 (summer); the sex ratio was always male biased (3M:1F). The age structure was not constant, with an increase of older individuals toward summer. The population density was positively correlated with temperature, relative humidity, and day length. The residence time was lower for males, while the vagility was lower for females; the increment of resources at forest edges seems to increase the likelihood of occurrence of both sexes. The results shown here suggest that South Brazilian populations of B. polystictus have high ecological demands for spring and summer conditions, avoiding winter in diapause. PMID- 26590143 TI - A Minimal Invasive Method to Forecast the Effects of Anthropogenic Disturbance on Tropical Cave Beetle Communities. AB - Many tropical landscapes are changing rapidly, with uncertain outcomes for biodiversity, landscape function, and the corresponding landscape services. Therefore, monitoring and adaptively managing the drivers and consequences of landscape change while sustaining the production of essential resources have become research and policy priorities. In this perspective, we have applied a recent framework, the stochastic dynamic methodology (StDM), with the purpose of understanding the effects of natural and anthropogenic disturbances on caves' integrity using cave beetle communities (Coleoptera) as ecological indicators. The proposed method was preceeded by a generalized linear model for discriminating significant relationships between the selected indicators, the structural changes in the caves, and the epigean habitats associated. The obtained results showed different ecological trends in response to the environmental changes. Overall, the simulation results seem to demonstrate the StDM reliability in determining the effects of habitat dynamics, that is, the expansion of agricultural activities, in areas near the caves in the structure of cave beetle communities. The applied method, based on universal information theoretic principles, can be easily implemented and interpreted by environmental managers and decision makers, enabling anticipating impacts and supporting the development of measures aimed at minimizing the identified problems. PMID- 26590144 TI - Unravelling the role of allochthonous aquatic resources to food web structure in a tropical riparian forest. AB - The role of matter and energy flow across ecosystem boundaries for the subsidized consumer populations is well known. However, little is known on the effects of allochthonous subsidies on food web structure and trophic niche dimensions of consumers in the tropics. We excluded allochthonous aquatic insects from tropical streams using greenhouse-type exclosures to test the influence of aquatic allochthonous subsidies on the trophic structure and niche dimensions of terrestrial predators using stable isotope methods. In exclosure treatments, abundance and biomass of terrestrial predators, and biomass of phytophages decreased and increased, respectively. Vegetation-living predators were more responsive to allochthonous inputs than those living on the ground. Overall, lower availability of allochthonous inputs did not affect community-wide metrics and niche width of predators. However, the niche width of some spider families had very low overlap between treatments, and others had wider isotopic niches in the control than in the exclusion treatment. Most of the C and N in predators living in control stretches came from aquatic subsidies, and those predators living in the exclusion treatments switched their diets to terrestrial sources, showing a preference of predators for allochthonous subsidies. Our results suggest that allochthonous subsidies are also relevant to tropical fauna living upon vegetation. Moreover, allochthonous resources may amplify the niche dimension of certain predators or considerably change the trophic niche of others. Our study highlights the importance of including modern isotopic tools in elucidating the role of allochthonous resources on the patterns of trophic structure and niche dimensions of consumers from donor ecosystems. PMID- 26590145 TI - Dissipation kinetics of emamectin benzoate and lufenuron residues in cabbage grown under field conditions. AB - Residue analysis of emamectin benzoate and lufenuron in cabbage matrices and soil was developed using a quick, easy, cheap, effective, rugged, and safe (QuEChERS) method and ultra high-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The samples were extracted with 1% acetic acid in acetonitrile (v/v) or 1% acetic acid in acetonitrile/water (5:1, v/v) and cleaned up by dispersive solid-phase extraction. Mean recoveries and relative standard deviations (RSDs) in all samples ranged 87.8-100.0 % and 3.6-12.6% for emamectin benzoate and 87.8-104.8 % and 6.2-11.5% for lufenuron, respectively. The validated method was used to evaluate the dissipation rate of emamectin benzoate and lufenuron in cabbage and soil as well as the residual levels in harvested cabbage and soil at different preharvest intervals (PHI). The half-lives of emamectin benzoate and lufenuron were 1.08-2.70 and 1.74-5.04 days in cabbage, and 1.42-4.01 and 0.94-6.18 days in soil, respectively. The terminal residues were below the China maximum residue limits (MRLs) at 3 days for emamectin benzoate (0.1 mg kg(-1)) and European Union MRLs at 5 days for lufenuron (0.5 mg kg(-1)), which suggested that 5 days could be recommended as the PHI for the commercial formulation of emamectin benzoate and lufenuron application in the Chinese cabbage field. PMID- 26590146 TI - Assessment of public perception and environmental compliance at a pulp and paper facility: a Canadian case study. AB - Communities across Canada rely heavily on natural resources for their livelihoods. One such community in Pictou County, Nova Scotia, has both benefited and suffered, because of its proximity to a pulp and paper mill (currently owned by Northern Pulp). Since production began in 1967, there have been increasing impacts to the local environment and human health. Environmental reports funded by the mill were reviewed and compared against provincial and federal regulatory compliance standards. Reports contrasted starkly to societal perceptions of local impacts and independent studies. Most environmental monitoring reports funded by the mill indicate some levels of compliance in atmospheric and effluent emissions, but when compliance targets were not met, there was a lack of regulatory enforcement. After decades of local pollution impacts and lack of environmental compliance, corporate social responsibility initiatives need implementing for the mill to maintain its social licence to operate. PMID- 26590147 TI - Effect of bacillus Calmette-Guerin vaccination on CD4+Foxp3+ T cells during acquired immune response to Mycobacterium tuberculosis infection. AB - Increasing information has shown that many newly emerging strains of Mycobacterium tuberculosis, including the highly prevalent and troublesome Beijing family of strains, can potently induce the emergence of Foxp3(+)CD4 Tregs Although the significance of this is still not fully understood, we have previously provided evidence that the emergence of this population can significantly ablate the protective effect of BCG vaccination, causing progressive fatal disease in the mouse model. However, whether the purpose of this response is to control inflammation or to directly dampen the acquired immune response is still unclear. In the present study, we have shown, using both cell depletion and adoptive transfer strategies, that Tregs can have either properties. Cell depletion resulted in a rapid, but transient, decrease in the lung bacterial load, suggesting release or temporary re-expansion of effector immunity. Transfer of Tregs into Rag2(-/-)or marked congenic mice worsened the disease course and depressed cellular influx of effector T cells into the lungs. Tregs from infected donors seemed to preferentially depress the inflammatory response and granulocytic influx. In contrast, those from BCG-vaccinated and then challenged donors seemed more focused on depression of acquired immunity. These qualitative differences might be related to increasing knowledge reflecting the plasticity of the Treg response. PMID- 26590148 TI - SIK inhibition in human myeloid cells modulates TLR and IL-1R signaling and induces an anti-inflammatory phenotype. AB - Macrophage polarization into a phenotype producing high levels of anti inflammatory IL-10 and low levels of proinflammatory IL-12 and TNF-alpha cytokines plays a pivotal role in the resolution of inflammation. Salt-inducible kinases synergize with TLR signaling to restrict the formation of these macrophages. The expression and function of salt-inducible kinase in primary human myeloid cells are poorly characterized. Here, we demonstrated that the differentiation from peripheral blood monocytes to macrophages or dendritic cells induced a marked up-regulation of salt-inducible kinase protein expression. With the use of 2 structurally unrelated, selective salt-inducible kinase inhibitors, HG-9-91-01 and ARN-3236, we showed that salt-inducible kinase inhibition significantly decreased proinflammatory cytokines (TNF-alpha, IL-6, IL-1beta, and IL-12p40) and increased IL-10 secretion by human myeloid cells stimulated with TLR2 and-4 agonists. Differently than in mouse cells, salt-inducible kinase inhibition did not enhance IL-1Ra production in human macrophages. Salt-inducible kinase inhibition blocked several markers of proinflammatory (LPS + IFN-gamma) polarized macrophages [M(LPS + IFN-gamma)] and induced a phenotype characterized by low TNF-alpha/IL-6/IL-12p70 and high IL-10. The downstream effects observed with salt-inducible kinase inhibitors on cytokine modulation correlated with direct salt-inducible kinase target (CREB-regulated transcription coactivator 3 and histone deacetylase 4) dephosphorylation in these cells. More importantly, we showed for the first time that salt-inducible kinase inhibition decreases proinflammatory cytokines in human myeloid cells upon IL-1R stimulation. Altogether, our results expand the potential therapeutic use of salt-inducible kinase inhibitors in immune-mediated inflammatory diseases. PMID- 26590150 TI - Barrier-induced dielectric counterion relaxation at super-low frequencies in salt free polyelectrolyte solutions. AB - Based on the thermally activated diffusion of counterions over the barrier of the electrostatic binding potential, we construct a scaling theory for the slow dielectric response in dilute and semi-dilute polyelectrolyte solutions. The theory is based on an analytic evaluation of the mean-escape time of a single counterion from the surface of a polyelectrolyte chain and uses a variational expression for the electrostatic potential of a charged cylinder including counterion condensation. This mean-escape time shows a range of characteristic power-law dependencies on the polyelectrolyte length and the polyelectrolyte monomer concentration. The existence of this novel dielectric mode at super-low frequencies reflects the wide spectrum of experimental findings for the super-low frequency dielectric relaxation mode and thereby helps to reconcile conflicting interpretations of experimental data in terms of conventional scaling laws. We also devise a scaling theory for the counterion condensation of finite-length polyelectrolyte chains at finite concentration, which allows us to include polyelectrolyte charge renormalization in dilute as well as semi-dilute solutions in a unified theoretical framework. PMID- 26590149 TI - WASp-dependent actin cytoskeleton stability at the dendritic cell immunological synapse is required for extensive, functional T cell contacts. AB - The immunological synapse is a highly structured and molecularly dynamic interface between communicating immune cells. Although the immunological synapse promotes T cell activation by dendritic cells, the specific organization of the immunological synapse on the dendritic cell side in response to T cell engagement is largely unknown. In this study, confocal and electron microscopy techniques were used to investigate the role of dendritic cell actin regulation in immunological synapse formation, stabilization, and function. In the dendritic cell-restricted absence of the Wiskott-Aldrich syndrome protein, an important regulator of the actin cytoskeleton in hematopoietic cells, the immunological synapse contact with T cells occupied a significantly reduced surface area. At a molecular level, the actin network localized to the immunological synapse exhibited reduced stability, in particular, of the actin-related protein-2/3 dependent, short-filament network. This was associated with decreased polarization of dendritic cell-associated ICAM-1 and MHC class II, which was partially dependent on Wiskott-Aldrich syndrome protein phosphorylation. With the use of supported planar lipid bilayers incorporating anti-ICAM-1 and anti-MHC class II antibodies, the dendritic cell actin cytoskeleton organized into recognizable synaptic structures but interestingly, formed Wiskott-Aldrich syndrome protein-dependent podosomes within this area. These findings demonstrate that intrinsic dendritic cell cytoskeletal remodeling is a key regulatory component of normal immunological synapse formation, likely through consolidation of adhesive interaction and modulation of immunological synapse stability. PMID- 26590151 TI - Stochastic analysis of the time evolution of laminar-turbulent bands of plane Couette flow. AB - This article is concerned with the time evolution of the oblique laminar turbulent bands of transitional plane Couette flow under the influence of turbulent noise. Our study is focused on the amplitude of modulation of turbulence (the bands). In order to guide the numerical study of the flow, we first perform an analytical and numerical analysis of a Stochastic Ginzburg Landau (GL) equation for a complex order parameter. The modulus of this order parameter models the amplitude of modulation of turbulence. Firstly, we compute the autocorrelation function of said modulus once the band is established. Secondly, we perform a calculation of average and fluctuations around the exponential growth of the order parameter. This type of analysis is similar to the Stochastic Structural Stability Theory (S3T). We then perform numerical simulations of the Navier-Stokes equations in order to confront these predictions with the actual behaviour of the bands. Computation of the autocorrelation function of the modulation of turbulence shows quantitative agreement with the model: in the established band regime, the amplitude of modulation follows an Ornstein-Uhlenbeck process. In order to test the S3T predictions, we perform quench experiments, sudden decreases of the Reynolds number from uniform turbulence, in which modulation appears. We compute the average evolution of the amplitude of modulation and the fluctuations around it. We find good agreement between numerics and modeling. The average trajectory grows exponentially, at a rate clearly smaller than that of the formation of laminar holes. Meanwhile, the actual time evolution remains in a flaring envelope, centered on the average, and expanding at the same rate. These results provide further validation of the stochastic modeling for the time evolution of the bands for further studies. Besides, they stress on the difference between the oblique band formation and the formation of laminar holes. PMID- 26590152 TI - Theoretical study of actin layers attachment and separation. AB - We use the theory of active gels to study theoretically the merging and separation of two actin dense layers akin to cortical layers of animal cells. The layers bind at a distance equal to twice the thickness of a free layer, thus forming a single dense layer, similar in this sense to a lamellipodium. When that unique layer is stretched apart, it is resilient to break apart up to a critical length larger than twice the thickness of a free layer. We show that this behavior can result from the high contractile properties of the actomyosin gel due to the activity of myosin molecular motors. Furthermore, we establish that the stability of the stretched single layer is highly dependent on the properties of the gel. Indeed, the nematic order of the actin filaments along the polymerizing membranes is a destabilizing factor. PMID- 26590153 TI - CORR Insights((r)): Bilateral Pars Defects at the L4 Vertebra Result in Increased Degeneration When Compared With Those at L5: An Anatomic Study. PMID- 26590154 TI - Association Between Angiopoietin-2 and Enterovirus 71 Induced Pulmonary Edema. AB - OBJECTIVE: To characterize pulmonary edema (PE) fluid induced by enterovirus 71 (EV71) infection, elucidate the relationship between angiopoietin-2 (Ang-2) and PE, and explore the pathogenesis of PE. METHODS: Clinical data were collected from critical infants with EV71 infection. The infants were grouped into PE, non PE, and control groups. The control group included infants in the preoperative period of elective inguinal hernia surgery. Biochemical changes in PE fluid were evaluated, and Ang-2 levels in serum and PE fluid were measured. Human pulmonary microvascular endothelial cells (HPMECs) were incubated with serum from the control and PE groups and human recombinant Ang-2 or serum from the PE group and human recombinant Ang-1, and changes in the intercellular junctions were recorded via immunofluorescence. RESULTS: Of the 161 infants with critical EV71 infection admitted to the hospital, 39 had PE. PE fluid was collected from 18 of these infants. The PE fluid-to-serum (P/S) ratio of total protein was 0.9 +/- 0.2, and all P/S ratios of albumin were 1.0 +/- 0.3. The Ang-2 level was higher in the non PE group (333.2 +/- 79.7 pg/ml) than in the control group (199.9 +/- 26.7 pg/ml), although without statistical significance (P = 0.115). The Ang-2 level in the PE group (2819.2 +/- 908.7 pg/ml) was higher than those in both the non-PE and the control groups (both, P < 0.001). Serum samples from the PE group had damaged cell junctions of confluent HPMEC monolayers that were reversed by Ang-1. CONCLUSIONS: The PE fluid of infants with EV71-induced PE was protein-rich, and elevated Ang-2 expression was associated with PE. The mechanism through which PE develops may be related to Ang-2-induced cell junction damage. PMID- 26590155 TI - Dengue Infection: Challenges and Way Forward. PMID- 26590156 TI - Knowledge of Cord Blood Banking in General Population and Doctors: A Questionnaire Based Survey. AB - OBJECTIVES: To assess the knowledge of the general population and the medical specialists about the purpose and utility of cord blood banking. METHODS: One hundred individuals from the general population and 100 clinicians from various departments were enrolled in the study between August 2013 and November 2013. RESULTS: Fifty eight percent of the doctors and 82 % of the lay persons did not know any indication or were not aware of the correct indications of the use of cord blood for transplantation. Around half of the lay persons (42 %) and doctors (37 %) thought that umbilical cord blood can be used to treat any genetic disorder including Duchenne muscular dystrophy and mental retardation. Nineteen percent of the doctors thought that umbilical cord blood can be used to treat thalassemia in the same child. CONCLUSIONS: The propaganda done by cord blood banks that cord blood is a biological insurance for the child is misleading and should be discouraged. The obstetricians and the pediatricians should take a central role in providing the correct information to would be parents to help them in taking a correct decision. PMID- 26590157 TI - Ameliorative effects of Qingfei Tongluo formula on experimental mycoplasmal pneumonia in mice. AB - Mycoplasma pneumoniae pneumonia (MPP) is a common disease in children. Qingfei Tongluo formula (QTF) has been used for the treatment of MPP clinically, but the chemical constituents and mechanism involved remain unclear. This study aimed to analyze the main chemical constituents and to explore the possible mechanism of action associated with QTF treatment of MPP. Liquid chromatography-mass spectrometry was employed to identify the compounds contained in the QTF extract. A BALB/c mouse model of MP infection was established. After treatment with QTF (0.85 and 1.70 g/kg) for 3 days, hematoxylin and eosin staining was performed in lung tissues for histological examination. Inflammatory cytokines were detected by ELISA. Western blot analysis was used for detecting phosphorylated proteins involved in MAPK and nuclear factor (NF)-kappaB signaling pathways. In the mouse model, a large amount of pulmonary interstitial infiltration of lymphocytes and plasmacytes were seen as well as bronchus and vasodilation congestion. Following QTF treatment, inflammation was alleviated significantly compared with the model group. Inflammatory cytokines [interleukin (IL)-6, transforming growth factor beta1, IL-8, IL-1beta and tumor necrosis factor-alpha] in bronchoalveolar lavage fluid were decreased dramatically. In addition, we found that QTF inhibited activation of phosphorylation of JNK, ERK and NF-kappaB. In conclusion, QTF alleviates MPP inflammation possibly via inhibitory activation of MAPK/NF-kappaB pathways, which can act as a new agent for MPP treatment. PMID- 26590158 TI - The influence of cold weather on the usage of emergency link calls: a case study in Hong Kong. AB - BACKGROUND: In response to an unexpected long cold spell in February 1996 which killed more than 100 older adults (mostly living alone) in Hong Kong, the Hong Kong Senior Citizen Home Safety Association established a Personal Emergency Link Service to provide emergency contact to the older adults, which uses a telephone system to render emergency relief and total care service around the clock. To facilitate the dynamic and efficient allocation of service resources, it is crucial to understand the factors linked with use of the services and number of hospital admissions arising from PE link service. METHODS: We initially use the Poisson generalized linear model (GLM) with polynomial effect functions of relevant covariates. If the time series of residuals from fitting the Poisson GLM reveals significant serial correlation, a Poisson generalized linear autoregressive moving average (GLARMA) model is refitted to the data to account for the auto-correlation among the time series of daily call numbers. If the data is overdispersed relative to the best fitting Poisson GLARMA model, then the negative binomial GLARMA model is refitted to account for any overdispersion. In all the models, dummy variables for weekdays and months are included to account for any cyclic trends due weekday effect or month of the year effect. The secular time trend is modeled by a polynomial function of calendar time over the study period. Finally any critical temperatures are identified by visually inspecting the graph of the effect function of temperature. RESULTS: The weekday and month effects are both significant with Monday seeing more PE Link calls than Sunday and June seeing less than January. Temperature has significant effect on the PE Link call rate with the effect highly nonlinear. A critical temperature, below which excessive increase in PE link calls that lead to hospital admissions, is identified to be around 15 degrees C. CONCLUSION: Identifying a threshold temperature which generates an excessive increase in the expected number of PE Link calls would be useful in service provision planning and support for elderly in need of hospital admission. PMID- 26590159 TI - Expected lifetime numbers, risks, and burden of osteoporotic fractures for 50 year old Chinese women: a discrete event simulation incorporating FRAX. AB - This work was undertaken to provide an estimation of expected lifetime numbers, risks, and burden of fractures for 50-year-old Chinese women. A discrete event simulation model was developed to simulate the lifetime fractures of 50-year-old Chinese women at average risk of osteoporotic fracture. Main events in the model included hip fracture, clinical vertebral fracture, wrist fracture, humerus fracture, and other fracture. Fracture risks were calculated using the FRAX(r) tool. Simulations of 50-year-old Chinese women without fracture risks were also carried out as a comparison to determine the burden of fractures. A 50-year-old Chinese woman at average risk of fracture is expected to experience 0.135 (95 % CI: 0.134-0.137) hip fractures, 0.120 (95 % CI: 0.119-0.122) clinical vertebral fractures, 0.095 (95 % CI: 0.094-0.096) wrist fractures, 0.079 (95 % CI: 0.078 0.080) humerus fractures, and 0.407 (95 % CI: 0.404-0.410) other fractures over the remainder of her life. The residual lifetime risk of any fracture, hip fracture, clinical vertebral fracture, wrist fracture, humerus fracture, and other fracture for a 50-year-old Chinese woman is 37.36, 11.77, 10.47, 8.61, 7.30, and 27.80 %, respectively. The fracture-attributable excess quality adjusted life year (QALY) loss and lifetime costs are estimated at 0.11 QALYs (95 % CI: 0.00-0.22 QALYs) and US $714.61 (95 % CI: US $709.20-720.02), totaling a net monetary benefit loss of US $1,104.43 (95 % CI: US $904.09-1,304.78). Chinese women 50 years of age are at high risk of osteoporotic fracture, and the expected economic and quality-of-life burden attributable to osteoporotic fractures among Chinese women is substantial. PMID- 26590160 TI - 2R,3S)-2,3-Octanediol, a Female-Produced Sex Pheromone of Megopis costipennis (Coleoptera: Cerambycidae: Prioninae). AB - During field screening trials of a number of known cerambycid pheromones in China, males of Megopis costipennis (White) (Coleoptera: Cerambycidae: Prioninae: Callipogonini) were found to be specifically attracted to racemic anti-2,3 octanediol, suggesting that one of the enantiomers of this compound might be a female-produced sex pheromone of this species. Analysis of volatiles produced by beetles of both sexes confirmed this hypothesis: females produced (2R,3S)-2,3 octanediol, whereas males did not, and in coupled gas chromatography electroantennogram detection analyses, antennae from male beetles responded strongly to this compound. In field trials, males were equally attracted to traps baited with either (2R,3S)-2,3-octanediol or racemic anti-2,3-octanediol, indicating that the enantiomeric (2S,3R)-2,3-octanediol does not antagonize attraction to the naturally produced enantiomer. Thus, the more economical racemic anti-2,3-octanediol can be used for trap baits for this species. Homologous 2,3-hexanediols previously had been identified as sex pheromones or sex attractants of prionine species in the genus Tragosoma Audinet-Serville of the tribe Meroscelisini. PMID- 26590161 TI - Can mental health interventions change social networks? A systematic review. AB - BACKGROUND: Social networks of patients with psychosis can provide social support, and improve health and social outcomes, including quality of life. However, patients with psychosis often live rather isolated with very limited social networks. Evidence for interventions targeting symptoms or social skills, are largely unsuccessful at improving social networks indirectly. As an alternative, interventions may directly focus on expanding networks. In this systematic review, we assessed what interventions have previously been tested for this and to what extent they have been effective. METHODS: A systematic review was conducted of randomised controlled trials, testing psychosocial interventions designed to directly increase the social networks of patients with psychosis. Searches of five online databases (PsycINFO, CINAHL, Cochrane Database, MEDLINE, Embase), hand searching of grey literature, and both forward and backward snowballing of key papers were conducted and completed on 12 December 2014. Trial reports were included if they were written in English, the social network size was the primary outcome, participants were >= 18 years old and diagnosed with a psychotic disorder. RESULTS: Five studies (n = 631 patients) met the complete inclusion criteria. Studies were from different countries and published since 2008. Four trials had significant positive results, i.e. an observable increase in patients' social network size at the end of the intervention. The interventions included: guided peer support, a volunteer partner scheme, supported engagement in social activity, dog-assisted integrative psychological therapy and psychosocial skills training. Other important elements featured were the presence of a professional, and a focus on friendships and peers outside of services and the immediate family. CONCLUSIONS: Despite the small number and heterogeneity of included studies, the results suggest that interventions directly targeting social isolation can be effective and achieve a meaningful increase in patients' networks. Thus, although limited, the existing evidence is encouraging, and the range of interventions used in the reported trials leave various options for future research and further improvements. Future research is needed to test the findings in different settings, identify which components are particularly effective, and determine to what extent the increased networks, over time, impact on patients' symptoms and quality of life. PMID- 26590162 TI - Hypoxic stress: impact on the modulation of TLR2, TLR4, NOD1 and NOD2 receptor and their down-stream signalling genes expression in catla (Catla catla). AB - The damage-associated molecular patterns (DAMPs) released from the damaged tissue/cells are recently reported as endogenous ligands to activate toll-like receptors (TLRs) and nucleotide binding and oligomerization domain (NOD) receptors signaling pathways. In the aquatic environment, reduction in dissolved oxygen (DO) concentration causes hypoxic stress resulting in tissue damage and patho-biological changes in fish. We envisaged the critical role of TLR and NOD receptors in recognizing DAMPs as endogenous ligands during hypoxic stress in fish. Catla (Catla catla) fingerlings (avg. wt ~56 g) was exposed to hypoxic stress (DO: 1-3 mg/L) for 1 and 24 h. After the designated time course, total RNA was extracted from gill, liver, kidney and blood, and modulation of TLRs (TLR2 and TLR4), NOD (NOD1 and NOD2) receptors, MyD88 (myeloid differentiation primary response gene 88), RICK (receptor interacting serine-threonine protein kinase-2), interleukin (IL)-6, IL-8 and IL-10 gene expression were analyzed by quantitative reverse transcriptase PCR assay. Significant (p < 0.05) up-regulation of some DAMPs {high-mobility group box 1 and heat shock protein-70}, TLRs and NOD receptors genes expressions were observed in the hypoxic fish tissues as compared to the control. Further investigation revealed inductive expression of MyD88, RICK, IL-6, IL-8 and IL-10 genes in the TLRs and NODs activated tissues of the hypoxic fish. These data together may suggest the important role of TLRs and NOD receptors signaling pathway in sterile inflammation and pathobiology of fish in hypoxic stress, and warrant further study to investigate the role of TLR and NOD receptors in abiotic stress management in aquaculture. PMID- 26590163 TI - Full genome characterization of the first G3P[24] rotavirus strain detected in humans provides evidence of interspecies reassortment and mutational saturation in the VP7 gene. AB - During the 2008-2009 rotavirus season of the Centers for Disease Control and Prevention New Vaccine Surveillance Network, one case of paediatric acute gastroenteritis associated with a rotavirus G14P[24] strain was identified. This was the first detection of the genotype G14 and P[24] in humans, and the first detection of the G14P[24] combination. To gain an insight into the origins and the evolution of this strain, we determined the complete ORF sequences of all 11 genes. A majority of the genes identified were similar to the simian strain TUCH, except for the VP1 and VP7 genes that clustered only distantly with the bovine and equine strains, respectively. In addition, this strain carried AU-1-like NSP2 and NSP4 genes. Using codon-partitioning and protein-based phylogenetic approaches, we determined that the VP7 genotype of strain 2009727118 was actually G3; therefore, the proposed full genomic classification of the 2009727118 strain is G3-P[24]-I9-R2-C3-M3-A9-N3-T3-E3-H6. These findings indicate the possibility that the 2009727118 strain originated by interspecies transmission and multiple reassortment events involving human, bovine and equine rotaviruses, resulting in the introduction of some genes into the genome of simian rotaviruses. Additionally, we found evidence of mutational saturation in the third codon position of the VP7 ORF which presented an issue with homoplasy in phylogenetic analyses. PMID- 26590165 TI - EZH2 Inhibition Blocks Multiple Myeloma Cell Growth through Upregulation of Epithelial Tumor Suppressor Genes. AB - Multiple myeloma is a plasma cell malignancy characterized by marked heterogeneous genomic instability including frequent genetic alterations in epigenetic enzymes. In particular, the histone methyltransferase Enhancer of Zeste Homolog 2 (EZH2) is overexpressed in multiple myeloma. EZH2 is the catalytic component of the polycomb repressive complex 2 (PRC2), a master transcriptional regulator of differentiation. EZH2 catalyzes methylation of lysine 27 on histone H3 and its deregulation in cancer has been reported to contribute to silencing of tumor suppressor genes, resulting in a more undifferentiated state, and thereby contributing to the multiple myeloma phenotype. In this study, we propose the use of EZH2 inhibitors as a new therapeutic approach for the treatment of multiple myeloma. We demonstrate that EZH2 inhibition causes a global reduction of H3K27me3 in multiple myeloma cells, promoting reexpression of EZH2-repressed tumor suppressor genes in a subset of cell lines. As a result of this transcriptional activation, multiple myeloma cells treated with EZH2 inhibitors become more adherent and less proliferative compared with untreated cells. The antitumor efficacy of EZH2 inhibitors is also confirmed in vivo in a multiple myeloma xenograft model in mice. Together, our data suggest that EZH2 inhibition may provide a new therapy for multiple myeloma treatment and a promising addition to current treatment options. Mol Cancer Ther; 15(2); 287-98. (c)2015 AACR. PMID- 26590164 TI - Unfolded-protein response-associated stabilization of p27(Cdkn1b) interferes with lens fiber cell denucleation, leading to cataract. AB - Failure of lens fiber cell denucleation (LFCD) is associated with congenital cataracts, but the pathobiology awaits elucidation. Recent work has suggested that mechanisms that direct the unidirectional process of LFCD are analogous to the cyclic processes associated with mitosis. We found that lens-specific mutations that elicit an unfolded-protein response (UPR) in vivo accumulate p27(Cdkn1b), show cyclin-dependent kinase (Cdk)-1 inhibition, retain their LFC nuclei, and are cataractous. Although a UPR was not detected in lenses expressing K6W-Ub, they also accumulated p27 and showed failed LFCD. Induction of a UPR in human lens epithelial cells (HLECs) also induced accumulation of p27 associated with decreased levels of S-phase kinase-associated protein (Skp)-2, a ubiquitin ligase that regulates mitosis. These cells also showed decreased lamin A/C phosphorylation and metaphase arrest. The suppression of lamin A/C phosphorylation and metaphase transition induced by the UPR was rescued by knockdown of p27. Taken together, these data indicate that accumulation of p27, whether related to the UPR or not, prevents the phosphorylation of lamin A/C and LFCD in maturing LFCs in vivo, as well as in dividing HLECs. The former leads to cataract and the latter to metaphase arrest. These results suggest that accumulation of p27 is a common mechanism underlying retention of LFC nuclei. PMID- 26590166 TI - Hemolysate-mediated platelet aggregation: an additional risk mechanism contributing to thrombosis of continuous flow ventricular assist devices. AB - Despite the clinical success and growth in the utilization of continuous flow ventricular assist devices (cfVADs) for the treatment of advanced heart failure, hemolysis and thrombosis remain major limitations. Inadequate and/or ineffective anticoagulation regimens, combined with high pump speed and non-physiological flow patterns, can result in hemolysis which often is accompanied by pump thrombosis. An unexpected increase in cfVADs thrombosis was reported by multiple major VAD implanting centers in 2014, highlighting the association of hemolysis and a rise in lactate dehydrogenase (LDH) presaging thrombotic events. It is well established that thrombotic complications arise from the abnormal shear stresses generated by cfVADs. What remains unknown is the link between cfVAD-associated hemolysis and pump thrombosis. Can hemolysis of red blood cells (RBCs) contribute to platelet aggregation, thereby, facilitating prothrombotic complications in cfVADs? Herein, we examine the effect of RBC-hemolysate and selected major constituents, i.e., lactate dehydrogenase (LDH) and plasma free hemoglobin (pHb) on platelet aggregation, utilizing electrical resistance aggregometry. Our hypothesis is that elements of RBCs, released as a result of shear-mediated hemolysis, will contribute to platelet aggregation. We show that RBC hemolysate and pHb, but not LDH, are direct contributors to platelet aggregation, posing an additional risk mechanism for cfVAD thrombosis. PMID- 26590167 TI - Alteration of substrate selection of antibiotic acylase from beta-lactam to echinocandin. AB - The antibiotic acylases belonging to the N-terminal nucleophile hydrolase superfamily are key enzymes for the industrial production of antibiotic drugs. Cephalosporin acylase (CA) and penicillin G acylase (PGA) are two of the most intensively studied enzymes that catalyze the deacylation of beta-lactam antibiotics. On the other hand, aculeacin A acylase (AAC) is known to be an alternative acylase class catalyzing the deacylation of echinocandin or cyclic lipopeptide antibiotic compounds, but its structural and enzymatic properties remain to be explored. In the present study, 3D homology models of AAC were constructed, and docking simulation with substrate ligands was performed for AAC, as well as for CA and PGA. The docking models of AAC with aculeacin A suggest that AAC has the deep narrow binding pocket for the long-chain fatty acyl group of the echinocandin molecule. To confirm this, CA mutants have been designed to form the binding pocket for the long acyl chain. Experimentally synthesized mutant enzymes exhibited lower enzymatic activity for cephalosporin but higher activity for aculeacin A, in comparison with the wild-type enzyme. The present results have clarified the difference in mechanisms of substrate selection between the beta-lactam and echinocandin acylases and demonstrate the usefulness of the computational approaches for engineering the enzymatic properties of antibiotic acylases. PMID- 26590168 TI - Regulatory Domains and Their Mechanisms. AB - The concept of gene regulation is being refined as our understanding of the role of enhancer elements grows. Although described more than 30 years ago, the mechanisms through which these cis-regulating elements operate remain under debate. With the recognition that most of the human genetic variation contributing to common disease risk lies outside of genes and probably in enhancers, unraveling these mechanisms becomes ever more important. Originally, a popular view was to consider regulatory elements as an entry site for the transcription machinery that could scan the intervening chromatin until the cognate core promoter was located. Now, the most prominent model for distal enhancer-promoter interaction involves direct enhancer/promoter contacts with a looping out of intervening chromatin. However, a rising awareness of the importance of chromatin architecture and organization forces us to consider enhancer-promoter communication in light of the polymer folding properties of chromatin. Here, we discuss how three-dimensional chromatin folding, topological domains, and the constrained motion, plasticity, and accessibility of chromatin could offer a structural basis for regulatory domains that greatly enhances the probability of enhancer-promoter and transcription factor-promoter interactions and gene activation. PMID- 26590169 TI - Large-Scale Chromatin Structure-Function Relationships during the Cell Cycle and Development: Insights from Replication Timing. AB - Chromosome architecture has received a lot of attention since the recent development of genome-scale methods to measure chromatin interactions (Hi-C), enabling the first sequence-based models of chromosome tertiary structure. A view has emerged of chromosomes as a string of structural units (topologically associating domains; TADs) whose boundaries persist through the cell cycle and development. TADs with similar chromatin states tend to aggregate, forming spatially segregated chromatin compartments. However, high-resolution Hi-C has revealed substructure within TADs (subTADs) that poses a challenge for models that attribute significance to structural units at any given scale. More than 20 years ago, the DNA replication field independently identified stable structural (and functional) units of chromosomes (replication foci) as well as spatially segregated chromatin compartments (early and late foci), but lacked the means to link these units to genomic map units. Genome-wide studies of replication timing (RT) have now merged these two disciplines by identifying individual units of replication regulation (replication domains; RDs) that correspond to TADs and are arranged in 3D to form spatiotemporally segregated subnuclear compartments. Furthermore, classifying RDs/TADs by their constitutive versus developmentally regulated RT has revealed distinct classes of chromatin organization, providing unexpected insight into the relationship between large-scale chromosome structure and function. PMID- 26590170 TI - The double-edged sword of the mammalian oocyte--advantages, drawbacks and approaches for basic and clinical analysis at the single cell level. AB - Oocytes are usually the largest cells in the body and as such offer unique opportunities for single-cell analysis. Unfortunately, these cells are also some of the rarest in the mammalian female, usually necessitating single-cell analysis. In cases of infertility in humans, determining the quality of the oocyte is often restricted to a morphological analysis or to the study of cellular behaviors in the developing embryo. Minimally invasive approaches could greatly assist the clinician to prioritize oocytes for fertilization or following fertilization, which embryo to transfer back into the woman. Transcriptomics of human and mouse oocytes may have great utility, and recently it was learned that the polar body faithfully reflects the transcript prevalence in the oocyte. The polar body may thus serve as a minimally invasive proxy for an oocyte in the clinic. In the mouse, the transcriptomes of oocytes from mice of the same strain are markedly similar; no significant differences are apparent in transcript prevalence or identity. In human oocytes however, the transcript pool is highly variable. This is likely the result of different histories of each oocyte, in the age of the donor woman, the different hormonal exposures and the prolonged time from specification of the primary oocyte to the fully grown and ovulated egg. This variability in human oocytes also emphasizes the need for cell-by-cell analysis of the oocytes in vitro; which oocytes have a better potential for fertilization and development? To this end, new imaging capabilities are being employed. For example, a single-cell analytical device for oocytes (the simple perfusion apparatus, or SPA) enables investigators to load multiple oocytes in individual wells, to visualize them on the microscope and to use controlled temperature and media flow by perfusion for optimal clinical applications. Recently, developed Raman microspectroscopy approaches suggest that this imaging modality may enable more in-depth analysis of the molecular characteristics of an oocyte that, in combination with the SPA and transcriptomic approaches, might assist the clinician to prioritize more effectively human oocytes and embryos for transfer into women. This review is intended to update the reader on the status of the examination of single oocytes from a variety of approaches and to emphasize areas that may be primed for advancement in the near future. PMID- 26590172 TI - Kinetic modeling and the rise of systems pharmacology. PMID- 26590171 TI - Identification of amino acid residues that determine the substrate specificity of mammalian membrane-bound front-end fatty acid desaturases. AB - Membrane-bound desaturases are physiologically and industrially important enzymes that are involved in the production of diverse fatty acids such as polyunsaturated fatty acids and their derivatives. Here, we identified amino acid residues that determine the substrate specificity of rat Delta6 desaturase (D6d) acting on linoleoyl-CoA by comparing its amino acid sequence with that of Delta5 desaturase (D5d), which converts dihomo-gamma-linolenoyl-CoA. The N-terminal cytochrome b5-like domain was excluded as a determinant by domain swapping analysis. Substitution of eight amino acid residues (Ser209, Asn211, Arg216, Ser235, Leu236, Trp244, Gln245, and Val344) of D6d with the corresponding residues of D5d by site-directed mutagenesis switched the substrate specificity from linoleoyl-CoA to dihomo-gamma-linolenoyl-CoA. In addition, replacement of Leu323 of D6d with Phe323 on the basis of the amino acid sequence of zebra fish Delta5/6 bifunctional desaturase was found to render D6d bifunctional. Homology modeling of D6d using recent crystal structure data of human stearoyl-CoA (Delta9) desaturase revealed that Arg216, Trp244, Gln245, and Leu323 are located near the substrate-binding pocket. To our knowledge, this is the first report on the structural basis of the substrate specificity of a mammalian front-end fatty acid desaturase, which will aid in efficient production of value-added fatty acids. PMID- 26590173 TI - Targeting BAFF/BLyS in lupus: is the glass half-full or half-empty? PMID- 26590174 TI - Value of ultrasonography as a marker of early response to abatacept in patients with rheumatoid arthritis and an inadequate response to methotrexate: results from the APPRAISE study. AB - OBJECTIVES: To study the responsiveness of a combined power Doppler and greyscale ultrasound (PDUS) score for assessing synovitis in biologic-naive patients with rheumatoid arthritis (RA) starting abatacept plus methotrexate (MTX). METHODS: In this open-label, multicentre, single-arm study, patients with RA (MTX inadequate responders) received intravenous abatacept (~10 mg/kg) plus MTX for 24 weeks. A composite PDUS synovitis score, developed by the Outcome Measures in Rheumatology European League Against Rheumatism (OMERACT-EULAR)-Ultrasound Task Force, was used to evaluate individual joints. The maximal score of each joint was added into a Global OMERACT-EULAR Synovitis Score (GLOESS) for bilateral metacarpophalangeal joints (MCPs) 2-5 (primary objective). The value of GLOESS containing other joint sets was explored, along with clinical efficacy. RESULTS: Eighty-nine patients completed the 24-week treatment period. The earliest PDUS sign of improvement in synovitis was at week 1 (mean change in GLOESS (MCPs 2-5): -0.7 (95% CIs -1.2 to -0.1)), with continuous improvement to week 24. Early improvement was observed in the component scores (power Doppler signal at week 1, synovial hyperplasia at week 2, joint effusion at week 4). Comparable changes were observed for 22 paired joints and minimal joint subsets. Mean Disease Activity Score 28 (C reactive protein) was significantly reduced from weeks 1 to 24, reaching clinical meaningful improvement (change >=1.2) at week 8. CONCLUSIONS: In this first international prospective study, the composite PDUS score is responsive to abatacept. GLOESS demonstrated the rapid onset of action of abatacept, regardless of the number of joints examined. Ultrasound is an objective tool to monitor patients with RA under treatment. TRIAL REGISTRATION NUMBER: NCT00767325. PMID- 26590175 TI - Giant Myelolipoma in the Spleen: A Rare Case Report and Literature Review. AB - Myelolipomas are benign tumors, consisting of hematopoietic cells and mature adipose tissue, which mainly occur within the adrenal gland. Extra-adrenal myelolipomas are rare, and fewer than 60 cases have been reported in the literature. Here, we report a case of intrasplenic myelolipoma in a 42-year-old man with more than 1 month of abdominal pain. Computed tomography scanning revealed a giant, heterogeneous, well-demarcated mass in the spleen. Splenectomy was performed, and an intrasplenic giant mass was completely excised. The diagnosis of myelolipoma was made based on morphological examination. To the best of our knowledge, this is the third reported case of myelolipoma in the human spleen. PMID- 26590177 TI - Lack of Understanding of Cervical Cancer and Screening Is the Leading Barrier to Screening Uptake in Women at Midlife in Bangladesh: Population-Based Cross Sectional Survey. AB - BACKGROUND: Cervical cancer (CCa) is the second most common cancer among women in Bangladesh. The uptake of CCa screening was less than 10% in areas where screening has been offered, so we investigated the awareness of CCa and CCa screening, and factors associated with women's preparedness to be screened. METHODS: A nationally representative, cross-sectional survey of women aged 30-59 years was conducted in 7 districts of the 7 divisions in Bangladesh, using a multistage cluster sampling technique. Factors associated with the awareness of CCa and screening uptake were investigated separately, using multivariable logistic regression. RESULTS: On systematic questioning, 81.3% and 48.6% of the 1,590 participants, whose mean age was 42.3 (+/-8.0) years, had ever heard of CCa and CCa screening, respectively. Having heard of CCa was associated with living in a rural area (adjusted odds ratio [OR]: 0.42; 95% confidence interval [CI]: 0.26-0.67), being 40-49 years old (OR: 1.59; 95% CI: 1.15-2.0), having no education (OR: 0.25; 95% CI: 0.16-0.38), and being obese (OR: 2.04; 95% CI: 1.23 3.36). Of the 773 women who had ever heard of CCa screening, 86% reported that they had not been screened because they had no symptoms and 37% did not know screening was needed. Only 8.3% had ever been screened. Having been screened was associated with being 40-49 years old (OR: 2.17; 95% CI: 1.19-3.94) and employed outside the home (OR: 3.83; 95% CI: 1.65-8.9), and inversely associated with rural dwelling (OR: 0.54; 95% CI: 0.30-0.98) and having no education (OR: 0.29; 95% CI: 0.10-0.85). CONCLUSION: Lack of awareness of CCa and of understanding of the concept of screening are the key barriers to screening uptake in women at midlife in Bangladesh. Targeted educational health programs are needed to increase screening in Bangladesh with the view to reducing mortality. PMID- 26590176 TI - Cardiac mesenchymal stromal cells are a source of adipocytes in arrhythmogenic cardiomyopathy. AB - AIM: Arrhythmogenic cardiomyopathy (ACM) is a genetic disorder mainly due to mutations in desmosomal genes, characterized by progressive fibro-adipose replacement of the myocardium, arrhythmias, and sudden death. It is still unclear which cell type is responsible for fibro-adipose substitution and which molecular mechanisms lead to this structural change. Cardiac mesenchymal stromal cells (C MSC) are the most abundant cells in the heart, with propensity to differentiate into several cell types, including adipocytes, and their role in ACM is unknown. The aim of the present study was to investigate whether C-MSC contributed to excess adipocytes in patients with ACM. METHODS AND RESULTS: We found that, in ACM patients' explanted heart sections, cells actively differentiating into adipocytes are of mesenchymal origin. Therefore, we isolated C-MSC from endomyocardial biopsies of ACM and from not affected by arrhythmogenic cardiomyopathy (NON-ACM) (control) patients. We found that both ACM and control C MSC express desmosomal genes, with ACM C-MSC showing lower expression of plakophilin (PKP2) protein vs. CONTROLS: Arrhythmogenic cardiomyopathy C-MSC cultured in adipogenic medium accumulated more lipid droplets than controls. Accordingly, the expression of adipogenic genes was higher in ACM vs. NON-ACM C MSC, while expression of cell cycle and anti-adipogenic genes was lower. Both lipid accumulation and transcription reprogramming were dependent on PKP2 deficiency. CONCLUSIONS: Cardiac mesenchymal stromal cells contribute to the adipogenic substitution observed in ACM patients' hearts. Moreover, C-MSC from ACM patients recapitulate the features of ACM adipogenesis, representing a novel, scalable, patient-specific in vitro tool for future mechanistic studies. PMID- 26590178 TI - Association between History of Gestational Diabetes and Exclusive Breastfeeding at Hospital Discharge. AB - BACKGROUND: Exclusive breastfeeding is recommended in the first 6 months of life, especially for infants born to women with a history of gestational diabetes mellitus (GDM). Yet, women with a history of GDM face challenges with exclusive breastfeeding in the early postpartum period, a critical period for setting up longer term breastfeeding success. Minimal research has been published on associated risk factors for not exclusively breastfeeding. OBJECTIVE: The purpose of this study was to examine the association between GDM and exclusive breastfeeding at hospital discharge. METHODS: We conducted a cross-sectional analysis including 2038 women who participated in the population-based Infant Feeding Practices Study II between May 2005 and June 2007. RESULTS: Gestational diabetes mellitus prevalence was 5.8%. The crude prevalence of exclusive breastfeeding at hospital discharge was 62.2% among women with GDM compared to 75.4% of women without GDM (P < .01). After adjusting for sociodemographic, behavioral, and anthropometric factors, the odds of exclusive breastfeeding were lower among women with GDM compared to women without diabetes (odds ratio = 0.59; 95% confidence interval, 0.39-0.92). Furthermore, women who had gestational weight gain (GWG) below the Institute of Medicine guidelines had lower odds of exclusive breastfeeding compared to women who had normal GWG (odds ratio = 0.62; 95% confidence interval, 0.45-0.85). CONCLUSION: Women with GDM history and women with inadequate GWG may need additional education to promote exclusive breastfeeding during maternal hospital stay. It is important for health care providers to assess both factors when providing education on exclusive breastfeeding and to support these women's breastfeeding efforts in the early postpartum period to maximize potential for longer term breastfeeding success. PMID- 26590179 TI - "It's Somebody Else's Milk": Unraveling the Tension in Mothers of Preterm Infants Who Provide Consent for Pasteurized Donor Human Milk. AB - BACKGROUND: Pasteurized donor human milk (DHM), rather than preterm infant formula, is recommended for premature infants when mother's milk is not available. OBJECTIVE: This study explored the maternal decision-making process in providing consent for DHM feedings. METHODS: In-depth semistructured interviews were conducted with 20 mothers of premature (mean gestational age = 27 weeks, birth weight = 942 grams) infants hospitalized in the neonatal intensive care unit (NICU) in this qualitative, descriptive study. Conventional content analysis was used to analyze the data. RESULTS: Although only 1 mother had any previous knowledge of DHM, all mothers provided consent for DHM because they "wanted what is best for my baby." Mothers trusted that DHM was better than formula when their infant's feeding requirements exceeded their own milk supply. However, most mothers described a tension between wanting their infants to receive only "their" milk and DHM being "somebody else's milk." This desire to be the only provider of human milk was more common than concerns about the quality and safety of DHM. The mothers' tension was mediated by trusting the NICU clinicians' recommendations, having adequate time to make an informed decision, observing the positive outcomes of DHM, and feeling empowered that they made the best decision for their infant. CONCLUSION: The experiences of these mothers reflect the importance of approaching mothers for consent only when DHM is needed, respecting mothers' beliefs and values about DHM, and providing help in mediating any tension with regard to their infants receiving "somebody else's milk." PMID- 26590180 TI - Middle cerebral artery aneurysm surgery after stent misplacement: A case report. AB - Stent misplacement during endovascular treatment of middle cerebral artery (MCA) aneurysms can cause challenges and be problematic, if clipping becomes necessary. This article reports on a 56-year-old woman with an unruptured, multi-lobulated MCA aneurysm, whom primarily refused surgery; therefore, she was scheduled for stent-assisted coiling. After successful deployment of the stent, it unfortunately then became snagged by the microcatheter and was pulled backwards. The subsequent surgical procedure (i.e. clipping of the MCA aneurysm) was challenging, due to the position of the dislodged stent. Such as misplacement of the stent is rarely documented: It resulted in the difficult handling of a MCA aneurysm. Aneurysms of the MCA should primarily be considered for surgical clipping. In conclusion, an increased risk for eventual surgery should be considered, in cases where endovascular treatments with stents are performed. PMID- 26590181 TI - It is time for consensus on return to play after injury: five key questions. PMID- 26590182 TI - Meteorological Factors Related to Emergency Admission of Elderly Stroke Patients in Shanghai: Analysis with a Multilayer Perceptron Neural Network. AB - BACKGROUND: The aim of this study was to predict the emergency admission of elderly stroke patients in Shanghai by using a multilayer perceptron (MLP) neural network. MATERIAL AND METHODS: Patients (>60 years) with first-ever stroke registered in the Emergency Center of Neurology Department, Shanghai Tenth People's Hospital, from January 2012 to June 2014 were enrolled into the present study. Daily climate records were obtained from the National Meteorological Office. MLP was used to model the daily emergency admission into the neurology department with meteorological factors such as wind level, weather type, daily maximum temperature, lowest temperature, average temperature, and absolute temperature difference. The relationships of meteorological factors with the emergency admission due to stroke were analyzed in an MLP model. RESULTS: In 886 days, 2180 first-onset elderly stroke patients were enrolled, and the average number of stroke patients was 2.46 per day. MLP was used to establish a model for the prediction of dates with low stroke admission (<=4) and those with high stroke admission (>=5). For the days with low stroke admission, the absolute temperature difference accounted for 40.7% of admissions, while for the days with high stroke admission, the weather types accounted for 73.3%. CONCLUSIONS: Outdoor temperature and related meteorological parameters are associated with stroke attack. The absolute temperature difference and the weather types have adverse effects on stroke. Further study is needed to determine if other meteorological factors such as pollutants also play important roles in stroke attack. PMID- 26590183 TI - Relapse pattern and second-line treatment following multimodality treatment for malignant pleural mesothelioma. AB - OBJECTIVES: To analyse the relapse pattern and influence of second-line treatment after recurrence of malignant pleural mesothelioma (MPM) in patients who had previously undergone multimodality treatment. METHODS: Between September 1999 and December 2013, 136 patients underwent macroscopic complete resection (MCR) by extrapleural pneumonectomy after induction chemotherapy for MPM. We analysed 106 patients who presented with recurrent disease until October 2014. Data were retrieved from our mesothelioma database, with additional information regarding precise localization gathered by reviewing the imaging and medical records. RESULTS: The overall recurrence rate was 78% (106/136 patients). The median freedom from recurrence was 9 months after surgery [95% confidence interval (95% CI) 7-10]. Local recurrence only was observed in 33 patients (31%), distant metastases only in 27 patients (26%) and simultaneous distant and local recurrence in 46 patients (43%). Local recurrence was observed significantly less frequently in patients having received adjuvant radiotherapy (19 vs 47%, P = 0.003), but there was no significant impact on overall survival (OS) [radiation: 22 months (95% CI 19-24); no-radiation: 23 months (95% CI 18-27), P = 0.6]. The median OS was 22 months (95% CI 21-24), median post-recurrence survival (PRS) was 7 months (95% CI 5-9) and patients with local recurrence only survived significantly longer (12 months, 95% CI 8-16) compared with patients with distant recurrence only (5 months, 95% CI 2-8) or distant plus local relapse (6 months, 95% CI 3-9; P = 0.04). A total of 78 patients received a second-line therapy after tumour recurrence: chemotherapy (n = 48), local radiotherapy (n = 9), surgery (n = 10) or a combination thereof (n = 11). Patients undergoing second line treatment survived significantly longer compared with patients not receiving therapy (P < 0.0005). The median PRS after surgery was significantly longer than that of patients receiving chemo-, radio- or chemo-radiotherapy (P = 0.04). CONCLUSIONS: Local recurrence of MPM remains the most frequent type of relapse even after multimodality treatment including MCR. In the present cohort, active treatment seems beneficial to the patient since surgical excision of local tumour relapse has good long-term outcome in selected patients. Thus, second-line treatment may prolong PRS; however, these results need to be confirmed in a prospective manner. PMID- 26590184 TI - Two staged modified substitution urethroplasty using appendix-free flap. AB - Reconstruction of long posterior urethra defect is technically challenging. Substitution urethroplasty is used in long, complex, recurrent posterior urethral strictures. This article presents a modified technique and the clinical outcome of two-stage substitution urethroplasty with appendix free flap and microvascular anastomosis. A three-year-old boy with a 5 cm iatrogenic posterior urethral defect was managed by urethral substitution using the appendix. An appendix-free flap was used according to anatomic limitations, employing the transposed inferior epigastric artery and saphenous vein to maintain conduit blood supply. The conduit was buried in the scrotum for 3 weeks and its viability monitored until the final reconstructive stage. Two-year follow-up with ultrasound and cystoscopy revealed satisfactory results. A well-vascularised bed and flap are the mainstays of substitution urethroplasty, so we suggest inferior epigastric artery perineal transposition and staged reconstruction as alternatives that may improve the blood supply of the neourethra. PMID- 26590185 TI - Primary glottic malignant melanoma of the larynx (PGMML): a very rare entity. AB - Primary glottic malignant melanoma of the larynx (PGMML) is a very rare clinical entity with less than 20 cases reported in the literature so far. The most frequently reported subsite in primary malignant melanomas of the larynx is the supraglottic larynx. The vocal cord as a subsite for primary malignant melanoma is very rare. The present case is a primary glottic malignant melanoma involving both vocal cords. PGMML may present early due to associated hoarseness of voice, unlike other non-cutaneous melanomas in the head and neck. Non-cutaneous malignant melanomas in the head and neck are historically very aggressive in nature and known for poor outcomes and survival. Most non-cutaneous melanomas described in the literature have been superficial spreading or ulcerative in nature, unlike the present case, in which proliferative, polypoidal growth was seen. No associated risk factor was present in this case. Every reported case of this rare entity further adds to the better understanding of tumour biology and expression. PMID- 26590186 TI - Bilateral shoulder septic arthritis in a fit and well 47-year-old man. AB - Bilateral septic arthritis of the shoulder is uncommon in the immunocompetent patient with no previous risk factors for joint infection, and is thus easily missed. Septic arthritis is associated with significant rates of morbidity and mortality. Early diagnosis and management is the key to a favourable outcome; septic arthritis should be considered as a differential diagnosis in the unwell patient presenting with shoulder pain and reduced range of joint movement. We present a case of a 47-year-old previously fit and well man with bilateral shoulder septic arthritis. We will also review the current literature on management and long-term outcomes of patients with septic arthritis of the glenohumeral joint. PMID- 26590187 TI - Novel oral anticoagulants and HIV: dabigatran use with antiretrovirals. AB - Compatibility of novel oral anticoagulants in patients with HIV taking combined antiretroviral therapy has not been established, with no published reports of successful concurrent use. We present a case where chronic anticoagulation was indicated in a patient with treated HIV and non-valvular atrial fibrillation who refused warfarin therapy. The patient tolerated the combination, with dabigatran blood levels within the expected range at a standard dosing regimen, without evidence of bleeding or other adverse outcomes. While further research is needed to establish the role of novel oral anticoagulants in patients taking antiretrovirals, this case suggests that dabigatran may be a viable option for selected patients. PMID- 26590188 TI - Ten-year follow-up of a giant prolactinoma. AB - Giant prolactinomas are rare pituitary tumours of which management can be a challenge. A 28-year-old man presented with headaches, visual impairment and behavioural changes. Clinically, the patient was found to have hypogonadism and bitemporal hemianopsia. A MRI demonstrated a pituitary tumour 76 mm in diameter and blood tests revealed a serum prolactin of 158,700 uU/mL (reference range 58 254). Initially, a craniotomy was performed. Immunohistochemistry of the tumour identified a prolactinoma with a high proliferative index and the patient was started on treatment with a dopamine agonist. A year later, neurological symptoms worsened due to regrowth of the lesion's cystic component, and so further surgery was performed. After 10 years of treatment with dopamine agonists, the prolactin levels decreased by 96.8%, there was an effective reduction in tumour size, and the neurological signs and symptoms resolved. PMID- 26590189 TI - Pseudo-renal failure: bladder rupture with urinary ascites. AB - We report a case of pseudo-renal failure caused by urinary ascites due to spontaneous bladder rupture following transurethral resection of a bladder tumour (TUR-BT). A 63-year-old man presented with 2 months of abdominal distension due to ascites. Laboratory findings showed elevated serum creatinine and hyperkalaemia. Peritoneal fluid urea, creatinine and potassium levels were greater than those in serum levels. CT scan showed partial wall thinning in the bladder wall, and cystography indicated fragility in the dome where the latest TUR-BT was performed. Pseudo-renal failure (laboratory abnormalities of acute kidney injury in the setting of normal kidney function) from urinary ascites and reverse intraperitoneal dialysis was diagnosed. Symptoms and laboratory abnormalities improved promptly with insertion of a urinary catheter. This report aims to increase recognition of urinary ascites when a patient with genitourinary surgical procedures or radiation therapy, or blunt abdominal trauma, presents with ascites and elevated creatinine simultaneously. PMID- 26590190 TI - Cardiac arrest induced by a giant uterine leiomyoma. PMID- 26590191 TI - A Novel in vitro Bioassay to Explore the Repellent Effects of Compounds Against Mosquito Aedes aegypti (Diptera: Culicidae). AB - Mosquitoes are vectors for many pathogens resulting in many deaths of humans. Repellents play an important role in reducing mosquito bites and the spread of mosquito-borne diseases. Currently, Klun & Debboun (K & D) and human-arm-based bioassay systems are used to identify repellent properties of compounds, extracts, and essential oils. Risks involved with human-arm-based systems are allergic reactions and limited replicates. We are reporting an in vitro bioassay method "NCNPR repellent bioassay (NCNPR-RB)" that can closely simulate the results of the cloth patch bioassay system used to determine repellency against mosquitoes. The NCNPRRB method uses heat to attract mosquito and edible collagen sheets as an alternate to human skin. Multiple plant compounds with documented repellency were tested. DEET (N,N-diethyl-3-methylbenzamide) was used as a positive control. Treatments were prepared in EtOH and applied in dosages ranging from 0.011-1.5mg/cm2 to a 20-cm2 collagen sheet. The number of mosquitoes commencing to bite per probe was recorded visually for 1 min. The minimum effective dosage (mg/cm2) of compounds: DEET (0.021), carvacrol (0.011), thymol (0.013), undecanoic acid (0.023), thymol methyl ether (0.269), and 2-nonanone (>0.375 mg/cm2) determined in NCNPRRB were similar to those reported in literature using a cloth patch bioassay system. The NCNPR-RB can be used to screen compounds with reasonable reproducibility of the data at a faster rate than the cloth patch bioassay, which involves the use of human subjects. PMID- 26590192 TI - Description of Psathyromyia (Psathyromyia) baratai sp. n. (Diptera: Psychodidae: Phlebotominae) From Cantareira State Park, Sao Paulo, Brazil. AB - The Shannoni complex consists of a group of sand fly species included in the subgenus Psathyromyia (Psathyromyia) Barretto, 1962, in which the females have banana-shaped spermathecae and the males have terminalia with digitiform parameres. The species included in the complex present morphological similarity, mainly among the females, and the males contribute most clearly to species differentiation. We describe a newspecies in the Shannoni complex, Psathyromyia baratai sp. n., on the basis of morphological and morphometric characters, a species which due to its great morphological similarity with Psathyromyia abonnenci, Psathyromyia limai, and Psathyromyia shannoni has been erroneously identified with one or other of them for >60 yr. PMID- 26590193 TI - Decomposition of Concealed and Exposed Porcine Remains in the North Carolina Piedmont. AB - We examined the decomposition and subsequent insect colonization of small pig carrion (Sus scrofa (L.)) placed in concealed and open environments during spring, summer, and fall in Raleigh, North Carolina, as a model for juvenile human remains. Remains were concealed in simulated attics in three manners, ranging from minimal to well-concealed. Concealment had a significant effect on the insect community colonizing the remains across all three seasons; the beetles Necrobia rufipes (DeGeer) (Cleridae) and Dermestes maculatus (DeGeer) (Coleoptera: Dermestidae) were the only species indicative of remains located indoors, whereas numerous fly (Diptera: Calliphoridae, Muscidae, Sepsidae, and Piophilidae) and beetle (Coleoptera: Silphidae, Staphylinidae, and Histeridae) species and an ant species (Hymenoptera: Formicidae, Prenolepis sp.) were indicative of remains located outdoors. Season also significantly affected the insect species, particularly the blow flies (Diptera: Calliphoridae) colonizing remains: Lucilia illustris (Meigen) was indicative of the spring, Cochliomyia macellaria (F.) and Chrysomya megacephala (F.) were indicative of the summer, and Calliphora vicina Robineau-Desvoidy and Calliphora vomitoria (L.) were indicative of the fall. In addition, across all seasons, colonization was delayed by 35-768 h, depending on the degree of concealment. These differences among the insect communities across seasons and concealment treatments, and the effects of concealment on colonization indicate that such information is important and should to be considered when analyzing entomological evidence for criminal investigations. PMID- 26590195 TI - Commentary on: Microbiologic Safety of the Transareolar Approach in Breast Augmentation. PMID- 26590196 TI - Microbiologic Safety of the Transareolar Approach in Breast Augmentation. AB - BACKGROUND: In aesthetic breast augmentation, especially by the transareolar approach, there is increasing concern regarding the occurrence of capsular contracture and its potential correlation with intraoperative implant contamination from putative endogenous breast flora of the nipple and lactiferous ducts. However, detectable bacteria cannot be considered synonymous with established resident microflora. OBJECTIVES: The authors sought to elucidate the existence of endogenous breast flora and assess the microbiologic safety of transareolar breast augmentation. METHODS: In this prospective study (BREAST-MF), the authors collected microbiologic samples from the breast skin, ductal tissue, and parenchyma of 39 consecutive female patients who underwent breast procedures in a plastic surgery clinic. Swabs collected pre-, intra-, and postoperatively were processed for bacterial and fungal growth. Positive cultures underwent identification through VITEK and MALDI-TOF, as well as antimicrobial susceptibility testing. RESULTS: Staphylococcus species accounted for 95 of 106 (89.6%) positive results from native breast skin, 15 of 18 (83.3%) positive results from decontaminated breast skin, and 4 of 4 (100%) positive results from the breast parenchyma. Methicillin resistance was present in 26.4% of S. epidermidis, 25.3% of S. hominis, and 71.4% of S. haemolyticus strains. CONCLUSIONS: During transareolar breast augmentation, in the nipple-areola region it is more likely to find bacteria populating the skin, rather than endogenous breast flora, as previously considered. Appropriate preoperative decontamination is essential for minimizing the risk of postoperative infections. LEVEL OF EVIDENCE 3: Risk. PMID- 26590194 TI - Genetic risk factors for the development of osteonecrosis in children under age 10 treated for acute lymphoblastic leukemia. AB - Osteonecrosis is a dose-limiting toxicity in the treatment of pediatric acute lymphoblastic leukemia (ALL). Prior studies on the genetics of osteonecrosis have focused on patients >=10 years of age, leaving the genetic risk factors for the larger group of children <10 years incompletely understood. Here, we perform the first evaluation of genetic risk factors for osteonecrosis in children <10 years. The discovery cohort comprised 82 cases of osteonecrosis and 287 controls treated on Children's Oncology Group (COG) standard-risk ALL protocol AALL0331 (NCT00103285, https://clinicaltrials.gov/ct2/show/NCT00103285), with results tested for replication in 817 children <10 years treated on COG protocol AALL0232 (NCT00075725, https://clinicaltrials.gov/ct2/show/NCT00075725). The top replicated single nucleotide polymorphisms (SNPs) were near bone morphogenic protein 7 [BMP7: rs75161997, P = 5.34 * 10(-8) (odds ratio [OR] 15.0) and P = .0498 (OR 8.44) in the discovery and replication cohorts, respectively] and PROX1 antisense RNA1 (PROX1-AS1: rs1891059, P = 2.28 * 10(-7) [OR 6.48] and P = .0077 [OR 3.78] for the discovery and replication cohorts, respectively). The top replicated nonsynonymous SNP, rs34144324, was in a glutamate receptor gene (GRID2, P = 8.65 * 10(-6) [OR 3.46] and P = .0136 [OR 10.8] in the discovery and replication cohorts, respectively). In a meta-analysis, the BMP7 and PROX1-AS1 variants (rs75161997 and rs1891059, respectively) met the significance threshold of <5 * 10(-8). Top replicated SNPs were enriched in enhancers active in mesenchymal stem cells, and analysis of annotated genes demonstrated enrichment in glutamate receptor and adipogenesis pathways. These data may provide new insights into the pathophysiology of osteonecrosis. PMID- 26590197 TI - Paradoxical Adipose Hyperplasia and Cellular Effects After Cryolipolysis: A Case Report. AB - Cryolipolysis is a noninvasive technique for the reduction of subcutaneous adipose tissue by controlled, localized cooling, causing adipocyte apoptosis, reportedly without affecting surrounding tissue. Although cryolipolysis has a low incidence of adverse side effects 33 cases of paradoxical adipose hyperplasia (PAH) have been reported and the precise pathogenesis of PAH is poorly understood. This present case study of PAH aims to characterize the pathological changes in the adipose tissue of PAH on a cellular level by using multiple different assays [hematoxy lin and eosin staining, LIVE/DEAD staining, BODIPY((r)) 558/568 C12 (4,4-Difluoro-5-(2-Thienyl)-4-Bora-3a,4a-Diaza-s-Indacene 3-dodecanoic acid) staining]. to identify the underlying mechanism of PAH and reduce the prevalence of PAH in the future. Tissue with PAH had fewer viable cells, significantly decreased quantities of interstitial cells (p = 0.04), and fewer vessels per adipose tissue area when compared to the control tissue. Adipocytes from the PAH tissue were on average slightly smaller than the control adipocytes. Adipocytes of PAH tissue had irregularly contoured edges when compared to the smooth, round edges of the control tissue. These findings from a neutral third party are contrary to prior reports from the inventors of this technique regarding effects of cryolipolysis on both the microvasculature and interstitial cells in adipose tissue. Our use of different assays to compare cryolipolysis-treated PAH tissue with untreated adipose tissue in the same patient showed adipose tissue that developed PAH was hypocellular and hypovascular. Contrary to prior reports from the inventors, cryolipolysis may cause vessel loss, which could lead to ischemia and/or hypoxia that further contributes to adipocyte death. LEVEL OF EVIDENCE 5: Risk. PMID- 26590199 TI - An embedded checklist in the Anesthesia Information Management System improves pre-anaesthetic induction setup: a randomised controlled trial in a simulation setting. AB - BACKGROUND: Anaesthesiologists work in a high stress, high consequence environment in which missed steps in preparation may lead to medical errors and potential patient harm. The pre-anaesthetic induction period has been identified as a time in which medical errors can occur. The Anesthesia Patient Safety Foundation has developed a Pre-Anesthetic Induction Patient Safety (PIPS) checklist. We conducted this study to test the effectiveness of this checklist, when embedded in our institutional Anesthesia Information Management System (AIMS), on resident performance in a simulated environment. METHODS: Using a randomised, controlled, observer-blinded design, we compared performance of anaesthesiology residents in a simulated operating room under production pressure using a checklist in completing a thorough pre-anaesthetic induction evaluation and setup with that of residents with no checklist. The checklist was embedded in the simulated operating room's electronic medical record. RESULTS: Data for 38 anaesthesiology residents shows a statistically significant difference in performance in pre-anaesthetic setup and evaluation as scored by blinded raters (maximum score 22 points), with the checklist group performing better by 7.8 points (p<0.01). The effects of gender and year of residency on total score were not significant. Simulation duration (time to anaesthetic agent administration) was increased significantly by the use of the checklist. CONCLUSION: Required use of a pre-induction checklist improves anaesthesiology resident performance in a simulated environment. The PIPS checklist as an integrated part of a departmental AIMS warrant further investigation as a quality measure. PMID- 26590198 TI - What methods are used to apply positive deviance within healthcare organisations? A systematic review. AB - BACKGROUND: The positive deviance approach focuses on those who demonstrate exceptional performance, despite facing the same constraints as others. 'Positive deviants' are identified and hypotheses about how they succeed are generated. These hypotheses are tested and then disseminated within the wider community. The positive deviance approach is being increasingly applied within healthcare organisations, although limited guidance exists and different methods, of varying quality, are used. This paper systematically reviews healthcare applications of the positive deviance approach to explore how positive deviance is defined, the quality of existing applications and the methods used within them, including the extent to which staff and patients are involved. METHODS: Peer-reviewed articles, published prior to September 2014, reporting empirical research on the use of the positive deviance approach within healthcare, were identified from seven electronic databases. A previously defined four-stage process for positive deviance in healthcare was used as the basis for data extraction. Quality assessments were conducted using a validated tool, and a narrative synthesis approach was followed. RESULTS: 37 of 818 articles met the inclusion criteria. The positive deviance approach was most frequently applied within North America, in secondary care, and to address healthcare-associated infections. Research predominantly identified positive deviants and generated hypotheses about how they succeeded. The approach and processes followed were poorly defined. Research quality was low, articles lacked detail and comparison groups were rarely included. Applications of positive deviance typically lacked staff and/or patient involvement, and the methods used often required extensive resources. CONCLUSION: Further research is required to develop high quality yet practical methods which involve staff and patients in all stages of the positive deviance approach. The efficacy and efficiency of positive deviance must be assessed and compared with other quality improvement approaches. PROSPERO REGISTRATION NUMBER: CRD42014009365. PMID- 26590201 TI - The problem with preventable deaths. PMID- 26590200 TI - A behaviourally anchored rating scale for evaluating the use of the WHO surgical safety checklist: development and initial evaluation of the WHOBARS. AB - BACKGROUND: Realising the full potential of the WHO Surgical Safety Checklist (SSC) to reduce perioperative harm requires the constructive engagement of all operating room (OR) team members during its administration. To facilitate research on SSC implementation, a valid and reliable instrument is needed for measuring OR team behaviours during its administration. We developed a behaviourally anchored rating scale (BARS) for this purpose. METHODS: We used a modified Delphi process, involving 16 subject matter experts, to compile a BARS with behavioural domains applicable to all three phases of the SSC. We evaluated the instrument in 80 adult OR cases and 30 simulated cases using two medical student raters and seven expert raters, respectively. Intraclass correlation coefficients were calculated to assess inter-rater reliability. Internal consistency and instrument discrimination were explored. Sample size estimates for potential study designs using the instrument were calculated. RESULTS: The Delphi process resulted in a BARS instrument (the WHOBARS) with five behavioural domains. Intraclass correlation coefficients calculated from the OR cases exceeded 0.80 for 80% of the instrument's domains across the SSC phases. The WHOBARS showed high internal consistency across the three phases of the SSC and ability to discriminate among surgical cases in both clinical and simulated settings. Fewer than 20 cases per group would be required to show a difference of 1 point between groups in studies of the SSC, where alpha=0.05 and beta=0.8. CONCLUSION: We have developed a generic instrument for comprehensively rating the administration of the SSC and informing initiatives to realise its full potential. We have provided data supporting its capacity for discrimination, internal consistency and inter-rater reliability. Further psychometric evaluation is warranted. PMID- 26590202 TI - High Frequency of Diarrheagenic Escherichia coli in HIV-Infected Patients and Patients with Thalassemia in Kerman, Iran. AB - This study was conducted on patients with thalassemia and HIV-infected patients to determine the frequency of diarrheagenic Escherichia coli in Kerman, Iran. We analyzed 68 and 49 E coli isolates isolated from healthy fecal samples of patients with thalassemia and HIV-infected patients, respectively. The E coli isolates were studied using a multiplex polymerase chain reaction to identify the enterotoxigenic E coli (ETEC), enterohemorrhagic E coli (EHEC), and enteropathogenic E coli (EPEC) groups. Statistical analysis was carried out to determine the correlation of diarrheagenic E coli between HIV-infected patients and patients with thalassemia using Stata 11.2 software. The frequency of having at least 1 diarrheagenic E coli was more common in patients with thalassemia (67.64%) than in HIV-infected patients (57.14%; P = .25), including ETEC (67.64% versus 57.14%), EHEC (33.82% versus 26.53%), and EPEC (19.11% versus 16.32%). The results of this study indicate that ETEC, EHEC, and EPEC pathotypes are widespread among diarrheagenic E coli isolates in patients with thalassemia and HIV-infected patients. PMID- 26590203 TI - Identification of Sequence Variation in the Apolipoprotein A2 Gene and Their Relationship with Serum High-Density Lipoprotein Cholesterol Levels. AB - BACKGROUND: Apolipoprotein A2 (APOA2) is the second major apolipoprotein of the high-density lipoprotein cholesterol (HDL-C). The study aim was to identify APOA2 gene variation in individuals within two extreme tails of HDL-C levels and its relationship with HDL-C level. METHODS: This cross-sectional survey was conducted on participants from Tehran Glucose and Lipid Study (TLGS) at Research Institute for Endocrine Sciences, Tehran, Iran from April 2012 to February 2013. In total, 79 individuals with extreme low HDL-C levels (<=5th percentile for age and gender) and 63 individuals with extreme high HDL-C levels (>=95th percentile for age and gender) were selected. Variants were identified using DNA amplification and direct sequencing. RESULTS: Screen of all exons and the core promoter region of APOA2 gene identified nine single nucleotide substitutions and one microsatellite; five of which were known and four were new variants. Of these nine variants, two were common tag single nucleotide polymorphisms (SNPs) and seven were rare SNPs. Both exonic substitutions were missense mutations and caused an amino acid change. There was a significant association between the new missense mutation (variant Chr.1:16119226, Ala98Pro) and HDL-C level. CONCLUSION: None of two common tag SNPs of rs6413453 and rs5082 contributes to the HDL-C trait in Iranian population, but a new missense mutation in APOA2 in our population has a significant association with HDL-C. PMID- 26590204 TI - Cues Matter: Learning Assistants Influence Introductory Biology Student Interactions during Clicker-Question Discussions. AB - The cues undergraduate biology instructors provide to students before discussions of clicker questions have previously been shown to influence student discussion. We further explored how student discussions were influenced by interactions with learning assistants (LAs, or peer coaches). We recorded and transcribed 140 clicker-question discussions in an introductory molecular biology course and coded them for features such as the use of reasoning and types of questions asked. Students who did not interact with LAs had discussions that were similar in most ways to students who did interact with LAs. When students interacted with LAs, the only significant changes in their discussions were the use of more questioning and more time spent in discussion. However, when individual LA student interactions were examined within discussions, different LA prompts were found to generate specific student responses: question prompts promoted student use of reasoning, while students usually stopped their discussions when LAs explained reasons for answers. These results demonstrate that LA prompts directly influence student interactions during in-class discussions. Because clicker discussions can encourage student articulation of reasoning, instructors and LAs should focus on how to effectively implement questioning techniques rather than providing explanations. PMID- 26590205 TI - UK science research agenda should be set by stronger single agency, review recommends. PMID- 26590206 TI - Detecting structural information of scatterers using spatial frequency domain imaging. AB - We demonstrate optical phantom experiments on the phase function parameter gamma using spatial frequency domain imaging. The incorporation of two different types of scattering particles allows for control of the optical phantoms' microscopic scattering properties. By laterally structuring areas with either TiO2 or Al2O3 scattering particles, we were able to obtain almost pure subdiffusive scattering contrast in a single optical phantom. Optical parameter mapping was then achieved using an analytical radiative transfer model revealing the microscopic structural contrast on a macroscopic field of view. As part of our study, we explain several correction and referencing techniques for high spatial frequency analysis and experimentally study the sampling depth of the subdiffusive parameter gamma. PMID- 26590208 TI - Sexual practices, myths and misconceptions among long distance truck drivers in North India. AB - BACKGROUND: Long distance truck drivers and helpers constitute a high risk group for human immunodeficiency virus /acquired immune deficiency syndrome (HIV/AIDS). Despite increasing awareness of HIV/AIDS and safe sex practices, they still have a high incidence of new cases of HIV. AIMS: This study carried out at an ART (anti-retroviral treatment) centre in North India aimed to evaluate the sexual myths and misconceptions prevalent among long distance drivers and helpers. DESIGN: This was a retrospective study carried out at apex ART centre. METHODS: Data were collected retrospectively from ART records of 129 long distance Truck drivers and 68 helpers. Details of socio-demographic characteristics, contact with commercial sex workers (CSW'S), pattern of condom usage with CSW'S and factors influencing it were studied. RESULTS: We found that a significant number of drivers and helpers had sexual contact with CSW's and out of these, 30% of drivers and 50% of helpers reported not using condoms and instead resorting to methods like washing genitalia after sex with battery water/urine to avoid getting HIV. There was no significant relationship between pattern of condom usage and educational status, marital status and age. We also found that certain myths like sex with young CSW's was less likely to cause sexually transmitted diseases (STD's) and HIV were also widespread. CONCLUSION: Owing to continuing prevalence of such sexual myths, long distance truck drivers and helpers do not use condoms while having sex with CSW's as they feel that they can enjoy sex with CSW's and still stay protected against STD's/HIV. It is imperative that this battery water/urine antiseptic myth be specifically targeted for better HIV control in this high risk group. PMID- 26590209 TI - NICE guideline aims to cut premature birth rates. PMID- 26590207 TI - Hypoxic regulation of the noncoding genome and NEAT1. AB - Activation of hypoxia pathways is both associated with and contributes to an aggressive phenotype across multiple types of solid cancers. The regulation of gene transcription by hypoxia-inducible factor (HIF) is a key element in this response. HIF directly upregulates the expression of many hundreds of protein coding genes, which act to both improve oxygen delivery and to reduce oxygen demand. However, it is now becoming apparent that many classes of noncoding RNAs are also regulated by hypoxia, with several (e.g. micro RNAs, long noncoding RNAs and antisense RNAs) under direct transcriptional regulation by HIF. These hypoxia regulated, noncoding RNAs may act as effectors of the indirect response to HIF by acting on specific coding transcripts or by affecting generic RNA-processing pathways. In addition, noncoding RNAs may also act as modulators of the HIF pathway, either by integrating other physiological responses or, in the case of HIF-regulated, noncoding RNAs, by providing negative or positive feedback and feedforward loops that affect upstream or downstream components of the HIF cascade. These hypoxia-regulated, noncoding transcripts play important roles in the aggressive hypoxic phenotype observed in cancer. PMID- 26590210 TI - The repABC Plasmids with Quorum-Regulated Transfer Systems in Members of the Rhizobiales Divide into Two Structurally and Separately Evolving Groups. AB - The large repABC plasmids of the order Rhizobiales with Class I quorum-regulated conjugative transfer systems often define the nature of the bacterium that harbors them. These otherwise diverse plasmids contain a core of highly conserved genes for replication and conjugation raising the question of their evolutionary relationships. In an analysis of 18 such plasmids these elements fall into two organizational classes, Group I and Group II, based on the sites at which cargo DNA is located. Cladograms constructed from proteins of the transfer and quorum sensing components indicated that those of the Group I plasmids, while coevolving, have diverged from those coevolving proteins of the Group II plasmids. Moreover, within these groups the phylogenies of the proteins usually occupy similar, if not identical, tree topologies. Remarkably, such relationships were not seen among proteins of the replication system; although RepA and RepB coevolve, RepC does not. Nor do the replication proteins coevolve with the proteins of the transfer and quorum-sensing systems. Functional analysis was mostly consistent with phylogenies. TraR activated promoters from plasmids within its group, but not between groups and dimerized with TraR proteins from within but not between groups. However, oriT sequences, which are highly conserved, were processed by the transfer system of plasmids regardless of group. We conclude that these plasmids diverged into two classes based on the locations at which cargo DNA is inserted, that the quorum-sensing and transfer functions are coevolving within but not between the two groups, and that this divergent evolution extends to function. PMID- 26590211 TI - Evolutionarily Dynamic, but Robust, Targeting of Resistance Genes by the miR482/2118 Gene Family in the Solanaceae. AB - Plants are exposed to pathogens around the clock. A common resistance response in plants upon pathogen detection is localized cell death. Given the irreversible nature of this response, multiple layers of negative regulation are present to prevent the untimely or misexpression of resistance genes. One layer of negative regulation is provided by a recently discovered microRNA (miRNA) gene family, miR482/2118. This family targets the transcripts of resistance genes in plants. We investigated the evolutionary history and specificity of this miRNA gene family within the Solanaceae. This plant family includes many important crop species, providing a set of well-defined resistance gene repertoires. Across 14 species from the Solanaceae, we identified eight distinct miR482/2118 gene family members. Our studies show conservation of miRNA type and number in the group of wild tomatoes and, to a lesser extent, throughout the Solanaceae. The eight orthologous miRNA gene clusters evolved under different evolutionary constraints, allowing for individual subfunctionalization of the miRNAs. Despite differences in the predicted targeting behavior of each miRNA, the miRNA-R-gene network is robust due to its high degree of interconnectivity and redundant targeting. Our data suggest that the miR482/2118 gene family acts as an evolutionary buffer for R-gene sequence diversity. PMID- 26590212 TI - Inferring Selective Constraint from Population Genomic Data Suggests Recent Regulatory Turnover in the Human Brain. AB - The comparative genomics revolution of the past decade has enabled the discovery of functional elements in the human genome via sequence comparison. While that is so, an important class of elements, those specific to humans, is entirely missed by searching for sequence conservation across species. Here we present an analysis based on variation data among human genomes that utilizes a supervised machine learning approach for the identification of human-specific purifying selection in the genome. Using only allele frequency information from the complete low-coverage 1000 Genomes Project data set in conjunction with a support vector machine trained from known functional and nonfunctional portions of the genome, we are able to accurately identify portions of the genome constrained by purifying selection. Our method identifies previously known human-specific gains or losses of function and uncovers many novel candidates. Candidate targets for gain and loss of function along the human lineage include numerous putative regulatory regions of genes essential for normal development of the central nervous system, including a significant enrichment of gain of function events near neurotransmitter receptor genes. These results are consistent with regulatory turnover being a key mechanism in the evolution of human-specific characteristics of brain development. Finally, we show that the majority of the genome is unconstrained by natural selection currently, in agreement with what has been estimated from phylogenetic methods but in sharp contrast to estimates based on transcriptomics or other high-throughput functional methods. PMID- 26590213 TI - The Utility of Genome Skimming for Phylogenomic Analyses as Demonstrated for Glycerid Relationships (Annelida, Glyceridae). AB - Glyceridae (Annelida) are a group of venomous annelids distributed worldwide from intertidal to abyssal depths. To trace the evolutionary history and complexity of glycerid venom cocktails, a solid backbone phylogeny of this group is essential. We therefore aimed to reconstruct the phylogenetic relationships of these annelids using Illumina sequencing technology. We constructed whole-genome shotgun libraries for 19 glycerid specimens and 1 outgroup species (Glycinde armigera). The chosen target genes comprise 13 mitochondrial proteins, 2 ribosomal mitochondrial genes, and 4 nuclear loci (18SrRNA, 28SrRNA, ITS1, and ITS2). Based on partitioned maximum likelihood as well as Bayesian analyses of the resulting supermatrix, we were finally able to resolve a robust glycerid phylogeny and identified three clades comprising the majority of taxa. Furthermore, we detected group II introns inside the cox1 gene of two analyzed glycerid specimens, with two different insertions in one of these species. Moreover, we generated reduced data sets comprising 10 million, 4 million, and 1 million reads from the original data sets to test the influence of the sequencing depth on assembling complete mitochondrial genomes from low coverage genome data. We estimated the coverage of mitochondrial genome sequences in each data set size by mapping the filtered Illumina reads against the respective mitochondrial contigs. By comparing the contig coverage calculated in all data set sizes, we got a hint for the scalability of our genome skimming approach. This allows estimating more precisely the number of reads that are at least necessary to reconstruct complete mitochondrial genomes in Glyceridae and probably non-model organisms in general. PMID- 26590216 TI - Online feedback from patients is succeeding in improving services, says report. PMID- 26590214 TI - Mitochondrial Involvement in Vertebrate Speciation? The Case of Mito-nuclear Genetic Divergence in Chameleons. AB - Compatibility between the nuclear (nDNA) and mitochondrial (mtDNA) genomes is important for organismal health. However, its significance for major evolutionary processes such as speciation is unclear, especially in vertebrates. We previously identified a sharp mtDNA-specific sequence divergence between morphologically indistinguishable chameleon populations (Chamaeleo chamaeleon recticrista) across an ancient Israeli marine barrier (Jezreel Valley). Because mtDNA introgression and gender-based dispersal were ruled out, we hypothesized that mtDNA spatial division was maintained by mito-nuclear functional compensation. Here, we studied RNA-seq generated from each of ten chameleons representing the north and south populations and identified candidate nonsynonymous substitutions (NSSs) matching the mtDNA spatial distribution. The most prominent NSS occurred in 14 nDNA encoded mitochondrial proteins. Increased chameleon sample size (N = 70) confirmed the geographic differentiation in POLRMT, NDUFA5, ACO1, LYRM4, MARS2, and ACAD9. Structural and functionality evaluation of these NSSs revealed high functionality. Mathematical modeling suggested that this mito-nuclear spatial divergence is consistent with hybrid breakdown. We conclude that our presented evidence and mathematical model underline mito-nuclear interactions as a likely role player in incipient speciation in vertebrates. PMID- 26590215 TI - Unexpectedly Streamlined Mitochondrial Genome of the Euglenozoan Euglena gracilis. AB - In this study, we describe the mitochondrial genome of the excavate flagellate Euglena gracilis. Its gene complement is reduced as compared with the well studied sister groups Diplonemea and Kinetoplastea. We have identified seven protein-coding genes: Three subunits of respiratory complex I (nad1, nad4, and nad5), one subunit of complex III (cob), and three subunits of complex IV (cox1, cox2, and a highly divergent cox3). Moreover, fragments of ribosomal RNA genes have also been identified. Genes encoding subunits of complex V, ribosomal proteins and tRNAs were missing, and are likely located in the nuclear genome. Although mitochondrial genomes of diplonemids and kinetoplastids possess the most complex RNA processing machineries known, including trans-splicing and editing of the uridine insertion/deletion type, respectively, our transcriptomic data suggest their total absence in E. gracilis. This finding supports a scenario in which the complex mitochondrial processing machineries of both sister groups evolved relatively late in evolution from a streamlined genome and transcriptome of their common predecessor. PMID- 26590217 TI - Imaging autofluorescence temporal signatures of the human ocular fundus in vivo. AB - We demonstrate real-time in vivo fundus imaging capabilities of our fluorescence lifetime imaging technology for the first time. This implementation of lifetime imaging uses light emitting diodes to capture full-field images capable of showing direct tissue contrast without executing curve fitting or lifetime calculations. Preliminary results of fundus images are presented, investigating autofluorescence imaging potential of various retina biomarkers for early detection of macular diseases. PMID- 26590218 TI - Differentiating cancerous tissues from noncancerous tissues using single-fiber reflectance spectroscopy with different fiber diameters. AB - Elastic light-scattering spectra acquired with single-fiber optical probes with diameters of 100, 200, 400, 600, 800, 1000, 1200, and 1500 MUm were used to differentiate cancerous from noncancerous prostate tissues. The spectra were acquired ex vivo on 24 excised prostate tissue samples collected from four patients. For each probe, the spectra and histopathology results were compared in order to investigate the correlation between the core diameters of the single fiber optical probe and successful differentiation between cancerous and noncancerous prostate tissues. The spectra acquired using probes with a fiber core diameter of 400 MUm or smaller successfully differentiated cancerous from noncancerous prostate tissues. Next, the spectra were acquired from monosized polystyrene microspheres with a diameter of 5.00+/-0.01 MUm to investigate the correlation between the core diameters of the probes and the Mie oscillations on the spectra. Monte Carlo simulations of the light distribution of the tissue phantoms were run to interrogate whether the light detected by the probes with different fiber core diameters was in the ballistic or diffusive regime. If the single-fiber optical probes detect light in the ballistic regime, the spectra can be used to differentiate between cancerous and noncancerous tissues. PMID- 26590219 TI - In situ microscopy using adjustment-free optics. AB - In the past years, in situ microscopy has been demonstrated as a technique for monitoring the concentration and morphology of moving microparticles in agitated suspensions. However, up until now, this technique can only achieve a high resolution if a certain manual or automated effort is established for continuous precise focusing. Therefore, the application of in situ microscopes (ISMs) as sensors is inhibited in the cases where unattended operation is required. Here, we demonstrate a high-resolution ISM which, unlike others, is built as an entirely rigid construction, requiring no adjustments at all. This ISM is based on a specially designed water immersion objective with numerical aperture = 0.75 and a working distance of 15 MUm. The objective can be built exclusively from off the-shelf parts and the front surface directly interfaces with the moving suspension. We show various applications of the system and demonstrate the imaging performance with submicron resolution within moving suspensions of microorganisms. PMID- 26590220 TI - Understanding Support Providers' Views of "Helpful" Responses to Sexual Assault Disclosures: The Impacts of Self-Blame and Physical Resistance. AB - Prior research on the factors associated with various disclosure responses has often been conducted on sexual assault victims and formal support providers, while informal helpers, who are the most common recipients of disclosures, have received far less attention. This experimental study examined potential informal helpers' views of disclosure reactions and their influence on the self-reported likelihoods of engaging in those responses. Undergraduate students at a large Canadian university ( N = 239) received vignettes describing a hypothetical sexual assault disclosure that varied on victim's self-blame and physical resistance, and then rated common disclosure reactions. The results revealed that participants' perceptions of various responses were at odds with victims' experiences, with many negative responses, such as victim blame and egocentrism, viewed as equally or more helpful than positive responses, such as emotional support. Moreover, when the victim blamed herself and did not physically resist, positive responses were seen as less helpful whereas negative responses were seen as more helpful, with some notable gender differences. Regression analyses indicated that the perceived helpfulness of each response was the strongest predictor of the likelihood of providing that response. Practical implications of these findings are discussed. PMID- 26590221 TI - How Childhood Maltreatment Profiles of Male Victims Predict Adult Perpetration and Psychosocial Functioning. AB - This study used latent class analysis to empirically identify subgroups of men based on their exposure to childhood maltreatment (i.e., emotional neglect and abuse, physical neglect and abuse, and sexual abuse). It then examined subgroups' differential perpetration of adult intimate partner violence (IPV; both psychological and physical), violence against peers, and sexual assault. Finally, we compared sociodemographic variables and psychosocial functioning across profiles to characterize the adult experiences of men in different maltreatment groups. The community sample consisted of 626 heterosexually active 21- to 30 year-old men. We identified four subgroups: Low Maltreatment (80% of the sample), Emotional and Physical Maltreatment (12%), Emotional and Sexual Maltreatment (4%), and Poly-Victimized (4%). The Low Maltreatment group had significantly lower IPV perpetration rates than the Emotional and Physical Maltreatment group, but groups did not significantly differ on peer violence or sexual assault perpetration rates. Overall, Poly-Victimized men were significantly worse off than the Low Maltreatment group regarding income, education level, and incarceration history. Their rates of recent anxiety and depression symptoms were also higher than those of Low Maltreatment men. Findings support the use of person-oriented techniques for deriving patterns of childhood maltreatment and how these patterns relate to psychological, behavioral, and social factors in adulthood. PMID- 26590222 TI - A Cumulative Risk Model of Child Physical Maltreatment Potential: Findings From a Community-Based Study. AB - Previous studies have identified the predictive risk factors of child physical maltreatment (CPM). However, a significant number of these studies assessed risk factors in isolation. The cumulative risk hypothesis postulates that health problems are caused by the accumulation of risk factors, independently of the presence or absence of specific risk indicators. Few studies examined the effect of cumulative risk on CPM potential. This study aimed to test two concurrent models of cumulative risk of CPM potential by investigating whether CPM potential was better predicted by a threshold cumulative risk model or a linear cumulative risk model. Data from the National Representative Study of Psychosocial Context of Child Abuse and Neglect in Portugal were used. Parents of school-age children ( N = 796) answered to self-report measures regarding sociodemographic variables, history of child maltreatment, psychological distress, and CPM potential. A cumulative risk index was computed, comprising 10 dichotomized risk factors. Evidence for a threshold cumulative effect was found. Additional bivariate logistic regressions revealed that the odds for high-potential CPM were dramatically higher for those parents with six or more risk factors when compared with parents with any one risk factor. By testing and confirming a threshold cumulative effect on CPM potential, it was possible to find a "trigger point" from which a dramatic increase in child physical maltreatment potential occurs. PMID- 26590223 TI - Sexual Assault Characteristics and Perceptions of Event-Related Distress. AB - Sexual assault (SA) is a potent psychological stressor, linked to harmful mental health outcomes in both the short- and long-term. Specific assault characteristics can add to the toxicity of SA events. Although research has assessed characteristics of the assault itself (e.g., force, penetration), few studies have examined the larger socioenvironmental context in which SA takes place. This was the purpose of the present study. Young adults ( N = 220; 80% female; 54% current students) reported on their most recent SA during college. Cross-sectional associations were tested via structural equation modeling to determine the contributions of socioenvironmental context and assault characteristics in predicting event-related distress. Socioenvironmental context from the most recent assault included assault setting, intoxication at the time of the assault, perpetrator relationship, and prior consensual sexual experiences with the perpetrator. We also examined assault characteristics, including physical force and penetration. Participants reported how upsetting the most recent assault was (a) at the time it occurred and (b) currently. Results revealed differential patterns for socioenvironmental context and assault characteristics based on the timing of distress (past or present). Notably, many of the socioenvironmental factors showed associations with distress above and beyond the powerful effects of physical force and penetration. These findings have important implications for our understanding of the unique factors that contribute to and maintain psychological distress in sexually victimized young adults. PMID- 26590224 TI - Knowledge uptake and translation: A matter of evidence or of philosophy. PMID- 26590226 TI - Approaches to culture and diversity: A critical synthesis of occupational therapy literature. AB - BACKGROUND: The 2007 position statement on diversity for the Canadian occupational therapy profession argued discussion was needed to determine the implications of approaches to working with cultural differences and other forms of diversity. In 2014, a new position statement on diversity was published, emphasizing the importance of social power relations and power relations between client and therapist, and supporting two particular approaches: cultural safety and cultural humility with critical reflexivity PURPOSE: This paper reviews and critically synthesizes the literature concerning culture and diversity published in occupational therapy between 2007 and 2014, tracing the major discourses and mapping the implications of four differing approaches: cultural competence, cultural relevance, cultural safety, and cultural humility. KEY ISSUES: Approaches differ in where they situate the "problem," how they envision change, the end goal, and the application to a range of types of diversity. IMPLICATIONS: The latter two are preferred approaches for their attention to power relations and potential to encompass a range of types of social and cultural diversity. PMID- 26590228 TI - Screening for sensory impairment in older adults: Training and practice of occupational therapists in Quebec. AB - BACKGROUND: The goal of occupational therapy education is to train generalists who can refine their knowledge after graduation according to the requirements of the professional environment. However, it is currently unclear to what extent sensory screening should be included in the educational curricula. PURPOSE: The purpose of this study was to examine the sensory screening education for and practice by occupational therapists working with older adults. METHOD: A cross sectional survey was used to collect data from members of the Quebec Order of Occupational Therapists. Descriptive statistics were used in the analysis. FINDINGS: Data from 102 respondents indicated that training on sensory impairment related topics was minimal and in stark contrast to the proportion who reported serving clients with a visual (92%), hearing (84%), or combined impairment (53%). IMPLICATIONS: Occupational therapy considers numerous aspects of physical, cognitive, and emotional well-being. The question remains as to what extent vision and hearing health should take their place among these priorities. PMID- 26590229 TI - Communities of practice: Exploring enablers and barriers with school health clinicians. AB - BACKGROUND: It is imperative that therapists keep pace with relevant knowledge and reflect on their practice. Community of practice (CoP) sessions provide clinicians with a forum to share stories, exchange information, and foster scholarly practice. Studies on CoPs in health care are limited. PURPOSE: The purpose of this study was to explore the enablers and barriers to participation in CoPs. METHOD: Occupational therapists and physiotherapists in a school health program participated in a questionnaire (n=18) and semi-structured interviews (n=14). Analyses were completed using descriptive statistics (questionnaires) and interpretative phenomenological analysis (interviews). FINDINGS: Six themes describing participation in CoPs emerged: structure-engagement, learning, growth becoming, fellowship-belonging, implementation-doing, and contributing influencing. The findings highlight the importance of situated learning, reflection, and creativity to influence practice through discussions of ideas, research, and resources in small supportive groups of like-minded individuals with an informal, self-directed structure. IMPLICATIONS: Features to consider when implementing CoPs in the workplace are discussed. PMID- 26590230 TI - Enhancing student occupational therapists' client-centred counselling skills. AB - BACKGROUND: Client-centred practice is the cornerstone of the occupational therapy profession. However, there has been little focus on how to teach students to be client-centred practitioners while engaged in counselling. PURPOSE: The purpose of this study was to examine the impact of the use of a client-completed rating scale on student occupational therapists' client-centred counselling skills. METHOD: A time-series design was used to measure the changes in students' counselling skills over time. Demographic information was collected prior to time one. An online questionnaire was administered after study completion to explore students' experiences of using the Session Rating Scale. FINDINGS: The impact of using the Session Rating Scale as a measure of students' client-centred counselling skills performance significantly improved over time. Most students valued using the rating scale and would recommend its use for future students. IMPLICATIONS: The process of supporting students to learn how to engage clients in providing timely feedback and using this feedback to design treatment sets the stage for integration and application of client-centred practice. PMID- 26590231 TI - The relationship between children's sensory processing patterns and their leisure preferences and participation patterns. AB - BACKGROUND: Sensory processing patterns may be associated with children's preferences for different activities; however, knowledge about how different sensory processing patterns may relate to children's participation in leisure activities is scarce. PURPOSE: This study investigated in what leisure activities children with extreme sensory processing patterns participate and if relationships exist between children's sensory processing patterns and their leisure preferences and participation patterns. METHOD: This correlational study analyzed data from children's Sensory Profiles and reported play and leisure preferences. All 91 children in the sample completed the Children's Assessment for Participation and Enjoyment (CAPE) and the Preferences for Activities of Children (PAC). Parents of children ages 6 to 10 years completed the Sensory Profile, and children ages 11 to 14 years completed the Adolescent/Adult Sensory Profile. FINDINGS: Children with different sensory processing patterns preferred both similar and distinct leisure activities. Low-registration quadrant summary z scores negatively correlated with CAPE overall diversity scores (rs=-.23, p=.03), sensitivity quadrant summary z scores negatively correlated with preferences for social activities (rs=-.23, p=.03) and preferences for skill-based activities (rs=-.22, p=.04), and avoiding quadrant summary z scores negatively correlated with preferences for social activities (rs=-.26, p=.01). IMPLICATIONS: Children's sensory preferences are related to leisure preferences and participation. PMID- 26590233 TI - Doctors underwent "extreme sleep deprivation" in studies of effect on patient deaths. PMID- 26590234 TI - Application of Sigmoidal Transformation Functions in Optimization of Micellar Liquid Chromatographic Separation of Six Quinolone Antibiotics. AB - A chemometrics approach has been used to optimize the separation of six quinolone compounds by micellar liquid chromatography (MLC). A Derringer's desirability function, a multicriteria decision-making (MCDM) method, was tested for evaluation of two different measures of chromatographic performance (resolution and analysis time). The effect of three experimental parameters on a chromatographic response function (CRF) expressed as a product of two sigmoidal desirability functions was investigated. The sigmoidal functions were used to transform the optimization criteria, resolution and analysis time into the desirability values. The factors studied were the concentration of sodium dodecyl sulfate, butanol content and pH of the mobile phase. The experiments were done according to the face-centered cube central composite design, and the calculated CRF values were fitted to a polynomial model to correlate the CRF values with the variables and their interactions. The developed regression model showed good descriptive and predictive ability (R(2) = 0.815, F = 6.919, SE = 0.038, [Formula: see text]) and used, by a grid search algorithm, to optimize the chromatographic conditions for the separation of the mixture. The efficiency of prediction of polynomial model was confirmed by performing the experiment under the optimal conditions. PMID- 26590235 TI - Microwave-Assisted Extraction and Purification of Arctiin and Arctigenin from Fructus Arctii by High-Speed Countercurrent Chromatography. AB - An efficient method for the rapid extraction, separation and purification of bioactive lignans, arctiin and arctigenin, from Fructus arctii by microwave assisted extraction coupled with high-speed countercurrent chromatography was developed. The optimal extraction conditions of arctiin and arctigenin were evaluated by orthogonal array. Arctigenin could be converted from arctiin by hydrochloric acid hydrolysis. The separations were performed at a preparative scale with two-phase solvents composed of ethyl acetate-ethanol-water (5 : 1 : 5, v/v/v) for arctiin, and n-hexane-ethyl acetate-ethanol-water (4 : 4 : 3 : 4, v/v/v/v) for arctigenin. From 500 mg of crude extract sample, 122.3 mg of arctiin and 45.7 mg of arctigenin were obtained with the purity of 98.46 and 96.57%, and the recovery of 94.3 and 81.6%, respectively. Their structures were determined by comparison with the high-performance liquid chromatography retention time of standard substance as well as UV, FT-IR, electrospray ion source (ESI)-MS, (1)H NMR and (13)C-NMR spectrum. According to the antioxidant activity assay, arctigenin had stronger 1,1-diphenyl-2-picrylhydrazyl free radicals scavenging activity. PMID- 26590236 TI - Determination of gamma-Aminobutyric Acid (GABA) in Rambutan Fruit cv. Rongrian by HPLC-ELSD and Separation of GABA from Rambutan Fruit Using Dowex 50W-X8 Column. AB - A high-performance liquid chromatography method coupled with an evaporative light scattering detector (ELSD) was validated for the determination of gamma aminobutyric acid (GABA) in rambutan fruit without any sample pretreatment or derivatization. In the concentration range of 0.05-1.0 mg/mL GABA, the ELSD response was linear with a correlation coefficient (r) >0.999. Limit of detection and limit of quantitation were found to be 0.7 and 2.0 ug/mL, respectively. The method enabled the complete separation of GABA in the aqueous extract of rambutan flesh from the impurity peaks at 45.7 min. The recoveries of sample added GABA were obtained in the range of 92.0-99.3%. Intraday and interday relative standard deviations were <5.3%. Repeatability of the extraction process showed the acceptable precision. From the analysis of GABA content in rambutan flesh, 0.71 +/- 0.23 mg of GABA was found in 1 g fresh weight. The recovery of GABA after passing through the Dowex 50W-X8 column was 96.65%. The analytical methodology could be potentially applied to the detection and quantification of GABA in other fruits and complex matrices when a sufficient quantity is available. PMID- 26590237 TI - Theoretical Models and QSRR in Retention Modeling of Eight Aminopyridines. AB - In this article, retention modeling of eight aminopyridines (synthesized and characterized at the Faculty of Pharmacy) in reversed-phase high performance liquid chromatography (RP-HPLC) was performed. No data related to their retention in the RP-HPLC system were found. Knowing that, it was recognized as very important to describe their retention behavior. The influences of pH of the mobile phase and the organic modifier content on the retention factors were investigated. Two theoretical models for the dependence of retention factor of organic modifier content were tested. Then, the most reliable and accurate prediction of log k was created, testing multiple linear regression model quantitative structure-retention relationships (MLR-QSRR) and support vector regression machine-quantitative structure-retention relationships (SVM-QSRR). Initially, 400 descriptors were calculated, but four of them (POM, log D, M SZX/RZX and m-RPCG) were included in the models. SVM-QSRR performed significantly better than the MLR model. Apart from aminopyridines, four structurally similar substances (indapamide, gliclazide, sulfamethoxazole and furosemide) were followed in the same chromatographic system. They were used as external validation set for the QSRR model (it performed well within its applicability domain, which was defined using a bounding box approach). After having described retention of eight aminopyridines with both theoretical and QSRR models, further investigations in this field can be conducted. PMID- 26590238 TI - Child Maltreatment and Migration: A Population-Based Study Among Immigrant and Native Adolescents in Switzerland. AB - BACKGROUND: Prevalence rates of child maltreatment (CM) can differ substantially between countries and ethnicities. Reasons, however, are complex and not sufficiently understood. METHOD: This epidemiological study examined prevalence and risk factors of various types of CM in a population-based representative sample of native and immigrant adolescents in Switzerland (N = 6,787). RESULTS: The prevalence of CM in general was lowest in the native group, higher in the Western immigrant group, and highest in the non-Western immigrant groups. An immigrant background was related to an overrepresentation of several risk factors for CM. Adjusted odds ratio of an immigrant background were still significant for physical and emotional abuse but not for neglect and sexual assault. CONCLUSIONS: Differences in the prevalence of CM across ethnographic origins are at least partially related to socioeconomic and ecologic risk factors. The distribution of risk factors may vary depending on the contexts of migration. PMID- 26590239 TI - NHS hospitals post record L1.6bn overspend in first six months of year. PMID- 26590240 TI - Making healthy eating and physical activity policy practice: process evaluation of a group randomized controlled intervention in afterschool programs. AB - This study describes the link between level of implementation and outcomes from an intervention to increase afterschool programs' (ASPs) achievement of healthy eating and physical activity (HE-PA) Standards. Ten intervention ASPs implemented the Strategies-To-Enhance-Practice (STEPs), a multi-component, adaptive intervention framework identifying factors essential to meeting HE-PA Standards, while 10 control ASPs continued routine practice. All programs, intervention and control, were assigned a STEPs for HE-PA index score based on implementation. Mixed-effects linear regressions showed high implementation ASPs had the greatest percentage of boys and girls achieving 30 min of moderate-to-vigorous physical activity (47.3 and 29.3%), followed by low implementation ASPs (41.3 and 25.0%), and control ASPs (34.8 and 18.5%). For healthy eating, high/low implementation programs served fruits and vegetables an equivalent number of days, but more days than control programs (74.0 and 79.1% of days versus 14.2%). A similar pattern emerged for the percent of days sugar-sweetened foods and beverages were served, with high and low implementation programs serving sugar-sweetened foods (8.0 and 8.4% of days versus 52.2%), and beverages (8.7 and 2.9% of days versus 34.7%) equivalently, but less often than control programs. Differences in characteristics and implementation of STEPs for HE-PA between high/low implementers were also identified. PMID- 26590241 TI - Using formative research to develop a nutrition education resource aimed at assisting low-income households in South Africa adopt a healthier diet. AB - As part of a comprehensive programme to prevent non-communicable disease in South Africa, there is a need to develop public education campaigns on healthy eating. Urban populations of lower socioeconomic status are a priority target population. This study involved formative research to guide the development of a nutrition resource appropriate to the budgetary constraints and information needs of poor households in the major urban centres of South Africa. Twenty-two focus groups were convened to explore the target audience's knowledge, beliefs, attitudes and practices as they related to healthy eating and their views about the proposed nutrition resource (N = 167). A brief questionnaire assessed eating and cooking practices among focus group participants. Key informant interviews with eight dieticians/nutritionists working with this population added to the focus group findings. The research identified important issues to take into account in the development of the resource. These included the need to: directly address prevalent misconceptions about healthy eating and unhealthy eating practices; increase self-efficacy regarding the purchasing and preparation of healthy food; represent diverse cultural traditions and consider the issues of affordability and availability of food ingredients. This study demonstrates the value of using formative research in the design of nutrition-related communication in a multicultural, poor, urban South African setting. PMID- 26590243 TI - Physician and patient perceptions of cultural competency and medical compliance. AB - To examine the relationship between the different perceptions of medical teams and their patients of the cultural competence of physicians, and the influence of this relationship on the conflict between them. Physicians' cultural competence (Noble A. Linguistic and cultural mediation of social services. Cultural competence of health care. Echo New Studio 2007; 91:18-28) might reduce this phenomenon. Structured questionnaires were distributed to 90 physicians working in outpatient clinics in a central hospital in Israel, and to 417 of their patients. Each physician had four to six sampled patients.The findings showed a significant negative correlation (r = -0.50, P < 0.05) between the physicians' perception of their cultural competence and the patients' perception of physician competence. The more patients perceive the physician as culturally competent, the more they comply with their medical recommendations. In addition, the findings show that ethnicity significantly affects patients' perception of the cultural competence of physicians, and their satisfaction with the medical care they receive. PMID- 26590242 TI - A randomized trial using motivational interviewing for maintenance of blood pressure improvements in a community-engaged lifestyle intervention: HUB city steps. AB - Little is known about the effective dose of motivational interviewing for maintaining intervention-induced health outcome improvements. The purpose of this study was to compare effects of two doses of motivational interviewing for maintaining blood pressure improvements in a community-engaged lifestyle intervention conducted with African-Americans. Participants were tracked through a 12-month maintenance phase following a 6-month intervention targeting physical activity and diet. For the maintenance phase, participants were randomized to receive a low (4) or high (10) dose of motivational interviewing delivered via telephone by trained research staff. Generalized linear models were used to test for group differences in blood pressure. Blood pressure significantly increased during the maintenance phase. No differences were apparent between randomized groups. Results suggest that 10 or fewer motivational interviewing calls over a 12-month period may be insufficient to maintain post-intervention improvements in blood pressure. Further research is needed to determine optimal strategies for maintaining changes. PMID- 26590244 TI - Understanding the determinants of Australian hospital nurses' hand hygiene decisions following the implementation of a national hand hygiene initiative. AB - Hand hygiene is the primary measure in hospitals to reduce the spread of infections, with nurses experiencing the greatest frequency of patient contact. The '5 critical moments' of hand hygiene initiative has been implemented in hospitals across Australia, accompanied by awareness-raising, staff training and auditing. The aim of this study was to understand the determinants of nurses' hand hygiene decisions, using an extension of a common health decision-making model, the theory of planned behaviour (TPB), to inform future health education strategies to increase compliance. Nurses from 50 Australian hospitals (n = 2378) completed standard TPB measures (attitude, subjective norm, perceived behavioural control [PBC], intention) and the extended variables of group norm, risk perceptions (susceptibility, severity) and knowledge (subjective, objective) at Time 1, while a sub-sample (n = 797) reported their hand hygiene behaviour 2 weeks later. Regression analyses identified subjective norm, PBC, group norm, subjective knowledge and risk susceptibility as the significant predictors of nurses' hand hygiene intentions, with intention and PBC predicting their compliance behaviour. Rather than targeting attitudes which are already very favourable among nurses, health education strategies should focus on normative influences and perceptions of control and risk in efforts to encourage hand hygiene adherence. PMID- 26590245 TI - A systematic review of training interventions addressing sexual violence against marginalized at-risk groups of women. AB - Women from marginalized groups working in occupations such as domestic work are at increased risk for sexual violence. Scarce evidence exists about training interventions targeting such groups. The article aims to identify community and workplace-based training interventions aiming to increase capacity among marginalized at-risk women to deal with sexual violence. A systematic review was applied. Inclusion criteria were English language published between 2003 and 2013; reporting on delivery and/or evaluation; focusing on any form of sexual violence; delivered to professionals, affected or at-risk women; targeting migrant, at-risk women or domestic workers. Data were extracted on the setting, content, evaluation process and target population. Four studies which focused on prevention or responding to sexual violence were included. One study provided sexual violence training to vulnerable female and one provided a HIV prevention intervention to marginalized women. Learning objectives included increasing knowledge around issues of sexual violence and/or gender and human rights, prevention and response strategies. Two studies aimed to train trainers. All studies conducted an outcome evaluation and two a process evaluation. It seems there is a gap on participatory empowerment training for marginalized women. Community train-the-trainer interventions are imperative to protect themselves and deal with the risk of sexual violence. PMID- 26590246 TI - 'Eh! I felt I was sabotaged!': facilitators' understandings of success in a participatory HIV and IPV prevention intervention in urban South Africa. AB - Participatory approaches to behaviour change dominate HIV- and intimate partner violence prevention interventions. Research has identified multiple challenges in the delivery of these. In this article, we focus on how facilitators conceptualize successful facilitation and how these understandings may undermine dialogue and critical consciousness, through a case study of facilitators engaged in the delivery of Stepping Stones and Creating Futures and ten focus-group discussions held with facilitators. All facilitators continually emphasized the importance of discussion and active engagement by participants. However, other understandings of successful facilitation also emerged, including group management--particularly securing high levels of attendance; ensuring answers provided by participants were 'right'; being active facilitators; and achieving behaviour change. These in various ways potentially undermined dialogue and the emergence of critical thinking. We locate these different understandings of success as located in the wider context of conceptualizations of autonomy and structure; historical experiences of work and education; and the ongoing tension between the requirements of rigorous research and those of participatory interventions. We suggest a new approach to training and support for facilitators is required if participatory interventions are to be delivered at scale, as they must be. PMID- 26590247 TI - Influence of perceived interactivity of a sexual health text message service on young people's attitudes, satisfaction and repeat use. AB - Sexual health text message services are becoming an increasingly popular way to reach young people with sexual health information. A variety of service types exist: some send automated messages on a set schedule; others provide personalized responses to individual questions. Young people's perceptions of interactivity, which is often based on system responsiveness, may vary. This study examines perceptions of interactivity for users of a two-way text message service that connects young people directly with a health educator and examines the relationship between perceived interactivity and attitudes toward the service, service satisfaction, and repeated service use. Data from 131 users in the southeastern U.S.A. were analysed. Perceived interactivity was associated with positive attitudes, user satisfaction and repeat use. Data suggest that for sexual health information seeking, young people may view a program as more useful if they perceive it is interactive. Services that provide a back-and-forth dialog between health educators and users may be perceived as interactive, and those perceptions of interactivity can influence attitudes toward the service as well as behaviors, such as using the service repeatedly. Since such services offer accurate and timely health information, repeated use allows for the additional exchange of health information and educational opportunities. PMID- 26590253 TI - Cathepsin S-Dependent Protease-Activated Receptor-2 Activation: A New Mechanism of Endothelial Dysfunction. PMID- 26590254 TI - UET: a database of evolutionarily-predicted functional determinants of protein sequences that cluster as functional sites in protein structures. AB - The structure and function of proteins underlie most aspects of biology and their mutational perturbations often cause disease. To identify the molecular determinants of function as well as targets for drugs, it is central to characterize the important residues and how they cluster to form functional sites. The Evolutionary Trace (ET) achieves this by ranking the functional and structural importance of the protein sequence positions. ET uses evolutionary distances to estimate functional distances and correlates genotype variations with those in the fitness phenotype. Thus, ET ranks are worse for sequence positions that vary among evolutionarily closer homologs but better for positions that vary mostly among distant homologs. This approach identifies functional determinants, predicts function, guides the mutational redesign of functional and allosteric specificity, and interprets the action of coding sequence variations in proteins, people and populations. Now, the UET database offers pre-computed ET analyses for the protein structure databank, and on-the-fly analysis of any protein sequence. A web interface retrieves ET rankings of sequence positions and maps results to a structure to identify functionally important regions. This UET database integrates several ways of viewing the results on the protein sequence or structure and can be found at http://mammoth.bcm.tmc.edu/uet/. PMID- 26590255 TI - deepBase v2.0: identification, expression, evolution and function of small RNAs, LncRNAs and circular RNAs from deep-sequencing data. AB - Small non-coding RNAs (e.g. miRNAs) and long non-coding RNAs (e.g. lincRNAs and circRNAs) are emerging as key regulators of various cellular processes. However, only a very small fraction of these enigmatic RNAs have been well functionally characterized. In this study, we describe deepBase v2.0 (http://biocenter.sysu.edu.cn/deepBase/), an updated platform, to decode evolution, expression patterns and functions of diverse ncRNAs across 19 species. deepBase v2.0 has been updated to provide the most comprehensive collection of ncRNA-derived small RNAs generated from 588 sRNA-Seq datasets. Moreover, we developed a pipeline named lncSeeker to identify 176 680 high-confidence lncRNAs from 14 species. Temporal and spatial expression patterns of various ncRNAs were profiled. We identified approximately 24 280 primate-specific, 5193 rodent specific lncRNAs, and 55 highly conserved lncRNA orthologs between human and zebrafish. We annotated 14 867 human circRNAs, 1260 of which are orthologous to mouse circRNAs. By combining expression profiles and functional genomic annotations, we developed lncFunction web-server to predict the function of lncRNAs based on protein-lncRNA co-expression networks. This study is expected to provide considerable resources to facilitate future experimental studies and to uncover ncRNA functions. PMID- 26590256 TI - STITCH 5: augmenting protein-chemical interaction networks with tissue and affinity data. AB - Interactions between proteins and small molecules are an integral part of biological processes in living organisms. Information on these interactions is dispersed over many databases, texts and prediction methods, which makes it difficult to get a comprehensive overview of the available evidence. To address this, we have developed STITCH ('Search Tool for Interacting Chemicals') that integrates these disparate data sources for 430 000 chemicals into a single, easy to-use resource. In addition to the increased scope of the database, we have implemented a new network view that gives the user the ability to view binding affinities of chemicals in the interaction network. This enables the user to get a quick overview of the potential effects of the chemical on its interaction partners. For each organism, STITCH provides a global network; however, not all proteins have the same pattern of spatial expression. Therefore, only a certain subset of interactions can occur simultaneously. In the new, fifth release of STITCH, we have implemented functionality to filter out the proteins and chemicals not associated with a given tissue. The STITCH database can be downloaded in full, accessed programmatically via an extensive API, or searched via a redesigned web interface at http://stitch.embl.de. PMID- 26590258 TI - MitoAge: a database for comparative analysis of mitochondrial DNA, with a special focus on animal longevity. AB - Mitochondria are the only organelles in the animal cells that have their own genome. Due to a key role in energy production, generation of damaging factors (ROS, heat), and apoptosis, mitochondria and mtDNA in particular have long been considered one of the major players in the mechanisms of aging, longevity and age related diseases. The rapidly increasing number of species with fully sequenced mtDNA, together with accumulated data on longevity records, provides a new fascinating basis for comparative analysis of the links between mtDNA features and animal longevity. To facilitate such analyses and to support the scientific community in carrying these out, we developed the MitoAge database containing calculated mtDNA compositional features of the entire mitochondrial genome, mtDNA coding (tRNA, rRNA, protein-coding genes) and non-coding (D-loop) regions, and codon usage/amino acids frequency for each protein-coding gene. MitoAge includes 922 species with fully sequenced mtDNA and maximum lifespan records. The database is available through the MitoAge website (www.mitoage.org or www.mitoage.info), which provides the necessary tools for searching, browsing, comparing and downloading the data sets of interest for selected taxonomic groups across the Kingdom Animalia. The MitoAge website assists in statistical analysis of different features of the mtDNA and their correlative links to longevity. PMID- 26590257 TI - Evolution of disorder in Mediator complex and its functional relevance. AB - Mediator, an important component of eukaryotic transcriptional machinery, is a huge multisubunit complex. Though the complex is known to be conserved across all the eukaryotic kingdoms, the evolutionary topology of its subunits has never been studied. In this study, we profiled disorder in the Mediator subunits of 146 eukaryotes belonging to three kingdoms viz., metazoans, plants and fungi, and attempted to find correlation between the evolution of Mediator complex and its disorder. Our analysis suggests that disorder in Mediator complex have played a crucial role in the evolutionary diversification of complexity of eukaryotic organisms. Conserved intrinsic disordered regions (IDRs) were identified in only six subunits in the three kingdoms whereas unique patterns of IDRs were identified in other Mediator subunits. Acquisition of novel molecular recognition features (MoRFs) through evolution of new subunits or through elongation of the existing subunits was evident in metazoans and plants. A new concept of 'junction MoRF' has been introduced. Evolutionary link between CBP and Med15 has been provided which explain the evolution of extended-IDR in CBP from Med15 KIX-IDR junction-MoRF suggesting role of junction-MoRF in evolution and modulation of protein-protein interaction repertoire. This study can be informative and helpful in understanding the conserved and flexible nature of Mediator complex across eukaryotic kingdoms. PMID- 26590259 TI - The UCSC Genome Browser database: 2016 update. AB - For the past 15 years, the UCSC Genome Browser (http://genome.ucsc.edu/) has served the international research community by offering an integrated platform for viewing and analyzing information from a large database of genome assemblies and their associated annotations. The UCSC Genome Browser has been under continuous development since its inception with new data sets and software features added frequently. Some release highlights of this year include new and updated genome browsers for various assemblies, including bonobo and zebrafish; new gene annotation sets; improvements to track and assembly hub support; and a new interactive tool, the "Data Integrator", for intersecting data from multiple tracks. We have greatly expanded the data sets available on the most recent human assembly, hg38/GRCh38, to include updated gene prediction sets from GENCODE, more phenotype- and disease-associated variants from ClinVar and ClinGen, more genomic regulatory data, and a new multiple genome alignment. PMID- 26590260 TI - miRTarBase 2016: updates to the experimentally validated miRNA-target interactions database. AB - MicroRNAs (miRNAs) are small non-coding RNAs of approximately 22 nucleotides, which negatively regulate the gene expression at the post-transcriptional level. This study describes an update of the miRTarBase (http://miRTarBase.mbc.nctu.edu.tw/) that provides information about experimentally validated miRNA-target interactions (MTIs). The latest update of the miRTarBase expanded it to identify systematically Argonaute-miRNA-RNA interactions from 138 crosslinking and immunoprecipitation sequencing (CLIP-seq) data sets that were generated by 21 independent studies. The database contains 4966 articles, 7439 strongly validated MTIs (using reporter assays or western blots) and 348 007 MTIs from CLIP-seq. The number of MTIs in the miRTarBase has increased around 7-fold since the 2014 miRTarBase update. The miRNA and gene expression profiles from The Cancer Genome Atlas (TCGA) are integrated to provide an effective overview of this exponential growth in the miRNA experimental data. These improvements make the miRTarBase one of the more comprehensively annotated, experimentally validated miRNA-target interactions databases and motivate additional miRNA research efforts. PMID- 26590261 TI - Modeling co-occupancy of transcription factors using chromatin features. AB - Regulation of gene expression requires both transcription factor (TFs) and epigenetic modifications, and interplays between the two types of factors have been discovered. However study of relationships between chromatin features and TF TF co-occupancy remains limited. Here, we revealed the relationship by first illustrating distinct profile patterns of chromatin features related to different binding events, including single TF binding and TF-TF co-occupancy of 71 TFs from five human cell lines. We further implemented statistical analyses to demonstrate the relationship by accurately predicting co-occupancy genome-widely using chromatin features including DNase I hypersensitivity, 11 histone modifications (HMs) and GC content. Remarkably, our results showed that the combination of chromatin features enables accurate predictions across the five cells. For individual chromatin features, DNase I enables high and consistent predictions. H3K27ac, H3K4me 2, H3K4me3 and H3K9ac are more reliable predictors than other HMs. Although the combination of 11 HMs achieves accurate predictions, their predictive ability varies considerably when a model obtained from one cell is applied to others, indicating relationship between HMs and TF-TF co-occupancy is cell type dependent. GC content is not a reliable predictor, but the addition of GC content to any other features enhances their predictive ability. Together, our results elucidate a strong relationship between TF-TF co-occupancy and chromatin features. PMID- 26590263 TI - Lynx: a knowledge base and an analytical workbench for integrative medicine. AB - Lynx (http://lynx.ci.uchicago.edu) is a web-based database and a knowledge extraction engine. It supports annotation and analysis of high-throughput experimental data and generation of weighted hypotheses regarding genes and molecular mechanisms contributing to human phenotypes or conditions of interest. Since the last release, the Lynx knowledge base (LynxKB) has been periodically updated with the latest versions of the existing databases and supplemented with additional information from public databases. These additions have enriched the data annotations provided by Lynx and improved the performance of Lynx analytical tools. Moreover, the Lynx analytical workbench has been supplemented with new tools for reconstruction of co-expression networks and feature-and-network-based prioritization of genetic factors and molecular mechanisms. These developments facilitate the extraction of meaningful knowledge from experimental data and LynxKB. The Service Oriented Architecture provides public access to LynxKB and its analytical tools via user-friendly web services and interfaces. PMID- 26590264 TI - MutationAligner: a resource of recurrent mutation hotspots in protein domains in cancer. AB - The MutationAligner web resource, available at http://www.mutationaligner.org, enables discovery and exploration of somatic mutation hotspots identified in protein domains in currently (mid-2015) more than 5000 cancer patient samples across 22 different tumor types. Using multiple sequence alignments of protein domains in the human genome, we extend the principle of recurrence analysis by aggregating mutations in homologous positions across sets of paralogous genes. Protein domain analysis enhances the statistical power to detect cancer-relevant mutations and links mutations to the specific biological functions encoded in domains. We illustrate how the MutationAligner database and interactive web tool can be used to explore, visualize and analyze mutation hotspots in protein domains across genes and tumor types. We believe that MutationAligner will be an important resource for the cancer research community by providing detailed clues for the functional importance of particular mutations, as well as for the design of functional genomics experiments and for decision support in precision medicine. MutationAligner is slated to be periodically updated to incorporate additional analyses and new data from cancer genomics projects. PMID- 26590262 TI - Comparative genomic analyses reveal a vast, novel network of nucleotide-centric systems in biological conflicts, immunity and signaling. AB - Cyclic di- and linear oligo-nucleotide signals activate defenses against invasive nucleic acids in animal immunity; however, their evolutionary antecedents are poorly understood. Using comparative genomics, sequence and structure analysis, we uncovered a vast network of systems defined by conserved prokaryotic gene neighborhoods, which encode enzymes generating such nucleotides or alternatively processing them to yield potential signaling molecules. The nucleotide-generating enzymes include several clades of the DNA-polymerase beta-like superfamily (including Vibrio cholerae DncV), a minimal version of the CRISPR polymerase and DisA-like cyclic-di-AMP synthetases. Nucleotide-binding/processing domains include TIR domains and members of a superfamily prototyped by Smf/DprA proteins and base (cytokinin)-releasing LOG enzymes. They are combined in conserved gene neighborhoods with genes for a plethora of protein superfamilies, which we predict to function as nucleotide-sensors and effectors targeting nucleic acids, proteins or membranes (pore-forming agents). These systems are sometimes combined with other biological conflict-systems such as restriction-modification and CRISPR/Cas. Interestingly, several are coupled in mutually exclusive neighborhoods with either a prokaryotic ubiquitin-system or a HORMA domain-PCH2 like AAA+ ATPase dyad. The latter are potential precursors of equivalent proteins in eukaryotic chromosome dynamics. Further, components from these nucleotide centric systems have been utilized in several other systems including a novel diversity-generating system with a reverse transcriptase. We also found the Smf/DprA/LOG domain from these systems to be recruited as a predicted nucleotide binding domain in eukaryotic TRPM channels. These findings point to evolutionary and mechanistic links, which bring together CRISPR/Cas, animal interferon-induced immunity, and several other systems that combine nucleic-acid-sensing and nucleotide-dependent signaling. PMID- 26590265 TI - Diversion of ADHD Stimulants and Victimization Among Adolescents. AB - OBJECTIVE: To examine whether a recent prescription for stimulant medication is associated with peer victimization among youth with attention deficit/hyperactivity disorder (ADHD). METHODS: Data from 4,965 adolescents attending five public schools who completed an annual web survey over 4 years were used to examine recent stimulant medication prescription and self-reported frequent victimization. RESULTS: Adolescents with ADHD and recent stimulant prescription reported more victimization than those without ADHD, but similar to adolescents with ADHD and no recent prescription. Adolescents with ADHD and past 12-month diversion of their prescribed stimulants were at greatest risk of 12 month frequent victimization compared with adolescents without ADHD and adolescents with ADHD but no recent prescription. Youth approached to divert reported more victimization than youth not approached. Youth who diverted reported more victimization than those who did not divert. CONCLUSIONS: Close parent-prescriber collaboration is needed to ensure effective medical treatment for ADHD without greater risk for victimization and treatment failure. PMID- 26590267 TI - Sustained remission in lupus nephritis: still a hard road ahead. AB - End-stage renal disease caused by lupus nephritis (LN) is an avoidable outcome yet there is considerable uncertainty and variability among nephrologists in their approaches to this disorder. This review discusses recent evidence relevant to the management of LN including recent consensus statements. Long-term results are encouraging compared with 30 years ago, but despite the use of the best available current therapies and achieving high levels of early clinical responses, the kidney often sustains long-term damage and nephritis relapses affect over 50%. Major hurdles to management include the complexity of the clinical presentation, histological features and serological tests, and the absence of reliable outcome predictors or markers of treatment response. The key serological and histopathological characteristics relevant to the practising nephrologist are reviewed, and the limitations of current disease activity markers discussed. There are many potential biomarkers under evaluation, and a framework for their validation is presented. Clinical trials of existing or newer agents for LN have typically been inconclusive and have raised problems of trial design and interpretation that are a barrier to new drug development. The major issues affecting clinical trial design and their potential solutions are summarized. PMID- 26590266 TI - Examining the robustness of the obesity paradox in maintenance hemodialysis patients: a marginal structural model analysis. AB - BACKGROUND: The inverse association between body mass index (BMI) and mortality observed in patients treated with maintenance hemodialysis (MHD), also known as the obesity paradox, may be a result of residual confounding. Marginal structural model (MSM) analysis, a technique that accounts for time-varying confounders, may be more appropriate to investigate this association. We hypothesize that after applying MSM, the inverse association between BMI and mortality in MHD patients is attenuated. METHODS: We examined the associations between BMI and all-cause mortality among 123 624 adult MHD patients treated during 2001-6. We examined baseline and time-varying BMI using Cox proportional hazards models and MSM while considering baseline and time-varying covariates, including demographics, comorbidities and markers of malnutrition and inflammation. RESULTS: The patients included 45% women and 32% African Americans with a mean age of 61(SD 15) years. In all models, BMI showed a linear incremental inverse association with mortality. Compared with the reference (BMI 25 to <27.5 kg/m(2)), a BMI of <18 kg/m(2) was associated with a 3.2-fold higher death risk [hazard ratio (HR) 3.17 (95% CI 3.05-3.29)], and mortality risks declined with increasing BMI with the greatest survival advantage of 31% lower risk [HR 0.69 (95% CI 0.64-0.75)] observed with a BMI of 40 to <45 kg/m(2). CONCLUSIONS: The linear inverse relationship between BMI and mortality is robust across models including MSM analyses that more completely account for time-varying confounders and biases. PMID- 26590269 TI - Time trends in causes of death after aneurysmal subarachnoid hemorrhage: A hospital-based study. AB - OBJECTIVE: To compare causes of in-hospital death after aneurysmal subarachnoid hemorrhage (aSAH) in 2 time periods within the same institution. METHODS: From a prospectively collected institutional database, we retrieved data on 844 consecutive patients with aSAH admitted <=3 days after ictus in 1999-2002 and 2009-2012. We assessed case-fatality <90 days and causes of in-hospital death and used Poisson regression analyses to calculate adjusted risk ratios (aRR) with corresponding 95% confidence intervals (CI) for change in individual causes of death, with the first time period as the reference group. RESULTS: Ninety-day case-fatality declined from 150/381 patients (39%) in 1999-2002 to 140/463 (30%) in 2009-2012 (aRR 0.74 [95% CI 0.62-0.88]). Compared with 1999-2002, the aRR for specific cause of in-hospital death in 2009-2012 was 1.06 (95% CI 0.72-1.56) for death from the initial bleeding, 0.47 (95% CI 0.31-0.71) for death from rebleeding, and 0.91 (95% CI 0.50-1.65) for death from delayed cerebral ischemia. Over time, the proportion of patients with in-hospital rebleeding declined from 90/381 (24%) to 78/463 (17%) (aRR 0.68 [95% CI 0.52-0.90]), median day of rebleeding from day 5 (IQR 1-10) to day 0 (IQR 0-1), and median day of aneurysm treatment from day 4 (IQR 2-13) to day 1 (IQR 1-2). CONCLUSIONS: An important contributor to the reduction in in-hospital death is the reduction in death from rebleeding, which probably results from earlier aneurysm treatment. Our results stress the need for early occlusion of the aneurysm and the need for other strategies that improve outcome by reducing the risk of rebleeding. PMID- 26590270 TI - 18F-FDG-PET correlates of cognitive impairment in ALS. AB - OBJECTIVE: To identify the metabolic signature of the various levels of cognitive deficits in amyotrophic lateral sclerosis (ALS) using 18F-2-fluoro-2-deoxy-d glucose-PET (18F-FDG-PET). METHODS: A total of 170 ALS cases consecutively enrolled at the ALS Center of Turin underwent brain 18F-FDG-PET and were classified as displaying normal cognition (ALS-Cn; n = 94), full-blown frontotemporal dementia (ALS-FTD; n = 20), executive or nonexecutive cognitive impairment not fulfilling FTD criteria (ALS-Ci; n = 37), prevalent behavioral changes (n = 9), or nonclassifiable impairment (n = 10) according to neuropsychological testing. Group comparisons of 18F-FDG-PET pattern were carried out among the cognitive subgroups. RESULTS: We found a significantly reduced frontal and prefrontal metabolism in ALS-FTD as compared to ALS-Cn, while ALS-Ci showed an intermediate metabolic behavior in frontal cortex, being hypometabolic as compared to ALS-Cn, and relatively hypermetabolic as compared to ALS-FTD. Hypometabolism in frontal regions was associated in all comparisons to hypermetabolism in cerebellum, midbrain, and corticospinal tracts: the more severe the cognitive decline, the larger the size of the cluster and the statistical significance of 18F-FDG uptake differences. CONCLUSIONS: This study demonstrated in a large cohort of patients with ALS a continuum of frontal lobe metabolic impairment reflecting the clinical and anatomic continuum ranging from pure ALS, through ALS with intermediate cognitive deficits, to ALS-FTD, and showing that patients with intermediate cognitive impairment display a characteristic metabolic pattern. Since 18F-FDG-PET allows us to estimate the cerebral lesion load in vivo in neurodegenerative diseases, it might be helpful to investigate in ALS its association with neuropsychological testing along the disease course to disclose the early metabolic signature of possible cognitive impairment. PMID- 26590271 TI - Land Spreading of Wastewaters from the Fruit-Packaging Industry and Potential Effects on Soil Microbes: Effects of the Antioxidant Ethoxyquin and Its Metabolites on Ammonia Oxidizers. AB - Thiabendazole (TBZ), imazalil (IMZ), ortho-phenylphenol (OPP), diphenylamine (DPA), and ethoxyquin (EQ) are used in fruit-packaging plants (FPP) with the stipulation that wastewaters produced by their application would be depurated on site. However, no such treatment systems are currently in place, leading FPP to dispose of their effluents in agricultural land. We investigated the dissipation of those pesticides and their impact on soil microbes known to have a key role on ecosystem functioning. OPP and DPA showed limited persistence (50% dissipation time [DT50], 0.6 and 1.3 days) compared to TBZ and IMZ (DT50, 47.0 and 150.8 days). EQ was rapidly transformed to the short-lived quinone imine (QI) (major metabolite) and the more persistent 2,4-dimethyl-6-ethoxyquinoline (EQNL) (minor metabolite). EQ and OPP exerted significant inhibition of potential nitrification, with the effect of the former being more persistent. This was not reflected in the abundance (determined by quantitative PCR [qPCR]) of the amoA gene of ammonia-oxidizing bacteria (AOB) and archaea (AOA). Considering the above discrepancy and the metabolic pattern of EQ, we further investigated the hypothesis that its metabolites and not only EQ were toxic to ammonia oxidizers. Potential nitrification, amoA gene abundance, and amoA gene transcripts of AOB and AOA showed that QI was probably responsible for the inhibition of nitrification. Our findings have serious ecological and practical implications for soil productivity and N conservation in agriculturally impacted ecosystems and stress the need to include metabolites and RNA-based methods when the soil microbial toxicity of pesticides is assessed. PMID- 26590272 TI - Tuning Chocolate Flavor through Development of Thermotolerant Saccharomyces cerevisiae Starter Cultures with Increased Acetate Ester Production. AB - Microbial starter cultures have extensively been used to enhance the consistency and efficiency of industrial fermentations. Despite the advantages of such controlled fermentations, the fermentation involved in the production of chocolate is still a spontaneous process that relies on the natural microbiota at cocoa farms. However, recent studies indicate that certain thermotolerant Saccharomyces cerevisiae cultures can be used as starter cultures for cocoa pulp fermentation. In this study, we investigate the potential of specifically developed starter cultures to modulate chocolate aroma. Specifically, we developed several new S. cerevisiae hybrids that combine thermotolerance and efficient cocoa pulp fermentation with a high production of volatile flavor active esters. In addition, we investigated the potential of two strains of two non-Saccharomyces species that produce very large amounts of fruity esters (Pichia kluyveri and Cyberlindnera fabianii) to modulate chocolate aroma. Gas chromatography-mass spectrometry (GC-MS) analysis of the cocoa liquor revealed an increased concentration of various flavor-active esters and a decrease in spoilage-related off-flavors in batches inoculated with S. cerevisiae starter cultures and, to a lesser extent, in batches inoculated with P. kluyveri and Cyb. fabianii. Additionally, GC-MS analysis of chocolate samples revealed that while most short-chain esters evaporated during conching, longer and more-fat-soluble ethyl and acetate esters, such as ethyl octanoate, phenylethyl acetate, ethyl phenylacetate, ethyl decanoate, and ethyl dodecanoate, remained almost unaffected. Sensory analysis by an expert panel confirmed significant differences in the aromas of chocolates produced with different starter cultures. Together, these results show that the selection of different yeast cultures opens novel avenues for modulating chocolate flavor. PMID- 26590273 TI - Defluviitalea phaphyphila sp. nov., a Novel Thermophilic Bacterium That Degrades Brown Algae. AB - Brown algae are one of the largest groups of oceanic primary producers for CO2 removal and carbon sinks for coastal regions. However, the mechanism for brown alga assimilation remains largely unknown in thermophilic microorganisms. In this work, a thermophilic alginolytic community was enriched from coastal sediment, from which an obligate anaerobic and thermophilic bacterial strain, designated Alg1, was isolated. Alg1 shared a 16S rRNA gene identity of 94.6% with Defluviitalea saccharophila LIND6LT2(T). Phenotypic, chemotaxonomic, and phylogenetic studies suggested strain Alg1 represented a novel species of the genus Defluviitalea, for which the name Defluviitalea phaphyphila sp. nov. is proposed. Alg1 exhibited an intriguing ability to convert carbohydrates of brown algae, including alginate, laminarin, and mannitol, to ethanol and acetic acid. Three gene clusters participating in this process were predicted to be in the genome, and candidate enzymes were successfully expressed, purified, and characterized. Six alginate lyases were demonstrated to synergistically deconstruct alginate into unsaturated monosaccharide, followed by one uronic acid reductase and two 2-keto-3-deoxy-d-gluconate (KDG) kinases to produce pyruvate. A nonclassical mannitol 1-phosphate dehydrogenase, catalyzing D-mannitol 1 phosphate to fructose 1-phosphate in the presence of NAD(+), and one laminarase also were disclosed. This work revealed that a thermophilic brown alga decomposing system containing numerous novel thermophilic alginate lyases and a unique mannitol 1-phosphate dehydrogenase was adopted by the natural ethanologenic strain Alg1 during the process of evolution in hostile habitats. PMID- 26590274 TI - Tyrosine Phosphorylation and Dephosphorylation in Burkholderia cenocepacia Affect Biofilm Formation, Growth under Nutritional Deprivation, and Pathogenicity. AB - Burkholderia cenocepacia, a member of the B. cepacia complex (Bcc), is an opportunistic pathogen causing serious chronic infections in patients with cystic fibrosis. Tyrosine phosphorylation has emerged as an important posttranslational modification modulating the physiology and pathogenicity of Bcc bacteria. Here, we investigated the predicted bacterial tyrosine kinases BCAM1331 and BceF and the low-molecular-weight protein tyrosine phosphatases BCAM0208, BceD, and BCAL2200 of B. cenocepacia K56-2. We show that BCAM1331, BceF, BCAM0208, and BceD contribute to biofilm formation, while BCAL2200 is required for growth under nutrient-limited conditions. Multiple deletions of either tyrosine kinase or low molecular-weight protein tyrosine phosphatase genes resulted in the attenuation of B. cenocepacia intramacrophage survival and reduced pathogenicity in the Galleria mellonella larval infection model. Experimental evidence indicates that BCAM1331 displays reduced tyrosine autophosphorylation activity compared to that of BceF. With the artificial substrate p-nitrophenyl phosphate, the phosphatase activities of the three low-molecular-weight protein tyrosine phosphatases demonstrated similar kinetic parameters. However, only BCAM0208 and BceD could dephosphorylate BceF. Further, BCAL2200 became tyrosine phosphorylated in vivo and catalyzed its autodephosphorylation. Together, our data suggest that despite having similar biochemical activities, low-molecular-weight protein tyrosine phosphatases and tyrosine kinases have both overlapping and specific roles in the physiology of B. cenocepacia. PMID- 26590275 TI - The Exiguobacterium sibiricum 255-15 GtfC Enzyme Represents a Novel Glycoside Hydrolase 70 Subfamily of 4,6-alpha-Glucanotransferase Enzymes. AB - The glycoside hydrolase 70 (GH70) family originally was established for glucansucrase enzymes found solely in lactic acid bacteria synthesizing alpha glucan polysaccharides from sucrose (e.g., GtfA). In recent years, we have characterized GtfB and related Lactobacillus enzymes as 4,6-alpha glucanotransferase enzymes. These GtfB-type enzymes constitute the first GH70 subfamily of enzymes that are unable to act on sucrose as a substrate but are active with maltodextrins and starch, cleave alpha1->4 linkages, and synthesize linear alpha1->6-glucan chains. The GtfB disproportionating type of activity results in the conversion of malto-oligosaccharides into isomalto/malto polysaccharides with a relatively high percentage of alpha1->6 linkages. This paper reports the identification of the members of a second GH70 subfamily (designated GtfC enzymes) and the characterization of the Exiguobacterium sibiricum 255-15 GtfC enzyme, which is also inactive with sucrose and displays 4,6-alpha-glucanotransferase activity with malto-oligosaccharides. GtfC differs from GtfB in synthesizing isomalto/malto-oligosaccharides. Biochemically, the GtfB- and GtfC-type enzymes are related, but phylogenetically, they clearly constitute different GH70 subfamilies, displaying only 30% sequence identity. Whereas the GtfB-type enzyme largely has the same domain order as glucansucrases (with alpha-amylase domains A, B, and C plus domains IV and V), this GtfC-type enzyme differs in the order of these domains and completely lacks domain V. In GtfC, the sequence of conserved regions I to IV of clan GH-H is identical to that in GH13 (I-II-III-IV) but different from that in GH70 (II-III-IV-I because of a circular permutation of the (beta/alpha)8 barrel. The GtfC 4,6-alpha glucanotransferase enzymes thus represent structurally and functionally very interesting evolutionary intermediates between alpha-amylase and glucansucrase enzymes. PMID- 26590276 TI - Influence of oxyR on Growth, Biofilm Formation, and Mobility of Vibrio parahaemolyticus. AB - Vibrio parahaemolyticus is a common marine food-borne enteropathogen. In this study, we examined the antioxidative activity, growth, biofilm formation, and cell mobility of an oxyR deletion mutant and its genetically complementary strain of V. parahaemolyticus. oxyR is the regulator of catalase and ahpC genes. Protection against extrinsic H2O2 and against the organic peroxides cumene hydroperoxide and tert-butyl hydroperoxide was weaker in the deletion mutant than in its parent strain. Expression of the major functional antioxidative genes, ahpC1 and VPA1418, was markedly decreased in the oxyR mutant. Growth of this mutant on agar medium was significantly inhibited by autoclaved 0.25% glucose and by 0.25% dipotassium hydrogen phosphate, 0.5% monosaccharides (glucose, galactose, xylose, and arabinose), or 114.8 mM phosphates. The inhibition of the growth of this oxyR mutant by extrinsic peroxides, autoclaved sugars, and phosphates was eliminated by the complementary oxyR gene or by the addition of catalase to the autoclaved medium, while no inhibition of growth was observed when filter-sterilized sugars were used. The formation of biofilm and swimming mobility were significantly inhibited in the oxyR mutant relative to that in the wild-type strain. This investigation demonstrates the antioxidative function of oxyR in V. parahaemolyticus and its possible roles in biofilm formation, cell mobility, and the protection of growth in heated rich medium. PMID- 26590277 TI - Isolation of Polyvalent Bacteriophages by Sequential Multiple-Host Approaches. AB - Many studies on phage biology are based on isolation methods that may inadvertently select for narrow-host-range phages. Consequently, broad-host-range phages, whose ecological significance is largely unexplored, are consistently overlooked. To enhance research on such polyvalent phages, we developed two sequential multihost isolation methods and tested both culture-dependent and culture-independent phage libraries for broad infectivity. Lytic phages isolated from activated sludge were capable of interspecies or even interorder infectivity without a significant reduction in the efficiency of plating (0.45 to 1.15). Two polyvalent phages (PX1 of the Podoviridae family and PEf1 of the Siphoviridae family) were characterized in terms of adsorption rate (3.54 * 10(-10) to 8.53 * 10(-10) ml/min), latent time (40 to 55 min), and burst size (45 to 99 PFU/cell), using different hosts. These phages were enriched with a nonpathogenic host (Pseudomonas putida F1 or Escherichia coli K-12) and subsequently used to infect model problematic bacteria. By using a multiplicity of infection of 10 in bacterial challenge tests, >60% lethality was observed for Pseudomonas aeruginosa relative to uninfected controls. The corresponding lethality for Pseudomonas syringae was ~ 50%. Overall, this work suggests that polyvalent phages may be readily isolated from the environment by using different sequential hosts, and this approach should facilitate the study of their ecological significance as well as enable novel applications. PMID- 26590278 TI - Processing-Dependent and Clonal Contamination Patterns of Listeria monocytogenes in the Cured Ham Food Chain Revealed by Genetic Analysis. AB - The quantitative and qualitative patterns of environmental contamination by Listeria monocytogenes were investigated in the production chain of dry-cured Parma ham. Standard arrays of surfaces were sampled in processing facilities during a single visit per plant in the three compartments of the food chain, i.e., ham production (19 plants) and postproduction, which was divided into deboning (43 plants) and slicing (25 plants) steps. The numbers of sampled surfaces were 384 in ham production, with 25 positive for L. monocytogenes, and 1,084 in postproduction, with 83 positives. Statistical analysis of the prevalence of contaminated surfaces showed that in ham production, contamination was higher at the beginning of processing and declined significantly toward the end, while in postproduction, prevalence rose toward the end of processing. Prevalence was higher in the deboning facilities than in slicing facilities and was dependent on the type of surface (floor/drainage > clothing > equipment). The qualitative pattern of contamination was investigated through an analysis of the survey isolates and a set of isolates derived from routine monitoring, including longitudinal isolations. Pulsed-field gel electrophoresis (PFGE) and whole-genome single-nucleotide polymorphism (SNP) analysis revealed a remarkable clonality of L. monocytogenes within plants, with the detection of 16 plant-specific clones out of 17 establishments with multiple isolates. Repeated detections of clonal isolates >6 months apart were also observed. Six was the maximum number of between-isolate differences in core SNPs observed within these clones. Based on the same six-SNP threshold, three clusters of clonal isolates, shared by six establishments, were also identified. The spread of L. monocytogenes within and between plants, as indicated by its clonal behavior, is a matter of concern for the hygienic management of establishments. PMID- 26590279 TI - A Livestock-Associated, Multidrug-Resistant, Methicillin-Resistant Staphylococcus aureus Clonal Complex 97 Lineage Spreading in Dairy Cattle and Pigs in Italy. AB - Pandemic methicillin-resistant Staphylococcus aureus (MRSA) clonal complex 97 (CC97) lineages originated from livestock-to-human host jumps. In recent years, CC97 has become one of the major MRSA lineages detected in Italian farmed animals. The aim of this study was to characterize and analyze differences in MRSA and methicillin-susceptible S. aureus (MSSA) mainly of swine and bovine origins. Forty-seven CC97 isolates, 35 MRSA isolates, and 6 MSSA isolates from different Italian pig and cattle holdings; 5 pig MRSA isolates from Germany; and 1 human MSSA isolate from Spain were characterized by macrorestriction pulsed field gel electrophoresis (PFGE) analysis, multilocus sequence typing (MLST), spa typing, staphylococcal cassette chromosome mec (SCCmec) typing, and antimicrobial resistance pattern analysis. Virulence and resistance genes were investigated by PCR and microarray analysis. Most of the isolates were of SCCmec type V (SCCmec V), except for two German MRSA isolates (SCCmec III). Five main clusters were identified by PFGE, with the German isolates (clusters I and II) showing 60.5% similarity with the Italian isolates, most of which (68.1%) grouped into cluster V. All CC97 isolates were Panton-Valentine leukocidin (PVL) negative, and a few (n = 7) tested positive for sak or scn. All MRSA isolates were multidrug resistant (MDR), and the main features were erm(B)- or erm(C)-mediated (n = 18) macrolide-lincosamide-streptogramin B resistance, vga(A)-mediated (n = 37) pleuromutilin resistance, fluoroquinolone resistance (n = 33), tet(K) in 32/37 tet(M)-positive isolates, and blaZ in almost all MRSA isolates. Few host associated differences were detected among CC97 MRSA isolates: their extensive MDR nature in both pigs and dairy cattle may be a consequence of a spillback from pigs of a MRSA lineage that originated in cattle as MSSA and needs further investigation. Measures should be implemented at the farm level to prevent spillover to humans in intensive farming areas. PMID- 26590280 TI - Validation of a Previously Developed Geospatial Model That Predicts the Prevalence of Listeria monocytogenes in New York State Produce Fields. AB - Technological advancements, particularly in the field of geographic information systems (GIS), have made it possible to predict the likelihood of foodborne pathogen contamination in produce production environments using geospatial models. Yet, few studies have examined the validity and robustness of such models. This study was performed to test and refine the rules associated with a previously developed geospatial model that predicts the prevalence of Listeria monocytogenes in produce farms in New York State (NYS). Produce fields for each of four enrolled produce farms were categorized into areas of high or low predicted L. monocytogenes prevalence using rules based on a field's available water storage (AWS) and its proximity to water, impervious cover, and pastures. Drag swabs (n = 1,056) were collected from plots assigned to each risk category. Logistic regression, which tested the ability of each rule to accurately predict the prevalence of L. monocytogenes, validated the rules based on water and pasture. Samples collected near water (odds ratio [OR], 3.0) and pasture (OR, 2.9) showed a significantly increased likelihood of L. monocytogenes isolation compared to that for samples collected far from water and pasture. Generalized linear mixed models identified additional land cover factors associated with an increased likelihood of L. monocytogenes isolation, such as proximity to wetlands. These findings validated a subset of previously developed rules that predict L. monocytogenes prevalence in produce production environments. This suggests that GIS and geospatial models can be used to accurately predict L. monocytogenes prevalence on farms and can be used prospectively to minimize the risk of preharvest contamination of produce. PMID- 26590281 TI - Expanding the Limits of Thermoacidophily in the Archaeon Sulfolobus solfataricus by Adaptive Evolution. AB - Extremely thermoacidophilic Crenarchaeota belonging to the order Sulfolobales flourish in hot acidic habitats that are strongly oxidizing. The pH extremes of these habitats, however, often exceed the acid tolerance of type species and strains. Here, adaptive laboratory evolution was used over a 3-year period to test whether such organisms harbor additional thermoacidophilic capacity. Three distinct cell lines derived from a single type species were subjected to high temperature serial passage while culture acidity was gradually increased. A 178 fold increase in thermoacidophily was achieved after 29 increments of shifted culture pH resulting in growth at pH 0.8 and 80 degrees C. These strains were named super-acid-resistant Crenarchaeota (SARC). Mathematical modeling using growth parameters predicted the limits of acid resistance, while genome resequencing and transcriptome resequencing were conducted for insight into mechanisms responsible for the evolved trait. Among the mutations that were detected, a set of eight nonsynonymous changes may explain the heritability of increased acid resistance despite an unexpected lack of transposition. Four multigene components of the SARC transcriptome implicated oxidative stress as a primary challenge accompanying growth at acid extremes. These components included accelerated membrane biogenesis, induction of the mer operon, and an increased capacity for the generation of energy and reductant. PMID- 26590282 TI - Establishment of Bacterial Herbicide Degraders in a Rapid Sand Filter for Bioremediation of Phenoxypropionate-Polluted Groundwater. AB - In this study, we investigated the establishment of natural bacterial degraders in a sand filter treating groundwater contaminated with the phenoxypropionate herbicides (RS)-2-(4-chloro-2-methylphenoxy)propanoic acid (MCPP) and (RS)-2-(2,4 dichlorophenoxy)propanoic acid (DCPP) and the associated impurity/catabolite 4 chlorophenoxypropanoic acid (4-CPP). A pilot facility was set up in a contaminated landfill site. Anaerobic groundwater was pumped up and passed through an aeration basin and subsequently through a rapid sand filter, which is characterized by a short residence time of the water in the filter. For 3 months, the degradation of DCPP, MCPP, and 4-CPP in the sand filter increased to 15 to 30% of the inlet concentration. A significant selection for natural bacterial herbicide degraders also occurred in the sand filter. Using a most-probable number (MPN) method, we found a steady increase in the number of culturable phenoxypropionate degraders, reaching approximately 5 * 10(5) degraders per g sand by the end of the study. Using a quantitative PCR targeting the two phenoxypropionate degradation genes, rdpA and sdpA, encoding stereospecific dioxygenases, a parallel increase was observed, but with the gene copy numbers being about 2 to 3 log units higher than the MPN. In general, the sdpA gene was more abundant than the rdpA gene, and the establishment of a significant population of bacteria harboring sdpA occurred faster than the establishment of an rdpA gene-carrying population. The identities of the specific herbicide degraders in the sand filter were assessed by Illumina MiSeq sequencing of 16S rRNA genes from sand filter samples and from selected MPN plate wells. We propose a list of potential degrader bacteria involved in herbicide degradation, including representatives belonging to the Comamonadaceae and Sphingomonadales. PMID- 26590283 TI - MvaT Family Proteins Encoded on IncP-7 Plasmid pCAR1 and the Host Chromosome Regulate the Host Transcriptome Cooperatively but Differently. AB - MvaT proteins are members of the H-NS family of proteins in pseudomonads. The IncP-7 conjugative plasmid pCAR1 carries an mvaT-homologous gene, pmr. In Pseudomonas putida KT2440 bearing pCAR1, pmr and the chromosomally carried homologous genes, turA and turB, are transcribed at high levels, and Pmr interacts with TurA and TurB in vitro. In the present study, we clarified how the three MvaT proteins regulate the transcriptome of P. putida KT2440(pCAR1). Analyses performed by a modified chromatin immunoprecipitation assay with microarray technology (ChIP-chip) suggested that the binding regions of Pmr, TurA, and TurB in the P. putida KT2440(pCAR1) genome are almost identical; nevertheless, transcriptomic analyses using mutants with deletions of the genes encoding the MvaT proteins during the log and early stationary growth phases clearly suggested that their regulons were different. Indeed, significant regulon dissimilarity was found between Pmr and the other two proteins. Transcription of a larger number of genes was affected by Pmr deletion during early stationary phase than during log phase, suggesting that Pmr ameliorates the effects of pCAR1 on host fitness more effectively during the early stationary phase. Alternatively, the similarity of the TurA and TurB regulons implied that they might play complementary roles as global transcriptional regulators in response to plasmid carriage. PMID- 26590284 TI - Substrate and Cofactor Range Differences of Two Cysteine Dioxygenases from Ralstonia eutropha H16. AB - Cysteine dioxygenases (Cdos), which catalyze the sulfoxidation of cysteine to cysteine sulfinic acid (CSA), have been extensively studied in eukaryotes because of their roles in several diseases. In contrast, only a few prokaryotic enzymes of this type have been investigated. In Ralstonia eutropha H16, two Cdo homologues (CdoA and CdoB) have been identified previously. In vivo studies showed that Escherichia coli cells expressing CdoA could convert 3 mercaptopropionate (3MP) to 3-sulfinopropionate (3SP), whereas no 3SP could be detected in cells expressing CdoB. The objective of this study was to confirm these findings and to study both enzymes in detail by performing an in vitro characterization. The proteins were heterologously expressed and purified to apparent homogeneity by immobilized metal chelate affinity chromatography (IMAC). Subsequent analysis of the enzyme activities revealed striking differences with regard to their substrate ranges and their specificities for the transition metal cofactor, e.g., CdoA catalyzed the sulfoxidation of 3MP to a 3-fold-greater extent than the sulfoxidation of cysteine, whereas CdoB converted only cysteine. Moreover, the dependency of the activities of the Cdos from R. eutropha H16 on the metal cofactor in the active center could be demonstrated. The importance of CdoA for the metabolism of the sulfur compounds 3,3'-thiodipropionic acid (TDP) and 3,3'-dithiodipropionic acid (DTDP) by further converting their degradation product, 3MP, was confirmed. Since 3MP can also function as a precursor for polythioester (PTE) synthesis in R. eutropha H16, deletion of cdoA might enable increased synthesis of PTEs. PMID- 26590285 TI - From Rare to Dominant: a Fine-Tuned Soil Bacterial Bloom during Petroleum Hydrocarbon Bioremediation. AB - Hydrocarbons are worldwide-distributed pollutants that disturb various ecosystems. The aim of this study was to characterize the short-lapse dynamics of soil microbial communities in response to hydrocarbon pollution and different bioremediation treatments. Replicate diesel-spiked soil microcosms were inoculated with either a defined bacterial consortium or a hydrocarbonoclastic bacterial enrichment and incubated for 12 weeks. The microbial community dynamics was followed weekly in microcosms using Illumina 16S rRNA gene sequencing. Both the bacterial consortium and enrichment enhanced hydrocarbon degradation in diesel-polluted soils. A pronounced and rapid bloom of a native gammaproteobacterium was observed in all diesel-polluted soils. A unique operational taxonomic unit (OTU) related to the Alkanindiges genus represented ~ 0.1% of the sequences in the original community but surprisingly reached >60% after 6 weeks. Despite this Alkanindiges-related bloom, inoculated strains were maintained in the community and may explain the differences in hydrocarbon degradation. This study shows the detailed dynamics of a soil bacterial bloom in response to hydrocarbon pollution, resembling microbial blooms observed in marine environments. Rare community members presumably act as a reservoir of ecological functions in high-diversity environments, such as soils. This rare-to-dominant bacterial shift illustrates the potential role of a rare biosphere facing drastic environmental disturbances. Additionally, it supports the concept of "conditionally rare taxa," in which rareness is a temporary state conditioned by environmental constraints. PMID- 26590286 TI - Determination of Evolutionary Relationships of Outbreak-Associated Listeria monocytogenes Strains of Serotypes 1/2a and 1/2b by Whole-Genome Sequencing. AB - We used whole-genome sequencing to determine evolutionary relationships among 20 outbreak-associated clinical isolates of Listeria monocytogenes serotypes 1/2a and 1/2b. Isolates from 6 of 11 outbreaks fell outside the clonal groups or "epidemic clones" that have been previously associated with outbreaks, suggesting that epidemic potential may be widespread in L. monocytogenes and is not limited to the recognized epidemic clones. Pairwise comparisons between epidemiologically related isolates within clonal complexes showed that genome-level variation differed by 2 orders of magnitude between different comparisons, and the distribution of point mutations (core versus accessory genome) also varied. In addition, genetic divergence between one closely related pair of isolates from a single outbreak was driven primarily by changes in phage regions. The evolutionary analysis showed that the changes could be attributed to horizontal gene transfer; members of the diverse bacterial community found in the production facility could have served as the source of novel genetic material at some point in the production chain. The results raise the question of how to best utilize information contained within the accessory genome in outbreak investigations. The full magnitude and complexity of genetic changes revealed by genome sequencing could not be discerned from traditional subtyping methods, and the results demonstrate the challenges of interpreting genetic variation among isolates recovered from a single outbreak. Epidemiological information remains critical for proper interpretation of nucleotide and structural diversity among isolates recovered during outbreaks and will remain so until we understand more about how various population histories influence genetic variation. PMID- 26590287 TI - Use of Substrate-Induced Gene Expression in Metagenomic Analysis of an Aromatic Hydrocarbon-Contaminated Soil. AB - Metagenomics allows the study of genes related to xenobiotic degradation in a culture-independent manner, but many of these studies are limited by the lack of genomic context for metagenomic sequences. This study combined a phenotypic screen known as substrate-induced gene expression (SIGEX) with whole-metagenome shotgun sequencing. SIGEX is a high-throughput promoter-trap method that relies on transcriptional activation of a green fluorescent protein (GFP) reporter gene in response to an inducing compound and subsequent fluorescence-activated cell sorting to isolate individual inducible clones from a metagenomic DNA library. We describe a SIGEX procedure with improved library construction from fragmented metagenomic DNA and improved flow cytometry sorting procedures. We used SIGEX to interrogate an aromatic hydrocarbon (AH)-contaminated soil metagenome. The recovered clones contained sequences with various degrees of similarity to genes (or partial genes) involved in aromatic metabolism, for example, nahG (salicylate oxygenase) family genes and their respective upstream nahR regulators. To obtain a broader context for the recovered fragments, clones were mapped to contigs derived from de novo assembly of shotgun-sequenced metagenomic DNA which, in most cases, contained complete operons involved in aromatic metabolism, providing greater insight into the origin of the metagenomic fragments. A comparable set of contigs was generated using a significantly less computationally intensive procedure in which assembly of shotgun-sequenced metagenomic DNA was directed by the SIGEX-recovered sequences. This methodology may have broad applicability in identifying biologically relevant subsets of metagenomes (including both novel and known sequences) that can be targeted computationally by in silico assembly and prediction tools. PMID- 26590288 TI - Purification and Host Specificity of Predatory Halobacteriovorax Isolates from Seawater. AB - Halobacteriovorax (formerly Bacteriovorax) is a small predatory bacterium found in the marine environment and modulates bacterial pathogens in shellfish. Four strains of Halobacteriovorax originally isolated in Vibrio parahaemolyticus O3:K6 host cells were separated from their prey by an enrichment-filtration-dilution technique for specificity testing in other bacteria. This technique was essential, since 0.45-MUm filtration alone was unable to remove infectious Vibrio minicells, as determined by scanning electron microscopy and cultural methods. Purified Halobacteriovorax strains were screened for predation against other V. parahaemolyticus strains and against Vibrio vulnificus, Vibrio alginolyticus, Escherichia coli O157:H7, and Salmonella enterica serovar Typhimurium DT104, all potential threats to seafood safety. They showed high host specificity and were predatory only against strains of V. parahaemolyticus. In addition, strains of Halobacteriovorax that were predatory for E. coli O157:H7 and S. Typhimurium DT104 were isolated from a tidal river at 5 ppt salinity. In a modified plaque assay agar, they killed their respective prey over a broad range of salinities (5 to 30 ppt). Plaques became smaller as the salinity levels rose, suggesting that the lower salinities were optimal for the predators' replication. These species also showed broader host specificity, infectious against each other's original hosts as well as against V. parahaemolyticus strains. In summary, this study characterized strains of Halobacteriovorax which may be considered for use in the development of broad-based biocontrol technologies to enhance the safety of commercially marketed shellfish and other foods. PMID- 26590289 TI - Diversity and Ecology of Viruses in Hyperarid Desert Soils. AB - In recent years, remarkable progress has been made in the field of virus environmental ecology. In marine ecosystems, for example, viruses are now thought to play pivotal roles in the biogeochemical cycling of nutrients and to be mediators of microbial evolution through horizontal gene transfer. The diversity and ecology of viruses in soils are poorly understood, but evidence supports the view that the diversity and ecology of viruses in soils differ substantially from those in aquatic systems. Desert biomes cover ~ 33% of global land masses, and yet the diversity and roles of viruses in these dominant ecosystems remain poorly understood. There is evidence that hot hyperarid desert soils are characterized by high levels of bacterial lysogens and low extracellular virus counts. In contrast, cold desert soils contain high extracellular virus titers. We suggest that the prevalence of microbial biofilms in hyperarid soils, combined with extreme thermal regimens, exerts strong selection pressures on both temperate and virulent viruses. Many desert soil virus sequences show low values of identity to virus genomes in public databases, suggesting the existence of distinct and as yet-uncharacterized soil phylogenetic lineages (e.g., cyanophages). We strongly advocate for amplification-free metavirome analyses while encouraging the classical isolation of phages from dominant and culturable microbial isolates in order to populate sequence databases. This review provides an overview of recent advances in the study of viruses in hyperarid soils and of the factors that contribute to viral abundance and diversity in hot and cold deserts and offers technical recommendations for future studies. PMID- 26590290 TI - Tolerance of Listeria monocytogenes to Quaternary Ammonium Sanitizers Is Mediated by a Novel Efflux Pump Encoded by emrE. AB - A novel genomic island (LGI1) was discovered in Listeria monocytogenes isolates responsible for the deadliest listeriosis outbreak in Canada, in 2008. To investigate the functional role of LGI1, the outbreak strain 08-5578 was exposed to food chain-relevant stresses, and the expression of 16 LGI1 genes was measured. LGI1 genes with putative efflux (L. monocytogenes emrE [emrELm]), regulatory (lmo1851), and adhesion (sel1) functions were deleted, and the mutants were exposed to acid (HCl), cold (4 degrees C), salt (10 to 20% NaCl), and quaternary ammonium-based sanitizers (QACs). Deletion of lmo1851 had no effect on the L. monocytogenes stress response, and deletion of sel1 did not influence Caco 2 and HeLa cell adherence/invasion, whereas deletion of emrE resulted in increased susceptibility to QACs (P < 0.05) but had no effect on the MICs of gentamicin, chloramphenicol, ciprofloxacin, erythromycin, tetracycline, acriflavine, and triclosan. In the presence of the QAC benzalkonium chloride (BAC; 5 MUg/ml), 14/16 LGI1 genes were induced, and lmo1861 (putative repressor gene) was constitutively expressed at 4 degrees C, 37 degrees C, and 52 degrees C and in the presence of UV exposure (0 to 30 min). Following 1 h of exposure to BAC (10 MUg/ml), upregulation of emrE (49.6-fold), lmo1851 (2.3 fold), lmo1861 (82.4-fold), and sigB (4.1-fold) occurred. Reserpine visibly suppressed the growth of the DeltaemrELm strain, indicating that QAC tolerance is due at least partially to efflux activity. These data suggest that a minimal function of LGI1 is to increase the tolerance of L. monocytogenes to QACs via emrELm. Since QACs are commonly used in the food industry, there is a concern that L. monocytogenes strains possessing emrE will have an increased ability to survive this stress and thus to persist in food processing environments. PMID- 26590292 TI - Studying abroad inclusively: Reflections by college students with and without intellectual disability. AB - Postsecondary education programs have increased opportunities for students with and without intellectual disabilities to study abroad as inclusive classes. Using open-coding qualitative techniques, the authors examined an inclusive study abroad group's daily reflective journals during a study abroad trip to London and Dublin. Three shared categories emerged from analysis: personal development, bonding/social inclusion, and learning from English and Irish adults with intellectual disabilities. Each group reported two distinct categories as well. Students with intellectual disabilities described the importance of mobility/transportation and fun, while their classmates without intellectual disabilities described the importance of inclusive learning and an increasing awareness of barriers to full participation for people with disabilities. Student constructed categories are used to describe the benefits of inclusive study abroad and build future inclusive international opportunities. PMID- 26590291 TI - Genomics of the Genus Bifidobacterium Reveals Species-Specific Adaptation to the Glycan-Rich Gut Environment. AB - Bifidobacteria represent one of the dominant microbial groups that occur in the gut of various animals, being particularly prevalent during the suckling period of humans and other mammals. Their ability to compete with other gut bacteria is largely attributed to their saccharolytic features. Comparative and functional genomic as well as transcriptomic analyses have revealed the genetic background that underpins the overall saccharolytic phenotype for each of the 47 bifidobacterial (sub)species representing the genus Bifidobacterium, while also generating insightful information regarding carbohydrate resource sharing and cross-feeding among bifidobacteria. The abundance of bifidobacterial saccharolytic features in human microbiomes supports the notion that metabolic accessibility to dietary and/or host-derived glycans is a potent evolutionary force that has shaped the bifidobacterial genome. PMID- 26590294 TI - 15-Hydroxyprostaglandin dehydrogenase-derived 15-keto-prostaglandin E2 inhibits cholangiocarcinoma cell growth through interaction with peroxisome proliferator activated receptor-gamma, SMAD2/3, and TAP63 proteins. PMID- 26590293 TI - Efficacy and safety of apixaban compared with aspirin in the elderly: a subgroup analysis from the AVERROES trial. AB - BACKGROUND: increasing age is associated with a higher prevalence of atrial fibrillation (AF), and higher risks of stroke and bleeding. We report the effects of apixaban versus acetylsalicylic acid (ASA) in older patients (>=75 years and >=85 years) compared with younger patients with AF unsuitable for vitamin K antagonists. METHODS: AVERROES (Apixaban Versus ASA to Prevent Stroke In AF Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment) trial (n = 5,599) included 1,898 patients >=75 years and 366 patients >=85 years. We compared the baseline characteristics and effects of apixaban compared with aspirin on clinical outcomes by age. RESULTS: compared with aspirin, apixaban was more efficacious for preventing strokes and systemic embolism in patients >=85 years (absolute rate [AR] 1%/year on apixaban versus 7.5%/year on aspirin; hazard ratio [HR] 0.14, 95% confidence interval [CI] 0.02-0.48) compared with younger patients (AR 1.7%/year on apixaban versus 3.4%/year on aspirin; HR 0.50, 95% CI 0.35-0.69) (P-value for interaction = 0.05). Major haemorrhage was higher in patients >=85 years compared with younger patients but similar with apixaban versus aspirin in both young and older individuals (4.9%/year versus 1.0%/year on aspirin and 4.7%/year versus 1.2%/year on apixaban) with no significant treatment by-age interaction (P-value = 0.65). CONCLUSIONS: older patients with AF are at particularly high risk of stroke if given aspirin and have substantially greater relative and absolute benefits from apixaban compared with younger patients with no greater risk of haemorrhage. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov number: NCT00496769. URL: https://clinicaltrials.gov/ct2/show/NCT00496769. PMID- 26590295 TI - Activation of cytosolic phospholipase A2alpha through nitric oxide-induced S nitrosylation. INVOLVEMENT OF INDUCIBLE NITRIC-OXIDE SYNTHASE AND CYCLOOXYGENASE 2. PMID- 26590296 TI - A novel positive feedback loop between peroxisome proliferator-activated receptor delta and prostaglandin E2 signaling pathways for human cholangiocarcinoma cell growth. PMID- 26590297 TI - Internal tandem duplication mutations in FLT3 gene augment chemotaxis to Cxcl12 protein by blocking the down-regulation of Rho-associated kinase via the Cxcl12/Cxcr4 signaling axis. PMID- 26590298 TI - The clinical use of corticosteroids in pregnancy. AB - BACKGROUND: The use of antenatal steroid therapy is common in pregnancy. In early pregnancy, steroids may be used in women for the treatment of recurrent miscarriage or fetal abnormalities such as congenital adrenal hyperplasia. In mid late pregnancy, the antenatal administration of corticosteroids to expectant mothers in anticipation of preterm birth is one of the most important advances in perinatal medicine; antenatal corticosteroids are now standard care for pregnancies at risk of premature delivery in high- and middle-income countries. The widespread uptake of this therapy is due to a compelling body of evidence demonstrating improved neonatal outcomes following antenatal corticosteroid exposure, stemming most notably from corticosteroid-driven maturation of fetal pulmonary function. As we approach the 50th anniversary of landmark work in this area by Liggins and Howie, it is apparent that much remains to be understood with regards to how we might best apply antenatal corticosteroid therapy to improve pregnancy outcomes at both early and mid to late gestation. METHODS: Drawing on advances in laboratory science, pre-clinical and clinical studies, we performed a narrative review of the scientific literature to provide a timely update on the benefits, risks and uncertainties regarding antenatal corticosteroid use in pregnancy. Three, well-established therapeutic uses of antenatal steroids, namely recurrent miscarriage, congenital adrenal hyperplasia and preterm birth, were selected to frame the review. RESULTS: Even the most well-established antenatal steroid therapies lack the comprehensive pharmacokinetic and dose-response data necessary to optimize dosing regimens. New insights into complex, tissue-specific corticosteroid signalling by genomic-dependent and independent mechanisms have not been used to inform corticosteroid treatment strategies. There is growing evidence that some fetal corticosteroid treatments are either ineffective, or may result in adverse outcomes, in addition to lasting epigenetic changes in a variety of homeostatic mechanisms. Nowhere is the need to better understand the intricacies of corticosteroid therapy better conveyed than in the findings of Althabe and colleagues who recently reported an increase in overall neonatal mortality and maternal morbidity in association with antenatal corticosteroid administration in low-resource settings. CONCLUSIONS: New research to clarify the benefits and potential risks of antenatal corticosteroid therapy is urgently needed, especially with regard to corticosteroid use in low-resource environments. We conclude that there is both significant scope and an urgent need for further research-informed refinement to the use of antenatal corticosteroids in pregnancy. PMID- 26590299 TI - Induction of intranuclear membranes by overproduction of Opi1p and Scs2p, regulators for yeast phospholipid biosynthesis, suggests a mechanism for Opi1p nuclear translocation. AB - In the yeast Saccharomyces cerevisiae, the expression of phospholipid biosynthetic genes is suppressed by the Opi1p negative regulator. Opi1p enters into the nucleoplasm from the nuclear membrane to suppress the gene expression under repressing conditions. The binding of Opi1p to the nuclear membrane requires an integral membrane protein, Scs2p and phosphatidic acid (PA). Although it is demonstrated that the association of Opi1p with membranes is affected by PA levels, how Opi1p dissociates from Scs2p is unknown. Here, we found that fluorescently labelled Opi1p accumulated on a perinuclear region in an Scs2p dependent manner. Electron microscopic analyses indicated that the perinuclear region consists of intranuclear membranes, which may be formed by the invagination of the nuclear membrane due to the accumulation of Opi1p and Scs2p in a restricted area. As expected, localization of Opi1p and Scs2p in the intranuclear membranes was detected by immunoelectron microscopy. Biochemical analysis showed that Opi1p recovered in the membrane fraction was detergent insoluble while Scs2p was soluble, implying that Opi1p behaves differently from Scs2p in the fraction. We hypothesize that Opi1p dissociates from Scs2p after targeting to the nuclear membrane, making it possible to be released from the membrane quickly when PA levels decrease. PMID- 26590300 TI - 5-Aminoimidazole-4-carboxyamide-1-beta-D-ribofranoside stimulates the rat enhancer of split- and hairy-related protein-2 gene via atypical protein kinase C lambda. AB - The 5'-AMP-activated protein kinase (AMPK) functions as a cellular energy sensor. 5-Aminoimidazole-4-carboxyamide-1-beta-D-ribofranoside (AICAR) is a chemical activator of AMPK. In the liver, AICAR suppresses expression of thephosphoenolpyruvate carboxykinase(PEPCK) gene. The rat enhancer of split- and hairy-related protein-2 (SHARP-2) is an insulin-inducible transcriptional repressor and its target is thePEPCKgene. In this study, we examined an issue of whether theSHARP-2gene expression is regulated by AICAR via the AMPK. AICAR increased the level of SHARP-2 mRNA in H4IIE cells. Whereas an AMPK inhibitor, compound-C, had no effects on the AICAR-induction, inhibitors for both phosphoinositide 3-kinase (PI 3-K) and protein kinase C (PKC) completely diminished the effects of AICAR. Western blot analyses showed that AICAR rapidly activated atypical PKC lambda (aPKClambda). In addition, when a dominant negative form of aPKClambda was expressed, the induction of SHARP-2 mRNA level by AICAR was inhibited. Calcium ion is not required for the activation of aPKClambda. A calcium ion-chelating reagent had no effects on the AICAR-induction. Furthermore, the AICAR-induction was inhibited by treatment with an RNA polymerase inhibitor or a protein synthesis inhibitor. Thus, we conclude that the AICAR-induction of theSHARP-2gene is mediated at transcription level by a PI 3-K/aPKClambda pathway. PMID- 26590301 TI - Novel working hypothesis for pathogenesis of hematological malignancies: combination of mutations-induced cellular phenotypes determines the disease (cMIP DD). AB - Recent progress in high-speed sequencing technology has revealed that tumors harbor novel mutations in a variety of genes including those for molecules involved in epigenetics and splicing, some of which were not categorized to previously thought malignancy-related genes. However, despite thorough identification of mutations in solid tumors and hematological malignancies, how these mutations induce cell transformation still remains elusive. In addition, each tumor usually contains multiple mutations or sometimes consists of multiple clones, which makes functional analysis difficult. Fifteen years ago, it was proposed that combination of two types of mutations induce acute leukemia; Class I mutations induce cell growth or inhibit apoptosis while class II mutations block differentiation, co-operating in inducing acute leukemia. This notion has been proven using a variety of mouse models, however most of recently found mutations are not typical class I/II mutations. Although some novel mutations have been found to functionally work as class I or II mutation in leukemogenesis, the classical class I/II theory seems to be too simple to explain the whole story. We here overview the molecular basis of hematological malignancies based on clinical and experimental results, and propose a new working hypothesis for leukemogenesis. PMID- 26590302 TI - Regulation of maintenance DNA methylation via histone ubiquitylation. AB - DNA methylation is one of the most stable but dynamically regulated epigenetic marks that act as determinants of cell fates during embryonic development through regulation of various forms of gene expression. DNA methylation patterns must be faithfully propagated throughout successive cell divisions in order to maintain cell-specific function. We have recently demonstrated that Uhrf1-dependent ubiquitylation of histone H3 at lysine 23 is critical for Dnmt1 recruitment to DNA replication sites, which catalyzes the conversion of hemi-methylated DNA to fully methylated DNA. In this review, we provide an overview of recent progress in understanding the mechanism underlying maintenance DNA methylation. PMID- 26590303 TI - Regulation of the TMEPAI promoter by TCF7L2: the C-terminal tail of TCF7L2 is essential to activate the TMEPAI gene. AB - We previously found that TCF7L2 could activate the TMEPAI gene efficiently, whereas LEF1 could not nearly augment its transcription. When we comprehended the functional difference(s) between TCF7L2 and LEF1 with respect to the activation of the TMEPAI gene, the C-terminal tail of TCF7L2 was needed to reveal its transcriptional activity as well as its interaction with Smad3. Consistently, both TCF7/TCF7L2 and LEF1/TCF7L2 chimeric proteins exhibited an activity similar to TCF7L2 in transcription and Smad3 binding in contrast with LEF1 and TCF7. Our data elaborated on the diverse activity among TCF/LEF family members with respect to the transcriptional regulation of the TMEPAI gene. PMID- 26590304 TI - Three-dimensional printed prototypes refine the anatomy of post-modified Norwood 1 complex aortic arch obstruction and allow presurgical simulation of the repair. AB - Three-dimensional (3D) printed prototypes of malformed hearts have been used for education, communication, presurgical planning and simulation. We present a case of a 5-month old infant with complex obstruction at the neoaortic to transverse arch and descending aortic junction following the neonatal modified Norwood-1 procedure for hypoplastic left heart syndrome. Digital 3D models were created from a routine 64-slice CT dataset; then life-size solid and magnified hollow models were printed with a 3D printer. The solid model provided further insights into details of the anatomy, whereas the surgical approach and steps of the operation were simulated on the hollow model. Intraoperative assessment confirmed the anatomical accuracy of the 3D models. The operation was performed in accordance with preoperative simulation: sliding autologous flaps achieved relief of the obstruction without additional patching. Knowledge gained from the models fundamentally contributed to successful outcome and improved patient safety. This case study presents an effective use of 3D models in exploring complex spatial relationship at the aortic arch and in simulation-based planning of the operative procedure. PMID- 26590305 TI - Results of Fontan operation in patients with congenitally corrected transposition of great arteries?. AB - OBJECTIVES: The purpose of this study was to examine the outcome after the Fontan operation in patients with congenitally corrected transposition of great arteries with ventricular septal defect and pulmonary stenosis (ccTGA-VSD-PS). METHODS: Patient- and procedure-related variables were analysed in 23 patients with ccTGA VSD-PS operated between April 2003 and April 2015. RESULTS: The mean age was 14.07 +/- 6.38 years (range 4-23, median 11 years), with 82% patients being male (19/23). Dextrocardia was present in 52% (12/23) of patients and left superior vena cava was present in 26% (6/23) of patients. Most patients underwent extracardiac Fontan (n = 18), whereas in 5 patients lateral tunnel Fontan was performed. All patients received polytetrafluoroethylene grafts of size 18-22 mm for extracardiac Fontan. In 8 patients, conduits were fenestrated to reduce the intraconduit pressure. The mean hospital stay was 15.7 +/- 11.24 days (5-60, median 14 days). The most common cause for prolonged hospital stay was pleural effusion in 5 patients (21.7%). One 7-year old patient developed conduit thrombosis, intracranial bleed, seizures and died. The mean follow-up was 46.4.4 +/- 32.2 months (range 8-142, median 42 months) and was available for 21 patients (91.3%). There was 1 mid-term non-cardiac death after 3 years of operation. Of the total, 85.7% (18/21) patients in follow-up are in NYHA class I, whereas 3 patients are in class II. The actuarial event-free survival rate was 81.8 +/- 13.2% at 10 years. CONCLUSIONS: In ccTGA-VSD-PS patients with non-routable VSD and in those with difficult options for biventricular repair, the Fontan approach provides satisfactory mid-term palliation. PMID- 26590307 TI - ERRATUM. PMID- 26590306 TI - Video-assisted thoracoscopic surgery versus open thoracotomy in pulmonary metastasectomy: a meta-analysis of observational studies. AB - BACKGROUND: Pulmonary metastasectomy via a traditional open thoracotomy is effective for the treatment of patients with pulmonary metastases. However, whether video-assisted thoracoscopic surgery (VATS) achieves similar clinical effects in terms of survival rates remains unclear. We conducted this meta analytic study to compare VATS with open thoracotomy for pulmonary metastasectomy. METHODS: Relevant studies were identified by searching PubMed from inception to December 2014. The overall and recurrence-free survival rates were measured in terms of hazard ratios (HRs) with VATS and open thoracotomy as the main outcomes. RESULTS: Eight studies were included in our meta-analysis, which included 337 patients in the VATS group and 485 patients in the open thoracotomy group. The overall survival rate in the VATS group was statistically significantly higher than that in the open thoracotomy group [HR, 0.69; 95% confidence interval (CI), 0.55-0.87; P = 0.002]. The VATS group still had a higher overall survival rate after exclusion of the one low-quality study (HR, 0.78; 95% CI, 0.59-1.03), but the result was not statistically significant (P = 0.075). No difference in the recurrence-free survival rate was found between the two groups (HR, 0.86; 95% CI, 0.69-1.08). The subgroup analysis showed no difference between the two groups in either the overall survival rate (HR, 0.72; 95% CI, 0.50-1.04) or the recurrence-free survival rate (HR, 0.79; 95% CI, 0.59 1.08) in patients with metastases from colorectal cancer. CONCLUSIONS: VATS is an alternative surgical approach for pulmonary metastasectomy in patients with resectable pulmonary metastases. Further large prospective studies are needed to identify the indications for VATS in patients with pulmonary metastases. PMID- 26590309 TI - Cellulose biosynthesis inhibitors - a multifunctional toolbox. AB - In the current review, we examine the growing number of existing Cellulose Biosynthesis Inhibitors (CBIs) and based on those that have been studied with live cell imaging we group their mechanism of action. Attention is paid to the use of CBIs as tools to ask fundamental questions about cellulose biosynthesis. PMID- 26590310 TI - Two key polymorphisms in a newly discovered allele of the Vitis vinifera TPS24 gene are responsible for the production of the rotundone precursor alpha-guaiene. AB - Rotundone was initially identified as a grape-derived compound responsible for the peppery aroma of Shiraz wine varieties. It has subsequently been found in black and white pepper and several other spices. Because of its potent aroma, the molecular basis for rotundone formation is of particular relevance to grape and wine scientists and industry. We have identified and functionally characterized in planta a sesquiterpene synthase, VvGuaS, from developing grape berries, and have demonstrated that it produces the precursor of rotundone, alpha-guaiene, as its main product. The VvGuaS enzyme is a novel allele of the sesquiterpene synthase gene, VvTPS24, which has previously been reported to encode VvPNSeInt, an enzyme that produces a variety of selinene-type sesquiterpenes. This newly discovered VvTPS24 allele encodes an enzyme 99.5% identical to VvPNSeInt, with the differences comprising just 6 out of the 561 amino acid residues. Molecular modelling of the enzymes revealed that two of these residues, T414 and V530, are located in the active site of VvGuaS within 4 A of the binding-site of the substrate, farnesyl pyrophosphate. Mutation of these two residues of VvGuaS into the corresponding polymorphisms in VvPNSeInt results in a complete functional conversion of one enzyme into the other, while mutation of each residue individually produces an intermediate change in the product profile. We have therefore demonstrated that VvGuaS, an enzyme responsible for production of the rotundone precursor, alpha-guaiene, is encoded by a novel allele of the previously characterized grapevine gene VvTPS24 and that two specific polymorphisms are responsible for functional differences between VvTPS24 alleles. PMID- 26590311 TI - Characterization of major ripening events during softening in grape: turgor, sugar accumulation, abscisic acid metabolism, colour development, and their relationship with growth. AB - Along with sugar accumulation and colour development, softening is an important physiological change during the onset of ripening in fruits. In this work, we investigated the relationships among major events during softening in grape (Vitis vinifera L.) by quantifying elasticity in individual berries. In addition, we delayed softening and inhibited sugar accumulation using a mechanical growth preventing treatment in order to identify processes that are sugar and/or growth dependent. Ripening processes commenced on various days after anthesis, but always at similarly low elasticity and turgor. Much of the softening occurred in the absence of other changes in berry physiology investigated here. Several genes encoding key cell wall-modifying enzymes were not up-regulated until softening was largely completed, suggesting softening may result primarily from decreases in turgor. Similarly, there was no decrease in solute potential, increase in sugar concentration, or colour development until elasticity and turgor were near minimum values, and these processes were inhibited when berry growth was prevented. Increases in abscisic acid occurred early during softening and in the absence of significant expression of the V. vinifera 9-cis-epoxycarotenoid dioxygenases. However, these increases were coincident with decreases in the abscisic acid catabolite diphasic acid, indicating that initial increases in abscisic acid may result from decreases in catabolism and/or exogenous import. These data suggest that softening, decreases in turgor, and increases in abscisic acid represent some of the earliest events during the onset of ripening. Later, physical growth, further increases in abscisic acid, and the accumulation of sugar are integral for colour development. PMID- 26590312 TI - Nonclassical CD4+CD49b+ Regulatory T Cells as a Better Alternative to Conventional CD4+CD25+ T Cells To Dampen Arthritis Severity. AB - Promising immunotherapeutic strategies are emerging to restore tolerance in autoimmune diseases by triggering an increase in the number and/or the function of endogenous regulatory T (Treg) cells, which actively control pathological immune responses. Evidence suggests a remarkable heterogeneity in peripheral Treg cells that warrants their better characterization in terms of phenotype and suppressive function, to determine which subset may be optimally suitable for a given clinical situation. We found that repetitive injections of immature dendritic cells expanded Foxp3-negative CD49b(+) Treg cells that displayed an effector memory phenotype. These expanded Treg cells were isolated ex vivo for transcriptome analysis and found to contain multiple transcripts of the canonical Treg signature shared mainly by CD25(+) but also by other subphenotypes. We characterized the CD49b(+) Treg cell phenotype, underscoring its similarities with the CD25(+) Treg cell phenotype and highlighting some differential expression patterns for several markers, including lymphocyte activation gene 3, KLRG1, CD103, ICOS, CTLA-4, and granzyme B. Comparison of the CD25(+) and CD49b(+) Treg cells' suppressive mechanisms, in vitro and in vivo, revealed the latter's potent suppressive activity, which was partly dependent on IL-10 secretion. Altogether, our results strongly suggest that expression of several canonical Treg cell markers and suppressive function could be Foxp3 independent, and underscore the therapeutic potential of IL-10-secreting CD49b(+) Treg cells in arthritis. PMID- 26590313 TI - Cutting Edge: DNA in the Lung Microenvironment during Influenza Virus Infection Tempers Inflammation by Engaging the DNA Sensor AIM2. AB - Innate sensing of nucleic acids lies at the heart of antiviral immunity. During viral infection, dying cells may also release nucleic acids into the tissue microenvironment. It is unknown what effect such host signals have on the quality or duration of the immune response to viruses. In this study, we uncovered an immune-regulatory pathway that tempers the intensity of the host response to influenza A virus (IAV) infection. We found that host-derived DNA accumulates in the lung microenvironment during IAV infection. Ablation of DNA in the lung resulted in increased mortality, increased cellular recruitment, and increased inflammation following IAV challenge. The released DNA, in turn, was sensed by the DNA receptor absent in melanoma 2. Aim2(-/-) mice showed similarly exaggerated immune responses to IAV. Taken together, our results identify a novel mechanism of cross-talk between pathogen- and damage-associated molecular pattern sensing pathways, wherein sensing of host-derived DNA limits immune-mediated damage to infected tissues. PMID- 26590314 TI - Cutting Edge: IL-36 Receptor Promotes Resolution of Intestinal Damage. AB - IL-1 family members are central mediators of host defense. In this article, we show that the novel IL-1 family member IL-36gamma was expressed during experimental colitis and human inflammatory bowel disease. Germ-free mice failed to induce IL-36gamma in response to dextran sodium sulfate (DSS)-induced damage, suggesting that gut microbiota are involved in its induction. Surprisingly, IL 36R-deficient (Il1rl2(-/-)) mice exhibited defective recovery following DSS induced damage and impaired closure of colonic mucosal biopsy wounds, which coincided with impaired neutrophil accumulation in the wound bed. Failure of Il1rl2(-/-) mice to recover from DSS-induced damage was associated with a profound reduction in IL-22 expression, particularly by colonic neutrophils. Defective recovery of Il1rl2(-/-) mice could be rescued by an aryl hydrocarbon receptor agonist, which was sufficient to restore IL-22 expression and promote full recovery from DSS-induced damage. These findings implicate the IL-36/IL-36R axis in the resolution of intestinal mucosal wounds. PMID- 26590315 TI - The Expression of BAFF Is Controlled by IRF Transcription Factors. AB - Patients with systemic lupus erythematosus (SLE) and primary Sjogren's syndrome (pSS) are typically characterized by the presence of autoantibodies and an IFN signature. The strength of the IFN-signature positively correlates with disease severity, suggesting that type I IFNs are active players in these diseases. BAFF is a cytokine critical for development and proper selection of B cells, and the targeting of BAFF has emerged as a successful treatment strategy of SLE. Previous reports have suggested that BAFF expression is directly induced by type I IFNs, but the precise mechanism for this remains unknown. In this article, we demonstrate that BAFF is a bona fide ISG and that IFN regulatory factors (IRFs) control the expression of BAFF. We identify IRF1 and IRF2 as positive regulators of BAFF transcription and IRF4 and IRF8 as potent repressors; in addition, we have mapped the precise binding site for these factors in the BAFF promoter. IFN beta injections induced BAFF expression mainly in neutrophils and monocytes, and BAFF expression in neutrophils from pSS patients strongly correlated with the strength of the IFN-signature. In summary, we show that BAFF expression is directly induced by type I IFNs via IRF1 and IRF2, whereas IRF4 and IRF8 are negative regulators of BAFF expression. These data suggest that type I IFN blockade in SLE and pSS patients will lead to downregulation of BAFF and a consequential reduction of autoreactive B cell clones and autoantibodies. PMID- 26590316 TI - Regulatory T Cell Induction and Retention in the Lungs Drives Suppression of Detrimental Type 2 Th Cells During Pulmonary Cryptococcal Infection. AB - Lethal disease caused by the fungus Cryptococcus neoformans is a consequence of the combined failure to control pulmonary fungal replication and immunopathology caused by induced type 2 Th2 cell responses in animal models. In order to gain insights into immune regulatory networks, we examined the role of regulatory T (Treg) cells in suppression of Th2 cells using a mouse model of experimental cryptococcosis. Upon pulmonary infection with Cryptococcus, Treg cells accumulated in the lung parenchyma independently of priming in the draining lymph node. Using peptide-MHC class II molecules to identify Cryptococcus-specific Treg cells combined with genetic fate-mapping, we noted that a majority of the Treg cells found in the lungs were induced during the infection. Additionally, we found that Treg cells used the transcription factor, IFN regulatory factor 4, to dampen harmful Th2 cell responses, as well as mediate chemokine retention of Treg cells in the lungs. Taken together, induction and IFN regulatory factor 4 dependent localization of Treg cells in the lungs allow Treg cells to suppress the deleterious effects of Th2 cells during cryptococcal infection. PMID- 26590317 TI - Conserved IL-2Rgammac Signaling Mediates Lymphopoiesis in Zebrafish. AB - The IL-2 receptor gamma common (IL-2Rgammac) chain is the shared subunit of the receptors for the IL-2 family of cytokines, which mediate signaling through JAK3 and various downstream pathways to regulate lymphopoiesis. Inactivating mutations in human IL-2Rgammac result in SCID, a primary immunodeficiency characterized by greatly reduced numbers of lymphocytes. This study used bioinformatics, expression analysis, gene ablation, and specific pharmacologic inhibitors to investigate the function of two putative zebrafish IL-2Rgammac paralogs, il 2rgammac.a and il-2rgammac.b, and downstream signaling components during early lymphopoiesis. Expression of il-2rgammac.a commenced at 16 h post fertilization (hpf) and rose steadily from 4-6 d postfertilization (dpf) in the developing thymus, with il-2rgammac.a expression also confirmed in adult T and B lymphocytes. Transcripts of il-2rgammac.b were first observed from 8 hpf, but waned from 16 hpf before reaching maximal expression at 6 dpf, but this was not evident in the thymus. Knockdown of il-2rgammac.a, but not il-2rgammac.b, substantially reduced embryonic lymphopoiesis without affecting other aspects of hematopoiesis. Specific targeting of zebrafish Jak3 exerted a similar effect on lymphopoiesis, whereas ablation of zebrafish Stat5.1 and pharmacologic inhibition of PI3K and MEK also produced significant but smaller effects. Ablation of il 2rgammac.a was further demonstrated to lead to an absence of mature T cells, but not B cells in juvenile fish. These results indicate that conserved IL-2Rgammac signaling via JAK3 plays a key role during early zebrafish lymphopoiesis, which can be potentially targeted to generate a zebrafish model of human SCID. PMID- 26590318 TI - Nck Binds to the T Cell Antigen Receptor Using Its SH3.1 and SH2 Domains in a Cooperative Manner, Promoting TCR Functioning. AB - Ligand binding to the TCR causes a conformational change at the CD3 subunits to expose the CD3epsilon cytoplasmic proline-rich sequence (PRS). It was suggested that the PRS is important for TCR signaling and T cell activation. It has been shown that the purified, recombinant SH3.1 domain of the adaptor molecule noncatalytic region of tyrosine kinase (Nck) can bind to the exposed PRS of CD3epsilon, but the molecular mechanism of how full-length Nck binds to the TCR in cells has not been investigated so far. Using the in situ proximity ligation assay and copurifications, we show that the binding of Nck to the TCR requires partial phosphorylation of CD3epsilon, as it is based on two cooperating interactions. First, the SH3.1(Nck) domain has to bind to the nonphosphorylated and exposed PRS, that is, the first ITAM tyrosine has to be in the unphosphorylated state. Second, the SH2(Nck) domain has to bind to the second ITAM tyrosine in the phosphorylated state. Likewise, mutations of the SH3.1 and SH2 domains in Nck1 resulted in the loss of Nck1 binding to the TCR. Furthermore, expression of an SH3.1-mutated Nck impaired TCR signaling and T cell activation. Our data suggest that the exact pattern of CD3epsilon phosphorylation is critical for TCR functioning. PMID- 26590319 TI - A cGAS-Independent STING/IRF7 Pathway Mediates the Immunogenicity of DNA Vaccines. AB - It has been known since the discovery of DNA vaccines >20 y ago that DNA vaccines can function as adjuvants. Our recent study reported the involvement of Aim2 as the sensor of DNA vaccines in eliciting Ag-specific Ab responses. Our findings indicated the presence of previously unrecognized innate immune response pathways in addition to the TLR9 pathway, which is mainly activated by the CpG motifs of DNA vaccines. Our data further demonstrated the requirement of type I IFN in DNA vaccine-induced immune responses via the Aim2 pathway, but the exact downstream molecular mechanism was not characterized. In the present study, we investigated the roles of the putative DNA sensor cyclic GMP-AMP synthase (cGas), as well as the downstream IFN regulatory factors (IRF) 3 and 7 in type I IFN induction and Ag-specific immune responses elicited by DNA vaccination. Our results showed that DNA vaccine-induced, Irf7-dependent signaling, as part of the Sting pathway, was critical for generation of both innate cytokine signaling and Ag-specific B and T cell responses. In contrast, Irf3 was not as critical as expected in this pathway and, more surprisingly, immune responses elicited by DNA vaccines were not cGas dependent in vivo. Data from this study provide more details on the innate immune mechanisms involved in DNA vaccination and further enrich our understanding on the potential utility of DNA vaccines in generating Ag-specific immune responses. PMID- 26590320 TI - ETS family transcriptional regulators drive chromatin dynamics and malignancy in squamous cell carcinomas. AB - Tumor-initiating stem cells (SCs) exhibit distinct patterns of transcription factors and gene expression compared to healthy counterparts. Here, we show that dramatic shifts in large open-chromatin domain (super-enhancer) landscapes underlie these differences and reflect tumor microenvironment. By in vivo super enhancer and transcriptional profiling, we uncover a dynamic cancer-specific epigenetic network selectively enriched for binding motifs of a transcription factor cohort expressed in squamous cell carcinoma SCs (SCC-SCs). Many of their genes, including Ets2 and Elk3, are themselves regulated by SCC-SC super enhancers suggesting a cooperative feed-forward loop. Malignant progression requires these genes, whose knockdown severely impairs tumor growth and prohibits progression from benign papillomas to SCCs. ETS2-deficiency disrupts the SCC-SC super-enhancer landscape and downstream cancer genes while ETS2-overactivation in epidermal-SCs induces hyperproliferation and SCC super-enhancer-associated genes Fos, Junb and Klf5. Together, our findings unearth an essential regulatory network required for the SCC-SC chromatin landscape and unveil its importance in malignant progression. PMID- 26590321 TI - Guanylate cyclase 1 relies on rhodopsin for intracellular stability and ciliary trafficking. AB - Sensory cilia are populated by a select group of signaling proteins that detect environmental stimuli. How these molecules are delivered to the sensory cilium and whether they rely on one another for specific transport remains poorly understood. Here, we investigated whether the visual pigment, rhodopsin, is critical for delivering other signaling proteins to the sensory cilium of photoreceptor cells, the outer segment. Rhodopsin is the most abundant outer segment protein and its proper transport is essential for formation of this organelle, suggesting that such a dependency might exist. Indeed, we demonstrated that guanylate cyclase-1, producing the cGMP second messenger in photoreceptors, requires rhodopsin for intracellular stability and outer segment delivery. We elucidated this dependency by showing that guanylate cyclase-1 is a novel rhodopsin-binding protein. These findings expand rhodopsin's role in vision from being a visual pigment and major outer segment building block to directing trafficking of another key signaling protein. PMID- 26590323 TI - Loop gain in severely obese women with obstructive sleep apnoea. AB - Our objective was to assess whether obstructive sleep apnoea (OSA) patients were characterised by a reduced central CO2 controller gain (CG) and an enhanced plant gain (PG). We matched three groups of women (n=10 per group) enrolled in a previous study (Essalhi et al., J. Asthma. 50: 565-572, 2013): obese women with a respiratory disturbance index (RDI)>=15/h and with a RDI<15, and lean women without OSA (RDI<5). Tidal ventilation recordings during wakefulness with end tidal PCO2 monitoring allowed the assessment of loop gain (LG) and its components (PG and CG). LG were similar for the three groups (p=0.844) while both PG and CG depicted significant differences (p=0.046 and p=0.011, respectively). Obese women with OSA were characterised by an increased PG and a reduced CG as compared to obese women without OSA. A negative relationship between CG and RDI (rho=-0.46, p=0.008) was evidenced. In conclusion, OSA in women is associated with a reduced central CO2 controller gain and an enhanced plant gain. PMID- 26590322 TI - The effect of age on the relationship between cardiac and vascular function. AB - Age-related changes in cardiac and vascular function are associated with increased risk of cardiovascular mortality and morbidity. The aim of the present study was to define the effect of age on the relationship between cardiac and vascular function. Haemodynamic and gas exchange measurements were performed at rest and peak exercise in healthy individuals. Augmentation index was measured at rest. Cardiac power output, a measure of overall cardiac function, was calculated as the product of cardiac output and mean arterial blood pressure. Augmentation index was significantly higher in older than younger participants (27.7 +/- 10.1 vs. 2.5 +/- 10.1%, P<0.01). Older people demonstrated significantly higher stroke volume and mean arterial blood pressure (P<0.05), but lower heart rate (145 +/- 13 vs. 172 +/- 10 beats/min, P<0.01) and peak oxygen consumption (22.5 +/- 5.2 vs. 41.2 +/- 8.4 ml/kg/min, P<0.01). There was a significant negative relationship between augmentation index and peak exercise cardiac power output (r=-0.73, P=0.02) and cardiac output (r=-0.69, P=0.03) in older participants. Older people maintain maximal cardiac function due to increased stroke volume. Vascular function is a strong predictor of overall cardiac function in older but in not younger people. PMID- 26590324 TI - Respiratory chemoreflex response inhibition by dorsomedian hypothalamic nucleus activation in rats. AB - Recent observations from our group seem to indicate that repeated stress-evoked dorsomedian hypothalamic nucleus (DMH) activation in rats can lead to persistent bradypnea. One possibility was that respiratory responses to peripheral chemoreceptor activation were reduced by DMH stimulation. In the present study, we therefore investigated the effect of minimal supra-threshold DMH stimulation on respiratory carotid chemoreflex responses. For this purpose, the chemoreflex was activated by potassium cyanide (KCN, 40MUg/rat, i.v.) during electrical and chemical stimulation of the DMH. In both situations, changes in breathing frequency but not tidal volume responses to KCN administration were reduced. These findings suggest that low DMH neurotransmission negatively affects respiratory chemoreflex responses and may be involved in stress-induced bradypnea. PMID- 26590326 TI - Sequence diversity of wheat mosaic virus isolates. AB - Wheat mosaic virus (WMoV), transmitted by eriophyid wheat curl mites (Aceria tosichella) is the causal agent of High Plains disease in wheat and maize. WMoV and other members of the genus Emaravirus evaded thorough molecular characterization for many years due to the experimental challenges of mite transmission and manipulating multisegmented negative sense RNA genomes. Recently, the complete genome sequence of a Nebraska isolate of WMoV revealed eight segments, plus a variant sequence of the nucleocapsid protein-encoding segment. Here, near-complete and partial consensus sequences of five more WMoV isolates are reported and compared to the Nebraska isolate: an Ohio maize isolate (GG1), a Kansas barley isolate (KS7), and three Ohio wheat isolates (H1, K1, W1). Results show two distinct groups of WMoV isolates: Ohio wheat isolate RNA segments had 84% or lower nucleotide sequence identity to the NE isolate, whereas GG1 and KS7 had 98% or higher nucleotide sequence identity to the NE isolate. Knowledge of the sequence variability of WMoV isolates is a step toward understanding virus biology, and potentially explaining observed biological variation. PMID- 26590325 TI - Replication-competent fluorescent-expressing influenza B virus. AB - Influenza B viruses (IBVs) cause annual outbreaks of respiratory illness in humans and are increasingly recognized as a major cause of influenza-associated morbidity and mortality. Studying influenza viruses requires the use of secondary methodologies to identify virus-infected cells. To this end, replication competent influenza A viruses (IAVs) expressing easily traceable fluorescent proteins have been recently developed. In contrast, similar approaches for IBV are mostly lacking. In this report, we describe the generation and characterization of replication-competent influenza B/Brisbane/60/2008 viruses expressing fluorescent mCherry or GFP fused to the C-terminal of the viral non structural 1 (NS1) protein. Fluorescent-expressing IBVs display similar growth kinetics and plaque phenotype to wild-type IBV, while fluorescent protein expression allows for the easy identification of virus-infected cells. Without the need of secondary approaches to monitor viral infection, fluorescent expressing IBVs represent an ideal approach to study the biology of IBV and an excellent platform for the rapid identification and characterization of antiviral therapeutics or neutralizing antibodies using high-throughput screening approaches. Lastly, fluorescent-expressing IBVs can be combined with the recently described reporter-expressing IAVs for the identification of novel therapeutics to combat these two important human respiratory pathogens. PMID- 26590327 TI - Identification of potential transmembrane protease serine 4 inhibitors as anti cancer agents by integrated computational approach. AB - Transmembrane protease serine 4 is a well known cell surface protease facilitating the extracellular matrix degradation and epithelial mesenchymal transition in hepatocellular carcinoma. Henceforth targeting transmembrane protease serine 4 is strongly believed to provide therapeutic intervention against hepatocellular carcinoma. Owing to lack of crystal structure for human transmembrane protease serine 4, we predicted its three dimensional structure for the first time in this study. Experimentally proven inhibitor-Tyroserleutide (TSL) against hepatocellular carcinoma via transmembrane protease serine 4 was used as a benchmark to identify structurally similar candidates from PubChem database to create the TSL library. Virtual screening of TSL library against modeled transmembrane protease serine 4 revealed the top four potential inhibitors. Further binding free energy (DeltaGbind) analysis of the potential inhibitors revealed the best potential lead compound against transmembrane protease serine 4. Drug likeliness nature of the top four potential hits were additionally analyzed in comparison to TSL to confirm on the best potential lead compound with the highest % of human oral absorption. Consequently, e pharmacophore mapping of the best potential lead compound yielded a six point feature. It was observed to contain four hydrogen bond donor sites (D), one positively ionizable site (P) and one aromatic ring (R). Such e-pharmacophore insight obtained from structural determinants by integrated computational analysis could serve as a framework for further advancement of drug discovery process of new anti-cancer agents with less toxicity and high specificity targeting transmembrane protease serine 4 and hepatocellular carcinoma. PMID- 26590328 TI - The neuroprotection of hypoxic preconditioning on rat brain against traumatic brain injury by up-regulated transcription factor Nrf2 and HO-1 expression. AB - Hypoxic preconditioning (HPC) increases the inherent tolerance of brain tissue suffering from severe hypoxia or ischemia insult by stimulating the protective ability of the brain. However, little is known concerning the effect of HPC on traumatic brain injury (TBI). We designed this study to investigate the effect of HPC on TBI and explore its underlying mechanisms. We found that HPC significantly alleviates neurological dysfunction, lessens brain edema, reduces cell apoptosis, increases neuronal survival, up-regulates the expressions of Nrf2 and HO-1, and decreases the inducer of protein carbonyls, 4-hydroxy-2-nonenal, and 8-hydroxy-2 deoxyguanosine in the brain tissue of rats 24h after brain injury. However, no influence was observed in normal rats after only 3d of hypoxic training. Results further indicated that HPC protects the brain against traumatic damage. This protective effect may be achieved by up-regulating Nrf2 and HO-1 expression and alleviating oxidative stress damage. PMID- 26590329 TI - Immunophenotype of mouse cerebral hemispheres-derived neural precursor cells. AB - Postnatally isolated neural precursor cells (piNPCs) from mouse cerebral tissue have been studied in cell-based therapeutic approaches for Experimental Autoimmune Encephalomyelitis (EAE). Transplantation experiments in EAE rodents revealed that piNPCs manage to integrate into the host tissue and ameliorate clinical symptoms. When cultured in vitro, mouse cerebral piNPCs form neurospheres consisting of immature cells positive for polysialylated neural adhesion molecule (PSA-NCAM) that differentiate mainly towards glial cells, but also neurons. Herein, we have characterized piNPCs immunophenotype, with flow cytometry. NPCs were positive for CD24, CD44, and CD133 though negative for CD15, CD184 and CD49d. This immunophenotype, determined for the first time, among cells isolated from neonates might be useful for the identification of NPC population aiming at the development of transplantation protocols. PMID- 26590330 TI - Towards the computational design and engineering of enzyme enantioselectivity: A case study by a carbonyl reductase from Gluconobacter oxydans. AB - In our previous work, a NAD(H)-dependent carbonyl reductase (GoCR) was identified from Gluconobacter oxydans, which showed moderate to high enantiospecificity for the reduction of different kinds of prochiral ketones. In the present study, the crystal structure of GoCR was determined at 1.65A resolution, and a computational strategy concerning substrate-enzyme docking and all-atom molecular dynamics (MD) simulation was established to help understand the molecular basis of enantiopreference and enantiorecognition for GoCR, and to further guide the design and engineering of GoCR enantioselectivity. For the reduction of ethyl 2 oxo-4-phenylbutyrate (OPBE), three binding pocket residues, Cys93, Tyr149, and Trp193 were predicted to play a critical role in determining the enantioselectivity. Through site-directed mutagenesis, single-point mutant W193A was constructed and proved to reduce OPBE to ethyl (R)-2-hydroxy-4-phenylbutyrate (R-HPBE) with a significantly improved ee of >99% compared to 43.2% for the wild type (WT). Furthermore, double mutant C93V/Y149A was proved to even invert the enantioselectivity of GoCR to afford S-HPBE at 79.8% ee. PMID- 26590331 TI - Visible aging signs as risk markers for ischemic heart disease: Epidemiology, pathogenesis and clinical implications. AB - Association of common aging signs (i.e., male pattern baldness, hair graying, and facial wrinkles) as well as other age-related appearance factors (i.e., arcus corneae, xanthelasmata, and earlobe crease) with increased risk of ischemic heart disease was initially described in anecdotal reports from clinicians observing trends in the physical appearance of patients with ischemic heart disease. Following these early observations numerous epidemiological studies have reported these associations. Since the prevalences of both visible aging signs and ischemic heart disease have a strong correlation with increasing age, it has been extensively debated whether the observed associations could be entirely explained by a common association with age. Furthermore, the etiologies of the visible aging signs are rarely fully understood, and pathophysiological explanations for these associations remain controversial, and are mostly speculative. As a consequence of inconsistent findings and lack of mechanistic explanations for the observed associations with ischemic heart disease, consensus on the clinical importance of these visible aging signs has been lacking. The aim of this review is for each of the visible aging signs to (i) review the etiology, (ii) to discuss the current epidemiological evidence for an association with risk of ischemic heart disease, and (iii) to present possible pathophysiological explanations for these associations. Finally this review discusses the potential clinical implications of these findings. PMID- 26590332 TI - New sequence variants detected at DXS10148, DXS10074 and DXS10134 loci. AB - A great amount of population and forensic genetic data are available for X-STRs supporting the need for having a common and accurate nomenclature among laboratories allowing for better communication, data exchange, and data comparison. DXS10148, DXS10074 and DXS10134 are commonly used X-STRs particularly due to their inclusion in the commercial kit Investigator Argus X-12 (Qiagen). Samples from West Africa and Iraq were sequenced for all three X-STRs allowing the detection of new DNA sequence variants. At DXS10148, variation was detected at four bases downstream from the flanking region from the repeat motif. The sequence AAGG-AAAG has been detected for the first time as a varying (AAGG-AAAG)1 3 motif, in the present work. One additional string when compared to the common one (AAGG-AAAG)2 adds eight bases to the fragment size of the tetranucleotide STR. This means that 2 repeats are added in these cases to the fragment size of the allele, while the presence of only one copy will reduce the expected allele size by 2 repeats. At DXS10074 two varying stretches consisting of AC and AG dinucleotide repeats were observed in the upstream flanking region, six bases from the main repeat core that also influence the expected allele size. DXS10134 revealed a simpler nomenclature in the Guinea-Bissau sample set when compared to the previously described allele nomenclature. This detected new hidden variation also has impact on the actual allele nomenclature at this locus as it contributes to a new class of short alleles so far undetected in other studies. PMID- 26590333 TI - Investigation of the presence of HPV related oropharyngeal and oral tongue squamous cell carcinoma in Mozambique. AB - BACKGROUND: Cervical cancer caused by the human papillomavirus (HPV) is endemic in East Africa. Recent, dramatic, increases in the incidence of oropharyngeal cancer in the United States and Europe are linked to the same high risk HPV genotypes responsible for cervical cancer. Currently, there is extremely limited data regarding the role of HPV in head and neck cancers in Africa. Evidence of HPV as an etiologic agent in head and neck cancers in Africa would have important prevention and treatment implications. METHODS: A retrospective single institution review of oral tongue and oropharyngeal squamous cell carcinomas diagnosed between 2005 and 2013 was performed. Individual case data for 51 patients with biopsy proven squamous cell carcinoma (SCC) from the oropharynx (n=22) and oral tongue (n=29) were identified. Formalin fixed, paraffin embedded biopsy samples were obtained and evaluated for p16 by immunohistochemistry and HPV genotype 16 specific oncogenes, E6 and E7, by PCR. RESULTS: All of the positive controls, but none of the oropharyngeal samples stained positively for p16. Two of the oral tongue samples stained positive for p16. None of the oropharyngeal or oral tongue cases demonstrated PCR products for HPV-16 E6 or E7. CONCLUSIONS: Though Mozambique has extremely high levels of HPV positive cervical cancer this study demonstrates an absence of HPV positive oropharyngeal or oral tongue squamous cell carcinoma within biopsy samples from a single referral hospital in Maputo, the capital of Mozambique. PMID- 26590334 TI - Childhood exposures among mothers and Hodgkin's lymphoma in offspring. AB - BACKGROUND: Childhood exposures in mothers, signaled by number of older and younger siblings, have lifelong consequences for aspects of immune function. We hypothesized that these may influence young adult-onset Hodgkin's lymphoma (HL) risk in offspring. MATERIALS AND METHODS: Swedish registers identified 2028 cases of young adult onset HL (diagnosed between ages 15-39 years) up to 2012 among those born since 1958; and 18,374 matched controls. Conditional logistic regression was used to assess HL risk associated with number of older and younger siblings of mothers. RESULTS: Having a mother with more than two older siblings is associated with lower HL risk, and the association is statistically significant for mothers with three or more siblings, compared with none. The adjusted odds ratios (and 95% confidence intervals) are 1.04 (0.93-1.16); 0.95 (0.81-1.10); and 0.81 (0.66-0.98) for one, two, and three or more older siblings, respectively. There is no association between number of mothers' younger siblings and HL risk. CONCLUSIONS: Exposures during the childhood of mothers may influence young onset adult HL risk in offspring, perhaps through vertical transmission of infectious agents, or through other long-term influences on maternal immune function. PMID- 26590335 TI - Measuring the effect of improvement in methodological techniques on data collection in the Gharbiah population-based cancer registry in Egypt: Implications for other Low- and Middle-Income Countries. AB - The purpose of this study was to describe and quantify procedures and methods that maximized the efficiency of the Gharbiah Cancer Registry (GPCR), the only population-based cancer registry in Egypt. The procedures and measures included a locally-developed software program to translate names from Arabic to English, a new national ID number for demographic and occupational information, and linkage of cancer cases to new electronic mortality records of the Ministry of Health. Data was compiled from the 34,058 cases from the registry for the years 1999 2007. Cases and registry variables about demographic and clinical information were reviewed by year to assess trends associated with each new method or procedure during the study period. The introduction of the name translation software in conjunction with other demographic variables increased the identification of detected duplicates from 23.4% to 78.1%. Use of the national ID increased the proportion of cases with occupation information from 27% to 89%. Records with complete mortality information increased from 18% to 43%. Proportion of cases that came from death certificate only, decreased from 9.8% to 4.7%. Overall, the study revealed that introducing and utilizing local and culture specific methodological changes, software, and electronic non-cancer databases had a significant impact on data quality and completeness. This study may have translational implications for improving the quality of cancer registries in LMICs considering the emerging advances in electronic databases and utilization of health software and computerization of data. PMID- 26590336 TI - Eating Locally: Microautophagy and Protein Turnover at the Synapse. AB - Mechanisms of local protein quality control in the presynaptic nerve terminal remain largely unknown. In this issue of Neuron, Uytterhoeven et al. (2015) describe a form of synaptic endosomal microautophagy controlling protein rejuvenation, critical for optimal synaptic activity. PMID- 26590337 TI - Bridging the Gap: Muscarinic M4 Receptors Promote Striatal Plasticity in Health and Disease. AB - In this issue of Neuron, Shen et al. (2015) demonstrate that the M4 muscarinic receptor regulates striatal plasticity. The authors use an M4-positive allosteric modulator, which facilitates long-term depression in direct pathway neurons and reverses aberrant plasticity in levodopa-induced dyskinesia. PMID- 26590338 TI - A Division of Light and Dark in the Visual Cortex. AB - The fate of ON-OFF receptive field segregation in the visual cortex has long eluded scrutiny. In this issue of Neuron, Smith et al. (2015) now reveal the intricate relationship between luminance polarity and orientation selectivity in the upper layers of ferret visual cortex. PMID- 26590339 TI - The What and Where of Visual Attention. AB - The selective processing of sensory input during attention is known to take many forms, and different forms of attention likely reflect varying underlying neural mechanisms. Bichot and colleagues (2015) identify neurons that appear specialized for the control of feature-based visual attention. PMID- 26590340 TI - Neurodata Without Borders: Creating a Common Data Format for Neurophysiology. AB - The Neurodata Without Borders (NWB) initiative promotes data standardization in neuroscience to increase research reproducibility and opportunities. In the first NWB pilot project, neurophysiologists and software developers produced a common data format for recordings and metadata of cellular electrophysiology and optical imaging experiments. The format specification, application programming interfaces, and sample datasets have been released. PMID- 26590341 TI - G Protein-Coupled Receptors: Dynamic Machines for Signaling Pain and Itch. AB - G protein-coupled receptors (GPCRs) are the major class of sensory proteins and a primary therapeutic target in the pathways to pain and itch. GPCRs are complex signaling machines. Their association with ligands, other receptors, and signaling and regulatory partners induces GPCRs to adopt distinct conformations and to traffic to microdomains within plasma and endosomal membranes. This conformational and positional dynamism controls GPCR signaling in time and space and defines the outcome of receptor activation. An understanding of the dynamic nature of GPCRs within primary sensory neurons and neighboring cells brings new insights into their contributions to the physiology and pathophysiology of pain and itch and provides novel opportunities for therapeutic intervention. PMID- 26590342 TI - Loss of MeCP2 in Parvalbumin-and Somatostatin-Expressing Neurons in Mice Leads to Distinct Rett Syndrome-like Phenotypes. AB - Inhibitory neurons are critical for proper brain function, and their dysfunction is implicated in several disorders, including autism, schizophrenia, and Rett syndrome. These neurons are heterogeneous, and it is unclear which subtypes contribute to specific neurological phenotypes. We deleted Mecp2, the mouse homolog of the gene that causes Rett syndrome, from the two most populous subtypes, parvalbumin-positive (PV+) and somatostatin-positive (SOM+) neurons. Loss of MeCP2 partially impairs the affected neuron, allowing us to assess the function of each subtype without profound disruption of neuronal circuitry. We found that mice lacking MeCP2 in either PV+ or SOM+ neurons have distinct, non overlapping neurological features: mice lacking MeCP2 in PV+ neurons developed motor, sensory, memory, and social deficits, whereas those lacking MeCP2 in SOM+ neurons exhibited seizures and stereotypies. Our findings indicate that PV+ and SOM+ neurons contribute complementary aspects of the Rett phenotype and may have modular roles in regulating specific behaviors. PMID- 26590343 TI - Correspondence between Resting-State Activity and Brain Gene Expression. AB - The relationship between functional brain activity and gene expression has not been fully explored in the human brain. Here, we identify significant correlations between gene expression in the brain and functional activity by comparing fractional amplitude of low-frequency fluctuations (fALFF) from two independent human fMRI resting-state datasets to regional cortical gene expression from a newly generated RNA-seq dataset and two additional gene expression datasets to obtain robust and reproducible correlations. We find significantly more genes correlated with fALFF than expected by chance and identify specific genes correlated with the imaging signals in multiple expression datasets in the default mode network. Together, these data support a population-level relationship between regional steady-state brain gene expression and resting-state brain activity. PMID- 26590344 TI - RAN Translation in Huntington Disease. AB - Huntington disease (HD) is caused by a CAG ? CTG expansion in the huntingtin (HTT) gene. While most research has focused on the HTT polyGln-expansion protein, we demonstrate that four additional, novel, homopolymeric expansion proteins (polyAla, polySer, polyLeu, and polyCys) accumulate in HD human brains. These sense and antisense repeat-associated non-ATG (RAN) translation proteins accumulate most abundantly in brain regions with neuronal loss, microglial activation and apoptosis, including caudate/putamen, white matter, and, in juvenile-onset cases, also the cerebellum. RAN protein accumulation and aggregation are length dependent, and individual RAN proteins are toxic to neural cells independent of RNA effects. These data suggest RAN proteins contribute to HD and that therapeutic strategies targeting both sense and antisense genes may be required for efficacy in HD patients. This is the first demonstration that RAN proteins are expressed across an expansion located in an open reading frame and suggests RAN translation may also contribute to other polyglutamine diseases. PMID- 26590345 TI - Hsc70-4 Deforms Membranes to Promote Synaptic Protein Turnover by Endosomal Microautophagy. AB - Synapses are often far from their cell bodies and must largely independently cope with dysfunctional proteins resulting from synaptic activity and stress. To identify membrane-associated machines that can engulf synaptic targets destined for degradation, we performed a large-scale in vitro liposome-based screen followed by functional studies. We identified a presynaptically enriched chaperone Hsc70-4 that bends membranes based on its ability to oligomerize. This activity promotes endosomal microautophagy and the turnover of specific synaptic proteins. Loss of microautophagy slows down neurotransmission while gain of microautophagy increases neurotransmission. Interestingly, Sgt, a cochaperone of Hsc70-4, is able to switch the activity of Hsc70-4 from synaptic endosomal microautophagy toward chaperone activity. Hence, Hsc70-4 controls rejuvenation of the synaptic protein pool in a dual way: either by refolding proteins together with Sgt, or by targeting them for degradation by facilitating endosomal microautophagy based on its membrane deforming activity. PMID- 26590346 TI - Phosphorylation of Complexin by PKA Regulates Activity-Dependent Spontaneous Neurotransmitter Release and Structural Synaptic Plasticity. AB - Synaptic plasticity is a fundamental feature of the nervous system that allows adaptation to changing behavioral environments. Most studies of synaptic plasticity have examined the regulated trafficking of postsynaptic glutamate receptors that generates alterations in synaptic transmission. Whether and how changes in the presynaptic release machinery contribute to neuronal plasticity is less clear. The SNARE complex mediates neurotransmitter release in response to presynaptic Ca(2+) entry. Here we show that the SNARE fusion clamp Complexin undergoes activity-dependent phosphorylation that alters the basic properties of neurotransmission in Drosophila. Retrograde signaling following stimulation activates PKA-dependent phosphorylation of the Complexin C terminus that selectively and transiently enhances spontaneous release. Enhanced spontaneous release is required for activity-dependent synaptic growth. These data indicate that SNARE-dependent fusion mechanisms can be regulated in an activity-dependent manner and highlight the key role of spontaneous neurotransmitter release as a mediator of functional and structural plasticity. PMID- 26590347 TI - M4 Muscarinic Receptor Signaling Ameliorates Striatal Plasticity Deficits in Models of L-DOPA-Induced Dyskinesia. AB - A balanced interaction between dopaminergic and cholinergic signaling in the striatum is critical to goal-directed behavior. But how this interaction modulates corticostriatal synaptic plasticity underlying learned actions remains unclear--particularly in direct-pathway spiny projection neurons (dSPNs). Our studies show that in dSPNs, endogenous cholinergic signaling through M4 muscarinic receptors (M4Rs) promoted long-term depression of corticostriatal glutamatergic synapses, by suppressing regulator of G protein signaling type 4 (RGS4) activity, and blocked D1 dopamine receptor dependent long-term potentiation (LTP). Furthermore, in a mouse model of L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) in Parkinson's disease (PD), boosting M4R signaling with positive allosteric modulator (PAM) blocked aberrant LTP in dSPNs, enabled LTP reversal, and attenuated dyskinetic behaviors. An M4R PAM also was effective in a primate LID model. Taken together, these studies identify an important signaling pathway controlling striatal synaptic plasticity and point to a novel pharmacological strategy for alleviating LID in PD patients. PMID- 26590348 TI - Modular Representation of Luminance Polarity in the Superficial Layers of Primary Visual Cortex. AB - The spatial arrangement of luminance increments (ON) and decrements (OFF) falling on the retina provides a wealth of information used by central visual pathways to construct coherent representations of visual scenes. But how the polarity of luminance change is represented in the activity of cortical circuits remains unclear. Using wide-field epifluorescence and two-photon imaging we demonstrate a robust modular representation of luminance polarity (ON or OFF) in the superficial layers of ferret primary visual cortex. Polarity-specific domains are found with both uniform changes in luminance and single light/dark edges, and include neurons selective for orientation and direction of motion. The integration of orientation and polarity preference is evident in the selectivity and discrimination capabilities of most layer 2/3 neurons. We conclude that polarity selectivity is an integral feature of layer 2/3 neurons, ensuring that the distinction between light and dark stimuli is available for further processing in downstream extrastriate areas. PMID- 26590350 TI - The development of a novel curriculum to address past sexual assault. PMID- 26590349 TI - pH-responsive hybrid quantum dots for targeting hypoxic tumor siRNA delivery. AB - Hypoxia is a characteristic of cancer and plays a key role in tumorigenesis, angiogenesis and resistance to cancer therapies. SiRNA treatment is effective against hypoxic tumors by gene silencing. However, siRNA delivery to the hypoxic regions of solid tumors still presents a challenge due to the distance from blood vessels and the increased presence of efflux transporters. Therefore, tumor therapies would be improved through the immediate development of an effective siRNA delivery system to hypoxic regions. To this end, we synthesized a system to deliver HIF-1alpha siRNA into hypoxic tumor cells. The system consists of a functional shell composed of 2-deoxyglucose (DG)-polyethylene glycol (PEG) connected with the compound of lipoic acid, lysine and 9-poly-d-arginine (LA-Lys 9R) by a hydrazone bond and a core of CdTe quantum dots (QDs). The molecular structure of DG-PEG-LA-Lys-9R was confirmed by liquid chromatography-mass spectrometry (LC-MS), nuclear magnetic resonance (NMR) spectroscopy, Fourier transform infrared spectroscopy (FTIR), and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The multifunctional CdTe QDs measured approximately 200 nm and showed excellent biocompatibility, perfect siRNA binding capability and enhanced hypoxic tumor targeting. Importantly, the system described here is pH-responsive with a hydrazone bond; therefore, it avoids GLUT1 receptor-mediated endocytic recycling, resulting in irreversible delivery of the siRNA. We used Western blots to confirm the superior gene silencing efficiency induced by the DG-PEG-LA-Lys-9R with hydrazone modified CdTe QDs. Here, we demonstrate high efficacy of the siRNA tumor delivery system using in vitro and in vivo experiments. In addition, these studies demonstrate that pH-responsive hybrid quantum dots show improved antitumor efficacy with decreased organ toxicity, indicating a promising siRNA delivery system for hypoxic cancer therapy. PMID- 26590351 TI - Photo-enhanced toxicity of fluoranthene to Gulf of Mexico marine organisms at different larval ages and ultraviolet light intensities. AB - Significant increases in toxicity have been observed as a result of polycyclic aromatic hydrocarbon (PAH) absorption of ultraviolet (UV) radiation in aquatic organisms. Early life stage aquatic organisms are predicted to be more susceptible to PAH photo-enhanced toxicity as a result of their translucence and tendency to inhabit shallow littoral or surface waters. The objective of the present study was to evaluate the sensitivity of varying ages of larval mysid shrimp (Americamysis bahia), inland silverside (Menidia beryllina), sheepshead minnow (Cyprinodon variegatus), and Gulf killifish (Fundulus grandis) to photo enhanced toxicity and to examine the correlation between photo-enhanced toxicity and organism pigmentation. Organisms were exposed to fluoranthene and artificial UV light at different larval ages and results were compared using median lethal concentrations (LC50s) and the lethal time-to-death (LT50s). In addition, a high UV light intensity, short-duration (4-h) experiment was conducted at approximately 24 W/m(2) of ultraviolet radiation A (UV-A) and compared with a low intensity, long-duration (12-h) experiment at approximately 8 W/m(2) of UV-A. The results indicated decreased toxicity with increasing age for all larval organisms. The amount of organism pigmentation was correlated with observed LC50 and LT50 values. High-intensity short-duration exposure resulted in greater toxicity than low-intensity long-duration UV treatments for mysid shrimp, inland silverside, and sheepshead minnow. Data from these experiments suggest that toxicity is dependent on age, pigmentation, UV light intensity, and fluoranthene concentration. PMID- 26590352 TI - Molecular Mechanisms Associated With Particulate and Soluble Heteroglycan Mediated Immune Response. AB - Immune responses are outcomes of complex molecular machinery which occur inside the cells. Unravelling the cellular mechanisms induced by immune stimulating molecules such as glycans and determining their structure-function relationship are therefore important factors to be assessed. With this viewpoint, the present study identifies the functional receptor binding unit of a well characterized heteroglycan and also delineates the cellular and molecular processes that are induced upon heteroglycan binding to specific cell surface receptors in immune cells. The heteroglycan was acid hydrolysed and it was revealed that 10-30 kDa fractions served as the functional receptor binding unit of the molecule. Increasing the size of 10-30 kDa heteroglycan showed prominent immune activity. The whole soluble heteroglycan was also conjugated with hyperbranched dendrimers so as to generate a particulate form of the molecule. Dectin-1 and TLR2 were identified as the major receptors in macrophages that bind to particulate as well as soluble form of the heteroglycan and subsequently caused downstream signaling molecules such as NF-kappabeta and MAPK to get activated. High levels of 1L-1beta and IL-10 mRNA were observed in particulate heteroglycan treated macrophages, signifying that increasing the size and availability of the heteroglycan to its specific receptors is pertinent to its biological functioning. Upregulated expression of PKC and iNOS were also noted in particulate heteroglycan treated RAW 264.7 cells than the soluble forms. Taken together, our results indicate that biological functions of immunomodulatory heteroglycan are dependent on their size and molecular weight. J. Cell. Biochem. 117: 1580-1593, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26590353 TI - Laparoscopic resection of recurrent ectopic hepatocellular carcinoma: A case report with review of the literature and guidelines for follow-up. AB - INTRODUCTION: Hepatocellular carcinoma (HCC) in ectopic liver tissue is extremely rare. PRESENTATION OF CASE: A 64-year-old woman presented initially with abdominal complaints. Computed tomography (CT) revealed a tumor in the diaphragm and laparoscopic resection of the tumor was performed. Histology showed HCC. During the next 4 years four more tumors, all of which showed HCC on histology and were located extrahepatically, was treated with laparoscopic resection. During this course the patient was followed with regular thoracoabdominal CT and measurement of serum alpha-fetoprotein (AFP). A negative magnetic resonance imaging (MRI) examination of the liver excluded a primary intrahepatic tumor. DISCUSSION: The literature available on ectopic HCC and the guidelines for management of HCC do not address the postoperative surveillance of patients undergoing curative treatment. A follow-up regime has been proposed by Hatzaras et al. (2014) to include cross-sectional imaging of the liver and measurement of serum AFP levels [1]. CT would be the preferred study of choice in a total radiologic investigation of the abdomen. While MRI is prone to artifacts due to movements, CT scans allows so rapid recordings that this no longer is an issue. An early investigation of the liver for intrahepatic HCC should nevertheless be performed early to exclude primary intrahepatic HCC. CONCLUSION: We recommend that patients with ectopic HCC should be followed every 6 months with measurement of AFP and abdominal CT imaging. MRI of the liver should be performed early to exclude primary intrahepatic HCC. PMID- 26590354 TI - Rab1 GTPases as oncogenes. PMID- 26590355 TI - Increased Rat Placental Fatty Acid, but Decreased Amino Acid and Glucose Transporters Potentially Modify Intrauterine Programming. AB - Regulation of placental nutrient transport significantly affects fetal development and may modify intrauterine growth restriction (IUGR) and fetal programming. We hypothesized that placental nutrient transporters are differentially affected both by utero-placental insufficiency and prenatal surgical stress. Pregnant rats underwent bilateral uterine artery and vein ligation (LIG), sham operation (SOP) or no operation (controls, C) on gestational day E19. Placentas were obtained by caesarean section 4 h (LIG, n=20 placentas; SOP, n=24; C, n=12), 24 h (LIG, n=28; SOP, n=20; C, n=12) and 72 h (LIG, n=20; SOP, n=20; C, n=24) after surgery. Gene and protein expression of placental nutrient transporters for fatty acids (h-FABP, CD36), amino acids (SNAT1, SNAT2) and glucose (GLUT-1, Connexin 26) were examined by qRT-PCR, western blot and immunohistochemistry. Interestingly, the mean protein expression of h-FABP was doubled in placentas of LIG and SOP animals 4, 24 (SOP significant) and 72 h (SOP significant) after surgery. CD36 protein was significantly increased in LIG after 72 h. SNAT1 and SNAT2 protein and gene expressions were significantly reduced in LIG and SOP after 24 h. Further significantly reduced proteins were GLUT-1 in LIG (4 h, 72 h) and SOP (24 h), and Connexin 26 in LIG (72 h). In conclusion, placental nutrient transporters are differentially affected both by reduced blood flow and stress, probably modifying the already disturbed intrauterine milieu and contributing to IUGR and fetal programming. Increased fatty acid transport capacity may affect energy metabolism and could be a compensatory reaction with positive effects on brain development. J. Cell. Biochem. 117: 1594-1603, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26590356 TI - Canada's Adverse Drug Reaction Reporting System: A Failing Grade. AB - An article in the National Post on suicidal effects associated with varenicline (Champix) highlights deficiencies in the Canadian spontaneous reporting system (SRS) for adverse drug reactions (ADRs). The issues of under-reporting, poor quality information, duplication of reports and lack of a population denominator of drug use are discussed. Canada's SRS is deficient. There are immediate and medium-term actions that could be instituted that would improve pharmacovigilance in Canada. However, education about appropriate prescribing, the recognition of ADRs, and the duty to report them is a key long-term strategy to improving the pharmacovigilance system and should be included at every opportunity in the training of healthcare professionals so that life-long habits are developed. In addition to changes at Health Canada, greater emphasis needs to be placed on training in therapeutics, understanding drug safety, and the responsibility of healthcare providers in reporting risks in the curricula of medical and nursing schools. PMID- 26590357 TI - HER-3: hub for escape mechanisms. PMID- 26590358 TI - Diuretics for transient tachypnoea of the newborn. AB - BACKGROUND: Transient tachypnoea of the newborn (TTN) results from delayed clearance of lung liquid and is a common cause of admission of full-term infants to neonatal intensive care units. The condition is particularly common after elective caesarean section. Conventional treatment involves appropriate oxygen administration and continuous positive airway pressure in some cases. Most infants receive antibiotic therapy. Hastening the clearance of lung liquid may shorten the duration of the symptoms and reduce complications. OBJECTIVES: To determine whether diuretic administration reduces the duration of oxygen therapy and respiratory symptoms and shortens hospital stay in term infants presenting with transient tachypnoea of the newborn. SEARCH METHODS: An updated search was carried out in September 2015 of the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library issue 9, 2015), MEDLINE via Ovid, EMBASE, PubMed, and CINAHL via OVID. SELECTION CRITERIA: We included randomised and quasi-randomised controlled trials that compared the effect of diuretics administration versus placebo or no treatment in infants of less than seven days of age, born at 37 or more weeks of gestation with the clinical picture of transient tachypnoea of the newborn. DATA COLLECTION AND ANALYSIS: We extracted and analysed data according to the methods outlined in the latest Cochrane Handbook for Systematic Reviews of Interventions. Two review authors assessed trial quality in each potentially eligible manuscript and two review authors extracted data. MAIN RESULTS: Our previous systematic review included two trials enrolling a total of 100 infants with transient tachypnoea of the newborn (Wiswell 1985; Karabayir 2006). The updated search revealed no new trials. Wiswell 1985 randomised 50 infants to receive either oral furosemide (2 mg/kg body weight at time of diagnosis followed by a 1 mg/kg dose 12 hours later if the tachypnoea persisted) or placebo. Karabayir 2006 randomised 50 infants to receive either intravenous furosemide (2 mg/kg body weight) or an equal volume of normal saline placebo. Neither trial reported on the need for respiratory support. Neither trial demonstrated a statistically significant impact of furosemide on transient tachypnoea of the newborn regarding duration of symptoms or length of hospitalisation. AUTHORS' CONCLUSIONS: Diuretics cannot be recommended as treatment for transient tachypnoea of the newborn and it should not be used unless additional data become available. This finding suggests that either furosemide is not effective in promoting resorption of lung fluid, or factors other than delayed resorption of this fluid contribute to the pathogenesis of transient tachypnoea of the newborn. The question remains as to whether furosemide given to the infant (or even to the mother before caesarean section) might shorten the duration of the illness. As elective caesarean section continues at a high level, these two interventions might be worthy of trials. PMID- 26590359 TI - The promotion of academic medicine through student-led initiatives. PMID- 26590360 TI - The derivation of effects threshold concentrations of lead for European freshwater ecosystems. AB - The main objective of the present study was to derive ecologically relevant effect threshold concentrations of (dissolved) Pb for selected European Union (EU) freshwater rivers, using the 2008 EU Voluntary Risk Assessment Report as a starting point and more advanced methodologies than those used in the Voluntary Risk Assessment Report. This included 1) implementing more robust quality criteria for selecting chronic toxicity data; 2) the conversion of total to dissolved Pb concentrations using a combination of an empirical equation relating inorganic Pb solubility and geochemical speciation modeling to account for effects of dissolved organic matter; 3) the use of bioavailability models for chronic toxicity for species belonging to 3 different trophic levels; and 4) the use of robust methods for large data set handling (such as species sensitivity distribution [SSD] analysis). The authors used published bioavailability models for an algal species (Pseudokirchneriella subcapitata) and a daphnid (Ceriodaphnia dubia) and developed a new model for the fathead minnow (Pimephales promelas). The research has shown that these models are also useful for, and reasonably accurate in, predicting chronic toxicity to other species, including a snail, a rotifer, midge larvae, and an aquatic plant (read-across). A comprehensive chronic toxicity data set for Pb was compiled, comprising 159 individual high-quality toxicity data for 25 different species. By applying the total dissolved conversion and the bioavailability models, normalized toxicity values were obtained, which were then entered into a SSD analysis. Based on the parametric best-fitting SSDs, the authors calculated that ecological threshold concentrations of Pb protecting 95% of freshwater species for 7 selected European freshwater scenarios were between 6.3 MUg dissolved Pb/L and 31.1 MUg dissolved Pb/L. PMID- 26590362 TI - Red Raspberry Phenols Inhibit Angiogenesis: A Morphological and Subcellular Analysis Upon Human Endothelial Cells. AB - Polyphenols are a class of natural compounds whose potential as antioxidant, anti inflammatory, and anti-angiogenesis has been reported in many pathological conditions. Red raspberry extract, rich in polyphenols, has been reported to exert anti-inflammatory effects and prevent cell proliferation in distinct animal models. However, the signaling pathways involved remain unknown. Herein, we used human microvascular endothelial cells (HMVECs) to determine the influence of red raspberry phenolic compound extract concentrations, ranging from 10 to 250 ug gallic acid equivalents (GAE)/mL, on endothelium viability (MTS assay), proliferation (BrdU incorporation), migration (injury assay), and capillary-like structures formation (Matrigel assay). Protein expression in cell lysates was determined by Western blot analysis. We showed that red raspberry extracts reduced cell viability (GI50 = 87,64 +/- 6,59 MUg GAE/mL) and proliferation in a dose-dependent manner. A significant abrogation of cells ability to migrate to injured areas, even at low concentrations, was observed by injury assay. Cell assembly into capillary-like structures on Matrigel also decreased in a dose dependent-manner for higher extract concentrations, as well as the number of branching points per unit of area. Protein expression analysis showed a dose dependent decrease in Phospho-VEGFR2 expression, implying abrogation of VEGF signaling activity. We also showed for the first time that red raspberry phenolic compounds induce the rearrangement of filamentous actin cytoskeleton, with an isotropy increase found for higher testing concentrations. Taken together, our findings corroborate the anti-angiogenic potential of red raspberry phenolic compounds and provide new insights into their mode of action upon endothelium. J. Cell. Biochem. 117: 1604-1612, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26590361 TI - Associations of FGF23 With Change in Bone Mineral Density and Fracture Risk in Older Individuals. AB - Elevated levels of the phosphate-regulating hormone fibroblast growth factor 23 (FGF23) have been linked to greater risk of fractures in some studies, especially among individuals with chronic kidney disease (CKD). We evaluated FGF23 as a risk factor for bone loss and fractures in the Health, Aging, and Body Composition (Health ABC) study, which is a prospective biracial cohort of well-functioning adults aged 70 to 79 years recruited at two clinical centers in the United States. The sample for the bone mineral density (BMD) analyses consisted of 2234 participants who had at least two serial total hip areal BMD measures. The fracture analyses included 2786 participants, 567 of whom sustained a fracture during a median follow up of 4.95 years. Linear mixed-effects models were used for longitudinal measurements of total hip areal BMD and the proportional subdistribution hazard regression model subject to competing risks of death was used for risk of fracture. The median FGF23 was 46.7 (interquartile range [IQR] 36.7 to 60.2) pg/mL. The mean annualized percent change in total hip areal BMD did not vary significantly according to FGF23 quartile in all participants (p for trend = 0.70), but the effect was modified by CKD status (adjusted p for interaction <0.001). Among participants with CKD, the unadjusted mean annualized percent change in total hip areal BMD was greater with higher levels of FGF23 (unadjusted p for trend = 0.02), but the trend was attenuated with adjustment for estimated glomerular filtration rate and parathyroid hormone (adjusted p for trend = 0.30). FGF23 was not significantly associated with fracture risk in crude (hazard ratio [HR] per doubling of FGF23, 0.97; 95% CI, 0.85 to 1.12) or adjusted models (HR per doubling of FGF23, 1.02; 95% CI, 0.86 to 1.22), and these findings were not modified by gender or CKD status. FGF23 levels are not associated with bone loss or fracture risk in older adults with low prevalence of CKD. PMID- 26590363 TI - Ellipsoid zone on optical coherence tomography: a review. AB - Emergence of the high-resolution optical coherence tomography has allowed better delineation of retinal layers, and many of the anatomical correlations of these layers have now been agreed upon. However, some anatomical correlates still remain contentious, such as the second hyper-reflective band, which is now termed ellipsoid zone. Despite the lack of consensus of the actual origin of the ellipsoid zone, there has been much interest in evaluating its integrity and intensity in different disease processes. This review paper aims to provide an overview of the ellipsoid zone and its clinical and research applications. PMID- 26590364 TI - Feasibility study on the use of methylation-specific MLPA for the 11p15 region on prenatal samples. PMID- 26590365 TI - Evodiamine Suppresses ABCG2 Mediated Drug Resistance by Inhibiting p50/p65 NF kappaB Pathway in Colorectal Cancer. AB - Evodiamine (Evo), extracted from the Chinese herbal medicine Evodia rutaecarpa, has cytotoxic effects on different types of human cancer cells. However, its effects on drug resistance and their molecular mechanism and therapeutic target in colorectal cancer are not well understood. In the present study, we observed that Evo inhibited cell growth and induced apoptosis in adose-and time-dependent manner in HCT-116/L-OHP cells. Moreover, Evo treatment reduced Rhodamine 123 accumulation and ATPase activity in HCT-116/L-OHP cells, indicating that Evo decreased the efflux function in HCT-116/L-OHP cells. Interestingly, phosphorylation of NF-kappaB pathway, particularly p50/p65, was also inhibited by Evo treatment. Furthermore the effect of Evo in reversing drug resistance and suppressing phosphorylation of NF-kappaB pathway were attenuated after treatment with the NF-kappaB activator (LPS). Additionally, Evo inhibited the tumor growth in a colorectal MDR cancer xenograft model and down regulated p-NF-kappaB level in vivo. Our study provided the first direct evidence that Evo can attenuate multidrug resistance by blocking p-NF-kappaB signaling pathway in human colorectal cancer. Evo could be a potential candidate for cancer chemotherapy. PMID- 26590366 TI - COmparison between COronary THrombus aspiration with Angiojet(r) or Export(r) catheter in patients with ST-elevation myocardial infarction submitted to primary angioplasty: The COCOTH Study. AB - AIMS: To compare the effects of two thrombus aspiration devices, the manual catheter Export(r) and the more complex and expensive mechanical Angiojet(r), on several indices of reperfusion in acute ST-elevation myocardial infarction (STEMI). METHODS AND RESULTS: Clinical, hemodynamic and procedural characteristics of 185 STEMI patients, randomized to treatment with Export (n=95) or Angiojet (n=90) during primary percutaneous coronary intervention (PPCI) were analyzed. The primary endpoint was ST-segment elevation reduction 90 min after culprit vessel re-opening. Secondary endpoints included variations in some angiographic parameters (TIMI Flow, TIMI Frame Count and Myocardial Blush Grade) and Infarct Size and Severity at myocardial scintigraphy. A significant reduction in ST-elevation was observed in both groups after PPCI without significant differences between the two groups. No significant difference between Angiojet vs. Export was observed in ST-segment resolution >50% and >= 70%, in TIMI Flow, TIMI Frame Count and Myocardial Blush Grade before vs. after PPCI and in Infarct Size and Severity. CONCLUSIONS: PPCI with thrombus aspiration was effective in both groups of patients, without differences in myocardial reperfusion and necrosis indices. These results could support the routine use of manual devices during PPCI, reserving the more expensive Angiojet in case of manual device failure and persistent or massive intracoronary thrombosis, with favorable implications in terms of cost containment. PMID- 26590367 TI - The MAO-B inhibitor deprenyl reduces the oral tremor and the dopamine depletion induced by the VMAT-2 inhibitor tetrabenazine. AB - Tetrabenazine (TBZ) is prescribed for the treatment of chorea associated with Huntington's disease. Via inhibition of the vesicular monoamine transporter (VMAT 2), TBZ blocks dopamine (DA) storage and depletes striatal DA; this drug also has been shown to induce Parkinsonian motor side effects in patients. Recently, TBZ was shown to induce tremulous jaw movements (TJMs) in rats and mice. TJMs are an oral tremor that has many of the characteristics of Parkinsonian tremor in humans. The present study focused upon the ability of the well-established antiparkinsonian agent deprenyl to attenuate the behavioral and neurochemical effects of 2.0mg/kg TBZ. Deprenyl is a selective and irreversible inhibitor of monoamine oxidase-B, and administration of deprenyl produced a dose-related suppression of TBZ-induced TJMs. A second experiment employed in vivo microdialysis to examine extracellular DA levels in the ventrolateral striatum, the neostriatal region most closely associated with the production of TJMs, after administration of TBZ and deprenyl. Consistent with the behavioral data, TBZ alone produced a biphasic effect on extracellular DA, with an initial increases followed by a prolonged decrease during the period in which TJMs are displayed. Co-administration of deprenyl with TBZ increased DA levels compared to rats treated with TBZ alone. These results provide support for use of TBZ as a rodent model of Parkinsonism, and future studies should utilize this model to evaluate putative anti-Parkinsonian agents. PMID- 26590368 TI - Alterations to prepulse inhibition magnitude and latency in adult rats following neonatal treatment with domoic acid and social isolation rearing. AB - Deficits in perceptual, informational, and attentional processing are consistently identified as a core feature in schizophrenia and related neuropsychiatric disorders. Neonatal injections of low doses of the AMPA/kainate agonist domoic acid (DOM) have previously been shown to alter various aspects of perceptual and attentional processing in adult rats. The current study investigated the effects of combined neonatal DOM treatment with isolation rearing on prepulse inhibition behaviour and relevant neurochemical measures, to assess the usefulness of these paradigms in modeling neurodevelopmental disorders. Daily subcutaneous injections of DOM (20 MUg/kg) or saline were administered to male and female rat pups from postnatal days (PND) 8-14. After weaning, rats were either housed alone or in groups of 4. Both the magnitude and latency of prepulse inhibition were determined in adulthood (approximately 4.5 months of age) and post-mortem brain tissue was assayed using Western blot. Social isolation alone significantly lowered PPI magnitude in male (but not female) rats while DOM treatment appeared to make animals refractory to this effect. Combining social isolation and DOM treatment caused an additive decrease in PPI startle latency. No statistically significant differences were found in the expression of D1, D2, TH, GAD65 or GAD67 protein in either the prefrontal cortex or hippocampus, although some tendencies toward differences were noted. We conclude that both neonatal low-dose DOM and social isolation affect prepulse inhibition in rats but that each paradigm exerts these effects through different neuronal signalling systems. PMID- 26590369 TI - Serum uric acid level as an indicator for CKD regression and progression in patients with type 2 diabetes mellitus-a 4.6-year cohort study. AB - BACKGROUND: To investigate the association of serum uric acid level with renal function change in patients with type 2 diabetes mellitus (T2DM). METHODS: T2DM patients who had been followed-up for at least 3 years were included. Participants were categorized into stable, progression, or regression groups according to their change in chronic kidney disease (CKD) stage. During the follow-up period, all numeric values of metabolic factors, including the uric acid level and the medication possession rate, were calculated in order to investigate their associations with CKD development. Multivariate Cox regression analyses were used to identify independent factors associated with change in CKD. RESULTS: A total of 2367 T2DM patients were enrolled in this study and followed up for a mean of 4.6 years. The numbers of patients in the stable, progression and regression groups were 1133 (47.9%), 487 (20.6%), and 747 (31.5%), respectively. The progression group had the highest serum uric acid level (6.9 +/ 1.8 mg/dL), and the regression group had the lowest uric acid level (5.4 +/- 1.5 mg/dL). In addition, we found that the serum uric acid level was an independent factor associated with CKD progression when the value exceeded 6.3 mg/dL. A lower uric acid level could be beneficial for CKD improvement in T2DM patients with stage 3-5 CKD. CONCLUSIONS: Our data indicated that the serum uric acid level is associated with CKD regression and progression and suggested that a high normal serum uric acid level should be closely monitored in patients with T2DM. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26590370 TI - Analysis of caveolin-1 and phosphoinositol-3 kinase expression in primary uveal melanomas. AB - BACKGROUND: To evaluate the regulation of blood supply in primary uveal melanomas through caveolin-1 (Cav-1)/phosphoinositol-3 kinase (PI3K). METHODS: The expression of Cav-1 and PI3K was analysed in 51 paraffin sections of metastatic (n = 30) and non-metastastic uveal melanomas (n = 21). Two trained observers quantified Cav-1 and PI3K immunofluorescensce expression by determining intensity of staining and percentage of positive cells. The expression was correlated with known prognostic factors. Besides angiogenesis by means of endoglin expression, the normal vasculature (von Willebrand Factor expression) was evaluated semi quantitatively. Vasculogenic mimicry (VM) was analysed by CD31/PAS staining. RESULTS: All examined specimens expressed Cav-1 with a mean of 90.34% Cav-1 positive cells (range, 3.23-100%). Metastatic disease was associated with a higher Cav-1 expression. The correlation of Cav-1 with well-established prognostic factors showed a significant association between Cav-1 expression and largest tumour diameter (P = 0.022), tumour node metastasis classification (P = 0.008) and invasion of optic nerve head (P = 0.048). PI3K was expressed by all uveal melanomas with a mean of 87.28% cells showing PI3K expression. A higher level of PI3K was significantly associated with larger height (P = 0.042) and progressed tumour node metastasis stage (P = 0.016). The percentage of PI3K and Cav-1 positive cells were significantly associated (P = 0.034). For PI3K and Cav 1 expression a non-significant association with VM was shown (P = 0.064 and P = 0.072, respectively). No correlation of PI3K or Cav-1 with angiogenesis or mature vasculature was seen (P > 0.05). CONCLUSIONS: Cav-1 expression may be especially up-regulated in larger uveal melanomas. As it was correlated with PI3K expression and VM in this series of uveal melanoma, Cav-1 might induce the formation of VM via the PI3K-signalling cascade. PMID- 26590371 TI - Sodium modelling to reduce intradialytic hypotension during haemodialysis for acute kidney injury in the intensive care unit. AB - AIM: Intradialytic hypotension often complicates haemodialysis for patients with acute kidney injury (AKI) and may impact renal recovery. Sodium modelling is sometimes used as prophylaxis against intradialytic hypotension in the chronic haemodialysis population, but there is little evidence for its use among critically ill patients with AKI. METHODS: A retrospective cohort with AKI requiring intermittent haemodialysis in the intensive care unit from 2001 to 2008 was used to study the association of prophylactic sodium modelling and multiple outcomes. Outcomes included a composite of in-hospital death or dialysis dependence at hospital discharge, as well as intradialytic hypotension, ultrafiltration goal achievement and net ultrafiltration volume. Associations were estimated using logistic regression, mixed linear models and generalized estimating equations adjusting for demographic and clinical characteristics. RESULTS: One hundred and ninety-one individuals who underwent 892 sessions were identified; sodium modelling was prescribed in 27.1% of the sessions. In adjusted analyses, sodium modelling was not significantly associated with intradialytic hypotension (P = 0.67) or with the ultrafiltration goal achievement (P = 0.06). Sodium modelling during the first dialysis session was numerically associated with lower risk for the composite of in-hospital death or dialysis dependence: adjusted odds ratio (95% confidence interval) 0.39 (0.15-1.02; P = 0.06); however, this association did not reach statistical significance. CONCLUSION: We did not observe statistically significant associations between sodium modelling and improved outcomes among AKI patients receiving intermittent dialysis in the intensive care unit. However, suggestive findings warrant further study. PMID- 26590372 TI - Quantitative, 3D Visualization of the Initiation and Progression of Vertebral Fractures Under Compression and Anterior Flexion. AB - The biomechanical mechanisms leading to vertebral fractures are not well understood. Clinical and laboratory evidence suggests that the vertebral endplate plays a key role in failure of the vertebra as a whole, but how this role differs for different types of vertebral loading is not known. Mechanical testing of human thoracic spine segments, in conjunction with time-lapsed micro-computed tomography, enabled quantitative assessment of deformations occurring throughout the entire vertebral body under axial compression combined with anterior flexion ("combined loading") and under axial compression only ("compression loading"). The resulting deformation maps indicated that endplate deflection was a principal feature of vertebral failure for both loading modes. Specifically, the onset of endplate deflection was temporally coincident with a pronounced drop in the vertebra's ability to support loads. The location of endplate deflection, and also vertebral strength, were associated with the porosity of the endplate and the microstructure of the underlying trabecular bone. However, the location of endplate deflection and the involvement of the cortex differed between the two types of loading. Under the combined loading, deflection initiated, and remained the largest, at the anterior central endplate or the anterior ring apophysis, depending in part on health of the adjacent intervertebral disc. This deflection was accompanied by outward bulging of the anterior cortex. In contrast, the location of endplate deflection was more varied in compression loading. For both loading types, the earliest progression to a mild fracture according to a quantitative morphometric criterion occurred only after much of the failure process had occurred. The outcomes of this work indicate that for two physiological loading modes, the vertebral endplate and underlying trabecular bone are critically involved in vertebral fracture. These outcomes provide a strong biomechanical rationale for clinical methods, such as algorithm-based qualitative (ABQ) assessment, that diagnose vertebral fracture on the basis of endplate depression. (c) 2015 American Society for Bone and Mineral Research. PMID- 26590373 TI - Effect of distance and delay in access to care on outcome of snakebite in rural north-eastern Nigeria. AB - INTRODUCTION: Snakebite envenoming is a major cause of morbidity and mortality in rural areas of the tropics. Timely administration of effective antivenom remains the mainstay of management. METHODS: The study was a quantitative descriptive study aimed at exploring the causes and effects of delay, distance and time taken to access care on snakebite outcomes in Nigeria. All prospective snakebite victims reporting to Kaltungo General Hospital were enrolled. Data on demography, date and time bitten, date and time admitted, site of bite, circumstances of snakebite, responsible snake, clinical features, 20-minute whole-blood clotting test, antivenom administered and outcome were recorded. Delay arising from use of traditional first aid (TFA), time elapsed from snakebite to presentation and the shortest distance from bite location to the hospital was calculated or obtained using a global positioning system. RESULTS: The association between delay before hospital presentation and poor outcome was not statistically significant, even though there was a 2% higher likelihood of poor outcome among those with a 1-hour delay compared to those without delay (odds ratio 1.02, 95% confidence interval 1.00-1.03). There was no difference in distance from bite location to hospital between those with a poor outcome (74) compared to those with a good outcome (325). Those with a poor outcome had more severe envenomation requiring more antivenoms and longer hospital stays. Given poor access to antivenom therapy at distant locations ≥100 km, victims were more likely to use TFA such as black 'snake' stone, with consequent prolonged delays. Antivenoms should be more readily available at distant places. CONCLUSIONS: Community education on avoiding potentially harmful TFA and prompt access to care is recommended. There is a need to provide snakebite care to multiple peripheral, relatively more rural inaccessible areas. PMID- 26590375 TI - Treatment Efficacy of NGF Nanoparticles Combining Neural Stem Cell Transplantation on Alzheimer's Disease Model Rats. AB - BACKGROUND: Alzheimer's disease (AD) is the most common type of dementia. It causes progressive brain disorder involving loss of normal memory and thinking skills. The transplantation of neural stem cells (NSCs) has been reported to improve learning and memory function of AD rats, and protects basal forebrain cholinergic neurons. Nerve growth factor - poly (ethylene glycol) - poly (lactic co-glycolic acid)-nanoparticles (NGF-PEG-PLGA-NPs) can facilitate the differentiation of NSCs in vitro. This study thus investigated the treatment efficacy of NGF-PEG-PLGA-NPs combining NSC transplantation in AD model rats. MATERIAL AND METHODS: AD rats were prepared by injection of 192IgG-saporin into their lateral ventricles. Embryonic rat NSCs were separated, induced by NGF-PEG PLGA-NPs in vitro, and were transplanted. The Morris water-maze test was used to evaluate learning and memory function, followed by immunohistochemical staining for basal forebrain cholinergic neurons, hippocampal synaptophysin, and acetylcholine esterase (AchE) fibers. RESULTS: Rats in the combined treatment group had significantly improved spatial learning ability compared to AD model animals (p<0.05). The number of basal forebrain cholinergic neurons, hippocampal synaptophysin, and AchE-positive fibers were all significantly larger than in the NSC-transplantation group, with no difference from control animals. CONCLUSIONS: NGF-PEG-PLGA-NPs plus NSC transplantation can significantly improve learning and memory functions of AD rats, replenish basal forebrain cholinergic neurons, and help form hippocampal synapses and AchE-positive fibers. These findings may offer practical support for and insight into treatment of Alzheimer's disease. PMID- 26590376 TI - Community-acquired pneumonia (CAP) hospitalizations and deaths: is there a role for quality improvement through inter-hospital comparisons? AB - OBJECTIVE: To assess between-hospital variations in standardized in-hospital mortality ratios of community-acquired pneumonia (CAP), and identify possible leads for quality improvement. DESIGN: We used an administrative database to estimate standardized in-hospital mortality ratios for 111 Belgian hospitals, by carrying out a set of hierarchical logistic regression models, intended to disentangle therapeutic attitudes and biases. To facilitate the detection of false-negative/positive results, we added an inconclusive zone to the funnel plots, derived from the results of the study. Data quality was validated by comparison with (i) alternative data from the largest Belgian Sickness Fund, (ii) published German hospital data and (iii) the results of an on-site audit. SETTING: All Belgian hospital discharge records from 2004 to 2007. STUDY PARTICIPANTS: A total of 111 776 adult patients were admitted for CAP. MAIN OUTCOME MEASURE: Risk-adjusted standardized in-hospital mortality ratios. RESULTS: Out of the 111 hospitals, we identified five and six outlying hospitals, with standardized mortality ratios of CAP consistently on the extremes of the distribution, as providing possibly better or worse care, respectively, and 18 other hospitals as having possible quality weaknesses/strengths. At the individuals' level of the analysis, adjusted odds ratios showed the paramount importance of old age, comorbidity and mechanical ventilation. The data compared well with the different validation sources. CONCLUSIONS: Despite the limitations inherent to administrative data, it seemed possible to establish inter-hospital differences in standardized in-hospital mortality ratios of CAP and to identify leads for quality improvement. Monitoring is needed to assess progress in quality. PMID- 26590377 TI - Acute Achilles Tendon Ruptures. PMID- 26590374 TI - Identification of Bone Marrow Cell Subpopulations Associated With Improved Functional Outcomes in Patients With Chronic Left Ventricular Dysfunction: An Embedded Cohort Evaluation of the FOCUS-CCTRN Trial. AB - In the current study, we sought to identify bone marrow-derived mononuclear cell (BM-MNC) subpopulations associated with a combined improvement in left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV), and maximal oxygen consumption (VO2 max) in patients with chronic ischemic cardiomyopathy 6 months after receiving transendocardial injections of autologous BM-MNCs or placebo. For this prospectively planned analysis, we conducted an embedded cohort study comprising 78 patients from the FOCUS Cardiovascular Cell Therapy Research Network (CCTRN) trial. Baseline BM-MNC immunophenotypes and progenitor cell activity were determined by flow cytometry and colony-forming assays, respectively. Previously stable patients who demonstrated improvement in LVEF, LVESV, and VO2 max during the 6-month course of the FOCUS-CCTRN study (group 1, n = 17) were compared to those who showed no change or worsened in one to three of these endpoints (group 2, n = 61) and to a subset of patients from group 2 who declined in all three functional endpoints (group 2A, n = 11). Group 1 had higher frequencies of B-cell and CXCR4+ BM-MNC subpopulations at study baseline than group 2 or 2A. Furthermore, patients in group 1 had fewer endothelial colony-forming cells and monocytes/macrophages in their bone marrow than those in group 2A. To our knowledge, this is the first study to show that in patients with ischemic cardiomyopathy, certain bone marrow derived cell subsets are associated with improvement in LVEF, LVESV, and VO2 max at 6 months. These results suggest that the presence of both progenitor and immune cell populations in the bone marrow may influence the natural history of chronic ischemic cardiomyopathy-even in stable patients. Thus, it may be important to consider the bone marrow composition and associated regenerative capacity of patients when assigning them to treatment groups and evaluating the results of cell therapy trials. PMID- 26590378 TI - Tandem DARTTM MS Methods for Methadone Analysis in Unprocessed Urine. AB - Current methods of methadone analysis in untreated urine are traditionally limited to enzyme immunoassays (EIA) while confirmation techniques require specimen processing (i.e., sample clean-up) before analyzing by gas or liquid chromatography coupled with mass spectrometry (GC-MS or LC-MS-MS). EIA and traditional confirmation techniques can be costly and, at times inefficient. As an alternative approach, we present Direct Analysis in Real Time (DARTTM) coupled with both time-of-flight and triple quadrupole linear ion trap (Q-TRAPTM) mass spectrometers for screening and confirming methadone in untreated urine specimens. These approaches require neither expensive kits nor sample clean-up for analysis. More importantly, the total combined analysis time for both screening and confirmation methods was <5 min per sample; in contrast to the 3-5 day process required by traditional EIA, GC-MS and LC-MS-MS techniques. To examine the fundamental protocol and its applicability for routine drug screening, studies were performed that included limits of detection, precision, selectivity and specificity, sample recovery and stability and method robustness. The methods described in this report were determined to be highly specific and selective; allowing for detection of methadone at 250 ng/mL, consistent with cutoffs for current EIA techniques (300 ng/mL). The results reported here demonstrate the DARTTM MS platform provides rapid and selective methadone analysis and the potential for providing savings of both time and resources compared with current analysis procedures. PMID- 26590379 TI - Cardiac pauses in competitive athletes: a systematic review examining the basis of current practice recommendations. AB - AIMS: It is generally recommended that individuals aspiring to competitive sports should undergo pre-participation cardiovascular assessment, particularly including arrhythmia risk evaluation. In regard to bradyarrhythmias, the 36th Bethesda Conference suggested that asymptomatic cardiac pauses <=3 s are 'probably of no significance', whereas longer 'symptomatic' pauses may be abnormal. This study focused on assessing the evidence for the '3 s' threshold. METHODS: A systematic literature search was undertaken including Embase (1980-) and Ovid Medline (1950-). The following MeSH terms were used in the database searches: Cardiac.mp & pause.mp. Additionally, pertinent publications found by review of citation lists of identified publications were examined. Individuals with reversible causes of bradyarrhythmia (e.g. drugs) were excluded. RESULTS: The study population comprised 194 individuals with cardiac pauses of 1.35-30 s. In 120 athletes, specific records for pause durations were provided, but it was not always clear whether pauses occurred at rest. Among these 120 athletes, 106 had pauses <=3 s, of whom 92 were asymptomatic and 14 were symptomatic. Fourteen athletes had pauses >3 s, of whom nine were asymptomatic and five were symptomatic. There were no deaths during follow-up (7.46 +/- 5.1 years). With respect to symptoms, the <=3 s threshold had a low-positive predictive value (35.7%) and low sensitivity (26.3%), but good negative predictive value (86.7%) and specificity (91%). CONCLUSION: While the evidence is not incontrovertible, the 3 s pause threshold does not adequately discriminate between potentially asymptomatic and symptomatic competitive athletes, and alone should not be used to exclude potential competitors. PMID- 26590380 TI - The beta-diversity of species interactions: Untangling the drivers of geographic variation in plant-pollinator diversity and function across scales. AB - PREMISE OF THE STUDY: Geographic patterns of biodiversity have long inspired interest in processes that shape the assembly, diversity, and dynamics of communities at different spatial scales. To study mechanisms of community assembly, ecologists often compare spatial variation in community composition (beta-diversity) across environmental and spatial gradients. These same patterns inspired evolutionary biologists to investigate how micro- and macro-evolutionary processes create gradients in biodiversity. Central to these perspectives are species interactions, which contribute to community assembly and geographic variation in evolutionary processes. However, studies of beta-diversity have predominantly focused on single trophic levels, resulting in gaps in our understanding of variation in species-interaction networks (interaction beta diversity), especially at scales most relevant to evolutionary studies of geographic variation. METHODS: We outline two challenges and their consequences in scaling-up studies of interaction beta-diversity from local to biogeographic scales using plant-pollinator interactions as a model system in ecology, evolution, and conservation. KEY RESULTS: First, we highlight how variation in regional species pools may contribute to variation in interaction beta-diversity among biogeographic regions with dissimilar evolutionary history. Second, we highlight how pollinator behavior (host-switching) links ecological networks to geographic patterns of plant-pollinator interactions and evolutionary processes. Third, we outline key unanswered questions regarding the role of geographic variation in plant-pollinator interactions for conservation and ecosystem services (pollination) in changing environments. CONCLUSIONS: We conclude that the largest advances in the burgeoning field of interaction beta-diversity will come from studies that integrate frameworks in ecology, evolution, and conservation to understand the causes and consequences of interaction beta diversity across scales. PMID- 26590381 TI - A randomized study comparing traditional monofilament knotted sutures with barbed knotless sutures for donor leg wound closure in coronary artery bypass surgery. AB - OBJECTIVES: Surgical knots on the suture line provide an anchoring function, but also represent a potential source of infection and irritation on the donor leg after coronary artery bypass surgery. Knotless barbed sutures were designed to prevent knot-related complications. This study compared knot-related wound complication rates between patients receiving traditional monofilament sutures and those receiving barbed knotless sutures for closure of the donor leg. METHODS: One hundred and forty-two patients were randomized into two groups. Group 1 (n = 70) received traditional monofilament sutures and Group 2 (n = 72) received barbed knotless sutures. All wounds were assessed on postoperative days 3 and 5 and weeks 2, 4 and 6 using a validated wound scoring system. Antibiotics usage and general practitioner and district nurse visits were recorded. RESULTS: No demographic differences were observed between groups. Leg wound skin closure times were significantly shorter in Group 2 compared with Group 1 (P < 0.001). Group 1 demonstrated a greater incidence of excessive scarring (P < 0.001), itching (P < 0.001), irritation (P < 0.001) and adverse skin tissue reactions (P < 0.001) than Group 2. Fewer general practitioner visits were recorded in Group 1 compared with Group 2 (P = 0.051). CONCLUSION: Knotless barbed suture usage significantly reduces the incidence of knot-related leg wound complications compared with traditional monofilament knotted sutures. This may be related to differences in the rate of absorption of the suture material or an associated decrease in the incidence of adverse skin tissue reactions that may delay postoperative wound healing. PMID- 26590382 TI - Is there a robust future for research in reproduction? PMID- 26590383 TI - Quantifying the burden of primary central nervous system malignancy. PMID- 26590384 TI - Cardiovascular outcomes at different on-treatment blood pressures in the hypertensive patients of the VALUE trial. AB - AIMS: Recent hypertension guidelines recommend that also in high cardiovascular (CV) risk, hypertensive patients blood pressure (BP) is lowered to <140/90 mmHg as no evidence is available supporting the lower target of <130/80 mmHg recommended in previous guidelines. Whether this represents the optimal treatment strategy is debated, however. METHODS AND RESULTS: The high CV risk hypertensive patients of the Valsartan Antihypertensive Long-term use Evaluation (VALUE) trial were divided into subgroups according to (i) the percentage of on-treatment visits in which BP was reduced to <140/90 or <130/80 mmHg or (ii) the mean systolic or diastolic BP (SBP/DBP) values achieved during the entire treatment period or up to the occurrence of an event. A progressive increase from <25 to >=75% of the visits in which BP was <140/90 mmHg was accompanied by a significant, progressive marked decrease in the covariate adjusted risk of CV morbidity and mortality, cause specific CV events (myocardial infarction, heart failure, and stroke), and all-cause mortality. Except for a persistent progressive decrease in stroke, no significant trend to a risk decrease occurred for a similar progressive increment of the proportion of visits with BP <130/80 mmHg. Increasing the proportion of visits with a BP <140/90 mmHg (but not <130/80 mmHg) was accompanied by a decreased risk of events also when differences in baseline risk were adjusted using a propensity score. Finally, compared with patients remaining at a mean on-treatment SBP >=140 or DBP >=90 mmHg, the risk of all events was markedly reduced when on-treatment mean SBP was lowered to a mean SBP of 130-139 mmHg or a mean DBP of 80-89 mmHg, whereas at on-treatment mean SBP <130 mmHg or DBP <80 mmHg, an additional risk reduction was found for stroke but for any other type of event, the risk of which remained similar or only slightly greater than that seen at the higher BP target. CONCLUSIONS: In the high CV risk, hypertensives of the VALUE trial reducing BP consistently to <140/90 mmHg had marked beneficial effects both when data were calculated as proportion of visits at BP target or as on-treatment mean BP. Reducing BP to <130/80 mmHg led only to some possible further benefit on stroke, whereas the risk of other outcomes remained substantially similar to or slightly greater than that seen at the higher target. Thus, aggressive BP reductions when CV risk is high may not offer substantial advantages, except perhaps in patients or conditions in which stroke risk is particularly common. PMID- 26590385 TI - Type 2 Diabetes and Depression: A Pilot Trial of an Integrated Self-management Intervention for Latino Immigrants. AB - PURPOSE: The purpose of the current study was to determine the feasibility, acceptability, and preliminary effectiveness of an integrated self-management intervention that simultaneously targets diabetes and depression self-management in a primary care clinic that serves the Latino immigrant community. METHODS: The integrated intervention included behavioral activation and motivational interviewing techniques. It was developed with patient, family member, and provider stakeholders, and it comprised 6 individual sessions, followed by 2 monthly booster sessions. Eighteen Latino immigrants participated in an open trial of the intervention. A1C levels were examined at baseline and postintervention. Participants also completed measures of depression, diabetes self-management behaviors, patient activation, and diabetes-related self-efficacy and gave open-ended feedback about the intervention. RESULTS: Feasibility of delivering the intervention in the primary care setting and acceptability to the target population were demonstrated. Among participants completing the intervention, A1C levels decreased significantly from baseline. A significant reduction in depressive symptoms and an improvement in diabetes self-management behaviors, patient activation, and diabetes-related self-efficacy were observed. Qualitative responses from participants indicated unilateral positive responses to the intervention and endorsed its continuation in the clinic. CONCLUSIONS: This pilot trial demonstrated the feasibility and acceptability of an integrated self-management intervention for diabetes and depression. In addition, preliminary data suggest that the intervention may have a positive impact on diabetes and depression-related outcomes. Further evaluation is warranted. PMID- 26590386 TI - Reply: Implementation of a Meningitis Care Bundle in the Emergency Room Reduces Mortality Associated With Acute Bacterial Meningitis. PMID- 26590387 TI - Potential compounds for the treatment of mitochondrial disease. AB - INTRODUCTION: Mitochondrial diseases are a group of heterogeneous disorders for which no curative therapy is currently available. Several drugs are currently being pursued as candidates to correct the underlying biochemistry that causes mitochondrial dysfunction. SOURCES OF DATA: A systematic review of pharmacological therapeutics tested using in vitro, in vivo models and clinical trials. Results presented from database searches undertaken to ascertain compounds currently being pioneered to treat mitochondrial disease. AREAS OF AGREEMENT: Previous clinical research has been hindered by poorly designed trials that have shown some evidence in enhancing mitochondrial function but without significant results. AREAS OF CONTROVERSY: Several compounds under investigation display poor pharmacokinetic profiles or numerous off target effects. GROWING POINTS: Drug development teams should continue to screen existing and novel compound libraries for therapeutics that can enhance mitochondrial function. Therapies for mitochondrial disorders could hold potential cures for a myriad of other ailments associated with mitochondrial dysfunction such as neurodegenerative diseases. PMID- 26590389 TI - Progression to Stage 4 chronic kidney disease and death, acute kidney injury and hospitalization risk: a retrospective cohort study. AB - BACKGROUND: Chronic kidney disease (CKD) Stage 4 is on the path to kidney failure, but there is little information on the risks associated with progression to Stage 4 per se. The objective of this study is to determine how progression from Stage 3 to Stage 4 CKD alters morbidity and mortality in a referred cohort of patients. METHODS: We conducted a retrospective cohort study consisting of 1607 patients with estimated glomerular filtration rate (eGFR) of 30-59 mL/min/1.73 m(2) referred to a nephrologist at a tertiary care center in Ontario, Canada, between January 2001 and December 2008. Interim progression from Stage 3 to Stage 4 chronic kidney disease was defined by two independent outpatient eGFR values <30 mL/min/1.73 m(2). Death, acute kidney injury (AKI) and all-cause hospitalizations subsequent to Stage 4 progression, but prior to the development of end-stage renal disease (ESRD), ascertained from administrative databases. RESULTS: The mean (standard deviation) baseline eGFR was 43 (8) mL/min/1.73 m(2). Over 2.66 years (interquartile range: 1.42-4.45), 344 (21%) patients progressed to Stage 4, 47 (3%) developed ESRD, 188 (12%) patients died, 143 (9%) were hospitalized with AKI and 688 (43%) were hospitalized for any reason. Compared with patients who did not progress to Stage 4, those who did progress had significantly higher adjusted risks of death [hazard ratio (HR) = 2.56, 95% confidence interval (95% CI): 1.75-3.75], AKI (HR = 2.32, 95% CI: 1.44-3.74) and all-cause hospitalization (HR = 1.87, 95% CI: 1.45-2.42). CONCLUSIONS: Progression from Stage 3 to Stage 4 CKD is associated with increased risks of death, AKI and hospitalization prior to ESRD. PMID- 26590390 TI - Perception, diagnosis and management of BK polyomavirus replication and disease in paediatric kidney transplant recipients in Europe. AB - BACKGROUND: BK polyomavirus (BKPyV)-associated nephropathy remains a challenge to the success of kidney transplantation, but its impact varies in different transplant programmes. METHODS: We investigated current practice through a web based questionnaire made available by the European Society for Paediatric Nephrology (ESPN). RESULTS: A total of 90 physicians (23% of 391 active members) from 27 countries participated in the study. BKPyV-associated nephropathy is seen in 1-5% of patients annually with treatment success in 30-60%, and graft loss in 10%. Quantitative BKPyV load testing is available to >90% of physicians. Screening is performed in urine alone in 26%, in urine and blood in 37% and in blood alone in 37%. Most physicians (47%) screen at month 1, 2, 3, 6, 9 and 12 post-transplant. For patients with baseline renal function and plasma BKPyV loads of 10 000-1 000 000 copies/mL, 50% report performing renal biopsies prior to intervention. Intervention consists of reducing immunosuppression first with mycophenolate (Myc) in 40%, first with calcineurin inhibitors (CNI) in 29% or with both in 31%. Changing immunosuppressive drugs is considered mainly for biopsy-proven nephropathy consisting of discontinuation of Myc in 75%, and switching from CNI to mTOR inhibitors (52%). Cidofovir, intravenous immunoglobulin G, leflunomide and fluoroquinolones are used in less than one third of this group. Furthermore, 66% of participants see a need for new antiviral drugs and new immmunosuppressive strategies, and almost 90% are willing to participate in future observational and interventional trials. CONCLUSION: This ESPN survey suggests that prompt translation of a positive screening test into reducing immunosuppression could improve outcomes. PMID- 26590391 TI - A systematic review of the safety and efficacy of distal coronary artery anastomotic devices in MIDCAB and TECAB surgery. AB - BACKGROUND: Minimally invasive direct coronary artery bypass (MIDCAB) and totally endoscopic coronary artery bypass (TECAB) techniques may improve recovery and reduce hospital stay following coronary artery bypass surgery (CABG). However, working in a limited space with indirect visualisation would greatly benefit from a simple, high-quality and reproducible automated distal anastomotic method. Several devices have been developed; however, their uptake has been limited due to uncertainty around their impact on patient outcomes. METHODS: A systematic review of the literature identified six studies, incorporating 139 subjects undergoing MIDCAB or TECAB surgery using a distal anastomotic device. RESULTS: The overall 30-day mortality was 0.7% (1/137). No cardiac specific mortality was observed. For each outcome of perioperative myocardial infarction (MI), postoperative stroke and haemorrhage, only a single event was observed for each (n=1/136, 1/138 and 1/136, respectively). The overall device failure rates were low, with the use of additional sutures only reported in a single case with the Magnetic Vascular Port (MVP) device. Anastomotic time ranged from a mean of 3.32 minutes with the MVP device to 20 minutes with the C-Port device. CONCLUSIONS: These results demonstrate the overall acceptable early outcomes of distal anastomotic devices for use in minimally invasive coronary bypass surgery. Future research should focus on designing adequately powered, comparative, randomised trials, focusing on major adverse cardiac and cerebrovascular events (MACCE) outcomes in both the short and long-term, with clear case-by-case reasons for device failure and a comparison of anastomotic times. In this way, we may determine whether such devices will facilitate the minimal access and robotic coronary procedures of the future. PMID- 26590392 TI - Epstein-Barr futile myocarditis requiring urgent orthotopic heart transplantation. AB - We present the case of a 37-year-old man who was diagnosed with an Epstein-Barr futile myocarditis. The diagnosis was made in the Accident and Emergency Department, with the input of portable echocardiography. The patient subsequently underwent an urgent orthotopic heart transplantation and he has now completely recovered. PMID- 26590393 TI - EVALUATION OF THE RELEASE CRITERIA FROM HOSPITAL OF THYROID CARCINOMA PATIENT TREATED WITH 131I. AB - Patients treated with high doses of 131I for thyroid cancer are generally hospitalised under isolation conditions for up to several days after treatment. The external dose rates from 192 randomised samples of thyroid carcinoma patients were measured at 1 m after 48 h of radioiodine dose administration. The results showed that 12 % of released patients had an external dose rate of >30 uSv h-1 (the release criterion set by the national regulations) whereas 42 % of them had an external dose rates between 11 and 20 uSv h-1 Ninety-two per cent of the patients were released after 48 h. The patient socio-economical conditions were taken into consideration to investigate unnecessary public exposure; only 36 % of the patients had one adult person living with them and 48 % of patients had no children. In addition, 68 % of patients declared that they use the public transport after discharge from hospital. The applied release criteria was successfully respected with a compliance ratio of 90 %, and it was adequate to maintain a suitable level of public radiation protection. PMID- 26590394 TI - MODEL-BASED ITERATIVE RECONSTRUCTION ENABLES THE EVALUATION OF THIN-SLICE COMPUTED TOMOGRAPHY IMAGES WITHOUT DEGRADING IMAGE QUALITY OR INCREASING RADIATION DOSE. AB - Computed tomography (CT) is one of the most important modalities in a radiological department. This technique not only produces images that enable radiological reports with high diagnostic confidence, but it may also provide an elevated radiation dose to the patient. The radiation dose can be reduced by using advanced image reconstruction algorithms. This study was performed on a Brilliance iCT, equipped with iDose(4) iterative reconstruction and an iterative model-based reconstruction (IMR) method. The purpose was to investigate the effect of reduced slice thickness combined with an IMR method on image quality compared with standard slice thickness with iDose(4) reconstruction. The results of objective and subjective image quality evaluations showed that a thinner slice combined with IMR can improve the image quality and reduce partial volume artefacts compared with the standard slice thickness with iDose(4) In conclusion, IMR enables reduction of the slice thickness while maintaining or even improving image quality versus iDose(4). PMID- 26590395 TI - RETROSPECTIVE ESTIMATION OF PATIENT DOSE-AREA PRODUCT IN THORACIC SPINE TOMOSYNTHESIS PERFORMED USING VOLUMERAD. AB - The aim of this study was to evaluate the use of a recently developed method of retrospectively estimating the patient dose-area product (DAP) of a chest tomosynthesis examination, performed using VolumeRAD, in thoracic spine tomosynthesis and to determine the necessary field-size correction factor. Digital imaging and communications in medicine (DICOM) data for the projection radiographs acquired during a thoracic spine tomosynthesis examination were retrieved directly from the modality for 17 patients. Using the previously developed method, an estimated DAP for the tomosynthesis examination was determined from DICOM data in the scout image. By comparing the estimated DAP with the actual DAP registered for the projection radiographs, a field-size correction factor was determined. The field-size correction factor for thoracic spine tomosynthesis was determined to 0.92. Applying this factor to the DAP estimated retrospectively, the maximum difference between the estimated DAP and the actual DAP was <3 %. In conclusion, the previously developed method of retrospectively estimating the DAP in chest tomosynthesis can be applied to thoracic spine tomosynthesis. PMID- 26590396 TI - Troponin-positive chest pain with unobstructed coronary arteries: incremental diagnostic value of cardiovascular magnetic resonance imaging. AB - AIMS: Troponin-positive chest pain patients with unobstructed coronaries represent a clinical dilemma. Cardiovascular magnetic resonance (CMR) imaging has an increasingly prominent role in the assessment of these patients; however, its utility in addition to expert clinical judgement is unclear. We sought to determine the incremental diagnostic value of CMR and the heterogeneity in diagnoses by experienced cardiologists when presented with blinded clinical and investigative data in this population. METHODS AND RESULTS: A total of 125 consecutive patients presenting to a tertiary centre between 2010 and 2014 with cardiac chest pain, elevated troponin (>29 ng/L), and unobstructed coronaries were enrolled and underwent CMR. A panel of three experienced cardiologists unaware of the CMR diagnosis and blinded to each other's assessment provided a diagnosis based on clinical and investigative findings. A consensus panel diagnosis was defined as two or more cardiologists sharing the same clinical diagnosis. Findings were classified into acute myocarditis, Takotsubo cardiomyopathy, acute myocardial infarction (AMI), or indeterminate. CMR provided a diagnosis in 87% of patients. Consensus panel diagnosis and CMR were concordant in 65/125 (52%) patients. There was an only moderate level of agreement between the three cardiologists (k = 0.47, P < 0.05) and a poor level of agreement between the consensus panel and CMR (k = 0.38, P < 0.05) with the most disagreement seen in patients with AMI diagnosed on CMR. CONCLUSION: The clinical diagnosis of patients with non-obstructive coronaries and positive troponin remains a challenge. The concordance between CMR and clinical diagnosis is poor. CMR provides a diagnosis in majority of these patients. PMID- 26590398 TI - Cardiac resynchronization therapy responders can be better identified by specific signatures in myocardial function. PMID- 26590397 TI - Three-dimensional left atrial blood flow characteristics in patients with atrial fibrillation assessed by 4D flow CMR. AB - AIMS: To apply 4D flow cardiac magnetic resonance (CMR) for the volumetric measurement of 3D left atrial (LA) blood flow to evaluate its potential to detect altered LA flow in patients with atrial fibrillation (AF) and to investigate associations of changes in systolic and diastolic LA flow with the current clinical risk score (CHA2DS2-VASc) used for the assessment of thromboembolic risk in AF. METHODS AND RESULTS: 4D flow CMR was performed in 40 patients with a history of AF (in sinus rhythm during CMR scan, age = 61 +/- 11 years), 20 age appropriate controls (59 +/- 7 years), and 10 young healthy volunteers (24 +/- 2 years) to measure in vivo time-resolved 3D LA blood flow. LA velocities were characterized with respect to atrial function and timing by calculating normalized LA flow velocity histograms during ventricular systole, early diastole, mid-late diastole, and the entire cardiac cycle. Mean, median, and peak LA velocity steadily decreased when comparing young volunteers, age-appropriate controls, and AF patients by 10-44% and 8-26% for early diastole and the entire cardiac cycle, respectively (P < 0.01 for all comparisons except median velocity for young vs. older volunteers and peak velocity for older volunteers and AF patients). There were moderate but significant inverse relationships between increased CHA2DS2-VASc score and reduced mean LA velocity (early diastole: r = 0.37, P < 0.001; entire RR-interval: r = -0.33, P = 0.005), median LA velocity (r = -0.33, P = 0.003; r = -0.25, P = 0.017), and peak velocity (r = -0.36, P = 0.001; r = -0.45, P < 0.001). LA flow indices also correlated significantly with age and LA volume (R2 = 0.44-0.62, P < 0.001), but not with left ventricular ejection fraction. CONCLUSION: Left atrial 4D flow CMR demonstrated significantly reduced LA blood flow velocities in patients with AF. Further study is needed to determine whether these measures can improve upon the CHA2DS2-VASc score for stroke risk prediction and enhance individual decisions on anticoagulation in patients with AF. PMID- 26590399 TI - Segmental peri-coronary epicardial adipose tissue volume and coronary plaque characteristics. AB - AIMS: Epicardial adipose tissue (EAT) has been proposed to modulate underlying coronary plaque features. The study aimed to determine the relation between segmental EAT (sEAT) volume, assessed by cardiac magnetic resonance (CMR), and underlying coronary plaque characteristics, as estimated by multidetector computed tomography (CT) (MDCT). METHODS AND RESULTS: The study included 32 male patients with stable angina pectoris and 11 age-matched healthy controls. For each CAD patient, sEAT volume around 8 coronary segments (3 in left anterior descending artery, 3 in right coronary artery, and 2 in left circumflex artery) was quantified by CMR. By MDCT, plaques in each coronary segment were characterized in terms of plaque volume, type, CT attenuation, and severity of luminal stenosis. Serum levels of adipokines were measured. Total EAT volume was significantly higher in CAD patients than in control group. Serum resistin showed significant correlation with EAT volume (r = 0.69, P < 0.001). Analysis of 256 coronary segments showed larger sEAT volume with increasing luminal stenosis of the corresponding segment (mild: 8.2 cm(3); moderate: 11 cm(3); severe: 11.8 cm(3), P < 0.001). sEAT volume was larger in segments with mixed than those with calcified or non-calcified plaques (12.1 vs. 10.2 vs. 9.5 cm(3), respectively, P = 0.015). sEAT volume was larger in segments with low CT attenuation non calcified plaques compared with non-calcified plaques with CT attenuation >30 HU (10.5 vs. 8.2 mm(3), P < 0.001). CONCLUSION: Peri-coronary epicardial adipose tissue volume is significantly associated with the extent and severity of coronary atherosclerosis and may be a determinant of plaque vulnerability. PMID- 26590400 TI - Imaging myocardial inflammation by CMR mapping: good getting better? PMID- 26590401 TI - Perivalvular extension of native mitral valve infective endocarditis with annular fistula and preserved valve function. PMID- 26590402 TI - EffectiveDB--updates and novel features for a better annotation of bacterial secreted proteins and Type III, IV, VI secretion systems. AB - Protein secretion systems play a key role in the interaction of bacteria and hosts. EffectiveDB (http://effectivedb.org) contains pre-calculated predictions of bacterial secreted proteins and of intact secretion systems. Here we describe a major update of the database, which was previously featured in the NAR Database Issue. EffectiveDB bundles various tools to recognize Type III secretion signals, conserved binding sites of Type III chaperones, Type IV secretion peptides, eukaryotic-like domains and subcellular targeting signals in the host. Beyond the analysis of arbitrary protein sequence collections, the new release of EffectiveDB also provides a 'genome-mode', in which protein sequences from nearly complete genomes or metagenomic bins can be screened for the presence of three important secretion systems (Type III, IV, VI). EffectiveDB contains pre calculated predictions for currently 1677 bacterial genomes from the EggNOG 4.0 database and for additional bacterial genomes from NCBI RefSeq. The new, user friendly and informative web portal offers a submission tool for running the EffectiveDB prediction tools on user-provided data. PMID- 26590403 TI - SBR-Blood: systems biology repository for hematopoietic cells. AB - Extensive research into hematopoiesis (the development of blood cells) over several decades has generated large sets of expression and epigenetic profiles in multiple human and mouse blood cell types. However, there is no single location to analyze how gene regulatory processes lead to different mature blood cells. We have developed a new database framework called hematopoietic Systems Biology Repository (SBR-Blood), available online at http://sbrblood.nhgri.nih.gov, which allows user-initiated analyses for cell type correlations or gene-specific behavior during differentiation using publicly available datasets for array- and sequencing-based platforms from mouse hematopoietic cells. SBR-Blood organizes information by both cell identity and by hematopoietic lineage. The validity and usability of SBR-Blood has been established through the reproduction of workflows relevant to expression data, DNA methylation, histone modifications and transcription factor occupancy profiles. PMID- 26590404 TI - FunTree: advances in a resource for exploring and contextualising protein function evolution. AB - FunTree is a resource that brings together protein sequence, structure and functional information, including overall chemical reaction and mechanistic data, for structurally defined domain superfamilies. Developed in tandem with the CATH database, the original FunTree contained just 276 superfamilies focused on enzymes. Here, we present an update of FunTree that has expanded to include 2340 superfamilies including both enzymes and proteins with non-enzymatic functions annotated by Gene Ontology (GO) terms. This allows the investigation of how novel functions have evolved within a structurally defined superfamily and provides a means to analyse trends across many superfamilies. This is done not only within the context of a protein's sequence and structure but also the relationships of their functions. New measures of functional similarity have been integrated, including for enzymes comparisons of overall reactions based on overall bond changes, reaction centres (the local environment atoms involved in the reaction) and the sub-structure similarities of the metabolites involved in the reaction and for non-enzymes semantic similarities based on the GO. To identify and highlight changes in function through evolution, ancestral character estimations are made and presented. All this is accessible through a new re-designed web interface that can be found at http://www.funtree.info. PMID- 26590405 TI - TSGene 2.0: an updated literature-based knowledgebase for tumor suppressor genes. AB - Tumor suppressor genes (TSGs) are a major type of gatekeeper genes in the cell growth. A knowledgebase with the systematic collection and curation of TSGs in multiple cancer types is critically important for further studying their biological functions as well as for developing therapeutic strategies. Since its development in 2012, the Tumor Suppressor Gene database (TSGene), has become a popular resource in the cancer research community. Here, we reported the TSGene version 2.0, which has substantial updates of contents (e.g. up-to-date literature and pan-cancer genomic data collection and curation), data types (noncoding RNAs and protein-coding genes) and content accessibility. Specifically, the current TSGene 2.0 contains 1217 human TSGs (1018 protein coding and 199 non-coding genes) curated from over 9000 articles. Additionally, TSGene 2.0 provides thousands of expression and mutation patterns derived from pan-cancer data of The Cancer Genome Atlas. A new web interface is available at http://bioinfo.mc.vanderbilt.edu/TSGene/. Systematic analyses of 199 non-coding TSGs provide numerous cancer-specific non-coding mutational events for further screening and clinical use. Intriguingly, we identified 49 protein-coding TSGs that were consistently down-regulated in 11 cancer types. In summary, TSGene 2.0, which is the only available database for TSGs, provides the most updated TSGs and their features in pan-cancer. PMID- 26590406 TI - CancerResource--updated database of cancer-relevant proteins, mutations and interacting drugs. AB - Here, we present an updated version of CancerResource, freely available without registration at http://bioinformatics.charite.de/care. With upcoming information on target expression and mutations in patients' tumors, the need for systems supporting decisions on individual therapy is growing. This knowledge is based on numerous, experimentally validated drug-target interactions and supporting analyses such as measuring changes in gene expression using microarrays and HTS efforts on cell lines. To enable a better overview about similar drug-target data and supporting information, a series of novel information connections are established and made available as described in the following. CancerResource contains about 91,000 drug-target relations, more than 2000 cancer cell lines and drug sensitivity data for about 50,000 drugs. CancerResource enables the capability of uploading external expression and mutation data and comparing them to the database's cell lines. Target genes and compounds are projected onto cancer-related pathways to get a better overview about how drug-target interactions benefit the treatment of cancer. Features like cellular fingerprints comprising of mutations, expression values and drug-sensitivity data can promote the understanding of genotype to drug sensitivity associations. Ultimately, these profiles can also be used to determine the most effective drug treatment for a cancer cell line most similar to a patient's tumor cells. PMID- 26590407 TI - GenBank. AB - GenBank((r)) (www.ncbi.nlm.nih.gov/genbank/) is a comprehensive database that contains publicly available nucleotide sequences for over 340 000 formally described species. Recent developments include a new starting page for submitters, a shift toward using accession.version identifiers rather than GI numbers, a wizard for submitting 16S rRNA sequences, and an Identical Protein Report to address growing issues of data redundancy. GenBank organizes the sequence data received from individual laboratories and large-scale sequencing projects into 18 divisions, and GenBank staff assign unique accession.version identifiers upon data receipt. Most submitters use the web-based BankIt or standalone Sequin programs. Daily data exchange with the European Nucleotide Archive (ENA) and the DNA Data Bank of Japan (DDBJ) ensures worldwide coverage. GenBank is accessible through the nuccore, nucest, and nucgss databases of the Entrez retrieval system, which integrates these records with a variety of other data including taxonomy nodes, genomes, protein structures, and biomedical journal literature in PubMed. BLAST provides sequence similarity searches of GenBank and other sequence databases. Complete bimonthly releases and daily updates of the GenBank database are available by FTP. PMID- 26590408 TI - Infections, infarction, and heart failure: prevention and management. PMID- 26590409 TI - The 2015 ESC Guidelines for the management of infective endocarditis. AB - Take-home message of the full 2015 ESC Guidelines, also endorsed by the European Association for Cardio-Thoracic Surgery, European Association of Nuclear Medicine, and European Society of Clinical Microbiology and Infectious Diseases. PMID- 26590410 TI - Matters of Size. PMID- 26590411 TI - When Science Is a Family Tradition. PMID- 26590412 TI - Siri, What Should I Eat? AB - Zeevi et al. report that extensive monitoring of a human cohort for variations in dietary intake, lifestyle, host phenotype, and the gut microbiome has enabled the development of a machine-learning algorithm that accurately predicts the individual glycemic response to meals, providing an important first step toward personalized nutrition. PMID- 26590413 TI - Potent Antibody Protection against an Emerging Alphavirus Threat. AB - Chikungunya virus recently caused large outbreaks world-wide. In this issue of Cell, Fox et al. describe several potently neutralizing antibodies against multiple alphaviruses. The structure of the virus in complex with one of the antibodies reveals the antibody-induced rearrangement and crosslinking of the viral surface proteins that result in neutralization. PMID- 26590414 TI - A Common Mechanism that Underpins Antibody Diversification. AB - Targeting of AID to antibody variable (V) regions results in somatic hypermutation, whereas its recruitment to switch (S) regions leads to class switch recombination. Yeap et al. find that the mechanism by which variable and switch regions recruit AID essentially is the same but that the two regions differ in the density of double-stranded DNA breaks that are generated. These lead to either point mutations in V exons in somatic hypermutation or deletion of intervening DNA sequences during class switch recombination. PMID- 26590415 TI - Microbiota's No Wasting Policy. AB - Schieber et al. demonstrate that a specific gut microbiota bacterial strain induces a host-mediated protection mechanism against inflammation-driven wasting syndrome. This salutary effect confers a net survival advantage against bacterial infection, without interfering with the host's pathogen load, revealing that host microbiota interactions regulate disease tolerance to infection. PMID- 26590416 TI - Improving Cancer Treatment via Mathematical Modeling: Surmounting the Challenges Is Worth the Effort. AB - Drug delivery schedules are key factors in the efficacy of cancer therapies, and mathematical modeling of population dynamics and treatment responses can be applied to identify better drug administration regimes as well as provide mechanistic insights. To capitalize on the promise of this approach, the cancer field must meet the challenges of moving this type of work into clinics. PMID- 26590418 TI - Personalized Nutrition by Prediction of Glycemic Responses. AB - Elevated postprandial blood glucose levels constitute a global epidemic and a major risk factor for prediabetes and type II diabetes, but existing dietary methods for controlling them have limited efficacy. Here, we continuously monitored week-long glucose levels in an 800-person cohort, measured responses to 46,898 meals, and found high variability in the response to identical meals, suggesting that universal dietary recommendations may have limited utility. We devised a machine-learning algorithm that integrates blood parameters, dietary habits, anthropometrics, physical activity, and gut microbiota measured in this cohort and showed that it accurately predicts personalized postprandial glycemic response to real-life meals. We validated these predictions in an independent 100 person cohort. Finally, a blinded randomized controlled dietary intervention based on this algorithm resulted in significantly lower postprandial responses and consistent alterations to gut microbiota configuration. Together, our results suggest that personalized diets may successfully modify elevated postprandial blood glucose and its metabolic consequences. VIDEO ABSTRACT. PMID- 26590419 TI - Htr2a-Expressing Cells in the Central Amygdala Control the Hierarchy between Innate and Learned Fear. AB - Fear is induced by innate and learned mechanisms involving separate pathways. Here, we used an olfactory-mediated innate-fear versus learned-fear paradigm to investigate how these pathways are integrated. Notably, prior presentation of innate-fear stimuli inhibited learned-freezing response, but not vice versa. Whole-brain mapping and pharmacological screening indicated that serotonin-2A receptor (Htr2a)-expressing cells in the central amygdala (CeA) control both innate and learned freezing, but in opposing directions. In vivo fiber photometry analyses in freely moving mice indicated that innate but not learned-fear stimuli suppressed the activity of Htr2a-expressing CeA cells. Artificial inactivation of these cells upregulated innate-freezing response and downregulated learned freezing response. Thus, Htr2a-expressing CeA cells serve as a hierarchy generator, prioritizing innate fear over learned fear. PMID- 26590417 TI - Establishment and Dysfunction of the Blood-Brain Barrier. AB - Structural and functional brain connectivity, synaptic activity, and information processing require highly coordinated signal transduction between different cell types within the neurovascular unit and intact blood-brain barrier (BBB) functions. Here, we examine the mechanisms regulating the formation and maintenance of the BBB and functions of BBB-associated cell types. Furthermore, we discuss the growing evidence associating BBB breakdown with the pathogenesis of inherited monogenic neurological disorders and complex multifactorial diseases, including Alzheimer's disease. PMID- 26590420 TI - Dopamine Neurons Encoding Long-Term Memory of Object Value for Habitual Behavior. AB - Dopamine neurons promote learning by processing recent changes in reward values, such that reward may be maximized. However, such a flexible signal is not suitable for habitual behaviors that are sustained regardless of recent changes in reward outcome. We discovered a type of dopamine neuron in the monkey substantia nigra pars compacta (SNc) that retains past learned reward values stably. After reward values of visual objects are learned, these neurons continue to respond differentially to the objects, even when reward is not expected. Responses are strengthened by repeated learning and are evoked upon presentation of the objects long after learning is completed. These "sustain-type" dopamine neurons are confined to the caudal-lateral SNc and project to the caudate tail, which encodes long-term value memories of visual objects and guides gaze automatically to stably valued objects. This population of dopamine neurons thus selectively promotes learning and retention of habitual behavior. PMID- 26590421 TI - Hippocampal Dopamine/DRD1 Signaling Dependent on the Ghrelin Receptor. AB - The ghrelin receptor (GHSR1a) and dopamine receptor-1 (DRD1) are coexpressed in hippocampal neurons, yet ghrelin is undetectable in the hippocampus; therefore, we sought a function for apo-GHSR1a. Real-time single-molecule analysis on hippocampal neurons revealed dimerization between apo-GHSR1a and DRD1 that is enhanced by DRD1 agonism. In addition, proximity measurements support formation of preassembled apo-GHSR1a:DRD1:Galphaq heteromeric complexes in hippocampal neurons. Activation by a DRD1 agonist produced non-canonical signal transduction via Galphaq-PLC-IP3-Ca(2+) at the expense of canonical DRD1 Galphas cAMP signaling to result in CaMKII activation, glutamate receptor exocytosis, synaptic reorganization, and expression of early markers of hippocampal synaptic plasticity. Remarkably, this pathway is blocked by genetic or pharmacological inactivation of GHSR1a. In mice, GHSR1a inactivation inhibits DRD1-mediated hippocampal behavior and memory. Our findings identify a previously unrecognized mechanism essential for DRD1 initiation of hippocampal synaptic plasticity that is dependent on GHSR1a, and independent of cAMP signaling. PMID- 26590422 TI - Descending Command Neurons in the Brainstem that Halt Locomotion. AB - The episodic nature of locomotion is thought to be controlled by descending inputs from the brainstem. Most studies have largely attributed this control to initiating excitatory signals, but little is known about putative commands that may specifically determine locomotor offset. To link identifiable brainstem populations to a potential locomotor stop signal, we used developmental genetics and considered a discrete neuronal population in the reticular formation: the V2a neurons. We find that those neurons constitute a major excitatory pathway to locomotor areas of the ventral spinal cord. Selective activation of V2a neurons of the rostral medulla stops ongoing locomotor activity, owing to an inhibition of premotor locomotor networks in the spinal cord. Moreover, inactivation of such neurons decreases spontaneous stopping in vivo. Therefore, the V2a "stop neurons" represent a glutamatergic descending pathway that favors immobility and may thus help control the episodic nature of locomotion. PMID- 26590424 TI - Post-transcriptional Wnt Signaling Governs Epididymal Sperm Maturation. AB - The canonical Wnt signaling pathway is of paramount importance in development and disease. An emergent question is whether the upstream cascade of the canonical Wnt pathway has physiologically relevant roles beyond beta-catenin-mediated transcription, which is difficult to study due to the pervasive role of this protein. Here, we show that transcriptionally silent spermatozoa respond to Wnt signals released from the epididymis and that mice mutant for the Wnt regulator Cyclin Y-like 1 are male sterile due to immotile and malformed spermatozoa. Post transcriptional Wnt signaling impacts spermatozoa through GSK3 by (1) reducing global protein poly-ubiquitination to maintain protein homeostasis; (2) inhibiting septin 4 phosphorylation to establish a membrane diffusion barrier in the sperm tail; and (3) inhibiting protein phosphatase 1 to initiate sperm motility. The results indicate that Wnt signaling orchestrates a rich post transcriptional sperm maturation program and invite revisiting transcription independent Wnt signaling in somatic cells as well. PMID- 26590423 TI - Calcium and SOL Protease Mediate Temperature Resetting of Circadian Clocks. AB - Circadian clocks integrate light and temperature input to remain synchronized with the day/night cycle. Although light input to the clock is well studied, the molecular mechanisms by which circadian clocks respond to temperature remain poorly understood. We found that temperature phase shifts Drosophila circadian clocks through degradation of the pacemaker protein TIM. This degradation is mechanistically distinct from photic CRY-dependent TIM degradation. Thermal TIM degradation is triggered by cytosolic calcium increase and CALMODULIN binding to TIM and is mediated by the atypical calpain protease SOL. This thermal input pathway and CRY-dependent light input thus converge on TIM, providing a molecular mechanism for the integration of circadian light and temperature inputs. Mammals use body temperature cycles to keep peripheral clocks synchronized with their brain pacemaker. Interestingly, downregulating the mammalian SOL homolog SOLH blocks thermal mPER2 degradation and phase shifts. Thus, we propose that circadian thermosensation in insects and mammals share common principles. PMID- 26590425 TI - K-Ras Promotes Tumorigenicity through Suppression of Non-canonical Wnt Signaling. AB - K-Ras and H-Ras share identical effectors and have similar properties; however, the high degree of tumor-type specificity associated with K-Ras and H-Ras mutations suggests that they have unique roles in oncogenesis. Here, we report that oncogenic K-Ras, but not H-Ras, suppresses non-canonical Wnt/Ca(2+) signaling, an effect that contributes strongly to its tumorigenic properties. K Ras does this by binding to calmodulin and so reducing CaMKii activity and expression of Fzd8. Restoring Fzd8 in K-Ras mutant pancreatic cells suppresses malignancy, whereas depletion of Fzd8 in H-Ras(V12)-transformed cells enhances their tumor initiating capacity. Interrupting K-Ras-calmodulin binding using genetic means or by treatment with an orally active protein kinase C (PKC) activator, prostratin, represses tumorigenesis in K-Ras mutant pancreatic cancer cells. These findings provide an alternative way to selectively target this "undruggable" protein. PMID- 26590427 TI - SnapShot: Hypoxia-Inducible Factors. AB - Molecular oxygen (O2) is a key substrate for mitochondrial ATP production and numerous intracellular biochemical reactions. The maintenance of O2 homeostasis is therefore essential for the survival of most species. During O2 deprivation, mammalian cells rely on multiple adaptations mediated by the hypoxia-inducible factors (HIFs), mTOR, autophagy, and the ER stress response. This SnapShot will summarize recent reports expanding our current understanding of HIF-dependent adaptations to low O2 levels. PMID- 26590426 TI - Coupling of mRNA Structure Rearrangement to Ribosome Movement during Bypassing of Non-coding Regions. AB - Nearly half of the ribosomes translating a particular bacteriophage T4 mRNA bypass a region of 50 nt, resuming translation 3' of this gap. How this large scale, specific hop occurs and what determines whether a ribosome bypasses remain unclear. We apply single-molecule fluorescence with zero-mode waveguides to track individual Escherichia coli ribosomes during translation of T4's gene 60 mRNA. Ribosomes that bypass are characterized by a 10- to 20-fold longer pause in a non canonical rotated state at the take-off codon. During the pause, mRNA secondary structure rearrangements are coupled to ribosome forward movement, facilitated by nascent peptide interactions that disengage the ribosome anticodon-codon interactions for slippage. Close to the landing site, the ribosome then scans mRNA in search of optimal base-pairing interactions. Our results provide a mechanistic and conformational framework for bypassing, highlighting a non canonical ribosomal state to allow for mRNA structure refolding to drive large scale ribosome movements. PMID- 26590428 TI - Comparison of computed tomography and magnetic resonance imaging in the discrimination of intraperitoneal and extraperitoneal rectal cancer: initial experience. AB - OBJECTIVES: To compare computed tomography (CT) and magnetic resonance imaging (MRI) in evaluation of intraperitoneal/extraperitoneal location of rectal cancers. METHODS AND MATERIALS: We assessed the identification of the anterior peritoneal reflection (APR) and the distance from the inferior edge of tumors to the anal verge and from the APR to the anal verge. RESULTS: Distances obtained with CT and MRI showed a strong correlation [Spearman's coefficient of rank correlation (rho): 0.995; P<.0001]. Magnetic resonance showed sensitivity of 100% (95% CI: 89.62-100.00%), specificity of 75% (95% CI: 20.34-95.88%), positive predictive value (PPV) of 97.14% (95% CI: 85.03-99.52%), and negative predictive value (NPV) of 100% (95% CI: 30.48-100.00%). CT showed a sensitivity of 100% (95% CI: 89.32-100.00%), specificity of 60% (95% CI: 15.40-93.51%), PPV of 94.29% (95% CI: 80.81-99.13%), and NPV of 100% (95% CI: 30.48-100.00%). CONCLUSIONS: CT demonstrated a potential supporting role in the evaluation of rectal cancer, showing a strong correlation with MRI. PMID- 26590429 TI - Anger profiles in social anxiety disorder. AB - Individuals with social anxiety disorder (SAD) exhibit elevated levels of anger and anger suppression, which are both associated with increased depression, diminished quality of life, and poorer treatment outcomes. However, little is known about how anger experiences differ among individuals with SAD and whether any heterogeneity might relate to negative outcomes. This investigation sought to empirically define anger profiles among 136 treatment-seeking individuals with SAD and to assess their association with distress and impairment. A latent class analysis was conducted utilizing the trait subscales of the State-Trait Anger Expression Inventory-2 as indicators of class membership. Analysis revealed four distinct anger profiles, with greatest distress and impairment generally demonstrated by individuals with elevated trait anger, a greater tendency to suppress the expression of anger, and diminished ability to adaptively control their anger expression. These results have implications for tailoring more effective interventions for socially anxious individuals. PMID- 26590430 TI - Fostering Further Successes in Vaccinology. PMID- 26590431 TI - Prospects for a Globally Effective HIV-1 Vaccine. AB - A globally effective vaccine strategy must cope with the broad genetic diversity of HIV and contend with multiple transmission modalities. Understanding correlates of protection and the role of diversity in limiting protective vaccines with those correlates is key. RV144 was the first HIV-1 vaccine trial to demonstrate efficacy against HIV-1 infection. A correlates analysis comparing vaccine-induced immune responses in vaccinated-infected and vaccinated-uninfected volunteers suggested that IgG specific for the V1V2 region of gp120 was associated with reduced risk of HIV-1 infection and that plasma Env IgA was directly correlated with infection risk. RV144 and recent non-human primate (NHP) challenge studies suggest that Env is essential and perhaps sufficient to induce protective antibody responses against mucosally acquired HIV-1. Whether RV144 immune correlates can apply to different HIV vaccines, to populations with different modes and intensity of transmission, or to divergent HIV-1 subtypes remains unknown. Newer prime-boost mosaic and conserved sequence immunization strategies aiming at inducing immune responses of greater breadth and depth as well as the development of immunogens inducing broadly neutralizing antibodies should be actively pursued. Efficacy trials are now planned in heterosexual populations in southern Africa and men who have sex with men in Thailand. Although NHP challenge studies may guide vaccine development, human efficacy trials remain key to answer the critical questions leading to the development of a global HIV-1 vaccine for licensure. PMID- 26590433 TI - Trials and Tribulations on the Path to Developing a Dengue Vaccine. AB - Dengue is a rapidly expanding global health problem. Development of a safe and efficacious tetravalent vaccine along with strategic application of vector control activities represents a promising approach to reducing the global disease burden. Although many vaccine development challenges exist, numerous candidates are in clinical development and one has been tested in three clinical endpoint studies. The results of these studies have raised numerous questions about how we measure vaccine immunogenicity and how these readouts are associated with clinical outcomes in vaccine recipients who experience natural infection. In this review the authors discuss the dengue vaccine pipeline, development challenges, the dengue vaccine-immunologic profiling intersection, and research gaps. PMID- 26590434 TI - Vaccines for Prevention of Group B Meningococcal Disease: Not Your Father's Vaccines. AB - For decades, there was no licensed vaccine for prevention of endemic capsular group B meningococcal disease, despite the availability of vaccines for prevention of the other most common meningococcal capsular groups. Recently, however, two new vaccines have been licensed for prevention of group B disease. Although immunogenic and considered to have an acceptable safety profile, there are many scientific unknowns about these vaccines, including effectiveness against antigenically diverse endemic meningococcal strains; duration of protection; whether they provide any herd protection; and whether there will be meningococcal antigenic changes that will diminish effectiveness over time. In addition, these vaccines present societal dilemmas that could influence how they are used in the U.S., including high vaccine cost in the face of a historically low incidence of meningococcal disease. These issues are discussed in this review. PMID- 26590432 TI - The March Toward Malaria Vaccines. AB - In 2013 there were an estimated 584,000 deaths and 198 million clinical illnesses due to malaria, the majority in sub-Saharan Africa. Vaccines would be the ideal addition to the existing armamentarium of anti-malaria tools. However, malaria is caused by parasites, and parasites are much more complex in terms of their biology than the viruses and bacteria for which we have vaccines, passing through multiple stages of development in the human host, each stage expressing hundreds of unique antigens. This complexity makes it more difficult to develop a vaccine for parasites than for viruses and bacteria, since an immune response targeting one stage may not offer protection against a later stage, because different antigens are the targets of protective immunity at different stages. Furthermore, depending on the life cycle stage and whether the parasite is extra- or intra cellular, antibody and/or cellular immune responses provide protection. It is thus not surprising that there is no vaccine on the market for prevention of malaria, or any human parasitic infection. In fact, no vaccine for any disease with this breadth of targets and immune responses exists. In this limited review, we focus on four approaches to malaria vaccines, (1) a recombinant protein with adjuvant vaccine aimed at Plasmodium falciparum (Pf) pre-erythrocytic stages of the parasite cycle (RTS,S/AS01), (2) whole sporozoite vaccines aimed at Pf pre erythrocytic stages (PfSPZ Vaccine and PfSPZ-CVac), (3) prime boost vaccines that include recombinant DNA, viruses and bacteria, and protein with adjuvant aimed primarily at Pf pre-erythrocytic, but also asexual erythrocytic stages, and (4) recombinant protein with adjuvant vaccines aimed at Pf and Plasmodium vivax sexual erythrocytic and mosquito stages. We recognize that we are not covering all approaches to malaria vaccine development, or most of the critically important work on development of vaccines against P. vivax, the second most important cause of malaria. Progress during the last few years has been significant, and a first generation malaria candidate vaccine, RTS,S/AS01, is under review by the European Medicines Agency (EMA) for its quality, safety and efficacy under article 58, which allows the EMA to give a scientific opinion about products intended exclusively for markets outside of the European Union. However, much work is in progress to optimize malaria vaccines in regard to magnitude and durability of protective efficacy and the financing and practicality of delivery. Thus, we are hopeful that anti-malaria vaccines will soon be important tools in the battle against malaria. PMID- 26590435 TI - Prospects for Broadly Protective Influenza Vaccines. AB - The development of vaccines that could provide broad protection against antigenically variant influenza viruses has long been the ultimate prize in influenza research. Recent developments have pushed us closer to this goal, and such vaccines may now be within reach. This brief review outlines the current approaches to broadly protective vaccines, and the probable hurdles and roadblocks to achieving this goal. PMID- 26590436 TI - Enhancing Vaccine Safety Capacity Globally: A Lifecycle Perspective. AB - Major vaccine safety controversies have arisen in several countries beginning in the last decades of 20th century. Such periodic vaccine safety controversies are unlikely to go away in the near future as more national immunization programs mature with near elimination of target vaccine-preventable diseases that result in relative greater prominence of adverse events following immunizations, both true reactions and temporally coincidental events. There are several ways in which vaccine safety capacity can be improved to potentially mitigate the impact of future vaccine safety controversies. This paper aims to take a "lifecycle" approach, examining some potential pre- and post-licensure opportunities to improve vaccine safety, in both developed (specifically U.S. and Europe) and low- and middle-income countries. PMID- 26590437 TI - Value of Post-Licensure Data on Benefits and Risks of Vaccination to Inform Vaccine Policy: The Example of Rotavirus Vaccines. AB - In 1999, the first rhesus-human reassortant rotavirus vaccine licensed in the U.S. was withdrawn within a year of its introduction after it was linked with intussusception at a rate of ~1 excess case per 10,000 vaccinated infants. While clinical trials of 60,000-70,000 infants of each of the two current live oral rotavirus vaccines, RotaTeq (RV5) and Rotarix (RV1), did not find an association with intussusception, post-licensure studies have documented a risk in several high and middle income countries, at a rate of ~1-6 excess cases per 100,000 vaccinated infants. However, considering this low risk against the large health benefits of vaccination that have been observed in many countries, including in countries with a documented vaccine-associated intussusception risk, policy makers and health organizations around the world continue to support the routine use of RV1 and RV5 in national infant immunization programs. Because the risk and benefit data from affluent settings may not be directly applicable to developing countries, further characterization of any associated intussusception risk following rotavirus vaccination as well as the health benefits of vaccination is desirable for low income settings. PMID- 26590438 TI - Pneumococcal Disease Prevention Among Adults: Strategies for the Use of Pneumococcal Vaccines. AB - Use of the pneumococcal conjugate vaccines among children in the U.S. since 2000 has dramatically reduced pneumococcal disease burden among adults. Significant vaccine-preventable morbidity and mortality from pneumococcal infections still remains, especially among older adults. The U.S. Advisory Committee on Immunization Practices (ACIP) has recently recommended the routine use of both pneumococcal conjugate (PCV13) and polysaccharide vaccines (PPSV23) for adults >=65 years. These recommendations were based on the remaining burden of illness among adults and the importance of non-bacteremic pneumonia prevention in light of new evidence confirming the efficacy of PCV13 to prevent pneumococcal pneumonia among older adults. This paper reviews the evidence that led ACIP to make recommendations for PCV13 and PPSV23 use among adults, and highlights potential gaps to be addressed by future studies to inform adult vaccination policy. The changing epidemiology of invasive pneumococcal disease and pneumonia should be closely monitored to evaluate the effectiveness and continued utility of the current vaccination strategy, and to identify future directions for pneumococcal disease prevention among older adults. PMID- 26590439 TI - Overview of Conventional Imaging-based Intervention in Clinical Practice. AB - This article presents an overview of image-guided interventions using conventionally available imaging modalities. It discusses technical and clinical aspects of the interventions, and also focuses on site-specific biopsies such as liver, spleen, renal, and soft tissue biopsies in the abdomen. It briefly discusses the emerging role of PET imaging and other technologies that will improve the diagnostic yield of image-guided biopsies. PMID- 26590440 TI - Special Techniques in PET/Computed Tomography Imaging for Evaluation of Head and Neck Cancer. AB - PET with fluorodeoxyglucose F 18 (FDG)/computed tomography (CT) imaging has significantly improved the management of head and neck cancer. FDG, however, is not tumor-specific and various image interpretation pitfalls may occur because of false-positive and -negative causes of FDG uptake. Routine imaging examination of head and neck malignancies does not yield all of the necessary data, even with the most advanced imaging technique. Specific interventions, such as use of different dynamic maneuvers and pharmacologic interventions, may provide useful information about the lesion. This article reviews the use of special techniques in FDG PET/CT imaging and whole-body FDG PET/CT imaging for evaluation of head and neck cancer. PMID- 26590441 TI - Recent Advances in Imaging of Small and Large Bowel. AB - The diagnosis of bowel pathology is challenging in view of the nonspecific clinical presentation. Currently, there are various imaging modalities available to reach an accurate diagnosis. These modalities include conventional techniques (radiographs, small bowel follow-through, conventional enteroclysis), ultrasonography, and cross-sectional examinations (computed tomography [CT] and MR imaging) as well as functional imaging modalities, such as PET-CT or PET-MR imaging. Each modality has its own advantages and disadvantages and can be used in isolation or combination. This review discusses the role of CT, MR imaging, and PET-CT in the evaluation of small and large bowel diseases. PMID- 26590443 TI - Role of PET/Computed Tomography in Radiofrequency Ablation for Malignant Pulmonary Tumors. AB - Radiofrequency ablation (RFA) is a useful tool for local control of unresectable pulmonary neoplastic lesions. However, RFA is limited to tumors smaller than 4 cm and peripheral lesions. The sensitivity and specificity of FDG-PET are higher than those of computed tomography. FDG-PET at 3 to 6 months after RFA is important for predicting recurrence. Complications associated with RFA, such as infection and abscess formation, which concentrate glucose in the ablation area, can cause false-positive findings in PET examination. Knowledge of the morphologic imaging features of these complications is important in avoiding these potential pitfalls. PMID- 26590442 TI - Diuretic 18F-Fluorodeoxyglucose PET/Computed Tomography in Evaluation of Genitourinary Malignancies. AB - The interpretation of fluorodeoxyglucose (FDG) PET/computed tomography (CT) is often challenging for pelvic pathologies because of the physiologic bowel and urinary tract activity. Intense radiotracer activity in urinary tract interferes in image interpretation and leads to false-negative results in diagnosis and detection of local recurrence and regional lymph node metastases. It is imperative to minimize unnecessary urinary bladder activity to improve the diagnostic yield of PET/CT. All the techniques described in the literature have their pros and cons. This article discusses FDG PET/CT in evaluation of urinary bladder cancer, cervical cancer, and ovarian cancer. PMID- 26590444 TI - Fluorodeoxyglucose-PET/Computed Tomography-Guided Biopsy. AB - PET/computed tomography (CT) combines the anatomic information from CT with PET metabolic characterization. 18F-fluorodeoxyglucose (FDG) PET is helpful to differentiate malignant lesions from benign ones, that usually show lower or no uptake. However, active inflammation or infectious disease might also present FDG uptake. Studies confirm the great value of PET/CT as the imaging method of choice for guiding biopsy procedures. Novel PET radiopharmaceuticals are also being investigated for guiding biopsies. PMID- 26590445 TI - Dual-time-point Imaging and Delayed-time-point Fluorodeoxyglucose-PET/Computed Tomography Imaging in Various Clinical Settings. AB - The techniques of dual-time-point imaging (DTPI) and delayed-time-point imaging, which are mostly being used for distinction between inflammatory and malignant diseases, has increased the specificity of fluorodeoxyglucose (FDG)-PET for diagnosis and prognosis of certain diseases. A gradually increasing trend of FDG uptake over time has been shown in malignant cells, and a decreasing or constant trend has been shown in inflammatory/infectious processes. Tumor heterogeneity can be assessed by using early and delayed imaging because differences between primary versus metastatic sites become more detectable compared with single time points. This article discusses the applications of DTPI and delayed-time-point imaging. PMID- 26590446 TI - Contrast Media in PET/Computed Tomography Imaging. AB - Is there a need for the contrast-enhanced PET/computed tomography (CT) scan or is the low-dose, non-contrast-enhanced PET/CT scan sufficient? The topic has been debated time and again. Although low-dose noncontrast CT serves the purpose of simple anatomic correlation and attenuation correction of PET images, many times patients have to undergo additional contrast-enhanced diagnostic imaging modalities, which may lead to a delay in decision-making. In this review, the authors have addressed various such issues related to the use of contrast agents and special techniques of clinical interest based on their utility in dual modality PET/CT. PMID- 26590447 TI - Special Techniques and Technical Advances in PET/Computed Tomographic Imaging. PMID- 26590449 TI - Effect of heat on firefighters' work performance and physiology. AB - Wildland firefighters often perform their duties under both hot and mild ambient temperatures. However, the direct impact of different ambient temperatures on firefighters' work performance has not been quantified. This study compared firefighters' work performance and physiology during simulated wildland firefighting work in hot (HOT; 32 degrees C, 43% RH) and temperate (CON; 19 degrees C, 56% RH) conditions. Firefighters (n=38), matched and allocated to either the CON (n=18) or HOT (n=20) condition, performed simulated self-paced wildland fire suppression tasks (e.g., hose rolling/dragging, raking) in firefighting clothing for six hours, separated by dedicated rest breaks. Task repetitions were counted (and converted to distance or area). Core temperature (Tc), skin temperature (Tsk), and heart rate were recorded continuously throughout the protocol. Urine output was measured before and during the protocol, and urine specific gravity (USG) analysed, to estimate hydration. Ad libitum fluid intake was also recorded. There were no differences in overall work output between conditions for any physical task. Heart rate was higher in the HOT (55+/-2% HRmax) compared to the CON condition (51+/-2% HRmax) for the rest periods between bouts, and for the static hose hold task (69+/-3% HRmax versus 65+/-3% HRmax). Tc and Tsk were 0.3+/-0.1 degrees C and 3.1+/-0.2 degrees C higher in the HOT compared to the CON trial. Both pre- and within- shift fluid intake were increased two-fold in the heat, and participants in the heat recorded lower USG results than their CON counterparts. There was no difference between the CON and HOT conditions in terms of their work performance, and firefighters in both experimental groups increased their work output over the course of the simulated shift. Though significantly hotter, participants in the heat also managed to avoid excessive cardiovascular and thermal strain, likely aided by the frequent rest breaks in the protocol, and through doubling their fluid intake. Therefore, it can be concluded that wildland firefighters are able to safely and efficiently perform their duties under hot conditions, at least over six hours. PMID- 26590450 TI - Temperature-dependent development in Chrysomela vigintipunctata (Coleoptera: Chrysomelidae), a stenothermal early-season breeder. AB - Chrysomela vigintipunctata (Scopoli) is a univoltine leaf beetle commonly encountered on willows across the Palearctic forest zone. The preimaginal development in this species takes place during a short time period, from May to June, because larvae are unable to consume mature leaves of the host plant. Therefore, the diet quality imposes a time constraint, and it was expected that the temperature dependence of development in C. vigintipunctata should be adaptively adjusted to the shortness and cool conditions of the favorable season. It was experimentally determined that this leaf beetle was stenothermal at the larval stage, required 275.5 degree-days above the threshold of 9.0 degrees C for total development from oviposition to adult emergence, and attained greater body mass at lower temperatures. However, in all of these aspects, the thermal ecology of C. vigintipunctata was similar to that of two related multivoltine species, C. populi and C. scripta. The interspecific similarity of thermal reaction norms for development rate and body size suggests that these reaction norms in C. vigintipunctata were unlikely to have been shaped by selection favoring faster development or growth early in the season. The results are discussed in terms of the "ecological fitting" concept, which states that a species may be successful in exploiting novel environments while retaining ecophysiological traits evolved elsewhere. PMID- 26590451 TI - Temperature preferences of African mole-rats (family Bathyergidae). AB - Many animals are able to detect small temperature differences and show strong temperature preferences during periods of rest and activity. Mammals inhabiting the subterranean ecotope can adapt their digging and foraging activity in shallow tunnels temporarily to periods with favourable ambient air and soil temperatures. Moreover, subterranean mammals have the unique opportunity to select for their nests in soil depths with certain, daily and seasonally constant temperatures. Our knowledge on nest temperatures in several species of subterranean mammals is based on measurements of temperatures in empty nests. We can expect, however, that the temperature in an occupied nest is higher (due to the "igloo effect"). We performed two experiments regarding the temperature preference in five species of African mole-rats (Bathyergidae, Rodentia: Fukomys anselli, F. mechowii, F. micklemi, Heliophobius argenteocinereus, and Heterocephalus glaber). In a first experiment, the animals were tested pairwise (except for the solitary silvery mole-rats, H. argenteocinereus, that were tested singly) in an apparatus consisting of seven chambers with a temperature gradient ranging between 16 and 37 degrees C (air temperature). While the smaller species (<110g; F. anselli, F. micklemi, H. glaber) chose chambers with average air temperatures around 29 degrees C, the larger mole-rats rested preferably at lower temperatures of approximately 25.6 degrees C (F. mechowii) and 27.7 degrees C (H. argenteocinereus). A strong negative correlation between body mass and preferred air temperature was detected across species. Thus, the results comply with the surface-volume-rule. Contrary to expectations, temperature preference of naked mole-rats (H. glaber) did not deviate from those of furred small mole-rats, but followed the general trend with smaller species preferring higher temperatures. In a second experiment, Ansell's mole-rats (F. anselli) were tested in groups of four, six and nine animals and the preferred temperatures were compared to the values obtained for pairs. The preferred mean air temperatures did not differ among the groups of different sizes. We discuss our findings in the light of ecophysiological adaptations to cope with the ambient conditions proposed by the "thermal stress hypothesis". Furthermore, we suggest that while soil temperature is decisive during digging as the mole-rats warm up or cool due to tight contact between body and soil (conduction), resting animals prevent heat loss through conduction by building a nest. PMID- 26590448 TI - Role of the Gut Microbiome in Uremia: A Potential Therapeutic Target. AB - Also known as the "second human genome," the gut microbiome plays important roles in both the maintenance of health and the pathogenesis of disease. The symbiotic relationship between host and microbiome is disturbed due to the proliferation of dysbiotic bacteria in patients with chronic kidney disease (CKD). Fermentation of protein and amino acids by gut bacteria generates excess amounts of potentially toxic compounds such as ammonia, amines, thiols, phenols, and indoles, but the generation of short-chain fatty acids is reduced. Impaired intestinal barrier function in patients with CKD permits translocation of gut-derived uremic toxins into the systemic circulation, contributing to the progression of CKD, cardiovascular disease, insulin resistance, and protein-energy wasting. The field of microbiome research is still nascent, but is evolving rapidly. Establishing symbiosis to treat uremic syndrome is a novel concept, but if proved effective, it will have a significant impact on the management of patients with CKD. PMID- 26590452 TI - Torpor expression in juvenile and adult Djungarian hamsters (Phodopus sungorus) differs in frequency, duration and onset in response to a daily cycle in ambient temperature. AB - In addition to morphological and physiological traits of short-day acclimatisation, Djungarian hamsters (Phodopus sungorus) from Central Asia exhibit spontaneous daily torpor to decrease energy demands during winter. Environmental factors such as food scarcity and low temperatures have been shown to facilitate the use of this temporal reduction in metabolism and body temperature. We investigated the effect of a daily cycle in ambient temperature on short-day acclimation and torpor expression in juvenile and adult Djungarian hamsters. The animals were exposed to a cold dark phase (6 degrees C) and a warmer light phase (18 degrees C) and were compared with control hamsters kept at a constant ambient temperature of 18 degrees C. Under constant conditions, torpor expression did not differ between adult and juvenile hamsters. Although the daily temperature cycle evoked an increased metabolic rate in adult and juvenile hamsters during the dark phase and strengthened the synchronization between torpor entrance and the beginning of the light phase, it did not induce the expected torpor facilitation. In adult hamsters, torpor expression profiles did not differ from those under constant conditions at all. In contrast, juvenile hamsters showed a delayed onset of torpor season, a decreased torpor frequency, depth and duration, as well as an increased number of early torpor terminations coinciding with the rise in ambient temperature after the beginning of the light phase. While the temperature challenge appeared to be of minor importance for energy balance and torpor expression in adult hamsters, it profoundly influenced the overall energy saving strategy of juvenile hamsters, promoting torpor alleviating active foragers over torpor-prone energy-savers. In addition, our data suggest a more efficient acclimation in juvenile hamsters under additional energy challenges, which reduces the need for torpor expression. PMID- 26590453 TI - Effect of salinity on the upper lethal temperature tolerance of early-juvenile red drum. AB - Previous work investigating the temperature tolerance of juvenile red drum ranging 18-50mm TL found evidence for positive size dependence (smaller fish less tolerant to higher temperatures) suggesting smaller size classes (<18mm TL) potentially may succumb to extreme summer water temperatures. Here, we explored the upper lethal temperature tolerance (ULT) in smaller-sized red drum which ranged from 10 to 20mm TL across multiple salinities to further understand the thermal limitations of this propagated game fish. In order to investigate the combined effect of temperature and salinity on ULT, temperature trials were conducted under three levels of salinity which commonly occur along the coast of Texas (25, 35, and 45ppt). The rate of temperature increase (+0.25 degrees C/h) was designed to mimic a natural temperature increase of a summer day in Texas. We determined that the lethal temperature at 50% (LT50) did not differ between the three salinities examined statistically; median lethal temperature for individuals exposed to 25ppt ranged from 36.4 to 37.7 degrees C, 35ppt ranged from 36.4 to 37.7 degrees C, and 45ppt ranged from 36.1 to 37.4 degrees C. Further, LT50 data obtained here for early-juvenile red drum did not differ from data of a similar experiment examining 25mm TL sized fish. PMID- 26590454 TI - The reliability of a heat acclimation state test prescribed from metabolic heat production intensities. AB - Acclimation state indicates an individual's phenotypic response to a thermally stressful environment, where changes in heat dissipation capacity are determined during a heat acclimation state test (HAST). Variations in thermoregulatory and sudomotor function are reported while exercising at intensities relative to maximal oxygen uptake. This inter-individual variation is not true when intensity is prescribed to elicit a fixed rate of metabolic heat production (Hprod). This study investigated the reliability of peak Tre and two composite measures (sweat gain and sweat setpoint) derived from indices of thermosensitivity during a HAST prescribed from Hprod intensities. Fourteen participants (mean+/-SD; age 23+/-3 years, stature 174+/-7cm, body mass 75.0+/-9.4kg, body surface area 1.9+/ 0.1m(2), peak oxygen consumption [VO2peak] 3.49+/-0.53Lmin(-1)) completed a lactate threshold-VO2peak test and two duplicate Hprod HASTs on a cycle ergometer. The HAST consisted of three, 30-min periods of exercise at fixed Hprod intensities relative to body mass (3, 4.5 and 6Wkg(-1)), within hot dry conditions (44.7+/-1.8 degrees C and 18.1+/-4.7% relative humidity). Peak Tre (38.20+/-0.36 vs. 38.16+/-0.42 degrees C, p=0.54), sweat setpoint (36.76+/-0.34 and 36.79+/-0.38 degrees C, p=0.68) and sweat gain (0.37+/-0.14 and 0.40+/ 0.18gs(-1) degrees C(-1), p=0.40) did not differ between HASTs. Typical error of measurement (TEM), coefficient variation (CV) and intra-class coefficient of correlation (ICC) were 0.19 degrees C, 0.5% and 0.80 for peak Tre, 0.21 degrees C, 0.6% and 0.65 for sweat setpoint and 0.09gs(-1) degrees C(-1), 28% and 0.68 for sweat gain, respectively. The use of fixed Hprod intensities relative to body mass is a reliable method for measuring Tre and ascertaining sweat setpoint during a HAST, whereas, sweat gain displays greater variability. A Hprod HAST appears sufficiently reliable for quantifying heat acclimation state, where TEM in peak Tre and sweat setpoint are small enough to identify physiologically meaningful improvements post-intervention. PMID- 26590455 TI - Is distribution of cold stenotherms constrained by temperature? The case of the Arctic fairy shrimp (Branchinecta paludosa O.F. Muller 1788). AB - Small water bodies in cold climate respond fast to global warming, and species adapted to such habitats may be valuable indicators for climate change. We investigated the geographical and physiological temperature limits of the Arctic fairy shrimp (Branchinecta paludosa), which is common in cold water arctic ponds, but at present retracts its range in alpine areas along its southern outreach of Norway. Seasonal logging of water temperatures along an altitudinal transect revealed an upper temperature limit of 12.7 degrees C for its presence, which closely matched a calculated upper temperature limit of 12.9 degrees C throughout its entire Norwegian range. Field data hence point to cold stenotherm features, which would be consistent with its Arctic, circumpolar distribution. Lab experiments, on the other hand, revealed a linear increase in respiration over 10 20 degrees C. When fed ad libitum somatic growth increased with temperature, as well, without negative physiological impacts of higher temperatures. The absence of Branchinecta paludosa in ponds warmer than 13 degrees C could still be due to a mismatch between temperature dependent metabolism and limited energy supply in these ultraoligotrophic water bodies. We discuss the concept of cold stenothermy in this context, and the impacts of regional warming on the future distribution of the Arctic fairy shrimp. PMID- 26590456 TI - Finite element modeling of haptic thermography: A novel approach for brain tumor detection during minimally invasive neurosurgery. AB - Intraoperative Thermal Imaging (ITI) is a novel neuroimaging method that can potentially locate tissue abnormalities and hence improves surgeon's diagnostic ability. In the present study, thermography technique coupled with artificial tactile sensing method called "haptic thermography" is utilized to investigate the presence of an abnormal object as a tumor with an elevated temperature relative to the normal tissue in the brain. The brain tissue is characterized as a hyper-viscoelastic material to be descriptive of mechanical behavior of the brain tissue during tactile palpation. Based on a finite element approach, Magnetic Resonance Imaging (MRI) data of a patient diagnosed to have a brain tumor is utilized to simulate and analyze the capability of haptic thermography in detection and localization of brain tumor. Steady-state thermal results prove that temperature distribution is an appropriate outcome of haptic thermography for the superficial tumors while heat flux distribution can be used as an extra thermal result for deeply located tumors. PMID- 26590457 TI - To bask or not to bask: Behavioural thermoregulation in two species of dasyurid, Phascogale calura and Antechinomys laniger. AB - Torpor is an important physiological process used to reduce body temperature and thus energy needs in mammals and birds. Rewarming from torpor can be costly. In some small mammals basking is used to reduce the cost of rewarming from torpor. The use and duration of basking was measured in two native Australian marsupials, the red-tailed phascogale (Phascogale calura) and kultarr (Antechinomys laniger), using a heat rock. Animals were observed via video cameras to determine whether they used basking behaviours and whether this behaviour was affected by food availability. Both species became accustomed to the heat rock as time progressed. Absence of food increased basking duration and frequency in some individuals but not all animals. Generally kultarrs basked for longer periods than phascogales, and kultarrs would bask at all hours of the day while phascogales showed a strict nocturnal regime (1900-0700h). The results demonstrate that basking may be an important behavioural adaptation of the kultarr; while the phascogale requires further research. PMID- 26590458 TI - Lack of supercooling evolution related to winter severity in a lizard. AB - As organisms move into higher latitudes, they may evolve physiological mechanisms to survive in harsher climates. One such mechanism is supercooling, the capacity to survive at subzero temperatures without freezing. While interspecific comparisons reveal greater thermal tolerances at higher latitudes in insects and vertebrates, evidence for intraspecific evolution in supercooling related to latitude is only evident in insects. We measured the supercooling points of lizards from 12 populations reared from hatch in common laboratory conditions to test for evolved differences in supercooling related to winter. Results indicate that winter harshness (depth or length) cannot explain supercooling points regardless of how data are analyzed, which suggests that populations have not evolved greater supercooling capacity. While our results are consistent with the idea that thermal physiology is evolutionarily conserved in vertebrates, we cannot reject several alternatives including the possibility that lizards are able to behaviorally avoid the extreme temperatures that would select for thermal evolution. PMID- 26590459 TI - Impact of thermal stress during incubation on gene expression in embryonic muscle of Peking ducks (Anasplatyrhynchos domestica). AB - Changes in temperature will influence poultry embryonic muscle development. However, little is known about the changes in molecular processes impacted by incubation temperature in avians. In this study, we investigated the effects of increasing the incubation temperature by 1 degrees C from day 11-20 on the embryonic and posthatch skeletal muscle development of the Peking duck, and identified the differentially expressed genes using RNA-seq of leg muscle tissues. The results showed that altering the incubation temperature had immediate and long-lasting effects on phenotypic changes in the embryonic and post-hatching muscle development. It was shown that expression levels of total 1370 genes were altered in muscle tissues by the thermal treatments. The gene ontology (GO) analyses indicated that cellular processes including metabolism, cell cycle, catalytic activity, and enzyme regulatory activity may have involved in the muscle mass impacted by thermal manipulation. TGF-beta and insulin pathways as two classical muscle development related pathways may also involve in regulating muscle mass. These data may be helpful for understanding the physiological and biochemical processes of muscle development under environmental treatments in embryonic avians. PMID- 26590460 TI - Changes in the fatty acid composition and regulation of antioxidant enzymes and physiology of juvenile genetically improved farmed tilapia Oreochromis niloticus (L.), subjected to short-term low temperature stress. AB - We evaluated the effect of cold shock on the fatty acid composition, antioxidant enzymes, and physiological responses of genetically improved farmed tilapia (GIFT). Experimental GIFT tilapia, a warm-water teleost, were initially acclimated at 28 degrees C and then transferred directly to 13 degrees C. Stress responses were monitored for 120h. There was a significant change in all parameters in response to the cold stressor (P<0.05). Serum cortisol levels increased from 336.93ng/ml to a peak of 1165.31ng/ml 24h after the initial cold shock, and declined rapidly thereafter. Serum glucose and cholesterol levels were significantly lower in the low temperature group than the control group at 120h (P<0.05). Acute low temperature stress enhanced superoxide dismutase, glutathione peroxidase, catalase, and glutathione levels in the liver of GIFT tilapia. The GIFT tilapia were able to selectively metabolize fatty acids for energy needs during the early period of exposure to low-temperature stress. During this time, they primarily used saturated fatty acids for energy. However as the duration of the stressor and loss of muscle fat increased, the fish began to metabolize long chain polyunsaturated fatty acids. Increased malondialdehyde was produced by oxidation of these fatty acids leading to oxidative damage. Our results provide insight into the changes in fatty acid metabolism physiology that allow GIFT tilapia juveniles to adapt to short-term cold stress. PMID- 26590461 TI - Seasonal thermal ecology of adult walleye (Sander vitreus) in Lake Huron and Lake Erie. AB - The purpose of this study was to characterize thermal patterns and generate occupancy models for adult walleye from lakes Erie and Huron with internally implanted biologgers coupled with a telemetry study to assess the effects of sex, fish size, diel periods, and lake. Sex, size, and diel periods had no effect on thermal occupancy of adult walleye in either lake. Thermal occupancy differed between lakes and seasons. Walleye from Lake Erie generally experienced higher temperatures throughout the spring and summer months than did walleye in Lake Huron, due to limnological differences between the lakes. Tagged walleye that remained in Saginaw Bay, Lake Huron (i.e., adjacent to the release location), as opposed to those migrating to the main basin of Lake Huron, experienced higher temperatures, and thus accumulated more thermal units (the amount of temperature units amassed over time) throughout the year. Walleye that migrated toward the southern end of Lake Huron occupied higher temperatures than those that moved toward the north. Consequently, walleye that emigrated from Saginaw Bay experienced thermal environments that were more favorable for growth as they spent more time within their thermal optimas than those that remained in Saginaw Bay. Results presented in this paper provide information on the thermal experience of wild fish in a large lake, and could be used to refine sex- and lake-specific bioenergetics models of walleye in the Great Lakes to enable the testing of ecological hypotheses. PMID- 26590462 TI - Thermoregulation and microhabitat choice in the polymorphic asp viper (Vipera aspis). AB - In ectotherms, thermoregulation strongly depends on environmental conditions, as well as on intrinsic factors, such as skin colour. Indeed, due to its physical properties, melanin pigments allow melanistic morphs to benefit of a more efficient thermoregulation compared to non-melanistic ones. Despite thermal benefits of melanism have often been highlighted under experimental conditions, such field data remain scarce. In this study, we investigated the influence of colouration on body temperature and microhabitat choice in a montane population of colour polymorphic asp viper (Vipera aspis) characterized by a strong presence of melanism (64%). Results highlighted a difference in internal body temperature, but only within gravid females, with melanistic individuals having higher body temperatures compared to non-melanistic ones. No differences were found when considering both sexes. We also showed that melanistic and non-melanistic vipers were found in different microhabitat types, i.e. melanistic snakes used areas marked by a scarcer sun exposure and by higher vegetation cover compared to non melanistic ones. This result has important implications. Indeed, besides providing a possible explanation for the lack of difference in body temperature (except for gravid females), it confirms that melanistic individuals can potentially use their efficient thermoregulation in order to inhabit less exposed and thermally unfavourable microhabitats. PMID- 26590463 TI - Effect of ambient temperature on evaporative water loss in the subterranean rodent Ctenomys talarum. AB - Subterranean rodents face unique thermoregulatory challenges. Evaporative water loss (EWL) is a crucial mechanism for maintaining heat balance in endotherms subjected to heat stress but also leads to potential dehydration. EWL depends on gradients of temperature and humidity between the surface of the individual and the surrounding environment. Underground burrows generally provide a stable water vapor saturated atmosphere which may impede evaporative heat loss (EHL). This will mainly occur when ambient temperature exceeds the upper limit of individual's thermoneutral zone, or when body temperature rises as result of digging activities. Here we evaluate the effect of ambient temperature on EWL and energy metabolism in the subterranean rodent Ctenomys talarum (tuco-tucos), which inhabits sealed burrows, but makes an extensive use of the aboveground environment. We observed that EWL is increased when ambient temperature rises above thermoneutrality; below this point, evaporation remains stable. Though EWL contributes to total heat loss by increasing ~1.3 times at 35 degrees C, dry thermal conductance is raised four times. In tuco-tucos' burrows both non evaporative and, to some extent, evaporative and behavioral mechanisms are essential for body temperature regulation, preventing overheating at high ambient temperatures in a water vapor-saturated atmosphere. PMID- 26590464 TI - Thermal preference, thermal resistance, and metabolic rate of juvenile Chinese pond turtles Mauremys reevesii acclimated to different temperatures. AB - The thermal acclimatory capacity of a particular species may determine its resilience to environmental change. Evaluating the physiological acclimatory responses of economically important species is useful for determining their optimal culture conditions. Here, juvenile Chinese three-keeled pond turtles (Mauremys reevesii) were acclimated to one of three different temperatures (17, 25 or 33 degrees C) for four weeks to assess the effects of thermal acclimation on some physiological traits. Thermal acclimation significantly affected thermal resistance, but not thermal preference, of juvenile M. reevesii. Turtles acclimated to 17 degrees C were less resistant to high temperatures than those acclimated to 25 degrees C and 33 degrees C. However, turtles increased resistance to low temperatures with decreasing acclimation temperature. The acclimation response ratio of the critical thermal minimum (CTMin) was lower than that of the critical thermal maximum (CTMax) for acclimation temperatures between 17 and 25 degrees C, but slightly higher between 25 and 33 degrees C. The thermal resistance range (i.e., the difference between CTMax and CTMin) was widest in turtles acclimated to the intermediate temperature (25 degrees C), and narrowest in those acclimated to low temperature (17 degrees C). The standard metabolic rate increased as body temperature and acclimation temperature increased, and the temperature quotient (Q10) between acclimation temperatures 17 and 25 degrees C was higher than the Q10 between 25 and 33 degrees C. Our results suggest that juvenile M. reevesii may have a greater resistance under mild thermal conditions resembling natural environments, and better physiological performance at relatively warm temperatures. PMID- 26590465 TI - The effects of acute versus chronic training status on pacing strategies of older men in a hot, humid environment. AB - The combined effects of age and training on the regulation of exercise performance may be confounded by the additional challenge of thermoregulation. Thus, the objective of this study was to compare the pacing strategy of older men who have recently completed 12 weeks of exercise training (acute) to men who have been regularly (>3 times/week) training for at least 6 months (chronic) in a hot, humid environment and to observe disparity, if any, between acute and chronic exercise training on thermoregulation. Eleven chronically trained men (OT) completed a familiarisation trial before returning after 7-10 days to repeat the protocol. Similarly, eight untrained men (OU-PRE) were familiarised and repeated the protocol before completing 12 weeks of exercise training. Post-training, the eight acutely trained men (OU-POST) returned to the laboratory for a third trial. All trials were conducted on a cycle ergometer at the same time of the day in a climate controlled chamber with a mean dry bulb temperature and relative humidity of 32.0 degrees C and 68%, respectively. OT consumed more water than OU-POST and OU-PRE (P<0.01) whilst no differences were observed in the OU with training. Voluntary activation of the knee extensors decreased by 11.3% (P<0.05) in the OU PRE after the cycling time trial. However, the decrease in voluntary activation observed in the OU-POST and OT after the cycling time trial were not significant. The OT maintained a higher power output compared with the OU-POST and OU-PRE except for the last sprint, whilst no significant differences in power output were observed between the OU-PRE and OU-POST. The rate of rise in core temperature was significantly higher in the OT compared with OU-POST (P<0.001) and OU-PRE (P<0.001). With more experience in training, the OT used an alternative hydration strategy compared with the OU-POST and OU-PRE to mitigate the effects of possible exercise hyperthermia, ultimately attaining a higher, but non-critical core temperature at the end of the cycling time trial. Twelve weeks of exercise training may not manifest in improved exercise performance per se, but could translate to improved performance of activities of daily and independent living. PMID- 26590466 TI - Temperature and age affect the life history characteristics and fatty acid profiles of Moina macrocopa (Cladocera). AB - Demographic responses and fatty acid profiles of Moina macrocopa were quantified under different temperature regimes (20 degrees C, 25 degrees C and 30 degrees C and diurnally variable 20-30 degrees C) and at fixed ration (10.65ugDWml(-1)) of Chlorella. Highest constant temperature (30 degrees C) reduced the density of M. macrocopa. The cladocerans under the fluctuating temperature regime too had lower population growth (about 50% lower than that at constant 25 degrees C). The survivorship of M. macrocopa was higher at 20 degrees C than that at 25 degrees C and 30 degrees C or at variable temperature regime. Gross and net reproductive rates were higher at 25 degrees C. At 20 degrees C, neonates had the highest proportion (67%) of myristic, palmitic and stearic acids while the adults had the lowest (26%) proportion. For both adults and neonates, palmitoleic, linoleic and linolenic comprised of 15-35% of the total fatty acids. Higher percentage (19%) of linoleic acid was present in adults than neonates (7%). Adults had linolenic acid level which was 3-times higher than in neonates. Linoleic and linolenic fatty acids decreased with increasing temperature for neonates and adults from 20 degrees C to 30 degrees C. The demographic responses and fatty acid profiles of M. macrocopa were discussed in relation to level and mode of temperature exposure. PMID- 26590467 TI - The impact of in utero heat stress and nutrient restriction on progeny body composition. AB - We recently demonstrated that in utero heat stress (IUHS) alters future tissue accretion in pigs, but whether this is a conserved response among species, is due to the direct effects of heat stress (HS) or mediated by reduced maternal feed intake (FI) is not clear. Study objectives were to compare the quantity and rate of tissue accretion in rats exposed to differing in utero thermal environments while eliminating the confounding effect of dissimilar maternal FI. On d3 of gestation, pregnant Sprague-Dawley rats (189.0+/-5.9g BW) were exposed to thermoneutral (TN; 22.2+/-0.1 degrees C; n=8), or HS conditions (cyclical 30 to 34 degrees C; n=8) until d18 of gestation. A third group was pair-fed to HS dams in TN conditions (PFTN; 22.2+/-0.1 degrees C; n=8) from d4 to d19 of gestation. HS increased dam rectal temperature (p=0.01; 1.3 degrees C) compared to TN and PFTN mothers, and reduced FI (p=0.01; 33%) compared to TN ad libitum fed controls. Although litter size was similar (p=0.97; 10.9 pups/litter), pup birth weight was reduced (p=0.03; 15.4%) in HS compared to PFTN and TN dams. Two male pups per dam [n=8 in utero TN (IUTN); n=8 IUHS; n=8 in utero PFTN (IUPFTN)] were selected from four dams per treatment based on similar gestation length, and body composition was determined using dual-energy x-ray absorptiometry (DXA) on d26, d46, and d66 of postnatal life. Whole-body fat content increased (p=0.01; 11.2%), and whole-body lean tissue decreased (p=0.01; 2.6%) in IUPFTN versus IUTN and IUHS offspring. Whole-body composition was similar between IUHS and IUTN offspring. Epididymal fat pad weight increased (p=0.03; 21.6%) in IUPFTN versus IUHS offspring. In summary and in contrast to pigs, IUHS did not impact rodent body composition during this stage of growth; however, IUPFTN altered the future hierarchy of tissue accretion. PMID- 26590468 TI - Thermal biology of prey (Melongena corona bispinosa, Strombus pugilis, Callinectes similis, Libinia dubia) and predators (Ocyurus chrysurus, Centropomus undecimalis) of Octopus maya from the Yucatan Peninsula. AB - On the Yucatan Peninsula there is an upwelling which allows access to a body of cold water that controls temperature in this area. This modulates the ecology and distribution of organisms that inhabit the continental shelf. The objective of this study was to determine the effect of different acclimation temperatures on the thermal biology of prey as mollusc, crustacean (Melongena corona bispinosa, Strombus pugilis, Callinectes similis, Libinia dubia) and predators as fish (Ocyurus chrysurus, Centropomus undecimalis) of Octopus maya. Octopus prey preferred temperatures between 23.5 degrees C and 26.0 degrees C, while predators preferred temperatures 26.4-28.5 degrees C. The species with largest thermal windows were M. corona bispinosa (328.8 degrees C(2)), C. similis (322.8 degrees C(2)), L. dubia (319.2 degrees C(2)), C. undecimalis (288.6 degrees C(2)), O. chrysurus (237.5 degrees C(2)), while the smallest thermal window was for S. pugilis (202.0 degrees C(2)). The acclimation response ratios (ARR) estimated for prey ranged from 0.24-0.55 in animals exposed to CTMax and 0.21-0.65 in those exposed to CTMin. Amongst predators, ARR ranged from 0.30 to 0.60 and 0.41 to 0.53 for animals exposed to CTMax and CTMin, respectively. Correlating the optimal temperature limits of prey and predators with surface temperatures on the continental shelf and those 4m deep showed that the main prey, Callinectes similis and L. dubia, shared a thermal niche and that an increase in temperature could force these species to migrate to other sites to find optimal temperatures for their physiological functions. As a consequence the continental shelf community would undergo a structural change. Predators were found to be near their optimal temperatures in surface temperatures on the continental shelf. We conclude that they would remain in the area in a warming scenario. The size of the thermal window was related to the type of ecosystem inhabited by these species. These ARR intervals allowed us to categorize the species as temperate or tropical, according to the oceanographic conditions that prevail on the Yucatan Peninsula. PMID- 26590469 TI - Effect of thermal manipulation during embryogenesis on liver heat shock protein expression in chronic heat stressed colored broiler chickens. AB - Thermal manipulation during embryogenesis has been shown to improve thermo tolerance in broilers. Heat shock proteins are a family of proteins produced in response to variety of stress and protect cells from damage. The aim of this study was to evaluate the effect of thermal manipulation (TM) during embryogenesis on HSP gene and protein expression in the embryos and in chronic heat stressed 42nd day old chicks. On 15th day of incubation, fertile eggs from two breeds-Naked neck (NN) and Punjab Broiler-2 (PB-2) were randomly divided in to two groups, namely Control (C) eggs were incubated under standard incubation conditions and Thermal Conditioning (TC) eggs were exposed to higher incubation temperature (40.5 degrees C) for 3h on 15th, 16th and 17th day of incubation. The chicks so obtained from each group were further subdivided and reared from 15th 42nd day as normal (N; 25+/-1 degrees C, 70% RH) and heat exposed (HE; 35+/-1 degrees C, 50% RH) resulting in four treatment groups (CN, CHE, TCN and TCHE). Embryos of two groups (C and TC) on 17th day and birds from four treatment groups on 42nd day were sacrificed. Liver was collected for analysis of gene expression by real-time PCR and protein expression by Western blot of Heat Shock Proteins (HSP 90 alpha, HSP 90 beta, HSP 70, HSP 60, HSP 27 and ubiquitin). The plasma collected on 42nd day was analyzed for biochemical parameters. Thermal challenging of embryos of both the breeds caused significant (P<=0.05) increase in all the HSPs gene and protein expression. The TCHE chicks had significantly (P<=0.05) lower HSPs gene and protein expressions and oxidative stress compared to CHE groups in both NN and PB-2. Based on these findings it can be concluded that TM during incubation provides adaptation to broiler chicks during chronic heat stress. PMID- 26590470 TI - High temperature induces apoptosis and oxidative stress in pufferfish (Takifugu obscurus) blood cells. AB - Water temperature is an important environmental factor in aquaculture farming that affects the survival and growth of organisms. The change in culture water temperature may not only modify various chemical and biological processes but also affect the status of fish populations. In previous studies, high temperature induced apoptosis and oxidative stress. However, the precise mechanism and the pathways that are activated in fish are still unclear. In the present study, we investigated the effects of high temperature (34 degrees C) on the induction of apoptosis and oxidative stress in pufferfish (Takifugu obscurus) blood cells. The data showed that high temperature exposure increased oxygen species (ROS), cytoplasmic free-Ca(2+) concentration and cell apoptosis. To test the apoptotic pathway, the expression pattern of some key apoptotic related genes including P53, Bax, caspase 9 and caspase 3 were examined. The results showed that acute high temperature stress induced up-regulation of these genes, suggesting that the p53-Bax pathway and the caspase-dependent apoptotic pathway could be involved in apoptosis induced by high temperature stress. Furthermore, the gene expression of antioxidant enzymes (Cu/Zn-SOD, Mn-SOD, CAT, GPx, and GR) and heat shock proteins (HSP90 and HSP70) in the blood cells were induced by high temperature stress. Taken together, our results showed that high temperature-induced oxidative stress may cause pufferfish blood cells apoptosis, and cooperatively activated p53-Bax and caspase-dependent apoptotic pathway. PMID- 26590471 TI - An invitation to measure insect cold tolerance: Methods, approaches, and workflow. AB - Insect performance is limited by the temperature of the environment, and in temperate, polar, and alpine regions, the majority of insects must face the challenge of exposure to low temperatures. The physiological response to cold exposure shapes the ability of insects to survive and thrive in these environments, and can be measured, without great technical difficulty, for both basic and applied research. For example, understanding insect cold tolerance allows us to predict the establishment and spread of insect pests and biological control agents. Additionally, the discipline provides the tools for drawing physiological comparisons among groups in wider studies that may not be focused primarily on the ability of insects to survive the cold. Thus, the study of insect cold tolerance is of a broad interest, and several reviews have addressed the theories and advances in the field. Here, however, we aim to clarify and provide rationale for common practices used to study cold tolerance, as a guide for newcomers to the field, students, and those wishing to incorporate cold tolerance into a broader study. We cover the 'tried and true' measures of insect cold tolerance, the equipment necessary for these measurement, and summarize the ecological and biological significance of each. Finally, we suggest a framework and workflow for measuring cold tolerance and low temperature performance in insects. PMID- 26590472 TI - Do sex, body size and reproductive condition influence the thermal preferences of a large lizard? A study in Tupinambis merianae. AB - Body temperature is a key factor in physiological processes, influencing lizard performances; and life history traits are expected to generate variability of thermal preferences in different individuals. Gender, body size and reproductive condition may impose specific requirements on preferred body temperatures. If these three factors have different physiological functions and thermal requirements, then the preferred temperature may represent a compromise that optimizes these physiological functions. Therefore, the body temperatures that lizards select in a controlled environment may reflect a temperature that maximizes their physiological needs. The tegu lizard Tupinambis merianae is one of the largest lizards in South America and has wide ontogenetic variation in body size and sexual dimorphism. In the present study we evaluate intraspecific variability of thermal preferences of T. merianae. We determined the selected body temperature and the rate at which males and females attain their selected temperature, in relation to body size and reproductive condition. We also compared the behavior in the thermal gradient between males and females and between reproductive condition of individuals. Our study show that T. merianae selected body temperature within a narrow range of temperatures variation in the laboratory thermal gradient, with 36.24+/-1.49 degrees C being the preferred temperature. We observed no significant differences between sex, body size and reproductive condition in thermal preferences. Accordingly, we suggest that the evaluated categories of T. merianae have similar thermal requirements. Males showed higher rates to obtain heat than females and reproductive females, higher rates than non-reproductive ones females. Moreover, males and reproductive females showed a more dynamic behavior in the thermal gradient. Therefore, even though they achieve the same selected temperature, they do it differentially. PMID- 26590473 TI - A multicenter, pediatric quality improvement initiative improves surgical wound class assignment, but is it enough? AB - BACKGROUND/PURPOSE: Surgical wound classification (SWC) is widely utilized for surgical site infection (SSI) risk stratification and hospital comparisons. We previously demonstrated that nearly half of common pediatric operations are incorrectly classified in eleven hospitals. We aimed to improve multicenter, intraoperative SWC assignment through targeted quality improvement (QI) interventions. METHODS: A before-and-after study from 2011-2014 at eleven children's hospitals was conducted. The SWC recorded in the hospital's intraoperative record (hospital-based SWC) was compared to the SWC assigned by a surgeon reviewer utilizing a standardized algorithm. Study centers independently performed QI interventions. Agreement between the hospital-based and surgeon SWC was analyzed with Cohen's weighted kappa and chi square. RESULTS: Surgeons reviewed 2034 cases from 2011 (Period 1) and 1998 cases from 2013 (Period 2). Overall SWC agreement improved from 56% to 76% (p<0.01) and weighted kappa from 0.45 (95% CI 0.42-0.48) to 0.73 (95% CI 0.70-0.75). Median (range) improvement per institution was 23% (7-35%). A dose-response-like pattern was found between the number of interventions implemented and the amount of improvement in SWC agreement at each institution. CONCLUSIONS: Intraoperative SWC assignment significantly improved after resource-intensive, multifaceted interventions. However, inaccurate wound classification still commonly occurred. SWC used in SSI risk-stratification models for hospital comparisons should be carefully evaluated. PMID- 26590474 TI - Long-term outcomes of four patients with tracheal agenesis who underwent airway and esophageal reconstruction. AB - PURPOSE: The aim of this study was to evaluate the long-term outcomes of four patients with tracheal agenesis who underwent airway and esophageal/alimentary reconstruction. MATERIALS AND METHODS: We reviewed the medical records of four long-term survivors of tracheal agenesis and collected the following data: age, sex, type of tracheal agenesis, method of reconstruction, nutritional management, and physical and neurological development. RESULTS: The patients consisted of three boys and one girl, who ranged in age from 77 to 109months. The severity of their condition was classified as Floyd's type I (n=2), II (n=1), or III (n=1). Mechanical respiratory support was not necessary in any of the cases. Esophageal/alimentary reconstruction was performed using the small intestine (n=2), a gastric tube (n=1), and the esophagus (n=1). The age at esophageal reconstruction ranged from 41 to 55months. All of the cases required enteral nutrition via gastrostomy. Three of the patients were able to swallow a small amount of liquid and one was able to take pureed food orally. The physical development of the subjects was moderately delayed-borderline in childhood. Neurological development was normal in two cases and slightly delayed in two cases. CONCLUSIONS: None of the long-term survivors of tracheal agenesis required the use of an artificial respirator, and their development was close to normal. Future studies should aim to elucidate the optimal method for performing esophageal reconstruction to allow tracheal agenesis patients to achieve their full oral intake. PMID- 26590475 TI - Two-dimensional gel electrophoretic detection of protein carbonyls derivatized with biotin-hydrazide. AB - Protein carbonyls are protein oxidation products that are often used to measure the magnitude of protein oxidative damage induced by reactive oxygen or reactive nitrogen species. Protein carbonyls have been found to be elevated during aging and in age-related diseases such as stroke, diabetes, and neurodegenerative diseases. In the present article, we provide detailed protocols for detection of mitochondrial protein carbonyls labeled with biotin-hydrazide followed by 2 dimensional isoelectric focusing (IEF)/SDS-PAGE and Western blotting probed with horse-radish peroxidase-conjugated streptavidin. The presented procedures can also be modified for detection of carbonylation of non-mitochondrial proteins. PMID- 26590476 TI - Identifying outliers and implausible values in growth trajectory data. AB - PURPOSE: To illustrate how conditional growth percentiles can be adapted for use to systematically identify implausible measurements in growth trajectory data. METHODS: The use of conditional growth percentiles as a tool to assess serial weight data was reviewed. The approach was applied to 86,427 weight measurements (kg) taken between birth and age 6.5 years in 8217 girls participating in the Promotion of Breast Feeding Intervention Trial in Belarus. A conditional mean and variance was calculated for each weight measurement, which reflects the expected weight at a current visit given the girl's previous weights. Measurements were flagged as outliers if they were more than 4 standard deviation (SD) above or below the expected (conditional) weight. RESULTS: The method identified 234 weight measurements (0.3%) from 216 girls as potential outliers. Review of these trajectories confirmed the implausibility of the flagged measurements, and that the approach identified observations that would not have been identified using a conventional cross-sectional approach (+/- 4 SD of the population mean) for identifying implausible values. Stata code to implement the approach is provided. CONCLUSIONS: Conditional growth percentiles can be used to systematically identify implausible values in growth trajectory data and may be particularly useful for large data sets where the high number of trajectories makes ad hoc approaches unfeasible. PMID- 26590478 TI - Transcranial Magnetic Stimulation Combined With Nicotine Replacement Therapy for Smoking Cessation: A Randomized Controlled Trial. AB - BACKGROUND: Further evidence suggests that repetitive Transcranial Magnetic Stimulation (rTMS) is an effective method to reduce tobacco craving among smokers. HYPOTHESIS: As relapse is common within a few days after smoking cessation, we hypothesized that combining the anti-craving effects of rTMS with Nicotine replacement therapy (NRT) to attenuate withdrawal symptoms could increase abstinence rates in smokers with severe nicotine dependence who quit smoking. METHODS: Thirty-seven smokers who failed to quit with the usual treatments were randomly assigned to two treatment groups to receive either active (n = 18) or sham (n = 19) 1-Hz rTMS of the right dorsolateral prefrontal cortex. The day after quitting smoking, each patient combined NRT (21-mg patch) with active or sham rTMS (10 sessions) for 2 weeks. Cessation support was then continued with NRT alone using lower-dose patches. Abstinence rates and self report craving scales were used to assess the therapeutic results during the combined treatment and for up to 12 weeks after quitting. RESULTS: At the end of the combined treatment, there were significantly more abstinent participants in the active rTMS group (n = 16) than in the sham rTMS group (n = 9) (P = 0.027). The craving scales analysis revealed that active rTMS (P = 0.011) but not sham rTMS (P = 0.116) led to a significant decrease in the compulsive factor. However, no lasting rTMS effect was found. CONCLUSIONS: 1-Hz rTMS combined with NRT improved the success rate of abstinence in smokers during tobacco cessation. The stimulation-induced reduction in compulsivity may explain this result. PMID- 26590479 TI - Transcranial Direct Current Stimulation Treatment in an Adolescent with Autism and Drug-Resistant Catatonia. PMID- 26590480 TI - Application and validation of superior spectrophotometric methods for simultaneous determination of ternary mixture used for hypertension management. AB - Telmisartan (TL), Hydrochlorothiazide (HZ) and Amlodipine besylate (AM) are co formulated together for hypertension management. Three smart, specific and precise spectrophotometric methods were applied and validated for simultaneous determination of the three cited drugs. Method A is the ratio isoabsorptive point and ratio difference in subtracted spectra (RIDSS) which is based on dividing the ternary mixture of the studied drugs by the spectrum of AM to get the division spectrum, from which concentration of AM can be obtained by measuring the amplitude values in the plateau region at 360nm. Then the amplitude value of the plateau region was subtracted from the division spectrum and HZ concentration was obtained by measuring the difference in amplitude values at 278.5 and 306nm (corresponding to zero difference of TL) while the total concentration of HZ and TL in the mixture was measured at their isoabsorptive point in the division spectrum at 278.5nm (Aiso). TL concentration is then obtained by subtraction. Method B; double divisor ratio spectra derivative spectrophotometry (RS-DS) and method C; mean centering of ratio spectra (MCR) spectrophotometric methods. The proposed methods did not require any initial separation steps prior the analysis of the three drugs. A comparative study was done between the three methods regarding their; simplicity, sensitivity and limitations. Specificity was investigated by analyzing the synthetic mixtures containing different ratios of the three studied drugs and their tablets dosage form. Statistical comparison of the obtained results with those found by the official methods was done, differences were non-significant in regard to accuracy and precision. The three methods were validated in accordance with ICH guidelines and can be used for quality control laboratories for TL, HZ and AM. PMID- 26590481 TI - Immunotoxic effects of environmental pollutants in marine mammals. AB - Due to their marine ecology and life-history, marine mammals accumulate some of the highest levels of environmental contaminants of all wildlife. Given the increasing prevalence and severity of diseases in marine wildlife, it is imperative to understand how pollutants affect the immune system and consequently disease susceptibility. Advancements and adaptations of analytical techniques have facilitated marine mammal immunotoxicology research. Field studies, captive feeding experiments and in vitro laboratory studies with marine mammals have associated exposure to environmental pollutants, most notable polychlorinated biphenyls (PCBs), organochlorine pesticides and heavy metals, to alterations of both the innate and adaptive arms of immune systems, which include aspects of cellular and humoral immunity. For marine mammals, reported immunotoxicology endpoints fell into several major categories: immune tissue histopathology, haematology/circulating immune cell populations, functional immune assays (lymphocyte proliferation, phagocytosis, respiratory burst, and natural killer cell activity), immunoglobulin production, and cytokine gene expression. Lymphocyte proliferation is by far the most commonly used immune assay, with studies using different organic pollutants and metals predominantly reporting immunosuppressive effects despite the many differences in study design and animal life history. Using combined field and laboratory data, we determined effect threshold levels for suppression of lymphocyte proliferation to be between b0.001 10 ppm for PCBs, 0.002-1.3 ppm for Hg, 0.009-0.06 for MeHg, and 0.1-2.4 for cadmium in polar bears and several pinniped and cetacean species. Similarly, thresholds for suppression of phagocytosis were 0.6-1.4 and 0.08-1.9 ppm for PCBs and mercury, respectively. Although data are lacking for many important immune endpoints and mechanisms of specific immune alterations are not well understood, this review revealed a systemic suppression of immune function in marine mammals exposed to environmental contaminants. Exposure to immunotoxic contaminants may have significant population level consequences as a contributing factor to increasing anthropogenic stress in wildlife and infectious disease outbreaks. PMID- 26590482 TI - Concentrations of antibiotics predicted to select for resistant bacteria: Proposed limits for environmental regulation. AB - There are concerns that selection pressure from antibiotics in the environment may accelerate the evolution and dissemination of antibiotic-resistant pathogens. Nevertheless, there is currently no regulatory system that takes such risks into account. In part, this is due to limited knowledge of environmental concentrations that might exert selection for resistant bacteria. To experimentally determine minimal selective concentrations in complex microbial ecosystems for all antibiotics would involve considerable effort. In this work, our aim was to estimate upper boundaries for selective concentrations for all common antibiotics, based on the assumption that selective concentrations a priori need to be lower than those completely inhibiting growth. Data on Minimal Inhibitory Concentrations (MICs) were obtained for 111 antibiotics from the public EUCAST database. The 1% lowest observed MICs were identified, and to compensate for limited species coverage, predicted lowest MICs adjusted for the number of tested species were extrapolated through modeling. Predicted No Effect Concentrations (PNECs) for resistance selection were then assessed using an assessment factor of 10 to account for differences between MICs and minimal selective concentrations. The resulting PNECs ranged from 8 ng/L to 64 MUg/L. Furthermore, the link between taxonomic similarity between species and lowest MIC was weak. This work provides estimated upper boundaries for selective concentrations (lowest MICs) and PNECs for resistance selection for all common antibiotics. In most cases, PNECs for selection of resistance were below available PNECs for ecotoxicological effects. The generated PNECs can guide implementation of compound-specific emission limits that take into account risks for resistance promotion. PMID- 26590483 TI - Lower muscle co-contraction in flutter kicking for competitive swimmers. AB - The purpose of this study was to examine the difference in muscle activation pattern and co-contraction of the rectus and biceps femoris in flutter-kick swimming between competitive and recreational swimmers, to better understand the mechanism of repetitive kicking movements during swimming. Ten competitive and 10 recreational swimmers swam using flutter kicks at three different velocities (100%, 90%, and 80% of their maximal velocity) in a swimming flume. Surface electromyographic signals (EMG) were obtained from the rectus (RF) and biceps femoris (BF), and lower limb kinematic data were obtained at the same time. The beginning and ending of one kick cycle was defined as when the right lateral malleolus reached its highest position in the vertical axis. The offset timing of muscle activation of RF in the recreational swimmers was significantly later at all velocities than in the competitive swimmers (47-48% and 26-33% of kick time of one cycle for recreational and competitive swimmers, respectively), although the kinematic data and other activation timing of RF and BF did not differ between groups. A higher integrated EMG of RF during hip extension and knee extension induced a higher level of muscle co-contraction between RF and BF in the recreational swimmers. These results suggest that long-term competitive swimming training can induce an effective muscle activation pattern in the upper legs. PMID- 26590486 TI - Obstetric and gynaecological problems in Australian general practice. PMID- 26590485 TI - Reconciling proteomics with next generation sequencing. AB - Both genomics and proteomics technologies have matured in the last decade to a level where they are able to deliver system-wide data on the qualitative and quantitative abundance of their respective molecular entities, that is DNA/RNA and proteins. A next logical step is the collective use of these technologies, ideally gathering data on matching samples. The first large scale so-called proteogenomics studies are emerging, and display the benefits each of these layers of analysis has on the other layers to together generate more meaningful insight into the connection between the phenotype/physiology and genotype of the system under study. Here we review a selected number of these studies, highlighting what they can uniquely deliver. We also discuss the future potential and remaining challenges, from a somewhat proteome biased perspective. PMID- 26590487 TI - Pelvic organ prolapse - a review. AB - BACKGROUND: Female pelvic floor dysfunction encompasses a number of prevalent clinical conditions including urinary and faecal incontinence, obstructed defaecation, sexual dysfunction and female pelvic organ prolapse (FPOP). The latter is the most common condition and most likely to require surgical treatment. Neither aetiology nor pathophysiology of FPOP is fully understood. OBJECTIVE: This review will focus on the diagnosis and management of FPOP in primary care, but will also refer to recent research into aetiology, diagnosis, management and prevention of this condition. DISCUSSION: Primary care physicians have a substantial role in the management of female pelvic organ prolapse (FPOP), as they are well placed to provide information to patients of all ages. This is particularly relevant during the childbearing years as childbirth has a central role in the aetiology of FPOP. PMID- 26590484 TI - Stance time variability during stair stepping before and after total knee arthroplasty: A pilot study. AB - The main objectives of this pilot study were to: (1) investigate stance time variability (STV) during stair stepping in older adults with osteoarthritis (OA) before and after total knee arthroplasty (TKA), and compare to an age- and sex matched group of healthy controls with native knees and (2) evaluate the relationship between quadriceps strength and STV during stair stepping before and after TKA. A prospective, observational, pilot study was carried out on 13 individuals (15% male, mean age 62.71+/-6.84years) before and after TKA using an instrumented stairway, patient-reported outcomes, timed stair stepping test, and quadriceps strength measures. At 6-months post-operatively, STV during stair descent was significantly greater in the TKA-GROUP compared to the CONTROL-GROUP, but was not significantly different at 12-months compared to controls. There were no significant differences in STV for stair ascent between the pre- and post operative visits, or compared to controls. There was a trend toward significance for the relationship between quadriceps strength and STV during stair ascent (P=0.059) and descent (P=0.073). Variability during stair stepping may provide an important, short-term rehabilitation target for individuals following TKA and may represent another parameter to predict declines in functional mobility. PMID- 26590488 TI - Management of persistent pelvic pain in girls and women. AB - BACKGROUND: Persistent pelvic pain (PPP) is estimated to affect 15-25% of women. Despite this, few guidelines for management are available and few medical practitioners feel adequately skilled to manage the complex range of symptoms that present. Given the numbers of girls and women affected, general practitioners (GPs) will see the majority of patients with this condition. OBJECTIVE: This article provides a practical framework for the clinical assessment and management of PPP in general practice. It aims to assist GPs care for these patients effectively and confidently. PPP is considered in four parts: pain from pelvic organs; the musculoskeletal response to pain; central sensitisation of nerve pathways; and the psychological sequelae of chronic pain. Management is supported by evidence where available, with useful references included for further reading. DISCUSSION: A GP with an interest in this area is in a good position to effectively care for the majority of women with pelvic pain, in conjunction with other health professionals including gynaecologists, pelvic physiotherapists, psychologists, pain physicians, dieticians and urologists as required. PMID- 26590489 TI - Localised provoked vestibulodynia (vulvodynia): assessment and management. AB - BACKGROUND: Vulvodynia is a chronic vulvar pain condition. Localised provoked vestibulodynia (LPV) is the most common subset of vulvodynia, the hallmark symptom being pain on vaginal penetration. Young women are predominantly affected. LPV is a hidden condition that often results in distress and shame, is frequently unrecognised, and women usually see a number of health professionals before being diagnosed, which adds to their distress and confusion. OBJECTIVE: The aim of this article is to inform health providers about the assessment and management of LPV. DISCUSSION: Diagnosis is based on history. Examination is used to support the diagnosis. Management is multidisciplinary and includes psychological, physical and pharmacological therapies. With appropriate intervention, most women can expect significant reduction in pain and improved quality of life. PMID- 26590490 TI - Your questions about complementary medicines answered: fish oil. AB - This is the third article in a series providing evidence-based answers to common questions about complementary medicines from consumers and healthcare professionals. PMID- 26590491 TI - Semont manoeuvre for vertigo assessment. AB - BACKGROUND: The Dix-Hallpike manoeuvre is performed for diagnosis and the Epley manoeuvre used for treatment of posterior canal benign paroxysmal positional vertigo (BPPV). However, musculoskeletal conditions may restrict utility of these manoeuvres. OBJECTIVE: The Semont and liberatory manoeuvres are described in this article. These manoeuvres are simple and highly effective for the diagnosis and treatment of posterior canal BPPV. DISCUSSION: The diagnosis of BPPV should not be missed as it can be diagnosed clinically and it is easily treated. PMID- 26590492 TI - Cicatricial alopecia - a case study. PMID- 26590493 TI - Diagnosis matters: the differing ?clinical trajectories for terminal prostate, ?lung and haematological cancers. AB - BACKGROUND: There is a belief that end-of-life care issues are similar for all cancer patients, irrespective of their primary cancer diagnosis. This exploratory study into the terminal trajectories of three common cancers challenges this belief. METHODS: A retrospective, systematic, and mixed qualitative and quantitative medical record review of 30 deceased patients in 2010 was performed between two Victorian networks. The last 90 days of life were examined in three equally distributed cancer groups - prostate, lung and haematological. RESULTS: The trajectories for the three malignancies differed in temporal, symptomatic, supportive and interventional characteristics. DISCUSSION: Our study suggests diagnosis does indeed matter. The varying symptomatology for the different cancers markedly influenced clinical management, utilisation of palliative care services and the site of care and site of death. Our study suggests potential areas for better collaboration between general practitioners, community and specialist palliative care services. Emerging work supports our findings, but this area warrants further research. PMID- 26590494 TI - Involuntary psychiatric treatment in the community: general practitioners and the implementation of community treatment orders. AB - BACKGROUND: There are no data about general practitioners' (GPs') involvement in involuntary psychiatric community treatment orders (CTOs). We examined stakeholder perspectives on the GP's role in this area. METHODS: Semi-structured interviews were conducted around CTO experiences with 38 participants: patients, carers, clinicians and Mental Health Review Tribunal members. Data were analysed using established qualitative methodologies. RESULTS: Sixteen participants specifically spoke about GPs. The analysis identified four themes in their accounts: GPs as 'instruments' of CTOs; GPs as primary caregivers within a CTO; GPs as 'outsiders'; and practical challenges for GPs. Within these themes, participants identified the value of GPs in the provision of care for people living with severe and persistent mental illness, the challenges of coercive processes and the dangers of GPs being isolated from them. DISCUSSION: GPs play an important role in the implementation of CTOs. Failure to better integrate GPs in the care of people on CTOs appears to be a significant shortcoming of its implementation. PMID- 26590495 TI - Consultation contexts and the acceptability of alcohol enquiry from general practitioners - a survey experiment. AB - BACKGROUND: General practitioners have a crucial role in detecting risky drinking in patients. However, little is known about how the context of the consultation affect patient acceptability of these discussions. METHODS: During one week in May 2014, adult patients seen at a community general practice in Sydney were randomised to receive one of two postal questionnaires. Participants rated the acceptability of alcohol enquiry in 20 vignettes of general practice consultations, either within a SNAP (smoking, nutrition, alcohol, physical activity) framework (intervention) or alone (control). RESULTS: Of the 441 patients who received the questionnaires, 144 returned completed and returned it. The intervention group rated an additional 2.1 (95% CI = 0.38-3.7, P = 0.016) vignettes as acceptable compared to the control group. Alcohol enquiry acceptability varied greatly between individual scenarios. DISCUSSION: Alcohol use assessment may be more acceptable to patients when it is framed within the SNAP framework, especially in certain presentations (eg diabetes management). PMID- 26590496 TI - Self-medication for cough and the common cold: information needs of consumers. AB - BACKGROUND: Despite the high use of over-the-counter (OTC) cough and cold medicines, little is known about Australia's cough and cold medicines information needs. The aim of this study was to identify gaps in consumers' perceived knowledge and concerns, to better target consumer medicines information and improve quality use of medicines. METHODS: We analysed cough-and-cold related enquiries from consumers who contacted an Australian national medicine call centre between September 2002 and June 2010. RESULTS: Of 5503 cough and cold calls, female callers made up 86% of the calls and 33% were related to children. Questions most frequently related to drug-drug interactions (29%). An analysis of narratives over an 18-month period (248 calls) revealed 20% of the calls concerned potentially clinically relevant interactions, particularly those involving psychotropic agents. DISCUSSION: The potential for interactions with cough and cold medicines purchased OTC is recognised by consumers. Patient information should address their concerns. Doctors should be aware of the common cough and cold interactions and communicate likely clinical symptoms to patients when prescribing medication to prevent potential harm. PMID- 26590497 TI - Rites of passage: improving refugee access to general practice services. AB - BACKGROUND: Refugees in Australia experience barriers in accessing healthcare services. The aim of this study was to analyse the factors influencing Afghan refugees' access to general practice. METHODS: A qualitative study on a single general practice in south-east Melbourne in 2013 was conducted. Data were collected using individual, semi-structured interviews and field observations. Data were analysed thematically and informed by the Penchansky and Thomas concept of access. RESULTS: The general practice utilised multiple strategies to improve access for refugees. Nevertheless, persistent barriers included language and cultural differences at reception, difficulties with transport to the practice, long wait times and the cost of care. DISCUSSION: This case study highlights the benefits of providing affordable, co-located, culturally responsive services with integrated interpreter and settlement agency support. Increasing the use of interpreters and translated materials at reception, and improving the coordination of patient transport assistance could enhance refugees' access to general practice. PMID- 26590498 TI - Online pathways for dementia care. AB - BACKGROUND: Dementia is one of the fastest growing diseases in Australia. General practitioners (GPs) are at the forefront of dementia diagnosis and management. However, the disease is complex and this can prevent timely diagnosis. A recent initiative in the Grampians region, Victoria, is addressing some of these challenges through a comprehensive, intuitive, online tool. OBJECTIVE: The aim of this article is to describe the process of developing and reasons for implementing the Dementia Pathways Tool, in the Grampians region, Victoria. DISCUSSION: Designed in collaboration with GPs and practice nurses, the Dementia Pathways Tool promotes awareness of the first signs of dementia. It offers an informed approach to diagnosis, referral and ongoing management of people with the symptoms of dementia. This Tool provides practitioners - irrespective of their practice location - with access to an intuitive, online web-based repository of information. The Tool is publicly available and therefore accessible to all practitioners and the general public. Initial indications from statistics of the website are positive, but an evaluation will help inform the potential for broader applications of this Tool in the future. PMID- 26590499 TI - A team care model of cervical ?screening in a general practice. AB - BACKGROUND: Cervical screening reduces the incidence and mortality rate of cervical cancer. General practices have opportunities to increase screening rates by modifying the model of service provided. OBJECTIVE: We provide an example of team-based cervical screening in a general practice and report the effectiveness of invitation letters for women with no record of a Pap smear. DISCUSSION: The practice sent invitation letters to women with no record of a Pap smear (or reason for not requiring one) to attend a visit to a women's health clinic comprising a visit to a GP of choice and then a nurse to perform the smear. Practice cervical screening data were collected over 45 months to investigate the impact of invitation letters. The quality of Pap smears performed by nurses was recorded. The biennial cervical screening rate improved by 11%. The percentage of women with no Pap smear recorded was reduced from 41.71% to 27.99%. The quality of the smears taken by the nurses was above the nationwide average. The data show that invitation letters contributed to improved cervical screening and that nurses were highly effective team members in the collection of Pap smears. PMID- 26590500 TI - General practice ethics: ?inter-professional responsibilities. PMID- 26590501 TI - Ethical research or research ethics? PMID- 26590502 TI - Patient portals: furthering the reality of patient partnership. PMID- 26590477 TI - Designing a broad-spectrum integrative approach for cancer prevention and treatment. AB - Targeted therapies and the consequent adoption of "personalized" oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy resistant immortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are not reliant upon the same mechanisms as those which have been targeted). To address these limitations, an international task force of 180 scientists was assembled to explore the concept of a low-toxicity "broad-spectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspects of relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a wide range of high-priority targets (74 in total) that could be modified to improve patient outcomes. For these targets, corresponding low-toxicity therapeutic approaches were then suggested, many of which were phytochemicals. Proposed actions on each target and all of the approaches were further reviewed for known effects on other hallmark areas and the tumor microenvironment. Potential contrary or procarcinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixed evidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of the relationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. This novel approach has potential to be relatively inexpensive, it should help us address stages and types of cancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for future research is offered. PMID- 26590503 TI - Aspirin and other non-steroidal anti-inflammatory drug prescriptions and survival after the diagnosis of head and neck and oesophageal cancer. AB - BACKGROUND: Aspirin and other NSAIDs are widely used as analgesics and the former is a preventative agent for vascular events. It is unclear whether their long term use affects cancer risk. Data on the chemopreventative role of these drugs on the mortality in patients with upper aerodigestive tract cancer (UADT) are insufficient. The aim of this study was to investigate the effect of aspirin and other NSAIDs on survival in UADT cancer patients. METHODS: An observational cohort study of patients with UADT cancer was undertaken using Primary Care Clinical Informatics Unit (PCCIU) database of electronic medical records in Scotland. Information was available on all prescriptions of aspirin and other NSAIDs before and after diagnosis. The main outcome measure was all-cause mortality. Cox regression was used for statistical data analysis. RESULTS: There were 2392 patients diagnosed with UADT cancer between 1996 and 2010. Mean age of patients was 66 years (SD 12) and most were male (63%). Median survival in head and neck (HNC) patients was 94 months, while median survival in oesophageal cancer patients was 10 months. For HNC improved survival was observed with aspirin prescription (ever vs never hazard ratio (HR) 0.56 95% Confidence Interval (CI) 0.44, 0.71), there was no association with Cyclooxygenase 2 Inhibitors (COX-2) prescriptions. Improved survival was observed with other NSAIDs prescription (ever vs never HR 0.74 95% CI 0.60, 0.90). For oesophageal cancer patients, improved survival was observed with aspirin prescriptions (ever vs never HR 0.54 95% CI 0.45, 0.64), COX-2 prescriptions (HR 0.78 95% CI 0.62, 0.98) and other NSAIDs (HR 0.67 95% CI 0.56, 0.80). CONCLUSIONS: Aspirin and other NSAIDs prescriptions after diagnosis are associated with a reduced all cause mortality in UADT cancer patients. PMID- 26590504 TI - Heparin versus 0.9% sodium chloride intermittent flushing for the prevention of occlusion in long term central venous catheters in infants and children. AB - BACKGROUND: Guidelines and clinical practice for the prevention of complications associated with central venous catheters (CVC) around the world vary greatly. Most institutions recommend the use of heparin to prevent occlusion, however there is debate regarding the need for heparin and evidence to suggest 0.9% sodium chloride (normal saline) may be as effective. The use of heparin is not without risk, may be unnecessary and is also associated with increased cost. OBJECTIVES: To assess the clinical effects (benefits and harms) of intermittent flushing of heparin versus normal saline to prevent occlusion in long term central venous catheters in infants and children. SEARCH METHODS: The Cochrane Vascular Trials Search Co-ordinator searched the Specialised Register (last searched April 2015) and the Cochrane Register of Studies (Issue 3, 2015). We also searched the reference lists of retrieved trials. SELECTION CRITERIA: Randomised controlled trials that compared the efficacy of normal saline with heparin to prevent occlusion of long term CVCs in infants and children aged up to 18 years of age were included. We excluded temporary CVCs and peripherally inserted central catheters (PICC). DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial inclusion criteria, trial quality and extracted data. Rate ratios were calculated for two outcome measures - occlusion of the CVC and central line-associated blood stream infection. Other outcome measures included duration of catheter placement, inability to withdraw blood from the catheter, use of urokinase or recombinant tissue plasminogen, incidence of removal or re-insertion of the catheter, or both, and other CVC-related complications such as dislocation of CVCs, other CVC site infections and thrombosis. MAIN RESULTS: Three trials with a total of 245 participants were included in this review. The three trials directly compared the use of normal saline and heparin, however, between studies, all used different protocols for the standard and experimental arms with different concentrations of heparin and different frequency of flushes reported. In addition, not all studies reported on all outcomes. The quality of the evidence ranged from low to very low because there was no blinding, heterogeneity and inconsistency between studies was high and the confidence intervals were wide. CVC occlusion was assessed in all three trials (243 participants). We were able to pool the results of two trials for the outcomes of CVC occlusion and CVC-associated blood stream infection. The estimated rate ratio for CVC occlusion per 1000 catheter days between the normal saline and heparin group was 0.75 (95% CI 0.10 to 5.51, two studies, 229 participants, very low quality evidence). The estimated rate ratio for CVC associated blood stream infection was 1.48 (95% CI 0.24 to 9.37, two studies, 231 participants; low quality evidence). The duration of catheter placement was reported to be similar between the two study arms, in one study (203 participants). AUTHORS' CONCLUSIONS: The review found that there was not enough evidence to determine the effects of intermittent flushing of heparin versus normal saline to prevent occlusion in long term central venous catheters in infants and children. Ultimately, if this evidence were available, the development of evidenced-based clinical practice guidelines and consistency of practice would be facilitated. PMID- 26590505 TI - Phase contrast STEM for thin samples: Integrated differential phase contrast. AB - It has been known since the 1970s that the movement of the center of mass (COM) of a convergent beam electron diffraction (CBED) pattern is linearly related to the (projected) electrical field in the sample. We re-derive a contrast transfer function (CTF) for a scanning transmission electron microscopy (STEM) imaging technique based on this movement from the point of view of image formation and continue by performing a two-dimensional integration on the two images based on the two components of the COM movement. The resulting integrated COM (iCOM) STEM technique yields a scalar image that is linear in the phase shift caused by the sample and therefore also in the local (projected) electrostatic potential field of a thin sample. We confirm that the differential phase contrast (DPC) STEM technique using a segmented detector with 4 quadrants (4Q) yields a good approximation for the COM movement. Performing a two-dimensional integration, just as for the COM, we obtain an integrated DPC (iDPC) image which is approximately linear in the phase of the sample. Beside deriving the CTFs of iCOM and iDPC, we clearly point out the objects of the two corresponding imaging techniques, and highlight the differences to objects corresponding to COM-, DPC-, and (HA) ADF-STEM. The theory is validated with simulations and we present first experimental results of the iDPC-STEM technique showing its capability for imaging both light and heavy elements with atomic resolution and a good signal to noise ratio (SNR). PMID- 26590506 TI - Fatiguing effect of multiple take-offs and landings in regional airline operations. AB - Fatigue is a risk factor for flight performance and safety in commercial aviation. In US commercial aviation, to help to curb fatigue, the maximum duration of flight duty periods is regulated based on the scheduled start time and the number of flight segments to be flown. There is scientific support for regulating maximum duty duration based on scheduled start time; fatigue is well established to be modulated by circadian rhythms. However, it has not been established scientifically whether the number of flight segments, per se, affects fatigue. To address this science gap, we conducted a randomized, counterbalanced, cross-over study with 24 active-duty regional airline pilots. Objective and subjective fatigue was compared between a 9-hour duty day with multiple take-offs and landings versus a duty day of equal duration with a single take-off and landing. To standardize experimental conditions and isolate the fatiguing effect of the number of segments flown, the entire duty schedules were carried out in a high-fidelity, moving-base, full-flight, regional jet flight simulator. Steps were taken to maintain operational realism, including simulated airplane inspections and acceptance checks, use of realistic dispatch releases and airport charts, real-world air traffic control interactions, etc. During each of the two duty days, 10 fatigue test bouts were administered, which included a 10-minute Psychomotor Vigilance Test (PVT) assessment of objective fatigue and Samn-Perelli (SP) and Karolinska Sleepiness Scale (KSS) assessments of subjective sleepiness/fatigue. Results showed a greater build-up of objective and subjective fatigue in the multi-segment duty day than in the single-segment duty day. With duty start time and duration and other variables that could impact fatigue levels held constant, the greater build-up of fatigue in the multi-segment duty day was attributable specifically to the difference in the number of flight segments flown. Compared to findings in previously published laboratory studies of simulated night shifts and nighttime sleep deprivation, the magnitude of the fatiguing effect of the multiple take-offs and landings was modest. Ratings of flight performance were not significantly reduced for the simulated multi-segment duty day. The US duty and flight time regulations for commercial aviation shorten the maximum duty duration in multi-segment operations by up to 25% depending on the duty start time. The present results represent an important first step in understanding fatigue in multi-segment operations, and provide support for the number of flight segments as a relevant factor in regulating maximum duty duration. Nonetheless, based on our fatigue results, a more moderate reduction in maximum duty duration as a function of the number of flight segments might be considered. However, further research is needed to include investigation of flight safety, and to extend our findings to nighttime operations. PMID- 26590507 TI - Accident-precipitating factors for crashes in turbine-powered general aviation aircraft. AB - General aviation (14CFR Part 91) accounts for 83% of civil aviation fatalities. While much research has focused on accident causes/pilot demographics in this aviation sector, studies to identify factors leading up to the crash (accident precipitating factors) are few. Such information could inform on pre-emptive remedial action. With this in mind and considering the paucity of research on turbine-powered aircraft accidents the study objectives were to identify accident precipitating factors and determine if the accident rate has changed over time for such aircraft operating under 14CFR Part 91. The NTSB Access database was queried for accidents in airplanes (<12,501lb) powered by 1-2 turbine engines and occurring between 1989 and 2013. We developed and utilized an accident precipitating factor taxonomy. Statistical analyses employed logistic regression, contingency tables and a generalized linear model with Poisson distribution. The "Checklist/Flight Manual Not Followed" was the most frequent accident precipitating factor category and carried an excess risk (OR 2.34) for an accident with a fatal and/or serious occupant injury. This elevated risk reflected an over-representation of accidents with fatal and/or serious injury outcomes (p<0.001) in the "non-adherence to V Speeds" sub-category. For accidents grouped in the "Inadequate Pre-Flight Planning/Inspection/Procedure" the "inadequate weather planning" sub-category accounted (p=0.036) for the elevated risk (OR 2.22) of an accident involving fatal and/or serious injuries. The "Violation FARs/AIM Deviation" category was also associated with a greater risk for fatal and/or serious injury (OR 2.59) with "Descent below the MDA/failure to execute the missed approach" representing the largest sub-category. Accidents in multi-engine aircraft are more frequent than their single engine counterparts and the decline (50%) in the turbine aircraft accident rate over the study period was likely due, in part, to a 6-fold increased representation of single engine airplanes. In conclusion, our study is the first to identify novel precursive factors for accidents involving turbine aircraft operating under 14CFR Part 91. This research highlights areas that should receive further emphasis in training/recurrency in a pre-emptive attempt to nullify candidate accident precipitating factor(s). PMID- 26590508 TI - 1-Piperazinylphthalazines as potential VEGFR-2 inhibitors and anticancer agents: Synthesis and in vitro biological evaluation. AB - In our endeavor towards the development of effective VEGFR-2 inhibitors, three novel series of phthalazine derivatives based on 1-piperazinyl-4-arylphthalazine scaffold were synthesized. All the newly prepared phthalazines 16a-k, 18a-e and 21a-g were evaluated in vitro for their inhibitory activity against VEGFR-2. In particular, compounds 16k and 21d potently inhibited VEGFR-2 at sub-micromolar IC50 values 0.35 +/- 0.03 and 0.40 +/- 0.04 MUM, respectively. Moreover, seventeen selected compounds 16c-e, 16g, 16h, 16j, 16k, 18c-e and 21a-g were evaluated for their in vitro anticancer activity according to US-NCI protocol, where compounds 16k and 21d proved to be the most potent anticancer agents. While, compound 16k exhibited potent broad spectrum anticancer activity with full panel GI50 (MG-MID) value of 3.62 MUM, compound 21d showed high selectivity toward leukemia and prostate cancer subpanels [subpanel GI50 (MG-MID) 3.51 and 5.15 MUM, respectively]. Molecular docking of compounds16k and 21d into VEGFR-2 active site was performed to explore their potential binding mode. PMID- 26590509 TI - Use of a fluorescence-based camera for monitoring occlusal surfaces of primary and permanent teeth. AB - BACKGROUND: Sound teeth and incipient lesions require regular monitoring to detect possible progression of caries early on. AIM: To evaluate the ability of the VistaProof (VP) fluorescence-based camera for monitoring occlusal surfaces. DESIGN: A total of 419 posterior teeth (205 primary molars, 145 permanent molars, and 69 premolars) of 35 patients were examined (average age: 9.1 years). The occlusal surfaces were classified visually according to the criteria of the International Caries Detection and Assessment System (ICDAS). VP measurements were performed at baseline (t1), and the examinations were repeated after six (t2) and twelve month (t3). Correlation between methods was calculated using Spearman's rank correlation coefficient (rs ). Wilcoxon test was used to monitor whether VP identified changes as well as ICDAS (alpha = 0.05). RESULTS: Correlations between ICDAS and VP were significantly positive (rs : 0.66-0.73, P < 0.001). No significant differences were found between all times for the ICDAS findings. Significant differences for the VP were ascertained for t1/t2 (P = 0.03). Results based on cluster randomization showed significant differences between ICDAS and VistaProof concerning the absence/presence of changes in the finding (P < 0.0005). CONCLUSION: Correlation between ICDAS and VP was strong. The VP supported the findings of visual examination for monitoring occlusal surfaces, although not all changes could be detected with respect to the visual findings. PMID- 26590510 TI - Personality disorders and suicide attempts in unipolar and bipolar mood disorders. AB - BACKGROUND: Comorbid personality disorders may predispose patients with mood disorders to suicide attempts (SAs), but factors mediating this effect are not well known. METHODS: Altogether 597 patients from three prospective cohort studies (Vantaa Depression Study, Jorvi Bipolar Study, and Vantaa Primary Care Depression Study) were interviewed at baseline, at 18 months, and in VDS and PC VDS at 5 years. Personality disorders (PDs) at baseline, number of previous SAs, life-charted time spent in major depressive episodes (MDEs), and precise timing of SAs during follow-up were determined and investigated. RESULTS: Overall, 219 (36.7%) patients had a total of 718 lifetime SAs; 88 (14.7%) patients had 242 SAs during the prospective follow-up. Having any PD diagnosis increased the SA rate, both lifetime and prospectively evaluated, by 90% and 102%, respectively. All PD clusters increased the rate of new SAs, although cluster C PDs more than the others. After adjusting for time spent in MDEs, only cluster C further increased the SA rate (by 52%). Mediation analyses of PD effects on prospectively ascertained SAs indicated significant mediated effects through time at risk in MDEs, but also some direct effects. LIMITATIONS: Findings generalizable only to patients with mood disorders. CONCLUSIONS: Among mood disorder patients, comorbid PDs increase the risk of SAs to approximately two-fold. The excess risk is mostly due to patients with comorbid PDs spending more time in depressive episodes than those without. Consequently, risk appears highest for PDs that most predispose to chronicity and recurrences. However, also direct risk-modifying effects of PDs exist. PMID- 26590511 TI - Anhedonia is associated with blunted reward sensitivity in first-degree relatives of patients with major depression. AB - BACKGROUND: Anhedonia is a cardinal feature of major depression and is hypothesized to be driven by low motivation, in particular blunted reward sensitivity. It has been suggested to be a marker that represents a genetic predisposition to this disorder. However, little is known about the mechanisms underlying this heightened risk in unaffected first-degree relatives of patients with major depression. We previously demonstrated abnormal reward biases in acutely depressed patients. The present study aimed to examine the development of reward bias in first-degree relatives of patients with major depression. METHODS: Forty-seven first-degree relatives of patients with major depression (26 females, age 18-52) and 60 healthy controls with no family history of depression (34 females, age 21-48) were recruited. A probabilistically rewarded difficult visual discrimination task, in which participants were instructed about the contingencies, was used to assess blunted reward sensitivity. A response bias towards the more frequently rewarded stimulus (termed "reward bias") was the primary outcome variable in this study. Participants also completed self-reported measures of anhedonia and depressive symptoms. RESULTS: Compared with the control group, relatives of patients with major depression with sub-clinical depressive symptoms displayed a blunted reward bias. Relatives without symptoms displayed largely intact motivational processing on both self-report and experimental measures. The degree of anhedonia was associated with attenuated reward bias in first-degree relatives of patients with major depression, especially in those with sub-clinical symptoms. LIMITATIONS: The study did not include a depressed patient group, which restricted our ability to interpret the observed group differences. CONCLUSIONS: Blunted reward sensitivity may be largely manifested in a subgroup of relatives with high levels of depressive symptoms. PMID- 26590512 TI - Associations of age with reward delay discounting and response inhibition in adolescents with bipolar disorders. AB - OBJECTIVES: Bipolar disorders' (BD) onset before age 18 is a potential marker for a more severe illness course. Adolescence is also a period of significant normative maturation of inhibitory control and reward-relevant decision-making processes, such as decreased delay discounting (i.e., decreased preference for smaller, immediate versus larger, delayed rewards). Adults with BD exhibit elevated delay discounting rates. Very little is known about developmental changes in delay discounting in adolescents with BD, or about associations between inhibitory control and delay discounting in BD. The present study addresses these questions. METHODS: The sample included 78 participants, ages 13 to 23, with BD or without history of mental illness. Group differences and group by age interaction effects on delay discounting (32 BD, 32 controls with valid responses), probability discounting (34 BD, 37 controls) and inhibitory control indices (34 BD, 38 controls) were assessed. RESULTS: Among healthy controls, less discounting of delayed rewards was associated with older age, whereas adolescents with BD did not show age-related associations. There were no group differences in probability discounting or inhibitory control. LIMITATIONS: The cross-sectional nature of the study cannot fully rule out the less likely interpretation of group differences in cohort effects. CONCLUSIONS: The lack of age-related improvement in delay tolerance in BD suggests disrupted development of executive control processes within reward contexts, which in turn may contribute to understanding more severe course of pediatric onset BD. Longitudinal studies are needed to examine delay discounting in relation to maturation of neural reward systems among adolescents with BD. PMID- 26590513 TI - Feasibility of a psychoeducational family intervention for people with bipolar I disorder and their relatives: Results from an Italian real-world multicentre study. AB - BACKGROUND: Despite several guidelines recommend the use of psychoeducational family interventions (PFIs) as add-on in the treatment of patients with bipolar I disorder, their implementation on a large scale remains limited. The aim of the present study is to identify obstacles for the feasibility of PFIs in routine care. METHODS: This was a multicentre, real-world, controlled, outpatient trial, carried out in 11 randomly recruited Italian mental health centres. Two mental health professionals from each center attended a modular training course on PFI and provided the intervention. Difficulties and benefits experienced by mental health professionals in implementing the intervention were assessed through the Family Intervention Schedule (FIS-R), which was administered six times. RESULTS: Sixteen out of the 22 recruited professionals completed the training and administered the PFI to 70 patients with bipolar I disorder and their relatives. The retention rate of families receiving the intervention was 93%. Mental health professionals reported high levels of organizational difficulties, several benefits in their daily clinical work and low levels of intervention-related difficulties. The most important organizational obstacles were related to the need to integrate the intervention with other work responsibilities and to the lack of time to carry out the intervention. These difficulties did not decrease over time. Intervention-related difficulties were rated as less problematic since the first time assessment and tended to improve over time. LIMITATIONS: Low number of recruited professionals; use of a not previously validated assessment instrument. CONCLUSIONS: PFIs are feasible in routine care for the treatment of patients with bipolar I disorder and their relatives, and main obstacles are related to the organization/structure of mental health centres, and not to the characteristics of the intervention itself. PMID- 26590514 TI - The classification of Obsessive-Compulsive and Related Disorders in the ICD-11. AB - BACKGROUND: To present the rationale for the new Obsessive-Compulsive and Related Disorders (OCRD) grouping in the Mental and Behavioural Disorders chapter of the Eleventh Revision of the World Health Organization's International Classification of Diseases and Related Health Problems (ICD-11), including the conceptualization and essential features of disorders in this grouping. METHODS: Review of the recommendations of the ICD-11 Working Group on the Classification for OCRD. These sought to maximize clinical utility, global applicability, and scientific validity. RESULTS: The rationale for the grouping is based on common clinical features of included disorders including repetitive unwanted thoughts and associated behaviours, and is supported by emerging evidence from imaging, neurochemical, and genetic studies. The proposed grouping includes obsessive compulsive disorder, body dysmorphic disorder, hypochondriasis, olfactory reference disorder, and hoarding disorder. Body-focused repetitive behaviour disorders, including trichotillomania and excoriation disorder are also included. Tourette disorder, a neurological disorder in ICD-11, and personality disorder with anankastic features, a personality disorder in ICD-11, are recommended for cross-referencing. LIMITATIONS: Alternative nosological conceptualizations have been described in the literature and have some merit and empirical basis. Further work is needed to determine whether the proposed ICD-11 OCRD grouping and diagnostic guidelines are mostly likely to achieve the goals of maximizing clinical utility and global applicability. CONCLUSION: It is anticipated that creation of an OCRD grouping will contribute to accurate identification and appropriate treatment of affected patients as well as research efforts aimed at improving our understanding of the prevalence, assessment, and management of its constituent disorders. PMID- 26590515 TI - Prevalence and course of anxiety disorders (and symptom levels) in men across the perinatal period: A systematic review. AB - BACKGROUND: Men's experiences of anxiety within the perinatal period can adversely impact themselves, their partner and infant. However, we know little about the prevalence and course of men's anxiety across the perinatal period. The current review is one of the first to systematically review the published literature. METHODS: Five databases (PubMed, PsycINFO, Cochrane, SCOPUS, and Web of Science) were searched to identify relevant papers published prior to April 2015. The literature search identified articles with data for expectant fathers (prenatal period) and/or fathers of an infant aged between 0 and 1 (postnatal period). The following data were extracted: (a) anxiety disorder prevalence (diagnostic clinical interviews), (b) 'high' anxiety symptom prevalence (above thresholds/cut-points on anxiety symptom scales) and (c) mean anxiety levels (anxiety symptom scales). Initially, 537 unique papers were identified. Subsequently, 43 papers met criteria for inclusion in the review. RESULTS: Prevalence rates for 'any' anxiety disorder (as defined by either diagnostic clinical interviews or above cut-points on symptom scales) ranged between 4.1% and 16.0% during the prenatal period and 2.4-18.0% during the postnatal period. The data reviewed suggest the course of anxiety across the perinatal period is fairly stable with potential decreases postpartum. LIMITATIONS: Wide variation in study measurement and methodology makes synthesis of individual findings difficult. Anxiety is highly comorbid with depression, and thus measures of mixed anxiety/depression might better capture the overall burden of mental illness. CONCLUSIONS: Anxiety disorders are common for men during the perinatal period. Both partners should be included in discussions and interventions focused on obstetric care and parent mental health during the perinatal period. PMID- 26590516 TI - Transcranial direct current stimulation reduces food-craving and measures of hyperphagia behavior in participants with Prader-Willi syndrome. AB - Prader-Willi syndrome (PWS) is a neurodevelopmental genetic disorder characterized by intellectual disabilities and insatiable appetite with compulsive eating leading to severe obesity with detrimental health consequences. Transcranial direct current stimulation (tDCS) has been shown to modulate decision-making and cue-induced food craving in healthy adults. We conducted a pilot double blind, sham-controlled, multicenter study of tDCS modulation of food drive and craving in 10 adult PWS participants, 11 adult obese (OB) and 11 adult healthy-weight control (HWC) subjects. PWS and OB subjects received five consecutive daily sessions of active or sham tDCS over the right dorsolateral prefrontal cortex (DLPFC), while HWC received a single sham and active tDCS in a crossover design. Standardized psychometric instruments assessed food craving, drive and hyperphagia by self-report and caregiver assessment over 30 days. Robust baseline differences were observed in severity scores for the Three-Factor Eating Questionnaire (TFEQ) and Dykens Hyperphagia Questionnaire (DHQ) for PWS compared to HWC while obese participants were more similar to HWC. Active tDCS stimulation in PWS was associated with a significant change from baseline in TFEQ Disinhibition (Factor II) (Z = 1.9, P < 0.05, 30 days) and Total Scores (Z = 2.3, P < 0.02, 30 days), and participant ratings of the DHQ Severity (Z = 1.8, P < 0.06, 5 days) and Total Scores (Z = 1.9, P < 0.05, 15 days). These findings support sustained neuromodulatory effects and efficacy of tDCS to reduce food drive and behaviors impacting hyperphagia in PWS. Transcranial direct current stimulation may represent a straight-forward, low risk and low cost method to improve care, management and quality of life in PWS. PMID- 26590517 TI - Multiple biomarkers biosensor with just-in-time functionalization: Application to prostate cancer detection. AB - We present a novel lab-on-a-chip (LOC) device for the simultaneous detection of multiple biomarkers using simple voltage measurements. The biosensor functionalization is performed in-situ, immediately before its use, facilitating reagents storage and massive devices fabrication. Sensitivity, limit of detection (LOD) and limit of quantification (LOQ) are tunable depending on the in-chip flown sample volumes. As a proof-of-concept, the system has been tested and adjusted to quantify two proteins found in blood that are susceptible to be used combined, as a screening tool, to diagnose prostate cancer (PCa): prostate specific antigen (PSA) and spondin-2 (SPON2). This combination of biomarkers has been reported to be more specific for PCa diagnostics than the currently accepted but rather controversial PSA indicator. The range of detection for PSA and SPON2 could be adjusted to the clinically relevant range of 1 to 10 ng/ml. The system was tested for specificity to the evaluated biomarkers. This multiplex system can be modified and adapted to detect a larger quantity of biomarkers, or different ones, of relevance to other specific diseases. PMID- 26590518 TI - Communication: Kohn-Sham theory for excited states of Coulomb systems. AB - For obtaining individual excited-state energies and densities of Coulomb electronic systems, by means of an energy stationary principle, it was shown previously that there exists a universal functional of the density, F(Coul)[rho], for the kinetic plus electron-electron repulsion part of the total energy. Here, we make knowledge of the existence of F(Coul)[rho] practical for calculation by identifying Ts (Coul)[rho], the non-interacting kinetic energy component of F(Coul)[rho], and by showing that Ts (Coul)[rho] may be computed exactly by means of orbitals that are obtained through a set of single-particle Kohn-Sham equations. Constraints for obtaining accurate approximations to the remaining unknown component of F(Coul)[rho] are presented. PMID- 26590519 TI - Communication: Global flux surface hopping in Liouville space. AB - Recent years have witnessed substantial progress in the surface hopping (SH) formulation of non-adiabatic molecular dynamics. A generalization of the traditional fewest switches SH (FSSH), global flux SH (GFSH) utilizes the gross population flow between states to derive SH probabilities. The Liouville space formulation of FSSH puts state populations and coherences on equal footing, by shifting the hopping dynamics from Hilbert to Liouville space. Both ideas have shown superior results relative to the standard FSSH in Hilbert space, which has been the most popular approach over the past two and a half decades. By merging the two ideas, we develop GFSH in Liouville space. The new method is nearly as straightforward as the standard FSSH, and carries comparable computational expense. Tested with a representative super-exchange model, it gives the best performance among all existing techniques in the FSSH series. The obtained numerical results match almost perfectly the exact quantum mechanical solutions. Moreover, the results are nearly invariant under the choice of a basis state representation for SH, in contrast to the earlier techniques which exhibit notable basis set dependence. Unique to the developed approach, this property is particularly encouraging, because exact quantum dynamics is representation independent. GFSH in Liouville space significantly improves accuracy and applicability of SH for a broad range of chemical and physical processes. PMID- 26590520 TI - Communication: Probing anomalous diffusion in frequency space. AB - Anomalous diffusion processes are usually detected by analyzing the time dependent mean square displacement of the diffusing particles. The latter evolves asymptotically as W(t) ~ 2Dalphat(alpha), where Dalpha is the fractional diffusion constant and 0 < alpha < 2. In this article we show that both Dalpha and alpha can also be extracted from the low-frequency Fourier spectrum of the corresponding velocity autocorrelation function. This offers a simple method for the interpretation of quasielastic neutron scattering spectra from complex (bio)molecular systems, in which subdiffusive transport is frequently encountered. The approach is illustrated and validated by analyzing molecular dynamics simulations of molecular diffusion in a lipid POPC bilayer. PMID- 26590521 TI - Nonadiabatic rate constants for proton transfer and proton-coupled electron transfer reactions in solution: Effects of quadratic term in the vibronic coupling expansion. AB - Rate constant expressions for vibronically nonadiabatic proton transfer and proton-coupled electron transfer reactions are presented and analyzed. The regimes covered include electronically adiabatic and nonadiabatic reactions, as well as high-frequency and low-frequency proton donor-acceptor vibrational modes. These rate constants differ from previous rate constants derived with the cumulant expansion approach in that the logarithmic expansion of the vibronic coupling in terms of the proton donor-acceptor distance includes a quadratic as well as a linear term. The analysis illustrates that inclusion of this quadratic term in the framework of the cumulant expansion framework may significantly impact the rate constants at high temperatures for proton transfer interfaces with soft proton donor-acceptor modes that are associated with small force constants and weak hydrogen bonds. The effects of the quadratic term may also become significant in these regimes when using the vibronic coupling expansion in conjunction with a thermal averaging procedure for calculating the rate constant. In this case, however, the expansion of the coupling can be avoided entirely by calculating the couplings explicitly for the range of proton donor-acceptor distances sampled. The effects of the quadratic term for weak hydrogen-bonding systems are less significant for more physically realistic models that prevent the sampling of unphysical short proton donor-acceptor distances. Additionally, the rigorous relation between the cumulant expansion and thermal averaging approaches is clarified. In particular, the cumulant expansion rate constant includes effects from dynamical interference between the proton donor-acceptor and solvent motions and becomes equivalent to the thermally averaged rate constant when these dynamical effects are neglected. This analysis identifies the regimes in which each rate constant expression is valid and thus will be important for future applications to proton transfer and proton-coupled electron transfer in chemical and biological processes. PMID- 26590522 TI - A practical and efficient diabatization that combines Lorentz and Laplace functions to approximate nonadiabatic coupling terms. AB - A fixed relation of alpha * beta = 1.397 between the alpha- and beta-parameters of a Lorentz function and a Laplace function that approximates nonadiabatic coupling terms and maximizes the overlap area between the two functions was found. The mixing angle corresponding to the geometric average between the potential couplings calculated using the individual path-integral of the two functions was then used in the construction of diabatic states and the coupling of the states. Employing the new method, the actual computation of nonadiabatic coupling terms at just a few geometries before and after the guessed conical intersection is enough, and the remaining steps are straightforward and almost automatic. The new method was tested for the one-dimensional LiF system and the two-dimensional space of the collinear case of NH3Cl, and promising results were achieved. PMID- 26590523 TI - Shapes of dominant transition paths from single-molecule force spectroscopy. AB - Recent single molecule measurements of biomolecular folding achieved the time resolution sufficient for observation of individual transition paths. This note discusses several ways in which transition path ensembles can be statistically analyzed to extract a single, "typical" transition path. Analytical approximations derived here for such a transition path further allow one to estimate dynamical parameters (such as the intramolecular diffusion coefficient) directly from the transition path shapes. PMID- 26590524 TI - Accelerating quantum instanton calculations of the kinetic isotope effects. AB - Path integral implementation of the quantum instanton approximation currently belongs among the most accurate methods for computing quantum rate constants and kinetic isotope effects, but its use has been limited due to the rather high computational cost. Here, we demonstrate that the efficiency of quantum instanton calculations of the kinetic isotope effects can be increased by orders of magnitude by combining two approaches: The convergence to the quantum limit is accelerated by employing high-order path integral factorizations of the Boltzmann operator, while the statistical convergence is improved by implementing virial estimators for relevant quantities. After deriving several new virial estimators for the high-order factorization and evaluating the resulting increase in efficiency, using ?Halpha + HbetaHgamma -> HalphaHbeta + ? Hgamma reaction as an example, we apply the proposed method to obtain several kinetic isotope effects on CH4 + ? H ? ? CH3 + H2 forward and backward reactions. PMID- 26590525 TI - A new approach to the method of source-sink potentials for molecular conduction. AB - We re-derive the tight-binding source-sink potential (SSP) equations for ballistic conduction through conjugated molecular structures in a form that avoids singularities. This enables derivation of new results for families of molecular devices in terms of eigenvectors and eigenvalues of the adjacency matrix of the molecular graph. In particular, we define the transmission of electrons through individual molecular orbitals (MO) and through MO shells. We make explicit the behaviour of the total current and individual MO and shell currents at molecular eigenvalues. A rich variety of behaviour is found. A SSP device has specific insulation or conduction at an eigenvalue of the molecular graph (a root of the characteristic polynomial) according to the multiplicities of that value in the spectra of four defined device polynomials. Conduction near eigenvalues is dominated by the transmission curves of nearby shells. A shell may be inert or active. An inert shell does not conduct at any energy, not even at its own eigenvalue. Conduction may occur at the eigenvalue of an inert shell, but is then carried entirely by other shells. If a shell is active, it carries all conduction at its own eigenvalue. For bipartite molecular graphs (alternant molecules), orbital conduction properties are governed by a pairing theorem. Inertness of shells for families such as chains and rings is predicted by selection rules based on node counting and degeneracy. PMID- 26590526 TI - Calculation of correlated initial state in the hierarchical equations of motion method using an imaginary time path integral approach. AB - Based on recent findings in the hierarchical equations of motion (HEOM) for correlated initial state [Y. Tanimura, J. Chem. Phys. 141, 044114 (2014)], we propose a new stochastic method to obtain the initial conditions for the real time HEOM propagation, which can be used further to calculate the equilibrium correlation functions and symmetrized correlation functions. The new method is derived through stochastic unraveling of the imaginary time influence functional, where a set of stochastic imaginary time HEOM are obtained. The validity of the new method is demonstrated using numerical examples including the spin-Boson model, and the Holstein model with undamped harmonic oscillator modes. PMID- 26590527 TI - Ab initio implementation of quantum trajectory mean-field approach and dynamical simulation of the N2CO photodissociation. AB - In this work, the recently introduced quantum trajectory mean-field (QTMF) approach is implemented and employed to explore photodissociation dynamics of diazirinone (N2CO), which are based on the high-level ab initio calculation. For comparison, the photodissociation process has been simulated as well with the fewest-switches surface hopping (FSSH) and the ab initio multiple spawning (AIMS) methods. Overall, the dynamical behavior predicted by the three methods is consistent. The N2CO photodissociation at lambda > 335 nm is an ultrafast process and the two C-N bonds are broken in a stepwise way, giving birth to CO and N2 as the final products in the ground state. Meanwhile, some noticeable differences were found in the QTMF, FSSH, and AIMS simulated time constants for fission of the C-N bonds, excited-state lifetime, and nonadiabatic transition ratios in different intersection regions. These have been discussed in detail. The present study provides a clear evidence that direct ab initio QTMF approach is one of the reliable tools for simulating nonadiabatic dynamics processes. PMID- 26590528 TI - Extending the applicability of Redfield theories into highly non-Markovian regimes. AB - We present a new, computationally inexpensive method for the calculation of reduced density matrix dynamics for systems with a potentially large number of subsystem degrees of freedom coupled to a generic bath. The approach consists of propagation of weak-coupling Redfield-like equations for the high-frequency bath degrees of freedom only, while the low-frequency bath modes are dynamically arrested but statistically sampled. We examine the improvements afforded by this approximation by comparing with exact results for the spin-boson model over a wide range of parameter space. We further generalize the method to multi-site models and compare with exact results for a model of the Fenna-Matthews-Olson complex. The results from the method are found to dramatically improve Redfield dynamics in highly non-Markovian regimes, at a similar computational cost. Relaxation of the mode-freezing approximation via classical (Ehrenfest) evolution of the low-frequency modes results in a dynamical hybrid method. We find that this Redfield-based dynamical hybrid approach, which is computationally more expensive than bare Redfield dynamics, yields only a marginal improvement over the simpler approximation of complete mode arrest. PMID- 26590529 TI - Ab initio approaches for the determination of heavy element energetics: Ionization energies of trivalent lanthanides (Ln = La-Eu). AB - An effective approach for the determination of lanthanide energetics, as demonstrated by application to the third ionization energy (in the gas phase) for the first half of the lanthanide series, has been developed. This approach uses a combination of highly correlated and fully relativistic ab initio methods to accurately describe the electronic structure of heavy elements. Both scalar and fully relativistic methods are used to achieve an approach that is both computationally feasible and accurate. The impact of basis set choice and the number of electrons included in the correlation space has also been examined. PMID- 26590530 TI - Relationship between entropy and diffusion: A statistical mechanical derivation of Rosenfeld expression for a rugged energy landscape. AB - Diffusion-a measure of dynamics, and entropy-a measure of disorder in the system are found to be intimately correlated in many systems, and the correlation is often strongly non-linear. We explore the origin of this complex dependence by studying diffusion of a point Brownian particle on a model potential energy surface characterized by ruggedness. If we assume that the ruggedness has a Gaussian distribution, then for this model, one can obtain the excess entropy exactly for any dimension. By using the expression for the mean first passage time, we present a statistical mechanical derivation of the well-known and well tested scaling relation proposed by Rosenfeld between diffusion and excess entropy. In anticipation that Rosenfeld diffusion-entropy scaling (RDES) relation may continue to be valid in higher dimensions (where the mean first passage time approach is not available), we carry out an effective medium approximation (EMA) based analysis of the effective transition rate and hence of the effective diffusion coefficient. We show that the EMA expression can be used to derive the RDES scaling relation for any dimension higher than unity. However, RDES is shown to break down in the presence of spatial correlation among the energy landscape values. PMID- 26590531 TI - Quantum dynamics on a three-sheeted six-dimensional ab initio potential-energy surface of the phosphine cation: Simulation of the photoelectron spectrum and the ultrafast radiationless decay dynamics. AB - A diabatic three-sheeted six-dimensional potential-energy surface has been constructed for the ground state and the lowest excited state of the PH3 (+) cation. Coupling terms of Jahn-Teller and pseudo-Jahn-Teller origin up to eighth order had to be included to describe the pronounced anharmonicity of the surface due to multiple conical intersections. The parameters of the diabatic Hamiltonian have been optimized by fitting the eigenvalues of the potential-energy matrix to ab initio data calculated at the CASSCF/MRCI level employing the correlation consistent triple-zeta basis. The theoretical photoelectron spectrum of phosphine and the non-adiabatic nuclear dynamics of the phosphine cation have been computed by propagating nuclear wave packets with the multiconfiguration time-dependent Hartree method. The theoretical photoelectron bands obtained by Fourier transformation of the autocorrelation function agree well with the experimental results. It is shown that the ultrafast non-radiative decay dynamics of the first excited state of PH3 (+) is dominated by the exceptionally strong Jahn-Teller coupling of the asymmetric bending vibrational mode together with a hyperline of conical intersections with the electronic ground state induced by the umbrella mode. Time-dependent population probabilities have been computed for the three adiabatic electronic states. The non-adiabatic Jahn-Teller dynamics within the excited state takes place within ~5 fs. Almost 80% of the excited-state population decay to the ground state within about 10 fs. The wave packets become highly complex and delocalized after 20 fs and no further significant transfer of electronic population seems to occur up to 100 fs propagation time. PMID- 26590532 TI - Path integral Monte Carlo simulations of H2 adsorbed to lithium-doped benzene: A model for hydrogen storage materials. AB - Finite temperature quantum and anharmonic effects are studied in H2-Li(+) benzene, a model hydrogen storage material, using path integral Monte Carlo (PIMC) simulations on an interpolated potential energy surface refined over the eight intermolecular degrees of freedom based upon M05-2X/6-311+G(2df,p) density functional theory calculations. Rigid-body PIMC simulations are performed at temperatures ranging from 77 K to 150 K, producing both quantum and classical probability density histograms describing the adsorbed H2. Quantum effects broaden the histograms with respect to their classical analogues and increase the expectation values of the radial and angular polar coordinates describing the location of the center-of-mass of the H2 molecule. The rigid-body PIMC simulations also provide estimates of the change in internal energy, DeltaUads, and enthalpy, DeltaHads, for H2 adsorption onto Li(+)-benzene, as a function of temperature. These estimates indicate that quantum effects are important even at room temperature and classical results should be interpreted with caution. Our results also show that anharmonicity is more important in the calculation of U and H than coupling-coupling between the intermolecular degrees of freedom becomes less important as temperature increases whereas anharmonicity becomes more important. The most anharmonic motions in H2-Li(+)-benzene are the "helicopter" and "ferris wheel" H2 rotations. Treating these motions as one dimensional free and hindered rotors, respectively, provides simple corrections to standard harmonic oscillator, rigid rotor thermochemical expressions for internal energy and enthalpy that encapsulate the majority of the anharmonicity. At 150 K, our best rigid-body PIMC estimates for DeltaUads and DeltaHads are 13.3 +/- 0.1 and -14.5 +/- 0.1 kJ mol(-1), respectively. PMID- 26590533 TI - Photodissociation dynamics of CH3C(O)SH in argon matrix: A QM/MM nonadiabatic dynamics simulation. AB - In this work, we have first employed the combined quantum mechanics/molecular mechanics (QM/MM) method to study the photodissociation mechanism of thioacetic acid CH3C(O)SH in the S1, T1, and S0 states in argon matrix. CH3C(O)SH is treated quantum mechanically using the complete active space self-consistent field and complete active space second-order perturbation theory methods; argon matrix is described classically using Lennard-Jones potentials. We find that the C-S bond fission is predominant due to its small barriers of ca. 3.0 and 1.0 kcal/mol in the S1 and T1 states. It completely suppresses the nearby C-C bond fission. After the bond fission, the S1 radical pair of CH3CO and SH can decay to the S0 and T1 states via internal conversion and intersystem crossing, respectively. In the S0 state, the radical pair can either recombine to form CH3C(O)SH or proceed to form molecular products of CH2CO and H2S. We have further employed our recently developed QM/MM generalized trajectory-based surface-hopping method to simulate the photodissociation dynamics of CH3C(O)SH. In 1 ps dynamics simulation, 56% trajectories stay at the Franck-Condon region; the S1 C-S bond fission takes place in the remaining 44% trajectories. Among all nonadiabatic transitions, the S1 -> S0 internal conversion is major (55%) but the S1 -> T1 intersystem crossing is still comparable and cannot be ignored, which accounts for 28%. Finally, we have found a radical channel generating the molecular products of CH2CO and H2S, which is complementary to the concerted molecular channel. The present work sets the stage for simulating photodissociation dynamics of similar thio-carbonyl systems in matrix. PMID- 26590534 TI - Rotational analysis of bands of the A - X transition of the C3Ar van der Waals complex. AB - Rotational analyses have been carried out for four of the strongest bands of the A-X transition of the C3Ar van der Waals complex, at 393 and 399 nm. These bands lie near the 02(-)0-000 and 04(-)0-000 bands of the A(1)Piu-X(1)Sigma(+) g transition of C3 and form two close pairs, each consisting of a type A and a type C band of an asymmetric top, about 4 cm(-1) apart. Only K" = even lines are found, showing that the complex has two equivalent carbon atoms (I = 0), and must be T-shaped, or nearly so. Strong a- and b-axis electronic-rotational (Coriolis) coupling occurs between the upper states of a pair, since they correlate with a (1)Piu vibronic state of C3, where the degeneracy is lifted in the lower symmetry of the complex. Least squares rotational fits, including the coupling, have given the rotational constants for both electronic states: the van der Waals bond lengths are 3.81 and 3.755 A, respectively, in the ground and excited electronic states. For the ground state our new quantum chemical calculations, using the Multi-Channel Time-Dependent Hartree method, indicate that the C3 unit is non linear, and that the complex does not have a rigid-molecule structure, existing instead as a superposition of arrowhead (?) and distorted Y-shaped (Y) structures. PMID- 26590535 TI - Hydrolysis of ammonia borane and metal amidoboranes: A comparative study. AB - A gas phase mechanistic investigation has been carried out theoretically to explore the hydrolysis pathway of ammonia borane (NH3BH3) and metal amidoboranes (MNH2BH3, M = Li,Na). The Solvation Model based on Density (SMD) has been employed to show the effect of bulk water on the reaction mechanism. Gibbs free energy of solvation has also been computed to evaluate the stabilization of the participating systems in water medium which directly affects the barrier heights in the potential energy surface of hydrolysis reaction. To validate the experimentally observed kinetics studies, we have carried out transition state theory calculations on these hydrolysis reactions. Our result shows that the hydrolysis of both the metal amidoboranes exhibits greatly improved kinetics over the neat NH3BH3 hydrolysis which corroborates well with the experimental observation. Between the two amidoboranes, hydrolysis of LiNH2BH3 is found to be kinetically favored over that of NaNH2BH3, making it a better candidate for releasing molecular hydrogen. PMID- 26590536 TI - Vibrational dynamics of aqueous hydroxide solutions probed using broadband 2DIR spectroscopy. AB - We employed ultrafast transient absorption and broadband 2DIR spectroscopy to study the vibrational dynamics of aqueous hydroxide solutions by exciting the O-H stretch vibrations of the strongly hydrogen-bonded hydroxide solvation shell water and probing the continuum absorption of the solvated ion between 1500 and 3800 cm(-1). We observe rapid vibrational relaxation processes on 150-250 fs time scales across the entire probed spectral region as well as slower vibrational dynamics on 1-2 ps time scales. Furthermore, the O-H stretch excitation loses its frequency memory in 180 fs, and vibrational energy exchange between bulk-like water vibrations and hydroxide-associated water vibrations occurs in ~200 fs. The fast dynamics in this system originate in strong nonlinear coupling between intra and intermolecular vibrations and are explained in terms of non-adiabatic vibrational relaxation. These measurements indicate that the vibrational dynamics of the aqueous hydroxide complex are faster than the time scales reported for long-range transport of protons in aqueous hydroxide solutions. PMID- 26590537 TI - Mobility propagation and dynamic facilitation in superionic conductors. AB - In an earlier work [V. A. Annamareddy et al., Phys. Rev. E 89, 010301(R) (2014)], we showed the manifestation of dynamical heterogeneity (DH)-the presence of clustered mobile and immobile regions-in UO2, a model type II superionic conductor. In the current work, we demonstrate the mechanism of dynamic facilitation (DF) in two superionic conductors (CaF2 and UO2) using atomistic simulations. Using the mobility transfer function, DF is shown to vary non monotonically with temperature with the intensity of DF peaking at temperatures close to the superionic transition temperature (Tlambda). Both the metrics quantifying DH and DF show remarkable correspondence implying that DF, in the framework of kinematically constrained models, underpins the heterogeneous dynamics in type II superionic conductors. PMID- 26590538 TI - Scaling of the dynamics of flexible Lennard-Jones chains: Effects of harmonic bonds. AB - The previous paper [A. A. Veldhorst et al., J. Chem. Phys. 141, 054904 (2014)] demonstrated that the isomorph theory explains the scaling properties of a liquid of flexible chains consisting of ten Lennard-Jones particles connected by rigid bonds. We here investigate the same model with harmonic bonds. The introduction of harmonic bonds almost completely destroys the correlations in the equilibrium fluctuations of the potential energy and the virial. According to the isomorph theory, if these correlations are strong a system has isomorphs, curves in the phase diagram along which structure, dynamics, and the excess entropy are invariant. The Lennard-Jones chain liquid with harmonic bonds does have curves in the phase diagram along which the structure and dynamics are invariant. The excess entropy is not invariant on these curves, which we refer to as "pseudoisomorphs." In particular, this means that Rosenfeld's excess-entropy scaling (the dynamics being a function of excess entropy only) does not apply for the Lennard-Jones chain with harmonic bonds. PMID- 26590539 TI - On the microscopic fluctuations driving the NMR relaxation of quadrupolar ions in water. AB - Nuclear Magnetic Resonance (NMR) relaxation is sensitive to the local structure and dynamics around the probed nuclei. The Electric Field Gradient (EFG) is the key microscopic quantity to understand the NMR relaxation of quadrupolar ions, such as (7)Li(+), (23)Na(+), (25)Mg(2+), (35)Cl(-), (39)K(+), or (133)Cs(+). Using molecular dynamics simulations, we investigate the statistical and dynamical properties of the EFG experienced by alkaline, alkaline Earth, and chloride ions at infinite dilution in water. Specifically, we analyze the effect of the ionic charge and size on the distribution of the EFG tensor and on the multi-step decay of its auto-correlation function. The main contribution to the NMR relaxation time arises from the slowest mode, with a characteristic time on the picosecond time scale. The first solvation shell of the ion plays a dominant role in the fluctuations of the EFG, all the more that the ion radius is small and its charge is large. We propose an analysis based on a simplified charge distribution around the ion, which demonstrates that the auto-correlation of the EFG, hence the NMR relaxation time, reflects primarily the collective translational motion of water molecules in the first solvation shell of the cations. Our findings provide a microscopic route to the quantitative interpretation of NMR relaxation measurements and open the way to the design of improved analytical theories for NMR relaxation for small ionic solutes, which should focus on water density fluctuations around the ion. PMID- 26590540 TI - Pairwise-additive force fields for selected aqueous monovalent ions from adaptive force matching. AB - Simple non-polarizable potentials were developed for Na(+), K(+), Cl(-), and Br( ) using the adaptive force matching (AFM) method with ab initio MP2 method as reference. Our MP2-AFM force field predicts the solvation free energies of the four salts formed by the ions with an error of no more than 5%. Other properties such as the ion-water radial distribution functions, first solvation shell water tilt angle distributions, ion diffusion constants, concentration dependent diffusion constant of water, and concentration dependent surface tension of the solutions were calculated with this potential. Very good agreement was achieved for these properties. In particular, the diffusion constants of the ions are within 6% of experimental measurements. The model predicts bromide to be enriched at the interface in the 1.6M KBr solution but predicts the ion to be repelled for the surface at lower concentration. PMID- 26590541 TI - Relation between pore size and the compressibility of a confined fluid. AB - When a fluid is confined to a nanopore, its thermodynamic properties differ from the properties of a bulk fluid, so measuring such properties of the confined fluid can provide information about the pore sizes. Here, we report a simple relation between the pore size and isothermal compressibility of argon confined in such pores. Compressibility is calculated from the fluctuations of the number of particles in the grand canonical ensemble using two different simulation techniques: conventional grand-canonical Monte Carlo and grand-canonical ensemble transition-matrix Monte Carlo. Our results provide a theoretical framework for extracting the information on the pore sizes of fluid-saturated samples by measuring the compressibility from ultrasonic experiments. PMID- 26590542 TI - Reduced dielectric response in spatially varying electric fields. AB - In this paper, the dynamical equation for polarization is derived. From this the dielectric response to a spatially varying electric field is analyzed showing a reduced response due to flux of polarization in the material. This flux is modeled as a diffusive process through linear constitutive relations between the flux and the gradient of the polarization. Comparison between the theory and molecular dynamics simulations confirms this effect. The effect is significant for small length scale electric field variations and the inclusion of the flux is thus important in nanoscale modeling of dielectric response. PMID- 26590543 TI - Ionic structure in liquids confined by dielectric interfaces. AB - The behavior of ions in liquids confined between macromolecules determines the outcome of many nanoscale assembly processes in synthetic and biological materials such as colloidal dispersions, emulsions, hydrogels, DNA, cell membranes, and proteins. Theoretically, the macromolecule-liquid boundary is often modeled as a dielectric interface and an important quantity of interest is the ionic structure in a liquid confined between two such interfaces. The knowledge gleaned from the study of ionic structure in such models can be useful in several industrial applications, such as in the design of double-layer supercapacitors for energy storage and in the extraction of metal ions from wastewater. In this article, we compute the ionic structure in a model system of electrolyte confined by two planar dielectric interfaces using molecular dynamics simulations and liquid state theory. We explore the effects of high electrolyte concentrations, multivalent ions, dielectric contrasts, and external electric field on the ionic distributions. We observe the presence of non-monotonic ionic density profiles leading to a layered structure in the fluid which is attributed to the competition between electrostatic and steric (entropic) interactions. We find that thermal forces that arise from symmetry breaking at the interfaces can have a profound effect on the ionic structure and can oftentimes overwhelm the influence of the dielectric discontinuity. The combined effect of ionic correlations and inhomogeneous dielectric permittivity significantly changes the character of the effective interaction between the two interfaces. PMID- 26590544 TI - Effect of ion polarization on longitudinal excitations in ionic melts. AB - A simplified model for a collective dynamics in ionic melts is proposed for the description of optic-like excitations. Within a polarization model of ionic melt, the analytical expressions for optic and relaxation dipole modes are obtained. The considered model allows one to describe a softening of frequency and an increase of damping of optic modes caused by polarization processes in comparison with the rigid-ion model. The contributions related with ion polarization to time correlation functions are calculated. PMID- 26590545 TI - Role of van der Waals corrections in first principles simulations of alkali metal ions in aqueous solutions. AB - By resorting to a novel implementation of the first-principles-based van der Waals correction (vdWC) based on maximally localized Wannier functions (MLWFs), we inspect its performance and assess its reliability for aqueous solutions of alkali metal ions. In our implementation of vdWCs, an efficient extrapolation scheme is introduced to allow for affordable first principles molecular dynamics avoiding the explicit recalculation of MLWFs at each step. We find that vdWCs, when added to the widely used revPBE gradient corrected functional, influence substantially both structural and dynamical properties of water molecules, with particular emphasis on the hydration shell of the alkali cations. These effects are more evident for strong structure-making and -breaking cationic species. Moreover, self-diffusion coefficients and reorientation correlation times of solvating water molecules change systematically, showing a trend in better agreement with experiments with respect to simulations neglecting the long-range dispersion contributions. PMID- 26590546 TI - The role of non-specific interactions in a patchy model of protein crystallization. AB - We use a coarse-grained model for generic proteins to investigate the formation of structures with P212121 symmetry, the most prevalent space group of protein crystals. To account for the string directionality of protein-protein interactions that has been suggested by previous studies, we represent proteins as spherical particles that are covered by a large number of small, attractive "patches" that are randomly distributed on the protein surface. Attractive interactions between two proteins can then involve several pairs of patches interacting simultaneously. Our results suggest that the unit cell with the lowest energy is not necessarily the one that grows fastest. Rather, growth is favoured if 1) new particles can attach with enough bonds to the growth front and 2) particles that attach in crystallographically inequivalent positions bind to the surface with similar strength [corrected]. We subsequently study the impact of interactions that are not part of crystalline contacts and find that when these non-specific interactions are few and weaker than the crystal contacts, both nucleation and growth are successful. If the proportion of non-specific interactions is increased, crystal growth is still possible in a small range of model temperature. PMID- 26590547 TI - Transferability and accuracy by combining dispersionless density functional and incremental post-Hartree-Fock theories: Noble gases adsorption on coronene/graphene/graphite surfaces. AB - The accuracy and transferability of the electronic structure approach combining dispersionless density functional theory (DFT) [K. Pernal et al., Phys. Rev. Lett. 103, 263201 (2009)] with the method of increments [H. Stoll, J. Chem. Phys. 97, 8449 (1992)], are validated for the interaction between the noble-gas Ne, Ar, Kr, and Xe atoms and coronene/graphene/graphite surfaces. This approach uses the method of increments for surface cluster models to extract intermonomer dispersion-like (2- and 3-body) correlation terms at coupled cluster singles and doubles and perturbative triples level, while periodic dispersionless density functionals calculations are performed to estimate the sum of Hartree-Fock and intramonomer correlation contributions. Dispersion energy contributions are also obtained using DFT-based symmetry-adapted perturbation theory [SAPT(DFT)]. An analysis of the structure of the X/surface (X = Ne, Ar, Kr, and Xe) interaction energies shows the excellent transferability properties of the leading intermonomer correlation contributions across the sequence of noble-gas atoms, which are also discussed using the Drude oscillator model. We further compare these results with van der Waals-(vdW)-corrected DFT-based approaches. As a test of accuracy, the energies of the low-lying nuclear bound states supported by the laterally averaged X/graphite potentials (X = (3)He, (4)He, Ne, Ar, Kr, and Xe) are calculated and compared with the best estimations from experimental measurements and an atom-bond potential model using the ab initio-assisted fine tuning of semiempirical parameters. The bound-state energies determined differ by less than 6-7 meV (6%) from the atom-bond potential model. The crucial importance of including incremental 3-body dispersion-type terms is clearly demonstrated, showing that the SAPT(DFT) approach effectively account for these terms. With the deviations from the best experimental-based estimations smaller than 2.3 meV (1.9%), the accuracy of the combined DFT and post-HF incremental scheme is established for all the noble-gas atoms. With relative deviations smaller than 4% and 11%, good agreement is also achieved by applying the vdW-corrected DFT treatments PBE-D3 and vdW-DF2 for noble-gas atoms heavier than neon. PMID- 26590548 TI - Monitoring the refinement of crystal structures with (15)N solid-state NMR shift tensor data. AB - The (15)N chemical shift tensor is shown to be extremely sensitive to lattice structure and a powerful metric for monitoring density functional theory refinements of crystal structures. These refinements include lattice effects and are applied here to five crystal structures. All structures improve based on a better agreement between experimental and calculated (15)N tensors, with an average improvement of 47.0 ppm. Structural improvement is further indicated by a decrease in forces on the atoms by 2-3 orders of magnitude and a greater similarity in atom positions to neutron diffraction structures. These refinements change bond lengths by more than the diffraction errors including adjustments to X-Y and X-H bonds (X, Y = C, N, and O) of 0.028 +/- 0.002 A and 0.144 +/- 0.036 A, respectively. The acquisition of (15)N tensors at natural abundance is challenging and this limitation is overcome by improved (1)H decoupling in the FIREMAT method. This decoupling dramatically narrows linewidths, improves signal to-noise by up to 317%, and significantly improves the accuracy of measured tensors. A total of 39 tensors are measured with shifts distributed over a range of more than 400 ppm. Overall, experimental (15)N tensors are at least 5 times more sensitive to crystal structure than (13)C tensors due to nitrogen's greater polarizability and larger range of chemical shifts. PMID- 26590549 TI - The transition to the metallic state in low density hydrogen. AB - Solid atomic hydrogen is one of the simplest systems to undergo a metal-insulator transition. Near the transition, the electronic degrees of freedom become strongly correlated and their description provides a difficult challenge for theoretical methods. As a result, the order and density of the phase transition are still subject to debate. In this work, we use diffusion quantum Monte Carlo to benchmark the transition between paramagnetic and anti-ferromagnetic body centered cubic atomic hydrogen in its ground state. We locate the density of the transition by computing the equation of state for these two phases and identify the phase transition order by computing the band gap near the phase transition. These benchmark results show that the phase transition is continuous and occurs at a Wigner-Seitz radius of rs = 2.27(3) a0. We compare our results to previously reported density functional theory, Hedin's GW approximation, and dynamical mean field theory results. PMID- 26590550 TI - Revealing spatially heterogeneous relaxation in a model nanocomposite. AB - The detailed nature of spatially heterogeneous dynamics of glycerol-silica nanocomposites is unraveled by combining dielectric spectroscopy with atomistic simulation and statistical mechanical theory. Analysis of the spatial mobility gradient shows no "glassy" layer, but the alpha-relaxation time near the nanoparticle grows with cooling faster than the alpha-relaxation time in the bulk and is ~20 times longer at low temperatures. The interfacial layer thickness increases from ~1.8 nm at higher temperatures to ~3.5 nm upon cooling to near bulk Tg. A real space microscopic description of the mobility gradient is constructed by synergistically combining high temperature atomistic simulation with theory. Our analysis suggests that the interfacial slowing down arises mainly due to an increase of the local cage scale barrier for activated hopping induced by enhanced packing and densification near the nanoparticle surface. The theory is employed to predict how local surface densification can be manipulated to control layer dynamics and shear rigidity over a wide temperature range. PMID- 26590551 TI - Extended two-temperature model for ultrafast thermal response of band gap materials upon impulsive optical excitation. AB - Thermal modeling and numerical simulations have been performed to describe the ultrafast thermal response of band gap materials upon optical excitation. A model was established by extending the conventional two-temperature model that is adequate for metals, but not for semiconductors. It considers the time- and space dependent density of electrons photoexcited to the conduction band and accordingly allows a more accurate description of the transient thermal equilibration between the hot electrons and lattice. Ultrafast thermal behaviors of bismuth, as a model system, were demonstrated using the extended two temperature model with a view to elucidating the thermal effects of excitation laser pulse fluence, electron diffusivity, electron-hole recombination kinetics, and electron-phonon interactions, focusing on high-density excitation. PMID- 26590552 TI - Phase behavior and second osmotic virial coefficient for competitive polymer solvation in mixed solvent solutions. AB - We apply our recently developed generalized Flory-Huggins (FH) type theory for the competitive solvation of polymers by two mixed solvents to explain general trends in the variation of phase boundaries and solvent quality (quantified by the second osmotic virial coefficient B2) with solvent composition. The complexity of the theoretically predicted miscibility patterns for these ternary mixtures arises from the competitive association between the polymer and the solvents and from the interplay of these associative interactions with the weak van der Waals interactions between all components of the mixture. The main focus here lies in determining the influence of the free energy parameters for polymer solvent association (solvation) and the effective FH interaction parameters {chialphabeta} (driving phase separation) on the phase boundaries (specifically the spinodals), the second osmotic virial coefficient B2, and the relation between the positions of the spinodal curves and the theta temperatures at which B2 vanishes. Our classification of the predicted miscibility patterns is relevant to numerous applications of ternary polymer solutions in industrial formulations and the use of mixed solvent systems for polymer characterization, such as chromatographic separation where mixed solvents are commonly employed. A favorable comparison of B2 with experimental data for poly(methyl methacrylate)/acetonitrile/methanol (or 1-propanol) solutions only partially supports the validity of our theoretical predictions due to the lack of enough experimental data and the neglect of the self and mutual association of the solvents. PMID- 26590553 TI - Curvature inducing macroion condensation driven shape changes of fluid vesicles. AB - We study the effect of curvature inducing macroion condensation on the shapes of charged deformable fluid interfaces using dynamically triangulated Monte Carlo simulations. In the weak electrostatic coupling regime, surface charges are weakly screened and the conformations of a vesicle, with fixed spherical topology, depend on the charge-charge interaction on the surface. While in the strong coupling regime, condensation driven curvature induction plays a dominant role in determining the conformations of these surfaces. Condensation itself is observed to be dependent on the induced curvature, with larger induced curvatures favoring increased condensation. We show that both curvature generation and curvature sensing, induced by the interplay of electrostatics and curvature energy, contribute to determination of the vesicle configurations. PMID- 26590554 TI - Dichotomous noise models of gene switches. AB - Molecular noise in gene regulatory networks has two intrinsic components, one part being due to fluctuations caused by the birth and death of protein or mRNA molecules which are often present in small numbers and the other part arising from gene state switching, a single molecule event. Stochastic dynamics of gene regulatory circuits appears to be largely responsible for bifurcations into a set of multi-attractor states that encode different cell phenotypes. The interplay of dichotomous single molecule gene noise with the nonlinear architecture of genetic networks generates rich and complex phenomena. In this paper, we elaborate on an approximate framework that leads to simple hybrid multi-scale schemes well suited for the quantitative exploration of the steady state properties of large-scale cellular genetic circuits. Through a path sum based analysis of trajectory statistics, we elucidate the connection of these hybrid schemes to the underlying master equation and provide a rigorous justification for using dichotomous noise based models to study genetic networks. Numerical simulations of circuit models reveal that the contribution of the genetic noise of single molecule origin to the total noise is significant for a wide range of kinetic regimes. PMID- 26590555 TI - Publisher's Note: "Near-field optical effect of a core-shell nanostructure in proximity to a flat surface" [J. Chem. Phys. 140, 044109 (2014)]. PMID- 26590558 TI - Developing a gender-based approach to chronic conditions and women's health: a qualitative investigation of community-dwelling women and service provider perspectives. AB - BACKGROUND: Chronic conditions contribute to over 70 % of Australia's total disease burden, and this is set to increase to 80 % by 2020. Women's greater longevity means that they are more likely than men to live with disability and have unique health concerns related to their gender based roles in society. Cultural and social issues can impact on women's health and are important to consider in health services planning and research. In this study, we aimed to identify barriers and facilitators to providing a gender-based approach to chronic conditions and women's health in an eastern metropolitan region of Australia. METHODS: Focus groups were used to engage both community-dwelling women who had chronic conditions and relevant professional stakeholders in the target area. Recorded proceedings underwent thematic analysis. RESULTS: Five focus groups were conducted with professional stakeholders and women community members in February and March 2014. Resultant themes included: women's disempowerment through interactions with health systems; social and economic constraints and caregiving roles act to exclude women from participating in self care and society; and empowerment can be achieved through integrated models of care that facilitate voice and enable communication and engagement. CONCLUSIONS: This study underscores the importance of including perspectives of sex and gender in health care services planning. Tailoring services to socio-demographic and cultural groups is critical in promoting access to health care services. Unique epidemiological trends, particularly the ageing of women and new migrant groups, require particular attention. PMID- 26590556 TI - Distinguishing bipolar and major depressive disorders by brain structural morphometry: a pilot study. AB - BACKGROUND: The clinical presentation of common symptoms during depressive episodes in bipolar disorder (BD) and major depressive disorder (MDD) poses challenges for accurate diagnosis. Disorder-specific neuroanatomical features may aid the development of reliable discrimination between these two clinical conditions. METHODS: For our sample of 16 BD patients, 19 MDD patients and 29 healthy volunteers, we adopted vertex-wise cortical based brain imaging techniques to examine cortical thickness and surface area, two components of cortical volume with distinct genetic determinants. Based on specific characteristics of neuroanatomical features, we then used support vector machine (SVM) algorithm to discriminate between patients with BD and MDD. RESULTS: Compared to MDD patients, BD patients showed significantly larger cortical surface area in the left bankssts, precuneus, precentral, inferior parietal, superior parietal and the right middle temporal gyri. In addition, larger volumes of subcortical regions were found in BD patients. In SVM discriminative analyses, the overall accuracy was 74.3 %, with a sensitivity of 62.5 % and a specificity of 84.2 % (p = 0.028). Compared to controls, larger surface area in the temporo parietal regions were observed in BD patients, and thinner cortices in fronto temporal regions were observed in MDD patients, especially in the medial orbito frontal area. CONCLUSIONS: These findings have demonstrated distinct spatially distributed variations in cortical thickness and surface area in patients with BD and MDD, suggesting potentially varying etiological and neuropathological processes in these two conditions. The employment of multimodal classification on disorder-specific biological features has shed light to the development of potential classification tools that could aid diagnostic decisions. PMID- 26590557 TI - Is L-methionine a trigger factor for Alzheimer's-like neurodegeneration?: Changes in Abeta oligomers, tau phosphorylation, synaptic proteins, Wnt signaling and behavioral impairment in wild-type mice. AB - BACKGROUND: L-methionine, the principal sulfur-containing amino acid in proteins, plays critical roles in cell physiology as an antioxidant and in the breakdown of fats and heavy metals. Previous studies suggesting the use of L-methionine as a treatment for depression and other diseases indicate that it might also improve memory and propose a role in brain function. However, some evidence indicates that an excess of methionine can be harmful and can increase the risk of developing Type-2 diabetes, heart diseases, certain types of cancer, brain alterations such as schizophrenia, and memory impairment. RESULTS: Here, we report the effects of an L-methionine-enriched diet in wild-type mice and emphasize changes in brain structure and function. The animals in our study presented 1) higher levels of phosphorylated tau protein, 2) increased levels of amyloid-beta (Abeta)-peptides, including the formation of Abeta oligomers, 3) increased levels of inflammatory response,4) increased oxidative stress, 5) decreased level of synaptic proteins, and 6) memory impairment and loss. We also observed dysfunction of the Wnt signaling pathway. CONCLUSION: Taken together, the results of our study indicate that an L-methionine-enriched diet causes neurotoxic effects in vivo and might contribute to the appearance of Alzheimer's like neurodegeneration. PMID- 26590560 TI - Analytical applications of MIPs in diagnostic assays: future perspectives. AB - Many efforts have been made to produce artificial materials with biomimetic properties for applications in binding assays. Among these efforts, the technique of molecular imprinting has received much attention because of the high selectivity obtainable for molecules of interest, robustness of the produced polymers, simple and short synthesis, and excellent cost efficiency. In this review, progress in the field of molecularly imprinted sorbent assays is discussed-with a focus on work conducted from 2005 to date. PMID- 26590561 TI - Microchamber arrays with an integrated long luminescence lifetime pH sensor. AB - A pH probe with a microsecond luminescence lifetime was obtained via covalent coupling of 6-carboxynaphthofluorescein (CNF) moieties to ruthenium-tris-(1,10 phenanthroline)(2+). The probe was covalently attached to amino-modified poly-(2 hydroxyethyl)methacrylate (pHEMA) and showed a pH-dependent FRET with luminescence lifetimes of 681 to 1260 ns and a working range from ca. pH 6.5 to 9.0 with a pKa of 7.79 +/- 0.14. The pH sensor matrix was integrated via spin coating as ca. 1- to 2-MUm-thick layer into "CytoCapture" cell culture dishes of 6 mm in diameter. These contained a microcavity array of square-shaped regions of 40 MUm length and width and 15 MUm depth that was homogeneously coated with the pH sensor matrix. The sensor layer showed fast response times in both directions. A microscopic setup was developed that enabled imaging of the pH inside the microchamber arrays over many hours. As a proof of principle, we monitored the pH of Escherichia coli cell cultures grown in the microchamber arrays. The integrated sensor matrix allowed pH monitoring spatially resolved in every microchamber, and the differences in cell growth between individual chambers could be resolved and quantified. PMID- 26590563 TI - Same procedure as last year, James ... same procedure as every year .... PMID- 26590562 TI - Survivorship and functional outcomes of patellofemoral arthroplasty: a systematic review. AB - PURPOSE: Historically poor results of survivorship and functional outcomes of patellofemoral arthroplasty (PFA) have been reported in the setting of isolated patellofemoral osteoarthritis. More recently, however, fairly good results of PFA were reported, but the current status of PFA outcomes is unknown. Therefore, a systematic review was performed to assess overall PFA survivorship and functional outcomes. METHODS: A search was performed using PubMed, Embase and Cochrane systems, and the registries were searched. Twenty-three cohort studies and one registry reported survivorship using Kaplan-Meier curve, while 51 cohort studies reported functional outcomes of PFA. RESULTS: Twelve studies were level II studies, while 45 studies were level III or IV studies. Heterogeneity was mainly seen in type of prosthesis and year the cohort started. Nine hundred revisions in 9619 PFAs were reported yielding 5-, 10-, 15- and 20-year PFA survivorships of 91.7, 83.3, 74.9 and 66.6 %, respectively, and an annual revision rate of 2.18. Functional outcomes were reported in 2587 PFAs with an overall score of 82.2 % of the maximum score. KSS and Knee Function Score were 87.5 and 81.6 %, respectively. CONCLUSION: This systematic review showed that fairly good results of PFA survivorship and functional outcomes were reported at short- and midterm follow-up in the setting of isolated patellofemoral osteoarthritis. Heterogeneity existed mainly in prosthesis design and year the cohort started. CLINICAL RELEVANCE: These results provide a clear overview of the current status of PFA in the setting of isolated patellofemoral osteoarthritis. LEVEL OF EVIDENCE: IV. PMID- 26590564 TI - Effects of total knee arthroplasty on ankle alignment in patients with varus gonarthrosis: Do we sacrifice ankle to the knee? AB - PURPOSE: Total knee arthroplasty is one of the most commonly preferred surgical methods in the treatment of patients with varus gonarthrosis. In this study, we aimed to evaluate the radiological changes observed in the ankles after total knee arthroplasty. METHODS: Between May 2012 and June 2013, 80 knees of 78 patients with varus deformity over 10 degrees underwent total knee arthroplasty. For each patient, full-leg standing radiographs were obtained pre- and post operatively. Mechanical and anatomical axes (HKA and AA), lateral distal femoral angle, medial proximal tibial angle, lateral distal tibial angle (LDTA), ankle joint line orientation angle (AJOA), tibial plafond talus angle (PTA) and talar shift were measured for each patient both pre- and post-operatively. RESULTS: Pre operatively, the mean HKA was 16.6 degrees and the mean AA was 10.41 degrees , both in favour of varus alignment. Post-operatively, the mean HKA decreased to 3.6 degrees and the mean AA to -2.1. The mean LDTA was 87.3 degrees . Before the operation, the mean AJOA was -7.6 degrees , opening to the medial aspect of the ankle, and it was 0.04 degrees after the operation and opening to the lateral aspect (p < 0.05). CONCLUSION: Our study reveals the changes occurring in the ankle after acute correction of long-standing varus deformity of the knee using total knee arthroplasty. In cases undergoing knee arthroplasty, effect of the acute change in the alignment of the knee on the ankle should be taken into consideration and the amount of correction should be calculated carefully in order not to damage the alignment of the ankle. LEVEL OF EVIDENCE: IV. PMID- 26590565 TI - Concomitant intra-articular glenohumeral injuries in displaced fractures of the lateral clavicle. AB - PURPOSE: To detect concomitant intra-articular glenohumeral injuries, in acute displaced fractures of the lateral clavicle, initially missed due to unfeasible clinical evaluation of the acutely injured shoulder. METHODS: All patients suffering from an acute displaced lateral clavicle fracture with indication to surgical treatment underwent diagnostic shoulder arthroscopy prior to open reduction and internal fixation. In case of therapy-relevant intra-articular glenohumeral injuries, subsequent surgical treatment was performed. RESULTS: Intra-articular injuries were found in 13 of 28 patients (46.4 %) with initially suspected isolated lateral clavicle fracture. Additional surgical treatment was performed in 8 of 28 cases (28.6 %). Superior labral anterior-posterior (SLAP) lesions were observed in 4 of 28 patients (14.3 %; SLAP II a: 1; II b: 1; III: 1; and IV: 1). Lesions of the pulley system were found in 3 of 28 patients (10.7 %; Habermeyer III degrees ). One partial articular supraspinatus tendon avulsion lesion (3.6 %) and one lesion of the subscapularis tendon (3.6 %; Fox and Romeo II degrees ) were observed. CONCLUSIONS: Traumatic concomitant glenohumeral injuries in lateral clavicle fractures seem to be more frequent than expected in general. Subsequent surgical treatment of these formerly missed but therapy relevant injuries may increase functional outcome and reduce complication rate. LEVEL OF EVIDENCE: IV. PMID- 26590566 TI - Unicompartmental knee arthroplasty versus total knee arthroplasty: Which type of artificial joint do patients forget? AB - PURPOSE: During recent years, there has been an intensive growth of interest in the patient's perception of functional outcome. The Forgotten Joint Score (FJS) is a recently introduced score that measures joint awareness of patients who have undergone knee arthroplasty and is less limited by ceiling effects. The aim of this study was to compare the FJS between patients who undergo medial unicompartmental knee arthroplasty (UKA) and patients who undergo total knee arthroplasty (TKA) 1 and 2 years post-operatively. METHODS: This prospective study compares the FJS at a minimum of one (average 1.5 years, range 1.0-1.9) and a minimum of 2 years (average 2.5 years, range 2.0-3.6) post-operatively between patients who underwent medial UKA and TKA. RESULTS: One-hundred and thirty patients were included. Sixty-five patients underwent medial UKA and 65 patients underwent TKA. At both follow-up points, the FJS was significantly higher in the UKA group (FJS 1 year 73.9 +/- 22.8, FJS 2 year 74.3 +/- 24.8) in contrast to the TKA group (FJS 1 year 59.3 +/- 29.5 (p = 0.002), FJS 2 year 59.8 +/- 31.5, (p = 0.004)). No significant improvement in the FJS was observed between 1- and 2-year follow-up of the two cohorts. CONCLUSION: Patients who undergo UKA are more likely to forget their artificial joint in daily life and consequently may be more satisfied. LEVEL OF EVIDENCE: II. PMID- 26590567 TI - Comparison of quadriceps muscle volume after unilateral total knee arthroplasty with and without tourniquet use. AB - PURPOSE: Determination of the effect of tourniquet use in total knee arthroplasty (TKA) on thigh and quadriceps muscle volume using magnetic resonance imaging (MRI). METHODS: A total of 148 knees of 74 patients (mean age 66.5 +/- 4.8 years; female/male, 62/12) with bilateral primary varus gonarthrosis underwent unilateral TKA with a tourniquet (Group A, n = 35) or without a tourniquet (Group B, n = 39). The total thigh volume and connective, bone, and muscle tissue volumes were stereologically measured on preoperative and postoperative MRI. The Knee Society Score (KSS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score were calculated to evaluate functional outcomes. RESULTS: After TKA, the knees of patients in Group A exhibited a significant decrease in all tissue measurements, except bone tissue volume; however, the knees of patients in Group B exhibited no significant difference in tissue measurements. Although no difference was found between the operated and contralateral non-operated thighs (4076.9 and 4073.4 cm(3), respectively) in Group B postoperatively at 1 month (p > 0.05), the operated thighs had lost 20 % of its volume in Group A postoperatively at 1 month (p < 0.001). A significant difference was found in all tissue measurements, except the connective and bone tissue volumes of the thigh between the operated and contralateral non-operated knees in Group A. No significant difference was identified between the operated and contralateral non-operated knees in Group B. The total WOMAC score was significantly higher, and the total KSS was significantly lower in Group A than in Group B during the postoperative follow-up period of 1-6 months (p < 0.001 for all) but not 12 months (n.s.). CONCLUSION: Tourniquet use in TKA decreases the thigh and quadriceps muscle volumes and postoperatively delays the recovery of knee function. Therefore, caution should be exercised for tourniquet use during TKA in daily clinical practice and using alternative methods for tourniquet application in preventing intraoperative blood loss. LEVEL OF EVIDENCE: III. PMID- 26590568 TI - Assessment of Event-Related EEG Power After Single-Pulse TMS in Unresponsive Wakefulness Syndrome and Minimally Conscious State Patients. AB - In patients without a behavioral response, non-invasive techniques and new methods of data analysis can complement existing diagnostic tools by providing a method for detecting covert signs of residual cognitive function and awareness. The aim of this study was to investigate the brain oscillatory activities synchronized by single-pulse transcranial magnetic stimulation (TMS) delivered over the primary motor area in the time-frequency domain in patients with the unresponsive wakefulness syndrome or in a minimally conscious state as compared to healthy controls. A time-frequency analysis based on the wavelet transform was used to characterize rapid modifications of oscillatory EEG rhythms induced by TMS in patients as compared to healthy controls. The pattern of EEG changes in the patients differed from that of healthy controls. In the controls there was an early synchronization of slow waves immediately followed by a desynchronization of alpha and beta frequency bands over the frontal and centro-parietal electrodes, whereas an opposite early synchronization, particularly over motor areas for alpha and beta and over the frontal and parietal electrodes for beta power, was seen in the patients. In addition, no relevant modification in slow rhythms (delta and theta) after TMS was noted in patients. The clinical impact of these findings could be relevant in neurorehabilitation settings for increasing the awareness of these patients and defining new treatment procedures. PMID- 26590569 TI - Gaming and Religion: The Impact of Spirituality and Denomination. AB - A previous investigation from Korea indicated that religion might modulate gaming behavior (Kim and Kim in J Korean Acad Nurs 40:378-388, 2010). Our present study aimed to investigate whether a belief in God, practicing religious behavior and religious denomination affected gaming behavior. Data were derived from a Western cohort of young men (Cohort Study on Substance Use Risk Factors, n = 5990). The results showed that a stronger belief in God was associated with lower gaming frequency and smaller game addiction scale scores. In addition, practicing religiosity was related to less frequent online and offline gaming. Finally, Christians gamed less frequently and had lower game addiction scale scores than subjects without religious denomination. In the future, these results could prove useful in developing preventive and therapeutic strategies for the Internet gaming disorder. PMID- 26590570 TI - Oral Alimentation in Neonatal and Adult Populations Requiring High-Flow Oxygen via Nasal Cannula. AB - Use of high-flow oxygen via nasal cannula (HFO2-NC) is increasingly common in intensive care unit (ICU) settings. Despite the critical interface between respiration and swallowing, and the high acuity of patients in ICUs, the impact of HFO2-NC on feeding and swallowing is unknown. The present prospective, single center, cohort study investigated the impact of HFO2-NC use on oral alimentation in neonatal and adult ICU patients. Oral alimentation status was evaluated in 100 consecutive ICU inpatients (50 neonatal and 50 adult) requiring HFO2-NC. Participant characteristics, respiratory support, successful initiation of oral feeding in neonates, and successful resumption of oral feeding in adults were recorded. Seventeen of 50 (34 %) neonates requiring HFO2-NC were deemed developmentally and medically appropriate by the neonatologist and nursing to begin oral alimentation. All 17 (100 %) were successful with initiation of oral feedings. Thirty-three of 50 (66 %) continued nil per os due to prematurity or medical conditions precluding oral alimentation at time of data collection. Thirty-nine of 50 (78 %) adults requiring HFO2-NC were deemed medically appropriate by the intensivist and nursing to resume oral alimentation (n = 34) or with a functional swallow without aspiration on FEES (n = 5). All 39 (100 %) resumed oral alimentation successfully. Eleven of 50 (22 %) continued nil per os due to severe respiratory issues precluding both swallow testing and oral alimentation at time of data collection. All developmentally and medically appropriate neonatal and adult patients requiring HFO2-NC were successful with either the introduction or resumption of oral alimentation. Patients requiring HFO2-NC who are identified as having feeding or swallowing issues should be referred for swallowing evaluations using the same criteria as patients who do not require HFO2-NC, as it is not the use of HFO2-NC but rather patient-specific determinants of feeding and swallowing readiness and their underlying medical conditions that impact readiness for oral alimentation status. PMID- 26590571 TI - Swallowing Kinematics and Factors Associated with Laryngeal Penetration and Aspiration in Stroke Survivors with Dysphagia. AB - The purpose of this study was to investigate swallowing kinematics and explore kinematic factors related with penetration-aspiration in patients with post stroke dysphagia. Videofluoroscopic images of 68 patients with post-stroke dysphagia and 34 sex- and age-matched healthy controls swallowing a thin liquid were quantitatively analyzed using two-dimensional motion digitization. The measurements included the movement distances and velocities of the hyoid and larynx, and the maximal tilt angles and angular velocities of the epiglottis. All velocity variables were significantly decreased in the stroke patients compared to the controls. There was a significant difference in the maximal horizontal displacement of the larynx, but there were no significant differences in other displacements of the larynx, the maximal displacements of the hyoid bone, and the maximum tilt angle of the epiglottis between the two groups. The maximal tilt angle of the epiglottis was lower in the aspiration subgroup than in the no penetration/aspiration and penetration subgroups as well as the controls. The maximal tilt angle from the y axis showed a dichotomous pattern at 90 degrees of the angle, and all 11 patients with an angle <90 degrees showed either penetration or aspiration. In the ROC curve of the angle for prediction of aspiration, the area under the curve was 0.725 (95 % CI 0.557-0.892, P = 0.008). This study suggested that sluggish rather than decreased hyolaryngeal movements during swallowing are a remarkable feature of post-stroke dysphagia. The association of reduced epiglottic movement with the risk of aspiration in patients with post-stroke dysphagia was supported by the quantitative analysis. PMID- 26590572 TI - Dysphagia in Parkinson's Disease. AB - More than 80 % of patients with Parkinson's disease (PD) develop dysphagia during the course of their disease. Swallowing impairment reduces quality of life, complicates medication intake and leads to malnutrition and aspiration pneumonia, which is a major cause of death in PD. Although the underlying pathophysiology is poorly understood, it has been shown that dopaminergic and non-dopaminergic mechanisms are involved in the development of dysphagia in PD. Clinical assessment of dysphagia in PD patients is challenging and often delivers unreliable results. A modified water test assessing maximum swallowing volume is recommended to uncover oropharyngeal dysphagia in PD. PD-specific questionnaires may also be useful to identify patients at risk for swallowing impairment. Fiberoptic endoscopic evaluation of swallowing and videofluoroscopic swallowing study are both considered to be the gold standard for evaluation of PD-related dysphagia. In addition, high-resolution manometry may be a helpful tool. These instrumental methods allow a reliable detection of aspiration events. Furthermore, typical patterns of impairment during the oral, pharyngeal and/or esophageal swallowing phase of PD patients can be identified. Therapy of dysphagia in PD consists of pharmacological interventions and swallowing treatment by speech and language therapists (SLTs). Fluctuating dysphagia with deterioration during the off-state should be treated by optimizing dopaminergic medication. The methods used during swallowing treatment by SLTs shall be selected according to the individual dysphagia pattern of each PD patient. A promising novel method is an intensive training of expiratory muscle strength. Deep brain stimulation does not seem to have a clinical relevant effect on swallowing function in PD. The goal of this review is giving an overview on current stages of epidemiology, pathophysiology, diagnosis, and treatment of PD associated dysphagia, which might be helpful for neurologists, speech-language therapists, and other clinicians in their daily work with PD patients and associated swallowing difficulties. Furthermore areas with an urgent need for future clinical research are identified. PMID- 26590573 TI - Lentivirus-mediated knockdown of CTDP1 inhibits lung cancer cell growth in vitro. AB - BACKGROUND: CTDP1 catalyzes serine phosphorylation and dephosphorylation of the mobile carboxy-terminal domain of the RNA polymerase II. It is conserved among eukarya and is essential for cell growth for its ability in regulation of transcription machinery. However, its function in the process of tumorigenesis is unclear. In the present study, we aim to explore the roles of CTDP1 in the progression of human lung cancer. To our knowledge, this is the first study that reports the functions of CTDP1 in human lung cancer. METHODS: We first detected the expression level of CTDP1 in four human lung cancer cell lines: H-125, H1299, LTEP-A-2 and NCI-H446 by semiquantitative RT-PCR. We compared the expression level of CTDP1 in lung cancer tissues and paired adjacent normal tissues on 29 pathologically confirmed patients by real-time quantitative PCR. To further explore the effect of CTDP1 on cell proliferation, a lentiviral vector expressing CTDP1 short hairpin RNA (shRNA) was constructed and infected into human lung cell lines H1299. Interference efficiency was determined by western blot analysis and real-time quantitative PCR. The effects of knockdown of CTDP1 on cell growth, cell cycle and apoptosis and cell colony formation were explored by Cellomics, fluorescence-activated cells sorting and fluorescence microscopy, respectively. RESULTS: CTDP1 was expressed in all four human lung cancer cell lines. The expression of CTDP1 in tumor tissues was significantly higher than paired adjacent normal tissues in 29 patients with lung cancer. The expression of CTDP1 was markedly reduced in cells infected with lentivirus delivering shRNA against CTDP1. Inhibition of CTDP1 expression significantly suppressed cell growth, induced G0/G1 phase arrest and repressed cell colony formation. CONCLUSIONS: Our results demonstrated that CTDP1 was upregulated in human lung cancer tissues. In addition, it implied that CTDP1 played an important role in cell proliferation and may be a useful therapeutic target in human lung cancer. PMID- 26590574 TI - CD4+ T cells from patients with acute myeloid leukemia inhibit the proliferation of bone marrow-derived mesenchymal stem cells by secretion of miR-10a. AB - BACKGROUND: The abnormality of bone marrow-derived mesenchymal stem cells (BM MSCs) has been reported to contribute to the pathogenesis of acute myeloid leukemia (AML). T cell immunodeficiencies play important roles in the progression of leukemia. This study investigated the effect of CD4+ T cells from AML patients on the proliferation of BM-MSCs. METHODS: The growth rate of BM-MSCs from AML patients and healthy donor was compared. CD4+ T cells were separated and identified from AML patients. Through co-culturing CD4+ T cells from AML patients and BM-MSCs from healthy, we detected the proliferation of BM-MSCs from healthy by MTT assay. qRT-PCR was performed to examine the expression of miR-10a. Luciferase reporter assay was used to analyze the regulation of miR-10a on the expression of BCL6. RESULTS: Here, we observed that BM-MSC from AML patients grew slower than that from healthy. CD4+ T cells from AML patients inhibited the proliferation of BM-MSCs through secreting miR-10a. In addition, miR-10a was found to target BCL6 and regulated its expression in transcription and translation levels. Correlation analysis revealed that the level of miR-10a in serum of AML patients was negatively correlated with BCL6 in BM-MSC. CONCLUSION: This study provides evidence that CD4+ T cells from AML patients suppress the proliferation of BM-MSCs via secreting miR-10a. PMID- 26590575 TI - Risk of neonatal mortality according to gestational age after elective repeat cesarean delivery. AB - PURPOSE: Despite the well-known neonatal morbidity risks after elective cesarean deliveries performed before 39 weeks, there are scarce data regarding mortality risks. The objective of this study was to calculate the risk of neonatal mortality after elective repeat cesarean delivery (ERCD) by gestational age. METHODS: The Linked Birth-Infant Death Data Files from the Vital Statistics Data of the Center for Disease Control and Prevention of the U.S. from 2004 to 2008 were analyzed. Only ERCD cases were included. Early death (<7 days), neonatal death (<28 days), and infant death (<1 year) were evaluated. A logistic regression model was used to calculate odds ratios. Cases delivered at 37-41 weeks were studied with 40 weeks as reference. RESULTS: A total of 483,052 cases were included for analysis. The distribution of rates and odds ratios for infant, neonatal and early death was U-shaped with the nadir at 39 weeks. There was a statistically significant increase in early death at 37 compared to 40 weeks' gestation [OR (95 %) CI = 1.929(1.172-3.176)]. No statistical increase was found in any of the other mortality risks. CONCLUSION: There is an increased risk in early death with ERCD performed at 37 weeks. Our study provides evidence of neonatal harm beyond the reported morbidity risks. PMID- 26590576 TI - Pelvic floor muscle training for female urinary incontinence: Does it work? AB - PURPOSE: Supervised pelvic floor muscle training in patients of stress and mixed urinary incontinence has been recommended. Our aim was to assess the utilisation and effectiveness of our supervised pelvic floor muscle training service and assess the impact of incontinence scores before physiotherapy on the subsequent results of physiotherapy. METHODS: All 271 patients referred to physiotherapy for symptoms of incontinence filled out the International Consultation on Incontinence Modular Questionnaire-Female Lower Urinary Tract Symptoms before starting treatment. Depending on pelvic floor muscle assessment, plans for exercises and follow up were made. If the strength of pelvic floor muscles was poor, electrical stimulation was offered. If awareness of the pelvic floor muscle contraction was poor, bio feedback was offered. Group sessions and vaginal cones were also used. Depending on the response to the treatment; patients were either discharged, referred to Urogynaecology clinic or continued physiotherapy. All patients who were discharged or referred for surgery were given a post treatment questionnaire to fill out. RESULTS: 79 (56 %) of 132 women with stress, 49 (51 %) of 98 with mixed and 27 (66 %) of 41 with urge incontinence reported successful control of symptoms (overall success 54 %). However, 65 % of women with incontinence scores of 0-5 before physiotherapy, 64 % with 6-10, 42 % with 11-15 and mere 28 % with 16-20 achieved success with physiotherapy. 27 (10 %) were lost to follow up. CONCLUSION: 1 in 2 women referred to physiotherapy for incontinence, achieved successful control of symptoms without the need for invasive investigations or surgery. However, poor incontinence scores before the start of physiotherapy is a poor prognostic indicator for success. 90 % women utilised the service. PMID- 26590577 TI - Sequence-specific 1H, 13C and 15N backbone resonance assignments of the plakin repeat domain of human envoplakin. AB - The plakin repeat domain is a distinctive hallmark of the plakin superfamily of proteins, which are found within all epithelial tissues. Plakin repeat domains mediate the interactions of these proteins with the cell cytoskeleton and are critical for the maintenance of tissue integrity. Despite their biological importance, no solution state resonance assignments are available for any homologue. Here we report the essentially complete (1)H, (13)C and (15)N backbone chemical shift assignments of the singular 22 kDa plakin repeat domain of human envoplakin, providing the means to investigate its interactions with ligands including intermediate filaments. PMID- 26590578 TI - Angular stable plates in proximal meta-epiphyseal tibial fractures: study of joint restoration and clinical and functional evaluation. AB - BACKGROUND: The tibial plateau fractures involve one of the main weight bearing joints of the human body. The goals of surgical treatment are anatomical reduction, articular surface reconstruction and high primary stability. The aim of this study was to evaluate the clinical and functional outcomes after internal plate fixation of this kind of fractures. MATERIALS AND METHODS: From January 2009 to December 2012, we treated 75 cases of tibial plateau fracture with angular stable plates. We used Rasmussen Score and the Knee Society Score for the clinical and functional evaluation. Twenty-five cases that underwent hardware removal had arthroscopic and CT evaluation of the joint. RESULTS: No complications occurred. The clinical and functional evaluation, performed by the KSS and Rasmussen Score, highlighted the high percentage of good-to-excellent results (over 90 %). In every case, the range of motion was good with flexion >90 degrees . Arthroscopy showed the presence of chondral damage in 100 % of patients. In all the cases, we found that X-ray images seem better than the CT images. CONCLUSIONS: Angular stable plates allow to obtain a good primary stability, permitting an early joint recovery with an excellent range of motion. Avoiding to perform a knee arthrotomy at the time of fracture reduction could prove to be an advantage in terms of functional recovery. The meniscus on the injured bone should be preserved in order to maintain good function of the joint. X-ray images remain the gold standard in checking the progression of post traumatic osteoarthritis. PMID- 26590579 TI - Infrequent Production of Xanthomegnin by Fungal Strains Recovered from Patients with Ocular Mycoses. AB - Mycotoxins are putative virulence factors of fungi that play an important role in the pathogenesis of fungal infections. Mycotoxin production has been used as a diagnostic marker for the early diagnosis of fungal diseases. Using high performance liquid chromatography, we investigated whether the fungal strains recovered from eye tissue samples obtained from patients with ocular mycoses produced the mycotoxin xanthomegnin. We tested 62 well-characterized strains of fungi, including Aspergillus spp. (n = 14), Exophiala spp. (n = 9), Fusarium spp. (n = 15), and several molds (n = 24). All isolates were identified to the species level using PCR and DNA sequencing of rRNA genes. We detected xanthomegnin activity (0.02 ug/ml) in one of the three Aspergillus flavus strains. However, we were unable to detect xanthomegnin in any of the other 61 fungal strains. Our result suggests that xanthomegnin production was infrequent in fungal strains recovered from patients with ocular mycoses. PMID- 26590580 TI - Ustilago echinata: Infection in a Mixed Martial Artist Following an Open Fracture. AB - Ustilago, a common fungal parasite of grains, is infrequently isolated as a pathogen in humans. We describe a case of Ustilago echinata infection following an open distal tibia fracture, review the current literature of this genus as a cause of invasive fungal infection in humans, and discuss management issues. PMID- 26590582 TI - Application of light-emitting diodes (LEDs) in cultivation of phototrophic microalgae: current state and perspectives. AB - The quality and regulation of the incident light is crucial in microalgae cultivation processes. Depending on wavelength, spectrum, and intensity, growth characteristics and biochemical composition of these organisms vary. With mainly fluorescent lamps (FL) used previously for illumination, such variabilities could not be studied adequately due to their broad emission spectrum. In contrast, light-emitting diodes (LEDs) emit a very narrow wavelength band and enable flexible photobioreactor designs due to their small size. This review provides a condensed overview on the application of LEDs in microalgal cultivation processes. It summarizes the current availability and applicability of LED technologies as an illumination source for research-focused photobioreactor systems. A particular focus is the use of narrow-wavelength LEDs to address fundamental as well as applied aspects of light color on algae biomass and value added compound formation. In this respect, the application of internal and external illumination systems is reviewed together with trends in the industrial use of LED systems to intensify algae process efficiency. PMID- 26590581 TI - Current surgical strategies for malignant pleural mesothelioma. AB - Malignant pleural mesothelioma (MPM) is associated with a poor prognosis. The main components of multimodality treatment include surgery, chemotherapy, and radiation therapy. Surgery remains controversial. Two procedures are currently offered: extrapleural pneumonectomy (EPP) and pleurectomy/decortication (P/D). The recent scientific literature suggests that P/D is a well-tolerated procedure, with the potential of becoming a default procedure in multimodality regimens. However, the precise treatment schemes and surgical procedures are yet to be established. In our study, we review the advantages and disadvantages of EPP and P/D, summarize the post-EPP and post-P/D observations (including mortality, morbidity, and median survival time), and discuss the choice of surgical technique (EPP vs. P/D). Moreover, we highlight the aspects of the multimodality treatments that are offered to MPM patients, including chemotherapy, radiotherapy, intensity-modulated radiation therapy, and other types of therapy. PMID- 26590583 TI - Applying trait-function relationships for microbial plant decomposition to predict medium longevity in pollution control biofilters. AB - Biofilters, bioreactors used for pollution control, can effectively treat a variety of odorous and hazardous emissions, but uncertain medium longevities and associated costs limit biofilter adoption. To improve medium-life estimations for biofilter end-users, litter bags were used to compare decay rates of common biofilter medium types and test the effects of nitrogen (N) enrichment and livestock production emissions on medium decay in a full-scale biofilter over a 27-month period. Generally, "by-product" media (mulch, corn cobs) decayed faster than hardwood media, with decay of softwood media the slowest. Analysis showed nutrient content was the best predictor of early-stage decay, while carbon fractions and nutrient content best predicted medium longevity. N amendments and N-rich barn emissions were found to hasten medium decay. By identifying decay rates and rate predictors specific for biofilter media, we provide biofilter engineers and farmers with a quantitative way to improve medium selection based on the trade-offs between medium cost and replacement frequency. PMID- 26590584 TI - Restriction modification system analysis and development of in vivo methylation for the transformation of Clostridium cellulovorans. AB - Clostridium cellulovorans, a cellulolytic bacterium producing butyric and acetic acids as main fermentation products, is a promising host for biofuel production from cellulose. However, the transformation method of C. cellulovorans was not available, hindering its genetic engineering. To overcome this problem, its restriction modification (RM) systems were analyzed and a novel in vivo methylation was established for its successful transformation in the present study. Specifically, two RM systems, Cce743I and Cce743II, were determined. R. Cce743I has the same specificity as LlaJI, recognizing 5'-GACGC-3' and 5'-GCGTC 3', while M. Cce743I methylates the external cytosine in the strand (5'-GACG(m)C 3'). R. Cce743II, has the same specificity as LlaI, recognizing 5'-CCAGG-3' and 5'-CCTGG-3', while M. Cce743II methylates the external cytosine of both strands. An in vivo methylation system, expressing M. Cce743I and M. Cce743II from C. cellulovorans in Escherichia coli, was then established to protect plasmids used in electrotransformation. Transformants expressing an aldehyde/alcohol dehydrogenase (adhE2), which converted butyryl-CoA to n-butanol and acetyl-CoA to ethanol, were obtained. For the first time, an effective transformation method was developed for metabolic engineering of C. cellulovorans for biofuel production directly from cellulose. PMID- 26590585 TI - Assessment of microbial viability in municipal sludge following ultrasound and microwave pretreatments and resulting impacts on the efficiency of anaerobic sludge digestion. AB - A range of ultrasonication (US) and microwave irradiation (MW) sludge pretreatments were compared to determine the extent of cellular destruction in micro-organisms within secondary sludge and how this cellular destruction translated to anaerobic digestion (AD). Cellular lysis/inactivation was measured using two microbial viability assays, (1) Syto 16(r) Green and Sytox(r) Orange counter-assay to discern the integrity of cellular membranes and (2) a fluorescein diacetate assay to understand relative enzymatic activity. A range of MW intensities (2.17-6.48 kJ/g total solids or TS, coinciding temperatures of 60 160 degrees C) were selected for comparison via viability assays; a range of corresponding US intensities (2.37-27.71 kJ/g TS, coinciding sonication times of 10-60 min at different amplitudes) were also compared to this MW range. The MW pretreatment of thickened waste activated sludge (tWAS) caused fourfold to fivefold greater cell death than non-pretreated and US-pretreated tWAS. The greatest microbial destruction occurred at MW intensities greater than 2.62 kJ/g TS of sludge, after which increased energy input via MW did not appear to cause greater microbial death. In addition, the optimal MW pretreatment (80 degrees C, 2.62 kJ/g TS) and corresponding US pretreatment (10 min, 60 % amplitude, 2.37 kJ/g TS) were administered to the tWAS of a mixed sludge and fed to anaerobic digesters over sludge retention times (SRTs) of 20, 14, and 7 days to compare effects of feed pretreatment on AD efficiency. The digester utilizing MW pretreated tWAS (80 degrees C, 2.62 kJ/g TS) had the greatest fecal coliform removal (73.4 and 69.8 % reduction, respectively), greatest solids removal (44.2 % TS reduction), and highest overall methane production (248.2 L CH4/kg volatile solids) at 14- and 7-day SRTs. However, despite the fourfold to fivefold increases in cell death upon pretreatment, improvements from the digester fed MW pretreated sludge were marginal (i.e., increases in efficiency of less than 3-10 %) and likely due to a smaller proportion of cells (10-20 %) in the polymeric network and mixed sludge fed to digesters. PMID- 26590586 TI - Cloning and characterization of a new laccase from Lactobacillus plantarum J16 CECT 8944 catalyzing biogenic amines degradation. AB - In our search for degrading activities of biogenic amines (BAs) in lactic acid bacteria, a protein annotated as laccase enzyme was identified in Lactobacillus plantarum J16 (CECT 8944). In this study, the gene of this new laccase was cloned and heterologously overexpressed in Escherichia coli. The recombinant laccase protein was purified and characterized biochemically. The purified laccase showed characteristic spectroscopic properties of blue multicopper oxidases. The enzyme has a molecular weight of ~ 62.5 kDa and activity toward typical laccase substrates 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and 2,6 dimethoxyphenol (2,6-DMP). The pH optima on ABTS and 2,6-DMP were 3.5 and 7.0, respectively. Kinetic constants Km and Vmax were of 0.21 mM and 0.54 U/mg for ABTS and 1.67 mM and 0.095 U/mg for 2,6-DMP, respectively. The highest oxidizing activity toward 2,6-DMP was obtained at 60 degrees C. However, after a preincubation step at 85 degrees C for 10 min, no residual activity was detected. It has been demonstrated that recombinant L. plantarum laccase oxidizes biogenic amines, mainly tyramine, and thus presents new biotechnological potential for the enzyme in eliminating toxic compounds present in fermented food and beverages. PMID- 26590587 TI - Binding and molecular dynamic studies of sesquiterpenes (2R-acetoxymethyl-1,3,3 trimethyl-4t-(3-methyl-2-buten-1-yl)-1t-cyclohexanol) derived from marine Streptomyces sp. VITJS8 as potential anticancer agent. AB - The main aim of the current study is to explore the bioactive potential of Streptomyces sp. VITJS8 isolated from the marine saltern. The cultural, biochemical, and morphological studies were performed to acquire the characteristic features of the potent isolate VITJS8. The 16Sr DNA sequencing was performed to investigate the phylogenetic relationship between the Streptomyces genera. The structure of the compound was elucidated by gas chromatography-mass spectrometry (GC-MS), infra-red (IR), and ultra-violet (UV) spectroscopic data analysis. The GC-MS showed the retention time at 22.39 with a single peak indicating the purity of the active compound, and the molecular formula was established as C14H9ONCl2 based on the peak at m/z 277 [M](+). Furthermore, separated by high-performance liquid chromatography (HPLC), their retention time (t r) 2.761 was observed with the absorption maxima at 310 nm. The active compound showed effective inhibitory potential against four clinical pathogens at 500 MUg/mL. The antioxidant activity was found effective at the IC50 value of 500 MUg/mL with 90 % inhibition. The 3-(4,5-dimethylthiazol-2-yl)-2,5-ditetrazolium bromide (MTT) assay revealed the cytotoxicity against HepG2 cells at IC50 of 250 MUg/mL. The progression of apoptosis was evidenced by morphological changes by nuclear staining. The DNA fragmentation pattern was observed at 250 MUg/mL concentration. Based on flow cytometric analysis, it was evident that the compound was effective in inhibiting the sub-G0/G1 phase of cell cycle. The in vitro findings were also supported by the binding mode molecular docking studies. The active compound revealed minimum binding energy of -7.84 and showed good affinity towards the active region of topoisomerase-2alpha that could be considered as a suitable inhibitor. Lastly, we performed 30 ns molecular dynamic simulation analysis using GROMACS to aid in better designing of anticancer drugs. Simulation result of root mean square deviation (RMSD) analysis showed that protein-ligand complex reaches equilibration state around 10 ns that illustrates the docked complex is stable. We propose the possible mechanism of sesquiterpenes to play a significant role in antitumor cascade. Hence, our studies open up a new facet for a potent drug as an anticancer agent. PMID- 26590588 TI - Effects of genetic modifications and fermentation conditions on 2,3-butanediol production by alkaliphilic Bacillus subtilis. AB - Two recombinants of alkaliphilic Bacillus subtilis LOCK 1086, constructed via different strategies such as cloning the gene encoding bacterial hemoglobin from Vitreoscilla stercoraria (vhb) and overexpression of the gene encoding acetoin reductase/2,3-butanediol dehydrogenase (bdhA) from B. subtilis LOCK 1086, did not produce more 2,3-butanediol (2,3-BD) than the parental strain. In batch fermentations, this strain synthesized 9.46 g/L in 24 h and 12.80 g/L 2,3-BD in 46 h from sugar beet molasses and an apple pomace hydrolysate, respectively. 2,3 BD production by B. subtilis LOCK 1086 was significantly enhanced in fed-batch fermentations. The highest 2,3-BD concentration (75.73 g/L in 114 h, productivity of 0.66 g/L * h) was obtained in the sugar beet molasses-based medium with four feedings with glucose. In a medium based on the apple pomace hydrolysate with three feedings with sucrose, B. subtilis LOCK 1086 produced up to 51.53 g/L 2,3 BD (in 120 h, productivity of 0.43 g/L * h). PMID- 26590589 TI - Evaluation of 3-hydroxybutyrate as an enzyme-protective agent against heating and oxidative damage and its potential role in stress response of poly(3 hydroxybutyrate) accumulating cells. AB - Poly(3-hydroxybutyrate) (PHB) is a common carbon- and energy-storage compound simultaneously produced and degraded into its monomer 3-hydroxybutyrate (3HB) by numerous bacteria and Archae in a metabolic pathway called the PHB cycle. We investigated 3HB as a chemical chaperone capable of protecting model enzymes, namely lipase and lysozyme, from adverse effects of high temperature and oxidation. Heat-mediated denaturation of lipase in the presence or absence of 3HB was monitored by dynamic light scattering (DLS) revealing a significant protective effect of 3HB which increased as its concentration rose. Furthermore, when compared at the same molar concentration, 3HB showed a greater protective effect than the well-known chemical chaperones trehalose and hydroxyectoine. The higher protective effect of 3HB was also confirmed when employing differential scanning calorimetry (DSC) and lysozyme as a model enzyme. Furthermore, 3HB was capable of protecting lipase not only against thermal-mediated denaturation but also against oxidative damage by Cu(2+) and H2O2; its protection was higher than that of trehalose and comparable to that of hydroxyectoine. Taking into account that the PHB-producing strain Cupriavidus necator H16 reveals a 16.5-fold higher intracellular concentration than the PHB non-producing mutant C. necator PHB(-4), it might be expected that the functional PHB cycle might be responsible for maintaining a higher intracellular level of 3HB which, aside from other positive aspects of functional PHB metabolism, enhances stress resistance of bacterial strains capable of simultaneous PHB synthesis and mobilization. In addition, 3HB can be used in various applications and formulations as an efficient enzyme stabilizing and enzyme-protecting additive. PMID- 26590590 TI - Application of urea-agarose gel electrophoresis to select non-redundant 16S rRNAs for taxonomic studies: palladium(II) removal bacteria. AB - The 16S ribosomal RNA (rRNA) gene has been the most commonly used sequence to characterize bacterial communities. The classical approach to obtain gene sequences to study bacterial diversity implies cloning amplicons, selecting clones, and Sanger sequencing cloned fragments. A more recent approach is direct sequencing of millions of genes using massive parallel technologies, allowing a large-scale biodiversity analysis of many samples simultaneously. However, currently, this technique is still expensive when applied to few samples; therefore, the classical approach is still used. Recently, we found a community able to remove 50 mg/L Pd(II). In this work, aiming to identify the bacteria potentially involved in Pd(II) removal, the separation of urea/heat-denatured DNA fragments by urea-agarose gel electrophoresis was applied for the first time to select 16S rRNA-cloned amplicons for taxonomic studies. The major raise in the percentage of bacteria belonging to genus Clostridium sensu stricto from undetected to 21 and 41 %, respectively, for cultures without, with 5 and 50 mg/L Pd(II) accompanying Pd(II) removal point to this taxa as a potential key agent for the bio-recovery of this metal. Despite sulfate-reducing bacteria were not detected, the hypothesis of Pd(II) removal by activity of these bacteria cannot be ruled out because a slight decrease of sulfate concentration of the medium was verified and the formation of PbS precipitates seems to occur. This work also contributes with knowledge about suitable partial 16S rRNA gene regions for taxonomic studies and shows that unidirectional sequencing is enough when Sanger sequencing cloned 16S rRNA genes for taxonomic studies to genus level. PMID- 26590591 TI - Post-warm-up muscle temperature maintenance: blood flow contribution and external heating optimisation. AB - PURPOSE: Passive muscle heating has been shown to reduce the drop in post-warm-up muscle temperature (Tm) by about 25% over 30 min, with concomitant sprint/power performance improvements. We sought to determine the role of leg blood flow in this cooling and whether optimising the heating procedure would further benefit post-warm-up T m maintenance. METHODS: Ten male cyclists completed 15-min sprint based warm-up followed by 30 min recovery. Vastus lateralis Tm (Tmvl) was measured at deep-, mid- and superficial-depths before and after the warm-up, and after the recovery period (POST-REC). During the recovery period, participants wore water-perfused trousers heated to 43 degrees C (WPT43) with either whole leg heating (WHOLE) or upper leg heating (UPPER), which was compared to heating with electrically heated trousers at 40 degrees C (ELEC40) and a non-heated control (CON). The blood flow cooling effect on Tmvl was studied comparing one leg with (BF) and without (NBF) blood flow. RESULTS: Warm-up exercise significantly increased Tmvl by ~3 degrees C at all depths. After the recovery period, BF Tmvl was lower (~0.3 degrees C) than NBF Tmvl at all measured depths, with no difference between WHOLE versus UPPER. WPT43 reduced the post-warm-up drop in deep-Tmvl (-0.12 degrees C +/- 0.3 degrees C) compared to ELEC40 (-1.08 +/- 0.4 degrees C) and CON (-1.3 +/- 0.3 degrees C), whereas mid- and superficial-Tmvl even increased by 0.15 +/- 0.3 and 1.1 +/- 1.1 degrees C, respectively. CONCLUSION: Thigh blood flow contributes to the post-warm-up Tmvl decline. Optimising the external heating procedure and increasing heating temperature of only 3 degrees C successfully maintained and even increased T mvl, demonstrating that heating temperature is the major determinant of post-warm up Tmvl cooling in this application. PMID- 26590592 TI - Non-genetic health professionals' attitude towards, knowledge of and skills in discussing and ordering genetic testing for hereditary cancer. AB - Non-genetic health professionals (NGHPs) have insufficient knowledge of cancer genetics, express educational needs and are unprepared to counsel their patients regarding their genetic test results. So far, it is unclear how NGHPs perceive their own communication skills. This study was undertaken to gain insight in their perceptions, attitudes and knowledge. Two publically accessible databases were used to invite NGHPs providing cancer genetic services to complete a questionnaire. The survey assessed: sociodemographic attributes, experience in ordering hereditary cancer genetic testing, attitude, knowledge, perception of communication skills (e.g. information giving, decision-making) and educational needs. Of all respondents (N = 49, response rate 11%), most have a positive view of their own information giving (mean = 53.91, range 13-65) and decision making skills (64-77% depending on topic). NGHPs feel responsible for enabling disease and treatment related behavior (89-91%). However, 20-30% reported difficulties managing patients' emotions and did not see management of long-term emotions as their responsibility. Correct answers on knowledge questions ranged between 41 and 96%. Higher knowledge was associated with more confidence in NGHPs' own communication skills (r(s) = .33, p = 0.03). Although NGHPs have a positive view of their communication skills, they perceive more difficulties managing emotions. The association between less confidence in communication skills and lower knowledge level suggests awareness of knowledge gaps affects confidence. NGHPs might benefit from education about managing client emotions. Further research using observation of actual counselling consultations is needed to investigate the skills of this specific group of providers. PMID- 26590593 TI - Neurological disease of Sehzade Cihangir in the Ottoman history: spinal dysraphism. PMID- 26590594 TI - Lipid levels in HIV-positive men receiving anti-retroviral therapy are not associated with copy number variation of reverse cholesterol transport pathway genes. AB - BACKGROUND: The exacerbation of HIV-1 associated dyslipidemia seen in a subset of patients receiving anti-retroviral therapy suggests that genetic factors put these individuals at greater risk of cardiovascular disease. Single nucleotide polymorphisms (SNPs) within genes of and influencing the reverse cholesterol transport (RCT) pathway are associated with lipid levels but little is known regarding their copy number variation (CNV). This form of quantitative genetic variation has the potential to alter the amount of gene product made, thereby also influencing lipid metabolism. RESULTS: To examine if CNV in RCT pathway genes was associated with altered serum lipid profiles in HIV-positive individuals receiving therapy, we designed a custom multiplex ligation-dependent probe amplification assay to screen 16 RCT genes within a subset of individuals from the Multicenter AIDS Cohort Study who show extreme lipid phenotypes. Verification of CNV was performed using a custom NanoString assay, and the Illumina HT-12 mRNA expression microarray was used to determine the influence of copy number on gene expression. Among the RCT genes, CNV was observed to be extremely rare. The only CNV seen was in the CETP gene, which showed a loss of copy in 1 of the 320 samples (0.3%) in our study. The genes in our study showed little variation in expression between individuals, and the variation seen was not related to any detected CNV. CONCLUSIONS: Whole gene CNV is uncommon in RCT pathway genes, and not a major factor in the development of highly active antiretroviral therapy (HAART) associated dyslipidemia. PMID- 26590595 TI - Analysis of the CD161-expressing cell quantities and CD161 expression levels in peripheral blood natural killer and T cells of systemic lupus erythematosus patients. AB - Expressed on the cell surface of most of NK cells and some T cells, CD161 has been shown to deliver inhibitory signal in human NK cells. To determine whether the CD161-expressing cell quantities and the cell surface expression levels of CD161 in NK and T cells were altered in systemic lupus erythematosus (SLE) patients, we analyzed the CD3, CD56 and CD161 expression patterns of peripheral blood lymphocytes by flow cytometric analysis to identify different NK and T cell subpopulations. The cell surface expression levels of CD161 were estimated by the mean florescence intensities (MFIs) of CD161. It was found that SLE patients had lower frequencies of CD161+CD56+CD3- and CD161+CD56+CD3+ cells among the lymphocyte population than normal controls, whereas the frequencies of CD161 CD56+CD3- and CD161+CD56-CD3+ cells were not statistically different between two groups. In addition, SLE patients also had decreased absolute counts of all CD161 expressing NK cells and T cells and had reduced frequencies of CD161+ cells in CD56+CD3-, CD56+CD3+ and CD56-CD3+ cell populations. Moreover, SLE patients had reduced MFIs of CD161 in CD161+CD56+CD3+ and CD161+CD56-CD3+, but not CD161+CD56+CD3-, cell populations. Our results indicated that CD161-expressing cell frequency and the CD161 expression levels were reduced in some NK and T cell subpopulations of SLE patients, suggesting possible important role of CD161 and CD161-expressing immune cells in the SLE pathogenesis. PMID- 26590596 TI - High expression of stathmin 1 is a strong prognostic marker in oral squamous cell carcinoma patients treated by docetaxel-containing regimens. AB - Stathmin 1 is an oncoprotein that regulates cell cycle by modulating microtubule dynamics and can cause uncontrolled cell proliferation in mutated state. The present study examined stathmin 1 expression in 49 patients with oral squamous cell carcinoma (OSCC) treated with docetaxel (Doc)-containing regimens by immunohistochemical staining. Moreover, we investigated the relationship between stathmin 1 expression and clinicopathological features, as well as the prognosis of above patients. Stathmin 1 could be detected in the cytoplasm of tumor cells in OSCC tissues though its expression level was variable. There was no correlation between stathmin 1 expression and patient gender, or age in OSCC. However, stathmin 1 expression of tumor cell was significantly correlated with T classification (P = 0.0017), N classification (P = 0.0171), stage (P < 0.0001), therapeutic efficacy (P < 0.0001), and patient outcome (P = 0.0387). In addition, high expression of stathmin 1 in tumor cells was associated with shorter overall survival (OS, P = 0.0017). Multivariate analysis also revealed that high expression of stathmin 1 was a predictor of reduced survival (P = 0.0241). These findings suggest that patients with OSCC tumors showing high expression of stathmin 1 might have poor therapeutic effects and worse clinical outcomes in OSCC treated with Doc-containing regimen. PMID- 26590597 TI - Ants Learn Aphid Species as Mutualistic Partners: Is the Learning Behavior Species-Specific? AB - In ant-aphid associations, many aphid species provide ants with honeydew and are tended by ants, whereas others are never tended and are frequently preyed upon by ants. In these relationships, ants must have the ability to discriminate among aphid species, with mutualistic aphids being accepted as partners rather than prey. Although ants reportedly use cuticular hydrocarbons (CHCs) of aphids to differentiate between mutualistic and non-mutualistic species, it is unclear whether the ability to recognize mutualistic aphid species as partners is innate or involves learning. Therefore, we tested whether aphid recognition by ants depends on learning, and whether the learning behavior is species-specific. When workers of the ant Tetramorium tsushimae had previously tended the cowpea aphid, Aphis craccivora, they were less aggressive toward this species. In addition, ants also reduced their aggressiveness toward another mutualistic aphid species, Aphis fabae, after tending A. craccivora, whereas ants remained aggressive toward the non-mutualistic aphid, Acyrthosiphon pisum, regardless of whether or not they had previous experience in tending A. craccivora. When ants were offered glass dummies treated with CHCs of these aphid species, ants that had tended A. craccivora displayed reduced aggression toward CHCs of A. craccivora and A. fabae. Chemical analyses showed the similarity of the CHC profiles between A. craccivora and A. fabae but not with A. pisum. These results suggest that aphid recognition of ants involves learning, and that the learning behavior may not be species-specific because of the similarity of CHCs between different aphid species with which they form mutualisms. PMID- 26590598 TI - Cyclophosphamide-responsive Lgi1-related limbic encephalitis with basal ganglia hypermetabolism. PMID- 26590600 TI - Experiences of using pro-eating disorder websites: a qualitative study with service users in NHS eating disorder services. AB - PURPOSE: Previous research into the impact of pro-eating disorder (pro-ED) websites has predominantly been undertaken using experimental and survey designs. Studies have used both clinical and non-clinical (college student) samples. The present study aimed to explore the underlying functions and processes related to the access and continued use of pro-ED websites within a clinical eating disorder population using a qualitative research design. METHODS: Participants were recruited through NHS community mental health teams and specialist eating disorder services within South Wales, UK. Face-to-face semi-structured interviews were conducted with seven adult women in treatment for an eating disorder who had disclosed current or historic use of pro-ED websites. Interviewees ranged in age from 20 to 40 years (M = 31.2; SD = 7.8). Constructivist Grounded Theory was used to analyse interview transcripts. RESULTS: Five key themes were identified within the data, namely fear; ambivalence; social comparisons; shame; and pro-ED websites maintaining eating disordered behaviour. The pro-ED websites appeared to offer a sense of support, validation and reassurance to those in the midst of an eating disorder, whilst simultaneously reinforcing and maintaining eating disordered behaviour. CONCLUSION: Themes are discussed in relation to implications and recommendations for clinical practice. Limitations of the present study and suggestions for future research are also outlined. PMID- 26590599 TI - Elevated plasma tumor necrosis factor-alpha receptor 2 and resistin are associated with increased incidence of kidney function decline in Chinese adults. AB - Adipokines and inflammatory markers have been linked to kidney disease in animal models; however, evidence from prospective human studies is sparse. Recruited from Beijing and Shanghai in 2005, a total number of 2220 non-institutionalized Chinese individuals aged 50-70 years with baseline estimated glomerular filtration rate (eGFR) >60 mL/min/1.73 m(2) were prospectively followed for 6 years. Plasma levels of resistin, retinol-binding protein 4 (RBP4), interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor-alpha receptor 2 (TNF R2) were determined at baseline. Kidney function decrease was assessed by measurements of eGFR over 6 years. Incident-reduced eGFR was defined as the onset of eGFR <60 mL/min/1.73 m(2), according to the Modification of Diet in Renal Disease Study Equation for Chinese. During the 6 years of follow-up, 333 (15.0 %) participants had incident-reduced eGFR. Each 1 standard deviation elevated concentration of resistin [relative risk (RR) 1.10; 95 % CI 1.00-1.24] and TNFR-2 (RR 1.30; 95 % CI 1.13-1.49) at baseline were significantly associated with a higher risk of incident-reduced eGFR. Comparing the highest with the lowest quartiles, the RR of incident-reduced eGFR was 1.43 (95 % CI 1.01-2.03) for resistin and 2.03 (95 % CI 1.41-2.93) for TNF-R2 (both P trend < 0.05) after adjustment for baseline demographic characteristics, lifestyle behaviors, BMI, plasma lipid profile, hypertension, and diabetes. These associations remained significant when further controlling for levels of RBP4, IL-6, and CRP, none of which was significantly associated with the risk of incident-reduced eGFR. In this prospective cohort study, elevated levels of resistin and TNF-R2, but not other adipokines and inflammatory markers, were independently associated with a greater risk of kidney function decline in middle-aged and elderly Chinese. PMID- 26590601 TI - Seeking a perfect body look: feeding the pathogenic impact of shame? AB - Shame feelings often lead individuals to adopt compensatory mechanisms, such as the minimization of the public display or disclosure of mistakes and the active promotion of perfect qualities, conceptualized as perfectionistic self presentation. Although perfectionism is considered a central characteristic of disordered eating, the investigation on the specific domain of body image-related perfectionistic self-presentation and on its relationship with psychopathology is still scarce. The main aim of the present study was exploring the moderator effect of body image-related perfectionistic self-presentation on the associations of shame with depressive symptomatology, and with eating psychopathology, in a sample of 487 women. Results revealed that body image related perfectionistic self-presentation showed a significant moderator effect on the relationships of external shame with depressive symptomatology, and with eating psychopathology severity, exacerbating shame's impact on these psychopathological indices. These findings appear to offer important clinical and investigational implications, highlighting the maladaptive character of such body image-focused strategies. PMID- 26590602 TI - Create, activate, destroy, repeat: Cdk1 controls proliferation by limiting transcription factor activity. AB - Progression through the cell cycle is controlled by a network of transcription factors that coordinate gene expression with cell-cycle events. One transcriptional activator in this network in budding yeast is the forkhead protein Hcm1, which controls the expression of genes that are transcribed during S-phase. Hcm1 activity is coordinated with the cell cycle via its regulation by cyclin-dependent kinase (Cdk1), which both activates Hcm1 and targets it for degradation, through phosphorylation of distinct sites. The mechanisms controlling the differential phosphorylation timing of the activating and destabilizing phosphosites are not clear. However, a recent study shows that the phosphatase calcineurin specifically removes activating phosphates from Hcm1 when cells are exposed to environmental stress, thus extinguishing its activity and slowing proliferation under unfavorable growth conditions. This regulatory mechanism, whereby a phosphatase actively alters the distribution of phosphosites on a cell cycle-regulatory transcription factor to elicit a change in cellular proliferation, adds an additional layer of complexity to the regulatory network controlling the cell cycle. Furthermore, this regulatory paradigm is likely to be a conserved mode of phosphoregulation that controls the cell cycle in diverse systems. PMID- 26590603 TI - Hibiscus rosa sinensis Linn. Petals Modulates Glycogen Metabolism and Glucose Homeostasis Signalling Pathway in Streptozotocin-Induced Experimental Diabetes. AB - The prevalence of diabetes mellitus is becoming more and more serious and reaches epidemic proportions worldwide. Scientific research is constantly looking for new agents that could be used as dietary functional ingredients in the fight against diabetes. The objective of the present study was to evaluate the effect of ethyl acetate fraction of Hibiscus rosa sinensis Linn. petals on experimental diabetes at a dose of 25 mg/kg body weight and it was compared with standard anti-diabetic drug metformin. The elevated levels of serum glucose (398.56 +/- 35.78) and glycated haemoglobin (12.89 +/- 1.89) in diabetic rats were significantly decreased (156.89 +/- 14.45 and 6.12 +/- 0.49, respectively) by Hibiscus rosa sinensis petals (EHRS) administration. Hepatotoxicity marker enzyme levels in serum were normalized. The fraction supplementation restored the glycogen content by regulating the activities of glycogen metabolizing enzymes. It significantly modulated the expressions of marker genes involved in glucose homeostasis signalling pathway. Histopathological analysis of liver and pancreas supported our findings. The overall effect was comparable with metformin. Hence, our study reveals the role of hibiscus petals for alleviation of diabetes complications, thus it can be propagated as a nutraceutical agent. PMID- 26590604 TI - Allergenic Potential of Tomatoes Cultivated in Organic and Conventional Systems. AB - Tomatoes (Lycopersicon esculentum Mill.) are a widely consumed vegetables and contain many health beneficial micronutrients. Unfortunately, they may also cause adverse allergic reactions in sensitized people. Many studies, conducted in recent years, indicate that organically produced vegetables have higher nutritional value, improved sensory quality and contain more health-enhancing bioactive compounds than vegetables grown under the conventional system. However, the relation between organic methods of cultivation and allergenic potential of tomatoes has received little scientific attention. This study analyzed samples of five tomato cultivars taken from organic and conventional systems over three consecutive years. The content of profilin, Bet v 1 and lipid transfer protein (LTP) analogues in tomato samples was determined using an indirect ELISA assay. Substantial quantities of these proteins were found in certain cultivars across all three years of cultivation. On the basis of these findings, organically grown tomatoes appear to offer little advantage over conventionally cultivated plants in terms of reduced allergenic potential. PMID- 26590605 TI - Effect of Allium flavum L. and Allium melanantherum Panc. Extracts on Oxidative DNA Damage and Antioxidative Enzymes Superoxide Dismutase and Catalase. AB - Allium flavum L. and Allium melanantherum Panc. are wild growing plants used in traditional diet in Balkan region. While chemical composition and some biological activities of A. flavum have been reported, A. melanantherum, as an endemic in the Balkan Peninsula, has never been comprehensively examined. After chemical characterization of A. melanantherum, we examined the protective effect of methanol extracts of both species against t-butyl hydro-peroxide (t-BOOH)-induced DNA damage and mutagenesis. The bacterial reverse mutation assay was performed on Escherichia coli WP2 oxyR strain. DNA damage was monitored in human fetal lung fibroblasts (MRC-5) with alkaline comet assay. Obtained results indicated that extracts reduced t-BOOH-induced DNA damage up to 70 and 72% for A. flavum and A. melanantherum extract, respectively, and showed no effect on t-BOOH-induced mutagenesis. Since the results indicated modulatory effect on cell-mediated antioxidative defense, the effect of extracts on total protein content, and superoxide dismutase (SOD) and catalase (CAT) amounts and activities were monitored. Both extracts increased total protein content, while the increase of enzyme amount and activity was obtained only with A. melanantherum extract and restricted to CAT. The activity of CuZnSOD family was not affected, while SOD1 and SOD2 amounts were significantly decreased, indicating potential involvement of extracellular CuZnSOD. Obtained results strongly support the traditional use of A. flavum and A. melanantherum in nutrition and recommend them for further study. PMID- 26590606 TI - The involvement of hematopoietic pre-B cell leukemia transcription factor interacting protein in regulating epithelial-mesenchymal transition of human spinal glioblastoma. AB - To date, hematopoietic pre-B cell leukemia transcription factor-interacting protein (HPIP), a co-repressor for the transcription factor PBX, has been involved into the initiation and onset in a wide variety of cancers. However, the molecular mechanisms underlying HPIP-induced epithelial-mesenchymal transition (EMT) in the spinal glioblastoma have been under investigation. In the present study, spinal glioblastoma tissues, U87, and U251 cell lines were used and subjected to in vitro assays, such as RT-PCR, and Western blot. Here, in vitro assays revealed that HPIP mRNA and protein were highly expressed in five cases of spinal glioblastoma tissues, compared with non-tumor tissues. Subsequently, in vitro experiments demonstrated HPIP promoted the U87 and U251 cell growth and regulated the G1/S phase transitions in U87 and U251 cell cycle, respectively, accompanied by the increased expression of cyclin A2, cyclin B1, and cyclin D1. Furthermore, HPIP increased the expression of N-cadherin, Slug, and MMP2, and decreased the expression of E-cadherin. By contrast, knockdown of HPIP reversed HPIP-induced EMT biomarkers, migration, and invasion in U87 and U251 cells. In conclusion, our findings identified HPIP plays an important role in the progression and EMT of spinal glioblastoma, by which cell growth is improved. Thus, HPIP gene or protein could act as a useful target in the clinical practice. PMID- 26590608 TI - American Sign Language Comprehension Test: A Tool for Sign Language Researchers. AB - The American Sign Language Comprehension Test (ASL-CT) is a 30-item multiple choice test that measures ASL receptive skills and is administered through a website. This article describes the development and psychometric properties of the test based on a sample of 80 college students including deaf native signers, hearing native signers, deaf non-native signers, and hearing ASL students. The results revealed that the ASL-CT has good internal reliability (alpha = 0.834). Discriminant validity was established by demonstrating that deaf native signers performed significantly better than deaf non-native signers and hearing native signers. Concurrent validity was established by demonstrating that test results positively correlated with another measure of ASL ability (r = .715) and that hearing ASL students' performance positively correlated with the level of ASL courses they were taking (r = .726). Researchers can use the ASL-CT to characterize an individual's ASL comprehension skills, to establish a minimal skill level as an inclusion criterion for a study, to group study participants by ASL skill (e.g., proficient vs. nonproficient), or to provide a measure of ASL skill as a dependent variable. PMID- 26590607 TI - The relationship between five non-synonymous polymorphisms within three XRCC genes and gastric cancer risk in a Han Chinese population. AB - We aimed to assess the association of five non-synonymous polymorphisms within three X-ray repair cross-complementing group (XRCC) genes with gastric cancer risk in Han Chinese. Genotyping was determined in 693 gastric cancer patients and 681 healthy controls. Statistical analyses were completed with SPSS (version 20.0) and Haplo.stats (version 1.6.11). The genotypes of XRCC1 gene rs25487 polymorphism (P = 0.003) differed significantly between patients and controls, even after the Bonferroni correction (P < 0.05/5), and this polymorphism was significantly associated with gastric cancer after adjusting for age, sex, body mass index, smoking, drinking, especially under a dominant model (odds ratio or OR; 95 % confidence interval or CI; P 1.59; 1.20-2.00; 0.001). In multiple-marker analysis, the most common allele combination was C-G-G-G-C (alleles in order of rs1799782, rs25489, rs25487, rs3218536, rs861539), which was overrepresented in controls relative to patients (adjusted simulated P = 0.0001). Contrastingly, the frequency of allele combination C-G-A-G-C was significantly higher in patients than in controls (adjusted simulated P = 0.0009), and this combination was associated with a strikingly increased risk of gastric cancer (OR; 95 % CI; P 2.39; 1.32-4.31; 0.0040) after the Bonferroni correction (P < 0.05/11) and adjusting for confounders. Our findings demonstrated that XRCC1 gene rs25487 polymorphism might play a leading role in pronounced susceptibility to gastric cancer in Han Chinese. PMID- 26590609 TI - The indigenous Somba cattle of the hilly Atacora region in North-West Benin: threats and opportunities for its sustainable use. AB - The objective of this study was to characterize the declining Somba cattle population in its production system context. Two-hundred-twenty-four (224) cattle farm-households were surveyed in the Boukombe district, the natural habitat of the breed in North-West Benin. Information on their socioeconomic characteristics and on their herd management practices were recorded using a semi-structured questionnaire. In addition, 15 body measurements were recorded from 102 adult cattle. Three types of breeders were distinguished: the owners-herders (54.0 %); the absentee owners (40.2 %) and the professional herders (5.8 %). The average cattle herd sizes were 4.7 +/- 3.70 and 58.6 +/- 22.83 heads for owner-managed and entrusted herds, respectively. Offtakes were more associated with sociocultural purposes (75.5 %) than market. While crop farming was the main occupation and income source of their owners, the Somba cattle were used for ploughing during the rainy season. In contrast to the widely accepted belief that this indigenous genetic resource is mainly threatened by crossbreeding and/or replacement, our findings suggest high mortalities due to diseases, feed and water shortages and poor reproduction management as the main causes of the decline of this cattle population. Somba cattle generally have short horns and a small body size. However, bulls have significantly (P <= 0.05) longer horns (21.2 +/- 16.44 cm against 13.9 +/- 7.21 cm), higher height at withers (99.7 +/- 6.97 cm against 95.9 +/- 5.76 cm) and body length (149.7 +/- 12.87 cm against 146.8 +/ 11.01 cm) than cows. All surveyed farmers expressed their willingness and readiness to participate in and contribute materially or financially to any program towards a sustainable use and preservation of this breed which they perceived as hardy and embedded in their culture. We therefore argue that strategies for its sustainable use and conservation should consist of simultaneously improving general herd management practices, organizing farmers and involving them in participatory breed improvement programs. PMID- 26590610 TI - Nitrogen metabolism, digestive parameters, and protein requirements for the maintenance of buffalo growth. AB - The objectives of this study were to evaluate the effect of crude protein (CP) levels in the diet of growing female buffaloes on nitrogen metabolism and estimate protein requirements for maintenance. Four female buffaloes were used, cannulated in the rumen, with an average initial body weight (BW) of 355 +/- 3.5 kg, in a Latin square (4 * 4) with four animals and four levels of CP in the diet (70, 90, 110, and 130 g/kg dry matter (DM)) composed of corn silage and concentrate. The increase in protein intake with increasing levels of dietary CP resulted in a higher concentration of ammonia in the rumen and higher ruminal disappearance of PB. However, omasal flow of protein increased linearly as did the efficiency of microbial protein synthesis. The CP levels affected DM intake and other nutrients positively, but there was no effect on nutrient total digestibility. Nitrogen (N) balance, when expressed relative to N intake, had an average value of 48.5 % observed across. The protein requirement for the maintenance of growing female buffaloes was 4.6 g CP/kg BW(0.75). PMID- 26590611 TI - Oxytocin receptor: Expression in the trigeminal nociceptive system and potential role in the treatment of headache disorders. AB - AIMS: Our studies investigated the location of oxytocin receptors in the peripheral trigeminal sensory system and determined their role in trigeminal pain. METHODS: Oxytocin receptor expression and co-localization with calcitonin gene-related peptide was investigated in rat trigeminal ganglion using immunohistochemistry. Enzyme-linked immunosorbent assay was used to determine the effects of facial electrocutaneous stimulation and adjuvant-induced inflammation of the temporomandibular joint on oxytocin receptor expression in the trigeminal ganglion. Finally, the effects of oxytocin on capsaicin-induced calcitonin gene related peptide release from dural nociceptors were investigated using isolated rat dura mater. RESULTS: Oxytocin receptor immunoreactivity was present in rat trigeminal neurons. The vast majority of oxytocin receptor immunoreactive neurons co-expressed calcitonin gene-related peptide. Both electrocutaneous stimulation and adjuvant-induced inflammation led to a rapid upregulation of oxytocin receptor protein expression in trigeminal ganglion neurons. Oxytocin significantly and dose-dependently decreased capsaicin-induced calcitonin gene related peptide release from dural nociceptors. CONCLUSION: Oxytocin receptor expression in calcitonin gene-related peptide containing trigeminal ganglion neurons, and the blockade of calcitonin gene-related peptide release from trigeminal dural afferents suggests that activation of these receptors may provide therapeutic benefit in patients with migraine and other primary headache disorders. PMID- 26590612 TI - A proposal for a novel rationale for critical effect size in dose-response analysis based on a multi-endpoint in vivo study with methyl methanesulfonate. AB - Methyl methanesulfonate, a well-known direct-acting genotoxicant, was assessed in a multi-endpoint study in rats using six closely spaced dose levels. The main goal of the study was to investigate the genotoxic response at very low doses and to analyse this response with dedicated statistical tools in order to find a Point of Departure (PoD) and related metrics. Software packages like PROAST or EPA-BMDS require the toxicologist to define a so-called critical effect size (CES) or benchmark response (BMR) and this choice has a large impact on the result of the PoD calculation. Currently, increases of 5%, 10% or 1 standard deviation over concurrent vehicle controls have been proposed for CES/BMR, values that may or may not be suited for all genotoxicity endpoints. Based on the data obtained in this study, we propose an endpoint specific CES approach that reflects the typical evaluation process of a regulatory acceptable genotoxicology study. However, we are aware that this ratio-based CES strategy will need to be more fully developed with additional experimentation and should be mainly seen as a starting point for scientific discussion. PMID- 26590613 TI - Physiological and transcriptional characterization of Saccharomyces cerevisiae engineered for production of fatty acid ethyl esters. AB - Saccharomyces cerevisiae has previously been engineered to become a cell factory for the production of fatty acid ethyl esters (FAEEs), molecules suitable for crude diesel replacement. To find new metabolic engineering targets for the improvement of FAEE cell factories, three different FAEE-producing strains of S. cerevisiae, constructed previously, were compared and characterized by quantification of key fluxes and genome-wide transcription analysis. From both the physiological and the transcriptional data, it was indicated that strain CB2I20, with high expression of a heterologous wax ester synthase gene (ws2) and strain BdJ15, containing disruptions of genes DGA1, LRO1, ARE1, ARE2 and POX1, which prevent the conversion of acyl-CoA to sterol esters, triacylglycerides and the degradation to acetyl-CoA, triggered oxidative stress that consequently influenced cellular growth. In the latter strain, stress was possibly triggered by disabling the buffering capacity of lipid droplets in encapsulating toxic fatty acids such as oleic acid. Additionally, it was indicated that there was an increased demand for NADPH required for the reduction steps in fatty acid biosynthesis. In conclusion, our analysis clearly shows that engineering of fatty acid biosynthesis results in transcriptional reprogramming and has a significant effect on overall cellular metabolism. PMID- 26590614 TI - A rare and unusual hyperkeratotic disorder. PMID- 26590615 TI - Comorbidities and risk factors among patients with schizophrenia. AB - General practitioners (GPs) are charged with maintaining a holistic approach to their patients' health. While most patients with schizophrenia attend public mental health services and/or non-government organisations supporting people with mental illness, 88.2% of people with a psychotic illness (the majority being schizophrenia or schizoaffective disorder) had visited a GP in the previous year. For at least 30-40% of people living with schizophrenia in Australia, ongoing management is provided by their GP alone. Moreover, there is evidence that patients with schizophrenia value the help provided by GPs. Patients with schizophrenia have reduced life expectancy. Overseas research (primarily from the UK and US) has found that the poor physical health of patients with schizophrenia can be attributed to a number of factors such as modifiable lifestyle risk factors and side effects of medication, compounded by causes intrinsic to the illness such as mental stress and loss of initiative. PMID- 26590616 TI - Management of mental ill health in people with autism spectrum disorder. AB - BACKGROUND: Adults with autism spectrum disorder (ASD) may require medical assessment and care, especially for mental health conditions. Although substantial knowledge and resources are available regarding the management of mental ill health in children with ASD, substantial gaps remain for adults with ASD. Diagnostic overshadowing, limitations of communication skills and the heterogeneous nature of this patient population can make practice in this area more challenging, and can contribute to poorer outcomes, including overprescribing of psychotropic medications. OBJECTIVE: This article aims to describe mental ill health and identify specific considerations for GPs during the assessment and management of adults with ASD. DISCUSSION: The incorporation of specific knowledge and adaptations in the areas of communication, awareness of physical health comorbidities, management of challenging behaviour, impact of the environment, role of carers and an approach that values neurodiversity has the potential to positively influence mental health outcomes of adults with ASD. PMID- 26590617 TI - Gender dysphoria. AB - BACKGROUND: Gender dysphoria is the distress or discomfort that may occur when a person's biological sex and gender identity do not align. The true prevalence of gender dysphoria is unknown in Australia because of varying definitions, different cultural norms and paucity of data. Individuals who identify as transgender are vulnerable, and have higher rates of discrimination, depression and suicidality, compared with the general population. OBJECTIVE: The aim of this article is to familiarise general practitioners (GPs) with the principles of transgender care so they may provide a safe and supportive environment for patients presenting with concerns. DISCUSSION: It is important to have a basic understanding of how to conduct an initial consultation of gender dysphoria even if it is an uncommon presentation in general practice. Management should be individualised and may involve a combination of social work, education, counselling, hormone therapy and surgery. PMID- 26590618 TI - Body dysmorphic disorder in men. AB - BACKGROUND: Body dysmorphic disorder (BDD) is a condition associated with a perceived defect or flaw in physical appearance and repetitive behaviours related to this perceived imperfection. BDD affects men and women approximately equally, although a variant called muscle dysmorphia occurs more frequently in males. OBJECTIVE: The aim of this article is to provide general practitioners (GPs) with information related to the identification and management of individuals with BDD, especially males. DISCUSSION: Diagnostic features, clinical presentation and screening tools for BDD are discussed. Recommendations for appropriate treatment and support are also supplied. PMID- 26590619 TI - Nailfold dermatoscopy in general practice. AB - BACKGROUND: Nailfold capillary examination can assist in distinguishing between primary Raynaud's phenomenon and secondary Raynaud's that is associated with a connective tissue disease. Dermatoscopy is a reliable technique in the evaluation of nailfold capillaries and assists in the diagnosis of connective tissue diseases such as scleroderma. OBJECTIVE: This article provides an overview of the usefulness of nailfold capillary dermatoscopy in rheumatic and non-rheumatic diseases, and includes the MDAD (morphology, diameter, architecture and density) approach to nailfold dermatoscopy. DISCUSSION: Dermatoscopes are useful devices in examining nailfold capillaries. Many general practitioners are skilled in dermatoscopy and are well placed to examine nailfold capillaries. The MDAD approach to nailfold dermatoscopy considers capillary morphology, diameter, architecture and density. In Raynaud's phenomenon, nailfold dermatoscopy assists in the diagnosis of an underlying connective tissue disease. PMID- 26590620 TI - Non-resolving eye injury. PMID- 26590621 TI - Should naltrexone be the first-line medicine to treat alcohol dependence in Aboriginal and Torres Strait Islander populations? An Australian perspective. AB - BACKGROUND: There is a pressing need to improve alcohol treatment services for Aboriginal and Torre Strait Islander peoples with alcohol dependence. One component of treatment is the use of medicines including naltrexone and acamprosate. Access to these medicines among the general drinking population is poor and, anecdotally, even worse for Aboriginal and Torre Strait Islander peoples who drink. OBJECTIVE: This article aims to review the relative efficacy and safety of naltrexone. It will also discuss reasons why it may be a preferable first-line pharmacotherapy for Aboriginal and Torre Strait Islander peoples with alcohol dependence who are seeking to change their drinking. DISCUSSION: The major effect of naltrexone is reducing episodic heavy drinking, a pattern often seen in Aboriginal and Torre Strait Islander peoples with alcohol dependence. Possible genetic and epigenetic factors, and practical considerations including once-daily dosing also make naltrexone an appealing agent in this population. PMID- 26590622 TI - An uncommon cause for a unilateral pleural effusion: Rheumatoid pleuritis. PMID- 26590623 TI - Female genital cosmetic surgery: Investigating the role of the general practitioner. AB - BACKGROUND: Labiaplasty, the surgical reduction of the labia minora, has significantly increased in demand in Australia. Although general practice is one gatekeeper for patients requesting labiaplasty, as a referral is necessary to claim Medicare entitlements, there is little information available to assist general practitioners (GPs) in managing these requests for female genital cosmetic surgery. METHODS: Semi-structured interviews were conducted with health professionals, including GPs, gynaecologists and plastic surgeons. Participants were recruited through the Victorian Primary Care Practice-based Research Network (VicReN), clinical teaching hospitals and snowball sampling. All interviews were digitally recorded, transcribed, and analysed using content and thematic analysis. RESULTS: Twenty-seven interviews were conducted. All participants were aware of genital labiaplasty; many had patients who were concerned about genital appearance, for which information had often been sought opportunistically. All participants agreed on the need for resources to inform women of normal genital appearance. DISCUSSION: This novel study demonstrates a need for clinical resources for GPs managing requests for genital labiaplasty. PMID- 26590624 TI - Patients want to know about the 'cardiac blues'. AB - BACKGROUND: Much attention has been given to identifying and supporting the minority of patients who develop severe clinical depression after a cardiac event. However, relatively little has been given to supporting the many patients who experience transient but significant emotional disturbance that we term the 'cardiac blues'. OBJECTIVE: The aim of this study was to investigate patients' preferences regarding information provision about cardiac blues. METHODS: One hundred and sixty consecutive cardiac patients admitted to two Victorian hospitals in Australia were interviewed three times over six months. They were asked about emotional issues, including information provision preferences. RESULTS: Four out of five (81%) patients would like to have received information about the cardiac blues, but only a minority received this information. CONCLUSION: Most patients want to know about cardiac blues. The development and evaluation of resources for health professionals and patients to support recovery through cardiac blues appears warranted. PMID- 26590625 TI - Alcohol enquiry by GPs - Understanding patients' perspectives: A qualitative study. AB - BACKGROUND: Patients' beliefs and attitudes toward receiving alcohol enquiry from general practitioners (GPs) are unclear. These need to be understood to implement pragmatic, early detection and brief intervention strategies. METHODS: We purposively sampled 23 participants from respondents of an earlier survey conducted in a general practice clinic in Sydney, Australia. Semi-structured interviews were conducted between June and August 2014, recorded, transcribed and analysed using grounded theory method to develop an explanatory model. RESULTS: There were three factors that influenced patients' acceptability of alcohol enquiry by GPs: * perceived relevance of the alcohol enquiry dialogue to the consultation * approach and language used in the patient-doctor interaction * unease regarding the moral and stigmatising dimension of alcohol consumption. DISCUSSION: Patients are positive towards the role of GPs in health promotion, but nonetheless have reservations towards engaging in alcohol discussions. Setting the context for alcohol dialogue, linking it to patients' agendas, collaborative consultation styles and respecting patients' sensitivity may improve acceptability. PMID- 26590626 TI - Fertility-awareness knowledge, attitudes and practices of women attending general practice. AB - BACKGROUND: Most women who attend assisted reproductive technology (ART) clinics believe women should receive fertility-awareness education when they first report trouble conceiving. Interest in fertility awareness among women who attend general practice is largely unknown. We aimed to measure fertility-awareness knowledge, attitudes and practices of women attending general practice. METHODS: A cross-sectional survey of women attending three different general practices was conducted. RESULTS: Of the respondents, 37.1% actively tried to improve their knowledge of fertility awareness, 9.8% were actively planning a pregnancy and 4.3% were using fertility awareness as contraception. Yet, only 2.1% of the overall sample correctly identified the fertile period of the menstrual cycle. Most respondents (92.2%) believed women should receive fertility-awareness education when they first report trouble conceiving. DISCUSSION: One-third of women who attend general practice show interest in fertility awareness, but far fewer can correctly identify the fertile period of the menstrual cycle. All women who report using fertility awareness as contraception should be counselled on their actual knowledge and advised accordingly. Concordant with our previous study of women who experience infertility, most women who attend general practice believe that women should receive fertility-awareness education when they first report trouble conceiving. Further research is needed to determine how best to do this. PMID- 26590627 TI - General practice ethics: Continuing medical education and the pharmaceutical industry. AB - This is the fifth in a six-part series on general practice ethics. Cases from practice are used to trigger reflection on common ethical issues where the best course of action may not be immediately apparent. The case presented in the article is an illustrative compilation and not based on specific individuals. PMID- 26590628 TI - Vaccination and the law. AB - BACKGROUND: Debate on whether vaccination should be made mandatory through law is vexed and centres on the rights of the community versus those of the individual - in particular, their right to make decisions in the best interest of their child. OBJECTIVE: This review examines the role that legislation and case law play in determining whether it is in the child's best interest to be protected against vaccine-preventable diseases. DISCUSSION: Legislating to make vaccination mandatory raises conflicting issues. Legal compulsion may impinge on a parent's right to choose what they consider is in the best interest of their child. The dilemma is whether achieving herd immunity, in particular the protection of children against serious and preventable diseases, justifies infringing on these rights. PMID- 26590629 TI - Towards an educational continuing professional development (EdCPD) curriculum for Australian general practice supervisors. AB - BACKGROUND: Within the apprenticeship model of general practice training, the majority of teaching and learning occurs in the practice under the guidance of the general practice supervisor. One of the foundations of a high-quality general practice training program is the delivery of relevant, evidence-based educational continuing professional development (EdCPD) for general practice supervisors. Despite The Royal Australian College of General Practitioners (RACGP) and the Australian College of Rural and Remote Medicine (ACRRM) standards requiring EdCPD, there is currently no standardised educational curriculum for Australian general practice supervisors. There are a number of emerging themes with significant implications for future general practice supervisor EdCPD. These include clinical supervision and structural issues, capacity constraints, and emerging educational issues. OBJECTIVE: We propose the development of a core curriculum for general practice supervisors that is competency-based and evidence based, and reflects the changing landscape of Australian general practice training. DISCUSSION: A national general practice supervisor core curriculum would provide standardisation, encourage collaboration, allow for regional adaptation, focus on developing competencies and require rigorous evaluation. PMID- 26590630 TI - Food insecurity in Australia: Implications for general practitioners. AB - BACKGROUND: In Australia, it would appear that food is abundant. For a proportion of people, however, accessing enough food to eat can be a daily or weekly struggle. OBJECTIVE: This article provides a summary about the prevalence, causes and consequences of food insecurity that affects vulnerable populations in Australia, and discusses the implications for general practitioners (GPs). DISCUSSION: It is estimated that 4% of Australians cannot access sufficient, safe and nutritious food. Food insecurity can be both a precursor to, and a by-product of, chronic disease and poverty. Patients who are food insecure may skip meals, eat cheap food and experience stress. They may show incredible resilience and skills in managing and masking this issue. Identifying this vulnerable population is of high importance to GPs as it has an impact on the work-up and care of such individuals. Effective links between welfare and health services are required to address patients' material, financial and environmental barriers to food security. PMID- 26590631 TI - 3D stereophotogrammetry in upper-extremity lymphedema: An accurate diagnostic method. AB - BACKGROUND: Upper-extremity lymphedema is a frequent complication in patients treated for breast cancer. Current diagnostic methods for the upper-extremity volume measurements are cumbersome or time consuming. The purpose of this study was to assess the validity and reliability of three-dimensional (3D) stereophotogrammetry for volume measurements in patients with upper-extremity lymphedema. METHOD: Patients with unilateral upper-extremity lymphedema were included. The water displacement volume measurement of both arms was performed using a standardized method. In addition, 3D stereophotogrammetry volume measurements were conducted. RESULTS: Eleven patients (22 arms) were included. The mean volumes obtained by 3D stereophotogrammetry and water displacement show a high correlation, with a Pearson's correlation coefficient of 0.99 (p = 0.01). The variance calculated by 3D stereophotogrammetry measurements (205 mL) was statistically significant less than that obtained via water displacement measurements (1540 mL) (p < 0.001). CONCLUSION: 3D stereophotogrammetry is an accurate method for measuring upper-extremity volume in patients with lymphedema and gives a lower variance value compared to that of the water displacement measurements. We recommend the use of this method in the diagnosis and follow-up of patients with lymphedema. PMID- 26590632 TI - Mannose-displaying fluorescent framboidal nanoparticles containing phenylboronic acid groups as a potential drug carrier for macrophage targeting. AB - Functional polymeric nanoparticles have been used for various applications in the biomaterials field. Recently, we reported phenylboronic acid-containing nanoparticles (PBA NPs) having an unique framboidal morphology, prepared in a single-step by the aqueous dispersion polymerization of N-acryloyl-3 aminophenylboronic acid (PBAAM) in the presence of poly(ethylene glycol) acrylamide (PEGAM) as a polymerizable dispersant and N,N'-methylenebisacrylamide (MBAM) as a crosslinker. In this study, we prepared mannosylated and fluorescent PBA NPs that could be used for different applications such as drug delivery and bioimaging. Fluorescent PBA NPs were synthesized by including the fluorescent Nile Blue acrylamide monomer in the reaction mixture during the dispersion polymerization of PBAAM. By using a carboxyl group-bearing PEGAM dispersant, carboxyl group-bearing PBA NPs were prepared that were modified with mannosamine to yield mannosylated PBA NPs. Cellular uptake studies showed that the mannosylated PBA NPs were selectively taken up by murine RAW264.7 macrophages. These results show that PBA NPs allow for flexible modification with various functionalities and could therefore be a potential platform for targeted delivery of drugs to macrophages. PMID- 26590633 TI - Needle-free buccal anesthesia using iontophoresis and amino amide salts combined in a mucoadhesive formulation. AB - Iontophoresis is a strategy to increase the penetration of drugs through biological membranes; however, its use has been underexplored in mucosa. The aim of this work was to investigate the influence of iontophoresis in the mucosal penetration of prilocaine hydrochloride (PCL) and lidocaine hydrochloride (LCL), which are largely used in dentistry as local anesthetics, when combined in the same formulation. Semisolid hydrogels containing these drugs either alone or in combination were developed at two different pHs (7.0 and 5.8) and presented adequate mechanical and mucoadhesive properties for buccal administration. The distribution coefficients between the mucosa and the formulations (Dm/f) and the in vitro mucosa permeation and retention rates were evaluated for both PCL and LCL. At pH 7.0, the combination of the drugs decreased the Dm/f of PCL by approximately 3-fold but did not change the Dm/f of LCL; iontophoresis increased the permeation rate of PCL by 12-fold and did not significantly change LCL flux compared with the passive permeation rate of the combined drugs. Combining the drugs also resulted in an increase in both PCL (86-fold) and LCL (12-fold) accumulation in the mucosa after iontophoresis at pH 7.0 compared with iontophoresis of the isolated drugs. Therefore, applying iontophoresis to a semisolid formulation of this drug combination at pH 7.0 can serve as a needle free strategy to speed the onset and prolong the duration of buccal anesthesia. PMID- 26590634 TI - Synthesis and characterization of a novel pH-thermo dual responsive hydrogel based on salecan and poly(N,N-diethylacrylamide-co-methacrylic acid). AB - Salecan is a water-soluble microbial polysaccharide produced by Agrobacterium sp. ZX09, a salt-tolerant strain isolated from a soil sample in our laboratory. Previous work inspired us salecan is a good candidate to fabricate hydrogels. Poly(N,N-diethylacrylamide) is one type of thermo sensitive polymer which is not investigated extremely as poly(N-isopropylacrylamide). Here, we report a novel pH thermo dual responsive hydrogel based on salecan and poly(N,N-diethylacrylamide co-methacrylic acid) semi-interpenetrating polymer networks (semi-IPNs). The physicochemical property of this hydrogel was investigated by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) and thermogravimetric analyses (TGA), rheological test and Scanning Electron Microscopy (SEM). It was interesting that the storage modulus (G') and pore size of the hydrogel could be tuned by adjusting the content of salecan and crosslinker. The pH-thermo dual responsive property was demonstrated by swelling behavior test: the swelling ratio of the hydrogel decreased continuously as the temperature increased from 25 degrees C to 37 degrees C, while it was pH-dependent as well. Especially, when exposed to a higher temperature (37 degrees C) and acidic environment (pH 4.0), drug-loaded hydrogel would have a quick release. Finally, the cytotoxicity of drug-free hydrogels was investigated on A549 and HepG2 cells, results showed that it was non-toxic while the DOX released from hydrogels had comparable cytotoxicity with respect to free DOX. In conclusion, the novel salecan/poly(N,N diethylacrylamide-co-methacrylic acid) semi-interpenetrating polymer network hydrogels were pH-thermo dual responsive and may be a promising candidate for drug delivery system. PMID- 26590635 TI - Dissecting How Mtb Makes Its Wall, Buffering Endosomal pH, and Discovery of Ribocil. AB - Each month, Chemistry & Biology Select highlights a selection of research reports from the recent literature. These highlights are a snapshot of interesting research done across the field of chemical biology. Our November 2015 selection includes an insight into non-overlapping biosynthetic pathways that lead to formation of Mycobacterium tuberculosis peptidoglycan, a new method to not only measure but also buffer the endosomal pH using nanoparticles, and a demonstration that non-coding RNAs can be a target for antibiotic discovery. PMID- 26590636 TI - An L-RNA Aptamer that Binds and Inhibits RNase. AB - L-RNA aptamers were developed that bind to barnase RNase and thereby inhibit the function of the enzyme. These aptamers were obtained by first carrying out in vitro selection of D-RNAs that bind to the full-length synthetic D-enantiomer of barnase, then reversing the mirror and preparing L-RNAs of identical sequence that similarly bind to natural L-barnase. The resulting L-aptamers bind L-barnase with an affinity of ~100 nM and function as competitive inhibitors of enzyme cleavage of D-RNA substrates. L-RNA aptamers are resistant to degradation by ribonucleases, thus enabling them to function in biological samples, most notably for applications in molecular diagnostics and therapeutics. In addition to the irony of using RNA to inhibit RNase, L-RNA aptamers such as those described here could be used to measure the concentration or inhibit the function of RNase in the laboratory or in biological systems. PMID- 26590637 TI - Combining Suppression of Stemness with Lineage-Specific Induction Leads to Conversion of Pluripotent Cells into Functional Neurons. AB - Sox2 is a key player in the maintenance of pluripotency and stemness, and thus inhibition of its function would abrogate the stemness of pluripotent cells and induce differentiation into several types of cells. Herein we describe a strategy that relies on a combination of Sox2 inhibition with lineage-specific induction to promote efficient and selective differentiation of pluripotent P19 cells into neurons. When P19 cells transduced with Skp protein, an inhibitor of Sox2, are incubated with a neurogenesis inducer, the cells are selectively converted into neurons that generate depolarization-induced sodium currents and action potentials. This finding indicates that the differentiated neurons are electrophysiologically active. Signaling pathway studies lead us to conclude that a combination of Skp with the neurogenesis inducer enhances neurogenesis in P19 cells by activating Wnt and Notch pathways. The present differentiation protocol could be valuable to selectively generate functionally active neurons from pluripotent cells. PMID- 26590638 TI - Optogenetic Inhibitor of the Transcription Factor CREB. AB - Current approaches for optogenetic control of transcription do not mimic the activity of endogenous transcription factors, which act at numerous sites in the genome in a complex interplay with other factors. Optogenetic control of dominant negative versions of endogenous transcription factors provides a mechanism for mimicking the natural regulation of gene expression. Here we describe opto-DN CREB, a blue-light-controlled inhibitor of the transcription factor CREB created by fusing the dominant negative inhibitor A-CREB to photoactive yellow protein (PYP). A light-driven conformational change in PYP prevents coiled-coil formation between A-CREB and CREB, thereby activating CREB. Optogenetic control of CREB function was characterized in vitro, in HEK293T cells, and in neurons where blue light enabled control of expression of the CREB targets NR4A2 and c-Fos. Dominant negative inhibitors exist for numerous transcription factors; linking these to optogenetic domains offers a general approach for spatiotemporal control of native transcriptional events. PMID- 26590639 TI - Molecular Basis of Spectral Diversity in Near-Infrared Phytochrome-Based Fluorescent Proteins. AB - Near-infrared fluorescent proteins (NIR FPs) engineered from bacterial phytochromes (BphPs) are the probes of choice for deep-tissue imaging. Detection of several processes requires spectrally distinct NIR FPs. We developed an NIR FP, BphP1-FP, which has the most blue-shifted spectra and the highest fluorescence quantum yield among BphP-derived FPs. We found that these properties result from the binding of the biliverdin chromophore to a cysteine residue in the GAF domain, unlike natural BphPs and other BphP-based FPs. To elucidate the molecular basis of the spectral shift, we applied biochemical, structural and mass spectrometry analyses and revealed the formation of unique chromophore species. Mutagenesis of NIR FPs of different origins indicated that the mechanism of the spectral shift is general and can be used to design multicolor NIR FPs from other BphPs. We applied pairs of spectrally distinct point cysteine mutants to multicolor cell labeling and demonstrated that they perform well in model deep tissue imaging. PMID- 26590640 TI - The Essential Role of Public Health in Preventing Disease, Prolonging Life, and Promoting Health of Cancer Survivors. PMID- 26590641 TI - Public Health Action Model for Cancer Survivorship. AB - Long-term objectives associated with cancer survivors have been suggested by Healthy People 2020, including increasing the proportion of survivors living beyond 5 years after diagnosis and improving survivors' mental and physical health-related quality of life. Prior to reaching these objectives, several intermediate steps must be taken to improve the physical, social, emotional, and financial well-being of cancer survivors. Public health has a role in developing strategic, actionable, and measurable approaches to facilitate change at multiple levels to improve the lives of survivors and their families. The social ecological model has been used by the public health community as the foundation of multilevel intervention design and implementation, encouraging researchers and practitioners to explore methods that promote internal and external changes at the individual, interpersonal, organizational, community, and policy levels. The survivorship community, including public health professionals, providers, policymakers, survivors, advocates, and caregivers, must work collaboratively to identify, develop, and implement interventions that benefit cancer survivors. The National Action Plan for Cancer Survivorship highlights public health domains and associated strategies that can be the impetus for collaboration between and among the levels in the social ecological model and are integral to improving survivor outcomes. This paper describes the Public Health Action Model for Cancer Survivorship, an integrative framework that combines the National Action Plan for Cancer Survivorship with the social ecological model to demonstrate how interaction among the various levels may promote better outcomes for survivors. PMID- 26590642 TI - Advancing Health Equity in Cancer Survivorship: Opportunities for Public Health. PMID- 26590643 TI - Evolution of a CDC Public Health Research Agenda for Low-Risk Prostate Cancer. AB - Men with prostate cancer face difficult choices when selecting a therapy for localized prostate cancer. Comparative data from controlled studies are lacking and clinical opinions diverge about the benefits and harms of treatment options. Consequently, there is limited guidance for patients regarding the impact of treatment decisions on quality of life. There are opportunities for public health to intervene at several decision-making points. Information on typical quality of life outcomes associated with specific prostate cancer treatments could help patients select treatment options. From 2003 to present, the Division of Cancer Prevention and Control at CDC has supported projects to explore patient information-seeking behavior post-diagnosis, caregiver and provider involvement in treatment decision making, and patient quality of life following prostate cancer treatment. CDC's work also includes research that explores barriers and facilitators to the presentation of active surveillance as a viable treatment option and promotes equal access to information for men and their caregivers. This article provides an overview of the literature and considerations that initiated establishing a prospective public health research agenda around treatment decision making. Insights gathered from CDC-supported studies are poised to enhance understanding of the process of shared decision making and the influence of patient, caregiver, and provider preferences on the selection of treatment choices. These findings provide guidance about attributes that maximize patient experiences in survivorship, including optimal quality of life and patient and caregiver satisfaction with information, treatment decisions, and subsequent care. PMID- 26590644 TI - Healthcare Expenditure Burden Among Non-elderly Cancer Survivors, 2008-2012. AB - INTRODUCTION: There is increasing concern regarding the financial burden of cancer on patients and their families. This study presents nationally representative estimates of annual out-of-pocket (OOP) burden among non-elderly cancer survivors and assesses the association between high OOP burden and access to care and preventive service utilization. METHODS: Using the 2008-2012 Medical Expenditure Panel Survey, 4,271 cancer survivors and 96,780 individuals without a history of cancer were identified, all aged 18-64 years. High annual OOP burden was defined as spending >20% of annual family income on OOP healthcare costs. Associations between high OOP burden and access to care were evaluated with multivariable logistic regression. Analyses were conducted in 2015. RESULTS: Compared with individuals without a cancer history, cancer survivors were more likely to report a high OOP burden (4.3% vs 3.4%, p=0.009) in adjusted analyses. High OOP burden was more common among cancer survivors who were poor (18.4%), with either public insurance (7.9%) or uninsured (5.7%), and not working (10.2%). Among cancer survivors, high OOP burden was associated with being unable to obtain necessary medical care (19.2% vs 12.5%, p=0.002), delaying necessary medical care (21.6% vs 13.8%, p=0.002), and lower breast cancer screening rates among age-appropriate women (63.2% vs 75.9%, p=0.02). CONCLUSIONS: High OOP burden is more common among adults with a cancer history than those without a cancer history. High OOP burden was associated with being unable to obtain necessary medical care, delaying necessary medical care, and lower breast cancer screening rates among women. PMID- 26590645 TI - Post-treatment Neurocognition and Psychosocial Care Among Breast Cancer Survivors. AB - INTRODUCTION: Chemotherapy for breast cancer has been associated with cognitive problems; however, the impact of adjuvant hormone therapy is less clear. No studies have explored provider discussions about cognitive concerns or factors associated with neurocognitive treatment. This study examined cognitive problems, factors associated with having a provider discussion, and receipt of neurocognitive treatment. METHODS: Female breast cancer survivors (N=2,537) from the Sister Study and the Two Sister Study who were at least 1 year post-treatment were surveyed in 2012 about their cancer therapies (confirmed by medical records); cognitive concerns; related provider discussions; and neurocognitive treatment. A total of 2,296 women were included in the current 2014 analysis. Extensive covariate information was also ascertained for predictive multivariate models. RESULTS: The prevalence of self-reported cognitive problems after treatment was 60%. Of those reporting cognitive problems, only 37% had discussed those concerns with a provider and 15% had been treated for cognitive symptoms. The odds of reported cognitive concerns that started during and after treatment were elevated for those who received only hormone therapy and no chemotherapy (OR=1.64, 95% CI=1.15, 2.33); chemotherapy and no hormone therapy (OR=5.63, 95% CI=3.52, 9.00); or both (OR=6.33, 95% CI=4.21, 9.54) compared with those reporting neither treatment. CONCLUSIONS: The high prevalence of cognitive concerns underscores the importance of monitoring breast cancer survivors for potential neurocognitive effects of hormone and chemotherapy, discussions with survivors about those concerns, and treatment referrals. Monitoring changes over time can help to evaluate both psychosocial and neurocognitive care provided for survivors. PMID- 26590646 TI - Awareness of Dietary and Alcohol Guidelines Among Colorectal Cancer Survivors. AB - INTRODUCTION: Although dietary habits can affect colorectal cancer (CRC) survivors' health, it is unclear how familiar survivors are with dietary guidelines, what they believe about healthy eating and alcohol consumption, and what hinders healthy dietary habits after cancer. This study assessed CRC survivors' familiarity with dietary guidelines, their eating and drinking habits, and perceived facilitators and barriers to healthy eating after cancer, including social support and self-efficacy for maintaining a healthy diet and limiting alcohol. METHODS: A total of 593 individuals (50% female; mean age, 74 years) diagnosed with CRC approximately 6 years prior to study entry in early 2010 were identified through California Cancer Registry records and participated in a cross sectional mailed survey assessing health behavior after cancer (46% adjusted response rate). Analyses were conducted in 2014-2015. RESULTS: Survivors were most familiar with-and most likely to follow-recommendations to choose low-fat foods; 15% had never heard of recommendations to limit alcohol. Survivors were more aware of recommendations involving messages to limit/avoid versus approach/choose certain foods. The most common barrier to a healthy diet involved the effort required (26%). Survivors received more family/friend support and provider recommendations for healthy eating than limiting alcohol. CONCLUSIONS: Results provide an overview of awareness of and adherence to dietary recommendations among CRC survivors, highlighting the need for increasing awareness of recommendations that are especially relevant for survivors. Suggestions are made for modifying diet-related messages to facilitate comprehension and recall among CRC survivors, and increasing awareness among groups with the lowest awareness levels. PMID- 26590647 TI - Factors Associated with Health-Related Quality of Life Among Colorectal Cancer Survivors. AB - INTRODUCTION: Assessment of health-related quality of life (HRQOL) can provide insights into cancer survivors' physical and mental functioning, their social relationships, and perceptions of their health and well-being. Understanding factors associated with HRQOL may help identify those who are at greater risk for diminished functioning and improve targeted delivery of health promotion programs. This analysis sought to assess sociodemographic and medical factors associated with HRQOL among colorectal cancer survivors and factors that may put survivors at risk for poor functioning. In addition, associations between BMI and physical activity and HRQOL were explored. METHODS: Data from a cross-sectional study of health behaviors among 593 long-term colorectal cancer survivors recruited through the California Cancer Registry in early 2010 were analyzed in late 2014 to early 2015. Multivariable linear and logistic regression models were used to assess factors associated with physical, mental, and overall HRQOL. RESULTS: The mean physical and mental HRQOL scores of survivors were 46.88 and 42.28, respectively, and lower than the population norm (50). Being older, having more comorbid conditions, and having had a recurrence were associated with lower physical and overall HRQOL, whereas being physically active was associated with higher physical and overall HRQOL. CONCLUSIONS: Findings highlight the need to encourage healthcare providers to promote physical activity among sedentary cancer survivors, even at modest levels. In addition, lower mental HRQOL scores may indicate a greater need to screen cancer survivors for psychosocial issues and link them with appropriate services. PMID- 26590648 TI - Connecting the Dots: Linking the National Program of Cancer Registries and the Needs of Survivors and Clinicians. AB - Cancer survivors, the medical community, public health professionals, researchers, and policymakers all need information about newly diagnosed cancer cases and deaths to better understand and address the disease burden. CDC collects cancer data on 96% of the U.S. population through the National Program of Cancer Registries. The National Program of Cancer Registries routinely collects data on all cancer occurrences, deaths, and the types of initial treatment received by the patients, and recently CDC has made advances in its cancer surveillance activities that have direct applicability to cancer survivorship research and care. This article examines CDC's innovative uses of the National Program of Cancer Registries infrastructure and data as a recruitment source for survivorship research studies and behavioral interventions; comparative effectiveness and patient-centered outcomes research; and the collection, consolidation, and dissemination of treatment summaries for cancer survivors and their providers. This paper also discusses long-term, idealistic plans for additional data linkages and sharing among public health, providers, and the cancer survivor through innovative concepts such as patient portals and rapid-learning health care. PMID- 26590649 TI - Evidence-Based Cancer Survivorship Activities for Comprehensive Cancer Control. AB - INTRODUCTION: One of six priorities of CDC's National Comprehensive Cancer Control Program (NCCCP) is to address the needs of cancer survivors within the local population served by individually funded states, tribes, and territories. This report examines cancer survivorship activities implemented in five NCCCP grantees, which have initiated evidence-based activities outlined in A National Action Plan for Cancer Survivorship: Advancing Public Health Strategies (NAP). METHODS: NCCCP action plans, submitted annually to CDC, from 2010 to 2014 were reviewed in February 2015 to assess implementation of cancer survivorship activities and recommended strategies consistent with the NAP. Four state-level and one tribal grantee with specific activities related to one of each of the four NAP strategies were chosen for inclusion. Brief case reports describing the initiation and impact of implemented activities were developed in collaboration with each grantee program director. RESULTS: New Mexico, South Carolina, Vermont, Washington state, and Fond Du Lac Band of Lake Superior Chippewa programs each implemented activities in surveillance and applied research; communication, education, and training; programs, policies, and infrastructure; and access to quality care and services. CONCLUSIONS: This report provides examples for incorporating cancer survivorship activities within Comprehensive Cancer Control programs of various sizes, demographic makeup, and resource capacity. New Mexico, South Carolina, Vermont, Washington state, and Fond Du Lac Band developed creative cancer survivorship activities that meet CDC recommendations. NCCCP grantees can follow these examples by implementing evidence-based survivorship interventions that meet the needs of their specific populations. PMID- 26590650 TI - Evaluation of a Web-Based Program for African American Young Breast Cancer Survivors. AB - INTRODUCTION: Among women aged <45 years, African Americans have the highest breast cancer incidence rates of any ethnic/racial group and disproportionately higher rates of mortality. Young breast cancer survivors (YBCSs) may require psychosocial and reproductive health support when navigating diagnosis, treatment, and follow-up care. To address these needs, the Young Sisters Initiative: A Guide to a Better You! Program (YSI) was developed, implemented, and evaluated. The purpose of this study was to assess implementation and fidelity; identify barriers and facilitators to implementation; and explore audience access, use, and perceived value of the YSI. METHODS: A mixed-method, process evaluation of the YSI using interviews, an online screener, and post-use survey was conducted with data collected and analyzed from February through August 2013. Thematic analysis of qualitative data was conducted without qualitative data analysis software. Survey data were analyzed using PASW Statistics, version 18. RESULTS: YSI core elements were implemented as intended. A total of 1,442 people visited the YSI website; 93% of breast cancer survivors who visited the site (and consented to be in the study) were African American; 75% of post-use survey YBCS respondents were very or somewhat satisfied with the YSI; and 70% of YBCS respondents said the YSI content was somewhat or very useful. CONCLUSIONS: Findings suggest the value of using the Internet, including social media, to provide African-American YBCSs who are newly diagnosed, in treatment, and post-treatment with reproductive and psychosocial information and support. Further implementation and evaluation of programs addressing the needs of YBCSs are needed. PMID- 26590651 TI - Public Health's Future Role in Cancer Survivorship. PMID- 26590652 TI - Season of birth and multiple sclerosis in Tunisia. AB - BACKGROUND: Recent studies on date of birth of multiple sclerosis (MS) patients showed an association between month of birth and the risk of developing MS. This association has not been investigated in an African country. OBJECTIVE: We aimed to determine if the risk of MS is associated with month of birth in Tunisia. METHODS: Data concerning date of birth for MS patients in Tunisia (n = 1912) was obtained. Birth rates of MS patients were compared with all births in Tunisia matched by year of birth (n = 11,615,912). We used a chi-squared analysis and the Hewitt's non-parametric test for seasonality. RESULTS: The distribution of births among MS patients compared with the control population was not different when tested by the chi-squared test. The Hewitt's test for seasonality showed an excess of births between May and October among MS patients (p = 0.03). The peak of Births of MS patients in Tunisia was in July and the nadir in December. CONCLUSION: Our data does support the seasonality hypothesis of month of birth as risk factor for MS in Tunisia. Low vitamin D levels during pregnancy could be a possible explanation that needs further investigation. PMID- 26590653 TI - Natalizumab-induced hepatic injury: A case report and review of literature. AB - Natalizumab is an alpha4-integrin monoclonal antibody used for treatment of relapsing multiple sclerosis (MS). At least and nearly 30 cases of liver failure in natalizumab-treated patients are listed in the post-marketing FDA adverse event reporting system (FAERS) and twelve patients with severe liver injury, including several after the first infusion, have been reported (Lisotti et al., 2012; Bezabeh et al., 2010; Martinez-Lapiscina et al., 2013; Michael et al., 2007; Hillen et al., 2015). Herein, we describe a case of a young woman with relapsing MS who developed acute liver injury after the second infusion of natalizumab. Liver biopsy demonstrated a mixed pattern of medication-induced injury or partially treated auto-immune hepatitis. Liver function normalized after natalizumab discontinuation and a subsequent liver biopsy showed resolution of hepatitis. The patient's MS has since been successfully treated with rituximab for over a year. We review the published cases of liver injury associated with natalizumab and those in the post-marketing FDA adverse event reporting system (FAERS). PMID- 26590654 TI - The Hungarian validation of the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) battery and the correlation of cognitive impairment with fatigue and quality of life. AB - BACKGROUND: Multiple Sclerosis (MS) causes not only somatic, but also cognitive impairment regardless of the patients' age or the course of the disease. The Brief International Cognitive Assessment for MS (BICAMS) test, published in 2011, is a short cognitive questionnaire: a fast, reliable, sensitive and specific tool for the evaluation of the patients' cognitive state. OBJECTIVES: Our primary objective was to assess the validity of the Hungarian version of the BICAMS test. Our secondary objective was to evaluate the impact of the cognitive impairment on the patient's quality of life and fatigue's impact on the patients' cognitive state. METHODS: 65 RR-MS patients and 65 age, sex and education matched healthy control (HC) subjects completed the test and were retested after 3 weeks. The patients also completed the MS Quality of Life 54 (MSQoL54) and the Fatigue Impact Scale (FIS) assessments. Group differences were calculated by paired sample T-tests. The test-retest reliability was measured by intraclass correlation coefficients. To analyze the difference between the test-retest performances of the two groups we used two-way repeated measures ANOVA where the BICAMS battery was the single composite outcome and one-way repeated measures ANOVA. To assess the impact of the cognitive decline on the patients' quality of life and fatigue's impact on the cognitive state, we examined the correlations between results in the BICAMS and the MSQoL54 and FIS. RESULTS: We found significant difference (p <= 0.001, p = 0.017 in the first CVLT-II assessment) between MS patients and members of the HC group in all four evaluated parameters of BICAMS test in both sessions. The correlation coefficients were very strong between the tests and retests (r > 0.8; p < 0.001; r = 0.678, p < 0.001 between the CVLT-II assessments). We found that the HC group performed significantly (p = 0.020) better in the retest sessions as compared to their original performance than the patients did and this difference is solely due to the difference between the CVLT-II performances. We have found significant negative correlation between the patients' cognitive function and the fatigue score (r < -0.3, p < 0.05). Seven of the MSQoL-54 subscales correlated with the BICAMS performance (r > 0.3; < 0 .05). CONCLUSIONS: The Hungarian version of the BICAMS test is a valid and reliable method for the evaluation of MS patients' cognitive function. It seems that because of the short retest period, the members of the HC group remembered the CVLT-II words thus performed better than the patients did. Also apparently fatigue can have a negative impact on the patients' cognitive state, and cognitive impairment could worsen the patients' quality of life. PMID- 26590656 TI - The ethics of placebo controlled clinical trials in NMO - A balance of risks. PMID- 26590655 TI - The disease-modifying effects of a Sativex-like combination of phytocannabinoids in mice with experimental autoimmune encephalomyelitis are preferentially due to Delta9-tetrahydrocannabinol acting through CB1 receptors. AB - Sativex((r)), an equimolecular combination of Delta(9)-tetrahydrocannabinol botanical drug substance (Delta(9)-THC-BDS) and cannabidiol-botanical drug substance (CBD-BDS), is a licensed medicine that may be prescribed for alleviating specific symptoms of multiple sclerosis (MS) such as spasticity and pain. However, further evidence suggest that it could be also active as disease modifying therapy given the immunomodulatory, anti-inflammatory and cytoprotective properties of their two major components. In this study, we investigated this potential in the experimental autoimmune encephalitis (EAE) model of MS in mice. We compared the effect of a Sativex-like combination of Delta(9)-THC-BDS (10 mg/kg) and CBD-BDS (10 mg/kg) with Delta(9)-THC-BDS (20 mg/kg) or CBD-BDS (20 mg/kg) administered separately by intraperitoneal administration to EAE mice. Treatments were initiated at the time that symptoms appear and continued up to the first relapse of the disease. The results show that the treatment with a Sativex-like combination significantly improved the neurological deficits typical of EAE mice, in parallel with a reduction in the number and extent of cell aggregates present in the spinal cord which derived from cell infiltration to the CNS. These effects were completely reproduced by the treatment with Delta(9)-THC-BDS alone, but not by CBD-BDS alone which only delayed the onset of the disease without improving disease progression and reducing the cell infiltrates in the spinal cord. Next, we investigated the potential targets involved in the effects of Delta(9)-THC-BDS by selectively blocking CB(1) or PPAR-gamma receptors, and we found a complete reversion of neurological benefits and the reduction in cell aggregates only with rimonabant, a selective CB(1) receptor antagonist. Collectively, our data support the therapeutic potential of Sativex as a phytocannabinoid formulation capable of attenuating EAE progression, and that the active compound was Delta(9)-THC-BDS acting through CB(1) receptors. PMID- 26590657 TI - Neuromyelitis optica spectrum disorder and multiple sclerosis: Differentiation by a multimodal approach. AB - BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) differs from multiple sclerosis (MS) by prognosis and approach to treatment, and it is thus important to distinguish NMOSD from MS. OBJECTIVE: We evaluated the structural brain abnormalities in patients with NMOSD and with relapsing-remitting MS (RRMS) using with MRI. METHODS: Twenty-one NMOSD patients with antibodies against aquaporin 4, 32 patients with RRMS, and current age- and sex- matched 39 healthy subjects underwent 3-T MRI. The differences in gray matter volume and fractional anisotropy (FA) value among the three groups were evaluated. RESULTS: There were significant global gray matter volume reductions of NMOSD and RRMS groups, compared to the healthy subjects. Significant and diffuse decreases in FA values were observed in both the NMOSD and RRMS patients. Significant gray matter volume and FA value reductions of the RRMS patients in the bilateral thalami and some regions were observed compared to the NMOSD patients. CONCLUSION: Larger brain structural changes were seen in the RRMS group compared to the NMOSD group, and among them, the thalamus was revealed as the important region for the discrimination of these two diseases. MRI analyses of the brain may be helpful in differentiating NMOSD from RRMS patients. PMID- 26590658 TI - A preliminary validation of the brief international cognitive assessment for multiple sclerosis (BICAMS) tool in an Irish population with multiple sclerosis (MS). AB - BACKGROUND: Cognitive impairment is common in multiple sclerosis (MS) irrespective of disease stage or subtype. It is typically underreported and neuropsychological testing can be required to detect more subtle evidence of cognitive impairment. The Brief International Cognitive Assessment in Multiple Sclerosis (BICAMS) was an initiative undertaken by a panel of experts with the primary objective of identifying a brief cognitive assessment tool that could be administered by healthcare professionals without formal neuropsychological training to identify early or subtle cognitive impairment among MS patients. OBJECTIVES: To validate BICAMS in Irish patients with MS and healthy controls. METHODS: Consecutive patients attending the MS outpatient department from January to April 2014 were recruited. Age, gender, education, handedness, MS subtype, expanded disability status scale (EDSS) and disease duration were recorded. They were administered BICAMS composed of Symbol Digit Modalities Test (SDMT), California Verbal Learning Test (CVLT-II) and Brief Visuospatial Memory Test (BVMT-R). Depression and anxiety were assessed using the Hospital Anxiety and Depression Scale (HADS). Control participants were composed of unaffected relatives, spouses or carers attending the clinic with a patient and were matched by age, gender and years of education. Impairment on individual tests was defined as -1.5 SD below reference group means. RESULTS: 67 patients [73% women; mean age: 43.9 yrs (12.1); mean years of education: 13.6 yrs (2.7)] and 66 controls [68% women; mean age 42.7 yrs (12.7); mean years of education: 14.1 yrs (3.2)] were recruited. Of the MS patient group: 70% were classified as having relapsing remitting MS, 28% secondary progressive MS and 2% primary progressive MS (PPMS). Mean EDSS scores were 1.8 (SD: 0.9), 5.7 (SD: 1.4) and 7.0 in each group respectively with mean disease duration of 10.2 (SD: 8.4) years, 20.6 (10.2) and 17 years. Mean scores and standard deviations for patients and control participants respectively were 46 (12.9) and 55.9 (10.9), p < 0.001; d = 0.83 for SDMT; 45.3 (10.2) and 52.8 (8.8), p < 0.001; d = 0.79 for CVLT-II and 17.9 (7.1) and 20.7 (6.6), p = 0.02; d = 0.41 for BVMT-R. Using regression based norms derived from the control sample only 43% of patients compared to 83% of control participants' results were within the normal range on all three tests. As expected higher rates of unemployment was seen amongst the patient population compared to control participants. Using the HADS 11 patients were classified as depressed and 13 as suffering from anxiety. Neither, these measures or the level of fatigue as measured by the MFIS was significantly associated with any of the three outcome measures (Pearson r < +/- 0.3). CONCLUSIONS: This study demonstrates that BICAMS is an easy test to administer and should be used as a basic tool to identify patients with cognitive impairment who may benefit from further neuropsychological assessment. Cognitive impairment can put patients at risk of poor self-management of disease including poor mediation adherence, and negatively impact on employment. Once identified appropriate support and monitoring can be put in place. BICAMS may also be used to help guide treatment decisions and rehabilitation. Further studies will be needed to assess its reliability over time and ability to detect meaningful changes. PMID- 26590660 TI - Placebo controlled trials in neuromyelitis optica are needed and ethical. AB - Currently, there are no approved treatments for NMO. All therapeutic studies in NMO have been either small, retrospective case series or uncontrolled prospective studies. Such studies are susceptible to inherent biases. As a consequence, conclusions regarding efficacy and safety from these studies may be erroneous. The optimal method for assessing therapeutic efficacy is the prospective, controlled trial with random treatment assignment that has the potential to control for multiple sources of bias. There is a significant unmet need for well designed clinical trials in NMO. Successfully conducted, well-controlled NMO trials that show proof of benefit will lead to regulatory approval and subsequent acceptance by payers resulting in broad therapeutic availability. The most direct method to prove efficacy is to compare an active treatment vs. no treatment or placebo control. However, because of the devastating nature of the disease some clinicians are reluctant to expose potential study patients to the risk of no treatment. The primary ethical concern in the case of placebo-control in NMO clinical trials rests on the relative merits of answering the scientific question regarding efficacy compared to the relative risk of exposure to harm in the placebo-control group. This article outlines the case for clinical equipoise in NMO by addressing the uncertainty regarding the relative scientific and clinical merits of current empirically used treatments and showing that a placebo arm is consistent with competent medical care. Because no currently available treatment has proven benefit, and because all therapies are known to potentially cause harm, placebo-control is not only ethical but is in some ways preferable to active comparator or add-on study designs. Without well-designed, placebo controlled trials, NMO patients may not have access to new treatments and will never know whether the therapies that they may be currently taking have risk to benefit profiles that clearly favor their use. PMID- 26590659 TI - Novel composite MRI scale correlates highly with disability in multiple sclerosis patients. AB - Understanding genotype-phenotype relationships or development/validation of biomarkers requires large multicenter cohorts integrated by universal quantification of crucial phenotypical traits, such as central nervous system (CNS) tissue destruction. We hypothesized that mathematical modeling-guided combination of biologically meaningful, semi-quantitative MRI elements characterized by high signal-to-noise ratio will provide such reliable, universal tool for measuring CNS tissue destruction. We retrospectively graded 15 elements in MRI scans performed in 419 untreated subjects with or without neurological diseases, while being blinded to their prospectively acquired clinical scores. We then used 305 subjects for disability-guided mathematical modeling to select and combine MRI elements that had non-redundant contributions to clinical disability, resulting in Combinatorial MRI Scale (COMRIS). We validated our model on the remaining 114 independent subjects. COMRIS requires 5-10 min per scan on average to compute and demonstrates highly significant (p < 0.0001) and validation consistent Spearman correlation coefficients (0.75, 0.76, and 0.65) for the expanded disability status scale (EDSS), Scripps neurological rating scale (SNRS), and symbol digit modality test (SDMT) measures of neurological disability, respectively. Because COMRIS is not greatly influenced by MRI scanners or protocols and can be computed even in the presence of some motion artifacts, it does not require censoring out patients and it provides comparable results across different cohorts. As such, it represents a broadly available clinical and research tool that can facilitate multicenter research studies and comparative analyses across patient cohorts and research projects. PMID- 26590661 TI - Mortality and comorbidities in patients with multiple sclerosis compared with a population without multiple sclerosis: An observational study using the US Department of Defense administrative claims database. AB - BACKGROUND: Data are limited for mortality and comorbidities in patients with multiple sclerosis (MS). OBJECTIVES: Compare mortality rates and event rates for comorbidities in MS (n=15,684) and non-MS (n=78,420) cohorts from the US Department of Defense (DoD) database. METHODS: Comorbidities and all-cause mortality were assessed using the database. Causes of death (CoDs) were assessed through linkage with the National Death Index. Cohorts were compared using mortality (MRR) and event (ERR) rate ratios. RESULTS: All-cause mortality was 2.9 fold higher in the MS versus non-MS cohort (MRR, 95% confidence interval [CI]: 2.9, 2.7-3.2). Frequent CoDs in the MS versus non-MS cohort were infectious diseases (6.2, 4.2-9.4), diseases of the nervous (5.8, 3.7-9.0), respiratory (5.0, 3.9-6.4) and circulatory (2.1, 1.7-2.7) systems and suicide (2.6, 1.3-5.2). Comorbidities including sepsis (ERR, 95% CI: 5.7, 5.1-6.3), ischemic stroke (3.8, 3.5-4.2), attempted suicide (2.4, 1.3-4.5) and ulcerative colitis (2.0, 1.7-2.3), were higher in the MS versus non-MS cohort. The rate of cancers was also higher in the MS versus the non-MS cohort, including lymphoproliferative disorders (2.2, 1.9-2.6) and melanoma (1.7, 1.4-2.0). CONCLUSIONS: Rates of mortality and several comorbidities are higher in the MS versus non-MS cohort. Early recognition and management of comorbidities may reduce premature mortality and improve quality of life in patients with MS. PMID- 26590662 TI - Neuro-oncology dilemma: Tumour or tumefactive demyelinating lesion. AB - Tumefactive demyelinating lesions (TDLs) are not an uncommon manifestation of demyelinating disease but can pose diagnostic challenges in patients without a pre-existing diagnosis of multiple sclerosis (MS) as well as in known MS patients. Brain tumours can also arise in MS patients and can be seen in chronic MS patients as co-morbidities. Delayed diagnosis or unnecessary intervention or treatment will affect the ultimate prognosis of these patients. In this article, we will review some typical cases illustrating the dilemma and review the information that helps to differentiate the two conditions. The intention is not to present an extensive differential diagnosis of both entities, but to examine some typical examples when the decision arises to decide between the two. We take a somewhat different approach, by presenting the cases in "real time", allowing the readers to consider in their own minds which diagnosis they favour, discussing in detail some of the pertinent literature, then revealing later the actual diagnosis. We would urge readers to consider re-visiting their first thoughts about each case after reading the discussion, before reading the follow up of each case. The overall objective is to highlight the real possibility of being forced to decide between these two entities in clinical practise, present a reasonable approach to help differentiate them and especially to focus on the possibility of TDLs in order to avoid unnecessary biopsy. PMID- 26590663 TI - Disability status and dental pathology in multiple sclerosis patients. AB - OBJECTIVE: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) leading to demyelination and neurodegeneration. The disease is plurifactorial, it being assumed that it is caused by an interaction between genes and the environment. Authors aimed to: (1) achieve better understanding of MS evolution; (2) identify, if any, significant associations between dental pathology and the clinical course of the disease in MS patients. METHOD: We performed a cross-sectional study on a group of 33 MS patients treated with immunomodulatory drugs (64% women and 36% men, with a mean age of 39.97 years). The data obtained from the medical records, through neurological assessment, oral and dental evaluation and the information collected by means of a questionnaire were grouped in: (1) items related to MS, (2) items related to dental health and (3) items regarding socio-demographic information. RESULTS: In our sample, disability status was significantly correlated to the number of relapses that occurred during the last year of disease and the total number of relapses. The immunomodulatory treatment significantly reduces the number of relapses in the first year of treatment, then the disease stabilizes. The disability level was highly dependent on the number of relapses that occurred in the most recent period of time. A percentage of 67.9% of the patients reported gingival bleeding. However, the bleeding was not significantly associated with the number of relapses from the last year, the degree of disability (EDSS) or type of immunomodulatory treatment. The only significant difference was identified between the EDSS scores and the presence/absence of dental amalgam fillings but the sample was too small to interpret this result. CONCLUSION: The study did not provide conclusive evidence regarding the association between amalgam restorations, periodontal disease and MS disability. PMID- 26590664 TI - Prevalence of multiple sclerosis in Brazil: A systematic review. AB - Epidemiological studies of multiple sclerosis (MS) conducted in Latin America have revealed prevalence rates of this disease from low to medium. The aim of this study was to gather and analyze surveys on prevalence conducted in Brazil, noting its variability in different regions. Systematic review was held in electronic databases and manual search in abstracts concerning ECTRIMS, LACTRIMS and Brazilian Congress of Neurology. Nineteen studies made reference to prevalence rates that ranged from 1.36/100,000 to 27.2/100.000 inhabitants. More studies on the epidemiology of MS in Brazil will be needed for a better assessment of its prevalence and profile. PMID- 26590665 TI - A placebo controlled trial for an NMO relapse prevention treatment: Ethical considerations. AB - This paper addresses the ethical acceptability of a proposed placebo controlled trial of a new intervention as a possible relapse prevention treatment for Neuromyelitis Optica (NMO). In the analysis of this controversial ethical issue, the author points out significant factors that are often overlooked or ignored, such as the life-long implications for study participants and others living with the disease, and also addresses commonly noted issues, such as vulnerability, benefits, harms, and justice that always require attention in research review. PMID- 26590667 TI - Primary spinal oligoastrocytoma mimicking longitudinally extensive transverse myelitis. AB - Longitudinally extensive transverse myelitis (LETM) is most commonly associated with neuromyelitis optica spectrum disorders (NMOSD). However, a wide range of etiologies may produce longitudinally extensive spinal cord lesions (LESCLs) on imaging. We highlight the case of a patient with a spinal cord tumor whose imaging showed LESCL and was diagnosed with LETM. He did not respond to immunosuppression and subsequently developed a progressive and protracted clinical course. Thoracic cord biopsy performed 6 years after symptom onset showed primary spinal oligoastrocytoma. We discuss the features that should raise suspicion of a neoplasm in the context of LESCL and serve a reminder that not all LESCLs are inflammatory. PMID- 26590666 TI - Eye and hand motor interactions with the Symbol Digit Modalities Test in early multiple sclerosis. AB - PURPOSE: Eye and hand motor dysfunction may be present early in the disease course of relapsing-remitting multiple sclerosis (RRMS), and can affect the results on visual and written cognitive tests. We aimed to test for differences in saccadic initiation time (SI time) between RRMS patients and healthy controls, and whether SI time and hand motor speed interacted with the written version of the Symbol Digit Modalities Test (wSDMT). METHODS: Patients with RRMS (N = 44, age 35.1 +/- 7.3 years), time since diagnosis < 3 years and matched controls (N = 41, age 33.2 +/- 6.8 years) were examined with ophthalmological, neurological and neuropsychological tests, as well as structural MRI (white matter lesion load (WMLL) and brainstem lesions), visual evoked potentials (VEP) and eye-tracker examinations of saccades. RESULTS: SI time was longer in RRMS than controls (p < 0.05). SI time was not related to the Paced Auditory Serial Addition Test (PASAT), WMLL or to the presence of brainstem lesions. 9 hole peg test (9HP) correlated significantly with WMLL (r = 0.58, p < 0.01). Both SI time and 9HP correlated negatively with the results of wSDMT (r = -0.32, p < 0.05, r = -0.47, p < 0.01), but none correlated with the results of PASAT. CONCLUSIONS: RRMS patients have an increased SI time compared to controls. Cognitive tests results, exemplified by the wSDMT, may be confounded by eye and hand motor function. PMID- 26590668 TI - Relationship between gait initiation and disability in individuals affected by multiple sclerosis. AB - This study analyzes how multiple sclerosis (MS) does affect one of the most common voluntary activities in life: the gait initiation (GI). The main aim of the work is to characterize the execution of this task by measuring and comparing relevant parameters based on center of pressure (COP) patterns and to study the relationship between these and the level of expanded disability status scale (EDSS). To this aim, 95 MS subjects with an average EDSS score of 2.4 and 35 healthy subjects were tested using a force platform during the transition from standing posture to gait. COP time-series were acquired and processed to extract a number of parameters related to the trajectory followed by the COP. The statistical analysis revealed that only a few measurements were statistically different between the two groups and only these were subsequently correlated with EDSS score. The correlation analysis underlined that a progressive alteration of the task execution can be directly related with the increase of EDSS score. These finding suggest that most of the impairment found in people with MS comes from the first part of the COP pattern, the anticipatory postural adjustments (APAs). The central nervous system performs APAs before every voluntary movement to minimize balance perturbation due to the movement itself. Gait Initiation's APAs consist in some ankle muscles contractions that induce a backward COP shift to the swing limb. The analysis here performed highlighted that MS affected patients have a reduced posterior COP shift that reveals that the anticipatory mechanism is impaired. PMID- 26590669 TI - Patient-reported outcomes in multiple sclerosis: Relationships among existing scales and the development of a brief measure. AB - Several patient-reported outcome (PRO) measures are commonly used in multiple sclerosis (MS) research, but the relationship among items across measures is uncertain. We proposed to evaluate the associations between items from a standard battery of PRO measures used in MS research and to develop a brief, reliable and valid instrument measure by combining these items into a single measure. Subjects (N = 537) enrolled in CLIMB complete a PRO battery that includes the Center for Epidemiologic Studies Depression Scale, Medical Outcomes Study Modified Social Support Survey, Modified Fatigue Impact Scale and Multiple Sclerosis Quality of Life-54. Subjects were randomly divided into two samples: calibration (n = 269) and validation (n = 268). In the calibration sample, an Exploratory Factor Analysis (EFA) was used to identify latent constructs within the battery. The model constructed based on the EFA was evaluated in the validation sample using Confirmatory Factor Analysis (CFA), and reliability and validity were assessed for the final measure. The EFA in the calibration sample revealed an eight factor solution, and a final model with one second-order factor along with the eight first-order factors provided the best fit. The model combined items from each of the four parent measures, showing important relationships among the parent measures. When the model was fit using the validation sample, the results confirmed the validity and reliability of the model. A brief PRO for MS (BPRO-MS) that combines MS-related psychosocial and quality of life domains can be used to assess overall functioning in mildly disabled MS patients. PMID- 26590670 TI - Multimodal neurophysiological evaluation of primary progressive multiple sclerosis - An increasingly valid biomarker, with limits. AB - BACKGROUND: The promising utility of multi-modality evoked potential batteries to objectively measure multi-tract dysfunction has been evaluated by several groups using different methods. OBJECTIVE: To independently evaluate the use of multi modality evoked potential batteries as surrogate biomarkers for both physical and cognitive status in a cohort of Primary Progressive Multiple Sclerosis patients and identify the most potentially useful scoring method of those described. METHODS: 28 Patients with Primary Progressive Multiple Sclerosis underwent clinical evaluation with Kurtzke's Modified EDSS and the Multiple Sclerosis Functional Composite (MSFC). 19 Participants also underwent the Minimal Assessment of Cognitive Function in Multiple Sclerosis. Visual, Brainstem Auditory, Somatosensory and Motor Evoked Potentials were recorded on all. Results were graded by variants of the Global Evoked Potential Score, Multiple Evoked Potential Score and Summation of Z transformed Evoked Potential Latencies for correlation against the clinical scores. CONCLUSIONS: Multi-modal evoked potential batteries generally show moderate and useful correlation with clinical status as measured by the regulatory standard of EDSS (r = .65 vs. mEPS p < .005) and MSFC (r = .39 vs. mEPS p < .05). The graded qualitative mEPS scoring system displayed the strongest relationship although the influence of scoring system applied appeared reassuringly minimal. Non-association with cognitive impairment is an important limitation however. PMID- 26590671 TI - Bladder and bowel dysfunction affect quality of life. A cross sectional study of 60 patients with aquaporin-4 antibody positive Neuromyelitis Optica spectrum disorder. AB - BACKGROUND: Transverse myelitis (TM) associated with Neuromyelitis Optica (NMO) can be severe and is well known to reduce mobility early in the disease. However the burden of bladder and bowel dysfunction is unknown and overlooked. We studied the frequency of bladder and bowel dysfunction and their impact on quality of life. METHODS: A cross-sectional study of 60 patients who had AQP4-IgG positive NMO associated TM was performed using the Bladder Control Scale, Lower Urinary Tract Quality of Life, Bowel Control Scale and Neurogenic Bowel Score, Short-Form 36 Health Survey and EDSS. The relationships between the variables were analysed with multiple linear regression. RESULTS: Fifty women and 10 men participated. 78% (47/60) patients reported bladder symptoms and a similar number reported bowel problems. 87% (52/60) patients reported either bladder or bowel dysfunction. 65% (39/60) developed residual symptoms after the first episode of myelitis and the remaining by the second episode. Both bladder and bowel dysfunction reduced quality of life and required modification of lifestyle in 83% (39/47) and 70% (33/47) respectively. CONCLUSION: Bladder and bowel dysfunction is very common in NMO associated myelitis developing early in the disease and significantly affects quality of life. PMID- 26590672 TI - Editors' Welcome. PMID- 26590674 TI - Nintedanib and ovarian cancer: standardise surgery in trials? PMID- 26590676 TI - Advances in Otoscopy. AB - Ear disease is a common condition in dogs and cats, and otoscopy should be performed on every case. Video-otoscopy is an incredible tool for the diagnosis, treatment, and management of ear disease. It may serve as a form of positive reinforcement, because the client can readily see progress made with treatment. This article focuses on the proper use of video-otoscopy for the diagnosis, treatment, and management of ear diseases in dogs and cats. Proper anatomy, equipment, and diagnostic understanding are required to minimize the risk of recurrent or chronic otitis, which is a source of discomfort for the patient and frustration for the owner and the clinician. PMID- 26590675 TI - Mechanisms of restriction of viral neuroinvasion at the blood-brain barrier. AB - The blood-brain barrier (BBB) consists of highly specialized cells including brain microvascular endothelial cells, astrocytes, microglia, pericytes, and neurons, which act in concert to restrict the entry of pathogens, immune cells, and soluble molecules into the central nervous system (CNS). If pathogens manage to cross the BBB and establish infection within the CNS, the BBB can open in a regulated manner to allow leukocyte transmigration into the CNS so that microbes, infected cells, and debris can be cleared. This review highlights how different inflammatory cytokines or signaling pathways disrupt or enhance BBB integrity in a way that regulates entry of neurotropic viruses into the CNS. PMID- 26590677 TI - Endoscopy. PMID- 26590679 TI - Understanding EMPA-REG OUTCOME. PMID- 26590680 TI - Understanding EMPA-REG OUTCOME. PMID- 26590681 TI - Understanding EMPA-REG OUTCOME. PMID- 26590682 TI - Preventing cardiovascular events with empagliflozin: at what cost? PMID- 26590683 TI - Non-linear association between smoking cessation and incident type 2 diabetes. PMID- 26590684 TI - Of rats and men: thyroid homeostasis in rodents and human beings. PMID- 26590685 TI - Of rats and men: thyroid homeostasis in rodents and human beings - Authors' reply. PMID- 26590686 TI - The artificial pancreas: challenges and opportunities. PMID- 26590687 TI - Weiping Jia: researching diabetes with Chinese characteristics. PMID- 26590688 TI - Influenza virus emitted by naturally-infected hosts in a healthcare setting. AB - BACKGROUND: The emergence of novel respiratory viruses such as avian influenza A(H7N9) virus and the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) highlights the importance of understanding determinants of transmission to healthcare workers (HCWs) and the public. OBJECTIVES: We aim to determine the viral content of the air emitted by symptomatic inpatients or long-term care residents with laboratory-confirmed influenza virus infection (emitters), and in the breathing zones of healthcare workers who attend to them. DESIGN: A prospective pilot study of patients with laboratory-confirmed influenza virus infection was undertaken. Air within 1m of the patient was sampled using a high volume air sampler. In addition, a lower volume air sampler was placed <1 m from the patient, with another >1 m from the patient. Viral RNA was recovered from the samplers and submitted for quantitative real time PCR. In addition, personal button samplers were provided to HCWs. RESULTS: The air emitted by 15 participants with laboratory-confirmed influenza virus infection was sampled. Of the patients infected with influenza A, viral RNA was recovered from the air emitted by 9/12 patients using the low-volume sampler; no viral RNA was detected from air emitted by patients with influenza B (n=3). Influenza virus RNA was recovered from one HCW's sampler. CONCLUSIONS: Patients with respiratory virus infection emit virus into the air which disperses to >1 m and may reach the breathing zone of a HCW. This pilot study highlights the feasibility and importance of conducting a larger-scale study to identify determinants of exposure and transmission from patient to HCW. PMID- 26590689 TI - Natural co-infection of influenza A/H3N2 and A/H1N1pdm09 viruses resulting in a reassortant A/H3N2 virus. AB - BACKGROUND: Despite annual co-circulation of different subtypes of seasonal influenza, co-infections between different viruses are rarely detected. These co infections can result in the emergence of reassortant progeny. STUDY DESIGN: We document the detection of an influenza co-infection, between influenza A/H3N2 with A/H1N1pdm09 viruses, which occurred in a 3 year old male in Cambodia during April 2014. Both viruses were detected in the patient at relatively high viral loads (as determined by real-time RT-PCR CT values), which is unusual for influenza co-infections. As reassortment can occur between co-infected influenza A strains we isolated plaque purified clonal viral populations from the clinical material of the patient infected with A/H3N2 and A/H1N1pdm09. RESULTS: Complete genome sequences were completed for 7 clonal viruses to determine if any reassorted viruses were generated during the influenza virus co-infection. Although most of the viral sequences were consistent with wild-type A/H3N2 or A/H1N1pdm09, one reassortant A/H3N2 virus was isolated which contained an A/H1N1pdm09 NS1 gene fragment. The reassortant virus was viable and able to infect cells, as judged by successful passage in MDCK cells, achieving a TCID50 of 10(4)/ml at passage number two. There is no evidence that the reassortant virus was transmitted further. The co-infection occurred during a period when co circulation of A/H3N2 and A/H1N1pdm09 was detected in Cambodia. CONCLUSIONS: It is unclear how often influenza co-infections occur, but laboratories should consider influenza co-infections during routine surveillance activities. PMID- 26590690 TI - Hepatitis E virus infections in children age 0-15, Uganda outbreak, 2007. AB - BACKGROUND: The epidemiology of hepatitis E virus (HEV) infections among children is not well understood, with some studies reporting that hepatitis E infections do not affect children. OBJECTIVES: We analyzed seroepidemiologic data collected during a hepatitis E outbreak in Uganda to determine prevalence of past and recent HEV infections among children aged 0-15 years. STUDY DESIGN: Individuals were randomly selected from a household census to participate in a seroprevalence survey. We analyzed data on IgM and IgG antibody to HEV among children aged 0-15 years. We categorized the study population by age group [aged 0-5, 6-10, and 11 15 years], and further stratified the youngest children [aged 0-1, 2-3, and 4-5 years]. Presence of IgG anti-HEV alone indicated past HEV infection, whereas recent infection was defined as presence of IgM anti-HEV with or without IgG anti HEV. RESULTS: Among children aged 0-15 years (N=244), prevalence of past HEV infection was 25.4% (62/244) and was highest among children aged 0-5 years [31.0% (27/87)]. Evidence of recent HEV infection was detected in 37.3% (91/244) of children aged 0-15 years. Among younger children, recent HEV infection increased with age from 4.3% (1/23) in children aged 0-1 year to 36.7% (11/30) in children aged 4-5 years. CONCLUSION: These data show that children are not spared from HEV infections. Illness during childhood in developing countries is common and HEV infections may be misdiagnosed as another acute illness, or under diagnosed. The lack of clinical care, HEV diagnostics, and surveillance in developing countries limit our full understanding of hepatitis E epidemiology. PMID- 26590691 TI - First report of an astrovirus type 5 gastroenteritis outbreak in a residential elderly care home identified by sequencing. AB - BACKGROUND: This is the report of an outbreak of human astrovirus type 5 gastroenteritis that occurred in a residential care home for older people in June 2013 in Tayside, Scotland, and which involved seven staff members and thirteen residents. This type of astrovirus has not been found in Scotland before and is rarely described in the literature. OBJECTIVES: Using molecular methods such as PCR and sequencing to detect the cause of this gastroenteritis outbreak and to contain the outbreak using Public Health measures. STUDY DESIGN: Following an epidemiological investigation, stool samples were sent for routine virology and microbiology testing at the local microbiology and virology laboratory and were found to be negative. Further testing with real-time PCR and gene sequencing at the West of Scotland Specialist Virology Centre was performed. Data on the epidemiology and the response to the outbreak was collected. RESULTS: All samples had a 99% match to human astrovirus type 5. The use of standard infection control precautions with the addition of transmission-based precautions most likely contained the spread of the virus in this situation. CONCLUSIONS: This report illustrates the importance of using PCR and sequencing to identify pathogens such as astrovirus in outbreaks of vomiting and diarrhoea in older people particularly if routine virology and microbiology tests are negative. PMID- 26590693 TI - Assessment of avoidance behaviour by earthworms (Lumbricus rubellus and Octolasion cyaneum) in linear pollution gradients. AB - Avoidance behaviour by earthworms is recognised as a valuable endpoint in soil quality assessment and has resulted in the development of a standardised test (ISO 17512-1, 2008) providing epigeic earthworms with a choice between test and control soils. This study sought to develop and evaluate an avoidance test utilising soil-dwelling earthworms in linear pollution gradients with Visible Implant Elastomer (VIE) tags used to identify individual organisms. Sequential experiments were established in laboratory-based mesocosms (0.6m*0.13m*0.1m) that determined the relative sensitivities (in terms of associated avoidance behaviour) of Octolasion cyaneum and Lumbricus rubellus at varying levels of polluted soil and also assessed the influence of introduction point on recorded movement within gradients. In an initial gradient (0%, 25%, 50%, 75%, 100% polluted soil), both species exhibited a clear avoidance response with all surviving earthworms retrieved (after 7 days) from the unpolluted soil. In a less polluted gradient (0%, 6.25%, 12.5%, 18.75%, 25%) L. rubellus were retrieved throughout the gradient while O. cyaneum were located within the 0% and 6.25% divisions, suggesting a species-specific response to polluted soil. Results also showed that the use of a linear pollution gradient system has the potential to assess earthworm avoidance behaviour and could provide a more ecologically relevant alternative to the ISO 17512: 2008 avoidance test. However, further work is required to establish the effectiveness of this procedure, specifically in initial chemical screening and assessment of single contaminant bioavailability, where uptake of pollutants by earthworms could be measured and directly related to the point of introduction and retrieval. PMID- 26590694 TI - Textile dye removal from aqueous solutions by malt bagasse: Isotherm, kinetic and thermodynamic studies. AB - The biosorption of orange solimax TGL 182% (OS-TGL) textile dye onto new and low cost biossorbent (malt bagasse) in aqueous solutions was investigated. The malt bagasse was characterized by Fourier transform infrared spectroscopy and specific surface area (BET method).Batch biosorption experiments were conducted in order to determine the following parameters: particles size, pH, agitation speed, temperature, contact time, biomass dosage, influence of the ionic strength and, finally, the influence of other textile dye on the OS-TGL biosorption. The optimum conditions for OS-TGL removal were obtained at pH 1.5, agitation speed of 150rpm, contact time of 180min and biomass dosage 2, 8gL(-1). The results show that the kinetics of biosorption followed a pseudo-second-order model and by increasing the temperature from 293 up to 313K, the biosorption capacity was improved. The Langmuir model showed better fit and the estimated biosorption capacity was 23.2mgg(-1). The negative values of Gibbs free energy, DeltaG degrees , and positive value of enthalpy, DeltaH degrees , confirm the spontaneous nature and endothermic character of the biosorption process. The results of the ionic strength effect indicated that the biosorption process under study had a strong tolerance in high salt concentrations. The removal capacity (>95%) was not affected with the presence of other textile dyes. PMID- 26590692 TI - Roles of natural killer cells in antiviral immunity. AB - Natural killer (NK) cells are important in immune defense against virus infections. This is predominantly considered a function of rapid, innate NK-cell killing of virus-infected cells. However, NK cells also prime other immune cells through the release of interferon gamma (IFN-gamma) and other cytokines. Additionally, NK cells share features with long-lived adaptive immune cells and can impact disease pathogenesis through the inhibition of adaptive immune responses by virus-specific T and B cells. The relative contributions of these diverse and conflicting functions of NK cells in humans are poorly defined and likely context-dependent, thereby complicating the development of therapeutic interventions. Here we focus on the contributions of NK cells to disease in diverse virus infections germane to human health. PMID- 26590673 TI - Standard first-line chemotherapy with or without nintedanib for advanced ovarian cancer (AGO-OVAR 12): a randomised, double-blind, placebo-controlled phase 3 trial. AB - BACKGROUND: Angiogenesis is a target in the treatment of ovarian cancer. Nintedanib, an oral triple angiokinase inhibitor of VEGF receptor, platelet derived growth factor receptor, and fibroblast growth factor receptor, has shown activity in phase 2 trials in this setting. We investigated the combination of nintedanib with standard carboplatin and paclitaxel chemotherapy in patients with newly diagnosed advanced ovarian cancer. METHODS: In this double-blind phase 3 trial, chemotherapy-naive patients (aged 18 years or older) with International Federation of Gynecology and Obstetrics (FIGO) IIB-IV ovarian cancer and upfront debulking surgery were stratified by postoperative resection status, FIGO stage, and planned carboplatin dose. Patients were randomly assigned (2:1) via an interactive voice or web-based response system to receive six cycles of carboplatin (AUC 5 mg/mL per min or 6 mg/mL per min) and paclitaxel (175 mg/m(2)) in addition to either 200 mg of nintedanib (nintedanib group) or placebo (placebo group) twice daily on days 2-21 of every 3-week cycle for up to 120 weeks. Patients, investigators, and independent radiological reviewers were masked to treatment allocation. The primary endpoint was investigator-assessed progression free survival analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01015118. FINDINGS: Between Dec 9, 2009, and July 27, 2011, 1503 patients were screened and 1366 randomly assigned by nine study groups in 22 countries: 911 to the nintedanib group and 455 to the placebo group. 486 (53%) of 911 patients in the nintedanib group experienced disease progression or death compared with 266 (58%) of 455 in the placebo group. Median progression-free survival was significantly longer in the nintedanib group than in the placebo group (17.2 months [95% CI 16.6-19.9] vs 16.6 months [13.9 19.1]; hazard ratio 0.84 [95% CI 0.72-0.98]; p=0.024). The most common adverse events were gastrointestinal (diarrhoea: nintedanib group 191 [21%] of 902 grade 3 and three [<1%] grade 4 vs placebo group nine [2%] of 450 grade 3 only) and haematological (neutropenia: nintedanib group 180 [20%] grade 3 and 200 (22%) grade 4 vs placebo group 90 [20%] grade 3 and 72 [16%] grade 4; thrombocytopenia: 105 [12%] and 55 [6%] vs 21 [5%] and eight [2%]; anaemia: 108 [12%] and 13 [1%] vs 26 [6%] and five [1%]). Serious adverse events were reported in 376 (42%) of 902 patients in the nintedanib group and 155 (34%) of 450 in the placebo group. 29 (3%) of 902 patients in the nintedanib group experienced serious adverse events associated with death compared with 16 (4%) of 450 in the placebo group, including 12 (1%) in the nintedanib group and six (1%) in the placebo group with a malignant neoplasm progression classified as an adverse event by the investigator. Drug-related adverse events leading to death occurred in three patients in the nintedanib group (one without diagnosis of cause; one due to non drug-related sepsis associated with drug-related diarrhoea and renal failure; and one due to peritonitis) and in one patient in the placebo group (cause unknown). INTERPRETATION: Nintedanib in combination with carboplatin and paclitaxel is an active first-line treatment that significantly increases progression-free survival for women with advanced ovarian cancer, but is associated with more gastrointestinal adverse events. Future studies should focus on improving patient selection and optimisation of tolerability. FUNDING: Boehringer Ingelheim. PMID- 26590695 TI - Acute toxicities of pharmaceuticals toward green algae. mode of action, biopharmaceutical drug disposition classification system and quantile regression models. AB - The acute toxicities of 36 pharmaceuticals towards green algae were estimated from a set of quantile regression models representing the first global quantitative structure-activity relationships. The selection of these pharmaceuticals was based on their predicted environmental concentrations. An agreement between the estimated values and the observed acute toxicity values was found for several families of pharmaceuticals, in particular, for antidepressants. A recent classification (BDDCS) of drugs based on ADME properties (Absorption, Distribution, Metabolism and Excretion) was clearly correlated with the acute ecotoxicities towards algae. Over-estimation of toxicity from our QSAR models was observed for classes 2, 3 and 4 whereas our model results were in agreement for the class 1 pharmaceuticals. Clarithromycin, a class 3 antibiotic characterized by weak metabolism and high solubility, was the most toxic to algae (molecular stability and presence in surface water). PMID- 26590697 TI - Source apportionment and health risk assessment of PM10 in a naturally ventilated school in a tropical environment. AB - This study aimed to investigate the chemical composition and potential sources of PM10 as well as assess the potential health hazards it posed to school children. PM10 samples were taken from classrooms at a school in Kuala Lumpur's city centre (S1) and one in the suburban city of Putrajaya (S2) over a period of eight hours using a low volume sampler (LVS). The composition of the major ions and trace metals in PM10 were then analysed using ion chromatography (IC) and inductively coupled plasma-mass spectrometry (ICP-MS), respectively. The results showed that the average PM10 concentration inside the classroom at the city centre school (82ug/m(3)) was higher than that from the suburban school (77ug/m(3)). Principal component analysis-absolute principal component scores (PCA-APCS) revealed that road dust was the major source of indoor PM10 at both school in the city centre (36%) and the suburban location (55%). The total hazard quotient (HQ) calculated, based on the formula suggested by the United States Environmental Protection Agency (USEPA), was found to be slightly higher than the acceptable level of 1, indicating that inhalation exposure to particle-bound non-carcinogenic metals of PM10, particularly Cr exposure by children and adults occupying the school environment, was far from negligible. PMID- 26590696 TI - Feasibility of lettuce cultivation in sophoroliplid-enhanced washed soil originally polluted with Cd, antibiotics, and antibiotic-resistant genes. AB - Vegetable cultivation in soils polluted with heavy metals, antibiotics and a high abundance of antibiotic-resistance genes (ARGs) can seriously threaten human health through the food chain. Therefore, novel techniques that not only remediate soil, but also ensure food security are urgently required. In the present study, two successive washings with 20gL(-1) of sophoroliplid solution plus ultrasonication (35kHz) were effective in extracting 71.2% Cd, 88.2% tetracycline, 96.6% sulfadiazine, and 100% roxithromycin. Simultaneously, relative abundance of ARGs (tetM, tetX, sulI, and sulII) was decreased to 10(-7) 10(-8) (ARG copies/16S copies). Further, lettuce cultivation in the 2nd washed soil showed significant improvement in vegetable growth indices (fresh/dry weight, root surface area, chlorophyll content and soluble protein content) and a decrease in isolate counts for antibiotic-resistant bacterial endophytes and ARG abundance in lettuce tissues. This combined cleanup strategy provides an environmentally friendly technology for ensuring vegetable security in washed soils. PMID- 26590698 TI - Reflex seizures triggered by cutaneous stimuli. AB - PURPOSE: Among the different precipitating stimuli for reflex seizures, Touch Induced Seizures (TIS) and Hot Water Seizures (HWS) are consistently described in different reports. The aim of this study was to analyze the clinical, EEG and image data of patients with TIS and HWS. METHODS: We retrospectively analyzed patients who were followed up in our Epilepsy Unit and had seizures triggered by these stimuli. All patients were studied with electroencephalography (EEG) and magnetic resonance (MR). RESULTS: We recruited six patients, including five men, with an age range of 30-64 years-old. Four patients had TIS; all them had focal motor seizures after the stimuli, with epileptic foci in the fronto-central regions associated with peri-central gyri lesions on MR. One patient had HWS related to a septo-optic dysplasia with periopercular polymicrogyria, and one patient had focal seizures that evolved into bilateral convulsions triggered by washing the mouth with cold water. We considered this last patient to have water contact-induced seizures (WCIS). CONCLUSIONS: Seizures in TIS are most likely focal, without impairment of awareness, and refractory to medical treatment. Antiepileptic drugs can prevent the progression to bilateral convulsion. The origins of such seizures seem to be related to small lesions or epileptogenic zones in the perirolandic areas. Lesional HWS and WCIS are focal seizures that involve impairment of consciousness or focal seizures that evolve to bilateral convulsion, are not such location specific and involve larger ictogenic areas. In both epilepsies, stimulus avoidance is the most effective treatment. PMID- 26590699 TI - alpha-Glucosidase and alpha-amylase inhibitors from Myrcia spp.: a stronger alternative to acarbose? AB - "Pedra hume caa" is the common name of five species of Myrcia genus used as traditional medicine for the treatment of diabetes mellitus. In this study, different extracts from Myrcia salicifolia, Myrcia sphaerocarpa, and Myrcia speciosa were investigated for the first time, to identify their phenolic compounds (being 3-O-rhamnoside derivatives of myricetin and quercetin the major ones) and in vitro inhibitory potential against alpha-glucosidase and alpha amylase. These extracts inhibited 90-500 times more alpha-glucosidase (IC50=0.7 to 4.1 MUg ml(-1)) than acarbose and displayed a mild inhibition against alpha amylase (IC50=6.1 to 29 MUg mL(-1)). PMID- 26590700 TI - Analytical approaches to investigate salt disproportionation in tablet matrices by Raman spectroscopy and Raman mapping. AB - It has always been challenging to use spectroscopic methods to analyze salt disproportionation in a multi-component tablet matrix due to the spectral interference generated by the various excipients. Although combining Raman spectroscopy and chemometrics can be a powerful approach to study the extent of salt disproportionation, it was found in the present study that bulk measurements and chemometric modeling have obvious limitations when the targeted component is present at low levels in the tablet. Hence, a two-step Raman mapping approach was developed herein to investigate salt disproportionation in tablets with a low drug loading (5% w/w). The first step is to locate the area of interest where the drug particles reside throughout the tablet surface by using a statistically optimized sampling method termed deliberate sub-sampling. The second step, referred to herein as close-step mapping, utilize a step by step mapping of the targeted area to find more details of salt disproportionation in the tablet regions where the drug is concentrated. By using this two-step Raman mapping approach, we successfully detected the existence of minor species embedded in multi-component low drug loading tablet matrices, where bulk measurements from routine techniques usually lack of sensitivity. This approach will help formulation scientists detect and understand salt disproportionation and in situ drug-excipients compatibility issues in low dose solid dosage formulations. PMID- 26590701 TI - A novel sensitive pathogen detection system based on Microbead Quantum Dot System. AB - A fast and accurate detection system for pathogens can provide immediate measurements for the identification of infectious agents. Therefore, the Microbead Quantum-dots Detection System (MQDS) was developed to identify and measure target DNAs of pathogenic microorganisms and eliminated the need of PCR amplifications. This nanomaterial-based technique can detect different microorganisms by flow cytometry measurements. In MQDS, pathogen specific DNA probes were designed to form a hairpin structure and conjugated on microbeads. In the presence of the complementary target DNA sequence, the probes will compete for binding with the reporter probes but will not interfere with the binding between the probe and internal control DNA. To monitor the binding process by flow cytometry, both the reporter probes and internal control probes were conjugated with Quantum dots that fluoresce at different emission wavelengths using the click reaction. When MQDS was used to detect the pathogens in environmental samples, a high correlation coefficient (R=0.994) for Legionella spp., with a detection limit of 0.1 ng of the extracted DNAs and 10 CFU/test, can be achieved. Thus, this newly developed technique can also be applied to detect other pathogens, particularly viruses and other genetic diseases. PMID- 26590702 TI - Common vs. independent limb control in sequential vertical aiming: The cost of potential errors during extensions and reversals. AB - The following study explored movement kinematics in two-component aiming contexts that were intended to modulate the potential cost of overshoot or undershoot errors in up and down directions by having participants perform a second extension movement (Experiment 1) or a reversal movement (Experiment 2). For both experiments, the initial movement toward a downward target took longer, and had lower peak acceleration and peak velocity than upward movements. These movement characteristics may reflect a feedback-based control strategy designed to prevent energy-consuming limb modifications against gravitational forces. The between component correlations of displacement at kinematic landmarks (i.e., trial-by trial correlation between the first and second components) increased as both components unfolded. However, the between-component correlations of extensions were primarily negative, while reversals were positive. Thus, movement extensions appear to be influenced by the use of continuous on-line sensory feedback to update limb position at the second component based on the position attained in the first component. In contrast, reversals seem to be driven by pre-planned feedforward procedures where the position of the first component is directly replicated in the second component. Finally, the between-component correlations for the magnitude of kinematic landmarks showed that aiming up generated stronger positive correlations during extensions, and weaker positive correlations toward the end of the first component during reversals. These latter results suggest the cost of potential errors associated with the upcoming second component directly influence the inter-dependence between components. Therefore, the cost of potential errors is not only pertinent to one-component discrete contexts, but also two-component sequence aims. Together, these findings point to an optimized movement strategy designed to minimize the cost of errors, which is specific to the two-component context. PMID- 26590704 TI - Editorial. PMID- 26590703 TI - Bearing the right to healthcare, autonomy and hope. AB - In this article, I discuss the significance of understanding within the context of the campaign for affordable and accessible HIV/AIDS treatments in South Africa, the transformational effects of the interplay between political rationality and affect for HIV-positive subjectivities. The article focuses on the policy tactics, in 2001, of the lobbying for a policy to prevent mother-to child-transmission of HIV. A close reading of the lobby groups' rationalization of healthcare as a fundamental human right reveals a strategic attempt to recast a sense of helplessness into self-responsibilization, which concurrently involved nourishing hope in the preferred future for women with HIV to be afforded the right to individual choice associated with self-determination. Therefore, the struggle for a policy to prevent mother-to-child-transmission of HIV - an exemplary initiative to reconstitute HIV-positive subjectivity - maneuvered within both rationalizing and emotive spaces. Ongoing engagement of the broader campaign's contribution to redefining being HIV-positive thus also necessitates accounting for the effects of the convergence of political rationality and emotion in its tactically emancipatory project. PMID- 26590705 TI - Identification and utilization of a new Erysiphe necator isolate NAFU1 to quickly evaluate powdery mildew resistance in wild Chinese grapevine species using detached leaves. AB - The most economically important disease of cultivated grapevines worldwide is powdery mildew caused by the biotrophic fungal pathogen Erysiphe necator. To integrate effective genetic resistance into cultivated grapevines, numerous disease resistance screens of diverse Vitis germplasm, including wild species, have been conducted to identify powdery mildew resistance, but the results have been inconsistent. Here, a new powdery mildew isolate that is infectious on grapevines, designated Erysiphe necator NAFU1 (En. NAFU1), was identified and characterized by phylogeny inferred from the internal transcribed spacer (ITS) of pathogen ribosomal DNA sequences. Three classical methods were compared for the maintenance of En. NAFU1, and the most convenient method was maintenance on detached leaves and propagation by contact with infected leaves. Furthermore, controlled inoculations of En. NAFU1 were performed using detached leaves from 57 wild Chinese grapevine accessions to quickly evaluate powdery mildew resistance based on trypan blue staining of leaf sections. The results were compared with previous natural epidemics in the field. Among the screened accessions inoculated with En. NAFU1, 22.8% were resistant, 33.3% were moderately resistant, and 43.9% were susceptible. None of the accessions assessed herein were immune from infection. These results support previous findings documenting the presence of race-specific resistance to E. necator in wild Chinese grapevine. The resistance of wild Chinese grapevine to En. NAFU1 could be due to programmed cell death. The present results suggest that En. NAFU1 isolate could be used for future large scale screens of resistance to powdery mildew in diverse Vitis germplasms and investigations of the interaction between grapevines and pathogens. PMID- 26590706 TI - Gender differences in quality of care experiences during hospital stay: A contribution to patient-centered healthcare for both men and women. AB - OBJECTIVES: Studies demonstrate that there are important gender differences in perceptions of medicinal care. Our aim is to investigate whether there are also gender differences in patients'quality of care experiences during their hospital stay. METHODS: In a cross-sectional survey, patients who were admitted to a university hospital were invited to complete a questionnaire. Answers were compared between men and women of different ages, education levels, and health assessments, using the independent t-test. A linear regression model was performed to investigate the relationship between patient characteristics and hospital assessments RESULTS: 4169 questionnaires were sent (41.8% returned). Women rated the hospital significantly (P=0.007) lower than men, especially higher educated women and women between the ages of 18 and 44 years. Behaviors of nurses were perceived to be unsatisfactory by significantly more female patients than male patients (P=0.016). One in six women wanted more privacy compared with one in ten men (P<0.001), and ten percent more women suffered from pain (P<0.001). CONCLUSION: Women, particularly those higher educated and between 45 and 64 years of age, assess hospital care significantly lower than men. IMPLICATIONS FOR PRACTICE: To optimize patients' assessments of hospital care, women require more gender-sensitive nursing care, more privacy, and better pain management than they receive at present. PMID- 26590707 TI - Substantial reduction in the number of amputations among patients with diabetes: a cohort study over 16 years. AB - AIMS/HYPOTHESIS: The aim of this study was to describe the trends in rates of amputation among individuals with and without diabetes. METHODS: We studied amputation rates in the County of Funen (approximately 0.5 million residents) during the period 1996-2011. Amputations were identified from the hospital administrative system, diabetes status by linkage with the Danish National Diabetes Register, and mortality and population data by extraction from Statistics Denmark. Amputation rates were analysed using proportional hazard models. We analysed the incidence of the first amputation at each level as well as the incidence of further amputations, subdivided by level of amputation. RESULTS: During the period 1996-2011, a total of 2,832 amputations were performed, of which 1,285 were among patients with diabetes and 1,547 among individuals without diabetes. Relative to persons without diabetes, patients with diabetes had an HR for below-ankle amputations (BAAs) of 14.7 for men and 7.5 for women, and for from-ankle-to-knee amputations (BKAs) of 7.6 and 8.4 for men and women, respectively. For above-knee amputations (AKAs) the numbers were 4.0 for men and 3.7 for women. We found an annual reduction in BAA rates among patients with diabetes of 9.8%, and the annual reduction in BKA for patients with diabetes was 15.1%. CONCLUSIONS/INTERPRETATION: The amputation rate in patients with diabetes is still several-fold higher than in persons without diabetes, but the improvements in diabetes care in recent years have resulted in a steady decline in amputation rates among patients with diabetes from this Danish cohort. PMID- 26590708 TI - Differences in foot sensitivity and plantar pressure between young adults and elderly. AB - OBJECTIVE: The understanding of foot sensitivity and plantar pressure contributes to the design of insoles, shoes, as well as to guide therapeutic interventions. Here we investigate differences in plantar pressure and foot sensitivity between young adults and community-dwelling elderly. METHODS: Thirty-eight participants (19 young adults and 19 elderly) underwent clinical assessment of foot sensitivity and upright standing with eyes open and closed for measurement of plantar pressure in each foot. Data were compared between feet, groups, and visual conditions. RESULTS: Foot sensitivity was lower in the elderly and, in contrast to young adults, differed between the foot regions (loss of sensitivity was primarily seen at the heel). Elderly shift plantar pressure to more distal foot zones, namely towards midfoot and forefoot. Asymmetries in foot sensitivity and plantar pressure were not observed. Visual condition did not influence plantar pressure distribution. CONCLUSIONS: The forward shift in plantar pressure (away from the insensitive heel) constitutes a strategy of elderly to maintain balance. PMID- 26590709 TI - Cancer Cells Hijack Gluconeogenic Enzymes to Fuel Cell Growth. AB - In this issue and the October 15th issue of Molecular Cell, studies by Montal et al. (2015) and Vincent et al. (2015) report that certain types of cancer cells utilize the gluconeogenic enzymes phosphoenolpyruvate carboxykinase (PEPCK) and phosphoenolpyruvate carboxykinase 2 (PCK2) to reprogram anabolic metabolism and support cell growth. PMID- 26590710 TI - Stopping the Clock with MYC. AB - In a recent paper in Cell Metabolism, Altman et al. (2015) report that MYC disrupts the molecular clock in cancer cells and describe a link between oncogenesis, circadian rhythms, and metabolism. PMID- 26590711 TI - Cancer's Fuel Choice: New Flavors for a Picky Eater. AB - Otto Warburg discovered that cancer cells exhibit a high rate of glycolysis in the presence of ample oxygen, a process termed aerobic glycolysis, in 1924 (Warburg et al., 1924). Since then we have significantly advanced our understanding of cancers' fuel choice to meet their demands for energy and for the production of biosynthetic precursors. In this review, we will discuss the preferred nutrients of cancer cells and how they are utilized to satisfy their bioenergetic and biosynthetic needs. In addition, we will describe how cell intrinsic and extrinsic factors such as oncogene mutations, nutrient and oxygen availability, and other microenvironmental factors influence fuel choice. PMID- 26590712 TI - Targeting Mitosis in Cancer: Emerging Strategies. AB - The cell cycle is an evolutionarily conserved process necessary for mammalian cell growth and development. Because cell-cycle aberrations are a hallmark of cancer, this process has been the target of anti-cancer therapeutics for decades. However, despite numerous clinical trials, cell-cycle-targeting agents have generally failed in the clinic. This review briefly examines past cell-cycle targeted therapeutics and outlines how experience with these agents has provided valuable insight to refine and improve anti-mitotic strategies. An overview of emerging anti-mitotic approaches with promising pre-clinical results is provided, and the concept of exploiting the genomic instability of tumor cells through therapeutic inhibition of mitotic checkpoints is discussed. We believe this strategy has a high likelihood of success given its potential to enhance therapeutic index by targeting tumor-specific vulnerabilities. This reasoning stimulated our development of novel inhibitors targeting the critical regulators of genomic stability and the mitotic checkpoint: AURKA, PLK4, and Mps1/TTK. PMID- 26590713 TI - Breast Tumor Heterogeneity: Source of Fitness, Hurdle for Therapy. AB - Tumor heterogeneity impinges on prognosis, response to therapy, and metastasis. As such, heterogeneity is one of the most important and clinically relevant areas of cancer research. Breast cancer displays frequent intra- and inter-tumor heterogeneity as the result of genetic and non-genetic alterations that often enhance the vigor of cancer cells. In-depth characterization and understanding of the origin of this phenotypic and molecular diversity is paramount to improving diagnosis, the definition of prognostic and predictive biomarkers, and the design of therapeutic strategies. Here, we summarize current knowledge about sources of breast cancer heterogeneity, its consequences, and possible counter-measures. We discuss especially the impact on tumor heterogeneity of the differentiation state of the cell-of-origin, cancer cell plasticity, the microenvironment, and genetic evolution. Factors that enhance cancer cell vigor are clearly detrimental for patients. PMID- 26590714 TI - Targeting the DNA Damage Response in Cancer. AB - An underlying hallmark of cancers is their genomic instability, which is associated with a greater propensity to accumulate DNA damage. Historical treatment of cancer by radiotherapy and DNA-damaging chemotherapy is based on this principle, yet it is accompanied by significant collateral damage to normal tissue and unwanted side effects. Targeted therapy based on inhibiting the DNA damage response (DDR) in cancers offers the potential for a greater therapeutic window by tailoring treatment to patients with tumors lacking specific DDR functions. The recent approval of olaparib (Lynparza), the poly (ADP-ribose) polymerase (PARP) inhibitor for treating tumors harboring BRCA1 or BRCA2 mutations, represents the first medicine based on this principle, exploiting an underlying cause of tumor formation that also represents an Achilles' heel. This review highlights the different concepts behind targeting DDR in cancer and how this can provide significant opportunities for DDR-based therapies in the future. PMID- 26590715 TI - Drugging Chromatin in Cancer: Recent Advances and Novel Approaches. AB - Chromatin regulatory mechanisms play a major role in the control of gene expression programs during normal development and are disrupted in specific disease states, particularly in cancer. Important mediators of chromatin regulatory processes can broadly be classified into writers, erasers, and readers of covalent chromatin modifications that modulate eukaryotic gene transcription and maintain the integrity of the genome. The reversibility and disease-specific nature of these chromatin states make these regulators attractive therapeutic targets. As such, there is an ever-increasing number of candidate therapies aimed at targeting cancer-associated chromatin states that are in various stages of preclinical and clinical development. In this review, we discuss recent advances that have been made in the rational therapeutic targeting of chromatin regulatory mechanisms and highlight certain cancers where there is a specific rationale to assess these therapeutic approaches. PMID- 26590716 TI - H3K4/H3K9me3 Bivalent Chromatin Domains Targeted by Lineage-Specific DNA Methylation Pauses Adipocyte Differentiation. AB - Bivalent H3K4me3 and H3K27me3 chromatin domains in embryonic stem cells keep active developmental regulatory genes expressed at very low levels and poised for activation. Here, we show an alternative and previously unknown bivalent modified histone signature in lineage-committed mesenchymal stem cells and preadipocytes that pairs H3K4me3 with H3K9me3 to maintain adipogenic master regulatory genes (Cebpa and Pparg) expressed at low levels yet poised for activation when differentiation is required. We show lineage-specific gene-body DNA methylation recruits H3K9 methyltransferase SETDB1, which methylates H3K9 immediately downstream of transcription start sites marked with H3K4me3 to establish the bivalent domain. At the Cebpa locus, this prevents transcription factor C/EBPbeta binding, histone acetylation, and further H3K4me3 deposition and is associated with pausing of RNA polymerase II, which limits Cebpa gene expression and adipogenesis. PMID- 26590717 TI - LncRNA Khps1 Regulates Expression of the Proto-oncogene SPHK1 via Triplex Mediated Changes in Chromatin Structure. AB - Although thousands of long noncoding RNAs (lncRNAs) have been discovered, very little is known about their mode of action. Here we functionally characterize an E2F1-regulated lncRNA named Khps1, which is transcribed in antisense orientation to the proto-oncogene SPHK1. Khps1 activates SPHK1 expression by recruiting the histone acetyltransferase p300/CBP to the SPHK1 promoter, which leads to local changes of the chromatin structure that ensures E2F1 binding and enhances transcription. Mechanistically, this is achieved by direct association of Khps1 with a homopurine stretch upstream of the transcription start site of SPHK1, which forms a DNA-RNA triplex that anchors the lncRNA and associated effector proteins to the gene promoter. The results reveal an lncRNA- and E2F1-driven regulatory loop in which E2F1-dependent induction of antisense RNA leads to changes in chromatin structure, facilitating E2F1-dependent expression of SPHK1 and restriction of E2F1-induced apoptosis. PMID- 26590719 TI - Principles and Biomechanical Considerations of Tendon Transfers. AB - Whether performed as a primary procedure or used to augment and support osseous reconstruction, tendon transfers are a key skill for the foot and ankle surgeon. Understanding the biomechanics preoperative and postoperatively is essential in performing appropriate procedures and in supporting patients through the rehabilitation process. Often the complexity of tendon transfer surgery is lost because it is deemed a soft tissue procedure and in theory should be less complex than osseous procedures. However, the dynamic nature of musculature and tendons require a deeper understanding of surgical and biomechanical concepts. PMID- 26590718 TI - [KIL-d] Protein Element Confers Antiviral Activity via Catastrophic Viral Mutagenesis. AB - Eukaryotic cells are targeted by pathogenic viruses and have developed cell defense mechanisms against viral infection. In yeast, the cellular extrachromosomal genetic element [KIL-d] alters killer activity of M double stranded RNA killer virus and confers cell resistance against the killer virus. However, its underlying mechanism and the molecular nature of [KIL-d] are unknown. Here, we demonstrate that [KIL-d] is a proteinaceous prion-like aggregate with non-Mendelian cytoplasmic transmission. Deep sequencing analyses revealed that [KIL-d] selectively increases the rate of de novo mutation in the killer toxin gene of the viral genome, producing yeast harboring a defective mutant killer virus with a selective growth advantage over those with WT killer virus. These results suggest that a prion-like [KIL-d] element reprograms the viral replication machinery to induce mutagenesis and genomic inactivation via the long-hypothesized mechanism of "error catastrophe." The findings also support a role for prion-like protein aggregates in cellular defense and adaptation. PMID- 26590720 TI - Flexor Digitorum Longus Tendon Transfer and Modified Kidner Technique in Posterior Tibial Tendon Dysfunction. AB - The modified Kidner procedure and flexor digitorum longus tendon transfer are common procedures used today when addressing posterior tibial tendon dysfunction. These techniques are often used in conjunction with a combination of osteotomies to correct flatfoot deformity, and have been proved to be reliable and predictable. PMID- 26590721 TI - Tibialis Anterior Tendon Transfer for Posterior Tibial Tendon Insufficiency. AB - The Cobb procedure is useful for addressing stage 2 posterior tibial tendon dysfunction and is often accompanied by a medial displacement calcaneal osteotomy and/or lateral column lengthening. The Cobb procedure can also be combined with selected medial column arthrodesis and realignment osteotomies along with equinus correction when indicated. PMID- 26590722 TI - Posterior Tibial Tendon Transfer. AB - When performed correctly with the right patient population, a tibialis posterior muscle/tendon transfer is an effective procedure. Many different methods have been established for fixating the tendon, each of which has its' own indications. Passing through the interosseous membrane is the preferred and recommended method and should be used unless this is not possible. Good surgical planning based on patient needs and expectations, along with excellent postoperative care including early range of motion and physical therapy minimizes risk of complications and allows for the optimal outcome to be achieved. PMID- 26590723 TI - Tibialis Anterior Tendon Transfer. AB - Tendon transfer procedures are used commonly for the correction of soft tissue imbalances and instabilities. The complete transfer and the split transfer of the tibialis anterior tendon are well-accepted methods for the treatment of idiopathic equinovarus deformity in children and adults. Throughout the literature, complete and split transfer have been shown to yield significant improvements in ankle and foot range of motion and muscle function. At present, there is insufficient evidence to recommend one procedure over the other, although the split procedure has been advocated for consistently achieving inversion to eversion muscle balance without overcorrection. PMID- 26590724 TI - Jones Tendon Transfer. AB - Hallux malleus is a deformity of the great toe. There is a dorsiflexion contracture at the metatarsophalangeal joint and plantar flexion of the interphalangeal joint. The deformity is commonly attributed to muscular imbalances of the various structures acting on the great toe. Jones tendon transfer is a procedure used to remove the deforming force to the clawed hallux. It is most often performed in conjunction with a hallux interphalangeal joint fusion. Typically there is a neurologic component causing a deformity to the entire foot, necessitating adjunct procedures. The Jones tendon transfer has shown to have reproducible results. PMID- 26590725 TI - Hibbs Tenosuspension. AB - Hibbs tenosuspension is an underutilized procedure when it comes to dealing with lesser toe pathology in conditions such as Charcot-Marie-Tooth disease. This article describes the procedure to transfer the extensor digitorum longus tendons into the peroneus tertius tendon to eliminate a deforming force and create a stabilizing force. PMID- 26590726 TI - Tendon Transfers for Management of Digital and Lesser Metatarsophalangeal Joint Deformities. AB - Managing digital and metatarsophalangeal joint (MTPJ) deformities can range from simple to complex and uniplanar to triplanar. Because of the complexity and variability of digital and MTPJ deformities, there are many procedures, and no 1 procedure has become the gold standard. Tendon transfers for digital and MTPJ deformities are just 1 treatment option, and usually they are not stand-alone procedures. Typically, a combination of procedures needs to be performed. This article describes the surgical technique and provides a review of the literature, including clinical results for tendon transfers of the central rays. PMID- 26590728 TI - Soft Tissue Balancing After Partial Foot Amputations. AB - Partial foot amputations have become common procedures for the foot and ankle surgeon as part of a limb salvage practice. These procedures are highly technique driven and there are many complex factors that affect the outcome and longevity. Appropriate surgical planning must be used with every partial foot amputation to ensure a plantigrade foot with the least potential for future breakdown. When performed appropriately, these amputations have great success with lower energy expenditure and decreased mortality compared with below-knee or above-knee amputations. PMID- 26590727 TI - Tendon Transfers and Salvaging Options for Hallux Varus Deformities. AB - Hallux varus is an infrequently encountered deformity of the first ray characterized by a medial deviation of the hallux on the first metatarsal head at the first metatarsal phalangeal joint. Iatrogenic flexible hallux varus often requires surgical repair to create a functional, pain-free, shoeable foot. Although arthrodesis remains the mainstay of treatment, many soft tissue transfer procedures have been described in the literature as joint-sparing alternatives to fusion. This article explores in detail the tendon transfer procedures that have been described for repair of flexible hallux varus deformity. PMID- 26590729 TI - Flexor Hallucis Longus Tendon Transfer for Calcific Insertional Achilles Tendinopathy. AB - Calcific insertional Achilles tendinopathy can result in significant pain and disability. Although some patients respond to nonoperative therapy, many patients are at risk for long-term morbidity and unpredictable clinical outcomes. There is no evidence-based data to support the timing of operative invention, choice of procedures, or whether equinus requires treatment. This article suggests the need for a classification system based on physical examination and imaging to help guide treatment. There is an obvious need for evidence-based studies evaluating outcomes and for properly conducted scientific research to establish appropriate treatment protocols. PMID- 26590730 TI - Combined Tendon and Bone Allograft Transplantation for Chronic Achilles Tendon Ruptures. AB - Combined flexor hallucis longus tendon transfer and bone-tendon allograft transplantation is a reasonable option for advanced distal-segment Achilles tendinopathy. This procedure provides anatomic restoration and improved function of the posterior muscle group without sacrificing the regional anatomy. Allograft transplantation is safe and does not require immunosuppressive therapy. The soft tissue envelope should be healthy because wound complications can be an issue. This procedure is especially helpful in patients with significant disability. PMID- 26590731 TI - Surgical Correction of Rigid Equinovarus Contracture Utilizing Extensive Soft Tissue Release. AB - Although deforming contractures of the lower extremities after acute cerebrovascular events are well documented in the literature, there is limited literature regarding specific surgical considerations for the correction of these deformities, which are nonosseus in nature. The equinovarus foot, regardless of its origin, is a challenging pathologic condition for the foot and ankle surgeon. It is critical to have a firm understanding of the cause and symptoms behind an equinovarus deformity before treatment. The clinical presentation is discussed with special attention to deformities in adults with rigid equinovarus deformities after cerebrovascular-related accidents or peripheral ischemic events. PMID- 26590732 TI - Catastrophic Failure of an Infected Achilles Tendon Rupture Repair Managed with Combined Flexor Hallucis Longus and Peroneus Brevis Tendon Transfer. AB - Deep infection is one of the most devastating complications following repair of an Achilles tendon rupture. Treatment requires not only culture-driven antibiotic therapy, but more importantly, appropriate debridement of some or even all of the Achilles tendon. This may necessitate delayed reconstruction of the Achilles tendon. The authors present a successful case of reconstruction of a chronically infected Achilles tendon in an otherwise healthy 43-year-old man via a multistaged approach using the flexor hallucis longus and peroneus brevis tendons. We also provide a brief review of the literature regarding local tendon transfer used in the reconstruction of Achilles tendon rupture. PMID- 26590733 TI - Complications of Tendon Surgery in the Foot and Ankle. AB - This article discusses four subsets of patients that have an increased risk of complications from tendon surgery in the foot and ankle: smokers, diabetics, and patients with peroneal or Achilles tendon pathology. Very little has been published on the complications of other tendon surgeries in the foot and ankle other than Achilles tendon repair. Data can be extrapolated from the general orthopedic literature and animal studies to help guide therapy and treatment options. The foot and ankle surgeon must take into account the entirety of the history and physical examination to develop a treatment plan that optimizes each patient's chance for a complication-free recovery. PMID- 26590734 TI - Tendon Reconstruction and Transfers of the Foot and Ankle. PMID- 26590735 TI - A New Look at Tendon Transfers and Soft Tissue Management in Foot and Ankle Reconstruction. PMID- 26590736 TI - Labial adhesion and urinary tract problems: The importance of genital examination. AB - BACKGROUND: Urinary tract infection (UTI) is a common bacterial illness in children. Delay in the treatment of UTI may lead to acute renal parenchymal damage and subsequent renal scarring. It is well established that several risk factors increase the tendency for UTI - one being labial adhesion (LA). OBJECTIVE: The purpose of this study was to emphasize the importance of genital examination in girls with nephrourologic symptoms, particularly UTIs, in order to detect LA. MATERIAL AND METHODS: Data were collected from the files of 46 girls with LA, including: the girl's age, thickness of LA, any recurrence and treatment options of LA, and the reason for admission to hospital. The LAs were grouped in terms of thickness as thin, moderate and dense, and also partial or complete. RESULTS: The average age of the girls at the first visit was 51.9 +/- 37.57 months (min-max: 3.5-157 months). Twenty-seven (58.7%) of the girls had history of recurrent UTI. There was a marked association between the presence of UTI and the type of adhesions. The percentages of UTIs in girls with complete and partial LA were 84.0% and 28.6%, respectively (P < 0.05). The percentages of UTIs in girls with thick and thin LA were 100% and 44.1%, respectively (P < 0.05). None of the girls' primary care physicians or pediatricians recognized LA at the time of a periodic health examination. DISCUSSION: In the present study, girls with complete and thick LA had a greater tendency towards having UTIs than those with partial and thin LA, respectively. After treatment of LA, the UTIs did not recur in any girls. None of the girls in this study had undergone a previous genital examination. Therefore, this study suggests that physicians do not often perform genital examinations. Limitations of this study were the small sample size and the short follow-up period. In addition, although all of the girls were examined by the same physician, the thickness of the membrane is subjective and solely depends on the physician's experience. CONCLUSIONS: This study showed that although genital examination is a routine part of a physical examination, it is not always performed. Therefore, it is recommend that genital examination should be performed in girls with nephrourologic complaints, particularly for UTI. By timeously determining the presence of LA, many unnecessary and invasive investigations could be avoided in these children. PMID- 26590737 TI - Images in emergency medicine. Man With Chest Pain. Acute non-ST elevation myocardial infarction. PMID- 26590738 TI - Images in emergency medicine. Young Boy With Shedding Nails. Onychomadesis. PMID- 26590739 TI - That's Some Weird Nail Polish You Got There! PMID- 26590740 TI - Commentary: Drugs and Driving. PMID- 26590741 TI - Change of shift. Trust. PMID- 26590742 TI - Change of shift. Give and Take. PMID- 26590743 TI - "Am I Having a Heart Attack, Doc?" Patient-Physician Communication for Possible Acute Coronary Syndromes: Answers to the July 2015 Journal Club Questions. PMID- 26590744 TI - Images in emergency medicine. Woman With Mass on Her Back. Lumbar hernia. PMID- 26590745 TI - The Spectrum of Pediatric Sepsis: "Septicemia" Misses Severe Cases. PMID- 26590746 TI - In reply. PMID- 26590747 TI - Efficacy of an Acute Pain Titration Protocol Driven by Patient Response to a Simple Query: Do You Want More Pain Medication? PMID- 26590748 TI - In reply. PMID- 26590749 TI - The Case for 1-Way Clinical Decision Rules in Emergency Medicine. PMID- 26590750 TI - In reply. PMID- 26590751 TI - Maximizing the Potential of Women in Emergency Medicine. Policy statement. PMID- 26590752 TI - A Culture of Safety in EMS Systems. Policy statement. PMID- 26590753 TI - Medical Direction of Mobile Integrated Health Care and Community Paramedicine Programs. Policy statement. PMID- 26590754 TI - Out-of-Hospital Severe Hemorrhage Control. Policy statement. PMID- 26590755 TI - Use of the Title "Doctor" in the Clinical Setting. Policy statement. PMID- 26590756 TI - Images in emergency medicine. Woman With Abdominal Pain and Diarrhea. Colitis. PMID- 26590757 TI - 1,3-Propanediol production from glycerol with a novel biocatalyst Shimwellia blattae ATCC 33430: Operational conditions and kinetics in batch cultivations. AB - Shimwellia blattae ATCC 33430 as biocatalyst in the conversion of 1,3-propanediol from glycerol is herein evaluated. Several operational conditions in batch cultivations, employing pure and raw glycerol as sole carbon source, were studied. Temperature was studied at shaken bottle scale, while pH control strategy, together with the influence of raw glycerol and its impurities during fermentation were studied employing a 2L STBR. Thereafter, fluid dynamic conditions were considered by changing the stirring speed and the gas supply (air or nitrogen) in the same scale-up experiments. The best results were obtained at a temperature of 37 degrees C, an agitation rate of 200rpm, with free pH evolution from 6.9 and subsequent control at 6.5 and no gas supply during the fermentation, employing an initial concentration of 30g/L of raw glycerol. Under these conditions, the biocatalyst is competitive, leading to results in line with other previous works in the literature in batch conditions, reaching a final concentration of 1,3-propanediol of 13.84g/L, with a yield of 0.45g/g and a productivity of 1.19g/(Lh) from raw glycerol. PMID- 26590758 TI - Reducing nitrogen loss and salinity during 'struvite' food waste composting by zeolite amendment. AB - Struvite formation during composting through supplementation of Mg and P salts conserved nitrogen but in the same time increased the electrical conductivity (EC) of the compost limiting its application. Therefore the present study aimed at utilizing zeolite to control the EC under 'struvite' composting of food waste. Zeolite at 5% and 10% (dry weight basis) was supplemented to the composting mass receiving Mg and P salts and compared with treatment with Mg and P salts only and the control without any amendment. Addition of Mg and P salts effectively buffered the pH to ~8.0 but also increased the EC of the compost to 6.45mS/cm. Co amendment with 10% zeolite effectively reduced the EC down to 2.82mS/cm and improved compost maturity. It also increased the adsorption of ammonium ions reducing ammonia loss to 18% resulting in higher total nitrogen content in the final compost. PMID- 26590759 TI - Influence of ionic conductivity in bioelectricity production from saline domestic sewage sludge in microbial fuel cells. AB - This study aimed at manipulating ionic conductivity (EC) to harvest the maximum electrical energy from seawater-based domestic wastewater sewage sludge (SWS), unique to only a few cities, through microbial fuel cell (MFC). SWS has never been investigated as a MFC substrate before, and thus the influence of high in situ EC on the energy recovery was unknown. In this study, the EC of the SWS was reduced through mixing it with fresh water-based domestic wastewater sewage sludge (FWS) or diluted 50% using deionized water while FWS and SWS were individually served as reference treatments. SWS:FWS mix (1:1) exhibited a maximum Coulombic efficiency of 28.6+/-0.5% at a COD removal of 59+/-3% while the peak power density was 20-fold higher than FWS. The improved performance was due to the lower ohmic internal resistance (36.8+/-4.2Omega) and optimal conductivity (12.8+/-0.2mScm(-1)). Therefore, dilution with FWS could enhance energy recovery from SWS. PMID- 26590760 TI - Nanobioconjugates of Candida antarctica lipase B and single-walled carbon nanotubes in biodiesel production. AB - Carboxylated single-walled carbon nanotubes (SWCNTCOOH) were used as support for covalent immobilization of Candida antarctica lipase B (CaL-B) using linkers with different lengths. The obtained nanostructured biocatalysts with low diffusional limitation were tested in batch mode in the ethanolysis of the sunflower oil. SWCNTCOOH-CaL-B proved to be a highly efficient and stable biocatalyst in acetonitrile (83.4% conversion after 4h at 35 degrees C, retaining >90% of original activity after 10 cycles). PMID- 26590761 TI - Reasons for optimism in the therapy of acute leukemia. AB - Distinct progress has been made in recent years in the therapy of acute leukemia. For acute myeloid leukemia (AML), this progress has been anchored in the increased understanding of genomic complexity. Multiple targets and the relationships among them pose new challenges along with new possibilities for the development of targeted therapies. A number of new drugs are in early clinical development for AML, one of which centers on the role of isocitrate dehydrogenase (IDH) in malignancy. Epigenetic modulation, intracellular pathways, and the microenvironment are all being explored for possible therapies to treat AML. Dramatic clinical progress has also been made in therapy of acute lymphoblastic leukemia (ALL) with the rapid approval of blinatumomab, a bispecific T-cell engager antibody. Yet caution must also be exercised-not every mutation is an epigenetic target and early publication of clinical data is often misleading. Until the survival outcome for adult patients with acute leukemia improves, further inquiry into the biology of the disease and progress in the development of new therapies are needed. PMID- 26590762 TI - Plasticity of hematopoietic stem cells. AB - Almost two decades ago, a number of cell culture and preclinical transplantation studies suggested the striking concept of the tissue-reconstituting ability of hematopoietic stem cells (HSCs). While this heralded an exciting time of radically new therapies for disorders of many organs and tissues, the concept was soon mired by controversy and remained dormant. This chapter provides a brief review of evidence for HSC plasticity including our findings based on single HSC transplantation in mouse. These studies strongly support the concept that HSCs are pluripotent and may be the source for the majority, if not all, of the cell types in our body. PMID- 26590763 TI - AML evolution from preleukemia to leukemia and relapse. AB - Dismal outcomes of acute myeloid leukemia (AML), especially in the elderly, are mainly associated with leukemia relapse and primary no response to initial therapy. This review will focus on AML relapse, and how a better understanding of the evolutionary stages that lead to relapse might help us improve disease outcome. The fact that the relapse rate for some AMLs is so high indicates that we do not truly understand the biology of relapse or possibly that we are not implementing our current understanding into, clinical practice. Therefore, this review will also aim to explore some of the current understanding of AML relapse biology in order to identify the gaps in our knowledge and translation. Accumulating evidence suggests that the root of relapse evolves even before the time of diagnosis, meaning that the complex clonal structure of AML is created before patients present to the clinic. Some of the clones that exist at diagnosis can survive chemotherapy and give rise to relapse. Accordingly, in order to better understand the mechanisms of relapse, we must consider both early and late steps in AML evolution. PMID- 26590764 TI - Impact of genomics in the clinical management of patients with cytogenetically normal acute myeloid leukemia. AB - Acute myeloid leukemia (AML) is a clinically and molecularly heterogeneous disease. Cytogenetics and FISH have contributed to the stratification of AML patients into favorable, intermediate, and unfavorable risk categories. However, until recently, the prognostic stratification and treatment decision for the intermediate risk category, mostly comprising AML patients with normal cytogenetics (CN-AML), has been difficult due to the scarce knowledge of the molecular alterations underlying this large AML subgroup (which accounts for about 50% of all adult AML). During the past decade, the discovery of numerous mutations associated with CN-AML has resulted in significant advances in the AML field. Here, we review the biological characteristics of the most common mutations underlying CN-AML and outline their clinical impact in the following settings: (i) definition of new molecular leukemia entities in the WHO classification; (ii) risk stratification of CN-AML patients according to mutational profile; and (iii) monitoring of minimal residual disease by specific quantitative molecular assays. PMID- 26590765 TI - Should minimal residual disease guide therapy in AML? AB - The prognostic power of minimal residual disease after therapy for acute leukemias is not in question. It is only logical that the finding of leukemic blast cells after therapy predicts for impending relapse or at least the need for additional treatment. Which level of what is called minimal residual disease (MRD) is clinically relevant, however, depends on the efficacy of the initial treatment as well as the treatment strategies available to target MRD. There are a multitude of additional factors that can alter the clinical significance of MRD, including the genotype of the patient's leukemic cells. The fact that methodologies of MRD detection are not standardized and thresholds for defining MRD positivity vary depending upon MRD detection method and the operator's skills or convictions only add to the complexity of MRD interpretation. While enormous efforts are devoted to enhancing the sensitivity of MRD detection, eg, by next generation sequencing, improvements of methods for detecting MRD per se will not automatically lead to a more reliable estimation of total tumor burden. Most importantly, even the best assay will yield accurate MRD results only if the tissue source for MRD determination is of good quality. Another aspect of potentially crucial importance is the heterogenous distribution of leukemic cells throughout the skeleton after treatment, recently demonstrated for acute myeloid leukemia (AML) by bone marrow imaging. Once technical difficulties of MRD measurement are resolved and better MRD-targeting drugs are developed, we still need to learn about alternate proposed mechanisms to explain MRD-independent prognostication, well described in acute lymphoid leukemia, before MRD can be included routinely in the guidance of therapy in AML. PMID- 26590766 TI - Should older adults with AML receive post-remission therapy? AB - The evolution of post-remission therapy in older adults has for the most part mirrored that for younger adults. However, the suitability of those regimens for an older population is less clear-cut, mainly due to poorer tolerance of therapy and a relatively higher level of disease resistance. Not only is intensive post remission therapy not appropriate for the majority of older adults, but the role of intensive induction therapy is also unclear. Treatment goals in patients over 55-65 years differ from those in younger patients and may not necessarily be curative but life-prolonging or purely palliative. This paper reviews treatments for older AML patients in an effort to shed some light on choosing appropriate therapy. PMID- 26590767 TI - IDH2 inhibition in AML: Finally progress? AB - Isocitrate dehydrogenase (IDH) catalyzes the conversion of isocitrate to alpha ketoglutarate. IDH occurs in three isoforms, IDH1, located in the cytoplasm, IDH2 located in the mitochondria, and IDH3, which functions as part of the TCA cycle. Mutations in the active site of IDH1 at position R132 and an analogous mutation in the IDH2 gene at position R172 have been discovered. Notably, many cases of acute myeloid leukemia (AML) have mutations in R172 and R140. The impact of these mutations and early results of inhibiting mutant IDH2 with the reversible inhibitor AG-221 are discussed in this review. PMID- 26590768 TI - Antibodies: Immunoconjugates and autologous cellular therapy in acute lymphoblastic leukemia. AB - Using a case study of a 57-year-old man with relapsed/refractory precursor-B (pre B) acute lymphoblastic leukemia (ALL), this review discusses treatment with immunoconjugates and autologous therapy in acute ALL. Three therapies- blinatumomab, inotuzumab, and CAR T cells--are considered here, each with advantages in specific clinical situations. These therapies represent some of the exciting advances that have been made in the treatment of ALL over the last several years. PMID- 26590769 TI - Is there a role for therapy after transplant? AB - Despite the steady increase in the number of stem cell transplants performed since 1980 and improvements in survival rates, disease relapse remains the major cause of death after HLA matched sibling and unrelated donor transplants for acute myeloid leukemia (AML). Given this situation, maintenance therapy after transplant may be an appropriate strategy to reduce the relapse rate and prolong survival. A number of agents are being investigated as maintenance therapy after stem cell transplant in AML patients, including azacitidine, decitabine, and other agents. This paper focuses on the role of maintenance treatment to reduce the risk of relapse after transplant. PMID- 26590770 TI - Hematopoietic cell transplantation for adults with acute myeloid leukemia with minimal residual disease. AB - Early trials of hematopoietic cell transplantation (HCT) for adults with acute myeloid leukemia (AML) did not generally include measurement of minimal residual disease (MRD) at the time of remission. However, the presence of MRD is now considered to be a powerful predictor of outcome for adults with AML in first complete remission. This raises the question of whether MRD positivity in first remission changes the indications for transplant or the transplant approach itself if patients do proceed to transplant with MRD present. This paper will begin to address these issues in adult AML. PMID- 26590771 TI - Recent developments in HLA-haploidentical transplantations. AB - While allogeneic hematopoietic stem cell transplantations have a curative potential, several patients with hematologic malignancies cannot avail themselves of this therapeutic option due to lack of matched donor availability. Although HLA-haploidentical transplantations were previously associated with poor outcomes, recent evidence with use of post transplantation cyclophosphamide indicate improved safety and efficacy. The following paper discusses the most recent developments in this area. PMID- 26590772 TI - Is there a best graft source of transplantation in acute myeloid leukemia? AB - Only 30% of patients in the US who require an allogeneic hematopoietic cell transplant will have a fully HLA matched sibling donor. The National Marrow Donor Program/Be the Match has grown to over 25 million unrelated donors. However, a fully matched unrelated donor may not be available for many patients, particularly for patients of diverse racial and ethnic backgrounds. Over the last 10 years, considerable progress has been made in alternative donor transplant with improvements in outcomes for umbilical cord blood (UCB), haploidentical (haplo) related donor, and mismatched unrelated donor (MMUD) for patients with acute myeloid leukemia. Retrospective studies indicate comparable survival for these three graft sources. In this chapter, we review the latest results for patients receiving alternative donor transplants, and discuss strategies for choosing the optimal donor for each individual patient. PMID- 26590774 TI - Motility in the epsilon-proteobacteria. AB - The epsilon-proteobacteria are a widespread group of flagellated bacteria frequently associated with either animal digestive tracts or hydrothermal vents, with well-studied examples in the human pathogens of Helicobacter and Campylobacter genera. Flagellated motility is important to both pathogens and hydrothermal vent members, and a number of curious differences between the epsilon-proteobacterial and enteric bacterial motility paradigms make them worthy of further study. The epsilon-proteobacteria have evolved to swim at high speed and through viscous media that immobilize enterics, a phenotype that may be accounted for by the molecular architecture of the unusually large epsilon proteobacterial flagellar motor. This review summarizes what is known about epsilon-proteobacterial motility and focuses on a number of recent discoveries that rationalize the differences with enteric flagellar motility. PMID- 26590773 TI - Role of intestinal microbiota in transplantation outcomes. AB - While allogeneic hematopoietic stem cell transplantations have a curative potential, infections and graft-versus-host disease remain significant problems. The intestinal microbiota can influence responses to cancer chemotherapy and the role of the microbiota in affecting allogeneic hematopoietic stem cell transplantation outcomes is increasingly appreciated. The following paper discusses the most recent developments in this area. PMID- 26590775 TI - Advances in Single-Photon Emission Computed Tomography Hardware and Software. AB - Nuclear imaging techniques remain today's most reliable modality for the assessment and quantification of myocardial perfusion. In recent years, the field has experienced tremendous progress both in terms of dedicated cameras for cardiac applications and software techniques for image reconstruction. The most recent advances in single-photon emission computed tomography hardware and software are reviewed, focusing on how these improvements have resulted in an even more powerful diagnostic tool with reduced injected radiation dose and acquisition time. PMID- 26590776 TI - Technical Aspects of Cardiac PET Imaging and Recent Advances. AB - As the number of myocardial perfusion single emission photon computed tomography studies performed in the United States has steadily declined over the past several years, an opposite trend can be seen for myocardial perfusion PET. This review covers basic technical aspects of cardiac PET imaging and recent advances that maximize the quality and efficiency of cardiac PET. The covered topics include radioisotopes used in cardiac PET and basics of acquisition and reconstruction, including time-of-flight techniques, PET detectors, attenuation correction, and respiratory gating techniques. PMID- 26590777 TI - Cardiovascular PET/MRI: Challenges and Opportunities. AB - Recently, systems combining PET and MRI have appeared on the market. The 2 main advantages of these systems over PET/computed tomography are the improved soft tissue contrast with MRI obtained without ionizing radiation and the potential for simultaneous acquisition of the PET and magnetic resonance images. However, its clinical acceptance has been slow for several reasons. Moreover, there are significant technical challenges that must be overcome from an image acquisition, processing, display, and laboratory workflow perspective for implementing cardiovascular PET/MRI on a routine clinical basis. The potential is high for PET/MRI to become a critical tool in the management of disease. PMID- 26590778 TI - Radionuclide Tracers for Myocardial Perfusion Imaging and Blood Flow Quantification. AB - Myocardial perfusion imaging is performed most commonly using Tc-99m-sestamibi or tetrofosmin SPECT as well as Rb-82-rubidium or N-13-ammonia PET. Diseased-to normal tissue contrast is determined by the tracer retention fraction, which decreases nonlinearly with flow. Reduced tissue perfusion results in reduced tracer retention, but the severity of perfusion defects is typically underestimated by 20% to 40%. Compared to SPECT, retention of the PET tracers is more linearly related to flow, and therefore, the perfusion defects are measured more accurately using N-13-ammonia or Rb-82. PMID- 26590779 TI - Automated Quantitative Nuclear Cardiology Methods. AB - Quantitative analysis of SPECT and PET has become a major part of nuclear cardiology practice. Current software tools can automatically segment the left ventricle, quantify function, establish myocardial perfusion maps, and estimate global and local measures of stress/rest perfusion, all with minimal user input. State-of-the-art automated techniques have been shown to offer high diagnostic accuracy for detecting coronary artery disease, as well as predict prognostic outcomes. This article briefly reviews these techniques, highlights several challenges, and discusses the latest developments. PMID- 26590780 TI - Stress-first Myocardial Perfusion Imaging. AB - Stress-first approaches to myocardial perfusion imaging provide diagnostically and prognostically accurate perfusion data equivalent to a full rest-stress study, save time in the imaging laboratory, and reduce the radiation exposure to patients and laboratory staff. Converting a nuclear cardiology laboratory from a conventional rest-stress strategy to a stress-first approach involves challenges such as the need for attenuation correction, triage of patients to an appropriate protocol, real-time review of stress images, and consideration of differential reimbursement. PMID- 26590781 TI - Clinical PET Myocardial Perfusion Imaging and Flow Quantification. AB - Cardiac PET imaging is a powerful tool for the assessment of coronary artery disease. Many tracers with different advantages and disadvantages are available. It has several advantages over single photon emission computed tomography, including superior accuracy and lower radiation exposure. It provides powerful prognostic information, which can help to stratify patients and guide clinicians. The addition of flow quantification enables better detection of multivessel disease while providing incremental prognostic information. Flow quantification provides important physiologic information, which may be useful to individualize patient therapy. This approach is being applied in some centers, but requires standardization before it is more widely applied. PMID- 26590782 TI - Long-Term Risk Assessment After the Performance of Stress Myocardial Perfusion Imaging. AB - Stress-rest myocardial perfusion imaging (MPI) is a potent method for assessing the presence and magnitude of inducible myocardial ischemia. Stress MPI currently faces increased scrutiny for its therapeutic effectiveness because of the emergence of other competing means for assessing clinical risk. New data have examined the usefulness stress-rest-MPI as a predictor for long-term clinical outcomes, in contrast to its traditional role for assessing short-term cardiovascular risk. These data indicates that temporal risk is highly influenced by both the magnitude of ischemia and various baseline clinical factors. An optimized assessment of stress MPI, which includes long-term risk prediction, might improve the potential future clinical effectiveness of this imaging modality. PMID- 26590783 TI - Radionuclide Assessment of Left Ventricular Dyssynchrony. AB - Phase analysis of gated myocardial perfusion single-photon emission computed tomography is a widely available and reproducible measure of left ventricular (LV) dyssynchrony, which also provides comprehensive assessment of LV function, global and regional scar burden, and patterns of LV mechanical activation. Preliminary studies indicate potential use in predicting cardiac resynchronization therapy response and elucidation of mechanisms. Because advances in technology may expand capabilities for precise LV lead placement in the future, identification of specific patterns of dyssynchrony may have a critical role in guiding cardiac resynchronization therapy. PMID- 26590784 TI - Radionuclide Imaging in Congestive Heart Failure: Assessment of Viability, Sarcoidosis, and Amyloidosis. AB - Radionuclide imaging provides both established and emerging diagnostic and prognostic tools to assist clinicians in the management of patients with ischemic cardiomyopathy, cardiac sarcoidosis, and cardiac amyloidosis. This review highlights the underlying pathophysiology of each entity and associated diagnostic and clinical challenges, and describes the available radionuclide imaging techniques. Specific protocols, advantages and disadvantages, comparison with other noninvasive imaging modalities, and discussion of the evolving role of hybrid imaging are also included. PMID- 26590785 TI - Clinical Applications of Myocardial Innervation Imaging. AB - Cardiac autonomic innervation plays an important role in regulating function. Adrenergic innervation imaging is possible with the norepinephrine analogue radiotracer iodine 123 meta-iodobenzylguanidine ((123)I-mIBG) and positron emitting tracers such carbon-11 hydroxyephedrine. (123)I-mIBG uptake is assessed globally via the heart to mediastinum ratio on planar images and regionally with tomographic imaging and has utility in various cardiac diseases. There is promise for guiding expensive invasive therapies such as implantable defibrillators, ventricular assist devices, and transplant. There are reports of utility in primary arrhythmic conditions, ischemic heart disease, and diabetes and after cardiac damaging chemotherapy. PMID- 26590786 TI - Radionuclide Imaging of Cardiovascular Infection. AB - Owing to expanding clinical indications, cardiac implantable electronic devices (CIEDs) are being increasingly used. Despite improved surgical techniques and the use of prophylactic antimicrobial therapy, the rate of CIED-related infection is also increasing. Infection is a potentially serious complication, with clinical manifestations ranging from surgical site infection and local symptoms in the region of the generator pocket to fulminant endocarditis. The utility of radionuclide imaging as a stand-alone noninvasive diagnostic imaging test in patients with suspected endocarditis has been less frequently examined. This article summarizes the recent advances in radionuclide imaging for evaluation of patients with suspected cardiovascular infections. PMID- 26590788 TI - Translational Coronary Atherosclerosis Imaging with PET. AB - Although still in its infancy, coronary atherosclerosis imaging with PET holds promise in improving understanding of the pathophysiologic processes that underlie plaque progression and adverse cardiovascular events. Fludeoxyglucose F 18 offers the potential to measure inflammatory activity within the plaque itself whereas fluoride F 18 allows detection of microcalcification, both of which are key characteristics of plaques at risk of rupture. Further work is required to improve these imaging techniques and to assess their ability to predict cardiac events prospectively. PMID- 26590789 TI - Translational Molecular Nuclear Cardiology. AB - Increased rollout and availability of preclinical imaging provides a foundation for development of novel molecular nuclear imaging agents. The current armamentarium of radiotracers available for nuclear cardiology allows for the interrogation of critical molecular processes involved in a myriad of cardiovascular disorders, including altered metabolism, ventricular remodeling, sympathetic neuronal activation, and systemic inflammation. Effective translational molecular imaging requires coordination of clinical need with tracer development and molecular biology, leading to the identification of ideal translational imaging compounds. PMID- 26590787 TI - Novel Applications of Radionuclide Imaging in Peripheral Vascular Disease. AB - Peripheral vascular disease (PVD) is a progressive atherosclerotic disease that leads to stenosis or occlusion of blood vessels supplying the lower extremities. Current diagnostic imaging techniques commonly focus on evaluation of anatomy or blood flow at the macrovascular level and do not permit assessment of the underlying pathophysiology associated with disease progression or treatment response. Molecular imaging with radionuclide-based approaches can offer novel insight into PVD by providing noninvasive assessment of biological processes such as angiogenesis and atherosclerosis. This article discusses emerging radionuclide based imaging approaches that have potential clinical applications in the evaluation of PVD progression and treatment. PMID- 26590790 TI - Frontiers of Nuclear Cardiology. PMID- 26590791 TI - Bi-directional effects of pituitary adenylate cyclase-activating polypeptide (PACAP) on fear-related behavior and c-Fos expression after fear conditioning in rats. AB - Pituitary adenylate cyclase-activating polypeptide (PACAP) is implicated in stress regulation and learning and memory. PACAP has neuromodulatory actions on brain structures within the limbic system that could contribute to its acute and persistent effects in animal models of stress and anxiety-like behavior. Here, male Sprague-Dawley rats were implanted with intracerebroventricular (ICV) cannula for infusion of PACAP-38 (0.5, 1, or 1.5 MUg) or vehicle followed 30 min later by fear conditioning. Freezing was measured early (1, 4, and 7 days) or following a delay (7, 10, and 13 days) after conditioning. PACAP (1.5 MUg) produced a bi-phasic response in freezing behavior across test days: relative to controls, PACAP-treated rats showed a reduction in freezing when tested 1 or 7 days after fear conditioning that evolved into a significant elevation in freezing by the third test session in the early, but not delayed, group. Corticosterone (CORT) levels were significantly elevated in PACAP-treated rats following fear conditioning, but not at the time of testing (Day 1). Brain c-Fos expression revealed PACAP-dependent alterations within, as well as outside of, areas typically implicated in fear conditioning. Our findings raise the possibility that PACAP disrupts fear memory consolidation by altering synaptic plasticity within neurocircuits normally responsible for encoding fear-related cues, producing a type of dissociation or peritraumatic amnesia often seen in people early after exposure to a traumatic event. However, fear memories are retained such that repeated testing and memory reactivation (e.g., re experiencing) causes the freezing response to emerge and persist at elevated levels. PACAP systems may represent an axis on which stress and exposure to trauma converge to promote maladaptive behavioral responses characteristic of psychiatric illnesses such as post-traumatic stress disorder (PTSD). PMID- 26590793 TI - Expression of the immediate early IE180 protein under the control of the hTERT and CEA tumor-specific promoters in recombinant pseudorabies viruses: Effects of IE180 protein on promoter activity and apoptosis induction. AB - Since the pseudorabies virus (PRV) genome encodes for a single immediate-early protein, IE180, we reasoned that this strong transactivating protein could represent a key regulatory switch that could be genetically manipulated in order to alter its tropism towards cancer cells. We therefore initiated studies to test whether the human telomerase reverse transcriptase (hTERT) and carcinoembryonic antigen (CEA) tumor promoters could functionally replace the IE180 promoter. We show that both promoters can functionally substitute the IE180 promoter in plasmid constructs and recombinant viruses, and observed that IE180 differentially auto-regulated each promoter tested, with PRV IE180 negatively regulating the hTERT promoter but positively hyper-activating the CEA promoter. Interestingly, we also observed that the recombinant PRV-TER and PRV-CEA viruses preferentially replicated in diverse cancer cell lines compared to control non cancer cells, and the PRV-CEA was capable of additionally inducing a profound apoptotic phenotype which we correlated to the overexpression of IE180. PMID- 26590792 TI - Rabbit CD200R binds host CD200 but not CD200-like proteins from poxviruses. AB - CD200 is a widely distributed membrane protein that gives inhibitory signals through its receptor (CD200R) on myeloid cells. CD200 has been acquired by herpesviruses where it has been shown to interact with host CD200R and downmodulate the immune system. It has been hypothesized that poxviruses have acquired CD200; but the potential orthologues show less similarity to their hosts. Myxoma virus M141 protein is a potential CD200 orthologue with a potent immune modulatory function in rabbits. Here, we characterized the rabbit CD200, CD200R and tested the CD200-like sequences for binding CD200R. No binding could be detected using soluble recombinant proteins, full length protein expressed on cells or myxoma virus infected cells. Finally, using knockdown models, we showed that the inhibitory effect of M141 on RAW 264.7 cells upon myxoma virus infection is not due to CD200R. We conclude that the rabbit poxvirus CD200-like proteins cause immunomodulation without utilizing CD200R. PMID- 26590794 TI - Evaluation of the maturation of individual Dengue virions with flow virometry. AB - High-throughput techniques are needed to analyze individual virions to understand how viral heterogeneity translates into pathogenesis since in bulk analysis the individual characteristics of virions are lost. Individual Dengue virions (DENV) undergo a maturation that involves a proteolytic cleavage of prM precursor into virion-associated M protein. Here, using a new nanoparticle-based technology, "flow virometry", we compared the maturation of individual DENV produced by BHK 21 and LoVo cells. The latter lacks the furin-protease that mediates prM cleavage. We found that prM is present on about 50% of DENV particles produced in BHK-21 cells and about 85% of DENV virions produced in LoVo, indicating an increase in the fraction of not fully matured virions. Flow virometry allows us to quantify the number of fully mature particles in DENV preparations and proves to be a useful method for studying heterogeneity of the surface proteins of various viruses. PMID- 26590795 TI - The genomic sequence of lymphocryptovirus from cynomolgus macaque. AB - Lymphocryptoviruses such as Epstein-Barr virus (EBV) cause persistent infections in human and non-human primates, and suppression of the immune system can increase the risk of lymphocryptovirus (LCV)-associated tumor development in both human and non-human primates. To enable LCV infection as a non-clinical model to study effects of therapeutics on EBV immunity, we determined the genomic DNA sequence of the LCV from cynomolgus macaque, a species commonly used for non clinical testing. Comparison to rhesus macaque LCV and human EBV sequences indicates that LCV from the cynomolgus macaque has the same genomic arrangement and a high degree of similarity in most genes, especially with rhesus macaque LCV. Genes showing lower similarity were those encoding proteins involved in latency and/or tumor promotion or immune evasion. The genomic sequence of LCV from cynomolgus macaque should aid the development of non-clinical tools for identifying therapeutics that impact LCV immunity and carry potential lymphoma risk. PMID- 26590796 TI - Two mutations in the vif gene of maedi-visna virus have different phenotypes, indicating more than one function of Vif. AB - Like most other lentiviruses, maedi-visna virus (MVV) requires Vif for replication in natural target cells and in vivo. Here, we show that Vif-deficient MVV accumulates G-A mutations in the sequence context characteristic of ovine APOBEC3, consistent with a role of MVV Vif in neutralizing APOBEC3. We studied two point mutations in the vif gene of MVV. One was a tryptophan to arginine mutation that affects the interaction with APOBEC3 and caused G-A hypermutation. The other mutation was a proline to serine mutation that together with a mutation in the capsid protein caused attenuated replication in fetal ovine synovial (FOS) cells but not in sheep choroid plexus (SCP) cells. There was no hypermutation associated with this mutation. These results suggest that MVV Vif exerts more than one function and that there may be interaction between Vif and the capsid. The results also suggest the involvement of an unknown host factor in MVV Vif function. PMID- 26590797 TI - Modulation of DNA damage response and induction of apoptosis mediates synergism between doxorubicin and a new imidazopyridine derivative in breast and lung cancer cells. AB - DNA damage response machinery (DDR) is an attractive target of cancer therapy. Modulation of DDR network may alter the response of cancer cells to DNA damaging anticancer drugs such as doxorubicin. The aim of the present study is to investigate the effects of a newly developed imidazopyridine (IAZP) derivative on the DDR after induction of DNA damage in cancer cells by doxorubicin. Cytotoxicity sulphrhodamine-B assay showed a weak anti-proliferative effect of IAZP alone on six cancer cell lines (MCF7, A549, A549DOX11, HepG2, HeLa and M8) and a normal fibroblast strain. Combination of IAZP with doxorubicin resulted in synergism in lung (A549) and breast (MCF7) cancer cells but neither in the other cancer cell lines nor in normal fibroblasts. Molecular studies revealed that synergism is mediated by modulation of DNA damage response and induction of apoptosis. Using constant-field gel electrophoresis and immunofluorescence detection of gamma-H2AX foci, IAZP was shown to inhibit the repair of doxorubicin induced DNA damage in A549 and MCF7 cells. Immunoblot analysis showed that IAZP suppresses the phosphorylation of the ataxia lelangiectasia and Rad3 related (ATR) protein, which is an important player in the response of cancer cells to chemotherapy-induced DNA damage. Moreover, IAZP augmented the doxorubicin-induced degradation of p21, activation of p53, CDK2, caspase 3/7 and phosphorylation of Rb protein. These effects enhanced doxorubicin-induced apoptosis in both cell lines. Our results indicate that IAZP is a promising agent that may enhance the cytotoxic effects of doxorubicin on some cancer cells through targeting the DDR. It is a preliminary step toward the clinical application of IAZP in combination with anticancer drugs and opens the avenue for the development of compounds targeting the DDR pathway that might improve the therapeutic index of anticancer drugs and enhance their cure rate. PMID- 26590798 TI - Variants in KCNJ11 and BAD do not predict response to ketogenic dietary therapies for epilepsy. AB - In the absence of specific metabolic disorders, predictors of response to ketogenic dietary therapies (KDT) are unknown. We aimed to determine whether variants in established candidate genes KCNJ11 and BAD influence response to KDT. We sequenced KCNJ11 and BAD in individuals without previously-known glucose transporter type 1 deficiency syndrome or other metabolic disorders, who received KDT for epilepsy. Hospital records were used to obtain demographic and clinical data. Two response phenotypes were used: >= 50% seizure reduction and seizure freedom at 3-month follow-up. Case/control association tests were conducted with KCNJ11 and BAD variants with minor allele frequency (MAF)>0.01, using PLINK. Response to KDT in individuals with variants with MAF<0.01 was evaluated. 303 Individuals had KCNJ11 and 246 individuals had BAD sequencing data and diet response data. Six SNPs in KCNJ11 and two in BAD had MAF>0.01. Eight variants in KCNJ11 and seven in BAD (of which three were previously-unreported) had MAF<0.01. No significant results were obtained from association analyses, with either KDT response phenotype. P-values were similar when accounting for ethnicity using a stratified Cochran-Mantel-Haenszel test. There did not seem to be a consistent effect of rare variants on response to KDT, although the cohort size was too small to assess significance. Common variants in KCNJ11 and BAD do not predict response to KDT for epilepsy. We can exclude, with 80% power, association from variants with a MAF of >0.05 and effect size >3. A larger sample size is needed to detect associations from rare variants or those with smaller effect sizes. PMID- 26590799 TI - Sleep problems in bipolar disorders: more than just insomnia. AB - OBJECTIVE: Sleep problems in bipolar disorder (BD) are common, but reported rates vary from 10% to 80%, depending on definitions, methodologies and management of potential confounding factors. This multicenter study seeks to address these issues and also compares BD cases with Hypersomnia as well as the more commonly investigated Insomnia and No Sleep Problem groups. METHOD: A cross-sectional comparison of sleep profiles in 563 BD I and II individuals who participated in a structured assessment of demographic, clinical, illness history and treatment variables. RESULTS: Over 40% cases met criteria for Insomnia and 29% for Hypersomnia. In univariate analysis, Insomnia was associated with BD II depression whilst Hypersomnia was associated with BD I depression or euthymia. After controlling for confounders and covariates, it was demonstrated that Hypersomnia cases were significantly more likely to be younger, have BD I and be prescribed antidepressants whilst Insomnia cases had longer illness durations and were more likely to be prescribed benzodiazepines and hypnotics. CONCLUSION: Whilst Insomnia symptoms are common in BD, Hypersomnia is a significant, frequently underexplored problem. Detailed analyses of large representative clinical samples are critical to extending our knowledge of differences between subgroups defined by sleep profile. PMID- 26590800 TI - Atypical phenotypes associated with pathogenic CHD7 variants and a proposal for broadening CHARGE syndrome clinical diagnostic criteria. AB - CHARGE syndrome (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth and/or development, Genital and/or urinary anomalies, and Ear malformations, including deafness and vestibular disorders) is a genetic condition characterized by a specific and recognizable pattern of features. Heterozygous pathogenic variants in the chromodomain helicase DNA-binding protein 7 (CHD7) are the major cause of CHARGE syndrome, and have been identified in 70 90% of individuals fulfilling clinical diagnostic criteria. Since 2004, when CHD7 was discovered as the causative gene for CHARGE syndrome, the phenotypic spectrum associated with pathogenic CHD7 variants has expanded. Predicted pathogenic CHD7 variants have been identified in individuals with isolated features of CHARGE including autism and hypogonadotropic hypogonadism. Here, we present genotype and phenotype data from a cohort of 28 patients who were considered for a diagnosis of CHARGE syndrome, including one patient with atypical presentations and a pathogenic CHD7 variant. We also summarize published literature on pathogenic CHD7 variant positive individuals who have atypical clinical presentations. Lastly, we propose a revision to current clinical diagnostic criteria, including broadening of the major features associated with CHARGE syndrome and addition of pathogenic CHD7 variant status as a major criterion. PMID- 26590801 TI - Photocatalytic and antibacterial activities of gold and silver nanoparticles synthesized using biomass of Parkia roxburghii leaf. AB - The present study reports a green approach for synthesis of gold (Au) and silver (Ag) nanoparticles (NPs) using dried biomass of Parkia roxburghii leaf. The biomass of the leaf acts as both reductant as well as stabilizer. The as synthesized nanoparticles were characterized by time-dependent UV-visible, Fourier transform infrared (FT-IR), powder X-ray diffraction (XRD), and transmission electron microscopy (TEM) analyses. The UV-visible spectra of synthesized Au and Ag NPs showed surface plasmon resonance (SPR) at 555 and 440 nm after 12h. Powder XRD studies revealed formation of face-centered cubic structure for both Au and Ag NPs with average crystallite size of 8.4 and 14.74 nm, respectively. The TEM image showed the Au NPs to be monodispersed, spherical in shape with sizes in the range of 5-25 nm. On the other hand, Ag NPs were polydispersed, quasi-spherical in shape with sizes in the range of 5-25 nm. Investigation of photocatalytic activities of Au and Ag NPs under solar light illumination reveals that both these particles have pronounced effect on degradation of dyes viz., methylene blue (MB) and rhodamine b (RhB). Antibacterial activity of the synthesized NPs was studied on Gram positive bacteria Staphylococcus aureus and Gram negative bacteria Escherichia coli. Both Au and Ag NPs showed slightly higher activity on S. aureus than on E. coli. PMID- 26590802 TI - Survival of spoilage bacteria subjected to sequential eugenol and temperature treatments. AB - Effects of a sequential application of eugenol and temperature on the survival of two model spoilage organisms, Staphylococcus carnosus LTH1502 and Escherichia coli K12 C600, were studied. To assess effects of a "temperature first antimicrobial later" treatment, cultures were treated with eugenol at 20, 37 and 42 degrees C at the beginning of the incubation period, and after 3h and 8h. To assess effects of an "antimicrobial first-temperature later" treatment, eugenol was added at the beginning of the incubation period at 37 degrees C and temperature was changed to 20 or 42 degrees C after 3 or 8h. Cell numbers were determined in regular intervals during the incubation period using plate counts. Partitioning of eugenol was measured by HPLC, and cell morphology was assessed by electron microscopy. Combined treatments were more effective against the Gram negative E. coli than against S. carnosus. Order of application influenced the effectiveness of treatments, especially at 42 degrees C. There, the temperature first-eugenol later treatment was less effective than other treatments, likely due to temperature-induced adaptation processes occurring in cellular membranes making them more resistant against a later eugenol treatment. Results are of significance in situations where combinations of sublethal stresses are used to build a hurdle concept for food preservation. PMID- 26590803 TI - Prevalence and determinants of stunting in under-five children in central Tanzania: remaining threats to achieving Millennium Development Goal 4. AB - BACKGROUND: The Millennium Development Goal No 4 (MDG 4) requires countries to scale up interventions addressing malnutrition and other immediate determinants of burden of disease among children to reduce child mortality by two thirds by 2015, which is this year. Whereas globally some achievements have been registered, under-nourishment remains a significant problem in some developing countries such as Tanzania. This study set out to estimate the extent of stunting and its associated determinants to assess the progress made thus far towards achieving MDG 4 in Tanzania. METHODS: A random sample of 678 households with under-five children was selected from two randomly selected wards of Kongwa district in Dodoma region, Tanzania. The WHO anthropometric calculator, which computes Z-scores using a reference population, was used to process the anthropometric measurement data taken from all the participants. Children with height for age Z-score of less than 2 were categorised as stunted and coded as 1 and the rest were coded as 0. Proportions of stunting were compared using the chi square test to determine the association between stunting and the independent variables. Multivariate logistic regression analysis was carried out to determine the Adjusted Odds Ratio (AOR) of the independent determinants of stunting. The cut-off for significant association was set at p = 0.05. All these analyses used the STATA 12 software. RESULTS: About half (49.7 %) of the children were stunted. This stunting was associated with belonging to households where the head of family was young (<35 years) (AOR = 0.67, 95 % CI 0.47-0.96, p = 0.031), young age of the mothers (AOR = 1.54, 95 % CI 1.06-2.24, p = 0.023), and economic variables such as owning a cellular phone (AOR = 0.66, 96 % CI 0.46-0.94, p = 0.023). CONCLUSIONS: Stunting was highly prevalent in Kongwa district despite general improvements in child nutritional status at the national level. Household characteristics and economic status were found to play a major role in child health. In this regard, disaggregated analyses are therefore important in identifying resilient areas in need of concerted efforts for the MDG 4 to be achieved nationwide. PMID- 26590804 TI - In vitro antibacterial and antibiotic-potentiation activities of the methanol extracts from Beilschmiedia acuta, Clausena anisata, Newbouldia laevis and Polyscias fulva against multidrug-resistant Gram-negative bacteria. AB - BACKGROUND: The present study was designed to investigate the antibacterial activities of the methanol extracts from different parts of Beilschmedia acuta Kosterm (Lauraceae), Clausena anisata (Willd) Hook (Rutaceae), Newbouldia laevis Seem (Bignoniaceae) and Polyscias fulva (Hiern) Harms (Araliaceae) as well as their synergistic effects with antibiotics against a panel of Gram-negative bacteria, including multi-drug resistant (MDR) phenotypes expressing active efflux pumps. METHODS: Broth microdilution method was used to determine the minimum inhibitory concentrations (MICs) and the minimum bactericidal concentrations (MBCs) of the extracts, as well as those of antibiotics in association with the most active ones, B. acuta, N. laevis and P. fulva. RESULTS: MIC values obtained indicate that extracts from the bark of B. acuta were active on all the 26 tested Gram-negative bacteria, with MICs ranging from values below 8 to 256 MUg/mL. Other samples displayed selective activities, their inhibitory effects being observed on 9 (34.62 %) of the 26 bacterial strains for N. laevis leaves extract, 6 (23.10 %) for both C. anisata leaves and roots extracts, 7 (26.9 %) and 4 (15.4 %) for leaves and roots extracts of P. fulva respectively. Extract from B. actua bark displayed the best antibacterial activity with MIC values below 100 MUg/mL against 16 (61.5 %) of the 26 tested microorganisms. The lowest MIC values (below 8 MUg/mL) were obtained with this extract against Escherichia coli W3110 and Klebsiella pneumoniae ATCC11296. The MIC values of this extract were lower than those of ciprofloxacin against E. coli W3110, Enterobacter aerogenes ATCC13048, CM64 and Providencia stuartii NAE16. At MIC/2, the best percentages of synergistic effects (100 %), were obtained with B. acuta bark extract and tetracycline (TET) as well as with P. fulva leaves extract and TET and kanamycin (KAN). CONCLUSION: The overall results of the present study provide information for the possible use of the studied plants and mostly Beilschmedia acuta in the control of bacterial infections including MDR phenotypes. PMID- 26590805 TI - A-kinase anchor protein 4 (AKAP4) a promising therapeutic target of colorectal cancer. AB - BACKGROUND: Colorectal cancer (CRC) ranks third among the estimated cancer cases and cancer related mortalities in the Western world. Early detection and efficient therapy of CRC remains a major health challenge. Therefore, there is a need to identify novel tumor markers for early diagnosis and treatment of CRC. METHODS: A-kinase anchor protein 4 (AKAP4) gene and protein expression was monitored by quantitative polymerase chain reaction (qPCR), reverse transcription (RT)-PCR and Western blotting in normal colon tissue lysate, normal colon epithelial cells and in colon cancer cell lines viz., Caco-2, COLO205, COLO320DM, HCT-15, HCT116, HT-29, SW480, and SW620. The effect of AKAP4 on cellular growth, migration and invasion abilities was studied using gene silencing approach. The role of AKAP4 in various pathways involved in cell cycle, apoptosis, senescence was investigated in in vitro and in human xenograft mouse model. RESULTS: Our studies showed that AKAP4 gene and protein expression was expressed in all colon cancer cells while no expression was detectable in normal colon cells. Ablation of AKAP4 led to reduced cellular growth, migration, invasion and increased apoptosis and senescence of CRC cells in in vitro assays and tumor growth in human xenograft mouse. Human colon xenograft studies showed a significant decrease in the levels of cyclins B1, D and E and cyclin dependent kinases such as CDK1, CDK2, CDK4 and CDK6. Interestingly, an up-regulation in the levels of p16 and p21 was also observed. Besides, an increase in the levels of pro apoptotic molecules AIF, APAF1, BAD, BID, BAK, BAX, PARP1, NOXA, PUMA and cyt-C and Caspase 3, 7, 8 and 9 was also found in cancer cells as well as in xenograft tissue sections. However, anti-apoptotic molecules BCL2, Bcl-xL, cIAP2, XIAP, Axin2 and Survivin were down regulated in these samples. Our data also revealed elevated expression of epithelial marker E-cadherin and down regulation of EMT markers N-cadherin, P-cadherin, SLUG, alpha-SMA, SNAIL, TWIST and Vimentin. Further ablation of AKAP4 resulted in the down regulation of invasion molecules matrix metalloproteinase MMP2, MMP3 and MMP9. CONCLUSION: AKAP4 appears to be a novel CRC-associated antigen with a potential for developing as a new clinical therapeutic target. PMID- 26590806 TI - In situ chlorophyll fluorescence kinetics as a tool to quantify effects on photosynthesis in Euphorbia cyparissias by a parasitic infection of the rust fungus Uromyces pisi. AB - BACKGROUND: Photosynthesis is the key process for plant growth and development. The determination of chlorophyll fluorescence kinetics allows the quantification of effects on photosynthetic processes triggered by environmental stress factors such as, e.g., the infection by fungal phytopathogens. The technique is non invasive, rapid and well suited for experimental field work. RESULTS: Healthy and Uromyces-infected plants of Euphorbia cyparissias were monitored directly in situ in the field using rapid fluorescence kinetics. Non-infected healthy plants show a typical maximum value for the relative variable fluorescence Fv/Fm of around 0.8 with occasional variation between the leaves from the plant top towards the base, while infected plants exhibited a strong gradient to low values at the base. The photosynthetic performance index (PI) showed a higher heterogeneity within the leaves in both plant types. CONCLUSIONS: The non-invasive and rapid measurement of chlorophyll fluorescence induction allows characterizing the photosynthetic capacity of healthy and infected plants and of parts of them directly in the field. The PI, is highly sensitive not only concerning infection, but also towards other local environmental influences. PMID- 26590807 TI - Telephone follow-up after day case tension-free vaginal tape insertion. AB - INTRODUCTION AND HYPOTHESIS: Post-operative review allows assessment of individual patient outcome, evaluation of any ongoing symptoms and an audit of departmental surgical outcome and therefore represents best clinical practice. Current TVT surgery follow-up practice varies widely, with most centres routinely seeing patients face to face in an outpatient setting. However, unnecessary outpatient attendance can be inefficient and inconvenient for patients and staff. One proposed alternative is telemedical follow-up, as introduced by our unit in 2010. We report on 5 years of experience with telephone follow-up. METHODS: The British Society of Urogynaecology (BSUG) database was searched for all cases of primary retropubic TVT slings performed by the unit in the period 1 January 2010 to 31 December 2014. Cases identified from the BSUG database then had their case notes reviewed. Patients having additional surgery were excluded from analysis. This yielded a cohort of 356 patients. No ethical approval was required for this investigation as it was a simple observational study (clinical audit). RESULTS: Two hundred and sixty-two patients were initially followed up via telephone; the remaining 94 were seen in a conventional outpatient clinic setting. Of the 262 followed up by telephone, 28 patients (10 %) subsequently required review in an outpatient clinic for a variety of reasons. CONCLUSIONS: Telephone follow-up is an appropriate mode of follow-up for uncomplicated primary incontinence surgery. By using telemedicine, 234 patients who would previously have been seen in clinic were followed up remotely, saving valuable clinic time for patients with greater clinical need. PMID- 26590808 TI - Body Composition in Individuals with Asymptomatic Osteoarthritis of the Knee. AB - Greater body mass index (BMI) is associated with a greater risk of osteoarthritis (OA). This study sought to investigate whether the association is mediated by fat mass or lean mass. The study involved 170 men and 488 women aged between 20 and 90 (average age: 55) who were randomly recruited from Ho Chi Minh City, Vietnam. The presence of knee OA was radiographically diagnosed based on the Kellgren Lawrence criteria. Lean mass (LM) and fat mass (FM) were obtained from the DXA whole body scan (Hologic QDR-4500). The relationship between OA, LM, and FM was analyzed by a series of multiple linear regression models which take into account the effects of gender and age. As expected, men and women with knee OA were older than those without OA (65 vs 51 year in men, and 64 vs 52 year in women). After adjusting for age, OA was associated with greater FM and percent body fat (PBF), but the association was only observed in women, not in men. There was no statistically significant difference in LM between OA and non-OA individuals. Moreover, after adjusting for age and BMI or PBF, bone density in OA patients was not significantly different from non-OA individuals. Women with OA of the knee have greater fat mass than non-OA individuals, and that there is no significant difference in bone density between OA and non-OA individuals. Thus, the association between body mass index and OA is mainly mediated by fat mass. PMID- 26590810 TI - Point-of-Care Phalangeal Bone Mineral Density Measurement Can Reduce the Need of Dual-Energy X-Ray Absorptiometry Scanning in Danish Women at Risk of Fracture. AB - Identifying persons with a high risk of osteoporotic fractures remains a challenge. DXA uptake in women with elevated risk of osteoporosis seems to be depending on distance to scanning facilities. This study aimed to investigate the ability of a small portable scanner in identifying women with reduced bone mineral density (BMD), and to define triage thresholds for pre-selection. Total hip and lumbar spine BMD was measured by dual-energy X-ray absorptiometry and phalangeal BMD by radiographic absorptiometry in 121 Danish women with intermediate or high 10-year fracture probability (aged 61-81 years). Correlation between the two methods was estimated using correlation coefficient (r) and Bland Altman plots. A moderate correlation between phalangeal BMD versus total hip (r = 0.47) and lumbar spine (r = 0.51), and an AUC on 0.80 was found. The mean difference between phalangeal T score and total hip T score/lumbar spine T score was low, and ranged from -0.26 SD to -0.31 SD depending on site and reference database used for calculation of T scores, but, large variation was seen at an individual level. When applying a triage approach approx. one-third of all DXA scan could be avoided and only 6 % of women in the low-risk group would be false negatives. PMID- 26590811 TI - A Cross-Sectional Study of the Association of VDR Gene, Calcium Intake, and Heel Ultrasound Measures in Early Adulthood. AB - The acquisition of a high adult peak bone mass (PBM) is considered an important determinant of osteoporotic risk later in life. Genetic and environmental factors determine optimal PBM acquisition in early adulthood. The aim of this study was to test the association of vitamin D receptor (VDR) gene polymorphisms and dietary calcium intake with the bone mass of young adults. The study population comprised a total of 305 individuals (mean age 20.41; SD 2.36) whose bone mass was assessed through heel ultrasound [quantitative ultrasound measurements (QUS)] measurements (BUA, dB/MHz). The FokI G/A, rs9729 G/T, and TaqI G/A polymorphisms were selected as genetic markers of VDR. A significant difference in BUA values was observed according to gender (females 82.96; SD 15.89 vs. males 97.72; SD 16.50; p < 0.00001). The mean dietary calcium intake of the study group (827.84 mg/day; SD 347.04) was lower than the dietary reference intake for young adults (1000 mg/day) and had no association with BUA. None of the three VDR polymorphisms tested showed an association with BUA. Similarly, the analysis of VDR 3' haplotypes, estimated using rs9729 and Taq1 as tag SNPs, did not reveal any significant association with QUS traits. Our results confirm the existence of different heel QUS for women and men, as well as a tendency towards low calcium consumption by young adults, and they also suggest that the VDR gene does not play a major role in the genetic determination of QUS parameter in early adulthood. PMID- 26590809 TI - Alkaline Phosphatase and Hypophosphatasia. AB - Hypophosphatasia (HPP) results from ALPL mutations leading to deficient activity of the tissue-non-specific alkaline phosphatase isozyme (TNAP) and thereby extracellular accumulation of inorganic pyrophosphate (PPi), a natural substrate of TNAP and potent inhibitor of mineralization. Thus, HPP features rickets or osteomalacia and hypomineralization of teeth. Enzyme replacement using mineral targeted TNAP from birth prevented severe HPP in TNAP-knockout mice and was then shown to rescue and substantially treat infants and young children with life threatening HPP. Clinical trials are revealing aspects of HPP pathophysiology not yet fully understood, such as craniosynostosis and muscle weakness when HPP is severe. New treatment approaches are under development to improve patient care. PMID- 26590812 TI - Non-invasive Assessment of Lower Limb Geometry and Strength Using Hip Structural Analysis and Peripheral Quantitative Computed Tomography: A Population-Based Comparison. AB - Hip fracture is the most significant complication of osteoporosis in terms of mortality, long-term disability and decreased quality of life. In the recent years, different techniques have been developed to assess lower limb strength and ultimately fracture risk. Here we examine relationships between two measures of lower limb bone geometry and strength; proximal femoral geometry and tibial peripheral quantitative computed tomography. We studied a sample of 431 women and 488 men aged in the range 59-71 years. The hip structural analysis (HSA) programme was employed to measure the structural geometry of the left hip for each DXA scan obtained using a Hologic QDR 4500 instrument while pQCT measurements of the tibia were obtained using a Stratec 2000 instrument in the same population. We observed strong sex differences in proximal femoral geometry at the narrow neck, intertrochanteric and femoral shaft regions. There were significant (p < 0.001) associations between pQCT-derived measures of bone geometry (tibial width; endocortical diameter and cortical thickness) and bone strength (strength strain index) with each corresponding HSA variable (all p < 0.001) in both men and women. These results demonstrate strong correlations between two different methods of assessment of lower limb bone strength: HSA and pQCT. Validation in prospective cohorts to study associations of each with incident fracture is now indicated. PMID- 26590813 TI - ESR1 and ESR2 polymorphisms in the BIG 1-98 trial comparing adjuvant letrozole versus tamoxifen or their sequence for early breast cancer. AB - Estrogen receptor 1 (ESR1) and ESR2 gene polymorphisms have been associated with endocrine-mediated physiological mechanisms, and inconsistently with breast cancer risk and outcomes, bone mineral density changes, and hot flushes/night sweats. DNA was isolated and genotyped for six ESR1 and two ESR2 single nucleotide polymorphisms (SNPs) from tumor specimens from 3691 postmenopausal women with hormone receptor-positive breast cancer enrolled in the BIG 1-98 trial to receive tamoxifen and/or letrozole for 5 years. Associations with recurrence and adverse events (AEs) were assessed using Cox proportional hazards models. 3401 samples were successfully genotyped for five SNPs. ESR1 rs9340799(XbaI) (T>C) variants CC or TC were associated with reduced breast cancer risk (HR = 0.82,95% CI = 0.67-1.0), and ESR1 rs2077647 (T>C) variants CC or TC was associated with reduced distant recurrence risk (HR = 0.69, 95% CI = 0.53-0.90), both regardless of the treatments. No differential treatment effects (letrozole vs. tamoxifen) were observed for the association of outcome with any of the SNPs. Letrozole-treated patients with rs2077647 (T>C) variants CC and TC had a reduced risk of bone AE (HR = 0.75, 95% CI = 0.58-0.98, P interaction = 0.08), whereas patients with rs4986938 (G>A) genotype variants AA and AG had an increased risk of bone AE (HR = 1.37, 95% CI = 1.01-1.84, P interaction = 0.07). We observed that (1) rare ESR1 homozygous polymorphisms were associated with lower recurrence, and (2) ESR1 and ESR2 SNPs were associated with bone AEs in letrozole treated patients. Genes that are involved in estrogen signaling and synthesis have the potential to affect both breast cancer recurrence and side effects, suggesting that individual treatment strategies can incorporate not only oncogenic drivers but also SNPs related to estrogen activity. PMID- 26590814 TI - Simvastatin prevents triple-negative breast cancer metastasis in pre-clinical models through regulation of FOXO3a. AB - We previously reported using statins was correlated with improved metastasis-free survival in aggressive breast cancer. The purpose of this study was to examine the effect of statins on metastatic colonization by triple-negative breast cancer (TNBC) cells. TNBC cell lines were treated with simvastatin and then studied for cell cycle progression and proliferation in vitro, and metastasis formation in vivo, following injection of statin-treated cells. Reverse-phase protein assay (RPPA) analysis was performed on statin-treated and control breast cancer cells. RNA interference targeting FOXO3a was used to measure the impact of simvastatin on FOXO3a-expressing cells. The prognostic value of FOXO3a mRNA expression was examined in eight public breast cancer gene expression datasets including 1479 patients. Simvastatin increased G1/S-phase arrest of the cell cycle and inhibited both proliferation and migration of TNBC cells in vitro. In vitro pre-treatment and in vivo treatment with simvastatin reduced metastases. Phosphorylated FOXO3a was downregulated after simvastatin treatment in (RPPA) analysis. Ectopic expression of FOXO3a enhanced mammosphere formation and migratory capacity in vitro. Knockdown of FOXO3a attenuated the effect of simvastatin on mammosphere formation and migration. Analysis of public gene expression data demonstrates FOXO3a mRNA downregulation was independently associated with shorter metastasis free survival in all breast cancers, as well as in TNBC breast cancers. Simvastatin inhibits in vitro endpoints associated with metastasis through a FOXO3a mechanism and reduced metastasis formation in vivo. FOXO3a expression is prognostic for metastasis formation in patient data. Further investigation of simvastatin as a cancer therapy is warranted. PMID- 26590815 TI - Health care workers in Pearl River Delta Area of China are not vaccinated adequately against hepatitis B: a retrospective cohort study. AB - BACKGROUNDS: Health-care workers' (HCWs) exposure to bodily fluids puts them at risk of hepatitis B virus HBV infection. This study investigated HBV vaccination practices and outcomes in HCWs and assessed postvaccination seroprotection across HCWs in different departments. METHODS: A survey of HCWs in a Chinese public general hospital was carried out with a retrospective cohort of 1420 hospital HCWs (458 males and 962 females). HBV vaccination status (10-MUg/dose used) was investigated in the cohort from vaccination records from the period of 1988 to 2008. Blood samples were collected and tested for hepatitis B surface antigen (HBsAg) and HBV antibodies (anti-HBs). RESULTS: The overall vaccination (complete course) and HBsAg carrier rates among HCWs were 40.42 % (574/1420) and 6.13 % (87/1420), respectively. Vaccination rates differed by department, with HCWs in internal medicine (39.5 %) and emergency (42.0 %) departments having particularly low rates. The natural infection rate was 7.53 % (107/1420) among HCWs. HCWs in the department of infectious diseases (vaccination rate, 57.8 %) had the highest rate of antibody produced by natural infection (88.2 %). CONCLUSION: The vaccination rate was a disappointingly low among HCWs in Pearl River Delta Area of China. HCWs working in infectious diseases departments and technicians were at particularly likely to have been infected with HBV. A concerted effort is needed to bring vaccination rates up among Chinese HCWs in Pearl River Delta Area of southern China. PMID- 26590816 TI - Pediatric incidental appendectomy: a systematic review. AB - Incidental appendectomy is the removal of the vermiform appendix accompanying another operation, without evidence of acute appendicitis. It is generally performed to eliminate the risk of future appendicitis. The risks and benefits of incidental appendectomy during various operations in children have been debated for over a century, but need to be revisited in light of innovations in medical practice, including minimally invasive surgery, improved imaging techniques, and use of the appendix as a tubular conduit for reconstruction. A detailed review was undertaken of the techniques, pathology, risks of appendectomy, utility of the appendix, and incidental appendectomy in the treatment of specific pediatric medical conditions. A comprehensive literature search was performed, and retrieved results were reviewed for relevance to the topic. The decision to perform a pediatric incidental appendectomy relies on informed consideration of the individual patient's co-morbid conditions, the indication for the initial operation, the future utility of the appendix, and the risk of future appendiceal pathology. The discussion includes a variety of situations and comorbid conditions that may influence a surgeon's decision to perform incidental appendectomy. PMID- 26590817 TI - Analysis of clinical features and outcomes for inflammatory myofibroblastic tumors in China: 11 years of experience at a single center. AB - PURPOSE: Inflammatory myofibroblastic tumor (IMT) is a rare benign neoplasm. The purpose of this study was to review the clinical characteristics, imaging and pathological features, and outcomes of children with IMTs from a single center in China. METHODS: A retrospective file review was conducted involving 23 cases of pathologically confirmed IMTs treated at the Children's Hospital between April 2003 and April 2014. RESULTS: The tumor locations included multiple anatomic sites, as follows: abdomen or pelvis (n = 17); lungs (n = 2); head and neck (n = 1); trunk (n = 1); and extremities (n = 2). The tumors were associated with various clinical presentations. The predominant symptoms included an anemic appearance, fevers, and an asymptomatic mass. Computed tomography scanning showed solid, heterogeneous, well-demarcated masses; the appearance of enhancement was variable. MRI appeared hypointense on T1-weighted images and hypointense or hyperintense on T2-weighted images. Immunohistochemical staining revealed anaplastic lymphoma kinase was negative in 11 of 13 cases tested. One patient quit treatment for the unresectable mass after biopsy and died 2 years later, and another patient with incompletely resection is alive at 30 months following chemotherapy. The remaining 21 cases had complete resections; one patient died due to a recurrence, and the other 20 patients survived and were tumor free. The follow-up ranged from 7 to 141 months, with a mean of 56 months. The 3-year OS was 88 % (95 % CI, 57-97 %). CONCLUSIONS: IMT is a benign neoplasm that rarely presents with malignant features. Complete resection is curative in most patients. ALK+ is variable for diagnosis. Close follow-up is necessary for patients who undergo surgical resection. PMID- 26590818 TI - Steroids after the Kasai procedure for biliary atresia: the effect of age at Kasai portoenterostomy. AB - The use of adjuvant steroids following Kasai porteoenterostomy (KPE) for biliary atresia is controversial. The aim of this study was twofold: a systematic review of published literature and an update of the clinical Kings College Hospital series to look for evidence of an effect of age on the outcome in a group of BA infants treated with high-dose steroids. This clinical study included infants treated between January 2006 and June 2014 who underwent KPE by day 70 of life and who received high-dose steroids (oral prednisolone starting 5 mg/kg/day). They were subdivided into cohorts according to age at which KPE was performed. The outcome measured was clearance of jaundice (<20 umol/L) by 6 months and native liver survival. R * C chi(2) analysis and log-rank tests were used, respectively, and P <= 0.05 was regarded as significant. 104 infants were included with a median age at KPE of 45 (range 12-70) days. 71/104 (67 %) cleared their jaundice by 6 months of age. Age-cohort analysis showed a trend (P = 0.03) favouring early KPE (e.g. 100 % of 11 infants operated on <30 days clearing their jaundice compared to 66 % of those operated on between 61 and 70 days). There was a significant native liver survival benefit for those operated on <45 days (5 year NLS estimate 69 versus 46 %; P = 0.05). Clearance of jaundice is related to the age at KPE in infants who receive high-dose steroids. Native liver survival appears to be improved as a result of this. This is the first study to show tangible longer-term benefit from high-dose steroids in biliary atresia. PMID- 26590819 TI - Successful minimally invasive surgery for primary hyperparathyroidism: influence of preoperative imaging and intraoperative parathyroid hormone levels. AB - PURPOSE: Adenoma is the main parathyroid disorder leading to primary hyperparathyroidism (PHP). Minimally invasive parathyroidectomy (MIP) is recognized as a valid procedure for adenoma-related PHP. It requires precise preoperative localization combining Tc-99m-MIBI (methoxy-isobutyl-isonitrile) scintigraphy and single-photon emission computed tomography (SPECT) with x-ray computed tomography (CT) and intraoperative confirmation of successful excision by change in intact parathormone (iPTH) levels. The study aim was to assess the surgery success in relation to these two parameters. METHODS: All patients operated on for PHP from 2005 to mid-2014 at our institution were retrospectively reviewed. MIP was performed in case of precise preoperative adenoma localization on scintigraphy, absence of past cervical surgery, and absence of concomitant thyroid resection necessity. In these patients, iPTH levels were monitored intraoperatively. Confirmation criteria for iPTH values were a return to normal level or a decrease >50 % of basal iPTH level. RESULTS: There were 197 PHP operations during the study period: 118 MIP and 79 bilateral neck explorations (BNEs). The MIP success rate was 95 % (112/118) with a preoperative MIBI scan +/- CT accurate in 94 % (111/118) of the patients and with correct iPTH in 90 % (106/118) of the cases. Among the 12 iPTH levels that did not meet the confirmation criteria, 10 returned to normal range by postoperative day 2. Treatment failure appeared in three patients (one BNE, two MIPs). CONCLUSIONS: Tc 99m-MIBI dual-phase scintigraphy with SPECT/CT is the key examination for functional and morphological parathyroid adenoma localization. If preoperative scintigraphy is obvious and intraoperative assessment is clear, one could possibly safely omit iPTH, as it may lead to unnecessary BNE in primary PHP. PMID- 26590820 TI - Detoxification and antioxidant effects of garlic and curcumin in Oreochromis niloticus injected with aflatoxin B1 with reference to gene expression of glutathione peroxidase (GPx) by RT-PCR. AB - The present study aims to investigate the effects of both garlic and curcumin through evaluating their therapeutic properties as antioxidants on liver and kidney functions, hepatic antioxidants and GPx gene expression against aflatoxicosis of O. niloticus. In total, 180 of tilapia were divided into ten groups; T1 represented the negative control fed on a basal diet, and T2 was injected with a single intraperitoneal (i.p.) dose of AFB1 (6 mg/kg b.w.). Fish in T3-T6 were fed on a basal diet supplemented with both garlic (T3 and T4) and curcumin (T5 and T6) at the two concentrations of 10 and 20 g/kg diet, respectively. Fish in T7-T10 groups were injected with AFB1 and fed on the garlic (T7 and T8) and curcumin (T9 and T10) dietaries. The results showed that AFB1 has significant potency for increasing the activity of plasma AST, ALT, creatinine and uric acid values, and hepatic MDA as well as for reducing the concentrations of plasma TP, AL, GL and hepatic activity of TAC, while AFB1 led to up-regulated GPx gene expression when compared to the control (T1). These harmful effects of AFB1 were alleviated due to the garlic and curcumin dietaries in some studied parameters. Garlic reflected the highest induction of gene expression (T7); however, curcumin showed significant down-regulated (T9). These results concluded that the effects of garlic were better than curcumin at the two concentrations and the low concentration of them is more beneficial than the high concentration when it used against AFB1 in O. niloticus. PMID- 26590821 TI - Determination of IL1 R2, ANTXR2, CARD9, and SNAPC4 single nucleotide polymorphisms in Iranian patients with ankylosing spondylitis. AB - Ankylosing spondylitis (AS) is a chronic inflammatory disease of unknown origin, while both genetic and environmental factors have been demonstrated to be etiologically involved. Recent genome-wide association and replication studies have suggested that anthrax toxin receptor 2 (ANTXR2), interleukin-1 receptor 2 (IL1R2), caspase recruitment domain-containing protein 9 (CARD9), and small nuclear RNA-activating complex polypeptide 4 (SNAPC4) seem to be associated with AS pathogenesis. This case-control study was performed on 349 unrelated AS patients and 469 age- and gender-matched healthy controls, to investigate whether these non-MHC genes (IL1R2 rs2310173, ANTXR2 rs4333130, CARD9 rs4077515, and SNAPC4 rs3812571) influence the AS risk in Iranian population. ANTXR2 rs4333130 allele C (p = 0.0328; OR 0.744, 95% CI 0.598-0.927) and genotype CC (p = 0.0108; OR 0.273, 95% CI 0.123-0.605) were found to be significantly protective against AS. No other associations were found between AS and studied genes. The association between ANTXR2 rs4333130 and AS was independent of HLA-B27 status. Moreover, we found clinical disease severity scores (BASDAI and BASFI) and pain score were higher in ANTXR2 rs4333130 CT genotype. However, we observed that CARD9 allele C (p = 0.012) and genotype CC (p = 0.012) were significant protective factors against AS only in HLA-B27-negative patients, and IL1R2 rs2310173 genotype GT was mildly protective against AS only in HLA-B27-negative status. These findings support the role of non-MHC pathogenic pathways in susceptibility to AS and warrants more comprehensive studies focusing on these non-MHC pathways for developing novel therapeutic strategies. PMID- 26590823 TI - Generation of airway epithelial cells with native characteristics from mouse induced pluripotent stem cells. AB - Airway epithelial cells derived from induced pluripotent stem (iPS) cells are expected to be a useful source for the regeneration of airway epithelium. Our preliminary study of embryoid body (EB) formation and the air-liquid interface (ALI) method suggested that mouse iPS cells can differentiate into airway epithelial cells. However, whether the cells generated from mouse iPS cells had the character and phenotype of native airway epithelial cells remained uninvestigated. In this study, we generated airway epithelial cells from EBs by culturing them under serum-free conditions supplemented with Activin and bFGF and by the ALI method and characterized the iPS cell-derived airway epithelial cells in terms of their gene expression, immunoreactivity, morphology, and function. Analysis by quantitative real-time reverse transcription-polymerase chain reaction(RT-PCR) revealed that the expression of the undifferentiated cell marker Nanog decreased time-dependently after the induction of differentiation, whereas definitive endoderm markers Foxa2 and Cxcr4 were transiently up-regulated. Thereafter, the expression of airway epithelium markers such as Tubb4a, Muc5ac, and Krt5 was detected by RT-PCR and immunostaining. The formation of tight junctions was also confirmed by immunostaining and permeability assay. Analysis by hematoxylin and eosin staining and scanning electron microscopy indicated that the cells generated from mouse iPS cells formed airway-epithelium-like tissue and had cilia, the movement of which was visualized and observed to be synchronized. These results demonstrate that the airway epithelial cells generated by our method have native characteristics and open new perspectives for the regeneration of injured airway epithelium. PMID- 26590824 TI - Expression and localization of GPR91 and GPR99 in murine organs. AB - Energy substrates and metabolic intermediates are proven ligands of a growing number of G-protein coupled receptors. In 2004, GPR91 and GPR99 were identified as receptors for the citric acid cycle intermediates, succinate and alpha ketoglutarate, respectively. GPR91 seems to act as a first responder to local stress and GPR99 participates in the regulation of the acid-base balance through an intrarenal paracrine mechanism. However, a systematic analysis of the distribution of both receptors in mouse organs is still missing. The aim of this study was to examine the expression of GPR91 and GPR99 in a large number of different murine organs both at mRNA and protein level. Whereas GPR91 mRNA was detectable in almost all organs, GPR99 mRNA was mainly expressed in neuronal tissues. Widespread expression of GPR91 was also detected at the protein level by western blotting and immunohistochemistry. In addition to neuronal cells, GPR99 protein was found in renal intercalated cells and epididymal narrow cells. Double labeling immunohistochemistry demonstrated the colocalization of GPR99 with the B1 subunit isoform of vacuolar H(+)-ATPases which is expressed only by a very limited number of cell types. In summary, our detailed expression analysis of GPR91 and GPR99 in murine tissues will allow a more directed search for additional functions of both receptors. PMID- 26590825 TI - The effect of water suppression on the hepatic lipid quantification, as assessed by the LCModel, in a preclinical and clinical scenario. AB - OBJECTIVE: To investigate the effect of water suppression on the hepatic lipid quantification, using the LCModel. MATERIALS AND METHODS: MR spectra with and without water suppression were acquired in the liver of mice at 4.7 T and patients at 3 T, and processed with the LCModel. The Cramer-Rao Lower Bound (CRLB) values of the seven lipid resonances were determined to assess the impact of water suppression on hepatic lipid quantification. A paired t test was used for comparison between the CRLBs obtained with and without water suppression. RESULTS: For the preclinical data, in the high (low) fat fraction subset an overall impairment in hepatic lipid quantification, i.e. an increase of CRLBs (no significant change of CRLBs) was observed in spectra acquired with water suppression. For the clinical data, there were no substantial changes in the CRLB with water suppression. Because (1) the water suppression does not overall improve the quantification of the lipid resonances and (2) the MR spectrum without water suppression is always acquired for fat fraction calculation, the optimal data-acquisition strategy for liver MRS is to acquire only the MR spectrum without water suppression. CONCLUSION: For quantification of hepatic lipid resonances, it is advantageous to perform MR spectroscopy without water suppression in a clinical and preclinical scenario (at moderate fields). PMID- 26590826 TI - No Sex or Age Difference in Dead-Reckoning Ability among Tsimane Forager Horticulturalists. AB - Sex differences in reproductive strategy and the sexual division of labor resulted in selection for and maintenance of sexual dimorphism across a wide range of characteristics, including body size, hormonal physiology, behavior, and perhaps spatial abilities. In laboratory tasks among undergraduates there is a general male advantage for navigational and mental-rotation tasks, whereas studies find female advantage for remembering item locations in complex arrays and the locations of plant foods. Adaptive explanations of sex differences in these spatial abilities have focused on patterns of differential mate search and routine participation in distinct subsistence behaviors. The few studies to date of spatial ability in nonindustrial populations practicing subsistence lifestyles, or across a wider age range, find inconsistent results. Here we examine sex- and age-based variation in one kind of spatial ability related to navigation, dead-reckoning, among Tsimane forager horticulturalists living in lowland Bolivia. Seventy-three participants (38 male) aged 6-82 years pointed a handheld global positioning system (GPS) unit toward the two nearest communities and the more distant market town. We find no evidence of sex differences in dead reckoning (p = 0.47), nor do we find any evidence of age-related decline in dead reckoning accuracy (p = 0.28). Participants were significantly more accurate at pointing toward the market town than toward the two nearest villages despite its being significantly farther away than the two nearest communities. Although Tsimane do show sexual dimorphism in foraging tasks, Tsimane women have extensive daily and lifetime travel, and the local environment lacks directional cues that typically enhance male navigation. This study raises the possibility that greater similarity in mobility patterns because of overlapping subsistence strategies and activities may result in convergence of some male and female navigation abilities. PMID- 26590827 TI - Studies on Absorption and Emission Characteristics of Inclusion Complexes of Some 4-Arylidenamino-5-phenyl-4H-1, 2, 4-triazole-3-thiols. AB - The inclusion complexes of a series of 4-arylidenamino-5-phenyl-4H-1, 2, 4 triazole-3-thiols have been prepared with beta-cyclodextrin. The compounds and their inclusion complexes have been characterized by studying their physical and spectral properties. The thermodynamic stability constant and free energy of activation have been determined to know the stability of inclusion complexes and type of host-guest relation. Finally, absorption, excitation and emission spectra of the compounds (4-arylidenamino-5-phenyl-4H-1, 2, 4-triazole-3-thiols) and their inclusion complexes have been taken. It is found that inclusion complex formation brings about a drastic change in absorption and fluorescence characteristic (both excitation and emission spectra) of newly synthesized compounds. PMID- 26590828 TI - Type 2 autoimmune pancreatitis: case report of a 9-year-old female and a review of the literature. AB - We report a case of autoimmune pancreatitis in a 9-year-old female who presented with persistent epigastric pain for 3 weeks. Magnetic resonance cholangiopancreatography (MRCP) showed both intrahepatic and extrahepatic biliary ductal dilatation. The common bile duct, along with the pancreatic duct, was noted to be dilated. Labs showed normal IgG and IgG4 levels and negative for autoimmune antibodies. Endoscopic ultrasound revealed the pancreatic head to be enlarged and surrounded by hypoechoic and lobulated lymph nodes. Biopsy of the pancreatic head showed chronic mildly active inflammation with fibrosis, acinar atrophy, and lymphocytic infiltrate. A diagnosis of autoimmune pancreatitis (AIP) was made, and she was treated with prednisone. The patient's symptoms improved quickly, and follow-up MRCP showed resolution of inflammatory changes and intrahepatic and pancreatic ductal dilatation. PMID- 26590822 TI - Chromosomal instability in mammalian pre-implantation embryos: potential causes, detection methods, and clinical consequences. AB - Formation of a totipotent blastocyst capable of implantation is one of the first major milestones in early mammalian embryogenesis, but less than half of in vitro fertilized embryos from most mammals will progress to this stage of development. Whole chromosomal abnormalities, or aneuploidy, are key determinants of whether human embryos will arrest or reach the blastocyst stage. Depending on the type of chromosomal abnormality, however, certain embryos still form blastocysts and may be morphologically indistinguishable from chromosomally normal embryos. Despite the implementation of pre-implantation genetic screening and other advanced in vitro fertilization (IVF) techniques, the identification of aneuploid embryos remains complicated by high rates of mosaicism, atypical cell division, cellular fragmentation, sub-chromosomal instability, and micro-/multi-nucleation. Moreover, several of these processes occur in vivo following natural human conception, suggesting that they are not simply a consequence of culture conditions. Recent technological achievements in genetic, epigenetic, chromosomal, and non-invasive imaging have provided additional embryo assessment approaches, particularly at the single-cell level, and clinical trials investigating their efficacy are continuing to emerge. In this review, we summarize the potential mechanisms by which aneuploidy may arise, the various detection methods, and the technical advances (such as time-lapse imaging, " omic" profiling, and next-generation sequencing) that have assisted in obtaining this data. We also discuss the possibility of aneuploidy resolution in embryos via various corrective mechanisms, including multi-polar divisions, fragment resorption, endoreduplication, and blastomere exclusion, and conclude by examining the potential implications of these findings for IVF success and human fecundity. PMID- 26590829 TI - Immune-modulating properties of ionizing radiation: rationale for the treatment of cancer by combination radiotherapy and immune checkpoint inhibitors. AB - Radiotherapy (RT) utilizes the DNA-damaging properties of ionizing radiation to control tumor growth and ultimately kill tumor cells. By modifying the tumor cell phenotype and the tumor microenvironment, it may also modulate the immune system. However, out-of-field reactions of RT mostly assume further immune activation. Here, the sequence of the applications of RT and immunotherapy is crucial, just as the dose and fractionation may be. Lower single doses may impact on tumor vascularization and immune cell infiltration in particular, while higher doses may impact on intratumoral induction and production of type I interferons. The induction of immunogenic cancer cell death seems in turn to be a common mechanism for most RT schemes. Dendritic cells (DCs) are activated by the released danger signals and by taking up tumor peptides derived from irradiated cells. DCs subsequently activate T cells, a process that has to be tightly controlled to ensure tolerance. Inhibitory pathways known as immune checkpoints exist for this purpose and are exploited by tumors to inhibit immune responses. Cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) on T cells are two major checkpoints. The biological concepts behind the findings that RT in combination with anti-CTLA-4 and/or anti-PD-L1 blockade stimulates CD8+ T cell-mediated anti-tumor immunity are reviewed in detail. On this basis, we suggest clinically significant combinations and sequences of RT and immune checkpoint inhibition. We conclude that RT and immune therapies complement one another. PMID- 26590830 TI - Romantic Relationship Experiences from Late Adolescence to Young Adulthood: The Role of Older Siblings in Mexican-Origin Families. AB - Youth's experiences with romantic relationships during adolescence and young adulthood have far reaching implications for future relationships, health, and well-being; yet, although scholars have examined potential peer and parent influences, we know little about the role of siblings in youth's romantic relationships. Accordingly, this study examined the prospective longitudinal links between Mexican-origin older and younger siblings' romantic relationship experiences and variation by sibling structural and relationship characteristics (i.e., sibling age and gender similarity, younger siblings' modeling) and cultural values (i.e., younger siblings' familism values). Data from 246 Mexican origin families with older (M = 20.65 years; SD = 1.57; 50 % female) and younger (M = 17.72 years; SD = .57; 51 % female) siblings were used to examine the likelihood of younger siblings' involvement in dating relationships, sexual relations, cohabitation, and engagement/marriage with probit path analyses. Findings revealed older siblings' reports of involvement in a dating relationship, cohabitation, and engagement/marriage predicted younger siblings' relationship experiences over a 2-year period. These links were moderated by sibling age spacing, younger siblings' reports of modeling and familism values. Our findings suggest the significance of social learning dynamics as well as relational and cultural contexts in understanding the links between older and younger siblings' romantic relationship experiences among Mexican-origin youth. PMID- 26590833 TI - Mitigating effect of Indian propolis against mitomycin C induced bone marrow toxicity. AB - A major drawback with cancer chemotherapy is its severe toxic effects on non target tissues. Assessment of natural products for their protective effect against anticancer drugs-induced toxicity is gaining importance in cancer biology. The present study was aimed at assessing the protective effect of hydroethanolic extract of Indian propolis (HEIP) against mitomycin C (MMC) induced genotoxicity and cytotoxicity. Swiss albino mice were injected with various doses of HEIP (100, 200, 300, 400, 600 and 800 mg/kg b. wt., i.p) 1 h prior to MMC (8 mg/kg, i.p.) injection. The geno- and cyto-toxicities were evaluated in mice by performing bone marrow micronucleus and TUNEL assays. In vitro antioxidant and lipid peroxidation inhibitory assays were carried out to understand the mechanism of the protective effects. The significant increase in the frequency of micronculeated cells (12.51 +/- 0.48), apoptotic cells (23.43 +/ 1.86) and reduction in P/N ratio (0.69 +/- 0.04) compared with control indicated the potential geno- and cytotoxic effects of MMC in bone marrow. Pretreatment with HEIP resulted in the significant recovery of the toxic effects induced by MMC. HEIP at 400 mg/kg b. wt. was found to be the optimum dose imparting the maximum protective effects. The in vitro antioxidant and lipid peroxidation inhibitory assays suggest that the extract possesses substantial free radical scavenging activities. In conclusion, HEIP possesses substantial geno- and cyto protective properties against MMC, which could be mediated through efficient free radical scavenging and inhibitory effect on lipid peroxidation. PMID- 26590832 TI - Interactions between benign prostatic hyperplasia (BPH) and prostate cancer in large prostates: a retrospective data review. AB - PURPOSE: To study the interaction between benign prostatic hyperplasia (BPH) and prostate cancer (PCa). METHODS: In this study, we performed a chart review of a cohort of 448 biopsy naive men. These men received a multi-core biopsy at our institution due to increased prostate-specific antigen (PSA) serum levels (>4 ng/ml) and/or suspicious findings on digital rectal examination in the years between 2008 and 2013. Utilizing PSA and transrectal ultrasound (TRUS) prostate volume, we obtained the PSA density (PSAD) for each individual. PSAD was calculated by dividing serum PSA concentration by TRUS prostate volume. RESULTS: Large prostates >65 g may secrete enough PSA to have a PSAD above the suggested cutoff of 0.15, yet 50 % patients have no histologic evidence of PCa, whereas prostates <35 g and an elevated PSAD of above 0.15 will have histologic evidence of PCa 70 % of the time. CONCLUSIONS: These results suggest that BPH in large prostates may be protective of PCa. The interaction of the different prostate zones, in particular the transition zone and peripheral zone, may play a significant role in the phenomenon observed in this study. However, sampling error may introduce bias that 12-16 core biopsies in larger prostates may be more likely missing the cancer lesion. PMID- 26590834 TI - Identification of a gene involved in the biosynthesis pathway of the terminal sugar of the archaellin N-linked tetrasaccharide in Methanococcus maripaludis. AB - In Methanococcus maripaludis, the three archaellins which comprise the archaellum are modified at multiple sites with an N-linked tetrasaccharide with the structure of Sug-4-beta-ManNAc3NAmA6Thr-4-beta-GlcNAc3NAcA-3-beta-GalNAc, where Sug is a unique sugar (5S)-2-acetamido-2,4-dideoxy-5-O-methyl-L-erythro-hexos-5 ulo-1,5-pyranose, so far found exclusively in this species. In this study, a six gene cluster mmp1089-1094, neighboring one of the genomic regions already known to contain genes involved with the archaellin N-glycosylation pathway, was examined for its potential involvement in the archaellin N-glycosylation or sugar biosynthesis pathway. The co-transcription of these six genes was demonstrated by RT-PCR. Mutants carrying an in-frame deletion in mmp1090, mmp1091 or mmp1092 were successfully generated. The Deltammp1090 deletion mutant was archaellated when examined by electron microscopy and mass spectrometry analysis of purified archaella showed that the archaellins were modified with a truncated N-glycan in which the terminal sugar residue and the threonine linked to the third sugar residue were missing. Both gene annotation and bioinformatic analyses indicate that MMP1090 is a UDP-glucose 4-epimerase, suggesting that the unique terminal sugar of the archaellin N-glycan might be synthesised from UDP-glucose or UDP-N acetylglucosamine with an essential early step in synthesis catalysed by MMP1090. In contrast, no detectable phenotype related to archaellin glycosylation was observed in mutants deleted for either mmp1091 or mmp1092 while attempts to delete mmp1089, mmp1093 and mmp1094 were unsuccessful. Based on its demonstrated involvement in the archaellin N-glycosylation pathway, we designated mmp1090 as aglW. PMID- 26590835 TI - Editorial Comments to the Special Issue of Neuropsychology Review on the Basic Neuroscience and Neuropsychology of Selective Movement Disorders. PMID- 26590836 TI - Psychiatric Comorbidity in Alcohol Dependence. AB - We review our clinical studies of psychiatric comorbidity in short-term and long term abstinent and in treatment naive alcoholics (STAA, LTAA and TNA). TNA ypically have less severe alcoholism than treated abstinent samples and evidence less severe psychiatric disturbance. Lifetime psychiatric diagnoses are the norm for STAA and LTAA but not for TNA. Individuals with alcohol and drug use disorders show greater antisocial personality disturbance, but do not show differences in the mood or anxiety domains or in borderline personality disorder (BPD) symptoms. The studies show that alcoholics can achieve and maintain abstinence in the face of ongoing mood, anxiety, or BPD problems. By contrast, for ASPD, LTAA essentially stop current antisocial behaviors in all seven domains of antisocial behaviors. We believe that ongoing antisocial behavior is not consistent with maintaining abstinence, and that LTAA modify their antisocial behavior despite continued elevated social deviance proneness and antisocial dispositionality. Abstinent individuals without lifetime psychiatric disorders and TNA show more (subdiagnostic threshold) psychiatric symptoms and abnormal psychological measures than non-alcoholic controls in the mood, anxiety, BPD, and antisocial domains. In summary, our studies show that although LTAA have achieved multi-year abstinence, they still report significant psychological distress compared to NAC. We believe this distress may negatively affect their quality of life. This suggests the importance of developing effective care models to address comorbid mental health problems in LTAA. We also show that antisocial personality disorder symptoms decline to the levels seen in normal controls, and that excluding individuals from research with a psychiatric diagnosis does not control for subdiagnostic psychiatric differences between alcoholics and controls. PMID- 26590837 TI - Gender differences in the impact of mental disorders and chronic physical conditions on health-related quality of life among non-demented primary care elderly patients. AB - PURPOSE: This paper aims to estimate the comorbidity of mental disorders and chronic physical conditions and to describe the impact of these conditions on health-related quality of life (HRQoL) in a sample of older primary care (PC) attendees by gender. METHODS: Cross-sectional survey, conducted in 77 PC centres in Catalonia (Spain) on 1192 patients over 65 years old. Using face-to-face interviews, we assessed HRQoL (SF-12), mental disorders (SCID and MINI structured clinical interviews), chronic physical conditions (checklist), and disability (Sheehan disability scale). We used multivariate quantile regressions to model which factors were associated with the physical component summary-short form 12 and mental component summary-short form 12. RESULT: The most frequent comorbidity in both men and women was mood disorder with chronic pain and arthrosis. Mental disorders mainly affected 'mental' QoL, while physical disorders affected 'physical' QoL. Mental disorders had a greater impact on HRQoL than chronic physical conditions, with mood and adjustment disorders being the most disabling conditions. There were some gender differences in the impact of mental and chronic physical conditions on HRQoL. Anxiety disorders and pain had an impact on HRQoL but only in women. Respiratory diseases had an effect on the MCS in women, but only affected the PCS in men. CONCLUSIONS: Mood and adjustment disorders had the greatest impact on HRQoL. The impact profile of mental and chronic physical conditions differs between genders. Our results reinforce the need for screening for mental disorders (mainly depression) in older patients in PC. PMID- 26590838 TI - Evaluation of mode equivalence of the MSKCC Bowel Function Instrument, LASA Quality of Life, and Subjective Significance Questionnaire items administered by Web, interactive voice response system (IVRS), and paper. AB - PURPOSE: To assess the equivalence of patient-reported outcome (PRO) survey responses across Web, interactive voice response system (IVRS), and paper modes of administration. METHODS: Postoperative colorectal cancer patients with home Web/e-mail and phone were randomly assigned to one of the eight study groups: Groups 1-6 completed the survey via Web, IVRS, and paper, in one of the six possible orders; Groups 7-8 completed the survey twice, either by Web or by IVRS. The 20-item survey, including the MSKCC Bowel Function Instrument (BFI), the LASA Quality of Life (QOL) scale, and the Subjective Significance Questionnaire (SSQ) adapted to bowel function, was completed from home on consecutive days. Mode equivalence was assessed by comparison of mean scores across modes and intraclass correlation coefficients (ICCs) and was compared to the test-retest reliability of Web and IVRS. RESULTS: Of 170 patients, 157 completed at least one survey and were included in analysis. Patients had mean age 56 (SD = 11), 53% were male, 81% white, 53% colon, and 47% rectal cancer; 78% completed all assigned surveys. Mean scores for BFI total score, BFI subscale scores, LASA QOL, and adapted SSQ varied by mode by less than one-third of a score point. ICCs across mode were: BFI total score (Web-paper = 0.96, Web-IVRS = 0.97, paper-IVRS = 0.97); BFI subscales (range = 0.88-0.98); LASA QOL (Web-paper = 0.98, Web-IVRS = 0.78, paper-IVRS = 0.80); and SSQ (Web-paper = 0.92, Web-IVRS = 0.86, paper-IVRS = 0.79). CONCLUSIONS: Mode equivalence was demonstrated for the BFI total score, BFI subscales, LASA QOL, and adapted SSQ, supporting the use of multiple modes of PRO data capture in clinical trials. PMID- 26590839 TI - Depression treatment and health-related quality of life among adults with diabetes and depression. AB - BACKGROUND: Previous findings regarding depression treatment and its consequences on health-related quality of life (HRQoL) of adults with diabetes were inconsistent and targeted certain groups of population. Therefore, there is a critical need to conduct a population-based study that focuses on a general population with diabetes and depression. OBJECTIVE: The primary aim of this study was to examine the physical and mental HRQoL associated with depression treatment during the follow-up year. METHODS: We adopted a longitudinal design using multiple panels (2005-2011) of the Medical Expenditure Panel Survey to create a baseline year and follow-up year. We included adults with diabetes and depression. We categorized the baseline depression treatment into: (1) antidepressant use only; (2) psychotherapy with or without antidepressants; and (3) no treatment. HRQOL was measured using SF-12 version 2 physical component summary (PCS) and SF-12 mental component summary (MCS) scores during both baseline year and follow-up year. Ordinary least squares (OLS) were used to estimate the association between depression treatment and the HRQoL measures. The OLS regression controlled for predisposing, enabling, need, external environment factors, personal health practices, and baseline HRQoL measures. RESULTS: After controlling for all the independent variables and the baseline PCS, individuals who received psychotherapy with or without antidepressants had higher PCS scores as compared to those without any treatment for depression (beta = 1.28, p < 0.001). Individuals who reported using only antidepressants had lower PCS scores (beta = -0.54, p < 0.001) as compared to those without depression treatment. On the contrary, individuals who reported receiving psychotherapy with or without antidepressants had lower MCS scores as compared to those without depression treatment (beta = -1.43, p < 0.001). Those using only antidepressants had higher MCS scores as compared to those without depression treatment (beta = 0.56, p < 0.001). CONCLUSION: The associations between depression treatment and the HRQoL varied by the type of depression treatment and the component of the HRQoL measures. PMID- 26590840 TI - Identification of the methyltransferase targeting C2499 in Deinococcus radiodurans 23S ribosomal RNA. AB - The bacterium Deinococcus radiodurans-like all other organisms-introduces nucleotide modifications into its ribosomal RNA. We have previously found that the bacterium contains a Carbon-5 methylation on cytidine 2499 of its 23S ribosomal RNA, which is so far the only modified version of cytidine 2499 reported. Using homology search, we identified the open reading frame DR_0049 as the primary candidate gene for the methyltransferase that modifies cytidine 2499. Mass spectrometric analysis demonstrated that recombinantly expressed DR0049 protein methylates E. coli cytidine 2499 both in vitro and in vivo. We also inactivated the DR_0049 gene in D. radiodurans through insertion of a chloramphenicol resistance cassette. This resulted in complete absence of the cytidine 2499 methylation, which all together demonstrates that DR_0049 encodes the methyltransferase producing m(5)C2499 in D. radiodurans 23S rRNA. Growth experiments disclosed that inactivation of DR_0049 is associated with a severe growth defect, but available ribosome structures show that cytidine 2499 is positioned very similar in D. radiodurans harbouring the modification and E. coli without the modification. Hence there is no obvious structure-based explanation for the requirement for the C2499 posttranscriptional modification in D. radiodurans. PMID- 26590841 TI - Treadmill exercise tests in persons with Parkinson's disease: responses and disease severity. AB - BACKGROUND AND AIMS: There is a paucity of information on cardiovascular responses with regard to the disease stage of Parkinson's disease (PD) when using an exercise test. Our purpose was to examine whether cardiovascular responses to the treadmill exercise test differed among persons with PD who have different disease severity. METHODS: Forty-five subjects with PD were studied (34 men and 11 women). The subjects underwent a treadmill exercise test using a modified Bruce protocol. Resting heart rate (HR), resting blood pressure (BP), maximal HR, maximal BP, exercise duration, maximum percentage HR and METs achieved after the treadmill exercise test were studied. RESULTS: Seventeen subjects were in Hoehn and Yahr Staging Scale (HY) 2, 16 were in HY 2.5, and 12 were in HY 3. HR increased significantly in all three stages. Systolic BP increased significantly in the HY 2 and 2.5, but not the HY 3. Diastolic BP did not change in any stage. Resting HR was lower in the HY 2 compared to the HY 3 and resting systolic BP was higher in HY 2 compared to the HY 2.5. The three HY stages were not different in exercise duration, HR and BP responses, maximum percentage HR achieved, and METs achieved. Fatigue was a primary reason to discontinue the test. There were no fall incidents in any of the tests. CONCLUSIONS: Cardiovascular responses to the treadmill exercise test did not vary with disease severity. Treadmill exercise tests were safe to perform in persons with PD. PMID- 26590842 TI - Reverse shoulder arthroplasty in older patients: is it worth it? A subjective functional outcome and quality of life survey. AB - BACKGROUND: Reverse shoulder arthroplasty (RSA) use has largely spread in the last decade. Doubts still exist, however, about its use in the elder population, because of high risk of complications and possibly limited cost-efficiency of the procedure. AIMS: Our work was aimed at defining the subjective outcome, complication and satisfaction rate, and perceived recovery of individual autonomy and quality of life after RSA, in a cohort of patients 79 or more years old at the time of surgery. METHODS: Between 2007 and 2012, 52 patients 79 years old or older received a RSA. In the setting of this study, 27 patients (31 shoulders) were available for clinical evaluation. The ASES score was used for subjective outcome evaluation, while the health-related quality of life was studied with the SF-12 form. An ad hoc questionnaire was used in order to evaluate the satisfaction rate and the recovery in individual autonomy. RESULTS: At 59,3 months mean follow-up, only one patient required revision due to periprosthetic fracture. ASES score attested at 78.2, and SF-12 scores showed values similar to the general age-matched population. Sensible improvement in perceived quality of life was described by 24 patients. When present, comorbidities were associated with lower results. DISCUSSION: RSA outcomes in the elderly are good in terms of function, satisfaction and quality of life recovery. Complications appear primarily linked to age-related conditions and comorbidities show critical association with lower results. CONCLUSIONS: Our study confirms that RSA represents a useful solution for end-stage shoulder disease also in the advanced age population. PMID- 26590843 TI - Structured exercise program prior to major cancer surgery improves cardiopulmonary fitness: a retrospective cohort study. AB - PURPOSE: To determine if cardiopulmonary exercise testing (CPET) was useful in predicting response to exercise in cancer patients preoperatively. A secondary aim was to explore if exercise was associated with improved postoperative outcomes. METHODS: A retrospective cohort study was performed on consecutive cancer patients from 2012 to 2014, referred for exercise prehabilitation and had two CPET preoperatively. RESULTS: Twenty-six patients were analysed. There was a significant overall increase in oxygen uptake at anaerobic threshold (AT) from 10.4 to 11.6 ml kg(-1) min(-1) (DeltaAT = 1.2 +/- 3.0 ml kg(-1) min(-1) [9 %]; p = 0.046); peak oxygen uptake (pVO2) from 16.0 to 17.7 ml kg(-1) min(-1) (DeltapVO2 = 1.7 +/- 2.4 ml kg(-1) min(-1) [9 %]; p = 0.002); and pVO2/BSA from 658 to 726 ml min(-1) m(-2); (DeltapVO2/BSA = 68 +/- 112.3 mL min(-1) m(2) [10 %]; p = 0.004). Fifty percent of patients were responders to exercise, defined as having >10 % increase in AT. Responders had a median increase in AT of 26 % [IQR 7 %, 45 %] with an absolute increase in AT of 2.5 ml kg(-1) min(-1) [IQR 1.1, 3.9] (p = 0.002) and a median increase in pVO2 of 22 % [IQR 11.5, 32.5 %] with an absolute increase in pVO2 of 3.8 ml.kg(-1).min(-1) [IQR 2.0, 5.7] (p < 0.001). Responders were more likely to have a lower baseline AT (9.1 ml kg(-1) min(-1); p = 0.002). CONCLUSIONS: Exercise improved cardiorespiratory fitness prior to major cancer surgery. Not all patients responded the same, with only 50 % of the study cohort being responders to exercise. A low AT, pVO2 and ratio of AT/pVO2 at baseline were good predictors of response to exercise, with a tendency for responders to suffer fewer major postoperative complications. PMID- 26590844 TI - Characteristics and outcomes of patients with advanced cancer evaluated by a palliative care team at an emergency center. A retrospective study. AB - PURPOSE: Patients with advanced cancer may be referred for a palliative care consultation (PC) from a hospital emergency center (EC) or as inpatients. However, research about symptoms and outcomes in patients with advanced cancer who receive PC at the EC is limited. METHODS: We reviewed demographic variables, frequency and intensity of symptoms (using the Edmonton Symptom Assessment Scale (ESAS)), PC interventions, time from admission to PC consultation, hospitalization duration, and discharge destination of 200 advanced cancer patients referred to PC services from the EC ("EC patients") and 200 matched advanced cancer inpatients referred to PC services ("inpatients") from January 1, 2010, through December 31, 2011. RESULTS: The median age for all patients was 56 years (range, 48-64 years); 222 (56 %) patients were female, and 243 (61 %) were white. There were no significant demographic differences between the EC patients and inpatients. The median time from admission to PC was 12 h (range, 7-23 h) for the EC patients and 24 h (24-96 h) for the inpatients (p < 0.0001). For EC patients and inpatients, symptoms at presentation for PC consultation included uncontrolled pain (83 and 45 %, respectively; p < 0.0001), nausea/vomiting/constipation (41 and 19 %, respectively; p < 0.0001), and dyspnea (29 and 19 %, respectively; p = 0.02). The medians and interquartile ranges of baseline symptom intensities for EC patients and inpatients, respectively, were as follows: pain, 7 (5-9) and 5 (2-8) (p < 0.0001); fatigue, 7 (4-8) and 6 (4-8) (p = 0.0517); and sleep, 6 (0-8) and 4 (1-7) (p = 0.1064). At follow-up, improvement was observed in pain (125/238 [53 %]), sleep (59/131 [45 %]), well being (32/82 [39 %]), fatigue (53/139 [38 %]), anxiety (51/132 [39 %]), appetite (46/132 [35 %]), dyspnea (49/160 [31 %]), nausea (52/170 [31 %]), depression (36/123 [29 %]), and drowsiness (37/126 [29 %]). After PC consultations, discharge/admission destinations for EC patients were as follows: home, 65 (33 %); home hospice, 13 (7 %); inpatient hospice, 8 (4 %); regular hospital floor, 65 (33 %); and PC unit, 46 (23 %). The median duration of hospitalization was 92 h (range, 69-114) for hospitalized EC patients and 125 h (range, 108-142) for inpatients (p < 0.0001). CONCLUSIONS: Referral to PC from the EC led to earlier delivery of PC with subsequent earlier control of symptoms. EC patients who received PC consultations and were hospitalized had shorter hospitalizations than PC referral in the inpatient area. More research is needed to describe the impact of PC services on symptom assessment and management and on goals and plan of care in patients with advanced illness admitted to the EC. PMID- 26590845 TI - EEG marker of inhibitory brain activity correlates with resting-state cerebral blood flow in the reward system in major depression. AB - Frontal alpha band asymmetry (FAA) is a marker of altered reward processing in major depressive disorder (MDD), associated with reduced approach behavior and withdrawal. However, its association with brain metabolism remains unclear. The aim of this study was to investigate FAA and its correlation with resting-state cerebral blood flow (rCBF). We hypothesized an association of FAA with regional rCBF in brain regions relevant to reward processing and motivated behavior, such as the striatum. We enrolled 20 patients and 19 healthy subjects. FAA scores and rCBF were quantified with the use of EEG and arterial spin labeling. Correlations of the two were evaluated, as well as the association with FAA and psychometric assessments of motivated behavior and anhedonia. Patients showed a left lateralized pattern of frontal alpha activity and a correlation of FAA lateralization with subscores of Hamilton Depression Rating Scale linked to motivated behavior. An association of rCBF and FAA scores was found in clusters in the dorsolateral prefrontal cortex bilaterally (patients), in the left medial frontal gyrus, in the right caudate head and in the right inferior parietal lobule (whole group). No correlations were found in healthy controls. Higher inhibitory right-lateralized alpha power was associated with lower rCBF values in prefrontal and striatal regions, predominantly in the right hemisphere, which are involved in the processing of motivated behavior and reward. Inhibitory brain activity in the reward system may contribute to some of the motivational problems observed in MDD. PMID- 26590846 TI - Decreased ribosomal DNA transcription in dorsal raphe nucleus neurons differentiates between suicidal and non-suicidal death. AB - An involvement of the central serotonergic system has been implicated in the pathogenesis of suicide. The dorsal raphe nucleus (DRN) is the main source of serotonergic innervation of forebrain limbic structures disturbed in suicidal behaviour. The study was carried out on paraffin-embedded brainstem blocks containing the DRN obtained from 27 suicide completers (predominantly violent) with unknown psychiatric diagnosis and 30 non-suicidal controls. The transcriptional activity of ribosomal DNA (rDNA) in DRN neurons as a surrogate marker of protein biosynthesis was evaluated by the AgNOR silver staining method. Significant decreases in AgNOR parameters suggestive of attenuated rDNA activity were found in the cumulative analysis of all DRN subnuclei in suicide victims versus controls (U test P values < 0.00001). Our findings suggest that the decreased activity of rDNA transcription in DRN neurons plays an important role in suicide pathogenesis. The method accuracy represented by the area under receiver operating characteristic curve (>80 %) suggests a diagnostic value of the observed effect. However, the possible application of the method in forensic differentiation diagnostics between suicidal and non-suicidal death needs further research. PMID- 26590847 TI - Antioxidant Properties of Fish Protein Hydrolysates Prepared from Cod Protein Hydrolysate by Bacillus sp. AB - Fermentative protein hydrolysates (FPH) were prepared with a proteolytic bacterium, Bacillus strain exhibiting high proteolytic activity. Three FPH with 1, 2, and 4 % of cod protein hydrolysate (CPH) and 0.5 % of yeast extract in the culture were prepared. The yields achieved varied between 30 and 58 % based on protein content. A general decrease of leucine, isoleucine, valine, alanine, arginine, threonine, proline, and glutamic acid was observed. All FPHs showed higher reducing power and DPPH radical scavenging activity than CPH, but similar ABTS radical scavenging activity. However, FPHs exhibited lower Cu(+2)-chelating activity than CPH. The ACE inhibitory activity of FPHs was not improved relatively to that recorded in CPH. The fermentative process seems to have potential to obtaining hydrolysates with improved biological activities or even to produce protein hydrolysates from native fish proteins. PMID- 26590848 TI - Enhanced H2 Production and Redirected Metabolic Flux via Overexpression of fhlA and pncB in Klebsiella HQ-3 Strain. AB - Genetic modifications are considered as one of the most important technologies for improving fermentative hydrogen yield. Herein, we overexpress fhlA and pncB genes from Klebsiella HQ-3 independently to enhance hydrogen molar yield. HQ-3 fhlA/pncB strain is developed by manipulation of pET28-Pkan/fhlA Kan(r) and pBBR1 MCS5/pncB Gm(r) as expression vectors to examine the synchronous effects of fhlA and pncB. Optimization of anaerobic batch fermentations is achieved and the maximum yield of biohydrogen (1.42 mol H2/mol of glucose) is produced in the range of pH 6.5-7.0 at 33-37 degrees C. Whole cell H2 yield is increased up to 40 % from HQ-3-fhlA/pncB, as compared with HQ-3-fhlA 20 % and HQ-3-pncB 12 % keeping HQ-3-C as a control. Mechanism of improved H2 yield is studied in combination with metabolic flux analysis by measuring glucose consumption and other metabolites including formate, succinate, 2,3 butanediol, lactate, acetate, ethanol, and hydrogen. The results suggest that under transient conditions, the increase in the total level of NAD by NAPRTase can enhance the rate of NADH dependent pathways, and therefore, final distribution of metabolites is changed. Combined overexpression of fhlA and pncB eventually modifies the energy and carbon balance leading to enhanced H2 production from FHL as well as by NADH pathway. PMID- 26590849 TI - Gastric cancer in the East and West: what should we learn from each other? PMID- 26590851 TI - Functional computed tomography in oncology and cardiovascular imaging: A key player in the era of precision medicine and radiogenomics. PMID- 26590852 TI - Time knowledge acquisition in children aged 6 to 11 years and its relationship with numerical skills. AB - Acquisition of time knowledge (TK; the correct representation and use of time units) is linked to the development of numerical abilities, but this relationship has not been investigated in children. The current study examined the acquisition of TK and its association with numerical skills. A total of 105 children aged 6 to 11 years were interviewed with our Time Knowledge Questionnaire (TKQ), developed for purposes of this study, and the Zareki-R, a battery for the evaluation of number processing and mental calculation. The TKQ assessed conventional time knowledge (temporal orientation, temporal sequences, relationships between time units, and telling the time on a clock), estimation of longer durations related to birthday and life span, and estimation of the duration of the interview. Time knowledge increased with age, especially from 6 to 8 years, and was strongly linked to numerical skills. Regression analyses showed that four numerical components were implicated in TK: academic knowledge of numbers and number facts (e.g., reading Arabic numerals, mental calculation), number line estimation (e.g., correspondence between a number and a distance), contextual estimation (e.g., many/few leaves on a tree, children in a family), and numerical tasks involving verbal working memory (e.g., comparison of numbers presented orally). Numerical correlations with TK varied according to children's age; subtests based on academic knowledge of numbers, working memory, and number line estimation were linked with TK in the younger children, but only contextual estimation was associated with TK in the older children. PMID- 26590850 TI - Revision of failed primary adjustable gastric banding to mini-gastric bypass: results in 48 consecutive patients. AB - Although laparoscopic adjustable gastric banding (LAGB) has been found to be a generally successful weight loss operation, many patients require revision for weight regain, mechanical complications or intolerance to restriction. We report our experience with laparoscopic mini-gastric bypass (LMGB) as a revisional procedure for failed primary LAGB. From June 2007 to November 2012, 48 patients, who had undergone LAGB, underwent revisional surgery to LMGB. Patient demographics, reasons for band removal, interval between removal and LMGB, operative times, complications, change in comorbidities, and weight loss were collected. The revisions to a mini-gastric bypass (MGB) were completed laparoscopically in all cases except in four, when the MGB was deferred because of gastric tube damage. Mean age was 38 years (range 20-59) and BMI was 43.4 +/- 4.2 kg/m(2); 82 % of patients were females. Revision was performed after a mean of 28.6 months. The mean hospital stay was 3.25 days. Within 60 days of the MGB, mortality and morbidity were nil. We observed a significant difference in mean BMI after 6 months' follow-up (P < 0.001). Diabetes remission was observed in 88 % of patients, apnea remission in 66 %, and hypertension remission in 66 % after LMGB (p < 0.001). Moreover, four patients with GERD were cured. All LAGB patients had positive outcomes after the conversion to MGB, with a mean gain of 1.7 points in the bariatric analysis and reporting outcome system questionnaire. Our results suggested that LMGB is a safe, feasible, effective and easy-to-perform revisional procedure for failed LAGB. PMID- 26590853 TI - Facial artery perforator flap for reconstruction of perinasal defects: An anatomical study and clinical application. AB - BACKGROUND: The concept of the facial artery perforator flap was developed for improved freedom during the reconstruction of perioral and perinasal defects. This flap enables tailor-made reconstruction and a shift from the traditional two stage procedure to a one-stage technique. In this cadaveric study, the authors quantify the number, length, and diameter of facial artery perforators (FAPs) and present their clinical experience with the FAP flap. METHODS: The authors performed 20 dissections of facial arteries (FAs). All FAPs greater than 0.5 mm were dissected to study the number, length, and diameter of FAPs. In addition, the authors report a case series of 15 perinasal defect reconstruction procedures performed using facial artery-based perforator flap. RESULTS: A total of 125 FAPs were dissected. We identified a mean of six FAPs per hemiface (range five to eight). The average length of all FAPs was 17.6 +/- 1.9 mm, and the mean diameter of the FAPs was 0.91 +/- 0.2. Fifteen patients underwent a perinasal defect reconstruction using a FAP flap with good aesthetic and functional results. CONCLUSIONS: The following study thus improves our understanding of FAP anatomy and clinical application and will enable the nasolabial fold to become the area where perinasal defect reconstruction using perforator flaps is performed. PMID- 26590854 TI - Effects of myclobutanil on soil microbial biomass, respiration, and soil nitrogen transformations. AB - A 3-month-long experiment was conducted to ascertain the effects of different concentrations of myclobutanil (0.4 mg kg(-1) soil [T1]; 1.2 mg kg(-1) soil [T3]; and 4 mg kg(-1) soil [T10]) on soil microbial biomass, respiration, and soil nitrogen transformations using two typical agricultural soils (Henan fluvo-aquic soil and Shanxi cinnamon soil). Soil was sampled after 7, 15, 30, 60, and 90 days of incubation to determine myclobutanil concentration and microbial parameters: soil basal respiration (RB), microbial biomass carbon (MBC) and nitrogen (MBN), NO(-)3-N and NH(+)4-N concentrations, and gene abundance of total bacteria, N2 fixing bacteria, fungi, ammonia-oxidizing archaea (AOA), and ammonia-oxidizing bacteria (AOB). The half-lives of the different doses of myclobutanil varied from 20.3 to 69.3 d in the Henan soil and from 99 to 138.6 d in the Shanxi soil. In the Henan soil, the three treatments caused different degrees of short-term inhibition of RB and MBC, NH(+)4-N, and gene abundance of total bacteria, fungi, N2-fixing bacteria, AOA, and AOB, with the exception of a brief increase in NO( )3-N content during the T10 treatment. The MBN (immobilized nitrogen) was not affected. In the Shanxi soil, MBC, the populations of total bacteria, fungi, and N2-fixing bacteria, and NH(+)4-N concentration were not significantly affected by myclobutanil. The RB and MBN were decreased transitorily in the T10 treatment. The NO(-)3-N concentrations and the abundance of both AOA and AOB were erratically stimulated by myclobutanil. Regardless of whether stimulation or suppression occurred, the effects of myclobutanil on the two soil types were short term. In summary, myclobutanil had no long-term negative effects on the soil microbial biomass, respiration, and soil nitrogen transformations in the two types of soil, even at 10-fold the recommended dosage. PMID- 26590855 TI - Mechanical ventilation after lung transplantation. AB - INTRODUCTION: To explore the hypothesis that early ventilation strategies influence clinical outcomes in lung transplantation, we have examined our routine ventilation practices in terms of tidal volumes (Vt) and inflation pressures. METHODS: A total of 124 bilateral lung transplants between 2010 and 2013 were retrospectively assigned to low (<6 mL/kg), medium (6-8 mL/kg), and high (>8 mL/kg) Vt groups based on ventilation characteristics during the first 6 hours after surgery. Those same 124 patients were also stratified to low-pressure (<25 cm H2O) and high-pressure (>=25 cm H2O) groups. RESULTS: Eighty percent of patients were ventilated using pressure control mode. Low, medium, and high Vt were applied to 10%, 43%, and 47% of patients, respectively. After correcting for patients requiring extracorporeal support, there was no difference in short-term to midterm outcomes among the different Vt groups. Low inflation pressures were applied to 61% of patients, who had a shorter length of intensive care unit stay (5 vs 12 days; P = .012), higher forced expiratory volume in 1 second at 3 months (77.8% vs 60.3%; P < .001), and increased 6-month survival rate (95% vs 77%; P = .008). CONCLUSION: Low Vt ventilation has not been fully adopted in our practice. Ventilation with higher inflation pressures, but not Vt, was significantly associated with poorer outcomes after lung transplantation. PMID- 26590856 TI - The prevalence rates of suicide are likely underestimated worldwide: why it matters. PMID- 26590858 TI - HRS collaborates with leading medical societies to launch a voluntary laboratory accreditation program and drive quality improvement. PMID- 26590857 TI - Enhancing Capabilities in health professions education. AB - OBJECTIVE: This article documents the results of ongoing summative program evaluation of a suite of postgraduate courses at The University of Western Australia designed to enhance the educational capabilities, academic leadership and scholarly output of health professionals. METHODS: Commencing students were invited to participate in this descriptive, longitudinal study that surveyed students at commencement and subsequently over a seven year period. Data was collected at baseline and follow-up in relation to the respondents' educational leadership responsibilities, promotions, involvement in new educational programs, and recognition for contributions towards student learning, educational scholarly outputs and involvement in training programs. RESULTS: The respondents came from a wide range of health professions and worked in various roles, with a quarter already holding leadership positions. During the follow-up period, half reported receiving a new promotion or moving to new positions requiring educational leadership. Those identifying as being involved with the development of new educational programs doubled and 34% received a new teaching award. Scholarly productivity doubled with 45% giving an oral presentation related to education, 21% publishing and 29% being successful in obtaining funding related to an education project. CONCLUSIONS: These postgraduate courses in health professions education appear to be positively influencing graduates' capabilities, especially in the areas of educational leadership skills and scholarly productivity. For those looking to develop a community of leaders in health professions education, the authors offer some suggestions. PMID- 26590859 TI - Highlights of the 26th congress of the ISFG in Krakow, Poland. PMID- 26590861 TI - Study of criteria influencing the success rate of DNA swabs in operational conditions: A contribution to an evidence-based approach to crime scene investigation and triage. AB - DNA is nowadays swabbed routinely to investigate serious and volume crimes, but research remains scarce when it comes to determining the criteria that may impact the success rate of DNA swabs taken on different surfaces and situations. To investigate these criteria in fully operational conditions, DNA analysis results of 4772 swabs taken by the forensic unit of a police department in Western Switzerland over a 2.5-year period (2012-2014) in volume crime cases were considered. A representative and random sample of 1236 swab analyses was extensively examined and codified, describing several criteria such as whether the swabbing was performed at the scene or in the lab, the zone of the scene where it was performed, the kind of object or surface that was swabbed, whether the target specimen was a touch surface or a biological fluid, and whether the swab targeted a single surface or combined different surfaces. The impact of each criterion and of their combination was assessed in regard to the success rate of DNA analysis, measured through the quality of the resulting profile, and whether the profile resulted in a hit in the national database or not. Results show that some situations-such as swabs taken on door and window handles for instance-have a higher success rate than average swabs. Conversely, other situations lead to a marked decrease in the success rate, which should discourage further analyses of such swabs. Results also confirm that targeting a DNA swab on a single surface is preferable to swabbing different surfaces with the intent to aggregate cells deposited by the offender. Such results assist in predicting the chance that the analysis of a swab taken in a given situation will lead to a positive result. The study could therefore inform an evidence-based approach to decision-making at the crime scene (what to swab or not) and at the triage step (what to analyse or not), contributing thus to save resource and increase the efficiency of forensic science efforts. PMID- 26590860 TI - Advancing forensic RNA typing: On non-target secretions, a nasal mucosa marker, a differential co-extraction protocol and the sensitivity of DNA and RNA profiling. AB - The forensic identification of human body fluids and tissues by means of messenger RNA (mRNA) profiling is a long studied methodology that is increasingly applied to casework samples. Previously, we have described an mRNA multiplex system that targets blood, saliva, semen, menstrual secretion, vaginal mucosa and skin (Lindenbergh et al. and van den Berge et al.). In this study we consider various topics to improve this mRNA profiling system or its use and adapt the method accordingly. Bodily secretions that may be encountered at a crime scene whilst not targeted by the multiplex-id est nasal mucosa, sweat, tears, faeces and urine-were examined for false positive signals. The results prompted us to identify a nasal mucosa marker that allows the discrimination of nasal mucosa from saliva or vaginal mucosa and nosebleed blood from peripheral blood. An updated version of the multiplex was prepared to which the nasal mucosa marker was added and in which markers for semen, vaginal mucosa and blood were replaced. Lactobacillus markers were regarded unsuitable as replacement for vaginal mucosa mRNA markers because of background signals on penile swabs that appeared devoid of female DNA. Furthermore, we provide approaches to deal with highly unbalanced mixtures. First, a differential extraction protocol was incorporated into a co extraction protocol to allow DNA and RNA analysis of separated non-sperm and sperm fractions. In a second approach, besides the standard multiplex, a customized multiplex is used which excludes markers for prevailing cell types. This allows the use of lower cDNA inputs for the prevailing cell types and higher inputs for cell types that appear masked. Additionally, we assessed the relation between the percentage of alleles or markers detected in DNA or RNA profiles when decreasing sample amounts are analysed. While blood, saliva, semen and menstrual secretion show the trend that DNA profiling is more sensitive than RNA profiling, the reverse is seen for skin and variable results occur for vaginal and nasal mucosa. Lastly, we show that replicates are useful for interpretation of RNA data, as variations can be found even for true technical replicates. Increased numbers of replicates (over four) do, however, not cancel out the impact of this variation on data interpretation. Overall, the results of this study further forensic RNA profiling. PMID- 26590862 TI - We be jammin': an update on pectin biosynthesis, trafficking and dynamics. AB - Pectins are complex polysaccharides that contain acidic sugars and are major determinants of the cohesion, adhesion, extensibility, porosity and electrostatic potential of plant cell walls. Recent evidence has solidified their positions as key regulators of cellular growth and tissue morphogenesis, although important details of how they achieve this regulation are still missing. Pectins are also hypothesized to function as ligands for wall integrity sensors that enable plant cells to respond to intrinsic defects in wall biomechanics and to wall degradation by attacking pathogens. This update highlights recent advances in our understanding of the biosynthesis of pectins, how they are delivered to the cell surface and become incorporated into the cell wall matrix and how pectins are modified over time in the apoplast. It also poses unanswered questions for further research into this enigmatic but essential class of carbohydrate polymers. PMID- 26590864 TI - Ultrasound-guided versus blind subacromial-subdeltoid bursa injection in adults with shoulder pain: A systematic review and meta-analysis. AB - OBJECTIVE: This systematic review and meta-analysis aimed to assess the effectiveness of ultrasound-guided (USG) versus blind (landmark-guided, LMG) corticosteroid subacromial-subdeltoid bursa injection in adults with shoulder pain. METHODS: The searches were performed on PubMed, Ovid MEDLINE, Ovid EMBASE, Ovid CochraneCENTRAL, Web of Science, Google Scholar, and Scopus from database inception through March 27, 2015. Studies were included trials comparing USG versus LSG injections for the treatment of adults with subacromial-subdeltoid bursitis. Two reviewers independently performed data extraction and appraisal of the studies. The outcome measures collected were the decreased VAS and SDQ scores, the increased shoulder function scores and shoulder abduction motion range, and the effective rate at 6 weeks after injection. RESULTS: Seven papers including 445 patients were reviewed; 224 received LMG injections and 221 received USG injections. There was a statistically significant difference in favor of USG for pain score [MD = 1.19, 95% CI (0.39, 1.98), P = 0.003] and SDQ score [MD = 5.01, 95% CI (1.82, 8.19), P = 0.02] at 6 weeks after injection. Also there was a statistically significant difference between the groups, with greater improvement reported of shoulder function scores [SMD = 0.89, 95% CI (0.56, 1.23), P < 0.001] and shoulder abduction motion range [MD 32.69, 95% CI (14.82, 50.56), P < 0.001] in the USG group. More effective rate was also reported with USG group and the difference was statistically significant [risk ratio = 1.6, 95% CI (1.02, 2.50), P = 0.04]. CONCLUSIONS: Ultrasound-guided corticosteroid injections potentially offer a significantly greater clinical improvement over blind SASD bursitis injections in adults with shoulder pain. PMID- 26590863 TI - Cytochrome P450 CYP71BE5 in grapevine (Vitis vinifera) catalyzes the formation of the spicy aroma compound (-)-rotundone. AB - (-)-Rotundone is a potent odorant molecule with a characteristic spicy aroma existing in various plants including grapevines (Vitis vinifera). It is considered to be a significant compound in wines and grapes because of its low sensory threshold and aroma properties. (-)-Rotundone was first identified in red wine made from the grape cultivar Syrah and here we report the identification of VvSTO2 as a alpha-guaiene 2-oxidase which can transform alpha-guaiene to (-) rotundone in the grape cultivar Syrah. It is a cytochrome P450 (CYP) enzyme belonging to the CYP 71BE subfamily, which overlaps with the very large CYP71D family and, to the best of our knowledge, this is the first functional characterization of an enzyme from this family. VvSTO2 was expressed at a higher level in the Syrah grape exocarp (skin) in accord with the localization of (-) rotundone accumulation in grape berries. alpha-Guaiene was also detected in the Syrah grape exocarp at an extremely high concentration. These findings suggest that (-)-rotundone accumulation is regulated by the VvSTO2 expression along with the availability of alpha-guaiene as a precursor. VvSTO2 expression during grape maturation was considerably higher in Syrah grape exocarp compared to Merlot grape exocarp, consistent with the patterns of alpha-guaiene and (-)-rotundone accumulation. On the basis of these findings, we propose that VvSTO2 may be a key enzyme in the biosynthesis of (-)-rotundone in grapevines by acting as a alpha guaiene 2-oxidase. PMID- 26590865 TI - High plasma omentin predicts cardiovascular events independently from the presence and extent of angiographically determined atherosclerosis. AB - BACKGROUND AND AIMS: No prospective data on the power of the adipocytokine omentin to predict cardiovascular events are available. We aimed at investigating i) the association of plasma omentin with cardiometabolic risk markers, ii) its association with angiographically determined coronary atherosclerosis, and iii) its power to predict cardiovascular events. METHODS: We measured plasma omentin in 295 patients undergoing coronary angiography for the evaluation of established or suspected stable coronary artery disease (CAD), of whom 161 had significant CAD with coronary artery stenoses >=50% and 134 did not have significant CAD. RESULTS: Over 3.5 years, 17.6% of our patients suffered cardiovascular events, corresponding to an annual event rate of 5.0%. At baseline, plasma omentin was not significantly associated with metabolic syndrome stigmata and did not differ significantly between patients with and subjects without significant CAD (17.2 +/ 13.6 ng/ml vs. 17.5 +/- 15.1 ng/ml; p = 0.783). Prospectively, however, cardiovascular event risk significantly increased over tertiles of omentin (12.1%, 13.8%, and 29.5%, for tertiles 1 through 3; ptrend = 0.003), and omentin as a continuous variable significantly predicted cardiovascular events after adjustment for age, gender, BMI, diabetes, hypertension, LDL cholesterol, HDL cholesterol, and smoking (standardized adjusted hazard ratio (HR) 1.41 [95% CI 1.16-1.72]; p < 0.001), as well as after additional adjustment for the presence and extent of significant CAD at baseline (HR 1.59 [95% CI 1.29-1.97, p < 0.001). CONCLUSION: From this first prospective evaluation of the cardiovascular risk associated with omentin we conclude that elevated plasma omentin significantly predicts cardiovascular events independently from the presence and extent of angiographically determined baseline CAD. PMID- 26590866 TI - (90)Sr in King Bolete Boletus edulis and certain other mushrooms consumed in Europe and China. AB - The (90)Sr activity concentrations released from a radioactive fallout have been determined in a range of samples of mushrooms collected in Poland, Belarus, China, and Sweden in 1996-2013. Measurement of (90)Sr in pooled samples of mushrooms was carried out with radiochemical procedure aimed to pre-isolate the analyte from the fungal materials before it was determined using the Low-Level Beta Counter. Interestingly, the Purple Bolete Imperator rhodopurpureus collected from Yunnan in south-western China in 2012 showed (90)Sr activity concentration at around 10 Bq kg(-1) dry biomass, which was greater when compared to other mushrooms in this study. The King Bolete Boletus edulis from China showed the (90)Sr activity in caps at around 1.5 Bq kg(-1) dry biomass (whole fruiting bodies) in 2012 and for specimens from Poland activity was well lower than 1.0 Bq kg(-1) dry biomass in 1998-2010. A sample of Sarcodonimbricatus collected in 1998 from the north-eastern region of Poland impacted by Chernobyl fallout showed (90)Sr in caps at around 5 Bq kg(-1) dry biomass. Concentration of (90)Sr in Bay Bolete Royoporus (Xerocomus or Boletus) badius from affected region of Gomel in Belarus was in 2010 at 2.1 Bq kg(-1) dry biomass. In several other species from Poland (90)Sr was at <0.5 to around 1.0 Bq kg(-1) dry biomass. Activity concentrations of (90)Sr in popular B. edulis and some other mushrooms collected from wild in Poland were very low (<1 Bq kg(-1) dry biomass), and values noted showed on persistence of this type of radioactivity in mushrooms over time passing from nuclear weapons tests and the Chernobyl nuclear power plant catastrophe. PMID- 26590867 TI - Benefits of biochar, compost and biochar-compost for soil quality, maize yield and greenhouse gas emissions in a tropical agricultural soil. AB - Soil quality decline represents a significant constraint on the productivity and sustainability of agriculture in the tropics. In this study, the influence of biochar, compost and mixtures of the two on soil fertility, maize yield and greenhouse gas (GHG) emissions was investigated in a tropical Ferralsol. The treatments were: 1) control with business as usual fertilizer (F); 2) 10 t ha(-1) biochar (B)+F; 3) 25 t ha(-1) compost (Com)+F; 4) 2.5 t ha(-1) B+25 t ha(-1) Com mixed on site+F; and 5) 25 t ha(-1) co-composted biochar-compost (COMBI)+F. Total aboveground biomass and maize yield were significantly improved relative to the control for all organic amendments, with increases in grain yield between 10 and 29%. Some plant parameters such as leaf chlorophyll were significantly increased by the organic treatments. Significant differences were observed among treatments for the delta(15)N and delta(13)C contents of kernels. Soil physicochemical properties including soil water content (SWC), total soil organic carbon (SOC), total nitrogen (N), available phosphorus (P), nitrate-nitrogen (NO3(-)N), ammonium-nitrogen (NH4(+)-N), exchangeable cations and cation exchange capacity (CEC) were significantly increased by the organic amendments. Maize grain yield was correlated positively with total biomass, leaf chlorophyll, foliar N and P content, SOC and SWC. Emissions of CO2 and N2O were higher from the organic amended soils than from the fertilizer-only control. However, N2O emissions generally decreased over time for all treatments and emission from the biochar was lower compared to other treatments. Our study concludes that the biochar and biochar-compost-based soil management approaches can improve SOC, soil nutrient status and SWC, and maize yield and may help mitigate greenhouse gas emissions in certain systems. PMID- 26590868 TI - Exposure to difenoconazole causes changes of thyroid hormone and gene expression levels in zebrafish larvae. AB - Difenoconazole was believed to induce a large suite of symptoms during zebrafish development, but little is known about the negative invisible effect known as endocrine disruption. In this study, zebrafish (Danio rerio) embryos were exposed to various concentrations of difenoconazole from fertilization to 120 h post fertilization (hpf), and the whole body content of thyroid hormone and gene transcription in the hypothalamic-pituitary-thyroid (HPT) axis were investigated. Results showed thyroxine (T4) levels were significantly decreased, while triiodothyronine (T3) concentrations were not changed. Moreover, the mRNA transcription of corticotrophin-releasing hormone (crh), thyroid-stimulating hormone (tshbeta), transthyretin (ttr), thyronine deiodinase (dio1 and dio2), uridine diphosphate glucuronosyltransferase (ugt1ab) in the HPT axis were significantly up-regulated, but the transcriptions of thyroglobulin (tg), sodium/iodide symporter (nis) and thyroid hormone receptors trbeta were not changed. The overall results showed that exposure to difenoconazole could alter thyroid hormone levels and gene transcription in zebrafish larvae, indicating thyroid endocrine disruption. PMID- 26590869 TI - A systematic review of studies evaluating Australian indigenous community development projects: the extent of community participation, their methodological quality and their outcomes. AB - BACKGROUND: Community development is a health promotion approach identified as having great potential to improve Indigenous health, because of its potential for extensive community participation. There has been no systematic examination of the extent of community participation in community development projects and little analysis of their effectiveness. This systematic review aims to identify the extent of community participation in community development projects implemented in Australian Indigenous communities, critically appraise the qualitative and quantitative methods used in their evaluation, and summarise their outcomes. METHODS: Ten electronic peer-reviewed databases and two electronic grey literature databases were searched for relevant studies published between 1990 and 2015. The level of community participation and the methodological quality of the qualitative and quantitative components of the studies were assessed against standardised criteria. RESULTS: Thirty one evaluation studies of community development projects were identified. Community participation varied between different phases of project development, generally high during project implementation, but low during the evaluation phase. For the majority of studies, methodological quality was low and the methods were poorly described. Although positive qualitative or quantitative outcomes were reported in all studies, only two studies reported statistically significant outcomes. DISCUSSION: Partnerships between researchers, community members and service providers have great potential to improve methodological quality and community participation when research skills and community knowledge are integrated to design, implement and evaluate community development projects. CONCLUSION: The methodological quality of studies evaluating Australian Indigenous community development projects is currently too weak to confidently determine the cost effectiveness of community development projects in improving the health and wellbeing of Indigenous Australians. Higher quality studies evaluating community development projects would strengthen the evidence base. PMID- 26590870 TI - Effects of antibiotic resistance genes on the performance and stability of different microbial aggregates in a granular sequencing batch reactor. AB - Antibiotic resistance genes (ARGs) have emerged as key factors in wastewater environmental contaminants and continue to pose a challenge for wastewater treatment processes. With the aim of investigating the performance of granular sludge system when treating wastewater containing a considerable amount of ARGs, a lab-scale granular sequencing batch reactor (GSBR) where flocculent and granular sludge coexisted was designed. The results showed that after inoculation of donor strain NH4(+)-N purification efficiency diminished from 94.7% to 32.8% and recovered to 95.2% after 10 days. Meanwhile, RP4 plasmid had varying effects on different forms of microbial aggregates. As the size of aggregates increased, the abundance of RP4 in sludge decreased. The residence time of RP4 in granules with particle size exceeding 0.9 mm (14 days) was far shorter than that in flocculent sludge (26 days). Therefore, our studies conclude that with increasing number of ARGs being detected in wastewater, the use of granular sludge system in wastewater treatment processes will allow the reduction of ARGs transmissions and lessen potential ecological threats. PMID- 26590871 TI - Secondary environmental impacts of remedial alternatives for sediment contaminated with hydrophobic organic contaminants. AB - This study evaluates secondary environmental impacts of various remedial alternatives for sediment contaminated with hydrophobic organic contaminants using life cycle assessment (LCA). Three alternatives including two conventional methods, dredge-and-fill and capping, and an innovative sediment treatment technique, in-situ activated carbon (AC) amendment, are compared for secondary environmental impacts by a case study for a site at Hunters Point Shipyard, San Francisco, CA. The LCA results show that capping generates substantially smaller impacts than dredge-and-fill and in-situ amendment using coal-based virgin AC. The secondary impacts from in-situ AC amendment can be reduced effectively by using recycled or wood-based virgin AC as production of these materials causes much smaller impacts than coal-based virgin AC. The secondary environmental impacts are highly sensitive to the dredged amount and the distance to a disposal site for dredging, the capping thickness and the distance to the cap materials for capping, and the AC dose for in-situ AC amendment. Based on the analysis, this study identifies strategies to minimize secondary impacts caused by different remediation activities: optimize the dredged amount, the capping thickness, or the AC dose by extensive site assessments, obtain source materials from local sites, and use recycled or bio-based AC. PMID- 26590872 TI - Dme-miR-314-3p modulation in Cr(VI) exposed Drosophila affects DNA damage repair by targeting mus309. AB - microRNAs (miRNAs) as one of the major epigenetic modulators negatively regulate mRNAs at post transcriptional level. It was therefore hypothesized that modulation of miRNAs by hexavalent Chromium [Cr(VI)], a priority environmental chemical, can affect DNA damage. In a genetically tractable model, Drosophila melanogaster, role of maximally up-regulated miRNA, dme-miR-314-3p, on DNA damage was examined by exposing the third instar larvae to 5.0-20.0 MUg/ml Cr(VI) for 24 and 48 h. mus309, a Drosophila homologue of human Bloom's syndrome and predicted as one of the potential targets of this miRNA, was confirmed as its target by 5'RLM-RACE assay. A significant down-regulation of mus309 was observed in dme-miR 314-3p overexpression strain (myo-gal4>UAS-miR-314-3p) as compared with that in parental strains (myo-gal4 and UAS-miR-314-3p) and in w(1118). A significant increase in DNA damage including double strand breaks generation was observed in exposed myo-gal4>UAS-miR-314 and mus309 mutants as compared with that in parental strain and in unexposed control. A significant down-regulation of cell cycle regulation genes (CycA, CycB and cdc2) was observed in these exposed genotypes. Collectively, the study demonstrates that dme-miR-314-3p can mediate the downregulation of repair deficient gene mus309 leading to increased DNA damage and cell cycle arrest in exposed organism which may affect Cr(VI) mediated carcinogenesis. PMID- 26590873 TI - Inflammatory MAPK and NF-kappaB signaling pathways differentiated hepatitis potential of two agglomerated titanium dioxide particles. AB - TiO2 nanoparticles (TiO2NPs) consumption and deposit in liver have possible implications for hepatitis risks. Specific signal dysregulation at early inflammatory responses needs to be characterized in TiO2NP-induced hepatopathy. MAPK and NF-kappaB signaling pathways are known to participate in inflammation and respond sensitively to chemical agents, making them preferable biomarkers for hepatitis. In the present study, dynamic activation of MAPK and NF-kappaB pathways were explored by immunoblotting and NF-kappaB luciferase reporter assay depending on characterization of TiO2NP agglomeration in human HepG2 cells. Inflammatory and cytotoxic potential of TiO2NPs were determined by qRT-PCR and WST-1 assay. AFM and TEM analyses uncovered ultrastructure damages underlying hepatotoxicity of TiO2NPs. Rod-like rutile agglomerated smaller and induced more pronounced cytotoxicity and immunogenicity than anatase. Correspondingly, though both rutile and anatase significantly activated p38, ERK1/2 and NF-kappaB pathways, rutile accelerated the maximum phosphorylation of ERK1/2 and elevated the potency of IkappaBalpha phosphorylation to its bell curve shape in comparison with a lower and sigmoid type of IkappaBalpha phosphorylation for anatase. Furthermore, cell elasticity indicated by Young's modulus and adhesion force increased accompanied with mitochondria damage, contributing to signal dysregulation and hepatotoxicity. The results suggested that differential activation of MAPK and NF-kappaB pathways could be early predictors for distinct hepatitis risks of two agglomerated TiO2NPs. PMID- 26590875 TI - Boron-doped bismuth oxybromide microspheres with enhanced surface hydroxyl groups: Synthesis, characterization and dramatic photocatalytic activity. AB - B-doped BiOBr photocatalysts were successfully synthesized via a facile solvothermal method with boric acid used as boron source. As-obtained products consist of novel hierarchical microspheres, whose nanosheet building units were formed by nanoparticles splicing. They showed dramatic photocatalytic efficiency toward the degradation of Rhodamine B (RhB) and phenol under the visible-light irradiation and the highest activity was achieved by 0.075B-BiOBr. The enhanced photocatalytic activity could be attributed to the enriched surface hydroxyl groups on B-doped BiOBr samples, which not only improved the adsorption of pollutant on the photocatalyst but also promoted the separation of photogenerated electron-hole pairs. In addition, it was found that the main reactive species responsible for the degradation of organic pollutant were h(+) and O2(-) radicals, instead of OH radicals. PMID- 26590874 TI - Multidisciplinary assessment of pesticide mitigation in soil amended with vermicomposted agroindustrial wastes. AB - Soil organic amendment affects biotic and abiotic processes that control the fate of pesticides, but the treatment history of the soil is also relevant. These processes were assessed in a multidisciplinary study with the aim of optimizing pesticide mitigation in soils. Soil microcosms pre-treated (E2) or not with diuron (E1) were amended with either winery (W) or olive waste (O) vermicomposts. Herbicide dissipation followed a double first-order model in E1 microcosms, but a single first-order model in E2. Also, diuron persistence was longer in E1 than in E2 (E1-DT50>200 day(-1), E2-DT50<16 day(-1)). The genetic structure of the bacterial community was modified by both diuron exposure and amendment. O vermicompost increased enzymatic activities in both experiments, but diuron degrading genetic potential (puhB) was quantified only in E2 microcosms in accordance with reduced diuron persistence. Therefore, O-vermicompost addition favoured the proliferation of diuron degraders, increasing the soil diuron depuration capability. PMID- 26590877 TI - Gas chromatographic separation of fatty acid esters of cholesterol and phytosterols on an ionic liquid capillary column. AB - Steryl esters are high molecular weight compounds (600-700g/mol) regularly present as a minor lipid class in animal and plant lipids. Different sterol backbones (e.g., cholesterol, beta-sitosterol and brassicasterol) which can be esterified with various fatty acids can result in highly complex steryl ester patterns in food samples. The gas chromatographic (GC) analysis of intact steryl esters is challenging, since high elution temperatures are required for their elution. On nonpolar GC phases, steryl esters with fatty acids with differing degree of unsaturation (e.g., oleate and linoleate) cannot be separated and there are only few polar columns available with sufficient temperature stability. In this study, we used gas chromatography with mass spectrometry (GC/MS) and analyzed intact steryl esters on a commercial room temperature ionic liquid (RTIL) column which was shortened to a length of 12m. The column separated the steryl esters both by total carbon number and by degree of unsaturation of the fatty acid. For instance, cholesteryl esters with stearic acid (18:0), oleic acid (18:1n-9), linoleic acid (18:2n-6) and alpha-linolenic acid (18:3n-3) could be resolved (R>=1.3) from each other. By analysis of synthesized standard substances, the elution orders for different steryl backbones and different fatty acids on a given sterol backbone could be determined. Analysis of spreads and plant oils allowed to determine retention times for 37 steryl esters, although a few co-elutions were observed. The ionic liquid column proved to be well-suited for the analysis of intact steryl esters. PMID- 26590876 TI - Pilot randomised trial of a brief intervention for comorbid substance misuse in psychiatric in-patient settings. AB - OBJECTIVE: This proof of principle study evaluated the effectiveness and feasibility of a brief motivational intervention, delivered in mental health in patient settings, to improve engagement in treatment for drug and alcohol misuse. METHOD: A randomised controlled trial using concealed randomisation, blind, independent assessment of outcome at 3 months. Participants were 59 new adult admissions, to six acute mental health hospital units in one UK mental health service, with schizophrenia related or bipolar disorder diagnoses, users of community mental health services and also misusing alcohol and/or drugs. Participants were randomised to Brief Integrated Motivational Intervention (BIMI) with Treatment As Usual (TAU), or TAU alone. The BIMI took place over a 2-week period and encouraged participants to explore substance use and its impact on mental health. RESULTS: Fifty-nine in-patients (BIMI n = 30; TAU n = 29) were randomised, the BIMI was associated with a 63% relative odds increase in the primary outcome engagement in treatment [OR 1.63 (95% CI 1.01-2.65; P = 0.047)], at 3 months. Qualitative interviews with staff and participants indicated that the BIMI was both feasible and acceptable. CONCLUSION: Mental health hospital admissions present an opportunity for brief motivational interventions focussed on substance misuse and can lead to improvements in engagement. PMID- 26590878 TI - Profile of bioactive compounds from grape pomace (Vitis vinifera and Vitis labrusca) by spectrophotometric, chromatographic and spectral analyses. AB - The aim of this study was to characterize grape pomace (GP) from winemaking byproducts of different grape samples (Cabernet Sauvignon-CS; Merlot-ME; Mix composed of 65% Bordeaux, 25% Isabel and 10% BRS Violet-MI and Terci-TE) with a view to exploiting its potential as a source of bioactive compounds and an alternative to the reuse of waste. Bioactive compounds such as individual phenolic compounds and polyunsaturated fatty acids (PUFA) were identified and quantified by spectrophotometric, chromatographic and spectral analyses. The sample of MI had the highest concentrations for total phenolic compounds and total flavonoids, while TE had the highest content for total monomeric anthocyanins. For all samples it was possible to identify 13 different anthocyanins by high performance liquid chromatography (HPLC) and mass spectrometry (MS). Moreover, the GP samples showed phenolic acids; flavan-3-ols such as catechin; flavonols such as quercetin, rutin and kaempferol; and stilbenes such as trans-resveratrol. Therefore, grape pomace can be considered a source for the recovery of phenolic compounds having antioxidant activity as well as a rich source of PUFA. Thus it can be used as an ingredient in the development of new food products, since it is suitable for human consumption, and a viable alternative both to adding nutritional value to food and to reduce environmental contamination. PMID- 26590879 TI - Highly sensitive method for simultaneous determination of nine alkaloids of Shuanghua Baihe tablets in human plasma by LC-MS/MS and its application. AB - Shuanghua Baihe tablets (SBT) is a traditional Chinese medicinal formula which has been used to treat recurrent aphthous stomatitis for many years. To study the pharmacokinetic profiles of berberine, epiberberine, coptisine, palmatine, jatrorrhizine, magnoflorine, berberrubine, corynoline and acetylcorynoline in human after administration of SBT, a sensitive liquid chromatography-tandem mass spectrometry method was developed and fully validated for the simultaneous quantification of these nine alkaloids in human plasma. After protein precipitation, the nine alkaloids in human plasma sample was separated on a Hanbon C18 (150mm*2.1mm, 5MUm) column with gradient elution using methanol and 0.5% formic acid water solution, and detected by a triple quadrupole mass spectrometer with an electrospray ionization source. It is a challenge to design different calibration ranges for different analytes in a bioanalytical method for simultaneous determination of multi-analytes in bio-samples. To ensure that each alkaloid in the plasma was determined accurately by the simultaneous quantitation method, the upper limits of quantification for the nine alkaloids were designed at 100, 300, 800, 1800 and 5000pg/mL, respectively, according to the maximum plasma concentration value of each alkaloid obtained from the pilot pharmacokinetic study. The lower limit of quantification was 15pg/mL for berberine, epiberberine, coptisine, magnoflorine, berberrubine, corynoline and acetylcorynoline, while for palmatine and jatrorrhizine it was 1.5pg/mL. This method was successfully applied to investigate the pharmacokinetic profiles of the nine alkaloids in healthy Chinese volunteers after a single oral administration of SBT. PMID- 26590880 TI - Separation of E. coli chaperonin groEL from beta-galactosidase without denaturation. AB - Chaperonins are a class of ubiquitous proteins that assist and accelerate protein folding in the cell. The Escherichia coli groEL is the best known and forms a complex with its co-chaperonin groES in the presence of ATP and assists in the folding of nascent and misfolded substrate proteins. The purification of recombinant groEL results in a nearly homogeneous sample that consistently co purifies with the major contaminant E. coli beta-galactosidase. Removal of beta galactosidase using column chromatography alone is exceedingly difficult. This is due to the fact that the overall size, surface charge, isoelectric point and hydrophobicity of groEL and beta-galactosidase are very similar. Therefore purification of groEL chaperonin to homogeneity requires denaturation of the complex into monomers with urea for separating the groEL from contaminating beta galactosidase followed by reassembly of the chaperonin complex. Here, we present a simple procedure for separating beta-galactosidase along with many other impurities from groEL preparations under non-denaturing conditions. The groEL is first salted out with 50% ammonium sulfate. This step also precipitates beta galactosidase but this is then salted out by the addition of magnesium chloride which leaves groEL in solution. All remaining contaminants are removed by column chromatography. PMID- 26590881 TI - One-pot preparation of a novel monolith for high performance liquid chromatography applications. AB - Various novel porous organic-based monoliths with the mode of hydrophobicity were synthesized by in situ free-radical crosslinking copolymerization and optimized for the separations of small molecules and high-performance reversed-phase chromatography (RP-chromatography). These monoliths contained co-polymers based on glycidyl methacrylate (GMA)/ethylene glycol dimethacrylate (EDMA)/tripropylene glycol diacrylate (TPGDA) or EDMA/TPGDA. A mixture of cetanol, methanol and poly (ethylene glycol) (PEG) was used as the porogen, with the ratio of these solvents being varied along with the polymerization temperature to generate a library of monoliths. The conditions were optimized and the resulting poly (GMA-co-TPGDA-co EDMA) monolith was investigated by infrared spectrometer (IR), field emission scanning electron microscope (FESEM), and mercury intrusion porosimetry (MIP), respectively. The column performance was assessed by the separation of a series of neutral solutes of benzene derivatives. The result demonstrated that the prepared monolith exhibited an RP-chromatographic behavior and relatively homogeneous structure, good permeability and separation performance. Moreover, the relative standard deviations (RSDs) of the retention factor values for benzene derivatives were less than 1.5% (n=7, column-to-column). The approach used in this study was extended to the separation of anilines. PMID- 26590882 TI - Effects of berberine and pomegranate seed oil on plasma phospholipid metabolites associated with risks of type 2 diabetes mellitus by U-HPLC/Q-TOF-MS. AB - A rapid and reliable ultra-performance liquid chromatography coupled with electrospray ionization/quadrupole-time-of-flight mass spectrometry (U-HPLC/Q-TOF MS) has been firstly used to analyze the changes of plasma phospholipids, in type 2 diabetes mellitus (T2DM) mice after administration of berberine and pomegranate seed oil (PSO). The separation of plasma phospholipids was carried out on an Acquity U-HPLC BEH C18 column (2.1mm*50mm, 1.7MUm, Waters) by linear gradient elution using a mobile phase consisting of 10mM ammonium formate in water and acetonitrile: isopropanol (1:1, v/v) mixed solution added by 0.25% water and 10mM ammonium formate. The method demonstrated a good precision and reproducibility. Linear regression analysis showed a good linearity. And potential biomarkers were discovered based on their mass spectra and chemometrics methods. The results demonstrated that the proposed U-HPLC/Q-TOF-MS method was successfully applied to analyze the dynamic changes of phospholipids components in plasma of T2DM mice after drug treatment and could provide a useful data base for meriting further study in humans and investigating pharmacological actions of drugs. PMID- 26590883 TI - Novel FANCI mutations in Fanconi anemia with VACTERL association. AB - Fanconi anemia (FA) is an inherited bone marrow failure syndrome caused by mutations in DNA repair genes; some of these patients may have features of the VACTERL association. Autosomal recessive mutations in FANCI are a rare cause of FA. We identified FANCI mutations by next generation sequencing in three patients in our FA cohort among several whose mutated gene was unknown. Four of the six mutations are novel and all mutations are likely deleterious to protein function. There are now 16 reported cases of FA due to FANCI of whom 7 have at least 3 features of the VACTERL association (44%). This suggests that the VACTERL association in patients with FA may be seen in patients with FANCI mutations more often than previously recognized. PMID- 26590884 TI - Merging strain-echo measurements with late gadolinium enhancement at cardiac MRI: An upcoming chance for advanced functional assessment of fibrosis in hypertrophic cardiomyopathy? PMID- 26590885 TI - Giant retroperitoneal cystic lymphangioma in a patient with Eisenmenger syndrome. PMID- 26590886 TI - Prognostic impact of macrophage migration inhibitory factor in patients with non ischemic heart failure undergoing endomyocardial biopsy. PMID- 26590887 TI - Surgical management of infected cardiac implantable electronic devices. AB - The growing use of cardiac implantable electronic devices (CIED) has led to infections requiring intervention. These are traditionally managed using a percutaneous transvenous approach to fully extract the culpable leads. Indications for such strategies are well-established and range from simple traction to the use of powered extraction tools including laser sheaths. Where such attempts fail, or if there are further complications, then there may be need for a cardiothoracic surgical approach. Limited evidence is currently available on the merits of individual strategies, and these are mainly drawn from case reports or series. Most utilise cardiopulmonary bypass, cardioplegic arrest and entry within the right atrium to allow direct visualisation of any vegetation and safely explant all CIED components whilst avoiding perforation, valvular and paravalvular damage. In this review, we describe a number of these and the unique challenges faced by surgeons when attempting to extract CIED. It is clear that future work should concentrate on creating clear consensus and guidelines on indications, risks and measures of efficacy outcomes for various surgical techniques. PMID- 26590888 TI - 'Real-world' haemorrhagic rates for warfarin and dabigatran using population level data in New Zealand. AB - BACKGROUND: Anticoagulants such as warfarin and dabigatran can significantly reduce the risk of stroke in individuals with atrial fibrillation that may lead to increased risk of bleeding, especially in older people. Evidence for bleeding risks with anticoagulants within the context of doses, multimorbidity and impaired renal function in real world setting is lacking. Therefore we aimed to assess and compare real world bleeding risks with warfarin and dabigatran. Secondary analyses involved examining risk of fatal haemorrhages. METHODS AND RESULTS: We formed two inception cohorts of propensity score (PS) matched older patients (>= 65 years), who initiated dabigatran or warfarin between July 2011 and December 2012. A total of 4835 dabigatran users were matched to 4385 warfarin users in dose independent binary PS matching. A dose dependent PS matching resulted in 2383 warfarin, 2153 dabigatran 150 mg and 3395 dabigatran 110 mg users. In the first cohort, compared to warfarin, the hazard ratios (95% confidence intervals) for dabigatran were 0.45 (0.37-0.55) for any haemorrhage; 1.16 (0.87-1.56) for gastrointestinal haemorrhage; and 0.29 (0.09-0.86) for intracerebral haemorrhage. Similar associations were observed in the first 30 days of treatment. In dose dependent matched cohort, the risk of any haemorrhage was lower in individuals receiving dabigatran 110 mg (HR; 95% CI: 0.40 (0.31 0.52)) and 150 mg (HR; 95% CI: 0.29 (0.19-0.41)) compared to warfarin. CONCLUSIONS: The risk of any haemorrhage and intracerebral haemorrhage was lower in dabigatran users compared to warfarin users. Importantly no increased risk of gastrointestinal haemorrhage was found in dabigatran users. The incidence rates for any haemorrhage were found to be higher in first 30 days of any anticoagulant treatment, but hazard ratios remained similar during the study period. PMID- 26590889 TI - Cardiac sarcoidosis: Matching speckle tracking echocardiography to macroscopic Ventricular pathology (a case report). PMID- 26590891 TI - Plaque morphologies and the clinical prognosis of acute coronary syndrome caused by lesions with intact fibrous cap diagnosed by optical coherence tomography. AB - BACKGROUND: Pathological studies have suggested that acute coronary syndrome (ACS) may be caused by culprit lesions with intact fibrous cap (IFC), including plaque erosions. This study sought to evaluate the morphological features and clinical outcomes of patients with ACS caused by lesions with IFC. METHODS: A total of 318 patients with ACS who underwent optical coherence tomography (OCT) of a culprit lesion were investigated. The culprit lesions were categorized as follows: those with plaque rupture (PR group), those with an IFC (IFC group), and those with a massive thrombus precluding plaque visualization (MT group). Intravascular ultrasound (IVUS) was performed in 297 patients. Clinical follow-up data were collected regarding adverse cardiac events, including death, myocardial infarction, revascularization, and congestive heart failure requiring hospitalization. RESULTS: Culprit lesions were categorized into 141 RPs, 131 IFCs, and 46 MTs. IFC group exhibited a smaller remodeling index and less frequently attenuated plaques on IVUS. Three hundred and seven patients (96.5%) were followed for a median follow-up duration of 576 days. Adverse cardiac events were observed in 93 patients (30.3%). Kaplan-Meier analysis demonstrated a significantly lower event rate in IFC group compared with the RP and MT groups. Cox proportional hazard analysis demonstrated that an IFC and multivessel disease were independent predictors of adverse events [hazard ratio 0.57, 95% confidence interval (CI) 0.33-0.98, p=0.043 and hazard ratio 1.72, 95% CI 1.09-2.73, p=0.021]. CONCLUSIONS: Culprit lesions with IFC showed smaller remodeling indices by IVUS, and were associated with better long-term prognosis compared with those with plaque rupture. PMID- 26590890 TI - Primary cardiac lymphoma: Two rare cases. PMID- 26590892 TI - Colpocleisis surgery in women over 80 years old with severe triple compartment pelvic organ prolapse. AB - OBJECTIVE: To compare outcomes of Le Fort colpocleisis surgery, between women over 80 years old and younger women. STUDY DESIGN: We searched the medical files for all consecutive women who underwent Le Fort colpocleisis as a primary or recurrent surgery for severe pelvic organ prolapse at our university-affiliated tertiary center between February 2007 and July 2013. Exclusion criteria for performance of the procedure were post-menopausal bleeding, pelvic malignancy, pelvic irradiation, and the desire to preserve coital function. The objective and subjective recurrence of prolapse, intraoperative and postoperative complications, and patient satisfaction were measured. RESULTS: Forty-seven women underwent Le Fort colpocleisis. Of them, 23 were above 80 years, mean age 84.0+/ 3.3, oldest: 91; and 24 were 80 years old and younger, mean age 70.8+/-6.1, youngest: 61. There were no intraoperative complications. Postoperative complications were recorded for 2 women with lower urinary tract infection and one woman had longer hospitalization time for warfarin treatment adjustment (9 days). Objective cure rates were 82.7% (19/23) and 83.3% (20/24), p=0.32, for women over 80, and women aged 80 and younger, respectively. The subjective cure rate was 86.7% (20/23) and 91.6% (22/24), respectively, p=0.28. CONCLUSIONS: Objective and subjective cure rates of Le Fort colpocleisis in women over age 80 years were similar to those for younger women. The complications were mild and few, and unrelated to age. This procedure may be offered for women over 80 years old with severe symptomatic pelvic organ prolapse and medical comorbidities. PMID- 26590893 TI - Silver nanoparticles provoke apoptosis of Dalton's ascites lymphoma in vivo by mitochondria dependent and independent pathways. AB - The aim of this report was to investigate the antitumor and apoptotic effects of silver nanoparticles (AgNPs) on the Dalton's ascites lymphoma cells in vivo. Thirty Swiss albino male mice were assigned into five groups of six each. Group I were intact animals. Group II animals served as tumor control injected with DAL cells intraperitonially. Group III induced animals received plant extract (17 mg/kg BW) and Group IV induced animals received AgNPs (35 MUg/kg BW). Group V induced animals received standard anticancer drug 5-Fluorouracil (5-FU, 20 MUg/kg BW). The treatment period was 10 days excluding the day of tumor injection. Tumor cells were collected after euthanizing the animals and real-time PCR was used to analyze p53, caspase-3, 8, 9, 12 and cytochrome C expressions. Results indicate that the AgNPs were efficient in prolongation of life span, reduction of tumor volume and body weight in tumor animals. All the apoptotic genes were upregulated by treatment with AgNPs. To conclude, the present study elicits that AgNPs are potent in antitumor activity and the molecular mechanism is by the induction of apoptosis through the mitochondrial dependent and independent pathways. PMID- 26590894 TI - Nanopolymersomes as potential carriers for rifampicin pulmonary delivery. AB - Tuberculosis (TB) has been stated as "the greatest killer worldwide due to a single infectious agent" behind the human immunodeficiency virus. Standard short term treatment includes the oral administration of a combination of "first-line" drugs. However, poor-patient compliance and adherence to the long-term treatments represent one of the mayor drawbacks of the TB therapy. An alternative to the oral route is the pulmonary delivery of anti-TB drugs for local or systemic administration. Nanotechnology offers an attractive platform to develop novel inhalable/respirable nanocarriers. The present investigation was focused on the encapsulation of rifampicin (RIF) (a "first-line" anti-TB drug) within nanopolymersomes (nanoPS) employing di- and tri-block poly(ethylene glycol) (PEG) poly(E-caprolactone) (PCL) based copolymers as biomaterials. The derivatives presented a number-average molecular weight between 12.2 KDa and 30.1 KDa and a hydrophobic/hydrophilic balance between 0.56 and 0.99. The nanoPS were able to enhance the apparent RIF aqueous solubility (up to 4.62 mg/mL) where the hydrodynamic diameters of the drug-loaded systems (1% w/v) were ranged between 65.8 nm and 94 nm at day 0 as determined by dynamic light scattering (DLS). Then, RIF-loaded systems demonstrated as excellent colloidal stability in aqueous media over 14 days with a spherical morphology as determined by transmission electron microscopy (TEM). Furthermore, RIF-loaded nano-sized PS promoted drug accumulation in macrophages (RAW 264.7) versus a drug solution representing promising results for a potential TB inhaled therapy. PMID- 26590895 TI - Chitosan/gelatin composite sponge is an absorbable surgical hemostatic agent. AB - Chitosan is a versatile biological material that is very well known for its hemostatic properties. The purpose of this study was to test the hemostatic properties of a chitosan composite obtained from silkworm pupae and gelatin. This spongy porous material was cross-linked with tannins and then freeze-dried under vacuum to obtain composites containing chitosan and gelatin in different proportions. Results showed that the best blood-clotting index (BCI) was achieved in vitro by a chitosan/gelatin sponge (CG) ratio of 5/5 (W/W). Furthermore, CG had the best hemostatic effect in rabbit artery bleeding and liver model tests compared to the two components separately. The better hemostatic effect of CG may be due to its ability to absorb blood platelets easily and to the higher liquid adsorption ratio. However, no obvious differences were observed in thrombin generation with both aPTT and PT tests. Cell toxicity tests with L929 cells showed that CG caused no obvious cytotoxicity. In addition, subcutaneous transplantation of CG into rabbits resulted in almost complete degradation of CG after 6 weeks, together with rich vascular generation and proliferation in the transplanted region. Thus, CG can be considered an effective absorbable hemostatic material. PMID- 26590896 TI - Conjugation of steroids with PAMAM nanoparticles. AB - We studied the binding process between polyamidoamine PAMAN-G4 dendrimer and testosterone and its aliphatic (alip) and aromatic (arom) dimers in aqueous solution at pH 7.4. Multiple spectroscopic methods, transmission electron microscopy (TEM) and molecular modeling were used to characterize the steroid binding process to PAMAM-G4 nanoparticles. Thermodynamic parameters DeltaS, DeltaH and DeltaG showed steroid-PAMAM bindings occur via hydrophobic, H-bonding and van der Waals contacts. The binding affinity is testosterone>testosterone aromatic dimer>testosterone-aliphatic dimer. Transmission electron microscopy showed significant changes in carrier morphology with major changes in the diameter of the polymer aggregate as steroid encapsulation occurred. Modeling also showed that testosterone is located in the interior cavity of PAMAM with the free binding energy of -9.36 kcal/mol, indicating of spontaneous steroid-polymer interaction at room temperature. PMID- 26590897 TI - Cellulose binding domain assisted immobilization of lipase (GSlip-CBD) onto cellulosic nanogel: characterization and application in organic medium. AB - A cbd gene was cloned into the C-terminal region of a lip gene from Geobacillus stearothermophilus. The native lipase (43.5 kDa) and CBD-Lip fusion protein (60.2 kDa) were purified to homogeneity by SDS-PAGE. A highly stable cellulosic nanogel was prepared by controlled hydrolysis of microcrystalline cellulose onto which the CBD-lip fusion protein was immobilized through bio-affinity based binding. The nanogel-bound lipase showed optimum activity at 55 degrees C, and it remains stable and active at pH 10-10.5. Furthermore, the immobilized lipase showed an over two-fold increase of relative activity in the presence of DMSO, isopropanol, isoamyl alcohol and n-butanol, but a mild activity decrease at a low concentration of methanol and ethanol. The immobilized biocatalyst retained ~50% activity after eight repetitive hydrolytic cycles. Enzyme kinetic studies of the immobilized lipase showed a 1.24 fold increase in Vmax and 5.25 fold increase in kcat towards p-NPP hydrolysis. Additionally, the nanogel bound lipase was tested to synthesize a biodiesel ester, ethyl oleate in DMSO. Kinetic analysis showed the km 100.5 +/- 4.3 mmol and Vmax 0.19 +/- 0.015 mmolmin(-1) at varied oleic acid concentration. Also, the values of km and Vmax at varying concentration of ethanol were observed to be 95.9 +/- 13.9 mmol and 0.22 +/- 0.013 mmolmin(-1) respectively. The maximum yield of ethyl oleate 111.2 +/- 1.24 mM was obtained under optimized reaction conditions in organic medium. These results suggest that this immobilized biocatalyst can be used as an efficient tool for the biotransformation reactions on an industrial scale. PMID- 26590898 TI - Biogenic selenium nanoparticles inhibit Staphylococcus aureus adherence on different surfaces. AB - The global issue of nosocomial infection is owing to bacterial colonization and biofilm formation on medical devices which primarily affects critically ill and/or immuno-compromised patients and also leads to malfunctioning of the devices. Therefore, it is desirable to prevent bacterial colonization on these devices by coating with a non toxic antimicrobial agent or bacterial adherence inhibitor. Here we have shown Bacillus licheniformis JS2 derived selenium nanoparticles (SeNPs) inhibit Staphylococcus aureus adherence and micro-colony formation on polystyrene, glass, and catheter surface. Results indicated that, the coating of these non toxic biogenic SeNPs, at a concentration of 0.5 mgSe/ml, prohibits bacterial load to more than 60% on glass and catheter surface, when incubated at 4 degrees C for 24h in phosphate buffered saline. Furthermore, confocal and electron microscopic observations strongly suggested the inhibition of biofilm and micro-colony formation on SeNP coated glass and catheter surfaces when cultured at 37 degrees C for 72 h in a nutrient rich medium. The study suggests that coating of biogenic SeNPs on medical devices could be an alternative approach for prevention of biofilm related infections. PMID- 26590899 TI - Impact of poly(lactic-co-glycolic acid) nanoparticle surface charge on protein, cellular and haematological interactions. AB - The initial interactions of nanoparticles with biomolecules have a great influence on its toxicity, efficacy, biodistribution and clearance. The present work is an attempt to understand the impact of surface charge of polymeric nanoparticles on its plasma protein and cellular interactions. Negative, near neutral and positively charged poly(lactic-co-glycolic acid) [PLGA] nanoparticles were prepared using casein, poly(vinyl alcohol) and poly(ethylene imine) respectively, as surface stabilizers. A significant temporal variation in the hydrodynamic diameter of PLGA nanoparticles was observed in the presence of plasma proteins, which correlated with the amount of proteins adsorbed to each surface. Positively charged particles displayed the maximum size variation and protein adsorption. Cellular uptake of differentially charged nanoparticles was also concurrent with the quantity of adsorbed proteins, though there was no significant difference in their cytotoxicity. Haematological interactions (haemolysis and plasma coagulation times) of positively charged nanoparticles were considerably different from near-neutral and negative nanoparticles. Collectively, the results point to the interplay between plasma protein adsorption and cellular interactions of PLGA nanoparticles, which is governed by its surface charge, thereby necessitating a rational design of nanoparticles. PMID- 26590900 TI - An efficient liposome based method for antioxidants encapsulation. AB - Apigenin is an antioxidant that has shown a preventive activity against different cancer and cardiovascular disorders. In this study, we encapsulate apigenin with liposome to tackle the issue of its poor bioavailability and low stability. Apigenin loaded liposomes are fabricated with food-grade rapeseed lecithin in an aqueous medium in absence of any organic solvent. The liposome particle characteristics, such as particle size and polydispersity are optimised by tuning ultrasonic processing parameters. In addition, to measure the liposome encapsulation efficiency accurately, we establish a unique high-performance liquid chromatography technique in which an alkaline buffer mobile phase is used to prevent apigenin precipitation in the column;. salt is added to separate lipid particles from the aqeuous phase. Our results demonstrate that apigenin encapsulation efficiency is nearly 98% that is remarkably higher than any other reported value for encapsulation of this compound. In addition, the average particle size of these liposomes is 158.9 +/- 6.1 nm that is suitable for the formulation of many food products, such as fortified fruit juice. The encapsulation method developed in this study, therefore have a high potential for the production of innovative, functional foods or nutraceutical products. PMID- 26590901 TI - Cancer prevention as part of precision medicine: 'plenty to be done'. AB - Cancer burden worldwide is projected to rise from 14 million new cases in 2012 to 24 million in 2035. Although the greatest increases will be in developing countries, where cancer services are already hard pressed, even the richest nations will struggle to meet demands of increasing patient numbers and spiralling treatment costs. No country can treat its way out of the cancer problem. Consequently, cancer control must combine improvements in treatment with greater emphasis on prevention and early detection. Cancer prevention is founded on describing the burden of cancer, identifying the causes and evaluating and implementing preventive interventions. Around 40-50% of cancers could be prevented if current knowledge about risk factors was translated into effective public health strategies. The benefits of prevention are attested to by major successes, for example, in tobacco control, vaccination against oncogenic viruses, reduced exposure to environmental and occupational carcinogens, and screening. Progress is still needed in areas such as weight control and physical activity. Fresh impetus for prevention and early detection will come through interdisciplinary approaches, encompassing knowledge and tools from advances in cancer biology. Examples include mutation profiles giving clues about aetiology and biomarkers for early detection, to stratify individuals for screening or for prognosis. However, cancer prevention requires a broad perspective stretching from the submicroscopic to the macropolitical, recognizing the importance of molecular profiling and multisectoral engagement across urban planning, transport, environment, agriculture, economics, etc., and applying interventions that may just as easily rely on a legislative measure as on a molecule. PMID- 26590903 TI - A randomised controlled trial of six weeks of home enteral nutrition versus standard care after oesophagectomy or total gastrectomy for cancer: report on a pilot and feasibility study. AB - BACKGROUND: Poor nutrition in the first months after oesophago-gastric resection is a contributing factor to the reduced quality of life seen in these patients. The aim of this pilot and feasibility study was to ascertain the feasibility of conducting a multi-centre randomised controlled trial to evaluate routine home enteral nutrition in these patients. METHODS: Patients undergoing oesophagectomy or total gastrectomy were randomised to either six weeks of home feeding through a jejunostomy (intervention), or treatment as usual (control). Intervention comprised overnight feeding, providing 50 % of energy and protein requirements, in addition to usual oral intake. Primary outcome measures were recruitment and retention rates at six weeks and six months. Nutritional intake, nutritional parameters, quality of life and healthcare costs were also collected. Interviews were conducted with a sample of participants, to ascertain patient and carer experiences. RESULTS: Fifty-four of 112 (48 %) eligible patients participated in the study over the 20 months. Study retention at six weeks was 41/54 patients (76 %) and at six months was 36/54 (67 %). At six weeks, participants in the control group had lost on average 3.9 kg more than participants in the intervention group (95 % confidence interval [CI] 1.6 to 6.2). These differences remained evident at three months (mean difference 2.5 kg, 95 % CI -0.5 to 5.6) and at six months (mean difference 2.5 kg, 95 % CI -1.2 to 6.1). The mean values observed in the intervention group for mid arm circumference, mid arm muscle circumference, triceps skin fold thickness and right hand grip strength were greater than for the control group at all post hospital discharge time points. The economic evaluation suggested that it was feasible to collect resource use and EQ-5D data for a full cost-effectiveness analysis. Thematic analysis of 15 interviews identified three main themes related to the intervention and the trial: 1) a positive experience, 2) the reasons for taking part, and 3) uncertainty of the study process. CONCLUSIONS: This study demonstrated that home enteral feeding by jejunostomy was feasible, safe and acceptable to patients and their carers. Whether home enteral feeding as 'usual practice' is a cost-effective therapy would require confirmation in an appropriately powered, multi-centre study. TRIAL REGISTRATION: UK Clinical Research Network ID 12447 (main trial, first registered 30 May 2012); UK Clinical Research Network ID 13361 (qualitative substudy, first registered 30 May 2012); ClinicalTrials.gov NCT01870817 (first registered 28 May 2013). PMID- 26590902 TI - Fine mapping of chromosome 5p15.33 based on a targeted deep sequencing and high density genotyping identifies novel lung cancer susceptibility loci. AB - Chromosome 5p15.33 has been identified as a lung cancer susceptibility locus, however the underlying causal mechanisms were not fully elucidated. Previous fine mapping studies of this locus have relied on imputation or investigated a small number of known, common variants. This study represents a significant advance over previous research by investigating a large number of novel, rare variants, as well as their underlying mechanisms through telomere length. Variants for this fine-mapping study were identified through a targeted deep sequencing (average depth of coverage greater than 4000*) of 576 individuals. Subsequently, 4652 SNPs, including 1108 novel SNPs, were genotyped in 5164 cases and 5716 controls of European ancestry. After adjusting for known risk loci, rs2736100 and rs401681, we identified a new, independent lung cancer susceptibility variant in LPCAT1: rs139852726 (OR = 0.46, P = 4.73*10(-9)), and three new adenocarcinoma risk variants in TERT: rs61748181 (OR = 0.53, P = 2.64*10(-6)), rs112290073 (OR = 1.85, P = 1.27*10(-5)), rs138895564 (OR = 2.16, P = 2.06*10(-5); among young cases, OR = 3.77, P = 8.41*10(-4)). In addition, we found that rs139852726 (P = 1.44*10(-3)) was associated with telomere length in a sample of 922 healthy individuals. The gene-based SKAT-O analysis implicated TERT as the most relevant gene in the 5p15.33 region for adenocarcinoma (P = 7.84*10(-7)) and lung cancer (P = 2.37*10(-5)) risk. In this largest fine-mapping study to investigate a large number of rare and novel variants within 5p15.33, we identified novel lung and adenocarcinoma susceptibility loci with large effects and provided support for the role of telomere length as the potential underlying mechanism. PMID- 26590904 TI - Patients with exercise-associated ventricular ectopy present evidence of myocarditis. AB - BACKGROUND: The origin and clinical relevance of exercise-induced premature ventricular beats (PVBs) in patients without coronary heart disease or cardiomyopathies is unknown. Cardiovascular magnetic resonance enables us to non invasively assess myocardial scarring and oedema. The purpose of our study was to discover any evidence of myocardial anomalies in patients with exercise-induced ventricular premature beats. METHODS: We examined 162 consecutive patients presenting palpitations and documented exercise-induced premature ventricular beats (PVBs) but no history or evidence of structural heart disease. Results were compared with 70 controls matched for gender and age. ECG-triggered, T2-weighted, fast spin echo triple inversion recovery sequences and late gadolinium enhancement were obtained as well as LV function and dimensions. RESULTS: Structural anomalies in the myocardium and/or pericardium were present in 85 % of patients with exercise-induced PVBs. We observed a significant difference between patients with PVBs and controls in late gadolinium enhancement, that is 68 % presented subepicardial or midmyocardial lesions upon enhancement, whereas only 9 % of the controls did so (p < 0.0001). More patients presented pericardial enhancement (35 %) or pericardial thickening (27 %) compared to controls (21 % and 13 %, p < 0.0001). Myocardial oedema was present in 37 % of the patients and in only one control, p < 0.0001. Left ventricular ejection fraction did not differ between patients and controls (63.1 +/- 7.9 vs. 64.7 +/- 7.0, p = 0.13). CONCLUSIONS: The majority of patients with exercise-associated premature ventricular beats present evidence of myocardial disease consistent with acute or previous myocarditis or myopericarditis. PMID- 26590905 TI - Approaches to management of complaints and notifications about health practitioners in Australia. AB - In 2005, the Australian Productivity Commission made a recommendation that a national health registration regimen and a consolidated national accreditation regimen be established. On 1 July 2010, the National Registration and Accreditation Scheme (NRAS) for health practitioners came into effect and the Australian Health Practitioner Regulation Agency (AHPRA) became the single national oversight agency for health professional regulation. It is governed by the Health Practitioner Regulation National Law Act (the National Law). While all states and territories joined NRAS for registration and accreditation, NSW did not join the scheme for the handling of complaints, but retained its existing co regulatory complaint-handling system. All other states and territories joined the national notification (complaints) scheme prescribed in the National Law. Because the introduction of NRAS brings with it new processes and governance around the management of complaints that apply to all regulated health professionals in all states and territories except NSW, where complaints management remains largely unchanged, there is a need for comparative analysis of these differing national and NSW approaches to the management of complaints/notifications about health professionals, not only to allow transparency for consumers, but also to assess consistency of decision making around complaints/notifications across jurisdictions. This paper describes the similarities and differences for complaints/notifications handling between the NRAS and NSW schemes and briefly discusses subsequent and potential changes in other jurisdictions. PMID- 26590906 TI - Toxicity of Water Accommodated Fractions of Estonian Shale Fuel Oils to Aquatic Organisms. AB - Estonia is the worldwide leading producer of the fuel oils from the oil shale. We evaluated the ecotoxicity of water accommodated fraction (WAF) of two Estonian shale fuel oils ("VKG D" and "VKG sweet") to aquatic species belonging to different trophic levels (marine bacteria, freshwater crustaceans and aquatic plants). Artificial fresh water and natural lake water were used to prepare WAFs. "VKG sweet" (lower density) proved more toxic to aquatic species than "VKG D" (higher density). Our data indicate that though shale oils were very toxic to crustaceans, the short-term exposure of Daphnia magna to sub-lethal concentrations of shale fuel oils WAFs may increase the reproductive potential of survived organisms. The weak correlation between measured chemical parameters (C10-C40 hydrocarbons and sum of 16 PAHs) and WAF's toxicity to studied species indicates that such integrated chemical parameters are not very informative for prediction of shale fuel oils ecotoxicity. PMID- 26590907 TI - Nacre-like hybrid films: Structure, properties, and the effect of relative humidity. AB - Functional materials often are hybrids composed of biopolymers and mineral constituents. The arrangement and interactions of the constituents frequently lead to hierarchical structures with exceptional mechanical properties and multifunctionality. In this study, hybrid thin films with a nacre-like brick-and mortar microstructure were fabricated in a straightforward and reproducible manner through manual shear casting using the biopolymer chitosan as the matrix material (mortar) and alumina platelets as the reinforcing particles (bricks). The ratio of inorganic to organic content was varied from 0% to 15% and the relative humidities from 36% to 75% to determine their effects on the mechanical properties. It was found that increasing the volume fraction of alumina from 0% to 15% results in a twofold increase in the modulus of the film, but decreases the tensile strength by up to 30%, when the volume fraction of alumina is higher than 5%. Additionally, this study quantifies and illustrates the critical role of the relative humidity on the mechanical properties of the hybrid film. Increasing the relative humidity from 36% to 75% decreases the modulus and strength by about 45% and triples the strain at failure. These results suggest that complex hybrid materials can be manufactured and tailor made for specific applications or environmental conditions. PMID- 26590908 TI - Low-temperature degradation of Y-TZP ceramics: A systematic review and meta analysis. AB - The aim of this study was to systematically review the literature to assess if low-temperature degradation (LTD) simulation in autoclave promotes deleterious impact on the mechanical properties and superficial characteristics of Y-TZP ceramics compared to the non-aged protocol. The MEDLINE via PubMed electronic database was searched with included peer-reviewed publications in English language and with no publication year limit. From 413 potentially eligible studies, 49 were selected for full-text analysis, 19 were included in the systematic review with 12 considered in the meta-analysis. Two reviewers independently selected the studies, extracted the data, and assessed the risk of bias. Statistical analysis was performed using RevMan 5.1, with random effects model, at a significance level of p<0.05. Descriptive analysis of monoclinic phase content data showed that aging in autoclave promotes an increase in m-phase content (ranging from 0% up to 13.4% before and 2.13% up to 81.4% after aging) with intensity associated to the material susceptibility and to the aging parameters (time, pressure and temperature). Risk of bias analysis showed that only 1 study presented high risk, while the majority showed medium risk. Five meta-analyzes (factor: aging*control) were performed considering global and subgroups analyzes (pressure, time, temperature and m-phase % content) for flexural strength data. In the global analysis a significant difference (p<0.05) was observed between conditions, favoring non-aging group. Subgroup analysis revealed statistical difference (p<0.05) favoring non-aging, for aging time >20h. However, for shorter aging times (<=20h), there was no difference between groups. Pressure subgroup analysis presented a statistical difference (p<0.05) only when a pressure >=2bar was employed, favoring non-aging group. Temperature subgroup analysis showed a statistical difference (p<0.05) only when temperature=134 degrees C was used, favoring the non-aging group. M-phase % content analysis presented statistical difference (p<0.05) when more than 50% of m-phase content was observed, favoring non-aging group. High heterogeneity was found in some comparisons. Aging in autoclave promoted low-temperature degradation, impacting deleteriously on mechanical properties of Y-TZP ceramics. However, the effect of LTD depends on some methodological parameters indicating that aging time higher than 20h; pressure >=2bar and temperature of 134 degrees C are ideal parameters to promote LTD effects, and that those effect are only observed when more than 50% m-phase content is observed. PMID- 26590909 TI - Rheological, mucoadhesive and textural properties of thermoresponsive polymer blends for biomedical applications. AB - The development of binary polymeric mixtures (polymer blends) containing bioadhesive and thermoresponsive polymers can provide new materials for biomedical applications, with higher contact, increased adhesion, prolonged residence time, protection, and in determined cases, secured absorption of an active agent from the site of application. Mixtures were prepared using a wide range of poloxamer 407 and Carbopol 971P((r)) amounts. The rheological (flow and oscillatory), sol-gel transition temperature, mechanical (hardness, compressibility, adhesiveness, cohesiveness and elasticity), softness, and mucoadhesive properties of formulations were investigated. Moreover, the interaction between the different proportions of polymers was also analyzed. Continuous shear and oscillatory rheometry identified the plastic flow with various degrees of thixotropy, besides the viscoelastic behavior of formulations. The determination of gelation temperature displayed values ranged from 27.17 to 41.09 degrees C. It was also found that low carbomer concentrations were enough to provide positive interaction parameter. However, the highest values were obtained for the polymeric blends with higher concentration of poloxamer 407. The mucoadhesion and softness index were greater in preparations containing 20% (w/w) poloxamer 407. The rheological, mechanical and mucoadhesive properties of the polymeric blends can be manipulated by changing the concentrations of the polymers and they suggest the blends are worthy of biomedical applications. PMID- 26590910 TI - Microstructure, mechanical property and metal release of As-SLM CoCrW alloy under different solution treatment conditions. AB - In the study, the microstructure, mechanical property and metal release behavior of selective laser melted CoCrW alloys under different solution treatment conditions were systemically investigated to assess their potential use in orthopedic implants. The effects of the solution treatment on the microstructure, mechanical properties and metal release were systematically studied by OM, SEM, XRD, tensile test, and ICP-AES, respectively. The XRD indicated that during the solution treatment the alloy underwent the transformation of gamma-fcc to epsilon hcp phase; the epsilon-hcp phase nearly dominated in the alloy when treated at 1200 degrees C following the water quenching; the results from OM, SEM showed that the microstructural change was occurred under different solution treatments; solution at 1150 degrees C with furnace cooling contributed to the formation of larger precipitates at the grain boundary regions, while the size and number of the precipitates was decreased as heated above 1100 degrees C with the water quenching; moreover, the diamond-like structure was invisible at higher solution temperature over 1150 degrees C following water quenching; compared with the furnace cooling, the alloy quenched by water showed excellent mechanical properties and low amount of metal release; as the alloy heated at 1200 degrees C, the mechanical properties of the alloy reached their optimum combination at UTS=1113.6MPa, 0.2%YS=639.5MPa, and E%=20.1%, whilst showed the lower total quantity of metal release. It is suggested that a proper solution treatment is an efficient strategy for improving the mechanical properties and corrosion resistance of As-SLM CoCrW alloy that show acceptable tensile ductility. PMID- 26590912 TI - Gender-Specific Associations in Age-Related Changes in Resting Energy Expenditure (REE) and MRI Measured Body Composition in Healthy Caucasians. AB - BACKGROUND: The effect of gender as well as gender-specific changes of fat free mass (FFM) and its metabolic active components (muscle mass and organ masses [OMs]) and fat mass (FM) on age-related changes in resting energy expenditure (REE) are not well defined. We hypothesized that there are gender differences in (1) the age-specific onset of changes in detailed body composition (2); the onset of changes in body composition-REE associations with age. METHODS: Using a cross sectional magnetic resonance imaging database of 448 Caucasian participants (females and males) with comprehensive data on skeletal muscle (SM) mass, adipose tissue (AT), OMs, and REE. RESULTS: We observed gender-specific differences in the onset of age-related changes in metabolic active components and REE. Declines in body composition and REE started earlier in females than in males for SM (29.4 vs 39.6 years), AT (38.2 vs 49.9 years), OM (34.7 vs 45.7 years), and REE (31.9 vs 36.8 years). The age-related decrease of AT was significantly higher in females than in males (-5.69kg/decade vs -0.59kg/decade). In females adjusted REEmFFM&FM (resting energy expenditure measured adjusted for FFM and FM) and REEmSM/OM/AT (resting energy expenditure measured adjusted for skeletal muscle and organ mass and adipose tissue) decreased by -145 kJ/d/decade and -604.8 kJ/d/ decade after the age of 35.2 respectively 34.3 years. SM was main determinant of REEm in females (R (2) = .67) and males (R (2) = .66) with remaining variance mainly explained by kidney mass (R (2) = .07) in females and liver mass (R (2) = .09) in males. CONCLUSION: We concluded that gender affects the age-related changes in body composition as well as changes in body composition-REE relationship. This trial was registered at linicaltrials.gov as NCT01737034. PMID- 26590913 TI - Abdominal Obesity and Low Skeletal Muscle Mass Jointly Predict Total Mortality and Cardiovascular Mortality in an Elderly Asian Population. AB - BACKGROUND: We investigated the combined impact of abdominal obesity and low skeletal muscle mass on cardiovascular and total mortality in an elderly Asian population. METHODS: A total of 1,485 elderly individuals (>=65 years) from Elderly Nutrition and Health Survey in Taiwan (1999-2000) were enrolled, and their survival status was followed using data from the National Death Registry. Skeletal muscle mass index (SMMI) was calculated by dividing skeletal muscle mass (kg) by height squared (m(2)). Low skeletal muscle mass was defined as the first quartile of SMMI. Abdominal obesity (high triglycerides plus waist circumference [HTGWC]) was defined as triglycerides >=150mg/dL and waist circumference >=90cm (men) and >=80cm (women). The Cox proportional hazard model was used to evaluate the combined impact of abdominal obesity and low SMMI on cardiovascular and total mortality. RESULTS: During follow-up (median 9.2 years), one third (n = 493) of subjects died from any cause, of which 34% (n = 168) were cardiovascular-related. Total and cardiovascular mortality were 4.2 and 1.4 per 100 person-years, respectively. Low SMMI and HTGWC were independently associated with total mortality in men, but only low SMMI was significantly associated in women. Those with both HTGWC and low SMMI had the highest mortality risk, with the cardiovascular mortality risk increased by >6.8-fold and 3.2-fold in men and women, respectively, compared with controls having normal SMMI and TGWC. CONCLUSIONS: Elderly individuals with abdominal obesity and low skeletal muscle mass have higher all-cause and cardiovascular mortality risk. PMID- 26590911 TI - Recent Developments in Understanding Brain Aging: Implications for Alzheimer's Disease and Vascular Cognitive Impairment. AB - As the population of the Western world is aging, there is increasing awareness of age-related impairments in cognitive function and a rising interest in finding novel approaches to preserve cerebral health. A special collection of articles in The Journals of Gerontology: Biological Sciences and Medical Sciences brings together information of different aspects of brain aging, from latest developments in the field of neurodegenerative disorders to cerebral microvascular mechanisms of cognitive decline. It is emphasized that although the cellular changes that occur within aging neurons have been widely studied, more research is required as new signaling pathways are discovered that can potentially protect cells. New avenues for research targeting cellular senescence, epigenetics, and endocrine mechanisms of brain aging are also discussed. Based on the current literature it is clear that understanding brain aging and reducing risk for neurological disease with age requires searching for mechanisms and treatment options beyond the age-related changes in neuronal function. Thus, comprehensive approaches need to be developed that address the multiple, interrelated mechanisms of brain aging. Attention is brought to the importance of maintenance of cerebromicrovascular health, restoring neuroendocrine balance, and the pressing need for funding more innovative research into the interactions of neuronal, neuroendocrine, inflammatory and microvascular mechanisms of cognitive impairment, and Alzheimer's disease. PMID- 26590914 TI - Alcohol consumption and rates of cancer screening: Is cancer risk overestimated? AB - PURPOSE: Alcohol consumption in moderation has been associated with incident breast and colorectal cancer. Whether these associations may be overestimated by more intensive screening among moderate consumers is unknown. This study examines the associations of alcohol consumption with cancer screening. METHODS: In six iterations (2002-2012) of the Behavioral Risk Factor Surveillance System, a telephone survey of US adults conducted by the Centers for Disease Control and Prevention, participants reported their alcohol use and recent screening for several cancers. We assessed whether alcohol use was associated with breast, cervical, and colorectal cancer screening after sample-weighted adjustment for sociodemographic and healthcare utilization factors. RESULTS: Among 2,191,483 survey respondents, 80.5 % (weighted prevalence) of eligible individuals reported having an up-to-date mammogram, 87.7 % having a Pap test, and 56.8 % having a colonoscopy/sigmoidoscopy. For all breast, cervical, and colorectal cancers, moderate consumers were more likely to report screening (84.7, 91.2, 61.1 %) than non-consumers, even after multivariate adjustment (adjusted prevalence ratios 1.04, 1.04, 1.07; p < 0.001 for all). Among binge consumers, the weighted prevalence was lower than that in non-binge consumers (binge vs non-binge moderate consumers 80.5 vs 85.5 %, 89.9 vs 91.8 %, 52.8 vs 63.3 %) but still higher than non-consumers for breast and cervical cancer screening. CONCLUSIONS: In the USA, moderate consumers consistently report a greater likelihood of breast, cervical, and colorectal cancer screening than do non-consumers. Given the likelihood of overdiagnosis, further study of alcohol consumption and cancer should include cancer-specific mortality, which is less sensitive to differences in screening and detection. PMID- 26590915 TI - Alcohol consumption and risk of myelodysplastic syndromes: a case-control study. AB - PURPOSE: Epidemiological studies on alcohol consumption and the risk of myelodysplastic syndromes (MDS) have been inconclusive. We evaluated the association between alcohol consumption and MDS risk in a Chinese population. METHODS: A hospital-based case-control study was conducted between 2012 and 2013 in Hangzhou, China. The analysis included 208 case-control pairs. Diagnosis of MDS was confirmed according to the 2008 World Health Organization classification system. Controls were individually matched to the cases by gender, birth quinquennium, and residential locality. Information on habitual alcohol consumption, diet, and lifestyle was sought from face-to-face interview using a validated questionnaire. Odds ratios (ORs) were calculated using conditional logistic regression. RESULTS: Fewer cases (36.5 %) were classified as alcohol drinkers compared with the controls (48.6 %). Compared with abstainers, the adjusted OR for alcohol drinkers was 0.41 (95 % CI 0.21-0.80), and significant reduced risks were found for light alcohol consumption (<=12.5 g/day of ethanol) and for wine consumption, adjusted ORs (95 % CIs) being 0.27 (0.12-0.61) and 0.12 (0.02-0.79), respectively. Compared with individuals who consumed neither alcohol nor cigarettes, the reduced risk associated with light alcohol consumption was only statistically significant among non-smokers (OR 0.19, 95 % CI 0.06-0.60). CONCLUSIONS: The findings suggest a favorable role of light alcohol consumption in MDS, particularly among non-smokers. PMID- 26590916 TI - Tracing carbon flow through coral reef food webs using a compound-specific stable isotope approach. AB - Coral reefs support spectacularly productive and diverse communities in tropical and sub-tropical waters throughout the world's oceans. Debate continues, however, on the degree to which reef biomass is supported by new water column production, benthic primary production, and recycled detrital carbon (C). We coupled compound specific stable C isotope ratio (delta(13)C) analyses with Bayesian mixing models to quantify C flow from primary producers to coral reef fishes across multiple feeding guilds and trophic positions in the Red Sea. Analyses of reef fishes with putative diets composed primarily of zooplankton (Amblyglyphidodon indicus), benthic macroalgae (Stegastes nigricans), reef-associated detritus (Ctenochaetus striatus), and coral tissue (Chaetodon trifascialis) confirmed that delta(13)C values of essential amino acids from all baseline C sources were both isotopically diagnostic and accurately recorded in consumer tissues. While all four source end-members contributed to the production of coral reef fishes in our study, a single-source end-member often dominated dietary C assimilation of a given species, even for highly mobile, generalist top predators. Microbially reworked detritus was an important secondary C source for most species. Seascape configuration played an important role in structuring resource utilization patterns. For instance, Lutjanus ehrenbergii showed a significant shift from a benthic macroalgal food web on shelf reefs (71 +/- 13 % of dietary C) to a phytoplankton-based food web (72 +/- 11 %) on oceanic reefs. Our work provides insights into the roles that diverse C sources play in the structure and function of coral reef ecosystems and illustrates a powerful fingerprinting method to develop and test nutritional frameworks for understanding resource utilization. PMID- 26590917 TI - The state and potential of social media in bladder cancer. AB - INTRODUCTION: Social media sites and services have become intimately woven into our interpersonal communications and have begun to stake a visible place in healthcare. Disease-specific Twitter hashtags, online patient groups and participation by patients, practitioners and advocacy groups are emblematic of this new paradigm. METHODS: A literature review and summary of resources and publications on bladder cancer and social media. RESULTS: A majority of Western patients have access to and use the Internet for health information. Urologists and oncologists have used bladder-cancer-specific messaging at international meetings infrequently as compared to prostate and other non-urologic cancers. An active community does participate in online discussion, with differences between medical practitioners and patients/advocates. Advice is given with the aim of unifying this discussion. PMID- 26590918 TI - Possible clinical effects of macrolides on the treatment of primary pulmonary mucosa-associated lymphoid tissue lymphoma. PMID- 26590919 TI - The efficacy of the administration of recombinant human soluble thrombomodulin in patients with DIC. AB - Efficacy of recombinant human soluble thrombomodulin (rhTM), which is frequently used to treat patients with disseminated intravascular coagulation (DIC), was compared with that of gabexate mesilate (GM), which was previously used routinely in the treatment of DIC patients in Japan. Although there was no significant difference in the resolution rates of the patients who were treated with rhTM and GM, the results of our analysis revealed that the mortality rate was significantly higher among infectious disease patients treated with GM than in those treated with rhTM. Levels of fibrinogen and fibrin degradation products (FDP), antithrombin (AT) activity, and thrombin AT complex (TAT) were significantly lower in the DIC patients with infectious diseases, while fibrinogen levels were high. FDP level, D-dimer, platelet count, PT ratio, and DIC score all showed significant improvement following rhTM treatment. There were no significant difference between survivors and non-survivors in terms of DIC score, FDP level, platelet count, AT activity, or in TAT, SF and PPIC levels before rhTM treatment. However, fibrinogen levels were significantly lower in non survivors than in survivors. These results indicate that rhTM may be superior to GM for the treatment of DIC. PMID- 26590921 TI - Evaluating Left-Censored Data Through Substitution, Parametric, Semi-parametric, and Nonparametric Methods: A Simulation Study. AB - In this study, an attempt was made to determine the degrees of bias in particular sampling sizes and methods. The aim of the study was to determine deviations from the median, the mean, and the standard deviation (SD) in different sample sizes and at different censoring rates for log-normal, exponential, and Weibull distributions in the case of full and censored data sampling. Thus, the concept of "censoring" and censoring types was handled in the first place. Then substitution, parametric (MLE), nonparametric (KM), and semi-parametric (ROS) methods were introduced for the evaluation of left-censored observations. Within the scope of the present study, the data were produced uncensored based on the different parameters of each distribution. Then the datasets were left-censored at the ratios of 5, 25, 45, and 65 %. The censored data were estimated through substitution (LOD and LOD/[Formula: see text]), parametric (MLE), semi-parametric (ROS), and nonparametric (KM) methods. In addition, evaluation was made by increasing the sample size from 20 to 300 by tens. Performance comparison was made between the uncensored dataset and the censored dataset on the basis of deviations from the median, the mean, and the SD. The results of simulation studies show that LOD/[Formula: see text] and ROS methods give better results than other methods in deviation from the mean in different sample sizes and at different censoring rates, while ROS gives better results than other methods in deviation from the median in almost all sample sizes and at almost all censoring rates. PMID- 26590920 TI - Internal tandem duplication of FLT3 deregulates proliferation and differentiation and confers resistance to the FLT3 inhibitor AC220 by Up-regulating RUNX1 expression in hematopoietic cells. AB - Internal tandem duplication in the FLT3 gene (FLT3/ITD), which is found in patients with acute myeloid leukemia (AML), causes resistance to FLT3 inhibitors. We found that RUNX1, a transcription factor that regulates normal hematopoiesis, is up-regulated in patients with FLT3/ITD(+) AML. While RUNX1 can function as a tumor suppressor, recent data have shown that RUNX1 is required for AML cell survival. In the present study, we investigated the functional role of RUNX1 in FLT3/ITD signaling. FLT3/ITD induced growth factor-independent proliferation and impaired G-CSF mediated myeloid differentiation in 32D hematopoietic cells, coincident with up-regulation of RUNX1 expression. Silencing of RUNX1 expression significantly decreased proliferation and secondary colony formation, and partially abrogated the impaired myeloid differentiation of FLT3/ITD(+) 32D cells. Although the number of FLT3/ITD(+) 32D cells declined after incubation with the FLT3/ITD inhibitor AC220, the cells became refractory to AC220, concomitant with up-regulation of RUNX1. Silencing of RUNX1 abrogated the emergence and proliferation of AC220-resistant FLT3/ITD(+) 32D cells in the presence of AC220. Our data indicate that FLT3/ITD deregulates cell proliferation and differentiation and confers resistance to AC220 by up-regulating RUNX1 expression. These findings suggest an oncogenic role for RUNX1 in FLT3/ITD(+) cells and that inhibition of RUNX1 function represents a potential therapeutic strategy in patients with refractory FLT3/ITD(+) AML. PMID- 26590922 TI - Risk Factors for Varicella Susceptibility Among Refugees to Toronto, Canada. AB - Several outbreaks of varicella have occurred among refugees. We aimed to estimate the prevalence of varicella susceptibility among refugees, and identify risk factors for varicella susceptibility. All refugees rostered at Crossroads Clinic in Toronto, Canada in 2011-2014 were included in our study. Varicella serology was assessed at the initial visit. Refugees' age, sex, education, time since arrival, and climate and population density of birth country were abstracted from the chart. Multivariate logistic regression was used to identify risk factors for varicella susceptibility. 1063 refugees were rostered at Crossroads Clinic during the study; 7.9 % (95 % CI 6.1, 9.7) were susceptible to varicella. Tropical climate (OR 3.20, 95 % CI 1.53, 6.69) and younger age (ORper year of age 0.92, 95 % CI 0.88-0.96) were associated with increased varicella susceptibility. These risk factors for varicella susceptibility should be taken into account to maximize the cost-effectiveness of varicella prevention strategies among refugees. PMID- 26590924 TI - Percutaneous thrombin injection under sonographic guidance for exclusion of non catheterizable post-pancreatitis pseudoaneurysm of the superior mesenteric artery: a minimally invasive and expeditious treatment option. AB - Post-pancreatitis pseudoaneurysms are not uncommon. They have a high associated mortality due to a propensity to rupture. Current standards of treatment advocate immediate intravascular interventions. We describe two cases of alcohol-related post-acute pancreatitis pseudoaneurysms arising from the second-order branches of the superior mesenteric artery (SMA) that were endoluminally inaccessible. Both cases were successfully treated with percutaneous thrombin injection into the pseudoaneurysm sac under ultrasound guidance. We suggest that endoluminally inaccessible pseudoaneurysms that are percutaneously accessible can be expeditiously treated with percutaneous thrombin injection. Further, due to the efficaciousness of this procedure, it could be considered as a first-line minimally invasive therapeutic option. PMID- 26590923 TI - Latina Workers in North Carolina: Work Organization, Domestic Responsibilities, Health, and Family Life. AB - This analysis describes the work organization and domestic work experienced by migrant Latinas, and explores the linkage between work and health. Twenty Latina workers in North Carolina with at least one child under age 12 completed in-depth interviews focused on their work organization, domestic responsibilities, work family conflict, health, and family health. Using a systematic qualitative analysis, these women described a demanding work organization that is contingent and exploitative, with little control or support. They also described demanding domestic roles, with gendered and unequal division of household work. The resulting work-family conflict affects their mental and physical health, and has negative effects on the care and health of their families. The findings from this study highlight that work stressors from an unfavorable work organization create work-family conflict, and that work-family conflict in this population has a negative influence on workers' health and health behaviors. PMID- 26590925 TI - Multilevel Analysis of Childbearing in Childhood in Tanzania's Rufiji District. AB - OBJECTIVES: To examine levels, trends and correlates of childbearing in childhood (CiC) in the Rufiji district of Tanzania from 2002 to 2010. METHODS: Using longitudinal data collected in, and by, the Rufiji health and demographic surveillance system in Tanzania from 2002 to 2010, all women who initiated childbearing in this period (n = 5491) were selected for analysis. CiC was defined as childbearing initiation before age 18. Data analysis involved one-way tabulations of each variable-most of which were socio-demographic-to obtain frequency distributions, cross-tabulations of CiC and each of the independent variables with a Chi square test for associations, and multivariate analysis using multilevel logistic regression to examine covariates of CiC. RESULTS: CiC was 44 % and remained constant over the 2002-2010 period (P = 0.623). The relative odds of CiC was significantly reduced by 83 percent among women with secondary or higher educational attainment relative to CiC among uneducated women (OR = 0.17, CI 0.12-0.23). Moreover, the odds of CiC significantly declines monotonically as relative household wealth increases by quintile (OR = 0.70, CI 0.57-0.86). CiC also declines significantly with employment and marital status of the respondent. CONCLUSIONS: CiC represents a challenging social and health problem. Forty-four percent of first time mothers in Rufiji district of Tanzania are of childhood age, and this has not changed over the past 9 years since 2002. Prioritizing girls' formal education-especially up to secondary level or higher as well as devising some economic empowerment modalities, may be worthwhile measures towards curbing CiC in the study area. PMID- 26590926 TI - Oxygen physiology: sensors and ion channels. PMID- 26590927 TI - Effect of hydroxymethylfurfural (HMF) on mortality of artificially reared honey bee larvae (Apis mellifera carnica). AB - Hydroxymethylfurfural (HMF) is a heat-formed, acid-catalyzed contaminant of sugar syrups, which find their way into honey bee feeding. As HMF was noted to be toxic to adult honey bees, we investigated the toxicity of HMF towards larvae. Therefore we exposed artificially reared larvae to a chronic HMF intoxication over 6 days using 6 different concentrations (5, 50, 750, 5000, 7500 and 10,000 ppm) and a control. The mortality was assessed from day 2 to day 7 (d7) and on day 22 (d22). Concentrations ranging from 5 to 750 ppm HMF did not show any influence on larval or pupal mortality compared to controls (p > 0.05; Kaplan Meier analysis). Concentrations of 7500 ppm or higher caused a larval mortality of 100%. An experimental LC50 of 4280 ppm (d7) and 2424 ppm (d22) was determined. The calculated LD50 was 778 ug HMF per larva on d7 and 441 ug HMF on d22. Additionally, we exposed adult honey bees to high concentrations of HMF to compare the mortality to the results from larvae. On d7 larvae are much more sensitive against HMF than adult honey bees after 6 days of feeding. However, on d22 after emergence adults show a lower LC50, which indicates a higher sensitivity than larvae. As toxicity of HMF against honey bees is a function of time and concentration, our results indicate that HMF in supplemental food will probably not cause great brood losses. Yet sublethal effects might decrease fitness of the colony. PMID- 26590928 TI - Effect of butyl paraben on the development and microbial composition of periphyton. AB - Parabens are extensively used as preservatives and bactericides in personal care and other consumer products, and are commonly found in wastewater and surface water as contaminants. However, few data are currently available on the ecotoxicity of parabens. Periphyton biofilm, a widely distributed microbial aggregate of ecological importance in aquatic environment, is frequently used for water quality monitoring, ecological restoration, and toxicity assessment. In this work, the effects of butyl paraben on the development and microbial composition of periphyton biofilm was studied in a laboratory experiment for 32 days using flow through channels. No effect was observed at the environmental relevant concentration level (0.5 MUg L(-1)) during the experiment. At the highest tested concentration level (5000 MUg L(-1)), following effects were noted: (1) inhibition on algae growth at the end of the experiment as indicated by the chlorophyll a and total biovolume; (2) inhibition of photosynthetic efficiency on day 24 as suggested by the maximal Photosystem II quantum yield (Fv/Fm); (3) decrease of the algal diversity on day 24 and 32 as reflected by the Pielou and Shannon-Weiner indices. Bacteria were less sensitive than algae in the periphyton biofilm, which showed no difference at all tested concentration levels as illustrated by the Biolog EcoPlatesTM analysis. Therefore, we conclude that environmental residues of butyl paraben have a very low risk to periphyton in aquatic ecosystems. PMID- 26590929 TI - Infections and mixed infections with the selected species of Borrelia burgdorferi sensu lato complex in Ixodes ricinus ticks collected in eastern Poland: a significant increase in the course of 5 years. AB - In the years 2008-2009 and 2013-2014, 1620 and 1500 questing Ixodes ricinus ticks, respectively, were examined on the territory of the Lublin province (eastern Poland). The presence of three pathogenic species causing Lyme disease was investigated: Borrelia burgdorferi sensu stricto, B. afzelii and B. garinii. The proportion of I. ricinus ticks infected with B. burgdorferi sensu lato showed a highly significant increase between 2008-2009 and 2013-2014, from 6.0 to 15.3%. A significant increase was noted with regard to all types of infections with individual species: single (4.7-7.8%), dual (1.2-6.6%), and triple (0.1-0.9%). When expressed as the percent of all infections, the frequency of mixed infections increased from 21.4 to 49.2%. Statistical analysis performed with two methods (by calculating of odds ratios and by Fisher's exact test) showed that the frequencies of mixed infections in most cases proved to be significantly greater than expected. The strongest associations were found between B. burgdorferi s. s. and B. afzelii, and between B. burgdorferi s. s. and B. garinii. They appeared to be highly significant (P < 0.0001) when assessed by two methods for 2013-2014, and for the sum of findings for both time periods. The proportions of the individual species detected in the mixed infections in 2008 2009 and 2013-2014 revealed highly significant increases for B. burgdorferi s. s. and B. garinii (from 33.9 to 71.1% and from 18.2 to 82.9%, respectively), and an insignificant decrease for B. afzelii (from 51.4 to 41.6%). The proportions of the species B. burgdorferi s. s., B. afzelii and B. garinii (with combined single and mixed infections) for 2008-2009 and 2013-2014 were: 51.2/44.0 %, 30.6/24.9% and 18.2/31.1%, respectively. In conclusion, our results seem to indicate the detrimental trend of the increasing infection rate of I. ricinus ticks with B. burgdorferi s. l. in eastern Poland, and dramatic enhancement of mixed infections with individual species, which may result in mixed infections of humans and exacerbation of the clinical course of Lyme disease cases on the studied area. PMID- 26590930 TI - Evaluation of DEET and eight essential oils for repellency against nymphs of the lone star tick, Amblyomma americanum (Acari: Ixodidae). AB - DEET and Eight commercially available essential oils (oregano, clove, thyme, vetiver, sandalwood, cinnamon, cedarwood, and peppermint) were evaluated for repellency against host-seeking nymphs of the lone star tick, Amblyomma americanum. Concentration-repellency response was established using the vertical paper bioassay technique for each essential oil and compared with that of N,N diethyl-3-methyl benzamide (DEET), a standard repellent compound present in many commercial repellent formulations. The effective concentration of DEET that repels 50% of ticks (EC50) was estimated at 0.02 mg/cm(2), while EC50s of the essential oils fall between 0.113 and 0.297 mg/cm(2). Based on EC50 estimates, oregano essential oil was the most effective among all essential oils tested, followed by clove, thyme, vetiver, sandalwood, cinnamon, cedarwood, and peppermint oils. None of the tested essential oils demonstrated a level of tick repellency found with DEET. Results from this study illustrated the challenge in search for more effective natural tick repellents. PMID- 26590933 TI - Improved segmentation of low-contrast lesions using sigmoid edge model. AB - PURPOSE: The intensity profile of an image in the vicinity of a tissue's boundary is modeled by a step/ramp function. However, this assumption does not hold in cases of low-contrast images, heterogeneous tissue textures, and where partial volume effect exists. We propose a hybrid algorithm for segmentation of CT/MR tumors in low-contrast, noisy images having heterogeneous/homogeneous or hyper /hypo-intense abnormalities. We also model a smoothed noisy intensity profile by a sigmoid function and employ it to find the true location of boundary more accurately. METHODS: A novel combination of the SVM, watershed, and scattered data approximation algorithms is employed to initially segment a tumor. Small and large abnormalities are treated distinctly. Next, the proposed sigmoid edge model is fitted to the normal profile of the border. The estimated parameters of the model are then utilized to find true boundary of a tissue. RESULTS: We extensively evaluated our method using synthetic images (contaminated with varying levels of noise) and clinical CT/MR data. Clinical images included 57 CT/MR volumes consisting of small/large tumors, very low-/high-contrast images, liver/brain tumors, and hyper-/hypo-intense abnormalities. We achieved a Dice measure of [Formula: see text] and average symmetric surface distance of [Formula: see text] mm. Regarding IBSR dataset, we fulfilled Jaccard index of [Formula: see text]. The average run-time of our code was [Formula: see text] s. CONCLUSION: Individual treatment of small and large tumors and boundary correction using the proposed sigmoid edge model can be used to develop a robust tumor segmentation algorithm which deals with any types of tumors. PMID- 26590931 TI - Prebiotic Vesicle Formation and the Necessity of Salts. AB - Self-assembly is considered one of the driving forces behind abiogenesis and would have been affected by the environmental conditions of early Earth. The formation of membranes is a key step in this process, and unlike large dialkyl membranes of modern cells the first membranes were likely formed from small single-chain amphiphiles, which are environment-sensitive. Fatty acids and their derivatives have been previously characterized in this role without concern for the concentrations of ionic solutes in the suspension. We determined the critical vesicle concentration (CVC) for three single-chain amphiphiles with increasing concentrations of NaCl. All amphiphile species had decreasing CVCs correlated to increasing NaCl concentrations. Decanoic acid and oleic acid were impacted more strongly than monoacylglycerol, likely because of electric shielding of the negatively charged headgroups in the presence of salt. There was no impact on the salt species as 100 mM NaBr, NaCl, and KCl all exhibited the same effect on CVC. This research shows the importance of salt in both the formation of life and in experimental design for aggregation experiments. PMID- 26590934 TI - Chronic groin pain, discomfort and physical disability after recurrent groin hernia repair: impact of anterior and posterior mesh repair. AB - Chronic pain and physical disability are well-known problems after primary groin hernia surgery, but the outcome after recurrent hernia surgery is much less known. PURPOSE: To study the impact of anterior mesh repair (AMR) and posterior mesh repair (PMR) on chronic pain and disability after first recurrent groin hernia surgery in a population-based cohort derived from the Swedish Hernia Register. METHODS: Consecutive unilateral, first and second recurrent hernia repairs, registered between 1998 and 2007, were included. Follow-up was performed in 2009 based on the Inguinal Pain Questionnaire (IPQ) and selective clinical examination, comparing prevalence of pain between AMR, endoscopic (E-PMR) and open posterior mesh repairs (O-PMR) after first recurrent repair. Chronic pain after a second recurrent repair was analysed. RESULTS: Altogether 671 first recurrent repairs were analysed: 329 AMRs, 161 E-PMRs and 181 O-PMRs. IPQ response rate was 70.6%. If the index repair was anterior, the E-PMR was associated with a lower risk of chronic pain and disability compared to AMR [OR 0.54 (CI 0.30-0.97), p = 0.039]. The risk of chronic pain increased after a second recurrent repair. A surgeon's annual volume >5 O-PMRs was related to a lower risk compared to <=5 [OR 0.42 (CI 0.19-0.94), p = 0.034]. CONCLUSION: Endoscopic repair for first recurrent groin hernia surgery, after an index anterior repair, was associated with less chronic pain, discomfort and disability compared to anterior approach. Chronic pain increased after a second recurrent repair. A high surgeon's volume reduced the risk of chronic pain after open posterior mesh repair. PMID- 26590939 TI - Cerebellopontine angle meningioma mimicking vestibular paroxysmia. PMID- 26590938 TI - Neuromyelitis optica presenting as intractable vomiting and hyperCKaemia. PMID- 26590935 TI - The complex and multifactorial relationship between testosterone deficiency (TD), obesity and vascular disease. AB - Testosterone deficiency (TD) is a well-established and recognized medical condition that contributes to several co-morbidities, including metabolic syndrome, visceral obesity and cardiovascular disease (CVD). More importantly, obesity is thought to contribute to TD. This complex bidirectional interplay between TD and obesity promotes a vicious cycle, which further contributes to the adverse effects of TD and obesity and may increase the risk of CVD. Testosterone (T) therapy for men with TD has been shown to be safe and effective in ameliorating the components of the metabolic syndrome (Met S) and in contributiong to increased lean body mass and reduced fat mass and therefore contributes to weight loss. We believe that appropriate T therapy in obese men with TD is a novel medical approach to manage obesity in men with TD. Indeed, other measures of lifestyle and behavioral changes can be used to augment but not fully replace this effective therapeutic approach. It should be noted that concerns regarding the safety of T therapy remain widely unsubstantiated and considerable evidence exists supporting the benefits of T therapy. Thus, it is paramount that clinicians managing obese men with TD be made aware of this novel approach to treatment of obesity. In this review, we discuss the relationship between TD and obesity and highlight the contemporary advancement in management of obesity with pharmacological and surgical approaches, as well as utilization of T therapy and how this intervention may evolve as a novel approach to treatment of obesity in men with TD . PMID- 26590936 TI - NUDT15 R139C-related thiopurine leukocytopenia is mediated by 6-thioguanine nucleotide-independent mechanism in Japanese patients with inflammatory bowel disease. AB - BACKGROUND: NUDT15 R139C (rs116855232) is a recently identified genetic factor responsible for thiopurine-induced leukocytopenia and hair loss. In this study, we investigated the association of NUDT15 R139C with 6-thioguanine nucleotide (6 TGN) levels and thiopurine-induced leukocytopenia in Japanese patients with inflammatory bowel disease (IBD). METHODS: Two hundred and sixty-four subjects (103 healthy volunteers and 161 IBD patients treated with thiopurines) were enrolled. Genotyping for NUDT15 R139C was performed using Custom TaqMan(r) SNP genotyping assays. RESULTS: The NUDT15 C/C, C/T, and T/T genotypes were 80.7, 18.2, and 1.1 %, respectively. The allelic frequency was 10.2 %. Among 161 IBD patients, there was no significant difference in 6-TGN levels among the NUDT15 genotypes. Forty-five patients (27.9 %) developed leukocytopenia (WBC <3000/MUl), and the C/T and T/T genotypes were significantly associated with the development of leukocytopenia (P = 1.7 * 10(-5)). In these patients, 6-TGN levels were not significantly different between NUDT15 genotypes. NUDT15 R139C was significantly associated with early (<8 weeks) (P = 1.03 * 10(-4)) and late (>8 weeks) leukocytopenia (P = 4.3 * 10(-4)). The decrease in WBC count at 2 and 4 weeks was significantly higher in patients with the C/T or T/T genotypes as compared to the patients with the C/C genotype. All patients with the T/T genotype (n = 2) developed early severe hair loss and severe leukocytopenia (<1000/MUl). The logistic regression analysis revealed that NUDT15 R139C was the sole genetic factor responsible for the thiopurine-induced leukocytopenia (P = 0.001). CONCLUSIONS: These results suggest that NUDT15 R139C-related thiopurine-induced leukocytopenia is mediated by a 6-TGN-independent mechanism. PMID- 26590940 TI - Food Access, Chronic Kidney Disease, and Hypertension in the U.S. AB - INTRODUCTION: Greater distance to full-service supermarkets and low income may impair access to healthy diets and contribute to chronic kidney disease (CKD) and hypertension. The study aim was to determine relationships among residence in a "food desert," low income, CKD, and blood pressure. METHODS: Adults in the 2003 2010 National Health and Nutrition Examination Survey (N=22,173) were linked to food desert data (www.ers.usda.gov) by Census Tracts. Food deserts have low median income and are further from a supermarket or large grocery store (>1 mile in urban areas, >10 miles in rural areas). Weighted regression was used to determine the association of residence in a food desert and family income with dietary intake; systolic blood pressure (SBP); and odds of CKD. Data analysis was performed in 2014-2015. RESULTS: Compared with those not in food deserts, participants residing in food deserts had lower levels of serum carotenoids (p<0.01), a biomarker of fruit and vegetable intake, and higher SBP (1.53 mmHg higher, 95% CI=0.41, 2.66) after adjustment for demographics and income. Residence in a food desert was not associated with odds of CKD (OR=1.20, 95% CI=0.96, 1.49). Lower, versus higher, income was associated with lower serum carotenoids (p<0.01) and higher SBP (2.00 mmHg higher for income-poverty ratio <=1 vs >3, 95% CI=1.12, 2.89), but also greater odds of CKD (OR=1.76 for income poverty ratio <=1 vs >3, 95% CI=1.48, 2.10). CONCLUSIONS: Limited access to healthy food due to geographic or financial barriers could be targeted for prevention of CKD and hypertension. PMID- 26590941 TI - Hot Food and Beverage Consumption and the Risk of Esophageal Cancer: A Meta Analysis. AB - CONTEXT: Esophageal cancer is a neoplasm with a poor prognosis. Its two histologic subtypes, esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC), have been associated with different risk factors. The possibility of an association between the consumption of hot food and beverages and esophageal cancer, especially ESCC, has long been suspected, presenting a potentially modifiable risk factor. A meta-analysis of existing observational studies was performed to provide a quantitative estimate of the risk of esophageal cancer associated with the consumption of hot food and drink. EVIDENCE ACQUISITION: A search was conducted through MEDLINE, PubMed, EMBASE, and Current Contents Connect to November 11, 2014. Pooled ORs and 95% CIs were calculated using a random effects model for the risk of esophageal cancer associated with the consumption of hot food and drink. Subgroup analyses were conducted for ESCC and EAC, as well as for studies that adjusted for tobacco smoking and alcohol consumption, two well-recognized risk factors for ESCC. EVIDENCE SYNTHESIS: Consumption of hot food and drink was associated with an increased risk of any esophageal cancer (OR=1.90, 95% CI=1.46, 2.48). Heterogeneity was observed. There was an increased risk of ESCC (OR=2.29, 95% CI=1.79, 2.93), which remained even after adjusting for significant confounding variables (OR=2.39, 95% CI=1.71, 3.33). The relationship was not significant for EAC. CONCLUSIONS: The consumption of hot food and beverages was associated with an increased risk of esophageal cancer, particularly ESCC. PMID- 26590942 TI - Relative Contributions of a Set of Health Factors to Selected Health Outcomes. AB - Although many researchers agree that multiple determinants impact health, there is no consensus regarding the magnitude of the relative contributions of individual health factors to health outcomes. This study presents a method to empirically estimate the relative contributions of health behaviors, clinical care, social and economic factors, and the physical environment to health outcomes using nationally representative county-level data and statistical approaches that account for potential sources of bias. The analyses for this study were conducted in 2014. Data were from the 2010-2013 County Health Rankings & Roadmaps. Data covered 2,996 of 3,141 U.S. counties. Ordinary least squares modeling was used as a baseline model. Multilevel latent growth curve modeling was used to estimate the relative contributions of health factors to health outcomes while accounting for measurement errors and state-specific characteristics. Almost half of the variance of health outcomes was due to state level variation rather than county-level variation. When adjusted for measurement errors and state-level variation using multilevel latent growth curve modeling, the relative contribution of clinical care decreased and that of social and economic factors increased compared with the baseline model. This study presents how potential sources of bias affected the estimates of the relative contributions of a set of modifiable health factors to health outcomes at the county level. Further verification of these approaches with other data sources could lead to a better understanding of the impact of specific health determinants to health outcomes, and will provide useful information on policy interventions. PMID- 26590943 TI - Social and Behavioral Information in Electronic Health Records: New Opportunities for Medicine and Public Health. PMID- 26590944 TI - Cisplatin selectively downregulated the frequency and immunoinhibitory function of myeloid-derived suppressor cells in a murine B16 melanoma model. AB - The objective of this study was to investigate the immunomodulatory effect of cisplatin (DDP) on the frequency, phenotype and function of myeloid-derived suppressor cells (MDSC) in a murine B16 melanoma model. C57BL/6 mice were inoculated with B16 cells to establish the murine melanoma model and randomly received treatment with different doses of DDP. The percentages and phenotype of MDSC after DDP treatment were detected by flow cytometry. The immunoinhibitory function of MDSC was analyzed by assessing the immune responses of cocultured effector cells through CFSE-labeling assay, detection of interferon-gamma production and MTT cytotoxic assay, respectively. Tumor growth and mice survival were monitored to evaluate the antitumor effect of combined DDP and adoptive cytokine-induced killer (CIK) cell therapy. DDP treatment selectively decreased the percentages, modulated the surface molecules and attenuated the immunoinhibitory effects of MDSC in murine melanoma model. The combination of DDP treatment and CIK therapy exerted synergistic antitumor effect against B16 melanoma. DDP treatment selectively downregulated the frequency and immunoinhibitory function of MDSC in B16 melanoma model, indicating the potential mechanisms mediating its immunomodulatory effect. PMID- 26590945 TI - Characterization of promoter of the tuberculosis-resistant gene intracellular pathogen resistance 1. AB - Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis, which most commonly affects the lungs and causes over 1.3 million people die annually. Variation in host genes is known to influence susceptibility to tuberculosis. Expression of the intracellular pathogen resistance 1 (Ipr1) gene could enhance the host resistance to mycobacterium. Here, we analyzed the coding region sequence and promoter of Ipr1 gene of mouse strains C57BL/6 and BALB/c. We found that the coding sequences of Ipr1 gene both in C57BL/6 and in BALB/c mice encode the same protein, while the Ipr1 promoter of BALB/c exists a short deletion and showed a slight of decreased transcriptional activity when compared with C57BL/6. Moreover, the optimal and minimal Ipr1 promoter was identified by luciferase assays using truncated reporter constructs, and the region from -293 to +95 bp showed the highest transcriptional activity and responsible for IFN-gamma stimulation. Furthermore, the results showed that IFN-gamma activates JAK/STAT and NF-kappaB signaling pathways to induce Ipr1 expression, and the signal transducer and activator of transcription 1 (Stat1) are critical for IFN-gamma induced Ipr1 expression, because overexpression of Stat1 promotes Ipr1 transcription, but knockdown of Stat1 reduced Ipr1 expression. Collectively, for the first time, our study characterizes Ipr1 promoter and investigates the positive and negative regulation of Ipr1 expression, providing basic data for application of Ipr1 in animal breeding. PMID- 26590946 TI - Influence of miR-30b regulating humoral immune response by genetic difference. AB - Investigation of genetic difference will be beneficial to researchers to understand the origins and nature of diseases. Previous studies have revealed that L-kynurenine (L-Kyn) level was changed significantly in patient with cancer and that miR-30b play different role in tumor cells and immune cells. Moreover, it has been also conformed that miR-30b involved in the process of L-Kyn-mediated suppression of humoral immune responses induced by lipopolysaccharide (LPS) in human normal B cells separated from volunteers' peripheral blood. Nevertheless, the miR-30b role regulating humoral immune response in B lymphoma cells has been still unclear due to the genetic difference between normal cells and tumor cells. The current study demonstrated that the selected concentration of L-Kyn (100, 1000 MUM) significantly reduced the immunoglobulin M secretion induced by LPS when compared with the control group in B lymphoma, CH12.LX, and BCL-1 cells, which had, at least, incomplete dependence on Aryl hydrocarbon receptor, the receptor of L-Kyn. In addition, although L-Kyn (100 MUM) significantly attenuated the expression of miR-30b in BCL-1 cells rather than in CH12.LX cells, no significant differences in the strength of L-Kyn-mediated suppression of humoral immune responses induced by LPS were detected by enzyme-linked immunosorbent assay between the LPS (10 MUg/ml) + L-Kyn (100 MUM) group and the LPS (10 MUg/ml) + L-Kyn (100 MUM) + miR-30b mimics/miR-30b inhibitor group in CH12.LX and BCL-1 cells, respectively. Further data also showed that mouse Bach2 mRNA was a novel target of miR-30b. These results suggest that genetic difference among cells has a great influence on the miR-30b role in the process of L-Kyn-mediated suppression of humoral immune responses induced by LPS. PMID- 26590947 TI - Induction of an antitumor response using dendritic cells transfected with DNA constructs encoding the HLA-A*02:01-restricted epitopes of tumor-associated antigens in culture of mononuclear cells of breast cancer patients. AB - Advances in oncoimmunology related to the definition of the basic mechanisms of the formation of antitumor immune response, as well as the opening of tumor associated antigens recognized by immune cells, allowed to start developing ways to influence the effector cells of the immune system to generate effective antitumor cytotoxic response. We investigated the possibility to stimulate an antitumor response in a culture of mononuclear cells of breast cancer patients by dendritic cells transfected with HLA-A*02:01-restricted DNA constructs. We isolated dendritic cells from peripheral blood monocytes and delivered our constructs to these cells by magnetic transfection. Additionally, a series of experiments with loading of dendritic cells with autologous tumor cell lysate antigens was conducted. We have shown that dendritic cells transfected with the HLA-A*02:01-restricted DNA constructs are effective in inducing an antitumor response in a culture of mononuclear cells of breast cancer patients. Dendritic cells transfected with DNA constructor dendritic cells loaded with lysate antigens revealed a comparable stimulated cytotoxic response of mononuclear cells to these two ways of antigen delivery. We conclude that using DNA constructs in conjunction with patient stratification by HLA type allows the application of transfected DCs as an effective method to stimulate antitumor immunity in vitro. PMID- 26590948 TI - Renal Involvement in Idiopathic Inflammatory Myopathies. AB - Renal involvement in idiopathic inflammatory myopathies is not as uncommon as was previously thought, as it develops in about one fifth of patients. Clinical presentation includes either acute kidney injury or chronic glomerulonephritis. The former usually develops abruptly during acute phases of rhabdomyolysis: in this case, kidney injury is caused by the toxic effects that myoglobinuria has on the kidney tubules, including cast formation and iron-induced oxidative stress and the development of a third space into the injured muscles. The latter instead has an autoimmune nature, a pleomorphic histological picture, and a more indolent course, with the exception of crescentic glomerulonephritis. Accurate diagnosis and management is crucial for these patients, as timely evaluation and treatment can prevent most of the complications. In the setting of rhabdomyolysis-induced acute kidney injury, the necessity of dialysis can be avoided through aggressive hydration and alkalinization, in order to force diuresis and avoid acidosis and hyperkalemia. In immune-mediated glomerulonephritis, renal biopsy is of undoubtedly value in the diagnostic process and can add prognostic and therapeutic information. In these forms, the development of chronic kidney disease can be prevented or at least delayed by the institution or modification of immunosuppressive treatment. Moreover, the use of drugs that inhibit the renin angiotensin-aldosterone system and some lifestyle modifications, such as smoking cessation, weight loss, and salt restriction have also value in reducing proteinuria and the progression of kidney damage. In this review, we have summarized the currently available evidence and the different case series in an attempt to provide the readers with the most complete and practical notions that are needed to handle these delicate patients. PMID- 26590949 TI - Drug-induced kidney disease: a study of the Japan Renal Biopsy Registry from 2007 to 2015. AB - INTRODUCTION: The Japan Renal Biopsy Registry (J-RBR) was started in 2007 by the Committee for the Standardization of Renal Pathological Diagnosis and the Committee for the Kidney Disease Registry of the Japanese Society of Nephrology. The purpose of this report is to clarify drug-induced kidney disease (DIKD) of renal biopsied cases in Japan. SUBJECTS AND METHODS: We analyzed the data of 26,535 cases that were registered in the J-RBR from 2007 to 2015. RESULTS: Based on clinical and pathological diagnoses, 328 cases (176 males and 152 females) of renal biopsy-proven DIKD were registered in the J-RBR from 2007 to 2015 (1.24 % of all cases). The frequency of DIKD increased with age. The number of cases peaked in the 6th-8th decade in all pathological categories, except for the number of chronic tubulointerstitial lesions (CTIL), which peaked in the 4th-5th decade. Overall, the frequency of DIKD was 3 times higher in the 7th decade than in the 2nd decade (1.86 vs. 0.62 %). The main clinical diagnoses were DIKD in 150 cases (45.7 %), nephrotic syndrome in 66 cases (20.1 %), chronic nephritic syndrome in 55 cases (16.8 %), and rapidly progressive glomerulonephritis in 30 cases (9.1 %). DIKD was registered as a secondary diagnosis in 136 cases (41.5 %). The pathological findings of these cases were glomerular lesions in 105 cases (32.0 %), acute tubulointerstitial lesions (ATIL) in 87 cases (26.5 %), CTIL in 72 cases (22.0 %), and sclerotic glomerular lesions and/or nephrosclerosis in 18 cases (5.5 %). ATIL and CTIL were mainly found in cases in which DIKD was diagnosed on the basis of the patient's clinical findings. In addition, nephrotic syndrome-related membranous nephropathy (MN) was the major cause of renal damage in 59.4 % of the cases involving glomerular injuries. According to the CGA risk classification, high-risk (red zone) cases accounted for 56.1 % of all cases of DIKD and 75.9, 64.9, and 33.3 % of the cases involving ATIL, CTIL, and glomerular injuries, respectively. The causative drugs were identified in 102 cases, including bucillamine in 38 cases of MN, gemcitabine in 3 cases of thrombotic microangiopathy, and other anticancer drugs in 14 cases (anti-vascular endothelial growth factor drugs in 3 cases and propyl thiouracil in 3 cases of anti-neutrophil cytoplasmic antibody-related nephritis). CONCLUSION: Our analysis of the J-RBR revealed that DIKD mainly affects elderly people in Japan. ATIL or CTIL were found in approximately half of the biopsied cases of DIKD, and one third involved glomerular lesions, mainly MN or clinical nephrotic syndrome. PMID- 26590950 TI - Stereoselective Pharmacokinetics of Ketoprofen After Oral Administration of Modified-Release Formulations in Caucasian Healthy Subjects. AB - BACKGROUND AND OBJECTIVES: Ketoprofen, a potent nonsteroidal anti-inflammatory drug, is clinically administered as a racemic mixture. One of the possible metabolism routes of ketoprofen is the inversion of the R- to S-enantiomer in the gastrointestinal tract. Ketoprofen, as a weak acid drug, might undergo recirculation through pancreatic/intestinal juices. The aim of the work was to investigate if a plasma-gastrointestinal tract recirculation of ketoprofen could explain its R-to-S chiral inversion after the oral administration of two modified release formulations: a gastro-resistant delayed-release tablet (Reference) and an extended-release-plus-immediate-release bilayer tablet (Test). METHODS: Sixteen healthy Caucasian volunteers (eight women and eight men) participated in a ketoprofen bioequivalence study. Both formulations were administered with and without food. In both cases, standard meals were given throughout the experiment. R- and S-enantiomers were measured separately using a validated HPLC-UV chiral method. Mean concentration-time profiles of ketoprofen enantiomers in plasma were obtained for men and women. Area under the plasma concentration-time curve, maximum ketoprofen plasma concentration, and time-to-peak were also computed for both isomers, both modes of administration, and both sexes. S/R concentration ratio was assessed as an indicator of enantiomer chiral inversion rate. RESULTS: Differences in the pharmacokinetics of S- and R-ketoprofen enantiomers were found after the Test administration. S-Ketoprofen presented a lower plasma exposure compared to R-enantiomer. However, the S/R concentration ratio increased 1 h (in men) and 2 h (in women) after meal intakes. This was related to pancreatic and/or intestinal and/or biliary secretions of the drug, followed by reabsorption and conversion of the R- to the S-isomer. The lower intestinal pH reported for men would lead to a higher oral bioavailability of the Test formulation and a higher reabsorption of both ketoprofen isomers in this sex. Hence, a higher rise of the S/R concentration ratio could be observed in men. No significant differences between isomers exposure were detected in both sexes after the Reference administration. Different lag times were observed after fed and fasting administration of this formulation; however, drug absorption coincided with food ingestion. Then, drug recirculation affected the S/R ratio from the beginning of drug exposure, minimizing the difference between isomers disposition. CONCLUSIONS: R-to-S conversion rate could be mainly associated with several passages of the drug through the intestinal mucosa. The concentration-time profiles of ketoprofen in plasma after the administration of both formulations evidenced R-to-S conversion of recirculating drug following meal intakes. PMID- 26590951 TI - Faculty perceptions of simulation programs in healthcare education. AB - OBJECTIVE: To identify faculty perceptions of simulation insertion in the undergraduate program, considering the advantages and challenges posed by this resource. METHODS: We conducted a qualitative study with intentional sampling according to pre-defined criteria, following a semi-structured outline regarding data saturation. We have interviewed 14 healthcare instructors from a teaching institution that employs simulation in its syllabi. RESULTS: The majority of the faculty interviewed considered the use of scenario, followed by debriefing, as an excellent teaching tool. However, the faculty also noted a number of difficulties, such as the workload necessary to assemble the scenario, the correlation between scenario goals and the competences of the program, the time spent with the simulation, and the ratio of students to faculty members. CONCLUSIONS: Faculties consider simulation an effective tool in the healthcare program and maintain that the main obstacle faced by them is the logistical demand. PMID- 26590952 TI - Germline Findings in Tumor-Only Sequencing: Points to Consider for Clinicians and Laboratories. AB - Precision oncology holds great potential to improve patient therapies and outcomes. Tumor sequencing is rapidly moving into clinical care as our understanding of the cancer genome and the availability of targeted therapies increase. Analysis of the cancer genome is most informative when paired with germline genomic DNA to delineate inherited and somatic variants. Although tumor only analysis remains the most common methodology for numerous reasons, it holds the potential to identify clinically significant germline variants. Here, we provide anticipatory guidance and points to consider for laboratories and clinicians regarding the potential for germline findings in tumor sequencing. PMID- 26590954 TI - Are self-etch adhesive systems effective in the retention of occlusal sealants? A systematic review and meta-analysis. AB - BACKGROUND: Occlusal sealants are an effective method for caries prevention, although the effectiveness of different application strategies has not been established yet. AIM: This systematic review compared the retention rate of sealants placed on occlusal surfaces following the use of self-etch adhesive systems and traditional acid etching, with or without the application of adhesive system. DESIGN: Literature searching was carried out until June 2015 in PubMed/MEDLINE, CENTRAL, and ClinicalTrials databases selecting randomized clinical trials that evaluated self-etch adhesive systems associated with pit and fissure sealants in primary or permanent molars comprising retention as outcome. From 683 potentially eligible studies, 10 were selected for full-text analysis and 5 were included in the meta-analysis. Two reviewers independently selected the studies, extracted the data, and assessed the bias risk. Pooled-effect estimates were obtained by comparing the retention failure rate between groups (self-etch systems vs acid etching with or without adhesive systems). RESULTS: Significant difference was found between groups, favoring the control group (prior acid etching) (P < 0.05), which showed lower failure rate in the retention of occlusal sealants. High heterogeneity was found on the meta-analysis. Most trials showed good evidence strength. CONCLUSIONS: Occlusal sealants applied with self-etch systems show lower retention throughout time than sealants applied in the conventional approach, regardless of the use of adhesive systems. PMID- 26590953 TI - Associations between body composition and lifestyle factors with bone mineral density according to time since menopause in women from Southern Brazil: a cross sectional study. AB - BACKGROUND: The aim of this study was to investigate whether body composition, dietary pattern and habitual physical activity are associated with BMD according to time since menopause in women from Southern Brazil with no clinical evidence of disease. METHODS: 99 participants were enrolled and anthropometry, body composition and BMD by dual energy x-ray absorptiometry, rest metabolic rate by indirect calorimetry, dietary pattern by semi quantitative food frequency questionnaire and habitual physical activity by pedometer were performed. RESULTS: Mean age was 55.2 +/- 4.9 years and mean time since menopause was 6.8 +/ 1.0 years. Weight, BMI, lean and fat mass and RMR were higher in women with less than 5 years since menopause with normal versus low bone mass. No differences were found in the studied variables between participants with normal or low bone mass and more than 5 years of menopause. Women with > 5 years since menopause had higher prevalence of osteoporosis, as well as lower BMD in all sites when compared to those with less time since menopause. Calories, carbohydrate, protein, fat and micronutrients intake were similar between groups. When the sample was adjusted for time since menopause, the odds ratio (OR) for low bone mass was 5.21 (95% CI 1.57-17.25, P = 0.004) for BMI <25 kg/m(2), for lean mass <37.5 Kg an OR of 4.4 (95% CI 1.64-11.80, P = 0.004, for fat mass <26.0 Kg an OR of 3.39 (95% CI 1.29-8.85, P = 0.010) and for the intake of vitamin A < 700 mcg/day an OR of 3.00 (95% CI 1.13-7.94, P = 0.012). Low meat and eggs intake or low protein intake did not influence the odds ratio for low bone mass. CONCLUSION: In this cross-sectional study with postmenopausal women with no clinical evidence of disease, time since menopause, low lean and fat mass were associated with low bone mass. Calories and macronutrients intake as well as habitual physical activity did not interfere with BMD, but participants were mostly sedentary. Further studies are needed in order to determine whether the adequate intake of specific food groups and the type of physical activity could attenuate the time since menopause impact on BMD. PMID- 26590955 TI - Dual genetic diagnoses: Atypical hand-foot-genital syndrome and developmental delay due to de novo mutations in HOXA13 and NRXN1. AB - We describe a male patient with dual genetic diagnoses of atypical hand-foot genital syndrome (HFGS) and developmental delay. The proband had features of HFGS that included bilateral vesicoureteric junction obstruction with ectopic ureters, brachydactyly of various fingers and toes, hypoplastic thenar eminences, and absent nails on both 4th toes and right 5th toe. The atypical features of HFGS present were bilateral hallux valgus malformations and bilateral preaxial polydactyly of the hands. Chromosomal microarray analysis identified a de novo 0.5 Mb deletion at 2p16.3, including the first four exons of the NRXN1 gene. Whole exome sequencing and subsequent Sanger sequencing identified a de novo missense mutation (c.1123G>T, p.Val375Phe) in exon 2 of the HOXA13 gene, predicted to be damaging and located in the homeobox domain. The intragenic NRXN1 deletion is thought to explain his developmental delay via a separate genetic mechanism. PMID- 26590956 TI - Occupational exposure to volatile anaesthetics: a systematic review. AB - BACKGROUND: The effects of long-term occupational exposure to small concentrations of volatile anaesthetics on health professionals are still uncertain despite the research literature available on this subject. AIMS: To analyse the existing literature on the health effects of volatile anaesthetics on exposed health professionals. METHODS: We performed a systematic review from March 2013 to January 2014. The literature was searched in the Medline and Cochrane libraries using the following keywords: 'Anaesthetics AND occupational health', 'Volatile anaesthetics AND occupational health', 'Sevoflurane AND occupational health' and 'Occupational surveillance AND anaesthetics', with no time limit. We used the Scottish Intercollegiate Guidelines Network to evaluate the quality of studies and to grade the recommendations. RESULTS: From 1429 articles retrieved from the databases and an additional 20 obtained from secondary sources, we excluded 1391 (95.9%). After excluding duplicate publications, we finally included 17 articles in the review. CONCLUSIONS: Evidence for adverse effects of volatile anaesthetics on exposed personnel is scarce and inconsistent, but there is no evidence of adverse effects when environmental levels are kept within legal threshold values. Further studies are needed to improve our knowledge of the effects of occupational exposure to volatile anaesthetics. New surveillance methods that include systematic data collection, clinical signs and biomarkers of exposure are required to formulate consistent and reproducible surveillance criteria for exposed personnel. PMID- 26590957 TI - Bronchial hyperresponsiveness. AB - BACKGROUND: Bronchial hyperresponsiveness (BHR) is often regarded as a 'hallmark' of asthma and bronchoprovocation testing is frequently performed to support a diagnosis of asthma. However, BHR is also found in a spectrum of other lung diseases and can be provoked by a variety of specific stimuli. AIMS: To review the pathophysiology of BHR, discuss various methods of testing for BHR and describe the epidemiology of BHR in a variety of previously studied populations. METHODS: We performed a systematic review of references identified using Medline and hand searches of identified articles. Because of space limitations, we have included those reports that seem most representative of the overall BHR literature. RESULTS: BHR can be induced by a variety of stimuli that trigger a number of different but overlapping physiological mechanisms. Bronchoprovocation testing can be performed using a variety of stimuli, various protocols and differing test criteria, yielding results that may be discordant. Elevated rates of BHR have been reported in studies of smokers, chronic obstructive pulmonary disease patients, atopics, athletes, exposed workers and the general population. CONCLUSIONS: Due to the prevalence of BHR in a spectrum of clinical patients and working populations, clinicians should be aware that BHR is not specific for asthma. When performed correctly, the greatest clinical value of BHR testing is to rule out suspected asthma in patients in whom testing is negative. Assessment of BHR also provides insights into the pathological mechanisms of airway disease. PMID- 26590958 TI - Identification of an antibacterial protein by functional screening of a human oral metagenomic library. PMID- 26590959 TI - Genetic diversity of Vibrio parahaemolyticus strains isolated from farmed Pacific white shrimp and ambient pond water affected by acute hepatopancreatic necrosis disease outbreak in Thailand. AB - Acute hepatopancreatic necrosis disease (AHPND) is an emerging shrimp disease that causes massive die-offs in farmed shrimps. Recent outbreaks of AHPND in Asia have been causing great losses for shrimp culture and have become a serious socioeconomic problem. The causative agent of AHPND is Vibrio parahaemolyticus, which is typically known to cause food-borne gastroenteritis in humans. However, there have been few reports of the epidemiology of V. parahaemolyticus AHPND strains, and the genetic relationship among AHPND strains is unclear. Here, we report the genetic characterization of V. parahaemolyticus strains isolated from AHPND outbreaks in Thailand. We found eight isolates from AHPND-suspected shrimps and pond water that were positive for AHPND markers AP1 and AP2. PCR analysis confirmed that none of these eight AP-positive AHPND strains possesses the genes for the conventional virulence factors affecting to humans, such as thermostable direct hemolysin (TDH), TDH-related hemolysin (TRH) and type III secretion system 2. Phylogenetic analysis by multilocus sequence typing showed that the AHPND strains are genetically diverse, suggesting that AHPND strains were not derived from a single genetic lineage. Our study represents the first report of molecular epidemiology of AHPND-causing V. parahaemolyticus strains using multilocus sequence typing, and provides an insight into their evolutionary mechanisms. PMID- 26590960 TI - Five putative nucleoside triphosphate diphosphohydrolase genes are expressed in Trichomonas vaginalis. AB - Trichomonas vaginalis is a protozoan that parasitizes the human urogenital tract causing trichomoniasis, the most common non-viral sexually transmitted disease. The parasite has unique genomic characteristics such as a large genome size and expanded gene families. Ectonucleoside triphosphate diphosphohydrolase (E NTPDase) is an enzyme responsible for hydrolyzing nucleoside tri- and diphosphates and has already been biochemically characterized in T. vaginalis. Considering the important role of this enzyme in the production of extracellular adenosine for parasite uptake, we evaluated the gene expression of five putative NTPDases in T. vaginalis. We showed that all five putative TvNTPDase genes (TvNTPDase1-5) were expressed by both fresh clinical and long-term grown isolates. The amino acid alignment predicted the presence of the five crucial apyrase conserved regions, transmembrane domains, signal peptides, phosphorylation and catalytic sites. Moreover, a phylogenetic analysis showed that TvNTPDase sequences make up a clade with NTPDases intracellularly located. Biochemical NTPDase activity (ATP and ADP hydrolysis) is responsive to the serum restrictive conditions and the gene expression of TvNTPDases was mostly increased, mainly TvNTPDase2 and TvNTPDase4, although there was not a clear pattern of expression among them. In summary, the present report demonstrates the gene expression patterns of predicted NTPDases in T. vaginalis. PMID- 26590961 TI - Prescription rates of the contraceptive implant in Australia 2008-2012: impact of patient age and area of residence. AB - Background Long-acting reversible contraceptives are an effective means of preventing unwanted pregnancies and associated negative consequences. The Sexual Health and Family Planning Association of Australia has called for efforts to address barriers to the uptake of long-acting reversible contraceptives (LARCs) in Australia, where LARC uptake is thought to be low, though comprehensive data describing use and associated factors is scarce. The aims of this study were to describe patterns of prescriptions for the etonogestrel-releasing subdermal implant (SDI) in Australia, 2008-2012, and associated factors. METHODS: Records of prescriptions written through Australia's Pharmaceutical Benefits Scheme from 2008 to 2012 were obtained, including patient age and geographic location. Direct, age-standardised rates (ASR) of prescriptions were calculated for each year and location, with multivariate analysis used to examine associations between prescription rates and patient age, location and proximity to family planning clinics (FPC) or Aboriginal Medical Services (AMS). RESULTS: ASR of prescriptions rose ~6% per year (OR 1.06, 95%CI: 1.05-1.06) from 13.05 per 1000 (2008) to 15.76 per 1000 (2012; P<0.01). Rates were highest among 15- to 19-year olds, increasing from 20.81 (2008) to 29.09 per 1000 (2012: P<0.01) and lowest among 45- to 49-year-olds, increasing from 3.37 to 3.73 per 1000 (P<0.01). ASR by location were significantly higher in regional than metropolitan areas. CONCLUSIONS: This is the first analysis of SDI prescriptions across all ages and regions of Australia. Uptake of SDI in Australia is increasing but remains low. Significant associations were found between prescription rates and patient age and residence in regional/remote areas. PMID- 26590962 TI - Efficacy and cost-effectiveness of intradiscal methylene blue injection for chronic discogenic low back pain: study protocol for a randomized controlled trial. AB - BACKGROUND: Low back pain (LBP) is a common health problem and a substantial part of LBP is presumed to be attributable to degeneration of the intervertebral disc. For patients suffering from intractable discogenic LBP, there are few evidence based effective interventional treatment options available. In 2010, the results of a randomized controlled trial (RCT) were published concerning "intradiscal methylene blue injection" (IMBI), in which this intervention appeared to be very successful in relieving discogenic pain. Therefore, we decided to repeat this study to investigate whether we could replicate the published results. The results of our preliminary feasibility study gave reason to set up an RCT. The aim of this RCT is to evaluate if IMBI is a more effective treatment of discogenic low back pain as an intradiscal placebo intervention, and furthermore, to assess the cost-effectiveness of this intervention. METHODS/DESIGN: Consecutive discogenic low back pain patients referred to four specialized pain treatment facilities are being screened for eligibility. After a positive standardized provocation discography and informed consent, patients are randomized into two groups. The treatment group receives an intradiscal injection with methylene blue, lidocaine, and contrast, and the control group receives intradiscal isotonic saline with lidocaine and contrast. Main outcome measures are pain at the 6-month follow-up, patient's global impression of change, cost effectiveness, quality of life, disability, and analgesic intake. DISCUSSION: The importance of this study is emphasized by the fact that for intractable discogenic low back pain patients, evidence-based effective pain treatments are rare. If this study establishes clinical success and cost-effectiveness, IMBI could become the "pain treatment of choice" for a selected group of patients with chronic discogenic low back pain for whom noninvasive treatment options have failed. TRIAL REGISTRATION: National Trial register NTR2547 Registered at 29 September 2010 and 31 March 2014. PMID- 26590965 TI - Marie A. Capitanio, MD, FACR (1930-2015). PMID- 26590963 TI - Endovascular repair for acute traumatic transection of the descending thoracic aorta: experience of a single centre with a 12-years follow up. AB - BACKGROUND: Most blunt aortic injuries occur in the proximal proximal descending aorta causing acute transection of this vessel. Generally, surgical repair of the ruptured segment of aorta is associated with high rates of morbidity and mortality and in this view endovascular treatment seems to be a valid and safer alternative. Aim of this article is to review our experience with endovascular approach for the treatment of acute traumatic rupture of descending thoracic aorta. METHODS: From April 2002 to November 2014, 11 patients (9 males and 2 females) were referred to our Department with a diagnosis of acute transection of thoracic aorta. Following preoperative Computed Tomography (CT) evaluation, thoracic endovascular aortic repair (TEVAR) with left subclavian artery coverage was performed. Follow-up consisted clinical and instrumental (CT, Duplex ultrasound) controls at discharge, 1, 3 and 6 months and yearly thereafter. RESULTS: At 12-year follow up, the overall survival for the entire patients cohort was 100 %, no major or minor neurological complications and no episode of left arm claudication occurred. Cardiovascular, respiratory and bleeding complications, in the early period, was represented by minor, non fatal events. No stent graft failure, collapse, leak or distal migration were detected at CT scan during the entire follow up period. CONCLUSIONS: According to our experience, despite the small number of patient population, TEVAR procedure with with left subclavian artery coverage, performed in emergency settings, seems to provide excellent long term results. TRIALS REGISTRATION: The protocol was registered at a public trials registry, www.clinicaltrials.gov (trial identifier NCT02376998 ). PMID- 26590966 TI - Enhanced biocatalytic activity of immobilized Pseudomonas cepacia lipase under sonicated condition. AB - The present work reports the use of biocatalyst and ultrasound for greener synthesis of cinnamyl propionate. The lipase Pseudomonas cepacia was immobilized on a copolymer of hydroxypropyl methyl cellulose and polyvinyl alcohol. This biocatalyst was u sed for ultrasound-assisted synthesis of cinnamyl propionate with the detailed optimization of various reaction parameters. Besides this, protocol was extended to synthesize various industrially important propionate esters. In addition to this, different enzyme-kinetic parameters such as r max and K m(vinyl propionate), K m(cinnamyl alcohol) and K i(cinnamyl alcohol) were studied which presented ordered bi-bi mechanism with an inhibition by cinnamyl alcohol. The developed biocatalyst demonstrated enhancement in catalytic activity and recyclability up to five recycles. Moreover, the biocatalyst was tested to investigate the effects of sonication via various characterization techniques such as scanning electron microscopy, thermogravimetry, and water content analysis. PMID- 26590967 TI - Pretreatment of fibrous biomass and growth of biosurfactant-producing Bacillus subtilis on biomass-derived fermentable sugars. AB - Pretreatment of six fibrous biomasses (switchgrass, alfalfa, soy hulls, soy fiber, DDGS and Baggase) and subsequent hydrolysis using cellulolytic enzymes at a 2.5% (v/v) and 5% (v/v) loading 2.5 (v/v) and 5% (v/v) loading was compared for higher amounts of sugars released. Soaking of biomasses of switchgrass, alfalfa, soy hulls and bagasse in 15% w/w ammonia was optimal at 60 degrees C for 12 h, followed by enzymatic hydrolysis, yielding 72, 70, 80 and 75% carbohydrate conversions, respectively. However, soaking in ammonia was not needed for soy fiber and DDGS as these contained very little lignin. Ultrasonication for 3 min @ 100% amplitude (170 uM) was found to be optimal for soy fiber and DDGS from which 77 and 83% carbohydrate conversion, respectively, was obtained following enzyme treatment at 5% (w/v) enzyme. The sugars released by enzymatic hydrolysis of pretreated biomass were utilized as an energy source by Bacillus subtilis in fermentation media at 2% (w/v) of concentration. In shake flask trials, cell growth was 15-20% higher on hydrolysates of ammonia-treated switchgrass and alfalfa vs. glucose-based control media due to the presence of a wider range of monomeric sugars (glucose, xylose, arabinose, mannose and galactose). In contrast, growth was less on soy hull hydrolysates prepared with ammonia pretreatment. PMID- 26590968 TI - Systematic analyses of the ultraviolet radiation resistance-associated gene product (UVRAG) protein interactome by tandem affinity purification. AB - Ultraviolet radiation resistance-associated gene product (UVRAG) was originally identified as a protein involved in cellular responses to UV irradiation. Subsequent studies have demonstrated that UVRAG plays as an important role in autophagy, a lysosome-dependent catabolic program, as a part of a pro-autophagy PIK3C3/VPS34 lipid kinase complex. Several recent studies have shown that UVRAG is also involved in autophagy-independent cellular functions, such as DNA repair/stability and vesicular trafficking/fusion. Here, we examined the UVRAG protein interactome to obtain information about its functional network. To this end, we screened UVRAG-interacting proteins using a tandem affinity purification method coupled with MALDI-TOF/MS analysis. Our results demonstrate that UVRAG interacts with various proteins involved in a wide spectrum of cellular functions, including genome stability, protein translational elongation, protein localization (trafficking), vacuole organization, transmembrane transport as well as autophagy. Notably, the interactome list of high-confidence UVRAG-interacting proteins is enriched for proteins involved in the regulation of genome stability. Our systematic UVRAG interactome analysis should provide important clues for understanding a variety of UVRAG functions. PMID- 26590969 TI - Daughter-Initiated Cancer Screening Appeals to Mothers. AB - Youth-initiated health interventions may provide a much needed avenue for intergenerational dissemination of health information among families who bear the greatest burden from unequal distribution of morbidity and mortality. The findings presented in this paper are from a pilot study of the feasibility and impact of female youth-initiated messages (mostly daughters) encouraging adult female relatives (mostly mothers) to obtain cancer screening within low-income African American families living in a Southern US state. Results are compared between an intervention and control group. Intervention group youth (n = 22) were exposed to a 60-min interactive workshop where they were assisted to prepare a factual and emotional appeal to their adult relative to obtain specific screening. The face-to-face workshops were guided by the Elaboration Likelihood Model (ELM) and the Theory of Planned Behavior (TPB). Control group girls (n = 18) were only provided with a pamphlet with information about cancer screening and specific steps about how to encourage their relative to obtain screening. Intervention youth (86 %) and adults (82 %) reported that the message was shared while 71 % in the control group reported sharing or receiving the message. Importantly, more women in the intervention group reported that they obtained a screen (e.g., mammogram, Pap smear) directly based on the youth's appeal. These findings can have major implications for youth-initiated health promotion efforts, especially among hard-to-reach populations. PMID- 26590970 TI - "I Hope I Go Out of this World Still Wanting to Learn More": Identity Work in a Lifelong Learning Institute. AB - Objectives : Research on the health-enhancing effects of later life activities gives limited attention to the age-segregated nature of many organizations; such consideration draws into focus identity processes contributing to these benefits. Studies also focus more on social than on educational organizations. We address these limitations by examining older adults' identity work within the Osher Lifelong Learning Institute (OLLI), a not-for-credit later life educational organization. Method : We use qualitative data from three sources: interviews with OLLI participants and staff (n = 32); observations at OLLI courses, events, and two regional conferences (118 hours); and content analysis of program materials. Data analyses followed a grounded theory approach. Results : Analyses revealed identity work allowing members to view themselves as "lifelong learners." This work involved four processes: (a) framing as a college experience, (b) distancing from nonacademic pursuits, (c) embracing the mature love of learning, and (d) (re)casting themselves as lifelong students. Discussion : Our study contributes to research on the benefits of later life activity by illuminating identity work processes operating within an age-segregated educational organization. These processes allow members to positively frame themselves as older adults; however, they not only reinforce stereotypes of younger and older adults but also devalue older adults unable to participate or uninterested in lifelong learning programs. PMID- 26590971 TI - Brief Report: Reduced Prioritization of Facial Threat in Adults with Autism. AB - Typically-developing (TD) adults detect angry faces more efficiently within a crowd than non-threatening faces. Prior studies of this social threat superiority effect (TSE) in ASD using tasks consisting of schematic faces and homogeneous crowds have produced mixed results. Here, we employ a more ecologically-valid test of the social TSE and find evidence of a reduced social TSE in adults with ASD (n = 21) relative to TD controls (n = 28). Unlike TD participants, the ASD group failed to show the normative advantage for detecting angry faces faster than happy faces, either within crowds of neutral or emotional faces. These findings parallel prior work indicating a reduced sensitivity in ASD to facial cues of untrustworthiness, and may reflect a vulnerability for evaluating social harm. PMID- 26590972 TI - Brief Report: Scurvy as a Manifestation of Food Selectivity in Children with Autism. AB - Scurvy was diagnosed in seven children at Boston Children's Hospital. All of the children had a developmental disorder and autism was the most common. They had a long-standing history of food selectivity with diets devoid of fruits and vegetables, and none of the children were supplemented with a multivitamin. They presented with limp, and an elaborate panel of tests and procedures were undertaken before the diagnosis of scurvy was made. Treatment with vitamin C led to rapid recovery of symptoms. This report emphasizes the importance of considering nutritional causes of musculoskeletal symptoms in children with autism and restrictive diets. PMID- 26590973 TI - Is anti-BP180 IgE associated with clinical phenotype? A reply to 'Levels of anti BP180 NC16A IgE do not correlate with severity of disease in the early stages of bullous pemphigoid'. PMID- 26590974 TI - Relation between sonic hedgehog pathway gene polymorphisms and basal cell carcinoma development in the Polish population. AB - In recent decades, increases have been observed in the incidence of nonmelanoma skin cancers, including basal cell carcinoma (BCC) and squamous cell carcinoma. BCC is the most common neoplasm in Caucasian populations. Sonic hedgehog (Shh) pathway impairment plays a key role in BCC pathogenesis, and there is evidence that Shh pathway genetic variations may predispose to BCC development. We genotyped 22 single-nucleotide polymorphisms (SNPs) in 4 Shh pathway genes: SHH, GLI, SMO, and PTCH. The study group consisted of 142 BCC patients and 142 age matched, sex-matched healthy subjects (controls). SNPs were assessed using the PCR-RFLP method. The genotype distribution for the polymorphisms in the rs104894049 331 A/T SHH, rs104894040 349 T/C SHH, and rs41303402 385 G/A SMO genes differed significantly between the BCC patients and the controls. The presence of CC genotype in the SHH rs104894040 349 T/C polymorphism was linked to the highest risk of BCC development (OR 87.9, p < 0.001). Other genotypes, such as the TT in SHH rs104894049 331 A/T and the GG in SMO rs41303402 385 G/A also statistically raised the risk of BCC, but these associations were weaker. Other investigated polymorphisms showed no statistical differences between patients and controls. The results obtained testify to the importance of the SHH and SMO gene polymorphisms in skin cancerogenesis. These results mainly underline the potential role of SHH3 rs104894040 349 T/C gene polymorphism in the development of skin basal cell carcinomas in patients of Polish origin. PMID- 26590975 TI - A Multiagent System for Integrated Detection of Pharmacovigilance Signals. AB - Pharmacovigilance is the scientific discipline that copes with the continuous assessment of the safety profile of marketed drugs. This assessment relies on diverse data sources, which are routinely analysed to identify the so-called "signals", i.e. potential associations between drugs and adverse effects, that are unknown or incompletely documented. Various computational methods have been proposed to support domain experts in signal detection. However, recent comparative studies illustrated that current methods exhibit high false-positive rates, significantly variable performance across different datasets used for analysis and events of interest, but also complementarity in their outcomes. In this regard, in order to reinforce accurate and timely signal detection, we elaborated through an agent-based approach towards systematic, joint exploitation of multiple heterogeneous signal detection methods, data sources and other drug related resources under a common, integrated framework. The approach relies on a multiagent system operating based on a collaborative agent interaction protocol, aiming to implement a comprehensive workflow that comprises of method selection and execution, as well as outcomes' aggregation, filtering, ranking and annotation. This paper presents the design of the proposed multiagent system, discusses implementation issues and demonstrates the applicability of the proposed solution in an example signal detection scenario. This work constitutes a step towards large-scale, integrated and knowledge-intensive computational signal detection. PMID- 26590976 TI - Situated Agents and Humans in Social Interaction for Elderly Healthcare: From Coaalas to AVICENA. AB - Assistive Technologies (AT) are an application area where several Artificial Intelligence techniques and tools have been successfully applied to support elderly or impeded people on their daily activities. However, approaches to AT tend to center in the user-tool interaction, neglecting the user's connection with its social environment (such as caretakers, relatives and health professionals) and the possibility to monitor undesired behaviour providing both adaptation to a dynamic environment and early response to potentially dangerous situations. In previous work we have presented COAALAS, an intelligent social and norm-aware device for elderly people that is able to autonomously organize, reorganize and interact with the different actors involved in elderly-care, either human actors or other devices. In this paper we put our work into context, by first examining what are the desirable properties of such a system, analysing the state-of-the-art on the relevant topics, and verifying the validity of our proposal in a larger context that we call AVICENA. AVICENA's aim is develop a semi-autonomous (collaborative) tool to promote monitored, intensive, extended and personalized therapeutic regime adherence at home based on adaptation techniques. PMID- 26590977 TI - Multi-Agent-Based Simulation of a Complex Ecosystem of Mental Health Care. AB - This paper discusses the creation of an Agent-Based Simulation that modeled the introduction of care coordination capabilities into a complex system of care for patients with Serious and Persistent Mental Illness. The model describes the engagement between patients and the medical, social and criminal justice services they interact with in a complex ecosystem of care. We outline the challenges involved in developing the model, including process mapping and the collection and synthesis of data to support parametric estimates, and describe the controls built into the model to support analysis of potential changes to the system. We also describe the approach taken to calibrate the model to an observable level of system performance. Preliminary results from application of the simulation are provided to demonstrate how it can provide insights into potential improvements deriving from introduction of care coordination technology. PMID- 26590978 TI - Bee Swarm Optimization for Medical Web Information Foraging. AB - The present work is related to Web intelligence and more precisely to medical information foraging. We present here a novel approach based on agents technology for information foraging. An architecture is proposed, in which we distinguish two important phases. The first one is a learning process for localizing the most relevant pages that might interest the user. This is performed on a fixed instance of the Web. The second takes into account the openness and the dynamicity of the Web. It consists on an incremental learning starting from the result of the first phase and reshaping the outcomes taking into account the changes that undergoes the Web. The whole system offers a tool to help the user undertaking information foraging. We implemented the system using a group of cooperative reactive agents and more precisely a colony of artificial bees. In order to validate our proposal, experiments were conducted on MedlinePlus, a benchmark dedicated for research in the domain of Health. The results are promising either for those related to Web regularities and for the response time, which is very short and hence complies the real time constraint. PMID- 26590979 TI - FoodWiki: a Mobile App Examines Side Effects of Food Additives Via Semantic Web. AB - In this article, a research project on mobile safe food consumption system (FoodWiki) is discussed that performs its own inferencing rules in its own knowledge base. Currently, the developed rules examines the side effects that are causing some health risks: heart disease, diabetes, allergy, and asthma as initial. There are thousands compounds added to the processed food by food producers with numerous effects on the food: to add color, stabilize, texturize, preserve, sweeten, thicken, add flavor, soften, emulsify, and so forth. Those commonly used ingredients or compounds in manufactured foods may have many side effects that cause several health risks such as heart disease, hypertension, cholesterol, asthma, diabetes, allergies, alzheimer etc. according to World Health Organization. Safety in food consumption, especially by patients in these risk groups, has become crucial, given that such health problems are ranked in the top ten health risks around the world. It is needed personal e-health knowledge base systems to help patients take control of their safe food consumption. The systems with advanced semantic knowledge base can provide recommendations of appropriate foods before consumption by individuals. The proposed FoodWiki system is using a concept based search mechanism that performs on thousands food compounds to provide more relevant information. PMID- 26590980 TI - Using Semantic Components to Represent Dynamics of an Interdisciplinary Healthcare Team in a Multi-Agent Decision Support System. AB - In healthcare organizations, clinical workflows are executed by interdisciplinary healthcare teams (IHTs) that operate in ways that are difficult to manage. Responding to a need to support such teams, we designed and developed the MET4 multi-agent system that allows IHTs to manage patients according to presentation specific clinical workflows. In this paper, we describe a significant extension of the MET4 system that allows for supporting rich team dynamics (understood as team formation, management and task-practitioner allocation), including selection and maintenance of the most responsible physician and more complex rules of selecting practitioners for the workflow tasks. In order to develop this extension, we introduced three semantic components: (1) a revised ontology describing concepts and relations pertinent to IHTs, workflows, and managed patients, (2) a set of behavioral rules describing the team dynamics, and (3) an instance base that stores facts corresponding to instances of concepts from the ontology and to relations between these instances. The semantic components are represented in first-order logic and they can be automatically processed using theorem proving and model finding techniques. We employ these techniques to find models that correspond to specific decisions controlling the dynamics of IHT. In the paper, we present the design of extended MET4 with a special focus on the new semantic components. We then describe its proof-of-concept implementation using the WADE multi-agent platform and the Z3 solver (theorem prover/model finder). We illustrate the main ideas discussed in the paper with a clinical scenario of an IHT managing a patient with chronic kidney disease. PMID- 26590981 TI - A Systematic Literature Review of Agents Applied in Healthcare. AB - Intelligent agents and healthcare have been intimately linked in the last years. The intrinsic complexity and diversity of care can be tackled with the flexibility, dynamics and reliability of multi-agent systems. The purpose of this review is to show the feasibility of applying intelligent agents in the healthcare domain and use the findings to provide a discussion of current trends and devise future research directions. A review of the most recent literature (2009-2014) of applications of agents in healthcare is discussed, and two classifications considering the main goal of the health systems as well as the main actors involved have been investigated. This review shows that the number of published works exhibits a growing interest of researchers in this field in a wide range of applications. PMID- 26590982 TI - Processing Diabetes Mellitus Composite Events in MAGPIE. AB - The focus of this research is in the definition of programmable expert Personal Health Systems (PHS) to monitor patients affected by chronic diseases using agent oriented programming and mobile computing to represent the interactions happening amongst the components of the system. The paper also discusses issues of knowledge representation within the medical domain when dealing with temporal patterns concerning the physiological values of the patient. In the presented agent based PHS the doctors can personalize for each patient monitoring rules that can be defined in a graphical way. Furthermore, to achieve better scalability, the computations for monitoring the patients are distributed among their devices rather than being performed in a centralized server. The system is evaluated using data of 21 diabetic patients to detect temporal patterns according to a set of monitoring rules defined. The system's scalability is evaluated by comparing it with a centralized approach. The evaluation concerning the detection of temporal patterns highlights the system's ability to monitor chronic patients affected by diabetes. Regarding the scalability, the results show the fact that an approach exploiting the use of mobile computing is more scalable than a centralized approach. Therefore, more likely to satisfy the needs of next generation PHSs. PHSs are becoming an adopted technology to deal with the surge of patients affected by chronic illnesses. This paper discusses architectural choices to make an agent based PHS more scalable by using a distributed mobile computing approach. It also discusses how to model the medical knowledge in the PHS in such a way that it is modifiable at run time. The evaluation highlights the necessity of distributing the reasoning to the mobile part of the system and that modifiable rules are able to deal with the change in lifestyle of the patients affected by chronic illnesses. PMID- 26590983 TI - Beliefs and values about intra-operative teaching and learning: a case study of surgical teachers and trainees. AB - Surgeons require advanced psychomotor skills, critical decision-making and teamwork skills. Much of surgical skills training involve progressive trainee participation in supervised operations where case variability, operating team interaction and environment affect learning, while surgical teachers face the key challenge of ensuring patient safety. Using a theoretical framework of situated learning including cognitive apprenticeship, we explored teachers' and trainees' beliefs and values about intra-operative training and reasons for any differences. A qualitative case study method was used where five teacher-trainee pairs participating in an observed teaching operation were separately interviewed about the same operation. Thematic analysis of transcribed interviews and observations was performed with iterative refinement and a reflexive approach was adopted throughout the study. We found that in all cases, teachers and trainees had shared recognition of learning about technical skills whereas they differed in three cases regarding non-technical skills such as surgical reasoning and team management. Factors contributing to teacher and trainee satisfaction with the process were successful trainee completion of operation without need for surgeon take-over, a positive learning environment and learning new things. Teaching learning behaviours observed and discussed were modeling, coaching and scaffolding, while exploration, reflection and articulation were less common. Our study reveals differing teacher and trainee perspectives of some aspects of intra operative training and surfaces new reasons other than amount of feedback and autonomy given. Factors contributing to different perspectives include teacher and trainee abilities, values and situational influences. Targeted teaching learning strategies could enhance intra-operative learning. PMID- 26590984 TI - Towards a program of assessment for health professionals: from training into practice. AB - Despite multifaceted attempts to "protect the public," including the implementation of various assessment practices designed to identify individuals at all stages of training and practice who underperform, profound deficiencies in quality and safety continue to plague the healthcare system. The purpose of this reflections paper is to cast a critical lens on current assessment practices and to offer insights into ways in which they might be adapted to ensure alignment with modern conceptions of health professional education for the ultimate goal of improved healthcare. Three dominant themes will be addressed: (1) The need to redress unintended consequences of competency-based assessment; (2) The potential to design assessment systems that facilitate performance improvement; and (3) The importance of ensuring authentic linkage between assessment and practice. Several principles cut across each of these themes and represent the foundational goals we would put forward as signposts for decision making about the continued evolution of assessment practices in the health professions: (1) Increasing opportunities to promote learning rather than simply measuring performance; (2) Enabling integration across stages of training and practice; and (3) Reinforcing point-in-time assessments with continuous professional development in a way that enhances shared responsibility and accountability between practitioners, educational programs, and testing organizations. Many of the ideas generated represent suggestions for strategies to pilot test, for infrastructure to build, and for harmonization across groups to be enabled. These include novel strategies for OSCE station development, formative (diagnostic) assessment protocols tailored to shed light on the practices of individual clinicians, the use of continuous workplace-based assessment, and broadening the focus of high-stakes decision making beyond determining who passes and who fails. We conclude with reflections on systemic (i.e., cultural) barriers that may need to be overcome to move towards a more integrated, efficient, and effective system of assessment. PMID- 26590985 TI - TRPM4 protein expression in prostate cancer: a novel tissue biomarker associated with risk of biochemical recurrence following radical prostatectomy. AB - BACKGROUND: Transient receptor potential cation channel, subfamily M, member 4 (TRPM4) messenger RNA (mRNA) has been shown to be upregulated in prostate cancer (PCa) and might be a new promising tissue biomarker. We evaluated TRPM4 protein expression and correlated the expression level with biochemical recurrence (BR) following radical prostatectomy (RP). MATERIAL AND METHODS: The study included 614 patients who had undergone RP. TRPM4 immunohistochemical staining was performed on samples of benign tissue, tissue containing PIN glands and PCa tissue using a commercially available polyclonal antibody. Staining intensity was recorded by two independent observers using a four-tired semi-quantitative grading system (0, 1+, 2+, 3+) converted into H-scores. Interobserver agreement was calculated by linear weighted kappa statistics. The association between staining intensity and BR was analysed using the Kaplan-Meier estimator and uni- and multiple Cox proportional hazard regression models. RESULTS: Significantly higher staining intensity was found in PCa glands compared to benign glands (p < 0.001). The concordance rate in TRPM4 staining intensities for benign, PIN and PCa tissue ranged from 86.0 to 91.5 %, corresponding to linear weighted kappa values of 0.566-0.789. After adjusting for patient and tumour characteristics, patients with a higher staining intensity in PCa glands compared to matched benign glands and an H-score equal to or above the median had an increased risk of BR (HR 1.79-2.62; p = 0.01-0.03 for the two observers) when compared to patients with a lower staining intensity. CONCLUSIONS: TRPM4 protein expression is widely expressed in benign and cancerous prostate tissue, with highest staining intensities found in PCa. Overexpression of TRPM4 in PCa (combination of high staining intensity and a high H-score) is associated with increased risk of BR after RP. PMID- 26590986 TI - Malignant transformation of bone marrow stromal cells induced by the brain glioma niche in rats. AB - Normal human embryonic stem cells (hESCs) can develop neoplastic cancer stem cell (CSC) properties after coculture with transformed hESCs in vitro. In the present study, the influence of the tumor microenvironment on malignant transformation of bone marrow stromal cells (BMSCs) was studied after allografting a mixture of enhanced green fluorescent protein (EGFP)-labeled BMSCs and C6 glioma cells into the rat brain to understand the influence of the cellular environment, especially the tumor environment, on the transformation of grafted BMSCs in the rat brain. We performed intracerebral transplantation in the rat brain using EGFP-labeled BMSCs coinjected with C6 tumor cells. After transplantation, the EGFP-labeled cells were isolated from the tumor using fluorescence-activated cell sorting, and the characteristics of the recovered cells were investigated. Glioma-specific biomarkers of the sorted cells and the biological characteristics of the tumors were analyzed. The BMSCs isolated from the cografts were transformed into glioma CSCs, as indicated by the marked expression of the glioma marker GFAP in glioma cells, and of Nestin and CD133 in neural stem cells and CSCs, as well as rapid cell growth, decreased level of the tumor suppressor gene p53, increased level of the oncogene murine double minute gene 2 (MDM2), and recapitulation of glioma tissues in the brain. These data suggest that BMSCs can be transformed into CSCs, which can be further directed toward glioma formation under certain conditions, supporting the notion that the tumor microenvironment is involved in transforming normal BMSCs into glial CSCs. PMID- 26590987 TI - Characterization, distribution, and risk assessment of heavy metals in agricultural soil and products around mining and smelting areas of Hezhang, China. AB - Mining and smelting have been releasing huge amount of toxic substances into the environment. In the present study, agricultural soil and different agricultural products (potato, Chinese cabbage, garlic bolt, corn) were analyzed to examine the source, spatial distribution, and risk of 12 elements (As, Be, Bi, Cd, Co, Cr, Cu, Hg, Ni, Pb, Sb, and Zn) in agricultural soil near mine fields, smelting fields, and mountain field around Hezhang County, west of Guizhou Province, China. Multivariate statistical analysis indicated that in mining area, As, Bi, Cd, Cu, Hg, Pb, Sb, and Zn were generated from anthropogenic sources; in smelting area, As, Be, Cd, Co, Cu, Pb, Sb, and Zn were derived from anthropogenic sources through zinc smelting ceased in 2004. The enrichment factors (EFs) and ecological risk index (RI) of soil in mining area are the most harmful, showing extremely high enrichment and very high ecological risk of As, Bi, Cd, Cu, Hg, Pb, Sb, and Zn. Zinc is the most significant enriched in the smelting area; however, mountain area has a moderate enrichment and ecological risk and do not present any ecological risk. According to spatial distribution, the concentrations depend on the nearby mining and smelting activities. Transfer factors (TFs) in the smelting area and mountain are high, implying a threat for human consumption. Therefore, further studies should be carried out taking into account the harm of those heavy metals and potential negative health effects from the consumption of agricultural products in these circumstances. PMID- 26590989 TI - Impact of medication therapy management in patients with Parkinson's disease. AB - BACKGROUND: Since the new German Apothekenbetriebsordnung was released, medication therapy management (MTM) has increased in importance. MTM is intended to improve the quality of life of patients. OBJECTIVES: The aim of this study was to improve the quality of life of patients with Parkinson's disease through an MTM by a community pharmacist. SETTING: The patients were recruited in cooperation with the Deutsche Parkinson Vereinigung e.V. (dPV) in Germany. Methods All patients were evaluated at baseline (t0) and after a follow-up of 4 months (t1). During the intervention period, the pharmacists implemented an MTM with standardized pharmaceutical care. Main outcome measure The effects of the interventions were measured by the Unified Parkinson Disease Rating Scale (UPDRS) and the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS UPDRS). RESULTS: In this study, 90 patients with Parkinson's disease were included. The most common intervention was to find a therapy for untreated comorbidities. The UPDRS or MDS-UPDRS improved significantly after the intervention period by a median change rate of 1 (p < 0.05) or rather 2 (p < 0.05) compared to the baseline. CONCLUSION: The study shows that the quality of life in Parkinson's disease patients improved significantly through MTM. PMID- 26590988 TI - Translational Epidemiologic Approaches to Understanding the Consequences of Early Life Exposures. AB - Prominent developmental theories posit a causal link between early-life exposures and later functioning. Yet, observed associations with early exposures may not reflect causal effects because of genetic and environmental confounding. The current manuscript describes how a systematic series of epidemiologic analyses that combine several genetically-informative designs and statistical approaches can help distinguish between competing theories. In particular, the manuscript details how combining the use of measured covariates with sibling-comparisons, cousin-comparisons, and additional designs can help elucidate the sources of covariation between early-life exposures and later outcomes, including the roles of (a) factors that are not shared in families, including a potential causal effect of the exposure; (b) carryover effects from the exposure of one child to the next; and (c) familial confounding. We also describe key assumptions and how they can be critically evaluated. Furthermore, we outline how subsequent analyses, including effect decomposition with respect to measured, plausible mediators, and quantitative genetic models can help further specify the underlying processes that account for the associations between early-life exposures and offspring outcomes. PMID- 26590990 TI - A novelly synthesized phenanthroline derivative is a promising DNA-damaging anticancer agent inhibiting G1/S checkpoint transition and inducing cell apoptosis in cancer cells. AB - PURPOSE: The study mainly aimed to determine the biological function of a novelly synthesized phenanthroimidazole derivative, named L233, and to explore its potential mechanisms. METHODS: Cell survival was examined using the MTT assays, and the DNA-damaging role of L233 was explored using the comet assay. Moreover, the western blotting assays and immunofluorescence assays were used to detect DNA damage biomarkers. Afterward, the flow cytometry was used to assess the effects of L233 on cell cycle distribution. As for the detection of cell apoptosis upon L233 treatment, the Hoechst 33342 staining, flow cytometry, and western blotting assays were all put into practice. RESULTS: We find that L233 inhibits tumor cell growth more efficiently and safely than cisplatin. Moreover, it is a DNA-damaging agent, interrupting the cell cycle G1/S checkpoint transition and inducing cell apoptosis by not only activating ATM/CHK1 signaling pathway, but also targeting CHK1 to reduce the expression of RAP80 and PARP-1 to compromise the DNA damage repair in tumor cells. CONCLUSIONS: In summary, L233 is a promising anticancer drug for the development of novel chemotherapies in the future. PMID- 26590991 TI - The possible meaning of fractional anisotropy measurement of the cervical spinal cord in correct diagnosis of amyotrophic lateral sclerosis. AB - Diagnosis of amyotrophic lateral sclerosis (ALS) is based on clinical criteria and electrophysiological tests (electromyography, and transcranial magnetic stimulation). In the search for ALS biomarkers, the role of imaging procedures is currently emphasized, especially modern MR techniques. MR procedures were performed on 15 ALS patients and a sex- and age-matched control group. The MR examinations were performed with a 1.5-T MR unit, and the protocol consisted of sagittal T1-weighed images, sagittal and axial T2-weighed images, and sagittal T2 weighed FAT SAT images followed by an axial diffusion tensor imaging (DTI) sequence of the cervical spinal cord. FA values in individual segments of the cervical spinal cord were decreased in the ALS group in comparison with the control group. After comparing FA values for anterior, posterior, and lateral corticospinal columns, the greatest difference was observed between the C2 and C5 segments. Spinal cord assessment with the use of FA measurements allows for confirmation of the motor pathways lesion in ALS patients. The method, together with clinical criteria, could be helpful in ALS diagnosis, assessment of clinical course, or even the effects of new drugs. The results also confirmed the theory of the generalized character of ALS. PMID- 26590992 TI - Association of the COQ2 V393A variant with risk of multiple system atrophy in East Asians: a case-control study and meta-analysis of the literature. AB - Recent studies in Japan have associated multiple system atrophy (MSA), a neurodegenerative disease of uncertain etiology, with polymorphism in the COQ2 gene. This led us to explore whether the same polymorphism is associated with MSA in Han Chinese and more broadly in East Asians. We conducted a case-control study with 82 Han Chinese with probable MSA and 484 gender- and age-matched healthy subjects, genotyping them using the ligase detection reaction. The results were meta-analyzed together with data from four previous studies to gain a broader picture of possible disease associations in East Asian populations. The COQ2 variants M78V and R337X were not detected in our Han Chinese patients or controls; only the heterozygous V393A variant (CT genotype) was detected. The frequency of this genotype was significantly higher in patients (7.3%) than in controls (1.86%; OR 4.17, 95% CI 1.44-12.04, p = 0.004). Subgroup analysis among patients showed a significant association of V393A with MSA involving cerebellar signs (MSA-C; OR 4.59, 95% CI 1.36-15.48, p = 0.007), but not with MSA involving parkinsonism (MSA-P). Meta-analysis of our results in Han Chinese with data from case-control studies in Japan, Korea, mainland China and Taiwan showed a significant association of V393A with MSA (OR 2.05, 95% CI 1.29-3.25, p = 0.002), which subgroup analysis showed to be significant for MSA-C (OR 2.75, 95% CI 1.98 3.84, p < 0.001) but not for MSA-P (OR 1.25, 95% CI 0.64-2.46, p = 0.51). These findings provide evidence that the previously reported association of COQ2 V393A polymorphism with increased risk of MSA in Japanese also applies to Han Chinese, as well as more broadly to other East Asian populations. This association may be particularly strong for MSA-C. PMID- 26590993 TI - Rehabilitation of hypomimia in Parkinson's disease: a feasibility study of two different approaches. AB - Parkinson's disease (PD) patients frequently have an impairment of facial expression both in voluntary and spontaneous emotional expression. Aim of this study was to evaluate the feasibility of a rehabilitation program for hypomimia in patients with PD, comparing two different approaches. Thirty-six patients with PD were included: 20 patients received a rehabilitative intervention for hypomimia either with a DVD showing exercises focused on facial muscles (PD-group A) or with a therapist-guided facial rehabilitation with a proprioceptive/recognition approach (PD-group-B). Sixteen patients (PD-Ctrl group) did not receive any treatment and served as control group. The feasibility of the proposed rehabilitation techniques was the main focus of this evaluation. We also evaluate the efficacy of the treatments by means of the sub-item 19 of the Unified Parkinson's disease Rating Scale motor score (UPDRS-III) and by a computerized analysis of facial expression (E-Motion), which was assessed prior to (T0) and after therapy (T1). The proposed rehabilitative program for the treatment of hypomimia was shown to be feasible. Our data show a significant improvement in UPDRS-III sub-item 19 in PD-group-B compared to PD-group-A, (p = 0.005) and to PD-Ctrl (p = 0.003) and in expressivity of fear in PD-group-B compared to PD-Ctrl (p = 0.01). The proposed rehabilitative program showed to be feasible. A larger multi-center trial is now warranted to establish its efficacy to improve facial expression over long time period. PMID- 26590994 TI - Dyspnea caused by osteochondroma of the clavicle head: a case report. AB - Osteochondroma is a benign cartilaginous neoplasm and is the most common benign bone tumor. Osteochondromas arising from the clavicular head are extremely rare and symptomatic cases are even less common. We report a 23-year-old man who presented with dyspnea due to tracheal displacement resulting from a clavicular osteochondroma. The patient underwent successful resection involving a trap-door thoracotomy. PMID- 26590995 TI - Use of general anaesthesia in paediatric dentistry: barriers to discriminate between true and false cases. AB - PURPOSE: The use of general anaesthesia (GA) has shown significant increase in child dental patients. This study aimed to assess whether behaviour management strategies can be the effective methods for decreasing the need for GA and its over-utilisation in paediatric dentistry. METHODS: The patients (n = 240) aged 3 6 years old were selected from referrals by paediatric dentists (PD) or general dentists (GD) for dental treatment under GA. Each child's behaviour during first and subsequent appointments was assessed using the Frankl Behaviour Rating Scale. A first visit included clinical examination and fluoride therapy. In all sessions, a hierarchy of anxiety-reducing behaviour guidance strategies was implemented over nine steps in a logical treatment order. RESULTS: Overall, 47.5% of children referred for dental treatments under GA were retrained to be treated routinely. False referrals were significantly higher in GD compared to PD group. 80.0% of the referred children by PD and 6.7% of those referred by GD were true GA cases and still needed GA. 20.1% of retrained children and 67.4% of true GA cases received conscious sedation. There was no significant change in the frequency of children considered uncooperative as the years of experience increased among GD, while this value was significant for PD. CONCLUSIONS: The findings may highlight the importance of using behaviour management techniques thoroughly prior to referring an uncooperative child for treatment under GA, and may discourage its over-utilisation. Specifically, these skill sets and their efficient practice should be improved among general dentists. PMID- 26590996 TI - Impact of microparticles derived from erythrocytes on fibrinolysis. AB - It has long been known that negatively charged membranes of erythrocyte-derived microparticles display procoagulant activity. However, relatively little is known about the possible fibrinolytic activity of such microparticles. This issue becomes particularly important during red blood cell storage, which significantly increases the number of microparticles. Whole blood was collected from 30 healthy donors. Microparticles were isolated on days 7, 14, 21, and 28 of erythrocyte storage. The effect of microparticles on the fibrinolytic activity of the donor plasma was determined by coagulation and optical (chromogenic substrate) methods. We demonstrated that erythrocyte microparticles had a prominent fibrinolytic activity which cleaves not only fibrin but also chromogenic substrates. Microparticles present fibrinolytic activity mainly due to the presence of plasminogen on them. Microparticles derived from erythrocytes significantly enhance cleavage of the chromogenic substrate by the streptokinase-plasminogen complex, but to a lesser extent accelerate euglobulin clot lysis time. Erythrocyte-derived microparticles display prominent fibrinolytic activity, which significantly decreases during storage of red blood cells. PMID- 26590997 TI - Extended venous thromboembolism prophylaxis after colorectal cancer surgery: the current state of the evidence. AB - There is level one evidence to support combined mechanical and chemical thromboprophylaxis for 7-10 days after colorectal cancer surgery, but there remains a paucity of data to support extended prophylaxis after discharge. The aim of this clinical review is to summarise the currently available evidence for extended venous thromboprophylaxis after elective colorectal cancer surgery. Clinical review of the major clinical guidelines and published clinical data evaluating extended venous thromboprophylaxis after elective colorectal cancer surgery. Five major guideline recommendations are outlined, and the results of the five published randomised controlled trials are summarised and reviewed with a specific focus on the efficacy and cost-effectiveness of extended heparin prophylaxis to prevent clinically relevant post-operative venous thromboembolism (VTE) after colorectal cancer surgery. Extended VTE prophylaxis after colorectal cancer surgery reduces the incidence of asymptomatic screen detected deep venous thrombosis (DVT) only, with no demonstrable reduction in symptomatic DVT, symptomatic PE, or VTE related death. Evidence for cost-effectiveness is limited. As the incidence of clinical VTE is very low in this patient subgroup overall, future research should be focused on higher risk patient subgroups in whom a reduction in VTE may be both more demonstrable and clinically relevant. PMID- 26590998 TI - Aquaporin gene expression and physiological responses of Robinia pseudoacacia L. to the mycorrhizal fungus Rhizophagus irregularis and drought stress. AB - The influence of arbuscular mycorrhiza (AM) and drought stress on aquaporin (AQP) gene expression, water status, and photosynthesis was investigated in black locust (Robinia pseudoacacia L.). Seedlings were grown in potted soil inoculated without or with the AM fungus Rhizophagus irregularis, under well-watered and drought stress conditions. Six full-length AQP complementary DNAs (cDNAs) were isolated from Robinia pseudoacacia, named RpTIP1;1, RpTIP1;3, RpTIP2;1, RpPIP1;1, RpPIP1;3, and RpPIP2;1. A phylogenetic analysis of deduced amino acid sequences demonstrated that putative proteins coded by these RpAQP genes belong to the water channel protein family. Expression analysis revealed higher RpPIP expression in roots while RpTIP expression was higher in leaves, except for RpTIP1;3. AM symbiosis regulated host plant AQPs, and the expression of RpAQP genes in mycorrhizal plants depended on soil water condition and plant tissue. Positive effects were observed for plant physiological parameters in AM plants, which had higher dry mass and lower water saturation deficit and electrolyte leakage than non-AM plants. Rhizophagus irregularis inoculation also slightly increased leaf net photosynthetic rate and stomatal conductance under well watered and drought stress conditions. These findings suggest that AM symbiosis can enhance the drought tolerance in Robinia pseudoacacia plants by regulating the expression of RpAQP genes, and by improving plant biomass, tissue water status, and leaf photosynthesis in host seedlings. PMID- 26590999 TI - MMP-2 Is Mainly Expressed in Arterioles and Contributes to Cerebral Vascular Remodeling Associated with TGF-beta1 Signaling. AB - There is increasing evidence to suggest that matrix metalloproteinases (MMPs) play a crucial role in vascular remodeling. It has been reported that hypoxia stimulated MMP-9 expression in brain endothelial cells and MMP-9 plays an important role in cerebral vascular remodeling. However, little is known about MMP-2 in the cerebral vessels remodeling. Herein, the aim of this study is to examine the class of vessel and cell type expressing MMP-2 in cerebral vessels and to investigate its potential role in vascular remodeling. In the present study, dual-immunofluorescence assay showed that MMP-2 was mainly expressed in arterioles. In addition, we found that MMP-2 expression in cerebral vessels was derived from endothelial cells, not astrocyte cells. Notably, in the normoxic central nervous system (CNS), there was no effect on vascular development, integrity, or endothelial proliferation when MMP-2 was knocked out, but lack of MMP-2 led to defective arteriolar remodeling and associated with transforming growth factor beta1 (TGF-beta1) signaling in CNS. Moreover, blocking TGF-beta with SB431542, a specific TGF-beta inhibitor, significantly reduced the messenger RNA (mRNA) and protein expression levels of MMP-2 in human umbilical vein endothelial cells (HUVECs). Our findings reveal that the level of MMP-2 is high in arteriolar endothelial cells and demonstrate a novel connection between MMP-2 and TGF-beta1 signaling in cerebral vascular remodeling. PMID- 26591000 TI - A novel perspective on neuron study: damaging and promoting effects in different neurons induced by mechanical stress. AB - A growing volume of experimental evidence demonstrates that mechanical stress plays a significant role in growth, proliferation, apoptosis, gene expression, electrophysiological properties and many other aspects of neurons. In this review, first, the mechanical microenvironment and properties of neurons under in vivo conditions are introduced and analyzed. Second, research works in recent decades on the effects of different mechanical forces, especially compression and tension, on various neurons, including dorsal root ganglion neurons, retinal ganglion cells, cerebral cortex neurons, hippocampus neurons, neural stem cells, and other neurons, are summarized. Previous research results demonstrate that mechanical stress can not only injure neurons by damaging their morphology, impacting their electrophysiological characteristics and gene expression, but also promote neuron self-repair. Finally, some future perspectives in neuron research are discussed. PMID- 26591001 TI - Rupatadine in Established Treatment Schemes Improves Chronic Spontaneous Urticaria Symptoms and Patients' Quality of Life: a Prospective, Non interventional Trial. AB - INTRODUCTION: Chronic spontaneous urticaria (CSU) is a common and hard to treat condition associated with a substantial negative impact on patients' quality of life (QoL). Clinical studies have shown that rupatadine is effective and safe in the treatment of CSU, but data from routine clinical care are scarce. Therefore, we assessed the effectiveness and tolerability of rupatadine in established dosages on CSU activity and patients' QoL in a routine daily practice setting. METHODS: This was an open, prospective, non-interventional study performed in 146 dermatological practices in Germany. CSU patients for whom treatment with rupatadine was indicated were eligible to participate. Key symptoms of urticaria activity and their impact on patients' QoL were assessed at the beginning and the end of treatment. Adverse events (AEs) and withdrawals, as well as the dosage regimens chosen, were documented. Patients and physicians were requested to rate effectiveness and tolerability of therapy at the final visit. All statistical analyses were descriptive. RESULTS: The majority of the 660 patients screened to be treated (median age 44 years, IQR = 31-59 years, n = 654) received rupatadine 10 mg tablets once (477 patients) or twice (105 patients) daily for a median time of 28 days. After treatment, 93.2% of the patients (606/650) reported a clear overall improvement of symptoms. Rupatadine significantly reduced the urticaria activity score (UAS7) as well as the frequency and severity of existing angioedema episodes. Similarly all domains of the urticaria-specific QoL questionnaire (CU-Q2oL) were markedly improved. The majority of physicians and patients rated rupatadine treatment as effective and well tolerated. There were 39 (5.9%) early treatment withdrawals, and 21 patients (3.2%) experienced AEs. CONCLUSION: Rupatadine when given according to the routine treating schemes improves symptoms and CU-Q2oL of CSU patients; the drug is also safe and well tolerated. FUNDING: Dr. R. Pfleger GmbH. PMID- 26591002 TI - Gene Expression and Correlation of Pten and Fabp4 in Liver, Muscle, and Adipose Tissues of Type 2 Diabetes Rats. AB - BACKGROUND: The aim of this work was to study the Fabp4 and Pten gene expression and correlation in the liver, muscle, and adipose tissues of type 2 diabetes mellitus (T2DM) rats. MATERIAL AND METHODS: Male Wistar rats (8 weeks old) were randomly divided into 2 groups (n=12/group): a control group fed a normal diet for 8 weeks and an experimental group fed a high-fat, high-sugar diet for 8 weeks and that received 25 mg/kg streptozotocin by intraperitoneal injection to induce T2DM. The random blood glucose, fasting blood glucose, and fasting insulin levels were measured. The expression of Pten and Fabp4 in the liver, muscle, and epididymal adipose tissues was estimated by real-time quantitative PCR. Pearson correlation coefficient analysis was used to investigate the expression correlation between Pten and Fabp4 in T2DM rats. RESULTS: The gene expressions of Pten and Fabp4 in the liver, muscle, and adipose tissues of T2DM rats were all significantly higher than those in the control group (P<0.05). Pten was highly expressed in the muscles and Fabp4 was highly expressed in muscle and adipose tissues. Furthermore, expressions of Fabp4 and Pten in the muscle and adipose tissues of T2DM rats were positively correlated (P<0.05), but not in the liver. CONCLUSIONS: The increased expression of PTEN and FABP4 in the adipose and muscles of T2DM rats may play an important role in the insulin resistance of T2DM. However, the mechanism by which these 2 genes function in T2DM needs further study. PMID- 26591003 TI - Airway clearance techniques for bronchiectasis. AB - BACKGROUND: People with non-cystic fibrosis bronchiectasis commonly experience chronic cough and sputum production, features that may be associated with progressive decline in clinical and functional status. Airway clearance techniques (ACTs) are often prescribed to facilitate expectoration of sputum from the lungs, but the efficacy of these techniques in a stable clinical state or during an acute exacerbation of bronchiectasis is unclear. OBJECTIVES: Primary: to determine effects of ACTs on rates of acute exacerbation, incidence of hospitalisation and health-related quality of life (HRQoL) in individuals with acute and stable bronchiectasis. Secondary: to determine whether:* ACTs are safe for individuals with acute and stable bronchiectasis; and* ACTs have beneficial effects on physiology and symptoms in individuals with acute and stable bronchiectasis. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register of trials from inception to November 2015 and PEDro in March 2015, and we handsearched relevant journals. SELECTION CRITERIA: Randomised controlled parallel and cross-over trials that compared an ACT versus no treatment, sham ACT or directed coughing in participants with bronchiectasis. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as expected by The Cochrane Collaboration. MAIN RESULTS: Seven studies involving 105 participants met the inclusion criteria of this review, six of which were cross over in design. Six studies included adults with stable bronchiectasis; the other study examined clinically stable children with bronchiectasis. Three studies provided single treatment sessions, two lasted 15 to 21 days and two were longer term studies. Interventions varied; some control groups received a sham intervention and others were inactive. The methodological quality of these studies was variable, with most studies failing to use concealed allocation for group assignment and with absence of blinding of participants and personnel for outcome measure assessment. Heterogeneity between studies precluded inclusion of these data in the meta-analysis; the review is therefore narrative.One study including 20 adults that compared an airway oscillatory device versus no treatment found no significant difference in the number of exacerbations at 12 weeks (low-quality evidence). Data were not available for assessment of the impact of ACTs on time to exacerbation, duration or incidence of hospitalisation or total number of hospitalised days. The same study reported clinically significant improvements in HRQoL on both disease-specific and cough-related measures. The median difference in the change in total St George's Respiratory Questionnaire (SGRQ) score over three months in this study was 7.5 units (P value = 0.005 (Wilcoxon)). Treatment consisting of high-frequency chest wall oscillation (HFCWO) or a mix of ACTs prescribed for 15 days significantly improved HRQoL when compared with no treatment (low-quality evidence). Two studies reported mean increases in sputum expectoration with airway oscillatory devices in the short term of 8.4 mL (95% confidence interval (CI) 3.4 to 13.4 mL) and in the long term of 3 mL (P value = 0.02). HFCWO improved forced expiratory volume in one second (FEV1) by 156 mL and forced vital capacity (FVC) by 229.1 mL when applied for 15 days, but other types of ACTs showed no effect on dynamic lung volumes. Two studies reported a reduction in pulmonary hyperinflation among adults with non-positive expiratory pressure (PEP) ACTs (difference in functional residual capacity (FRC) of 19%, P value < 0.05; difference in total lung capacity (TLC) of 703 mL, P value = 0.02) and with airway oscillatory devices (difference in FRC of 30%, P value < 0.05) compared with no ACTs. Low-quality evidence suggests that ACTs (HFCWO, airway oscillatory devices or a mix of ACTs) reduce symptoms of breathlessness and cough and improve ease of sputum expectoration compared with no treatment (P value < 0.05). ACTs had no effect on gas exchange, and no studies reported effects of antibiotic usage. Among studies exploring airway oscillating devices, investigators reported no adverse events. AUTHORS' CONCLUSIONS: ACTs appear to be safe for individuals (adults and children) with stable bronchiectasis and may account for improvements in sputum expectoration, selected measures of lung function, symptoms and HRQoL. The role of these techniques in acute exacerbation of bronchiectasis is unknown. In view of the chronic nature of bronchiectasis, additional data are needed to establish the short-term and long-term clinical value of ACTs for patient-important outcomes and for long-term clinical parameters that impact disease progression in individuals with stable bronchiectasis, allowing further guidance on prescription of specific ACTs for people with bronchiectasis. PMID- 26591005 TI - Raloxifene as an Adjunctive Treatment for Postmenopausal Women With Schizophrenia: A 24-Week Double-Blind, Randomized, Parallel, Placebo-Controlled Trial. AB - The potential therapeutic utility of estrogens in schizophrenia is increasingly being recognized. Raloxifene, a selective estrogen receptor modulator, appears to act similarly to estrogens on dopamine and serotonin brain systems. One previous trial by our team found that raloxifene was useful to improve negative, positive, and general psychopathological symptoms, without having the negative side effects of estrogens. In this study, we assess the utility of raloxifene in treating negative and other psychotic symptoms in postmenopausal women with schizophrenia exhibiting prominent negative symptoms. This was a 24-week, randomized, parallel, double-blind, placebo-controlled study. Patients were recruited from the inpatient and outpatient departments of Parc Sanitari Sant Joan de Deu, Hospital Universitari Institut Pere Mata, and Corporacio Sanitaria Parc Tauli. Seventy postmenopausal women with schizophrenia (DSM-IV) were randomized to either adjunctive raloxifene (38 women) or adjunctive placebo (32 women). Psychopathological symptoms were assessed at baseline and at weeks 4, 12, and 24 with the Positive and Negative Syndrome Scale (PANSS) and the Scale for the Assessment of Negative Symptoms (SANS). The addition of raloxifene (60 mg/d) to regular antipsychotic treatment significantly reduced negative (P = .027), general (P = .003), and total symptomatology (P = .005) measured with the PANSS during the 24-week trial, as compared to women receiving placebo. Also Alogia SANSS subscale improved more in the raloxifene (P = .048) than the placebo group. In conclusion, raloxifene improved negative and general psychopathological symptoms, compared with antipsychotic medication alone, in postmenopausal women with schizophrenia. These data replicate our previous results with a larger sample and a longer follow-up. TRIAL REGISTRATION: NCT01573637. PMID- 26591006 TI - The Dark Side of the Moon: Meta-analytical Impact of Recruitment Strategies on Risk Enrichment in the Clinical High Risk State for Psychosis. AB - BACKGROUND: The individual risk of developing psychosis after being tested for clinical high-risk (CHR) criteria (posttest risk of psychosis) depends on the underlying risk of the disease of the population from which the person is selected (pretest risk of psychosis), and thus on recruitment strategies. Yet, the impact of recruitment strategies on pretest risk of psychosis is unknown. METHODS: Meta-analysis of the pretest risk of psychosis in help-seeking patients selected to undergo CHR assessment: total transitions to psychosis over the pool of patients assessed for potential risk and deemed at risk (CHR+) or not at risk (CHR-). Recruitment strategies (number of outreach activities per study, main target of outreach campaign, and proportion of self-referrals) were the moderators examined in meta-regressions. RESULTS: 11 independent studies met the inclusion criteria, for a total of 2519 (CHR+: n = 1359; CHR-: n = 1160) help seeking patients undergoing CHR assessment (mean follow-up: 38 months). The overall meta-analytical pretest risk for psychosis in help-seeking patients was 15%, with high heterogeneity (95% CI: 9%-24%, I (2) = 96, P < .001). Recruitment strategies were heterogeneous and opportunistic. Heterogeneity was largely explained by intensive (n = 11, beta = -.166, Q = 9.441, P = .002) outreach campaigns primarily targeting the general public (n = 11, beta = -1.15, Q = 21.35, P < .001) along with higher proportions of self-referrals (n = 10, beta = .029, Q = 4.262, P = .039), which diluted pretest risk for psychosis in patients undergoing CHR assessment. CONCLUSIONS: There is meta-analytical evidence for overall risk enrichment (pretest risk for psychosis at 38 monhts = 15%) in help seeking samples selected for CHR assessment as compared to the general population (pretest risk of psychosis at 38 monhts=0.1%). Intensive outreach campaigns predominantly targeting the general population and a higher proportion of self referrals diluted the pretest risk for psychosis. PMID- 26591008 TI - Rapid identification of 6328 isolates of pathogenic yeasts using MALDI-ToF MS and a simplified, rapid extraction procedure that is compatible with the Bruker Biotyper platform and database. AB - Rapid and accurate identification of yeast isolates from clinical samples is essential, given their innately variable antifungal susceptibility profiles, and the proposal of species-specific antifungal susceptibility interpretive breakpoints. Here we have evaluated the utility of MALDI-ToF MS analysis for the identification of clinical isolates of pathogenic yeasts. A simplified, rapid extraction method, developed in our laboratory, was applied to 6343 isolates encompassing 71 different yeast species, which were then subjected to MALDI-ToF MS analysis using a Bruker Microflex and the resulting spectra were assessed using the supplied Bruker database. In total, 6328/6343 (99.8%) of isolates were correctly identified by MALDI-ToF MS. Our simplified extraction protocol allowed the correct identification of 93.6% of isolates, without the need for laborious full extraction, and a further 394 (6.2%) of isolates could be identified after full extraction. Clinically relevant identifications with both extraction methods were achieved using the supplied Bruker database and did not require the generation of bespoke, in-house databases created using profiles obtained with the adapted extraction method. In fact, the mean LogScores obtained using our method were as robust as those obtained using the recommended, published full extraction procedures. However, an in-house database can provide a useful additional identification tool for unusual or rarely encountered organisms. Finally, the proposed methodology allowed the correct identification of over 75% of isolates directly from the initial cultures referred to our laboratory, without the requirement for additional sub-culture on standardised mycological media. PMID- 26591007 TI - Mechanisms Underlying Footshock and Psychological Stress-Induced Abrupt Awakening From Posttraumatic "Nightmares". AB - BACKGROUND: Posttraumatic nightmares are a highly prevalent and distressing symptom of posttraumatic stress disorder (PTSD), but have been the subject of limited phenomenological investigations. METHODS: We utilized a communication box to establish PTSD symptoms in rats through exposure to footshock stress (FS) and psychological stress (PS). The immunohistochemical test and high-performance liquid chromatography with electrochemical detection were used to detect the activity and monoamine levels in the rats' arousal systems. RESULTS: Twenty-one days after traumatic stress, 14.17% of FS and 12.5% of PS rats exhibited startled awakening, and the same rats showed hyperfunction of the locus coeruleus/noradrenergic system and hypofunction of the perifornical nucleus/orexinergic system. Changes in serotonin levels in the dorsal raphe nucleus showed opposite trends in the FS and PS rats that were startled awake. No differences were found in other sleep/arousal systems. CONCLUSION: These results suggest that different clinically therapeutic strategies should be considered to treat different trauma-induced posttraumatic nightmares. PMID- 26591009 TI - In vitro susceptibility of antifungal drugs against Sporothrix brasiliensis recovered from cats with sporotrichosis in Brazil. AB - Sporotrichosis is an important subcutaneous mycosis of humans and animals. Classically, the disease is acquired upon traumatic inoculation of Sporothrix propagules from contaminated soil and plant debris. In addition, the direct horizontal transmission of Sporothrix among animals and the resulting zoonotic infection in humans highlight an alternative and efficient rout of transmission through biting and scratching. Sporothrix brasiliensis is the most virulent species of the Sporothrix schenckii complex and is responsible for the long lasting outbreak of feline sporotrichosis in Brazil. However, antifungal susceptibility data of animal-borne isolates is scarce. Therefore, this study evaluated the in vitro activity of amphotericin B, caspofungin, itraconazole, voriconazole, fluconazole, and ketoconazole against animal-borne isolates of S. brasiliensis. The susceptibility tests were performed through broth microdilution (M38-A2). The results show the relevant activity of itraconazole, amphotericin B, and ketoconazole against S. brasiliensis, with the following MIC ranges: 0.125-2, 0.125-4 and 0.0312-2 MUg/ml, respectively. Caspofungin was moderately effective, displaying higher variation in MIC values (0.25-64 MUg/ml). Voriconazole (2-64 MUg/ml) and fluconazole (62.5-500 MUg/ml) showed low activity against S. brasiliensis strains. This study contributed to the characterization of the in vitro antifungal susceptibility of strains of S. brasiliensis recovered from cats with sporotrichosis, which have recently been considered the main source of human infections. PMID- 26591004 TI - Friends or foes? Emerging insights from fungal interactions with plants. AB - Fungi interact with plants in various ways, with each interaction giving rise to different alterations in both partners. While fungal pathogens have detrimental effects on plant physiology, mutualistic fungi augment host defence responses to pathogens and/or improve plant nutrient uptake. Tropic growth towards plant roots or stomata, mediated by chemical and topographical signals, has been described for several fungi, with evidence of species-specific signals and sensing mechanisms. Fungal partners secrete bioactive molecules such as small peptide effectors, enzymes and secondary metabolites which facilitate colonization and contribute to both symbiotic and pathogenic relationships. There has been tremendous advancement in fungal molecular biology, omics sciences and microscopy in recent years, opening up new possibilities for the identification of key molecular mechanisms in plant-fungal interactions, the power of which is often borne out in their combination. Our fragmentary knowledge on the interactions between plants and fungi must be made whole to understand the potential of fungi in preventing plant diseases, improving plant productivity and understanding ecosystem stability. Here, we review innovative methods and the associated new insights into plant-fungal interactions. PMID- 26591010 TI - Update of phylogenetic and genetic diversity of Sporothrix schenckii sensu lato. AB - Sporothrix schenckii sensu lato causes subcutaneous mycosis. In this article we analysed its phylogeny and genetic diversity using calmodulin DNA sequences deposited in GenBank database. Population genetics indices were calculated, plus phylogenetic and haplotype network trees were built. Five clades with high values of posterior probability, 47 haplotypes and high diversity in the complex were found. Analysis of partial calmodulin sequences alignment revealed conserved and polymorphic regions that could be used as reference for taxonomic identification. The use of population genetics analysis allowed understanding the phylogenetic proximity of S. schenckii s. str. and S. brasiliensis; scarce genetic flow among them with low migration index and high ancestry coefficient was found. Similarly, S. globosa, S. mexicana and S. pallida sequences showed highly differentiated species with no genetic exchange. The phylogenetic tree suggests that S. mexicana shared a common ancestor with S. pallida; while S. globosa and S. brasiliensis are more related to S. schenckii s. str. and showed less haplotype diversity and restrictions in geographic distribution. In the haplotype network tree S. schenckii s. str. species displayed worldwide distribution without dispersion centres; while S. brasiliensis and S. globosa, exhibited Brazil and Euro-Asia as dispersion centres, respectively. Our data suggest that S. schenckii complex has been submitted to a divergent evolution process, probably due to the pressure of the environment and of the host. In contrast, S. brasiliensis could have been submitted to purifying selection or expansion process. PMID- 26591011 TI - [Current topics of periodontal tissue regeneration]. PMID- 26591012 TI - [Diagnosis and treatment of fungal rhinosinusitis]. PMID- 26591013 TI - [Current topics of hearing aid]. PMID- 26591014 TI - [Surgical procedure of preservative function and post operative care for laryngeal and pharyngeal cancer]. PMID- 26591015 TI - [Treatment of salivary stone using endoscopy]. PMID- 26591016 TI - [Laryngeoscopic approach for Lacrimal Apparatus Diseases]. PMID- 26591017 TI - In pursuit of the elusive life balance. Future Leaders introduce new wellness resources. PMID- 26591018 TI - Putting drug testing into practice. PMID- 26591019 TI - Boston pets' century-old guardian Angell. PMID- 26591020 TI - Program helps bring back lapsed patients Partners for Healthy Pets offers new program, convention sessions, other resources. PMID- 26591021 TI - Initiative focuses on racing integrity. AAEP's Prescription for Racing Reformto seek non-race day EIPH treatments. PMID- 26591022 TI - FDA surveying veterinarians on antiparasitic drug resistance. PMID- 26591023 TI - Findings of research misconduct. PMID- 26591024 TI - REPLY by AUTHORS. PMID- 26591025 TI - Preparedness for outbreaks of meningococcal meningitis due to Neisseria meningitidis serogroup C in Africa: recommendations from a WHO expert consultation. PMID- 26591026 TI - Progress towards poliomyelitis eradication: Pakistan, January 2014-September 2015. PMID- 26591027 TI - Monthly report on dracunculiasis cases, January- September 2015. PMID- 26591028 TI - [In search of a better future. Does the placid comfort?]. PMID- 26591029 TI - [First trimester uric acid and adverse pregnancy outcomes in patients with chronic glomerulonephritis during pregnancy]. AB - BACKGROUND: The association between hyperuricemia and adverse perinatal outcome has been studied on numerous occasions, particularly in relation to hypertension and preeclampsia. OBJECTIVES: The objective of this study is to analyze the predictive value of serum concentrations of uric acid during the first trimester of pregnancy for adverse perinatal outcome in women with glomerulopathies. MATERIAL AND METHODS: Twenty-five women diagnosed with glomerulonephritis at the Instituto Nacional de Perinatologia were included in this study. The determination of serum uric acid concentration was made between 7 and 12 weeks of gestation. RESULTS: We finding that Uric acid level in the first trimester showed a significant correlation with blood pressure in the third trimester (Spearman rho coefficient: 0.45, p = 0.04,), with weeks of gestation at birth (Spearman rho coefficient: -0.42, p 0.05), and with weight at birth (Spearman rho coefficient: 0.61 p = 0.003). CONCLUSIONS: The findings of our study suggest the clinical utility of determining and interpreting uric acid in the first trimester in patients with glomerulopathias and mild renal insufficiency (creatinine less than 1.4 mg/dL), and a threshold of 4.8 mg/dL to consider at which a patient can be considered at high risk of premature birth, low birth weight, and preeclampsia. PMID- 26591030 TI - [Mathew's clip, an alternative for removal of IUDs with no visible threads. Experience of Family Planning Service]. AB - BACKGROUND: The absence of IUD visible threads in the cervix is a complication of the intrauterine device. The IUD withdrawal in these cases was performed with Novak cannula or curettage instrumented under anesthesia and surgery. Its extraction with Mathew clip is an alternative. OBJECTIVE: To demostrate the effectiveness of the Mathew's clip as an alternatively for removal of intrauterine devices not visible threads. MATERIAL AND METHODS: A cross sectional, retrospective, descriptive study was conducted in from February 2012 to July 2014 at the Family Planning Service of Gynecology and Obstetrics of the General Hospital of Mexico "Dr. Eduardo Liceaga ". RESULTS: 106 patients (54%) had no visible threads; in 84 patients (81.5 %) it was removed with Novak, cannula; in 19 patients (18.4%) in which it was not possible, the removal was done with a Mathew's clip. DISCUSSION: Mathew' clip is an alternative in cases where it was not possible to remove the IUD with Novak cannula, 19 IUDs no visible threads were removed. CONCLUSIONS. Mathew clip for removal of intrauterine devices with no visible threads means less risk to the patient and a decrease in institutional costs. PMID- 26591031 TI - [Modified technique b-lynch compression suture with uterine atony]. AB - BACKGROUNDS: One of the leading causes of death in the worldwide is postpartum hemorrhage, one of the surgical resources is the use of uterine compression suture described by Christopher B-Lynch and some modifications of the technique. OBJECTIVE: To review the effectiveness of the modified technique describd by B Lynch in early postpartum hemorrhage secondary to uterine atony refractory to medical treatment. MATERIAL AND METHODS: We performed a descriptive and case study of cases of uterine atony treated with the B-Lynch modified technique in our center between march 2012 to september 2013. RESULTS: Hemorrhage was resolved in 21 patients. Obstetric hysterectomy was required in the remaining of two patient. CONCLUSIONS: The B-Lynch modified technique by our group is effective, safe and rapid in the treatment of uterine atony. However, obstetric hysterectomy may be required as a last resort when all other uterine- conserving techniques have failed. PMID- 26591032 TI - [Profile dipper/non-dipper in patient with severe preeclampsia, eclampsia and HELLP syndrome during pregnancy and puerperium]. AB - BACKGROUND: Blood pressure (BP) has a circadian rhythm, decreases at night and increases in the morning (dipper), have been observed in patients with impaired in this profile, increased at night and lower in the morning (no dipper) have increased cardiovascular risk. Preeclampsia-eclampsia complicates about 7% of pregnancies, preeclampsia is known to reverse the normal circadian cycle of the BP. OBJECTIVE: To determine the profile dipper/non-dipper in patients with severe preeclampsia, eclampsia and HELLP syndrome patients in Intensive Care and Obstetrics Hospital Juarez of Mexico. MATERIAL AND METHODS: 15 patients were reviewed, 10 with severe preeclampsia, 4 with HELLP syndrome and 1 eclampsia, systolic, diastolic, mean and pulse PA were analyzed during the day/night and pregnancy/postpartum. Using ratios pregnancy day/night pregnancy, puerperium day/night postpartum dipper/non-dipper profile is determined RESULTS: Maternal age 30 +/- 6.34 years, 7 primiparous (46%) 8 multiparous (54%), pregnancy was 31.67 +/- 4.59 weeks. In all but two results in the ratio of pulse pressure during pregnancy was not the result dipper raiser and did not change during the postpartum period. CONCLUSION: in all patients during pregnancy profile was observed no dipper no change during the postpartum period. The established treatment did not modify this result. So it is appropriate to establish strategies to change this behavior and try to get the patient to regain normal circadian BP rhythm. PMID- 26591033 TI - [Postpartum treatment without interrupting breastfeeding in a patient with Chagas disease]. AB - Chagas disease is a problem of global public health. It is caused by the protozoan Trypanosoma cruzi, which is acquired through exposure to infected triatomine feces, blood transfusion, organ transplantation, orally, by laboratory accidents and congenitally (mother-child); the latter is a public health problem in endemic countries and is the most common form in non-endemic countries. In Mexico, there are few studies on congenital transmission of Chagas disease. The majority of pregnant women with Chagas disease are chronic and asymptomatic, and there is a risk of products with low birth weight and abortions, yet most infants are asymptomatic and treatment in pregnancy is contraindicated. Here, we report a case of a 24-year-old who was diagnosed with Chagas disease by donating blood and confirmed by the State Laboratory of Public Health. Before starting treatment, 13 weeks pregnancy was detected and followed up until the birth; mother was seropositive for Chagas disease and child was negative by parasitological studies. Breastfeeding was initiated at birth and one month, after consulting with experts, treating the mother began with benznidazole for 45 days; in general, the treatment was well tolerated, but the patient remained seropositive. PMID- 26591034 TI - [Complicated ovarian ectopic pregnancy in the second trimester of pregnancy: report of a case]. AB - BACKGROUND: Ectopic pregnancy is one of the ginecobstetric conditions that contribute to increased maternal mortality by 10 to 15% of cases. Ovarian ectopic pregnancy is one of the rare cases and represents up to 3% of ectopic pregnancies. CASE: Female with 33 years old with lower abdominal pain, and pallor. Transvaginal ultrasound showed a live product with 15.3 weeks in left ovary and moderate hemoperitoneum. Exploratory laparotomy was performed with left salpingo-oophorectomy; postoperative course was satisfactory, discharged on the fourth day. CONCLUSION: Ovarian pregnancy is a rare form of presentation. Preoperative diagnosis is difficult and must have a high level of diagnostic suspicion with physical examination and imaging studies. Treatment will vary according to clinical and diagnostic precocity. PMID- 26591035 TI - [Postpartum left ovarian vein thrombosis: case report and literature review]. AB - BACKGROUND: Ovarian Vein Thrombosis is an uncommon complication of the puerperium. Its unspecific clinical presentation and its low incidence make it difficult to diagnose. CASE REPORT: A 36-year-old pregnant woman has a vaginal delivery at 39+2 weeks of gestation and develops left lumbar pain irradiated to the left iliac fossa. She is diagnosed of left ovarian vein thrombosis by sonography and TC and receives anticoagulant treatment. DISCUSSION: A high index of suspicion is the key to a correct diagnosis and treatment. Confirmation with modern imaging methods is crucial for the diagnosis and treatment nowadays. CONCLUSION: The best results and lower rate of complications are achieved with an early diagnosis and anticoagulant treatment. PMID- 26591036 TI - [Clinical implications of basic research in preeclampsia: immunological tolerance]. AB - Preeclampsia is one of the main causes of maternal and perinatal mortality in the world; however, the pathophysiologic pathways haven't been clearly elucidated. It is thought to result from a breakdown of maternal tolerance to paternal antigens in placenta that start an immune response against the trophoblast inducing a defective placentation and a hipoxic/isquemic environment which in turn triggers a systemic inflamatory response. This review gives an overview of the mechanims involved in maternal tolerance, how these are disrupted in preeclampsia, and how they contribute to the inflamatory response. PMID- 26591038 TI - [[Utilitarian considerations about two articles published in this issue]]. PMID- 26591039 TI - [Diagnostic of uterine sarcoma, review of 11 cases]. AB - BACKGROUND: Uterine sarcomas are rare but extremely aggressive malignant uterine pathology; mostly incidentally diagnosed at an advanced stage, with a higher aggressiveness and poor prognosis. OBJECTIVE: To determine the epidemiological profile of women with this diagnosis in Ginecopediatria Hospital, UMAE 48 of IMSS and its correlation with the literature. MATERIAL AND METHODS: A retrospective and observational study was done from 2007 to 2014 in UMAE 48, IMSS Leon, Guanajuato, in which the clinical records of patients with such diagnoses were reviewed. RESULTS: A total of 11 cases with age range 21-66 years had abnormal bleeding (82%), abdominal pain (64%), enlarged uterus (64%) and isolated elevation of lactic dehydrogenase (55%). The leiomyosarcoma accounted for 55%, sarcoma mixed Mullerian (SMM) 27% and endometrial stromal sarcoma (SEE) in 22% of cases. The stage I was the most frequent (55%) and histological type, which presented a more advanced stage was the SMM (stage IIIC). The hysterectomy with pelvic and paraaortic lymphadenectomy was the most common treatment (67%). The 45% of patients had tumor activity subsequent to treatment and the use of radiotherapy and chemotherapy was not associated with activity. CONCLUSION: Clinical features, risk factors and distribution of the presentation of the various sarcomas were according with previous studies, requiring further research to improve prognosis and survival in this type of tumor. PMID- 26591040 TI - [Effectiveness of supervised breast self-examination as educational strategy]. AB - BACKGROUND: Breast cancer is the leading cause of death from cancer in the female population; consequently, there are multiple prevention campaigns. Within these campaigns, a special emphasis is given on promoting monthly breast self examination; however, many women have never received formal education on proper method of self-examination. OBJECTIVE: To establish if the educational intervention we propose improves the breast self-examination technique. MATERIAL AND METHODS: A descriptive longitudinal study that included 52 women aged 20-40 years, attending a Family Medicine Unit of the Mexican Institute of Social Security, who were evaluated about self-examination technique before and after educational intervention, measured on a scale of 0 to 16. Statistical analysis was made with descriptive statistics and Student's t test. RESULTS: The mean age was 30.76 +/- 5.87 years. The mean baseline score was 3.13 +/- 2.55. The final average score after a month of the educational intervention was 10.69 +/- 2.74, which represents an increase in average score of 7.55 +/- 3.53. There was a significant increase in assessment scores after the educational intervention (p < 0.001). CONCLUSIONS: "Supervised breast self-examination" technique showed an increase in the ability of self-examination in patients. It can be considered an effective complementary method of teaching breast self-examination. PMID- 26591041 TI - [Laparoscopic myomectomy and use of electromechanical morcellator: clinical results in a series of cases]. AB - OBJECTIVE: to describe the clinical and operative characteristics of patients undergoing laparoscopic myomectomy and use of electromechanical morcellator for removal of tissue. MATERIAL AND METHODS: An observational, descriptive and retrospective study was done with the medical records of 65 patients that underwent laparoscopic myomectomy from July 2008 to July 2013. The clinical outcomes, including body mass index (BMI), pregnancies number, parity, previous abortions, indication of myomectomy, surgical findings, length of the procedure, operative bleeding, entry into the endometrial cavity, operative complications and conversion rate to laparotomy were collected and analyzed. RESULTS: The mean age and BMI of the patients were 33.1 years and 26.1 kg/m2, respectively. 64% of patients did not have any pregnancy and 33% had a history of one or more abortions. The most frequent indications for myomectomy were infertility (40%) and abnormal uterine bleeding (53%). The most frequent location of the fibroids was the intramural fundal (46%), with an average size of 6.5 cm (SD +/- 3.6). The number of myomas extracted ranged from 1 to 6. The mean operative time was 107.8 min (SD +/- 27.5) and the operative bleeding was 145.4 mL (SD +/- 42.2). There were no operative complications. The conversion rate to laparotomy was 2%. Power morcellation was used in all cases without complications. CONCLUSIONS: Laparoscopic myomectomy with electromechanical morcellator for tissue extraction in low risk patients for malignancy is a feasible procedure with a low conversion rate, minimal operative bleeding and the operative time similar to that reported for myomectomy performed by laparotomy. PMID- 26591042 TI - [Stress urinary incontinence treatment with modified technique tension-free vaginal tape obturator]. AB - OBJECTIVE: To evaluate the trans and postoperative complications and surgical results of Tension Free Vaginal Tape Obturator System (TVT-O) for stress urinary incontinence treatment in Angeles del Pedregal Hospital in a five year follow-up. MATERIAL AND METHODS: A retrospective, descriptive case series study with 67 patients was conducted in the Urogynecology Clinic in Hospital Angeles del Pedregal between January 2006 and December 2012. Patients with stress urinary incontinence treated by TVT-O were included. Complications and efficacy of the treatment are described in a 5 year follow-up. RESULTS: 29.9% of the patients had the urodynamic diagnosis of stress incontinence. The 55.2% of them had no other procedure done than the TVT-O. No transoperative complications were observed, but in the postoperative period, 2 (3.%) patients had urinary retention secondary to overcorrected urethra and 1 (1.5%) with intense groin pain. Two cases (3%) presented tape erosion to vagina at 18 months follow-up, with less than 5mm exposure areas. Average follow-up time was 2 years. 46.26% of patients completed a 5 years follow-up. Subjective and objective cures were obtained in all 67 patients. CONCLUSIONS: Tension free vaginal tape obturator system is a minimally invasive procedure that has excellent results (above 95%) in the treatment of stress urinary incontinence with a low rate of complications. Currently, it can be considered as the gold standard surgical treatment for stress urinary incontinence. PMID- 26591043 TI - [Ovarian ectopic pregnancy with little common clinical presentation. A case report and bibliographical review]. AB - Ovarian ectopic pregnancy is only 3% of all ectopic, with an incidence of 1:7,000 40,000. In the last 10 years, it has been a rise in incidence. Most patients have vaginal bleeding, abdominal pain and shock data. Less than 300-400 cases are reported in the literature. CASE: We present the case of a woman with ovarian ectopic pregnancy of 12 weeks of gestation, who have not suggestive clinical signs and whose diagnosis was incidental despite having a regular prenatal ultrasound. CONCLUSION: Ovarian pregnancy is a rare presentation; diagnosis is difficult and often suggested by clinical data, when clinical data fail, more studies are needed to integrate the diagnosis. PMID- 26591044 TI - [Spontaneous hemoperitoneum and clear cell tumor of ovary]. AB - Hemoperitoneum is a rare cause of acute abdomen, which is usually due to liver, spleen, hematologic and vascular causes. We should consider gynecological origin in women in reproductive age, being a rare etiology in postmenopausal. CLINICAL CASE: We report the case of a spontaneous hemoperitoneum in a postmenopausal woman as the first manifestation of an ovarian tumor, with exceptional pathological lineage: clear cell carcinoma. Hemoperitoneum is a suspected diagnosis before clinical symptoms of hypovolemic shock and acute abdomen, with decrease in hemoglobin. To treating underlying cause, which in this case was surgical, it's important the clinical suspect and the appropriate hemodynamic support of the patient. Despite the resolution of the acute, it is particularly important the subsequent clinical monitoring of the patient by the peculiarities of this type of tumors. PMID- 26591045 TI - [Primary hyperparathyroidism in pregnancy: a case report and bibliographical review]. AB - Primary hyperparathyroidism in pregnant women is an uncommon disease. It could be easily misdiagnosed because physiologic changes during pregnancy; in some cases, patients could remain asymptomatic maintaining elevated calcium serum levels, and this situation represents a threat to the health of both mother and fetus. Maternal complications of primary hyperparathyroidism include nepfhrolithiasis, pancreatitis, cardiac arrhythmias, hypertension, nausea and vomiting. Most commonly, the underlying aetiology is a solitary parathyroid adenoma whereby parathyroidectomy is the only cure. We present the case of a 21-year old patient, with primary hyperparathyroidism diagnosed in the third trimester of pregnancy, complicated with pancreatitis and gestational hypertension. We performed a caesarean section due to elevated calcium levels. Post-caesarean section, she was referred to a third level institute (National Institute of Cancerology of Mexico), were she undergone parathyroidectomy, with benign histopathological results. An appropriate medical/surgical management of hyperparathyroidism during pregnancy is necessary for avoiding maternal and fetal complications. PMID- 26591046 TI - [Supraventricular tachycardia in pregnant women at term: Case report]. AB - During pregnancy, a number of physiological changes occur which can predispose to arrhythmias. Symptoms can range from asymptomatic states to shortage of breath or palpitations, as also found in non-pregnant patients. Treatment is currently subject of scientific studies and there are different recommendations proposed by the main scientific societies. Hence, doubts and disputes raise when facing each case, firstly due to the concern about maternal and fetal well-being, and secondly to the possible complications inherent in the management of each drug. Clinical case: A case of a pregnant woman with 37 weeks of pregnancy, who presented supraventricular tachycardia without hemodynamic instability, is presented. According to the Spanish Society of Cardiology, guidelines an intravenous adenosine treatment was applied in a first instance. Since no reversion of the arrhythmic state was observed, the conduction of an electric countershock and termination of pregnancy by elective caesarean section was performed in agreement among Obstetrics, Intensive Care, Emergency Care and Pediatric Services. PMID- 26591047 TI - [Use of thromboelastography and thromboelastometry for the rational and opportune transfusion of hemoderivatives in obstetric hemorrhage]. AB - Obstetric hemorrhage is the leading cause of maternal mortality, responsible of 143,000 deaths every year. Thromboelastography is a tool that allows measuring the viscoelastic, dynamic and global properties of the blood, offering valuable information of coagulation alterations and help to guide early goal directed transfusional therapy. The purpose of this review is to evaluate the evidence of this tool in obstetric hemorrhage and the management of the associated coagulopathy. PMID- 26591048 TI - [THE ROLE OF microRNAs IN THE REGULATION OF MUSCLE METABOLTSM]. AB - MicroRNAs, class of the small RNA containing approximately 22 nucleotides take part in regulation of metabolism of skeletal muscles as enzymes, hormones and transcription factors. They are able to regulate the intensity of the translation process through complementary. interaction with mRNA. The review presents the results of studies published in the last two years, which increase the knowledge of the effects of microRNAs on the key stages of protein synthesis in skeletal muscle. The main attention is paid to achievements which open and specify a microRNA role in regulation of the signaling pathways that coordinate intracellular metabolism of skeletal muscles at different finctionni onneiilinnc nf then PMID- 26591049 TI - [EFFECT OF PRENATAL STRESS ON SEROTONERGIC NEURONS IN DORSAL RAPHE NUCLEUS AND ON PAIN BEHAVIOR DURING NEONATAL PERIOD]. AB - The effects of prenatal stress on immunocytochemical reaction on serotonin (5-HT) in the dorsal raphe nucleus (DRN) of the brainstem were investigated in 7-day-old male rat pups exposed to impact of pain in the formalin test (a control is an injection of saline). A strengthening effect of prenatal stress on pain behavior was revealed in animals in the formalin test. Prenatal stress decreased the number of 5-HT-immunoreactive neurons as compared with that in prenatally non stressed animals in both pups with inflammatory pain and the controls. There were no differences in the number of 5-HT-immunoreactive cells between pups with inflammatory pain and saline in both prenatally non-stressed animals and prenatally stressed ones. The data suggest that stress of maternal separation during the experiment hides the difference in immunocytochemical result in the rat pups with inflammatory pain and in the control. Thus, it was demonstrated for the first time that in 7-day-old rat pups the 5-HT-ergic neurons in DRN of the brainstem are a target of the prenatal stress. PMID- 26591050 TI - [EFFECTS OF ELECTRICAL STIMULATION OF NUCLEUS RETICULARIS PONTIS ORALIS ON THE SLEEP-WAKING STATES IN KRUSHINSKII-MOLODKINA STRAIN RATS]. AB - The effects of electrical stimulation of nucleus reticularis pontis oralis on the behavior and brain electrical activity during all phases of the sleep-waking cycle was studied in Krushinskii-Molodkina strain rats, which have an inherited predisposition to audiogenic seizures. Electrical stimulation with 7 Hz frequency in the deep stage of slow-wave sleep cause appearance the fast-wave sleep. Similar stimulation during fast-wave sleep periods did not effects on the electrographic patterns and EEG spectral characteristics of hippocampus, visual, auditory and somatocnen nrnrenc nf the cnrtey ThPe sfimul1stinns did nnt break a fast-wave sleenhut increased almost twice due the duration of these sleep episodes. After electrical stimulation by same frequency during the wakeftlness and superficial slow-wave sleep states, the patterns and spectral characteristics of brain electrical activity in rats showed no significant changes as compared with controls. The results of this study indicate that the state of the animals sleep-waking cycle at the time of stimulation is a critical variable that influences the responses which are induced by electrical stimulation of the nucleus reticularis pontis oralis. PMID- 26591051 TI - [SOUND SIGNALS OF DANGER ACTIVATE THE NITRERGIC SYSTEM OF THE MEDIAL PREFRONTAL CORTEX]. AB - In Sprague-Dawley rats by means of in vivo microdialysis, we have shown that presentation to rats-during conditioned fear expression of a sound conditioned stimulus previously paired with footshock (CS+) produces an increase in extracellular levels of citrulline (an NO co-product) in the medial prefrontal cortex. Presentation to the same rats of a different sound stimulus (not associated with footshock) (CS-) causes a very small increase in extracellular citrulline level. CS+ induced citrulline increase is prevented by infusions into the medial prefrontal cortex of Nomega-propyl-L-arginine (1 mM), a neuronal NO synthase inhibitor and it is not observed in control rats (same procedure, no footshock). These data indicate for the first time that sound signals of danger, but not safety signals activate nitrergic system of the medial prefrontal cortex. PMID- 26591052 TI - [INFLUENCE OF 29-40 AND 65-76 MCP-1 FRAGMENTS ON MYOCARDIUM MORPHOLOGY IN RATS AFTER T9CTHFMIA-R'FPFRFTTON]. AB - Monocyte chemotactic protein-1 (MCP-1) is a chemokine that stimulates monocytes and macrophage migration into the sites of acute of chronic inflammation. Our study shows morphological changes in ischemic myocardium followed by the administration of two synthetic structural fragments of MCP-1 that are monocyte/macrophage migration inductor peptide IX and peptide X an inhibitor. Results show that peptides can change time points of the inflammatory response in myocardium. Peptide IX administration leads to increased and accelerated inflammatory response, i. e. attracts an additional number of monocytes and macrophages into the inflammatory focus. The introduction of the peptide X observed prolonged inflammatory process with the overall gain signs of myocardial damage. PMID- 26591053 TI - [PHYSIOLOGICAL APPROACH TO RESTORING OSMOTIC HOMEOSTASIS IN RATS WITH HYPERNATREMIA]. AB - The aim of the study was a search of physiological approach to restoring osmotic homeostasis in rats with hypernatremia. Intraperitoneal administration of 1.8 ml/100 g BW 2.5% NaCl solution to Wistar rats induced hyperosmia (306 +/- 1 mOsm/kg H2O) and hypernatremia (150.3 +/- 0.3 mM in 60 min of experiment), increase in urinary sodium excretion (from 8 +/- 1 to 230 +/- 10 micromol/100 g BW for 2 h). Under these conditions enhancement of natriuresis up to 465 +/- 29 micromol/100 g BW and 667 +/- 24 micromol/100 g BW for 2 h was observed after injections of vasopressin analogue, deamino-vasotocin (dAVT, 0.05 microg/100 g BW), or loop diuretic, furosemide (1 mg/100 g BW), respectively. dAVT-induced natriuresis was accompanied by increase in solute-free water reabsorption; serum osmolality (301 +/- 1 mOsm/kg H2O) and sodium concentration (145.8 +/- 0.5 mM) were close to normal values by 60 min of experiment. Furosemide caused relatively greater excretion of water, than sodium; hypernatremia (150.2 +/- 0.4 mM) and hyperosmia (311 +/- 1 mOsm/kg H2O) persisted during 60 min of experiment. Thus, in rats with hypernatremia dAVT due to decrease in renal sodium reabsorption and increase in solute-free water reabsorption promotes recovery of serum osmolality and sodium concentration. PMID- 26591054 TI - [THROMBIN-MEDIATED EFFECTS OF BLOOD MICROPARTICLES ON FORMATION, STRUCTURE, AND STABILITY OF FIBRIN CLOTS]. AB - The effects of blood microparticles (MPs) on the dynamics of fibrin polymerization, clot structure and susceptibility to fibrinolysis were studied. Kinetics of fibrin polymerization, fibrinolysis, thrombin generation in platelet free, microparticle-depleted and microparticle-depleted plasma replenished with cephalin, from healthy donors were analyzed in parallel. MPs have profound effects on all stages of fibrin formation, decrease its turbidity. All parameters obtained in the absence of MPs were recovered after reconstitution of phospholipids. Thrombin generation rates were reduced in the absence of MPs. In the presence of MPs the fibrin networks had less poro us structures with thinner fibers, while clots formed in the absence of MPs had larger pores and were built of thicker fibers. Clots formed in the presence of MPs were significantly more resistant to fibrinolysis. Results show that normally circulating MPs can support the formation of stable clots at the sites of vascular injury. PMID- 26591055 TI - [DYNAMICS OF BLOOD PRESSURE AND QUANTITY INDICES OF ERYTHROCYTES IN SHR IN EARLY PERIOD OF ARTERIAL HYPERTENSION FORMING]. AB - The dynamics of arterial blood pressure and hematological parameters (RBC volume, RBC count, hematocrit) in young rats SHR and WKY strains in the period from the 5th to the 8th week after birth was investigated. At the age of 5 weeks, the levels of arterial blood pressure in rats studied strains were not significantly different. Starting from 6 weeks, systolic and diastolic blood pressure in SHR rats were significantly higher than the corresponding values of WKY rats of the same age. During the entire period of observation (from the 5th to 8th week) the number of red blood cells and hematocrit in SHR rats was significantly increased compared with the value of these parameters in WKY rats. Probably, an increased hematocrit can be one of the reasons of increasing the blood pressure in the early stages of hypertension development. PMID- 26591056 TI - [AMPLITUDE-FREQUENCY'S DEPENDENCE OF M-RESPONSE OF THE SKELETAL MUSCLE OF RATS WITH EXPERIMENTAL HYPERCORTICOIDIZM]. AB - In experiments over the mature white female rats the influence of the hypercorticoidizm (simulated by daily parenteral injection of hydrocortisone in a dose of 3 mg/kg/days for 30 days) on some parameters of the M-response of the forward tibial muscle with a different frequency of stimulation of the low-tibial nerve is studied. It is established that the hypercorticoidizm is followed by lengthening of the chronaxia of the forward tibial muscle at its indirect irritation (by 69 per cent), deterioration of stability of M-response's generation, lengthening of the latent period (by 30 per cent) and to reduction of amplitude (by 29 per cent) of single M-responses against increase in frequency of polyphase potentials (to 35 per cent). At animals with hypercorticoidizm in the range of low frequencies of nerve's stimulation (10-30 imp/s) periodic generation of higher-amplitude M-responses, than at control, against their low initial amplitude was observed, which can testify in a favor of an initial partial blocking of synapses. The hypercorticoidizm was followed more expressed, in comparison with control, decreasing of M-responses' amplitude in the process of increasing in frequency of low-tibial nerve's stimulation, decreasing in frequency of nerve's stimulation on achievement which inverse relationship between M-responses' amplitude and frequency of nerve's irritation was established. PMID- 26591057 TI - [THE INFLUENCE OF FATIGUE ON THE SENSORY GATING TEMPORAL PARAMETERS]. AB - The aim of the study was to investigate the influence of central fatigue and motor activity on sensory gating characteristics. The P50 component in a standard paired-click paradigm was used as a sensory gating index. The main attention was devoted to the P50 peak latency change in the fatigue development. It was found that the sustained muscle load leading to the fatigue development significantly reduced sensory gating and the P50 peak latency in response to the second stimulus of the pair. This may be due to the inhibitory process suppression underlying the sensory gating in the development of central fatigue. PMID- 26591058 TI - [QUANTITATIVE INDEXES OF SLOW PERIODICAL VOLUME FLUCTUATIONS INSIDE CRANIA-SPINAL SPACES]. AB - Process of circulatory-metabolic support of brain functioning is based on integration of cerebrovascular and CSF-circulatory systems as well scull mechanics, as united structural-functional system is accompanied by periodic volume--pressure fluctuations inside crania-spinal space. The frequency of them is widely variable (0.03-0.25 Hz), as well as its amplitude (0.3-1.2 of pulse wave value) and they exist in the most of its regions. Results of noninvasive studies of volunteers of groups (18-20 and 40-55 years old), that these fluctuations, reflect the functioning of the mechanism, responsible for brain circulatory metabolic supply, and the evaluation of these quantitative indices by means of spectral analysis with quantization 128 kHz could provide valuable information concerning functional integration of systems, responsible for circulatory-metabolic brain support. PMID- 26591059 TI - [GLOBULAR ACTIN IS THE PARTIALLY INTRINSICALLY DISORDERED PROTEIN WITH QUASI STATIONARY STRUCTURE]. AB - It is shown that the native globular actin (G-actin) is the thermodynamically unstable (quasi-stationary) form of the protein. This state is stabilized by Mg2+ (in vitro replaced by Ca2+). In vivo this state occurs as a result of complex energy-consuming post-translational folding processes including chaperone Hsp70, prefoldin and CCT complex, providing the formation of the native structure stabilized by Ca2+ and ATP. Structures formed by actin polypeptide chain constantly form complexes with their partners (chaperones Hsp70, prefoldin and chaperonin CCT in folding process, with an Mg ion and ATP in the native state, with numerous actin-binding proteins during the formation and functioning of the cell cytoskeleton, with myosin and other proteins of the muscle contraction in the muscle cells). Actin denaturation is accompanied by self-association of molecules, so the inactivated actin is the thermodynamically stable compact structure consisting of 14-16 protein molecules. Apparently, proteins with quasi stationary native state are widespread in nature. The emergence of these states is energy-consuming and is conjugated with the inability of the polypeptide chain to form the native compact structure without assistants (complex machinery of protein folding in the cell) and without interaction with their natural partners, in particular with metal ions. PMID- 26591060 TI - [CHARACTERISTIC OF THE CELLULAR SPHEROIDS, DERIVED FROM MESENCHYMAL STEM CELL LINES FROM BONE MARROW AND MUSCLE OF LIMB OF EARLY HUMAN EMBRYO]. AB - Cellular spheroids were derived from mesenchymal stem cell lines derived from 5-6 weeks embryo from different tissues of 5-6-week human embryo: bone marrow (FetMSC) and muscle of limb (M-FetMSC). Comparative analysis of the characteristics of these lines has been performed with 2D culturing in monolayer and 3D culturing in spheroids. The characteristics of cellular spheroids were obtained after 48 h after their formation from monolayer cultures on the 6th passage after decryopreservation. Spheroids in contrast to monolayer cultures are heterogeneous cell populations composed of fibroblast-like and epithelioid cells. Two-day spheroids are actively proliferating structure. Cell surface markers were analyzed using flow cytometry. Both in the monolayer cultures and cellular spheroids, this analysis has revealed the presence of expression of surface antigens CDD44, CD73, CD9O, CD105, HLA-ABC that are characteristic of human MSC, and the absence of expression if CD34 and HLA-DR. Nevertheless, the level of expression of CD90 and CD105 antigens was significantly lower in the spheroids as compared with corresponding monolayer cultures. Immunofluorescence and flow cytometry analysis of the expression of transcriptions factors and surface antigens characteristic of human embryonic stem cells showed the presence of expression of Sox-2 and SSEA-4 in 2D and 3D cultures. Lack of expression of Oct-4 in 2D cultures and its significant increase in 3D cultures has been found. Immunofluorescence analysis showed the presence of the markers of early differentiation in the derivates of three germ layers characteristic of human embryonic stem cells in the cellular spheroids of both lines, which coincides with 2D cultures of these lines. The directed osteogenic, chondrogenic and adipogenic differentiation of these lines has been shown. However, a number of differences has been found between monolayer cultures and spheroids. Adipogenic differentiation was more active in the cellular spheroids from cell line M-FetMSC a compared with corresponding monolayer cultures. Differences between the 2D and 3D cultures of both lines have been shown by the character of chondrogenic differentiation. The results obtained confirm the status of MSC for the cellular spheroids derived from monolayer cultured of cell lines FetMSC and M-FetMSC and apparently indicate a partial extension of their differentiation capacity as compared to monolayer cultured. PMID- 26591061 TI - [COMPARATIVE CYTOGENETIC ANALYSIS OF MONOLAYER AND SUSPENSION CHINESE HAMSTER OVARY CELL LINES CHO(dhfr-)]. AB - The karyotypes of CHO(dhfr-) and CHO(dhfr-)/susp Chinese hamster ovary cell lines were investigated with the use of GTG-staining. Modal chromosome set consists of 20 and 18 chromosomes respectively. The karyotypes of both cell lines were stable with constant ratio of normal chromosomes and chromosomes with structural rearrangements. Monosomy for chromosomes 1, 2, 4, 5, 8 was observed in both cell lines and for chromosome 9 in CHO(dhfr-)/susp cell line. The differences between CHO(dhfr-) cell lines studied by us consists of inclusion of part of chromosome 7 in der(6)t(1;6), rearrangement of del(5) and monosomy of chromosome 9. It was shown that in karyotypes of all CHO cell lines studied up today there are 5 common structurally chromosome rearrangements: del(2), inv(3), add(6), del(9) and mar1. In both CHO(dhfr-) cell lines investigated by us three unique chromosome rearrangements: del(1), der(6)t(1,6) and mar3 were revealed. Necessity of simultaneous GTG and FISH analysis of chromosomes rearrangements in the CHO cell lines under study is discussed. PMID- 26591062 TI - [PRODUCTION AND CHARACTERIZATION OF THE PANEL OF MONOCLONAL ANTIBODIES AGAINST HUMAN ENDOGLIN]. AB - Endoglin (CD105) is the marker of endothelial and mesenchymal stem cells and the component of TGF-beta, BMP-9 and BMP-10-binding receptor complexes. Its expression is significantly increased on blood vessels endothelium of ischemic tissues and growing tumors. Measurement of concentration of the soluble endoglin in the serum or urine is used as a method for diagnosing cancer and pregnancy disorders. The aim of this work was to create a novel family of monoclonal antibodies recognizing endoglin on the cell surface and in biological fluids. Murine myeloma cells' derived recombinant protein representing the whole extracellular part of endoglin was used as an antigen. F1(SJL/JxBALB/c) mice were the donors of immune splenocytes. Hybridoma screening procedures were performed using E. coli-produced copies of the antigen, endoglin-expressing immortalized human cell lines, and primary cultures of human mesenchymal stromal cells. Ten novel monoclonal antibodies recognizing at least eight distinct epitopes were produced. Eight antibodies bind membrane form of endoglin on the surface of normal and transformed human cells derived from different tissue sources. Two antibodies recognize linear antigenic determinants of the molecule and can be used to detect endoglin by western blot. Sandwich ELISA system was designed in order to measure soluble endoglin in cell culture medium. PMID- 26591063 TI - [COMPARATIVE STUDY OF Hrs AND OTHER ENDOSOMAL MARKERS CELLULAR LOCALIZATION IN DROSOPHILA MELANOGASTER SPERMATOGENESIS BY GFP-CHIMERICAL PROTEIN APPROACH]. AB - Acrosome is a special organelle in spermatozoids necessary for fertilizing oocyte and originates, according to various theories, either from Golgi apparatus, or from endosomes and lysosomes. One of the proteins, found at mammalian acrosome, is Hgs, a homologue of Drosophila melanogaster Hrs (Hepatocyte growth factor regulated tyrosine kinase substrate), a known marker of multivesicular bodies (MVBs). However, although Drosophila acrosome was extensively studied, it is yet unknown whether Hrs localizes at acrosome similar to Hgs and, more generally, whether the spectrum of acrosomal proteins in Drosophila is the same as in mammals. Hrs (hepatocyte growth factor regulated tyrosine kinase substrate) is the multidomain vesicular protein participating in the endosome-lysosome protein sorting. We demonstrated that two protein variants of the Drosophila Hrs are expressed in testes: a longer isoform B, and a shorter isoform A, which lacks VHS and FYVE domains that are necessary for anchoring Hrs in endosomes. We found that Hrs isoform B is concentrated at fusoma of spermatocytes in contrast to mammalian Hrs. This localization requires the C-terminus of the protein, starting from the aminoacid residue 383. In situ hybridization of hrs RNA probe showed that the gene is expressed early in spermatogenesis consistently with Hrs localization in early fusoma. Additionally, we demonstrated that Hrs is dispensable for cytokinesis. Finally, it was found that although Drosophila Hrs does not localize at acrosome, the other endosomal markers--Rab4, Rab7, and Rab11--are detected at the organelle. PMID- 26591064 TI - [THE EFFECT OF EPOXYGENASE INHIBITORS ON Ca(2+)-RESPONSES INDUCED BY GLUTOXIM AND MOLIXAN IN MACROPHAGES]. AB - Using Fura-2AM microfluorimetry the possible involvement of epoxygenase pathway of arachidonic acid metabolism in the effect of glutoxim and molixan on intracellular Ca2+ concentration in rat peritoneal macrophages was investigated. It was shown for the first time that preincubation of the macrophages with epoxygenase inhibitors, proadifen and econazole, significantly decreases the intracellular Ca2+ concentration increase induced by glutoxim and molixan. The addition of the epoxygenase inhibitors during the already developed store dependent Ca(2+)-entry induced by glutoxim or molixan partially inhibits Ca(2+) entry. The obtained data suggest the involvement of the products and/or enzymes of epoxygenase pathway of the arachidonic acid metabolism in the glutoxim and molixan effect on the Ca2+ signaling processes in macrophages. PMID- 26591065 TI - [IMPACT OF VARIOUS MULTIPLICITY OF INFECTION OF INFLUENZA A VIRUS ON PROLIFERATION AND APOPTOSIS INDUCTION IN CULTURED CELL LINES OF LYMPHOCYTIC AND MONOCYTIC ORIGIN (JURKAT, NC-37, THP-1 AND U-937)]. AB - The severity of disease caused by influenza A infection depends not only on biological characteristics of the virus but also on the number of viral particles than penetrate the body. T- and B-lymphocytes as well as monocytes (macrophages) play a key role in the development of cell-based and humoral immunity as well as influenza virus elimination from the body. The present study describes the effect of influenza A virus infection on cell proliferation and induction of apoptosis in human cultured cell lines of T-, B-lymphocytic and monocytic origin infected with various multiplicity of infection (moi). Low moi of the virus stimulated cell proliferation; maximal effect has been registered 3-4 days after infection. But the fate of T-cells, B-cells and monocytes after initial infection was different: Jurkat cells continued intense proliferation while proliferation of NC 37, THP-1 and U-937 cells lowered. Prolonged (for 3 passages) cultivation of Jurkat, NC-37 and U-937 cell lines has shown that infection of these cell lines not only with low but also with medium and high moi also leads to stimulation of proliferation. Using a variety of methods for the detection of viral reproduction has clearly shown that infection of non-permissive human T-, B-cells and monocytes with influenza A virus leads to latent infection. So, low moi interferes with normal formation of viral particles, which in turn might stimulate cell proliferation and then be followed by induction of apoptosis. Antiviral drags rimantadine and ribavirin suppressed virus-induced cell proliferation; at the same time, induction of apoptosis was suppressed only by rimantadine and was enhanced by ribavirin. The data obtained provide strong support for the role of influenza A virus in the observed effects. PMID- 26591066 TI - [ANALYSIS OF THE DINOFLAGELLATE PROROCENTRUM MINIMUM TRANSCRIPTOME: IDENTIFYING THE MEMBERS OF THE VOLTAGE-GATED CATION CHANNELS SUPERFAMILY]. AB - Dinoflagellates are an ecologically important group of aquatic single-cell eukaryotes. At the present time relatively little is known about physiological features that determine the role of these protists in natural ecosystems. Lack of knowledge on the diversity, structure, and functioning of dinoflagellate ion channels significantly hampers the interpretation of physiological reactions and adaptations in these microorganisms. We performed the analysis of the translated transcriptome databases that belong to two strains of the dinoflagellate Prorocentrum minimum in order to identify the members of the voltage-gated cation channels superfamily. We found out that transcriptomes of these potentially toxic microorganisms contained the homologues of: 1) inwardly rectifying potassium channels (K(ir)), 2) voltage-gated potassium channels (K(v)), 3) calcium activated potassium channels (K(Ca)), 4) cyclic nucleotide-gated channels (EAG and HCN/CNG), 5) TRPV and TRPP channels, 6) two-pore calcium channels TPC, 7) voltage-gated sodium (Na(v)) and calcium (Ca(v)) channels, 8) voltage-gated proton channels (H(v)). PMID- 26591067 TI - [STEREOMETRICAL AND HISTOCHEMICAL ORGANIZATION OF THE PIGS MIOMETRIUM]. AB - There are too functionally ambiguous layers in myometrium of pigs. One of them is inner circular and the other one is outer longitudinal layers of smooth muscle cells bundles. The length of myocytes in both layers of the myometrium was significantly increased deepening of gestation periods. Ratio of circular and longitudinal layers, connective tissue, vasculature of the myometrium is not the same in cranial, fetal and interfetal segments of horns. It changes depending on the physiological state. Glycogen, neutral glycoproteins, acidic sulfated glycoproteins and proteoglycans, hyaluronates, RNA, amino acids, lysine, histidine and arginine have been histochemically identified in the tissue components of the muscle tunic. Their dynamics and qualitative distribution have cellular and tissue specificity in different physiological periods. PMID- 26591068 TI - Botany in Edinburgh's Medical Curriculum. AB - In the early 18th century, at the founding of Edinburgh University Medical School, the study of botany was regarded as an essential component of medical training. Botanical teaching began as basic instruction in the recognition of medical plants, considered a vital aspect of a physician's Materia Medica studies. Over the next hundred years growing importance was given to the study of botany as a science, its popularity peaking under John Hutton Balfour's tenure as Professor (1845-1879). The relevance of botanical study later declined in the undergraduate medical curriculum until its cessation in 1961 .This paper considers the history of botanical studies in Edinburgh, including the reasons for its introduction and its changing importance over time. PMID- 26591069 TI - [Urban history and history of medicine: decompartmentalization and interdisciplinarity]. PMID- 26591070 TI - [Biographical sketch of Nicola(us) Florenas mentor of Andreas Vesalius]. PMID- 26591071 TI - History of the Emergence and Recognition of Syringomyelia in the 19th Century. AB - Charles-Prosper Ollivier d'Angers coined the term "syringomyelia" in 1827 to describe the presence of a cavity in the spinal cord, which he considered pathological in all cases. In 1882 in Germany, Otto von Kahler and Friedrich Schultze defined the clinical syndrome, which associated Duchenne-Aran muscular dystrophy of a limb with sensory dissociation. They explained the syndrome by the presence of an abnormal cavity, distinct from that found in the spinal cord of healthy adults. Although Guillaume Duchenne de Boulogne and Jean-Martin Charcot had observed cases in France, both failed to identify syringomyelia, whereas a family physician in Brittany, Augustin Morvan, described the clinical symptomatology using the term "analgesic whitlow" in 1883. Based on several dozen observations that they collated in their remarkable theses,Anna Bumler in Zurich in 1887 and Isidore Bruhl in Paris in 1890 established the complete clinical picture of syringomyelia, covering anatomic functional and pathological aspects. Whereas Charcot isolated pathologies by correlating clinical signs with anatomo pathological lesions, the isolation of syringomyelia initially involved an anatomo-pathological concept before the semiology was defined. In addition, this work would later enhance physiological understanding of sensory spinal pathways. PMID- 26591072 TI - From Reading Stones, Glasses and Contact Lenses to Intraocular Lenses & Ophthalmic Lasers--A Short Overview over the History of Visual Aids. AB - Alhazen, ibn al-Haytham, (965 Basra - c. 1040 in Cairo) was a Muslim polymath who made significant contributions to the principles of optics, being the first to recognize the optical effect by transparent objects in the 11th century. His insights led to a fundamental revolution, enabling older presbyopic persons to read again. Today many more options are available to help visually impaired people correct their sight defects. This article will give an historical overview of the sight aids which are available today and will describe the very first beginnings of the development of the "reading stone" or "glasses". Further, it will also give a chronological overview of more modern techniques, e.g., intraocular lenses, contact lenses and the options of refractive surgery. PMID- 26591073 TI - Vivisection and the Experiments of the Physiologist. AB - For centuries, animal dissection has been used to further knowledge and understanding of the internal workings of the human body. This was based upon the assumptions that comparative anatomy could yield understanding of human anatomy and that human physiology could be inferred from that of other mammals. Galen was an early proponent of animal dissection for this purpose. During the nineteenth century, with an increasing understanding of the role of science in medicine, there came a large increase in animal experimentation.This was accompanied by a growing unease about the conditions under which such work took place. PMID- 26591074 TI - [Of dentists united against Nazi oppression: the "rant" of Maurice Roy]. PMID- 26591075 TI - Medical Traditions: A New Research Centre. PMID- 26591076 TI - [What trends in Psychiatry?]. PMID- 26591077 TI - [Current therapies of borderline personality disorder]. AB - Borderline personality disorder (BPD) is a highly prevalent disorder characterized by identity disturbance, emotion dysregulation, interpersonal difficulties and self-damaging behaviours. Mental health professionals most of the time encounter difficulties in the care of these hard-to-treat patients mainly due to the frequent crises often leading to drop-outs. In this perspective, technical and theoretical changes to traditional psychotherapeutic approaches were developed. We here give the major principles that should be considered when treating BPD patients in order not only to reduce the risk of being iatrogenic but also to apply the current psychotherapeutic and psychiatric modalities internationally recognized to be efficient. PMID- 26591078 TI - [An exploration of sexual desire and sexual activities of women with psychosis]. AB - Most clinicians avoid discussing sexuality with patients with severe mental disorders. Sexual disturbances can be related to medication, to psychological issues such as self-stigma and anhedonia, and to the social context. We studied desire and sexual practices in women suffering from schizophrenia, in comparison with healthy women. Contrary to previous research, women with schizophrenia featured dyadic and individual desire similar to women of comparable age. Yet, only half of women with psychosis had sexual practice, either alone or with a partner. They were less satisfied with their activity, both in terms of function and psychological issues such as sexual self-esteem. This finding underscores the stigmatization these women suffer from, which prevents the opportunity of a possible improvement in this important interpersonal domain. PMID- 26591079 TI - [Bipolar disorders and self-stigma]. AB - Despite wide media coverage in recent years, the stigmatization of people with bipolar disorder still exists. Bipolar people also have their own tendency to self-stigmatize that is to integrate their beliefs, prejudices and stigmatizing behaviors. The consequences are important: shame, guilt, withdrawal and renunciation to lead one's own life according to personal values increasing therefore the risk of mood relapses. Self-stigma is rarely assessed in clinical practice and few strategies have been designed to face them efficiently. Recognizing self-stigmatizing beliefs and challenging them are the first steps of this vast endeavour. PMID- 26591080 TI - [The psychiatric hospital: a place where language is reconstructed through the group]. AB - Within the psychiatric hospital, the caregiver is faced with difficult choices regarding the <> to respond to the suffering of the patient, to accompany him and sometimes forcing him to accept care. The hospital is a place of pressures from within and from outside, where the caregiver must perform a balancing act, with multiple conflicting roles. He must respect patient rights and his resources, his safety and those of others, the understanding of his difficulties, the expectations of the family and the limits of reality. This care has a fundamental ethical dimension. The team discussion allows for a conflictual cooperation between caregivers, which makes possible caring for our patients in crisis. PMID- 26591081 TI - [Arson and pyromania, update 2015]. AB - While the fire constitutes a threat and provokes avoidance by the entire animal world, its control as lighting and maintenance is inseparable from the history of humankind. For 1% of the population that use is turned to harm, repeatedly and without objective reason, responding to the historical definition of pyromania. The profile of arsonists does not appear to be different from that of the general criminal population: alcohol abuse, nicotine, marijuana and antisocial personality do not make fire setters a special case. However positive fire experience lived in childhood, emotional avoidance and expertise in fire settings' control seems to be specific, as recidivism risk below that of the general criminal population. PMID- 26591082 TI - [Risk assessment in forensic psychiatric reports: what kind assessment instrument? What indicator? What practical?]. AB - Here we present results of studies conducted by the Research Unit of Legal Psychiatry and Psychology of Lausanne about risk assessment and protective factors in the evaluation of violence recidivism. It aims to help experts in considering the relevance and use of tools at their disposal. Particular attention is given to the significance of protective factors and impulsive dimensions, as to the inter-raters process that leads to the final deliberations. PMID- 26591083 TI - [Acute sigmoid diverticulitis: toward a more and more conservative treatment]. AB - Acute diverticulitis of the colon is a frequent pathology especially among elderly people and people of Caucasian origin. The prevalence is higher among sedentary people and in people with low-fiber diet. Its diagnosis is mainly based on computed tomography (CT) that allows guiding the therapeutic management. Over the last few years the treatment of acute diverticulitis has passably changed with in particular an evolution toward a restriction of the elective and emergency surgery indications and a reduction of the antiobiotherapy and hospitalization number. This article reviews the epidemiology, the diagnostic tools, and the management of this frequent digestive pathology. PMID- 26591085 TI - [New international equation of vaccinations and eradication]. PMID- 26591086 TI - [Advocacy]. PMID- 26591087 TI - [Knowing the genetic time of death? Meanwhile, read Hans Kung]. PMID- 26591088 TI - [In Process Citation]. PMID- 26591089 TI - [Anticoagulants after first pulmonary embolism: delaying relapse while balancing risk and benefit. ]. PMID- 26591090 TI - [Miscellaneous medical news: medical desert in Bretagne; "low cost" dental care; American tobacco]. PMID- 26591091 TI - Stable benefits but lower salaries noted in annual survey. PMID- 26591092 TI - Infection prevention tops list of readmission 'action items'. PMID- 26591093 TI - OR team uses evidence-based practices to reduce readmissions. PMID- 26591094 TI - Empowering staff yields high return on investment. PMID- 26591095 TI - Deadline looms for CMS orthopedic bundled care program. PMID- 26591096 TI - ASC survey respondents stepping up to meet challenges. PMID- 26591097 TI - Successful recruitment and retention of engaged employees--Part 2. PMID- 26591098 TI - Risk assessment and remedial action required to curb infections. PMID- 26591099 TI - A COMPARISON OF EFECTIVENESS, AND AN ASSESSMENT OF THE QUALITY OF LIFE OF PATIENTS AFTER LAPAROSCOPIC SLEEVE GASTRECTOMY AND ROUX-EN-Y GASTRIC BYPASS. AB - INTRODUCTION: Morbid obesity is nowadays one of the major problems of well developed countries. Treatment of this disease comprises many modalities, but the most successful are surgical ones. With the advent of laparoscopic operations it became clear that these are particularly useful for operation in obese patients due to their minimal invasiveness. The aim of the study was to compare the effectiveness and quality of life of patients operated on for morbid obesity by laparoscopic sleeve gastrectomy (LSG) and laparoscopic Roux-en-Y gastric by-pass (LRYGB) by one surgeon in one surgical centre. MATERIAL AND METHODS: Between 2006 2011 in the Department of General and Vascular Surgery, Szczecin-Zdunowo Specialist Hospital, 74 morbidly obese patients (54 F, 20 M) were operated on by two methods. Mean age (42.4 and 45 years), and body mass index (46.5 +/- 8.9 kg/m2 for LSG and 45.1 +/- 4.4 kg/m2 for LRYGB) respectively, were comparable. One surgeon in one centre performed LSG in 33 patients (24 F, 9 M) and LRYGB in 41 patients (30 F, 11 M). An independent observer evaluated patients at times of up to 6 months (37 pts), and after 7 months to 36 months (37 pts) postoperatively. Quality of life was assessed by the Gastrointestinal Quality of Life Index (GIQLI) questionnaire, with accessory questions concerning sexual, physical and other activities before and after intervention. RESULTS: There were no serious short or long term complications in either group of patients, although one patient in each group felt permanent postoperative discomfort (2.44% and 3.03%). Percentages of excess weight loss in both groups were similar and reached after 6 months 38.5% for LSG, 39.9% for LRYGB, and after 7-36 months 64.5% for LSG, 66.9% for LRYGB respectively. Quality of life assessment revealed significantly lower values in core symptoms for patients after LRYGB compared to LSG, but after LSG constipation was slightly more frequent. However, the general GIQLI score for patients after both types of surgery was statistically insignificant (110.6 for LSG versus 108.7 for LRYGB). In both groups sexual and physical activities significantly improved after operation. CONCLUSION: There were no significant differences in effectiveness and quality of life in patients after laparoscopic sleeve gastrectomy and laparoscopic Roux-en-Y gastric by-pass. PMID- 26591100 TI - [ACNE VULGARIS--AETIOLOGY, CLASSIFICATION, TREATMENT]. AB - A spotless skin is a rarity. Both women and men have different problems related to the complexion. One of the most common problems is acne, which affects an increasing number of people of all ages. Seborrhea skin areas rich in sebaceous glands, the formation of comedones, inflammation, and scars are characteristic for this disease. The aim of the study was to discuss the causes of acne vulgaris, methods of treatment, and proper care of the skin affected by this problem. PMID- 26591101 TI - [THE EFFECT OF THE APPLICATION OF THE KINESIOLOGY TAPING TECHNIQUE FOR MUSCLE RANGE OF MOTION OF THE LUMBAR SPINE, AND THE SUBJECTIVE PERCEPTION OF PAIN INTENSITY IN PATIENTS WITH BACK PAIN]. AB - INTRODUCTION: In an era of ubiquitous computing, a considerable part of the population, regardless of age group, spend more time in a sitting position. Long term, static loading of the spine increases muscle tension, leading to the occurrence of pain. Physiotherapy is recommended as primary and secondary prevention of spinal pain symptoms. The Kinesiology Taping Method is one of the many special methods of physiotherapy which is used during the episodes of back pain in the lumbosacral region. This method consists in sticking on a special tape, which is made of stretch cotton similar to human skin, using a variety of techniques for patch application. The present study evaluated the effect of the application of the Kinesiology Taping technique for muscle mobility in the lumbar spine and the subjective perception of pain intensity. MATERIAL AND METHODS: The study group consisted of 100 patients (89 women and 11 men) who experienced pain in the lumbar spine. To assess the mobility of the lumbar spine the Schober test was used. The subjective sensation of pain was assessed using the VAS (visual analogue scale). Measurements were taken four times: before gluing applications, immediately after taping, 7 days after application of the patch, and immediately after its removal. RESULTS: In response to the use of therapy, an increase of mobility of the lumbar spine in flexion front and back, and reduced pain was shown. CONCLUSIONS: Application of the muscle kinesiology taping technique is an effective method in reducing pain and increasing mobility of the lumbar spine. PMID- 26591102 TI - [MOLECULAR MECHANISM OF A CALORIC RESTRICTION DIET]. AB - The use of caloric restriction modulates the activity of FoxO proteins. FoxO is a key regulator of changes in the metabolism of carbohydrates. Under the influence of limited access to food FoxO proteins are activated. FOXO activation is done by deacetylation. The enzymes responsible for the deacetylation of proteins are called sirtuins. Sirtuins are NAD-dependent proteins, the activity of which is dependent on the metabolic status of the cell. Deacetylation of FoxO leads to an increase in the potential for increased interaction with DNA. In vivo studies have shown that under the influence of calorie restriction sirtuin levels increase in muscle, brain, kidney, or adipose tissue. PMID- 26591103 TI - [CHANGES IN BODY MASS AND BLOOD LIPID LEVELS IN PATIENTS UNDERGOING CALORIC RESTRICTION]. AB - INTRODUCTION: Caloric restriction is the only well-documented nutritional intervention prolonging the life of mammals. This method modifies the lipid levels in blood, controlling obesity and delaying the onset of many medical conditions associated with metabolic disorders. The aim of the study was to carry out a comparative analysis of lipid profile in patients on Mediterranean or CRON (Caloric Restriction with Optimal Nutrition) diets, before and after six weeks of dieting. MATERIAL AND METHODS: The following parameters were compared: total cholesterol, total lipids, triglycerides, LDL cholesterol, HDL cholesterol, and BMI. Additionally, we measured the levels of insulin, HOMA score, and anthropometric parameters. The comparative analysis demonstrated a statistically significant correlation between mild caloric restriction and blood lipid profile. Results from studies on patients who underwent six-week dietetic intervention indicated statistically significant changes in biochemical parameters due to caloric restrictions. Such changes were not found in subjects following the Mediterranean diet. The greatest decrease in the blood level of triglycerides was found in subjects on the CRON diet, LDL cholesterol, total cholesterol and total lipid levels also decreased. No significant changes if biochemical parameters were found in patients on the Mediterranean diet. CONCLUSIONS: A comparative analysis of all parameters demonstrated that the use of mild caloric restrictions with ensured supply of all necessary nutrients seems to be the most effective solution for reducing fatty tissue. PMID- 26591104 TI - THE INFLUENCE OF READING AND WRITING ON THE PREVALENCE OF MYOPIA. AB - PURPOSE: In this study we decided to answer the question of whether spending more time on reading and writing leads to higher prevalence of myopia. MATERIAL AND METHODS: A total of 70 people (140 eyes)--17 men and 53 women aged 18-29 years (mean 22.5 +/- 2.8) were examined. A questionnaire concerning the amount of time spent each day on reading and writing, as well as ophthalmic examination involving: visual acuity, anterior segment and fundus examination, keratometry, autorefractometry and axial length of the eyeball measurement (using IOL Master) were carried out in all participants. The refractive errors were described as spherical equivalents (SE). Hyperopia was defined to be SE higher than +0.5 Dsph, and emmetropia to be higher than -0.5 and lower than +0.5 Dsph. Myopia was defined to be with a SE lower than -0.5 Dsph. High myopia was defined as SE lower than -8, medium myopia in the range between -8 and -4, and low myopia lower than 0.5 and higher than -4 Dsph. The obtained results were typed into an Excel spreadsheet and analyzed statistically using Statistica 10 software. P values of < 0.05 were considered statistically significant. RESULTS: It was found that people with low myopia spent statistically more time on reading and writing than participants in the emmetropic group (5.8 +/- 2.4 vs 4.1 +/- 2.4 h/day, p = 0.003). A relationship between reading and writing and medium and high myopia and hyperopia was not observed (p > 0.05). CONCLUSION: Near visual work leads to higher prevalence of low myopia. PMID- 26591106 TI - [GLIOBLASTOMA MULTIFORME--THE PROGRESS OF KNOWLEDGE ON THE PATHOGENESIS OF CANCER]. AB - Glioblastoma multiforme is a particularly malignant form of primary brain tumor. This cancer represents 12-15% of all brain tumors. Despite advances in neurosurgery, radiation and chemotherapy, the average survival rate is only from 12.1 to 14.6 months. Glioblastoma multiforme is characterized by its diverse histological and cellular features. Like other malignant tumours, it is formed in a multi-stage process of somatic cell transformations, accumulating several genetic disorders. The last decade was a period of particular interest in stem cells. These cells have so far been identified in a variety of primary tumours in the brain. They are probably responsible for the recurrence and progression of cancer. Given the current state of knowledge, it is likely that modifications to the previously used morphological classification of tumours of the CNS will be made by the WHO, as well as the extension of its molecular criteria. In particular, such strategies are awaited for Glioblastoma multiforme--the most malignant primary tumor of the central nervous system, with so far very poor prognosis. PMID- 26591105 TI - [SHOULD PATIENTS WITH GIANT CELL ARTERITIS BE TESTED FOR AORTIC ANEURYSMS?]. AB - Aortitis is one of the manifestations of giant cell arteritis (GCA) and is included in its definition. There is a significantly increased risk of aortic aneurysm formation in GCA patients. In some GCA patients aortic aneurysm dissection is diagnosed only in autopsy. Monitoring of these patients, especially in long lasting disease, requires a doctor's awareness of the possibility of aneurysm formation and aortic aneurysm dissection. Based on the available reports it cannot be confirmed whether intensification of aortitis treatment in GCA prevents the development of aneurysms. This article presents an overview of the available literature and our own experience on a rational diagnosis of inflammation and aneurysms of the aorta in GCA, as well as the prospects for its prevention. PMID- 26591107 TI - [PROGRESS IN THE PATHOGENESIS, DIAGNOSIS AND TREATMENT OF SYSTEMIC ANCA ASSOCIATED VASCULITIS]. AB - Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is a group of systemic diseases characterized by necrotizing inflammation of small and medium size vessels, without immunologic deposits, and with the presence of specific serum antibodies. Recent genetic and cohort studies should improve the comprehension of the pathogenesis of AAV, the stratification of patients into homogenous groups, and lead to therapeutic implications. Immunosuppressive therapy of AAV includes two major periods: induction of remission and maintenance therapy. Therapy should be chosen individually, not only depending on the stage and severity of the disease, but also on genetic and some prognostic factors. Previous randomized trials and clinical observations show some possible limitations of treatment with cyclophosphamide and steroids. Rytuximab seems to be a good alternative in those patients in induction therapy as well as in maintenance therapy. PMID- 26591108 TI - [AN ANALYSIS OF THE INDICATIONS FOR, AND ASSESSMENT OF THE OUTCOMES OF SECONDARY SURGERY AFTER PRIMARY REPAIR OF INJURIES WITHIN THE UPPER LIMB]. AB - INTRODUCTION: The objective of the study was the analysis of the indications for, and assessment of the outcomes of secondary interventions after primary repair of injuries within the upper limb in the authors' institution--Department of General and Hand Surgery of the Pomeranian Medical University in Szczecin (a tertiary care unit). MATERIAL AND METHODS: Answers on questionnaires (including DASH) mailed to 33 patients were the subject of the analysis. The group consisted of 27 men and 6 women, mean age 36 years, in whom secondary interventions were performed at a mean of 8 months after primary surgery. RESULTS: Injuries were grouped in five categories: tendon lacerations, hand or finger amputations, nerve sections, complex tissue injuries, and isolated finger fractures. The most common cause of secondary intervention was incomplete finger movement and lack of opposition of the thumb. The most common operations included tenolysis, arthrolysis and opponensplasty. The outcomes of secondary surgery from patients' perspective were overall good: 13 (39%) patients reported significant improvement, 16 (48%) moderate, and only 4 (13%) patients had no benefit. Twenty five patients regained full, or almost full hand function (DASH scores 2-39), and 8 (24%) had moderately to severely impaired function (DASH 40-80). Twenty-eight patients returned to work. CONCLUSIONS: Primary repair of upper limb injuries (even severe) in the tertiary institution was adequate, and secondary interventions rarely necessary. The most common indication was incomplete finger movement caused by ineffective postoperative mobilization. The important role of rehabilitation for the final outcome of the treatment of hand injuries was emphasized. PMID- 26591109 TI - [ASSOCIATION OF ANTERIOR AND POSTERIOR URETHRAL VALVES. IS IT POSSIBLE TO RECOGNIZE THIS ASSOCIATION IN CLINICAL SIGNS AND RADIOLOGICAL EXAMINATIONS?]. AB - We present a rare association of anterior and posterior urethral valves. A 5 days old boy was admitted because of clinical presenation of lower urinary tract obstruction. A renal ultrasound and voiding cysto-urethrography revealed obstructive pathology in anterior urethra. On endoscopy an association of anterior and posterior urethral valves was recognized, and the valves were incised. Follow-up demonstrated improvement of preoperative signs. We try to recognize an association of anterior and posterior urethral valves in radiological examinations. PMID- 26591110 TI - [USE OF THE STRUCTURAL TENSEGRATION CONCEPT IN THE STECCO FASCIAL MANIPULATION METHOD]. AB - Low therapeutic efficacy in a number of cases involving the musculoskeletal system may be caused by a wrong diagnosis, the misunderstanding of the essence of the problem, pathogen or improper treatment. Therapy may be applied to the wrong area (at the site of pain) or may cover an area that is too small. The paper presents the theory of structural tensegrity (along with the anatomical and physiological grounds), which is based on a number of modern holistic therapies. One such method is the method of fascial manipulation by Stecco, described in outline in this article. This article also describes the structure and functions of the fascia since understanding of this structure was the cause of the emergence of new concepts and therapies. PMID- 26591111 TI - FUNCTIONAL DISORDERS OF THE TEMPOROMANDIBULAR JOINTS AS A FACTOR RESPONSIBLE FOR SLEEP APNOEA. AB - INTRODUCTION: Functional disorders of the temporomandibular joints (TMJ) in the contemporary population are considered by World Health Organization to be the third most frequent dental disease after caries and periodontitis. It is thought to affect 84% of the adult population. In patients aged 65 years and older these disorders become more severe and may affect up to 100% of this age group. MATERIAL AND METHOD: We examined 150 patients aged 35-70 years (mean age 46.5 years). All patients were diagnosed in 2006-2010 at the Department of Dental Prosthetics of the Pomeranian Medical University in Szczecin due to suspected more or less advanced functional disorders of the stomatognathic system, particularly TMJ. The severity of the disorders was identified using the Helkimo index. RESULTS: Functional disorders of the TMJ and mild sleep apnoea were diagnosed in 112 patients. Findings from the study indicated that the severity of sleep apnoea was positively correlated with the duration and severity of TMD. CONCLUSION: Most patients did not link the symptoms of sleep apnoea with dysfunctions of the stomatognathic system. PMID- 26591112 TI - [AN ANALYSIS OF THE CAUSES OF REFUSAL OF ADMISSION TO PATIENTS WITH SEVERE INJURIES AND AMPUTATIONS OF THE HAND REFERRED TO THE REPLANTATION SERVICE]. AB - INTRODUCTION: Total or partial upper limb amputation significantly reduces ability of normal functioning in the society. Development of microsurgical skills enabled to replantation of the amputated limb (or part) and to regain its partial or sometimes full function. MATERIAL AND METHODS: The study analyses the causes of refusal of admission to 55 of 141 patients referred to the replantation service of the Department of General and Hand Surgery PUM, over the period 2012 2013. RESULTS: The causes of denied admission included: injury without compromise of blood supply to the limb (35%), distal amputations (27%), crush injuries (11%), single finger amputation (9%), severe damage of the amputated part (9%) and lower limb amputations (5%). The age of the patient had no significant influence on the decision to refuse admission. The distance between the referring hospital and the replantation centre was statistically significantly shorter in accepted cases (252 km vs 496 km, p < 0.05). CONCLUSION: Our outcomes show a variety of causes of refusal. of admission to patients with severe trauma and amputation of the hand. The main factors influencing decision making regarding admission or denial were associated with the actual danger to the survival of the involved limb, and estimation/calculation of the chance for limb saving. PMID- 26591113 TI - INCREASING THE UPPER AIRWAY SPACE USING ORAL APPLIANCES IN PATIENTS WITH MILD SLEEP APNOEA CAUSED BY STOMATOGNATHIC DYSFUNCTIONS. AB - INTRODUCTION: Abnormal breathing can be caused by developmental malformations or anatomical variations in the upper airways. Stomatognathic diseases may significantly impair the patency of the upper respiratory tract. Treatment of advanced stomatognathic dysfunctions is difficult due to their multifactorial aetiology, and often involves many phases. Sleep apnoea is one of the most bothersome complications. The mainstay therapeutic strategy relies on modifying the position of the mandible against the maxilla, achieved by using different types of oral appliances. MATERIAL AND METHODS: The study was carried out in 2006 2010 on 92 patients (mean age 42.5 years) with diagnosed advanced dysfunction of the stomatognathic system. The treatment relied on the use of an orthodontic appliance (54 patients) or combined multi-phase therapy with splints used in the first phase (22 patients). Two different appliances were used (one of them was modified by the authors). Parameters assessed in the study included time to resolution of pain, reduction in the incidence of sleep apnoea, and improvement in nasal breathing. RESULTS: Change in the protrusion of the mandible not only relieved problems with the stomatognathic system, but also improved breathing in patients. The use of modified oral appliances reduced treatment duration and improved patients' comfort. Therefore, it may be useful in the treatment of patients with mild sleep apnoea. PMID- 26591114 TI - [THE VITAL PULP THERAPY IN PERMANENT TEETH]. AB - The vitality of dental pulp is essential for long-term tooth survival. The aim of vital pulp therapy is to preserve vital, healthy pulp tissue. This therapy's foundation is the elimination of bacteria from the dentin-pulp complex. The treatment option depends on the cause and extent of mineralised tooth tissue destruction. The outcome of such treatment is determined by accurate assessment of the pulp's status and the dentist's ability to predict the success of the therapy. The aim of this review is to facilitate the dentist in making a proper decision referring to vital pulp therapy in permanent teeth, and to provide an overview of new approaches in such treatment. PMID- 26591115 TI - [THE PREVALENCE AND CORRELATES OF MENSTRUAL PAIN IN HEALTHY UNIVERSITY STUDENTS]. AB - INTRODUCTION: Menstrual disorders generally affect the daily activities of females, and menstrual pain is a common gynaecological complaint in westernized societies. The aim of the study was to determine the prevalence of, and the factors related to, menstrual pain in young, healthy women. MATERIAL AND METHODS: Data from 600 university students were obtained during the cross sectional survey. Stu-dents were asked to complete an anonymous questionnaire. Information on the women's socioeconomic status, age at menarche, and menstrual cycle characteristics: i.e. the length and regularity of cycles, the duration of menstrual flow, and the occurrence of menstrual pain, headache and back pain during the cycles were asked about. Each person's height, weight and waist circumference were measured, and the following indices: BMI, WHR, and WHtR were calculated. RESULTS: 29.8% of the surveyed students reported the occurrence of moderate pain during menstruation, and 21.7% reported the occurrence of severe menstrual pain. Significant differences were observed in the prevalence of menstrual pain with relation to age at menarche and the amount and distribution of adipose tissue. Menstrual pain was more prevalent among women who experienced menarche at a younger age. Among overweight and obese students, as well as among students with abdominal obesity, menstrual pain was more frequent than among those with correct weight and correct waist circumference. Moreover, psychological stress was associated with menstrual pain. CONCLUSION: The results of this study show that a sig-nificant percentage of young women complain of menstrual pain. Menstrual pain is associated with early age at menarch, obesity and abdominal obesity. PMID- 26591116 TI - [THE SOCIAL DEMAND FOR PERINATAL SERVISES GIVEN BY MIDWIFES AMONG WOMEN FROM ZACHODNIOPOMORSKIE PROVINCE AND INVESTIGATE THE KNOWLEDGE BASE OF MEDICAL STAFF IN REGARD TO THE MIDWIFE'S RIGHTS AND DUTIES RESULTING FROM POLISH LAW]. AB - INTRODUCTION: The midwife's profession has evolved across the ages to become--in the vast majority of countries, including Poland--an independent medical occupation. The aim of this thesis was to define how big is the social demand for perinatal servises given by midwifes among women from Zachodniopomorskie province and investigate the knowledge base of medical staff in Zachodniopomorskie province in regard to the midwife's rights and duties resulting from Polish law. MATERIAL AND METHODS: Research was carried out from 1.10.2009 to 30.06.2010. It included 115 active midwifes in the city of Szczecin and beyond it (Zachodniopomorskie province). Additionally, 40 doctors, 99 nurses and 1 master of physiotherapy took part in the survey (all of them based in Zachodniopomorskie province). Research was also conducted among 150 women from the same province. The survey was presented in the form of a questionnaire. Since the available literature did not include a standardized research tool which could be used to achieve appointed goals a new method was devised. Results were subjected to mathematical and statistical analysis. CONCLUSIONS: After the compilation of results presented in this paper the following conclusions were made: 1. Some of the medical personnel who participated in the survey do not perceive midwifes as independent medical practitioners. 2. Most midwifes are aware of their rights and obligations outlined in Polish legislation. In their opinion the lack of independence in their profession is caused by unclear clauses and paragraphs in Polish law. The women who participated in the survey showed an interest in services provided by midwifes. 3. They stated that there is a common need for this kind of service. There are grounds to intensify the promotion of midwifery as an independent occupation. PMID- 26591117 TI - [SZCZECIN CITIZENS' KNOWLEDGE ABOUT RARE DISEASES]. AB - INTRODUCTION: The aim of the study was to assess knowledge about rare diseases among citizens of Szczecin (Poland). MATERIAL AND METHODS: The study was performed by questioning 242 adult customers of Turzyn Shopping Centre in Szczecin (149 females and 93 males). The survey was conducted in the shopping mall on 23 February 2013 (control group) and during the celebration of Rare Disease Day and the 12th Polish Nationwide Cystic Fibrosis Week ("Dolina Mukolinkow") on 2 March 2013 (research group). The research tool was a questionnaire devised by the authors and filled out by the writing authors interviewer's answers. RESULTS: In the study group more people knew about the existence of Rare Disease Day than in the control group (86.02% vs 57.72%, chi square test chi2 > chi2(1); 0.001, p < 0.001), but there was no significant difference between knowledge of when Rare Disease Day is celebrated. The definition of rare diseases compatible with the definition of the European Commission's Health and Consumer Protection was reported only in the control group by 4 people. Examples of rare diseases were reported by 74.19% of the respondents in the study group and by 65.10% in the control group (more than 130 diseases were mentioned altogether). Usually, respondents mentioned fewer examples than were asked about in the questionnaire. The aim of Rare Disease Day was accurately specified by 86.02% of persons in the study group and 87.92% in the control group. Rare Disease Day personally concerns 30.11% of respondents in the study group and 10.07% of persons in the control group (OR = 3.85, 95% CI 0.9 3.6, chi2 > chi2(1); 0.001, p < 0.001). CONCLUSIONS: The respondents from the research group knew more about Rare Disease Day and defined the idea of it as closed in a significantly higher degree than the control group. There was no significant difference in the detailed knowledge about rare diseases in either group. This might indicate the need to educate society and patients, along with their families. PMID- 26591118 TI - [POLISH CITIZENS' OPINIONS CONCERNING CO-PAYMENT FOR HOSPITALIZATION AND SUBSIDIES FOR NON-STANDARD BENEFITS]. AB - INTRODUCTION: Co-payment in the health sector operates in most healthcare systems in European countries. The aim of this study was knowledge of Polish citizens' opinions concerning healthcare services co-payment with respect to selected socio demographic factors. MATERIAL AND METHODS: The study was conducted using a diagnostic survey of 636 respondents, representing residents of the West Pomeranian region, Poland. RESULTS: The majority of respondents did not accept co payment for health services. CONCLUSIONS: Material situation and educational background impact on decisions concerning co-payment for hospital treatment. PMID- 26591120 TI - The Expanding Repertoire of Non Tuberculous Mycobacterial Infections: Focus on Rapidly Growing Mycobacteria Bloodstream Infections. PMID- 26591119 TI - HISTORY OF MEDICINE, SURGERY AND UROLOGY IN BRESLAU/WROCLAW. AB - The development of medicine in Breslau from the 14th century has been described and its famous physicians, above all Silesians, are introduced. The aim of the study is to present the development history of hospital services and the teaching of medicine, and also the development of urology in Breslau. Well known Breslau surgeons who were interested in surgery of the genitourinary system are also presented. The aim of the study is to present a brief history of Breslau medicine and surgery from its beginning to the end of World War II. The development of urology and its separation from surgery after World War II is also briefly described. Professor Florian Nowacki, Breslaus's first urologist, is also introduced. Extensive research was undertaken for the collection of literature and documents in German and Polish archives and libraries to prepare this study. PMID- 26591121 TI - Study of Clinical Profile of Patients of Non Alcoholic Fatty Liver Disease and its Association with Metabolic Syndrome. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is considered to be the commonest liver problem in the western world and is increasingly being recognised as a major cause of liver-related morbidity and mortality. It is known to be associated with various metabolic abnormalities, but not much information regarding association between the metabolic disease and the severity of fatty liver is available. AIMS: To study the clinical profile of patients of NAFLD with varying degrees of severity as diagnosed by ultrasonography and to study the correlation between the non-alcoholic fatty liver disease and metabolic syndrome along with its individual components. MATERIAL AND METHODS: The study was an observational and analytical study of patients diagnosed as NAFLD, attending OPD and indoor patients of the Department of Medicine, J A Group of hospitals. All patients diagnosed as NAFLD were investigated for metabolic syndrome according to the NCEP ATP 3 Criteria and a relationship between NAFLD and metabolic syndrome was studied. RESULTS: 51.4% of patients of NAFLD had metabolic syndrome and statistical significance was found in AST, diabetes mellitus and lipid profile. CONCLUSIONS: There is higher prevalence of all the components of metabolic syndrome in cases of NAFLD. Its early detection will help in modifying the disease course, delaying complications and will also play a major role in preventive cardiology. PMID- 26591122 TI - Intravascular Stent-related Endocarditis due to Rapidly Growing Mycobacteria : A New Problem in the Developing World. AB - We report five patients with infective endocarditis (IE) due to rapidly growing mycobacteria (RGM) which we postulate are related to the reuse of percutaneous transluminal angioplasty balloon catheters prior to the intravascular stent placement. The index procedure was performed at various institutes in different parts of the country. We call attention to diagnostic and therapeutic difficulties and the uniformly dismal outcome of RGM IE as well as the potential hazards of re-use of single-use devices. PMID- 26591123 TI - Correlation and Comparison of Various Anthropometric Measurements of Body Fat Distribution and Sagittal Abdominal Diameter as a Screening Tool for Cardio Metabolic Risk Factors and Ischaemic Heart Disease in Elderly Population. AB - OBJECTIVE: Primary objective of this study was to assess utility of sagittal abdominal diameter (SAD) as a cardio vascular risk predictor and compare various anthropometric measurement of body fat distribution in elderly patients. METHOD: Four hundred patients were enrolled in study. Elderly patients more than 60 year of age attending medical OPD, geriatric OPD and suitable indoor patients who were willing to participate in the study were included. RESULT: SAD was significantly higher in patient with ischaemic heart disease (group 1) than patient without ischaemic heart disease (Group 2) (P < 0.001 for male and female). SAD was better than WC to ascertain individual cardio metabolic risk factors in male, especially FBS (Pearson correlation .33 vs. .29), total cholesterol (Pearson correlation .24 vs. .20) as well as LDL cholesterol (Pearson correlation .13 vs. .05), while in female WC and SAD showed equal correlation with individual cardio metabolic risk factors. CONCLUSION: In patient with metabolic syndrome IHD group showed considerably higher mean SAD values. SAD also showed very good correlation with individual cardio metabolic risk factors especially in elderly male, while in female both SAD and.WC were almost equivalent. PMID- 26591124 TI - Viral Hepatitis in Pregnancy--A study of its Effect on Maternal and Foetal Outcome. AB - BACKGROUND AND AIMS: The outcome of Hepatitis during pregnancy has been observed to be widely different by various authors, ranging from the benign to fatal. A poor outcome has increasingly been observed in pregnant women suffering from Hepatitis in Central India. Hence, this study was undertaken to study the incidence, causative organisms and chief prognostic factors affecting the outcome of viral hepatitis in pregnant women. METHODS: Sixty-eight pregnant women reporting to the hospital with jaundice were enrolled as cases and their Haematological, Biochemical and Viral profiles were studied. Sixteen non- pregnant women were enrolled as controls and a similar workup was done. A comparison was done between the two groups We also divided the cases into two groups--survivors and non- survivors and tried to find out the factors predicting mortality. The unpaired student t test and chi square test were used to find out whether the differences were statistically significant. RESULTS: Viral Hepatitis in pregnancy caused a very high maternal mortality (19.1%) and foetal wastage (42.6%). Hepatitis E virus was the commonest causative organism (77.9%) responsible for viral hepatitis during pregnancy. It also caused the highest maternal mortality due to fulminant hepatic failure. Maternal mortality was significantly higher in those women presenting with features of encephalopathy, SIRS, high bilirubin levels and prolonged prothrombin time. Vertical transmission was noted in Hepatitis B and E. CONCLUSIONS: Hepatitis E is the chief causative organism causing fulminant hepatic failure in pregnant women in Central India. It lead to very high rates of maternal mortality and foetal wastage. PMID- 26591125 TI - The Changing Role of Dietary Protein Restriction in Management of Chronic Kidney Disease (CKD). AB - In the last 5 to 6 decades there has been a marked variation in use of dietary protein restriction (DPR) in treatment of patients with chronic kidney disease (CKD). Before availability of renal replacement therapy (RRT), DPR restriction was widely practised in uraemic patients to reduce generation of nitrogenous waste products and ameliorate uraemic symptoms. With availability of RRT, the interest in DPR was lost. There was a resurgence of interest in DPR when animal experimental studies suggested that DPR can retard the progression of CKD. Then there was concern about worsening nutritional status with DPR. This article reviews how the role of DPR in treatment of CKD as perceived by physicians has varied over the years and suggests a strategy that should be followed in India considering that RRT is available to a very small percentage of cases developing end stage kidney disease (ESKD). PMID- 26591126 TI - Endocardial Thickening in Hypertrophic Cardiomyopathy: A Lesser Known Fact. PMID- 26591127 TI - Bilateral Thoracic Outlet Syndrome Misdiagnosed as a Connective Tissue Disorder. PMID- 26591128 TI - Fatal Disseminated Mycobacterium chelonae Infection in an Immunocompromised Host- A Unique Presentation. AB - Disseminated disease due to rapidly growing non tuberculous mycobacteria especially in the immunocompromised host is being increasingly reported. The usual manifestations of disease being skin and soft tissue infection, post operative wound infection and pulmonary disease. We present a case of a disseminated infection due to Mycobacterium chelonae with features of chronic meningitis and knee joint arthritis in a patient with systemic lupus erythematosus on systemic steroids and mycophenolate. M chelonae was isolated from both synovial and cerebrospinal fluid and anti microbial therapy was initiated as per sensitivity results. However the patient's clinical condition continued to worsen and she succumbed to her illness. PMID- 26591129 TI - Case Series of Pancreatitis with Uncommon Presentations. AB - Acute pancreatitis is an inflammatory disease characterized by local tissue injury which can trigger a systemic inflammatory response. Vascular complications of pancreatitis are a major cause of morbidity and mortality. Pulmonary embolism in acute pancreatitis has been reported to be very rare. Cardiovascular complications include shock, hypovolemia, pericardial effusion, and even nonspecific ST-T changes in the electrocardiogram (ECG) mimicking acute myocardial infarction. Acute pancreatitis complicated with acute myocardial infarction has rarely been reported and the precise mechanisms of myocardial injury remain unclear. Here we report two cases of acute pancreatitis one with acute pulmonary thrombo embolism and other with acute myocardial injury. PMID- 26591130 TI - A Case Report of Post Rabipur (Purified Chick Embryo Rabies Vaccine) Acute Disseminated Encephalomyelitis. AB - Acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating disease that typically occurs following a viral infection or vaccination. The incidence of ADEM following vaccination has become very low since introduction of non-neural rabies vaccine and only few cases had been reported due to pure chick embryo derived rabies vaccine (PCERV). Here we are reporting a rare case of delayed post vaccinal ADEM. PMID- 26591131 TI - A Rare Cause of Dysphagia--Kommerell's Diverticulum. AB - A right-sided aortic arch with an aneurysm of the aberrant subclavian artery is a rare disease. We report a case of Kommerell's diverticulum of an aberrant left subclavian artery in a patient with a right-sided aortic arch with associated ventricular septal defect. Fewer than 50 cases have been reported in literature so far. Our patient presented with short duration of dysphagia without any syncope or left subclavian steal syndrome. The major morbidity was caused by Barrett's oesophagus with reflux and a mixed paraoesophageal and hiatal hernia. There was associated psoriasis. An attempt at repair was not undertaken because of the high operative risk and a small aneurysm. Left thoracotomy for direct repair of Kommerell's diverticulum is a simple and safe method. PMID- 26591132 TI - A Case of Tuberculous Colitis with Associated Takayasu's Arteritis. AB - Intestinal tuberculosis and Crohn's disease (CD) are two different granulomatous diseases affecting the intestinal tract with similarities in clinical presentation but different therapeutic strategies. Takayasu's arteritis (TA) is a graulomatous disease of aorta and its major branches. TA is associated with tuberculosis as well as CD. We present a case of Granulomatous colitis in a young female who was detected to have TA. She was initially diagnosed as a case of CD elsewhere four years previously and has been on immunosuppressive treatment. Repeat evaluation at our centre using endoscopic, radiological and histological criteria suggested a diagnosis of intestinal tuberculosis which was confirmed both by molecular biology techniques as well as by tissue cultures for mycobacterium tuberculosis. Herein we discuss the diagnostic challenge of distinguishing intestinal tuberculosis and CD in a tuberculous endemic country like India. Recent studies have analysed the immunological mechanisms explaining the association of TA and tuberculosis. These studies are important as they may give a clue for better targeted therapies and out come in TA. PMID- 26591133 TI - Reel Syndrome--A Variety of Twiddler's Syndrome. AB - Reel syndrome is an uncommon condition in which a patient's subconscious, inadvertent, or deliberate external manipulation of their cardiac pacemaker results in the movement of the transducer wires along its transverse axis. We report a clinical case of a 67 year old lady with permanent pacemaker presenting with pacemaker malfunction and was detected with reel syndrome. PMID- 26591134 TI - Hans Conrad Julius Reiter. PMID- 26591135 TI - Autism--Need for Awareness. PMID- 26591136 TI - Dangerously Candid: Detection of Yeast Cells in Peripheral Blood Smear in a Case of Candidaemia. PMID- 26591137 TI - Current Antiplatelet Agents in Acute Coronary Syndrome. PMID- 26591138 TI - Management of Hypertension: An Overview of Practice Trends in India. PMID- 26591139 TI - BEAT Survey: A Cross-sectional Study of Resting Heart Rate in Young (18-55 Year) Hypertensive Patients. AB - BACKGROUND: Studies in Caucasian population have shown that sustained elevation of heart rate (HR) is associated with increased cardiovascular mortality and morbidity in patients with heart failure (HF), myocardial infarction (MI). However, resting HR is not so well-studied in Indian hypertensive patients. MATERIALS AND METHODS: BEAT is a cross-sectional survey to evaluate the resting HR in young (18-55 years) patients in India. Also study aims to correlate it with age, BP and body mass index (BMI) along with smoking habit and past medical history like coronary artery disease. RESULTS: A total of 3743 patients (mean age 45.69 +/- 6.86 years; males 66.52%) were enrolled in study. Of them, 886 (23.67%) were diabetic, 712 (19.02%) had history of coronary artery disease and 818 (21.85%) had history of ever smoking.The average BMI was 26.15 (3.92) with majority of patients falling in either obese (19.85%) or overweight (53.42%) category. The average resting HR and BP were 82.79 +/- 10.41 bpm and 146.82 +/- 15.46/ 89.08 +/- 8.8 mmHg. HR was found to have correlation with SBP (r = 0.247, p < 0.01), DBP (r = 0.219, p < 0.01); to lower extent with BMI (r = 0.041, p < 0.05); but not with age (r = -0.012, NS). CONCLUSION: The resting HR is elevated in the Indian hypertensive patients. It was found to have correlation with BP and to lesser extent with BMI, whereas there was no correlation with age. The chronically elevated HR even in patients under treatment may have implication on cardiovascular mortality and morbidity. PMID- 26591140 TI - Hypertension Management and Antihypertensive Withdrawal--A Perspective. AB - INTRODUCTION: Hypertension is one of the commonest diseases to be managed on out patient basis. There are multiple guidelines advising us about its management. None of these however guide us in a detailed way regarding how and when to withdraw the antihypertensive drugs. METHODS: We interviewed some 80 doctors in the city of Pune to find their ways of managing hypertension. Simultaneously we also analyzed our data of hypertensive patients. RESULTS: We present our observations in this regard. CONCLUSION: We feel there is a need to try out antihypertensive drug reduction and/or withdrawal in select patients. These attempts can be successful in a significant number of patients. PMID- 26591141 TI - Awareness about Ethics Committee amongst the Medical Teachers in a Medical College. AB - INTRODUCTION: The Ethics Committees (EC) are established to safeguard the safety and rights of the subjects participating in a research study. No formal training about Ethics Committee is given to the medical students in undergraduate and post graduate education as a part of curriculum. AIMS AND OBJECTIVES: To study the awareness about the composition and functioning of EC amongst the medical teachers. METHODOLOGY: A prevalidated questionnaire was given to the medical teachers who consented to participate in the study, fill up the questionnaire immediately and return it. The questions consisted of knowledge about the composition of the EC and its functioning in general. RESULTS: Ninety two (51%) belonged to non-clinical branches; 88(49%) were clinicians. Forty (22%) had undergone ICH-GCP training (27 belong to clinical and 13 non-clinical branches). Forty four point four percent were well informed about the composition of EC in general. The most common wrong answer was "Dean" is the Chairperson of EC. CONCLUSIONS: As the years of experience as Faculty in Nair increased, the knowledge about the composition of EC's in general increased but the information about functioning of IEC did not improve significantly. The awareness about EC was significantly higher amongst the PG teachers. PMID- 26591142 TI - Comparative Study of Effectiveness and Resistance Profile of Chloroquine and Sulfadoxine-Pyrimethamine in Uncomplicated Plasmodium falciparum Malaria in Kolkata. AB - INTRODUCTION: Malaria is one of the major public health problems of the country. Factors responsible for reemergence of malaria in India was due to emergence and spread of chloroquine resistant Plasmodium falciparum strains across the country coupled with steady rise in insecticide resistance of the vector mosquitoes. Very little is known about the drug resistance status of P. falciparum in India. As per National Vector Borne Diseases Control Programme (NVBDCP), chloroquine is the drug of choice for uncomplicated P. falciparum cases and the combination of Artesunate and Sulfadoxine-Pyrimethamine (SP) is being used to treat the documented chloroquine-resistant uncomplicated cases. To evaluate the comparative effectiveness and resistance profile of Chloroquine vis-a-vis Sulfadoxine Pyrimethamine (SP) in uncomplicated Plasmodium falciparum cases as the first-line therapy a study was undertaken at the Malaria Clinic of Calcutta School of Tropical Medicine, Kolkata during the period from July 2007 to December 2007 at Kolkata Municipal Corporation, Kolkata. MATERIAL & METHODS: Following WHO protocol 2003, a total of 100 parasitologically confirmed Plasmodium falciparum cases were recruited as per the recruitment criteria. Among them, 50 patients were given Chloroquine and another 50 patients were given SP. Eight patients were excluded or lost to follow-up during the follow-up period because of failure to follow the protocol. RESULTS: It was observed that in the Chloroquine group out of 50 patients, 30 (60%) showed adequate clinical and parasitological response (ACPR), 15 (30%) had late treatment failure (LTF) and remaining 5 (10%) were lost during the follow up period (LFU). On the other hand in the SP group out of 50 patients, 46 (92%) showed ACPR and only one (2%) had LTF and 3 patients were LFU. The difference of LTF in Chloroquine and Sulfadoxine-pyrimethamine groups was statistically significant (p value < 0.05). Also there was statistically significant difference of the mean parasite clearance time (PCT) of Chloroquine (82.7 hours) and SP group (61.3 hours). CONCLUSIONS: Chloroquine failure rate was high which was well above the WHO recommended cut off threshold for drug policy change (> 10%), Sulfadoxine- Pyrimethamine can be used in place of Chloroquine as the first line drug in uncomplicated P. falciparum cases. PMID- 26591143 TI - Catching Dengue Early: Clinical Features and Laboratory Markers of Dengue Virus Infection. AB - BACKGROUND AND OBJECTIVES: Dengue fever is one of the most common tropical diseases worldwide. Early diagnosis of dengue helps in patient triage and timely management of dengue virus infection.This study was undertaken to note the early clinical features supported by detection of NS1 antigen for diagnosis of dengue virus infection. METHODOLOGY: In this study a total of 100 adult patients presenting with clinical features of dengue infection from January 2012 to December 2012 were studied.The diagnosis was confirmed with NS1 rapid diagnostic test (RDT) whose efficacy was later tested with IgM ELISA. RESULTS: In this study young males were predominantly affected. NS1 positivity was 68%. The sensitivity of NS1 in predicting dengue infection compared to IgM was 92.86% and specificity was 90% with strength of agreement considered to be 'very good' based on Kappa statistics. Clinical features like retro-orbital pain, myalgia, arthralgia, rashes and bleeding manifestations were significantly associated with NS1 positivity. Similarly icterus, oedema, hypotension, altered sensorium, thrombocytopenia and raised creatinine were significantly more in NS1 positive patients. Anomalously, SGOT was more than SGPT, which can help in differentiating dengue virus infection from other viral infections early in the course. CONCLUSION: We conclude that dengue infection, which possesses serious public health problem, can be diagnosed early with the help of clinical features like retro-orbital pain, myalgia, bleeding manifestations, thrombocytopenia and anomalously SGOT greater than SGPT that is supported by detection of NS1 antigen. PMID- 26591144 TI - Clinico-Radiological Profile and Outcome of Novel H1N1-Infected Patients During 2009 to 2014 Pandemic at Tertiary Referral Hospital in Rajasthan. AB - BACKGROUND: The 21st century Influenza A (H1N1) pandemic arrived during spring of 2009 and has posed a serious public health challenge world-wide. We describe the clinic-radiological profile and outcome of patients who were found H1N1 positive in Jawahar Lal Nehru Hospital, Ajmer of Rajasthan from 5th August 2009 to 31st May 2014. AIMS AND OBJECTIVES: Primary objective was to study clinical and radiological profile of the patients admitted with confirmed H1N1 infection. Secondary objective was to observe the risk factors and associated comorbid conditions with complications and need of mechanical ventilation and / or death among H1N1-infected patients MATERIALS AND METHODS: Hospitalized patient with laboratory-confirmed H1N1 flu by reverse transcriptase PCR during August 2009 to May 2014 in JLN Hospital, Ajmer, were included in this retrospective study. Data was collected from hospital isolation ward admission register. Statistical analysis was done by SPSS, version 16. Binary logistic regression was used to find out independent risk factors for morbidity. RESULTS: A total of 94 PCR confirmed H1N1-infected patients were included in the study, of them 32 (34%) males and 62 (66%) females. Median age was 35 years and median duration of symptoms before hospitalization was 5 days. Common presenting symptoms include fever 83 (88%), cough 79 (84%), breathlessness 67 (71%), rhinnorrhoea/ common cold 25 (26.5%), throat pain 13 (13.8%), chest pain 5 (5.3%) and haemoptysis 4 (4.2%). Bilateral crepitations were audible in 86 (91.4%) and tachypnoea in 73 (78%) cases. Co-morbidities were seen in 75 (79.7%) patients. Ventilatory support was required in 57 (60.6%) patients. On presentation, chest x-ray showed pulmonary opacities in 72 (76.5%) patients. We observed no significant side effects of oseltamivir 150 mg twice day dose for 5-7 days. Forty-one (43.6%) patients were cured and discharged from hospital, 53 (56.3%) patients died. Development of ARDS, involvement of bilateral lower zones of lungs in chest skiagram, requirement of mechanical ventilator and associated pregnancy (third trimester) were independent predictors of mortality. CONCLUSION: During evaluation period from 2009 to 2014, H1N1 influenza caused severe illness requiring hospitalization, including pneumonia, acute respiratory distress and complications involving renal, liver and cardiac dysfunction. Maximum patients were between age group of 20-40 year. Fever and cough were most common presenting symptoms. Common comorbidities were pregnancy, diabetes, hypertension, and obesity. Mortality rate was high in H1N1-infected patients with development of ARDS, associated pregnancy and patients who required ventilatory support. PMID- 26591145 TI - Blood Pressure Variability: Assessment, Prognostic Significance and Management. AB - Interest in blood pressure variability (BPV) as a cardiovascular risk factor has gained focus in recent times. Increased BPV places added strain on the cardiovascular (CV) system unrelated to its average value, leading to increased risk of target organ damage (TOD) and CV events. Recent data suggests that there is inter-drug variation in efficacy with calcium channel blockers (CCBs) such as Amlodipine proving superior to other drugs in reducing BPV. Addition of CCBs to other antihypertensive agents significantly reduces BPV; however the reverse is not true. PMID- 26591146 TI - Letter to Editor: Keeping the Dialogue Going. AB - Journals publish a variety of manuscripts under the section titled "Letters to the Editor". This communication discusses the important role played by letters written as a comment on an article previously published in the journal and provides suggestions regarding the way to write such letters. PMID- 26591147 TI - Isolated Myxomatous Flail Aortic Valve Causing Severe Aortic Regurgitation. PMID- 26591148 TI - Boomerang Sign. PMID- 26591149 TI - Disseminated Tuberculosis Masquerading as Metastatic Pancreatic Carcinoma. AB - Tuberculosis (TB) is highly prevalent in India, but TB of pancreas is rare. It is usually seen in patients with miliary TB and often in immunocompromised host as like in HIV positive patients. Pancreatic TB can present as pancreatic mass, pancreatic abscess or acute or chronic pancreatitis. Pancreatic involvement in tuberculosis can occur via haematological route by contiguity from the adjacent organs. In certain clinical settings, presence of pancreatic mass should alert clinicians regarding possibility of pancreatic TB, especially in endemic areas. With use of appropriate diagnostic tests and proper treatment it is potentially curable. PMID- 26591150 TI - Chronic Paraspinal Pain due to Multiple Aortic Aneurysms. AB - Aneurysms of the aorta are not uncommon, both of the thoracic aorta or the abdominal aorta and may be associated with congenital aortic valve diseases, cystic medial necrosis, Marfan's Syndrome or Ehlers-Danlos syndrome, or atherosclerosis. We report a case of a 46 year old smoker who had developed multiple aneurysms of the aorta in both the thoracic and abdominal parts and was incidentally diagnosed on work-up of a chronic back pain associated with venous prominence on left side of chest and left arm. PMID- 26591151 TI - Tetralogy of Fallot presenting with Right Ventricular Failure. AB - A 32 year old male patient was admitted with exertional dyspnea for long duration with features of right sided failure. On examination, it seemed to be a congenital cyanotic heart disease with decrease pulmonary flow. Echocardiography showed a malaligned VSD with pulmonary stenosis with severe AR and the total regurgitation volume was going to the RV instead of going to both the ventricles leading to dilatation of right ventricle and failure. PMID- 26591152 TI - Lymphomatous Infiltration of Kidneys. AB - Renal involvement in lymphoma usually occurs late in the course of the disease and is clinically silent. Acute kidney injury (AKI) is rare, with the reported incidence of 0.5% in the literature. We describe here a 20 years old female patient who presented with non-dialysis requiring AKI and renal biopsy showed lymphomatous infiltration of kidneys. Though renal function improved, patient died due to central nervous system involvement. PMID- 26591153 TI - LEOPARD Syndrome with Patent Ductus Arteriosus and Hypertrophic Cardiomyopathy. AB - A sixteen year old girl presented with history of hemoptysis of one week duration. She had history of dyspnea on exertion and frequent respiratory infections in childhood. She had short stature, hypertelorism, neurofibroma, cafe au lait spots and multiple lentigines. She had features of severe pulmonary hypertension and differential clubbing and cyanosis. A final diagnosis of LEOPARD syndrome with hypertrophic cardiomyopathy and patent ductus arteriosus (PDA) Eisenmenger syndrome was made. PMID- 26591154 TI - DRESS Syndrome: Drug Rash with Eosinophilia and Systemic Symptoms. AB - DRESS Syndrome is caused by exposure to certain medications that may cause fever, rash, inflammation of internal organs, lymphadenopathy and characteristic hematologic abnormalities such as eosinophilia, thrombocytopenia and atypical lymphocytosis. We herein report a case of DRESS syndrome who presented with fever and rash, secondary to sulfasalazine ingestion. Diagnosis of DRESS is often delayed, as several diseases have clinical and laboratory features similar to DRESS syndrome. PMID- 26591155 TI - Cryptostegia grandiflora Toxicity Manifesting as Hyperkalemia, Complete Heart Block and Thrombocytopenia. AB - Cardiac glycosides are widely available in botanic products and other naturally occurring substances worldwide. Accidental consumption of it leads to digitalis toxicity with varied systemic manifestations. We describe a case of consumption of extract of leaves of the Indian rubber vine plant (Crytostegia grandiflora) which led to gastrointestinal, cardiac, electrolyte, and hematological disturbances. PMID- 26591156 TI - Portosystemic Shunt Presenting as Rapidly Progressive Dementia. AB - Rapidly progressive dementia (RPD) is a challenging clinical problem in the elderly. It encompasses a wide range of diseases. Thorough clinical examination and a systematic approach is essential to find the cause of RPD. Early recognition of causes of RPD is important for early treatment and reversal of the pathology. We report a case of RPD due to portosystemic encephalopathy secondary to a large portosystemic shunt with preserved liver functions, in a previously healthy elderly male. He had pallidal hyperintensities on MRI brain that can be the clue to the diagnosis of portosystemic shunt and chronic liver disease in patients with RPD. PMID- 26591157 TI - Left Ventricular Mid-Cavity Hypertrophic Cardiomyopathy with Myeloproliferative Neoplasm Leading to Multiple Cerebral Emboli. AB - Here we present a case of 55 year old male who presented with lower respiratory tract infection and clinical findings of systolic murmur at apex and hepatosplenomegaly and later on multiple cerebral emboli which on further evaluation turned out to be myeloproliferative neoplasm associated with cardiac mass with left ventricular mid-cavity obstruction. PMID- 26591158 TI - Graham Robert Vivian Hughes. PMID- 26591159 TI - Wilson's Disease: Aspects of Diagnosis and Treatment. PMID- 26591160 TI - Reply from Author. PMID- 26591161 TI - Factors Modulating Blood HbA1C Level and Diabetic Retinopathy. PMID- 26591162 TI - From the Desk of Editor-in-Chief. PMID- 26591163 TI - Screening for Pulmonary Hypertension in Antiphospholipid Antibody Positive Lupus Erythematosus. PMID- 26591164 TI - Higher Incidence of Pulmonary Hypertension in Antiphospholipid Antibody Positive Lupus. AB - BACKGROUND: Antiphospholipid antibodies (APAs) are detected in 30-40% of SLE patients, but only few develop APLA syndrome. Incidence of pulmonary hypertension (PH) is reportedly high in APA positive patients; however, Indian data is missing. MATERIALS AND METHODS: This cross-sectional, observational study was conducted from Jan 2009 - Dec 2011, on 50 SLE patients, fulfilling ACR criteria. SLE patients were selected serially from OPD and IPD. Pregnant females and children were excluded.Tests for presence of anticardiolipin antibody, lupus anticoagulant and anti-beta2 glycoprotein antibody were performed in all patients. Pulmonary artery pressure, was measured on transthoracic 2DECHO, by TR jet and graded as, mild (25-40mm), moderate (40-60) and severe (> 60mm). CT - pulmonary angiography and lower limb venous Doppler were performed in patients of moderate and severe PH. RESULTS: Out of 50 patients, 46 were females, 4 males, aged 17-50 yrs. Twenty-three were positive for at least one APA, 14/23 ACLA positive, 3/23 positive for LA, 16/23 positive for anti beta2 glycoprotein antibodies, 11 were positive for 2 or more antibodies. Pulmonary hypertension was present in 11 out of 23 APA and 2 out of 27 APA negative patients, with moderate to severe PH in 7 out of 11 APA positive patients. Four out of 7 patients with moderate to severe PH tested positive for more than one APA and in higher titers. CT pulmonary angiography and lower limb venous Doppler were performed in 4 out of 7 patients with moderate and severe PH and were normal. Three patients with moderate PH expired. CONCLUSIONS: Lupus patients with APAs are more prone to develop PH, with a possibility of formation of microthrombi in the pathogenesis of PH. As regards treatment of PH, in addition of PH lowering drugs, place for anticoagulants or antiplatelet agents needs to be studied in PH with APA positive patients. PMID- 26591165 TI - Clinical Profile of Acute Rheumatic Fever Patients in a Tertiary Care Institute in Present Era. AB - INTRODUCTION: Rheumatic heart disease (RHD) is still a common cause of morbidity and mortality in India. Rheumatic fever commonly occurs between 5-15 yrs of age. Rheumatic activity is a common cause of deterioration of symptoms in a stable or undiagnosed case of RHD. MATERIAL AND METHODS: 41 consecutive patients of acute rheumatic activity were studied. Presenting symptoms were noted. Physical examination was done for major and minor Jone's criteria. Detailed cardiac examination was done. All underwent echocardiography. RESULTS: Mean age was 14.80 +/- 7.01 yrs, 26 were female and 15 were male. Joint pain was the commonest present complaint (29 patients), followed by fever in 17 patients, 32 had carditis, 26 had arthritis, 13 had subcutaneous nodules, 7 had chorea and one had erythema marginatum. In patients with carditis, 30 had mitral regurgitation (MR) only, 15 had MR with aortic regurgitation (AR). Out of 32 patients with carditis, 10 patients did not have any clinical evidence of carditis and were detected by echocardiography only. Six patients were known cases of rheumatic fever but had stopped penicillin prophylaxis. CONCLUSION: Commonest complaint in patients with rheumatic fever was joint pain followed by fever. In patients with carditis, all had MR, with 1/3rd of these patients having associated AR. 1/3rd of patients with carditis were detected by echo only and therefore, echo should be included in diagnostic criteria for acute rheumatic fever. None of the patients who developed rheumatic fever was on penicillin prophylaxis. PMID- 26591166 TI - Gel Foam Renal Artery Embolization for Life-threatening Renal Haemorrhage. AB - INTRODUCTION: Renal artery embolization (RAE) is an important treatment option for patients with acute renal haemorrhage. Many types of embolic agents are presently available. We describe here the use of gel foam embolization for the treatment of acute renal haemorrhage. MATERIAL AND METHODS: A total of 12 patients (10 males and 2 females) underwent RAE. The indications in all cases were persistent renal haemorrhage which was secondary to renal biopsy (10 cases), blunt trauma to abdomen (1 case) and percutaneous nephrostomy (1 case). Embolic agent used was gel foam in all but one case. Embolization was done by selective catheterization of the feeding segmental / lobar renal artery branches. RESULTS: Successful obliteration of the vascular malformation with no post-procedure complications were achieved in all cases. CONCLUSION: RAE with gel foam is a relatively inexpensive, safe, effective and minimally invasive procedure for the treatment of life-threatening renal haemorrhage, preserving healthy renal parenchyma and renal function. PMID- 26591167 TI - Post-Reteplase Evaluation of Clinical Safety & Efficacy in Indian Patients (Precise-In Study). AB - BACKGROUND: ST elevated myocardial infarction is a serious and life-threatening condition. In patients suitable for thrombolytic treatment, time is critical and reperfusion should be initiated as soon as possible. Reteplase is commonly used in the management of ST elevated myocardial infarction. OBJECTIVE: To assess the safety and efficacy of intravenous Retelex (Reteplase) injection in management of patients with ST elevated myocardial infarction in clinical practice. MATERIAL AND METHODS: An open label, non-comparative, multicentric, post-marketing observational study was conducted in > 18 years of patients with ST elevated myocardial infarction (STEMI) receiving Retelex. All patients received 20 units Retelex within 6 hours after the onset of acute myocardial infarction (AMI) symptoms. The dose was given as two 10 unit Intravenous injections each over two minutes 30 minutes apart. Evaluation criteria: Patients were followed on day 1, 3, 5/7 and 30. The primary evaluation criteria was total number of patients showing clinically successful thrombolysis based on 50% resolution of ST elevation in the maximum affected (adjacent) leads within 90-120 minutes of initiation of Reteplase and resolution of chest pain. Secondary evaluation criteria included percentage of patient requiring rescue percutaneous coronary intervention (PCI), percentage of patient underwent angioplasty or CABG after thrombolysis. Door to needle time was also recorded in patients receiving the study drug. Global assessment of efficacy and safety was done by patient as well as investigator. All adverse events were recorded for safety assessment. Statistical analysis: Mean and percentage were calculated for primary efficacy parameters i.e. 50% resolution of ST elevation and resolution of chest pain. Chi square test was used for comparing the difference between diabetes versus non diabetes patients for primary efficacy variables as well as for comparing the number of patients requiring rescue PCI, angioplasty and CABG between these two groups. RESULTS: A total of 228 patients were enrolled out of which 140 were having diabetes mellitus. Out of all patients, 68.9% had ST elevated anterior wall myocardial infarction. Resolution of 50% of ST elevation and resolution of chest pain was reported in 90.50% and 95.4% patients respectively. No significant difference was seen in primary efficacy variables between diabetes versus non diabetes patients (p = 0.1538 for 50% ST elevation resolution, p = 0.4031 resolution of chest pain). Rescue PCI was required by 7.6% patients while angioplasty and CABG was done in 22% and 16.8% patients, respectively. No significant difference was seen in diabetes versus non-diabetes patients requiring rescue PCI (p = 0.1059), angioplasty (p = 0.2172) and CABG (p = 0.9128). The incidence of adverse event in this study was 5.3%. CONCLUSION: Reteplase IV Injection-recombinant plasminogen activator is effective and well tolerated in the management of ST elevated myocardial infarction (STEMI) in Indian patients including diabetes patients. PMID- 26591168 TI - Profiling the Mortality due to Influenza A (H1N1) pdm09 at a Tertiary Care Hospital in Jaipur during the Current Season--January & February 2015. AB - BACKGROUND: The onset of winter of 2014-2015 saw an alarming spurt in influenza A (H1N1) pdm 09 leading to a significant mortality. Rajasthan was one of the foremost affected state bearing the frontal attack in which majority of deaths occurred early and in the young. OBJECTIVE: To sketch out the mortality profile with respect to demographic and clinical progression with an aim to identify the groups, this virus conspicuously picked up with a perspective to control some of the avoidable factors. METHODS: We analyzed the epidemiological data in 76 RT-PCR confirmed deaths of H1N1 patients that occurred between 1st January 2015 and 28 February 2015 over a period of 59 days at SMS Medical College Hospital, Jaipur. RESULTS: A total of 412 patients got hospitalized during two months period from 1st January 2015 to 28th February 2015, out of which 76 fatal cases presenting with category C symptoms along with radiological evidence of bilateral pneumonia were analyzed. 48.6% deaths occurred in the 18-40 years of age group. The mean age being 44.01 +/- 15.07 years. Females had a marginally increased mortality rate (F: M-1.23:1). The mean time of onset of symptoms to hospitalization was 6.79 +/- 4.63 days. Fifty-one (67.1% 0) patients were from urban areas, whereas 25 (32.89%) belonged to rural areas. Only 7.83% patients presented within 24 - 48 hours whereas 46% presented within 5 days of onset of symptoms. 66.9% succumbed within 5 days of hospitalization, despite of starting Oseltamivir in a dose of 150 mg/bd on the day of admission. 64.5% had predisposing risk factors. Bilateral pneumonia was observed in all the 76 patients, septicemia in 21.12%, MODS in 30.26% and AKI in 9.21%. CONCLUSIONS: The in-hospital mortality of 17.79% despite of starting Oseltamivir has raised concern about identifying the so called "Rapid Progressors" [66.9% succumbing within 5 days of hospitalization]. As a corollary of this analysis the authors are of the opinion that a rejig of the existing guidelines to identify and treat influenza like illness be made available at the national level. What factors promote rapid progression especially in a group without any predisposing risk condition should form the focus of future studies. As risk group individuals formed a major chunk of deaths, the need to vaccinate this group should form a scaffold on which future directions and interventions have to be built up to combat the morbidity and mortality. PMID- 26591169 TI - H1N1 Revisited After Six Years: Then and Now. PMID- 26591170 TI - Writing Case Reports: Contributing to Practice and Research. AB - Case reports describe a patient with unusual or unexpected features. They represent the oldest type of medical publication. They are about generating a new hypothesis and not about proving a hypothesis. Hence, despite being considered as the lowest level of evidence; they continue to be relevant for clinical practice, research and medical education. This article intends to provide guidance regarding writing a case report to those wishing to make a foray in scientific writing through reporting an interesting case. PMID- 26591171 TI - Haemorrhage in Posterior Reversible Encephalopathy Syndrome (PRES). PMID- 26591172 TI - Pseudo-aneurysm of Mitral-Aortic Intervalvular Fibrosa: An Imaging Perspective. PMID- 26591173 TI - Primary Sjogren's Syndrome Presenting as Flaccid Quadriparesis. AB - Primary Sjogren's syndrome is an autoimmune disease presenting classically as keratoconjunctivitis sicca. Renal involvement in Sjogrens's syndrome is less common, and the initial presentation with renal complications without any sicca symptoms is extremely rare. The renal involvement may present with symptoms arising from interstitial nephritis, mainly distal renal tubular acidosis. PMID- 26591174 TI - Tuberous Sclerosis and Polycystic Kidney Disease: A Rare Association. AB - Tuberous sclerosis complex (TSC) and autosomal dominant polycystic kidney disease (ADPKD) are two different genetic diseases. Although these two diseases are associated very rarely, the association is well recognized. This occurs due to a large deletion involving both PKD-1 and TSC-2 genes on chromosome 16. This is also known as TSC-2/PKD-1 contiguous gene syndrome. We report a 26-year-old female patient with TSC who presented with severe metabolic acidosis due to renal failure. She had palpable enlarged kidneys bilaterally. CT scan of abdomen revealed bilateral enlarged lobulated kidneys studded with multiple cysts which was consistent with the diagnosis of ADPKD. PMID- 26591175 TI - Pacemaker Lead Endocarditis Due to Trichosporon Species. AB - Pacemaker-related fungal endocarditis is an uncommon and unexpected complication. It is associated with high mortality rates. Due to nonspecific clinical symptoms, negative blood culture and delays in obtaining appropriate imaging studies; late diagnosis is common with fungal endocarditis. Hereby we are reporting a rare case of pacemaker lead endocarditis due to Trichosporon species. In literature we did not find any case of pacemaker-related endocarditis due to Trichosporon species. PMID- 26591176 TI - Primary Amoebic Meningoencephalitis. AB - Primary amoebic meningoencephalitis due to free living amoeba, also called 'brain eating amoeba', Naegleria fowleri, was detected in retroviral disease patient of 40 years who has history of using well water. Patient was admitted with severe headache, fever intermittent, nausea, vomiting and slurring of speech. CT scan and MRI scan findings were normal. CSF examination showed increased protein, low sugar and predominant lymphocytes. CSF was negative for cryptococcal antigen but wet mount preparation showed highly motile free living amoeba Naegleria fowleri. Patient was put on Amphotericin B, Metronidazole, Rifampicin in addition to ART and ATT and other supportive medications. His headache was relieved and patient improved and was discharged on request. Earlier eight cases have been reported from India of which four cases survived the acute episode. PMID- 26591177 TI - Diabetic Muscle Infarction (Myonecrosis): Underdiagnosed or Underreported? AB - Diabetic muscle infarction is a rare complication of diabetes. It is seen more in Type 1 DM than Type 2 DM, but in both it is associated with longer duration of diabetes, poor glycemic control with or without microvascular complications. We present a case report of a 47 year diabetic male, who presented with sudden onset of painful swelling of the left thigh muscles (vastus group). The patient had microvascular complications of diabetes. Apart for mild elevation of CPK and LDH other investigations were normal. MRI findings of left thigh showed T2 hyperintensities in the involved muscles which established the diagnosis. Muscle biopsy revealed necrosis of the muscle fibres, presence of inflammatory cell infiltrates and hyalinization of the blood vessels with luminal narrowing which is characteristic of diabetic muscle infarction. The patient was treated with immobilization, analgesics and adequate blood sugar control. This case highlights the rarity of finding vascular changes as well as the poor prognosis and the occurrence of fatal complications in near future. PMID- 26591178 TI - Autoimmune Polyglandular Syndrome Type 2 with Alopecia Universalis and Hypoparathyroidism. AB - A 46 years old female, presented with severe fatigue, nypotension ana hyperpigmentation. Her basal serum cortisol level at 8 a.m. was < 1.0 MUg/dl which suggested a diagnosis of Addison's disease. An association with latent autoimmune diabetes of adult and autoimmune hypothyroidism led to a diagnosis of Polyglandular Autoimmune Syndrome type II (PAS II). She also had alopecia universalis and hypoparathyroidism which are very rare in PAS type II syndrome. On treatment with hydrocortisone and fludrocortisone there was drastic improvement in the clinical features. PMID- 26591179 TI - Zygomycosis Presenting as Acute Bilateral Renal Artery Thrombosis in a Healthy Young Male. AB - We present a case of acute renal artery thrombosis due to disseminated zygomycosis in a healthy young adult male.The diagnosis of renal artery occlusion was made on contrast-enhanced CT (CECT) and confirmation of etiology was made only on post mortem biopsy. We suggest that the presence of vascular thrombosis on CECT in a patient presenting with febrile illness should be regarded as an indicator of possible infection by angiotropic fungi, such as zygomycosis, which could help clinician to pursue histological diagnosis aggressively. PMID- 26591180 TI - Codeine: A Relook at the Old Antitussive. AB - Cough is the most frequent complaint of patients seeking medical attention in general and hospital practice. Cough is controlled by treating the cause, however, when no cause can be found, symptomatic relief of cough must be considered. Treatment of dry cough resulting from increased sensitivity of the cough reflex remains a challenge in some subjects. Codeine in combination with other medicines has been a mainstay for the effective short-term symptomatic relief of dry or nonproductive cough in clinical practice. This article focuses on the current status of codeine as an antitussive formulation in the treatment of dry cough. Codeine is one of the centrally acting narcotic opioids approved for use as an antitussive, a prodrug that is bioactivated by CYP2D6 into morphine in the liver. The opioid effects of codeine are related to plasma morphine concentrations. Codeine is one of the most frequently used antitussive in clinical practice and has been widely regarded as the standard cough suppressant against which newer drugs are being evaluated. Codeine has an advantage as an antitussive because of its multifaceted effect as an analgesic and sedative along with cough suppression. However, codeine may have efficacy to suppress cough in humans only in specific situations. Caution is also needed to limit its use only when and as long as it is clinically necessary, particularly in children. PMID- 26591181 TI - George Hoyyt Whipple. PMID- 26591182 TI - Documentation of Clinical Profile and Prognostic Factors of Severe Falciparum Malaria. PMID- 26591183 TI - Reply from Author. PMID- 26591184 TI - Herbal Remedy is Natural and Safe. PMID- 26591185 TI - Leprous Polyneuritis Cranialis Mimicking Orbital Apex Syndrome. PMID- 26591186 TI - Reply from Author. PMID- 26591187 TI - The remarkable challenge and the great reward. PMID- 26591188 TI - [Great moments in renal transplantation]. AB - A selective review of some great moments in renal transplantation experienced or witnessed with some of the great architects of this epic. The path was strewn with hazards, sometimes halts or changes of attitude that harmed or helped some patients. PMID- 26591189 TI - [Kidney transplantation in pediatric patients: 18-year experience at Hotel-Dieu de France]. AB - INTRODUCTION: During the period from September 1993 to March 2011, 79 kidney transplants in children and adolescents less than 18 years old were performed in our department; fifty-six in the familial group and 13 in the cadaveric group. We report in this study: immunosuppression protocols, medical and surgical complications (including rejection episodes), graft and patient survival. MATERIAL AND METHODS: Immunosuppression protocol has been modified throughout those eighteen years. Induction therapy includes serum anti- lymphocyte + cyclosporine + azathioprine and prednisone. Since 2000, azathioprine was replaced by mycophenolate mofetil and since January 2005 cyclosporine was given as well as tacrolymus according to EBV status. Basiliximab-Simulect(r) was included in the protocol since 2010. RESULTS: Surgical complications were only two lymphoceles, reversible after surgical drainage in the peritoneum. Medical complications were mainly infections or rejections. Thirty-six episodes of rejection occurred: 7 in the commercial group, 16 in the familial group and 13 in the cadaveric group. At the end of the study, 9 patients returned to dialysis, 5 from the cadaveric group, 2 from the familial group and 2 from the commercial group. CONCLUSION: After eighteen years experience in kidney transplant, we believe that kidney transplant remains the optimal treatment for terminal renal failure even for children weighing less than 10 kg. The follow-up of pediatric patients with kidney transplant revealed different positive effects on growth, regular school attendance and psychomotor development. At the end of the study: 24 are at school, 12 at universities, 5 are attending specialized schools and 9 are active workers. PMID- 26591190 TI - [Successful familial kidney transplant in an infant weighing less than 10 kg: case report and review of the literature]. AB - We report the case of a Lebanese infant born by normal delivery at 40 weeks of gestation. Weight and height at birth were 3200 grams and 49 cm respectively. Serum creatinine in the first week of life was 323 mmol/l (normal value for age is less than 20 mmol/l). Kidney ultrasound confirmed diagnosis of hypoplastic small kidneys. Conservative treatment of renal failure was initiated from the first days of life. Conservative management of renal failure included careful attention to fluid balance, maintenance of adequate nutrition and correction of hyperkalemia, acidosis, hyperphosphatemia and prevention of renal osteodystrophy by the use of dietary phosphate binders and vitamin D analogs. After a slight decrease of serum creatinine in the first three months of life, creatininemia increased progressively despite conservative treatment associated to hyperkalemia and severe pruritis due to hyperphosphatemia. Faced with the progression of renal failure, we decided to start automated peritoneal dialysis at seven months of life. Weight and height were respectively 6200 g and 63 cm. Serum creatinine was 432 mmol/L. Pruritis improved after starting peritoneal dialysis as well as appetite. At 20 months of life and a weight of 9.7 kg, a familial kidney transplant was performed. Immunosuppressive treatment included SimulectO, on day 1 and day 4, associated to mycophenolate mofetil, tacrolymus and prednisolone. The immediate post-transplant period was complicated by urinay tract infection due to BSLE E. coli. After four episodes of urinary tract infection due to resistant E coli associated to a non obstructive stone of 15 mm in the allograft kidney, we performed two sessions of lithotripsy and placed a double J stent. Biochemical urinary analysis did not reveal any causes for lithiasis. Stone disappeared as well as infection after lithotripsy. Renal function is normal for age one year after the kidney transplant. To our knowledge, this is the first reported case of a successful kidney transplant in a Lebanese infant with kidney failure since birth with kidney transplant performed at less than 10 kg of weight on the transplant day. Peritoneal dialysis is the treatment of choice for infants with chronic kidney failure. Familial or cadaveric kidney transplant should be encouraged and performed even in infants weighing less than 10 kg allowing them to have normal growth as well as social and school integration. PMID- 26591191 TI - Milestones and Basic Principles. AB - Current shortage in organ donors led to the expansion of criteria for organ donation placing organ preservation as one cornerstone for successful transplant, graft function and survival. The historical work of Belzer and Collins paved the way for key descriptions of physiopathology of cell ischemia and protection (cytokines roles, oxidative stress, energy shift to lactic acidosis and perfusion pressure changes). Good preservation means immediate recovery of function and prevention of chronic rejection. Two cooling approaches are available: static (SCS: simple cold storage) suitable for all organs, and dynamic (HMP: hypothermic machines perfusion) designed for kidneys and liver. A thorough discussion of historically manufactured and widely sold preservation solutions e.g. EuroCollins, UW solution (Viaspan(r)) as well as current used solutions e.g. Custodiol(r) and the new Celsior is available in this review. Obviously, every single organ exhibits different tolerance to warm and cold ischemia depending on its nature and demands after transplant. Future perspectives of organ preservation may be hidden in hibernators which may hold the enigmas of perfect human organ preservation. PMID- 26591192 TI - PREGNANCY AND RENAL TRANSPLANTATION. AB - Pregnancy is common nowadays in kidney transplant female patients because of medical and surgical advances. However, pregnancy is a high risk one in these patients. Fertility is rapidly restored after the transplantation; thus, contraception is a good option in the first year. Adding to that, pregnancy can endanger the allograft function in the presence of hypertension, a moderate to severe kidney disease and proteinuria. Medical complications are more prevalent in kidney transplant population, such as infections, gestational hypertension and diabetes and anemia. Low birth weight infants and premature delivery are two other major concerns in this population. Acute rejection of the allograft is another major complication that can be avoided with close monitoring of the graft and convenient immunosuppression. Immunosuppressive drugs must be continued during pregnancy except for mycophenolic acid and sirolimus that can be teratogen. Delivery of kidney transplant patients should be vaginal and spontaneous. Cesarean section should be reserved for obstetrical indications. Prophylactic antibiotics should be administered for every invasive procedure. Patients treated with corticosteroids can breastfeed their babies. Kidney donating women can have a safe pregnancy but with a slight risk of gestational diabetes and hypertension. In summary, a multidisciplinary medical team should follow pregnant kidney transplant patients in a tertiary center. International and national registries are a must to collect data concerning this particular high-risk population in order to solve unanswered questions. PMID- 26591193 TI - [Infertility and kidney transplantation]. AB - Renal failure impairs the endocrine system, especially in women, due to hyperprolactinemia, altering fertility, ovulatory cycles, libido and growth in adolescents. Renal transplantation is considered the best solution to the problems of renal failure and and of dialysis, as evidenced by comparing the rate of hyperprolactinemia (100% in chronic renal failure, 60% in patients on dialysis and 35% in post-transplantation). Kidney transplant is less efficient for restoring perfect function of the hypothalamic-pituitary-gonadal axis due in part to the immunosuppressant regimens prescribed. When these drugs are properly managed, transplantation will restore near normal sexual function. PMID- 26591194 TI - LIVING DONOR NEPHRECTOMY: OPEN vs LAPARASCOPY. Renal Function and Complications. AB - OBJECTIVES: This study is to compare the short and long-term renal function between adult recipients of living laparoscopic and open donors (LR vs OR) to highlight the effect of the surgical technique on graft function. Moreover, we chose to compare the organic (hypertension, proteinuria, serum creatinine) and psychological (aspect of libido, need for anxiolytics) long-term effect of the surgery between laparoscopic and open donors (LD vs OD). METHODS: After census of adult recipients and living donors between 2003 and 2012, and after application of exclusion criteria and selection of homogeneous groups of donors and recipients, a retrospective cohort study was conducted between October 2008 and January 2012. In recipients, renal function in the short term was reported by the value of serum creatinine at +/- D5 post-op and the long-term values of serum creatinine at 6 and 12 months after surgery. Delayed graft function was defined by a serum creatinine value >= 2.5 mg/dl on D5 post-op. A questionnaire for donors was established. RESULTS: The two groups OR and LR were homogeneous concerning age, sex and body mass index (BMI). Different groups OD and LD, chosen according to the variable of interest, were made homogeneous. Despite a different warm ischemia time between the 2 groups (175.54 seconds in LR vs 44.67 seconds in OR, p < 0.001), renal function in the short- and long-term in recipients was not statistically different (At day 5, 1.54 vs 1.50 mg/dl, p = 0.781; at 6 months, 1.37 vs 1.38, p = 0.871; at 12 months, 1.34 vs 1.36, p = 0.569, in OR and LR respectively). Similarly, there was no significant statistical difference concerning organic and psychological complications between OD and LD except for a shorter period between hospital discharge and return to work in LD. CONCLUSION: In our center, renal function in the short- and long-term was similar in OR and LR. Apart from the advantages offered by the laparoscopic technique, organic and psychological long-term effects were similar between OD and LD. Nevertheless, laparoscopy seemed to facilitate kidney donation and is requested by almost all living donors independently of their social status. PMID- 26591195 TI - [Immunosuppressive protocols in kidney transplantation: with or without induction?]. AB - Kidney transplantation is the treatment of choice of end stage kidney disease. Over the years, kidney transplantation progressed tremendously, mainly by the improvement of immunosuppressive drugs used in the prevention of acute rejection. Since the introduction of cyclosporine in the 80s, many immunosuppressive protocols have been established. These protocols are characterized by two strategies: with or without induction. The agents used in induction therapies can be polyclonal or monoclonal antibodies. The decision of using induction therapy relies mainly on the evaluation of the immunological risk in the recipient. Even if protocols with induction have improved early results concerning acute rejection, the protocoles without induction seem justified in some candidates. The optimal immunosuppressive protocol is not yet established, and individualization of immunosuppressive treatment is necessary. PMID- 26591196 TI - DONOR SPECIFIC ANTI-HLA ANTIBODIES DETECTION AND IMPACT IN KIDNEY TRANSPLANTATION. AB - Kidney transplantation is now accepted to be the best treatment for end-stage renal disease. Despite the improvement of immunosuppressive therapy, there is still actually substantial loss of allografts, in part due to uncontrolled humoral immunity. For many years, the primary technique for the detection of anti HLA antibodies was the CDC (complement dependent cytotoxicity). The recent use of solid phase assays, mainly the Luminex technology allowed detection of antibodies at much lower levels, and it has been shown that these antibodies have negative impact on the graft survival. We herein review the principal techniques for anti HLA detection and the different presentations of humoral rejection. PMID- 26591197 TI - [Renal transplantation from ABO incompatible donors]. AB - ABC-incompatible (ABOi) living donor renal transplantation is being developed since the 80s, and may provide a significant source of organs. Blood group A and B antigens are expressed not only on red blood cells but also on renal vascular endothelial and renal epithelial membranes. Each individual has preformed natural antibodies against his/ her absent A and/or B antigens. These antibodies may directly damage the ABOi allograft and cause its diffuse thrombosis and primary non-function. ABOi allogratf recipients are conditioned with one dose of rituximab (as a "pharmacological splenectomy") and oral immunosuppressive treatment is introduced several days pre-operatively. Anti A/B titers are lowered by plasmapheresis or specific immunoadsorption. Close follow-up is mandatory in the first two weeks after transplantation, due to higher acute humoral rejection risk, until reaching an "accommodation" state. Thereafter, graft and patient survivals are the same as those of ABO compatible renal transplantations. PMID- 26591198 TI - CYTOMEGALOVIRUS INFECTION POST KIDNEY TRANSPLANT: What Should We Know Now? AB - Cytomegalovirus (CMV) remains one of the most important pathogen responsible for the morbidity and mortality of transplantation patients. The impact on recipients depends on the form of CMV infection knowing that 10% to 50% develop symptomatic disease while solid organ involvement if presumed (e.g. CMV nephritis) may have deleterious outcome and requires histopathology testing. Treatment with antivirals IV ganciclovir and valganciclovir is managed according to early diagnostic tools with quantitative nucleic acid testing (QNAT) and antigenemia that will indicate the extent of disease and monitor response to treatment. CMV prevention in particular conditions of high risk patients has proven to be beneficial, resistance to antivirals and CMV vaccines along with novel therapies are thoroughly discussed in this review describing the new perspectives of CMV infection management. PMID- 26591199 TI - [THE ANTIOXIDANT EFFECT OF DALARGIN IN PATIENTS WITH CORONARY HEART DISEASE AND METABOLIC SYNDROME]. AB - The aim of this study was to evaluate the effect of dalargin on the state of lipid peroxidation (LPO) and antioxidant system in patients with coronary heart disease (CHD) and on the background of metabolic syndrome (MS) in a group of 123 patients with stable coronary artery disease and MS (mean age 56.7 +/- 5.1 years). For this purpose, the blood redox potential (EP), total antioxidant activity (TAA), level of oxidized low density lipoproteins (LDL), and activity of superoxide dismutase (SOD) were compared between the group receiving a standard medical therapy (ST) for coronary heart disease (group 1, n = 63) and that with supplementary dalargin administration (ST + D) in a dose of 1 mg intranasally twice a day for 10 days (group 2, n = 60), using the same dose for 10 days in the next two months (total 3 courses over 3 months). It was found that patients with CHD + MS upon 3-month ST showed no statistically significant changes in parameters characterizing the oxidative potential of blood (EP) and antioxidant protection of blood (oxidized LDL level, SOD activity). The inclusion of dalargin into therapy (ST + D) led to a significant decrease in the oxidative stress parameters (blood EP by 10.5%, oxidized LDL level by 14%, p < 0.001) and increase in the blood antioxidant properties (SOD activity by 36.1%, TAA by 25.3%, p < 0.001). PMID- 26591200 TI - [OPTIMIZATION OF BRONCHODILATOR THERAPY FOR CHILDREN DURING ASTHMA EXACERBATION WITH ALLOWANCE FOR THE RISK OF DEVELOPMENT OF CARDIOHEMODYNAMIC DISORDERS]. AB - We have studied the effect of bronchodilator drugs representing three groups--b2 adrenomimetic (fenoterol), anticholinergic (ipratropium bromide), and combined preparation (fenoterol/ipratropium bromide)--on cardiohemodynamics in children with acute asthma exacerbation. It is established that incorrect choice of bronchodilator most significantly influences the parameters of blood pressure and blood flow rate in the pulmonary artery, mitral and tricuspid valves, and also contributes to the appearance of signs of diastolic dysfunction of the right and left ventricles. A model predicting the risk of cardiohemodynamic violations was created using the multiple regression method, which allows the probability of negative changes in the cardiovascular system on the background of bronchodilator therapy to be calculated within several minutes using data on the medical prehistory and the results of objective and instrumental examination of a patient. Using this model it is possible to optimize the bronchodilator treatment of acute asthma in children and also to prevent the formation of future complications of the cardiovascular system. PMID- 26591201 TI - [THE INFLUENCE OF NEW DIRECT ANTICOAGULANT THIAZOLINE AMMONIUM 4-CHLOROPHENYL-2 HYDROXY-4-OXO-2-BUTENOATE ON BLOOD COAGULATION INDICES]. AB - The influence of newly synthesized compound--thiazoline ammonium 4-chlorophenyl-2 hydroxy-4-oxo-2-butenoate (FS-169), which has a direct anticoagulant--on the indices of coagulation activity has been studied in rabbit blood plasma with the aid of an APG4-02-P coagulometer. It is established that FS-169 reliably extends the partial thromboplastin time by 122.2% (p < 0.001) and the prothrombin time by 49.1% (p = 0.001), increases the prothrombin index by 30.9% (p = 0.001), and decreases the prothrombin ratio and international normalized ratio by 40.0% (p = 0.001). At the same time FS-169 does not influence the thrombin time FS-169. PMID- 26591202 TI - [INFLUENCE OF DINITROSYL IRON COMPLEXES ON OXIDATIVE METABOLISM UNDER EXPERIMENTAL THERMAL TRAUMA CONDITIONS]. AB - We have studied the effect of dinitrosyl iron complexes (DNIC) on blood lipid peroxidation and antioxidant system under experimental thermal trauma (burn) conditions in three groups of rats, each containing 10 animals. Group 1 was intact control, groups 2 and 3 were subjected to model thermal trauma, and group 3 were daily intraperitoneally injected with 3 ml of 0.3 mM of aqueous DNIC solution for 10 days. In addition, the DNIC solution action was studied in vitro on isolated human blood with oxidative stress conditions induced by high doses of ozone. All blood samples (both in vitro and in vivo) were characterized with respect to lipid peroxidation, total antioxidant activity, and erythrocyte resistance to peroxidation. It is established that DNIC leads to optimization of blood pro- and antioxidant systems in animals subjected to thermal trauma associated with pronounced oxidative stress. This effect was manifested by clear reduction (normalization) of lipid peroxidation with noticeable increase in the antioxidant potential of blood plasma. This tendency was also observed for erythrocyte membranes. The antioxidant action of DNIC was also confirmed by the results of in vitro experiments on human blood with model of oxidative stress. PMID- 26591203 TI - [CHANGES IN THE FUNCTION OF LYMPHOCYTES AND CYTOKINE CONCENTRATION IN BLOOD CAUSED BY THE ACTION OF ATROPINE UNDER CONDITIONS OF ACUTE MALATHION INTOXICATION]. AB - It was established in experiments on noninbred albino rats that acute intoxication with malathion (0.75 LD50) reduced the function of Th1 cells more significantly than the function of Th2 lymphocyte, decreases the activity of B cells and NK cells, blood levels of TNFa, IL-1b and IL-6, IFN-g, IL-2, and IL-4, while not significantly affecting the concentration of IL-10 and IL-13. Atropine (10 mg/kg) under conditions of acute malathion intoxication improved the function of T cells and B lymphocytes, NK cells, as well as the synthesis of immunoregulatory cytokines IFN-g, IL-2, and IL-4. At the same time, atropine in malathion intoxicated rats had no effect on suppression of the synthesis of proinflammatory cytokines TNF, IL-1g and IL-6 as well as the content of anti inflammatory cytokines IL-10 and IL-13. PMID- 26591204 TI - [MODELING INFLAMMATORY EDEMA: ARE THE MODELS INTERCHANGEABLE]. AB - Experimental modeling of inflammatory edema by sub-plantar injection of carrageenan and formalin in mice and rats is widely used to evaluate potential anti-inflammatory activity of new drugs. This systematic analysis of published data showed that carrageenan induced paw edema model is used for evaluating the anti-inflammatory activity mostly in rats rather than mice. Formalin induced paw edema in rats and mice is used primarily for evaluation of the analgesic activity of drugs. Taken together, the results of this systematic review of available literature on edema modeling substantiate recommendation to use carrageenan paw edema in rats and formalin paw edema in mice as complementary, but not interchangeable models of inflammation. PMID- 26591205 TI - [MAXIMUM SINGLE DOSE OF COLLOIDAL SILVER NEGATIVELY AFFECTS ERYTHROPOIESIS IN VITRO]. AB - Erythroblastic islets (EI) of rat bone marrow were cultured for 24 h in the presence of silver nanoparticles (1.07 . 10(-4) mg/ml; 1.07 . 10(-3) mg/ml; and 1.07 . 10(-2) mg/mL). The colloidal silver at 1.07 . 10(-3) mg/ml concentration inhibited the formation of new Elby disrupting contacts of bone marrow macrophages with CFU-E (erythropoiesis de novo) by 65.3% (p < 0.05). Colloidal silver nanoparticles suppressed the reconstruction of erythropoiesis and inhibited the formation of new EI by disrupting contacts of CFU-E and central macrophages with matured erythroidal "crown" (erythropoiesis de repeto). The colloidal silver concentration of 1.07 . 10(-3) mg/ml in the culture medium also reduced the number of self-reconstructing EI by 67.5% (p <0.05), whereas 1.07 . 10(-2) mg/ml colloidal silver reduced this value by 93.7% (p < 0.05). Silver nanoparticles retarded maturation of erythroid cells at the stage of oxiphylic normoblast denucleation: 1.07 . 10(-3) mg/ml colloidal silver increased the number of mature El by 53% (p < 0.05). The retardation of erythropoiesis by colloidal silver in concentration equivalent to the maximum single dose is related to the effect of silver nanoparticles rather than glycerol present in the colloidal suspension. PMID- 26591206 TI - [CONTENT OF OXIDATIVE STRESS MARKERS IN BLOOD PLASMA UNDER THE ACTION OF EXTRACTS OF GRATIOLA OFFICINALIS L., HELICHRYSUM ARENARIUM (L.) MOENCH, AND ANTHOCYANIN FORMS OF ZEA MAYS L]. AB - The effect of aqueous solutions of dry ethanol extracts of Gratiola officinalis L., Helichrysum arenarium (L.) Moench, and anthocyanin forms of Zea mays L. on the dioxidin-induced lipid peroxidation in blood has been studied on rats. It is established that all these extracts are capable of reducing the amount of avera- ge-mass (AM) molecules and malonic dialdehyde (MDA) in rat blood plasma. The extract of Gratiola officinalis L. reduces the concentration of AM and MDA moleules by 43%. The extract of Helichrysum arenarium (L.) Moench reduces the concentration of AM molecules on the average by 18.66% (within 9.22 -34.81%) and MDA by 49.36% (within 34.12-79.75%). The Extract of anthocyanin forms of Zea mays L. does not reduce the concentration of AM mo- lecules, but reduces the amount of MDA in the blood of rats on average by 27.88% (within 21.58-37.82%) (p < 0.01). PMID- 26591207 TI - [EFFICACY OF CYCLOFERON LINIMENT IN THE COMBINED TREATMENT OF CHRONIC GINGIVITIS IN PATIENTS WITH CHRONIC INFECTIOUS DISEASES]. AB - In order to study the clinical-pathogenetic efficacy of using cycloferon liniment in the combined therapy of patients with gingivitis on the background of chronic infectious diseases (HIV infection, hepatitis C, brucellosis), medical examination and treatment of 42 patients with this diagnosis has been carried out. It is established, that the use of cycloferon liniment in the combined therapy decreases the infection load in periodontal recess and manifestation of local inflammation, normalizes the immunity indices, and reduces the level of endogenous intoxication. All these factors provide acceleration of the recuperation processes and decrease the frequency of recidivating. PMID- 26591208 TI - [ANALYSIS OF COMPLICATIONS POSTOPERATIVE CAUSES AND MORTALITY AFTER RADICAL TREATMENT FOR TUMORS OF THE LEFT ANATOMICAL SEGMENT OF THE PANCREAS]. AB - Radical surgery for tumors of the left anatomical and surgical segment of the pancreas proved for distal resection in various versions, central resection and enucleation of tumors. The causes of early postoperative complications and mortality in 129 patients aged from 14 to 81 years, operated on for neoplastic lesions of the left anatomical segment of the pancreas in the period from 2009 to 2014 were analysed. The influence of various factors of risk of complications and mortality were studied in particular, extended resection, for tumor invasion of adjacent organs, and adjacent vessels. PMID- 26591209 TI - [CLINICAL AND LABORATORY FEATURES OF ACUTE PANCREATITIS BILIARY ETIOLOGY COURSE IN PATIENTS WITH DIABETES MELLITUS]. AB - The dynamics of cytopathic hypoxia markers in patients with acute pancreatitis (AP) biliary etiology (BE), depending on the presence of concomitant diabetes mellitus (DM), which is an independent factor of premorbid severity increase and increase in the degree of operational and anesthetic risk. Markers of cytopathic hypoxia use as methods for early diagnosis of acute liver failure (ALF) and monitoring the effectiveness of its correction promising. In terms of cytopathic hypoxia may be at the stage of laboratory diagnostics to distinguish between destructive and non-destructive forms APBE, and for markers of endothelial dysfunction--destructive forms on the area and depth of destruction of the pancreas. PMID- 26591210 TI - [CONSERVATIVE THERAPY IN THE COMPLEX TREATMENT OF ACUTE NECROTIZING PANCREATITIS]. AB - Developed and implemented a phased differentiated treatment tactics in acute necrotizing pancreatitis, based on the theory of phase course of acute pancreatitis. Treatment started with conservative measures. Applications developed set of measures allowed us to achieve recovery of 39.53% patients without any instrumental interventions performans, including diapevtycal. Laparotomy reduced frequency performance of 57.14%--in the control group to 33.07%--in the main. Mortality in the main group was 6.72%; complication rate decreased 2.26 times; postoperative mortality was 9.83%. PMID- 26591211 TI - [FEATURES LIVER TRANSPLANTATION IN PORTAL VEIN THROMBOSIS]. AB - In 2012 - 2013 years in 265 patients for liver transplantation was performed, including in 224 (84.5%)--from a living donor, in 41 (15.5%)--from the dead body. Using a Foley catheter to stop bleeding, and the imposition of vascular sutures during endovenectomy in portal vein thrombosis (PVT) and its possible damage under all conditions. In particular, PVT IV degree (Grade IV) in order to restore blood flow in the graft using the left gastric and renal vein is an alternative, if they are cryopreserved vein may be suitably used. PMID- 26591212 TI - [FUNCTIONAL PLASTIC OF ANTERIOR ABDOMINAL WALL HERNIAS]. AB - In order to improve the treatment efficacy of postoperative anterior abdominal wall hernias the method of plastic with restoration of anatomical and physiological properties of the muscles of the anterior abdominal wall was used. After the intervention by the improved method, regardless of the location of the hernia defect yielded promising results for the conservation of anterior abdominal wall muscle function in 75% of cases completely restored functional ability of muscles recti abdomini. PMID- 26591213 TI - [SURGICAL TREATMENT MANAGEMENT OF ABDOMEN GUNSHOT INJURIES]. AB - The medical records of 100 patients with gunshot abdomen injuries were analysed. The damaging nature of the projectile, the nature of the damage and the combination with damage to other body parts were studied. The anesthesiologist- resuscitator and surgeon actions after hospitalisation of injured persons were postulated. The emergency victim examination was reduced to ultrasound and SCT. The indications for laparotomy in abdominal gunshot injuries were defined. Three most common variants of gunshot abdomen injuries were found. In surgical treatment we applied "damage control" strategy included the initial (abbreviated) operation, resuscitative therapy and final operation. The postoperative complications, couse of deaths was investigated. PMID- 26591214 TI - [PROGNOSTICATION OF LIMITED ACCUMULATIONS LIQUID INFECTION BY SEVERE ACUTE PANCREATITIS]. AB - The results of examination and treatment of 53 patients on limited accumulations of liquid (LAL) for severe acute pancreatitis (SAP) were analysed. In 62.5% of patients on acute aseptic LAL celebrated parapancreatyc liquid accumulation were determinened. Most (94.6%) patients infected by LAL revealed heterogeneity of their structure according ultrasonography, in 81.1%--secvestral mass in their cavity. Systemic inflammatory response syndrome (SIRS) observed both aseptic and infected LAL. Prognostically important criteria LAL infection in patients on SAP is the heterogeneity of echostructure in absence of a downward trend. Diagnostic puncture under ultrasound control and microbiological studies are safe methods of diagnosis by infected LAL in SAP. PMID- 26591215 TI - [SURGICAL TREATMENT OF NECK-RETROSTERNAL GOITER]. AB - Results of 91 patient with neck-retrosternal goiter localization operative treatment were analysed. The first degree of thyroid retrosternal part distribution by I. Cohen, H. Cho classification (1994) was observed in 41 patient, the second degree--in 28, the third degree i - n 17 and the fourth degree--in 5 patients. In most cases of neck--retrosternal goiter localization, operation can be performed from neck access, removel of the submerged part of thyroid gland needs to be begun with mobilization of neck part of lobe, the observance of the offered actions algorithm allows to prevent the origin of complications and get good postoperative results. PMID- 26591216 TI - [THE MECHANISMS OF ISCHEMIC MITRAL VALVE INSUFFICIENCY FORMATION]. AB - In clinic in the period from 2012 to 2014 in 142 patients were performed interventions on the mitral valve for coronary heart disease and ischemic mitral valve insufficiency (MVI). The majority of patients were able to work, its witness for social-economic significance of problem. The main reason of the ischemic MVI arised were the dilatation of mitral valve fibrousing and substitution of papillar muscles for left ventricle remodelling. Symmetrical deformation of mitral valve arised in most cases after anterior-septal myocardium infarction, left ventricle global remodelling and apical substitution of papillar muscles; asymmetrical ones--after posterior myocardial infarction for local left ventricle papillar muscles. PMID- 26591217 TI - [PECULIARITIES OF ROTATIONAL MOTION OF LEFT VENTRICULAR WALLS IN PATIENTS ON MITRAL VALVE INSUFFICIENCY]. AB - The peculiarities of rotational motion of left ventricular (LV) walls in patients on mitral valve insufficiency (MVI) were studied. In normal heart and MVI the rotation of basal and apical portions of the LV occurs in inter-reverse directions: the basal portion rotates clockwise and apical portion rotates counterclockwise. In patients with MVI the increase of the LV volumes is accompanied by compensatory rise of LV myocardium torsion up to (23.7 +/- 5.0)degrees. The increase of indices of LV myocardium torsion in MVI occurs due to basal portions of the heart only. This is a compensatory factor in preserving of normal cardiac output for a long period of time in such disease. PMID- 26591218 TI - [ROLE OF ULTRASONIC CAVITATION IN COMPLEX TREATMENT OF SUPPURATIVE-NECROTIC COMPLICATIONS OF DIABETIC FOOT SYNDROME]. AB - The microbial landscape of wounds with suppurative-necrotic complications in diabetic foot syndrome (DFS) was investigated. Capabilities by inhibiting the formation of bacterial biofilms using ultrasonic cavitation (USC) were determined. In 32 patients over the purulent necrotic complications DFS USC applied using the apparatus "Sonoca-180" company Soring (Germany), 20 patients performed a basic therapy. Qualitative and quantitative composition of microflora were determined by the results of microbiological investigations using parallel transmission electron microscopy dynamics with USC. In patients with DFS noted the formation of bacterial biofilms that contained clusters of microorganisms in a polysaccharide matrix and were fixed to the wound surface. In the microbial landscape of wounds dominated gram-negative microorganisms. Application of USC contributed to the rapid cleanse wounds. PMID- 26591219 TI - [INJECTING MATERIAL FOR SKIN REGENERATION LACERTA APPLICATION IN TREATMENT OF TROPHIC ULCERS IN PATIENTS WITH DIABETIC FOOT SYNDROME]. AB - Examined 22 patients with diabetes mellitus (DM) type II of neuropathic form of diabetic foot syndrome (DFS). In 12 patients (comparison group) local povidone iodine was used main in 10 (study group), except povidone-iodine, in the phase of exudation used tyrothricin in gel form, the granulation and epithelization phase, after cleaning the wounds, were injected intradermally 1 ml of injecting material for skin regeneration Lacerta. Trophic defects in 9 (90%) patients of the main group during the observation period healed completely, in the comparison group complete healing of the ulcer reached in 2 (16.7%) patients, the rest-wounds, although purified, however, were lethargic granulation, epithelization occurred very slowly. Consequently, the use of the proposed method allows to achieve more rapid healing of trophic ulcers that do not heal continued in patients of neuropathic forms of DFS. PMID- 26591220 TI - [SURGICAL TREATMENT OF TONSILLAR NECK PHLEGMON]. AB - In the period from 2010 to 2014 treated 76 patients (women - 12, men - 64) on the neck phlegmon of different origin. The first step of treatment was the throat sanation to eliminate etiological factor. Providing emergency care with abscess tonsillectomy. Further disclosed parapharynaeal abscess through tonsil bed niche or perform tonsillectomy in the "hot" periods for indicated. PMID- 26591221 TI - [SITS-TECHNOLOGY USE IN SURGICAL TREATMENT OF EXUDATIVE PLEURISY ON PARTIAL OBLITERATION OF PLEURAL CAVITY]. AB - The results of examination and treatment of 47 patients with pleural effusion of various origins on partialy obliteration pleural cavity was analysed. The efficiency SITS-technology (single-incision thoracoscopic surgery) use in the diagnosis and treatment of patients was proved. When using SITS-technology pleural exudation severity and duration decreased to (27 +/- 9)%. Reduce operation trauma and pain intensity and better cosmetic effects with SITS technology interventions was established. PMID- 26591222 TI - [POSSIBILITIES OF VACUUM THERAPY APPLICATION IN DISORDERS OF VENOUS OUTFLOW IN ISLET GRAFTS]. AB - The experience of "distressed" (problematic) flaps application in 33 patients with soft tissue defects over 2010-2014 years were analysed. It was proposed to use the local negative pressure for the prevention and treatment of complications associated with venous insufficiency or trombosis in using of plastics with vascularised complexes of tissues. Vacuum-therapy was conducted with the help of negative pressure apparatus "AGATE-Dnepr" (Ukraine) by attaching silver containing polyurethane sponge on the operating zone, covering the flap with the surrounding skin netting band "Grassolind". The recommended standard of negative pressure of 75-125 mm Hg, both in impulse and in continuous mode was used. The high efficiency of vacuum-therapy for survival of grafts has been demonstrated. Thus, it might be considered as an effective element of prevention and treatment of complications associated with venous insufficiency or trombosis using of vascularised tissue complex plastics of defects. PMID- 26591223 TI - [DIFFERENTIATED APPROACH TO CLOSING OF WOUND SURFACES TRUNK AND EXTREMITIES AFTER ITS MECHANICAL DAMAGE]. AB - The results of examination and treatment of 231 patients on defects covering tissues of the trunk and limbs were presented. The severity of the injury determined by classification A. V. Kaplan, O. M. Markova. In 10 patients wound treatment method used, developed in the clinic, using the combined preparation of hyaluronic acid with sodium succinate (Latsert), ensuring efficiency of treatment. Differentiated approach to the selection of closing wound surfaces method caused by mechanical damage, allowed to achieve satisfactory results in 97.84% of cases. PMID- 26591224 TI - [PREPARATIONS OF PAMIDRONOVIC ACID IN COMPLEX TREATMENT ON OSTEOGENESIS IMPERFECTA]. AB - Modern view of drug therapy in the complex treatment of orthopedic manifestations of osteogenesis imperfecta (OI) was submitted. Developed and tested system of drug correction of structural and functional state of bone tissue (BT) using drugs pamidronovic acid, depending on osteoporosis severity and type of disease. Such therapy is appropriate to apply both independently and in conjunction with surgery to correct deformations of long bones of the lower extremities. Effectiveness and feasibility of the proposed methods of drug therapy was proved, most patients resume features walking and support. PMID- 26591225 TI - [APPLICATION OF DEXMEDETOMIDIN FOR SEDATION OF PATIENTS IN ALCOHOL WITHDRAWAL STATE IN THE ICU]. AB - The efficacy and safety of sedation on 44 patients in alcohol withdrawal state (AWS) for use of intravenous dexmedetomidine infusion. Dexmedetomidine increased the duration of target sedation level to 20%, decreased the duration of excessive/insufficient sedation to 10%, it was associated with AWS symptoms regression, better communication with the patient, reduced consumption of benzodiazepines (BZD) from 40 to 30 mg per day and antypsihotics for control AWS symptoms. The common complications of dexmedetomidine infusion were bradycardia and hypotension. Dexmedetomidine could be an alternative drug for sedation patients with mild or moderate AWS and applied in addition to BZD and antipsyhotics in patients with severe AWS. PMID- 26591226 TI - [INFLUENCE OF AUTOLOGOUS CHONDROCYTES TRANSPLANTATION ON THE INTERVERTEBRAL DISC STATE IN EXPERIMENTAL MODEL OF OSTEOCHONDROSIS]. AB - The degenerative changes in the nucleus pulposus and fibrous ring of the intervertebral discs are the basis of spinal osteochondrosis. A large number of models, including biological, where some mechanisms of their development were worked out and studied, was used to study the morphogenesis and pathogenesis of degenerative spinal changes. The deserved place in the comparative experiments and especially the different methods of therapeutic effects on the tissues of the intervertebral discs in degenerative spinal changes is taken by the experimental methods. The biochemical changes of the intervertebral disc structures were analyzed under the administration of cultured autologous cell of nucleus pulposus suspension against a background of experimental model of rat osteochondrosis. PMID- 26591227 TI - [FEATURES OF PERIOPERATIVE MANAGEMENT OF PATIENTS IN ENDOVIDEOSURGICAL INTERVENTIONS. PART I. POSITION OF THE PATIENT ON THE OPERATING TABLE, THE INFLUENCE ON ORGAN SYSTEMS LIFE: HEMODYNAMIC]. PMID- 26591228 TI - Making the Most of a Retreat. AB - Use these strategies to make the most of your board retreat. PMID- 26591229 TI - VITAL STATS. AB - The board dashboard, a quick way to monitor hospital performance, must evolve as care and payment models change. PMID- 26591230 TI - 2016 American Hospital Association ENVIRONMENTAL SCAN. PMID- 26591231 TI - The Cost of Value-based Care. AB - Population health requires sophisticated systems that link payer, financial and clinical data. Prepare to spend even more on IT. PMID- 26591232 TI - Seeing the Big Picture. AB - Rick Pollack, the American Hospital Association's new president and CEO, shares his perspective on advocacy. PMID- 26591233 TI - Rethinking Rural Facilities. AB - As inpatient utilization declines in rural areas, health care organizations have an opportunity to create life enhancement centers. PMID- 26591234 TI - Burwell, and Enterprise Risk. AB - How your board addressed King v. Burwell offers insight into its risk oversight role. PMID- 26591235 TI - CHI's Governance Evolution. AB - A thorough board orientation and education program prepares Catholic Health Initiatives trustees to serve an evolving organization. PMID- 26591236 TI - 37% of hospitals perform cybersecurity incident response exercises annually. AB - Hospitals are taking a variety of steps to protect against and mitigate the damage of a cybersecurity breach. PMID- 26591237 TI - Succession Planning: Best Practices for Managing Organizational Risk. PMID- 26591238 TI - The most dangerous place on earth: My dental office? PMID- 26591239 TI - Rethinking how we educate dentists. PMID- 26591240 TI - Who bears the cost for the CPS dental program? PMID- 26591241 TI - Good business etiquette makes a strong first impression. PMID- 26591242 TI - Why take X-rays? PMID- 26591243 TI - Let's form a partnership. PMID- 26591244 TI - Army veteran gets a new lease on life. PMID- 26591245 TI - Harold Shavell has carved his niche. PMID- 26591246 TI - It's time for a universal licensure exam. PMID- 26591247 TI - Failure Mechanisms of Fibre Posts: A Literature Review. AB - AIM: To review the available evidence for the causes of failure of fibre posts. MATERIALS AND METHOD: A search of MEDLINE was conducted to retrieve available data on fibre posts used for restoration of endodontically treated teeth since 1980. The Cochrane Library was also separately searched for systematic reviews. Additionally, references of the retrieved articles were also hand searched for further relevant papers. All the selected papers were then critically appraised subject to meeting inclusion criteria. RESULTS: Nineteen prospective clinical trials were included after critical appraisal of the papers. Causes of failure of fibre posts were identified as follows: adhesive failure, root fracture, post fracture, endodontic failure, secondary caries and periodontal complications. Risk factors for each of the failures were investigated and evidence-based recommendations for minimising these complications are discussed. CONCLUSION: Although laboratory studies showed favourable mechanical and physical properties of fibre posts, clinically, there has been a wide range of failures mechanisms are reported in the literature. Adhesive failure was reported in 16 of the 19 trials, making it the most frequent cause of failure. The available evidence does not indicate a difference in short-term survival probability between metal or fibre posts. A number of risk factors, which affect the longevity of fibre posts, were identified and discussed. Since there is considerable heterogeneity in study designs and reported survival rates of included studies, longer-term well designed standardised clinical trails are required. PMID- 26591248 TI - The Effect of Water or Wax-based Binders on the Chemical and Morphological Characteristics of the Margin Ceramic-Framework Interface. AB - This study evaluated the effect of binder choice in mixing ceramic powder on the chemical and morphological features between the margin ceramic-framework interfaces. Titanium and zirconia frameworks (15 x 5 x 0.5 mm3) were veneered with margin ceramics prepared with two different binders, namely a) water/conventional or b) wax-based. For each zirconia framework material, four different margin ceramics were used: a- Creation Zi (Creation Willi Geller International); b- GC Initial Zr (GC America); Triceram (Dentaurum); and d- IPS emax (voclar Vivadent). For the titanium framework, three different margin ceramics were used: a- Creation Ti (Creation Willi Geller International); b- Triceram (Dentaurum); and c- VITA Titaniumkeramik (Vita Zahnfabrik). The chemical composition of the framework-margin ceramic interface was analyzed using Energy Dispersive X-ray Spectroscopy (EDS) and porosity level was quantified within the margin ceramic using an image program (ImageJ) from four random areas (100 x 100 pixels) on each SEM image. EDS analysis showed the presence of Carbon at the margin ceramic-framework interface in the groups where wax-based binder technique was used with the concentration being the highest for the IPS emax ZirCAD group. While IPS system (IPS ZirCAD and IPS Emax) presented higher porosity concentration using wax binder, in the other groups wax-based binder reduced the porosity of margin ceramic, except for Titanium - Triceram combination. PMID- 26591249 TI - Evaluation of Chlorine Dioxide Irrigation Solution on the Microhardness and Surface Roughness of Root Canal Dentin. AB - The aim of this study was to evaluate the effect of chlorine dioxide and various other more common irrigation solutions on the microhardness and surface roughness of root canal dentin. Fifty human maxillary central incisors were sectioned longitudinally and treated for 1 minute with 5 ml of the following aqueous solutions (v/v%): Group 1:13.8% chlorine dioxide, Group 2:17% ethylene diamine tetraacetic acid (EDTA). Group 3: 7% maleic acid, Group 4: 2.5% sodium hypochlorite (5ml/min), Group 5: Saline (control). Specimens were subjected to microhardness and surface roughness testing. Chlorine dioxide and sodium hypochlorite reduced the microhardness more than other test agents. The highest surface roughness was produced with maleic acid. Chlorine dioxide should be used cautiously during chemomechanical preparation of the root canal system in order to prevent untoward damage to the teeth. PMID- 26591250 TI - Assessment of Posterior Teeth Preparations for Metal-Ceramic Crowns. AB - OBJECTIVES: To evaluate teeth preparation designs for metal-ceramic crowns in private dental practice in Jordan. MATERIALS AND METHODS: One-hundred and seventy two dies were included. Different aspects of tooth preparations were quantified, analyzed and compared with the recommended guidelines. RESULTS: Almost 64% of preparations finish lines were positioned subgingivally. Shoulder finish lines were observed in 74.4% where-as 22.7% showed chamfer finish lines. Total occlusal convergence angles were 29.8 degrees in BL plane, 247 degrees in MD plane. CONCLUSIONS: Dental practitioners in private practice in Jordan did not fully adhere to the recommendedguidelines for tooth preparations for MCRs. PMID- 26591251 TI - Choosing the Right Dental Material and Making Sense of the Options: Evidence and Clinical Recommendations. AB - Decision-making is a fundamental aspect of clinical dentistry. Advances in technology and trends towards more conservative technologies have broadened the options available to patients and dentists, increasing the range of choices and opportunities to restore teeth. With such a broad range of dental materials, there are a number of factors to consider in making an appropriate choice. We present several decision-making dilemmas. Namely; how to restore worn lower anterior teeth, what to consider when replacing crowns, materials to consider when providing cuspal protection for posterior teeth, and finally the issues to consider when selecting a luting cement. The evidence supporting different clinical choices is considered in a discussion of the various dilemmas faced. PMID- 26591252 TI - Breast cancer prognostic markers: an overview of a changing menu. PMID- 26591253 TI - Hemoglobin screening using noninvasive methods. PMID- 26591254 TI - Blood you can trust: global trends in transfusion safety. PMID- 26591255 TI - The rise, fall and future of red blood cell transfusions. PMID- 26591256 TI - Molecular methods without nucleic acid amplification. PMID- 26591257 TI - Thinking beyond flu: the importance of other respiratory viruses in routine testing. PMID- 26591258 TI - Recent research shines spotlight on troponin. PMID- 26591259 TI - Slide makers and stainers: automating in the Hematology lab to improve efficiency. PMID- 26591260 TI - Slide preparation systems help to close hematology workflow gap. PMID- 26591261 TI - New approaches to screening for drug abuse. PMID- 26591262 TI - A multi-marker approach to diagnosing autoimmune diseases. PMID- 26591263 TI - Pathology practice management. PMID- 26591264 TI - AACC urges CMS to delay enforcing glucose monitor regulations. PMID- 26591267 TI - Networking in Nephrology Nursing. PMID- 26591266 TI - The Power of Nurses. PMID- 26591268 TI - Decreasing Infections in Nephrology Patient Populations: Back to Basics. AB - Infection is a leading cause of hospitalizations and deathfor nephrology patients, and a danger to the healthcare professionals who care for them. As primary caregivers, nurses are involved in the prevention, identification, and surveillance of infections and patient teaching associated with infection prevention. Results of a recent national survey revealed that there are many violations in adherence to proper infection control measures in nephrology practice settings, and the safety of this vulnerable patient population is being compromised. This article provides information on the results of the study and guidelines and best practices to decease infection rates, including the use of basic fundamentals of nursing practice, collaboration, and patient engagement. PMID- 26591269 TI - Vascular Access Transition: Experiences of Patients on Hemodialysis. AB - An interpretive descriptive design was used to explore the experiences of patients on hemodialysis who had utilized and transitioned from a central venous catheter (CVC) to an arteriovenous fistula (AVF). Eleven patients participated in semi-structured interviews that were analyzed using constant comparison. Within the larger context of living with end stage renal disease, participants described their vascular access experiences according to three main themes: impact, coping, and influencing factors. Accesses had physical, psychosocial, and lifestyle related impacts that participants coped with primarily by exercising control and gradually accepting, and were influenced by education, trust in healthcare providers, and family. Findings revealed a cumulative burden for many participants with AVF and the need to improve the patient experience of vascular accesses especially for those living in rural communities. PMID- 26591270 TI - Impact of an Educational Program for Advanced Practice Nurses on Knowledge of Kidney Disease Outcomes Quality Initiative Guidelines. AB - Patients with chronic kidney disease (CKD) are often referred to a nephrologist late. Contributing factors include primary care providers' lack of awareness of practice guidelines for treating kidney disease and their uncertainty of timing for referral to a nephrologist. The purpose of this quasi-experimental study was to determine if advanced practice nurses working in primary care are knowledgeable about the National Kidney Foundations Kidney Disease Outcomes Quality Initiative Guidelines, if a CKD education program increases knowledge, and if knowledge is retained. Fourteen advanced practice nurses participated in the study. The knowledge outcome was measured using a CKD knowledge-based survey. The results showed a significant increase in knowledge post-intervention; moreover, knowledge gained was retained at the one-month follow-up intervaL This evidence-based practice project was developed to promote timely referral to a nephrologist, which may then slow the progression of kidney disease, decrease morbidity and mortality, and reduce healthcare cost. PMID- 26591271 TI - Quality of Life and Self-Efficacy in Three Dialysis Modalities: Incenter Hemodialysis, Home Hemodialysis, and Home Peritoneal Dialysis. AB - Previous research has demonstrated improved outcomes for patients on dialysis who have better quality of life and self-efficacy, but has focused almost exclusively on those receiving hemodialysis. The goal of this study was to describe the quality of life and self-efficacy of patients receiving incenter hemodialysis versus those receiving a home dialysis modality (hemodialysis or peritoneal dialysis). The study utilized a correlational cross-sectional design and quota sampling methods. Participants were recruited from outpatient dialysis facilities and included 77 community dwelling adult patients who had been on dialysis for at least six months. Quality of life was measured using the Kidney Disease Quality of Life instrument, and self-efficacy was measured using the Strategies Used by People to Promote Health instrument. Findings suggest equal outcomes between treatment groups, with no contraindication to the use of home therapies. PMID- 26591272 TI - Asymptomatic Intradialytic Hypotension: The Need for Pre-Emptive Intervention. AB - Intradialytic hypotension (IDH) remains the most common severe side effect of hemodialysis despite numerous technological advancements. Recent evidence emphasises the significance of asymptomatic hypotensive episodes, as well as the hypoperfusive consequences of both relative blood pressure drops and repetitive, symptomatic events. This article reviews the physiological importance of rapid blood pressure decrease during hemodialysis, and highlights the pathological consequences of repeated asymptomatic and symptomatic hypoperfusive episodes. In proposing a view concerned with asymptomatic IDH, a practicalpre-emptive intervention is offered to improve the long-term outcomes of patients on hemodialysis. Ongoing monitoring of individual patient's mean arterial pressure (MAP) throughout the dialysis treatment can facilitate the identification of an asymptomatic hypotensive episode. A brief pause in ultrafiltration enables vascular refill and subsequent increase in MAP, allowing resumption of safe fluid removal. Such enhanced assessment results in a reduction off patient risk, allowing safe and optimal fluid removal. PMID- 26591273 TI - Quality of Life Intervention Planning: Pilot Study in Youth with Kidney Failure Who Are on Dialysis. AB - This pilot study assessed the feasibility and acceptability of a new quality of life (QOL) assessment and intervention methodology (AIM) for youth on dialysis and their caregivers. Thirty-nine patients and their caregivers participated in the QOL AIM, which incorporates patient-centered care practices to identify needs, choose interventions, and evaluate impact on QOL functioning. Participants found the QOL AIM to be feasible and acceptable, and were overall satisfied with perceived improvement in patient QOL functioning. The QOL AIM shows promise for QOL intervention planning. PMID- 26591274 TI - Tuberous Sclerosis Complex: One Woman's Search for Renal-Preserving Therapy. AB - Everolimus was very effective in the treatment of Anne, a patient with TSC and renal angiomyolipomas. Anne's renal tumors continue to shrink in size, with a decrease of more than 50% achieved to date, and her GFR remains in the normal range. She no longer experiences chronic back pain due to kidney tumors and is not taking pain medications. She is active and able to exercise daily, and her blood pressure remains within normal limits. Usually diagnosed in childhood, TSC requires life-long management. Patients can have many manifestations of the disease, and nurses need to be made aware of them because they often play a critical role in educating patients and their families (Agricola et al., 2013). Currently, there is a great need for education and awareness in the medical field regarding TSC. The disease is often overlooked, misdiagnosed, or mismanaged. Patients can be given misleading information, which may lead to unnecessary procedures and distress. Moreover, with the correct management, patients with TSC have a normal life expectancy and preserved renal function. PMID- 26591275 TI - New Nurse to Acute Nurse: A New Grad in Inpatient Dialysis. PMID- 26591276 TI - MEDICAL EDUCATION PARTNERSHIP (MEPI), ETHIOPIA: OBJECTIVES AND OVERVIEW OF KEY ACCOMPLISHMENTS. PMID- 26591277 TI - INTRODUCTION OF SIMULATION BASED MEDICAL EDUCATION AT ADDIS ABABA UNIVERSITY COLLEGE OF HEALTH SCIENCES: EXPERIENCE AND CHALLENGE. AB - BACKGROUND: As one of the countries in Sub-Saharan Africa with a low physician to population ratio, Ethiopia has sought to mitigate the problem by increasing the number of students enrolling in the existing medical schools. This increase in enrolment was not accompanied by expansion of clinical training venues, which has resulted in less patient contact time for each student. As part of the solution to fill the gap simulation-based teaching was introduced. OBJECTIVE: To describe the process of introducing Simulation based medical education (SBME) at Addis Ababa University College of Health Sciences, school of medicine. METHODS: Two rounds of intensive training was given by John Hopkins in collaboration with Medical Education partner Initiative (MEPI). to the core clinical educators to introduce them the six-step model of curriculum development for medical education and standardized patient (SP) techniques with the ultimate aim of introducing SPs in the teaching and learning process for medical students. The training included didactic and workshop elements, with group work and created complete educational modules. Each pre and post course assessment of experience and attitude were surveyed. Data was analyzed in aggregate using paired t -test to compare pre and post course means. RESULTS: There were total of 22 faculty members participated in the first group ,the majority of whom had no prior training in curriculum development or SBME and were skeptical of the value of SBME, as evidenced in their survey responses. (3.42/5 in Likert scale 1 = least 5 = most) at the end of the course the participant were comfortable with the concept of curriculum development the rating increased to 4.45/5 (P < 0.0001) and they embraced more favorable attitudes regarding the feasibility and desirability of simulation with Likert Scale 4.01/5 to 4.51 (P < 0.0001). In the second course, there were 16 participant and the majority had no prior experience with simulation and/or SP encounters. Their Baseline attitudes among participants in the second course were more favourable than in the first course, with a mean precourse Likert score of 4.24/5. Mean post course score was 4.43/5 (p = 0.1003), which did not represent a significant increase. The largest pre/post increases were seen for questions regarding accuracy of SP portrayal of specific clinical conditions (3.93 to 4.43, p = 0.0011), and enjoyability of incorporating SP activities into curricula (4.33 to 4.73, p = 0. 0281). After the course, the faculty remained particularly sceptical of the role of SPs in grading students (3.43/5). Both courses were well received, with 95% reporting they learned what they had hoped to learn. CONCLUSION: Training courses at CHS were successful for generating enthusiasm about simulation, and improving participant attitudes regarding the usefulness and feasibility of this educational method. PMID- 26591278 TI - PROMOTING GENDER EQUITY AT THE COLLEGE OF HEALTH SCIENCES, ADDIS ABABA UNIVERSITY, ETHIOPIA. AB - BACKGROUND: Ethiopia faces a dire shortage of human resources to meet the health care needs of its population of more than 90 million people. The government has implemented programs to expand the health care workforce, of which women are a growing and crucial component. Universities are working to identify and address gender inequity to help recruit and retain women. OBJECTIVE: This paper describes and analyzes a multi-institution grant-funded program to promote gender equity at Addis Ababa University-College of Health Sciences (AAU-CHS) in Ethiopia. METHODS: The primary intervention was to provide intensive short-term fellowships to mid level female faculty to facilitate their promotion into leadership positions. Secondary interventions included a series of gender equity meetings with students, residents and staff to elicit bottom-up concerns and recommendations for future action, as well as conducting a gender climate survey of female students and staff External consultants assisted with program implementation, monitoring and evaluation of the program. RESULTS: Initial outcomes demonstrate promising career advancement of women who participated in the fellowships. A comprehensive gender equity action plan was developed based upon results from the survey and meeting recommendations. This plan is being implemented by AAU-CHS faculty and administration. CONCLUSION: This program has been an initial success and may serve as a template for others who are working to promote gender equity. PMID- 26591279 TI - DETERMINANT FACTORS OF VISUAL INSPECTION WITH ACETIC ACID (VIA) POSITIVE LESIONS AMONG HIV POSITIVE WOMEN IN MEKELLE HOSPITAL, NORTHERN ETHIOPIA: A CASE CONTROL STUDY. AB - BACKGROUND: Cervical cancer is the second commonest type and third cause of cancer death among women in low-income countries. Women living with HIV/AIDS are at greater risk of developing cervical cancer. The study aimed to identify the determinant factors forsuspected precancerous cervical lesions among HIV- positive women in Mekelle hospital, Ethiopia. METHODS: Anunmatched case-control study was conducted among randomly selected HIV positive women in Mekelle hospital in 2014. In Mekelle Hospital, routine screening for lesions of the cervix uteri by visual inspection with acetic acid (VIA) is done in HIV positive women by trained nurses. Suspicious findings are treated by cryotherapy or referred to the Gynaecologist. A number of 116 cases, who had suspicious findings on VIA, and 232 HIV-positive controls without suspicious findings on VIA were randomly selected and enrolled into the study The determinant factors for precancerous cervical lesion were analyzed using multiple logistic regression and described as adjusted odds ratio (AOR). RESULTS: HIV positive women who had CD4 cells less than 350/mm3 were two times more likely to have precancerous cervical lesion compared to those with CD4 cells above 350/mm3. Women with two (AOR = 3.6; 95% CI: 1.7, 7.7) and three (AOR = 2.5; 95% CI: 1.2, 5.4) sexual partners were four and three times more likely to have precancerous cervical lesion, respectively, as compared to those who had one sexual partner. Age, History of STI and duration of ART had no influence on presence of VIA positive lesions in HIV positive women. CONCLUSION: CD4 count cells and number of sexual partners were predictors of VIA positive cervical lesion among HIV positive women. PMID- 26591281 TI - MAGNITUDE OF DISABILITY AND ASSOCIATED FACTORS AMONG PATIENTS IN BORU MEDA HOSPITAL, SOUTH WOLLO ZONE, AMHARA REGION, ETHIOPIA. AB - BACKGROUND: Leprosy is a chronic infectious disease affecting the skin and peripheral nerves. Early diagnosis and full course treatment are critical for preventing lifelong neuropathy and disability to minimize the occurrence of disability. OBJECTIVE: The objective of this study is to assess the magnitude of disability and associated factors among leprosy patients after treatment in Boru Meda Hospital. METHODS: Facility based cross sectional study was conducted among 128 leprosy patients registered at Boru Meda Hospital from January 1, 2010 to December 31, 2012. Data was collected from charts, entered into a computer, cleaned, edited using EPI Info Version 3.53 for windows and analyzed by SPSS. RESULTS: Five patients (4%) had Grade 2 disability at discharge; the remaining 123 (96%) were discharged with either disability grading 0 or disability grading 1, which are considered to be normal disability grading. Males and rural people were more affected by the diseases: 72% and 92% respectively. Sixty percent of disability occurred due to type one reaction. The mean age of patients and treatment duration were 39.3 years and 60 days respectively. Among the factors type of reaction was significantly associated with disability grading (P = 0.02). CONCLUSION AND RECOMMENDATION: Rural people and males are more affected by leprosy and the prevalence of disability is decreasing. This findings suggest that we need to work on awareness creation on rural people and patients with leprosy to see healthcare providers as early as possible. PMID- 26591280 TI - ASSESSMENT OF THE MAGNITUDE OF TEENAGE PREGNANCY AND ITS ASSOCIATED FACTORS AMONG TEENAGE FEMALES VISITING ASSOSA GENERAL HOSPITAL. AB - BACKGROUND: Teenage pregnancy is directly related to high incidence of pregnancy related complications contributing to maternal morbidity and mortality and social problems. There are no enough data on teenage pregnancy and related complications in Ethiopia and in Benishangul Gumuz region in particular. OBJECTIVE: To investigate the magnitude and factors associated with teenage pregnancy among teenage females visiting Assosa general hospital for health care services. METHODS: Facility-based quantitative cross-sectional study was carried out among 783 randomly selected teenage females using structured and pre-tested questionnaire from January to April 2014. RESULTS: Teenage pregnancy is estimated at 20.4% in this study. The median age of subjects at first sexual intercourse and at first marriage being 16 and 17 years respectively. High proportion of (46.8%) teenagers had engaged in premarital sex. Among sexually active teenage females, 46.7% experienced their first sexual encounter by coercion. Being young [AOR = 0.21, 95% CI = 0.06-0.67], single [AOR = 0.06, 95% CI = 0.03-0.12], housemaid [AOR = 3.93, 95% CI = 1.71-9.04] and use of family planning [AOR = 2.39, 95% CI = 1.20-4.75] have statistically significant association with teenage pregnancy. CONCLUSIONS AND RECOMMENDATIONS: A range offactors including age, marital status, level of education, occupational status, average family income and use of family planning have influence on teenage pregnancy in the study area. Behavioral change communication, strengthening school health program, empowering young women specifically the rural women, and promoting parent-children discussion on sexuality is recommended. PMID- 26591282 TI - RISK FACTORS ASSESSMENT OF DIABETIC FOOT ULCER USING THE SIXTY SECONDS SCREENING TOOL: A HOSPITAL BASED CROSS-SECTIONAL STUDY AT TIKUR ANBESSA SPECIALIZED HOSPITAL. AB - BACKGROUND: Diabetic foot ulcer is one of the most feared and common complications of diabetes. It is a major cause of disability, morbidity and mortality among diabetic patients and about 15% develop foot ulcers in their lifetime. Annual foot exam in diabetic patients and education on foot care is a cost effective way of preventing foot ulcers and amputations. METHODS: A hospital based cross-sectional study was conducted at Tikur Anbessa Specialized Hospital Diabetes Center on 200 participants using the 60 seconds diabetic foot ulcer screening tool from April to August 2014. RESULTS: A total of 200 patients were included in the study. The male to female ratio was 1 to 2.64 (55 to 145). The median age was 50 years (IQR, 39-59 years) and median duration of diabetes mellitus was 11 years (IQR, 6-11 years). Among the 200 patients, 169 (84.5%) had type 2 diabetes mellitus, whereas; 31(15.5%) had type 1 diabetes mellitus. Among the participants, only 9 (4.5%) had foot examination in the last 5 years. Thirty one (15.5%) participants had history of previous ulcer, 1 (0.5%) had history of amputation, 11 (5.5%) had deformity of shape and structure of the foot. Among the participants, 71 (35.5%) had at least one risk factor for the development of diabetic foot ulcer. CONCLUSION: Diabetic foot problems are common among the diabetic patients examined at Tikur Anbessa Specialized Hospital Diabetic Center. Screening for diabetic foot ulcer is a very easy practice which will take maximum of 60 seconds per patient. Despite this fact it is barely practiced for outpatients visiting the diabetic clinics. We stress the need for a clinical diagnosis of diabetic foot ulcers using the 60 seconds screening tool. PMID- 26591283 TI - PATTERNS OF COMPLICATIONS SEEN IN PATIENTS WITH HYPERTENSION ADMITTED TO TIKUR ANBESSA HOSPITAL: A RETROSPECTIVE ANALYSIS. AB - BACKGROUND: Complications due to undetected and uncontrolled hypertension have been recorded to be devastating. Among these are cerebrovascular, cardiovascular and renal complications. Lack of data on the patterns of these complications, combined with the notion that hypertension is only a problem of developed nations, has resulted in missed opportunities for early detection and treatment. METHOD: A retrospective cross-sectional study was performed through medical chart review of 106 hypertension patients who were admitted with complications of hypertension at Tikur Anbessa Specialized Hospital from Januaty 2013 to January 2014 E.C. RESULTS: A total of 106 medical charts of hypertensive patients were reviewed. Among the patients involved in the study, 51% were male, 45% were in their fifth and sixth decades and two third of them did not have any co morbidity. Sixty seven percent of these patients had cerebrovascular disease (stroke), 11% had stroke and hypertensive heart disease, 8% had stroke, hypertensive heart disease and chronic kidney disease (all three), and 5% had stroke with chronic kidney disease. However, there was no significant association between the considered variables and the outcome. CONCLUSION: This study has revealed most of the patients have stroke as a complication, therefore preventive or prophylactic measures should be encouraged to avail it. PMID- 26591284 TI - PATTERNS OF HYPERTENSIVE DISORDERS OF PREGNANCY AND ASSOCIATED FACTORS AT DEBRE BERHAN REFERRAL HOSPITAL, NORTH SHOA, AMHARA REGION. AB - BACKGROUND: Hypertensive Disorders of Pregnancy (HDP) represent the most common medical complication in pregnancy associated with significant maternal and perinatal morbidity and mortality worldwide. Identification of common maternal and perinatal morbidities associated with hypertensive disorders of pregnancy is important for policy makers to plan to alleviate the problem. OBJECTIVE: To assess the patterns of hypertensive disorders of pregnancy and associated factors in Debre Berhan Referral Hospital. METHOD: Institution-based retrospective cross sectional study was conducted by reviewing logbooks and patients charts. RESULT: Among 8626 women who got services in the hospital 340 (3.9%)had hypertensive disorders. The proportion of HDP shows an increasing trend from 1.8% in 2011 to 5.7% in 2014. Preeclampsia accounts for 67.4% of all case followed by eclampsia which account for 27.8%. In this study, HDP was associated with 35.4% preterm delivery, 30.8% fetal death, 39.4% low birth weight, 38.4% low APGAR score and 8.5% IUGR. About 15.8% of newborns born from mothers with HDP mothers needed resuscitation and 40.1% ICU admission. Maternal death occurs in 2.5% mothers who had HDP with the case fatality rate for eclampsia being 6.67%. HDP contributed for 35% of all maternal deaths. Of all mothers with HDP, 58% were primi-gravida ladies. CONCLUSION: The prevalence of HDP shows an increasing pattern over the last years. Preeclampsia and eclampsia together take the lion-share of HDP. Primi gravida women are affected more frequently than multi-gravida women with hypertensive disorders of pregnancy. HDP was associated with major adverse perinatal and maternal outcome. PMID- 26591285 TI - ETHIOPIAN MEDICAL SCHOOLS' RAPID SCALE-UPTO SUPPORT THE GOVERNMENT'S GOAL OF UNIVERSAL COVERAGE. PMID- 26591286 TI - BOVINE TUBERCULOSIS (BTB) AS A RISK FACTOR FOR DEVELOPING TUBERCULOSIS IN HUMANS IN THE RURAL COMMUNITY OF ETHIOPIA: A CASE-CONTROL STUDY. AB - AIM: The current study aimed at assessing BTB as a possible risk factor for human TB in the rural community of North Eastern and Western parts of Ethiopia. METHOD: A case-control design was conducted among cattle owning households with TB and without TB. Comparative cervical intradermal test using purified protein derivatives were used to test cattle. Reading of the reaction was done 72 +/- 4hrs after antigen injection. Based on the skin test reaction measurement, cattle categorized as negative, doubtful and positive. Questionnaires were used to collect the required factors. RESULTS: Thirty-five with TB and 105 households without TB participated in this study of which 49.3% and 61.4% had the habit of drinking raw milk and eating uncooked meat, respectively. About 70.7% knew about the chance of disease transmission from animals to humans. Among the TB households 31.43% shared their house with their cattle. Of the attendants, approximately 38% shared utensil. Based on > 2mms as a cutoff value 23.6% an overall apparent bovine tuberculosis (BTB) and 48.6% apparent BTB in households with TB were recorded. The odds for households having bovine TB in their cattle to get tuberculosis was more than 8 times (95% CI; 2.82-24.60) higher than those owned by households without TB. CONCLUSION: Bovine TB has been seen as an exposure to human pulmonary TB occurrence. A separate house for cattle should be constructed to minimize the fear of cross infections and further study regarding the possible infection of cattle with M. tuberculosis is suggested. Key wordsi bovine tuberculosis, households, human TB, M. tuberculosis, risk. PMID- 26591287 TI - MEDICAL AND NEUROLOGICAL COMPLICATIONS AMONG STROKE PATIENTS ADMITTED FOR INPATIENT CARE IN ADDIS ABABA, ETHIOPIA. AB - BACKGROUND AND PURPOSE: Medical and neurologic complications of acute stroke adversely impact patient outcome and in some cases can be preventable. There is scarcity of data in the African medical setup and none to date in our country to our knowledge. The current study aims to describe types and frequencies of neuro medical complications occurring in hospitalized patients after an acute stroke and to identify risk factors for development of these complications and the role of these factors on mortality. METHODS: A total of 71 patients with acute stroke (excluding Sub-arachnoid Hemorrhage) who were admitted to three hospitals in Addis Ababa from June 2008 to March 2009 were included in the study. These patients were prospectively followed until their discharge or death to look for the nature and frequency of neuro-medical complications. Basic demographic data, stroke related medical information, pre-existing medical conditions, admission laboratory and imaging findings were recorded. All events were documented for each patient using pre-defined medical complication using a data collection format. Descriptive and analytic statistical tests were performed to measure associations between risk and outcome factors. RESULTS: Stroke-complications were detected in 71.8% (51/71) of the study participants and the most frequent complication was aspiration pneumonia which occurred in 33.8% (24/71). Miscellaneous complications such as sepsis, hypokalemia exposure keratitis were detected in 25% (17/71) of stroke patients. Complications were more common in patients with severe neurologic deficit as measured by Glasgow coma scale (GSC) and old age. GCS < 12 and age > 40 years were both significantly associated with developments of complications after stroke (p < 0.05). A total of 17 (23%) patients died during their in-patient stay. GCS < 12 was significantly associated with mortality related to stroke in the admitted patients (p = 0.0002) while there was no association between old age and mortality. CONCLUSIONS: Complications after stroke are common and are major factors contributing to mortality. Being aware of the types of common complications and associated risk factors helps the clinical team involved in the care of stroke patients to make preparations and plans for the best possible care and to take preventive measures that will save a lot of lives with best possible use of meager resources available such as educating the population to avoid oral feeding for patients with altered mental state and physicians to evaluate gag reflex bedside swallowing test and proper positioning of patients to avoid aspiration pneumonia. GSC measurement at admission is an important predictor of complications and death following stroke. PMID- 26591288 TI - ACUTE ABDOMEN IN ADULTS: A TWO YEAR EXPERIENCE IN MEKELLE, ETHIOPIA. AB - BACKGROUND: The term acute abdomen denotes any sudden spontaneous non traumatic disorder whose main manifestation is in the abdominal area. It is one of the most commonly encountered emergencies in the practice of general surgery but there is no much study regarding the magnitude and pattern in Ethiopia and in the study area in particular. OBJECTIVE: The study was aimed at assessing the causes, pattern and outcomes of surgical regimen of acute abdomen in the study area. METHODS: This is a descriptive retrospective study conducted in all adult patients with acute abdomen admitted in Mekelle hospital from Sept, 2008 to August, 2010. Patient demographics, clinical features, white cell count levels, operative findings and outcomes were adequately recorded. Adequate recording has been maintained in the hospital. The source.and the study groups (N-299) were patients of adult age categories. RESULTS: A total of 2628 surgical procedures were performed during the study period. Of these, 299 cases were surgical emergency conditions for acute abdomen accounting for (11.4%) of all surgeries. During the. study period, there were 989 adult surgical emergency procedures of which 299 (30.2%) cases were laparotomies for acute abdomen. The age ranged from 15 years to 95 years (mean = 31.5 years). The male to female ratio was (M: F; 4.1:1). In this series, the most common symptoms were abdominal pain, vomiting and abdominal distention accounting for 299 (100.0%), 149 (49.8%) and 38 (16.4%) respectively. The frequent. clinical signs were tenderness, localized guarding and rebound tenderness accounting for 287 (96.0%), 269 (90.0%) and 139 (46.4%) respectively. Acute abdomen was most common between 20-29 years of age at a rate of 96 (32.1%) with male 74 (24.7%) preponderance. Acute appendicitis was the leading cause of acute abdomen accounting for 159 (53.2%) followed by small bowel obstruction 48 (16.0%), sigmoid volvulus 38 (12.7%) and PPUD 13 (4.3%). Of the surgically treated patients for acute abdomen 92 (30.8%) had post-operative complications other than deaths. The three commonest immediate post-operative complications observed were wound infection (19.7%), pneumonia (9.0%) and sepsis (2.0%). In this series, there were 19 deaths giving an overall mortality rate of (6.4%). The low rate of mortality observed in study may be attributed to early presentation, early diagnosis and prompt surgical interventions. CONCLUSION: The present study has depicted that acute abdomen commonly occurred in the 2nd to 3rd decades of life, majority caused by acute appendicitis and males were predominantly affected than females. Small bowel obstruction, sigmoid volvulus, PPUD and incarcerated hernias were other observed causes of acute abdomen. PMID- 26591289 TI - ACCEPTABILITY OF THE INVOLVEMENT OF HEALTH EXTENSION WORKERS (HEWS) IN MEDICAL ABORTION (MA): THE PERSPECTIVES OF CLIENTS, SERVICE PROVIDERS AND TRAINED HEWS IN EAST SHOA AND ARSI ZONES, OROMIYA REGION, ETHIOPIA. AB - BACKGROUND: Unsafe abortion remains a significant contributor of maternal morbidity and mortality in Ethiopia and other developing countries. Involvement of community based health workers, health extension workers (HEWs) in Ethiopia, is a vital step in increasing access and utilization of medical abortion and related services. In order to engage HEWs, it is important to understand the attitude of women and service providers. OBJECTIVE: To explore the acceptability of involvement of HEWs in medical abortion by women who seek services, by abortion service providers, and assess willingness and confidence of HEWs. METHODS: An exploratory in-depth interview was conducted at three purposively selected health facilities in Ethiopia; namely Marie Stopes International (MSI) Adama clinic, MSI Asella clinic and Adama Government Health Centre from July August, 2013. The interviews were transcribed verbatim and analysis was done using Atlas ti software. Themes were abstracted from coded text segments. The findings are presented using quotations, Atlas ti networks and queries. RESULTS: Thirty eight (26 eligibility, 12 follow up) women participated in the study and 9 HEWs and 7 service providers were interviewed. Almost all of the interviewed women, service providers and HEWs accepted HEWs involvement in medical abortion services. The HEWs expressed readiness and confidence. Concerns related to the involvement of HEWs included confidentiality, privacy, over dependence on abortion rather than preventing unwanted pregnancy, quality and poor referral system. CONCLUSIONS: Expansion of medical abortion services by involving HEWs can contribute to the reduction of abortion related morbidity and mortality. Concerns of the study population should be addressed by training HEWs for medical abortion, creating better awareness and advocacy among women and communities, addressing quality and referral issues with proper planning, implementing and monitoring of activities. PMID- 26591290 TI - PULMONARY COCCIDIODOMYCOSIS PRESENTING AS A MASS, AN UNCOMMON DISEASE ENTITY IN ETHIOPIA. AB - Coccidiodomycosis is a disease caused by the spores of the fungi coccidiodes immitis and pulmonary coccidiodomycosis comes after inhalation of the spores which are mainly found in desert areas of the United States, central and South America. Reported cases from outside the endemic areas have always history of travel to these areas. There are no reports so far from Ethiopia or the whole Africa. We report here a case of pulmonary coccidodomycosis with no history of travel to such areas. A 24 years old female patient from Samre, South-Eastern Tigray, presented with right side chest pain and productive cough of yellowish sputum which sometimes is blood streaked. She had completed anti-tuberculosis treatment without any improvement. With a preliminary diagnosis of pulmonary mass, surgical exploration was made and histology of the excised tissue showed appedrances consistent with pulmonary coccidioidomycosis. There was marked clinical and radiological improvement after three weeks of treatment with ketoconazole. Though there are no reported cases from Ethiopia and Africa as a whole, Coccidiodomycosis should be considered as differential diagnosis especially for patients from arid areas like that of our patient before any empirical treatment. PMID- 26591291 TI - TIP OF THE ICEBERG: INFECTIVE ENDOCARDITIS IN AN INTRAVENOUS DRUG USER. AB - Tricuspid valve infective endocarditis is a known complication of injecting drug use (IVDU) and is said to be rare in Africa. The most common etiological microbial agent of infective endocarditis (IE) in IVDU is Methicillin sensitive Staphylococcus aureus. Antibiotic treatment should start immediately after blood cultures have been obtained once IE is diagnosed. Treatment of IE in patients with IVDU is more difficult, and has a high recurrence rate due to medical non compliance and continuing IVDU. The status of IVDU in Ethiopia is not known. The updated strategies of diagnosis and treatment as well as prognosis of IE in an IVDU patient who presented with respiratory symptoms and later diagnosed with TV endocarditis will be discussed. PMID- 26591292 TI - THE TREND OF HIV/AIDS RELATED MORTALITY AMONG PRIMARY AND SECONDARY SCHOOL TEACHERS IN ADDIS ABABA, ETHIOPIA: USING A VERBAL AUTOPSY METHOD. AB - BACKGROUND: It is widely argued that school teachers in sub-Saharan Africa are being affected and will continue to be affected by the AIDS epidemic. Teachers are considered as a high-risk group with respect to HIV/AIDS, particularly in high prevalence countries, where the epidemic has devastating impact on the teaching profession OBJECTIVE: The aim of this study was to examine the trends of mortality among primary and secondary school teachers in Addis Ababa during this era of HIV/AIDS. METHODS: Data on teachers who died from November 2005 to October 2012 retrospectively and a longitudinal data for the new deaths during the year followed prospectively (November 2012 to October 2013) were included in the trend analysis. The data were obtainedfrom family members or care givers of 146 deceased teachers. Each completed verbal autopsy questionnaire was reviewed by two physicians independently. When assigned causes for deaths of teachers by two physicians were not in agreement, then the cases were given to a third physician/Internist. Cases with inconsistent causes of deaths by three physicians were labeled as "undetermined". Extended Mantel-Haenszel Chi-square for linear trend was used to check the significance of the trend by using SPSS version 20 and Open EPI software. RESULTS: The trend of total and HIV-related mortality among teachers declined from 45 (31%) to 22(15.2%) and 15 (10.3%) to 4 (2.7%) during the first two years /Nov. 2005-Oct. 2007/ and the last two years /Nov. 2011- Oct. 2013/ of the study period, respectively. Similarly, the proportionate mortality ratio between the total and HIV/AIDS related mortality declinedfrom 0.33 to. 0.18 during the corresponding period. The decline in the HIV/AIDS related mortality was statistically significant with Mantel Haenszel Chi-square = 7.04 (P < 0.01). CONCLUSIONS: The findings of this study demonstrated a statistically significant decline in total and HIV/AIDS related mortality among teachers in Ethiopia in the last 8 years. However, we suggest nationwide study on the impact of HIV/AIDS in the education sector for more representative data and better interventions. PMID- 26591293 TI - FOREIGN-BODIES IN THE EAR, NOSE AND ESOPHOGUS IN PEDIATRIC AGE GROUP, AT MEKELLE HOSPITAL ETHIOPIA. AB - BACKGROUND: The ingestion of foreign body is a common problem in children, some of which may cause damage or may be associated with toxicity. OBJECTIVE: To evaluate and analyze the pattern of foreign bodies in children in the esophagus, ears and nose with review of the techniques for removal in the emergency department. METHODS: From Sept 1, 2008 to May 30, 2010, a review of all children with foreign bodies in the esophagus, ears and in the nose was done to assess the patterns and treatment outcomes. The source and the study group were (N-72). Data concerning socio- demographics, characterization, presenting symptoms and signs, techniques of retrieval and outcomes were extracted and filled in a previously prepared protocol sheet. Descriptive analysis was done using SPSS- computer statistical software. RESULTS: During the study period, 72 children, victims of foreign bodies in the esophagus, ears and in the nose were included in the study. Of these 44 (61.1%), 28 (38.9%) were male and female children, respectively. The age ranged from 11 months to 14 years with (mean = 4 years). The most affected age group was between 0-5 years accounting for 46 (63.9%) followed by the age group between 6-10 years accounting for 20 (27.8%) of all cases. Males 44 (61.1%) were predominantly most affected than females 28 (38.8%). The location of foreign bodies in this study were in the ears 45 (62.5%), esophagus 17 (23.6%) and in the nose 10 (13.9%) in order of their frequency. Swallowed foreign bodies were successfully removed by Magill forceps. Foreign bodies in the ears and in the nose were removed by careful but different techniques depending on the type and the clinical condition of the patient at time of intervention. CONCLUSION: Our study revealed a higher number of patients with foreign bodies in the ears and in the esophagus. Only a small number ofpatients presented with FBS in the nose. Food items in the ears, in the nose and coins in the esophagus were items frequently observed. Early suspicion, early diagnosis and prompt intervention have attributed to reduce morbidities of major events. PMID- 26591294 TI - CERVICAL CANCER: ASSESSMENT OF DIAGNOSIS AND TREATMENT FACILITIES IN PUBLIC HEALTH INSTITUTIONS IN ADDIS ABABA, ETHIOPIA. AB - BACKGROUND: Cervical cancer is the second most common cancer in women globally and the leading cause of cancer deaths in women in low income countries. The majority of cervical cancer related deaths occur in the developing world. It is also an important public health problem in Ethiopia, a country without a well established control program for the disease. This study assessed the diagnostic and therapeutic facility for cervical cancer (including health providers' awareness of the disease) in Addis Ababa public health institutions which can be used to develop control strategies and to visualize the amount of resources required. METHODS: A cross-sectional study was conducted including all public health institutions in Addis Ababa in August 2010. Health providers' awareness of cervical cancer was assessed using a self-administered questionnaire. Checklist was used to register diagnostic and therapeutic infrastructure in each health facility. Data was analyzed using STATA. RESULTS: All health providers responded they had heard about cervical cancer. Half of the participants were able to identify common symptoms of the disease. Only 23% of the participants mentioned human papilloma virus (HPV) as the primary cause of cervical cancer. A significant association between awareness and profession was seen. Absence of skilled manpower, equipment and proper documentation was reported in the majority of the institutions. CONCLUSION: This study assessed the existing skilled man power and infrastructure to diagnose and treat cervical cancer in public institutions in Addis Ababa which is important to develop an effective cervical cancer control program. In addition, the study showed the more work that should be done to improve health providers' awareness in cervical cancer through education and training. PMID- 26591295 TI - PATTERN OF SPINE AND SPINAL CORD INJURIES IN TIKUR ANBESSA HOSPITAL, ETHIOPIA. AB - BACKGROUND: Spinal injury is a major cause of morbidity and mortality worldwide. Fall and Road traffic accident are the main etiologic factor. OBJECTIVE: The aim of this study was to asses local hospital patterns of spinal injury and compare them with published reports. METHODS AND PATIENTS: This is a hospital based cross sectional study of patterns of patients with spine and spinal cord injury seen at the Emergency OPD, Tikur Anbessa Specialized Teaching Hospital (TASTH), Department of Neurosurgery, Addis Ababa, Ethiopia in the period between April 2008 and March 2012. Data was collected using structured questionnaires. The variables included were the Socio-demographic such as age sex, distance of patients' residence area from the TAH. In addition to the above profiles, causes of injuries, Occupation, diagnosis, time spent between arrival andAdmission and decision taken at OPD level. Differences in proportions were examined using Chi square test. RESULTS: A statistically significant male predominance (84.9%) (p, 0.0001) was observed, the mean age was 32.8 years, with range 10 to 84 years. Mean duration of presentation to TASH was 4.3 days with a range 1 hour-60 days, Fall from height (P < 0.001) and Road traffic collisions were the main cause of spine and spinal cord injuries in 36.4% and 32.9% of the patients respectively. Most often the cervical spine was involved (33.0%), Sixty-nine (17.9%) patients had associated injuries, majority of respondents (25.5%) were farmers, Majority belonged to ASIA A grade. All the deaths, 7 (8.3%) occurred in patients with complete cervical spine lesion. CONCLUSION: Spinal injury was an important indication for neurosurgical consultations in our service. Complete cord injuries were more common than incomplete and the case incidence from fall was remarkably high. PMID- 26591296 TI - EVALUATING THE VALIDITY AND RELIABILITY OF CHEST RADIOGRAPHY IN THE DIAGNOSIS OF TUBERCULOSIS AMONG SMEAR NEGATIVE PULMONARY TUBERCULOSIS PATIENTS. AB - BACKGROUND: Tuberculosis (TB) is a mycobacterial infection mainly affecting the lungs. Early and correct diagnosis of sputum smear negative patients by chest radiography (CXR) is challenging since it depends on reader's ability to detect abnormal findings and to interpret it correctly. OBJECTIVES: To evaluate the validity and reliability of CXR the diagnosis of TB among smear negative pulmonary tuberculosis (PTB). METHODS: An institutional based cross-sectional study was conducted at seven selected health facilities from October 2011 to September 2012 on 159 adults aged 18 years and above who were newly diagnosed smear negative for PTB patients diagnosed using Chest X-ray (CXR). Morning sputum was collected and cultured from each patient using Lowenstein Jensen media. All the CXRs were revised by senior radiologists in conjunction with the principal investigator. A structured questionnaire was used to collect socio-demographic, clinical and radiological data. Sensitivity and specificity measures of the CXR findings were calculated in comparison to the gold standard sputum culture results. RESULTS: The mean (SD) age of patients involved in the study was 37.1 (16.7), ranging from 18 to 87 years. Of the total 159 smear negative PTB patients, the most common CXR finding was consolidation (40.3%) followed by cavitations (23.9%) and nodular lesions (17.0%). Sputum culture results showed that, 47 (29.6%) were culture positive, 103 (64.7%) were culture negative and 9 (5.6%) were contaminated. About 14% (22/159) of the study subjects were HIV positive. The sensitivity and specificity of CXR findings were 77.1% (37/48) and 36.9% (41/111), respectively. The positive and negative predictive values were 34.6% (3 7/107) and 78.8% (41/52), respectively. CONCLUSION: CXR can be used as supportive investigative modality to diagnose smear negative Pulmonary TB in conditions where TB culture is no more feasible. PMID- 26591297 TI - REDUCING PMTCT ATTRITION: PERSPECTIVES OF HIV+ WOMEN ON THE PREVENTION OF MOTHER TO-CHILD HIV SERVICES IN ADDIS ABABA, ETHIOPIA. AB - BACKGROUND: Only 41% of eligible Ethiopian women completed (PMTCT) therapy in 2012, with MTCT rate of 20%. OBJECTIVE: This study elicited the perspectives of HIV positive mothers on the situation and the unique beliefs, attitudes, cultural norms and individuals who have influence over them during their pregnancy. METHODS: The mixed-methods parent study included community level surveys, focus groups and in-depth individual interviews of HIV positive women with a child at least one year of age in Addis Ababa, Ethiopia: only focus group and interview data are presented here. All tools were completed in Amharic with English translation. RESULTS: 23 women completed in-depth interviews; 27 participated within 4 focus groups. The greatest barriers to PMTCT completion were: feelings of hopelessness and carelessness, lack of understanding of the efficacy of ARV, and negative religious influences. The advice to improve PMTCT adherence most frequently offered included increasing PLWHIV peer support and improving and extending current HIV educational efforts. Participants recommended that PLWHIV mothers be utilized in all PMTCT planning and interventions in the future. CONCLUSION: Maintaining the motivation to adhere to the entire PMTCT cascade requires that a PLWHIV mother understands the validity of the steps she is taking and receives support for the many challenges she faces. Engaging PLWHIV peers as active members of the health care workforce and expanding their use as educators and counselors is important. Health officials can consider these findings to develop innovative and effective PMTCT interventions. PMID- 26591298 TI - PENILE AGENESIS WITH CROSSED FUSED RENAL ECTOPIA. AB - Penile agenesis is one of the rarest urogenital anomalies with only less than 100 cases reported worldwide so far. Only 3 cases have been reported from Africa and to our knowledge none has been reported from our country Ethiopia. Viability depends on associated anomalies. Urogenital anomalies are the most common associated ones accounting for 54% of cases. This case report is unusual presentation, which is the first reported case of penile agenesis associated with left to right, crossed fused renal ectopia. PMID- 26591299 TI - SPLENIC TORTION IN A WANDERING SPLEEN: A CASE REPORT FROM AYDER REFERRAL HOSPITAL. AB - A 46 years old female patient presented with worsening of abdominal pain of 12 days duration & abdominal swelling of 15 years. On examination, she had an elliptical, mildly tender mass on the periumblical area extending to the right flank & the suprapubic area. It is mobile & firm in consistency. The intra op finding was huge spleen weighing 2 kgs, rotated 360 degrees clockwise, situated over the right side of the abdomen. This case report showed that a wandering spleen can present acutely with tortion mimicking acute abdomen. PMID- 26591300 TI - [Editorial from A.M.U.B. 's president]. PMID- 26591301 TI - [Editorial from the editor-in-chief]. PMID- 26591302 TI - [Prenatal screening: the example of Down's syndrome screening]. AB - Prenatal screening for Down's syndrome initially targeted high-risk pregnant women (> 35 years old). However, the vast majority of babies with Down's syndrome are born to younger women (as the majority of babies are born in this age category). It was first discovered that some serum analytes were altered in pregnancies affected with Down's syndrome (triple test). In the nineties, the association between an increased nuchal translucency measurement and trisomy 21 was noted. The use of this measurement in combination with serum markers has enabled an increased detection rate but still at the cost of a false positive rate of around five percent (combined test). Recently, major advances in sequencing technologies have allowed reasearchers to make use of the cell free fetal DNA in maternal blood. This new test (named non invasive prenatal test) made it into clinical use as early as 2011 in some countries. Its sensitivity is above 99 % for trisomy 21 and the false positive rate is very low. It is risk free and much more accurate than previous approaches. It is largely favored over an invasive test by high risk women (advanced maternal age or high-risk combined test). Its use is still restricted by a high cost which is for the moment still entirely beared by the patient. The availability of NIPT in our routine practice and the increased complexity of screening options have highlighted the need for a more dedicated counselling consultation before Down's syndrome screening is performed. PMID- 26591303 TI - [Newborn screening : the point of view of the paediatrician]. AB - Newborn screening is a public health effort that has changed the prognosis of some congenital diseases. Newborn screening programmes differ between countries in which it is organized. Demographic, epidemiological or economic factors play a role in the choice of the screening panel. In the French Community of Belgium, the programme focuses on 13 metabolic and endocrine diseases, hearing loss and hemoglobinopathies (Brussels and Liege). Newborn screening is a complex process that requires the involvement of all stakeholders : parent information, blood sampling or testing, lab analysis, follow-up of the results, initiate adequate care in case of positive test and genetic counselling. Newborn screening programmes will evolve in the next years. New therapeutic and diagnostic methods will make other genetic diseases candidates for screening. Whole genome sequencing may be the next expansion; it will create new opportunities but will pose new ethical dilemmas. We must all prepare now for future challenges. PMID- 26591304 TI - [Systematic follow-up of infants born preterm]. AB - Advances in pediatric medicine have enabled a decrease in perinatal mortality, especially among infants born preterm (< 32 weeks gestational age) or low birth weight (< 1.500 g). However, this population is exposed to a greater risk of neurological sequelae. This is why the creation of specific follow-up program are mandatory to screen at-risk children to offer them a support able to minimize the impact of prematurity on their future neurological development. PMID- 26591305 TI - [Vaccination of premature infants, a population at high risk of infection]. AB - The incidence of prematurity has steadily increased in Belgium these last years, reaching 7,9 % in 2010. Infections remain for these infants an important cause of morbidity and mortality during their hospitalization in the neonatal intensive care units as well as during their first months of life in the community. Despite the immaturity of their immune system, their ability to develop a protective immune response to most vaccines has been established. Instable very low birth weight prematures are at risk cardio- respiratory incidents after vaccine administration, but these incidents are transient and without consequences if they are monitored during and after vaccination. This paper reviews the current recommendations on the immunization of the premature infants. PMID- 26591306 TI - [Treatment of main chronic diseases in childhood from birth]. AB - Children suffering from chronic diseases are very quickly diagnosed by neonatal screening and follow-up of the mother during the pregnancy. Early screening and diagnosis are essential to obtain continuous improvement of the prognosis in term of treatment and psychosocial outcome. Multidisciplinary teams are now well organized to treat all the complications of the disease. Registers at national and international levels allow professionals to compare themselves and to evaluate the improvement of clinical status and mid-life expectancy. PMID- 26591307 TI - [Practical approach of lymphomas: major role of general practitioner who has to face all these emerging drugs]. AB - Malignant lymphoma and other lymphoproliferative disorders represent a group of malignant hemopathies where immunotherapy has allowed spectacular progresses over the last ten years. The recent W.H.O. classification, based upon tumor immunology, and cytogenetical anomalies, allows a better identification of each lymphoma and the comparison of homogeneous populations within various clinical studies. The increase in the incidence of non-Hodgkin lymphoma is related to the aging of the population as well as to other factors that are still to be analysed - a real challenge for the future. We have tried to offer an overview of the latest therapeutical advances while focusing on the major role of general practitioner. The most frequency askeed questions will be discussed. PMID- 26591308 TI - [Breast cancer screening: a better anamnesis and an informed choice]. AB - The goal of this article is to compare breast cancer screening national and international guidelines for defining a pragmatic and evidence-based attitude for primary care professionals in Belgium. A literature review was made in the main guidelines databases and in the belgian epidemiological and reimbursement databases. The decrease in breast cancer mortality this last decade reduce the screening efficiency by the same extent. Finally, it is recommended to propose systematically mammotest screening between 50 and 70 and to inform the patients by messages developed for this purpose by the KCE. Based on a simple family history, we can define three risk groups (KCE - strong recommendation, moderate evidence level). Start this anamnesis from 30 years old, seems to be logical regards to the exams which have to be done if the risk is very elevated. If the risk is elevated, it is recommended to propose annual mammography between 40 and 49 (KCE - weak recommendation - very low evidence level). If the risk is very elevated, refer to the secondary care. Supplementary data are needed to appreciate the influence of social health determinant on the breast cancer morbidity and mortality and to improve our vision of the screening benefice-risk trade-off. PMID- 26591309 TI - [Melanoma secondary prevention]. AB - Melanoma represents a major public health problem. Its incidence is constantly rising and the mortality rate can be frightfully important if the diagnosis is delayed. Melanoma also exerts a significant economical burden on the society. Therefore there is a need of concrete and pragmatic public health strategies in order to enhance melanoma prevention. Primary prevention of melanoma consists in avoiding excessive exposure to ultraviolet rays,'which represent the main risk factor for the disease occurrence. Secondary prevention is a synonym of melanoma early diagnosis and can be obtained by means of two methods : patients' self examination and medical examination. Both these examinations must be routinely and thoroughly performed, must be based on the ABCDE rule and the ugly duckling sign, and ideally must be aided by the use of total-body photography. Current international guidelines suggest that all cutaneous screenings should be performed using dermoscopy, a non-invasive imaging technique that allows improving considerably the diagnostic performance. More sophisticated imaging techniques, such as confocal microscopy, are also available in specialised centres. The current scientific evidence supports the efficacy of melanoma primary and secondary prevention programs as a tool to decrease melanoma mortality. Many skin cancer prevention campaigns have been organised worldwide. The most famous and successful in Europe is Euromelanoma. PMID- 26591310 TI - [Preventing cervical cancer]. AB - The incidence of cervical cancer has hopefully been dropping down in our industrialized countries since the introduction of both primary and secondary prevention. Nevertheless, it is still lethal in one out of two affected women though the introduction of cytological screening has dramatically reduced the mortality. Progressive diffusion of anti-HPV vaccination, the broadening of the viral types concerned, its association with existing screening measures and finally the introduction of viral detection as a screening tool must optimize the results already obtained. PMID- 26591311 TI - [Colorectal cancer: ten years of illusion of progress but advances are on the horizon]. AB - Recent years have basically been marked by a modest progress in digestive oncology. Biologic drugs such as anti-EGFR and antiangiogenic antibodies have improved the overall survival of patients with advanced colorectal cancer for a few months, but did not alter adjuvant treatment paradigms after curative resection of a locally advanced colon cancer or of liver metastases. With the exception of the RAS gene mutations, predictive of lack of effectiveness to anti EGFR antibodies, our knowledge of colon cancer tumor biology has hardly evolved. Long-awaited novelties come rather from fundamental discoveries about the different genomic subtypes of colorectal cancer and new immunotherapy approaches which both announce hopefully real giant leaps in the near future. PMID- 26591312 TI - [Skin sampling for the general practitioner]. AB - Skin samplings are easily performed in general practice. They include skin biopsies, nail clippings, skin scrappings, hair pluckings as well as trichograms. The different types of skin biopsies are curetage, shaving, punch and elliptic biopsies. They are most commonly used for the diagnosis of inflammatory skin conditions and cutaneous tumors. The biopsies are performed under local anesthesia and each has specific indications. Their complications are minimal. In order to obtain as much information as possible the lesion to be biopsied should be judiciously selected, harvested without being harmed and sent to a skin oriented pathologist. Nail clippings, skin scrapings and hair plucking allow diagnosis of superficial skin mycosis (tinea, pityriasis versicolor) and are mandatory before prescribing systemic treatment. Scrapping of an itch mite burrow may sometimes reveal the sarcopte. Trichogram may be useful in the work up of a hair loss. PMID- 26591313 TI - [Hemorrhoidal thrombosis: treatment at the consulting room]. AB - The hemorrhoidal thrombosis is an acute complication with no gravity but an emergency because of the severe pain. Oral or local medical treatments are rarely effective; they poorly relieve the pain. The realization of an incision with removal of the blood clot or of an excision is an easy procedure to perform in the consultation room. She brings an almost immediate pain relief. It only takes a few minutes and requires minimal equipment. PMID- 26591314 TI - [Intra-articular injections]. AB - It is not unusual for a specialist or general practitioner to be presented with a pathology which necessitates the use of an intra-articular injection of corticosteroids, hyaluronic acid or a local anaesthetic. It would seem to be interesting to update and to precise the techniques and methods of intraarticular injections which have appeared in recent international publications, when we know that 30 % of the injections given into the knee and so called "dry" are incorrect and, therefore, inefficient. The indication of an articular injection depends, firstly, on the diagnosis which should be done with great care; after which should be an objective analysis complete with secondary effects linked to both the injection and the product used. The conditions of asepsis, the choice of needles and quantities of the injection and even the ways of the injections should be reviewed in detail. The last studies clearly question the secondary effects of the cartilage degradations of the cortisone given as an intra articular injection and shows its efficiency on the pain and inflammatory phenomonen in osteoarthritis. Studies on hyaluronic acid are often contradictory going from a modest result to an important pain relief but it is necessary to be aware that the objective criteria are difficult to interpret. The use of local anaesthetics in intra-articular is limited by the few indications in view of the major risk of aggravating the pre-existing lesions by the disappearing signs of pain. PMID- 26591315 TI - [Management of chronic wounds in general practice in Belgium]. AB - GPs are frequently confronted with chronic wounds : pressure sores and leg ulcers. They must be able to diagnose and coordinate their prevention and treatment. For venous ulcers, arterial and diabetic foot wounds, they will systematically call on specialists in these pathologies. PMID- 26591316 TI - [Are orthopedic inner soles useful or not]. PMID- 26591317 TI - [The secondary prevention of osteoporosis needs a multidisciplinary approach]. AB - Enormous burden for our aging population and health care system, the hip fracture remains a major challenge to public health. Every year, there are over 15.000 hip fractures in Belgium. Nonetheless of the technical progress in surgery and the follow-up for, postoperation, the morbidity linked to this affection remains important because the vast majority of the patients will not recovered their previous autonomy after the fracture. The mortality is also high. Although it represents 14 % of the total osteoporotic fractures, the hip fractures account for 92 % of the costs caused by the disease, corresponding to 150.000.000 euros per year in Belgium. The present demographic evolution suggests that this amount will increase by 7 fold in 2050. Different epidemiological studies show that a large proportion of these fractures should have been avoided if the reason of the bone fragility, osteoporosis, had been previously diagnosed and treated. In this context, since several years, an increasing number of clinical paths - the Fracture Liaison Services (FLS) - have emerged all over the world. Brugmann Hospital has decided to implement such a model - focusing, by a systematic approach, to better connection and communication between available healthcare resources. PMID- 26591318 TI - [Therapeutic algorithm for low back pain]. AB - Low back pain (LBP) has become one of the greatest public health problems. The differentiation between specific and non-specific low back pain is mandatory. In the specific low back pain are classified all diseases whose etiology is well defined, quick and accurate diagnosis is required for specific treatment. Other types of low back pain can be considered non-specific. The management of acute low back pain is mainly based on analgesic treatment and early mobilization. Maintaining activity can prevent chronicity of LBP. Chronicity factors are multiple, mainly psycho-social and professional. The chronic low back pain treatment goals are the reduction of pain and better activity/participation to achieve the prevention of disability and maintaining work ability. Multidisciplinary treatment programs including personalized and guided physical therapy, cognitive behavioral therapy and short-term training programs will help to improve, restore and maintain the function in chronic low back pain. PMID- 26591319 TI - [Rehabilitation after total knee arthroplasty of hip and knee]. AB - Numbers of total hip and knee arthroplasties are increasing on a regular basis. Clinical pathways tend to shorten the duration of hospitalization in acute care after surgery. Therefore, the preoperative preparation of the patient and his abilities for postoperative rehabilitation should be carefully addressed. Before the surgical intervention, it is recommended that the patient receives an educational program and a physical preparation. After the surgical intervention, the patient can benefit from a home-based rehabilitation program supervised by a physiotherapist, if there were no preoperative reasons for prolonging the hospital stay and if the surgery took place without complications. Some patients may benefit from postsurgical rehabilitation in a specialized locomotor rehabilitation long-stay care unit. The indications for inpatient multidisciplinary rehabilitation are : two simultaneous arthroplasties, revision of a previous hip or knee arthroplasty, postsurgical complications, advanced age, comorbidities influencing the rehabilitation process, social difficulties, necessity for adaptation of the environment, insufficient or unadapted out patient (para)medical care. The goals of the rehabilitation treatment depend on the patient's characteristics and environment, on the properties of the prosthesis and on the postsurgical complications. The functional prognosis of a total joint arthroplasty of the knee or hip is excellent, provided that there are no post-surgical complications and that the patient benefits from adequate rehabilitation therapy. The present paper describes the different phases of rehabilitation treatment and the general and specific complications of total hip and knee arthroplasties that may influence the rehabilitation outcome. PMID- 26591320 TI - [News in the work-up of deep vein thrombosis (DVT)]. AB - Deep vein thrombosis (DVT) is a component of venous thromboembolism (VTE), the other being pulmonary embolism (PE). Its incidence is 1 to 2/1.000/year and nearly 1/100/year after 80 years. The major complication of DVT is PE which occurs in about 1/3 of cases, is often asymptomatic but can be fatal. Another common complication, occurring in 20-50 % of cases is the post-thrombotic syndrome (PTS) which is likely to alter the quality of life. Several issues remain unanswered when considering DVT. The optimal management of distal DVT versus proximal DVT is not well codified. The diagnostic approach to DVT is essential : it is based on the estimation of clinical probability, the possible use of D-dimer test and compression ultrasonography. The new direct oral anticoagulants (NOACs) have been proven effective in the phase 3 studies but when to use them and which to choose in the real life ? Wearing compression stockings to prevent the SPT is recommended: what is the definition of compression stockings and is there some evidence of their efficacy ? The purpose of this article is to provide some useful information to primary care physicians to address a DVT. PMID- 26591321 TI - [Rational approach and management of the dyspnoeic patient in general medical practice]. AB - Dyspnea represents 3-4 % of consultations at primary care medicine (general medicine, emergency medicine) and is found in 14 % of the interviewed general population. It is defined as an abnormal and uncomfortable breathing and can be classified according to the mode of appearance, the breathing pattern or the rhythm. Different classifications are used to specify the severity of the situation: visual analog scale, functional classification of the New York Heart Association, dyspnea modified scale from the Medical Research Council, ... Rare among young people, dyspnea often hides asthma; more prevalent among seniors, it is often secondary to chronic lung or heart disease. The rational approach is the same in general medicine and in the emergency room. The management starts with an assessment of the severity of the patient's clinical situation, via the early warning score. The critical patient requires to be managed according to the progressive and cyclical ABCDE approach. For non-critical patients, a traditional approach and a reasoned method are needed. In patients suffering from chronic obstructive pulmonary disease (COPD), the use of the Anthonissen criteria allows to orient toward a pulmonary superinfection or another cause of worsening dyspnea (cardiac, ...). In case of suspected pulmonary embolism, the Geneva score and the modified Wells score help to separate low, intermediate or high probability cases of pulmonary embolism. D-dimers have a very good negative predictive value in the low and middle risk group and pulmonary CT angiography applies only to a smaller group of dyspnoeic patients with a high probability of pulmonary embolism. Echocardiography has a prominent role to assess the LV systolic function, the search for pulmonary artery hypertension, the vascular filling state, etc. We speak of psychogenic dyspnea after having excluded the potentially serious pathologies. PMID- 26591322 TI - [What is the evidence to support screening for abdominal aortic aneurysm and what is the role of the primary care physicians ?]. AB - Abdominal aortic aneurysm is a serious and potentially fatal vascular disease. Surgical intervention is typically reserved for aneurysms 55 mm in diameter or greater. Randomized trials addressing the efficacy of ultrasound screening for abdominal aortic aneurysm have shown that screening reduced aneurysm-related mortality in men but not in women who have a lower prevalence of abdominal aortic aneurysm. Screening with ultrasonography is recommended in men 65 to 75 years of age with a history of smoking and is suggested in women in this age group if they have risk factors such as smoking and hypertension. Men and women with a family history of abdominal aortic aneurysm should undergo screening as well. Persons who have a stable aneurysm should undergo regular surveillance or operative intervention depending on aneurysm size. Primary care physicians have to play a key role before prescribing screening in assessing risks and benefits of repair in each patient. For persons with an aneurysm of less than 55 mm in diameter, the primary care physicians should provide information and interventions for the prevention of cardiovascular disease such as screening for and treating hypertension and interventions for tobacco cessation for smokers. The family physicians should also ensure that radiological monitoring of aneurysms is complete. PMID- 26591323 TI - [Cutaneous vascular anomalies in children]. AB - INTRODUCTION: Vascular anomalies, which are erroneously categorized under the term angiomas, are a highly heterogeneous group of lesions that are poorly understood and affect a mean of 5 to 10 % of children. The fortuitous discovery of propranolol's efficacy in one of these entities has made them a topical issue. OBJECTIVES: The paper's main objective is to inform family doctors of the various types of vascular anomalies, clarify their classification, and provide a common terminology. Its secondary objective is to provide a decision tree that enables primary care doctors to avoid diagnostic pitfalls, successfully detect cases, and optimize management. METHODS: Systematic review. CONCLUSIONS: According to a recent study, 71,3 % of publications use the term hemangioma erroneously, regardless of the authors' field. The key for family doctors is to use one international classification only, that of the International Society for the Study of Vascular Anomalies (ISSVA), in order to facilitate management and comprehension between the different healthcare levels. The diagnosis of vascular anomalies is clinical in 90 % of cases, so all family doctors can, whilst using a decision tree, diagnose a vascular anomaly and refer only those that are complex for specialist care. The most common vascular anomaly is infantile hemangioma in infants, which spontaneously regresses around the age of 5-7 years in 90 % of cases. Watchful waiting and regular follow-up suffice, therefore, in such settings. PMID- 26591324 TI - [Signs and symptoms of major neurocognitive disorders]. AB - Cognitive disorders are a common problem, especially for older people. Dementia, recently renamed "major neurocognitive disorder" in DSM-5 is a complex subject. Age, vascular risk factors, subjective decline and its objectivation, are all risk factor for such neurocognitive disorders. Face to minor neurocognitive disorder, decline seemed more associated with the presence of structural atrophy or functional metabolic modification. It seems however more and more clear that, at least actually, such a diagnosis should not be done as early as possible but well timely and individually correct. This patient-centred approach requires the peculiar involvement of its familial, general physician. But when early detection tools will be used, for any legitimate reason, it will also be important to address specialized teams. In case of neurocognitive disorders, particularly major, psychoeducative programs are the most effective therapeutic on both patient and caregiver qualities of live. Such multidisciplinary program of care for patients with neurocognitive disorder and his/her caregiver has just obtained a financial agreement via the specific protocol 3 and should be known to be efficient. PMID- 26591325 TI - [Non valvular atrial fibrillation: the place of the new anticoagulants]. AB - Atrial fibrillation (AF) increases the risk of mortality and stroke. The prevention of these complications is based on oral anticoagulants that are more efficient than salycilates. As compared with antivitamins K agents, new oral anticoagulants are promising for patients presenting non valvular atrial fibrillation because of lower cerebral hemorragic risk (with respect of assessment of renal function and therapeutic compliance). Available studies and recommendations are presented. PMID- 26591326 TI - [Management of severe arterial hypertension]. AB - Severe arterial hypertension is defined as a systolic blood pressure (BP) >=180 mmHg and/or a diastolic BP >= 110 mmHg. Initial assessment is to identify acute, ongoing, target-organ damage such as pulmonary edema, aortic dissection, ... (hypertensive emergency). If so, the patient requires urgent and specific management in a hospital setting. More commonly, however, BP in the severe range is relatively asymptomatic and not associated with end-organ damage (hypertensive urgency). Management can usually be carried out in the ambulatory setting. Severe hypertension should first be confirmed after a period of rest in a quiet room. If BP remains in the severe range, an antihypertensive drug can be initiated. Otherwise, the patient should be referred for further evaluation within a few days ; however, an antihypertensive treatment could be started immediately if there is concern that urgent outpatient follow-up cannot be ensured or if the patient is at high cardiovascular risk. The choice of the first drug should be tailored according to associated conditions and possible contraindications. Some guidelines recommend starting therapy with an antihypertensive combination of two drugs. In all cases, rapid and excessive reduction in BP, which could compromise organ perfusion, must be avoided, especially in elderly patients. In the short term (days), BP should be progressively lowered to < 160/100 mmHg. In the long term, a BP < 140/90 mmHg should be obtained. PMID- 26591327 TI - [The diagnosis of food allergies]. AB - The prevalence of food allergies is more than 5 %, rising currently. The clinical presentations are polymorphic and involve the skin, respiratory, vascular and gut systems. The diagnosis is based on the consistancy between the allergic history and the results of the specific IgE investigations. When the relationship between the history and the IgE sensitization is not significant, an oral challenge test with food is indicated under supervision of a reference center. New approach, based on dosage of specific IgE to different constituent (recombinant protein) of each allergen, can predict the severity of the reaction and the cross reactivity between allergens, in some patients. PMID- 26591328 TI - [Osteopathy and Evidence-Based Medicine]. PMID- 26591329 TI - [Anti-aging medicine: science or marketing ?]. AB - Anti-aging medicine is self defined as a preventive medicine, combining nutritional recommendations, dietary supplements, prescriptions for hormones and various aesthetic techniques. The essential aim is to reduce the risk of aging, both psychically, physically and aesthetically. Although many scientific studies in animals or in vitro models have demonstrated the deleterious role of oxidative stress and of hormonal, vitamin or trace elements deficiencies, the transposition to humans of these findings is marginal and does not justify the therapeutic proposals advocated by the anti aging medicine. These practices are mostly not based on any scientific basis both in the diagnostic and therapeutic fields. These approaches are particularly costly for gullible patients in search of well being and abused by a carefully organized marketing involving tacit complicity of doctors, laboratories and firms producing hormones and dietary supplements and various substances devoted for aesthetic purposes. PMID- 26591330 TI - [Alternative medicines and "Evidence-Based Medicine" a possible reconciliation?]. AB - The contrast between the efficiency of Evidence-Based Medicine (EBM), a scientific fact, and the popularity of Complementary and Alternative Medicines (CAM) is a paradox of the art of healing. EBM is based on the paradigm of positivism and materialism while CAM are based on those of relativism and vitalism. These paradigms are diametrically opposed and the aim of an integrative medicine is aporetic. However, EBM is today in a dead end. The objective proof of a disease according to the rules of EBM is often lacking face to the expectations of patients demanding their illness to be taken into account. EBM and CAM have thus to coexist. Lessons can be drawn from CAM : patient expectations should be given a meaning and be integrated in his or her psychosocial context. PMID- 26591331 TI - We Haven't Told Our Story. PMID- 26591332 TI - Arsenic Consumption in the United States. AB - Exposure limits for arsenic in drinking water and minimal risk levels (MRLs) for total dietary exposure to arsenic have long been established in the U.S. Multiple studies conducted over the last five years have detected arsenic in foods and beverages including juice, rice, milk, broth (beef and chicken), and others. Understanding whether or not each of these foods or drinks is a concern to certain groups of individuals requires examining which types of and how much arsenic is ingested. In this article, recent studies are reviewed and placed in the context of consumption patterns. When single sources of food or drink are considered in isolation, heavy rice eaters can be exposed to the most arsenic among adults while infants consuming formula containing contaminated organic brown rice syrup are the most exposed group among children. Most food and drink do not contain sufficient arsenic to exceed MRLs. For individuals consuming more than one source of contaminated water or food, however, adverse health effects are more likely. In total, recent studies on arsenic contamination in food and beverages emphasize the need for individual consumers to understand and manage their total dietary exposure to arsenic. PMID- 26591333 TI - Arsenic Content in American Wine. AB - Recent studies that have investigated arsenic content in juice, rice, milk, broth (beef and chicken), and other foods have stimulated an interest in understanding how prevalent arsenic contamination is in the U.S. food and beverage supply. The study described here focused on quantifying arsenic levels in wine. A total of 65 representative wines from the top four wine-producing states in the U.S. were analyzed for arsenic content. All samples contained arsenic levels that exceeded the U.S. Environmental Protection Agency (U.S. EPA) exposure limit for drinking water of 10 parts per billion (ppb) and all samples contained inorganic arsenic. The average arsenic detected among all samples studied was 23.3 ppb. Lead, a common co-contaminant to arsenic, was detected in 58% of samples tested, but only 5% exceeded the U.S. EPA exposure limit for drinking water of 15 ppb. Arsenic levels in American wines exceeded those found in other studies involving water, bottled water, apple juice, apple juice blend, milk, rice syrup, and other beverages. When taken in the context of consumption patterns in the U.S., the pervasive presence of arsenic in wine can pose a potential health risk to regular adult wine drinkers. PMID- 26591334 TI - Presence of Pathogenic Bacteria and Viruses in the Daycare Environment. AB - The number of children in daycare centers (DCCs) is rising. This increases exposure to microorganisms and infectious diseases. Little is known about which bacteria and viruses are present in the DCC environment and where they are located. In the study described in this article, the authors set out to determine the prevalence of pathogenic bacteria and viruses and to find the most contaminated fomites in DCCs. Fifteen locations in each DCC were sampled for bacteria, respiratory viruses, and gastrointestinal viruses. The locations were in the toilet, kitchen, and playroom areas and included nursery pillows, toys, and tables, among other things. Coliform bacteria were primarily found in the toilet and kitchen areas whereas nasopharyngeal bacteria were found mostly on toys and fabric surfaces in the playroom. Respiratory viruses were omnipresent in the DCC environment, especially on the toys. PMID- 26591335 TI - EHSB's Free Resources for Environmental Health Practitioners. PMID- 26591336 TI - Together at Last: Exploring Health and Environmental Information on the National Environmental Health Tracking Network. PMID- 26591337 TI - Of Similes, Metaphors, & Intimacy. PMID- 26591338 TI - [Kidney Diseases and Metabolic Disorders--Basics and Applications Required for General Physicians]. PMID- 26591339 TI - [Kidney diseases and metabolic disorders--Basics and applications required for general physicians. Topics: I. Disorders of water balance and sodium metabolism]. PMID- 26591340 TI - [Kidney diseases and metabolic disorders-Basics and applications required for general physicians. Topics: II. Disorder of carbohydrate metabolism]. PMID- 26591341 TI - [Kidney diseases and metabolic disorders--Basics and applications required for general physicians. Topics: III. Abnormalities in lipid metabolism in chronic kidney disease]. PMID- 26591342 TI - [Kidney diseases and metabolic disorders--basics and applications required for general physicians. Topics: IV. Uric acid metabolic disorder (relationship between liyperuricemia and CKD-CVD)]. PMID- 26591343 TI - [Kidney diseases and metabolic disorders--Basics and applications required for general physicians. Topics: V. Acid-base disorders and kidney disease]. PMID- 26591344 TI - [Kidney diseases and metabolic disorders-Basics and applications required for general physicians. Topics: VI. Chronic kidney disease and fragility fracture]. PMID- 26591345 TI - [Kidney diseases and metabolic disorders--Basics and applications required for general physicians. Topics: VII. Abnormality in phosphate metabolism]. PMID- 26591346 TI - [Kidney diseases and metabolic disorders--Basics and applications required for general physicians. Topics: VIII. Anemia and iron metabolism in chronic kidney disease]. PMID- 26591347 TI - [Kidney diseases and metabolic disorders--Basics and applications required for general physicians. Topics: IX. Impaired drug metabolism]. PMID- 26591348 TI - [Case report: A case of refractory empyema suspected of odontogenic infection after bilateral multifocal tumor shadows were shown]. PMID- 26591349 TI - [Case report; A twins case of anaphylaxis caused by ingestion of mite contaminated Okonomiyaki]. PMID- 26591350 TI - [The cutting-edge of medicine: Diagnosis and treatment of drug-induced liver injury]. PMID- 26591351 TI - [The cutting-edge of medicine; Sublingual immunotherapy for allergic rhinitis]. PMID- 26591352 TI - [Patient-Centered Medical Home: Suggestions for the Health Care Delivery System Reform in Japan: The Patient-Centered Medical Home Neighbor. The interface of Patient-Centered Medical Home with specialty/subspecialty practices]. PMID- 26591353 TI - [Clinical Guidelines of Integrative Medicine for Chronic Renal Failure]. PMID- 26591354 TI - [Clinical Guidelines of Integrative Medicine for Male Infertility (Trial Edition)]. PMID- 26591355 TI - [Treatment of Proteinuria in Chronic Glomerular Disease Patients with Pi-Shen Deficiency Complicated Damp-Heat Syndrome by Yishen Qingre Huashi Recipe: a Clinical Study]. AB - OBJECTIVE: To observe the therapeutic effect of Yishen Qingre Huashi Recipe (YQHR) in treating proteinuria of chronic glomerular disease patients with Pi Shen deficiency complicated damp-heat syndrome (PSDCDHS). METHODS: Totally 121 stage 1 -2 primary chronic glomerular disease patients with PSDCDHS were randomly assigned to the treated group (85 cases) and the control group (36 cases) according to 2:1. All patients received conventional and symptomatic treatment. Patients in the treated group took YQHR additionally, while those in the control group took Losartan Potassium Tablet (50 mg each time, once per day) additionally. The therapeutic course for all was 6 months. Changes of 24 h urine protein, blood urea nitrogen (BUN), serum creatinine(SCr), and estimated glomerular filtration rate (eGFR) were observed at different time points. And the difference in therapeutic effects were compared between the two groups. RESULTS: Compared with the control group after 6 months of treatment, 24 h urine protein obviously decreased in the treated group (P <0. 05). There was no statistical difference in SCr, BUN, or eGFR between the two groups after 6 months of treatment (P >0. 05). The total effective rate after 2, 4, and 6 months of treatment in the treated group was 77. 6% (66/85 cases), 82. 4% (70/85 cases), and 89. 4% (76/85 cases), respectively. They were 47. 2% (17/36 cases), 55. 6% (20/36 cases), and 61. 1% (22/36 cases) in the control group, respectively. Compared with before treatment in the treated group, the total effective effect after 6 months of treatment was higher than that after 2 months of treatment (chi2=4. 28, P <0. 01). Compared with the control group at the same time points, the total effective rate in the treated group after 2, 4, and 6 months of treatment was higher (chi2=10. 87, 9. 53, 13.16, P <0. 01). CONCLUSION: YQHR could significantly lower proteinuria in chronic glomerular disease patients with PSDCDHS, improve the clinical effect, thereby providing clinical evidence for treating chronic glomerular disease proteinuria from resolving dampness and clearing heat. PMID- 26591356 TI - [Correlation Study on Pathological Characteristics of Target Organs and Excess Evil Syndrome in IgA Nephropathy]. AB - OBJECTIVE: To explore the correlation between pathological characteristics of target organs and excess evil syndrome in IgA nephropathy. METHODS: Data were collected in multicenter cooperation. Totally 266 IgA nephropathy patients were typed into exogenous wind-heat affection syndrome (49 cases), lower energizer damp-heat syndrome (100 cases), damp-phlegm syndrome (43 cases), and blood stasis syndrome (74 cases). Meanwhile, percutaneous renal biopsy was performed in all patients for Hass classification, Oxford classification, Katafuchi integral, and Jiang's classification methods. The correlation between excess evil syndrome and pathological index was analyzed. RESULTS: Four syndrome types were correlated with their Hass levels (r = 0. 341, P <0. 01). Affection of exogenous wind-heat syndrome was correlated with segmental proliferation of endothelial cells and damaged active lesions of segmental capillary loops. Lower-energizer damp-heat syndrome was associated with Hass III level, destroying active lesions of capillary loops, segmental proliferation of endothelial cells, glomerular segmental lesions, focal interstitial infiltration of inflammatory cells, focal interstitial fibrosis and tubular atrophy. Blood stasis syndrome was associated with Hass IV level, glomerular sclerosis, segmental glomerulosclerosis (S)/adhesion, mesangial hypercellularity (M), angiohyalinosis, multi-foci interstitial infiltration of inflammatory cells, multi-foci interstitial fibrosis and tubular atrophy. Phlegm-damp syndrome had higher proportions of Hass I and III levels, but with no association with other pathological parameters. CONCLUSIONS: Excess evil syndrome was associated with partial pathological characteristics of IgA nephropathy. It could reflect pathological damage degree of target organs, activities, chronic lesions, and prognosis of IgA nephropathy to certain extent. Correlated pathological characteristics and its evolution could indicate excess evil syndrome types and their evolution rules. PMID- 26591357 TI - [Treatment of Asthenozoospermia Men with Shen-essence Deficiency Syndrome by Yishen Zhongzi Pill: a Clinical Study]. AB - OBJECTIVE: To observe the effect of Yishen Zhongzi Pill (YZP) on the sperm motility of Shen-essence deficiency syndrome (SEDS) patients. METHODS: Totally 144 patients were randomly assigned to the treatment group (71 cases) and the control group (73 cases). Ten cases dropped out during the therapeutic course. A total of 134 patients completed this clinical study, 67 in each group. Patients in the treatment group took YZP (6 g each time, twice daily), while those in the control group took Wuzi Yanzong Pill (6 g each time, twice daily). The therapeutic course for all was one month. Changes of the sperm motility, clinical efficacy, and Chinese medical symptoms scores were observed between the two groups before and after treatment. RESULTS: Compared with before treatment in the same group, percentages of class a spermatozoa and class a + b spermatozoa were enhanced in the two groups after treatment (P <0. 01). Besides, they were higher in treatment group than in the control group (P <0. 05). The total effective rate of the treatment group was 77. 61 % (52/67 cases), while it was 58. 21 % (39/67 cases) in the control group. It was better in the treatment group than in the control group (Z= -2. 914, P =0. 004). Compared with before treatment in the same group, scores for Chinese medical symptoms decreased in the two groups (P <0. 01). The difference of pre-post integrals was higher in the treatment group than in the control group (P <0. 01). CONCLUSION: YZP showed favorable effect in treating asthenospermia patients with SEDS and could effectively elevate the motility of sperm. PMID- 26591358 TI - [Effects of Wenyang Huazhuo Tongluo Recipe Containing Serum on Transforming Growth Factor beta1/ Smad Signaling Pathway of Skin Fibroblasts in Systemic Sclerosis]. AB - OBJECTIVE: To explore the effects of Wenyang Huazhuo Tongluo Recipe (WYHZTLR) containing serum on transforming growth factor beta1 (TGF-beta1)/Smad signaling pathway of skin fibroblasts in systemic sclerosis (SSc). METHODS: Totally 36 SSc patients were randomly assigned to Chinese medicine (CM) group, Western medicine (WM) group, and integrative medicine (IM) group according to random digit table, 12 in each group. Patients in the CM group took WYHZTLR decoction (one dose per day). Patients in the WM group took penicillamine tablet (0. 125 g each time, bid) and Prednisone Acetate Tablet (PAT 20 mg, qd). Patients in the IM group took penicillamine, PAT, and WYHZTLR decoction (in the same dosage of corresponding drugs as aforesaid). All patients were treated for one month to get drug containing serum. Besides, 10 untreated SSc patients' serum was taken as the control group. Healthy subjects' skin fibroblasts were originated from healthy skin tissue of the upper arms of 2 female patients undergoing plastic surgery. Corresponding serum of each group was added in the culture system of SSc patients' and healthy subjects' dermal fibroblasts respectively. Expression levels of TGF-beta1 receptor type I (TGF-beta1 RI), TGF-beta1 receptor II (TGF beta1 RII), p-Smad2/3 and Smad7 protein were examined by Western blot. Expression levels of collagen type I and collagen type III (Col-I, Col-III) mRNA were examined by reverse transcription PCR. Contents of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinases-1 (TIMP-1) in the supernatant of SSc, skin fibroblasts were examined by ELISA. RESULTS: Compared with the control group, expression levels of TGF-beta1 R I and p-Smad2/3 protein significantly decreased, but expression levels of Smad7 protein significantly increased in skin fibroblasts of SSc patients and healthy subjects of WM, CM, and IM groups (P <0.05, P <0. 01). Meanwhile, the expression level of TGF-beta1 RII decreased in the IM group (P <0. 05, P <0. 01). Compared with the WM group, expression levels of TGF-beta1 RI and p-Smad2/ 3 protein significantly decreased, but that of Srnad7 protein significantly increased in IM groups (P <0. 01). mRNA expression levels of Col-I and Col-II in SSc skin fibroblasts significantly decreased more in WM, CM, and IM groups than in the control group (P <0. 05, P <0. 01). Besides, the expression level of Col-III mRNA was significantly lower in the IM group than in the WM group (P <0.01). Compared with the control group, serum levels of MMP-9 and MMP-9/TIMP-1 ratios increased more obviously in WM, CM, and IM groups (P <0.05, P <0.01). But expression levels of TIMP-1 decreased significantly in CM and IM groups (P <0.01). Expression levels of MMP-9 and MMP 9/TIMP-1 ratios increased more in the IM group than in the WM group (P <0. 01). Expression levels of TIMP-1 decreased more in CM and IM groups than in the WM group (P <0.01). CONCLUSION: WYHZTLR containing serum could reduce expression levels of Col-I and Col-III possibly through regulating key signal molecules, such as TGF-beta1 RI, p-Smad2/3, and Smad7 in TGF-beta1/Smad signaling pathway of SSc skin fibroblasts, and inhibiting transduction of TGF-beta1/Smad signaling pathway. PMID- 26591359 TI - [Effect of Xinfeng Capsule on Lipoprotein Metabolism of Rheumatoid Arthritis Patients]. AB - OBJECTIVE: To explore the effect of Xinfeng Capsule (XC) on lipoprotein metabolism of rheumatoid arthritis (RA) patients. METHODS: Totally 180 RA patients were assigned to the experimental group and the control group by random digit table, 90 in each group. Patients in the experimental group took XC (three pills each time, three times daily), while those in the control group took Methotrexate Tablet (four tablets each time, once per week). One month consisted of one therapeutic course and all patients were treated for two therapeutic courses. A healthy control group consisting of 60 patients was also set up. Changes of lipoprotein indices, clinical efficacy, lipid metabolism, joint symptoms and signs, activity indicators were observed, and correlation analyses were performed. RESULTS: Compared with the healthy control group, expression levels of prealbumin (PA), globulin (GLO), high-density lipoprotein (HDL), apolipoprotein Al (Apo-A1) were lowered in RA patients (P <0. 05, P <0. 01). Correlation analyses showed that PA was negatively correlated with joint tenderness, morning stiffness time, disease activity score (DAS-28), C-reactive protein (CRP), interleukin (IL)-6, respectively. Total protein (TP) was negatively correlated with joint tenderness. GLO was negatively correlated with joint tenderness and DAS-28. HDL was negatively correlated with erythrocyte sedimentation rate (ESR) and endothelin (ET)-1. Apo-Al was negatively correlated with joint pain; Apo-B was negatively correlated with CRP; LDL was negatively correlated with morning stiffness time (P <0. 05, P <0. 01). Compared with before treatment, expression levels of PA, HDL, Apo-A1 , Apo-B, and serum IL-10 contents increased, and expression levels of ESR, CRP, IL-6, ET-1 , joint pain, joint swelling, morning stiffness time, and DAS-28 decreased in the experimental group (P <0. 05, P <0. 01). PA increased more after treatment than before treatment in the control group (P <0. 01). There was statistical difference in joint symptoms (except joint tenderness) and activity indices (except ET-1) in the control group (P <0. 05, P <0. 01). Compared with the control group after treatment, PA and HDL increased, ET-1 and duration of morning stiffness decreased in the experimental group (all P <0. 05). CONCLUSIONS: Lipoprotein metabolic disorder exists in RA patients, and it is associated with disease activity. XC could obviously improve lipoprotein metabolism and joint symptoms. PMID- 26591360 TI - [Treating Elderly Coronary Heart Disease Patients by Different Approaches of Percutaneous Coronary Intervention: an Observation of Clinical Efficacy]. AB - OBJECTIVE: To observe thee efficacy of different ways of percutaneous coronary intervention (PCI) for treating elderly coronary heart disease (CHD) patients. METHODS: Totally 470 elderly CHD patients were classified to three age brackets (equal to or more than 85 years old, 60 to 74 years old, 75 to 84 years old). They were assigned to the transradial intervention (TRI) group (236 cases) and the transfemoral intervention (TFI) group (234 cases) according to different intervention pathways. Correlated indices and postoperative clinical efficacy were compared between the two groups. RESULTS: A higher successful rate of surgery was obviously got in patients 85 years old or older than 85 than in those 60 to 74 years old and 75 to 84 years old (P <0. 05). The incidence of major cardiovascular events (MACE) was reduced at post-operative 12 and 24 months in patients 85 years old or older than 85 (P <0. 05). The case number for changing intervention pathway were increased in the TRI group with statistical difference (P <0. 05). Compared with the TFI group, the case number for changing intervention pathway was increased; the time for arteriopuncture, the time for catheterization, and the time for X-ray exposure were prolonged; the time for postoperative bedding were obviously shortened; the incidence of vascular complications at the puncture site were lowered. The incidence of postoperative 12-month MACE was lowered, all with statistical difference (all P <0. 05). The incidence of MACE within postoperative 24-month MACE decreased in patients 60 to 74 years old and 75 to 84 years old (P <0. 05). The incidence of MACE within postoperative 24 months increased in patients 85 years old or older than 85 of the TRI group with statistical difference (P <0. 05). CONCLUSION: TRI can be preferably chosen for PC in treating elderly CHD patients. PMID- 26591361 TI - [Treating Cancer-related Fatigue after Chemotherapy in Lung Cancer Patients by Yiqi Jianpi Recipe: a Clinical Study]. AB - OBJECTIVE: To evaluate the clinical efficacy of Yiqi Jianpi Recipe (YJR) in treating cancer-related fatigue (CRF) after chemotherapy in lung cancer patients. Methods Totally 124 lung cancer patients were assigned to the treatment group (63 cases) and the control group (61 cases) according to random digit table. All patients received pre-set chemotherapy regimens according their conditions. Patients in the treatment group took YJR Decoction from the 1st day of chemotherapy, one dose per day for 2 successive weeks, while those in the control group took no Chinese medical decoction. Changes of each dimensional scoring and the total scoring were observed by cancer fatigue scale (CFS) in the two groups one day before chemotherapy, on the 3rd day and the 14th day after chemotherapy. The degree of bone marrow depression and recombinant human granulocyte colony stimulating factor (rhG-CFS) doses were also observed after chemotherapy. RESULTS: Compared with one day before chemotherapy in the same group, scorings for emotional, perceptional, and somatologic dimensions, and the total scoring significantly increased on the 3rd day in the treatment group, as well as on the 3rd and the 14th day in the control group (P <0. 01). Scorings for emotional, perceptional, and somatologic dimensions, and the total scoring significantly decreased more at the fourteenth day after chemotherapy than at the 3rd day after chemotherapy (P <0. 01). There was statistical difference in the scoring for perceptional dimension at day 3 between the treatment group and the control group (P <0.01). However, scorings for emotional, perceptional, and somatologic dimensions, and the total scoring significantly decreased more at the fourteenth day after chemotherapy in the treatment group, with statistical difference when compared with those in the control group (P <0. 01). The occurrence rate of bone marrow depression was 70. 97% (44/62) in the treatment group and 68. 85% (42/61) in the control group. There was no significant difference in the occurrence rate between the two groups (chi2=0. 540, P >0.05). There was no statistical difference in rhG-CFS doses between the two groups (chi2=0. 696, P >0. 05). CONCLUSION: YJD could significantly relieve CRF after chemotherapy in lung cancer patients, and obviously attenuate the effect of CRF on their daily life. PMID- 26591362 TI - [Clinical Application of Immune-related Response Criteria in Evaluating Chinese Medical Treatme for Advanced Non-small Cell Lung Cancer]. AB - OBJECTIVE: To evaluate the applicability of immune-related response criteria (irRC) in treating non-small cell lung cancer (NSCLC) by Chinese medicine (CM). METHODS: Totally 97 stage III a-IV NSCLC patients were predominantly treated with comprehensive CM. Curative effects were evaluated by three methods such as Response Evaluation Criteria in Solid Tumors (RECIST), Oncologic Curative Effect Evaluation Criteria of Chinese Medicine in Solid Tumor (draft, abbreviated as CM criteria), and irRC. The correspondency and consistency between irRC, RECIST and CM criteria were analyzed and compared. The objectivity of irRC in evaluating curative effect of Chinese medical treatment for NSCLC was assessed. RESULTS: The correspondency rate of irRC to RECIST was 59. 79% with Kappa value of 0. 379 (U test, P <0. 01). The two criteria had certain correspondence, but with an unsatisfactory consistency. The correspondency rate of irRC to CM criteria rate was 83. 51% with Kappa value of 0.751 (U test, P <0. 01). The two criteria had good correspondence and consistency. CONCLUSIONS: CM criteria had good consistency with CM criteria in evaluating curative effect for Chinese medical treatment of advanced NSCLC. Its results could objectively reflect features and advantages of CM for treating advanced NSCLC. PMID- 26591363 TI - [Application of Bayes Probability Model in Differentiation of Yin and Yang Jaundice Syndromes in Neonates]. AB - OBJECTIVE: To study the application of Bayes probability model in differentiating yin and yang jaundice syndromes in neonates. METHODS: Totally 107 jaundice neonates who admitted to hospital within 10 days after birth were assigned to two groups according to syndrome differentiation, 68 in the yang jaundice syndrome group and 39 in the yin jaundice syndrome group. Data collected for neonates were factors related to jaundice before, during and after birth. Blood routines, liver and renal functions, and myocardial enzymes were tested on the admission day or the next day. Logistic regression model and Bayes discriminating analysis were used to screen factors important for yin and yang jaundice syndrome differentiation. Finally, Bayes probability model for yin and yang jaundice syndromes was established and assessed. RESULTS: Factors important for yin and yang jaundice syndrome differentiation screened by Logistic regression model and Bayes discriminating analysis included mothers' age, mother with gestational diabetes mellitus (GDM), gestational age, asphyxia, or ABO hemolytic diseases, red blood cell distribution width (RDW-SD), platelet-large cell ratio (P-LCR), serum direct bilirubin (DBIL), alkaline phosphatase (ALP), cholinesterase (CHE). Bayes discriminating analysis was performed by SPSS to obtain Bayes discriminant function coefficient. Bayes discriminant function was established according to discriminant function coefficients. Yang jaundice syndrome: y1= -21. 701 +2. 589 x mother's age + 1. 037 x GDM-17. 175 x asphyxia + 13. 876 x gestational age + 6. 303 x ABO hemolytic disease + 2.116 x RDW-SD + 0. 831 x DBIL + 0. 012 x ALP + 1. 697 x LCR + 0. 001 x CHE; Yin jaundice syndrome: y2= -33. 511 + 2.991 x mother's age + 3.960 x GDM-12. 877 x asphyxia + 11. 848 x gestational age + 1. 820 x ABO hemolytic disease +2. 231 x RDW-SD +0. 999 x DBIL +0. 023 x ALP +1. 916 x LCR +0. 002 x CHE. Bayes discriminant function was hypothesis tested and got Wilks' lambda =0. 393 (P =0. 000). So Bayes discriminant function was proved to be with statistical difference. To check Bayes probability model in discriminating yin and yang jaundice syndromes, coincidence rates for yin and yang jaundice syndromes were both 90% plus. CONCLUSION: Yin and yang jaundice syndromes in neonates could be accurately judged by Bayesian discriminating functions. PMID- 26591364 TI - [Anti-atherosclerotic Effects of Bear Bile Powder in Shexiang Tongxin Dripping Pill: a Mechanism Study]. AB - OBJECTIVE : To study the anti-atherosclerotic mechanism of bear bile powder (BBP) in Shexiang Tongxin Dripping Pill (STDP) , and to provide scientific evidence for treating atherosclerosis (AS) by its therapeutic characteristics of cool resuscitation. METHODS: AS model was duplicated using ApoE-/- gene knocked mice fed with high-fat diet. Thirty ApoE-/- deficient male mice were divided into four groups according to body weight using random digit table, i.e., the model group (A, n =9), the STDP group (B, n=E7), the STDP without BBP group (C, n =7), and the BBP group (D, n =9). Besides, another 9 C57BL/6J male mice of the same age were recruited as a normal control group (E). All mice in Group B, C, and D were respectively administered with corresponding drugs (30, 30, and 0. 33 mg/kg) by gastrogavage. Equal volume of normal saline was administered to mice in Group A and E. All medication lasted for 8 successive weeks. Serum levels of inflammatory cytokines such as interleukin 2 (IL-2), interleukin 6 (IL-6), tumor necrosis factor a (TNF-alpha), interferon y (IFNgamma), and oxidized low-density lipoprotein (ox-LDL) were measured by ELISA. Serum levels of malondialdehyde (MDA), activities of glutathione (GSH) and superoxide dismutase (SOD) were determined using biochemical assay. Contents of reactive oxygen species (ROS) in the aortic root was detected by dihydroethidum (DHE) fluorescent probe. Expression levels of microRNAs (such as miR-20, miR-21, miR-126, and miR-155) were detected by real-time PCR. RESULTS: The fluorescence intensity of the aorta was obviously enhanced in Group A. But it was obviously attenuated in Group B, C, and D, and the attenuation was the most in Group B. Compared with Group E, serum levels of IL-2, IL-6, TNF-alpha, IFN-gamma, oxLDL, and MDA all increased (P <0. 01), GSH contents and SOD activities decreased (P <0. 01), expression levels of miR-126, miR-21, and miR-155 in aorta increased (P <0. 01), and the expression level of miR-20 decreased in Group A (P<0. 01). Compared with Group A, serum levels of IL-2, IL-6, TNF-alpha, IFN-gamma, oxLDL, and MDA were all down regulated (P <0. 01), GSH contents and SOD activities were up-regulated (P <0. 01), expression levels of miR-126, miR-21, and miR-155 in aorta were down regulated in Group B, C, and D (P <0. 01). The expression level of miR20 was up regulated in Group B and D (P <0. 01). Compared with Group B, serum levels of IL 2, IL-6, TNF-alpha, IFN-gamma increased (P <0.01); GSH contents and SOD activities decreased, levels of MDA and oxLDL increased (P <0. 01) in Group C and D. Expression levels of miR-20 and miR-155 were down-regulated in Group C and D (P <0. 01). CONCLUSIONS: STDP played roles in significantly regulating inflammatory factors and oxidative stress factors. Its mechanism might be possibly associated with regulating expressions of miR-126, miR-21, miR-155, and miR-20 in aorta. BBP played significant roles in STDP. PMID- 26591365 TI - [Protective Effects of Cornus Officinalis Total Glycosides and Cornus Polysaccharides on Myocardial Mitochondria of Acute Myocardial Infarction Rats: an Experimental Study]. AB - OBJECTIVE: To observe the effect of Cornus Officinalis total glycosides (COTG) and Cornus polysaccharides (CP) on myocardial mitochondria and expression levels of glycogen synthase kinase-3beta (GSK-3beta) of acute myocardial infarction (AMI) rats. METHODS: The AMI rat model was established by ligating the left anterior descending branch of coronary artery. Rats were divided into 5 groups according to random digit table, i.e., the sham-operation group, the model group, the COTG prevention group, the CP treatment group, the COTG treatment group, 12 in each group. Normal saline was administered to rats in the normal control group and the model group by gastrogavage. Corresponding medication was respectively administered to rats in the rest 3 groups by gastrogavage. The cardiac function was detected by echocardiography and hemodynamics. The infarct size was determined by Masson trichrome staining. The expression of mitochondrial biogenesis genes such as a subunit of peroxisome proliferators-activated receptor gamma coactivator-1 (PGC-1alpha), PGC-1beta, nuclear respiratory factor-1 (NRF 1), and GSK-3P mRNA were detected by Real-time PCR. RESULTS: Compared with the sham-operation group, the myocardial infarction size increased, cardiac function decreased, the expression of PGC-1alpha, PGC-1beta, and NRF-1 mRNA decreased, and the expression of GSK-3beta mRNA increased (all P <0. 05). Compared with the model group, myocardial infarction sizes were reduced, cardiac function was improved, the expression of NRF-1 mRNA was elevated in the COTG prevention group, the CP treatment group, the COTG treatment group; the expression of the PGC 1alpha and PGC-1beta mRNA was elevated in the COTG prevention group and the CP treatment group; the expression of GSK-3beta mRNA was reduced in the CP treatment group (all P <0. 05). Compared with the CP prevention group, fractional shortening (FS) and aortic systolic blood pressure (SBP) increased in the CP treatment group; ejection fraction (EF) decreased in the CP treatment group; the expression of PGC-1alpha, PGC-1beta, NRF-1 mRNA were reduced in the the CP treatment group and the COTG treatment group; the expression of GSK-3beta mRNA decreased in the CP treatment group (all P <0. 05). Compared with the COTG treatment group, FS, EF, left ventricular end systolic pressure (LVESP), SBP, and the expression of GSK-3beta mRNA were reduced in the CP treatment group (P <0. 05). CONCLUSIONS: COTG and CP could improve cardiac function, reduce the myocardial infarction area, and promote biogenesis of myocardial mitochondria. Their protective effects on the mitochondria of cadiocytes might be achieved by GSK-3beta signalina pathway. PMID- 26591366 TI - [Yinxingye Capsule Intervened Vascular Endothelial Cell Apoptosis of Hyperhomocysteinemia Rats: an Experimental Study]. AB - OBJECTIVE: To explore targets of Chinese herbal medicine at cellular and molecular leve1s through an experimental study on Yinxingye Capsule (YC) intervening vascular endothelial cell apoptoeis of hyperhornocysteinemia (HHcy) rats. METHODS: The HHcy model was prepared in male Wistar rats. Totally 42 rats were randomly divided into 4 groups, i.e., the control group (n =10), the model group (n = 11), the YC group (n =11), the folic acid group (n =10). Carboxy methyl cellulose (CMC) solution (1%) was administered to rats in the control group by gastrogavage.3% methionine suspension at 1. 5 g/kg was administered to rats in the model group by gastrogavage. 3% methionine suspension at 1. 5 g/kg and folic acid suspension at 0. 06 g/kg was administered to rats in the folic acid group by gastrogavage. 3% methionine suspension at 1. 5 g/kg and YC at 0. 02 g/kg was administered to rats in the YC group by gastrogavage. Morphological changes of aortic tissue were observed by hematoxylin eosin (HE) staining. The plasma homocysteine (Hcy) level was detected in each group. The endothelium dependent diastolic functions of the thoracic aorta on different concentrations of sodium nitroprusside (SNP) and acetylcholine (Ach) were detected. Gene expressions of Bcl-2-associated X protein (BAX), inducible nitric oxide synthase (iNOS), c-Fos, cellular inhibitor of apoptosis protein 2 (c-IAP2) were detected by real time polymerase chain reaction (RT-PCR). RESULTS: Pathological results showed that thickening aortic endothelium, swollen and desquamated endothelial cells. Few foam cells could be seen in the model group. Myoma-like proliferation of smooth muscle cells in tunica media could also be seen. These pathological changes were milder in the YC group and the folic acid group. Compared with the control group, plasma Hcy levels increased in the model group (P <0. 05). The endothelium-dependent diastolic rates at 10(-6) and 10(-4)mol/L Ach and 10(-7) 10(-3)mol/L SNP all decreased in the model group (P <0. 01, P <0. 05). Gene expressions of Bax, c-Fos, and iNOS increased, but c-IAP2 gene expressions decreased in the model group (all P <0. 05). Compared with the model group, plasma Hcy levels decreased in the YC group and the folic acid group (P <0. 05). The endothelium-dependent diastolic rates increased in the YC group and the folic acid group at various SNP concentrations except 10(-6) mol/L SNP in the folic acid group. The endothelium-dependent diastolic rates increased in the YC group and the folic acid group at 10(-6) and 10(-4)mol/L Ach (all P <0. 05). Gene expressions of Bax, c-Fos, and iNOS decreased in the YC group and the folic acid group, but c-IAP2 gene expression increased in the folic acid group (all P <0. 05). CONCLUSION: YC could reduce plasma Hcy levels, down-regulate gene expressions of Bax, c-Fos, and iNOS, thereby reducing apoptosis of vascular endothelial cells, improving vascular endothelial function, and delaying atherosclerotic process. PMID- 26591367 TI - [Formula Optimization in Renshen Jianxin Capsule Based on Uniform Design and Anti myocardial Ischemia Effect]. AB - OBJECTIVE: To realize quadratic formula optimization of Renshen Jianxin Capsule (RJC) by screening Chinese herbs with major anti-myocardial ischemia effect in RJC and optimize their optimal dosages. METHODS: By following "uniform design pharmacodynamic experiment-mathematical modeling-formula optimization", authors employed U10(10(8)) uniform design in the experiment. Eight Chinese herbs contained in RJC were taken as observatory factors. Electrocardiograph (ECG) changes of myocardial ischemia induced by isoproterenol were taken as pharmacodynamic indices. The mathematical model between herbal factors and pharmacodynamic indices was established using stepwise regression analysis to screen Chinese herbs with major anti-myocardial ischemia effect. Their optimal dosages were optimized using the grid algorithm. RESULTS: The regression equation was y =1. 7889 -0. 3247 Ginseng xSalvia Miltiorrhiza -0. 0663 Astragalus membranaceus xOriental Waterplantain tuber. Forecasting factors included were Ginseng, Salvia Miltiorrhiza, Astragalus membranaceus, and Oriental Waterplantain tuber. The optimal formula dosage calculated by the grid algorithm was Ginseng 1. 62 g, Astragalus membranaceus 4. 62 g, Salvia Miltiorrhiza 2. 43 g, and Oriental Waterplantain tuber 1. 66 g. CONCLUSION: Uniform design combined with stepwise regression analysis and grid algorithm were able to realize quadratic formula optimization of RJC. PMID- 26591368 TI - [Adenosine Al Receptor Mediated Neuroprotection of Shenmai Injection on Rat Cerebral Ischemia/Reperfusion Injury: an Experimental Study]. AB - OBJECTIVE: To observe whether adenosine Al receptor (Al R) mediated neuroprotection of Shenmai Injection (SI) on rat cerebral ischemia/reperfusion (I/R) injury. METHODS: The focal cerebral I/R model was established by middle cerebral artery occlusion (MCAO). Totally 60 successfully modeled rats was divided into 5 groups according to randomized block principle, i.e., the model group, the SI group, the SI + AlR antagonist (1,3-dipropyl-8-cyclopentylxanthine, DPCPX) group, the AlR antagonist control group, and the dimethyl sulfoxide (DMSO) control group, 12 in each group. Besides, a sham-operation group was set up (n =12). SI at 15 mL/kg was peritoneally injected to mice in the SI group immediately after cerebral I/R. Equal volume of normal saline was injected to mice in the model group and the sham-operation group. DPCPX at 1 mg/mL was peritoneally injected to mice in the Al R antagonist control group 30 min before peritoneal injecting SI. DPCPX at 1 mg/kg and DMSO at 1 mL/kg were peritoneally injected to mice in the AlR antagonist control group and the DMSO control group 30 min immediately before cerebral I/R. Rats' neurobehavioral scores were assessed after 24 h reperfusion. The volume of cerebral infarction and Bcl-2 protein expression of cerebral infarction penumbra were also detected. Results Compared with the sham-operation group, neurobehavioral scores, the volume of cerebral infarction, and Bcl-2 protein expression increased (all P <0. 05). Compared with the model group, neurobehavioral scores and the volume of cerebral infarction obviously decreased, but Bcl-2 protein expression increased in the SI group (all P <0. 05). Compared with the SI group, neurobehavioral scores increased, the volume of cerebral infarction was obviously enlarged, and Bcl-2 protein expression was obviously reduced in the A1R antagonist control group (all P <0. 05). CONCLUSIONS: SI's neurobehavioral scores could be partially reversed in the Al R antagonist control group, the volume of cerebral infarction and Bcl-2 protein expression improved. AlR might possibly meditate neuroprotection of SI on MACO mire PMID- 26591369 TI - [Effect of Jianpi Yangzheng Xiaozheng Recipe on Apoptosis and Autophagy of Subcutaneous Transplanted Tumor in Nude Mice: an Experimental Study on Mechanism]. AB - OBJECTIVE: To observe the effect of Jianpi Yangzheng Xiaozheng Recipe (JYXR) on the tumor inhibition rate of subcutaneous transplanted tumor gastric cancer cell line MGC-803 in BALB/c nude mice, and to study its molecular mechanism of apoptosis and autophagy. METHODS: Gastric cancer cell line MGC-803 was subcutaneously inoculated to nude mice for preparing transplanted gastric cancer models. Totally 32 BALB/c nude mice were randomly divided into 4 groups according to random digit table, i.e., the negative control group, the positive control group, the high dose JYXR group, the low dose JYXR group, 8 in each group. Normal saline was administered to mice in the negative control group by gastrogavage. 5 fluorouracil (5-Fu) at 2. 5 mg/kg was administered to mice in the positive control group by gastrogavage. JYXR at 85 and 43 g/kg was administered to mice in the high dose JYXR group and the low dose JYXR group by gastrogavage, once per day for 10 successive days. The effect of JYXR on the tumor inhibition rate of subcutaneous transplanted tumor was observed. Effects of JYXR on gene expression levels of Bax, Bcl-2, Fas, Cyclin D1, Cyclin D2, and Cyclin D3 in transplanted tumor were observed by real-time PCR. Effects of JYXR on protein expression levels of Procaspase-3, Procaspase-8, Procaspase-9, cleaved-PARP, Beclin-1, and LC3B were detected using Western blot. RESULTS: (1) Compared with the negative control group, the tumor weight was obviously reduced in the rest three groups (P <0. 05). The tumor weight was higher in the high dose JYXR group and the low dose JYXR group than in the positive control group (P <0. 05). (2) Results of RT-PCR indicated that, compared with the negative control group, expression levels of Bax were up-regulated, but expression levels of Bcl-2, Cyclin D1, Cyclin D2, and Cyclin D3 were down-regulated in the positive control group and JYXR groups (P <0. 05). The expression level of Fas was up-regulated in the positive control group and the high dose JYXR group (P <0. 05). Compared with the positive control group, expression levels of Fas, and Bax were all down-regulated, but expression levels of Bcl-2, Cyclin D2, and Cyclin D3 were all up-regulated in the high dose JYXR group and the low dose JYXR group (all P <0. 05). The expression level of Cyclin D1 was down-regulated in the high dose JYXR group, but it was up-regulated in the low dose JYXR group ( both P <0. 05). (3) Results of Western blot showed, compared with the negative control group, expression levels of Procaspase-3, Procaspase-8, and Procaspase-9 were down-regulated, but expression levels of cleaved-PARP, Beclin-1, and LC3B II were up-regulated in the high dose JYXR group and the low dose JYXR group (all P <0.05). Compared with the negative control group, expression levels of Procaspase-3, Procaspase-8, Procaspase-9, and LC3B II were down-regulated, but expression levels of cleaved-PARP, Beclin-1, and LC3B I were up-regulated in the positive control group (all P <0. 05). CONCLUSIONS: JYXR showed significant inhibition on subcutaneous transplanted tumor gastric cancer cell line MGC-803 in BALB/c nude mice. Its mechanism might be associated with activating apoptosis and autophagy correlated factors. PMID- 26591370 TI - [Effect of Jiakangning Capsule on Thyroid Function and Akt/mTOR Signal Pathway of Graves' Disease Mice: an Experimental Study]. AB - OBJECTIVE: To observe the improvement of thyroid function and changes of Akt, p Akt, mammalian target of rapamycin (mTOR), and para-mTOR (p-mTOR) expression in Graves' disease (GD) mice after intervened by Jiakangning Capsule (JC), and to explore possible mechanism for JC in treating GD. METHODS: GD model was established by immunizing female BALB/c mice with thyroid stimulating hormone receptor A subunit (Ad-TSHRalpha-289). Totally 70 successfully modeled mice were divided into the model group (n =20), the JC intervened group (n =25), the Methimazole Tablet intervened group (n =25) according to random digit table. A normal control group (n =15) and a vehicle control group (n =20, injected with Ad null) were also set up. Mice in the JC intervened group were administered with JC suspension at the daily dose of 1. 5 g/kg by gastrogavag. Mice in the Methimazole intervened group were administered with Methimazole suspension at the daily dose of 2. 5 g/kg by gastrogavage. Equal volume of normal saline was administered to mice in the rest 3 groups by gastrogavage. All intervention lasted for 5 weeks. Six mice were selected from each group to observe pathological changes of thyroid tissues. Serum levels of thyroxine (T4), triiodothyronine (T3), thyroid stimulating hormone (TSH), and thyrotropin receptor antibody (TRAb) were analyzed by radioimmunoassay. Expression levels of Akt, p-Akt, mTOR, and p-mTOR in thyroid tissues were etermined by Western blot. RESULTS: (1) The thyroid gland in the GD model group showed proliferative changes, with enlarged follicles of various sizes. Interstitial stroma was filled with blood vessels. Structures of thyroid tissues in the JC intervened group and the Methimazole intervened group were significantly restored, and follicular hyperplasia was relieved. (2) Compared with the normal control group and the vehicle control group, levels of TRAb, T4, and T3 increased; ratios of P-Akt/beta-actin, p-Akt/Akt, p-mTOR/beta-actin, and p mTOR/mTOR also increased in the model group (all P <0. 01). Compared with the model group, levels of TRAb, T4, and T3 decreased in the JC intervened group and the Methimazole intervened group (P <0. 01); ratios of p-mTOR/beta-actin and pmTOR/mTOR decreased in the JC intervened group (P <0.01); ratios of P-Akt/beta actin, p-Akt/Akt, p-mTOR/beta-actin, and p-mTOR/mTOR decreased in the Methimazole intervened group (P <0. 05, P <0. 01). Conclusion JC could reduce thyroid hormonc levels of GD mice and lower expression levels of mTOR, and its mechanism for improving thyroid function of GD mice might be associated with this influence. PMID- 26591371 TI - [On Diagnosis and Treatment of Constipation from Translational Medicine]. AB - Clinical diagnosis and treatment of constipation lags behind relatively with unsatisfactory efficacy. Pathogeneses and molecular mechanisms for different types of constipation are waiting to be further clarified. New biomarkers and therapeutic targets for clinical diagnosis of constipation are so urgent. As for current problems in diagnosis and treatment of constipation, it is necessary to use the concept of translational medicine to break existing imprisonment of thinking, and find out new thinking ways of research methods, diagnosis and treatment approaches, thereby improving diagnosis and treatment levels. PMID- 26591372 TI - [The name Tao that can be given is not the usual Tao--On English Translation of Tao in Huangdi Neijing]. PMID- 26591373 TI - [A Severe H7N9 Bird Flu Virus Patient Complicated Acinetobacter baumannii Infection: a Syndrome Analysis of One Case]. PMID- 26591374 TI - [Progress of Chinese Materia Medica in Treating Pregnancy Immune Tolerance]. PMID- 26591375 TI - [Progress of Symptoms Burden in Lung Cancer Patients]. PMID- 26591376 TI - [Summary of the 10th International Conference on Complementary Medicine Research, 2015]. PMID- 26591377 TI - [Summary of the 4th Integrative Medical Forum on Gastrointestinal Functions and Dynamic Diseases]. PMID- 26591378 TI - Impact of diet on 24-hour intragastric pH profile in healthy horses. AB - An electrode incorporated into a polyethylene hose was introduced under endoscopic control into the stomach of six fasting adult horses for long-lasting pH measurements. The intragastric pH was recorded every four seconds for a period of 24 hours. The Warmblood horses were assigned randomly to receive hay ad libitum (H group); 1.5 kg hay/100 kg BW/day and 1 kg concentrate/100 kg BW/ day (C group) or protocol C plus 75 g pectin-lecithin supplement/100 kg BW/day (P group). The horses were adapted to each diet for 14 days. The 24-hour median pH value for protocol H (2.69) was significantly lower compared to protocol C (3.35) and P (3.44) (p < 0.05). The horses in protocol P had a significant higher percentage (40.1 %) of 24-hour intragastric pH values >= 4 than in protocol C (36.2 %) or in protocol H (25.3 %) (p < 0.05). PMID- 26591379 TI - Multicentric T-cell lymphoma accompa- nied by infiltration of the peripheral and central nervous system in a fattening pig. AB - Multicentric lymphomas, usually of B-cell origin, are rather common neoplasms in pigs, which usually affect lymph nodes and different organ systems. An uncommon manifestation of malignant lymphoma represents neoplastic peripheral nerve involvement, which has been reported in human medicine. So far, only single cases of lymphoma with manifestation in peripheral nerves (known as neurolymphomatosis) without leukemic conversion have been mentioned in different animal species others than swine. The present case report describes the occurrence of a multicentric T-cell lymphoma in a fattening pig with marked leukocytosis. The pig was presented with symptoms of lethargy, weight loss, and fever. Bone marrow aspirate contained all stages of granulocytic and erythrocytic precursors, and a remarkable large number of eosinophiles and undifferentiated blasts. At necropsy, the carcass showed generalized lymphadenopathy and severe hepatosplenomegaly. Histological findings included neoplastic round cell infiltrations in lymph nodes, bone marrow, tonsils, lung, spleen, liver, kidneys, urinary bladder, small and large intestine, and meninges. Additionally, neoplastic cells were present in the sciatic and medial plantar nerve of the left hind leg. The diagnosis T-cell lymphoma was confirmed immunohistochemically. To the author's knowledge, this work represents the first report of peripheral nerve involvement in a pig with multicentric T-cell lymphoma accompanied by CNS involvement and leukemia. PMID- 26591380 TI - Comparison of selected haematological and biochemical indices and behaviour patterns of pheasant hens kept in different housing systems during the laying period. AB - Selected haematological and biochemical indices and behaviour patterns were monitored in cage-housed pheasant hens during the peak-of-lay egg laying period. Lower counts of monocytes (p = 0.035) and concentrations of plasma biopterin (p = 0.020) and higher concentrations of plasma neopterin (p = 0.005) and plasma phosphorus (p = 0.025) were found in spectacles-fitted pheasant hens kept in conventional cages compared to non-spectacled hens kept in enriched cages. Even more pronounced effects of the housing system were revealed by analysis of the behaviour of pheasant hens: spectacles-fitted pheasant hens kept in conventional cages exhibited higher occurrences of movement (p = 0.045), stereotyped behaviour (p = 0.039), and aggression (p = 0.004), and lower rates of feeding (p = 0.009), drinking (p < 0.001), defecation (p = 0.038), preening (p = 0.013), and feather pecking (p < 0.001). Our results show that the relatively easy and inexpensive enrichment of the cage environment (two perches, a simple hideout) where breeding groups of common pheasants are housed during the laying period can significantly contribute to the health and welfare (including the ability to express natural behaviour patterns) of pheasants kept in commercial cage systems. PMID- 26591381 TI - [Treatment of Tritrichomonas foetus in a cat colony with delayed release ronidazole tablets in the small intestine]. AB - Seven abyssinian cats (two male, five female) showed intermittent green-yellow mucous diarrhoea, sometimes an inflammation of the anal region and faecal incontinence even after long-time treatment with fenbendazole against Giardia. During necropsy of one of the cats, which had to be euthanized due to another disease, the gut wall of small and large intestine appeared macroscopically thickened. Histological examination indicated flagellates in the lumen of the intestine (initiating at the jejunum) and in the crypts. However Giardia could be excluded. in this case. By PCR of the faeces Tritrichomonas (T) foetus was diagnosed in five of six cats of this colony. Five remaining animals (another cat had to be euthanized) were treated with about 30 mg per kg BW ronidazole p. o. (rededication; Ridzol 10% Bt(r), Dr. Hesse Tierpharma GmbH & Co. KG, Germany) daily over 14 days. The special gastro-resistant processing of the ronidazole should ensure a targeted effects. Animals were treated consecutively, isolated from the other cats and were daily examined clinically and neurologically. Neurotoxic adverse effects appeared slightly, therefore--as a precaution--the treatment of two cats was paused for one day. After treatment of all cats, T. foetus wasn't diagnosed by PCR over the period of 345 to > 800 days in any cat. One animal had dubious findings in the ninth week after treatment. Hence it was still kept isolated from the group and PCR showed a negative result at all times afterwards. The treatment protocol shows that elimination of problematic protozoal infections is possible in cat colonies. PMID- 26591382 TI - Associations between Mycobacterium paratuberculosis sero-status, milk quality parameters, and reproduction in dairy cows. AB - The objective of this study was to investigate the influence of Mycobocterium avium subsp. paratuberculosis (MAP) sero-status of dairy cows on different milk production variables and reproductive traits. The study was carried out on 40 herds from the region of Galicia (North-West Spain). These herds were randomly selected from a larger group that had taken part in a voluntary paratuberculosis control program since 2005, which involves regular serum sampling of every adult animal to run antibody-ELISA tests. Milk production and reproductive data were obtained from the "Dairy Herd Improvement Program (DHIP) of Galicia". All the gathered data were processed following a linear regression model. Results indicated that there was no significant effect of MAP sero-status on individual milk production variables. However, a significant difference was observed at the calving-to-first-insemination interval, with an average increase of 14 days in positive animals compared to negatives. It has to be taken into consideration that the paratuberculosis status was only defined by the serological status. Since para tb-infected animals may have antbodies or may not, para tb-positive animals can also be included in the sero-negative group of animals, which may bias the results. PMID- 26591383 TI - [Evaluation of an immunochromatographic dipstick test for the assessment of tetanus immunity in horses]. AB - Knowledge of tetanus immunity in equine patients is crucial in cases of injuries, elective surgeries, or when effective vaccination protocols are to be designed. The Fassisi(r) TetaCheck is a stall-side rapid test which was developed to address these issues. The purpose of the present study was to evaluate its performance parameters. To this end, the qualitative test results obtained by two blinded observers were compared to tetanus toxoid antibody levels from 99 serum samples, measured with a double antigen ELISA. Additionally the colour intensities of the test window were quantified using a camera and photo editing software. Assuming that the protective level of tetanus toxoid antibodies is >= 0.1 IE/ml, the tetanus quick stick (TQS) showed a sensitivity of 83.6% and a specificity of 100%. almost perfect (K = 0.88). Exchanging the observer did not affect the interpretation of theTQS (K = 0.80; K = 0.84). The definition of five distinct colour intensities of the "test window" enabled a clear differentiation of unprotected individuals from those with a protective immunity. There was a linear relationship between the objectively measured colour intensities and the tetanus toxoid antibody concentration (r2 = 0.74). The TQS thus proved to be a robust and reliable test in the stall-side assessment of tetanus immunity in horses. Its implementation in equine daily practice can help to avoid unnecessary immunizations in adult horses and therefore minimize vaccination side effects. PMID- 26591384 TI - [Causes, diagnostics and course of disease in 194 cats with anemia]. AB - Anemia is a common hematological alteration in cats. The objective of this study was to evaluate the frequency of different types of anemia and the course of disease in cats with a hematocrit (hct) < 0.26 l/l. In a period of 18 months 194 cats were included and assigned to different anemia groups based on history, physical examination and laboratory parameters. Most cats had acute blood loss anemia (BA; 75/194; 38.7%). Frequent causes were trauma (39/75), hematuria (13/75) and hemostatic disorders (9/75). Anemia of inflammatory and neoplastic disease (AID) occurred in 22.2% (43/194) and hemolytic anemia (HA) in 18% (35/194). Half of those were presumptively immune-mediated (IHA). Four cats were diagnosed with hemotropic mycoplasma infection. Rare causes of anemia included anemia of renal disease (ARD; 18/194; 9.3%) and intramedullary non-regenerative anemia (INR; 13/194; 6.7%). The latter either had retroviral infection (6/13) or neoplasia (6/13). In cats with HA and INR anemia was often severe and very severe (Hct < 0.14 l/l) and in cats with AID and ARD usually mild (Hct 0.20-0.25 l/l). Cats with BA had significantly lower total protein concentrations than those with INR (p = 0,001), HA, AID and CNE (p < 0,001) and those with HA most often had hyperbilirubinemia (21/27). Blood transfusions were primarily given to cats with BA (37/75) and HA (19/35), especially those with IHA (13/17). 69% of the patients survived the first 14 days after the anemia was detected for the first time. Cats with HA had the highest survival rate. PMID- 26591385 TI - Isolation and antimicrobial susceptibility of Streptococcus castoreus isolated from carcasses of European beavers (Castor fiber) in Germany. AB - Streptococcus (S.) castoreus was isolated from seven beavers (Castor fiber), which were found dead in the federal state of Brandenburg, Germany, and submitted to the Berlin-Brandenburg State laboratory for post mortem diagnostics. The isolates originated from various inflammatory processes where they were associated with other Gram negative and Gram positive aerobic and/or anaerobic bacteria (i. e. Actinobacillus sp., species of the Actinomycetaceae family, coliform bacteria, Fusobacterium sp., Prevotella sp.), but also from cloacal swabs. Testing their antimicrobial susceptibility, all S. castoreus isolates and the type strain S. castoreus (DSM 17536) were classified as being susceptible to penicillin G, ampicillin, amoxicillin-clavulanic acid, 1st generation cephalosporins, erythromycin, tetracycline, and chloramphenicole but intermediate to gentamicin. Considering both the polymicrobial flora isolated from the inflamed tissues and the fact that antimicrobials of a narrow spectrum (namely penicillins, 1st generation cephalosporins, macrolids and lincosamids) can be toxic to rodents, chloramphenicol might be a suitable drug for treatment of beavers suffering from S. castoreus (mixed)-bacterial infections. PMID- 26591386 TI - Tick-borne encephalitis in dogs: application of "nested real-time RT-PCR" for intravital virus detection. AB - Tick-borne encephalitis (TBE) virus is a tick-transmitted virus causing disorders of the nervous system in humans, monkeys, dogs and horses (rarely). At present the detection of TBE infection in dogs is performed by confirmation of seroconversion in paired samples of serum in clinical practice. The intention of the study was the assessment of the possible application of nested real-time RT PCR for detection of TBE virus in canine blood. The study was carried out in 2011 2012 using samples originating in the Czech Republic, South Moravian region (region with endemic occurrence of TBE). The dogs were randomly selected from the patients visiting the clinic during this time period. Of the total amount of 159 canine blood samples, 20 samples were tested with a PCR-positive result (12.6%). Out of these 20 animals, the neurological clinical symptoms typical of TBE were detected in seven dogs. PCR-positive results were found between March and November. Three dogs were tested with a competitive ELISA-positive result and a "nested real-time RT-PCR"-positive result concurrently. In the group of 159 dogs the value of seroprevalence was found to be 11.3%. PMID- 26591387 TI - [Pregnancy diagnosis by detection of pregnancy-associated glycopoteins in milk: evaluation of a commercial available ELISA]. AB - In order to increase fertility in modern dairy farming, the interval between first insemination and conception should be as short as possible. Therefore, one approach is to diagnose non pregnant animals early to re-inseminate them as soon as possible. Commercial milk pregnancy assays are available to detect throphoblast derived bovine pregnancy-associated glycoproteins (bPAG) in milk. The aim of the present study was first to evaluate pre-analytical factors interfering with the correct detection of bPAG in milk. To achieve this aim, the stability of the bPAG was tested after repeated freezing and thawing cycles, as well as after a storage of seven days at room temperature and at 37 degrees C. Secondly, the diagnostic performance of a commercially available PAG-ELISA was evaluated for pregnancy diagnosis between 28 to 60 days after artificial insemination by comparing the results with transrectal ultrasonography in a field study (n = 291 cows). After one freezing and thawing procedure the optical density (OD) increased and afterwards stayed stable. The storage of milk samples at room temperature had no effect on the OD, but after five days of storage at 37 degrees C the OD dropped sharply. It is therefore recommended to add an appropriate microbicidal preservative for shipment and storage of milk samples for bPAG analysis . The results of the field study showed that PAG-ELISA results and ultrasonography results agreed in 95.7% of the cases. Nine samples were tested as "false negative"and five as "false positive", however a re-check revealed that all "false positive"and "false negative" tested cows suffered from embryonic/fetal mortality. In conclusion, the pregnancy diagnostic by bPAG detection in milk samples is an accurate method to diagnose early pregnancy in lactating cows. PMID- 26591388 TI - Grazing behaviour and dry matter intake of llamas (Lama glama) and German black- head mutton sheep (Ovis orientalis forma aries) under Central European conditions. AB - The aim of the present study was to assess the behaviour of llamas (Lama glama) and German blackhead mutton sheep (Ovis orientalis forma aries) when kept under Central European grazing conditions. In total, six adult female sheep and six adult female llamas were observed by direct observation during one week, in which each group was observed for a total time of 24 h. The animals were kept on the same pasture, but the species were raised in separate plots. Forage height before and after the experimental period were determined using a rising plate meter to calculate the average daily dry matter intake (DMI). Llamas had a daily DMI of 0.85%/BW and sheep of 1.04%/BW, respectively. The following behaviours were recorded by direct observation: grazing standing up, grazing lying down, ruminating standing up, ruminating lying down, lying down, lying down lateral and standing. Both species grazed for more than 50% of the time. Ruminating was predominantly performed while standing and lying by sheep (about 50% of the night and 12% of the day) and while lying by llamas (54% of the night and 10% of the day). In conclusion, sheep and llamas differed in grazing behaviour and daily biorhythm. These differences indicate that sheep and llamas may not synchronize their behaviour when co-grazed, though particularly in co-grazing studies the observation period should be extended. PMID- 26591389 TI - Ultrasonographic examination of the elbow region in calves and cows--normal appearance. AB - The present study describes the normal ultrasonographic appearance of the elbow region in healthy Holstein Friesian calves (n = 12) and Holstein Friesian cows (n = 12). Using 7.5 MHz linear and 5,0 MHz convex probes the ultrasonographic appearance and dimensions of the lateral collateral ligament (LCL), medial collateral ligament (MCL), joint pouch (JP), joint capsule (JC), joint space, vessels, muscles, bursa, bone surface, growth plate, articular and apophyseal cartilage were studied and measured. The exam started on the lateral aspect by identification of the LCL and continued to cranial, medial and caudal sides. The diameter of the LCL ranged between 9.2-18.6 mm in cows and 1.7-8.3 mm in calves. The caudo-lateral JP was easily imaged at the level of the humero-radio-ulnar joint caudal of the LCL, however the cranial JP was hardly or not visualized. Experimental injection of 20-40 ml of water post-mortem produced a clear distension and imaging of the joint pouch. Eleven muscles of the elbow region were distinguished in calves and seven in cows. Positive correlations were noticed between the age and the body weight (BW) with all parameters measured in calves. However, in cows, the BW correlated with the skin-bone surface distance and the thickness of the LCL only. It is concluded that ultrasonography allowed consistent imaging of the normal anatomical structures of the elbow region in calves and cows, giving reference values for the evaluation of pathological alterations. PMID- 26591390 TI - [Osteolysis of the hip joint in an eastern river cooter (Pseudemys concinna concinna)]. AB - Lameness in freshwater turtles is rarely seen and is mostly caused by bite injuries, other traumata or inflammatory processes. A 17 year old female eastern river cooter which was pretreated for disseminated shell necrosis a few months ago was presented due to acute lameness of the right hind limb. Diagnostic imaging revealed complete lysis of the hip joint and was classified as necrotizing osteomyelitis by histopathology. Septicemic spreading of pathogens and thus a link to the previous shell necrosis could not be identified. The patient developed wound complications and died a few days after the surgical procedure. Postmortem, a pronounced subacute pneumonia was diagnosed as presumed cause of death, which has not been clinically manifest during the whole medical history. PMID- 26591391 TI - The Influence of Women Age and Successfulness of Intrauterine Insemination (IUI) Cycles. AB - OBJECTIVE: To evaluate the association between success and the benefit of repeated intrauterine insemination (IUI) cycles among women of different age groups. MATERIAL AND METHOD: A retrospective analysis of 466 IUI cycles from 221 patients treated in afertility center of a university hospital between 2005 and 2013. The female age was stratified as younger than 35 years, 35 to 40 years, and older than 40 years old. The outcomes were the biochemical pregnancy rate, clinical pregnancy rate, live birth rate, and miscarriage rate. Kaplan-Meier analysis of the suitability cycle in each age group was also performed. RESULTS: The average age ofpatients was 35.2+/-4.6 years (range 21 to 49 years). The overall biochemical pregnancy rate was 18.6%. The biochemical pregnancy rate significantly decreased with advancing female age groups (27.6%, 12.8%, and 7.1% infemale age group younger than 35 years, 35 to 40 years, and older than 40 years respectively, p = 0.008). The other pregnancy outcomes were not different among female age groups. In all age groups, the increment of the cumulative biochemical pregnancy rate was observed up to four cycles. CONCLUSION: The biochemical pregnancy rate of IUI cycle decreased with advancingfemale age; however clinical pregnancy rate, live birth rate, and miscarriage rate were not different among female age groups. We recommend performing up to four insemination cycles before proceeding to IVF/ICSI cycle. PMID- 26591392 TI - An Evaluation of Blood Glucose Measurement Using TRUEresult Blood Glucose Monitoring System. AB - BACKGROUND: Point of care testing using glucose meters that measure capillary blood are the most popular and widely used method for the routine monitoring ofblood glucose level. TR UEresult is one ofsuch commonly used blood glucose measuring tools with high accuracy and precision profile according to the manufacturer's data. OBJECTIVE: To evaluate the performance of TRUEresult in real life practice by examining the agreement between capillary and venous glucose result using TR UEresult and a laboratory plasma glucose. MATERIAL AND METHOD: The present study is a cross sectional analytical study. All the data were collected from the patients whose blood samples were drawn for the measurement of plasma glucose at the outpatient department of Srinagarind Hospital, Khon Kaen University Thailand. TR UEresult blood glucose monitoring system was used to perform blood glucose measurement in whole blood samples from capillary and veins. This was compared with plasma glucose result from the automated analyzer in the central laboratory, which was considered as reference method at Srinagarind Hospital. RESULTS: The ISO 15197:2013 criteria was used to determine technical accuracy of the TRUEresult tool. Blood glucose levels in whole blood sample from capillary and veins, as measured using the TRUEresult, were 88.24% and 92.16% of the acceptable bias limits. This is below the minimal acceptable criteria. When Parkes error grid analysis was used to define the significance in clinical decision, all the errors of blood glucose levels measured using the TRUEresult were within zone A and zone B, meaning that the errors have no or little influence on clinical decision. CONCLUSION: The blood glucose levels in whole bloodfrom capillary and veins measured using TR UEresult blood glucose monitoring was within acceptable accuracy limit. The observed error had no or little influence on clinical decision. PMID- 26591393 TI - Sustainable Effectiveness of Applying Trauma Team Activation in Managing Trauma Patients in the Emergency Department. AB - OBJECTIVE: To determine long term effectiveness of trauma team activation criteria by measuring emergency department length of stay (EDLOS) and 28-day mortality. MATERIAL AND METHOD: A 3-year retrospective cohort study conducted in adult trauma patients who met one of the trauma team activation criteria (shock, penetrating torso injury, post traumatic arrest, respiratory rate of less than 12 or more than 30, and pulse rate of more than 120). Specific demographic data, physiologic parameters, EDLOS, injury severity score (ISS), and 28-day mortality were prospectively recorded into the Trauma Registry database. Multiple logistic regression analysis was used to determine factors affecting mortality. The Institutional Review Board approval was obtained prior to undertaking the project. RESULTS: Two hundred eighty two patients with a mean age of35.1 years old were eligible. The median ISS was 25 (range, 13-30). The median EDLOS was 85 minutes (range, 50-135) and the 28-day mortality rate was 46.5%. The mean age was 31.7 years in the survival group and 38.7 years in the fatal group (p = 0.001). The median ISS was 17 in the survival group and 26 in the fatal group (p = 0.000) and the median EDLOS was 110 minutes in the survival group and 82 minutes in the fatal group (p = 0.034). When compared to data prior to the TTA application, the median time of EDLOS improvedsustainably from 184 to 85 minutes (p = 0.000) and the mortality rate decreased from 66.7% to 46.5% (p = 0.057). The parameters affecting patient mortality were older age, high ISS, and shorter EDLOS. CONCLUSION: Trauma team activation criteria significantly improved acute trauma care in the emergency department and decreased mortality. PMID- 26591394 TI - The Changes in Mean Platelet Volume after Using of Antiplatelet Drugs in Acute Ischemic Stroke: A Randomized Controlled Trial. AB - OBJECTIVE: To measure the changes of mean platelet volume (MPV) after using four antiplatelet drugs in acute non-cardioembolic ischemic stroke patients and assess the association of antiplatelets and MPV and stroke outcome. MATERIAL AND METHOD: Ischemic stroke survivors with National Institute of Health Stroke Scale (NIHSS) 8 were randomly allocated intofour groups, receiving aspirin, clopidogrel, combined aspirin and dipyridamole, and cilostazol. The change of MPV NIHSS, and modified Rankin Scale (mRS) were recorded at baseline and week 4 in all studied groups. MPV was measured using the standard automated blood test for complete blood count. RESULTS: Twenty-one subjects were included in this study. They comprised of five cases in each antiplatelet group, except for aspirin, which had six subjects. Male was 57%, and hypertension was the most common risk factor (61.9%). Most of participants (76%) had small vessel disease. At 4-week, MPVwas reduced and NIHSS, mRS were improved in every studied group. Clopidogrel sign ficantly reduced NIHSS score (p = 0.003), and it produced the greatest reduction in MPV compared to others. CONCLUSION: Every type of antiplatelets included in this study reduced MPV NIHSS, and mRS in acute non-cardioembolic stroke patients. Clopidogrel improved NIHSS the most. PMID- 26591395 TI - Comparison between the Efficacy of Switch Therapy and Conventional Therapy in Pediatric Community-Acquired Pneumonia. AB - OBJECTIVE: Compare the treatment outcomes ofswitch therapy and conventional therapy inpediatricpatients aged one month to five years old, diagnosed with community-acquired pneumonia who required hospitalization. MATERIAL AND METHOD: The present study was performed and approved by the Siriraj Research Ethics Committee. With informed consent, 57 patients whofitted the inclusion criteria were randomized into two groups, 1) the switch therapy group (SWT), who switched their method of receiving antibiotics from IV to oral within 24 hours after clinical improvement and body temperature under 37.8 degrees C at least eight hours, and 2) the control group, the group treated as routine general practice. Chi-square tests, Fisher's exact tests, unpaired t-tests, and Mann-Whitney U tests were used in analysis. A non-inferiority analysis to estimate 1-sided 95% CIs was performed to determine the greatest difference (worst case) between groups. RESULTS: There were no significant differences in age, sex, clinical presentations, and antibiotics provided between the two groups. A statistically significant reduction in length of hospital stay was found in the SWT group (P = 0.019), whereas the readmission rate for both groups was not significantly different (p = 0.66). Morbidity and mortality were not found in either groups. The SWT group demonstrated non-inferior efficacy comparing to control group (difference 20%; p<0. 001). CONCLUSION: In pediatric community-acquired pneumonia, early switching from administer IVantimicrobial agents to oral form when clinical signs improved were safe and effective. Switch therapy showed non inferiority outcomes compared to conventional therapy, and had advantages in shortening the length ofstay and indirectly lowering the cost of hospitalization. PMID- 26591396 TI - Cost-Effective and Potential Benefits in Three-Port Hand-Assisted Laparoscopic Sigmoidectomy. AB - OBJECTIVE: To demonstrate potential benefits of three-port hand-assisted laparoscopic sigmoidectomy (HALS) compared with open sigmoidectomy (OS) in terms of short-term outcomes and cost-benefit. MATERIAL AND METHOD: A retrospective review of a database of cases that matched 100 sigmoid cancer patients treated with sigmoidectomy at the Department of Surgery, Siriraj Hospital was performed. Short-term outcomes and costs of treatment were collected and analyzed. RESULTS: There were no differences in age, gender body mass index, American Society of Anesthesiologists' score, Charlson comorbidity index score, and previous surgery between OS and HALS groups. The three-port HALS group had significantly less blood loss (50 (5-400) mL vs. 120 (10-1,000) mL, p<0.001), faster time to regular diet (64.6+/-20.7 hours vs. 97.6+/-52.5 hours, p<0.001), and lower pain score (4.3+/-1.7 vs. 5.3+/-1.6, p = 0.008). The hospital-stay related cost was sign icantly lower in HALS group ($114 ($47-$789) vs. $190 ($57-$1,462), p0.05). No serious adverse events related to the studied drugs were found. CONCLUSION: No significant difference in the analyzed pharmacokineticparameters was found between the twoformulations of 50 mg cilostazol tablets. Therefore, it can be concluded that these two cilostazol tablet formulations were considered bioequivalent. PMID- 26591404 TI - The Distribution of Thai Mental State Examination Scores among Non-Demented Elderly in Suburban Bangkok Metropolitan and Associated Factors. AB - OBJECTIVE: To obtain the distribution of Thai Mental State Examination (TMSE) scores in the Thai population across different age groups and educational levels in men and women aged 50 years and older and its relationship with demographic factors. The different cutpoints in literate and illiterate participants and item performance in both groups were also determined. MATERIAL AND METHOD: Community dwelling participants aged 50 years and over were invited to join the study. Personal information, general health history, and specific illness questionnaires including the activities of daily living, designed by the Survey in Europe on Nutrition and the Elderly, a ConcertedAction (SENECA), and the Thai Mental State Examination (TMSE) were completed in the face-to-face interview. RESULTS: There were 4,459 participants with no specific reported conditions that could potentially influence cognitive performance. The mean (SD) age was 64.2 (7.9) years and mostparticipants were women (71.7%). The median (interquartile range) of the TMSE was 27 (25-29) and 23 (19-26) in literate and illiterate participants, respectively. The distribution of TMSE scores were reported here determined by age, gender and educational level. Percentage of correct response in each TMSE item was low in recall and calculation performance. TMSE score declined with age in both genders and had greater variation with increasing age. TMSE score also increased with increasing levels of education and better financial status. Gender was not associated with the TMSE score adjusting for age, educational level, and economic status. CONCLUSION: Age, education, and economic status have an influence on the TMSE performance. Controllingfor these three factors, genders does not contribute to significant differences in TMSE performance. Norms adjustedfor these factors should be considered before employing single cutpoints to identify impairment. PMID- 26591405 TI - Pulmonary Embolism and Subclavian Vein Thrombosis in a Patient with Parathyroid Carcinoma: Case Report and Review of Literature. AB - Parathyroid carcinoma is a rare etiology of primary hyperparathyroidism responsible for 0.4 to 5.2% of all primary hyperparathyroidism cases. The overt hyperparathyroid bone or renal disease with palpable neck mass, as well as severe hypercalcemia with extremely high parathyroid hormone, are clinical parameters raising the suspicionforparathyroid carcinoma. However a definite diagnosis can be confirmed only by examining the histopathology of the tumor. The curative treatment solely depends on an en bloc surgical approach. Therefore, preoperative clinical diagnosis of carcinoma is essentialfor optimal surgical planning. Thepresent study reported asymptomatic subclavian vein thrombosis andpulmonary embolism in parathyroid carcinoma, suggesting paraneoplastic syndrome of hypercoagulability in this cancer type. The presence of this paraneoplastic syndrome in a case of overt clinical hyperparathyroidism in addition to a palpable neck mass indicated the diagnosis of carcinoma preoperatively in the present patient, which led to an en bloc surgical plan. Since this paraneoplastic syndrome can be asymptomatic, the exploration ofthis syndrome by a commonly used imaging technique for parathyroid tumor localization, computerized tomography, would enable a preoperative diagnosis of cancer especially in an equivocal situation. PMID- 26591406 TI - Waterbirth. PMID- 26591407 TI - Why Are Mothers Dying? PMID- 26591408 TI - Tricks of the Trade. PMID- 26591410 TI - Waterbirth Anecdotes from Puerto Ordaz, Venezuela (1996-2013). PMID- 26591409 TI - The Birthing Pool Test. PMID- 26591411 TI - Water: The Elixir of Life. PMID- 26591413 TI - Fourth Baby Birth Story: Gia Rose. PMID- 26591412 TI - As Natural as Water: Waterbirth and Instinctual Birth. PMID- 26591414 TI - Waterbirth at Mountain Midwifery Center. PMID- 26591415 TI - Seeds, Soil, Homebirth & Permaculture. PMID- 26591416 TI - What We Learned about Waterbirth from a Case of Legionella. PMID- 26591417 TI - What a Difference a Little Water Makes. PMID- 26591418 TI - Overcoming Birthing Failure: My Waterbirth Story. PMID- 26591419 TI - The Changing Paradigm of Birth in South Africa. PMID- 26591420 TI - Through My Brown Eyes. PMID- 26591421 TI - Bridget Lee Fuller: Mayflower Myth vs. Historic Midwife. PMID- 26591422 TI - VBAC: Very Beautiful And Courageous. PMID- 26591423 TI - Mother Health International's Mission and Model. PMID- 26591424 TI - To Eat or Not to Eat: A Nuanced Analysis of the Placenta Question. PMID- 26591425 TI - What is your favorite part about being a midwife, doula or activist? PMID- 26591426 TI - How did you get your training? PMID- 26591427 TI - How did you communicate with your baby while s/he was still in your womb? PMID- 26591428 TI - [Electroencephalogram with Pharyngeal Electrodes to Identify the Origin of Diffuse Spike-Wave-Like Discharges in a Case of Palatal Tremor]. AB - Electromyographic artifacts are sometimes misinterpreted as epileptic discharges in scalp electroencephalograms (EEGs). In addition, the distribution of the epileptic discharges near the earlobe is often distorted by earlobe activation; therefore, these epileptic discharges may not be correctly diagnosed. Here, we report a case of palatal tremor in which diffuse spike-wave-like discharges were apparent on EEG. A 51-year-old woman was referred to our hospital because of transient loss of consciousness while driving. She had a past history of cerebral infarction, cerebellar hemorrhages, and symptomatic epilepsy. Magnetic resonance imaging findings showed T2 hyperintensity in the right inferior olivary nucleus. Single-photon emission computerized tomographic images demonstrated hypoperfusion of the left basal ganglion, bilateral thalamus, and bilateral anteroparietal lobes. Monopolar EEG recording showed diffuse spike-wave-like discharges with a frequency of 3-4 Hz cycle. To clarify the origin of these discharges, pharyngeal EEG recording simultaneously with conventional scalp electrodes was performed, which revealed that the discharges originated from the left pharynx. Rhythmic muscle contraction could be identified at the posterior pharynx and soft palate on close pharyngeal inspection. The electromyographic activities of the palatal tremor spread to the earlobe, and the activated earlobe electrodes apparently induced diffuse spike-wave-like discharges observed on monopolar EEG recording. PMID- 26591429 TI - [Familial Hemophagocytic Lymphohistiocytosis, That was Considered as Progressive Encephalitis before Sibling was Diagnosed]. AB - Familial hemophagocytic lymphohistiocytosis (FHL) is an autosomal recessive disorder that is clinically characterized by fever, hepatosplenomegaly, cytopenia and sometimes vague or dramatic central nervous system (CNS) dysfunction. FHL affecting the CNS imitates several neurologic disorders and may be misdiagnosed, in particular when family history is unknown. We report an autopsy case of FHL that was firstly considered as progressive encephalitis. FHL was suspected after sibling had been affected by hemophagocytosis and the same CNS symptoms. Histopathologically, lymphocytes and macrophages infiltrated into the meninges, perivascular space, and parenchyma of the brain. Those lymphocytes were positive for CD3, CD8, GranzymeB, and negative for CD4, perforin. FHL must be included in the differential diagnostic considerations in children with progressive encephalitis. PMID- 26591430 TI - [The Establishment and Reality of a Quality Management System--Chairmen's Introductory Remarks]. AB - Compared with clinical test data, the main ditterence from other forms of medical information is the objectivity of clinical test data. The value of clinical testing is basically to offer objective and reliable clinical test data for clinical practice both timely and promptly. A quality management system supports those practices, and the mission of a clinical test department is to embody the principle of accuracy assurance and reflect it in routine clinical testing. Accuracy management was previously a system to maintain and manage accurate reading, but it has developed into a system to assure data quality. It is considered necessary to use knowledge and skills on accuracy assurance and actively ensure the reliability of data. We therefore suggest the need for "a shift from accuracy assurance to quality management". PMID- 26591431 TI - [Development and Current Status of Quality Management Systems for Specimen Examination]. AB - ISO 15189:2003 was published as an International Standard in 2003 by Technical Committee ISO/TC212 of the International Organization for Standardization (ISO). This international standard based on ISO 9001 specifies requirements for competence and quality that are specific to medical laboratories. With the publication of this standard, we will have to markedly change our concept. We have to adopt methods to manage the causes of errors in measurement processes rather than methods to manage only the results of measurements. The new concept of the Quality Management System (QMS) which manages the result of measurements is summarized. With the publication of ISO 15189, the definition of the quality assurance of examination results became clearer and stricter. This report describes the contents of ISO 15189 and the method of enforcing it. PMID- 26591432 TI - [Quality Management System in Pathological Laboratory]. AB - Even compared to other clinical laboratories, the pathological laboratory conducts troublesome work, and many of the work processes are also manual. Therefore, the introduction of the systematic management of administration is necessary. It will be a shortcut to use existing standards such as ISO 15189 for this purpose. There is no standard specialized for the pathological laboratory, but it is considered to be important to a pathological laboratory in particular. 1. Safety nianagement of the personnel and environmental conditions. Comply with laws and regulations concerning the handling of hazardous materials. 2. Pre examination processes. The laboratory shall have documented procedures for the proper collection and handling of primary samples. Developed and documented criteria for acceptance or rejection of samples are applied. 3. Examination processes. Selection, verification, and validation of the examination procedures. Devise a system that can constantly monitor the traceability of the sample. 4. Post-examination processes. Storage, retention, and disposal of clinical samples. 5. Release of results. When examination results fall within established alert or critical intervals, immediately notify the physicians. The important point is to recognize the needs of the client and be aware that pathological diagnoses are always "the final diagnoses". PMID- 26591433 TI - [Development of Standards for Baseline Quality in Quality Management of Molecular Diagnostic Testing]. AB - As molecular-diagnostic testing is expanding in clinical use, the demand for its quality assurance is increasing. To this end, efforts towards quality management have been made regionally and globally. An entire testing procedure needs to be properly performed from the preanalytic, analytic, and postanalytic processes. Particularly, the preanalytic process largely affects the measurement and, thus, the result. The Japanese Committee for Clinical Laboratory and Standard developed the standard documents, such as that for the quality management of clinical specimens and best-practice guideline for quality assurance of molecular-genetic testing. These standard documents would provide not only the requirements as the best practice for testing, but also the basis of baseline quality and reliability. They can be used as the basis for assessment of the quality of practice in reimbursement coverage by payers and in certification or accreditation by a third party. PMID- 26591434 TI - [Application of Flow Cytometry in Clinical Laboratories and Its Future Direction, Focusing Upon Multicolor Flow Cytometry]. AB - Flow cytometry (FCM) has been introduced into clinical laboratories to determine the lineage and functional stage of differentiation of hematopoietic tumor cells using multiple immunophenotypic markers. Multi-parametric analysis, which simultaneously measures multiple cellular characteristics, not only provides a large amount of novel information for each sample studied, but also requires a reduced volume of the specimen and avoids redundancies of reagents within antibody panels. Through a series of novel developments in FCM hardware, software, and dye-chemistry, recently developed multicolor flow cytometers are capable of detecting 10 or more fluorochromes simultaneously and expeditiously, taking advantage of not only cluster analysis but also detecting rare cellular populations within complex materials. In this study, we applied the multicolor FCM technology for: i) T-cell lineage assessment in early T-cell precursor acute lymphoblastic leukemia, ii) detection of a rare neoplastic population in angioimmunoblastic T-cell lymphoma composed of a complex mixture of cells, iii) assessment of bone marrow infiltration of B-cell lymphoma, and iv) sensitive detection of multiple myeloma cells with the use of a combination of antibodies, which is applicable to monitoring the response to treatment. PMID- 26591435 TI - [Practice and Role of Team Approach to Medicine in Clinical Laboratory Medicine- Chairmen's Introductory Remarks]. AB - The Japanese Society of Laboratory Medicine has been running its own Medical Safety Committee, and holding a symposium on medical safety during the annual meeting every year. The activities based on a team approach to medicine play a critical role in the development of medical safety culture and the driving forward of medical safety in clinical practice. The best medical practice involves cooperation among information-sharing medical staff from a variety of professions, providing medical care based on medical safety, which patients hope for. It is hoped that the present symposium on medical safety can help drive medical safety into the future. PMID- 26591436 TI - [Good Practice of Clinical Physiology Examination for Patient Safety with a Team Based Approach: Quality Practice in Ultrasonographic Examination]. AB - For the safety of patient care, a team-based approach has been advocated as an effective measure. In clinical physiology examination, we have been making efforts to promote good practice for patient safety based on such an approach in Tokai University Hospital, as represented by quality practice in ultrasonographic examination. The entire process of ultrasonographic examination can be divided into three parts: pre-examination, examination, and post-examination processes. In each process of the examination, specific quality issues must be considered, eventually ensuring the quality and safety of patient care. A laboratory physician is responsible for not only quality assurance of examination, diagnosis, and reporting, but also patient safety. A laboratory physician can play a key role in all aspects of patient safety related to each process of the examination by taking a leadership role in the team-based approach. PMID- 26591437 TI - [Team Care for Patient Safety, TeamSTEPPS to Improve Nontechnical Skills and Teamwork--Actions to Become an HRO]. AB - It is important to develop safer medical systems and follow manuals of medical procedures for patient safety. However, these approaches do not always result in satisfactory results because of many human factors. It is known that defects of nontechnical skills are more important than those of technical skills regarding medical accidents and incidents. So, it is necessary to improve personal nontechnical skills and compensate for each other's defects based on a team approach. For such purposes, we have implemented TeamSTEPPS to enhance performance and patient safety in our hospital. TeamSTEPPS (team strategies and tools to enhance performance and patient safety) is a useful method to improve the nontechnical skills of each member and the team. In TeamSTEPPS, leadership to share mental models among the team, continuous monitoring and awareness for team activities, mutual support for workload and knowledge, and approaches to complete communication are summarized to enhance teamwork and patient safety. Other than improving nontechnical skills and teamwork, TeamSTEPPS is also very important as a High Reliability Organization (HRO). TeamSTEPPS is worth implementing in every hospital to decrease medical errors and improve patient outcomes and satisfaction. PMID- 26591438 TI - [Team Care and Patient Safety]. AB - The purpose of patient safety management is to nurture an environment which provides optimal care for each patient through the cooperation of each healthcare staff member based on the idea of team care. This is based on the safety culture of an organization that places value on sharing information. Laboratory medicine is expected to become more important in the areas of staff, patient, and community education. PMID- 26591439 TI - [Trends and Challenges of the Statutory Regulation of Molecular Genetic Tests]. AB - Advances in basic science have made it possible to characterize tumors at molecular levels and exploit the differences in the genetic makeup of tumors for personalized cancer treatment. Biomarker tests are essential to stratify patients with the same tumor histology for appropriate treatment. Such tests are developed together with drugs, involving mainly molecular genetic tests at present, and are called companion diagnostics (CDx). Under the universal health care system in Japan, molecular genetic tests are permitted in clinics, and the fees are reimbursed only when approved diagnostic reagents or kits are used. However, new tests are developed so fast that the regulation cannot keep up with the pace. To fill this gap, the framework of advanced medical technologies was introduced in 1984. In 2012, this framework was amended to classify medical technology using unapproved diagnostics or home-brew assays as advanced medical technologies A. In my talk at this symposium, trends and challenges of the statutory regulation of molecular genetic tests in Japan were discussed, followed by personal proposals to advance the clinical application of novel medical technologies in the field of personalized cancer treatment. PMID- 26591440 TI - [Companion Diagnostics Sub-Section of Anatomic Pathology Department in a Mid Sized General Hospital: Start Up and Maintenance]. AB - We introduce the establishment of a companion diagnostics sub-section of an anatomic pathology department in our mid-sized general hospital. Recent cancer pharmacotherapy targets are growth factor receptors and their associated signal transduction molecules. The presence or absence of mutations in these genes influences the effects of drugs on an individual tumor. Gene polymorphisms of anti-cancer drug metabolism-related enzymes are also closely associated with severe toxicity. Medical oncologists must have knowledge of gene alterations of growth factor receptors and associated signal transduction molecules and polymorphisms of anti-cancer drug metabolism-related enzymes in each case. Large numbers of cases with advanced cancers of the colon/rectum or lung are admitted to our mid-sized general hospital. Analyses of KRAS and EGFR gene mutations and UGT1A1 polymorphisms should be performed within an anatomic pathology department, in order to obtain results of genetic analysis and start tailor-made pharmacotherapy as soon as possible. Cost performance is not low. Executive members of the hospital decided to establish a new hospital which will focus on cancer surgery and pharmacotherapy, and it is scheduled to be completed in one year, next to the present building. So we, including the head of medical technologists, immediately proposed the start up of a companion diagnostics sub section in an anatomic pathology department. The executive members agreed with our proposal, and purchased a fully-automated genotyping system, IS-5320 (idensy IS-5320 ARKRAY). Companion diagnostics regarding molecular targeting pharmacotherapy should be performed even in a mid-sized general hospital. PMID- 26591441 TI - [UGT1A1 Genotyping for Proper Use of Irinotecan]. AB - Irinotecan is a camptothecin analog used worldwide for a broad range of solid tumors, including colorectal and lung cancers. It can cause severe adverse drug reactions, such as neutropenia or diarrhea. Irinotecan is metabolized to form active SN-38, which is further conjugated and detoxified by the UDP glucuronosyltransferase (UGT) 1A1 enzyme. Recent pharmacogenetic studies on irinotecan have revealed the impact of UGT1A1 polymorphisms on severe adverse effects. A variant in the promoter of the UGT1A1 gene, the UGT1A1 *28 allele, has been extensively studied, and pharmacogenetic relationships between the variant and severe toxicities of irinotecan have been reported. The US FDA and pharmaceutical companies revised the irinotecan label in 2005, and it now includes homozygosity for the UGT1A1*28 genotype as one of the risk factors for severe neutropenia. A variant in exon 1 of the UGT1A1 gene, the UGT1A1*6 allele, mainly found in East Asians, is also an important risk factor associated with severe neutropenia. The concurrence of UGT1A1*28 and UGT1A1*6, even when heterozygous, markedly alters the disposition of irinotecan, potentially increasing toxicity, which is now written on the label of irinotecan in Japan. For patients showing homozygosity for UGT1A1*28, *6, or compound heterozygosity for UGT1A1*6 and *28, dose reduction of irinotecan is strongly recommended. Genotyping tests for UGT1A1 *6 and *28 have been approved in Japan and are currently used in oncology practice. Moreover, a recent Phase 2 trial for FOLFIRINOX in Japan excluded patients who showed homozygosity for UGT1A1*28, *6, or compound heterozygosity for UGT1A1*6 and *28. At present, irinotecan chemotherapy based on a patient's UGT1A1 genetic status is scientifically reasonable. PMID- 26591442 TI - [Diagnostic Tests Approved by Ministry of Health and Welfare (January 2015)]. PMID- 26591443 TI - Abundance models improve spatial and temporal prioritization of conservation resources. AB - Conservation prioritization requires knowledge about organism distribution and density. This information is often inferred from models that estimate the probability of species occurrence rather than from models that estimate species abundance, because abundance data are harder to obtain and model. However, occurrence and abundance may not display similar patterns and therefore development of robust, scalable, abundance models is critical to ensuring that scarce conservation resources are applied where they can have the greatest benefits. Motivated by a dynamic land conservation program, we develop and assess a general method for modeling relative abundance using citizen science monitoring data. Weekly estimates of relative abundance and occurrence were compared for prioritizing times and locations of conservation actions for migratory waterbird species in California, USA. We found that abundance estimates consistently provided better rankings of observed counts than occurrence estimates. Additionally, the relationship between abundance and occurrence was nonlinear and varied by species and season. Across species, locations prioritized by occurrence models had only 10-58% overlap with locations prioritized by abundance models, highlighting that occurrence models will not typically identify the locations of highest abundance that are vital for conservation of populations. PMID- 26591444 TI - Mechanisms to explain purse seine bycatch mortality of coho salmon. AB - Research on fisheries bycatch and discards frequently involves the assessment of reflex impairment, injury, or blood physiology as means of quantifying vitality and predicting post-release mortality, but exceptionally few studies have used all three metrics concurrently. We conducted an experimental purse seine fishery for Pacific salmon in the Juan de Fuca Strait, with a focus on understanding the relationships between different sublethal indicators and whether mortality could be predicted in coho salmon (Oncorhynchus kisutch) bycatch. We monitored mortality using a ~24-h net pen experiment (N = 118) and acoustic telemetry (N = 50), two approaches commonly used to assess bycatch mortality that have rarely been directly compared. Short-term mortality was 21% in the net pen experiment (~24 h) and estimated at 20% for telemetry-tagged fish (~48-96 h). Mortality was predicted by injury and reflex impairment, but only in the net pen experiment. Higher reflex impairment was mirrored by perturbations to plasma ions and lactate, supporting the notion that reflex impairment can be used as a proxy for departure from physiological homeostasis. Reflex impairment also significantly correlated with injury scores, while injury scores were significantly correlated with plasma ion concentrations. The higher time-specific mortality rate in the net pen and the fact that reflexes and injury corresponded with mortality in that experiment, but not in the telemetry-tagged fish released into the wild could be explained partly by confinement stress. While holding experiments offer the potential to provide insights into the underlying causes of mortality, chronic confinement stress can complicate the interpretation of patterns and ultimately affect mortality rates. Collectively, these results help refine our understanding of the different sublethal metrics used to assess bycatch and the mechanisms that can lead to mortality. PMID- 26591445 TI - Predicting spatial variations of tree species richness in tropical forests from high-resolution remote sensing. AB - There is an increasing interest in identifying theories, empirical data sets, and remote-sensing metrics that can quantify tropical forest alpha diversity at a landscape scale. Quantifying patterns of tree species richness in the field is time consuming, especially in regions with over 100 tree species/ha. We examine species richness in a 50-ha plot in Barro Colorado Island in Panama and test if biophysical measurements of canopy reflectance from high-resolution satellite imagery and detailed vertical forest structure and topography from light detection and ranging (lidar) are associated with species richness across four tree size classes (>1, 1-10, >10, and >20 cm dbh) and three spatial scales (1, 0.25, and 0.04 ha). We use the 2010 tree inventory, including 204,757 individuals belonging to 301 species of freestanding woody plants or 166 +/- 1.5 species/ha (mean +/- SE), to compare with remote-sensing data. All remote-sensing metrics became less correlated with species richness as spatial resolution decreased from 1.0 ha to 0.04 ha and tree size increased from 1 cm to 20 cm dbh. When all stems with dbh > 1 cm in 1-ha plots were compared to remote-sensing metrics, standard deviation in canopy reflectance explained 13% of the variance in species richness. The standard deviations of canopy height and the topographic wetness index (TWI) derived from lidar were the best metrics to explain the spatial variance in species richness (15% and 24%, respectively). Using multiple regression models, we made predictions of species richness across Barro Colorado Island (BCI) at the 1-ha spatial scale for different tree size classes. We predicted variation in tree species richness among all plants (adjusted r2 = 0.35) and trees with dbh > 10 cm (adjusted r2 = 0.25). However, the best model results were for understory trees and shrubs (dbh 1-10 cm) (adjusted r2 = 0.52) that comprise the majority of species richness in tropical forests. Our results indicate that high-resolution remote sensing can predict a large percentage of variance in species richness and potentially provide a framework to map and predict alpha diversity among trees in diverse tropical forests. PMID- 26591446 TI - Do state-and-transition models derived from vegetation succession also represent avian succession in restored mine pits? AB - State-and-transition models are increasingly used as a tool to inform management of post-disturbance succession and effective conservation of biodiversity in production landscapes. However, if they are to do this effectively, they need to represent faunal, as well as vegetation, succession. We assessed the congruence between vegetation and avian succession by sampling avian communities in each state of a state-and-transition model used to inform management of post-mining restoration in a production landscape in southwestern Australia. While avian communities differed significantly among states classified as on a desirable successional pathway, they did not differ between desirable and deviated states of the same post-mining age. Overall, we concluded there was poor congruence between vegetation and avian succession in this state-and-transition model. We identified four factors that likely contributed to this lack of congruence, which were that long-term monitoring of succession in restored mine pits was not used to update and improve models, states were not defined based on ecological processes and thresholds, states were not defined by criteria that were important in structuring the avian community, and states were not based on criteria that related to values in the reference community. We believe that consideration of these four factors in the development of state-and-transition models should improve their ability to accurately represent faunal, as well as vegetation, succession. Developing state-and-transition models that better incorporate patterns of faunal succession should improve the ability to manage post disturbance succession across a range of ecosystems for biodiversity conservation. PMID- 26591447 TI - Shifts in dynamic regime of an invasive lady beetle are linked to the invasion and insecticidal management of its prey. AB - The spread and impact of invasive species may vary over time in relation to changes in the species itself, the biological community of which it is part, or external controls on the system. We investigate whether there have been changes in dynamic regimes over the last 20 years of two invasive species in the midwestern United States, the multicolored Asian lady beetle Harmonia axyridis and the soybean aphid Aphis glycines. We show by model selection that after its 1993 invasion into the American Midwest, the year-to-year population dynamics of H. axyridis were initially governed by a logistic rule supporting gradual rise to a stable carrying capacity. After invasion of the soybean aphid in 2000, food resources at the landscape level became abundant, supporting a higher year-to year growth rate and a higher but unstable carrying capacity, with two-year cycles in both aphid and lady beetle abundance as a consequence. During 2005 2007, farmers in the Midwest progressively increased their use of insecticides for managing A. glycines, combining prophylactic seed treatment with curative spraying based on thresholds. This human intervention dramatically reduced the soybean aphid as a major food resource for H. axyridis at landscape level and corresponded to a reverse shift towards the original logistic rule for year-to year dynamics. Thus, we document a short episode of major predator-prey fluctuations in an important agricultural system resulting from two biological invasions that were apparently damped by widespread insecticide use. Recent advances in development of plant resistance to A. glycines in soybeans may mitigate the need for pesticidal control and achieve the same stabilization of pest and predator populations at lower cost and environmental burden. PMID- 26591448 TI - Making spatial prioritizations robust to climate change uncertainties: a case study with North American birds. AB - Spatial prioritizations are essential tools for conserving biodiversity in the face of accelerating climate change. Uncertainty about species' responses to changing climates can complicate prioritization efforts, however, and delay conservation investment. In an effort to facilitate decision-making, we identified three hypotheses about species' potential responses to climate change based on distinct biological assumptions related to niche flexibility and colonization ability. Using 314 species of North American birds as a test case, we tuned separate spatial prioritizations to each hypothesis and assessed the degree to which assumptions about biological responses affected the perceived conservation value of the landscape and prospects for individual taxa. We also developed a bet-hedging prioritization to minimize the chance that incorrect assumptions would lead to valuable landscapes and species being overlooked in multispecies prioritizations. Collectively, these analyses help to quantify the sensitivity of spatial prioritizations to different assumptions about species' responses to climate change and provide a framework for enabling efficient conservation investment despite substantial biological uncertainty. PMID- 26591449 TI - Conservation implications of ameliorating survival of little brown bats with white-nose syndrome. AB - Management of wildlife populations impacted by novel threats is often challenged by a lack of data on temporal changes in demographic response. Populations may suffer rapid declines from the introduction of new stressors, but how demography changes over time is critical to determining long-term outcomes for populations. White-nose syndrome (WNS), an infectious disease of hibernating bats, has caused massive and rapid population declines in several hibernating species of bats in North America since the disease was first observed on the continent in 2006. Estimating annual survival rates and demographic trends among remnant colonies of hibernating bats that experienced mass mortality from WNS is needed to determine long-term population viability of species impacted by this disease. Using mark recapture data on infected little brown bats (Myotis lucifugus), we estimated the first apparent annual survival rates for four years following WNS detection at a site. We found strong support for an increasing trend in annual survival, which improved from 0.68 (95% CI = 0.44-0.85) to 0.75 (95% CI = 0.51-0.89) for males and 0.65 (95% CI = 0.44-0.81) to 0.70 (95% CI = 0.50-0.84) for females. These results suggest that stabilization at remnant colonies after mass mortality from WNS may be due to improved survival and not from immigration from other areas. Despite ameliorating survival, our stochastic matrix projection model predicts continued declines for little brown bat populations (lambda = 0.95), raising concern for the regional persistence of this species. We conducted a vital rate sensitivity analysis and determined that adult and juvenile survival, as opposed to fecundity, are the demographic parameters most important to target to maximize recovery potential of little brown bat populations in areas impacted by WNS. PMID- 26591450 TI - Testing the effects of ant invasions on non-ant arthropods with high-resolution taxonomic data. AB - Invasions give rise to a wide range of ecological effects. Many invasions proceed without noticeable impacts on the resident biota, whereas others shift species composition and even alter ecosystem function. Ant invasions generate a broad spectrum of ecological effects, but controversy surrounds the extent of these impacts, especially with regard to how other arthropods are affected. This uncertainty in part results from the widespread use of low-resolution taxonomic data, which can mask the presence of other introduced species and make it difficult to isolate the effects of ant invasions on native species. Here, we use high-resolution taxonomic data to examine the effects of Argentine ant invasions on arthropods on Santa Cruz Island, California. We sampled arthropods in eight pairs of invaded and uninvaded plots and then collaborated with taxonomic experts to identify taxa in four focal groups: spiders, bark lice, beetles, and ants. Spiders, bark lice, and beetles made up ~40% of the 9868 non-ant arthropod individuals sampled; the majority of focal group arthropods were putatively native taxa. Although our results indicate strong negative effects of the Argentine ant on native ants, as is well documented, invaded and uninvaded plots did not differ with respect to the richness, abundance, or species composition of spiders, bark lice, and beetles. One common, introduced species of bark louse was more common in uninvaded plots than in invaded plots, and including this species into our analyses changed the relationship between bark louse richness vs. L. humile abundance from no relationship to a significant negative relationship. This case illustrates how failure to differentiate native and introduced taxa can lead to erroneous conclusions about the effects of ant invasions. Our results caution against unqualified assertions about the effects of ant invasions on non ant arthropods, and more generally demonstrate that accurate assessments of invasion impacts depend on adequate information about species identity. PMID- 26591451 TI - The dynamics of avian influenza in Lesser Snow Geese: implications for annual and migratory infection patterns. AB - Wild water birds are the natural reservoir for low-pathogenic avian influenza viruses (AIV). However, our ability to investigate the epizootiology of AIV in these migratory populations is challenging and, despite intensive worldwide surveillance, remains poorly understood. We conducted a cross-sectional, retrospective analysis in Pacific Flyway Lesser Snow Geese, Chen caerulescens, to investigate AIV serology and infection patterns. We collected nearly 3000 sera samples from Snow Geese at two breeding colonies in Russia and Canada during 1993 1996 and swab samples from >4000 birds at wintering and migration areas in the United States during 2006-2011. We found seroprevalence and annual seroconversion varied considerably among years. Seroconversion and infection rates also differed between Snow Goose breeding colonies and wintering areas, suggesting that AIV exposure in this gregarious waterfowl species is likely occurring during several phases (migration, wintering, and potentially breeding areas) of the annual cycle. We estimated AIV antibody persistence was longer (14 months) in female geese compared to males (6 months). This relatively long period of AIV antibody persistence suggests that subtype-specific serology may be an effective tool for detection of exposure to subtypes associated with highly pathogenic AIV. Our study provides further evidence of high seroprevalence in Arctic goose populations, and estimates of annual AIV seroconversion and antibody persistence for North American waterfowl. We suggest future AIV studies include serology to help elucidate the epizootiological dynamics of AIV in wild bird populations. PMID- 26591452 TI - From genes to populations: how fisheries-induced evolution alters stock productivity. AB - By removing individuals with certain heritable characteristics such as large body size, harvesting may induce rapid evolutionary change in fish life history. There is controversy, however, as to the prevalence of fisheries-induced evolution (FIE) and to what extent it should be considered as part of sustainable resource management. Recent research has shown that FIE can be difficult to detect and its economic effects might not always be significant. Here, we show how population growth rate (r), a critical factor affecting sustainability and recovery, is affected by FIE through the analysis of a simulation model that demonstrates the link between individual-level genetic processes and stock dynamics. We examine how different levels of evolvability, fishing intensity, and density-dependence interact to influence r in three commercially harvested species: Atlantic cod (Gadus morhua), lake whitefish (Coregonus clupeaformis), and yellow perch (Perca flavescens). We demonstrate that at low harvest levels, evolution has minimal effect on r for all three species. However, at the harvest rates experienced by many fish stocks, evolution increases r and reduces the risk of collapse for cod and whitefish. During the initial stages of a harvest moratorium, a switch occurs, and r becomes reduced as a consequence of evolution. These results explain how evolution increases stock resilience, but also impedes recovery after periods of intense harvesting. PMID- 26591453 TI - Local and landscape effects in a host-parasitoid interaction network along a forest-cropland gradient. AB - Land-use driven habitat modification is a major driver of biodiversity loss and impoverishment of interaction diversity. This may affect ecosystem services such as pollination and biological control. Our objective is to analyze the effects of local (nesting environment: farms vs. tree stands) and landscape (forest-cropland gradient) factors on the structure and composition of a cavity-nesting bee-wasp (CNBW) community, their nests associates (henceforth parasitoids), and their interactions. We set up 24 nest-trapping stations in a fragmented, extensively farmed area of ~100 km2. We obtained 2035 nests containing 7572 brood cells representing 17 bee and 18 wasp species, attacked by 20 parasitoid species. Community structure and composition, as well as network structure, were much more dependent on local than on landscape factors. Host abundance and richness were higher in farms. In addition, host abundance was positively correlated to cropland cover. We also found highly significant differences between nesting environments in host community composition. Structure and composition of the parasitoid community were conditioned by the structure and composition of the host community. Network structure was affected by nesting environment but not by landscape factors. Interactions tended to be more diverse in farms. This result was mostly explained by differences in network size (greater in farms). However, generality was significantly higher in farms even after controlling for network size, indicating that differences in species' interaction patterns associated to differences in community composition between the two nesting environments are also affecting network structure. In conclusion, open habitats associated with extensively farmed exploitations favor local CNBW diversity (especially bees) and result in more complex host-parasitoid interaction networks in comparison to forested areas. The conservation value of this kind of open habitat is important in view of the progressive abandonment of extensively cultivated farmland taking place in Europe at the expense of agricultural intensification and reforestation. PMID- 26591454 TI - The effects of urbanization on population density, occupancy, and detection probability of wild felids. AB - Urbanization is a primary driver of landscape conversion, with far-reaching effects on landscape pattern and process, particularly related to the population characteristics of animals. Urbanization can alter animal movement and habitat quality, both of which can influence population abundance and persistence. We evaluated three important population characteristics (population density, site occupancy, and species detection probability) of a medium-sized and a large carnivore across varying levels of urbanization. Specifically, we studied bobcat and puma populations across wildland, exurban development, and wildland-urban interface (WUI) sampling grids to test hypotheses evaluating how urbanization affects wild felid populations and their prey. Exurban development appeared to have a greater impact on felid populations than did habitat adjacent to a major urban area (i.e., WUI); estimates of population density for both bobcats and pumas were lower in areas of exurban development compared to wildland areas, whereas population density was similar between WUI and wildland habitat. Bobcats and pumas were less likely to be detected in habitat as the amount of human disturbance associated with residential development increased at a site, which was potentially related to reduced habitat quality resulting from urbanization. However, occupancy of both felids was similar between grids in both study areas, indicating that this population metric was less sensitive than density. At the scale of the sampling grid, detection probability for bobcats in urbanized habitat was greater than in wildland areas, potentially due to restrictive movement corridors and funneling of animal movements in landscapes influenced by urbanization. Occupancy of important felid prey (cottontail rabbits and mule deer) was similar across levels of urbanization, although elk occupancy was lower in urbanized areas. Our study indicates that the conservation of medium- and large-sized felids associated with urbanization likely will be most successful if large areas of wildland habitat are maintained, even in close proximity to urban areas, and wildland habitat is not converted to low-density residential development. PMID- 26591455 TI - Life history differences influence the impacts of drought on two pond-breeding salamanders. AB - Drought is a strong density-independent environmental filter that contributes to population regulation and other ecological processes. Not all species respond similarly to drought, and the overall impacts can vary depending on life histories. Such differences can necessitate management strategies that incorporate information on individual species to maximize conservation success. We report the effects of a short-term drought on occupancy and reproductive success of two pond-breeding salamanders that differ in breeding phenology (fall vs. spring breeder) across an active military base landscape in Missouri, USA: We surveyed ~200 ponds for the presence of eggs, larvae, and metamorphs from 2011 to 2013. This period coincided with before, during, and after a severe drought that occurred in 2012. The two species showed contrasting responses to drought, where high reproductive failure (34% of ponds) was observed for the spring breeder during a single drought year. Alternatively, the fall breeder only showed a cumulative 8% failure over two years. The number of breeding ponds available for use in the fall decreased during the drought due to pond drying and/or a lack of re-filling. Estimates of occupancy probability declined for the fall-breeding salamander between 2012 and 2013, whereas occupancy probability estimates of the spring breeder increased post-drought. The presence of fish, hydroperiod, the amount of forest cover surrounding ponds, and canopy cover were all found to affect estimates of occupancy probabilities of each species. Pond clustering (distance to nearest pond and the number of ponds within close proximity), hydroperiod, forest cover, and canopy cover influenced both estimates of colonization and extinction probabilities. Our results show life history variation can be important in determining the relative susceptibility of a species to drought conditions, and that sympatric species experiencing the same environmental conditions can respond differently. Consideration of the spatial network and configuration of habitat patches that act as refuges under extreme environmental conditions will improve conservation efforts, such as the placement of permanent ponds for aquatic organisms. A better awareness of species-specific tolerances to environmental filters such as drought can lead to improved management recommendations to conserve and promote habitat for a greater diversity of species across landscapes of spatially connected populations. PMID- 26591456 TI - Structural habitat predicts functional dispersal habitat of a large carnivore: how leopards change spots. AB - Natal dispersal promotes inter-population linkage, and is key to spatial distribution of populations. Degradation of suitable landscape structures beyond the specific threshold of an individual's ability to disperse can therefore lead to disruption of functional landscape connectivity and impact metapopulation function. Because it ignores behavioral responses of individuals, structural connectivity is easier to assess than functional connectivity and is often used as a surrogate for landscape connectivity modeling. However using structural resource selection models as surrogate for modeling functional connectivity through dispersal could be erroneous. We tested how well a second-order resource selection function (RSF) models (structural connectivity), based on GPS telemetry data from resident adult leopard (Panthera pardus L.), could predict subadult habitat use during dispersal (functional connectivity). We created eight non exclusive subsets of the subadult data based on differing definitions of dispersal to assess the predictive ability of our adult-based RSF model extrapolated over a broader landscape. Dispersing leopards used habitats in accordance with adult selection patterns, regardless of the definition of dispersal considered. We demonstrate that, for a wide-ranging apex carnivore, functional connectivity through natal dispersal corresponds to structural connectivity as modeled by a second-order RSF. Mapping of the adult-based habitat classes provides direct visualization of the potential linkages between populations, without the need to model paths between a priori starting and destination points. The use of such landscape scale RSFs may provide insight into predicting suitable dispersal habitat peninsulas in human-dominated landscapes where mitigation of human-wildlife conflict should be focused. We recommend the use of second-order RSFs for landscape conservation planning and propose a similar approach to the conservation of other wide-ranging large carnivore species where landscape-scale resource selection data already exist. PMID- 26591457 TI - Using kernels and ecological niche modeling to delineate conservation areas in an endangered patch-breeding phenotype. AB - Efficient delineation of conservation areas is a great challenge in maintaining biodiversity. Kernel density estimators (KDEs) are a powerful tool in this perspective, but they have not been applied at the population level on patch distributed organisms. This would be particularly worthy for species that need broad habitats beyond those where they can be sampled; such as terrestrial lands for pond-breeding amphibians. The aim of this study was to compare different approaches for the identification of suitable areas for conservation: KDE, ecological niche modelling, and a combination of KDE and niche models. Paedomorphosis was chosen as a model system because this is an important form of intraspecific variation that is present in numerous taxa, but geographically localized within species and globally endangered. 277 ponds were sampled in one of the hotspots of paedomorphosis to determine the abundance and distribution of paedomorphs (i.e., individuals retaining gills at the adult stage) of the palmate newt (Lissotriton helveticus), with emphasis on the connections between the most valuable populations. KDEs gave insights into the surface areas required to balance the maintenance of certain number of connected ponds and the respective number of disjoint areas in which the whole population is divided. The inclusion of barriers in the models helped in accurately designing the limits of the areas to protect. Alone, habitat models were not able to successfully delineate the area to protect, but the integration between terrestrial suitable areas or barriers and KDE allowed an objective identification of areas required for conservation. Overall, the best performance was observed by the KDE integrating ecological barriers, and by the combination between KDE and niche modelling. In a broader perspective, KDEs are thus a pertinent tool in providing quantitative spatial measurements to delineate conservation areas based on patch-abundance data with a specific focus to connectivity. PMID- 26591458 TI - Dynamics of a recovering Arctic bird population: the importance of climate, density dependence, and site quality. AB - Intrinsic and extrinsic factors affect vital rates and population-level processes, and understanding these factors is paramount to devising successful management plans for wildlife species. For example, birds time migration in response, in part, to local and broadscale climate fluctuations to initiate breeding upon arrival to nesting territories, and prolonged inclement weather early in the breeding season can inhibit egg-laying and reduce productivity. Also, density-dependent regulation occurs in raptor populations, as territory size is related to resource availability. Arctic Peregrine Falcons (Falco peregrinus tundrius; hereafter Arctic peregrine) have a limited and northern breeding distribution, including the Colville River Special Area (CRSA) in the National Petroleum Reserve-Alaska, USA. We quantified influences of climate, topography, nest productivity, prey habitat, density dependence, and interspecific competition affecting Arctic peregrines in the CRSA by applying the Dail-Madsen model to estimate abundance and vital rates of adults on nesting cliffs from 1981 through 2002. Arctic peregrine abundance increased throughout the 1980s, which spanned the population's recovery from DDT-induced reproductive failure, until exhibiting a stationary trend in the 1990s. Apparent survival rate (i.e., emigration; death) was negatively correlated with the number of adult Arctic peregrines on the cliff the previous year, suggesting effects of density dependent population regulation. Apparent survival and arrival rates (i.e., immigration; recruitment) were higher during years with earlier snowmelt and milder winters, and apparent survival was positively correlated with nesting season maximum daily temperature. Arrival rate was positively correlated with average Arctic peregrine productivity along a cliff segment from the previous year and initial abundance was positively correlated with cliff height. Higher cliffs with documented higher productivity (presumably indicative of higher quality habitat), are a priority for continued protection from potential nearby development and disturbance to minimize population-level impacts. Climate change. may affect Arctic peregrines in multiple ways, including through access to more snow-free nest sites and a lengthened breeding season that may increase likelihood of nest success. Our work provides insight into factors affecting a population during and after recovery, and demonstrates how the Dail-Madsen model can be used for any unmarked population with multiple years of abundance data collected through repeated surveys. PMID- 26591459 TI - I Environmental DNA sampling is more sensitive than a traditional survey technique for detecting an aquatic invader. AB - Effective management of alien species requires detecting populations in the early stages of invasion. Environmental DNA (eDNA) sampling can detect aquatic species at relatively low densities, but few studies have directly compared detection probabilities of eDNA sampling with those of traditional sampling methods. We compare the ability of a traditional sampling technique (bottle trapping) and eDNA to detect a recently established invader, the smooth newt Lissotriton vulgaris vulgaris, at seven field sites in Melbourne, Australia. Over a four month period, per-trap detection probabilities ranged from 0.01 to 0.26 among sites where L. v. vulgaris was detected, whereas per-sample eDNA estimates were much higher (0.29-1.0). Detection probabilities of both methods varied temporally (across days and months), but temporal variation appeared to be uncorrelated between methods. Only estimates of spatial variation were strongly correlated across the two sampling techniques. Environmental variables (water depth, rainfall, ambient temperature) were not clearly correlated with detection probabilities estimated via trapping, whereas eDNA detection probabilities were negatively correlated with water depth, possibly reflecting higher eDNA concentrations at lower water levels. Our findings demonstrate that eDNA sampling can be an order of magnitude more sensitive than traditional methods, and illustrate that traditional- and eDNA-based surveys can provide independent information on species distributions when occupancy surveys are conducted over short timescales. PMID- 26591460 TI - Out-of-sample predictions from plant-insect food webs: robustness to missing and erroneous trophic interaction records. AB - With increasing biotic introductions, there is a great need for predictive tools to anticipate which new trophic interactions will develop and which will not. Phylogenetic constraint of interactions in both native and novel food webs can make some novel interactions predictable. However, many food webs are sparsely sampled, or may include inaccurate interactions. In such cases, it is unclear whether modeling methods are still useful to anticipate novel interactions. We ran bootstrap simulations of host-use models on a Lepidoptera-plant data set to remove native trophic records or add erroneous records in order to observe the effect of missing or erroneous data on the prediction of interactions with novel plants. We found that the model was robust to a large amount of missing interaction records, but lost predictive power with the addition of relatively few erroneous interaction records. The loss of predictive power with missing records was due to inaccuracy in estimating phylogenetic distance between native and novel hosts. Removal of interaction records proportionally to their encounter frequency in the field had little effect on the loss of predictive power. Host use models may have immediate value for predicting novel interactions from large, but sparsely sampled databases of trophic interactions. PMID- 26591461 TI - Temperature and depth mediate resource competition and apparent competition between Mysis diluviana and kokanee. AB - In many food webs, species in similar trophic positions can interact either by competing for resources or boosting shared predators (apparent competition), but little is known about how the relative strengths of these interactions vary across environmental gradients. Introduced Mysis diluviana shrimp interact with planktivorous fishes such as kokanee salmon (lacustrine Oncorhynchus nerka) through both of these pathways, and effective management depends on understanding which interaction is more limiting under different conditions. An "environmental matching" hypothesis predicts the ecological impacts of Mysis are maximized under cool conditions near its thermal optimum. In addition, we hypothesized Mysis is more vulnerable to predation by lake trout in relatively shallow waters, and therefore Mysis enhances lake trout density and limits kokanee through apparent competition more strongly in shallower habitats. We tested whether these hypotheses could explain food web differences between two connected lake basins, one relatively shallow and the other extremely deep. The shallower basin warmed faster, thermally excluded Mysis from surface waters for 75% longer, and supported 2.5-18 times greater seasonal production of cladoceran zooplankton than the deeper basin, standardized by surface area. Mysis consumed 14-22% less zooplankton in the shallower basin, and lower ratios of total planktivore consumption to zooplankton production (C:P) indicated less potential for resource competition with kokanee, consistent with environmental matching. Lake trout diets contained more Mysis in the shallower basin and at shallower sampling sites within both basins. The catch rate of lake trout was seven times greater and the predation risk for kokanee was 4-5 times greater in the shallower basin than in the deeper basin, consistent with stronger apparent competition in shallower habitats. Understanding how the strengths of these interactions are mediated by temperature and depth would enable managers to select appropriate strategies to address the unique combinations of conditions in hundreds of affected systems. PMID- 26591462 TI - Spatiotemporal variation in the relationship between landscape simplification and insecticide use. AB - Agrochemicals have numerous negative impacts on human health, ecosystem services, and ecological communities. Thus, their efficient use is an economic and ecological priority. Simplified landscapes may enhance insecticide use by reducing natural enemies and increasing connectivity of crops, but empirical tests of this theory are inconclusive. We explored the relationship between landscape simplification and insecticide use using longitudinal data from USDA Census of Agriculture spanning six censuses and 25 years (1987, 1992, 1997, 2002, 2007, 2012) for nearly 3000 counties across the continental United States. The effect of landscape simplification was highly variable spatially and temporally. Landscape simplification was consistently correlated with increased insecticide use in some regions, but not in others. Our results indicate that the landscape simplification-insecticide-use relationship is dynamic, and that national land use policy would benefit from actions that adequately reflect the spatial differences in the importance of landscape complexity to insecticide use. PMID- 26591463 TI - Geophysical features influence the climate change sensitivity of northern Wisconsin pine and oak forests. AB - Landscape-scale vulnerability assessment from multiple sources, including paleoecological site histories, can inform climate change adaptation. We used an array of lake sediment pollen and charcoal records to determine how soils and landscape factors influenced the variability of forest composition change over the past 2000 years. The forests in this study are located in northwestern Wisconsin on a sandy glacial outwash plain. Soils and local climate vary across the study area. We used the Natural Resource Conservation Service's Soil Survey Geographic soil database and published fire histories to characterize differences in soils and fire history around each lake site. Individual site histories differed in two metrics of past vegetation dynamics: the extent to which white pine (Pinus strobus) increased during the Little Ice Age (LIA) climate period and the volatility in the rate of change between samples at 50-120 yr intervals. Greater increases of white pine during the LIA occurred on sites with less sandy soils (R2 = 0.45, P < 0.0163) and on sites with relatively warmer and drier local climate (R2 = 0.55, P < 0.0056). Volatility in the rate of change between samples was positively associated with LIA fire frequency (R2 = 0.41, P < 0.0256). Over multi-decadal to centennial timescales, forest compositional change and rate-of change volatility were associated with higher fire frequency. Over longer (multi centennial) time frames, forest composition change, especially increased white pine, shifted most in sites with more soil moisture. Our results show that responsiveness of forest composition to climate change was influenced by soils, local climate, and fire. The anticipated climatic changes in the next century will not produce the same community dynamics on the same soil types as in the past, but understanding past dynamics and relationships can help us assess how novel factors and combinations of factors in the future may influence various site types. Our results support climate change adaptation efforts to monitor and conserve the landscape's full range of geophysical features. PMID- 26591464 TI - Sensitivity analysis of conservation targets in systematic conservation planning. AB - Systematic conservation planning has rapidly advanced in the past decade and has been increasingly incorporated in multiple studies and conservation projects. One of its requirements is a quantitative definition of conservation targets. While the Convention on Biological Diversity aims to expand the world's protected area network to 17% of the land surface, in many cases such uniform policy-driven targets may not be appropriate for achieving persistence of various species. Targets are often set arbitrarily, often because information required for the persistence of each species is unavailable or unknown in the focal region. Conservation planners therefore need to establish complementary novel approaches to address the gaps in setting targets. Here, we develop and present a novel method that aims to help guide the selection of conservation targets, providing support for decision makers, planners, and managers. This is achieved by examining the overall flexibility of the conservation network resulting from conservation prioritization, and aiming for greater flexibility. To test this approach we applied the decision support tool Marxan to determine marine conservation priority areas in the eastern Mediterranean Sea as a case study. We assessed the flexibility of the conservation network by comparing 80 different scenarios in which conservation targets were gradually increased and assessed by a range of calculated metrics (e.g., the percentage of the total area selected, the overall connectivity). We discovered that when conservation targets were set too low (i.e., below 10% of the distribution range of each species), very few areas were identified as irreplaceable and the conservation network was not well defined. Interestingly, when conservation targets were set too high (over 50% of the species' range), too many conservation priority areas were selected as irreplaceable, an outcome which is realistically infeasible to implement. As a general guideline, we found that flexibility in a conservation network is adequate when ~10-20% of the study area is considered irreplaceable (selection frequency values over 90%). This approach offers a useful sensitivity analysis when applying target-based systematic conservation planning tools, ensuring that the resulting protected area conservation network offers more choices for managers and decision makers. PMID- 26591465 TI - Measuring ecosystem capacity to provide regulating services: forest removal and recovery at Hubbard Brook (USA). AB - In this study, by coupling long-term ecological data with empirical proxies of societal demand for benefits, we measured the capacity of forest watersheds to provide ecosystem services over variable time periods, to different beneficiaries, and in response to discrete perturbations and drivers of change. We revisited one of the earliest ecosystem experiments in North America: the 1963 de-vegetation of a forested catchment at Hubbard Brook Experimental Forest in New Hampshire, USA. Potential benefits of the regulation of water flow, water quality, greenhouse gases, and forest growth were compared between experimental (WS 2) and reference (WS 6) watersheds over a 30-year period. Both watersheds exhibited similarly high capacity for flow regulation, in part because functional loads remained low (i.e., few major storm events) during the de-vegetation period. Drought mitigation capacity, or the maintenance of flows sufficient to satisfy municipal water consumption, was higher in WS 2 due to reduced evapotranspiration associated with loss of plant cover. We also assessed watershed capacity to regulate flows to satisfy different beneficiaries, including hypothetical flood averse and drought averse types. Capacity to regulate water quality was severely degraded during de-vegetation, as nitrate concentrations exceeded drinking water standards on 40% of measurement days. Once forest regeneration began, WS 2 rapidly recovered the capacity to provide safe drinking water, and subsequently mitigated the eutrophication potential of rainwater at a marginally higher level than WS 6. We estimated this additional pollution removal benefit would have to accrue for approximately 65-70 years to offset the net eutrophication cost incurred during forest removal. Overall, our results affirmed the critical role of forest vegetation in water regulation, but also indicated trade-offs associated with forest removal and recovery that partially depend on larger-scale exogenous changes in climate forcing and pollution inputs. We also provide a starting point for integrating long-term ecological research and modeling data into ecosystem services science. PMID- 26591466 TI - Linking spatial patterns of leaf litterfall and soil nutrients in a tropical forest: a neighborhood approach. AB - Leaf litter represents an important link between tree community composition, forest productivity and biomass, and ecosystem processes. In forests, the spatial distribution of trees and species-specific differences in leaf litter production and quality are likely to cause spatial heterogeneity in nutrient returns to the forest floor and, therefore, in the redistribution of soil nutrients. Using mapped trees and leaf litter data for 12 tree species in a subtropical forest with a well-documented history of land use, we: (1) parameterized spatially explicit models of leaf litter biomass and nutrient deposition; (2) assessed variation in leaf litter inputs across forest areas with different land use legacies; and (3) determined the degree to which the quantity and quality of leaf litter inputs and soil physical characteristics are associated with spatial heterogeneity in soil nutrient ratios (C:N and N:P). The models captured the effects of tree size and location on spatial variation in leaf litterfall (R2 = 0.31-0.79). For all 12 focal species, most of the leaf litter fell less than 5 m away from the source trees, generating fine- scale spatial heterogeneity in leaf litter inputs. Secondary forest species, which dominate areas in earlier successional stages, had lower leaf litter C:N ratios and produced less litter biomass than old-growth specialists. In contrast, P content and N:P ratios did not vary consistently among successional groups. Interspecific variation in leaf litter quality translated into differences in the quantity and quality (C:N) of total leaf litter biomass inputs and among areas with different land use histories. Spatial variation in leaf litter C:N inputs was the major factor associated with heterogeneity in soil C:N ratios relative to soil physical characteristics. In contrast, spatial variation soil N:P was more strongly associated with spatial variation in topography than heterogeneity in leaf litter inputs. The modeling approach presented here can be used to generate prediction surfaces for leaf litter deposition and quality onto the forest floor, a useful tool for understanding soil-vegetation feedbacks. A better understanding of the role of leaf litter inputs from secondary vegetation in restoring soil nutrient stocks will also assist in managing expanding secondary forests in tropical regions. PMID- 26591468 TI - Linking removal targets to the ecological effects of invaders: a predictive model and field test. PMID- 26591467 TI - Hypothesis-driven and field-validated method to prioritize fragmentation mitigation efforts in road projects. AB - The active field of connectivity conservation has provided numerous methods to identify wildlife corridors with the aim of reducing the ecological effect of fragmentation. Nevertheless, these methods often rely on untested hypotheses of animal movements, usually fail to generate fine-scale predictions of road crossing sites, and do not allow managers to prioritize crossing sites for implementing road fragmentation mitigation measures. We propose a new method that addresses these limitations. We illustrate this method with data from southwestern Gabon (central Africa). We used stratified random transect surveys conducted in two seasons to model the distribution of African forest elephant (Loxodonta cyclotis), forest buffalo (Syncerus caffer nanus), and sitatunga (Tragelaphus spekii) in a mosaic landscape along a 38.5 km unpaved road scheduled for paving. Using a validation data set of recorded crossing locations, we evaluated the performance of three types of models (local suitability, local least-cost movement, and regional least-cost movement) in predicting actual road crossings for each species, and developed a unique and flexible scoring method for prioritizing road sections for the implementation of road fragmentation mitigation measures. With a data set collected in <10 weeks of fieldwork, the method was able to identify seasonal changes in animal movements for buffalo and sitatunga that shift from a local exploitation of the site in the wet season to movements through the study site in the dry season, whereas elephants use the entire study area in both seasons. These three species highlighted the need to use species- and season-specific modeling of movement. From these movement models, the method ranked road sections for their suitability for implementing fragmentation mitigation efforts, allowing managers to adjust priority thresholds based on budgets and management goals. The method relies on data that can be obtained in a period compatible with environmental impact assessment constraints, and is flexible enough to incorporate other potential movement models and scoring criteria. This approach improves upon available methods and can help inform prioritization of road and other linear infrastructure segments that require impact mitigation methods to ensure long-term landscape connectivity. PMID- 26591469 TI - Response to Valderrama and Fields: effect of temperature on biomass production in models of invasive lionfish control. PMID- 26591470 TI - "Reflection will benefit the nursing profession". PMID- 26591471 TI - New competency checks from April. PMID- 26591472 TI - Call for global action on safe staffing levels. PMID- 26591473 TI - NHS chief urges government to 'rethink' immigration policy. PMID- 26591474 TI - Migration rules derail major nurse recruitment plans. PMID- 26591475 TI - Language test adopted for EU staff seeking NMC registration. PMID- 26591476 TI - Public views nursing as the most 'under-appreciated' profession. PMID- 26591477 TI - Public 'will' have say in maternity services review. PMID- 26591479 TI - Nurse debuts cannula use in community. PMID- 26591478 TI - Specialist palliative care nurses vital to choosing to die at home. PMID- 26591480 TI - "Nurses and midwives could be on the first plane home". PMID- 26591481 TI - "If we need more nurses, we need to fund university places". PMID- 26591482 TI - "Myers Briggs test could enable personal and reflective journey". PMID- 26591483 TI - Best-practice statements: should we use them? AB - Best-practice statements aim to facilitate evidence-based practice and improve care quality. They may improve care provision when developed using systematic, rigorous methods but there is no standardised approach for this and the support available may be limited. Methods used to develop, implement and monitor statements are not always transparent, and evaluation of their impact is inadequate. This article discusses their use as tools to facilitate evidence based practice and improve care, and the factors that can constrain or promote this. PMID- 26591484 TI - Staff and patient views on intentional rounding. AB - Intentional rounding is controversial, with growing evidence questioning its effectiveness. This article describes the planning stage of a quality improvement project to develop rounding undertaken by a London trust. Through a survey, interviews, observations and an audit, it was found that neither patients nor staff believed intentional rounding was effective in improving patient care. The system was not carried out as indicated by trust policy, and patients interviewed questioned the need for rounding. It is suggested that nurses and patients work together to develop a new model of inpatient care provision, with emphasis placed on an effective nurse-patient relationship. PMID- 26591485 TI - PART 2 of 5: SOCIOLOGY IN NURSING. Social class and its influence on health. AB - The article discusses how the distribution of health mirrors that of wealth. Poor health correlates with poor material circumstances but health inequalities persist across all classes. Health inequalities are more often seen in cultures where there is a more pronounced material divide. PMID- 26591486 TI - How do nurses experience reflective practice? AB - BACKGROUND: Reflective practice can raise the quality and consistency of nursing care, but there is little evidence of it being part of everyday culture and practice. AIM: To improve the incidence and quality of guided reflective practice. METHOD: Nurses from three trusts attended a focus group to gather experience, views and ideas of reflective practice/clinical supervision. The team also looked at supervision policies of nine trusts, best-practice examples and consulted nurse experts and leaders. RESULTS: Quantitative results showed that most nurses had some form of supervision but had little opportunity to question and discuss. Qualitative results revealed seven common themes. DISCUSSION: Project findings show a lack of organised and systematic reflection. CONCLUSION: New models of supervision and strengthened nurse leadership are needed to increase reflective practice among nurses. PMID- 26591487 TI - 60 Seconds with Janet Kellett. PMID- 26591488 TI - Pick your next career move. PMID- 26591489 TI - Conservative Dentistry: Are We There Yet? PMID- 26591490 TI - It's the Point of Transaction. PMID- 26591491 TI - FOCUS ON: Cosmetic Imaging. PMID- 26591492 TI - Dry Mouth Syndrome and the Emerging Role of Arginine-Based Technologies. PMID- 26591493 TI - Avoiding Subgingival Margins for Healthier Dentistry: Using a Supragingival Preparation Protocol. PMID- 26591494 TI - An Evaluation of Two Luting Cements. PMID- 26591495 TI - Atraumatic Removal of Mandibular Exostosis. PMID- 26591496 TI - Pre-Restorative Orthodontics: A Cornerstone of Comprehensive Care. PMID- 26591497 TI - Three-Dimensional Instrumentation: The Promise of Minimally Invasive Preparations. PMID- 26591498 TI - Treatment Planning for Dental Implants. PMID- 26591499 TI - To Graft or Not to Graft? Treating Vertical Bone Defects in the Aesthetic Zone. PMID- 26591500 TI - The Solid Zirconia Implant-Retained Prosthesis: An Excellent Full-Arch Alternative to the Fixed Hybrid Denture. PMID- 26591501 TI - Digitizing Implant Treatment: Abutment Design, Fabrication, and Provisionalization. PMID- 26591502 TI - SURVEYING YOUR NEEDS. PMID- 26591503 TI - THE RISE OF OPIOID ABUSE IN IOWA. PMID- 26591504 TI - PREPARATION CONTINUES FOR MEDICAID MANAGED CARE. PMID- 26591505 TI - THE COMING BUBBLE OF MEDICAL SCHOOL GRADUATES. PMID- 26591506 TI - TRANSITIONS OF CARE: THE PATIENT EXPERIENCE. PMID- 26591507 TI - [Neuroprotection of herbs promoting EPO on cerebral ischemia]. AB - Amounts of researches show that EPO is characterized with neurotrophic and neuroprotective manner, especially in brain stroke, which attracts a large numbers of researchers to study it. With the accumulating researches on its neuroprotection, many related mechanisms were revealed, such as antioxidant, anti apoptosis, angiogenesis, anti-inflammatory, which suggests a multiple targets role of EPO on brain stroke. However, because of the high risk of thromboembolism in clinical administration of rhEPO and its analogs, the herbs are potential to be a replacer for its less side effects. Many researchers suggested that a larger of herbs were founded having the action of increasing the endogenous EPO in the model of anemia and cerebral ischemia. At the same time, there herbs were also proved that they had the action of against cerebral ischemia while some without considering the role of EPO in the reports. Considering of the action of promoting EPO of these herbs and the neural protection of EPO, this essay mainly summarizes the studies of herbs promoting EPO in the cerebral ischemia and discusses the mechanism of regulating the EPO of these herbs, for the aim of finding the potential drugs against cerebral ischemia. PMID- 26591508 TI - [Relationship between efficacy exertion of diuretic traditional Chinese medicines and aquaporin]. AB - In recent years, the discovery and studies on aquaporin have made us have a more in-depth understanding about the physiological and pathological processes of water metabolism. Over years, however, there has been no quantitative study on the target sites of diuretic traditional Chinese medicines at the molecular level. In that case, aquaporin was found to been a new target molecule to explain the efficacy exertion of diuretic traditional Chinese medicines. By studying aquaporin, researchers can understand the implicit meaning of the diuretic effect of traditional Chinese medicines and conduct quantitative studies on the diuretic effect. So far, many scholars have conducted a series of studies in the traditional Chinese medicine field by using the findings on aquaporin and made certain advances. This article provides a summary about the efficacy exertion of diuretic traditional Chinese medicines through target molecule aquaporin. PMID- 26591509 TI - [Progress on cardiovascular protections and mechanism research of puerarin]. AB - Puerarin is one of the most important effective components of Pueraria lobata which exhibited classic estrogen-like biological activities and had remarkable cardiovascular protections in vivo and in vitro experiments. These protections of puerarin are mainly exhibited on improving the myocardial cells membrane potential and arrhythmia based on effecting the Na+, K+ , and Ca2+ channels,resisting myocardial fibrosis damage, diastolic effect on blood vessels, promoting angiogenesis, resisting calcification and atherosclerosis, improving blood flow, antiplatelet aggregation, reducing lipid and resisting diabetes. The main mechanisms are to improve the membrane potential and reduce cardiovascular damage caused by inflammation, oxidative stress and apoptosis, and the main regulated signal pathways are the PI3K/Akt, the NF-kappa B and the caspases. PMID- 26591510 TI - [Progress in study of antioxidant effects of Coptis chinensis and its major contributions to diabetes treatment/therapy]. AB - Coptis chinensis, a traditional Chinese medicine, has been found to have multiple pharmacological effects recently. Some research showed that C. chinensis has antioxidant effects, including scavenging oxygen free radicals, alleviating lipid peroxidation, enhancing activity of antioxidant enzymes, et al. C. chinensis may inhibit several classical pathological pathways in diabetes. C. chinensis is a potential medicine to prevent and treat diabetes mellitus and its complications. This review focuses on the recent research progress in the study of antioxidant effects of C. chinensis and its major contributions to diabetes treatment/therapy. PMID- 26591511 TI - [Dendrobium officinale cliff epiphytic cultivation method]. AB - To solve the issues of costly planting of facility cultivation method and inferior efficacy than wild herbs of Dendrobium officinale, the cliff epiphytic cultivation method was studied. To research the growth, agronomic traits, yield, polysaccharide and alcohol-soluble extract contents were measured on the D. officinale from different water regulation and cliff slope gradients treatments. The results showed that D. officinale epiphytic at 85 degrees-90 degrees cliff and sprayed water 1-2 h x d(-1) at the growing season can get better growth and obtain high yield, and the morphology has no different from wild cliff D. officinale, even in the environments without shade. The contents of polysaccharide and alcohol-soluble extract are closely related to the physiological ages, but significantly higher than the facility cultivation. It is possible that environmental stresses benefit the accumulation of polysaccharides, alcohol-soluble extract and other efficient ingredients. PMID- 26591512 TI - [Influence of diethyl sulfate (DES) mutagenesis on growth properties and pigment secondary metabolites of Phellinus igniarius]. AB - The diethyl sulfate (DES) mutagenesis was chosen for the mutagenic treatment to Phellinus igniarius, and the relationship of mutagenesis time and death rate was investigated with 0.5% DES. The differences of mycelial growth speed, liquid fermentation mycelia biomass, morphology and pigment classes of secondary metabolites production speed and antioxidant activities of metabolite products were discussed. The study displayed that DES mutagenesis could change mycelial morphology without obvious effect on mycelium growth, and the DES mutagenesis improved antioxidant activities of the active ingredients of P. igniarius and had more antioxidant activity of hypoxia/sugar PC12 nerve cells than that of P. igniarius. PMID- 26591513 TI - [Effect of topographical factors on podophyllotoxin content in Sinopodophyllum hexandrum and study on ecological suitability]. AB - In order to find the optimal topographical factor for regionslization, the content of cimetidine in 116 Sinopodophyllum hexandrum sample collected from Sichuan, Qinghai, Gansu, Tibet, Yunnan and Shaanxi provinces, was determined. Using mathematical statistics and geographical spatial analysis of GIS analysis, the relationship between content of podophyllotoxin and influencing factors including altitude gradient and gradient position was analyzed. It is found that the optimal altitude was 2 800 m to 3 600 m, the aspect of slope north or northeast and northwest and the slope 12 degrees to 65 degrees with a high suitability degree. Considering the artificial planting, the suitable planting area for S. hexandrum is comfirmed. The topographical factor is important for S. hexandrum regionalization, but has hardly effect on podophyllotoxin content. The results of the study provide an important scientific basis for S. hexandrum production development. But there are many factors which affect suitability index and podophyllotoxin content of S. hexandrum, it is necessary to consider other factors like climate and soil while exploitation and protection of S. hexandrum. PMID- 26591514 TI - [HRM identification of Chinese medicinal materials Mutong]. AB - High resolution melting (HRM), an important technology for genotyping and mutation scanning, has broad prospects in the authentification of traditional Chinese medicine. This paper selected universal trnH-psbA primers and used HRM to establish a new methods for identification of Akebia herbs. PCR was conduct at the annealing temperature of 58 degrees C and 35 cycles. The range of the DNA template concentration, the primer concentration and the Mg2+ ion concentration were further analyzed. The results showed the Tm values of Caulis Akebiae was (81.84 +/- 0.16), (85.28 +/- 0.16) degrees C and Caulis Clematidis Armandii was (83.22 +/- 0.19) degrees C and Caulis Aristolochiae manshuriensis was (81.67 +/- 0.14) degrees C, (84.24 +/- 0.10) degrees C with 5-125 mg - L-' DNA template, 0.4 MUmol x L(-1) primer, 2.0 mmol x L(-1) Mg2+. This method can achieve the authentification of Akebia herbs and is simple, fast, high-throughput, visual. PMID- 26591515 TI - [Identification of different varieties of Rhei Radix et Rhizoma based on chemical analysis]. AB - A HPLC method was established to determine the contents of the five anthraquinones and rhaponticin in the different varieties of Rhei Radix et Rhizoma. The difference existed in different varieties. The results showed that rhein and rhaponticin were marker substances which could be used to distinguish palm leaf groups rhubarb and wave leaf groups rhubarb. Authentic rhubarb didn't contain rhaponticin. Falsify rhubarb contains trace amounts of rhein. Rheum tanguticum contains abundant rhein. The ratio value of the content of rhein to chrysophanol could be used to distinguish R. tanguticum from the other two authentic varieties (R. palmatum and R. officinale). The content of rhaponticin varied largely in different varieties of wave leaf groups rhubarb. PMID- 26591516 TI - [Study on accumulation of polysaccharides and alcohol-soluble extracts contents of Dendrobium officinale leaves]. AB - This paper revealed the accumulation regularity of polysaccharides and alcohol soluble extracts contents of Dendrobium officinale leaves, which have provided basis for the development and utilization of the leaves. The polysaccharides and alcohol-soluble extracts contents of three D. officinale strains leaves collected in different growing periods were determined by phenol-sulfric acid method and hot-dip method respectively. The results showed that the content of polysaccharides in leaves was 4.45% -12.17%, and was about a quarter in stems. The alcohol-soluble extracts content in leaves was 7.45% - 29.34%, and was 1.5 times that of stems. The quality variation of polysaccharides in leaves was closely related to the phenophase. The leaves with lower level of metabolism in three stages: winter, early germination stage and deciduous period, which led to lower content of polysaccharides. The leaves at the vigorous growth stage with higher content of polysaccharides. The alcohol-soluble extracts were closely associated to the formation and germination of buds. The content of alcohol soluble extracts peaked before sprout, and promoted the growth of new shoots. PMID- 26591517 TI - [Identification of two varieties of Citri Fructus by fingerprint and chemometrics]. AB - Citri Fructus identification by fingerprint and chemometrics was investigated in this paper. Twenty-three Citri Fructus samples were collected which referred to two varieties as Cirtus wilsonii and C. medica recorded in Chinese Pharmacopoeia. HPLC chromatograms were obtained. The components were partly identified by reference substances, and then common pattern was established for chemometrics analysis. Similarity analysis, principal component analysis (PCA) , partial least squares-discriminant analysis (PLS-DA) and hierarchical cluster analysis heatmap were applied. The results indicated that C. wilsonii and C. medica could be ideally classified with common pattern contained twenty-five characteristic peaks. Besides, preliminary pattern recognition had verified the chemometrics analytical results. Absolute peak area (APA) was used for relevant quantitative analysis, results showed the differences between two varieties and it was valuable for further quality control as selection of characteristic components. PMID- 26591518 TI - [Comparative study on preparation of Polygoni Multiflori Radix based on hepatotoxic bioassay]. AB - Toxicity of different processed was evaluated Polygoni Multiflori Radix by determining the hepatotoxic potency for selecting processing technology. Process Polygoni Multiflori Radix using high pressure steamed, Black Bean high pressure steamed, atmospheric steamed for different time. Using normal human hepatocytes (L02) as evaluation model, hepatotoxic potency as index to evaluate hepatotoxic potency of different processed Polygoni Multiflori Radix. Analysis chemical composition of some processed products by UPLC-MS. Hepatotoxic bioassay method cloud evaluate the toxicity of different Polygoni Multiflori Radix samples. Different processing methods can reduce the toxicity of Polygoni Multiflori Radix, high pressure steamed three hours attenuated was better. Different processing methods have different effects on chemical constituents of Polygoni Multiflori Radix. Comparing with crude sample, the contents of gallic acid, 2,3,5,4-tetrahydroxyl diphenylethylene-2-O-glucoside, emodin-8-O-beta glucoside and emodin were decreased in processed products with 3 kinds of different methods. The change trend of 2,3,5,4-tetrahydroxyl diphenylethylene-2-O-glucoside content was similar with hepatotoxic potency. Different processing methods can reduce the toxicity of Polygoni Multiflori Radix. Processing methods and time attenuated obvious impact on toxicity. Recommended further research on the attehuated standard control of Polygoni Multiflori Radix concocted. PMID- 26591519 TI - [Optimization of vacuum belt drying process of Gardeniae Fructus in Reduning injection by Box-Behnken design-response surface methodology]. AB - To optimize the belt drying process conditions optimization of Gardeniae Fructus extract from Reduning injection by Box-Behnken design-response surface methodology, on the basis of single factor experiment, a three-factor and three level Box-Behnken experimental design was employed to optimize the drying technology of Gardeniae Fructus extract from Reduning injection. With drying temperature, drying time, feeding speed as independent variables and the content of geniposide as dependent variable, the experimental data were fitted to a second order polynomial equation, establishing the mathematical relationship between the content of geniposide and respective variables. With the experimental data analyzed by Design-Expert 8. 0. 6, the optimal drying parameter was as follows: the drying temperature was 98.5 degrees C , the drying time was 89 min, the feeding speed was 99.8 r x min(-1). Three verification experiments were taked under this technology and the measured average content of geniposide was 564. 108 mg x g(-1), which was close to the model prediction: 563. 307 mg x g(-1). According to the verification test, the Gardeniae Fructus belt drying process is steady and feasible. So single factor experiments combined with response surface method (RSM) could be used to optimize the drying technology of Reduning injection Gardenia extract. PMID- 26591520 TI - [Rapid discriminant analysis of sulfur fumigated Puerariae Lobatae Radix based on vertical and horizontal surfaces]. AB - Near-infrared (NIR) was used as rapid analysis method to identify the sulfur fumigated Puerariae Lobatae Radix. NIR spectra of the cross-sectional and longitudinal selection of samples were acquired. Principal component analysis was conducted. The samples were randomly selected. The different pretreatment methods were compared. Discriminant models were established for every type of spectra to calculate the recognition rate. The orthogonal test and nonparametric test were used to test data normality. The result showed that absorbance values of different sections were different due to the different structure, and the raw spectra were analyzed by PCA method. The result founded that the cumulative contribution rate was arrived at 99.2% while the PC numbers were arrived at 3. The pretreatment method based on the MSC + 1D + Savitzky-Golay was the best to establish the model. For the 50 models constructed with cross-section and longitudinal spectra and total spectra, the recognition rate were (94.4 +/- 0.66)%, (94.4 +/- 0.66)%, (95.3 +/- 0.65)%, respectively, and no difference was observed. The NIR method could be used to identify the sulfur fumigated Puerariae Lobatae Radix. PMID- 26591521 TI - [Purification technology of manninotirose in Rehmanniae Radix Praeparata by D-101 microporous adsorption resin]. AB - This paper was aim to optimize the purification technology of Rehmanniae Radix Praeparata extract with macroporous adsorption resin. With the content of manninotriose as index, the absorptive flow and time were investigated, as well as kinds, amount, flow of eluent. D-101 type macroporous adsorption resin was the best choice for the purification of manninotriose. The optimized parameters were as follows: the content of manninotriose at 161.16-53.72 mg x g(-1), absorption time 240 min, eluting solvent of purified water, volume flow at 1.5 BV x h(-1), and eluant volume at 6 BV. D-101 type macroporous adsorption resin could significantly increase the purity of Rehmanniae Radix Praeparata extract with the advantage of high absorption, remove most part of impurity, and the effect of semi-works production was better. PMID- 26591522 TI - [Determination of residual aluminium Ion in Huoxiang Zhengqi pellets by GFAAS with EDTA complexation extraction]. AB - To establish an EDTA complexation extraction pretreatment combining with GFAAS method for the determination of residual aluminium ion in Huoxiang zhengqi pellets without digestive treatment, systematical investigation was made on sample preparation, and EDTA was used for the complexation extraction of residual aluminium ion in samples. The pH, concentration and volume of extraction solution, the temperature and time of microwave extraction, and graphite furnace temperature program were investigated. The results were compared with the microwave digestion. It was showed that, 0.1 g of sample weight was added in 20 mL 0.05 mol x L(-1) EDTA solution (pH 3.5), followed by heating at 150 degrees C for 10 min in the microwave extraction device. The determination of GFAAS was performed at optimized detection wavelength (257.4 nm) as well as graphite furnace temperature program, the detection limits and quantification limits were 2.37 MUg x L(-1) and 7.89 MUg x L(-1), respectively. The precision (RSD) was less than 2.3%. The average recovery was 96.9% -101%. The present method is easy, rapid and accurate for the determination of residual aluminium ion in Huoxiang zhengqi pellets. PMID- 26591523 TI - [A new lactone derivative from plant endophytic fungus Periconia sp. F-31]. AB - To investigate the secondary metabolites of endophytic fungi Pericinia sp. F-31. Column chromatography on silica gel, Sephadex LH-20 and semi-preparative HPLC were used to separate and purify the compounds. Two compounds were isolated from the fermentation broth of Periconia sp. Their structures were identified as 5-(1 hydroxyhexyl) -6-methyl-2H-pyran-2-one (1) and 2-(3-hydroxy-4-methylphenyl) propanoic acid (2). Compound 1 was a new lactone compound, compound 2 was new natural product, and the NMR data of compound 2 was reported for the first time. PMID- 26591524 TI - [Isolation and structural identification of flavonoids from Aurantii Fructus]. AB - Aurantii Fructus is the dried and immature fruit of Citrus aurantium and its cultivars. To investigate the chemical constituents of Aurantii Fructus, the separation and purification of constituents were performed by column chromatography on silica gel LH-20, HW-40, ODS, PHPLC and PTLC. Fourteen flavonoids, including four flavone glycosides and ten polymethoxyflavones (PMFs) were isolated from the EtOAc fraction and Petroleum ether fraction of Aurantii Fructus and their structures were identified by physicochemical properties and spectral data (NMR and MS) as (2R) -and (2S)-6"-O-acetylprunin (1,2), naringenin 7-O-beta-D-glucopyranside (3), 5,7,4'-trihydroxy-8,3'-dimethoxyflavone-3-O-6"-(3 hydroxyl-3-methylglutaroyl)-beta-D-glucopyranoside(4), 4'-hydroxy-5,6, 7 trimethoxyflavone (5), natsudaidain (6), nobiletin (7), sinensetin (8), 5,6,7,4' tetramethoxyflavone (9), 5,7,8,4'-tetramethoxyflavone (10), 3,5,6,7,8,3',4' heptamethoxyflavone (11), tangeretin (12), 5-demethyl nobiletin (13), and 5 hydroxy-6,7,3', 4'-tetramethoxyflavone (14). Compound 3-5 s were isolated from this plant for the first time and compound 1 was a new one. PMID- 26591525 TI - [Chemical constituents from stems of Hedyotis hedyotidea and their immunosuppressive activity]. AB - Hedyotis hedyotidea has been traditionally used for the treatment of arthritis, cold, cough, gastro-enteritis, headstroke, etc. But few studies have screened the active compounds from extracts of H. hedyotidea. In this study, the structure of the chemical constituents from stems of H. hedyotidea were determined and the immunosuppressive activity of the compounds was evaluated. The compounds were separated and purified with silica gel, gel column chromatographies and preparative HPLC, and their structures were identified by spectral methods such as MS and NMR. Eleven compounds were obtained and identified as(6S,9S) vomifoliol (1), betulonic acid (2), betulinic acid (3), betulin(4), 3-epi betulinic acid (5), ursolic acid (6), beta-sitosterol (7), stigmast-4-en-3-one (8), 7beta-hydroxysitosterol (9), (3beta,7beta) -7-methoxystigmast-5-en-3-ol (10) and morindacin (11). This is the first report of compounds 1, 2, 4, 8, 9, 10 and 11 from H. hedyotidea. Compounds 1, 2 and 8-11 were firstly isolated from the genus Hedyotis, and compounds 9 and 10 were isolated from the family Rubiaceae for the first time. The immunosuppressive activity of these compounds was tested using the lymphocyte transsormationtest. Compounds 4, 6 and 9 showed significant immunosuppressive activity. PMID- 26591526 TI - [Isoflavones and flavans from Millettia nitida var. hirsutissima]. AB - The current study to separate and identify constituents from Millettia nitida var. hirsutissima. The compounds from Millettia nitida var. hirsutissima were isolated by means of various chromatographic techniques such as column chromatography over ODS and Sephadex LH-20, preparative HPLC, and the structures of these isolated compounds were identified through spectroscopic analyses. Nine isoflavonoids and two flavans were isolated and identified as 5-O-methy genistein (1), 7-hydroxy-3',4'-dimethoxyisoflavone (2), ononin (3), catechin (4), formononetin (5), genistein (6), calycosin (7), (-)-gallocatechin (8), sissotrin (9), wistin (10), daidzin (11). Compounds 1, 2, 9 are obtained from the genus Millettia for the first time,and compounds 4, 8 are isolated from this plant for the first time. PMID- 26591527 TI - [Secondary metabolites from a deep-sea-derived actinomycete Micrococcus sp. R21]. AB - To investigate cytotoxic secondary metabolites of Micrococcus sp. R21, an actinomycete isolated from a deep-sea sediment (-6 310 m; 142 degrees 19. 9' E, 10 degrees 54. 6' N) of the Western Pacific Ocean, column chromatography was introduced over silica gel, ODS, and Sephadex LH-20. As a result, eight compounds were obtained. By mainly detailed analysis of the NMR data, their structures were elucidated as cyclo(4-hydroxy-L-Pro-L-leu) (1), cyclo(L-Pro-L-Gly) (2), cyclo( L Pro-L-Ala) (3), cyclo( D-Pro-L-Leu) (4), N-beta-acetyltryptamine (5), 2 hydroxybenzoic acid (6), and phenylacetic acid (7). Compound 1 exhibited weak cytotoxic activity against RAW264. 7 cells with IC50 value of 9.1 MUmol x L(-1). PMID- 26591528 TI - [Study on antioxidant chemical constituents of Lonicera japonica leaves]. AB - Guided by the antioxidant activity, the EtOAc-soluble and n-butanol-soluble fractions of the 50% methanol extract of Lonicera japonica leaves were isolated and purified by various chromatorgraphic methods, and the structures were identified by spectral analysis and comparison to the data reported in literature. As a result, nine compounds were obtained and identified as 5-O caffeoylquinicacid (1), chlorogenicacid (2), 4-O-caffeoylquinicacid (3), luteolin 7-O-[alpha-L-arabinopyranosyl-(1 --> 6)] -beta-D-glucopyranoside (4), luteoloside (5), 3,4-di-O-caffeoylquinic acid (6), 3,5-di-O-caffeoylquinic acid (7), 4, 5-di O-caffeoylquinic acid (8) and luteolin (9). The antioxidant activity of the nine compounds were determined by using DPPH free radical scavenging method, and ascorbic acid was used as a positive control. Their antioxidant activities from high to low were 5 > 9 > 2 > 8 > 7 > 6 > 1 > 3 > 4. Among them, luteoloside (5) had the strongest antioxidant activity with an IC50 of 0.018 18 g x L(-1), and luteolin (IC50 0.023 6 g x L(-1)) and chlorogenicacid (IC50 0.035 17 g x L(-1)) ranks No. 2 and 3. Furthermore, the antioxidant activity of luteoloside and luteolin were stronger than that of ascorbic acid (IC50 0.027 54 g x L(-1)). These results gave a basis for the further study and utilization of L. japonica leaves. PMID- 26591529 TI - [Study on crocins reference extract and application on assay of Croci Stigma]. AB - High price and poor stability of both crocin-1 and crocin-2 reference substance have become obstacles to HPLC assay of Croci Stigma. A new method based on reference extract was proposed. In this study, the reference extract was prepared from gardenia yellow which is cheap and easy to get The content of crocin-1 and crocin-2 in reference extract was determined and factors affecting stability of reference extract were investigated. Twelve batches of Croci Stigma were analyzed with reference extract and reference substance respectively. The results showed no difference. The presented method is feasible for quality control of Croci Stigma and reference extract is suitable to replace reference substances in assay. PMID- 26591530 TI - [Study on inhibitory effect of calycosin on hepatic stellate cell activation in rats by up-regulating peroxisome proliferator-activated receptor gamma]. AB - To observe the effect of calycosin on the proliferation and activation of primary hepatic stellate cells (HSCs) in rats, and prove calycosin shows the effects through peroxisome proliferator-activated receptor gamma(PPARgamma) and farnesoid X receptor (FXR). The results indicated that calycosin could inhibit HSC proliferation and expressions of activation marker smooth muscle actin-alpha and type I collagen. With the increase in HSC activation time, FXR expression reduced, but with no notable impact from calycosin. Calycosin could up-regulate PPARgamma expression and its nuclear transition in a concentration-dependent manner. Its prohibitory effect on HSC activation could be blocked by PPARgamma antagonist. In conclusion, calycosin could inhibit HSC activation and proliferation, which may be related with the up-regulation of PPARgamma signal pathway. PMID- 26591531 TI - [Effect of cryptotanshinone on imatinib sensitivity and P-glycoprotein expression of chronic myeloid leukemia cells]. AB - Cryptotanshinone (CPT), a lipid soluble active compound in Salvia miltiorrhiza, has a significant inhibitory effect on multiple malignant tumors, e. g. chronic myeloid leukemia (CML) cells and can effectively enhance imatinib's chemotherapeutic effect. However, its functional molecular mechanism remained unclear. In this experiment, the authors conducted a systematic study on the effect of CPT on the imatinib sensitivity and P-glycoprotein (P-gp) expression in CML cells by using CML cells K562 and imatinib persister K562-R. The MTT assays were performed to determine CPT's impact on the inhibitory effect of imatinib. Annexin V-FITC/PI staining analysis was used to detect the changes in the cell apoptosis rate. The active changes in apoptosis regulatory proteins Caspase-3, Caspase-9 and PARP were determined by Western blot. After the cells were pretreated with the gradient concentration of CPT, the expression of P-gp was analyzed by Western blot and flow cytometry. The changes in intracellular concentrations of imatinib were determined by HPLC analysis. The results indicated that the pretreatment with CPT significantly increased the proliferation inhibiting and apoptosis inducing effects of imatinib on K562 and K562-R cells as well as the degradation product expression of pro-apoptotic proteins Caspase-3, Caspase-9 and PARP, with a significant difference with the control group (P < 0.01). However, CPT showed no impact on the P-gp expression in CML cells and the intracellular concentrations of imatinib. In summary, the findings suggested that CPT enhanced the sensitivity of CML cells to imatinib. Its mechanism is not dependent on the inhibition in P-gp expression and the increase in intracellular drug concentration. PMID- 26591532 TI - [Inhibitory effects of butyl alcohol extract of Baitouweng decoction on virulence factors of Candida tropicalis]. AB - OBJECTIVE: To investigate the effects of butyl alcohol extract of baitouweng decoction (BAEB) on the fungal cell surface hydrophobicity (CSH), filamentation and biofilm formation of Candida tropicalis. METHOD: Gradual dilution method was used to determine the MIC. XTT assay was applied to determine the SMIC80. Time Kill assay was employed to draw the Time-Kill curve. The water-hydrocarbon two phase assay was used to measure the cell surface hydrophobicity. Scanning electron microscopy (SEM) was applied to observe the morphological changes of the biofilm. Confocal laser scanning microscopy (CLSM) was applied to determine the thickness of the biofilm. The quantification real-time PCR (qRT-PCR) was used to detect expression changes of releated genes (UME6, ALST3 and NRG1). result: The MICs of BAEB against C. tropicalis strains are determined as 64-128 mg x L(-1). The SMIC80 s of BAEB against the biofilm of Candida tropicalis strains are determined as 256-512 mg x L(-1). Time-Kill curve results indicate that BAEB has a promise fungicidal effect at 256 and 512 mg x L(-1). SEM results shows that 512 mg x L(-1) BAEB can inhibit the formation of C. tropicalis biofilm on Silicone catheter, and the morphology of biofilm is also affected by BAEB. The thickness of C. tropicalis biofilm is reduced by BAEB according to CLSM results. Furthermore, qRT-PCR results indicate that expression of UME6 and ALST3 are significantly down-regulated by BAEB 256,512 mg x L(-1), and NRG1 is not affected by BAEB. CONCLUSION: BAEB inhibits effectively the CSH, filamentation and biofilm formation of VVC strains of C. tropicalis. PMID- 26591533 TI - [Effect of aralosides to contraction function and calcium transient of ischemia/reperfusion myocardial cells]. AB - To discuss the protective effect of aralosides (AS) on I/R-induced rat myocardial injury. The adult rat ventricular myocyte ischemia model was established through perfusion with sodium lactate perfusate and reperfusion with Ca(2+) -containing Tyrode's solution simulation. The cell contraction and ion concentration synchronization determination system was applied to detect the effect of AS on single I/R cell contraction and Ca2+ transients. According to the findings, AS could increase resting sarcomere length, contraction amplitude, +/- dL/dt(max), calcium transient amplitude and speed of post-reperfusion myocardial cells (P < 0.05, P < 0.01), and decrease in time for achieving 90.0% of maximum relaxation, time for achieving peak value, resting calcium ratio, contraction period [Ca2+] i, time for achieving 50.0% of maximum relaxation and attenuation rate of intracellular calcium transient (P < 0.05, P < 0.01). Therefore, it is suggested that AS improved the post-reperfusion cell contraction and injury of calcium homeostasis. PMID- 26591534 TI - [Effect of Shenxiong injection on inflammation injury of ischemia-reperfusion injury rats]. AB - To investigate the effect of Shenxiong injection on the inflammation injury of ischemia-reperfusion injury senile rats. Totally 84 Sprague-Dawley (SD) rats were randomly divided into six groups: the sham operation group, the model group, the Nimodipine group and the Shenxiong injection(low, middle, and high dosage) groups. The rat cerebral ischemia-reperfusion model was established through intraperitoneal injection for 3 d and middle cerebral artery occlusion (MCAO). Ater the reperfusion for 24 h, efforts were made to give neurological score, collect brains for TTC staining, detect tumor necrosis factor-alpha(TNF-alpha) and interleukin-1beta(IL-1beta) content in serum by enzyme-linked immunosorbent assay (ELISA) method and measure IL-1beta, ICAM-1 and MMP-9 mRNA expressions in hippocampal area by Real-time PCR (RT-PCR). According to the results, Shenxiong injection could decrease the cerebral infarction volume, greatly improved the neurological function and reduce IL-1beta, TNF-alpha, ICAM-1 and MMP-9 mRNA expressions and IL-1beta and TNF-alpha contents. In conclusion, Shenxiong injection shows the significant protective effect on ischemia-reperfusion injury in rats. Its mechanism may be related to the inhibition of inflammatory factor expression. PMID- 26591535 TI - [Study on anti-hyperlipidemia mechanism of high frequency herb pairs by molecular docking method]. AB - Traditional Chinese medicine (TCM) has definitely clinical effect in treating hyperlipidemia, but the action mechanism still need to be explored. Based on consulting Chinese Pharmacopoeia (2010), all the lipid-lowering Chinese patent medicines were analyzed by associated rules data mining method to explore high frequency herb pairs. The top three couplet medicines with high support degree were Puerariae Lobatae Radix-Crataegi Fructus, Salviae Miltiorrhizae Radix et Rhizoma-Crataegi Fructus, and Polygoni Multiflori Radix-Crataegi Fructus. The 20 main ingredients were selected from the herb pairs and docked with 3 key hyperlipidemia targets, namely 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), peroxisome proliferator activated receptor-alpha (PPAR-alpha ) and niemann-pick C1 like 1 (NPC1L1) to further discuss the molecular mechanism of the high frequency herb pairs, by using the docking program, LibDock. To construct evaluation rules for the ingredients of herb pairs, the root-mean square deviation (RMSD) value between computed and initial complexes was first calculated to validate the fitness of LibDock models. Then, the key residues were also confirmed by analyzing the interactions of those 3 proteins and corresponding marketed drugs. The docking results showed that hyperin, puerarin, salvianolic acid A and polydatin can interact with two targets, and the other five compounds may be potent for at least one of the three targets. In this study, the multi-target effect of high frequency herb pairs for lipid-lowering was discussed on the molecular level, which can help further researching new multi-target anti-hyperlipidemia drug. PMID- 26591536 TI - [Study on contribution of main components in Guizhi Fuling capsule based on molecular imprinting technique and activity screening]. AB - To clarify the active components in Guizhi Fuling capsule in treatment of intrinsic dysmenorrhea, pelvic inflammation and hysteromyoma, main components were gradually knocked out from the capsules, the effects of knockout capsules on uterine contraction, TNF-alpha secretion, murine splenocytes (SPL) and hysteromyoma cells proliferation were evaluated, respectively. The inhibition of capsules on uterine contraction was weakened by gradient knockout of paeoniflorin, paeonol, and amygdalin. The suppression of capsulte on TNF-alpha secretion was reduced by gradient knockout of gallic acid, cinnamaldehyde, pentagalloylglucose, and pachyman. The promotion of SPL cells proliferation was reversed by gradient knockout of gallic acid, paeoniflorin, cinnamaldehyde, quercetin, and pachyman. The depression of capsules on hysteromyoma cells proliferation was attenuated by gradient knockout of paeoniflorin, paeonol, pentagalloylglucose, and albiflorin. In conclusion, the compounds mentioned-above could be the key active basis of Guizhi Fuling capsule in treatment of intrinsic dysmenorrhea, pelvic inflammation and hysteromyoma. PMID- 26591537 TI - [Pharmacokinetics of loganin, ferulic acid and stilbene glucoside in Bushen Tongluo formula in vivo]. AB - To study the pharmacokinetics characteristic of loganin, ferulic acid and stilbene glucoside in rat plasma after oral administration of Bushen Tongluo formula. The plasma samples were treated by using liquid-liquid extraction technique, the concentrations were determined by HPLC-UV. Johnson spherigel C18 column (4.6 mm x 250 mm, 5 MUm) was adopted and eluted with the of mobile phase of methanol-water containing 0.01% glacial acetic acid in a gradient mode, with the flow rate at 1.0 mL x min(-1), column temperature at 30 degrees C and injection volume of 10 MUL. According to the findings, loganin was determined at 235 nm, ferulic acid and stilbene glucoside were determined at 320 nm, with the sample size of 10 MUL. The pharmacokinetic parameters of loganin, ferulic acid and stilbene glucoside were calculated by DAS 2. 0 software as follows: C(max) was (0.369 +/- 0.042), (0.387 +/- 0.071), (0.233 +/- 0.044) mg x L(-1); t(max) was (0.226 +/- 0.022), (0.282 +/- 0.031), (0.233 +/- 0.044) h; t(1/2beta) was (6.89 +/- 0.20), (10.73 +/- 0.11), (6.93 +/- 0.09) h; AUC(0-infinity) was (1.91 +/- 0.36), (3.22 +/- 0.52), (1.52 +/- 0.33) mg x h x L(-1); AUCO(0-t) was (1.62 +/- 0.33), (2.58 +/- 0.43), (1.30 +/- 0.30) mg x h x L(-1); CL was (20.2 +/- 4.0), (1.39 +/- 0.23), (31.7 +/- 6.9) L x h(-1) x kg(-1), respectively. The results showed that after the oral administration with Bushen Tongluo formula, loganin, ferulic acid and stilbene glucoside showed concentration-time curves in conformity with the two compartment model, with a rapid absorption, loganin and stilbene glucoside was excreted at a moderate speed, and ferulic acid was excreted slowly (but with the highest bioavailability). Bushen Tongluo formula can main maintain plasma concentration with three administrations everyday and so is suitable to be made into common oral preparation. PMID- 26591538 TI - [Common clinical medical combinations with Shenfu injection based on 25 704 electronic medical records]. AB - Shenfu injection is a common clinical medicine. To explore the common clinical medical combinations with Shenfu injection the real world, 25 704 patients who used Shenfu injection were selected from the hospital information system (HIS) database established by Clinical and Basic Research Institute for Traditional Chinese Medicine of China Academy of Chinese Medical Sciences. The association rules were applied in a correlation analysis on common medical combinations with Shenfu injection in the patients. According to the findings, when Shenfu injection was combined with a single medicine in clinic, the ratio of using Omeprazole, Lidocaine or Furosemide were respectively 22.19%, 20.32%, 19.61%; when Shenfu injection was combined with two medicines, the top three medical combinations were respectively midazolam + omeprazole (11.01%), lidocaine + omeprazole (10.8%) and propofol + midazolam (10.76%); when Shenfu injection was combined with three medicines, the top three medical combinations were respectively propofol + fentany + midazolam (8.83%), remifentanil + propofol + midazolam (8.77% ) and propofol + midazolam + omeprazole (8.77%). According to the further analysis, the combination of Shenfu injection and Propofol + Fentany + Midazolam may reduce the incidence of hypotension and bradycardia during anesthesia, accelerate recovery after anesthesia and relieve the synergistic effect after anesthesia. The combination of Shenfu injection and furosemide may show the synergistic effect in treating the acute left ventricular failure by reducing the returned blood volume and increasing the myocardial contractile force and vitality. The combination of Shenfu injection and Omeprazole may play the synergistic effect in shortening the digestive tract ulcer healing time, reducing the ulcer recurrence and preventing hemorrhagic shock and stress ulcer caused by shock in treating ulcer hemorrhage. PMID- 26591539 TI - [Correlation analysis on combined medication with of Xiyanping injection in treatment of lung infection in real world]. AB - To analyze the regularity in combined medication with Xiyanping injection (Xiyanping for short) in the real world by as- sociation rules. Totally 5 822 patients using Xiyanping injection was collected from the 18 Class III Grade I hospitals nationwide to study the combined medication information of the patient with lung infection and make the analysis by using association rules and Apriori. According to the results, major drugs combined with Xiyanping in treatment of lung infection included compound amino acid, inosine, coenzyme A, cytidine triphosphate, vitamin C. Common drugs combined with Xiyanping can be divided into 5 categories: nutrition support therapy (vitamin C, compound amino acid) , coenzymes (coenzyme A, cytidine triphosphate, inosine), expectorants and antiasthmatics (ambroxol, salbutamol, doxofylline), hormones (dexamethasone, budesonide), antibiotics (mainly cefminox). The main combined medicines mostly conformed to the regularity for drugs treating lung infection. In addition, there were two most common medical combination models: the model for Xiyanping combined a single medicine is Xiyanping + nutrition support therapy, while the model for Xiyanping combined two or more than two medicines is Xiyanping + nutrition support therapy + coenzyme. Pharmacologically, Xiyanping is mostly combined with western medicines with similar pharmacological effects to substitute or supplement the antibiotic effect in treating lung infection. However, further studies shall be conducted for the safety and rationality of the combined medication based on clinical practices, in order to provide reference for clinical medication. PMID- 26591540 TI - [Efficacy of compound Xiatianwu tablets in elderly patients with osteoporotic distal radius fractures]. AB - Xiatianwu tablet is based on the theory of traditional Chinese medicine (TCM), combined with modern TCM pharmacology and selected 33 famous traditional Chinese crude drugs to compose. Its recipe helps cure rheumatism, relax tendons, promote blood circulation to relieve pain, et al. Although Xiatianwu tablets are widely applied to clinical remedy such as rheumatic arthritis, lumbar disc hernia, osteoarthritis and so on, there is no report about its application in fracture. This article is to observe the efficacy of compound Xiatianwu tablets in elderly patients with osteoporotic distal radius fractures and its impact on the wrist function and complications. 180 elderly patients with osteoporotic distal radius fractures, from January 2011 to June 2014, were divided into observation group and control group by the method of random number table, each group had 90 cases. The control group were gave Caltrate D after manipulative reduction and plaster immobilization, observation group were treated with compound Xiatianwu tablets in the basis of the control group. Efficacy, wrist function and complication rates were observed in two groups after treatment. The excellent and good rate was 95.56% in observation group better than 77.78% in control group, the difference was statistically significant (chi2 = 4.712, P < 0.05). The complication rate in observation group was significantly lower compared with the control group (P < 0.05). This study shows that compound Xiatianwu tablets can improve the efficacy in elderly patients with osteoporotic distal radius fractures, reduce the incidence of complications and relieve the pain of patients which plays a significant role in improving the quality of life. PMID- 26591541 TI - [Study on scavenging activity to DPPH free radical of different polarity components in Guizhou Miao medicine "bod zangd dak"]. AB - The paper is aimed to search more natural plant antioxidants and further research and develop new medicinal plant resources in Guizhou. The Guizhou special miao medicine "bod zangd dak" was extracted with 60% ethanol. The antioxidant activity of the different polarity components separated from the extract was tested by DPPH method with ascorbic acid as positive control. The results showed that the IC50 of the different polarity components was as following: ascorbic acid (0.033 4 g x L(-1)) < ethyl acetate components (0.052 3 g x L(-1)) < total tannins components (0.054 9 g x L(-1)) < 60% ethanol extraction components (0.076 7 g x L(-1)) < butanol extraction components (0.110 g x L(-1)) < water-soluble polysaccharides components (0.168 g x L(-1)) < water extraction components (0.174 g x L(-1)) < water components after extraction (0.226 g x L(-1)) < total polysaccharides components (0.645 g x L(-1)). It is concluded that the different polarity components have different free radical scavenging activity and that provides a scientific basis for further search of the active ingredients and the activive mechanism. PMID- 26591542 TI - [Dissolution, absorption and bioaccumulation in gastrointestinal tract of mercury in HgS-containing traditional medicines Cinnabar and Zuotai]. AB - alpha-HgS is the main component of traditional Chinese medicine cinnabar, while beta-HgS is the main component of Tibetan medicine Zuotai. However, there was no comparative study on the dissolution and absorption in gastrointestinal tract and bioaccumulation in organs of mercury in Cinnabar, Zuotai, alpha-HgS and beta-HgS. In this study, the dissolution process of the four compounds in the human gastrointestinal tract was simulated to determine the mercury dissolutions and compare the mercury dissolution of different medicines and the dissolution promoting capacity of different solutions. To explore the absorption and bioaccumulation of cinnabar and Zuotai in organisms, mice were orally administered with clinical equivalent doses cinnabar and Zuotai. Meanwhile, a group of mice was given alpha-HgS and beta-HgS with the equivalent mercury with cinnabar, while another group was given beta-HgS and HgCl2 with the equivalent mercury with Zuotai. The mercury absorption and bioaccumulation capacities of different medicines in mice and their mercury bioaccumulation in different tissues and organs were compared. The experimental results showed a high mercury dissolutions of Zuotai in artificial gastrointestinal fluid, which was followed by beta-HgS, cinnabar and alpha-HgS. As for the mercury absorption and bioaccumulation in mice, HgCl2 was the highest, beta-HgS was the next, and a-HgS was slightly higher than cinnabar. The organs with the mercury bioaccumulation from high to low were kidney, liver and brain. This study is close to clinical practices and can provide reference for the clinical safe medication as well as a study model for the safety evaluation on heavy metal-containing medicines by observing the mercury dissolution, absorption, distribution and accumulation of mercury-containing medicines cinnabar and zuotai. PMID- 26591543 TI - [Post-marketing reevaluation for potential quality risk and quality control in clinical application of traditional Chinese medicines]. AB - The effective quality control in clinical practices is an effective guarantee for the authenticity and scientificity of the findings. The post-marketing reevaluation for traditional Chinese medicines (TCM) focuses on the efficacy, adverse reaction, combined medication and effective dose of drugs in the market by expanded clinical trials, and requires a larger sample size and a wider range of patients. Therefore, this increases the difficulty of quality control in clinical practices. With the experience in quality control in clinical practices for the post-marketing reevaluation for Kangbingdu oral for cold, researchers in this study reviewed the study purpose, project, scheme design and clinical practice process from an overall point of view, analyzed the study characteristics of the post-marketing reevaluation for TCMs and the quality control risks, designed the quality control contents with quality impacting factors, defined key review contents and summarized the precautions in clinical practices, with the aim to improve the efficiency of quality control of clinical practices. This study can provide reference to clinical units and quality control related personnel in the post-marketing reevaluation for TCMs. PMID- 26591544 TI - [Discussion on efficacy of traditional Chinese medicine "Zi-hua Qianhu" in Chinese Pharmacopoeia (2010 Edition)]. AB - To clarify the origin and application development of the traditional Chinese medicine " Zi-hua Qianhu" and " Qianhu", the medicinal literatures of past dynasties and modern researches were analysed. The plant Angelica decursivum was used as a substitute for traditional Chinese medicine "Angelica sinensis Radix" for a long historical period, it is used incorrectly for traditional Chinese medicine "Qianhu" due to origin research in modern times. The plant origin of "Qianhu" is Peucedanum praeruptorum. There are significant differences in clinical applications and chemical composition of the two drugs. The same efficacy description of "Zi-huaQianhu" and "Qianhu" could not stop "Zi-huaQianhu" used as "Qianhu" in practical application. Therefore, we need to further research for the plant A. decursivum, delimit its medicinal attribution. PMID- 26591545 TI - [Discussion of HPLC fingerprint of traditional Chinese medicine of Corydalis yanhusuo and its preparation]. AB - Fingerprint of traditional Chinese medicine (TCM) is in the guidance of the basic theory of TCM, according to the variety and quality of TCM and using a variety of analytical methods and technology, to establish the objective, overall and multi index comprehensive evaluation system. The TCM fingerprint in one of the strategic subjects for TCM modernization. As more and more technologies have been applied to the fingerprint research of TCM, it is sure to play a much more important role in many aspects, such as the quality control of TCM, the researches of efficient components, and the mechanism in TCM, and so on. The fingerprint technology includes many modern technologies such as high-pressure liquid chromatography (HPLC). Corydalis yanhusuo is an ancient TCM, and recent years appears many researches about fingerprint of C. yanhusuo. This paper generalizes the research in progresses in research and analytical methods on fingerprint technology of C. yanhusuo, processed products (vinegar), and painkillers, to provide the scientific basis for fingerprint method and quality control of C. yanhusuo. PMID- 26591546 TI - [Comorbidity of cardiovascular diseases and cancers: Problems in the diagnosis of cardiotoxic effects of chemo- and radiation therapy]. AB - Cardiovascular diseases (CVD) and cancers are the leaders in their prevalence and the major causes of death in economically developed countries, determining their high sociomedical significance in society. Improvement of methods for the early diagnosis and treatment of cancers has contributed to increases in relapse-free survival and life expectancy in these patients. At the same time, the new problems have emerged particularly in the development of various cardiovascular events/diseases when treating cancer, which may predict worse prognosis in patients and be an independent cause of death. To search for new markers of cardiotoxicity at early stages and to develop effective methods for the prevention and personalized treatment of cancer and CVD are the problems that can be solved only by joint efforts of cardiologists and oncologists. PMID- 26591547 TI - [Impact of a cold wave on disease course, hemodynamics, carbohydrate metabolism, and blood rheological properties in cardiac patents]. AB - AIM: To study the impact of cold waves on disease course, hemodynamics, lipid and carbohydrate metabolisms, oxidative stress, and blood rheological properties in patients with cardiovascular diseases (CVD). SUBJECTS AND METHODS: 24 men and 36 women (their mean age was 62.9+/-9.7 years) were examined; coronary heart disease (CHD) and hypertension were present in 40 and 95% of the patients, respectively; selected therapy remained unchanged throughout the entire period. The investigators measured blood pressure and pulse wave velocity (PWV), carried out biochemical blood tests, estimated plasma oxidized low-density lipoproteins (oxLDL) and malondialdehyde (MDA) and erythrocyte superoxide dismutase (SOD) activity, calculated a MDA/SOD ratio, determined blood viscosity; as well as assessed quality of life using a visual analogue scale (VAS) and a specially developed questionnaire. RESULTS: Female sex, CHD, type 2 diabetes mellitus (DM 2) were independent predictors of cardiovascular events (CVEs) in the frost period. The persons who had experienced CVEs in frost had higher baseline PWV. CVEs, such as hypertensive crisis, emergency calls, cardiac arrhythmias, and the larger number of adverse reactions, were more commonly recorded in frost. There was an increase in blood glucose levels, a decrease in oxLDL, a rise in eta2/eta1, and a reduction in plasma viscosity during frost and elevated glycation end product levels at visit 2. Conclusion. The cold wave is associated with the larger number of CVEs in some patients with CVD during selected therapy. CHD, DM-2, female sex are independent predictors of CVE in patients with CVD during the winter period. In this period, there were increases in the levels of glucose, glycation end products, and erythrocyte aggregation, and a reduction in plasma viscosity. PMID- 26591548 TI - [Cardiac involvement in thrombotic microangiopathies]. AB - AIM: To describe cardiac involvement in patients with acute thrombotic microangiopathy (TMA). MATERIALS AND METHODS: The case histories of 46 patients with proven TMA, including 17 patients diagnosed with atypical hemolytic uremic syndrome (aHUS) and 29 patients with catastrophic antiphospholipid syndrome (CAPS), were analyzed. RESULTS: Different documentarily verified signs of cardiac involvement were revealed in 6 (13%) patients (5 and 1 patients diagnosed as having aHUS and CAPS, respectively). Five patients developed myocardial involvement at disease onset in the presence of multiple organ dysfunction. CONCLUSION: Cases of cardiac involvement in TMA of various genesis are presented. The exact incidence of myocardial involvement and its prognostic value are unknown so far. PMID- 26591549 TI - [Alcohol anamnesis and a death place factor: Role in mortality rates due to leading cardiovascular diseases]. AB - AIM: To reveal the specific features of marital status and educational level in people who have died of leading circulatory diseases (CDs) in Arkhangelsk in relation to the place of death, alcohol anamnesis, and demographic characteristics (gender, life span). Materials and methods. Data on the diagnosed underlying cause of death, marital status, educational level, and place of death were copied from 4137 medical death certificates (form 106/y-08) of all those who had died in Arkhangelsk in 1 July to 30 June 2012. Data on patients registered at a psychoneurology dispensary as having a diagnosis of alcohol-induced mental and behavioral disorders (F10) were copied. The data were statistically processed using the procedures of binary and multinomial logistic regression analysis. RESULTS: A total of 2101 people (50.8% of the total number of deaths) died of CDs (ICD-10 Class IX) in the study period. Male sex and a compromised alcohol anamnesis were associated with untimely death (less than 60 years of age) from acute conditions in ICD-10 Class IX. Male sex, a compromised alcohol anamnesis, and negative characteristics of marital and educational statuses were related to untimely death from chronic conditions in ICD-10 Class IX. Single people having a lower educational level and a compromised alcohol anamnesis statistically more frequently died of CDs outside a health care facility. CONCLUSION: The results of the investigation suggest that there is inequality in the excess risk of death from leading CDs among the representatives of different social population groups in Arkhangelsk, as well as nonequivalence in their interaction with the public health system. PMID- 26591550 TI - [Right ventricular dilatation in patients with coronary heart disease without myocardial infarction: According to the data of the Coronary Angiography Surgery Registry]. AB - AIM: To identify factors associated with right ventricular (RV) dilatation in patients with coronary heart disease (CHD) without prior myocardial infarction (Ml). SUBJECTS AND METHODS: Out of 16 839 patents from the Coronary Angiography Surgery Registry, the investigators selected patients with >75% stenosis in at least one coronary artery without acute or prior MI: 75 patients with echocardiographically detected RV dilatation and 1134 without RV dilatation. RESULTS: Among the patients with RV dilatation, there were more men (92% versus 80.2%; p=0.01 2). In this group, the mean body mass index (BMI) was higher (31.7+/-5.2 kg/m2 versus 30.1+/-4.7 kg/m2; p=0.01 9); there was more commonly higher NYHA functional class (FC) (III) chronic heart failure (CHF) (22.2% versus 12.5%; p=0.002), clinically relevant mitral regurgitation (29.4% versus 4.0%; all ps<0.001), and cardiac rhythm and conduction disturbances (45.5% versus 17.8%; p<0.001) in rarer severe FC (III-IV) exertional angina (30.3% versus 52.8%; p=0.007). The groups were different as evidenced by coronarography and major blood biochemical indicators. Decreased myocardial contractility (odds ratio (OR), 4.22; p=0.002), male sex (OR, 4.03;p=0.007), cardiac rhythm and conduction disturbances (OR, 2.98; p<0.001), clinically relevant mitral regurgitation (OR, 2.34; p=0.001); higher FC CHF (OR, 1.87; p=0.034), BMI (OR, 1.08; p=0.01 0), and lower FC exertional angina (OR, 0.42; p=0.001) demonstrated an independent relationship to RV dilatation, as evidenced by a multivariateanalysis. CONCLUSION: In the patients with CHD without MI, RV dilatation is independently related to male sex, left ventricular functional characteristics, and higher BMI. PMID- 26591551 TI - [The levels of osteoprotegerin, transforming growth factor-beta, and some cytokines in women with coronary heart disease concurrent with severe osteoporosis]. AB - AIM: To determine the serum level of cytokines in women with coronary heart disease (CHD) concurrent with osteoporosis (OP) and in those with isolated CHD; to assess a relationship of the levels of cytokines, osteoprotegerin (OPG), and transforming growth factor-beta (TGF-beta) to the ten-year absolute risk of osteoporotic fractures, the presence of fractures in the history, and that of CHD; and to establish the role of elevated cytokine levels in the development of future fractures. SUBJECTS AND METHODS: A cross-sectional cohort study included 98 women (mean age, 71.2?8.6 years) with CHD. Forty-eight patients had CHD concurrent with severe OP. The Fracture Risk Assessment Tool (FRAX) was applied to estimate a ten-year absolute risk for fractures in all the patients. The serum levels of OPG, TGF-beta, interleukin (IL)-1beta, IL-4, IL-6, IL-8, and IL-10, and tumor necrosis factor-a (TNF-alpha) were measured by enzyme immunoassay. RESULTS: The women with comorbidity were found to have higher levels of OPG, TGF-beta, IL 6, IL-8, IL-10, and TNF-alpha than those with isolated CHID. There was a direct correlation between fractures, CHID, and IL-10 and TNF-alpha levels and an inverse relationship between fractures, CHD, and IL-8; between CHD and OPG levels. Conclusion. The women with comorbidity were noted to have elevated levels of proinflammatory cytokines and OPG; a correlation was between cytokine levels and fractures and CHD. Increased OPG and IL-6 levels are independent predictors of fractures. PMID- 26591552 TI - [Clinical effectiveness of pioglitazone in the combination treatment of patients with asthma concurrent with coronary heart disease]. AB - AIM: To investigate the clinical effectiveness of pioglitazone in the combination treatment of patients with asthma concurrent with coronary heart disease (CHD). SUBJECTS AND METHODS: Fifty patients aged 40-75 years with asthma concurrent with CHD were examined. External respiratory function (ERF), electrocardiograms, blood pressure (BP), and anthropometric measurements were assessed in all the patients. Blood and urine laboratory values and high-sensitivity C-reactive protein (hs CRP) concentrations were estimated; endothelial function was determined measuring endothelium-dependent and endothelium-independent vasodilation (EDVD and EIVD). The patients were randomized into a comparison group receiving only standard therapy and a study group taking pioglitazone as part of combination therapy for 3 months. RESULTS: At the randomization stage prior to pioglitazone combination therapy, the patient groups did not statistically significantly differ in basic clinical and anamnestic data. Three-month standard therapy resulted in stabilization of ERF and endothelial function. During the treatment, there were increases in the frequency of asthma symptoms and the duration of angina attacks, however, there was a decline in hs-CRP levels (p<0.001). Incorporation of pioglitazone into the standard treatment regimen of patients with asthma concurrent with CHD improved clinical disease control, decreased the degree of bronchial obstruction and the frequency of angina pain and asthma attacks using nitroglycerin and salbutamol, lowered systolic and diastolic blood pressure, improved EDVD (increases in the maximum linear velocity of blood flow after a test for reactive hyperemia (RH), index of reactivity (IR), and A% brachial artery (BA) diameter) and EIVD (increases in IR and A% BA diameter), and reduced systemic inflammation from hs-CRP values (p<0.001) and hypercholesterolemia from total cholesterol levels (p<0.02). CONCLUSION: The incorporation of pioglitazone in the combination therapy of patients with asthma concurrent with CHD improves the clinical course of the diseases and increases their control, reduces systemic inflammation, and improves endothelial functional activity. PMID- 26591553 TI - [Impact of chronic obstructive pulmonary disease on one-year prognosis in patients with ST-segment elevation myocardial infarction]. AB - AIM: To assess the role of chronic obstructive pulmonary disease (COPD) in the development of unfavorable outcomes of long-term (one-year) prognosis of ST elevation myocardial infarction (STEMI). SUBJECTS AND METHODS: A total of 529 patients diagnosed with STEMI and no age limits were examined. Group 1 included 65 (12.3%) patients with previously diagnosed COPD; Group 2 consisted of 464 (87.7%) patients without COPD. One-year prognosis was studied in 384 (81.5%) patients. The investigators evaluated the following endpoints: evolving recurrent myocardial infarction (MI), progressive angina pectoris, decompensated chronic heart failure (CHF), repeat percutaneous coronary interventions, stroke, and death. RESULTS: The prevalence of COPD was 12.3% in the patients with STEM]. Unfavorable one-year prognosis was significantly more often registered in the comorbidity group regardless of age, gender, and smoking status. COPD increased the risk of combined endpoints by 1.9 times within a year after MI and that of decompensated CHD by 2.6 times during a year after STEM. CONCLUSION: COPD may be an independent risk factor for unfavorable outcomes during a year after MI. PMID- 26591554 TI - [Cardiorenal prognosis in kidney dysfunction patients undergoing cardiac surgery]. AB - AIM: To evaluate the impact of cardiac surgical procedures on cardiac and renal functions within 12 months after surgery in patients with a history of chronic kidney disease (CKD). SUBJECTS AND METHODS: A total of 875 patients (464 men and 411 women) aged 32 to 68 years (62.3+/-5.2 years), including 396 patients who had undergone heart valve replacement under extracorporeal circulation, 422 who had aortocoronary and/or mammary coronary artery bypass, and 57 who had a combination of these operations, were examined. According to the baseline glomerular filtration rate (GFR), the patients were divided into 2 groups: 1) 508 patients with preserved kidney function (GFR, higher than 90 ml/min/1.73 m2); 2) 367 with CKD (GFR, 89 to 60 ml/min/1.73 m2). Results. In Group 2, early postoperative cardiovascular events were noted significantly more frequently and mortality proved to be higher than in Group 1. By the end of the first year of a follow-up, CKD was diagnosed in 5.4% of the patients in Group 1. In Group 2, CKD regressed in 54.1 % of the patients and, on the contrary, progressed in 9.5%. In Group 2, programmed hemodialysis was performed in 15 (4.4%) patients. Overall mortality was significantly higher in patients with a postoperative glomerular filtration fall in both Groups 1 and 2 (7.5 and 8.4%, respectively). Long-term cardiovascular events were significantly more common in patients with progressive CKD and postoperative kidney dysfunction. CONCLUSION: A slight decrease in glomerular filtration makes the immediate prognosis of cardiac surgery poorer. The late cardiorenal prognosis mainly depends on changes in kidney function; regression of CKD is noted in 50% of the cases. PMID- 26591555 TI - [Approaches to therapy for pulmonary hypertension: Role of the endothelin receptor antagonist bosentan]. AB - Pulmonary hypertension (PH) is a specific clinical group of severe and rare diseases with similar morphological, hemodynamic, and therapeutic characteristics. Despite the fact that there have been international conciliative documents and advances in drug therapy for PH, the long-term prognosis of the.disease in these patients remains rather poor. Clinical trials have demonstrated that bosentan therapy in patients with PH improves pulmonary hemodynamics and exercise endurance and delays the development of the disease. According to the data of long-term studies, as compared to the historical control, bosentan used as a first-line drug can improve survival in PH patients. PMID- 26591556 TI - [Pleiotropic effects of atorvastatin in rheumatoid arthritis patients with no history of cardiovascular diseases]. AB - AIM: To evaluate the effect of atorvastatin (liprimar) on the laboratory values of inflammation and blood lipid composition in rheumatoid arthritis (RA) patients with no history of cardiovascular diseases (CVD). Subjects and methods. Fifty women with grade II RA activity according to DAS28 and radiologic (erosive) Stages I-III were examined; the patients were not former or current smokers; all were seropositive; their mean age was 50.2+/-9.9 years. All the patients with RA were divided into 2 groups: Group 1 took no atorvastatin and continued to receive standard previously prescribed therapy; Group 2 used atorvastatin in a dose of 20 mg. Lipidogram readings and the levels of Apo-A and Apo-B, neopterin, tumor necrosis factor-alpha, C-reactive protein, sP-selectin, sE-selectin, interleukin (IL)-6, IL-10, IL-12, and matrix metalloproteinases 3 and 9 were assessed. RESULTS: The patients with RA show obvious blood lipid composition impairments. Incorporation of atorvastatin (liprimar) into combination therapy for RA not only causes a considerable reduction in total cholesterol, low-density lipoprotein cholesterol, triglycerides, and apo-B levels, but also positively affects the inflammatory activity of the disease, by lowering the level of proinflammatory cytokines and increasing that of the anti-inflammatory cytokine IL-10. CONCLUSION: The above changes may underlie the prevention of CVD complications in patients with RA. PMID- 26591557 TI - [Mineralocorticoid receptor antagonists in the treatment of patients with chronic heart failure. Positions in 2015]. AB - Mineralocorticoid receptor antagonists (MCRA) are part of standard medical therapy for heart failure (HF). The clinical efficacy of MCRA in patients with systolic HF has been proven by randomized clinical trials. The efficacy of this drug group in patients with chronic HF with preserved left ventricular systolic function and the advent and practical introductions of safer new-generation MCRA remain to be answered. PMID- 26591558 TI - [Heat and cardiovascular diseases: A review of epidemiological surveys]. AB - The review summarizes epidemiologic data on the effects of heat on cardiovascular morbidity and mortality. Patients with heart failure and cardiac arrhythmias are most susceptible to negative heat exposure. At the same time, measures aimed at preserving the health of the population lead to a considerable reduction in losses associated with an abnormal rise in air temperature. PMID- 26591559 TI - [Acetylsalicylic acid for the prevention of primary myocardial infarction and ischemic stroke]. AB - There is evidence that acetylsalicylic acid (ASA) is effective in preventing events in a number of cardiovascular diseases. However, there is a number of unresolved problems concerning the efficiency and suitability of its use as an agent for the prevention of cardiovascular events (CVEs) (myocardial infarction (Ml) and/or ischemic stroke (IS) and/or death) in subjects without any clinical manifestations and/or diagnosed coronary heart disease (primary prevention of CVEs). The aim of the review is to compare the current recommendations of, professional communities for the.use of ASA as an agent for the primary prevention of CVEs, to analyze cohort studies and meta-analyses that are not included in the above recommendations (2013-2014), and to consider particular issues on ASA administration (resistance to ASA; barriers to its preventive use). The analysis performed suggests that there is no convincing evidence that it is reasonable to use ASA as a population-wide prevention strategy. The studies and meta-analyses often show conflicting data, which is likely to be associated with the clinical features of population groups included in the studies, with the presence or absence of ASA resistance and motivation for therapy. According to the current clinical recommendations, the results of studies and meta-analysis, and expert's opinions, deciding whether it is expedient to use ASA as an agent for the prevention of primary MI and/or IS and death from atherosclerostic vascular events should be based on the assessment of an individual's risks for the above disorders, which are related to a risk for hemorrhages due to ASA intake. PMID- 26591560 TI - [Silent myocardial ischemia in acute coronary syndrome]. AB - The given review considers the pathogenesis, diagnosis, and clinical significance of silent myocardial ischemia (SMI) in individual patient groups. It discusses the problem of SMI in acute coronary syndrome (ACS), the possible causes of SMI and the specific features of its diagnosis. It also indicates that there is a need for 12-lead ECG telemonitoring in intensive care unit patients with ACS to intraoperatively correct patient management and treatment policy. PMID- 26591561 TI - [Hereditary pheochromocytoma-associated syndromes. Part 1]. AB - Pheochromocytoma (PCC)/paraganglioma is a catecholamine-secreting tumor of the paraganglion. The hereditary variants of PCC have been previously considered to occur in 10% of cases. The latest researches have clearly demonstrated that the hereditary cause of chromaffin tumors is revealed in a much larger number of patients. There have been the most investigated NF, RET, VHL, SDHD, SDHC, and SDHB gene mutations. New EGLN1/PHD2, KIF1B, SDH5/SDHAF2, IDH1, TMEM127, SDHA, MAX, and HIF2A gene mutations have been recently discovered. This review describes new ideas of the genetic bases of PCC. The authors discuss criteria for patient referral for genetic examination on the basis of the phenotypic.manifestations of mutations, such as a malignant course, bilateral adrenal lesion, and age at disease manifestations. Recommendations are determined for carriers to screen for the components of hereditary pathology. PMID- 26591562 TI - [Role of measurement of fractional flow reserve in coronary artery atherosclerosis]. AB - The paper considers coronary flow in health and coronary flow autoregulation in health and disease. It gives basic methods used to estimate coronary flow reserve in patients with coronary atherosclerosis. The physiological bases for determining fractional flow reserve are presented. Clinical trials investigating the use of fractional flow reserve in patients with coronary heart disease are analyzed. PMID- 26591563 TI - [Magnesium deficiency and stress: Issues of their relationship, diagnostic tests, and approaches to therapy]. AB - Magnesium plays an important role in the functions of the central nervous system. It takes part in the regulation of the cell membrane, the transmembrane transport of calcium and sodium ions, and metabolic reactions that produce, accumulate, transfer, and utilize energy, free radicals, and their oxidation products. The magnesium-containing substances include many sequestered antigens, such as glial fibrillary acidic protein, S100, and neuron-specific enolase; magnesium may act as a neuroprotector that is able to modulate the regulation of blood-brain barrier permeability. Investigations have demonstrated a relationship between the manifestations of stress reactions (anxiety, autonomic dysfunction, and maladjustment) and magnesium deficiency (MD). Thus, mental and physical stresses cause an increase in magnesium elimination from the body. MD in turn enhances a response to stress, by paradoxically aggravating its sequels. Compensation for MD increases the ability of the nervous system to resist stress. The valid diagnosis of MD present difficulties; namely, a blood magnesium concentration decrease below 0.8 mmol/l is evidence of MD; but the constant blood level of magnesium may be long maintained due to its release from the bone tissue depot. So it is necessary to keep in mind the clinical manifestations of MD. The authors have developed and tested a simple rapid MD assessment test and a stress resistance self-rating test. The proposed tests will help to screen stress resistance and MD in outpatient settings. PMID- 26591564 TI - [Consecutive formation of the functions of high-, low-density and very-low density lipoproteins during phylogenesis. Unique algorithm of the effects of lipid-lowering drugs]. AB - During phylogenesis, all fatty acids (FA) were initially transported to cells by apoA-I high-density lipoproteins (HDL) in polar lipids. Later, active cellular uptake of saturated, monoenoic and unsaturated FA occurred via triglycerides (TG) in low-density lipoproteins (LDL). Active uptake of polyenoic FA (PUFA) required the following: a) PUFA re-esterified from polar phospholipids into nonpolar cholesteryl polyesters (poly-CLE), b) a novel protein, cholesteryl ester transfer protein (CETP), initiated poly-CLE transformation from HDL to LDL. CETP formed blood HDL-CETP-LDL complexes in which poly-CLE spontaneously came from polar lipids of TG in HDL to nonpolar TG in LDL. Then ligand LDLs formed and the cells actively absorbed PUFA via apoB-100 endocytosis. Some animal species (rats, mice, dogs) developed a spontaneous CETP-minus mutation followed by population death from atherosclerosis. However, there was another active CETP-independent uptake formed during phylogenesis; the cells internalized poly-CLE in HDL. Since apoA-I had no domain-ligand, another apoE/A-I ligand formed; the cells began synthesizing apoE/A-1 receptors. In cells of rabbits and primates absorbed cells PUFA consecutively: HDL-->LDL-->apoB-100 endocytosis; those of rats and dogs did HDL directly: HDL-->anoE/A-I endocytosis. In the rabbits, CETP was high, apoE in HDL was low, and the animals were sensitive to exogenous hypercholesterolemia. In the rats, CETP was low and ApoE in HDL-was high, and the animals were resistant to hypercholesterolemia. Reduced bioavailability of PUFA during their consecutive cellular uptake and develdpment of intercellular PUFA deficiency are fundamental to the pathogenesis of atherosclerosis. PMID- 26591565 TI - [Yakov Maksimovich Vakhrushev (on the occasion of the 75th anniversary of his birth)]. PMID- 26591566 TI - [EXTRACELLULAR VESICLES: INTERCELLULAR INFORMATION FLOW AND MEDICAL APPLICATIONS]. AB - The major features of extracellular vesicles secreted by mammalian cells are considered. Cell activation caused by formation of pathology stimulates the secretion acutely. The vesicles (exosomes, microvesicles) are enriched with annexin V, tetraspanin, miRNA. Exosomes are enriched especially by integrins, heat shock proteins. Microvesicles contain elevated amounts of tissue factors, phosphatidylserine, mRNA. The vesicles carry information about the pathological process, and microvesicles contain more proteins characteristic of inflammation and death than exosomes. They are important mediators of inflammation and infection in the body, have different effects on the immune system and the processes of carcinogenesis and neurodegeneration. However, antigenic profiles of extracellular vesicles differ not profoundly in various pathologies and so far they help diagnostics limitedly. The vesicles carry signals of genetic reprogramming of the cells and epigenetic stimulation, connected with both protein factors and mRNA and miRNA. Profiles of miRNA vesicles produced by the various pathological sources are studied actively and are useful as indicators of source and stage of cancer. Some ways of therapeutic use of the vesicles are also considered. PMID- 26591567 TI - [THE ROLE OF HEME-CONTAINING GLOBINS IN HYPOXIC NO-SIGNALING OF VERTEBRATE CELLS]. AB - Nitric oxide is one of the most important signaling molecule of living organisms. It may be produced by two ways: from arginine by means of NO-syntases and from nitrite by means of nitrite reductases. The last way is realized mostly at hypoxic state of organisms and heme-containing globins of vertebrates (hemoglobin, myoglobin, cytoglobin, neuroglobin) mediate the transformation of NO2 into NO by means of their nitrite reductase activities. Hypoxic NO-signaling depends on oxygen concentration and is important for exercise, vascular hypoxic vasodilation, myocardial preconditioning and angiogenesis. Data of scientific literature of last 15 years show that the nitrite-reductase activity of heme containing globins was used for oxygen sensing and ROS/RNS defence at early stages of life evolution. PMID- 26591568 TI - [STIMULATION OF HaCaT KERATINOCYTES AND RATS MESENCHYMAL STROMAL CELLS PROLIFERATION BY FEMTOSECOND LASER PULSES]. AB - The influence of femtosecond laser pulses on the proliferative activity of HaCaT keratinocytes and mesenchymal stromal cells (MSC) rats was studied. The growth media was exposed by laser pulses with wavelength 590 nm and duration 30 fs. The dependence of proliferative activity of cells on the dose was showed in the range 6-4299 J/cm2. Proliferative activity was assessed by the number of cells after 1 day after exposure. For both cell cultures obtained similar dose dependence: an increase in cell proliferation (32-54% for HaCaT and 19% for MSK) occurs when using lower doses, while higher doses no changes the rate of proliferation of cells. Conducted physical and chemical analysis found no increase in the concentration of active forms of oxygen in the culture medium. The impact of femtosecond laser pulses has led to the generation in culture medium acoustic oscillations in the range of 0.5 to 6.0 kHz. It is assumed that the increase in proliferative activity of cells, can be caused by mechanical effects of acoustic waves generated in the environment of optical breakdown in the focus of the laser radiation. PMID- 26591569 TI - [CELLS FORM AND THEIR SENSITIVITY TO LYTIC ACTIVITY OF NATURAL KILLER CELLS UNDER THE ANTIOXIDANT ACTION]. AB - The present paper is an attempt to estimate the influence of cell surface morphology changes to functional activity under the effect of antioxidant, N acetylcysteine (NAC), and alpha-lipoic asid (ALA). Two experimental parameters were used to characterize transformed fibroblasts 3T3-SV40 status. The functional one was the cell sensitivity to lysis by natural killer (NK) mouse splenocytes, and morphology index (cell form index) was a cell area. We showed that addition of NAC or ALA to the cell medium caused fast decrease of cell area and changes of cell form. On the other hand, their sensitivity to lysis NK cells gradually and significantly decreased. Then we compared NAC or ALA effect with the effects of other substances, which were non-antioxidants but caused cell responses which concurred with of antioxidants, at least partly. They were: latrunculin B, desorganizing actin filaments (as both antioxidants), OTZ reducing ROS level in the cell (as NAC), BSO (inhibitor of glutathione synthesis), increasing ROS level in the cell (as ALA), antibodies to gelatinases, MMP-2 and MMP-9 inactivating their activities (as both antioxidants). The results obtained showed a correlation between changes of morphology index and functional activity, sensitivity to lysis by NK cells. We suppose that geometry of cell surface might be a functional indicator of cell reaction to the antioxidant. PMID- 26591570 TI - [COMPARATIVE CHARACTERISTICS OF uNOS-POSITIVE STRUCTURES IN THE CNS OF SOME SPECIES OF CRUSTACEANS]. AB - We conducted a comparative study of NO-ergic system in the CNS of 10 species of crustaceans subclass Malacostraca, belonging to orders Stomatopoda and Decapoda, with a common habitat in Ussuri Bay (Sea of Japan). Both similar characteristics and differences in content and distribution of universal NO-synthase (uNOS) were revealed in homologous parts of the brain and ventral nerve cord of the investigated species of crustaceans. We discuss the involvement of nitric oxide in the regulation of physiological functions of decapod crustaceans and its role in the processes of adaptation to the environmental conditions. PMID- 26591571 TI - [THE INFLUENCE OF THE PREPARATION PRETREATMENT ON IN SITU DETECTION OF 5 METHYLCYTOSINE IN METAPHASE CHROMOSOMES AND IN INTERPHASE NUCLEI]. AB - Qualitative and quantitate analysis of DNA methylation in situ at the level of cells, chromosomes and chromosomal domains is extremely important for the diagnosis and treatment of various diseases, the study of ageing and the consequences of environmental impacts. An important question arises, whether the revealed in situ methylation pattern reflects DNA methylation per se and (or) availability of the DNA for antibodies, which in turn depends on the peculiarities of chromatin structure and chromosome condensation. These events can lead to an incorrect evaluation of the actual pattern of DNA methylation. To avoid this shortcoming as far as possible, we have modified the most widely used method of revealing 5-methylcytosine in situ with monoclonal antibodies. Here we have shown that the detection of DNA methylation staining of chromosomes including C-heterochromatin, chromosomal arms and sister chromatids is drastically dependent on pretreatment of chromosomal preparations for immunocytochemical study using fluorescent antibodies. Using undifferentiated stem cells of mouse embryonal carcinoma line F9, it has been found that change in preparations storage results in a sharp fluorescence decrease up to complete disappearance of the signal in centromeric heterochromatin. With the help of the method described in the work, we have first revealed the asymmetry of sister chromatids methylation in metaphase chromosomes of F9 cell and lymphocytes of human periphery blood. This may lead to asymmetry of transcriptional signature of daughter cells after division. The proposed here modification of 5-methylcytosine detection in situ provides a more complete characterization of methylation of chromosomes and chromosomal domains, compared to previously published methods. PMID- 26591572 TI - [FUNCTIONAL STATE OF SCORPION FISH SCORPAENA PORCUS L. NUCLEATED ERYTHROCYTES UNDER DOSED HYPOXIA]. AB - Hypoxia is a wide spread phenomena throughout the world's aquatic systems. This paper investigates the functional state of scorpion fish red blood cells under acute hypoxia between 0.57-8.17 mg O2/l (in vitro) by assessing of the fluorescence of Rhodamine 123 (R123) and Fluorescein diacetate (FDA). Acute hypoxia induced a significant increase in the fluorescence of both fluorochromes (R123 - 12-60, FDA - 30-184%). This reaction is based on a probable decrease in erythrocyte membrane permeability. The reduction of functional ionic channels in red blood cells delays FDA in the cytoplasm and lowers the energy costs required for transmembrane cationic gradient maintenance, which reflects an intensification of R123 fluorescence. PMID- 26591574 TI - [ANALGESIC EFFECT OF TROPALGIN ON THERMAL PAIN IN RATS WITH DIFFERENT PAIN THRESHOLDS]. AB - Experiments on rats divided into two groups (with high and low pain sensitivity) were used to assess the effect of tropalgin, a new derivative of tropine, in thermal pain tests (tail-flick and hot plate). Tropalgin was found to possess an analgesic effect comparable to that of reference sodium metamizole. ED50 of tropalgin was 2 mg/kg for intraperitoneal administration. The duration of the analgesic effect of tropalgin in rats low pain sensitivity was longer than in animals highly sensitive to pain. It is suggested that the analgesic effect of tropalgin can be related to the adenosine liberating action of this drug. PMID- 26591573 TI - [THE INFLUENCE OF MEXIDOL AND 2-ETHYL-6-METHYL-3-HYDROXYPYRIDINE HEMISUCCINATE ON LIPOFUSCINE CONTENT IN RAT BRAIN UNDER LOCAL PERMANENT ISCHEMIA CONDITIONS]. AB - Experiments on rats showed that 6- and 12-day course treatment by mexidol or 2 ethyl-6-methyl-3-hydroxypyridine hemisuccinate (at doses 200 mg/kg, i.p.) prevented the lipofuscin level increase in rat brain tissue, caused by occlusion of the left middle cerebral artery, both in the damaged and intact (right) cerebral hemispheres. Mexidol significantly decreased the concentration of lipofuscine after 12-days treatment, whereas 2-ethyl-6-methyl-3-hydroxypiridine hemisuccinate markedly decreased lipofuscine levels already after 6-day treatment. PMID- 26591575 TI - [INFLUENCE OF NITRIC OXIDE AND ALPHA-TOCOPHEROL ON STRUCTURAL CHANGES IN PLACENTA DURING VIOLATION OF UTEROPLACENTAL CIRCULATION IN WHITE RATS]. AB - We have studied the effect of nitric oxide and alpha-tocopherol on morphological changes in the placenta of white rats during pregnancy complicated by disorders of the uterine and placental circulation. Violation of the uteroplacental circulation was reproduced by the method of M. M. Vartanova (1984). In white rats with violated uteroplacental blood circulation, the use of L-arginine methyl ester compensates for disturbances of the fetoplacental blood flow. It is established that an increase in nitric oxide and the inhibition of free radical processes in the placenta of experimental animals under conditions of artificially created pathology of pregnancy belong to pathogenetic rather than sanogenetic factors. PMID- 26591576 TI - [USING MEXICOR TO CORRECT THE FUNCTIONAL PARAMETERS OF RED BLOOD CELLS IN RATS WITH TRAUMATIC BRAIN INJURY MODEL]. AB - The effect of mexicor on the functional characteristics of erythrocytes under conditions of post-traumatic period has been studied on rats with traumatic brain injury (TBI) model. TBI leads to an increase in the aggregation of erythrocytes by 143% (p = 0.003), increases the concentration of malonic dialdehyde (MDA) by 40% (p = 0.006), and decreases the electrophoretic mobility of erythrocytes by 22% (p = 0.005) relative to the levels of these indices in intact animals. The administration of mexicor (8.0 mg/day, injected intraperitoneally twice per day for 12 days) upon TBI led to a maximum reduction in the MDA concentration by 61% (p = 0.03) and decreased the aggregation of erythrocytes by 36% (p = 0.01), increased the electrophoretic mobility of erythrocytes by 20% (p = 0.003) on the 3rd day of posttraumatic period, and increased the concentrations of 2,3 diphosphoglycerate by 23% (p = 0.02) on the 7th day as compared to the positive control. The most pronounced changes under the action of mexicor were observed within 3 - 7 days after the onset of TBI. The obtained data show the efficacy of mexicor in the treatment of rats with TBI model, which is manifested by a 40% (p = 0.02) shorter period of recovery of the functional parameters of red blood cells in comparison to the positive control. PMID- 26591577 TI - [THE EFFECT OF ACTH-(4-7)-PGP PEPTIDE ON LIPID PEROXIDATION IN LIVER AND ACTIVITY OF SERUM TRANSAMINASES IN RATS UNDER ACUTE AND CHRONIC IMMOBILIZATION STRESS CONDITIONS]. AB - The effect of ACTH-(4-7)-PGP (semax) intraperitoneal injection at doses of 5, 50, 150 and 450 MUg/kg b.w. on the free-radical oxidation and the activity of serum transaminases in Wistar male rats subjected to acute and chronic immobilization stress has been studied. It was found that the peptide administration in the entire dose range studied produced antioxidant effect in hepatocytes and significantly increased the activity of serum ALT and AST at a dose of 450 MUg/kg under chronic stress conditions. On the contrary, prooxidant effects were observed at a drug dose of 150 mg/kg under acute stress conditions, and the direction of changes in the ALT and AST values activity depended on the semax dose. The ALT activity was decreased at doses of 5 and 50 MUg/kg, but increased at a dose of 450 MUg/kg. The AST activity was already reliably increased at a dose of 5 MUg/kg. PMID- 26591578 TI - [THE USE OF "REAMBERIN" AS BIOLOGICAL RESPONSE MODIFIER TO INCREASE THE NATURAL KILLER CELLS' CYTOTOXICITY IN PATIENTS WITH LUNG TUBERCULOSIS]. AB - The effect of the drug "Reamberin" cytotoxic activity of natural killer cells (EC) in an experimental model in the blood samples of patients with pulmonary tuberculosis and healthy donors. Simulation acute systemic inflammation by adding to the culture medium of BCG. After 48 hours, selection was performed mononuclear peripheral blood by gradient centrifugation tests set cytotoxic tumor cell line K 562. Revealed the stimulating effect of the drug "Reamberin" cytotoxic activity of natural killer cells. Metabolic Correction has had a positive impact on the energy metabolism of blood natural killer cells, to increase their survial and cytotoxicity. PMID- 26591579 TI - [BETA-III TUBULIN AS A POTENTIAL TARGET FOR BLOCKING INVASIVE GROWTH OF MALIGNANT EPITHELIAL TUMORS]. AB - Invasive growth is the first step of metastatic cascade in the growth of malignant tumors. The mobility of cells, which is a necessary factor of the invasive growth of malignant tumors, is closely linked to the dynamic structure of cytoskeleton. An important role in cell motility is played by microtubules and actin microfilaments. Microtubules consist of tubulin--a heterodimer comprising alpha and beta subunits, which can be represented by different isotypes. The appearance of beta-III tubulin in a tumor is essential for chemoresistance and prognosis of some tumors in humans. This study focuses on determining the possibility of using beta-III tubulin as a target molecule for the suppression of invasive growth. It is established that blocking of the beta-III tubulin expression in colorectal cancer cells does not affect their viability, but reduces the cell adhesion to the extracellular matrix by 40% for HT-29 (? = 0.0044) and by 15% (p = 0.0436) for HCT 116) and produces a four-fold decrease in the invasive activity (p = 0.0000 and 0.0001, respectively). These facts allow considering beta-III tubulin as a target molecule in the development of antitumor drugs. PMID- 26591580 TI - [MELATONIN TREATMENT OF AUTOIMMUNE AND ALLERGIC PATHOLOGY]. AB - Some autoimmune and allergic diseases (systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, atopic dermatitis, etc.) are accompanied with disturbances of the natural production of hormone melatonin by pineal gland and peripheral tissues. The administration of melatonin to animals and humans with such pathologies demonstrated showed a protective effect. It is proposed to carry out additional investigations of the possibility of using melatonin for the treatment of autoimmune disorders, after which it can be introduced into clinical practice. PMID- 26591581 TI - [EMPIRICAL ANTIBACTERIAL PROPHYLAXIS IN EMERGENCY SURGERY]. AB - The main principles of selecting antibacterial drugs for prophylactic therapy of patients prior to surgery of gastrointestinal tract, vessels, skin, and soft tissues are considered. Special attention is devoted to antibacterial prophylaxis in co-morbid patients, in particular those with chronic renal insufficiency, chronic liver disorder, decompensated diabetes mellitus, and allergy to beta lactam antibiotics. All proposed schemes are optimized with respect to three criteria: clinical effectiveness, economic feasibility, and epidemiologic safety (stopping the selection of poly-resistant microbial families). PMID- 26591582 TI - [Yurii Dmitrievich Ignatov, Academician of the Russian Academy of Medical Sciences (On His 75th Birthday)]. PMID- 26591583 TI - [T-LYMPHOCYTES AND TISSUE GROWTH FACTORS]. AB - Lympnoici regulation, in aciaition to ensuring tne protection of tne antigen, is aimecl at maintaining a qualitative, quantitative, structural and functional integrity of the body. T-lymphocytes and growth factors are involved in cell proliferation, differentiation, and tissue and organ regeneration. Lymphocyte's, sensitivity to homeostasis changes and their morphogenetic function are connected with a large number of receptors to bioactive substances and with their ability to syn- thesize and secrete hormones and tissue growth factors. At the same time tissue growth factors are involved in the development of thymocytes, in the differentiation of T helper and cytotoxic lymphocytes. Growth factors modulate the functions of Thl, Th2, Treg, Thl7, Th9. The important aspects of the interaction of T cells and EGF, TGF-P, FGF, VEGF, PlGF, HGF/SF in normal and pathological conditions are shown in this review. PMID- 26591584 TI - [THE INHIBITORY EFFECT OF GLYCINE AND GABA ON MONOSYNAPTIC EPSPs IN THE FROG SPTNAL MOTONFUCTYNMR]. AB - In this research we have studied the inhibitory effect of glycine and GABA on the monosynaptic EPSPs induced by microstimulation of presynaptic fibers close to the frog lumbar motoneurones. Monosynaptic EPSPs had two components mediated by AMPA/KA (78%) and NMDA (22%) receptors. Both inhibitory mediators considerably decreased EPSP's decay time by 33.4 +/- 4.0% (n = 18) for glycine and by 40.2 +/- 3.6% (n = 18) for GABA. The decrease of EPSP's decay time was reduced after blockade ofNMDA receptors by AP5. The time characteristics were recovered in the normal saline. Glycine and GABA inhibited NMDA component of EPSPs to a greater extent than AMPA/KA component. It was confirmed by our previous data about the predominant inhibitory effect of glycine and GABA on responses induced by NMDA (as compared with AMPA and KA) application to motoneurone membrane. PMID- 26591585 TI - [THE EFFECT OF SEROTONIN ON THE INOTROPIC FUNCTION OF MYOCARDIUM OF THE LEFT VENTRICLE OF IMMATURE SPONTANEOUSLY HYPERTENSIVE RATS]. AB - The mechanisms of the serotonin effect on the inotropic function of the myocardium of the left ventricle of immature spontaneously hypertensive rats (SHR) are unexplored. It was found that systolic arterial blood pressure of 5-6 weeks SHR rats is 147.5 mm Hg, which is statistically significantly higher (more than 25 mm Hg) than in the same age of normotensive control Wistar- Kyoto rats. The weight of the heart, of the left ventricle myocardium, of the ventricular septum, of the aorta and the force of contraction of the left ventricle of 5-6 week-old SHR rats are increased significantly compared with the control. 0.1 pM serotonin increases and 1.0 pM and 10.0 AM serotonin reduce the force of contraction of the left ventricular myocardium in hypertensive rats, but there is a dose-dependent increase of the force of contraction in the control. Serotonin reduces the time of contraction of the myocardium of the left ventricular of SHR rats, these reactions are less pronounced as compared to the control. PMID- 26591586 TI - [MIMICKING ISCHEMIC PRECONDITIONING PHENOMENON THROUGH THE IMPACT ON THE CANNABINOID RECEPTORS: ROLE OF PROTEIN KINASE AND NO-SYNTHASE]. AB - It was established that CB 1-receptors stimulation mimic preconditioning phenomena. Since the cardioprotective effect of cannabinoid HU-210 is occurred both in the experiments in vivo and in the experiments in vitro there are reasons to believe that the protective effect of HU-210 is me- diated via an activation of cardiac CB1-receptors. It is established that the cardioprotective effect of cannabinoid HU-2 10 is depends upon a stimulation ofprotein kinase C whereas NO synthase is not involved in protective impact of CB1-receptor stimulation. PMID- 26591587 TI - [INVOLVEMENT OF NO-SYNTHASE IN THE INFARCT REDUCING EFFECT OF CONTINUOUS CHRONIC NORMOBARTC HYPOXTA]. AB - It was investigated the role of inducible and endothelial NO-synthase (NOS) in the infaret reducing effect of chronic continuous normobaric hypoxia (CCNH) on the model of coronary artery occlusion and reperfusion in rats. Rats were subjected to hypoxic exposure (12% O2 during 21 days). It has found that CCNH causes an increase in total levels of nitrate and nitrite in deproteinized blood serum in 1.5-fold and 2-fold in myocardium compared with intact animals. This effect is manifested in intact animals and in rats with a 20 minute coronary artery occlusion and reperfusi- on. Chronic continuous normobaric hvoxia exhibited infarct soaring effect. which does not manifest after pretreatment with NO-synthase inhibitor NAME (10 mg/kg intravenously), the selective inhibitor of inducible NOS S-methylisothiourea (3 mg/kg intraperitoneally), but remained after blocking neuronal NOS with 7-nitronidazol (50 mg/kg intravenously). The findings suggest that the inducible NO-synthase and nitric oxide play an important role in the implementation of the infaret limiting effect of chronic continuous normobaric hvnoxia. PMID- 26591588 TI - [THE INFLUENCE OF OPIOID PEPTIDES ON LIPID PEROXIDATION AND ANTIOXIDANT ENZYME ACTIVITY IN RATS AFTER SWIMMING STRESS]. AB - It was established in experiments on rats, that injection of opioid peptides DAGO (a selective igonist of opioid mu-receptors), DSLET (a selective agonist of opioid delta-receptors) or dynorpiin A (1-13) (a selective agonist of opioid kappa-receptors) decreased the stress-induced activatin of lipid peroxidation in liver tissue and plasma. A selective agonist of opioid mu-receptors) AGO manifested the most expressed activity. The using of investigating peptides caused the increase of superoxiddismutase activity in liver tissue. The reinforcement of catalase activity was )bserved in DSLET or dynorphin A (1-13). DAGO decreased its activity. The peptide effects of lifferent directions oncatalase activity in plasma were established. These effects can be explained y the stress-limiting action of peptides in entire organism, the peculiarities of opioid receptors spreading in liver tissue and by the influence of preceded load with non-complete oxidized sub stances after intensive swimming on the opioid receptor affinity. PMID- 26591589 TI - [ROLE OF CAPSAICIN-SENSITIVE NERVES IN THE REGULATION OF DEHYDROEPIANDROSTERONE SULFATE BLOOD CONTENT UNDER NORMAL AND FRUCTOSE-INDUCED METABOLIC SYNDROME]. AB - The effects of the stimulation of capsaicin-sensitive nerves (capsaicin, 1 mg/kg, s/c) and their eafferentation (capsaicin, 150 mg/kg, s/c) on the blood content of dehydroepiandrosterone sulfate (DHEAS) was investigated in normal rats and rats with fructose-induced metabolic syndrome (12.5% fructose solution, 10 weeks). An increase in blood of tryglyceride, lipid peroxidation, glucose (fasting and after loading glucose, 2 mg/kg, i/p) was considered as symptoms of metabolic syndrome. It was shown that in normal rats drinking tap water the stimulation of capsaicin sensitive nerves resulted in the increase of DHEAS content while their deafferentation reduced the concentration of this hormone in the blood. The fructose diet caused the decrease in content of DHEAS, triglyceridemia, lipid peroxidation, impaired tolerance glucose. In rats with the metabolic syndrome the stimulation capsaicin-sensitive nerves prevented the fructose-induced decrease of DHEAS content as well as decreased the symptoms of metabolic syndrome. In fructose fed rats the stimulation-induced effects were prevented by the deafferentation of capsaicin-sensitive nerves. It is suggested that capsaicin sensitive nerves contribute both to the regulation of blood content of DHEAS under normal and fructose-induced metabolic syndrome. PMID- 26591590 TI - [AN ANIMAL MODEL OF INTENTIONAL TREMOR]. AB - The paper describes a model of intentional form of tremor developed in experiments in animals. Experiments with lesion of nucleus caudatus revealed the important role of this structure to regulate normal relationships between activity of reciprocal muscles under producing the non stereotypic forms of motor behavior. The model may be used to study the etiology and pathogenesis of intentional tremor as well as for preclinical testing of pharmacological drugs potentially perspective for correction of given form of diskinesia in humans. PMID- 26591591 TI - [ACOUSTIC FEATURES OF VOCALIZATIONS, REFLECTING THE DISCOMFORT AND COMFORT STATE OF INFANTS AGED THREE AND SIX MONTHS]. AB - The paper presented the possibility of recognition by adult the comfort and discomfort state of 3 and 6 months old infant's on the base of their vocalizations. The acoustic features of the vocalizations that are important for the recognition of the infant state of the characteristics of voice was described. It is shown that discomfort vocalizations differ from comfort ones on the basis of the average and maximum values of pitch, pitch values in the central and final part of the vocalization. A mathematical model is proposed and described a classification function signal of discomfort and comfort. Was found that the vocalizations of infants attributable adults with a probability of 0.75 and above the categories of comfort and discomfort with high reliability are recognized by the mathematical model based on a classification function. PMID- 26591592 TI - [EFFECTS OF MUSIC-ACOUSTIC SIGNALS, ONLINE CONTROLLED BY EEG OSCILLATORS OF THE SUBJECT]. AB - The effects of 2 variants of the method of musical EEG neurofeedback, in which the dominant spectral components of subject's EEG (EEG oscillators) are online converted to music-like signals similar by timbre to flute sounds, have been studied. In the first case, these music-like signals were smoothly varying by the pitch and intensity in accordance with the current amplitude of the EEG oscillator. In the second case, the same variations of flute-like sound were accompanied by such musical element as rhythm. After the single exposure, the modifications of subject's brain activity and positive changes in psycho physiological state of the subject have been found. Particularly pronounced effects were observed under rhythmically organized music-like stimuli. PMID- 26591593 TI - [Thermodynamic Analysis of Two State Transitions under High Pressure. Theoretical Consideration]. AB - Possible effects of high pressure on heat denaturation of biopolymers have been analyzed. The study was made using an equilibrium model of transition between two states. Equations used to determine the dependence of thermodynamic parameters of transition (enthalpy, entropy and transition temperature) on pressure were formulated. Pressure may have both stabilizing and destabilizing effects on the macromolecule structure depending on the change in the volume upon transition. The dependence of the transition temperature on pressure cannot have local extremums. It is demonstrated that depending on the increment (jump) of the partial expansion coefficient and the change of the transition temperature, the enthalpy of transition can both grow with the pressure growth or decrease. It is also .shown that when the pressure grows, the changes in the volume and enthalpy under denaturation cannot change their signs. PMID- 26591594 TI - [The Relaxation Model of Ideal Folding in a Homogeneous Viscous Medium]. AB - The problem of 3D biopolymer structure formation is investigated by the methods of a theory of stochastic dynamics. The variational principle for. elementary displacement and velocity of conformational movements and its implications for the folding process of the polymer chain in a viscous medium are formulated. The result is a most smooth decrease in potential energy during conformational relaxation of the system (a timid mountain-skier principle), which is in consistence with the Onsager principle for kinetics in weakly nonequilibrium systems. The model is in accordance with the results of molecular simulations of the similar systems. The relationship between the structure of the multidimensional potential energy surface and folding kinetics is discussed. The model of a parabolic energy funnel formed by non-bonded interactions is developed. The folding kinetics in the parabolic model of energy funnel is almost close to exponential law. PMID- 26591595 TI - [Structural and Dipole Structure Peculiarities of Hoogsteen Base Pairs Formed in Complementary Nucleobases according to ab initio Quantum Mechanics Studies]. AB - Ab initio quantum mechanics studies for the detection of structure and dipole structure peculiarities of Hoogsteen base pairs relative to Watson-Crick base pairs, were performed during our work. These base pairs are formed as a result of complementary interactions. It was revealed, that adenine-thymine Hoogsteen base pair and adenine-thymine Watson-Crick base pairs can be formed depending on initial configuration. Cytosine-guanine Hoogsteen pairs are formed only when cytosine was originally protonated. Both types of Hoogsteen pairs have noticeable difference in the bond distances and angles. These differences appeared in purine as well as in pyrimidine parts of the pairs. Hoogsteen pairs have mostly shorter hydrogen bond lengths and significantly larger angles of hydrogen bonds and larger angles between the hydrogen bonds than Watson-Crick base pairs. Notable differences are also observed with respect to charge distribution and dipole moment. Quantitative data on these differences are shown in our work. It is also reported that the values of local parameters (according to Cambridge classification of the parameters which determine DNA properties) in Hoogsteen base pairs, are greatly different from Watson-Crick ones. PMID- 26591596 TI - [About the Spatial Organization of Double-stranded DNA Molecules in the Cholesteric Liquid-crystalline Phase and Dispersion Particles of this Phase]. AB - The answer to a question on the organization of molecules in a cholesteric phase is well enough proved in case of low molecular mass compounds. However, in case of double-stranded nucleic acids molecules the unequivocal answer to such question is a subject of discussions. In this work an attempt to generalize the well known literary data on the structure of the cholesteric phase formed by double-stranded DNA molecules was undertaken. Besides the experimental results of authors describing the packing of these molecules in the cholesteric liquid crystalline dispersion particles are added to these data. Comparison of the results obtained offers the possibility to come out with an assumption of high probability of the existence of both the short-range positional and long-range orientational order in arrangement of double-stranded DNA molecules in a liquid crystalline phase, and in the particles of dispersions of this phase generated under certain conditions. The occurrence of the orientational order, i.e. rotation of 'quasinematic' layers of double-stranded DNA molecules by a small angle, defines the formation of spatially twisted (cholesteric) structure with characteristic for it physical and chemical properties. PMID- 26591597 TI - [Technological Perspectives in Developing Carbon Nanotube-based DNA-modified Biosensors]. AB - In this research we investigated the response of DNA-modified carbon nanotubes in the presence of thrombin and albumin. We analyzed aptamer-carbon nanotube interactions by Raman spectroscopy and by analyzing resistance after each step of biosensor assembly. We have shown that intensity of G-band decreases due to interconnection of aptamer and carbon nanotube and this also evaluates in decrease of sensor structure resistance. The response of the sensor exposed to thrombin and albumin differs essentially from each other. This fact serves as the prerequisite for the development of a highly selective biosensor. Results of this investigation can be used in creation of new generation of personal health monitoring systems. PMID- 26591598 TI - [Physicochemical Properties of Histone H2A and Modified Histone H2A-TAT Complexes with Plasmid DNA]. AB - Histone H2A can deliver transgenic DNA into mammalian cells in vitro. The ability of DNA delivery in vivo is a question of the further work, but it is possible to estimate factors in in vitro experiments, which affect delivery in vivo. The first step in this direction was to determine sizes and zeta-potentials of histone H2A complexes with DNA. In this work, we produced recombinant histone H2A and its modification, containing TAT-peptide from human immunodeficiency virus TAT protein, which is capable of enhancing macromolecule delivery into mammalian cells. The effective diameters and zeta-potentials of histones-DNA complexes were estimated. Complexes of histone H2A and complexes of modified histone H2A-TAT with DNA had positive zeta-potentials. Complexes of histone H2A with DNA had an effective diameter of about 200 nm. Histone modification with TAT-peptide led to aggregation and formation of massive particles of about 1 MUm in diameter. PMID- 26591599 TI - [Pulse-modulated Electromagnetic Radiation of Extremely High Frequencies Protects Cellular DNA against Damaging Effect of Physico-Chemical Factors in vitro]. AB - Using a comet assay technique, we investigated protective effects of. extremely high frequency electromagnetic radiation in combination with the damaging effect of X-ray irradiation, the effect of damaging agents hydrogen peroxide and methyl methanesulfonate on DNA in mouse whole blood leukocytes. It was shown that the preliminary exposure of the cells to low intensity pulse-modulated electromagnetic radiation (42.2 GHz, 0.1 mW/cm2, 20-min exposure, modulation frequencies of 1 and 16 Hz) caused protective effects decreasing the DNA damage by 20-45%. The efficacy of pulse-modulated electromagnetic radiation depended on the type of genotoxic agent and increased in a row methyl methanesulfonate--X rays--hydrogen peroxide. Continuous electromagnetic radiation was ineffective. The mechanisms of protective effects may be connected with an induction of the adaptive response by nanomolar concentrations of reactive oxygen species formed by pulse-modulated electromagnetic radiation. PMID- 26591600 TI - [Photoreactivating Activity of Bioluminescence: Repair of UV-damaged DNA of Escherichia coli Occurs with Assistance of lux-Genes of Marine Bacteria]. AB - The UV resistance of luminescent bacteria Escherichia coli AB1886 uvrA6 (pLeo1) containing the plasmid with luxCDABE genes of marine bacteria Photobacterium leiognathi is approximately two times higher than the UV resistance of non luminous bacteria E. coli AB1886 uvrA6. Introduction of phr::kan(r) mutations (a defect in the functional activity of photolyase) into the genome of E. coli AB1886 uvrA6 (pLeo1) completely removes the high UV resistance of the cells. Therefore, photoreactivation that involves bacterial photolyase contributes mainly to the bioluminescence-induced DNA repair. It is shown that photoreactivating activity of bioluminescence of P. leiognathi is about 2.5 times lower compared with that one induced by a light source with lambda > 385 nm. It is also shown that an increase in the bioluminescence intensity, induced by UV radiation in E. coli bacterial cells with a plasmid containing the luxCD ABE genes under RecA-LexA-regulated promoters, occurs only 25-30 min later after UV irradiation of cells and does not contribute to DNA repair. A quorum sensing regulatory system is not involved in the DNA repair by photolyase. PMID- 26591601 TI - [Evolution of non-Coding RNAs in Drosophila melanogaster Genome]. AB - Non-coding RNAs are important regulatory molecules that function due to their specific RNA secondary structure. The secondary RNA structure depends on RNA sequence. It can be represented as a combination of loops, stems and pseudoknot regions. By the structure formation, each separate local part of a RNA structure as well as the whole molecule tend to achieve the minimum of free energy. New mutations may change the free energy of the current RNA structure and thus change the optimal one and change the function of the molecule. The chance to change the structure for a mutation depends on where it is located in the secondary RNA structure. In this research we studied natural selection acting on loop and stem regions of ncRNA of five classes. We tried to associate their selection characteristics to the changes of free energy value. We considered Drosophila melanogaster genome. PMID- 26591602 TI - [Efficiency of non-Photochemical Fluorescence Quenching of Phycobilisomes by the Orange Carotenoid Protein]. AB - We report on theoretical efficiency of non-photochemical fluorescense quenching of phycobilisomes by the orange carotenoid protein. The created 3D computer model of the three-cylindrical phycobilisomes core allowed us to determine the distances between centers of mass of all phycobilin chromophores of the core and calculate the time and an average number of energy migration steps for the resulting non-radiative excitation transfer from the phycobilisomes to photosystem II. The obtained kinetic scheme equations for a way of energy transfer confirm the incomplete interception of energy flow in the phycobilisomes core by the orange carotenoid protein. Theoretical estimation of the rate of phycobilisomes quenching is in good agreement with experimental data. PMID- 26591603 TI - [Evaluation of Photo- and Cytotoxicity of Chlorin e6 Ester Derivatives and Their Liposomal Forms]. AB - Photophysical characteristics and photosensitizing activity of the chlorin e6 dimethyl and trimethyl ester derivatives in various solution and their liposomal forms were studied. It was shown that in lipid vesicles chlorin e6 ester derivatives are predominantly in the monomeric state and possess optimal photophysical properties and high photochemical activity. The rate of redistribution of the chlorin e6 dimethyl ester from lipid vesicle to cells was higher as compared with that one of the chlorin e6 trimethyl ester. The increase of the serum concentration in the incubation medium has a different effect on processes of accumulation of the liposomal forms of the chlorin e6 dimethyl and trimethyl ester derivatives by the cells. Cell culture studies showed that application of liposomal forms of the chlorin e6 dimethyl and trimethyl ester derivatives significantly decreases their cytotoxicity but keeps high cytotoxic effect of photodynamic activity of the chlorin e6 ester derivatives. PMID- 26591604 TI - [The Effect of NT-1505 on a Membrane Structure of Endoplasmic Reticulum in vivo]. AB - The effect of neuroprotector NT-1505 on endoplasmic reticulum membranes was studied. It was shown that the dynamics of changes in lipid and near-protein areas microviscosity of endoplasmic reticulum membranes at drug administration is of an antibate nature. This points to the absence of pathological disturbances in the membrane structure. Membrane microviscosity was measured by electron paramagnetic resonance spin labeling of 2,2,6,6-tetramethyl-4-capryloyl oxylpiperidine-1-oxyl (lipid probe) and 5,6-benzo-2,2,6,6-tetramethyl-1,2,3,4 tetrahydro-gamma-carboline-3-oxyl (near protein probe). To obtain more complete information about changes in membrane structure under the action of neuroprotector NT-1505 the temperature dependence of rotational diffusion correlation time was measured in the temperature range of 283-317 K (10-44 degrees C). The two structural transitions were characterized for both areas of .membranes of control group in temperature intervals 16-20 degrees C and 32-38 degrees C which were still present after NT-1505 introduction. Therefore, NT-1505 has no significant effect on membrane structure of the endoplasmic reticulum. PMID- 26591605 TI - [Selective Heating of Membrane-forming Holes in Teflon Film Exposed to Decimeter Waves]. AB - Calculations of heating of membrane-forming holes in Teflon film exposed to decimeter waves were performed. The dependence of the temperature increment in holes on the geometry of holes, electrolyte concentration, and decimeter wave frequency was studied. The kinetics of heating depending on the hole diameter was also obtained. It was concluded that the observed in the experiment effects of the decimeter wave on bilayer lipid membranes resulted from the elevated concentration of decimeter electromagnetic waves in membrane-forming hole that led to selective heating of electrolyte in hole and bilayer lipid membranes. PMID- 26591606 TI - [Lamellar Inclusion Bodies in the Retinal Pigment Epithelium of Diurnal Rodents]. AB - The ultrastructure of the retinal pigment epithelium of a diurnal rodent (Brandt's vole) was described taking into account 1) the functions of the pigment epithelium as a participant in the renewal of photoreceptor outer segment and. 2) digestion of outer segment membranes into phagosomes of the retinal pigment epithelium. The myeloid bodies were observed after exposure of the pigment epithelium to light (200 lux, 4 hours) and darkness (0,1 lux, 1,5-hour). In the cytoplasm of the pigment epithelium of the vole no myeloid bodies were observed. Instead of it small lamellar bodies, which have the spiral form and size (from - 200 to 400 nm) were found. The structure of these lamellar bodies was described. Furthermore, the structures, which were presumably responsible for the transport of the digested material, were revealed. The evidence of it is the presence of 1) dense precipitate in the apical domain of the pigment epithelium and 2) microtubules which participate in transport of this precipitate. PMID- 26591607 TI - [Prospects for Application of Gases and Gas Hydrates to Cryopreservation]. AB - In the present review, we tried to evaluate the known properties of gas hydrates and gases participating in the formation of gas hydrates from the point of view of the mechanisms of cryoinjury and cryoprotection, to consider the papers on freezing biological materials in the presence of inert gases, and to analyze the perspectives for the development of this direction. For the purpose, we searched for the information on the physical properties of gases and gas hydrates, compared processes occured during the formation of gas hydrates and water ice, analyzed the influence of the formation and growth of gas hydrates on the structure of biological objects. We prepared a short review on the biological effects of xenon, krypton, argon, carbon dioxide, hydrogen sulfide, and carbon monoxide especially on hypothermal conditions and probable application of these properties in cryopreservation technologies. The description of the existing experiments on cryopreservation of biological objects with the use of gases was analyzed. On the basis of the information we found, the most perspective directions of work in the field of cryopreservation of biological objects with the use of gases were outlined. An attempt was made to forecast the potential problems in this field. PMID- 26591608 TI - [Own Chemiluminescence of Planarian Neoblasts during Regeneration]. AB - We investigated the kinetics of the luminescence induced by reactive oxygen species in planarians during regeneration process. It was found that regeneration is accompanied with changes in the concentration of reactive oxygen species correlating with energy-intensive processes such as oxidative stress, caused by damage to cell membranes in the dissection of the planarian, phagocytosis of dying cells and mitosis of neoblasts. We showed for the first time that there is an opportunity of registering the physiological state of pluripotent stem cells at the level of the organism in vivo. PMID- 26591609 TI - [Numerical Analysis of Particle Trajectories in Living Cells under Uncertainty Conditions]. AB - We have developed a numerical method for the analysis of particle trajectories in living cells, where a type of movement is determined by Akaike's information criterion, while model parameters are identified by a weighted least squares method. The method is realized in computer software, written in the Java programming language, that enables us to automatically conduct the analysis of trajectories. The method is tested on synthetic trajectories with known parameters, and applied to the analysis of replication complexes in cells, infected with hepatitis C virus. Results of the analysis are in agreement with available data on the movement of biological objects along microtubules. PMID- 26591610 TI - [Mutagenic Activity of Four Aminoazo Compounds with Different Carcinogenicity for Rat Liver in the Ames Test]. AB - In this paper in the bacterial Ames test we compared the mutagenicity of four aminoazo compounds, previously studied by other researchers and used for activation of rat liver enzymes, with the carcinogenicity in the rat liver. It was found that in the Ames test they have mutagenic activity, however, this activity does not correlate quantitatively with rat sensitivity to their hepatocarcinogenic action. Thus, the most active carcinogen 3'-methyl-4 dimethylaminoazobenzene causes mutations almost 2.5 times less than weakly carcinogenic ortho-aminoazotoluene, and exactly the same number of mutations as non-carcinogenic N,N-diethyl-4-aminoazobenzene. PMID- 26591611 TI - [Analysis for the Persistence of Various Regimens of Heart Rate Dynamics by Computer Modeling]. AB - A computer modeling revealed the following three regimens of heart rate dynamics: linear dynamics, "1st degree chaos", and "2nd degree chaos". This work was designed to study the persistence of these regimens by the method of Hurst. Our investigation showed that the Hurst index is highest for "2nd degree chaos" (H = 0,671 +/- 0,028). The Hurst index for the "1st degree chaos" regimen was lower than that for "2nd degree chaos" (H = 0,473 +/- 0,015). An increased persistence of cardiac rhythmogenesis in the "2nd degree chaos" regimen illustrates the non stationarity and prognostic instability of these processes, which contributes to a high risk of heart diseases. PMID- 26591612 TI - [Elucidation of the Tubular Leaflet Geometry of the Aortic Heart Valve Prosthesis by Finite Element Analysis]. AB - This paper presents the analysis of relationships between geometrical parameters of the tubular leaflet apparatus and its functional characteristics. In addition, the degree of the influence of deformation of different zones of leaflets on its ability to perform its function is evaluated in this work. The outcomes of this study could be helpful in developing new models of the transcatheter prosthetic heart valves leaflet apparatus or analyzing existing in-clinical transcatheter aortic valve implantation prostheses. PMID- 26591613 TI - [Life Span of F1 Progeny of Female Drosophila Exposed to Low Intensity Terahertz Irradiation]. AB - Virgin female fruit flies were stressed by placement into a confined space without food for 3 hours. Some flies were subjected to terahertz irradiation (0,1 2,2 THz) for the last 30 min. Irradiated and nonirradiated females were then copulated with males. We investigated the F1 progeny of fruit flies with mature and immature oocytes at the moment of irradiation (days of oviposition: 1-2 and 9 10 after irradiation). Life span of individual flies was evaluated. It was demonstrated that terahertz radiation does not influence the absolute and average lifespan of the F1 progeny in both sexes. In response to terahertz irradiation the sexual dimorphism was detected. Survival curves of males, developed from mature and immature oocytes at the time of irradiation, differ significantly from the appropriate control, whereas in the case of females the survival curves are similar to the control. It is concluded that terahertz radiation has a remote effect on a survival of the F1 male progeny. PMID- 26591614 TI - [Fluorescent Indices of Bean Leaves Treated with Sodium Fluoride]. AB - It is shown that the treatment of bean leaves with NaF in concentration of 10(-2) M resulted in the alteration of fluorescent indices registered by the method of pulse fluorimetry. Fluorescent parameters F(0) and F(m) decreased, but the ratio F(v)/F(m) = (F(m) - F(0))/F(m), characterizing the maximal photochemical activity of photosystem II remained invariable. Photochemical fluorescence quenching (qP) was higher than in control during the first minutes of illumination with the actinic light, and it markedly decreased with the following illumination. Nonphotochemical quenching (qN), in contrary, decreased at the beginning of illumination, and then increased. Photosynthetic activity as characterizing by the ratio (F(M) - F(T))/F(T) reduced after the leaf treatment with NaF. Results obtained are interpreted proceeding, on the one hand, from the influence of NaF on redistribution of excitation energy between photosystem II and photosystem I and its inhibitory effect on the ATPase complex and Kalvin-Benson cycle, on the other. PMID- 26591615 TI - [Early Development under Microgravity Conditions]. AB - The review is devoted to various aspects of early development under the space flight conditions. The different possible cell mechanosensors are considered. Structural and functional changes in the cells, predominantly, in non-muscle ones, were discussed. The results of the different experiments with the embryos of fish, amphibians, birds and mammals under microgravity conditions are shown discussing possible reasons for the development of morphological changes. PMID- 26591616 TI - [On the Effect of alpha-Tocopherol on Protein Kinase C Activity in vitro]. AB - The effect of the antioxidant alpha-tocopherol on rat brain protein kinase C activity as a model to study bimodal dose-dependent effect has been investigated. Enzyme activity has been monitored photometrically with a luciferase reporter assay that measures ADP produced by posphorylation. The inhibition of protein kinase C activity by alpha-tocopherol was found at the concentration range from 10(-3) to 10(-6) M with no effect of ultra low doses of the antioxidant (below. 10(-12) M). The absence of bimodal dose-dependent effect may be associated with the enzyme source. PMID- 26591617 TI - [Lotka-Volterra Model of Competition between Two Species and Gause Experiments: Is There Any Correspondence?]. AB - Analysis of deviations between trajectories of Lotka-Volterra model of competition between two species and G.F. Gause experimental time series on combined cultivation of Paramecium aurelia and Paramecium caudatum shows that with rather big probability there is no correspondence between model and experimental datasets. Testing of sets of deviations was provided on symmetry with. respect to origin (Kolmogorov-Smirnov, Lehmann-Rosenblatt, Wald-Wolfowitz, and Munn-Whitney criterions) and on existence/absence of serial correlation in sequences of residuals (Swed-Eisenhart and "jumps up-jumps down" tests). PMID- 26591618 TI - An alcohol-free cetylpyridinium chloride (CPC) mouthrinse. PMID- 26591619 TI - Mouthwashes: Rationale for use. AB - PURPOSE: To update the rationale for the use of mouthwashes and summarize data on the incorporation of an antibacterial, cetylpyridinium chloride (CPC), into a new mouthwash formulation. Data from various published articles are reviewed which demonstrate the value of mouthwashes. Also this Special Issue provides research supporting the efficacy of 0.075% cetylpyridinium chloride in a new, alcohol-free mouthwash formulation (Colgate Total). RESULTS: Benefits of mouthwashes include improving the reduction of plaque biofilm as an adjunct to oral hygiene, killing bacteria in areas difficult to reach by normal oral hygiene, killing bacteria on non-tooth oral surfaces, reaching bacteria subgingivally by placement in an irrigator, and supporting a positive effect on oral health by reducing bacteremia from oral micro-organisms. The benefits of including CPC in this new formulation are demonstrated by in vitro and clinical studies which demonstrate the efficacy of this formulation of CPC on biofilm as well as an effect on the reduction of plaque and gingivitis in three clinical studies. PMID- 26591620 TI - Antibacterial efficacy of a cetylpyridinium chloride-based mouthrinse against Fusobacterium nucleatum and in vitro plaques. AB - PURPOSE: To assess the antimicrobial effects of a fluoride-free and alcohol-free mouthrinse containing 0.075% CPC (test rinse, TR) compared with an otherwise identical CPC-free control rinse (CR). METHODS: Activity against laboratory cultures of Fusobacterium nucleatum, a bacterium associated with gingival disease, was determined using viable counting following 30-second exposures to TR and CR. Effects against intact saliva-derived plaque biofilms were quantified using confocal microscopy coupled with three-dimensional image analyses (viability profiling). RESULTS: Short exposures to TR caused significant inactivation of F. nucleatum, as determined by viable counting (c. 3 log reduction compared to the control rinse, P < 0.05). Confocal microscopy revealed extensive inactivation of complex oral biofilms following treatment with TR; biofilms were significantly less viable than those exposed to CR and three dimensional images revealed extensive zones of dead bacteria even within plaque depths. In conclusion, this investigation demonstrates that the CPC-containing mouthrinse has significant antibacterial efficacy against oral bacteria associated with gingival disease and significantly inactivated plaque biofilm in comparison to a relevant control. PMID- 26591621 TI - Efficacy of two fluoride-free, alcohol-free mouthwashes containing 0.075% or 0.07% CPC in controlling established dental plaque and gingivitis over a 6-week period on adults in Puerto Rico. AB - PURPOSE: To evaluate the clinical efficacy of two commercially available, fluoride-free, alcohol-free mouthwashes containing either 0.075% or 0.07% cetylpyridinium chloride (CPC) in controlling established dental plaque and gingivitis compared to a non-antibacterial control mouthwash. METHODS: A 6-week double-blind, randomized clinical trial was conducted in Trujillo Alto, Puerto Rico. Recruited subjects were randomly assigned to one of three treatment groups: (1) a fluoride-free, alcohol-free mouthwash containing 0.075% CPC (TG); (2) a fluoride-free, alcohol-free mouthwash containing 0.07% CPC (PC); and (3) a fluoride-free, alcohol-free mouthwash without antibacterial agent (NC). Subjects were instructed to rinse with the assigned mouthwash, after tooth brushing, twice daily (morning and evening). After 4 and 6 weeks of product use, subjects were examined for gingivitis (Whole Mouth Gingival, Gingival Interproximal, Gingival Severity Indexes) and plaque (Whole Mouth Plaque, Plaque Interproximal, and Plaque Severity Indexes) parameters. ANCOVA and post hoc Tukey's pair-wise comparisons (alpha = 0.05) were performed for treatment group comparisons. RESULTS: A total of 132 subjects were screened; 120 were enrolled; and 116 completed the study. After 6 weeks of product use, participants who rinsed with the CPC-containing mouthwashes exhibited statistically significant (P < 0.05) reductions in all the gingivitis and plaque parameters evaluated, whereas in those using the non-antibacterial mouthwash, significant reductions were only observed in whole mouth and interproximal plaque scores. No statistically significant (P > 0.05) differences were observed, with respect to the gingival and plaque parameters, between the two CPC-containing mouthwashes. PMID- 26591622 TI - Efficacy of CPC and essential oils mouthwashes compared to a negative control mouthwash in controlling established dental plaque and gingivitis: A 6-week, randomized clinical trial. AB - PURPOSE: To evaluate the clinical efficacy of a mouthwash containing 0.075% cetylpyridinium chloride (CPC) in a fluoride-free, alcohol-free base and a mouthwash containing essential oils in a fluoride-free, 21.6% alcohol base as compared to a fluoride-free, alcohol-free non-antibacterial mouthwash in controlling established dental plaque and gingivitis after 6 weeks of twice daily use. METHODS: A 6-week, parallel-group, randomized double blind clinical trial was conducted in Santo Domingo, Dominican Republic. Recruited subjects were randomly assigned to one of three treatment groups: (1) a mouthwash containing 0.075% CPC in a fluoride-free, alcohol-free base (CPC); (2) a commercially available mouthwash containing essential oils in a fluoride-free, 21.6% alcohol base (EO); or (3) a fluoride-free, alcohol-free non-antibacterial mouthwash (NC). Subjects were instructed to rinse with the assigned mouthwash, after tooth brushing, twice daily (morning and evening). After 4 and 6 weeks of product use, subjects were examined for gingivitis (Whole Mouth Gingival, Gingival Interproximal, Gingival Severity Indexes) and plaque (Whole Mouth Plaque, Plaque Interproximal, and Plaque Severity Indexes) parameters. For treatment group comparisons, ANCOVA and post hoc Tukey's pair-wise comparisons (alpha = 0.05) were performed. RESULTS: 132 subjects were screened; 120 were enrolled; and 116 completed the study. After 6 weeks of product use, subjects using the CPC and EO mouthwashes exhibited statistically significant (P < 0.001) reductions of all gingival and plaque measurements compared to subjects using the NC mouthwash. Subjects using the CPC mouthwash did not exhibit a statistically significant (P > 0.05) reduction with respect to gingival severity and all plaque measures (Whole, Interproximal, and Severity) when compared to EO mouthwash. Subjects using the CPC mouthwash exhibited statistically significant (P < 0.05) reductions in Gingival Index scores of 5.1% (P = 0.005), and Gingival Interproximal Index scores of 5.5% (P = 0.016) relative to subjects using the EO mouthwash. These reductions were not considered clinically significant. PMID- 26591623 TI - Randomized clinical trial of two oral care regimens in reducing and controlling established dental plaque and gingivitis. AB - PURPOSE: To evaluate the efficacy of a test regimen (TR) integrating the use of a commercially available triclosan, PVM/MA copolymer, and sodium fluoride containing toothpaste, an alcohol-free, fluoride-free cetylpyridinium chloride (CPC) mouthwash, and a manual toothbrush with cheek and tongue cleaner compared to a negative control regimen (NCR) integrating a commercially available 0.76% sodium monofluorophosphate toothpaste, a manual toothbrush and a fluoride-free and alcohol-free non-antibacterial mouthwash in the reduction and control of established plaque and gingivitis after 4 weeks of product use. METHOD: A 4-week, two-cell, double-blind, parallel-group, randomized clinical study was conducted in Cedar Knolls, New Jersey, USA. Recruited subjects were randomly assigned to two regimens: (1) a commercially available toothpaste containing triclosan, PVM/MA copolymer, and 0.243% sodium fluoride, a manual toothbrush with cheek and tongue cleaner, and commercially available mouthwash containing 0.075% CPC in a fluoride-free and alcohol-free base (TR), or (2) a commercially available 0.76% sodium monofluorophosphate toothpaste, a manual toothbrush with rounded/polished bristles, and a fluoride-free and alcohol-free non-antibacterial mouthwash (NCR). Subjects were examined for dental plaque and gingivitis. Gingival, Gingival Severity, Gingival Interproximal, Plaque, Plaque Severity and Plaque Interproximal Index scores were calculated. For regimen comparison, independent t test and ANCOVA analyses were performed. RESULTS: 130 subjects were screened; 120 enrolled; and 115 subjects completed the randomized clinical trial (RCT). After 4 weeks of product use, subjects using TR exhibited statistically significant (P < 0.001) reductions of 22.3%, 27.8% and 20.4% in mean Gingival, Gingival Severity and Gingival Interproximal Index scores, respectively, as compared to subjects using NCR. After 4 weeks of product use, subjects using TR exhibited statistically significant (P < 0.001) reductions of 28.2%, 60.7% and 27.6% in mean Plaque, Plaque Severity and Plaque Interproximal Index scores, respectively, as compared to subjects using NCR. PMID- 26591624 TI - Pathological spectrum in recurrences of glioblastoma multiforme. AB - INTRODUCTION: Glioblastoma (GBM) is the most frequent primary malignant brain tumour. Despite advances in treatment its prognosis remains poor. Histological features of GBM are well known. On the contrary histological description of recurrences is still not available. The aim of this study was to describe the morphological, immunohistochemical and molecular features of recurrent GBMs. METHODS: 25 recurrent GBMs, diagnosed after 2005, were collected. All patients had undergone an adjuvant treatment regimen (temozolomide and/or radiotherapy). All cases were immunostained using anti-GFAP, Olig2 and Nogo-A antisera. MGMT and IDH1 status was reassessed. Features of the recurrences were compared with those of primary GBMs, time of recurrence and survival. RESULTS: Recurrences were divided morphologically into three groups: 1) recurrences displaying the same features of primary GBM, were highly cellular, had the fastest progression and the worst prognosis; 2) recurrences changing dramatically morphological appearance, had a slightly longer survival, 3) poorly cellular recurrences, with sparse neoplastic cells intermingled with reactive and necrotic tissue, displayed the slowest progression and longer survival. MGMT and IDH1 status remained unchanged between primary tumours and recurrences. DISCUSSION: GBM histological subtypes display different reactions to adjuvant treatments, offering a possible role in predicting different recurrence and survival time. PMID- 26591625 TI - The major prognostic factors of thymomas: about a Tunisian study of 100 cases. AB - AIM: Thymomas are characterised by their rarity, histologic variability and peculiar patterns of recurrence. Herein, we present the experience of a single institution and aim to highlight the major prognostic factors of these tumours. MATERIALS AND METHODS: We present a retrospective study on 100 thymomas diagnosed between 1994 and 2011. Statistical analyses were performed using version 18.0 SPSS. The Kaplan Meier method was used to estimate survival, and survival curves were compared using the Log-Rank test. A p < 0.05 was considered statistically significant. RESULTS: 50 men and 50 women underwent surgical resection for thymoma. Radiologic findings highlighted a diagnosis of thymoma in 51% of cases. The thymomas were classified as stage I in 25 cases, stage II in 47 cases, stage III in 25 cases and stage IV in 3 cases. According to the WHO classification, tumours were classified as type A in 14 cases, type AB in 24 cases, type B1 in 17 cases, type B2 in 20 cases, type B3 in 8 cases, B1/B2 in 8 cases and B2/B3 in 9 cases. The mean survival of patients was 136 months. Age, sex, tumour size, WHO classification and Masaoka stage were evaluated as prognostic factors. Univariate analysis showed that the major prognostic factors were WHO classification (p = 0.019) and Masaoka Stage (p = 0.0001). CONCLUSION: Our results place emphasis on the prognostic value of WHO classification and Masaoka stage in thymomas; in addition, the necessity of improving reproducibility of microscopic classification to avoid discrepancies among prognostic groups is highlighted. PMID- 26591626 TI - An unusual tumour of the lung. AB - We report a case of a 51-year-old woman with a solitary mast cell tumour of the lung, a rare neoplasm with only three previously-reported cases reported in the literature. Unlike previous cases, the tumour in the present case was bulky, measuring 14 cm in diameter and budding into the segmental bronchus. Histologically, it showed proliferation of typical metachromatic mast cells intermingled with undifferentiated cells with a ratio of 3:1. The neoplastic mast cells stained strongly with tryptase, CD117, CD68 and CD45, CD14 and CD33; whereas the undifferentiated cells lacked all these markers and expressed EMA and cytokeratin. Histological examination of bone marrow and laboratory data were unremarkable. To our knowledge, this is the fourth case of solitary extracutaneous mastocytoma of the lung. The differentiating features of this neoplasm and a review of literature are presented. PMID- 26591627 TI - Jejunal lymphangioma: an unusual cause of intussusception in an adult patient. AB - Adult intussusception is a relatively rare clinical entity. Almost 90% of cases of intussusception in adults are secondary to a pathologic condition that serves as a lead point. Lymphangioma of the small bowel is an unusual tumour that has been rarely reported to cause intussusception. In this paper, we present a rare case of adult intussusception due to jejunal lymphangioma. A 22-year-old female patient with a medical history significant for anaemia presented with intermittent colicky abdominal pain, diarrhoea and oedema of the inferior limbs for the past three months. Ultrasonography and CT scan revealed a typical target sign with dilated intestinal loops. At laparotomy, a jejuno-jejunal intussusception was found. Partial resection of the jejunum was performed. Macroscopic examination of the surgical specimen revealed a pedunculated polyp measuring 2 cm in diameter. Histological sections of the polyp revealed in the lamina propria and submucosal layer of the jejunum several markedly dilated thin walled lymphatic spaces lined with single layers of flat endothelial cells. The final pathologic diagnosis was submucosal lymphangioma. This case report indicates that intussusception, although rare in adults, should be considered in the differential diagnosis of abdominal pain. Moreover, it should be taken into consideration that lymphangioma is one of the possible lesions that can cause intussusception. PMID- 26591628 TI - Segmental infarction of the testis: can frozen sections avoid orchidectomy? AB - Segmental infarction (SI) of the testis is a rare condition that can masquerade as a mass lesion, thus requiring exclusion of tumour. If clinical exams do not exclude a neoplastic lesion with certainty, orchidectomy is usually performed. A case of SI of the testis is presented; the use of frozen section of the enucleated mass demonstrated the ischaemic nature of the lesion, so avoiding orchidectomy. The 8 year follow-up was uneventful. The use of frozen section in SI could permit the selection of cases in which testicular-sparing surgery should be considered. PMID- 26591629 TI - Multifocal sclerosing angiomatoid nodular transformation of the spleen in a patient with simultaneous metachronous liver metastasis after colon cancer surgery: a first case report. AB - Sclerosing angiomatoid nodular transformation of the spleen (SANT) is a benign, extremely rare vascular lesion of the spleen with unknown pathogenesis. SANT is often discovered incidentally, and can sometimes be found in patients with a history of cancer. Based on absent definitive radiological signs and varying growth patterns, distinction from malignant processes such as metastasis can be very difficult. Therefore, surgical resection of the spleen is indicated in most cases of patients with history of cancer. We report a case of a bifocal manifestation of SANT in the spleen in a patient with history of colon cancer and newly-diagnosed metachronous liver metastases. PMID- 26591630 TI - A rare cause of death in infancy: idiopathic infantile arterial calcification. AB - The aim of this paper is to report the autopsy findings of an Idiopathic Infantile Arterial Calcification-new-born male and describe its follow-up. Y.R, a 23-days-old male, hasn't any relevant personal past medical or family history. The baby was weighing 3.2 kg at birth. He was breast fed and appeared to be perfectly normal. In the last 24 hours, he presented to the family doctor with vomitis, refuse of feeds without fever or diarrhea. He was diagnosed as having gastroenteritis and was medicated accordingly. A few hours later, he had an hematemese episode associated with facial cyanosis. Death occurred despite cardio pulmonary resuscitation. Forensic autopsy was required. The macroscopic examination showed a bilateral pleural liquid effusion without any other abnormalities. Microscopic investigation revealed a generalized arterial calcification of all organs. Idiopathic arterial calcification is primarily a disease of infancy. It is characterized pathologically by generalized arterial calcification within the internal elastic lamina, associated with intimal fibrous proliferation. Death occur often in the first sixth months due to heart failure. PMID- 26591631 TI - Cytopathology in the diagnostic appraisal of uncommon malignant neoplastic lesions. AB - Cytology and fine needle aspiration (FNA) cytology are accepted means of diagnosing and typing of common forms of malignant tumors. However, their usefulness for diagnosing less common neoplasms is not clearly established and this study was designed to examine this. We report four unusual cases of patients with malignant neoplasms in which cytology and fine needle aspiration cytology or aspiration biopsy (FNAC, FNAB) contributed significantly in establishing the diagnosis. These cases facilitate the diagnostic capabilities of cytology over a wide spectrum of neoplasms including rare lymphoproliferative disorders and carcinomas. PMID- 26591632 TI - Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) and multiple pulmonary epithelioid hemangioendothelioma (PEH): a case report. AB - We report a case of a 76-year-old female with multiple lung nodules (Fig. 1 Rx). Pathologic evaluation of the lower left video-assisted thoracoscopic surgery (VATS) lobectomy VATS-lobectomy showed four nodules that were described as pulmonary epithelioid hemangio-endothelioma (PEH); the immunohistochemical stains showed that the neoplastic cells expressed CD31, a variable expression for factor VIII and a low expression of CD34. In the remaining parenchyma of the lobe, multiple nests of neuroendocrine cells were observed with immunohistochemical confirmation, and the diagnosis was diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH). To our knowledge, the association between PEH and DIPNECH has never been described in the literature. PMID- 26591633 TI - HISTORY OF OTONEUROSURGERY AND SURGICAL TREATMENT OF MENIERE'S DISEASE. PMID- 26591634 TI - RADICAL HYSTERECTOMY IN SURGICAL TREATMENT OF INVASIVE CERVICAL CANCER AT THE DEPARTMENT OF GYNECOLOGY AND OBSTETRICS IN NOVI SAD IN THE PERIOD 1993-2013. AB - INTRODUCTION: During the period from 1993 - 2013, 175 women with invasive cervical cancer underwent radical hysterectomy sec. Wertheim-Meigs at the Department of Gynecology and Obstetrics, Clinical Center of Vojvodina in Novi Sad. Indications for radical hysterectomy comprise histopathologically confirmed invasive cervical cancer in stages I B 1- II B according to the International Federation of Gynecology and Obstetrics. MATERIAL AND METHODS: Stage ofthe disease or extent of the disease spread to the adjacent structures was assessed in accordance with the International Federation of Gynecology and Obstetrics staging system from 2009. Exclusion criteria were all other stages of this disease: I A and stages higher than II B, as well as the absence of definite histological confirmation of the cervical cancer (primary endometrial or vaginal cancer which infiltrates the uterine cervix). Prior the operation, the following had to be done: the imaging of pelvis and abdomen, chest X-ray in two directions, electrocardiography, internist and anesthesiological examination. RESULTS: The patients' age ranged from 24-79 years (x : 46 years), and the operation duration was 120-300 minutes (x : 210 min.). Stage I B 1 was found in 64.6% of operated patients, 14.8% of the patients were in stage I B 2, 9.1% were in stage II A and 11.4% were in stage II B. Blood loss during the operation ranged from 50-800 ml (on average 300 ml), and the number ofremoved lymph nodes per operation was 14-75 (x : 32). Intraoperative and postoperative complications developed in 6.8% of and 17.7% of patients, respectively. Recurrence was reported in 22(12.5%) patients, most often in paraaortic lymph nodes (3.4%) and parametria (2.8%), while the overall 5-year survival rate was 87% until 2008. CONCLUISION: Wertheim-Meigs radical hysterectomy is a basic surgical technique for the treatment of initial stages of invasive cervical cancer. PMID- 26591635 TI - DEPRESSIVE DISORDERS IN STUDENT POPULATION - COMPARATIVE STUDY CONDUCTED IN 2007 AND 2014. AB - INTRODUCTION: The aim of this study was to determine the frequency of depressive symptomatology and its distinctive manifestations in student population in the interval of7 years. MATERIAL AND METHODS: A sample of 790 students from the University of Novi Sad was asked questions about depression by means of the Patient Health Questionnaire 9 in 2007 and 2014. RESULTS: The results show that the frequency of depression in student population ranges from 12.4% to 16.5%. Comparing the samples, in 2014 there were more mildly and severely depressed students, while the number of moderately depressed students was significantly lower. Suicidal thoughts were present in about 32% to 45% of depressive students and in about 7% of the total sample. The higher presence of depression was confirmed among female students in both study samples. CONCLUSION: The percentage of depressed students is stable over time. Symptomatology is very specific and suicidal thoughts are present in a great number of depressed students. Therefore, early diagnosis is essential. PMID- 26591636 TI - ARTICULATION OF SPEECH SOUNDS OF SERBIAN LANGUAGE IN CHILDREN AGED SIX TO EIGHT. AB - INTRODUCTION: Phonetic and phonological system of the healthy members of one linguistic community is fully formed around 8 yedrs of age. The auditory and articulatory habits are established with age and tend to be more difficult to be upgraded and completed later. MATERIAL AND METHODS: The research was done as a cross-sectional study, conducted at the preschool institution "Radosno detinjstvo" and primary school "Branko Radicevic" in Novi Sad. It included 66 children of both genders, aged 6 to 8. The quality of articulation was determined according to the Global Articulation Test by working with each child individually. RESULTS: In each individual vowel, plosive, nasal, lateral and fricative, the quality of articulation was statistically significantly better in the first graders compared to the preschool children (p<0.01). In each affricate, except for the sound /c/, the quality of articulation was statistically significantly better in the first graders than in the preschool children (p<0.01). The quality of articulation of all speech sounds was statistically significantly better in the first graders than in the preschool children (p<0.01). DISCUSSION AND CONCLUSION: The most common disorder of articulation is distortion, while only substitution and substitution associated with distortion are less common. Omission does not occur in children from 6 to 8 years of age. Girls have slightly better quality of articulation. The articulatory disorders are more common in preschool children than in children who are in the first grade of primary school. The most commonly mispronounced sounds belong to the group of affricates and fricatives. PMID- 26591637 TI - SEXUAL BEHAVIOR OF STREET CHILDREN. AB - INTRODUCTION: Street children and youth are at risk of getting engaged in different behaviors including risky sexual behavior, which adversely affects their development and health. The aim of this study was to examine sexual behavior of street children and youth, and the risks and consequences associated with sexual behavior. MATERIAL AND METHODS: A pilot study was conducted on a sample of 50 users of the Drop-in Centre for Street Children in Novi Sad, from 10 to 19 years of age. The study was conducted by a psychologist through structured interviews, with prior consent of the adolescent and parent. RESULTS: Among the respondents who were sexually active, 41.2% had had the first sexual intercourse by the age of 12, their median age at that time being 14 years, while the age at the time of the first sexual intercourse is 16 years in the general population of Serbia. The majority of sexually active adolescents had several partners, one male adolescent had sex with a person of the same sex, and one was paid for sex. Very few respondents used a condom. Among 15 male sexually active respondents, three (ages 11, 12 and 14) were forced to have unwanted sexual intercourse, and a quarter of adolescents (three boys and one girl) were forced to do something unwanted during sex. CONCLUSION: Despite a small and unrepresentative sample, the results of this study indicate serious problems and significant risks associated with sexual behavior of children and young people who live and work in streets. This pilot study suggests that it is necessary to conduct new research on sexual behavior of street children and youth on a representative sample and with appropriate methodology. The results of a new study should be used to plan and carry out appropriate preventive measures regarding sexual behavior of street children. PMID- 26591639 TI - PHARMACOGENOMIC DETERMINANTS OF RESPONSE TO CARDIOVASCULAR DRUGS. AB - Cardiovascular diseases are the leading cause of morbidity and mortality worldwide. Despite considerable advances in cardiovascular pharmacology, significant inter-individual variability in response to drugs affects both their efficacy and safety profile. Drug-gene associations have emerged as important factors determining a spectrum of response to therapy. Pharmacogenomic interactions in cardiovascular medicine are also involved in etiology of adverse effects that may be life-threatening, such as statin-induced myopathy or a hemorrhage/thrombosis event during anticoagulant therapy. Introduction of genetic tests prior to the initiation of therapy and implementation of genetically-guided therapy represent a step forward to achieving a goal of individualized medicine in cardiology, already present in recommendations for warfarin and clopidogrel. However, further investigations addressing genomic predictors of variability in response to drugs are still needed and translating these findings into routine clinical practice remains a substantial challenge. PMID- 26591638 TI - PARAMETERS OF HEMODIALYSIS ADEQUACY AND PATIENTS' SURVIVAL DEPENDING ON TREATMENT MODALITIES. AB - INTRODUCTION: Retrospective studies showed that hemodiafiltration was associated with a reduced risk of mortality compared with standard hemodialysis in the patients with end-stage renal disease. Recently, a few prospective randomized clinical trials found no advantage in survival with hemodiafiltration as compared with high-flux hemodialysis and low-flux hemodialysis. The aim of this study was to compare the parameters of hemodialysis adequacy and two-year survival of patients depending on the modality of hemodialysis. MATERIAL AND METHODS: A total of 159 hemodialysis patients were divided into 3 groups according to the type of hemodialysis treatment: group A - low-flux hemodialysis, group B - high-flux hemodialysis, and group C - hemodiafiltration. All patients had the same duration of hemodialysis sessions. The analysis included average one-year biochemical parameters, and two-year survival of patients. RESULTS: The patients on hemodiafiltration were significantly younger, they had longer dialysis vintage and higher index of dialysis adequancy as compared with the patients on low-flux hemodialysis and high-flux hemodialysis, but without a difference between the two latter groups. Compared to the patients on low-flux hemodialysis, the patients on hemodiafiltration and high-flux hemodialysis had significantly higher hemoglobin value with less frequent erythropoietin stimulating agent use. According to Kaplan-Meier survival analysis, the patients on hemodiafiltration and high-flux hemodialysis had significantly better two-year survival than the patients on low flux hemodialysis. Cox proportional hazards model confirmed that high-flux hemodialysis caused a significantly lower relative risk of mortality (56% reduction) compared to low-flux hemodialysis (hazard ratio 0.44; P=0.026), and hemodiafiltration caused a 58% reduction in the relative risk of mortality compared to low-flux dialysis (hazard ratio 0.42; P=0.105), but without a statistical significance. CONCLUSION: This study has demonstrated two-year survival benefit with high-flux hemodialysis and hemodiafiltration compared with low-flux hemodialysis. There was no difference in survival between high-flux hemodialysis and hemodiafiltration groups. PMID- 26591640 TI - THINGS THAT CAN BE CHANGED IN EARLY INTERVENTION IN CHILDHOOD. AB - INTRODUCTION: Early intervention implies a model of support focused on a child, family and a broader community from early childhood. The aim of this study was to analyze the elements of the successful early intervention in childhood, as well as to assess the role of a special educator and rehabilitator and level of their involvement in implementing the program on the territory of Novi Sad. MATERIAL AND METHODS: The study sample included 100 parents of children with disabilities (aged 3-7), who completed the questionnaire designed for the purposes of this research, based on a similar questionnaire design. RESULTS: Speech delay is one of the most common reasons (over 50%) why parents seek professional help. By the end of the first year of life of their child, 43% of parents responded that they had noticed the first problems, that is, a problem was identified in 25% of children of this age group, and the same number was included in the treatment. About 55% of children were involved in organized treatment from 3 years of age onwards. Special educators and rehabilitators are usually involved in treatment when the team consists of three or more professionals. CONCLUSIONS: It is necessary to improve early intervention services, to educate staff, and provide conditions which would make it possible to overcome the existing disadvantages in treating children from an early age. In addition, the involvement of special education and rehabilitation professionals in treatment teams since children's early age is vital. PMID- 26591641 TI - HUMAN SUBCUTANEOUS DIROFILARIASIS - CASE REPORT. AB - INTRODUCTION: Human dirofilariasis is a zoonotic disease caused by Dirofilaria repens and Dirofilaria immitis. It usually presents as a nodular lesion in the lung, subcutaneous tissues or eyes. In animals, dirofilariasis is a very common disease with serious cardiovascular and respiratory manifestations. If adequate therapy is not given at the beginning ofthe disease, dirofilariasis can lead to animal death. On the contrary, human dirofilariasis is frequently mild, sporadic and asymptomatic disease. Complications in humans are very rare. In Europe, human dirofilariasis is a very rare zoonotic disease even in endemic areas such as Italy, Spain and the Mediterranean. CASE REPORT: The authors reported the case of a 43-year-old male with a subcutaneous nodule caused by Dirofilaria repens. The patient who lives in Budva, Montenegro, had a nodule in the right-hand side of the anterior abdominal walljust below the sternum with maximum diameter of 3 cm. His health condition was good and all laboratory analyses were normal. The lesion was surgically removed and the histopathological examination confirmed the parasitic infection by Dirofilaria repens. After surgical excision, the patient was treated with dual antimicrobial therapy (100 mg doxycycline per os twice a day for 28 days and 200 mg albendazole per os twice a day for 10 days). CONCLUSION: It is very difficult to make the diagnosis of a subcutaneous nodule. The difficulties arise in the differential diagnosis because subcutaneous nodules are suspected to be malignant neoplasm or other pathologies such as tuberculosis, fungal infections, sebaceous cysts, hamartomas, abscesses, and so on. Although human dirofilariasis is a rare disease, the number of reported cases has recently been increasing worldwide. PMID- 26591642 TI - CHRONICLE OF THE "ANGLO-YUGOSLAV CHILDREN'S HOSPITAL" IN SREMSKA KAMENICA. AB - As a peacetime work of Katherine S. Macphail (Glasgow, 1887- St.Andrews, 1974) MB ChB (Bachelor of Medicine and Surgery), the Anglo-Serbian Children's Hospital in Belgrade was established after World War I, and the English-Yugoslav Children's Hospital for Treatment of Osteoarticular Tuberculosis was founded in Sremska Kamenica in 1934. Situated on the Fruska Gora slope, the hospital-sanatorium was a well-equipped medical institution with an operating theatre and x-ray machine providing very advanced therapy, comparable to those in Switzerland and England: aero and heliotherapy, good quality nourishment, etc. In addition, school lessons were organized as well as several types of handwork as the work-therapy. It was a privately owned hospital but almost all the children were treated free of cost. The age for admission was up to 14. During the period from 1934 to 1937, around 458 children underwent hospital treatment, most of them with successful results. During the war years the Sanatorium was closed but after the war it was reactivated. In 1948 by the act of final nationalization of all medical institutions in the communist Yugoslavia, the hospital was transformed into a ward of orthopedic surgery under the supervision of the referent departments in Belgrade and Novi Sad. Today, hospital is out of work and deprived of its humanitarian mission. The building is neglected and in ruins although it has been proclaimed the national treasure by the Regional Institute for Protection of Monuments of Culture. PMID- 26591643 TI - [Is there unused capacity in our brain?]. AB - Although a great deal of research has been performed on special abilities occurring in connection with developmental disorders and injuries, their biological background remains unknown. It is tempting to think that understanding of the mechanism of generation of special ability would help each of us to liberate our brain capacity and direct it in a desired manner. Poor knowledge of the general functioning principle of the brain remains an essential restriction against establishing whether there is extra capacity in the brain and whether its liberation is possible now or in the near future. Model-based brain research is rising to the central position in understanding the functional principle. PMID- 26591644 TI - [Pitfalls in psychopharmacological drug use]. AB - Psychiatric drug therapy is based on diagnoses and controlled examinations Psychiatric illnesses or disorders are, however, heterogenous conditions in their nature and treatment response. It is not possible to know beforehand whether a drug is beneficial or actually harmful for an individual patient. In practice, the use of psychopharmacological drugs is actually experimental, and success will require critical monitoring of the response, flexibility and good pharmacotherapeutic rapport. The pitfall in the use of all psychopharmacological drugs is cessation of effective treatment and, on the other hand, unnecessary medication that sometimes involves even dangerous adverse effects. PMID- 26591645 TI - [Designer-drug overdose patients treated by Helsinki Emergency Medical Services in 2009-2012]. AB - BACKGROUND: Designer drug abuse has increased during the last decade. MATERIAL AND METHODS: Retrospective study of designer drug overdoses in Helsinki emergency medical services (EMS) 2009-2012. Use of drugs was self-reported or from other people present. RESULTS: There were 98 patients (72% male), median age 30 years. The majority reported MDPV and polysubstance abuse. Only 15% were administered medication by EMS and 69 were transported. In the emergency department 53% required specific care, mostly benzodiazepines. Most (78%) were discharged within less than 24 hours. Infectious complications were the main reason for admission. CONCLUSIONS: Designer drug overdose patients require drug administration rarely on scene, but quite often in the emergency department, usually sedation. Admissions are rare. PMID- 26591646 TI - [Performance and cardiorespiratory fitness: from exercise physiology to clinical decision-making]. AB - Cardiorespiratory fitness is indicated by the body's ability to transport oxygen from the surrounding air to the contracting muscle, and the muscle's capacity to use oxygen. Cardiorespiratory fitness relies on the effective integration of the cardiovascular pulmonary, hematologic, and skeletal muscle systems. Maximal oxygen uptake is considered the best measure of cardiorespiratory fitness. A low level of maximal oxygen uptake is associated with a markedly increased cardiovascular and all-cause mortality both in healthy subjects and cardiac patients. Randomized, controlled trials are still needed, however, to further clarify the value of the assessment of cardiorespiratory fitness in clinical decision-making. PMID- 26591647 TI - [Physical activity in the treatment and rehabilitation of chronic diseases]. AB - A suitable amount of properly conducted and performed physical activity improves the functional capacity and quality of life of persons having a chronic disease. Regular endurance exercise and muscular strength training can also alleviate central risk factors of atherosclerotic disease. Exercise-based rehabilitation reduces mortality among patients with coronary artery disease or cardiac failure. In practice, exercise counseling and guidance is included as part of disease management and lifestyle guidance. This requires knowledge, competence and time resources from the physician. In addition, a clinical pathway involving health and exercise professionals is needed to support the implementation of exercise programs. PMID- 26591648 TI - [Physical activity among growing children]. AB - Lack of physical activity poses a risk to the health and well-being of growing children, and should also be considered at a medical consultation. According to recommendations, those of 7 to 18 years of age should carry out at least one hour of physical activity daily. Of the Finnish school-aged children, 50% of the elementary school children but only 17% of the secondary school children follow the physical activity recommendations. Some children exercise and play sports in abundance, and in their case it should be especially made sure that the prevention and, when necessary, treatment of exercise-related injuries, overexertion and eating disorders are taken care of. PMID- 26591649 TI - [Health hazards of physical inactivity]. AB - Obesity and non-communicable diseases and related costs increase with physical inactivity. In addition to the lack of recreational exercise, a sedentary lifestyle also seems to have a negative effect of health, independently of other lifestyle and risks. New means, as well as multidisciplinary and multiprofessional collaboration, are required in order to improve health and well being on the population level and to reduce health-related costs. New, more effective operational models are also needed in health communication in order to achieve the desired and more permanent results. PMID- 26591650 TI - [Physical activity of the elderly - what kind of and what for?]. AB - Starting to exercise is beneficial even at an older age. Versatile exercise improving the condition of the respiratory and circulatory system, muscle strength and mobility is effective for maintaining functional capacity, especially among those having an already impaired mobility and functional capacity. Physical exercise can slow down the progress of bone loss, and intense exercise may even serve to increase the bone density in an elderly person. The main focus of physical activity aiming at the prevention of failings and fractures is in training that improves balance and muscular strength in the lower extremities. Endurance exercise and strength training seem to diminish the impairment of cognitive functions. PMID- 26591651 TI - Androgen deprivation therapy and cardiovascular risk. PMID- 26591652 TI - Seizure classification key to epilepsy management. AB - The diagnosis of epilepsy carries significant implications for physical, psychosocial and financial wellbeing as well as a small but significant increased risk of mortality. The diagnosis is often incorrect, potentially in up to 20% of cases, so should be revisited if seizures are not responding to treatment. Evidence indicates that misdiagnosis is significantly more common among nonspecialists. SIGN recommends that the diagnosis of epilepsy should be made by an epilepsy specialist, ideally in the setting of a dedicated first seizure or epilepsy clinic. An incorrect diagnosis of epilepsy can be harmful. There is an exhaustive list of epilepsy mimics that can result in misdiagnosis and expose patients to unnecessary treatment with antiepileptic drugs. Diagnosis relies primarily on the history. Investigations can support the diagnosis but cannot make it in isolation, and negative investigation findings are common in epilepsy. Brain imaging will be undertaken in most patients with epilepsy, but is not routinely required in those with a definite diagnosis of genetic generalised epilepsy. The EEG has limitations and can sometimes cloud rather than clarify the diagnostic picture. Distinguishing between a genetic generalised epilepsy and a focal epilepsy is vital as this influences investigation, treatment and prognosis. Generally medication should not be started following a single seizure except in specific circumstances or in cases where the risk of recurrence is high. PMID- 26591653 TI - Early accurate diagnosis crucial in multiple sclerosis. AB - In around 85% of cases, multiple sclerosis (MS) starts with an acute neurological episode, a clinically isolated syndrome, which is considered to be the first clinical episode of relapsing-remitting MS (RRMS). It is characterised by the presence of acute relapses, after which there is normally good functional recovery. About 15-20 years after symptom onset, most patients develop secondary progressive MS, characterised by a gradual and irreversible neurological decline. MS affects women more frequently than men, with a ratio of 2-3:1. In RRMS the disease generally starts in the late 20s. Symptom onset in those with primary progressive MS occurs around the age of 40. Clinical relapses in RRMS reflect acute inflammation in the CNS, resulting in specific clinical syndromes including optic neuritis, myelitis, brainstem/cerebellum syndrome and supratentorial syndrome. In progressive MS, progression generally presents with gradual loss of power in the lower limbs, which may be asymmetric. It is often accompanied by sensory disturbances in the lower limbs, bladder and bowel symptoms. Investigations need to rule out conditions that can mimic an inflammatory demyelinating disease of the CNS and determine the presence of dissemination in space and dissemination in time of the inflammatory-demyelinating disease. There is no confirmatory test for MS and it remains essentially a clinical diagnosis. PMID- 26591654 TI - Diagnosing and treating diverticular disease. AB - It is important to distinguish between diverticulosis, the presence of asymptomatic diverticula, and diverticular disease which refers to symptomatic cases which can present with acute or chronic symptoms. Chronic symptoms range from mild intermittent abdominal cramps to the more severe picture of chronic abdominal pain and occasional rectal bleeding. In contrast, acute diverticulitis refers to acute inflammation in the diverticula. Low dietary fibre intake is reported to increase the risk of diverticular disease. In the UK, the prevalence rises from approximately 5% of people in their 40s to almost 50% of those above the age of 80. It is estimated that 20% of patients with diverticulosis will develop symptoms at some point in their lifetime. Diverticular disease can be confirmed radiologically or endoscopically. Referral of patients with symptomatic diverticular disease to secondary care is not indicated unless: the symptoms affect their quality of life; the pain is not controlled by paracetamol; new symptoms develop which require further investigation; there are concerns about the possibility of an alternative diagnosis or patients develop red flag symptoms. Even in patients with established diverticulosis, a change in the clinical picture with development of red flag symptoms warrants urgent referral to rule out lower gastrointestinal malignancy. Patients with suspected uncomplicated acute diverticulitis should be assessed according to their level of pain and associated systemic features of sepsis. In those where pain is controlled and there are no signs of systemic sepsis or multiple comorbidities, the patient may be treated in primary care. PMID- 26591655 TI - Allergic reactions. PMID- 26591656 TI - THE TRAGEDY OF GLYCOSURIA. 1915. PMID- 26591657 TI - Today's facts will be tomorrow's fallacies. PMID- 26591658 TI - [Animal Staphylococcus felis with the potential to infect human skin]. AB - INTRODUCTION: Breaking interspecies barrier by microorganisms has become in the recent years an alarming phenomenon that threatens public health worldwide. An important potential interspecies transmission risk factor is close contact animal human including occupational exposure of pet breeders and veterinarians. MATERIAL AND METHODS: The features of Staphylococcus felis ZMF 13 strain isolated from a swab from a cat's wound connected with potential pathogenicity were investigated. Results: The virulence factors of strain found were hydroxamate siderophores, production of invasins - intracellular proteolytic and lipolytic enzymes and the ability of biofilm production. The ability of bacteriocin-like substance production was also observed. The substance has an antagonistic activity against bacteria belong to physiological flora of the human skin which may be important in breaking the colonization resistance of human organism. Although the strain of S. felis ZMF 13 was methicillin-susceptible it demonstrated the constutive type of MLSB resistance mechanism. The genes ermA, msrB, linA connected with macrolide, lincosamides and streptogramin B resistance were detected. CONCLUSIONS: The current evidence suggest that Staphylococcusfelis has a number of features that can be crucial in its potential interspecies transmission. PMID- 26591659 TI - [Differentiation of spa types and staphylococcal cassette chromosome mec (SCCmec) in clinical methicillin-resistant Staphylococcus aureus isolated in medical sites of Gdansk region]. AB - INTRODUCTION: Methicillin-resistant Staphylococcus aureus bacteria are one of the key etiological factors of hospital-acquired and community-acquired infections. MRSA strains have an ability of causing a broad spectrum infections: from a relatively mild skin infections to severe life-threatening systemic infections. They are characterized by multi-drug resistance, virulence of a number of factors, may clonally spread within the hospitals and between hospitals. METHODS: The study embraced a number of 75 isolates of MRSA isolated from patients of 7 medical sites of the Gdansk region within the period of six months (June to December 2013). Strains have derived from various clinical materials, both of hospitalized patients (n=59) and outpatient (n=16). The isolates were tested for the susceptibility to antimicrobial agents accordance with the guidelines EUCAST. To estimate of the variability of occurrence of S. aureus clones used were standard spa gene, consisting in the amplified polymorphic region of the X gene encoding the protein A gene (spa). After receiving the results, a spa types were identified using international database Ridom Spa Server (www.spaserver.ridom.de). To determine the polymorphism cassette carrying the inecA gene from MRSA strains, used typing five major chromosomal cassette SCCmec (I-V) by multiplex PCR. RESULTS: MRSA population genetic analysis carried out on the basis of typing SCCmec cassettes and spa gene has showed a predominance of strains with SCCmec type II casette (46.7%) and SCCmec IV casette (38.7%). Less frequently detected were strains containing SCCmec I cassette (12.0%) and SCCmec III cassette (2.6%). Spa typing revealed the presence of 13 gene types in MRSA. The most frequently observed spa types were: t151 (24.0%), t003 (16.0%) in strains of the SCCmec II cassette and t437 (16.0%) and t008 (14.8%) in the isolates with SCCmec cassette IV, whereas staphylococcus with the type of spa t011 (12.0%) had SCCmec cassette I. CONCLUSIONS: In our population most frequent strains cassette SCCmec II (46.7%), in most representing types of spa t151 (51.4%) and t003 (34.3%), generally resistant not only to beta-lactam antibiotics, but as erythromycin, clindamycin and norfloxacin (82.8%), the more frequently they were isolated from patients than a hospital outpatient centers. The strains SCCmec IV that represent the majority of outpatient centers (68.8%), the most represented type t437 (41.4%) and often occurred in hospital centers. PMID- 26591660 TI - [The Neisseria gonorhoeae and Chlamydia trachomatis coinfection in patients of Department of Dermatology and Venereology Medical University of Warsaw]. AB - INTRODUCTION: The aim of the study was to investigate the coexistence of N. gonorrhoeae and C. trachomatis infections in patients of Department of Dermatology and Venereology in Warsaw. METHODS: We investigated the urethral, cervical, anal and pharyngeal speci mens from 140 symptomatic and asymptomatic patients of Department of Dermatology and Venereology in Warsaw using the Real Time PCR method. Real Time PCR DUPLICalpha(r) RealTime Neisseria gonorrhoeae and DUPLICalpha(r) RealTime Chlamydia trachomatis 2nd Generation Detection Kits (Euroclone(r))was performed on termocycler Smart Cycler(r) Dx. For DNA isolation the Bact Extra Pure Kit (Euroclone(r)) was used. RESULTS: 22 samples were positive for C. trachomatis and 28 were positive for N. gonorrhoeae. Both infections coexisted in nine patients (6.4%). In our investigations, in opposition to results from other centers, gonorrhoea was more prevalent than C. trachomatis infection. The chlamydial infection coexisted in 32.1% with gonorrhea and gonorrhea coexisted with chlamydial infection in 40.9%. CONCLUSIONS: The coinfection with Neisseria gonorrhoeae and Chlamydia trachomatis occurs very often. According IUSTI and CDC recommendations patients with one kind of sexually transmitted disease (STI) diagnosed should be tested for the others. It is especially true in the case of gonorrhea and Chlamydia trachomatis infection. In IUSTI and CDC recommendations treatment for Chlamydia trachomatis is indicated in patients with gonorrhea. PMID- 26591661 TI - [Analysis of laboratory tests results for Salmonella infections performed since 2008 to 2014 in Poland]. AB - INTRODUCTION: Next to official surveillance system in Poland, established by Public Statistic Act in 1995, other surveillance data collection system exists - historically connected with Ministry of Health Decree, which is not in force from 1995 y. Data in this system comes from National Sanitary Inspection laboratories and contains results of clinical samples examinations for Salmonella and Shigella presence. MATERIAL AND METHODS: Analysed data were collected since 2007 to 2014 y. Database has been created, which contains data - results of Salmonella / Shigella (SS) detection in faecal samples, rectal swabs, urine samples, blood samples collected from patients, people exposed in outbreaks, Salmonella carriers, food workers and other people. RESULTS: The number of performed tests for SS in 2014 is 447033. Systematic decrease of this number has been observed since 2008. Most common material tested for SS was stool samples, then rectal swabs. Number of Salmonella identification going down each year during analysed time. The highest decrease in group of sick people has been observed. Most common serotype in 2008-2014 years was S. Enteritidis, then S. Typhimurium. Only in 2010 y. second most common serotype was S. Mbandaka. In 2014 y. highest number of S. enterica 1,4,[5],12:i:- has been observed (37 cases). CONCLUSIONS: The reason of decreased number of performed SS test and positive Salmonella results is unclear. One of theories is decreased level of quality of SS diagnostic. From the other hand, decreased number of false-positive Salmonella identification outside of National Sanitary Inspection laboratories is observed. This demonstrates improving quality of Salmo nella diagnostic in laboratories performing such tests. High disproportion between number of Salmonella cases in described database and official notification system is observed. It comes from, that both systems collect different data. Both systems could exist independently and could supplement each-other. PMID- 26591662 TI - [Inosine pranobex - cytotoxic activities and effect of on replication of human parainfluenza viruses (HPIV-2, HPIV-4), entroviruses (CA16, EV71) and adenoviruses (HAdV-2, HAdV-5) in vitro]. AB - INTRODUCTION: There are no specific antivirals designed for many viral infections. Inosine pranobex (PI) is a purine nucleoside that is involved in a wide variety of intracellular biochemical processes. The mechanism of action in human body is still unclear but numerous studies have demonstrated that this drug inhibits viral replication and exhibit pleiotropic effect. We evaluated in vitro effect of inosine pranobex (PI) on replication of human viruses: parainfluenza viruses (HPIV-2, HPIV-4), entroviruses A (CA16, EV71) and adenoviruses C (HAdV-2, HAdV-5). MATERIALS AND METHODS: In the present study, cytotoxic effect of inosine pranobex was assessed using A549 cell line exposed to different concentrations of compound (PI: 50-800 ig/mL) for 48 hours. Cytotoxic effect of inosine pranobex was assessed visually using light, inverted microscopy Olympus CK2 under 400x magnification and by the MTT colorimetric assay. Antiviral effect was estimated according to the reduction of virus titer. The yield reduction assay (YRA), which evaluates the ability of the PI (50-800 ug/mL) to inhibit virus multiplication in cell cultures, was applied. The cytopathic effect of the virus was evaluated 48 h after infection ofA549 cell cultures with viruses by means of light, inverted microscopy. The Reed-Muench statistical method was used to determine the 50% end point (IC50) (yield reduction assay, YRA) in the presence of inosine pranobex with the controlled one. RESULTS: There were no morphological changes, as assessed visually, in cell cultures treated with PI. MTT cytotoxicity assay confirmed microscopic observations. The viability of cells in the presence of the tested compounds was average 98, 36 %. After conducting the experiments and analyzing the results we noticed that higher concentrations of PI strongly inhibited multiplication of all viruses. PI weakly reduced the titer of infectious enteroviruses and HPIV-4 as compared with the control. Adenoviruses showed the highest sensitivity to the antiviral activity of PI, however, increasing concentrations of PI up to 800 ug /ml slightly enhanced the antiviral activity of 400 ug/ml PI. CONCLUSIONS: Our study demonstrated that inosine pranobex shows no cytotoxic activity on the A549 cell line. In conducted study was observed that adenoviruses (HAdV-2 and HAdV-5) and HPIV-2 have the highest sensitivity to the antiviral activity of inosine pranobex from all tested viral strains. PMID- 26591663 TI - [Development of TaqMan-based real-time PCR assay for detection of Epstein-Barr virus DNA]. AB - INTRODUCTION: Epstein-Barr virus (EBV) is a human herpesvirus which infects almost all of the world's population subclinically during childhood and thereafter remains for a life. Immunocompromised persons often show active EBV infection, which may progress to virus-associated lymphoproliferative disorders. Many clinical researches show a strong role for viral load measurement in predicting and monitoring EBV-associated diseases, especially in immunosuppressed patients. The aim of this work was to design and to optimize novel real-time PCR assay for detection and quantification of Epstein-Barr virus DNA. MATERIALS AND METHODS: In described experiment TaqMan chemistry-based primers and probes were designed to specific EBV sequence of BALF5 viral gene. To test laboratory utility of the designed method, 80 sera samples, positive for EBV DNA in routine investigations, were also analyzed and 1st International WHO WBV Standard was applied for recalculation of the results to international units. RESULTS: Developed real-time PCR assay gave positive result only in the samples containing genetic material of EBV. Mean viral load of the 80 clinical samples tested was 2,838 and 3,241 log10 copies/ml for analyzed and reference method, respectively. Correction with EBV Standard led to equalization of these results (3,229 and 3,244 log10 international units/ml respectively). CONCLUSIONS: The obtained data indicate that this TaqMan-based qPCR assay is accurate, rapid and reliable method for the diagnosis and monitoring of EBV DNAemia in clinical samples, coming from immunosuppressed individuals. PMID- 26591664 TI - [Novel multiplex real-time PCR assay for detection and differentiation of herpes simplex virus type 1 and 2 DNA]. AB - INTRODUCTION: Herpes simplex viruses type 1 and 2 are the cause of world spread multiple infections with different course and severity. The aim of this work was to design and to optimize multiplex real-time PCR assay for simultaneous detection of HSV-1 and HSV-2. The second aim of the project was to check if the designed method is laboratory useful analyzing different clinical specimens. MATERIALS AND METHODS: In this experiment primers and probes were designed to specific viral sequences: for HSV-1 to the gene of viral DNA polymerase; for HSV 2 to the UL5 sequence. For performing qPCR assay TaqMan chemistry was used. Reference strains HSV-I McIntyre and HSV-2 MS were used as a positive control. To test laboratory utility of the designed method 58 different clinical specimens were analyzed. RESULTS: Developed multiplex real-time PCR gave positive result only in the samples containing genetic material of HSV-1/2. Of the 58 clinical samples tested, 27 proved to be positive for HSV-1 and 17 for HSV-2. The 7 samples showed the presence of both types of DNA herpes simplex virus, and 7 others were found for both HSV-1 and HSV-2 negative. CONCLUSIONS: Obtained results show that the designed method is highly specific and can possibly be used to simultaneously detect and differentiate HHV-1/2. Both high specificity and very short time of analysis have great importance in diagnosing immunocompromised patients, which ought to be diagnosed quickly and effectively in order to provide appropriate treatment. PMID- 26591665 TI - [Insects as model organisms to study the pathogenesis of fungal infections and evaluation of potential antimycotics]. AB - Systemic fungal infections are becoming an increasingly important problem. Exploring the development of mechanisms of pathogenesis, immune response of the human organism and the search for new potential antifungal agents requires in vivo testing. Mice, rats and rabbits are indispensable model organisms for this type of study. Unfortunately, such a kinds of studies carried out on a large scale are associated with high costs as well as with logistical and ethical problems. This paper reports proposal for the use of insects as model organisms to study the development of systemic fungal infections and analysis of biological activities of antifungal agents. PMID- 26591666 TI - [Selection of disposable personal protective equipment for work with samples containing highly pathogenic microorganisms]. AB - Emerging microbiological threats, such as SARS, Ebola, MERS-CoV, anthrax, cause necessity of considering how effectively protect laboratory workers against dangerous pathogens which might be present in clinical samples. The article presents requirements for personal protective equipment (PPE) in microbiological laboratories and examples of selection and application of disposable PPE. PMID- 26591667 TI - "Condoms make you lose both the child and pleasure": perceptions on contraceptives use in Malawi. AB - A qualitative study comprising 91 focus group discussions (FGDs) of adult married men and women and 21 key informant interviews (Klls) was conducted in Malawi in 2008. The purpose of the study was to explore the knowledge, perceptions and practices towards contraceptives and family planning. Data were analyzed using content analysis. The perceived effectiveness, physical health gains and socio economic benefits of contraceptives and/or family planning were well recognized by the study participants. Covert use of contraceptives by women was despised by both men and women and considered a punishable offence. Women reported men as less likely to provide support for contraceptive use. A woman's own relatives were reported to be more likely to support contraceptive use, while her in-laws and friends identified as not as supportive. Concerns regarding adverse health effects of hormonal contraceptive use included vaginal bleeding and delayed return to fertility. Unwanted social or personal consequences were that vaginal bleeding or spotting as a consequence of hormonal contraceptive use limited women's availability to their male partners for sex, that a woman who was using contraceptives was not fulfilling her childbearing responsibilities and that contraceptive use promoted extramarital sex as there was no more fear of pregnancy. Having a wide range of contraceptives in health facilities or community sources, a supportive healthcare and supportive social network could improve contraceptive uptake. PMID- 26591668 TI - Causes for antiretroviral regimen change among HIV/AIDS patients in Addis Ababa, Ethiopia. AB - Highly active antiretroviral therapy has markedly decreased the morbidity and mortality due to HIV/AIDS. Once antiretroviral therapy (ART) is initiated, patients generally remain on medications indefinitely. A switch in the antiretroviral regimen is often necessary because of both acute and chronic toxicities, concomitant clinical conditions, and development of virologic failure. The objective of this study was to assess the causes of initial highly active antiretroviral therapeutic regimen changes among patients on ART in Addis Ababa, Ethiopia. This was a retrospective cross-sectional study conducted from January 1 to March 1, 2010 in two primary hospitals and one health centre in central Ethiopia. Information cards of HIV/AIDS patients who have had their antiretroviral regimen switched were reviewed. Data from patients below 18 years old and those who did not switch HAART regimen were excluded. Data were then analyzed using SPSS for windows version 16.0. A total of 300 patients' information card was reviewed and the mean age of the patients was 38.6+/-7 years. Females accounted for 59% (177) of the total patients. The most common first regimen before first switch was D4T/3TC/NVP (63%) and D4T/3TC/EFV (18%). The main reasons for modification were toxicity (65%), co-morbidity (25%), pregnancy (5%) and treatment failure (3%). The main types of toxicities observed were peripheral neuropathy (39%), rash (20%) and anaemia (13.33%). Drug toxicity was the main reason for modification of initial antiretroviral regimen and initial Efavirenz-based regimens are less likely to be changed. The occurrence of drug toxicity should be assessed early among patients commencing HAART and health professionals should be empowered to make appropriate regimen changes. PMID- 26591669 TI - Knowledge, attitude and practices on family planning services among adolescents in secondary schools in Hai District, northern Tanzania. AB - Almost 65% of the Tanzanian population is under the age of 24 and almost 20 % of the population is aged 15-24 years. Yet, this important group faces many significant health challenges, such as early sexual debut, early pregnancies, risky behaviours and sexually transmitted infections. The objective of this study was to assess knowledge, attitudes and practices on family planning services among adolescents in secondary schools in Hai District in northern Tanzania. A cross sectional study was conducted between April and June 2011 among 316 randomly selected students in 10 secondary schools using a self administered pre tested questionnaire. Median age of participants was 17 years (15-19 years). Two thirds (67.4%) of the respondents had adequate level of knowledge on family planning services (FPS) and the most popular source of information was the radio (65.8 %). Being in a lower class (chi2 =8.6; P<0.02) and attending co education schools (chi2 =12.9; P< 0.001) were predictors of inadequate level of knowledge on FPS. Most, 71.2% (225/316) respondents reported that FPS should not be used by adolescents and mentioned several reasons against its use. Less than 6 % (18/316) of all respondents had used FPS in their lifetime, with 44.4 % (8/18) in the past month, 33.3 %(6/18) in the past year, and 22.3 % (4/18) in the past 5 years. In conclusion, most secondary school students in Hai District do not utilize family planning services despite of adequate level of knowledge on FPS. Interventions to improve utilization of FPS among secondary school students should address barriers to low utilization of FPS mentioned in this study. PMID- 26591670 TI - Reducing microscopy-based malaria misdiagnosis in a low-resource area of Tanzania. AB - Misdiagnosis of malaria is a major problem in Africa leading not only to incorrect individual level treatment, but potentially the acceleration of the spread of drug resistance in low-transmission areas. In this paper we report on the outcomes of a simple intervention that utilized a social entrepreneurship approach (SEA) to reduce misdiagnosis associated with hospital-based microscopy of malaria in a low-transmission area of rural Tanzania. A pre-post assessment was conducted on patients presenting to the hospital outpatient department with malaria and non-malaria like symptoms in January 2009 (pre-intervention) and June 2009 (post-intervention). All participants were asked a health seeking behavior questionnaire and blood samples were taken for local and quality control microscopy. Multivariate logistic regression was conducted to determine magnitude of misdiagnosis with local microscopy pre- versus- post intervention. Local microscopy pre-intervention specificity was 29.5% (95% CI = 21.6% - 38.4%) whereas the post intervention specificity was 68.6% (95% CI = 60.2% - 76.2%). Both pre and post intervention sensitivity were difficult to determine due to an unexpected low number of true positive cases. The proportion of participants misdiagnosed pre-intervention was 70.2% (95%CI = 61.3%-78.0%) as compared to 30.6% (95%CI = 23.2%-38.8%) post-intervention. This resulted in a 39.6% reduction in misdiagnosis of malaria at the local hospital. The magnitude of misdiagnosis for the pre-intervention participants was 5.3 (95%CI = 3.1-9.3) that of the post intervention participants. In conclusion, this study provides evidence that a simple intervention can meaningfully reduce the magnitude of microscopy-based misdiagnosis of malaria for those individuals seeking treatment for uncomplicated malaria. We anticipate that this intervention will facilitate a valuable and sustainable change in malaria diagnosis at the local hospital. PMID- 26591671 TI - The changing profile of cutaneous leishmaniasis agent in a central province of Iran. AB - Cutaneous leishmaniasis in Iran is usually caused by Leishmania major or L. tropica. However, the direct examination or the cultures of biopsies for diagnosis are not very sensitive. The objective of this study was to identify the responsible species obtained from patients suspected of cutaneous leishmaniasis referred to the reference laboratory atYazd in Iran during 2010-2011 using parasitological and molecular assays. After completing a clinical/epidemiologic data questionnaire for 145 patients with suspected skin lesions, scraping samples were collected. Each specimen was examined using both direct microscopy and molecular assay using polymerase chain reaction-restriction length polymorphism (PCR-RFLP). Location of the lesions included 47.7% on hands, 30.7% on face, 15.4% on feet, and the remainder on other regions. Out of 145 samples, Leishman body was observed in 52 by direct smear and 73 by PCR assay. Molecular assay indicated 36 cases as L. major, 36 cases as L. tropica and one case as unknown. In conclusion, molecular-characterization showed changing profile of Leishmania species in the study area which may have implications on treatment and/or control strategies. PMID- 26591672 TI - Human and animal Campylobacteriosis in Tanzania: A review. AB - The thermotolerant species of Campylobacter have become very important in public health, particularly as agents of infectious diarrhoea in human beings. Though the mechanism by which they cause disease is yet to be fully explained, they have been recognized as the leading cause of bacterial enteritis in both developed and developing countries. The organisms colonize different animal species without causing any symptoms of disease; and humans acquire infections through contact with or consumption of contaminated meat especially raw/undercooked poultry meat. The growing trend of antibiotic resistant Campylobacter isolates continues to pose significant public health challenges. In this review we present the available information generated in Tanzania about Campylobacter infections in humans and animals. We conducted a structured literature search of PUBMED and ScienceDirect electronic databases and identified 15 articles. Studies on humans reported Campylobacter infections in both symptomatic and asymptomatic subjects; with higher prevalence in children under the age of five years. Studies on animals found colonization of both domestic and wild species. Among isolates, some demonstrated antimicrobial resistance. The available information for both human and animal Campylobacteriosis in the country is sparse. It however provides an insight of the bacteriological and epidemiological aspects of Campylobacter infections in the country and eventually creates more awareness on the need to develop control strategies. Since the organism is zoonotic its control strategies should adopt the "One Health" approach involving collaborative efforts from veterinary and human medicine. PMID- 26591673 TI - Self-inflicted serious injuries among adolescents in Zambia. AB - Injuries are a growing cause of morbidity and mortality in the world. Data from Southern Africa are limited, possibly because of limited research prioritization of the issue and pre-occupation with communicable diseases. This study was conducted to estimate the prevalence of, and assess factors associated with, self inflicted serious injuries among in-school adolescents in Zambia. We used data collected from the 2004 Zambia Global School-Based Health Survey to estimate prevalence of self-inflicted serious injury within the past 12 months. Logistic regression analysis was conducted to assess the association between selected predictor variables and reported history of having seriously injured oneself. Out of 2,136 adolescents who participated in the Zambia 2004 Global School-based Student Health Survey, 927 (43.4%) reported seriously injuring themselves. Of these who reported injuries, 110 (11.9%) reported seriously injuring themselves on purpose. The following variables were associated with history of self inflicted injury: worry; sadness; suicidal behaviour; history of ever having been drunk and marijuana use. Reported history of injury and self-inflicted injury among in-school adolescents in Zambia are common. History of self-inflicted injury was associated with other lifestyle and psychological concerns among the study participants. PMID- 26591674 TI - Effect of vertical oscillatory pressure on disability of patients with chronic mechanical low back pain using Roland Morris Disability questionnaire. AB - Prevalence of low back pain (LBP) among Africans is rising. Many adults in any given year experience low back pain at one time or the other, this should be of concern. It is then imperative to research into how to reduce the disability caused by LBP. The objective of this study was to assess the effect of Vertical Oscillatory Pressure (VOP) on the pain and disability of patients with mechanical low back pain. A total of 84 patients (34 males and 50 females) diagnosed with mechanical low back pain were purposely selected to participate in the study after obtaining their consent. The pain intensity of all the patients was assessed individually using Present Pain Intensity (PPI) on the first day of their appointment in addition to other examinations. Roland-Morris Disability Questionnaire (RMDQ) was also administered to all patients individually on the first day of report to the clinic. This is pre test record. VOP was then administered to each patient twice in a week for 6 weeks making 12 treatment sessions. Pain intensity and disability were assessed regularly every week of appointment for the 6-week period using PPI and RMDQ (post-test) by another physiotherapist in order to avoid bias. The difference between the first week score of RMDQ and the 6th week score was calculated and the percentage of improvement was determined. Dependent t-test was used to compare the pre and post test values and an alpha level of 0.05 was set as level of significance. An independent t-test was used to analyse the difference between male and female values. Result revealed that the maximum complaint of patients using RMDQ showed a significant disability for males but not for females, and the rate of improvement of male was higher than that of females. There were significant differences (P<.00 1) between the pre-test and post test measurements of PPI and RMDQ, respectively. The rate of improvement in males was significantly higher than that of females. The study concluded that VOP can be useful in ameliorating pain and disability of patients with low back pain. PMID- 26591675 TI - Safe injections and waste management among healthcare workers at a regional hospital in northern Tanzania. AB - Unsafe injections and substandard waste management are public health issues exposing healthcare workers and the community to the risk of infections. The objective of this study was to assess the knowledge and practice of safe injections and health care waste management among healthcare workers at a regional hospital in northern Tanzania. This cross sectional descriptive study was conducted in a regional hospital in northern Tanzania. Data was collected through a self-administered questionnaire with additional observations of the incinerator, injections, waste practices, and the availability of medical supplies. Data was analysed in SPSS descriptive statistics and chi-square tests were performed. A total of 223 of 305 (73%) healthcare workers from different cadres were included in the study. The majority of healthcare workers had adequate knowledge and practice of safe injections, but inadequate knowledge about waste management. The majority of the staff reported knowledge of HIV as a risk factor, however, had less knowledge about other blood-borne infections. Guidelines and posters on post exposure prophylaxes and waste management -were present at the hospital, however, the incinerator had no fence or temperature gauge. In conclusion, healthcare workers reported good knowledge and practice of injections, and high knowledge of HIV transmission routes. However, the hospital is in need of a well functioning incinerator and healthcare workers require sufficient medical supplies. There was a need for continual training about health care waste management and avoidance of blood-borne pathogens that may be transmitted through unsafe injections or poor health care waste management. PMID- 26591676 TI - Large neurofibroma of the labia majora: A case report. AB - Neurofibromatosis is an autosomal dominant progressive disorder with an incidence of approximately 1 in 3000 live births. Its recognized features include hyper pigmented skin lesions (cafe-au-lait spots), neurofibromas, iris hamartomas, macrocephaly, central nervous system tumours, defects of the skull and facial bones, and vascular lesions. Involvement of the external genitalia is extremely unusual. This report describes a case of a vulva neurofibroma in a 15-years old teenage girl with no history of trauma or features of Von Recklinghausen's disease. Treatment involved total excision of the tumour under spinal anaesthesia. The diagnosis of neurofibroma was confirmed by histological examination which showed spindle shaped cells with wavy nuclei arranged in a loose myxomatous stroma. No further treatment was offered but the patient was counselled on the possibility of recurrence. She was seen one month after excision and there were no signs of recurrence. PMID- 26591677 TI - Efficacy and safety of Xinfeng capsule in patients with rheumatoid arthritis: a multi-center parallel-group double-blind randomized controlled trial. AB - OBJECTIVE: To evaluate the efficacy. and safety of Xinfeng capsule in patients suffering rheumatoid arthritis (RA). METHODS: A multi-center parallel-group designed, double-blind, randomized, controlled trial was conducted. Totally 304 RA patients were assigned to two groups: one group was administered Xinfeng capsule (XFC) plus the placebo of leflunomide and the other given leflunomide (LEF) plus the placebo of XFC for twelve weeks. The clinical and laboratory parameters were compared at baseline and fourth, eighth, and twelfth weeks. RESULTS: After twelve-week treatment, patients in two groups all showed some trend of effectiveness when compared in terms of American Rheumatism Association (ACR) recommended 20%, 50%, 70% improvement criteria, but it was insignificant. The validity in ameliorate modified disease activity score (DAS28) and laboratory indexes as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF) were also found no difference. The score of health assessment questionnaire (HAQ), self-rating anxiety scale (SAS), self-rating depression scale (SDS) and quality of life questionnaire with rheumatoid arthritis (RAQOL) both lower than the first week and the changes showed no difference. However, the score of SDS dropped more in XFC group than in the other. A total of 147 adverse reaction cases were reported, which shows no difference between the two groups. The most common adverse reactions were hepatic impairment, anemia, leukocytopenia, epigastric discomfort and phalacrosis. CONCLUSION: XFC demonstrated better improvement in the scores of SDS and compared with those of LEF group. PMID- 26591678 TI - Effect of electroacupuncture on muscle state and infrared thermogram changes in patients with acute lumbar muscle sprain. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) on force-displacement value (FDV) of muscle state and the temperature index of infrared thermogram in patients with acute lumbar muscle sprain. METHODS: Patients with acute lumbar muscle sprain were randomly divided into a medication group and an EA group. The medication group (n = 60) were treated with diclofenac sodium dual release enteric-coated capsules, 75 mg per day for 7 days. The EA group (n = 60) received EA at bilateral Houxi (SI 3), Jiaji (EX-B2), and Ashi points, at 20-30 mm depth and 10-25 Hz frequency for 20 min daily for 7 days. Muscle states were determined by measuring FDVs of the bilateral lumbar muscle with a Myotonometer fast muscle state detector. The temperature index of the lumbar skin was measured before and after treatment with a Fluke Ti30 non-refrigerated focal plane infrared thermal imaging detector. RESULTS: There were no significant pre-treatment differences between the medication group and the EA group in mean FDV (P = 0.052) or temperature index of the lumbar skin (P = 0.25). The cure rate was 63.3% in the EA group and 53.3% in the medication group. The total efficacy in the EA group (93.3 %) was not significantly different from that in the medication group (86.6 %, P = 0.204). After treatment, the mean FDV of the lumbar muscle significantly increased in both groups (P < 0.05 for both groups); the FDV increase in the EA group was significantly higher than in the medication group (P = 0.015). The temperature index was also significantly increased in both groups (P < 0.05 for both groups); the infrared thermogram in the EA group indicated significantly greater recovery compared to the medication group (P = 0.026). CONCLUSION: Both EA and diclofenac sodium markedly improved acute lumbar sprain, but EA better improved the rehabilitation and regeneration of FDVs and temperature index of infrared thermogram of the muscle. PMID- 26591679 TI - Effect of soothing-liver and nourishing-heart acupuncture on early selective serotonin reuptake inhibitor treatment onset for depressive disorder and related indicators of neuroimmunology: a randomized controlled clinical trial. AB - OBJECTIVE: To observe the effect of soothing-liver and nourishing-heart acupuncture on selective serotonin reuptake inhibitor (SSRIs) treatment effect onset in patients with depressive disorder and related indicators of neuroimmunology. METHODS: Overall, 126 patients with depressive disorder were randomly divided into a medicine and acupuncture-medicine group using a random number table. Patients were treated for 6 consecutive weeks. The two groups were evaluated by the Montgomery-Asberg Depression Rating Scale (MADRS) and Side Effects Rating Scale (SERS) to assess the effect of the soothing-liver and nourishing-heart acupuncture method on early onset of SSRI treatment effect. Changes in serum 5-hydroxytryptamine (5-HT) and inflammatory cytokines before and after treatment were recorded and compared between the medicine group and the acupuncture-medicine group. RESULTS: The acupuncture-medicine group had significantly lower MADRS scores at weeks 1, 2, 4, and 6 after treatment compared with the medicine group (P < 0.01). The acupuncture group had significantly lower SERS scores at weeks 1, 2, 4, and 6 after treatment compared with the medicine group (P < 0.01). At 6 weeks after treatment, serum 5-HT in the acupuncture medicine group was significantly higher compared with the medicine group (P < 0.01). Interleukin-6 (IL-6) in the acupuncture-medicine group was significantly lower than that in the medicine group (P < 0.01), whereas there was no significant difference in IL-1beta between the groups (P > 0.05). Anti inflammatory cytokines IL-4 and IL-10 were significantly higher in the acupuncture-medicine group compared with the medicine group (P < 0.01, P < 0.05, respectively). CONCLUSION: The soothing-liver and nourishing-heart acupuncture method can effectively accelerate the onset of SSRI effects when treating depressive disorder and can significantly reduce the adverse reactions of SSRIs. Moreover, acupuncture can enhance serum 5-HT and regulate the balance of pro inflammatory cytokines and anti-inflammatory cytokines. PMID- 26591680 TI - Effect of a Traditional Chinese Medicine combined therapy on adolescent idiopathic scoliosis: a randomized controlled trial. AB - OBJECTIVE: To evaluate the effectiveness of a combined Traditional Chinese Medicine (TCM) therapy versus conventional treatment on adolescent idiopathic scoliosis. METHODS: One hundred twenty outpatients with mild and moderate adolescent idiopathic scoliosis were randomly divided into a TCM group (TCMG) and a brace group (CG). TCMG patients underwent Daoyin, Tuina, and acupotomology therapies. CG patients were treated with a Milwaukee brace. Each patient's Cobb angle was measured after 12 and 24 months of treatment, and pulmonary function was determined after 12 months of treatment. Average electromyogram (AEMG) ratio of the surface electromyogram was measured after 6 and 12 months of treatment and followed-up after 18 and 24 months. RESULTS: The Cobb angle significantly decreased in both groups after 12 months of treatment compared with before treatment (P< 0.05). The percentages of original Cobb angle in TCMG and CG were 51.4% and 47.8% (P > 0.05) after 12 months and 62.5% and 34.7% (P < 0.05) after 24 months, respectively. Pulmonary function significantly improved after 12 months in TCMG (P < 0.05) but significantly decreased in CG (P < 0.05). The AEMG ratio was significantly lower (P < 0.01) and tended to remain at 1 after stopping treatment in TCMG, but increased in CG (P < 0.05). CONCLUSION: TCM combined therapy can prevent the progression of scoliosis. The AEMG ratio is a promising index that could replace radiography in the evaluation of treatment effect and progression in scoliosis. PMID- 26591681 TI - Preventative effect of massage on gastric volvulus in infants with gastroesophageal reflux-induced pneumonia. AB - OBJECTIVE: To study the preventative effects of massage on gastric volvulus (GV) in infants with gastroesophageal reflux (GER)-induced pneumonia. METHODS: One hundred and eighty GV with GER-induced pneumonia inpatients were divided randomly into four groups: basic treatment 1 (n = 60), basic treatment 2 (n = 30), massage treatment 1 (n = 60) and massage treatment 2 (n = 30). Clinical examinations selected between groups 1 and 2 were different. Radiography of the upper gastrointestinal tract using iodine-containing contrast was assessed in group 1 before and after treatment, whereas 24-h pH monitoring of the distal esophagus was assessed in group 2 before and after treatment. Symptom scores and chest radiography were assessed in all groups upon hospital admission and after procedures. Clinical effects were estimated after procedures in all groups. The prevalence of severe pneumonia among the four groups was compared. RESULTS: Massage treatment groups showed a significantly higher percentage of cure and total effect (P < 0.05, P < 0.01) and a lower prevalence of recurrence (but with no statistic difference, P > 0.05) than basic treatment groups. Furthermore, massage treatment groups had remarkably lower scores for symptoms and signs (P < 0.05, P < 0.01), especially for choking on milk, than basic treatment groups. There was significant attenuation of chest inflammation (P < 0.05, P < 0.01), GV (P < 0.05, P < 0.01) and GER (P < 0.05, P < 0.01) in massage treatment groups compared with those in basic treatment groups. Finally, massage treatment groups demonstrated a lower prevalence of severe pneumonia than basic treatment groups (P < 0.05). CONCLUSION: Massage treatment can prevent GV with GER-induced pneumonia in infants by timely correction of stomach rotation and subsequent attenuation of GER. PMID- 26591682 TI - Efficacy of Shenzhuo formula on diabetic kidney disease: a retrospective study. AB - OBJECTIVE: To observe the efficacy of a traditional Chinese medicine, Shenzhuo formula, on patients with diabetic kidney disease (DKD). METHODS: Eighty-eight outpatients with DKD were enrolled. Changes in estimated glomerular filtration rate (eGFR), creatinine clearance, serum creatinine, blood-urea-nitrogen, albuminuria, glycosylated hemoglobin (HbA1C), blood pressure, and lipid profile were measured and analyzed before and after intervention with Shenzhuo formula for 1, 3, 6, 9, 12, and 18 months. RESULTS: Compared with the baseline amounts, serum creatinine decreased, and eGFR and creatinine clearance increased, significantly after intervention for 1, 3, 6, 9, 12, and 18 months (all P < 0.05). Mean eGFR increased by 2.11 mL/min per 1.73 m2/y after 18-month treatment. Urinary protein at 24 h decreased significantly after 1, 3, 9, and 12 months (P < 0.05). HbA1C decreased significantly (P < 0.05) after 3, 6, 9, 12, and 18 months, and systolic blood pressure decreased significantly (P < 0.05) after 1, 3, and 6 months. Total cholesterol decreased significantly (P < 0.05) after 1, 3, 6, and 18 months. Triglyceride and low-density lipoprotein-cholesterol decreased significantly (P < 0.05) after 1 and 3 months. CONCLUSION: Shenzhuo formula can improve eGFR and possibly slow DKD progression. Shenzhuo formula can also lower HbA1C, lipid levels and blood pressure. PMID- 26591683 TI - Characteristics of blood glucose excursions in type 2 diabetes mellitus patients with three different Traditional Chinese Medicine syndromes. AB - OBJECTIVE: To explore the characteristics of blood glucose excursions of type 2 diabetes mellitus patients with three different Traditional Chinese Medicine (TCM) syndromes. METHODS: One hundred and nine patients with type 2 diabetes mellitus were recruited from the Department of Endocrinology and the Department ***of TCM of the Sixth People's Hospital affiliated to Shanghai Jiao Tong University. Subjects were divided into three groups according to TCM syndrome: intrinsic Damp (n = 42), Yin deficiency and internal Heat (n = 25), and Qi and Yin deficiency (n = 42). Subcutaneous interstitial glucose was monitored with a continuous glucose monitoring system for 3 consecutive days to investigate the glycemic profile in each group. Plasma C-peptide levels were measured, and an arginine test was taken in 10 patients randomly selected from each group. Glucose data and glycemic variability were analyzed to investigate the differences among the groups. The change in C-peptide levels and the results from arginine trial were used to evaluate beta cell function. RESULTS: Indicators reflecting blood glucose level were the highest in subjects with Yin deficiency and internal Heat syndrome, and parameters reflecting glycemic variability were the lowest in those with Qi and Yin deficiency syndrome. The change in C-peptide levels showed that subjects with Qi and Yin deficiency syndrome had the best beta cell function among the three groups; this was confirmed by the arginine trial. CONCLUSION: Patients with Qi and Yin deficiency syndrome had a more stable blood glucose profile, as glycemic variability was higher in those with intrinsic Damp syndrome and those with Yin deficiency and internal Heat syndrome. PMID- 26591684 TI - Correlation between Traditional Chinese Medicine symptom patterns and serum concentration of zinc, iron, copper and magnesium in patients with hepatitis B and associated liver cirrhosis. AB - OBJECTIVE: To investigate the correlation between the patterns of Traditional Chinese Medicine (TCM) syndromes and the serum concentration of zinc, iron, copper and magnesium of patients with chronic hepatitis B (CHB) and hepatitis B virus (HBV)-induced liver cirrhosis. METHODS: A total of 86 patients were included in the study between March 1, 2009 and January 1, 2010. All were diagnosed with CHB or HBV-induced liver cirrhosis according to the diagnosis standard of the Chinese Medical Association. Fasting serum concentrations of zinc, iron, copper and magnesium were measured. Patients were classified into different patterns of TCM symptoms according to TCM theory and clinical experience. RESULTS: In the HBV-induced liver cirrhosis group, the mean zinc concentration in patients with the TCM pattern of stagnation of fluid-Dampness was lower than that in patients with obstruction of collaterals by Blood stasis (P < 0.034). In the CHB group, the mean magnesium concentration in patients with toxic Heat flourishing was significantly lower than that in those with Damp-Heat in the Liver and Gallbladder, and those with Liver depression and Spleen deficiency (P < 0.021). The concentrations of iron and copper showed little difference among the different TCM symptom patterns. CONCLUSION: The serum zinc and magnesium concentrations correlated with certain TCM patterns of symptoms in patients with HBV-induced liver cirrhosis and CHB. It may be helpful to interpret the pathogenic change in the TCM symptom patterns in liver cirrhosis and CHB, and also to conduct clinical treatment of the diseases based on identified TCM patterns. PMID- 26591685 TI - Comparative effects of artemisia vulgaris and charcoal moxa stimulating Zhongwan (CV 12) on body temperature in healthy participants: a cross-over single-blind randomized study. AB - OBJECTIVE: To evaluate the efficacy, safety, satisfaction, discomfort and patient preference of moxa cones of artemisia vulgaris and charcoal moxa. METHODS: This comparative study of moxibustion treatment with Artemisia vulgaris and charcoal moxa cone stimulating Zhongwan (CV 12) is a cross-over single-blinded, randomized clinical trial. A total of 40 healthy subjects (24 males and 16 females) participated in this study. Two subjects dropped out of the trial. Thirty-eight subjects were treated with Artemisia vulgaris and charcoal moxa cones for 30 min in a cross-over design. After treatment, the patients underwent a 30 minute waiting period, and then the temperatures at Tanzhong (CV 17), Zhongwan (CV 12) and Guanyuan (CV 4) were measured using digital infrared thermal imaging. RESULTS: After the use of Artemisia vulgaris moxa, the patients' body temperatures were slightly lowered at Tanzhong (CV 17), Zhongwan (CV 12) and Guanyuan (CV 4), but the changes were not statistically significant. After the use of charcoal moxa, the patients' body temperatures were somewhat increased at Zhongwan (CV 12) and Guanyuan (CV 4), but the changes were not statistically significant. After Artemisia vulgaris moxa use, the body temperature difference between Zhongwan (CV 12) and Guanyuan (CV 4) was significantly increased. After charcoal moxa use, the body temperature difference between Tanzhong (CV 17) and Zhongwan (CV 12) was significantly decreased in males and in the whole group. This change was caused by the difference in the moxibustion type and by gender differences. CONCLUSION: This pilot study found that moxibustion did not raise the body temperature, but temperature differences between acupoints were affected. Further large-scale randomized controlled trials are needed for the effect of moxibustion on body temperature. PMID- 26591686 TI - Optimization of parameters of Yi Zhi Chan Tuina manipulation promotes peripheral circulation. AB - OBJECTIVE: To explore the most effective parameters of Yi Zhi Chan Tuina manipulation for improving peripheral blood circulation. METHODS: A total of 45 volunteers were recruited from Pudong district in Shanghai, China, from October to December 2010, and randomly divided into nine groups using computer-generated random numbers. Participants received Yi Zhi Chan Tuina manipulation on Chengjin (BL 56) acupoint; each group received a particular combination of manipulation force and treatment time. We used a two-factor, three-level factorial design to examine the effects of force and treatment time on changes in popliteal artery average volume flow, pulsatility index, and vessel diameter to determine the optimal parameter group. Outcomes were assessed at baseline and after Tuina manipulation by interviewers blind to treatment group status. RESULTS: After manipulation, two of the nine groups showed an increase in popliteal artery volume flow. An inter-participants effect test showed that for main effect of time, F = 0.331, P = 0.720; for main effect of force, F = 2.934, P = 0.066; and for the force-time interaction effect, F = 1.072, P = 0.385, indicating no interaction between force and time. However, a pairwise comparison of the three levels of time showed that a treatment time of 10 min was significantly more effective than that of 2 min (P = 0.024). A pairwise comparison of light force, medium force, and heavy force showed a statistically significant effect for medium force (P = 0.035). CONCLUSION: Yi Zhi Chan Tuina manipulation with vertical force of 9.31 N for 10 min is most effective in improving peripheral circulation. PMID- 26591687 TI - Effect of salvianolic acid A and C compatibility on inflammatory cytokines in rats with unilateral ureteral obstruction. AB - OBJECTIVE: To investigate the effect of salvianolic acid A and C component molecules, which are involved in drug compatibility, on inflammatory cytokine expression that affects human chemokine ligand 5 (CCL5) and chemokine ligand 10 (CXCL10) levels in rats with unilateral ureteral obstruction (UUO). METHODS: Fifty Sprague Dawley rats were randomly divided into five groups: normal, model, salvianolic acid A, salvianolic acid C and salvianolic acid A and C groups. The normal group was used as the control, and the other groups of rats had a UUO model established. The control group had free access to food and water, and the other groups received the corresponding drugs for 2 weeks. After the last administration, urine beta2-microglobulin (beta 2-MG) and N-acetyl-beta-D glucosaminidase (NAG) levels were analyzed. After 24 h, all rats were sacrificed and the serum was analyzed for creatinine (Cr) and blood urea nitrogen (BUN) levels. Rat kidneys were removed, and CCL5 and CXCL10 inflammatory cytokine mRNA expression was measured using real-time fluorescent quantitative reverse transcription-polymerase chain reaction (RT-PCR). Kidney fibrosis was observed using hematoxylin-eosin (HE) staining and Masson trichrome staining. RESULTS: In the salvianolic acid A and salvianolic acid C treatment groups, serum Cr and urine NAG levels were significantly lower than in the model group (both P < 0.05). In all treatment groups, urine beta2-MG levels were significantly lower than in the model group (all P < 0.05). Compared with model group, the pathological changes and collagen deposition improved to varying degrees (both P < 0.05). CCL5 and CXCL10 mRNA expression decreased to different degrees compared with the model group (both P < 0.05). CONCLUSION: Salvianolic acid A and C are component molecules of drug compatibility, and they may protect renal function and improve tubular function and renal pathology to a certain degree in UUO. This improvement may be related to a reduction in inflammatory cytokines CCL5 and CXCL10 secretion in the UUO rat kidney. PMID- 26591688 TI - Effect of warming Yang and removing blood stasis method on matrix metalloproteinases / tissue inhibitor metalloproteinases levels secreted by cultured endometrial cells from patients with endometriosis. AB - OBJECTIVE: To investigate the effect of Chinese medicines using the warming Yang and removing blood stasis method on levels of matrix metalloproteinases (MMPs)/tissue inhibitor metalloproteinases (TIMPs) secreted by cultured endometrial cells from patients with endometriosis. METHODS: Ectopic and eutopic endometrial cells obtaind from 15 endometriosis patients were cultured in vitro, and divided randomly into five groups: high dose; moderate dose; low dose; nemestran; blank control. The three dose groups were treated with a decoction prepared according to the principle of warming Yang and removing blood stasis; nemestran and 0.9% NaCl were administered to the nemestran group and balnk control group, respectively. Eutopic endometrial cells obtaind from 10 hysteromyoma patients were cultured in vitro, as the normal control group, 0.9% NaCl were administered to the normal control group. Cell culture supernatants were collected and levels of matrix metalloproteinase-1 (MMP-1), matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), tissue inhibitor metalloproteinase-1 (TIMP-1) and tissue inhibitor metalloproteinase-2 (TIMP-2) detected by enzyme-linked immuno sorbent assay (ELISA). RESULTS: Compared with the normal control group, levels of MMP-1, MMP-2, and MMP-9 in eutopic and ectopic endometrium cell supernatants in the blank control group were increased, whereas levels of TIMP-1 and TIMP-2 were decreased (P < 0.05). Compared with the blank control group, levels of MMP-1 and MMP-2 in ectopic and eutopic endometrium cell supernatants cultured in low-dose, middle-dose, and high-dose groups were decreased, whereas levels of TIMP-1 and TIMP-2 were increased significantly (P < 0.05). CONCLUSION: The warming Yang and removing blood stasis method affects expression of MMPs and TIMPs. PMID- 26591689 TI - Effect of electronic stimulation at Neiguan (PC 6) acupoint on gene expression of adenosine triphosphate-sensitive potassium channel and protein kinases in rats with myocardial ischemia. AB - OBJECTIVE: To investigate the effects of electronic stimulation at acupoints Neiguan (PC 6) and Lieque (LU 7) on the gene expression of the adenosine triphosphate (ATP)-Sensitive potassium channel (KATP: Kir6.1, Kir6.2, SUR2A, and SUR2B) and protein kinases (PKA, PKG, and PKCbeta2) in myocardial cells of rats with myocardial ischemia (MI) induced by isoproterenol (ISO). METHODS: Rats were randomly divided into a control, model, Neiguan (PC 6), Lieque (LU 7), and non acupoint groups. The MI model was established by injecting rats with ISO. Electro acupuncture treatment was given to the acupuncture groups, once a day for 7 days. Gene expression was analyzed with real-time PCR. RESULTS: The gene expression of KATP and protein kinases in the model group was higher than those in the control group (P < 0.05). After acupuncture treatment, the KATP and protein kinase expression levels were significantly lower in the Neiguan (PC 6) and Lieque (LU 7) groups compared with the mod- el group (P < 0.05). The Neiguan (PC 6) group lowered these levels significantly more than that of the Lieque (LU 7) group (P < 0.05). No significant differences were observed between the model and non acupoint groups (P> 0.05). CONCLUSION: Our findings suggest that electronic needling of Neiguan (PC 6) can both reduce the gene expression of KATP and protein kinases in rats with ISO-induced MI. PMID- 26591690 TI - Role of transient receptor potential vanilloid subetype 1 in the increase of thermal pain threshold by moxibustion. AB - OBTECTIVE: To explore the role of transient receptor potential vanilloid subetype 1 (TRPV1) in the increase of the thermal pain threshold by moxibustion. METHODS: Forty Kunming mice (20 +/- 2) g were randomized into control group, capsaicin group, capsazepine group, moxibustion group and moxibustion + capsazepine (MC) group with 8 mice in each, and 16 C57BL/6 wild-type mice (18 +/- 2) g were randomized into wild-type (WT) control group and WT moxibustion group with 8 mice in each, and 14 TRPV1 knockout mice (18 +/- 2) g were randomized into knockout (KO) control group and KO moxibustion-group with 7 in each. Each mouse in the capsaicin group was subcutaneously injected with the amount of 0.1 mL/10 g into L5 and L6 spinal cords; each mouse in the capsazepine group was intraperitoneally injected with the amount of 0.1 mL/10 g. Similarly, each mouse in the moxibustion group was given a suspended moxibustion with specially-made moxa-stick for 20 min on L5 and L6 spinal cords. Each mouse in MC group was intraperitoneally injected with the amount of 0.1 mL/1 0 g first, then after 15 min was given a suspended moxibustion for 20 min on L5 and L6 spinal cords. Each mouse in WT moxibustion group and KO moxibustion group was given a suspended moxibustion with specially made moxa-stick for 20 min on L5 and L6 spinal cords. The control group, WT control group and KO control group were of no treatment in any way. After all treatments were completed, the digital-display measurement instrument for thermal pain was used to measure the threshold of thermal pain in each group respectively. RESULTS: Compared with the control group, the thresholds of thermal pain in the moxibustion group and MC group were significantly increased (P <0.01); no significant changes in the thresholds in the capsaicin group and the capsazepine group (P > 0.05); compared with moxibustion group, he threshold of thermal in MC group was obviously decreased (P < 0.01). Compared with WT control group, the threshold of thermal pain in WT moxibustion group was significantly increased (P < 0.01); compared with KO control group, no changes in the threshold in KO moxibustion group (P > 0.05). CONCLUSION: TRPV1 participated in the process of increasing the threshold of thermal pain by stimulating L5 and L6 of mice spinal cord with burning mosa-stick. PMID- 26591691 TI - Pharmacokinetic interaction of Acacia catechu with CYP1A substrate theophylline in rabbits. AB - OBJECTIVE: To investigate the effect of black catechu (BC) on the pharmacokinetics of theophylline (CYP1A2 substrate, with narrow therapeutic index) in rabbits. METHODS: In the present investigation the effect of BC on the pharmacokinetics of theophylline, a CYP1A2 substrate was determined. In the study, BC (264 mg/kg, p. o.) or saline (control group) was given to rabbits for 7 consecutive days and on the 8th day theophylline (16 mg/kg) was administered orally one hour after BC or saline treatment. Blood samples were withdrawn at different time intervals (0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 and 36 h) from the marginal ear vein. RESULTS: The pretreatment of rabbits with BC resulted in a significant increase in maximum blood concentration, time of peak concentration and area under the concentration time profile curve until last observation which was about 41.32%, 35.71% and 15.03%, respectively. While decreases in clearance, volume of distribution, and half-life were observed. It is suggested that BC pretreatment decreases the CYP1A metabolic activity leading to increase in bioavailability and decrease in oral clearance of theophylline, which may be due to inhibition of CYP1A. CONCLUSION: BC can significantly alter theophylline pharmacokinetics in vivo possibly due to inhibition of CYP1A and P-glycoprotein activity. Based on these results, precaution should be exercised when administering BC with CYP1A substrate. PMID- 26591692 TI - Oxalate contents of commonly used Chinese medicinal herbs. AB - OBJECTIVE: To assess the total and soluble oxalate contents of commonly used Chinese medicinal herbs. METHODS: Twenty-two Chinese medicinal herbs were extracted in both acid and water prior to determination of total and soluble oxalate, respectively. Oxalate was assayed in herbal extracts using a well established enzymatic procedure. RESULTS: Among the 22 medicinal herbs, there was significant variation in oxalate content; Houttuynia cordata contained the highest amount of soluble oxalate (2146 mg/100 g) and Selaginella doederleinii contained the lowest amount (71 mg/ 100 g). CONCLUSION: The results indicated that different Chinese medicinal herbs, even from the same family, contain significantly different amounts of oxalate. In susceptible individuals, the use of medicinal herbs with the highest oxalate contents could increase risk of kidney stone formation. PMID- 26591693 TI - Health related quality of life: is it another comprehensive evaluation indicator of Chinese medicine on acquired immune deficiency syndrome treatment? AB - Health related quality of life (HRQOL) can better reflect changes in acquired immune deficiency syndrome (AIDS) patients and inform economic evaluation of AIDS treatment services, and the assessment of HRQOL can help us to detect problems that may influence the progression of the disease, hence HRQOL has become a particularly important assessment indictor for HIV comprehensive interventions. Being a multi-angle, multi-level, and diversified complex intervention, roles of Chinese medicine (CM) in AIDS treatment have been recognized and accepted by more and more patients, and HRQOL has been widely used to evaluate the comprehensive management effects of CM on AIDS. In this article, the authors analyze the definition and measurement of HRQOL, measurement of HRQOL of HIV/AIDS patients and effects of CM on AIDS, and give some reasonable advices for the usage of the scale of HRQOL. The authors hold that some new HRQOL instruments specific for CM treatment of AIDS should be developed and further prospective studies should be carried out to demonstrate the practicality, reliability and validity of HRQOL as an evaluation indictor for CM treatment of AIDS. PMID- 26591694 TI - Applications of pain-related evoked potentials and short-latency somatosensory evoked potentials in acupuncture research: a narrative review. AB - OBJECTIVE: To review and discuss the Chinese and English literature on the use of pain-related evoked potentials (PREP) and short-latency somatosensory EP (SLSEP) in acupuncture research. METHODS: China National Knowledge Infrastructure Database and MEDLINE were searched for the following key words: acupuncture and PREP or SLSEP. RESULTS: Thirty-seven articles were included in the review. Researchers usually use PREPs to study the analgesic effect of acupuncture, observe influential factors, or for mechanistic exploration. In the SLSEP studies, researchers focused on response characteristics of acupuncture, acupoint specificity, and influential factors of the treatment. There were some problems with the study design and conclusions. CONCLUSION: Researchers could use PREP and SLSEP to objectively validate the effects of acupuncture and explore its mechanisms using nerve electrophysiology. Further studies can benefit from observing more acupoints' effects using PREPs or SLSEPs and investigating the placebo effect of acupuncture. PMID- 26591695 TI - Motorcycle accidents: morbidity and associated factors in a city of northeast of Brazil. AB - Motorcycle accidents are becoming a public health problem in developing world. The objective of this paper was to assess the factors related to morbidity and mortality among victims of motorcycle accidents in a trauma center. An analysis of 9,734 medical records of patients hospitalized for external causes at the Regional Emergency and Trauma Hospital of Campina Grande, Paraiba, Brazil, from January to December 2009 was done. The cases of accidents with motorcycles accounted for 20.8% of all hospital care, mostly affecting men (85.8%) aged 21-29 years old (33.9%). Legs and feet (55.2%) and arms and hands (26.9%) were the most affected parts of the body. There was significant association between the occurrence of motorcycle accident and injuries on the face (p = 0.001), the chest (p < 0.001), arms and hands (p = 0.004) and legs and feet (p < 0.001). Multiple lesions were present in 40.4% of the cases; and the majority (80.6%) involved fractures. Amputation and functional impairment were observed in 15.3% and 4.3% of the victims, respectively. Vascular lesions in the lower limbs had a 3.5 times higher chance of occurrence among injured motorcyclists. Fatal accidents accounted for 1.3% of the injured victims. In conclusion, motorcycle accidents affect men, predominantly, most of them being young, causing fractures and multiple lesions, mainly in the lower limbs. There is need for greater incentive to actions concerning traffic safety education focusing on motorcyclists, as well as greater control by competent authorities as regards to the use of motorcycles in the country. PMID- 26591696 TI - Predictors of outcome among patients with obstructive jaundice at Bugando Medical Centre in north-western Tanzania. AB - Despite recent advances both in preoperative diagnosis and postoperative care, obstructive jaundice still contributes significantly to high morbidity and mortality. A prospective study was undertaken to identify predictors of outcome among patients with obstructive jaundice at Bugando Medical Centre in north western Tanzania. A total of 138 patients were studied. The male to female ratio was 1:1.6. The median age of patients was 58 years. Patients with malignant obstructive jaundice were older than those of benign type (P < 0.001). Ca head of pancreas (65.1%) was the commonest malignant cause of jaundice where as choledocholithiasis (51.9%) was the commonest benign cause. Twelve (9.7%) patients were HIV positive with a median CD 4+ count of 342 cells/MUl. A total of 130 (94.2%) patients underwent surgical treatment and the remaining 8 (5.8%) patients were unfit for surgery. The complication rate was 30.4% mainly due to surgical site infections and it was significantly influenced by malignant causes, WBC count > 10 X 109/l and HIV infection with low CD4 (200 cells/MUl) (p < 0.0001). The median hospital stay and mortality rate were 18 days and 20.3%, respectively. A low haematocrit and presence of postoperative complications were the main predictors of the hospital stay (P < 0.001), whereas age > 60 years, prolonged duration of jaundice, malignant causes, high bilirubin levels, HIV infection with low CD4+ count (200 cells/ MUl) and presence of postoperative complications significantly predicted mortality (P < 0.001). In conclusion, our study highlighted the important factors that predict the outcome of patients presenting with obstructive jaundice at BMC; therefore attention should be focused to these factors so as to improve the outcome of these patients. PMID- 26591697 TI - Triple assessment as a preoperative diagnostic tool for breast cancer at Bugando Medical Centre in northwestern Tanzania. AB - The triple assessment in the pre-operative evaluation of breast cancer has been practiced in some hospitals in Tanzania. However, its validity and reliability has not been evaluated in any hospital in the country including the study area. This cross-sectional study was conducted at Bugando Medical Centre in northwestern Tanzania to determine the validity, reliability and applicability of triple assessment as an alternative to conventional open biopsy in the pre operative diagnosis of breast cancer. A total of 212 female patients aged 35 years and above were studied. All patients underwent clinical evaluation, mammography and fine needle aspiration cytology. Histopathology was done to confirm the diagnosis. One hundred and twenty (56.6%) patients with a median age of 36 years had benign lesions and the remaining ninety-two (43.4%) with a median age of 47 years had breast cancer (P = 0.002). With triple assessment, 92 patients were diagnostic for malignancy and 120 benign, respectively confirmed by histopathology. The Sensitivity, Specificity, Positive Predictive Value, Negative Predictive Value and Accuracy were 100.0%. There were no false positive or false negative results. The Kappa statistic for the combination was 1.0 implying excellent agreement with histopathology. The majority of patients (59.9%) underwent triple assessment on the same day with results being available to the patient within 24 to 72 hours. The triple assessment is an accurate and quick method for the evaluation of breast cancer and can be applied as a safe alternative for open biopsy when it is concordant. PMID- 26591698 TI - Abdominal trauma experience over a two-year period at a tertiary hospital in north-western Tanzania: a prospective review of 396 cases. AB - Abdominal trauma continues to be a major cause of trauma admissions all over the world and contributes significantly to high morbidity and mortality. A descriptive prospective study was conducted at Bugando Medical Centre in north western Tanzania to describe our experience on the management of abdominal trauma outlining the causes, injury characteristics and treatment outcome of these patients. Statistical data analysis was done using SPSS programme. A total of 396 patients were studied. Male to female ratio was 3.2: 1. The median age was 28 years. More than three quarter of patients sustained blunt abdominal injuries. Road traffic accidents (RTAs) were the most common cause of injury accounting for 64.9% of cases. None of our patients received any pre-hospital care. The spleen was the most common injured organ in blunt abdominal trauma occurring in 176 (75.9%) patients, while in penetrating injury; gastrointestinal tract was the most common in 24 (10.3%) patients. One hundred twenty-four (31.3%) patients had associated extra-abdominal injuries of which the head/neck region (46.8%) was commonly affected. A total of 232 (58.6%) patients were treated surgically with a negative laparotomy rate of 7.8%. Complication and mortality rates were 20.7% and 17.9% respectively. The age of patients, presence of associated extra-abdominal injuries, severity of injury (Kampala Trauma Score II <= 6), admission Systolic Blood Pressure < 90mnHg, injury-arrival time > 24 hours and presence of postoperative complications mainly surgical site infections significantly predicted mortality (p < 0.001). The overall median length of hospital stay was 12 days. Patients who had severe trauma (KTS II <= 6) and those with associated injuries stayed longer in the hospital (p < 0.001). Abdominal trauma resulting from RTAs is still rampant in our environment and remains a major source of morbidity and mortality. Preventive strategies should be focused on reduction of road traffic accidents, violent crimes and social conflicts. PMID- 26591699 TI - Inequalities in health care and behaviour in patients with diabetes and concurrent hypertension in Lahore, Pakistan. AB - The global healthcare delivery system is largely inequitable and patients suffer inequalities in relation to their socioeconomic status (SES). In this study, we applied univariate measures to predict the SES in a sample of patients. We investigated the relationship between patient's SES, adherence to drug, dietary intake and health behaviour. We also investigated if inequalities exist in physician's choice on multisource oral solid hypoglycaemic and antihypertensive drugs in a sample of male type II diabetes mellitus patients with concurrent hypertension. Questionnaires were administered on patients (N = 500) with diabetes mellitus and concurrent hypertension to determine their SES, prescribed drugs, dietary regime and health behaviour in Lahore, Pakistan. Correlation was determined using chi-square test for category characteristics, Kruskall-Wallis or ANOVA for continuous data variables non-normal or normally distributed data, respectively. The patient's SES was indicated by univariate like income, occupation, and education. Patients with high SES were more adherent to drug, dietary intake and health behaviour (Chi2 = 13.16, p < 0.001; 34.71, p < 0.0001; 79.24, p < 0.0001, respectively). Patients with lower SES were prescribed cheaper hypoglycaemic and antihypertensive alternatives than their richer counterparts (p < 0.0001). Socioeconomic differentials exist within urban communities; these differentials have direct effects on healthcare delivery and patient health. PMID- 26591700 TI - Influence of gender on prevalence of overweight and obesity in Nigerian schoolchildren and adolescents. AB - Overweight and obesity are serious health concerns for children. However, only a few studies have investigated the influence of gender on prevalence of overweight and obesity in children and adolescents in Nigeria. The objective of this study was to investigate gender influence on prevalence of overweight and obesity among Nigerian school children and adolescents. Information on age and gender of the participants was collected from the school register. Data on height, weight and BMI was collected using standard techniques. A total of 9,014 children and adolescents (male = 4392; female = 4622), aged 2-18 years, from 28 randomly selected schools were analyzed. Overweight and obesity were determined using the International Obesity Task Force cut-off points by age and gender. Males had higher BMI than females at age group 2-6 years, whereas females had higher BMI than males at age groups 11-14 years and 15-18 years. Females had significantly higher prevalence of overweight (P < 0.05) than males at age group 11-14 and 15 18 years. However, there was no gender difference in the prevalence of obesity from childhood through adolescence. In conclusion, BMI is larger in males in early childhood but larger in females in during adolescence. More female adolescents are at risk of obesity than males. PMID- 26591701 TI - Plague in Tanzania: an overview. AB - Human plague remains a public health concern in Tanzania despite its quiescence in most foci for years, considering the recurrence nature of the disease. Despite the long-standing history of this problem, there have not been recent reviews of the current knowledge on plague in Tanzania. This work aimed at providing a current overview of plague in Tanzania in terms of its introduction, potential reservoirs, possible causes of plague persistence and repeated outbreaks in the country. Plague is believed to have been introduced to Tanzania from the Middle East through Uganda with the first authentication in 1886. Xenopsylla brasiliensis, X. cheopis, Dinopsyllus lypusus, and Pulex irritans are among potential vectors while Lophuromys spp, Praomys delectorum, Graphiurus murinus, Lemniscomys striatus, Mastomys natalensis, and Rattus rattus may be the potential reservoirs. Plague persistence and repeated outbreaks in Tanzania are likely to be attributable to a complexity of factors including cultural, socio-economical, environmental and biological. Minimizing or preventing people's proximity to rodents is probably the most effective means of preventing plague outbreaks in humans in the future. In conclusion, much has been done on plague diagnosis in Tanzania. However, in order to achieve new insights into the features of plague epidemiology in the country, and to reorganize an effective control strategy, we recommend broader studies that will include the ecology of the pathogen, vectors and potential hosts, identifying the reservoirs, dynamics of infection and landscape ecology. PMID- 26591702 TI - Bizarre presentation of bilateral ovarian leiomyoma: a case report. AB - Primary leiomyoma of the ovary is rarely described in literature. It accounts for 0.5-1% of all benign ovarian tumours. Bilateral ovarian leiomyoma are rare and only few cases have been described. In this report, we describe a case of 29-year old nulliparous, Tanzanian lady presented with one-year history of abdominal swelling and secondary amenorrhea. Examination revealed a palpable, suprapubic mass, and a pelvic ultrasound showed features of ovarian tumour. An explorative laparotomy was performed to confirm the diagnosis. A bilateral salpingo oophrectomy and hysterectomy was performed for huge bilateral ovarian tumours. Histopathological examination confirmed ovarian leiomyoma. Challenges remain in the management of bilateral primary ovarian tumours, especially for young and nulliparous women. Pre-laparotomy diagnostic measures are important so as to know the type of the tumour you are dealing with and plan the appropriate management. PMID- 26591703 TI - Evidence of Yersinia pestis DNA in rodents in plague outbreak foci in Mbulu and Karatu Districts, northern Tanzania. AB - Human plague remains a public health concern in Tanzania despite its quiescence in most foci for years, considering the recurrence nature of the disease. Appreciable researches have involved serological screening of rodents, fleas and humans but none has involved molecular detection and hence proving the presence of Yersinia pestis in rodents in the most recent affected foci, Mbulu and Karatu districts in northern Tanzania. The objective of the current study was to employ a simple PCR to detect Yersinia pestis plasminogen activator (pla) gene in various potential mammalian hosts/reservoirs. The study was conducted in five villages in Mbulu and one in Karatu districts during the period of no disease outbreak. Rodents and small wild carnivores were captured, anaesthetized, identified, sexed and autopsied. Liver, spleen, heart and lung specimens were collected and DNA extracted after which PCR was used to detect the Y. pestis pla gene. A total of 517 small mammals were captured; of which, 493 (95.4%) were from Mbulu and 24 (4.6%) from Karatu. Two Mastomys natalensis (one from each district) and one Gerbilliscus sp. in Mbulu district were positive for Y. pestis pla gene. In conclusion, our results have provided a proof on the presence of Y. pestis in the two rodent species (Mastomys natalensis and Gerbilliscus sp.) and thus providing indicative evidence that the two are potential reservoirs of the pathogen and hence may be responsible for maintaining the same during periods of no disease outbreaks. PMID- 26591704 TI - Comparison of sampling techniques for Rift Valley Fever virus potential vectors, Aedes aegypti and Culex pipiens complex, in Ngorongoro District in northern Tanzania. AB - We investigated mosquito sampling techniques with two types of traps and attractants at different time for trapping potential vectors for Rift Valley Fever virus. The study was conducted in six villages in Ngorongoro district in Tanzania from September to October 2012. A total of 1814 mosquitoes were collected, of which 738 were collected by CDC light traps and 1076 by Mosquito Magnet trapping technique. Of the collected mosquitoes, 12.46% (N = 226) were Aedes aegypti and 87.54% (N = 1588) were Culex pipiens complex. More mosquitoes were collected outdoors using Mosquito Magnets baited with octenol attractant, 36.38% (N =660) followed by indoor trapping using CDC light traps without attractant, 29.60% (N = 537). Most of Ae. aegypti mosquitoes were collected outdoor using Mosquito Magnets, 95% (N = 214) whereas Cx. pipiens complex were trapped both indoor using CDC light traps without attractant and outdoors using both CDC light traps baited with carbon dioxide (CO2) sachets and Mosquito Magnets. Analysis on the differences in abundance of mosquitoes trapped by different techniques using Generalized Linear Models was statistically significance at p-value < 0.05 for both species. Three hours mosquito collections show differing patterns in activity, most Ae. aegypti species were collected primarily during the first and last quarters of the day. Cx pipiens complex was active throughout the night, early evening and early morning then decreased markedly during the day time. The results presented in this paper emphasize the possibility of using Mosquito Magnets in order to efficiently capture these potential RVF vectors. PMID- 26591705 TI - Factors associated with flea infestation among the different rodent species in Mbulu and Karatu districts, northern Tanzania. AB - Flea infection with the bacterium, Yersinia pestis is acquired from reservoirs which include several rodents and other small mammals. In areas that are endemic of plague, reservoirs of Y. pestis and various flea vectors are responsible for perpetuating existence of the disease. The objective of this cross sectional study was to investigate the magnitude and factors associated with flea infestation among different rodent species of northern Tanzania, where outbreaks of plague have been recently reported. House rodents were trapped with box traps, while field and forest rodents were trapped with Sherman live traps. Fleas were removed from the rodents by using shoe-shining brush and were identified to genus level. Among the captured rodents, Rattus rattus (26.5%), Lophuromys flavopunctatus (16.5%), Praomys delectorum (16.2%) and Mastomys natalensis (32.3%) were most abundant rodent species, accounting for 91% of all species. Altogether, 805 fleas belonging to nine species were collected from 61% of the captured rodents. The most common fleas were Xenopsylla spp.; Dinopsyllus spp and Ctenophthalmus spp. Fleas were found to be highly abundant in M. natalensis, R. rattus, P. delectorum and L .flavopunctatus. Most of rodents were heavily infested with various flea species. These flea species probably play an important role in the transmission of plague in these two districts. We conclude that rodent species was the most important risk factor associating with flea infestation among the rodent population. Therefore, measures for control and prevention of plague in this area should particularly target rodents associated with high intensity of flea infestation. PMID- 26591706 TI - High prevalence of tuberculosis diagnosed during autopsy examination at Muhimbili National Hospital in Dar es Salaam, Tanzania. AB - The primary aims of tuberculosis (TB) control programmes is early diagnosis and prompt treatment of infectious cases to limit transmission. Failure to diagnose and adequately treat TB could lead to premature death and unrecognized transmission of Mycobacterium tuberculosis. The proportion of missed TB cases has not been reported in Tanzania. The objective of this study was to quantify the number of cases of TB identified by autopsy. Deceased morbid bodies from Muhimbili National Hospital were involved. Retrieval of admission, diagnostic and other important records used to manage the patient after admission was done. Demographic information, site and type of disease, past medical history, chest x ray report, clinical diagnosis and cause of death reported upon death certification were recorded. Lung tissues, lymphnodes and blood clots for HIV testing were collected. Biopsy tissues were processed through Ziehl Nielsen staining and examined by microscopy. The study involved 74 deceased individuals where 56 (75.7%) were males. Information for duration of seeking health care before death was available for 41 (55.4%) subjects. Thirty-four (45.9%) cases received diagnosis before death. The main diagnoses were pneumonia 10 (13.5%), heart failure 6 (8.1%), AIDS-related illnesses 6 (6.8%) and malaria 5 (6.8%). The main clinical findings were wasting (51/74 (68.9%)) and abnormal fluid collection in different body cavities, 61 (50.8%). In 24 out of 71 (33.8%) biopsies acid fast bacilli (AFB) were detected. Records of lymphnodes examination were available in 63 cases and 22 of them had AFB. Twenty-two (34.9%) from the paratracheal and hilar lymphnodes were observed to have AFB. HIV was detected by ELISA in 19 (33.3%) out of 57 deceased, and 12 (63.2%) of the HIV positive deceased were co-infected with TB. Out of the 22 cases positive for AFB on tissue biopsies 12 (54.5%) were HIV positive. There is a high number of TB cases diagnosed after death that could not be detected before they died. There is a need for increased awareness and to include post-mortem data in the annual statistics of TB for precise reporting of the magnitude of the TB burden in the country. PMID- 26591707 TI - Feeding practices and nutritional status of infants in Morogoro Municipality, Tanzania. AB - Breast feeding practice especially exclusive breast feeding (EBF) is a major determinant of child growth and development. In Tanzania, most women breastfeed their infants for long periods, but many introduce alternative feeding too early in life. The objective of this study was to determine factors affecting EBF and the relationship between feeding practices and the nutritional status of infants. This cross-sectional survey, using a semi-structured questionnaire, was conducted in Morogoro Municipality in Tanzania. The study involved lactating women recruited from five randomly selected health facilities. Demographic, clinical, knowledge and practices related to infant feeding as well as infant anthropometric information were collected. Infant nutritional status was assessed based on weight-for-age, height-for-age and weight- for- height. There were wide variations in knowledge and practice of breastfeeding among women. Majority (92%) of the respondents gave colostrums to infants although more than 50% did not know its benefits. Eight percent of the respondents discarded colostrums on the account that it is not good for their neonates. Only 23.1% of the respondents thought that infants should be breastfed exclusively during the first six months of infancy. Ninety-eight percent of infants < 1 month of age received breast milk only, compared with 28.5% of infants aged 2-3 months and 22.3% among those who were above 3 months of age. No child in the >= 4 months old was exclusively breastfed. Over 80% of the infants had normal weights, 13% were stunted and 8% wasted. EBF was associated with higher scores for height- for- age Z (P < 0.05) and weight- for- height Z (P < 0.01). Age, education level and occupation of respondents were important predictors of EBF. Overall, breast feeding practices in the study population were largely suboptimal. As a result, considerable proportions of children had poor health indicators. Thus, correct breastfeeding practices should be supported and promoted to improve the well-being of children. PMID- 26591708 TI - Factors contributing to delay in commencement of immunisation in Nigerian infants. AB - Delay in receipt of immunisation may result in a child being susceptible to vaccine preventable diseases for prolonged periods. Identification of factors which contribute to delay in receipt of immunisation will help in developing targeted interventions. This study examined prospectively factors contributing to delay in the commencement of infant immunisation in Benin City, Nigeria. This was a cross-sectional descriptive study of 153 consecutive mothers of infants presenting for their first immunisation at the Institute of Child Health Child Welfare Clinic of the University of Benin, Benin City. Reasons for not presenting in the first 24 hours were ascertained and associations between various factors and delay in commencement of immunisation were examined. Of the 153 mothers only 2 (1.3%) brought their babies for immunisation within 24 hours of birth while 66 (43.1%) brought their babies in the first week of life. The most cited reason (30.3%) for not presenting within 24 hours of birth was that BCG, one of the immunisations that should be given at birth is given only on a specific day. Mothers who did not know that immunisation should commence at birth (P = 0.0054), those from low socioeconomic class (P = 0.0056) and those with less than 12 years of schooling (P = 0.0001) were significantly less likely to bring their babies for immunisation in the first week of life. Delivery outside of health facilities was also associated with later presentation for immunisation (P = 0.0069). In conclusion, there is significant delay in the receipt of birth doses of immunisation. Change in clinic practices to enable daily immunisation as well as education of health care personnel on the importance of timely commencement of immunisation will ensure timeliness of receipt of birth doses of vaccines. PMID- 26591709 TI - Fistulectomy versus fistulotomy with marsupialisation in the treatment of low fistula-in- ano: a prospective randomized controlled trial. AB - Low fistula-in-ano has traditionally been treated with fistulectomy and fistulotomy. Recent studies have shown that marsupialisation of the fistulotomy wounds can reduce the healing time. A randomized clinical trial was conducted at Bugando Medical Centre in north-western Tanzania between January 2008 and December 2012 to compare the efficacy of fistulectomy versus fistulotomy with marsupialisation in the treatment of low fistula in ano. Patients were randomized into two groups, namely Group A (fistulectomy) and Group B (fistulotomy with marsupialisation). A total of 162 patients were enrolled in the study and randomly assigned to Group A (n = 82) and Group B (n = 80). Both groups were comparable with respect to age, sex ratio, duration of symptoms, type of fistula and radial distance of the external opening from the anal verge. The mean healing time was statistically significantly longer in group A than in group B (P = 0.002). The duration of postoperative wound discharge was statistically significantly shorter in group B than in group A (P = 0.012). There was no statistically significant difference in the mean operating time, mean operation wound size, mean postoperative pain score, rate of surgical site infection and postoperative hospital stay between the two groups (P > 0.05). None of the patients in either group had recurrence or was found to have anal incontinence. No differences in the extent of adverse effects of surgery on the physical, social and sexual lives of the patients in the two groups. We conclude that in comparison to a fistulectomy, a fistulotomy with marsupialisation results in faster wound healing and a shorter duration of wound discharge and should therefore be recommended as a standard surgical procedure in the treatment of low fistula-in-ano. PMID- 26591710 TI - The male circumcision: the oldest ancient procedure, its past, present and future roles. AB - Circumcision, a surgical removal of male prepuce has existed throughout human history, and it appears it shall exist until humanity ends. During its entire existence, there have been changing reasons or indications from cultural, traditional, religious and currently medical, and it has vehemently been criticized by some individuals for different reasons and in different countries. Emergency of new diseases particularly Human Immunodeficient virus (HIV) has brought the ancient procedure back on spot light, this has come as a result of recent studies which have demonstrated that it does not only reduces significantly the rate of HIV infection, as well as penile cancer and cervical cancer. This has lead to massive male circumcision campaigns in areas with low prevalence of circumcision. On the other hand the socio-cultural and sexual aspects of male circumcision have been studied but often ignored. This article will therefore increase awareness of male circumcision and the increasing roles with time, recommend up scaling of medical male circumcision and possible safe circumcision training to tradition circumcisers. PMID- 26591711 TI - Massive upper gastrointestinal bleeding and diffuse benign gastric inflammatory hyperplastic polyps in a 19 year old patient: a case report. AB - Benign gastric inflammatory hyperplasic polyps are benign lesions that rarely occur in young age. We report a case of diffuse benign gastric inflammatory hyperplastic polyps in a 19 year old male patient who presented with cough, nausea, and haematemesis. In the presented case symptoms such as nausea and vomiting are non specific and may complicate in reaching a prompt diagnosis. We also highlight the importance of gastrointestinal tract (GIT) endoscopy in the diagnosis of GIT diseases. PMID- 26591712 TI - Factors associated with, and echocardiographic findings of heart failure among HIV infected patients at a tertiary health care facility in Dar es Salaam, Tanzania. AB - Cardiovascular diseases, including heart failure are a known complication of Human Immunodeficiency Virus (HIV) infection globally. The objective of this study was to describe factors associated with, and echocardiographic findings of heart failure among HIV infected patients at a tertiary health care facility in Dar es Salaam, Tanzania. Clinical, laboratory and echocardiographic assessment was performed in all HIV-infected patients presenting with cardiac complaints at the medical department, Muhimbili National Hospital between September 2009 and April 2010. HF was diagnosed clinically and confirmed by echocardiography. Of the 102 HIV-infected patients with cardiac complaints 50 (49%) were in HF. Commonest causes of HF were hypertensive heart disease, pulmonary hypertension and dilated cardiomyopathy. In multivariate analysis male gender (OR 4.03), low education (OR 4.91), previous history of tuberculosis (OR 3.01), and low haemoglobin (OR 0.83), were independently associated with the diagnosis of HF (p<0.05 for all). In conclusion, heart failure is common in HIV-infected patients with cardiac complaints, and is associated with both modifiable and non-modifiable factors. PMID- 26591713 TI - Relationship between alpha+-thalassaemia and glutathione-S-transferases polymorphisms in children with severe malaria in Tanzania. AB - Alpha+-thalassaemia is well known for conferring partial protection to severe malaria. On the other, Glutathione-S-transferase (GST) polymorphism has recently been associated to severe malaria in children. A retrospective cross sectional study was carried out to determine the relationship between genotypic polymorphisms of alpha+-thalassaemia and glutathione-S-transferase in children with severe malaria. A total of 148 DNA samples from children aged between 3 and 15 years with mild and severe malaria were retrieved and determined by polymerase chain reaction. Children with Glutathione-S-transferase-pil (GSTP1)-polymorphism were observed to have three fold risk (OR = 2.9; 95% CI =1.3- 6.1; P = 0.006) of developing severe malaria compared to mild malaria in Mnyuzi in Korogwe District, north-eastern, Tanzania. In the presence of Glutathione-S-transferase-pil polymorphism, children were found to have 3% decreased protective effect of alpha+-thalassaemia polymorphisms (homozygotes and heterozygotes) against severe malaria although this was not statistically significant [OR = 0.81 (95% CI = 0.5 1.5; P = 0.5) to OR =0.78(95% CI = 0.4-1.5; P = 0.44)]. We conclude that Glutathione-S-transferase-pil polymorphism increases risk of developing severe malaria due to Plasmodium falciparum in children. The observed inverse relationship between GSTP1 polymorphisms and alpha-thalassaemia to children with severe malaria need further investigation. PMID- 26591714 TI - The prevalence of Chlamydia trachomatis infection among infertile males and its association with abnormal semen characteristics in Delta State, Nigeria. AB - Chlamydia trachomatis is the most common cause of sexually transmitted diseases that is not of viral origin and there is accumulating evidence of a significant role played by this pathogen in causing male factor infertility. This study thus aimed to determine the prevalence of C. trachomatis among infertile males and to evaluate their association with fertility status and abnormal semen characteristics. This study included 215 infertile male subjects who visited a major fertility clinic in Warri, Delta state, Nigeria. Forty apparently healthy males without complaints of infertility were enrolled as controls. Blood samples were collected from patients aseptically using venous puncture and semen samples were obtained after masturbation. C. trachomatis IgG antibodies were assayed for in blood specimens using the Dot rapid Assay Kit flow through Ct cassette and positive samples were further screened with an enzyme immunoassay technique. Semen samples were analyzed following World Health Organization guidelines. Forty two (19.5%) out of 215 infertile male subjects were found sero-positive for C. trachomatis. C. trachomatis was significantly associated with male infertility when compared to controls (P<0.001). Age groups 20-29 years (43.3%) and 30-39 years (22.1%) significantly had higher prevalence of C. trachomatis (P<0.001), as compared to age groups 40-49 (7.9%) and > 50 years (3.7%). Sero-positivity for C. trachomatis antibodies was significantly associated with oligozoospermia (22.5%) and azospermia (61.5%) than with teratozoospermia (7.3%) and asthenozoospermia (6.3%) (P<0.001). The prevalence of C. trachomatis among infertile males was high; there was an association between C. trachomatis infection and poor semen characteristics and infertility. There is need for routine screening for the pathogen in males with complaints of infertility so as to rule out this potentially correctable/reversible cause of infertility. PMID- 26591715 TI - Morpho-physiological features associated with menopause: recent knowledge and areas for future work. AB - Menopause is the permanent cessation of menstruation resulting from loss of ovarian follicular activity which happens as a result of depletion of primary follicles which is basically an aging effect. Depletion of ovarian follicles is reflected as declined production of oestradiol which is currently known to be central to the morphologic and physiological changes that happen during the climacteric, menopause and post menopause periods. The cessation of oestradiol production is much more pronounced in tissues with oestrogen receptors such as bones, brain, blood vessels, central nervous system and the skin. But generally little is known on the subject and in particular the bioactive substances involved in the process such that there are some symptoms that menopause women experience which not only defy clinicians but also challenge the management of the condition. This article is presented to shade light to what is currently known, what is not known and stimulate future research which may reveal more understanding and advance our knowledge on management of women throughout the climacteric and menopausal periods. PMID- 26591716 TI - Epilepsy and tropical parasitic infections in Sub-Saharan Africa: A review. AB - Several reports have suggested that the high prevalence of epilepsy in sub Saharan Africa is associated with the high prevalence of parasitic infections affecting the central nervous system. Though epidemiological evidence suggests an association between parasitic infections and epilepsy, the biological causal relationship has not been fully demonstrated for many of these infections. The objective of this paper is to review the available epidemiological evidence on the links between parasitic infections and epilepsy, the pathogenesis and the current gap of knowledge indicating the areas requiring further research. Data for this review were identified and collected using manual and electronic search strategies of published and unpublished sources. In Sub-Saharan Africa, the epidemiology of epilepsy remains unclear and given the differing study designs, the results of available epidemiological studies are difficult to interpret and compare. Evidence from surveys reported a median prevalence of 1.5%. Co-infection of parasitic infections and epilepsy in sub-Saharan Africa are common, particularly in areas characterized by poor hygiene standards. There is an epidemiological link on the association between epilepsy and various parasitic infections. However, the biological causal relationship requires further investigation in adequately designed studies. In conclusion, although several epidemiological and case control studies indicate a relationship between parasitic agents and epilepsy in sub-Saharan Africa, there is a considerable gap of knowledge on the cause and magnitude of the association. Thus, there is an urgent need for systematic epidemiological studies to understand the burden of epilepsy in areas endemic due to preventable parasitic infections, to prove a causal relationship, and to understand the impact of controlling these parasitic diseases on reduction of the burden of epilepsy. PMID- 26591717 TI - Comprehensive health workforce planning: re-consideration of the primary health care approach as a tool for addressing the human resource for health crisis in low and middle income countries. AB - Although the Human Resources for Health (HRH) crisis is apparently not new in the public health agenda of many countries, not many low and middle income countries are using Primary Health Care (PHC) as a tool for planning and addressing the crisis in a comprehensive manner. The aim of this paper is to appraise the inadequacies of the existing planning approaches in addressing the growing HRH crisis in resource limited settings. A descriptive literature review of selected case studies in middle and low income countries reinforced with the evidence from Tanzania was used. Consultations with experts in the field were also made. In this review, we propose a conceptual framework that describes planning may only be effective if it is structured to embrace the fundamental principles of PHC. We place the core principles of PHC at the centre of HRH planning as we acknowledge its major perspective that the effectiveness of any public health policy depends on the degree to which it envisages to address public health problems multi dimensionally and comprehensively. The proponents of PHC approach in planning have identified inter-sectoral action and collaboration and comprehensive approach as the two basic principles that policies and plans should accentuate in order to make them effective in realizing their pre-determined goals. Two conclusions are made: Firstly, comprehensive health workforce planning is not widely known and thus not frequently used in HRH planning or analysis of health workforce issues; Secondly, comprehensiveness in HRH planning is important but not sufficient in ensuring that all the ingredients of HRH crisis are eliminated. In order to be effective and sustainable, the approach need to evoke three basic values namely effectiveness, efficiency and equity. PMID- 26591718 TI - Impact of training traditional birth attendants on maternal mortality and morbidity in Sub-Saharan Africa. AB - This paper presents discussion on impact of training traditional birth attendants (TBAs) on overall improvement of reproductive health care with focus on reducing the high rate of maternal and new-born mortality in rural settings in sub-Saharan Africa. The importance of TBAs for years has been denied by professional western trained health practitioners and other scientists until during the late 1980s, when World Health Organization through Safe motherhood 1987 found TBAs have a significant role in reducing maternal and new-born mortality. Trained TBAs in sub Sahara Africa can have positive impact on reducing maternal and new-born mortality if the programme is well implemented with systematic follow-up after training. This could be done through joint meeting between health workers and TBAs as feed and learning experience from problem encountered in process of providing child delivery services. TBAs can help to break socio-cultural barriers on intervention on reproductive health programmes. However projects targeting TBAs should not be of hit and run; but gradually familiarize with the target group, build trust, transparency, and tolerance, willing to learn and creating rappour with them. In this paper, some case studies are described on how trained TBAs can be fully utilized in reducing maternal and new-born mortality rate in rural areas. What is needed is to identify TBAs, map their distribution and train them on basic primary healthcare related to child deliveries and complications which need to be referred to conventional health facilities immediately. PMID- 26591719 TI - Integrating reproductive and child health and HIV services in Tanzania: Implication to policy, systems and services. AB - In Tanzania, reproductive health and HIV services are coordinated by the Ministry of Health and Social Welfare in two separate units namely Reproductive and Child Health Section and the National AIDS Control Programme. The importance of integrating the two services that are vertically run is expected to improve access to and uptake of key essential services and extend coverage to underserved and vulnerable populations and thus minimizing missed opportunities. Experts around the world recognize the central role of Sexual and Reproductive Health (SRH) services in preventing HIV infection. Evidence suggests that improving access to contraception for women to prevent pregnancy is an important and cost effective way to prevent HIV-positive births. Integrating SRH and HlV services therefore verifies its importance for improving maternal and child health as well as leading to prevention of HIV infection. The primary objective of this review was to gain an understanding of the current linkages between SRH and HIV within Tanzania's policies, programmes, systems and services. Policy documents, guidelines, national laws, and published reports on SRH and HIV were reviewed. The majority of the reviewed documents mentioned fundamentals of integration between SRH and HIV. Majority of policies and guidelines both in family planning (FP) and HIV documents mandate bi-directional linkages. This review suggests that there are linkages between the two services and can be operationalised together. However, policies and guidelines only specify services to be integrated without due consideration of resources and structural orientation for linked services. PMID- 26591720 TI - How rational are indications for emergency caesarean section in a tertiary hospital in Tanzania? AB - The rate of caesarean section (CS) at Muhimbili National Hospital (MNH) in Tanzania has been on progressive increase for past three decades. Concerns have been raised if this increase is justified by rational decisions but no study so far has investigated this problem. The aim of the study was to find out whether decisions made for CS comply with a set of locally made standards, with an assumption that if the standards are met, then the increase in CS rate seen at MNH is genuine. The five most common indications for CS were identified from the obstetric electronic data base. Most common indications included obstructed labour, cephalopelvic disproportion (CPD), failure to progress, repeat CS and foetal distress. Criteria for the best practice for each indication were developed based on the National guidelines and local expert consensus. Information extracted from the case notes, antenatal cards and partographs were compared to the standard audit criteria and the decision judged as standard or substandard. Three hundred forty five women had a decision made for emergency CS. Repeat CS was the most frequent indication (30.2%), followed by obstructed labour (14.4%) and foetal distress (13.6%). Audit of 324 women's files showed that 30% of women had substandard decisions for CS mostly in the foetal distress group (59.1%) and least in the repeat CS group (9.1%). Among the-324 mothers with decision for emergency CS, 279 (86.1%) delivered by CS as decided and 45 (13.9%) delivered vaginally before CS could be performed. Women who delivered vaginally after decision for CS and the nulliparous women had significantly more substandard decisions compared to those delivered by CS and parous women respectively. In conclusion, a substantial proportion of decisions for emergency CS made in the hospital is substandard and may contain women in whom surgical intervention could be avoided. This calls for a need to improve quality of assessment and decision before performing CS. PMID- 26591721 TI - Anti-tuberculosis drug resistance pattern among pulmonary tuberculosis patients with or without HIV infection in Mwanza, Tanzania. AB - Anti-tuberculosis drug resistance is a major problem in tuberculosis (TB) control, particularly multi-drug resistance TB (MDR-TB). The objective of this study was to determine the prevalence of primary and acquired anti-TB drug resistance among newly diagnosed pulmonary TB (PTB) and relapse cases. Sputa were collected from newly diagnosed and relapse PTB patients. Drug susceptibility tests (DST) were performed on sputum culture positive isolates of Mycobacterium tuberculosis using resistance ratio method on four first-line anti-TB drugs: rifampicin, isoniazid, ethambutol and streptomycin. Demographic and anthropometric information was collected and HIV status was determined. Of the 523 culture positive isolates, DST results were available for 503 (96%), 455 were new and 48 were relapse cases. Resistance to at least one of the four drugs was observed in 7.8% (39/503) of the isolates, 7.3% (33/455) were new and 12.5% (6/48) were from relapse cases. Mono resistance to isoniazid was higher in both among new 45.5% (15/33) and relapse 50.0% (3/6) cases. Resistance to rifampicin and streptomycin alone was equal 4/33 (12.1%) and only among new cases. Resistance to ethambutol alone was only one among new cases. Overall MDR-TB prevalence was 2.4% (12/503), nine were new and three were relapse cases. MDR-TB was 17.9% (7/39) for rifampicin and isoniazid. Prevalence of HIV was 43.3% and was similar among new and relapse cases and not risk factor for drug resistance. Majority of PTB patients (52%) had BMI below 18 kg/m2. Those with BMI greater than 18 kg/m2 were more likely to develop drug resistance than those with BMI below 18 kg/m2 (P=0.004). With the resurgence of TB and the high prevalence of HIV among TB patients, prevalence of drug resistance is still low both among new and relapses cases. Despite the current low drug resistance, there is a need for continuous monitoring of the resistance. PMID- 26591722 TI - Lost to follow up and clinical outcomes of HIV adult patients on antiretroviral therapy in care and treatment centres in Tanga City, north-eastern Tanzania. AB - Scaling up of Antiretroviral (ARV) drugs is crucial and should be a perpetual venture in developing countries in-order to increase the survival period of HIV/AIDS individuals. In Tanzania, information on the rate of patients considered as lost to follow up during treatment with ARVs is scarce. The objective of this study was to determine the rate of lost to follow up and treatment outcome among patients attending two care and treatment clinics (CTCs) in Tanga City in north eastern Tanzania. A descriptive observational study was carried out on cohorts from Tanga AIDS Working Group and Bombo Regional Hospital. The total number of patients identified as "lost to follow up" were 89 of which 14 (15.7%) died. Among those who died, 3 (21.4%) died between the second week and 3 months after ARV initiation. Of those still alive (84.3%; 75/89), 25% (19/75) were still on ARVs, whereas 47 (62.7%) self transferred to other CTCs. Proper patient documentation with actual residence address is a crucial aspect for adherence. Similarly, frequent prompt tracing of patient should be part of any drug interventional programme linking facility and communities. PMID- 26591723 TI - Audit of clinical-laboratory practices in haematology and blood transfusion at Muhimbili National Hospital in Tanzania. AB - In Tanzania, there is paucity of data for monitoring laboratory medicine including haematology. This therefore calls for audits of practices in haematology and blood transfusion in order to provide appraise practice and devise strategies that would result in improved quality of health care services. This descriptive cross-sectional study which audited laboratory practice in haematology and blood transfusion at Muhimbili National Hospital (MNH) aimed at assessing the pre-analytical stage of laboratory investigations including laboratory request forms and handling specimen processing in the haematology laboratory and assessing the chain from donor selection, blood component processing to administration of blood during transfusion. A national standard checklist was used to audit the laboratory request forms (LRF), phlebotomists' practices on handling and assessing the from donor selection to administration 6f blood during transfusion. Both interview and observations were used. A total of 195 LRF were audited and 100% of had incomplete information such as patients' identification numbers, time sample ordered, reason for request, summary of clinical assessment and differential diagnoses. The labelling of specimens was poorly done by phlebotomists/clinicians in 82% of the specimens. Also 65% (132/202) of the blood samples delivered in the haematology laboratory did not contain the recommended volume of blood. There was no laboratory request form specific for ordering blood and there were no guidelines for indication of blood transfusion in the wards/ clinics. The blood transfusion laboratory section was not participating in external quality assessment and the hospital transfusion committee was not in operation. It is recommended that a referral hospital like MNH should have a transfusion committee to provide an active forum to facilitate communication between those involved with transfusion, monitor, coordinate and audit blood transfusion practices as per national guidelines. PMID- 26591724 TI - Sexual dysfunction during primiparous and multiparous women following vaginal delivery. AB - Normal sexual functioning comprises of sexual activity together with transition through the phases from arousal to relaxation with no problem. Delivery has different effects on body organs, especially, on genitalia the disorder of which can cause sexual dysfunctions. In this study, an attempt is made to compare postpartum sexual dysfunction among primiparous and multiparous women. This descriptive cross sectional study was done on 564 primiparous (331) and multiparous (233) women chosen from among those who were present at health and clinical centres in Yazd, Iran. Data were gathered through a questionnaire consisting of demographics and questions related to sexual problems before and after 3-6 months of delivery. Both open-ended and closed items were included in the questionnaire. The questionnaire was developed in consultation with two health educators, a midwife, two gynaecologists and an expert in questionnaire validation. All registered data were analyzed by SPSS-15 software. Dyspareunia was shown to decrease after pregnancy in both primigravidae and multigravidae women (P<0.05). Libido decreased during multigravidae (P<0.05) while the difference was not significant during primigravidaes (P>0.05). Also, vaginal loosening was significantly increased in multigravid women (P<0.05) while it did not significantly change in primigravidae (P>0.05). The difference was not significant in primigravidae nor in multigravidae according to post coital bleeding, post coital itching, an-orgasmia, oral sex and anal sex. In conclusion, based on the results of this study, delivery has limited effects on sexual function of primiparous and multiparous women. Contradictory results of similar studies show the need for a precise critical appraisal and finding pitfalls of previous studies. Designing more valid surveys with larger sample size to determine the effects of delivery and parity on sexual function is recommended. PMID- 26591725 TI - Stage at diagnosis, clinicopathological and treatment patterns of breast cancer at Bugando Medical Centre in north-western Tanzania. AB - Breast cancer, although reported to be the commonest female malignancy worldwide has not been extensively studied in north-western Tanzania. The aim of this retrospective review was to describe in our setting, the stage at diagnosis, clinicopathological and treatment patterns among patients with breast cancer. Data were analyzed using SPSS software system. A total of 384 patients were studied. The median age was 45 years (range 21 to 78 years). The male to female ratio was 1: 46.8. Most of the patients were premenopausal (63.8%) and presented late with advanced breast cancer disease. Majority of patients (63.0%) presented with stage III disease. Lymph node and distant metastasis at the time of diagnosis was reported in 70.8% and 21.4% of patients, respectively. Invasive ductal carcinoma (91.7%) was the most frequent histopathological type and most patients (63.8%) had poorly differentiated tumour. Patients with tumour size greater than 6cm had significantly high rate of lymph node metastasis (P=0.001) and presence of necrosis within the tumour (P=0.012) compared to patients with tumour size less than 6cm in diameter. Patients younger than 45 years had significantly high rate of lymph node metastasis compared to the patients above this age (P=0.0 11). Mastectomy was the main modality of treatment that was used in 99.5% of the patients. Adjuvant chemotherapy and radiotherapy was reported in 44.8% and 11.7% of patients, respectively. Hormonal therapy (tamoxifen) was given postoperatively to all patients. The overall five-year survival rate was 21.8%. The age of patient at diagnosis, stage of disease, extent of lymph node involvement and histological grade were found to be independent predictors of overall survival rate (P<0.001). Local recurrence was 17.7% and it was significantly related to the stage of disease (P=0.003) and non-adherent to adjuvant therapy (P=0.021). Breast cancer patients in this region are relatively young premenopausal women and mostly present late with advanced stage and high rate of lymph node metastasis. There is need to improve public enlightenment of breast cancer and set up screening centres to encourage early presentations. PMID- 26591726 TI - Cellular responses against Schistosoma mansoni in immunized Balb/c mice with soluble proteins from intermediate host, Biomphalaria pfeifferi. AB - Scores of millions of people around the world are infected by Schistosoma mansoni causing considerable morbidity, mortality and loss of productivity. Safe chemotherapeutic agents have been used though there are challenges of re infection due to resistance. Both epidemiological and experimental data suggest that acquired cell mediated immunity play significant roles in regulating the intensity of S. mansoni infection as well as its patho-physiologic sequelae. Improved control of this trematode parasite may be obtained with immunization to enhance the resistance of individuals to risk of infection. This study investigated the cellular responses of mice immunized with soluble proteins from foot and digestive gland of the vector snail and challenged with S. mansoni. The proteins were used to immunize the experimental groups then challenged with the S. mansoni. The experimental groups were FT (immunized with foot protein) and DG (immunized with digestive gland). The parameters, which were analyzed to demonstrate protection, included; the worm counts and cellular (IFN-gamma, IL-5 cytokines) responses. It was observed that, the experimental groups showed significant protection in terms of worm reduction and immune responses. The group vaccinated with foot protein showed higher protection (87.5%) as compared to the group vaccinated with the digestive gland (50%) in terms of worm reduction. Cytokines (IFN-gamma and IL-5) production was present in different levels during the assay time points which showed an aspect of protection. The Foot protein of the vector showed more immunizing power than the digestive gland. Research towards utilizing the two proteins as feasible vaccine candidates is encouraged. PMID- 26591727 TI - Early Marjolin's ulcer developing in a penile human bite scar of an adult patient presenting at Bugando Medical Centre, Tanzania: A case report. AB - Marjolin's ulcer is a rare but well documented cutaneous malignancy that arises in a scar or chronic ulcer, and is characterized by an aggressive course. The latent period from the injury to the appearance of cancer has been reported to be 25-40 years. Early occurring Marjolin's ulcer has rarely been described in the literature and its development in a penile human bite scar is still rare. We report a rare case of a 33 year-old patient who presented with an early appearance of Marjolin's ulcer developing in a penile human bite scar. On histological examination it was found to be poorly differentiated squamous cell carcinoma. He was managed by total penile amputation. Five months after surgery, the patient presented to our surgical outpatient clinic with inguinal lymph node metastases and distant metastases to the lung, liver and bones. However, the patient died shortly after admission. This report highlights the possibility of early appearance of Marjolin's ulcer arising from a chronic ulcer or healed scar in an unusual sites such as the penis. It is therefore recommended that all chronic ulcers should be thoroughly investigated at presentation, to avoid labelling malignancies 'chronic ulcers', leading to delay in appropriate treatment. Early recognition and aggressive treatment of Marjolin's ulcers and close follow-up are urgently needed to improve outcomes in our environment. PMID- 26591728 TI - Imperforate hymen presenting with massive haematocolpos and acute urinary retention in a teenage girl: A case report. AB - Imperforate hymen is relatively rare but it is the most frequently encountered obstructive anomaly of the female lower genital tract. The clinical presentation vary significantly from patient to patient depending on the age at diagnosis but in most cases the diagnosis is missed in early childhood and therefore the diagnosis is made after puberty when the patient present with haematocolpos, heamatometra.or both. When this happens, the presentation could even be tricky because the patient may presents with unlikely symptoms apart from cryptomenorhoea like, urinary retention or bowel obstruction or both. Here we present a 16 years old girl with imperforate hymen and presented with history of lower abdominal pain and distension associated with acute urinary retention. She was treated by hymenotomy and improved dramatically and was discharge 6th day post operatively. This case report is presented to address to clinicians the possibility of imperforate hymen with haematocolpos as a differential diagnosis in adolescent girls particularly those who have not started having their menses in their teens and present with acute urinary retention so that their external genitalia are carefully examined to exclude the possibility of imperforate hymen as a cause of acute urinary retention due to the haematocolpos. PMID- 26591729 TI - Access to subsidized artemether-lumefantrine from the private sector among febrile children in rural setting in Kilosa, Tanzania. AB - The World Health Organization aims at universal access to effective antimalarial treatment by the year 2015. Consequently, an enormous financial resource has been invested on Artemisinin Combination Therapy (ACT) subsidy. In Tanzania, strategies to increase access of artemether-lumufantrine (ALu) rural areas, where the burden is highest, includes subsidy to the Faith-based Organisations (FBO) facilities and accredited drug dispensing outlets (ADDOs). This study was done to assess the extent to which children suffering from malaria access ALu from the private sector in rural areas. A total of 1,235 under fives randomly selected from 12 rural villages were followed up at home on weekly basis for six months in Kilosa district in 2008. Using a structured questionnaire, caretakers were interviewed about the child's history of fever in the past 7 days; type of treatment given and the source. Baseline data were obtained on demographic characteristics, caretakers' knowledge about malaria and social economic indicators of the household. Of the 1,235 children followed-up, 740 care-seeking visits were recorded, of which, 264 (35.7%) were made at government health facilities and nearly a quarter (24.1%; 178/740) at ordinary shops that sell general merchandize including rice and sugar. Only 22% of the caretakers sought care from FBO and ADDOs. While 686 (86.6%) of the episodes were treated with antimalarials, only 319 (43%) received ALu, the recommended antimalarial. Majority (83%) of the visits made at government facilities were prescribed with ALu compared to less than half who went to FBO facilities (40.0%) and ADDOs (25.0%). In conclusion, this study has shown that less than a quarter of fever episodes suspected to be malaria in rural areas were made at FBO facilities and ADDOs, of which, less than half were treated with ALu. This shows that ALu subsidy to formal private sector does not adequately reach children in rural areas, where the malaria burden is highest. This cast some doubts if the target of universal access to effective antimalarial, by 2015, will be reached. There is need to consider enlisting the services of community health workers in the efforts to improve access to ALu in rural areas. Further research is needed to explore providers' / dispensers' preference for non-recommended antimalarials in the private sector and caretakers' preference for ordinary shops. PMID- 26591730 TI - Scepticism towards insecticide treated mosquito nets for malaria control in rural community in north-western Tanzania. AB - Despite existence of effective tools for malaria control, malaria continues to be one of the leading killer diseases especially among under-five year children and pregnant women in poor rural populations of Sub Saharan Africa. In Tanzania Mainland the disease contributes to 39.4% of the total OPD attendances. In terms of mortality, malaria is known to be responsible for more than one third of deaths among children of age below 5 years and also contributes for up to one fifth of deaths among pregnant women. This paper is based on a study conducted in a rural community along the shores of Lake Victoria in Mwanza region, North Western Tanzania. The study explores reasons for scepticism and low uptake of insecticide treated mosquito nets (ITNs) that were promoted through social marketing strategy for malaria control prior to the introduction of long lasting nets (LLN). The paper breaks from traditional approach that tend to study low uptake of health interventions in terms of structural practical constraints- cost, accessibility, everyday priorities--or in terms of cognition--insufficient knowledge of benefits e.g. ignorance of public health messages. This paper has shown that, the majority of people who could afford the prices of ITNs and who knew where to obtain the insecticides did not necessarily buy them. This suggests that, although people tend to report cost-related factors as a barrier against the use of ITNs, there are other critical concerns at work. Without underestimating the practical factors, our study have recommended to consider critical examinations of those other concerns that hinder optimal utilization of ITN for malaria control, and the basis for those concerns. PMID- 26591731 TI - Influence of enteric bacteria, parasite infections and nutritional status on diarrhoea occurrence among 6-60 months old children admitted at a Regional Hospital in Morogoro, Tanzania. AB - While nutritional, microbiological and immunological factors have been implicated in childhood diarrhoea in many countries, there is limited aetiological information in Morogoro Region of Tanzania. A case-control study was conducted to establish whether diarrhoea in 6-60 months old children admitted at a Regional Hospital in Morogoro, was attributable to enteric bacteria and/or parasites and the contribution of under-nutrition, as measured by weight-for-age below -2 SD. From January to September 2011, children admitted at the Hospital with (cases) and without diarrhoea (controls), were obtained by convenience sampling. Children's stool, weights, ages and information on socioeconomic, feeding, water and sanitation factors were obtained. Stool samples were analysed for Escherichia coli O157, Shigella dysentriae, Campylobacter jejuni, Salmonella species and enteric parasites. Logistic regression was used to identify their association with diarrhoea occurrence; and survival analysis used to assess associated risk, using associated-hazard ratios (HR). Commonest bacteria isolated were Salmonella, more from controls, 45 (29.6%), than cases, 25 (16.6%); S. dysentriae and C. jejuni were only isolated from cases, while E coli O157 was not found. Enteric parasites were least prevalent; 4 (2.6%) for cases and 2 (1.3%) for controls. Although under-weight children had 38% increased risk of having diarrhoea than normal ones, this was not significant (HR = 0.98, p=0.928). Other factors found to significantly. (p<0.05) influence diarrhoea occurrence included age when breastfeeding stopped, food(s) given, feeding utensils and the child's toilet. In conclusion, childhood diarrhoea occurrence should warrant microbiological testing, for timely, appropriate treatment and prevention of transmission to others. Prevention and control measures for diarrhoea in children in Morogoro should include adequate breastfeeding, proper disposal of children's faeces and feeding children using cups rather than bottles. The increased occurrence of diarrhoea among malnourished children, particularly upon breast milk withdrawal, gives food and nutrition prominence among control measures. PMID- 26591732 TI - Low sputum smear positive tuberculosis among pulmonary tuberculosis suspects in a tertiary hospital in Mwanza, Tanzania. AB - Early diagnosis of tuberculosis (TB) and prompt initiation of treatment are essential for an effective tuberculosis control programme. In many resource limited settings microscopic diagnosis is still the pivotal tool in the diagnosis of pulmonary TB. This study aimed at evaluating laboratory microscopic diagnosis of tuberculosis in a tertiary hospital in Mwanza, Tanzania. This retrospective hospital based study reviewed consecutively from TB registry and patients' files a total of 5,922 TB suspects who submitted their sputum for examination between January 2007 and May 2010 at Bugando Medical Centre (BMC). Among TB suspects (mean age=36.1+/-13.6 years) female accounted for 54.1% of the patients. The prevalence of HIV among TB patients was 59.4%. The sputum smear positivity rate among the TB suspects was 6.1%; the rate was higher in HIV positive than in HIV negative patients (9.9 % versus 3.2%, P-value < 0.001). The overall positivity rate for the first smear was 94.2% with an incremental percentage yield of 5.2% and 0.6% for the second and third smears, respectively. The study found that 28.6% of patients who were positive in the first smear did not return for the second smear. The risk factors among smear positive TB patients were co-illness (32.5%), previous history of TB (7.5%) and history of positive TB contact (4.7%). These findings also show that as CD4+ T Cells count increases, the quantity AFB in sputum smear also increase although not statistically significant. The sputum smear positivity rate at Bugando Medical Centre is low and more than a quarter of initial TB suspects who were positive in the first smear were lost to follow up posing a threat of continuous transmission of tuberculosis to the community. The finding of more sputum smear positivity rate among HIV positive than HIV negative patients at BMC requires a prospective study to ascertain whether it is a reality or a coincidence. PMID- 26591733 TI - APOPO's tuberculosis research agenda: achievements, challenges and prospects. AB - This article describes Anti-Persoonsmijnen Ontmijnende Product Ontwikkeling (APOPO) recent use of specially trained African giant pouched rats as detectors of pulmonary tuberculosis in people living in Tanzania. It summarizes the achievements and challenges encountered over the years and outlines future prospects. Since 2008, second-line screening by the rats has identified more than 2000 tuberculosis-positive patients who were missed by microscopy at Direct Observation of Treatment--Short Course centres in Tanzania. Moreover, data that are reviewed herein have been collected with respect to the rats' sensitivity and specificity in detecting tuberculosis. Findings strongly suggest that scent detecting rats offer a quick and practical tool for detecting pulmonary tuberculosis and within the year APOPO's tuberculosis-detection project will be extended to Mozambique. As part of its local capacity building effort, APOPO hires and trains Tanzanians to play many important roles in its TB detection project and provides research and training opportunities for Tanzanian students. PMID- 26591734 TI - Sanitary practices and occurrence of zoonotic conditions in cattle at slaughter in Morogoro Municipality, Tanzania: implications for public health. AB - As meat consumption is increasing worldwide to cover for protein demands, also raise concerns and challenges regarding meat hygiene and safety. The current one year follow up study aimed at investigating on sanitary practices and occurrence of zoonotic conditions, during post-mortem examination, in cattle at slaughter in Morogoro Municipality abattoir. Sanitary practices were assessed through direct observation where as routine post-mortem inspection procedures were employed to detect zoonotic conditions in cattle at slaughter. During the study period a total of 30,713 cattle were slaughtered and inspected at the abattoir. Results revealed poor hygienic practices at the level of abattoir surrounding, the slaughter operation area, personnel as well as meat vans. Whole carcasses, lungs, livers, hearts and heads were condemned due to zoonotic conditions at rates of 0.026%, 1.96%, 1.61%, 0.02% and 0.21% respectively. Bovine tuberculosis, Cysticercus bovis cysts, fasciolosis and hydatidosis were the responsible zoonotic conditions for the condemnations. Bovine tuberculosis was a leading zoonotic cause of condemnations accounting for 95.7% of lungs and 100% of all head and carcass condemnations. Cysticercus bovis cysts were ranking the second in serving as causes of condemnations closely followed by fasciolosis and lastly hydatidosis. Occurrence of disease conditions with zoonotic implication in cattle at slaughter, meant for human consumption, may pose significant economic and public health risks to especially disaster-prone marginalized communities. Thus, there is a need to introduce appropriate control measures of livestock diseases to minimize the rate of infection; and eventually reduce economic losses and safeguard public health. PMID- 26591735 TI - In vitro analysis of the cariogenic and erosive potential of paediatric antitussive liquid oral medications. AB - We evaluated in vitro the cariogenic and erosive potential of antitussive liquid oral medications for paediatric use. Fifteen paediatric liquid antitussives were sampled. The endogenous pH was evaluated by potentiometry, titratable acidity was measured according to the method adopted by the Association of Official Analytical Chemists, total soluble solids content (TSSC) readings were performed by Brix refractometry using the Abbe refractometer, and the total sugar content was determined according to the Fehling methodology. The experiments were performed in triplicate and the obtained data were entered in the Excel software, analyzed and presented by descriptive statistics (means and standard deviations). Endogenous pH values ranged from 2.49 +/- 0.09 (Iodetox(r)) to 6.75 +/- 0.005 (Carbocysteine(r)) and twelve medications showed pHs below the critical value of 5.5 for enamel demineralization. Iodetox(r) (0.021 +/- 0.01) presented the lowest titratable acidity and Aerofrin(r) (1.171 +/- 0.01) presented the highest titratable acidity. Celergin(r) presented the highest TSSC (62.26 +/- 0.40) and Acetyleysteine(r) (100 mg granules bags) presented the lowest TSSC (3.25 +/- 0.43). Only 5 medications contained sugar, with total sugar content ranging from 35.93% +/- 6.65 (Iodetox(r)) to 59.60% DP +/- 6.66 (Celergin(r)). The paediatric antitussive medications showed low endogenous pH, some of them even below the critical value for enamel dissolution (pH<5.5). These antitussives are potentially cariogenic and erosive to dental structures if used frequently because of the high titratable acidity and high sugar concentration, especially when adequate oral clearance is not performed after administration of each dose. PMID- 26591736 TI - Oral health experience during pregnancy and dental service utilization in Bariadi District, Tanzania. AB - A substantial proportion of pregnant women reports experiencing oral health problems during pregnancy. However, most of them perceive that such problems are normal in pregnancy and hence do not seek dentist consultation. The objective of this study was to determine the prenatal oral health experience and the utilization of dental care services among pregnant women attending reproductive and child health clinics in Bariadi District in Tanzania. Data was collected using a questionnaire-guided interview. Key variables were socio-demographic characteristics of pregnant women, oral health experience, and dental visits during pregnancy with reasons and treatment received. A total of 305 pregnant women (mean age=25.7 years) were involved in the study. Most of the listed oral health problems during pregnancy were reported by women with 2+ children. The frequent oral health problems among the pregnant women were bleeding gums (22.6%, N=69), pain in gums (21.6%, N=66), swollen gums (21.3%, N=65), dental pain (30.5, N=93), and tooth decay (25.6%, n=78). However, only 31.8% (N=97) visited a dental clinic for consultation most whom, were those with three or more children (chi2=.682; P=002). The pregnant women who had visited a dentist in the past 12 months were 11.1% (N=34), mostly those aged >24 years and those with informal employment (P<0.05). Curative and preventive treatments were received more significantly by the urban and with formal employment (P<0.01). In conclusion, pregnant women in Bariadi, Tanzania experiences substantial oral health problems for which they do not often utilize dentists for consultation and management during pregnancy. Dentists and other health workers should therefore, intensify dental screening, emphasizing active family and community participation as part of regular prenatal care. PMID- 26591737 TI - Accuracy in diagnosis of postpartum haemorrhage using visual estimation of blood loss versus change in haematocrit in a tertiary teaching hospital in Tanzania. AB - Postpartum haemorrhage is the leading cause of maternal death in the developing country and yet is poorly diagnosed due to inaccurate measurement of blood loss following delivery. A study was carried out at Muhimbili National Hospital (MNH) Tanzania between October 2005 and January 2006 to determine the accuracy of visual estimation of blood loss (VEBL) in comparison to laboratory measurement of blood loss in diagnosis of primary postpartum haemorrhage (PPH). A total of 426 pregnant women who were in active phase of labour were recruited and their venous blood was drawn for estimation of haematocrit before delivery and 12 hours thereafter. Active management of third stage of labour was conducted by giving 101U of oxytocin (intramuscularly or intravenously) and this was followed by visual estimation of blood loss. The proportion of patients who developed PPH was then determined by both methods. The mean duration of third stage of labour was 8.3 minutes and mean blood loss was 164.9 ml. The prevalence of PPH was 8.9% and 16.2% by VEBL and changes in haematocrit, respectively. Change in haematocrit in diagnosis of PPH was found to be more accurate, specific with high positive predictive values compared to VEBL. The need for additional uterotonics was 5.8% and the commonest labour complications associated with PPH were second degree tear, retained placenta and EUA for continued bleeding. In conclusion, VEBL using calibrated vessel will increase accuracy where conventional method using non calibrated method is used for diagnosis of PPH. Service providers working in labour wards need to be trained on how to estimate blood loss using simulated methods so as to increase their long term memory and accuracy in diagnosis of post-partum haemorrhage, hence provision of immediate intervention. PMID- 26591738 TI - Malignant mixed Mullerian tumour of the prolapsed cervix: A case report. AB - Malignant mixed Mullerian tumour is a rare gynaecological tumour commonly presenting with vaginal bleeding, abdominal pain or mass in the uterine cavity, cervix or vagina. The neoplasms are commonly seen in postmenopausal women although it has been observed in younger women. Ovaries and the corpus of the uterus are commonly involved, whereas involvement of the cervix and vagina is rare. A 37 year-old Tanzania lady para 7 with a previous history of two genital polypectomies presented with history of recurrent vaginal mass which was associated with abnormal vaginal bleeding and foul smelling discharge. Vaginal examination revealed a prolapsed uterus with giant fungating cervical mass which was ulcerated, friable, and bled easily on touch. Impression was grade three uterine prolapse with infected cervical polyp/cervical sarcoma. Excision of the tumour through trans-vaginal hysterectomy was performed, no lymphadenopathy was found, no adnexa abnormalities, and no involvement of the vaginal wall. Histological diagnosis of Malignant mixed Mullerian tumour of the cervix was made. Patient recovery was unremarkable; however she was lost to follow up. The patient's mass was initially suspected to be prolapsed uterus with decubitus ulcer but the histological results were of a malignant condition. Lack of clear management guidelines for some rare mixed tumours remains a challenge for clinicians in low resource settings. PMID- 26591739 TI - Mono-parasite infection versus co-infections in Tanzania: the need to revise our research focus. PMID- 26591740 TI - Clinical manifestations and outcomes of severe malaria among children admitted at Rungwe and Kyela district hospitals in south-western Tanzania. AB - Malaria remains as an important public health and a major cause of childhood death and paediatric hospital admission in sub-Saharan Africa. This prospective hospital based cross sectional study was conducted from April 2007 to April 2008. The main objective was to assess clinical manifestations and outcomes of severe malaria in children admitted to district hospital in Rungwe and Kyela in south western Tanzania. A total of 1371 children were selected as screening group of which 409 (29.8%) were tested positive for malaria. Mean age of the children was 2.7 (95%CI= 2.5, 2.8) years and the majority (86%) were under five years of age. The proportion of children severe malaria in Rungwe was significantly higher than that of Kyela by 21.3% (P=0.002). The common symptoms of severe malaria during admission were convulsions (50.9%) compensated shock (30.6%), prostration (29.1%) and symptomatic severe anaemia (14.9%). The case fatality rate (CFR) was 4.6% and the cure rate (CR) was 95.4%. Children with suspected severe acidosis and symptomatic severe anemia were 4.8 (95%CI=1.6, 14.6) and 5.5 (95%CI 1.1, 28.2), respectively, more likely to die compared to those without these symptoms. The proportion of deaths among children presenting >=5 symptoms was 32.1% higher than among those presenting one symptom (OR =0.50, 95%CI 0.125-2.000; P=0.000). Convulsions and compensated shock were the leading symptoms at admission. Suspected severe acidosis and symptomatic severe anemia were the predictors of mortality for children. In order to reduce mortality among admitted children with severe malaria there is a need for health providers to deploy strategic management of fatal prognostic factors. In conclusion, convulsion and compensated shock were the leading symptoms among children at admission and that suspected severe acidosis and symptomatic severe anemia were the predictors of mortality. It is therefore important to emphasis early diagnosis and prompt treatment of severe cases of malaria to minimize mortality among children. PMID- 26591741 TI - Dermatological malignancies at a University Teaching Hospital in north-western Tanzania: a retrospective review of 154 cases. AB - Dermatological malignancies are among the most common form of cancers and the global incidence has been increasing at an alarming rate. A retrospective study was conducted to determine the prevalence, histopathological pattern, anatomical distribution and treatment outcome of dermatological malignancies at Bugando Medical Centre in North-western Tanzania. Data were collected from patients' files kept in the Medical record department; the surgical wards, operating theatre and histopathology laboratory and analyzed using Statistical package for social sciences system. A total of 154 patients with a histopathological diagnosis of dermatological malignancy were studied. Generally, males outnumbered females by a ratio of 1.4:1. The majority of patients were in the 5th and 6th decades of life. Malignant melanoma was the most common dermatological malignancy (67.5%) followed by Kaposi's sarcoma (10.4%), Squamous cell carcinoma (8.4%) and Basal cell carcinoma (7.8%). The lower limbs were the most frequent site accounting for 55.8%. Wide local excision was the most common surgical procedure performed in 79.2% of cases. Post-operative wound infection was the most common complication in 58.3% of patients. Mortality rate was 3.8%. Dermatological malignancies are more prevalent in our setting. A high index of suspicion is needed to avoid labelling malignancies "chronic ulcers" and all suspected lesions should be biopsed. PMID- 26591742 TI - Geriatric injuries among patients attending a regional hospital in Shinyanga Tanzania. AB - Geriatric injuries pose a major challenge to surgeons and general practitioners in developing countries. The objective of this study was to determine the prevalence, injury characteristics and outcomes of geriatric injury among patients at Shinyanga Regional Hospital in Tanzania. Data was collected using a pre-tested, coded questionnaire and analyzed using SPSS computer system. A total of 94 geriatric trauma patients constituting 22.7% of all trauma admissions were studied. The male to female ratio was 1.4:1. Their mean age was 68.5 years (ranged 60-98 years). Premorbid illness was reported in 38.3% of patients. Most injuries were intentional in fifty-three (56.4%) patients. Assaults, falls and road traffic crashes were the mechanism of injuries in 52.1%, 19.1% and 11.7% of cases, respectively. The majority of cases of assault were females accounting for 64.6%. The majority of injuries (81.9%) occurred at home. Pre-hospital care was recorded in 5.3% of cases. The musculoskeletal (72.3%) and head (66.0%) regions were commonly affected. Soft tissue injuries (wounds) (89.4%) and fractures (52.2%) were the most common type of injuries. The majority of patients (90.4%) underwent surgical treatment of which wound debridement was the most common procedure performed in 91.8% of cases. Complication rate was 39.4%. The mean length of hospital stay was 28.6 days (ranged 1-124 days). The length of hospital stay was significantly longer in patients with co-morbidities, long bone fractures and those with complications (P<0.05). Mortality rate was 14.9% and it was significantly related to advanced age, presence of pre-morbid illness, high injury severity score, severe head injuries and the need for ventilatory support (P<0.05). In conclusion, traumatic injuries in elderly constitute a major but preventable public health problem in Shinyanga region and contribute significantly to high morbidity and mortality. Urgent preventive measures focusing at the root causes of the injuries and early appropriate treatment is highly needed to reduce the occurrence, morbidity and mortality associated with these injuries. PMID- 26591743 TI - Protective effect of the leaves of Vitex negundo against ethanol-induced cerebral oxidative stress in rats. AB - The present study investigated the effect of the various fractions of hydromethanolic extract of the leaves of Vitex negundo (Verbenaceae) against ethanol-induced cerebral oxidative stress in rats. Cerebral oxidative stress was induced by the administration of 20% ethanol (5 ml/100 gbw) for a period of 28 days. The petroleum ether (PEF), chloroform (CF), ethylacetate (EAF) and residual (RF) fractions at a dose of 200 mg/kgbw orally were simultaneously administered with ethanol for 28 days. alpha-tocopherol at a dose of 100 mg/kg orally was used as the standard. Administration of ethanol resulted in a significant elevation in serum biochemical parameters like aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), uric acid, triglycerides and lipoprotein levels. In addition there was a significant (P<0.01) elevation in malondialdehyde (MDA) and lipid hydroperoxide (LH) levels and a significant (P<0.01) reduction in enzymatic and non-enzymatic antioxidants in the brain tissue. Histopathological examination of the brain tissue of the ethanol treated animals showed marked gliosis. Simultaneous administration of the fractions prevented the enzymatic leakage and elevation of serum uric acid, triglycerides and lipoprotein levels. All the fractions (except the residual fraction) prevented the rise in lipid peroxidation and enhanced the antioxidant enzymes. Further, histopathological examination revealed that the fractions of V. negundo offered a significant protection against ethanol toxicity in rat brain. The activity exhibited by the chloroform fraction is comparable to that of the standard. The present study reveals that the leaf of V negundo has protective action on the brain, which could be attributed to its antioxidant potential. PMID- 26591744 TI - Indigenous to Tanzania. AB - The objective of this study was to evaluate free radical scavenging capacity of crude extracts from forest basidiomycetous fungi, domestic zygomycetous fungi and marine ascomycetous fungi. Lethal concentration values that kill 50% of the brine shrimps (LC50) were determined from 19 fungal extracts using brine shrimp test (BST). The LC50 values of fungal extract ranged between 0.28-40 MUg/ml. The basidiomycetous (Lactarius volemoides) was the most toxic fungi with LC50 of 0.28 MUg/ml while ascomycete Pichia guilliermondii showed the least toxicity with LC50 of 40 MUg/ml. The concentrations of eleven fungal extracts were further evaluated on their ability to scavenge free radical using 1-diphenyl-2-picrylhydrazyl (alpha,alpha-diphenyl-beta-picrylhydrazyl) (DPPH) as a dye reagent for spectrophotometric assay at 517 nm. The extract concentrations that decreased the initial DPPH radical by 50% (EC50) were determined. The EC50 values ranged from 19-60.4 MUg/ml ascorbic acid equivalents. Extracts from an edible but undomesticated basidiomycetous fungus isolated from Miombo forest and identified as Termitomyces microcarpus showed the highest scavenging effect with EC50 at 19 MUg/ml while that from ascomycete Candida tropicalis showed the least EC50 at 60.4 MUg/ml. These results draw attention to wild undomesticated Miombo fungi as potential source of nutritional supplements worth further investigation. PMID- 26591745 TI - Emergency peripartum hysterectomies at Muhimbili National Hospital, Tanzania: a review of cases from 2003 to 2007. AB - A retrospective review of all cases of emergency peripartum hysterectomy performed between January 1, 2003 and December 31, 2007 at Muhimbili National Hospital was done to determine the incidence, indications and complications, background characteristics, antenatal care attendance, referral status, and maternal and foetal outcomes. There were 55,152 deliveries during the study period and 165 cases of emergency peripartum hysterectomy, giving the incidence of emergency peripartum hysterectomy of 3 per 1000 deliveries. The main indication was uterine rupture (79%) followed by severe post-partum haemorrhage due to uterine atony (12.7%). The case fatality rate was 10.3% where as perinatal mortality rate was 7.7 per 1000 deliveries. The common complication identified intraoperatively was severe haemorrhage which accounted for 39.4% where as intensive care unit admissions (14.4%) and febrile morbidity (12.4%) were common after the operation. Blood was ordered in all cases but in 31 cases it was indicated that it was not available. Seventy nine patients received blood transfusion with the maximum number of units given to one patient being eight. Twenty two patients were given fresh frozen plasma (FFP), the median number of units given was two (range = 1-6). In conclusion, emergency peripartum hysterectomy is a life saving procedure and very common at MNH. The most common indication was ruptured uterus followed by severe postpartum haemorrhage. More than half of the patients underwent emergency peripartum hysterectomy were referred from other health facilities with ruptured or suspected ruptured uterus. The procedure was associated with unacceptably high maternal and perinatal morbidity and mortality. PMID- 26591746 TI - Birth preparedness and complication readiness among women in Mpwapwa district, Tanzania. AB - Avoidable mortality and morbidity remains a formidable challenge in many developing countries like Tanzania. Birth preparedness and complication readiness by mothers are critical in reducing morbidities and mortalities due to these complications. The aim of this study was to assess knowledge and practices with respect to birth preparedness and complication readiness among women in Mpwapwa district in Tanzania. A total of 600 women who became pregnant and or gave birth two years preceding the survey were interviewed. Among them 587 (97.8%) attended antenatal clinic (ANC) at least once during their last pregnancy. Two thirds of those who attended ANC made four or more visits. The median gestation age at booking for antenatal care was 16 weeks. However, 73.9% the women booked after 16 weeks of gestation. Two thirds of the women were 20-34 years old and had at least primary education level. Three hundred and forty six (57.7%) had parity between two and four. Only 14.8% of the women knew three or more obstetric danger signs. The obstetric danger signs most commonly known included vaginal bleeding during pregnancy (19%), foul smelling vaginal discharge (15%) and baby stops moving (14.3%). The majority (86.2%) of the women had decisions made on place of delivery, a person to make final decision, a person to assist during delivery, someone to take care of the family and a person to escort her to health facility. Majority (68.1%) of the women planned to be delivered by skilled attendant. One third of the women planned to deliver at home in the absence of a skilled birth attendant. In the bivariate analysis, age of the woman, education, marital status, number of ANC visits and knowing >=3 obstetric danger signs were associated with birth preparedness and complication readiness. In multivariate logistic regression analysis, women with primary education and above were twice more likely to be prepared and ready for birth and complications. Women who knew >=3 obstetric danger signs were 3 times more likely to be prepared for birth and complications. In conclusion, women with higher level of education and those who knew obstetric complications were more prepared for birth and complications. Further studies are recommended to find out why women do not prepare for birth or complications especially that need blood transfusion. PMID- 26591747 TI - The potential of involving traditional practitioners in the scaling up of male circumcision in the context of HIV prevention in Tanzania. AB - Male circumcision (MC) has been practiced worldwide for religious, cultural, social and medical reasons. Recent studies in Africa have indicated MC to be highly protective against HIV transmission. However, incorporating MC in HIV/AIDS prevention programme will increase its demand in Tanzania where traditional male circumcision is common and the health care system is weak. The objective of this study was to determine the challenges and opportunities of involving traditional practitioners in scaling up safe MC in the context of HIV prevention in Tanzania. The study was conducted in Monduli, Bahi and Mkuranga districts of Tanzania. Both quantitative and qualitative methods were employed. Household survey involved community members from the selected villages. In-depth interviews involved traditional practitioners and key informants at national, district and facility levels. A total of 601 householders were interviewed. Most (71.4%) household respondents preferred traditional MC as it was part of their culture and tradition. A similar response was obtained from other respondents. It was mostly preferred because it was used as an initiation school, turning of boys to warriors and sense of social cohesion. Only 228 (37.9%) of the respondents were aware of the adverse events associated with MC. The most frequently mentioned adverse effects were severe bleeding (65.0%), delayed wound healing (17.5%) and wound sepsis (8.4%). The risk of acquiring HIV through male circumcision practice was poorly known among community members except medical respondents. Single unsterilized local surgical equipment was used to circumcise several initiates. It was observed that interference with traditional values associated with circumcision to be the main hindrance of linkage between traditional and conventional practitioners. On the other hand it was reported that there was no policy or guidelines on Traditional MC (TMC). Most of respondents supported the efforts to establish and promote formal linkages between traditional and conventional practitioners. In conclusion, under the current HIV pandemic and TMC being prevalent in Tanzania, it is high time for the government to establish a linkage between traditional and conventional practitioners for safe practices in order to minimize HIV transmission. PMID- 26591748 TI - Key considerations in scaling up male circumcision in Tanzania: views of the urban residents in Tanzania. AB - Male circumcision (MC) reduces the risk of sexually transmitted infections (STI) including HIV. The WHO and UNAIDS recommend male circumcision as an additional intervention to prevent HIV infection. Tanzania is embarking on activities to scale up safe male circumcision for HIV prevention and other related health benefits. In line with this, it is crucial to assess views of the population using specific groups. This paper describes perceptions on male circumcision and strategies of enhancing uptake of male circumcision in urban Tanzania using members of the police force. This cross sectional survey was conducted among members of the police force in Dar es Salaam Tanzania from January 2010 to July 2010. The police officer serves as a source of the clinical trial participants in on-going phase I/II HIV vaccine trials. Three hundred and thirteen (313) police officers responded to a self-administered questionnaire that comprised of socio demographic characteristics, reasons for not circumcising, perceptions regarding circumcision, methods of enhancing male circumcision, communication means and barriers to promote circumcision. This was followed by a physical examination to determine male circumcision status. The prevalence of circumcision was 96%. Most (69%) reported to have been circumcised in the hospital. The reported barriers to male circumcision among adults and children were: anticipation of pain, cost, fear to lose body parts, and lack of advice for adult's circumcision. Sensitization of parents who take children to the reproductive and child health services was recommended by most respondents as the appropriate strategy to promote male circumcision. The least recommended strategy was for the women to sensitize men. Use of radio programs and including male circumcision issues in school curricula as means of enhancing community sensitization regarding male circumcision were also highly recommended. Other recommendations include use of public media, seminars at work and issuance of circumcision regulations by health authorities. In conclusion, the present study reveals male circumcision was common in a selected urban population. There are various barriers and channels of communication regarding male circumcision. In view of scaling male circumcision in Tanzania, use of radio messages, inclusion of male circumcision in the school curricula and sensitization at the reproductive and child health clinics are likely to promote early medical male circumcision. PMID- 26591749 TI - Risk factors for anaemia among HIV infected children attending HIV care and treatment clinic at Muhimbili National Hospital in Dar es Salaam, Tanzania. AB - There is paucity of data describing the risk factors for anaemia among HIV infected children in Tanzania. This cross sectional study aimed at determining the contributing factors for anaemia among HIV-infected children attending Muhimbili National Hospital in Dar es Salaam. Both univariate and multivariate logistic regression analyses were performed to identify possible factors associated with anaemia in HIV-infected children. In this study a total of 75 (44%) patients among 167 recruited HIV children aged 6 months to 59 months were found to be anaemic (Hg<11 g/dl). Multivariate logistic regression demonstrated that not being on HAART (OR 3.40, 95%CI (1.20-9.60), having CD4% <25% (OR 2.30, 95%CI (1.20-34.60), having a history of tuberculosis (TB) (OR 3.23, 95%CI (1.10 9.70) and having hookworm infestation (OR 5.97, 95%CI (1.92-18.4) were independent risk factors for anaemia among HIV infected children. The analyses also showed that being HIV positive for >= 2.5 years resulted into a low risk of severe anaemia compared to being HIV positive for < 2.5 years. Taking multivitamins (OR 0.07, 95%, CI (0.020-0.30) and antihelminthics (OR 0.27, 95%CI (0.10-0.74) were also protective against anaemia in children. Similar factors (with exception of using antihelmintics) were associated with severe anaemia. In conclusion the factors associated with anaemia in HIV infected children were multifactorial in nature. Efforts to correct anaemia in HIV infected children should include use of HAART and treatment of infections such as TB and hookworms. PMID- 26591750 TI - Understanding the link between trafficking in persons and HIV and AIDS risk in Tanzania. AB - The magnitude of trafficking in persons in Tanzania is unknown. Consequently, available information on health risks of persons trafficked for different forms of exploitation is extremely scanty. We conducted a baseline study in eight administrative regions of Tanzania using both qualitative and quantitative methods to generate data on the health conditions of trafficked persons to inform trafficking in persons control measures through HIV and AIDS interventions. Study participants included the national, regional and district community development officers, district medical officers, local government leaders, managers or representatives of non-governmental organizations involved in anti-trafficking in persons activities, members of the community and victims. Findings indicated that common forms of labour into which persons are trafficked include domestic services, agriculture (farming), construction, mining/quarrying, fishing, lumbering and manufacturing. Trafficked persons are reported to be exposed to risks like overcrowding, long working hours, psychological problems, physical injuries, impotence, breathing problems and sexually transmitted infections including HIV. It is concluded that the reported occupational hazards in industries where trafficked persons are forced into are not specific to trafficked persons as they affect all labourers. However, the underground nature of the trafficking in persons process increases health problems and risks, including the vulnerability to HIV infection. More tailored research is needed, especially to find means of how to reach out and provide services to this particular vulnerable population, validate labour forms of exploitation into which persons are trafficked to enable the integration or mainstreaming of HIV and AIDS and trafficking in persons at the policy and programmatic levels. In addition, findings would facilitate the understanding of the link between increased risk of IRV and trafficking in persons. PMID- 26591751 TI - Factors affecting HIV counselling and testing among adults in Muheza District, Tanzania. AB - HIV/AIDS is one of the major public health problems affecting people worldwide. Counselling and testing is a process by which an individual undergoes confidential counselling to enable him/her to make an informed choice about his or her HIV status and to take appropriate actions. The objective of this study was to assess factors affecting HIV counselling and testing (HCT) among adults in Muheza district in north-eastern Tanzania. A total of 394 adults were interviewed using a standardized questionnaire. The majority of the study participants were females (N=213; 54.1%). Most of the respondents were either in or have completed secondary education. Almost two thirds of the study population (262) was not married. Seventy one percent of all participants viewed HCT positively. A significant proportion of married (17.7%) and un-married (16.5%) participants judged HCT as not essential as it would not change the test result. Sixty-eight percent of the respondents did not consider themselves at risk and most of them (71%) were married. Importantly, 26% reported being scared of discrimination. In conclusion our study results demonstrate that only half of the study population had adequate knowledge of HCT. Being married was considered as a 'protective' factor in terms HIV risk which indicates a misconception. These findings underscore the importance of proper HIV counselling and testing in this community so as to bridge the knowledge gap. It further demonstrates the need to address in detail misconceptions during HIV counselling and testing. PMID- 26591752 TI - Child and adolescent injury in Africa - still underappreciated and understudied. PMID- 26591753 TI - Impact of insecticide treated mosquito nets and low dose monthly diethylcarbamazine on lymphatic filariasis infection between 1999 and 2004 in two endemic communities of north-eastern Tanzania. AB - Lymphatic filariasis (LF) is among the poverty related neglected tropical diseases earmarked for elimination using mass drug administration (MDA) strategy. Additional use of insecticide treated mosquito nets (ITNs) might enhance elimination of LF infection. Between August 1998 and July 1999, all individuals aged 8 months from Magoda and Mpapayu villages in north-eastern Tanzania, were administered with monthly low dose diethylcarbamazine (DEC) at a dosage of 50mg in children aged < 15 years and 100mg in adults aged >= 15 years. ITNs were also distributed to Magoda in December 1998 and to Mpapayu in March 2001. The main objective of our study was to assess the impact of ITNs and low dose DEC on microfilaria (mf) prevalence and intensity and incidence of new mf infections. Four annual cross-sectional surveys were conducted between 1999 and 2004 in the two villages to screen for Wuchereria bancrofti microfilariae in individuals aged >= 1 year. Overall, 80% of the population in Magoda and 66% in Mpapayu were covered during these surveys. Results revealed a significant decrease in both mf prevalence and intensity in both villages. Furthermore, there was a steady decrease in mf incidence in Magoda; with 36.7 cases per 1000 person years in 2000 and 7.4 in 2004. In Mpapayu, the incidence initially increased from 20.8 cases in 2000 to 24.3 in 2001 and then decreased to 7.2 cases in 2004. Individuals using ITNs in Magoda had significantly lower risk of mf (OR=0.681; 95%CI: 0.496-0.934); and the risk of new infections was reduced by 58.8% (95%CI: 30.3-75.4). These results suggest that when MDA is complemented with ITNs there is high likelihood to half filariasis transmission within a shorter period than using chemotherapy alone. PMID- 26591754 TI - Prevalence of bacterial vaginosis and associated factors among pregnant women attending at Bugando Medical Centre, Mwanza, Tanzania. AB - Bacterial vaginosis (BV) is an extremely common reproductive tract condition worldwide with reported high prevalence among African population. Factors associated with this condition include preterm labour, premature rupture of membranes, preterm delivery and possibly spontaneous abortion. Nevertheless, antenatal screening and treatment is not routinenly available in most poor resource countries including Tanzania. A cross-sectional descriptive study was conducted among delivering women at Bugando Medical Centre (BMC), Mwanza, Tanzania to determine the magnitude of the BV using the Nugent's criteria and to document factors associated with the condition. A total of 284 women who presented for delivery at BMC labour ward from February to March 2011 were recruited into the study. For each consented women, a vaginal swab was taken, samples collected tested and a Nugent's score of at least seven indicated bacterial vaginosis. Overall, bacterial vaginosis was diagnosed in 28.5% (n=81) of all participants. Gardnerella was the commonest morphotypes found in approximately 66.2% (n=188) of all participants while 11.6% (33 participants) had Mobilincus. There were no evidence for the association between bacterial vaginosis having formal education, (OR, 1.42[95%CI, 0.29-6.97; p=0.6671). Urban residence (OR, 1.29 [95% CI, 0.76-2.19; p=0.352]), ever delivered before (OR 0.66[95%CI, 0.39-1.12; p=0.126]), vaginal practice to enhance dry sex (OR, 1. 16[95%CI, 0.43-3.17; p=0.768]) or wet sex (OR 1.31[95%CI, 0.46-3.7; p=0.613]), gestation age less than 37 weeks (OR 0.82[95%CI, 0.45-1.51; p=0.534]) and HIV infection (OR 0.90[95%CI, 0.28-2.92; p=0.863]) were not associated with bacterial vaginosis. Bacterial vaginosis is common among women delivering at Bugando Medical Centre and more studies to include antenatal clinic attendees initiating care are required to reliably document the magnitude the condition. PMID- 26591755 TI - High prevalence of tuberculosis among adults with fever admitted at a tertiary hospital in north-western Tanzania. AB - Tuberculosis is a leading cause of death in developing countries where HIV is endemic. This hospital based study was done to estimate the magnitude of pulmonary and extra-pulmonary tuberculosis and to determine predictors of tuberculosis among febrile adults admitted at Bugando Medical Centre (BMC), Mwanza, Tanzania. A total of 346 adults febrile patients admitted in medical wards were studied. Sputum for AFB microscopy and chest X-rays was used to diagnose tuberculosis. Clinical features were collected using standardized data collection tool. HIV testing and CD4 counts were determined. Data were analyzed using STATA version 11 software. Of 346 febrile adults patients 116 (33.5%) were diagnosed to have tuberculosis; of which 79 (68.1%) and 37 (31.9%) had pulmonary tuberculosis (PTB) and extra-pulmonary tuberculosis, respectively. Smear negative PTB were more common in HIV positive than in HIV negative patients (50% vs. 18.5%, p=0.007). Extra-pulmonary tuberculosis was more common in HIV positive patients than pulmonary tuberculosis (86.4% vs. 13.6%), p=0.000 1). On multivariate logistic regression analysis the predictors of tuberculosis were; age above 35 years (OR =2.38, p=0.007), cardinal symptoms (OR=37, p<0.0001), pleural effusion (OR=24, p=0.0001), and HIV status (OR =3.2, p=0.0001). Of 79 patients with PTB, 48 (60.7%) were AFB smear positive and 31 (39.3%) were AFB smear negative. HIV patients with smear negative tuberculosis had significantly lower CD4 count than IV patients with smear positive tuberculosis (63.5 cells/ul versus 111.5 cells/ul) [Mann-Whitney test p=0.0431]]. No different in mortality was observed between patients with TB and those without TB admitted in BMC medical wards (28.5% vs. 23.0%, p= 0.13 18). Tuberculosis is the commonest cause of fever among adults patients admitted at BMC and is predicted by age above 35 years, positive HIV status, cardinal PTB symptoms, and pleural effusion. Routinely TB screening is highly recommended among adults with fever, cough, night sweating and wasting in countries where HIV is endemic. PMID- 26591756 TI - Evaluation of the KEMRI Hep-cell II test kit for detection of hepatitis B surface antigens in Tanzania. AB - Hepatitis B surface antigen (HBsAg) is one of the most important serological markers used to diagnose acute and chronic hepatitis B infection. The objective of the current evaluation was to assess the operational characteristics of the Kenya Medical Research Institute (KEMRI) Hep-cell II against an ELISA Exsym HBsAg in the detection of hepatitis B surface antigens. To evaluate the Hep-cell II test, blood samples were collected from blood donors and processed for detection of HBsAg using Hep-cell II based on the test principle and procedure outlined by the manufacturer. ELISA Axsym HBsAg test was used as golden standard. Of the 400 samples tested, 287 (71.8%) were positive by Hep-cell test and 295 (73.8%) were positive by the ELISAAxsym. Hep-cell test had a sensitivity of 98.6% and specificity of 95.96%. Similar values of sensitivity and specificity of the Hep cell test were obtained even when Bayesian Analysis Model was applied. The positive and negative predictive values of Hep-cell test were 98.61% and 95.96%, respectively. The positive and negative diagnostic likelihood ratios of Hep-cell test were 24.4% and 0.0145, respectively. In conclusion, the Hep-cell test is useful for detecting hepatitis B virus and the high likelihood ratio observed suggests that it may be useful in blood screening. However, it may be necessary to evaluate for cost-effectiveness and robustness in field conditions before the test is recommended for use. PMID- 26591757 TI - A case-control study of factors associated with non-adherent to antiretroviral therapy among HIV infected people in Pwani Region, eastern Tanzania. AB - Non-adherence is one of the major causes of treatment failure which leads to increased morbidity and mortality caused by opportunistic infections. Optimal anti-retroviral therapy (ART) adherence is essential for maximal suppression of viral replication and long term survival of patients. In order to develop effective public health interventions in the context of scaling ART services to peripheral areas, it is important to evaluate factors associated with non adherence among HIV-infected individuals in Pwani Region. The purpose of this study was to identify factors related to non-adherence to ART among HIV infected people in Pwani Region eastern of Tanzania. A case-control study was carried out at Tumbi Hospital and Chalinze Health Centre in Pwani Region in eastern Tanzania. A structured questionnaire was used to assess non-adherence and adherence to doses instruction and time schedule. Patients with less than 95% adherence were defined as cases while those with more than 95% adherence became controls. A structured questionnaire containing factors known to be associated with non adherence to ART in similar settings was administered. Univariate and multivariate conditional logistic regression was performed to identify factors associated with non-adherence. A total of 79 cases and 237 controls matched by age and sex were studied. A high proportion of cases and controls (77.2% and 84.8%) had good knowledge ofART benefits, adherence and eligibility. Majority of cases (73.3%) and controls (69.2%) used public transport to access ART services. More than half of cases (53.2%) missed clinic appointments due to lack of bus fare or other reasons and was associated with ART non adherence (mOR 4.2, 95%CI, 2.2-8.1 and 2.1,95%CI 1.2-4.2). Disclosure to confidants only and failure to disclose HIV-test positive status were associated with non adherence (mOR 3.3, 95%CI 1.3-8.5 and 2.3, 95%CI 1.2-7.1). Alcohol use was associated with non adherence to ART (mOR 1.9, 95%CI 1.4-3.7). Patients who were not satisfied with providers were more likely to be non adherence to ART (mOR 2.0, 95%CI 1.2-3.8). In conclusion, these findings show that adherence is a process which is depended on local specific adherence factors. Adherence improvement strategies need to consider site specific adherence determinants, patient experiences and concerns. PMID- 26591758 TI - The burden of intentional injuries in Mwanza City, north-western Tanzania: a tertiary hospital survey. AB - Intenionai injuries are an emerging silent epiaemic in developing countries ana contribute significantly to global injury burden. A descriptive prospective study was conducted to establish the prevalence, contributing factors, injury pattern and treatment outcome of intentional injuries at Bugando Medical Centre in Northwestern Tanzania. Data was collected using a pre-tested, coded questionnaire and analyzed using SPSS software version 17.0. A total of 1642 (23.7%) patients with intentional injuries were studied. Of these, 97.7% resulted from interpersonal violence (homicide) and 2.3% were self-inflicted (suicide). Males outnumbered females by a ratio of 2.2:1. Their median age was 24 years. The majority of injuries (53.5%) occurred at home. Criminal violence was the most common reason for intentional injuries accounting for 52.1% of cases. In women, domestic violence was responsible for 64.6% of the admissions. Poverty, lack of education, unemployment and alcohol abuse were the most common contributing factors to intentional injuries. Blunt and sharp objects (48.6%) were the most common weapons used. Gunshot injuries were recorded in 11.6% of cases. The head/neck was commonly affected in 49.2%. Soft tissue injuries (87.3%) were the most frequent type of injuries. The majority (90.1%) of patients were treated surgically. Complication rate was 15.0%.The median hospital stay was 26 days (range 1 day to 114 days). Patients with long bone fractures and those who had complications stayed longer in the hospital (P < 0.001). Mortality rate was 13.3%. The mortality rate was significantly high in patients with severe injuries (Injury Severity Score > 15), severe head injuries and those who needed intensive care unit (ICU) admissions and ventilatory support (P< 0.001). Intentional injuries are an emerging but neglected epidemic in Mwanza City and contribute significantly to high morbidity and mortality. Urgent preventive measures targeting at the root causes of violence such as poverty, unemployment, and alcohol abuse will reduce the incidence of these injuries in our setting. PMID- 26591759 TI - Socio-demographic and behavioural correlates of oral health related quality of life among Tanzanian adults: A national pathfinder survey. AB - In response to the growing recognition of quality of life measurement in health care, indicators that address the social and psychological consequences of oral disorders have been developed to complement conventional clinical assessment. The objective of this study was to determine socio-demographic and behavioural correlates of oral health related quality of life (OHRQoL) among Tanzanian adults. The national pathfinder survey methodology described in the WHO Oral Health Surveys - Basic Methods was used to obtain a total of 1,759 Tanzanian adults aged 18 years and above. In line with the pathfinder methodology clusters were purposively selected to represent cities, towns and rural areas. In each cluster individuals were stratified by age and sex. The outcome variable was the OHRQoL in terms of oral impacts on daily performances (OIDP). Frequency distribution, bivariate analyses, and generalized linear models using log binomial regression models were performed by SPSS version 15. About half (49.1%) of the respondents reported at least one oral impact during a period of three months before the survey. Difficulty in chewing was the most prevalent impact affecting 3 9.9% of participants. A higher proportion of those who reported poor conditions of teeth had difficulties in chewing and sleeping was often interrupted. Multivariate analysis indicated that those who perceived their teeth conditions to be good (PR=0.38; CI: 0.32-0.44), were of younger age (PR=0.84; CI: 0.77-0.90), and had visited a dentist during the past five years or more (PR=0.84; CI: 0.77-0.90) and were less likely to have an oral impact. On the other hand those who restricted their sugar consumption (PR=1.12; CI: 1.03 0.1.22) were more likely to have an impact on at least one daily performance. It is concluded that the prevalence of OIDP was high while perceived teeth conditions and age varied with OHRQoL in terms of OIDP in the expected direction. Those who visited the dental clinic in the recent past had more impacts than those who did not. The findings of this study confirm the usefulness of subjective indicators in explaining peoples' suffering. In this regard it is recommended that in the next national pathfinder survey traditional clinical oral health indicators should be complemented with subjective indicators in order to obtain triangulated data for planning oral health services in Tanzania. PMID- 26591760 TI - Uterine rupture: a retrospective analysis of causes, complications and management outcomes at Muhimbili National Hospital in Dar es Salaam, Tanzania. AB - Rupture of the gravid uterus is an obstetric catastrophe that is associated with complications that include massive blood loss, hysterectomy, and damage to the genitourinary tract. It is a serious complication that is associated with high maternal and perinatal morbidity and mortality. We conducted a retrospective review of case notes (from 2003 to 2009) to determine the incidence, causes, complications and foetal/maternal outcome among women with a diagnosis of ruptured uterus at Muhimbili National Hospital (MNH) in Dar es Salaam Tanzania. Case notes with diagnosis of ruptured uterus were retrieved from the records department and information on maternal demographic characteristics, surgical intervention, maternal and perinatal outcome were collected using a check list. Where information was inadequate it was sought from the obstetric database. Obtained data was cleaned and analyzed using PASW statistics 18 software. Out of 72,570 deliveries 163 cases of ruptured uterus were recorded in seven years, making an incidence of 2.25 per 1000 births. Most ruptures (38%) resulted from neglected obstructed labour and scared uterus (33.6%). Major obstetric haemorrhage (>1500 ml) was the most frequently encountered complication followed by sepsis. Subtotal hysterectomy was the most common (73.6%) surgical intervention. Maternal and perinatal case fatality rates were 12.9%, and 96.3% respectively. Ruptured uterus contributed to 6.6% of all maternal deaths. These findings underscores the need for proper monitoring of labour both in the referring facilities and at MNH and improvement of comprehensive emergence obstetric care at all levels of health care to avoid unnecessary delays in care. PMID- 26591761 TI - Prevention and management of malaria in under-five children in Tanzania: a review. AB - In 2010, an estimated 216 million cases and 655,000 deaths due to malaria occurred worldwide. Of these, about 81% and 91%, respectively were reported from the African Region, mostly affecting children under-the age of five. In Tanzania, malaria remains to be the leading cause of high morbidity and mortality. It is responsible for more than one-third of all deaths, 39.4% of all health care visits, and 33.4% of all hospital admissions among children under the age of 5 years. The objective of this article was to provide a systematic review of the literature to summarize the knowledge of the most important aspects of prevention and management of malaria in under-five children in Tanzania. The focus was on health care seeking decision-making and understanding the magnitude of the gap between ownership and use of insecticide treated mosquito nets (ITNs). The review considered published and unpublished literature covering a period from 2002 to the end of July 2012. The information used in this review was obtained through a Google search using specific keywords. Results show that across zones the difference between ownership and use of ITNs among under fives was insignificant. This finding is consistent with a reduction in the proportion of children with suspected of malaria taking antimalarial drugs. Nevertheless, differences exist between zones in terms of both coverage of ownership and use of ITNs. Regarding health care seeking-decision making the literature reviewed indicated that caretakers generally, had a good biomedical understanding of febrile illnesses both in terms of types and symptoms. However, a frequent belief was that symptoms related to convulsions were not associated with malaria, hence cannot be cured in modern health care system. Moreover, some caretakers self-treated symptoms, which trigger others to seek medical care, thus end up delaying to seek medical care. In additional, most of the studies reviewed were designed within the health belief framework. There is a dearth of evidence documenting adherence to prescribed medications. PMID- 26591762 TI - [Social determinants of chronic diseases related behaviors in primary school students in Beijing City]. AB - OBJECTIVE: To identify social determinants of chronic diseases related behaviors in primary school students in Beijing, China. METHODS: Cross-sectional study was designed and a two-stage (districts and schools) stratified (school type) cluster (classes) sampling method was adopted. Haidian and Fengtai districts were chosen firstly. One state and one private school with more migrant children were chosen in each district, paired with two state primary schools with more permanent resident children. Two classes from grades 4, 5 and 6 from each primary school were selected, all students in which and their parents were included as study subjects. A self-designed questionnaire was adopted to collect demographic information, chronic diseases related behaviors and knowledge from students and their parents. Overall, a total of 1604 paired samples of students and parents were obtained from eight primary schools. Eleven self-reported behaviors were grouped into three, which were trying smoking, dietary intake frequency (vegetables, fruit, milk, and breakfast intake, salty foods, fatty diets), sedentary life style (reading, watching TV and playing PC continuously more than one hour, and having physical activities both in school and at home). According to the number of risk behaviors, three groups were classified as low (0 - 1), medium (2 - 3), and high (4 + ). ANOVA, Chi-square test and ordinal logistic regression analysis were adopted to find the influence of demographic characteristics, school types, social economic status (SES) , students' health knowledge, and parents' health knowledge and behaviors on students' number of risk behaviors. RESULTS: Ordinal logistic regression analysis showed boys (OR = 1. 26, 95% CI 1. 03 - 1. 53) and older (OR = 1. 25, 95% CI 1. 14 - 1. 37) were risk factors for more risk behaviors. Higher SES scores (OR = 0. 84,95% CI 0. 73 0. 95) and higher students' health knowledge scores (OR = 0. 87, 95% CI 0. 83 - 0. 91), and better parents' health behaviors scores (OR = 0. 87, 95% CI 0. 83 - 0. 91) were protective factors for the number of risk behaviors. Household registration status and school types had no significant impact yet. Boys (OR = 1. 39, 95% CI 1. 08 -1.79) and lower SES scores (OR =0. 85, 95% CI 0. 73 -1. 00) were significant risk factors for more risk behaviors among migrant students, compared with those in residents students, while other factors had similar impact between two groups. CONCLUSION: Family social and economic status, students' health knowledge and parents' behaviors would have great impact on students' health behaviors cultivation. PMID- 26591763 TI - [Prevalence and risk factors of overweight and obesity among planed pregnancy couples in Chongqing City]. AB - OBJECTIVE: To understand the epidemic situation of overweight and obese among planned pregnancy couples in Chongqing City. METHODS: Proportional stratified random cluster sampling method was adopted to select 11 953 cases of planned gestational couples from 19 counties in Chongqing from April to December, 2013, for questionnaire survey, physical examination and blood sampling test. The main contents of the questionnaire included demographic characteristics, smoking and drinking history, life and other economic pressures. Physical examination included height, weight, and blood pressure. RESULTS: Among the 11 953 subjects, the mean body mass index (BMI) was 21. 13 +/- 2. 78. The overweight rate was 10. 88% (95% CI 10. 32% - 11. 44%). The obesity rate was 2. 20% (95% CI 1. 94% -2. 46%). The standardized overweight rate was 19. 81% (95% CI 19. 10% -20. 53%). The standardized obesity rate was 3. 47% (95% CI 3. 14% - 3. 80%). The overweight, obesity ratio was 4. 94. The prevalence of overweight and obesity increased with age, and decreased with the increasing of educational level. Non conditional logistic regression analysis showed that multiple factors such as 25 years of age or older, living in the "one hour economic zone" and southeast Chongqing region, hypertension, occupation for business or unemployment were more prone to overweight, while factors such as 35 years of age or older, living in the "one hour economic zone" and southeast Chongqing region, hypertension, occupation for business or unemployment were more prone to obesity. High school education and above was the protective factor for obesity and overweight. CONCLUSION: Overweight and obesity are in low prevalence state among planned pregnancy couples in Chongqing. The main influence factors of overweight and obesity are age, living region, occupation and educational level. PMID- 26591764 TI - [Proteomic study on HaCaT cell membrane proteins after exposed to silica nanomaterials]. AB - OBJECTIVE: To identify the differential expression of membrane proteins after HaCaT cell was treated with 15 nm silica nanomaterials (SiO2). METHODS: The HaCaT cells were cultured for 24 h under 15 nm SiO2 in various concentrations (2. 5, 5. 0, 10. 0 mg/L), and ddH2O were used as control. The cell viability were measured with CCK-8 assay. The membrane proteins of SiO2-treated group (10. 0 mg/L) and controls were extracted by ProteoExtract subcellular proteome extraction kit. The differentially expressed membrane proteins were analyzed by a two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption/ionization tandem time-of-flight mass spectrometry (MALDI-TOF-MS). Bioinformatics analysis was used to reveal the biological functions and predict transmembrane domains of differential expressed proteins. The expression of differential membrane proteins were measured by Western blot analysis. RESULTS: The cell viability was significantly decreased with the increases of 15 nm SiO2 exposure levels. After treatment with 2. 5, 5. 0, 10. 0 mg/L of 15nm SiO2, the cell viability was assessed to (91. 3% +/- 6. 1%), (81. 7% +/- 7. 0%) and (74. 0% +/- 2. 6%) of control level (P < 0. 05), respectively. In the proteomic analysis, a total of 10 proteins were identified as differential expression in the SiO2 treated simples compared with controls. Among these, 7 of these proteins were predicted as membrane proteins with at least one significant transmembrane domain. The most dominant function that the identified proteins involved in was binding and structural molecule activity. The differential expression of G protein-coupled receptor 179 (GPR 179) and L-plastin (LCP1) were verified by Western-blot analysis under 15nm SiO2 exposure in various concentrations. CONCLUSION: The exposure of 15 nm SiO2 can significantly reduce the cell proliferation and induce a down-regulation of membrane protein expression in HaCaT cells. PMID- 26591765 TI - [Distribution characteristics of atmospheric pollutants and their effects on human health in Lanzhou City]. AB - OBJECTIVE: To evaluate the distribution characteristics of atmospheric pollutants in Lanzhou City and their health-effects on daily respiratory disease hospital admissions. METHODS: Using the same period atmospheric pollutants (PM10, SO2 and NO2) data, meteorological data and daily respiratory disease hospital admissions data, from 2001 to 2009 in Lanzhou, to analysis of the distribution of three air pollutants(PM10, SO2 and NO2), and their correlation with meteorological factors. On this basis, a time series semi-parametric generalized additive model (GAM) was used to analyze the exposure-effect relationship between air pollution and daily respiratory disease hospital admissions. RESULTS: The concentrations of PM10 and SO2 showed a decreased trends during the study period of 9 years, and NO2 showed weakly fluctuations and remained substantially unchanged. The highest concentrations of the three pollutants were presented in the winter and the lowest value were presented in the summer. PM10 concentration monthly distribution was bimodal distribution, SO2 and NO2 were unimodal distribution. There were significantly correlation between meteorological factors and pollutants. The results showed that there was certain lag effect of three kinds of air pollutants on daily respiratory disease hospital admissions. The lag time of three air pollutants all were 0 - 6 day moving average (avg06). An increase of 10 ug/m in PM10, SO2 and NO2 were significantly associated with the excess risk (ER) of 0. 45%, 1. 35% and 3. 02% for all respiratory hospital admissions. CONCLUSION: The ambient NO2, SO2 and PM10 concentrations have an adverse effect on daily hospital admissions for respiratory diseases of residents in Lanzhou City. PMID- 26591766 TI - [Interaction of polymorphisms of monocyte chemoattractant protein-1 receptor CCR2 gene 190A/G, nicotinamide adenine dinucleotide phosphate oxidase subunit p22phox gene C242T and cigarette smoking increases the risk of nonalcoholic fatty liver disease]. AB - OBJECTIVE: To investigate the interaction of polymorphisms of monocyte chemoattractant protein-I (MCP-1) receptor CCR2 gene 190A/G, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit p22phox gene C242T and cigarette smoking in nonalcoholic fatty liver disease (NAFLD ). METHODS: The genetic polymorphisms of MCP-1 receptor CCR2 gene 190A/G and NADPH oxidase subunit p22phox gene C242T were analyzed by the technique of polymerase chain reaction restriction fragment length polymorphisms (PCR-RFLP) in peripheral blood leukocytes of 600 NAFLD cases and 600 healthy persons. RESULTS: The frequencies of 190A/G (GG) and C242T (TT) were 50. 17% and 50. 00% in NAFLD cases and 23. 83% and 24. 17% in healthy controls, respectively. There were significant differences in the frequencies between the two groups (chi2 = 88. 8462, P = 0. 0031, chi2 = 85. 8100, P = 0. 0039). The risk of NAFLD with 190A/G (GG) was significantly higher than those with 190A/G (AA + AG) (OR = 3. 2171, 95% CI 1. 9351 - 5. 2184). The individuals who carried with C242T (TT) had a high risk of NAFLD (OR = 3. 1379, 95% CI 1. 7973 - 5. 2362). Combined analysis of the polymorphisms showed that percentage of 190A/G (GG)/C242T (TT) in NAFLD and control groups was 39. 67% and 13. 00%, respectively (chi2 = 118. 3021, P =0. 0017). The people who carried with 190A/G (GG)/C242T (TT) had a high risk of NAFLD (OR =5. 0211, 95% CI 3. 1853 -7. 7926). The cigarette smoking rate of the case group was significantly higher than that in the control group (chi2 = 92. 2234, P = 0. 0025), smokers have a higher risk of lung cancer than non-smokers (OR = 3. 3032, 95% CI 1. 9147 -5. 7413 ), and statistic analysis suggested an interaction between cigarette smoking and 190A/G (GG) and C242T (TT) which increase risk of NAFLD (r = 3. 9983, r = 3. 8553 ). CONCLUSION: 190A/G (GG), C242T (TT) and cigarette smoking are the risk factors in NAFLD, and the significant interactions between genetic polymorphisms of 190A/G (GG), C242T (TT) and cigarette smoking added the risk of NAFLD. PMID- 26591767 TI - [A study of sub-healthy status of community residents and its relevant factors in Fuzhou City]. AB - OBJECTIVE: To evaluate the sub-healthy status of community residents and its main relevant factors. METHODS: The proportional stratified random sampling was selected to take the sample of 5000 community residents from two communities in Fujian province. The sub-healthy status and its main influence factors were measured with the method of physical examination and questionnaire. RESULTS: The women, the oldest group (>=60 years old) and the divorce/widowed group were found to have the higher scores of sub-health status than others (P <0. 05). Multivariate analysis showed that female, age, education level and irregular eating were the main risk factors for the three dimensions of sub-health status. Divorced or widowed statue was unfavorable factors for physical and psychological sub-health status. Quit smoking was found to be significant risk factor for psychological and social sub-health status. Body mass index (BMI) was related to physical sub-health status, alone. While physical exercise was the main protective factor for sub-health status. CONCLUSION: Improving behavioral habits, maintaining stable family, maintaining normal BMI may be important to prevent sub health status among community residents. PMID- 26591768 TI - [Cross-sectional association between foods rich in protein and body composition among children and adolescents in Chengdu City]. AB - OBJECTIVE: To examine the association between foods rich in protein and body composition among children and adolescents in Chengdu. METHODS: With cluster sampling, a total of 2029 children and adolescents aged 7 - 15 years were recruited in Chengdu as the participants. Information about consumption of foods rich in protein was collected from food frequency questionnaire and anthropometric measurement was conducted to calculate the indices of body composition, percentage of body fatness (BF%), fat mass index (FMI) and fat free mass index (FFMI). Wilcoxon signed rank test was used to compare BF%/FMI/FFMI between food intake groups. RESULTS: Among boys, compared with moderate and higher intake group of red meat, BF% was higher in the low intake group (P <0. 05). FFMI was highest in the higher intake group of red meat and white meat, however, in the lower egg intake group, FFMI was highest (P < 0. 05). Among girls, BF% and FMI were higher in the lower intake group of bean, fish, egg, dairy and dairy product than the moderate and high intake group (P <0. 05). FFMI was positively associated with consumption of red meat and was highest in-the lower intake group of egg and dairy (P <0. 05). CONCLUSION: Red meat intake is positively associated with fat free mass in boys and girls. Only in girls, the consumption of bean/fish/egg/dairy and dairy product is primarily associated with fat mass. The different influence between genders needs to be further studied. PMID- 26591769 TI - [Analysis on prevalence and influence factors of smoking and drinking among middle shool students of Tujia and Miao in Xiangxi Area]. AB - OBJECTIVE: To understand the prevalence and influence factors of smoking and drinking among middle shool students of Tujia and Miao in Xingxi Area. METHODS: By the method of layered, random and total sampling, questionnaire survey about smoking and alcohol drinking was taken to 2360 Tujia and Miao students. Logistic regression analysis was used to analyze the influence factors. RESULTS: The rates of try smoking and drinking were 39. 92% and 64. 87% . The rates of current smoking and drinking were 20. 04% and 26. 36%, the rates of smoking-drinking at the same was 12. 37%. The rates of start smoking and drinking before 13 years old were 30. 00% and 31. 95%. Logistic regression analysis result showed that the risk factors of current smoking were schoolboy (OR = 9. 765, P = 0. 000) and suicidal ideation (OR = 2. 139, P = 0. 000), the protective factors were city(OR = 0. 678, P = 0. 020)and school record (average OR = 0. 580, P = 0. 003,above average or good OR = 0. 477, P = 0. 002). The risk factors of current drinking were senior school (OR = 1. 438, P = 0. 005 ), Tujia (OR = 1. 784, P = 0. 000), mother' s degree of education(junior or senior school OR = 1. 330, P = 0. 045, college and above OR = 2. 938, P = 0. 000), depression (OR = 1. 570, P = 0. 004)and fight (OR = 1. 755, P =0. 000), the protective factor was school record (above average or good OR = 0. 646, P = 0. 019). The risk factors of smoking drinking at the same were schoolboy (OR = 7. 246, P = 0. 000), left-behind children (OR = 1. 412, P = 0. 023), lonely (seldom or sometimes OR = 1. 646, P = 0. 030, often or always OR = 2. 193, P = 0. 006), insomnia (often or always OR = 2. 396, P = 0. 001), depression (OR = 1. 552, P =0. 018), fight (OR = 3. 432, P = 0. 000)and suicidal ideation (OR = 1. 918, P = 0. 001),the protective factors were in dad mood (seldom or sometimes OR = 0. 362, P = 0. 000, often or always OR = 0. 386, P =0. 001) and school record (average OR =0. 587, P =0. 001, above average or good OR = 0. 354, P =0. 000). CONCLUSION: Tujia and Miao boys were more prone to smoking and smoking-drinking, the risk of smoking-drinking was significantly increased because of depression, fight and suicidal ideation, good school record was the protective factor of smoking, drinking and smoking drinking. PMID- 26591770 TI - [Analysis on the neglected conditions and influence factors of middle school students aged 12 to 17 years old in rural areas of Shaanxi Province and Chongqing City]. AB - OBJECTIVE: 10 learn about the neglected conditions and intuence factors of middle school students aged 12 to 17 years old in rural areas of Shaanxi Province and Chongqing City. METHODS: The scale and evaluation method formulated in "The Normal Value of Evaluation on the Neglect of Middle School Students from 12 to 17 Years Old in Rural China" was adopted. 2257 respondents among which there were 1157 male students and 1,100 female students in the rural areas of Shaanxi Province and Chongqing City were selected according to the principle of multi stage stratified cluster sampling. The severe degree of neglect was reflected through the indicator of neglect degree. The method of binary Logistic regression analysis was adopted to analyze the influence factors of neglect. Results The total neglect degree of respondents was (51. 80 +/- 9. 06). The neglect degree of middle school students in the rural areas of Chongqing was (53. 21 +/- 9. 03). The neglect degree of middle school students in the rural areas of Shaanxi was 50. 50 8. 90. The statistical significance was found in the difference between the two groups (U =6. 17, P <0. 01). The neglect degree of male students was (51. 93 +/- 8. 67) while the neglect degree of female students was (51. 66 +/- 9. 46). The statistical significance was not found in the difference between the two groups of total neglect degree of different sexes (U = 0. 60, P > 0. 05). The statistical significance was noticed in the differences of neglect degrees of middle school students in different grades at all levels (P <0. 05). The neglect degrees of junior three and senior three students were relatively high. Their total neglect degrees were (53. 54 +/- 9. 70) and (53. 36 +/- 8. 69) respectively. Except social neglect and safety neglect, there was statistical significance in the differences of neglect degrees of students with different family backgrounds at all levels (P <0. 01). The neglect degree of middle school students in a remarried family was the highest. The total neglect degree was (56. 92 +/- 8. 83). The factors influencing the neglect of middle school students were shown in the result of Logistic regression analysis, including the educational level of their fathers, whether they had a separate room, family types, whether the working places of their parents changed in one year, whether the incomes of their parents decreased in one year, their relationship with their parents and the relationship between their parents. CONCLUSION: The neglected conditions of middle school students in the rural areas of Shaanxi Province and Chongqing City are relatively severe and the factors influencing the neglect of children include the educational level of their fathers, whether they have a separate room, family types, whether the working places of their parents changed in one year, whether the incomes of their parents decrease in one year, their relationship with their parents and the relationship between their parents. PMID- 26591771 TI - [Analysis of family influence factors of quality of life about vision]. AB - OBJECTIVE: To explore the QOL About Vision of students and its family influence factors. METHODS: 4096 students and 3740 parents were chosen from 8 primary and middle schools by stratified cluster random sampling in the suburbs and the urban area of Chongqing, surveyed with questionnaire by a QOL about vision for primary and middle school students, Family factors questionnaire (including parents' education, occupation, be myopia or not,family economic status etc.). RESULTS: The total score of QOL about vision among boys (92. 13 +/- 12. 50) were more than girls > (90. 08 +/- 12. 82), more and more as grade-grouping (96. 39 +/- 9. 72 >90. 35 +/-12. 07 >83. 45 +/- 13. 46). The total score of rural students (91. 46 +/- 12. 87) were more than that of urban students > (90. 84 +/- 12. 54). The results for single factor analysis indicated that there were significant difference between different parents' degree of education,distance between eye and TV set, whether or not encouraging movement. The results of general linear regression analysis indicated that parents' degree of education and distance between eye and TV set were main factors which influence the students' QOL about vision. CONCLUSION: Family factors were main factors of QOL about vision.family should be one of the key intervention place. PMID- 26591772 TI - [Genome-wide association studies on the developmental dyslexia children]. AB - OBJECTIVE: To find out the potential polymorphisms of gene with developmental dyslexia children. METHODS: From January 2010 to December 2013, 121 cases children with developmental dyslexia and 117 cases health children as the control were enrolled into the study. The potential polymorphisms of gene were found by case-control study strategies based on the Affymetrix Genome-Wide SNP 6. 0 microarray and pathway analysis. RESULTS: Genotypes and allele frequencies of rs331142 and rs12495133 from DYX1C1 gene, rs11629841 and rs3743205 from ROBOl gene between cases and control groups were significantly different (P < 0. 05). CONCLUSION: Polymorphism of rs331142 and rs12495133 from DYX1C1 gene, rs11629841 and rs3743205 from ROB01 gene may associate with developmental dyslexia children. PMID- 26591773 TI - [Effect of occupational stress on neurotransmitters in petroleum workers]. AB - OBJECTIVE: To explore the effects of occupational stress on neurotransmitters in petroleum workers. METHODS: 178 petroleum workers with the length of service >= 1 year were recruited to the subjects by the questionnaire of OSI-R. The levels of 5-hydroxy tryptamine (5-HT), norepinephrine (NE), neuropeptide Y (NPY) and substance P (SP) in serum were measured. The subjects were classified into 3 groups according to the scores of occupational stress. RESULTS: The levels of 5 HT NE and SP for over 15 working years were higher than those of less than 15 years (P < 0. 05). There were differences (P < 0. 05) on 5-HT, NE, NPY and SP in different occupational stress degree groups, multiple comparison showed high. occupational stress group was higher than those of low occupational stress group. Multivariate correlation analysis showed that the occupational stress and sleep quality component scores correlated positively with the 5-HT, NE and SP (P < 0. 05) and correlated inversely with NPY in petroleum workers (P < 0. 05). CONCLUSION: Occupational stress in petroleum workers is correlated with serum monoamine and neuropeptides neurotransmitters, and it may affect serum levels of monoamine and neuropeptides neurotransmitters. PMID- 26591774 TI - [Survey and evaluation of heavy metal in the major vegetables in Shaanxi Province]. AB - OBJECTIVE: To evaluate the contamination condition of the Pb, Cd, Hg and As in ten kinds of vegetables in Shaanxi Province. METHODS: The Pb and Cd contents were determined by inductively coupled plasma mass spectrometry, and the As contents were determined by hydride generation-atomic fluorescence spectrometry, and the Hg contents were determined by mercury vapourmeter. One factor contamination index was employed to evaluate the metal pollution situation of different types of vegetables. Moreover, the health risk after intake of those heavy metals through vegetables were described. RESULTS: In ten kinds of vegetables of Shaanxi Province, the Pb contents in cowpea reached the alertness level, while the contents of Cd, Hg and As were below the safety level. What' s more, the contents of the Pb, Cd, Hg and As were below the safety level in other nine vegetables, and the over standard rate of were Hg > Pb > Cd > As. CONCLUSION: The contamination extents of Pb, Cd, Hg and As in ten kinds of vegetables in Shaanxi Province were low. PMID- 26591775 TI - [Survey on the status of health effects and relationship between indices of health effects of population in environment cadmium polluted area in Hezhang County, Guizhou Province]. AB - OBJECTIVE: To investigate health status of general population in environment cadmium polluted area in Hezhang County, Guizhou Province. Methods The subjects were selected by random sampling from the local resident. The urine samples were collected and detected for cadmium, N-acetyl-beta-D-glucosaminidase (NAG) and beta2-microglobulin (beta2-MG). ICP-MS (inductively coupled plasma-mass spectrometry) was used to determine Cd concentrations. beta2-MG was determined using radioimmunoassay. NAG and creatinine was measured by spectrophotometry. RESULTS: Urinary screening was carried out and 1351 urine samples were collected, 948 samples from polluted area and 403 samples from control area. There were significant difference for urine Cd between polluted and control population. The mean value of urinary Cd in polluted area and control area were 8. 79 ug/g Cr and 2. 93 ug/g Cr respectively, There was significant difference for Cd between pollution and control population(P <0. 05). The positive ratio of urinary Cd in polluted area and control area were 10. 8% and 1. 2% respectively. There were no significant difference for beta2-MG and NAG between pollution and control population. The cooperation positive rate of population in polluted and control area were 1. 6% and 0. 5% respectively. CONCLUSION: There were potential health risk in the environmental cadmium polluted area, Cd, beta2-MG and NAG should be used together to assess the health risk of environmental cadmium pollution comnletely. PMID- 26591776 TI - [Modification effects of ozone on the relationship between PM10 and daily mortality in three cities, China]. AB - OBJECTIVE: To estimate the modification effects of ozone on the relationship between PM10 and daily mortality. METHODS: Daily total non-accidental, cardiovascular and respiratory motality data in Beijing, Shanghai and Suzhou from 2001 to 2008 were collected from the Center for Disease Control and Prevention of each city. The concentration of PM10 and ozone and other Meteorology data during the study period were abtained from the national air quality monitoring network. A generalized additive model (GAM) were used to estimate the acute effects of air pollution on daily mortality in the three cities. The time-series method were applied to analyze the association between air pollution and daily mortality. In order to analyze the interaction effect between PM10 and ozone, ozone were stratified into three levels (<=5% . as low from 5% - 95% . as moderate, >95%, as high) and then analyzed the effect of PM10. A Meta analysis was used to describe the effect of PM10 in all the cities. RESULTS: With the increment of ozone, PM10 corresponded to an increase of total, cardiovascular and respiratory mortality in Beijing, Shanghai and Suzhou. The result of the Meta analyses showed that on the days of "low" ozone, a 10 ug/m3 increment in PM10 corresponded to a 0.47% (95% CI - 0. 74%, 1. 67%) decrease in total mortality, 0. 36% (95% CI - 0. 59%, 1. 31%) decrease in cardiovascular mortality, and 0. 69% (95% CI - 0. 52%, 1. 90%) decrease in respiratory mortality. When it was moderate, the increment was 0.45% (95% CI 0. 26%, 0. 63%), 0. 16% (95% CI - 2. 26%, 1. 95%) and 0. 57% (95% CI 0. 13%, 1. 02%). The increment was 0. 82% (95% CI 0. 24% , 1. 39%), 0. 37% (95% CI 0. 07%, 0. 66% ) and 1. 13% (95% CI - 0. 67% , 2. 92%) while the.zone was high. CONCLUSION: Ozone could modify the effect of PM10 on the daily mortality. PMID- 26591777 TI - [The lipid metabolism based on the energy metabolism technology in obese mice induced by a high-fat diet]. AB - OBJECTIVE: To ingvestigate effects of long-term high-fat diet on the energy and lipid metabolism. METHODS: 20 SPF male C57BL/6 mice were randomly divided into a control group fed a basic diet and a high-fat group fed a high-fat diet. Indirect calorimetry measurement was done to mearue total energy expenditure and metabolism in the mice at the 12th week. Multi-row quantitative CT was applied to detect body fat content and distribution in the mice. At the end of the experiment the mice were killed, and blood and liver were collected to detect the bio6hemical and histopathological indicators. RESULTS: In comparison with the control group, the mice fed high-fat diet increased energy intake, body and visceral fat content and levels of fatty acid oxidation were significantlyincreased (P <0. 05). Fasting blood glucose, blood lipid, insulin and fatty acid content in liver and serum were significantly higher than those in the control group(P <0. 05). Pathology examinations showed hepatocytes steatosis, mitochondria and other organelles structural damage in the high-fat mice. CONCLUSION: Long-term high-fat diet can lead to excessive energy intake, lipid dysmetabolism, abdominal obesity, hyperlipidemia, fatty liver and insulin resistance. PMID- 26591778 TI - [Effect of high-fat diet and food restriction on energy metabolism in obesity prone and obesity-resistant rats]. AB - OBJECTIVE: To explore the effect of high-fat diet and food restriction on energy metabolism in obesity-prone (OP) and obesity-resistant (OR) rats. METHODS: Sixty male Sprague-Dawley (SD) rats were divided into OP, OR and control groups according to their body weight gain after fed with high-fat diet for 3 wk. OP and OR groups were fed with high-fat diet in the following 12 wk to promote the development of obesity. Then one-half of the rats of each group began to food restriction and were allowed access to 50% of their individual baseline mean daily food intake each day, while the other half were maintained on ad libitum food for 2 wk. Basal metabolic rate (BMR), resting metabolic rate (RMR) of each group were measured by indirect calorimetry during the high-fat diet feeding and food restriction conditions. After the rats were sacrificed, body fat content was measured. RESULTS: OR rats had significantly higher BMR and RMR than the other two groups during high-fat diet feeding condition. There was no significant difference between OP and control group. Food restriction led to a reduction in BMR and RMR in all groups. OR rats showed a significantly greater reduction. OP group showed a significant decrease in body fat weight and fat content during the food restriction period, while there was no significant differences in OR rats. CONCLUSION: There are significant differences between OP and OR rats in BMR and RMR either in high-fat diet feeding condition or food restricted state. OR rat has the ability to sense and respond to energy imbalance more accurately than OP rat. PMID- 26591779 TI - [Effect of four kinds of drinking water on hepatic and renal function and zinc and iron concentrations of different organs in mice]. AB - OBJECTIVE: To explore the effect of different drinking water on hepatic and renal function and zinc and iron concentrations of different organs in mice. METHODS: Zinc and iron concentrations were measured in pure water, tap water, mineral water and filtered tap-water, respectively. 80 ICR mice (half male and half female) were randomly divided into four groups and fed with pure water (control group), tap water, mineral water and filtered tap-water, respectively. After 90 days, blood samples were taken from the eyeballs of mice. The contents of serum ALT, TP, BUN, UA and Cr were analyzed. Then mice were killed and livers, kidneys, hearts, pancreas, brains were removed immediately to determinate zinc and iron concentrations. Simultaneously morphological changes of liver and kidney paraffin section were observed. RESULTS: Contents of serum Cr in filtered tapwater group (36. 00 +/- 8. 83 umol/L) were lower than those of pure water group(44. 83 +/- 12. 64 umol/L), tap water group (44. 56 +/- 10. 52 umo/L) and mineral water group (43. 79 +/- 10. 53 umol/L) (P < 0. 05). The zinc concentrations of livers and kidneys (33. 17 +/- 6. 18 and 16. 69 +/- 8. 12 ug/g) in pure water group was lower than that of filtered tap-water group 45. 31 +/- 7. 32 and 22. 61+/- 6. 01ug/g) P < 0. 05). A significant negative correlation (r = - 0. 300) emerged between the serum Cr and the zinc concentration of kidney in mice P < 0. 05). CONCLUSIONN: Long-term drinking filtered tap-water is beneficial to the glomerular filtration barrier, and it may be related to the increase of zinc levels in kidney. PMID- 26591780 TI - [Measurement and analysis of oxidative stress-related elements in blood components of chronic unpredictable mild stress rats]. AB - OBJECTIVE: To study the effects of chronic unpredictable mild stress (CUMS) on the concentrations and distribution of elements related to oxidative stress in plasma and erythrocyte. METHODS: The rats were randomly divided into two groups, CUMS group and the control. The CUMS group received 28 days stress. Then 17 kinds of elements in plasma and erythrocyte were detected and the correlation ships between elements were analysed, then make comparison between two groups. RESULTS: The concentrations of Mo and B in plasma and Se in erythrocyte were higher in CUMS group than control (P <0. 05). The levels of Sn, Cr, Th and T1 in plasma as well as Mn and Pb in erythrocyte were lower in CUMS group (P < 0. 05). The strength and direction of correlation ships between elements were changed in CUMS group. There had a negative correlation with Fe in plasma in control (r = - 0. 581, P = 0. 018), but a positive correlation in CUMS (r = 0. 473, P = 0. 035), the same with Th-Mg (control: r = - 0. 610, P = 0. 012; CUMS: r = 0. 596, P = 0. 006). CONCLUSION: Concentrations and distribution of elements related to oxidative stress are changedby CUMS, most of the elements increased are related to anti-oxidative stress, while the reduced elements are prooxidative stress. PMID- 26591781 TI - [Inhibitory effect on Microcystis aeruginosa as well as separation and identification of the allelochemicals of Allium cepa]. AB - OBJECTIVE: To uncover the inhibition of Allium cepa (onion) on Microcystis aeruginosa, and identify the allelochemicals in onion. METHODS: The inhibition of different concentrations of onion bulb and onion leaf water extracts on M. aeruginosa were investigated, and the allelochemicals of onion bulb were extracted and identified by organic solvent and GC-MS, repectively. RESULTS: Both onion bulb and onion leaf water extracts had, to different degree, inhibitory effect on the growth of M. aeruginosa. Compared with the control group, the onion bulb and onion leaf extracts treatment groups were lower than the control group in the same period, and the inhibitory effect were more obvious with the increase of the water extract concentrations. The inhibition ratios of water extracts from onion bulb to M. aeruginosat were 100% on the fifth day, except 5 ml/L water extract treatment group. And the inhibition ratio of 40 ml/L water extract treatment group from onion leaf to M. aeruginosat was 97. 4% on the sixth day. The main allelochemicals in onion includes tris (hydroxymethyl) nitromethane, nonanoic acid, capric acid and methane sulfonic anhydride. CONCLUSION: The inhibition of onion bulb water extracts on Microcystis aeruginosa are very strong and better than onion leaf water extracts. PMID- 26591782 TI - [The cardiac injury effect of microwave radiation on rabbit and its mechanism]. AB - OBJECTIVE: To investigate the cardiac injury effect of different intensities microwave radiation on rabbits and its possible mechanism. METHODS: Rabbits were radiated by intensity of 50, 100, 150 and 200 mW/cm2 2450 MHz microwave for 20 min. 6 h after microwave radiation, the heart tissue was taken. ATP and mitochondria complex IV and V were measured in myocardial cells. The changes of myocardial tissue were observed by light microscopic. The expression of Caspase-3 and HSP 70 were detected by western blotting. RESULTS: The activity of ATP and mitochondria complex IV and V decreased significantly compared with normal control in cardiac tissue. 100, 150 and 200 mW/cm2 microwave radiation group vs. control group (P <0. 05). The HE staining result showed that myocardial cell appears edema, muscle fiber malalignment, cells appeared obvious injury. Results of western blotting showed that the expression of Caspase-3 and HSP 70 protein increased significantly in different dosage radiation group (P <0. 05). CONCLUSION: Microwave radiation has injury effect on rabbit heart. The possible mechanism may be related with inducing cell apoptosis by changing of stress level in myocardial cell. PMID- 26591783 TI - [Dietary intake and risk assessment of diisononyl phthalate (DINP) in Chinese population]. AB - OBJECTIVE: To study DINP concentration level in the main food, evaluate DINP dietary intake level in Chinese population and its potential health risks. METHODS: Based on the deterministic assessment model, using concentration level of 25 kinds of food in 2011 - 2013 and Chinese national nutrition and health survey data in 2002, to calculate dietary intake of DINP in Chinese population. RESULTS: The average DINP concentration level in 24 kinds of foods was 0. 24 mg/kg, and the maximum value was 9. 55 mg/kg. In whole population, average dietary intake of DINP was 4. 39 ug/kg bw per day, only 2. 93% of TDI. The dietary intake of DINP in children aged 2 to 6 years old was highest, with an average of 8. 91 ug/kg bw per day, 5. 94% of the TDI. The dietary intake of DINP in children aged 7 to 12 years old was lower than 2 to 6 years old children, with an average of 6.53 ug/kg bw per day, 4. 35% of TDI. The dietary intake of DINP in high consumer(P97. 5) in all population was 8. 35 ug/kg bw per day, 5. 57% of the TDI. The range of dietary intake of DINP in high consumer (P97. 5) in each group (grouping by gender and age) was from 13. 84 to 5.44 ug/kg bw per day, which were all lower than the TDI. CONCLUSION: The dietary intake of DINP in different populations is considerably below the TDI and any health risk that would be expected to occur at this intake level is negligible. PMID- 26591784 TI - [Women and women's health]. PMID- 26591785 TI - [Women, forgotten by clinical research]. AB - For years, women were underrepresented in clinical studies. But the effect of many drugs differ among women and men, due to pharmacokinetic and pharmacodynamic differences. As a result, there is a lack of information on therapeutic or adverse effets of drugs and, more generally, a lack of knowledge on diseases, leading more frequently to sub-optimal medical care in women. This underrepresentation is due to various factors, including the social role of women or ethical issues about pregnancy. The need for adequate representation of women in clinical studies is a social as well as medical concern, that implies political and legal changes. PMID- 26591786 TI - [Preconceptuel evaluation and treatement of intercurrent diseases-follow up of pregnancies in the doctor's office]. AB - Preconceptional evaluation should be extended to all women in reproductive age. It includes, among others, screening for infections, evaluation of immunity against infectious agents detrimental to the fetus and, in high risk cases, detection of genetically transmitted diseases. Furthermore, any medication needs to be evaluated for potential embryotoxicity and teratogenicity. During pregnancy, diseases that may appear trivial in other circumstances can become complex due to the potentially harmful secondary effects of medication and radiodiagnostic tests on the motherand fetus. Knowledge not only of the list of drugs that can be safely used during pregnancy, but also of their special dosages, as well as of the potential risks of radiation of radiologic tests is essential to good clinical management. PMID- 26591787 TI - [Contraception and abortion: an update in 2015]. AB - Family doctors can play an important role in preventing unplanned pregnancies. This article addresses the different contraceptives methods available in Switzerland, which are classified in 2 groups and recommends using the GATHER approach (Greet, Ask, Tell, Help, Explain, Return) to promote compliance. LARC (long acting reversible contraceptives) can be recommended to any woman who needs a reliable birth control method. These contraceptives require minimum effort for high efficiency. Further explanation regarding the use of an emergency contraception must be provided when short action contraceptives are chosen. Switzerland's abortion rate is one of the lowest in the world. Medical abortion tends to be more and more prominent. Under certain circumstances, it can be self administered at home. PMID- 26591788 TI - [Women and mental health]. AB - Women's mental health is determined not only by individual factors, in which genetics and hormones play a role, but also by relational and community factors. Women of any age more frequently suffer from certain mental disorders and have more comorbidity rates. Specificities in women exist in clinical presentations, as well as in the use of psychotropic medication, the incidence of side effets and in adherence to care. The role of primary care physicians is crucial for the prevention and detection of mental disorders in women, particularly in vulnerable ones, as well as in their psychological support, organization and continuity of care. A comprehensive approach is required, which includes measures against isolation, insecurity, stigmatization and inequality. PMID- 26591789 TI - [Causes of death in woman, between heart and cancer]. AB - Cardiovascular diseases are the first cause of death in women, while cancers come second. Increased tobacco use in women causes a higher incidence of both lung cancer and cardiovascular diseases. The end of the hormonal substitution, since it was identified as increasing breast cancer risk, has produced a decreased incidence of the later, while cardiovascular diseases keep increasing after menopausal. These examples highlight the necessity of medical studies taking into consideration women specificities, as well as of an individual weighting of risk factors by physicians. PMID- 26591790 TI - [Fifty feminine shades of domestic violence: time for doctors to get involved!]. AB - Domestic violences are very common and constitute a criminal offence. Women are mainly victims but can also be perpetrators. Domestic violences have a major health impact on people, families and society. The primary care physician holds a major role in the targeted detection of domestic violences and their prevention. He must know their specificities and adapt his response according to the situations. This specific response does not prevent a rational approach: we propose to distinguish between different types of women's vulnerability. Management must involve an efficient network taking into account individual, family, community and social factors. In this context, use of regularly updated information from official websites is mandatory. PMID- 26591791 TI - [Which treatment choose for menopause? Representations and uses of French Speaking Switzerland women]. AB - In medical literature, menopause is defined as a hormone deficiency which creates many inconveniences and even pathologies that need to be treated. Based on in depth interviews with 21 women coming from French-Speaking Switzerland, this article, in a socio-anthropological perspective, looks at the use by women of the available therapies. It shows that the management practices are diversified and differ according to menopause representations, prevalence of menopause symptoms, but also depending on the benefits and disadvantages attributed to either therapy. Surprisingly, the Hormone replacement, although perceived as the most efficient therapy is not the most used due to the harmful effects that many women associate to it. PMID- 26591792 TI - [Doubt is useful!]. PMID- 26591793 TI - [Anti-HPV vaccines: they are proven to be safe and do not provoke autoimmune diseases]. PMID- 26591794 TI - [What's hidden behind the troubling hypothesis of Alzheimer's disease transmission?]. PMID- 26591795 TI - [Mindfulness based cognitive therapy, a real alternative to antidepressants treatment to prevent relapse?]. PMID- 26591796 TI - [Mr. Fignon, we found cancer cells...metastases...]. PMID- 26591797 TI - [Interdisciplinary health care team: yes! drunken bathtub: no!]. PMID- 26591798 TI - The company we keep. PMID- 26591799 TI - Prepare your practice for a meaningful use audit. PMID- 26591800 TI - RACs await new contracts: What your practice needs to know now. PMID- 26591801 TI - Benchmarking 501: Graduate studies in cost allocation. PMID- 26591802 TI - New Medicare CCM essentials guide includes beneficiary consent form. PMID- 26591803 TI - Going solo as a nurse-managed practice. PMID- 26591804 TI - Map out payment collection steps to ID opportunities for improvement. PMID- 26591805 TI - LINKS in a CHAIN. Cultural shifts increase transparency among physicians and improve patient scores. PMID- 26591806 TI - 20-20 hindsight: Choosing hospital employment and returning to independence. PMID- 26591807 TI - Drawing outside the lines. A new crop of doctors focuses on root of patients' issues to curtail spending, improve outcomes. PMID- 26591808 TI - Changes in acquisition patterns. Health systems rely on due diligence, physician engagement to ensure successful alignment. PMID- 26591809 TI - Translating data into honest, relevant information that affects patient care. PMID- 26591811 TI - Does being hired as a practice administrator mean you're a building manager, too? PMID- 26591810 TI - Where alignment meets success: Physician-hospital leadership communities. New skills required for true leadership. PMID- 26591812 TI - Diving into tranquility, staying calm and smart in choppy waters. PMID- 26591813 TI - Historical Perspectives on Fresh Air, Sunshine, and Public Health. PMID- 26591814 TI - Children of the Sun: Heliotherapy and Tubercular Children. PMID- 26591815 TI - Nursing on the Boston Floating Hospital. PMID- 26591816 TI - Genetically Modified Foods at the Intersection of the Regulatory Landscape and Constitutional Jurisprudence. AB - An ecosystem...[y] ou always intervene and change something in it, but there's no way of knowing what all the downstream effects will be or how it might affect the environment. We have such a miserably poor understanding of how the organism develops from its DNA that I would be surprised if we don't get one rude shock after another. PMID- 26591817 TI - Inappropriate Referral: The Use of Primary Jurisdiction in Food-Labeling Litigation. PMID- 26591818 TI - The Implementation of the Food Safety Modernization Act and the Strength of the Sustainable Agriculture Movement. AB - In the wake of growing public concerns over salmonella outbreaks and other highly publicized food safety issues, Congress passed the FDA Food Safety Modernization Act in 2011, which placed more stringent standards on food growing and packaging operations. In negotiations preceding the Act's passage, farmers of local, sustainable food argued that these rules would unduly burden local agricultural operations or, at the extreme, drive them out of business by creating overly burdensome rules. These objections culminated in the addition of the Tester-Hagan Amendment to the Food Safety Modernization Act, which created certain exemptions for small farms. Proposed Food and Drug Administration (FDA) rules to implement the Act threatened to weaken this victory for small farm groups, however, prompting a loud response from small farmers and local food proponents. The FDA's second set of proposed rules, issued in September 2014 in response to these and other complaints, were, perhaps surprisingly, responsive to small farmers' concerns. Using comments submitted to the FDA, this article explores the responses of the agriculture industry and public health organizations, as well as small farm groups, consumers of local food, and sustainable agriculture interests (which, for simplicity, I alternately describe as comprising the "sustainable agriculture" or "small farm" movement), to three aspects of the FDA's proposed rules--involving manure application, on-farm packing activities, and exemptions for very small farms--to assess the strength of the sustainable agriculture movement. The rules involving manure application and on-farm packing, it turns out, reveal little about the independent political strength of the local food movement, as large industry groups also objected to these provisions. But for the third issue discussed here--exemptions for very small farms--the interests of sustainable agriculture groups were directly opposed to both industry and public health organizations, and yet prevailed. This suggests that the high salience of locavore and "slow food" issues might have allowed relatively small, dispersed interests to overcome traditional obstacles to political organization, and that the sustainable agriculture movement has indeed become an effective political force. PMID- 26591819 TI - The Illusion of Autonomy in "Food" Litigation. PMID- 26591820 TI - Deregulation, Distrust, and Democracy: State and Local Action to Ensure Equitable Access to Healthy, Sustainably Produced Food. AB - Environmental, public health, alternative food, and food justice advocates are working together to achieve incremental agricultural subsidy and nutrition assistance reforms that increase access to fresh fruits and vegetables. When it comes to targeting food and beverage products for increased regulation and decreased consumption, however, the priorities of various food reform movements diverge. This article argues that foundational legal issues, including preemption of state and local authority to protect the public's health and welfare, increasing First Amendment protection for commercial speech, and eroding judicial deference to legislative policy judgments, present a more promising avenue for collaboration across movements than discrete food reform priorities around issues like sugary drinks, genetic modification, or organics. Using the Vermont Genetically Modified Organism (GMO) Labeling Act litigation, the Kauai GMO Cultivation Ordinance litigation, the New York City Sugary Drinks Portion Rule litigation, and the Cleveland Trans Fat Ban litigation as case studies, I discuss the foundational legal challenges faced by diverse food reformers, even when their discrete reform priorities diverge. I also 'explore the broader implications of cooperation among groups that respond differently to the "irrationalities" (from the public health perspective) or "values" (from the environmental and alternative food perspective) that permeate public risk perception for democratic governance in the face of scientific uncertainty. PMID- 26591821 TI - Transparency for Food Consumers: Nutrition Labeling and Food Oppression. PMID- 26591822 TI - What's in Store: A Vision for Healthier Retail Environments through Better Collaboration. PMID- 26591823 TI - Addressing Consumer Confusion Surrounding "Natural" Food Claims. PMID- 26591824 TI - Dietary Supplements are Not all Safe and Not all Food: How the Low Cost of Dietary Supplements Preys on the Consumer. AB - Dietary supplements are regulated as food, even though the safety and efficacy of some supplements are unknown. These products are often promoted as 'natural.' This leads many consumers to fail to question the supplements' safety, and some consumers even equate 'natural' with safe. But, 'natural' does not mean safe. For example, many wild berries and mushrooms are dangerous although they are natural. Another example is tobacco--a key ingredient in cigarettes: it is natural, but overwhelming studies have established the harm of cigarette smoke. The Food and Drug Administration (FDA) requires safety and efficacy testing prior to market entry for drugs. In contrast, the FDA only has limited ability to regulate the entry of new dietary supplements into the marketplace because supplements are treated as food. Two main arguments support the current regulatory structure of dietary supplements: (1) cost and (2) access. But lower cost and increased access to dietary supplements do not necessary have any relationship to safety and efficacy. Manufacturers' marketing techniques tout the health benefits of their supplements. Meanwhile, consumers are ingesting supplements without scientific studies indicating whether or not they are harmful. The FDA Food Safety and Modernization Act, signed into law on January 4, 2011, did not address the safety concerns regarding dietary supplements. This article discusses the regulatory deficiencies concerning dietary supplements and proposes novel solutions to address this specific sector of the food supply. This article advocates for the use of scientific data to support a multi-tiered classification system to ensure that dietary supplements on the market are safe. PMID- 26591825 TI - The Food Safety Modernization Act: Implications for U.S. Small Scale Farms. AB - The Food Safety Modernization Act (FSMA) reforms law governing the safety of human and animal foods produced for consumption in the United States. Recognizing the challenges that the proposed regulations would impose on small farms, Congress included an amendment to exempt small farms from the full scope of FSMA requirements. This special treatment and other issues left unaddressed by FSMA, however, present challenges for buyers of small farm products and is inducing a private sector response to these regulatory gaps. This Article reviews the current treatment of small farms under FSMA and explores some key impacts and implications of FSMA on these organizations. Particular consideration is given to the unintended consequences of the Tester-Hagan Amendment and the unaddressed issue of liability for foodborne illness. PMID- 26591826 TI - The Codex Alimentarius Commission, Corporate Influence, and International Trade: A Perspective on FDA's Global Role. PMID- 26591827 TI - A Coordinated Approach to Food Safety and Land Use Law at the Urban Fringe. AB - Much has been written about the rise of the local food movement in urban and suburban areas. This essay tackles an emerging outgrowth of that movement: the growing desire of urban and suburban dwellers to engage rural areas where food is produced not only to obtain food but also as a means of tourism and cultural activity. This represents a potentially much-needed means of economic development for rural areas and small farmers who are increasingly dependent on non-farm income for survival. The problem, however, is that food safety and land use laws struggle to keep up with these changes, waffling between over-regulation and de regulation. This essay posits a legal path forward to steer clear of regulatory extremes and to help the local food movement grow and prosper at the urban fringe. We must cultivate our garden. PMID- 26591828 TI - Whole Foods: The FSMA and the Challenges of Defragmenting Food Safety Regulation. PMID- 26591829 TI - If FDA Does Not Regulate Food, Who Will? A Study of Hormones and Antibiotics in Meat Production. PMID- 26591830 TI - Repositioning Generics: The Comparative Value of Liability in FDA's Proposed Rule on Labeling. PMID- 26591831 TI - Let Fear Reign. PMID- 26591832 TI - Clinicopathologic Review: LINEAR FISSURED ULCERATIONS IN THE ORAL CAVITY. PMID- 26591833 TI - Dr. Stephen T. Radack III Addresses the Annual Meeting. PMID- 26591834 TI - Dr. Linda Himmelberger receives PDA Distinguished Service Award. PMID- 26591835 TI - Dr. David Russell Honored with PDA Public Service Award. PMID- 26591836 TI - Dr. Steven Jefferies Honored with PDA Recognition Award. PMID- 26591837 TI - Dr. Wade I. Newman, Incoming President, Addresses PDA's Annual Meeting. PMID- 26591838 TI - Meet Your PDA President--Dr. Wade Newman. PMID- 26591840 TI - ICD-10: CRUNCH TIME. PMID- 26591839 TI - CMS Intros ICD-10 Coordination Center, Ombudsman Role. PMID- 26591841 TI - KNOW MORE, MANAGE BETTER. PMID- 26591842 TI - FROM PROMISE TO PRACTICE - TO PRODUCING RESULTS. PMID- 26591843 TI - ROUNDTABLE: RESOLVING TERMINOLOGY CONFLICTS. PMID- 26591844 TI - Population Maven. PMID- 26591845 TI - Current Perceptions and Practices (KAP) about Leprosy among Leprosy Patients: A Comparative Study between High Prevalent & Low Prevalent Districts of West Bengal. AB - A cross sectional observational study was conducted to assess knowledge, attitude and practices about leprosy among leprosy patients in six districts of West Bengal. Total patients selected for the study were 300; of them 185 patients were from three high prevalent districts and 115 from three low prevalent districts of West Bengal. 56.33% patients were male and 43.67% were female. Most of the patients (85.67%) belonged to Hindu community and 60% from socially backward group. 64.33% patients lived below poverty line. Thirty five percentage of patients had correct knowledge that leprosy is caused by a bacteria. Patients from high prevalent districts (41.62%) have better knowledge than those from low prevalent areas (26.09%). Difference was found to be statistically significant (p = 0.006). Correct knowledge about spread of leprosy through cough & sneezing, of the patients from high prevalent districts (30.81%) was more than those from low prevalent districts (14.78%) (p = 0.001). 74.05% patients from high prevalent districts could tell one or other forms of clinical presentation of a leprosy patients, while 56.52% from low prevalent areas could mention it correctly (p = 0.01). About infectiousness, duration of treatment, complications, patients from high prevalent districts showed better knowledge that those from low prevalent districts. Similarly, Attitude of the patients towards leprosy was found to be more adverse in low prevalent areas. 90% patients have idea that leprosy was curable, but only 51.67% patients heard about MDT. Place of residence (high prevalent districts) & level of education (secondary & above) attributed to better knowledge score of the patients, whereas Place of residence (high prevalent districts) & age (younger age group) attributed to better attitude score of the patients. PMID- 26591846 TI - Saliva as a Diagnostic Tool for Measurement of Total Antioxidant Capacity in Children with Leprosy and Born to Leprosy Parent. AB - The aim of the study is to assess the role of saliva as a diagnostic tool for measurement of total antioxidant capacity in children with leprosy and children born to leprosy parent. One hundred fifty children in the age group of 4-15 years were split into three equal groups: children with leprosy (CL) and children born to leprotic parents (CLP) and healthy children. Vitamin C level was measured in saliva of children spectrophotometrically at 695nm by Phosphomolybdenum method. Data were determined with student's unpaired t test and one way ANOVA. The result of the study showed that children with leprosy exhibited significantly decreased salivary total antioxidant capacity as compared to healthy controls. Antioxidant Vitamin C was higher in the Paucibacillary leprosy (PB) than those of Multibacillary type (MB) (P < 0.001). As age advanced, there was a gradual increase in total antioxidant capacity in both the control and study groups and the results were highly significant statistically. Saliva is an easy medium. PMID- 26591847 TI - Unusual Presentation of Necrotic Erythema Nodosum Leprosum on Scalp: A Case Report. AB - Lepra reactions are acute episodes occurring during the disease process of leprosy and are of 2 types: type 1 or reversal reaction and type 2 reaction or erythema odosumleprosum (ENL). In the episodes of lepra reaction several parts are affected including face and extremities like oral cavity. In the present case report we reported a rare case of lepromatous leprosy with necrotic ENL involving scalp apart from the usual sites. A 58 year old married male presented to us with complaints of spontaneous onset, recurrent eruption of multiple reddish raised painful lesions. Biopsy from the infiltrated skin over the back showed atrophic epidermis, free Grenz zone, diffuse and periadnexal macrophage granulomas with predominant mononuclear infiltrate, appandageal atrophy, fibrosis around the neural structures and leukocytoclastic vasculitis. Fites stain showed strong positivity for M. leprae. His routine blood investigations showed anemia (Hb = 7.8 gm%), neutrophil leukocytosis (TLC = 17,600, DLC = P66L28M4E2) and raised ESR (80 mm in the first hour). These bullous and necrotic lesions in leprosy may be a manifestation of severe type II reactions in patients with very high bacillary load. PMID- 26591848 TI - Lepromatous leprosy: An Unusual Presentation. AB - A 25 year old man presented with loss of sensations over both hands and feet and extreme difficulty in passing urine. On examination, an indurated sclerotic plaque was present on shaft of penis and scrotum in addition to other features of lepromatous leprosy. Skin biopsy from the penile lesion showed presence of a large number of acid fast bacilli with a BI of 6+ extending into the epidermis and histopathology showed absence of Grenz zone and presence of foamy macrophages in the dermis up to the dermo-epidermal junction. PMID- 26591849 TI - Does Leprosy Need a Stronger Surveillance System Now? A point of view article. AB - Multi Drug Therapy (MDT) for leprosy was introduced by WHO in 1982 and the programme has been implemented for more than 3 decades. The main presumption out of the PR based elimination was that with reduction of disease load below 1 per 10000 persons, the transmission of leprosy would be arrested resulting in disappearance of the disease. MDT made the disease description, definition and epidemiological indicators so different that it ceases to be like any other disease. To eliminate the leprosy totally from the country needs following activities: 1. Scaling up of some sentinel sites (SS) to surveillance units (SUs), 2. Source of information, 3. Authentication and standardisation, 4. Generation of own data, 5. Need for a skin smear laboratory, 6. Promoting referral of suspects for DST. PMID- 26591850 TI - THE IMPORTANCE OF DIETARY CARBOHYDRATE IN HUMAN EVOLUTION. AB - ABSTRACT We propose that plant foods containing high quantities of starch were essential for the evolution of the human phenotype during the Pleistocene. Although previous studies have highlighted a stone tool-mediated shift from primarily plant-based to primarily meat-based diets as critical in the development of the brain and other human traits, we argue that digestible carbohydrates were also necessary to accommodate the increased metabolic demands of a growing brain. Furthermore, we acknowledge the adaptive role cooking played in improving the digestibility and palatability of key carbohydrates. We provide evidence that cooked starch, a source of preformed glucose, greatly increased energy availability to human tissues with high glucose demands, such as the brain, red blood cells, and the developing fetus. We also highlight the auxiliary role copy number variation in the salivary amylase genes may have played in increasing the importance of starch in human evolution following the origins of cooking. Salivary amylases are largely ineffective on raw crystalline starch, but cooking substantially increases both their energy-yielding potential and glycemia. Although uncertainties remain regarding the antiquity of cooking and the origins of salivary amylase gene copy number variation, the hypothesis we present makes a testable prediction that these events are correlated. PMID- 26591851 TI - HOW DO MICROBIAL POPULATIONS AND COMMUNITIES FUNCTION AS MODEL SYSTEMS? AB - Microbial model systems have made major contributions across the life sciences. Their influence extends beyond strictly microbiological research to inform and enhance general biological understanding. To cast light on how microbial populations and communities function as model systems, we examine their use in historical and contemporary research on evolutionary and ecological dynamics. We assess the pros and cons of microbial model systems, and identify specific ways in which they benefit research. Analyzing microbial model systems is of particular value as biologists become increasingly aware of the microbial world and its interactions with the rest of life. PMID- 26591852 TI - HUMAN ALTRUISM AND COOPERATION EXPLAINABLE AS ADAPTATIONS TO PAST ENVIRONMENTS NO LONGER FULLY EVIDENT IN THE MODERN WORLD. AB - Evolutionary theory predicts rigorous competition in nature and selfish behavior is thus seen as its inevitable consequence. Evidence of altruistic and cooperative behavior therefore appears at odds with evolutionary theory. However, evolutionary psychology suggests that past environments may be different from the current environments that humans inhabit. Here it is hypothesized that competition in two past environments might have led to strategies that favored altruism and cooperation toward nonkin. First, the expansion of the human brain is seen as requiring long-term, quality parental investment to sustain it. Altruistic displays could well have signaled an ability and willingness to provide such parental investment in a potential mate and been favored as a result. Second, the development of extra-somatic weapons is seen as leading to competition within hominin groups becoming more costly as disputes would have become lethal. A cooperative strategy could have achieved greater net fitness if the benefits of reduced involvement in such lethal disputes exceeded the costs of cooperation. Genes associated with human altruism and cooperation toward nonkin could thus have increased infrequency and come to be expressed in modern human populations despite the environments in which they evolved no longer being fully evident in the modern world. PMID- 26591853 TI - [ENDOSCOPIC RESECTIONS FOR BENIGN TUMORS OF DUODENAL PAPILLA MAGNA]. AB - The results of endoscopic interventions, performed in 63 patients, suffering benign tumors of duodenal papilla magna (DPM) in Department of Laparoscopic Surgery and Choledocholithiasis in 2005-2014 yrs, were studied. Total one-staged papillectomy was performed in 15 patients, fragmentary total papillectomy--12, local resection of DPM--11, adenomectomy--25. Complicated have had occur in 8 (12.7%) patients. All the patients are alive. PMID- 26591854 TI - [RANDOMIZED CONTROLLED COMPARATIVE INVESTIGATION OF EFFICACY OF LAPAROSCOPIC PLICATION OF BIG GASTRIC CURVATURE AND LAPAROSCOPIC SLEEVE GASTRECTOMY]. AB - Laparoscopic plication (LP) of gastric big curvature (GBC) constitutes a new bariatric restrictive procedure, which has mechanism quite similar to that of a laparoscopic sleeve gastrectomy (LSG), but without danger for the sutures insufficiency development. The efficacy and safety of LSG and LP GBC were compared. Analysis of complications, the body mass (BM) index loss, an extra BM loss, an appetite loss, severity of the concomitant diseases course was conducted in accordance to results of the repeat examination. In 2 yrs the loss of extra BM have constituted the loss of an extra BM, accordingly, (42.4 +/- 18) and (78.9 +/ 20)%; in 3 yrs - (28.5 +/- 23) and (72.8 +/- 22)%. Thus, LP GBC is less effective, then LSG, in the treatment of morbid obesity. PMID- 26591855 TI - [CHOICE OF THE TREATMENT TACTICS IN PATIENTS, SUFFERING POSTOPERATIVE HERNIA OF ANTERIOR ABDOMINAL WALL WITH CONCOMITANT MORBID OBESITY]. AB - Experience of treatment of 73 patients, suffering postoperative hernia of anterior abdominal wall with concomitant obesity, was presented. In 31 (42.5%) of them in a period of reduction and stabilization of a body mass the allohernioplasty as a second stage after bariatric operation was done, and in 9 (42.5%)--simultant bariatric operations with hernioplasty and dermatolipectomy. During a follow-up period after bariatric operation and hernioplasty the hernia recurrence have occurred in 3 (9.1%) patients, after hernioplasty--in 11 (33.3%), witnessing high efficacy of staged treatment in such patients. PMID- 26591856 TI - [CRITERIONS OF EFFICACY OF THE SOFT TISSUES ELECTRIC WELDING FOR THE HEMOSTASIS GUARANTEEING IN LAPAROSCOPIC OPERATIONS]. AB - Possibilities of application of generator for electric welding of soft tissues, used for hemostasis in laparoscopic operations, were studied. There was established, that while doing laparoscopic operation a biological welding of tissues secures a safe intra- and postoperative hemostasis, reduction of intra- and postoperative morbidity rate. PMID- 26591857 TI - [COMBINATION OF LAPAROLIFTING WITH DOSATED CARBOXYPNEUMOPERITONEUM WHILE PERFORMANCE OF MINIINVASIVE INTERVENTIONS FOR BILIARY CALCULOUS DISEASE]. AB - Comparative analysis of the treatment results in 97 patients for biliary calculous disease, complicated by choledocholithiasis, using the stressed standard carboxyperitoneum method (12 mm Hg) and the dosed one lift-assisted carboxyperitoneum (4 - 6 mm Hg), was conducted. Perioperative indices of hemodynamics arid postoperative pain syndrome severity were considered the criterions of the stressor-like and the damaging action. The results obtained witness trustworthy a more safe effect of the method of the labor space creation. PMID- 26591858 TI - [MINIINVASIVE SURGICAL INTERVENTIONS FOR AN ACUTE NECROTIC PANCREATITIS]. AB - A differentiated staged surgical tactics for treatment of an acute necrotic pancreatitis, based on theory of an acute necrotic pancreatitis phased course, was elaborated and introduced. Sanation and drainage under ultrasonographic control have promoted the patients state stabilization with further stage of laparotomic intervention, in 26.87% of patients of the main group were a residual interventions performed, while in a control group--in 13.19%. Efficacy of a videocontrolled sanation and drainage of retroperitoneal space, using nephroscope, was proved. New methods of miniinvasive surgical treatment of pancreonecrosis, the septic-purulent complications prophylaxis were elaborated. The rate of laparotomy performance was reduced from 57.14%--in a control group down to 33.07%--in the main group. Lethality in the main group was 6.72%, postoperative lethality--9.83%, a morbidity rate in patients have reduced in 2.26 times. PMID- 26591859 TI - [SURGICAL TACTICS IN CHRONIC PANCREATITIS WITH SIGNS OF BILIARY HYPERTENSION]. AB - The results of treatment of 84 patients for chronic pancreatitis with the biliary hypertension signs were depicted. In 83 patients operative interventions were performed, and in 1--positive results were achieved after pancreatic cyst puncture under ultrasonographic control. In 51 patients the conduction of Frey operation have permitted to achieve a lower pressure inside biliary system, in 25 -the additional procedures were applied for a biliary hypertension elimination. In 20 patients a method of pressure measurement in biliary system was used. PMID- 26591860 TI - [TRANSPAPILLARY INTERVENTIONS FOR AN ACUTE PANCREATITIS]. AB - Experience of the endoscopic retrograde pancreatocholangiography performance in emergency (in 4-6 h after admittance to hospital) in 513 patients with suggestion for biliary acute pancreatitis (AP) presence was adduced. In 451 (87.9%) patients preliminary diagnosis was confirmed: in 402 (89.1%)--calculous cholecystitis, complicated by choledocholithiasis, was revealed, in 49 (10.9%)--residual choledocholithiasis. Establishment of biliary genesis of an AP assumes performance of endoscopic papillosphincterotomy and choledocholithextraction. Biliary causes of an AP were excluded in 62 (12.1%) patients, in 34 (54.8%) of them characteristic changes in duodenum were revealed, in 13 (21.0%)--destructive changes of pancreatic ductal system. While diagnosis of an AP of nonbiliary origin a conservative tactics of treatment was selected. PMID- 26591861 TI - [CORRELATIONAL RELATIONSHIP BETWEEN DURATION OF A "COLD" ISCHEMIA PERIOD, THROMBOCYTOPENIA AND SEVERITY OF A HEPATIC REPERFUSIVE DAMAGE IN PATIENTS AFTER ITS TRANSPLANTATION]. AB - Reperfusive hepatic damage, one of the severe complications after hepatic transplantation, occurs immediately after inclusion of the donor organ into the blood circulation of a recipient. It is considered one of principal causes of early rejection of the transplant. Connection between thrombocytopenia in a patient and duration of period of a donor's "cold" hepatic ischemia was studied. The changes in microcirculation due to the thrombocytes accumulation (sequestration) in a sinusoid vessels constitutes a main target in the ischemic reperfusive damage of the liver. During the first days after hepatic transplantation the thrombocytes quantity have reduced, the correlation dependence between this process and duration of a "cold" ischemia and functional activity of a liver transplanted was established. PMID- 26591862 TI - [SURGICAL TREATMENT OF THE FACE CAPILLARY MALFORMATION]. AB - Results of surgical treatment of 37 patients for the head and neck capillary malformations were analyzed. Optimal surgical tactics, depending on the malformation form and localization, was proposed. Restitution of the tissues defect after excision of malformation, using the flaps transposition, have permitted to achieve good esthetic results. PMID- 26591863 TI - [STUDYING OF BIOMECHANICAL PROPERTIES OF SKIN IN THE MASTOID REGION WHILE THE COSMETIC OTOPLASTY PERFORMANCE]. AB - The present methods for a droopy ears correction do not guarantee the optimal cosmetic effect achievement. Optimal borders of deformity in cutaneo-adiposal flap of the mastoid region while cosmetic otoplasty performance were studied. Basing on analysis of biomechanical investigations, there were determined the optimal corners of stretching and direction of the strength vector in cutaneo adiposal flaps while otoplasty performance, securing conditions for surgical intervention performance with preservation of a natural topographo-anatomical ratios in the head and neck tissues. PMID- 26591864 TI - [EFFICACY OF WELDING TECHNOLOGY AS A PRINCIPAL METHOD OF DISSECTION AND HEMOSTASIS IN ENDOCRINAL SURGERY]. AB - Today in the clinic all surgical interventions on endocrinal organs are conducted, using welding technology. Comparative analysis of the operative interventions efficacy, performed applying a standard method (control group) and using welding technology (the main group), was conducted. Performance of operations, using electric welding technologies have permitted to reduce the operative intervention duration by 20 - 30%, the blood loss volume--by 30 - 50%, a postoperative pain syndrome severity and the analgetics expense--by 20%, a postoperative stationary treatment duration--by 1-2 days. PMID- 26591865 TI - [ANALYSIS OF THE SURGICAL TREATMENT RESULTS IN THE THYROID GLAND DISEASES]. AB - The results of surgical treatment of the thyroid gland diseases were analyzed, including the specific morbidity rate, cosmetic effect of the operation, stationary treatment of patients duration, the operation radicalism. Improvement of the operation methods and introduction of modern electric surgical instruments have permitted to reduce the operation duration, the surgical access length, the rate of postoperative hypocalcaemia occurrence, duration of the patients stationary treatment. PMID- 26591866 TI - [APPLICATION OF A ONE-PORTED VIDEOTHORACOSCOPY IN DIAGNOSIS AND TREATMENT OF A PLEURAL EXUDATE]. AB - The results of examination and treatment of 71 patients for pleural exudates (PE) of various origin were analyzed. The efficacy of application of a one-ported thoracoscopy in diagnosis and treatment of a PE in patients with noncomplicated course of intrathoracic pathological processes was proved. The reduction of the PE quantity by (15 +/- 4)% and duration of exudation by (15 +/- 9)% was noted after performance of a one-ported thoracoscopic interventions, reduction of operative trauma and subjective sensation of pain, as well as best cosmetic effect. PMID- 26591867 TI - [PECULIARITIES OF METHOD AND RESULTS OF PLASTY, USING INTESTINAL SEGMENT, FOR IATROGENIC INJURY OF URETER]. AB - Basing on analysis of the examination and treatment results in 53 patients, suffering iatrogenic injury of ureter (IIU), the indications for ureteric reconstruction using intestinal segment were the ureter long irreversible changes, while renal function preserved. A segmental ureteric plasty was done in 8 (15.1%) patients, a subtotal one--in 16 (30.2%), total--in 14 (26.4%), and bilateral--in 15 (28.3%). With the objective to prevent the bladder-intestinal reflux occurrence a distal part of the intestinal transplant was modeled. In 35 (66%) patients 2 - 3 cm of distal part of intestinal mucosa were turned out with the wrap formation. In 18 (34%) patients the creation of antireflux wrap was added by its modeling in a kind of intraileal plasty with formation of two separate channels in the intestinal-bladder anastomosis region. While performance of intraileal plasty of the bladder-intestinal reflux have occurred in 2 (11.1%) patients, and after procedure with the wrap formation--in 13 (37.1%). PMID- 26591868 TI - [PLASTY, USING THIN CUTANEO-ADIPOSAL FLAPS OF ANTERIOR ABDOMINAL WALL, FOR INJURIES OF THE WRIST AND THUMBS]. AB - Experience of a late plasty, using a thin cutaneo-adiposal flaps of abdominal wall of a full-layered wounds of soft tissues of the thumbs and a wrist in 6 injured persons, was presented. Critical postoperative complications and the flaps loss were not observed. Parts of the edge necrosis of the flaps in 3 patients were excised, the wound suturing was done or autodermoplasty, in 1 of them osteosequesterectomy was performed. The reconstruction purpose--restoration of the cover tissues and revascularization of the thumbs and wrists defects--was achieved in all the patients. PMID- 26591869 TI - [PECULIARITIES OF PERIOPERATIVE MANAGEMENT OF PATIENTS IN ENDOVIDEOSURGICAL INTERVENTIONS. Part II. GAS EXCHANGE, MECHANICS OF THE LUNGS, CENTRAL NERVOUS SYSTEM, FUNCTION OF THE LIVER, KIDNEYS, SELECTION OF ANESTHETICS, INTENSIVE THERAPY, CONTRAINDICATIONS]. PMID- 26591870 TI - [OBSERVATION OF SPONTANEOUS RUPTURA OF PHEOCHROMOCYTOMA RIGHT ADRENAL GLAND]. PMID- 26591871 TI - [OBSERVATION OF A COMPLETE TRANSPOSITION OF VENA CAVA INFERIOR]. PMID- 26591872 TI - [80 YEARS OF GENERAL SURGERY SUBFACULTY No2 OF NATIONAL MEDICAL UNIVERSITY OF O. O. BOGOMOLETS]. PMID- 26591873 TI - [BECOMING ENDOCRINE SURGERY IN UKRAINE. KYIV SCHOOL OF ENDOCRINE SURGEONS]. PMID- 26591874 TI - Preface. PMID- 26591875 TI - The evaluation of anthropogenic impact on the ecological stability of landscape. AB - The model area is the northern surrounding of the water reservoir Zemplinska Irava in the east of Slovakia. Selection of the examined territory and the time horizons was not random. The aim was to capture the intensity level of anthropogenic impact on the values of the coefficient of ecological stability after the construction of water reservoir, Zempifnska Irava. The contribution evaluates ecological stability of landscape in the years 1956 and 2009 by GIS technology, using two methods. The first method determines the rate of ecological stability of landscape on the basis of the significance of land cover classes in the regular network of squares (the real size of the square is 0.5 square km). The second method determines the ecological stability of landscape secondary on the basis of the man influence on the landscape. A comparison of two methods has been made, as well as interpretation of the output data (e.g., monitoring the impact of marginal land cover classes with the minimal surfaces in the grid of square at the fluctuation of the index of ecological stability, respectively, it considers the possibilities to streamline the research results using homogeneous spatial units) and it also allows to track the changes in the ecological stability of the landscape in chronological development. PMID- 26591876 TI - Modeling and mapping potential distribution of Crimean juniper (Juniperus excelsa Bieb.) using correlative approaches. AB - Modeling and mapping potential distribution of living organisms has become an important component of conservation planning and ecosystem management in recent years. Various correlative and mechanistic methods can be applied to build predictive distributions of living organisms in terrestrial and marine ecosystems. Correlative methods used to predict species' potential distribution have been described as either group discrimination techniques or profile techniques. We attempted to determine whether group discrimination techniques could perform as well as profile techniques for predicting species potential distributions, using elevation (ELVN), parent material (ROCK), slope (SLOP), radiation index (RI) and topographic position index (TPI)) as explanatory variables. We compared potential distribution predictions made for Crimean juniper (Juniperus excelsa Bieb.) in the Yukan Gokdere forest district of the Mediterranean region, Turkey, applying four group discrimination techniques (discriminate analysis (DA), logistic regression analysis (LR), generalized addictive model (GAM) and classification tree technique (CT)) and two profile techniques (a maximum entropy approach to species distribution modeling (MAXENT), the genetic algorithm for rule-set prediction (GARP)). Visual assessments of the potential distribution probability of the applied models for Crimean juniper were performed by using geographical information systems (GIS). Receiver-operating characteristic (ROC) curves were used to objectively assess model performance. The results suggested that group discrimination techniques are better than profile techniques and, among the group discrimination techniques, GAM indicated the best performance. PMID- 26591877 TI - Relations between the land use and land capability classification in Kucuk Menderes River Basin. AB - The aim of this study was to analyze the relation between land use and land classes in Kucuk Menderes river basin in terms of sustainable utilization of natural resources. Landsat satellite images were used to determine the current land use, and remote sensing method was used for processing these images. Land capability classification reflects the natural environment potential of an area. The area occupied by agriculturally important lands depends on this classification. According to this, 34% were included in the 1st, 2nd, and 3rd class lands, 3% in the 4th class land, 7% in the 6th class land, 53% in the 7th class land, and 3% in the 8th class land. The most important land covers in the basin were; forest (21%), dry farming (21%), irrigated farming (17%), maquisgarrigue (11%), exposed surface (8%), settlements (3%) and water surface (2%). There was an inconsistency between the land capability classes and their usage. While the area occupied by 1st, 2nd, 3rd and 4th class lands, which should be used as agricultural lands covered 37%, the area occupied by the agricultural lands already covered 38%. This situation seemed consistent in terms of ratio, however, the fact was that 1st, 2nd, 3rd and 4th class lands were used for settlement (6%) and meadow pasture (20%); while the 5th, 6th, 7th and 8th class lands were used for agriculture (32%) and settlements (3%). This leads to some negative consequences. The massive erosion (60%) on the basin affects the lands that were inclined and lacking vegetation-cover. Basin lands became useless as a result of land degradation and erosion. To prevent this, a land use pattern suitable for the natural environment potentials of the region (land capability classes) should be used. PMID- 26591878 TI - Making agriculture greener. AB - The application of sewage sludge has been a worldwide agricultural practice for many years. The present study aimed to investigate the effects of sewage sludge (Ss) has on the physiological parameters of maize (Zea mays L cvs. PR37NO1). 2 g dm(-3) and 4 g dm(-3) of sewage sludge were examined in hydroponic experiment. Some metal contents (Al, Cr, Mn, Na, Zn) in the shoots and roots of maize were taken. Living bacteria containing fertilizers (LBCF) were examined on how the treatments modify heavy metal uptakes. Dry matter accumulations in shoots and roots, length of shoots and roots of maize were measured. Chlorophyll contents were determined by using spectrophotometer methods. The dry matter accumulation and length of shoots decreased, the dry matter of roots increased in all of the treatments compared to the nutrient solution without treatment (control). Increased chlorophyll a, b and carotene contents were observed at 4 g dm(-3) Ss and 4 g dm(-3) Ss + bio fertilizer treatments. PMID- 26591879 TI - Desertification risk in Kakheti Region, East Georgia. AB - Desertification or land degradation in drylands is caused by various factors. The most important of these is climate change, a significant global ecological problem. Desertification, like erosion, as an environmental process of ecosystem degradation, is often caused by human activity. It is a common misconception that droughts cause desertification. Well-managed lands can recover from drought if the rains return. These practices help to control erosion and maintain productivity during periods when moisture is available. Traditionally, the most vulnerable territories considered under the threat of desertification in Georgia is Kakheti region (East Georgia), which has been selected as one of the priority investigation area. In Eastern Georgia, intervals of atmospheric precipitation do not coincide with the phases of water demand of plants. In recent decades as a result of more frequent droughts in Kakheti, the region has already lost hundreds, thousands of hectares of fertile land. Based on the contemporary climate warming projections, the temperature is expected to increase and precipitation to decrease. This will lead to an increase in evaporation and reduction of river flow. Under such conditions the danger of desertification is evident. To mitigate the negative effects of desertification, it is recommended to put forward set of adaptation activities through rehabilitation of water use systems, prevention of loss of water, reconstruction and expansion of irrigation canals, accumulation of unused autumn-winter river water and spring floods in reservoirs, developing an optimal scheme of distributing water resources among water users, device windbreaks and work on breeding of drought resistant varieties, preparation of water volume forecasts of rivers and their role in planning of water use; application of apply drip and sprinkler irrigation, using artificial precipitation following increase as a result of active influence on clouds. All these activities will provide means for suspending desertification process, create ecological safety for the environment and improve the economic well-being of population. PMID- 26591880 TI - Analysis of land use changes near large water bodies in Ukraine using GIS. AB - Analysis of land use and land cover changes in Ukraine were evaluated with special attention given to the interaction of land and water resources. The rational fresh water management in agriculture under future climate change conditions is of great importance. The hydrological regime of a river has huge impact on the environment of the surrounding area. Creating reservoirs, changes the landscape of river valleys and lake basins. Changes in the hydrological regime of the river and the process taking place in the coastal zone are reflected in land cover, wildlife and micro-climatic conditions. In the area closer to the shore line of the reservoir, there is greater amplitude of fluctuations in the level of ground water due to low rate of filtration behind fluctuations in the level of the reservoir. The interaction of water reservoirs with the environment, especially with the nature of the catchment area is substantially different from the natural water bodies. Analysis was done using GIS and remotely sensed data of land use near large water reservoirs and processed statistically. The ratio of arable lands and forested territories and future analysis of land use has been discussed. PMID- 26591881 TI - Complex evaluation of climate-change--an example from Georgia's landscapes. AB - The purpose of this study was to develop spatial-temporal model of Georgia's landscapes, which gives a chance to determine the current tendencies of landscape changes in different landscapes, such as humidity/aridity, increase/decrease of bio-productivity, etc. The model used gives possibility to reveal causes of mosaic changes, associated with global climate change. The studywas based on the conception of spatial-temporal analysis and synthesis of landscapes. It was carried out in different landscapes across Georgia. The daily geo-conditions and annual dynamics of landscapes was determined by analyzing some long-term data collected from meteorological stations. As a complex value, daily geo-conditions of landscapes were analyzed. On the bases of inventory of landscapes, GIS technology and thematic mapping, main tendencies in the landscapes were developed. Arid, Semiarid, Semi-humid landscapes occupied a great area, which formed approximately 1/3 part of the whole territory of Georgia. These include 8 types, 11 sub-types of landscapes and 24 genera. The main share of these landscapes was concentrated in East Georgia, but some semi-humid areas were spread in West Georgia. The influence of climate change was evaluated considering several parameters, such as change of forest area, share of agricultural land in the total area of landscape, degree of fragmentation of landscapes and productivity of vegetation. PMID- 26591882 TI - Impacts of anthropogenic factors on land degradation during the anthropocene in Turkey. AB - The aim of the present study was to determine the factors that effected the beginning of the Anthropogenic Era (human age) in Turkey and formation of biomes. Destruction of vegetation, soil erosion and land degradation are the most important factors in the formation of anthropogenic biomes in Turkey. For this reason, first of all, a literature review about land degradation, which has been going on for past 300 years in Turkey, and about its causes was made. Changes that have occurred over the last 70 years were studied with the help of aerial photos and satellite images. In addition, studies we have conducted in the last 35 years have contributed substantially to the determination of the extent of the destruction of vegetation and land degradation in Turkey. As a result of research based on literature reviews and fieldwork, the impact of humans on the natural habitat were identified, and the current situation was studied. The findings about the current situation that emerged due to human impact were then transferred to an electronic environment, and a map of anthropogenic biomes was produced with the help of ArcGIS Desktop software. Based on the results obtained, one can say that the natural habitat has considerably changed over the last 200 years; vegetation has been damaged, and land degradation has become faster because of human activities. These results indicate that 97% of natural biomes have become anthropogenic biomes, and this change has become more obvious during 20h century in Turkey. The results also show that the change has been more influential after 1950. PMID- 26591883 TI - Bioaccumulation of heavy metals by the leaves of Robinia pseudoacacia as a bioindicator tree in industrial zones. AB - The study is a part of research project on using short rotation plantations in biomass production. The aim of this investigation was to determine the accumulation characteristics of Robinia pseudoacacia leaves as a biomonitor of heavy-metal pollution in the industrial regions in Bulgaria. The study was carried out in 25-year-old plantations located in close vicinity of industrial area Devnia, Eastern Bulgaria. Devnia is a zone, highly contaminated by cement factories, nitrogen fertilizers and polyvinylchloride factories. Controls were similarly aged plantations on a background area 15 km away from the emission sources. The concentration of nutrients and heavy metals in the leaves of damaged and control plants were investigated. Decreased levels of total nitrogen (6%), total phosphorous (11%), potassium (36%) and magnesium (3%) were detected in September for polluted trees as compared to control trees. Lead content (30.7 mg kg(-1)) was 1.38 times higher as compared to control, whereas accumulation of zinc (19.0 mg kg2) about 1.37 times more than control. An excessive accumulation of copper in the leaves collected from the polluted area (17.2 mg kg(-1)) was 2.15 times higher than control. The concentrations of Pb, Zn and Cu in the contaminated soil under black locust plantation were 38.2, 77.4 and 101.3 mg kg( 1), respectively. Our results showed that the leaves of R. pseudoacacia accumulated Pb, Zn and Cu in parallelity with their increase in the contaminated soil. R. pseudoacacia may be considered as a good biomonitor of soil pollution especially with Cu, and at lower extent for Pb and Zn in the industrial region of Devnia. PMID- 26591884 TI - Stakeholder participation to watershed management: A case study from Beysehir Lake Basin. AB - This study addresses Beyehir Lake Basin, which is the largest freshwater lake in Turkey. The aim of the study was to explore the knowledge, perceptions and behaviors of local communities regarding; the critical problems of the basin; technical and political situation of the water management in the basin; possible strategies ensuring positive change towards the sustainability of the basin; and the watershed management strategies which could contribute to success in this case. The participatory level of the local water users of the basin was also examined. The results revealed that local communities were aware of the basin's problems and contribution of the participatory approaches to watershed management. Also, collaboration between the public and public institutions was accepted as key to successful watershed management. The stakeholders, who considered that current water policies to solve the problems of the basin were ineffectual, relied on the local environmental groups more than central government and local authorities regarding their water policies. PMID- 26591885 TI - Determination of seasonal changes in wetlands using CHRIS/Proba Hyperspectral satellite images: A case study from Acigol (Denizli), Turkey. AB - The changes in wetlands that occur through natural processes, as well as through industrialization and agricultural activities, are decreasing and even annihilating the living spaces of endemic species. Acigol (Denizli, Turkey), which is a suitable habitat for flamingos (Phoenicopterus ruber), is a lake that is affected by seasonal anomalies as a result of being shallow. Acigol, which is fed by precipitation, groundwater and the springs that occur along tectonic faults, has no water output other than evaporation and industrial activities. In addition to natural factors, it is important to determine the changes in the wetlands of Acig6l, where industrial salt is produced, in order to reveal the micro-ecological equilibrium, the relationship between climate and natural life, and regulation of industrial activities. Remote sensing tools are frequently used in determination of changes in wetlands. Changes in coastlines, water level and area covered by water are parameters that can be examined by remote sensing while investigating wetlands. In this study, the water-covered area was examined using remote sensing. Within the scope of this study, CHRIS/Proba Mode 2 (water bandset) hyperspectral satellite images, acquired on 9/17/2011 for the season and on 6/18/2012 - 6/19/2012 forwet season, were used in orderto present the seasonal changes in Acigol, during one hydrogeological period. The processes of noise reduction, cloud screening, atmospheric correction, geometric correction, and identification of wetlands have been implemented on the CHRIS/Proba images. In determining the water-covered areas, the Normalized Difference Water Index (NDWI) was used. It was determined that W6 (560 nm) and W18 (1015 nm) and W2 (447 nm) and W18 (1015 nm) band combinations were most appropriate to be used in NDWI to demonstrate the water-land separation. Using Proba-NDWI image, it was established that an area of 27.4 km2 was covered with water during dry season, and 61.2 km2 was covered during wet season. The results indicated that; since the lake water area is directly affected by seasonal and annual climatic anomalies, water used by industrial facilities has to be drawn out of the lake in reasonable amount. PMID- 26591886 TI - Soil quality changes in response to their pollution by heavy metals, Georgia. AB - The present study deals with the composition, migration and accumulation of heavy metals in irrigated soils, plants and partially natural waters; and also, establishing the possible sources of pollution and their impact on environmental situation. The content of toxic elements in the irrigated soils adjacent to ore mining and processing enterprise were studied. Content of toxic elements in the irrigated soils adjacent to ore mining, showed that more than half of territory was seriously polluted by copper and zinc. Some part of the area were considered catastrophically polluted. Expressed technogenesis taking place influenced irrigation. Heavy metals like copper, zinc and manganese negative by effected the properties of soil, thus composition and soil-forming processes taking place in the soil. It was especially well represented in the deterioration of hydro physical potential of the soil. Irrigation of agricultural land plots by water, polluted with heavy metals changed the pH. Balanced correlation among solid, liquid and gas phases was disrupted. In highly polluted soil, the cementing processes took place that sharply increased the bulk density of the soil, deteriorated the porosity of soil and reduced water permeability critically. PMID- 26591887 TI - Investigation of grapevine photosynthesis using hyperspectral techniques and development of hyperspectral band ratio indices sensitive to photosynthesis. AB - The photosynthetic rate of 9 different grapevines were analyzed with simultaneous photosynthesis and spectroradiometric measurements on 08.08.2012 (veraison) and 06.09.2012 (harvest). The wavelengths and spectral regions, which most properly express photosynthetic rate, were determined using correlation and regression analysis. In addition, hyperspectral band ratio (BR) indices sensitive to photosynthesis were developed using optimum band ratio (OBRA) method. The relation of BR results with photosynthesis values are presented with the correlation matrix maps created in this study. The examinations were performed for both specific dates (i.e., veraison and harvest) and also in aggregate (i.e., correlation between total spectra and photosynthesis data). For specific dates wavelength based analysis, the photosynthesis were best determined with -0.929 correlation coefficient (r) 609 nm of yellow region at veraison stage, and -0.870 at 641 nm of red region at harvest stage. For wavelength based aggregate analysis, 640 nm of red region was found to be correlated with 0.921 and -0.867 r values respectively and red edge (RE) (695 nm) was found to be correlated with 0.922 and -0.860 r values, respectively. When BR indices results were analyzed with photosynthetic values for specific dates, -0.987 r with R8../R, at veraison stage and -0.911 r with R696/R944 at harvest stage were found most correlated. For aggregate analysis of BR, common BR presenting great correlation with photosynthesis for both measurements was found to be R632/R971 with -0.974, 0.881 r values, respectively and other R610/R760 with -0.976, -0.879 r values. The final results of this study indicate that the proportion of RE region to a region with direct or indirect correlation with photosynthetic provides information about rate of photosynthesis. With the indices created in this study, the photosynthesis rate of vineyards can be determined using in-situ hyperspectral remote sensing. The findings of this study would enable cost efficient, rapid and effective control of viticulture activities. PMID- 26591888 TI - Medical aspects of atmosphere pollution in Tbilisi, Georgia. AB - Climate change and its impact on ecosystems is one of the main problem of 21st century. Increase in green house gas in the atmosphere was regarded as an important cause. Atmospheric composition had significantly changed due to intensive technogenic pollution. Increase in aerosol (solid, liquid and gas) concentration had serious impact on human health and raised the level of risk factors for longevity of life. Despite, global character of climatic change and its intensity in numerous ways was influenced by local specificity of regions, their geographical location and meteorological factors. A study on the atmospheric quality (quantitative and percentage estimation of aerosols) of Georgia was carried out. Also the assessment of impact of meteorological and ecological conditions on human health was made for Tbilisi city. A relation between contaminants and meteorological factors was evaluated, particularly gas pollutants were strongly correlated with each other due to their photochemical activity; positive correlation (0.65; 0.69) between air temperature and pollutants. All the contaminants showed negative correlation with relative humidity, due to hydrolyzing ability. On the basis of multi-factorial statistical analysis, correlation between ambulance call, weather type, atmosphere pollution index, change in ground ozone quantity and earth magnetic field were determined. Atmospheric pollution due to dust, carbon, sulfur and nitrogen oxides, ground ozone quantity in Tbilisi significantly exceeded maximum permissible level, that effected human health. PMID- 26591889 TI - Indicator species of essential forest tree species in the Burdur district. AB - The forests of Burdur district for long have been subjected to over grazing and individual selection. As a result of this, majority of the forest areas in the district were degraded. In the district, afforestation efforts included majority of forestry implementations. It is well known that selecting suitable species plays an important role for achieving afforestation efforts. In this context, knowing the indicator species among the target species would be used in afforestation efforts, studies on the interrelationships between environmental factors and target species distribution is vital for selecting suitable species for a given area. In this study, Anatolian Black pine (Pinus nigra), Red pine (Pinus brutia), Crimean juniper (Juniperus excelsa) and Taurus cedar (Cedrus libani), essential tree species, were considered as target species. The data taken from 100 sample plots in Burdur district was used. Interspecific correlation analysis was performed to determine the positive and negative indicator species among each of the target species. As a result of ICA, 2 positive (Berberis crataegina, Juniperus oxycedrus), 2 negative (Phillyrea latifolia, Quercus coccifera) for Crimean Juniper, I positive (Juniperus oxycedrus), 3 negative (Onopordium acanthium, Fraxinus ornus, Phillyrea latifolia) for Anatolian black pine, 3 positive (Paliurus spina-christi, Quercus coccifer, Crataegus orientalis), 2 negative (Berberis crataegina, Astragalus nanus) for Red pine and 3 positive (Berberis crataegina, Rhamnus oleoides, Astragalus prusianus) 2 negative (Paliurus spina-christi, Quercus cerris) for Taurus cedarwere defined as indicator plant species. In this way, practical information was obtained for selecting the most suitable species, among the target species, for afforestation efforts in Burdur district. PMID- 26591890 TI - Vegetation ecology of the Princes' Islands, Istanbul-Turkey. AB - The aim of this paper was to evaluate phytoecological and phytosociological characteristics of the vegetation distributed in Princes' Islands (Istanbul/Turkey). Field studies were carried out during 2002-2010 following the classical Braun-Blanquet method. The data obtained from the research area on characteristics of two associations belonging to maquis vegetation was analyzed. One of these associations was new and its detailed description, typification and syntaxonomy are mentioned. The associations identified were: Arbuto unedonis Phillyretum latifoliae ass. nova and Phillyreo latifoliae-Pinetum brutiae. The physical and chemical characteristics of soil like saturation (%), pH, P20, (kg da-), K20 (kg da1), CaCO, (%), total salt (%) and organic matter (%) are presented as well. Relationship between vegetation, ecological characteristics and their protection against biotic pressures were discussed together with phytosociological and phytoecological features of the associations and was compared with similar other studies. PMID- 26591891 TI - Effects of logging and recovery process on avian richness and diversity in hill dipterocarp tropical rainforest-Malaysia. AB - The effects of logging and recovery process on avian richness and diversity was compared in recently logged and thirty year post-harvested hill dipterocarp tropical rainforest, using mist-netting method. Atotal of 803 bird individuals representing 86 bird species and 29 families (i.e., 37.90% from recently logged forest and 62.10% from thirty year post-harvested forest) were captured from October 2010 to September, 2012. Twenty one bird species were commonly captured from both types of forests, 37 bird species were caught only in thirty year post harvested forest and 28 bird species were caught only from recently logged forest. Arachnothera longirostra--Little Spiderhunter, Malacopteron magnum- Rufous-crowned Babbler, Alophoixus phaeocephalus -Yellow-bellied Bulbul and Meiglyptes tukki--Buff-necked Woodpecker were the most abundant four bird species in the thirty year post-harvested forest. On the contrary, seven bird species, i.e., Trichastoma rostratum - White-chested Babbler, Lacedo pulchella - Banded Kingfisher, Picus miniaceus--Banded Woodpecker, Enicurus ruficapillus - Chestnut naped Forktail, Anthreptes simplex--Plain Sunbird, Muscicapella hodgsoni--Pygmy Blue Flycatcher and Otus rufescens--Reddish Scope Owl were considered as the rarest (i.e., each represented only 0.12%). Likewise, A. longirostra, Pycnonotus eythropthalmos - Spectacled Bulbul, P. simplex--Cream-vented Bulbul and Merops viridis--Blue-throated Bee-eater were the most dominant and Copsychus malabaricus -White-rumped Shama Eurylaimus javanicus--Banded Broadbill /xos malaccensis - Streaked Bulbul and Harpactes diardii--Diard's Trogon (each 0.12%) were the rarest bird species in recently logged forest. CAP analysis indicated that avian species in thirty year post-harvested forest were more diverse and evenly distributed than recently logged forest. However, recently logged forest was rich in bird species than thirty year post- harvested forest. The results revealed that logging and retrieval process affect bird species richness and diversity. However, bird species may respond differently from habitat to habitat, i.e., forest logging causes disturbance of some avian species while recovery process may replace the loss of vegetation and harbour a wide array of avian species richness and diversity. PMID- 26591892 TI - Morphology, anatomy and cytology of critically endangered endemic Asperula daphneola from, West Anatolia, Turkey. AB - Asperula daphneola, which belongs to Rubiaceae family, is only distributed on Nif Mountain. The present study investigates the species anatomically, morphologically and cytologically, laying the basis for future biosystematic studies as well as introducing this endemic taxa. A. daphneola seeds were 1.3-1.8 X 2.3-2.9 mm; ovate; seed surface was prominent and channelled; dorsal type was convex, hispid hairs all over; hylar zone type recessed; yellowish green colour. Type of pollen were stephanocolpate and had 6 colpus with tectate structure. The chromosome number in A. daphneola was counted as 2n=20. PMID- 26591893 TI - The largest forest fires in Portugal: the constraints of burned area size on the comprehension of fire severity. AB - Portugal is a European country with highest forest fires density and burned area. Since beginning of official forest fires database in 1980, an increase in number of fires and burned area as well as appearance of large and catastrophic fires have characterized fire activity in Portugal. In 1980s, the largest fires were just a little bit over 10,000 ha. However, in the beginning of 21st century several fires occurred with a burned area over 20,000 ha. Some of these events can be classified as mega-fires due to their ecological and socioeconomic severity. The present study aimed to discuss the characterization of large forest fires trend, in order to understand if the largest fires that occurred in Portugal were exceptional events or evidences of a new trend, and the constraints of fire size to characterize fire effects because, usually, it is assumed that larger the fire higher the damages. Using Portuguese forest fire database and satellite imagery, the present study showed that the largest fires could be seen at the same time as exceptional events and as evidence of a new fire regime. It highlighted the importance of size and patterns of unburned patches within fire perimeter as well as heterogeneity of fire ecological severity, usually not included in fire regime description, which are critical to fire management and research. The findings of this research can be used in forest risk reduction and suppression planning. PMID- 26591894 TI - Possibility for using of two Paulownia lines as a tool for remediation of heavy metal contaminated soil. AB - One-year-old two Paulownia lines (Ptomentosa x fortunei--TF 01 and R elongata x fortunei--EF 02) were grown, as pot experiment, in soil collected from the field of waste depository of Kremikovtzi ferrous metallurgical industry near Sofia. The soil was heavily polluted with Cd. Metals content (Ca, Mg, K, Na, Cd, Cu, Pb, Zn and Fe) in soil and its distribution in roots, stems and leaves of both lines was studied. The results showed that Ca and K accumulated more in stem, Mg, Na, Fe and Cd in root, while Pb, Cu and Zn in the leaves of both lines. The bloaccumulation factor (BF) and translocation factor (TF) were evaluated in order to determine the potential of plants in removing metals from contaminated soil. The BF for Fe, Pb, Cu and Zn in TF 01 line exceeded that of EF 02 line--5.6; 1.03; 1.20; 1.14 times, respectively. TF was higher in TF 01 line for Fe, Pb and Cd (6.0; 1.92 and 1.03, respectively), but not for Cu and Zn. The success of phytoremediation depends on plant growth and restricted distribution of heavy metals in shoots. Our results showed that stem length and total leaf area of Paulownia elongata x fortunei were higher than Paulownia tomentosa x fortuneibut BF for Cu and Zn and TF for Pb was less. BF for Cd was 1.7 times higher and TF for Zn was 1.03 times higher in Paulownia elongata x fortunei. Selected two lines (P. tomentosa x fortunei--TF 01 and P elongataxfortunei--EF02) were accumulators of Cu, Zn and Cd. Paulownia tomentosax fortunei accumulated more Pb and Zn in aboveground parts, while Paulownia elongata x fortunei--accumulated Zn only. These lines proved to be a promising species for phytoremediation of heavy metal polluted soils due to high biomass productivity. PMID- 26591895 TI - Environmental relationships of the vascular flora alongside the railway tracks between Haydarpasa and Gebze (Istanbul-Kocaeli/Turkey). AB - The vascular flora alongside the railway track between Haydarpasa and Gebze in Turkey was investigated and the floristic features of the study area are presented here. The investigation was undertaken during 2003-2009. In total 194 plant taxa were determined. Out of these 174 were naturally growing and 20 were exotics and cultivated. Native taxa within the flora belonged to 135 genera and 50 families, exotic and cultivated taxa belonged to 20 genera and 15 families. The members of Dicotyledonae constituted of 82.76% and Monocotyledonae 16.09% of the native taxa. The highest number of these taxa belonged to Asteraceae family (25 species), while the exotics were from Rosaceae (5 species). The plant distributional features, phytogeographical elements, life forms, archaeophytes and neophytes and status of invasive plants have also been included. PMID- 26591896 TI - Woody vegetation of Sile and its environs (Istanbul Turkey) and destruction of the area. AB - The woody vegetation of Sile district (Istanbul/Turkey), and its characteristics in conjunction with its environs are presented in this study. The field studies were performed using classic Braun-Blanquet method during 2003-2010 periods. In the present study three associations, two from forest vegetation and one from maquis vegetation, were characterized in the field. One of these associations is new and its description, typification and syntaxonomy was proposed. Phytosociological and phytoecological features of all three associations were compared with their relatives and related discussion was done accordingly. The associations described in the present study were as follows: Phillyreo-Lauretum nobilis, Smilaco-Castanetum sativae, Fago orientalis-Quercetum ibericae ass. nova. Furthermore, some soil properties such as saturation, organic matter, pH, CaCO, K2O and P2O5 were analyzed. Relationship between vegetations, their ecological characteristics and protection of these vegetations against biotic pressures are outlined in the present work. PMID- 26591897 TI - Water quality and benthic fauna biodiversity in a unique small wetland at Messinia, Greece. AB - The wetland of Aghios Floros is located in the Prefecture of Messinia (S. W. Peloponnese, Greece) and occupies a small area, covered permanentlywith water. Flooding of the surrounding area is defended by an artificial channel that discharge large quantity of water into Pamisos River in whose river basin the Aghios Floros station belongs. At the sampling site various physico-chemical and conventional pollution parameters as well as hydrochemical variables were measured during the wet and the dry period of 2011. The hydromorphological and multihabitat approach of RIVPACS method was applied in situ, which gives an overall image of the landscape. The site was classified as 'Good' according to the Greek River Nutrient Classification System (GR.NCS) and the benthic macroinvertebrate fauna assemblages that dominated the area pointed out a 'Good' biological status as well. The biotic and abiotic sample processing, carried out in compliance with the demands of the Water Framework Directive, in general revealed high ecological status of the station. Specifically, a rich diversity and abundance of some macroinvertebrate families was recorded and regarding the aquatic flora the area is dominated by the water lilies species of Nymphaea alba which are unique in the area of Peloponnese. PMID- 26591898 TI - Ecology, anatomy and morphology of Orchis spitzelii in Turkey. AB - In the present study reveals the morphological, anatomical and ecological characteristic of Orchis spitzelii in Turkey. Plant materials of Orchis spitzefli were collected from 17 different population, between 2010-2013 in Turkey. Orchis spitzelii samples were analyzed for 19 morphological, 20 anatomical and 18 soil characters and habitat properties. As a result, the minimum length of plantwas 200 mm and maximum 500 mm, minimum length of underground part was 25 mm and maximum 94 mm. Number of leaves varied between 3-9. According to habitat definition, Orchis spitzelii grew up to 500 m to 2100 m. Also, Pinus nigra forests and glades were most common habitat of Orchis spitzeii, found generally over calcareous soils. PMID- 26591899 TI - Challenges in the 2016 Medicare OPPS Proposed Rule. PMID- 26591900 TI - Stanford Health Care Creates Universal Registration. PMID- 26591901 TI - Educating Patients About Health Insurance Can Drive Loyalty, Revenues. PMID- 26591902 TI - Factors contributing to communication skills development in cochlear implanted children. AB - BACKGROUND/AIM: Over the last 10 years more than 300 persons received cochlear implant in Serbia and more than 90% of the recipients were children under 10 years of age. The program of cochlear implantation includes postoperative rehabilitation in which cognitive, integrative and developmental methods are used. The study was conducted to reveal factors affecting communication performance (CP) of cochlear implanted (Cl) children. Special attention was focused on the influence of the duration and intensity of rehabilitation and hearing age on further development of communication skills. METHODS: A group of 30 CI children (13 boys and 17 girls) aged 2 to 5 years was enrolled in the study. All of the children had average intelligence and no other developmental disorder. They lived in families and attended rehabilitative seances 3 to 5 times a week. Their parents/caregivers answered structured questionnaire about functioning after pediatric cochlear implantation (FAPCI) and the results were the subject of detailed statistical analysis. RESULTS: Analysis of variance did not show any difference between the boys and the girls regarding FAPCI achievements (F(1, 28) = 2.909; p = 0.099) and age aberration in CP score (F(1,28) = 0.114, p = 0.738). Correlation analysis showed a statistically significant difference in FAPCI scores related to hearing age and duration of rehabilitation. Regression analysis (enter method) showed that model consisting of indipendent variables significantly contributed to prediction of overall FAPCI scores and Adjusted R2 value could explain 32% difference in communication skills of participants in this study. CONCLUSION: Communication skills of CI children evaluated by FAPCI are falling behind normatives for normal hearing children 18.6 months on the average. Hearing age, duration and intensity of rehabilitation have positive predictive value for communication skills development. Later identification of hearing loss and later cochlear implantation lead to delayed development of communication skills. PMID- 26591904 TI - Better Together: Co-Location of Dental and Primary Care Provides Opportunities to Improve Oral Health. AB - Community Health Centers (CHCs) are one of the principal safety-net providers of health care for low-income and uninsured populations. Co-locating dental services in primary care settings provides an opportunity to improve access to dental care. Yet this study of California CHCs that provide primary care services shows that only about one-third of them co-located primary and dental care services on site. An additional one-third were members of multisite organizations in which at least one other site provided dental care. The remaining one-third of CHC sites had no dental care capacity. Policy options to promote co-location include requiring on-site availability of dental services, providing infrastructure funding to build and equip dental facilities, and offering financial incentives to provide dental care and recruit dental providers. PMID- 26591906 TI - Models of Care for High-Need, High-Cost Patients: An Evidence Synthesis. AB - This brief analyzes experts' reviews of evidence about care models designed to improve outcomes and reduce costs for patients with complex needs. It finds that successful models have several common attributes: targeting patients likely to benefit from the intervention; comprehensively assessing patients' risks and needs; relying on evidence-based care planning and patient monitoring; promoting patient and family engagement in self-care; coordinating care and communication among patients and providers; facilitating transitions from the hospital and referrals to community resources; and providing appropriate care in accordance with patients' preferences. Overall, the evidence of impact is modest and few of these models have been widely adopted in practice because of barriers, such as a lack of supportive financial incentives under fee-for-service reimbursement arrangements. Overcoming these challenges will be essential to achieving a higher performing health care system for this patient population. PMID- 26591905 TI - U.S. health care from a global perspective: spending, use of services, prices, and health in 13 countries. AB - This analysis draws upon data from the Organization for Economic Cooperation and Development and other cross-national analyses to compare health care spending, supply, utilization, prices, and health outcomes across 13 high-income countries: Australia, Canada, Denmark, France, Germany, Japan, Netherlands, New Zealand, Norway, Sweden, Switzerland, the United Kingdom, and the United States. These data predate the major insurance provisions of the Affordable Care Act. In 2013, the U.S. spent far more on health care than these other countries. Higher spending appeared to be largely driven by greater use of medical technology and higher health care prices, rather than more frequent doctor visits or hospital admissions. In contrast, U.S. spending on social services made up a relatively small share of the economy relative to other countries. Despite spending more on health care, Americans had poor health outcomes, including shorter life expectancy and greater prevalence of chronic conditions. PMID- 26591907 TI - Preface: The Status of Pediatric Solid Tumors in 2015. PMID- 26591908 TI - [The minor difference]. PMID- 26591909 TI - [The basic tenet and cornerstone of every health care system]. PMID- 26591910 TI - ["Also highlight the economic benefits"]. PMID- 26591911 TI - [The woman at the source of the initiative]. PMID- 26591912 TI - [Moments of happiness in nursing]. PMID- 26591913 TI - ["Doing what one does best"]. PMID- 26591914 TI - ["Women campaign for equality"]. PMID- 26591915 TI - [Documenting lifelong learning online]. PMID- 26591916 TI - [Better day by day - for a lifetime]. PMID- 26591917 TI - [Strategies of family caregivers]. PMID- 26591918 TI - [Wound dressings for preventing postoperative wound infection]. PMID- 26591919 TI - [In the "yes - but" loop]. PMID- 26591920 TI - [The luck of being a woman]. PMID- 26591921 TI - ["I bring my piece to the puzzle of knowledge?"]. PMID- 26591922 TI - [Promoting a complementary approach]. PMID- 26591923 TI - [Participate in the group? ... but why?]. PMID- 26591924 TI - [The other half of the sky]. PMID- 26591925 TI - ["Good morning princess]. PMID- 26591926 TI - [Perseverance and passion]. PMID- 26591927 TI - Ebola. PMID- 26591928 TI - The resilience web: Interconnections, links and traps. AB - Business continuity management is an essential contributor to resilience that allows organisations to maintain their viability and functionality--and, in many cases, growth and profitability. The ability to achieve and maintain necessary resilience within a changing operating environment can be influenced by multiple factors. This paper considers the potential damaging influences upon organisations and analyses, and evaluates the range and depth of linkages between them or groups of them. While each influence has its own specific causes, effects, timescales and nuances, some will be unique to it and some will recur elsewhere. Moreover, these influences may cause impacts in isolation or may combine to cause or to deepen the effect of other problems or issues on the organisation. The 'resilience web' makes it possible to look externally from the organisation at the centre and to think in depth about anticipation, response and recovery by recognising and identifying synergies, connections and consequences. PMID- 26591929 TI - Assessing surge capacity expansion plan awareness and attitudes: A survey of Connecticut hospitals. AB - This study aimed to ascertain levels of awareness and attitudes of healthcare professionals within four hospital personnel categories, regarding their facility's surge capacity expansion plan. The exploratory descriptive study used a 14-question electronic survey to collect data from hospital personnel in four labour categories. A total of 292 hospital staff from 32 Connecticut hospitals completed the survey, including executive staff mid-level management staff incident command hospital staff and emergency planning contacts. The strongest levels of agreement were found to be: the need for an emergency planning contact, understanding surge expansion roles and responsibilities, and provision of enhanced training and heightened participation in drills and exercises. Statistical significance was found when comparing hospital personnel categories in seven of the 14 survey questions that related to time at hospital, understanding personal role in surge event, understanding staff role in surge event, participating in events to increase surge awareness, understanding alternative care facility roles and responsibilities, understanding incident command system (ICS) roles and responsibilities and the needfor ICS training. Findings demonstrate that some personnel perceive that their institutions are sub optimally prepared to expand surge capacity. Education and training are important factors that contribute to improving these perceptions and help guide institutional preparedness and response efforts. PMID- 26591930 TI - Healthcare system resiliency: The case for taking disaster plans further--Part 1. AB - To establish true healthcare resiliency, and to better position healthcare organisations to provide effective response, continuity, resumption and recovery of fundamental services and operations during serious incidents and disasters, the disaster planning process must evolve into an integrated approach of four contingency planning disciplines that holistically examine the end-to-end, all hazard response continuum. This process also needs to incorporate and scale multifarious organisational levels and, when required, the health sector. This paper is the first component of two independent, but related, pieces. It will examine the typical state of disaster preparedness and plans in healthcare, examine the worth and value of honing disaster plans, and will introduce two recommended contingency planning disciplines: enterprise risk management and emergency response planning. For each discipline, a case will be made for its inclusion into the overall disaster planning process, including examination of background information, benefits, how it improves disaster planning, and other resources helpful to the reader. The second paper, in afuture issue of the Journal of Business Continuity & Emergency Planning, will introduce business continuity management--including IT disaster recovery--and crisis communications as the third and fourth contingency planning disciplines needed for a fully integrated approach. The opinions expressed in this paper are those of the authors and may not be entirely those of the organisation. PMID- 26591931 TI - Development and implementation of a business continuity management risk index. AB - This paper will present the building blocks for developing and implementing the BCM risk index; whether it is used as a comprehensive metric for risk or preparedness. This paper introduces the concept of a business continuity management (BCM) risk index--a comprehensive metric that measures and reports the status of the primary 'intended outcome' of the BCM programme to top management. In addition to measuring the primary programme output,;the BCM risk index can be used to demonstrate the overall value of the BCM programme to executive management. This is accomplished because the BCM risk index allows quantitative measurement of current risk levels and their comparison with established risk tolerances. The BCM Risk Index can provide executive management with reports on the risk level of individual business units, departments, subsidiaries or the enterprise in a way that drives both risk management and BCM initiatives. The name 'risk index' can be misleading, however. The BCM risk index concept can also be used to measure preparedness levels. In fact, implementation at DTE Energy has resulted in calling it the 'preparedness index', which is used to measure and report preparedness levels rather than risk levels. PMID- 26591932 TI - Achieving enhanced organisational resilience by improved management of risk: Summary of research into the principles of resilience and the practices of resilient organisations. AB - There have been many high-profile incidents in recent times that have affected both individual organisations and large parts of society. In response to these disasters and their consequences, there has been increasing focus on the concept of 'resilience'. Airmic worked with Cranfield School of Management to investigate the features of resilient organisations and whether common characteristics could be identified. The research summarised in this paper discovered five principles that increase an organisation's level of resilence. The paper also reports on the actions taken by organisations to embed these resilience principles into four main business enablers. These business enablers in combination represent the business model of the organisation. The overall conclusion of the research was that, in order to achieve a state of enhanced resilience, organisations need to be aware of risks and threats they face and then combine the actions required to be 'risk compliant' with the ability to be 'risk responsive'. PMID- 26591933 TI - Stakeholders' experiences with US hospital emergency preparedness--Part 2. AB - This study examined, via qualitative phenomenology, important stakeholders' experiences with US hospital emergency preparedness, finding that their experiences varied from positive and effective to frustrating, time-consuming and inefficient. The findings centred on four themes: the importance of funding; collaboration, communication and coordination; the role of government; and hospital leadership buy-in. Together, these findings suggest that issues such as a lack of performance metrics, insufficient funding, inadequate surge capacity, confusing federal guidelines and accreditation requirements and an overall lack of coordination in hospitals' abilities to manage emergency incidents continue to plague the US healthcare system. Exploring, and now understanding, these experiences can support the field in maintaining elements that work and recognising and applying solutions to its short-comings. This is the second of two papers on the subject, the first of which appeared in a previous issue of this journal, examining the study's methodological approach, data analysis, main results and implications for practice. PMID- 26591934 TI - [Nursing professionals should be "public authority"]. PMID- 26591935 TI - [RESILIENCE AND NURSE CARE]. AB - Resilience is a dynamic and evolving process, that varies according to the circumstances, the features of the trauma, the context, the stage of life in which the person is, culture and learning we had. Largely depends on the art of extending the arm to ask for help and also the art to attempt it with significant relationships. From the belief that the nursing profession is called to provide resilience tutoring, we review the keys by which we consider these professionals potential resilience tutors. PMID- 26591936 TI - [FROM THE SILENCE AND THE OBEDIENCE, TO THE INNOVATION AND THE VISIBILITY]. AB - Nursing process has been influenced and modified throughout history by different factors, as familiar, social and cultural aspects. Basically, the vocation has made nursing a tremendously servile and dedicated profession, which is drowning out its initiative and its innovation. Protectionist influences towards the profession, are the main barrier to the innovation, effective leadership and to different ways of thinking. Furthermore, the professional silence and the obedience to other disciplines, have slowed professional progress and the visibility of patient care. Nowadays, more than before, there is clearly perceived in the nursing staff a sense of helplessness and legally defenceless. At the same time, a lack of professional ideology and a sense of underused and undervalued profession. This undermines the development of innovation and effective leadership. Besides, it must be taken into account that the inviolability of personal approach and the invisibility of our profession are related to the professional silence. This fact has a direct effect on nurse's leadership team. PMID- 26591937 TI - [PAIN MANAGEMENT IN PATIENTS OF RAPID RECOVERY (RR) PROGRAM IN TOTAL KNEE ARTHROPLASTY (TKA)]. AB - Total knee arthroplasty (TKA) is a surgery consisting on the artificial joint replacement, due to a traumatic injury or a degenerative process or arthrosis. This surgery causes an important pain to patients, and sometimes affects negatively on their recovery. The choice of the prostheses will depend on the anatomical features of the patient and the surgeon criterion. The concept of a "rapid recovery surgery" was introduced in 1997 by Khelet and meant the beginning of the Fast Track model or the Rapid Recovery (RR) linked to an accelerated rehabilitation, an early discharge and the optimization of all the aspects of pre, intra and post-operative patient experience. Fast recovery is a surgical process which aims to achieve maximum autonomy of the patient through education, pain control and early mobilization. The key of the rapid recovery is to get the involvement of the patient thanks to the empowerment, which means a preoperative patient education that will help to reduce anxiety and it will make easier to engage in their own recovery. Furthermore the patient will take part of an effective post-operative physical therapy, using all the necessary tools to increase their ability to manage their own health problems. The empowerment of these patients is part of the Nursing Model in the Hospital Clinic de Barcelona (HCB), adopted by the Nursing Management in December of 2012. In Catalonia, until the start of the RR surgery, 14,132 interventions in 2008 where done by TKA conventional surgery, needing subsequent conventional hospitalization. This article describes the care and outcomes of nurse interventions, defined in the RR of TKA clinical way, which is focused on the pain's minimization and the impact on patients' mobilization. It was performed in a monographic unit from a tertiary level hospital in Barcelona in 2013. PMID- 26591938 TI - [THE CHAIR OF BIRTHS: A RESOURCE COMPANION OF VERTICALITY IN CHILDBIRTH]. AB - In primitive cultures, women chose to give birth in upright positions such as squatting or sitting, because these positions stimulate a physiological birth. In this way, in order to make easier the delivery support tools such as birthing chair (BC) are discovered. Later, with the medicalization of childbirth, the lithotomy position was introduced as standard practice, with the aim of promoting comfort to the birth attendant. Currently, this position is still prevalent in the hospital environment. The World Health Organization recommendations, stresses the importance of providing impartial information on birthing positions to women, so that she will decide how to give birth without professional influence as a limiting factor in maternal posture. The aim of this review is to make known the utility of the BC, the advantages and disadvantages associated with it, to make it an available resource in vertical childbirth. The BC is a low rise seat horseshoe shaped stable and sturdy structure, and sitting in the chair women acquire squatting position, considered the most natural. The BC is considered a useful tool for childbirth upright. Giving birth using the BC seems to be protective against episiotomies and Kristeller maneuver, provides comfort and empowerment of women and helps them to have a more positive birth experience. PMID- 26591939 TI - [SANITARY WASTE IN THE HOSPITAL SETTING: ATTITUDE OF HEALTH PROFESSIONALS TOWARD ADVANCED MANAGEMENT OF SANITARY WASTE]. AB - OBJECTVE: The aim of this study was to assess the attitude of nurse assistants, nurses, physicians, and lab technicians about advanced management of medical waste. METHODS: Cross-sectional study of Attitude and explanatory variable degree of concordance between Attitude, Knowledge, and Risk Perception. The sample size was 176 health professionals from three hospitals in,the Barcelona area. A questionnaire of 44 items with responses measured on a Likert scale type questions and free and spontaneous association and incomplete sentences was used. RESULTS: Mean Attitude of health professionals surveyed was 4.40, with a standard deviation of 0.4 on a scale of 1-5, where 1 is considered a very negative and five a very positive Attitude. According to the values obtained with the Professional Category, the nurse assistants had an average value of 4.45 in Attitude, followed by nurses (4.36), physicians (4.27), and lab technicians (4.47). In the Pearson correlation, coefficients between Attitude, Risk Perception, Global Assessment, and level of Knowledge, values of r = 0.172 andp = 0.023 were obtained, r = -0.156 and p = 0.039 and r = 0.013 and p = 0.865 respectively. The mean values of the variables Knowledge, Risk Perception, Attitude, and Overall Rating were significantly different (ANOVA) in Knowledge level, according to Professional Category and Welfare Service, but not in other categories. CONCLUSIONS: The results of the current study suggest that health professionals generally have a very positive Attitude towards the management of medical waste. A significant relationship between Attitude and Risk Perception and Overall Rating was observed. In terms of the analysis of Variance, there was a significant difference in the level of Knowledge according to the Professional Category and the Assistance Service. PMID- 26591940 TI - [NURSE PEDIATRIC EMERGENCY VALUATION IN PRIMARY CARE: QUALITY RECORD AND PATIENTS AND NURSES SATISFACTION WITH TOOL VEUPAP]. AB - OBJECTIVE: To value the degree of completion of VEUPAP record, the level of satisfaction of the accompanists otcrilaren witn nursing care and nurse satisfaction. DESIGN: Descriptive study. There was valued the cumplimentation of record of global and specific form by nurse according to defined quality criteria. The satisfaction of the accompanists was valued by the AMABLE questionnaire, the nurses satisfaction with the use of VEUPAP by the CSLPS-EAP and the personal accomplishment in the work by the MBI in his validated Spanish version. RESULTS: 266 VEUPAP cases were evaluated. The general compliance of the items exceeds 95 (92-98) %, except for three items. Completion of protocols fever, respiratory distress, gastrointestinal, and abdominal pain is 95 (92-98) %, 93(90-96) %, 90 (86-94) %--and 67 (61-73) % respectively. More than 95 (93-97) % users referring to be satisfied with the nurses attention. The 100 (100-100) % of the nurses are very satisfied with their tasks and activities and personal accomplishment they get, 88(84-92) % with the quality of patient care and achievement of objectives. All feel quite satisfied with their degree of autonomy. Job instability represents 50(44-56) % of dissatisfaction. The EE is low for 94% of nurses and a medium for 6%, the DP high for 17% and low for 13% and the PA low for 53% and medium for 47%. CONCLUSIONS: Quality of registration, user satisfaction and the nurse who provides care satisfaction are three cornerstones of pediatric emeraency care. VEUPAP impacts positively on these three aspects. PMID- 26591941 TI - [Health education]. PMID- 26591942 TI - [Interview with Dr. Guillermo J. Garcia Sola President of the Scientific Committee of the XXII National Congress of the Spanish Association of Nursing of Digestive Pathology]. PMID- 26591943 TI - [Conclusions of the XIV National and IX International Congress of Nursing History "A century caring for society." Santander, 7-9 may 2015]. PMID- 26591944 TI - [The European University empowers the multi-professional collaboration and teamwork to ensure the professional excellence of nurses]. PMID- 26591945 TI - [The 10 most "optimistic" hospitals of Spain receive their award in Valencia. Madrid will host the Second Edition of the Optimistic Hospital Awards in may 2016]. PMID- 26591946 TI - [I Meeting on nursing ethics]. PMID- 26591947 TI - Drug-induced iatrogenesis: medication safety in a nursing home for the elderly. PMID- 26591948 TI - A clinical primer of the role of gut microbiome in health and disease. AB - Gut microbiome represents the total microbes present in the gastrointestinal tract including the genes they encode. These microbes primarily exist in a reciprocal state with the host contributing several important functions such as carbohydrates fermentation, vitamin biosynthesis and regulation of the immune system. The gut microbiome represents a dynamic organ, which responds to changes in the host, such as genetics and age, as well as environment such as diet and antibiotics. While these microbes can adapt to change, any disturbance in this host-microbe equilibrium has the potential to initiate a cascade of events leading to a disease phenotype. In this review we highlight the emerging role of gut microbiome in different gastrointestinal and systemic diseases, the role of current therapies and development of future therapies targeting the gut microbiome as a potential mode of treatment. PMID- 26591949 TI - Primary hepatic lymphoma. AB - Primary hepatic lymphoma (PHL) is a lymphoproliferative disorder confined to the liver without evidence of involvement of spleen, lymph nodes, bone marrow or other lymphoid structures. This is in contrast to Non Hodgkin's Lymphoma (NHL) that often involves the liver as a secondary manifestation. PHL is a rare disease and constitutes 0.016% of all cases of NHL. PHL typically occurs in middle aged men, and usually the chief presenting symptoms are non specific which includes right upper quadrant pain, B symptoms like fever and weight loss and constitutional symptoms. Most frequent physical finding is hepatomegaly which occurs in 75% of patients. Jaundice is rare and present only in less than 5% of patients. Majority of PHL originates from B cells. The blood investigations and imaging findings are nonspecific. Histopathology is essential and confirms the diagnosis. Treatment modalities include combination of surgical resection, chemotherapy and radiotherapy. The prognosis without therapy is grim. The prognosis and management of PHL is different from hepatocellular carcinoma or metastatic disease, hence it is essential to differentiate it from these diseases. The purpose of this review is to emphasize the importance of accurate diagnosis before implementing therapeutic plan for any hepatic space occupying lesion in liver. PMID- 26591950 TI - Role of endoscopic retrograde cholangiography in ruptured hepatic hydatid cyst. AB - AIM: To report endoscopic retrograde cholangiopancreatography (ERCP) findings of intrabiliary hydatid cyst rupture. MATERIAL AND METHODS: A retrospective study of cases with intrabiliary rupture of hydatid cyst was conducted. A total of 4 cases (all female with a mean age of 32 years) were included. ERCP and ultrasound data were evaluated. Assessment involved number, location, size, internal and wall characteristics of cyst; intrahepatic biliary radicle dilatation (IHBRD); common bile duct (CBD) dilatation and evidence of extrabiliary rupture on ultrasound. ERCP evaluation included IHBRD, CBD dilatation, communication between cysts and intrahepatic biliary radicles (IHBR) and filling defects within the IHBR and CBD. Treatment details were also obtained. RESULTS: A total of 5 cysts were evaluated in 4 patients. Left lobe cysts were most common (n=4). Segment II/III were the most commonly affected segments (n=3). Cyst outline was smooth and cystobiliary communication noted in all cases. Deformation of cyst wall was noted in 2 cases. Isolated (left or right) IHBRD lateralised to the side of the cyst was most common (n=4). CBD dilatation was seen in all cases with a mean calibre of 1.4 cm. Concomitant extrabiliary rupture was seen in 3 cases. Endoscopic management was done in all cases without complications. Three patients underwent surgical excision after a mean period of 8 weeks following ERCP. CONCLUSION: Isolated IHBRD lateralized to the side of hydatid cyst with CBD dilatation is the commonest ERCP finding of intrabiliary rupture of hydatid cyst. PMID- 26591951 TI - Non-alcoholic fatty liver disease prevalence and associated risk factors--A study from rural sector of Maharashtra. AB - BACKGROUND AND AIM: Nonalcoholic Fatty Liver Disease (NAFLD) is the most common cause of chronic liver diseases and hardly any studies have been reported about its prevalence from rural India. This study aims at assessing the prevalence of NAFLD rural sector from Maharashtra (India) and study the risk factors associated with the disease. METHODS: The study was conducted on 410 individuals from villages in the vicinity of Nanded town attending a tertiary care hospital; out of which 302 individuals were considered for analysis. Detailed history, physical examination, anthropometric measurements, laboratory investigations were done. Diagnosis of NAFLD was based on ultrasonographic findings. RESULTS: Prevalence of NAFLD was found be 28.1%. Mean BMI in NAFLD patients (25.38 +/- 6.58 kg/m2) was significantly higher (p = 0.002) than that of normal group (22.85 +/- 4.70 kg/m2). Metabolic syndrome and diabetes showed a significant association with NAFLD (p < 0.0001). The biochemical investigations of fasting blood sugar (FBS), total cholesterol (TC), triglycerides (TG) and total cholesterol to high density lipoprotein ratio (TC/HDL) showed significant difference between the two groups. CONCLUSION: Prevalence of NAFLD was found be 28.1%. Study confirms that the increased BMI, metabolic syndrome, increased fasting blood glucose and serum triglycerides are potentially strong indicators of NAFLD. PMID- 26591952 TI - Gastrointestinal bleeding in acute pancreatitis: etiology, clinical features, risk factors and outcome. AB - BACKGROUND: There is paucity of data on the effect of interventions on risk of gastrointestinal bleeding (GIB) in acute pancreatitis (AP). METHODS: Retrospective study of records of patients with AP and GIB. RESULTS: 16 (3.7%) patients (14 males; mean age 39.3 +/- 12.8 years) had gastrointestinal bleeding. Two patients had peptic ulcer disease related GIB. The cause of GIB in remaining patients was: pseudoaneurysms in 5, gastrointestinal fistulization in 4, and no identifiable lesion in 5. Two patients with pseudoaneurysms were treated with angioembolisation whereas 3 needed surgery. The patients with gastrointestinal fistula had complicated course and 3 of these 4 patients died due to sepsis and multi organ failure. Rest 5 patients with no identifiable lesion were managed conservatively and there was no recurrence of GIB. Of the 14 patients with AP related GIB, a previous intervention had been done in 11(79%) patients. Fifty three patients (12.7%) without GIB died whereas 5 (31.2%) patients with GIB succumbed to the illness (p = 0.04). CONCLUSIONS: The majority of our patients of AP with GIB had antecedent history of interventions. The mortality was higher in patients with GIB, which was not due to hemorrhage but to sepsis and related complications. PMID- 26591953 TI - Autoimmune hepatitis in India: single tertiary referral centre experience. AB - BACKGROUND AND AIMS: Autoimmune hepatitis is considered to be rare in Asia Pacific region. There a few long term studies available. This study was planned to estimate the burden, natural history of AIH and challenges associated with management in a single non-transplant tertiary referral center. METHODS: Prospectively maintained data of patients treated as AIH was screened and patients who qualified AIH by retrospective application of simplified criteria's were enrolled. 181 patients qualified. 125 patients with substantial follow up (65 Definite AIH; 81 females; median age 46, range 8 - 79) were included in study. RESULTS: Prevalence of AIH was 1.3% and 8.74% amongst all liver disease patients and chronic liver disease respectively. 89 patients qualified as Type I AIH, 14 as type II AIH and 22 were autoimmune markers negative. Modes of presentation was acute liver failure (n = 8), chronic hepatitis (n = 17), cirrhosis (n = 89), 50 patients were decompensated), ACLF (n = 7), while 2 were clinically asymptomatic. 19 patients had preceding history of drug intake. 33 patients didn't undergo pretreatment liver biopsy. Prednisolone alone was the predominant immunosuppressive agent used, especially in decompensated cirrhotics and those with acute liver failure. First remission rates after first immunosuppression course were 60%, 85% and 63% in type I, type II and autoantibody negative groups. After a median follow up of 7 years (range 1 - 17 years), 15 patients died (12 of liver related complications) and 2 underwent liver transplantation. Failure to normalize ALT had a high hazard ratio predicting liver related death or transplantation. 11 patients had improvement on repeat liver biopsy, with 5 showing complete cirrhosis reversal. 40 patients are on long term maintenance immunosuppression. CONCLUSION: AIH, though uncommon, needs to be kept in mind as early treatment is associated with significantly good long-term prognosis. PMID- 26591954 TI - Obstructive jaundice secondary to paracoccidioidomycosis. PMID- 26591955 TI - Gastrointestinal stromal tumor mimicking a prostatic abscess. PMID- 26591956 TI - Hemorrhagic acute pancreatitis following percutaneous transhepatic biliary drainage: a rare and serious complication. PMID- 26591957 TI - Serous cystadenoma of pancreas: imaging diagnosis. PMID- 26591958 TI - Hilar traumatic neuroma masquerading as Klatskin tumor. PMID- 26591959 TI - Recurrent diarrhea: an unusual case of lupus enteritis. PMID- 26591960 TI - Multifocal pancreatoblastoma with pseudocyst in a 2-year-old boy. PMID- 26591961 TI - Extra-osseous Ewing's sarcoma presenting as obstructive jaundice. PMID- 26591962 TI - Isolated retrovesical hydatid cyst presenting with obstructive uropathy and bilateral lower limb edema. PMID- 26591963 TI - Duplication of transverse colon in an adult presenting as chronic diarrhea. PMID- 26591964 TI - Ultrasound guided transrectal catheter drainage of pelvic collections. AB - The transrectal approach to draining deep-seated pelvic collections may be used to drain The transrectal approach to draining deep-seated pelvic collections may be used to drain intra-abdominal collections not reached by the transabdominal approach. We discuss 6 patients with such pelvic collections treated with transrectal drainage using catheter placement via Seldinger technique. Transrectal drainage helped achieve clinical and radiological resolution of pelvic collections in 6 and 5 of 6 cases, respectively. It simultaneously helped avoid injury to intervening bowel loops and neurovascular structures using real time visualization of armamentarium used for drainage. Radiation exposure from fluoroscopic/CT guidance was avoided. Morbidity and costs incurred in surgical exploration were reduced using this much less invasive ultrasound guided transrectal catheter drainage of deep-seated pelvic collections. PMID- 26591965 TI - Ultrasonographic demonstration of inner tube sign: a tropical dilemma. AB - INTRODUCTION: Ultrasonographic demonstration of intra biliary parallel lines or "inner tube sign" is considered diagnostic for biliary ascariasis in regions where ascariasis is endemic. PATIENTS & METHODS: 148 patients with inner tube sign on ultrasonography were evaluated. In most, diagnosis was confirmed by ultrasonographic demonstration of restitution of normal appearance of bile duct with passage of round worms in vomitus or faeces. RESULTS: Diagnosis was confirmed in 122 of 148 patients. 26 patients were lost to follow-up. Biliary ascariasis was responsible for the sign "parallel lines" in 113 patients. Of the remaining, intrabiliary stents were responsible for the "inner tube sign" in six whereas in three it was due to hydatid membranes following intrabiliary rupture of hydatid cyst. CONCLUSION: Biliary ascariasis is the commonest cause of inner tube sign in the tropics. However, this sign can also be produced by biliary stents and hydatid membranes. Awareness of these possibilities is essential for sonologists in the tropics. PMID- 26591966 TI - Do Sleep Disorders Predispose to the Development of Type 2 Diabetes Mellitus? PMID- 26591967 TI - A Comparative Study of Skin Prick Test versus Serum-Specific IgE Measurement in Indian Patients with Bronchial Asthma and Allergic Rhinitis. AB - BACKGROUND: Skin prick testing (SPT) is the 'gold standard' in the assessment of allergic sensitivity to inhalant allergens. Serum-specific immunoglobulin E (SSIgE) measurement is a complementary test. SPT is performed with antigen extracts from India while SSIgE utilises extracts derived from European antigens. OBJECTIVE: To evaluate the performance of allergic assessment by SSIgE against cockroach, housefly and mosquito aeroallergens which are frequently implicated in driving respiratory allergies in India considering SPT as the 'gold standard'. METHODS: Twenty patients (mean age 28.5 years; range 15-50 years) diagnosed to have bronchial asthma and/or rhinitis underwent SPT. The SSIgE levels were obtained at the same visit. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of SSIgE testing were calculated using SPT as the 'gold standard'. The correlation between SPT grading and SSIgE levels was also evaluated. RESULTS: The sensitivity of SSIgE testing to each of the 3 aero-allergens was > 85%. The PPV of cockroach and mosquito SSIgE was > 85%; housefly SSIgE had PPV of 68.7%. The two tests were in agreement in 85% (cockroach), 90% (mosquito) and 55% (housefly). There was a significant correlation between the grades of SPT reactions and SSIgE levels. CONCLUSIONS: The SSIgE has higher sensitivity and PPV, but lacks specificity. Higher sensitivity with low specificity leads to increased false positive diagnosis of allergic disease. Unlike allergenic pollens, however, insect antigen extracts from different regions seem to give comparable results, and can thus, reliably be used in the evaluation of allergy. PMID- 26591968 TI - A Study of Depression in Adult Patients with Bronchial Asthma Presenting to a Tertiary Care Hospital in Eastern India. AB - BACKGROUND: Bronchial asthma is a serious global health problem. Depression, the most common mood disorder, is often found to be higher among people with chronic health conditions like bronchial asthma. METHODS: Patients with newly diagnosed to have bronchial asthma (n = 100) who fulfilled the study criteria were evaluated for depression with Beck Depression Inventory (BDI) score. Severity and level of bronchial asthma control were determined as per Global Initiative for Asthma (GINA) guidelines. Subjective asthma severity was assessed by Perceived Control of Asthma Questionnaire. Follow-up evaluation was done after three months of asthma management with the same study tools. RESULTS: In our study population, 65% asthma patients showed depression on first visit (95% Confidence interval [CI] 55.65-74.35). Correlation coefficient between subjective asthma severity and severity of depression was -0.945 (p < 0.001) while correlation coefficient between objective asthma severity and depression severity was 0.066 (p = 0.515). In follow-up visit after asthma management 63% patients still had depression (95% CI 53.54-72.46). Correlation coefficient between objective asthma control and depression severity was 0.1 (p = 0.320). Correlation coefficient between subjective asthma severity and severity of depression was -0.979 (p < 0.001). CONCLUSIONS: Our observational study suggests that depression is highly prevalent in asthma patients. There is a high inverse correlation between depression and patient's perception of asthma control. However, no significant correlation could be observed between objective measures of asthma severity and depression. PMID- 26591969 TI - Interpretation of Spirometry: Selection of Predicted Values and Defining Abnormality. AB - Spirometry is the most frequently performed investigation to evaluate pulmonary function. It provides clinically useful information on the mechanical properties of the lung and the thoracic cage and aids in taking management-related decisions in a wide spectrum of diseases and disorders. Few measurements in medicine are so dependent on factors related to equipment, operator and the patient. Good spirometry requires quality assured measurements and a systematic approach to interpretation. Standard guidelines on the technical aspects of equipment and their calibration as well as the test procedure have been developed and revised from time-to-time. Strict compliance with standardisation guidelines ensures quality control. Interpretation of spirometry data is based only on two basic measurements--the forced vital capacity (FVC) and the forced expiratory volume in 1 second (FEV1) and their ratio, FEV1/FVC. A meaningful and clinically useful interpretation of the measured data requires a systematic approach and consideration of several important issues. Central to interpretation is the understanding of the development and application of prediction equations. Selection of prediction equations that are appropriate for the ethnic origin of the patient is vital to avoid erroneous interpretation. Defining abnormal values is a debatable but critical aspect of spirometry. A statistically valid definition of the lower limits of normal has been advocated as the better method over the more commonly used approach of defining abnormality as a fixed percentage of the predicted value. Spirometry rarely provides a specific diagnosis. Examination of the flow-volume curve and the measured data provides information to define patterns of ventilatory impairment. Spirometry must be interpreted in conjunction with clinical information including results of other investigations. PMID- 26591970 TI - Massive Recurrent Pleural Effusion in a 35-Year-Old Non-Smoking Male. PMID- 26591971 TI - Isolated Endobronchial Capillary Haemangioma: A Rare Cause of Haemoptysis in Adult. AB - Endobronchial capillary haemangioma is a very rare benign tumour in adults. The clinical presentation and management of adult capillary haemangiomas involving the tracheo-bronchial tree is not yet established. We present a case of an isolated capillary haemangioma of the left main bronchus detected during the evaluation of an adult male presented with haemoptysis. The lesion was managed successfully bronchoscopically. PMID- 26591972 TI - A 54-Year-Old Man with Tracheomegaly, Tracheal Diverticulas and Bronchiectasis- Mounier-Kuhn Syndrome. AB - Mounier-Kuhn syndrome is a rare idiopathic clinical, radiological and bronchoscopic disorder characterised by abnormal dilatation of the tracheo bronchial tree. The usual presentation is with recurrent lower respiratory tract infections. Herein, we report the case of an adult male who was diagnosed to have Mounier-Kuhn syndrome based on radiographic finding of a tracheal diameter of 45.5 mm on computed tomography and dynamic complete collapse of the tracheo bronchial tree on forced expiration, observed during ronchoscopy. PMID- 26591973 TI - Swyer-James-Macleod Syndrome: A Rare Entity. AB - Swyer-James-MacLeod syndrome is a radiological entity characterised by hyperlucency of one or more lobes or of the entire lung associated with decreased number and diameter of ipsilateral peripheral pulmonary vessels resulting in difficult visibility of the arterial network, and unobstructed bronchial system. We report the case of a 12-year-old girl who presented with chief complaint of pain in the chest. Chest radiograph (postero-anterior view) showed hyperlucent left lung field with increased lung volume and shift of the mediastinum to the right side. Contrast-enhanced computed tomography (CECT) of the chest showed hyperlucency and diminished vascularity in the upper lobe and lingula of left lung with hyperinflation of the pulmonary parenchyma. On the basis of clinical and radiological findings, the patient was diagnosed to have Swyer-James-MacLeod syndrome. PMID- 26591974 TI - Eosinophilic Granulomatosis with Polyangitis Presenting as Cardiac Tamponade. AB - Eosinophilic granulomatosis with polyangitis (EGPA; earlier called Churg-Strauss syndrome) is a small-vessel necrotising vasculitis typically characterised by asthma, lung infiltrates, extra-vascular necrotising granulomas and hyper eosinophilia. Cardiac disease is a major contributor to disease-related deaths in EGPA. We describe the case of a 39-year-old woman with late onset asthma, allergic rhinosinusitis, and high extra-vascular and peripheral blood eosinophilia, presenting with peripheral neuropathy and pericardial effusion. Early therapy with intravenous corticosteroids led to resolution of the pericardial effusion and significant clinical improvement. The present case also highlights the importance of being vigilant about potentially fatal cardiac complications in patients with EGPA. PMID- 26591975 TI - Co-existence of Bronchiectasis and Chronic Obstructive Pulmonary Disease. AB - We present the case of a 56-year-old male who presented with cough and breathlessness. Chest radiograph (postero-anterior view) showed bulla and signs of hyperinflation in the right upper zone with cystic shadows in the left lower zone. Spirometry showed severe irreversible airflow obstruction with restriction and decreased diffusion capacity for carbon monoxide. On high resolution computed tomography (HRCT), right upper lobe bulla with emphysematous changes and left lower lobe cystic bronchiectasis were seen. Considering its rarity of occurrence and paucity of data in literature regarding co-existence of bronchiectasis with emphysema, this case is being reported. PMID- 26591976 TI - Wegener's Granulomatosis: Are We Still Missing It? AB - We report the case of an 18-year-old female who was mis-diagnosed as a smear negative pulmonary tuberculosis and advised standard antituberculosis treatment. She later presented with clinio-radiological worsening and thrombosis of superficial veins of the lower extremity. Cytoplasmic anti-neutrophil cytoplasmic antibody and computed tomography-guided lung biopsy confirmed the diagnosis of Wegener's granulomatosis. The rare association of superficial vein thrombosis with lung manifestation is highlighted here as also the need for a high index of clinical suspicion to avoid a missed or delayed diagnosis. PMID- 26591977 TI - A normobaric gas exposure animal chamber and its validation in hyperoxia exposure. AB - We are living in an environment full of gases, and any change in the concentration of a component of the air or contaminants (usually toxic) in the air may significantly threaten human health. Thus, to investigate the influence of gases in animal models it is helpful to elucidate the pathogenesis of gas related injury. Although there are devices used for gas exposure in animals, there are still limitations in the establishment of these animal models, such as the change in gas concentration during the refreshing of water, food and litter, and the contamination of toxic gases released by animals. Herein, we freshly prepared a chamber for normobaric gas exposure. During the exposure in this chamber, the refreshing of water, food and litter does not require opening of the chamber. The chamber gases are continuously circulated and filtered, and the gas concentration remains very stable. To validate the feasibility of this chamber, rats were exposed to pure oxygen as an example. Results showed that rats with hyperoxia-induced lung injury simulated by pure oxygen exposure displayed the representative characteristics as observed in humans: shortness of breath, lung edema, alveolar septal rupture, infiltration of inflammatory cells, oxidative and inflammatory injury. This suggests that it is feasible to establish animal models using this chamber for the investigation of gas toxicity. PMID- 26591978 TI - Postural stability in patients with decompression sickness evaluated by means of Quantitative Romberg testing. AB - OBJECTIVE: The present study was designed to retrospectively evaluate the use of quantitative Romberg's testing on postural stability during the course of hyperbaric oxygen (HBO2) therapy in patients presenting with decompression sickness (DCS). METHODS: The Quantitative Romberg test was used to evaluate postural stability in 33 patients with DCS treated between May 2009 and August 2014. Postural stability was assessed before and after each session of HBO2 therapy. Patients were allocated into groups according to whether they presented with vertigo or not. RESULTS: Significantly higher sway values obtained with the Quantitative Romberg test were observed in the group of DCS with vertigo relative to DCS without vertigo and healthy controls. A stepwise improvement in postural instability for DCS patients with vertigo was found following HBO2 therapy. After three treatments of HBO2, postural stability was found to be within the normal range of healthy controls. CONCLUSIONS: The Quantitative Romberg test offers the the clinician a fast, reliable and objective set of parametrical data to document postural instability in patients with either confirmed or suspected DCS. PMID- 26591979 TI - Effect of hyperbaric oxygen on lipoprotein subfractions in diabetic patients. AB - OBJECTIVES: Favorable metabolic changes have been observed in many in vitro and animal studies after application of hyperbaric oxygen (HBO2). Metabolic changes after hyperbaric oxygen therapy, especially focused on lipoprotein subfractions, have not been described in humans. Our aim was to investigate possible alteration in concentration of lipoprotein subfractions in diabetic patients after hyperbaric oxygen therapy. METHODS: 58 Type 2 diabetic patients were enrolled in a prospective matched case-control study. A total of 31 underwent hyperbaric oxygen therapy, and 27 were included in the control group without HBO2 exposure. Fasting concentrations of lipoprotein subfractions were measured by electrophoresis in polyacrylamide gel 24 hours before and 24 hours after hyperbaric sessions performed at 2.5 atmospheres absolute for 15 days. Homeostatic model assessment of insulin resistance, C-peptide and glycemic variability were assessed before and after therapy. RESULTS: We observed decreased subfractions of very-low-density lipoprotein (VLDL), intermediate density lipoprotein (IDL 3), LDL 1, LDL 2 and LDL 3-7 after hyperbaric oxygen treatment. In addition, the IDL 1 subfraction, as well as the concentration of C peptide, increased significantly in the treatment arm. Glycemic variability improved after therapy. No differences were observed in the control group. CONCLUSION: Hyperbaric oxygen therapy is connected with antiatherogenic metabolic changes. This study demonstrates that hyperbaric oxygen therapy may hold potential for inducing metabolic changes in diabetic patients that may decrease their cardiovascular risk. PMID- 26591980 TI - An evaluation of the redox state in professional scuba divers. AB - Taking into consideration limited data regarding molecular interactions during and after diving, this investigation was intended to determine the oxidative status of divers before and after scuba diving by monitoring the oxidative status parameters. The prevalence study included a group of 32 male professional police scuba divers, 32 +/- 5.1 years old. The examination took place twice: in a resting state before scuba diving and immediately after the dive (to 30 meters for 30 minutes). The oxidative status of the scuba divers was determined by measuring levels of the following oxidative stress markers: the index of lipid peroxidation (measured as TBARS), nitrites (NO2-), superoxide anion radical (O2* ), hydrogen peroxide (H2O2), superoxide dismutase (SOD) and catalase (CAT). Statistically significant increases in levels of NO2- and TBARS were observed after the dive, while there were no statistically relevant changes in levels of O2*-, H2O2, SOD and CAT. Our results have shown that a dive with these characteristics only slightly disturbs redox homeostasis, without serious intermolecular changes that can lead to prominent oxidative stress. PMID- 26591981 TI - Continuous bladder irrigation in the monoplace hyperbaric chamber: Two case reports. AB - INTRODUCTION: Radiation-induced hemorrhagic cystitis is a serious side effect of radiation therapy. Anemia requiring transfusion can ensue. Treatment methods include bladder irrigation, fulguration, and hyperbaric oxygen (HBO2) therapy. Failure of treatment leads to cystectomy associated with a high risk of severe complications (42%) and mortality (16%). Continuous bladder irrigation (CBI) is often required to prevent further clot formation. HBO2 supports the healing process of radiation cystitis. In patients requiring CBI, the time in HBO2 can help cause clot accumulation and obstruction. We describe a method of providing CBI in a monoplace hyperbaric chamber. MATERIALS AND METHODS: An IV to catheter adapter is used, allowing an IV pump to control CBI flow into the chamber. Drainage is collected in an extra-large (2- to 5-liter) bag. The rate is set so the volume does not exceed the bag's capacity. The bag is placed in a manner that precludes spilling and allows monitoring of outflow. RESULTS: CBI was successfully maintained. Brief cases are presented and issues discussed. SUMMARY/CONCLUSIONS: CBI is easily maintained in a monoplace hyperbaric chamber, with readily available equipment allowing for uninterrupted CBI of hemorrhagic cystitis. HBO2 helps mitigate the potential side effects of other interventions in a previously irradiated area. PMID- 26591982 TI - Spontaneous cerebral gas embolism and pulmonary arteriovenous malformation: a case report. AB - Pulmonary barotrauma can cause cerebral arterial gas embolism (CAGE) from pulmonary overdistension of alveoli forcing gas into the pulmonary vasculature. We report a case of CAGE in a man found to have occult pulmonary arteriovenous malformation (PAVM) and undiagnosed obstructive sleep apnea (OSA). A 46-year-old man was admitted to the hospital for an acute seizure and left-sided weakness, with telangiectasias on his lower lip and tongue. Brain-computed tomography (CT) showed gas emboli in the right hemisphere. Chest CT revealed a 1.8-cm PAVM in the posterior right costophrenic sulcus. A transthoracic echocardiogram showed no intracardiac shunt or patent foramen ovale. He was treated with phenytoin, lidocaine and hyperbaric oxygen. The PAVM was occluded with a detachable balloon followed by coil embolization. Polysomnography revealed severe obstructive sleep apnea, which was treated with CPAP. Seven years later, the patient was functioning at his pre-event baseline. We propose the CAGE was caused by high negative intrathoracic pressures while breathing against an obstructed upper airway, with air entrainment into the PAVM and subsequent arterialization. PMID- 26591983 TI - Low forced expiratory flow rates and forceful exhalation as a cause for arterial gas embolism during submarine escape training: a case report. AB - A 26-year-old male U.S. Navy submariner suffered an arterial gas embolism during pressurized submarine escape training. Routine pretraining medical screening revealed no history of asthma, pneumothorax or recent respiratory infection. Pulmonary function testing and posterioranterior/lateral chest X-ray were normal. He forcefully exhaled at the start of his ascent and developed neurological abnormalities including lightheadedness with lower extremity weakness and paresthesias after surfacing. He fully recovered after a U.S. Navy Treatment Table 6. This case represents the first report of an arterial gas embolism since the U.S. Navy resumed pressurized submarine escape training utilizing the Submarine Escape and Immersion Equipment suit. We discuss possible contributing factors and propose that his AGE was caused by pulmonary barotrauma due to a combination of low forced expiratory flow rates and an overly forceful exhalation during his ascent. PMID- 26591984 TI - A cutis marmorata in which the presence of intravascular air was confirmed by CT: A case report. PMID- 26591985 TI - Editorial: Fifty years of health services in Tanzania: What next? PMID- 26591986 TI - The epidemiology and socio-economic impact of rift valley fever epidemics in Tanzania: a review. AB - Rift Valley Fever (RVF) is an acute, mosquito-borne viral disease that has a significant global threat to humans and livestock. This review was conducted to provide comprehensive update on Rift Valley Fever (RVF) in Tanzania, with particular attention devoted to trend of occurrence, epidemiological factors, socio-economic impact and measures which were applied to its control. Information presented in this paper was obtained through extensive literature review. RVF occurred for the first time in Tanzania in 1930. This was followed by periodic epidemics of 10-20 years, i.e., 1947, 1957, 1977, 1997 and 2007. During the latest disease outbreak in 2007 (the expanded to cover wider area of the country) 52.4% (n=21) of regions in Tanzania mainland were affected and majority (72.7, n=11) of the regions had concurrent infections in human and animals. Phylogenetic comparison of nucleotide and amimo acid sequences revealed different virus strains between Kenya and Tanzania. Epidemiological factors that were considered responsible for the previous RVF epidemics in Tanzania included farming systems, climatic factors, vector activities and presence of large population of ruminant species, animal movements and food consumption habits. The disease caused serious effects on rural people's food security and household nutrition and on direct and indirect losses to livestock producers in the country. Psycho-social distress that communities went through was enormous, which involved the thinking about the loss of their family members and/or relatives, their livestock and crop production. Socially, the status of most livestock producers was eroded in their communities. Steps taken to combat epidemics included restriction of animal movements, ban of the slaughter of cattle and vaccination of livestock and health education. PMID- 26591987 TI - Malaria entomological profile in Tanzania from 1950 to 2010: a review of mosquito distribution, vectorial capacity and insecticide resistance. AB - In Sub Saharan Africa where most of the malaria cases and deaths occur, members of the Anopheles gambiae species complex and Anophelesfunestus species group are the important malaria vectors. Control efforts against these vectors in Tanzania like in most other Sub Saharan countries have failed to achieve the set objectives of eliminating transmission due to scarcity of information about the enormous diversity of Anopheles mosquito species and their susceptibility status to insecticides used for malaria vector control. Understanding the diversity and insecticide susceptibility status of these vectors and other factors relating to their importance as vectors (such as malaria transmission dynamics, vector biology, ecology, behaviour and population genetics) is crucial to developing a better and sound intervention strategies that will reduce man-vector contact and also manage the emergency of insecticide resistance early and hence .a success in malaria control. The objective of this review was therefore to obtain the information from published and unpublished documents on spatial distribution and composition of malaria vectors, key features of their behaviour, transmission indices and susceptibility status to insecticides in Tanzania. All data available were collated into a database. Details recorded for each data source were the locality, latitude/longitude, time/period of study, species, abundance, sampling/collection methods, species identification methods, insecticide resistance status, including evidence of the kdr allele, and Plasmodium falciparum sporozoite rate. This collation resulted in a total of 368 publications, encompassing 806,273 Anopheles mosquitoes from 157 georeferenced locations being collected and identified across Tanzania from 1950s to 2010. Overall, the vector species most often reported included An. gambiae complex (66.8%), An. funestus complex (21.8%), An. gambiae s.s. (2.1%) and An. arabiensis (9%). A variety of sampling/ collection and species identification methods were used with an increase in molecular techniques in recent decades. Only 32.2% and 8.4% of the data sets reported on sporozoite analysis and entomological inoculation rate (EIR), respectively which highlights the paucity of such important information in the country. Studies demonstrated efficacy of all four major classes of insecticides against malaria vectors in Tanzania with focal points showing phenotypic resistance. About 95% of malaria entomological data was obtained from northeastern Tanzania. This shows the disproportionate nature of the available information with the western part of the country having none. Therefore it is important for the country to establish entomological surveillance system with state of the art to capture all vitally important entomological indices including vector bionomics in areas of Tanzania where very few or no studies have been done. This is vital in planning and implementing evidence based malaria vector control programmes as well as in monitoring the current malaria control interventions. PMID- 26591988 TI - Response to Rift Valley Fever in Tanzania: Challenges and Opportunities. AB - Rift Valley Fever (RVF) is an arthropod borne viral disease affecting livestock (cattle, sheep, goats and camels), wildlife and humans caused by Phlebovirus. The disease occurs in periodic cycles of 4-15 years associated with flooding from unusually high precipitations in many flood-prone habitats. Aedes and Culex spp and other mosquito species are important epidemic vectors. Because of poor living conditions and lack of knowledge on the pathogenesis of RVF, nomadic pastoralists and agro-pastoralists are at high risk of contracting the disease during epidemics. RVF is a professional hazard for health and livestock workers because of poor biosafety measures in routine activities including lack of proper Personal Protective Equipment (PPE). Direct exposure to infected animals can occur during handling and slaughter or through veterinary and obstetric procedures or handling of specimens in laboratory. The episodic nature of the disease creates special challenges for its mitigation and control and many of the epidemics happen when the governments are not prepared and have limited resource to contain the disease at source. Since its first description in 1930s Tanzania has recorded six epidemics, three of which were after independence in 1961. However, the 2007 epidemic was the most notable and wide spread with fatal human cases among pastoralists and agro-pastoralists concurrent with high livestock mortality. Given all the knowledge that exist on the epidemiology of the disease, still the 2006/2007 epidemic occurred when the government of Tanzania was not prepared to contain the disease at source. This paper reviews the epidemiology, reporting and outbreak-investigation, public awareness, preparedness plans and policy as well as challenges for its control in Tanzania. PMID- 26591989 TI - Is sickle cell disease sufficiently prioritized in policy and socio-economic research on diseases in Tanzania? Lessons for the past 50 years. AB - Catastrophic health consequences associated with chronic and genetic disorders, including those related to sickle cell disease (SCD) remain lowly measured and understood. Illnesses associated with SCD, especially the, sickle cell anaemia (SCA) pose significant tolls to individual patients and their families and contribute to poverty due to loss in production and retardation of economic development. This paper synthesises evidence from systematic literature reviews on policy priorities both in theory and practice and studies carried out on SCD. The review was systematically done by drawing evidence from published and unpublished literature searched through online search engines and other sources. The magnitude of SCA problem is yet to be adequately measured and documented in terms of the scale of its prevalence in many countries including Tanzania. However, a few reports available pinpoint Tanzania as one of the African countries with a large number of patients with SCD. Social stigma and discrimination against patients with SCD pose psychological affect to either the individual patients or their family members and this is partly due to low community knowledge on this disease on one hand and the perceived socio-economic disturbances associated with the disease that at times reduce the morale of caregivers/ takers in families to attend patients. A few studies so far seem to have much focused on the medical dimensions of the disease usually reported at health facilities therefore, failing to establish the actual magnitude and socio economic consequences of the disease, thus limiting the room for more informed policy decisions. Unfortunately, the inadequate public policy and research attention to this disease indicates that there is need for revisiting research and policy agenda towards making a difference in its interventions, and this include creation of public awareness and prioritizing research. ' PMID- 26591990 TI - Maternal health in fifty years of Tanzania independence: Challenges and opportunities of reducing maternal mortality. AB - High rate of maternal death is one of the major public health concerns in Tanzania. Most of maternal deaths are caused by factors attributed to pregnancy, childbirth and poor quality of health services. More than 80% of maternal deaths can be prevented if pregnant women access essential maternity care and assured of skilled attendance at childbirth as well as emergency obstetric care. The objective of this review was to analyse maternal mortality situation in Tanzania during the past 50 years and to identify efforts, challenges and opportunities of reducing it. This paper was written through desk review of key policy documents, technical reports, publications and available internet-based literature. From 1961 to 1990 maternal mortality ratio in Tanzania had been on a downward trend from 453 to 200 per 100,000 live births. However, from 1990's there been an increasing trend to 578 per 100,000 live births. Current statistics indicate that maternal mortality ratio has dropped slightly in 2010 to 454 per 100,000 live births. Despite a high coverage (96%) in pregnant women who attend at least one antenatal clinic, only half of the women (51%) have access to skilled delivery. Coverage of emergence obstetric services is 64.5% and utilization of modern family planning method is 27%. Only about 13% of home deliveries access post natal check-up. Despite a number of efforts maternal mortality is still unacceptably high. Some of the efforts done to reduce maternal mortality in Tanzania included the following initiatives: reproductive and child survival; increased skilled delivery; maternal death audit; coordination and integration of different programs including maternal and child health services, family planning, malaria interventions, expanded program on immunization and adolescent health and nutrition programmes. These initiatives are however challenged by inadequate access to maternal health care services. In order to considerably reduce maternal deaths some of recommended strategies include: (i) strengthening the health system to provide skilled attendance during child birth; (ii) upgrading rural health centres to provide emergency obstetric services; (iii) providing adolescent and male friendly family planning services; (iv) strengthening public private partnership to ensure continuum of care; (v) supporting operational research to answer the immediate concerns of the health system; and (vi) strengthening community participation and women empowerment to take role of their own health and the family at large. In conclusion, maternal mortality ratio in Tanzania is unacceptably high and still very far from reaching the millennium development goals. Maternal health care services should focus on ensuring there is continuum of care through strengthening the health system; provision of good quality of health care in a well organized referral health system and operation research to support programme implementation. PMID- 26591991 TI - Public health concern and initiatives on the priority action towards non communicable diseases in Tanzania. AB - Tanzania is already facing challenges caused by existing burden of communicable diseases, and the growing trend of nonconununicable diseases (NCDs), which raises a lot of concerns and challenges. The objective of this review is to provide broad insight of the "silent epidemic" of NCDs, existing policies, strategies and interventions, and recommendations on prioritized actions. A review of existing literature including published articles, technical reports, and proceedings from national and international NCDs meetings was carried out. The burden, existing interventions, socio-economic impact, lessons learnt, and potential for expanding cost effective interventions in Tanzania were explored. Challenges to catch up with global momentum on NCD agenda were identified and discussed. The review has indicated that the burden of NCDs and its underlying risk factors in Tanzania is alarming, and affects people of all socio-economic status. The costs of health care for managing NCDs are high, and thus impoverishing the already poor people. The country leadership has a high political commitment; there are policies and strategies, which need to be implemented to address the growing NCD burden. In conclusion, NCDs in Tanzania are a silent rising health burden and has enormous impact on an individual and country's social-economical status. From the experience of other countries, interventions for NCDs are affordable, feasible and some are income generating. Multisectoral approach, involving national and international partners has a unique role in intensifying action on NCDs. Tanzania should strategize on implementation research on how to adapt the interventions and apply multi-sectoral approach to control and prevent NCDs in the country. PMID- 26591992 TI - Non communicable diseases in Tanzania: a call for urgent action. AB - Globally there is evidence of the growing burden of Non Communicable diseases (NCDs) especially in developing countries including Tanzania. This paper summarises the review of published papers on the magnitude of Non Communicable Diseases in the country. Current opportunities for management and control of NCDs are also explored. In this review diseases such as diabetes and hypertension have been shown to have increased over the years. Prevalence of risk factors such as obesity, dyslipidemia and smoking has been shown to be high with clear gender and urban rural differences. Generally there is paucity of national representative data on the burden of risk factors and prevalence of non-communicable diseases. The main risk factors for NCDs namely smoking, alcohol intake, unhealthy diet and low physical activity are prevalent in both rural and urban communities. The socio-demographic and economic transition has a big role in the current rise of non-communicable diseases in Tanzania. There are initiatives to control the burden of non-communicable diseases in the country. However there is need to focus more on primary prevention at population level targeting interventions to reduce exposure to tobacco, reduce alcohol intake, reduce salt intake, promote healthy diets and physical activity. For the prevention and control of NCDs, there needs to be a continuum from primary to tertiary prevention and a scope of interventions from the community level up to the national level. Community-based interventions are needed targeting the risk factors for primary prevention. In addition, secondary prevention measures are needed targeting those at high risk to ensure that they are identified early through a high risk targeted screening for early identification and appropriate care. Effective policies are needed to support such interventions. PMID- 26591993 TI - Are we prepared for emerging and re-emerging diseases? Experience and lessons from epidemics that occurred in Tanzania during the last five decades. AB - This paper reviews preparedness for containing and controlling emerging and re emerging diseases drawing lessons from disease events that occurred in animal and human populations in the last five decades (1961-2011). A comprehensive analysis based on retrieval and analysis of grey and published literature as well as reported cases was carried out to document type and trend of occurrence of emerging and re-emerging infectious diseases in different parts of Tanzania. Overall, the majority of diseases reported in the country were viral in nature followed by bacterial diseases. The trend for the occurrence shows a number of new emerging diseases as well as re-occurrence of old diseases in both animal (domestic and wild) and human populations. In humans, the major disease epidemics reported in the last five decades include cholera, influenza A H1N1, plague and rubella. In animals, the major epidemic diseases reported were Contagious Bovine Pleuropneumonia, Contagious Caprine Pleuropneumonia, Peste des petits ruminants and Giraffe Ear and Skin Diseases. Some epidemics have been reported in both human and animal populations including Rift Valley fever and anthrax. The emergence of the 'fit-for purpose' approaches and technologies such as the discipline of One Health, use of participatory epidemiology and disease surveillance and mobile technologies offers opportunity for optimal use of limited resources to improve early detection, diagnosis and response to disease events and consequently reduced impact of such diseases in animal and human populations. PMID- 26591994 TI - Fifty years of tsetse control in Tanzania: challenges and prospects for the future. AB - Tsetse flies are the vectors of trypanosomes, the causative organisms of trypanosomiasis, nagana, in animals and sleeping sickness in man. In Tanzania, tsetse transmitted trypanosomiasis is one of the most important disease affecting both animals and humans. About 40% of land suitable for grazing and areas with high agricultural potential are currently tsetse infested. It is estimated that about 4.4 million livestock and 4 million people are at risk of contracting tsetse borne trypanosomiasis. African animal trypanosomiasis (AAT) causes loss in animals due to mortality and reduced milk yield, which is estimated at US$ 7.98 million annually. Even after 50 years of independence, Human African Trypanosomiasis (HAT) or Sleeping Sickness is still one of the major public health problems with about 300 cases being reported annually. Tsetse control has been sporadic and uncoordinated hence no tangible results have been accrued since independence despite the fact that technologies which have facilitated tsetse control in other places are available. Fifty years of independence have seen shrinkage of tsetse belt to 43% in 16 surveyed regions. Opportunities for future are wide open if tsetse control will involve all stakeholders, who are directly or indirectly affected by the tsetse problem; if tsetse and trypanosomiasis eradication will adopt an area wide and participatory approach with emphasis on environmentally and user friendly techniques for expanded livestock sector; improved food security and livelihood in affected communities, for achievement of the millennium development goals. PMID- 26591995 TI - Impact of climate change on human health and health systems in Tanzania: a review. AB - Climate change (CC) has a number of immediate and long-term impacts on the fundamental determinants of human health. A number of potential human health effects have been associated either directly or indirectly with global climate change. Vulnerability to the risks associated with CC may exacerbate ongoing socio-economic challenges. The objective of this review was to analyse the potential risk and vulnerability in the context of climate-sensitive human diseases and health system in Tanzania. Climate sensitive vector- and waterborne diseases and other health related problems and the policies on climate adaptation in Tanzania during the past 50 years are reviewed. The review has shown that a number of climate-associated infectious disease epidemics have been reported in various areas of the country; mostly being associated with increase in precipitation and temperature. Although, there is no single policy document that specifically addresses issues of CC in the country, the National Environmental Management Act of 1997 recognizes the importance of CC and calls for the government to put up measures to address the phenomenon. A number of strategies and action plans related to CC are also in place. These include the National Biodiversity Strategy and Action Plan, the National Action Programme, and the National Bio-safety Framework. The government has put in place a National Climate Change Steering Committee and the National Climate Change Technical Committee to oversee and guide the implementation of CC activities in the country. Recognizing the adverse impacts of natural disasters and calamities, the government established a Disaster Management Division under the Prime Minister's Office. Epidemic Preparedness and Response Unit of the Ministry of Health and Social Welfare is responsible for emergency preparedness, mostly disease outbreaks. However, specific climate changes associated with human health issues are poorly addressed in the MoHSW strategies and the national health research priorities. In conclusion, CC threatens to slow, halt or reverses the progress the country has made or is making to achieve its national and millennium development goals. It is therefore important that Tanzania prepares itself to appropriately address CC impact on human health. It is equally important that policy makers and other stakeholders are engaged in a process to update and adapt priorities, mobilize resources and build interdisciplinary research and implementation capacity on climate change and its mitigation. PMID- 26591996 TI - Challenges and opportunities in building health research capacity in Tanzania: a case of the National Institute for Medical Research. AB - Capacity building is considered a priority for health research institutions in developing countries to achieve the Millennium Development Goals by 2015. However, in many countries including Tanzania, much emphasis has been directed towards human resources for health with the total exclusion of human resources for health research. The objective of this study was to systematically investigate the capacity building process for the Tanzanian National Institute for Medical Research (NIMR) over a 30-year period and identify the challenges and opportunities in creating a critical mass of multi-disciplinary research scientists that is required for achieving the intended health benefits. A desk review of personnel database was conducted for information covering 1980-2009 on academic qualifications, training, research experience and research output. The current staff curriculum vitae (CV) were reviewed to gather information on researchers' employment record, training, training support, area of expertise and scientific output. Interviews were conducted with a cross section of researchers on capacity development aspects using a self-administered questionnaire. In-depth interviews were also conducted with the current and former NIMR Management to seek information on capacity development challenges. A review was also done on staff personal files, annual reports, strategic plans and other occasional documents. A total of 163 CV were assessed; of these, 76.7% (125) were for Research Scientists (RS), 20.9% (34) Laboratory Technologists (LT) and 2.4% (4) for System Analysts. The Institute had 13 research scientists upon its establishment. Since 1980, NIMR has recruited a total of 185 Research Scientists. By 2009, NIMR had a total scientific workforce of 170 staff (RS= 82.4%; LT= 17.6%). Of the 140 RSs, 37 (26.4%), were first degree; 77 (55.5%) second degree while 26 (18.6%) were PhD degree holders. Of the total of 78 researchers interviewed, 55 (70.5%) indicated to have accessed postgraduate training through their personal efforts and 23 through institutional arrangement. Sixty (77%) respondents were satisfied with their tenure at NIMR. Seventy (89%) indicated that they had not at any point considered leaving NIMR. Most (79%) research scientists were recruited while holding a first degree, a few (17%) with second degree while only one (0.7%) holding a PhD degree. NIMR has experienced a research scientist attrition rate of 17.5%. Staff retention factors included availability of training opportunities; passion for conducting research; and good career prospects. Despite having a training programme, the institute has never at any moment been able to hold its own training resources. Being a public research institution, NIMR receives its core funding from the government of the United Republic of Tanzania. The bulk of the funding appears to be spent on personnel emoluments that take up to 85% (mean = 66%) of the allocated budget. In conclusion, the current NIMR's research capacity building is dependent mainly on foreign funding and personal initiatives. There is an urgent need to increase local funding for capacity building and conduct of research. A programme should be put in place to ensure sustainability of the capacity building process. PMID- 26591997 TI - [Characterizing Beijing's Airborne Bacterial Communities in PM2.5 and PM1 Samples During Haze Pollution Episodes Using 16S rRNA Gene Analysis Method]. AB - During 8th-14th Jan., 2013, severe particulate matter (PM) pollution episodes happened in Beijing. These air pollution events lead to high risks for public health. In addition to various PM chemical compositions, biological components in the air may also impose threaten. Little is known about airborne microbial community in such severe air pollution conditions. PM2.5 and PM10 samples were collected during that 7-day pollution period. The 16S rRNA gene V3 amplification and the MiSeq sequencing were performed for analyzing these samples. It is found that there is no significant difference at phylum level for PM2.5 bacterial communities during that 7-day pollution period both at phylum and at genus level. At genus level, Arthrobacter and Frankia are the major airborne microbes presented in Beijing winter.samples. At genus level, there are 39 common genera (combined by first 50 genera bacterial of the two analysis) between the 16S rRNA gene analysis and those are found by Metagenomic analysis on the same PM samples. Frankia and Paracoccus are relatively more abundant in 16S rRNA gene data, while Kocuria and Geodermatophilus are relatively more abundant in Meta-data. PM10 bacterial communities are similar to those of PM2.5 with some noticeable differences, i.e., at phylum level, more Firmicutes and less Actinobacteria present in PM10 samples than in PM2.5 samples, while at genus level, more Clostridium presents in PM10 samples. The findings in Beijing were compared with three 16S rRNA gene studies in other countries. Although the sampling locations and times are different from each other, compositions of bacterial community are similar for those sampled at the ground atmosphere. Airborne microbial communities near the ground surface are different from those sampled in the upper troposphere. PMID- 26591998 TI - [Distribution Characteristics and Source Analysis of Dustfall Trace Elements During Winter in Beijing]. AB - The dustfall content is one of the evaluation indexes of atmospheric pollution. Trace elements especially heavy metals in dustfall can lead to risks to ecological environment and human health. In order to study the distribution characteristics of trace elements, heavy metals pollution and their sources in winter atmospheric dust, 49 dustfall samples were collected in Beijing City and nearby during November 2013 to March 2014. Then the contents (mass percentages) of 40 trace elements were measured by Elan DRC It type inductively coupled plasma mass (ICP-MS). Test results showed that more than half of the trace elements in the dust were less than 10 mg x kg(-1); about a quarter were between 10-100 mg x kg-1); while 7 elements (Pb, Zr, Cr, Cu, Zn, Sr and Ba) were more than 100 mg x kg(-1). The contents of Pb, Cu, Zn, Bi, Cd and Mo of winter dustfall in Beijing city.were respectively 4.18, 4.66, 5.35, 6.31, 6.62, and 8.62 times as high as those of corresponding elements in the surface soil in the same period, which went beyond the soil background values by more than 300% . The contribution of human activities to dustfall trace heavy metals content in Beijing city was larger than that in the surrounding region. Then sources analysis of dustfall and its 20 main trace elements (Cd, Mo, Nb, Ga, Co, Y, Nd, Li, La, Ni, Rb, V, Ce, Pb, Zr, Cr, Cu, Zn, Sr, Ba) was conducted through a multi-method analysis, including Pearson correlation analysis, Kendall correlation coefficient analysis and principal component analysis. Research results indicated that sources of winter dustfall in Beijing city were mainly composed of the earth's crust sources (including road dust, construction dust and remote transmission of dust) and the burning of fossil fuels (vehicle emissions, coal combustion, biomass combustion and industrial processes). PMID- 26591999 TI - [Pollution Characteristics of Aldehydes and Ketones Compounds in the Exhaust of Beijing Typical Restaurants]. AB - Aldehydes and ketones compounds, as one of the components in the exhaust of restaurants, are a class of volatile organic compounds (VOCs) with strong chemical reactivity. However, there is no systematic study on aldehydes and ketones compounds in the exhaust of restaurants. To further clarify the food source emission levels of aldehydes and ketones compounds and controlling measures, to access city group catering VOCs emissions control decision-making basis, this study selected 8 Beijing restaurants with different types. The aldehydes and ketones compounds were sampled using DNPH-silica tube, and then ultra performance liquid chromatography was used for quantitative measurement. The aldehydes and ketones concentrations of reference volume condition from 8 restaurants in descending order were Roasted Duck restaurant, Chinese Style Barbecue, Home Dishes, Western Fast-food, School Canteen, Chinese Style Fast food, Sichuan Cuisine, Huaiyang Cuisine. The results showed that the range of aldehydes and ketones compounds (C1-C9) concentrations of reference volume condition in the exhaust of restaurants was 115.47-1035.99 microg x m(-3). The composition of aldehydes and ketones compounds in the exhaust of sampled restaurants was obviously different. The percentages of C1-C3 were above 40% in the exhaust from Chinese style restaurants. Fast food might emit more C4-C9 aldehydes and ketones compounds. From the current situation of existing aldehydes and ketones compounds control, the removal efficiency of high voltage electrostatic purifiers widely used in Beijing is limited. PMID- 26592000 TI - [Emission Characteristics of Vehicle Exhaust in Beijing Based on Actual Traffic Flow Information]. AB - The basic data of traffic volume, vehicle type constitute and speed on road networks in Beijing was obtained fly modei simulation and field survey. Based on actual traffic flow information and. emission factors data with temporal and spatial distribution features, emission inventory of motor vehicle exhaust in Beijing was built on the ArcGIS platform, meanwhile, the actual road emission characteristics and spatial distribution of the pollutant emissions were analyzed. The results showed that the proportion of passenger car was higher than 89% on each type of road in the urban, and the proportion of passenger car was the highest in suburban roads as well while the pickup truck, medium truck, heavy truck, motorbus, tractor and motorcycle also occupied a certain proportion. There was a positive correlation between the pollutant emission intensity and traffic volume, and the emission intensity was generally higher in daytime than nighttime, but the diurnal variation trend of PM emission was not clear for suburban roads and the emission intensity was higher in nighttime than daytime for highway. The emission intensities in urban area, south, southeast and northeast areas near urban were higher than those in the western and northern mountainous areas with lower density of road network. The ring roads in urban and highways in suburban had higher emission intensity because of the heavy traffic volume. PMID- 26592001 TI - [Chemical Compositions in PM2.5 and Its Impact on Visibility in Summer in Pearl River Delta, China]. AB - Aerosol samples of PM2.5 were collected simultaneously at 6 sites from five cities (Guangzhou urban, Conghua (suburban of Guangzhou), Foshan, Dongguan, Shenzhen and Zhubai) in Pearl River Delta region during the summer of 2010. The concentrations of organic carbon (OC), elemental carbon (EC) and water-soluble ions were determined by thermal/optical carbon analyzer and ion chromatography, respectively. The characteristics of PM2, OC, EC and ions, spatial distribution were discussed. Moreover, ambient light extinction coefficients were reconstructed by IMPROVE formula. The results showed that spatial distribution characteristics of PM2.5. and its chemical compositions were obviously different. The PM2.5 in Guangzhou, Foshan and Dongguan were higher than those in Zhuhai and Shenzhen. The contributions of (NH4)2SO4, OM, EC and NH4NO3 to ambient light extinction coefficient were 39%, 31%, 12% and 13%, respectively. PMID- 26592002 TI - [Health Risk Assessment of Tunnel Workers Based on the Investigation and Analysis of Occupational Exposure to PM10]. AB - The health risk of tunnel workers' occupational exposure to PM10, was evaluated applying public health exposure evaluation nodel. A questionnaire survey of 250 tunnel workers was conducted in a construction site of Ma-zhu Highway in Hubei Province, and the concentrations of PM10 were monitored. The results showed that the PM10 exposure concentrations of different types of tunnel workers were extremely high. Compared with the limited value, the PM10 exposure concentrations were 83 times, 18 times, 8 times, 9 times Emd 9 times for excavation workers, blasting workers, supporting workers, slag-out workers and secondary-lining workers, respectively. For secondary-lining workers, the average daily exposure time was the longest, which was 11.48 h x d(-1), and the energy metabolism rate was also the highest, which was 1067.43 kj x (m2 x h)(-1). Regarding the inhalation rates, secondary-lining workers could be classified to high-level working intensity, and the other four types of tunnel workers could he classified to middle-level working intensity. The health risk assessment results showed that all tunnel workers had health risk. High exposure concentration of PM10 was the main reason for excavation workers' highest hazard quotient, and it was the same for the blasting workers. The reason for secondary-lining workers' high hazard quotient was that they had higher inhalation rates and longer average daily exposure time. In order to reduce the health risk of tunnel workers, firstly the workers should be equipped with appropriate respiratory protective equipment; secondly an appropriate tunnel working standard should be developed to set a reasonable working-years for reducing the exposure time. PMID- 26592003 TI - [Analysis on Emission Inventory and Temporal-Spatial Characteristics of Pollutants from Key Coal-Fired Stationary Sources in Jiangsu Province by On-Line Monitoring Data]. AB - Emission inventory of air pollutants is the key to understand the spatial and temporal distribution of atmospheric pollutants and to accurately simulate the ambient air quality. The currently established emission inventories are still limited on spatial and temporal resolution which greatly influences the numerical prediction accuracy of air quality. With coal-fired stationary sources considered, this study analyzed the total emissions and monthly variation of main pollutants from them in 2012 as the basic year, by collecting the on-line monitoring data for power plants and atmospheric verifiable accounting tables of Jiangsu Province. Emission factors in documents are summarized and adopted. Results indicated that the emission amounts of SO2, NOx, TSP, PM10, PM2.5, CO, EC, OC, NMVOC and NH3 were 106.0, 278.3, 40.9, 32.7, 21.7, 582.0, 3.6, 2.5, 17.3 and 2.2 kt, respectively. They presented monthly variation with high emission amounts in February, March, July, August and December and low emissions in September and October. The reason may be that more coal are consumed which leads to the increase of pollutants emitted, to satisfy the needs, of heat and electricity power supply in cold and hot periods. Local emission factors are needed for emission inventory studies and the monthly variation should be considered when emission inventories are used in air quality simulation. PMID- 26592004 TI - [Hydrogen and Oxygen Isotopic Compositions of Precipitation and Its Water Vapor Sources in Eastern Qaidam Basin]. AB - Stable hydrogen and oxygen isotopes can be used as a tracer to analyze water vapor sources of atmospheric precipitation. We choose Golmud and Delingha as our study areas, Golmud locates in the south of Qaidam basin, and Delingha locates in the northeast. Based on the analysis of monthly change of hydrogen and oxygen isotopic compositions of precipitation during June to September of 2010, and the relationship between deltaD and delta18O in precipitation, we investigated the water vapor sources of precipitation in eastern Qaidam basin. The results show that: (1) meteoric water line between June to September in Golmud is: deltaD = 7.840 delta18O - 4.566 (R2 = 0.918, P < 0.001), and in Delingha is: deltaD = 7.833 delta18O + 8.606 (R2 = 0.986, P < 0.001). The slopes and intercepts of meteoric water line between June to September in both Golmud and Delingha are lower than the global average, and the intercept in Golmud is only -4.566, which indicates the extremely arid climate condition. (2) the delta18O content of precipitation is much higher in Golmud in early July, it shows the enrichment of some heavier isotopes. However, the delta18O content of precipitation becomes lower from late July to early September, especially for the late September. The 8180 content of precipitation in Delingha is higher in June to August than that in late September. (3) the water vapor sources of precipitation in Golmud and Delingha are different, Golmud area is the northern border of Qinghai-Tibet Plateau where the southwest monsoon can reach, and the southwest monsoon brings water vapors of precipitation, but the water vapors of precipitation in Delingha are mainly from local evaporation. PMID- 26592005 TI - [Distribution Characteristics of Sedimentary Pigments in the Changjiang Estuary and Zhe-Min Coast and its Implications]. AB - Compositions and contents of sedimentary pigments were examined using high performance liquid chromatography in order to discuss the spatial distributions of phytoplankton primary production, phytoplankton functional type and the preservation efficiency of phytoplankton pigments and their influencing factors. The results showed that: chloropigments [Chlorins, including chlorophyll-a (Chl a) and pheopigments (Pheo-a), such as pheophytin-a (PHtin-a), pheophorbide-a (PHide-a), pPheophytin-a (pPHtin-a), sterol chlorin esters (SCEs) and carotenol chlorin esters (CCEs)] were the major type of sedimentary pigments. The nutrients inputs from Changjiang Diluted Water and upwelling in the Zhe-Min coastal mud area were the major cause for the patchy distribution with high sedimentary chloropigment contents. Carotenoid contents showed no trending changes and exhibited high values in the Changjiang Estuary and Zhe-Min Coasts. Based on the relative proportions of each diagnostic carotenoid to the total diagnostic carotenoids in the sediments, the relative contributions of diatoms, dinoflagellates, prymnesiophytes, prasinophytes, cryptophytes and cyanobacterias in the phytoplankton fuctional types were 48.8% +/- 17.4%, 10.7% +/- 11.5%, 8.1% +/- 7.2%, 18.6% +/- 8.2%, 9.4% +/- 6.4% and 4.3% +/- 3.2%, respectively. The preference for external environmental conditions (e.g., nutrient level and water salinity) was the main cause for the decreasing trends of diatoms and dinoflagellates proportions and the increasing trends of prasinophytes, cryptophytes and cyanobacterias seawards. Based on the spatial distribution of Chl-a/Pheo-a ratios, the higher preservation efficiencies of sedimentary pigments in the coastal regions (e.g., outer edge of maximum turbidity zone in the Changjiang Estuary, mouth of the Hangzhou Bay and upwelling region in the Zhe-Min Coast) were mainly due to the higher sedimentation rate and seasonal occurrences of hypoxia in bottom water, and these regions with higher sedimentary pigment preservation efficiencies were probably ideal areas for the marine eco environmental evolutions. The bad sedimentary environment caused by the water exchange inside and outside of Hangzhou Bay was the dominant reason for the low sedimentary pigment contents and preservation efficiencies in this region. PMID- 26592006 TI - [Nutrients Input Characteristics of the Yangtze River and Wangyu River During the "Water Transfers on Lake Taihu from the Yangtze River"]. AB - Overall 20 surface water samples were collected from the Yangtze River, the Wangyu River and the Gonghu Bay (Lake Taihu) to clarify the pollution characteristics of nitrogen and phosphorus during 2 sample stages of "Water Transfers on Lake Taihu from the Yangtze River" in August and December of 2013 respectively. The results showed that the mass concentrations of NO2- -N, NO3- N, NH4+ -N and TN in the Gonghu Bay were lower than those of the Yangtze River and Wangyu River during the 2 water transfer processes. However, there was higher level of DON content in the Gonghu Bay than that of the Yangtze River and Wangyu River. The percentages of various N species showed that NO3- -N was the major N species in the Yangtze River and Wangyu River during the 2 water transfer processes. TP contents in samples collected from the Yangtze River displayed a constant trend compared with the Wangyu River. However, the percentages of various P species were different with each other during the 2 water transfer processes. Mass concentrations of DON and TP in surface water in August were higher than those in December and the contents of NO3- -N and TDP were lower in August than those in December. In general, NO3- -N and TPP were the main N and P species in Wangyu River from the Yangtze River. NO3- -N, PO4(3-) -P and TPP were the main N and P species in Gonghu Bay from Wangyu River during the 2 water transfer processes. PMID- 26592007 TI - [Pollution Characteristics of Surface Runoff of Typical Town in Chongqing City]. AB - Six kinds of impermeable underlying surface, cement tile roof, asbestos roof, cement flat roof, residential concrete pavement, asphalt pavement of restaurants, asphalt pavement of oil depot, and a combined sewer overflow canal in the Jiansheng town of Dadukou district in Chongqing city were chosen as sample plots to study the characteristics of nutritional pollutants and heavy metals in town runoff. The research showed that the average mass concentrations of TSS, COD, TN, TP in road runoff were (1681.2 +/- 677.2), (1154.7 +/- 415.5), (12.07 +/- 2.72), (3.32 +/- 1.15) mgL(-1), respectively. These pollutants were higher than those in roof runoff which were (13.3 +/- 6.5), (100.4 +/- 24.8), (3.58 +/- 0.70), (0.10 +/- 0.02) mg x L(-1), respectively. TDN accounted for 62.60% +/- 34.38% of TN, and TDP accounted for 42.22% +/- 33.94% of TP in the runoff of impermeable underlying surface. Compared with the central urban runoff, town runoff in our study had higher mass concentrations of these pollutants. The mass concentrations of TSS, COD, TDN, TN, TDP and TP in the combined sewer overflow were (281.57 +/- 308.38), (231.21 +/- 42.95), (8.16 +/- 2.78), (10.60 +/- 3.94), (0.38 +/- 0.23) and (1.51 +/- 0.75) mg x L(-1), respectively. The average levels of heavy metals in this kind of runoff did not exceed the class VI level of the surface water environmental quality standard. Most pollutants in the combined sewer overflow had first flush. However, this phenomenon was very rare for TSS. There was a significant positive correlation between TSS and COD, TP in the combined sewer overflow. And this correlation was significant between NH4+ -N and TP, TDP, TN, TDP. However, a negative correlation existed between NO3- -N and all other indicators. PMID- 26592008 TI - [Effect of Water and Sediment Regulation on the Transport of Particulate Organic Carbon in the Lower Yellow River]. AB - Both natural processes and human activities in river basins have important impacts on the transport of riverine organic carbon (OC). Better understanding of the riverine OC transport processes is critical for the studies of global carbon cycling. Suspended particulate matters collected from the Lijin Station in the lower Yellow River during the water and sediment regulation ( WSR) period in 2012 (19 June-20 July) were analyzed for grain size, particulate OC (POC) and stable carbon isotopic ratios (delta13C) to investigate-the sources, composition, abundance of POC and the effect of WSR on the transport of POC. The results showed that the WSR in 2012 could be divided into two stages according to the variation of water and sediment discharges: the water-release stage (WRS) and the sediment-release stage (SRS). Variations of the water discharge, sediments, POC and delta13C in these two stages reflected the impacts of WSR on the sources of particulate matters and associated OC. The water discharge in the WRS stage was the highest (4270 m3 x s(-1)), and the sediments scoured from the riverbed in the lower reaches were the major source of suspended particulate matters in this stage, therefore the particles were characterized by relatively coarse grain size (13.9 microm in average of median grain size), low POC (avg. 0.38%) and relatively enriched and constant delta13C (-24.2% per hundred +/- 0.3% per hundred), probably because POC in the sediments scoured from the riverbed had old radiocarbon ages and high degradation. The suspended particulate matters in the SRS stage were mainly derived from the upstream reservoirs and flushed riverbanks due to local rainstorm, and the POC age was relatively young, thus this stage was characterized by high concentration of suspended particulate matters (up to 17.8 kg x m(-3)), fine particles (5.9 microm in average of median grain size), high POC (avg. 0.50%), and depleted and varied delta13C values (-24.8% per hundred +/- 0.6% per hundred). Variation of daily POC flux had similar pattern with sediment discharge, and the total POC flux during the water and sediment regulation period was 1.13 x 10(5) tons, accounting for 12% of the total POC flux in 2012. Compared with previous years, the total water discharge during the WSR period in 2012 has increased, while the total sediment flux and POC flux have reduced. In general, WSR played an important role on the transport of POC in the Yellow River. And furthermore, there was significant difference in the sources, composition and transport of POC in different stages of WSR. PMID- 26592009 TI - [Concentration and Source of Dissolved Organic Carbon in Snowpits of the Tibetan Plateau]. AB - Snowpit samples of three glaciers (Laohugou NO. 12 Glacier (LHG), Small Dongkemadi Glacier on Mount Tanggula (TGL) and East Ronghuk Glacier on Mount Everest (ZF)) in the Tibetan Plateau were collected. Concentrations of DOC and major ions were analyzed. The results showed that average DOC concentrations of the snowpits of LHG, TGL and ZF were (250.30 +/- 157.10), (216.92 +/- 142.82) and (152.50 +/- 56.11) microg x L(-1), respectively. DOC of TGL and ZF accounted for large parts of total values of DOC and ions. Correspondingly, DOC of LHG accounted for small part (only 5%), because LHG was located at north China and intensively influenced by natural mineral dust, which caused high concentrations of Ca2+ (the highest value could reach 5299.18 microg x L(-1)) and consequently low percentage of DOC of snowpit samples. Correlation and PCA analyses were used to study the sources of DOC. DOC was significantly correlated with Ca2+, Mg2+, K+ and SO4(2-). Additionally, PCA further indicated that the main potential source of DOC was the natural source of mineral dust. Meanwhile, anthropogenic pollutants (e.g., biomass, fossil combustion and agricultural related pollutants) could also not be ignored. Moreover, the carbon depositional fluxes of three snowpits were roughly estimated, and the values of LHG, TGL and ZF snowpits were 189.23, 132.76 and 128.44 mg (m2 x a)(-1), respectively, which played a significant role in the carbon cycle in this region and was also helpful for the study of glaciers fluctuation. PMID- 26592010 TI - [Variations of Inorganic Carbon and its Impact Factors in Surface-Layer Waters in a Groundwater-Fed Reservoir in Karst Area, SW China]. AB - In order to understand the inorganic carbon cycle of the groundwater-fed reservoir in karst area, Dalongdong Reservoir, which is located at Shanglin County, Guangxi Zhuang Autonomous Region, China, was investigated from 12th to 20th July, 2014. Concentration of dissolved inorganic carbon (DIC), delta13C of DIC (delta13C(DIC)), partial CO2 pressure (pCO2) and CO2 flux across water-air interface were studied by observation in situ and high-resolution diel monitoring. Results show that: (1) DIC concentration and water pCO2 increased from upstream area to downstream area [DIC(average)): from 122.88 to 172.02 mg x L(-1), pCO2(average) : from 637.91 x 10(-6) to 1399.97 x 10(-6)], while delta13C(DIC) decreased from upstream area to downstream area [delta13C(DIC(average): from -4.34% per hundred to -6.97% per hundred] in the reservoir. (2) CO2 efflux across water-air interface varied from 7.11 to 335.54 mg x (m2 x h)(-1) with mean of 125.03 mg x (m2 x h)(-1) in Dalongdong reservoir surface-layer waters, which was the source of atmospheric CO2. CO2 effluxes across water-air interface in upstream area [mean 131.73 mg x (m2 x h)(-1)] and downstream area [mean 170.25 mg x (m2 x h)(-1)] were higher than that in middle area [mean 116.05 mg x (m2 x h))(-1)] in the reservoir. (3) Water pCO2 and CO2 efflux across water-air interface showed similar characteristics of diel variations, which decreased in daylight and increased in night and showed a negative correlation with chlorophyll a (Chla). Possible reasons of research results are found as follows: (1) DIC concentration, water pCO2 and delta13C(DIC) are influenced by biomass of phytoplankton, turbidity, conductivity, the depth of water and transparency, while CO2 efflux across water-air interface is controlled by both of biomass of phytoplankton and wind speed. (2) Photosynthesis, respiration and vertical motion of phytoplankton possibly affect diel variations of DIC cycle in the groundwater-fed reservoir in karst area. PMID- 26592011 TI - [Modeling the Influencing Factors of Karstification and Karst Carbon Cycle in Laboratory]. AB - To analyze the influencing factors of karstification and karst carbon cycle, a simulation experiment was carried out and 6 soil columns were designed. The results showed that the content of H2O4, hydrodynamic condition and thickness of the soil had important influence on karstification and karst carbon cycle. For the soil columns which were covered by the same thickness of soil, the concentrations of Ca2+ + Mg2+ and SO4(2-) followed the order of B20-2 > B20-1 > B20-3, B50-2 > B50-1 > B50-3. This meant that input of H2SO4 enhanced the karstification and increasing infiltration water had significant dilution effect on the chemical properties. For the soil columns with different thickness of soil but with the same slag pile and hydrodynamic conditions, the concentrations of Ca2+ + Mg2+ and SO4(2-) followed the order of B50-1 > B20-1, B50-2 > B20-2, B50-3 > B20-3. It was demonstrated that more carbonate rock was dissolved under the thick soil columns. In addition, the net consumption of CO2 mainly depended on the content of H2SO4 in this experiment due to slight contribution of H2CO3 to carbonate rock dissolution. More content of H2SO4 brought about less net consumption of C02, but B50-2 was an exception. Organic matter and other nutrients might be input into deep soil with the slag pile, and they promoted the production of soil C)2. Therefore, more CO2 was consumed due to the increased contribution of H2CO to karstification. PMID- 26592012 TI - [Distribution Characteristics and Ecological Risk Assessment of HCHs and DDTs in Surface Water Bodies in Xinxiang]. AB - In order to investigate the distribution characteristics and ecological risk of HCHs and DDTs in the surface water of Xinxiang, 18 surface water samples were collected from from Xinxiang and the concentrations of HCHs and DDTs were determined. The ecological risk of HCHs and DDTs was evaluated using the overlapping areas of probability density function and safety threshold methods. The results showed that the levels of total HCHs (sum of 2 HCHs) and total DDTs (sum of DDTs) in 18 samples detected by GC-ECD ranged from 1.28 ng x L(-1) to 49.2 ng x L(-1) and from 0.42 ng x L(-1) to 12.3 ng x L(-1), respectively. In comparison with those reported for other rivers around the world, the levels of HCHs and DDTs in surface water from Xinxiang ranked middle. The main cause for HCHs and DDTs residues in the studied area was usage of lindane and technical DDTs as revealed by the isomer ratios. The ecological risk evaluation was based on the exposure concentration and available chronic toxicity data of p,p'-DDT, gamma-HCHs and DDD, and the overlapping areas of probability density function and safety threshold methods both showed that the ecological risk of these three OCPs to aquatic organism was in the order of DDD > gamma-HCHs > p,p'-DDT. And the probability of exposure concentration exceeding the 10% value of the toxicity data for DDD. Gamma-HCHs and p,p'-DDT was 10.2%, 5.94%, 0.01%, respectively. PMID- 26592013 TI - [Comparison Study of the Alkanes in Different Aquifer Medium Under Qingmuguan Underground System]. AB - Dissolved alkanes were collected from Dalv spring and Jiangjia spring from July to November, 2013, and were quantitatively analyzed by the gas chromatography mass spectrometer (GC-MS). The results show that the total content of dissolved alkanes in Dalv spring is 175-3279 ng x L(-1), with a mean value of 1011 ng x L( 1). In Jiangjia spring, the total content of dissolved alkanes is 282-775 ng x L( 1), with a mean value of 527 ng x L(-1). Ratios of the content of alkanes with high carbon number( C25-C32) to the total alkanes vary from 27.89% to 52.92% in Dalv spring, and 23.66% to 49.73% in Jangjia spring. Combined with CPI and OEP the relative contribution to the dissolved alkanes of higher plants are increasing in Dalv spring, however, it is different in Jiangjia spring. In addition, the values of L/H couldn't reflect different organic contributions to the dissolved alkanes, and the values of TAR may relate with rainfall. PMID- 26592014 TI - [Spatial Distribution Characteristics of Different Species Mercury in Water Body of Changshou Lake in Three Gorges Reservoir Region]. AB - An investigation on the concentrations and the spatial distribution characteristics of different species of mercury in the water body of Changshou Lake in Three Gorges Reservoir region was carried out based on the AreGIS statistics module. The results showed that the concentration of the total mercury in Changshou Lake surface water ranged from 0.50 to 3.78 ng x L(-1), with an average of 1.51 ng x L(-1); the concentration of the total MeHg (methylmercury) ranged from 0.10 to 0.75 ng x L(-1), with an average of 0.23 ng x L(-1). The nugget effect value of total mercury in surface water (50.65%), dissolved mercury (49.80%), particulate mercury (29.94%) and the activity mercury (26.95%) were moderate spatial autocorrelation. It indicated that the autocorrelation was impacted by the intrinsic properties of sediments (such as parent materials and rocks, geological mineral and terrain), and on the other hand it was also disturbed by the exogenous input factors (such as aquaculture, industrial activities, farming etc). The nugget effect value of dissolved methylmercury (DMeHg) in Changshou lake surface water (3.49%) was less than 25%, showing significant strong spatial autocorrelation. The distribution was mainly controlled by environmental factors in water. The proportion of total MeHg in total Hg in Changshou Lake water reached 30% which was the maximum ratio of the total MeHg to total Hg in freshwater lakes and rivers. It implied that mercury was easily methylated in the environment of Chanashou Lake. PMID- 26592015 TI - [Influence of Marine Aquaculture Around Coal Power Plant on Mercury Species Change in Auuatic Ecological Environment]. AB - To investigate the influence of marine aquaculture around coal power plant on Hg species change in aquatic ecological environment, the fish farming area in Xiangshan Harbor, Zhejiang province, was studied. The concentrations of different Hg species in sea water collected from marine aquaculture sites (MS) and references sites (RS) were measured. The result showed that the total mercury (THg) concentration in the surface water reached 83.0 pmol x L(-1) +/- 97.1 pmol x L(-1). Dissolved Hg (DHg) in pore water of core sediment decreased with the increasing depth. Meanwhile, the DHg content in pore water above 10 cm was significantly higher (P < 0.001) than that below 10 cm, which confirmed the influence of coal-fired power plants on the surrounding areas. THg concentration in MS (96.5 pmol x L(-1) +/- 133 pmol x L(-1)) was higher than that in RS (69.5 pmol x L(-1) +/- 39.4 pmol x L(-1)), which was mainly resulted from the accumulation of sewage discharge by the employees and fish feed material in sediments during breeding that were further released to the overlying water. Methylmercury concentration in pore water of MS (24.0 pmol x L(-1) +/- 16.7 pmol x L(-1)) was also significantly higher than that in RS (6.60 pmol x L(-1) +/- 5.11 pmol x L(-1)), which demonstrated that marine aquaculture activities promoted the methylmercury production by increasing the accumulation of organic matter in sediment. PMID- 26592016 TI - [Using delta34S-SO4(2-) and Delta15N-NO3-, delta18O-NO3- to Trace the Sources of Sulfur and Nitrate in Lihu Lake Undergound Water, Guangxi, China]. AB - To reveal the temporal and spatial variation pattern of groundwater chemistry in Lihu Lake and explore the causes for the change of water quality through analysis of sulfur isotope and nitrogen-oxygen isotope, so as to provide scientific basis for reasonable exploitation and protection of karst water resources. Several groundwater samples, collected from January to December in 2010 and May, October in 2014 were monitored to analyze the chemical composition of conventional water and the characteristics of delta34S-SO4(2-), and delta15N-NO3-. The results showed that: (1) The hydrochemical type of the underground water was HCO3-Ca type and effected by the seasonal precipitation and human activity, the temporal and spatial variation of the main cations was obvious. (2) The sulfur concentration in the underground river was slightly decreased since the operation of the sewage plant, however, the sulfur concentration was still high. The nitrate pollution aggravated in the year 2014 compared to 2010. Impacted by human activity, the concentration of sulfur and nitrate was higher in the upstream Nandan river, Layi cave and the midstream Liangfeng cave, and Gantianba than in the downstream Xiaolong cave. (3) The delta34S-SO4(2-) value ranged from -4.12%o to -0.93%o. It was inferred that the emission of sulfur oxides through burning coal resulted in the rainwater acidification, which input a large amount of SO4(2-) into the underground water in the form of acid rain. (4) The delta15N-N03- value ranged from 0.26%o to 11.58%o, with an average value of 7.61%o, the delta18O-NO3- value ranged from -2.33%o to 21.76%o, with an average value of 9.38%o. In combination of the composition analysis of nitrogen-oxygen isotope of nitrate, it was believed that soil organic nitrogen, manure and sewage were the main sources of nitrate in the groundwater and the main causes for aggravation of nitrate pollution of the underground water. PMID- 26592017 TI - [Ecological Effects of Algae Blooms Cluster: The Impact on Chlorophyll and Photosynthesis of the Water Hyacinth]. AB - The response of chlorophyll and photosynthesis of water hyacinth leaves in different concentrations of clustered algae cells was studied in the simulation experiment, and the aim was to reveal the mechanism of the death of aquatic plants during algae blooms occurred through studying the physiological changes of the macrophytes, so as to play the full function of the ecological restoration of the plants. And results showed the dissolved oxygen quickly consumed in root zone of aquatic plants after algae blooms gathered and showed the lack of oxygen (DO < 0.2 g x L(-1)); and the ORP was lower than -100 mV after 1 d, and it declined to 200 mV at the end of the experiment. There were lots of nutrients releasing to the water after the algae cell died and concentration of DTN in treatment 1 and 2 were 44.49 mg x L(-1) and 111.32 mg x L(-1), and the content of DTP were 2.57 mg x L(-1) and 9.10 mg x L(-1), respectively. The NH4+ -N concentrations were as high as 32.99 mg x L(-1) and 51.22 mg x L(-1), and the root zone with the anoxia, strong reducing, higher nutrients environment had a serious stress effects to the aquatic plants. The macrophytes photosynthesis reduced quickly and the plant body damaged with the intimidation of higher NH4+ -N concentration (average content was 45.6 mg x L(-1)) and hypoxia after algae cell decomposed. The average net photosynthesis rate, leaf transpiration rate of the treatment 2 reduced to 3.95 micromol (M2 x S)(-1), 0.088 micromol x (m2 x s)(-1), and only were 0.18 times, 0.11 times of the control group, respectively, at the end of the experiment, the control group were 22 micromol x (m2 x s)(-1), 0.78 micromol x (M2 x s)(-1). Results indicated the algae bloom together had the irreversible damage to the aquatic plants. Also it was found large amounts of new roots and the old roots were dead in the treatment 1, but roots were all died in the treatment 2, and leaves were yellow and withered. Experiment results manifested that the serious environment caused by the algae blooms together was the main reason of the death of aquatic plants during the summer. So in the practice of ecological restoration, it should avoid the harm to the plant after the algae bloom cells gathered and decomposed, so as to play the purification function of the plant in the ecological rehabilitation project. PMID- 26592018 TI - [Influence of Natural Dissolved Organic Matter on the Passive Sampling Technique and its Application]. AB - This paper studied the effects of different concentrations of natural dissolved organic matter (DOM) on the passive sampling technique. The results showed that the presence of DOM affected the organic pollutant adsorption ability of the membrane. For lgK(OW), 3-5, DOM had less impact on the adsorption of organic matter by the membrane; for lgK(OW), > 5.5, DOM significantly increased the adsorption capacity of the membrane. Meanwhile, LDPE passive sampling technique was applied to monitor PAHs and PAEs in pore water of three surface sediments in Taizi River. All of the target pollutants were detected in varying degrees at each sampling point. Finally, the quotient method was used to assess the ecological risks of PAHs and PAEs. The results showed that fluoranthene exceeded the reference value of the aquatic ecosystem, meaning there was a big ecological risk. PMID- 26592019 TI - [Adhesion Force Analysis of Protein Fouling of PVDF Ultrafiltration Membrane Using Atomic Force Microscope]. AB - To determine the fouling behavior of bovine serum albumin (BSA) on differet hydropniic PVDF ultrafiltration membrane over a range of pH, atomic force microscopy (AFM) and self-made colloidal probes were used to detect the microscopic adhesion forces of membrane-BSA and BSA-BSA, respectively. The results showed a positive correlation between the flux decline extent and the membrane-foulant adhesion force in the initial filtration stage, whereas the foulant-foulant interaction force was closely related to the membrane fouling in the later filtration stage. Moreover, the membrane-BSA adhesion interaction was stronger than the BSA-BSA adhesion interaction, which indicated that the fouling was mainly caused by the adhesion interaction between membrane and foulant. At the same pH, the adhesion force between PA membrane-BSA was smaller than that of PP membrane-BSA, illustrating the more hydrophilic the membrane was, the better the antifouling ability it had. The adhesion force between BSA-BSA fouled PA membrane was similar to that between BSA-BSA fouled PP membrane. These results confirmed that elimination of the membrane-BSA adhesion force is important to control the protein fouling of membranes. PMID- 26592020 TI - [Influence of CNTs on Photodegradation of Salbutamol in Water Environment]. AB - The influence of CNTs on the photolysis of organic pollutant was investigated by studying the photodegradation kinetics of SAL under 1000 W Xenon lamp, in the presence of three kinds of CNTs (SCNT, MWNT-COOH, MWNT-OH). In addition, the interaction between CNTs and Fe3" was also investigated. The results showed that the photodegradation of salbutamol followed pseudo-first-order kinetics, which could be inhibited by all three kinds of CNTs through light screening effect. Formation of singlet oxygen was detected during the photolysis, using the molecular probe furfuryl alcohol. All three kinds of CNTs could absorb electrons through competition, i.e., inhibit SAL photodegradation by light screening effect; meanwhile, the CNTs could generate singlet oxygen through photoexcitation to promote the photodegradation reaction. Both mechanisms coexisted, and in most cases, the inhibition effect was dominant. In addition, CNTs could inactivate the photoactive substance Fe3 in the water body by electrostatic adsorption, and affect the photochemical behavior of organic pollutants in natural water body. PMID- 26592021 TI - [Preparation of beta-In2S3 and Catalytic Degradation of Oxytetracycline Under Solar Light Irradiation]. AB - The preparation of beta-In2S3 nanomaterial was carried out by reacting In (NO3)3 with thioacetamide through hydrothermal process at 120 degrees C for 12 h. The size and morphology of In2S3 were characterized by the scanning electron microscope (SEM), transmission electron microscopy (TEM) and X-ray diffraction (XRD) while the degradation efficiency was evaluated by the photocatalytic degradation of oxytetracycline under natural sunlight. The results revealed that beta-In2S3 nanoparticles are made up of nanosheets with a length of 15-30 nm and with high efficient catalytic performance, in which more than 98% of the initial oxytetracycline (30 mg x L(-1)) was degraded in 4 h. Furthermore, the prepared pG In2 S3 can be recycled and kept efficient catalytic performance above 85% even after reusing for four times, which reflected the good stability and relative photocatalytic activity of In2S3. PMID- 26592022 TI - [Nitrogen Release Performance of Sediments in Drainage Pipeline]. AB - The effects of soil and water ratio, pH, temperature and rotation on the nitrogen transformation of sediment in drainage pipeline were investigated in this study. The experimental results for the four impact factors indicated that ammonia nitrogen was the main existing form for nitrogen release from the sediment to the overlying water, the concentration of ammonia nitrogen was uptrend, reaching the maximum in four to six days, and it went down till to the end of experiments. While the variation trend of nitrate nitrogen concentration was opposite to that of ammonia nitrogen. The factor of pH influenced most in the release of ammonia nitrogen among the four factors, then was the disturbance, and the temperature had a minimal impact. The release of ammonia nitrogen followed the descending order of pH 6.3 > pH 8.0 > pH 9.6, and the maximum concentrations were 54.0, 30.9 and 26.7 mg x L(-1) respectively. The higher soil and water ratio and the longer agitation time under the same agitation speed were, the higher ammonia nitrogen concentration was obtained. An increase in temperature promoted the conversion of ammonia nitrogen to the nitrate nitrogen, and speeded up the decrease of total nitrogen in the overlying water. PMID- 26592023 TI - [Analysis of Precipitation Formation in Biofilm CANUN Reactor and its effect on Nitrogen Removal]. AB - A CANON reactor with polymeric sponge as carrier was started by incubating sludge from another CANON reactor using synthetic inorganic ammonia-rich wastewater as raw water, and was operated at 30 degrees C +/- 1 degree C, pH 6.92-8.52. The precipitation on the surface of carriers was studied in this paper, including influence on nitrogen removal efficiency, causes for formation and composition. The results showed that: (1) the precipitation could influence the distribution of substrate to undermine the performance of CANON reactors; (2) the precipitation was calcium carbohydrate; (3) the production of precipitation may be a common result of four effects that were the regulatory effect of microorganisms on pH value, stripping effect, the role of extracellular polymers, adsorption of sponge and simultaneous chemical, biological reactions; (4) once the precipitation formed, it was difficult to recover to normal. Therefore, some measures are necessary to avoid precipitation, including: (1) raw water pretreatment to reduce the concentrations of Ca2 and Mg2. (2) ensuring short-cut nitrification stable, which could avoid increase of pH because of reduction of DO; (3) we can choose other carriers to reduce precipitation, which must ensure the optimal total nitrogen removal performance and stable short-cut nitrification. PMID- 26592024 TI - [Optimization of Energy Saving Measures with ABR-MBR Integrated Process]. AB - High energy consumption and membrane fouling are important factors that limit the wide use of membrane bioreactor (MBR). In order to reduce energy consumption and delay the process of membrane fouling, the process of anaerobic baffled reactor (ABR)-MBR was used to treat domestic sewage. The structure of the process and conditions of nitrogen and phosphorus removal were optimized in this study. The results showed that energy consumption was reduced by 43% through optimizing the structure of ABR-MBR process. Meanwhile, the process achieved a high level of COD, NH: -N, TN and TP removal, with the average removal efficiencies of 91%, 85%, 76% and 86%, respectively. In addition, the added particulate media could effectively delay membrane fouling, while the formation process of membrane fouling was changed. The extracted amount of carbohydrates increased while the amount of proteins decreased. Finally, the potential was enhanced for the practical application of MBR. PMID- 26592025 TI - [Abundance and Community Composition of Ammonia-Oxidizing Archaea in Two Completely Autotrophic Nitrogen Removal over Nitrite Systems]. AB - Ammonia oxidation is the first and rate-limiting step of nitrification, which was thought to be only performed by ammonia-oxidizing bacteria (AOB). In recent years, ammonia-oxidizing archaea (AOA) was also confirmed to take part in ammonia oxidation. The diversity and abundance of AOA have been investigated in various environments, however, little is known regarding the AOA in the completely autotrophic nitrogen removal over nitrite (CANON) wastewater treatment process. In this study, the abundance and diversity of AOA were investigated in the biofilm and flocculent activated sludge collected in a lab-scale (L) CANON system and a pilot-scale (P) CANON systems, respectively. The quantitative real time PCR (qPCR) was applied to investigate the abundance of AOA and the diversity of AOA was determined by polymerase chain reaction (PCR), cloning and sequencing. The qPCR results showed that the average abundance of AOA amoA gene of L and P was 2.42 x 10(6) copies x g(-1) dry sludge and 6.51 x 10(6) copies x g(-1) dry sludge, respectively. The abundance of AOA in biofilm was 10.1-14.1 times higher than that in flocculent activated sludge. For P system, the abundance of AOA in flocculent activated sludge was 1.8 times higher than that in biofilm. The results indicated that the abundance of AOA might be affected by different sludge morphology. The diversity of AOA in P system was extremely limited, only one OTU was observed, which was classified into Nitrosopumilus subcluster 5.2. The diversity of AOA in L system was higher, eight OTUs were observed, which were classified into five genera: Nitrososphaera subcluster 9, subcluster 8.1, subcluster 4.1, subcluster 1.1 and Nitrosopumilus subcluster 5.2. The diversity and abundance of AOA were different in CANON systems with different sludge morphology. AOA may play an important role in ammonia oxidation in CANON system. PMID- 26592026 TI - [Formation Mechanism of Aerobic Granular Sludge and Removal Efficiencies in Integrated ABR-CSTR Reactor]. AB - Anaerobic Baffled Reactor (ABR) was altered to make an integrated anaerobic aerobic reactor. The research investigated the mechanism of aerobic sludge granulation, under the condition of continuous-flow. The last two compartments of the ABR were altered into aeration tank and sedimentation tank respectively with seeded sludge of anaerobic granular sludge in anaerobic zone and conventional activated sludge in aerobic zone. The HRT was gradually decreased in sedimentation tank from 2.0 h to 0.75 h and organic loading rate was increased from 1.5 kg x (M3 x d)(-1) to 2.0 kg x (M3 x d)(-1) while the C/N of 2 was controlled in aerobic zone. When the system operated for 110 days, the mature granular sludge in aerobic zone were characterized by compact structure, excellent sedimentation performance (average sedimentation rate was 20.8 m x h( 1)) and slight yellow color. The system performed well in nitrogen and phosphorus removal under the conditions of setting time of 0.75 h and organic loading rate of 2.0 kg (m3 x d)(-1) in aerobic zone, the removal efficiencies of COD, NH4+ -N, TP and TN were 90%, 80%, 65% and 45%, respectively. The results showed that the increasing selection pressure and the high organic loading rate were the main propulsions of the aerobic sludge granulation. PMID- 26592027 TI - [Distribution Characteristics and Risk Assessment of Organochlorine residues in Surface Soil of Pearl River Delta Economic Zone]. AB - The contents of 17 Organochlorine pesticides (OCPs) of 605 samples collected from the surface of agriculture land from Pearl River Delta Economic Zone were determined by gas chromatography with electron capture detector (GC-ECD). The residual characteristics, sources and ecological risk of OCPs were also analyzed. The results showed that the detection rate of OCPs was 97.85%. The mean value of residue level was 20.67 microg x kg(-1), with the highest value of 649.33 microg x kg(-1). The main contaminants included DDTs, HCHs, endosulfan sulfate and methoxychlor. Compared with the soils of other cities, the levels of HCHs and DDTs in the studied area were arranged from low to middle levels. The OCPs were obviously regionally distributed. High content areas were mainly distributed in the central area with dense population, intense industrial and agricultural activities. The residue levels in different types of lands were significantly different: the arable land > garden land > woodland. Especially, the residue level was the highest in the vegetable land. Source analysis indicated that the HCHs might come from the use of lindane. DDTs in soil mainly came from early residues, but the dicofol might be the important source in partial area. Comparing the contents of HCHs and DDTs with our National Standard (GB 15618 2008), the qualified rates of the first and second standard of HCHs were 97.5% and 100%, respectively, and the DDTs were 95.5% and 97.7%, respectively. According to the risk assessment, DDTs may still have some potential ecological impact on the studied area. PMID- 26592028 TI - [Risk Assessment of Heavy Metal Contamination in Farmland Soil in Du'an Autonomous County of Guangxi Zhuang Autonomous Region, China]. AB - For a comprehensive understanding of the pollution characteristics and ecological risk of heavy metals of farmland soil in Du'an Autonomous County of Guangxi Zhuang Autonomous Region, China, this study evaluated the cadmium (Cd), arsenic (As), nickel (Ni), zinc (Zn), chromium (Cr), antimony (Sb), copper (Cu) and lead ( Pb) pollution situation using the single factor index, the Nemerow pollution index and the Hakanson ecological risk index. The results showed that heavy-metal pollution of farmland soil in Du'an County was serious. 74.6% of the soil samples had heavy metals concentrations higher than the Grade II of National Soil Environmental Quality Standard (GB 15618-1995). The over standard rates of Cd, As, Ni, Zn, Cr, Sb, Cu, Pb were 70.6%, 42.9%, 34.9%, 19.8%, 19.6%, 2.94%, 1.59%, 0.79%, respectively. Cd and As were the main contaminants in Du'an County, the pollution was far more serious than those of the national and Guangxi Zhuang Autonomous Region. In terms of the ecological risk, heavy metals of farmland soil in Du'an County showed a "middle" ecological risk, with Cd accounting for 88% of the total ecological risk. The north-west of Jiudu Town and the zone between Bao'an Town and Dongmiao Town were two areas with high ecological risk in Du'an County. The contamination of farmland soils in Du'an County was caused by two main sources, whereas the pollution of As and Sb of farmland soils near Diaojiang River was mainly caused by the upstream mining industry. PMID- 26592029 TI - [Assessment of Heavy Metal Pollution and its Health Risk of Surface Dusts from Parks of Kaifeng, China]. AB - Fifty-two dust samples were collected from four parks [Longting Park (P(L)), Tieta Park (P(T)), Qingmingshanghe Park (P(Q)), Xiangguosi Park (P(X))] located in Kaifeng City, China. Concentrations of Hg and As in dusts were measured by atomic fluorescence spectrometry (AFS), while Cr, Cu, Zn, Pb, Ni and Cd were analyzed by inductively coupled plasma mass-spectrometry (ICP-MS). The heavy metal pollution of dust was assessed using Geo-accumulation index (Igeo) and pollution load index (PLI). The health risk due to exposure to heavy metals in dust was assessed using the model recommended by USEPA. The non-carcinogen (HI) and carcinogen health risks (TCR) were also calculated to evaluate the potential risks to adults. The results showed that the average contents of Hg, Cu, Zn, Cd and Pb were much higher than those in control samples and the background values of fluvo-aquic soil in China. The samples were seriously polluted by Hg and Pb, besides, there was.moderate pollution, slight pollution of Cu and Zn, and no pollution of As, Cr and Ni. The PLI from the 4 Parks indicated that there was serious heavy metals pollution of dust in P(X), moderate pollution in P%, and slight pollution in P(T) and P(Q). The average HI of heavy metals in the four Parks was lower than one. The average HI decreased in the order of P(L) > P(X), > P(T) > P(Q), while the average TCR decreased in the order of P(L) > P(Q) > P(x) > P(T). The contribution rate of HQ(As) to HI was about 43.51% , and that of CR(As) to TCR was about 70.11%. PMID- 26592030 TI - [Responses of Soil and Plant 15N Natural Abundance to Long-term N Addition in an N-Saturated Pinus massoniana Forest in Southwest China]. AB - Increasing N deposition in China will possibly cause N saturation of forest ecosystem, further resulting in a series of serious environmental problems. In order to explore the response of forest ecosystem to N deposition in China, and further evaluate and predict the N status of ecosystem, the 15N natural abundance (delta 15N) of soil and plants was measured in a typical Masson pine (Pinus massoniana) forest in southwest China to examine the potential use of delta 15N enrichment factor (epsilon(p/s)) as an effective indicator of N status. Long-term high N addition could significantly increase delta 15N of soil and plants, which was suggested by an on-going N fertilizing experiment with NH4NO3 or NaNO3 for 7 years. Meanwhile, delta 15N of soil and plants under NH, deposition was significantly higher than that under NO- deposition, suggesting different responses of ecosystem to different N-forms of deposition. The "N enrichment factor (epsilon(p/s)) had positive correlations with N deposition, N nitrification, and N leaching in the soil water. Linear correlation between "N enrichment factor and N deposition was found for all Masson pine forests investigated in this and previous studies in China, demonstrating that 15N enrichment factor could be used as an indicator of N status. The NH3 emission control should also be carried out accompanying with NOx emission control in the future, because NH4- deposition had significantly greater impact on the forest ecosystem than NO3- deposition with the same equivalence. PMID- 26592031 TI - [Latitudinal Changes in Plant Stoichiometric and Soil C, N, P Stoichiometry in Loess Plateau]. AB - Field investigations and sampling were conducted in Loess Plateau, including Fu County, Ganquan County, Ansai County, Jingbian County and Hengshan County and Yuyang District. Our objective was to examine changes of leaf and soil stoichiometry characteristics along latitudinal gradient in Loess Plateau, and to provide references for the prediction of soil nutrient status of the ecosystem and constraints of plant nutrition elements in Loess Plateau. The results showed that (1) Across the 35.95 degrees-38.36 degrees N latitude gradient, leaf C, N and P stoichiometry were ranging from 336.95 to 477.38 mg x g(-1) for C, from 18.09 to 33.173 mg x g(-1) for N and from 1.07 to 1.73 mg x g(-1) for P, the arithmetic means were 442.9 mg x g(-1), 25.79 mg x g(-1) and 1.37 mg x g(-1), separately, the variation coefficients were 11.9%, 17.4% and 13.3%. There were obvious correlation between leaf C, N, P and latitude, leaf C, C : N ratio and C: P ratio significantly decreased with the increasing latitude, while leaf N and P significantly increased with the increasing latitude. The relationship between N: P ratio and latitude was not significant. (2) The content of soil organic C and soil total N decreased with increasing latitude and soil layer. In contrast, with the increase of latitude, soil P increased and then decreased. In the 0-10 cm, 10 20 cm soil layers, soil C: N ratio did not change significantly with latitude, while in the 20-40 cm layer, C: N ratio decreased obviously, but soil C: P and N: P ratios decreased with the increasing latitude in all soil layers. (3) Leaf C, C: N and C: P ratios were correlated to soil organic C, soil total N and soil total P in all soil layers, leaf N and P were correlated to soil organic C and soil total N, while leaf N: P ratio was not correlated to soil organic C, soil total N and soil total P. There was a certain correlation between the leaf C, N, P and latitude, however, the correlations between leaf and soil C, N, P were inconsistent. These results demonstrate that the plants were under P limitation in Loess Plateau. PMID- 26592032 TI - [Open-top Chamber for in situ Research on Response of Mercury Enrichment in Rice to the Rising Gaseous Elemental Mercury in the Atmosphere]. AB - In situ research was conducted on the response of mercury enrichment in rice organs to elevated gaseous elemental mercury (GEM) with open-top chambers (OTCs) fumigation experiment and soil Hg enriched experiment. The results showed that Hg concentrations in roots were generally correlated with soil Hg concentrations (R = 0.9988, P < 0.05) but insignificantly correlated with air Hg concentrations (P > 0.05), indicating that Hg in rice roots was mainly from soil. Hg concentrations in stems increased linearly (R(B) = 0.9646, R(U) = 0.9831, P < 0.05) with elevated GEM, and Hg concentrations in upper stems were usually higher than those in bottom stems in OTCs experiment. Hg concentrations in bottom stems were generally correlated with soil Hg concentrations (R = 0.9901, P < 0.05) and second-order polynomial (R = 0.9989, P < 0.05) was fitted for Hg concentrations in upper stems to soil Hg concentrations, and Hg concentrations in bottom stems were usually higher than those in upper stems in soil Hg enriched experiment, indicating the combining impact of Hg from air and soil on the accumulation of mercury in stems. Hg concentrations in foliage were significantly correlated (P < 0.05) with air Hg and linearly correlated with soil Hg (R = 0.9983, P = 0.0585), implying that mercury in foliage was mainly from air and some of Hg in root from soil was transferred to foliage through stem. Based on the function in these filed experiments, it was estimated that at least 60%-94% and 56%-77% of mercury in foliage and upper-stem of rice was from the atmosphere respectively, and yet only 8%-56% of mercury in bottom-stem was attributed to air. Therefore, mercury in rice aboveground biomass was mainly from the atmosphere, and these results will provide theoretical basis for the regional atmospheric mercury budgets and the model of mercury cycling. PMID- 26592033 TI - [Influence of Uranium in Pteris vittata L. Inoculated by Arbuscular Mycorrhizal Fungus]. AB - A pot experiment was carried out to explore the annual changes by bioremediation inoculated with 30 g Glomus versiorme in Pteris vittata L. The results showed that mycorrhizal colonization was the lowest in September 2013 (57.14%), and was the highest in March 2014 (75.20%), following the tendency firstly increasing and then decreasing. The dry biomass was markedly high in Gv than that in CK, especially in roots. The total U was significantly higher in Gv than that in CK, and was fixed predominantly into roots. The media in Gv showed less U than that in CK. It was absorbed the most to iron and manganese oxidable U and sulfide U, and each U species declined accompanying the time prolongation. In addition, bioconcentration factors were higher in Gv compared to those of CK, and both treatments were above 1. Positive relationship was found between mycorrhizal colonization and bioconcentration factors. Therefore, U uptake was enhanced inoculated by Gv, and the symbiont in arbuscular mycorrhizal fungus and Pteris vittata L. had a potential to remediate U polluted soil. PMID- 26592034 TI - [Impact on the Microbial Biomass and Metabolic Function of Carbon Source by Black Soil During Rice Cultivation]. AB - The effects of rice cultivation to the black soil microbial communities, which the experimentation area of Shuangyang District Agricultural Technology Extension Station in Changchun city, Jilin Province of northeastern China, were studied by using the method of phospholipid fatty acids and Biolog ECO-microplate culture. Results showed that the content of organic matter in space was the highest, fewer in the field, and the minimum in the rhizosphere, that change trend of total nitrogen and organic matter was similar in soil. The quantity of organic matter in summer sample was the highest. The microbial fun6tional diversity was significantly higher in summer than that in spring and autumn and showed no significant difference between spring and autumn. For summer and the lowest in winter, Shannon-Wiener index and Pielou index of the space were higher than the field and the rhizosphere. The time of microbial growth into the stable period and peak value of the average well color development were different in all samples, that the time was 216 h, 192 h, 216 h, 120 h, which varied from 0.52 0.84, 0.82-1.28, 0.40-0.84, 0.05-0.48, respectively. The result showed that the time of microbial growth into the stable period was similar in spring and autumn, the highest was in summer and the lowest was in winter. Above all, these results would provide more important characteristics of microbial features in the degradation and restoration process of the quality of the black soil habitat scientifically. PMID- 26592035 TI - [Effect of Decomposing Products of Immobilized Carriers on Desorption of Pyrene in Contaminated Soil]. AB - Batch experiments were conducted to investigate the effect of soluble and insoluble decomposing products (decomposed for 1 day and 120 day; noted by DP1 and DP120, respectively) from immobilized carriers (corncob) on the desorption of pyrene in PAH-contaminated soil (120 d ageing, 20 mg x kg(-1)). It was found that (1) adding decomposing products of immobilized carriers could not only increase the rapidly desorbing fraction, but also improve the desorption rate of pyrene. The desorption rates of pyrene increased from 20% to 81.8% and 84.5% because of adding insoluble DP1 and DP120, and from 40% to 89.6% and 88.5% because of adding soluble DP1 and DP120. (2) The sorption amounts of pyrene by insoluble DP1 and.DP120 were 9. 4 and 16. 6 times higher than that by natural corncob, respectively. The sorption amounts of XAD-2 resins were increased by 1.5 and 3.1 times due to the added soluble DP1 and DP120, respectively. These results indicated that decomposing products of immobilized carries could improve the desorption of pyrene by sorption or activation in contaminated soil. PMID- 26592036 TI - [Solidification/Stabilization of Chromite Ore Processing Residue (COPR) Using Zero-Valent Iron and Lime-Activated Ground Granulated Blast Furnace Slag]. AB - The solidification/stabilization (S/S) of chromite ore processing residue (COPR) was performed using zero-valent iron (ZVI) and lime-activated ground granulated blast furnace slag (GGBFS). The degree of Cr immobilization was evaluated using the leaching procedure, mineral composition analysis and morphology analysis. Semi-dynamic leaching tests were implemented to investigate the potential for reusing the final treatment product as a readily available construction material. The results showed that after reduction, all of the S/S treated COPR samples met the pollution control limit of bricks and building block products (Chinese standard HJ/T 301-2007) produced with COPR for total Cr (0.3 mg x L(-1)), the compressive strength of all the S/S samples could meet the compressive strength standard (15 MPa) for producing clay bricks, and Cr existed as the specie that bound to Fe/Mn oxides in the S/S samples. At the same time, all of the S/S treated specimens tested were suitable for utilization at certain levels. PMID- 26592037 TI - [Stabilization of Cadmium Contaminated Soils by Ferric Ion Modified Attapulgite (Fe/ATP)--Characterizations and Stabilization Mechanism]. AB - Ferric ion modified attapulgite (Fe/ATP) was prepared by impregnation and its structure and morphology were characterized. The toxicity characteristic leaching procedure (TCLP) was used to evaluate the effect of Cadmium( Cd) stabilization in soil with the addition of attapulgite (ATP) and Fe/ATP. The stabilization mechanism of Cd was further elucidated by comparing the morphologies and structure of ATP and Fe/ATP before and after Cd adsorption. Fe/ATP exhibited much better adsorption capacity than ATP, suggesting different adsorption mechanisms occurred between ATP and Fe/ATP. The leaching concentrations of Cd in soil decreased by 45% and 91% respectively, with the addition of wt. 20% ATP and Fe/ATP. The former was attributed to the interaction between Cd2 and --OH groups by chemical binding to form inner-sphere complexes in ATP and the attachment between Cd2+ and the defect sites in ATP framework. Whereas Cd stabilization with Fe/ATP was resulted from the fact that the active centers (--OH bonds or O- sites) on ATP could react with Fe3+ giving Fe--O--Cd-- bridges, which helped stabilize Cd in surface soil. What'more, the ferric oxides and metal hydroxides on the surface of ATP could interact with Cd, probably by the formation of cadmium ferrite. In conclusion, Fe/ATP, which can be easily prepared, holds promise as a potential low-cost and environmental friendly stabilizing agent for remediation of soil contaminated with heavy metals. PMID- 26592038 TI - [Improving Agricultural Safety of Soils Contaminated with Polycyclic Aromatic Hydrocarbons by In Situ Bioremediation]. AB - In order to reduce the risk of enrichment of polycyclic aromatic hydrocarbons (PAHs) in crops, reduce the potential hazards of food-sourced PAHs to human and increase the agricultural safety of PAHs contaminated soils, the bio-augmented removal of polycyclic aromatic hydrocarbons (PAHs) was investigated through in situ remediation by introducing Rhodobacter sphaeroides (RS) into the agricultural soil contaminated by PAHs. The 50-times diluted RS was sprayed on leaf surface (in area B) or irrigated to roots (in area D). The treatment of spraying water of the equal amount was taken as the control (A) and the wheat field without any treatment as the blank (CK). Treatments were conducted since wheat seeding. Soil and wheat samples were collected in the mature period to analyze the changes of community structure of the soil microorganisms and the concentration of PAHs in soils and investigate the strengthening and restoration effects of RS on PAHs contaminated soils. Compared to the CK Area, the areas B and D revealed that the variation ratio of phospholipid fatty acids (PLFAs) that were the biomarker of soil microorganisms was 29.6%, and the ratio of total PAHs removed was increased 1.59 times and 1.68 times, respectively. The dry weight of wheat grain of 50 spikes was increased by 8.95% and 12.5%, respectively, and the enrichment factor of total PAHs was decreased by 58.9% and 62.2% respectively in the wheat grains. All the results suggested that RS reduced enrichment of PAHs in wheat grains and increased wheat yield, which had great exploitation and utilization potentiality in repairing and improving the agricultural safety of the soils contaminated with PHAs. PMID- 26592039 TI - [Competence of Cd Phytoremediation in Cd-OCDF Co-contaminated Soil Using Mirabilis jalapa L]. AB - Soil contamination by heavy metals and persistent organic pollutants tends to be severe. Pot experiment was conducted to investigate the phytoremediation of cadmium (Cd) in Cd-OCDF Co-contaminated Soil by Mirabilis jalapa L., using OCDF and Cd as the model pollutants of persistent organic pollutants and heavy metals, to study. the growth responses of plant and OCDF effects on phytoremediation of Cd. The results showed that during three months of planting the height and dry biomass of Mirabilis jalapa L. decreased slightly when the Cd concentration was not higher than 200 mg x kg(-1), and the plant exhibited high tolerance to Cd and OCDF. Compared with the Cd single pollution, OCDF had no significant effect on the height and root biomass of Mirabilis jalapa L. When the concentration of Cd was 200 mg x kg(-1) and the concentration of OCDF was 500 microg x kg(-1), the shoot biomass was reduced by 22.19%. In other treatments, OCDF showed no significant inhibition to the shoot biomass of Mirabilis jalapa L., but increased the shoot biomass in some treatments. Compared with single Cd pollution, when the concentration of Cd was 200 mg x kg(-1) and the concentration of OCDF was 100 microg x kg(-1), the Cd accumulation of root was reduced by 34.44%. When the concentration of Cd was 400 mg x kg(-1) and the concentration of OCDF was 100 microg x kg(-1), the Cd accumulation in root and leaf was reduced by 7.93% and 18.09%, respectively. In other treatments, OCDF promoted the extraction and accumulation of Cd by root, stem and leaf of Mirabilis jalapa L. from soil to some degree. So using Mirabilis jalapa L. to remediate Cd from high Cd concentration and OCDF cocontaminated soil is feasible. PMID- 26592040 TI - [Effects of Soil Moisture on Phytoremediation of As-Containinated Soils Using As Hyperaccumulator Pteris vittata L]. AB - A pot experiment was carried out to study the effects of soil moisture on the growth and arsenic uptake of As-hyperaccumulator Pteris vittata L. The results showed that the remediation efficiency of As was the highest when the soil moisture was between 35%-45%. P. vittata grew best under 45% water content, and its aboveground and underground plant dry weights were 2.95 g x plant(-1) and 11.95 g x plant(-1), respectively; the arsenic concentration in aboveground and roots was the highest under 35% water content, and 40% content was the best for accumulation of arsenic in P. vittata. Moreover, controlling the soil moisture to 35%-45% enhanced the conversion of As(V) to As(III) in aboveground plant, and promoted arsenic detoxification in P. vittata. These above results showed that soil moisture played an important role in the absorption and transport of arsenic by P. vittata. The results of this study can provide important guidance for the large-scale planting of P. vittata and the moisture management measures in engineering application. PMID- 26592041 TI - [Effects of Phosphate Rock and Decomposed Rice Straw Application on Lead Immobilization in a Contaminated Soil]. AB - The soils treated with phosphate rock (PR) and oxalic acid activated phosphate rock (APR) mixed with decomposed rice straw were incubated in different moisture conditions for 60 days to study the effect on the basic property of the soil and on the speciation variation of Pb. The results showed that all these three types of immobilizing materials increased the pH, the Olsen-P, the exchangeable Ca and the soil cation exchange capacity, and APR showed more obvious effect; the pH and the exchangeable Ca of soil in the flooding treatment were higher than those in normal water treatment (70%), but the Olsen-P of soil in normal water treatment was a little bit more. These materials reduced exchangeable Ph fraction, and converted it into unavailable fraction. But the APR was better than raw PR in immobilizing lead, and the exchangeable Pb fraction was reduced by 40.3% and 24.2%, compared with the control, respectively, and the immobilization effect was positively correlated with the dosage. Decomposed rice straw could transform the exchangeable Ph fraction in soil into organic-bound fraction, while the flooding treatment changed it into the Fe-Mn oxide-bound and residue fractions. PMID- 26592042 TI - [Residue and Degradation of Roxarsone in the System of Soil-Vegetable]. AB - The field experiment was developed for simulating the residues, transformation and degradation in soil-vegetable system of Roxarsone contained in organic fertilizer. Under the treatment, the yield of Brassica chinensis decreased in low Roxarsone concentration with a decline by 15% to 32% compared with the control group; there had an accumulating role of vegetables to arsenic, and the root was the main part; total content of arsenic in the soil was positively correlated with the dose of the applied Roxarsone; total arsenic in soil first increased and then decreased with the planting time prolonged and peaked at 12.94 mg x kg(-1), while the level of inorganic arsenic in the soil stabilized after 30 d, which accounting for 66.75% to 98.56% of the total arsenic; there existed a positively significant correlation of total arsenic content between the Brassica chinensis and the soil as well as the arsenic enrichment factor of vegetables; the degradation rate of Roxarsone in soil was slow, there was still some Roxarsone remained in soil after 45 d when added the organic fertilizer which containing Roxarsone with the dose higher than 5 000 kg x hm(-2); Roxarsone could significantly increase the number of bacteria in the soil, and low concentration showed an inhibited role in the growth of fungi and actinomyces, while high concentration of Roxarsone promoted the growth. PMID- 26592043 TI - [Acute Toxicity and Safety Assessment of Three Typical Organic Pollutants to Two Aquatic Organisms]. AB - Acute toxic effects of three typical organic pollutants 1 ,2,4-trichlorobenzene (1,2,4-TCB), nitrobenzene and chlorpyrifos were investigated using Tetrahymena thermophila and Limnodrilus hoffmeisteri as living test organisms under laboratory conditions. The results showed that with the increase of pollutants' concentration and the extension of time, toxicity of the three kinds of pollutants significantly enhanced, and the mortality of two kinds of aquatic organisms also had a rising trend, and an obvious dose-effect relationship. The 96 h-LC50. values of 1 ,2, 4-TCB, nitrobenzene and chlorpyrifos were 71.88, 285.76, and 5.50 mg x L(-1) for L. hoffmeisteri and 15.58, 140.22, and 14.69 mg x L(-1) for T. thermophila. These results showed that the toxicity among the three typical pollutants to T. thermophila was 1 , 2,4-TCB > chlorpyrifos > nitrobenzene. Findings were able to provide more information on water quality criteria and more data on their toxicity to indigenous aquatic organisms in China. PMID- 26592044 TI - [Effects of Oil Pollutants on the Performance of Marine Benthonic Microbial Fuel Cells and Its Acceleration of Degradation]. AB - Degradation of oil pollutants under the sea is slow for its oxygen-free environment which has caused long-term harm to ocean environment. This paper attempts to accelerate the degradation of the sea oil pollutants through electro catalysis by using the principle of marine benthonic microbial fuel cells (BMFCs). The influence of oil pollutants on the battery performance is innovatively explored by comparing the marine benthonic microbial fuel cells ( BMFCs-A) containing oil and oil-free microbial fuel cells (BMFCs-B). The acceleration effect of BMFCs is investigated by the comparison between the oil degrading rate and the number of heterotrophic bacteria of the BMFCs-A and BMFCs B on their anodes. The results show that the exchange current densities in the anode of the BMFCs-A and BMFCs-B are 1. 37 x 10(-2) A x m(-2) and 1.50 x 10(-3) A x m(-2) respectively and the maximum output power densities are 105.79 mW x m(-2) and 83.60 mW x m(-2) respectively. The exchange current densities have increased 9 times and the maximum output power density increased 1. 27 times. The anti polarization ability of BMFCs-A is improved. The heterotrophic bacteria numbers of BMFCs-A and BMFCs-C on their anodes are (66 +/- 3.61) x 10(7) CFU x g(-1) and (7.3 +/- 2.08) x 10(7) CFU x g(-1) respectively and the former total number has increased 8 times, which accelerates the oil-degrading rate. The degrading rate of the oil in the BMFCs-A is 18.7 times higher than that in its natural conditions. The BMFCs can improve its electrochemical performance, meanwhile, the degradation of oil pollutants can also be accelerated. A new model of the marine benthonic microbial fuel cells on its acceleration of oil degradation is proposed in this article. PMID- 26592045 TI - [Microwave In-situ Regeneration of Cu-Mn-Ce/ZSM Catalyst Adsorbed Toluene and Distribution of Bed Temperature]. AB - Microwave in-situ regeneration of Cu-Mn-Ce/ZSM catalyst adsorbed toluene, distribution of fixed bed temperature, adsorption breakthrough curves of the catalyst after several regenerations and characterizations of the catalyst by BET and SEM were investigated in this study. The research indicated that regeneration effect of the catalyst adsorbed was excellent under conditions of microwave power 117 W, air flow 0.5 m3 x h(-1) and catalyst dosage of 800 g. Toluene desorbed was oxidized onto the surface of the catalyst, and the adsorption capacity of the catalyst was recovered simultaneously. Under microwave irradiation, bed temperature decreased slowly from inside to outside in horizontal level, and increased gradually from down to up in vertical level so that the highest temperature reached 250-350 degrees C at the upper sites of the bed. Sintering and agglomeration occurred on the surface of the catalyst in the course of regeneration so that the special surface area and micropore volume of the catalyst were reduced and breakthrough time was shortened, which was verified by six adsorption breakthrough curves and related characteristics of the catalyst. However, the structure of the catalyst was steady after two regenerations, and adsorption breakthrough time was kept at 70 min. The result showed that the changes of surface morphology and pore structure were positively correlated with the distribution of bed temperature. PMID- 26592046 TI - [Impact of Thermal Treatment on Biogas Production by Anaerobic Digestion of High solid-content Swine Manure]. AB - Livestock manure is a kind of waste with high organic content and sanitation risk. In order to investigate the impact of thermal treatment on the anaerobic digestion of high-solid-content swine manure, 70 degrees C thermal treatment was conducted to treat raw manure (solid content 27.6%) without any dilution. The results indicated that thermal treatment could reduce the organic matters and improve the performance of anaerobic digestion. When the thermal treatment time was 1d, 2d, 3d, 4d, the VS removal rates were 15.1%, 15.5%, 17.8% and 20.0%, respectively. The methane production rates (CH4/VSadd) were 284.4, 296.3, 309.2 and 264.4 mL x g(-1), which was enhanced by 49.7%, 55.9%, 62.7% and 39.2%, respectively. The highest methane production rate occurred when the thermal treatment time was 3d. The thermal treatment had an efficient impact on promoting the performance of methane production rate with a suitable energy consumption. On the other hand, thermal treatment could act as pasteurization. This showed that thermal treatment would be of great practical importance. PMID- 26592047 TI - [Impact of Phosphogypsum Wastes on the Wheat Growth and CO2 Emissions and Evaluation of Economic-environmental Benefit]. AB - Phosphogypsum is a phosphorus chemical waste which has not been managed and reused well, resultantly, causing environmental pollution and land-occupation. Phosphogypsum wastes were used as a soil amendment to assess the effect on wheat growth, yield and CO2 emissions from winter wheat fields. Its economic and environmental benefits were analyzed at the same time. The results showed that wheat yield was increased by 37.71% in the treatment of phosphogypsum of 2 100 kg x hm(-2). Compared with the control treatment, throughout the wheat growing season, CO2 emission was accumulatively reduced by 3% in the treatment of phosphogypsum waste of 1050 kg x hm(-2), while reduced by 8% , 10% , and 6% during the jointing stage, heading date and filling period of wheat, respectively; while CO2 emission was accumulatively reduced by 7% in the treatment of phosphogypsum waste of 2 100 kg x hm(-2) throughout the wheat growing season, as reduced by 11% , 4% , and 12% during the reviving wintering stage, heading date and filling period of wheat, respectively. It was better for CO2 emission reduction in the treatment of a larger amount of phosphogypsum waste. In the case of application of phosphogypsum waste residue within a certain range, the emission intensity of CO2 ( CO2 emissions of per unit of fresh weight or CO2 emissions of per unit of yield) , spike length, fresh weight and yield showed a significantly negative correlation--the longer the ear length, the greater fresh weight and yield and the lower the CO2 emissions intensity. As to the carbon trading, phosphogypsum utilization was of high economic and environmental benefits. Compared with the control, the ratio of input to output changed from 1: 8.3 to 1: 10.7, which in the same situation of investment the output could be increased by 28.92% ; phosphogypsum as a greenhouse gas reducing agent in the wheat field, it could decrease the cost and increase the environmental benefit totally about 290 yuan per unit of ton. The results demonstrated phosphogypsum wastes could obviously decrease the CO2 emission from field soil and had a great potential to control agricultural greenhouse gases. Hopefully it has an important application perspective for the low-carbon, ecological and sustainable agricultural development. PMID- 26592048 TI - [Status Quo, Uncertainties and Trends Analysis of Environmental Risk Assessment for PFASs]. AB - This study systematically combed the definition and change of terms, category and application of perfluoroalkyl and polyfluoroalkyl substances (PFASs) in international academic, focusing on the environmental risk and exposure assessment of PFASs, to comprehensively analyze the current status, uncertainties and trends of PFASs' environmental risk assessment. Overall, the risk assessment of PFASs is facing a complicated situation involving complex substance pedigrees, various types, complex derivative relations, confidential business information and risk uncertainties. Although the environmental risk of long-chain PFASs has been widely recognized, the short-chain PFASs and short-chain fluorotelomers as their alternatives still have many research gaps and uncertainties in environmental hazards, environmental fate and exposure risk. The scope of risk control of PFASs in the international community is still worth discussing. Due to trade secrets and market competition, the chemical structure and risk information of PFASs' alternatives are generally lack of openness and transparency. The environmental risk of most fluorinated and non-fluorinated alternatives is not clear. In total, the international research on PFASs risk assessment gradually transfer from long-chain perfluoroalkyl acids (PFAAs) represented by perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) to short chain PFAAs, and then extends to other PFASs. The main problems to be solved urgently and researched continuously are: the environmental hazardous assessment indexes, such as bioaccumulation and environmental migration, optimization method, the environmental release and multimedia environmental fate of short chain PFASs; the environmental fate of neutral PFASs and the transformation and contribution as precursors of short-chain PFASs; the risk identification and assessment of fluorinated and non-fluorinated alternatives of PFASs. PMID- 26592049 TI - Establishing and implementing Demographic Surveillance System as a tool for monitoring health interventions in Korogwe District, northastern Tanzania. AB - In the Korogwe demographic surveillance system (DSS) site in north-eastern Tanzania, information on vital events such as births, deaths and migration has been collected since its establishment in 2005. The aim was to obthin demographic and epidemiological indices to be used in the evaluation of health related interventions which have been undertaken in the area. Period covered is up to December 2010. Baseline survey was conducted in 14 villages of Korogwe district in October 2005 and DSS was launched in January 2006 years. Demographic, social economic status, immunisation coverage and birth history data was collected during the follow-up and each household was visited every 4 months. Estimates of mortality levels were derived from deaths that were collected during household visits. Birth history data were used to estimate the lifetime and period fertility of women aged 15-49 years. Estimates of crude migration and age specific migration rates were derived from the number of people moving in or out of the DSS site and the person-years lived. The population at baseline survey was 25,264 individuals in 5,853 households. The percentage of deaths was higher among adult aged 15-60 years compared to other age groups. The probability of dying among males (376/1000) aged 15-60 years was higher than females (339/1000) in the same age group. The lifetime and period fertility estimates were 5.6 and 5.1 children per woman respectively. Women aged 30-34 years are expected to have 3-4 children at the end of their childbearing age. Migration were higher at the youngest ages, lower rates at the 10-14 years age groups, a peak at the 20-24 ages, and a gradual decline up to the oldest ages. Majority of households in rural areas 51.8% were 1 in low socioeconomic status compared to 40.3% in urban areas which were in high socio-economic status. About 74% and 55.5% of the children received BCG and measles vaccination, respectively. In conclusion, Korogwe DSS has provided useful data which was utilised in planning malaria vaccine trials. Findings from the DSS will also be used in planning of future clinical trials and by the District authorities as input for health and other development planning purposes, including setting of crucial priorities. PMID- 26592050 TI - Bacteriology and antibiogram of pathogens from wound infections at Dessie Laboratory, North-east Ethiopia. AB - Wound infections result in sepsis, limb loss, long hospital stays, higher costs, and are responsible for significant human mortality and morbidity worldwide. The aim of this study was to investigate the profile of pathogens cultured from wound infection and determine the antimicrobial susceptibility patterns. A retrospective analysis of bacterial pathogens and their antimicrobial susceptibility was done on wound swab samples that have been cultured at Dessie Regional Laboratory from 2003 to 2010. Antimicrobial susceptibility tests were done using disc diffusion technique as per the standard of Kirby-Bauer method. The mean age of male and female patients was 31.2 and 29.8 years, respectively with male to female ratio of 1:1.6. Out of 599 wound swab samples analyzed, 422 (70.5%) were culture positive. A total of 500 bacteria from 422 positive cases were identified. Seventy eight (18.5%) of the culture had double infections. Staphylococcus aureus was the most frequently isolated pathogen which accounted for 208 (41.6%) of isolates followed by Pseudomonas spp. 92 (18.4%), E. coli 82 (16.4%), Proteus spp. 55 (11.0%), Enterobacter spp. 21 (4.2%), and Citrobacter spp. 21 (4.2%), Kle.bsiella spp. 12 (2.4%) and Coagulate negative staphylococcus 9 (1.8%). Amoxicillin had the highest resistance rate 78.9%, followed by tetracycline 76.1% and erythromycin (63.9%). The sensitivity rates of norfloxacin, ciprofloxacin and gentamicin were 95.1%, 91.8% and 85%, respectively. The overall multiple antimicrobial resistances rate was 65.2% and only 13% of the isolates were sensitive to all antimicrobial agents tested. The most frequently isolated bacteria were sensitive to ciprofloxacin, gentamicin, cloxacillin and norfloxacin. These antimicrobials are considered as appropriate antimicrobials for empirical treatment of wound infections. Periodic surveillance of aetiology and drug susceptibility both in the community and hospital settings is recommended. PMID- 26592051 TI - HIV and parasitic co-infections among patients seeking care at health facilities in Tanzania. AB - Untreated tropical parasitic co-infections appear to speed the progression of HIV 1 disease. However, to date, there have been few studies conducted in resource limited settings to ascertain the interaction of parasitic co-infection where HIV/AIDS management largely depends on CD4+ T lymphocyte cells counts and WHO clinical staging. This study aimed to determine the prevalence of parasites, their association with CD4+ T lymphocyte cells changes and clinical manifestation of HIV-infection in patients attending HIV/AIDS management clinics in Tanzania. Adult HIV-infected patients registering for the first time at HIV/AIDS management clinics were recruited; with physical examination and laboratory tests performed at baseline and after 6 months. Patients were assigned a clinical stage and scr.eened for helminths and Plasmodium sp. co-infection, CD4+ T lymphocyte cells, haemoglobin and HIV-1 p24 antigen. Of the 421 HIV-1 infected patients studied, 198 (47.0%) were co-infected with one or more parasites. Of those studied, 93/421(22.1%) had helminth only co-infection, and 50/421 (12.9%) had Plasmodium sp only co-infection. Mixed Plasmodium sp and helminth co-inf6ction was diagnosed in 55/421 (13.0%) patients. Helminths frequently diagnosed included: hookworm 65/421(15.4%), Schistosomiasis 49/421(11.6%), Strongyloides stercoralis 57/421(13.5%), and Ascaris lumbricoides 54/421(12.8%). No statistical association was found between CD4+ T lymphocyte cells < 200/ 1, or WHO clinical stage III/ IV with parasite co-infections (AOR 1.2, 95%CI 0.8-1.8). Anaemia was common in parasite co-infected patients (32.8% vs. 18.8%). Parasite co-infection was associated with risk of anaemia (AOR 2.1, 95%CI 1.3-3.2). In multivariable logistic regression analysis, baseline CD4+ T lymphocyte cells <200/V1 was significantly associated with CD4+ T lymphocyte cells <20041 (AOR 2.4, 95%CI 1.3 4.7) at six months. HIV-1 P24 antigen mean concentration was higher in parasite co- infected patients (ranges 47.6 to 56.9) as compared to patients without parasite co-infection (5.5). We have looked at one set of parasites and found high prevalence of malaria and helminth co-infection in HIV-infected individuals. Given the available reports on health impacts of helminth co-infection in HIV/AIDS patients and the anecdotal reports of helminths health effects in HIV uninfected persons, helminths and other prevalent parasites should not be ignored in HIV/AIDS programs. Based on local helminth epidemiology and HIV-infected cohort specific helminths co-infection prevalence data, mass treatment of soil transmitted helminths can be incorporated into HIV/AIDS management programmes. PMID- 26592052 TI - Food insecurity and coping strategies among people living with HIV in Dar es Salaam, Tanzania. AB - Food insecurity and malnutrition seriously impedes efforts to control HIV/AIDS in resource poor countries. This study was carried out to assess food security, and coping strategies among people living with HIV/AIDS (PLHIV) attending Care and Treatment Centre (CTC) in Dar es Salaam, Tanzania. A structured questionnaire was used to interview randomly selected adults (18 years) who were HIV positive who have just been eligible for anti-retroviral treatment (ART) in a CTC or one who has started ART but not more than four weeks has elapsed. A total of 446 (females=67.9%; males= 32.1%) people living with HIV/AIDS attending CTC were interviewed. About three quarters (73.1%) of the respondents were 25-44 years old and most (43.9%) were married. Two thirds (66.7%) of the respondents had primary school education. Seventy percent reported to have a regular income and 63.7% with a monthly income of less than US$ 154. More than half (52.2%) of the respondents were food insecure. Food insecurity was similar in both males (54.6%) and females (51.2%). However, food insecurity was least (48.2%) among those who were single and highest (57.7%) among those cohabiting. Low level of food insecurity was associated with having completed primary education (Adjusted OR=0.27; 95% CI, 0.09-0.82) and high income (>US $154) (OR=0.10; 95% CI, 0.01 0.67). Reporting two or less meals increased the likelihood of food insecurity (OR=4.2; 95% CI1.7-9.8). Low frequency of meals was significantly more prevalent (18.6%) among those. 45 years than among 35-44 years old respondents (6.7%) (P=0.04). Borrowing money (55.8%) and taking less preferred foods (53.3%) were the most common coping strategies. In conclusion, food insecurity is a significant problem among people living with HIV in Dar es Salaam which might significantly affect compliance to care and support. The study suggests that counselling of PLHIV before anti-retroviral treatment programmes should devise special strategies targeting those with low education, low income and low frequency of meals. PMID- 26592053 TI - Provider-initiated HIV testing and counseling in Mbeya City, south-western Tanzania: knowledge and practice of health care providers. AB - Provider-initiated testing and counseling (PITC) is a routine HIV counseling and testing offered to adult clients attending at health care facilities. In Tanzania PITC started in 2007, with the aim of increasing early HIV diagnosis and timely access to care, treatment and support services. The objective of this study was to assess the level of knowledge and practice of health care providers on PITC. This cross sectional study was conducted in April-May 2010 among nurses and clinicians working in the government health care facilities in Mbeya City, south western Tanzania. Self-administered questionnaire was used to obtain relevant information from the study participants. A total of 402 (95% response rate) care providers were interviewed. Their mean (+/- SD) age was 41 +/- 9.5 years. The majority 304 (76%) were nurses. Their duration of practice ranged from 4 months to 39 years. All the care providers reported to be aware of PITC services. However, 35% of them had inadequate knowledge of PITC and 269 (67%) reported to have ever offered PITC services. Median number of clients attended per week was 3 (IQR, 1-6 clients). Participants who had attended special training on PITC were 6 fold more likely to offer PITC services [OR = 6.2, 95% CI = 3.7-10.2; P < 0.001] than those who had not attended. In conclusion more than one-third of health providers do not routinely offer PITC in Mbeya City, leading to missed opportunity for early HIV diagnosis. On job and in-service training to improve PITC knowledge and supportive supervision for those trained is required. PMID- 26592054 TI - Knowledge, treatment seeking and preventive practices in respect of malaria among patients with HIV attending Lagos University Teaching Hospital, Nigeria. AB - The synergistic interaction between Human Immunodeficiency virus (HIV) disease and malaria makes it mandatory for patients with HIV to respond appropriately in preventing and treating malaria. Such response will help to control the two diseases. This study assessed the knowledge of 495 patients attending the HIV clinic, in Lagos University Teaching Hospital, Nigeria. Their treatment seeking, preventive practices with regards to malaria, as well as the impact of socio demographic / socioeconomic status were assessed. Out of these patients, 245 (49.5%) used insecticide treated bed nets; this practice was not influenced by sociodemographic or socioeconomic factors. However, knowledge of the cause, knowledge of prevention of malaria, appropriate use of antimalarial drugs and seeking treatment from the right source increased with increasing level of education (P < 0.05). A greater proportion of the patients, 321 (64.9%) utilized hospitals, pharmacy outlets or health centres when they perceived an attack of malaria. Educational intervention may result in these patients seeking treatment from the right place when an attack of malaria fever is perceived. PMID- 26592055 TI - Pain management among adult patients with fractures of long bones at Muhimbili Orthopaedic Institute in Dar es Salaam, Tanzania. AB - Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage and is one of the leading complaints in emergency departments (EDs). Despite the important and the advantages of pain control, still patients do not receive appropriate attention. The objective of this study was to assess pain management among adult patients with fractures of long bones at Muhimbili Orthopaedic Institute in Dar es Salaam, Tanzania. A descriptive Cross-sectional study design (Hospital based) was used. A total of 250 patients aged 18-60 years old with fractures of long bones were recruited from March to June 2008. Structured questionnaires and observation guide were used to collect data. Verbal rating scale was used, to determine the intensity of pain. The study shows that there is no documentation for pain assessment or reassessment at Emergency Department. Slightly above half (54%; 135/250) of patients were not given analgesics. The commonest analgesic given was diclofenac sodium (46%). There was no patient given opioids (pethedine/ morphine). The rate of analgesics administration or splinting before and after admission did not differ between sexes (P=0.314 vs. P= 0.230) and (P=0.314 vs. P= 0.114), respectively. Almost half (47.0%) of them spent >20 min to 1 hour before the administration of analgesics. After administration of analgesia 76% of the patients continued to have severe to moderate pain. A large proportion (62.4%; N=156/250) of the patients scored their pain as severe. Of these, 28 (17.9%) patients received analgesia within 20 min, 42 (26.9%) after 30-60 min and 73 (46.8%) were not given analgesics at all. In conclusion pain at Muhimbili Orthopaedic Institute is under treated. It is important that this is addressed properly to minimize pains among patients attending hospitals for fracture management. PMID- 26592056 TI - Spatial variability in the density, distribution and vectorial capacity of anopheline species in Rufiji district, south-eastern Tanzania. AB - Malaria transmission varies from one area to another and there are also local difference in time and space. The objective of the study was to determine the local variability of entomological parameters namely, mosquito abundance, human biting rate (HBR), sporozoite rate for Plasmodiumfalciparum and entomological inoculation rate (EIR). The study was carried out in Rufiji District south eastern Tanzania from October 2001 and September 2004. Adult mosquitoes were collected indoors by CDC light traps. PCR was employed to identify the species within the Anopheles gambiae complex. ELISA was used to determine the sporozoite rate. Over a three year sampling period a total of 64,875 female mosquitoes were caught using light-traps, and of these 28% were Anopheles gambiae complex, 25% An. funestus Giles, 1% An. pharoensis Theobald, 46% Culex species and the rest were Mansonia uniformis Theobald. Mosquito abundance and species composition varied seasonally, spatially and between years. Using PCR, three members of the Anopheles gambiae complex namely An. gambiae s.s. Giles (69%), An. arabiensis Paton (23%) and An. merus D6nitz (7%) were confirmed to occur in the study area. Plasmodiumfalciparum circumsporozoite antigen (CSA) rates were 3.5% for An. gambiae complex and 2.3% for An. funestus. The mean EIR ranged from 28-275 infective bites/person/year. Transmission indices varied over short distances, seasonally and between years. In conclusion, malaria transmission indices in the study area are one of the highest in Tanzania; and there is high variability of entomological parameters over a small geographical area. PMID- 26592057 TI - In vitro activity of cefepime against extended spectrum p-lactamase-producing Escherichia coli and Klebsiella pneumoniae from clinical specimens at Bugando Medical Centre, Mwanza, Tanzania. AB - There is an increase in isolation of extended spectrum beta-lactamase (ESBL) producing isolates from clinical samples worldwide. In developing countries the treatment option of ESBL producing isolates is limited. Recently fourth generation cephalosporins have been introduced for use in Tanzania. This study was done to determine in vitro activity of cefepime against ESBL producing clinical isolates. Disc diffusion testing was performed to 235 ESBL producing isolates; of which 73 (31%) were Escherichia coli and 162 (69%) Klebsiella pneumoniae. The sensitivity rate of E. coli and K pneumoniae to cefepime were 15.1% and 4.3%, respectively (P=0.012); intermediate sensitivity rate was observed in 13.7% for E. coli and 19.8% for K. pneumoniae. The mean zones of inhibition diameter among sensitive isolates were 24.9mm and 20.0mm for E coli and K. pneumonia, respectively (P=0.0085). Cefepime is less active against ESBL producing organisms; hence the use.of this drug should be guided using local resistance profile. PMID- 26592058 TI - Resting behaviour of Anopheles gambiae s.l. and its implication on malaria transmission in Uyui District, western Tanzania. AB - An entomological survey to determine resting behaviour and species composition of malaria vectors was carried out in Uyui District in western Tanzania in May 2009. Mosquitoes were collected using indoor resting catch, window exit trap and outdoor "bed-net" techniques. The mosquitoes were identified using morphological key and polymerase chain reaction (PCR). A total of 672 Anopheles gambiae sensu lato were collected. Of these, 661 (98.4%) were collected outdoor whereas few (1.6%) were collected indoor. The exit trap catch: mechanical aspirator catch ratio was 1:1.75. The overall indoor resting density of An. gambiae s.l. as determined by mechanical aspirator and exit trap was 0.7 and 0.5 mosquitoes per room, respectively. The overall density of the host-seeking as determined by bed net trap outdoor was 44.1 mosquitoes per person. A sample of 44 specimens taken randomly from morphologically identified An.gambiae s.l. population was further analyzed to species level using PCR techniques. Of these 44 specimens 26 (59%) and 18 (41%) were Anopheles arabiensis and Anopheles gambiae sensu stricto respectively. This study contributes to the understanding of the distribution of malaria vectors with respect to species composition and their resting behaviour that could contribute to vector control operations in western Tanzania. A longitudinal study considering dry and wet seasons is recommended to provide more information on the seasonal distribution, abundance and biting behaviour of malaria vectors in the study area. PMID- 26592059 TI - Management of congenital absence of the cervix: A case report. AB - Cervical agenesis or dysgenesis is an extremely rare congenital anomaly. Conservative surgical approach to these patients involves uterovaginal anastomosis, cervical canalization, and cervical reconstruction. In failed conservative surgery, total hysterectomy is the treatment of choice. Success of reconstructive surgery depends on the amount of cervical tissue available. Hence, congenital absence of the cervix is a complex surgical problem and should be dealt with after thorough evaluation. We report an 18-year-old girl presented with primary amenorrhoea and cyclic monthly abdominal pain. Initial attempted reconstructive surgery failed and hysterectomy was done. At laparotomy, there was only fibrous tissue and no cervical tissue at all. No findings related to endometriosis were observed. The uterus was removed and sectioning the fibrous tissue level of the blind vaginal cuff. Gross tissue examination showed a non communicating uterine cavity, filled with menstrual blood of about 200 ms and a diffusely hypertrophy myometrium. The cervix was absent. Microscopically, there was no cervical tissue in the specimen; the uterine muscles had evidence of adenomyosis. In conclusion, recanalization and cervical reconstruction procedures may be performed on carefully selected patients, consideration should be directed to the presence of adequate cervical stroma absence of which warrants hysterectomy. PMID- 26592060 TI - Screening for Insulin Resistance in Polycystic Ovary Syndrome: Views of Physician Members of the American Society for Reproductive Medicine. AB - OBJECTIVE: To determine practice patterns for insulin resistance (IR) evaluation and management in women with polycystic: ovary syndrome (PCOS) among physician members of the American Society for Reproductive Medicine (ASRM). STUDY DESIGN: Cross-sectional survey using a web-based questionnaire. RESULTS: A total of 205 members responded. Respondents were board-certified (94%), or board-eligible (6%), in obstetrics and gynecology. Sixty-four percent of the respondents use the Rotterdam 2003 Criteria for a diagnosis of PCOS. Two-thirds (68%) screenfor IR in women with PCOS. Respondents who screen for IR were more likely to also screen for diabetes and impaired glucose tolerance (OR 3.37, 95% CI 1.48-7.21). The 2 hour oral glucose tolerance test with glucose and insulin concentrations was the most common IR screening test used (45%). Metformin therapy was used by 33% of respondents for, "all women with PCOS who have IR." The majority (68%) responded that there is a need for a committee opinion from ASRM on IR testing in PCOS. CONCLUSION: Two-thirds of ASRM physician members surveyed screen women with PCOS for IR in spite of the lack of general consensus on the need for such screening from endocrine societies. PMID- 26592061 TI - Text Messaging to Improve Preventive Health Attitudes and Behaviors During Pregnancy: A Prospective Cohort Analysis. AB - OBJECTIVE: To delineate the effects of text messages sent to pregnant women to promote preventive health beliefs and behaviors. STUDY DESIGN: A prospective cohort analysis was performed among women who participated in a randomized, controlled trial aimed at improving preventive health. Participants (158 pregnant women enrolled from 2010-2012) received 12 weekly text messages encouraging preventive health behaviors (tobacco cessation, condom use for disease prevention, nutrition optimization, seat belt use, breastfeeding). Pre- and postintervention surveys assessed preventive health beliefs and practices. RESULTS: At follow-up, participants agreed that receiving text messages changed their beliefs about targeted preventive health behaviors: smoking (50%), sexually transmitted disease prevention (72%), prenatal vitamins (83%), seat belt use (68%), nutritious foods (84%), and breastfeeding (68%). Many participants reported more frequent engagement in target behaviors at follow-up than at baseline: decreased tobacco use (among 41% of smokers), more consistent condom use (among 7% of sexually active participants), more prenatal vitamin intake (32%), more frequent seatbelt use (32%), more frequent healthy food intake (41%), and intention to breastfeed longer (21%). CONCLUSION: Pregnant women receiving text messages promoting preventive health reported improvements in targeted beliefs and behaviors, suggesting that text messaging may be used for health promotion during pregnancy. PMID- 26592062 TI - Mitochondrial D-loop Variations in Infertile Women Undergoing in Vitro Fertilization-Embryo Transfer. AB - OBJECTIVE: To show a high frequency of human mitochondrial DNA (mtDNA) D-loop variations present in infertile women undergoing in vitro fertilization-embryo transfer (IVF-ET) and the variation's potential relevance as a predictive marker in the IVF-ET. STUDY DESIGN: The entire mtDNA D-loop region was amplified in 3 overlapping polymerase chain reaction fragments, and the variations were evaluated through direct DNA sequencing methods in 156 infertile women undergoing IVF-ET. RESULTS: A total of 48 variations were found at 47 positions in the D loop of all patients. The incidence of variations (particularly 16191 C --> T [p = 0.0321, 16519 T --> C [p = 0.0431, 326 A --> G [p = 0.0031, and 432 A --> C [p = 0.042) was significantly higher in patients with top quality embryo rate 41.84% (p = .0.004). However, variations were not significantly associated with the fertilization rate (p = 0.846), cleavage rate (p = 1.000), pregnancy rate (p = 0.839), implantation rate (p = 0.911), or miscarriage rate (p = 0.658). CONCLUSION: Our data suggest that the increase in mtDNA variations in the peripheral blood from infertile women could have a predictive value for the outcomes of infertile women undergoing IVF-ET. PMID- 26592063 TI - Does a History-Indicated Cerclage Affect Gestational Age at Delivery in Women with Evidence of Recurrent Cervical Insufficiency? AB - OBJECTIVE: To determine whether women with recurrent evidence of cervical insufficiency (CI) and with a history-indicated cerclage (HIC) placed at the beginning of the second trimester will deliver later than the index case. STUDY DESIGN: Retrospective case-control study of singleton pregnancy with history consistent CI. Patients had a cerclage placed between 12 and 16 weeks of gestation. Transvaginal cervical measurement was done between 18 and 24 weeks. Those with a cervical measurement 25 mm were considered to have recurrent CI (Group A). Gestational age at delivery of the index case (Group C) and the cerclage patients (Groups A and B), which are the same patients as Group C, was compared using Student's t test. They have the same genetics and anatomy. RESULTS: A total of 124 women had an HIC. Sixteen (13%) had recurrent CI (Group A). Comparing cases, the proximate average age at delivery was 22 weeks as compared with 33 weeks and 3 days for those with a cerclage (p < 0.001) (Group A vs. B). In those with a cervical length > 25 mm (Group B), 96 (89%) had a term delivery. In the index cases 64% delivered at 22 weeks or less (Group C). CONCLUSION: Cerclage in those patients with recurrent CI has a significantly improved outcome as compared with the index case. This minimizes pregnancy loss. PMID- 26592064 TI - Association Between Body Mass Index and Patient-Centered Outcomes After Hysterectomy. AB - OBJECTIVE: To assess whether body mass index (BMI) was associated with self reported pain, well-being, or procedure satisfaction in the 3 months after hysterectomy. STUDY DESIGN: Prospective cohort study that recruited women undergoing hysterectomy. Data was collected over 1 year for 245 women. RESULTS: BMI was not associated with pain either at baseline or in the 3 months after surgery versus no pain; odds ratio [OR] = 1.0, 95% confidence interval [CI] 0.97 1.03, p = 0.88 for a 1 unit increase in BMI) or being fully satisfied with the procedure (versus not fully satisfied; OR = 1.01, 95% CI 0.97-1.04, p = 0.77 for a 1unit increase in BMI). Similarly, patient's perception of well-being was also not influenced by BMI as reflected in their well-being score (0.98 increase in score, 95% CI 0.95-1.02, p = 0.40, for a 1-unit increase in BMI). CONCLUSION: The data from this prospectively studied cohort of women who had undergone hysterectomy suggest that BMI is not associated with self-report of pain, well being, -or procedure satisfaction in the 3 month after surgery. PMID- 26592065 TI - Basal Follicle-Stimulating Hormone or Inhibin B Combined with Age as Predictors of Pregnancy After Treatment by Donor Sperm Insemination. AB - OBJECTIVE: To evaluate the clinical significance of basal reproductive hormones and basal inhibin B (INHB) combined with age on predicting the outcomes of artificial insemination with donor sperm (AID). STUDY DESIGN: A retrospective analysis was performed in 1,772 patients who underwent AID at the Department of Assisted Re- production, Tongji Medical College, from 2009-2011. We compared the age and The levels of basal menstrual cycle day 3 reproductive hormones and INHB regarding the pregnancy rates after AID treatment. RESULTS: There was a low clinical pregnancy rate in women with a basal follicle-stimulating hormone (FSH) >= 15 IU/L or a basal INHB < 25 ng/mL. An age-related decrease in the pregnancy rate was found also. Moreover, the pregnancy rate dropped remarkably when the FSH x age value was > 500, and it rose to 70.6% when the INHB / age value was > 10. CONCLUSION: Basal FSH and basal INHB are closely correlated with clinical pregnant rates in AID treatment. Furthermore, FSH x age and INHB / age could be used as an optimal tool for predicting AID outcomes. PMID- 26592066 TI - Emotional Impact of Reduced Access to Assisted Reproductive Care. AB - OBJECTIVE: To evaluate the impact of cessation of fertility services on patients with infertility. STUDY DESIGN: A cross-sectional, anonymous mail survey was conducted in a university hospital setting. A total of 281 female infertility patients treated from 2003-2006 were mailed surveys. The main outcome measures of the study were the Perceived Stress Scale 10 (PSS-10) and the Impact of Events Scale (IES). RESULTS: Of the 281 patients, 175 (62.3%) responded to the questionnaire. Of those, 51 (29.1%) reported being affected by the closure. The majority (58.9%) reported a somewhat or very negative impact on their perceived quality of life. Affected patients were more likely than unaffected patients to have an elevated PSS-10 result (odds ratio [OR] 2.1, 95% confidence interval [CI] 1.04-4.3). No significant difference was seen in IES results, with 90.2% of affected and 81.5% of unaffected patients scoring in the high distress range (OR 2.1, 95% CI 0.77-5.65). Self-reported average stress levels were reduced following news of resumption of services (3.3, scale 1-10) as compared to both prior to (5.1) and during (7.4) the closure. CONCLUSION: When fertility services are discontinued, there may be significant emotional distress among the population affected. Health care providers should be aware of the impact infertility has on stress-coping and quality of life and be prepared to offer psychological services. PMID- 26592067 TI - Analysis of the Screening Results for 3,564 Student Sperm Donors in Hubei Province, China. AB - OBJECTIVE: To determine the reasons for the elimination of student sperm donors after semen analysis, physical examination, and laboratory tests in the Hubei Provincial Human Sperm Bank. Understanding the status of student sperm donors can provide a valid reference for the screening work of sperm banks. STUDY DESIGN: The screening data from 3,564 student sperm donors in Hubei Provincial Human Sperm Bank from January 1, 2010-April 30, 2013, were retrospectively analyzed. RESULTS: A total of 733 students (20.57%) qualified for semen analysis in the human sperm bank, whereas 602 students (16.89%) completed the sperm donation procedure. The main reasons for elimination were as follows: unqualified semen parameters (2,748 cases), failed semen extraction (83 cases), sexually transmitted diseases (44 cases), hereditary or chromosomal disorders (44 cases), and hepatitis B infection (25 cases). Education level and temperature/climate possibly affect semen quality. CONCLUSION: Unqualified semen parameters were the main reason for elimination among student sperm donors. Human sperm banks should promote reproductive health knowledge and information on improving semen quality among students when promoting sperm donation. PMID- 26592068 TI - Prevalence and Risk Factors of Infertility for Han, Uygur, and Kazakh Ethnicities in Xinjiang Rural Residents. AB - OBJECTIVE: To estimate the prevalence and associated factors of current infertility for Han, Uygur, and Kazakh ethnicities in Xinjiang rural residents. Chinese Uygur, Kazakh, and Han populations represent > 90% of the total population of the Xinjiang Uygur Autonomous Region, and their customs, culture, and food consumption are different. The effect of ethnic differences on infertility risk factors is rarely studied. STUDY DESIGN: A cross-sectional study of 5,086 married and common-law couples, with a female partner aged 18-49, living in Hami, Kuche, or Xinyuan counties in Xinjiang, China. General information for the study subjects, including demographic characteristics, life customs, sexual history, history of contraception use, and history of disease, was collected by questionnaire. General health, gynecologic examinations, and sociodemographic characteristics were also carried out. RESULTS: A total of 5,086 females from Xinjiang Province were surveyed, including 493 with infertility. The standardized prevalence rate of infertility was 9.7% (95% CI 8.9-10.5), and the prevalence of infertility in Han, Uygur, and Kazakh ethnicities was 6.8% (95% CI 5.7-7.9), 10.9% (95% CI 8.0-13.8), and 10.1% (95% CI 7.4-12.8), respectively. CONCLUSION: The present study suggests that the prevalence of infertility was lower in the Han as compared to the Kazakh and Uygur ethnicities. PMID- 26592069 TI - Decline of Plasmacytoid Dendritic Cells and Their Subsets in Normal Pregnancy Are Related with Hormones. AB - OBJECTIVE: To analyze the frequency of plasmacytoid dendritic cells (pDCs) in pregnancy, especially their subsets, by flow cytometry in each trimester and in the postpartum period. STUDY DESIGN: Peripheral blood was collected from pregnant women in each trimester and from non-pregnant women. Serum hormones were detected by ELISA, while pDCs and their subsets were detected by flow cytometer. Then correlation between them was further analyzed. RESULTS: Both pDCs and their subsets declined as pregnancy progressed. Further experiments indicate that estradiol and progesterone are significantly negatively correlated with this change. CONCLUSION: Our findings increase the knowledge of pDC subsets in healthy pregnant conditions. PMID- 26592070 TI - Cannabinoid Hyperemesis Syndrome During Pregnancy: A Case Report. AB - BACKGROUND: Cannabinoid hyperemesis syndrome (CHS) is a syndrome characterized by chronic marijuana use, cyclic vomiting, and compulsive bathing. Given the similarities this syndrome shares with hyperemesis gravidarum, it is likely that this is a highly underdiagnosed syndrome. We present a case of severe nausea and vomiting during pregnancy that met the criteria for CHS. CASE: This case outlines the course of recurrent nausea and vomiting due to cannabinoid hyperemesis in a pregnant patient and illustrates the similarities between hyperemesis gravidarum and CHS and the value of obtaining a complete history that includes the use of marijuana. CONCLUSION: Recognition of this syndrome will aid in patient care, lessen the economic burden of an extensive workup, and hopefully lessen provider frustration with diagnosis and treatment of a common and underdiagnosed entity. PMID- 26592071 TI - Low-grade Endometrial Stromal Sarcoma Primarily Arising in the Vagina: A Case Report. AB - BACKGROUND: Endometrial stromal sarcoma (ESS) is a rareform of endometrial cancer, comprising < 0.2% of all uterine malignancies and 10% of all uterine sarcomas. To date, the English-language literature contains 6 reports of extrauterine ESS arising primarily in the vagina. We describe the seventh such case, and the first case in which the origin is at the introitus of the vagina. CASE: A 43-year-old, nulligravid, Caucasian woman presented for an annual gynecologic examination and was found to have an asymptomatic 5 x 5-mm, rubbery, soft tissue mass at the 5 o'clock position of the vaginal introitus. As has been reported in several cases of low-grade ESS, this case originated at a site of endometriosis. CONCLUSION: Based on our experience as well as a thorough review of the literature, it appears that early stage low-grade ESS arising in the vagina can be treated effectively with surgical resection followed by close observation for recurrence. PMID- 26592072 TI - Heterotopic Gestation with Twin Intrauterine Implantation Following Transfer of Three Developmentally-delayed Embryos from Cryopreserved Oocytes: A Case Report. AB - BACKGROUND: In vitro fertilization (IVF) data suggest improved live birth rates for embryos transferred at the blastocyst versus the cleavage stage. Embryos that have not reached the blastocyst stage by day 5 postthaw have diminished potential for implantation and live birth. Few data exist regarding embryogenesis and optimal timing of transfer for embryos derived from previously cryopreserved oocytes, but we report the case of 100% implantation following transfer of 3 developmentally-delayed embryos derived from cryopreserved oocytes. CASE: A 38 year-old woman cryopreserved 20 oocytes for the purpose of future childbearing. At age 42 she returned to thaw and fertilize 8 oocytes using donor sperm. Embryos were cultured to day 5 postthaw, at which time 1 morula and 2 cleavage-stage embryos were available for transfer. Three-embryo transfer resulted in a heterotopic tubal pregnancy and twin intrauterine gestation. Laparoscopic salpingectomy was performed for the ectopic gestation. The twin intrauterine pregnancy spontaneously reduced to singleton, and the patient delivered a live born infant. CONCLUSION: While heterotopic and multifetal pregnancy are known risks of multiembryo transfer, 3 lesser-quality embryos derived from cryopreserved oocytes would be unlikely to have high implantation potential. Future studies are needed to delineate timing of embryogenesis events in previously cryopreserved oocytes. PMID- 26592073 TI - Fertility Preservation Through Oocyte Cryopreservation in a Patient with Ovarian Dysgerminocarcinoma: A Case Report. AB - BACKGROUND: This case evaluates a 20-year-old patient diagnosed with recurrent dysgerminoma who desired fertility preservation. CASE: A 20-year-old woman, GOPO, with a history of fertility-preserving right salpingo-oophorectomy and staging for dysgerminoma presented with interval change of a 5-cm left ovarian solid mass on ultrasound evaluation concerning for recurrent carcinoma. She underwent controlled ovarian hyperstimulation with injectable gonadotropins followed by transvaginal oocyte retrieval immediately followed by laparotomy, at which time ovarian dysgerminoma was confirmed. Completion total abdominal hysterectomy, left salpingo-oophorectomy, and exploratory surgery were performed. Forty-five oocytes were obtained, of which 37 mature oocytes were isolated and cryopreserved. The patient had an unremarkable postoperative course and was discharged home. CONCLUSION: Oncofertility preservation through oocyte cryopreservation may be considered a viable option for young women with ovarian cancer. PMID- 26592074 TI - Uterine Scar Dehiscence Associated with Misoprostol Cervical Priming for Surgical Abortion: A Case Report. AB - BACKGROUND: Cervical priming prior to pregnancy termination is a common treatment. Both osmotic agents such as laminaria and Dilapan or pharmacologic agents such as misoprostol and mifepristone have been used for this purpose. CASE: A 30-year-old patient with a previous cesarean delivery was undergoing surgical termination of pregnancy at 13 weeks' gestation for a lethal fetal malformation. During preoperative cervical priming with misoprostol the uterine scar dehisced. Interval laparoscopic repair was performed. CONCLUSION: Uterine scar dehiscence can occur with misoprostol preoperative cervical priming for second trimester surgical termination of pregnancy. PMID- 26592075 TI - Reactivation of Goodpasture Disease During the Third Trimester of Pregnancy: A Case Report. AB - BACKGROUND: Active Goodpasture disease (GD) in pregnancy is extremely rare and can result in significant maternal and fetal morbidity. Relapse of GD in a subsequent pregnancy has not been reported. Factors associated with a relapse of GD are unknown. CASE: A woman in her second pregnancy presented with clinical findings of preeclampsia and biopsy evidence of GD in the third trimester. Her first puerperium was also complicated by GD, requiring temporary hemodialysis. After her second pregnancy she developed terminal renal failure. CONCLUSION: Active GD is extremely rare in pregnancy and has never been reported in 2 successive pregnancies in the same patient. Pregnancy and preeclampsia may be risk factors for a GD relapse, and women with GD contemplating pregnancy should be counseled accordingly. PMID- 26592076 TI - Vulvar Syringoma in a Postmenopausal Woman: A Case Report. AB - BACKGROUND: First described in 1872, syringomas are common intraepidermal sweat gland tumors most often found in women during adolescence. Frequent involvement areas are the lower eyelids and malar areas; vulvar involvement is relatively rare. These lesions often appear as small, separate, yellowish papules of about 1 3 mm in size and are generally associated with increased vulvar discomfort and itching.They typically occur in multiples and are bilateral and symmetrical. CASE: A 52-year-old, postmenopausal woman presented with vulvar pruritis and was diagnosed with syringomas after vulvar biopsy in our polyclinics. CONCLUSION: Vulvar syringoma should be included in the differential diagnosisf or itchy and papular lesions of vulvae in a postmenopausal woman. PMID- 26592077 TI - Outcome of Nonpersonalized Human Papillomavirus Vaccinations During Postconization Follow-up: A Report of Two Cases. AB - BACKGROUND: The human papillomavirus (HPV) vaccine was conceived to prevent new HPV infections among uninfected young women. From the initial intentions, its use has been extended to older women and also tested as a therapeutic tool. We report two HPV vaccination outcomes during postconization follow-up. CASES: Two young women, with different clinical histories, were subjected to HPV vaccine after a loop electrosurgical excision procedure for high-grade cervical intraepithelial neoplasia (CIN) and persisting low-grade CIN. During follow-up both women experienced a worsening of cervical lesions, which resulted in invasive cervical cancer and severe dysplasia, respectively. CONCLUSION: Limited to our experience, a nonpersonalized HPV vaccine administration during postconization follow-up was expensive and unnecessary. PMID- 26592078 TI - Massive Subchorionic Placental Cyst and Poor Fetal Growth: A Case Report. AB - BACKGROUND: Large placental cysts are unusual and rarely have significant impact on pregnancy. CASE: We present a case of a progressively enlarging placental cyst, to 13 cm, which ultimately led to delivery due to suboptimal fetal growth and umbilical cord entrapment against the uterine wall. Review of the literature, including inconsistent nomenclature and pathologic findings, will be discussed. CONCLUSION: Large subchorionic placental cysts may be associated with suboptimal fetal growth. Serial ultrasound studies are indicated in these cases to evaluate fetal risk and potential umbilical cord involvement to aid in the appropriate timing of delivery. PMID- 26592079 TI - The Unappreciated Ramifications of the "Triple Obstetric Tragedy". AB - The untimely death of a young Princess of Wales reverberated around the world in August 1997. Diana, Princess of Wales, was not, however, the first holder of that title to suffer an early demise. Princess Charlotte of Wales was fifteen years younger and died exactly one hundred and eighty years earlier. A national feeling of grief and desolation consumed the nation in the same way as it did following the death of the "People's Princess" in the twentieth century. Her death during childbirth led to a change in the practice of obstetrics and a succession crisis in the British monarchy. But were the consequences of the fateful night of 6th November 1817 to be even more profound, indirectly contributing to war in Europe a century later? PMID- 26592080 TI - Women who Worked with Marie Curie. AB - Marie Curie directed a research laboratory for 28 years. Between 1906 and 1934, forty five women worked under her guidance. Some were, and are, well-known in their own countries as their first woman full professor such as Ellen Gleditsch or Margaret von Wrangel, but for twenty eight of them, who were often French, nothing has ever been written. The strong presence of women in Marie Curie's laboratory has often been highlighted and has been considered as an exception, and the result of deliberate choice. Of course, these women did not choose this workplace by accident. They knew its director was a woman, a laureate of one, and after 1911, two Nobel Prizes, who was leading a well-equipped laboratory with an important radioactive source. But how did Marie Curie selected her collaborators among the many applications she received? Was her choice influenced by gender? A prosopographical research based on genealogical researches and new sources explains this presence contextually and sheds light on several questions : where did these women come from, what were their social and geographic origins, did they occupy any specific cultural or technical area inside Curie's lab, what future did they have after the laboratory? Through their lives, we can question the existence, or not, of a one profile of the female researcher in scientific areas in France. PMID- 26592081 TI - From Georgia to Jerusalem: some Medical Aspects of "The Knight in the Panther's Skin" by Shota Rustaveli. AB - The Georgian poet Rustaveli wrote his epic poem The Knight in the Panther's Skin around 1200. He knew the works of Hippocrates and Galen, and believed in the unity of body and soul.Thereare many references to health and medicine in the poem, and we shall highlight some of them. In 1185 Rustaveli left Georgia and settled in Jerusalem. There he lived and died at the Monastery of the Cross, where he was buried. PMID- 26592082 TI - Nazi Dental Gold: from Dead Bodies to Swiss Banks. AB - On the 23rd of September 1940 SS Reichsfurher Heinrich Himmler, gave the SS doctors orders to collect the gold teeth from the mouths of those killed in death camps. Here we ask: who were the SS dentists who are directly implicated in that collection, what were the figures behind the process and how did the Nazis conduct this retrieval of gold? Here we give the answers for the first time... PMID- 26592083 TI - Echoes from the anatomical theater of Padua: Fabrici on the nervous system. AB - Girolamo Fabrici d'Acquapendente, never published a systematic description nor an iconographic record of the nervous system except for the series of 21 pictures, entitled De Anatomia Capitis Cerebri Nervorum, stored in the Biblioteca Marciana of Venice. PMID- 26592084 TI - [Amedee Latour (1805-1882) Physician, journalist, mutualist]. AB - AmedeeLatour (1805-1882), native Toulousain and grand-son of a professor of medicine, came to Paris to study, prior to support his doctoral thesis in 1834, bringing his "Proposals on art cure ". He has not practiced much medicine in Paris, but quickly focused toward medical journalism, writing articles in various scientific publications, particularly L'Union medicale from 1847 to 1882. He acquainted with several prominent medical doctors of the nineteenth century, especially Professor Andral. General Secretary of the French medical Congress in 1845, he was also the initiator and founder of the Social Security Association provident and mutual aid doctors in France. Member of the Public Health Advisory Committee, he was elected partner of the Academy of Medicine in 1870. Furthermore, from March to May 1870 AmedeeLatour became a refugee in his modest country house in Chatillon-sous-Bagneux and wrote a personal journal called "Journal of the bombing from April 4 to May 28", published in L'Unionmedicale the next July. He was able to describe the consequences of the bombing in his city of adoption during the Parisian insurrection, and his role as doctor and member of the city council during this period. He was buried in the cemetery of the city. PMID- 26592085 TI - Public Health Policies and Practices of the Ottoman Empire with Special Reference to the Gallipoli Campaign. AB - OBJECTIVE: To review the selected historiographic and contemporary literature that examined the Ottoman public health practices and policies with special reference to the Gallipoli campaign during the First World War. To date, no work has been published surrounding the Ottoman public health policies and responses during the battle of Gallipoli. METHODS: A historiographic methodology was used to examine relevant primary and secondary publications using ten academic electronic databases. RESULTS: The literature discussed pre-war Hapsburg efforts to improve the Ottoman medical infrastructure, the activities of military medical students and units at Gallipoli, quarantine and vaccination procedures, and general medical issues throughout the empire during the war. CONCLUSION: Access to the official Turkish archives and translating relevant official documents into English are warranted. This represents an opportunity for military and public health historians to examine and identify relevant public health practices and policies that the Ottoman Empire implemented during the First World War and, in particular, the Gallipoli campaign. PMID- 26592086 TI - Synthetic biology. A tribute to S. Leduc (1853-1939, Nantes, France) and an Answer to the Return of Vitalism. AB - A very large number of articles about vitalism have been published since 1894 in the journal Science. Vitalism is a theory according to which living organisms appear to possess something more than inanimate objects. The "vital principle" is minted in 1778 by Barthez in "Les nouveaux elements de la science de l'homme", (Stahl talks of phlogiston for chemistry). In their view, the life of the whole is not the simple sum of the life of the components. Such a view was hatched in response to the Cartesian mechanist interpretation of living matter as proposed by Galileo and Descartes. Vitalist intuition was revived in the XXth century by new researchers such as Henri Bergson ("l'elan vital" or 'vital force') in France and Hans Driesch ("entelechy") in Germany. Could this view of life now be making a comeback in biology? PMID- 26592087 TI - In-Yeast Engineering of a Bacterial Genome Using CRISPR/Cas9. AB - One remarkable achievement in synthetic biology was the reconstruction of mycoplasma genomes and their cloning in yeast where they can be modified using available genetic tools. Recently, CRISPR/Cas9 editing tools were developed for yeast mutagenesis. Here, we report their adaptation for the engineering of bacterial genomes cloned in yeast. A seamless deletion of the mycoplasma glycerol 3-phosphate oxidase-encoding gene (glpO) was achieved without selection in one step, using 90 nt paired oligonucleotides as templates to drive recombination. Screening of the resulting clones revealed that more than 20% contained the desired deletion. After manipulation, the overall integrity of the cloned mycoplasma genome was verified by multiplex PCR and PFGE. Finally, the edited genome was back-transplanted into a mycoplasma recipient cell. In accordance with the deletion of glpO, the mutant mycoplasma was affected in the production of H2O2. This work paves the way to high-throughput manipulation of natural or synthetic genomes in yeast. PMID- 26592088 TI - Thermochemical and Kinetics of Hydrazine Dehydrogenation by an Oxygen Atom in Hydrazine-Rich Systems: A Dimer Model. AB - The kinetics of the reaction of N2H4 with oxygen depends sensitively on the initial conditions used. In oxygen-rich systems, the rate constant shows a conventional positive temperature dependence, while in hydrazine-rich setups the dependence is negative in certain temperature ranges. In this study, a theoretical model is presented that adequately reproduces the experimental results trend and values for hydrazine-rich environment, consisting of the hydrogen abstraction from the hydrazine (N2H4) dimer by an oxygen atom. The thermochemical properties of the reaction were computed using two quantum chemical approaches, the coupled cluster theory with single, double, and noniterative triple excitations (CCSD(T)) and the M06-2X DFT approach with the aug-cc-pVTZ and the maug-cc-pVTZ basis sets, respectively. The kinetic data were calculated with the improved canonical variational theory (ICVT) using a dual level methodology to build the reaction path. The tunneling effects were considered by means of the small curvature tunneling (SCT) approximation. Potential wells on both sides of the reaction ((N2H4)2 + O -> N2H4...N2H3 + OH) were determined. A reaction path with a negative activation energy was found leading, in the temperature range of 250-423 K, to a negative dependence of the rate constant on the temperature, which is in good agreement with the experimental measurements. Therefore, the consideration of the hydrazine dimer model provides significantly improved agreement with the experimental data and should be included in the mechanism of the global N2H4 combustion process, as it can be particularly important in hydrazine-rich systems. PMID- 26592089 TI - Cichoric Acid Reverses Insulin Resistance and Suppresses Inflammatory Responses in the Glucosamine-Induced HepG2 Cells. AB - Cichoric acid, a caffeic acid derivative found in Echinacea purpurea, basil, and chicory, has been reported to have bioactive effects, such as anti-inflammatory, antioxidant, and preventing insulin resistance. In this study, to explore the effects of CA on regulating insulin resistance and chronic inflammatory responses, the insulin resistance model was constructed by glucosamine in HepG2 cells. CA stimulated glucosamine-mediated glucose uptake by stimulating translocation of the glucose transporter 2. Moreover, the production of reactive oxygen, the expression of COX-2 and iNOS, and the mRNA levels of TNF-alpha and IL 6 were attenuated. Furthermore, CA was verified to promote glucosamine-mediated glucose uptake and inhibited inflammation through PI3K/Akt, NF-kappaB, and MAPK signaling pathways in HepG2 cells. These results implied that CA could increase glucose uptake, improve insulin resistance, and attenuate glucosamine-induced inflammation, suggesting that CA is a potential natural nutraceutical with antidiabetic properties and anti-inflammatory effects. PMID- 26592090 TI - Noninvasive approach for enhancing small interfering RNA delivery percutaneously. AB - INTRODUCTION: Topically applied small interfering RNA (siRNA) can be an effective treatment for skin disorders. Using noninvasive strategies can be a safe and effective siRNA-permeation-enhancement approach for facilitating skin delivery. It has been demonstrated that noninvasive approaches for enhancing siRNA transport provide some advantages, including enhanced storage stability, targeted delivery, improved permeability and increased bioavailability. AREAS COVERED: This review describes recent developments using noninvasive approaches for siRNA absorption enhancement. This review systematically introduces the concepts and enhancement mechanisms of the techniques, highlighting the potential of these techniques for increasing gene absorption via the skin. These techniques include nanomedicine, penetration enhancers, matrix-based delivery, microneedles, iontophoresis, electroporation and lasers. These modalities are useful for enhancing the permeation of a wide variety of siRNA for treating skin cancers, gene-related diseases, immune-related diseases and cutaneous wounds. EXPERT OPINION: The potential use of the noninvasive approaches affords a new treatment for topical siRNA application with significant efficacy. Further studies using a large group for humans or patients are needed to confirm and clarify the findings in animal studies. Although a safe and nontoxic outcome is claimed, the possible adverse effects and irritation elicited by the noninvasive techniques cannot be ignored. PMID- 26592091 TI - Suppression of basal and carbon nanotube-induced oxidative stress, inflammation and fibrosis in mouse lungs by Nrf2. AB - The lungs are susceptible to oxidative damage by inhaled pathogenic agents, including multi-walled carbon nanotubes (MWCNT). The nuclear factor erythroid 2 related factor 2 (Nrf2) has been implicated in regulating the body's defense against oxidative stress. Here, we analyzed the function of Nrf2 in the lungs. Under a basal condition, Nrf2 knockout (KO) mice showed apparent pulmonary infiltration of granulocytes, macrophages and B and T lymphocytes, and elevated deposition of collagen fibers. Exposure to MWCNT (XNRI MWNT-7, Mitsui, Tokyo, Japan) by pharyngeal aspiration elicited rapid inflammatory and fibrotic responses in a dose (0, 5, 20 and 40 MUg) and time (1, 3, 7 and 14 d)-dependent manner. The responses reached peak levels on day 7 post-exposure to 40 MUg MWCNT, evidenced by massive inflammatory infiltration and formation of inflammatory and fibrotic foci, which were more evident in Nrf2 KO than wild-type (WT) lungs. At the molecular level, Nrf2 protein was detected at a low level under a basal condition, and was dramatically increased by MWCNT in WT, but not Nrf2 KO, lungs. Activation of Nrf2 was inversely correlated with induced expression of fibrosis marker genes and profibrotic cytokines. Furthermore, the levels of ROS and oxidative stress were remarkably higher in Nrf2 KO than WT lungs under a physiological condition, and were dramatically increased by MWCNT, with the increase significantly more striking in KO lungs. The findings reveal that Nrf2 plays an important role in suppressing the basal and MWCNT-induced oxidant production, inflammation and fibrosis in the lungs, thereby protecting against MWCNT lung toxicity. PMID- 26592092 TI - Manipulation of heart rate variability can modify response to anger-inducing stimuli. AB - Research suggests that heart rate variability (HRV) is a physiological indicator of the flexibility of the autonomic nervous system and can provide an objective measure of an individual's ability to appropriately match emotional responses to environmental demands. The present study investigated whether angry response to emotional stimuli was related to HRV, and whether manipulation of HRV using biofeedback could change the anger response in a healthy adult population. Fifty eight participants received HRV biofeedback (n = 29) or an active control condition (n = 29). HRV measures included standard deviation of normal-to-normal intervals (SDNN), low-frequency (LF) and high-frequency (HF) power, and was recorded across three sessions: baseline, training, and anger induction. The anger induction procedure resulted in increased subjective experience of anger, as well as physiological changes. The biofeedback group had higher HRV than active controls both during the training session (SDNN and LF HRV) and during anger induction (LF HRV). HRV during anger induction was significantly associated with self-reported emotional response for participants receiving biofeedback but not for active controls. Results provide support for HRV as an index of emotion regulation, specifically anger. Further research is needed to determine whether long-term HRV biofeedback can have a lasting effect on managing anger. PMID- 26592093 TI - Volar plate versus k-wire fixation of distal radius fractures. AB - The optimal management of distal radius fractures remains controversial. The aim of this study was to compare the radiographic and functional outcomes of 318 patients who underwent k-wire fixation or volar plating for fractures of the distal radius. Patients were aged between 20 and 65 years and followed for a mean of 32 months. The mean values for volar tilt, radial inclination, radial length and ulnar variance were all significantly better in the volar plate group. Malunion occurred in 13.2% of patients undergoing k-wiring and 4% of patients treated with a volar plate (p<0.007). Higher values for radial inclination, radial length and volar tilt correlated with better functional outcome as measured by disabilities of the arm shoulder and hand (DASH) and patient rated wrist evaluation (PRWE) scores. Lower values for ulnar variance correlated with better functional outcome. Although volar plate treatment resulted in a superior radiological outcome, there was no evidence that this translated into a superior functional outcome (DASH 13.12 vs. 11.25, p=0.28) (PRWE 17.56 vs. 16.31, p=0.69). The k-wiring procedure remains a suitable inexpensive option for simple fractures. Volar plating should be reserved for complex fractures that cannot be reduced by closed means. PMID- 26592094 TI - Femoral neck fractures in children and the role of early hip decompression in final outcome. AB - BACKGROUND: Femoral neck fractures in children are very rare and account for about 1% of all paediatric fractures. The aim of this retrospective study was to analyse the clinical and radiographic outcome in paediatric femoral neck fracture and to review the role of early decompression of the hip in the final outcome. PATIENTS AND METHODS: The study was performed at the Department of Paediatric Orthopaedics and Traumatology, University Children's Hospital in Belgrade, Serbia from January 1996 to January 2010. The study included 28 patients, 12 female and 16 male, aged 4-14 years. Patients who were aged over 14 years or who had pathological femoral neck fractures or metabolic disturbances were excluded from the study. The type of neck fracture was determined according to the Delbet and Colonna classification. The patients were treated using different surgical procedures: closed reduction and cast immobilisation, closed reduction and percutaneous fixation with Kirschner wires (K-wires), closed reduction and fixation with cannulated screws and open reduction with Wagner plate stabilisation. The final outcome was evaluated using the clinical outcome (based on the Howorth-Ferguson scale), radiographic outcome and occurrence of complications. RESULTS: The median age of patients included in the study was 10.75 years and the average follow up was 9 years. According to the Delbet classification, there was one patient with type I, eight patients with type II, 16 patients with type III and three patients with type IV femoral neck fracture. Based on the Colonna classification, there were 23 displaced and five non displaced femoral neck fractures. Decompression of the hip was performed in 21 patients. Avascular necrosis (AVN) developed as the main complication in 11 patients. The final outcome was excellent in 14 patients, good in four patients and poor in 14 patients. CONCLUSION: Our study unequivocally confirms the positive effect of urgent treatment on the incidence of AVN as well as on the outcome. We have established a 12-hour interval after injury as an optimal time limit for commencing treatment. Unambiguously positive effects of hip decompression on the incidence of AVN were also noted. We found similar efficiency for open and needle hip decompression. PMID- 26592095 TI - A Convenient Strategy for Designing a Soft Nanospace: An Atomic Exchange in a Ligand with Isostructural Frameworks. AB - Direct observation of gas molecules confined in the nanospace of porous materials by single-crystal X-ray diffraction (SXRD) technique is significant because it leads to deep insight into the adsorption mechanism and the actual state of the adsorbents in molecular level. A recent study revealed that flexibility is one of the important factors to achieve periodic guest accommodation in the nanospace enabling direct observation of gas molecules. Here, we report a convenient strategy to tune the framework flexibility by just an atomic exchange in a ligand, which enables us to easily construct a soft nanospace as the best platform to study gas adsorption. Indeed, we succeeded to observe C2H2 and CO2 molecules confined in the pores of a flexible porous coordination polymer (PCP-N) in different configurations using SXRD measurement, whereas gas molecules in a rigid framework (PCP-C) isostructural to PCP-N were not seen crystallographically. The result of the coincident in situ powder X-ray diffraction and adsorption measurement for PCP-N unambiguously showed that the framework could flexibly transform to trap gas molecules with a commensurate fashion. In addition, for PCP-N, we found that the adsorbed gas molecules induced significant structural change involving dimensional change of the pore from one dimensional to three-dimensional, and subsequently, additional gas molecules formed periodic molecular clusters in the nanospace. PMID- 26592096 TI - Polarization Control of Morphological Pattern Orientation During Light-Mediated Synthesis of Nanostructured Se-Te Films. AB - The template-free growth of well ordered, highly anisotropic lamellar structures has been demonstrated during the photoelectrodeposition of Se-Te films, wherein the orientation of the pattern can be directed by orienting the linear polarization of the incident light. This control mechanism was investigated further herein by examining the morphologies of films grown photoelectrochemically using light from two simultaneous sources that had mutually different linear polarizations. Photoelectrochemical growth with light from two nonorthogonally polarized same-wavelength sources generated lamellar morphologies in which the long axes of the lamellae were oriented parallel to the intensity-weighted average polarization orientation. Simulations of light scattering at the solution-film interface were consistent with this observation. Computer modeling of these growths using combined full-wave electromagnetic and Monte Carlo growth simulations successfully reproduced the experimental morphologies and quantitatively agreed with the pattern orientations observed experimentally by considering only the fundamental light-material interactions during growth. Deposition with light from two orthogonally polarized same wavelength as well as different-wavelength sources produced structures that consisted of two intersecting sets of orthogonally oriented lamellae in which the relative heights of the two sets could be varied by adjusting the relative source intensities. Simulations of light absorption were performed in analogous, idealized intersecting lamellar structures and revealed that the lamellae preferentially absorbed light polarized with the electric field vector along their long axes. These data sets cumulatively indicate that anisotropic light scattering and light absorption generated by the light polarization produces the anisotropic morphology and that the resultant morphology is a function of all illumination inputs despite differing polarizations. PMID- 26592097 TI - A study of mastoid pneumatisation and the presence of cholesteatoma in 393 patients. AB - OBJECTIVES: This study aimed to evaluate the relationship between cholesteatoma formation and the degree of mastoid pneumatisation, and to assess the relationship between the location of cholesteatoma and the degree of mastoid pneumatisation. METHODS: Data on all patients undergoing mastoid exploration for cholesteatoma between 1993 and 2011 were collected prospectively. Basic demographics, the degree of mastoid pneumatisation and cholesteatoma site were recorded. RESULTS: A total of 393 patients (222 males and 171 females) underwent surgery for cholesteatoma. Patients' mean age was 37 years (range, 6-79 years). Pneumatisation of the mastoid was sclerotic in 23 per cent (n = 90), diploic in 16.7 per cent (n = 66) and cellular in 60.3 per cent of cases (n = 237) (p < 0.001). Atticoantral disease was present in 88.9 per cent of sclerotic, 95.4 per cent of diploic and 91.1 per cent of cellular mastoids. Middle-ear cholesteatoma was present in 54.4 per cent of sclerotic, 56 per cent of diploic and 51.9 per cent of cellular mastoids. CONCLUSION: The findings demonstrate the presence of cholesteatoma in well-pneumatised mastoids. It is hypothesised that a well pneumatised mastoid may lead to cholesteatoma formation. PMID- 26592099 TI - Multiple trait genetic evaluation of clinical mastitis in three dairy cattle breeds. AB - In 2010, a routine genetic evaluation on occurrence of clinical mastitis in three main dairy cattle breeds-- Montbeliarde (MO), Normande (NO) and Holstein (HO)- was implemented in France. Records were clinical mastitis events reported by farmers to milk recording technicians and the analyzed trait was the binary variable describing the occurrence of a mastitis case within the first 150 days of the first three lactations. Genetic parameters of clinical mastitis were estimated for the three breeds. Low heritability estimates were found: between 2% and 4% depending on the breed. Despite its low heritability, the trait exhibits genetic variation so efficient genetic improvement is possible. Genetic correlations with other traits were estimated, showing large correlations (often>0.50, in absolute value) between clinical mastitis and somatic cell score (SCS), longevity and some udder traits. Correlation with milk yield was moderate and unfavorable (rho=0.26 to 0.30). High milking speed was genetically associated with less mastitis in MO (rho=-0.14) but with more mastitis in HO (rho=0.18). A two-step approach was implemented for routine evaluation: first, a univariate evaluation based on a linear animal model with permanent environment effect led to pre-adjusted records (defined as records corrected for all non-genetic effects) and associated weights. These data were then combined with similar pre adjusted records for others traits in a multiple trait BLUP animal model. The combined breeding values for clinical mastitis obtained are the official (published) ones. Mastitis estimated breeding values (EBV) were then combined with SCSs EBV into an udder health index, which receives a weight of 14.5% to 18.5% in the French total merit index (ISU) of the three breeds. Interbull genetic correlations for mastitis occurrence were very high (rho=0.94) with Nordic countries, where much stricter recording systems exist reflecting a satisfactory quality of phenotypes as reported by the farmers. They were lower (around 0.80) with countries supplying SCS as a proxy for the international evaluation on clinical mastitis. PMID- 26592100 TI - Msxb is a core component of the genetic circuitry specifying the dorsal and ventral neurogenic midlines in the ascidian embryo. AB - The tail ascidian larval peripheral nervous system is made up of epidermal sensory neurons distributed more or less regularly in ventral and dorsal midlines. Their formation occurs in two-steps: the ventral and dorsal midlines are induced as neurogenic territories by Fgf9/16/20 and Admp respectively. The Delta2/Notch interaction then controls the number of neurons that form. The genetic machinery acting between the inductive processes taking place before gastrulation and neuron specification at tailbud stages are largely unknown. The analysis of seven transcription factors expressed in the forming midlines revealed an unexpected complexity and dynamic of gene expression. Their systematic overexpression confirmed that these genes do not interact following a linear cascade of activation. However, the integration of our data revealed the distinct key roles of the two upstream factors Msxb and Nkx-C that are the earliest expressed genes and the only ones able to induce neurogenic midline and ESN formation. Our data suggest that Msxb would be the primary midline gene integrating inputs from the ventral and dorsal inducers and launching a pan midline transcriptional program. Nkx-C would be involved in tail tip specification, in maintenance of the pan-midline network and in a posterior to anterior wave controlling differentiation. PMID- 26592101 TI - Improving the Prediction of Absolute Solvation Free Energies Using the Next Generation OPLS Force Field. AB - Explicit solvent molecular dynamics free energy perturbation simulations were performed to predict absolute solvation free energies of 239 diverse small molecules. We use OPLS2.0, the next generation OPLS force field, and compare the results with popular small molecule force fields-OPLS_2005, GAFF, and CHARMm-MSI. OPLS2.0 produces the best correlation with experimental data (R(2) = 0.95, slope = 0.96) and the lowest average unsigned errors (0.7 kcal/mol). Important classes of compounds that performed suboptimally with OPLS_2005 show significant improvements. PMID- 26592098 TI - Biofilm models of polymicrobial infection. AB - Interactions between microbes are complex and play an important role in the pathogenesis of infections. These interactions can range from fierce competition for nutrients and niches to highly evolved cooperative mechanisms between different species that support their mutual growth. An increasing appreciation for these interactions, and desire to uncover the mechanisms that govern them, has resulted in a shift from monomicrobial to polymicrobial biofilm studies in different disease models. Here we provide an overview of biofilm models used to study select polymicrobial infections and highlight the impact that the interactions between microbes within these biofilms have on disease progression. Notable recent advances in the development of polymicrobial biofilm-associated infection models and challenges facing the study of polymicrobial biofilms are addressed. PMID- 26592102 TI - Origin of Fluorescence in 11-cis Locked Bovine Rhodopsin. AB - The excited state lifetime of bovine rhodopsin (Rh) increases from ca. 100 fs to 85 ps when the C11?C12 bond of its chromophore is locked by a cyclopentene moiety (Rh5). To explain such an increase, we employed ab initio multiconfigurational quantum chemistry to construct computer models of Rh and Rh5 and to investigate the shape of their excited state potential energy surfaces in a comparative way. Our results show that the observed Rh5 fluorescence (lambdamax(f) = 620 nm) is due to a previously unreported locally excited intermediate whose lifetime is controlled by a small energy barrier. The analysis of the properties and decay path of such an intermediate provides useful information for engineering rhodopsin variants with augmented fluorescence efficiencies. PMID- 26592103 TI - The Effect of Newly Developed OPLS-AA Alanyl Radical Parameters on Peptide Secondary Structure. AB - Recent studies using ab initio calculations have shown that Calpha-centered radical formation by H-abstraction from the backbone of peptide residues has dramatic effects on peptide structure and have suggested that this reaction may contribute to the protein misfolding observed in Alzheimer's and Parkinson's diseases. To enable the effects of Calpha-centered radicals to be studied in longer peptides and proteins over longer time intervals, force-field parameters for the Calpha-centered Ala radical were developed for use with the OPLS force field by minimizing the sum of squares deviation between the quantum chemical and OPLS-AA energy hypersurfaces. These parameters were used to determine the effect of the Calpha-centered Ala radical on the structure of a hepta-alanyl peptide in molecular dynamics (MD) simulations. A negligible sum-of-squares energy deviation was observed in the stretching parameters, and the newly developed OPLS-AA torsional parameters showed a good agreement with the LMP2/cc-pVTZ(-f) hypersurface. The parametrization also demonstrated that derived force-field bond length and bond angle parameters can deviate from the quantum chemical equilibrium values, and that the improper torsional parameters should be developed explicitly with respect to the coupled torsional parameters. The MD simulations showed planar conformations of the Calpha-containing residue (Alr) are preferred and these conformations increase the formation of gamma-, alpha-, and pi-turn structures depending on the position in the turn occupied by the Alr residue. Higher-ordered structures are destabilized by Alr except when this residue occupies position "i + 1" of the 310-helix. These results offer new insight into the protein-misfolding mechanisms initiated by H-abstraction from the Calpha of peptide and protein residues. PMID- 26592104 TI - Determining Geometrically Stable Domains in Molecular Conformation Sets. AB - Detecting significant conformational changes occurring in biomolecules is a challenging task, especially when considering tens to hundreds of thousands of conformations. Conformational variability can be described by dividing a biomolecule into dynamic domains, i.e., by finding compact fragments that move as coherent units. Typical approaches, based on calculating a dynamical cross correlation matrix, are limited by their inability to reveal correlated rotations and anticorrelated motions. We propose a geometric approach for finding dynamic domains, where we compare traces of atomic movements in a pairwise manner, and search for their best superposition. A quaternion representation of rotation is used to simplify the complex calculations. The algorithm was implemented in a Java graphical program: Geometrically Stable Substructures (GeoStaS). The program processes PDB and DCD binary files with large structural sets for proteins, nucleic acids, and their complexes. We demonstrate its efficiency in analyzing (a) ensembles of structures generated by NMR experiments and (b) conformation sets from biomolecular simulations, such as molecular dynamics. The results provide a clear description of the molecular movements even for large biomolecules. Compared to a standard dynamic cross-correlation matrix, our algorithm detects the correlations in both translational and rotational motions. PMID- 26592105 TI - Global ab Initio Potential Energy Surfaces for Low-Lying Doublet States of NO3. AB - We report analytical global potential energy surfaces (PESs) for three low-lying doublet states (D0, D1, and D2) of NO3. The fits are made on roughly 74000 MS CAS(17e,13o)PT2/aug-cc-pVTZ calculations of electronic energies, where these PESs are invariant of permutations of oxygen atoms. The surfaces describe two roaming pathways for NO3 -> NO2-----O -> NO + O2 involving different electronic states discovered in the photolysis of NO3 [ Xiao, H. Y. et al. J. Phys. Chem. Lett.2011, 2, 934 ]. These pathways become accessible at excess energy of ~210 kJ/mol above the ground-state global minimum of NO3. The ab initio data below 360 kJ/mol are reproduced very well by the fitted PESs with the fitting rms errors of less than 5.5 kJ/mol for all the three states. Moreover, key local minima and energy profiles along the roaming pathways on the fitted PESs are compared with those on the ab initio PESs. In addition, potential contour maps in the roaming region are also compared. These careful evaluations of the fitted PESs suggest that the present fitted PESs are well suited for future dynamics calculations of this system. PMID- 26592106 TI - A Toolkit for the Analysis of Free-Energy Perturbation Calculations. AB - As computational power inexorably continues to grow, harnessing the capabilities of novel processing units and architectures, free-energy calculations are progressively brought to the level of routine modeling tools for exploring the thermodynamic properties of increasingly larger molecular assemblies. Within these premises, free-energy perturbation (FEP) arguably represents the most commonly chosen approach for tackling transformations of a chemical nature between thermodynamic states. To augment the accuracy, the precision, and, hence, the reliability of these calculations, a number of good practices have been established. In the present contribution, a new toolkit, coined ParseFEP, is proposed to follow these prescriptions in a user-friendly environment. Written as a Tcl plugin, it allows FEP calculations carried out using the popular molecular dynamics package NAMD to be analyzed seamlessly within the visualization platform VMD. The potential of the toolkit is probed through a number of illustrative examples, which demonstrate cogently how pathological cases, often related to convergence issues, can be detected and remedied by means of a pictorial approach. PMID- 26592107 TI - Development, Implementation, and Application of an Analytic Second Derivative Formalism for the Normalized Elimination of the Small Component Method. AB - Analytical second derivatives for the normalized elimination of the small component (NESC) method are derived for the first time and implemented for the routine calculation of NESC vibrational frequencies and other second order molecular properties using the scalar relativistic form of NESC. Using response theory, the second derivatives of the transformation matrix U connecting the large and the pseudolarge components of the relativistic wave function are correctly derived. The 24 derivative terms involving the NESC Hamiltonian and the NESC renormalization matrix are individually tested, and their contributions to the energy Hessian are calculated. The influence of a finite nucleus model and that of the picture change is determined. Different ways of speeding up the calculation of the NESC second derivatives are tested. It is shown that second order properties can routinely be calculated in combination with Hartree-Fock, density functional theory, Moller-Plesset perturbation theory, and any other electron correlation corrected quantum chemical method provided analytic second derivatives are available in the nonrelativistic case. The general applicability of the analytic NESC Hessian is demonstrated by benchmark calculations for NESC/DFT calculations involving up to 1500 basis functions. PMID- 26592108 TI - A Hierarchy of Methods for the Energetically Accurate Modeling of Isomerism in Monosaccharides. AB - The performance of different wave-function-based and density functional theory (DFT) methods was evaluated with respect to the prediction of relative energies for gas-phase monosaccharide isomers. A test set of 58 structures was employed, representing all forms of isomerism encountered in d-aldohexoses. The set was built from eight hexopyranose epimers by deriving subsets of isomers that include hydroxymethyl rotamers, anomers, ring conformers, furanose, and open-chain forms. Each subset of isomers spans a different energy range and involves various stereoelectronic effects. Reference energy values were obtained with coupled cluster calculations extrapolated to the complete basis set limit, CCSD(T)/CBS. The tested CBS-extrapolated ab initio methods include various types of Moller Plesset (MP) perturbation theory and the localized paired natural orbital coupled electron pair approach (LPNO-CEPA). Extensive benchmarking of DFT methods was carried out with 31 functionals. The results allow us to establish a hierarchy of methods that forms a reference guide for further computational studies. Among wave-function-based methods, LPNO-CEPA proved indistinguishable from CCSD(T), offering a promising alternative for a reference method that can be applied to larger systems. MP2 and SCS-MP2 follow closely, surpassing SOS-MP2 and MP3. The mPW2PLYP-D double hybrid and the Minnesota M06-2X hybrid meta-GGA are the best performing density functionals and are directly competitive with wave-function based ab initio methods. Among the remaining functionals, B3PW91, TPSSh, mPW1PW91, and PBE0 yield the best results on average, while PBE is the best general-purpose GGA functional, surpassing meta-GGAs and several hybrids such as B3LYP. The choice of method strongly depends on the type of isomerism that needs to be considered, since many DFT methods perform well for purely conformational isomerism, but most of them fail to describe ring versus open-chain isomerism, where LYP-based GGA functionals perform particularly poorly. PMID- 26592109 TI - Performance of PNOF5 Natural Orbital Functional for Radical Formation Reactions: Hydrogen Atom Abstraction and C-C and O-O Homolytic Bond Cleavage in Selected Molecules. AB - Radical formation through hydrogen abstraction and C-C and O-O homolytic bond cleavage from selected molecules is investigated by use of natural orbital functional theory in its PNOF5 natural orbital functional implementation, and the results are compared to high-level ab initio complete active space self consistent field (CASSCF) and complete active space with second-order perturbation theory (CASPT2) methods and experimental data. It is observed that PNOF5 is able to treat the strong electron correlation effects along the homolysis of X-H (X = C, N, O) and X-X (X = C, O) bonds, leading, in general, to the correct trends in the corresponding bond strengths and a good description of the resultant electronic structure for these radicals. In general, PNOF5 bond energies are lower than the experimental ones, because of partial lack of dynamical electron correlation. However, the part of dynamical electron correlation recovered by PNOF5 allows it to give more accurate results than CASSCF methods with a minimum window required to treat near-degeneracy effects. In addition, inspection of the natural orbital occupancies with respect to the CASSCF ones shows an outstanding performance of PNOF5 in treating degenerate and quasidegenerate states, giving a correct description of diradicals and diradicaloids formed upon C-C cleavage in cyclopropane and derivatives. PMID- 26592110 TI - Benchmark Quasi-Variational Coupled Cluster Calculations of Multiple Bond Breaking. AB - We present further evidence that closed-shell single-reference coupled cluster theory can be used as a reliable predictive tool even when multiple chemical bonds are broken, provided that a near-variational, rather than a projective, ansatz is used. Building on the Optimized-orbital Quasi-Variational Coupled Cluster Doubles (OQVCCD) method by adding the standard perturbative treatment of triple excitations, the OQVCCD(T) method provides outstanding accuracy for the dissociation of multiply bonded molecules and other problems involving strong nondynamic correlation of the electrons. We find that in the case of singly bonded molecules, OQVCCD and OQVCCD(T) perform similarly to the equivalent Brueckner Coupled Cluster Doubles approaches, BCCD and BCCD(T). However, when multiple bonds are broken, such as in acetylene and dicarbon, OQVCCD(T) is capable of predicting both qualitatively and quantitatively accurate potential energy curves, unlike the standard methods based on traditional coupled cluster theory, and for approximately the same computational cost. PMID- 26592112 TI - Many-Overlapping-Body (MOB) Expansion: A Generalized Many Body Expansion for Nondisjoint Monomers in Molecular Fragmentation Calculations of Covalent Molecules. AB - A common approach to approximating the full electronic energy of a molecular system is to first divide the system into nonoverlapping (disjoint) fragments and then compute the two-body or three-body fragment-fragment interactions using a many-body expansion. In this paper, we demonstrate that, by using a set of fragments which overlap with each other, a many-body expansion converges much faster than using nonoverlapping fragments. A new hierarchical fragmentation scheme is therefore proposed which generalizes the many-body expansion expressions and describes a simple procedure for generating the set of overlapping monomers. This method is referred to as the many-overlapping-body (MOB) expansion and is evaluated with two example systems: four dendritic isomers of C29H60 and 10 conformational isomers of a polypeptide molecule. In both examples, the MOB methodology significantly improves the two-body corrected energies. PMID- 26592111 TI - Calculating Off-Site Excitations in Symmetric Donor-Acceptor Systems via Time Dependent Density Functional Theory with Range-Separated Density Functionals. AB - Time-dependent density functional theory with range-separated hybrid functionals is used to calculate off-site excitations involving transitions between spatially separated orbitals in weakly coupled systems. Although such off-site excitations involve charge transfer, orbital degeneracy in symmetrical systems results in linear combinations of off-site excitations with equal weights and therefore zero net charge-transfer character. Like other types of off-site excitations, such "hidden" charge-transfer excitations are not accurately captured by conventional density functionals. We show that the recently introduced Baer-Neuhauser-Livshitz range-separated hybrid functional accurately characterizes such hidden off-site excitation energies via applications to the ethene dimer model system and to dye functionalized silsesquioxanes. PMID- 26592113 TI - Density-Functional Errors in Alkanes: A Real-Space Perspective. AB - Density-functional theory (DFT) approximations are known to give systematic errors for isodesmic reaction energies of n-alkanes to form ethane. Several explanations have been proposed, involving both the exchange or correlation nature of the problem and its distance range (i.e., medium-range or long-range interactions). In this work, a new isodesmic reaction is defined to demonstrate that the reaction energy differences originate from localized interactions between contiguous CH2 units in the n-alkane, i.e., from 1,3 interactions. Furthermore, we introduce a real-space interpretation of the error based on changes in electron density, described by our recently developed Non-Covalent Interactions (NCI) method. The reduced density gradient has smaller values for noncovalent 1,3 interactions in n-alkane reactants compared to ethane products. The gradient contribution to the exchange energy is consequently reduced, giving a constant energy bias against each propane unit in an n-alkane. Differences in exchange energy for grid points within the NCI regions are shown to be responsible for the reaction-energy errors. This is also demonstrated to be the source of error in Diels-Alder addition barrier heights obtained with GGA-based hybrid functionals. PMID- 26592114 TI - Electronic and Vibrational Nonlinear Optical Properties of Five Representative Electrides. AB - The electrides have a very special electronic structure with diffuse excess electrons not localized on any specific atom. Such systems are known to have huge electronic nonlinear optical (NLO) properties. Here, we determine and analyze the vibrational, as compared to the electronic, NLO properties for a representative set of electrides: Li@Calix, Na@Calix, Li@B10H14, Li2(*+)TCNQ(*-), and Na2(*+)TCNQ(*-). The static and dynamic vibrational (hyper)polarizabilities are computed by the nuclear relaxation method (with field-induced coordinates and the infinite optical frequency approximation) at the UB3LYP level using a hybrid Pople basis set. In general, the static vibrational betavec and gamma? exceed the corresponding static electronic property values by up to an order of magnitude. The same comparison for dynamic vibrational hyperpolarizabilities shows a smaller ratio. For the intensity-dependent refractive index (IDRI) and dc-Kerr processes, the ratio is on the order of unity or somewhat larger; it is less for the dc Pockels and the electric field induced second harmonic (EFISH) effects (as well as the static alpha) but still important. The role of anharmonicity, motion of the alkali atoms, and substitution of Na for Li is discussed along with specific aspects of the charge distribution associated with the excess electron. PMID- 26592115 TI - Crystal Polymorphism in Oxalyl Dihydrazide: Is Empirical DFT-D Accurate Enough? AB - Crystalline oxalyl dihydrazide has five experimentally known polymorphs whose energetics are governed by subtle balances between intra- and intermolecular interactions, providing a severe challenge for theoretical crystal structure modeling. Previous work has shown that many common density functional methods that neglect van der Waals dispersion cannot correctly describe this system, but it has been argued that empirically dispersion-corrected DFT-D performs much better. Here, we examine these crystals with second-order Moller-Plesset perturbation theory (MP2) and related levels of theory using the fragment-based hybrid many-body interaction method. The energetics prove sensitive to the treatment of electron-electron correlation, the basis set, many-body induction, three-body dispersion, and zero-point contributions. Nevertheless, our best predictions for the polymorph energy ordering based on dispersion-corrected MP2C calculations agree with the available experimental data. In contrast, lower levels of theory, including the common B3LYP-D* and D-PW91 dispersion-corrected density functional approximations, fail to reproduce experimental observations and/or the high-level calculations. PMID- 26592116 TI - Theoretical Study of the Cytochrome P450 Mediated Metabolism of Phosphorodithioate Pesticides. AB - The toxicity of phosphorodithioate pesticides is due to the formation of the active oxane product through desulfurization by cytochrome P450 enzymes, both in humans and insects. During this desulfurization, inhibition of cytochrome P450 and a loss of heme has been observed. Here, we study the mechanism of desulfurization and inhibition with density functional theory, using the B3LYP functional with and without dispersion correction. The results show that a reaction mechanism initiated by sulfur oxidation is most likely, with a reaction barrier of 47 kJ/mol. The sulfur oxidation is followed by a ring-closing mechanism with a barrier of 28 kJ/mol relative to the sulfur-oxidized intermediate. The enzymatic contribution to the ring-closing is very small. It is also shown that the apparent loss of heme might be due to the formation of a previously unknown inhibition complex, which changes the aromatic conjugation of the porphyrin ring. We also show that including dispersion correction has significant effects on a ring closure transition state (~30 kJ/mol), whereas effects on the other steps in the reaction are relatively small (4-15 kJ/mol). PMID- 26592117 TI - Revisiting Vibrational Circular Dichroism Spectra of (S)-(+)-Carvone and (1S,2R,5S)-(+)-Menthol Using SimIR/VCD Method. AB - The VCD spectra of (S)-(+)-carvone and (1S,2R,5S)-(+)-menthol are recalculated using the DFT method with extended conformation and configuration spaces. The calculated individual and averaged spectra are compared against observed ones using the previously reported similarity index, SV. It is found that the SV population forms approximately two normal distributions, depending on whether a spectrum matches the observed one or not. This statistical character can be used to estimate the error in absolute configuration (AC) assessments. To avoid erroneous AC assignments and incomplete conformation searching, it is advisible to employ a minimum |SV| of 0.2 and maximize it using conformation averaging. It is demonstrated that this approach is suitable and robust for flexible chiral molecules. PMID- 26592118 TI - On the N1-H and N3-H Bond Dissociation in Uracil by Low Energy Electrons: A CASSCF/CASPT2 Study. AB - The dissociative electron-attachment (DEA) phenomena at the N1-H and N3-H bonds observed experimentally at low energies (<3 eV) in uracil are studied with the CASSCF/CASPT2 methodology. Two valence-bound pi(-) and two dissociative sigma(-) states of the uracil anionic species, together with the ground state of the neutral molecule, are proven to contribute to the shapes appearing in the experimental DEA cross sections. Conical intersections (CI) between the pi(-) and sigma(-) are established as the structures which activate the DEA processes. The N1-H and N3-H DEA mechanisms in uracil are described, and experimental observations are interpreted on the basis of two factors: (1) the relative energy of the (U-H)(-) + H fragments obtained after DEA with respect to the ground-state equilibrium structure (S0) of the neutral molecule (threshold for DEA) and (2) the relative energy of the CIs also with respect to S0 (band maxima). The pi1(-) state is found to be mainly responsible for the N1-H bond breaking, whereas the pi2(-) state is proved to be involved in the cleavage of the N3-H bond. PMID- 26592119 TI - Analysis of Excitonic and Charge Transfer Interactions from Quantum Chemical Calculations. AB - A procedure for a detailed analysis of excited states in systems of interacting chromophores is proposed. By considering the one-electron transition density matrix, a wealth of information is recovered that may be missed by manually analyzing the wave function. Not only are the position and spatial extent given, but insight into the intrinsic structure of the exciton is readily obtained as well. For example, the method can differentiate between excitonic and charge resonance interactions even in completely symmetric systems. Four examples are considered to highlight the utility of the approach: interactions between the npi* states in a formaldehyde dimer, excimer formation in the naphthalene dimer, stacking interaction in an adenine dimer, and the excitonic band structure in a conjugated phenylenevinylene oligomer. PMID- 26592120 TI - Frenkel and Charge-Transfer Excitations in Donor-acceptor Complexes from Many Body Green's Functions Theory. AB - Excited states of donor-acceptor dimers are studied using many-body Green's functions theory within the GW approximation and the Bethe-Salpeter equation. For a series of prototypical small-molecule based pairs, this method predicts energies of local Frenkel and intermolecular charge-transfer excitations with the accuracy of tens of meV. Application to larger systems is possible and allowed us to analyze energy levels and binding energies of excitons in representative dimers of dicyanovinyl-substituted quarterthiophene and fullerene, a donor acceptor pair used in state of the art organic solar cells. In these dimers, the transition from Frenkel to charge transfer excitons is endothermic and the binding energy of charge transfer excitons is still of the order of 1.5-2 eV. Hence, even such an accurate dimer-based description does not yield internal energetics favorable for the generation of free charges either by thermal energy or an external electric field. These results confirm that, for qualitative predictions of solar cell functionality, accounting for the explicit molecular environment is as important as the accurate knowledge of internal dimer energies. PMID- 26592121 TI - Chemiluminescence of Coelenterazine and Fluorescence of Coelenteramide: A Systematic Theoretical Study. AB - A systematic investigation of the structural and spectroscopic properties of coelenteramide has been performed at the TD-CAM-B3LYP/6-31+G(d,p) level of theory, including various fluorescence and chemiluminescence states. The influence of geometric conformations, solvent polarity, protonation state, and the covalent character of the O-H bond of the hydroxyphenyl moiety were carefully studied. Striking differences in geometries and electronic structures among the states responsible for light emission were characterized. All fluorescence states can be described as a limited charge transfer process for a planar amide moiety. However, the chemiluminescence state is characterized by a much larger charge transfer that takes place over a longer distance. Moreover, the chemiluminescent coelenteramide structure exhibits an amide moiety that is no longer planar, in agreement with recent, more accurate ab initio results [Roca-Sanjuan et al. J. Chem. Theory Comput.2011, 7, 4060]. Because the chemiluminescence state appears to be completely dark, a new mechanism is tentatively introduced for this process. PMID- 26592122 TI - QM/MM Prediction of the Stark Shift in the Active Site of a Protein. AB - Recent developments in the biophysical characterization of proteins have provided a means of directly measuring electrostatic fields by introducing a probe molecule to the system of interest and interpreting photon absorption in the context of the Stark effect. To fully account for this effect, the development of accurate atomistic models is of paramount importance. However, suitable computational protocols for evaluating Stark shifts in proteins are yet to be established. In this work, we present a comprehensive computational method to predict the change in absorption frequency of a probe functional group as a direct result of a perturbation in its surrounding electrostatic field created by a protein environment, i.e., the Stark shift. We apply the method to human aldose reductase, a key protein enzyme that catalyzes the reduction of monosaccharides. We develop a protocol based on a combination of molecular dynamics and moving domain QM/MM methods, which achieves quantitative agreement with experiment. We outline the difficulties in predicting localized electrostatic field changes within a protein environment, and by extension the Stark shift, due to a protein site mutation. Furthermore, the combined use of Stark effect spectroscopy and computational modeling is used to predict the protonation state of ionizable residues in the vicinity of the electrostatic probe. PMID- 26592123 TI - Benchmark Database for Ylidic Bond Dissociation Energies and Its Use for Assessments of Electronic Structure Methods. AB - We report a database of 18 ylidic bond dissociation energies obtained by using highly accurate quantum mechanical methods, and we use it to test approximate electronic structure methods. The new benchmark database is called YBDE18 and is used to test a large number of electronic structure methods, including eight wave function methods and 98 density functional exchange-correlation functionals. Among them, we include some very recent density functionals, including the SOGGA11 GGA functional, the SOGGA11-X hybrid GGA functional, the M11-L local meta GGA functional, and the M11 range-separated hybrid meta-GGA functional. We also consider other functionals of these classes plus a local spin density approximation, global-hybrid meta-GGAs, range-separated hybrid GGAs, doubly hybrid GGAs, and doubly hybrid meta-GGAs. We found M05-2X-D3, MPWB1K-D3, M05-2X, LC-BLYP, PBE0-D3, and MC3MPWB to be the best DFT methods for this database. Although they do not place in the top four overall, our new-generation functionals show overall competitive performances; each of the new functionals provides the smallest mean signed error within its class, while in terms of mean unsigned errors, SOGGA11 is the best GGA, and SOGGA11-X and M11-L are among the first three best functionals in their categories, global-hybrid GGA and local meta-GGA. The best local functionals are VSXC and M06-L, the best global-hybrids are M05-2X, M08-HX, M06-2X, and MPWB1K, and the best range-separated hybrids are LC-BLYP, omegaB97, omegaB97X, and M11. PMID- 26592124 TI - Accurate Prediction of Noncovalent Interaction Energies with the Effective Fragment Potential Method: Comparison of Energy Components to Symmetry-Adapted Perturbation Theory for the S22 Test Set. AB - Noncovalent interactions play an important role in the stabilization of biological molecules. The effective fragment potential (EFP) is a computationally inexpensive ab initio-based method for modeling intermolecular interactions in noncovalently bound systems. The accuracy of EFP is benchmarked against the S22 and S66 data sets for noncovalent interactions [Jurecka, P.; Sponer, J.; Cerny, J.; Hobza, P. Phys. Chem. Chem. Phys.2006, 8, 1985; Rezac, J.; Riley, K. E.; Hobza, P. J. Chem. Theory Comput.2011, 7, 2427]. The mean unsigned error (MUE) of EFP interaction energies with respect to coupled-cluster singles, doubles, and perturbative triples in the complete basis set limit [CCSD(T)/CBS] is 0.9 and 0.6 kcal/mol for S22 and S66, respectively, which is similar to the MUE of MP2 and SCS-MP2 for the same data sets, but with a greatly reduced computational expense. Moreover, EFP outperforms classical force fields and popular DFT functionals such as B3LYP and PBE, while newer dispersion-corrected functionals provide a more accurate description of noncovalent interactions. Comparison of EFP energy components with the symmetry-adapted perturbation theory (SAPT) energies for the S22 data set shows that the main source of errors in EFP comes from Coulomb and polarization terms and provides a valuable benchmark for further improvements in the accuracy of EFP and force fields in general. PMID- 26592125 TI - Improved Atoms-in-Molecule Charge Partitioning Functional for Simultaneously Reproducing the Electrostatic Potential and Chemical States in Periodic and Nonperiodic Materials. AB - We develop a nonempirical atoms-in-molecules (AIM) method for computing net atomic charges that simultaneously reproduce chemical states of atoms in a material and the electrostatic potential V(r) outside its electron distribution. This method gives accurate results for a variety of periodic and nonperiodic materials including molecular systems, solid surfaces, porous solids, and nonporous solids. This method, called DDEC/c3, improves upon our previously published DDEC/c2 method (Manz, T. A.; Sholl, D. S. J. Chem. Theory Comput. 2010, 6, 2455-2468) by accurately treating nonporous solids with short bond lengths. Starting with the theory all AIM charge partitioning functionals with spherically symmetric atomic weights must satisfy, the form of the DDEC/c3 functional is derived from first principles. The method is designed to converge robustly by avoiding conditions that lead to nearly flat optimization landscapes. In addition to net atomic charges, the method can also compute atomic multipoles and atomic spin moments. Calculations performed on a variety of systems demonstrate the method's accuracy, computational efficiency, and good agreement with available experimental data. Comparisons to a variety of other charge assignment methods (Bader, natural population analysis, electrostatic potential fitting, Hirshfeld, iterative Hirshfeld, and iterative stockholder atoms) show that the DDEC/c3 net atomic charges are well-suited for constructing flexible force-fields for atomistic simulations. PMID- 26592126 TI - Application of Adaptive QM/MM Methods to Molecular Dynamics Simulations of Aqueous Systems. AB - The difference-based adaptive solvation quantum mechanics/molecular mechanics (adQM/MM) method (J. Chem. Theory Comput.2009, 5, 2212) as implemented in the Amber software was applied to the study of several chemical processes in solution. The adQM/MM method is based on an efficient selection scheme that enables quantum-mechanical treatment of the active region of a molecular system in solution taking explicitly into account diffusion of solvent molecules between the QM and the MM regions. Specifically, adQM/MM molecular dynamics simulations are carried out to characterize (1) the free energy profiles of halide exchange SN2 reactions in water, (2) the hydration structure of the Cl(-) ion, and (3) the solvation structure of the zwitterionic form of glycine in water. A comparison is made with the results obtained using standard MM and QM/MM methods as well as with the available fully QM and experimental data. In all cases, it is shown that the adaptive QM/MM simulations provide a physically realistic description of the system of interest. PMID- 26592127 TI - Adaptive Resolution Simulation (AdResS): A Smooth Thermodynamic and Structural Transition from Atomistic to Coarse Grained Resolution and Vice Versa in a Grand Canonical Fashion. AB - The AdResS method in molecular dynamics (MD) allows, in a grand canonical (GC) fashion, to change on-the-fly the number of degrees of freedom of a system, allowing to pass from atomistic (AT) to coarse-grained (CG) resolution and vice versa as a function of the position of the molecule in the simulation box. The coupling of resolutions is made in a thermodynamically consistent way, though in the current formulation, in the region where the molecule changes resolution, neither thermodynamic nor structural properties can be preserved. Here we propose an extension of the method where basic thermodynamic and structural properties can be systematically controlled also in the transition region; this assures a very smooth change from one molecular representation to the other. Moreover, we provide a rigorous argument which shows that if in the region where the molecules change resolution the radial distribution function (RDF) is the same as in the AT and CG region, then the AT region is, from the statistical point of view, equivalent to a subsystem embedded in a larger full AT system, at least up to a second order approximation. PMID- 26592128 TI - Efficient Quantum Simulations of Metals within the Gamma-Point Approximation: Application to Carbon and Inorganic 1D and 2D Materials. AB - Molecular dynamics simulations using quantum mechanics for the electronic system, i.e., within the Born-Oppenheimer or related Car-Parrinello approximation, became feasible and popular in recent years for very large systems. The most common setup for these simulations is the supercell method in conjunction with the Gamma point approximation. Here we provide a tool which is useful to choose the supercell of the considered system such that it makes it appear to have either an as large as possible band gap (optimized for Car-Parrinello setup) or the metallic character reflected at the Gamma point (e.g., fold the Dirac point to the Gamma point for graphene and carbon nanotubes) in order to monitor the metallic character in a trajectory. We address carbon nanotubes, graphene, and inorganic TS2 analogues with T = Re, Nb. We further provide a simple Huckel code, which allows checking the electronic states close to the Fermi level within the Gamma-point approximation, and we test its predictions against the density functional-based tight-binding approach. PMID- 26592129 TI - Assessment of Common Simulation Protocols for Simulations of Nanopores, Membrane Proteins, and Channels. AB - Molecular dynamics (MD) simulation has become a common technique to study biological systems. Transport of small molecules through carbon nanotubes and membrane proteins has been an intensely studied topic, and MD simulations have been able to provide valuable predictions, many of which have later been experimentally proven. Simulations of such systems pose challenges, and unexpected problems in commonly used protocols and methods have been found in the past few years. The two main reasons why some were not found before are that most of these newly discovered errors do not lead to unstable simulations. Furthermore, some of them manifest themselves only after relatively long simulation times. We assessed the reliability of the most common simulations protocols by MD and stochastic dynamics (SD) or Langevin dynamics, simulations of an alpha hemolysin nanochannel embedded in a palmitoyloleoylphosphatidylcholine (POPC) lipid bilayer. Our findings are that (a) reaction field electrostatics should not be used in simulations of such systems, (b) local thermostats should be preferred over global ones since the latter may lead to an unphysical temperature distribution, PMID- 26592130 TI - Structural Determinants of Cisplatin and Transplatin Binding to the Met-Rich Motif of Ctr1: A Computational Spectroscopy Approach. AB - The cellular uptake of cisplatin and of other platinum-based drugs is mediated by the high-affinity copper transporter Ctr1. The eight-residue long peptide called Mets7 (MTGMKGMS) mimics one of extracellular methionine (Met)-rich motifs of Ctr1. It is an excellent model for investigating the interaction of platinum drugs with Ctr1 under in vitro and in vivo conditions. Some of us have shown that (i) Cisplatin loses all of its ligands upon reaction with Mets7 and the metal ion binds to the three Met residues and completes its coordination shell with a fourth ligand that can be a chloride or a water/hydroxyl oxygen. (ii) Transplatin loses only the chlorido ligands, which are replaced by Met residues. Here, we provide information on the structural determinants of cisplatin/Mets7 and transplatin/Mets7 adducts by computational methods. The predictions are validated against EXAFS, NMR, and CD spectra. While EXAFS gives information restricted to the metal coordination shell, NMR provides information extended to residue atoms around the coordination shell, and finally, CD provides information about the overall conformation of the peptide. This allows us to elucidate the different reaction modes of cisplatin and transplatin toward the peptide, as well as to propose the platinated peptides [PtX](+)-(M*TGM*KGM*S) (X = Cl(-), OH(-)) and trans[Pt(NH3)2](2+)-(M*TGM*KGMS) as the most relevant species occurring in water solution. PMID- 26592131 TI - Distribution of Reciprocal of Interatomic Distances: A Fast Structural Metric. AB - We present a structural metric based on the Distribution of Reciprocal of Interatomic Distances (DRID) for evaluating geometrical similarity between two conformations of a molecule. A molecular conformation is described by a vector of 3N orientation-independent DRID descriptors where N is the number of molecular centroids, for example, the non-hydrogen atoms in all nonsymmetric groups of a peptide. For two real-world applications (pairwise comparison of snapshots from an explicit solvent simulation of a protease/peptide substrate complex and implicit solvent simulations of reversible folding of a 20-residue beta-sheet peptide), the DRID-based metric is shown to be about 5 and 15 times faster than coordinate root-mean-square deviation (cRMSD) and distance root-mean-square deviation (dRMSD), respectively. A single core of a mainstream processor can perform about 10(8) DRID comparisons in one-half a minute. Importantly, the DRID metric has closer similarity to kinetic distance than does either cRMSD or dRMSD. Therefore, DRID is suitable for clustering molecular dynamics trajectories for kinetic analysis, for example, by Markov state models. Moreover, conformational space networks and free energy profiles derived by DRID-based clustering preserve the kinetic information. PMID- 26592132 TI - An Extension and Further Validation of an All-Atomistic Force Field for Biological Membranes. AB - Biological membranes are versatile in composition and host intriguing molecular processes. In order to be able to study these systems, an accurate model Hamiltonian or force field (FF) is a necessity. Here, we report the results of our extension of earlier developed all-atomistic FF parameters for fully saturated phospholipids that complements an earlier parameter set for saturated phosphatidylcholine lipids (J. Phys. Chem. B, 2012, 116, 3164-3179). The FF, coined Slipids (Stockholm lipids), now also includes parameters for unsaturated phosphatidylcholine and phosphatidylethanolamine lipids, e.g., POPC, DOPC, SOPC, POPE, and DOPE. As the extended set of parameters is derived with the same philosophy as previously applied, the resulting FF has been developed in a fully consistent manner. The capabilities of Slipids are demonstrated by performing long simulations without applying any surface tension and using the correct isothermal-isobaric (NPT) ensemble for a range of temperatures and carefully comparing a number of properties with experimental findings. Results show that several structural properties are very well reproduced, such as scattering form factors, NMR order parameters, thicknesses, and area per lipid. Thermal dependencies of different thicknesses and area per lipid are reproduced as well. Lipid diffusion is systematically slightly underestimated, whereas the normalized lipid diffusion follows the experimental trends. This is believed to be due to the lack of collective movement in the relatively small bilayer patches used. Furthermore, the compatibility with amino acid FFs from the AMBER family is tested in explicit transmembrane complexes of the WALP23 peptide with DLPC and DOPC bilayers, and this shows that Slipids can be used to study more complex and biologically relevant systems. PMID- 26592133 TI - Identifying Allosteric Binding Sites in Proteins with a Two-State Go Model for Novel Allosteric Effector Discovery. AB - Allostery is a common mechanism of controlling many biological processes such as enzyme catalysis, signal transduction, and metabolic regulation. The use of allostery to regulate protein activity is an important and promising strategy in drug discovery and biological network regulation. In order to modulate protein activity by allostery, predictive methods need to be developed to discover allosteric binding sites. In the present study, we developed a new approach to identify allosteric sites in proteins based on the coarse-grained two-state Go model. Starting from the concept that allostery is a conformation population shift process, we first constructed an ensemble of two functional states of a protein and tuned the energy landscape to bias one state. We then added perturbations to a binding site and monitored the population distribution of the new ensemble. If population redistribution occurred, then the binding perturbed site was predicted as a potential allosteric site. Our approach successfully identified all the known allosteric sites in a set of test proteins. Several new allosteric sites in the test proteins were also predicted. By use of one of the new allosteric sites predicted from Escherichia coli phosphoglycerate dehydrogenase (PGDH), novel allosteric regulating molecules were screened by molecular docking and enzymatic assay. Three novel allosteric inhibitors were discovered and their binding modes were confirmed by mutation experiments and competitive assay. The IC50 of the strongest inhibitor discovered was 21 MUM, which is comparable to that of the native allosteric inhibitor l-serine. The novel allosteric site discovered in PGDH is l-serine-independent, and inhibitors targeting this site can be used as novel regulators of the E. coli serine synthesis pathway. Our approach for allosteric site prediction is generally applicable and the predicted sites can be used in discovering novel allosteric regulating molecules. PMID- 26592134 TI - How Many Ligands Can Be Bound by Magnesium-Porphyrin? A Symmetry-Adapted Perturbation Theory Study. AB - The stability of complexes of magnesium-porphyrin with one or two identical ligands from the set water, pyridine, imidazole, acetate, acetonitrile, dimethyl sulfoxide (DMSO), ethyl acetate, or acetylacetone was examined using symmetry adapted perturbation theory (SAPT) for minimum geometries obtained by density functional theory (DFT). The nonadditive contributions to the interaction energy of the porphyrin ring with two ligands were also included and found to be very small in almost all cases. The stability of the complexes under standard conditions is predicted on the basis of the free Gibbs energy. The analysis of individual components of the SAPT interaction energy allows us to explain why the complexation of the second ligand is not energetically preferred in some cases. PMID- 26592135 TI - Erratum: Polarized Molecular Orbital Chemistry. 2. The PMO Method. PMID- 26592136 TI - Added value of fetal MRI in fetuses with suspected brain abnormalities on neurosonography: a systematic review and meta-analysis. AB - PURPOSE: To evaluate the additional diagnostic value of fetal Magnetic Resonance Imaging (MRI) in fetuses with suspected brain abnormalities identified with advanced neurosonography (NS). METHODS: A systematic literature search was performed for studies reporting on a comparison between diagnosis with NS and MRI, in fetuses suspected for brain abnormalities. Abnormalities detected on NS were compared with those detected on MRI as well as with postnatal imaging findings to assess the added value of fetal MRI. RESULTS: We included 27 articles, reporting on 1184 cases in which NS and MRI diagnosis were compared. In 65% of cases [773/1184] fetal NS and fetal MRI diagnosis agreed completely. In 23% [312/1184], MRI showed additional or different pathology. In 8% [99/1184], MRI rejected the NS diagnosis with normal brain as conclusion. For 454 cases a comparison with postnatal imaging could be made. Compared to the postnatal diagnosis, fetal MRI diagnosis agreed completely in 80% [364/454] and fetal NS in 54% [243/454] (difference 27%, 95% CI 21-33%). Additional abnormalities were found on postnatal imaging in 36% [164/454] after NS and in 14% [61/454] after fetal MRI. CONCLUSIONS: This meta-analysis shows that fetal MRI in addition to NS improves diagnostic accuracy in detecting brain abnormalities. PMID- 26592137 TI - "Float first and kick for your life": Psychophysiological basis for safety behaviour on accidental short-term cold water immersion. AB - INTRODUCTION: Accidental cold-water immersion (CWI) evokes the life threatening cold shock response (CSR) which increases the risk of drowning. Consequently, the safety behaviour selected is critical in determining survival; the present advice is to 'float first' and remain stationary (i.e. rest). We examined whether leg only exercise (i.e., treading water; 'CWI-Kick') immediately on CWI could reduce the symptoms of the CSR, offset the reduction in cerebral blood flow that is known to occur and reduce the CSR's symptoms of breathlessness. We also examined whether perceptual responses instinctive to accidental CWI were exacerbated by this alternative behaviour. We contrasted CWI-Kick to a 'CWI-Rest' condition and a thermoneutral control (35 degrees C); 'TN-Rest'. METHOD: Seventeen participants were tested (9 males, 8 females). All immersions were standardised; water temperature in cold conditions (i.e., 12 degrees C) was matched +/-/0.5 degrees C within participant. Middle cerebral artery blood flow velocity (MCAv) and cardiorespiratory responses were measured along with thermal perception (sensation and comfort) and dyspnoea. Data were analysed using repeated measures ANOVA (alpha level of 0.05). RESULTS: MCAv was significantly reduced in CWI-Rest (-6 (9)%; 1st minute of immersion) but was offset by leg only exercise immediately on cold water entry; CWI-Kick MCAv was never different to TN-Rest (-3 (16)% cf. 5 (4)%). All CWI cardiorespiratory and perceptual responses were different to TN-Rest but were not exacerbated by leg only exercise. DISCUSSION: Treading water may aid survival by offsetting the reduction in brain blood flow velocity without changing the instinctive behavioural response (i.e. perceptions). "Float first - and kick for your life" would be a suitable amendment to the water safety advice. PMID- 26592138 TI - Protective effect of tetrahydropalmatine against d-galactose induced memory impairment in rat. AB - Aging is associated with Alzheimer's disease (AD), cardiovascular disease and cancer. Oxidative stress is considered as a major factor that accelerates the aging process. d-galactose (d-gal), a reducing sugar, induces oxidative stress resulting in alteration in mitochondrial dynamics and apoptosis of neurons. To understand the ability of tetrahydropalmatine (THP) to ameliorate memory impairment caused by aging, we investigated the effect of THP on d-gal induced memory impairment in rats. Subcutaneous injection of d-gal (100mg/kg/d) for 8weeks caused memory loss as detected by the Morris water maze and morphologic abnormalities of neurons in the hippocampus regions and cortex of rat brain. THP treatment ameliorated d-gal induced memory impairment associated with the decrease of malondialdehyde (MDA) and nitric oxide (NO) contents, as well as the increase of glutathione (GSH) levels, superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activities. THP treatment was also found to reverse the abnormality of acetylcholine (ACh) levels and acetylcholinesterase (AChE) activities. In addition, treatment with THP could decrease the expression of nuclear factor kappa (NF-kappaB) and glial fibrillary acidic protein (GFAP) which prevented the neuroinflammation and memory impairment in the d-gal treated rats. Taken together, these results clearly demonstrated that subcutaneous injection of d-gal produced memory deficits, meanwhile THP could protect neuron from d-gal insults and improve cognition. This study provided an experimental basis for clinical application of THP in AD therapy. PMID- 26592139 TI - Tunable Fluorescent Silica-Coated Carbon Dots: A Synergistic Effect for Enhancing the Fluorescence Sensing of Extracellular Cu2+ in Rat Brain. AB - Carbon quantum dots (CDs) combined with self-assembly strategy have created an innovative way to fabricate novel hybrids for biological analysis. This study demonstrates a new fluorescence platform with enhanced selectivity for copper ion sensing in the striatum of the rat brain following the cerebral calm/sepsis process. Here, the fabrication of silica-coated CDs probes is based on the efficient hybridization of APTES which act as a precursor of organosilane self assembly, with CDs to form silica-coated CDs probes. The fluorescent properties including intensity, fluorescence quantum yield, excitation-independent region, and red/blue shift of the emission wavelength of the probe are tunable through reliable regulation of the ratio of CDs and APTES, realizing selectivity and sensitivity-oriented Cu(2+) sensing. The as-prepared probes (i.e., 3.33% APTES 0.9 mg mL(-1) CDs probe) show a synergistic amplification effect of CDs and APTES on enhancing the fluorescence signal of Cu(2+) detection through fluorescent self quenching. The underlying mechanism can be ascribed to the stronger interaction including chelation and electrostatic attraction between Cu(2+) and N and O atoms containing as well as negatively charged silica-coated CDs than other interference. Interestingly, colorimetric assay and Tyndall effect can be observed and applied to directly distinguish the concentration of Cu(2+) by the naked eye. The proposed fluorescent platform here has been successfully applied to monitor the alteration of striatum Cu(2+) in rat brain during the cerebral calm/sepsis process. The versatile properties of the probe provide a new and effective fluorescent platform for the sensing method in vivo sampled from the rat brain. PMID- 26592140 TI - Arguments and sources on Italian online forums on childhood vaccinations: Results of a content analysis. AB - BACKGROUND: Despite being committed to the immunization agenda set by the WHO, Italy is currently experiencing decreasing vaccination rates and increasing incidence of vaccine-preventable diseases. Our aim is to analyze Italian online debates on pediatric immunizations through a content analytic approach in order to quantitatively evaluate and summarize users' arguments and information sources. METHODS: Threads were extracted from 3 Italian forums. Threads had to include the keyword Vaccin* in the title, focus on childhood vaccination, and include at least 10 posts. They had to have been started between 2008 and June 2014. High inter-coder reliability was achieved. Exploratory analysis using k means clustering was performed to identify users' posting patterns for arguments about vaccines and sources. RESULTS: The analysis included 6544 posts mentioning 6223 arguments about pediatric vaccinations and citing 4067 sources. The analysis of argument posting patterns included users who published a sufficient number of posts; they generated 85% of all arguments on the forum. Dominating patterns of three groups were identified: (1) an anti-vaccination group (n=280) posted arguments against vaccinations, (2) a general pro-vaccination group (n=222) posted substantially diverse arguments supporting vaccination and (3) a safety focused pro-vaccination group (n=158) mainly forwarded arguments that questioned the negative side effects of vaccination. The anti-vaccination group was shown to be more active than the others. They use multiple sources, own experience and media as their cited sources of information. Medical professionals were among the cited sources of all three groups, suggesting that vaccination-adverse professionals are gaining attention. CONCLUSIONS: Knowing which information is shared online on the topic of pediatric vaccinations could shed light on why immunization rates have been decreasing and what strategies would be best suited to address parental concerns. This suggests there is a high need for developing automated approaches to detect misleading or false information on the Internet. PMID- 26592142 TI - Pertussis vaccination during pregnancy in Belgium: Results of a prospective controlled cohort study. AB - Vaccination during pregnancy has been recommended in some countries as a means to protect young infants from severe infection. Nevertheless, many aspects are still unknown and possible blunting of the infant's immune responses by maternal antibodies, is one of the concerns with maternal vaccination. We report the first prospective controlled cohort study in women and infants on the effects of using Boostrix((r)), a combined tetanus, diphtheria and acellular pertussis vaccine, during pregnancy. The primary aim was to measure the influence of this booster dose on the titer and duration of the presence of maternal antibodies in the infants and assess possible interference with infant immune responses. In a controlled cohort study, 57 pregnant women were vaccinated with Tdap vaccine (Tetanus Diphtheria acellular Pertussis, Boostrix, GSK Biologicals), at a mean gestational age of 28.6 weeks. A control group of pregnant women (N=42) received no vaccine. Antibody geometric mean concentrations (GMCs) against tetanus (TT), diphtheria (DT), pertussis toxin (PT), filamentous haemagglutinin (FHA) and pertactin (Prn) were measured with commercial ELISA tests in samples taken preceding maternal vaccination and one month afterwards, at delivery and from the cord blood, and in infants before and 1 month after the primary series of 3 pertussis containing hexavalent vaccines. Infants born to vaccinated women had significantly higher GMC at birth and during the first 2 months of life for all vaccine antigens compared to the offspring of unvaccinated women, thereby closing the susceptibility gap for pertussis in infants. However, blunting was noticed for infant diphtheria and pertussis toxin vaccine responses (p<0.001) in the infants from vaccinated women after the primary vaccination schedule (weeks 8,12 and 16). Since pertussis vaccination has been recommended during pregnancy already, the results of this study support that recommendation and provide additional scientific evidence to document possible interference by maternal antibodies. PMID- 26592141 TI - Effect on nasopharyngeal pneumococcal carriage of replacing PCV7 with PCV13 in the Expanded Programme of Immunization in The Gambia. AB - INTRODUCTION: In 2011, two years after the introduction of 7-valent Pneumococcal conjugate vaccine (PCV7), the Gambian immunization programme replaced PVC7 with PCV13 (13-valent). Our objective was to assess the additional impact of PCV13 on prevalence of pneumococcal nasopharyngeal carriage. METHODS: We recruited healthy Gambian infants who had received three PCV doses. Nasopharyngeal swabs were collected from infants and their mothers during two cross-sectional surveys (CSS) conducted in infants vaccinated with PCV7 (CSS1) and vaccinated with PCV13 (CSS2). Pneumococci were isolated and serotyped following standardized methods. Whole genome sequencing was performed on non-typable pneumococcus isolated in CSS1 and CSS2. RESULTS: 339 and 350 infants and their mothers were recruited in CSS1 and CSS2, respectively. Overall prevalence of pneumococcal carriage was 85.4% in infants. Among infants, prevalence of vaccine type (VT) carriage was lower in CSS2 [9.4% versus 4.9% (p=0.025) for PCV7-VT; 33.3% versus 18.3% (p<0.001) for PCV13-VT and 23.9% versus 13.7% (p=0.001) for the 6 additional serotypes included in PCV13]. At CSS2, there was a decrease of serotypes 6A (from 15.3% to 5.7%, p<0.001) and 19F (from 5.6% to 1.7%, p=0.007), and an increase of non-typable pneumococci (0.3-6.0%, p<0.001), most of which (82.4%) were from typable serotype backgrounds that had lost the ability to express a capsule. Prevalence of overall and VT carriage in mothers was similar in CSS1 and CSS2. CONCLUSIONS: Replacing PCV7 for PCV13 rapidly decreased prevalence of VT carriage among vaccinated Gambian infants. An indirect effect in mothers was not observed yet. Vaccine-driven selection pressure may have been responsible for the increase of non-typable isolates. PMID- 26592143 TI - Heme A synthase in bacteria depends on one pair of cysteinyls for activity. AB - Heme A is a prosthetic group unique for cytochrome a-type respiratory oxidases in mammals, plants and many microorganisms. The poorly understood integral membrane protein heme A synthase catalyzes the synthesis of heme A from heme O. In bacteria, but not in mitochondria, this enzyme contains one or two pairs of cysteine residues that are present in predicted hydrophilic polypeptide loops on the extracytoplasmic side of the membrane. We used heme A synthase from the eubacterium Bacillus subtilis and the hyperthermophilic archeon Aeropyrum pernix to investigate the functional role of these cysteine residues. Results with B. subtilis amino acid substituted proteins indicated the pair of cysteine residues in the loop connecting transmembrane segments I and II as being essential for catalysis but not required for binding of the enzyme substrate, heme O. Experiments with isolated A. pernix and B. subtilis heme A synthase demonstrated that a disulfide bond can form between the cysteine residues in the same loop and also between loops showing close proximity of the two loops in the folded enzyme protein. Based on the findings, we propose a classification scheme for the four discrete types of heme A synthase found so far in different organisms and propose that essential cysteinyls mediate transfer of reducing equivalents required for the oxygen-dependent catalysis of heme A synthesis from heme O. PMID- 26592144 TI - Analysis of photosystem II biogenesis in cyanobacteria. AB - Photosystem II (PSII), a large multisubunit membrane protein complex found in the thylakoid membranes of cyanobacteria, algae and plants, catalyzes light-driven oxygen evolution from water and reduction of plastoquinone. Biogenesis of PSII requires coordinated assembly of at least 20 protein subunits, as well as incorporation of various organic and inorganic cofactors. The stepwise assembly process is facilitated by numerous protein factors that have been identified in recent years. Further analysis of this process requires the development or refinement of specific methods for the identification of novel assembly factors and, in particular, elucidation of the unique role of each. Here we summarize current knowledge of PSII biogenesis in cyanobacteria, focusing primarily on the impact of methodological advances and innovations. This article is part of a Special Issue entitled Organization and dynamics of bioenergetic systems in bacteria, edited by Conrad Mullineaux. PMID- 26592145 TI - Effects of arundic acid, an astrocytic modulator, on the cerebral and respiratory functions in severe hypoxia. AB - Mild hypoxia increases ventilation, but severe hypoxia depresses it. The mechanism of hypoxic ventilatory depression, in particular, the functional role of the cerebrum, is not fully understood. Recent progress in glial physiology has provided evidence that astrocytes play active roles in information processing in various brain functions. We investigated the hypothesis that astrocytic activation is necessary to maintain the cerebral function and ventilation in hypoxia, by examining the responses of EEG and ventilation to severe hypoxia before and after administration of a modulator of astrocytic function, arundic acid, in unanesthetized mice. Ventilatory parameters were measured by whole body plethysmography. When hypoxic ventilatory depression occurred, gamma frequency band of EEG was suppressed. Arundic acid further suppressed ventilation, and the EEG power was suppressed in a dose-dependent manner. Arundic acid also suppressed hypoxia-induced c-Fos expression in the hypothalamus. We conclude that severe hypoxia suppresses the cerebral function which could reduce the stimulus to the brainstem resulting in ventilatory depression. Astrocytic activation in hypoxia may counteract both cerebral and ventilatory suppression. PMID- 26592146 TI - Expansion of bubbles under a pulsatile flow regime in decompressed ovine blood vessels. AB - After decompression of ovine large blood vessels, bubbles nucleate and expand at active hydrophobic spots on their luminal aspect. These bubbles will be in the path of the blood flow within the vessel, which might replenish the supply of gas supersaturated plasma in their vicinity and thus, in contrast with our previous estimations, enhance their growth. We used the data from our previous study on the effect of pulsatile flow in ovine blood vessels stretched on microscope slides and photographed after decompression from hyperbaric exposure. We measured the diameter of 46 bubbles in 4 samples taken from 3 blood vessels (pulmonary artery, pulmonary vein, and aorta) in which both a "multi-bubble active spot" (MBAS)--which produces several bubbles at a time, and at least one "single-bubble active spot" (SBAS)--which produces a single bubble at a time, were seen together. The linear expansion rate for diameter in SBAS ranged from 0.077 to 0.498 mm/min and in MBAS from 0.001 to 0.332 mm/min. There was a trend toward a reduced expansion rate for bubbles in MBAS compared with SBAS. The expansion rate for bubbles in an MBAS when it was surrounded by others was very low. Bubble growth is related to gas tension, and under a flow regime, bubbles expand from a diameter of 0.1 to 1mm in 2-24 min at a gas supersaturation of 620 kPa and lower. There are two phases of bubble development. The slow and disperse initiation of active spots (from nanobubbles to gas micronuclei) continues for more than 1h, whereas the fast increase in size (2-24 min) is governed by diffusion. Bubble based decompression models should not artificially reduce diffusion constants, but rather take both phases of bubble development into consideration. PMID- 26592147 TI - Modulation of rat skeletal muscle microvascular O2 pressure via KATP channel inhibition following the onset of contractions. AB - Vascular hyperpolarization mediated, in part, by the ATP-sensitive K(+) (KATP) channel contributes to exercise-induced increases in skeletal muscle O2 delivery. We hypothesized that KATP channel inhibition via glibenclamide (GLI) would speed the fall of microvascular O2 driving pressure (PO2mv; set by the O2 delivery-O2 utilization ratio), during muscle contractions. Spinotrapezius muscle PO2mv (phosphorescence quenching) was measured in 12 adult Sprague Dawley rats during 180s of 1-Hz twitch contractions (~ 6 V) under control and GLI (5mg/kg) conditions. The total mean PO2mv response time was greater with GLI (i.e., slowed; control: 42.0 +/- 14.2, GLI: 79.5 +/- 14.7s, p<0.05). A clear undershoot of the contracting steady-state PO2mv was evident with GLI (15.6 +/- 5.3%, p<0.05) but not control (2.3 +/- 1.6%, p>0.05). This indicates that KATP channel inhibition does not speed PO2mv kinetics per se during small muscle mass contraction. However, it does induce a transient mismatch of O2 delivery-O2 utilization, lowers PO2mv, and delays attainment of the contracting steady-state. PMID- 26592148 TI - Lung function, transfusion, pulmonary capillary blood volume and sickle cell disease. AB - Lung function abnormalities occur in children with sickle cell disease (SCD) and may be associated with elevated pulmonary blood volume. To investigate that association, we determined whether blood transfusion in SCD children acutely increased pulmonary capillary blood volume (PCBV) and increased respiratory system resistance (Rrs5). Measurements of Rrs5 and spirometry were made before and after blood transfusion in 18 children, median age 14.2 (6.6-18.5) years. Diffusing capacity for carbon monoxide and nitric oxide were assessed to calculate the PCBV. Post transfusion, the median Rrs5 had increased from 127.4 to 141.3% predicted (p<0.0001) and pulmonary capillary blood volume from 39.7 to 64.1 ml/m2 (p<0.0001); forced expiratory volume in one second (p=0.0056) and vital capacity (p=0.0008) decreased. The increase in Rrs5 correlated with the increase in PCBV (r=0.50, p=0.0493). Increased pulmonary capillary blood volume may at least partially explain the lung function abnormalities in SCD children. PMID- 26592149 TI - Production of Diethyl Terephthalate from Biomass-Derived Muconic Acid. AB - We report a cascade synthetic route to directly obtain diethyl terephthalate, a replacement for terephthalic acid, from biomass-derived muconic acid, ethanol, and ethylene. The process involves two steps: First, a substituted cyclohexene system is built through esterification and Diels-Alder reaction; then, a dehydrogenation reaction provides diethyl terephthalate. The key esterification reaction leads to improved solubility and modulates the electronic properties of muconic acid, thus promoting the Diels-Alder reaction with ethylene. With silicotungstic acid as the catalyst, nearly 100% conversion of muconic acid was achieved, and the cycloadducts were formed with more than 99.0% selectivity. The palladium-catalyzed dehydrogenation reaction preferentially occurs under neutral or mildly basic conditions. The total yield of diethyl terephthalate reached 80.6% based on the amount of muconic acid used in the two-step synthetic process. PMID- 26592150 TI - Pc2-mediated SUMOylation of WWOX is essential for its suppression of DU145 prostate tumorigenesis. AB - Tumor suppressor WW domain-containing oxidoreductase (WWOX) is depleted in various cancer types. Here we report that WWOX is modified by small ubiquitin like modifier (SUMO) proteins and represses DU145 prostate cancer tumorigenesis in a SUMOylation-dependent manner. Ectopic WWOX was shown to associate with SUMO2/3 or E2 Ubc9. Furthermore, we revealed that WWOX SUMOylation was promoted by E3 ligase polycomb2 (Pc2), and that WWOX associated with Pc2. Meanwhile, anisomycin-induced activator protein-1 (AP-1) activity was markedly diminished by co-expression of SUMO and WWOX. Also, WWOX wild type (WT), but not WWOX SUMO mutant (K176A) markedly reduced both DU145 prostate cancer cell proliferation and xenograft tumorigenesis. Collectively, our findings demonstrate that SUMO modification of WWOX is essential for its suppressive activity for DU145 prostate cancer tumorigenesis. PMID- 26592151 TI - Cystatin C attenuates insulin signaling transduction by promoting endoplasmic reticulum stress in hepatocytes. AB - It has been reported that cystatin c (Cys C) closely correlates with metabolic disorders such as obesity and diabetes. However, it is still unknown whether Cys C plays a role for these disorders. Our results showed that the insulin signal transduction was largely impaired by Cys C in hepatocytes. In myotubes, however, the insulin signal transduction was not affected. Following experiments revealed that Cys C could induce endoplasmic reticulum stress (ER stress) in hepatocytes, whereas Cys C had no such an effect in myotubes. The alleviation of ER stress by 4-Phenyl butyric acid (4-PBA) restored the impaired insulin signal transduction in Cys C-treated hepatocytes. These results provided direct evidence that, by inducing ER stress, Cys C impairs insulin signal transduction in hepatocytes. PMID- 26592153 TI - Editorial. PMID- 26592152 TI - Specific mutations in mammalian P4-ATPase ATP8A2 catalytic subunit entail differential glycosylation of the accessory CDC50A subunit. AB - P4-ATPases, or flippases, translocate phospholipids between the two leaflets of eukaryotic biological membranes. They are essential to the physiologically crucial phospholipid asymmetry and involved in severe diseases, but their molecular structure and mechanism are still unresolved. Here, we show that in an extensive mutational alanine screening of the mammalian flippase ATP8A2 catalytic subunit, five mutations stand out by leading to reduced glycosylation of the accessory subunit CDC50A. These mutations may disturb the interaction between the subunits. PMID- 26592154 TI - Cutaneous biodistribution of ionizable, biolabile aciclovir prodrugs after short duration topical iontophoresis: Targeted intraepidermal drug delivery. AB - The objective was to determine the cutaneous biodistribution of aciclovir (ACV), that is, the amount of drug as a function of depth within the skin following topical iontophoretic administration of amino acid ester prodrugs of ACV (ACV-X, where X=Arg, Ile or Val). The results were compared to those obtained with marketed formulations of aciclovir and penciclovir (PCV), and following topical iontophoresis of ACV. Quantification of molecules as a function of position in the skin was achieved by snap-freezing and cryotoming skin samples to obtain coarse or fine lamellae with a thickness of either 100 MUm or 20 MUm. The molecules--ACV, ACV-X or PCV--were extracted and quantified by validated UHPLC MS/MS analytical methods. Passive delivery of ACV or PCV from marketed cream and ointment formulations after application for 60 min resulted in modest cutaneous deposition (QDEP,ACV and QDEP,PCV<2 nmol/cm(2)). Moreover, ACV and PCV were found mainly in the stratum corneum or superficial viable epidermis. The levels in the deeper skin layers (100-200 MUm), corresponding to the basal epidermis and adjacent area, where the virus would be found, were negligible. In contrast, iontophoresis of ACV-Ile or ACV-Arg for only 10 min at 0.25 mA/cm(2) resulted in much greater deposition of ACV species at the same skin depths (100-200 MUm): for ACV-Ile - QDEP,ACV and QDEP,ACV-Ile were 17.2 +/- 6.9 nmol/cm(2) and 8.2 +/- 1.3 nmol/cm(2), respectively; in the case of ACV-Arg there was complete bioconversion and only ACV was recovered (QDEP,ACV was 41.2 +/- 9.2 nmol/cm(2)). In the higher resolution biodistribution studies, with 20 MUm lamellae, short duration iontophoresis at 0.25 mA/cm(2) for only 5 min of ACV-Arg or ACV-Ile still enabled considerable amounts of ACV species to be delivered to the basal epidermis and neighboring layers (QDEP,ACV was 4.0 +/- 1.6 nmol/cm(2) and 6.1 +/- 1.7 nmol/cm(2), respectively). Iontophoresis of ACV under the same conditions resulted in negligible ACV deposition in these layers. Subsequent studies into the iontophoresis of ACV-Ile using a hydrogel revealed no statistically significant differences between QDEP,ACV in full-thickness porcine and human skins (13.4+/-1.5nmol/cm(2) and 12.4+/-1.4nmol/cm(2), respectively), validating the porcine model. In order to improve ACV-Ile stability, dry fast dissolving thin film formulations were also prepared. These were placed in contact with conducting hydrogels in situ immediately prior to iontophoresis. In addition to the improved stability, iontophoretic delivery of ACV-Ile from the thin film was also superior to that from hydrogel alone. Following iontophoresis of ACV-Ile using fast dissolving films, QDEP,ACV was 29.1+/-1.0nmol/cm(2), and the amount in the basal epidermis area was 2.7+/-0.1nmol/cm(2). Short duration iontophoresis for 5min of ACV-Ile from aqueous solution, hydrogel or fast dissolving film resulted in supra-therapeutic concentrations of ACV in the basal epidermis and its adjacent area. PMID- 26592155 TI - Effect of polymer species and concentration on the production of mefenamic acid nanoparticles by media milling. AB - The effect of four structurally different polymer species (hydroxypropylcellulose, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer and polyvinyl alcohol) on the production of mefenamic acid nanoparticles during media milling has been studied. It was found that product particle sizes are strongly determined by the type of polymeric stabiliser as well as by its concentration at constant process conditions. With respect to small product particle sizes an optimum excipient concentration was identified and adjusted for colloidal stability of the drug nanosuspensions. Furthermore, it was found that overdosing of excipients must be omitted to suppress ripening due to enhanced solubilisation phenomena. Hence, the smallest product particle sizes were obtained using a polymeric stabiliser which exhibits a high affinity to the model drug compound and a low solubilisation capacity. Affinities of each polymer species to mefenamic acid and corresponding surface concentrations were determined using straightforward and simple viscosity measurements of the supernatant. A relationship between polymer affinity, solubilisation capacity and limiting product particle size has been observed, which supports the hypothesis that final product particle sizes are rather determined by the solid-liquid equilibrium than by pure mechanical fracture. PMID- 26592156 TI - beta-Cyclodextrin complexation as an effective drug delivery system for meropenem. AB - Following the preparation of an inclusion complex of beta-cyclodextrin and meropenem, methods based on FT-IR, Raman and DSC were used for its characterization. An analysis of changes in the stability of meropenem after complexation showed that the complex may serve as a valuable delivery system significantly contributing to enhanced meropenem stability in aqueous solutions and in the solid phase. Due to a sustained transfer of meropenem from the cavity of the cyclodextrin it was possible to maintain a constant desired meropenem concentration over a period of 20 h, as confirmed by a release study. An evaluation of microbial activity not only demonstrated that the bactericidal action of meropenem was not stopped as a result of complexation but even pointed to greater growth inhibition in certain clinically important strains. The fact that investigations of meropenem stability and microbial activity proposed the carbonyl groups as those domains of a meropenem molecule that are instrumental in the formation of a complex with beta-cyclodextrin supports the findings of theoretical studies based on molecular modeling. PMID- 26592157 TI - Tamper-proof tablets for distinction between counterfeit and originator drugs through PEG coding. AB - Counterfeit drugs are a major threat to public health. Current efforts focus on serialization of the secondary packaging which do not allow to trace the individual unit. As a proof of concept, we intended to mark each tablet for its unambiguous recognition. Spiking monodisperse PEGs into tablet coating solutions at concentrations as low as 3 ppm was instrumental to "write" a code into each tablet film which was readily read upon isolation and LC-MS/MS analysis. Different qualities and amounts of monodisperse polyethylene glycols can be used for coding solid drug products. The approach is limited to cases in which PEGs are not present for formulation purposes as excipients, as coding against this background was unfeasible. PMID- 26592158 TI - A point mutation in the glutamate-gated chloride channel of Plutella xylostella is associated with resistance to abamectin. AB - The diamondback moth, Plutella xylostella, is a global pest of cruciferous vegetables. Abamectin resistance in a field population of P. xylostella was introgressed into the susceptible Roth strain. The resulting introgression strain Roth-Abm showed 11 000-fold resistance to abamectin compared with Roth. An A309V substitution at the N-terminus of the third transmembrane helix (M3) of the glutamate-gated chloride channel of P. xylostella (PxGluCl) was identified in Roth-Abm. The frequency of the V309 allele of PxGluCl was 94.7% in Roth-Abm, whereas no such allele was detected in Roth. A subpopulation of Roth-Abm was kept without abamectin selection for 20 generations to produce a revertant strain, Roth-Abm-D. Abamectin resistance in Roth-Abm-D declined to 1150-fold compared with Roth, with the V309 allele frequency decreased to 9.6%. After treatment of the Roth-Abm-D strain with 80 mg/l abamectin the V309 allele frequency in the survivors increased to 55%. This demonstrates that the A309V mutation in PxGluCl is strongly associated with a 10-fold increase in abamectin resistance in Roth Abm relative to Roth-Abm-D. Homology modelling and automated ligand docking results suggest that the A309V substitution allosterically modifies the abamectin binding site, as opposed to directly eliminating a key binding contact. Other resistance mechanisms to abamectin in Roth-Abm are discussed besides the A309V mutation of PxGluCl. PMID- 26592159 TI - Vittel criteria for severe trauma triage: Characteristics of over-triage. AB - AIM: Over-triage rates related to the use of Vittel criteria are unknown. We compared severe stable trauma patients with and without significant visceral injuries. STUDY DESIGN: A single-centre retrospective analysis of a single-centre prospective cohort. PATIENTS AND METHODS: Trauma patients with at least one positive Vittel criterion from June 2010 to January 2012 in a level-1 trauma centre. Initial management included a systematic whole-body scanner. All significant lesions in stable trauma patients were recorded. RESULTS: A total of 252 trauma patients were admitted. One hundred and twenty were stable. In this group without vital distress, 72 (60%) had at least one occult lesion, 21 (17.5%) had an isolated orthopaedic injury and 27 (22.5%) had no injury. Thoracic injuries accounted for 44% of visceral injuries, abdominal for 17%, spinal for 16% and cerebral for 15%. Overall, the over-triage rate was 19%. Surgery for significant visceral injury was performed in 13 patients (18%) and arteriography in 4 patients (5.5%). Admission in an intensive care unit was required for 13 patients with occult injuries and for one patient without such a lesion (18% versus 2%, P=0.008). Hospital stays were longer in the group with visceral injuries (4+/-7 versus 9+/-8days; P=0.006). CONCLUSION: Vittel criteria use in trauma patients induces an acceptable over-triage rate. A large proportion of stable trauma patients have occult lesions. These visceral injuries frequently require special care. These data highlight the imperative need to transport major trauma patients immediately to a dedicated trauma centre and supports whole-body scanner use. PMID- 26592160 TI - Layered Electron Acceptors by Dimerization of Acenes End- Capped with 1,2,5 Thiadiazoles. AB - Layered electron acceptors D1-4 equipped with terminal 1,2,5-thiadiazole groups have been constructed using a one-pot protocol of acene dimerization. Their molecular structures are determined using single-crystal X-ray diffraction analysis. Photophysical and electrochemical properties of these molecules present a marked dependence on conjugation length and molecular geometry. An aggregation induced emission peak and an intramolecular excimer emission (IEE) band were observed for D2 and D4, respectively. This work paves the way for the efficient synthesis of layered heteroacenes. PMID- 26592161 TI - Dynamic Assessment of Social Cognition in Individuals with Multiple Sclerosis: A Pilot Study. AB - It has recently been reported that individuals with multiple sclerosis (MS) are impaired on tasks requiring emotional processing and social cognition, including tasks of Theory of Mind (ToM) and facial affect recognition. The current pilot study examined the ability of individuals with MS to understand and interpret lies and sarcasm using a dynamic task: The Awareness of Social Inference Test (TASIT). Fifteen individuals with MS and 15 healthy controls (HCs) performed the Social Inference-Enriched subtest of the TASIT, in which they viewed video-taped social interactions in which lies and sarcasm are presented. Additionally, tests of cognition were also administered to better understand the relationship between specific cognitive abilities and the ability to understand lies and sarcasm. The MS group showed impairments in the ability to interpret and understand lies and sarcasm relative to HCs. These impairments were correlated with several cognitive abilities including processing speed, working memory, learning and memory, and premorbid IQ. The results indicate that the TASIT is a sensitive measure of social cognition in individuals with MS. Furthermore, performance on the TASIT was related to cognitive abilities. Results are discussed in terms of social cognition deficits in MS and how they relate to cognitive abilities. (JINS, 2016, 22, 83-88). PMID- 26592162 TI - Isolation-by-distance-and-time in a stepping-stone model. AB - With the great advances in ancient DNA extraction, genetic data are now obtained from geographically separated individuals from both present and past. However, population genetics theory about the joint effect of space and time has not been thoroughly studied. Based on the classical stepping-stone model, we develop the theory of Isolation by distance and time. We derive the correlation of allele frequencies between demes in the case where ancient samples are present, and investigate the impact of edge effects with forward-in-time simulations. We also derive results about coalescent times in circular and toroidal models. As one of the most common ways to investigate population structure is principal components analysis (PCA), we evaluate the impact of our theory on PCA plots. Our results demonstrate that time between samples is an important factor. Ancient samples tend to be drawn to the center of a PCA plot. PMID- 26592163 TI - Early maternal separation and responsiveness to thermal nociception in rodent offspring: A meta-analytic review. AB - Although numerous animal studies have assessed the impact of maternal separation upon pain sensitivity, overall conclusions are difficult to draw about the literature in light of mixed patterns of findings. In this research, a meta analysis was performed to assess effects of early maternal separation on sensitivity to nociceptive thermal stimulation in rodent offspring and to identify moderators that might explain variable results between studies. Fifteen studies comprising 19 rodent offspring samples (N=1642) fulfilled all selection criteria. Analyses indicated that rodent offspring exposed to early maternal separation had longer response latencies (RLs) reflecting lower sensitivity to nociceptive thermal stimulation compared to non-separated controls. Heightened effect size heterogeneity was also evident. Moderator analyses indicated variable findings between studies were partially or fully explained by operationalizations of maternal separation (early handling vs. maternal separation), type of noxious stimuli, age of testing, receipt of injections during separation, sex composition of samples, and publication year. Biobehavioral underpinnings of overall group differences and moderator effects are posited in the discussion. PMID- 26592164 TI - Impulsivity trait in the early symptomatic BACHD transgenic rat model of Huntington disease. AB - Impulsivity trait was characterized in 3-5 months old BACHD rats, a transgenic model of Huntington disease, using (1) the delay discounting task to assess cognitive/choice impulsivity, and (2) the Differential Reinforcement of Low Rate of Responding task to evaluate motor/action impulsivity. Transgenic animals showed a high level of choice impulsivity and, to a lesser extent, action impulsivity. Our results provide the first evidence that the transgenic BACHD rat (TG5 line) displays impulsivity disorder as early as 3 months old, as described in early symptomatic HD patients, thus adding to the face validity of the rat model. PMID- 26592165 TI - Fractal dimensions: A new paradigm to assess spatial memory and learning using Morris water maze. AB - Morris water maze has been widely used for analysis of cognitive functions and relies on the time taken by animal to find the platform i.e. escape latency as a parameter to quantify spatial memory and learning. However, escape latency is confounded by swimming speed which is not necessarily a cognitive factor. Rather, path length may be a more appropriate and reliable parameter to assess spatial learning. This paper presents fractal dimension as a new paradigm to assess spatial memory and learning in animals. Male wistar rats were administrated with pentylenetetrazole and scopolamine to induce chronic epilepsy and dementia respectively. Fractal dimension of the random path followed by the animals on Morris water maze was analyzed and statistically compared among different experimental groups; the results suggest that fractal dimension is more reliable and accurate parameter to assess cognitive deficits compared to escape latency. Thus, the present study suggests that fractal dimensions could be used as an independent parameter to assess spatial memory and learning in animals using Morris water maze. PMID- 26592166 TI - Modeling the Nonlinear Motion of the Rat Central Airways. AB - Advances in volumetric medical imaging techniques allowed the subject-specific modeling of the bronchial flow through the first few generations of the central airways using computational fluid dynamics (CFD). However, a reliable CFD prediction of the bronchial flow requires modeling of the inhomogeneous deformation of the central airways during breathing. This paper addresses this issue by introducing two models of the central airways motion. The first model utilizes a node-to-node mapping between the discretized geometries of the central airways generated from a number of successive computed tomography (CT) images acquired dynamically (without breath hold) over the breathing cycle of two Sprague-Dawley rats. The second model uses a node-to-node mapping between only two discretized airway geometries generated from the CT images acquired at end exhale and at end-inhale along with the ventilator measurement of the lung volume change. The advantage of this second model is that it uses just one pair of CT images, which more readily complies with the radiation dosage restrictions for humans. Three-dimensional computer aided design geometries of the central airways generated from the dynamic-CT images were used as benchmarks to validate the output from the two models at sampled time-points over the breathing cycle. The central airway geometries deformed by the first model showed good agreement to the benchmark geometries within a tolerance of 4%. The central airway geometry deformed by the second model better approximated the benchmark geometries than previous approaches that used a linear or harmonic motion model. PMID- 26592167 TI - The increase of intrinsic excitability of layer V pyramidal cells in the prelimbic medial prefrontal cortex of adult mice after peripheral inflammation. AB - Symptoms including depression and hypofunction of cognitive and decision-making are commonly associated with chronic pain. Recent studies have shown that the state of the medial prefrontal cortex (mPFC) neurons is important in diverse high order cognitive and emotional activity in animals and humans. The mPFC layer V neurons mainly integrate information from other brain areas. The abnormal activity and function of pyramidal neurons influence the signal processing in the mPFC. Here we observed the changes of the excitability of the prelimbic mPFC neurons by whole-cell current-clamp recordings in adult mouse with inflammatory pain induced by complete Freund's adjuvant (CFA). Results showed that resting membrane potential and membrane input resistance did not differ between CFA treated and control animals. Single action potential (AP) did not differ in terms of amplitude, but rheobase, half AP duration, and decay time were significantly decreased, and voltage threshold was more hyperpolarized in CFA group. Although the firing adaptation did not differ in two groups, the repetitive AP firing number and initial firing rate were significantly increased in CFA group. These data suggest that the increase in the intrinsic excitability of prelimbic mPFC layer V pyramidal neurons may be involved, at least in part in peripheral inflammatory pain. PMID- 26592168 TI - Effects of physical exercise training in DNA damage and repair activity in humans with different genetic polymorphisms of hOGG1 (Ser326Cys). AB - The main purpose of this pilot study was to investigate the possible influence of genetic polymorphisms of the hOGG1 (Ser326Cys) gene in DNA damage and repair activity by 8-oxoguanine DNA glycosylase 1 (OGG1 enzyme) in response to 16 weeks of combined physical exercise training. Thirty-two healthy Caucasian men (40-74 years old) were enrolled in this study. All the subjects were submitted to a training of 16 weeks of combined physical exercise. The subjects with Ser/Ser genotype were considered as wild-type group (WTG), and Ser/Cys and Cys/Cys genotype were analysed together as mutant group (MG). We used comet assay in conjunction with formamidopyrimidine DNA glycoslyase (FPG) to analyse both strand breaks and FPG-sensitive sites. DNA repair activity were also analysed with the comet assay technique. Our results showed no differences between DNA damage (both strand breaks and FPG-sensitive sites) and repair activity (OGG1) between genotype groups (in the pre-training condition). Regarding the possible influence of genotype in the response to 16 weeks of physical exercise training, the results revealed a decrease in DNA strand breaks in both groups, a decrease in FPG-sensitive sites and an increase in total antioxidant capacity in the WTG, but no changes were found in MG. No significant changes in DNA repair activity was observed in both genotype groups with physical exercise training. This preliminary study suggests the possibility of different responses in DNA damage to the physical exercise training, considering the hOGG1 Ser326Cys polymorphism. PMID- 26592169 TI - New ring-rearranged metabolite of 20-hydroxyecdysone obtained by base-catalyzed auto-oxidation. PMID- 26592170 TI - Incorporation of cyclic azobenzene into oligodeoxynucleotides for the photo regulation of DNA hybridization. AB - Cyclic azobenzene carboxylic acid was synthesized using a shortened route. After reaction with D-threolinol, the resulting cyclic azobenzene-D-threolinol (cAB Thr) building block was transformed into the corresponding DMTr-protected phosphoramidite, and incorporated into oligodeoxynucleotides at various positions and frequencies by solid phase synthesis. The melting temperatures of these modified oligonucleotides were determined by UV spectrometry. Photo-regulation of cAB-Thr-modified oligonucleotides with their complementary sequence was evaluated by Fluorescence Resonance Energy Transfer experiments using a fluorescein-Black Hole Quencher pair. Results suggest that while cis-cAB destabilizes DNA duplexes, trans-cAB can be accommodated in double stranded DNA. PMID- 26592171 TI - Protective effect and mechanism of action of lupane triterpenes from Cornus walteri in cisplatin-induced nephrotoxicity. AB - The present study reports a renoprotective effect and the mechanism of action of lupane triterpenes isolated from Cornus walteri in cisplatin-induced renal toxicity. A phytochemical investigation of the MeOH extract of the stems and stem bark of C. walteri resulted in the isolation and identification of twelve lupane triterpenes. Among these, betulinic acid, 29-oxobetulinic acid, betulin 3 acetate, and lupeol ameliorated cisplatin-induced nephrotoxicity to 80% of the control value at 125 MUM. Upregulated phosphorylation of JNK, ERK, and p38 following cisplatin treatment were markedly decreased after co-treatment with betulinic acid, 29-oxobetulinic acid, betulin 3-acetate, and lupeol. In addition, the protein expression level of cleaved caspase-3 and the percentage of apoptotic cells were also significantly reduced after co-treatment with betulinic acid, 29 oxobetulinic acid, betulin 3-acetate, and lupeol. These results show that blocking the MAPK signaling cascade plays a critical role in mediating the renoprotective effect of betulinic acid, 29-oxobetulinic acid, betulin 3-acetate, and lupeol isolated from C. walteri extract. PMID- 26592172 TI - Bioreductive deprotection of 4-nitrobenzyl group on thymine base in oligonucleotides for the activation of duplex formation. AB - Oligonucleotides containing 4-O-(4-NO2-benzyl)thymine residues were synthesized to assess potential prodrug-type action against hypoxic cells. These modified oligonucleotides were incapable of stable duplex formation under non-hypoxic conditions. However, following deprotection of the thymine residues under bioreductive conditions, the deprotected oligonucleotides were able to form stable duplexes with target oligonucleotides. PMID- 26592173 TI - Modeling the intracellular replication of influenza A virus in the presence of defective interfering RNAs. AB - Like many other viral pathogens, influenza A viruses can form defective interfering particles (DIPs). These particles carry a large internal deletion in at least one of their genome segments. Thus, their replication depends on the co infection of cells by standard viruses (STVs), which supply the viral protein(s) encoded by the defective segment. However, DIPs also interfere with STV replication at the molecular level and, despite considerable research efforts, the mechanism of this interference remains largely elusive. Here, we present a mechanistic mathematical model for the intracellular replication of DIPs. In this model, we account for the common hypothesis that defective interfering RNAs (DI RNAs) possess a replication advantage over full-length (FL) RNAs due to their reduced length. By this means, the model captures experimental data from yield reduction assays and from studies testing different co-infection timings. In addition, our model predicts that one important aspect of interference is the competition for viral proteins, namely the heterotrimeric viral RNA-dependent RNA polymerase (RdRp) and the viral nucleoprotein (NP), which are needed for encapsidation of naked viral RNA. Moreover, we find that there may be an optimum for both the DI RNA synthesis rate and the time point of successive co-infection of a cell by DIPs and STVs. Comparing simulations for the growth of DIPs with a deletion in different genome segments suggests that DI RNAs derived from segments which encode for the polymerase subunits are more competitive than others. Overall, our model, thus, helps to elucidate the interference mechanism of DI RNAs and provides a novel hypothesis why DI RNAs derived from the polymerase encoding segments are more abundant in DIP preparations. PMID- 26592174 TI - Sequence and phylogenetic analyses of novel totivirus-like double-stranded RNAs from field-collected powdery mildew fungi. AB - The identification of mycoviruses contributes greatly to understanding of the diversity and evolutionary aspects of viruses. Powdery mildew fungi are important and widely studied obligate phytopathogenic agents, but there has been no report on mycoviruses infecting these fungi. In this study, we used a deep sequencing approach to analyze the double-stranded RNA (dsRNA) segments isolated from field collected samples of powdery mildew fungus-infected red clover plants in Japan. Database searches identified the presence of at least ten totivirus (genus Totivirus)-like sequences, termed red clover powdery mildew-associated totiviruses (RPaTVs). The majority of these sequences shared moderate amino acid sequence identity with each other (<44%) and with other known totiviruses (<59%). Nine of these identified sequences (RPaTV1a, 1b and 2-8) resembled the genome of the prototype totivirus, Saccharomyces cerevisiae virus-L-A (ScV-L-A) in that they contained two overlapping open reading frames (ORFs) encoding a putative coat protein (CP) and an RNA dependent RNA polymerase (RdRp), while one sequence (RPaTV9) showed similarity to another totivirus, Ustilago maydis virus H1 (UmV H1) that encodes a single polyprotein (CP-RdRp fusion). Similar to yeast totiviruses, each ScV-L-A-like RPaTV contains a -1 ribosomal frameshift site downstream of a predicted pseudoknot structure in the overlapping region of these ORFs, suggesting that the RdRp is translated as a CP-RdRp fusion. Moreover, several ScV-L-A-like sequences were also found by searches of the transcriptome shotgun assembly (TSA) libraries from rust fungi, plants and insects. Phylogenetic analyses show that nine ScV-L-A-like RPaTVs along with ScV-L-A-like sequences derived from TSA libraries are clustered with most established members of the genus Totivirus, while one RPaTV forms a new distinct clade with UmV-H1, possibly establishing an additional genus in the family. Taken together, our results indicate the presence of diverse, novel totiviruses in the powdery mildew fungus populations infecting red clover plants in the field. PMID- 26592176 TI - The possibility of renal function recovery in chronic hemodialysis patients should not be overlooked: Single center experience. AB - Chronic hemodialysis is implemented when irreversible loss of kidney function occurs. Sometimes renal recovery is overlooked. From January 2005 to December 2014, we identified 28 patients hemodialyzed for more than 3 months who had renal replacement therapy discontinued. The group consisted of 17 (57.7%) males and 11 (42.3%) females. Patients were 18-87 years old. Time of hemodialysis ranged from 3 to 97 months. Of note, 14 (50%) patients were referred from local dialysis units for solution of vascular access problems. In 13 (46.2%) patients dialysis was abandoned within the first 6 months, in 5 (17.8%) patients between 6 and 12 months, and in 10 (35.7%) patients beyond 12 months. Estimated dialysis-free survival was 94.4% (SE 0.054) and 82% (SE 0.095) at 12 and 24 months, respectively. All physicians must be aware of possible kidney function improvement. In patients with preserved diuresis fall in periodical urea or creatinine measurements might be a sign of renal recovery. PMID- 26592175 TI - Genome-wide association study-identified SNPs (rs3790844, rs3790843) in the NR5A2 gene and risk of pancreatic cancer in Japanese. AB - We genotyped 2 SNPs (rs3790844 T/C and rs3790843 G/A) in the NR5A2 gene that were identified in a genome-wide association study (GWAS) of pancreatic cancer in populations of mainly European ancestry, and we examined their associations with pancreatic cancer risk in a case-control study of 360 patients and 400 control subjects in Japan. Unconditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). The SNPs were in linkage disequilibrium (r(2) = 0.80). For rs3790843, the multivariable-adjusted OR was 0.75 (95% CI: 0.41-1.36) and 0.60 (95%CI: 0.33-1.08) for subjects with the AG and AA genotype, respectively, compared to subjects with the GG genotype. The per allele OR was 0.78 (0.62-0.99) (P = 0.046). For rs3790844, the multivariable adjusted OR was 0.65 (95% CI: 0.37-1.14) and 0.47 (95%CI: 0.27-0.83) for subjects with the CT and CC genotype, respectively, compared to subjects with the TT genotype. The per allele OR was 0.70 (0.56-0.89) (P = 0.003). Our case-control study found that rs3790843 and rs3790844 in the NR5A2 gene are associated with pancreatic cancer risk in Japanese subjects. The direction of association is consistent with the prior findings from GWASs. PMID- 26592177 TI - Vitamin D-Cellular Ca2+ link to obesity and diabetes. AB - The vitamin D hormone 1,25-Dihydroxyvitamin D3 (1,25(OH)2D3)-induced cellular Ca2+ signals regulate apoptosis in adipocytes and insulin secretion from pancreatic beta-cells, and low vitamin D status is considered a risk factor for obesity and type 2 diabetes. The anti-obesity effects of 1,25(OH)2D3 in mature adipocytes are determined by its activity to generate, via multiple Ca2+ signaling pathways, a sustained increase in intracellular Ca2+ followed by activation of the Ca2+-dependent initiators and effectors of apoptosis. In pancreatic beta-cells, 1,25(OH)2D3 induces synchronous Ca2+ oscillations, which pattern pulsatile insulin secretion from these cells. An increased intake of vitamin D3 in a high fat diet-induced obesity mouse model is associated with a decreased weight of white adipose tissue due to induction of apoptosis and the improved blood markers related to adiposity, diabetes, and vitamin D status (plasma concentrations of glucose, insulin, adiponectin, 25-hydroxyvitamin D, and 1,25(OH)2D3). High vitamin D3 intake is also effective in increasing the mineral content of growing bone in obese mice via regulatory effects mediated by 1,25(OH)2D3-parathyroid hormone axis. The 1,25(OH)2D3-dependent cellular Ca2+ signaling can be important for maintaining the normal levels of apoptosis in adipose tissue and insulin secretion from pancreatic beta-cells. An increased intake of vitamin D may contribute to the prevention of obesity, type 2 diabetes, and bone disorders associated with these diseases. PMID- 26592178 TI - A Physicochemical Study of the Effects of Acidity on the Distribution and Antioxidant Efficiency of Trolox in Olive Oil-in-Water Emulsions. AB - The efficiency of antioxidants to inhibit the oxidation of lipid-based emulsions depends on several factors including their nature and their concentration at the reaction site. Here, we have analyzed the effects of acidity and of surfactant concentration on the distribution and efficiency of the vitamin E analog Trolox (TR) in stripped olive oil-in-water emulsions stabilized with Tween 20. The distribution was assessed in the intact emulsions by employing a kinetic method that exploits the reaction between the hydrophobic 4-hexadecylbenzenediazonium ions and TR. Kinetic results are interpreted on the grounds of the pseudophase model. The effects of TR on the oxidative stability of the emulsion were determined at different pH values by monitoring the formation of conjugated dienes over time. The results show that the efficiency of TR increases upon increasing pH even though its concentration in the interfacial region decreases. PMID- 26592179 TI - Nine members of a family of nine-membered cyclic coordination clusters; Fe6Ln3 wheels (Ln = Gd to Lu and Y). AB - We report a family of isostructural nonanuclear Fe(III)-Ln(III) cyclic coordination clusters [Fe(III)(6)Ln(III)(3)(MU-OMe)9(vanox)6(benz)6]. (Ln = Tb (1), Dy (2), Ho (3), Er (4), Tm (5), Yb (6), Lu (7), Y (8) and Gd (9)), containing an odd number of metal ions. The planar cyclic coordination cluster cores are built up from three [Fe2Ln] subunits. PMID- 26592181 TI - A novel self-assembled platform for the ratiometric fluorescence detection of spermine. AB - A novel self-assembled platform where the micelles of a pyrene derivative act as the shell and squaraine (SQ) as the nucleus was constructed for the ratiometric near infrared (NIR) fluorescence detection of urinary spermine with high selectivity. In addition, the platform can be used to detect spermine with multiple channels by the naked eye. PMID- 26592182 TI - Unveiling the peculiar hydrogen bonding behavior of solvated N-heterocyclic carbenes. AB - To investigate the hydrogen bonding and its dynamics of N-heterocyclic carbenes (NHCs) in solution, a molecular mechanical force field was fitted for the homologous series of 1,3-dialkylimidazol-2-ylidenes. During the exploration of the potential energy surface of the water/1,3-dimethylimidazol-2-ylidene system, it was observed for the first time that the carbene is prone to interaction with hydrogen bond donor molecules also from the rather unusual "on top" orientation, where the direction of the interplay is perpendicular to the plane of the NHC's ring. The fitting of the force field parameters for imidazol-2-ylidenes was found to be the best in the case of a two-site model, which reproduces not only the strength, but also the direction dependency of hydrogen bonding. With the aid of this tool, curious, hitherto unknown types of hydrogen bonding could be unveiled for NHCs. In the case of non-hydrogen bonding solvents, carbenes tend to form short lived, but structurally influental hydrogen bonds between each other via ring hydrogen atoms and the divalent carbon atoms. The chemically highly important hydrogen bond dynamics of NHCs was found to be facilitated by three center hydrogen bonding, where two alcohol molecules bind to a carbene, which is allowed only by the aforementioned relatively strong interaction between the NHC and the hydrogen bond donor in the "on top" orientation. The latter finding has significant effects on processes that involve this kind of replacement, such as the selective transesterification reactions, and the mechanism of proton exchange on azolium rings. PMID- 26592180 TI - Engraftment of human induced pluripotent stem cell-derived hepatocytes in immunocompetent mice via 3D co-aggregation and encapsulation. AB - Cellular therapies for liver diseases and in vitro models for drug testing both require functional human hepatocytes (Hum-H), which have unfortunately been limited due to the paucity of donor liver tissues. Human pluripotent stem cells (hPSCs) represent a promising and potentially unlimited cell source to derive Hum H. However, the hepatic functions of these hPSC-derived cells to date are not fully comparable to adult Hum-H and are more similar to fetal ones. In addition, it has been challenging to obtain functional hepatic engraftment of these cells with prior studies having been done in immunocompromised animals. In this report, we demonstrated successful engraftment of human induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells (iPS-H) in immunocompetent mice by pre engineering 3D cell co-aggregates with stromal cells (SCs) followed by encapsulation in recently developed biocompatible hydrogel capsules. Notably, upon transplantation, human albumin and alpha1-antitrypsin (A1AT) in mouse sera secreted by encapsulated iPS-H/SCs aggregates reached a level comparable to the primary Hum-H/SCs control. Further immunohistochemistry of human albumin in retrieved cell aggregates confirmed the survival and function of iPS-H. This proof-of-concept study provides a simple yet robust approach to improve the engraftment of iPS-H, and may be applicable to many stem cell-based therapies. PMID- 26592183 TI - CO2 adsorption of three isostructural metal-organic frameworks depending on the incorporated highly polarized heterocyclic moieties. AB - A systematic investigation of CO2 adsorption behavior in three metal-organic frameworks was executed. The three MOFs adopted the same NbO-type structure, except that the organic ligands were grafted with different highly polarized heterocyclic moieties, namely, oxadiazole, thiadiazole, and selenadiazole, respectively. After activation, the three MOF materials, ZJNU-41a showed different surface areas and pore volumes depending on the incorporated heterocyclic rings attached to the organic ligands as well as the MOF's stabilities. Among the three MOF materials, exhibited an impressive CO2 uptake capacity of 97.4 cm(3) (STP) g(-1) at 298 K and 1 atm, which is comparable and even superior to those reported in NbO-type MOFs. In particular, when the molecular dipole of the attached heterocyclic moieties increases, the CO2 uptake also increases, which was further supported by comprehensive quantum chemical calculations. This work demonstrates that the introduction of highly polarized heterocyclic functional groups into frameworks is a promising approach to target porous metal-organic framework materials with improved CO2 adsorption performance. PMID- 26592185 TI - Amyloid Templated Gold Aerogels. AB - Amyloid fibril-based ultralow-density aerogels are designed by functionalization with gold nanoparticles and microcrystals, leading to hybrids of unprecedented lightness and functionality. By changing the colloidal gold shape, size, and concentration, the gold composition can be tuned to reach contents >=20 kt equivalent, yet at densities ~10(3) lighter than any equivalent gold alloys, and combining unique features such as porosity, catalytic properties, pressure sensing, and autofluorescence. PMID- 26592184 TI - P2*7 purinergic signaling in dilated cardiomyopathy induced by auto-immunity against muscarinic M2 receptors: autoantibody levels, heart functionality and cytokine expression. AB - Autoantibodies against the M2 receptors (M2AChR) have been associated with Dilated Cardiomyopathy (DCM). In the heart, P2*7 receptors influence electrical conduction, coronary circulation and response to ischemia. They can also trigger pro-inflammatory responses and the development of neurological, cardiac and renal disorders. Here, P2*7(-/-) mice displayed an increased heart rate and ST segment depression, but similar exercise performance when compared to wild type (WT) animals. After immunization with plasmid containing M2AChR cDNA sequence, WT mice produced anti-M2AChR antibodies, while P2*7(-/-) mice showed an attenuated production. Despite this, WT and P2*7(-/-) showed left ventricle cavity enlargement and decreased exercise tolerance. Transfer of serum from M2AChR WT immunized mice to naive recipients led to an alteration in heart shape. P2*7(-/-) mice displayed a significant increase in the frequency of spleen regulatory T cells population, which is mainly composed by the FoxP3(+)CD25(-) subset. M2AChR WT immunized mice showed an increase in IL-1beta, IFNgamma and IL-17 levels in the heart, while P2*7(-/-) group produced lower amounts of IL-1beta and IL-17 and higher amounts of IFNgamma. These results pointed to previously unnoticed roles of P2*7 in cardiovascular and immune systems, and underscored the participation of IL-17 and IFNgamma in the progress of autoimmune DCM. PMID- 26592186 TI - An Apoferritin-based Drug Delivery System for the Tyrosine Kinase Inhibitor Gefitinib. AB - Anticancer drug Gefitinib encapsulated within human heavy chain apoferritin by diffusion allows pH-controlled sustained release of cargo. The combination of increased cellular uptake, and potent and enhanced antitumor activity against the HER2 overexpressing SKBR3 cell line compared to Gefitinib alone, makes it a promising carrier for delivery of drugs to tumor sites. PMID- 26592187 TI - A case of netherton syndrome: successful treatment with omalizumab and pulse prednisolone and its effects on cytokines and immunoglobulin levels. AB - CONTEXT: Netherton syndrome (NS) is associated with the mutation in the SPINK5 gene, which codes LEKTI (lymphoepithelial Kazaltype related inhibitor), a serine protease inhibitor. As a result of aging coupled with immune deficiency, clinical symptoms may vary. METHODS: The patient was presented to our clinic with sparse and brittle hair along with pruritic, erythematous and scaling cutaneous lesions. The patient underwent a clinical examination and laboratory analyzes. Based on the clinical and laboratory findings, the patient was diagnosed with NS. Moreover, CRP, Complement-3 (C3), C4 IL-4, IL-5, IL-1beta and IL-17A levels of serum were investigated as an apoptotic marker and a negative marker for inflammation. RESULTS: Having undergone omalizumab treatment and a short-term (4 months) later, he had a decreased IgE, Ig G, prolactin, CRP, IL-4, IL-5, IL-1beta and IL-17A levels. The IgA, IgM and C3, C4 levels were insignificant between before and after Omalizumab treatment. CONCLUSION: To the best of our knowledge, this is the first time that an association between omalizumab and NS was documented. In conclusion allergic skin symptoms (pruritus, erythema and desquamation) and mucosal symptoms decreased in the patient. PMID- 26592188 TI - Transplantation: New tool for prediction of ESRD risk in living kidney donor candidates. PMID- 26592191 TI - Acute kidney injury: Buffered crystalloids or saline in the ICU--a SPLIT decision. PMID- 26592190 TI - Hypertension pharmacogenomics: in search of personalized treatment approaches. AB - Cardiovascular and renal diseases are associated with many risk factors, of which hypertension is one of the most prevalent. Worldwide, blood pressure control is only achieved in ~50% of those treated for hypertension, despite the availability of a considerable number of antihypertensive drugs from different pharmacological classes. Although many reasons exist for poor blood pressure control, a likely contributor is the inability to predict to which antihypertensive drug an individual is most likely to respond. Hypertension pharmacogenomics and other 'omics' technologies have the potential to identify genetic signals that are predictive of response or adverse outcome to particular drugs, and guide selection of hypertension treatment for a given individual. Continued research in this field will enhance our understanding of how to maximally deploy the various antihypertensive drug classes to optimize blood pressure response at the individual level. This Review summarizes the available literature on the most convincing genetic signals associated with antihypertensive drug responses and adverse cardiovascular outcomes. Future research in this area will be facilitated by enhancing collaboration between research groups through consortia such as the International Consortium for Antihypertensives Pharmacogenomics Studies, with the goal of translating replicated findings into clinical implementation. PMID- 26592189 TI - The emerging role of coagulation proteases in kidney disease. AB - A role of coagulation proteases in kidney disease beyond their function in normal haemostasis and thrombosis has long been suspected, and studies performed in the past 15 years have provided novel insights into the mechanisms involved. The expression of protease-activated receptors (PARs) in renal cells provides a molecular link between coagulation proteases and renal cell function and revitalizes research evaluating the role of haemostasis regulators in renal disease. Renal cell-specific expression and activity of coagulation proteases, their regulators and their receptors are dynamically altered during disease processes. Furthermore, renal inflammation and tissue remodelling are not only associated, but are causally linked with altered coagulation activation and protease-dependent signalling. Intriguingly, coagulation proteases signal through more than one receptor or induce formation of receptor complexes in a cell specific manner, emphasizing context specificity. Understanding these cell specific signalosomes and their regulation in kidney disease is crucial to unravelling the pathophysiological relevance of coagulation regulators in renal disease. In addition, the clinical availability of small molecule targeted anticoagulants as well as the development of PAR antagonists increases the need for in-depth knowledge of the mechanisms through which coagulation proteases might regulate renal physiology. PMID- 26592192 TI - Chronic kidney disease: suPAR in CKD. PMID- 26592193 TI - Chronic kidney disease: Treatment of hepatitis C virus infection in patients with CKD. PMID- 26592195 TI - Social problem solving in carers of young people with a first episode of psychosis: a randomized controlled trial. AB - AIM: Caring for young people with first-episode psychosis is difficult and demanding, and has detrimental effects on carers' well-being, with few evidence based resources available to assist carers to deal with the problems they are confronted with in this situation. We aimed to examine if completion of a self directed problem-solving bibliotherapy by first-time carers of young people with first-episode psychosis improved their social problem solving compared with carers who only received treatment as usual. METHODS: A randomized controlled trial was carried out through two early intervention psychosis services in Melbourne, Australia. A sample of 124 carers were randomized to problem-solving bibliotherapy or treatment as usual. Participants were assessed at baseline, 6- and 16-week follow-up. RESULTS: Intent-to-treat analyses were used and showed that recipients of bibliotherapy had greater social problem-solving abilities than those receiving treatment as usual, and these effects were maintained at both follow-up time points. CONCLUSIONS: Our findings affirm that bibliotherapy, as a low-cost complement to treatment as usual for carers, had some effects in improving their problem-solving skills when addressing problems related to the care and support of young people with first-episode psychosis. PMID- 26592194 TI - TRIM33 switches off Ifnb1 gene transcription during the late phase of macrophage activation. AB - Despite its importance during viral or bacterial infections, transcriptional regulation of the interferon-beta gene (Ifnb1) in activated macrophages is only partially understood. Here we report that TRIM33 deficiency results in high, sustained expression of Ifnb1 at late stages of toll-like receptor-mediated activation in macrophages but not in fibroblasts. In macrophages, TRIM33 is recruited by PU.1 to a conserved region, the Ifnb1 Control Element (ICE), located 15 kb upstream of the Ifnb1 transcription start site. ICE constitutively interacts with Ifnb1 through a TRIM33-independent chromatin loop. At late phases of lipopolysaccharide activation of macrophages, TRIM33 is bound to ICE, regulates Ifnb1 enhanceosome loading, controls Ifnb1 chromatin structure and represses Ifnb1 gene transcription by preventing recruitment of CBP/p300. These results characterize a previously unknown mechanism of macrophage-specific regulation of Ifnb1 transcription whereby TRIM33 is critical for Ifnb1 gene transcription shutdown. PMID- 26592196 TI - Chlorpromazine inhibits mitochondrial apoptotic pathway via increasing expression of tissue factor. AB - Chlorpromazine (CPZ) is a widely used antipsychotic drug with antagonistic effect on dopamine receptors. Accumulating evidence has shown that CPZ plays a neuroprotective role in various models of toxicity and apoptosis. However, the underlying mechanism contributing to this protective effect remains unclear. Here, we evaluate the effect of CPZ on mitochondrial apoptotic pathway in the neuron system. Higher levels of B-cell lymphoma-2 (Bcl-2) and tissue factor (TF) but lower apoptotic rate were found in hippocampus of CPZ-treated schizophrenic patients compared with non-antipsychotic treated controls. Additionally, both short-term and long-term treatment of CPZ in rats could up-regulate the levels of Bcl-2 and TF with no cytotoxic effects. In the in vitro experiment, expression of Bcl-2 was up-regulated in the C6 glioma cells transfected with pEGFP-N1-TF recombinant plasmid. Furthermore, in another independent rat model of apoptosis, compared with the group administrated with alcohol only, the brains of the CPZ pretreated rats showed lower expression of cleaved caspase-3, cytochrome c and Bax, but higher expression of Bcl-2 and TF. Our data demonstrate that CPZ exerts its neuronal protective effects through inhibiting the activation of mitochondrial apoptotic pathway by up-regulating TF expression, thus providing new insight into CPZ function and application. PMID- 26592197 TI - NLRC5 regulates TGF-beta1-induced proliferation and activation of hepatic stellate cells during hepatic fibrosis. AB - Therapeutic management of liver fibrosis remains an unsolved clinical problem. Hepatic accumulation of extracellular matrix, mainly collagen, is mediated by the production of transforming growth factor-beta1 (TGF-beta1) in hepatic stellate cells (HSCs). NLRC5, the largest member of the NLR protein family, has recently been identified as a critical regulator of immune responses. Novel evidence shows that NLRC5 is an important negative modulator of inflammatory pathways. Herein, we determined the regulation of NLRC5 in liver fibrogenesis and its underlying mechanisms. We have shown that NLRC5 was upregulated in human liver fibrotic tissues. Overexpression of NLRC5 resulted in an upregulation of collagen 1 and alpha-smooth muscle actin expression in HSC LX-2 cells, which was inhibited by NLRC5 knockdown with its siRNA. Furthermore, NLRC5 deficiency significantly suppressed TGF-beta1-induced proliferation but increased apoptosis (i.e., increased caspases-3, DR4 and DR5) in LX-2 cells. In addition, knockdown of NLRC5 promoted the activation of NF-kappaB signaling pathways but abrogated phosphorylation of Smad2 and Smad3 proteins in response to TGF-beta1. These results indicate that NLRC5 is a potent pro-fibrogenic molecule for HSC activation through TGF-beta1/Smad and NF-kappaB signaling pathways. NLRC5 inhibition would be a promising therapeutic avenue for treating hepatic fibrosis. PMID- 26592198 TI - Silicon nanowire and carbon nanotube hybrid for room temperature multiwavelength light source. AB - The realization of an innovative hybrid light source operating at room temperature, obtained by embedding a carbon nanotube (CNT) dispersion inside a Si nanowire (NW) array is reported. The NW/CNT system exhibits a peculiar photoluminescence spectrum, consisting of a wide peak, mainly observed in the visible range, due to quantum confined Si NWs, and of several narrower IR peaks, due to the different CNT chiralities present in the dispersion. The detailed study of the optical properties of the hybrid system evidences that the ratio between the intensity of the visible and the IR emissions can be varied within a wide range by changing the excitation wavelength or the CNT concentration; the conditions leading to the prevalence of one signal with respect to the other are identified. The multiplicity of emission spectra obtainable from this composite material opens new perspectives for Si nanostructures as active medium in light sources for Si photonics applications. PMID- 26592199 TI - Social outcomes in adult survivors of childhood cancer compared to the general population: linkage of a cohort with population registers. AB - OBJECTIVE: Self-reported data show differences in social outcomes (not being married/having a registered partnership; not living independently; using social benefits) for childhood cancer survivors compared with their peers. We aimed to determine differences in these social outcomes between survivors and the general population using national register data and explored associated risk factors. METHODS: We performed medical record linkage between a single-centre cohort of 1768 >= 5-year survivors of childhood cancer (diagnosed 1966-2001) and two national registers (1999-2011) and obtained a random reference sample matched on gender and year of birth per survivor. We used multivariable logistic regression to calculate in adult survivors of childhood cancer (born before 1990) the odds of the specified social outcomes at the end of follow-up in both groups. Within the survivors, we analysed risk factors for the social outcomes. RESULTS: We retrieved data from 1283 adult childhood cancer survivors and 25 082 reference persons. Survivors had higher odds (odds ratio; 95% confidence interval) of not being married (1.2; 1.07-1.42), not living independently (1.7; 1.41-2.00) and using social benefits (2.3; 1.98-2.69) compared with reference persons. Radiotherapy to head and/or neck, and an original central nervous system tumour diagnosis negatively influenced all social outcomes examined in childhood cancer survivors. CONCLUSIONS: National register data show differences between social outcomes in childhood cancer survivors and the general population, especially for survivors treated with radiotherapy to head and/or neck and those originally diagnosed with central nervous system tumours. Development and implementation of effective targeted support strategies to improve social outcomes of childhood cancer survivors needs consideration. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26592200 TI - Favorable change of lipid profile after carbamazepine withdrawal. AB - OBJECTIVE: Patients treated with carbamazepine (CBZ) have increased serum levels of total cholesterol (TC), high-density lipoproteins (HDL), and low-density lipoproteins (LDL). We aimed to investigate whether these changes of serum lipids are reversible after CBZ withdrawal. MATERIAL AND METHODS: We used a prospective, randomized double-blinded design. A total of 160 patients who had been seizure free on anti-epileptic drug monotherapy for more than 2 years were included and randomized to withdrawal or not. The intervention was completed by 150 (80 females, 53%) patients. Serum samples from before and 4 months after completed withdrawal or no withdrawal were obtained from 130 patients (63 females, 48%). Of these, 84 were treated with CBZ, 28 with valproate, nine with phenytoin, four with phenobarbital, and five with lamotrigine. Of the patients who had been treated with CBZ, 47 were randomized to the withdrawal group, and 37 were randomized to the non-withdrawal group. RESULTS: Among the CBZ-treated patients, a significant decrease in serum levels of TC, LDL, and apolipoprotein B (ApoB) were found in the withdrawal group compared with the non-withdrawal group. Mean differences in change were as follows: TC 0.68 mmol/l (P = 0.005, CL - 1.15 to 0.21); LDL - 0.67 mmol/l (P = 0.001, CL - 1.03 to -0.29); ApoB - 0.13 g/l (P = 0.02, CL - 0.23 to -0.03). No significant changes in HDL, apolipoprotein A, and C reactive protein were detected. CONCLUSION: Our results indicate that CBZ may have unfavorable effects on serum levels of TC, LDL, and ApoB. However, these changes seem to be reversible even after years of treatment. PMID- 26592201 TI - Pragmatic perspective on aerobic scope: peaking, plummeting, pejus and apportioning. AB - A major challenge for fish biologists in the 21st century is to predict the biotic effects of global climate change. With marked changes in biogeographic distribution already in evidence for a variety of aquatic animals, mechanistic explanations for these shifts are being sought, ones that then can be used as a foundation for predictive models of future climatic scenarios. One mechanistic explanation for the thermal performance of fishes that has gained some traction is the oxygen and capacity-limited thermal tolerance (OCLTT) hypothesis, which suggests that an aquatic organism's capacity to supply oxygen to tissues becomes limited when body temperature reaches extremes. Central to this hypothesis is an optimum temperature for absolute aerobic scope (AAS, loosely defined as the capacity to deliver oxygen to tissues beyond a basic need). On either side of this peak for AAS are pejus temperatures that define when AAS falls off and thereby reduces an animal's absolute capacity for activity. This article provides a brief perspective on the potential uses and limitations of some of the key physiological indicators related to aerobic scope in fishes. The intent is that practitioners who attempt predictive ecological applications can better recognize limitations and make better use of the OCLTT hypothesis and its underlying physiology. PMID- 26592202 TI - Hepatitis B virus efficiently infects non-adherent hepatoma cells via human sodium taurocholate cotransporting polypeptide. AB - Sodium taurocholate cotransporting polypeptide (NTCP) has been reported as a functional receptor for hepatitis B virus (HBV) infection. However, HBV could not efficiently infect HepG2 cells expressing NTCP (NTCP-HepG2 cells) under adherent monolayer-cell conditions. In this study, NTCP was mainly detected in the basolateral membrane region, but not the apical site, of monolayer NTCP-HepG2 cells. We hypothesized that non-adherent cell conditions of infection would enhance HBV infectivity. Non-adherent NTCP-HepG2 cells were prepared by treatment with trypsin and EDTA, which did not degrade NTCP in the membrane fraction. HBV successfully infected NTCP-HepG2 cells at a viral dose 10 times lower in non adherent phase than in adherent phase. Efficient infection of non-adherent NTCP HepG2 cells with blood-borne or cell-culture-derived HBV was observed and was remarkably impaired in the presence of the myristoylated preS1 peptide. HBV could also efficiently infect HepaRG cells under non-adherent cell conditions. We screened several compounds using our culture system and identified proscillaridin A as a potent anti-HBV agent with an IC50 value of 7.2 nM. In conclusion, non adherent host cell conditions of infection augmented HBV infectivity in an NTCP dependent manner, thus providing a novel strategy to identify anti-HBV drugs and investigate the mechanism of HBV infection. PMID- 26592204 TI - Angiotensin converting enzyme (ACE) inhibitory and antihypertensive activities of protein hydrolysate from meat of Kacang goat (Capra aegagrus hircus). AB - BACKGROUND: The meat of Kacang goat has potential for production of a protein hydrolysate. Functional ingredients from protein hydrolysate of Kacang goat meat were determined by the consistency of angiotensin-converting enzyme (ACE) inhibitory activity and antihypertensive effect. This study examined the potency of Kacang goat protein hydrolysate in ACE inhibition and antihypertensive activity. RESULT: Protein hydrolysates of Kacang goat meat were prepared using sequential digestion of endo-proteinase and protease complex at several concentrations and hydrolysis times. The highest ACE inhibitory activity resulted from a hydrolysate that was digested for 4 h with 5 g kg(-1) of both enzymes. An ACE inhibitory peptide was purified and a novel peptide found with a sequence of Phe-Gln-Pro-Ser (IC50 value of 27.0 umol L(-1) ). Both protein hydrolysates and a synthesised peptide (Phe-Gln-Pro-Ser) demonstrated potent antihypertensive activities in spontaneously hypertensive rats. CONCLUSION: Protein hydrolysate of Kacang goat meat produced by sequential digestion with endo-proteinase and protease complex has great potential as a functional ingredient, particularly as an antihypertensive agent. (c) 2015 Society of Chemical Industry. PMID- 26592205 TI - De Novo Design of Xeno-Metallo Coiled Coils. AB - Bioinorganic chemists aspire to achieve the same exquisite and highly controlled inorganic chemistry featured in biology. An exciting mimetic approach involves the use of miniature artificial protein scaffolds designed de novo (often based on the coiled coil (CC) scaffold), for reproducing native metal ion sites and their function. Recently, there is increased interest, instead, in the design of xeno-metal sites within CC assemblies. This involves incorporating either non biological metal ions, cofactors or non-proteinogenic amino acid ligands for metal ion coordination, whilst retaining a minimal CC protein scaffold. Using this approach, one should be able to create functional designs with unique and unusual properties, which combine the advantages of both biology and 'traditional' non-biological inorganic chemistry. It is the recent progress with respect to the design of xeno-metallo CCs which will be discussed in this Focus Review. PMID- 26592203 TI - RDoC and translational perspectives on the genetics of trauma-related psychiatric disorders. AB - Individuals with a history of child abuse are at high risk for depression, anxiety disorders, aggressive behavior, and substance use problems. The goal of this paper is to review studies of the genetics of these stress-related psychiatric disorders. An informative subset of studies that examined candidate gene by environment (GxE) predictors of these psychiatric problems in individuals maltreated as children is reviewed, together with extant genome wide association studies (GWAS). Emerging findings on epigenetic changes associated with adverse early experiences are also reviewed. Meta-analytic support and replicated findings are evident for several genetic risk factors; however, extant research suggests the effects are pleiotropic. Genetic factors are not associated with distinct psychiatric disorders, but rather diverse clinical phenotypes. Research also suggests adverse early life experiences are associated with changes in gene expression of multiple known candidate genes, genes involved in DNA transcription and translation, and genes necessary for brain circuitry development, with changes in gene expression reported in key brain structures implicated in the pathophysiology of psychiatric and substance use disorders. The finding of pleiotropy highlights the value of using the Research Domain Criteria (RDoC) framework in future studies of the genetics of stress-related psychiatric disorders, and not trying simply to link genes to multifaceted clinical syndromes, but to more limited phenotypes that map onto distinct neural circuits. Emerging work in the field of epigenetics also suggests that translational studies that integrate numerous unbiased genome-wide approaches will help to further unravel the genetics of stress-related psychiatric disorders. PMID- 26592206 TI - Gender difference in platelet aggregation and reactivity induced by recombinant human erythropoietin. PMID- 26592207 TI - How do we develop and implement a preoperative anemia clinic designed to improve perioperative outcomes and reduce cost? AB - Treatment of anemia is one of the four pillars of patient blood management programs. Preoperative anemia is common and associated with increased perioperative morbidity after surgery and increased rates of blood transfusion. Effective treatment of preoperative anemia, however, requires advanced screening, diagnosis, and initiation of therapy weeks before elective surgery. Here we describe the development and implementation of a preoperative anemia screening and treatment program at Duke University Hospital. PMID- 26592208 TI - A transparent projection screen based on plasmonic Ag nanocubes. AB - A transparent and colourless projection screen is fabricated by depositing a silver nanocube sub-monolayer on a titania thin film. Backward scattering of the silver nanocubes is enhanced by titania in the blue and red regions, to which human eyes are less sensitive. As a result, this screen, which is cost-effective even for large areas, allows projection of full colour images. PMID- 26592210 TI - Expanding the Scope of Hypervalent Iodine Reagents for Perfluoroalkylation: From Trifluoromethyl to Functionalized Perfluoroethyl. AB - A series of new hypervalent iodine reagents based on the 1,3-dihydro-3,3-dimethyl 1,2-benziodoxole and 1,2-benziodoxol-3-(1H)-one scaffolds, which contain a functionalized tetrafluoroethyl group, have been prepared, characterized, and used in synthetic applications. Their corresponding electrophilic fluoroalkylation reactions with various sulfur, oxygen, phosphorus, and carbon centered nucleophiles afford products that feature a tetrafluoroethylene unit, which connects two functional moieties. A related lambda(3) -iodane that contains a fluorophore was shown to react with a cysteine derivative under mild conditions to give a thiol-tagged product that is stable in the presence of excess thiol. Therefore, these new reagents show a significant potential for applications in chemical biology as tools for fast, irreversible, and selective thiol bioconjugation. PMID- 26592209 TI - Elevated Extinction Rates as a Trigger for Diversification Rate Shifts: Early Amniotes as a Case Study. AB - Tree shape analyses are frequently used to infer the location of shifts in diversification rate within the Tree of Life. Many studies have supported a causal relationship between shifts and temporally coincident events such as the evolution of "key innovations". However, the evidence for such relationships is circumstantial. We investigated patterns of diversification during the early evolution of Amniota from the Carboniferous to the Triassic, subjecting a new supertree to analyses of tree balance in order to infer the timing and location of diversification shifts. We investigated how uneven origination and extinction rates drive diversification shifts, and use two case studies (herbivory and an aquatic lifestyle) to examine whether shifts tend to be contemporaneous with evolutionary novelties. Shifts within amniotes tend to occur during periods of elevated extinction, with mass extinctions coinciding with numerous and larger shifts. Diversification shifts occurring in clades that possess evolutionary innovations do not coincide temporally with the appearance of those innovations, but are instead deferred to periods of high extinction rate. We suggest such innovations did not cause increases in the rate of cladogenesis, but allowed clades to survive extinction events. We highlight the importance of examining general patterns of diversification before interpreting specific shifts. PMID- 26592211 TI - Key findings to expedite the diagnosis of hyper-IgE syndromes in infants and young children. AB - BACKGROUND: Hyper-IgE syndromes (HIES) are primary immunodeficiency disorders characterized by elevated serum IgE, eczema, and recurrent infections. Despite the availability of confirmatory molecular diagnosis of several distinct HIES entities, the differentiation of HIES particularly from severe forms of atopic dermatitis remains a challenge. The two most common forms of HIES are caused by mutations in the genes STAT3 and DOCK8. METHODS: Here, we assess the clinical and immunologic phenotype of DOCK8- and STAT3-HIES patients including the cell activation, proliferation, and cytokine release after stimulation. RESULTS: Existing HIES scoring systems are helpful to identify HIES patients. However, those scores may fail in infants and young children due to the age-related lack of clinical symptoms. Furthermore, our long-term observations showed a striking variation of laboratory results over time in the individual patient. Reduced memory B-cell counts in concert with low specific antibody production are the most consistent findings likely contributing to the high susceptibility to bacterial and fungal infection. In DOCK8-HIES, T-cell lymphopenia and low IFN gamma secretion after stimulation were common, likely promoting viral infections. In contrast to STAT3-HIES, DOCK8-HIES patients showed more severe inflammation with regard to allergic manifestations, elevated activation markers (HLA-DR, CD69, CD86, and CD154), and significantly increased inflammatory cytokines (IL1 beta, IL4, IL6, and IFN-gamma). CONCLUSION: Differentiating HIES from other diseases such as atopic dermatitis early in life is essential for patients because treatment modalities differ. To expedite the diagnosis process, we propose here a diagnostic workflow. PMID- 26592212 TI - Goodness-of-fit test for meta-analysis. AB - Meta-analysis is a very useful tool to combine information from different sources. Fixed effect and random effect models are widely used in meta-analysis. Despite their popularity, they may give us misleading results if the models don't fit the data but are blindly used. Therefore, like any statistical analysis, checking the model fitting is an important step. However, in practice, the goodness-of-fit in meta-analysis is rarely discussed. In this paper, we propose some tests to check the goodness-of-fit for the fixed and random effect models with assumption of normal distributions in meta-analysis. Through simulation study, we show that the proposed tests control type I error rate very well. To demonstrate the usefulness of the proposed tests, we also apply them to some real data sets. Our study shows that the proposed tests are useful tools in checking the goodness-of-fit of the normal models used in meta-analysis. PMID- 26592213 TI - The power and importance of abstracts. PMID- 26592214 TI - Yoga therapy in an individual with spinal cord injury: A case report. AB - No known research addresses the effects of yoga in those with spinal cord injury (SCI), yet yoga has the potential to improve many impairments commonly associated with SCI. This case report documents the outcomes of a yoga program in an individual with an SCI. The participant was a 59-year-old male who sustained an incomplete C3-C6 SCI. He practiced Hatha yoga for 60-min sessions, twice per week for 12 weeks and despite neurological injury, was able to complete a yoga program with modifications. Improvements were noted in balance; endurance; flexibility; posture; muscle strength of the hip extensors, hip abductors and knee extensors; and in performance of functional goals. No changes were noted in gait velocity, satisfaction in performance of goals or in overall quality of life. The participant was able to practice yoga even though he used an assistive device to walk. PMID- 26592215 TI - Results of chiropractic scoliosis rehabilitation treatment at two years post skeletal maturity in identical female twins. AB - BACKGROUND: Scoliosis treatment guidelines for non-operative management suggest that patients should be followed for two years beyond skeletal maturity to appropriately evaluate treatment effect. This report outlines the results of identical twin girls' treatment with chiropractic rehabilitation treatment at two years post skeletal maturity. FINDINGS: The twins participated in a treatment lasting two weeks, followed by home care maintenance and periodic follow-ups for they reached skeletal maturity. Two year follow up showed reduced Cobb angles of 19 degrees and 15 degrees , respectively. CONCLUSION: Identical twin girls who were evaluated two years after skeletal maturity showed clinically significant improvements in Cobb angle measurements. Controlled, prospective study design for future patients treated in this manner will provide greater insight into how the treatment may have impacted the observed changes. PMID- 26592216 TI - The forearm positioning changes electromyographic activity of upper limb muscles and handgrip strength in the task of pushing a load cart. AB - The aim of the present study was to analyse the electromyographic activity of the upper limb muscles as well as the handgrip strength during the activity of pushing a load cart. Eighteen healthy male right-handed volunteers (21.50 +/- 2.77 years old) took part in the study. Electrodes were placed on upper trapezius fibres, brachial biceps, brachial triceps, and extensors and flexors of wrist and fingers. The original handle of the load cart was replaced by two handgrip systems mounted on load cells, thus allowing the handgrip strength to be measured according to the wrist position variation, that is, wrists in neutral position with pronated forearm (WN-PF) or in ulnar deviation with forearm in neutral position (WUD-NF). The signals generated by the load cells during manoeuvre of the load cart and the electromyographic signals were simultaneously captured. Signal processing was performed by using a specific routine developed for analysis of root mean square (RMS) and median frequency (MF). Greater handgrip strength occurred in WN-PF position. In maximal isometric contraction, the RMS of the flexors and extensors showed greater electromyographic activity in WN-PF (intra-muscles) and extensors position (inter-muscles). Decreased handgrip strength in the latter stages of the circuit, with variation of the RMS and MF of all muscles tested. One can conclude that electromyographic activity and handgrip strength are both affected during the phases of an elliptical displacement of the load cart. PMID- 26592217 TI - Effectiveness of conventional physical therapy and Pilates' method in functionality, respiratory muscle strength and ability to exercise in hospitalized chronic renal patients: A study protocol of a randomized controlled trial. AB - BACKGROUND: Patients with chronic kidney disease can present compromised functional abilities, and hospitalization may further contribute to their health deterioration and loss of functional independence. OBJECTIVES: To compare the effectiveness between Pilates Method and Conventional Physical Therapy in functionality, exercise capacity and respiratory muscle strength in hospitalized patients with chronic kidney disease. METHODS: 56 patients will be randomized into Control (usual care) or Pilates groups. Functionality (Barthel Index), exercise capacity (Step Test) and respiratory muscle strength (Manovacuometry) will be evaluated during pre-intervention, after the 5th and 10th sessions or at discharge in both groups. The statistical analysis will be calculated using linear mixed models and based on intention-to-treat. The level of significance will be set at alpha = 5%. This study is the first to develop a Pilates protocol for hospitalized chronic renal failure patients and the results will provide additional treatment options for these patients and for physiotherapists. PMID- 26592218 TI - A pilot study on the effects of low frequency repetitive transcranial magnetic stimulation on lower extremity spasticity and motor neuron excitability in patients after stroke. AB - PURPOSE: To evaluate the effect of low frequency, repetitive transcranial magnetic stimulation (rTMS) on the lower extremity spasticity and motor neuron excitability in patients after stroke. METHODS: Seven patients after stroke aged 42-78 years were included in this pretest-posttest clinical trial. The rTMS at 1 Hz and duration of 20 min was applied to the intact leg motor cortex for five consecutive sessions. Primary outcome measures were the Modified Modified Ashwoth Scale (MMAS) and the H(max)/M(max) ratio. Measurements were taken at baseline (T0), after the last treatment (5th) session (T1), and at 1 week follow up (T2). RESULTS: Clinically assessed ankle plantar flexor spasticity (p = 0.05) improved significantly after treatment at T1. Knee extensor spasticity scored 0 after treatment at T1 and T2. The H(max)/M(max) ratio showed no statistically significant improvement after treatment. CONCLUSION: The pilot data indicate that the inhibitory rTMS of the intact leg motor cortex in patients after stroke may improve the lower extremity spasticity. PMID- 26592219 TI - Comparison of the effects of remote after-effects of static contractions for different upper-extremity positions and pinch-force strengths in patients with restricted wrist flexion range of motion. AB - The objective of the study was to examine the after-effects of static contractions of upper extremity muscles in different shoulder joint positions and at different pinch-force strengths on the maximal active range of motion (MAROM) and wrist agonist/antagonist IEMG activities for patients with restricted wrist flexion range of motion (ROM) due to upper limb pain and dysfunction. The subjects were 10 outpatients (3 males, 7 females) with restricted wrist joints. These subjects performed four static contractions of upper extremity muscles in neutral and diagonal shoulder joint positions and with weak and strong pinch force strengths in random order. Two-way repeated measures analysis of variance showed that the change in MAROM was significantly larger (P < 0.05) after diagonal-strong static contractions than after neutral-weak static contractions. There were no significant correlations between changes in MAROM and IEMG activities. These results indicate that shoulder joint position and pinch-force strength should be considered for effective induction of remote after-effects of static contractions for increasing MAROM for restricted wrist flexion ROM. PMID- 26592220 TI - Electromyographic activity of rectus abdominis muscles during dynamic Pilates abdominal exercises. AB - OBJECTIVE: To assess the electrical behaviour of the upper rectus abdominis (URA) and lower rectus abdominis (LRA) by electromyography (EMG) during the following dynamic Pilates abdominal exercises: roll up, double leg stretch, coordination, crisscross and foot work. The results were compared with EMG findings of traditional abdominal exercises (sit up and crunch). METHODS: Seventeen female subjects (with no experience of the Pilates method) were recruited. The URA and LRA were evaluated while 12 isotonic contractions were performed using the Pilates principles or traditional abdominal exercises. The data were normalised by a maximal voluntary isometric contraction. Normality was accepted, and ANOVA followed by Tukey test was used to determine data differences (P < 0.05). RESULTS: Pilates exercises double leg stretch, coordination, crisscross and foot work promoted greater muscle activation than traditional exercises, mainly in URA. Thus, these exercises have the potential to be prescribed for muscle strengthening programmes. PMID- 26592221 TI - Pilates versus general exercise effectiveness on pain and functionality in non specific chronic low back pain subjects. AB - Low back pain (LBP) is one of the most common causes of disability, and the Pilates method has been associated with improvements in symptoms. The purpose of this study was to assess the effectiveness of the Pilates method, when compared to general exercises, on pain and functionality after eight weeks (16 sessions, 2*/week) and a follow-up of three months, in subjects with non-specific chronic low back pain (NSCLBP). A randomised controlled trial composed of 22 subjects was proposed. Subjects were allocated into two groups: the Pilates group (PG) (n = 11) and the general exercise group (GEG) (n = 11). The PG protocol was based on the Pilates method and the GEG performed exercises to manage NSCLBP. There were no differences between the groups. When analysed over time, the GEG demonstrated improvements in functionality between baseline and the end of treatment (P = .02; Cohen'sd- = 0.34) and baseline and follow-up (P = .04; Cohen'sd- = 0.31). There were no differences between the Pilates and general exercises with regard to pain and functionality in NSCLBP subjects but general exercises were better than Pilates for increasing functionality and flexibility. PMID- 26592222 TI - Effects of strength and balance training on the mobility, fear of falling and grip strength of elderly female fallers. AB - The aim of this study was to evaluate the effects of virtual reality and strength training on the balance, fear of falling and handgrip strength of older women with a history of falls. The fear of falling, mobility and grip strength were evaluated in 11 elderly fallers (72.4 +/- 5.2 years). The faller group was submitted to 12 weeks of virtual reality and muscle strength training. The results showed improvement in mobility (p = 0.0004) and in the fear of falling (p = 0.002). No significant difference was observed for hand grip strength. It can be concluded that virtual reality and muscle strength interventions are beneficial for mobility and fear of falling in older women with a history of falls. PMID- 26592223 TI - Characterization of chronic pain in breast cancer survivors using the McGill Pain Questionnaire. AB - The aim of the present study was to characterize pain in breast cancer survivors using the McGill Pain Questionnaire (MPQ). A descriptive, cross-sectional study was conducted with 30 women aged 30-80 years who had been submitted to treatment for breast cancer (surgery and complementary treatment) at least 12 months earlier with reports of pain related to the therapeutic procedures. Pain was characterized using the full-length version of the MPQ, which is made up of 78 descriptors divided into four categories: sensory (ten items), affective (five items), evaluative (one item) and miscellaneous (four items). Two indices were also used to measure pain through the use of the descriptors: the number of words chosen (NWC) and the pain rating index (PRI). The most frequent descriptive terms were "agonizing" (n = 16; 53.3%), "tugging" (n = 15; 50%), "sore" (n = 14; 46.7%), "wretched" (n = 14; 46.7%), "troublesome" (n = 13; 43.3%) and "spreading" (n = 11; 36.7%). The sensory category had the highest PRI value based on the descriptors chosen (mean: 0.41). Women with chronic pain following treatment for breast cancer employed the "agonizing", "tugging" and "sore" descriptors with greatest frequency and rated pain in the sensory category as having the greatest impact. PMID- 26592224 TI - Functional Knee Extension Test (FKET): Inter-rater palpatory agreement and visual analysis during a non-weight bearing functional assessment of the knee. AB - OBJECTIVE: The purpose of this study was to evaluate the inter-rater reliability of the Functional Knee Extension Test (FKET), a non-weight bearing functional assessment of the knee that is utilized within clinical practice. METHODS: The design was a single-session, test-retest reliability study. Active knee extension was assessed and documented by each examiner for each of the visual, palpatory and vastus medialis obliqus (VMO) components of the FKET on fifty-seven healthcare professionals. RESULTS: The Kappa (kappa) statistic for the inter rater reliability for the visual, palpatory and VMO variables of the FKET were slight-to-fair (0.13-0.26), fair-to-moderate (0.39-0.50), and moderate-to-almost perfect (0.57-0.93) reliability, respectively. The p-values for all variables, besides 'Visual RIGHT: TibTubExt' and 'Visual LEFT: TibTubExt' indicated statistically significant evidence of agreement above random guessing. Estimates for kappa on the 'VMO Quantity: No contact' and 'VMO Timing: Start then stop' variables could not be calculated as ratings only existed across one row of the crosstabulation. CONCLUSION: This study demonstrated that the palpatory and VMO components of the FKET have sufficient reliability to justify utilization within clinical practice. Future research is needed to determine whether the implementation of a functional knee assessment protocol, including the FKET could enhance levels of reliability in clinical decision-making of knee function. PMID- 26592225 TI - The Torsional Upper Crossed Syndrome: A multi-planar update to Janda's model, with a case series introduction of the mid-pectoral fascial lesion as an associated etiological factor. AB - The Upper Crossed Syndrome (UCS) was presented by Janda to introduce neuromotor aspects of upper body muscle imbalances, describing sagittal plane postural asymmetries as barriers to recovery from chronic locomotor system pain syndromes. The UCS describes muscle imbalances of key antagonists causing forward postures of the head and shoulders and associated changes in the spinal curves particularly an increased thoracic kyphosis - as well as changed function in the shoulder girdle. The role of fascial tissue has gained remarkable interest over the past decade, previously emphasizing its anatomic compartmental and binding role, while more recently emphasizing load transfer, sensory and kinetic chain function. The authors introduce the Mid-Pectoral Fascial Lesion (MPFL) as a myofascial disorder, describing 11 ipsilateral chest wall cases. While managing these cases, the authors encountered and subsequently designated the Torsional Upper Crossed Syndrome (TUCS) as a multi-planar addition to Janda's classic sagittal plane model. This article integrates published updates regarding the role of posture and fascia with the effects of chest wall trauma and a newly described associated postural syndrome as illustrated with this case series. An effective therapeutic approach to release the MPFL is then briefly described. PMID- 26592226 TI - Acute effects of instrument assisted soft tissue mobilization vs. foam rolling on knee and hip range of motion in soccer players. AB - The aim of the present investigation was to evaluate the acute effects of foam rolling (FR) and a new form of instrument-assisted soft tissue mobilization (IASTM), Fascial Abrasion Technique TM (FAT) on hip and knee range of motion in soccer players. Twenty male soccer players randomly allocated into FR and FAT group (n = 10 each). Passive knee flexion and straight leg raise tests were measured before, immediately after and 24 h after intervention (FR or FAT). The FR group applied a 2-min quadriceps and hamstrings rolling, while FAT group received a 2-min application of FAT to the quadriceps and hamstrings muscles. Both groups significantly improved knee and hip ROM (p < 0.05), with higher gains observed in FAT group (10-19% vs. 5-9%). At 24 h post-treatment, only FAT group preserved most of the gains in ROM (7-13%; p < 0.05). These results support the use of the newly developed IASMT, Fascial Abrasion Technique TM and FR for increasing lower extremity ROM of athletes. PMID- 26592227 TI - "But we're infinitely more complex than a car": A systems approach to health & performance. PMID- 26592228 TI - The over-pronated foot - A new paradigm. PMID- 26592229 TI - Correlation between neck slope angle and deep cervical flexor muscle thickness in healthy participants. AB - The purpose of this study was to clarify the correlation between neck slope angle and deep cervical flexor muscle thickness in healthy subjects. Forty-two healthy male (20.7 +/- 2.6 years old) participated in this study. Neck slope angle was measured in a relaxed sitting posture. The deep cervical flexor muscle thickness was measured in a relaxed supine posture. The correlations between neck slope angle and normalized muscle thickness relative to body mass index were determined using Pearson's correlation coefficient. There was a moderate positive correlation between neck slope angle and normalized muscle thickness (r = 0.414, P = 0.006). The result demonstrated that participants with lower neck slope angles had smaller muscle thicknesses of the deep cervical flexor muscles. It appears that the deep cervical flexor muscle thickness might be associated with neck slope angle in a relaxed sitting posture. PMID- 26592230 TI - The effect of motor control and tactile acuity training on patients with non specific low back pain and movement control impairment. AB - BACKGROUND: Movement control impairment is a clinical subgroup of non-specific low back pain which can be assessed reliably. There is a strong correlation between tactile acuity and movement control suggesting these two treatments might have additive effects. The first research aim was to determine if patients with a motor control impairment demonstrated improvement in outcome with combined tactile acuity and motor control training. The second aim was to determine if tactile acuity training enhanced the effect of motor control training. METHOD: The primary study was a single-arm cohort study conducted in three physiotherapy practices in the German-speaking part of Switzerland. 40 patients (23 males and 17 females) suffering from non-specific low back pain (NSLBP) and movement control impairment were treated. Patients were assessed at baseline and immediately post treatment. Treatment included exercises to lumbopelvic control and graphesthesia training to improve tactile acuity. Treatment effects were evaluated using the Roland Morris disability questionnaire (RMQ) and the patient specific functional scale (PSFS). The performance on a set of six movement control tests and lumbar two-point discrimination were also assessed. The results of this cohort study were compared with a historic control group which was comparable with the primary study but included only motor control exercises. RESULTS: All the outcomes improved significantly with the combined training (RMQ 2.2 pts., PSFS - 2.8 pts.; MCTB - 2.02 pts. & TPD - 17.07 mm; all p < 0.05). In comparison to the outcomes of the historic control, there was no significant differences in movement control, patient-specific functional complaints or disability between the groups. CONCLUSIONS: The results of this study, based on a before and after intervention comparison, showed that outcome improved significantly following combined tactile acuity and motor control training. However, compared to an earlier study, the tactile acuity training did not have an additional effect to the results. The use of historical controls does not control for allocation bias and the results obtained here require verification in a randomized controlled trial. PMID- 26592231 TI - Learning the Single Leg Dead Lift. PMID- 26592232 TI - A critical overview of the current myofascial pain literature - October 2015. AB - The number of publications about myofascial pain and trigger points (TrP) seems to increase every year. In the current overview we include 27 articles published in past months. The Basic Review section includes articles about the presence and characteristics of TrPs in various neck and shoulder muscles, the correlation between referred pain from active TrPs and knee osteoarthritis, and an anatomical study exploring whether the location of TrPs may be related to the nerve innervation of muscles. Zuil-Escobar and colleagues from Spain considered the intra-rater reliability of the identification of latent TrPs in several leg muscles and the possible correlation of TrP and the presence of a lower medial longitudinal arch. In the section on manual approaches, contributing author Rob Grieve and colleagues continue their studies of TrPs in the lower extremity muscles, while Mendez-Rebolledo and colleagues studied the impact of cross taping and compression. Dry needling (DN) continues to be a topic of interest. We included twelve papers addressing a wide range of topics, such as the effectiveness and safety of DN, and the impact of DN on proprioception, spasticity, and fibromyalgia. Two papers investigated the utilization of repetitive transcranial magnetic stimulation and laser on TrPs, The final section on other clinical studies and reviews includes 8 papers. The studies originated in thirteen different countries with Spain leading the charts with 7 contributions to the literature, followed by Brazil with four. As we have mentioned in previous editions of this literature overview, many studies suffer from very small sample sizes, which makes it difficult to reach definitive conclusions. Nevertheless, myofascial pain continues to be a topic of interest to researchers and clinicians around the globe. PMID- 26592233 TI - Effects of self-myofascial release: A systematic review. AB - BACKGROUND: Self-myofascial release (SMFR) is a type of myofascial release performed by the individual themselves rather than by a clinician, typically using a tool. OBJECTIVES: To review the literature regarding studies exploring acute and chronic clinical effects of SMFR. METHODS: PubMed and Google Scholar databases were searched during February 2015 for studies containing words related to the topic of SMFR. RESULTS: Acutely, SMFR seems to increase flexibility and reduce muscle soreness but does not impede athletic performance. It may lead to improved arterial function, improved vascular endothelial function, and increased parasympathetic nervous system activity acutely, which could be useful in recovery. There is conflicting evidence whether SMFR can improve flexibility long term. CONCLUSION: SMFR appears to have a range of potentially valuable effects for both athletes and the general population, including increasing flexibility and enhancing recovery. PMID- 26592234 TI - Compliance of patients wearing an orthotic device or orthopedic shoes: A systematic review. AB - BACKGROUND: Alongside the positive effects of use of orthotic devices for the lower extremities (ODLE) and orthopedic shoes, complaints and criticism by users possibly lead to non-compliance. OBJECTIVE: The purpose is to determine the compliance of patients wearing an ODLE or orthopedic shoes and to describe the main reasons for using and not using. METHODS: Different online databases were searched for articles about patients' compliance with regard to an ODLE or orthopedic shoes. A methodological quality control was conducted. RESULTS: Ten studies (1576 patients) were included. The data revealed between 6 and 80% not users. Several reasons for not using the orthotic device were described (e.g. pain, discomfort and cosmetically unacceptable). CONCLUSIONS: The high percentage of patients who are not wearing the prescribed orthotic devices leads to a high financial loss for society and a waste of therapeutic effort. These results should be taken into account during the design, construction and selection process of orthotic devices. PMID- 26592235 TI - Distal regulatory element of the STAT1 gene potentially mediates positive feedback control of STAT1 expression. AB - We previously identified a distal regulatory element located approximately 5.5-kb upstream of the signal transducer and activator of transcription 1 (STAT1) gene, thereafter designating it as 5.5-kb upstream regulatory region (5.5URR). In this study, we investigated the functional roles of 5.5URR in the transcriptional regulation of STAT1 gene. A chromosome conformation capture assay indicated physical interaction of 5.5URR with the STAT1 core promoter. In luciferase reporter assays, 5.5URR-combined STAT1 core promoter exhibited significant increase in reporter activity enhanced by forced STAT1 expression or interferon (IFN) treatment, but STAT1 core promoter alone did not. The 5.5URR contained IFN stimulated response element and GAS sites, which bound STAT1 complexes in electrophoretic mobility shift assays. Consistently, chromatin immunoprecipitation (ChIP) assays of HEK293 cells with Halo-tagged STAT1 expression indicated the association of Halo-tagged STAT1 with 5.5URR. ChIP assays with IFN treatment demonstrated that IFNs promoted the recruitment of Halo tagged STAT1 to 5.5URR. Forced STAT1 expression or IFN treatment increased the expression of endogenous STAT1 and other IFN signaling pathway components, such as STAT2, IRF9 and IRF1, besides IFN-responsive genes. Collectively, the results suggest that 5.5URR may provide a regulatory platform for positive feedback control of STAT1 expression possibly to amplify or sustain the intracellular IFN signals. PMID- 26592236 TI - Spontaneous instabilities and stick-slip motion in a generalized Hebraud-Lequeux model. AB - We revisit the Hebraud-Lequeux (HL) model for the rheology of jammed materials and argue that a possibly important time scale is missing from HL's initial specification. We show that our generalization of the HL model undergoes interesting oscillating instabilities for a wide range of parameters, which lead to intermittent, stick-slip flows under constant shear rate. The instability we find is akin to the synchronization transition of coupled elements that arises in many different contexts (neurons, fireflies, financial bankruptcies, etc.). We hope that our scenario could shed light on the commonly observed intermittent, serrated flows of glassy materials under shear. PMID- 26592238 TI - Risk of left atrial appendage thrombus in patients scheduled for ablation for atrial fibrillation: beyond the CHA2DS2VASc score. AB - INTRODUCTION: Atrial fibrillation (AF) increases the risk of thromboembolic events by promoting clot formation in the left atrial appendage (LAA). Transesophageal echocardiography (TEE) is routinely used to exclude the presence of an LAA thrombus before AF ablation. So far, it has not been established what is the optimal combination of noninvasive parameters for thromboembolic risk stratification in this setting and whether patients at very low risk require TEE. OBJECTIVES: The aim of the study was to assess predisposing factors for an LAA thrombus in patients scheduled for AF ablation and to identify those patients in whom preprocedural TEE is not necessary. PATIENTS AND METHODS: In consecutive 151 patients (107 men; mean age, 57 +/-10 years) the type of AF and renal function were assessed in addition to the CHA2DS2VASc score to improve thromboembolic risk stratification. RESULTS: An LAA thrombus or dense echo contrast with a strong suspicion of a probable thrombus was detected in 15 patients (10%). Diabetes, age of 65 years or older, persistent AF, and estimated glomerular filtration rate (eGFR) of less than 60 ml/min/1.73 m2 were predictors of the LAA thrombus. A multivariate logistic regression analysis showed that only persistent AF and an eGFR of less than 60 ml/min/1.73 m2 were independent predictors of the LAA thrombus. The receiver operating characteristic curves showed that the greatest area under the curve (0.845) was achieved for the CHA2DS2VASc-AFR (CHA2DS2VASc plus the type of AF and renal function); the difference was not significant. A CHA2DS2VASc-AFR score of 2 or greater or a CHA2DS2VASc score of 1 or greater identified patients with the LAA thrombus with a sensitivity of 100% (and specificity of 54% and 36%, respectively). CONCLUSIONS: In patients scheduled for AF ablation, an LAA thrombus or dense echo contrast is a relatively common finding despite routine anticoagulant treatment. The addition of AF type and renal function to the CHA2DS2VASc score slightly improves thromboembolic risk stratification and may help identify patients who do not need preprocedural TEE. PMID- 26592237 TI - P16-specific DNA methylation by engineered zinc finger methyltransferase inactivates gene transcription and promotes cancer metastasis. AB - BACKGROUND: P16 DNA methylation is well known to be the most frequent event in cancer development. It has been reported that genetic inactivation of P16 drives cancer growth and metastasis, however, whether P16 DNA methylation is truly a driver in cancer metastasis remains unknown. RESULTS: A P16-specific DNA methyltransferase (P16-dnmt) expression vector is designed using a P16 promoter specific engineered zinc finger protein fused with the catalytic domain of dnmt3a. P16-dnmt transfection significantly decreases P16 promoter activity, induces complete methylation of P16 CpG islands, and inactivates P16 transcription in the HEK293T cell line. The P16-Dnmt coding fragment is integrated into an expression controllable vector and used to induce P16-specific DNA methylation in GES-1 and BGC823 cell lines. Transwell assays show enhanced migration and invasion of these cancer cells following P16-specific DNA methylation. Such effects are not observed in the P16 mutant A549 cell line. These results are confirmed using an experimental mouse pneumonic metastasis model. Moreover, enforced overexpression of P16 in these cells reverses the migration phenotype. Increased levels of RB phosphorylation and NFkappaB subunit P65 expression are also seen following P16-specific methylation and might further contribute to cancer metastasis. CONCLUSION: P16 methylation could directly inactivate gene transcription and drive cancer metastasis. PMID- 26592240 TI - Human mesenchymal stem cells and derived extracellular vesicles induce regulatory dendritic cells in type 1 diabetic patients. AB - AIMS/HYPOTHESIS: Mesenchymal stem cells (MSCs) can exert an immunosuppressive effect on any component of the immune system, including dendritic cells (DCs), by direct contact, the release of soluble markers and extracellular vesicles (EVs). We evaluated whether MSCs and MSC-derived EVs have an immunomodulatory effect on monocyte-derived DCs in type 1 diabetes. METHODS: Bone marrow derived MSCs were characterised and EVs were obtained by ultracentrifugation. DCs were differentiated from CD14(+) cells, obtained from nine type 1 diabetic patients at disease onset, pulsed with antigen GAD65 and cultured with MSCs or EVs. Levels of DC maturation and activation markers were evaluated by flow cytometry. GAD65 pulsed DCs and autologous CD14(-) cell were co-cultured and IFN-gamma enzyme linked immunosorbent spot responses were assayed. Secreted cytokine levels were measured and Th17 and regulatory T cells were analysed. RESULTS: MSC- and EV conditioned DCs acquired an immature phenotype with reduced levels of activation markers and increased IL-10 and IL-6 production. Conditioned DC plus T cell co cultures showed significantly decreased IFN-gamma spots and secretion levels. Moreover, higher levels of TGF-beta, IL-10 and IL-6 were detected compared with unconditioned DC plus T cell co-cultures. Conditioned DCs decreased Th17 cell numbers and IL-17 levels, and increased FOXP3(+) regulatory T cell numbers. EVs were internalised by DCs and EV-conditioned DCs exhibited a similar effect. CONCLUSIONS/INTERPRETATION: In type 1 diabetes, MSCs induce immature IL-10 secreting DCs in vitro, thus potentially intercepting the priming and amplification of autoreactive T cells in tissue inflammation. These DCs can contribute to the inhibition of inflammatory T cell responses to islet antigens and the promotion of the anti-inflammatory, regulatory responses exerted by MSCs. PMID- 26592242 TI - Is beta-catenin neutralization cross-involved in the mechanisms mediated by natalizumab action? AB - Aberrant activation of Wnt/beta-catenin signaling pathway is commonly associated to cancer development. However, molecular mechanisms controlling Wnt/beta-catenin signaling pathway have been clarified only in part. Here, we show that beta catenin is differently modulated in patients with multiple sclerosis (MS), displaying that different pharmacological treatments used for clinical MS management cause different nuclear expression levels of beta-catenin. Proteins extracted by peripheral blood mononuclear cells were assessed to evaluate the western blot expression levels of beta-catenin. Analyzing our results, we realized that beta-catenin is totally inhibited by Natalizumab and could have a role in MS management. This could offer new promising studies focused on the possible therapeutic control of beta-catenin translocation. PMID- 26592241 TI - Adipose-derived lipocalin 14 alleviates hyperglycaemia by suppressing both adipocyte glycerol efflux and hepatic gluconeogenesis in mice. AB - AIMS/HYPOTHESIS: Growing evidence supports that dysregulation of adipose tissue derived factors contributes to the pathogenesis of diabetes and its complications. Since our global gene profiling analysis has identified lipocalin 14 (LCN14)-a secretory protein with lipid-binding properties-as a potential adipokine highly expressed in white adipose tissue (WAT), this study aims to explore the metabolic roles of LCN14 in obese mice, and to investigate the functional mechanisms involved. METHODS: Immunoassays and western blotting were performed to determine the circulating level and tissue distribution of LCN14, respectively. Recombinant adeno-associated virus (rAAV)-mediated gene delivery was used to overexpress LCN14 in diet-induced obese (DIO) mice and the effects on glucose and lipid metabolism were examined. RESULTS: LCN14 is expressed predominantly in WAT. Both circulating levels of LCN14 and its expression in adipose tissues are repressed in DIO and genetically inherited diabetic (db/db) mice. Overexpression of LCN14 by rAAV-mediated gene delivery in DIO mice significantly increased insulin sensitivity in major metabolic tissues and ameliorated hyperglycaemia by inhibiting hepatic gluconeogenesis. The reduced hepatic glucose production is attributed to the suppressive effects of LCN14 on the expression of gluconeogenic genes and on glycerol efflux in adipocytes, possibly by reducing the expression of aquaporin-7. CONCLUSIONS/INTERPRETATION: Reduced LCN14 expression is involved in the pathogenesis of obesity-related metabolic dysregulation. LCN14 exerts its beneficial effects on glucose homeostasis and insulin sensitivity via its actions in both adipocytes and hepatocytes. PMID- 26592243 TI - The Role of miR-124 in Drosophila Alzheimer's Disease Model by Targeting Delta in Notch Signaling Pathway. AB - Alzheimer's disease (AD) is a neurodegenerative disorder which mainly affects elderly population. MicroRNAs (miRNA) are small RNA molecules that fine-tune gene expression at posttranscriptional level and exert important functions in AD. MicroRNA-124 (miR-124) is a kind of miRNA abundantly expressed in the central nervous system. It is highly conserved from Caenorhabditis elegans to humans. However, its function in AD is still elusive. In this study, we found miR-124 was significantly down-regulated in AD flies. miR-124 mutant flies showed impaired climbing ability and shortened lifespan. In contrast, miR-124 expression rescued locomotive defects of AD flies. Using microarray analysis to test gene expression profiles of miR-124 mutant flies, we found that Notch signaling pathway was potentially targeted by miR-124. Further experiments showed that miR-124 regulated Notch ligand Delta expression by acting on specific site of Delta 3'UTR. In addition, reduced Delta expression by RNA interference extended lifespan and ameliorated learning defects of AD Drosophila. Notch inhibitor DAPT could also alleviate AD phenotypes, which confirmed our findings. In conclusion, our study indicates that miR-124 plays neuroprotective roles in AD Drosophila by targeting Delta in Notch signaling pathway, which helps further our understanding of miRNAs in the molecular pathology of AD. PMID- 26592244 TI - Plasma Mitochondrial DNA Levels as a Biomarker of Lipodystrophy Among HIV infected Patients Treated with Highly Active Antiretroviral Therapy (HAART). AB - Lipodystrophy is a common complication in HIV-infected patients taking highly active antiretroviral therapy. Its early diagnosis is crucial for timely modification of antiretroviral therapy. We hypothesize that mitochondrial DNA in plasma may be a potential marker of LD in HIV-infected individuals. In this study, we compared plasma mitochondrial DNA levels in HIV-infected individuals and non-HIV-infected individuals to investigate its potential diagnostic value. Total plasma DNA was extracted from 67 HIV-infected patients at baseline and 12, 24 and 30 months after initiating antiretroviral therapy. Real-time quantitative PCR was used to determine the mitochondrial DNA levels in plasma. Lipodystrophy was defined by the physician-assessed presence of lipoatrophy or lipohypertrophy in one or more body regions. The mitochondrial DNA levels in plasma were significantly higher at baseline in HIV-infected individuals than in non-HIV infected individuals (p<0.05). At month 30, 33 out of 67 patients (49.2%) showed at least one sign of lipodystrophy. The mean plasma mitochondrial DNA levels in lipodystrophy patients were significantly higher compared to those without lipodystrophy at month 24 (p<0.001). The receiver operating curve analysis demonstrated that using plasma mitochondrial DNA level (with cut-off value <5.09 log10 copies/ml) as a molecular marker allowed identification of patients with lipodystrophy with a sensitivity of 64.2% and a specificity of 73.0%. Our data suggest that mitochondrial DNA levels may help to guide therapy selection with regards to HIV lipodystrophy risk. PMID- 26592245 TI - Gene Microarray Analyses of Daboia russelli russelli Daboiatoxin Treatment of THP 1 Human Macrophages Infected with Burkholderia pseudomallei. AB - Burkholderia pseudomallei is the causative agent of melioidosis and represents a potential bioterrorism threat. In this study, the transcriptomic responses of B. pseudomallei infection of a human macrophage cell model were investigated using whole-genome microarrays. Gene expression profiles were compared between infected THP-1 human monocytic leukemia cells with or without treatment with Daboia russelli russelli daboiatoxin (DRRDbTx) or ceftazidime (antibiotic control). Microarray analyses of infected and treated cells revealed differential upregulation of various inflammatory genes such as interleukin-1 (IL-1), IL-6, tumor necrosis factor-alpha (TNF-alpha), cyclooxygenase (COX-2), vascular endothelial growth factor (VEGF), chemokine C-X-C motif ligand 4 (CXCL4), transcription factor p65 (NF-kB); and several genes involved in immune and stress responses, cell cycle, and lipid metabolism. Moreover, following DRR-DbTx treatment of infected cells, there was enhanced expression of the tolllike receptor 2 (TLR-2) mediated signaling pathway involved in recognition and initiation of acute inflammatory responses. Importantly, we observed that highly inflammatory cytokine gene responses were similar in infected cells exposed to DRR-DbTx or ceftazidime after 24 h. Additionally, there were increased transcripts associated with cell death by caspase activation that can promote host tissue injury. In summary, the transcriptional responses during B. pseudomallei infection of macrophages highlight a broad range of innate immune mechanisms that are activated within 24 h post-infection. These data provide insights into the transcriptomic kinetics following DRR-DbTx treatment of human macrophages infected with B. pseudomallei. PMID- 26592246 TI - Targeting HOTAIR Induces Mitochondria Related Apoptosis and Inhibits Tumor Growth in Head and Neck Squamous Cell Carcinoma in vitro and in vivo. AB - Homeobox (HOX) transcript antisense RNA (HOTAIR), a long nuclear-retained noncoding RNA (lncRNA), is overexpressed in a variety of human cancers. Increasing evidence shows that HOTAIR plays a vital role in cancer initiation and progression by affecting cell cycle progress, apoptosis and invasion. However, whether HOTAIR serves as a target of therapeutic potential and the underlying mechanism in head and neck squamous cell carcinoma (HNSCC) is still unclear. Thus, we employed a HOTAIR specific siRNA to deplete its expression in two human HNSCC cell lines, Tca8113 and Tscca. The flow cytometry (FCM) analysis showed that HOTAIR depletion induced tumor cell apoptosis in vitro. JC-1 probe examination showed that the mitochondrial membrane potential was changed significantly by HOTAIR blockage. Mitochondrial calcium uptake 1(MICU1) dependent cell death was induced by HOTAIR depletion. Protein expression analysis indicated that mitochondrial related cell death pathway (Bcl-2, BAX, Caspase-3, Cleaved Caspase-3, Cytochrome c) involved in HOTAIR dependent apoptosis process. Moreover, a Tscca derived xenograft tumor model was employed to further validate that injection of HOTAIR siRNA inhibited tumor growth. In summary, we suggested that HOTAIR inhibition could be developed as a new therapeutic in HNSCC treatments. PMID- 26592248 TI - Beyond Lipoprotein Receptors: Learning from Receptor Knockouts Mouse Models about New Targets for Reduction of the Atherosclerotic Plaque. AB - Atherosclerosis and its complications represent the leading death cause worldwide, despite many therapeutic developments. Atherosclerosis is a complex, multistage disease whereby perturbed lipid metabolism leads to cholesterol accumulation into the vascular walls and plaque formation. Generation of apoE-/- and LDLR-/- atherosclerosis mouse models opened the avenue for investigating the mechanisms of action for specific molecules. We focus herein on the involvement of non-lipoprotein receptors in atherogenesis, as revealed by their total or site specific ablation in the aforementioned murine models. The receptors reviewed span a broad range, from molecules related to lipid metabolism (adiponectin receptors) to molecules whose connection with atherogenesis is less obvious (cannabinoid receptors). We also outline cross-transplantation studies which allowed uncoupling the lipid modulating effects from the inflammatory ones. For certain receptors, since knockouts were unavailable, pharmacological data are presented instead. We emphasize the contribution of the receptors to the pathology, based on functional criteria, such as oxidative stress, immune response, inflammation, angiogenesis. Controversial aspects regarding the pro- or anti- atherogenic activity of some receptors are highlighted. We assume these discrepancies are due to the experimental setup, animal models used, tissue specific action, various isoforms analyzed, divergent signaling or cross-talk between metabolic and immune pathways. Understanding the influences of cellular receptors in the progression of atherosclerosis allows their modulation towards an antiatherogenic phenotype. The experimental studies in animal models were in some cases successfully extrapolated to humans leading to atheroma reduction, and we expect this to occur even to a greater extent, based on the newest achievements. PMID- 26592247 TI - Regulation of Eye Development by Protein Serine/Threonine Phosphatases-1 and -2A. AB - The protein serine/threonine phosphatases-1 and -2A are major cellular phosphatases, playing a fundamental role in organisms from prokaryotes to eukaryotes. They contribute to 90% dephosphorylation in eukaryote proteins. In the eye, both phosphatases are highly expressed and display important functions in regulating normal eye development. Moreover, they are implicated in pathogenesis through modulation of stress-induced apoptosis. Here we review the recent progresses on these aspects. PMID- 26592249 TI - Fibroblast Growth Factor-Inducible 14: Multiple Roles in Tumor Metastasis. AB - Metastasis, the main cause of mortality in cancer patients, is a complex process consisting of several sequential, interlinked, and highly-selective steps. Fibroblast growth factor-inducible 14 (Fn14) is one member of the tumor necrosis factor receptor family, which is influential in controlling cell division, life, and death. The role of Fn14 in tumor metastasis regulation is slowly being unraveled, including roles in the regulation of the epithelial-mesenchymal transition, angiogenesis, cytoskeleton modulation, extracellular matrix degradation and inflammation. This review will focus on recent studies that demonstrate the involvement of Fn14 in tumor progression and will briefly describe various pathways of Fn14-regulated metastasis. Finally, future prospects will be discussed for the potential role of Fn14 as a predictive marker and therapeutic agent for tumor metastasis suppression. PMID- 26592250 TI - Extracellular Citrate in Health and Disease. AB - Citrate is one of the major substrates for intracellular metabolism. The extracellular level of citrate is stable in blood but varies locally, with slightly increased levels in brain and high levels in prostate. Recent metabolomics research suggests that citrate level is a potential harbinger of different pathophysiological states; its decrease has been correlated with male infertility, brain diseases and metastatic cancer. In this review we discuss the role of citrate as an energy substrate for sperm. We also review the function of citrate released by astrocytes in the normal operation of neurons, and consequently we suggest a potential role of neuronal plasma membrane citrate transporters in mental disorders. Finally, we review recent relevant publications studying blood, urine and tissue citrate levels in cancer patients and hypothesize that extracellular citrate supports cancer cell metabolism critical for metastasis. Despite the importance of extracellular citrate in physiological and pathophysiological processes, surprisingly little is known about citrate synthesis in specialized cells, or about citrate transporters controlling citrate movement across various membranes. Determination of the molecular origin of citrate transporters in astrocytes, sperm and cancer cells could offer novel therapeutic targets and the possibility to pharmacologically regulate citrate release and uptake for preventing male infertility, treating mental diseases and targeting cancer. PMID- 26592251 TI - Downregulation of betaine homocysteine methyltransferase (BHMT) in hepatocellular carcinoma associates with poor prognosis. AB - Betaine homocysteine methyltransferase (BHMT) catalyzes the synthesis of methionine using betaine and homocysteine (Hcy), which is restricted to the liver and kidney. Impaired BHMT pathway has been associated with hepatocellular carcinogenesis in Bhmt-/- mice model, and decreased BHMT was observed in a small sample of human hepatocellular carcinoma (HCC) patients. However, the prognostic significance of BHMT in HCC has not been elucidated. This study aimed to examine the expression of BHMT in HCC and investigate the relationship between its expression and prognosis of HCC patients. BHMT expression was analyzed in 68 paired HCC samples (HCC tissues vs matched adjacent non-cancerous liver tissues), 115 paraffin-embedded HCC sections (primary cohort), and 65 paraffin-embedded HCC sections (validation cohort) using immunohistochemistry (IHC). The results of IHC analysis showed that BHMT was decreased in tumorous tissues in 85.2 % (58/68) of cases compared to the corresponding adjacent non-tumorous liver tissues. Further correlation analyses indicated that the decreased BHMT expression was closely correlated with serum alpha-fetoprotein (AFP) (p = 0.011), tumor size (p = 0.039), and vascular invasion (p = 0.017). Moreover, HCC patients with low BHMT expression had shorter overall survival (OS) and time to recurrence (TTR) than those with high BHMT expression in both primary cohort (p < 0.0001) and validation cohort (p < 0.05) assessed by the Kaplan-Meier method. In addition, multivariate analysis showed that BHMT was an independent prognostic factor for OS and TTR in the two cohorts (all p < 0.005). Collectively, our study demonstrated that BHMT could be served as a potential prognostic marker for HCC patients. PMID- 26592252 TI - EZH2 mediates ATO-induced apoptosis in acute myeloid leukemia cell lines through the Wnt signaling pathway. AB - In this study, we examined the mechanisms associated with EZH2 mediation of apoptosis and chemoresistance to arsenic trioxide (ATO) in acute myeloid leukemia (AML) cell lines through the Wnt/beta-catenin signaling pathway. The induction of spontaneous apoptosis observed in multiple EZH2-silenced leukemic cell lines was assessed by flow cytometry, and levels of Wnt/beta-catenin-related expression were determined by western blot analysis. In comparison with AML control cells, EZH2-knockdown cells exhibited increased apoptosis and significant downregulation of beta-catenin expression, as well as decreases in GSK-3beta phosphorylation and beta-catenin activation (p < 0.05 for all measurements). Additionally, EZH2 knockdown sensitized AML cells to induced cell death following administration of chemotherapeutic ATO. Our results suggested that EZH2 in leukemic cell lines might inhibit ATO-induced apoptosis and that EZH2 may be a potential therapeutic target in AML patients undergoing ATO treatment. Our findings provide new insights into the role of ATO and EZH2 in regulating AML progression. PMID- 26592253 TI - Unusual placement of intrathecal baclofen pumps: report of two cases. AB - Intrathecal baclofen delivery via implantable pump represents an important modality for symptomatic relief in patients with chronic spasticity. Pumps are routinely implanted subcutaneously in the anterior abdominal wall. We describe two unusual cases where skin-related complications necessitated revision surgery in order to relocate the pump to alternative sites. The first patient was an international power canoeist, whose strenuous exercise programme interfered with his pump's original siting. The second patient was a cachectic university student with a history of cerebral palsy, who maintained low body mass despite attempted weight gain. The relocation of these two intrathecal devices to the medial compartment of the right thigh and right iliac fossa, respectively, is described. PMID- 26592254 TI - Gene-activated fat grafts for the repair of spinal cord injury: a pilot study. AB - BACKGROUND: Spinal cord injury (SCI) is a complex disease requiring a concerted multi-target approach. The most appropriate combination of therapeutic gene, cellular vehicle, and space filling scaffold still has to be determined. We present an approach that employs syngeneic adipose tissue serving as a three dimensional biological implant, source of progenitor cells, and delivery system for therapeutic genes. In this pilot experiment, we evaluated the feasibility and short-term effects using gene-activated autologous fat grafts after SCI. METHODS: An experimental SCI model was established in syngeneic Fischer 344 rats by a T9 T10 hemimyelonectomy. Fat tissue was harvested from two donor rats. Animals were divided into four groups and treated with either (i) fat grafts activated by an adenoviral vector carrying the human NT-3 cDNA, (ii) or BDNF, (iii) or with untreated fat grafts or (iv) remained untreated. Animals were euthanized either 7 or 21 days after surgery, and spinal cord tissue was investigated by histological and immunohistochemical methods. RESULTS: NT-3 and BDNF were produced by gene activated fat grafts for at least 21 days in vitro and in vivo. Fat tissue grafts remained stable at the site of implantation at 7 days and at 21 days. Neither BDNF-activated nor NT-3-activated fat graft had a detectable limiting effect on the neuronal degeneration. BDNF recruited microglia to perilesional site and attenuated their inflammatory response. CONCLUSIONS: Gene-activated syngeneic fat tissue serves as a three-dimensional biological material delivering therapeutic molecules to the site of SCI over an extended period of time. The BDNF-fat graft attenuated the inflammatory response. Whether these findings translate into functional recovery will require extended observation times. PMID- 26592255 TI - Iridium-Based High-Sensitivity Oxygen Sensors and Photosensitizers with Ultralong Triplet Lifetimes. AB - The photophysics of a series of bichromophoric molecules featuring an intramolecular triplet energy transfer between a triscyclometalated iridium(III) complex and covalently linked organic group are studied. By systematically varying the energy gap (0.1-0.3 eV) between the donor (metal complex) and acceptor (pyrene unit), reversible triplet energy transfer processes with equilibrium constant K ranging from ca. 500 to 40 000 are established. Unique photophysical consequences of such large K values are observed. Because of the highly imbalanced forward and backward energy transfer rates, triplet excitons dominantly populate the acceptor moiety in the steady state, giving rise to ultralong luminescence lifetimes up to 1-4 ms. Because the triscyclometalated Ir and triplet pyrene groups both impart relatively small nonradiative energy loss, decent phosphorescence quantum yields (Phi = 0.1-0.6) are attained in spite of the exceptionally prolonged excited states. By virtue of such precious combination of long-lived triplet state and high Phi, these bichromophoric molecules can serve as highly sensitive luminescent sensors for detecting trace amount of O2 and as potent photosensitizers for producing singlet oxygen even under low-oxygen content conditions. PMID- 26592256 TI - Understanding the Constitutive and Induced Biosynthesis of Mono- and Sesquiterpenes in Grapes (Vitis vinifera): A Key to Unlocking the Biochemical Secrets of Unique Grape Aroma Profiles. AB - The present review integrates current knowledge on mono- and sesquiterpenes in grapes with a special focus on biochemical and physiological aspects. Recent research has impressively shown the prominence of terpenoid metabolism in grapevine (Vitis sp). The 69 putatively functional mono- and sesquiterpene synthases that were identified by the analysis of the updated 12-fold sequencing and assembly of the grapevine genome deliver the scaffolds for structural diversity and display a surprising expansion of the terpene synthase (TPS) gene family in grapevine when compared to other plants like Arabidopsis thaliana (32 TPS). While monoterpenes occur as highly functionalized compounds and are stored as their corresponding glycoconjugates in berry tissues, sesquiterpenes are mainly present as unsaturated hydrocarbons and accumulate in the epicuticular wax layer of intact berries. Interestingly, both groups of terpenes appear to be involved as volatile organic compounds in plant defense and their biosynthesis is enhanced via the jasmonic acid signaling pathway. These novel aspects will help to understand how environmental cues affect the genes and enzymes of various metabolic pathways of relevant wine aroma compounds with numerous links to enology and wine flavor chemistry. PMID- 26592257 TI - Assembly of Mid-Nanometer-Sized Gold Particles Capped with Mixed Alkanethiolate SAMs into High-Coverage Colloidal Films. AB - We investigated the influence of the mixed n-alkanethiolate self-assembled monolayer (SAM) formed on gold nanoparticles (AuNPs: 50.0 +/- 3.2 nm in diameter) on their assembly into colloidal films. Dodecanethiol and octadecanethiol were selected as the short- and long-chain alkanethiols, respectively. The mixed SAMs were formed by immersing AuNPs in a mixed alkanethiol solution at different molar ratios. Au colloidal films were fabricated on indium tin oxide substrates by our previously reported hybrid method. The composition of the two alkanethiolates in the SAM was deduced from the intensity ratio of two Raman bands at 1080 and 1105 cm(-1). The surface coverage of the colloidal films increased by forming equimolar or dodecanethiolate-dominant mixed SAMs on AuNPs instead of a pure dodecanethiolate or octadecanethiolate SAM. The highest coverage exceeded 80%. This improvement is attributed to the high dispersion stability of AuNPs covered with equimolar or dodecanethiolate-dominant mixed SAMs. PMID- 26592258 TI - Broadband Near-Infrared to Visible Upconversion in Quantum Dot-Quantum Well Heterostructures. AB - Upconversion is a nonlinear process in which two, or more, long wavelength photons are converted to a shorter wavelength photon. It holds great promise for bioimaging, enabling spatially resolved imaging in a scattering specimen and for photovoltaic devices as a means to surpass the Shockley-Queisser efficiency limit. Here, we present dual near-infrared and visible emitting PbSe/CdSe/CdS nanocrystals able to upconvert a broad range of NIR wavelengths to visible emission at room temperature. The synthesis is a three-step process, which enables versatility and tunability of both the visible emission color and the NIR absorption edge. Using this method, one can achieve a range of desired upconverted emission peak positions with a suitable NIR band gap. PMID- 26592259 TI - Understanding the Radical Nature of an Oxidized Ruthenium Tris(thiolate) Complex and Its Role in the Chemistry. AB - The spectroscopically observable tris(thiolate) complex [Ru(dppbt)3](+) (1(+)) (dppbt = diphenylphosphinobenzenethiolate) is reported to have chemistry based on thiyl-radical character. High-level ab initio methods predict the ground-state electronic structure of 1(+) to be an open-shell diradical singlet state with antiferromagnetic coupling between (S = 1/2) Ru(III) and (S = 1/2) S pz, rather the previous description based on a diradical state involving two S p orbitals. These new results provide an improved understanding of the experimental chemistry of 1(+) and related species. PMID- 26592260 TI - [FAAF](-) (A = O, S, Se, Te) or How Electrostatic Interactions Influence the Nature of the Chemical Bond. AB - The present contribution analyzes the special bonding situation of the [FAAF](-) anions (A = O, S, Se, Te), where the addition on an extra charge turns the covalent A-A bond of the neutral into a charge-shift (CS) bond. By means of theoretical calculations, we demonstrate that electrostatic interactions produced by negative point charges can transform the covalent A-A bond in the A2(+) cation into a CS one. Consequently, the electric field created by the fluorine atoms can be behind the unusual bonding situation of [FAAF](-), showing how electrostatic interactions can influence and alter the nature of the chemical bond. PMID- 26592261 TI - Designing the Redox-Driven Switching of Ferro- to Antiferromagnetic Couplings in Organic Diradicals. AB - Switching of the magnetic exchange coupling from ferro- to antiferromagnetic or vice versa in a single molecule is an appealing but rarely occurring phenomenon in molecular magnetism. Here, we report this for an unprecedented pure organic system, computationally designed by tailoring a conformationally restricted, known nitroxide-diradical (Rajca et al. J. Am. Chem. Soc. 2007, 129, 10159). This ferro- to antiferromagnetic coupling switching of an "m-phenylene" based diradical is governed by a stereoelectronic effect and controlled by a redox driven chemical reaction. PMID- 26592262 TI - Quantum Trajectory-Electronic Structure Approach for Exploring Nuclear Effects in the Dynamics of Nanomaterials. AB - A massively parallel, direct quantum molecular dynamics method is described. The method combines a quantum trajectory (QT) representation of the nuclear wave function discretized into an ensemble of trajectories with an electronic structure (ES) description of electrons, namely using the density functional tight binding (DFTB) theory. Quantum nuclear effects are included into the dynamics of the nuclei via quantum corrections to the classical forces. To reduce computational cost and increase numerical accuracy, the quantum corrections to dynamics resulting from localization of the nuclear wave function are computed approximately and included into selected degrees of freedom representing light particles where the quantum effects are expected to be the most pronounced. A massively parallel implementation, based on the message passing interface allows for efficient simulations of ensembles of thousands of trajectories at once. The QTES-DFTB dynamics approach is employed to study the role of quantum nuclear effects on the interaction of hydrogen with a model graphene sheet, revealing that neglect of nuclear effects can lead to an overestimation of adsorption. PMID- 26592263 TI - Passive Membrane Permeability: Beyond the Standard Solubility-Diffusion Model. AB - The spontaneous diffusion of solutes through lipid bilayers is still a challenge for theoretical predictions. Since permeation processes remain beyond the capabilities of unbiased molecular dynamics simulations, an alternative strategy is currently adopted to gain insight into their mechanism and time scale. This is based on a monodimensional description of the translocation process only in terms of the position of the solute along the normal to the lipid bilayer, which is formally expressed in the solubility-diffusion model. Actually, a role of orientational and conformational motions has been pointed out, and the use of advanced simulation techniques has been proposed to take into account their effect. Here, we discuss the limitations of the standard solubility-diffusion approach and propose a more general description of membrane translocation as a diffusion process on a free energy surface, which is a function of the translational and rotational degrees of freedom of the molecule. Simple expressions for the permeability coefficient are obtained under suitable conditions. For fast solute reorientation, the classical solubility-diffusion equation is recovered. Under the assumption that well-defined minima can be identified on the free energy landscape, a mechanistic interpretation of the permeability coefficient in terms of all possible permeation paths is given. PMID- 26592264 TI - Representability and Transferability of Kirkwood-Buff Iterative Boltzmann Inversion Models for Multicomponent Aqueous Systems. AB - We discuss the application of the Kirkwood-Buff iterative Boltzmann inversion (KB IBI) method for molecular coarse-graining (Ganguly et al. J. Chem. Theory Comput. 2012, 8, 1802) to multicomponent aqueous mixtures. Using a fixed set of effective single-site solvent-solvent potentials previously derived for binary urea-water systems, solute-solvent and solute-solute KB-IBI coarse-grained (CG) potentials have been derived for benzene in urea-water mixtures. Preferential solvation and salting-in coefficients of benzene are reproduced in quantitative agreement with the atomistic force field model. The transferability of the CG models is discussed, and it is shown that free energies of formation of hydrophobic benzene clusters obtained from simulations with the CG model are in good agreement with results obtained from all-atom simulations. The state-point representability of the CG models is discussed with respect to reproducing thermodynamic quantities such as pressure, isothermal compressibility, and preferential solvation. Combined use of KB-IBI and pressure corrections in deriving single-site CG models for pure-water, binary mixtures of urea and water, and ternary mixtures of benzene in urea-water at infinite benzene dilution provides an improved scheme to representing the atomistic pressure and the preferential solvation between the solution components. It is also found that the application of KB-IBI leads to a faster and improved convergence of the pressure and potential energy compared to the IBI method. PMID- 26592265 TI - Thermodynamical Description of a Quasi-First-Order Phase Transition from the Well Tempered Ensemble. AB - We explore the performance of the well-tempered ensemble combined with parallel tempering (PT-WTE) in obtaining a thermodynamical description of a given molecular system. We carefully explain the theoretical procedure employed to extract all the relevant thermodynamical quantities from a PT-WTE simulation. As a specific molecular system, we consider a Lennard-Jones cluster of 147 particles, which is a prototypical case of a finite-size system exhibiting a quasi-first-order phase transition, characterized by a range of temperatures where two distinct phases are thermodynamically stable and coexist. Two separate PT-WTE simulations, which investigate the thermodynamical behavior on different levels of detail, give equally accurate descriptions of the critical phase coexistence region, indicating the good quality of the PT-WTE results. The positive performance observed here clearly demonstrates that the PT-WTE approach is an effective option when thermodynamical properties are needed. PMID- 26592266 TI - Behavior of the Position-Spread Tensor in Diatomic Systems. AB - The behavior of the Position-Spread Tensor (Lambda) in a series of light diatomic molecules (either neutral or negative ions) is investigated at a Full Configuration Interaction level. This tensor, which is the second moment cumulant of the total position operator, is invariant with respect to molecular translations, while its trace is also rotationally invariant. Moreover, the tensor is additive in the case of noninteracting subsystems and can be seen as an intrinsic property of a molecule. In the present work, it is shown that the longitudinal component of the tensor, Lambda?, which is small for internuclear distances close to the equilibrium, tends to grow if the bond is stretched. A maximum is reached in the region of the bond breaking, then Lambda? decreases and converges toward the isolated-atom value. The degenerate transversal components, Lambda?, on the other hand, usually have a monotonic growth toward the atomic value. The Position Spread is extremely sensitive to reorganization of the molecular wave function, and it becomes larger in the case of an increase of the electron mobility, as illustrated by the neutral-ionic avoided crossing in LiF. For these reasons, the Position Spread can be an extremely useful property that characterizes the nature of the wave function in a molecular system. PMID- 26592267 TI - Off-Center Gaussian Functions, an Alternative Atomic Orbital Basis Set for Accurate Noncovalent Interaction Calculations of Large Systems. AB - Proper description of noncovalent interactions requires, among other things, the use of diffuse atomic orbital (AO) basis sets. However, the presence of diffuse functions, especially in extended molecular systems, can lead to linear dependent AO basis sets. This in turn results, for example, in molecular orbital optimization problems or, when dependencies are removed in unpredictable and possibly geometry-dependent accuracy fluctuations. In this work, an alternative approach is proposed which suffers no linear dependence problems and delivers comparably accurate noncovalent interaction energies. An algorithm is proposed and implemented to construct a grid of off-center s-type Gaussian functions surrounding the molecule; substituting the presence of atom-centered diffuse basis functions. While the number of basis functions in the grid is comparable to the number of diffuse basis functions in aug-cc-pVXZ (for each cardinality number "X") basis sets for small molecular systems, the ratio becomes more favorable with increasing system size. The grid is constructed in a way that it is unique for a molecule (monomer) and, thus, independent of noncovalent complex/cluster geometry. The grid parameters, such as the density of grid points and s-function exponents, are obtained via optimization toward the S22 data set on the MP2 level. The quality, transferability, and versatility of the grid is tested on the S66 data set as well as on several cuts through the potential energy surface for noncovalent complexes, such as methyl-guanine...methyl-cytosine conversion from stacked to hydrogen-bonded structure. PMID- 26592268 TI - Nuclear Velocity Perturbation Theory of Vibrational Circular Dichroism. AB - We report the first implementation of vibrational circular dichroism (VCD) within density functional theory (DFT) using the nuclear velocity perturbation (NVP) theory. In order to support VCD calculations in large-scale systems such as solvated (bio)molecules and supramolecular assemblies, we have chosen a plane wave electronic structure code (CPMD). This implementation allows the incorporation of fully anharmonic effects in VCD spectra on the basis of ab initio molecular dynamics simulations. On the conceptual level, we compare our NVP results for rigid molecules with an existing implementation based on the magnetic field perturbation (MFP) technique using a Gaussian basis set and find an excellent agreement. Regarding numerical aspects, we analyze our results for their correct origin dependence and gauge invariance of the physical observables. The correlation with experimental data is very satisfactory, with certain deviations mainly due to the level of electronic structure theory used. PMID- 26592269 TI - Charge Transfer from Regularized Symmetry-Adapted Perturbation Theory. AB - The charge-transfer (CT) together with the polarization energy appears at second and higher orders in symmetry-adapted perturbation theory (SAPT). At present there is no theoretically compelling way of isolating the charge-transfer energy that is simultaneously basis-set independent and applicable for arbitrary intermolecular separation. We argue that the charge-transfer can be interpreted as a tunneling phenomenon and can therefore be defined via regularized SAPT. This leads to a physically convincing, basis-independent definition of the charge transfer energy that captures subtleties of the process, such as the asymmetry in the forward and backward charge transfer, as well as secondary transfer effects. With this definition of the charge-transfer the damping needed for polarization models can be determined with a level of confidence hitherto not possible. PMID- 26592270 TI - Exploring Chemical Space with the Alchemical Derivatives. AB - In this paper, we verify the usefulness of the alchemical derivatives in the prediction of chemical properties. We concentrate on the stability of the transmutation products, where the term "transmutation" means the change of the nuclear charge at an atomic site at constant number of electrons. As illustrative transmutations showing the potential of the method in exploring chemical space, we present some examples of increasing complexity starting with the deprotonation, continuing with the transmutation of the nitrogen molecule, and ending with the substitution of isoelectronic B-N units for C-C units and N units for C-H units in carbocyclic systems. The basis set influence on the qualitative and quantitative accuracies of the alchemical predictions was investigated. The alchemical deprotonation energy (from the second order Taylor expansion) correlates well with the vertical deprotonation energy and can be used as a preliminary indicator for the experimental deprotonation energy. The results of calculations for the BN derivatives of benzene and pyrene show that this method has great potential for efficient and accurate scanning of chemical space. PMID- 26592271 TI - Implementation of Two-Component Time-Dependent Density Functional Theory in TURBOMOLE. AB - We report the efficient implementation of a two-component time-dependent density functional theory proposed by Wang et al. (Wang, F.; Ziegler, T.; van Lenthe, E.; van Gisbergen, S.; Baerends, E. J. J. Chem. Phys. 2005, 122, 204103) that accounts for spin-orbit effects on excitations of closed-shell systems by employing a noncollinear exchange-correlation kernel. In contrast to the aforementioned implementation, our method is based on two-component effective core potentials as well as Gaussian-type basis functions. It is implemented in the TURBOMOLE program suite for functionals of the local density approximation and the generalized gradient approximation. Accuracy is assessed by comparison of two-component vertical excitation energies of heavy atoms and ions (Cd, Hg, Au(+)) and small molecules (I2, TlH) to other two- and four-component approaches. Efficiency is demonstrated by calculating the electronic spectrum of Au20. PMID- 26592272 TI - Noncollinear Spin States for Density Functional Calculations of Open-Shell and Multi-Configurational Systems: Dissociation of MnO and NiO and Barrier Heights of O3, BeH2, and H4. AB - When the spins of molecular orbitals are allowed to be aligned with different directions in space rather than being aligned collinearly, the resulting noncollinear spin orbitals add extra flexibility to variational optimization of the orbitals, and solutions obtained with collinear spin orbitals may be unstable with respect to becoming noncollinear in the expanded variational space. The goal of the present work is to explore whether and in what way the molecular orbitals of the Kohn-Sham density functional theory become noncollinear when fully optimized for multi-reference molecules, transition states, and reaction paths. (We note that a noncollinear determinant has intermediate flexibility between a collinear determinant and a linear combination of many collinear determinants with completely independent coefficients. However, the Kohn-Sham method is defined to involve the variational optimization of a single determinant, and a noncollinear determinant represents the limit of complete optimization in the Kohn-Sham scheme.) We compare the results obtained with the noncollinear Kohn Sham (NKS) scheme to those obtained with the widely used unrestricted Kohn-Sham (UKS) scheme for two types of multi-reference systems. For the dissociation of the MnO and NiO transition metal oxides, we find UKS fails to dissociate to the ground states of neutral atoms, while NKS dissociates to the correct limit and predicts potential energy curves that vary smoothly at intermediate bond lengths. This is due to the instability of UKS solutions at large bond distances. For barrier heights of O3, BeH2, and H4, NKS is shown to stabilize the multi reference transition states by expanding the variational space. Although the errors vary because they are closely coupled with the capability of the employed exchange-correlation functionals in treating the multi-configurational states, these findings demonstrate that results with collinear spin orbitals should be further scrutinized, and future development of exchange-correlation functionals for multi-reference systems should incorporate the flexibilities of NKS. PMID- 26592273 TI - Efficient Parallel All-Electron Four-Component Dirac-Kohn-Sham Program Using a Distributed Matrix Approach II. AB - We propose a new complete memory-distributed algorithm, which significantly improves the parallel implementation of the all-electron four-component Dirac Kohn-Sham (DKS) module of BERTHA (J. Chem. Theory Comput. 2010, 6, 384). We devised an original procedure for mapping the DKS matrix between an efficient integral-driven distribution, guided by the structure of specific G-spinor basis sets and by density fitting algorithms, and the two-dimensional block-cyclic distribution scheme required by the ScaLAPACK library employed for the linear algebra operations. This implementation, because of the efficiency in the memory distribution, represents a leap forward in the applicability of the DKS procedure to arbitrarily large molecular systems and its porting on last-generation massively parallel systems. The performance of the code is illustrated by some test calculations on several gold clusters of increasing size. The DKS self consistent procedure has been explicitly converged for two representative clusters, namely Au20 and Au34, for which the density of electronic states is reported and discussed. The largest gold cluster uses more than 39k basis functions and DKS matrices of the order of 23 GB. PMID- 26592274 TI - Unitary Optimization of Localized Molecular Orbitals. AB - A unified formalism and its implementation is presented for Foster-Boys, fourth moment, Pipek-Mezey, and Edmiston-Ruedenberg type localization schemes of molecular orbitals through unitary optimization of the localizing transform matrix using a recently proposed algorithm [ Abrudan ; et al. Signal Processing 2009 , 89 , 1704 ]. A conjugate gradient algorithm is used with an efficient line search method. The option of using complex valued orbitals is included. Applications to fullerenes from C20 to C100, as well as benzene and arachic acid are presented, showing the capability of the method, which has been implemented in ERKALE, an open source program for electronic structure calculations of atoms and molecules. PMID- 26592275 TI - MPI/OpenMP Hybrid Parallel Algorithm of Resolution of Identity Second-Order Moller-Plesset Perturbation Calculation for Massively Parallel Multicore Supercomputers. AB - A new algorithm for massively parallel calculations of electron correlation energy of large molecules based on the resolution of identity second-order Moller Plesset perturbation (RI-MP2) technique is developed and implemented into the quantum chemistry software NTChem. In this algorithm, a Message Passing Interface (MPI) and Open Multi-Processing (OpenMP) hybrid parallel programming model is applied to attain efficient parallel performance on massively parallel supercomputers. An in-core storage scheme of intermediate data of three-center electron repulsion integrals utilizing the distributed memory is developed to eliminate input/output (I/O) overhead. The parallel performance of the algorithm is tested on massively parallel supercomputers such as the K computer (using up to 45 992 central processing unit (CPU) cores) and a commodity Intel Xeon cluster (using up to 8192 CPU cores). The parallel RI-MP2/cc-pVTZ calculation of two layer nanographene sheets (C150H30)2 (number of atomic orbitals is 9640) is performed using 8991 node and 71 288 CPU cores of the K computer. PMID- 26592276 TI - Incremental CCSD(T)(F12*)|MP2: A Black Box Method To Obtain Highly Accurate Reaction Energies. AB - In this work we present a new partitioning scheme for the incremental approach in combination with the efficient (F12*) approximation for explicitly correlated coupled cluster (J. Chem. Phys. 2010, 132, 231102). Furthermore we establish a black-box truncation scheme which provides chemical accuracy for the absolute energies of 81 molecules and 51 reaction energies. The errors in the absolute CCSD(T)/cc-pVTZ-F12 energies due to the local approximations are characterized by mean = -0.24 kJ/mol, sigma = 0.49 kJ/mol, mae = 0.37 kJ/mol, rmsd = 0.54 kJ/mol, and range = 3.63 kJ/mol. For the reaction energies we find mean = 0.07 kJ/mol, sigma = 0.49 kJ/mol, mae = 0.33 kJ/mol, rmsd = 0.49 kJ/mol, and range = 2.40 kJ/mol. On the basis of these findings it is evident that the incremental scheme provides highly accurate CCSD(T) energies of benchmark quality. PMID- 26592277 TI - Development of a "First Principles" Water Potential with Flexible Monomers: Dimer Potential Energy Surface, VRT Spectrum, and Second Virial Coefficient. AB - The development of a "first principles" water potential with flexible monomers (MB-pol) for molecular simulations of water systems from gas to condensed phases is described. MB-pol is built upon the many-body expansion of the intermolecular interactions, and the specific focus of this study is on the two-body term (V2B) representing the full-dimensional intermolecular part of the water dimer potential energy surface. V2B is constructed by fitting 40,000 dimer energies calculated at the CCSD(T)/CBS level of theory and imposing the correct asymptotic behavior at long-range as predicted from "first principles". The comparison of the calculated vibration-rotation tunneling (VRT) spectrum and second virial coefficient with the corresponding experimental results demonstrates the accuracy of the MB-pol dimer potential energy surface. PMID- 26592278 TI - Revisiting the Nonadiabatic Process in 1,2-Dioxetane. AB - Determining the ground and excited-state decomposition mechanisms of 1,2 dioxetane is essential to understand the chemiluminescence and bioluminescence phenomena. Several experimental and theoretical studies has been performed in the past without reaching a converged description. The reason is in part associated with the complex nonadiabatic process taking place along the reaction. The present study is an extension of a previous work (De Vico, L.; Liu, Y.-J.; Krogh, J. W.; Lindh, R. J. Phys. Chem. A 2007, 111, 8013-8019) in which a two-step mechanism was established for the chemiluminescence involving asynchronous O-O' and C-C' bond dissociations. New high-level multistate multi configurational reference second-order perturbation theory calculations and ab initio molecular dynamics simulations at constant temperature are performed in the present study, which provide further details on the mechanisms and allow to rationalize further experimental observations. In particular, the new results explain the high ratio of triplet to singlet dissociation products. PMID- 26592279 TI - Reconsidering Dispersion Potentials: Reduced Cutoffs in Mesh-Based Ewald Solvers Can Be Faster Than Truncation. AB - Long-range dispersion interactions have a critical influence on physical quantities in simulations of inhomogeneous systems. However, the perceived computational overhead of long-range solvers has until recently discouraged their implementation in molecular dynamics packages. Here, we demonstrate that reducing the cutoff radius for local interactions in the recently introduced particle particle particle-mesh (PPPM) method for dispersion [Isele-Holder et al., J. Chem. Phys., 2012, 137, 174107] can actually often be faster than truncating dispersion interactions. In addition, because all long-range dispersion interactions are incorporated, physical inaccuracies that arise from truncating the potential can be avoided. Simulations using PPPM or other mesh Ewald solvers for dispersion can provide results more accurately and more efficiently than simulations that truncate dispersion interactions. The use of mesh-based approaches for dispersion is now a viable alternative for all simulations containing dispersion interactions and not merely those where inhomogeneities were motivating factors for their use. We provide a set of parameters for the dispersion PPPM method using either ik or analytic differentiation that we recommend for future use and demonstrate increased simulation efficiency by using the long-range dispersion solver in a series of performance tests on massively parallel computers. PMID- 26592280 TI - A Polarizable and Transferable PHAST CO2 Potential for Materials Simulation. AB - Reliable PHAST (Potentials with High Accuracy Speed and Transferability) intermolecular potential energy functions for CO2 have been developed from first principles for use in heterogeneous systems, including one with explicit polarization. The intermolecular potentials have been expressed in a transferable form and parametrized from nearly exact electronic structure calculations. Models with and without explicit many-body polarization effects, known to be important in simulation of interfacial processes, are constructed. The models have been validated on pressure-density isotherms of bulk CO2 and adsorption in three metal organic framework (MOF) materials. The present models appear to offer advantages over high quality fluid/liquid state potentials in describing CO2 interactions in interfacial environments where sorbates adopt orientations not commonly explored in bulk fluids. Thus, the nonpolar CO2-PHAST and polarizable CO2-PHAST* potentials are recommended for materials/interfacial simulations. PMID- 26592281 TI - Leveraging Symmetries of Static Atomic Multipole Electrostatics in Molecular Dynamics Simulations. AB - Multipole (MTP) electrostatics provides the means to describe anisotropic interactions in a rigorous and systematic manner. A number of earlier molecular dynamics (MD) implementations have increasingly relied on the use of molecular symmetry to reduce the (possibly large) number of MTP interactions. Here, we present a CHARMM implementation of MTP electrostatics in terms of spherical harmonics. By relying on a systematic set of reference-axis systems tailored to various chemical environments, we obtain an implementation that is both efficient and scalable for (bio)molecular systems. We apply the method to a series of halogenated compounds to show (i) energy conservation; (ii) improvements in reproducing thermodynamic properties compared to standard point-charge (PC) models; (iii) performance of the code; and (iv) better stabilization of a brominated ligand in a target protein, compared to a PC force field. The implementation provides interesting perspectives toward a dual PC/MTP resolution, a la QM/MM. PMID- 26592282 TI - Elastic Network Models of Nucleic Acids Flexibility. AB - Elastic network models (ENMs) are a useful tool for describing large scale motions in protein systems. While they are well validated in the context of proteins, relatively little is known about their applicability to nucleic acids, whose different architecture does not necessarily warrant comparable performance. In this study we thoroughly evaluate and optimize the efficiency of popular ENMs for capturing RNA and DNA flexibility. We also introduce two alternative models in which the strength of elastic connections at a coarse-grained level is governed by distance distribution at atomic resolution. For each of the considered ENMs we report the optimal length of spring connections as well as the scaling of elastic force constants that provides the best agreement of vibrational frequencies with normal modes based on atomic force field. In order to determine the absolute values of force constants we introduce a novel method based on the overlap of pseudoinverse of Hessian matrices. PMID- 26592284 TI - Simulating One-Photon Absorption and Resonance Raman Scattering Spectra Using Analytical Excited State Energy Gradients within Time-Dependent Density Functional Theory. AB - A parallel implementation of analytical time-dependent density functional theory gradients is presented for the quantum chemistry program NWChem. The implementation is based on the Lagrangian approach developed by Furche and Ahlrichs. To validate our implementation, we first calculate the Stokes shifts for a range of organic dye molecules using a diverse set of exchange-correlation functionals (traditional density functionals, global hybrids, and range-separated hybrids) followed by simulations of the one-photon absorption and resonance Raman scattering spectrum of the phenoxyl radical, the well-studied dye molecule rhodamine 6G, and a molecular host-guest complex (TTF?CBPQT(4+)). The study of organic dye molecules illustrates that B3LYP and CAM-B3LYP generally give the best agreement with experimentally determined Stokes shifts unless the excited state is a charge transfer state. Absorption, resonance Raman, and fluorescence simulations for the phenoxyl radical indicate that explicit solvation may be required for accurate characterization. For the host-guest complex and rhodamine 6G, it is demonstrated that absorption spectra can be simulated in good agreement with experimental data for most exchange-correlation functionals. However, because one-photon absorption spectra generally lack well-resolved vibrational features, resonance Raman simulations are necessary to evaluate the accuracy of the exchange-correlation functional for describing a potential energy surface. PMID- 26592283 TI - [Not Available]. PMID- 26592285 TI - Statistical Validation of Absolute Configuration Assignment in Vibrational Optical Activity. AB - Chiroptical spectroscopy usually requires theoretically computed spectra to assist in the elucidation of the absolute configuration of samples for which experimental spectra have been recorded. Due to the inherently different nature of these two types of spectra, perfect agreement is quasi impossible. Several methods exist to quantify the degree of similarity between the two spectra, but rather limited work has been done to evaluate the robustness of the similarity between theory and experiment. In this work, a novel method is described to determine the statistical significance of the numerical degree of similarity between experimental and calculated vibrational circular dichroism spectra and to offer valuable support for performing absolute configuration assignments. The approach is successfully applied to a number of quinolizidine alkaloids. PMID- 26592286 TI - Ground- and Excited-State Geometry Optimization of Small Organic Molecules with Quantum Monte Carlo. AB - We present a comparative study of the geometry optimization in the gas phase of acrolein, acetone, methylenecyclopropene, and the propenoic acid anion with special emphasis on their excited-state structures, using quantum Monte Carlo (QMC), multireference perturbation theory (CASPT2 and NEVPT2), second-order approximate coupled cluster (CC2), and time-dependent density functional theory (TDDFT). We find that, for all molecules, the geometries optimized with QMC in its simplest variational (VMC) flavor are in very good agreement with the perturbation results both in the ground and the excited states of either n -> pi* or pi -> pi* character. Furthermore, the quality of the QMC structures is superior to those obtained with the CC2 method, which overestimates the CO bond in all n -> pi* excitations, or to the symmetry-adapted-cluster configuration interaction (SAC-CI) approach, which gives a poorer description of the CC bonds in the excited states. Finally, the spread in the TDDFT structures obtained with several current exchange-correlation functionals is large and does not reveal a clear relation between the defining features of the functionals and the quality of the optimized structures. In summary, our findings demonstrate the good performance of QMC in optimizing the geometries of these molecules, also in cases where other correlated or TDDFT approaches are inaccurate, and indicate that the method represents a robust reference approach for future structural studies also of larger systems. PMID- 26592287 TI - SPAM: A Simple Approach for Profiling Bound Water Molecules. AB - A method that identifies the hydration shell structure of proteins and estimates the relative free energies of water molecules within that hydration shell is described. The method, which we call "SPAM" (maps spelled in reverse), utilizes explicit solvent molecular dynamics (MD) simulations to capture discrete hydration sites at the water-protein interface and computes a local free energy measure from the distribution of interaction energies between water and the environment at a specific site. SPAM is able to provide a qualitative estimate of the thermodynamic profile of bound water molecules that correlates nicely with well-studied structure-activity relationships and observed binding "hot spots". This is demonstrated in retrospective analyses of HIV1 protease and hen egg white lysozyme, where the effects of water displacement and solvent binding have been studied extensively. The simplicity and effectiveness of SPAM allow for prospective application during the drug discovery process. PMID- 26592288 TI - A Polarizable and Transferable PHAST N2 Potential for Use in Materials Simulation. AB - A polarizable and transferable intermolecular potential energy function, potentials with high accuracy, speed, and transferability (PHAST), has been developed from first principles for molecular nitrogen to be used in the modeling of heterogeneous processes such as materials sorption and separations. A five site (van der Waals and point charge) anisotropic model, that includes many-body polarization, is proposed. It is parametrized to reproduce high-level electronic structure calculations (CCSD(T) using Dunning-type basis sets extrapolated to the CBS limit) for a representative set of dimer potential energy curves. Thus it provides a relatively simple yet robust and broadly applicable representation of nitrogen. Two versions are developed, differing by the type of mixing rules applied to unlike Lennard-Jones potential sites. It is shown that the Waldman Hagler mixing rules are more accurate than Lorentz-Berthelot. The resulting potentials are demonstrated to be effective in modeling neat nitrogen but are designed to also be useful in modeling N2 interactions in a large array of environments such as metal-organic frameworks and zeolites and at interfaces. In such settings, capturing anisotropic forces and interactions with (open and coordinated) metals and charged/polar environments is essential. In developing the potential, it was found that adding a seemingly redundant dimer orientation, slip-parallel (S), improved the transferability of the potential energy surface (PES). Notably, one of the solid phases of nitrogen was not as accurately represented energetically without including S in the representative set. Liquid simulations, however, were unaffected and worked equally well for both potentials. This suggests that accounting for a wide variety of configurations is critical in designing a potential that is intended for use in heterogeneous environments where many orientations, including those not commonly explored in the bulk, are possible. Testing and validation of the potential are achieved via simulations of a thermal distribution of trimer geometries compared to analogous high level electronic structure calculations and molecular simulations of bulk pressure-density isotherms across the vapor, supercritical, and liquid phases. Crystal lattice parameters and energetics of the alpha-N2 and gamma-N2 solid phases are also evaluated and determined to be in good agreement with experiment. Thus the proposed potential is shown to be efficacious for gas, liquid, and solid use, representing both disordered and ordered configurations. PMID- 26592289 TI - Probing the Statistical Validity of the Ductile-to-Brittle Transition in Metallic Nanowires Using GPU Computing. AB - We perform a large-scale statistical analysis (>2000 independent simulations) of the elongation and rupture of gold nanowires, probing the validity and scope of the recently proposed ductile-to-brittle transition that occurs with increasing nanowire length [Wu et al. Nano Lett. 2012, 12, 910-914]. To facilitate a high throughput simulation approach, we implement the second-moment approximation to the tight-binding (TB-SMA) potential within HOOMD-Blue, a molecular dynamics package which runs on massively parallel graphics processing units (GPUs). In a statistical sense, we find that the nanowires obey the ductile-to-brittle model quite well; however, we observe several unexpected features from the simulations that build on our understanding of the ductile-to-brittle transition. First, occasional failure behavior is observed that qualitatively differs from that predicted by the model prediction; this is attributed to stochastic thermal motion of the Au atoms and occurs at temperatures as low as 10 K. In addition, we also find that the ductile-to-brittle model, which was developed using classical dislocation theory, holds for nanowires as small as 3 nm in diameter. Finally, we demonstrate that the nanowire critical length is higher at 298 K relative to 10 K, a result that is not predicted by the ductile-to-brittle model. These results offer practical design strategies for adjusting nanowire failure and structure and also demonstrate that GPU computing is an excellent tool for studies requiring a large number of independent trajectories in order to fully characterize a system's behavior. PMID- 26592290 TI - Multiscale Modeling of Chemistry in Water: Are We There Yet? AB - This paper critically evaluates the state of the art in combined quantum mechanical/molecular mechanical (QM/MM) approaches to the computational description of chemistry in water and supplies guidelines for the setup of customized multiscale simulations of aqueous processes. We differentiate between structural and dynamic performance, since some tasks, e.g., the reproduction of NMR or UV-vis spectra, require only structural accuracy, while others, i.e., reaction mechanisms, require accurate dynamic data as well. As a model system for aqueous solutions in general, the approaches were tested on a QM water cluster in an environment of MM water molecules. The key difficulty is the description of the possible diffusion of QM molecules into the MM region and vice versa. The flexible inner region ensemble separator (FIRES) approach constrains QM solvent molecules within an active (QM) region. Sorted adaptive partitioning (SAP), difference-based adaptive solvation (DAS), and buffered-force (BF) are all adaptive approaches that use a buffer zone in which solvent molecules gradually adapt from QM to MM (or vice versa). The costs of SAP and DAS are relatively high, while BF is fast but sacrifices conservation of both energy and momentum. Simulations in the limit of an infinitely small buffer zone, where DAS and SAP become equivalent, are discussed as well and referred to as ABRUPT. The best structural accuracy is obtained with DAS, BF, and ABRUPT, all three of similar quality. FIRES performs very well for dynamic properties localized deep within the QM region. By means of elimination DAS emerges as the best overall compromise between structural and dynamic performance. Eliminating the buffer zone (ABRUPT) improves efficiency and still leads to surprisingly good results. While none of the many new flavors are perfect, all together this new field already allows accurate description of a wide range of structural and dynamic properties of aqueous solutions. PMID- 26592291 TI - Critical Importance of van der Waals Stabilization in Strongly Chemically Bonded Surfaces: Cu(110):O. AB - We provide strong evidence that different reconstructed phases of the oxidized Cu(110) surface are stabilized by the van der Waals (vdW) interactions. These covalently bonded reconstructed surfaces feature templates that are an integral part of the surfaces and are bonded on the bare metal surface by a combination of chemical and physical bonding. The vdW stabilization in this class of systems affects predominantly the intertemplate Cu-O interactions in structures sparsely populated by these templates. The conventional dispersionless density functional theory (DFT) methods fail to model such systems. We find a failure to describe the thermodynamics of the different phases that are formed at different oxygen exposures and spurious minima on the potential energy surface of a diffusing surface adatom. To overcome these issues, we employ a range of different DFT methods that account for the missing vdW correlations. Surprisingly, despite vast conceptual differences in the different formulations of these methods, they yield physically identical results for the Cu(110):O surface phases, provided the massive screening effects in the metal are taken into account. Contrary, the vibrational contribution does not consistently stabilize the experimentally observed surface structures. The van der Waals surface stabilization, so far deemed to play only a minor role in hard-bonded surfaces, is suggested to be a more general key feature for this and other related surfaces. PMID- 26592292 TI - [Not Available]. PMID- 26592293 TI - Incrementally Corrected Periodic Local MP2 Calculations: I. The Cohesive Energy of Molecular Crystals. AB - A method for accurate calculations of the cohesive energy of molecular crystals is presented. The cohesive energy is evaluated as a sum of several components. The major contribution is captured by periodic Hartree-Fock (HF) coupled with the local Moller-Plesset perturbation theory of second order (LMP2) with a triple zeta basis set. Post-MP2 corrections and corrections for the basis set incompleteness are calculated from inexpensive incremental calculations with finite clusters. This is an essential improvement with respect to the periodic LMP2 method and allows for results of benchmark quality for crystalline systems. The proposed technique is superior to the standard incremental scheme as concerns the cluster size and basis set convergence of the results. In contrast to the total energy or electron correlation energy, which are evaluated in standard incremental calculations, post-MP2 and basis set corrections are rather insensitive to approximations and converge quickly both in terms of the order of the increments and the number of terms at a given order. Evaluation of the incremental corrections within the sub-kJ/mol precision requires computing very few of the most compact two-center and three-center non-embedded clusters, making the whole correction scheme computationally inexpensive. This method as well as alternative routes to compute the cohesive energy via the incremental scheme are tested on two molecular crystals: carbon dioxide (CO2) and hydrogen cyanide (HCN). PMID- 26592294 TI - Molecular Dynamics Simulations Accelerated by GPU for Biological Macromolecules with a Non-Ewald Scheme for Electrostatic Interactions. AB - A molecular dynamics (MD) simulation program for biological macromolecules was implemented with a non-Ewald scheme for long-ranged electrostatic interactions and run on a general purpose graphics processing unit (GPU). We recently developed several non-Ewald methods to compute the electrostatic energies with high precision. In particular, the zero-dipole summation (ZD) method, which takes into account the neutralities of charges and dipoles in a truncated subset, enables the calculation of electrostatic interactions with high accuracy and low computational cost, and its algorithm is simple enough to be implemented in a GPU. We developed an MD program with the space decomposition algorithm, myPresto/psygene, and applied it to several biological macromolecular systems with GPUs implementing the ZD method. Rapid computing performance with high accuracy was obtained. PMID- 26592295 TI - Replica-Averaged Metadynamics. AB - A statistical mechanics description of complex molecular systems involves the determination of ensembles of conformations that represent their Boltzmann distributions. The observable properties of these systems can be then predicted by calculating averages over such ensembles. In principle, given accurate energy functions and efficient sampling methods, these ensembles can be generated by molecular dynamics simulations. In practice, however, often the energy functions are known only approximately and the sampling can be carried out only in a limited manner. We describe here a method that enables to increase simultaneously both the quality of the energy functions and of the extent of the sampling in a system-dependent manner. The method is based on the incorporation of experimental data as replica-averaged structural restraints in molecular dynamics simulations and exploits the metadynamics framework to enhance the sampling. The application to the case of alpha-conotoxin SI, a 13-residue peptide that has been characterized extensively by experimental measurements, shows that the approach that we describe enables accurate free energy landscapes to be generated. The analysis of these landscapes indicates the presence of a low population state in equilibrium with the native state in which the only aromatic residue of alpha conotoxin SI is exposed to the solvent, which is a feature that may predispose the peptide to interact with its partners. PMID- 26592296 TI - Evaluation of Protein Elastic Network Models Based on an Analysis of Collective Motions. AB - Elastic network models (ENMs) are valuable tools for investigating collective motions of proteins, and a rich variety of simple models have been proposed over the past decade. A good representation of the collective motions requires a good approximation of the covariances between the fluctuations of the individual atoms. Nevertheless, most studies have validated such models only by the magnitudes of the single-atom fluctuations they predict. In the present study, we have quantified the agreement between the covariance structure predicted by molecular dynamics (MD) simulations and those predicted by a representative selection of proposed coarse-grained ENMs. We then contrast this approach with the comparison to MD-predicted atomic fluctuations and comparison to crystallographic B-factors. While all the ENMs yield approximations to the MD predicted covariance structure, we report large and consistent differences between proposed models. We also find that the ability of the ENMs to predict atomic fluctuations is correlated with their ability to capture the covariance structure. In contrast, we find that the models that agree best with B-factors model collective motions less reliably and recommend against using B-factors as a benchmark. PMID- 26592297 TI - Surface-Tension Replica-Exchange Molecular Dynamics Method for Enhanced Sampling of Biological Membrane Systems. AB - Conformational sampling is fundamentally important for simulating complex biomolecular systems. The generalized-ensemble algorithm, especially the temperature replica-exchange molecular dynamics method (T-REMD), is one of the most powerful methods to explore structures of biomolecules such as proteins, nucleic acids, carbohydrates, and also of lipid membranes. T-REMD simulations have focused on soluble proteins rather than membrane proteins or lipid bilayers, because explicit membranes do not keep their structural integrity at high temperature. Here, we propose a new generalized-ensemble algorithm for membrane systems, which we call the surface-tension REMD method. Each replica is simulated in the NPgammaT ensemble, and surface tensions in a pair of replicas are exchanged at certain intervals to enhance conformational sampling of the target membrane system. We test the method on two biological membrane systems: a fully hydrated DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine) lipid bilayer and a WALP23-POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) membrane system. During these simulations, a random walk in surface tension space is realized. Large-scale lateral deformation (shrinking and stretching) of the membranes takes place in all of the replicas without collapse of the lipid bilayer structure. There is accelerated lateral diffusion of DPPC lipid molecules compared with conventional MD simulation, and a much wider range of tilt angle of the WALP23 peptide is sampled due to large deformation of the POPC lipid bilayer and through peptide-lipid interactions. Our method could be applicable to a wide variety of biological membrane systems. PMID- 26592298 TI - Effects of Phospholipid Composition on the Transfer of a Small Cationic Peptide Across a Model Biological Membrane. AB - The transfer of a lysine amino acid analogue across phospholipid membrane models was investigated using molecular-dynamics simulations. The evolution of the protonation state of this small peptide as a function of its position inside the membrane was studied by determining the local pKa by means of free-energy calculations. Permeability and mean-first-passage time were evaluated and showed that the transfer occurs on the submillisecond time scale. Comparative studies were conducted to evaluate changes in the pKa arising from differences in the phospholipid chemical structure. We compared, hence, the effect of an ether vs an ester linkage of the lipid headgroup as well as linear vs branched lipid tails. The study reveals that protonated lysine residues can be buried further inside an ether lipid membrane than an ester lipid membrane, while branched lipids are found to stabilize less the charged form compared to their unbranched lipid chain counterparts. PMID- 26592299 TI - Estimation of Interaction Potentials through the Configurational Temperature Formalism. AB - Molecular interaction potentials are difficult to measure experimentally and hard to compute from first principles, especially for large systems such as proteins. It is therefore desirable to estimate the potential energy that underlies a thermodynamic ensemble from simulated or experimentally determined configurations. This inverse problem of statistical mechanics is challenging because the various potential energy terms can exhibit subtle indirect and correlated effects on the resulting ensemble. A direct approach would try to adapt the force field parameters such that the given configurations are highly probable in the resulting ensemble. But this would require a full simulation of the system whenever a parameter changes. We introduce an extension of the configurational temperature formalism that allows us to circumvent these difficulties and efficiently estimate interaction potentials from molecular configurations. We illustrate the approach for various systems including fluids and a coarse-grained protein model. PMID- 26592300 TI - Solvent Binding Analysis and Computational Alanine Scanning of the Bovine Chymosin-Bovine kappa-Casein Complex Using Molecular Integral Equation Theory. AB - We demonstrate that the relative binding thermodynamics of single-point mutants of a model protein-peptide complex (the bovine chymosin-bovine kappa-casein complex) can be calculated accurately and efficiently using molecular integral equation theory. The results are shown to be in good overall agreement with those obtained using implicit continuum solvation models. Unlike the implicit continuum models, however, molecular integral equation theory provides useful information about the distribution of solvent density. We find that experimentally observed water-binding sites on the surface of bovine chymosin can be identified quickly and accurately from the density distribution functions computed by molecular integral equation theory. The bovine chymosin-bovine kappa-casein complex is of industrial interest because bovine chymosin is widely used to cleave bovine kappa casein and to initiate milk clotting in the manufacturing of processed dairy products. The results are interpreted in light of the recent discovery that camel chymosin is a more efficient clotting agent than bovine chymosin for bovine milk. PMID- 26592301 TI - Exact Ligand Solid Angles. AB - Steric demands of a ligand can be quantified by the area occluded by the ligand on the surface of an encompassing sphere centered at the metal atom. When viewed as solid spheres illuminated by the metal center, the ligand atoms generally cast a very complicated collective shadow onto the encompassing sphere, causing mathematical difficulties in computing the subtended solid angle. Herein, an exact, analytic solution to the ligand solid angle integration problem is presented based on a line integral around the multisegmented perimeter of the ligand shadow. The solution, which is valid for any ligand bound to any metal center, provides an excellent method for analyzing geometric structures from quantum chemical computations or X-ray crystallography. Over 275 structures of various metals bound to diverse mono- and multidentate ligands were optimized using B3LYP density functional theory to exhibit exact solid angle (Omega degrees ) computations. Among the intriguing Omega degrees solutions, Pd(xantphos) and ferrocene exhibit holes in their ligand shadows, and Fe(EDTA)(2-) has a surprisingly simple shadow defined by only four arcs, despite having a multitude of overlaps among individual shadow cones. PMID- 26592302 TI - Double-Ended Surface Walking Method for Pathway Building and Transition State Location of Complex Reactions. AB - Toward the activity prediction with large-scale computations, here a double-ended surface walking (DESW) method is developed for connecting two minima on a potential energy surface (PES) and locating the associated transition state (TS) using only the first derivatives. The method operates two images starting from the initial and the final states, respectively, to walk in a stepwise manner toward each other. The surface walking involves repeated bias potential addition and local relaxation with the constrained Broyden dimer method to correct the walking direction. We apply the method to a model PES, a large set of gas phase Baker reactions, and complex surface catalytic reactions, which demonstrates that the DESW method can establish a low energy pathway linking two minima even without iterative optimization of the pathway, from which the TS can be located readily. By comparing the efficiency of the new method with the existing methods, we show that the DESW method is much less computationally demanding and is applicable for reactions with complex PESs. We hope that the DESW method may be integrated with the PES sampling methods for automated reaction prediction. PMID- 26592303 TI - NIR-Vis-UV Light-Responsive Actuator Films of Polymer-Dispersed Liquid Crystal/Graphene Oxide Nanocomposites. AB - To take full advantage of sunlight for photomechanical materials, NIR-vis-UV light-responsive actuator films of polymer-dispersed liquid crystal (PDLC)/graphene oxide (GO) nanocomposites were fabricated. The strategy is based on phase transition of LCs from nematic to isotropic phase induced by combination of photochemical and photothermal processes in the PDLC/GO nanocomposites. Upon mechanical stretching of the film, both topological shape change and mesogenic alignment occurred in the separated LC domains, enabling the film to respond to NIR-vis-UV light. The homodispersed GO flakes act as photoabsorbent and nanoscale heat source to transfer NIR or VIS light into thermal energy, heating the film and photothermally inducing phase transition of LC microdomains. By utilizing photochemical phase transition of LCs upon UV-light irradiation, one azobenzene dye was incorporated into the LC domains, endowing the nanocomposite films with UV-responsive property. Moreover, the light-responsive behaviors can be well controlled by adjusting the elongation ratio upon mechanical treatment. The NIR vis-UV light-responsive PDLC/GO nanocomposite films exhibit excellent properties of easy fabrication, low-cost, and good film-forming and mechanical features, promising their numerous applications in the field of soft actuators and optomechanical systems driven directly by sunlight. PMID- 26592304 TI - A Toolbox of Diverse Promoters Related to Methanol Utilization: Functionally Verified Parts for Heterologous Pathway Expression in Pichia pastoris. AB - The heterologous expression of biosynthetic pathways for pharmaceutical or fine chemical production requires suitable expression hosts and vectors. In eukaryotes, the pathway flux is typically balanced by stoichiometric fine-tuning of reaction steps by varying the transcript levels of the genes involved. Regulated (inducible) promoters are desirable to allow a separation of pathway expression from cell growth. Ideally, the promoter sequences used should not be identical to avoid loss by recombination. The methylotrophic yeast Pichia pastoris is a commonly used protein production host, and single genes have been expressed at high levels using the methanol-inducible, strong, and tightly regulated promoter of the alcohol oxidase 1 gene (PAOX1). Here, we have studied the regulation of the P. pastoris methanol utilization (MUT) pathway to identify a useful set of promoters that (i) allow high coexpression and (ii) differ in DNA sequence to increase genetic stability. We noticed a pronounced involvement of the pentose phosphate pathway (PPP) and genes involved in the defense of reactive oxygen species (ROS), providing strong promoters that, in part, even outperform PAOX1 and offer novel regulatory profiles. We have applied these tightly regulated promoters together with novel terminators as useful tools for the expression of a heterologous biosynthetic pathway. With the synthetic biology toolbox presented here, P. pastoris is now equipped with one of the largest sets of strong and co-regulated promoters of any microbe, moving it from a protein production host to a general industrial biotechnology host. PMID- 26592307 TI - Trabectedin for the treatment of breast cancer. AB - INTRODUCTION: Trabectedin is an anti-tumor compound registered in Europe and in several other countries, for the second-line treatment of soft tissue sarcoma (STS) and for ovarian cancer in combination with liposomal doxorubicin. Trabectedin inhibits cancer cell proliferation mainly affecting the transcription regulation. Trabectedin also acts as a modulator of tumor microenvironment by reducing the number of tumor associated macrophages (TAM). Because of its unique mechanism of action, trabectedin has the potential to act as antineoplastic agent also in several solid malignancies, including breast cancer (BC). AREAS COVERED: This article reviews the preclinical and clinical data of trabectedin focusing on development in metastatic BC (mBC). Comments regarding the nature and the results of these trials are included. EXPERT OPINION: Trabectedin is thought to have a crucial activity with defective DNA-repair machinery and also in modulating the tumor micro-environment and the immune-system of cancer patients. From the current available data, we recognize a potential activity of trabectedin in mBC and support the renewed efforts to better elucidate the value of trabectedin in this indication. PMID- 26592308 TI - Staphylokinase and ABO group phenotype: new players in Staphylococcus aureus implant-associated infections development. AB - AIM: To identify bacterial and/or clinical features involved in the pathogenesis of Staphylococcus aureus implant-associated infections (IAI). MATERIALS & METHODS: In total, 57 IAI S. aureus and 31 nasal carriage (NC) S. aureus isolates were studied. Staphylococcus aureus genetic background was obtained by microarray analysis. Multilocus sequence typing was performed to determine clonal complexes (CC). Biofilm production was investigated by resazurin and crystal violet methods. RESULTS: Staphylokinase gene was associated with the occurrence of S. aureus IAI. Patients' ABO blood group phenotype was associated with IAI S. aureus genetic background. CC8 S. aureus strains produce more biofilm than others and carry particular alleles of bbp gene. CONCLUSION: This study identifies some predictive markers for S. aureus IAI. PMID- 26592309 TI - The unexpected benefits of the national piperacillin/tazobactam shortage on antibiotic stewardship. PMID- 26592311 TI - Unlike adults, children and adolescents show predominantly increased neural activation to social exclusion by members of the opposite gender. AB - The effects of group membership on brain responses to social exclusion have been investigated in adults, revealing greater anterior cingulate responses to exclusion by members of one's in-group (e.g., same-gender). However, social exclusion is a critical aspect of peer relations in youth and reaches heightened salience during adolescence, a time when social anxiety disorders are also emergent. While the behavioral and neural correlates of social exclusion in adolescence have been extensively explored, the effects of group membership on peer rejection are less clear. The current study used functional magnetic resonance imaging (fMRI) to investigate the differential neural correlates of being excluded by peers of one's same- versus opposite-gender during an online ball-toss game. Participants were a group of typically developing children and adolescents (7-17 years). As predicted, anterior cingulate cortex showed a main effect of social exclusion versus fair play. However, unlike a previous adult study, this region did not show increased activation to same-gender exclusion. Instead, several regions differentiating same- versus opposite-gender exclusion were exclusively more sensitive to exclusion by one's opposite gender. These results are discussed in the context of adolescent socio-emotional development. PMID- 26592312 TI - Effects of whole linseed and rumen-protected conjugated linoleic acid enriched diets on beef quality. AB - Instrumental assessments and sensory tests were performed to evaluate the effects of diet and postmortem ageing time (1, 7 and 21 days) on beef quality. A total of 48 Friesian calves were randomly allocated to four dietary treatments: control, whole linseed (10% linseed), conjugated linoleic acid (CLA) (2% protected CLA), and whole linseed+CLA (10% linseed and 2% protected CLA). Animals were slaughtered at 458+/-16.6 kg live weight and 11 months of age. Ageing was more significant than diet on most instrumental parameters. Meat from linseed enriched diets had greater drip loss (P?0.001) and intramuscular fat (P?0.01) than meat from animals fed CLA. Beef aged for 7 and 21 days had lower cooking losses (P?0.01) and shear force (P?0.001) than beef aged for 1 day. Lightness was affected only by display time. The addition of CLA in the diet increased hue and yellowness, whereas the inclusion of linseed decreased these values, as well as increased redness. Linseed in the diet decreased fat odour (P?0.05), but increased beef (P?0.01) and liver (P?0.05) flavours. Meat aged for 21 days was significantly more rancid (P?0.001), even under vacuum storage. Several organoleptic properties were improved with the inclusion of linseed in the diet, whereas they remained unaffected by the inclusion of CLA. PMID- 26592310 TI - Torsins: not your typical AAA+ ATPases. AB - Torsin ATPases (Torsins) belong to the widespread AAA+ (ATPases associated with a variety of cellular activities) family of ATPases, which share structural similarity but have diverse cellular functions. Torsins are outliers in this family because they lack many characteristics of typical AAA+ proteins, and they are the only members of the AAA+ family located in the endoplasmic reticulum and contiguous perinuclear space. While it is clear that Torsins have essential roles in many, if not all metazoans, their precise cellular functions remain elusive. Studying Torsins has significant medical relevance since mutations in Torsins or Torsin-associated proteins result in a variety of congenital human disorders, the most frequent of which is early-onset torsion (DYT1) dystonia, a severe movement disorder. A better understanding of the Torsin system is needed to define the molecular etiology of these diseases, potentially enabling corrective therapy. Here, we provide a comprehensive overview of the Torsin system in metazoans, discuss functional clues obtained from various model systems and organisms and provide a phylogenetic and structural analysis of Torsins and their regulatory cofactors in relation to disease-causative mutations. Moreover, we review recent data that have led to a dramatically improved understanding of these machines at a molecular level, providing a foundation for investigating the molecular defects underlying the associated movement disorders. Lastly, we discuss our ideas on how recent progress may be utilized to inform future studies aimed at determining the cellular role(s) of these atypical molecular machines and their implications for dystonia treatment options. PMID- 26592313 TI - Length and height percentiles for children in the South-East Asian Nutrition Surveys (SEANUTS). AB - OBJECTIVE: Health and nutritional information for many countries in the South East Asian region is either lacking or no longer up to date. The present study aimed to calculate length/height percentile values for the South-East Asian Nutrition Survey (SEANUTS) populations aged 0.5-12 years, examine the appropriateness of pooling SEANUTS data for calculating common length/height percentile values for all SEANUTS countries and whether these values differ from the WHO growth references. DESIGN: Data on length/height-for-age percentile values were collected. The LMS method was used for calculating smoothened percentile values. Standardized site effects (SSE) were used for identifying large or unacceptable differences (i.e. $?mid?! ?rm SSE ?!?mid$ >0.5) between the pooled SEANUTS sample (including all countries) and the remaining pooled SEANUTS samples (including three countries) after weighting sample sizes and excluding one single country each time, as well as with WHO growth references. SETTING: Malaysia, Thailand, Vietnam and Indonesia. SUBJECTS: Data from 14202 eligible children were used. RESULTS: From pair-wise comparisons of percentile values between the pooled SEANUTS sample and the remaining pooled SEANUTS samples, the vast majority of differences were acceptable (i.e. $?mid?! ?rm SSE ?!?mid$ <=0.5). In contrast, pair-wise comparisons of percentile values between the pooled SEANUTS sample and WHO revealed large differences. CONCLUSIONS: The current study calculated length/height percentile values for South East Asian children aged 0.5-12 years and supported the appropriateness of using pooled SEANUTS length/height percentile values for assessing children's growth instead of country-specific ones. Pooled SEANUTS percentile values were found to differ from the WHO growth references and therefore this should be kept in mind when using WHO growth curves to assess length/height in these populations. PMID- 26592314 TI - Polyphenols and non-alcoholic fatty liver disease: impact and mechanisms. AB - Non-alcoholic fatty liver disease (NAFLD) is considered to be the hepatic component of the metabolic syndrome and its prevalence is rapidly increasing due to its strong association with insulin resistance and obesity. At present, given that NAFLD is highly prevalent and therapies are limited, much attention is focused on identifying effective dietary strategies for the prevention and treatment of the disease. Polyphenols are a group of plant bioactive compounds whose regular consumption have been associated with a reduction in the risk of a number of metabolic disorders associated with NAFLD. Here we review the emerging and relatively consistent evidence from cell culture and rodent studies showing that select polyphenols positively modulate a variety of contributors to the NAFLD phenotype, through diverse and complementary mechanisms of action. In particular, the reduction of de novo lipogenesis (via sterol regulatory element binding protein 1c) and increased fatty acid beta-oxidation, presumably involving AMP-activated protein kinase activation, will be discussed. The indirect antioxidant and anti-inflammatory properties of polyphenols which have been reported to contribute to the amelioration of NAFLD will also be addressed. In addition to a direct study of the liver, rodent studies have provided insight into the impact of polyphenols on adipose tissue function and whole body insulin sensitivity, which are likely to in part modulate their impact on NAFLD development. Finally an overview of the limited data from clinical trials will be given along with a discussion of the dose extrapolation from animal studies to human subjects. PMID- 26592315 TI - Wood Dust: A Trigger for Rheumatoid Arthritis? PMID- 26592316 TI - Electrocardiogram Changes From Ranolazine or From Takotsubo? PMID- 26592317 TI - The Reply. PMID- 26592318 TI - The influence of rough lipopolysaccharide structure on molecular interactions with mammalian antimicrobial peptides. AB - The influence of Escherichia coli rough lipopolysaccharide chemotype on the membrane activity of the mammalian antimicrobial peptides (AMPs) human cathelicidin (LL37) and bovine lactoferricin (LFb) was studied on bilayers using solid state (2)H NMR (ssNMR) and on monolayers using the subphase injection technique, Brewster angle microscopy (BAM) and neutron reflectivity (NR). The two AMPs were selected because of their differing biological activities. Chain deuterated dipalmitoylphosphatidylcholine (d62-DPPC) was added to the LPS samples, to highlight alterations in the system properties caused by the presence of the different LPS chemotypes and upon AMP challenge. Both LPS chemotypes showed a temperature dependent influence on the packing of the DPPC molecules, with a fluidizing effect exerted below the DPPC phase transition temperature (Tm), and an ordering effect observed above the Tm. The magnitude of these effects was influenced by LPS structure; the shorter Rc LPS promoted more ordered lipid packing compared to the longer Ra LPS. These differential ordering effects in turn influenced the penetrative activity of the two peptides, as the perturbation induced by both AMPs to Ra LPS-containing models was greater than that observed in those containing Rc LPS. The NR data suggests that in addition to penetrating into the monolayers, both LL37 and LFb formed a non-interacting layer below the LPS/DPPC monolayer. The overall activity of LL37, which showed a deeper penetration into the model membranes, was more marked than that of LFb, which appeared to localise at the interfacial region, thus providing evidence for the molecular origins of their different biological activities. PMID- 26592319 TI - Association between Strongyloides stercoralis infection and cortisol secretion in alcoholic patients. AB - A higher prevalence of Strongyloides stercoralis infections has been reported in alcoholic patients compared to nonalcoholic patients living in the same area. Excessive alcohol consumption increases the levels of endogenous corticosteroids that subsequently enhance the fecundity of S. stercoralis parthenogenetic females. These corticosteroids also enhance the transformation of rhabditiform larvae into infective filariform larvae by mimicking the effect of the ecdysteroid hormones produced by the parasite, thus leading to autoinfection. In addition, alterations in the intestinal barrier and host immune response contribute to the development of hyperinfection and severe strongyloidiasis in alcoholic patients. The aim of this study was to evaluate the frequency of S. stercoralis infections in alcoholic patients and to determine the association between S. stercoralis infection and endogenous cortisol levels. The frequency of infection was evaluated in 332 alcoholic and 92 nonalcoholic patients. The parasitological diagnosis was carried out by agar plate culture, the modified Baermann-Moraes method and spontaneous sedimentation. The immunological diagnosis was performed using an ELISA with anti-S. stercoralis IgG. The cortisol levels were measured in serum samples by ELISA. The frequency of S. stercoralis infection in alcoholic patients was 23.5% (78/332), while in nonalcoholic patients, it was 5.4% (5/92) (p<0.05). The cortisol levels were higher in alcoholic than in nonalcoholic patients (p<0.05). However, among the alcoholic patients, the cortisol levels did not differ between S. stercoralis-infected and uninfected patients (p>0.05). As demonstrated in this work, 81.3% (26/32) of patients with a high parasite load, considered as more than 11 larvae per gram of feces, presented serum cortisol levels above the normal reference value (24 mg/dL). High endogenous cortisol levels in alcoholic patients were not associated to susceptibility to S. stercoralis infection, however once infected, this may lead to a high parasite load. PMID- 26592320 TI - A Chemopreventive Cocktail on the Rocks. PMID- 26592321 TI - The Changing Landscape of Inflammatory Bowel Disease: East Meets West. PMID- 26592322 TI - Fibroblast growth factor 21 attenuates hepatic fibrogenesis through TGF beta/smad2/3 and NF-kappaB signaling pathways. AB - Fibroblast growth factor 21 (FGF-21) is a secreted protein, which has anti diabetic and lipocaic effects, but its ability to protect against hepatic fibrosis has not been studied. In this study, we investigated the ability of FGF 21 to attenuate dimethylnitrosamine (DMN)-induced hepatic fibrogenesis in mice and the mechanism of its action. Hepatic fibrosis was induced by injection of DMN, FGF-21 was administered to the mice once daily in association with DMN injection till the end of the experiment. Histopathological examination, tissue 4 hydroxyproline content and expressions of smooth muscle alpha-actin (alpha-SMA) and collagen I were measured to assess hepatic fibrosis. Ethanol/PDGF-BB activated hepatic stellate cells (HSCs) were used to understand the mechanisms of FGF-21 inhibited hepatic fibrogenesis. Results showed that FGF-21 treatment attenuated hepatic fibrogenesis and was associated with a significant decrease in intrahepatic fibrogenesis, 4-hydroxyproline accumulation, alpha-SMA expression and collagen I deposition. FGF-21 treatment inhibited the activation of HSCs via down-regulating the expression of TGF-beta, NF-kappaB nuclear translocation, phosphorylation levels of smad2/3 and IkappaBalpha. Besides, FGF-21 treatment caused activated HSC apoptosis with increasing expression of Caspase-3, and decreased the ratio of Bcl-2 to Bax. In conclusion, FGF-21 attenuates hepatic fibrogenesis and inhibits the activation of HSC warranting the use of FGF-21 as a potential therapeutic agent in the treatment of hepatic fibrosis. PMID- 26592323 TI - The concept of bio-corona in modulating the toxicity of engineered nanomaterials (ENM). AB - Besides the wide use of engineered nanomaterials (ENM) in technical products, their application spectrum in biotechnology and biomedicine is steadily increasing. In complex physiological environments the physico-chemical properties and the behavior of nanoparticles (NPs) are challenging to characterize. Biomolecules rapidly adsorb to the nanomaterial, leading to the formation of the protein/biomolecule corona, which critically affects the nanomaterials' (patho)biological and technical identities. This formation can trigger an immune response and affect nanoparticles' toxicity and targeting capabilities. In this review, we provide a survey of recent findings on the (protein)corona nanoparticle interaction and discuss how the corona modulates both cytotoxicity and the immune response as well as to improve the efficacy of targeted delivery of nanocarriers. PMID- 26592324 TI - Thiol redox biology of trypanosomatids and potential targets for chemotherapy. AB - Trypanosomatids are the causative agents of African sleeping sickness, Chagas' disease, and the different forms of leishmaniasis. This family of protozoan parasite possesses a trypanothione-based redox metabolism that provides the reducing equivalents for various vital processes such as the biosynthesis of DNA precursors and the detoxification of hydroperoxides. Almost all enzymes of the redox pathway proved to be essential and therefore fulfil one crucial prerequisite for a putative drug target. Trypanothione synthetase and trypanothione reductase are present in all trypanosomatids but absent from the mammalian host which, in addition to the essentiality, renders them highly specific. The chemotherapy research on both enzymes is further supported by the availability of high-throughput screening techniques and crystal structures. In this review we focus on the recent advances and limitations in the development of lead compounds targeting trypanothione synthetase and trypanothione reductase. We present an overview of the available inhibitors and discuss future perspectives including other components of the parasite-specific redox pathway. PMID- 26592325 TI - Use of Electronic Cigarettes by Adolescents. PMID- 26592326 TI - Internationally Comparative Research on Minority and Immigrant Adolescents' Social, Emotional, and Behavioral Development. PMID- 26592327 TI - Parental Attitudes and Beliefs Regarding the Nine-Valent Human Papillomavirus Vaccine. AB - PURPOSE: The purpose of the study was to explore parents' attitudes and beliefs about the nine-valent human papillomavirus vaccine (HPV9). METHODS: Online focus groups were conducted in January, 2015. The U.S. national sample of parents was recruited to four groups: (1) two groups of parents of HPV unvaccinated daughters aged 9-12 years and (2) two groups of parents of vaccinated daughters aged 11-17 years. RESULTS: Participants were 43 parents of vaccinated daughters and 38 parents of unvaccinated daughters. Results indicated low and variable levels of knowledge about HPV, related cancers, and vaccination (e.g., parents unaware vaccine is recommended for boys). Parents were encouraged that HPV9 covered more types, and many said they want the "better" vaccine. Parents of unvaccinated girls wondered whether they should delay vaccination until HPV9 was available, whereas parents of vaccinated girls wondered whether their daughters could be revaccinated with HPV9. Concerns were related to adverse reactions and side effects, whether another new vaccine will be released after HPV9, HPV mutation (i.e., will HPV types change over time--thereby necessitating multiple vaccines?), and cost. Physician recommendation was identified as the most important facilitator of vaccination, with participants wanting providers to exhibit high levels of confidence in and knowledge about HPV vaccines. Last, parents also viewed the prospective idea of a 2-dose HPV9 vaccine as positive. CONCLUSIONS: HPV9 recently became available in the United States and has the potential to offer greater cancer prevention if widespread acceptance and uptake occur. Understanding parental perceptions and questions about HPV9 will be important for clinical messaging about this vaccine. PMID- 26592328 TI - Food Insecurity and the Burden of Health-Related Social Problems in an Urban Youth Population. AB - PURPOSE: Our study objectives were to (1) determine the prevalence of food insecurity; (2) examine the association between presence and level of food insecurity with other health-related social problems; and (3) assess the predictive values of a two-item food insecurity screen in an urban youth population. METHODS: Patients aged 15-25 years completed a Web-based screening tool. Validated questions were used to identify problems in seven health-related social domains (food insecurity, health care access, education, housing, income insecurity, substance use, and intimate partner violence). Chi-square and Kruskal Wallis tests and logistic regression models controlled for age, sex, and race/ethnicity, assessed the association between food insecurity and health related social problems. Predictive values of a two-item food insecurity screen compared with the United States Department of Agriculture Food Security Survey were calculated. RESULTS: Among 400 patients (mean age 18 years; 69.2% female; 54.6% black; 58.9% public insurance), 32.5% screened positive for food insecurity. Increasing food insecurity level was significantly associated with cumulative burden of social problems (p < .001). In adjusted analyses, food insecurity was associated with problems with health care access (aOR = 2.6, 95% confidence interval [CI] 1.7-4.1), education (aOR = 2.8, 95% CI 1.6-5.1), housing (aOR = 2.8, 95% CI 1.8-4.4), income insecurity (aOR = 2.3, 95% CI 1.2-4.5), and substance use (aOR = 2.5, 95% CI 1.5-4.3). The two-item screen demonstrated sensitivity of 88.5% and specificity of 84.1%. CONCLUSIONS: One-third of youth in sample experienced food insecurity, which was strongly associated with presence of other health-related social problems. The two-item screen effectively detected food insecurity. Food insecurity screening may lead to identification of other health-related social problems that when addressed early may improve adolescent health. PMID- 26592329 TI - Adrenarche and the Emotional and Behavioral Problems of Late Childhood. AB - PURPOSE: Mental and behavioral disorders increase in prevalence with the passage through puberty. Yet the first symptoms for many children emerge between seven and 11 years, before the pubertal rise in gonadal hormones. A possibility that symptom onset may be linked to the adrenarchal rise in androgens has been little explored. METHODS: The Childhood to Adolescence Transition Study recruited a stratified random sample of 1,239 eight-nine year olds from primary schools in Melbourne, Australia. Saliva samples were assayed for dehydroepiandrosterone, dehydroepiandrosterone-sulphate (DHEA-S), and testosterone. Emotional and behavioral problems were assessed through parental report on the Strengths and Difficulties Questionnaire. RESULTS: In males, high levels of all androgens were associated with greater total difficulties and peer problems. Higher dehydroepiandrosterone and testosterone were associated with emotional symptoms and DHEA-S with conduct problems. In females, DHEA-S was associated with peer problems. CONCLUSIONS: In late childhood, androgens are associated with emotional and behavioral problems in males, raising a possibility that the adrenarchal transition plays a contributing role. If so, the late primary school years may prove to be an important phase for preventing the onset of mental health and behavioral problems in boys. PMID- 26592330 TI - An Analysis of Adolescent Content in South Africa's Contraception Policy Using a Human Rights Framework. AB - PURPOSE: To evaluate whether the updated South African national contraception policy and guidelines adequately address the needs of adolescents. METHODS: We used the World Health Organization (WHO) guidance and recommendations on ensuring human rights in the provision of contraceptive information and services as an analytic framework. We assessed the South African policy in relation to each WHO summary recommendation. Specifically, we determined where normative guidance pertaining to adolescents is present and whether it is adequate, normative guidance pertaining to all populations but not specifically adolescents is present, or normative guidance for that recommendation is missing from the policy. We developed an analytic table to discuss with coauthors and draw conclusions. RESULTS: We found specific guidance for adolescents relating to 6/9 WHO summary recommendations and 11/24 subrecommendations. Adolescents are highlighted throughout the policy as being at risk for discrimination or coercion, and laws protecting the rights of adolescents are cited. Confidentiality of services for young people is emphasized, and youth-friendly services are described as a key element of service delivery. Areas to strengthen include the need for normative guidance ensuring both availability of contraceptive information and services for young people and adolescent participation in development of community programs and services. CONCLUSIONS: South Africa's contraception policy and guidelines are comprehensive and forward looking. Nevertheless, there are gaps that may leave adolescents vulnerable to discrimination and coercion and create barriers to accessing contraceptive services. These findings provide insight for the revision and development of adolescent health policies in South Africa and other settings. PMID- 26592331 TI - Age and Intimate Partner Violence: An Analysis of Global Trends Among Women Experiencing Victimization in 30 Developing Countries. AB - PURPOSE: Young women are at elevated risk of violence victimization, yet generalizable evidence on age at which abuse first occurs is lacking. This analysis provides new descriptive evidence on age and duration into partnership of women's first intimate partner violence (IPV) victimization. METHODS: Data come from ever married women ages of 15-49 years in nationally representative Demographic and Health Surveys in 30 countries collected from 2005 to 2014 in Africa, Asia, Eastern Europe, and Latin America and the Caribbean. Descriptive analysis is performed. RESULTS: Approximately 29.0% (95% confidence interval [CI]: 28.8, 29.3) of women reported any physical or sexual IPV. Among ever married women who first experienced violence post-union, abuse began, on average, 3.5 years (95% CI 3.4, 3.5), after union formation. Approximately 38.5% (95% CI 37.9, 39.0) and 67.5% (95% CI 67.0, 68.1) of those ever experiencing abuse did so within 1 year and 3 years, respectively, of union formation. Regionally, average years into union of abuse initiation showed little variation and average age at first abuse among once married women is 22.1 years. CONCLUSIONS: Results imply that primary prevention for IPV must take place on average before first union before age 19 years, to capture the most relevant and at risk target population. Resources allocated toward risk factors in childhood and adolescence may be most effective in combating initiation of IPV globally. Despite this finding, there remains a lack of evidence on effective interventions for primary prevention of abuse during women's early years in developing settings. PMID- 26592332 TI - Relationship Context and Intimate Partner Violence From Adolescence to Young Adulthood. AB - PURPOSE: To assess changes in self-reported intimate partner violence (IPV) experience from adolescence through young adulthood. To examine whether individual change in indicators of relationship context--qualities and dynamics of the relationship, changes in partners, and relationship type (dating, cohabiting, and married)--were associated with change in self-reports of IPV. METHODS: Drawing on longitudinal population-based data, the Toledo Adolescent Relationships Study, we used fixed-effects models to estimate within-person change in associations between features of respondents' intimate relationships and the proportion of relationships with IPV from adolescence through young adulthood. Analyses focused on 1,146 young men and women ages 13-29 years (51% female). Items measuring IPV were from the Conflict Tactics Scale. RESULTS: More than half of respondents (53%) experienced discontinuity in IPV across relationships. Among those reporting violence, the vast majority (87%) did not experience violence in all of their relationships. Age-related patterns were similar for men and women with IPV peaking in young adulthood. Infidelity, frequency of disagreements, and partner continuity were associated with a higher proportion of relationships with IPV. Improvements in the nature and character of romantic relationships were associated with a lower accumulation of IPV experiences. CONCLUSIONS: IPV, although prevalent, does not represent a consistent experience. As young adults develop higher quality relationships they move toward desistance from IPV. Yet, variability in these experiences is observed, supporting previous calls for programs that promote the development of healthy relationships among adolescents and young adults. PMID- 26592333 TI - Time-Varying Risk Factors and Sexual Aggression Perpetration Among Male College Students. AB - PURPOSE: Preventing sexual aggression (SA) can be informed by determining if time varying risk factors differentiate men who follow different sexual aggression risk trajectories. METHODS: Data are from a longitudinal study with 795 college males surveyed at the end of each of their 4 years of college in 2008-2011. Repeated measures general linear models tested if changes in risk factors corresponded with sexual aggression trajectory membership. RESULTS: Changes in the risk factors corresponded with SA trajectories. Men who came to college with a history of SA but decreased their perpetration likelihood during college showed concurrent decreases in sexual compulsivity, impulsivity, hostile attitudes toward women, rape supportive beliefs, perceptions of peer approval of forced sex, and perceptions of peer pressure to have sex with many different women, and smaller increases in pornography use over their college years. Conversely, men who increased levels of SA over time demonstrated larger increases in risk factors in comparison to other trajectory groups. CONCLUSIONS: The odds that males engaged in sexual aggression corresponded with changes in key risk factors. Risk factors were not static and interventions designed to alter them may lead to changes in sexual aggression risk. PMID- 26592334 TI - Improving Self-Management Skills Through Patient-Centered Communication. AB - PURPOSE: We tested relationships between patient-centered communication (PCC), relatedness to health care providers, and autonomy around health care management among youth with and without mobility limitations (MLs) and examined whether the relationship between PCC and autonomy was mediated by how connected youth feel to their health care providers. METHODS: Stratified multiple regression models were used to examine predicted associations for youth with and without MLs. RESULTS: PCC was significantly associated with relatedness to health care providers and autonomy for managing health care among youth with and without MLs. After controlling for covariates, evidence of mediation was observed among youth without MLs but not for youth with MLs. CONCLUSIONS: For youth without MLs, mediation suggests that youth's connection to their health care provider contributes to higher levels of health-related autonomy. For youth with MLs, independent of feeling connected to health care providers, more frequent PCC resulted in higher levels of health-related autonomy. PMID- 26592335 TI - Associations Between Active Commuting to School, Body Fat, and Mental Well-being: Population-Based, Cross-Sectional Study in China. AB - PURPOSE: Little is known about patterns of active commuting to school (ACS) among school-aged children in China. This study examines mode of transport to school in China and associations with physical and mental well-being among national representative children. METHODS: Data came from National Puberty Research Collaboration. Commuting mode to school was self-reported and categorized as three categories: walking, cycling, and passive commuting to school. Body mass index, percentage body fat (PBF, measured by skinfold thickness), waist circumference (WC) was measured, and depressive symptoms was assessed by Children's Depression Inventory. RESULTS: A total of 12,151 girls and 9,445 boys from grade 4 to grade 12 participated in this study. Totally 39.9% of Chinese children walked and 15.9% cycled to school, 44.2% traveled by passive commuting mode. ACS was predictive of lower body mass index, PBF, and WC. Children who commuted via active modes had body mass index, PBF, and WC scores of .167 (95% confidence interval [CI] .274-.060), .566 (95% CI .270-.862), and .724 (95% CI .423-1.025) points lower, respectively, than those who used passive transport. ACS was associated with .855 lower odds of being obese (p < .001) and .907 lower (p < .001) odds of having depressive symptoms compared with children using passive transport. CONCLUSIONS: ACS is correlated with better physical and mental well-being. Sustainable transport planning aimed at increasing active travel to school among Chinese children and adolescents is in great need. PMID- 26592336 TI - The comparison of penetration depth of two different photosensitizers in root canals with and without smear layer: An in vitro study. AB - BACKGROUND: The main objective of this study is to evaluate the penetration depth of suggested photosensitizers in the lateral wall of the human root canal. MATERIALS & METHODS: Forty extracted single-rooted human teeth with straight canals that extracted for periodontal reasons were collected and stored in the sterile saline until employment in the experiment. Teeth were decoronated to a standard 12mm root segment using diamond disc. After instrumentation of specimens, the external root surface was sealed with two layers of nail polish to avoid environmental contamination. The apical foramen was subsequently closed with composite material. Teeth were divided randomly in two major groups consist of indocyanine green solution (ICG) and tolonium chloride solution (TCH) with and without EDTA in their subgroups. Specimens in all groups grooved longitudinally with a diamond disc and split in two halves with a stainless steel chisel. The measurements were done by the stereo microscope under 20* magnification in three zones of each specimen and the penetration depth of dye was measured. RESULTS: The results of this study showed that the mean of lateral penetration depth of ICG (224.04MUm) was significantly (P<0.05) higher than TCH (70.15MUm). Regarding to the influence of EDTA, in ICG group without consideration to the different regions, the usage of EDTA improved the mean of lateral penetration depth of ICG, but this improvement was not statistically significant (P>0.05). CONCLUSION: Further to the findings of this study, it could be assumed that ICG could penetrate in deeper regions of the root canal wall. PMID- 26592337 TI - Relationship between the blood perfusion values determined by laser speckle imaging and laser Doppler imaging in normal skin and port wine stains. AB - OBJECTIVE: Laser Doppler imaging (LDI) and laser speckle imaging (LSI) are two major optical techniques aiming at non-invasively imaging the skin blood perfusion. However, the relationship between perfusion values determined by LDI and LSI has not been fully explored. METHODS: 8 healthy volunteers and 13 PWS patients were recruited. The perfusions in normal skin on the forearm of 8 healthy volunteers were simultaneously measured by both LDI and LSI during post occlusive reactive hyperemia (PORH). Furthermore, the perfusions of port wine stains (PWS) lesions and contralateral normal skin of 10 PWS patients were also determined. In addition, the perfusions for PWS lesions from 3 PWS patients were successively monitored at 0, 10 and 20min during vascular-targeted photodynamic therapy (V-PDT). The average perfusion values determined by LSI were compared with those of LDI for each subject. RESULTS: In the normal skin during PORH, power function provided better fits of perfusion values than linear function: powers for individual subjects go from 1.312 to 1.942 (R(2)=0.8967-0.9951). There was a linear relationship between perfusion values determined by LDI and LSI in PWS and contralateral normal skin (R(2)=0.7308-0.9623), and in PWS during V-PDT (R(2)=0.8037-0.9968). CONCLUSION: The perfusion values determined by LDI and LSI correlate closely in normal skin and PWS over a broad range of skin perfusion. However, it still suggests that perfusion range and characteristics of the measured skin should be carefully considered if LDI and LSI measures are compared. PMID- 26592338 TI - The hippo pathway core cassette regulates asymmetric cell division. AB - Asymmetric cell division (ACD) is a crucial process during development, homeostasis, and cancer. Stem and progenitor cells divide asymmetrically, giving rise to two daughter cells, one of which retains the parent cell self-renewal capacity, while the other is committed to differentiation. Any imbalance in this process can induce overgrowth or even a cancer-like state. Here, we show that core components of the Hippo signaling pathway, an evolutionarily conserved organ growth regulator, modulate ACD in Drosophila. Hippo pathway inactivation disrupts the asymmetric localization of ACD regulators, leading to aberrant mitotic spindle orientation and defects in the generation of unequal-sized daughter cells. The Hippo pathway downstream kinase Warts, LATS1-2 in mammals, associates with the ACD modulators Inscuteable and Bazooka in vivo and phosphorylates Canoe, the ortholog of Afadin/AF-6, in vitro. Moreover, phosphosite mutant Canoe protein fails to form apical crescents in dividing neuroblasts in vivo, and the lack of Canoe phosphorylation by Warts leads to failures of Discs Large apical localization in metaphase neuroblasts. Given the relevance of ACD in stem cells during tissue homeostasis, and the well-documented role of the Hippo pathway as a tumor suppressor, these results represent a potential route for perturbations in the Hippo signaling to induce tumorigenesis via aberrant stem cell divisions. PMID- 26592340 TI - Central-complex control of movement in the freely walking cockroach. AB - To navigate in the world, an animal's brain must produce commands to move, change direction, and negotiate obstacles. In the insect brain, the central complex integrates multiple forms of sensory information and guides locomotion during behaviors such as foraging, climbing over barriers, and navigating to memorized locations. These roles suggest that the central complex influences motor commands, directing the appropriate movement within the current context. Such commands are ultimately carried out by the limbs and must therefore interact with pattern generators and reflex circuits that coordinate them. Recent studies have described how neurons of the central complex encode sensory information: neurons subdivide the space around the animal, encoding the direction or orientation of stimuli used in navigation. Does a similar central-complex code directing movement exist, and if so, how does it effect changes in the control of limbs? Recording from central-complex neurons in freely walking cockroaches (Blaberus discoidalis), we identified classes of movement-predictive cells selective for slow or fast forward walking, left or right turns, or combinations of forward and turning speeds. Stimulation through recording wires produced consistent trajectories of forward walking or turning in these animals, and those that elicited turns also altered an inter-joint reflex to a pattern resembling spontaneous turning. When an animal transitioned to climbing over an obstacle, the encoding of movement in this new context changed for a subset of cells. These results indicate that encoding of movement in the central complex participates in motor control by a distributed, flexible code targeting limb reflex circuits. PMID- 26592339 TI - Warts phosphorylates mud to promote pins-mediated mitotic spindle orientation in Drosophila, independent of Yorkie. AB - Multicellular animals have evolved conserved signaling pathways that translate cell polarity cues into mitotic spindle positioning to control the orientation of cell division within complex tissue structures. These oriented cell divisions are essential for the development of cell diversity and the maintenance of tissue homeostasis. Despite intense efforts, the molecular mechanisms that control spindle orientation remain incompletely defined. Here, we describe a role for the Hippo (Hpo) kinase complex in promoting Partner of Inscuteable (Pins)-mediated spindle orientation. Knockdown of Hpo, Salvador (Sav), or Warts (Wts) each result in a partial loss of spindle orientation, a phenotype previously described following loss of the Pins-binding protein Mushroom body defect (Mud). Similar to orthologs spanning yeast to mammals, Wts kinase localizes to mitotic spindle poles, a prominent site of Mud localization. Wts directly phosphorylates Mud in vitro within its C-terminal coiled-coil domain. This Mud coiled-coil domain directly binds the adjacent Pins-binding domain to dampen the Pins/Mud interaction, and Wts-mediated phosphorylation uncouples this intramolecular Mud interaction. Loss of Wts prevents cortical Pins/Mud association without affecting Mud accumulation at spindle poles, suggesting phosphorylation acts as a molecular switch to specifically activate cortical Mud function. Finally, loss of Wts in Drosophila imaginal disc epithelial cells results in diminished cortical Mud and defective planar spindle orientation. Our results provide new insights into the molecular basis for dynamic regulation of the cortical Pins/Mud spindle positioning complex and highlight a novel link with an essential, evolutionarily conserved cell proliferation pathway. PMID- 26592341 TI - Sensorimotor decision making in the zebrafish tectum. AB - An animal's survival depends on its ability to correctly evaluate sensory stimuli and select appropriate behavioral responses. When confronted with ambiguous stimuli, the brain is faced with the task of selecting one action while suppressing others. Although conceptually simple, the site and substrate of this elementary form of decision making is still largely unknown. Zebrafish larvae respond to a moving dot stimulus in either of two ways: a small object (potential prey) evokes approach, whereas a large object (potential predator) is avoided. The classification of object size relies on processing in the optic tectum. We genetically identified a population of cells, largely comprised of glutamatergic tectal interneurons with non-stratified morphologies, that are specifically required for approach toward small objects. When these neurons are ablated, we found that the behavioral response is shifted; small objects now tend to elicit avoidance. Conversely, optogenetic facilitation of neuronal responses with channelrhodopsin (ChR2) enhances approaches to small objects. Calcium imaging in head-fixed larvae shows that a large proportion of these neurons are tuned to small sizes. Their receptive fields are shaped by input from retinal ganglion cells (RGCs) that are selective for prey identity. We propose a model in which valence-based decisions arise, at a fundamental level, from competition between dedicated sensorimotor pathways in the tectum. PMID- 26592342 TI - The role of vibrations in population divergence in the red mason bee, Osmia bicornis. AB - Differences in female preference for certain male characteristics can be a driving force for population divergence and speciation [1-4]. During precopulation, females of the red mason bee, Osmia bicornis, choose suitable males based on, among other criteria, their thoracic vibrations [5]. These vibrations are thought to be a signal of a male's fitness with females choosing the strongest males that can vibrate for the longest time [5]. The precise role of such vibrational signals, however, has not been determined by bioassays, and the vibrations might also play a role in species recognition [6]. There are two main subspecies of O. bicornis in Europe distinguishable only by a single morphological trait [7] (Figure S1). We therefore developed a new bioassay allowing us to impose the vibrations of one live male onto another in order to discern possible selective mate choice by females from O. bicornis originating from different regions of Europe. Females showed strong preference for males from their own region, and male vibrations were the main signal involved in this choice. Thus, vibrational signals encode not only fitness but also information about the region of origin indicating that divergence exists between the different European O. bicornis populations, which might ultimately lead to speciation. These results provide new insights into the scope of vibrational communication in bees, a group previously considered to rely predominantly on chemical signals [8, 9]. Our newly developed method should shed further light on many exciting questions concerning vibrational communication in bees and other animal taxa. PMID- 26592343 TI - Evolutionary trade-off between vocal tract and testes dimensions in howler monkeys. AB - Males often face a trade-off between investments in precopulatory and postcopulatory traits [1], particularly when male-male contest competition determines access to mates [2]. To date, studies of precopulatory strategies have largely focused on visual ornaments (e.g., coloration) or weapon morphology (e.g., antlers, horns, and canines). However, vocalizations can also play an important role in both male competition and female choice [3-5]. We investigated variation in vocal tract dimensions among male howler monkeys (Alouatta spp.), which produce loud roars using a highly specialized and greatly enlarged hyoid bone and larynx [6]. We examined the relative male investment in hyoids and testes among howler monkey species in relation to the level of male-male competition and analyzed the acoustic consequences of variation in hyoid morphology. Species characterized by single-male groups have large hyoids and small testes, suggesting high levels of vocally mediated competition. Larger hyoids lower formant frequencies, probably increasing the acoustic impression of male body size and playing a role analogous to investment in large body size or weaponry. Across species, as the number of males per group increases, testes volume also increases, indicating higher levels of postcopulatory sperm competition, while hyoid volume decreases. These results provide the first evidence of an evolutionary trade-off between investment in precopulatory vocal characteristics and postcopulatory sperm production. PMID- 26592344 TI - A Brazilian social bee must cultivate fungus to survive. AB - The nests of social insects provide suitable microenvironments for many microorganisms as they offer stable environmental conditions and a rich source of food [1-4]. Microorganisms in turn may provide several benefits to their hosts, such as nutrients and protection against pathogens [1, 4-6]. Several examples of symbiosis between social insects and microorganisms have been found in ants and termites. These symbioses have driven the evolution of complex behaviors and nest structures associated with the culturing of the symbiotic microorganisms [5, 7, 8]. However, while much is known about these relationships in many species of ants and termites, symbiotic relationships between microorganisms and social bees have been poorly explored [3, 4, 9, 10]. Here, we report the first case of an obligatory relationship between the Brazilian stingless bee Scaptotrigona depilis and a fungus of the genus Monascus (Ascomycotina). Fungal mycelia growing on the provisioned food inside the brood cell are eaten by the larva. Larvae reared in vitro on sterilized larval food supplemented with fungal mycelia had a much higher survival rate (76%) compared to larvae reared under identical conditions but without fungal mycelia (8% survival). The fungus was found to originate from the material from which the brood cells are made. Since the bees recycle and transport this material between nests, fungus would be transferred to newly built cells and also to newly founded nests. This is the first report of a fungus cultivation mutualism in a social bee. PMID- 26592345 TI - Context odor presentation during sleep enhances memory in honeybees. AB - Sleep plays an important role in stabilizing new memory traces after learning [1 3]. Here we investigate whether sleep's role in memory processing is similar in evolutionarily distant species and demonstrate that a context trigger during deep sleep phases improves memory in invertebrates, as it does in humans. We show that in honeybees (Apis mellifera), exposure to an odor during deep sleep that has been present during learning improves memory performance the following day. Presentation of the context odor during wake phases or novel odors during sleep does not enhance memory. In humans, memory consolidation can be triggered by presentation of a context odor during slow-wave sleep that had been present during learning [3-5]. Our results reveal that deep-sleep phases in honeybees have the potential to prompt memory consolidation, just as they do in humans. This study provides strong evidence for a conserved role of sleep-and how it affects memory processes-from insects to mammals. PMID- 26592346 TI - Towards a characterization of the structural determinants of specificity in the macrocyclizing thioesterase for deoxyerythronolide B biosynthesis. AB - Type I polyketide synthases (PKSs) are giant multidomain proteins that synthesize many therapeutics and other natural products. The synthesis proceeds by a thiotemplate mechanism whereby intermediates are covalently attached to the PKS. The release of the final polyketide is catalyzed by the terminal thioesterase (TE) domain through hydrolysis, transesterification, or macrocyclization. The PKS 6-deoxyerythronolide B synthase (DEBS) produces the 14-membered macrolide core of the clinically important antibiotic erythromycin. The TE domain of DEBS (DEBS TE) has well-established, empirically-defined specificities for hydrolysis or macrocyclization of native and modified substrates. We present efforts towards understanding the structural basis for the specificity of the thioesterase reaction in DEBS TE using a set of novel diphenyl alkylphosphonates, which mimic substrates that are specifically cyclized or hydrolyzed by DEBS TE. We have determined structures of a new construct of DEBS TE alone at 1.7A, and DEBS TE bound with a simple allylphosphonate at 2.1A resolution. Other, more complex diphenyl alkylphosphonates inhibit DEBS TE, but we were unable to visualize these faithful cyclization analogs in complex with DEBS TE. This work represents a first step towards using DEBS TE complexed with sophisticated substrate analogs to decipher the specificity determinants in this important reaction. PMID- 26592348 TI - Two Leptinotarsa uridine diphosphate N-acetylglucosamine pyrophosphorylases are specialized for chitin synthesis in larval epidermal cuticle and midgut peritrophic matrix. AB - Uridine diphosphate-N-acetylglucosamine-pyrophosphorylase (UAP) is involved in the biosynthesis of chitin, an essential component of the epidermal cuticle and midgut peritrophic matrix (PM) in insects. In the present paper, two putative LdUAP genes were cloned in Leptinotarsa decemlineata. In vivo bioassay revealed that 20-hydroxyecdysone (20E) and an ecdysteroid agonist halofenozide activated the expression of the two LdUAPs, whereas a decrease in 20E by RNA interference (RNAi) of an ecdysteroidogenesis gene LdSHD and a 20E signaling gene LdFTZ-F1 repressed the expression. Juvenile hormone (JH), a JH analog pyriproxyfen and an increase in JH by RNAi of an allatostatin gene LdAS-C downregulated LdUAP1 but upregulated LdUAP2, whereas a decrease in JH by silencing of a JH biosynthesis gene LdJHAMT had converse effects. Thus, expression of LdUAPs responded to both 20E and JH. Moreover, knockdown of LdUAP1 reduced chitin contents in whole larvae and integument samples, thinned tracheal taenidia, impaired larval-larval molt, larval-pupal ecdysis and adult emergence. In contrast, silencing of LdUAP2 significantly reduced foliage consumption, decreased chitin content in midgut samples, damaged PM, and retarded larval growth. The resulting larvae had lighter fresh weights, smaller body sizes and depleted fat body. As a result, the development was arrested. Combined knockdown of LdUAP1 and LdUAP2 caused an additive negative effect. Our data suggest that LdUAP1 and LdUAP2 have specialized functions in biosynthesizing chitin in the epidermal cuticle and PM respectively in L. decemlineata. PMID- 26592349 TI - Comparative transcriptome analysis of Bombyx mori spinnerets and Filippi's glands suggests their role in silk fiber formation. AB - The spinneret is located at the end of silk glands in the silkworm, Bombyx mori. The Filippi's gland (FG), which communicates with the silk gland, is considered an accessory to the latter. Although these two organs have been known for centuries, only their morphology has been studied. Their gene expression profiles and physiological roles are still unknown. Aided by next-generation sequencing, we profiled more than 11000 transcripts from the spinneret and FG of silkworm larvae on day 3 of the fifth instar (L5D3) and wandering stage (W1) in this study. A total of 59 ion-transporting protein genes and 106 cuticle protein genes were identified in the spinneret. To analyze the dynamic changes in the expression of spinneret genes, differential expression analysis was performed, and 1452 differentially expressed genes (DEGs) were identified in spinneret tissue harvested on L5D3 and W1 of the silkworm larvae. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment of the DEGs revealed that the spinneret had active ion-transporting, chitin binding, and energy metabolism processes at W1. Based on these data, we hypothesized that the role of the spinneret is to provide a favorable physiological environment for the silk fiber formation. Furthermore, differential expression analysis and GO enrichment of the DEGs in the FG suggested a possible role of this gland in transporting small solutes such as ions, sugars and amino acids to the silk gland. Our findings pave a way for further functional explanation of the spinneret and FG. PMID- 26592350 TI - EWGWS insert in Plasmodium falciparum ookinete surface enolase is involved in binding of PWWP containing peptides: Implications to mosquito midgut invasion by the parasite. AB - There are multiple stages in the life cycle of Plasmodium that invade host cells. Molecular machinery involved is such host-pathogen interactions constitute excellent drug targets and/or vaccine candidates. A screen using a phage display library has previously demonstrated presence of enolase on the surface of the Plasmodium ookinete. Phage-displayed peptides that bound to the ookinete contained a conserved motif (PWWP) in their sequence. Here, direct binding of these peptides with recombinant Plasmodium falciparum enolase (rPfeno) was investigated. These peptides showed specific binding to rPfeno, but failed to bind to other enolases. Plasmodium spp enolases are distinct in having an insert of five amino acids ((104)EWGWS(108)) that is not found in host enolases. The possibility of this insert being the recognition motif for the PWWP containing peptides was examined, (i) by comparing the binding of the peptides with rPfeno and a deletion variant Delta-rPfeno lacking (104)EWGWS(108), (ii) by measuring the changes in proton chemical shifts of PWWP peptides on binding to different enolases and (iii) by inter-molecular docking experiment to locate the peptide binding site. Results from these studies showed that the pentapeptide insert of Pfeno indeed constitutes the binding site for the PWWP domain containing peptide ligands. Search for sequences homologous to phage displayed peptides among peritrophic matrix proteins resulted in identification of perlecan, laminin, peritrophin and spacran. The possibility of these PWWP domain-containing proteins in the peritrophic matrix of insect gut to interact with ookinete cell surface enolase and facilitate the invasion of mosquito midgut epithelium is discussed. PMID- 26592351 TI - Computational pathology: Exploring the spatial dimension of tumor ecology. AB - Tumors are evolving ecosystems where cancer subclones and the microenvironment interact. This is analogous to interaction dynamics between species in their natural habitats, which is a prime area of study in ecology. Spatial statistics are frequently used in ecological studies to infer complex relations including predator-prey, resource dependency and co-evolution. Recently, the emerging field of computational pathology has enabled high-throughput spatial analysis by using image processing to identify different cell types and their locations within histological tumor samples. We discuss how these data may be analyzed with spatial statistics used in ecology to reveal patterns and advance our understanding of ecological interactions occurring among cancer cells and their microenvironment. PMID- 26592352 TI - Alcohol and liver disease in Europe--Simple measures have the potential to prevent tens of thousands of premature deaths. AB - In the World Health Organisation European Region, more than 2,370,000 years of life are lost from liver disease before the age of 50; more than lung cancer, trachea, bronchus, oesophageal, stomach, colon, rectum and pancreatic cancer combined. Between 60-80% of these deaths are alcohol related, a disease for which no pharmaceutical therapy has yet been shown to improve long-term survival. The toxicity of alcohol is dose related at an individual level, and is dose related at a population level; overall liver mortality is largely determined by population alcohol consumption. Trends in alcohol consumption correlate closely with trends in overall liver mortality, with 3-5-fold decreases or increases in liver mortality in different European countries over the last few decades. The evidence base for alcohol control measures aimed at reducing population alcohol consumption has been subjected to rigorous evaluation; most recently by the Organisation for Economic Co-Operation and Development (OECD). Effective alcohol policy measures reduce alcohol mortality, including mortality from liver disease. The most effective and cost effective measures have been summarised by the OECD and the World Health Organisation: regular incremental above inflation tax increases, a minimum price for alcohol, effective protection of children from alcohol marketing and low level interventions from clinicians. Simple, cheap and effective changes to alcohol policy by European Institutions and member states have the potential to dramatically reduce liver mortality in Europe. PMID- 26592353 TI - Reply to "Is the post-transplant survival the unique Holy Grail?". PMID- 26592354 TI - FibroGENE: A gene-based model for staging liver fibrosis. AB - BACKGROUND & AIMS: The extent of liver fibrosis predicts long-term outcomes, and hence impacts management and therapy. We developed a non-invasive algorithm to stage fibrosis using non-parametric, machine learning methods designed for predictive modeling, and incorporated an invariant genetic marker of liver fibrosis risk. METHODS: Of 4277 patients with chronic liver disease, 1992 with chronic hepatitis C (derivation cohort) were analyzed to develop the model, and subsequently validated in an independent cohort of 1242 patients. The model was assessed in cohorts with chronic hepatitis B (CHB) (n=555) and non-alcoholic fatty liver disease (NAFLD) (n=488). Model performance was compared to FIB-4 and APRI, and also to the NAFLD fibrosis score (NFS) and Forns' index, in those with NAFLD. RESULTS: Significant fibrosis (?F2) was similar in the derivation (48.4%) and validation (47.4%) cohorts. The FibroGENE-DT yielded the area under the receiver operating characteristic curve (AUROCs) of 0.87, 0.85 and 0.804 for the prediction of fast fibrosis progression, cirrhosis and significant fibrosis risk, respectively, with comparable results in the validation cohort. The model performed well in NAFLD and CHB with AUROCs of 0.791, and 0.726, respectively. The negative predictive value to exclude cirrhosis was>0.96 in all three liver diseases. The AUROC of the FibroGENE-DT performed better than FIB-4, APRI, and NFS and Forns' index in most comparisons. CONCLUSION: A non-invasive decision tree model can predict liver fibrosis risk and aid decision making. PMID- 26592356 TI - Natural killer cell biology illuminated by primary immunodeficiency syndromes in humans. AB - Natural killer (NK) cells are innate immune cytotoxic effector cells well known for their role in antiviral immunity and tumor immunosurveillance. In parts, this knowledge stems from rare inherited immunodeficiency disorders in humans that abrogate NK cell function leading to immune impairments, most notably associated with a high susceptibility to viral infections. Phenotypically, these disorders range from deficiencies selectively affecting NK cells to complex general immune defects that affect NK cells but also other immune cell subsets. Moreover, deficiencies may be associated with reduced NK cell numbers or rather impair specific NK cell effector functions. In recent years, genetic defects underlying the various NK cell deficiencies have been uncovered and have triggered investigative efforts to decipher the molecular mechanisms underlying these disorders. Here we review the associations between inherited human diseases and NK cell development as well as function, with a particular focus on defects in NK cell exocytosis and cytotoxicity. Furthermore we outline how reports of diverse genetic defects have shaped our understanding of NK cell biology. PMID- 26592357 TI - COMPUTED TOMOGRAPHIC ANATOMY AND CHARACTERISTICS OF RESPIRATORY ASPERGILLOSIS IN JUVENILE WHOOPING CRANES. AB - Respiratory diseases are a leading cause of morbidity and mortality in captivity reared, endangered whooping cranes (Grus americana). Objectives of this retrospective, case series, cross-sectional study were to describe computed tomography (CT) respiratory anatomy in a juvenile whooping crane without respiratory disease, compare CT characteristics with gross pathologic characteristics in a group of juvenile whooping cranes with respiratory aspergillosis, and test associations between the number of CT tracheal bends and bird sex and age. A total of 10 juvenile whooping cranes (one control, nine affected) were included. Seven affected cranes had CT characteristics of unilateral extrapulmonary bronchial occlusion or wall thickening, and seven cranes had luminal occlusion of the intrapulmonary primary or secondary bronchi. Air sac membrane thickening was observed in three cranes in the cranial and caudal thoracic air sacs, and air sac diverticulum opacification was observed in four cranes. Necropsy lesions consisted of severe, subacute to chronic, focally extensive granulomatous pathology of the trachea, primary bronchi, lungs, or air sacs. No false positive CT scan results were documented. Seven instances of false negative CT scan results occurred; six of these consisted of subtle, mild air sacculitis including membrane opacification or thickening, or the presence of small plaques found at necropsy. The number of CT tracheal bends was associated with bird age but not sex. Findings supported the use of CT as a diagnostic test for avian species with respiratory disease and tracheal coiling or elongated tracheae where endoscopic evaluation is impractical. PMID- 26592358 TI - A Sampling Framework for Uncertainty in Individual Environmental Decisions. AB - Decisions in the environmental and in particular the climate domain are burdened with uncertainty. Here, we focus on uncertainties faced by individuals when making decisions about environmental behavior, and we use the statistical sampling framework to develop a classification of different sources of uncertainty they encounter. We then map these sources to different public policy strategies aiming to help individuals cope with uncertainty when making environmental decisions. PMID- 26592355 TI - PTSD co-morbid with HIV: Separate but equal, or two parts of a whole? AB - Approximately 30 million people currently live with HIV worldwide and the incidence of stress-related disorders, such as post-traumatic stress disorder (PTSD), is elevated among people living with HIV as compared to those living without the virus. PTSD is a severely debilitating, stress-related psychiatric illness associated with trauma exposure. Patients with PTSD experience intrusive and fearful memories as well as flashbacks and nightmares of the traumatic event(s) for much of their lives, may avoid other people, and may be constantly on guard for new negative experiences. This review will delineate the information available to date regarding the comorbidity of PTSD and HIV and discuss the biological mechanisms which may contribute to the co-existence, and potential interaction of, these two disorders. Both HIV and PTSD are linked to altered neurobiology within areas of the brain involved in the startle response and altered function of the hypothalamic-pituitary-adrenal axis. Collectively, the data highlighted suggest that PTSD and HIV are more likely to actively interact than to simply co-exist within the same individual. Multi-faceted interactions between PTSD and HIV have the potential to alter response to treatment for either independent disorder. Therefore, it is of great importance to advance the understanding of the neurobiological substrates that are altered in comorbid PTSD and HIV such that the most efficacious treatments can be administered to improve both mental and physical health and reduce the spread of HIV. PMID- 26592359 TI - Genome-wide RNA-Seq analysis of breast muscles of two broiler chicken groups differing in shear force. AB - In this study, a whole transcriptome analysis of breast muscles was conducted in broiler chicken groups differing in shear force. Shear force is a determinant of tenderness, which in turn is one of the most important parameters of meat quality in chickens. In our analysis, a total of 11,560 transcripts and 9824 genes per sample were identified. In chickens with more tender meat, up-regulation of 19 genes and down-regulation of 49 genes was observed. The up-regulated gene group included the ASB2 gene, which is probably involved in the meat conversion process, as its product results in the degradation of filamins, proteins which form muscle fibres. In the down-regulated gene group, genes which play a role in lipogenesis (THRSP, PLIN1) and in collagen synthesis (P4HA3, LEPREL4, PCOLCE2, COL16A1, COL20A1, VWA1) were detected. Their presence suggests the involvement of the extracellular matrix in the determination of meat tenderness. Thus, our study identified a pool of genes that may participate in the tenderisation process in broiler chickens. PMID- 26592360 TI - Assembling Supramolecular Dye-Sensitized Photoelectrochemical Cells for Water Splitting. AB - The method used to assemble dye-sensitized photoelectrochemical (DS-PEC) devices plays a vital role in determining its photoactivity and stability. We report a simple and effective method to assemble supramolecular DS-PECs introducing PMMA as support material and a catalyst modified with long carbon chains as photoanodes. The long carbon chains in combination with PMMA allow to better immobilize the catalyst. DS-PECs obtained by this simple method have display excellent photoactivities and stabilities. A photocurrent density of 1.1 mA cm( 2) and a maximum IPCE of 9.5 % have been obtained with a 0.2 V vs NHE external bias. PMID- 26592361 TI - Breaking Down Chemical Weapons by Metal-Organic Frameworks. AB - Seek and destroy: Filtration schemes and self-detoxifying protective fabrics based on the Zr(IV)-containing metal-organic frameworks (MOFs) MOF-808 and UiO-66 doped with LiOtBu have been developed that capture and hydrolytically detoxify simulants of nerve agents and mustard gas. Both MOFs function as highly catalytic elements in these applications. PMID- 26592362 TI - Discrimination of the sensory quality of the Coffea arabica L. (cv. Yellow Bourbon) produced in different altitudes using decision trees obtained by the CHAID method. AB - BACKGROUND: Knowledge of the sensory profile of coffee quality, associated with genetic and environmental factors, is of utmost importance for the international market, as well as for the productive sector. In this context, the goal of this study was to classify the quality of Coffea arabica L., cv. Yellow Bourbon, according to different scores obtained through sensory evaluations based on the Specialty Coffee Association of America protocol (SCAA), and by means of decision trees resulting from applying the CHAID method (chi-square automatic interaction detection). To that end, we used a database with the sensory characteristics of cv. Yellow Bourbon and the environmental characteristics of the Mantiqueira de Minas region, State of Minas Gerais, Brazil. RESULTS: The method used exhibited promising results regarding accuracy and success rates in order to discriminate coffee sensory quality as a function of the production environment. The results obtained clearly show the effect of the coffee growing environment on the Yellow Bourbon variety, resulting in notable sensory differences in the beverage. CONCLUSION: It was possible to discriminate cv. Yellow Bourbon coffee samples, the sensory evaluations of which resulted in scores of >=88 points, which are associated with growing environments at altitudes of >=1200 m. (c) 2015 Society of Chemical Industry. PMID- 26592363 TI - Regioselective, Asymmetric Formal Hydroamination of Unactivated Internal Alkenes. AB - We report the regioselective and enantioselective formal hydroamination of unsymmetrical internal alkenes catalyzed by a copper catalyst ligated by DTBM SEGPHOS. The regioselectivity of the reaction is controlled by the electronic effects of ether, ester, and sulfonamide groups in the homoallylic position. The observed selectivity underscores the influence of inductive effects of remote substituents on the selectivity of catalytic processes occurring at hydrocarbyl groups, and the method provides direct access to various 1,3-aminoalcohol derivatives with high enantioselectivity. PMID- 26592364 TI - Opioids in COPD: the 'whole picture' includes results from real-world, population based observational studies. PMID- 26592365 TI - Curcumin attenuates memory deficits and the impairment of cholinergic and purinergic signaling in rats chronically exposed to cadmium. AB - This study investigated the protective effect of curcumin on memory loss and on the alteration of acetylcholinesterase and ectonucleotidases activities in rats exposed chronically to cadmium (Cd). Rats received Cd (1 mg/kg) and curcumin (30, 60, or 90 mg/kg) by oral gavage 5 days a week for 3 months. The animals were divided into eight groups: vehicle (saline/oil), saline/curcumin 30 mg/kg, saline/curcumin 60 mg/kg, saline/curcumin 90 mg/kg, Cd/oil, Cd/curcumin 30 mg/kg, Cd/curcumin 60 mg/kg, and Cd/curcumin 90 mg/kg. Curcumin prevented the decrease in the step-down latency induced by Cd. In cerebral cortex synaptosomes, Cd exposed rats showed an increase in acetylcholinesterase and NTPDase (ATP and ADP as substrates) activities and a decrease in the 5'-nucleotidase activity. Curcumin was not able to prevent the effect of Cd on acetylcholinesterase activity, but it prevented the effects caused by Cd on NTPDase (ATP and ADP as substrate) and 5'-nucleotidase activities. Increased acetylcholinesterase activity was observed in different brain structures, whole blood and lymphocytes of the Cd-treated group. In addition, Cd increased lipid peroxidation in different brain structures. Higher doses of curcumin were more effective in preventing these effects. These findings show that curcumin prevented the Cd mediated memory impairment, demonstrating that this compound has a neuroprotective role and is capable of modulating acetylcholinesterase, NTPDase, and 5'-nucleotidase activities. Finally, it highlights the possibility of using curcumin as an adjuvant against toxicological conditions involving Cd exposure. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 32: 70-83, 2017. PMID- 26592367 TI - Flow Cytometric Chromosomal Sex Sorting of Stallion Spermatozoa Induces Oxidative Stress on Mitochondria and Genomic DNA. AB - To date, the only repeatable method to select spermatozoa for chromosomal sex is the Beltsville sorting technology using flow cytometry. Improvement of this technology in the equine species requires increasing awareness of the modifications that the sorting procedure induces on sperm intactness. Oxidative stress is regarded as the major damaging phenomenon, and increasing evidence regards handling of spermatozoa - including sex sorting - as basic ground for oxidative damage. The aim of this study was to disclose whether the flow cytometric sorting procedure increases the production of reactive oxygen species (ROS), and to identify if ROS production relates to DNA damage in sorted spermatozoa using specific flow cytometry-based assays. After sorting, oxidative stress increased from 26% to 33% in pre- and post-incubation controls, to 46% after sex sorting (p < 0.05). Proportions of DNA fragmentation index post-sorting were approximately 10% higher (31.3%); an effect apparently conduced via oxidative DNA damage as revealed by the oxyDNA assay. The probable origin of this increased oxidative stress owes the removal of enough seminal plasma due to the unphysiological sperm extension, alongside a deleterious effect of high pressure on mitochondria during the sorting procedure. PMID- 26592369 TI - Cows' milk exclusion diet during infancy: Is there a long-term effect on children's eating behaviour and food preferences? AB - BACKGROUND: Dietary restriction during infancy may influence later eating behaviour. The aim of this study was to determine whether consuming a cows' milk exclusion (CME) diet during infancy affects eating habits in later childhood, once cows' milk has been reintroduced into the diet. METHODS: Children were recruited from two large birth cohort studies in the UK. A small number of participants were recruited from allergy clinic. Two groups were recruited: an experimental group of children who had consumed a CME diet during infancy and a control group, who had consumed an unrestricted diet during infancy. Parents and children completed questionnaires regarding eating behaviour and food preferences. RESULTS: In total, 101 children of mean age 11.5 years were recruited (28 CME and 73 controls). The CME group scored significantly higher on 'slowness of eating' and on the combined 'avoidant eating behaviour' construct (p < 0.01). The number of foods avoided and symptoms was associated with higher levels of avoidant eating behaviour (p < 0.05). The CME group rated liking for several dairy foods (butter, cream, chocolate, full fat milk and ice cream) significantly lower than the control group (p < 0.05), although there were no significant differences seen for any other category of food. CONCLUSION: This study demonstrated that consuming a CME diet during infancy has persistent and long-term effects on eating habits and food preferences. To reduce future negative eating behaviours, children's exclusion diets need to be as varied as possible and reintroduction of cows' milk products closely monitored. PMID- 26592368 TI - Cascade plasmapheresis as preconditioning regimen for ABO-incompatible renal transplantation: a single-center experience. AB - BACKGROUND: Removal of anti-ABO is an important component of the preconditioning regimen for ABO-incompatible (ABOi) renal transplant. Cascade plasmapheresis (CP) is one of the extracorporeal methods of antibody removal, others being conventional plasma exchange (PE) and immunoadsorption. There is no previous published experience with CP in this context. The purpose of this study was to present an early experience with this approach. STUDY DESIGN AND METHODS: Consecutive ABOi renal transplant recipients in whom CP was used for pre- and posttransplant anti-ABO removal were included. All the patients received intravenous rituximab 2 weeks before transplant. After 1 week, CP was started along with oral tacrolimus and mycophenolate sodium. Alternate-day CP was done to attain immediate pretransplant antibody titer of not more than 8. RESULTS: Fifteen ABOi renal transplant recipients had baseline (pretreatment) antibody titers ranging from 16 to 512. Desensitization rate was 100%. The mean number of procedures before transplant to achieve titer of not more than 8 was 3.27 +/- 1.39. Patient survival was 93% and death-censored graft survival was 87%. Biopsy proven acute rejection was seen in three patients (20%), one (6.67%) being acute antibody mediated rejection. The complication rate during CP was 4% and two patients had bleeding complication after surgery. Posttransplant infection rate was 13%. CONCLUSION: Based on limited number of patients, we conclude that CP is a safe and effective extracorporeal method for pretransplant ABO antibody removal in patients undergoing ABOi transplant. Patients undergoing CP met target preoperative antibody titers and the clinical outcomes were acceptable. PMID- 26592370 TI - Recent advances in telemetry for estimating the energy metabolism of wild fishes. AB - Metabolic rate is a critical factor in animal biology and ecology, providing an objective measure that can be used in attributing a cost to different activities and to assessing what animals do against some optimal behaviour. Ideally, metabolic rate would be estimated directly by measuring heat output but, until recently, this has not been easily tractable with fishes so instead metabolic rate is usually estimated using indirect methods. In the laboratory, oxygen consumption rate is the indirect method most frequently used for estimating metabolic rate, but technical requirements preclude the measurement of either heat output or oxygen consumption rate in free-ranging fishes. There are other field methods for estimating metabolic rate that can be used with mammals and birds but, again, these cannot be used with fishes. Here, the use of electronic devices that record body acceleration in three dimensions (accelerometry) is considered. Accelerometry is a comparatively new telemetric method for assessing energy metabolism in animals. Correlations between dynamic body acceleration (DBA) and oxygen consumption rate demonstrate that this will be a useful proxy for estimating activity-specific energy expenditure from fishes in mesocosm or field studies over extended periods where other methods (e.g. oxygen consumption rate) are not feasible. DBA therefore has potential as a valuable tool for attributing cost to different activities. This could help in gaining a full picture of how fishes make energy-based trade-offs between different levels of activity when faced with conflicting or competing demands arising from increased and combined environmental stressors. PMID- 26592371 TI - Registered nurses' perceptions of new nursing graduates' clinical competence: A systematic integrative review. AB - Over the past decade, many questions have been raised about graduates' clinical competence and fitness for practice upon completion of their undergraduate education. Despite the significance of this issue, the perspectives of registered nurses have rarely been examined. This systematic review explores the perceptions of experienced registered nurses regarding the clinical competence of new nursing graduates. Original research studies published between 2004-2014 were identified using electronic databases, reference lists, and by searching "grey literature." Papers were critically reviewed and relevant data extracted and synthesized using an approach based on Preferred Reporting Items for Systematic Reviews and Meta Analysis. From 153 studies initially identified, 15 original research papers were included. Four main research themes were identified: clinical/technical skills, critical thinking, interaction/communication, and overall readiness for practice. Areas of concern in relation to the clinical competence of new nursing graduates specifically related to two themes: critical thinking and clinical/technical skills. Further research is required on strategies identified within the literature with the ultimate aim of ensuring new nursing graduates are safe and competent practitioners. PMID- 26592372 TI - Literature Review and Profile of Cancer Diseases Among Afghan Refugees in Iran: Referrals in Six Years of Displacement. AB - BACKGROUND: There is a paucity of research on the profile of cancers among displaced populations, specifically Afghan refugees in Iran. This study illustrates the pattern of cancers in this population, and highlights the challenges of cancer care in displaced people with the intent that this data will facilitate appropriate allocation of resources to improve care in this population. MATERIAL AND METHODS: This was a retrospective cross-sectional study, in which we collected the demographics and profile of cancers among Afghan refugees from 2005 to 2010 from referrals to the United Nations High Commissioner for Refugees (UNHCR) offices in Iran. Accrued evidence by other studies published between January 1993 and July 2014 pertaining to cancer diagnoses in refugees from Afghanistan, Tibet, Syria, Jordan, and Iraq was reviewed. RESULTS: Cancer diagnoses accounted for 3083 of 23 152 total referrals, with 49% female and 51% male cases; 23.3% were 0-17 years of age, 61.2% were 18-59, and 15.5% were above 60. The most common health referral for females and males (0-17) was malignant neoplasms of lymphatic and hematopoietic tissue, accounting for 34.2%. In the age groups 18-59 and above 60 for both male and females it was malignant neoplasm of the digestive system, occurring in 26.3% and 48.7%, respectively. CONCLUSIONS: In the setting of humanitarian crises especially war, cancer diagnoses among refugees is a major health burden both on the host countries and the international community with serious implications considering the recent growing trend in the Middle Eastern countries. The prevalence of certain cancer diagnoses among refugees, like gastrointestinal, respiratory, breast, and genitourinary cancers necessitates a multidirectional approach, primarily aimed at prevention and early detection. International partnerships are essential for improvement in cancer surveillance service availability, and delivery of the standard of care, in an overall effort to reduce the human cost, monetary, and resource associated burdens of cancer. Recommendations to implement effective prevention and management goals as well as improved record keeping in the refugee setting and the acquisition of secure and sustainable funding sources should be implemented in collaboration with global humanitarian agencies like UNHCR. PMID- 26592366 TI - Bridging the Gap: From 2D Cell Culture to 3D Microengineered Extracellular Matrices. AB - Historically the culture of mammalian cells in the laboratory has been performed on planar substrates with media cocktails that are optimized to maintain phenotype. However, it is becoming increasingly clear that much of biology discerned from 2D studies does not translate well to the 3D microenvironment. Over the last several decades, 2D and 3D microengineering approaches have been developed that better recapitulate the complex architecture and properties of in vivo tissue. Inspired by the infrastructure of the microelectronics industry, lithographic patterning approaches have taken center stage because of the ease in which cell-sized features can be engineered on surfaces and within a broad range of biocompatible materials. Patterning and templating techniques enable precise control over extracellular matrix properties including: composition, mechanics, geometry, cell-cell contact, and diffusion. In this review article we explore how the field of engineered extracellular matrices has evolved with the development of new hydrogel chemistry and the maturation of micro- and nano- fabrication. Guided by the spatiotemporal regulation of cell state in developing tissues, techniques for micropatterning in 2D, pseudo-3D systems, and patterning within 3D hydrogels will be discussed in the context of translating the information gained from 2D systems to synthetic engineered 3D tissues. PMID- 26592373 TI - Two cases of upper lip correction using multipolydioxanone scaffold. PMID- 26592374 TI - Divergent Synthesis of Multisubstituted Tetrahydrofurans and Pyrrolidines via Intramolecular Aldol-type Trapping of Onium Ylide Intermediates. AB - This paper reports a divergent strategy for the synthesis of multisubstituted tetrahydrofurans and pyrrolidines, starting from easily accessible beta hydroxyketones or beta-aminoketones to react with diazo compounds. Under Rh(II) catalysis, this transformation is proposed to proceed through a metal-carbene induced oxonium ylide or ammonium ylide formation followed by an intramolecular aldol-type trapping of these active intermediates. A series of highly substituted tetrahydrofurans and pyrrolidines are synthesized in high yields with good to excellent diastereoselectivities. Preliminary biological evaluations revealed that both types of heterocycles show good PTP1B inhibitory activities. PMID- 26592375 TI - Incidence and risk conditions of ischemic stroke in older adults. AB - OBJECTIVE: The objective of this study was to investigate incidence and mortality from ischemic stroke in older adults with specific underlying chronic conditions, evaluating the influence of these conditions in developing stroke. MATERIALS & METHODS: Population-based cohort study involving 27,204 individuals >=60 years old in Southern Catalonia, Spain. All cases of hospitalization from ischemic stroke (confirmed by neuro-imaging) were collected from 01/12/2008 until 30/11/2011. Incidence rates and 30-day mortality were estimated according to age, sex, chronic illnesses, and underlying conditions. Multivariable Cox regression analysis was used to calculate Hazards Ratio (HR) and estimate the association between baseline conditions and risk of developing stroke. RESULTS: Mean incidence rate reached 453 cases per 100,000 person-years. Maximum rates appeared among individuals with history of prior stroke (2926 per 100,000), atrial fibrillation (1815 per 100,000), coronary artery disease (1104 per 100,000), nursing-home residence (1014 per 100,000), and advanced age >=80 years (1006 per 100,000). Thirty-day mortality was 13% overall, reaching 21% among patients over 80 years. Age [HR: 1.06; 95% confidence interval (CI): 1.04-1.07], history of prior stroke (HR: 5.08; 95% CI: 3.96-6.51), history of coronary artery disease (HR: 1.65; 95% CI: 1.21-2.25), atrial fibrillation (HR: 2.96; 95% CI: 2.30-3.81), diabetes mellitus (HR: 1.55; 95% CI: 1.23-1.95), and smoking (HR: 1.64; 95% CI: 1.15-2.34) emerged independently associated with an increased risk of ischemic stroke. CONCLUSION: Incidence and mortality from ischemic stroke remains considerable. Apart from age and history of atherosclerosis (prior stroke or coronary artery disease), atrial fibrillation, diabetes, and smoking were the underlying conditions most strongly associated with an increased risk. PMID- 26592376 TI - Population genomics of yeasts: towards a comprehensive view across a broad evolutionary scale. AB - With the advent of high-throughput technologies for sequencing, the complete description of the genetic variation that occurs in populations, also known as population genomics, is foreseeable but far from being reached. Explaining the forces that govern patterns of genetic variation is essential to elucidate the evolutionary history of species. Genetic variation results from a wide assortment of evolutionary forces, among which mutation, selection, recombination and drift play major roles in shaping genomes. In addition, exploring the genetic variation within a population also corresponds to the first step towards dissecting the genotype-phenotype relationship. In this context, yeast species are of particular interest because they represent a unique resource for studying the evolution of intraspecific genetic diversity in a phylum spanning a broad evolutionary scale. Here, we briefly review recent progress in yeast population genomics and provide some perspective on this rapidly evolving field. In fact, we truly believe that it is of interest to supplement comparative and early population genomic studies with the deep sequencing of more extensive sets of individuals from the same species. In parallel, it would be more than valuable to uncover the intraspecific variation of a large number of unexplored species, including those that are closely and more distantly related. Altogether, these data would enable substantially more powerful genomic scans for functional dissection. PMID- 26592377 TI - Transfusion strategy in hematological intensive care unit: study protocol for a randomized controlled trial. AB - BACKGROUND: Packed red blood cell (PRBC) transfusion is required in hematology patients treated with chemotherapy for acute leukemia, autologous (auto) or allogeneic (allo) hematopoietic stem cell transplantation (HSCT). In certain situations like septic shock, hip surgery, coronary disease or gastrointestinal hemorrhage, a restrictive transfusion strategy is associated with a reduction of infection and death. A transfusion strategy using a single PRBC unit has been retrospectively investigated and showed a safe reduction of PRBC consumption and costs. We therefore designed a study to prospectively demonstrate that the transfusion of a single PRBC unit is safe and not inferior to standard care. METHODS: The 1versus2 trial is a randomized trial which will determine if a single-unit transfusion policy is not inferior to a double-unit transfusion policy. The primary endpoint is the incidence of severe complication (grade >= 3) defined as stroke, transient ischemic attack, acute coronary syndrome, heart failure, elevated troponin level, intensive care unit transfer, death, new pulmonary infiltrates, and transfusion-related infections during hospital stays. The secondary endpoint is the number of PRBC units transfused per patient per hospital stay. Two hundred and thirty patients will be randomized to receive a single unit or double unit every time the hemoglobin level is less than 8 g/dL. All patients admitted for induction remission chemotherapy, auto-HSCT or allo HSCT in hematology intensive care units will be eligible for inclusion. Sample size calculation has determined that a patient population of 230 will be required to prove that the 1-unit PRBC strategy is non-inferior to the 2-unit PRBC strategy. Hemoglobin threshold for transfusion is below 8 g/dL. Estimated percentage of complication-free hospital stays is 93 %. In a non-inferiority hypothesis, the number of patients to include is 230 with a power of 90 % and an alpha risk of 5 %. TRIAL REGISTRATION: 14-128; Clinicaltrials.gov NCT02461264 (registered on 3 June 2015). PMID- 26592380 TI - Prodigious Effects of Concentration Intensification on Nanoparticle Synthesis: A High-Quality, Scalable Approach. AB - Realizing the promise of nanoparticle-based technologies demands more efficient, robust synthesis methods (i.e., process intensification) that consistently produce large quantities of high-quality nanoparticles (NPs). We explored NP synthesis via the heat-up method in a regime of previously unexplored high concentrations near the solubility limit of the precursors. We discovered that in this highly concentrated and viscous regime the NP synthesis parameters are less sensitive to experimental variability and thereby provide a robust, scalable, and size-focusing NP synthesis. Specifically, we synthesize high-quality metal sulfide NPs (<7% relative standard deviation for Cu2-xS and CdS), and demonstrate a 10-1000-fold increase in Cu2-xS NP production (>200 g) relative to the current field of large-scale (0.1-5 g yields) and laboratory-scale (<0.1 g) efforts. Compared to conventional synthesis methods (hot injection with dilute precursor concentration) characterized by rapid growth and low yield, our highly concentrated NP system supplies remarkably controlled growth rates and a 10-fold increase in NP volumetric production capacity (86 g/L). The controlled growth, high yield, and robust nature of highly concentrated solutions can facilitate large-scale nanomanufacturing of NPs by relaxing the synthesis requirements to achieve monodisperse products. Mechanistically, our investigation of the thermal and rheological properties and growth rates reveals that this high concentration regime has reduced mass diffusion (a 5-fold increase in solution viscosity), is stable to thermal perturbations (~64% increase in heat capacity), and is resistant to Ostwald ripening. PMID- 26592381 TI - Revisiting the Exact Relation between Potential of Mean Force and Free-Energy Profile. AB - Constraints are convenient in the calculation of free energy profiles via molecular dynamics simulations, but they subtly alter the phase space distribution. In a recent letter of a related title in this journal, Wong and York [J. Chem. Theory Comput. 2012, 8, 3998-4003] suggest replacing Fixman's mass metric correction with its inverse and adding a Jacobian contribution to the potential of mean constraint force. This letter refutes both suggestions, discusses the underlying interpretation problems, and provides supporting numerical simulations. PMID- 26592379 TI - Metal Organic Frameworks Derived Hierarchical Hollow NiO/Ni/Graphene Composites for Lithium and Sodium Storage. AB - Ni-based metal organic frameworks (Ni-MOFs) with unique hierarchical hollow ball in-ball nanostructure were synthesized by solvothermal reactions. After successive carbonization and oxidation treatments, hierarchical NiO/Ni nanocrystals covered with a graphene shell were obtained with the hollow ball-in ball nanostructure intact. The resulting materials exhibited superior performance as the anode in lithium ion batteries (LIBs): they provide high reversible specific capacity (1144 mAh/g), excellent cyclability (nearly no capacity loss after 1000 cycles) and rate performance (805 mAh/g at 15 A/g). In addition, the hierarchical NiO/Ni/Graphene composites demonstrated promising performance as anode materials for sodium-ion batteries (SIBs). Such a superior lithium and sodium storage performance is derived from the well-designed hierarchical hollow ball-in-ball structure of NiO/Ni/Graphene composites, which not only mitigates the volume expansion of NiO during the cycles but also provides a continuous highly conductive graphene matrix to facilitate the fast charge transfer and form a stable SEI layer. PMID- 26592382 TI - Computational Prediction for Singlet- and Triplet-Transition Energies of Charge Transfer Compounds. AB - Our work reveals a high dependence on charge-transfer (CT) amounts for the optimal Hartree-Fock percentage in the exchange-correlation functional of time dependent density functional theory (TD-DFT) and the error of a vertical transition energy calculated by a given functional. Using these relations, the zero-zero transition energies of the first singlet and first triplet excited states of various CT compounds are accurately reproduced. (3)CT and locally excited triplet ((3)LE) states are well distinguished and calculated independently. PMID- 26592383 TI - Routine Microsecond Molecular Dynamics Simulations with AMBER on GPUs. 2. Explicit Solvent Particle Mesh Ewald. AB - We present an implementation of explicit solvent all atom classical molecular dynamics (MD) within the AMBER program package that runs entirely on CUDA-enabled GPUs. First released publicly in April 2010 as part of version 11 of the AMBER MD package and further improved and optimized over the last two years, this implementation supports the three most widely used statistical mechanical ensembles (NVE, NVT, and NPT), uses particle mesh Ewald (PME) for the long-range electrostatics, and runs entirely on CUDA-enabled NVIDIA graphics processing units (GPUs), providing results that are statistically indistinguishable from the traditional CPU version of the software and with performance that exceeds that achievable by the CPU version of AMBER software running on all conventional CPU based clusters and supercomputers. We briefly discuss three different precision models developed specifically for this work (SPDP, SPFP, and DPDP) and highlight the technical details of the approach as it extends beyond previously reported work [Gotz et al., J. Chem. Theory Comput. 2012, DOI: 10.1021/ct200909j; Le Grand et al., Comp. Phys. Comm. 2013, DOI: 10.1016/j.cpc.2012.09.022].We highlight the substantial improvements in performance that are seen over traditional CPU-only machines and provide validation of our implementation and precision models. We also provide evidence supporting our decision to deprecate the previously described fully single precision (SPSP) model from the latest release of the AMBER software package. PMID- 26592384 TI - First and Second One-Electron Reduction of Lumiflavin in Water-A First Principles Molecular Dynamics Study. AB - Flavins are ubiquitously found in nature as cofactors in proteins that regulate electron and proton transfer reactions. The electron and proton affinities of flavins are modulated by their molecular environment. Using density functional theory based molecular dynamics simulations, we have studied the first and second reduction reactions of the prototypical flavin named lumiflavin in aqueous solution. We find that the reduction potential, calculated using free energy perturbation simulations, has the typical parabolic shape as predicted by Marcus' theory of electron transfer. The water solvent structure undergoes significant changes within the first coordination shell upon lumiflavin reduction. These structural changes account largely for the reorganization free energy term in the measured redox potential. However, in the second reduction reaction, from semiquinone to fully reduced lumiflavin, also the inner-sphere reorganization contributes significantly via the increased "butterfly" bending of the flavin. This butterfly bending causes a deviation from the linear response approximation that underlies Marcus' theory of electron transfer. PMID- 26592385 TI - Automatic Differentiation of the Energy within Self-consistent Tight-Binding Methods. AB - We present and implement the calculation of analytical n-order geometric derivatives of the energy obtained within the framework of the density functional based tight binding approach. The use of automatic differentiation techniques allows a unique implementation for the calculation of derivatives up to any order providing that the computational facilities are sufficient. As first applications, the derivatives are used to build an analytical potential energy surface around the optimized geometry of acetylene. We also discuss the relevant anharmonic contributions that have to be considered when building such an analytical potential energy surface for acetylene, ethylene, ethane, benzene, and naphtalene. PMID- 26592386 TI - Performance of DFT Methods in Momentum Space: Quantum Similarity Measures versus Moments of Momentum. AB - The quality of momentum space electron densities obtained from a large array of density functionals is investigated through careful numerical comparison with the density obtained using reference CCSD calculations. Using a test set of 68 closed shell molecules in their ground state and 77 different computational methods, including coupled cluster, MP2 perturbation theory, Hartree-Fock, and a total of 74 DFT functionals, including long-range corrected functionals, we confirm that DFT momentum densities generally show poorer agreement with the reference than MP2 densities. The performance of DFT functionals varies significantly with only 8 DFT functionals outperforming Hartree-Fock with respect to electron momentum densities and their spherically averaged counterparts. PMID- 26592387 TI - Assessment of Density Functional Theory for Describing the Correlation Effects on the Ground and Excited State Potential Energy Surfaces of a Retinal Chromophore Model. AB - In the quest for a cost-effective level of theory able to describe a large portion of the ground and excited potential energy surfaces of large chromophores, promising approaches are rooted in various approximations to the exact density functional theory (DFT). In the present work, we investigate how generalized Kohn-Sham DFT (GKS-DFT), time-dependent DFT (TDDFT), and spin restricted ensemble-DFT (REKS) methods perform along three important paths characterizing a model retinal chromophore (the penta-2,4-dieniminium cation) in a region of near-degeneracy (close to a conical intersection) with respect to reference high-level multiconfigurational wave function methods. If GKS-DFT correctly describes the closed-shell charge transfer state, only TDDFT and REKS approaches give access to the open-shell diradical, one which sometimes corresponds to the electronic ground state. It is demonstrated that the main drawback of the usual DFT-based methods lies in the absence of interactions between the charge transfer and the diradicaloid configurations. Hence, we test a new computational scheme based on the State-averaged REKS (SA-REKS) approach, which explicitly includes these interactions into account. The State-Interaction SA-REKS (SI-SA-REKS) method significantly improves on the REKS and the SA-REKS results for the target system. The similarities and differences between DFT and wave function-based approaches are analyzed according to (1) the active space dimensions of the wave function-based methods and (2) the relative electronegativities of the allyl and protonated Schiff base moieties. PMID- 26592388 TI - A Guided Self-Consistent-Field Method for Excited-State Wave Function Optimization: Applications to Ligand-Field Transitions in Transition-Metal Complexes. AB - A guided self-consistent field (SCF) method is presented in this paper. This method uses the eigenspace update-and-following idea to improve the SCF method for optimizing wave functions that are higher-energy solutions to the Roothaan Hall equation. In this method, the eigenvectors of the previous SCF step are used to prediagonalize the current Fock/Kohn-Sham matrix, preserving the ordering of orbital occupations. When the subject of interest is an excited state of the same spin symmetry as the ground state, the initial guess of excited wave function is improved with a preconditioning step. The preconditioning step is an SCF iteration applied to the beta spin manifold if the initial guess is generated by orbital permutation in the alpha spin manifold. This simple preconditioning step gives rise to more-stable SCF convergence using the algorithm presented herein. The guided SCF method is used to optimize ligand-field excited states in tetrahedral transition-metal complexes, and calculate DeltaSCF excitation energies. The calculated ligand-field transition energies are compared with those obtained from orbital energy differences, linear response time-dependent density functional theory, and experiments. The excitation energies obtained using the method presented in this work show a significant improvement over orbital energy differences and linear response method. PMID- 26592389 TI - Performance of Density Functional Theory for Second Row (4d) Transition Metal Thermochemistry. AB - The performances of 22 density functionals, including generalized gradient approximation (GGA), hybrid GGAs, hybrid-meta GGAs, and range-separated and double hybrid functionals, in combination with the correlation consistent basis sets and effective core potentials, have been gauged for the prediction of gas phase enthalpies of formation for the TM-4d set, which contains 30 second row transition metal-containing molecules. The enthalpies of formation determined by the 22 density functionals were compared to those generated via the relativistic pseudopotential correlation consistent Composite Approach (rp-ccCA), which has a goal of reproducing energies akin to those from CCSD(T,FC1)-DK/aug-cc pCVinfinityZ-DK calculations. B3LYP/cc-pVTZ-PP optimized geometries were used in this study, though structures determined by other functionals also were examined. Of the functionals employed, the double hybrid functionals, B2GP-PLYP and mPW2 PLYP, yielded the best overall results with mean absolute deviations (MADs) from experimental enthalpies of formation of 4.25 and 5.19 kcal mol(-1), respectively. The GGA functionals BP86 and PBEPBE resulted in deviations from experiment of nearly 100 kcal mol(-1) for molecules such as molybdenum carbonyls. The omegaB97X D functional, which includes the separation of exchange energy into long-range and short-range contributions and includes a dispersion correction, resulted in an MAD of 6.52 kcal mol(-1). PMID- 26592390 TI - Critical Test of Some Computational Chemistry Methods for Prediction of Gas-Phase Acidities and Basicities. AB - Gas-phase acidities and basicities were calculated for 64 neutral bases (covering the scale from 139.9 kcal/mol to 251.9 kcal/mol) and 53 neutral acids (covering the scale from 299.5 kcal/mol to 411.7 kcal/mol). The following methods were used: AM1, PM3, PM6, PDDG, G2, G2MP2, G3, G3MP2, G4, G4MP2, CBS-QB3, B1B95, B2PLYP, B2PLYPD, B3LYP, B3PW91, B97D, B98, BLYP, BMK, BP86, CAM-B3LYP, HSEh1PBE, M06, M062X, M06HF, M06L, mPW2PLYP, mPW2PLYPD, O3LYP, OLYP, PBE1PBE, PBEPBE, tHCTHhyb, TPSSh, VSXC, X3LYP. The addition of the Grimmes empirical dispersion correction (D) to B2PLYP and mPW2PLYP was evaluated, and it was found that adding this correction gave more-accurate results when considering acidities. Calculations with B3LYP, B97D, BLYP, B2PLYPD, and PBE1PBE methods were carried out with five basis sets (6-311G**, 6-311+G**, TZVP, cc-pVTZ, and aug-cc-pVTZ) to evaluate the effect of basis sets on the accuracy of calculations. It was found that the best basis sets when considering accuracy of results and needed time were 6-311+G** and TZVP. Among semiempirical methods AM1 had the best ability to reproduce experimental acidities and basicities (the mean absolute error (mae) was 7.3 kcal/mol). Among DFT methods the best method considering accuracy, robustness, and computation time was PBE1PBE/6-311+G** (mae = 2.7 kcal/mol). Four Gaussian-type methods (G2, G2MP2, G4, and G4MP2) gave similar results to each other (mae = 2.3 kcal/mol). Gaussian-type methods are quite accurate, but their downside is the relatively long computational time. PMID- 26592391 TI - Removal of Basis-Set Artifacts in Kohn-Sham Potentials Recovered from Electron Densities. AB - Kohn-Sham effective potentials recovered from Gaussian-basis-set electron densities exhibit large oscillations and asymptotic divergences not found in exact potentials and in functional derivatives of approximate density functionals. We show that the detailed structure of these oscillations and divergences is almost exclusively determined by the basis set in terms of which the reference density is expressed, and is almost independent of the density functional or wave function method used for computing the density. Based on this observation, we propose a smoothening scheme in which most basis-set artifacts in a Kohn-Sham potential recovered from a given density are removed by subtracting the oscillation profile of the exchange-only local-density approximation potential computed in the same basis set as the reference density. The correction allows one to obtain smooth Kohn-Sham potentials from electron densities even for small Gaussian basis sets and greatly reduces discrepancies between the original (input) density and the density obtained from the reconstructed potential. PMID- 26592392 TI - Tests of Exchange-Correlation Functional Approximations Against Reliable Experimental Data for Average Bond Energies of 3d Transition Metal Compounds. AB - One of the greatest challenges for the theoretical study of transition-metal containing compounds is the treatment of intrinsically multiconfigurational atoms and molecules, which require a multireference (MR) treatment in wave function theory. The accuracy of density functional theory for such systems is still being explored. Here, we continue that exploration by presenting the predictions of 42 exchange-correlation (xc) functionals of 11 types [local spin density approximation (LSDA), generalized gradient approximation (GGA), nonseparable gradient approximation (NGA), global-hybrid GGA, meta-GGA, meta-NGA, global hybrid meta-GGA, range-separated hybrid GGA, range-separated hybrid meta-GGA, range-separated hybrid meta-NGA, and DFT augmented with molecular mechanics damped dispersion (DFT-D)]. DFT-D is tested both for Grimme's DFT-D3(BJ) model with Becke-Johnson damping and for omegaB97X-D, which has the empirical atom-atom dispersion parametrized by Chai and Head-Gordon. The Hartree-Fock (HF) method has also been included because it can be viewed as a functional with 100% HF exchange and no correlation. These methods are tested against a database including 70 first-transition-row (3d) transition-metal-containing molecules (19 single reference molecules and 51 MR molecules), all of which have estimated experimental uncertainties equal to or less than 2.0 kcal/mol in the heat of formation. We analyze the accuracy in terms of the atomization energy per bond instead of the enthalpy of formation of the molecule because it allows us to test electronic energies without the possibility of cancellation of errors in electronic energies with errors in vibrational energies. All the density functional and HF wave functions have been optimized to a stable solution, in which the spatial symmetry is allowed to be broken to minimize the energy to a stable solution. We find that tau-HCTHhyb has the smallest mean unsigned error (MUE) in average bond energy, in particular 2.5 kcal/mol, for the full set of 70 molecules, and it also gives the smallest MUE for MR systems. For single reference systems, MPW1B95 has the best performance, with an MUE of 1.6 kcal/mol. Among local functionals, which are the least expensive, the best performance (MUE = 3.4 kcal/mol) for the total database is achieved by OreLYP. It is observed that adding HF exchange does not guarantee better accuracy for GGAs or for the NGA, but inclusion of the kinetic energy densities can benefit the GGAs and NGA calculations. The metal hydrides and metal oxides are demonstrated to be the most difficult bond types to predict, and CrO3, FeH, CrO, VH, and MnS are found to be the most difficult molecules to predict. The middle transition metals (V, Cr, and Mn) lead to larger errors on average than either the early or late transition metals. PMID- 26592393 TI - Electrostatic Potential of Insulin: Exploring the Limitations of Density Functional Theory and Force Field Methods. AB - We show that standard density functional theory leads to large errors in the electron density distribution compared to reference second order Moller-Plesset perturbation theory (MP2) calculations for the insulin molecule and zwitterionic peptides, while range-separated versions perform much better. The error is quantified in terms of the electrostatic potential (ESP) on a molecular surface, which shows that standard density functional theory incorrectly predicts partial electron transfer from anionic to cationic sites. In addition, we compare the MP2 calculated ESPs to those predicted by commonly used force fields. Several fixed charge force fields display very similar performances with rather large errors, while polarizable force fields significantly reduce the error. Solvation enhances the molecular ESP, which is partly accounted for by fixed charge force fields, but polarizable force fields again perform significantly better. PMID- 26592394 TI - Extrapolation to the Gold-Standard in Quantum Chemistry: Computationally Efficient and Accurate CCSD(T) Energies for Large Molecules Using an Automated Thermochemical Hierarchy. AB - The CCSD(T) method is known as the gold-standard in quantum chemistry and has been the method of choice in quantum chemistry for over 20 years to obtain accurate bond energies and molecular properties. Its computational cost formally scales as the seventh power of the size of the system and can be prohibitive for large molecules. As part of our efforts to reduce the computational cost of the CCSD(T) method yet retain its accuracy, we present a simple, efficient, and user friendly protocol to extrapolate to CCSD(T) energies in conjunction with MP2 energies. The method is based on the automated error-canceling thermochemical hierarchy previously developed by us called the Connectivity-Based Hierarchy (CBH). For a test set containing 30 diverse nonaromatic organic molecules and biomonomers, we obtain highly accurate extrapolated CCSD(T) energies (with a mean absolute error of only 0.2-0.3 kcal/mol with different basis-set). Additionally, the work also features the successful extrapolation to CCSD energies using a similar protocol. PMID- 26592395 TI - A Case for Soft Error Detection and Correction in Computational Chemistry. AB - High performance computing platforms are expected to deliver 10(18) floating operations per second by the year 2022 through the deployment of millions of cores. Even if every core is highly reliable the sheer number of them will mean that the mean time between failures will become so short that most application runs will suffer at least one fault. In particular soft errors caused by intermittent incorrect behavior of the hardware are a concern as they lead to silent data corruption. In this paper we investigate the impact of soft errors on optimization algorithms using Hartree-Fock as a particular example. Optimization algorithms iteratively reduce the error in the initial guess to reach the intended solution. Therefore they may intuitively appear to be resilient to soft errors. Our results show that this is true for soft errors of small magnitudes but not for large errors. We suggest error detection and correction mechanisms for different classes of data structures. The results obtained with these mechanisms indicate that we can correct more than 95% of the soft errors at moderate increases in the computational cost. PMID- 26592396 TI - DFTB Parameters for the Periodic Table: Part 1, Electronic Structure. AB - A parametrization scheme for the electronic part of the density-functional based tight-binding (DFTB) method that covers the periodic table is presented. A semiautomatic parametrization scheme has been developed that uses Kohn-Sham energies and band structure curvatures of real and fictitious homoatomic crystal structures as reference data. A confinement potential is used to tighten the Kohn Sham orbitals, which includes two free parameters that are used to optimize the performance of the method. The method is tested on more than 100 systems and shows excellent overall performance. PMID- 26592397 TI - Multi-state Approach to Chemical Reactivity in Fragment Based Quantum Chemistry Calculations. AB - We introduce a multistate framework for Fragment Molecular Orbital (FMO) quantum mechanical calculations and implement it in the context of protonated water clusters. The purpose of the framework is to address issues of nonuniqueness and dynamic fragmentation in FMO as well as other related fragment methods. We demonstrate that our new approach, Fragment Molecular Orbital Multistate Reactive Molecular Dynamics (FMO-MS-RMD), can improve energetic accuracy and yield stable molecular dynamics for small protonated water clusters undergoing proton transfer reactions. PMID- 26592398 TI - Exploring Energy Landscapes: Metrics, Pathways, and Normal-Mode Analysis for Rigid-Body Molecules. AB - We present new methodology for exploring the energy landscapes of molecular systems, using angle-axis variables for the rigid-body rotational coordinates. The key ingredient is a distance measure or metric tensor, which is invariant to global translation and rotation. The metric is used to formulate a generalized nudged elastic band method for calculating pathways, and a full prescription for normal-mode analysis is described. The methodology is tested by mapping the potential energy and free energy landscape of the water octamer, described by the TIP4P potential. PMID- 26592399 TI - Substituent Effects on Menshutkin-Type Reactions in the Gas Phase and Solutions: Theoretical Approach from the Orbital Interaction View. AB - In this study, we developed a method to interpret the mechanism of acceleration for Menshutkin-type reactions in solutions theoretically, from the orbital interaction view, utilizing the through-space/bond (TS/TB) interaction analysis in the polarizable continuum model (PCM). Different method levels were tested to determine the substituent effects on the reactions of NH3 attacking para substituted benzyl bromide. The geometrical structures and Mulliken charge distributions were analyzed to elucidate the substituent effects on the SN2 reaction center. The results of Mulliken charge analysis showed that the para substituted benzyl group (-C6H4Y) received negative charge through the reaction process, and both electron-donating and electron-withdrawing substituents Y made C6H4Y groups receive greater charges. Solvent effects on the structures of transition states (T-S(s)) were significant. The structures of T-S(s) were found to be exhibiting longer bond lengths in solutions, especially in polar solvents such as water. Our TS/TB-PCM analysis method can predict the substituent effects in solutions by evaluating contributions from orbital interactions in question. The orbital interaction analysis results revealed that the key orbital interactions for stabilizing the T-S(s) of the systems with substituents Y = NH2 and NO2 in water were n(NH2)-pi*(ph) (ph = phenyl) and pi(ph)-pi*(NO2) interactions, respectively. Stronger interactions between pi*(ph) and sigma*(Calpha-Br) occurred because of the n(NH2)-pi*(ph) and pi(ph)-pi*(NO2) interactions that resulted when para-substituents -NH2 and -NO2, respectively, were added to the system. These stronger pi*(ph)-sigma*(Calpha-Br) interactions stabilized the transition state and enabled the Br leaving group to leave more easily. PMID- 26592400 TI - Quantitatively Correct UV-vis Spectrum of Ferrocene with TDB3LYP. AB - The ultraviolet-visible light (UV-vis) absorption spectrum of ferrocene is modeled with time-dependent density functional theory employing LSDA, BLYP, B3LYP, and CAM-B3LYP functionals in combination with 6-31G*, 6-31+G*, CC-PVTZ, and aug-CC-PVTZ basis sets. With the exception of LSDA, all functionals predict a reasonable Fe-CP distance of ~1.67 A. Diffuse functions are essential for the strongly allowed states at high energy but of lesser consequence for the visible range of the spectrum. Dipole forbidden states are examined with vibrationally excited structures, obtained from the normal modes of the infrared (IR) spectrum. Despite earlier claims, TDB3LYP predicts the UV-vis spectrum of ferrocene quantitatively correct. TDBLYP predicts a large number of spurious charge transfer states, TDCAM-B3LYP and TDwB97XD are correct in the low-energy region but overestimate the energy of strongest peak of the spectrum by 0.8 eV. The amount of charge transfer involved in "d-d transitions" is equal to that in "charge-transfer states". PMID- 26592401 TI - Quadrupolar NMR Spin Relaxation Calculated Using Ab Initio Molecular Dynamics: Group 1 and Group 17 Ions in Aqueous Solution. AB - Electric field gradient (EFG) fluctuations for the monoatomic ions (7)Li(+), (23)Na(+), (35)Cl(-), (81)Br(-), and (127)I(-) in aqueous solution are studied using Car-Parrinello ab initio molecular dynamics (aiMD) simulations based on density functional theory. EFG calculations are typically performed with 1024 ion solvent configurations from the aiMD simulation, using the Zeroth Order Regular Approximation (ZORA) relativistic Hamiltonian. Autocorrelation functions for the spherical EFG tensor elements are computed, transformed into the corresponding spectral densities (under the extreme narrowing condition), and subsequently converted into NMR quadrupolar relaxation rates for the ions. The relaxation rates are compared with experimental data. The order of magnitude is correctly predicted by the simulations. The computational protocol is tested in detail for (81)Br(-). PMID- 26592402 TI - Role of Solvent on Charge Transfer in 7-Aminocoumarin Dyes: New Hints from TD-CAM B3LYP and State Specific PCM Calculations. AB - Time-dependent B3LYP and CAM-B3LYP calculations have been used to investigate the absorption and emission energies as well as to shed light on the formation of the twisted intramolecular charge transfer state (TICT) in Coumarin-152 (C152) embedded in cyclohexane, acetonitrile, and water solvents. The bulk solvent effects have been included by using the linear-response (LR) and State-Specific (SS) models in the framework of the so-called polarizable continuum method (PCM). The results demonstrate that the choice of the exchange-correlation functional and of the PCM model is critical to reproduce the experimental data in the most accurate way. In particular, it has been observed that both the solvatochromic and Stokes' shifts are well reproduce by CAM-B3LYP/SSPCM calculations performed on the S0 and S1 geometries of C152 optimized at the B3LYP/LRPCM level of theory, whereas not accurate Stokes' shifts are computed with CAM-B3LYP/SSPCM calculations carried out on the CAM-B3LYP/LRPCM optimized structures. This is attributed to the incorrect (underestimated) solvation energy provided by LRPCM, which could lead to misleading results especially for charge-transfer excited state structures in polar solvents. Instead, B3LYP/LRPCM excited state optimizations seem to provide a reasonable geometry for a simple 'error cancellation' effect due to the balance among the B3LYP overstabilization of charge transfer states and the LRPCM underestimation of the solute-solvent binding energy when the former is in a polar solvent. Finally, CAM-B3LYP/SSPCM calculations, in very good agreement with experimental evidence, show that the formation of an accessible TICT state is possible for C152 and that the crossing between S0 and S1 states at a dihedral angle of around 70 degrees occurs only in polar solvents. PMID- 26592403 TI - General Time Dependent Approach to Vibronic Spectroscopy Including Franck-Condon, Herzberg-Teller, and Duschinsky Effects. AB - An effective time-dependent (TD) approach to compute vibrationally resolved optical spectra from first principles is presented for the computation of one photon electronic spectra induced by either electric or magnetic transition dipoles or by their mutual interaction, namely absorption, emission, and circular dichroism. Particular care has been devoted to generality, modularity, and numerical stability including all the contributions that play a role at the harmonic level of approximation, namely Franck-Condon, Herzberg-Teller, and Dushinsky (i.e., mode mixing) effects. The implementation shares the same general framework of our previous time-independent (TI) model, thus allowing an effective integration between both approaches with the consequent enhancement of their respective strengths (e.g., spectrum completeness and straightforward account of temperature effects for the TD route versus band resolution and assignment for the TI route) using a single set of starting data. Implementation of both models in the same general computer program allows comprehensive studies using several levels of electronic structure description together with effective account of environmental effects by atomistic and/or continuum models of different sophistication. A few medium-size molecules (furan, phenyl radical, anthracene, dimethyloxirane, coumarin 339) have been studied in order to fully validate the approach. PMID- 26592404 TI - Automated Search for Minimum Energy Conical Intersection Geometries between the Lowest Two Singlet States S0/S1-MECIs by the Spin-Flip TDDFT Method. AB - Automated search for minimum energy conical intersection geometries between the lowest two singlet states (S0/S1-MECIs) was performed by combining the anharmonic downward distortion following (ADDF) method, the seam model function (SMF) approach, and the spin-flip (SF) TDDFT method. SMF/ADDF has been employed previously in automated searches for MECIs on potential energy surfaces (PESs) with expensive multireference methods. In this work, we adopt the SF-TDDFT method that enables efficient optimization of S0/S1-MECIs in the framework of TDDFT. To evaluate the performance of the present approach, it was applied to ethylene and 1,3-butadiene. The present method automatically gave unknown S0/S1-MECIs as well as all previously reported ones. Therefore, the present hybrid method of SMF/ADDF and SF-TDDFT is shown to be a promising approach to locate S0/S1-MECIs of large systems automatically with modest computational costs. PMID- 26592405 TI - Raman Spectra of Liquid Water from Ab Initio Molecular Dynamics: Vibrational Signatures of Charge Fluctuations in the Hydrogen Bond Network. AB - We report the first ab initio simulations of the Raman spectra of liquid water, obtained by combining first principles molecular dynamics and density functional perturbation theory. Our computed spectra are in good agreement with experiments, especially in the low frequency region. We also describe a systematic strategy to analyze the Raman intensities, which is of general applicability to molecular solids and liquids, and it is based on maximally localized Wannier functions and effective molecular polarizabilities. Our analysis revealed the presence of intermolecular charge fluctuations accompanying the hydrogen bond (HB) stretching modes at 270 cm(-1), in spite of the absence of any Raman activity in the isotropic spectrum. We also found that charge fluctuations partly contribute to the 200 cm(-1) peak in the anisotropic spectrum, thus providing insight into the controversial origin of such peak. Our results highlighted the importance of taking into account electronic effects in interpreting the Raman spectra of liquid water and the key role of charge fluctuations within the HB network; they also pointed at the inaccuracies of models using constant molecular polarizabilities to describe the Raman response of liquid water. PMID- 26592406 TI - Band Gaps and Optical Spectra of Chlorographene, Fluorographene and Graphane from G0W0, GW0 and GW Calculations on Top of PBE and HSE06 Orbitals. AB - The band structures of three graphene derivatives (chlorographene, fluorographene, and graphane) were analyzed at three levels of many-body GW theory (G0W0, GW0, and GW) constructed over GGA (PBE) and screened hybrid HSE06 orbitals. DFT band gap values obtained with the HSE06 functional were notably larger than those from PBE calculations but were significantly lower than band gaps from all GW calculations. On the other hand, all GW-type calculations gave similar band gaps despite some differences in band structures. The band gap (4.9 eV at the highest GW-HSE06 level) was predicted to be smaller than that of fluorographene (8.3 eV) or graphane (6.2 eV). However, chlorographene can be considered a wide-band gap insulator analogous to fluorographene and graphane. Using the Bethe-Salpeter equation, optical absorptions of graphene derivatives were found to be at significantly lower energies due to large binding energies of excitons (1.3, 1.9, and 1.5 eV for chlorographene, fluorographene, and graphane, respectively). Point defects lowered band gaps and absorption energies. Taking into account the low concentration of defects in this type of material, their effect on the discussed electronic properties was rather small. PMID- 26592407 TI - Relative Free Energies for Hydration of Monovalent Ions from QM and QM/MM Simulations. AB - Methods directly evaluating the hydration structure and thermodynamics of physiologically relevant cations (Na(+), K(+), Cl(-), etc.) have wide ranging applications in the fields of inorganic, physical, and biological chemistry. All atom simulations based on accurate potential energy surfaces appear to offer a viable option for assessing the chemistry of ion solvation. Although MD and free energy simulations of ion solvation with classical force fields have proven their usefulness, a number of challenges still remain. One of them is the difficulty of force field benchmarking and validation against structural and thermodynamic data obtained for a condensed phase. Hybrid quantum mechanical/molecular mechanical (QM/MM) models combined with sampling algorithms have the potential to provide an accurate solvation model and to incorporate the effects from the surrounding, which is often missing in gas-phase ab initio computations. Herein, we report the results from QM/MM free energy simulations of Na(+)/K(+) and Cl(-)/Br(-) hydration where we simultaneously characterized the relative thermodynamics of ion solvation and changes in the solvation structure. The Flexible Inner Region Ensemble Separator (FIRES) method was used to impose a spatial separation between QM region and the outer sphere of solvent molecules treated with the CHARMM27 force field. FEP calculations based on QM/MM simulations utilizing the CHARMM/deMon2k interface were performed with different basis set combinations for K(+)/Na(+) and Cl(-)/Br(-) perturbations to establish the dependence of the computed free energies on the basis set level. The dependence of the computed relative free energies on the size of the QM and MM regions is discussed. The current methodology offers an accurate description of structural and thermodynamic aspects of the hydration of alkali and halide ions in neat solvents and can be used to obtain thermodynamic data on ion solvation in condensed phase along with underlying structural properties of the ion-solvent system. PMID- 26592408 TI - Protein-Protein Docking Using EMAP in CHARMM and Support Vector Machine: Application to Ab/Ag Complexes. AB - In this work, we have (i) evaluated the ability of the EMAP method implemented in the CHARMM program to generate the correct conformation of Ab/Ag complex structures and (ii) developed a support vector machine (SVM) classifier to detect native conformations among the thousands of refined Ab/Ag configurations using the individual components of the binding free energy based on a thermodynamic cycle as input features in training the SVM. Tests on 24 Ab/Ag complexes from the protein-protein docking benchmark version 3.0 showed that based on CAPRI evaluation criteria, EMAP could generate medium-quality native conformations in each case. Furthermore, the SVM classifier could rank medium/high-quality native conformations mostly in the top six among the thousands of refined Ab/Ag configurations. Thus, Ab-Ag docking can be performed using different levels of protein representations, from grid-based (EMAP) to polar hydrogen (united-atom) to all-atom representation within the same program. The scripts used and the trained SVM are available at the www.charmm.org forum script repository. PMID- 26592409 TI - Effect of Geometry Optimizations on QM-Cluster and QM/MM Studies of Reaction Energies in Proteins. AB - We have examined the effect of geometry optimization on energies calculated with the quantum mechanical (QM) cluster, combined QM and molecular mechanics (QM/MM), and big-QM approaches (very large single-point QM calculations taken from QM/MM optimized structures, including all atoms within 4.5 A of the minimal active site, all buried charged groups in the protein, and truncations moved at least three residues away from the active site). We studied a simple proton-transfer reaction between His-79 and Cys-546 in the active site of [Ni,Fe] hydrogenase and optimize QM systems of 50 different sizes (56-362 atoms). Geometries optimized with QM/MM are stable and reliable, whereas QM-cluster optimizations give larger changes in the structures and sometimes lead to large distortions in the active site if some hydrogen-bond partners to the metal ligands are omitted. Keeping 2-3 atoms for each truncated residue (rather than one) fixed in the optimization improves the results but does not solve all problems for the QM-cluster optimizations. QM-cluster energies in vacuum and a continuum solvent are insensitive to the geometry optimizations with a mean absolute change upon the optimizations of only 4-7 kJ/mol. This shows that geometry optimizations do not decrease the dependence of QM-cluster energies on how the QM system is selected; there is still a ~60 kJ/mol difference between calculations in which groups have been added to the QM system according to their distance to the active site or based on QM/MM free-energy components. QM/MM energies do not show such a difference, but they converge rather slowly with respect to the size of the QM system, although the convergence is improved by moving truncations away from the active site. The big-QM energies are stable over the 50 different optimized structures, 57 +/- 1 kJ/mol, although some smaller trends can be discerned. This shows that both QM-cluster geometries and energies should be interpreted with caution. Instead, we recommend QM/MM for geometry optimizations and energies calculated by the big-QM approach. PMID- 26592410 TI - Overcoming the Rare Event Sampling Problem in Biological Systems with Infinite Swapping. AB - Infinite swapping (INS) is a recently developed method to address the rare event sampling problem. For INS, an expanded computational ensemble composed of a number of replicas at different temperatures is used, similar to the widely used parallel tempering (PT) method. While the basic concept of PT is to sample various replicas of the system at different temperatures and exchange information between the replicas occasionally, INS uses the symmetrized distribution of configurations in temperature space, which corresponds to the infinite swapping limit of PT. The effect of this symmetrization and the enhanced information exchange between replicas is evaluated for three different biological systems representing different sampling problems in biology: (1) blocked alanine dipeptide, which is a small system and therefore optimal to evaluate sampling efficiency quantitatively, (2) Villin headpiece, which is used as a test case for the protein folding process, and (3) neuroglobin, which is used to evaluate the effects of enhanced information exchange between replicas for sampling the substate space of a folded protein. For these three test systems, PINS is compared to PT, and it is found that in all cases the sampling with PINS is substantially more efficient. PMID- 26592411 TI - Mechanism and Kinetics of Acetyl-Lysine Binding to Bromodomains. AB - Bromodomains are four-helix bundle proteins that specifically recognize acetylation of lysine side chains on histones. The available X-ray structures of bromodomain/histone tail complexes show that the conserved Asn residue in the loop between helices B and C is involved in a hydrogen bond with the acetyl lysine side chain. Here we analyze the spontaneous binding of acetyl-lysine to the bromodomain TAF1(2) by the first molecular dynamics simulations of histone mark binding to an epigenetic reader protein. Multiple events of reversible association sampled along the unbiased simulations allow us to determine the pathway and kinetics of binding. The simulations show that acetyl-lysine has two major binding modes in TAF1(2) one of which corresponds to the available crystal structures and is stabilized by a hydrogen bond to the conserved Asn side chain. The other major binding mode is more buried than in the crystal structures and is stabilized by two hydrogen bonds with conserved residues of the loop between helices Z and A. In the more buried binding conformation, three of the six structured water molecules at the bottom of the binding pocket are displaced by the acetyl-lysine side chain. The kinetic analysis shows that the two binding modes interconvert on a faster time scale with respect to the association/dissociation process. The atomic-level description of the binding pathway and binding modes is useful for the design of small molecule modulators of histone binding to bromodomains. PMID- 26592412 TI - Fe(III)-Heme Complexes with the Amyloid Beta Peptide of Alzheimer's Disease: QM/MM Investigations of Binding and Redox Properties of Heme Bound to the His Residues of Abeta(1-42). AB - Pursuant to our previous paper [J. Chem. Theory Comput. 2012, 8, 5150-5158], the structures of complexes between Abeta(1-42) and ferriheme (Fe(III)-heme-H2O) were determined by application of Amber and ONIOM(B3LYP/6-31G(d):Amber) methodology. Attachment at each of the three His residues was investigated. As well as direct bonding of the iron to the His residue, bonding is augmented by formation of secondary salt bridges between the carboxylate groups of the heme and positively charged residues of Abeta (at His13, by Lys16 and the N-terminus; at His14, by Lys16; at His6, by Arg5). The results indicate a slight preference for His13 followed by His6 and His14, with the lowest 10 structures lying within 30 kJ mol( 1) of each other. The absolute binding affinities are predicted to be approximately 30-40 kJ mol(-1). Standard reduction potentials (E degrees ) are calculated for various Fe(III)/Fe(II) couples. Regardless of the point of attachment of the heme, E degrees values are approximately -0.6 V relative to the standard hydrogen electrode. PMID- 26592413 TI - Computational Alanine Scanning Mutagenesis-An Improved Methodological Approach for Protein-DNA Complexes. AB - Proteins and protein-based complexes are the basis of many key systems in nature and have been the subject of intense research in the last decades, in an attempt to acquire comprehensive knowledge of reactions that take place in nature. Computational Alanine Scanning Mutagenesis approaches have been extensively used in the study of protein interfaces and in the determination of the most important residues for complex formation, the Hot-spots. However, as it is usually applied to the study of protein-protein interfaces, we tried to modify and apply it to the study of protein-DNA interfaces, which are also crucial in nature but have not been the subject of as much research. In this work, we carry out MD simulations of seven protein-DNA complexes and tested the influence of the variation of different parameters on the determination of the binding free energy terms (DeltaDeltaGbinding) of 78 mutations: solvent representation, internal dielectric constant, Linear and Nonlinear Poisson-Boltzmann equation, Generalized Born model, simulation time, number of structures analyzed, number of MD trajectories, force field used, and energetic terms involved. Overall, this new approach gave an average error of 1.55 kcal/mol, and P, R, F1, accuracy, and specificity values of 0.78, 0.50, 0.61, 0.77, and 0.92, respectively. This improved computational alanine scanning mutagenesis approach may serve as a tool to explore the behavior of this important class of complexes. PMID- 26592414 TI - Computing pKa Values with a Mixing Hamiltonian Quantum Mechanical/Molecular Mechanical Approach. AB - Accurate computation of the pKa value of a compound in solution is important but challenging. Here, a new mixing quantum mechanical/molecular mechanical (QM/MM) Hamiltonian method is developed to simulate the free-energy change associated with the protonation/deprotonation processes in solution. The mixing Hamiltonian method is designed for efficient quantum mechanical free-energy simulations by alchemically varying the nuclear potential, i.e., the nuclear charge of the transforming nucleus. In pKa calculation, the charge on the proton is varied in fraction between 0 and 1, corresponding to the fully deprotonated and protonated states, respectively. Inspired by the mixing potential QM/MM free energy simulation method developed previously [H. Hu and W. T. Yang, J. Chem. Phys. 2005, 123, 041102], this method succeeds many advantages of a large class of lambda-coupled free-energy simulation methods and the linear combination of atomic potential approach. Theory and technique details of this method, along with the calculation results of the pKa of methanol and methanethiol molecules in aqueous solution, are reported. The results show satisfactory agreement with the experimental data. PMID- 26592415 TI - Efficient Modeling of NMR Parameters in Carbon Nanosystems. AB - Rapid growth of nanoscience and nanotechnology requires new and more powerful modeling tools. Efficient theoretical modeling of large molecular systems at the ab initio and Density Functional Theory (DFT) levels of theory depends critically on the size and completeness of the basis set used. The recently designed variants of STO-3G basis set (STO-3Gel, STO-3Gmag), modified to correctly predict electronic and magnetic properties were tested on simple models of pristine and functionalized carbon nanotube (CNT) systems and fullerenes using the B3LYP and VSXC density functionals. Predicted geometries, vibrational properties, and HOMO/LUMO gaps of the model systems, calculated with typical 6-31G* and modified STO-3G basis sets, were comparable. The (13)C nuclear isotropic shieldings, calculated with STO-3Gmag and Jensen's polarization consistent pcS-2 basis sets, were also identical. The STO-3Gmag basis sets, being half the size of the latter one, are promising alternative for studying (13)C nuclear magnetic shieldings in larger size CNTs and fullerenes. PMID- 26592416 TI - Ambient Filtration Method To Rapidly Prepare Highly Conductive, Paper-Based Porous Gold Films for Electrochemical Biosensing. AB - Thin gold films offer intriguing material properties for potential applications including fuel cells, supercapacitors, and electronic and photonic devices. We describe here an ambient filtration method that provides a simple and novel way to generate rapidly porous and thin gold films without the need for sophisticated instruments, clean-room environments, and any postgrowth process or sintering steps. Using this approach, we can fabricate highly conductive gold films composed of gold nanoparticles layered atop a matrix of metallic single-walled carbon nanotubes on mixed cellulose ester filter paper within 20 min. These hybrid films (thickness ~40 nm) exhibit fast electron transfer and excellent electrocatalytic properties that are similar to purchased gold films, but with a larger electroactive surface that lends itself to more sensitive analyte detection. We used the neurotransmitters dopamine and serotonin as benchmark analytes to demonstrate that our hybrid gold films can clearly discriminate the presence of both molecules in a mixture with resolution that greatly exceeds that of either purchased gold slides or electrodeposited gold films. Importantly, we postulate that this new approach could readily be generalized for the rapid fabrication of films from various other metals under ambient conditions, and could also be used as a prelude to transferring the resulting films onto glass or other flexible substrates. PMID- 26592417 TI - Prader-Willi Syndrome: Clinical Genetics and Diagnostic Aspects with Treatment Approaches. AB - BACKGROUND: Prader-Willi syndrome (PWS) is a neuro-developmental genetic disorder due to lack of expression of genes inherited from the paternal chromosome 15q11 q13 region with three main genetic subtypes. These include paternal 15q11-q13 deletion (about 70% of cases), maternal uniparental disomy 15 or both 15s from the mother (20-30% of cases), and defects in the imprinting center (1-3%) which controls the expression of imprinted genes in this chromosome region. Clinical manifestations include infantile hypotonia with a poor suck resulting in failure to thrive, short stature, small hands/feet and hypogonadism/hypogenitalism due to growth and other hormone deficiencies, hyperphagia and excessive weight gain with obesity and cognitive and behavioral problems including obsessive compulsions, tantrums and self-injury. The phenotype is likely related to hypothalamic dysfunction. OBJECTIVE: Hyperphagia and obesity with related complications are major causes of morbidity and mortality in PWS requiring accurate diagnosis, appropriate medical management and treatment; the major objective of our report. METHODS AND RESULTS: An extensive review of the literature was undertaken including genetics, clinical and behavioral aspects, and updated health-related information addressing the importance of early diagnosis and treatment of individuals with Prader-Willi syndrome. A searchable, bulleted and formatted list of topics related to this obesity syndrome was provided utilizing a Table of Contents approach for the clinical practitioner. CONCLUSIONS: Physicians and other health care providers can use this review with clinical, genetic and treatment summaries divided into sections that are pertinent in the context of clinical practice. Finally, frequently asked questions by clinicians, families and other interested participants will be addressed. PMID- 26592419 TI - Development of a Gravid Uterus Model for the Study of Road Accidents Involving Pregnant Women. AB - Car accident simulations involving pregnant women are well documented in the literature and suggest that intra-uterine pressure could be responsible for the phenomenon of placental abruption, underlining the need for a realistic amniotic fluid model, including fluid-structure interactions (FSI). This study reports the development and validation of an amniotic fluid model using an Arbitrary Lagrangian Eulerian formulation in the LS-DYNA environment. Dedicated to the study of the mechanisms responsible for fetal injuries resulting from road accidents, the fluid model was validated using dynamic loading tests. Drop tests were performed on a deformable water-filled container at acceleration levels that would be experienced in a gravid uterus during a frontal car collision at 25 kph. During the test device braking phase, container deformation induced by inertial effects and FSI was recorded by kinematic analysis. These tests were then simulated in the LS-DYNA environment to validate a fluid model under dynamic loading, based on the container deformations. Finally, the coupling between the amniotic fluid model and an existing finite-element full-body pregnant woman model was validated in terms of pressure. To do so, experimental test results performed on four postmortem human surrogates (PMHS) (in which a physical gravid uterus model was inserted) were used. The experimental intra-uterine pressure from these tests was compared to intra uterine pressure from a numerical simulation performed under the same loading conditions. Both free fall numerical and experimental responses appear strongly correlated. The relationship between the amniotic fluid model and pregnant woman model provide intra-uterine pressure values correlated with the experimental test responses. The use of an Arbitrary Lagrangian Eulerian formulation allows the analysis of FSI between the amniotic fluid and the gravid uterus during a road accident involving pregnant women. PMID- 26592420 TI - Electrochemical biofilm control: a review. AB - One of the methods of controlling biofilms that has widely been discussed in the literature is to apply a potential or electrical current to a metal surface on which the biofilm is growing. Although electrochemical biofilm control has been studied for decades, the literature is often conflicting, as is detailed in this review. The goals of this review are: (1) to present the current status of knowledge regarding electrochemical biofilm control; (2) to establish a basis for a fundamental definition of electrochemical biofilm control and requirements for studying it; (3) to discuss current proposed mechanisms; and (4) to introduce future directions in the field. It is expected that the review will provide researchers with guidelines on comparing datasets across the literature and generating comparable datasets. The authors believe that, with the correct design, electrochemical biofilm control has great potential for industrial use. PMID- 26592418 TI - The pregnane X receptor in tuberculosis therapeutics. AB - INTRODUCTION: Among the infectious diseases, tuberculosis (TB) remains the second most common cause of death after HIV. TB treatment requires the combination of multiple drugs including the rifamycin class. However, rifamycins are activators of human pregnane X receptor (PXR), a transcription factor that regulates drug metabolism, drug resistance, energy metabolism and immune response. Rifamycin mediated PXR activation may affect the outcome of TB therapy. AREAS COVERED: This review describes the role of PXR in modulating metabolism, efficacy, toxicity and resistance to anti-TB drugs; as well as polymorphisms of PXR that potentially affect TB susceptibility. EXPERT OPINION: The wide range of PXR functions that mediate drug metabolism and toxicity in TB therapy are often underappreciated and thus understudied. Further studies are needed to determine the overall impact of PXR activation on the outcome of TB therapy. PMID- 26592421 TI - Intracranial abscesses over the last four decades; changes in aetiology, diagnostics, treatment and outcome. AB - Background The development of modern medicine has resulted in changes in the predisposing conditions, clinical picture, treatment and results of treatment of intracranial abscesses. This study sought to evaluate these changes in a hospital district. Methods A retrospective analysis of the clinical data of all patients treated due to intracranial abscesses at a tertiary referral centre, between 1970 2012. Results The total number of intracranial abscesses was 166. The incidence of intracranial abscesses was 0.33/100 000/year (2000-2012). The most common predisposing conditions were infection of the ear-, nose- and throat region (22%), odontogenic infection (15%) and cardiac anomaly (13%). Lately (2000-2012), infections of the ear-, nose- and throat region (15%) and cardiac anomalies (5%) have become less common, whereas odontogenic infections (32%) have become more common. The most common pathogens belong to Streptococcus spp (42%), Fusobacteriae (14%), Actinomycetales (8%) and Staphylococcus spp (8%). Most patients (66%) experienced a favourable recovery; the proportion of patients with favourable outcome enabling return to prior occupation rose over time, from 12% in 1970-1989 to 24% in 1990-2012. Conclusions The predisposing conditions for intracranial abscesses have changed markedly within the study period. Odontogenic infections have become a common predisposing condition, whereas infections of the ear-, nose- and throat region and cardiac malformations are nowadays less common as predisposing conditions compared to at the beginning of the study period. The proportion of patients with favourable outcome enabling return to prior occupation seems to have increased with time. PMID- 26592422 TI - Soft spherical nanostructures with a dodecagonal quasicrystal-like order. AB - We develop a theory which predicts curvature-related structural peculiarities of soft spherical nanostructures with a dodecagonal local arrangement of subunits. Spherical templates coated with a thin film of a soft quasicrystal (QC)-forming material constitute the most promising direction to realize these nanostructures. Disordered and perfect spherical nanostructures are simulated using two approaches. The first of them models a random QC-like spherical nanostructure with extended curvature-induced topological defects similar to scars in colloidal spherical crystals. The second approach is inspired by the physics of viral capsids. It deals with the most regular spherical nanostructures with a local QC like order derived from three well-known planar dodecagonal tilings. We explain how the additional QC-like degrees of freedom assist the nanostructure stabilization and determine the point defect number and location without extended scar formation. Unusual for nanoassemblies snub cube geometry is shown to be the most energetically favorable global organization of these spherical QC nanostructures. PMID- 26592423 TI - Nanostructured porous RuO2/MnO2 as a highly efficient catalyst for high-rate Li O2 batteries. AB - Despite the recent advancements in Li-O(2) (or Li-air) batteries, great challenges still remain to realize high-rate, long-term cycling. In this work, a binder-free, nanostructured RuO(2)/MnO(2) catalytic cathode was designed to realize the operation of Li-O(2) batteries at high rates. At a current density as high as 3200 mA g(-1) (or ~1.3 mA cm(-2)), the RuO(2)/MnO(2) catalyzed Li-O(2) batteries with LiI can sustain stable cycling of 170 and 800 times at limited capacities of 1000 and 500 mA h g(-1), respectively, with low charge cutoff potentials of ~4.0 and <3.8 V, respectively. The underlying mechanism of the high catalytic performance of MnO(2)/RuO(2) was also clarified in this work. It was found that with the catalytic effect of RuO(2), Li(2)O(2) can crystallize into a thin-sheet form and realize a conformal growth on sheet-like delta-MnO(2) at a current density up to 3200 mA g(-1), constructing a sheet-on-sheet structure. This crystallization behavior of Li(2)O(2) not only defers the electrode passivation upon discharge but also renders easy decomposition of Li(2)O(2) upon charge, leading to low polarizations and reduced side reactions. This work provides a unique design of catalytic cathodes capable of controlling Li(2)O(2) growth and sheds light on the design of high-rate, long-life Li-O(2) batteries with potential applications in electric vehicles. PMID- 26592424 TI - Delivering carbide ligands to sulfide-rich clusters. AB - The propensity of the terminal ruthenium carbide Ru(C)Cl2(PCy3)2 (RuC) to form carbide bridges to electron-rich transition metals enables synthetic routes to metal clusters with coexisting carbide and sulfide ligands. Electrochemical experiments show the Ru=C ligand to exert a relatively large electron-withdrawing effect compared with PPh3, effectively shifting redox potentials. PMID- 26592426 TI - Internal conversion outcompetes autodetachment from resonances in the deprotonated tetracene anion continuum. AB - Photoelectron velocity-map imaging and electronic structure calculations have been used to study the temporary anion (resonance) dynamics of the closed-shell site-specific deprotonated tetracene anion (C18H11(-)) in the hv = 3.26 eV (380 nm) to 4.13 eV (300 nm) range. In accord with a recent frequency-, angle-, and time-resolved photoelectron imaging study on a related but open-shell polyaromatic radical anion (Chem. Sci., 2015, 6, 1578-1589), population of pi* resonances situated in the detachment continuum efficiently recover the ground electronic state of the anion through ultrafast non-adiabatic dynamics, followed by characteristic statistical electron loss (thermionic emission). The combined electron yield of direct photodetachment and autodetachment from the optically accessed resonances in C18H11(-) is several orders of magnitude smaller than thermionic emission from the ground electronic electronic state in the photon energy range studied. This result implies a resilience to prompt photoejection from UV radiation, and the ability of neutral PAH-like species to capture a free electron and form a long-lived molecular anion that ultimately decays by thermionic emission on a millisecond timescale. The attachment mechanism applies to polyaromatic species that cannot support dipole-bound states, and may provide an additional route to forming anions in astrochemical environments. PMID- 26592425 TI - Looking for reward in all the wrong places: dopamine receptor gene polymorphisms indirectly affect aggression through sensation-seeking. AB - Individuals with genotypes that code for reduced dopaminergic brain activity often exhibit a predisposition toward aggression. However, it remains largely unknown how dopaminergic genotypes may increase aggression. Lower-functioning dopamine systems motivate individuals to seek reward from external sources such as illicit drugs and other risky experiences. Based on emerging evidence that aggression is a rewarding experience, we predicted that the effect of lower functioning dopaminergic functioning on aggression would be mediated by tendencies to seek the environment for rewards. Caucasian female and male undergraduates (N = 277) were genotyped for five polymorphisms of the dopamine D2 receptor (DRD2) gene; they reported their previous history of aggression and their dispositional reward-seeking. Lower-functioning DRD2 profiles were associated with greater sensation-seeking, which then predicted greater aggression. Our findings suggest that lower-functioning dopaminergic activity puts individuals at risk for violence because it motivates them to experience aggression's hedonically rewarding qualities. PMID- 26592427 TI - Assessment of Self-Adhesive Resin Composites: Nondestructive Imaging of Resin Dentin Interfacial Adaptation and Shear Bond Strength. AB - Shear bond strength (SBS) and the interfacial adaptation (IA) of self-adhesive resin (SAR) composites to dentin were evaluated. Two SARs [Vertise Flow (VTF) and Fusio Liquid Dentin (FLD)] were evaluated and compared with a conventional restorative system [adhesive: OptiBond FL and composite: Herculite Precis (OBF/HP)]. Human third molars were used for SBS testing and IA imaging (n=7) using optical coherence tomography (OCT). Flattened dentin disks were prepared and the composites were applied into molds (2.4 mm diameter) that were positioned on dentin. Samples were subjected to SBS testing and OCT analysis, which considered an increase in signal intensity at the bonded interface as evidence of internal gaps. SBS data were analyzed by one-way analysis of variance and Tukey's test and IA data (% distribution of high brightness values) by Kruskal-Wallis and Dunn's test (p<=0.05). No statistically significant difference in SBS was observed between VTF (13.9+/-3.6 MPa) and FLD (11.3+/-3.2 MPa), whereas OBF/HP showed higher average strength (27.3+/-6.1 MPa). However, there was a statistically significant difference in IA when VTF (33.3%) was compared with FLD (1.2%) and OBF/HP (1.5%). The conventional restorative system exhibited superior SBS performance compared with SARs. However, the IA of FLD to dentin had values that were not significantly different from OBF/HP. PMID- 26592428 TI - Core-shell nano-FeS2@N-doped graphene as an advanced cathode material for rechargeable Li-ion batteries. AB - We report the formation of core-shell nano-FeS2@N-doped graphene as a novel cathode material and its mechanism for use in rechargeable Li-ion batteries. A benefit of the amount of FeS2 nano-crystals as the core for Li-ion storage with high capacity and using coated N-doped graphene as the shell is that FeS2@N graphene exhibits a remarkable specific energy (950 W h kg(-1) at 0.15 kW g(-1)) and higher specific power (543 W h kg(-1) at 2.79 kW g(-1)) than commercial rechargeable LIB cathodes, as well as stable cycling performance (~600 W h kg(-1) at 0.75 kW g(-1) after 400 cycles). PMID- 26592429 TI - Reply to Jones et al. PMID- 26592430 TI - Electrodiagnostic Testing and Treatment for Carpal Tunnel Syndrome in Canada. AB - OBJECTIVES: 1) Assess which electrodiagnostic studies Canadian clinicians use to aid in the diagnosis of carpal tunnel syndrome (CTS). 2) Assess whether Canadian clinicians follow the American Association of Neuromuscular & Electrodiagnostic Medicine/American Academy of Neurology/American Academy of Physical Medicine and Rehabilitation Practice Parameter for Electrodiagnostic Studies in CTS. 3) Assess how Canadian clinicians manage CTS once a diagnosis has been established. METHODS: In this prospective observational study, an electronic survey was sent to all members of the Canadian Neuromuscular Group (CNMG) and the Canadian Association of Physical Medicine and Rehabilitation (CAPM&R) Neuromuscular Special Interest Group. Questions addressed which electrodiagnostic tests were being routinely used for the diagnosis of carpal tunnel syndrome. Management recommendations for CTS was also explored. RESULTS: Of the 70 individuals who completed the survey, fourteen different nerve conduction study techniques were reported. Overall, 36/70 (51%) of participants followed the AANEM/AAN/AAPM&R Practice Parameter. The standard followed by the fewest of our respondents with 64% compliance (45/70) was the use of a standard distance of 13 to 14 cm with respect to the median sensory nerve conduction study. Regarding management, 99% would recommend splinting in the case of mild CTS. In moderate CTS, splinting was recommended by 91% of clinicians and 68% would also consider referral for surgery. In severe CTS, most recommended surgery (93%). CONCLUSIONS: There is considerable variability in terms of which electrodiagnostic tests Canadian clinicians perform for CTS. Canadian clinicians are encouraged to adhere to the AANEM/AAN/AAPM&R Practice Parameter for Electrodiagnostic Studies in CTS. PMID- 26592431 TI - Outbreak of coral-eating Crown-of-Thorns creates continuous cloud of larvae over 320 km of the Great Barrier Reef. AB - Coral reefs are in decline worldwide due to a combination of local and global causes. Over 40% of the recent coral loss on Australia's Great Barrier Reef (GBR) has been attributed to outbreaks of the coral-eating Crown-of-Thorns Seastar (CoTS). Testing of the hypotheses explaining these outbreaks is hampered by an inability to investigate the spatio-temporal distribution of larvae because they resemble other planktotrophic echinoderm larvae. We developed a genetic marker and tested it on 48 plankton samples collected during the 2014 spawning season in the northern GBR, and verified the method by PCR amplification of single larva. Surprisingly, most samples collected contained CoTS larvae. Larvae were detected 100 km south of current outbreaks of adult seastars, highlighting the potential for rapid expansion of the outbreak. A minimum estimate suggested that larvae numbers in the outbreak area (>10(10)) are about 4 orders of magnitude higher than adults (~10(6)) in the same area, implying that attempts to halt outbreaks by removing adults may be futile. PMID- 26592432 TI - Reduction of phase noise in nanowire spin orbit torque oscillators. AB - Spin torque oscillators (STOs) are compact, tunable sources of microwave radiation that serve as a test bed for studies of nonlinear magnetization dynamics at the nanometer length scale. The spin torque in an STO can be created by spin-orbit interaction, but low spectral purity of the microwave signals generated by spin orbit torque oscillators hinders practical applications of these magnetic nanodevices. Here we demonstrate a method for decreasing the phase noise of spin orbit torque oscillators based on Pt/Ni80Fe20 nanowires. We experimentally demonstrate that tapering of the nanowire, which serves as the STO active region, significantly decreases the spectral linewidth of the generated signal. We explain the observed linewidth narrowing in the framework of the Ginzburg-Landau auto-oscillator model. The model reveals that spatial non uniformity of the spin current density in the tapered nanowire geometry hinders the excitation of higher order spin-wave modes, thus stabilizing the single-mode generation regime. This non-uniformity also generates a restoring force acting on the excited self-oscillatory mode, which reduces thermal fluctuations of the mode spatial position along the wire. Both these effects improve the STO spectral purity. PMID- 26592434 TI - A new flow diverter stent for direct treatment of intracranial aneurysm. AB - The use of a stand-alone flow diverter (FD) stent has demonstrated itself as an efficacious endovascular approach to intracranial aneurysm treatment. FD stents that are currently available adopt an interwoven braided design. The relatively low radial stiffness intrinsic to this design could cause difficulty in deployment and poor stent-wall apposition, leading to high complication rates. A new FD stent is proposed to overcome the problems of the interwoven FD stents. The new device is manufactured from a Nitinol tube through a laser-cutting technique, and its unique structure allows for both low porosity and high packaging efficiency. Computational simulation using Abaqus has been conducted to investigate the radial stiffness and longitudinal flexibility of the new device. The new device exhibits high radial stiffness when compared to interwoven FD stents and superior longitudinal flexibility. Results from on-going in-vivo experiments and CFD simulations have also demonstrated the efficacy of the new device as a FD stent. PMID- 26592433 TI - Lipidomic Profiling of Liver Tissue from Obesity-Prone and Obesity-Resistant Mice Fed a High Fat Diet. AB - Obesity is a multifactorial health problem resulting from genetic, environmental, and behavioral factors. A particularly interesting aspect of obesity is the differences observed in response to the same high-fat diet (HFD). In this study, we performed lipidomic profiling on livers from HFD-fed C57BL/6J mice using ultra performance liquid chromatography-quadrupole time-of-flight mass spectrometry. Mice were divided into three groups: normal diet (ND), HFD-obesity prone (HFD OP), and HFD-obesity resistant (HFD-OR). Principal components analyses showed a difference between the HFD-OP and HFD-OR groups. Individuals in the HFD-OR group were closer to those in the ND group compared with those in the HFD-OP group. In particular, phosphocholine (PC) and triglyceride (TG) levels differed significantly depending on the length of the acyl chain and degree of unsaturation, respectively. PC species were either positively or negatively correlated with concentrations of glucose, insulin, leptin, and hepatic cholesterol according to the length of the acyl chain. Decreased expression of the scavenger receptor B1 and ATP-binding cassette A1 in HFD-OP mice indicated that the acyl chain length of PC species may be related to high-density lipoprotein cholesterol metabolism. This study demonstrates that lipidomic profiling is an effective approach to analyzing global lipid alterations as they pertain to obesity. PMID- 26592436 TI - Material modeling of cardiac valve tissue: Experiments, constitutive analysis and numerical investigation. AB - A key element of the cardiac cycle of the human heart is the opening and closing of the four valves. However, the material properties of the leaflet tissues, which fundamentally contribute to determine the mechanical response of the valves, are still an open field of research. The main contribution of the present study is to provide a complete experimental data set for porcine heart valve samples spanning all valve and leaflet types under tensile loading. The tests show a fair degree of reproducibility and are clearly indicative of a number of fundamental tissue properties, including a progressively stiffening response with increasing elongation. We then propose a simple anisotropic constitutive model, which is fitted to the experimental data set, showing a reasonable interspecimen variability. Furthermore, we present a dynamic finite element analysis of the aortic valve to show the direct usability of the obtained material parameters in computational simulations. PMID- 26592435 TI - Superoxide mediates tight junction complex dissociation in cyclically stretched lung slices. AB - We found that stretching Type I rat alveolar epithelial cell (RAEC) monolayers at magnitudes that correspond to high tidal-volume mechanical ventilation results in the production of reactive oxygen species, including nitric oxide and superoxide. Scavenging superoxide with Tiron eliminated the stretch-induced increase in cell monolayer permeability, and similar results were reported for rats ventilated at large tidal volumes, suggesting that oxidative stress plays an important role in barrier impairment in ventilator-induced lung injury associated with large stretch and tidal volumes. In this communication we show that mechanisms that involve oxidative injury are also present in a novel precision cut lung slices (PCLS) model under identical mechanical loads. PCLSs from healthy rats were stretched cyclically to 37% change in surface area for 1 hour. Superoxide was visualized using MitoSOX. To evaluate functional relationships, in separate stretch studies superoxide was scavenged using Tiron or mito-Tempo. PCLS and RAEC permeability was assessed as tight junction (TJ) protein (occludin, claudin-4 and claudin-7) dissociation from zona occludins-1 (ZO-1) via co-immunoprecipitation and Western blot, after 1h (PCLS) or 10min (RAEC) of stretch. Superoxide was increased significantly in PCLS, and Tiron and mito-Tempo dramatically attenuated the response, preventing claudin-4 and claudin-7 dissociation from ZO-1. Using a novel PCLS model for ventilator-induced lung injury studies, we have shown that uniform, biaxial, cyclic stretch generates ROS in the slices, and that superoxide scavenging that can protect the lung tissue under stretch conditions. We conclude that PCLS offer a valuable platform for investigating antioxidant treatments to prevent ventilation-induced lung injury. PMID- 26592437 TI - A 3D reconstruction method of the body envelope from biplanar X-rays: Evaluation of its accuracy and reliability. AB - The aim of this study was to propose a novel method for reconstructing the external body envelope from the low dose biplanar X-rays of a person. The 3D body envelope was obtained by deforming a template to match the surface profiles in two X-rays images in three successive steps: global morphing to adopt the position of a person and scale the template's body segments, followed by a gross deformation and a fine deformation using two sets of pre-defined control points. To evaluate the method, a biplanar X-ray acquisition was obtained from head to foot for 12 volunteers in a standing posture. Up to 172 radio-opaque skin markers were attached to the body surface and used as reference positions. Each envelope was reconstructed three times by three operators. Results showed a bias lower than 7mm and a confidence interval (95%) of reproducibility lower than 6mm for all body parts, comparable to other existing methods matching a template onto stereographic photographs. The proposed method offers the possibility of reconstructing body shape in addition to the skeleton using a low dose biplanar X rays system. PMID- 26592438 TI - Comparing the mechanical properties of the porcine knee meniscus when hydrated in saline versus synovial fluid. AB - As research progresses to find a suitable knee meniscus replacement, accurate in vitro testing becomes critical for feasibility and comparison studies of mechanical integrity. Within the knee, the meniscus is bathed in synovial fluid, yet the most common hydration fluid in laboratory testing is phosphate buffered saline (PBS). PBS is a relatively simple salt solution, while synovial fluid is a complex non-Newtonian fluid with multiple lubricating factors. As such, PBS may interact with meniscal tissue differently than synovial fluid, and thus, the hydration fluid may be an important factor in obtaining accurate results during in vitro testing. To evaluate these effects, medial porcine menisci were used to evaluate tissue mechanics in tension (n=11) and compression (n=15). In all tests, two samples from the same meniscus were taken, where one sample was hydrated in PBS and the other was hydrated in synovial fluid. Statistical analysis revealed no significant differences between the mean mechanical properties of samples tested in PBS compared to synovial fluid; however, compressive testing revealed the variability between samples was significantly reduced if samples were tested in synovial fluid. For example, the compressive Young's Modulus was 12.69+/ 7.49MPa in PBS versus 12.34+/-4.27MPa in synovial fluid. These results indicate testing meniscal tissue in PBS will largely not affect the mean value of the mechanical properties, but performing compression testing in synovial fluid may provide more consistent results between samples and assist in reducing sample numbers in some experiments. PMID- 26592439 TI - Biomechanical demands of the 2-step transitional gait cycles linking level gait and stair descent gait in older women. AB - Stair descent is an inherently complex form of locomotion posing a high falls risk for older adults, specifically when negotiating the transitional gait cycles linking level gait and descent. The aim of this study was to enhance our understanding of the biomechanical demands by comparing the demands of these transitions. Lower limb kinematics and kinetics of the 2-step transitions linking level and descent gait at the top (level-to-descent) and the bottom (descent-to level) of the staircase were quantified in 36 older women with no falls history. Despite undergoing the same vertical displacement (2-steps), the following significant (p<.05) differences were observed during the top transition compared to the bottom transition: reduced step velocity; reduced hip extension and increased ankle dorsiflexion (late stance/pre-swing); reduced ground reaction forces, larger knee extensor moments and powers (absorption; late stance); reduced ankle plantarflexor moments (early and late stance) and increased ankle powers (mid-stance). Top transition biomechanics were similar to those reported previously for continuous descent. Kinetic differences at the knee and ankle signify the contrasting and prominent functions of controlled lowering during the top transition and forward continuance during the bottom transition. The varying musculoskeletal demands encountered during each functional sub-task should be addressed in falls prevention programmes with elderly populations where the greatest clinical impact may be achieved. Knee extensor eccentric power through flexion exercises would facilitate a smooth transition at the top and improving ankle plantarflexion strength during single and double limb stance activities would ease the transition into level gait following continuous descent. PMID- 26592440 TI - Evaluation of Reference Genes for RT-qPCR Studies in the Seagrass Zostera muelleri Exposed to Light Limitation. AB - Seagrass meadows are threatened by coastal development and global change. In the face of these pressures, molecular techniques such as reverse transcription quantitative real-time PCR (RT-qPCR) have great potential to improve management of these ecosystems by allowing early detection of chronic stress. In RT-qPCR, the expression levels of target genes are estimated on the basis of reference genes, in order to control for RNA variations. Although determination of suitable reference genes is critical for RT-qPCR studies, reports on the evaluation of reference genes are still absent for the major Australian species Zostera muelleri subsp. capricorni (Z. muelleri). Here, we used three different software (geNorm, NormFinder and Bestkeeper) to evaluate ten widely used reference genes according to their expression stability in Z. muelleri exposed to light limitation. We then combined results from different software and used a consensus rank of four best reference genes to validate regulation in Photosystem I reaction center subunit IV B and Heat Stress Transcription factor A- gene expression in Z. muelleri under light limitation. This study provides the first comprehensive list of reference genes in Z. muelleri and demonstrates RT-qPCR as an effective tool to identify early responses to light limitation in seagrass. PMID- 26592441 TI - Noncontact conductivity and dielectric measurement for high throughput roll-to roll nanomanufacturing. AB - Advances in roll-to-roll processing of graphene and carbon nanotubes have at last led to the continuous production of high-quality coatings and filaments, ushering in a wave of applications for flexible and wearable electronics, woven fabrics, and wires. These applications often require specific electrical properties, and hence precise control over material micro- and nanostructure. While such control can be achieved, in principle, by closed-loop processing methods, there are relatively few noncontact and nondestructive options for quantifying the electrical properties of materials on a moving web at the speed required in modern nanomanufacturing. Here, we demonstrate a noncontact microwave method for measuring the dielectric constant and conductivity (or geometry for samples of known dielectric properties) of materials in a millisecond. Such measurement times are compatible with current and future industrial needs, enabling real-time materials characterization and in-line control of processing variables without disrupting production. PMID- 26592442 TI - The coffee-machine bacteriome: biodiversity and colonisation of the wasted coffee tray leach. AB - Microbial communities are ubiquitous in both natural and artificial environments. However, microbial diversity is usually reduced under strong selection pressures, such as those present in habitats rich in recalcitrant or toxic compounds displaying antimicrobial properties. Caffeine is a natural alkaloid present in coffee, tea and soft drinks with well-known antibacterial properties. Here we present the first systematic analysis of coffee machine-associated bacteria. We sampled the coffee waste reservoir of ten different Nespresso machines and conducted a dynamic monitoring of the colonization process in a new machine. Our results reveal the existence of a varied bacterial community in all the machines sampled, and a rapid colonisation process of the coffee leach. The community developed from a pioneering pool of enterobacteria and other opportunistic taxa to a mature but still highly variable microbiome rich in coffee-adapted bacteria. The bacterial communities described here, for the first time, are potential drivers of biotechnologically relevant processes including decaffeination and bioremediation. PMID- 26592443 TI - Migration and horizontal gene transfer divide microbial genomes into multiple niches. AB - Horizontal gene transfer is central to microbial evolution, because it enables genetic regions to spread horizontally through diverse communities. However, how gene transfer exerts such a strong effect is not understood. Here we develop an eco-evolutionary model and show how genetic transfer, even when rare, can transform the evolution and ecology of microbes. We recapitulate existing models, which suggest that asexual reproduction will overpower horizontal transfer and greatly limit its effects. We then show that allowing immigration completely changes these predictions. With migration, the rates and impacts of horizontal transfer are greatly increased, and transfer is most frequent for loci under positive natural selection. Our analysis explains how ecologically important loci can sweep through competing strains and species. In this way, microbial genomes can evolve to become ecologically diverse where different genomic regions encode for partially overlapping, but distinct, ecologies. Under these conditions ecological species do not exist, because genes, not species, inhabit niches. PMID- 26592444 TI - The molecular basis of lysine 48 ubiquitin chain synthesis by Ube2K. AB - The post-translational modification of proteins by ubiquitin is central to the regulation of eukaryotic cells. Substrate-bound ubiquitin chains linked by lysine 11 and 48 target proteins to the proteasome for degradation and determine protein abundance in cells, while other ubiquitin chain linkages regulate protein interactions. The specificity of chain-linkage type is usually determined by ubiquitin-conjugating enzymes (E2s). The degradative E2, Ube2K, preferentially catalyses formation of Lys48-linked chains, but like most E2s, the molecular basis for chain formation is not well understood. Here we report the crystal structure of a Ube2K~ubiquitin conjugate and demonstrate that even though it is monomeric, Ube2K can synthesize Lys48-linked ubiquitin chains. Using site directed mutagenesis and modelling, our studies reveal a molecular understanding of the catalytic complex and identify key features required for synthesis of degradative Lys48-linked chains. The position of the acceptor ubiquitin described here is likely conserved in other E2s that catalyse Lys48-linked ubiquitin chain synthesis. PMID- 26592445 TI - Oxidative stress enables Epstein-Barr virus-induced B-cell transformation by posttranscriptional regulation of viral and cellular growth-promoting factors. AB - Infection of human B lymphocytes by Epstein-Barr virus (EBV) leads to the establishment of immortalized lymphoblastoid cell lines (LCLs) that are widely used as a model of viral oncogenesis. An early consequence of infection is the induction of DNA damage and activation of the DNA damage response, which limits the efficiency of growth transformation. The cause of the DNA damage remains poorly understood. We have addressed this question by comparing the response of B lymphocytes infected with EBV or stimulated with a potent B-cell mitogen. We found that although the two stimuli induce comparable proliferation during the first 10 days of culture, the EBV-infected blasts showed significantly higher levels of DNA damage, which correlated with stronger and sustained accumulation of reactive oxygen species (ROS). Treatment with ROS scavengers decreased DNA damage in both mitogen-stimulated and EBV-infected cells. However, while mitogen induced proliferation was slightly improved, the proliferation of EBV-infected cells and the establishment of LCLs were severely impaired. Quenching of ROS did not affect the kinetics and magnitude of viral gene expression but was associated with selective downregulation of the viral LMP1 and phosphorylated cellular transcription factor STAT3 that have key roles in transformation. Analysis of the mechanism by which high levels of ROS support LMP1 expression revealed selective inhibition of viral microRNAs that target the LMP1 transcript. Our study provides novel insights into the role of EBV-induced oxidative stress in promoting B-cell immortalization and malignant transformation. PMID- 26592446 TI - Tetraspanin CD82 regulates bone marrow homing of acute myeloid leukemia by modulating the molecular organization of N-cadherin. AB - Communication between acute myeloid leukemia (AML) and the bone marrow microenvironment is known to control disease progression. Therefore, regulation of AML cell trafficking and adhesion to the bone marrow is of significant interest. In this study, we demonstrate that differential expression of the membrane scaffold CD82 modulates the bone marrow homing of AML cells. By combining mutational analysis and super-resolution imaging, we identify membrane protein clustering by CD82 as a regulator of AML cell adhesion and bone marrow homing. Cluster analysis of super-resolution data indicates that N-linked glycosylation and palmitoylation of CD82 are both critical modifications that control the microdomain organization of CD82 as well as the nanoscale clustering of associated adhesion protein, N-cadherin. We demonstrate that the inhibition of CD82 glycosylation increases the molecular packing of N-cadherin and promotes the bone marrow homing of AML cells. In contrast, we find that the inhibition of CD82 palmitoylation disrupts the formation and organization of N-cadherin clusters and significantly diminishes bone marrow trafficking of AML. Taken together, these data establish a mechanism where the membrane organization of CD82, through specific posttranslational modifications, regulates N-cadherin clustering and membrane density, which impacts the in vivo trafficking of AML cells. As such, these observations provide an alternative model for targeting AML where modulation of protein organization within the membrane may be an effective treatment therapy to disrupt the bone marrow homing potential of AML cells. PMID- 26592447 TI - p53 mutations cooperate with oncogenic Kras to promote adenocarcinoma from pancreatic ductal cells. AB - Pancreatic cancer is one of the most lethal malignancies, with virtually all patients eventually succumbing to their disease. Mutations in p53 have been documented in >50% of pancreatic cancers. Owing to the high incidence of p53 mutations in PanIN 3 lesions and pancreatic tumors, we interrogated the comparative ability of adult pancreatic acinar and ductal cells to respond to oncogenic Kras and mutant Tp53(R172H) using Hnf1b:CreER(T2) and Mist1:CreER(T2) mice. These studies involved co-activation of a membrane-tethered GFP lineage label, allowing for direct visualization and isolation of cells undergoing Kras and mutant p53 activation. Kras activation in Mist1(+) adult acinar cells resulted in brisk PanIN formation, whereas no evidence of pancreatic neoplasia was observed for up to 6 months following Kras activation in Hnf1beta(+) adult ductal cells. In contrast to the lack of response to oncogenic Kras alone, simultaneous activation of Kras and mutant p53 in adult ductal epithelium generated invasive PDAC in 75% of mice as early as 2.5 months after tamoxifen administration. These data demonstrate that pancreatic ductal cells, whereas exhibiting relative resistance to oncogenic Kras alone, can serve as an effective cell of origin for pancreatic ductal adenocarcinoma in the setting of gain-of function mutations in p53. PMID- 26592448 TI - Kras(G12D) induces EGFR-MYC cross signaling in murine primary pancreatic ductal epithelial cells. AB - Epidermal growth factor receptor (EGFR) signaling has a critical role in oncogenic Kras-driven pancreatic carcinogenesis. However, the downstream targets of this signaling network are largely unknown. We developed a novel model system utilizing murine primary pancreatic ductal epithelial cells (PDECs), genetically engineered to allow time-specific expression of oncogenic Kras(G12D) from the endogenous promoter. We show that primary PDECs are susceptible to Kras(G12D) driven transformation and form pancreatic ductal adenocarcinomas in vivo after Cdkn2a inactivation. In addition, we demonstrate that activation of Kras(G12D) induces an EGFR signaling loop to drive proliferation. Interestingly, pharmacological inhibition of EGFR fails to decrease Kras(G12D)-activated ERK or PI3K signaling. Instead our data provide novel evidence that EGFR signaling is needed to activate the oncogenic and pro-proliferative transcription factor c MYC. EGFR and c-MYC have been shown to be essential for pancreatic carcinogenesis. Importantly, our data link both pathways and thereby explain the crucial role of EGFR for Kras(G12D)-driven carcinogenesis in the pancreas. PMID- 26592449 TI - Glutaminolysis as a target for cancer therapy. AB - Cancer cells display an altered metabolic circuitry that is directly regulated by oncogenic mutations and loss of tumor suppressors. Mounting evidence indicates that altered glutamine metabolism in cancer cells has critical roles in supporting macromolecule biosynthesis, regulating signaling pathways, and maintaining redox homeostasis, all of which contribute to cancer cell proliferation and survival. Thus, intervention in these metabolic processes could provide novel approaches to improve cancer treatment. This review summarizes current findings on the role of glutaminolytic enzymes in human cancers and provides an update on the development of small molecule inhibitors to target glutaminolysis for cancer therapy. PMID- 26592451 TI - Oleanolic acid activates daf-16 to increase lifespan in Caenorhabditis elegans. AB - Oleanolic acid (OA) is an active ingredient in natural plants. It has been reported to possess a variety of pharmacological activities, but very little is known about its effects of anti-aging. We investigate here whether OA has an impact on longevity in vivo, and more specifically, we have examined effects of OA on the lifespan and stress tolerance in Caenorhabditis elegans (C. elegans). Our results showed that OA could extend the lifespan, increase its stress resistance and reduce the intracellular reactive oxygen species (ROS) in wild type worms. Moreover, we have found that OA-induced longevity may not be associated with the calorie restriction (CR) mechanism. Our mechanistic studies using daf-16 loss-of-function mutant strains (GR1307) indicated that the extension of lifespan by OA requires daf-16. In addition, OA treatment could also modulate the nuclear localization, and the quantitative real-time PCR results revealed that up-regulation of daf-16 target genes such as sod-3, hsp-16.2 and ctl-1 could prolong lifespan and increase stress response in C. elegans. This study overall uncovers the longevity effect of OA and its underpinning mechanisms. PMID- 26592452 TI - Ghrelin enhances cue-induced bar pressing for high fat food. AB - Ghrelin is an orexigenic hormone produced by the stomach that acts on growth hormone secretagogue receptors (GHSRs) both peripherally and centrally. The presence of GHSRs in the ventral tegmental area (VTA) suggests that ghrelin signaling at this level may increase the incentive value of palatable foods as well as other natural and artificial rewards. The present investigation sought to determine if ghrelin plays a role in relapse to such foods following a period of abstinence. To achieve this, thirty-six male Long Evans rats were trained to press a lever to obtain a high fat chocolate food reward on a fixed ratio schedule of 1. Following an extinction period during which lever presses were not reinforced, rats were implanted with a cannula connected to a minipump that continuously delivered ghrelin, a GHSR antagonist ([d-Lys-3]-GHRP-6), or saline in the VTA for 14days. One week later, food reward-associated cues, food reward priming, and an overnight fast were used to induce reinstatement of the lever pressing response. Our results indicate that intra-VTA ghrelin enhances cue induced reinstatement of responses for palatable food pellets. To the extent that the reinstatement paradigm is considered a valid model of relapse in humans, this suggests that ghrelin signaling facilitates relapse to preferred foods in response to food cues through GHSR signaling in the VTA. PMID- 26592450 TI - Nucleic acid targeting: towards personalized therapy for head and neck cancer. AB - In light of a detailed characterization of genetic aberrations in cancer, nucleic acid targeting represents an attractive therapeutic approach with significant translational potential. Head and neck squamous cell carcinoma (HNSCC) is a leading cause of cancer deaths worldwide with stagnant 5-year survival rates. Advances in conventional treatment have done little to improve survival and combined chemoradiation is associated with significant adverse effects. Recent reports have characterized the genetic alterations in HNSCC and demonstrated that mutations confer resistance to conventional and molecular targeted therapies. The ability to use specific nucleic acid sequences to inhibit cancer-associated genes including non-druggable targets facilitates personalized medicine approaches with less adverse effects. Additionally, advances in drug delivery mechanisms have increased the transfection efficiency aiding in greater therapeutic responses. Given these advances, the stage has been set to translate the information garnered from genomic studies into personalized treatment strategies. Genes involved in the tumor protein 53 and epidermal growth factor receptor pathways have been extensively investigated and many promising preclinical studies have shown tumor inhibition through genetic modulation. We, and others, have demonstrated that targeting oncogene expression with gene therapy approaches is feasible in patients. Other methods such as RNA interference have proven to be effective and are potential candidates for clinical studies. This review summarizes the major advances in sequence-specific gene modulation in the preclinical setting and in clinical trials in head and neck cancer patients. PMID- 26592454 TI - Effects of chronic mild stress on behavioral and neurobiological parameters - Role of glucocorticoid. AB - Major depression is thought to originate from maladaptation to adverse events, particularly when impairments occur in mood-related brain regions. Hypothalamus pituitary-adrenal (HPA) axis is one of the major systems involved in physiological stress response. HPA axis dysfunction and high glucocorticoid concentrations play an important role in the pathogenesis of depression. In addition, astrocytic disability and dysfunction of neurotrophin brain-derived neurotrophin factor (BDNF) greatly influence the development of depression and anxiety disorders. Therefore, we investigated whether depressive-like and anxiety like behaviors manifest in the absence of glucocorticoid production and circulation in adrenalectomized (ADX) rats after chronic mild stress (CMS) exposure and its potential molecular mechanisms. The results demonstrate that glucocorticoid-controlled rats showed anxiety-like behaviors but not depression like behaviors after CMS. Molecular and cellular changes included the decreased BDNF in the hippocampus, astrocytic dysfunction with connexin43 (cx43) decreasing and abnormality in gap junction in prefrontal cortex (PFC). Interestingly, we did not find any changes in glucocorticoid receptor (GR) or its chaperone protein FK506 binding protein 51 (FKBP5) expression in the hippocampus or PFC in ADX rats subjected to CMS. In conclusion, the production and circulation of glucocorticoids are one of the contributing factors in the development of depression-like behaviors in response to CMS. In contrast, the effects of CMS on anxiety-like behaviors are independent of the presence of circulating glucocorticoids. Meanwhile, stress decreased GR expression and enhanced FKBP5 expression via higher glucocorticoid exposure. Gap junction dysfunction and changes in BDNF may be associated with anxiety-like behaviors. PMID- 26592453 TI - Two-hit exposure to polychlorinated biphenyls at gestational and juvenile life stages: 1. Sexually dimorphic effects on social and anxiety-like behaviors. AB - Endocrine disrupting chemicals (EDCs) are widespread environmental contaminants that affect many neuroendocrine functions. The brain is particularly vulnerable to EDCs during critical periods of gestational development when gonadal hormones exert organizational effects on sexually dimorphic behaviors later in life. Peripubertal development is also a time of continued neural sensitivity to organizing effects of hormones, yet little is known about EDC actions at these times. We sought to determine effects of prenatal or juvenile exposures to a class of EDCs, polychlorinated biphenyls (PCBs) at human-relevant dosages on development, physiology, and social and anxiety-related behaviors later in life, and the consequences of a second juvenile "hit" following prenatal treatment. We exposed male and female Sprague-Dawley rats to PCBs (Aroclor 1221, 1mg/kg/day, ip injection) and/or vehicle during prenatal development (embryonic days 16, 18, 20), juvenile development (postnatal days 24, 26, 28), or both. These exposures had differential effects on behaviors in sex and age-dependent ways; while prenatal exposure had more effects than juvenile, juvenile exposure often modified or unmasked the effects of the first hit. Additionally, females exhibited altered social and anxiety behavior in adolescence, while males displayed small but significant changes in sociosexual preferences in adulthood. Thus, the brain continues to be sensitive to organizing effects of EDCs through juvenile development. As humans are exposed to EDCs throughout multiple periods in their life, these findings have implications for our understanding of EDC effects on physiology and behavior. PMID- 26592455 TI - Hormonal predictors of women's extra-pair vs. in-pair sexual attraction in natural cycles: Implications for extended sexuality. AB - In naturally cycling women, Roney and Simmons (2013) examined hormonal correlates of their desire for sexual contact. Estradiol was positively associated, and progesterone negatively associated, with self-reported desire. The current study extended these findings by examining, within a sample of 33 naturally cycling women involved in romantic relationships, hormonal correlates of sexual attraction to or interests in specific targets: women's own primary partner or men other than women's primary partner. Women's sexual interests and hormone (estradiol, progesterone, and testosterone) levels were assessed at two different time points. Whereas estradiol levels were associated with relatively greater extra-pair sexual interests than in-pair sexual interests, progesterone levels were associated with relatively greater in-pair sexual interests. Both hormones specifically predicted in-pair sexual desire, estradiol negatively and progesterone positively. These findings have implications for understanding the function of women's extended sexuality - their sexual proceptivity and receptivity outside the fertile phase, especially during the luteal phase. PMID- 26592456 TI - Neutron protein crystallography: A complementary tool for locating hydrogens in proteins. AB - Neutron protein crystallography is a powerful tool for investigating protein chemistry because it directly locates hydrogen atom positions in a protein structure. The visibility of hydrogen and deuterium atoms arises from the strong interaction of neutrons with the nuclei of these isotopes. Positions can be unambiguously assigned from diffraction at resolutions typical of protein crystals. Neutrons have the additional benefit to structural biology of not inducing radiation damage in protein crystals. The same crystal could be measured multiple times for parametric studies. Here, we review the basic principles of neutron protein crystallography. The information that can be gained from a neutron structure is presented in balance with practical considerations. Methods to produce isotopically-substituted proteins and to grow large crystals are provided in the context of neutron structures reported in the literature. Available instruments for data collection and software for data processing and structure refinement are described along with technique-specific strategies including joint X-ray/neutron structure refinement. Examples are given to illustrate, ultimately, the unique scientific value of neutron protein crystal structures. PMID- 26592457 TI - Responsiveness of researchers is as important as responsiveness of study participants. PMID- 26592458 TI - Differential action of medically important Indian BIG FOUR snake venoms on rodent blood coagulation. AB - Snakebite is a global health problem affecting millions of people. According to WHO, India has the highest mortality and/or morbidity due to snakebite. In spite of commendable research on Indian BIG FOUR venomous species; Naja naja and Bungarus caeruleus (elapid); Daboia russelii and Echis carinatus (viperid), no significant progress has been achieved in terms of diagnosis and management of biting species with appropriate anti-snake venom. Major hurdle is identification of offending species. Present study aims at differentiation of Indian BIG FOUR snake venoms based on their distinguish action on rodent blood coagulation. Assessment of coagulation alterations by elapid venoms showed negligible effect on re-calcification time, prothrombin time, activated partial thromboplastin time and factors assay (I, II, V, VIII and X) both in vitro and in vivo. However, viperid venoms demonstrated significant anticoagulant status due to their remarkable fibrinogen degradation potentials as supported by fibrinogenolytic activity, fibrinogen zymography and rotational thromboelastometry. Though results provide hint on probable alterations of Indian BIG FOUR snake venoms on blood coagulation, the study however needs validation from human victim's samples to ascertain its reliability for identification of biting snake species. PMID- 26592459 TI - The Notch intracellular domain integrates signals from Wnt, Hedgehog, TGFbeta/BMP and hypoxia pathways. AB - Notch signaling is a highly conserved signal transduction pathway that regulates stem cell maintenance and differentiation in several organ systems. Upon activation, the Notch receptor is proteolytically processed, its intracellular domain (NICD) translocates into the nucleus and activates expression of target genes. Output, strength and duration of the signal are tightly regulated by post translational modifications. Here we review the intracellular post-translational regulation of Notch that fine-tunes the outcome of the Notch response. We also describe how crosstalk with other conserved signaling pathways like the Wnt, Hedgehog, hypoxia and TGFbeta/BMP pathways can affect Notch signaling output. This regulation can happen by regulation of ligand, receptor or transcription factor expression, regulation of protein stability of intracellular key components, usage of the same cofactors or coregulation of the same key target genes. Since carcinogenesis is often dependent on at least two of these pathways, a better understanding of their molecular crosstalk is pivotal. PMID- 26592460 TI - SARM modulates MyD88-mediated TLR activation through BB-loop dependent TIR-TIR interactions. AB - Toll-like receptors (TLRs) recognise invading pathogens and initiate an innate immune response by recruiting intracellular adaptor proteins via heterotypic Toll/interleukin-1 receptor (TIR) domain interactions. Of the five TIR domain containing adaptor proteins identified, Sterile alpha- and armadillo-motif containing protein (SARM) is functionally unique; suppressing immune signalling instead of promoting it. Here we demonstrate that the recombinantly expressed and purified SARM TIR domain interacts with both the major human TLR adaptors, MyD88 and TRIF. A single glycine residue located in the BB-loop of the SARM TIR domain, G601, was identified as essential for interaction. A short peptide derived from this motif was also found to interact with MyD88 in vitro. SARM expression in HEK293 cells was found to significantly suppress lipopolysaccharide (LPS) mediated upregulation of inflammatory cytokines, IL-8 and TNF-alpha, an effect lost in the G601A mutant. The same result was observed with cytokine activation initiated by MyD88 expression and stimulation of TLR2 with lipoteichoic acid (LTA), suggesting that SARM is capable of suppressing both TRIF- and MyD88- dependent TLR signalling. Our findings indicate that SARM acts on a broader set of target proteins than previously thought, and that the BB-loop motif is functionally important, giving further insight into the endogenous mechanisms used to suppress inflammation in immune cells. PMID- 26592461 TI - Recommendations of the Scientific Committee of the Italian Beckwith-Wiedemann Syndrome Association on the diagnosis, management and follow-up of the syndrome. AB - Beckwith-Wiedemann syndrome (BWS) is the most common (epi)genetic overgrowth cancer predisposition disorder. Given the absence of consensual recommendations or international guidelines, the Scientific Committee of the Italian BWS Association (www.aibws.org) proposed these recommendations for the diagnosis, molecular testing, clinical management, follow-up and tumor surveillance of patients with BWS. The recommendations are intended to allow a timely and appropriate diagnosis of the disorder, to assist patients and their families, to provide clinicians and caregivers optimal strategies for an adequate and satisfactory care, aiming also at standardizing clinical practice as a national uniform approach. They also highlight the direction of future research studies in this setting. With recent advances in understanding the disease (epi)genetic mechanisms and in describing large cohorts of BWS patients, the natural history of the disease will be dissected. In the era of personalized medicine, the emergence of specific (epi)genotype-phenotype correlations in BWS will likely lead to differentiated follow-up approaches for the molecular subgroups, to the development of novel tools to evaluate the likelihood of cancer development and to the refinement and optimization of current tumor screening strategies. CONCLUSIONS: In this article, we provide the first comprehensive recommendations on the complex management of patients with Beckwith-Wiedemann syndrome. PMID- 26592462 TI - N-acetylcysteine Facilitates Self-Imposed Abstinence After Escalation of Cocaine Intake. AB - BACKGROUND: N-acetylcysteine (NAC) has been suggested to prevent relapse to cocaine seeking. However, the psychological processes underlying its potential therapeutic benefit remain largely unknown. METHODS: We investigated the hallmark features of addiction that were influenced by chronic NAC treatment in rats given extended access to cocaine: escalation, motivation, self-imposed abstinence in the face of punishment, or propensity to relapse. For this, Sprague Dawley rats were given access either to 1 hour (short access) or 6 hours (long access [LgA]) self-administration (SA) sessions until LgA rats displayed a robust escalation. Rats then received daily saline or NAC (60 mg/kg, intraperitoneal) treatment and were tested under a progressive ratio and several consecutive sessions in which lever presses were punished by mild electric foot shocks. RESULTS: NAC increased the sensitivity to punishment in LgA rats only, thereby promoting abstinence. Following the cessation of punishment, NAC-treated LgA rats failed to recover fully their prepunishment cocaine intake levels and resumed cocaine SA at a lower rate than short access and vehicle-treated LgA rats. However, NAC altered neither the escalation of SA nor the motivation for cocaine. At the neurobiological level, NAC reversed cocaine-induced decreases in the glutamate type 1 transporter observed in both the nucleus accumbens and the dorsolateral striatum. NAC also increased the expression of Zif268 in the nucleus accumbens and dorsolateral striatum of LgA rats. CONCLUSIONS: Our results indicate that NAC contributes to the restoration of control over cocaine SA following adverse consequences, an effect associated with plasticity mechanisms in both the ventral and dorsolateral striatum. PMID- 26592464 TI - Hand-portable liquid chromatographic instrumentation. AB - Over the last four decades, liquid chromatography (LC) has experienced an evolution to smaller columns and particles, new stationary phases and low flow rate instrumentation. However, the development of person-portable LC has not followed, mainly due to difficulties encountered in miniaturizing pumps and detectors, and in reducing solvent consumption. The recent introduction of small, non-splitting pumping systems and UV-absorption detectors for use with capillary columns has finally provided miniaturized instrumentation suitable for high performance hand-portable LC. Fully integrated microfabricated LC still remains a significant challenge. Ion chromatography (IC) has been successfully miniaturized and applied for field analysis; however, applications are mostly limited to inorganic and small organic ions. This review covers advancements that make possible more rapid expansion of portable forms of LC and IC. PMID- 26592465 TI - Back-flushing and heart cut capillary gas chromatography using planar microfluidic Deans' switching for the separation of benzene and alkylbenzenes in industrial samples. AB - Planar microfluidic devices coupled with modern electronic pressure control have allowed gas chromatography (GC) practitioners to easily manipulate chromatographic systems to achieve heart cut and back-flushing configurations. These planar microfluidic devices have enhanced the connectivity between different components of GC instrumentation and have improved the inertness and minimised system dead volumes compared to classical chromatographic unions and valves. In the present contribution the setup and configuration of two multidimensional GC (MDGC) platforms is described for achieving the separation and quantification of trace level target C6-C8 alkylbenzenes in styrene monomer and IsoparaffinTM solvents, using flame ionisation detection (FID). The performance of these MDGC platforms indicated excellent retention time (0.2% relative standard deviation, RSD) and peak area repeatability (1% RSD) for all analytes of interest. The limit of detection (LOD) was 0.8 mg kg(-1) for benzene in styrene monomer, and 2.4-2.8 mg kg(-1) for C6-C8 alkylbenzenes such as benzene, toluene, ethylbenzene and xylene in IsoparaffinTM solvent. PMID- 26592463 TI - Neuron-Targeted Caveolin-1 Improves Molecular Signaling, Plasticity, and Behavior Dependent on the Hippocampus in Adult and Aged Mice. AB - BACKGROUND: Studies in vitro demonstrate that neuronal membrane/lipid rafts (MLRs) establish cell polarity by clustering progrowth receptors and tethering cytoskeletal machinery necessary for neuronal sprouting. However, the effect of MLR and MLR-associated proteins on neuronal aging is unknown. METHODS: Here, we assessed the impact of neuron-targeted overexpression of an MLR scaffold protein, caveolin-1 (Cav-1) (via a synapsin promoter, SynCav1), in the hippocampus in vivo in adult (6-month-old) and aged (20-month-old) mice on biochemical, morphologic, and behavioral changes. RESULTS: SynCav1 resulted in increased expression of Cav 1, MLRs, and MLR-localization of Cav-1 and tropomyosin-related kinase B receptor independent of age and time post gene transfer. Cav-1 overexpression in adult mice enhanced dendritic arborization within the apical dendrites of hippocampal cornu ammonis 1 and granule cell neurons, effects that were also observed in aged mice, albeit to a lesser extent, indicating preserved impact of Cav-1 on structural plasticity of hippocampal neurons with age. Cav-1 overexpression enhanced contextual fear memory in adult and aged mice demonstrating improved hippocampal function. CONCLUSIONS: Neuron-targeted overexpression of Cav-1 in the adult and aged hippocampus enhances functional MLRs with corresponding roles in cell signaling and protein trafficking. The resultant structural alterations in hippocampal neurons in vivo are associated with improvements in hippocampal dependent learning and memory. Our findings suggest Cav-1 as a novel therapeutic strategy in disorders involving impaired hippocampal function. PMID- 26592466 TI - Taser-Related Testicular Trauma. AB - The Thomas A. Swift's Electric Rifle (Taser) is an electrical weapon designed as a nonlethal means to subdue violent or fleeing subjects. Several reports have been published on the safety and efficacy of, as well as injury profile from, police Tasers. Documented urologic involvement is rare. The sequela of an electrical current from a Taser gun to the testis in regard to both short- and long-term functions is unknown. Herein we present a case of penetrating trauma to the scrotum from a Taser dart. PMID- 26592467 TI - The Change of Testosterone Secretion During the Treatment of Alpha-1 Blocker in Patients with Benign Prostatic Hyperplasia. AB - OBJECTIVE: To investigate the correlation between testosterone levels and lower urinary tract symptoms (LUTS) and bladder outlet obstruction (BOO), to evaluate the change in testosterone secretion during treatment for LUTS, and to determine the factors that influence testosterone secretion. METHODS: This was an open labeled, single-center, prospective study of 110 outpatients with LUTS caused by benign prostatic hyperplasia. Silodosin, an alpha-1 blocker that is not known to affect testosterone secretion, was administered to the patients. Before administration and 1 year after administration, serum testosterone level was measured, and the International Prostate Symptom Score and a urodynamic study were used to assess subjective and objective symptoms. RESULTS: A total of 104 patients with a mean age of 70.4 years were included in the analysis. According to pretreatment evaluation, no statistically significant correlations existed between the serum total testosterone level and the International Prostate Symptom Score (r = -0.08, P = .44) or BOO index (r = 0.04, P = .68). One year after silodosin administration, the mean serum testosterone level significantly increased from 5.09 to 5.52 ng/mL (P <.001). Additionally, a significant positive correlation was observed between the change in testosterone level and improvement in the BOO index (r = 0.52, P <.001). CONCLUSION: In patients with benign prostatic hyperplasia, treatment with silodosin significantly increased testosterone secretion, and improvements in objective symptoms such as BOO were found to be the factors that influenced testosterone secretion. PMID- 26592468 TI - Pediatric Urologists' Personal Point-of-view of Health Related Quality of Life. AB - OBJECTIVE: To assess pediatric urologists' understanding and use of health related quality of life (HRQOL) resources in clinical practice. HRQOL is becoming an increasingly vital part of patient care. Although HRQOL has been evaluated and instruments have been developed for its assessment for several pediatric conditions, it is underrepresented in pediatric urology. METHODS: A SurveyMonkey 7-item questionnaire was sent to the members of the Society for Pediatric Urology. The questions inquired as to knowledge of surveys available, views on appropriate age for beginning discussion of HRQOL, patients' and providers' ability to assess patient HRQOL, and the need for disease-specific surveys. RESULTS: One-hundred and eighteen providers (37.6%) completed the survey. Remarkably, 85.6% of the responders believe disease-focused HRQOL instruments would be useful for specific urologic diseases; however, only 14.4% of the providers state use of any HRQOL instrument. Only 5 unique measures were reported. The majority felt the age at which patients can start reporting his or her HRQOL is 6-8 (41.3%) or 9-11 (31.2%) years. A preponderance of providers believed both themselves and parents could "somewhat" evaluate the patient HRQOL, but the majority believe it is important to inquire about parents' perceptions of patient HRQOL. CONCLUSION: The overwhelming majority of pediatric urologists believe HRQOL is important but only a minority utilize the available instruments. Further studies are needed to develop instruments to fill this essential gap. PMID- 26592469 TI - Reply by the Authors. PMID- 26592471 TI - Evaluation of adaptogenic-like property of methyl jasmonate in mice exposed to unpredictable chronic mild stress. AB - This study was undertaken to evaluate the adaptogenic-like activity of methyl jasmonate (MJ) in mice exposed to unpredictable chronic mild stress (UCMS). Male Swiss mice were treated with MJ (25-100mg/kg, i.p.) 30 min before exposure to UCMS daily for 14 days prior to testing for memory and anxiety. Thereafter, the blood glucose and serum corticosterone levels were estimated using glucometer and ELISA. The brain concentrations of malondialdehyde (MDA) and glutathione (GSH) were estimated using spectrophotometer. Brain histology and the population of healthy neurons in the hippocampal regions were also assessed. MJ reversed anxiety and memory impairment produced by UCMS, which suggest adaptogenic-like property. The reduction in the weight of adrenal gland and liver in MJ-treated groups further indicates adaptogenic activity. It further decreases the blood glucose and serum corticosterone levels in UCMS-mice. Also, MJ decreases the concentrations of MDA and elevated the levels of GSH in the brain of mice exposed to UCMS. Brain histology revealed that MJ attenuated UCMS-induced degeneration and death of neuronal cells in the pyramidal layer of the cornu ammonis 3 (CA3) and the sub-granular zone of the dentate gyrus of the hippocampus. Moreover, MJ decreased the population of dead neuronal cells of the pyramidal layer of the CA3 and the sub-granular zone of the dentate gyrus of the UCMS-mice, which suggests neuroprotection. Taken together, these findings suggest that MJ demonstrated adaptogenic-like activity in mice; which might be related to modulation of serum corticosterone levels, inhibition of oxidative stress and neuroprotection. PMID- 26592470 TI - Flumazenil decreases surface expression of alpha4beta2delta GABAA receptors by increasing the rate of receptor internalization. AB - Increases in expression of alpha4betadelta GABAA receptors (GABARs), triggered by fluctuations in the neurosteroid THP (3alpha-OH-5alpha[beta]-pregnan-20-one), are associated with changes in mood and cognition. We tested whether alpha4betadelta trafficking and surface expression would be altered by in vitro exposure to flumazenil, a benzodiazepine ligand which reduces alpha4betadelta expression in vivo. We first determined that flumazenil (100 nM-100 MUM, IC50=~1 MUM) acted as a negative modulator, reducing GABA (10 MUM)-gated current in the presence of 100 nM THP (to increase receptor efficacy), assessed with whole cell patch clamp recordings of recombinant alpha4beta2delta expressed in HEK-293 cells. Surface expression of recombinant alpha4beta2delta receptors was detected using a 3XFLAG reporter at the C-terminus of alpha4 (alpha4F) using confocal immunocytochemical techniques following 48 h exposure of cells to GABA (10 MUM)+THP (100 nM). Flumazenil (10 MUM) decreased surface expression of alpha4F by ~60%, while increasing its intracellular accumulation, after 48 h. Reduced surface expression of alpha4beta2delta after flumazenil treatment was confirmed by decreases in the current responses to 100 nM of the GABA agonist gaboxadol. Flumazenil-induced decreases in surface expression of alpha4beta2delta were prevented by the dynamin blocker, dynasore, and by leupeptin, which blocks lysosomal enzymes, suggesting that flumazenil is acting to increase endocytosis and lysosomal degradation of the receptor. Flumazenil increased the rate of receptor removal from the cell surface by 2-fold, assessed using botulinum toxin B to block insertion of new receptors. These findings may suggest new therapeutic strategies for regulation of alpha4beta2delta expression using flumazenil. PMID- 26592472 TI - Anti-inflammatory effects and antioxidant activity of dihydroasparagusic acid in lipopolysaccharide-activated microglial cells. AB - The activation of microglia and subsequent release of toxic pro-inflammatory factors are crucially associated with neurodegenerative disease, characterized by increased oxidative stress and neuroinflammation, including Alzheimer and Parkinson diseases and multiple sclerosis. Dihydroasparagusic acid is the reduced form of asparagusic acid, a sulfur-containing flavor component produced by Asparagus plants. It has two thiolic functions able to coordinate the metal ions, and a carboxylic moiety, a polar function, which may enhance excretion of the complexes. Thiol functions are also present in several biomolecules with important physiological antioxidant role as glutathione. The aim of this study is to evaluate the anti-inflammatory and antioxidant potential effect of dihydroasparagusic acid on microglial activation in an in vitro model of neuroinflammation. We have used lipopolysaccharide to induce an inflammatory response in primary rat microglial cultures. Our results suggest that dihydroasparagusic acid significantly prevented lipopolysaccharide-induced production of pro-inflammatory and neurotoxic mediators such as nitric oxide, tumor necrosis factor-alpha, prostaglandin E2, as well as inducible nitric oxide synthase and cyclooxygenase-2 protein expression and lipoxygenase activity in microglia cells. Moreover it effectively suppressed the level of reactive oxygen species and affected lipopolysaccharide-stimulated activation of mitogen activated protein kinase, including p38, and nuclear factor-kB pathway. These results suggest that dihydroasparagusic acid's neuroprotective properties may be due to its ability to dampen induction of microglial activation. It is a compound that can effectively inhibit inflammatory and oxidative processes that are important factors of the etiopathogenesis of neurodegenerative diseases. PMID- 26592473 TI - An approach to improve the resolution of helical filaments with a large axial rise and flexible subunits. AB - Single particle analysis is widely used for three-dimensional reconstruction of helical filaments. Near-atomic resolution has been obtained for several well ordered filaments. However, it is still a challenge to achieve high resolution for filaments with flexible subunits and a large axial rise per subunit relative to pixel size. Here, we describe an approach that improves the resolution in such cases. In filaments with a large axial rise, many segments must be shifted a long distance along the filament axis to match with a reference projection, potentially causing loss of alignment accuracy and hence resolution. In our study of myosin filaments, we overcame this problem by pre-determining the axial positions of myosin head crowns within segments to decrease the alignment error. In addition, homogeneous, well-ordered segments were selected from the raw data set by checking the assigned azimuthal rotation angle of segments in each filament against those expected for perfect helical symmetry. These procedures improved the resolution of the filament reconstruction from 30 A to 13 A. This approach could be useful in other helical filaments with a large axial rise and/or flexible subunits. PMID- 26592474 TI - Ultrastable gold substrates: Properties of a support for high-resolution electron cryomicroscopy of biological specimens. AB - Electron cryomicroscopy (cryo-EM) allows structure determination of a wide range of biological molecules and specimens. All-gold supports improve cryo-EM images by reducing radiation-induced motion and image blurring. Here we compare the mechanical and electrical properties of all-gold supports to amorphous carbon foils. Gold supports are more conductive, and have suspended foils that are not compressed by differential contraction when cooled to liquid nitrogen temperatures. These measurements show how the choice of support material and geometry can reduce specimen movement by more than an order of magnitude during low-dose imaging. We provide methods for fabrication of all-gold supports and preparation of vitrified specimens. We also analyse illumination geometry for optimal collection of high resolution, low-dose data. Together, the support structures and methods herein can improve the resolution and quality of images from any electron cryomicroscope. PMID- 26592477 TI - Hyaluronic acid for anticancer drug and nucleic acid delivery. AB - Hyaluronic acid (HA) is widely used in anticancer drug delivery, since it is biocompatible, biodegradable, non-toxic, and non-immunogenic; moreover, HA receptors are overexpressed on many tumor cells. Exploiting this ligand-receptor interaction, the use of HA is now a rapidly-growing platform for targeting CD44 overexpressing cells, to improve anticancer therapies. The rationale underlying approaches, chemical strategies, and recent advances in the use of HA to design drug carriers for delivering anticancer agents, are reviewed. Comprehensive descriptions are given of HA-based drug conjugates, particulate carriers (micelles, liposomes, nanoparticles, microparticles), inorganic nanostructures, and hydrogels, with particular emphasis on reports of preclinical/clinical results. PMID- 26592478 TI - Ginsenoside Rg1 prevents cerebral and cerebellar injury induced by obstructive jaundice in rats via inducing expression of TIPE-2. AB - The aim of the study was to analyze the effect of Ginsenoside Rg1 (Rg1) on cerebral and cerebellar injury in experimental obstructive jaundice (OJ). OJ was done by ligature and section of extrahepatic biliary duct. Rg1 was injected intraperitoneally (10 mg kg(-1)d(-1) or 20 mg kg(-1) d(-1)). Comparison of serum total bile salts (TBA), total bilirubin (TBil), direct bilirubin (DBil), TNF alpha, IL-6 and IL-1beta among groups. Malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) were determined, also apoptosis and mRNA and protein levels of TIPE2 (TNF-alpha inducible protein 8-like 2) were tested in cerebrum and cerebellum. Our results showed that Rg1 reduced MDA and apoptosis in cerebrum and cerebellum induced by OJ, also GSH and antioxidant enzyme activity were raised obviously in rats treated with Rg1. Moreover, decreased mRNA and protein levels of TIPE2 in OJ rats and Rg1 could improve the decreased mRNA and protein levels of TIPE2 in OJ rats. In conclusion, Rg1 decreased oxidative stress and apoptosis, also recovered the antioxidant status and mRNA and protein levels of TIPE2 in the cerebrum and cerebellum of OJ rats. PMID- 26592479 TI - Chronic exposure to aluminum and risk of Alzheimer's disease: A meta-analysis. AB - A meta-analysis was performed to investigate whether chronic exposure to aluminum (Al) is associated with increased risk of Alzheimer's disease (AD). Eight cohort and case-control studies (with a total of 10567 individuals) that met inclusion criteria for the meta-analysis were selected after a thorough literature review of PubMed, Web of Knowledge, Elsevier ScienceDirect and Springer databases up to June, 2015. The Newcastle-Ottawa Scale (NOS) was used to assess the quality of included studies. Q test and I(2) statistic were used to examine heterogeneity between selected studies. The overall odds ratio (OR) was calculated using a fixed-effect model because no significant heterogeneity between studies was found. No publication bias was observed based on a funnel plot and Egger's test. Results showed that individuals chronically exposed to Al were 71% more likely to develop AD (OR: 1.71, 95% confidence interval (CI), 1.35-2.18). The finding suggests that chronic Al exposure is associated with increased risk of AD. PMID- 26592480 TI - Alterations of prefrontal cortical microRNAs in methamphetamine self administering rats: From controlled drug intake to escalated drug intake. AB - Drug addiction is a process that transits from recreative and regular drug use into compulsive drug use. The two patterns of drug use, controlled drug intake and escalated drug intake, represent different stages in the development of drug addiction; and escalation of drug use is a hallmark of addiction. Accumulating studies indicate that microRNAs (miRNAs) play key regulatory roles in drug addiction. However, the molecular adaptations in escalation of drug use, as well as the difference in the adaptations between escalated and controlled drug use, remain unclear. In the present study, 28 altered miRNAs in the prefrontal cortex (PFC) were found in the groups of controlled methamphetamine self-administration (1h/session) and escalated self-administration (6h/session), and some of them were validated. Compared with saline control group, miR-186 was verified to be up regulated while miR-195 and miR-329 were down-regulated in the rats with controlled methamphetamine use. In the rats with escalated drug use, miR-127, miR 186, miR-222 and miR-24 were verified to be up-regulated while miR-329 was down regulated compared with controls. Furthermore, bioinformatic analysis indicated that the predicted targets of these verified miRNAs involved in the processes of neuronal apoptosis and synaptic plasticity. However, the putative regulated molecules may be different between controlled and escalated drug use groups. Taken together, we detected the altered miRNAs in rat PFC under the conditions of controlled methamphetamine use and escalated use respectively, which may extend our understanding of the molecular adaptations underlying the transition from controlled drug use to addiction. PMID- 26592481 TI - Short-term treadmill exercise increased tau insolubility and neuroinflammation in tauopathy model mice. AB - Physical exercise has been identified as a preventive measure for Alzheimer's disease (AD), one of the neuropathological hallmarks of which, neurofibrillary tangles, consist of hyperphosphorylated insoluble tau. Previous studies demonstrated that long-term treadmill exercise reduced tau hyperphosphorylation and insolubility; however, whether short-term treadmill exercise (STE) alters tau modifications currently remains unknown. In the present study, we attempted to characterize the effects of STE on tau solubility and determine its relationship with neuroinflammation using tauopathy model mice (Tg601), which express wild type human tau. The results obtained showed that 3 weeks of non-shock treadmill exercise in Tg601 and non-transgenic female mice markedly increased insoluble tau. An analysis of phosphorylation patterns indicated that changes in tau solubility were related to an increase in phosphorylation at the tau C-terminal end. The results of immunohistochemical analyses revealed that STE increased the number of Iba-1-positive microglial cells in the hippocampus. Elevations in the levels of the lipid peroxidation markers, 4-hydroxy-trans-2-noneal and malondialdehyde, indicated the presence of oxidative stress. Moreover, higher levels of cytokines, IL-1beta and IL-18, and chemokines, CXCL-1 and CXCL-12, supported neuroinflammation. PMID- 26592482 TI - Betaine reverses the memory impairments in a chronic cerebral hypoperfusion rat model. AB - Vascular dementia (VaD) is the second reason for the cognitive decline in aged people, but the effective therapy is still missing. The chronic cerebral hypoperfusion (CCH) had been widely found in VaD patients and is thought to be the key reason for cognitive impairment. Betaine is a natural product that had been implicated in many biological processes and had been used for the therapy of some neurodegenerative disease, such as Alzheimer's disease. In this study, we reported that betaine treatment could rescue the memory deficits induced by two vessel occlusion (2-VO), a widely used CCH rat model. Betaine also restored the expression of PSD93, PSD95 and MAP2 to preserve the synaptic functions. Furthermore, betaine could reduce the oxidative stress by suppressing the MDA and ROS and enhancing the SOD and GSH. Overall, betaine treatment is able to rescue the memory deficits in CCH rats, which provide an experimental basis for the therapy of VaD. PMID- 26592483 TI - DF2755A, a novel non-competitive allosteric inhibitor of CXCR1/2, reduces inflammatory and post-operative pain. AB - The activation of CXCR1/2 has been implicated in the genesis of inflammatory and postoperative pain. Here, we investigated a novel orally acting allosteric inhibitor of CXCR1/2 (DF2755A) and evaluated its antinociceptive effect in several models of inflammatory and post-operatory pain. DF2755A was tested in vitro for efficacy in the chemotaxis assay, selectivity and toxicity. In vivo, C57Bl/6 mice were treated orally with DF2755A and the following experiments were performed: pharmacokinetic profile; inflammatory hyperalgesia models using electronic pressure meter test; neutrophil migration assay assessed by myeloperoxidase assay. DF2755A selectively inhibited neutrophil chemotaxis induced by CXCR1/2 ligands without effect on CXCL8 binding to neutrophils. A single mutation of the allosteric site at CXCR1 abrogated the inhibitory effect of DF2755A on CXCL8-induced chemotaxis. DF2755A given orally was well absorbed (88.2%), and it was able to reduce, in a dose (3-30mg/kg)-dependent manner, inflammatory hyperalgesia induced by carrageenan, LPS and CXCL1/KC as well as neutrophil recruitment and IL-1beta production. In addition, DF2755A was able to reduce post-incisional nociception. Therapeutic treatment with DF2755A reduced CFA-induced inflammatory hyperalgesia even when injected intrathecally. The present results indicate that DF2755A is a novel selective allosteric inhibitor of CXCR1/2 with a favorable oral pharmacokinetic profile. Furthermore, the results might suggest that DF2755A might be a candidate of a novel therapeutic option to control inflammatory and post-operative pain. PMID- 26592484 TI - The diagnosis of double-crush lesion in the L5 lumbar nerve using diffusion tensor imaging. AB - BACKGROUND CONTEXT: A double-crush lesion is a condition in which the lumbar nerve is compressed both medially and laterally in the spinal canal, where diagnosis can be very difficult, and is a factor leading to poor surgical success rates. PURPOSE: Diffusion tensor imaging (DTI) was used to determine DTI parameter fractional anisotropy (FA) values and apparent diffusion coefficient (ADC) in both intraspinal column lesions alone and in double-crush lesions. STUDY DESIGN: This study used a prospective study. PATIENT SAMPLE: Of the 56 cases (mean age: 72.2 years) that underwent laminectomy for lumbar spinal stenosis at our clinic between April 2013 to March, 2015, 10 cases with L5 radiculopathy caused by L4-L5 stenosis (Intraspinal stenosis group (Group I); mean age: 74.7 years), and 5 cases with persistent symptoms caused by L5 foraminal stenosis despite L4-L5 decompression surgery (Double-crush group (Group D); mean age: 77.6 years) were targeted. One patient in Group D was diagnosed through microendoscopic intrapedicular partial pediculotomy and the remaining four cases by nerve root infiltration. Five healthy cases (mean age: 54 years) were studied as controls. OUTCOME MEASURES: Intraspinal zone (Iz), nerve root (N), and extraforaminal zone (Ez) were established as the regions of interest, and the L5 nerve FA and ADC values were determined on the affected side. METHODS: Diffusion tensor imaging was performed prospectively by 1.5T magnetic resonance imaging before surgery, and DTI parameters of L5 nerve were evaluated in all patients and healthy volunteers. Student t test was used for group comparisons, and a p<.05 was considered statistically significant. RESULTS: Fractional anisotropy values (Iz, N, Ez) were 0.415, 0.448, and 0.517, respectively, increasing as sites became more distal. Group I values were 0.335, 0.393, and 0.484, and Group D values were 0.296, 0.367, and 0.360. Compared with the healthy volunteers, Group D had significantly lower Iz (p<.05) and Ez (p<.001) values, while Group I had significantly lower Iz (p<.05) values. In Group D, Ez FA values were significantly lower (p<.001) than in Group I. Apparent diffusion coefficient values (Iz, N, Ez) in the healthy control group were 1.270 mm2/s, 1.151 mm2/s, and 0.937 mm2/s with values decreasing as sites grew distal. In Group I, the ADC values were 1.406 mm2/s, 1.184 mm2/s, and 1.001 mm2/s, while in Group D they were 1.551 mm2/s, 1.412 mm2/s, and 1.329 mm2/s. Compared with the healthy volunteers, Iz (p<.05) and Ez (p<.05) values were significantly higher in Group D. The N (p<.01) and Ez (p<.001) ADC values were significantly higher in Group D than in Group I. CONCLUSIONS: Depending on where the nerve was compressed, changes in DTI parameters revealed nerve damage (low FA values and increased ADC) in the intraspinal canal in the Intraspinal Group, and over a widespread area in the Double-crush Group spanning the medial to lateral spinal canal. Our research suggests that in cases where double crush is suspected before surgery, failed back surgery syndrome may be prevented by evaluating DTI images. PMID- 26592485 TI - 180 degrees kyphosis of both the vertebral column and the aorta. PMID- 26592486 TI - North American Spine Society Presidential Address. PMID- 26592487 TI - Pakistani women's use of mental health services and the role of social networks: a systematic review of quantitative and qualitative research. AB - Pakistani women in the UK are an at-risk group with high levels of mental health problems, but low levels of mental health service use. However, the rates of service use for Pakistani women are unclear, partly because research with South Asian women has been incorrectly generalised to Pakistani women. Further, this research has been largely undertaken within an individualistic paradigm, with little consideration of patients' social networks, and how these may drive decisions to seek help. This systematic review aimed to clarify usage rates, and describe the nature of Pakistani women's social networks and how they may influence mental health service use. Ten journal databases (ASSIA, CINAHL Plus, EMBASE, HMIC, IBSS, MEDLINE, PsycINFO, Social Sciences Abstracts, Social Science Citation Index and Sociological Abstracts) and six sources of grey literature were searched for studies published between 1960 and the end of March 2014. Twenty-one studies met inclusion criteria. Ten studies (quantitative) reported on inpatient or outpatient service use between ethnic groups. Seven studies (four quantitative, three qualitative) investigated the nature of social networks, and four studies (qualitative) commented on how social networks were involved in accessing mental health services. Pakistani women were less likely than white (British) women to use most specialist mental health services. No difference was found between Pakistani and white women for the consultation of general practitioners for mental health problems. Pakistani women's networks displayed high levels of stigmatising attitudes towards mental health problems and mental health services, which acted as a deterrent to seeking help. No studies were found which compared stigma in networks between Pakistani women and women of other ethnic groups. Pakistani women are at a considerable disadvantage in gaining access to and using statutory mental health services, compared with white women; this, in part, is due to negative attitudes to mental health problems evident in social support networks. PMID- 26592488 TI - Can interpersonal hypersensitivity under subconscious condition explain paranoid symptom in schizophrenia? AB - INTRODUCTION: Interpersonal hypersensitivity is often observed in schizophrenia and has been associated with psychopathological deficits in schizophrenia. Here, we investigated dysfunctions of interpersonal information processing in schizophrenia at both conscious and subconscious levels. METHODS: The experiment included 143 schizophrenia patients and 59 healthy controls. A continuous flashing suppression approach based on binocular rivalry was employed, which included two modes: invisible (subconscious) and visible (conscious). The accuracy and reaction time of a Gabor patch direction-detection task were assessed under three types of stimuli in both modes: images with no person (type 1), images with two to three noncommunicating persons (type 2), and images with more than three communicating individuals (type 3). RESULTS: In the visible mode, the accuracy of the Gabor patch direction-detection task in the case group was significantly lower than in the control group for the third type of stimuli (P = 0.015). In the invisible mode, however, the accuracy was higher in the case group than in the control group (P = 0.037). The response time difference of the Gabor patch direction-detection task for the third type of images in the invisible mode was negatively correlated with the duration of the illness (P = 0.008). DISCUSSION: These findings suggest that schizophrenia patients exhibit attentional bias to interpersonal interaction behaviors at both conscious and subliminal levels but toward opposite directions. Our findings shed light on the subconscious deficits under the paranoid symptom in schizophrenia. PMID- 26592490 TI - Review article: the current treatment of non-cardiac chest pain. AB - BACKGROUND: Non-cardiac chest pain is one of the most common functional gastrointestinal disorders. By recognising that gastro-oesophageal reflux disease (GERD), oesophageal dysmotility and oesophageal hypersensitivity are the main underlying mechanisms of NCCP, a more directed therapeutic approach has been developed. AIM: To determine the value of the current therapeutic modalities for NCCP. METHODS: Electronic (Pubmed/Medline/Cochrane central) and manual search. RESULTS: Double-dose PPI treatment for two months is a reasonable first choice approach in patients with NCCP because GERD is the most common aetiology. Studies evaluating the role of medical therapy in NCCP patients with hypercontractile oesophageal motility suggest a limited value to muscle relaxants like calcium channel blockers (nifedipine, diltiazem), nitrates and sildenafil. While most trials evaluating pain modulators are small and many are not placebo-controlled, these type of medications appear efficacious in both patients with NCCP due to oesophageal dysmotility and those with functional chest pain. Cognitive behavioural therapy has been extensively studied in patients with functional chest pain with good results. Other psychological techniques such as hypnotherapy, group therapy or coping skills have been scarcely studied but appear to be effective in NCCP patients. CONCLUSION: Medical, endoscopic and surgical therapeutic options are available for the treating physician, although some patients with non-cardiac chest pain may require a multimodal therapeutic approach. PMID- 26592489 TI - Chronic insufficient sleep and diet quality: Contributors to childhood obesity. AB - OBJECTIVE: To examine associations of chronic insufficient sleep with diet and whether diet explains the sleep-adiposity relationship. METHODS: In Project Viva, 1,046 parents reported children's sleep duration at 6 m and annually until midchildhood (7 y). The main exposure was a sleep curtailment score (6 m-7 y) ranging from 0 (maximal curtailment) to 13 (adequate sleep). In mid-childhood, parents reported children's diet; researchers measured height/weight. Multivariable linear regression assessed associations of sleep with diet (Youth Healthy Eating Index [YHEI]); sleep with BMI z-score adjusting for YHEI; and, secondarily, joint associations of sleep and YHEI with BMI. RESULTS: Mean (SD) sleep and YHEI scores were 10.21 (2.71) and 58.76 (10.37). Longer sleep duration was associated with higher YHEI in mid-childhood (0.59 points/unit sleep score; 95% CI: 0.32, 0.86). Although higher YHEI was associated with lower BMI z-score ( 0.07 units/10-point increase; 95% CI: -0.13, -0.01), adjustment for YHEI did not attenuate sleep-BMI associations. Children with sleep and YHEI scores below the median (<11 and <60) had BMI z-scores 0.34 units higher (95% CI: 0.16, 0.51) than children with sleep and YHEI scores above the median. CONCLUSIONS: While parent reported diet did not explain inverse associations of sleep with adiposity, both sufficient sleep and high-quality diets are important to obesity prevention. PMID- 26592491 TI - Practical Organocatalytic Synthesis of Functionalized Non-C2-Symmetrical Atropisomeric Biaryls. AB - An organic acid catalyzed direct arylation of aromatic C(sp(2))-H bonds in phenols and naphthols for the preparation of 1,1'-linked functionalized biaryls was developed. The products are non-C2-symmetrical, atropoisomeric, and represent previously untapped chemical space. Overall this transformation is operationally simple, does not require an external oxidant, is readily scaled up (up to 98 mmol), and the structurally diverse 2,2'-dihydroxy biaryl (i.e., BINOL-type), as well as 2-amino-2'-hydroxy products (i.e., NOBIN-type) are formed with complete regioselectivity. Density-functional calculations suggest that the quinone and imino-quinone monoacetal coupling partners are exclusively arylated at their alpha-position by an asynchronous [3,3]-sigmatropic rearrangement of a mixed acetal species which is formed in situ under the reaction conditions. PMID- 26592492 TI - Extraction methods of Amaranthus sp. grain oil isolation. AB - BACKGROUND: Amaranthus sp. is a fast-growing crop with well-known beneficial nutritional values (rich in protein, fat, dietary fiber, ash, and minerals, especially calcium and sodium, and containing a higher amount of lysine than conventional cereals). Amaranthus sp. is an underexploited plant source of squalene, a compound of high importance in the food, cosmetic and pharmaceutical industries. RESULTS: This paper has examined the effects of the different extraction methods (Soxhlet, supercritical fluid and accelerated solvent extraction) on the oil and squalene yield of three genotypes of Amaranthus sp. grain. The highest yield of the extracted oil (78.1 g kg(-1) ) and squalene (4.7 g kg(-1) ) in grain was obtained by accelerated solvent extraction (ASE) in genotype 16. Post hoc Tukey's HSD test at 95% confidence limit showed significant differences between observed samples. Principal component analysis (PCA) and cluster analysis (CA) were used for assessing the effect of different genotypes and extraction methods on oil and squalene yield, and also the fatty acid composition profile. Using coupled PCA and CA of observed samples, possible directions for improving the quality of product can be realized. CONCLUSION: The results of this study indicate that it is very important to choose both the right genotype and the right method of extraction for optimal oil and squalene yield. (c) 2015 Society of Chemical Industry. PMID- 26592493 TI - Single-Handed Towards Nanosized Organic Molecules. AB - Hand in hand: Enantiopure reactants have been used to generate rigid molecular tweezers by Buchwald-Hartwig aminations. These result in the phenazine units curving in only one direction with formation of one product exclusively. PMID- 26592494 TI - Enalapril and the VEGFA gene: Personalized medicine in hypertension therapy. PMID- 26592495 TI - Quality of assessment and counselling offered by community pharmacists and medication sale without prescription to patients presenting with acute cardiac symptoms: a simulated client study. AB - PURPOSE: Self-medication is common worldwide. However, the prevalence of sale of prescription medications without prescription and the quality of assessment and counselling provided by community pharmacists to cardiac patients is unknown. We sought to determine the prevalence of prescription medication sales and explore how pharmacists assess and counsel patients with acute cardiac conditions. METHODS: Six hundred community pharmacies in the two largest cities in Saudi Arabia were selected. Two simulated clients presented either an acute coronary syndrome (ACS) scenario or an acute heart failure (AHF) scenario to the pharmacists. Descriptive statistics and regression models were used to analyse and present the collected data. RESULTS: Of 600 pharmacies, 379 (63.2%) sold various prescription medications to simulated patients without prescription. Assessment and counselling provided by pharmacists were inadequate. Almost a quarter of pharmacists did not ask simulated patients any questions; 52% asked one or two questions; and only 24% asked three or more questions. Only 28 pharmacists (4.7%) inquired about drug allergies; 48.5% instructed simulated patients on the dosage and frequency of the sold medications; 21.6% provided instruction on treatment duration; and 19.4% gave instructions on dose, frequency, and duration of treatment. Compared to AHF, ACS simulated patients were more likely to be asked about other symptoms and comorbidities (59.7% vs. 48.7%, p = 0.007 and 46.3% vs. 37.3%, p = 0.005, respectively) and were more likely to be advised to go to hospital (70.3% vs. 56.3%, p < 0.001). CONCLUSIONS: The sale of prescription medications by community pharmacists to simulated cardiac patients without prescription is very common; assessment and counselling qualities are suboptimal. PMID- 26592496 TI - Immunoexpression patterns for Hypoxia-inducible Factor-1alpha and von Hippel Lindau protein, in relation to Hsp90, of human brain tumors. AB - The pathogenesis of many tumors, including brain tumors, has been associated with hypoxia, which induces the transcriptional activity of hypoxia-inducible Factor 1alpha (HIF-1alpha). HIF-1alpha is normally degradated by the von Hippel-Lindau protein (pVHL) but, in hypoxia, pVHL/HIF-1alpha interaction is inhibited resulting in the nuclear accumulation of HIF-1alpha. Hsp90 (Heat shock protein 90), as a chaperone protein, plays a critical role for both stabilization of HIF 1alpha and degradation of pVHL. The aim of this study was to estimate immunohistochemically the expression levels of HIF-1alpha and pVHL, in relation to Hsp90, in different types of human brain tumors (42 gliomas, 9 medulloblastomas, and 38 meningiomas) using specific antibodies. The tumors were further divided into two groups according to the age of patients (>=19 years old or ?19 years old). Nuclear, for HIF-1alpha, and cytoplasmic, for pVHL and Hsp90, localization was detected in a high percentage of tumor cells in the majority of tumors. In astrocytomas, a significant, grade-dependent relationship for HIF 1alpha immunoexpression was observed (p?0.05). Furthermore, there was a significant correlation between pVHL and Hsp90 immunoexpression (p?0.01). The group of >=19 years old patients with glioblastomas (WHO grade IV) demonstrated significantly increased immunoexpression for HIF-1alpha compared to pVHL (p?0.0001) and Hsp90 expression (p?0.01). In medulloblastomas, a significant correlation of HIF-1alpha with Hsp90 immunoexpression (p?0.05) was found. In meningiomas, no significant correlation for the expression of the three proteins was detected (p>=0.05). These results indicate that HIF-1alpha/pVHL/Hsp90 interactions may be implicated in biology of different types of brain tumors through different signaling mechanisms. PMID- 26592497 TI - PET monitoring angiogenesis of infarcted myocardium after treatment with vascular endothelial growth factor and bone marrow mesenchymal stem cells. AB - Angiogenesis is a key factor for post-ischemic repair of the infarcted myocardium. This study aims to monitor angiogenesis of infarcted myocardium with a positron emission tomography (PET) imaging agent, (18)F-alfatide II ((18)F-AlF NOTA-E[PEG4-c(RGDfk)]2), targeting alphavbeta3 integrin after treatment with vascular endothelial growth factor (VEGF) gene and/or bone marrow mesenchymal stem cells (BMSCs). Sprague-Dawley (SD) rats underwent left coronary artery ligation and were randomly divided into four groups: normal saline control, Ad VEGF, BMSCs, and Ad-VEGF + BMSCs (n = 4/group). The induced myocardial infarction (MI) was confirmed by electrocardiogram (ECG) with ST-segment elevation, and (99m)Tc-MIBI SPECT imaging showing defected myocardial perfusion. Alfatide II PET was performed to monitor angiogenesis at different time points after the therapy. The ratios of Alfatide II tracer uptake in the infarcted myocardium to normal myocardium in all four groups were analyzed. The PET results were validated by ex vivo tissue biodistribution, autoradiography, and immunofluorescence staining. At 1 week after therapy, elevated RGD peptide tracer uptake at the infarcted myocardium was observed in all four groups. The infarct to normal heart ratio of Alfatide II tracer for the three treatment groups was significantly higher than that of the control group (3.94 +/- 0.20 for VEGF group, 3.77 +/- 0.16 for BMSCs group and 4.86 +/- 0.08 for the combination group vs. 3.01 +/- 0.03 for the control group, P < 0.005, P < 0.005, P < 0.0001, respectively). The combination treatment group demonstrated higher contrast than the two single treatment groups. Similar results were also observed at 4 weeks after treatment. Autoradiography showed similar trend to that of PET results. Immunohistochemical staining showed expression of VEGF protein and the presence of adenovirus in the myocardium. The patterns of vascular density and integrin alphavbeta3 expression were measured by CD31 and CD61 immunostaining analysis, and were consistent with the PET results. (18)F-alfatide II PET could reflect angiogenesis of infarcted myocardium after VEGF gene and BMSCs therapy and further provide a non-invasive way of monitoring therapy response of myocardial infarction. PMID- 26592498 TI - Mass spectrometric studies of the reaction of a blocked arginine with diketonic alpha-dicarbonyls. AB - The modification of arginine residues by diketonic alpha-dicarbonyls, in structural proteins and enzymes studies, is a process known for decades. The chemistry of these reaction processes is, however, not fully understood. Moreover, modification of arginine residues by reaction with alpha-dicarbonyls in glycation has also not been completely elucidated. Aspects related to the early stages of the condensation of arginine with one dicarbonyl molecule, leading to the formation of dihydroxyimidazolidines and their dehydrated forms, in particular, are here approached in more detail. Taking into consideration the usually rapid kinetics involved in the formation of the early reaction product species, we decided to use fast, sensitive and selective analytical techniques, such as electrospray ionization mass spectrometry (ESI-MS) and tandem mass spectrometry (ESI-MS(n)) to monitor the reactions of a blocked arginine (acetyl arginine) with several selected diketonic alpha-dicarbonyls, to identify and characterize the mentioned transient species and to probe the reaction mechanism involved. Compounds grouped into two different classes according to their structural similarity were identified, namely acetyl-dihydroxyimidazolidines and acetyl-bis(dihydroxyimidazolidines), together with their dehydrated species. The former compounds are known to exist in solution. The reactivity of acetyl bis(dihydroxyimidazolidines) seems to be different from that of acetyl dihydroxyimidazolidines. To note that dehydration appears to be reinforced in acetyl-bis(dihydroxyimidazolidines) chemistry with respect to acetyl dihydroxyimidazolidine chemistry, while both structurally related compounds involve mostly dihemiaminals reactivity. Two different ion structures are proposed for single dehydrated acetyl-bis(dihydroxyimidazolidines), concerning the two more symmetrical and two more asymmetrical dicarbonyls reacted. In acetyl bis(dihydroxyimidazolidines) formation, we concluded that the importance of single dehydration relies on the rapid minimization of sterics and energetics of the reaction moieties formed. These reactions occur also in a selective way, regarding the two compound structures proposed for single dehydrated acetyl bis(dihydroxyimidazolidines). Further considerations are also established for the formation of single dehydrated acetyl-bis(dihydroxyimidazolidines). An explanation for the reversible nature of the reaction of arginine with diketonic dicarbonyls is also provided. This study reinforces the potential of the fast, sensitive and selective electrospray ionization mass spectrometry techniques for the investigation of transient species and their mechanistics, that might otherwise not be feasible by means of the most commonly used spectroscopic techniques. PMID- 26592499 TI - Evaluation of GX1 and RGD-GX1 peptides as new radiotracers for angiogenesis evaluation in experimental glioma models. AB - Gliomas are the most common type among all central nervous system tumors. The aggressiveness of gliomas is correlated with the level of angiogenesis and is often associated with prognosis. The aim of this study is to evaluate the novel GX1 peptide and the heterodimer RGD-GX1 radiolabeled with technetium-99m, for angiogenesis detection in glioma models. Radiolabeling and radiochemical controls were assessed for both radioconjugates. In vitro binding studies in glioma tumor cells were performed, as well as biodistribution in SCID mice bearing tumor cells, in order to evaluate the biological behavior and tumor uptake of the radiocomplexes. Blocking and imaging studies were also conducted. MicroSPECT/CT images were acquired in animals with experimentally implanted intracranial tumor. Open field activity was performed to evaluate behavior, as well as perfusion and histology analysis. The radiochemical purity of both radiotracers was greater than 96 %. In vitro binding studies revealed rather similar binding profi le for each molecule. The highest binding was for RGD-GX1 peptide at 120 min in U87MG cells (1.14 +/- 0.35 %). Tumor uptake was also favorable for RGD-GX1 peptide in U87MG cells, reaching 2.96 +/- 0.70 % at 1 h p.i. with 47 % of blocking. Imaging studies also indicated better visualization for RGD-GX1 peptide in U87MG cells. Behavior evaluation pointed brain damage and histology studies confirmed actual tumor in the uptake site. The results with the angiogenesis seeking molecule (99m)Tc-HYNIC-E-[c(RGDfk)-c(GX1)] were successful, and better than with (99m)Tc HYNIC-PEG4-c(GX1). Future studies targeting angiogenesis in other glioma and nonglioma tumor models are recommended. PMID- 26592500 TI - Antitumor effects of deguelin on H460 human lung cancer cells in vitro and in vivo: Roles of apoptotic cell death and H460 tumor xenografts model. AB - Deguelin, a naturally occurring rotenoid of the flavonoid family, is known to be an Akt inhibitor, to have chemopreventive activities and anti-tumor effect on several cancers. In this study, investigation to elucidate the effect of deguelin on apoptotic pathways in human lung cancer cells and on the anti-tumor effect in lung cancer xenograft nu/nu mice was performed. In vitro studies, found that deguelin induced cell morphological changes, and decreased the percentage of viability through the induction of apoptosis in H460 lung cancer cells. Deguelin triggered apoptosis in H460 cells was also confirmed by DAPI staining, DNA gel electrophoresis, and Annexin V-FITC staining and these effects are dose-dependent manners. It was also found that deguelin promoted the Ca2+ production and activation of caspase-3 but decreased the level of DeltaPsim in H460 cells. Western blots indicated that the protein levels of cytochrome c, AIF, and pro apoptotic Bax and Bak protein were increased, but the anti-apoptotic Bcl-2 and Bcl-x were decreased that may have led to apoptosis in H460 cells after exposure to deguelin. It was also confirmed by confocal laser microscope examination that deguelin promoted the release of AIF from mitochondria to cytosol. In vivo studies, found that in immunodeficient nu/nu mice bearing H460 tumor xenografts showed that the deguelin significantly suppressed tumor growth. Deguelin might be a potential therapeutic agent for the treatment of lung cancer in the future. This finding might fully support a critical event for deguelin via induction of apoptotic cell death and H460 tumor xenografts model against human lung cancer. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 32: 84-98, 2017. PMID- 26592501 TI - Rapid Optical Cavity PCR. AB - Recent outbreaks of deadly infectious diseases, such as Ebola and Middle East respiratory syndrome coronavirus, have motivated the research for accurate, rapid diagnostics that can be administered at the point of care. Nucleic acid biomarkers for these diseases can be amplified and quantified via polymerase chain reaction (PCR). In order to solve the problems of conventional PCR--speed, uniform heating and cooling, and massive metal heating blocks--an innovative optofluidic cavity PCR method using light-emitting diodes (LEDs) is accomplished. Using this device, 30 thermal cycles between 94 degrees C and 68 degrees C can be accomplished in 4 min for 1.3 MUL (10 min for 10 MUL). Simulation results show that temperature differences across the 750 MUm thick cavity are less than 2 degrees C and 0.2 degrees C, respectively, at 94 degrees C and 68 degrees C. Nucleic acid concentrations as low as 10(-8) ng MUL(-1) (2 DNA copies per MUL) can be amplified with 40 PCR thermal cycles. This simple, ultrafast, precise, robust, and low-cost optofluidic cavity PCR is favorable for advanced molecular diagnostics and precision medicine. It is especially important for the development of lightweight, point-of-care devices for use in both developing and developed countries. PMID- 26592502 TI - Reactivity Controlling Factors for an Aromatic Carbon-Centered sigma,sigma,sigma Triradical: The 4,5,8-Tridehydroisoquinolinium Ion. AB - The chemical properties of the 4,5,8-tridehydroisoquinolinium ion (doublet ground state) and related mono- and biradicals were examined in the gas phase in a dual cell Fourier-transform ion cyclotron resonance (FT-ICR) mass spectrometer. The triradical abstracted three hydrogen atoms in a consecutive manner from tetrahydrofuran (THF) and cyclohexane molecules; this demonstrates the presence of three reactive radical sites in this molecule. The high (calculated) electron affinity (EA=6.06 eV) at the radical sites makes the triradical more reactive than two related monoradicals, the 5- and 8-dehydroisoquinolinium ions (EA=4.87 and 5.06 eV, respectively), the reactivity of which is controlled predominantly by polar effects. Calculated triradical stabilization energies predict that the most reactive radical site in the triradical is not position C4, as expected based on the high EA of this radical site, but instead position C5. The latter radical site actually destabilizes the 4,8-biradical moiety, which is singlet coupled. Indeed, experimental reactivity studies show that the radical site at C5 reacts first. This explains why the triradical is not more reactive than the 4 dehydroisoquinolinium ion because the C5 site is the intrinsically least reactive of the three radical sites due to its low EA. Although both EA and spin-spin coupling play major roles in controlling the overall reactivity of the triradical, spin-spin coupling determines the relative reactivity of the three radical sites. PMID- 26592503 TI - Topic shift impairs pronoun resolution during sentence comprehension: Evidence from event-related potentials. AB - This study investigated how topic shift and topic continuation influence pronoun interpretation in Chinese. ERPs recorded on pronouns in topic structure showed stronger and earlier late positive responses (P600) for the topic-shift than for the topic-continuation conditions. However, in nontopic structure where the subject (denoting only subjecthood), rather than the topic (denoting both topichood and subjecthood), acted as the antecedent of the pronoun, almost indistinguishable P600 responses were obtained on the pronoun regardless of whether it was referring to the subject (i.e., subject continuation) or the object (i.e., subject shift). Moreover, stronger and earlier P600 responses were elicited by pronouns in the topic-shift than in the subject-shift conditions, although there was no difference between the topic-continuation and the subject continuation conditions. These findings suggest that topic shift results in greater difficulty in the resolution stage of referential processing, although the bonding process is not sensitive to the manipulation of topic status, and that topic has a privileged cognitive status relative to other nontopic entities (e.g., subject) in real-time language processing. PMID- 26592504 TI - Uterine adenosarcomas are mesenchymal neoplasms. AB - Uterine adenosarcomas (UAs) are biphasic lesions composed of a malignant mesenchymal (ie stromal) component and an epithelial component. UAs are generally low-grade and have a favourable prognosis, but may display sarcomatous overgrowth (SO), which is associated with a worse outcome. We hypothesized that, akin to breast fibroepithelial lesions, UAs are mesenchymal neoplasms in which clonal somatic genetic alterations are restricted to the mesenchymal component. To characterize the somatic genetic alterations in UAs and to test this hypothesis, we subjected 20 UAs to a combination of whole-exome (n = 6), targeted capture (n = 13) massively parallel sequencing (MPS) and/or RNA sequencing (n = 6). Only three genes, FGFR2, KMT2C and DICER1, were recurrently mutated, all in 2/19 cases; however, 26% (5/19) and 21% (4/19) of UAs harboured MDM2/CDK4/HMGA2 and TERT gene amplification, respectively, and two cases harboured fusion genes involving NCOA family members. Using a combination of laser-capture microdissection and in situ techniques, we demonstrated that the somatic genetic alterations detected by MPS were restricted to the mesenchymal component. Furthermore, mitochondrial DNA sequencing of microdissected samples revealed that epithelial and mesenchymal components of UAs were clonally unrelated. In conclusion, here we provide evidence that UAs are genetically heterogeneous lesions and mesenchymal neoplasms. PMID- 26592505 TI - Dietary emulsifiers from milk and soybean differently impact adiposity and inflammation in association with modulation of colonic goblet cells in high-fat fed mice. AB - SCOPE: Enhanced adiposity and metabolic inflammation are major features of obesity that could be impacted by dietary emulsifiers. We investigated in high fat fed mice the effects of using a new polar lipid (PL) emulsifier from milk (MPL) instead of soybean lecithin (soybean PL [SPL]) on adipose tissue and intestinal mucosa function. METHODS AND RESULTS: Four groups of C57BL6 mice received for 8 wks a low-fat (LF) diet or a high-fat diet devoid of PLs or an high-fat diet including MPL (high-fat-MPL) or SPL (high-fat-SPL). Compared with high-fat diet, high-fat-SPL diet increased white adipose tissue (WAT) mass (p < 0.05), with larger adipocytes (p < 0.05) and increased expression of tumor necrosis factor alpha, monochemoattractant protein-1, LPS-binding protein, and leptin (p < 0.05). This was not observed with high-fat-MPL diet despite similar dietary intakes and increased expression of fatty acid transport protein 4 and microsomal TG transfer protein, involved in lipid absorption, in upper intestine (p < 0.05). High-fat-MPL mice had a lower expression in WAT of cluster of differentiation 68, marker of macrophage infiltration, versus high-fat and high fat-SPL mice (p < 0.05), and more goblet cells in the colon (p < 0.05). CONCLUSIONS: Unlike SPL, MPL in the high-fat diet did not induce WAT hypertrophy and inflammation but increased colonic goblet cells. This supports further clinical exploration of different sources of dietary emulsifiers in the frame of obesity outbreak. PMID- 26592506 TI - Ten-year observational follow-up of PROactive: a randomized cardiovascular outcomes trial evaluating pioglitazone in type 2 diabetes. AB - AIMS: To conduct a 10-year, observational follow-up of patients completing PROactive to investigate whether trends of cardiovascular benefit with pioglitazone and imbalances in specific malignancies persisted over time. METHODS: Macrovascular endpoints and malignancies were compared based on original randomization to pioglitazone or placebo and 'any' versus 'no' pioglitazone use for bladder and prostate cancer. RESULTS: Of 4873 patients completing the PROactive trial, 74% entered the follow-up. During follow-up (mean 7.8 years), there were no statistically significant differences in the primary [all-cause mortality, myocardial infarction (MI), cardiac intervention, stroke, major leg amputation, leg revascularization] or main secondary (death, MI, stroke) endpoints for subjects originally randomized to pioglitazone and placebo, except for leg amputations during follow-up [4.1% pioglitazone, 5.6% placebo; hazard ratio 0.74, 95% confidence interval (CI) 0.55-0.99; p = 0.046]. During follow-up, the incidence of total malignancies was similar between groups; bladder cancer was reported in 0.8% of patients (n = 14) in the pioglitazone versus 1.2% (n = 21) in the placebo group [relative risk (RR) 0.65, 95% CI 0.33-1.28], and prostate cancer was reported in 44 men (3.7%) in the pioglitazone versus 29 men (2.5%) in the placebo group (RR 1.47, 95% CI 0.93-2.34). CONCLUSIONS: The trends of macrovascular benefits of pioglitazone compared with placebo during PROactive did not persist in the absence of continued pioglitazone during this 10-year follow-up. Trends of decreased bladder cancer and increased prostate cancer were observed in the pioglitazone group during follow-up; however, these imbalances should be interpreted with caution because of the limitations of the observational study design. PMID- 26592507 TI - Insulin resistance, role of metformin and other non-insulin therapies in pediatric type 1 diabetes. AB - Type 1 diabetes mellitus (T1DM) in youth is a challenging chronic medical condition. Its management should address not only the glycemic control but also insulin resistance and cardiovascular disease risk factors which are increasingly recognized to be present in youth with TID. Current knowledge on the mechanisms of insulin resistance in T1DM is reviewed. The use of adjunctive therapies that are beneficial to achieve adequate glycemic control while mitigating the effects of insulin resistance are discussed with a focus on metformin therapy and an overview of other new pharmacologic agents. PMID- 26592508 TI - Anticancer bioactive peptides suppress human colorectal tumor cell growth and induce apoptosis via modulating the PARP-p53-Mcl-1 signaling pathway. AB - AIM: We have reported novel anticancer bioactive peptides (ACBPs) that show tumor suppressive activities in human gastric cancer, leukemia, nasopharyngeal cancer, and gallbladder cancer. In this study, we investigated the effects of ACBPs on human colorectal cancer and the underlying mechanisms. METHODS: Cell growth and apoptosis of human colorectal tumor cell line HCT116 were measured using cell proliferation assay and flow cytometry, respectively. The expression levels of PARP, p53 and Mcl1A were assessed with Western blotting and immunohistochemistry. For evaluation of the in vivo antitumor activity of ACBPs, HCT116 xenograft nude mice were treated with ACBPs (35 MUg/mL, ip) for 10 days. RESULTS: Treatment of HCT116 cells with ACBPs (35 MUg/mL) for 4-6 days significantly inhibited the cell growth. Furthermore, treatment of HCT116 cells with ACBPs (35 MUg/mL) for 6-12 h significantly enhanced UV-induced apoptosis, increased the expression of PARP and p53, and decreased the expression of Mcl-1. Administration of ACBPs did not change the body weight of HCT116 xenograft nude mice, but decreased the tumor growth by approximately 43%, and increased the expression of PARP and p53, and decreased the expression of Mcl-1 in xenograft mouse tumor tissues. CONCLUSION: Administration of ACBPs inhibits human colorectal tumor cell growth and induces apoptosis in vitro and in vivo through modulating the PARP-p53-Mcl-1 signaling pathway. PMID- 26592509 TI - Platycodin D induces apoptosis and triggers ERK- and JNK-mediated autophagy in human hepatocellular carcinoma BEL-7402 cells. AB - AIM: Platycodin D, the main saponin isolated from Chinese herb Platycodonis Radix, exhibits anticancer activities against various cancer cell lines. Here we evaluated its anticancer action against human hepatocellular carcinoma cells in vitro and in vivo, and elucidated the relationship between platycodin D-induced apoptosis and autophagy. METHODS: The viability of human hepatocellular carcinoma BEL-7402 cells was evaluated with MTT assay, and the apoptosis was examined using Annexin V/PI and Hoechst 33342 staining assays. Monodansylcadaverine (MDC) staining was used to label autophagic vacuoles. The proteins were detected using Western blot analysis. For studying its anticancer action in vivo, platycodin D (5 and 10 mg. kg(-1).d(-1)) was intraperitoneally injected to BEL-7402-bearing mice for 21 days. RESULTS: Platycodin D (5-40 MUmol/L) inhibited the cell proliferation in vitro with IC50 values of 37.70+/-3.99, 24.30+/-2.30 and 19.70+/ 2.36 MUmol/L at 24, 48 and 72 h, respectively. Platycodin D (5-20 MUmol/L) dose dependently increased BEL-7402 cell apoptosis, increased the Bax/Bcl-2 ratio and the levels of cleaved PARP and cleaved caspase-3, and decreased the level of Bcl 2. Furthermore, platycodin D (5-20 MUmol/L) induced autophagy in BEL-7402 cells, as evidenced by formation of cytoplasmic vacuoles, increased amounts of LC3-II, and increased numbers of MDC-positive cells. Pretreatment with the autophagy inhibitor chloroquine (5 MUmol/L) or BAF (50 nmol/L) significantly enhanced platycodin D-induced proliferation inhibition and apoptosis. Moreover, platycodin D (20 MUmol/L) activated the ERK and JNK pathways in BEL-7402 cells, and simultaneous blockage of the two pathways effectively suppressed platycodin D induced autophagy and enhanced platycodin D-induced apoptosis. In BEL-7402 bearing mice, platycodin D (10 mg.kg(-1)*d(-1)) significantly reduced relative tumor volume with decreased body weight. CONCLUSION: Platycodin D not only inhibits the proliferation of BEL-7402 cells but also suppresses BEL-7402 xenograft tumor growth. Platycodin D-induced cell proliferation inhibition and apoptosis are amplified by co-treatment with autophagy inhibitors. PMID- 26592510 TI - Cultured Mycelium Cordyceps sinensis allevi!ates CCl4-induced liver inflammation and fibrosis in mice by activating hepatic natural killer cells. AB - AIM: Recent evidence shows that cultured mycelium Cordyceps sinensis (CMCS) effectively protects against liver fibrosis in mice. Here, we investigated whether the anti-fibrotic action of CMCS was related to its regulation of the activity of hepatic natural killer (NK) cells in CCl4-treated mice. METHODS: C57BL/6 mice were injected with 10% CCl4 (2 mL/kg, ip) 3 times per week for 4 weeks, and received CMCS (120 mg.kg(-1).d(-1), ig) during this period. In another part of experiments, the mice were also injected with an NK cell-deleting antibody ASGM-1 (20 MUg, ip) 5 times in the first 3 weeks. After the mice were sacrificed, serum liver function, and liver inflammation, hydroxyproline content and collagen deposition were assessed. The numbers of hepatic NK cells and expression of NKG2D (activation receptor of NK cells) on isolated liver lymphocytes were analyzed using flow cytometry. Desmin expression and cell apoptosis in liver tissues were studied using desmin staining and TUNEL assay, respectively. The levels of alpha-SMA, TGF-beta, RAE-1delta and RAE-1epsilon in liver tissues were determined by RT-qPCR. RESULTS: In CCl4-treated mice, CMCS administration significantly improved liver function, attenuated liver inflammation and fibrosis, and increased the numbers of hepatic NK cells and expression level of NKG2D on hepatic NK cells. Furthermore, CMCS administration significantly decreased desmin expression in liver tissues, and increased TUNEL staining adjacent to hepatic stellate cells. Injection with NK cell-deleting ASGM 1 not only diminished the numbers of hepatic NK cells, but also greatly accelerated liver inflammation and fibrosis in CCl4-treated mice. In CCl4-treated mice with NK cell depletion, CMCS administration decelerated the rate of liver fibrosis development, and mildly upregulated the numbers of hepatic NK cells but without changing NKG2D expression. CONCLUSION: CMCS alleviates CCl4-induced liver inflammation and fibrosis via promoting activation of hepatic NK cells. CMCS partially reverses ASGM-1-induced depletion of hepatic NK cells. PMID- 26592512 TI - Effects of neferine on Kv4.3 channels expressed in HEK293 cells and ex vivo electrophysiology of rabbit hearts. AB - AIM: Neferine is an isoquinoline alkaloid isolated from seed embryos of Nelumbo nucifera (Gaertn), which has a variety of biological activities. In this study we examined the effects of neferine on Kv4.3 channels, a major contributor to the transient outward current (I(to)) in rabbit heart, and on ex vivo electrophysiology of rabbit hearts. METHODS: Whole-cell Kv4.3 currents were recorded in HEK293 cells expressing human cardiac Kv4.3 channels using patch clamp technique. Arterially perfused wedges of rabbit left ventricles (LV) were prepared, and transmembrane action potentials were simultaneously recorded from epicardial (Epi) and endocardial (Endo) sites with floating microelectrodes together with transmural electrocardiography (ECG). RESULTS: Neferine (0.1-100 MUmol/L) dose-dependently and reversibly inhibited Kv4.3 currents (the IC50 value was 8.437 MUmol/L, and the maximal inhibition at 100 MUmol/L was 44.12%). Neferine (10 MUmol/L) caused a positive shift of the steady-state activation curve of Kv4.3 currents, and a negative shift of the steady-state inactivation curve. Furthermore, neferine (10 MUmol/L) accelerated the inactivation but not the activation of Kv4.3 currents, and markedly slowed the recovery of Kv4.3 currents from inactivation. Neferine-induced blocking of Kv4.3 currents was frequency-dependent. In arterially perfused wedges of rabbit LV, neferine (1, 3, and 10 MUmol/L) dose-dependently prolonged the QT intervals and action potential durations (APD) at both Epi and Endo sites, and caused dramatic increase of APD10 at Epi sites. CONCLUSION: Neferine inhibits Kv4.3 channels likely by blocking the open state and inactivating state channels, which contributes to neferine-induced dramatic increase of APD10 at Epi sites of rabbit heart. PMID- 26592511 TI - Toll-like receptors: potential targets for lupus treatment. AB - Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by the loss of tolerance to self-nuclear antigens. Accumulating evidence shows that Toll-like receptors (TLRs), previously proven to be critical for host defense, are implicated in the pathogenesis of autoimmune diseases by recognition of self-molecules. Genome-wide association studies, experimental mouse models and clinical sample studies have provided evidence for the involvement of TLRs, including TLR2/4, TLR5, TLR3 and TLR7/8/9, in SLE pathogenesis. A number of downstream proteins in the TLR signaling cascade (such as MyD88, IRAKs and IFN alpha) are identified as potential therapeutic targets for SLE treatment. Numerous antagonists targeting TLR signaling, including oligonucleotides, small molecular inhibitors and antibodies, are currently under preclinical studies or clinical trials for SLE treatment. Moreover, the emerging new manipulation of TLR signaling by microRNA (miRNA) regulation shows promise for the future treatment of SLE. PMID- 26592513 TI - Regulation of PP2Cm expression by miRNA-204/211 and miRNA-22 in mouse and human cells. AB - AIM: The mitochondrial targeted 2C-type serine/threonine protein phosphatase (PP2Cm) is encoded by the gene PPM1K and is highly conserved among vertebrates. PP2Cm plays a critical role in branched-chain amino acid catabolism and regulates cell survival. Its expression is dynamically regulated by the nutrient environment and pathological stresses. However, little is known about the molecular mechanism underlying the regulation of PPM1K gene expression. In this study, we aimed to reveal how PPM1K expression is affected by miRNA-mediated post transcriptional regulation. METHODS: Computational analysis based on conserved miRNA binding motifs was applied to predict the candidate miRNAs that potentially affect PPM1K expression. Dual-luciferase reporter assay was performed to verify the miRNAs' binding sites in the PPM1K gene and their influence on PPM1K 3'UTR activity. We further over-expressed the mimics of these miRNAs in human and mouse cells to examine whether miRNAs affected the mRNA level of PPM1K. RESULTS: Computational analysis identified numerous miRNAs potentially targeting PPM1K. Luciferase reporter assays demonstrated that the 3'UTR of PPM1K gene contained the recognition sites of miR-204 and miR-211. Overexpression of these miRNAs in human and mouse cells diminished the 3'UTR activity and the endogenous mRNA level of PPM1K. However, the miR-22 binding site was found only in human and not mouse PPM1K 3'UTR. Accordingly, PPM1K 3'UTR activity was suppressed by miR-22 overexpression in human but not mouse cells. CONCLUSION: These data suggest that different miRNAs contribute to the regulation of PP2Cm expression in a species specific manner. miR-204 and miR-211 are efficient in both mouse and human cells, while miR-22 regulates PP2Cm expression only in human cells. PMID- 26592514 TI - ROS activates JNK-mediated autophagy to counteract apoptosis in mouse mesenchymal stem cells in vitro. AB - AIM: Transplantation of mesenchymal stem cells (MSCs) for the treatment of diabetic erectile dysfunction (ED) is hampered by apoptosis of the transplanted cells. In diabetic ED, there is increased oxidative stress and decreased NO in the corpora cavernosa, and reactive oxygen species (ROS) induce apoptosis of the transplanted cells. In this study we examined whether and how autophagy was involved in ROS-induced apoptosis of MSCs. METHODS: Mouse C3H10 MSCs were treated with H2O2 to simulate the high oxidative condition in diabetic ED. Cell viability was measured using MTT assay. Apoptosis was analyzed by flow cytometry. Apoptosis and autophagy-related proteins were detected with Western blot assays. Intracellular autophagosome accumulation was studied using transmission electron microscopy. RESULTS: Treatment of MSCs with H2O2 (50-400 MUmol/L) inhibited the cell viability in concentration- and time-dependent manners. Furthermore, H2O2 (300 MUmol/L) induced apoptosis, as well as activated autophagy in MSCs. Pretreatment with lysosome inhibitor chloroquine (10 MUmol/L) or PI3K inhibitor 3 methyladenine (5 mmol/L) significantly enhanced H2O2-induced cell death. Pretreatment with JNK inhibitor SP600125 (10 MUmol/L) abrogated H2O2-induced accumulation of LC3-II, and attenuated H2O2-induced reduction of Bcl-2 levels in MSCs. CONCLUSION: ROS induce autophagy to counteract apoptosis in MSCs by activation of JNK. Thus, augmentation of autophagy may reduce apoptosis, prolonging MSC survival and improving MSC-based therapeutic efficacy for diabetic ED. PMID- 26592515 TI - Isoflavones and phytosterols contained in Xuezhikang capsules modulate cholesterol homeostasis in high-fat diet mice. AB - AIM: Xuezhikang (XZK), an extract of red yeast rice, has been widely used in traditional Chinese medicine to treat cardiovascular disease. Three fractions F1, F2 and F3 (primarily containing isoflavones, monacolins or phytosterols, respectively) are extracted from Xuezhikang capsules. In this study we evaluated the lipid-lowering effects of these fractions and explored the potential mechanisms of actions. METHODS: Mice treated with a high-fat diet (HFD) were orally administered lovastatin (10 mg.kg(-1).d(-1)), XZK (1200 mg.kg(-1).d(-1)), F1 (27.5 mg.kg(-1).d(-1)), F2 (11.3 mg.kg(-1).d(-1)) or F3 (35 mg.kg(-1).d(-1)) for 10 weeks. Lipids were measured using commercial enzymatic kits, and the mRNA and protein levels of genes involved in cholesterol and bile acid homeostasis were evaluated using qRT-PCR and Western blot analysis, respectively. RESULTS: XZK increased the fecal excretion of lipids and bile acids, reduced serum TC, TG and LDL-C levels by 40%, 55% and 46%, respectively, and increased serum HDL-C by 31%. Administration of F1 repressed serum TC and TG by 24% and 52%, respectively, and elevated hepatic synthesis of CYP7A1. It also increased hepatic elimination of bile acids in the fecal excretions by 79% through upregulating BSEP and downregulating NTCP. Administration of F3 decreased serum TC, TG and LDL-C levels by 33%, 29% and 39%, respectively, and increased serum HDL-C by 28%, significantly reduced intestinal absorption of cholesterol by inhibiting the transcription of NPC1L1, and elevated excretion of TC, FC and CE by 96%, 72% and 101%, respectively. Administration of F2 showed pharmacological effects similar to those of lovastatin. CONCLUSION: Isoflavones and phytosterols in XZK exert cholesterol-lowering effects in HFD mice through mechanisms that differ from those of lovastatin. Isoflavones and phytosterols act in a complimentary manner: through enhancing the elimination of bile acids and reducing intestinal cholesterol absorption, respectively. PMID- 26592516 TI - Evaluating a physiologically based pharmacokinetic model for predicting the pharmacokinetics of midazolam in Chinese after oral administration. AB - AIM: To evaluate the SimCYP simulator ethnicity-specific population model for predicting the pharmacokinetics of midazolam, a typical CYP3A4/5 substrate, in Chinese after oral administration. METHODS: The physiologically based pharmacokinetic (PBPK) model for midazolam was developed using a SimCYP population-based simulator incorporating Chinese population demographic, physiological and enzyme data. A clinical trial was conducted in 40 Chinese subjects (the half was females) receiving a single oral dose of 15 mg midazolam. The subjects were separated into 4 groups based on age (20-50, 51-65, 66-75, and above 76 years), and the pharmacokinetics profiles of each age- and gender-group were determined, and the results were used to verify the PBPK model. RESULTS: Following oral administration, the simulated profiles of midazolam plasma concentrations over time in virtual Chinese were in good agreement with the observed profiles, as were AUC and Cmax. Moreover, for subjects of varying ages (20-80 years), the ratios of predicted to observed clearances were between 0.86 and 1.12. CONCLUSION: The SimCYP PBPK model accurately predicted the pharmacokinetics of midazolam in Chinese from youth to old age. This study may provide novel insight into the prediction of CYP3A4/5-mediated pharmacokinetics in the Chinese population relative to Caucasians and other ethnic groups, which can support the rational design of bridging clinical trials. PMID- 26592517 TI - Carvacrol protects neuroblastoma SH-SY5Y cells against Fe(2+)-induced apoptosis by suppressing activation of MAPK/JNK-NF-kappaB signaling pathway. AB - AIM: Carvacrol (2-methyl-5-isopropylphenol), a phenolic monoterpene in the essential oils of the genera Origanum and Thymus, has been shown to exert a variety of therapeutic effects. Here we examined whether carvacrol protected neuroblastoma SH-SY5Y cells against Fe(2+)-induced apoptosis and explored the underlying mechanisms. METHODS: Neuroblastoma SH-SY5Y cells were incubated with Fe(2+) for 24 h, and the cell viability was assessed with CCK-8 assay. TUNEL assay and flow cytometric analysis were performed to evaluate cell apoptosis. The mRNA levels of pro-inflammatory cytokines and NF-kappaB p65 were determined using qPCR. The expression of relevant proteins was determined using Western blot analysis or immunofluorescence staining. RESULTS: Treatment of SH-SY5Y cells with Fe(2+) (50-200 MUmol/L) dose-dependently decreased the cell viability, which was significantly attenuated by pretreatment with carvacrol (164 and 333 MUmol/L). Treatment with Fe(2+) increased the Bax level and caspase-3 activity, and decreased the Bcl-2 level, resulting in cell apoptosis. Furthermore, treatment with Fe(2+) significantly increased the gene expression of IL-1beta, IL-6 and TNF alpha, and induced the nuclear translocation of NF-kappaB. Treatment with Fe(2+) also significantly increased the phosphorylation of p38, ERK, JNK and IKK in the cells. Pretreatment with carvacrol significantly inhibited Fe(2+)-induced activation of NF-kappaB, expression of the pro-inflammatory cytokines, and cell apoptosis. Moreover, pretreatment with carvacrol inhibited Fe(2+)-induced phosphorylation of JNK and IKK, but not p38 and ERK in the cells. CONCLUSION: Carvacrol protects neuroblastoma SH-SY5Y cells against Fe(2+)-induced apoptosis, which may result from suppressing the MAPK/JNK-NF-kappaB signaling pathways. PMID- 26592518 TI - Preclinical pharmacokinetics of TPN729MA, a novel PDE5 inhibitor, and prediction of its human pharmacokinetics using a PBPK model. AB - AIM: TPN729MA is a novel selective PDE5 inhibitor currently under clinical development in China for the treatment of erectile dysfunction. In this study we characterized its preclinical pharmacokinetics (PK) and predict its human PK using a physiologically based pharmacokinetic (PBPK) model. METHODS: The preclinical PK of TPN729MA was studied in rats and dogs. Human clearance (CL) values for TPN729MA were predicted from various allometric methods and from intrinsic CL determined in human liver microsomes. Human PK and plasma concentration versus time profiles of TPN729MA were predicted by using a PBPK model in GastroPlus. Considering the uncertainties in the prediction, a preliminary human study was conducted in 3 healthy male volunteers with an oral dose of 25 mg. RESULTS: After a single intravenous administration of TPN729MA at a dose of 1 mg/kg in rats and 3 mg/kg in dogs, the plasma CL was 69.7 mL.min( 1).kg(-1) in rats and 26.3 mL.min(-1).kg(-1) in dogs, and the steady-state volumes of distribution (V(ss)) were 7.35 L/kg in rats and 6.48 L/kg in dogs. The oral bioavailability of TPN729MA was 10% in rats and above 34% in dogs. Profiles of predicted plasma concentration versus time were similar to those observed in humans at 25 mg, and the predicted T(max), C(max) and AUC values were within 2 fold of the observed values. CONCLUSION: TPN729MA demonstrates good preclinical PK. This compound is a valuable candidate for further clinical development. This study shows the benefits of using a PBPK model to predict PK in humans. PMID- 26592519 TI - The new antihypertensive drug iptakalim activates ATP-sensitive potassium channels in the endothelium of resistance blood vessels. AB - AIM: To investigate the mechanisms underlying the activation of ATP-sensitive potassium channels (K(ATP)) by iptakalim in cultured rat mesenteric microvascular endothelial cells (MVECs). METHODS: Whole-cell KATP currents were recorded in MVECs using automated patch clamp devices. Nucleotides (ATP, ADP and UDP) were added to the internal perfusion system, whereas other drugs were added to the cell suspension on NPC-1 borosilicate glass chips. RESULTS: Application of iptakalim (10 and 100 MUmol/L) significantly increased the whole-cell K(ATP) currents, which were prevented by the specific K(ATP) blocker glibenclamide (1.0 MUmol/L). The opening of K(ATP) channels by iptakalim depended upon the intracellular concentrations of ATP or NDPs: iptakalim activated K(ATP) channels when the intracellular ATP or NDPs were at 100 or 1000 MUmol/L, and was ineffective when the non-hydrolysable ATP analogue ATPgammaS (1000 MUmol/L) was infused into the cells. In contrast, the K(ATP) opener pinacidil activated K(ATP) channels when the intracellular concentrations of ATP or NDPs ranged from 10 to 5000 MUmol/L, and even ATPgammaS (1000 MUmol/L) was infused into the cells. CONCLUSION: Iptakalim activates K(ATP) channels in the endothelial cells of resistance blood vessels with a low metabolic status, and this activation is dependent on both ATP hydrolysis and ATP ligands. PMID- 26592520 TI - Sirt1 is involved in decreased bone formation in aged apolipoprotein E-deficient mice. AB - AIM: Apolipoprotein E (ApoE) plays an important role in the transport and metabolism of lipids. Recent studies show that bone mass is increased in young apoE(-/-) mice. In this study we investigated the bone phenotype and metabolism in aged apoE(-/-) mice. METHODS: Femurs and tibias were collected from 18- and 72 week-old apoE(-/-) mice and their age-matched wild-type (WT) littermates, and examined using micro-CT and histological analysis. Serum levels of total cholesterol, oxidized low-density lipoprotein (ox-LDL) and bone turnover markers were measured. Cultured bone mesenchymal stem cells (BMSCs) from tibias and femurs of 18-week-old apoE(-/-) mice were used in experiments in vitro. The expression levels of Sirt1 and Runx2 in bone tissue and BMSCs were measured using RT-PCR and Western blot analysis. RESULTS: Compared with age-matched WT littermates, young apoE(-/-) mice exhibited high bone mass with increased bone formation, accompanied by higher serum levels of bone turnover markers OCN and TRAP5b, and higher expression levels of Sirt1, Runx2, ALP and OCN in bone tissue. In contrast, aged apoE(-/-) mice showed reduced bone formation and lower bone mass relative to age-matched WT mice, accompanied by lower serum OCN levels, and markedly reduced expression levels of Sirt1, Runx2, ALP and OCN in bone tissue. After BMSCs were exposed to ox-LDL (20 MUg/mL), the expression of Sirt1 and Runx2 proteins was significantly increased at 12 h, and then decreased at 72 h. Treatment with the Sirt1 inhibitor EX527 (10 MUmol/L) suppressed the expression of Runx2, ALP and OCN in BMSCs. CONCLUSION: In contrast to young apoE(-/-) mice, aged apoE(-/-) mice showe lower bone mass than age-matched WT mice. Long-lasting exposure to ox-LDL decreases the expression of Sirt1 and Runx2 in BMSCs, which may explain the decreased bone formation in aged apoE(-/-) mice. PMID- 26592522 TI - Dual Lewis Acid/Lewis Base Catalyzed Acylcyanation of Aldehydes: A Mechanistic Study. AB - A mechanistic investigation, which included a Hammett correlation analysis, evaluation of the effect of variation of catalyst composition, and low temperature NMR spectroscopy studies, of the Lewis acid-Lewis base catalyzed addition of acetyl cyanide to prochiral aldehydes provides support for a reaction route that involves Lewis base activation of the acyl cyanide with formation of a potent acylating agent and cyanide ion. The cyanide ion adds to the carbonyl group of the Lewis acid activated aldehyde. O-Acylation by the acylated Lewis base to form the final cyanohydrin ester occurs prior to decomplexation from titanium. For less reactive aldehydes, the addition of cyanide is the rate determining step, whereas, for more reactive, electron-deficient aldehydes, cyanide addition is rapid and reversible and is followed by rate-limiting acylation. The resting state of the catalyst lies outside the catalytic cycle and is believed to be a monomeric titanium complex with two alcoholate ligands, which only slowly converts into the product. PMID- 26592521 TI - Aconine inhibits RANKL-induced osteoclast differentiation in RAW264.7 cells by suppressing NF-kappaB and NFATc1 activation and DC-STAMP expression. AB - AIM: Aconiti Lateralis Radix Preparata is a traditional Chinese medicine used to treat chronic arthritis and is highly effective against rheumatoid arthritis. However, the effects of aconine, a derivative of aconitum alkaloids, on osteoclasts, which can absorb bone, remain unknown. Here, we investigated the effects of aconine on osteoclast differentiation and bone resorption in vitro. METHODS: The viability of mouse leukemic monocyte/macrophage cell line RAW264.7 was measured using CCK-8 assays. Osteoclast differentiation was induced by incubation of RAW264.7 cells in the presence of RANKL, and assessed with TRAP staining assay. Bone resorption was examined with bone resorption pits assay. The expression of relevant genes and proteins was analyzed using RT-PCR and Western blots. The activation of NF-kappaB and nuclear factor of activated T-cells (NFAT) was examined using stable NF-kappaB and NFATc1 luciferase reporter gene systems, RT-PCR and Western blot analysis. RESULTS: Aconine (0.125, 0.25 MUmol/L) did not affect the viability of RAW264.7 cells, but dose-dependently inhibited RANKL induced osteoclast formation and bone resorptive activity. Furthermore, aconine dose-dependently inhibited the RANKL-induced activation of NF-kappaB and NFATc1 in RAW264.7 cells, and subsequently reduced the expression of osteoclast-specific genes (c-Src, beta3-Integrin, cathepsin K and MMP-9) and the expression of dendritic cell-specific transmembrane protein (DC-STAMP), which played an important role in cell-cell fusion. CONCLUSION: These findings suggest that aconine inhibits RANKL-induced osteoclast differentiation in RAW264.7 cells by suppressing the activation of NF-kappaB and NFATc1 and the expression of the cell cell fusion molecule DC-STAMP. PMID- 26592523 TI - Emergency Major Abdominal Surgical Procedures in Older Adults: A Systematic Review of Mortality and Functional Outcomes. AB - OBJECTIVES: To systematically review the current literature on mortality and functional outcomes after emergency major abdominal surgery in older adults. DESIGN: Systematic literature search and standardized data collection of primary research publications from January 1994 through December 2013 on mortality or functional outcome in adults aged 65 and older after emergency major abdominal surgery using PubMed, EMBASE, Web of Science, Cochrane, and CINAHL. Bibliographies of relevant reports were also hand-searched to identify all potentially eligible studies. SETTING: Systematic review of retrospective and cohort studies using Preferred Reporting Items for Systematic reviews and Meta Analyses, Meta-analysis Of Observational Studies in Epidemiology, Strengthening the Reporting of Observational Studies in Epidemiology, and A Measurement Tool to Assess Systematic Reviews guidelines. PARTICIPANTS: Older adults. MEASUREMENTS: Articles were assessed using a standardized quality scoring system based on study design, measurement of exposures, measurement of outcomes, and control for confounding. RESULTS: Of 1,459 articles screened, 93 underwent full-text review, and 20 were systematically reviewed. In-hospital and 30-day mortality of all older adults exceeded 15% in 14 of 16 studies, where reported. Older adults undergoing emergency major abdominal surgery consistently had higher mortality across study settings and procedure types than younger individuals undergoing emergency procedures and older adults undergoing elective procedures. In studies that stratified older adults, odds of death increased with age. None of these studies examined postoperative functional status, which precluded including functional outcomes in this review. Differences in exposures, outcomes, and data presented in the studies did not allow for quantification of association using metaanalysis. CONCLUSION: Age independently predicts mortality after emergency major abdominal surgery. Data on changes in functional status of older adults who undergo these procedures are lacking. PMID- 26592525 TI - Multifunctional Fullerene Derivative for Interface Engineering in Perovskite Solar Cells. AB - In perovskite based planar heterojunction solar cells, the interface between the TiO2 compact layer and the perovskite film is critical for high photovoltaic performance. The deep trap states on the TiO2 surface induce several challenging issues, such as charge recombination loss and poor stability etc. To solve the problems, we synthesized a triblock fullerene derivative (PCBB-2CN-2C8) via rational molecular design for interface engineering in the perovskite solar cells. Modifying the TiO2 surface with the compound significantly improves charge extraction from the perovskite layer. Together with its uplifted surface work function, open circuit voltage and fill factor are dramatically increased from 0.99 to 1.06 V, and from 72.2% to 79.1%, respectively, resulting in 20.7% improvement in power conversion efficiency for the best performing devices. Scrutinizing the electrical properties of this modified interfacial layer strongly suggests that PCBB-2CN-2C8 passivates the TiO2 surface and thus reduces charge recombination loss caused by the deep trap states of TiO2. The passivation effect is further proven by stability testing of the perovskite solar cells with shelf lifetime under ambient conditions improved by a factor of more than 4, from ~40 h to ~200 h, using PCBB-2CN-2C8 as the TiO2 modification layer. This work offers not only a promising material for cathode interface engineering, but also provides a viable approach to address the challenges of deep trap states on TiO2 surface in planar perovskite solar cells. PMID- 26592524 TI - Tumor Presence Induces Global Immune Changes and Enhances Nanoparticle Clearance. AB - Long-circulating nanoparticles are essential for increasing tumor accumulation to provide therapeutic efficacy. While it is known that tumor presence can alter the immune system, very few studies have explored this impact on nanoparticle circulation. In this report, we demonstrate how the presence of a tumor can change the local and global immune system, which dramatically increases particle clearance. We found that tumor presence significantly increased clearance of PRINT hydrogel nanoparticles from the circulation, resulting in increased accumulation in the liver and spleen, due to an increase in M2-like macrophages. Our findings highlight the need to better understand interactions between immune status and nanoparticle clearance, and suggest that further consideration of immune function is required for success in preclinical and clinical nanoparticle studies. PMID- 26592526 TI - Cross-talk between bone morphogenetic proteins and inflammatory pathways. AB - Pro-inflammatory cytokines and bone morphogenetic proteins are generally studied separately and considered to be elements of different worlds, immunology and developmental biology. Varas and colleagues report that these factors show cross talk in rheumatoid arthritis synoviocytes. They show that pro-inflammatory cytokines not only stimulate the production of bone morphogenetic proteins but that these endogenously produced bone morphogenetic proteins interfere with the effects of pro-inflammatory cytokines on synoviocytes. PMID- 26592528 TI - Fragment-Based Discovery of Subtype-Selective Adenosine Receptor Ligands from Homology Models. AB - Fragment-based lead discovery (FBLD) holds great promise for drug discovery, but applications to G protein-coupled receptors (GPCRs) have been limited by a lack of sensitive screening techniques and scarce structural information. If virtual screening against homology models of GPCRs could be used to identify fragment ligands, FBLD could be extended to numerous important drug targets and contribute to efficient lead generation. Access to models of multiple receptors may further enable the discovery of fragments that bind specifically to the desired target. To investigate these questions, we used molecular docking to screen >500 000 fragments against homology models of the A3 and A1 adenosine receptors (ARs) with the goal to discover A3AR-selective ligands. Twenty-one fragments with predicted A3AR-specific binding were evaluated in live-cell fluorescence-based assays; of eight verified ligands, six displayed A3/A1 selectivity, and three of these had high affinities ranging from 0.1 to 1.3 MUM. Subsequently, structure-guided fragment-to-lead optimization led to the identification of a >100-fold-selective antagonist with nanomolar affinity from commercial libraries. These results highlight that molecular docking screening can guide fragment-based discovery of selective ligands even if the structures of both the target and antitarget receptors are unknown. The same approach can be readily extended to a large number of pharmaceutically important targets. PMID- 26592529 TI - Temperature- and pH-Responsive Benzoboroxole-Based Polymers for Flocculation and Enhanced Dewatering of Fine Particle Suspensions. AB - Random copolymers based on N-isopropylacrylamide (NIPAAm) containing 2-aminoethyl methacrylamide hydrochloride (AEMA) and 5-methacrylamido-1,2-benzoboroxole (MAAmBo) were synthesized and subsequently evaluated for their performance in solid-liquid separation at various pH and temperatures. The strong interactions between benzoboroxole residues and kaolin hydroxyl groups were evaluated for the first time in the flocculation of fine particle suspensions. The lower critical solution temperatures (LCSTs) of PAMN decreases because of the hydrophobic nature of the benzoboroxole moieties, resulting in strong hydrophobic interaction at temperatures higher than the LCSTs. Temperature and pH responsive polymer, P(AEMA51-st-MAAmBo76-st-NIPAM381) (denoted as PAMN) shows the ability to induce fastest settling at a low dosage of 25 ppm and under the condition of pH 9 and 50 degrees C. The accelerated settling rate is considered to be due to the strong adhesion of benzoboroxole residues to the kaolin hydroxyl groups, the electrical double layer force, and the hydrophobic force. During condensation phase, increasing the pH of sediment to pH 11 could attain the most compact structure. Random copolymers containing benzoboroxole groups act as dispersants (due to pH responsive character) rather than flocculants at pH 11, providing repulsive force that enables particles to rearrange their position and consolidate well. Through a two-step solid-liquid separation including settling phase and consolidation phase, rapid settling and compact sediment are feasible simultaneously. PMID- 26592530 TI - Role of lycopene in preventing lipid peroxidation products, in commercial infant milk formula. AB - OBJECTIVES: The aim of the study was to investigate whether lycopene from natural sources (tomato extract) is able to protect newborns milk formula, against oxidative damage caused by exposure to hydroxyl radicals, and is there a difference between milk substitutes from various sources. METHODS: Four commercial brands of infant milk formula: two of the formulas were dairy milk (A d and B-d) and two were based on soy bean vegan milk (A-s and B-s), were exposed to ionizing radiation radical (.OH). Lipid peroxidation was determined by measuring malondialdehyde (MDA) using thiobarbituric acid reactive substance test (TBARS). RESULTS: When suspensions containing the four brands of formula were subjected to oxidizing media produced by ionizing radiation (hydroxyl radicals), lipid peroxidation increased linearly as a function of the irradiation dose (R = 0.99). It was found that lycopene in a concentration of 0.6 mM, reduced the radiation damage only in the soy-based formula; decrease of ~40% of the damage achieved in B-s, and ~20% reduction in the damage caused to A-s, significantly p < 0.01. CONCLUSIONS: Lycopene in dairy milk did not protect against hydroxyl radicals; however, lycopene found to protect against hydroxyl radicals in soy milk. This result suggests different mechanisms of radical production that arises from high iron levels present in the soy milk and involving the high-valent iron peroxo species. PMID- 26592531 TI - Memorability in Context: A Heuristic Story. AB - We examined children's ability to employ a metacognitive heuristic based on memorability expectations to reduce false recognitions, and explored whether these expectations depend on the context in which the items are presented. Specifically, 4-, 6-, and 9-year-old children were presented with high-, medium-, and low-memorability words, either mixed together (Experiment 1) or separated into two different lists (Experiment 2). Results revealed that only children with a higher level of executive functioning (9-year-olds) used the memorability-based heuristic when all types of items were presented within the same list. However, all children, regardless of age or executive level, implemented the metacognitive rule when high- and low-memorability words were presented in two separate lists. Moreover, the results of Experiment 2 showed that participants processed medium memorability words more conservatively when they were presented in a low- than in a high-memorability list, suggesting that children's memorability expectations are sensitive to list-context effects. PMID- 26592532 TI - Retrospective Evaluations of Sequences: Testing the Predictions of a Memory-Based Analysis. AB - Retrospective evaluation (RE) of event sequences is known to be biased in various ways. The present paper presents a series of studies that examined the suggestion that the moments that are the most accessible in memory at the point of RE contribute to these biases. As predicted by this memory-based analysis, Experiment 1 showed that pleasantness ratings of word lists were biased by the presentation position of a negative item and by how easy the negative information was to retrieve. Experiment 2 ruled out the hypothesis that these findings were due to the dual nature of the task called upon. Experiment 3 further manipulated the memorability of the negative items--and corresponding changes in RE were as predicted. Finally, Experiment 4 extended the findings to more complex stimuli involving event narratives. Overall, the results suggest that assessments were adjusted based on the retrieval of the most readily available information. PMID- 26592533 TI - The Color Red Supports Avoidance Reactions to Unhealthy Food. AB - Empirical evidence suggests that the color red acts like an implicit avoidance cue in food contexts. Thus specific colors seem to guide the implicit evaluation of food items. We built upon this research by investigating the implicit meaning of color (red vs. green) in an approach-avoidance task with healthy and unhealthy food items. Thus, we examined the joint evaluative effects of color and food: Participants had to categorize food items by approach-avoidance reactions, according to their healthfulness. Items were surrounded by task-irrelevant red or green circles. We found that the implicit meaning of the traffic light colors influenced participants' reactions to the food items. The color red (compared to green) facilitated automatic avoidance reactions to unhealthy foods. By contrast, approach behavior toward healthy food items was not moderated by color. Our findings suggest that traffic light colors can act as implicit cues that guide automatic behavioral reactions to food. PMID- 26592534 TI - Rapid Serial Auditory Presentation: A New Measure of Statistical Learning in Speech Segmentation. AB - The Rapid Serial Visual Presentation procedure is a method widely used in visual perception research. In this paper we propose an adaptation of this method which can be used with auditory material and enables assessment of statistical learning in speech segmentation. Adult participants were exposed to an artificial speech stream composed of statistically defined trisyllabic nonsense words. They were subsequently instructed to perform a detection task in a Rapid Serial Auditory Presentation (RSAP) stream in which they had to detect a syllable in a short speech stream. Results showed that reaction times varied as a function of the statistical predictability of the syllable: second and third syllables of each word were responded to faster than first syllables. This result suggests that the RSAP procedure provides a reliable and sensitive indirect measure of auditory statistical learning. PMID- 26592535 TI - The importance of drug transporters in human pluripotent stem cells and in early tissue differentiation. AB - INTRODUCTION: Drug transporters are large transmembrane proteins which catalyse the movement of a wide variety of chemicals, including drugs as well as xeno- and endobiotics through cellular membranes. The major groups of these proteins include the ATP-binding cassette transporters which in eukaryotes work as ATP fuelled drug 'exporters' and the Solute Carrier transporters, with various transport directions and mechanisms. AREAS COVERED: In this review, we discuss the key ATP-binding cassette and Solute Carrier drug transporters which have been reported to contribute to the function and/or protection of undifferentiated human stem cells and during tissue differentiation. We review the various techniques for studying transporter expression and function in stem cells, and the role of drug transporters in foetal and placental tissues is also discussed. We especially focus on the regulation of transporter expression by factors modulating cell differentiation properties and on the function of the transporters in adjustment to environmental challenges. EXPERT OPINION: The relatively new and as yet unexplored territory of transporters in stem cell biology may rapidly expand and bring important new information regarding the metabolic and epigenetic regulation of 'stemness' and the early differentiation properties. Drug transporters are clearly important protective and regulatory components in stem cells and differentiation. PMID- 26592536 TI - Characterizations and Correlations of Wall Shear Stress in Aneurysmal Flow. AB - Wall shear stress (WSS) is one of the most studied hemodynamic parameters, used in correlating blood flow to various diseases. The pulsatile nature of blood flow, along with the complex geometries of diseased arteries, produces complicated temporal and spatial WSS patterns. Moreover, WSS is a vector, which further complicates its quantification and interpretation. The goal of this study is to investigate WSS magnitude, angle, and vector changes in space and time in complex blood flow. Abdominal aortic aneurysm (AAA) was chosen as a setting to explore WSS quantification. Patient-specific computational fluid dynamics (CFD) simulations were performed in six AAAs. New WSS parameters are introduced, and the pointwise correlation among these, and more traditional WSS parameters, was explored. WSS magnitude had positive correlation with spatial/temporal gradients of WSS magnitude. This motivated the definition of relative WSS gradients. WSS vectorial gradients were highly correlated with magnitude gradients. A mix WSS spatial gradient and a mix WSS temporal gradient are proposed to equally account for variations in the WSS angle and magnitude in single measures. The important role that WSS plays in regulating near wall transport, and the high correlation among some of the WSS parameters motivates further attention in revisiting the traditional approaches used in WSS characterizations. PMID- 26592537 TI - Numerical simulation of iontophoresis in the drug delivery system. AB - The architecture and composition of stratum corneum act as barriers and limit the diffusion of most drug molecules and ions. Much effort has been made to overcome this barrier and it can be seen that iontophoresis has shown a good effect. Iontophoresis represents the application of low electrical potential to increase the transport of drugs into and across the skin or tissue. Iontophoresis is a noninvasive drug delivery system, and therefore, it is a useful alternative to drug transportation by injection. In this study, we present a numerical model and effects of electrical potential on the drug diffusion in the buccal tissue and the stratum corneum. The initial numerical results are in good comparison with experimental observation. We demonstrate that the application of an applied voltage can greatly improve the efficacy of localized drug delivery as compared to diffusion alone. PMID- 26592539 TI - Editorial: Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells: Ushering of a New Era in Personalized Cell Therapies. PMID- 26592538 TI - Management of gout in the real world: current practice versus guideline recommendations. AB - OBJECTIVES: Gout is a chronic, extremely painful disease that is potentially curable when treated effectively. Unfortunately approximately one-half of patients with gout are inadequately controlled. METHODS: We surveyed 315 primary care physicians in the United States and Europe to investigate current practice in the real world, as distinct from recommendations in guidelines. RESULTS: Our survey on 1657 patients found that regular testing of serum uric acid, in conformity with the guidelines, was conducted by approximately 50% of physicians. Advice to patients on diet and lifestyle was less well implemented, and identification of overweight/obese patients was inconsistent. CONCLUSION: Improvements in practice by physicians would include comprehensive assessment of the patient, adoption of regular monitoring during treatment, and the provision of patient education on adherence and lifestyle. PMID- 26592540 TI - Statement of Retraction. PMID- 26592541 TI - Optimizing packing fraction in granular media composed of overlapping spheres. AB - What particle shape will generate the highest packing fraction when randomly poured into a container? In order to explore and navigate the enormous search space efficiently, we pair molecular dynamics simulations with artificial evolution. Arbitrary particle shape is represented by a set of overlapping spheres of varying diameter, enabling us to approximate smooth surfaces with a resolution proportional to the number of spheres included. We discover a family of planar triangular particles, whose packing fraction of phi ~ 0.73 is among the highest experimental results for disordered packings of frictionless particles. We investigate how phi depends on the arrangement of spheres comprising an individual particle and on the smoothness of the surface. We validate the simulations with experiments using 3D-printed copies of the simplest member of the family, a planar particle consisting of three overlapping spheres with identical radius. Direct experimental comparison with 3D-printed aspherical ellipsoids demonstrates that the triangular particles pack exceedingly well not only in the limit of large system size but also when confined to small containers. PMID- 26592542 TI - Synthesis and anti-cancer activity of 1,4-disubstituted imidazo[4,5-c]quinolines. AB - The synthesis and anti-cancer activity evaluation of fused imidazoquinoline compounds is reported in this paper. Yb(OTf)3 has been utilized as a catalyst for the synthesis of 1,4-diaryl substituted imidazo[4,5-c]quinolines via a modified Pictet-Spengler approach. The desired imidazole ring was synthesized from imines using TosMIC (toluenesulfonylmethyl isocyanide) and subsequently functionalized at the C-4 position yielding an imidazoquinoline skeleton. Importantly, the final step was carried out without the aid of any prefunctionalization to obtain the resultant compounds in good yields. The synthesized compounds, when screened for anti-cancer activity, revealed the highest activity with 4-(2-bromophenyl)-1 phenyl-1H-imidazo[4,5-c]quinoline (IC50: 103.3 MUM). PMID- 26592543 TI - Photoassisted oxidation of ruthenium(II)-photocatalysts Ru(bpy)3(2+) and Ru(bpz)3(2+) to RuO4: orthogonal tandem photoredox and oxidation catalysis. AB - Common photoredox catalysts Ru(bpy)3(2+) and Ru(bpz)3(2+) are rapidly converted into Ruthenium(viii)-oxide through continuous visible light irradiation in the presence of NaIO4 or H5IO6. This hitherto unreported photoassisted catalyst oxidation was utilized in the development of tandem catalytic protocols which combine a photoredox reaction with a subsequent RuO4-mediated oxidation. The new concept was demonstrated through one-pot radical cation Diels-Alder (RCDA)/1,5 diene cyclisation sequences. PMID- 26592544 TI - Tailoring properties of porous Poly (vinylidene fluoride) scaffold through nano sized 58s bioactive glass. AB - The biological properties of porous poly (vinylidene fluoride) (PVDF) scaffolds fabricated by selective laser sintering were tailored through nano-sized 58s bioactive glass. The results showed that 58s bioactive glass distributed evenly in the PVDF matrix. There were some exposed particles on the surface which provided attachment sites for biological response. It was confirmed that the scaffolds had highly bioactivity by the formation of bone-like apatite in simulated body fluid. And the bone-like apatite became dense with the increase in 58s bioactive glass and culture time. Moreover, the scaffolds were suitable for cell adhesion and proliferation compared with the PVDF scaffolds without 58s bioactive glass. The research showed that the PVDF/58s bioactive glass scaffolds had latent application in bone tissue engineering. PMID- 26592546 TI - Thiophene functionalized silicon-containing aggregation-induced emission enhancement materials: applications as fluorescent probes for the detection of nitroaromatic explosives in aqueous-based solutions. AB - Two novel aggregation-induced emission enhancement (AIEE) molecules, namely, 3,4 diphenyl-2,5-di(2-thienyl)phenyltrimethylsilane (DPTB-TMS) and bis[3,4-diphenyl- 2,5-di(2-thienyl)phenyl]methylphenylsilane (DPTB-TMS) were designed and synthesized. The optical properties of the two silanes were completely opposite to the traditional luminescent materials. Unlike the aggregation caused quenching, they all emit faint fluorescence in the dispersed state, while emission intensity increased sharply in aggregate states. Fluorescence spectra showed that the two compounds exhibited AIEE properties and that is due to the weak pi-pi stacking caused by the restriction of intramolecular rotations of dye segments, particularly the -SiMe3 and thienyl groups in the aggregate state. As fluorescent (FL) probes, the fluorescence quenching behavior was further investigated. Thanks to the richer-electron thiophene groups, both compounds showed good performance in detecting nitroaromatics, especially picric acid (PA). The two AIEE FL probes exhibited better quenching efficiency in aqueous-based than in organic-based solutions. For DPTB-MPS, the addition of 80 MUM nitrobenzene, 60 MUM m-nitrobenzene and 40 MUM PA resulted in about 50% quenching in aqueous solutions. The quenching mechanism would be electron transfer from silanes to nitroaromatics. This work provides a basis for designing organic silanes with "abnormal" but useful optical properties and FL probes with AIEE properties for the detection of nitroaromatics. PMID- 26592545 TI - Recent progress in continuous and semi-continuous processing of solid oral dosage forms: a review. AB - CONTEXT: Continuous processing is an innovative production concept well known and successfully used in other industries for many years. The modern pharmaceutical industry is facing the challenge of transition from a traditional manufacturing approach based on batch-wise production to a continuous manufacturing model. OBJECTIVE: The aim of this article is to present technological progress in manufacturing based on continuous and semi-continuous processing of the solid oral dosage forms. METHODS: Single unit processes possessing an alternative processing pathway to batch-wise technology or, with some modification, an altered approach that may run continuously, and are thus able to seamlessly switch to continuous manufacturing are briefly presented. Furthermore, the concept of semi-continuous processing is discussed. Subsequently, more sophisticated production systems created by coupling single unit processes and comprising all the steps of production, from powder to final dosage form, were reviewed. Finally, attempts of end-to-end production approach, meaning the linking of continuous synthesis of API from intermediates with the production of final dosage form, are described. RESULTS: There are a growing number of scientific articles showing an increasing interest in changing the approach to the production of pharmaceuticals in recent years. Numerous scientific publications are a source of information on the progress of knowledge and achievements of continuous processing. These works often deal with issues of how to modify or replace the unit processes in order to enable seamlessly switching them into continuous processing. A growing number of research papers concentrate on integrated continuous manufacturing lines in which the production concept of "from powder to tablet" is realized. Four main domains are under investigation: influence of process parameters on intermediates or final dosage forms properties, implementation of process analytical tools, control-managing system responsible for keeping continuous materials flow through the whole manufacturing process and the development of new computational methods to assess or simulate these new manufacturing techniques. The attempt to connect the primary and secondary production steps proves that development of continuously operating lines is possible. CONCLUSION: A mind-set change is needed to be able to face, and fully assess, the advantages and disadvantages of switching from batch to continuous mode production. PMID- 26592547 TI - Attitudes to statistics in primary health care physicians, Qassim province. AB - Aim To investigate primary health care (PHC) physicians' attitudes to statistics, their self-reported knowledge level, and their perceived training needs in statistics. BACKGROUND: In spite of realization of the importance of statistics, inadequacies in physicians' knowledge and skills have been found, underscoring the need for in-service training. Understanding physicians' attitudes to statistics is vital in planning statistics training. METHODS: The study was based on theory of planned behavior. A cross-sectional survey of all PHC physicians was conducted in Qassim province, from August to October 2014. Attitudes to statistics were determined by a self-administered questionnaire. The attitudes were assessed on four subscales including general perceptions; perceptions of knowledge and training; perceptions of statistics and evidence-based medicine; and perceptions of future learning. Findings Of 416 eligible participants, 338 (81.25%) responded to the survey. On a scale of 1-10, the majority (73.6%) of the participants self-assessed their level of statistics knowledge as five or below. The attitude scores could have a minimum of 20 and a maximum of 100, with higher scores showing a positive attitude. The participants showed a positive attitude with the mean score of 71.14 (+/-7.73). Out of the four subscales, 'perceptions of statistics and evidence-based medicine' subscale scored the highest, followed by 'perceptions of future learning'. CONCLUSION: PHC physicians have a positive attitude to statistics. However, they realize their gaps in knowledge in statistics, and are keen to fill these gaps. Statistics training, resulting in improved statistics knowledge is expected to lead to clinical care utilizing evidence-based medicine, and thus improvement to health care services. PMID- 26592548 TI - Fabrication and characterization of a highly sensitive hydroquinone chemical sensor based on iron-doped ZnO nanorods. AB - Herein, we report the development of a simple and highly sensitive hydroquinone (HQ) chemical sensor based on an electrochemically activated iron-doped (Fe doped) zinc oxide nanorod (ZnO NR) modified screen-printed electrode (SPE). The Fe-doped ZnO NRs were prepared using a hydrothermal process and their morphological, crystal, compositional and optical properties were characterized in detail. The detailed characterizations showed that the NRs are densely grown, well-crystalline and possess a wurtzite hexagonal phase. The fabricated HQ electrochemical sensor exhibited high sensitivity of 18.60 MUA mM(-1) cm(-2) and a very low experimental detection limit of 0.51 MUM. Our results demonstrate that simply prepared doped ZnO nanomaterials are promising candidates to fabricate highly sensitive electrochemical sensors. PMID- 26592549 TI - Highly efficient and durable PtCo alloy nanoparticles encapsulated in carbon nanofibers for electrochemical hydrogen generation. AB - PtCo/CNFs exhibit extraordinary catalytic activity and durability for hydrogen evolution reaction, even approaching the performance of the commercial Pt/C catalyst, which can be attributed to the alloy structure and the encapsulation of PtCo alloy nanoparticles in CNFs. PMID- 26592550 TI - The effect of a pathology clinic on the mental state and adjustment of patients with breast cancer. AB - OBJECTIVE: In this study, we examine whether a pathology clinic, conducted by pathologists, a novel medical tool that provides an explanation for the diagnosis of a cancer, can influence the mental state and adjustment of breast cancer patients. METHOD: We created a paper-based questionnaire and interviewed targeted breast cancer patients, who had undergone radical surgery, before and after they visited the clinic. RESULTS: We found that there may be increased motivation for treatment, a greater sense of reassurance, and reduced anxiety (as indicated by the Hospital Anxiety and Depression Scale (HADS)) in the group that attended the clinic. SIGNIFICANCE OF RESULTS: Our results suggest that visiting the pathology clinic may reduce anxiety over the short term. On the other hand, Mental Adjustment to Cancer (MAC) Anxious Preoccupation scores were significantly higher in this group as well, both before and after attendance, compared to the group that did not attend. The attending group may have reduced anxiety by such actions as collecting medical data on the cause of their anxiety and adopting healthier behaviors. Our findings suggest that appropriate emotional support and provision of medical information are very important in dealing with patient anxiety. PMID- 26592551 TI - Flying beyond Gray's Anatomy: A psychologist's experience in palliative care and psycho-oncology. AB - A clinical fellowship provides opportunities for health professionals to learn specialist skills from experienced mentors in "real-world" environments. In 2010 2011, I had the opportunity to complete a palliative care and psycho-oncology clinical fellowship in a public hospital. I found ways to integrate academic training into my practice and become a more independent psychologist. In this essay, I aim to share my experience with others and highlight key learnings and challenges I encountered. In providing psychosocial care, I learned to adapt my psychological practice to a general hospital setting, learning about the medical concerns, and life stories of my patients. I faced challenges navigating referral processes and had opportunities to strengthen my psychotherapy training. In the fellowship, I engaged in educational activities from the more familiar psychological skills to observing surgical teams at work. I also developed confidence facilitating groups and an interest in group psychological support for young adult offspring of people with cancer. I was able to engage participants with haematological cancer in qualitative research about their experiences of corticosteroid treatment. In this process, I came to understand the complexity of chemotherapy regimens. Overseeing my development were multiple supervisors, offering unique insights that I could take in and integrate with my personal practice and worldview. Throughout this process I became increasingly tuned into my own process, the impact of the work, and developed self-care routines to help disconnect from my day. I also reflected on my experiences of loss and grief and developed a deeper understanding of myself as a person. I use the metaphor of a parachuting journey to illustrate various aspects of my learning. PMID- 26592552 TI - RA-XII inhibits tumour growth and metastasis in breast tumour-bearing mice via reducing cell adhesion and invasion and promoting matrix degradation. AB - Cancer cells acquire invasive ability to degrade and adhere to extracellular matrix (ECM) and migrate to adjacent tissues. This ultimately results metastasis. Hence, the present study investigated the in vitro effects of cyclopeptide glycoside, RA-XII on cell adhesion, invasion, proliferation and matrix degradation, and its underlying mechanism in murine breast tumour cells, 4T1. The effect of RA-XII on tumour growth and metastasis in 4T1-bearing mice was also investigated. Our results showed that RA-XII inhibited tumour cell adhesion to collagen, fibronectin and laminin, RA-XII also reduced the expressions of vascular cell adhesion molecule, intracellular adhesion molecule and integrins, and integrin binding. In addition, RA-XII significantly inhibited breast tumour cell migration via interfering cofilin signaling and chemokine receptors. The activities of matrix metalloproteinase-9 and urokinase-type of plasminogen activator, and the expressions of ECM-associated proteinases were attenuated significantly by RA-XII. Furthermore, RA-XII induced G1 phase arrest and inhibited the expressions of cyclins and cyclin-dependent kinases. RA-XII inhibited the expressions of molecules in PI3K/AKT, NF-kappaB, FAK/pSRC, MAPK and EGFR signaling. RA-XII was also shown to have anti-tumour, anti-angiogenic and anti-metastatic activities in metastatic breast tumour-bearing mice. These findings strongly suggested that RA-XII is a potential anti-metastatic agent for breast cancer. PMID- 26592554 TI - Lack of Patient Understanding of Hospital-Acquired Infection Data Published on the Centers for Medicare and Medicaid Services Hospital Compare Website. AB - BACKGROUND: Public reporting of hospital quality data is a key element of US healthcare reform. Data for hospital-acquired infections (HAIs) are especially complex. OBJECTIVE: To assess interpretability of HAI data as presented on the Centers for Medicare and Medicaid Services Hospital Compare website among patients who might benefit from access to these data. METHODS: We randomly selected inpatients at a large tertiary referral hospital from June to September 2014. Participants performed 4 distinct tasks comparing hypothetical HAI data for 2 hospitals, and the accuracy of their comparisons was assessed. Data were presented using the same tabular formats used by Centers for Medicare and Medicaid Services. Demographic characteristics and healthcare experience data were also collected. RESULTS: Participants (N=110) correctly identified the better of 2 hospitals when given written descriptions of the HAI measure in 72% of the responses (95% CI, 66%-79%). Adding the underlying numerical data (number of infections, patient-time, and standardized infection ratio) to the written descriptions reduced correct responses to 60% (55%-66%). When the written HAI measure description was not informative (identical for both hospitals), 50% answered correctly (42%-58%). When no written HAI measure description was provided and hospitals differed by denominator for infection rate, 38% answered correctly (31%-45%). CONCLUSIONS: Current public HAI data presentation methods may be inadequate. When presented with numeric HAI data, study participants incorrectly compared hospitals on the basis of HAI data in more than 40% of the responses. Research is needed to identify better ways to convey these data to the public. PMID- 26592553 TI - MLN4924 Synergistically Enhances Cisplatin-induced Cytotoxicity via JNK and Bcl xL Pathways in Human Urothelial Carcinoma. AB - Cisplatin-based chemotherapy is the primary treatment for metastatic bladder urothelial carcinoma. However, the response rate is only 40-65%. This study investigated the anti-tumor effect and underlying mechanisms of the combination of cisplatin and the NEDD8-activating enzyme inhibitor MLN4924 in human bladder urothelial carcinoma. The combination of cisplatin and MLN4924 exerted synergistic cytotoxicity on two high-grade bladder urothelial carcinoma cell lines, NTUB1 and T24 (combination index <1). MLN4924 also potentiated the cisplatin-induced apoptosis and activation of caspase-3 and -7, phospho-histone H2A.X and PARP. c-Jun N-terminal kinase (JNK) activation and a down-regulation of B-cell lymphoma-extra large (Bcl-xL) were also observed during cisplatin and MLN4924 treatment. Inhibition of JNK activation partially restored cell viability and Bcl-xL expression. Bcl-xL overexpression also rescued cell viability. MLN4924 significantly potentiated cisplatin-induced tumor suppression in urothelial carcinoma xenograft mice. In summary, MLN4924 synergistically enhanced the anti tumor effect of cisplatin via an increase in DNA damage, JNK activation and down regulation of Bcl-xL in urothelial carcinoma cells. These findings provide a new therapeutic strategy for the treatment of bladder cancer. PMID- 26592555 TI - Expanding the scope of Metal-Free enantioselective allylic substitutions: Anthrones. AB - The highly enantioselective asymmetric allylic alkylation of Morita-Baylis Hillman carbonates with anthrones is presented. The reaction is simply catalyzed by cinchona alkaloid derivatives affording the final alkylated products in good yields and excellent enantioselectivities. PMID- 26592556 TI - Exploring comprehensive within-motif dependence of transcription factor binding in Escherichia coli. AB - Modeling the binding of transcription factors helps to decipher the control logic behind transcriptional regulatory networks. Position weight matrix is commonly used to describe a binding motif but assumes statistical independence between positions. Although current approaches take within-motif dependence into account for better predictive performance, these models usually rely on prior knowledge and incorporate simple positional dependence to describe binding motifs. The inability to take complex within-motif dependence into account may result in an incomplete representation of binding motifs. In this work, we applied association rule mining techniques and constructed models to explore within-motif dependence for transcription factors in Escherichia coli. Our models can reflect transcription factor-DNA recognition where the explored dependence correlates with the binding specificity. We also propose a graphical representation of the explored within-motif dependence to illustrate the final binding configurations. Understanding the binding configurations also enables us to fine-tune or design transcription factor binding sites, and we attempt to present the configurations through exploring within-motif dependence. PMID- 26592557 TI - Characterization of iron metabolism and erythropoiesis in erythrocyte membrane defects and thalassemia traits. AB - BACKGROUND AND AIMS: Erythropoiesis is closely related to iron metabolism in a balanced homeostasis. Analyses of diverse erythroid and iron metabolism disorders have shown that disrupted erythropoiesis negatively affects iron homeostasis and vice versa. The aim of this study was to characterize the relationship between erythropoietic activity and iron homeostasis in pediatric patients with erythrocyte membrane defects and thalassemia traits. METHODS: Selected markers of erythropoietic activity (erythropoietin, soluble transferrin receptor - sTfR and growth differentiation factor 15) and iron status parameters (serum iron, ferritin and hepcidin) were evaluated in pediatric patients with erythrocyte membrane defects and thalassemia traits. RESULTS: The patients with erythrocyte membrane defects and thalassemia traits had altered iron homeostasis due to disturbed erythropoiesis. In comparison with healthy controls, they had a normal to low hepcidin/ferritin ratio and concomitantly elevated sTfR. CONCLUSION: The findings suggest that pediatric patients with erythrocyte membrane defects and thalassemia traits are more susceptible to iron overload than the general population and that the (hepcidin/ferritin)/sTfR ratio can be used to monitor any worsening of the disease. PMID- 26592558 TI - Three-step stacking of cationic analytes by field-enhanced sample injection, sweeping, and micelle to solvent stacking in capillary electrophoresis. AB - The sensitivity enhancement factor (SEF) in field enhanced sample injection (FESI) in capillary electrophoresis is dictated by the conductivity ratio. The higher the conductivity ratio (using very low conductivity sample diluents such as water), the higher the SEF. Here, we improved the performance of FESI by combination with sweeping and micelle to solvent stacking (MSS) in a well-defined three-step stacking procedure using model cationic drugs. The separation was by capillary zone electrophoresis (CZE) using 100mM phosphoric acid as background solution (BGS). Under the experimental conditions studied, the SEF (vs. typical injection in CZE) range of FESI using a conductivity ratio of 10, 100, and 1000 (sample diluent with conductivity 10, 100, and 1000* lower than the BGS, respectively) was 5-6, 33-50, and 272-393, respectively. The SEF range of three step stacking was 308-891, 2188-6463, and 3088-6499, correspondingly. The SEF enhancement factor due to three-step stacking (SEF of three-step stacking divided by SEF of FESI) was from 11 to 161. We evaluated the performance of proposed procedure using a conductivity ratio of 10 (10mM phosphoric acid as diluent) which is the minimum requirement for field-enhancement. The strategy was as follows: long FESI (e.g., 420s at 10kV) to form an overloaded stacked zone; sweeping (e.g., 315s at -10kV) with 10mM sodium dodecyl sulfate micelles; and MSS by injection (6s at 50mbar) of 30% acetonitrile. The strategy was studied in terms of sweeping and MSS conditions, FESI/sweeping time ratio, and FESI time at constant FESI/sweeping ratio. Analytical figures of merit including linearity, LOD (S/N=3), and repeatability (intraday and interday) were determined. Moreover, sample matrix effect was studied using acetone treated plasma sample. PMID- 26592559 TI - Flavoromics approach in monitoring changes in volatile compounds of virgin rapeseed oil caused by seed roasting. AB - Two varieties of rapeseed (one high oleic - containing 76% of oleic acid, and the other - containing 62% of oleic acid) were used to produce virgin (pressed) oil. The rapeseeds were roasted at different temperature/time combinations (at 140-180 degrees C, and for 5-15min); subsequently, oil was pressed from the roasted seeds. The roasting improved the flavour and contributed to a substantial increase in the amount of a potent antioxidant-canolol. The changes in volatile compounds related to roasting conditions were monitored using comprehensive gas chromatography-mass spectrometry (GC*GC-ToFMS), and the key odorants for the non roasted and roasted seeds oils were determined by gas chromatography-olfactometry (GC-O). The most important compounds determining the flavour of oils obtained from the roasted seeds were dimethyl sulphide, dimethyltrisulfide, 2,3-diethyl-5 methylpyrazine, 2,3-butenedione, octanal, 3-isopropyl-2-methoxypyrazine and phenylacetaldehyde. For the oils obtained from the non-roasted seeds, the dominant compounds were dimethylsulfide, hexanal and octanal. Based on GC*GC ToFMS and principal component analysis (PCA) of the data, several compounds were identified that were associated with roasting at the highest temperatures regardless of the rapeseed variety: these were, among others, methyl ketones (2 hexanone, 2-heptanone and 2-octanone). PMID- 26592560 TI - An on-line high-performance liquid chromatography-diode-array detector-multi stage mass spectrometry-deoxyribonucleic acid-4',6-diamidino-2-phenylindole fluorescence detector system for screening the DNA-binding active compounds in Fufang Banbianlian Injection. AB - Fufang Banbianlian Injection (FBI), a well-known traditional Chinese medicine formula, has been recently approved and extensively used as a newly anti inflammatory and anti-tumor drug. This prescription comprises an equal ratio of three traditional Chinese herbs, Lobelia chinensis Lour, Scutellaria barbata D. Don and Hedyotis diffusa Willd. The relationships between its chemical compositions and activities have not been understood well yet. To investigate the ingredients and their DNA-binding activities in FBI, an on-line high-performance liquid chromatography-diode-array detector-multi-stage mass spectrometry deoxyribonucleic acid-4',6-diamidino-2-phenylindole-fluorescence detector (HPLC DAD-MS(n)-DNA-DAPI-FLD) system was developed using a combination of chromatographic, mass spectrometric and fluorescent detection techniques. 4',6 Diamidino-2-phenylindole (DAPI) specifically binds to three ATT base pairs on the DNA minor groove, and thus can be used as a fluorescent probe for screening active compounds that compete ATT sequences with DAPI. Using this system, 21 of 58 identified or tentatively characterized compounds in FBI showed DNA-binding activities, with most of the active compounds being flavone glycosides. In addition, the structure-activity relationships of these active compounds suggested that conjugated planar structures are favorable for DNA-binding activities, and adjacent hydroxyl groups in flavonoids can significantly improve their activities. This is, to the best of our knowledge, the first application of DAPI as a fluorescent probe for the screening of DNA-binding active compounds in complex samples. PMID- 26592561 TI - Robust estimation of thermodynamic parameters (DeltaH, DeltaS and DeltaCp) for prediction of retention time in gas chromatography - Part II (Application). AB - For this work, an analysis of parameter estimation for the retention factor in GC model was performed, considering two different criteria: sum of square error, and maximum error in absolute value; relevant statistics are described for each case. The main contribution of this work is the implementation of an initialization scheme (specialized) for the estimated parameters, which features fast convergence (low computational time) and is based on knowledge of the surface of the error criterion. In an application to a series of alkanes, specialized initialization resulted in significant reduction to the number of evaluations of the objective function (reducing computational time) in the parameter estimation. The obtained reduction happened between one and two orders of magnitude, compared with the simple random initialization. PMID- 26592562 TI - Hybrid ion mobility and mass spectrometry as a separation tool. AB - Ion mobility spectrometry (IMS) coupled to mass spectrometry (MS) has seen spectacular growth over the last two decades. Increasing IMS sensitivity and capacity with improvements in MS instrumentation have driven this growth. As a result, a diverse new set of techniques for separating ions by their mobility have arisen, each with characteristics that make them favorable for some experiments and some mass spectrometers. Ion mobility techniques can be broken down into dispersive and selective techniques based upon whether they pass through all mobilities for later analysis by mass spectrometry or select ions by mobility or a related characteristic. How ion mobility techniques fit within a more complicated separation including mass spectrometry and other techniques such as liquid chromatography is of fundamental interest to separations scientists. In this review we explore the multitude of ion mobility techniques hybridized to different mass spectrometers, detailing current challenges and opportunities for each ion mobility technique and for what experiments one technique might be chosen over another. The underlying principles of ion mobility separations, including: considerations regarding separation capabilities, ion transmission, signal intensity and sensitivity, and the impact that the separation has upon the ion structure (i.e., the possibility of configurational changes due to ion heating) are discussed. PMID- 26592563 TI - Performance comparison of partial least squares-related variable selection methods for quantitative structure retention relationships modelling of retention times in reversed-phase liquid chromatography. AB - The relative performance of six multivariate data analysis methods derived from or combined with partial least squares (PLS) has been compared in the context of quantitative structure-retention relationships (QSRR). These methods include, GA (genetic algorithm)-PLS, Monte Carlo uninformative variable elimination (MC-UVE), competitive adaptive reweighted sampling (CARS), iteratively retaining informative variables (IRIV), variable iterative space shrinkage approach (VISSA) and PLS with automated backward selection of predictors (autoPLS). A set of 825 molecular descriptors was computed for 86 suspected sports doping compounds and used for predicting their gradient retention times in reversed-phase liquid chromatography (RPLC). The correlation between molecular descriptors selected by each technique and the retention time was established using the PLS method. All models derived from a selected subset of descriptors outperformed the reference PLS model derived from all descriptors, with very small demands of computational time and effort. A performance comparison indicated great diversity of these methods in selecting the most relevant molecular descriptors, ranging from 28 for CARS to 263 for MC-UVE. While VISSA provided the lowest degree of over-fitting for the training set, CARS demonstrated the best compromise between the prediction accuracy and the number of selected descriptors, with the prediction error of as low as 46s for the external test set. Only ten descriptors were found to be common for all models, with the characteristics of these descriptors being representative of the retention mechanism in RPLC. PMID- 26592564 TI - Towards a new class of heavy ion doped magnetic semiconductors for room temperature applications. AB - The article presents, using Bi doped ZnO, an example of a heavy ion doped oxide semiconductor, highlighting a novel p-symmetry interaction of the electronic states to stabilize ferromagnetism. The study includes both ab initio theory and experiments, which yield clear evidence for above room temperature ferromagnetism. ZnBi(x)O(1-x) thin films are grown using the pulsed laser deposition technique. The room temperature ferromagnetism finds its origin in the holes introduced by the Bi doping and the p-p coupling between Bi and the host atoms. A sizeable magnetic moment is measured by means of x-ray magnetic circular dichroism at the O K-edge, probing directly the spin polarization of the O(2p) states. This result is in agreement with the theoretical predictions and inductive magnetometry measurements. Ab initio calculations of the electronic and magnetic structure of ZnBi(x)O(1-x) at various doping levels allow to trace the origin of the ferromagnetic character of this material. It appears, that the spin orbit energy of the heavy ion Bi stabilizes the ferromagnetic phase. Thus, ZnBi(x)O(1-x) doped with a heavy non-ferromagnetic element, such as Bi, is a credible example of a candidate material for a new class of compounds for spintronics applications, based on the spin polarization of the p states. PMID- 26592565 TI - Mesoporous Silica Gel-Based Mixed Matrix Membranes for Improving Mass Transfer in Forward Osmosis: Effect of Pore Size of Filler. AB - The efficiency of forward osmosis (FO) process is generally limited by the internal concentration polarization (ICP) of solutes inside its porous substrate. In this study, mesoporous silica gel (SG) with nominal pore size ranging from 4 30 nm was used as fillers to prepare SG-based mixed matrix substrates. The resulting mixed matrix membranes had significantly reduced structural parameter and enhanced membrane water permeability as a result of the improved surface porosity of the substrates. An optimal filler pore size of ~9 nm was observed. This is in direct contrast to the case of thin film nanocomposite membranes, where microporous nanoparticle fillers are loaded to the membrane rejection layer and are designed in such a way that these fillers are able to retain solutes while allowing water to permeate through them. In the current study, the mesoporous fillers are designed as channels to both water and solute molecules. FO performance was enhanced at increasing filler pore size up to 9 nm due to the lower hydraulic resistance of the fillers. Nevertheless, further increasing filler pore size to 30 nm was accompanied with reduced FO efficiency, which can be attributed to the intrusion of polymer dope into the filler pores. PMID- 26592567 TI - Editorial Comment. PMID- 26592566 TI - Active site coupling in Plasmodium falciparum GMP synthetase is triggered by domain rotation. AB - GMP synthetase (GMPS), a key enzyme in the purine biosynthetic pathway performs catalysis through a coordinated process across two catalytic pockets for which the mechanism remains unclear. Crystal structures of Plasmodium falciparum GMPS in conjunction with mutational and enzyme kinetic studies reported here provide evidence that an 85 degrees rotation of the GATase domain is required for ammonia channelling and thus for the catalytic activity of this two-domain enzyme. We suggest that conformational changes in helix 371-375 holding catalytic residues and in loop 376-401 along the rotation trajectory trigger the different steps of catalysis, and establish the central role of Glu374 in allostery and inter-domain crosstalk. These studies reveal the mechanism of domain rotation and inter-domain communication, providing a molecular framework for the function of all single polypeptide GMPSs and form a solid basis for rational drug design targeting this therapeutically important enzyme. PMID- 26592568 TI - Atomistic Design of Favored Compositions for Synthesizing the Al-Ni-Y Metallic Glasses. AB - For a ternary alloy system promising for obtaining the so-called bulk metallic glasses (BMGs), the first priority issue is to predict the favored compositions, which could then serve as guidance for the appropriate alloy design. Taking the Al-Ni-Y system as an example, here we show an atomistic approach, which is developed based on a recently constructed and proven realistic interatomic potential of the system. Applying the Al-Ni-Y potential, series simulations not only clarify the glass formation mechanism, but also predict in the composition triangle, a hexagonal region, in which a disordered state, i.e., the glassy phase, is favored energetically. The predicted region is defined as glass formation region (GFR) for the ternary alloy system. Moreover, the approach is able to calculate an amorphization driving force (ADF) for each possible glassy alloy located within the GFR. The calculations predict an optimized sub-region nearby a stoichiometry of Al80Ni5Y15, implying that the Al-Ni-Y metallic glasses designed in the sub-region could be the most stable. Interestingly, the atomistic predictions are supported by experimental results observed in the Al-Ni-Y system. In addition, structural origin underlying the stability of the Al-Ni-Y metallic glasses is also discussed in terms of a hybrid packing mode in the medium-range scale. PMID- 26592570 TI - Development and validation of a method for the quantification of extractable perfluoroalkyl acids (PFAAs) and perfluorooctane sulfonamide (FOSA) in textiles. AB - In textiles, like outdoor clothing, per- and polyfluoroalkyl substances (PFASs) are often used for durable water repellency (DWR) of the final products. The analytical performance to determine the concentration of these chemicals available for exposure to humans and to the environment need to be established. Here a method for the extraction and analysis of one class of PFASs, namely perfluoroalkyl acids (PFAAs), in outdoor clothing was developed and validated. The PFAAs which were validated, included perfluoroalkyl carboxylic acids (PFCAs) (C4-C14), and perfluoroalkane sulfonic acids (PFSAs) (C4, C6, C7, C8). In addition, perfluorooctane sulfonamide (FOSA) was included in this study. The method was based on an organic solvent extraction and analysis by high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). No further cleaning was needed. Two commonly used organic solvent compositions were evaluated for the optimal extraction, i.e. methanol and acetone/acetonitrile (80:20, v/v), and the number and duration of the sequential extractions were optimized. Results showed that two sequential extractions with 5mL methanol and an extraction time of 30min gave an optimal performance with an extraction efficiency of >90%. The influence of matrix on the quantification of PFAAs was studied. This indicated ion suppression due to different matrix effects or sorption behavior to specific textile samples. Validation of the entire method showed overall recoveries of>80% and relative standard deviations (RSDs) of<9% (n=3) for repeatability and <20% (n=3) for reproducibility. This is the first validation of an analytical method for the analysis of extractable PFCAs, PFSAs and FOSA associated to textiles, which is of high importance due to the regulation of PFAAs in textile. PMID- 26592569 TI - Detection of HIT antibody dependent platelet aggregation using novel surface imprinting approach. AB - We present a fast, robust and straightforward spin force assisted surface imprinting approach for activated platelets and demonstrate that Heparin induced thrombocytopenia (HIT) platelet aggregation can be measured by this approach. A critical and challenging step in functional assays for HIT is platelet separation from the healthy donor's platelet-rich plasma (PRP). Our approach using surface imprinted polymer (MIP) for measurements on a quartz crystal microbalance with dissipation (QCM-D) enables monitoring of platelet aggregation directly in PRP thus eliminating the challenge of platelet separation. This is the first report of platelet imprinting. We also provide proof of principle that QCM-D technology can be applied for functional measurements of HIT antibodies. PMID- 26592571 TI - A strategy for comprehensive identification of sequential constituents using ultra-high-performance liquid chromatography coupled with linear ion trap Orbitrap mass spectrometer, application study on chlorogenic acids in Flos Lonicerae Japonicae. AB - The analytical methodologies for evaluation of multi-component system in traditional Chinese medicines (TCMs) have been inadequate or unacceptable. As a result, the unclarity of multi-component hinders the sufficient interpretation of their bioactivities. In this paper, an ultra-high-performance liquid chromatography coupled with linear ion trap-Orbitrap (UPLC-LTQ-Orbitrap)-based strategy focused on the comprehensive identification of TCM sequential constituents was developed. The strategy was characterized by molecular design, multiple ion monitoring (MIM), targeted database hits and mass spectral trees similarity filter (MTSF), and even more isomerism discrimination. It was successfully applied in the HRMS data-acquisition and processing of chlorogenic acids (CGAs) in Flos Lonicerae Japonicae (FLJ), and a total of 115 chromatographic peaks attributed to 18 categories were characterized, allowing a comprehensive revelation of CGAs in FLJ for the first time. This demonstrated that MIM based on molecular design could improve the efficiency to trigger MS/MS fragmentation reactions. Targeted database hits and MTSF searching greatly facilitated the processing of extremely large information data. Besides, the introduction of diagnostic product ions (DPIs) discrimination, ClogP analysis, and molecular simulation, raised the efficiency and accuracy to characterize sequential constituents especially position and geometric isomers. In conclusion, the results expanded our understanding on CGAs in FLJ, and the strategy could be exemplary for future research on the comprehensive identification of sequential constituents in TCMs. Meanwhile, it may propose a novel idea for analyzing sequential constituents, and is promising for quality control and evaluation of TCMs. PMID- 26592572 TI - The construction and testing of the portable Hg(2+) ultrasonic calibrator for the control of mercury speciation systems. AB - During fuel combustion mercury, as Hg(0) and Hg(2+) forms, is emitted to the atmosphere. Effective reduction of mercury emission requires applying speciation systems for emission control and research. An important part of all mercury determination and speciation systems are the calibrators. Calibrators are responsible for the accuracy of mercury determination and, in consequence, the effective reduction of mercury emission. The aim of the work was to construct a portable HgCl2 calibrator. The purpose of the device was the control of mercury speciation systems for continuous measurements and study of HgCl2 sorption. As a result of previously conducted research, the portable Hg(2+) ultrasonic calibrator was designed, constructed and tested. The ultrasonic calibrator generates a stable stream of HgCl2 (RSD=2.8% for CHg=28ug/m(3)). The correlation between theoretical and reading concentration of HgCl2 was R(2)=0.9983. The average recovery of HgCl2 was 95%. The advantages of the ultrasonic Hg(2+) calibrator are: high accuracy and selectivity, low pressure of HgCl2 stream and very low cost of production. The calibrator was successfully tested, both in the laboratory and in the power plant, during a preliminary study on HgCl2 sorption on a fly ash filter. PMID- 26592573 TI - Optimization of the derivatization protocol of pentacyclic triterpenes prior to their gas chromatography-mass spectrometry analysis in plant extracts. AB - This paper focuses on the application of a two-level full factorial design to optimize the key derivatization step before the GC-FID and GC-MS analysis of pentacyclic triterpenes. The derivatization reaction was screened for influential factors and statistically significant parameters with a p value less than 0.05. A multi-response optimization based on a desirability function was then applied, while simultaneously considering overall detection enhancement of compounds. Results showed that derivatization using N,O bis(trimethylsilyl)trifluoroacetamide (BSTFA) and trimethylchlorosilane (TMCS) in pyridine (22:13:65v/v/v) for 2h at 30 degrees C was the most efficient method of derivatizing all the hydroxyl and carboxylic acid groups contained in the triterpene structures. The validity of the method was demonstrated using GC-MS analyzes of a mixture containing eleven standards (beta-amyrin, alpha-amyrin, lupeol, erythrodiol, uvaol, betulin, oleanolic acid, betulinic acid, ursolic acid, maslinic acid and corosolic acid). These compounds are representative of different classes of terpene compounds bearing different functional groups such as alcohols, diols, and carboxylic acids. The derivatization procedure was then tested on four plant extracts: apple pomace, salvia sclarea (dried leaves and flowers), sea buckthorn (Hyppophae rhammnoides L.) berries, and B. serrata resin. The identification of triterpenes was based on the comparison of their retention time and mass spectra to those of standards. The presence of compounds already identified in the literature was confirmed and new ones such as maslinic and corosolic acids were identified in apples, sea buckthorn and salvia sclarea. PMID- 26592574 TI - Characterization of ceramic hydroxyapatite surface by inverse liquid chromatography in aquatic systems. AB - The novel approach for hydroxyapatite (HA) surface characterization was proposed. The main aim of this investigation was to estimate surface properties of HA as a biomaterial in real system i.e. in simulated body fluid (SBF). One of the method, which might be used to reflect the influence of liquid environment on sorption properties of material being surrounded by this liquid, is called inverse liquid chromatography (ILC). The lowercase letters of LFER equation (e, s, a, b, v) served for this characterization. The sorption abilities of examined material were also estimated for two different aqueous mobile phases: deionized water and water solution of 0.1M Na2HPO4. It enabled to observe the change in physiochemical properties of surface, considered in Abraham model, dependence on ions concentration in the mobile phase. Moreover pH of every aquatic solution, normally about 7, was adjusted to 5.5 and 9 to observe the influence of hydrogen and hydroxyl ions concentration on HA sorption properties. PMID- 26592575 TI - Electrochemical sensing of mesalazine and its N-acetylated metabolite in biological samples using functionalized carbon nanotubes. AB - A rapid analytical method without the time-consuming separation step was developed to simultaneously determine mesalazine and its N-acetylated metabolite. A simply designed electrochemical sensor with functionalized carbon nanotubes in a Nafion matrix was constructed for this purpose. The presence of the nanocomposite modifier on the electrode surface significantly affects the voltammetric response of target analytes. The morphology of the modified surface was investigated by scanning electron microscopy. The effect of modifier amount on the sensor performance was investigated in order to obtain the most favorable response of mesalazine since it was found in lower concentration limits in real samples then its metabolite due to the rapid drug elimination and the slightly slower renal metabolite excretion. Under optimal conditions, the anodic peak currents measured by square-wave voltammetry increased linearly after short accumulation of 30s in the range of 5.0*10(-8)-2.5*10(-6)M and 1.0*10(-7)-5.0*10( 6)M for drug and metabolite, respectively. In addition to stable response, the sensor has excellent performance associated with high sensitivity (2.33*10(7) and 8.37*10(6)uAM(-1) for drug and metabolite, respectively). The synergistic effect of the carbon nanotubes and Nafion polymer film yielded detection limit of 1.2*10(-8)M for mesalazine and 2.6*10(-8)M for its metabolite that is comparable to known chromatographic methods. Due to the easy preparation and regeneration, the proposed sensor opens new opportunity for fast, simple and sensitive analysis of drug and its metabolite in human serum samples as well as direct quantification of mesalazine in delayed-release formulations. PMID- 26592576 TI - Ultra trace analysis of PAHs by designing simple injection of large amounts of analytes through the sample reconcentration on SPME fiber after magnetic solid phase extraction. AB - A simple solventless injection method was introduced based on the using of a solid-phase microextraction (SPME) fiber for injection of large amounts of the analytes extracted by the magnetic solid phase extraction (MSPE) procedure. The resulted extract from MSPE procedure was loaded on a G-coated SPME fiber, and then the fiber was injected into the gas chromatography (GC) injection port. This method combines the advantages of exhaustive extraction property of MSPE and the solvent-less injection of SPME to improve the sensitivity of the analysis. In addition, the analytes were re-concentrated prior to inject into the gas chromatography (GC) inlet because of the organic solvent removing from the remaining extract of MSPE technique. Injection of the large amounts of analytes was made possible by using the introduced procedure. Fourteen polycyclic aromatic hydrocarbons (PAHs) with different volatility were used as model compounds to investigate the method performance for volatile and semi-volatile compounds. The introduced method resulted in the higher enhancement factors (5097-59376), lower detection limits (0.29-3.3pgmL(-1)), and higher sensitivity for the semi-volatile compounds compared with the conventional direct injection method. PMID- 26592577 TI - Gold nanoclusters-based chemiluminescence resonance energy transfer method for sensitive and label-free detection of trypsin. AB - A chemiluminescence resonance energy transfer (CRET) platform was developed for sensitive and label-free detection of protease by using trypsin as a model analyte. In this CRET platform, bis(2,4,6-trichlorophenyl)oxalate-hydrogen peroxide chemiluminescence (CL) reaction was utilized as an energy donor and bovine serum albumin (BSA)-stabilized gold nanoclusters (Au NCs) as an energy acceptor. The BSA-stabilized Au NCs triggered the CRET phenomenon by accepting the energy from TCPO-H2O2 CL reaction, thus producing intense CL. In the presence of trypsin, the protein template of BSA-stabilized Au NCs was digested, which frustrated the energy transfer efficiency between the CL donor and the BSA stabilized Au NCs, leading to a significant decrease in the CL signal. The decreased CL signal was proportional to the logarithm of trypsin concentration in the range of 0.01-50.0ug mL(-1). The detection limit for trypsin was 9ng mL(-)(1) and the relative standard deviations were lesser than 3% (n=11). This Au NCs based CRET platform was successfully applied to the determination of trypsin in human urine samples, demonstrating its potential application in clinical diagnosis. PMID- 26592578 TI - Evaluation of two passive samplers for the analysis of organophosphate esters in the ambient air. AB - Both polyurethane foam (PUF) and sorbent-impregnated PUF (SIP) passive air sampling (PAS) methods were deployed and compared separately for the analysis of organophosphate esters (OPEs) in outdoor atmospheric environment. During an continuous period of 84 days, parallel samples were also collected by a high volume active air sampler (HV-AAS) to assess the contamination levels and to calibrate uptake parameters of PAS. The total concentration of OPEs in both particulate and gaseous phases ranged from 1.50 to 5.64ng m(-3) in ambient air. Tris(2-chloroisopropyl) phosphate (TCPP) was the dominating analog, representing 78+/-9% of total OPE concentration. SIP-PAS showed longer linear-phase sampling period for TCPP, and accumulated more amount of the most volatile triethyl phosphate (TEP) and tributyl phosphate (TBP) homologues, while similar sorption performances of both PAS methods were found for most of the semi-volatile OPEs. Linear sampling rates in PUF-PAS and SIP-PAS disks were calculated for individual OPEs except for TEP and TBP, and the average uptake rates (3.3+/-1.1 and 3.5+/ 1.7m(3)d(-1), respectively) were close to the acknowledged value (4m(-3)d(-1)) for persistent organic pollutants. Besides, isotopic labeled D15-Triphenyl phosphate (TPhP) could be used as a viable depuration compound to calculate site specific sampling rates of OPEs, with a linear loss of up to ~60% at the end of deployment time. PMID- 26592579 TI - Feasibility of halogen determination in noncombustible inorganic matrices by ion chromatography after a novel volatilization method using microwave-induced combustion. AB - A microwave-induced combustion (MIC) system based on the volatilization process was applied for subsequent halogen determination from noncombustible inorganic matrices. Portland cement samples were selected to demonstrate the feasibility of the proposed method, allowing the subsequent determination of Cl and F by ion chromatography (IC). Samples were mixed with high-purity microcrystalline cellulose, wrapped with a polyethylene film and combusted in quartz closed vessels pressurized with oxygen (20bar). Water and NH4OH (10, 25 or 50m mol L( 1)) were evaluated for Cl and F absorption, but water was selected, using 5min of reflux after volatilization. Final solutions were also suitable for analysis by pontentiometry with ion-selective electrode (ISE) for both analytes, and no difference was found when comparing the results with IC. The accuracy of the proposed method for Cl was evaluated by analysis of certified reference materials (CRMs), and agreement with certified values ranged from 98% to 103%. Results were also compared to those using the procedure recommended by the American Society of Testing and Materials (ASTM) for the determination of total chlorides (C114-13), and no difference was found. Volatilization by MIC using a mixture of cement, cellulose and a biological CRM was carried out in order to evaluate the accuracy for F, and recovery was about 96%. The proposed method allowed suitable limits of detection for Cl and F by IC (99 and 18mg kg(-1), respectively) for routine analysis of cement. Using the proposed method, a relatively low standard deviation (<7%), high throughput (up to eight samples can be processed in less than 30min) and lower generation of laboratory effluents, when compared to the ASTM method, were obtained. Therefore, the method for volatilization of Cl and F by MIC and subsequent determination by IC can be proposed as a suitable alternative for cement analysis. PMID- 26592580 TI - A potential tool for diagnosis of male infertility: Plasma metabolomics based on GC-MS. AB - Male infertility has become an important public health problem worldwide. Nowadays the diagnosis of male infertility frequently depends on the results of semen quality or requires more invasive surgical intervention. Therefore, it is necessary to develop a novel approach for early diagnosis of male infertility. According to the presence or absence of normal sexual function, the male infertility is classified into two phenotypes, erectile dysfunction (ED) and semen abnormalities (SA). The aim of this study was to investigate the GC-MS plasma profiles of infertile male having erectile dysfunction (ED) and having semen abnormalities (SA) and discover the potential biomarkers. The plasma samples from healthy controls (HC) (n=61) and infertility patients with ED (n=26) or with SA (n=44) were analyzed by gas chromatography-mass spectrometry (GC-MS) for discrimination and screening potential biomarkers. The partial least squares discriminant analysis (PLS-DA) was performed on GC-MS dataset. The results showed that HC could be discriminated from infertile cases having SA (AUC=86.96%, sensitivity=78.69%, specificity=84.09%, accuracy=80.95%) and infertile cases having ED (AUC=94.33%, sensitivity=80.33%, specificity=100%, accuracy=87.36%). Some potential biomarkers were successfully discovered by two commonly used variable selection methods, variable importance on projection (VIP) and original coefficients of PLS-DA (beta). 1,5-Anhydro-sorbitol and alpha-hydroxyisovaleric acid were identified as the potential biomarkers for distinguishing HC from the male infertility patients. Meanwhile, lactate, glutamate and cholesterol were the found to be the important variables to distinguish between patients with erectile dysfunction from those with semen abnormalities. The plasma metabolomics may be developed as a novel approach for fast, noninvasive, and acceptable diagnosis and characterization of male infertility. PMID- 26592581 TI - Synthesis of nano-sized cyanide ion-imprinted polymer via non-covalent approach and its use for the fabrication of a CN(-)-selective carbon nanotube impregnated carbon paste electrode. AB - Nano-sized CN(-)-imprinted polymer was synthesized by the copolymerization of methyl methacrylic acid (MAA), vinyl pyridine (VP) and ethylene glycol dimethacrylate in the presence of cyanide ion. The obtained polymeric nanoparticles were incorporated with carbon paste electrode (CPE) to produce a CN(-)-selective electrode. Functional monomer kind had crucial influence on the efficiency of the sensor. The presence of both VP and MAA in the structure of the imprinted polymer improved the sensing characteristics of the electrode. Also, the mole ratio of MAA/VP, cross-liker kind, cross-linker amount, solvent kind and amount were found to be effective factors in the electrode behavior. Presence of little amount of multi-walled carbon nanotubes (MWCNTs) in the CPE improved the detection range and response time of the electrode at the expense of small decrease in Nernstian slope. The electrode, containing CN(-)-imprinted polymer and MWCNTs showed a dynamic linear range of 1*10(-6)-1*10(-1)mol L(-1), Nernstian slope of 46.3+/-(0.6) mV and detection limit of 7.5*10(-7)mol L(-1); whereas, the same electrode in the absence of MWCNTs led to linear range, Nernstian slope and detection limit of 1*10(-5)-1*10(-1)molL(-1), 55.3+/-(0.7) mV and 8*10(-6)mol L( 1), respectively. The utility of the electrodes was checked by determination of cyanide ion in some real samples. PMID- 26592582 TI - A novel and label-free biosensors for uracil-DNA glycosylase activity based on the electrochemical oxidation of guanine bases at the graphene modified electrode. AB - Uracil-DNA glycosylase (UDG) as an important base excision repair enzymes is widely distributed in organism, and it plays a crucial role in sustaining the genome integrity. Therefore, it is significant to carry out the analysis of UDG activity. In this present work, a novel and label-free electrochemical sensing platform for the sensitive detection of uracil DNA glycosylase (UDG) activity has been developed. Herein, the graphene modified glassy carbon (GC) electrode was prepared. And two complementary DNA strands were hybridized to form dsDNA (P1P2). In the presence of UDG, the uracil bases in P1P2 were specifically hydrolyzed, inducing the unwinding of the DNA duplex, and accompanied by the release of P1. Thus, the released P1 was adsorbed onto the graphene/GC electrode surface via pi pi stacking. By investigating the electrochemical behavior of P1 at the graphene/GC electrode, the electrochemical oxidation of guanine bases in P1 was obviously observed. Therefore, using the current responses of guanine base in P1 as a signal indicator, UDG activity can be simply determined with high sensitivity, and the detectable lowest concentration is 0.01U/mL. This present design does not need covalent attachment of redox indicator to DNA, preventing participation of redox labels in the background. Meanwhile, the proposed strategy for the assay of UDG activity also has a remarkable sensitivity due to the excellent properties of graphene, which could increase both the immobilization amount of released ssDNA and the conductivity of the sensing system. All these elucidate that this developed protocol may lay a potential foundation for the sensitive detection of UDG activity in clinical diagnosis. PMID- 26592583 TI - Reusable electrochemical sensor for bisphenol A based on ionic liquid functionalized conducting polymer platform. AB - The toxicity of bisphenol A (BPA) has attracted considerable attention, and the reported electrochemical sensors for BPA need further improvement in reusability due to serious surface fouling. In this study, a composite film is designed aiming to provide both an accurate and repeatable platform for BPA determination. The conducting poly(3,4-ethylenedioxythiophene) film (PEDOT) and ionic liquid 1 butyl-3-methylimidazolium bromide (BMIMBr) were modified onto screen-printed carbon electrodes (SPCE) by electropolymerization and drop/spin methods, respectively. The surface characteristics of the composite film were characterized by field emission scanning electron microscopy (FE-SEM), X-ray photoelectron spectroscopy (XPS) and surface water contact angle experiments. The composite film-modified electrodes exhibited a linear response to BPA in the range of 0.1-500uM in pH 7.0 phosphate buffer solution (PBS) under optimized flow injection amperometry. The method sensitivity and detection limit (S/N=3) were 0.2661MUA MUM(-1) (2.419MUA MUM(-1)cm(-2)) and 0.02uM, respectively. A relative standard deviation of 1.95% was obtained for 77 successive measurements of 10uM BPA, and the repeatability outperformed previously reported work. The proposed method was applied to detect BPA released from plastic water bottles using the standard addition method, and satisfactory recoveries were obtained. The electrochemical assay was validated by comparison with the chromatographic method, and the results showed good agreement between the two methods. PMID- 26592584 TI - Determining the composition of ammonia/water mixtures using short-wave near infrared spectroscopy. AB - This paper proposes a methodology based on short-wave near-infrared spectroscopy to determine the ammonia content of ammonia/water mixtures with ammonia mass fraction in the range 0.35-0.65. Establishing this methodology meant modeling the relationship between the pressure bar (15-25)bar, temperature (20-50) degrees C and composition of the ammonia-water in the mixture (0.35-0.65 in ammonia mass fraction) with absorbance at 1033nm. The experiments were designed to optimize experimental work. A 2(3) factorial design+3 center points was used to establish and analyze the significance of the variables in the absorbance using analysis of variance (ANOVA). A linear model for absorbance was obtained using the least squares method. The trueness of the results versus the values obtained was assessed using a reference method; density measurement was chosen for this study. The accuracy of the results in terms of root-mean-square deviation (RMSD) was 3.7%. The methodology proposed represents a fast alternative for the "in-situ" measurement of the ammonia composition of ammonia-water mixtures in absorption refrigeration systems. PMID- 26592587 TI - A new analytical protocol for the determination of 62 endocrine-disrupting compounds in indoor air. AB - The objective of this study was to develop and validate a new analytical protocol for simultaneous determination of 62 semi-volatile organic compounds in both phases of indoor air. Studied compounds belong to several families: polybrominated diphenyl ethers, polychlorinated biphenyls, hexachlorobenzene, pentachlorobenzene, phthalates, polyaromatic hydrocarbons, parabens, tetrabromobisphenol A, bisphenol A, hexabromocyclododecane, triclosan, alkylphenols, alkylphenol ethoxylates, synthetic musks (galaxolide and tonalide) and pesticides (lindane and cypermethrin). A medium volume sampling system was used to collect simultaneously these endocrine-disrupting compounds (EDCs) from the gaseous and particulate phases. An accelerated solvent extraction method was optimized to obtain all EDCs in a single extract by atmospheric phase. Their extraction from the sorbents and their analysis by liquid and gas chromatography mass spectrometry (LC/MS/MS, GC/MS and GC/MS/MS) was validated using spiked sorbents (recovery study and analytical uncertainty analysis by fully nested design). The developed protocol achieved low limits of quantification (<0.5ng m( 3)) and low uncertainty values (<5ng m(-3)) for all compounds. Once validated, the method was applied to indoor air samples from four locations (a house, an apartment, a day nursery and an office) and compared to literature to confirm its efficiency. All target EDCs were quantified in the samples and were primarily present in the gaseous phase. The major contaminants found in indoor air were, in descending order, phthalates, synthetic musks, alkylphenols and parabens. PMID- 26592590 TI - Development of a novel, fast, sensitive method for chromium speciation in wastewater based on an organic polymer as solid phase extraction material combined with HPLC-ICP-MS. AB - Speciation analysis of inorganic chromium in wastewater is of great significance for the monitoring of environmental pollution. In this work, N,N-bis(2 aminoethyl)ethane-1,2-diamine functionalized poly(chloromethyl styrene-co styrene) was synthesized, characterized and used as the adsorbent to preconcentrate chromium species in environmental waters by on line solid-phase extraction (SPE). The trace speciation analysis of Cr(III) and Cr(VI) in wastewater has been used by short-column high-performance liquid chromatography hyphenated to inductively coupled plasma spectrometry (HPLC-ICP-MS) after on-line SPE. Cr(III) and Cr(VI) have been adsorbed on the anion exchange column after transforming the cationic Cr(III) to an anionic [Cr(III)-EDTA](-) complex devoid of re-dox reagent, and then eluted rapidly (within seconds) with a very low concentration of tetrabutylammonium hydroxide (TBAH) solution. This method provides a reliable on-line preconcentration method and detection coupled technique. Under the optimized conditions, high enrichment factors have been obtained for Cr(VI) and [Cr(III)-EDTA](-) with 30mL sample solution up to 105 and 128, respectively. The low detection limits of 0.0068ng mL(-1) and 0.0041ng mL( 1), with the relative standard deviations (RSDs) of 4.3% and 3.6% were obtained for Cr(VI) and [Cr(III)-EDTA](-), respectively. The developed method was validated by analyzing Certified Reference Materials GSBZ50027-94, and the spike tests were also performed. At the same time, thanks to the merit of simple operation, rapid adsorption/desorption dynamics, high enrichment and low LODs, the established method was applied to analyze three wastewater samples from different discharge port. PMID- 26592588 TI - Biosynthesis of CdS nanoparticles: A fluorescent sensor for sulfate-reducing bacteria detection. AB - CdS nanoparticles were synthesized with an environmentally friendly method by taking advantage of the characteristic metabolic process of sulfate-reducing bacteria (SRB), and used as fluorescence labels for SRB detection. The presence of CdS nanoparticles was observed within and immediately surrounded bacterial cells, indicating CdS nanoparticles were synthesized both intracellularly and extracellularly. Moreover, fluorescent properties of microbial synthesized CdS nanoparticles were evaluated for SRB detection, and a linear relationship between fluorescence intensity and the logarithm of bacterial concentration was obtained in the range of from 1.0*10(2) to 1.0*10(7)cfu mL(-1). The proposed SRB detection method avoided the use of biological bio-recognition elements which are easy to lose their specific recognizing abilities, and the bacterial detection time was greatly shortened compared with the widely used MPN method which would take up to 15 days to accomplish the detection process. PMID- 26592585 TI - A novel aeration-assisted homogenous liquid-liquid microextration for determination of thorium and uranium in water and hair samples by inductively coupled plasma-mass spectroscopy. AB - A novel method based on aeration-assisted homogeneous liquid-liquid microextraction using high density solvent is presented, which is combined with inductively coupled plasma-mass spectroscopy in which simultaneous preconcentration and determination of thorium and uranium with arsenazo III as the chelating reagent is carried out. To achieve optimum conditions, several parameters such as pH, concentration of arsenazo III, extraction and homogenous solvent types and their volumes, salt concentration and extraction time were investigated. Under which, the calibration graphs were linear in the range of 0.5 600.0ng L(-1) for thorium and 0.3-550.0ng L(-1) for uranium. Good linearities were obtained for both analytes with R(2) values larger than 0.9990. The limits of detection (LOD, 3Sb/m, n=5) of this method were 0.12 and 0.09ng L(-1), and the enrichment factors were estimated to be 370 and 410 for thorium and uranium, respectively. The proposed method was applied to determine the thorium and uranium in human hair and different environmental water samples. Acceptable recoveries ranged from 99.4% to 100.7% with standard deviation of 0.05 to 0.17. PMID- 26592589 TI - A solid device based on doped hybrid composites for controlling the dosage of the biocide N-(3-aminopropyl)-N-dodecyl-1,3-propanediamine in industrial formulations. AB - A colorimetric composite device is proposed to determine the widely used biocide N-(3-aminopropyl)-N-dodecyl-1,3-propanediamine (ADP).This sensing device is based on a film of 1,2-Naphthoquinone-4-sulfonate (NQS) embedded into polydimethylsiloxane-tetraethylortosilicate-SiO2 nanoparticles composite (PDMS TEOS-SiO2NPs). Semiquantitative analysis can be performed by visual inspection. Digitalized image or diffuse reflectance (DR) measurements can be carried out for quantitative analysis. Satisfactory detection limit (0.018%, w/v) and relative standard deviations <12% were achieved. The proposed device has been applied for the determination of ADP in detergent industrial formulations with recovery values between 80% and 112%. The method has been successfully validated, showing its high potential to control and monitor this compound because the device is easy to prepare and use, robust, portable, stable over time and cost effective. This device allows a green, simple and rapid approach for the analysis of samples without pretreatment and does not require highly trained personnel. These advantages give the proposed kit good prospects for implementation in several industries. PMID- 26592586 TI - A novel nonenzymatic amperometric hydrogen peroxide sensor based on CuO@Cu2O nanowires embedded into poly(vinyl alcohol). AB - A new, very simple, rapid and inexpensive nonenzymatic amperometric sensor for hydrogen peroxide (H2O2) detection is proposed. It is based on the immobilization of cupric/cuprous oxide core shell nanowires (CuO@Cu2O-NWs) in a poly(vinyl alcohol) (PVA) matrix directly drop casted on a glassy carbon electrode surface to make a CuO@Cu2O core shell like NWs PVA embedded (CuO@Cu2O-NWs/PVA) sensor. CuO nanowires with mean diameters of 120-170nm and length in the range 2-5MUm were grown by a simple catalyst-free thermal oxidation process based on resistive heating of pure copper wires at ambient conditions. The oxidation process of the copper wire surface led to the formation of a three layered structure: a thick Cu2O bottom layer, a CuO thin intermediate layer and CuO nanowires. CuO nanowires were carefully scratched from Cu2O layer with a sharp knife, dispersed into ethanol and sonicated. Then, the NWs were embedded in PVA matrix. The morphological and spectroscopic characterization of synthesized CuO-NWs and CuO@Cu2O-NWs/PVA were performed by transmission electron microscopy (TEM), selected area diffraction pattern (SAD), scanning electron microscopy (SEM) and X ray photoelectron spectroscopy (XPS) analysis. Moreover a complete electrochemical characterization of these new CuO@Cu2O-NWs/PVA modified glassy carbon electrodes was performed by Cyclic Voltammetry (CV) and Cronoamperometry (CA) in phosphate buffer (pH=7; I=0.2) to investigate the sensing properties of this material against H2O2. The electrochemical performances of proposed sensors as high sensitivity, fast response, reproducibility and selectivity make them suitable for the quantitative determination of hydrogen peroxide substrate in batch analysis. PMID- 26592592 TI - Based on magnetic graphene oxide highly sensitive and selective imprinted sensor for determination of sunset yellow. AB - A new imprinted material based on beta-cyclodextrin/ionic liquid/gold nanoparticles functionalized magnetic graphene oxide has been successfully synthesized and modified to the glassy carbon electrode surface to constructed imprinted electrochemical sensor to detect sunset yellow. The sensitivity and electrochemical response of the electrode can be improved by nanomaterials. The surface morphology and crystal structure of the hybrid nanomaterial has been characterized by scanning electron microscopy, X-ray diffraction, Fourier transform infrared spectroscopy. The electrochemical behaviors of the hybrid nanomaterials based sensor were evaluated through cyclic voltammetry and electrochemical impedance spectroscopy. Under the optimized conditions, the proposed electrochemical sensor showed a fast rebinding dynamics, which was successfully applied to sunset yellow detection with a wide linear range from 5.0*10(-9) to 2.0*10(-6)mol L(-1) and a detection limit of 2.0*10(-9)mol L(-1). The electrochemical sensor has been successfully applied in the determination of SY in spiked water samples, mirinda drink and minute maid, and the recoveries for the standards added are 97-105%. PMID- 26592591 TI - Spectrophotometric total reducing sugars assay based on cupric reduction. AB - As the concentration of reducing sugars (RS) is controlled by European legislation for certain specific food and beverages, a simple and sensitive spectrophotometric method for the determination of RS in various food products is proposed. The method is based on the reduction of Cu(II) to Cu(I) with reducing sugars in alkaline medium in the presence of 2,9-dimethyl-1,10-phenanthroline (neocuproine: Nc), followed by the formation of a colored Cu(I)-Nc charge transfer complex. All simple sugars tested had the linear regression equations with almost equal slope values. The proposed method was successfully applied to fresh apple juice, commercial fruit juices, milk, honey and onion juice. Interference effect of phenolic compounds in plant samples was eliminated by a solid phase extraction (SPE) clean-up process. The method was proven to have higher sensitivity and precision than the widely used dinitrosalicylic acid (DNS) colorimetric method. PMID- 26592593 TI - Chemiluminescent aptasensor capable of rapidly quantifying Escherichia Coli O157:H7. AB - Cost-effective and easy-to-use biosensor was developed for the rapid quantification and monitoring of Escherichia (E.) Coli O157:H7 in sample using E. Coli O157:H7 aptamer, graphene oxide (GO)/iron nanocomposites, and guanine chemiluminescence detection. E. Coli O157:H7 aptamer-conjugated 6 carboxyfluorescein (6-FAM) with excellent specificity captured E. Coli O157:H7 in a sample when the mixture was incubated for 1h at 37 degrees C. Free E. Coli O157:H7 aptamers remaining in sample after the incubation were removed with GO/iron nanocomposites based on the principle of pi-pi stacking interaction between free aptamer and GO/iron nanocomposites. Then, E. Coli O157:H7 bound with aptamer-conjugated 6-FAM in sample emitted strong light when guanine chemiluminescent reagents (e.g., 3,4,5-trimethoxylphenylglyoxal hydrate, Tetra-n propylammonium hydroxide) were added in the sample. The strength of light emitted in guanine chemiluminescence reaction was proportionally enhanced with the increase of E. Coli O157:H7 concentration. The limit of detection (LOD) of biosensor capable of quantifying E. Coli O157:H7 with good accuracy, precision, and reproducibility was as low as 4.5*10(3)cfu/ml. We expect that the rapid analytical system can be applied in the field of food safety as well as public health. PMID- 26592595 TI - A novel near-infrared fluorescent platform with good photostability and the application for a reaction-based Cu(2+) probe in living cells. AB - Most of the near-infrared (NIR) fluorescent copper ion probes are coordination based, and the fluorescence enhancement is between 10 and 20 folds. Herein, a novel NIR fluorescent dye named CSCN with excellent photostability and a reaction based Cu(2+) NIR probe named CSCN-Cu were reported. CSCN exhibited good photostability toward photo irradiation. CSCN-Cu showed lower background fluorescent interference and over 40-fold fluorescence enhancement in NIR region, it also exhibited good selectivity toward Cu(2+) in Hepes solution. Biotic experiments demonstrated that CSCN-Cu possessed low toxicity and successfully imaged Cu(2+) in living cells under the conditions performed. PMID- 26592594 TI - A novel graphene nanodots inlaid porous gold electrode for electrochemically controlled drug release. AB - A uniform graphene nanodots inlaid porous gold electrode was prepared via ion beam sputtering deposition (IBSD) and mild corrosion chemistry. HRTEM, SEM, AFM and XPS analyses revealed the successful fabrication of graphene nanodots inlaid porous gold electrode. The as-prepared porous electrode was used as pi-orbital rich drug loading platform to fabricate an electrochemically controlled drug release system with high performance. pi-orbital-rich drugs with amino mioety, like doxorubicin (DOX) and tetracycline (TC), were loaded into the graphene nanodots inlaid porous gold electrode via non-covalent pi-pi stacking interaction. The amino groups in DOX and TC can be easily protonated at acidic medium to become positively-charged NH3(+), which allow these drug molecules to be desorbed from the porous electrode surface via electrostatic repulsion when positive potential is applied at the electrode. The drug loading and release experiment indicated that this graphene nanodots inlaid porous gold electrode can be used to conveniently and efficiently control the drug release electrochemically. Not only did our work provide a benign method to electrochemically controlled drug release via electrostatic repulsion process, it also enlighten the promising practical applications of micro electrode as a drug carrier for precisely and efficiently controlled drug release via embedding in the body. PMID- 26592596 TI - Polymer monolith microextraction using poly(butyl methacrylate-co-1,6-hexanediol ethoxylate diacrylate) monolithic sorbent for determination of phenylurea herbicides in water samples. AB - In this study, recently developed 1,6-hexanediol ethoxylate diacrylate (HEDA) based polymeric monoliths were utilized as sorbents for efficient extraction of phenylurea herbicides (PUHs) from water samples. The HEDA-based monolithic sorbents were prepared in a fused silica capillary (0.7mm i.d., 4.5-cm long) for polymer monolith microextraction (PMME). The experimental parameters of PMME microextraction including sample loading speed, pH of sample solution, composition of elution solvent, and addition of salt were optimized to efficiently extract PUHs from environmental water samples. The extracted PUHs were determined using ultra-high performance liquid chromatography (UHPLC) with UV-photodiode array detection. The extraction recoveries for PUHs-spiked water samples were 91.1-108.1% with relative standard deviations lower than 5%. The linearity range was 0.025-25ngmL(-1) for each PUH and the detection limits of PUHs were estimated at 0.006-0.019ng mL(-1). In addition, good intra-day/inter day precision (0.1-8.7%/0.2-8.9%) and accuracy (92.0-108.0%/96.5-105.2%) of the proposed method were obtained. The extraction capacity of the monolith-filled capillary was also determined to be approximately 1MUg. Moreover, each monolith filled capillary could be reused up to 8 times without carry-over. According to the European Union regulations, the allowed permissible limit of any single herbicide in drinking water is 0.1ng mL(-1). This permissible level fell in the linear range examined in this study. In addition, the proposed method provided detection limits lower than the allowed permissible level, which demonstrated the feasibility of utilizing the HEDA-based monolithic sorbent to perform PMME for determining contaminants, such as PUHs, in environmental application. PMID- 26592597 TI - Simple synthesis of carboxyl-functionalized upconversion nanoparticles for biosensing and bioimaging applications. AB - We report a simple one-step hydrothermal method for the synthesis of hydrophilic luminescent upconversion nanoparticles (UCNPs) using malonic acid as the stabilizer and functional agent. Using this method, two UCNPs with different colors of upconversion luminescence were synthesized. The surface of the as prepared UCNPs was capped with carboxyl groups, which not only resulted in the UCNPs having good dispersity in water, but also allowed further conjugation with other functional molecules, thus indicating the potential applications in biosensing and bioimaging. To demonstrate this, amino-labeled single-stranded DNA (ssDNA) was conjugated on the surface of the UCNPs. Based on the different absorption and luminescence quenching abilities of graphene oxide (GO) to ssDNA modified UCNPs before and after exonuclease I (Exo I)-triggered hydrolysis of ssDNA, a detection platform was developed for the detection of Exo I activity with a detection limit of 0.02U mL(-1). The prepared hydrophilic UCNPs were also used successfully for in vivo upconversion luminescence imaging of nude mice. PMID- 26592598 TI - Classification of 7 monofloral honey varieties by PTR-ToF-MS direct headspace analysis and chemometrics. AB - Honey, in particular monofloral varieties, is a valuable commodity. Here, we present proton transfer reaction-time of flight-mass spectrometry, PTR-ToF-MS, coupled to chemometrics as a successful tool in the classification of monofloral honeys, which should serve in fraud protection against mispresentation of the floral origin of honey. We analyzed 7 different honey varieties from citrus, chestnut, sunflower, honeydew, robinia, rhododendron and linden tree, in total 70 different honey samples and a total of 206 measurements. Only subtle differences in the profiles of the volatile organic compounds (VOCs) in the headspace of the different honeys could be found. Nevertheless, it was possible to successfully apply 6 different classification methods with a total correct assignment of 81 99% in the internal validation sets. The most successful methods were stepwise linear discriminant analysis (LDA) and probabilistic neural network (PNN), giving total correct assignments in the external validation sets of 100 and 90%, respectively. Clearly, PTR-ToF-MS/chemometrics is a powerful tool in honey classification. PMID- 26592599 TI - A label-free multi-functionalized graphene oxide based electrochemiluminscence immunosensor for ultrasensitive and rapid detection of Vibrio parahaemolyticus in seawater and seafood. AB - A label-free electrochemiluminescence (ECL) immunosensor for ultrasensitive and rapid detection of marine pathogenic bacterium Vibrio parahaemolyticus (VP) in seawater and seafood was developed based on multi-functionalized graphene oxide, which was prepared with N-(4-aminobutyl)-N-ethylisoluminol (ABEI) and VP antibody (anti-VP) simultaneously immobilized on the surface of magnetic graphene oxide (nanoFe3O4@GO). ABEI and anti-VP acted as the electrochemiluminophore and the capture device for VP respectively. Good conductivity and two-dimensional structure of the nanoFe3O4@GO enabled all the ABEI, immobilized on GO, electrochemically active and thus improved the detection sensitivity. Under optimal conditions, the ECL intensity decreased with increasing logarithmic concentrations of VP in the range of 10-10(8)CFU/mL, with a detection limit of 5CFU/mL for seawater and 5CFU/g for seafood. This ECL immunosensor showed high specificity, stability and reproducibility for the detection of VP. In addition, the ECL immunosensor has been successfully used to determine the concentration of VP in seawater and seafood rapidly, with a recovery of 94.4-112.0% and RSD 4.1 11.7%. Therefore, the developed immunosensor shows great prospect for practical application. PMID- 26592600 TI - Digital movie-based on automatic titrations. AB - This study proposes the use of digital movies (DMs) in a flow-batch analyzer (FBA) to perform automatic, fast and accurate titrations. The term used for this process is "Digital movie-based on automatic titrations" (DMB-AT). A webcam records the DM during the addition of the titrant to the mixing chamber (MC). While the DM is recorded, it is decompiled into frames ordered sequentially at a constant rate of 26 frames per second (FPS). The first frame is used as a reference to define the region of interest (ROI) of 28*13pixels and the R, G and B values, which are used to calculate the Hue (H) values for each frame. The Pearson's correlation coefficient (r) is calculated between the H values of the initial frame and each subsequent frame. The titration curves are plotted in real time using the r values and the opening time of the titrant valve. The end point is estimated by the second derivative method. A software written in C language manages all analytical steps and data treatment in real time. The feasibility of the method was attested by application in acid/base test samples and edible oils. Results were compared with classical titration and did not present statistically significant differences when the paired t-test at the 95% confidence level was applied. The proposed method is able to process about 117-128 samples per hour for the test and edible oil samples, respectively, and its precision was confirmed by overall relative standard deviation (RSD) values, always less than 1.0%. PMID- 26592601 TI - Potentiometric RuO2-Ta2O5 pH sensors fabricated using thick film and LTCC technologies. AB - The paper reports on the preparation, properties and application of potentiometric pH sensors with thick film RuO2-Ta2O5 sensing electrode and Ag/AgCl/KCl reference electrode screen printed on an alumina substrate. Furthermore, it presents fabrication procedure and characterization of a new miniaturized pH sensor on LTCC (low temperature cofired ceramics) substrate, destined for wireless monitoring. The crystal structure, phase and elemental composition, and microstructure of the films were investigated by X-ray diffractometry, Raman spectroscopy, scanning electron microscopy and energy dispersive spectroscopy. Potentiometric characterization was performed in a wide pH range of 2-12 for different storage conditions and pH loops. The advantages of the proposed thick film pH sensors are: (a) low cost and easy fabrication, (b) excellent sensitivity close to the Nernstian response (56mV/pH) in the wide pH range, (c) fast response, (d) long lifetime, (e) good reproducibility, (f) low hysteresis and drift effects, and (g) low cross-sensitivity towards Li(+), Na(+) and K(+) as interfering ions. The applicability of the sensors for pH measurement of river, tap and distilled water, and some drinks was also tested. PMID- 26592602 TI - Simultaneous determination of cobalt and nickel in vitamin B12 samples using high resolution continuum source atomic absorption spectrometry. AB - Nickel and cobalt were simultaneously assayed in vitamin B12 formulations by using atomic spectrometry. The proposed method is based on a compromise between the proximity of specific Ni and Co spectral lines and the relative abundances of the analytes in the samples. The analytes were found in concentrations ranging from 9.48 to 26.20ug L(-1) (Ni) and from 156.90 to 279.25mg L(-1) (Co) in the commercial samples of vitamin B12. The limits of detection and quantification were 1.21 and 3.64mg L(-1) for Co and 0.39 and 1.19ug L(-1) for Ni. Sample cleanup was not necessary for the determinations, and the interferences were discussed. PMID- 26592603 TI - Determination of ultraviolet filters in bathing waters by stir bar sorptive dispersive microextraction coupled to thermal desorption-gas chromatography-mass spectrometry. AB - In this work, a new approach that combines the advantages of stir bar sorptive extraction (SBSE) and dispersive solid phase extraction (DSPE), i.e. stir bar sorptive-dispersive microextraction (SBSDuE), is employed as enrichment and clean up technique for the sensitive determination of eight lipophilic UV filters in water samples. The extraction is accomplished using a neodymium stir bar magnetically coated with oleic acid-coated cobalt ferrite magnetic nanoparticles (MNPs) as sorbent material, which are detached and dispersed into the solution at high stirring rate. When stirring is stopped, MNPs are magnetically retrieved onto the stir bar, which is subjected to thermal desorption (TD) to release the analytes into the gas chromatography-mass spectrometry (GC-MS) system. The SBSDuE approach allows for lower extraction time than SBSE and easier post-extraction treatment than DSPE, while TD allows for an effective and solvent-free injection of the entire quantity of desorbed analytes into GC-MS, and thus achieving a high sensitivity. The main parameters involved in TD, as well as the extraction time, were evaluated. Under the optimized conditions, the method was successfully validated showing good linearity, limits of detection and quantification in the low ngL(-1) range and good intra- and inter-day repeatability (RSD<12%). This accurate and sensitive analytical method was applied to the determination of trace amounts of UV filters in three bathing water samples (river, sea and swimming pool) with satisfactory relative recovery values (80-116%). PMID- 26592604 TI - Fluorescence of the Flavin group in choline oxidase. Insights and analytical applications for the determination of choline and betaine aldehyde. AB - Choline oxidase (ChOx) is a flavoenzyme catalysing the oxidation of choline (Ch) to betaine aldehyde (BA) and glycine betaine (GB). In this paper a fundamental study of the intrinsic fluorescence properties of ChOx due to Flavin Adenine Dinucleotide (FAD) is presented and some analytical applications are studied in detail. Firstly, an unusual alteration in the excitation spectra, in comparison with the absorption spectra, has been observed as a function of the pH. This is ascribed to a change of polarity in the excited state. Secondly, the evolution of the fluorescence spectra during the reaction seems to indicate that the reaction takes place in two consecutive, but partially overlapped, steps and each of them follows a different mechanism. Thirdly, the chemical system can be used to determine the Ch concentration in the range from 5*10(-6)M to 5*10(-5)M (univariate and multivariate calibration) in the presence of BA as interference, and the joint Ch+BA concentration in the range 5*10(-6)-5*10(-4)M (multivariate calibration) with mean errors under 10%; a semiquantitative determination of the BA concentration can be deduced by difference. Finally, Ch has been successfully determined in an infant milk sample. PMID- 26592605 TI - Gradient liquid chromatographic retention time prediction for suspect screening applications: A critical assessment of a generalised artificial neural network based approach across 10 multi-residue reversed-phase analytical methods. AB - For the first time, the performance of a generalised artificial neural network (ANN) approach for the prediction of 2492 chromatographic retention times (tR) is presented for a total of 1117 chemically diverse compounds present in a range of complex matrices and across 10 gradient reversed-phase liquid chromatography (high resolution) mass spectrometry methods. Probabilistic, generalised regression, radial basis function as well as 2- and 3-layer multilayer perceptron type neural networks were investigated to determine the most robust and accurate model for this purpose. Multi-layer perceptrons most frequently yielded the best correlations in 8 out of 10 methods. Averaged correlations of predicted versus measured tR across all methods were R(2)=0.918, 0.924 and 0.898 for the training, verification and test sets respectively. Predictions of blind test compounds (n=8 84 cases) resulted in an average absolute accuracy of 1.02+/-0.54min for all methods. Within this variation, absolute accuracy was observed to marginally improve for shorter runtimes, but was found to be relatively consistent with respect to analyte retention ranges (~5%). Finally, optimised and replicated network dependency on molecular descriptor data is presented and critically discussed across all methods. Overall, ANNs were considered especially suitable for suspects screening applications and could potentially be utilised in bracketed-type analyses in combination with high resolution mass spectrometry. PMID- 26592606 TI - Determination of silicon and aluminum in silicon carbide nanocrystals by high resolution continuum source graphite furnace atomic absorption spectrometry. AB - The determination of Al contaminant and the main component Si in silicon carbide (SiC) nanocrystals with the size-distribution of 1-8nm dispersed in an aqueous solution was developed using high-resolution continuum source graphite furnace atomic absorption spectrometry (HR-CS-GFAAS). The vaporization/atomization processes were investigated in a transversally heated graphite atomizer by evaporating solution samples of Al and Si preserved in various media (HCl, HNO3). For Si, the best results were obtained by applying a mixture of 5ug Pd plus 5ug Mg, whereas for Al, 10ug Mg (each as nitrate solution) was dispensed with the samples, but the results obtained without modifier were found to be better. This way a maximum pyrolysis temperature of 1200 degrees C for Si and 1300 degrees C for Al could be used, and the optimum (compromise) atomization temperature was 2400 degrees C for both analytes. The Si and Al contents of different sized SiC nanocrystals, dispersed in aqueous solutions, were determined against aqueous (external) calibration standards. The correlation coefficients (R values) of the calibrations were found to be 0.9963 for Si and 0.9991 for Al. The upper limit of the linear calibration range was 2mg/l Si and 0.25mg/l Al. The limit of detection was 3ug/l for Si and 0.5ug/l for Al. The characteristic mass (m0) was calculated to be 389pg Si and 6.4pg Al. The Si and Al content in the solution samples were found to be in the range of 1.0-1.7mg/l and 0.1-0.25mg/l, respectively. PMID- 26592607 TI - Cleavable DNA-protein hybrid molecular beacon: A novel efficient signal translator for sensitive fluorescence anisotropy bioassay. AB - Due to its unique features such as high sensitivity, homogeneous format, and independence on fluorescent intensity, fluorescence anisotropy (FA) assay has become a hotspot of study in oligonucleotide-based bioassays. However, until now most FA probes require carefully customized structure designs, and thus are neither generalizable for different sensing systems nor effective to obtain sufficient signal response. To address this issue, a cleavable DNA-protein hybrid molecular beacon was successfully engineered for signal amplified FA bioassay, via combining the unique stable structure of molecular beacon and the large molecular mass of streptavidin. Compared with single DNA strand probe or conventional molecular beacon, the DNA-protein hybrid molecular beacon exhibited a much higher FA value, which was potential to obtain high signal-background ratio in sensing process. As proof-of-principle, this novel DNA-protein hybrid molecular beacon was further applied for FA bioassay using DNAzyme-Pb(2+) as a model sensing system. This FA assay approach could selectively detect as low as 0.5nM Pb(2+) in buffer solution, and also be successful for real samples analysis with good recovery values. Compatible with most of oligonucleotide probes' designs and enzyme-based signal amplification strategies, the molecular beacon can serve as a novel signal translator to expand the application prospect of FA technology in various bioassays. PMID- 26592608 TI - Green analytical chemistry introduction to chloropropanols determination at no economic and analytical performance costs? AB - In this study we perform ranking of analytical procedures for 3-monochloropropane 1,2-diol determination in soy sauces by PROMETHEE method. Multicriteria decision analysis was performed for three different scenarios - metrological, economic and environmental, by application of different weights to decision making criteria. All three scenarios indicate capillary electrophoresis-based procedure as the most preferable. Apart from that the details of ranking results differ for these three scenarios. The second run of rankings was done for scenarios that include metrological, economic and environmental criteria only, neglecting others. These results show that green analytical chemistry-based selection correlates with economic, while there is no correlation with metrological ones. This is an implication that green analytical chemistry can be brought into laboratories without analytical performance costs and it is even supported by economic reasons. PMID- 26592609 TI - Exploring methods for compositional and particle size analysis of noble metal nanoparticles in Daphnia magna. AB - The identification and quantification of the bioaccumulation of noble metal engineered nanoparticles (ENPs) by aquatic organisms is of great relevance to understand the exposure and potential toxicity mechanisms of nanoscale materials. Four analytical scenarios were investigated in relation to various sized and composed noble metal (gold (Au), platinum (Pt) and silver (Ag)) ENPs during acute, short-term exposure of Daphnia (D.) magna. Next to the total elemental quantification of absorbed ENPs by D. magna, especially information on the size and particle distribution of ENPs in D. magna is of relevance. Dissolution of the exposed biological material prior to measurement by asymmetric flow field flow fractionation coupled to inductively coupled plasma mass spectrometry (AF4-ICPMS) is challenging because the ENPs must stay stable regarding to particle size and composition. Next to dissolution of exposed D. magna by tetra methyl ammonium hydroxide (TMAH), a new enzymatic dissolution approach was explored by using trypsin. The presence of various sized and composed ENPs has been confirmed by AF4-ICPMS but the chosen dissolution medium was crucial for the results. TMAH and trypsin led to comparable results for medium-sized (50nm) noble metals ENPs in exposed D. magna. But it was also shown that the dissolution of biological materials with smaller (<5nm) ENPs led to different results in particle size and elemental concentration depending on the selected dissolution medium. A significant uptake of Au and Pt ENPs by D. magna or adsorption to particles occurred because only 1-5% of the exposed ENPs remained in the exposure medium. PMID- 26592610 TI - Switch-on fluorescence scheme for antibiotics based on a magnetic composite probe with aptamer and hemin/G-quadruplex coimmobilized nano-Pt-luminol as signal tracer. AB - A selective and facile fluorescence "switch-on" scheme is developed to detect antibiotics residues in food, using chloramphenicol (CAP) as model, based on a novel magnetic aptamer probe (aptamer-Pt-luminol nanocomposite labeled with hemin/G-quadruplex). Firstly, the composite probe is prepared through the immuno reactions between the capture beads (anti-dsDNA antibody labeled on magnetic Dynabeads) and the nanotracer (nano-Pt-luminol labeled with double-strand aptamer, as ds-Apt, and hemin/G-quadruplex). When the composite probe is mixed with CAP, the aptamer preferentially reacted with CAP to decompose the double strand aptamer to ssDNA, which cannot be recognized by the anti-dsDNA antibody on the capture probes. Thus, after magnetic separation, the nanotracer can be released into the supernatant. Because the hemin/G-quadruplex and PtNPs in nanotracer can catalyze luminol-H2O2 system to emit fluorescence. Thus a dual amplified "switch-on" signal appeared, of which intensity is proportional to the concentration of CAP between 0.001 and 100ng mL(-1) with detection limit of 0.0005ng mL(-1) (S/N=3). Besides, our method has good selectivity and was employed for CAP detection in real milk samples. The results agree well with those from conventional gas chromatograph-mass spectrometer (GC-MS). The switch on signal is produced by one-step substitution reaction between aptamer in nanotracer and target. When the analyte is changed, the probe can be refabricated only by changing the corresponding aptamer. Thus, all features above prove our strategy to be a facile, feasible and selective method in antibiotics screening for food safety. PMID- 26592611 TI - A label-free DNAzyme fluorescence biosensor for amplified detection of Pb(2+) based on cleavage-induced G-quadruplex formation. AB - DNAzyme-based catalytic beacons have been widely studied for both in vivo and in vitro molecular detection. However, only a few label-free catalytic beacons with excellent analytical performance have been reported so far. In this work, by combining a catalytic DNAzyme for amplified sensing through enzymatic turnover with cleavage-induced G-quadruplex formation, a label-free DNAzyme biosensor was developed for amplified "turn-on" fluorescence detection of Pb(2+) with a detection limit of 3nM. The method is very competitive compared to many other labeled or label-free methods with or without signal amplification. Due to the inherent specificity of the GR-5 DNAzyme, the method also exhibits excellent selectivity. This biosensor successfully detected Pb(2+) in river water samples with high sensitivity and selectivity. Such a method might provide a universal DNAzyme-based sensing platform for sensitive detection of various targets both in environmental and biomedical fields. PMID- 26592612 TI - 3D-front-face fluorescence spectroscopy and independent components analysis: A new way to monitor bread dough development. AB - Following bread dough development can be a hard task as no reliable method exists to give the optimal mixing time. Dough development is linked to the evolution of gluten proteins, carbohydrates and lipids which can result in modifications in the spectral properties of the various fluorophores naturally present in the system. In this paper, we propose to use 3-D-front-face-fluorescence (3D-FFF) spectroscopy in the 250-550nm domain to follow the dough development as influenced by formulation (addition or not of glucose, glucose oxidase and ferulic acid in the dough recipe) and mixing time (2, 4, 6 and 8min). In all the 32 dough samples as well as in flour, three regions of maximum fluorescence intensities have been observed at 320nm after excitation at 295nm (Region 1), at 420nm after excitation at 360nm (Region 2) and 450nm after excitation at 390nm (Region 3). The principal components analysis (PCA) of the evolution of these maxima shows that the formulations with and without ferulic acid are clearly separated since the presence of ferulic acid induces a decrease of fluorescence in Region 1 and an increase in Regions 2 and 3. In addition, a kinetic effect of the mixing time can be observed (decrease of fluorescence in the Regions 1 and 2) mainly in the absence of ferulic acid. The analysis of variance (ANOVA) on these maximum values statistically confirms these observations. Independent components analysis (ICA) is also applied to the complete 3-D-FFF spectra in order to extract interpretable signals from spectral data which reflect the complex contribution of several fluorophores as influenced by their environment. In all cases, 3 signals can be clearly separated matching the 3 regions of maximal fluorescence. The signals corresponding to regions 1 and 2 can be ascribed to proteins and ferulic acid respectively, whereas the fluorophores associated with the 3rd signal (corresponding to region 3) remain unidentified. Good correlations are obtained between the IC score values of the 3 signals and the fluorescence intensities in Region 1, Region 2 and Region 3. Ferulic acid addition increases fluorescence in Region 2 and decreases fluorescence in Region 1, probably via a reabsorption of the protein fluorescence by ferulic acid. These phenomena are less pronounced when glucose oxidase is present. The enzymatic oxidation of ferulic acid by the glucose oxidase-peroxidase association could explain some of these effects. PMID- 26592613 TI - Biosensing of glucose in flow injection analysis system based on glucose oxidase quantum dot modified pencil graphite electrode. AB - A novel amperometric glucose biosensor was proposed in flow injection analysis (FIA) system using glucose oxidase (GOD) and Quantum dot (ZnS-CdS) modified Pencil Graphite Electrode (PGE). After ZnS-CdS film was electrochemically deposited onto PGE surface, GOD was immobilized on the surface of ZnS-CdS/PGE through crosslinking with chitosan (CT). A pair of well-defined reversible redox peak of GOD was observed at GOD/CT/ZnS-CdS/PGE based on enzyme electrode by direct electron transfer between the protein and electrode. Further, obtained GOD/CT/ZnS-CdS/PGE offers a disposable, low cost, selective and sensitive electrochemical biosensing of glucose in FIA system based on the decrease of the electrocatalytic response of the reduced form of GOD to dissolved oxygen. Under optimum conditions (flow rate, 1.3mL min(-1); transmission tubing length, 10cm; injection volume, 100MUL; and constant applied potential, -500mV vs. Ag/AgCl), the proposed method displayed a linear response to glucose in the range of 0.01 1.0mM with detection limit of 3.0uM. The results obtained from this study would provide the basis for further development of the biosensing using PGE based FIA systems. PMID- 26592614 TI - Fast low-pressurized microwave-assisted extraction of benzotriazole, benzothiazole and benezenesulfonamide compounds from soil samples. AB - Benzotriazoles (BTRs), benzothiazoles (BTs) and benzenesulfonamides (BSAs), compounds largely used in industrial and household applications, are ubiquitous emerging contaminants. In this work a novel, straightforward procedure for the simultaneous determination of two BTRs (1H-benzotriazole, 5-methyl-1H benzotriazole), three BTs (benzothiazole, 2-hydroxybenzothiazole, 2 methylthiobenzothiazole) and two BSAs (benzenesulfonamide, toluenesulfonamide) in soil has been developed. The target analytes were extracted from soil by a single low-pressurized microwave-assisted extraction (MAE) cycle (120 degrees C, 10min) and quantified by high-performance liquid chromatography with UV detection. For all the seven analytes, quantitative extraction yields (72-119%, n=4) were observed from recovery tests on soil samples (1g) spiked with 5, 10 and 50mg kg( 1), using 4mL water-methanol (85:15) as extracting solution. For the lower concentrations levels (100, 250 and 500MUg kg(-1)), the analytes were extracted from soil samples (2-3g) using 6mL methanol, and the extract was pre-concentrated by evaporation before analysis; recoveries in the range 70-117% were obtained (n=4). Suitable intra-day and inter-day precision were observed, with values of relative standard deviation generally below 6% and 11% (n=4), respectively. Linearity was evaluated in the concentration range 0.5-10mg L(-1) by matrix matched standards, obtaining r(2)>0.9996. The experimental method quantification limit (MQL) was 100MUg kg(-1). The entire procedure has been successfully applied to the analysis of real impacted soil samples. PMID- 26592616 TI - Monitoring of nitrite, nitrate, chloride and sulfate in environmental samples using electrophoresis microchips coupled with contactless conductivity detection. AB - This report describes the development of an analytical methodology on microchip electrophoresis (ME) devices coupled with capacitively coupled contactless conductivity detection (C(4)D) to monitor inorganic anions in environmental samples. The buffer composition as well as detection operating parameters were optimized to achieve the best separation selectivity and detector sensitivity, respectively. Electrophoretic separations of Cl(-), NO3(-), SO4(2-) and NO2(-) were successfully performed within 60s using a running buffer composed of 30mmol L(-1) latic acid and 15mmol L(-1)l-histidine (His). The best detectability levels were found applying a sinusoidal wave with 1100-kHz-frequency and 60-Vpp amplitude. Quantitative analyzes of inorganic anions were carried out in the presence of Cr2O7(2-) ion as internal standard (IS), which ensured great repeatability in terms of migration times (<1%) and peak areas (6.2-7.6%) for thirty consecutive injections. The analytical performance revealed a linear behavior for concentration ranges between 0-120MUmol L(-1) (Cl(-), NO2(-) and NO3(-)) and 0-60MUmol L(-1) (SO4(2-)) and limits of detection (LODs) varying from 2.0 to 4.9MUmol L(-1). The concentration levels of anionic species were determined in aquarium, river and biofertilizer samples with recovery values between 91% and 105%. The nitrification steps associated with conversion of ammonium to nitrite followed by the conversion of nitrite to nitrate were successfully monitored in a simulated environment without fishes during a period of twelve weeks. Lastly, the monitoring of anionic species was carried out during eight weeks in an aquarium environment containing ten fishes from Danio rerio (Ciprynidae). The recorded data revealed the absence of nitrite and a gradual increase on the ammonium and nitrate concentration levels during eight weeks, thus suggesting the direct conversion of ammonium to nitrate. Based on the data herein reported, the proposed analytical methodology can be used for routine environmental analysis. PMID- 26592615 TI - Electrochemical immunosensor for ethinylestradiol using diazonium salt grafting onto silver nanoparticles-silica-graphene oxide hybrids. AB - This work describes the preparation of an electrochemical immunosensor for ethinylestradiol (EE2) based on grafting of diazonium salt of 4-aminobenzoic acid onto a glassy carbon electrode modified with silver nanoparticles/SiO2/graphene oxide hybrid followed by covalent binding of anti-ethinylestradiol (anti-EE2) to activated carboxyl groups. A competitive immunoassay was developed for the determination of the hormone using peroxidase-labeled ethinylestradiol (HRP-EE2) and measurement of the amperometric response at -200mV in the presence of hydroquinone (HQ) as redox mediator. The calibration curve for EE2 exhibited a linear range between 0.1 and 50ng/mL (r(2)=0.996), with a detection limit of 65pg/mL. Interference studies with other hormones related with EE2 revealed the practical specificity of the developed method for the analyte. A good reproducibility, with RSD=4.5% (n=10) was also observed. The operating stability of a single bioelectrode modified with anti-EE2 was maintained at least for 15 days when it was stored at 4 degrees C under humid conditions between measurements. The developed immunosensor was applied to the analysis of spiked urine with good results. PMID- 26592617 TI - Chelating resin immobilizing carboxymethylated polyethyleneimine for selective solid-phase extraction of trace elements: Effect of the molecular weight of polyethyleneimine and its carboxymethylation rate. AB - The effect of the molecular weight of polyethyleneimine (PEI), defined as a compound having two or more ethyleneamine units, and of its carboxymethylation rate (CM/N), represented by the ratio of ion-exchange capacity to the amount of N on the resin, on the selective solid-phase extraction ability of the chelating resin immobilizing carboxymethylated (CM) PEI was investigated. The chelating resins (24 types) were prepared by immobilization of diethylenetriamine, triethylenetetramine, tetraethylenepentamine, pentaethylenehexamine, PEI300 (MW=ca. 300), and PEI600 (MW=ca. 600) on methacrylate resins, followed by carboxymethylation with various amounts of sodium monochloroacetate. When resins with approximately the same CM/N ratio (0.242-0.271) were used, the recovery of Cd, Co, Cu, Fe, Ni, Pb, Ti, Zn, and alkaline earth elements increased with increasing the molecular weight of PEIs under acidic and weakly acidic conditions; however, the extraction behavior of Mo and V was only slightly affected. This was probably due to the increase in N content of the resin, resulting in an increase in carboxylic acid groups; the difference in the molecular weight of PEIs immobilized on the resin exerts an insignificant influence on the selective extraction ability. The CM/N ratio considerably affected the extraction behavior for various elements. Under acidic and neutral conditions, the recovery of Cd, Co, Cu, Fe, Ni, Pb, Ti, and Zn increased with increasing CM/N values. However, under these conditions, the recovery of alkaline earth elements was considerably low when a resin with low CM/N ratio was used. This is presumably attributed to the different stability constants of the complexes of these elements with aminocarboxylic acids and amines, and to the electrostatic repulsion between the elements and the protonated amino groups in the CM-PEI. The recovery of Mo and V decreased or varied with increasing CM/N values, suggesting that the extraction of these elements occurred mainly by the anion-exchange reaction. For the separation and preconcentration of trace elements in samples containing large amounts of alkali and alkaline earth elements, the CM-PEI600 resin with CM/N=0.131 (Cu(II) extraction capacity, 0.37mmol g(-)(1)) was found to be the most suitable because it scarcely extracts alkali and alkaline earth elements under acidic and neutral conditions. This resin proved to be convenient for separating and preconcentrating Cd, Co, Cu, Fe, Mn, Mo, Ni, Pb, V, and Zn in the certified reference materials (EnviroMAT EU-L-1 wastewater and ES-L-1 ground water) and commercially available table salt. PMID- 26592618 TI - Calibration transfer from powder mixtures to intact tablets: A new use in pharmaceutical analysis for a known tool. AB - Calibration transfer is commonly used for spectra obtained in different spectrometers or other conditions. This paper proposed the use of calibration transfer between spectra recorded for the same samples in different physical forms. A new method was developed for the direct determination of nevirapine in solid pharmaceutical formulations based on diffuse reflectance near infrared spectroscopy (NIRS) and partial least squares (PLS). This method was developed with 50 powder mixtures and then, successfully extended to the quantification in intact tablets by using calibration transfer with double window piecewise direct standardization (DWPDS). This chemometric strategy provided good results with a small number of tablet transfer samples, only seven, prepared out of the narrow range of active principle ingredients (API) content around the nominal value of the formulation (100%). The method was fully validated in the working range of 83.0-113.9% of nevirapine and the use of DWPDS allowed to significantly decreasing the root mean square error of prediction (RMSEP) from 4.8% (tablets predicted by a model built with only powder samples) to 2.6%. The range of relative errors decreased from -5.1/8.7% to -4.6/3.3%. Considering that the amount of raw materials demanded for preparing tablets is up to ten times higher than for powder mixtures, this type of application is of particular interest in pharmaceutical analysis. In the context of process analytical technology (PAT), the use of the same multivariate model in different steps of the production is very advantageous, saving time and labor. PMID- 26592619 TI - Preparation of monodisperse porous poly(glycidylmethacrylate-co ethylenedimethacrylate) microspheres and their application as stationary phase for superheated water HPLC. AB - Monodisperse porous poly(glycidylmethacrylate-co-ethylenedimethacrylate) (poly(GMA-co-EDMA) beads) with a diameter of 3MUm each were custom synthesized by a single-step swelling and polymerization method. Small sizes (1.2MUm) with polystyrene seed templates of low molecular weight were prepared by the addition of 1,1-diphenylethylene to control the polymerization reaction. Polystyrene seed particles were swollen directly by a mixture of methacrylate monomers and porogen. By swelling polystyrene seed particles with tetrahydrofuran as the porogen, a surface area of 108m(2)g(-1) was achieved. The porous polymer microspheres were evaluated as stationary phase for liquid chromatography using superheated water as a mobile phase. Chromatographic performance at different temperatures was studied, along with analyte and column stability. The results confirm that the particles were stable under superheated water conditions. There was almost no change to the retention properties during the 160 sequential injections of a standard mixture (uracil, pyridine, phenol, dimethyl phthalate and N,N-dimethylaniline) at 150 degrees C. The chromatographic peaks show good symmetry with an efficiency of up to 47,000 platesm(-1) under realistic separation conditions. Thermal decomposition of analytes (aldicarb sulfone, oxamyl, aldicarb and benomyl) separated under different column temperatures, was evaluate. Chromatograms of pesticide standard mixtures separated in the temperature range of 100-140 degrees C displayed good separation. The detection limits of 1.2 and 1.6mg L(-1) for benomyl and aldicarb were obtained when the separation was performed at 120 degrees C with flow rate of 0.4mL min(-1) water. However these pesticides were decomposed at the separation temperature above 140 degrees C. PMID- 26592620 TI - Miniaturized metal oxide pH sensors for bacteria detection. AB - It is well known that the metabolic activity of some microorganisms results in changes of pH of the culture medium, a phenomenon that can be used for detection and quantification of bacteria. However, conventional glass electrodes that are commonly used for pH measurements are bulky, fragile and expensive, which hinders their application in miniaturized systems and encouraged to the search for alternatives. In this work, two types of metal oxide pH sensors have been tested to detect the metabolic activity of the bacterium Escherichia coli (E. coli). These pH sensors were produced on silicon chips with platinum metal contacts, onto which thin layers of IrOx or Ta2O5 were incorporated by two different methods (electrodeposition and e-beam sputtering, respectively). In order to facilitate measurement in small sample volumes, an Ag/AgCl pseudo-reference was also screen-printed in the chip and was assayed in parallel to an external Ag/AgCl reference electrode. As it is shown, the developed sensors generated results indistinguishable from those provided by a conventional glass pH electrode but could be operated in significantly smaller sample volumes. After optimization of the detection conditions, the metal oxide sensors are successfully applied for detection of increasing concentrations of viable E. coli, with detection of less than 10(3)cfu mL(-1) in undiluted culture medium in just 5h. PMID- 26592621 TI - A simple and fast method for the inspection of preservatives in cheeses and cream by liquid chromatography- electrospray tandem mass spectrometry. AB - In this work, a simplified extraction and short time of analysis method for the simultaneous determination of natamycin, nisin and sorbic acid in cheeses and cream by reverse phase liquid chromatography-electrospray-tandem mass spectrometry was developed. Full validation was performed according to the Commission Decision 2002/657/EC criteria and method applicability was checked on several samples, aiming to inspect their compliance with regulatory limits. The method was linear in the concentration ranges of 0-10mg kg(-1) (natamycin), 0 25mg kg(-1) (nisin) and 0 20mg kg(-1) (sorbic acid). Samples of the three most consumed types of cheese (fresh, pasta filata and ripened) in Brazil and cream (ultra high temperature and pasteurized, 20-30% fat content) were assessed. A surprising rate of non-compliance was observed, especially among ripened grated cheeses, since 80% of samples were above the maximum limit for sorbic acid with an average concentration of 2766.3+/-10.8mg kg(-1). Moreover, a major non compliance for the cream samples was observed. The proposed method can be applied as an efficient tool for the inspection of preservatives in cheeses and cream. PMID- 26592622 TI - Enhanced forensic discrimination of pollutants by position-specific isotope analysis using isotope ratio monitoring by (13)C nuclear magnetic resonance spectrometry. AB - In forensic environmental investigations the main issue concerns the inference of the original source of the pollutant for determining the liable party. Isotope measurements in geochemistry, combined with complimentary techniques for contaminant identification, have contributed significantly to source determination at polluted sites. In this work we have determined the intramolecular (13)C profiles of several molecules well-known as pollutants. By giving additional analytical parameters, position-specific isotope analysis performed by isotope ratio monitoring by (13)C nuclear magnetic resonance (irm (13)C NMR) spectrometry gives new information to help in answering the major question: what is the origin of the detected contaminant? We have shown that isotope profiling of the core of a molecule reveals both the raw materials and the process used in its manufacture. It also can reveal processes occurring between the contamination site 'source' and the sampling site. Thus, irm-(13)C NMR is shown to be a very good complement to compound-specific isotope analysis currently performed by mass spectrometry for assessing polluted sites involving substantial spills of pollutant. PMID- 26592623 TI - Paper-based analytical device for instrumental-free detection of thiocyanate in saliva as a biomarker of tobacco smoke exposure. AB - This work describes a fast and simple assay for in situ detection of thiocyanate, i.e., a biomarker of tobacco smoke exposure, in human saliva. The assay is based on the formation of an iron(III)-thiocyanate colored complex in a paper-based sensing platform and subsequent image analysis using a scanner as detection device. Experimental parameters influencing the color intensity of the complex were fully evaluated, including the selection of detection conditions, type of paper substrate, test zone dimensions and composition as well as the stability of the paper-based device. Under optimal conditions, the detection limit was 0.06mM of thiocyanate, and the repeatability, expressed as relative standard deviation, was 3%. The proposed method, characterized by its simplicity, portability and low sample consumption, was applied to the detection of thiocyanate in a series of human saliva samples. Average thiocyanate levels in the ranges 0.28-0.87mM and 0.78-4.28mM were found for non-smokers and smokers, respectively. Recovery studies were carried out at two concentration levels, showing recovery values in the range of 96.1-103.6%. PMID- 26592624 TI - Use of quantum dots as mass and fluorescence labels in microarray biosensing. AB - In this work, we demonstrate the efficacy of a Quantum Dot (QD) mass label strategy to enhance sensitivity in an interferometric technique called interferometric reflectance imaging sensor (IRIS). This biomass detection platform confers the advantage of absolute mass quantification and lower cost, easily implementable equipment. We discuss the advantages of this label when used in parallel with fluorescence detection. QDs represent a unique opportunity to improve sensitivity in both mass-label detection methods due to their large detectable mass, as well as in fluorescence detection, as they fluoresce without quenching. Streptavidin-conjugated QDs (SA-QDs) have been investigated as such a dual-role probe because of their large shape and mass, their 655nm emission peak for fluorescent detection platforms, and their robust insensitivity to photobleaching and quenching. In particular we explored their dual role in a microarrays immunoassay designed to detect antibodies against beta-lactoglobulin, a common milk allergen. The SA-QDs formed a large detectable monolayer of 6.2ng/mm(2) in the saturation conditions, a mass signal corroborated by previous studies by Platt et al.. PMID- 26592625 TI - Optimization of parameters affecting signal intensity in an LTQ-orbitrap in negative ion mode: A design of experiments approach. AB - A multistage optimization of all the parameters affecting detection/response in an LTQ-orbitrap analyzer was performed, using a design of experiments methodology. The signal intensity, a critical issue for mass analysis, was investigated and the optimization process was completed in three successive steps, taking into account the three main regions of an orbitrap, the ion generation, the ion transmission and the ion detection regions. Oleuropein and hydroxytyrosol were selected as the model compounds. Overall, applying this methodology the sensitivity was increased more than 24%, the resolution more than 6.5%, whereas the elapsed scan time was reduced nearly to its half. A high resolution LTQ Orbitrap Discovery mass spectrometer was used for the determination of the analytes of interest. Thus, oleuropein and hydroxytyrosol were infused via the instruments syringe pump and they were analyzed employing electrospray ionization (ESI) in the negative high-resolution full-scan ion mode. The parameters of the three main regions of the LTQ-orbitrap were independently optimized in terms of maximum sensitivity. In this context, factorial design, response surface model and Plackett-Burman experiments were performed and analysis of variance was carried out to evaluate the validity of the statistical model and to determine the most significant parameters for signal intensity. The optimum MS conditions for each analyte were summarized and the method optimum condition was achieved by maximizing the desirability function. Our observation showed good agreement between the predicted optimum response and the responses collected at the predicted optimum conditions. PMID- 26592626 TI - Anti-idiotypic VHH phage display-mediated immuno-PCR for ultrasensitive determination of mycotoxin zearalenone in cereals. AB - Immunoassay is frequently used to analyze mycotoxin contamination. However, the introduction of mycotoxins or their conjugates in conventional immunoassay threatens the safety of individuals and the environment. The variable domain of heavy-chain antibodies (VHHs) can be used as alternative compounds to produce anti-idiotypic antibodies, which work as non-toxic surrogate reagents in immunoassay. In this work, anti-zearalenone (ZEN) monoclonal antibody (mAb) was used as the target for biopanning anti-idiotypic VHH from a naive alpaca VHH phage display library. After four panning cycles, one anti-idiotypic VHH phage clone (Z1) was isolated and the Z1 based phage ELISA for ZEN showed a half inhibitory concentration (IC50) of 0.25+/-0.02ng/mL, a linear range of 0.11 0.55ng/mL, and a limit of detection (LOD) of 0.08ng/mL. Furthermore, the phage particles of Z1 were also applied to immuno-polymerase chain reaction (PD-IPCR), which supplied both the detection antigens and deoxyribonucleic acid (DNA) templates. Compared with that of phage ELISA, the LOD of Z1 based PD-IPCR was 12 fold improved, with a detection limit of 6.5pg/mL and a linear range of 0.01 100ng/mL. The proposed method was then validated with liquid chromatography tandem mass spectrometry (LC-MS/MS). Results showed the reliability of PD-IPCR for the determination of ZEN in cereal samples. The use of anti-idiotypic VHH phage as non-toxic surrogate and signal-amplification function of PCR make it a promising method for actual ZEN analysis in cereals. PMID- 26592627 TI - An innovative method based on quick, easy, cheap, effective, rugged, and safe extraction coupled to desorption electrospray ionization-high resolution mass spectrometry for screening the presence of paralytic shellfish toxins in clams. AB - The capabilities of desorption electrospray ionization-high resolution mass spectrometry (DESI-HRMS) were tested for screening the presence of some paralytic shellfish toxins in clams. A quick, easy, cheap, effective, rugged, and safe (QuEChERS) approach is proposed for sample clean-up. QuEChERS extraction was optimized by using a full factorial design followed by the multicriteria method of the desirability functions. Quantitation limits in the microgram per kilogram range proved reliability of the method for the detection of the investigated toxins in accordance to the rules laid down by European legislation. The optimized QuEChERS-DESI-HRMS based-method allowed for a rapid reliable screening of the investigated compounds at levels of interest, thus being useful for high throughput analyses. PMID- 26592628 TI - Estimation of chlorophyll-a concentration of different seasons in outdoor ponds using hyperspectral imaging. AB - Chlorophyll a (Chl-a) is regarded as one of the important components to estimate water quality and sustainability of freshwater aquaculture operations. In the current study, a hyperspectral imaging (HSI) system was used to determine the effect of season models on the accuracy of Chl-a estimation in outdoor aquaculture ponds. A visible and near infrared hyperspectral imaging system (400 1000nm) was used to measure surface spectral reflectance (R) of water collected from outdoor ponds in four different seasons. Firstly, values of surface spectral reflectance (R) were amplified by a baseline correction (740nm). Two-band, three band and four-band spectral reflectance were used to compute Chl-a concentration and a new cross band ratio algorithm with six wavelengths was proposed in the study. Results indicated that two-band model established based on reflectance ratio (R702/R666) had better performances for Chl-a prediction with determination coefficients (r(2)) of 0.908 than those by (R675(-1)-R691(-1))*R743 and (R675(-1) R691(-1))/(R743(-1)-R691(-1)) models with r(2) of 0.902 and 0.896, respectively. Six optimal wavelengths (410, 682, 691, 966, 972, and 997) were identified using successive projections algorithm (SPA). The optimized regression model (R410(-1) R966(-1))/(R682(-1)-R972(-1))/(R691(-1)-R997(-1)) showed best result with r(2) of 0.961 for Chl-a prediction. Model of cross band ratio algorithm with six wavelengths was mapped to each pixel in the image to display Chl-a component in outdoor ponds under four different seasons. The current study showed that it was feasible to use the HSI system for monitoring the influence of seasons for outdoor aquaculture water quality. PMID- 26592629 TI - Polydimethylsiloxane microfluidic chemiluminescence immunodevice with the signal amplification strategy for sensitive detection of human immunoglobin G. AB - A polydimethylsiloxane (PDMS) microfluidic chemiluminescence (CL) immunodevice for sensitive detection of human immunoglobin G (IgG) with the signal amplification strategy was developed in this work. The immunodevice was prepared by covalently immobilizing capture antibodies (Abs) on the silanized microchannel of microfluidic chip. Gold nanoparticles (AuNPs) functionalized with a high molar ratio of horseradish peroxidase (HRP) were used as an Ab label for signal amplification. Using a sandwich immunoassay, the multi-HRP conjugated AuNPs can catalyze the luminol-H2O2 CL system to achieve the high sensitivity. In addition, the double spiral flow-channel was adopted here, which can still contribute to the high sensitivity. Based on signal amplification strategy, the performance of human IgG tests revealed a lower detection limit (DL) of 0.03ng/mL and showed an increase of 7.4-fold in detection sensitivity compared to a commercial Ab-HRP conjugation. This microfluidic immunodevice can provide an alternative approach for sensitive detection of human IgG in the field of clinic diagnostic and therapeutic. PMID- 26592630 TI - Selective enrichment and determination of monoamine neurotransmitters by CU(II) immobilized magnetic solid phase extraction coupled with high-performance liquid chromatography-fluorescence detection. AB - In this paper, iminodiacetic acid-Cu(II) functionalized Fe3O4@SiO2 magnetic nanoparticles were prepared and used as new adsorbents for magnetic solid phase extraction (MSPE) of six monoamine neurotransmitters (MNTs) from rabbit plasma. The selective enrichment of MNTs at pH 5.0 was motivated by the specific coordination interaction between amino groups of MNTs and the immobilized Cu(II). The employed weak acidic extraction condition avoided the oxidation of MNTs, and thus facilitated operation and ensured higher recoveries. Under optimal conditions, the recoveries of six MNTs from rabbit plasma were in the range of 83.9-109.4%, with RSD of 2.0-10.0%. When coupled the Cu(II) immobilized MSPE with high-performance liquid chromatography-fluorescence detection, the method exhibited relatively lower detection limits than the previously reported methods, and the method was successfully used to determine the endogenous MNTs in rabbit plasma. The proposed method has potential application for the determination of MNTs in biological samples. Also, the utilization of coordination interaction to improve the selectivity might open another way to selectively enrich small alkaloids from complex samples. PMID- 26592631 TI - A water soluble and fast response fluorescent turn-on copper complex probe for H2S detection in zebra fish. AB - According to the displacement method, herein we reported a water soluble copper complex [Cu(MaT-cyclen)2] as a fluorescent probe for the detection of H2S. For this, 1-((1-((10-methylanthracen-9-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl) 1,4,7,10-tetraazacyclododecane (MaT-cyclen) was synthesized first. To improve its solubility in aqueous media, sodium acetate group was introduced into 8-hydroxy-2 quinoline successfully. MaT-cyclen was chelated with Cu(II) to form [Cu(MaT cyclen)2] complex, which displayed high sensitivity and selectivity for H2S over the other possible competitive substances on the basis of forming CuS. Meanwhile, [Cu(MaT-cyclen)2] displayed rapid response (<1min), well reversibility, lowest detection limit (205nM), and high sensitivity for recognizing H2S in aqueous solution. Furthermore, its potential utility for biological applications was confirmed by fluorescence imaging of H2S in live cells as well as in zebra fish. PMID- 26592632 TI - Electrochemical detection of nanomolar dopamine in the presence of neurophysiological concentration of ascorbic acid and uric acid using charge coated carbon nanotubes via facile and green preparation. AB - Negatively charged multi-walled carbon nanotubes (MWCNTs) were prepared using simple sonication technique with non-toxic citric acid (CA) for the electrochemical detection of dopamine (DA). CA/MWCNTs were placed on glassy carbon (GC) electrodes by drop-casting method and then electrochemical determinations of DA were performed in the presence of highly concentrated ascorbic acid (AA). For the comparison of the charge effect on MWCNTs surface, positively charged polyethyleneimine (PEI)/MWCNT/GC electrode and pristine MWCNT/GC electrode were also prepared. Contrary to conventional GC electrode, all three types of MWCNT modified electrodes (CA/MWCNT/GC, PEI/MWCNT/GC, and pristine MWCNT/GC) can discriminate ~MUM of DA from 1mM AA using cyclic voltammetry (CV) and differential pulse voltammetry (DPV) due to the inherent electrocatalytic effect of MWCNTs. Compared to positively charged PEI/MWCNT/GC and pristine MWCNT/GC electrodes, negatively charged CA/MWCNT/GC electrode remarkably enhanced the electrochemical sensitivity and selectivity of DA, showing the linear relationship between DPV signal and DA concentration in the range of 10-1000nM even in the presence of ~10(5) times concentrated AA, which is attributed to the synergistic effect of the electrostatic interaction between cationic DA molecules and negatively charged MWCNTs and the inherent electrocatalytic property of MWCNT. As a result, the limit of detection (LOD) of DA for CA/MWCNT/GC electrode was 4.2nM, which is 5.2 and 16.5 times better than those for MWCNT/GC electrode and PEI/MWCNT/GC electrode even in the presence of 1mM AA. This LOD value for DA at CA/MWCNT/GC electrode is one of the lowest values compared to the previous reports and is low enough for the early diagnosis of neurological disorder in the presence of physiological AA concentration (~0.5mM). In addition, the high selectivity and sensitivity of DA at CA/MWCNT/GC electrode were well kept even in the presence of both 1mM AA and 10MUM uric acid (UA) as similar as neurophysiological concentration. PMID- 26592633 TI - Rapid assessment of bioactive phenolics and methylxanthines in spent coffee grounds by FT-NIR spectroscopy. AB - Spent coffee grounds (SCGs) are a great source of bioactive compounds with interest to pharmaceutical and cosmetic industries. Phenolics and methylxanthines are the main health related compounds present in SCG samples. Content estimation of these compounds in SCGs is of upmost importance in what concerns their profitable use by waste recovery industries. In the present work, near-infrared spectroscopy (NIRS) was proposed as a rapid and non-destructive technique to assess the content of three main phenolics (caffeic acid, (+)-catechin and chlorogenic acid) and three methylxanthines (caffeine, theobromine and theophylline) in SCG samples obtained from different coffee brands and diverse coffee machines. The content of these compounds was determined for 61 SCG samples by HPLC coupled with diode-array detection. Partial least squares (PLS) regression based models were calibrated to correlate diffuse reflectance NIR spectra against the reference data for the six parameters obtained by HPLC. Spectral wavelength selection and number of latent variables were optimized by minimizing the cross-validation error. PLS models showed good linearity with a coefficient of determination for the prediction set (Rp(2)) of 0.95, 0.92, 0.88, 071 and 0.84 for caffeine, caffeic acid, (+)-catechin, chlorogenic acid and theophylline, respectively. The range error ratio (RER) was higher for caffeine (17.8) when compared to other compounds (12.0, 10.1, 7.6 and 9.2, respectively for caffeic acid, (+)-catechin, chlorogenic acid and theophylline). Moreover, the content of caffeine could be used to predict the antioxidant properties of SCG samples (R=0.808, n=61), despite not presenting this property itself. The results obtained confirmed that NIRS is a suitable technique to screen SCG samples unveiling those with high content of bioactive compounds, which are interesting for subsequent extraction procedures. PMID- 26592634 TI - A reversible fluorescence probe for detection of ClO(-)/AA redox cycle in aqueous solution and in living cells. AB - Based on the reversible redox reaction of 4-amino-2,2,6,6-tetramethyl-piperidin-1 ol with oxidative ClO(-) and reductive ascorbic acid (AA), a reversible fluorescent probe, incorporating 4-amino-2,2,6,6-tetramethyl-piperidin-1-ol group into a 7-nitrobenzoxadiazole (NBD) fluorophore, was synthesized and studied for the cyclic detection of ClO(-)/AA in aqueous solution. The NBD-based probe displayed sensitive and selective On-Off-On fluorescent responses to ClO(-)/AA and was successfully applied to monitor the ClO(-)/AA redox cycle in living HeLa cells under physiological conditions. PMID- 26592635 TI - Small angle light scattering assay for the detection of malaria infection. AB - The diagnosis of malaria, caused by Plasmodium spp., still remains a challenging process. Especially in low-income countries, a rapid user-friendly method is needed for the efficient care of the patient. A small-angle light scattering device consisting of hardware and software was developed. Using the DNA-binding dye SYBR Green, malaria infections could be distinguished in healthy red blood cells infected with Plasmodium. Subsequently, samples from parasite positive and negative patients living in a hyper-endemic area of Kinshasa, DRC were assessed. The scatter profiles were distinct and malaria infection could be detected using the Giemsa stain. Although these results are preliminary, they indicate that the device has the potential to be used as a new diagnostic tool for the detection of Malaria infection. PMID- 26592637 TI - A simple method for the multi-elemental analysis of organic fertilizer by slurry sampling and total reflection X-ray fluorescence. AB - A simple and fast method for the multi-elemental determination of 18 inorganic constituents (P, S, Cl, K, Ca, Ti, Cr, V, Mn, Fe, Ni, Cu, Zn, Br, Rb, Sr, Ba and Pb) in organic fertilizers employing slurry sampling and total reflection X-ray fluorescence (TXRF) is presented. A 2(3) factorial design with a central point was employed to optimize the slurry sampling procedure. The internal standard and instrumental conditions were optimized by univariate studies. The selectivity of the method to determining Se, As, Pb, Cr, Ni and Cd was assessed. The accuracy was evaluated by the analysis of four standard reference materials (SRM). The recoveries varied from 72% to 114%. For most of the elements, good agreement was achieved between the certified value and the value measured in the SRM. The relative standard deviation (RSD %) ranged from 0.5% to 14%. The evaluated method was applied to the determination of analytes in the press cake of palm, castor, curcas, sunflower, fodder turnip, white lupin, rapeseed and pequi, and their potential to be used as organic fertilizer was evaluated in accordance with Brazilian legislation. PMID- 26592636 TI - Direct extraction of lead (II) from untreated human blood serum using restricted access carbon nanotubes and its determination by atomic absorption spectrometry. AB - Oxidized carbon nanotubes were covered with layers of bovine serum albumin to result in so-called restricted-access carbon nanotubes (RACNTs). This material can extract Pb(2+) ions directly from untreated human blood serum while excluding all the serum proteins. The RACNTs have a protein exclusion capacity of almost 100% and a maximum Pb(2+) adsorption capacity of 34.5mg g(-1). High resolution transmission electron microscopy, scanning transmission electron microscopy and energy dispersive spectroscopy were used to confirm the BSA layer and Pb(2+) adsorption sites. A mini-column filled with RACNTs was used in an on-line solid phase extraction system coupled to a thermospray flame furnace atomic absorption spectrometry. At optimized experimental conditions, the method has a detection limit as low as 2.1ug L(-1), an enrichment factor of 5.5, and inter- and intra day precisions (expressed as relative standard deviation) of <8.1%. Recoveries of the Pb(2+) spiked samples ranged from 89.4% to 107.3% for the extraction from untreated human blood serum. PMID- 26592638 TI - A three-dimensional silver nanoparticles decorated plasmonic paper strip for SERS detection of low-abundance molecules. AB - The fabrication of SERS substrates, which can offer the advantages of strong Raman signal enhancement with good reproducibility and low cost, is still a challenge for practical applications. In this work, a simple three-dimensional (3D) paper-based SERS substrate, which contains plasmonic silver-nanoparticles (AgNPs), has been developed by the silver mirror reaction. This paper strip was characterized by scanning electron microscopy (SEM), atomic force microscopy (AFM), X-ray diffraction (XRD), etc. Pretreatment of the paper as well as the reaction time, temperature, and reagent concentrations for the silver mirror reaction were varied for further studies. With the optimized experimental parameters, the AgNPs synthesized and distributed in-situ on the paper strip could give more favorable SERS performance. The limit of detection (LOD) as low as 10(-11)M for Rhodamine 6G (R6G) and 10(-9)M for p-aminothiophenol (p-ATP) plus wide linear range for the log-log plot of Raman intensity versus analyte concentration were achieved. The detection of R6G in rain water was also carried out successfully. The merits of this protocol include low cost, easy operation, high sensitivity and acceptable stability, which make it ideal for the detection of environmental samples in trace amounts. PMID- 26592639 TI - Highly selective enrichment of baicalin in rat plasma by boronic acid functionalized core-shell magnetic microspheres: Validation and application to a pharmacokinetic study. AB - To the best of our knowledge, this study is the first to successfully apply a novel, highly selective enrichment technique based on boronic acid-functionalized core-shell magnetic microspheres (BA-Fe3O4@SiO2-Au@mSiO2) with a large surface area and uniform pore size, to determine the baicalin concentration in rat plasma by HPLC. By taking advantage of the special interaction between boronic acid and baicalin under alkaline conditions, as well as the microspheres' size exclusion ability, baicalin was selectively extracted from protein-rich biosamples, such as plasma, without any other pretreatment procedure except for a 10-min vortexing step. BA-Fe3O4@SiO2-Au@mSiO2 microsphere-adsorbed baicalin was straightforwardly and rapidly isolated from the matrix using a magnet. Baicalin was subsequently eluted from the microspheres under acidic conditions for 2min for further HPLC analysis. The extraction conditions, such as the amount of microspheres added, adsorption time, adsorption pH, and elution time and pH, were also determined. Furthermore, method validation, including the linear range, detection limit, precision, accuracy, and recovery, were determined. This newly developed method based on BA-Fe3O4@SiO2-Au@mSiO2 microspheres is a simple, accurate, selective, and green analytical preparatory technique for analyzing baicalin in rat plasma. This study will be further novel research on the analysis of complex plasma samples and the pharmacokinetics of drugs similar to baicalin. PMID- 26592640 TI - Development of a voltammetric assay, using screen-printed electrodes, for clonazepam and its application to beverage and serum samples. AB - This paper describes the development of an electrochemical assay based on screen printed carbon sensors for the determination of clonazepam in serum and in wine. The cyclic voltammetric behaviour of the drug was investigated and the effects of pH and scan rate on the peak current and peak potential determined. Two reduction peaks were recorded on the initial negative going scan, which were considered to result from the 2e(-), 2 H(+) reduction of the 4,5-azomethine and from the 4e(-), 4 H(+) reduction of the 7-NO2 to a hydroxylamine. On the return positive going scan an oxidation peak was seen, which was considered to result from the 2e(-), 2 H(+) oxidation (O1) of the hydroxylamine to the corresponding nitroso species. At pH 11 the solution of clonazepam was found to turn from clear to yellow in colour and the voltammetric signal of the O1 oxidation process was found to be adsorptive in nature, this was exploited in the development of an adsorptive stripping voltammetric assay. Experimental conditions were then optimised for the differential pulse adsorptive voltammetric measurement of clonazepam in wine and serum samples. It was shown that these analyses could be performed on only 100uL of sample which was deposited on the sensor surface. Mean recoveries of 79.53% (%CV=9.88%) and 88.22% (%CV=14.1%) were calculated for wine fortified with 3.16ug/mL and serum fortified with 12.6ug/mL. PMID- 26592641 TI - A signal-on electrochemical DNA biosensor based on potential-assisted Cu(I) catalyzed azide-alkyne cycloaddition mediated labeling of hairpin-like oligonucleotide with electroactive probe. AB - A novel electrochemical biosensor was developed for the signal-on detection of sequence-specific DNA by exploiting potential-assisted Cu(I)-catalyzed azide alkyne cycloaddition (phiCuAAC) as an efficient approach for the labeling of hairpin-like oligonucleotide (hairpin) with electroactive probe. The hairpins, dually labeled with thiol and azide at either terminal, were firstly self assembled on gold electrode and served as the capture probes for the specific recognition of target DNA. Upon hybridization with target DNA, the surface confined hairpins were unfolded, liberating the azide-containing terminals away from electrode surface. Subsequently, the unfolded hairpins were conveniently and efficiently labeled with ethynylferrocene (EFC) via the phiCuAAC. The quantitatively labeled EFC was finally measured via differential pulse voltammetry (DPV) for the signal-on electrochemical detection of sequence specific DNA. The biosensor presented a good linear response over the range from 1pM to 1nM with a detection limit of 0.62pM. Results also revealed that it was highly specific and held a good detection capability in serum samples. Furthermore, the ability to chemoselectively label hairpin-like oligonucleotide with signal reporter by electrical addressing, together with the simplicity and efficiency of the phiCuAAC, makes it compatible with microfluidic devices and microelectrode arrays to achieve the miniaturized and multiplexed detections. PMID- 26592642 TI - Nanobody medicated immunoassay for ultrasensitive detection of cancer biomarker alpha-fetoprotein. AB - Immunoassay for cancer biomarkers plays an important role in cancer prevention and early diagnosis. To the development of immunoassay, the quality and stability of applied antibody is one of the key points to obtain reliability and high sensitivity for immunoassay. The main purpose of this study was to develop a novel immunoassay for ultrasensitive detection of cancer biomarker alpha fetoprotein (AFP) based on nanobody against AFP. Two nanobodies which bind to AFP were selected from a phage display nanobody library by biopanning strategy. The prepared nanobodies are clonable, thermally stable and applied in both sandwich enzyme linked immunoassay (ELISA) and immuno-PCR assay for ultrasensitive detection of AFP. The limit detection of sandwich ELISA setup with optimized nanobodies was 0.48ng mL(-1), and the half of saturation concentration (SC50) value was 6.68+/-0.56ng mL(-1). These nanobodies were also used to develop an immuno-PCR assay for ultrasensitive detection of AFP, its limit detection values was 0.005ng mL(-1), and the linear range was 0.01-10,000ng mL(-1). These established immunoassays based on nanobodies were highly specific to AFP and with negligible cross reactivity with other tested caner biomarkers. Furthermore, this novel concept of nanobodies mediated immunoassay may provide potential applications in a general method for the ultrasensitive detection of various cancer biomarkers. PMID- 26592643 TI - Multicommuted flow injection method for fast photometric determination of phenolic compounds in commercial virgin olive oil samples. AB - A multicommuted flow injection method has been developed for the determination of phenolic species in virgin olive oil samples. The method is based on the inhibitory effect of antioxidants on a stable and colored radical cation formation from the colorless compound N,N-dimethyl-p-phenylenediamine (DMPD(*+)) in acidic medium in the presence of Fe(III) as oxidant. The signal inhibition by phenolic species and other antioxidants is proportional to their concentration in the olive oil sample. Absorbance was recorded at 515nm by means of a modular fiber optic spectrometer. Oleuropein was used as the standard for phenols determination and 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (trolox) was the reference standard used for total antioxidant content calculation. Linear response was observed within the range of 250-1000mg/kg oleuropein, which was in accordance with phenolic contents observed in commercial extra virgin olive oil in the present study. Fast and low-volume liquid-liquid extraction of the samples using 60% MeOH was made previous to their insertion in the flow multicommuted system. The five three-way solenoid valves used for multicommuted liquid handling were controlled by a homemade electronic interface and Java-written software. The proposed approach was applied to different commercial extra virgin olive oil samples and the results were consistent with those obtained by the Folin Ciocalteu (FC) method. Total time for the sample preparation and the analysis required in the present approach can be drastically reduced: the throughput of the present analysis is 8 samples/h in contrast to 1sample/h of the conventional FC method. The present method is easy to implement in routine analysis and can be regarded as a feasible alternative to FC method. PMID- 26592644 TI - Detection of human genome mutations associated with pregnancy complications using 3-D microarray based on macroporous polymer monoliths. AB - Analysis of variations in DNA structure using a low-density microarray technology for routine diagnostic in evidence-based medicine is still relevant. In this work the applicability of 3-D macroporous monolithic methacrylate-based platforms for detection of different pathogenic genomic substitutions was studied. The detection of nucleotide replacements in F5 (Leiden G/A, rs6025), MTHFR (C/T, rs1801133) and ITGB3 (T/C, rs5918), involved in coagulation, and COMT (C/G, rs4818), TPH2 (T/A, rs11178997), PON1 (T/A rs854560), AGTR2 (C/A, rs11091046) and SERPINE1 (5G/4G, rs1799889), associated with pregnancy complications, was performed. The effect of such parameters as amount and type of oligonucleotide probe, amount of PCR product on signal-to-noise ratio, as well as mismatch discrimination was analyzed. Sensitivity and specificity of mutation detections were coincided and equal to 98.6%. The analysis of SERPINE1 and MTHFR genotypes by both NGS and developed microarray was performed and compared. PMID- 26592645 TI - Square wave voltammetric detection by direct electroreduction of paranitrophenol (PNP) using an organosmectite film-modified glassy carbon electrode. AB - This work describes the development of a low-cost and reliable adsorptive stripping voltammetric method for the detection of PNP in water. Organoclays were prepared by intercalation in various loading amounts of cetyltrimethylammonium ions (CTA(+)) in the interlayer space of a smectite-type clay mineral. Their structural characterization was achieved using several techniques including X-ray diffraction (XRD), N2 adsorption-desorption (BET method) and Fourier Transform Infrared spectroscopy (FTIR) that confirmed the intercalation process and the presence of the surfactant ions within the clay mineral layers. Using [Fe(CN)6](3 ) and [Ru(NH3)6](3+) as redox probes, the surface charge and the permeability of the starting clay mineral and its modified counterparts were assessed by multisweep cyclic voltammetry, when these materials were coated on the surface of a glassy carbon electrode (GCE). In comparison with the bare GCE, the organoclay modified electrodes exhibited more sensitive response towards the reduction of paranitrophenol (PNP). Under optimized conditions, a calibration curve was obtained in the concentration range from 0.2 to 5.2umolL(-1); leading to a detection limit of 3.75*10(-8)molL(-1) (S/N=3). After the study of some interfering species on the electrochemical response of PNP, the developed sensor was successfully applied to the electroanalytical quantification of the same pollutant in spring water. PMID- 26592646 TI - Disposable competitive-type immunoassay for determination of aflatoxin B1 via detection of copper ions released from Cu-apatite. AB - A disposable electrochemical immunosensor was developed for detection of aflatoxin B1 (AFB1) based on stripping voltammetric detection of copper ions released from Cu-apatite. AFB1 antibody (Ab) was firstly fixed on the gold nanoparticle (Au NPs) modified screen-printed carbon electrode (SPCE). AFB1 bovine serum albumin (AFB1-BSA) conjugate was labeled with Cu-apatite, and then competed with AFB1 for binding to the Ab. Copper ions were released from Cu apatite through acidolysis and stripping voltammetry signal of the copper ions was used for the detection. The Cu-apatite increased the amount of loaded copper ions, and the anodic stripping strategy performed in the micro electrolytic cell of the SPCE simplified the detection procedure and further amplified the electrochemical signal. This immunosensor could detect AFB1 over a wide concentration range from 0.001 to 100ng mL(-1) with a detection limit of 0.2pg mL(-1). The low cost, high sensitive, rapid and accurate method may find widely potential application in the detection of other toxic or harmful substances. PMID- 26592647 TI - Iron oxide functionalized graphene oxide as an efficient sorbent for dispersive micro-solid phase extraction of sulfadiazine followed by spectrophotometric and mode-mismatched thermal lens spectrometric determination. AB - A simple and rapid dispersive micro-solid phase extraction (DMSPE) combined with mode-mismatched thermal lens spectrometry as well as fiber optic linear array spectrophotometry was developed for the separation, extraction and determination of sulfadiazine. Graphene oxide was synthesized using the modified Hummers method and functionalized with iron oxide nanoparticles by means of a simple one step chemical coprecipitation method. The synthesized iron oxide functionalized graphene oxide was utilized as an efficient sorbent in DMSPE of sulfadiazine. The retained analyte was eluted by using 180uL of a 6:4 mixture of methanol/acetic acid solution and was spectrophotometrically determined based on the formation of an azo dye through coupling with thenoyltrifluoroacetone. Under the optimized conditions, with the application of spectrophotometry technique and with a sample volume of 100mL, the method exhibited a linear dynamic range of 3-80ug L(-1) with a detection limit of 0.82ug L(-1), an enrichment factor of 200 as well as the relative standard deviations of 2.6% and 4.3% (n=6) at 150ug L(-1) level of sulfadiazine for intra- and inter-day analyses, respectively. Whereas, through the application of the thermal lens spectrometry and a sample volume of 10mL, the method exhibited a linear dynamic range of 1-800ug L(-1) with a detection limit of 0.34ug L(-1) and the relative standard deviations of 3.1% and 5.4% (n=6) at 150ug L(-1) level of sulfadiazine for intra- and inter-day analyses, respectively. The method was successfully applied to the determination of sulfadiazine in milk, honey and water samples. PMID- 26592648 TI - Attenuated total reflectance-mid infrared spectroscopy (ATR-MIR) coupled with independent components analysis (ICA): A fast method to determine plasticizers in polylactide (PLA). AB - Compliance of plastic food contact materials (FCMs) with regulatory specifications in force, requires a better knowledge of their interaction phenomena with food or food simulants in contact. However these migration tests could be very complex, expensive and time-consuming. Therefore, alternative procedures were introduced based on the determination of potential migrants in the initial material, allowing the use of mathematical modeling, worst case scenarios and other alternative approaches, for simple and fast compliance testing. In this work, polylactide (PLA), plasticized with four different plasticizers, was considered as a model plastic formulation. An innovative analytical approach was developed, based on the extraction of qualitative and quantitative information from attenuated total reflectance (ATR) mid-infrared (MIR) spectral fingerprints, using independent components analysis (ICA). Two novel chemometric methods, Random_ICA and ICA_corr_y, were used to determine the optimal number of independent components (ICs). Both qualitative and quantitative information, related to the identity and the quantity of plasticizers in PLA, were retrieved through a direct and fast analytical method, without any prior sample preparations. Through a single qualitative model with 11 ICs, a clear and clean classification of PLA samples was obtained, according to the identity of plasticizers incorporated in their formulations. Moreover, a quantitative model was established for each formulation, correlating proportions estimated by ICA and known concentrations of plasticizers in PLA. High coefficients of determination (higher than 0.96) and recoveries (higher than 95%) proved the good predictability of the proposed models. PMID- 26592649 TI - Rapid detection and quantification of the marine toxic algae, Alexandrium minutum, using a super-paramagnetic immunochromatographic strip test. AB - The dinoflagellates of Alexandrium genus are known to be producers of paralytic shellfish toxins that regularly impact the shellfish aquaculture industry and fisheries. Accurate detection of Alexandrium including Alexandrium minutum is crucial for environmental monitoring and sanitary issues. In this study, we firstly developed a quantitative lateral flow immunoassay (LFIA) using super paramagnetic nanobeads for A. minutum whole cells. This dipstick assay relies on two distinct monoclonal antibodies used in a sandwich format and directed against surface antigens of this organism. No sample preparation is required. Either frozen or live cells can be detected and quantified. The specificity and sensitivity are assessed by using phytoplankton culture and field samples spiked with a known amount of cultured A. minutum cells. This LFIA is shown to be highly specific for A. minutum and able to detect reproducibly 10(5)cells/L within 30min. The test is applied to environmental samples already characterized by light microscopy counting. No significant difference is observed between the cell densities obtained by these two methods. This handy super-paramagnetic lateral flow immnunoassay biosensor can greatly assist water quality monitoring programs as well as ecological research. PMID- 26592650 TI - A simple and rapid creatinine sensing via DLS selectivity, using calix[4]arene thiol functionalized gold nanoparticles. AB - A new, simple, ultra-sensitive and selective approach has been reported for the "on spot" colorimetric detection of creatinine based on calix[4]arene functionalized gold nanoparticles (AuNPs) with excellent discrimination in the presence of other biomolecules. The lower detection limit of the method is 2.16nM. The gold nanoparticles and p-tert-butylcalix[4]arene were synthesized by microwave assisted method. Specifically, in our study, we used dynamic light scattering (DLS) which is a powerful method for the determination of small changes in particle size, improved selectivity and sensitivity of the creatinine detection system over colorimetric method. The nanoassembly is characterized by Transmission electron microscopy (TEM), DLS, UV-vis and ESI-MS spectroscopy, which demonstrates the binding affinity due its ability of hydrogen bonding and electrostatic interaction between -NH group of creatinine and pSDSC4. It exhibits fast response time (<60s) to creatinine and has long shelf-life (>5 weeks). The developed pSDSC4-AuNPs based creatinine biosensor will be established as simple, reliable and accurate tool for the determination of creatinine in human urine samples. PMID- 26592651 TI - Water spectral pattern as holistic marker for water quality monitoring. AB - Online water quality monitoring technologies have been improving continuously. At the moment, water quality is defined by the respective range of few chosen parameters. However, this strategy requires sampling and it cannot provide evaluation of the entire water molecular system including various solutes. As it is nearly impossible to monitor every single molecule dissolved in water, the objective of our research is to introduce a complimentary approach, a new concept for water screening by observing the water molecular system changes using aquaphotomics and Quality Control Chart method. This approach can continuously provide quick information about any qualitative change of water molecular arrangement without taking into account the reason of the alteration of quality. Different species and concentrations of solutes in aqueous systems structure the water solvent differently. Aquaphotomics investigates not the characteristic absorption bands of the solute in question, but the solution absorption at vibrational bands of water's covalent and hydrogen bonds that have been altered by the solute. The applicability of the proposed concept is evaluated by monitoring the water structural changes in different aqueous solutions such as acid, sugar, and salt solutions at millimolar concentration level and in ground water. The results show the potential of the proposed approach to use water spectral pattern monitoring as bio marker of water quality. Our successful results open a new venue in water quality monitoring by offering a quick and cost effective method for continuous screening of water molecular arrangement. Instead of the regular analysis of individual physical or chemical parameters, with our method - as a complementary tool - the structural changes of water molecular system used as a mirror reflecting even small disturbances in water can indicate the necessity of further detailed analysis by conventional methods. PMID- 26592653 TI - Optimized elemental analysis of fluorescence lamp shredder waste. AB - Fluorescence lamps contain considerable amounts of rare earth elements (REE). Several recycling procedures for REE recovery from spent lamps have been established. However, despite their economic importance, the respective recycling is scarce so far, with an REE recovery rate of less than 1%. A reliable analysis of REE and other relevant metals like Yttrium is crucial for a thorough and complete recovery process. This applies both to the solid matter and aqueous phase, since most of the recycling processes include wet-chemical steps. We tested seven different reagent mixtures for microwave-assisted digestion of fluorescent lamp shredder, including hydrofluoric acid, perchloric acid, and hydrogen peroxide. We determined the concentrations of 25 of the most relevant rare earth and other trace elements (Al, P, Ti, V, Cr, Fe, Ni, Cu, Ga, Ge, As, Y, Ag, Cd, Sn, Sb, La, Ce, Eu, Gd, Tb, W, Au, Hg, and Pb) in the respective dilutions. Two independent digestions, one a mixture of perchlorid/nitric/hydrofluoric acid and the other aqua regia, showed the highest concentrations of 23 of these elements, excluding only Sn and Tb. The REE concentrations in the tested lamp shredder sample (stated in g/kg) were 10.2 (Y), 12.1 (La), 7.77 (Ce), 6.91 (Eu), 1.90 (Gd), and 4.11 (Tb). PMID- 26592652 TI - Multiplex protein pattern unmixing using a non-linear variable-weighted support vector machine as optimized by a particle swarm optimization algorithm. AB - Most of the proteins locate more than one organelle in a cell. Unmixing the localization patterns of proteins is critical for understanding the protein functions and other vital cellular processes. Herein, non-linear machine learning technique is proposed for the first time upon protein pattern unmixing. Variable weighted support vector machine (VW-SVM) is a demonstrated robust modeling technique with flexible and rational variable selection. As optimized by a global stochastic optimization technique, particle swarm optimization (PSO) algorithm, it makes VW-SVM to be an adaptive parameter-free method for automated unmixing of protein subcellular patterns. Results obtained by pattern unmixing of a set of fluorescence microscope images of cells indicate VW-SVM as optimized by PSO is able to extract useful pattern features by optimally rescaling each variable for non-linear SVM modeling, consequently leading to improved performances in multiplex protein pattern unmixing compared with conventional SVM and other exiting pattern unmixing methods. PMID- 26592654 TI - Comparison of impedimetric detection of DNA hybridization on the various biosensors based on modified glassy carbon electrodes with PANHS and nanomaterials of RGO and MWCNTs. AB - In this research, we have developed lable free DNA biosensors based on modified glassy carbon electrodes (GCE) with reduced graphene oxide (RGO) and carbon nanotubes (MWCNTs) for detection of DNA sequences. This paper compares the detection of BRCA1 5382insC mutation using independent glassy carbon electrodes (GCE) modified with RGO and MWCNTs. A probe (BRCA1 5382insC mutation detection (ssDNA)) was then immobilized on the modified electrodes for a specific time. The immobilization of the probe and its hybridization with the target DNA (Complementary DNA) were performed under optimum conditions using different electrochemical techniques such as cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). The proposed biosensors were used for determination of complementary DNA sequences. The non-modified DNA biosensor (1-pyrenebutyric acid-N- hydroxysuccinimide ester (PANHS)/GCE), revealed a linear relationship between ?Rct and logarithm of the complementary target DNA concentration ranging from 1.0*10(-16)molL(-1) to 1.0*10(-10)mol L(-1) with a correlation coefficient of 0.992, for DNA biosensors modified with multi-wall carbon nanotubes (MWCNTs) and reduced graphene oxide (RGO) wider linear range and lower detection limit were obtained. For ssDNA/PANHS/MWCNTs/GCE a linear range 1.0*10(-17)mol L(-1) 1.0*10(-10)mol L(-1) with a correlation coefficient of 0.993 and for ssDNA/PANHS/RGO/GCE a linear range from 1.0*10(-18)mol L(-1) to 1.0*10(-10)mol L( 1) with a correlation coefficient of 0.985 were obtained. In addition, the mentioned biosensors were satisfactorily applied for discriminating of complementary sequences from noncomplementary sequences, so the mentioned biosensors can be used for the detection of BRCA1-associated breast cancer. PMID- 26592655 TI - Impedimetric quantification of cells encapsulated in hydrogel cultured in a paper based microchamber. AB - Recently, 3D cell culture technique was proposed to provide a more physiologically-meaningful environment for cell-based assays. With the development of microfluidics technology, cellular response can be quantified by impedance measurement technique in a real-time and non-invasive manner. However, handling of these microfluidic systems requires a trained engineering personnel and the operation is not compatible to traditional biological research laboratories. In this work, we incorporated the impedance measurement technique to paper-based 3D cell culture model and demonstrated non-invasive quantification of cells encapsulated in hydrogel during the culture course. A cellulose filter paper was patterned with an array of circular microchambers. Cells were encapsulated in hydrogel and loaded to the microchambers for culturing cells in 3D environment. At the preset schedule during the culture course, the paper was placed on a glass substrate with measurement electrodes for the impedance measurement. Cells in each microchamber was represented by impedance magnitude and cell proliferation could be studied over time. Also, conventional bio-assay was performed to further confirm the feasibility of the impedimetric quantification of cells encapsulated in hydrogel cultured in the paper-based microchamber. This technique provides a convenient, fast, and non-invasive approach to monitor cells cultured in 3D environment. It has potential to be developed for routine 3D cell culture protocol in biological research laboratories. PMID- 26592656 TI - Simple and rapid determination of trace iodide by cathodic stripping voltammetry. AB - This work establishes a highly sensitive and simple stripping voltammetric method for the direct determination of trace iodide. In the presence of abounding bromide and appropriate amount of cetylpyridine bromide (CPB), the iodine was accumulated on the glassy carbon electrode surface as ion association complex (CPBI2Br). After accumulation for a period of time, a linear sweep potential with negative scanning was applied and the I2 in CPBI2Br was reduced again into the solution. Under the optimization conditions, the stripping signals (peak current) were linear relationship with iodide concentration in range of 3.81*10(-3)ug/mL to 0.114 MUg/mL and 0.127MUg/mL to 2.54MUg/mL, with a detection limit of 1.02ng/mL (S/N=3) for a accumulation time of 180s. Determination of trace iodine in pharmaceutical sample, kelp and table salt were performed with high accuracy and satisfactory recovery results. PMID- 26592657 TI - Development of magnetic molecularly imprinted polymers for solid phase extraction of cocaine and metabolites in urine before high performance liquid chromatography - tandem mass spectrometry. AB - A magnetic molecularly imprinted polymer (MMIP) has been synthesized and applied for cocaine (COC) and metabolites (benzoylecgonine, BZE; cocaethylene, CE; and ecgonine methyl ester, EME) recognition/pre-concentration in urine samples. The MMIP has been prepared using COC as a template molecule, ethylene dimethacrylate (EDMA) as a functional monomer, divinylbenzene (DVB) as a cross-linker, Fe3O4 magnetite as a magnetic component, and 2,2'-azobisisobutyronitrile (AIBN) as an initiator. The best results (MIP layer on the surface of the magnetic nanoparticles) and physical properties of the prepared MMIP were obtained when assisting the synthesis procedure with ultrasounds (325W, 37kHz, 30 degrees C, 4h). After solid phase extraction (SPE) with the prepared adsorbent material, analytes were determined by high performance liquid chromatography - tandem mass spectrometry (HPLC-MS/MS). Variables affecting the SPE process (batch mode) were fully evaluated. Optimum retention of analytes (1.8mL of urine and 50mg of MMIP) was achieved by fixing the urine pH at 5.5 (use of a KH2PO4/NaOH, pH 5.5 buffer solution), and magnetic stirring (25 degrees C, 700rpm) for 10min. Elution was performed by using 2mL of a dichloromethane/2-propanol/ammonium hydroxide (75:20:5) mixture under ultrasounds (325W, 35kHz, room temperature) for 5min. The method was validated according to the guidance for bioanalytical method validation of the US Department of Health and Human Services, Food and Drug Administration. The detection limits were in the range of 0.39-1.4ngL(-1). The relative standard deviations of intra- and inter-day tests ranged from 5 to 11% and from 3 to 11%, respectively. Analytical recoveries were in the range of 79 106% when spiking drug-free urine samples at three concentration levels. Good results were also obtained after analyzing an FDT +25% control material. The applicability of the method was proved for screening/quantifying COC, BZE, CE and EME in several samples from poly-drug abusers. PMID- 26592658 TI - IgA and IgG1 reactivities assessed by flow cytometry mirror clinical aspects of infants with ocular congenital toxoplasmosis. AB - This study intended to apply the flow cytometric analysis of IgA and IgG reactivity and intracytoplasmic cytokine analysis to understand and decode the clinical aspects of infants with ocular congenital toxoplasmosis. The Toxoplasma gondii-infected infants (TOXO) were subdivided according to their clinical aspects based on the absence (NRL), presence of active (ARL), active/cicatricial (ACRL) or cicatricial retinochoroidal lesions (CRL) and compared to non-infected controls (NI). The reactivity of anti-T. gondii IgG subclasses resembles the clinical aspects of ocular lesions. IgG and IgG1 discriminate infants with cicatricial lesions (ACRL and CRL) from both ARL and NLR. IgG2 and IgG3 are particularly higher in ACRL and CRL as compared to NLR. No differences were observed when IgG4 reactivity was evaluated. Thus, the results indicated that the reactivity patterns of IgA, IgG and IgG subclasses are able to discriminate ARL, ACRL and CRL from NLR or NI. IgA and IgG subclasses are relevant serological biomarkers with diagnostic and prognostic applicability, respectively. Moreover, IgA and IgG1 were closely related to cytokine production by innate/adaptive immunity cells. IgA reactivity was directly associated to TNF-alpha-derived from neutrophils, monocytes and CD8(+) T-cells, while IgG1 was inversely correlated with IFN-gamma-producing CD4(+) and CD8(+) T-cells but positively correlated with IL-10(+) B-cells. These findings provide insights on the relationship between the cytokine production by innate/adaptive immunity and the antibody pattern of infants with ocular congenital toxoplasmosis. In addition, the present study supports the use of flow cytometric serology as a potential tool for the diagnosis and monitoring of ocular lesions in T. gondii-infected infants in the clinical setting. PMID- 26592659 TI - Estrogens down-regulate the stem cell factor (SCF)/c-KIT system in prostate cells: Evidence of antiproliferative and proapoptotic effects. AB - The development of prostate cancer (PCa) is intimately associated with the hormonal environment, and the sex steroids estrogens have been implicated in prostate malignancy. However, if some studies identified estrogens as causative agents of PCa, others indicated that these steroids have a protective role counteracting prostate overgrowth. The tyrosine kinase receptor c-KIT and its ligand, the stem cell factor (SCF), have been associated with the control of cell proliferation/apoptosis and prostate carcinogenesis, and studies show that estrogens regulate their expression in different tissues, though, in the case of prostate this remains unknown. The present study aims to evaluate the role of 17beta-estradiol (E2) in regulating the expression of SCF/c-KIT in human prostate cell lines and rat prostate, and to investigate the consequent effects on prostate cell proliferation and apoptosis. qPCR, Western Blot, and immuno(cito)histochemistry analysis showed that E2-treatment decreased the expression of SCF and c-KIT both in human prostate cells and rat prostate. Furthermore, the diminished expression of SCF/c-KIT was underpinned by the diminished prostate weight and reduced proliferation index. On the other hand, the results of TUNEL labelling, the increased activity of caspase-3, and the augmented expression of caspase-8 and Fas system in the prostate of E2-treated animals indicated augmented apoptosis in response to E2. The obtained results demonstrated that E2 down-regulated the expression of SCF/c-KIT system in prostate cells, which was associated with antiproliferative and proapoptotic effects. Moreover, these findings support the protective role of estrogens in PCa and open new perspectives on the application of estrogen-based therapies. PMID- 26592660 TI - Lactate's effect on human neuroblastoma cell bioenergetic fluxes. AB - Lactate, once considered a metabolic dead-end, has been recently proposed to support neuron bioenergetics. To better understand how lactate specifically influences cell energy metabolism, we studied the effects of lactate supplementation on SH-SY5Y human neuroblastoma cell bioenergetic fluxes. Lactate supplementation increased cell respiration, there was no change in respiratory coupling efficiency, and lactate itself appeared to directly support the respiratory flux increase. Conversely, lactate supplementation reduced the glycolysis flux. This apparent pro-aerobic shift in the respiration:glycolysis ratio was accompanied by post-translational modifications and compartmental redistributions of proteins that respond to and modify bioenergetic fluxes, including cAMP-response element binding protein (CREB), p38 mitogen-activated protein kinases (p38 MAPK), AMP-activated protein kinase (AMPK), peroxisome proliferator activated receptor gamma coactivator 1 beta (PGC-1beta), Akt, mammalian target of rapamycin (mTOR), and forkhead box protein O1 (FOXO1). mRNA levels for PGC-1beta, nuclear respiratory factor 1 (NRF1), and cytochrome c oxidase subunit 1 (COX1) increased. Some effects depended on the direct presence of lactate, while others were durable and evident several hours after lactate was removed. We conclude lactate can be used to manipulate cell bioenergetics. PMID- 26592661 TI - Arsenic trioxide suppresses cell growth and migration via inhibition of miR-27a in breast cancer cells. AB - Accumulating evidence has demonstrated that arsenic trioxide (ATO) exhibits its anti-cancer activities in a variety of human malignancies. Recent studies have revealed that ATO regulated multiple microRNAs (miRNAs) in human cancers. However, the exact mechanism of ATO-mediated tumor suppressive function has not been fully elucidated. In the present study, we explore whether ATO governed oncogenic miR-27a in breast cancer cells by multiple methods such as MTT assay, RT-PCR, Wound healing assay, Western blotting analysis, migration, Transwell invasion assay, and transfection. Our results showed that ATO inhibited cell growth, migration, invasion, and induced cell apoptosis in breast cancer cells. Further molecular analysis dissected that ATO inhibited miR-27a expression in breast cancer cells. Moreover, inhibition of miR-27a suppressed cell growth, migration, invasion, and trigged cell apoptosis, whereas overexpression of miR 27a enhanced cell growth, motility, and inhibited apoptosis in breast cancer cells. Notably, we found that miR-27a inhibitor treatment potentiates ATO-induced breast cancer cell growth inhibition, apoptosis and motility inhibition. However, overexpression of miR-27a partly abrogated ATO-mediated anti-tumor activity. Our findings provide a novel anti-tumor mechanism of ATO involved in miR-27a for the treatment of breast cancer. PMID- 26592662 TI - Lyso-globotriaosylceramide downregulates KCa3.1 channel expression to inhibit collagen synthesis in fibroblasts. AB - Fabry disease is an X-linked lysosomal storage disorder that is caused by a deficiency of alpha-galactosidase A. The disease ultimately manifests as multiple organ dysfunctions owing to excessive accumulation of globotriaosylceramide (Gb3). Among the several complications of Fabry disease, ascending thoracic aortic aneurysm is relatively common, which is classically associated with connective tissue disorders characterized by abnormal defects or deficiencies in structural proteins such as collagen and elastin. Although an elevated Gb3 level is regarded as a prerequisite for the manifestations of Fabry disease, only this excess accumulation cannot explain the pathophysiology of these complications. Recently, an increased plasma level of lyso-Gb3 was suggested as a new biomarker in Fabry disease. Therefore, the aim of this study was to assess the effects of lyso-Gb3 on the pathogenesis of thoracic ascending aortic aneurysms in Fabry disease, with a particular focus on the responses related to aortic remodeling by fibroblasts. We found that lyso-Gb3 inhibited the growth of fibroblasts, as well as their differentiation into myofibroblasts, and collagen expression. Moreover, all of these compromised responses could be attributed to the effects of lyso-Gb3 on downregulation of KCa3.1 channel expression, and these impairments could be rescued when activating the KCa3.1 channel or increasing intracellular Ca(2+) concentration. This study provides new evidence that lyso-Gb3 inhibits the differentiation into myofibroblasts and collagen synthesis of fibroblasts owing to decreased Ca(2+) levels by KCa3.1 channel dysfunction. These findings suggest that the KCa3.1 channel can serve as a new target to attenuate and prevent development of ascending thoracic aortic aneurysm in Fabry disease. PMID- 26592663 TI - Impact of age and sex on the development of atherosclerosis and expression of the related genes in apoE deficient mice. AB - Development of atherosclerosis is a chronic pathological process. ApoE deficient (apoE(-/-)) mice spontaneously develop atherosclerotic lesions. However, the impact of age and sex on lesions and expression of the related genes have not been fully elucidated. In this study, we collected blood and tissue samples from normal chow fed male and female apoE(-/-) mice at different ages, and determined serum lipids, PCSK9 levels, en face aortic lesions and expression of some pro- or anti-atherogenic genes. We determined that lesion development was clearly associated with age, and more lesions in males than females (12.6 +/- 1.7% vs. 8.9 +/- 1.1% at 8 months old, P < 0.05). Associated with age, serum total, LDL- and HDL-cholesterol and PCSK9 levels increased with more PCSK9 in females than males (313 +/- 31 ng/mL vs. 239 +/- 28 ng/mL at 8 months old, P < 0.05); expression of liver LDLR and ABCA1 decreased while of SR-BI increased; expression of macrophage ABCA1 and SR-BI decreased but of CD36 increased. Estrogen and tamoxifen induced ABCA1 and SR-BI expression, respectively, in macrophages isolated from female mice at the different age. Taken together, our study suggests that aging facilitates lesion development in apoE(-/-) mice with greater effect on male mice. The lesion development is also related to expression of pro- or anti-atherogenic genes in tissues, particularly in macrophages. PMID- 26592664 TI - Zscan10 is dispensable for maintenance of pluripotency in mouse embryonic stem cells. AB - Zinc finger and SCAN domain-containing 10 (Zscan10, also known as Zfp206) encodes a transcription factor that has been reported to be involved in the maintenance of pluripotency in mouse embryonic stem (ES) cells. Here we generated inducible knockout ES cells for Zscan10 using the Cre-loxP system and analyzed its function. We succeeded in establishing Zscan10-null ES cells and confirmed their pluripotency by the generation of chimeric embryos. Our results clearly indicate that Zscan10 is dispensable for the ability of self-renewal and differentiation in ES cells. PMID- 26592665 TI - Radiosensitizing effect of PSMC5, a 19S proteasome ATPase, in H460 lung cancer cells. AB - The function of PSMC5 (proteasome 26S subunit, ATPase 5) in tumors, particularly with respect to cancer radioresistance, is not known. Here, we identified PSMC5 as a novel radiosensitivity biomarker, demonstrating that radiosensitive H460 cells were converted to a radioresistance phenotype by PSMC5 depletion. Exposure of H460 cells to radiation induced a marked accumulation of cell death-promoting reactive oxygen species, but this effect was blocked in radiation-treated H460 PSMC5-knockdown cells through downregulation of the p53-p21 pathway. Interestingly, PSMC5 depletion in H460 cells enhanced both AKT activation and MDM2 transcription, thereby promoting the degradation of p53 and p21 proteins. Furthermore, specific inhibition of AKT with triciribine or knockdown of MDM2 with small interfering RNA largely restored p21 expression in PSMC5-knockdown H460 cells. Our data suggest that PSMC5 facilitates the damaging effects of radiation in radiation-responsive H460 cancer cells and therefore may serve as a prognostic indicator for radiotherapy and molecular targeted therapy in lung cancer patients. PMID- 26592666 TI - Epigenetic regulation of glucose-stimulated osteopontin (OPN) expression in diabetic kidney. AB - Diabetes nephropathy (DN) is the leading cause of end stage renal disease and it affects up to 40% of diabetic patients. In addition to hyperglycemia, genetic factors are thought to contribute to the development of DN, but few if any genetic factors have been convincingly linked to DN. Other possible mechanisms may involve epigenetic regulation of glucose-stimulated gene activity which was suggested to explain long-term effects of poor glycemic control on risk of diabetic complications, often referred to as metabolic memory. Osteopontin (OPN) is one of the genes upregulated in kidneys from diabetic mouse models as well as humans with DN, and suggested to play an important role in the pathogenesis of DN. In this study, we demonstrated that OPN gene expression is upregulated in the kidneys of a hyperglycemia diabetes mouse model SUR1-E1506K, and glucose stimulated OPN gene expression is strongly associated with increases in activating histone marks H3K9ac, H3K4me1 and H3K4me3 and decrease in inactivating mark H3K27me3 in the promoter region of OPN gene. These findings were replicated in human mesangial cells treated with high glucose. Further proof for the involvement of histone acetylation and methylation in glucose-induced changes in OPN gene expression was obtained by manipulating histone modifications thereby OPN gene expression by histone deacetylase (HDAC) inhibitor trichostatin A and histone methyltransferase (HMT) inhibitor MM-102. We conclude that glucose is a potent inducer of histone acetylation and methylation, which in turn leads to upregulation of OPN gene expression. Treatment targeting histone marks may therefore represent an alternative method to protect kidneys from deleterious effects of glucose. PMID- 26592667 TI - Switches of stimulus tagging frequencies interact with the conflict-driven control of selective attention, but not with inhibitory control. AB - Selective attention and its adaptation by cognitive control processes are considered a core aspect of goal-directed action. Often, selective attention is studied behaviorally with conflict tasks, but an emerging neuroscientific method for the study of selective attention is EEG frequency tagging. It applies different flicker frequencies to the stimuli of interest eliciting steady state visual evoked potentials (SSVEPs) in the EEG. These oscillating SSVEPs in the EEG allow tracing the allocation of selective attention to each tagged stimulus continuously over time. The present behavioral investigation points to an important caveat of using tagging frequencies: The flicker of stimuli not only produces a useful neuroscientific marker of selective attention, but interacts with the adaptation of selective attention itself. Our results indicate that RT patterns of adaptation after response conflict (so-called conflict adaptation) are reversed when flicker frequencies switch at once. However, this effect of frequency switches is specific to the adaptation by conflict-driven control processes, since we find no effects of frequency switches on inhibitory control processes after no-go trials. We discuss the theoretical implications of this finding and propose precautions that should be taken into account when studying conflict adaptation using frequency tagging in order to control for the described confounds. PMID- 26592668 TI - A qualitative study exploring parental perspectives and involvement in health visiting services during the Health Visitor Implementation Plan in the South West of England. AB - Internationally, there is a strong interest in engaging the public more widely in both the development and governance of public services. This study aimed to explore family perspectives on the introduction of a new policy initiative called the 'Health Visitor Implementation Plan' (Department of Health [2011] Health Visitor Implementation Plan 2011-15: A Call to Action) and their experiences of the new health visitor service provision. The policy aimed to increase the health visitor workforce by 4200 additional practitioners between 2011 and 2015, in parallel with introducing a new service model to provide comprehensive and accessible support for parents with children 0-5 years. Using a qualitative approach, data were collected via semi-structured interviews and focus groups with 22 parents between March 2013 and March 2014. Questions focused around the extent to which the new service met parental expectation and need. Participants were recruited through Children's Centres and interviewed during established group sessions. Analysis was conducted using thematic analysis and constant comparative methods. The participants were asked to share their experiences of the health visiting service and their views on this national policy initiative. Although asked to comment on the policy at nation and local level, their responses were predominantly around personal experience. Parents welcomed the increase in workforce capacity and positive experiences centred on health visitors who were caring, knowledgeable, skilled and facilitated positive outcomes. Many of the negative experiences were seen to be due to poor relationships between the parent and the health visitor. Parents were influenced by the communication skills and personal attributes of the individual health visitors, including time to listen. The strength of parental opinion indicated that parents are willing to contribute to service development, consequently policy makers and health visitors themselves need to have clarity around the purpose and mechanism of parental involvement if meaningful partnership is to become a reality. PMID- 26592669 TI - Human Factors and Ophthalmic Drug Packaging: Time for a Global Standard. PMID- 26592670 TI - Simulation Surgical Teaching in Ophthalmology. PMID- 26592671 TI - Melanomalytic Glaucoma. PMID- 26592672 TI - Optic Nerve Head Avulsion: Clinical, Radiographic, and Sonographic Correlations. PMID- 26592673 TI - Vitreous Vortex: A Unique Case of Vitreomacular Adhesion. PMID- 26592674 TI - Changes in the Corneal Architecture Following Corneal Hydrops. PMID- 26592675 TI - Appearance of Schnabel's Cavernous Degeneration of the Optic Nerve: Four Weeks Before Enucleation for Melanoma. PMID- 26592676 TI - Follicular Hybrid Cyst of the Eyelid. PMID- 26592677 TI - Re: Meuer et al.: The epidemiology of vitreoretinal interface abnormalities as detected by spectral-domain optical coherence tomography: the Beaver Dam Eye Study (Ophthalmology 2015;122:787-95). PMID- 26592678 TI - Re: Jiang et al.: Optic nerve head changes after short-term intraocular pressure elevation in acute primary angle-closure suspects (Ophthalmology 2015;122:730-7). PMID- 26592679 TI - Reply: To PMID 25556116. PMID- 26592680 TI - Reply: To PMID 25556115. PMID- 26592681 TI - Re: Parsa et al.: Nonarteritic anterior ischemic optic neuropathy (NAION): a misnomer. Rearranging pieces of a puzzle to reveal a nonischemic papillopathy caused by vitreous separation (Ophthalmology 2015;122:439-42). PMID- 26592682 TI - Reply: To PMID 25703466. PMID- 26592683 TI - Re: Parsa et al.: Nonarteritic anterior ischemic optic neuropathy (NAION): a misnomer. Rearranging pieces of a puzzle to reveal a nonischemic papillopathy caused by vitreous separation (Ophthalmology 2015;122:439-42). PMID- 26592684 TI - Re: Parsa et al.: Nonarteritic anterior ischemic optic neuropathy (NAION): a misnomer. Rearranging pieces of a puzzle to reveal a nonischemic papillopathy caused by vitreous separation (Ophthalmology 2015;122:439-42). PMID- 26592686 TI - Reply: To PMID 25703466. PMID- 26592685 TI - Reply: To PMID 26592683. PMID- 26592687 TI - Post-nuclear disaster evacuation and survival amongst elderly people in Fukushima: A comparative analysis between evacuees and non-evacuees. AB - BACKGROUND: Considering the health impacts of evacuation is fundamental to disaster planning especially for vulnerable elderly populations; however, evacuation-related mortality risks have not been well-investigated. We conducted an analysis to compare survival of evacuated and non-evacuated residents of elderly care facilities, following the Great East Japan Earthquake and subsequent Fukushima Dai-ichi nuclear power plant incident on 11th March 2011. OBJECTIVE: To assess associations between evacuation and mortality after the Fukushima nuclear incident; and to present discussion points on disaster planning, with reference to vulnerable elderly populations. METHODS: The study population comprised 1,215 residents admitted to seven elderly care facilities located 20-40km from the nuclear plant in the five years before the incident. Demographic and clinical characteristics were obtained from medical records. Evacuation histories were tracked until mid 2013. Main outcome measures are hazard ratios in evacuees versus non-evacuees using random-effects Cox proportional hazards models, and pre and post-disaster survival probabilities and relative mortality incidence. RESULTS: Experiencing the disasters did not have a significant influence on mortality (hazard ratio 1.10, 95% confidence interval: 0.84-1.43). Evacuation was associated with 1.82 times higher mortality (95% confidence interval: 1.22-2.70) after adjusting for confounders, with the initial evacuation from the original facility associated with 3.37 times higher mortality risk (95% confidence interval: 1.66-6.81) than non evacuation. CONCLUSIONS: The government should consider updating its requirements for emergency planning for elderly facilities and ensure that, in a disaster setting, these facilities have the capacity and support to shelter in place for at least sufficient time to adequately prepare initial evacuation. PMID- 26592688 TI - Effects of clustering of multiple lifestyle-related behaviors on blood pressure in adolescents from two observational studies. AB - BACKGROUD: Several lifestyle-related behaviors are associated with cardiovascular health outcomes in adolescents. To examine the associations between clustered lifestyle-related behaviors and blood pressure (BP) levels in adolescents. METHODS: Participants were recruited by multistage random cluster in two cross sectional studies; one conducted in 2006 and 2007 in ten cities from nine European countries: Athens and Heraklion in Greece, Dortmund in Germany, Ghent in Belgium, Lille in France, Pecs in Hungary, Rome in Italy, Stockholm in Sweden, Vienna in Austria, and Zaragoza in Spain; and another conducted in 2007 one city in Brazil (Maringa/PR). Systolic BP (SBP) and diastolic BP (DBP) (outcomes) and clustered behaviors (weekly consumption of fruits and vegetables, weekly consumption of sugar-sweetened beverages, sleep duration, screen time and physical activity) were analyzed. RESULTS: The Healthy Eating cluster was negatively associated with DBP in European girls, beta=-2.46 (-4.62; -0.30), and with SBP in Brazilian boys, beta=-2.79 (-3.10; -0.15). Furthermore, the Unhealthy Eating cluster was associated with increased SBP in European girls, beta=4.54 (1.29; 7.79), and in Brazilian boys, beta=4.10 (0.80; 7.40). CONCLUSION: The Healthy Eating cluster was associated with lower blood pressure, whereas the Unhealthy Eating cluster was associated with increased SBP in adolescents. PMID- 26592689 TI - Ready for a goodbye to tobacco? - Assessment of support for endgame strategies on smoking among adults in a Danish regional health survey. AB - OBJECTIVES: To assess support for a future ban on smoking and for increasing tobacco taxes in Denmark, and to explore if support differed across sex, age, educational attainment, smoking status and intention to quit. METHODS: Data from a 2013 health survey representative of the population aged >=16years in the Capital Region of Denmark (N=41,356, response rate=43.5) was linked with data on sex, age and education from central registers. Participants were asked if they supported: 1) a future ban on smoking in Denmark, and 2) increased taxes on tobacco products. Subgroup differences were explored using logistic regression. RESULTS: 30.6% supported a future ban on smoking, while 59.0% supported increased taxes. Women were less supportive of a future ban (OR=0.83 (0.78-0.88)) and more supportive of increasing taxes (OR=1.11 (1.06-1.18)) than men. Support for both measures was higher among the youngest. Only small differences were found in ban support across educational attainment, while support for taxes increased with increasing education. Support for both measures were greatest among never smokers (OR=2.66 (2.40-2.93) and OR=9.69 (8.83-10.63)) compared to daily smokers. Smokers intending to quit were two to three times as likely to support a future ban or increased taxes compared to smokers with no quit intensions. CONCLUSION: One third supported a future ban on smoking, while six out of ten supported increasing taxes. This first Danish study of support for more radical tobacco control adds to the growing literature on tobacco endgame and sets a baseline for future assessments of public support. PMID- 26592690 TI - Prostate cancer screening practices and diagnoses in patients age 50 and older, Southeastern Michigan, pre/post 2012. AB - INTRODUCTION: Studies investigating the regional impact of the 2012 U.S. Preventive Services Task Force (USPSTF) recommendation against the use of prostate specific antigen (PSA) screening for prostate cancer have been limited. METHODS: A retrospective cohort study was conducted on men age 50years and older in Southeastern Michigan pre (n=3647) and post (n=3618) USPSTF recommendation. PSA screening, transrectal ultrasound, and prostate biopsy rates were evaluated pre/post using a generalized piecewise linear model with a Poisson distribution, and log link. A knot was placed at year 2011 to estimate pre/post slope coefficients. Generalized estimating equations were used to estimate the marginal probability of a prostate diagnosis as a logistic function of pre and post period, and comorbidities. RESULTS: PSA utilization significantly increased (beta=0.28; 95% CI: 0.25, 0.31) during the pre-period, but significantly decreased in the post-period (beta=-0.29; 95% CI: -0.34, -0.25). Prostate biopsies decreased pre (beta=-0.16; 95% CI: -0.25, -0.08) and did not change post (beta=0.01; 95% CI: -0.09, 0.12). Transrectal ultrasounds were stable pre (beta=0.16; 95% CI: -0.03, 0.35) and significantly decreased post (beta=-0.27; 95% CI: -0.50, -0.04). Patients in the post-period had a decreased probability of having a diagnosis of prostate cancer (OR: 0.81; 95% CI: 0.74-0.89) compared to the pre-period. CONCLUSION: Our study demonstrates how PSA tests are still being frequently used in Southeastern Michigan. Further research is needed to better understand regional variation in prostate cancer screening practices in the U.S. PMID- 26592691 TI - A systematic review and meta-analysis of moderate-to-vigorous physical activity levels in elementary school physical education lessons. AB - OBJECTIVE: To examine elementary school students' moderate-to-vigorous physical activity (MVPA) levels during physical education (PE) lessons. METHODS: A systematic search of nine electronic databases was conducted (PROSPERO2014:CRD42014009649). Studies were eligible if they were in English; published between 2005-April 2014; assessed MVPA levels in PE lessons of elementary school children (aged four-12years); and used an objective MVPA measure. Two reviewers retrieved articles, assessed risk of bias, and performed data extraction. The findings were synthesised using a meta-analysis. RESULTS: The search yielded 5132 articles. Thirteen studies from nine countries met the inclusion criteria. Eight studies measured MVPA through observational measures, five used accelerometry and one used heart rate monitoring. The percentage of PE lesson time spent in MVPA ranged between 11.4-88.5%. Meta-analysis of seven studies (4 direct observations; 4 accelerometers) found that children spent a mean (95% CI) 44.8 (28.2-61.4)% of PE lesson time in MVPA. When measured using direct observation and accelerometers, children spent 57.6 (47.3-68.2) and 32.6 (5.9-59.3)% of PE lesson time in MVPA, respectively. The review has limitations; the search strategy was restricted to studies in English; theses, dissertations and conference abstracts were excluded; and six studies that provided insufficient data were excluded from the meta-analysis. CONCLUSION: MVPA levels during elementary school PE lessons do not meet the United States Centre for Disease Control and Prevention and the United Kingdom's Association of Physical Education recommendation (50% of lesson time), but is higher than estimated in the previous review (34.2%). Interventions to increase MVPA in PE lessons are needed. PMID- 26592692 TI - Incidence and potential risk factors of obesity among Tehranian adults. AB - AIM: Evaluating the incidence of obesity and its risk factors among Tehranian adults. MATERIAL & METHODS: In this population-based cohort, non-obese participants, aged >=20years, were followed for development of obesity (Body Mass Index (BMI) >=30). Incidence density and cumulative incidence rates of obesity were calculated for each sex. Cox proportional hazard regression was used to determine the association of potential obesity risk factors including: age, BMI, metabolic syndrome, waist circumference (WC), smoking, marital status, education, and physical activity. RESULT: A total of 7257 participants (3536 men) were followed for a median of 8years. At baseline, mean age, BMI and WC were 41.3+/ 14.6years, 25.1+/-2.9kg/m(2) (24.9+/-3kg/m(2) men and 25.2+/-3kg/m(2) women), and 84.8+/-9.8cm (87.06+/-9.2cm men and 82.6+/-9.9cm women) respectively. During the follow-up, 1345 participants (876 women) developed obesity contributing to cumulative incidences of 31.3% (CI: 29.9%-32.7%), 38.1% (CI: 36.2%-40.1%), and 23.4% (CI: 21.6%-25.3%) for the whole population, women, and men, respectively. Corresponding incidence density rates per 1000 person-year were 25.9 (CI: 24.5 27.3), 33.67 (CI: 31.5-36.0), and 18.0 (CI: 16.5-19.7), respectively. Highest incidence rates were observed during their 40s and 20s for women and men, respectively. Participants with metabolic syndrome, lower educational level, higher BMI and WC, were at higher risk of obesity development in both sexes. CONCLUSION: High incidence of obesity was observed among Tehranian adults with higher incidence of obesity in women. Different modifiable variables may act as risk factors for obesity development which should be targeted to control the epidemic of obesity. PMID- 26592693 TI - Recruitment: A Critical Leadership Task. PMID- 26592694 TI - Identification, gene expression and immune function of the novel Bm-STAT gene in virus-infected Bombyx mori. AB - Genes in the signal transducer and activator of transcription (STAT) family are vital for activities including gene expression and immune response. To investigate the functions of the silkworm Bombyx mori STAT (Bm-STAT) gene in antiviral immunity, two Bm-STAT gene isoforms, Bm-STAT-L for long form and Bm STAT-S for short form, were cloned. Sequencing showed that the open reading frames were 2313 bp encoding 770 amino acid residues for Bm-STAT-L and 2202 bp encoding 734 amino acid residues for Bm-STAT-S. The C-terminal 42 amino acid residues of Bm-STAT-L were different from the last 7 amino acid residues of Bm STAT-S. Immunofluorescence showed that Bm-STAT was primarily distributed in the nucleus. Transcription levels of Bm-STAT in different tissues were determined by quantitative PCR, and the results revealed Bm-STAT was mainly expressed in testes. Western blots showed two bands with molecular weights of 70 kDa and 130 kDa in testes, but no bands were detected in ovaries by using anti-Bm-STAT antibody as the primary antibody. Expression of Bm-STAT in hemolymph at 48 h post infection with B. mori macula-like virus (BmMLV) was slightly enhanced compared with controls, suggesting a weak response induced by infection with BmMLV. Hemocyte immunofluorescence showed that Bm-STAT expression was elevated in B. mori nucleopolyhedrovirus (BmNPV)-infected cells. Moreover, resistance of BmN cells to BmNPV was reduced by downregulation of Bm-STAT expression and increased by upregulation. Resistance of BmN cells to BmCPV was not significantly improved by upregulating Bm-STAT expression. Therefore, we concluded that Bm-STAT is a newly identified insect gene of the STAT family. The JAK-STAT pathway has a more specialized role in antiviral defense in silkworms, but JAK-STAT pathway is not triggered in response to all viruses. PMID- 26592696 TI - A switchable Gquadruplex device with the potential of a nanomachine for anticancer drug detection. AB - The unique ability of living systems to translate biochemical reactions into mechanical work has inspired the design of synthetic DNA motors which generate nanoscale motion via controllable conformational change. It is believable that G quadruplex structures in certain regions of the genome may play a role in the poor maintenance of genomic stability, which is a characteristic of many types of cancers. In this regards, formation and stabilization of the quadruplex structures at the telomeric repeats is an effective way to hamper the telomere extension and blocking the elongation step. Here, we report a DNA machine for selective Gquadruplex-binding ligand recognition, based on a conformational change; the forces exerted by the precise DNA machine for Gquadruplex conformational change were probed via an electrical signal transducer electrochemically by differential pulse voltammetry and cyclic voltammetry. The proposed machine was prepared by modifying the screen-printed graphite electrode (SPE) with the synthesized SBA-N-propylpipyrazine-N-(2-mercaptopropane-1-one) (SBA@NPPNSH) mesoporous structures and Au nanoparticles (AuNPs). The thiolated functionalized groups of SBA@NPPNSH structures can help for preconcentration of the synthesize AuNPs on the surface. Then SH-G4DNA was linked to the modified electrode by an AuNPsS bond. The morphology of constructed machine was characterized by the Field emission scanning electron microscope (FESEM). PMID- 26592695 TI - High-Throughput Screening (HTS) by NMR Guided Identification of Novel Agents Targeting the Protein Docking Domain of YopH. AB - Recently we described a novel approach, named high-throughput screening (HTS) by NMR that allows the identification, from large combinatorial peptide libraries, of potent and selective peptide mimetics against a given target. Here, we deployed the "HTS by NMR" approach for the design of novel peptoid sequences targeting the N-terminal domain of Yersinia outer protein H (YopH-NT), a bacterial toxin essential for the virulence of Yersinia pestis. We aimed at disrupting the protein-protein interactions between YopH-NT and its cellular substrates, with the goal of inhibiting indirectly YopH enzymatic function. These studies resulted in a novel agent of sequence Ac-F-pY-cPG-d-P-NH2 (pY=phosphotyrosine; cPG=cyclopentyl glycine) with a Kd value against YopH-NT of 310 nm. We demonstrated that such a pharmacological inhibitor of YopH-NT results in the inhibition of the dephosphorylation by full-length YopH of a cellular substrate. Hence, potentially this agent represents a valuable stepping stone for the development of novel therapeutics against Yersinia infections. The data reported further demonstrate the utility of the HTS by NMR approach in deriving novel peptide mimetics targeting protein-protein interactions. PMID- 26592697 TI - Structural characterization and immunomodulating activity of polysaccharide from Dendrobium officinale. AB - A neutral heteropolysaccharide (DOP-1-1) consisted by mannose and glucose (5.9:1) with an average molecular weight at about 1.78*10(5) Da was purified from Dendrobium officinale. Based on Fourier transform infrared spectrum (FT-IR) and nuclear magnetic resonance (NMR) spectra, it suggested that partial structure of DOP-1-1 is an O-acetylated glucomannan with beta-d configuration in pyranose sugar forms. The immunomodulatory activity of DOP-1-1 was evaluated by secretion level of cytokine (interleukin (IL)-1beta and IL-10) and tumor necrosis factor (TNF)-alpha in vitro. Our results suggested that DOP-1-1 could stimulate cytokine production (TNF-alpha, IL-1beta) in cells. These findings demonstrated that the purified polysaccharide from D. officinale presented significant immune modulating activities. Furthermore, by Western-blot we can found that the signaling pathways of DOP-1-1 induced immune activities involving ERK1/2 and NF kB. As to antioxidant activity, DOP-1-1 hadn't showed remarkable scavenging capacity of 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) in contrast with other studies of polysaccharides from D. officinale. PMID- 26592698 TI - Tapioca starch blended alginate mucoadhesive-floating beads for intragastric delivery of Metoprolol Tartrate. AB - The objective of the study was to develop tapioca starch blended alginate mucoadhesive-floating beads for the intragastric delivery of Metoprolol Tartrate (MT). The beads were prepared by ionotropic gelation method using calcium chloride as crosslinker and gas forming calcium carbonate (CaCO3) as floating inducer. The alginate gel beads having 51-58% entrapped MT showed 90% release within 45 min in gastric medium (pH 1.2). Tapioca starch blending markedly improved the entrapment efficiency (88%) and sustained the release for 3-4 h. A 12% w/w HPMC coating on these beads extended the release upto 9-11 h. In vitro wash off and buoyancy test in gastric media revealed that the beads containing CaCO3 has gastric residence of more than 12 h. In vitro optimized multi-unit formulation consisting of immediate and sustained release mucoadhesive-floating beads (40:60) showed good initial release of 42% MT within 1h followed by a sustained release of over 90% for 11 h. Pharmacokinetic study performed in rabbit model showed that the relative oral bioavailability of MT after administration of oral solution, sustain release and optimized formulation was 51%, 67% and 87%, respectively. Optimized formulation showed a higher percent inhibition of isoprenaline induced heart rate in rabbits for almost 12 h. PMID- 26592699 TI - Effect of hydrolysed cellulose nanowhiskers on properties of montmorillonite/polylactic acid nanocomposites. AB - Polylactic acid (PLA) nanocomposites reinforced with hybrid montmorillonite/cellulose nanowhiskers [MMT/CNW(SO4)] were prepared by solution casting. The CNW(SO4) nanofiller was first isolated from microcrystalline cellulose using acid hydrolysis treatment. PLA/MMT/CNW(SO4) hybrid nanocomposites were prepared by the addition of various amounts of CNW(SO4) [1-9 parts per hundred parts of polymer (phr)] into PLA/MMT nanocomposite at 5 phr MMT content, based on highest tensile strength values as reported previously. The biodegradability, thermal, tensile, morphological, water absorption and transparency properties of PLA/MMT/CNW(SO4) hybrid nanocomposites were investigated. The Biodegradability, thermal stability and crystallinity of hybrid nanocomposites increased compared to PLA/MMT nanocomposite and neat PLA. The highest tensile strength of hybrid nanocomposites was obtained by incorporating 1 phr CNW(SO4) [~ 36 MPa]. Interestingly, the ductility of hybrid nanocomposites increased significantly by 87% at this formulation. The Young's modulus increased linearly with increasing CNW(SO4) content. This is due to the relatively good dispersion of nanofillers in the hybrid nanocomposites, as revealed by transmission electron microscopy. Fourier transform infrared spectroscopy indicated the formation of some polar interactions. In addition, water resistance of the hybrid nanocomposites improved and the visual transparency of neat PLA film did not affect by addition of CNW(SO4). PMID- 26592700 TI - Dibutyrylchitin nanoparticles as novel drug carrier. AB - Chitin is a ubiquitous renewable biopolymer that is significantly distributed in the natural world. Biopolymeric nanoparticles (Nps) have been developed for various biomedical applications by researchers. Here, chitin derivative, dibutyrylchitin Nps (DBC) was synthesized as a nanocarrier for drug delivery using butyric anhydride and perchloric acid as a catalyst under heterogeneous conditions. The structural characterization was analyzed by FT-IR and FE SEM study showed spherical particles in a size range of 80-90 nm. The physiochemical evaluation involves swelling behavior and in vitro biodegradation studies. The results of in vitro hemolytic assay validate the blood compatibility of the prepared system. Drug release profiles indicate that 5-flourouracil (Fu) loaded dibutyrylchitin Nps (DBC-Fu) gives the enhanced drug release in acidic pH when compared to neutral pH. The encapsulation efficiency of DBC-Fu was found to be 90%. The confocal analysis also confirmed the uptake of both DBC and DBC-Fu Nps by A549 cell lines. Hence, this study shows that the DBC have the potential to be used as a drug carrier and also for other biomedical applications. PMID- 26592701 TI - Production and characterization of cellulose reinforced starch (CRT) films. AB - Starch from Tamarind seed is considered to be a nonedible and inexpensive component, with many industrial applications. Extraction and characterization of tamarind seed starch was carried out for the synthesis of biopolymer. Tamarind seeds were collected, cleaned and further roasted, decorticated, and pulverized to get starch powder. Total starch content present in each tamarind seed is estimated to be around 65-70%. About 84.68% purified starch can be recovered from the tamarind seed. Defatted Tamarind seed starch has an amylose content of 27.55 wt.% and 72.45 wt.% of amylopectin. Morphological (SEM) and X-ray diffraction were used to evaluate crystallinity. Likewise, TGA and DSC of starch have also been analyzed. Thermal properties of starch obtained from tamarind seeds showed good thermal stability when compared to other starch sources such as Mesquite seed and Mango kernel. This study proved that the tamarind seed starch can be used as a potential biopolymer material. Thermo-stable biofilms were produced through initial optimization studies. Predictive response surface quadratic models were constructed for prediction and optimization of biofilm mechanical properties. Correlation coefficient values were calculated to me more than 0.90 for mechanical responses which implies the fitness of constructed model with experimental data. PMID- 26592702 TI - Production and structural elucidation of exopolysaccharide from endophytic Pestalotiopsis sp. BC55. AB - There is a little information on exopolysaccharide production by endophytic fungi. In this investigation endophytic Pestalotiopsis sp. BC55 was used for optimization of exopolysaccharide production. One variable at a time method and response surface methodology were adopted to find out the best culture conditions and medium compositions for maximum exopolysaccharide production. The organism produced maximum exopolysaccharide (4.320 +/- 0.022 g/l EPS) in 250 ml Erlenmeyer flask containing 75 ml potato dextrose broth supplemented with (g%/l) glucose, 7.66; urea, 0.29; CaCl2, 0.05 with medium pH 6.93; after 3.76 days of incubation at 24 degrees C. Exopolysaccharide [EPS (EP-I)] produced by this organism have Mw ~2*10(5)Da with a melting point range of 122-124 degrees C. Structural elucidation of the EPS (PS-I) was carried out after a series of experiments. Result indicated the presence of only (1->3)-linked beta-d-glucopyranosyl moiety. The structure of the repeating unit was established as - ->3)-beta-d-Glcp-(1->. PMID- 26592703 TI - IMAGING DIAGNOSIS-URETHROVAGINAL FISTULA CAUSED BY A MIGRATING GRASS AWN IN THE VAGINA. AB - A young intact female dog was presented with urinary incontinence. Abdominal ultrasound revealed the presence of hyperechoic linear structures within the cranial vagina suggestive of foreign material. A computed tomography (CT) retrograde vaginourethrogram demonstrated the presence of a fistulous tract between the urethra and vagina. A presumptive diagnosis of urethrovaginal fistula due to migration of foreign material was made. The grass awn was removed with vaginoscopic-guided retrieval. Fourteen days later, surgical repair of the fistula and an ovariohysterectomy were done. This case report emphasizes the usefulness of CT for diagnosis and precise anatomical localization of genitourinary tract fistulas. PMID- 26592704 TI - Oligonucleotide-Based Mimetics of Hepatocyte Growth Factor. AB - Oligonucleotide-based hepatocyte growth factor (HGF) mimetics are described. A DNA aptamer to Met, a cognate receptor for HGF, was shown to induce Met activation when used in dimer form. The most potent aptamer dimer, ss-0, which was composed solely of 100-mer single-stranded DNA, exhibited nanomolar potency. Aptamer ss-0 reproduced HGF-induced cellular behaviors, including migration and proliferation. The present work sheds light on oligonucleotides as a novel chemical entity for the design of growth factor mimetics. PMID- 26592705 TI - Perceived parenting stress in the course of postpartum depression: the buffering effect of maternal bonding. AB - Research investigating maternal bonding and parenting stress in the course of postpartum depression is lacking. Aim of the study was to investigate the development and potential mediation of both constructs in the course of postpartum depression. n = 31 mothers with postpartum depression according to DSM IV and n = 32 healthy controls completed the German version of the Postpartum Bonding Questionnaire and the Parenting Stress Index at two measuring times: acute depression (T1) and remission (T2). At T1, the clinical group reported lower bonding and higher parenting stress. Bonding was found to partially mediate the link between maternal diagnosis and parenting stress. Furthermore, the clinical group reported lower bonding and higher parenting stress averaged over both measurement times. However, at T2, the clinical group still differed from the controls even though they improved in bonding and reported less parenting stress. A significant increase of bonding was also observed in the control group. Maternal bonding seems to buffer the negative impact of postpartum depression on parenting stress. The results emphasize the need for interventions focusing on maternal bonding and mother-infant interaction in order to prevent impairment of the mother-child relationship. PMID- 26592706 TI - Investigating the Influence of (Deoxy)fluorination on the Lipophilicity of Non-UV Active Fluorinated Alkanols and Carbohydrates by a New log P Determination Method. AB - Property tuning by fluorination is very effective for a number of purposes, and currently increasingly investigated for aliphatic compounds. An important application is lipophilicity (log P) modulation. However, the determination of log P is cumbersome for non-UV-active compounds. A new variation of the shake flask log P determination method is presented, enabling the measurement of log P for fluorinated compounds with or without UV activity regardless of whether they are hydrophilic or lipophilic. No calibration curves or measurements of compound masses/aliquot volumes are required. With this method, the influence of fluorination on the lipophilicity of fluorinated aliphatic alcohols was determined, and the log P values of fluorinated carbohydrates were measured. Interesting trends and changes, for example, for the dependence on relative stereochemistry, are reported. PMID- 26592707 TI - Inhibitory control training for appetitive behaviour change: A meta-analytic investigation of mechanisms of action and moderators of effectiveness. AB - Inhibitory control training (ICT) is a novel intervention in which participants learn to associate appetitive cues with inhibition of behaviour. We present a meta-analytic investigation of laboratory studies of ICT for appetitive behaviour change in which we investigate candidate mechanisms of action, individual differences that may moderate its effectiveness, and compare it to other psychological interventions. We conducted random-effects generic inverse variance meta-analysis on data from 14 articles (18 effect sizes in total). Participants who received ICT chose or consumed significantly less food or alcohol compared to control groups (SMD = 0.36, 95% CIs [0.24, 0.47]; Z = 6.18, p < .001; I(2) = 71%). Effect sizes were larger for motor (Go/No-Go and Stop Signal) compared to oculomotor (Antisaccade) ICT. The effects of ICT on behaviour were comparable to those produced by other psychological interventions, and effects of ICT on food intake were greater in participants who were attempting to restrict their food intake. The magnitude of the effect of ICT on behaviour was predicted by the proportion of successful inhibitions but was unrelated to the absolute number of trials in which appetitive cues were paired with the requirement to inhibit, or the contingency between appetitive cues and the requirement to inhibit. The effect of ICT on cue devaluation (primarily assessed with implicit association tests) was not statistically significant. Our analysis confirms the efficacy of ICT for short-term behaviour change in the laboratory, and we have demonstrated that its effectiveness may depend on pairings between appetitive cues and successful inhibition. We highlight the need for further research to translate these findings outside of the laboratory. PMID- 26592708 TI - Protective effects of chicken egg yolk antibody (IgY) against experimental Vibrio splendidus infection in the sea cucumber (Apostichopus japonicus). AB - Vibrio splendidus is one of the most harmful pathogens associated with skin ulceration syndrome in the sea cucumber (Apostichopus japonicus) due to its high virulence and frequency of appearance. The objective of this study was to determine the effectiveness of chicken egg yolk antibody (IgY) against V. splendidus infection in the sea cucumber. Whole V. splendidus cells were used as an immunogen to immunize 20 White Leghorn hens (25 weeks old). IgY was produced from egg yolks obtained from these immunized hens using water dilution, two-step salt precipitation and ultrafiltration. The purity of the IgY produced was approximately 83%. Enzyme-linked Immunosorbent Assay indicated a high specificity for IgY with a maximum antibody titer of 320,000. The growth of V. splendidus in liquid medium was significantly inhibited by IgY in a dose-dependent manner at concentrations ranging from 1 to 10 mg/mL. The protective effects of IgY were evaluated in sea cucumber by intraperitoneally injecting anti-V. splendidus IgY antibodies (10 mg/mL) or immersing the sea cucumber in aqueous IgY (1 g/L) after an intraperitoneal injection of V. splendidus. Intraperitoneal injection resulted in an 80% survival while immersion resulted in a 75% survival during the 11-day experimental period. The survival rates were significantly higher than the positive control and the non-specific IgY group (P < 0.05). As well, the bacterial burden in the respiratory tree, intestine and coelomic liquid was significantly (P < 0.05) lower in sea cucumber treated with specific IgY than those treated with non-specific IgY. The phagocytosis of coelomocytes for V. splendidus in the presence of specific IgY was significantly (P < 0.05) higher than that obtained with non-specific IgY or without IgY, suggesting that specific IgY enhanced phagocytic activity. The current work suggests that specific IgY has potential for protecting sea cucumbers against V. splendidus infection. PMID- 26592709 TI - Gctf: Real-time CTF determination and correction. AB - Accurate estimation of the contrast transfer function (CTF) is critical for a near-atomic resolution cryo electron microscopy (cryoEM) reconstruction. Here, a GPU-accelerated computer program, Gctf, for accurate and robust, real-time CTF determination is presented. The main target of Gctf is to maximize the cross correlation of a simulated CTF with the logarithmic amplitude spectra (LAS) of observed micrographs after background subtraction. Novel approaches in Gctf improve both speed and accuracy. In addition to GPU acceleration (e.g. 10-50*), a fast '1-dimensional search plus 2-dimensional refinement (1S2R)' procedure further speeds up Gctf. Based on the global CTF determination, the local defocus for each particle and for single frames of movies is accurately refined, which improves CTF parameters of all particles for subsequent image processing. Novel diagnosis method using equiphase averaging (EPA) and self-consistency verification procedures have also been implemented in the program for practical use, especially for aims of near-atomic reconstruction. Gctf is an independent program and the outputs can be easily imported into other cryoEM software such as Relion (Scheres, 2012) and Frealign (Grigorieff, 2007). The results from several representative datasets are shown and discussed in this paper. PMID- 26592710 TI - Formation of biomineral iron oxides compounds in a Fe hyperaccumulator plant: Imperata cylindrica (L.) P. Beauv. AB - We report a detailed work of composition and location of naturally formed iron biominerals in plant cells tissues grown in iron rich environments as Imperata cylindrica. This perennial grass grows on the Tinto River banks (Iberian Pyritic Belt) in an extreme acidic ecosystem (pH~2.3) with high concentration of dissolved iron, sulphate and heavy metals. Iron biominerals were found at the cellular level in tissues of root, stem and leaf both in collected and laboratory cultivated plants. Iron accumulated in this plant as a mix of iron compounds (mainly as jarosite, ferrihydrite, hematite and spinel phases) was characterized by X-ray diffraction (XRD), X-ray absorption spectroscopy (XAS), Mossbauer spectroscopy (MS), magnetometry (SQUID), electron microscopy with energy dispersive X-ray spectroscopy (SEM-EDX; TEM-EDX; HRSTEM). A low fraction of phosphorous was detected in this iron hyperaccumulator plant. Root and rhizomes tissues present a high proportion of ferromagnetic iron oxide compounds. Iron oxides-rich zones are localized in electron dense intra and inter-cellular aggregates that appear as dark deposits covering the inner membrane and organelles of the cell. This study aims to contribute to a better understanding of the mechanisms of accumulation, transport, distribution of iron in Imperata cylindrica. PMID- 26592711 TI - Myeloid cell distribution and activity in multiple sclerosis. AB - Multiple sclerosis (MS) is a demyelinating disease in which an exacerbated immune response provokes oligodendrocyte loss and demyelination, the hallmarks of this neurological disease. The destruction of myelin due to the uncontrolled activity of the invading immune cells leads to the formation of MS plaques. Among the different leukocytes that participate in the immune response associated with MS, the role of myeloid cells has been analyzed extensively (i.e. macrophages, dendritic cells -DCs- and neutrophils). Hence, in this review we will summarize what is known about the distribution, expression and markers available to study myeloid cells, and their histopathology, not only in a standard animal model of MS (autoimmune experimental encephalomyelitis -EAE) but also in MS tissue. In this review, we will not only refer to mature myeloid cells but also to the undifferentiated and almost unexplored myeloid-derived suppressor cells (MDSCs). The active role of MDSCs in the prompt resolution of an immune episode is gaining importance, yet is still the subject of some debate. Finally, the similarities and differences between MS and EAE are discussed, particularly in terms of myeloid cell phenotype, activity and the markers used. PMID- 26592712 TI - Hyperacute Methotrexate Pneumonitis in a Patient With Crohn's Disease. PMID- 26592713 TI - Cytomorphology is often insufficient to categorize non-small-cell lung carcinoma on FNA specimens. AB - OBJECTIVES: To determine the accuracy and reproducibility of differentiating between squamous cell carcinoma (SCC) and adenocarcinoma (ADC) on fine-needle aspiration (FNA) specimens. METHODS: Fifty cases of NSCLC diagnosed by FNA having either concurrent core biopsies or resection as a diagnostic reference standard were selected. FNA slides were reviewed independently by five blinded observers. Two rounds of review were performed. Cases were initially categorized as SCC, favor SCC, NSCLC (type indeterminate), favor ADC, or ADC; while the indeterminate category was eliminated in the second round of review. RESULTS: The interobserver agreement was 0.22 and 0.1 with and without the indeterminate category, respectively. The overall accuracy for differentiating between SCC and ADC of the lung was 65% with the indeterminate category and 66% without. CONCLUSION: Overall, the low interobserver agreement in our study indicates that accurate subclassification between the NSCLCs often cannot be made by cytomorphology alone. PMID- 26592714 TI - Role of dorsal hippocampal orexin-1 receptors in memory restoration induced by morphine sensitization phenomenon. AB - The present study was examined the blockade of CA1 orexin-1 receptors (OX1Rs) of the dorsal hippocampus in the induction or expression phase on morphine sensitization-induced memory restoration using the Morris water maze (MWM) apparatus. Results showed that pre-training administration of morphine (5mg/kg, s.c.) increases escape latency and traveled distance, while does not alter swimming speed. This supports the impairing effect of morphine on the spatial memory acquisition in male adult rats. Also, in the retrieval session (probe trial) this treatment decreased the time spent in the target quadrant. Moreover, morphine-induced sensitization (15 or 20mg/kg, s.c.; once daily for 3days and followed by 5days no drug treatment) restored the memory acquisition/retrieval deficit which had been induced by pre-training administration of morphine (5mg/kg, s.c.). Intra-CA1 microinjection of subthreshold doses of SB-334867 (OX1Rs antagonist; 10, 20 and 40nmol/rat), 5min before morphine (20mg/kg/day*3days, s.c.; induction phase for morphine sensitization) did not alter restoration of memory acquisition/retrieval produced by the morphine sensitization phenomenon. In contrast, microinjection of subthreshold doses of SB 334867 (10, 20 and 40nmol/rat) into the CA1 region in the training session, 5min prior to morphine (5mg/kg, s.c.; expression phase for morphine sensitization) blocked the spatial memory acquisition/retrieval in morphine-sensitized rats. In conclusion, these findings show that morphine sensitization reverses morphine induced amnesia. Furthermore, the blockade of CA1 OX1Rs in the expression phase, but not in the induction phase, disrupts memory restoration induced by morphine sensitization. PMID- 26592715 TI - MicroRNA expression is altered in lateral septum across reproductive stages. AB - MicroRNAs (miRNAs) inhibit RNA targets and may contribute to postpartum central nervous system (CNS) gene expression changes, although this has never been tested. In the present study, we directly evaluated miRNA levels using RNA sequencing during reproduction in female mice in the lateral septum (LS). We found the reliable and robust changes of miRNAs away from the virgin stage at the three other stages, namely pregnant, day 1 postpartum, and day 8 postpartum. For a given miRNA that was significantly different from the virgin condition in more than one group, the direction of change was always the same. Overall, we identified 32 upregulated miRNAs and 25 downregulated miRNAs that were consistently different from the virgin state. 'Arm switching' occurs for miR-433 3 and miR-7b. Unexpectedly, a third of upregulated miRNAs (relative to virgin) were highly localized within the 12qF1 region of chromosome 12 that includes the Dlk1-Dio3 gene cluster implicated in stem cell and neuronal differentiation. Over 1500 genes were targeted by multiple upregulated miRNAs with about 100 genes targeted by five or more miRNAs. Over 1000 genes were targeted by multiple downregulated miRNAs with about 50 genes targeted by five or more miRNAs. Half of the target genes were regulated by up and downregulated miRNAs, indicating homeostatic regulation. Transcriptional regulation was the most enriched pathway for genes linked to up or down regulated miRNAs. Other enriched pathways included protein kinase activity (e.g., MAP kinase), CNS development, axon guidance, neurotrophin signaling, neuron development/differentiation, and neurogenesis. Previously published postpartum LS gene expression changes were enrichment for LS miRNA targets, as expected. Surprisingly, postpartum gene expression changes from other regions were also enriched against LS miRNA targets, suggesting a core group of miRNAs may act across the CNS during reproduction. Together, we directly examine miRNAs and find significant alterations in the postpartum brain. PMID- 26592716 TI - Thyroid hormone is required for the pruning of afferent type II spiral ganglion neurons in the mouse cochlea. AB - Afferent connections to the sensory inner (IHCs) and outer hair cells (OHCs) in the cochlea refine and functionally mature during the thyroid hormone (TH) critical period of inner ear development that occurs perinatally in rodents. In this study, we investigated the effects of hypothyroidism on afferent type II innervation to outer hair cells using the Snell dwarf mouse (Pit1(dw)). Using a transgenic approach to specifically label type II spiral ganglion neurons (SGNs), we found that lack of TH causes persistence of excess type II SGN connections to the OHCs, as well as continued expression of the hair cell functional marker, otoferlin (OTOF), in the OHCs beyond the maturation period. We also observed a concurrent delay in efferent attachment to the OHCs. Supplementing with TH during the early postnatal period from postnatal day (P) 3 to P4 reversed the defect in type II SGN pruning but did not alter OTOF expression. Our results show that hypothyroidism causes a defect in the large-scale pruning of afferent type II SGNs in the cochlea, and a delay in efferent attachment and the maturation of OTOF expression. Our data suggest that the state of maturation of hair cells, as determined by OTOF expression, may not regulate the pruning of their afferent innervation. PMID- 26592717 TI - Sox2 functionally interacts with betaAPP, the betaAPP intracellular domain and ADAM10 at a transcriptional level in human cells. AB - Sox2 (SRY (Sex-determining region Y)-related high mobility group (HMG) box 2) is a transcription factor that serves key roles in controlling the balance between stem cells maintenance and commitment to differentiated lineages throughout the lifetime. Importantly, Sox2 deficiency results in early embryonic lethality whereas the down-regulation of Sox2 expression triggers neurodegeneration in the adult mouse brain. Moreover, Sox2 is decreased in the brain of Alzheimer's disease (AD) patients and co localizes with the beta-amyloid precursor protein (betaAPP) in stem cells. Here we report the existence of functional interactions between Sox2 and betaAPP, the betaAPP intracellular domain AICD50 and the alpha secretase ADAM10 in human cells. We first show, as observed in embryonic stem cells, that betaAPP overexpression in HEK293 cells results in an increase of Sox2 immunoreactivity and we further establish the transcriptional nature of this pathway. Moreover, overexpression of the pro-apoptotic C-terminal betaAPP-derived AICD50 metabolite leads to the down-regulation of Sox2 transcription whereas the pharmacological inhibition of endogenous AICD production increases Sox2 expression in both HEK293 and SH-SY5Y cell lines. In addition, we demonstrate that Sox2 is a potent activator of the non amyloidogenic processing of betaAPP as shown by the Sox2-dependent augmentation of ADAM10 catalytic activity, immunoreactivity, promoter transactivation and mRNA levels with no modification of the activity and the expression of the beta-secretase BACE1. Finally, the fact that gamma-secretase inhibition induces an increase of ADAM10 protein levels in SH-SY5Y cells further supports the occurrence of functional AICD/Sox2/ADAM10 interactions. Altogether, our study identifies and characterizes new functional cross-talks between Sox2 and proteins involved in AD, thereby adding support to the view that Sox2 likely behaves as a protective factor during the development of this neurodegenerative disease. PMID- 26592718 TI - Feedback from visual cortical area 7 to areas 17 and 18 in cats: How neural web is woven during feedback. AB - To investigate the feedback effect from area 7 to areas 17 and 18, intrinsic signal optical imaging combined with pharmacological, morphological methods and functional magnetic resonance imaging (fMRI) was employed. A spatial frequency dependent decrease in response amplitude of orientation maps was observed in areas 17 and 18 when area 7 was inactivated by a local injection of GABA, or by a lesion induced by liquid nitrogen freezing. The pattern of orientation maps of areas 17 and 18 after the inactivation of area 7, if they were not totally blurred, paralleled the normal one. In morphological experiments, after one point at the shallow layers within the center of the cat's orientation column of area 17 was injected electrophoretically with HRP (horseradish peroxidase), three sequential patches in layers 1, 2 and 3 of area 7 were observed. Employing fMRI it was found that area 7 feedbacks mainly to areas 17 and 18 on ipsilateral hemisphere. Therefore, our conclusions are: (1) feedback from area 7 to areas 17 and 18 is spatial frequency modulated; (2) feedback from area 7 to areas 17 and 18 occurs mainly ipsilaterally; (3) histological feedback pattern from area 7 to area 17 is weblike. PMID- 26592719 TI - Length-dependent axo-terminal degeneration at the neuromuscular synapses of type II muscle in SOD1 mice. AB - In motor neuron diseases, there is a prolonged period of time before any clinical symptoms begin to appear. During this time, distal axonal degeneration, or "dying back" axonopathy, begins to occur before the onset of clinical symptoms and motor neuron death. This preclinical degeneration is a hallmark of motor neuron diseases in both animal models and human patients. Generally, in muscles with mixed fiber types, distal degeneration occurs in fast-fatigable alpha-motor axons innervating type IIb muscle fibers before axons innervating slow, type I muscle fibers. We investigated whether the "dying back" axonopathy in a pure fast fatigable alpha-motor axon nerve is a length-dependent process. The lateral thoracic nerve (LTN) exclusively consists of motor nerves that innervate the very thin cutaneous maximus muscle (CMM) that solely contains type II neuromuscular synapses. We characterized the LTN and CMM synapses both morphologically and physiologically in the superoxide dismutase 1 (SOD1) mutant mouse model of amyotrophic lateral sclerosis (ALS). By 60days of age, there was a significant "dying back" phenomenon at the caudal region while the rostral region remained intact. The longer axons innervating the caudal region appear to be more susceptible to degeneration in the SOD1 mouse indicating that the axonal degeneration of motor neurons innervating type II fibers is a length-dependent process. Additionally, we identified how the simplicity of the LTN-CMM system offers a better method to investigate axon degeneration in an ALS mouse model and may be used to investigate possible therapeutic compounds for axon protection and regeneration. PMID- 26592720 TI - Maternal creatine supplementation affects the morpho-functional development of hippocampal neurons in rat offspring. AB - Creatine supplementation has been shown to protect neurons from oxidative damage due to its antioxidant and ergogenic functions. These features have led to the hypothesis of creatine supplementation use during pregnancy as prophylactic treatment to prevent CNS damage, such as hypoxic-ischemic encephalopathy. Unfortunately, very little is known on the effects of creatine supplementation during neuron differentiation, while in vitro studies revealed an influence on neuron excitability, leaving the possibility of creatine supplementation during the CNS development an open question. Using a multiple approach, we studied the hippocampal neuron morphological and functional development in neonatal rats born by dams supplemented with 1% creatine in drinking water during pregnancy. CA1 pyramidal neurons of supplemented newborn rats showed enhanced dendritic tree development, increased LTP maintenance, larger evoked-synaptic responses, and higher intrinsic excitability in comparison to controls. Moreover, a faster repolarizing phase of action potential with the appearance of a hyperpolarization were recorded in neurons of the creatine-treated group. Consistently, CA1 neurons of creatine exposed pups exhibited a higher maximum firing frequency than controls. In summary, we found that creatine supplementation during pregnancy positively affects morphological and electrophysiological development of CA1 neurons in offspring rats, increasing neuronal excitability. Altogether, these findings emphasize the need to evaluate the benefits and the safety of maternal intake of creatine in humans. PMID- 26592721 TI - Evaluation of liposomal nanocarriers loaded with ETB receptor agonist, IRL-1620, using cell-based assays. AB - One common feature of most neurodegenerative diseases, including Alzheimer's disease (AD) and stroke, is the death of neuronal cells. Neuronal cell death is associated with apoptosis, generation of reactive oxygen species and oxidative stress. Neuronal cell death pathways can be reversed by endothelin B receptor agonist, IRL-1620, which was found to enhance neuroprotection by promoting vascular and neuronal growth in a rodent stroke model. Previous studies conducted at our institution indicated that the treatment with IRL-1620 significantly improved neurological and motor function while reducing oxidative stress and overall infarct area. IRL-1620 is a hydrophilic, 15 amino acid peptide and has a molecular weight of 1820Da. In this study, we have encapsulated IRL-1620 in PEGylated liposomes in order to enhance its efficacy. Each batch of liposomes encapsulating IRL-1620 was evaluated for particle size, polydispersity index, and charge (zeta potential) over a period of time to determine their stability. A dose-response bar graph was plotted based on the effect of neuroprotection by free IRL-1620 on differentiated neuronal PC-12 cells. The 1nM concentration was found to have the highest cell viability. The liposomes loaded with IRL-1620 were tested on differentiated neuronal PC-12 cells for their neuroprotective ability against apoptosis caused by removal of nerve growth factor (NGF) against free (non-encapsulated) IRL-1620. The liposomal IRL-1620 was found to proliferate the growth of serum-deprived differentiated PC-12 cells significantly (p<0.0001). In the western blot analysis, the expression of the anti-apoptotic marker, BCL-2 was found to be increased, and that of pro-apoptotic marker, BAX was found to be decreased with liposomal IRL-1620. The effects were found to be independent of the NGF levels. Finally the free IRL-1620 was found to cause neuronal outgrowth equivalent to the 75ng/ml NGF treatment. PMID- 26592722 TI - GABA withdrawal syndrome: GABAA receptor, synapse, neurobiological implications and analogies with other abstinences. AB - The sudden interruption of the increase of the concentration of the gamma aminobutyric acid (GABA), determines an increase in neuronal activity. GABA withdrawal (GW) is a heuristic analogy, with withdrawal symptoms developed by other GABA receptor-agonists such as alcohol, benzodiazepines, and neurosteroids. GW comprises a model of neuronal excitability validated by electroencephalogram (EEG) in which high-frequency and high-amplitude spike-wave complexes appear. In brain slices, GW was identified by increased firing synchronization of pyramidal neurons and by changes in the active properties of the neuronal membrane. GW induces pre- and postsynaptic changes: a decrease in GABA synthesis/release, and the decrease in the expression and composition of GABAA receptors associated with increased calcium entry into the cell. GW is an excellent bioassay for studying partial epilepsy, epilepsy refractory to drug treatment, and a model to reverse or prevent the generation of abstinences from different drugs. PMID- 26592724 TI - Mathematical modeling and simulation in animal health. Part I: Moving beyond pharmacokinetics. AB - The application of mathematical modeling to problems in animal health has a rich history in the form of pharmacokinetic modeling applied to problems in veterinary medicine. Advances in modeling and simulation beyond pharmacokinetics have the potential to streamline and speed-up drug research and development programs. To foster these goals, a series of manuscripts will be published with the following goals: (i) expand the application of modeling and simulation to issues in veterinary pharmacology; (ii) bridge the gap between the level of modeling and simulation practiced in human and veterinary pharmacology; (iii) explore how modeling and simulation concepts can be used to improve our understanding of common issues not readily addressed in human pharmacology (e.g. breed differences, tissue residue depletion, vast weight ranges among adults within a single species, interspecies differences, small animal species research where data collection is limited to sparse sampling, availability of different sampling matrices); and (iv) describe how quantitative pharmacology approaches could help understanding key pharmacokinetic and pharmacodynamic characteristics of a drug candidate, with the goal of providing explicit, reproducible, and predictive evidence for optimizing drug development plans, enabling critical decision making, and eventually bringing safe and effective medicines to patients. This study introduces these concepts and introduces new approaches to modeling and simulation as well as clearly articulate basic assumptions and good practices. The driving force behind these activities is to create predictive models that are based on solid physiological and pharmacological principles as well as adhering to the limitations that are fundamental to applying mathematical and statistical models to biological systems. PMID- 26592723 TI - Effects of microwave pretreatment and transglutaminase crosslinking on the gelation properties of soybean protein isolate and wheat gluten mixtures. AB - BACKGROUND: The integration of soybean protein isolate (SPI) with wheat gluten (WG) crosslinked via microbial transglutaminase (MTGase) may enhance the formation of epsilon-(gamma-glutamyl)lysine covalent bonds, because SPI is rich in lysine and WG contains more glutamine. Microwave pretreatment may accelerate enzymatic reactions. In this study, we aimed to elucidate the effects of microwave pretreatment on the gelation properties of SPI and WG crosslinked with MTGase. RESULTS: Interestingly, the gel strength, water-holding capacity (WHC) and storage modulus (G') values of MTGase-induced SPI/WG gels were dramatically improved with increasing microwave power. Moreover, the MTGase crosslinking reaction promoted the formation of disulfide bonds, markedly reducing the free SH group and soluble protein content of gels. Fourier transform infrared spectroscopic analysis of SPI/WG gels showed that microwave pretreatment increased the proportion of alpha-helices and beta-turns and decreased the proportion of beta-sheets. Results from scanning electron microscopy indicated that the MTGase-induced SPI/WG gels had denser and more homogeneous microstructures after microwave pretreatment. CONCLUSION: The effect of microwave pretreatment is useful in advancing gelation characters of MTGase-induced SPI/WG gels and provides the possibility for expanding the application of food protein. (c) 2015 Society of Chemical Industry. PMID- 26592726 TI - Systematic implications of brain morphology in potamotrygonidae (Chondrichthyes: Myliobatiformes). AB - The gross brain morphology, brain proportions, and position of cranial nerves in all four genera (Potamotrygon, Plesiotrygon, Paratrygon, and Heliotrygon) and 11 of the species of the Neotropical stingray family Potamotrygonidae were studied to provide new characters that may have a bearing on internal potamotrygonid systematics. The brain was also studied in four other stingray (Myliobatiformes) genera (Hexatrygon, Taeniura, Dasyatis, and Gymnura) to provide a more inclusive phylogenetic context for the interpretation of features of the brain in potamotrygonids. Our results indicate, based on neuroanatomical characters, that the genera Paratrygon and Heliotrygon are sister groups, as are the genera Potamotrygon and Plesiotrygon, agreeing with previous morphological and molecular phylogenetic studies. Both groups of genera share distinct conditions of the olfactory tracts, telencephalon and its central nuclei, hypophysis and infundibulum, morphology and orientation of the metencephalic corpus cerebelli, orientation of the glossopharyngeal nerve, and overall encephalic proportions. The corpus cerebelli of Paratrygon and Heliotrygon is interpreted as being more similar to the general batoid condition and, given their phylogenetic position highly nested within stingrays, is considered secondarily derived, not plesiomorphically retained. Our observations of the corpus cerebelli of stingrays, including Hexatrygon, corroborate that the general stingray pattern previously advanced by Northcutt is derived among batoids. The morphology of the brain is shown to be a useful source of phylogenetically informative characters at lower hierarchical levels, such as between genera and species, and thus, has significant potential in phylogenetic studies of elasmobranchs. PMID- 26592725 TI - The thermogenic responses to overfeeding and cold are differentially regulated. AB - OBJECTIVE: Brown adipose tissue (BAT) is a highly metabolic tissue that generates heat and is negatively associated with obesity. BAT has been proposed to mediate both cold-induced thermogenesis (CIT) and diet-induced thermogenesis (DIT). Therefore, it was investigated whether there is a relationship between CIT and DIT in humans. METHODS: Nine healthy men (23 +/- 3 years old, 23.0 +/- 1.8 kg m( 2) ) completed 20 min of cold exposure (4 degrees C) 5 days per week for 4 weeks. Before and after the intervention, CIT (the increase in resting metabolic rate at 16 degrees C relative to 22 degrees C) was measured by a ventilated hood indirect calorimeter, whereas DIT was measured as the 24-h thermic response to 1 day of 50% overfeeding (TEF150% ) in a respiratory chamber. RESULTS: After the cold intervention, CIT more than doubled from 5.2% +/- 14.2% at baseline to 12.0% +/- 11.1% (P = 0.05), in parallel with increased sympathetic nervous system activity. However, 24-h energy expenditure (2,166 +/- 206 vs. 2,118 +/- 188 kcal day(-1) ; P = 0.15) and TEF150% (7.4% +/- 2.7% vs. 7.7% +/- 1.6%; P = 0.78) were unchanged. Moreover, there was no association between CIT and TEF150% at baseline or post intervention, nor in their changes (P >= 0.47). CONCLUSIONS: Cold acclimation resulted in increased CIT but not TEF150% . Therefore, it is likely that CIT and DIT are mediated by distinct regulatory mechanisms. PMID- 26592727 TI - Bi-layered zirconia/fluor-apatite bridges supported by ceramic dental implants: a prospective case series after thirty months of observation. AB - OBJECTIVE: The aim of this study was to determine the success and survival rate of all-ceramic bi-layered implant-supported three-unit fixed dental prostheses (IS-FDPs) 3 years after implant placement. MATERIAL AND METHODS: Thirteen patients (seven males, six females; age: 41-78 years) received two one-piece ceramic implants (alumina-toughened zirconia) each in the region of the premolars or the first molar and were finally restored with adhesively cemented bi-layered zirconia-based IS-FDPs (3 in the maxilla, 10 in the mandible) composed of CAD/CAM fabricated zirconia frameworks pressed-over with fluor-apatite glass-ceramic ingots. At prosthetic delivery and the follow-ups after 1, 2 and 3 years, the restorations were evaluated using modified United States Public Health Service (USPHS) criteria. Restorations with minor veneer chippings, a small-area occlusal roughness, slightly soundable restoration margins, minimal contour deficiencies and tolerable color deviations were regarded as success. In case of more distinct defects that could, however, be repaired to a clinically acceptable level, IS FDPs were regarded as surviving. Kaplan-Meier plots were used for the success/survival analyses. To verify an impact on subjective patients' perceptions, satisfaction was evaluated by visual analog scales (VAS). RESULTS: All patients were seen 3 years after implant installation. No IS-FDP had to be replaced, resulting in 100% survival after a mean observation period of 29.5 months (median: 30.7). At the 3-year follow-up, 7/13 IS-FDPs showed a veneer chipping, 13/13 an occlusal roughness and 12/13 minimal deficiencies of contour/color. Since six restorations showed a major chipping and/or a major occlusal roughness, the Kaplan-Meier success rate was 53.8%. However, patients' significantly improved perceptions of function, esthetics, sense, and speech at prosthetic delivery remained stable over time. CONCLUSION: Bi-layered zirconia/fluor-apatite IS-FDPs entirely survived the observation period but showed a high frequency of technical complications. Nevertheless, the treatment highly satisfied patients' expectations. PMID- 26592728 TI - Nanoscale Platelet Formation by Monounsaturated and Saturated Sophorolipids under Basic pH Conditions. AB - The self-assembly behavior of the yeast-derived bolaamphiphile sophorolipid (SL) is generally studied under acidic/neutral pH conditions, at which micellar and fibrillar aggregates are commonly found, according to the (un)saturation of the aliphatic chain: the cis form, which corresponds to the oleic acid form of SL, spontaneously forms micelles, whereas the saturated form, which corresponds to the stearic acid form of SL, preferentially forms chiral fibers. By using small angle light and X-ray scattering (SLS, SAXS) combined with high-sensitivity transmission electron microscopy imaging under cryogenic conditions (cryo-TEM), the nature of the self-assembled structures formed by these two compounds above pH 10, which is the pH at which they are negatively charged due to the presence of a carboxylate group, has been explored. Under these conditions, these compounds self-assemble into nanoscale platelets, despite the different molecular structures. This work shows that the electrostatic repulsion forces generated by COO(-) mainly drive the self-assembly process at basic pH, in contrast with that found at pH below neutrality, at which self-assembly is driven by van der Waals forces and hydrogen bonding, and thus, is in agreement with previous findings on carbohydrate-based gemini surfactants. PMID- 26592730 TI - Vortex-assisted liquid-liquid microextraction for the rapid screening of short chain chlorinated paraffins in water. AB - The rapid screening of trace levels of short-chain chlorinated paraffins in various aqueous samples was performed by a simple and reliable procedure based on vortex-assisted liquid-liquid microextraction combined with gas chromatography and electron capture negative ionization mass spectrometry. The optimal vortex assisted liquid-liquid microextraction conditions for 20 mL water sample were as follows: extractant 400 MUL of dichloromethane; vortex extraction time of 1 min at 2500 * g; centrifugation of 3 min at 5000 * g; and no ionic strength adjustment. Under the optimum conditions, the limit of quantitation was 0.05 MUg/L. Precision, as indicated by relative standard deviations, was less than 9% for both intra- and inter-day analysis. Accuracy, expressed as the mean extraction recovery, was above 91%. The vortex-assisted liquid-liquid microextraction with gas chromatography and electron capture negative ionization mass spectrometry method was successfully applied to quantitatively extract short chain chlorinated paraffins from samples of river water and the effluent of a wastewater treatment plant, and the concentrations ranged from 0.8 to 1.6 MUg/L. PMID- 26592729 TI - Ageing and gastrointestinal sensory function: altered colonic mechanosensory and chemosensory function in the aged mouse. AB - KEY POINTS: Remarkably little is known about how age affects the sensory signalling pathways in the gastrointestinal tract despite age-related gastrointestinal dysfunction being a prime cause of morbidity amongst the elderly population High-threshold gastrointestinal sensory nerves play a key role in signalling distressing information from the gut to the brain. We found that ageing is associated with attenuated high-threshold afferent mechanosensitivity in the murine colon, and associated loss of TRPV1 channel function. These units have the capacity to sensitise in response to injurious events, and their loss in ageing may predispose the elderly to lower awareness of GI injury or disease. ABSTRACT: Ageing has a profound effect upon gastrointestinal function through mechanisms that are poorly understood. Here we investigated the effect of age upon gastrointestinal sensory signalling pathways in order to address the mechanisms underlying these changes. In vitro mouse colonic and jejunal preparations with attached splanchnic and mesenteric nerves were used to study mechanosensory and chemosensory afferent function in 3-, 12- and 24-month-old C57BL/6 animals. Quantitative RT-PCR was used to investigate mRNA expression in colonic tissue and dorsal root ganglion (DRG) cells isolated from 3- and 24-month animals, and immunohistochemistry was used to quantify the number of 5-HT expressing enterochromaffin (EC) cells. Colonic and jejunal afferent mechanosensory function was attenuated with age and these effects appeared earlier in the colon compared to the jejunum. Colonic age-related loss of mechanosensory function was more pronounced in high-threshold afferents compared to low-threshold afferents. Chemosensory function was attenuated in the 24-month colon, affecting TRPV1 and serotonergic signalling pathways. High-threshold mechanosensory afferent fibres and small-diameter DRG neurons possessed lower functional TRPV1 receptor responses, which occurred without a change in TRPV1 mRNA expression. Serotonergic signalling was attenuated at 24 months, but TPH1 and TPH2 mRNA expression was elevated in colonic tissue. In conclusion, we saw an age-associated decrease in afferent mechanosensitivity in the mouse colon affecting HT units. These units have the capacity to sensitise in response to injurious events, and their loss in ageing may predispose the elderly to lower awareness of GI injury or disease. PMID- 26592731 TI - alpha-Arylation/Heteroarylation of Chiral alpha-Aminomethyltrifluoroborates by Synergistic Iridium Photoredox/Nickel Cross-Coupling Catalysis. AB - Direct access to complex, enantiopure benzylamine architectures using a synergistic iridium photoredox/nickel cross-coupling dual catalysis strategy has been developed. New C(sp(3))-C(sp(2)) bonds are forged starting from abundant and inexpensive natural amino acids. PMID- 26592732 TI - Treatment intensification with an insulin degludec (IDeg)/insulin aspart (IAsp) co-formulation twice daily compared with basal IDeg and prandial IAsp in type 2 diabetes: a randomized, controlled phase III trial. AB - AIMS: To evaluate the efficacy and safety of two insulin intensification strategies for patients with type 2 diabetes previously treated with basal insulin--insulin degludec (IDeg) and insulin aspart (IAsp)--administered as a co formulation (IDegAsp) or as a basal-bolus regimen (IDeg and IAsp in separate injections). METHODS: This 26-week, open-label, treat-to-target, phase IIIb, non inferiority trial randomized patients (1 : 1) to IDegAsp twice daily with main meals (n = 138; IDegAsp group) or IDeg once daily and IAsp 2-4 times daily (n = 136; IDeg+IAsp group). RESULTS: After 26 weeks, the mean glycated haemoglobin (HbA1c) level was 7.0% (53 mmol/mol) for the IDegAsp group and 6.8% (51 mmol/mol) for the IDeg+IAsp group (Delta%HbA1c from baseline -1.31 and -1.50%, respectively). The non-inferiority of IDegAsp versus IDeg+IAsp was not confirmed for mean change in HbA1c [estimated treatment difference (ETD) 0.18, 95% confidence interval (CI) -0.04, 0.41; p = non-significant]. No significant differences were observed in the proportion of patients achieving HbA1c <7.0% (56.5 and 59.6%, respectively). IDegAsp treatment resulted in a significantly lower total daily insulin dose, a smaller change in body weight, numerically lower rates of confirmed hypoglycaemia (self-reported plasma glucose <3.1 mmol/l; rate ratio 0.81; p = non-significant), and nocturnal confirmed hypoglycaemic episodes (rate ratio 0.80; p = non-significant) versus IDeg+IAsp. Patient reported outcome scores for social functioning were significantly higher for IDegAsp versus IDeg+IAsp (ETD 2.2; 95% CI 0.3, 4.1; p < 0.05). CONCLUSIONS: Both intensification strategies effectively improved glycaemic control. Although non inferiority was not confirmed, there were no significant differences between the groups that could affect clinical utility. PMID- 26592734 TI - Metal-Free Allene-Based Synthesis of Enantiopure Fused Polycyclic Sultones. AB - The controlled metal-free preparation of fused delta-sultone derivatives has been developed starting from hydroxyallenynes. The use of 2-(3,3-diethyltriaz-1-enyl) 4-methylbenzene-1-sulfonyl chloride in a sulfonylation/rearrangement sequence gives access to 1,3-dien-2-yl arenesulfonates. These functionalized enynes suffered a direct cyclization/desaturation radical cascade, allowing the synthesis of a variety of enynyl [1,2]oxathiine 1,1-dioxides. Stereoselective cyclization of the readily formed core through intramolecular Diels-Alder reaction has also been demonstrated, affording beta-lactam- and glucofuranoside fused delta-sultone polycycles. These selective reactions have been studied experimentally and additionally, their reaction mechanisms have been investigated computationally by means of density functional theory calculations. PMID- 26592733 TI - Food-specific response inhibition, dietary restraint and snack intake in lean and overweight/obese adults: a moderated-mediation model. AB - BACKGROUND/OBJECTIVES: The relationship between response inhibition and obesity is currently unclear. This may be because of inconsistencies in methodology, design limitations and the use of narrow samples. In addition, dietary restraint has not been considered, yet restraint has been reported to moderate performance on behavioural tasks of response inhibition. The aim of this study was to investigate performance on both a food-based and a neutral stimuli go/no-go task, which addresses current design limitations, in lean and overweight/obese adults. The moderating role of dietary restraint in the relationship between body composition, response inhibition and snack intake was also measured. SUBJECTS/METHODS: Lean and overweight/obese, males and females (N=116) completed both a food-based and neutral category control go/no-go task, in a fully counterbalanced repeated-measures design. A bogus taste-test was then completed, followed by a self-report measure of dietary restraint. RESULTS: PROCESS moderated-mediation analysis showed that overweight/obese, compared with lean, participants made more errors on the food-based (but not the neutral) go/no-go task, but only when they were low in dietary restraint. Performance on the food based go/no-go task predicted snack intake across the sample. Increased intake in the overweight, low restrainers was fully mediated by increased errors on the food-based (but not the neutral) go/no-go task. CONCLUSIONS: Distinguishing between high and low restrained eaters in the overweight/obese population is crucial in future obesity research incorporating food-based go/no-go tasks. Poor response inhibition to food cues predicts overeating across weight groups, suggesting weight loss interventions and obesity prevention programmes should target behavioural inhibition training in such individuals. PMID- 26592735 TI - No Direct Survival Effect of Light to Moderate Alcohol Drinking in Community Dwelling Older Adults. AB - OBJECTIVES: To assess the relationship between light to moderate alcohol consumption and mortality, particularly accounting for baseline health status and physical activity. DESIGN: Prospective, longitudinal, population-based study. SETTING: The Pianoro Study, which consisted of community-dwelling older adults in three towns in northern Italy. PARTICIPANTS: Noninstitutionalized individuals of both sexes aged 65 and older (N = 5,256; 2,318 abstainers, 2,309 light to moderate drinkers (<=2 alcoholic units/d)). MEASUREMENTS: Baseline information about demographic characteristics, lifestyle factors, physical activity (Physical Activity Scale for the Elderly (PASE)), perceived health status (visual analog scale (VAS)), dependency level, risk factors, and previous cardiovascular events was obtained using a structured questionnaire. Follow-up information was obtained 6 years later from 2,752 survivors, and mortality information was obtained from death certificates. RESULTS: Male sex, being physically active, and good health status were independently associated with light to moderate drinking (P < .001). An apparent protective effect of light to moderate drinking on mortality was evident in the unadjusted analysis and after adjusting for age, sex, risk factors, and cardiovascular events (adjusted hazard ratio (aHR) = 0.77, 95% confidence interval (CI) = 0.68-0.88, P < .001), but after also adjusting for PASE and VAS, the relationship was no longer significant (aHR = 0.92, 95% CI = 0.80-1.05, P = .19). Follow-up physical activity was associated with baseline alcohol consumption; baseline physical activity did not predict alcohol consumption during follow-up. CONCLUSION: After accounting for health status and physical activity, light to moderate alcohol drinking had no direct protective effect on mortality. PMID- 26592736 TI - Expression, purification, and characterization of mouse nesfatin-1 in Escherichia coli. AB - Nesfatin-1 is a newly discovered satiety molecule expressed mainly in the hypothalamic nuclei. It suppresses both short-term and long-term appetite. Six synthetic deoxyoligonucleotides overlapped by PCR encoding nesfatin-1 were cloned into a pET28a vector after the hexa-histidine-tagged multiple cloning sites sequence with an enterokinase recognition site incorporated in-between. The recombinant plasmid was transformed into Escherichia coli strain Rosetta to express the fusion protein, which constituted 27% of the total cell proteins. After purified by Ni-sepharose affinity chromatography, the fusion protein was treated with enterokinase to release nesfatin-1. The nesfatin-1 sample was further purified with reverse-phase high performance liquid chromatography (HPLC), and its molecular weight was determined by mass spectrometry. The biological activities of recombinant nesfatin-1 were also assessed using in vivo animal models. The method described here promises to produce about 8 mg biologically active nesfatin-1 with homogeneity over 98% from 1-L shaking flask culture of E. coli, which can be considered as an easy and cost-effective way to synthesize nesfatin-1. PMID- 26592737 TI - Predicting Partition Coefficients with a Simple All-Atom/Coarse-Grained Hybrid Model. AB - The solvation free energy is an essential quantity in force field development and in numerous applications. Here, we present the estimation of solvation free energies in polar (water, hexanol, octanol, and nonanol) and in apolar (hexane, octane, and nonane) media. The estimates are produced using molecular dynamics simulations employing a simple all-atom/coarse-grained hybrid model (AA/ELBA) and are therefore very efficient. More than 150 solutes were taken from the Minnesota solvation database and represent small, organic molecules. The mean absolute deviation for the different solvents ranges between 2.0 and 4.1 kJ/mol, and the correlation coefficient ranges between 0.78 and 0.99, indicating that the predictions are accurate. Outliers are identified, and potential avenues for improvements are discussed. Furthermore, partition coefficients between water and the organic solvents were estimated, and the percentage of the predictions that has the correct sign ranges between 74% (for octane) and 92% (for octanol and hexanol). Finally, membrane/water partition coefficients are replaced with hexane/water and octanol/water partition coefficients, and the latter is found to be as accurate as the expensive membrane calculations, indicating a wider application area. PMID- 26592739 TI - Near-Infrared Light-Activatable Microneedle System for Treating Superficial Tumors by Combination of Chemotherapy and Photothermal Therapy. AB - Because of the aggressive and recurrent nature of cancers, repeated and multimodal treatments are often necessary. Traditional cancer therapies have a risk of serious toxicity and side effects. Hence, it is crucial to develop an alternative treatment modality that is minimally invasive, effectively treats cancers with low toxicity, and can be repeated as required. We developed a light activatable microneedle (MN) system that can repeatedly and simultaneously provide photothermal therapy and chemotherapy to superficial tumors and exert synergistic anticancer effects. This system consists of embeddable polycaprolactone MNs containing a photosensitive nanomaterial (lanthanum hexaboride) and an anticancer drug (doxorubicin; DOX), and a dissolvable poly(vinyl alcohol)/polyvinylpyrrolidone supporting array patch. Because of this supporting array, the MNs can be completely inserted into the skin and embedded within the target tissue for locoregional cancer treatment. When exposed to near infrared light, the embedded MN array uniformly heats the target tissue to induce a large thermal ablation area and then melts at 50 degrees C to release DOX in a broad area, thus destroying tumors. This light-activated heating and releasing behavior can be precisely controlled and switched on and off on demand for several cycles. We demonstrated that the MN-mediated synergistic therapy completely eradicated 4T1 tumors within 1 week after a single application of the MN and three cycles of laser treatment. No tumor recurrence and no significant body weight loss of mice were observed. Thus, the developed light-activatable MN with a unique embeddable feature offers an effective, user-friendly, and low toxicity option for patients requiring long-term and multiple cancer treatments. PMID- 26592738 TI - Mitochondrial Dysfunction Launches Dexamethasone-Induced Skeletal Muscle Atrophy via AMPK/FOXO3 Signaling. AB - Muscle atrophy occurs in several pathologic conditions such as diabetes and chronic obstructive pulmonary disease (COPD), as well as after long-term clinical administration of synthesized glucocorticoid, where increased circulating glucocorticoid accounts for the pathogenesis of muscle atrophy. Others and we previously reported mitochondrial dysfunction in muscle atrophy-related conditions and that mitochondria-targeting nutrients efficiently prevent kinds of muscle atrophy. However, whether and how mitochondrial dysfunction involves glucocorticoid-induced muscle atrophy remains unclear. Therefore, in the present study, we measured mitochondrial function in dexamethasone-induced muscle atrophy in vivo and in vitro, and we found that mitochondrial respiration was compromised on the 3rd day following after dexamethasone administration, earlier than the increases of MuRF1 and Fbx32, and dexamethasone-induced loss of mitochondrial components and key mitochondrial dynamics proteins. Furthermore, dexamethasone treatment caused intracellular ATP deprivation and robust AMPK activation, which further activated the FOXO3/Atrogenes pathway. By directly impairing mitochondrial respiration, FCCP leads to similar readouts in C2C12 myotubes as dexamethasone does. On the contrary, resveratrol, a mitochondrial nutrient, efficiently reversed dexamethasone-induced mitochondrial dysfunction and muscle atrophy in both C2C12 myotubes and mice, by improving mitochondrial function and blocking AMPK/FOXO3 signaling. These results indicate that mitochondrial dysfunction acts as a central role in dexamethasone-induced skeletal muscle atrophy and that nutrients or drugs targeting mitochondria might be beneficial in preventing or curing muscle atrophy. PMID- 26592741 TI - Direct-Write, Self-Aligned Electrospinning on Paper for Controllable Fabrication of Three-Dimensional Structures. AB - Electrospinning, a process that converts a solution or melt droplet into an ejected jet under a high electric field, is a well-established technique to produce one-dimensional (1D) fibers or two-dimensional (2D) randomly arranged fibrous meshes. Nevertheless, the direct electrospinning of fibers into controllable three-dimensional (3D) architectures is still a nascent technology. Here, we apply near-field electrospinning (NFES) to directly write arbitrarily shaped 3D structures through consistent and spatially controlled fiber-by-fiber stacking of polyvinylidene fluoride (PVDF) fibers. An element central to the success of this 3D electrospinning is the use of a printing paper placed on the grounded conductive plate and acting as a fiber collector. Once deposited on the paper, residual solvents from near-field electrospun fibers can infiltrate the paper substrate, enhancing the charge transfer between the deposited fibers and the ground plate via the fibrous network within the paper. Such charge transfer grounds the deposited fibers and turns them into locally fabricated electrical poles, which attract subsequent in-flight fibers to deposit in a self-aligned manner on top of each other. This process enables the design and controlled fabrication of electrospun 3D structures such as grids, walls, hollow cylinders, and other 3D logos. As such, this technique has the potential to advance the existing electrospinning technologies in constructing 3D structures for biomedical, microelectronics, and MEMS/NMES applications. PMID- 26592740 TI - Synthesis and Bioactivities of Kanamycin B-Derived Cationic Amphiphiles. AB - Cationic amphiphiles derived from aminoglycosides (AGs) have been shown to exhibit enhanced antimicrobial activity. Through the attachment of hydrophobic residues such as linear alkyl chains on the AG backbone, interesting antibacterial and antifungal agents with a novel mechanism of action have been developed. Herein, we report the design and synthesis of seven kanamycin B (KANB) derivatives. Their antibacterial and antifungal activities, along with resistance/enzymatic, hemolytic, and cytotoxicity assays were also studied. Two of these compounds, with a C12 and C14 aliphatic chain attached at the 6" position of KANB through a thioether linkage, exhibited good antibacterial and antifungal activity, were poorer substrates than KANB for several AG-modifying enzymes, and could delay the development of resistance in bacteria and fungi. Also, they were both relatively less hemolytic than the known membrane targeting antibiotic gramicidin and the known antifungal agent amphotericin B and were not toxic at their antifungal MIC values. Their oxidation to sulfones was also demonstrated to have no effect on their activities. Moreover, they both acted synergistically with posaconazole, an azole currently used in the treatment of human fungal infections. PMID- 26592742 TI - Projecting Fish Mercury Levels in the Province of Ontario, Canada and the Implications for Fish and Human Health. AB - Fish mercury levels appear to be increasing in Ontario, Canada, which covers a wide geographical area and contains about 250 000 lakes including a share of the North American Great Lakes. Here we project 2050 mercury levels in Ontario fish, using the recently measured levels and rates of changes observed during the last 15 years, and present potential implications for fish and human health. Percentage of northern Ontario waterbodies where sublethal effects of mercury on fish can occur may increase by 2050 from 60% to >98% for Walleye (WE), 44% to 59 70% for Northern Pike (NP), and 70% to 76-92% for Lake Trout (LT). Ontario waterbodies with unrestricted fish consumption advisories for the general population may deteriorate from 24-76% to <1-33% for WE, 40-95% to 1-93% for NP, and 39-89% to 18-86% for LT. Similarly, Ontario waterbodies with do not eat advisories for the sensitive population may increase from 32-84% to 73-100% for WE, 9-72% to 12-100% for NP, and 19-71% to 24-89% for LT. Risk to health of Ontario fish and humans consuming these fish may increase substantially over the next few decades if the increasing mercury trend continues and updated advisories based on continued monitoring are not issued/followed. PMID- 26592743 TI - Epigarcinol and isogarcinol isolated from the root of Garcinia ovalifolia induce apoptosis of human promyelocytic leukemia (HL-60 cells). AB - BACKGROUND: Plants from garcinia genus have been used for centuries against several diseases. OBJECTIVE: This study aimed to investigate the mechanism of apoptosis induced by epigarcinol and isogarcinol isolated from the root of Garcinia ovalifolia (Clusiaceae) on human promyelocytic leukemia (HL-60 cells). METHODS: Epigarcinol and isogarcinol were isolated from the root of G. ovalifolia by using column chromatography method. The antiproliferative property of these molecules and fractions were assessed with 3-(4, 5-dimethylthiazol-2-yl)-2, 5 diphenyltetrazolium bromide (MTT) assay. The light fluorescence microscope was utilized to observe the morphological changes of HL-60 cells after 24 h treatment. Early apoptosis and cell cycle distribution were analyzed by using flow cytometry (FCM). RESULTS: The results showed that epigarcinol and isogarcinol inhibited the proliferation of HL-60 and PC-3 cells in a concentration-dependent manner with IC50 varying between 4 and 76 ug/mL depending on the cell line and the molecule. The apoptosis rate and the number of apoptotic cells significantly increased with the augmentation of the concentration of the molecules. The results of flow cytometry (FCM) indicated that epigarcinol and isogarcinol induced significant G2/S arrest of HL-60 cells, the disruption of mitochondrial membrane potential and reactive oxygen species (ROS) generation. CONCLUSION: These results indicated that epigarcinol and isogarcinol demonstrated in vitro antiproliferative properties and induce apoptosis of HL-60 cells which is related to the G2/S arrest, and it exerts its apoptotic effect through the loosing of mitochondrial membrane potential. PMID- 26592745 TI - Developments in mechanical thrombectomy devices for the treatment of acute ischemic stroke. AB - Several recent prospective randomized controlled trials of endovascular stroke therapy using latest generation thrombectomy devices, so called stent-retrievers, have shown significantly improved clinical outcome compared to the standard treatment with intra-venous thrombolysis using r-tPA alone. Despite some differences in inclusion criteria between these studies, all required non invasive vessel imaging to proof occlusion of a major brain supplying vessel. Furthermore, in most studies additional imaging techniques were used to exclude patients with already established large cerebral infarction or unfavorable collateral or penumbral status. Patients with small infarct volume, severe neurological deficits and in whom thrombectomy can be initiated within the first 6 hours after symptom onset seem to benefit the most. Therefore, mechanical thrombectomy using stent-retrievers in addition to intra-venous thrombolysis is recommended for the treatment of acute ischemic stroke with proven major vessel occlusion in the anterior circulation. PMID- 26592746 TI - New Pyrano[2,3-d:6,5-d']dipyrimidine Derivatives-Synthesis, in vitro Cytotoxicity and Computational Studies. AB - A new series of pyrano[2,3-d:6,5-d']dipyrimidine derivatives were synthesized and evaluated for their in vitro anticancer activity. The structures of all the synthesized compounds were confirmed by 1H NMR, 13C NMR, 15N NMR, HR-MS and FT-IR spectral analyses. The cytotoxic activities of these compounds against four human cancer (HeLa, SKBR-3, HepG2, and Caco-2) cell lines were determined. The synthesized compounds showed high selectivity, and four compounds (5e, 5f, 5g and 5i) showed excellent potent cytotoxicity against HeLa, SKBR-3, and HepG2 cancer cell lines. Furthermore, four other compounds (5a, 5c, 5b and 5d) have exhibited significant cytotoxicity activity in the SKBR-3 and HepG2 cell lines respectively, with moderate cytotoxicity seen in the HeLa cell line. Additionally, a molecular docking study was conducted to predict the anti-cancer behavior of the synthesized compounds via inhibition of the allosteric site of Human Kinesin Eg5. PMID- 26592747 TI - A Novel Method to Synthesize 4-Aryl-1H-1,2,3-Triazoles and its Antihepatoma Activity. AB - A novel synthetic method of 4-substituted aryl-1H-1,2,3-triazoles from arylglyoxaldoxime semicarbazone with sodium dithionite and O2 was found to be safer than the Huisgen azide- alkyne dipolar cycloaddition. A total of 17 new structures of 4-substituted aryl-1H-1,2,3- triazoles were characterized by 1H NMR, 13C NMR, ESI-MS. Subsequently, their in vitro antihepatoma activities were evaluated on human hepatoma QGY-7703, Bel-7402 and SMMC-7721 cell lines and mouse fibroblast cells L-929 by MTS assay. Among them, 5k exhibited excellent activity against QGY-7703 (GI50 = 0.0232 MUM), while 5p and 5q displayed good activity (GI50 = 0.103 MUM and GI50 = 0.182 MUM) against the growth of SMMC-7721 cell lines. Furthermore, 5k, 5p and 5q showed slight selectivity of inhibition on hepatoma cell lines over normal cell line L-929. PMID- 26592748 TI - Subject-Specific Computational Modeling of Evoked Rabbit Phonation. AB - When developing high-fidelity computational model of vocal fold vibration for voice production of individuals, one would run into typical issues of unknown model parameters and model validation of individual-specific characteristics of phonation. In the current study, the evoked rabbit phonation is adopted to explore some of these issues. In particular, the mechanical properties of the rabbit's vocal fold tissue are unknown for individual subjects. In the model, we couple a 3D vocal fold model that is based on the magnetic resonance (MR) scan of the rabbit larynx and a simple one-dimensional (1D) model for the glottal airflow to perform fast simulations of the vocal fold dynamics. This hybrid three dimensional (3D)/1D model is then used along with the experimental measurement of each individual subject for determination of the vocal fold properties. The vibration frequency and deformation amplitude from the final model are matched reasonably well for individual subjects. The modeling and validation approaches adopted here could be useful for future development of subject-specific computational models of vocal fold vibration. PMID- 26592749 TI - Neuroprotective effects of Tilia americana var. mexicana on damage induced by cerebral ischaemia in mice. AB - Tilia americana var. mexicana (T. americana) is a plant widely used in Mexico for its medicinal properties on the central nervous system. In the present study, we designed a protocol to investigate the neuroprotective effects of non-polar and polar extracts of T. americana on damage induced by cerebral ischaemia in mice. Vehicle or extracts were administered immediately after ischaemia. Functional neurological deficit, survival percentage and infarct area were determined in each experimental group. Results showed that groups treated with non-polar or polar extracts of T. americana had increased survival rate, improved neurological deficits and diminished the infarct area in relation to the ischaemic group. In conclusion, this study confirms the neuroprotective activity of T. americana, suggests a possible synergism between non-polar and polar constituents and supports its potential as a useful aid in the clinical management of stroke. PMID- 26592750 TI - Inhibition of Rho-Associated Protein Kinase Increases the Angiogenic Potential of Mesenchymal Stem Cell Aggregates via Paracrine Effects. AB - The aggregation of multiple cells, such as mesenchymal condensation, is an important biological process in skeletal muscle development, osteogenesis, and adipogenesis. Due to limited in vivo study model systems, a simple and effective in vitro three-dimensional (3D) aggregation system is required to study the mechanisms of multicellular aggregation and its applications. We first generated controlled mesenchymal stem cell (MSC) aggregates using a bioprinting technique to monitor their aggregation and sprouting. We induced the angiogenic potential of the MSCs through chemical inhibition of the Rho/Rho-associated protein kinase (ROCK) pathway, which led to hairy sprouting in the aggregates. The angiogenic potential of this 3D construct was then tested by subcutaneously implanting the Matrigel with 3D MSC aggregates in a rat. Treatment of 3D MSCs with the ROCK inhibitor, Y27632, increased their angiogenic activity in vivo. The gene expressions and histological staining indicated that angiogenesis and neovascularization were mainly regulated by the paracrine factors secreted from human 3D MSC constructs. Our results demonstrate the enhancement of the angiogenic potential of the MSC constructs through the secretion of vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) by the inhibition of the Rho/ROCK pathway. PMID- 26592751 TI - GPR 120: The Potential Target for Obesity Treatment. AB - BACKGROUND: G protein coupled receptor 120 (GPR120) is a class of receptors in the gastrointestinal tract (GIT) that is implicated in nutrient sensing and body weight regulation. Functions of GPR120 are thought to be mediated by the release of a group of hormones known as incretins, such as glucagon like peptide 1 (GLP 1) and gastric inhibitory polypeptide (GIP). METHODS: We have searched PubMed with the keywords "GPR120","GLP-1" and "obesity". Relevant studies were retrieved and included in the review. RESULTS: Recently, many exogenous compounds have been investigated in their role in the release of GLP-1 and in causing weight loss in obese rats. However, some results question the putative role of GPR120 in metabolic homeostasis. CONCLUSION: Herein, we evaluate the potential use of GPR120 as a target receptor in obesity and found it to be ubiquitous throughout the GIT, with various functions in each site. In order to find the optimal drug, the role of GPR120 in each site needs to be defined and selectivity of the potential drug needs to be studied to ensure the success of this growing line of obesity management. PMID- 26592752 TI - Planar chiral desymmetrization of a two-layered cyclophane and control of dynamic helicity through the arrangement of two nonstereogenic centers. AB - We designed a planar chiral two-layered cyclophane, which is inherently achiral but desymmetrized by the arrangement of two nonstereogenic centers. We demonstrate the control of dynamic helicity that is generated by the helical twisting of two-layered planes in the cyclophane, where methyl and cyclohexylmethyl groups act as directing groups. PMID- 26592753 TI - A versatile approach to flavones via a one-pot Pd(II)-catalyzed dehydrogenation/oxidative boron-Heck coupling sequence of chromanones. AB - A variety of flavones were expediently synthesized from readily accessible chromanones via a one-pot sequence involving Pd(II)-catalyzed dehydrogenation and oxidative boron-Heck coupling with arylboronic acid pinacol esters. In particular, the use of arylboronic acid pinacol esters was found to significantly improve the yield of the reaction. PMID- 26592754 TI - Formulation optimization of aprepitant microemulsion-loaded silicated corn fiber gum particles for enhanced bioavailability. AB - The present investigation was aimed at development of silicate corn fiber gum (SCFG) particles as superior solid carrier for the preparation of Aprepitant (APT)-loaded self-emulsifying powder (SEP) system. 2(4) D-optimal mixture design with three level process variables was employed to develop SCFG particles, utilizing flow descriptors and hydrophobicity descriptors as response variables. The results indicated that blending of CFG (51.4% w/w) and magnesium silicate (MS) (48.6% w/w) using freeze-drying technique was found to have highest desirability (0.904). The developed SEP showed highest oil desorbing capacity, low self-emulsification time and highest drug content. It was observed that SCFG SEP (F2 formulation) showed lowest PDI (0.2445 +/- 0.03) as well as smallest particle size (127 +/- 5.8 nm). The droplets were uniform and maintain their integrity after reconstitution (TEM analysis). Furthermore, APT-loaded SEP showed enhanced in vitro dissolution (4 folds) and ex vivo performance (7-fold enhanced Papp) as compared to pure APT. Furthermore, in vivo pharmacokinetic study showed that significant enhancement (p > 0.05) in Cmax was evident with APT-loaded F2 (SCFG-SEP) (1.93-fold) and F4 (Aerosil 200-SEP) (1.58-fold). The data also suggested increase in absorption rate when APT incorporated into SCFG-SEP. Thus, findings pointed toward enhanced bioavailability of APT when loaded into SCFG particles. Overall, the developed SCFG particles could be considered as a better alternative to already available solid carrier(s). PMID- 26592755 TI - Statement of Retraction. PMID- 26592756 TI - Bright white-light emission from Ag/SiO2/CdS-ZnS core/shell/shell plasmon couplers. AB - Well-defined plasmon couplers (PCs) that comprise a Ag core overcoated with a SiO(2) shell with controlled thickness, followed by a monolayer of CdS-ZnS core shell quantum dots (QDs) were synthesized to modify the emission from trap-rich CdS-ZnS QDs by adjusting the distance between the QDs and Ag nanoparticles (NPs). When the thickness of the SiO(2) shell was 10 nm, because the shell could effectively suppress the non-radiative energy transfer from the semiconductor QDs to the metal NPs and the localized surface plasmon resonance (LSPR) of the Ag NPs spectrally matched the emission peak of the CdS-ZnS QDs to bring about strong plasmon coupling, optimum enhancements of the surface state emission (SSE) (17 times) and band-edge emission (BEE) (4 times) were simultaneously realized and the SSE to BEE intensity ratio was increased to 55%. As a result, a bright white light source with 1931 Commission Internationale d'Eclairage (CIE) chromaticity coordinates of (0.32, 0.34) was realized by the superposition of the two emissions. The experimental results from Ag/SiO(2)/CdSe-ZnS and the Ag/SiO(2)/CdS:Mn-ZnS core/shell/shell PCs indicated that suppressing the non radiative decay rate (k(nr)) was the underlying mechanism for plasmon coupling fluorescence enhancement. PMID- 26592757 TI - Primary health care registered nurses' types in implementation of health promotion practices. AB - Aim This study aimed to identify and reach consensus among primary health care participants [registered nurses (RNs) who receive clients, directors of nursing, senior physicians, health promotion officers, and local councillors] on the types of service provider that RNs who receive clients represent in the implementation of health promotion practices in primary health care in Eastern Finland. BACKGROUND: There is an increasing focus on public health thinking in many countries as the population ages. To meet the growing needs of the health promotion practices of populations, advance practice has been recognized as effective in the primary health care setting. The advance practice nurses share many common features, such as being RNs with additional education, possessing competencies to work independently, treating clients in both acute and primary care settings, and applying a variety of health promotion practices into nursing. METHODS: The two-stage modified Delphi method was applied. In round one, semi structured interviews were conducted among primary health care participants (n=42) in 11 health centres in Eastern Finland. In round two, a questionnaire survey was conducted in the same health centres. The questionnaire was answered by 64% of those surveyed (n=56). For data analysis, content analysis and descriptive statistics were used. Findings This study resulted in four types of service provider that RNs who receive clients represented in the implementation of health promotion practices in the primary health care setting in Eastern Finland. First, the client-oriented health promoter demonstrated four dimensions, which reached consensus levels ranging between 82.1 and 89.3%. Second, the developer of health promotion practices comprised four dimensions, which reached consensus levels between 71.4 and 85.7%. Third, the member of multi-professional teams of health promotion practices representing three dimensions, with consensus levels between 69.6 and 82.1%. Fourth, the type who showed interest towards health policy reached a consensus level of 55.4% in this study. PMID- 26592758 TI - A simulation study of the electrostriction effects in dielectric elastomer composites containing polarizable inclusions with different spatial distributions. AB - Controlled actuation of electroactive polymers with embedded high dielectric nanoparticles is theoretically analyzed. If the inclusions are placed randomly in the elastomer body, the composite always contracts along the direction of the applied field. For a simple cubic distribution of inclusions, contraction occurs if the applied field is directed along the [001] direction of the lattice. For inclusions occupying the sites of other lattice structures such as body-centered or face-centered cubic crystals, the composite elongates along the field direction if it is applied along the [001] direction. The stability of the elongation against the imperfectness of the lattice site positions and the distortion ratio of the initial structures are examined. Finite elongation windows show up for the initially distorted body-centered cubic and face-centered cubic crystals as a function of the distortion ratio of the initial structure. The existence of these elongation windows are also predicted from the analysis of the electrostatic energy of the distorted body-centered cubic and face-centered cubic lattice structures. Our results indicate that the electrostriction effect, which is the main contribution to the actuation of low aspect-ratio composites, strongly depends on the geometry of the spatial distribution of nanoparticles, and can thereby largely be tuned. PMID- 26592759 TI - Synthesis and photocatalytic activity of porous bismuth oxychloride hexagonal prisms. AB - Porous BiOCl hexagonal prisms have been successfully prepared through a simple solvothermal route. These novel BiOCl HPs with porous structures are assembled from nanoparticles and exhibit high activity and selectivity toward the photocatalytic aerobic oxidation of benzyl alcohol to benzaldehyde and degradation of methyl orange. PMID- 26592760 TI - Pyrene-biimidazole based Ru(II) and Os(II) complexes as highly efficient probes for the visible and near-infrared detection of cyanide in aqueous media. AB - Two pyrenyl-biimidazole based mononuclear Ru(II) and Os(II) complexes of the type [(bpy)2M(Py-BiimzH2)](2+) (M = Ru(II) and Os(II)), where Py-BiimzH2 = 10-(1-H imidazole-2-yl)-9H-pyreno[4,5-d]imidazole and bpy = 2,2'-bipyridine, have been synthesized and thoroughly characterized in this work using various analytical tools and spectroscopic techniques. These complexes were designed to recognize and sense cyanide ions in pure aqueous media. The single crystal X-ray structure of the Ru(II) complex shows that the compound is crystallized in a monoclinic system with the P2(1)/c space group. Both complexes show intense absorptions throughout the entire UV-vis region and also exhibit luminescence at room temperature. In case of Os(II), both the absorption and emission bands stretched up to the NIR region and thus a more bio-friendly condition for the detection of the anions is provided. Both steady state and time-resolved studies suggest that the emission originates predominantly from the (3)MLCT excited state mainly centered in the [M(bpy)2](2+) moiety of the complexes which is only slightly affected by the pyrene moiety. The electrochemical properties of the complexes are characterized using one reversible metal-centered oxidation and several ligand-centered reduction processes. The anion sensing properties of the complexes in both acetonitrile and pure aqueous media were thoroughly examined through different channels such as absorption, steady state and time-resolved emission spectroscopic methods and cyclic and square wave voltammetric measurements. Both complexes possess a very high selectivity towards cyanide ions in aqueous media in the presence of an excess of other anions. Moreover, the complexes display a visual detection of cyanide ions with a very low detection limit of the order of 10(-8) M. Finally, theoretical calculations employing density functional theory (DFT) and time-dependent density functional theory (TD DFT) were carried out to elucidate the details of the electronic structure and transitions involved in the complexes and their cyanide adducts. PMID- 26592761 TI - Identification of Bacillus strains by MALDI TOF MS using geometric approach. AB - Microorganism identification by MALDI TOF mass-spectrometry is based on the comparison of the mass spectrum of the studied organism with those of reference strains. It is a rapid and reliable method. However, commercial databases and programs are mostly designed for identification of clinically important strains and can be used only for particular mass spectrometer models. The need for open platforms and reference databases is obvious. In this study we describe a geometric approach for microorganism identification by mass spectra and demonstrate its capabilities by analyzing 24 strains belonging to the Bacillus pumilus group. This method is based on representing mass spectra as points on a multidimensional space, which allows us to use geometric distances to compare the spectra. Delimitation of microorganisms performed by geometric approach correlates well with the results of molecular phylogenetic analysis and clustering using Biotyper 3.1. All three methods used allowed us to reliably divide the strains into two groups corresponding to closely related species, Bacillus pumilus and Bacillus altitudinis. The method developed by us will be implemented in a Web interface designed for using open reference databases for microorganism identification. The data is available at http://www.bionet.nsc.ru/mbl/database/database.html. PMID- 26592763 TI - Assessment of Clostridium difficile Burden in Patients Over Time With First Episode Infection Following Fidaxomicin or Vancomycin. AB - In patients with first episode Clostridium difficile infection treated with vancomycin or fidaxomicin, more patients receiving fidaxomicin achieved at least 2 log10 colony-forming units/g reduction in spores at the follow-up visit (P=.02). Similar to published literature, a higher proportion of patients receiving fidaxomicin demonstrated sustained clinical response. PMID- 26592762 TI - Structure of human carbamoyl phosphate synthetase: deciphering the on/off switch of human ureagenesis. AB - Human carbamoyl phosphate synthetase (CPS1), a 1500-residue multidomain enzyme, catalyzes the first step of ammonia detoxification to urea requiring N-acetyl-L glutamate (NAG) as essential activator to prevent ammonia/amino acids depletion. Here we present the crystal structures of CPS1 in the absence and in the presence of NAG, clarifying the on/off-switching of the urea cycle by NAG. By binding at the C-terminal domain of CPS1, NAG triggers long-range conformational changes affecting the two distant phosphorylation domains. These changes, concerted with the binding of nucleotides, result in a dramatic remodeling that stabilizes the catalytically competent conformation and the building of the ~35 A-long tunnel that allows migration of the carbamate intermediate from its site of formation to the second phosphorylation site, where carbamoyl phosphate is produced. These structures allow rationalizing the effects of mutations found in patients with CPS1 deficiency (presenting hyperammonemia, mental retardation and even death), as exemplified here for some mutations. PMID- 26592764 TI - Probing the character of ultra-fast dislocations. AB - Plasticity is often controlled by dislocation motion, which was first measured for low pressure, low strain rate conditions decades ago. However, many applications require knowledge of dislocation motion at high stress conditions where the data are sparse, and come from indirect measurements dominated by the effect of dislocation density rather than velocity. Here we make predictions based on atomistic simulations that form the basis for a new approach to measure dislocation velocities directly at extreme conditions using three steps: create prismatic dislocation loops in a near-surface region using nanoindentation, drive the dislocations with a shockwave, and use electron microscopy to determine how far the dislocations moved and thus their velocity at extreme stress and strain rate conditions. We report on atomistic simulations of tantalum that make detailed predictions of dislocation flow, and find that the approach is feasible and can uncover an exciting range of phenomena, such as transonic dislocations and a novel form of loop stretching. The simulated configuration enables a new class of experiments to probe average dislocation velocity at very high applied shear stress. PMID- 26592765 TI - Robust Light State by Quantum Phase Transition in Non-Hermitian Optical Materials. AB - Robust light transport is the heart of optical information processing, leading to the search for robust light states by topological engineering of material properties. Here, it is shown that quantum phase transition, rather than topology, can be strategically exploited to design a novel robust light state. We consider an interface between parity-time (PT) symmetric media with different quantum phases and use complex Berry phase to reveal the associated quantum phase transition and topological nature. While the system possesses the same topological order within different quantum phases, phase transition from PT symmetry to PT breaking across the interface in the synthetic non-Hermitian metamaterial system facilitates novel interface states, which are robust against a variety of gain/loss perturbations and topological impurities and disorder. The discovery of the robust light state by quantum phase transition may promise fault tolerant light transport in optical communications and computing. PMID- 26592766 TI - Theory of mind and executive function during middle childhood across cultures. AB - Previous studies with preschoolers have reported "East-West" contrasts in children's executive function (East>West) and theory of mind (East 1, and constructed the interaction network of the top 3 up- and down-regulated genes using STRING. Besides, the modules of network were analyzed with Cytoscape and screened out with Mcode plugin, and the functional annotation of the genes involved in the modules was analyzed with BiNGO (Biological Networks Gene Ontology). RESULTS: Firstly, totally 101 differentially expressed genes were identified in FH samples compared with control samples, the genes ranked in top 3 up- and down-regulated genes were selected. Then, basing on the interaction network of these selected genes, ribosomal L24 domain containing 1 (RSL24D1) and cytochrome c oxidase subunit VIIb (COX7B) showed a central position in the interaction network, and also exited in the modules of the network. The functional annotation of the genes in modules showed that COX7B was associated with oxidative phosphorylation. CONCLUSIONS: COX7B might play vital roles in FH via oxidative phosphorylation system, and might be potential target in the treatment of FH. PMID- 26592841 TI - A novel mutation of the androgen receptor gene in familial complete androgen insensitivity syndrome. AB - OBJECTIVE: Androgen insensitivity syndrome (AIS) is characterized by androgen receptor (AR) dysfunction. Its main characteristic is a female phenotype in an individual with a 46, XY karyotype. The molecular basis of this disorder was investigated in two individuals with familial AIS. PATIENTS AND METHODS: The diagnoses of the two individuals were confirmed using ultrasonography, hormonal analysis, operative findings, and a histopathological study. Blood samples were collected, and the AR genes were analyzed using PCR and direct sequencing. RESULTS: Clinical and laboratory testing confirmed the two individuals' diagnoses of CAIS. DNA sequencing analysis of the genomes of these patients revealed a novel mutation of c.2107T > C in exon 4 of the AR gene, which results in a transformation of the protein p.S703P. The individuals' mother possesses a heterozygous allele, implying that she is a heterozygous carrier of the mutant gene. CONCLUSIONS: These findings suggested that this previously undescribed novel mutation of the AR gene is the cause of CAIS in this family. PMID- 26592842 TI - Analysis of persistence of human papillomavirus infection in men evaluated by sampling multiple genital sites. AB - OBJECTIVE: Although human papillomavirus (HPV) infection has been studied extensively in women, data on male infection are limited. The purpose of this study was to investigate persistence of HPV infection at multiple genital sites in men and to define potential associations with socio-behavioural characteristics. PATIENTS AND METHODS: Penile, urethral and seminal specimens were tested by the INNO-LiPA HPV system (Innogenetics) and a PCR assay. Persistence was defined as the detection of same HPV type at >= 2 consecutive visits. The Kaplan-Meier method and the log-rank test were applied to estimate the likelihood of persistence. RESULTS: A total of 50 men (median age: 33 years) were followed for a median of 14.7 months. Altogether, 49%, 36%, 26% and 11% of baseline HPV-positive men had 6-, 12-, 18- and 24-month persistent infection with any HPV type, respectively. The 6-, 12- and 18- month persistence was more common for oncogenic HPV infections; 24-month persistence was similar. The median duration of persistence was 21.7 months for any HPV. The median duration of persistence for any HPV type was significantly longer in the penile sample (22.5 months, 95% CI: 18.3-26.7) than the semen sample (15.3 months, 95% CI: 14.5 16.1). CONCLUSIONS: Over a third of type-specific HPV infections in men remained persistent over a 24-month period. The median duration of HPV infection was longer in penile samples compared to seminal samples. As being increasing the attention of HPV vaccination as a potential preventive approach also for men, it is imperative to obtain additional insight on natural history of HPV infection in men, particularly as far as incidence and duration are concerned. PMID- 26592843 TI - The impact of obstructive sleep apnea syndrome on renin and aldosterone. AB - OBJECTIVE: Obstructive Sleep Apnoea Syndrome (OSAS) is a respiratory disorder characterized by recurrent airflow obstruction caused by total or partial collapse of the upper airway. OSAS is an established independent factor of cardiovascular risk together with other risk factors such as smoking and increased lipids. The aim of our study was to measure serum levels of aldosterone and renin in OSAS patients that did not suffer from arterial hypertension and compare them to matched healthy subjects in order to reveal the impact of chronic intermittent hypoxia on the renin-angiotensin-aldosterone system. PATIENTS AND METHODS: The patients that enrolled in this study were 19 OSAS patients who had undergone overnight polysomnography and had an Apnoea Hypopnoea Index (AHI) greater than 10 events/hour. They were compared to 20 healthy non-OSAS closely matched controls. Serum aldosterone and direct renin concentration were measured by radioimmunoassay. RESULTS: Aldosterone concentration follows a diurnal variation; therefore, all blood samples were obtained at the same time (6 AM). There were no significant differences in serum aldosterone levels between the two studied groups of OSAS patients and the healthy subjects group (140.6 pg/ml +/- 25.2 vs. 133.2 pg/ml +/- 18.5 with p = 0.223). Similar were the results for the renin levels (25.0 +/- 6.9 vs. 24.9 +/- 4.4 with p = 0.360). CONCLUSIONS: Our study suggests that patients with OSAS, but without existing hypertension have aldosterone and renin levels similar to healthy subjects. According to our findings a direct connection between OSAS and the development of arterial hypertension may not be established via sympathetic system activation. PMID- 26592844 TI - Passive transfer of lipopolysaccharide-derived myeloid-derived suppressor cells inhibits asthma-related airway inflammation. AB - OBJECTIVE: Myeloid-derived suppressor cells (MDSCs) have recently been implicated in the pathogenesis of asthma through inhibiting T cell response. However, the issue of whether Lipopolysaccharide (LPS)-derived MDSCs regulate the immune response in an asthma environment is currently unclear. We sought to characterize the pathogenic function of various subtypes of MDSCs in asthma mediated by ovalbumin in mice model, in order to show that LPS-induced MDSCs can shift the balance back to normal in a Th2-dominant asthmatic environment. MATERIALS AND METHODS: Subgroups of MDSCs with Ly6C+Ly6G+, Ly6C-Ly6G+, Ly6C+Ly6G- or Ly6C-Ly6G- expression were isolated by flow cytometry and were co-cultured with spleen lymphocytes. The proportion of Th1, Th2, or Treg cells in the treated spleen lymphocytes were analyzed by flow cytometry. In an ovalbumin (OVA)-induced mouse asthma model, mice were intravenously injected (tail vein) by MDSCs with specific marker, then the lung function and tissue pathology, IL-4 content in bronchoalveolar lavage fluid (BALF) and peripheral blood, and proportion of Th1, Th2, or Treg cells in peripheral blood were analyzed. RESULTS: Ly6C+Ly6G+ MDSCs transferred into asthmatic mice via intravenous injection suppressed the infiltration of inflammatory cells into the lung and Th2 cytokine in BALF and blood. We observed a significant increase of Treg cells in the spleen lymphocytes co-cultured with Ly6C+Ly6G+, Ly6C-Ly6G+, Ly6C+Ly6G-, Ly6C-Ly6G- or CD11b+ MDSCs. The adoptive transfer of Ly6C+Ly6G+, Ly6C-Ly6G+, CD11b+ MDSCs resulted in decrease of Penh, total cell number, eosinophil and neutrophil percentage in BALF, and concentration of IL-4 in BALF and serum, thus improving the inflammatory injury, histopathology and lung function in the mice with asthma. The up-regulation of the Th1/Th2 ratio and Treg frequency were observed after adoptive transfer of Ly6C+Ly6G+, Ly6C-Ly6G+, Ly6C+Ly6G-, Ly6C-Ly6G- and CD11b+ MDSCs. CONCLUSIONS: The LPS-derived MDSCs with specific markers were able to suppress natural inflammatory response and improve inflammatory injury through reversing Th1/Th2 ratio, increasing Treg proportion and decreasing IL-4 concentration. These findings imply that LPS-derived MDSCs inhibit Th2 cell medicated response against allergen. We propose that asthma may be effectively targeted using a novel MDSC-based cell therapy approach. PMID- 26592845 TI - Ethical governance in biobanks linked to electronic health records. AB - In the last years an alternative to traditional research projects conducted with patients has emerged: it is represented by the pairing of different type of disease biobanks specimens with Electronic Health Records (EHRs). Even if informed consent remains one of the most contested issues of biobank policy, other ethical challenges still require careful attention, given that additional issues are related to the use of EHRs. In this new way of doing research harmonization of governance is essential in practice, with the aim to make the most use of resources at our disposal, and sharing of samples and data among researchers under common policies regulating the distribution and the use. A biobank-specific Ethics Committee could be seen as a new and type of Ethics Committee, that we suggest to be applied to each biobank, with possible different functions. In particular, considering the possible use of electronic health record data linked to biological specimens in biobanking research, this specific Ethics Committee could draft best practice and ethical guidelines for the utilisation of the EHRs as a tool for genetic research, addressing concerns on accessibility, return of results and privacy and help to educate patients and healthcare providers. PMID- 26592846 TI - Assessment of the stability of exogenous gamma hydroxybutyric acid (GHB) in stored blood and urine specimens. AB - OBJECTIVE: The aim of this work is to test the stability of exogenous GHB in whole blood and urine samples collected from living and deceased GHB free-users, spiked with known concentrations of GHB and stored at different temperatures (-20 degrees C, 4 degrees C and 20 degrees C) up to 4 weeks. MATERIALS AND METHODS: GHB was added to GHB-free ante-mortem blood and urine samples at the concentration of 5 and 10 mg/L, respectively whereas in post-mortem blood and urine specimens at 50 and 10 mg/L respectively. All samples were stored at three different temperatures: -20 degrees C, 4 degrees C and 20 degrees C and extracted and analyzed at three days, 1 week, 2 weeks, 3 and 4 weeks in duplicate. No preservatives were added. GHB was quantified by GC-MS after LLE according to a previously published method. RESULTS: Post-mortem blood specimens showed a reduction of GHB levels higher than 10% only after a period of 4 weeks of storage for samples kept at +4 degrees C and +20 degrees C, whereas samples stored at -20 degrees C showed a mean reduction of 8.7%. In post-mortem urine samples, there was a mean reduction of GHB levels higher than 20% at all storage temperatures, after 4 weeks of storage. Ante-mortem blood samples showed a reduction of GHB levels lower than 10% only after 3 days of storage at -20 degrees C and at +4 degrees C (samples stored at +20 degrees C showed a mean reduction of 10.4%). After 4 weeks of storage, there was a mean reduction of GHB concentrations higher than 20% at all storage temperatures. Ante-mortem urine samples showed a reduction of GHB levels higher than 10% after just 3 days of storage for samples kept at all tested temperatures. After 4 weeks of storage, there was a mean reduction of GHB concentrations higher than 25% at all storage temperatures. CONCLUSIONS: According to our findings, it would be useful to perform GHB analysis both in blood and urine specimens within 3 days of sampling and the specimens should be stored at -20 degrees C or 4 degrees C in order to avoid instability issues. PMID- 26592848 TI - The prevention of analgesic opioids abuse: expert opinion. AB - Opioids are drugs of reference for the treatment of moderate to severe pain. Their proper use and a periodic assessment of the patient are crucial to prevent misuse. A multidisciplinary group suggests strategies for all stakeholders involved in the management of pain and suggests the importance of the doctor patient relationship. PMID- 26592847 TI - Potential role of bioavailable curcumin in weight loss and omental adipose tissue decrease: preliminary data of a randomized, controlled trial in overweight people with metabolic syndrome. Preliminary study. AB - OBJECTIVE: This randomized, controlled study aims to evaluate the tolerability and the efficacy of curcumin in overweight subjects affected from metabolic syndrome, with a focus on impaired glucose intolerance and android-type fat accumulation. PATIENTS AND METHODS: Forty-four subjects, selected among those who after 30 days of diet and intervention lifestyle have shown a weight loss < 2%, have been treated for further 30 days either with curcumin complexed with phosphatidylserine in phytosome form or with pure phosphatidylserine. Outcomes concerning anthropometric measurements and body composition were analyzed at enrollment and after 30 and 60 days. RESULTS: Curcumin administration increased weight loss from 1.88 to 4.91%, enhanced percentage reduction of body fat (from 0.70 to 8.43%), increased waistline reduction (from 2.36 to 4.14%), improved hip circumference reduction from 0.74 to 2.51% and enhanced reduction of BMI (from 2.10 to 6.43%) (p < 0.01 for all comparisons). Phosphatidylserine did not show any statistical significant effect. Tolerability was very good for both treatments, and no drop-out was reported. CONCLUSIONS: Although preliminary, our findings suggest that a bioavailable form of curcumin is well-tolerated and can positively influence weight management in overweight people. PMID- 26592849 TI - Benign vs. malignant inferolateral early repolarization: Focus on the T wave. AB - BACKGROUND: Inferolateral early repolarization (ER) is highly prevalent and is associated with idiopathic ventricular fibrillation (VF). OBJECTIVE: The purpose of this study was to evaluate the potential role of T-wave parameters to differentiate between malignant and benign ER. METHODS: We compared the ECGs of patients with ER and VF (n = 92) with control subjects with asymptomatic ER (n = 247). We assessed J-wave amplitude, QTc interval, T-wave/R-wave (T/R) ratio in leads II and V5, and presence of low-amplitude T waves (T-wave amplitude <0.1 mV and <10% of R-wave amplitude in lead I, II, or V4-V6). RESULTS: Compared to controls, the VF group had longer QTc intervals (388 ms vs. 377 ms, P = .001), higher J-wave amplitudes (0.23 mV vs. 0.17 mV, P <.001), higher prevalence of low amplitude T waves (29% vs. 3%, P <.001), and lower T/R ratio (0.18 vs. 0.30, P <.001). Logistic regression analysis demonstrated that QTc interval (odds ratio [OR] per 10 ms: 1.15, 95% confidence interval [CI} 1.02-1.30), maximal J-wave amplitude (OR per 0.1 mV: 1.68, 95% CI 1.23-2.31), lower T/R ratio (OR per 0.1 unit: 0.62, 95% CI 0.47-0.81), presence of low-amplitude T waves (OR 3.53, 95% CI 1.26-9.88). and presence of J waves in the inferior leads (OR 2.58, 95% CI 1.18 5.65) were associated with malignant ER. CONCLUSION: Patients with malignant ER have a higher prevalence of low-amplitude T waves, lower T/R ratio (lead II or V5), and longer QTc interval. The combination of these parameters with J-wave amplitude and distribution of J waves may allow for improved identification of malignant ER. PMID- 26592850 TI - Unmasking atrial repolarization to assess alternans, spatiotemporal heterogeneity, and susceptibility to atrial fibrillation. AB - BACKGROUND: Detection of atrial repolarization waves free of far-field signal contamination by ventricular activation would allow investigation of atrial electrophysiology and factors that influence susceptibility to atrial tachycardia and atrial fibrillation (AF). OBJECTIVE: The purpose of this study was to identify means for high-resolution intracardiac recording of atrial repolarization (Ta) waves using standard clinical electrocatheters and to assess fundamental electrophysiologic properties relevant to AF risk. METHODS: In alpha chloralose anesthetized Yorkshire pigs, we studied effects of vagus nerve stimulation (VNS) on PTa and QT intervals and effects of acute atrial ischemia or administration of intrapericardial acetylcholine followed by intravenous epinephrine on susceptibility to AF. RESULTS: Electrocatheters with closely spaced (1-mm) electrode pairs yielded high-resolution tracings of atrial repolarization waves. These recordings permitted detection of differential effects of right or left VNS, which shortened atrial PTa interval by 30% vs. 21% (P <.01) and lengthened QT interval by 1.5% vs. 9%, respectively (P < .05). During atrial ischemia, STa segments were elevated 3.4-fold (P < .01), and the threshold for inducing AF was reduced 3.1-fold (P = .004). Ischemia amplified atrial T-wave alternans (TWAa) and spatiotemporal heterogeneity (TWHa) by 23- and 13-fold, respectively, in inverse correlation to AF threshold (r = 0.74, P <.01; r = 0.61, P = .03). TWAa and TWHa increased by 4.5- and 2-fold shortly before autonomically triggered atrial premature beats and AF. CONCLUSION: This study used standard electrocatheters to demonstrate that TWAa and TWHa analysis provides means to assess vulnerability to AF without provocative electrical stimuli. These parameters could be evaluated in the clinical electrophysiology laboratory to determine risk for this prevalent arrhythmia and efficacy of contemporary and new agents. PMID- 26592851 TI - Impact of touch imprint cytology on imaging-guided core needle biopsies: An experience from a large academic medical center laboratory. AB - BACKGROUND: Imaging-guided core needle biopsy is a minimally invasive and effective tissue sampling method. Touch imprint cytology (TIC) can provide immediate on-site preliminary interpretation and adequacy of core needle biopsy. We investigated on-site TICs' impact on minimizing the number of core needle biopsy passes required for diagnosis. METHODS: Five hundred and sixty imaging guided CNBs with TICs including 393 malignant lesions, 136 benign lesions, 29 nondiagnostic specimens, and 2 atypical lesions were reviewed for adequacy, preliminary interpretation, final histological diagnosis, and the number of core needle biopsy passes. RESULTS: The adequacy rate determined by on-site TICs was 76%, with 50% for benign lesions, and 88% for malignant lesions. The correlation rate between TICs' preliminary interpretation and histological diagnosis was 91%, with 100% for benign lesions and 89% for malignant lesions. In malignant lesions, the adequacy rate was lowest in cases with sarcomas (58%), followed by hepatocellular carcinoma and renal cell carcinoma. When all cases are stratified by locations, the adequacy rate determined by on-site TICs was lowest in lesions from soft tissue (45%), followed by pelvic mass or kidney. The average number of cores was 4.1 per case in adequate specimens, significantly lower than that in specimens without TICs. In contrast, the average number of cores was 7.1 per case in inadequate specimens, significantly greater than that in specimens without TICs. CONCLUSIONS: On-site TICs showed its usefulness in reducing the number of cores required for adequate diagnostic materials. In the meantime, TICs accurately provided preliminary interpretations, especially in adequate malignant carcinoma cases. PMID- 26592852 TI - Tyrosinase inhibitory constituents from a polyphenol enriched fraction of rose oil distillation wastewater. AB - During the water steam distillation process of rose flowers, the non-volatile phenolic compounds remain in the waste. We recently developed a strategy to separate rose oil distillation water (RODW) into a polyphenol depleted water fraction and a polyphenol enriched fraction (RF20-SP207). Bioassay-guided investigation of RF20-SP207 led to the isolation of quercetin, kaempferol and ellagic acid. Their structures were elucidated by spectroscopic analysis as well as by comparison with literature data. Tyrosinase inhibition studies were performed with RF20-SP207, fractions I-IV, and the isolated compounds of the most active fraction. RF20-SP207 strongly inhibited the enzyme with an IC50 of 0.41 MUg/mL. From the tested fractions only fraction IV (IC50=5.81 MUg/mL) exhibited strong anti-tyrosinase activities. Quercetin, kaempferol and ellagic acid were identified in fraction IV and inhibited mushroom tyrosinase with IC50 values of 4.2 MUM, 5.5 MUM and 5.2 MUM, respectively, which is approximately 10 times more potent than that of the positive control kojic acid (56.1MUM). The inhibition kinetics, analyzed by Lineweaver-Burk plots, indicated that RF20-SP207 and fraction IV are uncompetitive inhibitors of tyrosinase when l-tyrosine is used as a substrate. A mixed inhibition was determined for ellagic acid, and a competitive inhibition for quercetin and kaempferol. In conclusion, the recovered polyphenol fraction RF20-SP207 from RODW was found to be a potent tyrosinase inhibitor. This value-added product could be used as an active ingredient in cosmetic products related to hyperpigmentation. PMID- 26592853 TI - Flavanones of Erythrina livingstoniana with antioxidant properties. AB - Six new flavanones (1-6), together with six known compounds were isolated from Erythrina livingstoniana. Their structures were elucidated on the basis of NMR data and HRMS(n) fragmentation pathway and by comparison with literature data. Compounds 5, 7 and 8 showed remarkable DPPH free radical scavenging efficacies. The compounds, however, did not demonstrate an anti-inflammatory potential when tested using a PGE2 (prostaglandin E2) competitive enzyme immunoassay. The plausible biosynthetic pathways of the isolated compounds are described. PMID- 26592854 TI - Prenylated 2-arylbenzofuran derivatives with potent antioxidant properties from Chlorophora regia (Moraceae). AB - Extracts of Chlorophora regia are frequently used in Ghana in traditional medicine. There is, however, no reported data on the chemical composition of the plant. Comprehensive phytochemical investigation of the stem bark of C. regia resulted in the isolation of three new prenylated 2-arylbenzofuran derivatives, regiafuran A-C (1-3), and one new prenylated flavonol (4), together with fifteen known compounds (5-19). Their structures were elucidated by combined spectroscopic analysis of their NMR and HRESI-MS(n) data. Compounds 1, 2, 5, 9 and 15 exhibited remarkable free radical scavenging properties with IC50 values of 1.9 MUg/ml, 2.4 MUg/ml, 2.2 MUg/ml, 2.1 MUg/ml and 1.8 MUg/ml, respectively, compared to the standard trolox (IC50 1.1 MUg/ml). The isolated compounds did not, however, show any anti-inflammatory potential when tested using a PGE2 (prostaglandin E2) competitive enzyme immunoassay. PMID- 26592855 TI - A game of hide and seek between avirulence genes AvrLm4-7 and AvrLm3 in Leptosphaeria maculans. AB - Extending the durability of plant resistance genes towards fungal pathogens is a major challenge. We identified and investigated the relationship between two avirulence genes of Leptosphaeria maculans, AvrLm3 and AvrLm4-7. When an isolate possesses both genes, the Rlm3-mediated resistance of oilseed rape (Brassica napus) is not expressed due to the presence of AvrLm4-7 but virulent isolates toward Rlm7 recover the AvrLm3 phenotype. Combining genetic and genomic approaches (genetic mapping, RNA-seq, BAC (bacterial artificial chromosome) clone sequencing and de novo assembly) we cloned AvrLm3, a telomeric avirulence gene of L. maculans. AvrLm3 is located in a gap of the L. maculans reference genome assembly, is surrounded by repeated elements, encodes for a small secreted cysteine-rich protein and is highly expressed at early infection stages. Complementation and silencing assays validated the masking effect of AvrLm4-7 on AvrLm3 recognition by Rlm3 and we showed that the presence of AvrLm4-7 does not impede AvrLm3 expression in planta. Y2H assays suggest the absence of physical interaction between the two avirulence proteins. This unusual interaction is the basis for field experiments aiming to evaluate strategies that increase Rlm7 durability. PMID- 26592856 TI - Investigating the Joint Development of Approach Bias and Adolescent Alcohol Use. AB - BACKGROUND: We investigated the joint development between implicit approach bias and early adolescent alcohol use, and examined whether the link between approach bias and alcohol use was moderated by working memory (WM). METHODS: The current study used data from a 2-year, 4-wave online sample of 378 Dutch early adolescents (mean age 14.9 years, 64.8% female). First, using latent growth curve modeling, we examined trajectories of approach bias and alcohol use over time. Second, we examined relations between baseline approach bias and WM and the development of alcohol use. Third, we examined the joint development of approach bias and alcohol use. Fourth, we examined whether the nature of this joint development varied for different levels of WM. RESULTS: Unconditional growth curve model analyses indicated that the functional forms of alcohol use and cognitive bias were best captured by quadratic and linear trajectories, respectively. We found that cognitive bias decreased over time. We found no significant relations between baseline predictors and observed increases in alcohol use. We found relations between the intercepts, but not to growth factors, in the joint development of alcohol use and approach bias. WM was not found to moderate relations between growth in approach bias and alcohol use in this sample. CONCLUSIONS: While we observed evidence of association between approach bias and alcohol use at baseline, there was no evidence of relations between development trajectories of the two. These findings replicate prior research demonstrating a role of implicit approach bias in predicting early adolescent alcohol use but do not demonstrate, in a light drinking early adolescent sample, the importance of interrelations between changes in approach bias and alcohol use over time, or a moderating role of WM. It is important to consider the potential consequences of repeated online approach bias assessment (e.g., changes in stimulus valence) when interpreting these results. PMID- 26592857 TI - Preventing excessive gestational weight gain among African American women: A randomized clinical trial. AB - OBJECTIVE: Evidence is lacking regarding effective weight control treatments in pregnancy for ethnic minority women with obesity. This study evaluated whether a technology-based behavioral intervention could decrease the proportion of African American women with overweight or obesity who exceeded Institute of Medicine (IOM) guidelines for gestational weight gain. METHODS: We conducted a two-arm pilot randomized clinical trial. Participants were 66 socioeconomically disadvantaged African American pregnant women (12.5 +/- 3.7 weeks' gestation; 36% overweight, 64% obesity) recruited from two outpatient obstetric practices at Temple University between 2013 and 2014. We randomized participants to usual care (n = 33) or a behavioral intervention (n = 33) that promoted weight control in pregnancy. The intervention included: (1) empirically supported behavior change goals; (2) interactive self-monitoring text messages; (3) biweekly health coach calls; and (4) skills training and support through Facebook. RESULTS: The intervention reduced the proportion of women who exceeded IOM guidelines compared to usual care (37% vs. 66%, P = 0.033). Intervention participants gained less weight during pregnancy (8.7 vs. 12.3 kg, adjusted mean difference: -3.1 kg, 95% CI: -6.2 to -0.1). No group differences in neonatal or obstetric outcomes were found. CONCLUSIONS: The intervention resulted in lower prevalence of excessive gestational weight gain. PMID- 26592858 TI - Monoamine Oxidase Inhibitory Activity of Ferulic Acid Amides: Curcumin-Based Design and Synthesis. AB - Ferulic acid has structural similarity with curcumin which is being reported for its monoamine oxidase (MAO) inhibitory activity. Based on this similarity, we designed a series of ferulic acid amides 6a-m and tested for their inhibitory activity on human MAO (hMAO) isoforms. All the compounds were found to inhibit the hMAO isoforms either selectively or non-selectively. Nine compounds (6a, 6b, 6g-m) were found to inhibit hMAO-B selectively, whereas the other four (6c-f) were found to be non-selective. There is a gradual shift from hMAO-B selectivity (6a,b) to non-selectivity (6c-f) as there is an increase in chain length at the amino terminus. In case of compounds having an aromatic nucleus at the amino terminus, increasing the carbon number between N and the aromatic ring increases the potency as well as selectivity toward hMAO-B. Compounds 6f, 6j, and 6k were subjected to membrane permeability and metabolic stability studies by in vitro assay methods. They were found to have a better pharmacokinetic profile than curcumin, ferulic acid, and selegiline. In order to understand the structural features responsible for the potency and selectivity of 6k, we carried out a molecular docking simulation study. PMID- 26592859 TI - Management of anticoagulated patients in implant therapy: a clinical comparative study. AB - OBJECTIVES: This prospective clinical comparative study aimed to analyze the postoperative bleeding risk of patients continuing their anticoagulation therapy (AT) and undergoing implant surgery and bone grafting procedures. MATERIALS AND METHODS: The treatments ranged from the insertion of single or multiple dental implants over implant exposures to sinus floor augmentation and vertical and/or lateral bone grafting with autologous bone grafts. The patients of the test groups (AT groups) were treated with platelet aggregation inhibitors (PAIs), Vitamin-K inhibitors, Vitamin-K inhibitor withdrawal bridged with heparin (LMWH), or new/direct oral anticoagulants (NOACs/DOACs). Patients of the control group were non-anticoagulated (non-AT group). Surgical procedures were performed in the same manner in all groups. Pre, intra, and postoperative data concerning the treatment, extent of the surgery and bleedings was recorded and statistically evaluated. RESULTS: There were seven postoperative bleedings in 564 patients (1.2%), four in the AT groups (3.4%), and three in the non-AT group (0.6%). No thromboembolic complication occurred in the whole observation period. The invasiveness of the surgical procedure had no statistically significant effect on bleeding frequencies. Patients taking Vitamin-K inhibitors had a significantly higher risk of a postoperative bleeding compared to patients without any AT (P = 0.038). Two patients were hospitalized due to the severity of the bleeding as a precautionary measure (one in the non-AT and one in the PAI group). All bleedings were easily controllable with local hemostatic measures. There was no postoperative bleeding recorded for patients taking DOACs. CONCLUSIONS: Anticoagulation therapy should be continued in patients undergoing implant surgery and bone grafting procedures avoiding thromboembolic complications. Surgeons should always apply the most minimally invasive approach to reduce postoperative risks and be able to apply local hemostatic measures in terms of a bleeding complication. PMID- 26592860 TI - Selective enrichment and separation of phosphotyrosine peptides by thermosensitive molecularly imprinted polymers. AB - Novel thermosensitive molecularly imprinted polymers were successfully prepared using the epitope imprinting approach in the presence of the mimic template phenylphosphonic acid, the functional monomer vinylphosphonic acid-Ti(4+) , the temperature-sensitive monomer N-isopropylacrylamide and the crosslinker N,N' methylenebisacrylamide. The ratio of the template/thermosensitive monomers/crosslinker was optimized, and when the ratio was 2:2:1, the prepared thermosensitive molecularly imprinted polymers had the highest imprinting factor. The synthetic thermosensitive molecularly imprinted polymers were characterized by Fourier transform infrared spectroscopy to reveal the combination and elution processes of the template. Then, the adsorption capacity and thermosensitivity was measured. When the temperature was 28 degrees C, the imprinting factor was the highest. The selectivity and adsorption capacity of the thermosensitive molecularly imprinted polymers for phosphotyrosine peptides from a mixture of three tailor-made peptides were measured by high-performance liquid chromatography. The results showed that the thermosensitive molecularly imprinted polymers have good selectivity for phosphotyrosine peptides. Finally, the imprinted hydrogels were applied to specifically adsorb phosphotyrosine peptides from a sample mixture containing phosphotyrosine and a tryptic digest of beta casein, which demonstrated high selectivity. After four rebinding cycles, 78.9% adsorption efficiency was still retained. PMID- 26592863 TI - From an Isolable Acyclic Phosphinosilylene Adduct to Donor-Stabilized Si=E Compounds (E=O, S, Se). AB - Reaction of the arylchlorosilylene-NHC adduct ArSi(NHC)Cl [Ar=2,6-Trip2C6H3; NHC=(MeC)2(NMe)2C:] 1 with one molar equiv of lithium diphenylphosphanide affords the first stable NHC-stabilized acyclic phosphinosilylene adduct 2 (ArSi(NHC)PPh2), which could be structurally characterized. Compound 2, when reacted with one molar equiv selenium and sulfur, affords the silanechalcogenones 4 a and 4 b (ArSi(NHC)(=E)PPh2, 4 a: E=Se, 4 b: E=S), respectively. Conversion of 2 with an excess of Se and S, through additional insertion of one chalcogen atom into the Si=P bond, leads to 3 a and 3 b (ArSi(NHC)(=E)-E-P(=E)Ph2, 3 a: E=Se, 3 b: E=S), respectively. Additionally, the exposure of 2 to N2O or CO2 yielded the isolable NHC-stabilized silanone 4 c, Ar(NHC)(Ph2P)Si=O. PMID- 26592861 TI - A Self-Assembled Respiratory Chain that Catalyzes NADH Oxidation by Ubiquinone-10 Cycling between Complex I and the Alternative Oxidase. AB - Complex I is a crucial respiratory enzyme that conserves the energy from NADH oxidation by ubiquinone-10 (Q10) in proton transport across a membrane. Studies of its energy transduction mechanism are hindered by the extreme hydrophobicity of Q10, and they have so far relied on native membranes with many components or on hydrophilic Q10 analogues that partition into membranes and undergo side reactions. Herein, we present a self-assembled system without these limitations: proteoliposomes containing mammalian complex I, Q10, and a quinol oxidase (the alternative oxidase, AOX) to recycle Q10H2 to Q10. AOX is present in excess, so complex I is completely rate determining and the Q10 pool is kept oxidized under steady-state catalysis. The system was used to measure a fully-defined K(M) value for Q10. The strategy is suitable for any enzyme with a hydrophobic quinone/quinol substrate, and could be used to characterize hydrophobic inhibitors with potential applications as pharmaceuticals, pesticides, or fungicides. PMID- 26592862 TI - Solution-printed organic semiconductor blends exhibiting transport properties on par with single crystals. AB - Solution-printed organic semiconductors have emerged in recent years as promising contenders for roll-to-roll manufacturing of electronic and optoelectronic circuits. The stringent performance requirements for organic thin-film transistors (OTFTs) in terms of carrier mobility, switching speed, turn-on voltage and uniformity over large areas require performance currently achieved by organic single-crystal devices, but these suffer from scale-up challenges. Here we present a new method based on blade coating of a blend of conjugated small molecules and amorphous insulating polymers to produce OTFTs with consistently excellent performance characteristics (carrier mobility as high as 6.7 cm(2) V( 1) s(-1), low threshold voltages of<1 V and low subthreshold swings <0.5 V dec( 1)). Our findings demonstrate that careful control over phase separation and crystallization can yield solution-printed polycrystalline organic semiconductor films with transport properties and other figures of merit on par with their single-crystal counterparts. PMID- 26592864 TI - Masculinities and ethnicities: Ethnic differences in drive for muscularity in British men and the negotiation of masculinity hierarchies. AB - Although relatively little is known about ethnic differences in men's drive for muscularity, recent theoretical developments suggest that ethnic minority men may desire greater muscularity to contest their positions of relative subordinate masculinity. This study tested this hypothesis in a sample of 185 White, 180 Black British, and 182 South Asian British men. Participants completed self report measures of drive for muscularity, need for power, adherence to traditional cultural values, and ethnic group affiliation. Taking into account between-group differences in body mass index, results indicated that White men had significantly lower drive for muscularity than Black and South Asian men, who were not significantly different from each other. In addition, greater need for power was significantly associated with higher drive for muscularity in ethnic minority, but not White, men. Greater adherence to traditional cultural values, but not ethnic group affiliation, was associated with lower drive for muscularity in all ethnic groups. These results suggest that ethnic minority men may desire greater muscularity as a means of negotiating masculinity and attendant ideals of appearance. PMID- 26592865 TI - Optimization of thermophilic trans-isoprenyl diphosphate synthase expression in Escherichia coli by response surface methodology. AB - We optimized the heterologous expression of trans-isoprenyl diphosphate synthase (IDS), the key enzyme involved in the biosynthesis of trans-polyisoprene. trans Polyisoprene is a particularly valuable compound due to its superior stiffness, excellent insulation, and low thermal expansion coefficient. Currently, trans polyisoprene is mainly produced through chemical synthesis and no biotechnological processes have been established so far for its large-scale production. In this work, we employed D-optimal design and response surface methodology to optimize the expression of thermophilic enzymes IDS from Thermococcus kodakaraensis. The design of experiment took into account of six factors (preinduction cell density, inducer concentration, postinduction temperature, salt concentration, alternative carbon source, and protein inhibitor) and seven culture media (LB, NZCYM, TB, M9, Ec, Ac, and EDAVIS) at five different pH points. By screening only 109 experimental points, we were able to improve IDS production by 48% in close-batch fermentation. PMID- 26592867 TI - Overcoming the Barrier on Time Step Size in Multiscale Molecular Dynamics Simulation of Molecular Liquids. AB - We propose and validate a new multiscale technique, the extrapolative isokinetic Nose-Hoover chain orientational (EINO) motion multiple time step algorithm for rigid interaction site models of molecular liquids. It nontrivially combines the multiple time step decomposition operator method with a specific extrapolation of intermolecular interactions, complemented by an extended isokinetic Nose-Hoover chain approach in the presence of translational and orientational degrees of freedom. The EINO algorithm obviates the limitations on time step size in molecular dynamics simulations. While the best existing multistep algorithms can advance from a 5 fs single step to a maximum 100 fs outer step, we show on the basis of molecular dynamics simulations of the TIP4P water that our EINO technique overcomes this barrier. Specifically, we have achieved giant time steps on the order of 500 fs up to 5 ps, which now become available in the study of equilibrium and conformational properties of molecular liquids without a loss of stability and accuracy. PMID- 26592866 TI - Development and Biological Evaluation of Inkjet Printed Drug Coatings on Intravascular Stent. AB - Inkjet-printing technology was used to apply biodegradable and biocompatible polymeric coatings of poly(d,l-lactide) with the antiproliferative drugs simvastatin (SMV) and paclitaxel (PCX) on coronary metal stents. A piezoelectric dispenser applied coating patterns of very fine droplets (300 pL) and inkjet printing was optimized to develop uniform, accurate and reproducible coatings of high yields on the stent strut. The drug loaded polymeric coatings were assed by scanning electron microscopy (SEM), atomic force microscopy (AFM), and transition thermal microscopy (TTM) where a phase separation was observed for SMV/PLA layers while PCX showed a uniform distribution within the polymer layers. Cytocompatibility studies of PLA coatings showed excellent cell adhesion with no decrease of cell viability and proliferation. In vivo stent implantation studies showed significant intrastent restenosis (ISR) for PCX/PLA and PLA plain coatings similar to marketed Presillion (bare metal) and Cypher (drug eluting) stents. The investigation of several cytokine levels after 7 days of stent deployment showed no inflammatory response and hence no in vivo cytotoxicity related to PLA coatings. Inkjet printing can be employed as a robust coating technology for the development of drug eluting stents compared to the current conventional approaches. PMID- 26592868 TI - Kepler Predictor-Corrector Algorithm: Scattering Dynamics with One-Over-R Singular Potentials. AB - An accurate and efficient algorithm for dynamics simulations of particles with attractive 1/r singular potentials is introduced. The method is applied to semiclassical dynamics simulations of electron-proton scattering processes in the Wigner-transform time-dependent picture, showing excellent agreement with full quantum dynamics calculations. Rather than avoiding the singularity problem by using a pseudopotential, the algorithm predicts the outcome of close-encounter two-body collisions for the true 1/r potential by solving the Kepler problem analytically and corrects the trajectory for multiscattering with other particles in the system by using standard numerical techniques (e.g., velocity Verlet, or Gear Predictor corrector algorithms). The resulting integration is time-reversal symmetric and can be applied to the general multibody dynamics problem featuring close encounters as occur in electron-ion scattering events, in particle antiparticle dynamics, as well as in classical simulations of charged interstellar gas dynamics and gravitational celestial mechanics. PMID- 26592869 TI - Large-Scale MP2 Calculations on the Blue Gene Architecture Using the Fragment Molecular Orbital Method. AB - Benchmark timings are presented for the fragment molecular orbital method on a Blue Gene/P computer. Algorithmic modifications that lead to enhanced performance on the Blue Gene/P architecture include strategies for the storage of fragment density matrices by process subgroups in the global address space. The computation of the atomic forces for a system with more than 3000 atoms and 44 000 basis functions, using second order perturbation theory and an augmented and polarized double-zeta basis set, takes ~7 min on 131 072 cores. PMID- 26592870 TI - Performance of Effective Core Potentials for Density Functional Calculations on 3d Transition Metals. AB - The performance of popular Hartree-Fock-based effective core potentials in Hartree-Fock and density functional calculations of 3d transition metals has been evaluated by basis-set convergence studies for ten cases: the equilibrium bond dissociation energy (De) for dissociation of ground-state Ti2 to ground and excited atoms, the ground-state dissociation energies of FeO, Cu2, ScH, TiH, Sc2, Fe2, and TiV(+), and the first excitation energy (Ex) of Ti atom. Each case is studied with 11 or 13 density functionals. For comparison, the accuracy of the all-electron def2-TZVP basis set is tested with both relativistic and nonrelativistic treatments. Convergence and accuracy are assessed by comparing to relativistic all-electron calculations with a nearly complete relativistic basis set (NCBS-DK, which denotes the cc-pV5Z-DK basis set for 3d metals and hydrogen and the ma-cc-pV5Z-DK basis set for oxygen) and to nonrelativistic all-electron calculations with a nearly complete nonrelativistic basis set (NCBS-NR, which denotes the cc-pV5Z basis set for 3d metals and hydrogen and the ma-cc-pV5Z basis set for oxygen). As compared to NCBS-DK results, all ECP calculations perform worse than def2-TZVP all-electron relativistic calculations when averaged over all 130 data (13 functionals and ten test cases). The compact effective potential (CEP) relativistic effective core potential (RECP) combined with a valence basis set developed for the many-electron Dirac-Fock (MDF10) RECP performs best in effective core potential calculations and has an average basis-set incompleteness error of 3.7 kcal/mol, which is much larger than that (0.9 kcal/mol) of def2-TZVP relativistic all-electron results. Hence, the def2-TZVP relativistic all-electron calculations are recommended for accurate DFT calculations on 3d transition metals. In addition to our general findings, we observed that all kinds of density functionals do not show the same trends. For example, when ECPs are used with hybrid functionals, which sometimes are not recommended for calculations of transition metal systems, they are found to perform better at achieving the basis set limit than when used with local functionals and meta-GGA functionals. The most successful combination of RECP and basis set has a basis-set incompleteness error of 1.7-2.4 kcal/mol for hybrid generalized gradient approximations, which is smaller than that of nonrelativistic NCBS calculations (whose average basis set incompleteness error for hybrid functionals is 2.7-2.9 kcal/mol). The average basis-set incompleteness error in Hartree-Fock calculations is 1.0-4.4 kcal/mol for five of the ECP basis sets but is 5.8-10.8 kcal/mol for six others. PMID- 26592871 TI - Fully Relativistic Calculations of Faraday and Nuclear Spin-Induced Optical Rotation in Xenon. AB - Nuclear spin-induced optical rotation (NSOR) arising from the Faraday effect may constitute an advantageous novel method for the detection of nuclear magnetization. We present first-principles nonrelativistic and relativistic, two- and four-component, basis-set limit calculations of this phenomenon for xenon. It is observed that only by utilization of relativistic methods may one qualitatively reproduce experimental liquid-state NSOR data. Relativistic effects lower the results by 50% as compared to nonrelativistic values. Indeed, relativistic Hartree-Fock calculations at the four-component or exact two component (X2C) level account for the discrepancy between experimental results and earlier nonrelativistic theory. The nuclear magnetic shielding constant of traditional nuclear magnetic resonance as well as the Verdet constant parametrizing optical rotation due to an external magnetic field were also calculated. A comparison between results obtained using Hartree-Fock and density functional theory methods at relativistic and nonrelativistic levels, as well as coupled cluster methods at the nonrelativistic level, was carried out. Completeness-optimized basis sets were employed throughout, for the first time in fully relativistic calculations. Full relativity decreases the Verdet constant by 4%. X2C theory decreases the absolute value of NSOR by 10-20% as compared to the four-component data, while for Verdet constants, the results are only slightly smaller than the fully relativistic values. For both properties, two-component calculations decrease the computational time by roughly 90%. Density-functional methods yield substantially larger values of NSOR than the Hartree-Fock theory or experiments. Intermolecular interactions are found to decrease NSOR and, hence, compensate for the electron correlation effect. PMID- 26592872 TI - Intercalation of Transition Metals into Stacked Benzene Rings: A Model Study of the Intercalation of Transition Metals into Bilayered Graphene. AB - Structures of neutral metal-dibenzene complexes, M(C6H6)2 (M = Sc-Zn), are investigated by using Moller-Plesset second order perturbation theory (MP2). The benzene molecules change their conformation and shape upon complexation with the transition metals. We find two types of structures: (i) stacked forms for early transition metal complexes and (ii) distorted forms for late transition metal ones. The benzene molecules and the metal atom are bound together by delta bonds which originate from the interaction of pi-MOs and d orbitals. The binding energy shows a maximum for Cr(C6H6)2, which obeys the 18-electron rule. It is noticeable that Mn(C6H6)2, a 19-electron complex, manages to have a stacked structure with an excess electron delocalized. For other late transition metal complexes having more than 19 electrons, the benzene molecules are bent or stray away from each other to reduce the electron density around a metal atom. For the early transition metals, the M(C6H6) complexes are found to be more weakly bound than M(C6H6)2. This is because the M(C6H6) complexes do not have enough electrons to satisfy the 18-electron rule, and so the M(C6H6)2 complexes generally tend to have tighter binding with a shorter benzene-metal length than the M(C6H6) complexes, which is quite unusual. The present results could provide a possible explanation of why on the Ni surface graphene tends to grow in a few layers, while on the Cu surface the weak interaction between the copper surface and graphene allows for the formation of a single layer of graphene, in agreement with chemical vapor deposition experiments. PMID- 26592873 TI - Eigensystem Representation of the Electronic Susceptibility Tensor for Intermolecular Interactions within Density Functional Theory. AB - We present an efficient implementation of the electronic susceptibility tensor within density functional theory. The susceptibility is represented by means of its eigensystem, which is computed using an iterative Lanczos diagonalization technique for the susceptibility tensor within density functional perturbation theory. We show that a representation in a finite basis of eigenstates is sufficiently accurate to compute the linear response of the electronic density to external potentials. Once the eigensystem representation is computed, the actual response computation can be done at very low computational cost. The method is applied to the water molecule in a dipole field as a benchmark system. The results illustrate the potential of the approach for the first-principles calculation of supramolecular interactions in complex disordered systems in the condensed phase. PMID- 26592874 TI - Bathochromic Shift in Green Fluorescent Protein: A Puzzle for QM/MM Approaches. AB - We present an extensive investigation of the vertical excitations of the anionic and neutral forms of wild-type green fluorescent protein using time-dependent density functional theory (TDDFT), multiconfigurational perturbation theory (CASPT2), and quantum Monte Carlo (QMC) methods within a quantum mechanics/molecular mechanics (QM/MM) scheme. The protein models are constructed via room-temperature QM/MM molecular dynamics simulations based on DFT and are representative of an average configuration of the chromophore-protein complex. We thoroughly verify the reliability of our structures through simulations with an extended QM region, different nonpolarizable force fields, as well as partial reoptimization with the CASPT2 approach. When computing the excitations, we find that wave function as well as density functional theory methods with long-range corrected functionals agree in the gas phase with the extrapolation of solution experiments but fail in reproducing the bathochromic shift in the protein, which should be particularly significant in the neutral case. In particular, while all methods correctly predict a shift in the absorption between the anionic and neutral forms of the protein, the location of the theoretical absorption maxima is significantly blue-shifted and too close to the gas-phase values. These results point to either an intrinsic limitation of nonpolarizable force-field embedding in the computation of the excitations or to the need to explore alternative protonation states of amino acids in the close vicinity of the chomophore. PMID- 26592875 TI - Evaluating London Dispersion Interactions in DFT: A Nonlocal Anisotropic Buckingham-Hirshfeld Model. AB - In this work, we present a novel model, referred to as BH-DFT-D, for the evaluation of London dispersion, with the purpose to correct the performance of local DFT exchange-correlation functionals for the description of van der Waals interactions. The new BH-DFT-D model combines the equations originally derived by Buckingham [Buckingham, A. D. Adv. Chem. Phys1967, 12, 107] with the definition of distributed multipole polarizability tensors within the Hirshfeld method [Hirshfeld, F.L. Theor. Chim. Acta1977, 44, 129], resulting in nonlocal, fully anisotropic expressions. Since no damping function has been introduced yet into the model, it is suitable in its present form for the evaluation of dispersion interactions in van der Waals dimers with no or negligible overlap. The new method is tested for an extended collection of van der Waals dimers against high level data, where it is found to reproduce interaction energies at the BH-B3LYP D/aug-cc-pVTZ level with a mean average error (MAE) of 0.20 kcal/mol. Next, development steps of the model will consist of adding a damping function, analytical gradients, and generalization to a supramolecular system. PMID- 26592876 TI - Peculiar Transformations in the CxHxP4-x (x = 0-4) Series. AB - In the current work, we performed a systematic study of the CxHxP4-x (x = 0-4) series using an unbiased CK global minimum and low-lying isomers search for the singlet and triplet P4-C4H4 species at the B3LYP/6-31G** level of theory. The selected lowest isomers were recalculated at the CCSD(T)/CBS//B3LYP/6-311++G** level of theory. We found that the transition from a three-dimensional tetrahedron-like structure to a planar structure occurs at x = 3, where planar isomers become much more stable than the tetrahedral structures due to significantly stronger pi bonds between carbon atoms in addition to increasing strain energy at the carbon atom in the tetrahedral environment. PMID- 26592877 TI - Advanced Corrections of Hydrogen Bonding and Dispersion for Semiempirical Quantum Mechanical Methods. AB - Semiempirical quantum mechanical methods with corrections for noncovalent interactions, namely dispersion and hydrogen bonds, reach an accuracy comparable to much more expensive methods while being applicable to very large systems (up to 10 000 atoms). These corrections have been successfully applied in computer assisted drug design, where they significantly improve the correlation with the experimental data. Despite these successes, there are still several unresolved issues that limit the applicability of these methods. We introduce a new generation of both hydrogen-bonding and dispersion corrections that address these problems, make the method more robust, and improve its accuracy. The hydrogen bonding correction has been completely redesigned and for the first time can be used for geometry optimization and molecular-dynamics simulations without any limitations, as it and its derivatives have a smooth potential energy surface. The form of this correction is simpler than its predecessors, while the accuracy has been improved. For the dispersion correction, we adopt the latest developments in DFT-D, using the D3 formalism by Grimme. The new corrections have been parametrized on a large set of benchmark data including nonequilibrium geometries, the S66x8 data set. As a result, the newly developed D3H4 correction can accurately describe a wider range of interactions. We have parametrized this correction for the PM6, RM1, OM3, PM3, AM1, and SCC-DFTB methods. PMID- 26592878 TI - Alternative Mechanisms in Hydrogen Production by Aluminum Anion Clusters. AB - Possible mechanisms for the reaction of aluminum anion clusters with water have been studied theoretically using density functional theory for four different size clusters. Our results confirm the previously found (Reber et al. J. Phys. Chem. A2010, 114, 6071) importance of Lewis-acid and Lewis-base sites on the cluster in the size specificity of the reactivity. However, alternative viable mechanisms have been found using both Langmuir-Hinshelwood and Eley-Rideal kinetics. Grotthuss-like mechanisms appear to be the most energetically favorable. We show that while the superatom theory successfully predicts reactivity of smaller clusters, it is less useful for the larger clusters. PMID- 26592879 TI - Improving Sampling by Exchanging Hamiltonians with Efficiently Configured Nonequilibrium Simulations. AB - Molecular simulations aim to sample all of the thermodynamically important states; when the sampling is inadequate, inaccuracy follows. A widely used technique to enhance sampling in simulations is Hamiltonian exchange. This technique introduces auxiliary Hamiltonians under which sampling is computationally efficient and attempts to exchange the molecular states among the auxiliary and the original Hamiltonians. The effectiveness of Hamiltonian exchange depends in part on the probability that the trial exchanges can be accepted, which involves good choices of auxiliary Hamiltonians and a good method of generating the trial exchanges. In this paper, we investigate nonequilibrium simulations as trial exchange generators and develop a theoretical model for the efficiency of Hamiltonian exchange and an algorithm to better configure such simulations. We show that properly configured nonequilibrium simulations can modestly increase the overall efficiency of Hamiltonian exchange. PMID- 26592880 TI - Cation-pi and pi-pi Interactions in Aqueous Solution Studied Using Polarizable Potential Models. AB - Polarizable potential models for the interaction of Li(+), Na(+), K(+), and NH4(+) ions with benzene are parametrized based on ab initio quantum mechanical calculations. The models reproduce the ab initio complexation energies and potential energy surfaces of the cation-pi dimers. They also reproduce the cooperative behavior of "stacked", cation-pi-pi trimers and the anticooperative behavior of "sandwiched", pi-cation-pi trimers. The NH4(+) model is calibrated to reproduce the energy of the NH4(+)-H2O dimer and yields correct free energy of hydration and hydration structure without further adjustments. The models are used to investigate cation-pi interactions in aqueous solution by calculating the potential of mean force between each of the four cations and a benzene molecule and by analyzing the organization of the solvent as a function of the cation benzene separation. The results show that Li(+) and Na(+) ions are preferentially solvated by water and do not associate with benzene, while K(+) and NH4(+) ions bind benzene with 1.2 and 1.4 kcal/mol affinities, respectively. Molecular dynamics simulations of NH4(+) and of K(+) in presence of two benzene molecules in water show that cation-pi and pi-pi affinities are mutually enhanced compared to the pairwise affinities, confirming that the cooperativity of cation-pi and pi pi interactions persists in aqueous solution. PMID- 26592881 TI - A Multi-Objective Approach to Force Field Optimization: Structures and Spin State Energetics of d(6) Fe(II) Complexes. AB - The next generation of force fields (FFs), regardless of the accuracy of the potential energy representation, will always have parameters that must be fitted in order to reproduce experimental and/or ab initio data accurately. Single objective methods have been used for many years to automate the obtaining of parameters, but this leads to ambiguity. The solution depends on the chosen weights and is therefore not unique. There have been few advances in solving this problem, which thus remains a major hurdle for the development of empirical FF methods. We propose a solution based on multi-objective evolutionary algorithms (MOEAs). MOEAs allow the FF to be tuned against the desired objectives and offer a powerful, efficient, and automated means to reparameterize FFs, or even discover the parameters for a new potential. Here, we illustrate the application of MOEAs by reparameterizing the ligand field molecular mechanics (LFMM) FF recently reported for modeling spin crossover in iron(II)-amine complexes (Deeth et al. J. Am. Chem. Soc.2010, 132, 6876). We quickly recover the performance of the original parameter set and then significantly improve it to reproduce the geometries and spin state energy differences of an extended series of complexes with RMSD errors in Fe-N and N-N distances reduced from 0.06 A to 0.03 A and spin state energy difference RMSDs reduced from 1.5 kcal mol(-1) to 0.2 kcal mol(-1). The new parameter sets highlight, and help resolve, shortcomings both in the non LFMM FF parameters and in the interpretation of experimental data for several other Fe(II)N6 amine complexes not used in the FF optimization. PMID- 26592882 TI - RASPT2/RASSCF vs Range-Separated/Hybrid DFT Methods: Assessing the Excited States of a Ru(II)bipyridyl Complex. AB - The excited states of the trans(Cl)-Ru(bpy)Cl2(CO)2 (bpy = bypyridyl) transition metal (TM) complex are assessed using the newly developed second-order perturbation theory restricted active space (RASPT2/RASSCF) method. The delicate problem of partitioning the RAS subspaces (RAS1, RAS2, and RAS3) is addressed, being the choice of the RAS2 the bottleneck to obtain a balanced description of the excited states of different nature when TMs are present. We find that the RAS2 should be composed by the correlation orbitals involved in covalent metal ligand bonds. The level of excitations within the RAS1 and RAS3 subspaces is also examined. The performance of different flavors of time-dependent density functional theory including pure, hybrid, meta-hybrid, and range-separated functionals in the presence of solvent effects is also evaluated. It is found that none of the functionals can optimally describe all the excited states simultaneously. However, the hybrid M06, B3LYP, and PBE0 functionals seem to be the best compromise to obtain a balanced description of the excited states of trans(Cl)-Ru(bpy)Cl2(CO)2, when comparing with the experimental spectrum. The conclusions obtained in this molecule should pave the road to properly treat excited states of larger Ru-polypyridyl complexes, which are of particular interest in supramolecular chemistry. PMID- 26592883 TI - Infrared Spectroscopy of Fluxional Molecules from (ab Initio) Molecular Dynamics: Resolving Large-Amplitude Motion, Multiple Conformations, and Permutational Symmetries. PMID- 26592884 TI - The Absorption Spectrum of Cytosine Tautomers: Beyond the Static Approach. AB - The absorption spectrum of cytosine in water has been studied by combining Car Parrinello molecular dynamics (MD) with a multiconfigurational perturbation theory treatment of the electronic structure. The MD simulations were performed for four different tautomeric forms of cytosine in a unit cell with 60 water molecules. The relative energies and transition dipole moments of a large number of excited states have been calculated on a representative sample of conformations along the MD trajectories. In this way, the broad experimental peaks can be decomposed, and the effect of the distortions on the nature of the excited states can be assessed. The loss of planarity of the molecule is significant, and hence, the excited states can no longer be defined as pure n -> pi* or pi -> pi* excitations. We propose an analysis to assign the different transitions according to the main contribution. The keto N1H form turns out to be the most stable one, and the calculated spectra of this tautomer show good agreement with experimental measurements. The mixed npi*/pipi* character of some states leads to a significant increase of intensity in spectral regions dominated by the dark npi* transitions considering a planar structure. PMID- 26592885 TI - Tuned Range-Separated Time-Dependent Density Functional Theory Applied to Optical Rotation. AB - For range-separated hybrid density functionals, the consequences of using system specific range-separation parameters (gamma) in calculations of optical rotations (ORs) are investigated. Computed ORs at three wavelengths are reported for methyloxirane, norbornenone, beta-pinene, [6]helicene, [7]helicene, and two derivatives of [6]helicene. The gamma parameters are adjusted such that Kohn-Sham density functional calculations satisfy the condition -epsilon(HOMO)(N) = IP. For beta-pinene, the behavior of the energy as a function of fractional total charge is also tested. For the test set of molecules, comparisons of ORs with available coupled-cluster and experimental data indicate that the gamma "tuning" leads to improved results for beta-pinene and the helicenes and does not do too much harm in other cases. PMID- 26592886 TI - Encapsulation Influence on EPR Parameters of Spin-Labels: 2,2,6,6-Tetramethyl-4 methoxypiperidine-1-oxyl in Cucurbit[8]uril. AB - Encapsulation of a nitroxide spin label into a host cavity can prolong the lifetime of the spin label in biological tissues and other environments. Although such paramagnetic supramolecular complexes have been extensively studied experimentally, there is yet little understanding of the role of the encapsulation on the magnetic properties of the spin labels and their performance at the atomistic level. In this work, we approach this problem by modeling encapsulation induced changes of the magnetic properties of spin labels for a prototypical paramagnetic guest-host complex, 2,2,6,6-tetramethyl-4 methoxypiperidine-1-oxyl, enclosed in the hydrophobic cavity of cucurbit[8]uril, using state-of-the-art hybrid quantum mechanics/molecular mechanics methodology. The results allow a decomposition of the encapsulation shift of the electronic g tensor and the nitrogen isotropic hyperfine coupling constant of nitroxide radical into a set of distinct contributions associated with the host cavity confinement and with changes of the local solvent environment of the spin label upon encapsulation. It is found that the hydrophobic cavity of cucurbit[8]uril only weakly influences the electronic g-tensor of the 2,2,6,6-tetramethyl-4 methoxypiperidine-1-oxyl but induces a significant encapsulation shift of the nitrogen hyperfine coupling constant. The latter is caused by the change of topology of the hydrogen bonding network and the nature of the hydrogen bonds around the spin label induced by the hydrophobic cavity of the inclusion host. This indirect effect is found to be more important than the direct influence of the cavity exerted on the radical. The ramification of this finding for the use of approximate methods for computing electron paramagnetic resonance spectra of spin labels and for designing optimal spin labels based on guest-host templates is discussed. PMID- 26592887 TI - Performance of Cluster Expansions of Coverage-Dependent Adsorption of Atomic Oxygen on Pt(111). AB - A density functional theory (DFT) database of 66 Pt(111)/O formation energies is presented. We fit this database of formation energies to a range of cluster expansions (CEs) of systematically increasing size and flexibility. We find that the performance of the CE depends upon the property or properties of interest. Pair-wise CEs with up to third nearest neighbor interactions poorly predict all metrics. CEs with five to eight pairwise interactions and one to two triplet interactions predicted formation energies and most ground states accurately but predicted average and differential adsorption energies with modest errors. A larger CE captures average and differential adsorption energies as well as formation energies and ground states. The choice of figures in the CEs is also examined. Pair-wise figures and the linear, 1-1-3, triplet are necessary to obtain CEs that qualitatively reproduce the examined properties; however, other figures are more interchangeable. The electronic and strain components of the adsorbate-adsorbate interactions is studied by comparing a CE of DFT formation energies in which atoms were not allowed to relax to the CEs of the relaxed surface. On an unrelaxed Pt surface, interactions are shorter-ranged interactions and more repulsive at first nearest neighbor separation. PMID- 26592888 TI - Anion Binding by Electron-Deficient Arenes Based on Complementary Geometry and Charge Distribution. AB - Extended electron-deficient arenes are investigated as potential neutral receptors for polyanions. Anion binds via sigma interaction with extended arenes, which are composed solely of C and N ring atoms and CN substituents. As a result, the positive charge on the aromatic C is enhanced, consequently maximizing binding strength. Selectivity is achieved because different charge distributions can be obtained for target anions of a particular geometry. The halides F(-) and Cl(-) form the most stable complex with 6, while the linear N3(-) interacts most favorably with 7. The trigonal NO3(-) and tetrahedral ClO4(-) fit the 3-fold rotational axis of 6 but do not form stable complexes with 5 and 7. The Y-shaped HCOO(-) forms complexes with 4, 5, and 7, with the latter being the most stable. Thus, the anion complexes exhibit strong binding and the best geometrical fit between guest and host, reminiscent of Lego blocks. PMID- 26592889 TI - Noncovalent Interactions in SIESTA Using the vdW-DF Functional: S22 Benchmark and Macrocyclic Structures. AB - We investigate the performance of the vdW-DF functional of Dion et al. implemented in the SIESTA code. In particular, the S22 data set and several calixarene-based host-guest structures are examined to assess the performance of the functional. The binding energy error statistics for the S22 data set reveal that the vdW-DF functional performs very well when compared to a range of other methods of treating dispersion in density functional theory, and to vdW-DF implementations in other codes. For the calixarene host-guest structures, the structural properties and binding energies are compared to previous experimental and computational studies, and in most cases we find that vdW-DF provides superior results to other computational studies. PMID- 26592890 TI - The Fast-Folding Mechanism of Villin Headpiece Subdomain Studied by Multiscale Distributed Computing. AB - The fast-folding mechanism of a 35-residue mini-protein, villin headpiece subdomain (HP35), was investigated using folding free energy landscape analysis with the multiscale free energy landscape calculation method (MSFEL). A major and a minor folding pathway were deduced from the folding free energy landscape. In the major folding pathway, the formation of helices II and III was the rate limiting step in the transition to an intermediate state, triggered by the folding of the PLWK motif. HP35 then folds into the native structure through the formation of the hydrophobic core located at the center of the three-helix bundle. Mutations in the motif and hydrophobic core that suppressed folding into the native state drastically changed the folding free energy landscape compared to the wild type protein. In the minor folding pathway, nucleation of the hydrophobic core preceded formation of the motif. PMID- 26592891 TI - Parameterization of PACE Force Field for Membrane Environment and Simulation of Helical Peptides and Helix-Helix Association. AB - The recently developed PACE force field was further parametrized so that it can be applied to the studies of membrane systems. Parameters for the interactions between united-atom protein particles and lipid hydrophobic tails were developed by reproducing the solvation free energies of small organic molecules in hexadecane. Interactions between protein particles and lipid heads were parametrized by fitting the potential of mean force of the corresponding all-atom simulation. The force field was applied to the study of five helical peptides in membrane environments. The calculated tilt angles of WALP and GWALP and their mutations are in good agreement with experimental data. The association of two glycophorin A (GpA) helices was simulated for 6 MUs. Root-mean-square-deviation of the simulated dimer from the nuclear magnetic resonance structure was found to be 0.272 nm, better than all results obtained so far. These findings demonstrate the high accuracy and applicability of the PACE force field in studying membrane proteins. PMID- 26592892 TI - Characterization of the Ligand Receptor Encounter Complex and Its Potential for in Silico Kinetics-Based Drug Development. AB - The study of drug-receptor interactions has largely been framed in terms of the equilibrium thermodynamic binding affinity, an in vitro measure of the stability of the drug-receptor complex that is commonly used as a proxy measure of in vivo biological activity. In response to the growing realization of the importance of binding kinetics to in vivo drug activity we present a computational methodology for the kinetic characterization of drug-receptor interactions in terms of the encounter complex. Using trajectory data from multiple Brownian dynamics simulations of ligand diffusion, we derive the spatial density of the ligand around the receptor and show how it can be quantitatively partitioned into different basins of attraction. Numerical integration of the ligand densities within the basins can be used to estimate the residence time of the ligand within these diffusive binding sites. Simulations of two structurally similar inhibitors of Hsp90 exhibit diffusive binding sites with similar spatial structure but with different ligand residence times. In contrast, a pair of structurally dissimilar inhibitors of MDM2, a peptide and a small molecule, exhibit spatially distinct basins of attraction around the receptor, which in turn reveal differences in ligand orientational order. Thus, our kinetic approach provides microscopic details of drug-receptor dynamics that provide novel insight into the observed differences in the thermodynamic binding affinities for the two inhibitors, such as the differences in the entropic contributions to binding. The characterization of the encounter complex, in terms of the structure, topology, and dynamics of diffusive binding sites, offers a new perspective on ligand-receptor interactions and the potential for greater insight into drug action. The method, which requires no prior knowledge of the bound state, is a first step toward the incorporation of ligand kinetics into in silico drug development protocols. PMID- 26592893 TI - QM/MM Reweighting Free Energy SCF for Geometry Optimization on Extensive Free Energy Surface of Enzymatic Reaction. AB - We developed a quantum mechanical/molecular mechanical (QM/MM) free energy geometry optimization method by which the geometry of a quantum chemically treated (QM) molecule is optimized on a free energy surface defined with thermal distribution of the surrounding molecular environment obtained by molecular dynamics simulation with a molecular mechanics (MM) force field. The method called QM/MM reweighting free energy self-consistent field combines a mean field theory of QM/MM free energy geometry optimization developed by Yamamoto (Yamamoto, T. J. Chem. Phys.2008, 129, 244104) with a reweighting scheme for updating the MM distribution introduced by Hu et al. (Hu, H., et al. J. Chem. Phys.2008, 128, 034105) and features high computational efficiency suitable for exploring the reaction free energy surface of extensive protein conformational space. The computational efficiency with improved treatment of a long-range electrostatic (ES) interaction using the Ewald summation technique permits one to take into account global conformational relaxation of an entire protein of an enzyme in the free energy geometry optimization of its reaction center. We applied the method to an enzymatic reaction of a substrate complex of psychrophilic alpha-amylase from Antarctic bacterium Pseudoalteromonas haloplanktis and succeeded in geometry optimizations of the reactant and the product of the catalytic reaction that involve large conformational changes of protein loops adjacent to the reaction center on time scales reaching sub microseconds. We found that the adjacent loops in the reactant and the product form in different conformations and produce catalytic ES potentials on the reaction center. PMID- 26592894 TI - 50 Years of Lifson-Roig Models: Application to Molecular Simulation Data. AB - Simple helix-coil transition theories have been indispensable tools in the analysis of data reporting on the reversible folding of alpha-helical polypeptides. They provide a transferable means to not only characterize different systems but to also compare different techniques, viz., experimental probes monitoring helix-coil transitions in vitro or biomolecular force fields in silico. This article addresses several issues with the application of Lifson-Roig theory to helix-coil transition data. We use computer simulation to generate two sets of ensembles for the temperature-controlled, reversible folding of the 21 residue, alanine-rich FS peptide. Ensembles differ in the rigidity of backbone bond angles and are analyzed using two distinct descriptors of helicity. The analysis unmasks an underlying phase diagram that is surprisingly complex. The complexities give rise to fitted nucleation and propagation parameters that are difficult to interpret and that are inconsistent with the distribution of isolated residues in the alpha-helical basin. We show that enthalpies of helix formation are more robustly determined using van't Hoff analysis of simple measures of helicity rather than fitted propagation parameters. To overcome some of these issues, we design a simple variant of the Lifson-Roig model that recovers physical interpretability of the obtained parameters by allowing bundle formation to be described in simple fashion. The relevance of our results is discussed in relation to the applicability of Lifson-Roig models to both in silico and in vitro data. PMID- 26592895 TI - Correction to "SHARC - Ab Initio Molecular Dynamics with Surface Hopping in the Adiabatic Representation Including Arbitrary Couplings" [J. Chem. Theory Comput.2011, 7, 1253-1258]. PMID- 26592896 TI - Simultaneous First-Order Valence and Oxygen Vacancy Order/Disorder Transitions in (Pr0.85Y0.15)0.7Ca0.3CoO3-delta via Analytical Transmission Electron Microscopy. AB - Perovskite cobaltites have been studied for years as some of the few solids to exhibit thermally driven spin-state crossovers. The unanticipated first-order spin and electronic transitions recently discovered in Pr-based cobaltites are notably different from these conventional crossovers, and are understood in terms of a unique valence transition. In essence, the Pr valence is thought to spontaneously shift from 3+ toward 4+ on cooling, driving subsequent transitions in Co valence and electronic/magnetic properties. Here, we apply temperature dependent transmission electron microscopy and spectroscopy to study this phenomenon, for the first time with atomic spatial resolution, in the prototypical (Pr0.85Y0.15)0.70 Ca0.30CoO3-delta. In addition to the direct spectroscopic observation of charge transfer between Pr and Co at the 165 K transition (on both the Pr and O edges), we also find a simultaneous order/disorder transition associated with O vacancies. Remarkably, the first order valence change drives a transition between ordered and random O vacancies, at constant O vacancy density, demonstrating reversible crystallization of such vacancies even at cryogenic temperatures. PMID- 26592897 TI - DFT Calculations and ROESY NMR Data for the Diastereochemical Characterization of Cytotoxic Tetraterpenoids from the Oleoresin of Abies balsamea. AB - Eight non-carotenoid tetraterpenoids, abibalsamins C-J (3-10), were isolated from the oleoresin of Abies balsamea. Their chemical structures were determined based on analysis of 1D/2D NMR and MS data. The assignment of their relative configurations was accomplished using homonuclear coupling constants in tandem with ROESY data. However, the presence of two stereogenic centers on a flexible side chain complicated the characterization. In silico models and ROESY data were analyzed in order to assign relative configurations of the isolated tetraterpenoids. Abibalsamins B and H-J showed moderate cytotoxicity against human A549 lung carcinoma cells, with IC50 values ranging between 6.7 and 10 MUM. PMID- 26592898 TI - One-Step Synthesis of Precursor Oligomers for Organic Photovoltaics: A Comparative Study between Polymers and Small Molecules. AB - Two series of oligomers TQ and rhodanine end-capped TQ-DR were synthesized using a facile one-step method. Their optical, electrical, and thermal properties and photovoltaic performances were systematically investigated and compared. The TQ series of oligomers were found to be amorphous, whereas the TQ-DR series are semicrystalline. For the TQ oligomers, the results obtained in solar cells show that as the chain length of the oligomers increases, an increase in power conversion efficiency (PCE) is obtained. However, when introducing 3 ethylrhodanine into the TQ oligomers as end groups, the PCE of the TQ-DR series of oligomers decreases as the chain length increases. Moreover, the TQ-DR series of oligomers give much higher performances compared to the original amorphous TQ series of oligomers owing to the improved extinction coefficient (epsilon) and crystallinity afforded by the rhodanine. In particular, the highly crystalline oligomer TQ5-DR, which has the shortest conjugation length shows a high hole mobility of 0.034 cm(2) V(-1) s(-1) and a high PCE of 3.14%, which is the highest efficiency out of all of the six oligomers. The structure-property correlations for all of the oligomers and the TQ1 polymer demonstrate that structural control of enhanced intermolecular interactions and crystallinity is a key for small molecules/oligomers to achieve high mobilities, which is an essential requirement for use in OPVs. PMID- 26592899 TI - Odor Events in Surface and Treated Water: The Case of 1,3-Dioxane Related Compounds. AB - A study has been carried out to identify the origin of the odorous compounds at trace levels detected in surface waters and in Barcelona's tap water (NE Spain) which caused consumer complaints. The malodorous compounds were 2,5,5-trimethyl 1,3-dioxane (TMD) and 2-ethyl-5,5-dimethyl-1,3-dioxane (2EDD) which impart a distinctive sickening or olive-oil odor to drinking water at low ng/L levels. Flavor profile analysis (FPA) or threshold odor number (TON) were used for organoleptic purposes. Levels up to 749 ng/L for TMD and 658 ng/L for 2EDD were measured at the entrance of the drinking water treatment plant. Three wastewater treatment plants (WWTPs) using industrial byproducts coming from resin manufacturing plants to promote codigestion were found to be the origin of the event. Corrective measures were applied, including the prohibition to use these byproducts for codigestion in the WWTPs involved. A similar event was already recorded in the same area 20 years ago. PMID- 26592900 TI - Robot-assisted total hip arthroplasty. AB - Precise and accurate biomechanical reconstruction during total hip arthroplasty (THA) is essential for durable long-term survivorship. Accurate fit of cementless hip implants is also crucial to reduce micromotion between the bone-implant interfaces to allow for stable osseointegration. Robotic technology aims to minimize potential human errors and improve implant alignment and fit, and address persisting concerns with modern-day cementless THA. Although robotic THA dates back to the early 1990s, concerns with increased operating times, costs, and complications led to its withdrawal. However, semi-active systems have renewed interest in robot-assisted joint arthroplasty. We reviewed the current technology, its potential benefits, and the reported clinical and radiographic outcomes. Early evidence suggests that robotic use may lead to more accurate reconstruction of radiographic parameters, such as implant positioning, fit, center-of-rotation, and leg-length discrepancy. Further research is needed to determine if these will translate into better outcomes and improved implant longevity to justify increased costs. PMID- 26592901 TI - Measuring Three-Dimensional Thorax Motion Via Biplane Radiographic Imaging: Technique and Preliminary Results. AB - Measures of scapulothoracic motion are dependent on accurate imaging of the scapula and thorax. Advanced radiographic techniques can provide accurate measures of scapular motion, but the limited 3D imaging volume of these techniques often precludes measurement of thorax motion. To overcome this, a thorax coordinate system was defined based on the position of rib pairs and then compared to a conventional sternum/spine-based thorax coordinate system. Alignment of the rib-based coordinate system was dependent on the rib pairs used, with the rib3:rib4 pairing aligned to within 4.4 +/- 2.1 deg of the conventional thorax coordinate system. PMID- 26592902 TI - Characterisation of commercial Perna canaliculus samples and development of extemporaneous oral veterinary paste formulations containing Perna. AB - Perna canaliculus is a nutritional supplement recently studied and highly recommended for its anti-inflammatory effects in both animals and humans. In this study, the physicochemical properties, the microbiological quality, the total lipid content and fatty acids composition of three commercial samples of Perna powder were determined. Subsequently, three simple formulations of extemporaneous oral pastes containing Perna were prepared and designed for veterinary use. Their microbiological stability was assessed after 1-month storage at either room temperature or 35 degrees C. The results demonstrated that commercial Perna samples lack homogeneity, in regard to some technological properties and fatty acid composition; therefore, a preliminary characterisation of commercial Perna samples is recommended to assure the quality of formulations containing this nutritional supplement. Oral paste formulations are easy and simple to prepare and show good physical and microbiological stability, suggesting their large scale production. PMID- 26592903 TI - From the Editor's Desk. PMID- 26592904 TI - Comparison of MMF with prednisone in terms of rejection and duration of activity of transplant in rabbits that underwent retroperitoneal heterotopic heart transplantation. AB - AIM: In this study, mycophenolate mofetil (MMF) and methylprednisolone (MP) were compared in terms of rejection and duration of activity of the transplant in New Zealand rabbits that underwent retroperitoneal heart transplantation. METHODS: Retroperitoneal heart transplantation was performed in New Zealand white rabbits. The animals were divided into two groups. MMF group (group 1) (10 donors, 10 recipients): 12.5 mg/kg MMF was administered orally for two days prior to the surgery; MP group (group 2) (nine donors, nine recipients): 2 mg/kg MP was administered intramuscularly for two days prior to the surgery. After the operation, we waited until all motor activity in the transplanted heart had stopped. The transplant was then removed and the recipient was sacrificed. A donor in the MP group was excluded since it died before the motor activity had stopped. RESULTS: No statistically significant difference was found between the groups in terms of rejection score (p = 0.865). However, duration of motor activity was found to be statistically significantly longer in the MMF group, compared to the MP group (p = 0.013). CONCLUSION: In this experimental study, MMF was similar to MP in terms of rejection but had better efficacy in terms of duration of motor activity of the transplant. PMID- 26592905 TI - Right ventricular function and its relationship with grade of hepatosteatosis in non-alcoholic fatty liver disease. AB - OBJECTIVE: This study was designed to assess right ventricular systolic and diastolic function and its relationship with grade of hepatosteatosis (HS) in non alcoholic fatty liver disease (NAFLD) patients using conventional and tissue Doppler echocardiography. METHODS: NAFLD was diagnosed in 32 individuals (15 males, 17 females; 59% were grade I HS, 41% grade II-III HS) by means of ultrasonography. Twenty-two individuals, whose ultrasonography data did not show HS, comprised the control group (11 males, 11 females) and were included in the study. Right ventricular systolic and diastolic function and their relationship with grade of HS were assessed by conventional and tissue Doppler echocardiography. Additionally, right ventricular global function was assessed by myocardial performance index (MPI). RESULTS: When compared by conventional echocardiographic parameters, there were no significant differences between the two groups. With tissue Doppler parameters, the tricuspid annulus peak early diastolic velocity and ratio of early-to-late diastolic velocity were lower in the patients than in the controls (p = 0.03, p = 0.02, respectively). The isovolumetric relaxation time and MPI were significantly higher (p < 0.001, p < 0.001, respectively) in the patient group. HS grade was positively correlated with right ventricular isovolumetric relaxation time and MPI index (r = 0.295, p = 0.03, r = 0.641, p < 0.001, respectively). CONCLUSION: These results show that right ventricular diastolic dysfunction (RVDD) in patients with NAFLD and degree of HS was associated with RVDD. PMID- 26592906 TI - Evaluation of left atrial mechanical function and atrial conduction abnormalities in Maras powder (smokeless tobacco) users and smokers. AB - OBJECTIVE: In Turkey, a type of smokeless tobacco called Maras powder (MP) is widely used in the south-eastern region. Smokeless tobacco is found in preparations for chewing and for absorption by the nasal and oral mucosae. The purpose of this study was to investigate whether MP damages intra- and inter atrial conduction delay and left atrial (LA) mechanical function as much as cigarette smoking. METHOD: A total of 150 chronic MP users (50 males, 32.5 +/- 5.4 years), smokers (50 males, 32.1 +/- 6.0 years) and controls (50 males, 30.1 +/- 5.8 years) were included in the study. LA volumes were measured echocardiographically according to the biplane area-length method. Atrial electromechanical coupling was measured with tissue Doppler imaging and LA mechanical function parameters were calculated. RESULTS: The LA passive emptying fraction was significantly decreased and LA active emptying volume (LAAEV) was significantly increased in the MP group (p = 0.012 and p = 0.024, respectively), and the LA active emptying fraction (LAAEF) was significantly increased in the smokers (p = 0.003). There was a positive correlation between the amount of MP used and smoking (pack years) with LAAEV and LAAEF (r = 0.26, p = 0.009 and r = 0.25, p = 0.013, respectively). Lateral atrial electromechanical intervals (PA) were significantly higher in MP users, and the septal mitral PA was statistically higher in the smokers (p = 0.05 and p = 0.04, respectively). CONCLUSION: We suggest that atrial electromechanical coupling intervals were prolonged and LA mechanical function was impaired in MP users and smokers, but there was no significant difference between the MP users and smokers. These findings may be markers of subclinical cardiac involvement and tendency for atrial fibrillation. PMID- 26592907 TI - Postoperative atrial fibrillation in patients with left atrial myxoma. AB - INTRODUCTION: The aim of this study was to determine the factors associated with postoperative atrial fibrillation (AF) in patients with left atrial (LA) myxoma. METHODS: Thirty-six consecutive patients with LA myxoma (10 men, mean age: 49.3 +/- 15.7 years), who were operated on between March 2010 and July 2012, were included in this retrospective study. Pre-operative electrocardiograms and echocardiographic examinations of each patient were reviewed. RESULTS: Postoperative AF developed in 10 patients, whereas there was no evidence of paroxysmal AF after resection of the LA myxoma in the remaining 26 patients. The patients who developed AF postoperatively were significantly older than those who did not develop AF (median: 61.5 vs 46 years; p = 0.009). Among the electrocardiographic parameters, only P-wave dispersion differed significantly between postoperative AF and non-AF patients (median: 57.6 vs 39.8 ms, p = 0.004). Logistic regression analysis revealed P- wave dispersion (OR: 1.11, 95% CI: 1.003-1.224, p = 0.043) and age (OR: 1.13, 95% CI: 1.001-1.278, p = 0.048) as independent predictors of postoperative AF in our cohort of patients. CONCLUSIONS: P-wave dispersion is a simple and useful parameter for the prediction of postoperative AF in patients with LA myxoma. PMID- 26592908 TI - Sickle cell trait is not associated with chronic kidney disease in adult Congolese patients: a clinic-based, cross-sectional study. AB - OBJECTIVE: The aim of this study was to evaluate the determinants of chronic kidney disease (CKD) with special emphasis on sickle cell trait (SCT). METHODS: Three hundred and fifty-nine patients (171 men and 188 women), aged 18 years or older, with reduced kidney function (eGFR < 90 ml/min/1.73 m(2)) and seen at secondary and tertiary healthcare in Kinshasa were consecutively recruited in this cross-sectional study. Serum creatinine and haemoglobin electrophoresis were performed in each patient. CKD was defined as < 60 ml/min/1.73 m(2). Logistic regression analysis was used to assess determinants of CKD with a special emphasis on SCT. A p-value < 0.05 defined the level of statistical significance. RESULTS: SCT was present in 19% of the study population; its frequency was 21 and 18% (p > 0.05) in patients with and without CKD, respectively. In multivariate analysis, sickle cell trait was not significantly (OR: 0.38; 95% CI: 0.559-1.839; p = 0.235) associated with CKD; the main determinants were dipstick proteinuria (OR: 1.86; 95% CI: 1.094-3.168; p = 0.02), the metabolic syndrome (OR: 1.69; 95% CI: 1.033-2.965; p = 0.03), haemoblobin >= 12 g/dl (OR: 0.36; 95% CI: 0.210 0.625; p = 0.001), and personal history of hypertension (OR: 2.16; 95% CI: 1.202 3.892; p = 0.01) and of diabetes mellitus (OR: 2.35; 95% CI: 1.150-4.454; p = 0.001). CONCLUSION: SCT was not an independent determinant of CKD in the present case series. Traditional risk factors emerged as the main determinants of CKD. PMID- 26592909 TI - Prevalence of anaemia among patients with heart failure at the Brazzaville University Hospital. AB - BACKGROUND: Heart failure (HF) is a frequent cause of ospitalisation in cardiology. Its prognosis depends on several risk factors, one of which is anaemia. OBJECTIVES: We aimed to determine the prevalence of anaemia in patients with heart failure, and evaluate its impact on their prognosis. METHODS: This article describes a cross-sectional study with prospective collection of data, carried out from 1 January to 31 December 2010 in the Department of Cardiology at Brazzaville University Hospital, Congo. Patients admitted for heart failure were included. Anaemia was defined as a haemoglobin level < 12 g/dl for men and < 11 g/dl for women. RESULTS: In total, 130 men (47.8%) and 142 women (52.2%) were recruited, mean age 56.9 +/- 16.5 years. The prevalence of anaemia was 42%. Average levels of haemoglobin were 9.4 +/- 1.8 and 13.8 +/- 4.9 g/dl for the anaemic (A) and non-anaemic (NA) patients, respectively (p = 0.0001). Two hundred and forty-nine patients (91.5%) were in NYHA functional class III-IV. Forty-seven patients (17.3%) were on oral anticoagulation and 15 (5.5%) were on aspirin. The average duration of hospital stay was 19.1 +/- 16.7 days, without a significant difference between the A and NA groups (19.4 +/- 12 vs 18.8 +/- 13.8 days; p = 0.79, respectively). Total mortality rate was 17%, with a significant difference between the A and NA groups (26 vs 10%; p = 0.001). CONCLUSION: This preliminary study showed a high prevalence of anaemia in patients with heart failure, and it had a negative effect on the prognosis. PMID- 26592910 TI - An antibiotic recipe for an arrhythmic disaster. AB - We describe the case of a patient who developed torsade de pointes during temporary pacemaker insertion after administration of intravenous erythromycin. The case highlights the dangers of administering drugs that prolong the QT interval in patients with complete atrioventricular block, and we discuss the underlying pathophysiological recipe that can lead to a potential arrhythmic disaster. PMID- 26592911 TI - AfricaPCR 2015, a brief report back. PMID- 26592912 TI - South African hospital the first in the Middle East, Africa, central Asia and Turkey to implant the world's smallest, minimally invasive cardiac pacemaker. PMID- 26592913 TI - Parental knowledge and practices on infant teething, Taif, Saudi Arabia. AB - BACKGROUND: Parents' false beliefs about signs and symptoms associated with teething have been documented in many studies around the world. This study was conducted to assess parental knowledge on infant teething process and to investigate parents' practices used to alleviate teething disturbances. METHODS: A cross-sectional survey was conducted among parents of children of 6 months-5 years old in Taif, Saudi Arabia during April 2013. Convenience method of sampling was adopted and the data was collected by mean of a structured-questionnaire. Data was processed by SPPS. Logistic regression analysis was performed. P value <0.05 was considered statistically significant. RESULTS: Overall, of 493 participants were included in the final analysis with mean age 35 years. Females constituted more than two-third. All the parents attributed one or more of the listed signs and symptoms to teething process. Desire to bite, fever, gum irritation, increased salivation and diarrhea were the most reported signs and symptoms of teething by 459 (93.1%), 429 (87%), 415 (84.2%), 414 (84%) and 409 (83%) of the parents respectively. The only predictor of ascribing fever as a sign of infant teething was female gender (P = 0.001). However, female gender (P < 0.001), residence (P = 0.039) and educational level (P = 0.006) were found to be significantly associated with ascribing diarrhea as one of the teething symptoms. Only 91 (18.5%) of the parents responded correctly to all questions designed to assess their knowledge on teething process. CONCLUSIONS: Wide gaps in parents' knowledge and practices related infant teething was identified. Educational interventions are needed to upgrade parents' knowledge and improve their practices regarding infant teething process. PMID- 26592915 TI - Analyzing Biological Performance of 3D-Printed, Cell-Impregnated Hybrid Constructs for Cartilage Tissue Engineering. AB - Three-dimensional (3D) bioprinting of hybrid constructs is a promising biofabrication method for cartilage tissue engineering because a synthetic polymer framework and cell-impregnated hydrogel provide structural and biological features of cartilage, respectively. During bioprinting, impregnated cells may be subjected to high temperatures (caused by the adjacent melted polymer) and process-induced mechanical forces, potentially compromising cell function. This study addresses these biofabrication issues, evaluating the heat distribution of printed polycaprolactone (PCL) strands and the rheological property and structural stability of alginate hydrogels at various temperatures and concentrations. The biocompatibility of parameters from these studies was tested by culturing 3D hybrid constructs bioprinted with primary cells from embryonic chick cartilage. During initial two-dimensional culture expansion of these primary cells, two morphologically and molecularly distinct cell populations ("rounded" and "fibroblastic") were isolated. The biological performance of each population was evaluated in 3D hybrid constructs separately. The cell viability, proliferation, and cartilage differentiation were observed at high levels in hybrid constructs of both cell populations, confirming the validity of these 3D bioprinting parameters for effective cartilage tissue engineering. Statistically significant performance variations were observed, however, between the rounded and fibroblastic cell populations. Molecular and morphological data support the notion that such performance differences may be attributed to the relative differentiation state of rounded versus fibroblastic cells (i.e., differentiated chondrocytes vs. chondroprogenitors, respectively), which is a relevant issue for cell-based tissue engineering strategies. Taken together, our study demonstrates that bioprinting 3D hybrid constructs of PCL and cell-impregnated alginate hydrogel is a promising approach for cartilage tissue engineering. PMID- 26592916 TI - Diagnosing binge eating disorder in a primary care setting. AB - Binge eating disorder (BED), now recognized as a distinct eating disorder in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, is the most prevalent eating disorder. Although nearly half of individuals with BED are obese, BED also occurs in nonobese individuals. Despite the relatively high percentage of weight loss treatment-seeking individuals meeting BED criteria, primary care physicians may not be familiar with or have ever diagnosed BED. Many providers may also have difficulty distinguishing BED as a contributory factor in obesity. This review differentiates BED from other causes of obesity by describing how obese individuals with BED differ from obese individuals without BED and from nonobese individuals with BED in areas including psychopathology, behavior, genetics, physiology, quality of life and productivity. The ways in which health-care providers can identify individuals who may have BED are also highlighted so the proper course of treatment is pursued. Overall, obese individuals with BED demonstrate a number of key characteristics that differentiate them from obese individuals without eating disorders, including increased impulsivity in response to food stimuli with loss of control over eating, resulting in the consumption of more calories. They also experience significant guilt and other negative emotions following a meal. In addition, individuals with BED patients have more psychiatric comorbidity, display more psychopathology, exhibit longer binge durations, consume more meals as snacks during the day and have less dietary restraint compared with individuals with BED who are not obese. However, the differences between individuals with BED who are obese versus not obese are not as prominent. Taken together, the evidence appears to support the conclusion that BED is a unique and treatable neurobehavioral disorder associated with distinct behavioral and psychological profiles and distinct medical and functional outcomes, and that it is not merely a subtype of obesity. PMID- 26592917 TI - Spindle-shaped nanoscale yolk/shell magnetic stirring bars for heterogeneous catalysis in macro- and microscopic systems. AB - A new type of spindle-shaped nanoscale yolk/shell magnetic stirring bar containing noble metal nanoparticles was prepared. The as-synthesized Pd-Fe@meso SiO2 not only showed impressive activity and stability as a heterogeneous catalyst in a macroscopic flask system, but also acted as an efficient nanoscale magnetic stir bar in a microscopic droplet system. PMID- 26592918 TI - Liposomal fusidic acid as a potential delivery system: a new paradigm in the treatment of chronic plaque psoriasis. AB - Chronic plaque psoriasis is an inflammatory skin disease affecting 2-3% of the world population. With increasing understanding of the progress of disease and its causes, bacterial infection is reported to be one of the potential reasons. In this regard, fusidic acid (FA), a steroidal antibiotic, has been a drug of choice which could play an important role by virtue of its unique mechanism of action. Despite many topical formulations of FA in practice, drug-delivery issues like permeability in the prevailing infectious conditions and stability of the drug are yet the challenges not been covered so far from the formulation development perspective. For these issues, liposomes, on account of their carrier specific properties, have been suggested as delivery tools to fulfill the expectations. In the present work, FA liposomes (FA-LP) were prepared and characterized for its varied traits such as size (420-740 nm), surface charge, morphology, percent skin permeation (>75%), and retention (1.620 +/- 0.8 mg/cm(2)). Confocal laser scanning microscope (CLSM) images revealed appreciable cell-uptake of fluorescent dye-loaded liposomes. In stability, FA-LP proved to be stable with respect to drug leakage and vesicle size. In vivo studies using the mouse tail model, FA-LP, are found significantly better (p < 0.05) vis-a-vis conventional one with improved efficacy in and around the target site by the carrier-effect. Hence, the work suggests for the possibility of a better FA liposome-based formulation as a potential option in addressing the infectious challenges of psoriasis. PMID- 26592920 TI - Electronically modified amine substituted alkynols for regio-selective synthesis of dihydrofuran derivatives. AB - An efficient and simple approach has been developed for the regio-selective synthesis of iodo-substituted dihydrofurans from amine substituted alkynols. The resulting iodo-substituted dihydrofurans have been further diversified by C-C couplings and C-N coupling reactions to afford a diverse range of substituted dihydrofuran derivatives. PMID- 26592919 TI - Post-kala-azar dermal leishmaniasis and leprosy: case report and literature review. AB - BACKGROUND: Post-kala-azar dermal leishmaniasis (PKDL) is a dermal complication of visceral leishmaniasis (VL), which may occur after or during treatment. It has been frequently reported from India and the Sudan, but its occurrence in South America has been rarely reported. It may mimic leprosy and its differentiation may be difficult, since both diseases may show hypo-pigmented macular lesions as clinical presentation and neural involvement in histopathological investigations. The co-infection of leprosy and VL has been reported in countries where both diseases are endemic. The authors report a co-infection case of leprosy and VL, which evolved into PKDL and discuss the clinical and the pathological aspects in the patient and review the literature on this disease. CASE PRESENTATION: We report an unusual case of a 53-year-old female patient from Alagoas, Brazil. She presented with leprosy and a necrotizing erythema nodosum, a type II leprosy reaction, about 3 month after finishing the treatment (MDT-MB) for leprosy. She was hospitalized and VL was diagnosed at that time and she was successfully treated with liposomal amphotericin B. After 6 months, she developed a few hypo pigmented papules on her forehead. A granulomatous inflammatory infiltrate throughout the dermis was observed at histopathological examination of the skin biopsy. It consisted of epithelioid histiocytes, lymphocytes and plasma cells with the presence of amastigotes of Leishmania in macrophages (Leishman's bodies). The diagnosis of post-kala-azar dermal leishmaniasis was established because at this time there was no hepatosplenomegaly and the bone marrow did not show Leishmania parasites thus excluding VL. About 2 years after the treatment of PKDL with liposomal amphotericin B the patient is still without PKDL lesions. CONCLUSION: Post-kala-azar dermal leishmaniasis is a rare dermal complication of VL that mimics leprosy and should be considered particularly in countries where both diseases are endemic. A co-infection must be seriously considered, especially in patients who are non-responsive to treatment or develop persistent leprosy reactions as those encountered in the patient reported here. PMID- 26592921 TI - Inclusion of Cu nano-cluster 1D arrays inside a C3-symmetric artificial oligopeptide via co-assembly. AB - A peptide sequence N(3)-GVGV-OMe (G: glycine; V: valine) was attached to a benzene 1,3,5-tricarboxamide (BTA) derivative via"click chemistry" to afford a C(3)-symmetric artificial oligopeptide. The key feature of this oligopeptide is that the binding sites (triazole groups formed by click reaction) are located at the center, while the three oligopeptide arms with a strong tendency to assemble are located around it, which provides inner space to accommodate nanoparticles via self-assembly. The inclusion of Cu nanoclusters and the formation of one dimensional (1D) arrays inside the nanofibers of the C(3)-symmetric artificial oligopeptide assembly were observed, which is quite different from the commonly observed nanoparticle growth on the surface of the pre-assembled oligopeptide nanofibers via the coordination sites located outside. Our finding provides an instructive concept for the design of other stable organic-inorganic hybrid 1D arrays with the inorganic nanoparticles inside. PMID- 26592924 TI - Surface-functionalized monolayered nanodots of a transition metal oxide and their properties. AB - Lateral size, surface chemistry, and properties are varied in inorganic monolayers based on a transition metal-oxide. A variety of inorganic monolayers with their emergent properties have been studied in recent decades. However, it is not easy to tune the lateral size, surface chemistry, and dispersibility of monolayers by typical synthetic methods. In the present work, a new approach is developed for the simultaneous surface functionalization and exfoliation of the precursor nanocrystals in a nonpolar organic medium. We obtained monolayered nanodots of a titanium oxide less than 5 nm in lateral size with surface functionalization by an alkylamine (C14H29NH2) and dihydroxynaphthalene (DHN) in toluene. The bandgap energy of the monolayers was changed by the lateral size and surface functionalization. The present study suggests versatile potentials of the monolayers with tuned size, surface chemistry, and properties. PMID- 26592923 TI - Recovering function and surviving treatments are primary motivators for health behavior change in patients with head and neck cancer: Qualitative focus group study. AB - OBJECTIVE: Against medical advice, head and neck cancer (HNC) patients have been shown to continue to smoke and misuse alcohol post-diagnosis and treatment. This study aimed to better understand the barriers to and facilitators of health behavior change (HBC) in HNC patients. METHOD: We conducted nine focus groups following a standard protocol. Eligible patients were diagnosed less than three years previously with a primary HNC and selected using maximum variability sampling (gender, age, cancer stage, smoking, and alcohol misuse). Thematic analysis was conducted using NVivo 10 software. RESULTS: Participants were mostly men (79%), 65 years of age (SD = 10.1), and married/common-law (52%, n = 15). Mean time from diagnosis was 19 months (SD = 12.3, range = 5.0-44.5), and most had advanced cancer (65.5%, n = 19). Participants provided a larger than anticipated definition of health behaviors, encompassing both traditional (smoking, drinking, diet, exercise, UV protection) and HNC-related (e.g., dental hygiene, skin care, speech exercises, using a PEG, gaining weight). The main emerging theme was patient engagement, that is, being proactive in rehabilitation, informed by the medical team, optimistic, flexible, and seeking support when needed. Patients were primarily motivated to stay proactive and engage in positive health behaviors in order to return to normal life and reclaim function, rather than to prevent a cancer recurrence. Barriers to patient engagement included emotional aspects (e.g., anxiety, depression, trauma, demoralization), symptoms (e.g., fatigue, pain), lack of information about HBC, and healthcare providers' authoritarian approach in counseling on HBC. We found some commonalities in barriers and facilitators according to behavior type (i.e., smoking/drinking/UV protection vs. diet/exercise). SIGNIFICANCE OF RESULTS: This study underlines the key challenges in addressing health behaviors in head and neck oncology, including treatment-related functional impairments, symptom burden, and the disease's emotional toll. This delicate context requires health promotion strategies involving close rehabilitative support from a multidisciplinary team attentive to the many struggles of patients both during treatments and in the longer-term recovery period. Health promotion in HNC should be integrated into routine clinical care and target both traditional and HNC related behaviors, emphasizing emotional and functional rehabilitation as key components. PMID- 26592922 TI - Optimal use of bendamustine in hematologic disorders: Treatment recommendations from an international consensus panel - an update. AB - Bendamustine has achieved widespread international regulatory approval and is a standard agent for the treatment for chronic lymphocytic leukemia (CLL), indolent non-Hodgkin lymphoma and multiple myeloma. Since approval, the number of indications for bendamustine has expanded to include aggressive non-Hodgkin lymphoma and Hodgkin lymphoma and novel targeted therapies, based on new bendamustine regimens/combinations, are being developed against CLL and lymphomas. In 2010, an international panel of bendamustine experts met and published a set of recommendations on the safe and effective use of bendamustine in patients suffering from hematologic disorders. In 2014, this panel met again to update these recommendations since the clarification of issues including optimal dosing and management of bendamustine-related toxicities. The aim of this report is to communicate the latest consensus on the use of bendamustine, permitting the expansion of its safe and effective administration, particularly in new combination therapies. PMID- 26592925 TI - Even the normal is abnormal: N-heterocyclic carbene C(2) binding to a phosphaalkene without breaking the P=C pi-bond. AB - The reaction of MesP=CPh2 with the least sterically demanding N-heterocyclic carbene (NHC = IMe) results in formation of the 'abnormal' (C(4)-substituted) 4 phosphino-NHC (1). In contrast, reaction with Me2IMe gives the unprecedented 'normal' C(2) adduct, Me2IMe -> P(Mes)=CPh2 (2). Particularly striking is the asymmetric and weak bonding of the NHC to the P=C moiety in 2. DFT calculations indicate that the P=C natural bond order in 2 (1.54) still reflects significant pi-character to the bond (cf. MesP=CPh2: NBO = 1.98). Further computational analysis suggests that pi-delocalization into the remote C-phenyl substituents is key to stabilizing the NHC adduct. PMID- 26592926 TI - Novel crown-ether-methylenediphosphonotetrathioate hybrids as Zn(II) chelators. AB - Hybrids of methylenediphosphonotetrathioate and crown-ether (MDPT-CE) were synthesized forming 7-,8-,9-,10- and 13-membered rings. Both 7- and 13-membered ring-containing compounds were found to be highly stable to air-oxidation for at least four weeks. These hybrids bind Zn(II) by both MDPT and CE moieties, forming a 2 : 1 L : Zn(II) complex. Interestingly, the 13-membered ring MDPT-CE showing a high affinity to Zn(II) (Ka 3 +/- 0.5 * 10(6) mol(-2) L(2)) does not bind Li(I) or Na(I). The 13-Membered MDPT-CE hybrid is a promising water-soluble, air stable, high-affinity Zn(II)-chelator, exhibiting selectivity to Zn(II) vs. Mg(II), Na(I), and Li(I). PMID- 26592927 TI - A high-density immunoblotting methodology for quantification of total protein levels and phosphorylation modifications. AB - The components of many signaling pathways have been identified and there is now a need to conduct quantitative data-rich temporal experiments for systems biology and modeling approaches to better understand pathway dynamics and regulation. Here we present a modified Western blotting method that allows the rapid and reproducible quantification and analysis of hundreds of data points per day on proteins and their phosphorylation state at individual sites. The approach is of particular use where samples show a high degree of sample-to-sample variability such as primary cells from multiple donors. We present a case study on the analysis of >800 phosphorylation data points from three phosphorylation sites in three signaling proteins over multiple time points from platelets isolated from ten donors, demonstrating the technique's potential to determine kinetic and regulatory information from limited cell numbers and to investigate signaling variation within a population. We envisage the approach being of use in the analysis of many cellular processes such as signaling pathway dynamics to identify regulatory feedback loops and the investigation of potential drug/inhibitor responses, using primary cells and tissues, to generate information about how a cell's physiological state changes over time. PMID- 26592928 TI - Mimosoid legume plastome evolution: IR expansion, tandem repeat expansions, and accelerated rate of evolution in clpP. AB - The Leguminosae has emerged as a model for studying angiosperm plastome evolution because of its striking diversity of structural rearrangements and sequence variation. However, most of what is known about legume plastomes comes from few genera representing a subset of lineages in subfamily Papilionoideae. We investigate plastome evolution in subfamily Mimosoideae based on two newly sequenced plastomes (Inga and Leucaena) and two recently published plastomes (Acacia and Prosopis), and discuss the results in the context of other legume and rosid plastid genomes. Mimosoid plastomes have a typical angiosperm gene content and general organization as well as a generally slow rate of protein coding gene evolution, but they are the largest known among legumes. The increased length results from tandem repeat expansions and an unusual 13 kb IR-SSC boundary shift in Acacia and Inga. Mimosoid plastomes harbor additional interesting features, including loss of clpP intron1 in Inga, accelerated rates of evolution in clpP for Acacia and Inga, and dN/dS ratios consistent with neutral and positive selection for several genes. These new plastomes and results provide important resources for legume comparative genomics, plant breeding, and plastid genetic engineering, while shedding further light on the complexity of plastome evolution in legumes and angiosperms. PMID- 26592929 TI - Biophysical Regulation of Chromatin Architecture Instills a Mechanical Memory in Mesenchymal Stem Cells. AB - Mechanical cues direct the lineage commitment of mesenchymal stem cells (MSCs). In this study, we identified the operative molecular mechanisms through which dynamic tensile loading (DL) regulates changes in chromatin organization and nuclear mechanics in MSCs. Our data show that, in the absence of exogenous differentiation factors, short term DL elicits a rapid increase in chromatin condensation, mediated by acto-myosin based cellular contractility and the activity of the histone-lysine N-methyltransferase EZH2. The resulting change in chromatin condensation stiffened the MSC nucleus, making it less deformable when stretch was applied to the cell. We also identified stretch induced ATP release and purinergic calcium signaling as a central mediator of this chromatin condensation process. Further, we showed that DL, through differential stabilization of the condensed chromatin state, established a 'mechanical memory' in these cells. That is, increasing strain levels and number of loading events led to a greater degree of chromatin condensation that persisted for longer periods of time after the cessation of loading. These data indicate that, with mechanical perturbation, MSCs develop a mechanical memory encoded in structural changes in the nucleus which may sensitize them to future mechanical loading events and define the trajectory and persistence of their lineage specification. PMID- 26592930 TI - Lipid-Protein Interactions in the Regulated Betaine Symporter BetP Probed by Infrared Spectroscopy. AB - The Na(+)-coupled betaine symporter BetP senses changes in the membrane state and increasing levels of cytoplasmic K(+) during hyperosmotic stress latter via its C terminal domain and regulates transport activity according to both stimuli. This intriguing sensing and regulation behavior of BetP was intensively studied in the past. It was shown by several biochemical studies that activation and regulation depends crucially on the lipid composition of the surrounding membrane. In fact, BetP is active and regulated only when negatively charged lipids are present. Recent structural studies have revealed binding of phosphatidylglycerol lipids to functional important parts of BetP, suggesting a functional role of lipid interactions. However, a regulatory role of lipid interactions could only be speculated from the snapshot provided by the crystal structure. Here, we investigate the nature of lipid-protein interactions of BetP reconstituted in closely packed two-dimensional crystals of negatively charged lipids and probed at the molecular level with Fourier transform infrared (FTIR) spectroscopy. The FTIR data indicate that K(+) binding weakens the interaction of BetP especially with the anionic lipid head groups. We suggest a regulation mechanism in which lipid-protein interactions, especially with the C-terminal domain and the functional important gating helices transmembrane helice 3 (TMH3) and TMH12, confine BetP to its down-regulated transport state. As BetP is also activated by changes in the physical state of the membrane, our results point toward a more general mechanism of how active transport can be modified by dynamic lipid protein interactions. PMID- 26592931 TI - Fear of falling and foot pain, impairment and disability in rheumatoid arthritis: a case-control study. AB - Fear of falling, foot pain, impairment and disability are commonly reported in rheumatoid arthritis (RA). However, the relationship between fear of falling and foot pain, impairment and disability has not been investigated in established RA. The aim of the study was to evaluate the relationship between fear of falling and foot pain, walking velocity and foot impairment and disability in women with established RA. A secondary aim was to evaluate differences between fear of falling, foot pain, walking velocity and foot impairment and disability in women with established RA and age- and sex-matched control participants. Twenty-one women with established RA and twenty-one age- and sex-matched controls were assessed for fear of falling, foot pain, foot impairment and disability and walking velocity. Pearson's r-correlations were used to examine relationships between fear of falling and the foot measures. Independent samples t tests evaluated the differences in fear of falling and foot measures between the two groups. In people with RA, significant correlations were found between fear of falling and foot impairment (r = 0.53, p = 0.015), foot disability (r = 0.77, p <0.001) and walking velocity (r = 0.56, p < 0.001). No correlation was found between fear of falling and foot pain (r = 0.36; p = 0.11). Significant differences between cases and control participants were found between fear of falling (p = 0.001), foot impairment (p = 0.004) and foot disability (p < 0.001). Foot impairment and disability relates to fear of falling in women with established RA. A better understanding of fear of falling in people with established RA may contribute to more efficient falls assessments in order to identify at risk individuals. PMID- 26592932 TI - Identification of HDAC6-Selective Inhibitors of Low Cancer Cell Cytotoxicity. AB - The histone deacetylases (HDACs) occur in 11 different isoforms, and these enzymes regulate the activity of a large number of proteins involved in cancer initiation and progression. The discovery of isoform-selective HDAC inhibitors (HDACIs) is desirable, as it is likely that such compounds would avoid some of the undesirable side effects found with the first-generation inhibitors. A series of HDACIs previously reported by us were found to display some selectivity for HDAC6 and to induce cell-cycle arrest and apoptosis in pancreatic cancer cells. In the present work, we show that structural modification of these isoxazole based inhibitors leads to high potency and selectivity for HDAC6 over HDAC1-3 and HDAC10, while unexpectedly abolishing their ability to block cell growth. Three inhibitors with lower HDAC6 selectivity inhibit the growth of cell lines BxPC3 and L3.6pl, and they only induce apoptosis in L3.6pl cells. We conclude that HDAC6 inhibition alone is insufficient for disruption of cell growth, and that some degree of class 1 HDAC inhibition is required. Moreover, the highly selective HDAC6Is reported herein that are weakly cytotoxic may find use in cancer immune system reactivation. PMID- 26592933 TI - Proteasome inhibitors attenuated cholesterol-induced cardiac hypertrophy in H9c2 cells. AB - The Ubiquitin proteasome system (UPS) plays roles in protein degradation, cell cycle control, and growth and inflammatory cell signaling. Dysfunction of UPS in cardiac diseases has been seen in many studies. Cholesterol acts as an inducer of cardiac hypertrophy. In this study, the effect of proteasome inhibitors on the cholesterol-induced hypertrophic growth in H9c2 cells is examined in order to observe whether UPS is involved in cardiac hypertrophy. The treatment of proteasome inhibitors MG132 and Bortezomib markedly reduced cellular surface area and mRNA expression of beta-MHC in cholesterol-induced cardiac hypertrophy. In addition, activated AKT and ERK were significantly attenuated by MG132 and Bortezomib in cholesterol- induced cardiac hypertrophy. We demonstrated that cholesterol- induced cardiac hypertrophy was suppressed by proteasome inhibitors. Thus, regulatory mechanism of cholesterol- induced cardiac hypertrophy by proteasome inhibitors may provide a new therapeutic strategy to prevent the progression of heart failure. [BMB Reports 2016; 49(5): 270-275]. PMID- 26592934 TI - Anti-septic effects of dabrafenib on HMGB1-mediated inflammatory responses. AB - A nucleosomal protein, high mobility group box 1 (HMGB1) is known to be a late mediator of sepsis. Dabrafenib is a B-Raf inhibitor and initially used for the treatment of metastatic melanoma therapy. Inhibition of HMGB1 and renewal of vascular integrity is appearing as an engaging therapeutic strategy in the administration of severe sepsis or septic shock. Here, we examined the effects of dabrafenib (DAB) on the modulation of HMGB1-mediated septic responses. DAB inhibited the release of HMGB1 and downregulated HMGB1-dependent inflammatory responses by enhancing the expressions of cell adhesion molecules (CAMs) in human endothelial cells. In addition, treatment with DAB inhibited the HMGB1 secretion by CLP and sepsis-related mortality and pulmonary injury. This study demonstrated that DAB could be alternative therapeutic options for sepsis or septic shock via the inhibition of the HMGB1 signaling pathway. [BMB Reports 2016; 49(4): 214 219]. PMID- 26592935 TI - Single-molecule fluorescence measurements reveal the reaction mechanisms of the core RISC, composed of human Argonaute 2 and a guide RNA. AB - In eukaryotes, small RNAs play important roles in both gene regulation and resistance to viral infection. Argonaute proteins have been identified as a key component of the effector complexes of various RNA-silencing pathways, but the mechanistic roles of Argonaute proteins in these pathways are not clearly understood. To address this question, we performed single-molecule fluorescence experiments using an RNA-induced silencing complex (core-RISC) composed of a small RNA and human Argonaute 2. We found that target binding of core-RISC starts at the seed region of the guide RNA. After target binding, four distinct reactions followed: target cleavage, transient binding, stable binding, and Argonaute unloading. Target cleavage required extensive sequence complementarity and accelerated core-RISC dissociation for recycling. In contrast, the stable binding of core-RISC to target RNAs required seed-match only, suggesting a potential explanation for the seed-match rule of microRNA (miRNA) target selection. PMID- 26592936 TI - Emerging roles of exosomes in cancer invasion and metastasis. AB - Recent evidence has indicated that nano-sized vesicles called "exosomes" mediate the interaction between cancer cells and their microenvironment and play a critical role in the development of cancers. Exosomes contain cargo consisting of proteins, lipids, mRNAs, and microRNAs that can be delivered to different types of cells in nascent as well as distant locations. Cancer cell-derived exosomes (CCEs) have been identified in body fluids such as urine, plasma, and saliva from patients with cancer. Although their content depends on tumor type and stage, CCEs merit consideration as prognostic and diagnostic markers, as vehicles for drug delivery, and as potential therapeutic targets because they could transport various oncogenic elements. In this review, we summarize recent advances regarding the role of CCEs in cancer invasion and metastasis, as well as its potential clinical applications. PMID- 26592937 TI - Lineage re-commitment of CD4CD8alphaalpha intraepithelial lymphocytes in the gut. AB - The gastrointestinal tract forms the largest surface in our body with constantly being exposed to various antigens, which provides unique microenvironment for the immune system in the intestine. Accordingly, the gut epithelium harbors the most T lymphocytes in the body as intraepithelial lymphocytes (IELs), which are phenotypically and functionally heterogeneous populations, distinct from the conventional mature T cells in the periphery. IELs arise either from pre committed thymic precursors (natural IELs) or from conventional CD4 or CD8alphabeta T cells in response to peripheral antigens (induced IELs), both of which commonly express CD8alpha homodimers (CD8alphaalpha). Although lineage commitment to either conventional CD4 T helper (Th) or cytotoxic CD8alphabeta T cells as well as their respective co-receptor expression are mutually exclusive and irreversible process, CD4 T cells can be redirected to the CD8 IELs with high cytolytic activity upon migration to the gut epithelium. Recent reports show that master transcription factors for CD4 and CD8 T cells, ThPOK (Th-inducing BTB/ POZ Kruppel-like factor) and Runx3 (Runt related transcription factor 3), respectively, are the key regulators for re-programming of CD4 T cells to CD8 lineage in the intestinal epithelium. This review will focus on the unique differentiation process of IELs, particularly lineage re-commitment of CD4 IELs. PMID- 26592939 TI - The time has come to standardize (123)I-MIBG heart-to-mediastinum ratios including planar and SPECT methods. PMID- 26592938 TI - MRI versus 68Ga-PSMA PET/CT for gross tumour volume delineation in radiation treatment planning of primary prostate cancer. AB - PURPOSE: Multiparametric magnetic resonance imaging (mpMRI) is widely used in radiation treatment planning of primary prostate cancer (PCA). Focal dose escalation to the dominant intraprostatic lesions (DIPL) may lead to improved PCA control. Prostate-specific membrane antigen (PSMA) is overexpressed in most PCAs. (68)Ga-labelled PSMA inhibitors have demonstrated promising results in detection of PCA with PET/CT. The aim of this study was to compare (68)Ga-PSMA PET/CT with MRI for gross tumour volume (GTV) definition in primary PCA. METHODS: This retrospective study included 22 patients with primary PCA analysed after (68)Ga PSMA PET/CT and mpMRI. GTVs were delineated on MR images by two radiologists (GTV MRIrad) and two radiation oncologists separately. Both volumes were merged leading to GTV-MRIint. GTVs based on PET/CT were delineated by two nuclear medicine physicians in consensus (GTV-PET). Laterality (left, right, and left and right prostate lobes) on mpMRI, PET/CT and pathological analysis after biopsy were assessed. RESULTS: Mean GTV-MRIrad, GTV-MRIint and GTV-PET were 5.92, 3.83 and 11.41 cm(3), respectively. GTV-PET was significant larger then GTV-MRIint (p = 0.003). The MRI GTVs GTV-MRIrad and GTV-MRIint showed, respectively, 40 % and 57 % overlap with GTV-PET. GTV-MRIrad and GTV-MRIint included the SUVmax of GTV PET in 12 and 11 patients (54.6 % and 50 %), respectively. In nine patients (47 %), laterality on mpMRI, PET/CT and histopathology after biopsy was similar. CONCLUSION: Ga-PSMA PET/CT and mpMRI provided concordant results for delineation of the DIPL in 47 % of patients (40 % - 54 % of lesions). GTV-PET was significantly larger than GTV-MRIint. (68)Ga-PSMA PET/CT may have a role in radiation treatment planning for focal radiation to the DIPL. Exact correlation of PET and MRI images with histopathology is needed. PMID- 26592940 TI - Nuclear medicine training and practice in the UK. PMID- 26592941 TI - High instability of a nematicidal Cry toxin plasmid in Bacillus thuringiensis. AB - In bacterial pathogens, virulence factors are often carried on plasmids and other mobile genetic elements, and as such, plasmid evolution is central in understanding pathogenicity. Bacillus thuringiensis is an invertebrate pathogen that uses plasmid-encoded crystal (Cry) toxins to establish infections inside the host. Our study aimed to quantify stability of two Cry toxin-encoding plasmids, BTI_23p and BTI_16p, under standard laboratory culturing conditions. These two plasmids are part of the genome of the B. thuringiensis strain MYBT18679, which is of particular interest because of its high pathogenicity towards nematodes. One of the plasmids, BTI_23p, was found to be highly unstable, with substantial loss occurring within a single growth cycle. Nevertheless, longer term experimental evolution in the absence of a host revealed maintenance of the plasmid at low levels in the bacterial populations. BTI_23p encodes two nematicidal Cry toxins, Cry21Aa2 and Cry14Aa1. Consistent with previous findings, loss of the plasmid abolished pathogenicity towards the nematode Caenorhabditis elegans, which could be rescued by addition of Cry21Aa2-expressing Escherichia coli. These results implicate BTI_23p as a plasmid that is required for successful infection, yet unstable when present at high frequency in the population, consistent with the role of Cry toxins as public goods. PMID- 26592942 TI - Identification and characterization of an insect toxin protein, Bb70p, from the entomopathogenic fungus, Beauveria bassiana, using Galleria mellonella as a model system. AB - An insect-toxic protein, Bb70p, was purified from Beauveria bassiana 70 using ammonium sulfate precipitation, ion exchange chromatography, and gel filtration. Bb70p has a high affinity for anion exchangers and 2D electrophoresis results revealed a single spot with a molecular weight of 35.5 kDa and an iso-electric point of ~4.5. Bb70p remains active from 4 to 60 degrees C, within a pH range of 4-10, but is more active in slightly acidic pH. A pure protein, Bb70p does not have any carbohydrate side chains. The protein caused high mortality by intra haemocelic injection into Galleria mellonella with LD50 of 334.4 MUg/g body weight and activates the phenol oxidase cascade. With a partial amino acid sequence comparison using the NCBI database, we showed no homology to known toxin proteins of entomopathogenic fungi. Thus, Bb70p appears to be an insect toxin protein, demonstrating novelty. Identification of this insect-toxic protein presents potential to enhance the virulence of B. bassiana through genetic manipulation. PMID- 26592943 TI - High-resolution NMR spectroscopy in inhomogeneous fields. AB - High-resolution NMR spectroscopy, providing information on chemical shifts, J coupling constants, multiplet patterns, and relative peak areas, is a mainstream tool for analysis of molecular structures, conformations, compositions, and dynamics. Generally, a homogeneous magnetic field is a prerequisite for obtaining high-resolution NMR information. Magnetic field inhomogeneity, whether from non ideal experimental conditions or from intrinsic magnetic susceptibility discontinuities in samples, represents a hurdle for applications of high resolution NMR. Numerous techniques have been proposed for measuring high resolution NMR spectra free from the influence of inhomogeneous magnetic fields. Besides developments and improvements in NMR instrumentation, various types of experimental approaches have been established for recovering NMR information in inhomogeneous magnetic fields. Three main types are systematically described in this review. In addition, other high-resolution NMR approaches or data processing methods are also briefly described. All high-resolution NMR approaches covered in this review have individual advantages and disadvantages in practical applications, and no one technique is applicable to all practical circumstances. Hence, they are complementary for high-resolution NMR applications in inhomogeneous fields. The underlying mechanisms of these approaches are presented, together with analyses of their applicability and efficiency. PMID- 26592945 TI - Applications of high dimensionality experiments to biomolecular NMR. AB - High dimensionality NMR experiments facilitate resonance assignment and precise determination of spectral parameters such as coupling constants. Sparse non uniform sampling enables acquisition of experiments of high dimensionality with high resolution in acceptable time. In this review we present and compare some significant applications of NMR experiments of dimensionality higher than three in the field of biomolecular studies in solution. PMID- 26592946 TI - Nuclear magnetic resonance studies of tunneling in quantum solids at very low temperatures. AB - A review is given of recent NMR experiments at ultra-low temperatures that explore properties of quantum fluids and solids in regimes where unusual dynamics characterizes the low temperature behavior. It is shown how careful analysis of the NMR spin-spin and spin-lattice relaxation rates and spectral properties can determine fundamental thermodynamic features that are otherwise difficult to observe using standard thermodynamic methods. The review focuses on the observation of the diffusion of vacancies and isotopic impurities in solid hydrogen and solid helium by quantum tunneling at low temperatures. PMID- 26592944 TI - Magnetic resonance elastography (MRE) in cancer: Technique, analysis, and applications. AB - Tissue mechanical properties are significantly altered with the development of cancer. Magnetic resonance elastography (MRE) is a noninvasive technique capable of quantifying tissue mechanical properties in vivo. This review describes the basic principles of MRE and introduces some of the many promising MRE methods that have been developed for the detection and characterization of cancer, evaluation of response to therapy, and investigation of the underlying mechanical mechanisms associated with malignancy. PMID- 26592947 TI - Spatial reorientation experiments for NMR of solids and partially oriented liquids. AB - Motional reorientation experiments are extensions of Magic Angle Spinning (MAS) where the rotor axis is changed in order to average out, reintroduce, or scale anisotropic interactions (e.g. dipolar couplings, quadrupolar interactions or chemical shift anisotropies). This review focuses on Variable Angle Spinning (VAS), Switched Angle Spinning (SAS), and Dynamic Angle Spinning (DAS), all of which involve spinning at two or more different angles sequentially, either in successive experiments or during a multidimensional experiment. In all of these experiments, anisotropic terms in the Hamiltonian are scaled by changing the orientation of the spinning sample relative to the static magnetic field. These experiments vary in experimental complexity and instrumentation requirements. In VAS, many one-dimensional spectra are collected as a function of spinning angle. In SAS, dipolar couplings and/or chemical shift anisotropies are reintroduced by switching the sample between two different angles, often 0 degrees or 90 degrees and the magic angle, yielding a two-dimensional isotropic-anisotropic correlation spectrum. Dynamic Angle Spinning (DAS) is a related experiment that is used to simultaneously average out the first- and second-order quadrupolar interactions, which cannot be accomplished by spinning at any unique rotor angle in physical space. Although motional reorientation experiments generally require specialized instrumentation and data analysis schemes, some are accessible with only minor modification of standard MAS probes. In this review, the mechanics of each type of experiment are described, with representative examples. Current and historical probe and coil designs are discussed from the standpoint of how each one accomplishes the particular objectives of the experiment(s) it was designed to perform. Finally, applications to inorganic materials and liquid crystals, which present very different experimental challenges, are discussed. The review concludes with perspectives on how motional reorientation experiments can be applied to current problems in chemistry, molecular biology, and materials science, given the many advances in high-field NMR magnets, fast spinning, and sample preparation realized in recent years. PMID- 26592948 TI - Plant phenolics are detoxified by prophenoloxidase in the insect gut. AB - Plant phenolics are a group of important secondary metabolites that are toxic to many animals and insects if ingested at high concentrations. Because most insects consume plant phenolics daily, they have likely evolved the capacity to detoxify these compounds. Here, we used Drosophila melanogaster, Bombyx mori and Helicoverpa armigera as models to study the metabolism of plant phenolics by prophenoloxidases. We found that insect foreguts release prophenoloxidases into the lumen, and that the survival of prophenoloxidase-deletion mutants was impaired when fed several plant phenolics and tea extracts. Using l-DOPA as a model substrate, biochemical assays in large Lepidopteran insects demonstrated that low levels of l-DOPA are rapidly metabolized into intermediates by phenoloxidases. Feeding with excess l-DOPA showed that the metabolic intermediate 5,6-dihydroxyindole reached the hindgut either by passing directly through the midgut, or by transport through the hemolymph. In the hindgut, 5,6 dihydroxyindole was further oxidized by prophenoloxidases. Intermediates exerted no toxicity in the hemocoel or midgut. These results show that plant phenolics are not toxic to insects unless prophenoloxidase genes are lost or the levels of phenolics exceed the catalytic activity of the gut prophenoloxidases. PMID- 26592949 TI - Scattering-type scanning near-field optical microscopy with reconstruction of vertical interaction. AB - Scattering-type scanning near-field optical microscopy provides access to super resolution spectroscopic imaging of the surfaces of a variety of materials and nanostructures. In addition to chemical identification, it enables observations of nano-optical phenomena, such as mid-infrared plasmons in graphene and phonon polaritons in boron nitride. Despite the high lateral spatial resolution, scattering-type near-field optical microscopy is not able to provide characteristics of near-field responses in the vertical dimension, normal to the sample surface. Here, we present an accurate and fast reconstruction method to obtain vertical characteristics of near-field interactions. For its first application, we investigated the bound electromagnetic field component of surface phonon polaritons on the surface of boron nitride nanotubes and found that it decays within 20 nm with a considerable phase change in the near-field signal. The method is expected to provide characterization of the vertical field distribution of a wide range of nano-optical materials and structures. PMID- 26592950 TI - A pulmonary tuberculosis outbreak in a long-term care facility. AB - In long-term care facilities (LTCFs), the elderly are apt to be infected because those with latent tuberculosis infections (LTBIs) are at an increased risk for reactivation and post-primary TB disease. We report an outbreak of TB in staff and residents in a LTCF. An outbreak investigation was conducted after two TB cases were reported from the LTCF. A tuberculin skin test (TST), bacteriological examination and chest radiograph were administered to all facility staff and residents. An outbreak is defined as at least two epidemiologically linked cases that have identical Mycobacterium tuberculosis genotype isolates. This outbreak infected eight residents and one staff member, who were confirmed to have TB in a LTCF between September 2011 and October 2012. Based on the Becker method, the latent and infectious periods were estimated at 223.6 and 55.9 days. Two initial TST-negative resident contacts were diagnosed as TB cases through comprehensive TB screening. Observing elderly people who have a negative TST after TB screening appears to be necessary, given the long latent period for controlling a TB outbreak in a LTCF. It is important to consider providing LTBI treatment for elderly contacts. PMID- 26592951 TI - Differential cognitive actions of norepinephrine a2 and a1 receptor signaling in the prefrontal cortex. AB - The prefrontal cortex (PFC) supports cognitive and behavioral processes that guide goal directed behavior. Moreover, dysregulated prefrontal cognitive dysfunction is associated with multiple psychiatric disorders. Norepinephrine (NE) signaling in the PFC is a critical modulator of prefrontal cognition and is targeted by a variety of drugs used to treat PFC-dependent cognitive dysfunction. Noradrenergic modulation of PFC-dependent cognition is complex, with concentration and receptor-specific actions that are likely dependent on neuronal activity state. Recent studies indicate that within the PFC, noradrenergic alpha1 and alpha2 receptors exert unique modulatory actions across distinct cognitive processes that allow for context-dependent modulation of cognition. Specifically, high affinity post-synaptic alpha2 receptors, engaged at moderate rates of NE release associated with moderate arousal levels, promote working memory. In contrast, lower affinity alpha1 receptors, engaged at higher rates of release associated with high arousal conditions (e.g. stress), impair working memory performance while promoting flexible attention. While these and other observations were initially interpreted to indicate high rates of NE release promotes the transition from focused to flexible/scanning attention, recent findings indicate that alpha1 receptors promote both focused and flexible attention. Collectively, these observations indicate that while alpha2 and alpha1 receptors in the PFC differentially modulate distinct cognitive processes, this cannot be simply ascribed to differential roles of these receptors in 'focused' vs. 'flexible' cognitive processes. Translationally, this information indicates that: (1) not all tests of prefrontal cognitive function may be appropriate for preclinical programs aimed at specific PFC-dependent disorders and (2) the treatment of specific PFC cognitive deficits may require the differential targeting of noradrenergic receptor subtypes. This article is part of a Special Issue entitled SI: Noradrenergic System. PMID- 26592952 TI - Greater sensitivity of the cortical face processing system to perceptually equated face detection. AB - Face detection, the perceptual capacity to identify a visual stimulus as a face before probing deeper into specific attributes (such as its identity or emotion), is essential for social functioning. Despite the importance of this functional capacity, face detection and its underlying brain mechanisms are not well understood. This study evaluated the roles that the cortical face processing system, which is identified largely through studying other aspects of face perception, play in face detection. Specifically, we used functional magnetic resonance imaging (fMRI) to examine the activations of the fusifom face area (FFA), occipital face area (OFA) and superior temporal sulcus (STS) when face detection was isolated from other aspects of face perception and when face detection was perceptually-equated across individual human participants (n=20). During face detection, FFA and OFA were significantly activated, even for stimuli presented at perceptual-threshold levels, whereas STS was not. During tree detection, however, FFA and OFA were responsive only for highly salient (i.e., high contrast) stimuli. Moreover, activation of FFA during face detection predicted a significant portion of the perceptual performance levels that were determined psychophysically for each participant. This pattern of result indicates that FFA and OFA have a greater sensitivity to face detection signals and selectively support the initial process of face vs. non-face object perception. PMID- 26592953 TI - Laminin-332 sustains chemoresistance and quiescence as part of the human hepatic cancer stem cell niche. AB - BACKGROUND & AIMS: Cancer stem cells (CSCs) are thought to be persistent in tumours due to their chemoresistance and to cause relapse and metastasis. Hepatic carcinomas displaying hepatic progenitor cell (HPC) features have been associated with a poor prognosis, though it remains unclear how CSCs relate to these different histological subtypes. METHODS: Candidate CSCs were isolated using the side population (SP) technique from primary tissue samples diagnosed as keratin(K)19-negative or -positive hepatocellular carcinoma (HCC) or as combined hepatocellular/cholangiocarcinoma and analysed for gene and protein expression. The effect of laminin-332 was analysed in vitro by using HCC cell lines and in vivo using a xenograft mouse model. RESULTS: The size of the SP correlated with the degree of HPC features found in human hepatic cancer, and also showed an elevated mRNA expression of biliary/HPC markers and the extracellular matrix marker LAMC2, the gene encoding the laminin gamma2-chain. Immunopositivity for the gamma2-chain of laminin-332 was seen in the extracellular matrix surrounding small HPC-like tumour cells with a low proliferation rate. In vitro, laminin-332 increased K19 expression, phosphorylated mTOR and decreased phospho-histone H3 expression, indicating reduced cell mitosis. The effect of laminin-332 was enhanced upon mTORC1 inhibition and diminished when inhibiting mTORC1+C2. Resistance to doxorubicin and sorafenib treatment, and the SP fraction increased in the coated condition. In vivo, laminin-332 reduced tumour growth and sustained K19 expression. CONCLUSIONS: In this study we identified a prominent role for laminin-332 as part of the specialised CSC niche in maintaining and supporting cell 'stemness', which leads to chemoresistance and quiescence. PMID- 26592954 TI - The management of newborns with esophageal atresia and right aortic arch: A systematic review or still unsolved problem. AB - AIM OF THE STUDY: The management of newborns with esophageal atresia (EA) and right aortic arch (RAA) is still an unsolved problem. This study provides a systematic review of epidemiology, diagnosis, management and short-term results of children with EA and RAA. MATERIALS AND METHODS: The PubMed database was searched for original studies on children with EA and RAA. In each study, data were extracted for the following outcomes: number of patients, associated anomalies, type of surgical repair, morbidity and mortality rate. RESULTS: Eight studies were selected, including 54 patients with EA and RAA. RAA was encountered in 3.6% of infants. Preoperative detection of RAA was reported in 7 of them. In these patients, primary anastomosis was achieved through the right approach in 3 (thoracotomy in 2 and thoracoscopy in 1) while the left approach was the primary choice in 4 (thoracotomy in 2 and thoracoscopy in 2). No significant differences were found between the right and left approaches with regard to leaks (P=0.89), strictures (P=1) or mortality (P=1). In 47/54 patients (87%) RAA was noted during right thoracotomy, and primary anastomosis was achieved through the same approach in 29 (61.7%); conversion to other approaches (left thoracotomy or esophageal substitution) was performed in 15 children (38.3%). No significant differences were found between primary left thoracotomy (LT) and LT after RT with regard to leaks (P=0.89), strictures (P=1) or mortality (P=1). CONCLUSIONS: Skills and preferences of the surgeon still guide the choice of surgical approach even when preoperatively faced with RAA. A multicenter, prospective randomized study is strongly required. PMID- 26592955 TI - Twenty years' experience for reduction of ileocolic intussusceptions by saline enema under sonography control. AB - BACKGROUND: Ultrasonography is a well-established efficient diagnostic tool for ileocolic intussusceptions in children. It can also be used to control hydrostatic reduction by saline enemas. This reduction method presents the advantage of avoiding radiations. Parents can even stay with their children during the procedure, which is comforting for both. The purpose of this study was to present our 20 years' experience in intussusception reductions using saline enema under ultrasound control and to assess its efficiency and safety. MATERIAL AND METHODS: This retrospective single center study included patients with ileocolic intussusceptions diagnosed by ultrasound between June 1993 and July 2013. We excluded the data of patients with spontaneous reduction or who underwent primary surgery because of contraindications to hydrostatic reduction (peritonitis, medium or huge abdominal effusion, ischemia on Doppler, bowel perforation). A saline enema was infused into the colon until the reduction was sonographically confirmed. The procedure was repeated if not efficient. Light sedation was practiced in some children. RESULTS: Eighty-tree percent of the reductions were successful with a median of 1 attempt. Reduction success decreased with the number of attempts but was still by 16% after 4 attempts. The early recurrence rates were 14.5%, and 61.2% of those had a successful second complete reduction. Forty-six patients needed surgery (11 of them had a secondary intussusception). Sedation multiplies success by 10. In this period, only one complication is described. CONCLUSION: Ultrasound guided intussusception reduction by saline enema is an efficient and safe procedure. It prevents exposure of a young child to a significant amount of radiation, with similar success rate. We had very low complication rate (1/270 cases or 30/00). The success rate could be increased by standardized procedures including: systematic sedation, trained radiologists, accurate pressure measurement, and number and duration of attempts. PMID- 26592956 TI - Rectal biopsies for Hirschsprung disease: Patient characteristics by diagnosis and attending specialty. AB - PURPOSE: Hirschsprung disease (HD) is diagnosed with rectal biopsy. At our institution two services perform these biopsies: pediatric surgery and gastroenterology. Our objective was to review our institutional experience with rectal biopsies to diagnose HD and compare patients and outcomes between the two services. METHODS: We reviewed all children undergoing a rectal biopsy for the evaluation of HD at our institution over a 10-year period. Comparisons were made using multiple logistic regression models. RESULTS: We identified 518 children who underwent rectal biopsy for evaluation of HD; 451/518 (87%) were adequate and 56/518 (11%) were positive for HD. A positive biopsy was more likely with delayed passage of meconium (p<0.001), obstructive symptoms (p<0.001), trisomy 21 (p<0.001), full-term gestation (p=0.03), and male gender (p=0.02). Pediatric surgeons biopsied younger patients with more classic symptoms for HD compared to gastroenterologists. Pediatric surgeons were more likely to take adequate (OR 6.0, 95% CI 2.9-12.4, p<0.001) and positive biopsies (OR 6.7 95% CI 2.1-21.2, p=0.001) compared to gastroenterologists. CONCLUSION: Infants with classic symptoms can reliably be diagnosed with HD by a pediatric surgeon. The work up for HD in older children with constipation should be a collaborative effort between pediatric surgery and gastroenterology. PMID- 26592957 TI - Body fatness charts based on BMI and waist circumference. AB - OBJECTIVE: To present percent body fat (PBF) charts based on body mass index (BMI) and waist circumference (WC) which can supplement current public health guidelines for obesity. METHODS: Based on data from the National Health and Nutrition Examination Survey (NHANES) III for 18- to 65-year-olds, a semi parametric spline approach was utilized, in which no specific functional forms for BMI and WC are assumed, to depict graphically the relationship between BMI, WC, and PBF. Four distinct PBF charts were created, categorized by gender and ethnicity which are based on data from 2,170 white females, 1,902 African American females, 1,905 white males, and 1,635 African American males. RESULTS: PBF prediction based on the semi-parametric spline model outperformed competing linear models. For men, BMI is largely inconsequential, and WC plays a primary role in determining PBF levels. For women, the interaction between BMI and WC is more complex. To have low body fat, women would need to watch both their BMI and WC measurements carefully. CONCLUSIONS: PBF charts, which incorporate information from three dimensions that are as simple to read as a BMI chart to help determine a person's level of fatness, were proposed. PMID- 26592959 TI - Two new reversible naphthalimide-based fluorescent chemosensors for Hg(2.). AB - Naphthalimide-based fluorescent probes 1 and 2 were synthesized, and were designed to form probe-Hg complexes through Hg(2+) ions coordinated to the amide group and imidazole group. They showed high sensitivity and were selective 'naked eye' chemosensors for Hg(2+) in phosphate buffer. The fluorescence of compounds 1 and 2 could be quenched up to 90% by the addition of Hg(2+) . Reversible probes can detect Hg(2+) ions over a wide pH range (7.0-10.0). Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26592958 TI - Biochar as an electron shuttle for reductive dechlorination of pentachlorophenol by Geobacter sulfurreducens. AB - The reductive dechlorination of pentachlorophenol (PCP) by Geobacter sulfurreducens in the presence of different biochars was investigated to understand how biochars affect the bioreduction of environmental contaminants. The results indicated that biochars significantly accelerate electron transfer from cells to PCP, thus enhancing reductive dechlorination. The promotion effects of biochar (as high as 24-fold) in this process depend on its electron exchange capacity (EEC) and electrical conductivity (EC). A kinetic model revealed that the surface redox-active moieties (RAMs) and EC of biochar (900 degrees C) contributed to 56% and 41% of the biodegradation rate, respectively. This work demonstrates that biochars are efficient electron mediators for the dechlorination of PCP and that both the EC and RAMs of biochars play important roles in the electron transfer process. PMID- 26592960 TI - Monitoring of dipeptidyl peptidase-IV (DPP-IV) activity in patients with mucopolysaccharidoses types I and II on enzyme replacement therapy - Results of a pilot study. AB - OBJECTIVES: Mucopolysaccharidoses (MPSs) are a group of rare, inherited metabolic disorders which result from the lack of one of the lysosomal enzymes responsible for the degradation of glycosaminoglycans. Early recognition of MPS is important as it enables prompt implementation of enzyme replacement therapy (ERT). Dipeptidyl peptidase-IV (DPP-IV) is a ubiquitous ectopeptidase which activity has been associated with the cell surface protein CD26. Our aims were to investigate plasma DPP-IV activity in untreated patients with MPS type II in comparison to control individuals and to evaluate changes of DPP-IV during ERT in MPS I or II patients. DESIGN AND METHODS: One MPS I and five MPS II patients were treated with ERT for up to 19 months. DPP-IV activity was measured in plasma with a colorimetric method using Gly-Pro-p-nitroanilide as a substrate. The reference intervals were observed in 17 healthy donors and in 9 MPS II individuals before ERT implementation. RESULTS: DPP-IV activity ranged from 557 to 1959 nmol/ml/h (median and interquartile range: 1453 [955- 1554], n = 17) in plasma of control samples. In 9 untreated MPS II individuals, DPP-IV activity was higher and ranged from 2565 to 5968 nmol/ml/h (median and interquartile range: 4458 [4031-5161]). In 6 MPS patients receiving ERT, DPP-IV activity ranged from 2984 to 8628 nmol/ml/h. No declining tendency was observed during the treatment. CONCLUSIONS: DPP-IV activity is a good, newa nd valuable biomarker distinguishing between MPS and healthy individuals. However, it is not a useful marker of treatment efficacy and is unsuitable for monitoring. PMID- 26592961 TI - Hippocampal atrophy but not white-matter changes predicts the long-term cognitive response to cholinesterase inhibitors in Alzheimer's disease. AB - INTRODUCTION: This study aimed to investigate the feasibility of predicting the long-term effects of cholinesterase inhibitors (ChEI) with common clinical neuroimaging parameters of Alzheimer's disease, including medial temporal lobe atrophy (MTA) and white matter hyperintensity (WMH). METHOD: A cohort of 353 patients with very mild to moderate Alzheimer's disease received cholinesterase inhibitors and were followed for a median of 46.6 months. Baseline clinical data, including age, educational level, Clinical Dementia Rating (CDR), Taiwanese Mental State Examination (TMSE), and visual scoring for MTA and WMH were tested as possible predictive factors that influence the survival from a TMSE decline of at least 3 points. RESULTS: During the follow-up period, 162(46%) patients had a significant TMSE decline. Patients with age-adjusted prominent MTA had a significantly shorter TMSE-decline free interval than those without (43.4 +/- 4.5 months vs. 68.2 +/- 9.5 months, log rank test p-value =0.001). However, the severity of WMH does not significantly influence cognitive outcomes. Cox regression analysis identified that younger age at the time of starting ChEI (p < 0.0005) and higher total MTA scores (p = 0.002) predict a more rapid TMSE decline under ChEI therapy. CONCLUSIONS: Younger age at the time of starting ChEI and higher visual scoring of MTA may imply a more advanced Alzheimer's pathology. WMH load is not a prognostic indicator of treatment response to ChEI. PMID- 26592962 TI - Polyethylenimine-based polyplex delivery of self-replicating RNA vaccines. AB - Self-amplifying replicon RNA (RepRNA) are large molecules (12-14 kb); their self replication amplifies mRNA template numbers, affording several rounds of antigen production, effectively increasing vaccine antigen payloads. Their sensitivity to RNase-sensitivity and inefficient uptake by dendritic cells (DCs) - absolute requirements for vaccine design - were tackled by condensing RepRNA into synthetic, nanoparticulate, polyethylenimine (PEI)-polyplex delivery vehicles. Polyplex-delivery formulations for small RNA molecules cannot be transferred to RepRNA due to its greater size and complexity; the N:P charge ratio and impact of RepRNA folding would influence polyplex condensation, post-delivery decompaction and the cytosolic release essential for RepRNA translation. Polyplex-formulations proved successful for delivery of RepRNA encoding influenza virus hemagglutinin and nucleocapsid to DCs. Cytosolic translocation was facilitated, leading to RepRNA translation. This efficacy was confirmed in vivo, inducing both humoral and cellular immune responses. Accordingly, this paper describes the first PEI polyplexes providing efficient delivery of the complex and large, self-amplifying RepRNA vaccines. FROM THE CLINICAL EDITOR: The use of self-amplifying replicon RNA (RepRNA) to increase vaccine antigen payloads can potentially be useful in effective vaccine design. Nonetheless, its use is limited by the degradation during the uptake process. Here, the authors attempted to solve this problem by packaging RepRNA using polyethylenimine (PEI)-polyplex delivery vehicles. The efficacy was confirmed in vivo by the appropriate humoral and cellular immune responses. This novel delivery method may prove to be very useful for future vaccine design. PMID- 26592963 TI - Haematopoiesis in Marsupials. AB - Marsupials are a group of mammals that give birth to immature young lacking mature immune tissues at birth, and are unable to mount their own specific immune defence. Their immune tissues develop in a non-sterile ex-utero environment unlike that of eutherian mammals such as ourselves. Marsupials are therefore ideal models for studying the development of immune tissues, in particular haematopoiesis, yet relatively little has been investigated. Most studies have been restricted to histological or immunohistological studies, however some factors likely to be involved, based on eutherian studies in haematopoiesis, have been isolated and characterised, including a few key markers, and some cell signaling and regulation molecules, mostly involved in lymphocytopoiesis. However the role of many molecules in haematopoiesis is largely presumed. We currently lack much of the rudimentary information regarding time of appearance and expression levels of these molecules, and no functional studies have been conducted. This paper reviews our knowledge of marsupial haematopoiesis to date, and highlights the need for future research in marsupials to gain further insights into the evolution of haematopoiesis. PMID- 26592966 TI - Cyclen Grafted with poly[(Aspartic acid)-co-Lysine]: Preparation, Assembly with Plasmid DNA, and in Vitro Transfection Studies. AB - Development of safe and effective gene carriers is the key to the success of gene therapy. Nowadays, it is still required to develop new methods to improve nonviral gene delivery efficiency. Herein, copolymers of poly[(aspartic acid)-co lysine] grafted with cyclen (cyclen-pAL) were designed and evaluated for efficient gene delivery. Two copolymers with different Asp/Lys block ratios were prepared and characterized by NMR and gel permeation chromatography analysis. Agarose gel retardation, circular dichroism, and fluorescent quenching assays showed the strong DNA-binding and protection ability for the title compounds. Atomic force microscopy studies clearly delineated uniform DNA globules with a diameter around 100 nm, induced by cyclen-pAL. By grafting cyclen on Asp, relatively high gene delivery efficiency and low cytotoxicity of the modified copolymers were achieved compared with their parent compounds. The present work might help to develop strategies for design and modification of polypeptide copolymers, which may also be applied to favorable gene expression and delivery. PMID- 26592964 TI - Pathogen-associated molecular patterns activate expression of genes involved in cell proliferation, immunity and detoxification in the amebocyte-producing organ of the snail Biomphalaria glabrata. AB - The anterior pericardial wall of the snail Biomphalaria glabrata has been identified as a site of hemocyte production, hence has been named the amebocyte producing organ (APO). A number of studies have shown that exogenous abiotic and biotic substances, including pathogen associated molecular patterns (PAMPs), are able to stimulate APO mitotic activity and/or enlarge its size, implying a role for the APO in innate immunity. The molecular mechanisms underlying such responses have not yet been explored, in part due to the difficulty in obtaining sufficient APO tissue for gene expression studies. By using a modified RNA extraction technique and microarray technology, we investigated transcriptomic responses of APOs dissected from snails at 24 h post-injection with two bacterial PAMPs, lipopolysaccharide (LPS) and peptidoglycan (PGN), or with fucoidan (FCN), which may mimic fucosyl-rich glycan PAMPs on sporocysts of Schistosoma mansoni. Based upon the number of genes differentially expressed, LPS exhibited the strongest activity, relative to saline-injected controls. A concurrent activation of genes involved in cell proliferation, immune response and detoxification metabolism was observed. A gene encoding checkpoint 1 kinase, a key regulator of mitosis, was highly expressed after stimulation by LPS. Also, seven different aminoacyl-tRNA synthetases that play an essential role in protein synthesis were found to be highly expressed. In addition to stimulating genes involved in cell proliferation, the injected substances, especially LPS, also induced expression of a number of immune-related genes including arginase, peptidoglycan recognition protein short form, tumor necrosis factor receptor, ficolin, calmodulin, bacterial permeability increasing proteins and E3 ubiquitin-protein ligase. Importantly, significant up-regulation was observed in four GiMAP (GTPase of immunity-associated protein) genes, a result which provides the first evidence suggesting an immune role of GiMAP in protostome animals. Moreover, altered expression of genes encoding cytochrome P450, glutathione-S-transferase, multiple drug resistance protein as well as a large number of genes encoding enzymes associated with degradation and detoxification metabolism was elicited in response to the injected substances. PMID- 26592965 TI - Haematopoiesis in molluscs: A review of haemocyte development and function in gastropods, cephalopods and bivalves. AB - Haematopoiesis is a process that is responsible for generating sufficient numbers of blood cells in the circulation and in tissues. It is central to maintenance of homeostasis within an animal, and is critical for defense against infection. While haematopoiesis is common to all animals possessing a circulatory system, the specific mechanisms and ultimate products of haematopoietic events vary greatly. Our understanding of this process in non-vertebrate organisms is primarily derived from those species that serve as developmental and immunological models, with sparse investigations having been carried out in other organisms spanning the metazoa. As research into the regulation of immune and blood cell development advances, we have begun to gain insight into haematopoietic events in a wider array of animals, including the molluscs. What began in the early 1900's as observational studies on the morphological characteristics of circulating immune cells has now advanced to mechanistic investigations of the cytokines, growth factors, receptors, signalling pathways, and patterns of gene expression that regulate molluscan haemocyte development. Emerging is a picture of an incredible diversity of developmental processes and outcomes that parallels the biological diversity observed within the different classes of the phylum Mollusca. However, our understanding of haematopoiesis in molluscs stems primarily from the three most-studied classes, the Gastropoda, Cephalopoda and Bivalvia. While these represent perhaps the molluscs of greatest economic and medical importance, the fact that our information is limited to only 3 of the 9 extant classes in the phylum highlights the need for further investigation in this area. In this review, we summarize the existing literature that defines haematopoiesis and its products in gastropods, cephalopods and bivalves. PMID- 26592967 TI - Neonatal hyperoxia induces alterations in neurotrophin gene expression. AB - Each year in the United States, nearly 500,000 infants a year are born prematurely. Babies born before 35 weeks gestation are often placed on ventilators and/or given supplemental oxygen. This increase in oxygen, while critical for survival, can cause long-term damage to lungs, retinas and brains. In particular, hyperoxia causes apoptosis in neurons and alters glial activity. Brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) are members of the neurotrophin family of proteins that function to promote the growth, differentiation and development of the nervous system. We hypothesized that hyperoxia can alter the regulation of these genes and by doing so adversely affect the development of the brain. We predicted that mice exposed to hyperoxic conditions would have differences in BDNF and GDNF mRNA expression and relative level of methylated promoter regions coinciding with differences in the relative levels of DNMT1 and DNMT3a mRNA expression. To test this hypothesis, newborn C57Bl/6 mice and their littermates were placed in hyperoxic or normoxic conditions from postnatal day 7 to 12. There were significant decreases in BDNF mRNA expression in the prefrontal cortex following hyperoxia, but a significant increase in the isocortex. GDNF mRNA expression was significantly increased in both the isocortex and prefrontal cortex following hyperoxia. DNMT1 mRNA expression was significantly decreased in the isocortex but significantly increased in the prefrontal following hyperoxia. Together these data suggest that short-term exposure to hyperoxic conditions can affect the regulation and expression of BDNF and GDNF potentially leading to alterations in neural development. PMID- 26592968 TI - Postencephalitic epilepsy and drug-resistant epilepsy after infectious and antibody-associated encephalitis in childhood: Clinical and etiologic risk factors. AB - To define the risk factors for postencephalitic epilepsy (PE) and drug-resistant epilepsy (DRE) in childhood following infectious and autoimmune encephalitis, we included 147 acute encephalitis patients with a median follow-up of 7.3 years (range 2-15.8 years). PE was defined as the use of antiepileptic drugs (AEDs) for >=24 months, and DRE was defined as the persistence of seizures despite >=2 appropriate AEDs at final follow-up. PE and DRE were diagnosed in 31 (21%) and 15 (10%) of patients, respectively. The features during acute encephalitis predictive of DRE (presented as odds ratio [OR] with confidence intervals [CIs]) were status epilepticus (OR 10.8, CI 3.4-34.3), visual disturbance (6.4, 1.4 29.9), focal seizures (6.2, 1.9-20.6), magnetic resonance imaging (MRI) hippocampal/amygdala involvement (5.0, 1.7-15.4), intensive care admission (4.7, 1.4-15.4), use of >3 AEDs (4.5, 1.2-16.1), MRI gadolinium enhancement (4.1, 1.2 14.2), any seizure (3.9, 1.1-14.4), and electroencephalography (EEG) epileptiform discharges (3.9, 1.3-12.0). On multivariable regression analysis, only status epilepticus remained predictive of DRE in all models. DRE was common in herpes simplex virus (3/9, 33%) and unknown (8/40, 20%) encephalitis, but absent in acute disseminated encephalomyelitis (ADEM) (0/32, 0%), enterovirus (0/18), and anti-N-methyl-d-aspartate receptor-NMDAR encephalitis (0/9). We have identified risk factors for DRE and demonstrated "high-risk," and "low-risk" etiologies. PMID- 26592969 TI - Living ROMP Synthesis and Redox Properties of Diblock Ferrocene/Cobalticenium Copolymers. AB - Using the third-generation Grubbs catalyst, the living ring-opening metathesis polymerization of ferrocene/cobalticenium copolymers is conducted with theoretical numbers of 25 monomer units for each block, and their redox and electrochemical properties allow using the Bard-Anson electrochemical method to determine the number of metallocenyl units in each block. PMID- 26592970 TI - Preparation and evaluation of a molecularly imprinted sol-gel material as the solid-phase extraction adsorbents for the specific recognition of cloxacilloic acid in cloxacillin. AB - Highly selective molecularly imprinted polymers on the surface of silica gels were prepared by a sol-gel process and used as solid-phase extraction adsorbents for the specific recognition, enrichment and detection of cloxacilloic acid in cloxacillin. The obtained polymers were characterized by scanning electron microscopy, FTIR spectroscopy, nitrogen adsorption and desorption, elemental analysis and thermogravimetric analysis. The imprinted polymers not only possessed high adsorption capacity (6.5 MUg/mg), but also exhibited fast adsorption kinetics (they adsorb 80% of the maximum amount within 20 min) and excellent selectivity (the imprinted factor was 3.6). A method using the imprinted polymers as solid-phase extraction adsorbents coupled with high performance liquid chromatography was established with good specificity, linearity (r = 0.9962), precision (ranging from 0.5 to 6.7%), accuracy (ranging from 93.9 to 97.7%) and extraction recoveries (ranging from 78.8 to 89.8%). The limits of detection and quantification were 0.07 and 0.25 mg/g, respectively. This work could provide a promising method in the enrichment, extraction and detection of allergenic impurities in the manufacture, storage and application of cloxacillin. PMID- 26592971 TI - Highly Efficient Light-Driven TiO2-Au Janus Micromotors. AB - A highly efficient light-driven photocatalytic TiO2-Au Janus micromotor with wireless steering and velocity control is described. Unlike chemically propelled micromotors which commonly require the addition of surfactants or toxic chemical fuels, the fuel-free Janus micromotor (diameter ~1.0 MUm) can be powered in pure water under an extremely low ultraviolet light intensity (2.5 * 10(-3) W/cm(2)), and with 40 * 10(-3) W/cm(2), they can reach a high speed of 25 body length/s, which is comparable to common Pt-based chemically induced self-electrophoretic Janus micromotors. The photocatalytic propulsion can be switched on and off by incident light modulation. In addition, the speed of the photocatalytic TiO2-Au Janus micromotor can be accelerated by increasing the light intensity or by adding low concentrations of chemical fuel H2O2 (i.e., 0.1%). The attractive fuel free propulsion performance, fast movement triggering response, low light energy requirement, and precise motion control of the TiO2-Au Janus photocatalytic micromotor hold considerable promise for diverse practical applications. PMID- 26592973 TI - Pleural fluid extramedullary hematopoiesis case report with review of the literature. AB - Extramedullary hematopoiesis (EMH) is the trilineage formation of normal blood cells outside of the bone marrow. While predominantly seen in the spleen and liver, EMH rarely occurs in serous effusions. Accurate diagnosis requires recognition of megakaryocytes and other precursor hematopoietic elements. We present a case of pleural fluid EMH in a patient with primary myelofibrosis and developing leukemia, with a review of the literature, prognostic implications and diagnostic challenges. PMID- 26592974 TI - Thermomechanical Stress in Cryopreservation Via Vitrification With Nanoparticle Heating as a Stress-Moderating Effect. AB - This study focuses on thermomechanical effects in cryopreservation associated with a novel approach of volumetric heating by means on nanoparticles in an alternating electromagnetic field. This approach is studied for the application of cryopreservation by vitrification, where the crystalline phase is completely avoided-the cornerstone of cryoinjury. Vitrification can be achieved by quickly cooling the material to cryogenic storage, where ice cannot form. Vitrification can be maintained at the end of the cryogenic protocol by quickly rewarming the material back to room temperature. The magnitude of the rewarming rates necessary to maintain vitrification is much higher than the magnitude of the cooling rates that are required to achieve it in the first place. The most common approach to achieve the required cooling and rewarming rates is by exposing the specimen's surface to a temperature-controlled environment. Due to the underlying principles of heat transfer, there is a size limit in the case of surface heating beyond which crystallization cannot be prevented at the center of the specimen. Furthermore, due to the underlying principles of solid mechanics, there is a size limit beyond which thermal expansion in the specimen can lead to structural damage and fractures. Volumetric heating during the rewarming phase of the cryogenic protocol can alleviate these size limitations. This study suggests that volumetric heating can reduce thermomechanical stress, when combined with an appropriate design of the thermal protocol. Without such design, this study suggests that the level of stress may still lead to structural damage even when volumetric heating is applied. This study proposes strategies to harness nanoparticles heating in order to reduce thermomechanical stress in cryopreservation by vitrification. PMID- 26592972 TI - Calcium signalling in salivary gland physiology and dysfunction. AB - Studies over the past four decades have established that Ca(2+) is a critical factor in control of salivary gland function and have led to identification of the critical components of this process. The major ion transport mechanisms and ion channels that are involved in fluid secretion have also been established. The key event in activation of fluid secretion is an increase in [Ca(2+) ]i triggered by inositol 1,4,5-trisphosphate (IP3 )-induced release of Ca(2+) from ER via the IP3 receptor (IP3 R). IP3 Rs determine the site of initiation and the pattern of the [Ca(2+) ]i signal in the cell. However, Ca(2+) entry into the cell is required to sustain the elevation of [Ca(2+) ]i and fluid secretion and is mediated by the store-operated Ca(2+) entry (SOCE) mechanism. Orai1, TRPC1, TRPC3 and STIM1 have been identified as critical components of SOCE in these cells. Cells finely tune the generation and amplification of [Ca(2+) ]i signals for regulation of cell function. An important emerging area is the concept that unregulated [Ca(2+) ]i signals in cells can directly cause cell damage, dysfunction and disease. Alternatively, aberrant [Ca(2+) ]i signals can also amplify and increase the rates of cell damage. Such defects in Ca(2+) signalling have been described in salivary glands in conjunction with radiation-induced loss of salivary gland function as well as in the salivary defects associated with the autoimmune exocrinopathy Sjogren's syndrome. Such defects have been associated with altered function or expression of key Ca(2+) signalling components, such as STIM proteins and TRP channels. These studies offer new avenues for examining the mechanisms underlying the disease and development of novel clinical targets and therapeutic strategies. PMID- 26592975 TI - Depletion of elongation initiation factor 4E binding proteins by CRISPR/Cas9 enhances the antiviral response in porcine cells. AB - Type I interferons (IFNs) are key mediators of the innate antiviral response in mammalian cells. Elongation initiation factor 4E binding proteins (4E-BPs) are translational controllers of interferon regulatory factor 7 (IRF-7), the "master regulator" of IFN transcription. Previous studies have suggested that mouse cells depleted of 4E-BPs are more sensitive to IFNbeta treatment and had lower viral loads as compared to wild type (WT) cells. However, such approach has not been tested as an antiviral strategy in livestock species. In this study, we tested the antiviral activity of porcine cells depleted of 4E-BP1 by a Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated protein-9 nuclease (Cas9) genome engineering system. We found that 4E-BP1 knockout (KO) porcine cells had increased expression of IFNalpha and beta, IFN stimulated genes, and significant reduction in vesicular stomatitis virus titer as compare to WT cells. No phenotypical changes associated with CRISPR/Cas9 manipulation were observed in 4E-BP1 KO cells. This work highlights the use of the CRISPR/Cas9 system to enhance the antiviral response in porcine cells. PMID- 26592977 TI - Medical, psychological and socio-economic implications of chronic hand eczema: a cross-sectional study. AB - BACKGROUND: Hand eczema (HE) is a common skin disease with major medical psychological and socio-economic implications. Onset and prognosis of HE are determined by individual as well as environmental factors. So far, most epidemiological data on HE have been reported from Scandinavian and recently German studies. OBJECTIVE: To investigate the characteristics and medical care of patients with chronic HE (CHE) in Switzerland, and identify risk factors. METHODS: In this cross-sectional study, data from patients with chronic HE were obtained by means of medical history, dermatological examination and patient questionnaires. Multiple logistic regression analysis was applied to identify risk factors for high severity and dermatology life quality index (DLQI). RESULTS: In seven dermatology departments, 199 patients (mean age 40.4 years, 50.8% female) with CHE (mean duration 6.6 years) were enrolled. Moderate to severe HE was reported by 70.9% of patients, and was associated with age <30 or >50 years, localization of lesions and pruritus. Because of the CHE, 37.3% of patients were on sick leave over the past 12 months, 14.8% had changed or lost their job. Practically all patients applied topical therapy, 21% were treated with alitretinoin, and 21% with psoralen plus UVA light (PUVA). The effects on the health-related quality of life was moderate to large in 33.7% and 39.4% of CHE patients, respectively. Factors associated with a high impact on DLQI (mean 9.7 +/- 5.8) were female sex, lesions on back of the hands and pruritus as well as mechanical skin irritation and wearing gloves. CONCLUSION: In agreement with recent studies, the Swiss data demonstrate the high impact of CHE on medical well being, patient quality of life and work ability. As it is associated with an intense use of health care services, high rate of sick leave, job loss and change, CHE may cause a high socio-economic burden. PMID- 26592976 TI - Saturated fatty acids regulate retinoic acid signalling and suppress tumorigenesis by targeting fatty acid-binding protein 5. AB - Long chain fatty acids (LCFA) serve as energy sources, components of cell membranes and precursors for signalling molecules. Here we show that these biological compounds also regulate gene expression and that they do so by controlling the transcriptional activities of the retinoic acid (RA)-activated nuclear receptors RAR and PPARbeta/delta. The data indicate that these activities of LCFA are mediated by FABP5, which delivers ligands from the cytosol to nuclear PPARbeta/delta. Both saturated and unsaturated LCFA (SLCFA, ULCFA) bind to FABP5, thereby displacing RA and diverting it to RAR. However, while SLCFA inhibit, ULCFA activate the FABP5/PPARbeta/delta pathway. We show further that, by concomitantly promoting the activation of RAR and inhibiting the activation of PPARbeta/delta, SLCFA suppress the oncogenic properties of FABP5-expressing carcinoma cells in cultured cells and in vivo. The observations suggest that compounds that inhibit FABP5 may constitute a new class of drugs for therapy of certain types of cancer. PMID- 26592979 TI - Real-time quantification of oxidative stress and the protective effect of nitroxide antioxidants. AB - Nitroxides have been exploited as profluorescent probes for the detection of oxidative stress. In addition, they deliver potent antioxidant action and attenuate reactive oxygen species (ROS) in various models of oxidative stress, with these results ascribed to superoxide dismutase or redox and radical scavenging actions. Our laboratory has developed a range of novel, biostable, isoindoline nitroxide-based antioxidants, DCTEIO and CTMIO. In this study we compared the efficiency of these novel compounds as antioxidant therapies in reducing ROS both in vivo (rat model) and in vitro (661W photoreceptor cells), with the established antioxidant resveratrol. By assessing changes in fluorescence intensity of a unique redox-responsive probe in the rat retina in vivo, we evaluated the ability of antioxidant therapy to (1) ameliorate ROS production and (2) reverse the accumulation of ROS after complete, acute ischemia followed by reperfusion (I/R). I/R injury induced a marked decrease in fluorescence intensity over 60 min of reperfusion, which was successfully ameliorated with each of the antioxidants. DCTEIO and CTMIO reversed the accumulation of ROS when administered intraocularly post ischemic insult, whereas, the effect of resveratrol was not significant. We also investigated our novel agents' capacity to prevent ROS-mediated metabolic dysfunction in the 661W photoreceptor cell line. Cellular stress induced by the oxidant, tert-butyl hydroperoxide, resulted in a loss of spare mitochondrial respiratory capacity (SMRC) and in the extracellular acidification rate in 661W cells. DCTEIO antioxidant administration successfully reduced the loss of SMRC. Together, these findings show we can quantify dynamic changes in cellular oxidative status in vivo and suggest that nitroxide-based antioxidants may provide greater protection against oxidative stress than the current state-of-the-art antioxidant treatments for ROS-mediated diseases. PMID- 26592981 TI - Challenges in the Use of Administrative Data for Heart Failure Services Research. PMID- 26592982 TI - Should We Start Community Screening for Left Ventricular Dysfunction? PMID- 26592983 TI - Role of Magnetic Exchange Interactions in the Magnetization Relaxation of {3d-4f} Single-Molecule Magnets: A Theoretical Perspective. AB - Combined density functional and ab initio calculations are performed on two isomorphous tetranuclear {Ni3 (III) Ln(III) } star-type complexes [Ln=Gd (1), Dy (2)] to shed light on the mechanism of magnetic exchange in 1 and the origin of the slow magnetization relaxation in complex 2. DFT calculations correctly reproduce the sign and magnitude of the J values compared to the experiments for complex 1. Acute ?Ni-O-Gd bond angles present in 1 instigate a significant interaction between the 4fxyz orbital of the Gd(III) ion and 3d${{_{x{^{2}}- y{^{2}}}}}$ orbital of the Ni(II) ions, leading to rare and strong antiferromagnetic Ni???Gd interactions. Calculations reveal the presence of a strong next-nearest-neighbour Ni???Ni antiferromagnetic interaction in complex 1 leading to spin frustration behavior. CASSCF+RASSI-SO calculations performed on complex 2 suggest that the octahedral environment around the Dy(III) ion is neither strong enough to stabilize the mJ |+/-15/2> as the ground state nor able to achieve a large ground-state-first-excited-state gap. The ground-state Kramers doublet for the Dy(III) ion is found to be the mJ |+/-13/2> state with a significant transverse anisotropy, leading to very strong quantum tunneling of magnetization (QTM). Using the POLY_ANISO program, we have extracted the JNiDy interaction as -1.45 cm(-1) . The strong Ni???Dy and next-nearest-neighbour Ni???Ni interactions are found to quench the QTM to a certain extent, resulting in zero-field SMM behavior for complex 2. The absence of any ac signals at zero field for the structurally similar [Dy(AlMe4 )3 ] highlights the importance of both the Ni???Dy and the Ni???Ni interactions in the magnetization relaxation of complex 2. To the best of our knowledge, this is the first time that the roles of both the Ni???Dy and Ni???Ni interactions in magnetization relaxation of a {3d 4f} molecular magnet have been established. PMID- 26592984 TI - Visible-Light-Triggered Drug Release from TiO2 Nanotube Arrays: A Controllable Antibacterial Platform. AB - In this work, we use a double-layered stack of TiO2 nanotubes (TiNTs) to construct a visible-light-triggered drug delivery system. The key for visible light drug release is a hydrophobic cap on the nanotubes containing Au nanoparticles (AuNPs). The AuNPs allow for a photocatalytic scission of the hydrophobic chain under visible light. To demonstrate this principle, we loaded ampicillin (AMP) into the lower part of the TiO2 nanotube stack, triggered visible-light-induced release, and carried out antibacterial studies. The release from the platform becomes most controllable if the drug is silane-grafted in the hydrophilic bottom layer for drug storage. Thus, visible light photocatalysis can also determine the release kinetics of the active drug from the nanotube wall. PMID- 26592985 TI - One-Year Clinical Outcome of Pulmonary Vein Isolation Using the Second-Generation Cryoballoon: A Meta-Analysis. AB - BACKGROUND: The second-generation cryoballoon (CB-2G) is a promising technique to treat atrial fibrillation (AF). It is necessary to summarize and analyze the available data on 1-year clinical outcome of pulmonary vein isolation (PVI) with CB-2G. METHODS: PubMed and the Web of Science were searched in May 2015. Studies that reported the 1-year clinical success rates after PVI using CB-2G were included. The 1-year clinical success rates were pooled using the random-effect model. Complication rates and acute success rates were also analyzed. Subgroup analyses were conducted based on AF type and ablation strategy. RESULTS: Fifteen studies involving 2,363 AF patients met the inclusion criteria. The overall clinical success rate of PVI using CB-2G was 81%. A total of 82% of paroxysmal AF patients and 70% of persistent AF patients were in stable sinus rhythm 1 year after the procedure. The clinical success rates of the "no-bonus" strategy were 81% in all patients, 82% in paroxysmal AF patients, and 73% in persistent AF patients. The corresponding success rates of the "bonus" strategy were 81%, 83%, and 63%. Acute success rate was high. The overall rates of phrenic nerve palsy (PNP) and other procedure-related complications were 5.8% and 1.5%, respectively. Compared with "bonus" strategy, there was a trend of fewer PNPs in "no-bonus" strategy (4.6% vs 6.5%). CONCLUSIONS: CB-2G is highly effective in the treatment of both paroxysmal AF and persistent AF. The "no-bonus" strategy is as effective as the "bonus" strategy in terms of 1-year clinical outcome. PMID- 26592986 TI - Rare medical manifestations of severe restricting and purging: "Zebras," missed diagnoses, and best practices. AB - OBJECTIVE: Medical problems that arise due to severe restricting and/or purging may be misdiagnosed or suboptimally treated, from outpatient clinics to top medical hospitals. A symptom may be presumed to be a psychological manifestation of the eating disorder and inappropriately dismissed for further medical evaluation. Alternatively, a detailed medical workup may be performed, overlooking a classic relationship between starvation and a physical finding, which delays referral to eating disorder care. This review article focuses on rare medical issues (also called "zebras" in medical training), diagnoses that may be missed in patients with eating disorders, and best practices for management, organized by organ system. METHOD: A PubMed search was performed, using search terms "eating disorder," "anorexia nervosa," and "bulimia nervosa" in combination with different words for each organ system and known medical manifestations of severe eating disorders, with high quality and relevant studies from the past 20 years cited. DISCUSSION: Adults with eating disorders may present with extreme organ dysfunction and atypical signs and symptoms of typical medical problems. Timely diagnosis, risk awareness, appropriate treatment, and avoidance of harm are all vital. With judicious management and nutritional rehabilitation, most of these complications will significantly improve or resolve. (c) PMID- 26592987 TI - Routine detection of Clostridium difficile in Western Australia. AB - Despite increasing infection rates, Clostridium difficile is not currently routinely tested for in all diarrhoeal faecal specimens in Australia. In July 2014, all diarrhoeal specimens submitted to a diagnostic laboratory in Western Australia were surveyed to determine the true prevalence of C. difficile. In total, 1010 diarrhoeal non-duplicate faecal specimens were received during the month. Testing for C. difficile was requested, or the criteria for a C. difficile investigation were met, for 678 specimens which were investigated by PCR for the tcdB gene using the BD MAX platform, followed by toxigenic culture on PCR positive samples. The remaining 332 specimens, with either no C. difficile test request or the criteria for a C. difficile investigation were not met, were examined by toxigenic culture. All isolates were PCR ribotyped. C. difficile was the most commonly detected diarrhoeal pathogen among all specimens. The overall prevalence of C. difficile in all 1010 specimens was 6.4%; 7.2% in the routinely tested group, and 4.8% in the non-requested group. The proportion of non requested positive detections among all cases was 24.6%. Community-onset infection was present in 50.8% of all cases. The median age of all CDI cases was 60.0 years and the age range in CDI patients in the routine group was 0.6-96.6 years (median 72.7 years), compared to 0.2-2.3 years (median 0.8 years) in the non-requested group. The most common ribotype (RT) found was RT 014/020 (34.1% in the routine group, 43.8% in the non-requested group), followed by RTs 002, 056, 005 and 018. While the routine testing group and the non-requested group differed markedly in age and patient classification, C. difficile was the most common cause of diarrhoea in hospitals and the community in Western Australia. The significance of finding C. difficile in the community paediatric population requires further study. PMID- 26592988 TI - Helper NLR proteins NRC2a/b and NRC3 but not NRC1 are required for Pto-mediated cell death and resistance in Nicotiana benthamiana. PMID- 26592989 TI - ST-elevation myocardial infarction following systemic inflammatory response syndrome. AB - Systemic inflammatory response syndrome (SIRS) complicated with ST-elevation myocardial infarction has rarely been reported, and the precise mechanisms of myocardial injury remain unclear. Here, we present a case involving a 45-year-old man who developed SIRS secondary to diabetes-induced infection, and who ultimately developed ST-elevation myocardial infarction with acute heart failure, fulminant diabetes, acute liver dysfunction, acute kidney dysfunction and rhabdomyolysis. The patient eventually recovered due to early detection, correct diagnosis and powerful treatment. Clinicians should be aware of this new type of myocardial infarction, which is induced by inflammatory injury, but is not due to a primary coronary event such as plaque erosion and/or rupture, fissuring or dissection. PMID- 26592990 TI - A fatal complication after repair of post-infarction ventricular septal rupture: heparin-induced thrombocytopenia with thrombosis. AB - Heparin-induced thrombocytopenia (HIT) is a rare but potentially devastating and life-threatening complication from using heparin. HIT not only causes thrombocytopenia, but it also carries an increased risk for fatal thrombotic complications. In this report, we describe the case of a patient in whom fatal HIT developed after successful surgical repair of a posterior post-infarction ventricular septal rupture with cardiopulmonary bypass. PMID- 26592991 TI - Treatment of right ventricular perforation during percutaneous coronary intervention. AB - Percutaneous coronary intervention (PCI) is widely used to treat stenotic coronary arteries caused by coronary heart disease. Coronary artery perforation is a rare but dreaded complication of PCI. Here, we report the successful treatment of a patient with coronary perforation of the right ventricular cavity. To our knowledge, this is the first report of its kind. The patient was a 69-year old woman with intermittent chest tightness and chest pain of about five years' duration who was hospitalised for severe chest tightness and pain persisting for three days. She had a history of hypertension and hyperlipidaemia; routine admission examination showed no other abnormalities. Results of routine blood, urine and stool tests, liver and kidney function, clotting time, electrocardiogram, chest radiography and echocardiography were normal. Although coil embolisation rather than balloon is safe and effective for treating coronary artery perforation, it may be not the best choice overall. If the perforation breaks through into the right ventricle, we may just monitor closely rather than treat. That course may be beneficial for patients in that it reduces the risk of myocardial cell necrosis. This case provides useful information for the treatment of such patients in the future. PMID- 26592993 TI - Wilfred van Gunsteren: 35 Years of Biomolecular Simulation. PMID- 26592992 TI - An unusual cause of a large fibrinous pericardial effusion. AB - The commonest cause of a large fibrinous pericardial effusion in sub-Saharan Africa is tuberculosis. There are, however, limited resources available for making a definitive diagnosis of tuberculous pericarditis. The diagnosis is largely based on clinical criteria. There is a risk of misdiagnosing less-common causes of large fibrinous pericardial effusions. We present a patient who had a pericardial angiosarcoma that was initially thought to be a tuberculous pericardial effusion, and discuss the challenges in making a definitive diagnosis of tuberculosis. PMID- 26592994 TI - Probing the Structure and Dynamics of Proteins by Combining Molecular Dynamics Simulations and Experimental NMR Data. AB - NMR experiments provide detailed structural information about biological macromolecules in solution. However, the amount of information obtained is usually much less than the number of degrees of freedom of the macromolecule. Moreover, the relationships between experimental observables and structural information, such as interatomic distances or dihedral angle values, may be multiple-valued and may rely on empirical parameters and approximations. The extraction of structural information from experimental data is further complicated by the time- and ensemble-averaged nature of NMR observables. Combining NMR data with molecular dynamics simulations can elucidate and alleviate some of these problems, as well as allow inconsistencies in the NMR data to be identified. Here, we use a number of examples from our work to highlight the power of molecular dynamics simulations in providing a structural interpretation of solution NMR data. PMID- 26592995 TI - On the Use of Experimental Observations to Bias Simulated Ensembles. AB - Historically, experimental measurements have been used to bias biomolecular simulations toward structures compatible with those observations via the addition of ad hoc restraint terms. We show how the maximum entropy formalism provides a principled approach to enforce concordance with these measurements in a minimally biased way, yielding restraints that are linear functions of the target observables and specifying a straightforward scheme to determine the biasing weights. These restraints are compared with instantaneous and ensemble-averaged harmonic restraint schemes, illustrating their similarities and limitations. PMID- 26592996 TI - A Flexible, Grid-Enabled Web Portal for GROMACS Molecular Dynamics Simulations. AB - Molecular dynamics simulations are becoming a standard part of workflows in structural biology. They are used for tasks as diverse as assessing molecular flexibility, probing conformational changes, assessing the impact of mutations, or gaining information about molecular interactions. However, performing a successful simulation requires sufficient computational resources, familiarity with the simulation software, and experience in the setup of a system and the analysis of the resulting trajectories. These considerations become especially critical in large-scale parametric MD simulations. Offering such tools to a wide user community requires a robust and versatile, but user-friendly, facility for molecular dynamics simulations with access to vast computational resources. Here, we present the GROMACS grid-enabled Web portal for the setup and execution of molecular dynamics simulation on the WeNMR grid infrastructure, a distributed network of computational resources within the European Grid Initiative. The Web portal aims at ease-of-use through automated setup of the simulation system using best-practice protocols, yet allowing for tuning of key parameters. Alternatively, the simulation can be started from preconfigured GROMACS simulation systems. Performing multiple lengthy calculations using multiple processors on the WeNMR grid infrastructure ensures scalability. The combination of analysis routines for quality assurance and automatic recovery in case of failures provides a reliable platform for MD simulations. The GROMACS Web portal is embedded within the services of the WeNMR Virtual Research Community (VRC) accessible from http://www.wenmr.eu/wenmr/nmr-services . It is freely accessible upon registration with a valid X509 personal certificate with the enmr.eu Virtual Organization (VO). PMID- 26592997 TI - Inverse Laplace Transform of Multidimensional Relaxation Data Without Non Negativity Constraint. AB - An algorithm based on Tikhonov regularization in generalized form is described to perform an inverse Laplace transform of multidimensional data without a non negativity (NN) constraint for spectrum conditioning. Uniform penalty (UP) regularization is used to reduce the requirement for NN, and a further penalty is introduced for zero-crossing (ZC) of the spectrum. This ZC term is weighted with the slope of the curve, which does not prevent negative modes in the spectrum but makes nonphysical undershooting in the vicinity of narrow peaks more expensive. The performance of this algorithm is demonstrated using synthetic data, and the optimization of the free parameters for calculating the regularization matrix is discussed. PMID- 26592998 TI - Relaxation Matrix Analysis of Spin Diffusion for the NMR Structure Calculation with eNOEs. AB - NMR structure determination is usually based on distance restraints extracted semiquantitatively from cross peak volumes or intensities in NOESY spectra. The recent introduction of exact NOEs (eNOE) by Vogeli et al. opens an avenue for the ensemble-based structure determination of proteins on the basis of eNOE-derived quantitative distance restraints. We present an approach to extract eNOE from build-up curve intensities. For the determination of eNOEs, spin diffusion is a major source of errors. A full relaxation matrix analysis is used to calculate the spin diffusion contribution to the NOESY cross peaks of each individual spin pair of interest. A software program is written, which requires as input the peak intensities from the various NOESY spectra as well as a 3D structure of the protein. This structure can be either an X-ray structure or an NMR structure determined with the conventional approach. The outputs of the program are the eNOE rates, the autorelaxation rates, as well as graphs and quality factors from the individual NOE build-up curves for semiautomated analysis of the derived rates. The protocol is straightforward, and the program integrates well into the current structure calculation workflow. PMID- 26592999 TI - Alchemical Free Energy Differences in Flexible Molecules from Thermodynamic Integration or Free Energy Perturbation Combined with Driven Adiabatic Dynamics. AB - Alchemical free energy simulations are commonly used to calculate relative binding or solvation free energies in molecular systems. The convergence of alchemical free energy calculations is often hampered by inefficient sampling of the conformational degrees of freedom, which remain trapped in metastable substates. Here, we show that thermodynamic integration (TI) or free energy perturbation (FEP) can be combined with the recent driven adiabatic free energy dynamics (dAFED) method, in order to enhance conformational sampling along a set of chosen collective variables. The resulting TI-dAFED or FEP-dAFED methods are validated on a two-dimensional analytical problem. The ability of these methods to provide accurate free energy differences for realistic molecular systems is demonstrated by calculating the enantiomerization free energy of the alanine dipeptide in explicit solvent. PMID- 26593000 TI - The Solvation Structure of Na(+) and K(+) in Liquid Water Determined from High Level ab Initio Molecular Dynamics Simulations. AB - Knowledge of the hydration structure of Na(+) and K(+) in the liquid phase has wide ranging implications in the field of biological chemistry. Despite numerous experimental and computational studies, even basic features such as the coordination number of these alkali ions in liquid water, thought to play a critical role in selectivity, continue to be the subject of intensive debates. Simulations based on accurate potential energy surfaces offer one approach to resolve these issues by providing reliable results on ion hydration. In this article, we report the results from molecular dynamics simulations of Na(+) and K(+) hydration based on a novel and rigorous strategy designed to overcome the challenges of QM/MM simulations of solvent molecules in the liquid phase. In this method, which we call Flexible Inner Region Ensemble Separator (FIRES), the ion and a fixed number of nearest water molecules form a dynamical and flexible inner region that is represented with high level ab initio quantum mechanical (QM) methods, while the water molecules from the surrounding bulk form an outer region that is represented by a polarizable molecular mechanical (MM) force field. Simulations yield rigorously correct thermodynamic averages as long as the solvent molecules in the flexible inner and outer regions are not allowed to exchange. Extensive FIRES simulations were carried out based on a QM/MM model in which the Na(+) or K(+) ion and the 12 nearest water molecules were represented by high level ab initio methods (RI-MP2/def2-TZVP and density functional theory with PBE/def2-TZVP), while the surrounding MM water molecules were represented by the polarizable SWM4-NDP potential. On the basis of these results, the ion coordination numbers are estimated to be within the range of 5.7-5.8 for Na(+) and 6.9-7.0 for K(+). PMID- 26593001 TI - Preferential Solvation of Triglycine in Aqueous Urea: An Open Boundary Simulation Approach. AB - Solvation free energies of peptides in water decrease with increasing urea concentration and therefore lead to increased solubility. In this work, we study the solvation thermodynamics of a triglycine in aqueous urea solutions at room temperature T = 300 K. We perform our analysis within the framework of the Kirkwood-Buff theory of liquid mixtures, developed for open systems. For this purpose, we use a recently proposed approach to study liquid mixtures within an "effective" open boundary simulation scheme (AdResS). We couple a small open boundary all-atom (explicit) region to a much larger coarse-grained particle reservoir. This coupling allows the free exchange of particles in thermodynamic equilibrium. Our approach preserves correct particle fluctuations that are important for studying the concentration driven conformational transition of (bio)molecules. PMID- 26593002 TI - Calculation of Derivative Thermodynamic Hydration and Aqueous Partial Molar Properties of Ions Based on Atomistic Simulations. AB - The raw ionic solvation free energies calculated on the basis of atomistic (explicit-solvent) simulations are extremely sensitive to the boundary conditions and treatment of electrostatic interactions used during these simulations. However, as shown recently [Kastenholz, M. A.; Hunenberger, P. H. J. Chem. Phys.2006, 124, 224501 and Reif, M. M.; Hunenberger, P. H. J. Chem. Phys.2011, 134, 144104], the application of an appropriate correction scheme allows for a conversion of the methodology-dependent raw data into methodology-independent results. In this work, methodology-independent derivative thermodynamic hydration and aqueous partial molar properties are calculated for the Na(+) and Cl(-) ions at P degrees = 1 bar and T(-) = 298.15 K, based on the SPC water model and on ion-solvent Lennard-Jones interaction coefficients previously reoptimized against experimental hydration free energies. The hydration parameters considered are the hydration free energy and enthalpy. The aqueous partial molar parameters considered are the partial molar entropy, volume, heat capacity, volume compressibility, and volume-expansivity. Two alternative calculation methods are employed to access these properties. Method I relies on the difference in average volume and energy between two aqueous systems involving the same number of water molecules, either in the absence or in the presence of the ion, along with variations of these differences corresponding to finite pressure or/and temperature changes. Method II relies on the calculation of the hydration free energy of the ion, along with variations of this free energy corresponding to finite pressure or/and temperature changes. Both methods are used considering two distinct variants in the application of the correction scheme. In variant A, the raw values from the simulations are corrected after the application of finite difference in pressure or/and temperature, based on correction terms specifically designed for derivative parameters at P degrees and T(-). In variant B, these raw values are corrected prior to differentiation, based on corresponding correction terms appropriate for the different simulation pressures P and temperatures T. The results corresponding to the different calculation schemes show that, except for the hydration free energy itself, accurate methodological independence and quantitative agreement with even the most reliable experimental parameters (ion-pair properties) are not yet reached. Nevertheless, approximate internal consistency and qualitative agreement with experimental results can be achieved, but only when an appropriate correction scheme is applied, along with a careful consideration of standard-state issues. In this sense, the main merit of the present study is to set a clear framework for these types of calculations and to point toward directions for future improvements, with the ultimate goal of reaching a consistent and quantitative description of single-ion hydration thermodynamics in molecular dynamics simulations. PMID- 26593003 TI - Linear Scaling Self-Consistent Field Calculations with Millions of Atoms in the Condensed Phase. AB - In this work, the applicability and performance of a linear scaling algorithm is investigated for three-dimensional condensed phase systems. A simple but robust approach based on the matrix sign function is employed together with a thresholding matrix multiplication that does not require a prescribed sparsity pattern. Semiempirical methods and density functional theory have been tested. We demonstrate that self-consistent calculations with 1 million atoms are feasible for simple systems. With this approach, the computational cost of the calculation depends strongly on basis set quality. In the current implementation, high quality calculations for dense systems are limited to a few hundred thousand atoms. We report on the sparsities of the involved matrices as obtained at convergence and for intermediate iterations. We investigate how determining the chemical potential impacts the computational cost for very large systems. PMID- 26593004 TI - Combining a Dissociative Water Model with a Hybrid QM/MM Approach-A Simulation Strategy for the Study of Proton Transfer Reactions in Solution. AB - An implementation strategy for a dissociative water potential in hybrid QM/MM simulations is outlined. As the knowledge of the time-dependent topology is crucial for the assignment of solvent molecules to the QM or MM subregion, proton transfer events and the associated change of the molecular composition have to be monitored as the simulation is progressing. A simple and effective update criterion is proposed, which was found to be an efficient tool to identify sustained proton transfer reactions. The resulting topology data enable the application of the dissociative solvent model in QM/MM simulations and serve as a reference for the analysis of time-dependent properties such as the proton hopping rate and the diffusion coefficient. For the latter, an interpolation scheme is proposed linking subsequent proton transfer events into a single diffusive entity. Suitable settings of key parameters for the topology update and the interpolation scheme have been determined by analyzing MD trajectories of an excess proton in water and 1 M HCl. The resulting values for the proton hopping rate and the diffusion coefficient are well within the range estimated by EVB models and CPMD approaches. An investigation of the hydrolytic conversion of As(III) to [As(OH)2](+) serves as an exemplary application of the dissociative model in a QM/MM simulation study. PMID- 26593005 TI - Exploring the Multidimensional Free Energy Surface of Phosphoester Hydrolysis with Constrained QM/MM Dynamics. AB - The mechanism of the hydrolysis of phosphate monoesters, a ubiquitous biological reaction, has remained under debate. We here investigated the hydrolysis of a nonenzymatic model system, the monomethyl phosphate dianion, by hybrid quantum mechanical and molecular mechanical simulations. The solvation effects were taken into account with explicit water. Detailed free energy landscapes in two dimensional and three-dimensional space were resolved using the multidimensional potential of mean constraint force, a newly developed method that was demonstrated to be powerful for free energy calculations along multiple coordinates. As in previous theoretical studies, the associative and dissociative pathways were indistinguishable. Furthermore, the associative pathway was investigated in great detail. We propose a rotation of an O-H bond in the transition between two pentacoordinated structures, during which an overall transition state was identified with an activation energy of 50 kcal/mol. This is consistent with experimental data. The results support a concerted proton transfer from the nucleophilic water to the phosphate group, and then to the leaving group. PMID- 26593006 TI - Trivalent Uranium Complex As a Catalyst to Promote the Functionalization of Carbon Dioxide and Carbon Disulfide: A Computational Mechanistic Study. AB - We report our recent DFT mechanistic study on the functionalization of CO2 and CS2 promoted by a trivalent uranium complex (Tp*)2UCH2Ph. In the calculations, the uranium atom is described by a quasi-relativistic 5f-in-core ECP basis set (LPP) developed for the trivalent uranium cation, which was qualified by the calculations with a quasi-relativistic small core ECP basis set (SPP) for uranium. According to our calculations, the functionalization proceeds in a stepwise manner, and the CO2 or CS2 does not interact with the central uranium atom to form a stable complex prior to the reaction due to the steric hindrance from the bulky ligands but directly cleaves the U-C (benzyl) bond by forming a C C covalent bond. The released coordination site of uranium is concomitantly occupied by one chalcogen atom of the incoming molecule and gives an intermediate with the uranium atom interacting with the functionalized CO2 or CS2 in an eta(1) fasion. This step is followed by a reorientation of the (dithio)carboxylate side chain of the newly formed PhCH2CE2(-) (E = O, S) ligand to give the corresponding product. Energetically, the first step is characterized as the rate-determining step with a barrier of 9.5 (CO2) or 25.0 (CS2) kcal/mol, and during the reaction, the chalcogen atoms are reduced, while the methylene of the benzyl group is oxidized. Comparison of the results from SPP and LPP calculations indicates that our calculations qualify the use of an LPP treatment of the uranium atom toward a reasonable description of the model systems in the present study. PMID- 26593007 TI - SQUEEZE-E: The Optimal Solution for Molecular Simulations with Periodic Boundary Conditions. AB - In molecular simulations of macromolecules, it is desirable to limit the amount of solvent in the system to avoid spending computational resources on uninteresting solvent-solvent interactions. As a consequence, periodic boundary conditions are commonly used, with a simulation box chosen as small as possible, for a given minimal distance between images. Here, we describe how such a simulation cell can be set up for ensembles, taking into account a priori available or estimable information regarding conformational flexibility. Doing so ensures that any conformation present in the input ensemble will satisfy the distance criterion during the simulation. This helps avoid periodicity artifacts due to conformational changes. The method introduces three new approaches in computational geometry: (1) The first is the derivation of an optimal packing of ensembles, for which the mathematical framework is described. (2) A new method for approximating the alpha-hull and the contact body for single bodies and ensembles is presented, which is orders of magnitude faster than existing routines, allowing the calculation of packings of large ensembles and/or large bodies. 3. A routine is described for searching a combination of three vectors on a discretized contact body forming a reduced base for a lattice with minimal cell volume. The new algorithms reduce the time required to calculate packings of single bodies from minutes or hours to seconds. The use and efficacy of the method is demonstrated for ensembles obtained from NMR, MD simulations, and elastic network modeling. An implementation of the method has been made available online at http://haddock.chem.uu.nl/services/SQUEEZE/ and has been made available as an option for running simulations through the weNMR GRID MD server at http://haddock.science.uu.nl/enmr/services/GROMACS/main.php . PMID- 26593008 TI - Optimizing the Accuracy and Efficiency of Fast Hierarchical Multipole Expansions for MD Simulations. AB - Based on p'th order Cartesian Taylor expansions of Coulomb interactions and on hierarchical decompositions of macromolecular simulation systems into hierarchies of nested, structure-adapted, and adaptively formed clusters of increasing size, fast multipole methods are constructed for rapid and accurate calculations of electrostatic interactions. These so-called SAMMp algorithms are formulated through totally symmetric and traceless tensors describing the multipole moments and the coefficients of local Taylor expansions. Simple recursions for the efficient evaluation and shifting of multipole moments are given. The required tensors are explicitly given up to order p = 4. The SAMMp algorithms are shown to guarantee the reaction principle. For systems with periodic boundaries, a reaction field (RF) correction is applied, which introduces at distances beyond the "minimum image convention" boundary a dielectric continuum surrounding each cluster at the top level of coarse graining. The correctness of the present SAMMp implementation is demonstrated by analyzing the scaling of the residuals and by checking the numerical accuracy of the reaction principle for a pair of distant molecular ions in vacuum. Molecular dynamics simulations of pure water and aqueous solutions containing artificial ions, which are enclosed by periodic boundaries, demonstrate the stability and low-noise behavior of SAMMp/RF. PMID- 26593009 TI - Efficient Algorithms for Langevin and DPD Dynamics. AB - In this article, we present several algorithms for stochastic dynamics, including Langevin dynamics and different variants of Dissipative Particle Dynamics (DPD), applicable to systems with or without constraints. The algorithms are based on the impulsive application of friction and noise, thus avoiding the computational complexity of algorithms that apply continuous friction and noise. Simulation results on thermostat strength and diffusion properties for ideal gas, coarse grained (MARTINI) water, and constrained atomic (SPC/E) water systems are discussed. We show that the measured thermal relaxation rates agree well with theoretical predictions. The influence of various parameters on the diffusion coefficient is discussed. PMID- 26593010 TI - Enhanced Sampling in Free Energy Calculations: Combining SGLD with the Bennett's Acceptance Ratio and Enveloping Distribution Sampling Methods. AB - One of the key requirements for the accurate calculation of free energy differences is proper sampling of conformational space. Especially in biological applications, molecular dynamics simulations are often confronted with rugged energy surfaces and high energy barriers, leading to insufficient sampling and, in turn, poor convergence of the free energy results. In this work, we address this problem by employing enhanced sampling methods. We explore the possibility of using self-guided Langevin dynamics (SGLD) to speed up the exploration process in free energy simulations. To obtain improved free energy differences from such simulations, it is necessary to account for the effects of the bias due to the guiding forces. We demonstrate how this can be accomplished for the Bennett's acceptance ratio (BAR) and the enveloping distribution sampling (EDS) methods. While BAR is considered among the most efficient methods available for free energy calculations, the EDS method developed by Christ and van Gunsteren is a promising development that reduces the computational costs of free energy calculations by simulating a single reference state. To evaluate the accuracy of both approaches in connection with enhanced sampling, EDS was implemented in CHARMM. For testing, we employ benchmark systems with analytical reference results and the mutation of alanine to serine. We find that SGLD with reweighting can provide accurate results for BAR and EDS where conventional molecular dynamics simulations fail. In addition, we compare the performance of EDS with other free energy methods. We briefly discuss the implications of our results and provide practical guidelines for conducting free energy simulations with SGLD. PMID- 26593011 TI - Dynamics in Sequence Space for RNA Secondary Structure Design. AB - We have implemented a method for the design of RNA sequences that should fold to arbitrary secondary structures. A popular energy model allows one to take the derivative with respect to composition, which can then be interpreted as a force and used for Newtonian dynamics in sequence space. Combined with a negative design term, one can rapidly sample sequences which are compatible with a desired secondary structure via simulated annealing. Results for 360 structures were compared with those from another nucleic acid design program using measures such as the probability of the target structure and an ensemble-weighted distance to the target structure. PMID- 26593012 TI - Spin-Orbit Coupling and Potential Energy Functions of Ar2(+) and Kr2(+) by High Resolution Photoelectron Spectroscopy and ab Initio Quantum Chemistry. AB - The dependence of the spin-orbit-coupling constant of the six low-lying electronic states of Ar2(+) and Kr2(+) on the internuclear distance R has been calculated ab initio. The spin-orbit-coupling constant varies by about 10% over the range of internuclear distances relevant for the interpretation of the high resolution photoelectron spectra of Ar2 and Kr2 and can be accurately represented by a Morse-type function for the states of ungerade electronic symmetry and by an exponentially decreasing function for the states of gerade symmetry. The spin orbit-coupling constant is larger than the asymptotic value (at R -> infinity) for the gerade states and smaller for the ungerade states. The calculated R dependent spin-orbit-coupling constants were used to derive a new set of potential energy functions for the low-lying electronic states of Ar2(+) and Kr2(+) and to quantify the errors resulting from the widely used approach consisting of approximating the spin-orbit-coupling constant by its asymptotic value. The effects of the R dependence on the potential energy functions of the six low-lying electronic states of the homonuclear rare-gas dimer ions are found to be very small for Ar2(+) (and by inference also for Ne2(+)) but significant for Kr2(+). The shifts arising in calculations of the potential energy functions from a neglect of the R dependence of the spin-orbit-coupling constant are the result of the interplay between the differences between the binding energies of the relevant (2)Pi and (2)Sigma(+) states, the magnitude of the spin-orbit coupling constant, and the magnitude and sign of the deviations between the R dependent spin-orbit-coupling constant and its asymptotic value at large internuclear distances. PMID- 26593013 TI - Efficient and Accurate Free Energy Calculations on Trypsin Inhibitors. AB - Several combinations of free energy calculation methods have been applied to determine the relative free energies of binding between eight para-substituted benzamidines in complex with the serine protease trypsin. With the aim to improve efficiency and maintain accuracy, the linear response approximation (LRA), linear interaction energy (LIE) and third power fitting (TPF) are combined with the one step perturbation (OSP) to determine the polar and apolar contributions to the free energy, respectively. It is shown that the combination TPF/OSP gives the most accurate results and is 4.5 times more efficient than the rigorous thermodynamic integration (TI). By projecting the electrostatic preorganization energy from the OSP simulations, an increase in efficiency of a factor 7.5 can even be achieved. Loss of accuracy with respect to the TI data is limited to 3.9 and 5.6 kJ/mol, respectively, making it an attractive approach for lead optimization programs in drug research. PMID- 26593014 TI - Water-Driven Cavity-Ligand Binding: Comparison of Thermodynamic Signatures from Coarse-Grained and Atomic-Level Simulations. AB - The role of water (thermo)dynamics is crucial in molecular recognition and self assembly. Here, we study a prototype cavity-ligand system as a model for hydrophobic noncovalent binding. Two alternative molecular dynamics simulation resolutions are employed and the resulting structural, dynamic, and thermodynamic properties compared: first, a coarse-grained (CG) resolution based on the previously reported and validated methane-like M solute and mW water models; second, an atomic-level (AL) resolution based on the popular OPLS united atom methane and the TIP4P water models. The CG model reproduces, as a function of the cavity-ligand distance, (1) the water occupancy of the cavity, (2) the cavity ligand potential of mean force (free energy) and its temperature dependence, and (3) some of the major qualitative features of the thermodynamic signatures (free energy, enthalpy, and entropy) for cavity-ligand association of the AL model. The limits of the CG and AL models in this context are also discussed with comparison to experimental data. Our study suggests that CG simulation with models that include the translational contribution of water and anisotropic "hydrogen-bond" like interactions could reproduce the thermodynamics of molecular recognition and water-driven assembly in complex macromolecular systems and nanoscale processes with convenient computational time savings. PMID- 26593015 TI - New Interaction Parameters for Charged Amino Acid Side Chains in the GROMOS Force Field. PMID- 26593016 TI - Can Continuum Thermodynamics Characterize Wenzel Wetting States of Water at the Nanometer Scale? AB - We address the question of how solid-liquid surface free energy is affected by nanometer scale roughness. We proceed through molecular dynamics calculations of the solid-liquid surface free energy of water in a collapsed wetting state on rough nonpolar surfaces characterized by an array of parallel linear grooves. We establish a continuum equation based on Wenzel and Cassie-Baxter approaches to predict the solid-liquid surface free energy variations of systems, where the vertical and horizontal surfaces of the groove have different interactions with water and where the groove geometry can be varied. We show that the molecular simulations results agree with the prediction of the continuum equation under the condition that the groove is wider than three water molecular diameters and deeper than one molecular diameter. PMID- 26593017 TI - Molecular Dynamics Simulations of Star Polymeric Molecules with Diblock Arms, a Comparative Study. AB - We have performed all atom explicit solvent molecular dynamics simulations of three different star polymeric systems in water, each star molecule consisting of 16 diblock copolymer arms bound to a small adamantane core. The arms of each system consist of an inner "hydrophobic" block (either polylactide, polyvalerolactone, or polyethylene) and an outer hydrophilic block (polyethylene oxide, PEO). These models exhibit unusual structure very close to the core (clearly an artifact of our model) but which we believe becomes "normal" or bulk like at relatively short distances from this core. We report on a number of temperature-dependent thermodynamic (structural/energetic) properties as well as kinetic properties. Our observations suggest that under physiological conditions, the hydrophobic regions of these systems may be solid and glassy, with only rare and shallow penetration by water, and that a sharp boundary exists between the hydrophobic cores and either the PEO or water. The PEO in these models is seen to be fully water-solvated at low temperatures but tends to phase separate from water as the temperature is increased, reminiscent of a lower critical solution temperature exhibited by PEO-water mixtures. Water penetration concentration and depth is composition and temperature dependent with greater water penetration for the most ester-rich star polymer. PMID- 26593018 TI - Coarse-Grained and Atomistic Simulations of the Salt-Stable Cowpea Chlorotic Mottle Virus (SS-CCMV) Subunit 26-49: beta-Barrel Stability of the Hexamer and Pentamer Geometries. AB - A combination of coarse-grained (CG) and atomistic simulations provides a suitable computational framework to study unstructured regions of proteins, for which experimental data are often lacking or limited. In this work, we combine CG and atomistic simulations with clustering algorithms and free energy reweighting methods to explore the conformational equilibrium of certain regions of the salt stable cowpea chlorotic mottle virus (SS-CCMV). In particular, we focus on the geometry of converging strands (residues 26-49) from contacting subunits at the 3 fold (hexamer) and 5-fold (pentamer) symmetry points of the capsid. We show the following: (i) The simulations reproduce the experimentally observed beta-barrel for the hexamer. (ii) The pentamer geometry is unable to stabilize a beta-barrel conformation; it assumes various states instead, again in accordance with the experimental results which do not indicate a well-defined structure for the pentameric interface. (iii) Atomistic simulations of the backmapped CG structures remain relatively stable, indicative of plausible CG conformations and slow kinetics on the atomistic level. PMID- 26593019 TI - Temperature-Accelerated Sampling and Amplified Collective Motion with Adiabatic Reweighting to Obtain Canonical Distributions and Ensemble Averages. AB - In molecular simulations, accelerated sampling can be achieved efficiently by raising the temperature of a small number of coordinates. For collective coordinates, the temperature-accelerated molecular dynamics method or TAMD has been previously proposed, in which the system is extended by introducing virtual variables that are coupled to these coordinates and simulated at higher temperatures (Maragliano, L.; Vanden-Eijnden, E. Chem. Phys. Lett.2005, 426, 168 175). In such accelerated simulations, steady state or equilibrium distributions may exist but deviate from the canonical Boltzmann one. We show that by assuming adiabatic decoupling between the subsystems simulated at different temperatures, correct canonical distributions and ensemble averages can be obtained through reweighting. The method makes use of the low-dimensional free energy surfaces that are estimated as Gaussian mixture probability densities through maximum likelihood and expectation maximization. Previously, we proposed the amplified collective motion method or ACM. The method employs the coarse-grained elastic network model or ANM to extract collective coordinates for accelerated sampling. Here, we combine the ideas of ACM and of TAMD to develop a general technique that can achieve canonical sampling through reweighting under the adiabatic approximation. To test the validity and accuracy of adiabatic reweighting, first we consider a single n-butane molecule in a canonical stochastic heat bath. Then, we use explicitly solvated alanine dipeptide and GB1 peptide as model systems to demonstrate the proposed approaches. With alanine dipeptide, it is shown that sampling can be accelerated by more than an order of magnitude with TAMD while correct distributions and canonical ensemble averages can be recovered, necessarily through adiabatic reweighting. For the GB1 peptide, the conformational distribution sampled by ACM-TAMD, after adiabatic reweighting, suggested that a normal simulation suffered significantly from insufficient sampling and that the reweighted ACM-TAMD distribution may present significant improvements over the normal simulation in representing the local conformational ensemble around the folded structure of GB1. PMID- 26593020 TI - Comparison of QM-Only and QM/MM Models for the Mechanism of Tungsten-Dependent Acetylene Hydratase. AB - We report a comparison of QM-only and QM/MM approaches for the modeling of enzymatic reactions. For this purpose, we present a QM/MM case study on the formation of vinyl alcohol in the catalytic cycle of tungsten-dependent acetylene hydratase. Three different QM regions ranging from 32 to 157 atoms are designed for the reinvestigation of the previously suggested one-water attack mechanism. The QM/MM calculations with the minimal QM region M1 (32 atoms) yield a two-step reaction profile, with an initial nucleophilic attack followed by the protonation of the formed vinyl anion intermediate, as previously proposed on the basis of QM only calculations on cluster model M2 (116 atoms); however, the overall QM/MM barrier with M1 is much too high, mainly due to an overestimate of the QM/MM electrostatic repulsions. QM/MM calculations with QM region M2 (116 atoms) fail to reproduce the published QM-only results, giving a one-step profile with a very high barrier. This is traced back to the strong electrostatic influence of the two neighboring diphosphate groups that were neglected in the QM-only work but are present at the QM/MM level. These diphosphate groups and other electrostatically important nearby residues are included in QM region M3 (157 atoms). QM/MM calculations with M3 recover the two-step mechanism and yield a reasonable overall barrier of 16.7 kcal/mol at the B3LYP/MM level. They thus lead to a similar overall mechanistic scenario as the previous QM-only calculations, but there are also some important variations. Most notably, the initial nucleophilic attack becomes rate limiting at the QM/MM level. A modified two water attack mechanism is also considered but is found to be less favorable than the previously proposed one-water attack mechanism. Detailed residue interaction analyses and comparisons between QM/MM results with electronic and mechanical embedding and QM-only results without and with continuum solvation show that the protein environment plays a key role in determining the mechanistic preferences in acetylene hydratase. The combined use of QM-only and QM/MM methods provides a powerful approach for the modeling of enzyme catalysis. PMID- 26593021 TI - Enthalpy-Entropy of Cation Association with the Acetate Anion in Water. AB - Negatively charged carboxylate and phosphate groups on biomolecules have different affinity for Na(+) and K(+) ions. We performed molecular simulations and studied the pair potential of mean force between monovalent cations and the carboxylate group of the acetate anion in aqueous solution at 298 K. The simulations indicate that a larger affinity of Na(+) over K(+) in the contact ion pair (CIP) state is of entropic origin with the CIP state becoming increasingly populated at higher temperature. Differences between the osmotic activities of these two ions are however governed by interactions with acetate in the solvent shared ion pair (SIP) state as was previously shown (Hess, B.; van der Vegt, N. F. A. Proc. Natl. Acad. Sci. U.S.A.2009, 106, 13296). SIP states with Na(+) are slightly more stable than SIP states with K(+), resulting in a smaller osmotic activity of sodium. We discuss the different affinities of Na(+) and K(+) in the SIP state in terms of an enthalpy-entropy reinforcement mechanism which involves a water-mediated hydrogen-bonding interaction between the oppositely charged ions. SIP states are enthalpically favorable and become decreasingly populated at higher temperature. PMID- 26593022 TI - Identifying Metastable States of Folding Proteins. AB - Recent molecular dynamics simulations of biopolymers have shown that in many cases the global features of the free energy landscape can be characterized in terms of the metastable conformational states of the system. To identify these states, a conceptionally and computationally simple approach is proposed. It consists of (i) an initial preprocessing via principal component analysis to reduce the dimensionality of the data, followed by k-means clustering to generate up to 10(4) microstates, (ii) the most probable path algorithm to identify the metastable states of the system, and (iii) boundary corrections of these states via the introduction of cluster cores in order to obtain the correct dynamics. By adopting two well-studied model problems, hepta-alanine and the villin headpiece protein, the potential and the performance of the approach are demonstrated. PMID- 26593023 TI - On the Contribution of Linear Correlations to Quasi-harmonic Conformational Entropy in Proteins. AB - We study the contribution of linear, pairwise atom-positional correlations (covariances) to absolute and relative conformational entropy as calculated by quasi-harmonic analysis of molecular dynamics (MD) trajectories (SQH and DeltaSQH). By analyzing a total of 25 MUs of MD simulations of ubiquitin and six of its binding partners in bound and unbound states, and 2.4 MUs of simulations of eight different proteins in phosphorylated and unphosphorylated states, we show that DeltaSQH represents a remarkably constant fraction of a quasi-harmonic entropy change obtained if one ignores the contribution of covariance terms and uses mass-weighted atom-positional variances only (DeltaSVAR). In other words, the relative contribution of linear correlations to conformational entropy change for different proteins and in different biomolecular processes appears to be largely constant. Based on this, we establish an empirical relationship between relative quasi-harmonic conformational entropy and changes in crystallographic B factors induced by different processes, and we use it to estimate conformational entropic contribution to the free energy of binding for a large set of protein complexes based on their X-ray structures. Our results suggest a simple way for relating other types of dynamical observables with conformational entropy in the absence of information on correlated motions, such as in the case of NMR order parameters. PMID- 26593024 TI - The Effect of Temperature, Cations, and Number of Acyl Chains on the Lamellar to Non-Lamellar Transition in Lipid-A Membranes: A Microscopic View. AB - Lipopolysaccharides (LPS) are the main constituent of the outer bacterial membrane of Gram-negative bacteria. Lipid-A is the structural region of LPS that interacts with the innate immune system and induces inflammatory responses. It is formed by a phosphorylated beta-d-glucosaminyl-(1->6)-alpha-N-glucosamine disaccharide backbone containing ester-linked and amide-linked long-chain fatty acids, which may vary in length and number depending on the bacterial strains and the environment. Phenotypical variation (i.e., number of acyl chains), cation type, and temperature influence the phase transition, aggregate structure, and endotoxic activity of Lipid-A. We have applied an extension of the GROMOS force field 45a4 carbohydrate parameter set to investigate the behavior of hexa- and pentaacylated Lipid-A of Pseudomonas aeruginosa at two temperatures (300 and 328 K) and in the presence of mono- and divalent cations (represented by Ca(2+) and Na(+), respectively) through molecular dynamics simulations. The distinct phase of Lipid-A aggregates was characterized by structural properties, deuterium order parameters, the molecular shape of the lipid units (conical versus cylindrical), and molecular packing. Our results show that Na(+) ions induce a transition from the lamellar to nonlamellar phase. In contrast, the bilayer integrity is maintained in the presence of Ca(2+) ions. Through these findings, we present microscopic insights on the influence of different cations on the molecular behavior of Lipid-A associated with the lamellar to nonlamellar transition. PMID- 26593025 TI - QM/MM-Based Fitting of Atomic Polarizabilities for Use in Condensed-Phase Biomolecular Simulation. AB - Accounting for electronic polarization effects in biomolecular simulation (by using a polarizable force field) can increase the accuracy of simulation results. However, the use of gas-phase estimates of atomic polarizabilities alphai usually leads to overpolarization in condensed-phase systems. In the current work, a combined QM/MM approach has been employed to obtain condensed-phase estimates of atomic polarizabilities for water and methanol (QM) solutes in the presence of (MM) solvents of different polarity. In a next step, the validity of the linear response and isotropy assumptions were evaluated based on the observed condensed phase distributions of alphai values. The observed anisotropy and low average values for the polarizability of methanol's carbon atom in polar solvents was explained in terms of strong solute-solvent interactions involving its adjacent hydroxyl group. Our QM/MM estimates for atomic polarizabilities were found to be close to values used in previously reported polarizable water and methanol models. Using our estimate for alphaO of methanol, a single set of polarizable force field parameters was obtained that is directly transferable between environments of different polarity. PMID- 26593026 TI - Characterization of Protein Conformational Changes with Sparse Spin-Label Distance Constraints. AB - The combination of site-directed spin labeling with pulse EPR distance measurements can provide a moderate number of distance constraints on the nanometer length scale for proteins in different states. By adapting an existing algorithm (Zheng, W.; Brooks, B. R. Biophys. J. 2006, 90, 4327) to the problem, we address the question to what extent conformational change can be characterized when the protein structure is known for one of the states, whereas only a sparse set of distance constraints between spin labels is available for the other state. We find that the type and general direction of the conformational change can be recognized, while the amplitude may be uncertain. PMID- 26593027 TI - Computational Study of the pKa Values of Potential Catalytic Residues in the Active Site of Monoamine Oxidase B. AB - Monoamine oxidase (MAO), which exists in two isozymic forms, MAO A and MAO B, is an important flavoenzyme responsible for the metabolism of amine neurotransmitters such as dopamine, serotonin, and norepinephrine. Despite extensive research effort, neither the catalytic nor the inhibition mechanisms of MAO have been completely understood. There has also been dispute with regard to the protonation state of the substrate upon entering the active site, as well as the identity of residues that are important for the initial deprotonation of irreversible acetylenic inhibitors, in accordance with the recently proposed mechanism. Therefore, in order to investigate features essential for the modes of action of MAO, we have calculated pKa values of three relevant tyrosine residues in the MAO B active site, with and without dopamine bound as the substrate (as well as the pKa of the dopamine itself in the active site). The calculated pKa values for Tyr188, Tyr398, and Tyr435 in the complex are found to be shifted upward to 13.0, 13.7, and 14.7, respectively, relative to 10.1 in aqueous solution, ruling out the likelihood that they are viable proton acceptors. The altered tyrosine pKa values could be rationalized as an interplay of two opposing effects: insertion of positively charged bulky dopamine that lowers tyrosine pKa values, and subsequent removal of water molecules from the active site that elevates tyrosine pKa values, in which the latter prevails. Additionally, the pKa value of the bound dopamine (8.8) is practically unchanged compared to the corresponding value in aqueous solution (8.9), as would be expected from a charged amine placed in a hydrophobic active site consisting of aromatic moieties. We also observed potentially favorable cation-pi interactions between the -NH3(+) group on dopamine and aromatic moieties, which provide a stabilizing effect to the charged fragment. Thus, we offer here theoretical evidence that the amine is most likely to be present in the active site in its protonated form, which is similar to the conclusion from experimental studies of MAO A (Jones et al. J. Neural Trans.2007, 114, 707-712). However, the free energy cost of transferring the proton from the substrate to the bulk solvent is only 1.9 kcal mol(-1), leaving open the possibility that the amine enters the chemical step in its neutral form. In conjunction with additional experimental and computational work, the data presented here should lead toward a deeper understanding of mechanisms of the catalytic activity and irreversible inhibition of MAO B, which can allow for the design of novel and improved MAO B inhibitors. PMID- 26593028 TI - Folding-Reaction Coupling in a Self-Cleaving Protein. AB - Backbone torsional strain has been implicated as a cause of rate enhancement in a class of autoprocessing proteins performing proteolysis and protein splicing. In the autoproteolytic protein domain SEA, folding and proteolytic activity have experimentally been shown to be coupled with about 7 kcal/mol of folding free energy available for catalysis. Here, we have examined the catalytic strategy of SEA with molecular dynamics simulations, potential of mean force free energy profiles, and B3LYP/6-311G(d,p) density functional calculations. A quantitative estimate of the free energy stored as protein strain (about 8 kcal/mol), that is available for catalyzing the cleavage reaction, is obtained and found to be in excellent agreement with thermodynamic and kinetic data. It is further shown that there is strong coupling between folding and reaction coordinates leading to reactant state destabilization in the direction of folding and transition state stabilization along the reaction coordinate. This situation is different from the preorganized active site model in that the fully folded transition state stabilizing structure is not realized until the reaction barrier is surmounted. PMID- 26593029 TI - Mixing Atomistic and Coarse Grain Solvation Models for MD Simulations: Let WT4 Handle the Bulk. AB - Accurate simulation of biomolecular systems requires the consideration of solvation effects. The arrangement and dynamics of water close to a solute are strongly influenced by the solute itself. However, as the solute-solvent distance increases, the water properties tend to those of the bulk liquid. This suggests that bulk regions can be treated at a coarse grained (CG) level, while keeping the atomistic details around the solute. Since water represents about 80% of any biological system, this approach may offer a significant reduction in the computational cost of simulations without compromising atomistic details. We show here that mixing the popular SPC water model with a CG model for solvation (called WatFour) can effectively mimic the hydration, structure, and dynamics of molecular systems composed of pure water, simple electrolyte solutions, and solvated macromolecules. As a nontrivial example, we present simulations of the SNARE membrane fusion complex, a trimeric protein-protein complex embedded in a double phospholipid bilayer. Comparison with a fully atomistic reference simulation illustrates the equivalence between both approaches. PMID- 26593030 TI - Structure and Dynamics of Liquid Water from ab Initio Molecular Dynamics Comparison of BLYP, PBE, and revPBE Density Functionals with and without van der Waals Corrections. AB - We investigate the accuracy provided by different treatments of the exchange and correlation effects, in particular the London dispersion forces, on the properties of liquid water using ab initio molecular dynamics simulations with density functional theory. The lack of London dispersion forces in generalized gradient approximations (GGAs) is remedied by means of dispersion-corrected atom centered potentials (DCACPs) or damped atom-pairwise dispersion corrections of the C6R(-6) form. We compare results from simulations using GGA density functionals (BLYP, PBE, and revPBE) with data from their van der Waals (vdW) corrected counterparts. As pointed out previously, all vdW-corrected BLYP simulations give rise to highly mobile water whose softened structure is closer to experimental data than the one predicted by the bare BLYP functional. Including vdW interactions in the PBE functional, on the other hand, has little influence on both structural and dynamical properties of water. Augmenting the revPBE functional with either damped atom-pairwise dispersion corrections or DCACP evokes opposite behaviors. The former further softens the already under structured revPBE water, whereas the latter makes it more glassy. These results demonstrate the delicacy needed in describing weak interactions in molecular liquids. PMID- 26593031 TI - Hydrated Ionic Liquids with and without Solute: The Influence of Water Content and Protein Solutes. AB - In this computational study, the network of 1-ethyl-3-methylimidazolium trifluoromethanesulfonate/water mixtures is analyzed in the presence (and absence) of the protein ubiquitin and a zinc finger motif. Thereby, common radial distribution functions are decomposed into contributions from different Voronoi shells, and the mutual orientation of cations, anions, and water in the bulk phase as a function of the water mole fraction is discussed. Single particle translation and the reorientation of the dipolar axis seem to follow hydrodynamic relations. Using the body-fixed frame as an alternative reference system, translation and rotation can be decomposed into contributions along and about the axes of a well-defined orthogonal trihedron, thus elucidating the principal motions of the cations and anions as a function of the water mole fraction. The structural dipolar orientation may be correlated with single particle dynamics and can be characterized by the static collective Kirkwood order parameter. PMID- 26593032 TI - A GROMOS Parameter Set for Vicinal Diether Functions: Properties of Polyethyleneoxide and Polyethyleneglycol. AB - An extension 53A6OXY+D to the GROMOS 53A6OXY force field is reported that includes an accurate description of the vicinal diether function. The calibration is based on the model compound 1,2-dimethoxyethane (DXE) and involves a fitting of the relevant torsional-energy parameters against quantum-mechanical (QM) rotational energy profiles for the OCCO and CCOC dihedral angles in vacuum, followed by a validation against experimental conformer populations in the pure liquid and in aqueous mixtures. A systematic comparison between the 53A6, 56A6CARBO, 53A6OXY, and 53A6OXY+D parameter sets is also performed in terms of these properties, as well as in terms of the thermodynamic properties of dimethylether (DME), diethylether (DEE), 1-methoxypropane (MPH), and DXE. Finally, the new parameter set is further validated in the context of polyethers, namely polyethyleneoxide (PEO) and polyethylenegycol (PEG). The 53A6OXY+D set reproduces well the QM rotational profiles of DXE in vacuum (by calibration), the conformational populations of DXE in the pure liquid and in aqueous mixtures, and the experimental thermodynamic pure-liquid and (polar and nonpolar) solvation properties of DME, DEE, MPH, and DXE. In particular, it accounts appropriately for the gauche-effect, both in its solvent-independent stereoelectronic component and in its solvent-dependent dielectric-screening component. In contrast to 53A6OXY, it also suggests a higher affinity of DXE for water compared to octanol, in agreement with the experimental partition coefficient. In the context of aqueous polyethers, the calculated size (Flory) exponent (nug = 0.61) for the molecular-weight dependence of the radius of gyration and persistence length (Lp = 0.39 +/- 0.04 nm) agree well with estimates based on experiment or previous simulations with other force fields. The simulations also suggest a picture of aqueous polyethers as "water sponges", in which the diether function "adsorbs" an essentially constant number of water molecules corresponding to first-shell hydrogen-bonded saturation of its oxygen atoms, with a tendency to include other ether oxygen atoms along the chain in the second shell, resulting in "water bridging". PMID- 26593033 TI - The Effect of Environment on the Structure of a Membrane Protein: P-Glycoprotein under Physiological Conditions. AB - The stability of the crystal structure of the multidrug transporter P glycoprotein proposed by Aller et al. (PDBid 3G5U ) has been examined under different environmental conditions using molecular dynamics. We show that in the presence of the detergent cholate, the structure of P-glycoprotein solved at pH 7.5 is stable. However, when incorporated into a cholesterol-enriched POPC membrane in the presence of 150 mM NaCl, the structure rapidly deforms. Only when the simulation conditions closely matched the experimental conditions under which P-glycoprotein is transport active was a stable conformation obtained. Specifically, the presence of Mg(2+), which bound to distinct sites in the nucleotide binding domains (NBDs), and the double protonation of the catalytic histidines (His583 and His1228) and His149 were required. While the structure obtained in a membrane environment under these conditions is very similar to the crystal structure of Aller et al., there are several key differences. The NBDs are in direct contact, reminiscent of the open state of MalK. The angle between the transmembrane domains is also increased, resulting in an outward motion of the intracellular loops. Notably, the structures obtained from the simulations provide a better match to a range of experimental cross-linking data than does the original 3G5U-a crystal structure. This work highlights the effect small changes in environmental conditions can have of the conformation of a membrane protein and the importance of representing the experimental conditions appropriately in modeling studies. PMID- 26593034 TI - Impact of lifestyle-related disease on conversion and reversion in patients with mild cognitive impairment: after 12 months of follow-up. AB - OBJECTIVE: The objective of the study is to investigate whether the lifestyle related disease (LSRD) hypertension, type II diabetes mellitus, and lipid abnormality are associated with conversion and reversion in patients with mild cognitive impairment (MCI) over 12 months of follow-up. METHODS: One hundred and thirteen patients with MCI were prospectively enrolled and longitudinally assessed. Methods used include mini-mental state examination, the Japanese version of the cognitive subscale of the Alzheimer's Disease Assessment Scale, the Clinical Dementia Rating, the Frontal Assessment Battery, the Neuropsychiatric Inventory, magnetic resonance imaging, and quantitative single photon emission computed tomography. In addition, laboratory examinations of glucose and lipids were also performed. All measurements were performed at first intake and again at the end of the 12-month follow-up. Conversion was identified as a change in Clinical Dementia Rating from 0.5 to 1 and reversion as a change from 0.5 to 0. RESULTS: Patients with MCI with reversion had lower comorbid lipid abnormality at baseline and higher cognitive and behaviour function across the 12 month follow-up compared with those with no change or conversion. Patients without comorbid LSRD had lower systolic pressure and lower glucose and triglyceride levels at baseline, as well as less cognitive decline compared with other groups across the follow-up period. CONCLUSIONS: The absence of lipid abnormality at baseline may contribute to reversion in patients with MCI. The presence of multiple LSRD was associated with cognitive decline. Our results highlight the contribution of multiple LSRD on increasing conversion and decreasing reversion in patients with MCI. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26593035 TI - Tunable zero-field ferromagnetic resonance frequency from S to X band in oblique deposited CoFeB thin films. AB - Tunable zero-field ferromagnetic resonance frequency in wide range is very useful for the application of microwave devices. We performed an investigation of the static and high frequency magnetic properties for oblique sputtered CoFeB thin films. The static magnetic results revealed that oblique sputtered CoFeB thin films possess well defined in-plane uniaxial magnetic anisotropy, which increases monotonically from 50.1 to 608.8 Oe with the increasing of deposition angle from 10 degrees to 70 degrees . Continuous modification of the resonance frequency of CoFeB thin films in a range of 2.83-9.71 GHz (covers three microwave bands including S, C and X bands) has been achieved. This behavior can be explained as the result of the microstructure due to the self-shadowing effect mainly. These CoFeB thin films with tunable magnetic properties may be good candidates for usage in microwave devices. PMID- 26593037 TI - Effect of Chicoric Acid on Mast Cell-Mediated Allergic Inflammation in Vitro and in Vivo. AB - Chicoric acid (dicaffeoyl-tartaric acid), is a natural phenolic compound found in a number of plants, such as chicory (Cichorium intybus) and Echinacea (Echinacea purpurea), which possesses antioxidant, anti-inflammatory, antiviral, and analgesic activities. Although these biological effects of chicoric acid have been investigated, there are no reports of its antiallergic-related anti inflammatory effects in human mast cells (HMC)-1 or anaphylactic activity in a mouse model. Therefore, we investigated the antiallergic-related anti inflammatory effect of chicoric acid and its underlying mechanisms of action using phorbol-12-myristate 13-acetate plus calcium ionophore A23187 (PMACI) stimulated HMC-1 cells. Chicoric acid decreased the mRNA expression of pro inflammatory cytokines, such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-1beta. We studied the inhibitory effects of chicoric acid on the nuclear translocation of nuclear factor kappa B (NF-kappaB) and activation of caspase-1. However, mitogen-activated protein kinase (MAPK) activation was not sufficient to abrogate the stimulus. In addition, we investigated the ability of chicoric acid to inhibit compound 48/80-induced systemic anaphylaxis in vivo. Oral administration of chicoric acid at 20 mg/kg inhibited histamine release and protected mice against compound 48/80-induced anaphylactic mortality. These results suggest that chicoric acid has an antiallergic-related anti-inflammatory effect that involves modulating mast cell-mediated allergic responses. Therefore, chicoric acid could be an efficacious agent for allergy-related inflammatory disorders. PMID- 26593036 TI - The activity of protein phosphatase 5 towards native clients is modulated by the middle- and C-terminal domains of Hsp90. AB - Protein phosphatase 5 is involved in the regulation of kinases and transcription factors. The dephosphorylation activity is modulated by the molecular chaperone Hsp90, which binds to the TPR-domain of protein phosphatase 5. This interaction is dependent on the C-terminal MEEVD motif of Hsp90. We show that C-terminal Hsp90 fragments differ in their regulation of the phosphatase activity hinting to a more complex interaction. Also hydrodynamic parameters from analytical ultracentrifugation and small-angle X-ray scattering data suggest a compact structure for the Hsp90-protein phosphatase 5 complexes. Using crosslinking experiments coupled with mass spectrometric analysis and structural modelling we identify sites, which link the middle/C-terminal domain interface of C. elegans Hsp90 to the phosphatase domain of the corresponding kinase. Studying the relevance of the domains of Hsp90 for turnover of native substrates we find that ternary complexes with the glucocorticoid receptor (GR) are cooperatively formed by full-length Hsp90 and PPH-5. Our data suggest that the direct stimulation of the phosphatase activity by C-terminal Hsp90 fragments leads to increased dephosphorylation rates. These are further modulated by the binding of clients to the N-terminal and middle domain of Hsp90 and their presentation to the phosphatase within the phosphatase-Hsp90 complex. PMID- 26593038 TI - Design of a Nanostructured Active Surface against Gram-Positive and Gram-Negative Bacteria through Plasma Activation and in Situ Silver Reduction. AB - Nowadays there is an increasing focus for avoiding bacterial colonization in a medical device after implantation. Bacterial infection associated with prosthesis implantation, or even along the lifetime of the implanted prosthesis, entails a serious problem, emphasized with immunocompromised patients. This work shows a new methodology to create highly hydrophobic micro-/nanostructured silver antibacterial surfaces against Gram-positive and Gram-negative bacteria, using low-pressure plasma. PDMS (polydimethylsiloxane) samples, typically used in tracheal prosthesis, are coated with PFM (pentafluorophenyl methacrylate) through PECVD (plasma enhance chemical vapor deposition) technique. PFM thin films offer highly reactive ester groups that allow them to react preferably with amine bearing molecules, such as amine sugar, to create controlled reductive surfaces capable of reducing silver salts to a nanostructured metallic silver. This micro /nanostructured silver coating shows interesting antibacterial properties combined with an antifouling behavior causing a reduction of Gram-positive and Gram-negative bacteria viability. In addition, these types of silver-coated samples show no apparent cytotoxicity against COS-7 cells. PMID- 26593039 TI - Iron-Catalyzed Direct Diazidation for a Broad Range of Olefins. AB - Reported herein is a new iron-catalyzed diastereoselective olefin diazidation reaction which occurs at room temperature (1-5 mol% of catalysts and d.r. values of up to >20:1). This method tolerates a broad range of both unfunctionalized and highly functionalized olefins, including those that are incompatible with existing methods. It also provides a convenient approach to vicinal primary diamines as well as other synthetically valuable nitrogen-containing building blocks which are difficult to obtain with alternative methods. Preliminary mechanistic studies suggest that the reaction may proceed through a new mechanistic pathway in which both Lewis acid activation and iron-enabled redox catalysis are crucial for selective azido-group transfer. PMID- 26593040 TI - Towards plant pangenomics. AB - As an increasing number of genome sequences become available for a wide range of species, there is a growing understanding that the genome of a single individual is insufficient to represent the gene diversity within a whole species. Many studies examine the sequence diversity within genes, and this allelic variation is an important source of phenotypic variation which can be selected for by man or nature. However, the significant gene presence/absence variation that has been observed within species and the impact of this variation on traits is only now being studied in detail. The sum of the genes for a species is termed the pangenome, and the determination and characterization of the pangenome is a requirement to understand variation within a species. In this review, we explore the current progress in pangenomics as well as methods and approaches for the characterization of pangenomes for a wide range of plant species. PMID- 26593041 TI - Development of a BR-UASB-DHS system for natural rubber processing wastewater treatment. AB - Natural rubber processing wastewater contains high concentrations of organic compounds, nitrogen, and other contaminants. In this study, a treatment system composed of a baffled reactor (BR), an upflow anaerobic sludge blanket (UASB) reactor, and a downflow hanging sponge (DHS) reactor was used to treat natural rubber processing wastewater in Vietnam. The BR showed good total suspended solids removal of 47.6%, as well as acidification of wastewater. The UASB reactor achieved a high chemical oxygen demand (COD) removal efficiency of 92.7% +/- 2.3% and energy recovery in the form of methane with an organic loading rate of 12.2 +/- 6.6 kg-COD.m-3.day-1. The DHS reactor showed a high performance in residual organic matter removal from UASB effluent. In total, the system achieved high level total COD removal of 98.6% +/- 1.2% and total suspended solids removal of 98.0% +/- 1.4%. Massive parallel 16S rRNA gene sequencing of the retained sludge in the UASB reactor showed the predominant microbial phyla to be Bacteroidetes, Firmicutes, Proteobacteria, WWE1, and Euryarchaeota. Uncultured bacteria belonging to the phylum Bacteroidetes and Phylum WWE1 were predominant in the UASB reactor. This microbial assemblage utilizes the organic compounds contained in natural rubber processing wastewater. In addition, the methane-producing archaea Methanosaeta sp. and Methanolinea sp. were detected. PMID- 26593042 TI - Transcatheter Closure of Atrial Septal Defect with Attenuated Anterior Rim after Transcatheter Aortic Valve Implantation: Can It Be Carried out as a Single Procedure? AB - Transcatheter aortic valve replacement (TAVR) has emerged as a highly effective minimally invasive treatment for symptomatically critical aortic stenosis (AS) in patients at high or prohibitive surgical risk. We report a case of staged transcatheter management of critical AS combined with an atrial septal defect (ASD) with attenuated anterior superior rim. The clinical result of this case suggests that both procedures can be safely performed simultaneously. Therefore, combined transcatheter treatment may appear as a possible strategy in patients with concomitant cardiac conditions. PMID- 26593044 TI - Synthesis of two distinct pyrrole moiety-containing arenes from nitroanilines using Paal-Knorr followed by an indium-mediated reaction. AB - Synthesis of arenes substituted with two differently substituted-pyrrole moieties was investigated. A Paal-Knorr condensation reaction of nitroanilines with 1,4 diketone to nitrophenyl-1H-pyrroles followed by an indium-mediated reduction triggered coupling reaction with another kind of 1,4-diketone resulted in two distinct pyrrole-containing arenes, variously substituted 1-((1H-pyrrol-1 yl)phenyl)-1H-pyrroles, in reasonable yield. PMID- 26593045 TI - Cold/hot pad differentiating assay of property differences of Mahuang and Maxingshigan decoctions. AB - CONTEXT: Chinese medicines with different cold/hot properties have various pharmacological actions on multiple organisms. OBJECTIVE: The objective of this study was to explore the cold/hot property differences of traditional Chinese medicine formulas of Mahuang and Maxingshigan decoctions. MATERIALS AND METHODS: A novel cold/hot pad differentiating assay method based on the Intelligent Animal Temperature Tropism Behavior monitoring system at 20 degrees C (cold pad) and 30 degrees C (hot pad) was introduced to investigate the variability of temperature tropism among the mice treated by 0.4 mL/20 g (drug volume/body weight) of Mahuang decoction and Maxingshigan decoction, respectively. Meanwhile, the oxygen consumption and activities of adenosine triphosphatase (ATPase) were measured to explore the energy metabolism mechanism. RESULTS: Results showed that the differences between cold/hot properties of Mahuang decoction and Maxingshigan decoction were significant (p < 0.05). Mahuang decoction produced significant synergic effect (a combination index of 1.60), while Maxingshigan decoction expressed significant antagonistic effect (a combination index of 0.35). The changes of energy metabolism including ATPase activity and oxygen consumption might be the possible factors to result in the differences. Those influences tended to be coherent with the definition of cold/hot properties of Chinese medicines based on traditional Chinese medicinal theory. CONCLUSIONS: The results indicated that the method based on cold/hot pad differentiating array could objectively and quantitatively represent the cold/hot properties of different compatibilities of traditional Chinese medicines in an ethological way according to the changes of animal's temperature tropism. These findings would provide some experimental basis and data references as well as a novel evaluation method for the study of the regularity of recipe composition. PMID- 26593043 TI - Dead-end intermediates in the enterobacterial common antigen pathway induce morphological defects in Escherichia coli by competing for undecaprenyl phosphate. AB - Bacterial morphology is determined primarily by the architecture of the peptidoglycan (PG) cell wall, a mesh-like layer that encases the cell. To identify novel mechanisms that create or maintain cell shape in Escherichia coli, we used flow cytometry to screen a transposon insertion library and identified a wecE mutant that altered cell shape, causing cells to filament and swell. WecE is a sugar aminotransferase involved in the biosynthesis of enterobacterial common antigen (ECA), a non-essential outer membrane glycolipid of the Enterobacteriaceae. Loss of wecE interrupts biosynthesis of ECA and causes the accumulation of the undecaprenyl pyrophosphate-linked intermediate ECA-lipid II. The wecE shape defects were reversed by: (i) preventing initiation of ECA biosynthesis, (ii) increasing the synthesis of the lipid carrier undecaprenyl phosphate (Und-P), (iii) diverting Und-P to PG synthesis or (iv) promoting Und-P recycling. The results argue that the buildup of ECA-lipid II sequesters part of the pool of Und-P, which, in turn, adversely affects PG synthesis. The data strongly suggest there is competition for a common pool of Und-P, whose proper distribution to alternate metabolic pathways is required to maintain normal cell shape in E. coli. PMID- 26593047 TI - Enantioselective [4+4] photodimerization of anthracene-2,6-dicarboxylic acid mediated by a C2-symmetric chiral template. AB - A chiral template was constructed from 7-ethynyl-1,5,7-trimethyl-3 azabicyclo[3.3.1]nonan-2-one by Sonogashira cross-coupling with 4,4'' diiodoterphenyl and was shown to bind the title compound strongly by hydrogen bonding resulting in enantioselectivities of up to 55% enantiomeric excess (ee) in the [4+4] anthracene photodimerization. PMID- 26593048 TI - The total synthesis and stereochemical assignment of scytonemin A. AB - The total synthesis of scytonemin A and its C-9 epimer, as well as elucidation of the absolute stereochemistry of natural scytonemin A is described. PMID- 26593049 TI - Gene therapy for human osteoarthritis: principles and clinical translation. AB - INTRODUCTION: Osteoarthritis (OA) is the most prevalent chronic joint disease. Its key feature is a progressive articular cartilage loss. Gene therapy for OA aims at delivering gene-based therapeutic agents to the osteoarthritic cartilage, resulting in a controlled, site-specific, long-term presence to rebuild the damaged cartilage. AREAS COVERED: An overview is provided of the principles of gene therapy for OA based on a PubMed literature search. Gene transfer to normal and osteoarthritic cartilage in vitro and in animal models in vivo is reviewed. Results from recent clinical gene therapy trials for OA are discussed and placed into perspective. EXPERT OPINION: Recombinant adeno-associated viral (rAAV) vectors enable to directly transfer candidate sequences in human articular chondrocytes in situ, providing a potent tool to modulate the structure of osteoarthritic cartilage. However, few preclinical animal studies in OA models have been performed thus far. Noteworthy, several gene therapy clinical trials have been carried out in patients with end-stage knee OA based on the intraarticular injection of human juvenile allogeneic chondrocytes overexpressing a cDNA encoding transforming growth factor-beta-1 via retroviral vectors. In a recent placebo-controlled randomized trial, clinical scores were improved compared with placebo. These translational results provide sufficient reason to proceed with further clinical testing of gene transfer protocols for the treatment of OA. PMID- 26593050 TI - Native Point Defects in CaS: Focus on Intrinsic Defects and Rare Earth Ion Dopant Levels for Up-converted Persistent Luminescence. AB - We studied native point defects as well as Eu and Dy ion doping in CaS by the simple DFT + Hubbard U method. The electronic properties and formation energies of native point defects and dopants have been discussed. We found the neutral S vacancy has the lowest energy of 0.62 eV under the Ca-rich limit. The Schottky pair is another dominant defect with a cost of 1.51 eV per defect site from S rich to Ca-rich chemical potential limits. Our calculations on the thermodynamic transition levels confirm the experimental observed intrinsic blue two-peak broad band emissions stimulated by near-infrared range irradiation for undoped CaS. Both Eu and Dy show an energetic favorable trend to be substitutionally doped in the CaS lattice. All of the positive charge states of the Eu ion contribute localized recombination trapping level in the gap while having very deep donor transition levels. The neutral state of Dy contributes to the occupied 4f level localized 1.3 eV below the conduction band edge with very shallow donor type transition level (0/+) of 0.56 eV below the conduction band. All of the positive charge states of Dy have two shallow 5d levels with 0.4 and 0.6 eV below the conduction band. In this work, we further analyzed that the Dy dopant contributed deeper trap levels in the CaS materials that can store the electron carriers with more evenly, wider, and deeper range of levels distributed so that they lengthen the decay-time of the persistent luminescence. The related 980 nm photo stimulated luminescence is actualized with the help of native defects like VS(0), VS(+), and STK(-) as relay centers for a possible up-converted luminescence. We also summarized a narrow doping limit energy which has been determined as 1.33 eV constantly in CaS independent to different chemical potential limits. This gives a solid theoretical reference for lanthanide ion doping experiments in CaS. PMID- 26593051 TI - Single molecule magnet behavior observed in a 1-D dysprosium chain with quasi-D5h symmetry. AB - Two one-dimensional (1-D) chain complexes with pentagonal bipyramidal Dy(III) centers have been synthesized and magnetically characterized. Field-induced single molecule magnet behavior has been revealed in both compounds, which is still rarely reported in a lanthanide compound with a pentagonal bipyramidal coordination geometry. Their crystal field parameters and orientations of the magnetic easy axes were obtained from the simulation of the magnetic data and the electrostatic model calculation. PMID- 26593052 TI - Spiritual care in the training of hospice volunteers in Germany. AB - OBJECTIVE: Hospice volunteers often encounter questions related to spirituality. It is unknown whether spiritual care receives a corresponding level of attention in their training. Our survey investigated the current practice of spiritual care training in Germany. METHOD: An online survey sent to 1,332 hospice homecare services for adults in Germany was conducted during the summer of 2012. We employed the SPSS 21 software package for statistical evaluation. RESULTS: All training programs included self-reflection on personal spirituality as obligatory. The definitions of spirituality used in programs differ considerably. The task of defining training objectives is randomly delegated to a supervisor, a trainer, or to the governing organization. More than half the institutions work in conjunction with an external trainer. These external trainers frequently have professional backgrounds in pastoral care/theology and/or in hospice/palliative care. While spiritual care receives great attention, the specific tasks it entails are rarely discussed. The response rate for our study was 25.0% (n = 332). SIGNIFICANCE OF RESULTS: A need exists to develop training concepts that outline distinct contents, methods, and objectives. A prospective curriculum would have to provide assistance in the development of training programs. Moreover, it would need to be adaptable to the various concepts of spiritual care employed by the respective institutions and their hospice volunteers. PMID- 26593053 TI - Moving graphene devices from lab to market: advanced graphene-coated nanoprobes. AB - After more than a decade working with graphene there is still a preoccupying lack of commercial devices based on this wonder material. Here we report the use of high-quality solution-processed graphene sheets to fabricate ultra-sharp probes with superior performance. Nanoprobes are versatile tools used in many fields of science, but they can wear fast after some experiments, reducing the quality and increasing the cost of the research. As the market of nanoprobes is huge, providing a solution for this problem should be a priority for the nanotechnology industry. Our graphene-coated nanoprobes not only show enhanced lifetime, but also additional unique properties of graphene, such as hydrophobicity. Moreover, we have functionalized the surface of graphene to provide piezoelectric capability, and have fabricated a nano relay. The simplicity and low cost of this method, which can be used to coat any kind of sharp tip, make it suitable for the industry, allowing production on demand. PMID- 26593054 TI - Zigzag-edge related ferromagnetism in MoSe2 nanoflakes. AB - Outstanding magnetic properties are highly desired for two-dimensional ultrathin semiconductor nanosheets for their potential applications in nano-electronics and spintronics. Here, ultrathin MoSe2 nanoflakes with plenty of edges were prepared via an efficient chemical vapor deposition method. The magnetic measurement results indicate that the sample exhibits strong ferromagnetic behaviour with a saturation magnetization of 1.4 emu g(-1) at room temperature, where the ferromagnetism persists up to 700 K, revealing the high Curie temperature of this material. Density functional theory spin-polarized calculations predict that strong ferromagnetic moments in MoSe2 nanoflakes are attributed to the zigzag edges. Our findings also suggest that the MoSe2 nanoflakes with a high density of edge spins could be used to fabricate spintronic devices, which are circuits utilizing the spin of the electron to process and store information. PMID- 26593055 TI - Voice pedagogy-what do we need? AB - The final keynote panel of the 10th Pan-European Voice Conference (PEVOC) was concerned with the topic 'Voice pedagogy-what do we need?' In this communication the panel discussion is summarized, and the authors provide a deepening discussion on one of the key questions, addressing the roles and tasks of people working with voice students. In particular, a distinction is made between (1) voice building (derived from the German term 'Stimmbildung'), primarily comprising the functional and physiological aspects of singing; (2) coaching, mostly concerned with performance skills; and (3) singing voice rehabilitation. Both public and private educators are encouraged to apply this distinction to their curricula, in order to arrive at more efficient singing teaching and to reduce the risk of vocal injury to the singers concerned. PMID- 26593056 TI - Experiments and Model for Serration Statistics in Low-Entropy, Medium-Entropy, and High-Entropy Alloys. AB - High-entropy alloys (HEAs) are new alloys that contain five or more elements in roughly-equal proportion. We present new experiments and theory on the deformation behavior of HEAs under slow stretching (straining), and observe differences, compared to conventional alloys with fewer elements. For a specific range of temperatures and strain-rates, HEAs deform in a jerky way, with sudden slips that make it difficult to precisely control the deformation. An analytic model explains these slips as avalanches of slipping weak spots and predicts the observed slip statistics, stress-strain curves, and their dependence on temperature, strain-rate, and material composition. The ratio of the weak spots' healing rate to the strain-rate is the main tuning parameter, reminiscent of the Portevin-LeChatellier effect and time-temperature superposition in polymers. Our model predictions agree with the experimental results. The proposed widely applicable deformation mechanism is useful for deformation control and alloy design. PMID- 26593059 TI - Assessing the impact of removal scenarios on population viability of a threatened, long-lived avian scavenger. AB - The removal of eggs or chicks from wild populations to create captive populations, reinforce free-ranging populations or reintroduce species into the wild is a restoration tool that requires an assessment of potential detrimental effects upon the donor population. This is an absolute prerequisite when wild donor populations are scarce and small. Here, we forecast the population trend of the largest European population of the bearded vulture (Gypaetus barbatus) over the next 30 years under different demographic and management scenarios (removal of eggs, chicks or fledglings). Projections derived from the combination of a PDP model (Population Dynamic P-system) and a Box-Behnken design would lead to a decline in 77% of all 57 scenarios analysed. Among the 13 scenarios predicting a population increase, only 4 seem realistic in terms of growth rate (0.04%-1.01%), at least if current age at first breeding and productivity would remain constant over time. Our simulations thus suggest that most extraction scenarios would have detrimental effects on the demography of the donor population. Release of captive born young or removal of only the second hatched chick for subsequent captive rearing and translocation into the wild appear to represent much better supplementation and reintroduction options in this threatened species. PMID- 26593060 TI - eIF5A1/RhoGDIalpha pathway: a novel therapeutic target for treatment of spinal cord injury identified by a proteomics approach. AB - Spinal cord injury (SCI) is frequently accompanied by a degree of spontaneous functional recovery. The underlying mechanisms through which such recovery is generated remain elusive. In this study, we observed a significant spontaneous motor function recovery 14 to 28 days after spinal cord transection (SCT) in rats. Using a comparative proteomics approach, caudal to the injury, we detected difference in 20 proteins. Two of these proteins, are eukaryotic translation initiation factor 5A1 (eIF5A1) that is involved in cell survival and proliferation, and Rho GDP dissociation inhibitor alpha (RhoGDIalpha), a member of Rho GDI family that is involved in cytoskeletal reorganization. After confirming the changes in expression levels of these two proteins following SCT, we showed that in vivo eIF5A1 up-regulation and down-regulation significantly increased and decreased, respectively, motor function recovery. In vitro, eIF5A1 overexpression in primary neurons increased cell survival and elongated neurite length while eIF5A1 knockdown reversed these results. We found that RhoGDIalpha up-regulation and down-regulation rescues the effect of eIF5A1 down-regulation and up-regulation both in vivo and in vitro. Therefore, we have identified eIF5A1/RhoGDIalpha pathway as a new therapeutic target for treatment of spinal cord injured patients. PMID- 26593061 TI - Surveillance of antenatal influenza vaccination: validity of current systems and recommendations for improvement. AB - BACKGROUND: Although influenza vaccination is recommended during pregnancy as standard of care, limited surveillance data are available for monitoring uptake. Our aim was to evaluate the validity of existing surveillance in Western Australia for measuring antenatal influenza immunisations. METHODS: The self reported vaccination status of 563 women who delivered between April and October 2013 was compared against three passive data collection sources: a state-wide antenatal influenza vaccination database maintained by the Department of Health, a public maternity hospital database, and a private health service database. Sensitivity, specificity, and positive and negative predictive values were calculated for each system using self-report as the "gold standard." RESULTS: The state-wide antenatal vaccination database detected 45.7 % (95 % CI: 40.1-51.4 %) of influenza vaccinations, the public maternity hospital database detected 66.7 % (95 % CI: 55.1-76.9 %), and the private health service database detected 29.1 % (95 % CI: 20.5-39.4 %). Specificity exceeded 90 % and positive predictive values exceeded 80 % for each system. Sensitivity was lowest for women whose antenatal care was provided by a private obstetrician. CONCLUSIONS: Existing resources for surveillance of antenatal influenza vaccinations detect 29-67 % of vaccinations. Considering the importance of influenza immunisation as a public health intervention, particularly in pregnant women, improvements to routine monitoring of influenza vaccination is warranted. PMID- 26593062 TI - Structure-Activity Relationship Studies of Amino Acid Substitutions in Radiolabeled Neurotensin Conjugates. AB - Radiolabeled derivatives of the peptide neurotensin (NT) and its binding sequence NT(8-13) have been studied as potential imaging probes and therapeutics for NT-1 receptor-positive cancer. However, a direct comparison of reported NT analogues, even if radiolabeled with the same radionuclide, is difficult because different techniques and models have been used for preclinical evaluations. In an effort to identify a suitable derivative of NT(8-13) for radiotracer development, we herein report a side-by-side in vitro comparison of radiometallated NT derivatives bearing some of the most commonly reported amino acid substitutions in their sequence. Performed investigations include cell internalization experiments, determinations of receptor affinity, measurements of the distribution coefficient, and blood serum stability studies. Of the [(177)Lu]-1,4,7,10 tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-labeled examples studied, analogues of NT(8-13) containing a short hydrophilic tetraethylene glycol (PEG4 ) spacer between the peptide and the radiometal complex, and a minimum number of substitutions of amino acid residues, exhibited the most promising properties in vitro. PMID- 26593063 TI - High-Mannose Specific Lectin and Its Recombinants from a Carrageenophyta Kappaphycus alvarezii Represent a Potent Anti-HIV Activity Through High-Affinity Binding to the Viral Envelope Glycoprotein gp120. AB - We previously reported that a high-mannose binding lectin KAA-2 from the red alga Kappaphycus alvarezii, which is an economically important species and widely cultivated as a source of carrageenans, had a potent anti-influenza virus activity. In this study, the full-length sequences of two KAA isoforms, KAA-1 and KAA-2, were elucidated by a combination of peptide mapping and complementary DNA (cDNA) cloning. They consisted of four internal tandem-repeated domains, which are conserved in high-mannose specific lectins from lower organisms, including a cyanobacterium Oscillatoria agardhii and a red alga Eucheuma serra. Using an Escherichia coli expression system, an active recombinant form of KAA-1 (His tagged rKAA-1) was successfully generated in the yield of 115 mg per liter of culture. In a detailed oligosaccharide binding analysis by a centrifugal ultrafiltration-HPLC method with 27 pyridylaminated oligosaccharides, His-tagged rKAA-1 and rKAA-1 specifically bound to high-mannose N-glycans with an exposed alpha1-3 mannose in the D2 arm as the native lectin did. Predicted from oligosaccharide binding specificity, a surface plasmon resonance analysis revealed that the recombinants exhibit strong interaction with gp120, a heavily glycosylated envelope glycoprotein of HIV with high association constants (1.48 - 1.61 * 10(9) M(-1)). Native KAAs and the recombinants inhibited the HIV-1 entry at IC50s of low nanomolar levels (7.3-12.9 nM). Thus, the recombinant proteins would be useful as antiviral reagents targeting the viral surface glycoproteins with high-mannose N-glycans, and the cultivated alga K. alvarezii could also be a good source of not only carrageenans but also this functional lectin(s). PMID- 26593064 TI - Quantitative Selection Analysis of Bacteriophage phiCbK Susceptibility in Caulobacter crescentus. AB - Classical molecular genetics uses stringent selective conditions to identify mutants with distinct phenotypic responses. Mutations giving rise to less pronounced phenotypes are often missed. However, to gain systems-level insights into complex genetic interaction networks requires genome-wide assignment of quantitative phenotypic traits. In this paper, we present a quantitative selection approach coupled with transposon sequencing (QS-TnSeq) to globally identify the cellular components that orchestrate susceptibility of the cell cycle model bacterium Caulobacter crescentus toward bacteriophage phiCbK infection. We found that 135 genes representing 3.30% of the Caulobacter genome exhibit significant accumulation of transposon insertions upon phiCbK selection. More than 85% thereof consist of new factors not previously associated with phage phiCbK susceptibility. Using hierarchical clustering of dose-dependent TnSeq datasets, we grouped these genes into functional modules that correlate with different stages of the phiCbK infection process. We assign phiCbK susceptibility to eight new genes that represent novel components of the pilus secretion machinery. Further, we demonstrate that, from 86 motility genes, only seven genes encoding structural and regulatory components of the flagellar hook increase phage resistance when disrupted by transposons, suggesting a link between flagellar hook assembly and pili biogenesis. In addition, we observe high recovery of Tn5 insertions within regulatory sequences of the genes encoding the essential NADH:ubiquinone oxidoreductase complex indicating that intact proton motive force is crucial for effective phage propagation. In sum, QS-TnSeq is broadly applicable to perform quantitative and genome-wide systems-genetics analysis of complex phenotypic traits. PMID- 26593065 TI - Carpal tunnel and median nerve volume changes after tunnel release in patients with the carpal tunnel syndrome: a magnetic resonance imaging (MRI) study. AB - PURPOSE: Our aim was to study the dynamics of the post-surgical canal and nerve volumes and their relationships to objective [electromyoneurography (EMNG)] and subjective (pain) outcomes. METHODS: Forty-seven patients with carpal tunnel syndrome (CTS) (median age 52, range 23-75 years) with a prominent narrowing of the median nerve within the canal (observed during carpal tunnel release) were evaluated clinically using EMNG and magnetic resonance imagining (MRI) before and at 90 and 180 days post-surgery. RESULTS: Canal and nerve volumes increased, EMNG findings improved and pain resolved during the follow-up. Increase in tunnel volume was independently associated with increased nerve volume. A greater post surgical nerve volume was independently associated with a more prominent resolution of pain, but not with the extent of EMNG improvement, whereas EMNG improvement was not associated with pain resolution. CONCLUSIONS: Data confirm that MRI can detect even modest changes in the carpal tunnel and median nerve volume and that tunnel release results in tunnel and nerve-volume increases that are paralleled by EMNG and clinical improvements. Taken together, these observations suggest that MRI could be used to objectivise persistent post surgical difficulties in CTS patients. Level of evidence 3 (follow-up study). PMID- 26593067 TI - Comment on Roessler et al.: Short-term follow up after implantation of a cell free collagen type I matrix for the treatment of large cartilage defects of the knee. PMID- 26593066 TI - Long-term results of surgically treated calcaneal fractures: an analysis with a minimum follow-up period of twenty years. AB - PURPOSE: Long-term results after treatment of calcaneal fractures are rare. For this reason, we conducted a retrospective follow-up after a minimum of 20 years post surgery. METHODS: Between 1990 and 1994, a total of 66 patients received surgical treatment for displaced calcaneal fractures. At that time, osteosynthesis was performed using small, one-third tubular plates. After collecting empirical data, we conducted a follow-up at least 20 years post surgery using X-ray imaging and clinical questionnaires (AOFAS and SF-36 questionnaire). RESULTS: It was possible to recruit a total of 22/66 patients (33 %) after a mean of 22 years (range, 20-24) post surgery. With regard to the AOFAS scores (mean value, 74 points), 12 showed very good or good results, four showed average and six poor results. Patients with orthopaedic shoes also had low AOFAS scores. The Boehler's angle had been increased from +2 degrees prior to surgery to +21 degrees post-operatively. At the time of follow-up, the mean value was +17 degrees . The angle correlated with the AOFAS score. Also, the SF-36 physical score was clearly reduced when compared to a general population, and correlated significantly with the AOFAS score. CONCLUSION: There is still no evidence that open reduction and internal fixation of calcaneal fractures results in better outcomes than conservative therapy. This has been confirmed by our long-term results that provided disillusioning results: in a small population, only 55 % of the patients showed very good or good clinical overall results. Furthermore, SF 36 showed impaired physical subscores, which correlated significantly with the AOFAS. PMID- 26593068 TI - Space resource utilisation: a novel indicator to quantify species competitive ability for light. AB - Species richness and productivity are two fundamental aspects of ecosystems. As a result, the relationship between species richness and productivity has been widely studied. A series of fertilisation experiments in an alpine meadow on the Tibetan Plateau were performed to study the relationship between species richness and productivity. In this paper, we present a novel indicator, i.e., space resource utilisation (SRU), which is calculated by a volume formula (V(i) = h(i) . S(i); h(i) = plant height of species i, S(i) = quadrat area * percent cover of species i). SRU more fully reflected species competitive ability for light in both horizontal and vertical dimensions compared with plant height and cover. We used this novel indicator to investigate the effects of SRU on the changes in species richness and productivity following fertilisation. We found that the SRU of the community was correlated with increasing productivity and decreasing species richness following fertilisation and was a better predictor of species richness than productivity. The changes in SRU following fertilisation vary among species. These results demonstrate that SRU can be a more useful tool in explaining plant biodiversity loss and predicting the fate of different species than each of height, cover and productivity. PMID- 26593070 TI - Parthenogenetic reproduction demonstrated in the diploid Spasalus puncticollis (Le Peletier & Serville 1825), n. stat., from the Antilles (Coleoptera, Scarabaeoidea, Passalidae). AB - Only females were observed in Spasalus crenatus (Mac Leay 1819) in the Antilles, from Puerto Rico to Saint-Vincent, whereas both sexes are in Trinidad and on the continent. No difference in endo- and ectodermic female genitalia could be noticed between the two populations. Chromosomes of specimens from Guadeloupe reveal a 26,XX karyotype, as in females of various sexual species of Passalini, which demonstrates its diploidy. Breedings were developed with isolated immature stages. After nine years, descendants from a single female are demonstrating their parthenogenetic reproduction. This is the first recorded parthenogenesis in Passalidae and a rare telytoky in diploid insects. Relationships between parthenogenesis, diploidy and insularity are discussed in the scheme of geographical parthenogenesis. No discriminant morphological character on adults could be found between the two populations, except the total length. The modes of reproduction distinguishing the two geographically separated populations suggest the presence of two taxa: S. crenatus on the continent and Trinidad; the parthenote S. puncticollis (Le Peletier & Serville 1825), n. stat., on the Arc of the Antilles. PMID- 26593069 TI - Genotyping of Giardia duodenalis isolates in asymptomatic children attending daycare centre: evidence of high risk for anthroponotic transmission. AB - Giardia duodenalis is a common intestinal parasite infecting children attending daycare centres. This study aimed to verify Giardia occurrence and the genotypes of isolates infecting children aged 0-6 years and workers at a daycare centre in the state of Sao Paulo, Brazil. The families of children who tested positive for Giardia, were asked to provide stool samples from household members and their dogs. Samples (123 children, 14 centre employees, 44 household members, 19 children after treatment, and 20 dogs) were examined for intestinal parasites using concentration methods. DNA extracted from all samples was submitted for polymerase chain reaction (PCR) testing and the amplicons generated were used for multilocus sequence typing of beta-giardin (bg), triose phosphate isomerase (tpi) and glutamate dehydrogenase (gdh) genes. Giardia was detected in 15.9% and 28.6% of the 220 samples by microscopy and PCR, respectively. Analysis of sequences retrieved from 29 isolates revealed both assemblages A (31%) and B (69%). Sub assemblages AII, BIII and BIV were identified and the alignment of the bg, gdh and tpi sequences revealed the presence of some single nucleotide polymorphisms, especially in assemblage B sequences. The higher predominance of assemblage B and the identification of the AII type support the view that anthroponotic transmission appears to be an important route of transmission in environments that concentrate children at an age when poor hygiene practices make them more vulnerable to such infection. PMID- 26593071 TI - Cytoprotection of pancreatic beta-cells and hypoglycemic effect of 2 hydroxypropyl-beta-cyclodextrin: sertraline complex in alloxan-induced diabetic rats. AB - Sertraline, a selective inhibitor of serotonin reuptake, is widely used as antidepressant in diabetic patients for improvement of depression and glycemic control. Sertraline is poorly soluble in water, which limits its oral applicability. In this work we tried to improve the pharmaceutical properties of sertraline by complexation with 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD) and evaluated the efficacy of the HPbetaCD:sertraline complex in prevention of alloxan-induced lesions in rats. The solubility of sertraline increased in the presence of HPbetaCD and the association constant for sertraline and HPbetaCD was equal to 4000 +/- 1000 M(-1). Two-week treatment of diabetic animals with the HPbetaCD:sertraline complex improved pancreatic islet morphology and beta-cell survival, which, in turn, reduced the severity of diabetes, as evidenced by lowering of blood glucose and glycated hemoglobin contents as well as normalization of serum insulin level and insulin sensitivity (HOMA-IR). The effect of the HPbetaCD:sertraline complex was strongly expressed in comparison with the antidiabetic effect of both the monopreparations, HPbetaCD and sertraline. It is suggested that the cyclodextrin derivative increased the pharmacological effect of sertraline, probably due to enhanced drug bioavailability. PMID- 26593073 TI - Update on Molecular Biology of Lung Development--Transcriptomics. AB - This article highlights some of the significant advances in our understanding of lung developmental biology made over the last few years, which challenge existing paradigms and are relevant to a fundamental understanding of this process. Additional comments address how these new insights may be informative for chronic lung diseases that occur, or initiate, in the neonatal period. This is not meant to be an exhaustive review of the molecular biology of lung development. For a more comprehensive, contemporary review of the cellular and molecular aspects of lung development, readers can refer to recent reviews by others. PMID- 26593072 TI - GPI-AP release in cellular, developmental, and reproductive biology. AB - Glycosylphosphatidylinositol-anchored proteins (GPI-APs) contain a covalently linked GPI anchor located on outer cell membranes. GPI-APs are ubiquitously conserved from protozoa to vertebrates and are critical for physiological events such as development, immunity, and neurogenesis in vertebrates. Both membrane anchored and soluble GPI-APs play a role in regulating their protein conformation and functional properties. Several pathways mediate the release of GPI-APs from the plasma membrane by vesiculation or cleavage. Phospholipases and putative substrate-specific GPI-AP-releasing enzymes, such as NOTUM, glycerophosphodiesterase 2, and angiotensin-converting enzyme, have been characterized in mammals. Here, the protein modifications resulting from the cleavage of the GPI anchor are discussed in the context of its physiological functions. PMID- 26593074 TI - Postnatal Infections and Immunology Affecting Chronic Lung Disease of Prematurity. AB - Premature infants suffer significant respiratory morbidity during infancy with long-term negative consequences on health, quality of life, and health care costs. Enhanced susceptibility to a variety of infections and inflammation play a large role in early and prolonged lung disease following premature birth, although the mechanisms of susceptibility and immune dysregulation are active areas of research. This article reviews aspects of host-pathogen interactions and immune responses that are altered by preterm birth and that impact chronic respiratory morbidity in these children. PMID- 26593077 TI - Evidence-Based Pharmacologic Therapies for Prevention of Bronchopulmonary Dysplasia: Application of the Grading of Recommendations Assessment, Development, and Evaluation Methodology. AB - Bronchopulmonary dysplasia (BPD) is the most common chronic complication of extreme preterm birth. The authors applied the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology to pharmacologic therapies found to prevent BPD. Caffeine and vitamin A are the only medications shown in high-quality studies to prevent BPD without the risk of clinically important adverse effects. Dexamethasone is effective for the prevention of BPD; but for many infants, the increased risks of hypertrophic cardiomyopathy, gastrointestinal perforation, and cerebral palsy outweigh this benefit. Several medications are currently under investigation for the prevention of BPD, but few are novel agents. PMID- 26593075 TI - Role of Ureaplasma Respiratory Tract Colonization in Bronchopulmonary Dysplasia Pathogenesis: Current Concepts and Update. AB - Respiratory tract colonization with the genital mycoplasma species Ureaplasma parvum and Ureaplasma urealyticum in preterm infants is a significant risk factor for bronchopulmonary dysplasia (BPD). Recent studies of the ureaplasmal genome, animal infection models, and human infants have provided a better understanding of specific virulence factors, pathogen-host interactions, and variability in genetic susceptibility that contribute to chronic infection, inflammation, and altered lung development. This review provides an update on the current evidence supporting a causal role of ureaplasma infection in BPD pathogenesis. The current status of antibiotic trials to prevent BPD in Ureaplasma-infected preterm infants is also reviewed. PMID- 26593078 TI - Mechanical Ventilation and Bronchopulmonary Dysplasia. AB - Mechanical ventilation is an important potentially modifiable risk factor for the development of bronchopulmonary dysplasia. Effective use of noninvasive respiratory support reduces the risk of lung injury. Lung volume recruitment and avoidance of excessive tidal volume are key elements of lung-protective ventilation strategies. Avoidance of oxidative stress, less invasive methods of surfactant administration, and high-frequency ventilation are also important factors in lung injury prevention. PMID- 26593076 TI - Biomarkers, Early Diagnosis, and Clinical Predictors of Bronchopulmonary Dysplasia. AB - The pathogenesis of bronchopulmonary dysplasia (BPD) is multifactorial, and the clinical phenotype of BPD is extremely variable. Several clinical and laboratory biomarkers have been proposed for the early identification of infants at higher risk of BPD and for determination of prognosis of infants with a diagnosis of BPD. The authors review available literature on prediction tools and biomarkers of BPD, using clinical variables and biomarkers based on imaging, lung function measures, and measurements of various analytes in different body fluids that have been determined to be associated with BPD either in a targeted manner or by unbiased omic profiling. PMID- 26593079 TI - Impact of Nutrition on Bronchopulmonary Dysplasia. AB - Bronchopulmonary dysplasia (BPD) remains a common morbidity of prematurity. Although the pathogenesis of BPD is recognized to be both multifactorial and complex, the role of nutrition in the pathophysiology of BPD is typically limited to management after a diagnosis has been made. Infants born small for gestational age and those who experience postnatal growth failure are more likely to have BPD. Therapies for lung disease, such as fluid restriction, diuretics, and corticosteroids, can negatively impact postnatal growth. Future research is needed to optimize nutritional strategies in the neonatal intensive care unit and following hospital discharge. PMID- 26593080 TI - Oxygen Saturation Targeting and Bronchopulmonary Dysplasia. AB - Oxygen saturation targeting is widely used in neonatal intensive care, but the optimal target range in very preterm infants has been uncertain and is the subject of recent debate and research. This review briefly discusses the technology of oxygen monitoring and the role of oxygen toxicity in preterm infants. The background to the recent trials of oxygen saturation targeting in acute and continuing care of very preterm infants is reviewed, and the findings and implications of the recent trials, particularly with respect to bronchopulmonary dysplasia, are discussed. PMID- 26593081 TI - Hypoxic Episodes in Bronchopulmonary Dysplasia. AB - Hypoxic episodes are troublesome components of bronchopulmonary dysplasia (BPD) in preterm infants. Immature respiratory control seems to be the major contributor, superimposed on abnormal respiratory function. Relatively short respiratory pauses may precipitate desaturation and bradycardia. This population is predisposed to pulmonary hypertension; it is likely that pulmonary vasoconstriction also plays a role. The natural history has been well characterized in the preterm population at risk for BPD; however, the consequences are less clear. Proposed associations of intermittent hypoxia include retinopathy of prematurity, sleep disordered breathing, and neurodevelopmental delay. Future study should address whether these associations are causal relationships. PMID- 26593083 TI - Airway Disease and Management in Bronchopulmonary Dysplasia. AB - This article presents an overview of the diagnosis and management of airway problems encountered in infants with severe bronchopulmonary dysplasia (BPD). Respiratory failure in premature infants develops as a result of parenchymal and airway diseases. The survival of increasingly premature infants and the ventilatory support required by premature lungs may result in airway disease. The management of respiratory failure depends on whether it is primarily caused by parenchymal versus airway diseases. Continuous airway pressure early in the neonatal period has favorably changed the incidence of BPD. This article discusses the indications, timing, and guidelines for care of tracheotomy. PMID- 26593084 TI - Newer Imaging Techniques for Bronchopulmonary Dysplasia. AB - Imaging has played a vital role in the clinical assessment of bronchopulmonary dysplasia (BPD) since its first recognition. In this review, how chest radiograph, computerized tomography (CT), nuclear medicine, and MRI have contributed to the understanding of BPD pathology and how emerging advancements in these methods, including low-dose and quantitative CT, sophisticated proton and hyperpolarized-gas MRI, influence the future of BPD imaging are discussed. PMID- 26593082 TI - Pulmonary Hypertension and Vascular Abnormalities in Bronchopulmonary Dysplasia. AB - Despite advances in the care of preterm infants, these infants remain at risk bronchopulmonary dysplasia (BPD), which results in prolonged need for supplemental oxygen, recurrent respiratory exacerbations, and exercise intolerance. Recent investigations have highlighted the important contribution of the developing pulmonary circulation to lung development, showing that these infants are also at risk for pulmonary vascular disease (PVD), including pulmonary hypertension (PH) and pulmonary vascular abnormalities. Several epidemiologic studies have delineated the incidence of PH in preterm infants and the impact on outcomes. These studies have also highlighted gaps in the understanding of PVD in BPD. PMID- 26593085 TI - Bronchopulmonary Dysplasia and Chronic Lung Disease: Stem Cell Therapy. AB - Bronchopulmonary dysplasia (BPD), a major complication of premature birth, still lacks safe and effective treatment. Mesenchymal stem cells (MSCs) have been proven to ameliorate critical aspects of the BPD pathogenesis. MSCs seem to exert therapeutic effects through the paracrine secretion of anti-inflammatory, antioxidant, antiapoptotic, trophic, and proangiogenic factors. Although these findings are promising, understanding the mechanism of action of MSCs and MSC manufacturing is still evolving. Several aspects can affect the efficacy of MSC therapy. Further research is required to optimize this potentially game-changing treatment but the translation of regenerative cell therapies for patients has begun. PMID- 26593087 TI - Bronchopulmonary Dysplasia--The Search for Answers Continues. PMID- 26593088 TI - Why the Bronchopulmonary Dysplasia Improvement Curve Lags Behind. PMID- 26593086 TI - The Natural History of Bronchopulmonary Dysplasia: The Case for Primary Prevention. AB - Brochopulmonary dysplasia (BPD) is the most common form of chronic lung disease in infancy. At present, BPD primarily occurs in extremely premature infants (23 28 weeks of gestation) born during the late canalicular/early saccular stage of lung development. This article summarizes the current knowledge of the life course of BPD by emphasizing recent or key articles notating its natural history from the newborn period through adulthood and building the case for a continued focus on its primary prevention. PMID- 26593089 TI - Fatal coma in a young adult due to late-onset urea cycle deficiency presenting with a prolonged seizure: a case report. AB - INTRODUCTION: Unexplained hyperammonemic coma in adults can be a medical dilemma in the absence of triggering factors and known comorbidities. Ornithine transcarbamylase deficiency presents most commonly with hyperammonemic coma. Although a rare disorder, ornithine transcarbamylase deficiency is the most common of the urea cycle disorders, which can occur both in children, and less commonly, in adults. The urea cycle disorder is usually acquired as an X-linked trait, and very rarely, similar to our reported case, may be acquired as a "new" mutation. Mutations that lead to later-onset presentations may lead to life threatening disease and may be unrecognized, particularly when the first clinical symptoms occur in adulthood. CASE PRESENTATION: We report the case of a previously healthy 17-year-old white man who developed a prolonged seizure and a rapid decline in mental status leading to coma over a 3-day period. Analysis of the OTC gene showed a 119G variant, which was identified in exon 2 of the OTC gene by sequencing. CONCLUSIONS: A diagnosis of ornithine transcarbamylase deficiency should be considered in adult patients who present with unexplained hyperammonemic coma and for all adult patients presenting with cryptogenic new onset seizure and laboratory finding of elevated blood ammonia levels. This reported case highlights the importance of early recognition of this potentially reversible cause of life-threatening encephalopathy, as timely recognition and appropriate treatment can be lifesaving. PMID- 26593090 TI - Structure and substrate selectivity of the 750-kDa alpha6beta6 holoenzyme of geranyl-CoA carboxylase. AB - Geranyl-CoA carboxylase (GCC) is essential for the growth of Pseudomonas organisms with geranic acid as the sole carbon source. GCC has the same domain organization and shares strong sequence conservation with the related biotin dependent carboxylases 3-methylcrotonyl-CoA carboxylase (MCC) and propionyl-CoA carboxylase (PCC). Here we report the crystal structure of the 750-kDa alpha6beta6 holoenzyme of GCC, which is similar to MCC but strikingly different from PCC. The structures provide evidence in support of two distinct lineages of biotin-dependent acyl-CoA carboxylases, one carboxylating the alpha carbon of a saturated organic acid and the other carboxylating the gamma carbon of an alpha beta unsaturated acid. Structural differences in the active site region of GCC and MCC explain their distinct substrate preferences. Especially, a glycine residue in GCC is replaced by phenylalanine in MCC, which blocks access by the larger geranyl-CoA substrate. Mutation of this residue in the two enzymes can change their substrate preferences. PMID- 26593091 TI - Distinct Eligibility Traces for LTP and LTD in Cortical Synapses. AB - In reward-based learning, synaptic modifications depend on a brief stimulus and a temporally delayed reward, which poses the question of how synaptic activity patterns associate with a delayed reward. A theoretical solution to this so called distal reward problem has been the notion of activity-generated "synaptic eligibility traces," silent and transient synaptic tags that can be converted into long-term changes in synaptic strength by reward-linked neuromodulators. Here we report the first experimental demonstration of eligibility traces in cortical synapses. We demonstrate the Hebbian induction of distinct traces for LTP and LTD and their subsequent timing-dependent transformation into lasting changes by specific monoaminergic receptors anchored to postsynaptic proteins. Notably, the temporal properties of these transient traces allow stable learning in a recurrent neural network that accurately predicts the timing of the reward, further validating the induction and transformation of eligibility traces for LTP and LTD as a plausible synaptic substrate for reward-based learning. PMID- 26593092 TI - Accumbal D1R Neurons Projecting to Lateral Hypothalamus Authorize Feeding. AB - Feeding satisfies metabolic need but is also controlled by external stimuli, like palatability or predator threat. Nucleus accumbens shell (NAcSh) projections to the lateral hypothalamus (LH) are implicated in mediating such feeding control, but the neurons involved and their mechanism of action remain elusive. We show that dopamine D1R-expressing NAcSh neurons (D1R-MSNs) provide the dominant source of accumbal inhibition to LH and provide rapid control over feeding via LH GABA neurons. In freely feeding mice, D1R-MSN activity reduced during consumption, while their optogenetic inhibition prolonged feeding, even in the face of distracting stimuli. Conversely, activation of D1R-MSN terminals in LH was sufficient to abruptly stop ongoing consumption, even during hunger. Direct inhibition of LH GABA neurons, which received input from D1R-MSNs, fully recapitulated these findings. Together, our study resolves a feeding circuit that overrides immediate metabolic need to allow rapid consumption control in response to changing external stimuli. VIDEO ABSTRACT. PMID- 26593093 TI - Competing Neural Ensembles in Motor Cortex Gate Goal-Directed Motor Output. AB - Unit recordings in behaving animals have revealed the transformation of sensory to motor representations in cortical neurons. However, we still lack basic insights into the mechanisms by which neurons interact to generate such transformations. Here, we study cortical circuits related to behavioral control in mice engaged in a sensory detection task. We recorded neural activity using extracellular and intracellular techniques and analyzed the task-related neural dynamics to reveal underlying circuit processes. Within motor cortex, we find two populations of neurons that have opposing spiking patterns in anticipation of movement. From correlation analyses and circuit modeling, we suggest that these dynamics reflect neural ensembles engaged in a competition. Furthermore, we demonstrate how this competitive circuit may convert a transient, sensory stimulus into a motor command. Together, these data reveal cellular and circuit processes underlying behavioral control and establish an essential framework for future studies linking cellular activity to behavior. PMID- 26593095 TI - Influence of clinician referral on Nebraska women's decision-to-abortion time. AB - OBJECTIVE: To assess the association of clinician referral with decision-to abortion time. STUDY DESIGN: We conducted a cross-sectional survey of women seeking abortion at all three Nebraska abortion clinics. We defined referral as direct (information for an abortion clinic), inappropriate (information for a clinic that does not provide abortions) or no referral. Women reported when they recognized their pregnancy, decided to seek abortion and contacted a clinician. The primary outcome - decision-to-abortion time - was time from certain decision to abortion. We used multivariate linear regression analysis, controlling for potential confounders. RESULTS: Participants (n=356) were a mean of 26.8+/ 5.3years old, primarily white (62%), unmarried (88%) and urban (87%), with a mean gestational duration of 8(2/7)weeks (S.D.+/-20days). Forty-six percent (164) had contacted a clinician and 30% (104) had discussed abortion with one before their abortion. Of those, 30% received a direct referral, 6% received an inappropriate referral and 64% received no referral. Decision-to-abortion time did not vary by referral type [mean difference compared with direct referral: inappropriate referral, 1.1days, 95% confidence interval (CI) -13.4 to 15.6, p=.88; no referral, -0.4days, 95% CI -7.0 to 6.3]. The most common reasons cited for delay in obtaining an abortion were an inability to get an earlier appointment (105/263, 40%) and time needed to raise money to pay for the abortion (73/263, 28%). CONCLUSION: While neither occurrence of referral nor type was associated with decision-to-abortion times, women in Nebraska continue to face barriers to timely abortion care. IMPLICATIONS: Additional research is needed to explore whether quality clinician referral improves abortion access and whether increased resources should be dedicated to improving referral patterns. PMID- 26593094 TI - Atypical Visual Saliency in Autism Spectrum Disorder Quantified through Model Based Eye Tracking. AB - The social difficulties that are a hallmark of autism spectrum disorder (ASD) are thought to arise, at least in part, from atypical attention toward stimuli and their features. To investigate this hypothesis comprehensively, we characterized 700 complex natural scene images with a novel three-layered saliency model that incorporated pixel-level (e.g., contrast), object-level (e.g., shape), and semantic-level attributes (e.g., faces) on 5,551 annotated objects. Compared with matched controls, people with ASD had a stronger image center bias regardless of object distribution, reduced saliency for faces and for locations indicated by social gaze, and yet a general increase in pixel-level saliency at the expense of semantic-level saliency. These results were further corroborated by direct analysis of fixation characteristics and investigation of feature interactions. Our results for the first time quantify atypical visual attention in ASD across multiple levels and categories of objects. PMID- 26593096 TI - Room temperature large-scale synthesis of layered frameworks as low-cost 4 V cathode materials for lithium ion batteries. AB - Li-ion batteries (LIBs) are considered as the best available technology to push forward the production of eco-friendly electric vehicles (EVs) and for the efficient utilization of renewable energy sources. Transformation from conventional vehicles to EVs are hindered by the high upfront price of the EVs and are mainly due to the high cost of LIBs. Hence, cost reduction of LIBs is one of the major strategies to bring forth the EVs to compete in the market with their gasoline counterparts. In our attempt to produce cheaper high-performance cathode materials for LIBs, an rGO/MOPOF (reduced graphene oxide/Metal-Organic Phosphate Open Framework) nanocomposite with ~4 V of operation has been developed by a cost effective room temperature synthesis that eliminates any expensive post synthetic treatments at high temperature under Ar/Ar-H2. Firstly, an hydrated nanocomposite, rGO/K2[(VO)2(HPO4)2(C2O4)].4.5H2O has been prepared by simple magnetic stirring at room temperature which releases water to form the anhydrous cathode material while drying at 90 degrees C during routine electrode fabrication procedure. The pristine MOPOF material undergoes highly reversible lithium storage, however with capacity fading. Enhanced lithium cycling has been witnessed with rGO/MOPOF nanocomposite which exhibits minimal capacity fading thanks to increased electronic conductivity and enhanced Li diffusivity. PMID- 26593097 TI - Embodied simulation in exposure-based therapies for posttraumatic stress disorder a possible integration of cognitive behavioral theories, neuroscience, and psychoanalysis. AB - Exposure to the trauma memory is the common denominator of most evidence-based interventions for posttraumatic stress disorder (PTSD). Although exposure-based therapies aim to change associative learning networks and negative cognitions related to the trauma memory, emotional interactions between patient and therapist have not been thoroughly considered in past evaluations of exposure based therapy. This work focuses on recent discoveries of the mirror-neuron system and the theory of embodied simulation (ES). These conceptualizations may add a new perspective to our understanding of change processes in exposure-based treatments for PTSD patients. It is proposed that during exposure to trauma memories, emotional responses of the patient are transferred to the therapist through ES and then mirrored back to the patient in a modulated way. This process helps to alleviate the patient's sense of loneliness and enhances his or her ability to exert control over painful, trauma-related emotional responses. ES processes may enhance the integration of clinical insights originating in psychoanalytic theories-such as holding, containment, projective identification, and emotional attunement-with cognitive behavioral theories of learning processes in the alleviation of painful emotional responses aroused by trauma memories. These processes are demonstrated through a clinical vignette from an exposure based therapy with a trauma survivor. Possible clinical implications for the importance of face-to-face relationships during exposure-based therapy are discussed. PMID- 26593098 TI - NF-kappaB-inducing kinase is essential for B-cell maintenance in mice. AB - NF-kappaB-inducing kinase (NIK) is a key mediator of the noncanonical NF-kappaB signaling pathway, which is critical for normal B-cell development and function. It is well established that the complete deletion of NIK in mice results in defective B cells and impaired secondary lymphoid organogenesis. To address the role of NIK deficiency specifically in B cells, we generated a new mouse strain for the conditional deletion of this kinase. Deletion of NIK during B-cell development results in a drastic reduction of mature B cells from the transitional 2 stage on, while B-1 B cells are less affected. Moreover, deletion of NIK in the germinal centers decreases the numbers of germinal center B cells and impairs the ability of NIK-deficient B cells to develop into class-switched cells in vivo. This new mouse strain will be helpful for studying the role of NIK in different cell types of the body. PMID- 26593100 TI - Building a framework for theory-based ethnographies for studying intergenerational family food practices. AB - The growing rates of (childhood) obesity worldwide are a source concern for health professionals, policy-makers, and researchers. The increasing prevalence of associated diseases-such as diabetes, cardiovascular diseases, and psychological problems-shows the impact of obesity on people's health, already from a young age. In turn, these problems have obvious consequences for the health care system, including higher costs. However, the treatment of obesity has proven to be difficult, which makes prevention an important goal. In this study, we focus on food practices, one of the determinants of obesity. In recent years, it has become increasingly clear that interventions designed to encourage healthy eating of children and their families are not having the desired impact, especially among groups with a lower socioeconomic background (SEB). To understand why interventions fail to have an impact, we need to study the embedded social and cultural constructions of families. We argue that we need more than just decision-making theories to understand this cultural embeddedness, and to determine what cultural and social factors influence the decision-making process. By allowing families to explain their cultural background, their capabilities, and their opportunities, we will gain new insights into how families choose what they eat from a complex set of food choices. We have thus chosen to build a framework based on Sen's capability approach and the theory of cultural schemas. This framework, together with a holistic ethnographic research approach, can help us better understand what drives the food choices made in families. The framework is built to serve as a starting point for ethnographic research on food choice in families, and could contribute to the development of interventions that are embedded in the cultural realities of the targeted groups. PMID- 26593099 TI - Rescue of neonatal cardiac dysfunction in mice by administration of cardiac progenitor cells in utero. AB - Striated preferentially expressed gene (Speg) is a member of the myosin light chain kinase family. We previously showed that disruption of the Speg gene locus in mice leads to a dilated cardiomyopathy with immature-appearing cardiomyocytes. Here we show that cardiomyopathy of Speg(-/-) mice arises as a consequence of defects in cardiac progenitor cell (CPC) function, and that neonatal cardiac dysfunction can be rescued by in utero injections of wild-type CPCs into Speg(-/ ) foetal hearts. CPCs harvested from Speg(-/-) mice display defects in clone formation, growth and differentiation into cardiomyocytes in vitro, which are associated with cardiac dysfunction in vivo. In utero administration of wild-type CPCs into the hearts of Speg(-/-) mice results in CPC engraftment, differentiation and myocardial maturation, which rescues Speg(-/-) mice from neonatal heart failure and increases the number of live births by fivefold. We propose that in utero administration of CPCs may have future implications for treatment of neonatal heart diseases. PMID- 26593101 TI - Are vegans the same as vegetarians? The effect of diet on perceptions of masculinity. AB - Food and food consumption matters in interpersonal interactions. Foods consumed can affect how a person is perceived by others in terms of morality, likeability, and gender. Food consumption can be used as a strategy for gendered presentation, either in terms of what foods are consumed or in the amount of food consumed. Finally, foods themselves are associated with gender. Previous research (Browarnik, 2012; Ruby & Heine, 2011) shows inconsistent patterns in the association between vegetarianism and masculinity. The current research conceptually replicates and extends this research by including the explicit label of vegetarian. The four studies in this article provide increased information about the effects of diet on gendered perceptions. Study 1 shows that vegetarian and omnivorous targets are rated equally in terms of masculinity. Study 2 shows that perceptions of vegetarians and vegans are similar, though comparing this research with past research indicates that perceptions of vegetarians are more variable. Study 3 shows that veganism leads perceptions of decreased masculinity relative to omnivores. Finally, Study 4 tests one possible mechanism for the results of Study 3, that it is the choice to be vegan that impacts perceptions of gender. Implications include increased knowledge about how meatless diets can affect the perceptions of gender in others. Multiple directions for future research are discussed. PMID- 26593102 TI - Picking fruit from our backyard's trees: The meaning of nostalgia in shaping Latinas' eating practices in the United States. AB - Based on a focus group study conducted in New York City (NYC), this paper examines the traditional staples (i.e., nostalgic foods) that Latinas regularly consume in the U.S., along with their beliefs regarding the impact of such foods on weight gain and related body image. Our research findings highlight the "double-bind" of nostalgic foods, defined by Latinas' retention of highly caloric familiar items along with their progressive abandonment of fresh produce and fruits. Despite participants' efforts to eat healthy staples from their homelands, they mostly kept foods perceived as unhealthy (e.g., fatty meats, fried foods). This phenomenon was informed by the "same-food paradox," represented by Latinas' beliefs that the same traditional foods that would make them lose weight in their native countries would lead them to gain weight in the U.S. Our qualitative data show that participants' concerns about their weight gain in the U.S. is in tune with their general body dissatisfaction, as indicated by our quantitative results. Finally, our findings reveal the role of stress in promoting Latinas' deleterious daily habits, including their consumption of fat saturated snacks. Overall, these results speak to the cultural and structural barriers to healthy eating that financially strapped study participants experienced in NYC. In order to design successful public health interventions targeting Latinas, the nostalgic aspects of food preferences should be considered in conjunction with the barriers that keep them from engaging with healthier lifestyles in the U.S. PMID- 26593103 TI - Recollections of pressure to eat during childhood, but not picky eating, predict young adult eating behavior. AB - Picky eating is a childhood behavior that vexes many parents and is a symptom in the newer diagnosis of Avoidant/Restrictive Food Intake Disorder (ARFID) in adults. Pressure to eat, a parental controlling feeding practice aimed at encouraging a child to eat more, is associated with picky eating and a number of other childhood eating concerns. Low intuitive eating, an insensitivity to internal hunger and satiety cues, is also associated with a number of problem eating behaviors in adulthood. Whether picky eating and pressure to eat are predictive of young adult eating behavior is relatively unstudied. Current adult intuitive eating and disordered eating behaviors were self-reported by 170 college students, along with childhood picky eating and pressure through retrospective self- and parent reports. Hierarchical regression analyses revealed that childhood parental pressure to eat, but not picky eating, predicted intuitive eating and disordered eating symptoms in college students. These findings suggest that parental pressure in childhood is associated with problematic eating patterns in young adulthood. Additional research is needed to understand the extent to which parental pressure is a reaction to or perhaps compounds the development of problematic eating behavior. PMID- 26593104 TI - Comparison of virulence factors and capsular types of Streptococcus agalactiae isolated from human and bovine infections. AB - Streptococcus agalactiae is a leading cause of human and bovine infections. A total of 194 S. agalactiae isolates, 55 isolates from bovines and 139 from humans, were analyzed for capsular types, virulence genes (scpB, hly, rib, bca and bac) and mobile genetic elements (IS1548 and GBSi1) using polymerase chain reaction (PCR) and multiplex PCR. Capsular type III was predominant (61%), followed by types V, II, Ib, and IV. The scpB, hly, bca and bac virulence genes were only found among human isolates. Twelve and 2 distinct virulence gene profiles were identified among human and bovine isolates respectively. The virulence gene profiles scpB- hly- IS1548- rib-bca (51%) and scpB- hly- IS1548- bca (19%) were only predominant among human isolates. The rib gene was the most common virulence gene in both human and bovine isolates. The study showed a high prevalence of virulence genes in S. agalactiae strains isolated from human infections, these result can support the idea that S. agalactiae isolated from humans and bovines are generally unrelated and probably belonged to separate populations. PMID- 26593106 TI - Body Composition in Children and Adolescents with Osteogenesis Imperfecta. AB - OBJECTIVE: To use peripheral quantitative computed tomography to determine the cross-sectional area (CSA) of subcutaneous fat and muscle (fat CSA, muscle CSA) in transverse forearm scans in patients with osteogenesis imperfecta (OI). STUDY DESIGN: Fat and muscle CSA were quantified in 266 individuals (142 female) aged 5 20 years who had a diagnosis of OI type I, III, or IV and who had mutations in COL1A1 or COL1A2. Results were compared with those of 255 healthy controls. RESULTS: In a subgroup of 39 patients with OI type I, % fat CSA correlated closely with total body percentage fat mass as determined by dual-energy x-ray absorptiometry (R(2) = 0.69; P < .001). In the entire study cohort, muscle CSA adjusted for age, sex, and forearm length was lower in OI type I and III than in controls (P < .05 each), but fat CSA was similar between OI types and controls. No relationship between the type of disease-causing mutation in the COL1A1 or COL1A2 genes and fat CSA or muscle CSA was found. CONCLUSIONS: Children and adolescents with OI have low muscle size but a normal amount of subcutaneous fat at the forearm. PMID- 26593105 TI - Effect of Expectation of Care on Adherence to Antihypertensive Medications Among Hypertensive Blacks: Analysis of the Counseling African Americans to Control Hypertension (CAATCH) Trial. AB - Novel ideas are needed to increase adherence to antihypertensive medication. The current study used data from the Counseling African Americans to Control Hypertension (CAATCH) study, a sample of 442 hypertensive African Americans, to investigate the mediating effects of expectation of hypertension care, social support, hypertension knowledge, and medication adherence, adjusting for age, sex, number of medications, diabetes, education, income, employment, insurance status, and intervention. Sixty-six percent of patients had an income of $20,000 or less and 56% had a high school education or less, with a mean age of 57 years. Greater expectation of care was associated with greater medication adherence (P=.007), and greater social support was also associated with greater medication adherence (P=.046). Analysis also showed that expectation of care mediated the relationship between hypertension knowledge and medication adherence (P<.05). Expectation of care and social support are important factors for developing interventions to increase medication adherence among blacks. PMID- 26593107 TI - Early Reticulocytosis and Anemia Are Associated with Abnormal and Conditional Transcranial Doppler Velocities in Children with Sickle Cell Anemia. AB - OBJECTIVE: To improve prediction of sickle cell anemia severity at an early age, we evaluated whether absolute reticulocyte count (ARC) or hemoglobin (Hb) levels during early infancy (2-6 months of age) in patients with sickle cell anemia predict the risk of later developing an abnormal (abTCD) or conditional (cdTCD) Transcranial Doppler (TCD). STUDY DESIGN: We used chart review to identify 121 consecutive patients who underwent TCD screening and had steady state ARC and Hb levels recorded between 2 and 6 months of age. Cox regression analysis was used to determine the relationship between ARC, Hb levels, and risk of developing cdTCD/abTCD over time. RESULTS: Mean ARC in early infancy was highest and mean Hb lowest in those children with abTCDs and cdTCDs. Cox regression analysis revealed that those subjects with an ARC >=200 K/MUL in early infancy had nearly 3 times the risk of having an abTCD/cdTCD than the group with an ARC <200 K/MUL, and patients with a Hb <8.5 g/dL had 2.7 times the risk of having an abTCD/cdTCD. CONCLUSIONS: These data suggest that both elevated ARC and low baseline Hb during early infancy are associated with an increased risk of developing a cdTCD or abTCD later in childhood. PMID- 26593108 TI - Behavioural sensitisation to MK-801 is dose-dependent and independent of environmental context. AB - The pathophysiology of schizophrenia is associated with disturbed glutamate signalling, particularly via a dysfunction of the N-methyl-d-aspartate (NMDA) receptor. In rodents, behavioural sensitisation to the NMDA receptor antagonist MK-801 is proposed to recapitulate aspects of the NMDA receptor hypofunction hypothesis of schizophrenia. The aim of this study was to determine the modulatory role of MK-801 dose and environmental context on the development and expression of MK-801-induced behavioural sensitisation. Sprague Dawley rats were administered saline or varying doses of MK-801 (i.p.) once daily for 7 days and locomotor activity was recorded. After 5 days of withdrawal, rats were challenged with their respective dose to test for sensitisation. From this experiment a sensitising dose was obtained. In the second experiment the magnitude of sensitisation was compared between rats that were treated in either a home or test environmental context. Rats treated with 0.25mg/kg MK-801 developed robust sensitisation when challenged after withdrawal. Rats treated with lower (0.1mg/kg) or higher (0.5mg/kg) doses of MK-801 did not develop locomotor sensitisation. Sensitisation to 0.25mg/kg MK-801 developed equally between rats treated in the home or test context. The study shows that male Sprague Dawley rats develop behavioural sensitisation to repeated injections of MK-801. The development of sensitisation is selective to MK-801 dose in an inverted-U dose response fashion. In this paradigm MK-801 induced sensitisation was expressed similarly between groups treated in two distinct environmental contexts. PMID- 26593110 TI - Meta-analysis of the association of the SLC6A3 3'-UTR VNTR with cognition. AB - The gene coding for the dopamine transporter (DAT), SLC6A3, contains a 40-base pair variable number of tandem repeats (VNTR) polymorphism (rs28363170) in its 3' untranslated region. This VNTR has been associated with attention deficit hyperactivity disorder (ADHD) and has been investigated in relation to cognition and brain function. Here, we report the results of a comprehensive meta-analysis with meta-regression examining the association of the VNTR with different domains of cognition in healthy adults. We extracted data from 28 independent studies and carried out meta-analyses for associations with working memory (k=10 samples, N=1193 subjects), inhibition (k=8 samples, N=829 subjects), executive functions including inhibition (k=10 samples, N=984 subjects), attention (k=6 samples, N=742 subjects) and declarative long-term memory (k=5 samples, N=251 subjects). None of the investigated dimensions showed significant associations with the VNTR (all p>0.26). Meta-regression including year of publication, gender, age, ethnicity and percentage of 10R-homozygotes similarly did not attain significance. We conclude that there is no evidence that rs28363170 may be a significant predictor of cognitive function in healthy adults. PMID- 26593109 TI - Object and spatial memory after neonatal perirhinal lesions in monkeys. AB - The contribution of the perirhinal cortex (PRh) to recognition memory is well characterized in adults, yet the same lesions have limited effect on recognition of spatial locations. Here, we assessed whether the same outcomes will follow when perirhinal lesions are performed in infancy. Monkeys with neonatal perirhinal (Neo-PRh) lesions and control animals were tested in three operant recognition tasks as they reached adulthood: Delayed Nonmatching-to-Sample (DNMS) and Object Memory Span (OMS), measuring object recognition, and Spatial Memory Span (SMS), measuring recognition of spatial locations. Although Neo-PRh lesions did not impact acquisition of the DNMS rule, they did impair performance when the delays were extended from 30s to 600s. In contrast, the same neonatal lesions had no impact on either the object or spatial memory span tasks, suggesting that the lesions impacted the maintenance of information across longer delays and not memory capacity. Finally, the magnitude of recognition memory impairment after the Neo-PRh lesions was similar to that previously observed after adult-onset perirhinal lesions, indicating minimal, or no, functional compensation after the early PRh lesions. Overall, the results indicate that the PRh is a cortical structure that is important for the normal development of mechanisms supporting object recognition memory. Its contribution may be relevant to the memory impairment observed with human cases of temporal lobe epilepsy without hippocampal sclerosis, but not to the memory impairment found in developmental amnesia cases. PMID- 26593111 TI - Environmental control of microRNAs in the nervous system: Implications in plasticity and behavior. AB - The discovery of microRNAs (miRNAs) a little over 20 years ago was revolutionary given that miRNAs are essential to numerous physiological and physiopathological processes. Currently, several aspects of the biogenic process of miRNAs and of the translational repression mechanism exerted on their targets mRNAs are known in detail. In fact, the development of bioinformatics tools for predicting miRNA targets has established that miRNAs have the potential to regulate almost all known biological processes. Therefore, the identification of the signals and molecular mechanisms that regulate miRNA function is relevant to understanding the role of miRNAs in both pathological and adaptive processes. Recently, a series of studies has focused on miRNA expression in the brain, establishing that their levels are altered in response to various environmental factors (EFs), such as light, sound, odorants, nutrients, drugs and stress. In this review, we discuss how exposure to various EFs modulates the expression and function of several miRNAs in the nervous system and how this control determines adaptation to their environment, behavior and disease state. PMID- 26593112 TI - Identification and Characterization of a Novel Constitutional PIK3CA Mutation in a Child Lacking the Typical Segmental Overgrowth of "PIK3CA-Related Overgrowth Spectrum". AB - Activating somatic PIK3CA mutations underlie a growing heterogeneous spectrum of segmental overgrowth disorders. We report the identification and evaluation of a novel de novo constitutional PIK3CA mutation (NM_006218.2:c.335T>A, p.Ile112Asn) in a child with congenital megalencephaly and macrosomia. Functional characterization of patient cells using a variety of endpoints demonstrates increased phosphatidylinositol-3-kinase (PI3K) activity. The mutation lies in a linker region adjacent to the p85 (PIK3R2) binding domain of the p110alpha (PIK3CA) catalytic subunit of PI3K. We show that altered stoichiometry within the p85-p110 complex likely underlies the hyperactive PI3K-AKT-mTOR signaling in this instance. Our findings expand upon the recently proposed "PIK3CA-related overgrowth spectrum" associated with PIKC3A mutations and PI3K hyperactivation, adding constitutional PIK3CA mutations as an underlying cause of megalencephaly and macrosomia in newborns. PMID- 26593113 TI - Sheathless capillary electrophoresis-mass spectrometry for anionic metabolic profiling. AB - The performance of CE coupled on-line to MS via a sheathless porous tip sprayer was evaluated for anionic metabolic profiling. A representative metabolite mixture and biological samples were used for the evaluation of various analytical parameters, such as peak efficiency (plate numbers), migration time and peak area repeatability, and LODs. The BGE, i.e. 10% acetic acid (pH 2.2), previously used for cationic metabolic profiling was now assessed for anionic metabolic profiling by using MS detection in negative ion mode. For test compounds, RSDs for migration times and peak areas were below 2 and 11%, respectively, and plate numbers ranged from 60 000 to 40 0000 demonstrating a high separation efficiency. Critical metabolites with low or no retention on reversed-phase LC could be efficiently separated and selectively analyzed by the sheathless CE-MS method. An injection volume of only circa 20 nL resulted in LODs between 10 and 200 nM (corresponding to an amount of 0.4-4 fmol), which was an at least tenfold improvement as compared to LODs obtained by conventional CE-MS approaches for these analytes. The methodology was applied to anionic metabolic profiling of glioblastoma cell line extracts. Overall, a sheathless CE-MS method has been developed for highly efficient and sensitive anionic metabolic profiling studies, which can also be used for cationic metabolic profiling studies by only switching the MS detection and separation voltage polarity. PMID- 26593114 TI - Demographics. AB - There is a large proportion of minority youth involved in the juvenile justice system. Disproportionate minority contact (DMC) occurs when the proportion of any ethnic group is higher at any given stage in the juvenile justice process than the proportion of this group in the general population. There are several theories explaining the presence and persistence of DMC. This article reviews the history of DMC and the theories and implications of this problem. It discusses several targets for interventions designed to reduce DMC and offer resources in this area. PMID- 26593115 TI - Civil and Constitutional Rights of Adjudicated Youth. AB - Mental health clinicians serving child and adolescent patients are frequently asked to evaluate youth who have been arrested for various offenses or who are otherwise involved with the juvenile justice system. To help orient clinicians and other stakeholders involved with such cases, this article describes the evolution of the juvenile justice system and summarizes the history and current status of the civil and constitutional rights of youth involved in the adjudicatory process. This article also points out key areas in which due process rights are still evolving, particularly in the case of status offenders. PMID- 26593116 TI - Mental Health Screening and Assessment of Detained Youth. AB - The effective rehabilitation of detained youth begins with optimal screening of their mental health needs as they enter the juvenile delinquency system. The Massachusetts Youth Screening Instrument-Version 2 is the most used and empirically proven tool to screen juveniles. Juvenile facilities should consider the use of screening instruments like the Massachusetts Youth Screening Instrument-Version 2 as close to intake as feasible. Mental health professionals working in these systems of care will then need adequate resources to assess the mental health needs according to a biopsychosocial model of these youth. PMID- 26593117 TI - Transfer of Juvenile Cases to Criminal Court. AB - The first juvenile court was founded in 1899 with the focus on rehabilitation of a juvenile offender as opposed to punishment in adult court. Determining culpability and disposition for adolescents has become a source of much discussion. With serious crimes, juvenile delinquents may be transferred from juvenile court to adult criminal court; this practice became more prevalent in the past century. However, growing knowledge of adolescent development has mitigated the culpability of youth offenders and resulted in judicial decisions influential to juvenile dispositions. PMID- 26593118 TI - Juvenile Competency to Stand Trial. AB - Competency to stand trial is interpreted as a protected due process right for all defendants and is defined as a defendant's fundamental knowledge and understanding of the criminal charges being filed, roles and procedures within the courtroom, and a general ability to work with the defense counsel. Questions of competency are most often raised by the judge, defense, or the prosecution, and competency evaluations are most often completed by psychiatrists or psychologists with forensic training or work experience. Mental illness, intellectual disability, developmental disorders, and developmental immaturity are the 4 main factors considered in most juvenile competency evaluations. PMID- 26593119 TI - The Role of the Child and Adolescent Psychiatrist in the Adjudicatory Assessment. AB - When courts look to mental health professionals to help inform legal decisions, psychiatrists are key members of the skilled clinicians qualified to respond. Child and adolescent psychiatrists are in a unique position to apply their diagnostic acumen and expertise in psychopharmacology to adjudicatory assessments. Key components of these evaluations include diagnostic assessment, risk assessment, treatment amenability, and specific recommendations for available treatment. This article culls guidelines for adjudicatory assessments from the existing peer-reviewed literature, including the use of structured professional judgment tools, the avoidance of dual agency, and the measured use of juvenile psychopathy assessment tools. PMID- 26593120 TI - Mental Health Care of Detained Youth and Solitary Confinement and Restraint Within Juvenile Detention Facilities. AB - Justice-involved youth are a complex and heterogeneous population with extremely high rates of mental disorder, trauma, and numerous other psychosocial stressors. Although working with this population has several challenges it can be highly rewarding for clinicians and a powerful opportunity for prevention of subsequent problems. Psychosocial interventions remain some of the most robust and effective interventions targeting specific developmental deficits common in this population. Medication treatment is also often appropriate. Seclusion may be clinically appropriate in some cases and is seen as distinct from disciplinary interventions such as isolation or solitary confinement, which are generally not appropriate. PMID- 26593121 TI - Juvenile Sex Offenders. AB - Public policy has tended to treat juvenile sex offenders (JSOs) as adult sex offenders in waiting, despite research that contradicts this notion. Although as a group, JSOs are more similar to general delinquents than to adult sex offenders, atypical sexual interests and sexual victimization during childhood may be a pathway for sexual offending that differentiates some JSOs from their nonsexually delinquent peers. Developmental considerations must be considered in risk assessment evaluations of these youth. This article reviews theories of sexual offending in youth, risk factors for juvenile offending and reoffending, psychopathology in JSOs, risk assessment, and treatment. PMID- 26593122 TI - Juvenile Firesetting. AB - Juvenile firesetting is a significant cause of morbidity and mortality in the United States. Male gender, substance use, history of maltreatment, interest in fire, and psychiatric illness are commonly reported risk factors. Interventions that have been shown to be effective in juveniles who set fires include cognitive behavior therapy and educational interventions, whereas satiation has not been shown to be an effective intervention. Forensic assessments can assist the legal community in adjudicating youth with effective interventions. Future studies should focus on consistent assessment and outcome measures to create more evidence for directing evaluation and treatment of juvenile firesetters. PMID- 26593123 TI - Understanding and Responding to the Needs of Commercially Sexually Exploited Youth: Recommendations for the Mental Health Provider. AB - Mental health providers are frequently at the forefront of addressing the multifaceted needs of commercially sexually exploited youth. This article provides an overview of the definition of commercial sexual exploitation of children and relevant legislation including the shift toward decriminalization of commercially sexually exploited youth. To provide clinicians with tools needed to deliver competent care to this population, a review of risk factors for commercial sexual exploitation of children and the role of the clinician in identification, assessment, and treatment of commercially sexually exploited youth are discussed. PMID- 26593124 TI - Community-Based Alternatives to Incarceration and Assessment and Community-Based Planning for Probation/Community-Based Alternative. AB - There is growing concern regarding the current treatment of juvenile offenders within the justice system. Most mental health professionals would agree that it is best to adopt a rehabilitative approach toward delinquent youths, but current practices do not always follow this principle. Youth incarceration is a costly and often debilitative process. There is growing evidence for community-based alternatives that aim to rehabilitate juvenile delinquents. Some of these interventions have proved to be successful in the prevention of delinquent acts. PMID- 26593125 TI - Juvenile Delinquency. PMID- 26593126 TI - Novel MEFV variant Q311H in an incomplete Behcet's disease patient with recurrent epididymitis. PMID- 26593127 TI - Flexibility of C3h -Symmetrical Linkers in Tris-oligonucleotide-Based Tetrahedral Scaffolds. AB - Flexibility of tris-oligonucleotides is determined by the length of their connecting hydrocarbon chains. Tris-oligonucleotides are branched DNA building blocks with three oligonucleotide arms attached to a C3h -symmetrical linker core at these chains. Four tris-oligonucleotides hybridise into a tetrahedral nanocage by sequence-determined self-assembly. The influence of methylene, ethylene and propylene chains was studied by synthesising sets of tris-oligonucleotides and analysing the relative stability of the hybridisation products against digestion by mung bean nuclease by using gel electrophoresis. Linkers with ethylene chains showed sufficient flexibility, whereas methylene-chain linkers were too rigid. Tris-oligonucleotides based on the latter still formed tetrahedral scaffolds in intermixing experiments with linkers of higher flexibility. Thus, a new generation of versatile isocyanurate-based linkers was established. PMID- 26593128 TI - Conscientiousness and mindfulness in midlife coping: An assessment based on MIDUS II. AB - Research has demonstrated that conscientious individuals tend to engage in planful problem solving to cope with stressful situations. Likewise, mindful individuals tend to favour approach-based coping and are less likely to engage in avoidant coping strategies. To examine whether conscientiousness and mindfulness determined agentic coping behaviour, hierarchical linear regressions were conducted using data from 602 participants drawn from the National Survey of Midlife Development in the United States (MIDUS) Study II and MIDUS II Biomarker Project. Personality responses were derived from the five-factor model inventory, gathered at a single time-point. Results revealed that conscientiousness predicted problem-focused coping (p < 0.001; beta = 0.23) and inversely predicted emotion-focused coping respectively (p < 0.001; beta = -0.14), even after controlling for remaining Big Five and confounding variables. Mindfulness also predicted problem-focused coping (p < 0.001; beta = 0.21). Neuroticism predicted emotion-focused coping (p < 0.001; beta = 0.40). These findings suggest that conscientiousness and mindfulness may contribute to coping responses in potentially healthful ways, highlighting new evidence regarding the potential protective role of conscientiousness. PMID- 26593129 TI - This Cochrane Review is closed: deciding what constitutes enough research and where next for pulmonary rehabilitation in COPD. PMID- 26593131 TI - In situ detection of histone variants and modifications in mouse brain using imaging mass spectrometry. AB - Histone posttranslational modifications and histone variants control the epigenetic regulation of gene expression and affect a wide variety of biological processes. A complex pattern of such modifications and variants defines the identity of cells within complex organ systems and can therefore be used to characterize cells at a molecular level. However, their detection and identification in situ has been limited so far due to lack of specificity, selectivity, and availability of antihistone antibodies. Here, we describe a novel MALDI imaging MS based workflow, which enables us to detect and characterize histones by their intact mass and their correlation with cytological properties of the tissue using novel statistical and image analysis tools. The workflow allows us to characterize the in situ distribution of the major histone variants and their modification in the mouse brain. This new analysis tool is particularly useful for the investigation of expression patterns of the linker histone H1 variants for which suitable antibodies are so far not available. PMID- 26593130 TI - The zebrafish pinball wizard gene encodes WRB, a tail-anchored-protein receptor essential for inner-ear hair cells and retinal photoreceptors. AB - KEY POINTS: The zebrafish pinball wizard (pwi) mutant is deaf and blind. The pwi phenotype includes a reduced auditory startle response and reduced visual evoked potentials, suggesting fatigue of synaptic release at ribbon synapses in hair cells and photoreceptors. The gene defective in the pwi mutant is WRB, a protein homologous to the yeast protein Get1, which is involved in the insertion of 'tail anchored' membrane proteins. Many tail-anchored proteins are associated with synaptic vesicles, and both vesicles and synaptic ribbons are reduced in synaptic regions of hair cells in pwi. Abnormal processing of synaptic vesicle proteins important for ribbon synapses can explain the pwi phenotype. ABSTRACT: In a large scale zebrafish insertional mutagenesis screen, we identified the pinball wizard (pwi) line, which displays a deafness and blindness phenotype. Although the gross morphology and structure of the pwi larval inner ear was near normal, acoustic startle stimuli evoked smaller postsynaptic responses in afferent neurons, which rapidly fatigued. In the retina, similarly, an abnormal electroretinogram suggested reduced transmission at the photoreceptor ribbon synapse. A functional deficit in these specialized synapses was further supported by a reduction of synaptic marker proteins Rab3 and cysteine-string protein (CSP/Dnajc5) in hair cells and photoreceptors, as well as by a reduction of the number of both ribbons and vesicles surrounding the ribbons in hair cells. The pwi gene encodes a homologue of the yeast Get1 and human tryptophan-rich basic (WRB) proteins, which are receptors for membrane insertion of tail-anchored (TA) proteins. We identified more than 100 TA proteins expressed in hair cells, including many synaptic proteins. The expression of synaptobrevin and syntaxin 3, TA proteins essential for vesicle fusion, was reduced in the synaptic layers of mutant retina, consistent with a role for the pwi/WRB protein in TA-protein processing. The WRB protein was located near the apical domain and the ribbons in hair cells, and in the inner segment and the axon of the photoreceptor, consistent with a role in vesicle biogenesis or trafficking. Taken together, our results suggest that WRB plays a critical role in synaptic functions in these two sensory cells, and that disrupted processing of synaptic vesicle TA proteins explains much of the mutant phenotype. PMID- 26593132 TI - Cellular Players in the Immunopathogenesis of Sarcoidosis. AB - Current hypotheses on the pathogenesis of sarcoidosis assume that it is induced by a nondegradable antigen inducing immune reactions, which are mediated by a panel of immune cells of the innate and adoptive immune system. This immune reaction leads to an accumulation of immune cells that is mainly alveolar macrophages, T cells, and neutrophils in the lung. As the antigen persists and cannot be eliminated, the ongoing immune reaction results in granuloma formation and remodeling of the lung. The current review aims to elucidate the different roles of the cellular players in the immunopathogenesis of sarcoidosis. PMID- 26593134 TI - Genetics of Sarcoidosis. AB - Sarcoidosis is a disease with highly variable presentation and progression; although it is hypothesized that disease phenotype is related to genetic variation, how much of this variability is driven by genetic factors is not known. The HLA region is the most strongly and consistently associated genetic risk factor for sarcoidosis, supporting the notion that sarcoidosis is an exposure-mediated immunologic disease. Most of the genetic etiology of sarcoidosis remains unknown in terms of the specific variants that increase risk in various populations, their biologic functions, and how they interact with environmental exposures. PMID- 26593133 TI - The Etiologic Role of Infectious Antigens in Sarcoidosis Pathogenesis. AB - Sarcoidosis is a granulomatous disease of unknown etiology, most commonly involving the lung, skin, lymph node, and eyes. Molecular and immunologic studies continue to strengthen the association of sarcoidosis with infectious antigens. Independent studies report the presence of microbial nucleic acids and proteins within sarcoidosis specimens. Complementary immunologic studies also support the role of infectious agents in sarcoidosis pathogenesis. Case reports and clinical trials have emerged regarding the efficacy of antimicrobials. They support increasing efforts to identify novel therapeutics, such as antimicrobials, that will have an impact on the observed increase in sarcoidosis morbidity and mortality. PMID- 26593135 TI - The Diagnosis of Sarcoidosis. AB - Sarcoidosis is a diagnosis of exclusion; there exists neither a pathognomonic clinical feature nor a perfect diagnostic test. Missed diagnosis and overdiagnosis are common. A careful history and physical examination look for "footprints" of sarcoidosis or features suggesting alternative diagnoses. Some presentations are classic and do not require tissue confirmation. A tissue biopsy should be performed if doubt exists. Sampling intrathoracic disease by transbronchial or ultrasound-guided biopsy of mediastinal lymph nodes provide high diagnostic yield with low complication rates. Even with tissue confirmation, diagnosis is never secure and follow-up is required to be fully confident of the diagnosis. PMID- 26593136 TI - Chest Imaging. AB - Chest imaging has a central role in the diagnosis and monitoring of sarcoidosis. For staging of pulmonary disease on chest radiograph, Scadding stages are still widely used. High-resolution CT (HRCT), however, is more accurate in visualizing the various manifestations of pulmonary sarcoidosis as well its complications. A generally accepted HRCT scoring system is lacking. Fluorodeoxyglucose F 18 positron emission tomography can visualize disease activity better than conventional makers in a significant proportion of patients. In patients with extensive changes on HRCT but no parenchymal fluorodeoxyglucose F 18 uptake, prudence with regard to initiation or intensification of immunosuppressive treatment is warranted. PMID- 26593138 TI - Pulmonary Sarcoidosis. AB - Sarcoidosis is a systemic disease, with lung involvement in almost all cases. Abnormal chest radiography is usually a key step for considering diagnosis. Lung impact is investigated through imaging; pulmonary function; and, when required, 6 minute walk test, cardiopulmonary exercise testing, or right heart catheterization. There is usually a reduction of lung volumes, and forced vital capacity is the most accurate parameter to reflect the impact of pulmonary sarcoidosis with or without pulmonary infiltration at imaging. Various evolution patterns have been described. Increased risk of death is associated with advanced pulmonary fibrosis or cor pulmonale, particularly in African American patients. PMID- 26593137 TI - Identifying Novel Biomarkers in Sarcoidosis Using Genome-Based Approaches. AB - This article briefly reviews conventional biomarkers used clinically to (1) support a diagnosis and (2) monitor disease progression in patients with sarcoidosis. Potential new biomarkers identified by genome-wide screening and the approaches to discover these biomarkers are described. PMID- 26593139 TI - Neurosarcoidosis. AB - Neurosarcoidosis is known as the great mimicker and may appear similar to lymphoma, multiple sclerosis, and other diseases affecting the nervous system. Although definitive diagnosis requires histologic confirmation of the affected neural tissue, characteristic clinical manifestations, gadolinium-enhanced MRI patterns and specific cerebrospinal fluid findings can help support the diagnosis in the absence of neural biopsy. An understanding of the common clinical presentations and diagnostic findings is central to the evaluation and management of neurosarcoidosis. PMID- 26593140 TI - Cardiac Sarcoidosis. AB - Studies suggest clinically manifest cardiac involvement occurs in 5% of patients with pulmonary/systemic sarcoidosis. The principal manifestations of cardiac sarcoidosis (CS) are conduction abnormalities, ventricular arrhythmias, and heart failure. Data indicate that an 20% to 25% of patients with pulmonary/systemic sarcoidosis have asymptomatic (clinically silent) cardiac involvement. An international guideline for the diagnosis and management of CS recommends that patients be screened for cardiac involvement. Most studies suggest a benign prognosis for patients with clinically silent CS. Immunosuppression therapy is advocated for clinically manifest CS. Device therapy, with implantable cardioverter defibrillators, is recommended for some patients. PMID- 26593142 TI - Cutaneous Sarcoidosis. AB - The skin is the second most common organ affected in sarcoidosis, which can affect patients of all ages and races, with African American women having the highest rates of sarcoidosis in the United States. The cutaneous manifestations are protean and can reflect involvement of sarcoidal granulomas within the lesion or represent reactive non-specific inflammation, as seen with erythema nodosum. Systemic work-up is necessary in any patient with cutaneous involvement of sarcoidal granulomas, and treatment depends on other organ involvement and severity of clinical disease. Skin-directed therapies are first line for mild disease, and immunomodulators or immunosuppressants may be necessary. PMID- 26593143 TI - Pulmonary Hypertension in Sarcoidosis. AB - Pulmonary hypertension is a complication of sarcoidosis leading to dyspnea and associated with increased morbidity and mortality. Sarcoidosis-associated pulmonary hypertension (SAPH) can be due to several factors, including vascular involvement by the granulomatous inflammation, compression of the pulmonary arteries by adenopathy, fibrotic changes within the lung, and left ventricular diastolic dysfunction. Several case series have suggested that some patients with SAPH benefit from specific therapy for pulmonary hypertension. A randomized, placebo-controlled trial found 16 weeks' bosentan therapy to be associated with significant improvement in pulmonary artery pressure. Future studies may better define who would respond to treatment of pulmonary hypertension. PMID- 26593141 TI - Ocular Sarcoidosis. AB - Sarcoidosis is one of the leading causes of inflammatory eye disease. Ocular sarcoidosis can involve any part of the eye and its adnexal tissues and may cause uveitis, episcleritis/scleritis, eyelid abnormalities, conjunctival granuloma, optic neuropathy, lacrimal gland enlargement, and orbital inflammation. Glaucoma and cataract can be complications from inflammation itself or adverse effects from therapy. Ophthalmic manifestations can be isolated or associated with other organ involvement. Patients with ocular sarcoidosis can present with a wide range of clinical presentations and severity. Multidisciplinary approaches are required to achieve the best treatment outcomes for both ocular and systemic manifestations. PMID- 26593144 TI - Severe Sarcoidosis. AB - In sarcoidosis, reduction in mortality and the prevention of disability due to major organ involvement are treatment goals. Thus, it is important to recognize severe disease and identify patients at higher risk of progression to severe disease. In this article, fibrotic lung disease and cardiac sarcoidosis are reviewed as the major contributors to sarcoidosis mortality and morbidity. In the absence of a standardized definition of severe pulmonary disease, a multidisciplinary approach to clinical staging is suggested, based on symptoms, pulmonary function tests, and imaging findings at presentation, integrated with the duration of disease and longitudinal disease behavior during early follow-up. PMID- 26593145 TI - Consequences of Sarcoidosis. AB - Sarcoidosis is a multisystem disorder of unknown cause(s). Less specific disabling symptoms, including fatigue and physical impairments, may have a major influence on the daily activities and the social and professional lives of the patients, resulting in a reduced quality of life. A multidisciplinary approach focusing on somatic and psychosocial aspects is recommended. Patients self perceived knowledge about the importance of exercise and lifestyle should be improved. Developing the most appropriate therapeutic approach for sarcoidosis requires careful consideration of the possible impact of fatigue, small fiber neuropathy related symptoms, pain, cognitive functioning, and coping strategies. Personalized medicine and appropriate communication are beneficial. PMID- 26593146 TI - Quality of Life Assessment in Sarcoidosis. AB - Quantifying health-related quality of life (HRQL) and specific patient symptoms has developed to include rigorous techniques to develop patient-reported outcome measures (PROs). PROs may assess objectively the impact of a therapeutic intervention in a clinical sarcoidosis trial, and may be useful in following HRQL. Item response theory may lead to the construction of PROs that allow for the development of short forms, the PRO to be focused on specific areas along the continuum of the trait being studied, and the development of computer-adaptive testing where HRQL can be assessed accurately using very few items. PMID- 26593147 TI - Treatment of Sarcoidosis. AB - Treatment of sarcoidosis is not required in all patients with the diagnosis. The decision to treat and the strategy for how to treat usually require input and shared decision making by the patient. Some common consequences of sarcoidosis are not caused by granulomatous inflammation, but may be the dominant disease manifestation and should be actively considered when formulating a treatment plan. The medication regimen should be tailored to each patient. Steroid-sparing medications should be prescribed early as part of a long-term strategy. PMID- 26593148 TI - Sarcoidosis. PMID- 26593149 TI - Household-level predictors of maternal mental health and systemic inflammation among infants in Mwanza, Tanzania. AB - OBJECTIVES: Household conditions and culturally/socially variable childcare practices influence priming of the inflammatory response during infancy. Maternal mental health may partially mediate that effect. Among mother-infant dyads in Mwanza, Tanzania, we hypothesized that poorer maternal mental health would be associated with adverse household ecology, lower social capital, and greater inflammation among infants under the age of one; and that mental health would mediate any effects of household ecology/social capital on inflammation. METHODS: We collected dried blood spots from mother-infant dyads (N = 88) at health centers near Mwanza, Tanzania. To assess household ecology and social capital, we conducted interviews with mothers using the Household Food Insecurity Access Scale, the MacArthur Subjective Social Status Scale, and a household wealth inventory. We employed the Hopkins Symptom Checklist to assess maternal mental health. A high-sensitivity C-reactive protein (CRP) assay was used to quantify inflammation. RESULTS: Severe food insecurity (OR: 5.16), lower subjective social status (r = -0.32), and lower household wealth (r = -0.26) were associated with high symptoms of maternal depression. Lower household wealth (r = -0.21) and severe food insecurity (OR: 2.52) were associated with high anxiety. High depression symptoms (OR: 2.56) and severe food insecurity (OR: 2.77) each were associated with greater-than-median infant CRP. However, mediation was not supported. CONCLUSIONS: Maternal mental health should be considered alongside nutritional status, pathogen exposure, and education as a potential driver of very early innate immune system development. Proximal mechanisms warrant further investigation. Am. J. Hum. Biol. 28:461-470, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26593150 TI - Experimentally Derived Kinetic Model for Sensor-Based Gait Monitoring. AB - A method for estimating gait parameters (shank, thigh, and stance leg angles) from a single, in situ, scalar acceleration measurement is presented. A method for minimizing the impact of errors due to unpredictable variations in muscle actuation and acceleration measurement biases is developed. This is done by determining the most probable gait progression by minimization of a cost function that reflects the size of errors in the gait parameters. In addition, a model for gait patterns that takes into account their variations due to walking speed is introduced and used. The approach is tested on data collected from subjects in a gait study. The approach can estimate limb angles with errors less than 6 deg (one standard deviation) and, thus, is suitable for many envisioned gait monitoring applications in nonlaboratory settings. PMID- 26593152 TI - Multiple Cycloaddition Reactions of Ketones with a beta-Diketiminate Al Compound. AB - A beta-diketiminate Al compound (1) with an exocyclic double bond reacts with two equivalents each of benzophenone and 2-benzoylpyridine in a [4+2] cycloaddition to generate bicyclic and tricyclic compounds 2 and 3, respectively. Compound 2 consists of six- and eight-membered aluminium rings, whereas 3 has two five- and one eight-membered ring. Compounds 2 and 3 were characterized by a number of analytical tools including single-crystal X-ray diffraction. The quantum mechanical calculations suggest that the dissociation of the solvent molecule from 1 would lead to an active species 1A having two 1,4-dipolar 4pi electron moieties, in which the electrophilic site is the Al atom and the nucleophilic positions are polarized exocyclic and endocyclic C=C pi bonds. The detailed mechanistic study shows that the dipolarophiles, benzophenone, and 2 benzoylpyridine undergo double cycloaddition with two 1,4-dipolar 4pi electron moieties of 1A. Herein, the addition of one molecule of the dipolarophile promotes the addition of the second one. PMID- 26593151 TI - Behavioral and neurophysiological evidence that lateral paracapsular GABAergic synapses in the basolateral amygdala contribute to the acquisition and extinction of fear learning. AB - The lateral/basolateral amygdala (BLA) is crucial to the acquisition and extinction of Pavlovian fear conditioning, and synaptic plasticity in this region is considered to be a neural correlate of learned fear. We recently reported that activation of BLA beta3-adrenoreceptors (beta3-ARs) selectively enhances lateral paracapsular (LPC) feed-forward GABAergic inhibition onto BLA pyramidal neurons, and that intra-BLA infusion of a beta3-AR agonist reduces measures of unconditioned anxiety-like behavior. Here, we utilized a combination of behavioral and electrophysiological approaches to characterize the role of BLA LPCs in the acquisition of fear and extinction learning in adult male Long-Evans rats. We report that intra-BLA microinjection of beta3-AR agonists (BRL37344 or SR58611A, 1MUg/0.5MUL/side) prior to training fear conditioning or extinction blocks the expression of these behaviors 24h later. Furthermore,ex vivo low frequency stimulation of the external capsule (LFS; 1Hz, 15min), which engages LPC synapses, induces LTP of BLA fEPSPs, while application of a beta3-AR agonist (SR58611A, 5MUM) induces LTD of fEPSPs when combined with LFS. Interestingly, fEPSP LTP is not observed in recordings from fear conditioned animals, suggesting that fear learning may engage the same mechanisms that induce synaptic plasticity at this input. In support of this, we find that LFS produces LTD of inhibitory postsynaptic currents (iLTD) at LPC GABAergic synapses, and that this effect is also absent following fear conditioning. Taken together, these data provide preliminary evidence that modulation of LPC GABAergic synapses can influence the acquisition and extinction of fear learning and related synaptic plasticity in the BLA. PMID- 26593153 TI - Localized Epidermal Drug Delivery Induced by Supramolecular Solvent Structuring. AB - The preferential localization of drug molecules in the epidermis of human skin is considered advantageous for a number of agents, but achieving such a delivery profile can be problematic. The aim of the present study was to assess if the manipulation of solvent supramolecular structuring in the skin could be used to promote drug residence in the epidermal tissue. Skin deposition studies showed that a 175-fold increase in the epidermal loading of a model drug diclofenac (138.65 +/- 11.67 MUg.cm(-2)), compared to a control (0.81 +/- 0.13 MUg.cm(-2)), could be achieved by colocalizing the drug with a high concentration of propylene glycol (PG) in the tissue. For such a system at 1 h postdose application, the PG flux into the skin was 9.3 mg.cm(2).h(-1) and the PG-water ratio in the epidermis was 76:24 (v/v). At this solvent ratio infrared spectroscopy indicated that PG rich supramolecular structures, which displayed a relatively strong physical affinity for the drug, were formed. Encouraging the production of the PG-rich supermolecular structures in the epidermis by applying diclofenac to the skin using a high PG loading dose (240 MUg.cm(-2)) produced an epidermal-transdermal drug distribution of 6.8:1. However, generating water-rich solvent supermolecular structures in the epidermis by applying diclofenac using a low PG loading dose (2.2 MUg.cm(-2)) led to a loss of preferential epidermal localization of diclofenac in the tissue (0.7:1 epidermal-transdermal drug distribution). This change in diclofenac skin deposition profile in response to PG variations and the accompanying FTIR data supported the notion that supramolecular solvent structures could control drug accumulation in the human epidermis. PMID- 26593154 TI - Weight bias internalization, emotion dysregulation, and non-normative eating behaviors in prebariatric patients. AB - OBJECTIVE: Weight bias internalization (WBI) is associated with eating disorder psychopathology and non-normative eating behaviors among individuals with overweight and obesity, but has rarely been investigated in prebariatric patients. Based on findings demonstrating a relationship between emotion dysregulation and eating behavior, this study sought to investigate the association between WBI and eating disorder psychopathology as well as non normative eating behaviors (i.e., food addiction, emotional eating, and eating in the absence of hunger), mediated by emotion dysregulation. METHOD: Within a consecutive multicenter study, 240 prebariatric patients were assessed using self report questionnaires. The mediating role of emotion dysregulation was examined using structural equation modeling. RESULTS: The analyses yielded no mediational effect of emotion dysregulation on the association between WBI and eating disorder psychopathology. However, emotion dysregulation fully mediated the associations between WBI and emotional eating as well as eating in the absence of hunger. Further, emotion dysregulation partially mediated the relationship between WBI and food addiction symptoms. DISCUSSION: Prebariatric patients with high levels of WBI are at risk for non-normative eating behaviors, especially if they experience emotion regulation difficulties. These findings highlight the importance of interventions targeting WBI and improving emotion regulation skills for the normalization of eating behavior in prebariatric patients. PMID- 26593155 TI - CDR3 clonotype and amino acid motif diversity of BV19 expressing circulating human CD8 T cells. AB - Generating a detailed description of human T cell repertoire diversity is an important goal in the study of human immunology. The circulation is the source of most T cells used for studies in humans. Here we use high throughput sequencing of TCR BV19 transcripts from CD8 T cells derived from unmanipulated PBMC from an older HLA-A2 individual to provide a quantitative and qualitative description of the clonotypic CDR3 nucleotide and amino acid composition of the TCR beta-chain from this subset of circulating CD8 T cells. Aggregated samples from six time points spanning ~1.5 years were analyzed to smooth possible temporal fluctuation. BV19 encompasses the well studied RS-encoding clonotypes involved in recognition of the M1(58-66) epitope from influenza A in HLA-A2 individuals. The clonotype distribution was diverse, complex and self-similar. The amino acid composition was generally skewed in favor of glycines and there were specific amino acids observed at higher frequency at the NDN start position. The motif repertoire distribution was also diverse, complex and self-similar with respect to CDR3 length, NDN start and length. PMID- 26593157 TI - A Chemical Inhibitor of the Skp2/p300 Interaction that Promotes p53-Mediated Apoptosis. AB - Skp2 is thought to have two critical roles in tumorigenesis. As part of the SCF(Skp2) ubiquitin ligase, Skp2 drives the cell cycle by mediating the degradation of cell cycle proteins. Besides the proteolytic activity, Skp2 also blocks p53-mediated apoptosis by outcompeting p53 for binding p300. Herein, we exploit the Skp2/p300 interaction as a new target for Skp2 inhibition. An affinity-based high-throughput screen of a combinatorial cyclic peptoid library identified an inhibitor that binds to Skp2 and interferes with the Skp2/p300 interaction. We show that antagonism of the Skp2/p300 interaction by the inhibitor leads to p300-mediated p53 acetylation, resulting in p53-mediated apoptosis in cancer cells, without affecting Skp2 proteolytic activity. Our results suggest that inhibition of the Skp2/p300 interaction has a great potential as a new anticancer strategy, and our Skp2 inhibitor can be developed as a chemical probe to delineate Skp2 non-proteolytic function in tumorigenesis. PMID- 26593156 TI - The genetic architecture of leaf number and its genetic relationship to flowering time in maize. AB - The number of leaves and their distributions on plants are critical factors determining plant architecture in maize (Zea mays), and leaf number is frequently used as a measure of flowering time, a trait that is key to local environmental adaptation. Here, using a large set of 866 maize-teosinte BC2 S3 recombinant inbred lines genotyped by using 19,838 single nucleotide polymorphism markers, we conducted a comprehensive genetic dissection to assess the genetic architecture of leaf number and its genetic relationship to flowering time. We demonstrated that the two components of total leaf number, the number of leaves above (LA) and below (LB) the primary ear, were under relatively independent genetic control and might be subject to differential directional selection during maize domestication and improvement. Furthermore, we revealed that flowering time and leaf number are commonly regulated at a moderate level. The pleiotropy of the genes ZCN8, dlf1 and ZmCCT on leaf number and flowering time were validated by near-isogenic line analysis. Through fine mapping, qLA1-1, a major-effect locus that specifically affects LA, was delimited to a region with severe recombination suppression derived from teosinte. This study provides important insights into the genetic basis of traits affecting plant architecture and adaptation. The genetic independence of LA from LB enables the optimization of leaf number for ideal plant architecture breeding in maize. PMID- 26593158 TI - Molecular nature of alpha-globin genes in the Saudi population. AB - Alpha-thalassemia (alpha-thal) is a disorder caused by the deletion of single or double alpha-globin genes, and/or point mutations in the alpha-globin genes. There are 2 common types of alpha-globin genes; HBA2 and HBA1. Recently, it has been discovered that the HBA2 gene is replaced by a unique HBA12 gene convert in 5.7% of the Saudi population. The alpha-globin genes have been emerging as a molecular target for the treatment of beta-thalassemia (beta-thal). Hence, it is essential to understand the molecular nature of alpha-globin genes to treat the most prevalent hemoglobin disorders, such as sickle cell disease, alpha-thal, and beta-thal prevalent in the Kingdom of Saudi Arabia. Thirty-two different alpha globin genotypes have been observed in the Saudi population. This review outlines the classification of the alpha-globin genes on the basis of their molecular nature and complex combinations of alpha-globin genes, and their variants predominant in Saudis. PMID- 26593159 TI - The pathogenesis of the clinical features of oral-facial-digital syndrome type I. AB - Oral-facial-digital syndrome type I (OFDI) is an X-linked syndrome, which has several craniofacial and limb features; and hence, patients frequently present to craniofacial and plastic surgeons. Oral-facial-digital syndrome type I is caused by mutations in the CXORF5 gene. The gene product is one of the basal body proteins of a slim microtubule-based organelle called the "primary cilium". Most of the clinical features of OFDI patients are related to dysfunctions of the primary cilium leading to abnormal Hedgehog signal transduction, depressed planar cell polarity pathway, and errors in cell cycle control. PMID- 26593160 TI - The variations of peroneus digiti quinti muscle and its contribution to the extension of the fifth toe. A cadaveric study. AB - OBJECTIVES: To investigate the origin, prevalence, and possible effects of peroneus digiti quinti muscle (PDQ) on the fifth toe, to find out the variations of PDQ by determining the relationship between peroneus brevis muscle (PB) and PDQ, and to reveal its importance for the applications in foot and ankle surgery. METHODS: This study was conducted at the Faculty of Medicine, Kahramanmaras Sutcu Imam University, Kahramanmaras, Turkey between September 2013 and June 2014. The study was a prospective dissection of cadaveric lower limbs. Twenty five amputated lower limbs were stored in the freezer at -15 degrees C. The legs were dissected; prevalence and variations of peroneus digiti quinti were investigated. RESULTS: Peroneus digiti quinti muscle was found in 8 (32%) of 25 dissected lower limbs. However, 2 different tendon extensions were found at 3 (37.5%) of 8, and 5 (62.5%) of them were determined to have a single tendon. CONCLUSION: The incidence, dimensions, length, and insertions of peroneus digiti quinti are important in the evaluation and treatment of functional loss of the fifth toe, lateral foot deformities, and tendon problems behind the lateral malleolus of the ankle. PMID- 26593161 TI - Clinical utility of dabigatran in United Arab Emirates. A pharmacovigilance study. AB - OBJECTIVES: To provide early data regarding clinical utility of dabigatran in Al Ain, United Arab Emirates (UAE). METHODS: This was an ethics approved retrospective cross sectional study. We retrieved a total of 76 patients who were using dabigatran from September to December 2014 in the Cardiology Clinic at Al Ain Hospital, Al-Ain, UAE. The primary analysis was designed to test the frequency of bleeding events (rate) with dabigatran 75, 110, and 150 mg. RESULTS: The mean age +/- standard deviation of cohort was 67.9 +/- 1.5 years (range; 29 98 years), composed of males (52.6%) with mean age of 66.3 +/- 1.7 years, and females (47.4%) with mean age of 69.6 +/- 1.1 years. The highest age group was those between 61-80 years (60.5%). Most comprised the age strata of <=75 years (73.7%). The main indication for dabigatran use was atrial fibrillation. The rate of bleeding with dabigatran was 18/76 (23.7%), and melena was the leading cause of bleeding 8/76 (10.7%). The hospitalization rate was 67.1%, dabigatran withdrawal rate was 0.01%, and mortality rate was 6.5%. The cohort had exhibited incidences of minor bleeding with one fatal major bleeding, high co-morbidities, admission, and readmission, which was not directly linked to dabigatran. We did not identify any relation of death due to dabigatran. CONCLUSION: Dabigatran is a suitable alternative to warfarin obviating the need for repetitive international normalized ratio monitoring, however, it may need plasma drug monitoring. PMID- 26593162 TI - Can pre-implantation biopsies predict renal allograft function in pediatric renal transplant recipients? AB - OBJECTIVES: To determine the utility of pre-implantation renal biopsy (PIB) to predict renal allograft outcomes. METHODS: This is a retrospective review of all patients that underwent PIB from January 2003 to December 2011 at the Great Ormond Street Hospital for Children in London, United Kingdom. Thirty-two male patients (56%) aged 1.5-16 years (median: 10.2) at the time of transplantation were included in the study and followed-up for 33 (6-78) months. The results were compared with 33 controls. RESULTS: The PIB showed normal histopathological findings in 13 patients (41%), mild chronic vascular changes in 8 (25%), focal tubular atrophy in one, moderate to severe chronic vascular change in 3, mild to moderate acute tubular damage in 6, and tissue was inadequate in one subject. Delayed graft function (DGF) was observed in 3 patients; 2 with vascular changes in PIB, and one with normal histopathological findings. Two subjects with PIB changes lost their grafts. The estimated glomerular filtration rate at 3-, and 6 months post-transplantation was lower in children with abnormal PIB changes compared with those with normal PIB. There was one case of DGF in the control group, and 4 children lost their grafts including the one with DGF. CONCLUSION: Pre-implantation renal biopsy can provide important baseline information of the graft with implications on subsequent medical treatment for pediatric renal transplant recipients. PMID- 26593163 TI - Favorable therapeutic response of osteoporosis patients to treatment with intravenous zoledronate compared with oral alendronate. AB - OBJECTIVES: To evaluate the efficacy of orally-administered alendronate compared with intravenously-administered zoledronate. METHODS: This prospective study was carried out at Barts Health HNS Trust between April 2010 and March 2012. This study compares changes in bone mineral density (BMD) in 234 patients treated with 2 bisphosphonates: alendronate taken orally, and zoledronate administered intravenously. One hundred and eighteen patients received alendronate at 70 mg/week, while 116 patients received zoledronate once annually. Dual energy x-ray absorptiometry was used to measure BMD of the left hip and anterior-posterior spine (lumbar L1-L4) skeletal sites at baseline, and at one-, and 2-years post treatment. RESULTS: This study provides evidence that lumbar spine BMD increased by 3.6% in patients receiving alendronate, and 5.7% in patients receiving zoledronate after 2 years compared with baseline values (p=0.0001 for both). Total hip BMD decreased in patients treated with alendronate by 0.4% but increased in patients receiving zoledronate by 0.8% (p=0.0001). CONCLUSION: This study provides evidence that zoledronate is more effective than alendronate in treating patients with osteoporosis and with no gastrointestinal (GI) serious side effects. Furthermore, zoledronate appears to have the added advantage of a better safety profile in patients suffering from GI intolerance of oral bisphosphonates. PMID- 26593164 TI - Osteoporosis treatment with zoledronic acid in pediatric population at a university hospital in Western Saudi Arabia. A 13-year experience. AB - OBJECTIVES: To highlight the clinical benefit, efficacy, and safety of zoledronic acid (ZA) therapy in children and adolescents with primary and secondary osteoporosis. METHODS: This is a retrospective observational study of 131 children and adolescents visiting the Pediatric Endocrine Clinic at King Abdulaziz University Hospital, Jeddah, Kingdom of Saudi Arabia, between January 2002 and January 2015. Clinical and laboratory data were collected for each patient and adverse events were evaluated. RESULTS: The mean patient age was 11.43 years. There was a significant decrease in the number of fractures after ZA treatment for primary osteoporosis (p=0.000) and in secondary osteoporosis (p=0.005). There was a significant decrease in both osteocalcin (p=0.001) and C terminal telopeptide (p=0.003) in patients with primary osteoporosis, as well as osteocalcin (p=0.003) and C-terminal telopeptide (p=0.008) in patients with secondary osteoporosis after treatment. CONCLUSION: The use of ZA in children and adolescent appears to have favorable effects on fracture rate and quality of life, including pain and mobility in symptomatic individuals. Intravenous ZA is comparable to other bisphosphonate agents in its efficacy and safety and features a more convenient infusion protocol with no documented long-term complications, thus, we advise its use in pediatric population. PMID- 26593165 TI - Prostatic diseases under focus in a university hospital in Eastern Saudi Arabia. A 15-year experience. AB - OBJECTIVES: To explore the spectrum of pathologies diagnosed in prostatic biopsies of Saudi men, and test whether the frequency of diagnosing the malignant fraction has been changed over the last 15 years, and assess the association between chronic inflammation (CI) with both benign prostatic hyperplasia (BPH) and cancer (PCa), and investigate the histological findings of cases presented with acute urinary retention (AUR) clinically. METHODS: This is a retrospective cohort study including all prostatic biopsies accessed in the files in the Surgical Pathology Laboratory of King Fahd University Hospital, Alkhobar, Kingdom of Saudi Arabia over 15 years (1999-2013) for Saudi men. Age, procedure indication, and final diagnoses were retrieved and slides were reviewed. RESULTS: There were 360 cases included in this study with a median age of 65 year-old. The BPH comprised the most (64.7%), while PCa accounted for 89 cases, 13.5% of which were incidental. Most cases of both BPH and PCa were diagnosed in the seventh decade. The frequency of diagnosing PCa did not show a solid rise or fall over time. Chronic inflammation is more related to BPH than to PCa. Only CI showed a significant statistical association with AUR. CONCLUSION: Prostatic diseases show a stable trend over time. While CI is a common dominator for both BPH and PCa, it is associated more with BPH. Among all histological findings, only CI is related to the clinical presentation of AUR. PMID- 26593166 TI - Decline in menarcheal age among Saudi girls. AB - OBJECTIVES: To estimate age at menarche and to assess trends in menarcheal age among Saudi women. METHODS: A prospective longitudinal study was conducted among healthy prepubertal female school children and adolescents from September 2006 to July 2012 in Riyadh, Kingdom of Saudi Arabia. Study participants were invited from diverse socioeconomic backgrounds. Tanner stage, height, weight, body mass index, and socioeconomic parameters including parent's level of education were collected. Age at menarche was compared with maternal age at menarche. RESULTS: The study included 265 girls and mothers. Mean+/-standard deviation (SD) age at menarche for girls was 13.08 +/- 1.1 years, and their distribution category across the <=10 years was 4 (1.5%), 11-14 years was 239 (90.2%), and >=15 years was 22 (8.3%) girls. Anthropometric measurements, mother's level of education, and family income were not statistically significant determining factors associated with age at menarche. Mean +/- SD age at menarche for mothers was 13.67 +/- 1.4 years, and their distribution category across the <=10 years was 7 (2.6%), 11-14 years was 172 (64.9%), and >=15 years was 86 (32.5%). Girls attained menarche at younger age compared with their mothers (p less than 0.0001). A downward secular trend in age of menarche was observed (Cuzick test for trend = 0.049). CONCLUSION: Saudi girls attain menarcheal age earlier than their mothers, reflecting a downward secular trend in menarcheal age. PMID- 26593167 TI - Perception of the faculty regarding problem-based learning as an educational approach in Northwestern Saudi Arabia. AB - OBJECTIVES: To assess the knowledge, attitudes, and practice of medical teachers regarding problem-based learning (PBL) in Northwestern Saudi Arabia. METHODS: This is a cross-sectional study conducted in the College of Medicine, Taibah University, Al Madinah Al Munawarah, Kingdom of Saudi Arabia, at the beginning of the academic year 2014/2015 where the PBL method had recently been introduced. Medical academic staff (n=110) were invited to participate in the study. Data about staff sociodemographic characteristics, PBL knowledge, attitudes, and practice were collected via a pre-designed structured questionnaire. The collected data were analyzed using appropriate statistical methods. RESULTS: The overall response rate was 77.3% (85 out of 110). The proportion of staff having good PBL knowledge was 76.5% (95% CI= 68.5%-84.5%), with the higher proportion being observed among the male staff (79.1%), professors (86%), and associate professors (88%). Significantly higher positive perceptions were found among male and clinical sciences staff. The PBL practice of the studied staff was 35%, with a statistically significant difference observed between male and female staff. Problem-based learning practice was also higher among clinical staff (42%), associate professors (40%), and professors (38%). CONCLUSION: A considerably high proportion of the studied medical staff was found to have good knowledge and favorable attitudes towards PBL. Training courses by the college should be considered for the staffs who have not previously engaged in such learning methods, as well for the junior and new staff. PMID- 26593168 TI - Evaluation of mini-implant sites in the posterior maxilla using traditional radiographs and cone-beam computed tomography. AB - OBJECTIVES: To evaluate the accuracy of using routine 2-dimensional (2D) radiographs (panoramic and periapical) when evaluating the position of orthodontic temporary anchorage devices (mini-implants) in the maxilla, and to compare the results to 3-dimensional cone-beam computed tomography (CBCT). METHODS: This cross-sectional study was conducted at King Abdulaziz University, Faculty of Dentistry, Jeddah, Kingdom of Saudi Arabia from February 2014 to January 2015. Panoramic and periapical radiographs were used to examine the position of mini-implants in relation to the adjacent roots. Rating of mini implants position was performed by 82 dentists from different specialties, using 2D images according to the following criteria: 1) away from the root; 2) mini implant tip appears touching the lamina dura; and 3) mini-implant overlays the lamina dura. The results were compared with CBCT findings. RESULTS: There was no difference between dentists from different specialties when rating the position of the mini-implants (Cronbach's alpha=0.956). The accuracy of the periapical images was 45.1%, while the panoramic images 33.6%. However, both panoramic and periapical radiographs were significantly inaccurate when assessing the mini implant position when compared with the CBCT findings (p=0.0001). CONCLUSION: Three-dimensional CBCT technology allows better visualization of mini-implant placement. The use of CBCT when assessing the position of mini-implants is recommended. PMID- 26593169 TI - Effectiveness of benzocaine in reducing deep cavity restoration and post extraction stress in dental patients. AB - OBJECTIVES: To investigate the effectiveness of topical anesthetic, 20% benzocaine in relieving pain and stress in patients following deep cavity restoration and extraction of teeth under local anesthesia (LA). METHODS: A prospective clinical trial was conducted from October 2014 until April 2015 at Taibah University, Al Madinah Al Munawarah, Kingdom of Saudi Arabia. Forty-five patients were included in the 20% benzocaine group, and 46 in the normal saline group. Evaluation of the dental stress was made pre-operatively and immediately post-operative treatment using the visual analogue scale (VAS). Furthermore, discomfort of the injections were recorded by the patients after each treatment on standard 100 mm VAS, tagged at the endpoints with "no pain" (0 mm) and "unbearable pain" (100 mm). RESULTS: There were statistically significant differences between the mean stress scores for patients in the benzocaine and normal saline groups post-operatively (p=0.002). There were significant differences between the mean pain scores for patients in the post buccal injection (p=0.001), post palatal injection (p=0.01), and the post inferior alveolar nerve block groups (p=0.02). Buccal, palatal, and inferior alveolar nerve block injections were more painful for patients in the normal saline group than the benzocaine group. CONCLUSION: This investigation has demonstrated that post-operative stress associated with deep cavity restoration and dental extractions under LA can be reduced by the application of topical anesthetic (20% benzocaine) at the operative site for intra-oral injections. PMID- 26593170 TI - A rare case of giant fibrovascular polyp of the esophagus. AB - Fibrovascular polyps of the esophagus are rare, benign, and submucosal tumor-like lesions, their course is usually indolent until reaching enormous proportions. The most frequent symptoms are dysphagia, vomiting, and weight loss. Surgical excision is the treatment of choice, since endoscopic removal is not always feasible. We report a case of a 59-year-old man with a giant fibrovascular polyp who complained of progressive dysphagia. The lesion was resected by left cervical approach. The patient remains symptom-and recurrence-free within one-year of follow-up. PMID- 26593171 TI - Atrial fibrillation cardioversion following acupuncture. AB - Atrial fibrillation (AF) is the most common arrhythmia and it is an independent risk for serious events. Acupuncture has been growing in popularity in the West, and there are reports of its benefits in treating AF. We report a 57-year-old man who was admitted after having an allergic reaction to amiodarone administered to treat paroxysmal AF with fast ventricular response. Cardioversion with intravenous propafenone was uneventful. Before an attempt of electric cardioversion, he was treated with acupuncture as additional therapy to peroral propafenone. After acupuncture treatment consisting of 10 treatments during 30 days period, both immediate cardioversion to sinus rhythm and no paroxysmal AF during 30 days period were recorded. PMID- 26593172 TI - Glutaric aciduria type 1 as a cause of dystonic cerebral palsy. AB - Glutaric aciduria type 1 (GA1) is an inherited inborn error of metabolism caused by a deficiency of the enzyme glutaryl Co-A dehydrogenase (GCDH). Here, we report a 14-month-old Saudi boy with GA1 who presented with severe dystonia and was mis diagnosed as cerebral palsy (CP). He presented to our institute with encephalopathy following an episode of gastroenteritis. His physical examination showed dystonia and spastic quadriplegia. His investigations revealed elevated both urinary 3-hydroxy glutaric acid, and serum glutarylcarnitine. The DNA analysis confirmed homozygosity for a mutation in the GCDH-coding gene (c.482G greater than A; p.R161Q). This case alerts pediatricians to consider GA1 as a differential diagnosis of children presenting with dystonic CP. PMID- 26593173 TI - The effect of positive end-expiratory pressure on inflammatory cytokines during laparoscopic cholecystectomy. AB - OBJECTIVES: To investigate effects of the positive end-expiratory pressure (PEEP) application of 10 cm H2O on the plasma levels of cytokines during laparoscopic cholecystectomy. METHODS: A prospective study was conducted on 40 patients who presented to the Department of General Surgery, Medical Faculty, Turgut Ozal University, Ankara, Turkey scheduled for laparoscopic cholecystectomy operation during a 10 month period from September 2012 to June 2013. Forty patients scheduled for laparoscopic cholecystectomy operation were randomly divided into 2 groups; ventilation through zero end-expiratory pressure (ZEEP) (0 cm H2O PEEP) (n=20), and PEEP (10 cm H2O PEEP) (n=20). All patients were ventilated with 8 ml/kg TV. Levels of interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, IL 10, and transforming growth factor (TGF)-beta1 were measured in the pre- and post operatively collected samples. RESULTS: Blood samples of 30 patients' were analyzed for plasma cytokine levels, and 10 were excluded from the study due to hemolysis. Post-operative plasma IL-6 levels were observed to be significantly higher than the pre-operative patients (p=0.035). Post-operative plasma TGF-beta1 levels in the PEEP group was found significantly higher compared with the pre operative group levels (p=0.033). However, there were no significant differences in the pre- and post-operative plasma cytokine levels between the 2 groups. CONCLUSION: The application of PEEP of 10 cm H2O, which has known beneficial effect on respiratory mechanics, does not have any effect on systemic inflammatory response undergoing pneumoperitoneum during laparoscopic cholecystectomy surgery. PMID- 26593174 TI - Extracranial non-vestibular head and neck schwannomas. AB - OBJECTIVES: To retrospectively describe our 10-year experience with extracranial non-vestibular head and neck schwannomas by presenting their clinical features, diagnostic methods, surgical decisions, and treatment outcomes. METHODS: This is a retrospective study conducted at the Department of Otolaryngology, Head and Neck Surgery, Shanghai Jiao Tong University Affiliated Shanghai First People's Hospital, Shanghai, China. The medical records of 46 patients diagnosed with schwannoma in the extracranial head and neck region as confirmed on paraffin embedded sections from January 2003 to December 2012 were reviewed. RESULTS: All tumors were benign, and 52% presented as asymptomatic palpable solitary masses. Compressive symptoms, which can represent meaningful indicators of the nerve of origin were commonly noted. The most common nerve of origin was the brachial plexus (n=13, 28.3%). CONCLUSION: While postoperative histopathologic examination is still the gold standard, fine needle aspiration cytology, CT scan, and magnetic resonance imaging may be useful in the diagnosis of schwannomas. As schwannomas are radioresistant, and as, despite their benign nature, can cause severe secondary symptoms, the best treatment of choice is complete excision with preservation of functions. PMID- 26593175 TI - Usage of venous thromboembolism prophylaxis at a tertiary care hospital in Aseer region of Saudi Arabia. PMID- 26593176 TI - A qualitative exploration of the major challenges facing pharmacovigilance in Saudi Arabia. PMID- 26593177 TI - The prevalence and genotype diversity of Human Rotavirus A circulating in Thailand, 2011-2014. AB - Human rotavirus A (RVA) is the major infectious virus causing acute watery diarrhea in children, especially those younger than 5 years of age, and is a major public health problem in Thailand. Outbreaks of this virus have been reported worldwide. Besides the common genotypes, unusual genotypes providing evidence of inter-species transmission have also been described. Therefore, the aim of this study was to investigate the prevalence and genotypes of RVA in Thailand. A total of 688 samples were collected from children who were hospitalized with acute diarrhea in Chumphae Hospital in Khon Kaen and Chulalongkorn Hospital in Bangkok. RVA was detected using one-step RT-PCR and the genotypes were evaluated by sequencing. Overall, 204 of the 688 samples (30%) were positive for RVA. Nine genotypes were identified: three common in humans (G1P[8] [53%], G2P[4] [18%], G3P[8] [12%]), one feline-like (G3P[9] [1%]), four porcine-like (G4P[6] [0.5%], G5P[6] [0.5%], G9P[8] [0.5%], G12P[6] [1.5%]), and one bovine-like (G8P[8] [13%]). The variation in virus genotypes and the animal like genotypes detected in this study suggested that a high diversity of RVA types is circulating in the Thai population. Therefore, continuous molecular epidemiological monitoring of RVA is essential and has implications for the national vaccination program. PMID- 26593179 TI - Thirty Years of Geometry Optimization in Quantum Chemistry and Beyond: A Tribute to Berny Schlegel. PMID- 26593178 TI - Prevalence of anti-Toxoplasma gondii antibody in domestic horses in Japan. AB - The present study is the first report that investigated the seroprevalence of Toxoplasma gondii infection in domestic horses in various prefectures of Japan and analyzed risk factors for seropositivity. We performed a latex agglutination test for riding/racing horses from 11 prefectures in Japan (783 samples) and 4 groups of Japanese native horses (254 samples). The total seroprevalence of anti T. gondii antibody in horses examined in this study was 4.24% (44/1037). As for riding/racing horses, we did not find a statistically different T. gondii seroprevalence between sampling prefectures. In contrast, seroprevalence of T. gondii in older horses (>21 years) was significantly higher than that in younger horses (<5 years and 11-15 years). There was no significant difference in T. gondii seroprevalence between riding/racing horses and Japanese native horses. Logistical regression analysis revealed that age, but not sex and usage, is a significant risk factor of T. gondii infection for domestic horses in Japan. These findings suggest that domesticated horses in Japan can be horizontally infected with T. gondii by ingestion of food or water contaminated with oocysts. PMID- 26593180 TI - A Relation Between the Eikonal Equation Associated to a Potential Energy Surface and a Hyperbolic Wave Equation. AB - The potential energy surface (PES) of a molecule can be decomposed into equipotential hypersurfaces. We show in this article that the hypersurfaces are the wave fronts of a certain hyperbolic partial differential equation, a wave equation. It is connected with the gradient lines, or the steepest descent, or the steepest ascent lines of the PES. The energy seen as a reaction coordinate plays the central role in this treatment. PMID- 26593181 TI - Constructing Periodic Phase Space Orbits from ab Initio Molecular Dynamics Trajectories to Analyze Vibrational Spectra: Case Study of the Zundel (H5O2(+)) Cation. AB - A method of analysis is introduced to probe the spectral features obtained from ab initio molecular dynamics simulations. Here, the instantaneous mass-weighted velocities are projected onto irreducible representations constructed from discrete time translation groups comprising operations that invoke the time domain symmetries (or periodic phase space orbits) reflected in the spectra. The projected velocities are decomposed using singular value decomposition (SVD) to construct a set of "modes" pertaining to a given frequency domain. These modes now include all anharmonicities, as sampled during the dynamics simulations. In this approach, the underlying motions are probed in a manner invariant with respect to coordinate transformations, operations being performed along the time axis rather than coordinate axes, making the analysis independent of choice of reference frame. The method is used to probe the underlying motions responsible for the doublet at ~1000 cm(-1) in the vibrational spectrum of the H5O2(+), Zundel cation. The associated analysis results are confirmed by projecting the Fourier transformed velocities onto the harmonic normal mode coordinates and a set of mass-weighted, symmetrized Jacobi coordinates. It is found that the two peaks of the doublet are described and differentiated by their respective contributions from the proton transfer, water-water stretch, and water wag coordinates, as these are defined. Temperature dependent effects are also briefly noted. PMID- 26593182 TI - Gaussian Expansions of Orbitals. PMID- 26593183 TI - Performance of Gradient-Corrected and Hybrid Density Functional Theory: Role of the Underlying Local Density Approximation and the Gradient Correction. AB - We have analyzed the performance of several widely used density functional theory procedures, namely B-P86, B-PW91, B-LYP, B3-P86, B3-PW91, and B3-LYP, for the E3 set of thermochemical properties. Each of these procedures employs a local density approximation (LDA) functional and a gradient correction for the correlation energy. We find that the VWN3 LDA functional in B-P86, B-PW91, B3 P86, and B3-PW91 leads to extremely large deviations from benchmark values for heats of formation (as large as -455.6 kJ mol(-1) for the B-PW91(VWN3) value for azulene!) and that VWN3 also gives significant errors in the calculated ionization energies and electron affinities. The PW91 gradient correction generally performs much better than P86 for heats of formation, and we propose that this is because P86 severely violates a uniform scaling condition that PW91 almost satisfies. Thus, of the procedures that we have examined, we recommend the use of the VWN5 or PW92 forms of LDA, preferably in combination with the PW91 gradient correction. Our results confirm previous findings that VWN3 is a more suitable LDA than VWN5 for B3-LYP, and we attribute this to fortuitous error cancellation between understabilization of molecules by LYP and overstabilization by VWN3. PMID- 26593184 TI - Deconstructing the ONIOM Hessian: Investigating Method Combinations for Transition Structures. AB - Developments in biochemistry and materials sciences have led to increasing interest in the reactivity of large chemical systems, presenting theoretical and computational challenges that can be addressed with hybrid methods such as ONIOM. Here, we show that the diagonalized ONIOM Hessian can be partitioned/deconstructed into contributions from the individual subcalculations indicating the curvature of their potential energy surfaces (PESs)-without increasing the computational cost. The resulting pseudofrequencies have particular application in the study of transition structures and higher-order saddle points with ONIOM, where we find that an imaginary frequency may result from combining subcalculations for which the corresponding vibrational frequencies are all real. Two cycloaddition reactions, including functionalization of a 150 atom (5,5) single-walled carbon nanotube, demonstrate how this analysis of pseudofrequencies allows identification of critical points where further exploratory work should be carried out to ensure that the ONIOM PES correctly approximates the target. PMID- 26593185 TI - Electronic and Magnetic Properties of Kremer's tris-Hydroxo Bridged Chromium Dimer: A Challenge for DFT. AB - We present computations of the zero field splitting constants in a tris-hydroxo bridged chromium dimer (Kremer's dimer). A comparison is given of broken symmetry density functional theory (DFT) and multiconfigurational ab initio methods for evaluating ZFS constants. Kremer's dimer is known to be antiferromagnetically coupled, with the spin ladder order of E(S = 0) < E(S = 1) < E(S = 2) < E(S = 3). The B3LYP functional gives the order E(S = 0) < E(S = 3) < E(S = 1) < E(S = 2), and similar results are obtained for other density functionals (PBE, M06, M06-L, and TPSS). In contrast, we find that simple CASSCF calculations yield a correct spin ladder. DFT poorly reproduces the experimental D splitting values, while the CASSCF technique coupled with quasi-degenerate perturbation theory qualitatively reproduces D for all the spin states. State-optimized orbitals result in more accurate spin state energies and D values compared to state-averaged orbitals. Inclusion of spin-spin coupling is found to be essential for both the magnitude and sign of D. The rhombic splitting parameter is found to be near zero, which is comparable to experimental results for which the analysis assumed C3h symmetry. PMID- 26593186 TI - A Valence Bond Description of the Prefulvene Extended Conical Intersection Seam of Benzene. AB - The permutational isomers of the prefulvene-like minimum energy conical intersection lie on an extended conical intersection seam, where they are connected by higher symmetry structures. Here, we present a VB analysis of the electronic states involved along this extended seam. The VB method produces a spin-exchange density (ie. a bonding pattern) that provides the basis to assign resonance structures to the states. The results show that in the high symmetry region of the seam, the character of the states is dominated by the positive and negative combination of the Kekule structures, (A+B) and (A-B). The low energy parts of the seam, comprised of lower symmetry conical intersection structures, are stabilized by mixing with the Dewar resonance structures. This feature is responsible for the stability of the benzvalene-like conical intersections. The validity of the VB model is confirmed by calculating the branching space vectors at this level of theory, which are in good agreement with the CASSCF calculated vectors. The VB analysis has also allowed us to complete our picture of the global seam, since it has provided the clue to locate a conical intersection saddle point that interconverts two minima of the prefulvene conical intersection where the carbon bent out of the plane is inverted and rotated by 60 degrees . This saddle point has a benzvalene-like geometry, in agreement with the VB picture. PMID- 26593187 TI - Energetics and Mechanism of the Hydrogenation of XHn for Group IV to Group VII Elements X. AB - High-level ab initio calculations of the NESC/SOC/CCSD(T)/cc-pV5Z type (NESC, Normalized Elimination of the Small Component; SOC, spin-orbit coupling corrections using the Breit-Pauli Hamiltonian) are employed to determine the energetics of the 18 hydrogenation reactions XHn + H2 -> XHn+1 + H with X = F, Cl, Br, I, O, S, Se, Te, N, P, As, Sb, Bi, C, Si, Ge, Sn, and Pb. Accurate reaction and activation enthalpies as well as the corresponding free energies are obtained by calculating vibrational, thermochemical, and entropy corrections with a cc-pVTZ basis set. Also calculated are accurate X-H bond dissociation enthalpies at 298 K. The reaction mechanism of all 18 reactions is analyzed using the unified reaction valley approach (URVA) and UMP2/6-31G(d,p) to determine each reaction valley with high accuracy (step size 0.005 to 0.03 amu(1/2) bohr). By analyzing the reaction path curvature, the mechanism can be partitioned into four to six reaction phases, in which the reaction complex XHn...H2 undergoes specific chemical transformations. The fate of the reaction complex is determined at an early stage in the entrance channel. Curvature peaks reflect the strength of the bonds being broken or formed and provide the basis for a quantitative justification of the Hammond-Leffler postulate. PMID- 26593188 TI - Exploring Copper Oxide Cores Using the Projected Hartree-Fock Method. AB - Coupled binuclear copper oxide cores are present in the active sites of some of the very common metalloenzymes found in most living organisms. The correct theoretical description of the interconversion between the two dominant structural isomers of this core, namely, side-on MU-eta(2):eta(2) peroxodicopper(II) and bis(MU-oxo)-dicopper(III), is challenging since it requires a method that can provide a balanced description of static and dynamic correlations. We investigate this problem using our recently developed projected Hartree-Fock method (PHF). Here, the spin and complex conjugation symmetries of the trial wave function are deliberately broken and restored in a variation-after projection scheme. The projected wave function carries good quantum numbers, has multireference character, and accounts for static and some dynamic correlation. Most importantly, the calculations are done at a mean-field computational cost allowing us to address large systems at a modest expense. The interconversion is studied here for the bare [Cu2O2](2+) core using a variety of projection methods (SUHF, SGHF, KSUHF, KSGHF). The results seem to be on par with much more demanding traditional multireference methods. PMID- 26593189 TI - Can Metallapyrimidines Be Aromatic? A Computational Study into a New Class of Metallacycles. AB - The aromaticity of a series of metallapyrimidines involving second row transition metals was examined using density functional theory. Nucleus independent chemical shifts (NICS) placed above the ring (NICS(1)zz) were used to gauge the amount of aromaticity. Natural chemical shielding analysis (NCS) was employed to decompose the chemical shifts in terms of diamagnetic and paramagnetic contributions from individual molecular orbitals. While NICS(1)zz for niobapyrimidine, [(pz)2(Nb pyr)](0), suggested slightly aromatic character, the NCS analysis shows this is due to the diamagnetic (field-free) contribution. Instead, the positive paramagnetic (field-induced) contribution suggests that niobapyrimidine may be slightly antiaromatic. A series of d(0) metallapyrimidines, [(pz)2(M-pyr)] with M = Y(III), Zr(IV), Nb(V), Mo(VI), Tc(VII), demonstrated similar behavior. Variation of the number of metal d electrons in a series of M(V) metallapyrimidines, [(pz)2(M-pyr)] where M = Mo, Tc, Ru, and Rh, showed strong evidence for aromaticity, with NICS(1)zz values of -15.4, -36.0, -31.6, and 22.4, respectively, that are comparable to benzene (-28.7). NCS analysis of the Tc(V), Ru(V), and Rh(V) complexes shows that aromaticity is favored by an unoccupied d-pi orbital that serves as an acceptor to facilitate conjugation in the metallapyrimidine ring. This unoccupied orbital is not sufficient as the d(0) series of complexes demonstrated, and we propose that the occupied d-delta orbital prevents bond localization and enables aromaticity in these metallacycles. PMID- 26593190 TI - Merging Active-Space and Renormalized Coupled-Cluster Methods via the CC(P;Q) Formalism, with Benchmark Calculations for Singlet-Triplet Gaps in Biradical Systems. AB - We have recently developed a flexible form of the method of moments of coupled cluster (CC) equations and the CC(P;Q) hierarchy, which enable one to correct the CC and equation-of-motion CC energies obtained with unconventional truncations in the cluster and excitation operators [Shen, J.; Piecuch, P. Chem. Phys.2012, 401, 180; J. Chem. Phys.2012, 136, 144104]. One of the CC(P;Q) methods is a novel hybrid scheme, abbreviated as CC(t;3), in which the results of CC calculations with singles, doubles, and active-space triples, termed CCSDt, are corrected for the triple excitations missing in CCSDt using the expressions that are reminiscent of the completely renormalized (CR) CC approach known as CR-CC(2,3). We demonstrate that the total electronic energies of the lowest singlet and triplet states, and the singlet-triplet gaps in biradical systems, including methylene, (HFH)(-), and trimethylenemethane, resulting from the CC(t;3) calculations agree with those obtained with the full CC approach with singles, doubles, and triples to within fractions of a millihartree, improving the results of the noniterative triples CCSD(T), CCSD(2)T, and CR-CC(2,3) and hybrid CCSD(T) h calculations, and competing with the best multireference CC data. PMID- 26593191 TI - A Density Functional with Spherical Atom Dispersion Terms. AB - A new hybrid density functional, APF, is introduced, which avoids the spurious long-range attractive or repulsive interactions that are found in most density functional theory (DFT) models. It therefore provides a sound baseline for the addition of an empirical dispersion correction term, which is developed from a spherical atom model (SAM). The APF-D empirical dispersion model contains nine adjustable parameters that were selected based on a very small training set (15 noble gas dimers and 4 small hydrocarbon dimers), along with two computed atomic properties (ionization potential and effective atomic polarizability) for each element. APF-D accurately describes a large portion of the potential energy surfaces of complexes of noble gas atoms with various diatomic molecules involving a wide range of elements and of dimers of small hydrocarbons, and it reproduces the relative conformational energies of organic molecules. The accuracy for these weak interactions is comparable to that of CCSD(T)/aug-cc-pVTZ calculations. The accuracy in predicting the geometry of hydrogen bond complexes is competitive with other models involving DFT and empirical dispersion. PMID- 26593192 TI - Fragment Molecular Orbital Molecular Dynamics with the Fully Analytic Energy Gradient. AB - Fragment molecular orbital molecular dynamics (FMO-MD) with periodic boundary conditions is performed on liquid water using the analytic energy gradient, the electrostatic potential point charge approximation, and the electrostatic dimer approximation. Compared to previous FMO-MD simulations of water that used an approximate energy gradient, inclusion of the response terms to provide a fully analytic energy gradient results in better energy conservation in the NVE ensemble for liquid water. An FMO-MD simulation that includes the fully analytic energy gradient and two body corrections (FMO2) gives improved energy conservation compared with a previously calculated FMO-MD simulation with an approximate energy gradient and including up to three body corrections (FMO3). PMID- 26593193 TI - Using Efficient Predictor-Corrector Reaction Path Integrators for Studies Involving Projected Frequencies. AB - Projected frequencies along a reaction pathway are necessary for computing reaction rates using variational transition state theory or reaction path Hamiltonian methods. The projected frequency analysis is quite sensitive to the accuracy of the reaction path integration. This work demonstrates that second- and first-order predictor-corrector reaction path integrators can be used for computing projected frequencies with high confidence. It is shown that these methods perform equally well with a variety of numerical integration step sizes and that, without a substantive loss in accuracy, Hessian updating can be used with both methods for stepping along the reaction path at points between those where projected frequencies are required. PMID- 26593194 TI - Quasi-Continuous Interpolation Scheme for Pathways between Distant Configurations. AB - A quasi-continuous interpolation (QCI) scheme is introduced for characterizing physically realistic initial pathways from which to initiate transition state searches and construct kinetic transition networks. Applications are presented for peptides, proteins, and a morphological transformation in an atomic cluster. The first step in each case involves end point alignment, and we describe the use of a shortest augmenting path algorithm for optimizing permutational isomers. The QCI procedure then employs an interpolating potential, which preserves the covalent bonding framework for the biomolecules and includes repulsive terms between unconstrained atoms. This potential is used to identify an interpolating path by minimizing contributions from a connected set of images, including terms corresponding to minima in the interatomic distances between them. This procedure detects unphysical geometries in the line segments between images. The most difficult cases, where linear interpolation would involve chain crossings, are treated by growing the structure an atom at a time using the interpolating potential. To test the QCI procedure, we carry through a series of benchmark calculations where the initial interpolation is coupled to explicit transition state searches to produce complete pathways between specified local minima. PMID- 26593195 TI - Mechanism of the Reduction of an Oxidized Glutathione Peroxidase Mimic with Thiols. AB - N,N-dimethylbenzylamine-2-selenol is a well-known, efficient glutathione peroxidase mimic. This compound reduces peroxides through a three-step catalytic mechanism, of which the first step has been well-characterized computationally. The mechanism for the reaction of N,N-dimethylbenzylamine-2-selenenic acid with a thiol, the second step in the catalytic cycle, is studied using reliable electronic structure techniques. Two different mechanisms are identified, using either a thiol or a deprotonated thiolate as the nucleophile. It is found that the lowest energy barrier mechanism incorporates two explicit solvent molecules to shuttle the thiol hydrogen to the leaving hydroxyl group, while the alternative mechanism using the thiolate has a barrier four times higher. PMID- 26593196 TI - Exploring Potential Energy Surfaces of Large Systems with Artificial Force Induced Reaction Method in Combination with ONIOM and Microiteration. AB - Development of efficient methods for finding chemical reaction pathways has been one of the central subjects of theoretical chemistry. Recently, the artificial force induced reaction (AFIR) method enabled automated search for associative reaction pathways between multiple reactant molecules and has been applied to reactions involving a few tens of atoms. To expand its applicability to large systems, we combined it with the geometrical microiteration technique. With this extension, full optimization of transition state structures of enzymatic reactions in the protein became possible within the QM/MM framework. Performance of the microiteration-AFIR method was tested for a single water catalyzed Aldol reaction in (H2O)299 cluster and for an enzymatic reaction of the isopenicillin N synthase, where the potential energy surfaces were calculated by the ONIOM(QM/MM) method. These numerical tests demonstrated that the present method is promising in predicting reaction pathways that take place within an active site (consisting of tens of atoms) in a very large environment such as protein and solution. PMID- 26593197 TI - Elucidation of Strong Cooperative Effects Caused by Dispersion Interactions in a Recognition-Mediated Diels-Alder Reaction. AB - Cooperative effects caused by dispersion interactions between dienes and dienophiles in a so-called self-replicating system have been evaluated by density functional theory. A variety of functionals is tested for the elucidation of reactant complex stabilities. Dispersion interactions between dienes and dienophiles result in additional stabilizations of up to 10 kcal mol(-1). These effects should be taken into account in future experimental studies and can be exploited to design more efficient systems. PMID- 26593198 TI - Application of Gaussian Electrostatic Model (GEM) Distributed Multipoles in the AMOEBA Force Field. AB - We present the inclusion of distributed multipoles obtained from the Gaussian Electrostatic Model (GEM) into the AMOEBA force field. As a proof of principle, we have reparametrized water and alanine di-peptide. The GEM distributed multipoles (GEM-DM) have been obtained at the same levels of theory as those used for the original AMOEBA parametrization. The use of GEM allows the derivation of the distributed multipoles from the analytical fit to the molecular density or the numerical fit to the molecular electrostatic potential (mESP). In addition, GEM-DM are intrinsically finite of the highest order of the auxiliary basis used for the GEM fit. We also present the fitting of multipoles for the di-methyl imidazolium/chloride (DMIM(+)-Cl(-)) ionic liquid pair. Results for intermolecular Coulomb for all test systems show very good agreement. MD simulations for a reparametrized AMOEBA water model with GEM-DM provide results on par with the original AMOEBA force field for a series of bulk properties including liquid density and enthalpy of vaporization. A package for the calculation of GEM Hermite coefficients and derived distributed multipoles using the numerical procedure is also presented and released under the GNU public license. PMID- 26593199 TI - Exploring Potential Energy Surfaces of Electronic Excited States in Solution with the EOM-CCSD-PCM Method. AB - The effect of the solvent on the structure of a molecule in an electronic excited state cannot be neglected. However, the computational cost of including explicit solvent molecules around the solute becomes rather onerous when an accurate method such as the equation of motion coupled cluster singles and doubles (EOM CCSD) is employed. Solvation continuum models like the polarizable continuum model (PCM) provide an efficient alternative to explicit models, since the solvent conformational average is implicit and the solute-solvent mutual polarization is naturally accounted for. In this work, the coupling of EOM-CCSD and PCM in a state specific approach is presented for the evaluation of energy and analytic energy gradients. Also, various approximations are explored to maintain the computational cost comparable to gas phase EOM-CCSD. Numerical examples are used to test the different schemes. PMID- 26593200 TI - Theoretical Determination of One-Electron Oxidation Potentials for Nucleic Acid Bases. AB - The oxidation potentials for N-methyl substituted nucleic acid bases guanine, adenine, cytosine, thymine, uracil, xanthine, and 8-oxoguanine were computed using B3LYP and CBS-QB3 with the SMD solvation model. Acid-base and tautomeric equilibria present in aqueous solution were accounted for by combining standard redox potentials with calculated pKa and tautomerization energies to produce an ensemble averaged pH dependent potential. Gas phase free energies were computed using B3LYP/aug-cc-pVTZ//B3LYP/6-31+G(d,p) and CBS-QB3. Solvation free energies were computed at the SMD/B3LYP/6-31+G(d,p) level of theory. Compared to experimental results, calculations with the CBS-QB3 level of theory have a mean absolute error (MAE) of ca. 1 kcal/mol for the gas phase proton affinity/gas phase basicity and an MAE of ca. 0.04 eV for the adiabatic/vertical ionization potentials. The B3LYP calculations have a MAE of ~2 kcal/mol for the proton affinity/gas phase basicity data but systematically underestimated ionization potentials by 0.14-0.21 eV. Solvent cavities for charged solute species were rescaled uniformly by fitting computed pKa data to experimentally measured pKa values. After solvent cavity scaling, the MAEs for computed pKa's compared to experimental results are 0.7 for B3LYP and 0.9 for CBS-QB3. In acetonitrile, the computed E degrees (XH(+*)/XH) redox potentials are systematically lower than experimentally measured potentials by 0.21 V for CBS-QB3 and 0.33 V for B3LYP. However, the redox potentials relative to adenine are in very good agreement with experimental results, with MAEs of 0.10 V for CBS-QB3 and 0.07 V for B3LYP. In aqueous solution, B3LYP and CBS-QB3 have MAEs of 0.21 and 0.19 V for E7(X(*),H(+)/XH). Replacing the methyl substituent with ribose changes the calculated E7 potentials by 0.1-0.2 V. The calculated difference between the guanine and adenine oxidation potentials is too large compared to experimental results, but the calculated difference between guanine and 8-oxoguanine is in good agreement with the measured values. PMID- 26593201 TI - Adsorption of Organic Molecules on Kaolinite from the Exchange-Hole Dipole Moment Dispersion Model. AB - Intermolecular interactions between organic molecules and clay minerals are important in a wide range of chemical applications, ranging from oil-sands petroleum extraction to environmental chemistry and catalysis. The binding energies between each of benzene, n-hexane, pyridine, 2-propanol, and water and the kaolinite surface are calculated using density functional theory with the exchange-hole dipole moment dispersion model. The dominant noncovalent interactions are found to be hydrogen bonding for pyridine, 2-propanol, and water, OH-pi interactions for benzene, and CH-O interactions for n-hexane. All molecules considered are more strongly bound to the hydrophilic alumina face, rather than the hydrophobic siloxane face, of kaolinte. PMID- 26593202 TI - A Composite Energy Treatment for Sterically Hindered Cluster Models for the Si(100) Surface. AB - Cluster models representing multiple dimer rows on the Si(100) surface suffer from unfavorable and unphysical steric interactions between hydrogen link atoms. A novel composite energy method is proposed to cancel such undesirable interactions present in the cluster model. In our composite method, the unphysical repulsive interaction energy between excised fragments (defined from the cluster model) is replaced by individual noninteracting fragments along with a Lennard-Jones-type repulsion term between the neighboring link atoms. The resulting composite energy and the associated gradients consist of well-defined individual subsystem calculations and can be used to perform geometry optimizations using such cluster models without additional constraints. Despite small differences from an ideal Si(100) reconstructed surface, this model can be used to investigate and analyze important surface chemical reactions. Results of allylic mercaptan adsorption on a Si(100) dimer using our proposed cluster model are reported to demonstrate the novel method's robustness. PMID- 26593203 TI - Right- and Left-Handed Helices, What is in between? Interconversion of Helical Structures of Alternating Pyridinedicarboxamide/m-(phenylazo)azobenzene Oligomers. AB - Some unnatural polymers/oligomers have been designed to adopt a well-defined, compact, three-dimensional folding capability. Azobenzene units are common linkages in these oligomer designs. Two alternating pyridinedicarboxamide/m (phenylazo)azobenzene oligomers that can fold into both right- and left-handed helices were studied computationally in order to understand their dynamical properties. Helical structures were shown to be the global minima among the many different conformations generated from the Monte Carlo simulations, and extended conformations have higher potential energies than compact ones. To understand the interconversion process between right- and left-handed helices, replica-exchange molecular dynamic (REMD) simulations were performed on both oligomers, and with this method, both right- and left-handed helices were successfully sampled during the simulations. REMD trajectories revealed twisted conformations as intermediate structures in the interconversion pathway between the two helical forms of these azobenzene oligomers. This mechanism was observed in both oligomers in current study and occurred locally in the larger oligomer. This discovery indicates that the interconversion between helical structures with different handedness goes through a compact and partially folded structure instead of globally unfold and extended structure. This is also verified by the nudged elastic band (NEB) calculations. The temperature weighted histogram analysis method (T-WHAM) was applied on the REMD results to generate contour maps of the potential of mean force (PMF). Analysis showed that right- and left-handed helices are equally sampled in these REMD simulations. In large oligomers, both right- and left handed helices can be adopted by different parts of the molecule simultaneously. The interconversion between two helical forms can occur in the middle of the helical structure and not necessarily at the termini of the oligomer. PMID- 26593204 TI - The Binding of Fe(II)-Heme to the Amyloid Beta Peptide of Alzheimer's Disease: QM/MM Investigations. AB - The structures of complexes between Abeta(1-42) and ferroheme (Fe(II)-heme) were determined by application of Amber and ONIOM(B3LYP/6-31G(d):Amber) methodology. Attachment at each of the three His residues was investigated. In each case, direct bonding of the iron to the His residue is augmented by the formation of secondary salt bridges between the carboxylate groups of the heme and positively charged residues of Abeta (at His13, by Lys16 and the N-terminus; at His14, by both Lys16 and Lys28; at His6, by Arg5) or by H-bonding and hydrophobic interactions (at His6, by Asp7 or Phe20). The results indicate a slight preference for His13 followed by His6 and His14, with the lowest eight structures lying within 36 kJ mol(-1) of each other. The methodology is not precise enough to permit a definitive statement as to the relative stabilities, nor to the absolute binding affinities, which are predicted to be less than 70 kJ mol(-1). The results bear on the question of how heme and copper may bind simultaneously to Abeta. They confirm that the reduced species can bind independently, Cu(+) at His13-His14 and Fe(II)-heme at His6. PMID- 26593205 TI - A Local Rigid Body Framework for Global Optimization of Biomolecules. AB - We present a local rigid body framework for simulations of biomolecules. In this framework, arbritrary sets of atoms may be treated as rigid bodies. Such groupings reduce the number of degrees of freedom, which can result in a significant reduction of computational time. As benchmarks, we consider global optimization for the tryptophan zipper (trpzip 1, 1LE0; using the CHARMM force field) and chignolin (1UAO; using the AMBER force field). We use a basin-hopping algorithm to find the global minima and compute the mean first encounter time from random starting configurations with and without the local rigid body framework. Minimal groupings are used, where only peptide bonds, termini, and side chain rings are considered rigid. Finding the global minimum is 4.2 and 2.5 times faster, respectively, for trpzip 1 and chignolin, within the local rigid body framework. We further compare O(10(5)) low-lying local minima to the fully relaxed unconstrained representation for trpzip 1 at different levels of rigidification. The resulting Pearson correlation coefficients, and thus the apparent intrinsic rigidity of the various groups, appear in the following order: side chain rings > termini > trigonal planar centers >= peptide bonds ? side chains. This approach is likely to be even more beneficial for structure prediction in larger biomolecules. PMID- 26593206 TI - Automated Transition State Searches without Evaluating the Hessian. AB - Accurate and speedy determination of transition structures (TSs) is essential for computational studies on reaction pathways, particularly when the process involves expensive electronic structure calculations. Many search algorithms require a good initial guess of the TS geometry, as well as a Hessian input that possesses a structure consistent with the desired saddle point. Among the double ended interpolation methods for generation of the guess for the TS, the freezing string method (FSM) is proven to be far less expensive compared to its predecessor, the growing string method (GSM). In this paper, it is demonstrated that the efficiency of this technique can be improved further by replacing the conjugate gradient optimization step (FSM-CG) with a quasi-Newton line search coupled with a BFGS Hessian update (FSM-BFGS). A second crucial factor that affects the speed with which convergence to the TS is achieved is the quality and cost of the Hessian of the energy for the guessed TS. For electronic structure calculations, the cost of calculating an exact Hessian increases more rapidly with system size than the energy and gradient. Therefore, to sidestep calculation of the exact Hessian, an approximate Hessian is constructed, using the tangent direction and local curvature at the TS guess. It is demonstrated that the partitioned-rational function optimization algorithm for locating TSs with this approximate Hessian input performs at least as well as with an exact Hessian input in most test cases. The two techniques, FSM and approximate Hessian construction, therefore can significantly reduce costs associated with finding TSs. PMID- 26593207 TI - Transition State Search Using a Guided Direct Inversion in the Iterative Subspace Method. AB - A transition state optimization method using a guided energy-represented direct inversion in the iterative subspace (gEn-DIIS) algorithm is introduced and compared with the quasi-Newton rational function optimization (RFO) method. A hybrid technique that employs a combination of RFO and guided DIIS methods at various stages of convergence is presented. A set of test molecules is optimized for comparison using the hybrid method with gEn-DIIS and the traditional RFO methods. The gEn-DIIS method presented here exhibits fast optimization and is shown to be advantageous for difficult optimizations where the reaction path is flat. PMID- 26593208 TI - Oncogenic miR-9 is a target of erlotinib in NSCLCs. AB - EGFR-targeted cancer therapy is a breakthrough in non-small cell carcinoma. miRNAs have been proved to play important roles in cancer. Currently, for the role of miRNAs in EGFR-targeted cancer therapy is unclear. In this study, first we found that erlotinib reduced the expression of miR-9. MiR-9 expression was increased in human lung cancer tissues compared with peripheral normal tissues, and miR-9 promoted the growth of NSCLC cells. Overexpression of miR-9 decreased the growth inhibitory effect of erlotinib. Second, miR-9 decreased FoxO1 expression by directly inhibition of its mRNA translation. Adenovirus-mediated overexpression of FoxO1 or siRNA-mediated downregulation of FoxO1 negatively regulated cell growth. And exogenous overexpression FoxO1 reduced the pro-growth effect of miR-9. Finally, we found that erlotinib upregulated FoxO1 protein expression. Moreover, overexpression of miR-9 decreased erlotinib-induced FoxO1 expression, and overexpression of FoxO1 enhanced the growth inhibitory effects of erlotinib. Additionally, we found that erlotinib downregulates miR-9 expression through suppressing the transcrption of miR-9-1 and enhanced DNA methylation maybe involved. These findings suggest that oncogenic miR-9 targeted FoxO1 to promote cell growth, and downregulation of this axis was involved in erlotinib's growth inhibitory effects. Clarifying the regulation of miRNAs by erlotinib may indicate novel strategies for enhancing EGFR-targeted cancer therapy. PMID- 26593209 TI - Ultrathin niobium nanofilms on fiber optical tapers--a new route towards low-loss hybrid plasmonic modes. AB - Due to the ongoing improvement in nanostructuring technology, ultrathin metallic nanofilms have recently gained substantial attention in plasmonics, e.g. as building blocks of metasurfaces. Typically, noble metals such as silver or gold are the materials of choice, due to their excellent optical properties, however they also possess some intrinsic disadvantages. Here, we introduce niobium nanofilms (~10 nm thickness) as an alternate plasmonic platform. We demonstrate functionality by depositing a niobium nanofilm on a plasmonic fiber taper, and observe a dielectric-loaded niobium surface-plasmon excitation for the first time, with a modal attenuation of only 3-4 dB/mm in aqueous environment and a refractive index sensitivity up to 15 MUm/RIU if the analyte index exceeds 1.42. We show that the niobium nanofilm possesses bulk optical properties, is continuous, homogenous, and inert against any environmental influence, thus possessing several superior properties compared to noble metal nanofilms. These results demonstrate that ultrathin niobium nanofilms can serve as a new platform for biomedical diagnostics, superconducting photonics, ultrathin metasurfaces or new types of optoelectronic devices. PMID- 26593210 TI - Anti-apoptotic effect of modified Chunsimyeolda-tang, a traditional Korean herbal formula, on MPTP-induced neuronal cell death in a Parkinson's disease mouse model. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The modified-Chungsimyeolda-tang (DG) is an important traditional Korean herbal formula used in traditional oriental medicine for treatment of cerebrovascular disorders, including stroke. The formula is based on the book "Dongui Sasang Shinpyun". AIM OF THE STUDY: In the previous studies, the neuroprotective effect of DG is demonstrated in an in vitro Parkinson's disease (PD) model, and in this study, the 1-Methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) animal model of PD is used to evaluate the behavioral effect of DG and possible mechanism through anti-apoptosis of DG. 6 Hydroxydopamine (6-OHDA) also is used to evaluate the anti-apoptosis effect of DG in SH-SY5Y cells. MATERIALS AND METHODS: MPTP was used to evaluate the behavioral damage and neurotoxicity in mice. The bradykinesia symptom was measured by a Pole test and a Rota-rod test in mice. Also the loss of tyrosine hydroxylase (TH) positive neurons induced by MPTP was examined by an immunohistochemical assay. The DG-mediated anti-apoptosis effect was measured using an immunoblotting assay with apoptosis-related markers such as Bax and cleaved caspase-3. DG and 1-methyl 4-phenylpyridinium (MPP(+)) were co-treated with primary dopaminergic neurons to evaluate the protective effect of DG. The expression of caspase-3 and PARP was measured to detect the protective effect of DG from the damage by 6-OHDA. RESULTS AND CONCLUSIONS: The treatment with DG resulted in prophylactic effects on MPTP induced Parkinsonian bradykinesia and the immunohistochemical analysis showed that DG provided the neuroprotection against the MPP(+)-induced dopaminergic neurons loss through the anti-apoptosis effect. The present results suggested that it might be possible to use DG for the prevention of substantia nigra pars compacta (SNpc) degeneration induced by exposure to the toxic substances, such as MPTP/MPP(+), in PD mouse model. PMID- 26593211 TI - Anti-osteoporosis effect of Epimedium via an estrogen-like mechanism based on a system-level approach. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Epimedium is a popular traditional herbal medicine worldwide that has long been used to relieve osteoporosis. The estrogenic properties of the herb are conferred by several phytoestrogens, such as flavonoids, lignans, and steroids. However, the poor understanding on the estrogen-like mechanism of Epimedium at the molecular and system levels limits the applications of this herb in osteoporosis treatment. MATERIALS AND METHODS: In this study, systems pharmacology was established to investigate the relationship between Epimedium and estrogen against osteoporosis by integrating active component screening, drug-likeness evaluation, herb feature mapping, target prediction and validation, and network analysis. RESULTS: A total of 77 active components that possessed similar structural features to estrogen as determined using herb feature mapping were selected from Epimedium by oral bioavailability prediction and drug-likeness evaluation. Twenty three osteoporosis-related targets were obtained from the active components of Epimedium as potential targets, 11 of which were common targets with estrogen. All osteoporosis-related targets were further mapped to compound-target and target-pathway networks. Results displayed that Epimedium can exert anti osteoporosis effects by directly regulating the 11 estrogen-related targets and a set of target proteins on five estrogen-related pathways. CONCLUSION: This study explained the estrogen-like mechanism of Epimedium in preventing and treating osteoporosis, and provided a new standpoint for exploring the traditional herbal medicine against osteoporosis. PMID- 26593212 TI - Pharmacokinetic and pharmacodynamic herb-drug interaction of Andrographis paniculata (Nees) extract and andrographolide with etoricoxib after oral administration in rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Andrographis paniculata Nees (Acanthacae) is commonly used medicinal plant in the traditional. Unani and Ayurvedic medicinal systems. It has broad range of pharmacological effects such as hepatoprotective, antioxidant, antivenom, antifertility, inhibition of replication of the HIV virus, antimalarial, antifungal, antibacterial, antidiabetic, suppression of various cancer cells and anti-inflammatory properties. Andrographolide (AN) is one of the active constituent of the A. paniculata Nees extract (APE). They have been found in many traditional herbal formulations in India and proven to be effective as anti-inflammatory drug AIM OF THE STUDY: To evaluate the pharmacokinetic and pharmacodynamic (anti-arthritic) herb-drug interactions of A. paniculata Nees extract (APE) and pure andrographolide (AN) with etoricoxib (ETO) after oral co-administration in wistar rats. MATERIALS AND METHODS: After oral co administration of APE (200mg/Kg) and AN (60mg/kg) with ETO (10mg/kg) in rats, drug concentrations in plasma were determined using HPLC method. The main pharmacokinetic parameters of Cmax, tmax, t1/2, MRT, Vd, CL, and AUC were calculated by non-compartment model. Change in paw volume, mechanical nociceptive threshold, mechanical hyperalgesia, histopathology and hematological parameters were evaluated to study antiarthritic activity. RESULTS: Co-administration of ETO with APE and pure AN decreased systemic exposure level of each compound in vivo. The Cmax, AUC, t1/2 of ETO was decreased whereas Vd and CL of ETO was increased significantly after co-administration of ETO with pure AN and APE. In pharmacodynamic study, ETO alone and ETO+APE (10+200mg/kg) groups exhibited significant synergistic anti-arthritic activity as compared to groups ETO+AN, APE and AN alone. CONCLUSION: The results obtained from this study suggested that ETO, APE and pure AN existed pharmacokinetic herb-drug interactions in rat which is correlated with anti-arthritic study. Physicians and patients using A. paniculata should have the knowledge about its possible herb-drug interaction with ETO. PMID- 26593213 TI - Anti-inflammatory sesquiterpenes from Costus speciosus rhizomes. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Costus speciosus (Koen ex. Retz.) Sm. (crepe ginger, family Costaceae) is an ornamental plant used in traditional medicine for the treatment of inflammation, rheumatism, bronchitis, fever, headache, asthma, flatulence, constipation, helminthiasis, leprosy, skin diseases, hiccough, anemia, as well as burning sensation on urination. AIM OF THE STUDY: The present study is designed to isolate and identify the active compounds from C. speciosus rhizomes and measure their anti-inflammatory activities. MATERIALS AND METHODS: The n-hexane-CHCl3 soluble fraction of the MeOH extract of C. speciosus rhizomes has been subjected to a repeated column chromatography, including normal silica gel and RP-18 column to give eight compounds. The structures of these compounds were established by UV, IR, 1D ((1)H and (13)C), and 2D ((1)H-(1)H COSY, NOESY, HSQC, and HMBC) NMR experiments and HRESIMS data. In addition, the anti inflammatory activity of compounds 1-8 was evaluated by measuring the levels IL 6, IL-1beta, TNF-alpha, COX-2, lipoxgenase-5, and PGE2 using enzyme-linked immunosorbent assay. RESULTS: The n-hexane-CHCl3 soluble fraction afforded a new eudesmane acid, specioic acid (8), along with seven known compounds, 22,23 dihydrospinasterone (1), dehydrodihydrocostus lactone (mokko lactone) (2), dehydrocostus lactone (3), stigmasterol (4), arbusculin A (5), santamarine (douglanin) (6), and reynosin (7). Compounds 1, 4, and 5-7 were isolated for the first time C. speciosus. Compounds 1-4 displayed potent anti-inflammatory activity, while 7 and 8 showed moderate activity. Compounds 1-8 exhibited a concentration-related decrease in the levels of IL-1beta, IL-6, TNF-alpha, PGE2, lipoxgenase-5, and COX-2. Compounds 5 and 6 did not significantly decrease levels of different cytokines, PGE2, lipoxgenase-5, and COX-2 from PHA treatment at 1 uM. However, all tested compounds significantly decreased cytokines, PGE2, lipoxgenase-5, and COX-2 levels at concentration 100 uM. It is noteworthy that compounds 1-4 had the highest activity, where it lowered levels of cytokines, PGE2, lipoxgenase-5, and COX-2 to the extent that was no statistical difference from the control group. Thus, they decreased proinflammatory cytokines (IL-1beta, IL-6, and TNF-alpha) with decreased level of the target enzymes (COX-2 and lipoxgenase-5) and subsequent reduction of its inflammatory product (PGE2). CONCLUSION: Good anti-inflammatory activities exhibited of the isolated compounds from C. speciosus corroborate the usefulness of this plant in the traditional treatment of inflammation and related symptoms. PMID- 26593214 TI - Outcomes after stroke in patients receiving adjuvant therapy with traditional Chinese medicine: A nationwide matched interventional cohort study. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The use of traditional Chinese medicine (TCM) was high in stroke patients but limited information was available on whether TCM is effective on post-stroke outcomes. The aim of this study is to compare the outcomes of stroke patients with and without receiving adjuvant TCM therapy. MATERIALS AND METHODS: Using Taiwan's National Health Insurance Research Database, we conducted a nationwide cohort study and selected hospitalized stroke patients receiving routine care with (n=1734) and without (n=1734) in-hospital adjuvant TCM therapy by propensity score matching procedures. The adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of poststroke complications and mortality associated with in-hospital adjuvant TCM therapy were calculated. The use of medical resource was also compared between stroke patients with and without adjuvant TCM therapy. RESULTS: Compared with hospitalized stroke patients receiving routine care alone, hospitalized stroke patients receiving routine care and adjuvant TCM therapy exhibited decreased risks of urinary tract infection (HR 0.82, 95% CI 0.68-1.00), pneumonia (HR 0.60, 95% CI 0.47-0.76), epilepsy (HR 0.67, 95% CI 0.49-0.96), gastrointestinal hemorrhage (HR 0.68, 95% CI 0.47-0.98), and mortality (HR 0.37, 95% CI 0.19-0.70) within 3 months after stroke admission. The corresponding 6-month HRs for urinary tract infection, pneumonia, gastrointestinal hemorrhage, and mortality were 0.83, 0.63, 0.64, and 0.40, respectively. Less use and expenditure of hospitalization were found in those received adjuvant TCM therapy. CONCLUSIONS: Hospitalized stroke patients who received routine care and adjuvant TCM therapy exhibited reduced adverse outcomes after admission within a 6-month follow-up period. PMID- 26593215 TI - A comparative ethnopharmacological analysis of traditional medicine used against respiratory tract diseases in Mauritius. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Despite laudable advances in conventional medicine, respiratory tract diseases (RTD) induced morbidity and mortality continue to inflict a substantial burden on healthcare systems worldwide. Similarly, in the tropical island of Mauritius, 13,320 hospital admissions and 8.2% mortality rates were attributed to RTD solely in the year 2013. Consequently, the therapeutic benefits and relief experienced with traditional medicine (TM) against RTD by the local inhabitants cannot be underestimated. The present study aims to report and quantitatively determine the extent of utilization of plant based therapies and other miscellaneous TM preparations concocted against RTD over the island. Additionally, a similarity index was generated which is indicative of the extent of harmonisation of individual plant species against RTD when the uses mentioned in the study are compared to previous ethnobotanical studies. MATERIALS AND METHODS: Data was compiled using a semi structured questionnaire via face-to-face interviews with TM users and practitioners (n=384). Three quantitative ethnopharmacological indices (the use value (UV), informant consensus factor (ICF), and ethnobotanicity index (EI)) were calculated. We also calculated the similarity ratio, similarity percentage, new uses for each plant species and percentage of new use against RTD to compare primary data collected in the present study. RESULTS: Fifty five plants were documented to be in use against 18 RTD. The most used plant species belonged to the following taxa; Lamiaceae (9%), Fabaceae (7%) and Rutaceae (7%). Thirty two plants recorded in this study have been reported to be used against RTD in previous ethnobotanical studies, of which 22 of these plants have been attributed new uses against RTD based on the results of the present study. The remaining 23 plants species have been recorded for the first time to be used traditionally against RTD. Altogether, 81 different recipes were concocted from the medicinal plants and the most common route of administration was oral intake. Common methods of obtaining medicinal plants were from the wild, cultivation and as imported herbal products. Cough was the most common RTD managed by plant species. The largest proportion of plants were employed against cold. The preference ranking both for UV placed Curcuma longa L., Zingiber officinale Roscoe, Citrus*limonia Osbeck and Cymbopogon citratus (DC.) Stapf as the most useful plant species. Only a small proportion of the indigenous plants (7.73%) proved to be useful in TM. CONCLUSION: This study provides empirical primary ethnopharmacological data on the use of TM to manage and/or treat RTD and can contribute in preserving indigenous knowledge in Mauritius. It is anticipated that these primary data will open new avenues to identify novel drugs that can help to alleviate sufferings. PMID- 26593216 TI - Flavonoids and phenylethanoid glycosides from Lippia nodiflora as promising antihyperuricemic agents and elucidation of their mechanism of action. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Lippia nodiflora has been traditionally used in the Ayurvedic, Unani, and Sidha systems, as well as Traditional Chinese Medicine (TCM) for the treatment of knee joint pain, lithiasis, diuresis, urinary disorder and swelling. AIM OF THE STUDY: The present study aims to investigate the antihyperuricemic effect of the L. nodiflora methanol extract, fractions, and chemical constituents and their mechanism of action in the rat model. MATERIALS AND METHODS: The mechanisms were investigated by performing xanthine oxidase inhibitory, uricosuric, and liver xanthine oxidase/xanthine dehydrogenase (XOD/XDH) inhibitory studies in potassium oxonate- and hypoxanthine-induced hyperuricemic rats. The plant safety profile was determined using acute toxicity study. The molecular docking of the active compound to the xanthine oxidase was simulated using computer aided molecular modeling analysis. RESULTS: Oral administration of methanol extract showed a dose-dependent reduction effect on the serum uric acid level of hyperuricemic rats. F3 was the most potent fraction in lowering the serum uric acid level of hyperuricemic rats. Bioactivity-guided purification of F3 afforded two phenylethanoid glycosides, arenarioside (1) and verbascoside (2) and three flavonoids, 6-hydroxyluteolin (3), 6-hydroxyluteolin-7 O-glycoside (4), and nodifloretin (5). The highest serum uric acid reduction effect was exhibited by 3 (66.94%) in hyperuricemic rats, followed by 5 (55.97%), 4 (49.16%), 2 (29.03%), and 1 (22.08%) at 0.2 mmol/kg. Dose-response investigation on 3 at doses of 0.05, 0.1, and 0.3 mmol/kg produced a significant dose-dependent reduction on the serum uric acid level of hyperuricemic rats. Repeated administration of F3 or 3 to the hyperuricemic rats for 10 continuous days resulted in a significant and progressive serum uric acid lowering effect in hyperuricemic rats. In contrast, methanol extract and F3 did not reduce serum uric acid level of normoruricemic rats. In addition, F4 significantly increased the uric acid excretion of hyperuricemic rats at 200mg/kg. No toxic effect was observed in rats administered with 5000 mg/kg of methanol extract or F3. CONCLUSION: The potential application of L. nodiflora against hyperuricemia in the animal in accordance with its traditional uses has been demonstrated in the present study for the first time. The antihyperuricemic effect possessed by L. nodiflora was contributed mainly by liver XOD/XDH inhibitory activities and partially by uricosuric effect. Flavonoids mainly accountable for the uric acid lowering effect of L. nodiflora through the inhibition of XOD/XDH activities. PMID- 26593217 TI - Quorum-Quenching and Matrix-Degrading Enzymes in Multilayer Coatings Synergistically Prevent Bacterial Biofilm Formation on Urinary Catheters. AB - Bacteria often colonize in-dwelling medical devices and grow as complex biofilm communities of cells embedded in a self-produced extracellular polymeric matrix, which increases their resistance to antibiotics and the host immune system. During biofilm growth, bacterial cells cooperate through specific quorum-sensing (QS) signals. Taking advantage of this mechanism of biofilm formation, we hypothesized that interrupting the communication among bacteria and simultaneously degrading the extracellular matrix would inhibit biofilm growth. To this end, coatings composed of the enzymes acylase and alpha-amylase, able to degrade bacterial QS molecules and polysaccharides, respectively, were built on silicone urinary catheters using a layer-by-layer deposition technique. Multilayer coatings of either acylase or amylase alone suppressed the biofilm formation of corresponding Gram-negative Pseudomonas aeruginosa and Gram-positive Staphylococcus aureus. Further assembly of both enzymes in hybrid nanocoatings resulted in stronger biofilm inhibition as a function of acylase or amylase position in the layers. Hybrid coatings, with the QS-signal-degrading acylase as outermost layer, demonstrated 30% higher antibiofilm efficiency against medically relevant Gram-negative bacteria compared to that of the other assemblies. These nanocoatings significantly reduced the occurrence of single-species (P. aeruginosa) and mixed-species (P. aeruginosa and Escherichia coli) biofilms on silicone catheters under both static and dynamic conditions. Moreover, in an in vivo animal model, the quorum quenching and matrix degrading enzyme assemblies delayed the biofilm growth up to 7 days. PMID- 26593218 TI - Substituted cyclopentanes, tetrahydrofurans and pyrrolidines as orexin-1-receptor antagonists for treatment of various CNS disorders (WO2015/055994; WO2015/124932; WO2015/124934). AB - The three patent applications WO2015/055994, WO2015/124932 and WO2015/124934 from Takeda Pharmaceuticals describe antagonists for the orexin-1 receptor, based on saturated substituted five-membered carbo- or heterocycles. According to the patent applications, the compounds have utility in therapeutic areas such as schizophrenia and other psychotic disorders, anxiety or addiction disorders, among others. The patent applications together describe almost 300 examples, and for most of them activity data, determined by Fluorescence Imaging Plate Reader (FLIPR) technology on the orexin-1 as well as the orexin-2 receptor, are disclosed. Structurally, the building blocks used to prepare the compounds are reminiscent of other orexin antagonist programs recently disclosed in the literature. However, the templates used are novel in the orexin antagonist field and are probably the key feature for the selectivity of the derivatives towards the orexin-1 receptor. PMID- 26593220 TI - Simple and eco-friendly fabrication of superhydrophobic textile for oil/water separation. AB - Superhydrophobic and superoleophilic material was successfully prepared by the coating of Polyvinyl alcohol (PVA) onto the surface of cotton textile and subsequent hydrophobic modification. The formation of PVA with rough structure and hydrophobicity was confirmed with scanning electron microscopy and investigation of the wetting behavior of water on the textile. The coated textile is water repellant and can be used as a material for separating various oil/water mixture with a high separation efficiency up to 91%. Due to its simple fabrication process, low cost, excellent recyclability and durability, and high separation efficiency, the as-prepared textile can be considered as promising material for practical oil/water separation. PMID- 26593219 TI - Dose-Dependent Response of Personal Glucose Meters to Nicotinamide Coenzymes: Applications to Point-of-Care Diagnostics of Many Non-Glucose Targets in a Single Step. AB - We report a discovery that personal glucose meters (PGMs) can give a dose dependent response to nicotinamide coenzymes, such as the reduced form of nicotinamide adenine dinucleotide (NADH). We have developed methods that take advantage of this discovery to perform one-step homogeneous assays of many non glucose targets that are difficult to recognize by DNAzymes, aptamers, or antibodies, and without the need for conjugation and multiple steps of sample dilution, separation, or fluid manipulation. The methods are based on the target induced consumption or production of NADH through cascade enzymatic reactions. Simultaneous monitoring of the glucose and L-lactate levels in human plasma from patients with diabetes is demonstrated and the results are comparable to those from current standard test methods. Since a large number of commercially available enzymatic assay kits utilize NADH in their detection, this discovery will allow the transformation of almost all of these clinical lab tests into POC tests that use a PGM. PMID- 26593221 TI - A systematic literature review of nutrition interventions in vending machines that encourage consumers to make healthier choices. AB - Internationally, vending machines are scrutinized for selling energy-dense nutrient-poor foods and beverages, and the contribution to overconsumption and subsequent risk of obesity. The aim of this review is to determine the efficacy of nutrition interventions in vending machine in eliciting behaviour change to improve diet quality or weight status of consumers. Electronic databases Cochrane, EMBASE, CINAHL, Science Direct and PubMed were searched from inception. INCLUSION CRITERIA: (i) populations that have access to vending machines; (ii) nutrition interventions; (iii) measured outcomes of behaviour change (e.g. sales data, dietary intake or weight change); and (iv) experimental trials where controls were not exposed to the intervention. Risk of bias was assessed independently by two researchers, and higher quality research formed the basis of this qualitative review. Twelve articles from 136 searched were included for synthesis. Intervention settings included schools, universities and workplaces. Reducing price or increasing the availability increased sales of healthier choices. The results of point-of-purchase nutrition information interventions were heterogeneous and when measured changes to purchases were small. This review offers evidence that pricing and availability strategies are effective at improving the nutritional quality foods and beverages purchased from vending machines. Evidence on how these interventions alter consumer's overall diet or body mass index is needed. PMID- 26593222 TI - Right Coronary Artery Aneurysm with Fistula to the Coronary Sinus, Persistent Left Superior Vena Cava, Ruptured Anterior Leaflet Chordae Tendineae with Severe Mitral Regurgitation. PMID- 26593223 TI - The global regulatory system Csr senses glucose through the phosphoenolpyruvate: carbohydrate phosphotransferase system. AB - A novel connection between two regulatory systems controlling crucial biological processes in bacteria, the carbon storage regulator (Csr) system and the glucose specific phosphotransferase system (PTS), is reported by Leng et al. in this issue. This involves the interaction of unphosphorylated EIIA(Glc), a component of the glucose-specific PTS, with the CsrD protein, which accelerates the decay of the CsrB and CsrC small RNAs via RNase E in Escherichia coli. As unphosphorylated EIIA(G) (lc) is generated in the presence of glucose, the PTS thus acts as a sensor of glucose for the Csr system. Interestingly, another pathway can operate for communication between the Csr system and the glucose specific PTS. The absence of glucose generates phosphorylated EIIA(Glc) , which activates the enzyme adenylate cyclase to produce cyclic adenosine monophosphate (cAMP) that, in turn, binds to the regulator cAMP receptor protein (CRP). Leng et al. show that the complex cAMP-CRP modestly reduces CsrB decay independently of CsrD. On the other hand, a previous study indicates that the complex cAMP-CRP positively regulates the transcription of CsrB and CsrC in Salmonella enterica. Therefore, EIIA(G) (lc) could work as a molecular switch that regulates the activity of the Csr system, in response to its phosphorylation state determined by the presence or absence of glucose, in order to control gene expression. PMID- 26593224 TI - Cervical spondylodiscitis secondary to insertion of voice prosthesis. PMID- 26593225 TI - Sleep disturbance and deficits of sustained attention following stroke. AB - OBJECTIVE: To simultaneously investigate the prevalence of and impact that the poststroke complications of daytime sleepiness, poor sleep quality, depression, and fatigue may be having upon deficits of sustained attention, as assessed using the Psychomotor Vigilance Task (PVT). METHOD: Twenty-two patients with stroke (mean age: 68.23 +/- 12.17 years) and 20 healthy control participants (mean age: 68.1 +/- 9.5 years) completed subjective measures of daytime sleepiness, sleep quality, fatigue, and depression and an objective measure of sustained attention as assessed using the PVT. RESULTS: Patients with stroke compared to controls showed heightened levels of fatigue (p = .001, eta(2) = .29) and depression (p = .002, eta(2) = .23), plus greater deficits of sustained attention as reflected by poorer performance across all PVT outcome measures including: slower mean reaction times (p = .002, eta(2) = .22); increased number of lapses (p = .002, eta(2) = .24); and greater variability in reaction time (RT) responses (p = .016, eta(2) = .15). Reaction time distribution analysis suggested that daytime sleepiness and sleep quality had little influence across PVT performance; however, depressive symptomology was associated with longer RT responses, indicative of inattention, and fatigue impacted upon the entire distribution of PVT responses. CONCLUSIONS: PVT performance illustrated significant deficits across the domain of sustained attention for patients with stroke in comparison to healthy controls, in terms of inattention as well as slower sensory-motor speed. The common poststroke complications of depressive symptomology and fatigue appear to be associated with these deficits in sustained attention, warranting further investigation. PMID- 26593226 TI - Design, synthesis and anticancer activities of novel otobain derivatives. AB - A series of novel racemic otobain derivatives was designed and synthesised using 2-piperonyl-1,3-dithianes in the conjugate addition-alkylation to 5H-furan-2-one, followed by cationic cyclisation. All the synthesised compounds were consequently evaluated for their anticancer activity against several human cancers in vitro. The efficacy of the most active compound 27g was comparable with etoposide, with IC50 values ranging from 1.06 MUM to 4.16 MUM in different cancer cell lines. Notably, compound 27g strongly induced cell cycle arrest and increased the expression of mitosis-specific markers MPM-2 and phosphorylated histone H3, but it did not trigger cell apoptosis. Further a colony formation assay showed that compound 27g effectively inhibited the anchor growth of lung cancer cells in a dose-dependent manner. More importantly, compound 27g at 40 mg kg(-1) significantly suppressed tumour volume (P < 0.01) and tumour weight (P < 0.05) in a human lung cancer cell xenograft mouse model without causing systematic toxicity in mice. Our findings indicated that compound 27g has significant potential for further drug development. PMID- 26593227 TI - The anticancer effects of biodegradable nanomagnetic dual natural components on the leptin gene expression in lung cancer. AB - Lung cancer is an invasive and progressive, fatal disease with few treatment choices and poor overall survival rates in nonsurgical stages. Leptin (LEP), an adipocyte derivative cytokine, participates in carcinogenesis. Increased amounts of systemic and pulmonary LEP indicate lung cancer. Curcumin (CUR) and silibinin (SIL) are herbal compounds which have many anticancer properties, but they have hydrophobic structures and low solubility in water. In this study, evaluated CUR SIL dual drug-loaded poly (E-caprolactone) [PCL]-co-poly ethylene glycol (PEG) magnetic nanoparticles (MNPs) were used to determine the inhibitory effect on LEP gene expression. The physicochemical properties of free and CUR-SIL-loaded PCL PEG were fully characterized. The cytotoxic effect of CUR-SIL-loaded PCL-PEG magnetic nanoparticles was determined by MTT assay. Afterward, the inhibition of LEP gene expression was specified through real-time PCR. Results indicated that CUR-SIL cytotoxicity is time- and dose-dependent. CUR-SIL loaded MNPs showed the IC50 limit in lower concentrations in comparison to net CUR-SIL. CUR-SIL loaded MNPs reduced LEP expression more than net CUR-SIL. These results revealed the possibilities of CUR-SIL-loaded MNPs as a natural and effective antitumor drug delivery system to fight lung tumors. PMID- 26593228 TI - Improved oxidation of aromatic and aliphatic hydrocarbons using rate enhancing variants of P450Bm3 in combination with decoy molecules. AB - Enzyme performance can be improved using decoy molecules or engineered variants to accelerate the activity without affecting selectivity. Here we combine a rate accelerator variant of cytochrome P450Bm3 with decoy molecules to enhance the oxidation activity of a range of small organic molecules. This combined approach offers superior biocatalytic efficiency without modifying the product distribution. PMID- 26593229 TI - An S = 12 semiquinoid radical-bridged Mn6 wheel complex assembled from an asymmetric redox-active bridging ligand. AB - The asymmetric redox-active ligand 4,5-bis(pyridine-2-carboxamido)-1,2-catechol ((N,O)LH4) is prepared and metalated to afford the hexanuclear complex [Mn6((N,O)L)6](6-). Structural analysis and magnetic measurements reveal this complex to feature Mn(II) ions bridged by (N,O)L(3-) radicals, which are antiferromagnetically coupled to give an S = 12 ground state. PMID- 26593230 TI - Cell-based therapies for the treatment of idiopathic pulmonary fibrosis (IPF) disease. AB - INTRODUCTION: During the last few decades, cell-based therapies have shown great potential to treat patients with lung diseases. It has been proposed that the administration of cells into an injured lung could be considered as a therapeutic method to repair and replace lost lung tissue. Using this method, transplanted cells with the ability to proliferate and differentiate into alveolar cells, have been suggested as a therapeutic strategy for IPF treatment. AREAS COVERED: In this review, the latest investigations using various types of cells for IPF therapy have been presented. The cells studied for cell-based therapies in IPF are lung alveolar epithelial cells, lung resident stem cells and exogenous adult stem cells such as MSCs. EXPERT OPINION: After many years of investigation, the use of cell-based therapies to treat IPF is still at the experimental phase. Problems include bioethical issues, safety of cell transplantation, routes of delivery and the dose and timing of administration. Further investigations are necessary to establish the best strategy for using cell-based therapies effectively for the treatment of IPF. PMID- 26593231 TI - Comparative Study of Aluminum Complexes Bearing N,O- and N,S-Schiff Base in Ring Opening Polymerization of epsilon-Caprolactone and L-Lactide. AB - A series of Al complexes bearing Schiff base and thio-Schiff base ligands were synthesized, and their application for the ring-opening polymerization of epsilon caprolactone (CL) and l-lactide (LA) was studied. It was found that steric effects of the ligands caused higher polymerization rate and most importantly the Al complexes with N,S-Schiff base showed significantly higher polymerization rate than Al complexes with N,O-Schiff base (5-12-fold for CL polymerization and 2-7 fold for LA polymerization). The reaction mechanism of CL polymerization was investigated by density functional theory (DFT). The calculations predicted a lower activation energy for a process involved with an Al complex bearing an N,S Schiff base ligand (17.6 kcal/mol) than for that of an Al complex bearing an N,O Schiff base ligand (19.0 kcal/mol), and this magnitude of activation energy reduction is comparable to the magnitude of rate enhancement observed in the experiment. The reduction of activation energy was attributed to the catalyst substrate destabilization effect. Using a sulfur-containing ligand to decrease the activation energy in the ring-opening polymerization process may be a new strategy to design a new Al complex with high catalytic activity. PMID- 26593232 TI - Assessing the effects of model Maillard compound intake on iron, copper and zinc retention and tissue delivery in adult rats. AB - The behaviour of dietary Maillard reaction compounds (MRP) as metal chelating polymers can alter mineral absorption and/or retention. Our aim in this study was to analyse the long-term effects of the consumption of model MRP from glucose lysine heated for 90 min at 150 degrees C (GL) on iron, copper and zinc whole body retention and tissue delivery. For 88 days, weaning rats were fed a Control diet or one containing 3% GL, until reaching the adult stage. During the experimental period a mineral balance was conducted to investigate the mineral retention. At day 88, the animals were sacrificed, blood was drawn for haemoglobin determination and some organs were removed. Copper and zinc balances were unaffected (Cu: 450 vs. 375 MUg; Zn: 6.7 vs. 6.2 mg for Control and GL groups, respectively) and no change was observed in whole-body delivery. Iron retention, too, was unaltered (11.2 mg for Control and GL groups) but due to the tendency toward decreased body weight in the GL group (248 vs. 233 g for the Control and GL groups), whole-body iron concentration was 13% higher in the GL group than in the Control group. Absorbed iron accumulated particularly in the liver (144 vs. 190 MUg g(-1) for the Control and GL groups), thus reducing haemoglobin levels. The long-term intake of MRP induced iron accumulation in the body but this did not result in enhanced iron functionality, since the haemoglobin concentration declined. Taking into account the findings of our research group's studies of young and adult rats, we now corroborate the hypothesis that the negative effect of GL MRP consumption on iron functionality takes place regardless of the animals' stage of life. PMID- 26593233 TI - Young clinicians dealing with death: Problems and opportunities. AB - OBJECTIVE: The formation of a strong bond between patients and therapists can lead to successful treatment outcomes. Yet, little is known about the mechanisms that function to control this relationship. The objective of this case report was to examine the ruptures and repairs in the working alliance between a young therapist and an elderly caregiver, and to suggest ways in which to deal with age related challenges to such an alliance. METHOD: In order to examine the ruptures and repairs in a working alliance, this case report reflects on the interdependent relationship among therapist variables, patient variables, and the therapeutic alliance. The clinical experience presented describes a newly educated psychologist's struggles to overcome the challenges in forming a strong working alliance with an elderly dying cancer patient's spouse. The spouse was enrolled in the DOMUS study (Clinicaltrials.gov: NTC01885637), an ongoing randomized controlled trial of a patient-and-caregiver intervention for facilitating the transition from an oncology ward to palliative at-home care, and then bereavement. As part of the DOMUS study, the patient and spouse received a psychological intervention based on existential-phenomenological therapy. RESULTS: A therapist's therapeutic approach to breaking down age-related barriers to communication matters greatly. The existential-phenomenological method of epoche offers a way to effectively address ruptures and repairs in a working alliance, as it enhances the therapist's openness to learning. In addition, the insights of senior supervisors can promote a therapist's openness to learning. SIGNIFICANCE OF RESULTS: In conclusion, the method of epoche benefits the working alliance in several ways, as it enhances personal insight and provides methods for repairing an alliance. The reflections in this paper may be applied to clinical settings in oncology, gerontology, and palliative care, which are likely to be of great interest to young clinicians experiencing age-related challenges in their daily work. PMID- 26593234 TI - Ultra-capacitor flexible films with tailored dielectric constants using electric field assisted assembly of nanoparticles. AB - In this study, the chaining and preferential alignment of barium titanate nanoparticles (100 nm) through the thickness direction of a polymer matrix in the presence of an electric field is shown. Application of an AC electric field in a well-dispersed solution leads to the formation of chains of nanoparticles in discrete rows oriented with their primary axis in the E-field direction due to dielectrophoresis. The change in the orientation of these chains was quantified through statistical analysis of SEM images and was found to be dependent on E field, frequency and viscosity. When a DC field is applied a distinct layer consisting of dense particles was observed with micro-computed tomography. These studies show that the increase in DC voltage leads to increase in the thickness of the particle rich layer along with the packing density also increasing. Increasing the mutual interactions between particles due to the formation of particle chains in the "Z"-direction decreases the critical percolation concentration above which substantial enhancement of properties occurs. This manufacturing method therefore shows promise to lower the cost of the products for a range of applications including capacitors by either enhancing the dielectric properties for a given concentration or reduces the concentration of nanoparticles needed for a given property. PMID- 26593235 TI - Mitochondrial DNA panmixia in the little brown seastar Echinaster spinulosus suggests a recent population expansion. AB - In North America, the Atlantic-Gulf discontinuity depicts genetic breaks between populations distributed along the Florida peninsula. This study examines 83 specimens of E. spinulosus obtained from seven locations along the Florida coast to examine phylogeographic patterns, population structure and examine historical demographic patterns. Analyses of 511 bp from the cytochrome oxidase 1 (COI) mitochondrial gene inferred no significant genetic structure for E. spinulosus along either side of the Florida coast nor was there a genetic discontinuity associated with a "Gulf-Atlantic" split. Population-based statistical analyses revealed no significant degree of genetic differentiation (Fst, p < 0.05) among populations, thus indicating substantial gene flow. Similarly, summary statistics (Fu's Fs, mismatch distributions) were significant indicating that there has been a population increase in the recent past. Recent range expansion, possibly due to a leading edge effect, combined with some level of contemporary larval mixing seems to be the main source of panmixia in this species. PMID- 26593236 TI - X-ray diffraction and high-resolution TEM observations of biopolymer nanoskin covered metallic copper fine particles: preparative conditions and surface oxidation states. AB - Metallic copper fine particles used for electro conductive pastes were prepared by the chemical reduction of cupric oxide microparticles in the presence of gelatin. After reduction, the fine particles were collected by decantation with pH control and washing, followed by drying at a moderate temperature. The surface oxidation state of the obtained copper fine particles could be considerably varied by altering the pH of the particle dispersion, as shown by X-ray diffraction and high-resolution transmission electron microscopy. Our results strongly indicate that decantation under a nitrogen atmosphere can prevent the oxidation of copper fine particles but a slight oxidation was found. PMID- 26593237 TI - Tuning the Quantum Efficiency of Random Lasers - Intrinsic Stokes-Shift and Gain. AB - We report the theoretical analysis for tuning the quantum efficiency of solid state random lasers. Vollhardt-Wolfle theory of photonic transport in disordered non-conserving and open random media, is coupled to lasing dynamics and solved positionally dependent. The interplay of non-linearity and homogeneous non radiative frequency conversion by means of a Stokes-shift leads to a reduction of the quantum efficiency of the random laser. At the threshold a strong decrease of the spot-size in the stationary state is found due to the increase of non radiative losses. The coherently emitted photon number per unit of modal surface is also strongly reduced. This result allows for the conclusion that Stokes shifts are not sufficient to explain confined and extended mode regimes. PMID- 26593239 TI - MIG-seq: an effective PCR-based method for genome-wide single-nucleotide polymorphism genotyping using the next-generation sequencing platform. AB - Restriction-enzyme (RE)-based next-generation sequencing methods have revolutionized marker-assisted genetic studies; however, the use of REs has limited their widespread adoption, especially in field samples with low-quality DNA and/or small quantities of DNA. Here, we developed a PCR-based procedure to construct reduced representation libraries without RE digestion steps, representing de novo single-nucleotide polymorphism discovery, and its genotyping using next-generation sequencing. Using multiplexed inter-simple sequence repeat (ISSR) primers, thousands of genome-wide regions were amplified effectively from a wide variety of genomes, without prior genetic information. We demonstrated: 1) Mendelian gametic segregation of the discovered variants; 2) reproducibility of genotyping by checking its applicability for individual identification; and 3) applicability in a wide variety of species by checking standard population genetic analysis. This approach, called multiplexed ISSR genotyping by sequencing, should be applicable to many marker-assisted genetic studies with a wide range of DNA qualities and quantities. PMID- 26593241 TI - Designing Irreversible Inhibitors--Worth the Effort? AB - Despite the unquestionable success of numerous irreversible drugs that are currently in clinical use, such as acetylsalicylic acid (Aspirin) and penicillin, the number of such approved drugs is much lower than that of noncovalent drugs. Over the years, the potential off-target effects of these types of compounds have been the primary concern that has hampered their development. However, their remarkable advantages over noncovalent drugs and a better analysis of the risks have decreased the widespread skepticism surrounding them. The design of irreversible inhibitors is a challenge, particularly considering that in some cases their efficacy is due to complex and unexpected mechanisms of action. In this review the main advantages of irreversible inhibition are summarized, and the complexity of certain covalent modification mechanisms is highlighted with selected examples. PMID- 26593243 TI - Exploring the effect of the spatial scale of fishery management. AB - For any spatially explicit management, determining the appropriate spatial scale of management decisions is critical to success at achieving a given management goal. Specifically, managers must decide how much to subdivide a given managed region: from implementing a uniform approach across the region to considering a unique approach in each of one hundred patches and everything in between. Spatially explicit approaches, such as the implementation of marine spatial planning and marine reserves, are increasingly used in fishery management. Using a spatially explicit bioeconomic model, we quantify how the management scale affects optimal fishery profit, biomass, fishery effort, and the fraction of habitat in marine reserves. We find that, if habitats are randomly distributed, the fishery profit increases almost linearly with the number of segments. However, if habitats are positively autocorrelated, then the fishery profit increases with diminishing returns. Therefore, the true optimum in management scale given cost to subdivision depends on the habitat distribution pattern. PMID- 26593240 TI - Multiple Sources of Infection and Potential Endemic Characteristics of the Large Outbreak of Dengue in Guangdong in 2014. AB - A large outbreak of dengue, with the most documented cases, occurred in Guangdong China in 2014. Epidemiological studies and phylogenetic analysis of the isolated dengue virus (DENV) showed this outbreak was attributed to multiple sources and caused by at least two genotypes of DENV-1 (Genotypes I and III) and two genotypes of DENV-2 (Cosmopolitan and Asian I Genotypes). A retrospective review and phylogenetic analysis of DENV isolated in Guangdong showed that DENV-1 Genotype I strains were reported continuously during 2004-2014, Genotype III strains were reported during 2009-2014 ; DENV-2 Cosmopolitan and Asian I Genotype strains were reported continuously during 2012-2014. At least 45,171 cases were reported in this outbreak, with 65.9% of the patients in the 21-55-year-old group. A trend toward a decrease in the daily newly emerged cases lagged by approximately 20 days compared with the mosquito density curve. Several epidemiological characteristics of this outbreak and the stably sustained serotypes and genotypes of DENV isolated in Guangdong suggest that Guangdong has been facing a threat of transforming from a dengue epidemic area to an endemic area. The high temperature, drenching rain, rapid urbanization, and pandemic of dengue in Southeast Asia may have contributed to this large outbreak of dengue. PMID- 26593244 TI - Influence of cervical preflaring on apical transportation in curved root canals instrumented by reciprocating file systems. AB - BACKGROUND: The aim of this study was to evaluate the influence of cervical preflaring on apical transportation in curved root canals prepared using the Reciproc and WaveOne reciprocating file systems. METHODS: Sixty curved canals were instrumented using Reciproc R25 and WaveOne Primary files, with and without preflaring (n = 15). A double-digital technique was used to digitally superimpose the file before instrumentation (#15 K-file) on the final apical reciprocating file (#25/08). The angle between the tip of the initial and final file was measured and recorded. Groups were compared using the Kruskal-Wallis test, and significance was set at p < 0.05. RESULTS: The mean and standard deviation for apical transportation was 0.93 +/- 2.48 for the Reciproc Group, 0.84 +/- 1.94 for the Preflaring + Reciproc Group, 0.40 +/- 1.14 for the WaveOne Group, and 0.83 +/ 2.20 for the Preflaring + WaveOne Group. No statistically significant differences were found among the groups (p = 0.9509). CONCLUSIONS: Under the conditions of this study, cervical preflaring did not influence apical transportation in curved root canals instrumented using Reciproc R25 and the WaveOne Primary files. Based on the in vitro measurements of apical transportation, the reciprocating files may be used without preflaring in curved root canals. PMID- 26593246 TI - A prolonged outbreak of Salmonella Infantis associated with pork products in central Germany, April-October 2013. AB - One of the largest and longest Salmonella outbreaks in Germany within the last 10 years occurred in central Germany in 2013. To identify vehicles of infection, we analysed surveillance data, conducted a case-control study and food traceback. We identified 267 cases infected with Salmonella Infantis with symptom onset between 16 April and 26 October 2013 in four neighbouring federal states. Results of our study indicated that cases were more likely to have eaten raw minced pork from local butcher's shops [odds ratio (OR) 2.5, 95% confidence interval (CI) 1.1-5.8] and have taken gastric acid-reducing or -neutralizing medication (OR 3.8, 95% CI 1.3-13) than controls. The outbreak was traced back to contaminated raw pork products found in different butcher's shops supplied by one slaughterhouse, to pigs at one farm and to an animal feed producer. Characterization of isolates of human, food, animal, feed, and environmental origin by phage-typing and pulsed field gel electrophoresis confirmed the chain of infection. Insufficient hygiene standards in the slaughterhouse were the most probable cause of the ongoing transmission. We recommend that persons taking gastric acid suppressants should refrain from consuming raw pork products. Improving and maintaining adequate hygiene standards and process controls during slaughter is important to prevent future outbreaks. PMID- 26593245 TI - Characterizing Types of Human Mobility to Inform Differential and Targeted Malaria Elimination Strategies in Northeast Cambodia. AB - Human population movements currently challenge malaria elimination in low transmission foci in the Greater Mekong Subregion. Using a mixed-methods design, combining ethnography (n = 410 interviews), malariometric data (n = 4996) and population surveys (n = 824 indigenous populations; n = 704 Khmer migrants) malaria vulnerability among different types of mobile populations was researched in the remote province of Ratanakiri, Cambodia. Different structural types of human mobility were identified, showing differential risk and vulnerability. Among local indigenous populations, access to malaria testing and treatment through the VMW-system and LLIN coverage was high but control strategies failed to account for forest farmers' prolonged stays at forest farms/fields (61% during rainy season), increasing their exposure (p = 0.002). The Khmer migrants, with low acquired immunity, active on plantations and mines, represented a fundamentally different group not reached by LLIN-distribution campaigns since they were largely unregistered (79%) and unaware of the local VMW-system (95%) due to poor social integration. Khmer migrants therefore require control strategies including active detection, registration and immediate access to malaria prevention and control tools from which they are currently excluded. In conclusion, different types of mobility require different malaria elimination strategies. Targeting mobility without an in-depth understanding of malaria risk in each group challenges further progress towards elimination. PMID- 26593248 TI - Tandem mass spectrometry multiplex analysis of methylated and non-methylated urinary Gb3 isoforms in Fabry disease patients. AB - BACKGROUND: Fabry disease is a lysosomal storage disorder leading to the accumulation of glycosphingolipids in biological fluids and tissues. Globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) are currently used for Fabry screening and diagnosis. However, these biomarkers are not always increased in Fabry patients with residual enzyme activity. We recently identified 7 urinary methylated Gb3-related isoforms. The aims of this study were (1) to develop and validate a novel LC-MS/MS method for the relative quantification of methylated and non-methylated Gb3 isoforms normalized to creatinine, (2) to evaluate these biomarkers in Fabry patients and healthy controls, and (3) to assess correlations between biomarker urinary excretion with age, gender, treatment and genotype of patients. METHODS: Urine samples from 150 Fabry patients and 95 healthy controls were analyzed. Samples were purified and injected in the tandem mass spectrometer working in positive electrospray ionization. Relative quantification was performed for 15 methylated and non methylated Gb3 isoforms. RESULTS: Significant correlations (p<0.001) were established between Gb3 isoform concentrations, gender and treatment. Five patients with the late-onset cardiac mutation p.N215S showed abnormal concentrations of methylated Gb3 isoforms compared to their non-methylated homologues. CONCLUSIONS: Methylated Gb3 isoforms might be helpful urinary biomarkers for Fabry patients with late-onset cardiac variant mutations. PMID- 26593247 TI - Does low peritoneal glucose load protect from the development of left ventricular hypertrophy in peritoneal dialysis patients? AB - BACKGROUND: Left ventricular hypertrophy (LVH) is a major predictor of the development of cardiovascular events that is considered the main cause of morbidity and mortality in peritoneal dialysis (PD) patients. This study aimed to evaluate retrospectively the impact of low peritoneal glucose load on left ventricular mass (LVM) in PD patients. METHODS: 36 patients who were on continuous ambulatory PD for at least a period of 2 years enrolled in the study. Of them, 23 patients received only glucose-based solutions (GBS) [high peritoneal glucose load group (HPGL group)] from the start of PD, and 13 patients received AAS in combination with GBS when their serum albumin decreased to levels <3.5 g/dl [low peritoneal glucose load group (LPGL group)]. AAS was substituted with 1.36 % GBS when serum albumin rose to >=3.5 g/dl and restarted when serum albumin fell to <3.5 g/dl. Medical history, physical findings, echocardiographic, laboratory and hydration status data from the first month of PD and after 24 months, were obtained from each patient's medical records. RESULTS: Mean LVM index (LVMI) increased in both groups (p <= 0.010). The increment in mean LVMI was higher in HPGL group compared to LPGL group (p = 0.006). At 24 months: peritoneal glucose load index (PGLI), fluid overload, mean arterial pressure (MAP), HbA1c and hsCRP were higher in HPGL group (p <= 0.010), while 24 h ultrafiltration, weekly Kt/V, serum albumin levels and RRF were higher in LPGL group (p <= 0.025). The increment (Delta between the values of each parameter from the start of PD and after 24 months) in PGLI, fluid overload, MAP, HbA1c and hsCRP values were higher in HPGL group (p < 0.001). CONCLUSIONS: Low peritoneal glucose load may be associated with a protective effect from the development of LVH in PD patients. PMID- 26593249 TI - Calcium alginate as a rectal bulking agent. Experimental pilot study to determine its migratory trend and locoregional reaction. PMID- 26593250 TI - Synergistic cytotoxic effects of bortezomib and CK2 inhibitor CX-4945 in acute lymphoblastic leukemia: turning off the prosurvival ER chaperone BIP/Grp78 and turning on the pro-apoptotic NF-kappaB. AB - The proteasome inhibitor bortezomib is a new targeted treatment option for refractory or relapsed acute lymphoblastic leukemia (ALL) patients. However, a limited efficacy of bortezomib alone has been reported. A terminal pro-apoptotic endoplasmic reticulum (ER) stress/unfolded protein response (UPR) is one of the several mechanisms of bortezomib-induced apoptosis. Recently, it has been documented that UPR disruption could be considered a selective anti-leukemia therapy. CX-4945, a potent casein kinase (CK) 2 inhibitor, has been found to induce apoptotic cell death in T-ALL preclinical models, via perturbation of ER/UPR pathway. In this study, we analyzed in T- and B-ALL preclinical settings, the molecular mechanisms of synergistic apoptotic effects observed after bortezomib/CX-4945 combined treatment. We demonstrated that, adding CX-4945 after bortezomib treatment, prevented leukemic cells from engaging a functional UPR in order to buffer the bortezomib-mediated proteotoxic stress in ER lumen. We documented that the combined treatment decreased pro-survival ER chaperon BIP/Grp78 expression, via reduction of chaperoning activity of Hsp90. Bortezomib/CX-4945 treatment inhibited NF-kappaB signaling in T-ALL cell lines and primary cells from T-ALL patients, but, intriguingly, in B-ALL cells the drug combination activated NF-kappaB p65 pro-apoptotic functions. In fact in B-cells, the combined treatment induced p65-HDAC1 association with consequent repression of the anti-apoptotic target genes, Bcl-xL and XIAP. Exposure to NEMO (IKKgamma) binding domain inhibitor peptide reduced the cytotoxic effects of bortezomib/CX 4945 treatment. Overall, our findings demonstrated that CK2 inhibition could be useful in combination with bortezomib as a novel therapeutic strategy in both T- and B-ALL. PMID- 26593253 TI - Age-related Changes in Respiratory Function and Daily Living. A Tentative Model Including Psychosocial Variables, Respiratory Diseases and Cognition. AB - Changes in respiratory function are common in older populations and affect quality of life, social relationships, cognitive function and functional capacity. This paper reviews evidence reported in medical and psychological journals between 2000 and 2014 concerning the impact of changes in respiratory function on daily living in older adults. A tentative model establishes relationships involving respiratory function, cognitive function and functional capacities. The conclusion stresses the need for both longitudinal studies, to establish causal pathways between respiratory function and psychosocial aspects in aging, and intervention studies. PMID- 26593251 TI - Targeting PDK1 with dichloroacetophenone to inhibit acute myeloid leukemia (AML) cell growth. AB - Pyruvate dehydrogenase kinase-1 (PDK1), a key metabolic enzyme involved in aerobic glycolysis, is highly expressed in many solid tumors. Small molecule compound DAP (2,2-dichloroacetophenone) is a potent inhibitor of PDK1. Whether targeting PDK1 with DAP can inhibit acute myeloid leukemia (AML) and how it works remains unknown. In this study, we evaluated the effect of inhibition of PDK1 with DAP on cell growth, apoptosis and survival in AML cells and identified the underlying mechanisms. We found that treatment with DAP significantly inhibited cell proliferation, increased apoptosis induction and suppressed autophagy in AML cells in vitro, and inhibited tumor growth in an AML mouse model in vivo. We also showed that inhibition of PDK1 with DAP increased the cleavage of pro-apoptotic proteins (PARP and Caspase 3) and decreased the expression of the anti-apoptotic proteins (BCL-xL and BCL-2) and autophagy regulators (ULK1, Beclin-1 and Atg). In addition, we found that DAP inhibited the PI3K/Akt signaling pathway. Furthermore, we demonstrated that PDK1 interacted with ULK1, BCL-xL and E3 ligase CBL-b in AML cells, and DPA treatment could inhibit the interactions. Collectively, our results indicated that targeting PDK1 with DAP inhibited AML cell growth via multiple signaling pathways and suggest that targeting PDK1 may be a promising therapeutic strategy for AMLs. PMID- 26593252 TI - Epigenetic repression of PDZ-LIM domain-containing protein 2 promotes ovarian cancer via NOS2-derived nitric oxide signaling. AB - Ovarian cancer constitutes one of the most lethal gynaecological malignancies worldwide and currently no satisfactory therapeutic approaches have been established. Therefore, elucidation of molecular mechanisms to develop targeted therapy of ovarian cancer is crucial. PDLIM2 is critical to promote ubiquitination of nuclear p65 and thus its role in inflammation has been highlighted recently. We demonstrate that PDLIM2 is decreased in both ovarian high-grade serous carcinoma and in various human ovarian cancer cell lines compared with normal ovary tissues and human ovarian surface epithelial cells (HOSE). Further functional analysis revealed that PDLIM2 is epigenetically repressed in ovarian cancer development and inhibition of PDLIM2 promoted ovarian cancer growth both in vivo and in vitro via NOS2-derived nitric oxide signaling, leading to recruitment of M2 type macrophages. These results suggest that PDLIM2 might be involved in ovarian cancer pathogenesis, which could serve as a promising therapeutic target for ovarian cancer patients. PMID- 26593254 TI - Ecology and Epidemiology of Lyme Borreliosis. AB - Lyme borreliosis is a zoonotic, tick-borne disease that infects humans worldwide. The disease is currently recognized as the most common vector-borne disease in Europe and North America. Disease is caused by several genospecies of the Borrelia burgdorferi sensu lato complex. Humans are at high risk of infection in regions where highly competent reservoirs are the primary hosts for the subadult stages of the tick, in contrast to regions where less competent or refractory animals feed ticks. Human infections are also most frequently associated with spring and summer months when the nymph stage of the tick is active. PMID- 26593255 TI - Borrelia burgdorferi Pathogenesis and the Immune Response. AB - Borrelia burgdorferi is the tick-borne etiologic agent of Lyme disease. The spirochete must negotiate numerous barriers in order to establish a disseminated infection in a mammalian host. These barriers include migration from the feeding tick midgut to the salivary glands, deposition in skin, manipulation or evasion of the localized host immune response, adhesion to and extravasation through an endothelial barrier, hematogenous dissemination, and establishment of infection in distal tissue sites. Borrelia burgdorferi proteins that mediate many of these processes and the nature of the host response to infection are described. PMID- 26593256 TI - Clinical Manifestations and Treatment of Lyme Disease. AB - Lyme disease is the most common tick-borne illness in the United States and is also seen in areas of Europe and Asia. The growing deer and Ixodes species tick populations in many areas underscore the importance of clinicians to properly recognize and treat the different stages of Lyme disease. Controversy regarding the cause and management of persistent symptoms following treatment of Lyme disease persists and is highlighted in this review. PMID- 26593257 TI - Nervous System Lyme Disease. AB - Nervous system involvement occurs in 10% to 15% of patients infected with the tick-borne spirochetes Borrelia burgdorferi, B afzelii, and B garinii. Peripheral nervous system involvement is common. Central nervous system (CNS) involvement, most commonly presenting with lymphocytic meningitis, causes modest cerebrospinal fluid (CSF) pleocytosis. Parenchymal CNS infection is rare. If the CNS is invaded, however, measuring local production of anti-B burgdorferi antibodies in the CSF provides a useful marker of infection. Most cases of neuroborreliosis can be cured with oral doxycycline; parenteral regimens should be reserved for patients with particularly severe disease. PMID- 26593258 TI - Lyme Disease Diagnosis: Serology. AB - Serology is the mainstay of confirmation of Lyme borreliosis; direct detection has limited application. Because standardized 2-tier testing (STTT) has been commonly used since the mid 1990s, standardization and performance have improved. STTT detection of early, localized infection is poor; that of late disease is good. The best indicator of stage 1 infection, erythema migrans, is presented in the majority of US cases and should prompt treatment without testing. Clinical and epidemiologic correlates should be carefully assessed before ordering STTT. STTT has great value in confirming extracutaneous infection. Recent developments promise to improve performance, particularly in early disease detection. PMID- 26593259 TI - Alternatives to Serologic Testing for Diagnosis of Lyme Disease. AB - Although serologic testing remains the gold standard for laboratory diagnosis of Lyme disease, the antibody response may take several weeks to increase greater than the limit of detection. Because of this extended time frame, it is necessary to identify new diagnostic methods for earlier diagnosis and appropriate treatment of Lyme disease. Alternative diagnostic modalities, such as Borrelia culture or nucleic acid amplification testing, may be beneficial in specific clinical scenarios. In early phases of acute infection, before the development of an immune response, detection of Borrelia DNA from clinical specimens may help establish the diagnosis sooner than serologic methods. PMID- 26593260 TI - Lyme Disease Coinfections in the United States. AB - Lyme disease in North America is caused by infection with the spirochetal bacterium Borrelia burgdorferi and transmitted by Ixodes scapularis and Ixodes pacificus ticks. These ticks also have the potential to transmit a rapidly expanding list of other pathogenic bacteria, viruses, and parasites, including Anaplasma phagocytophilum, Babesia microti, deer tick (Powassan) virus, Borrelia miyamotoi, and the Ehrlichia muris-like organism. Coinfections with B burgdorferi and these other agents are often difficult to diagnose and may go untreated, and thus contribute significantly to patient morbidity and mortality from tick-borne infections. PMID- 26593261 TI - Relapsing Fever Borreliae: A Global Review. AB - Relapsing fever borreliae were notorious and feared infectious agents that earned their place in history through their devastating impact as causes of both epidemic and endemic infection. They are now considered more as an oddity, and their burden of infection is largely overshadowed by other infections such as malaria, which presents in a similar clinical way. Despite this, they remain the most common bacterial infection in some developing countries. Transmitted by soft ticks or lice, these fascinating spirochetes have evolved a myriad of mechanisms to survive within their diverse environments. PMID- 26593262 TI - Borrelia miyamotoi Disease: Neither Lyme Disease Nor Relapsing Fever. AB - Borrelia miyamotoi disease (BMD) is a newly recognized borreliosis globally transmitted by ticks of the Ixodes persulcatus species complex. Once considered to be a tick symbiont with no public health implications, B miyamotoi is increasingly recognized as the agent of a nonspecific febrile illness often misdiagnosed as acute Lyme disease without rash, or as ehrlichiosis. The frequency of its diagnosis in the northeastern United States is similar to that of human granulocytic ehrlichiosis. A diagnosis of BMD is confirmed by polymerase chain reaction analysis of acute blood samples, or by seroconversion using a recombinant glycerophosphodiester phosphodiesterase enzyme immunoassay. BMD is successfully treated with oral doxycycline or amoxicillin. PMID- 26593263 TI - Methods to Prevent Tick Bites and Lyme Disease. AB - Current approaches for prevention of tick bites, Lyme disease, and other tick borne diseases are described. Particular attention is paid to 4 risk-reduction strategies: (i) avoiding risk areas; (ii) personal protective measures that reduce the risk of tick bites or transmission of the agent of Lyme disease, Borrelia burgdorferi; (iii) reducing the number of infected ticks in the environment; and (iv) use of prophylactic antibiotic treatments following a bite to prevent clinical Lyme disease. PMID- 26593264 TI - Tickborne Borrelia Infections: Beyond Just Lyme Disease. PMID- 26593265 TI - Increased Default Mode Network Connectivity in Individuals at High Familial Risk for Depression. AB - Research into the pathophysiology of major depressive disorder (MDD) has focused largely on individuals already affected by MDD. Studies have thus been limited in their ability to disentangle effects that arise as a result of MDD from precursors of the disorder. By studying individuals at high familial risk for MDD, we aimed to identify potential biomarkers indexing risk for developing MDD, a critical step toward advancing prevention and early intervention. Using resting state functional connectivity MRI (rs-fcMRI) and diffusion MRI (tractography), we examined connectivity within the default mode network (DMN) and between the DMN and the central executive network (CEN) in 111 individuals, aged 11-60 years, at high and low familial risk for depression. Study participants were part of a three-generation longitudinal, cohort study of familial depression. Based on rs fcMRI, individuals at high vs low familial risk for depression showed increased DMN connectivity, as well as decreased DMN-CEN-negative connectivity. These findings remained significant after excluding individuals with a current or lifetime history of depression. Diffusion MRI measures based on tractography supported the findings of decreased DMN-CEN-negative connectivity. Path analyses indicated that decreased DMN-CEN-negative connectivity mediated a relationship between familial risk and a neuropsychological measure of impulsivity. Our findings suggest that DMN and DMN-CEN connectivity differ in those at high vs low risk for depression and thus suggest potential biomarkers for identifying individuals at risk for developing MDD. PMID- 26593266 TI - Effect of the Putative Lithium Mimetic Ebselen on Brain Myo-Inositol, Sleep, and Emotional Processing in Humans. AB - Lithium remains the gold standard in treating bipolar disorder but has unwanted toxicity and side effects. We previously reported that ebselen inhibits inositol monophosphatase (IMPase) and exhibits lithium-like effects in animal models through lowering of inositol. Ebselen has been tested in clinical trials for other disorders, enabling us to determine for the first time the effect of a blood-brain barrier-penetrant IMPase inhibitor on human central nervous system (CNS) function. We now report that in a double-blind, placebo-controlled trial with healthy participants, acute oral ebselen reduced brain myo-inositol in the anterior cingulate cortex, consistent with CNS target engagement. Ebselen decreased slow-wave sleep and affected emotional processing by increasing recognition of some emotions, decreasing latency time in the acoustic startle paradigm, and decreasing the reinforcement of rewarding stimuli. In summary, ebselen affects the phosphoinositide cycle and has CNS effects on surrogate markers that may be relevant to the treatment of bipolar disorder that can be tested in future clinical trials. PMID- 26593268 TI - Association between delivery of small-for-gestational-age neonate and long-term maternal chronic kidney disease. AB - OBJECTIVE: To investigate whether delivery of a small for gestational age (SGA) neonate poses a risk for subsequent long-term maternal renal disease. STUDY DESIGN: A population-based study was conducted. Comparison was performed regarding the incidence of long-term renal morbidity in a cohort of women with and without a previous delivery of a SGA neonate. Deliveries occurred during a 25 year period, with a mean follow-up duration of 11.2 years. Renal morbidity included kidney transplantation, chronic renal failure and hypertensive renal disease. Cox proportional hazards model was used to estimate the adjusted hazards ratio (HR) for renal-related hospitalizations and mortality. RESULTS: Out of 99 342 deliveries that met the inclusion criteria, 10 701 (10.7%) occurred in patients who had at least one previous delivery of a SGA neonate. During the follow-up period, patients with a delivery of an SGA neonate had higher rates of renal-related hospitalizations (0.2% versus 0.1%; OR = 1.6, 95% CI 1.01-2.5; p = 0.04). In a Cox proportional hazards model, adjusted for confounders, previous delivery of a SGA neonate was independently associated with subsequent maternal renal-related hospitalizations (adjusted HR, 1.7; 95% CI 1.1-2.8). CONCLUSION: Delivery of a SGA neonate is an independent risk factor for long-term maternal renal disease. PMID- 26593269 TI - Recurrent intestinal intussusception in an adult due to intestinal pseudopolyps not associated with inflammatory bowel disease: a case report. AB - INTRODUCTION: Intestinal intussusception is very rare in adults and, unlike in children, it is due to an organic cause, mainly benign or malignant tumors, in 90 % of cases. Recurrent intussusception in an adult is even more exceptional, and in the case reported it was due to repeated occurrence of intestinal pseudopolyps, which is exceptional according to the literature. Preoperative diagnosis is difficult, and surgery is always indicated because a tumor is usually present. The surgical procedure may be controversial, as some would prefer desintussusception before resection, while others would advocate initial resection because of the risk of dissemination if a malignant lesion exists. CASE PRESENTATION: We report the case of a 34-year-old Caucasian man who underwent emergency laparoscopic surgery for intestinal obstruction and was found to have a jejunal intussusception. Polyps or pseudopolyps, some of them large and causing the intussusception, were seen in the surgical specimen. Our patient had also undergone surgery for intussusception 10 years before, after which the pathological report also noted the presence of these formations. CONCLUSIONS: Recurrent intussusception in adults due to the presence of intestinal pseudopolyps is exceptional and, to the best of our knowledge, this is the first such case reported. PMID- 26593267 TI - Recessive Mutations in RTN4IP1 Cause Isolated and Syndromic Optic Neuropathies. AB - Autosomal-recessive optic neuropathies are rare blinding conditions related to retinal ganglion cell (RGC) and optic-nerve degeneration, for which only mutations in TMEM126A and ACO2 are known. In four families with early-onset recessive optic neuropathy, we identified mutations in RTN4IP1, which encodes a mitochondrial ubiquinol oxydo-reductase. RTN4IP1 is a partner of RTN4 (also known as NOGO), and its ortholog Rad8 in C. elegans is involved in UV light response. Analysis of fibroblasts from affected individuals with a RTN4IP1 mutation showed loss of the altered protein, a deficit of mitochondrial respiratory complex I and IV activities, and increased susceptibility to UV light. Silencing of RTN4IP1 altered the number and morphogenesis of mouse RGC dendrites in vitro and the eye size, neuro-retinal development, and swimming behavior in zebrafish in vivo. Altogether, these data point to a pathophysiological mechanism responsible for RGC early degeneration and optic neuropathy and linking RTN4IP1 functions to mitochondrial physiology, response to UV light, and dendrite growth during eye maturation. PMID- 26593270 TI - Oligodeoxynucleotide inhibition of Toll-like receptors 3, 7, 8, and 9 suppresses cytokine production in a human rheumatoid arthritis model. AB - Toll-like receptors (TLRs) are innate immune receptors that respond to both exogenous and endogenous stimuli and are suggested to contribute to the perpetuation of chronic inflammation associated with rheumatoid arthritis (RA). In particular, the endosomal TLRs 3, 7, 8, and 9 have more recently been postulated to be of importance in RA pathogenesis. In this study, pan inhibition of the endosomal TLRs by a phosphorothioate-modified inhibitory oligodeoxynucleotide (ODN) is demonstrated in primary human B cells, macrophages, and RA fibroblasts. Inhibition of TLR8 was of particular interest as TLR8 has been associated with RA pathogenesis in both human and murine arthritis models. ODN1411 competitively inhibited TLR8 signaling and was observed to directly bind to a purified TLR8 ectodomain, suggesting inhibition was through a direct interaction with the receptor. Addition of ODN1411 to human RA synovial membrane cultures significantly inhibited spontaneous cytokine production from these cultures, suggesting a potential role for one or more of the endosomal TLRs in inflammatory cytokine production in RA and the potential for inhibitory ODNs as novel therapies. PMID- 26593271 TI - Mechanistic analysis of a synthetic inhibitor of the Pseudomonas aeruginosa LasI quorum-sensing signal synthase. AB - Pseudomonas aeruginosa is an opportunistic Gram-negative pathogen responsible for many human infections. LasI is an acyl-homoserine lactone synthase that produces a quorum-sensing (QS) signal that positively regulates numerous P. aeruginosa virulence determinants. The inhibition of the LasI protein is therefore an attractive drug target. In this study, a novel in silico to in vitro complementation was applied to screen thiazolidinedione-type compounds for their ability to inhibit biofilm formation at concentrations not affecting bacterial growth. The compound (z)-5-octylidenethiazolidine-2, 4-dione (TZD-C8) was a strong inhibitor of biofilm formation and chosen for further study. Structural exploration of in silico docking predicted that the compound had high affinity for the LasI activity pocket. The TZD-C8 compound was also predicted to create hydrogen bonds with residues Arg30 and Ile107. Site-directed mutagenesis (SDM) of these two sites demonstrated that TZD-C8 inhibition was abolished in the lasI double mutant PAO-R30D, I107S. In addition, in vitro swarming motility and quorum sensing signal production were affected by TZD-C 8, confirming this compound alters the cell to cell signalling circuitry. Overall, this novel inhibitor of P. aeruginosa quorum sensing shows great promise and validates our mechanistic approach to discovering inhibitors of LuxI-type acyl-homoserine lactone synthases. PMID- 26593272 TI - Extinction risk of soil biota. AB - No species lives on earth forever. Knowing when and why species go extinct is crucial for a complete understanding of the consequences of anthropogenic activity, and its impact on ecosystem functioning. Even though soil biota play a key role in maintaining the functioning of ecosystems, the vast majority of existing studies focus on aboveground organisms. Many questions about the fate of belowground organisms remain open, so the combined effort of theorists and applied ecologists is needed in the ongoing development of soil extinction ecology. PMID- 26593273 TI - Different forms of prefrontal theta burst stimulation for executive function of medication- resistant depression: Evidence from a randomized sham-controlled study. AB - BACKGROUND: Even during symptomatic remission, many patients with medication resistant depression (MRD) still demonstrate impaired cognitive function, especially executive function (EF). Theta-burst transcranial magnetic stimulation (TBS) modulates cortical excitability and may treat MRD. Evidences from previous studies show that intermittent TBS (iTBS) produces cortical excitatory effects, while continuous TBS (cTBS) produces a reduction of cortical excitability. EF is highly dependent on prefrontal activity, but the effects of different forms of prefrontal TBS on EF remain unknown. METHODS: 60 MRD patients were recruited and randomly assigned to one of four groups. Treatment was determined by the group to which an individual was assigned; A: cTBS 1800pulses/session; B: iTBS 1800pulses/session; C: a combination of cTBS+iTBS, 1800pulses/session for each; and D: sham TBS. Wisconsin Card Sorting Test (WCST) for the performance of EF was evaluated before and after 10 daily treatment sessions RESULTS: Repeated measures ANOVA, with each WCST index at baseline and 2weeks after TBS as within-subject factors, demonstrated that a statistically significant interaction of TBS groups (G) and antidepressant responses [(R), responses were defined as >50% reduction of depression scores after 2-weeks TBS treatment] on the before-versus-after changes of all WCST indexes (G*R, p<0.05). Responders in Group B, but not in the other groups, showed a significant improvement in WCST performance. Only nonresponders in Group A showed a trend for EF worsening. CONCLUSIONS: Our findings showed that left prefrontal iTBS, not right prefrontal cTBS, improved EF, and this can be independent from its antidepressant effects. PMID- 26593274 TI - Accessibility to tuberculosis control services and tuberculosis programme performance in southern Ethiopia. AB - BACKGROUND: Despite the expansion of health services and community-based interventions in Ethiopia, limited evidence exists about the distribution of and access to health facilities and their relationship with the performance of tuberculosis (TB) control programmes. We aim to assess the geographical distribution of and physical accessibility to TB control services and their relationship with TB case notification rates (CNRs) and treatment outcome in the Sidama Zone, southern Ethiopia. DESIGN: We carried out an ecological study to assess physical accessibility to TB control facilities and the association of physical accessibility with TB CNRs and treatment outcome. We collected smear positive pulmonary TB (PTB) cases treated during 2003-2012 from unit TB registers and TB service data such as availability of basic supplies for TB control and geographic locations of health services. We used ArcGIS 10.2 to measure the distance from each enumeration location to the nearest TB control facilities. A linear regression analysis was employed to assess factors associated with TB CNRs and treatment outcome. RESULTS: Over a decade the health service coverage (the health facility-to-population ratio) increased by 36% and the accessibility to TB control facilities also improved. Thus, the mean distance from TB control services was 7.6 km in 2003 (ranging from 1.8 to 25.5 km) between kebeles (the smallest administrative units) and had decreased to 3.2 km in 2012 (ranging from 1.5 to 12.4 km). In multivariate linear regression, as distance from TB diagnostic facilities (b-estimate=-0.25, p<0.001) and altitude (b-estimate=-0.31, p<0.001) increased, the CNRs of TB decreased, whereas a higher population density was associated with increased TB CNRs. Similarly, distance to TB control facilities (b-estimate=-0.27, p<0.001) and altitude (b-estimate=-0.30, p<0.001) were inversely associated with treatment success (proportion of treatment completed or cured cases). CONCLUSIONS: Accessibility to TB control services improved despite the geographic variations. TB CNRs were higher in areas where people had better access to diagnostic and treatment centres. Community-based interventions also played an important role for the increased CNRs in most areas. PMID- 26593275 TI - Acceleration of amyloidogenesis and memory impairment by estrogen deficiency through NF-kappaB dependent beta-secretase activation in presenilin 2 mutant mice. AB - Nearly 7-10 million people are living with Alzheimer's disease (AD) worldwide. Senile plaques composed of beta-amyloid (Abeta) are a pathological hallmark of Alzheimer's disease. Presenilin 2 (PS2) mutations increase Abeta generation in the brains of AD patients. The Abeta is generated through the sequential cleavage of amyloid precursor protein by beta- and gamma-secretases. Additionally, increasing evidences suggest that estrogen can reduce the development of AD via regulation of beta-secretases activity and beta-site APP-cleaving enzyme (BACE1) expression. But the underlying correlation mechanism of Abeta generation by PS2 mutations and estrogen remains to be clarified. To investigate the anti amyloidogenesis effect of estrogen in a PS2 mutative condition, we examined memory impairment in ovariectomized PS2 mutation (N141I) mice in which cognitive function was assessed by the Morris water maze test and passive avoidance test. In addition, Western blot analysis, immunostaining, immunofluorescence staining, ELISA and enzyme activity assays were used to examine the degree of Abeta deposition in the brains. In the present study, Abeta accumulated more in the ovariectomized PS2 mutant mice brain, and greatly worsened memory impairment and glial activation as well as neurogenic inflammation. In parallel with increased memory impairment, activity of beta-secretase and expression of the BACE1 increased inovariectomized PS2 mutant mice. Much higher activity of NF-kappaB was observed by EMSA in ovariectomized PS2 mutant mice. In addition, the Abeta level was decreased by treatment of beta-estradiol through inhibiting BACE1 expression in PS2 transfacted PC12 cells. These results suggest that mutation of PS2 can lead to NF-kappaB mediate amyloidogensis, and this effect can be amplified by the absence of estrogen. PMID- 26593276 TI - Glycogen synthase kinase 3 is part of the molecular machinery regulating the adaptive response to LPS stimulation in microglial cells. AB - Repeated stimulation of TLR4 signaling by lipopolysaccharide (LPS) in microglia induces a state of tolerance/sensitization consisting in the reprogramming of the expression of pro-inflammatory genes in favor of anti-inflammatory ones. The molecular mechanisms underlying this adaptive response are far to be elucidated. Glycogen synthase kinase 3 (GSK3) has emerged as crucial regulator of TLR signaling, mediating the balance between pro- and anti-inflammatory functions in both periphery and central nervous system. The present study extends this notion identifying GSK3 as part of the molecular machinery regulating the LPS-adaptive response in microglial cells, by using primary microglial cultures and organotypic hippocampal slices (OHSCs). We found that lithium chloride (LiCl), a widely used GSK3 inhibitor and the mainstay treatment for bipolar disorder, reinforced the LPS adaptive response by enhancing both downregulation of pro inflammatory genes (inducible nitric oxide synthase, interleukin 1beta, interleukin 6, tumor necrosis factor alpha), and upregulation of genes typically associated to anti-inflammatory functions (interleukin 10 and MRC1). The effects of GSK3 inhibition were mimicked by Wnt3a, added exogenously, and reversed by Inhibitor of Wnt-Response-1-endo, a pharmacological disruptor of the canonical Wnt/beta-catenin pathway, and GW9662, a selective peroxisome proliferator activated receptor gamma antagonist, suggesting that these two pathways are involved in the regulation of LPS-tolerance/sensitization by GSK. Finally, LiCl treatment of OHSCs enhanced the protective functional consequences of the microglial adaptive response to LPS on oligodendrocyte maturation, as indicated by MBP mRNA upregulation. These results further indicate GSK3 as key component in the orchestration of neuroinflammation and target for neuroprotective strategies. PMID- 26593277 TI - Adverse Event Rates Associated with Transforaminal and Interlaminar Epidural Steroid Injections: A Multi-Institutional Study. AB - BACKGROUND: Transforaminal epidural steroid injections (TFESI) have demonstrated efficacy and effectiveness in treatment of radicular pain. Despite little evidence of efficacy/effectiveness, interlaminar epidural steroid injections (ILESI) are advocated by some as primary therapy for radicular pain due to purported greater safety. OBJECTIVE: To assess immediate and delayed adverse event rates of TFESI and ILESI injections at three academic medical centers utilizing International Spine Intervention Society practice guidelines. METHODS: Quality assurance databases from a Radiology and two physical medicine and rehabilitation (PM&R) practices were interrogated. Medical records were reviewed, verifying immediate and delayed adverse events. RESULTS: There were no immediate major adverse events of neurologic injury or hemorrhage in 16,638 consecutive procedures in all spine segments (14,956 TFESI; 1,682 ILESI). Vasovagal reactions occurred in 1.2% of procedures, more frequently (P = 0.004) in TFESI (1.3%) than ILESI (0.5%). Dural punctures occurred in 0.06% of procedures, more commonly after ILESI (0.2% vs 0.04%, P = 0.006). Delayed follow up on PM&R patients (92.5% and 78.5, next business day) and radiology patients (63.1%, 2 weeks) identified no major adverse events of neurologic injury, hemorrhage, or infection. There were no significant differences in delayed minor adverse event rates. Central steroid response (sleeplessness, flushing, nonpositional headache) was seen in 2.6% of both TFESI and ILESI patients. 2.1% of TFESI and 1.8% of ILESI patients reported increased pain. No long-term sequelae were seen from any immediate or delayed minor adverse event. CONCLUSIONS: Both transforaminal and ILESI are safely performed with low immediate and delayed adverse event rates when informed by evidence-based procedural guidelines. By demonstrating comparable safety, this study suggests that the choice between ILESI and TFESIs can be based on documented efficacy and effectiveness and not driven by safety concerns. PMID- 26593278 TI - Preliminary assessment of contaminants in the sediment and organisms of the Swartkops Estuary, South Africa. AB - Urban estuaries are susceptible to metal and organic pollution, yet most remain understudied in South Africa with respect to the presence, concentrations and distribution of contaminants. Metal and organic chemical concentrations were assessed in sediment and organisms from different trophic levels in the lower reaches of the Swartkops Estuary. Species sampled included Upogebia africana (Malacostraca: Upogebiidae), Gilchristella aestuaria (Clupeidae), Psammogobius knysnaensis (Gobiidae), Mugil cephalus (Mugilidae), Lichia amia (Carangidae), Argyrosomus japonicus (Sciaenidae), Pomadasys commersonnii (Haemulidae) and Larus dominicanus (Avis: Laridae). This study is one of the most comprehensive studies to date assessing pollution levels in a food web in estuaries in South Africa. Due to biomagnification, higher concentrations of Arsenic, Lead, Mercury and Cadmium were found in the juveniles stages of popular angling fishes. High concentrations of Cadmium and Arsenic were recorded in the liver of L. amia, A. japonicus and P. commersonnii which exceed international quality food guidelines. Eggs from the gull, L. dominicanus, showed detectable concentrations of PCBs. PMID- 26593279 TI - Current levels, composition profiles, source identification and potentially ecological risks of polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) in the surface sediments from Bohai Sea. AB - Polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) were analyzed to assess the environmental quality in the surface sediments from Bohai Sea (BS), China. Concentrations of ?37PCBs, ?7PBDEs and BDE-209 were 0.157-1.699, 0.100-0.479 and 0.464-6.438 ng/g (dry weight), respectively. All of these concentrations decreased generally from the coastal areas towards the outer sea, indicating intensive influences of anthropogenic activities. Principal component analysis (PCA) coupled with multiple linear regression (MLR) revealed that 82.1% of the PCBs in BS came from direct discharge of local anthropogenic activities, 16.3% from surface runoff of contaminated soils and 1.6% from atmospheric deposition. PBDEs were mainly derived from the usage and dismantling of products containing commercial Penta-, Octa- and Deca-BDEs. According to sediment quality guidelines (SQGs), the ecological risks of PCBs could be negligible, and penta- and deca-BDE homologs might be the major contributors of ecological risks in the BS sediments. PMID- 26593280 TI - Equilibrium passive sampling as a tool to study polycyclic aromatic hydrocarbons in Baltic Sea sediment pore-water systems. AB - Solid Phase Microextraction (SPME) was applied to provide the first large scale dataset of freely dissolved concentrations for 9 polycyclic aromatic hydrocarbons (PAHs) in Baltic Sea sediment cores. Polydimethylsiloxane (PDMS) coated glass fibers were used for ex-situ equilibrium sampling followed by automated thermal desorption and GC-MS analysis. From the PAH concentrations in the fiber coating we examined (i) spatially resolved freely dissolved PAH concentrations (Cfree); (ii) baseline toxicity potential on the basis of chemical activities (a); (iii) site specific mixture compositions; (iv) diffusion gradients at the sediment water interface and within the sediment cores and (v) site specific distribution ratios. Contamination levels were low in the northern Baltic Sea, moderate to elevated in the Baltic Proper and highest in the Gulf of Finland. Chemical activities were well below levels expected to cause narcosis to benthos organisms. The SPME method is a very sensitive tool that opens new possibilities for studying the PAHs at trace levels in marine environments. PMID- 26593281 TI - Effects of extremely low frequency electromagnetic fields (100MUT) on behaviors in rats. AB - Recently, extremely low frequency electromagnetic fields (ELF-EMF) have received considerable attentions for their potential pathogenicity. In the present study, we explored the effects of ELF-EMF on behaviors of adult male rats. Sixty adult male rats were randomly divided into two groups, the sham exposure group and the 50Hz/100MUT ELF-EMF exposure group. During the 24 weeks exposure, body weight, as well as food and water intake were recorded. Results showed that food and water intake and the body weight of the rats were not affected by the exposure. After 24 weeks exposure, open field test and elevated plus maze were conducted to evaluate the anxiety-like behavior, the tail suspension test and forced swim test were conducted to evaluate depression-like behavior and Morris water maze and fear conditioning tests were used to evaluate the cognitive and memory ability. Exposure to ELF-EMF did not induce any anxiety-like or depression-like behaviors compared with the sham exposure. Moreover, the cognitive and memory ability was not impaired by the ELF-EMF exposure. Furthermore, ELF-EMF exposure did not affect the morphology and histology of the brain. In conclusion, 24 weeks exposure to 50Hz/100MUT ELF-EMF had no effect on the behaviors of the adult male rats. PMID- 26593282 TI - Comparison of methods probing the intracellular redox milieu in Plasmodium falciparum. AB - Glutathione plays a crucial role in the redox regulation of the malaria parasite Plasmodium falciparum and is linked to drug resistance mechanisms, especially in resistance against the antimalarial drug chloroquine (CQ). The determination of the glutathione-dependent redox potential was recently established in living parasites using a cytosolically expressed biosensor comprising redox-sensitive green fluorescent protein coupled to human glutaredoxin 1 (hGrx1-roGFP2). In order to further elucidate redox changes induced by antimalarial drugs and to consolidate the application spectrum of the ratiometric biosensor we systematically compared it to other methods probing thiol and redox metabolism. Among these methods were cell disruptive and non-disruptive approaches including spectrophotometric assays with Ellman's reagent and naphthalene dicarboxyaldehyde as well as molecular probes such as ThiolTrackerTM Violet and the dichlorofluorescein-based probe CM-H2DCFDA. To directly compare the methods, blood stages of the CQ-sensitive P. falciparum 3D7 strain were challenged with the oxidative agent diamide and the antimalarial drugs artemisinin and CQ for 1h, 4h, and 24h. For all conditions, dose-dependent changes in the different redox parameters could be monitored which are compared and discussed. We furthermore detected slight differences in thiol status of parasites transiently transfected with hGrx1-roGFP2 in comparison with control 3D7 cells. In conclusion, ThiolTrackerTM Violet and, even more so, the hGrx1-roGFP2 probe reacted reliably and sensitively to drug induced changes in intracellular redox metabolism. These results were substantiated by classical cell disruptive methods. PMID- 26593283 TI - PEX6 is Expressed in Photoreceptor Cilia and Mutated in Deafblindness with Enamel Dysplasia and Microcephaly. AB - Deafblindness is part of several genetic disorders. We investigated a consanguineous Egyptian family with two siblings affected by congenital hearing loss and retinal degeneration, initially diagnosed as Usher syndrome type 1. At teenage, severe enamel dysplasia, developmental delay, and microcephaly became apparent. Genome-wide homozygosity mapping and whole-exome sequencing detected a homozygous missense mutation, c.1238G>T (p.Gly413Val), affecting a highly conserved residue of peroxisomal biogenesis factor 6, PEX6. Biochemical profiling of the siblings revealed abnormal and borderline plasma phytanic acid concentration, and cerebral imaging revealed white matter disease in both. We show that Pex6 localizes to the apical extensions of secretory ameloblasts and differentiated odontoblasts at early stages of dentin synthesis in mice, and to cilia of retinal photoreceptor cells. We propose PEX6, and possibly other peroxisomal genes, as candidate for the rare cooccurrence of deafblindness and enamel dysplasia. Our study for the first time links peroxisome biogenesis disorders to retinal ciliopathies. PMID- 26593284 TI - Differential effects of antifungal agents on expression of genes related to formation of Candida albicans biofilms. AB - The purpose of this study was to analyse specific molecular mechanisms involved in the intrinsic resistance of C. albicans biofilms to antifungals. We investigated the transcriptional profile of three genes (BGL2, SUN41, ECE1) involved in Candida cell wall formation in response to voriconazole or anidulafungin after the production of intermediate and mature biofilms. C. albicans M61, a well-documented biofilm producer strain, was used for the development of intermediate (12 h and 18 h) and completely mature biofilms (48 h). After exposure of cells from each biofilm growth mode to voriconazole (128 and 512 mg l(-1)) or anidulafungin (0.25 and 1 mg l(-1)) for 12-24 h, total RNA samples extracted from biofilm cells were analysed by RT-PCR. The voriconazole and anidulafungin biofilm MIC was 512 and 0.5 mg l(-1) respectively. Anidulafungin caused significant up-regulation of SUN41 (3.7-9.3-fold) and BGL2 (2.2-2.8 fold) in intermediately mature biofilms; whereas, voriconazole increased gene expression in completely mature biofilms (SUN41 2.3-fold, BGL2 2.1-fold). Gene expression was primarily down-regulated by voriconazole in intermediately, but not completely mature biofilms. Both antifungals caused down-regulation of ECE1 in intermediately mature biofilms. PMID- 26593285 TI - Multiple Conformations of the Loop Region Confers Heat-Resistance on SsArd1, a Thermophilic NatA. AB - Structural comparison indicates that the loop region between beta3 and beta4 of SsArd1 is extended relative to the corresponding region in mesophilic Nats, and forms a plastic hydrogen-bond network mainly at two serine residues. Strikingly, two single-point mutants showed ~3 degrees C decrease in melting temperature, and two other variants showed ~7 degrees C decrease; this correlated with significantly reduced enzymatic activity. To our knowledge, this is the first discovery of a loop region capable of remarkably improving protein thermostability. This provides a novel route to engineer heat-resistant proteins. PMID- 26593286 TI - Electromembrane extraction using two separate cells: A new design for simultaneous extraction of acidic and basic compounds. AB - Simultaneous extraction of acidic and basic analytes from a sample is seen to be a challenging task. In this work, a novel and efficient electromembrane extraction (EME) method based on two separate cells was applied to simultaneously extract and preconcentrate two acidic drugs (naproxen and ibuprofen) along with a basic drug (ketamine). Once both cells were filled with the sample solution, basic drug was extracted from one cell with the other cell used to extract acidic drugs. The employed supported liquid membranes for the extraction of acidic and basic drugs were 2-ethyl hexanol and 1-octanol, respectively. Under an applied potential of 250 V in the course of the extraction process, acidic, and basic drugs were extracted from a 3.0 mL aqueous sample solution into 25 MUL acceptor solutions. The pH values of the donor and acceptor solutions in the cathodic cell were 5.0 and 1.5, respectively, the corresponding values in the anodic cell were, however, 8.0 and 12.5, respectively. The rates of recovery obtained within 20 min of extraction time at a stirring rate of 750 rpm ranged from 45 to 54%. With correlation coefficients ranging from 0.990 to 0.996, the proposed EME technique provided good linearity over a concentration range of 20-1000 ng/mL. The LOD for all drugs was found to be 6.7 ng/mL, while reproducibility ranged from 7 to 12% (n = 5). Finally, applying the proposed method to determine and quantify the drugs in urine and wastewater samples, satisfactory results were achieved. PMID- 26593287 TI - The Gut-Liver Axis in Primary Sclerosing Cholangitis. AB - Dysregulation of the key genetic, immunologic, and microbiome compounds of the gut-liver axis is the basis for inflammatory bowel disease (IBD) and primary sclerosing cholangitis (PSC). This creates opportunities to accelerate therapies that have been traditionally developed for IBD to be used in PSC to the benefit of both diseases. Shared genetic susceptibility loci has yielded important clues into the pathogenesis of PSC-IBD. Understanding of the critical links between PSC and IBD are essential in designing clinical care pathways for these complex patients. PMID- 26593289 TI - Making Sense of Autoantibodies in Cholestatic Liver Diseases. AB - Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are the most common chronic cholestatic liver diseases (CLD) in adults and are associated with immune mechanisms. PBC is considered a model autoimmune disease, and more than 90% of patients present very specific autoantibodies against mitochondrial antigens. Whether PSC should be considered an autoimmune or merely immune mediated disease is still under debate. This review addresses the clinical relevance of autoantibodies in CLD and their pathogenic mechanisms and illustrates the technology available for appropriate autoantibody detection. PMID- 26593290 TI - New Thoughts on Immunoglobulin G4-Related Sclerosing Cholangitis. AB - Immunoglobulin G4 (IgG4)-related sclerosing cholangitis (IgG4-SC) is the biliary manifestation of the multisystem IgG4-related disease. IgG4-SC presents with biliary strictures and/or masses that can bear a striking similarity to other malignant and inflammatory diseases. Diagnosis is based on a combination of clinical, biochemical, radiological, and histologic findings with careful exclusion of malignant disease. Corticosteroids are the mainstay of treatment with good clinical, biochemical, and radiological responses. This review provides a comprehensive overview of the current knowledge of the prevalence, clinical features, radiology and histology findings, diagnosis, treatment, natural history, and pathophysiology of IgG4-SC. PMID- 26593288 TI - The Immunogenetics of Autoimmune Cholestasis. AB - The immune-mediated hepatobiliary diseases, primary biliary cirrhosis and primary sclerosing cholangitis are relatively rare, albeit and account for a significant amount of liver transplant activity and liver-related mortality globally. Precise disease mechanisms are yet to be described although a contributory role of genetic predisposition is firmly established. In addition to links with the major histocompatibility complex, a number of associations outside this region harbor additional loci which underscore the fundamental role of breaks in immune tolerance and mucosal immunogenicity in the pathogenesis of autoimmune biliary disease. We provide an overview of these key discoveries before discussing putative avenues of therapeutic exploitation based on existing findings. PMID- 26593291 TI - Primary Sclerosing Cholangitis: Multiple Phenotypes, Multiple Approaches. AB - Primary sclerosing cholangitis (PSC) is a heterogeneous, idiopathic, inflammatory disorder frequently associated with inflammatory bowel diseases. PSC patients may be classified into several subphenotypes. Investigations of pediatric, nonwhite, and female PSC patients have revealed distinguishing features. The natural history of PSC is variable in progression with numerous possible clinical outcomes. PSC patients may suffer bacterial cholangitis, cholangiocarcinoma, or colorectal adenocarcinoma. Treatments focusing on bile acid therapy and immunosuppression have not proven beneficial. Interest in PSC and international collaboration has led to improved understanding of the heterogeneity and the genetic structure and introduced possible effective therapeutics. PMID- 26593292 TI - Cancer Risk and Surveillance in Primary Sclerosing Cholangitis. AB - Primary sclerosing cholangitis (PSC) is a chronic, progressive disease characterized by inflammatory and fibrosing strictures of the biliary tree. PSC is associated with a high lifetime risk of hepatobiliary and colorectal cancers. The nature of the carcinogenic process in PSC is not well established. The lack of diagnostic methods for early detection and the limited therapeutic options for cholangiocarcinoma constitute a major challenge in the current handling of PSC patients. The article reviews the risk for cancer development in PSC and discusses surveillance strategies for PSC-associated cancers. PMID- 26593293 TI - Sclerosing Cholangitis in Children and Adolescents. AB - Sclerosing cholangitis in pediatric age is a severe disease, often associated with inflammatory bowel disease. It recognizes different etiologies. Management and prognosis depend on the underlying cause. A high proportion of patients have autoimmune features similar to those of autoimmune hepatitis and respond biochemically to immunosuppression, although bile duct disease progresses in half of them leading to liver transplant. The disease can recur after transplant. Severity of liver disease and risk of recurrence after transplant are linked to the severity of bowel disease. PMID- 26593294 TI - Novel Therapies on Primary Biliary Cirrhosis. AB - All patients with primary biliary cirrhosis (PBC) and abnormal liver biochemistry should be considered for specific therapy. Ursodeoxycholic acid (UDCA) is the only FDA-approved drug for treating PBC. Approximately 40% of patients with PBC respond incompletely to treatment with UDCA, thus having increased risk of death or need for liver transplantation. No second-line therapies for patients with inadequate response to UDCA therapy have been approved. This review provides a current perspective on potential new approaches to treatment in PBC, and highlights some of the challenges we face in evaluating and effectively implementing those treatments. PMID- 26593295 TI - Understanding and Treating Fatigue in Primary Biliary Cirrhosis and Primary Sclerosing Cholangitis. AB - Fatigue is a significant problem for patients with primary biliary cirrhosis and although experienced less by patients with primary sclerosing cholangitis, a minority still report significant fatigue. Fatigue is the symptom with the greatest impact on quality of life, particularly when associated with social dysfunction. The pathogenesis of fatigue in cholestatic liver disease is complex, poorly understood, and probably has central and peripheral components. Managing fatigue in cholestatic liver disease presents a challenge for clinicians given the complexity and its numerous associations. This article presents a structured approach to managing fatigue in cholestatic liver disease to improve fatigue severity and quality of life. PMID- 26593296 TI - Utility of Noninvasive Markers of Fibrosis in Cholestatic Liver Diseases. AB - Methods of liver fibrosis assessment have changed considerably in the last 20 years, and noninvasive markers now have been recognized as major first-line tools in the management of patients with chronic viral hepatitis infection. But what about the efficiency and utility of these surrogate indices for the more uncommon chronic cholestatic liver diseases, namely primary biliary cirrhosis and primary sclerosing cholangitis? This article provides clinicians with a global overview of what is currently known in the field. Both diagnostic and prognostic aspects of noninvasive markers of fibrosis in cholestatic liver diseases are presented and discussed. PMID- 26593297 TI - Total Parenteral Nutrition-Induced Cholestasis: Prevention and Management. AB - When cholestasis occurs in patients receiving total parenteral nutrition, it is the result of many pathogenic pathways converging on the hepatic acinus. The result may be a temporary rise in liver function tests. The resulting fibrosis, portal hypertension, and jaundice are hallmarks of type 3 intestinal-associated liver disease to which children are more susceptible than adults. The key to prevention is in identifying high-risk scenarios, meticulous monitoring, and personalized prescription of parenteral nutrition solutions combined with an active approach in reducing the impact of inflammatory events when they occur by prompt use of antibiotics and line locks. PMID- 26593298 TI - New Insights on Intrahepatic Cholestasis of Pregnancy. AB - Intrahepatic cholestasis of pregnancy (ICP) is characterized by maternal pruritus, and elevated serum transaminases and bile acids. Genetic defects in at least 6 canalicular transporters have been found. Association studies stress the variability of genotypes, different penetrance, and influence of environmental factors. Serum autotaxin is a sensitive, specific, and robust diagnostic marker. Elevated maternal bile acids correlate with fetal complications. Long-term sequelae for mothers include the gallstone risk and chronic liver disease. There is an association between ICP and hepatitis C. Current treatment is ursodeoxycholic acid, owing to benefits on pruritus, liver function, safety, and decreased rates of adverse effects. PMID- 26593299 TI - Liver Transplantation for Cholestatic Liver Diseases in Adults. AB - Liver transplantation (LT) is an established lifesaving therapy for patients with cholestatic liver diseases, including primary cholestatic diseases, namely primary sclerosing cholangitis and primary biliary cirrhosis, as well as secondary forms of cholestatic liver disease, including those with cholestatic complications of LT needing a retransplant. Patients with cholestatic liver diseases can be transplanted for complications of end-stage liver disease or for disease-specific symptoms before the onset of end-stage liver disease. These patients should be regularly assessed. Patient survival after LT for cholestatic liver diseases is generally better than for other indications. PMID- 26593300 TI - Advances in Cholestatic Liver Diseases. PMID- 26593301 TI - Olodaterol and vilanterol detection in sport drug testing. AB - The possibility of the detection of olodaterol and vilanterol, two novel beta2 agonists, in human urine for the purpose of sport drug testing was investigated. Compounds of interest were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) employing methods commonly used in the World Anti-Doping Agency (WADA) accredited laboratories. For both substances, the respective parent compound was found to be a suitable target analyte for monitoring therapeutic dose administration. PMID- 26593302 TI - Treatment of Muscle Wasting: An Overview of Promising Treatment Targets. PMID- 26593303 TI - Prevalence of Mental Health Disorders Among Caregivers of Patients With Alzheimer Disease. AB - OBJECTIVE: The overall prevalence of mental health disorders among caregivers of patients with Alzheimer disease (AD) remains unclear. This meta-analysis aims to evaluate the prevalence of various mental health disorders among caregivers of patients with AD globally and to determine factors that predispose to development of the aforementioned, namely gender of caregiver, gender of patient, and caregiver-patient relationship. METHODS: A total of 17 studies were eligible for systematic review and meta-analysis. A meta-analysis of published work was performed using the random effect model. Data analysis was done with RevMan 5.3. A total of 10,825 caregivers were assessed. RESULTS: The aggregate prevalence of depression among caregivers was 34.0%, anxiety at 43.6%, and use of psychotropic drugs at 27.2%. Meta-analysis revealed the odds of having of depression was 1.53 times higher in female caregivers (95% confidence interval [CI] 1.29-1.83; I(2) = 7%; Z = 4.78; P < .001), 1.86 times higher in caregivers to male care-recipients (95% CI 1.66-2.08; I(2) = 40%; Z = 10.86; P < .001), and 2.51 times higher in spousal caregivers (95% CI 1.68-3.76; I(2) = 55%; Z = 4.49; P < .001). CONCLUSION: Caregivers of patients with AD have a higher prevalence of mental health disorders, particularly depression and anxiety, as compared with the general population and with their counterparts caring for patients with other illnesses. The higher prevalence is mainly observed in female caregivers, caregivers with male care-recipients, and caregivers who have a spousal relationship with care-recipients. Prevalence of anxiety was also notably higher in this cohort but more research needs to be done in this area. PMID- 26593304 TI - Sociodemographic and Clinical Changes Over Time of Individuals Evaluated for Cognitive Disturbances: Good or Bad News? AB - In recent years, "prevention" and "early diagnosis" have been growingly discussed and explored in the field of cognitive disorders. Such increased attention to cognitive disturbances and neurodegenerative conditions may constitute a key step for achieving early/timely diagnosis of dementing illnesses. At the same time, it may generate possible issues (such as a greater proportion of negative diagnostic procedures with potential misuse of resources) that should be acknowledged by health care systems. In this report, we present exploratory analyses aimed at investigating the sociodemographic and clinical changes over time of all the individuals who have been cognitively assessed in a Memory Clinic between 2002 and 2014. Overall, individuals evaluated for cognitive disturbances have gradually become younger, more educated, and less impaired in cognitive and physical functions at their first cognitive assessment. To date, nearly 1 of 4 individuals completing a neuropsychological evaluation has no objective cognitive deficits, thus presenting subjective cognitive complaints. Based on these findings, the development and implementation of strategies for improving the referral to memory clinics is strongly needed. PMID- 26593305 TI - Informed Consent for Psychotropic Medication Use: A Novel Approach to Changing Physician Behavior. PMID- 26593306 TI - A Longitudinal Study of Transitions Between Informal and Formal Care in Alzheimer Disease Using Multistate Models in the European ICTUS Cohort. AB - BACKGROUND: We aimed to describe longitudinal patterns of care in community dwelling European patients with Alzheimer disease (AD), and determine patient-, caregiver-, and country-related predictors of transitions across different care levels. METHODS: Two-year follow-up data from ICTUS cohort (1375 patients with AD, 12 countries) were analyzed using multistate Markov models to describe transitions across states of care and identify their predictors. RESULTS: Of the patients, 61.3% stayed in the same state during follow-up, and only 9.5% experienced >=2 changes between states. Six-month transition probabilities were 11% for informal to formal care and 13% for formal to informal care (in the community). Older age, male gender, poorer cognitive and behavioral scores, and country of residence were associated with transitioning from informal to formal care, but only country of residence was associated with the reverse transition. DISCUSSION: Changes between different types of care were rare during follow-up, and country factors in particular influenced these transitions. PMID- 26593307 TI - Effects of Mild Cognitive Impairment on the Development of Fear of Falling in Older Adults: A Prospective Cohort Study. AB - OBJECTIVES: The aim of this study was to determine whether mild cognitive impairment (MCI) affects the development of fear of falling (FoF) in older adults. DESIGN: Prospective cohort study. SETTING: The Obu Study for Health Promotion in the Elderly, Japan. PARTICIPANTS: A total of 1700 community-dwelling people aged 65 years or older without FoF at baseline participated. MEASUREMENTS: FoF and related variables, such as physical function, self-rated health, depression, and total number of medication doses, were investigated at baseline. Participants also underwent cognitive tests and were divided into cognitive healthy and MCI. Fifteen months after the baseline measurements, we collected information about the status of FoF and fall incidence during the 15-month follow up. RESULTS: At the 15-month follow-up survey, 452 participants (26.5%) reported the development of FoF. Logistic regression analysis showed that MCI (odds ratio [95% CI] = 1.41 [1.07-1.87]) and a fall incident (3.00 [2.23-4.07]) during follow up independently predicted the development of FoF, after controlling for demographic factors, physical function, self-rated health, and depression. The odds ratio for the development of FoF in participants with both MCI and a fall incident compared with those without them was 7.34 (4.06-13.3), after controlling for confounding factors. CONCLUSION: MCI predicts the new onset of FoF in older adults, especially when they have experience with falling. Aside from the risk of falling, it is suggested that individuals with MCI are an at-risk population for FoF and related negative consequences in terms of postfall syndrome. PMID- 26593308 TI - Adaptive responses of cell hydration to a low temperature arrest. AB - Slow cooling leads to a passive dehydration of cells, whereas rehydration during warming reflects the active regain of functionality. The ability to modulate such an energy demanding process could be instrumental in optimizing the cryo-arrest of living systems. In the present study, various levels of hypertonic stress were used to disturb the water content of cells and to define the energy profiles of aquaporins and (Na(+) conducting) cation channels during rehydration. Na(+) import was found to be the rate-limiting step in water restoration, whereas aquaporins merely played a permissive role. Indeed, regulated Na(+) import was increased 2-fold following cryo-arrests, thus facilitating the osmotic rehydration of cells. Freezing temperatures increased cell viscosity with a remarkable hysteresis and viscosity was a trigger of cation channels. The peptide hormone vasopressin was a further activator of channels, increasing the viability of post-cryo cells considerably. Hence, the hormone opens the path for a novel class of cryo-protectants with an intrinsic biological activity. PMID- 26593309 TI - Aminophylline for bradyasystolic cardiac arrest in adults. AB - BACKGROUND: In cardiac ischaemia, the accumulation of adenosine may lead to or exacerbate bradyasystole and diminish the effectiveness of catecholamines administered during resuscitation. Aminophylline is a competitive adenosine antagonist. Case studies suggest that aminophylline may be effective for atropine resistant bradyasystolic arrest. OBJECTIVES: To determine the effects of aminophylline in the treatment of patients in bradyasystolic cardiac arrest, primarily survival to hospital discharge. We also considered survival to admission, return of spontaneous circulation, neurological outcomes and adverse events. SEARCH METHODS: For this updated review, we searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL, LILACS, ClinicalTrials.gov and WHO International Clinical Trials Registry Platform in November 2014. We checked the reference lists of retrieved articles, reviewed conference proceedings, contacted experts and searched further using Google. SELECTION CRITERIA: All randomised controlled trials comparing intravenous aminophylline with administered placebo in adults with non-traumatic, normothermic bradyasystolic cardiac arrest who were treated with standard advanced cardiac life support (ACLS). DATA COLLECTION AND ANALYSIS: Two review authors independently reviewed the studies and extracted the included data. We contacted study authors when needed. Pooled risk ratio (RR) was estimated for each study outcome. Subgroup analysis was predefined according to the timing of aminophylline administration. MAIN RESULTS: We included five trials in this analysis, all of which were performed in the prehospital setting. The risk of bias was low in four of these studies (n = 1186). The trials accumulated 1254 participants. Aminophylline was found to have no effect on survival to hospital discharge (risk ratio (RR) 0.58, 95% confidence interval (CI) 0.12 to 2.74) or on secondary survival outcome (survival to hospital admission: RR 0.92, 95% CI 0.61 to 1.39; return of spontaneous circulation: RR 1.15, 95% CI 0.89 to 1.49). Survival was rare (6/1254), making data about neurological outcomes and adverse events quite limited. The planned subgroup analysis for early administration of aminophylline included 37 participants. No one in the subgroup survived to hospital discharge. AUTHORS' CONCLUSIONS: The prehospital administration of aminophylline in bradyasystolic arrest is not associated with improved return of circulation, survival to admission or survival to hospital discharge. The benefits of aminophylline administered early in resuscitative efforts are not known. PMID- 26593310 TI - Genetic dissection of maize seedling root system architecture traits using an ultra-high density bin-map and a recombinant inbred line population. AB - Maize (Zea mays) root system architecture (RSA) mediates the key functions of plant anchorage and acquisition of nutrients and water. In this study, a set of 204 recombinant inbred lines (RILs) was derived from the widely adapted Chinese hybrid ZD958(Zheng58 * Chang7-2), genotyped by sequencing (GBS) and evaluated as seedlings for 24 RSA related traits divided into primary, seminal and total root classes. Significant differences between the means of the parental phenotypes were detected for 18 traits, and extensive transgressive segregation in the RIL population was observed for all traits. Moderate to strong relationships among the traits were discovered. A total of 62 quantitative trait loci (QTL) were identified that individually explained from 1.6% to 11.6% (total root dry weight/total seedling shoot dry weight) of the phenotypic variation. Eighteen, 24 and 20 QTL were identified for primary, seminal and total root classes of traits, respectively. We found hotspots of 5, 3, 4 and 12 QTL in maize chromosome bins 2.06, 3.02-03, 9.02-04, and 9.05-06, respectively, implicating the presence of root gene clusters or pleiotropic effects. These results characterized the phenotypic variation and genetic architecture of seedling RSA in a population derived from a successful maize hybrid. PMID- 26593311 TI - Is It Time to Start Treating Asymptomatic Hyperuricemia? PMID- 26593312 TI - Pregnancy and CKD: Lessons on Communication From Patients. PMID- 26593313 TI - Optimizing Central Venous Catheter Primary Prevention Trials in Hemodialysis Patients. PMID- 26593314 TI - Restricting Metformin in CKD: Continued Caution Warranted. PMID- 26593315 TI - In Reply to 'Restricting Metformin in CKD: Continued Caution Warranted'. PMID- 26593316 TI - Methodological Concerns About a Systematic Review and Meta-analysis of the Mortality Risk of Darbepoetin Alfa Versus Epoetin Alfa. PMID- 26593318 TI - The Sacred Trust. PMID- 26593317 TI - Resolution of Antibody-Mediated Rejection After Autotransplantation of a Kidney Allograft From the Recipient Back to the Donor. PMID- 26593319 TI - Quiz Page December 2015: Polyuria Following Kidney Transplantation. PMID- 26593320 TI - AJKD Atlas of Renal Pathology: AL Amyloidosis. PMID- 26593321 TI - AJKD Atlas of Renal Pathology: Light Chain Deposition Disease. PMID- 26593322 TI - AJKD Atlas of Renal Pathology: Hereditary and Other Non-AL Amyloidoses. PMID- 26593323 TI - Adiponectin, hemoglobin, and cardiovascular risk in an indigenous siberian population. AB - OBJECTIVES: Adipose tissue hypoxia appears to play a role in promoting chronic inflammation and the development of obesity-related cardiovascular and metabolic diseases, yet the underlying mechanisms are not well understood. The aim of the present research is to examine whether adiponectin levels (an adipocyte-derived hormone with anti-inflammatory properties) are inversely correlated with hemoglobin levels in an indigenous Siberian population. METHODS: The study was conducted among 252 Yakut adults (>=18 years; 135 females) from Berdygestiakh, Sakha Republic, Russia. Measurements included anthropometric dimensions (body mass index [BMI], waist circumference [WC], and percent body fat) and blood levels of hemoglobin and adiponectin. RESULTS: Yakut females had higher adiponectin concentrations than males (15.1 +/- 9.8 vs. 11.7 +/- 10.6 ug/ml; P < 0.001), whereas males had higher hemoglobin levels (14.4 +/- 1.4 vs. 12.6 +/- 1.5 g/dL; P < 0.001). Body composition measures in both sexes were negatively associated with adiponectin and positively associated with hemoglobin. After adjusting for central adiposity and smoking, adiponectin levels were negatively correlated with hemoglobin levels in men (P < 0.05), but not in women (P = 0.511). CONCLUSIONS: This investigation provides some support for the involvement of hypoxia-related dysregulation of adiponectin associated with obesity and potentially cardiovascular disease. Am. J. Hum. Biol. 28:580-583, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26593324 TI - Hemodynamic Characterization of Geometric Cerebral Aneurysm Templates Treated With Embolic Coils. AB - Embolic coiling is one of the most effective treatments for cerebral aneurysms (CAs), largely due to the hemodynamic modifications that the treatment effects in the aneurysmal environment. However, coiling can have very different hemodynamic outcomes in aneurysms with different geometries. Previous work in the field of biofluid mechanics has demonstrated on a general level that geometry is a driving factor behind aneurysmal hemodynamics. The goal of this study was to relate two specific geometric factors that describe CAs (i.e., dome size (DS) and parent vessel contact-angle (PV-CA)) and one factor that describes treatment (i.e., coil packing density (PD)) to three clinically relevant hemodynamic responses (i.e., aneurysmal root-mean-square velocity (Vrms), aneurysmal wall shear stress (WSS), and cross-neck flow (CNF)). Idealized models of basilar tip aneurysms were created in both virtual and physical forms to satisfy two-level multifactorial experimental designs. Steady and pulsatile flow hemodynamics were then evaluated in the virtual models using computational fluid dynamics (CFD) (before and after virtual treatment with finite element (FE) embolic coil models), and hemodynamics were also evaluated in the physical models using particle image velocimetry (PIV) (before and after treatment with actual embolic coils). Results showed that among the factors considered, PD made the greatest contributions to effects on hemodynamic responses in and around the aneurysmal sac (i.e., Vrms and WSS), while DS made the greatest contributions to effects on hemodynamics at the neck (i.e., CNF). Results also showed that while a geometric factor (e.g., PV-CA) may play a relatively minor role in dictating hemodynamics in the untreated case, the same factor can play a much greater role after coiling. We consider the significance of these findings in the context of aneurysmal recurrence and rupture, and explore potential roles for the proposed methods in endovascular treatment planning. PMID- 26593325 TI - Skeletal muscle Ca(2+) mishandling: Another effect of bone-to-muscle signaling. AB - Our appreciation of crosstalk between muscle and bone has recently expanded beyond mechanical force-driven events to encompass a variety of signaling factors originating in one tissue and communicating to the other. While the recent identification of new 'myokines' has shifted some focus to the role of muscle in this partnership, bone-derived factors and their effects on skeletal muscle should not be overlooked. This review summarizes some previously known mediators of bone-to-muscle signaling and also recent work identifying a new role for bone derived TGF-beta as a cause of skeletal muscle weakness in the setting of cancer induced bone destruction. Oxidation of the ryanodine receptor/calcium release channel (RyR1) in skeletal muscle occurs via a TGF-beta-Nox4-RyR1 axis and leads to calcium mishandling and decreased muscle function. Multiple points of potential therapeutic intervention were identified, from preventing the bone destruction to stabilizing the RYR1 calcium channel. This new data reinforces the concept that bone can be an important source of signaling factors in pathphysiological settings. PMID- 26593327 TI - Multifunctional Tricarbazolo Triazolophane Macrocycles: One-Pot Preparation, Anion Binding, and Hierarchical Self-Organization of Multilayers. AB - Programming the synthesis and self-assembly of molecules is a compelling strategy for the bottom-up fabrication of ordered materials. To this end, shape-persistent macrocycles were designed with alternating carbazoles and triazoles to program a one-pot synthesis and to bind large anions. The macrocycles bind anions that were once considered too weak to be coordinated, such as PF6 (-) , with surprisingly high affinities (beta2 =10(11) M(-2) in 80:20 chloroform/methanol) and positive cooperativity, alpha=(4 K2 /K1 )=1200. We also discovered that the macrocycles assemble into ultrathin films of hierarchically ordered tubes on graphite surfaces. The remarkable surface-templated self-assembly properties, as was observed by using scanning tunneling microscopy, are attributed to the complementary pairing of alternating triazoles and carbazoles inscribed into both the co-facial and edge-sharing seams that exist between shape-persistent macrocycles. The multilayer assembly is also consistent with the high degree of molecular self-association observed in solution, with self-association constants of K=300 000 M(-1) (chloroform/methanol 80:20). Scanning tunneling microscopy data also showed that surface assemblies readily sequester iodide anions from solution, modulating their assembly. This multifunctional macrocycle provides a foundation for materials composed of hierarchically organized and nanotubular self-assemblies. PMID- 26593328 TI - Aripiprazole, a partial dopamine agonist to improve adolescent anorexia nervosa-A case series. AB - Anorexia nervosa (AN) is a severe and complex psychiatric disorder and no medication has been approved for its treatment. This case series in youth with severe, recurrent AN supports the hypothesis that dopamine receptor agonists could be helpful in supporting fear extinction during eating disorder focused psychotherapy and therefore support recovery from AN. (c) 2015 Wiley Periodicals, Inc. (Int J Eat Disord 2016; 49:529-533). PMID- 26593329 TI - Nanohole Array-Directed Trapping of Mammalian Mitochondria Enabling Single Organelle Analysis. AB - We present periodic nanohole arrays fabricated in free-standing metal-coated nitride films as a platform for trapping and analyzing single organelles. When a microliter-scale droplet containing mitochondria is dispensed above the nanohole array, the combination of evaporation and capillary flow directs individual mitochondria to the nanoholes. Mammalian mitochondria arrays were rapidly formed on chip using this technique without any surface modification steps, microfluidic interconnects, or external power sources. The trapped mitochondria were depolarized on chip using an ionophore with results showing that the organelle viability and behavior were preserved during the on-chip assembly process. Fluorescence signal related to mitochondrial membrane potential was obtained from single mitochondria trapped in individual nanoholes revealing statistical differences between the behavior of polarized vs depolarized mammalian mitochondria. This technique provides a fast and stable route for droplet-based directed localization of organelles-on-a-chip with minimal limitations and complexity, as well as promotes integration with other optical or electrochemical detection techniques. PMID- 26593326 TI - The emerging role of skeletal muscle oxidative metabolism as a biological target and cellular regulator of cancer-induced muscle wasting. AB - While skeletal muscle mass is an established primary outcome related to understanding cancer cachexia mechanisms, considerable gaps exist in our understanding of muscle biochemical and functional properties that have recognized roles in systemic health. Skeletal muscle quality is a classification beyond mass, and is aligned with muscle's metabolic capacity and substrate utilization flexibility. This supplies an additional role for the mitochondria in cancer-induced muscle wasting. While the historical assessment of mitochondria content and function during cancer-induced muscle loss was closely aligned with energy flux and wasting susceptibility, this understanding has expanded to link mitochondria dysfunction to cellular processes regulating myofiber wasting. The primary objective of this article is to highlight muscle mitochondria and oxidative metabolism as a biological target of cancer cachexia and also as a cellular regulator of cancer-induced muscle wasting. Initially, we examine the role of muscle metabolic phenotype and mitochondria content in cancer-induced wasting susceptibility. We then assess the evidence for cancer-induced regulation of skeletal muscle mitochondrial biogenesis, dynamics, mitophagy, and oxidative stress. In addition, we discuss environments associated with cancer cachexia that can impact the regulation of skeletal muscle oxidative metabolism. The article also examines the role of cytokine-mediated regulation of mitochondria function, followed by the potential role of cancer-induced hypogonadism. Lastly, a role for decreased muscle use in cancer-induced mitochondrial dysfunction is reviewed. PMID- 26593330 TI - A proton spectroscopy study of white matter in children with autism. AB - White matter abnormalities have been described in autism spectrum disorder (ASD) with mounting evidence implicating these alterations in the pathophysiology of the aberrant connectivity reported in this disorder. The goal of this investigation is to further examine white matter structure in ASD using proton magnetic resonance spectroscopy ((1)H MRS). Multi-voxel, short echo-time in vivo(1)H MRS data were collected from 17 male children with ASD and 17 healthy age- and gender-matched controls. Key (1)H MRS metabolite ratios relative to phosphocreatine plus creatine were obtained from four different right and left white matter regions. Significantly lower N-acetylaspartate/creatine ratios were found in the anterior white matter regions of the ASD group when compared to controls. These findings reflect impairment in neuroaxonal white matter tissue and shed light on the neurobiologic underpinnings of white matter abnormalities in ASD by implicating an alteration in myelin and/or axonal development in this disorder. PMID- 26593331 TI - Genotype frequency of human neutrophil antigen-3 polymorphisms in the Yi, Han, and Tibetan populations of China. AB - BACKGROUND: Human neutrophil antigen-3 (HNA-3) alloantibodies can cause fatal transfusion-related acute lung injury (TRALI). Most frequencies of SLC44A2 alleles encoding the HNA-3a/b antigens have been established in Han individuals by polymerase chain reaction with sequence-specific priming (PCR-SSP). We sequenced SLC44A2 gene fragments and determined allele frequencies in three ethnicities of China. STUDY DESIGN AND METHODS: Genomic DNA was extracted from 448 samples of 100 blood donors of Yi ethnicity in Xichang, Liangshan; 248 Han in Nanjing, Jiangsu; and 100 Tibetan in Lhasa, Tibet. A PCR-SSP was applied to determine the phase of two single-nucleotide polymorphisms (SNPs); SLC44A2 haplotypes were constructed. RESULTS: In the 567 nucleotides of the SLC44A2 gene covered by our sequencing approach in Han individuals, we detected the known 331 44G>A (rs12972963) and 461G>A (rs2288904) polymorphisms. In the 243 nucleotides sequenced in Yi and Tibetan populations, we detected the known 461G>A and 503 15T>C (rs1560711) polymorphisms. A PCR-SSP for the common HNA-3a/b SNP was 100% concordant. The frequencies of the HNA-3a allele were 0.58, 0.66, and 0.69 in Yi, Han (Nanjing), and Tibetan, respectively (0.42, 0.34, and 0.31 for HNA-3b). CONCLUSIONS: The Yi population of China had the highest frequency of blood donors at risk of harboring anti-HNA-3a compared to any population studied so far. We confirmed that the underlying SLC44A2*2 allele is more common in China than in any European or African populations. PMID- 26593332 TI - ARVC/D and the dyad: A long distance relationship? PMID- 26593333 TI - Single-coil and dual-coil defibrillator leads and association with clinical outcomes in a complete Danish nationwide ICD cohort. AB - BACKGROUND: The best choice of defibrillator lead in patients with routine implantable cardioverter-defibrillator (ICD) is not settled. Traditionally, most physicians prefer dual-coil leads but the use of single-coil leads is increasing. OBJECTIVE: The purpose of this study was to compare clinical outcomes in patients with single- and dual-coil leads. METHODS: All 4769 Danish patients 18 years or older with first-time ICD implants from 2007 to 2011 were included from the Danish Pacemaker and ICD Register. Defibrillator leads were 38.9% single-coil leads and 61.1% dual-coil leads. The primary end point was all-cause mortality. Secondary end points were lowest successful energy at implant defibrillation testing, first shock failure in spontaneous arrhythmias, structural lead failure, and lead extraction outcomes. RESULTS: Single-coil leads were associated with lower all-cause mortality with an adjusted hazard ratio of 0.85 (95% confidence interval 0.73-0.99; P = .04). This finding was robust in a supplementary propensity score-matched analysis. However, dual-coil leads were used in patients with slightly higher preimplant morbidity, making residual confounding by indication the most likely explanation for the observed association between lead type and mortality. The lowest successful defibrillation energy was higher using single-coil leads (23.2 +/- 4.3 J vs 22.1 +/- 3.9 J; P < .001). No significant differences were observed for other secondary end points showing high shock efficacies and low rates of lead failures and extraction complications. CONCLUSION: Shock efficacy is high for modern ICD systems. The choice between single-coil and dual-coil defibrillator leads is unlikely to have a clinically significant impact on patient outcomes in routine ICD implants. PMID- 26593334 TI - Four-Component Approach to N-Substituted Phenothiazines under Transition-Metal Free Conditions. AB - An efficient synthesis of N-substituted phenothiazines has been developed from readily available amines, cyclohexanones, and elemental sulfur. The combination use of KI/DMSO in an oxygen atmosphere significantly improved the reaction yields. PMID- 26593335 TI - Rg1 prevents myocardial hypoxia/reoxygenation injury by regulating mitochondrial dynamics imbalance via modulation of glutamate dehydrogenase and mitofusin 2. AB - PURPOSE: Mitochondrial dysfunction is a prominent feature of ischemia heart disease but the underlying mechanism of dynamics (fusion/fission) is still unclear. Here we investigated a novel function and underlying mechanism of Rg1 on an in vitro cardiomyocyte model of hypoxia/reoxygenation (H/R). METHODS: Cellular cytotoxicity was evaluated by MTT, mitochondrial viable staining, and cardiac marker detection. Mitochondrial function was evaluated by ATP content measurement, MMP determination, ROS, OCR and ECAR assay. Mitochondrial dynamics was investigated by Live-cell imaging with time-lapse fluorescence microscopy and morphological features were evaluated by the high-content image analysis. Mitochondrial fusion and fission-related proteins, GDH were determined by Western blot, RT-PCR and immunofluorescence. RESULTS: Rg1 moderated GDH dysregulation and then protected against H/R-induced cellular damage and mitochondrial dysfunction in a dose-dependent manner. Rg1 significantly increased mitochondrial length, reduced the number of cells with fragmented mitochondria and up-regulated the MFN2 expression finally leading to preventing the imbalance of mitochondrial dynamics following H/R. Knock-down of MFN2 by specific siRNA completely abolished the ability of Rg1 to cell survival by H/R. CONCLUSION: Rg1 through modulation of GDH and MFN2 maintained mitochondrial dynamics that resulted in protection against H/R-induced cardiomyocyte injury. All these results put forward a new protective mechanism of Rg1 on the therapeutic potential in cardiac I/R disorders. PMID- 26593336 TI - Fate of follicular ovarian cysts in early postpartum dairy cows treated with PRID/PGF or PRID/PGF plus eCG. AB - OBJECTIVE: To ultrasonographically investigate the effect of administration of exogenous progesterone using a progesterone-releasing intravaginal device (PRID), with or without the addition of equine chorionic gonadotropin (eCG), to cows with cystic ovarian disease (COD) in the first month postpartum. MATERIAL AND METHOD: Thirty-three dairy cows (n = 11/group) diagnosed with COD between day 20 and 30 postpartum were randomly assigned to treatment groups (TG) PRID/PGF and PRID/PGF+eCG or a control group (CG). The CG remained untreated during the 20-day study period, which started on the day the diagnosis was made (day 0). Cows of group PRID/PGF received a PRID, which was removed on day 10, at which time PGF2alpha was given intravenously. Cows of the PRID/PGF+eCG group additionally received eCG on day 7 intravenously. Ovarian ultrasonography and blood sampling for measurement of plasma progesterone (P4) and estradiol-17beta (E2) were done on days 0, 7, 10, 13, and 20 in the TG and on days 0, 10, and 20 in the CG. RESULTS: On day 0, all cows had follicular cysts, six of which developed into luteal cysts in the CG. The mean cyst diameter remained unchanged in the CG and decreased in the TG by day 20 (p < 0.01). All treated cows ovulated and formed at least one corpus luteum (CL) after PRID removal, but only two control cows ovulated (p < 0.05). Of 12 ovulatory follicles in the TG dominant on day 7, eight formed a CL with a cavity, whereas of 10 ovulatory follicles in the same groups, dominant on day 10, only one formed a CL with a cavity (p < 0.05). The diameters of follicles, that formed a CL with a cavity, were larger on day 10 (p < 0.01). Mean P4 concentrations on day 0 were <= 1 ng/ml in all groups. P4 concentration increased during treatment and decreased below 1 ng/ml after PRID removal (p < 0.05). CONCLUSION AND CLINICAL RELEVANCE: Treatment with PRID alone led to resolution of COD in all cows and therefore the additional benefit of eCG could not be critically assessed. CL with a cavity more often originate from larger and older dominant ovulatory follicles. PMID- 26593337 TI - Neuron Image Analyzer: Automated and Accurate Extraction of Neuronal Data from Low Quality Images. AB - Image analysis software is an essential tool used in neuroscience and neural engineering to evaluate changes in neuronal structure following extracellular stimuli. Both manual and automated methods in current use are severely inadequate at detecting and quantifying changes in neuronal morphology when the images analyzed have a low signal-to-noise ratio (SNR). This inadequacy derives from the fact that these methods often include data from non-neuronal structures or artifacts by simply tracing pixels with high intensity. In this paper, we describe Neuron Image Analyzer (NIA), a novel algorithm that overcomes these inadequacies by employing Laplacian of Gaussian filter and graphical models (i.e., Hidden Markov Model, Fully Connected Chain Model) to specifically extract relational pixel information corresponding to neuronal structures (i.e., soma, neurite). As such, NIA that is based on vector representation is less likely to detect false signals (i.e., non-neuronal structures) or generate artifact signals (i.e., deformation of original structures) than current image analysis algorithms that are based on raster representation. We demonstrate that NIA enables precise quantification of neuronal processes (e.g., length and orientation of neurites) in low quality images with a significant increase in the accuracy of detecting neuronal changes post-stimulation. PMID- 26593339 TI - Coarse Grained Simulations of the Electrolytes at the Water-Air Interface from Many Body Dissipative Particle Dynamics. AB - Modeling interfacial properties is a major challenge for mesoscopic simulation methods. Many-body dissipative particle dynamics (MDPD) is then a promising method to model heterogeneous systems at long time and length scales. However no rule exists to obtain a set of MDPD parameters capable to reproduce the thermodynamic properties of a molecular system of a specific chemistry. In this letter, we provide a general multiscale method to obtain a set of parameters from atomistic simulations using Flory-Huggins theory (FH) to be used with dissipative particle dynamics. We demonstrate the high quality and the transferability of the resulting parameters on the salt concentration dependence of surface tension. We also show the specificity of inorganic salt at the water-air interface. Our results indicate that the increase of surface tension with the salt concentration cannot be explained in terms of the charge image concept based on the Wagner, Onsager, and Samaras theory but rather in terms of the ion hydration. PMID- 26593338 TI - Modeling the consequences of the demise and potential recovery of a keystone species: wild rabbits and avian scavengers in Mediterranean landscapes. AB - Restoration of demised keystone-species populations is an overriding concern in conservation biology. However, since no population is independent of its environment, progress is needed in predicting the efficacy of restoration in unstable ecological contexts. Here, by means of Population Dynamics P-system Models (PDP), we studied long-term changes in the population size of Egyptian vultures (Neophron percnopterus) inhabiting a Natural Park, northern Spain, to changes in the numbers of wild rabbits (Oryctolagus cuniculus), a keystone species of Mediterranean ecosystems that have suffered >90% population decline after a hemorrhagic disease outbreak. Low availability of rabbit carcasses leads Egyptian vultures to extend their foraging activities to unprotected areas with higher non-natural mortality whereas growing numbers of griffon vultures (Gyps fulvus), a dominant competitor, progressively monopolize trophic resources resulting in a focal population decrease. Modeling shows that, even if keystone species populations recover in core protected areas, the return to the original studied population size may be unfeasible, due to both the high non-natural mortality rates in humanized areas and long-term changes in the scavenger guild structure. Policy decisions aimed to restore keystone-species should rely on holistic approaches integrating the effects of spatial heterogeneity on both producer and consumer populations as well as within-guild processes. PMID- 26593340 TI - Fast Atomistic Molecular Dynamics Simulations from Essential Dynamics Samplings. AB - We present a new method for fast molecular dynamics simulations in cases where the new trajectories can be considered a perturbation or a combination of previously stored ones. The method is designed for the postgenomic scenario, where databases such as MoDEL will store curated equilibrium trajectories of all biomolecules (proteins, nucleic acids, etc.) of human interest. We demonstrate that the approach outlined here can, with accuracy and great computational efficiency, reproduce and extend original trajectories, describe dynamical effects due to perturbations (e.g., protein-ligand and protein-protein interactions and protein mutations) and predict the dynamics of large polymeric systems built up from previously studied fragments. The method can work simultaneously with low- and high-resolution pictures of the macromolecule, allowing the level of detail to be matched to that required for obtaining the information of biological interest. PMID- 26593341 TI - Block-Localized Wavefunction (BLW) Based Two-State Approach for Charge Transfers between Phenyl Rings. AB - The block-localized wave function (BLW) method is the simplest and most efficient variant of ab initio valence bond (VB) theory which defines electron-localized resonance states following the conventional VB concepts. Here, a BLW-based two state approach is proposed to probe the charge/hole transfer reactions within the Marcus-Hush model. With this approach, both the electronic coupling and reorganization energies can be derived at the ab initio level. Pilot applications to the electron/hole transfers between two phenyl rings are presented. Good exponential correlation between the electronic coupling energy and the donor acceptor distance is shown, whereas the inner-sphere reorganization shows little geometric dependency. Computations also support the assumption in Marcus theory that the thermal electron transfer barrier (DeltaG*), which is a sum of the reaction barrier (DeltaEa) for electron/hole transfer and the coupling energy (VAB), is a quarter of the reorganization energy (lambda). PMID- 26593342 TI - The Lack of Resonance Problem in Coherent Control with Real-Time Time-Dependent Density Functional Theory. AB - We will show that adiabatic real-time TDDFT predicts a time- and energy-dependent electronic structure of molecules, which makes it hard to combine TDDFT with coherent control schemes that depend on resonance conditions. In this study, we use sequences of ultrashort pulses, separated by long intervals of field free evolution, to illustrate this phenomenon for two molecules and two functionals. In coherent control scenarios, long laser pulses, with many oscillation periods, excite the system continuously and, in this way produce, a time-dependent electronic structure. PMID- 26593343 TI - Practically Efficient and Robust Free Energy Calculations: Double-Integration Orthogonal Space Tempering. AB - The orthogonal space random walk (OSRW) method, which enables synchronous acceleration of the motions of a focused region and its coupled environment, was recently introduced to enhance sampling for free energy simulations. In the present work, the OSRW algorithm is generalized to be the orthogonal space tempering (OST) method via the introduction of the orthogonal space sampling temperature. Moreover, a double-integration recursion method is developed to enable practically efficient and robust OST free energy calculations, and the algorithm is augmented by a novel theta-dynamics approach to realize both the uniform sampling of order parameter spaces and rigorous end point constraints. In the present work, the double-integration OST method is employed to perform alchemical free energy simulations, specifically to calculate the free energy difference between benzyl phosphonate and difluorobenzyl phosphonate in aqueous solution, to estimate the solvation free energy of the octanol molecule, and to predict the nontrivial Barnase-Barstar binding affinity change induced by the Barnase N58A mutation. As demonstrated in these model studies, the DI-OST method can robustly enable practically efficient free energy predictions, particularly when strongly coupled slow environmental transitions are involved. PMID- 26593344 TI - Steady-State Electrodiffusion from the Nernst-Planck Equation Coupled to Local Equilibrium Monte Carlo Simulations. AB - We propose a procedure to compute the steady-state transport of charged particles based on the Nernst-Planck (NP) equation of electrodiffusion. To close the NP equation and to establish a relation between the concentration and electrochemical potential profiles, we introduce the Local Equilibrium Monte Carlo (LEMC) method. In this method, Grand Canonical Monte Carlo simulations are performed using the electrochemical potential specified for the distinct volume elements. An iteration procedure that self-consistently solves the NP and flux continuity equations with LEMC is shown to converge quickly. This NP+LEMC technique can be used in systems with diffusion of charged or uncharged particles in complex three-dimensional geometries, including systems with low concentrations and small applied voltages that are difficult for other particle simulation techniques. PMID- 26593345 TI - Serial Generalized Ensemble Simulations of Biomolecules with Self-Consistent Determination of Weights. AB - Serial generalized ensemble simulations, such as simulated tempering, enhance phase space sampling through non-Boltzmann weighting protocols. The most critical aspect of these methods with respect to the popular replica exchange schemes is the difficulty in determining the weight factors which enter the criterion for accepting replica transitions between different ensembles. Recently, a method, called BAR-SGE, was proposed for estimating optimal weight factors by resorting to a self-consistent procedure applied during the simulation (J. Chem. Theory Comput.2010, 6, 1935-1950). Calculations on model systems have shown that BAR-SGE outperforms other approaches proposed for determining optimal weights in serial generalized ensemble simulations. However, extensive tests on real systems and on convergence features with respect to the replica exchange method are lacking. Here, we report on a thorough analysis of BAR-SGE by performing molecular dynamics simulations of a solvated alanine dipeptide, a system often used as a benchmark to test new computational methodologies, and comparing results to the replica exchange method. To this aim, we have supplemented the ORAC program, a FORTRAN suite for molecular dynamics simulations (J. Comput. Chem.2010, 31, 1106 1116), with several variants of the BAR-SGE technique. An illustration of the specific BAR-SGE algorithms implemented in the ORAC program is also provided. PMID- 26593346 TI - Interpretation and Quantification of Magnetic Interaction through Spin Topology. AB - This work develops a formalism to quantify the interaction among unpaired spins from the ground state spin topology. Magnetic systems where the spins are coupled through direct exchange and superexchange are chosen as references. Starting from a general Hamiltonian, an effective Hamiltonian is obtained in terms of spin density which is utilized to compute exchange coupling constants in magnetic systems executing direct exchange. The high-spin-low-spin energy gap, required to extract the coupling constant, is obtained through the broken symmetry approach within the framework of density functional theory. On the other hand, a perturbative approach is adopted to address the superexchange process. Spin transfer in between the sites in the exchange pathway is found to govern the magnetic nature of a molecule executing superexchange. The metal-ligand magnetic interaction is estimated using the second order perturbation energy for ligand to metal charge transfer and spin densities on the concerned sites. Using the present formalism, the total coupling constant in a superexchange process is also partitioned into the contributions from metal-ligand and metal-metal interactions. Sign and magnitude of the exchange coupling constants, derived through the present formalism, are found to be in parity with those obtained using the well-known spin projection technique. Moreover, in all of the cases, the ground state spin topology is found to complement the sign of coupling constants. Thus, the spin topology turns into a simple and logical means to interpret the nature of exchange interaction. The spin density representation in the present case resembles McConnell's spin density Hamiltonian and in turn validates it. PMID- 26593347 TI - Stereographic Projection of Density Functions (DF) and the Holographic Electronic Density Theorem (HEDT). AB - Mezey's holographic electronic density theorem is discussed from the point of view of stereographic projection techniques. Such a mathematical procedure is analyzed in depth from the point of view of first-order density functions; the procedure is then extended to any relevant quantum chemical function. This endeavor provides the background to construct a Holographic General Function Theorem (HGFT) for multivariate well-behaved functions. Stereographic projections, applied first as a way to obtain pictures of molecular quantum chemical functions, are shown to provide a flexible and original vantage point for visualizing, from any location and any chosen perspective, the form of any well-behaved function, irrespective of the number of variables involved. The pictographic possibilities of the HGFT are explored and exploited in several examples. PMID- 26593348 TI - The Quest for Metal-Metal Quadruple and Quintuple Bonds in Metal Carbonyl Derivatives: Nb2(CO)9 and Nb2(CO)8. AB - The synthesis by Power and co-workers of the first metal-metal quintuple bond (Science2005, 310, 844) is a landmark in inorganic chemistry. The 18-electron rule suggests that Nb2(CO)9 and Nb2(CO)8 are candidates for binary metal carbonyls containing metal-metal quadruple and quintuple bonds, respectively. Density functional theory (MPW1PW91 and BP86) indeed predicts structures having very short Nb-Nb distances of ~2.5 A for Nb2(CO)9 and ~2.4 A for Nb2(CO)8 as well as relatively large Nb-Nb Wiberg bond indices supporting these high formal Nb-Nb bond orders. However, analysis of the frontier molecular orbitals of these unbridged structures suggests formal Nb=Nb triple bonds and 16-electron metal configurations. This contrasts with an analysis of the frontier orbitals in a model chromium(I) alkyl linear CH3CrCrCH3, which confirms the generally accepted presence of chromium-chromium quintuple bonds in such molecules. The presence of Nb=Nb triple bonds rather than quadruple or quintuple bonds in the Nb2(CO)n (n = 9, 8) structures frees up d(xy) and d(x(2)-y(2)) orbitals for dpi->ppi* back bonding to the carbonyl groups. The lowest energy Nb2(CO)n structures (n = 9, 8) are not these unbridged structures but structures having bridging carbonyl groups of various types and formal Nb-Nb orders no higher than three. Thus, the two lowest energy Nb2(CO)9 structures have Nb=Nb triple bond distances of ~2.8 A and three semibridging carbonyl groups, leading to a 16-electron configuration rather than an 18-electron configuration for one of the niobium atoms. The lowest energy structure of the highly unsaturated Nb2(CO)8 is unusual since it has a formal single Nb-Nb bond of length ~3.1 A and two four-electron donor eta(2)-MU-CO groups, thereby giving each niobium atom only a 16-electron configuration. PMID- 26593349 TI - Analytic Calculation of Contact Densities and Mossbauer Isomer Shifts Using the Normalized Elimination of the Small-Component Formalism. AB - The analytic linear response formalism for the calculation of the effective contact densities rho in the context of the normalized elimination of the small component (NESC) method is developed and implemented. The formalism is tested for the calculation of contact densities and contact density differences in a series of mercury cations and mercury-containing molecules. The calculations carried out at the NESC/SCF, NESC/MP2, and NESC/CCSD levels of theory demonstrate high sensitivity of the contact density to the local coordination environment and the oxidation state of mercury. The NESC/MP2 results are in a very good agreement with the NESC/CCSD ones, which suggests that the former method can be used as a cost-effective alternative to high-level ab initio calculations. PMID- 26593350 TI - A Multiconfigurational Perturbation Theory and Density Functional Theory Study on the Heterolytic Dissociation Enthalpy of First-Row Metallocenes. AB - The heterolytic dissociation enthalpy of a series of first-row metallocenes M(C5H5)2, M = V, Mn, Fe, and Ni, was studied by (restricted) multiconfigurational perturbation theory and density functional theory. The results were compared directly to the experimental values, taking into account all necessary contributions to the relative energy. Of the tested functionals, B3LYP performs best in reproducing the binding energy, while the PBE0 functional gives the best structures. High quality multiconfigurational perturbation calculations were also carried out, demonstrating the superior performance of a larger, restricted active space. The spin crossover behavior of manganocene is correctly predicted by multiconfigurational perturbation theory as opposed to the three functionals B3LYP, PBE0, and M06, which (severely) overstabilize the high-spin with respect to the low-spin state. PMID- 26593351 TI - Benchmark Calculations of the Energies for Binding Excess Electrons to Water Clusters. AB - State-of-the-art ADC(2), EOM-EA-CCSD, and EOM-EA-CCSD(2) many-body methods are used to calculate the energies for binding an excess electron to selected water clusters up to (H2O)24 in size. The systems chosen for study include several clusters for which the Hartree-Fock method either fails to bind the excess electron or binds it only very weakly. The three theoretical methods are found to give similar values of the electron binding energies. The reported electron binding energies are the most accurate to date for such systems, and these results should prove especially valuable as benchmarks for testing model potential approaches for describing the interactions of excess electrons with water clusters and bulk water. PMID- 26593352 TI - Range-Separated Exchange Functionals with Slater-Type Functions. AB - An implementation of range-separated density functionals utilizing the Yukawa potential and Slater-type functions is described. The density-functional part of the range-separated regime is straightforward. The exact exchange part makes use of established methods for evaluating exchange integrals over Slater-type functions but still requires new one- and two-center integrals. Equations for the one-center integrals are derived. The two-center integrals are evaluated through a combination of new equations and techniques taken from procedures for evaluating two-center Coulomb integrals over Slater-type functions. In a first application, the performance of range-separated functionals in the prediction of transition metal thermochemistry is evaluated using a database of average ligand removal energies. The range-separated functionals perform better than a GGA parent and similarly to commonly used hybrid and meta-hybrid functionals. The results were relatively insensitive to the chosen value of the attenuation parameter. PMID- 26593353 TI - Complexes with a Single Metal-Metal Bond as a Sensitive Probe of Quality of Exchange-Correlation Functionals. AB - The electronic structure of the vanadium dimer complex [V(C5H5)]2Pn with a single metal-metal bond was characterized, and the energies of higher spin states were evaluated. To simplify evaluation of orbital contributions to bonding between atoms and fragments, occupancy-perturbed bond orders were introduced. The structure and experimentally determined singlet-triplet gap in this complex can be used to test the quality of modern exchange-correlation functionals. Most generalized gradient approximation (GGA) functionals were determined to be quite suitable to reproduce the metal-metal distance and the single-triplet energy gap in [V(C5H5)]2Pn. Further accuracy improvement can be achieved by using empirical dispersion corrections. Hybrid exchange-correlation functionals, including the B3LYP functional, performed poorly for both structural and energy predictions. The hybrid functionals significantly overestimate the stability of the singlet state with the antiferromagnetically coupled high-spin metal ions relative to the lowest-energy triplet state and the singlet state with stronger metal-metal interactions. Thus, these XC functionals are not quite suitable for computational studies of multinuclear 3d transition metal complexes with weak-to-intermediate metal-metal bonding. PMID- 26593354 TI - Dioxygen Activation by a Non-Heme Iron(II) Complex: Theoretical Study toward Understanding Ferric-Superoxo Complexes. AB - We present a systematic study using density functional theory (DFT) and coupled cluster (CCSD(T)) computations with an aim of characterizing a non-heme ferric superoxo complex [(TMC)Fe(O2)](2+) (TMC = 1,4,8,11-tetramethyl-1,4,8,11 tetraazacyclotetradecane) that was proposed to perform allylic C-H activation of cyclohexene (Lee, Y.-M. et al. J. Am. Chem. Soc.2010, 132, 10668). As such, we investigated a series of iron-O2 species without and with a sixth ligand bound to the iron ion in different O2 coordination modes (end-on and side-on) and different spin states. Most of the iron-O2 complexes were found to be iron(III) superoxo species, Fe(III)(O2(-)), with high-spin (S = 5/2) or intermediate-spin (S = 3/2) ferric centers coupled ferromagnetically or antiferromagnetically to the superoxide anion radical. One iron(IV)-peroxo state, Fe(IV)(O2(2-)), was also examined. The preference for ferromagnetic or antiferromagnetic coupling modes between the superoxo and ferric radicals was found to depend on the FeOO angle, where a side-on tilt favors ferromagnetic coupling whereas the end-on tilt favors antiferromagnetic states. Experimental findings, e.g., the effects of solvent, spin state, and redox potential of non-heme Fe(II) complexes on O2 activation, were corroborated in this work. Solvent effects were found to disfavor O2 binding, relative to the unbound ferrous ion and O2. The potential H-abstraction reactivity of the iron(III)-superoxo species was considered in light of the recently proposed exchange-enhanced reactivity principle (Shaik, S.; Chen, H.; Janardanan, D. Nat. Chem.2011, 3, 19). It is concluded that localization and/or decoupling of an unpaired electron in the d-block of high-spin Fe(III) center in the S = 2 and 3 ferric-superoxo complexes during H abstractions enhances exchange stabilization and may be the root cause of the observed reactivity of [(TMC)Fe(O2)](2+). PMID- 26593355 TI - The Variational Structure of Gradient Extremals. AB - The gradient extremals can be taken as a representation of reaction paths. We prove that this type of curve possesses a variational nature. We report the conditions such that these curves have the character of a minimal curve. Finally we discuss the relations between the points of these curves being turning points with respect to other special points of the potential energy surface, like the valley-ridge inflection points. PMID- 26593356 TI - How to Convert SPME to P3M: Influence Functions and Error Estimates. AB - We demonstrate explicitly how the two seemingly different particle mesh Ewald methods, the smooth particle mesh Ewald (SPME) and the particle-particle particle mesh (P3M), can be mathematically transformed into each other. This allows us in particular to convert the error estimate of the P3M method in the energy conserving scheme (also known as "P3M with analytic differentiation") into an error estimate for the SPME method, via a simple change of the lattice Green function. Our error estimate is valid for any values of the SPME parameters (mesh size, spline interpolation order, Ewald splitting parameter, real-space cutoff distance), including odd orders of splines. The problem with the self-forces is avoided thanks to an analytical formula that allows to subtract them directly within the particle mesh calculation. Plots of the accuracy of the SPME forces are provided for a wide range of parameter values. The main use of the error estimate is to allow a simulation program to scan quickly the multidimensional parameter space to find the best set of parameters to achieve a target accuracy at the smallest computational cost. As a byproduct, we show how a SPME code can be transformed into a P3M version by changing a few lines of code. We demonstrate also that the P3M lattice Green function can be approximated by a closed form expression, computable on-the-fly, that provides essentially the same accuracy as the full function. PMID- 26593357 TI - Membrane Protein Simulations Using AMBER Force Field and Berger Lipid Parameters. AB - AMBER force fields are among the most commonly used in molecular dynamics (MD) simulations of proteins. Unfortunately, they lack a specific set of lipid parameters, thus limiting its use in membrane protein simulations. In order to overcome this limitation we assessed whether the widely used united-atom lipid parameters described by Berger and co-workers could be used in conjunction with AMBER force fields in simulations of membrane proteins. Thus, free energies of solvation in water and in cyclohexane, and free energies of water to cyclohexane transfer, were computed by thermodynamic integration procedures for neutral amino acid side-chains employing AMBER99, AMBER03, and OPLS-AA amino acid force fields. In addition, MD simulations of three membrane proteins in a POPC lipid bilayer, the beta2 adrenergic G protein-coupled receptor, Aquaporin-1, and the outer membrane protein Omp32, were performed with the aim of comparing the AMBER99SB/Berger combination of force fields with the OPLS-AA/Berger combination. We have shown that AMBER99SB and Berger force fields are compatible, they provide reliable free energy estimations relative to experimental values, and their combination properly describes both membrane and protein structural properties. We then suggest that the AMBER99SB/Berger combination is a reliable choice for the simulation of membrane proteins, which links the easiness of ligand parametrization and the ability to reproduce secondary structure of AMBER99SB force field with the largely validated Berger lipid parameters. PMID- 26593358 TI - Exploration of Protein Conformational Change with PELE and Meta-Dynamics. AB - Atomistic molecular simulation methods are now able to explore complex protein or protein-ligand dynamical space in a tractable way with methods such as meta dynamics or adaptive biasing force. However, many of these methods either require a careful selection of reaction coordinates or the knowledge of an initial pathway of some kind. Thus, it is important that effective methods are developed to produce this pathway data in an efficient fashion. PELE, a proven protein ligand sampling code, has been developed to provide rapid protein sampling in highly flexible cases, using a reduced network model eigen problem approach. The resulting method is able to rapidly sample configuration space with very general driving information. When applied to ubiquitin, PELE was able to reproduce RMSD and average force data found in molecular dynamics simulations. PELE was also applied to explore the opening/closing transition of T4 lysozyme. A meta-dynamics exploration using a low energy pathway validated that the configurations explored by PELE represent the most populated regions of phase space. PELE and meta dynamics explorations also discovered a low free energy region where a large cross-domain helix of T4 lysozyme is broken in two. There is previous NMR evidence for the validity of this unfolded helix region. PMID- 26593359 TI - Transferability of Various Molecular Property Tensors in Vibrational Spectroscopy. AB - Transfers of polarizability, dipole, and energy derivatives from smaller fragments enable extension of ab initio vibrational spectral simulations to larger molecules. The accuracy of the transfer, however, varies according to the molecule and the tensor type. Recent works (J. Chem. Theory Comput.2011, 7, 1867 and Coll. Czech. Chem. Commun.2011, 76, 567) questioned the accuracy of the tensor transfer for Raman optical activity (ROA) spectra. To estimate relative errors, the current study systematically compares transfer properties for four spectral types (ROA, Raman, vibrational circular dichroism (VCD), and infrared absorption (IR)). As test molecules, polyglycine and polyproline peptides in polyproline II and alpha-helical conformations were used. The results indicate that the discrepancies could be caused by variation of the transfer parameters but not by fundamental differences in the ROA tensor properties. In particular, when done consistently, the transferred electric and magnetic dipole derivatives, polarizability tensors, and harmonic force field provided a reasonable convergence of all spectra for transfers with increasing sizes of the fragments. The polarized spectroscopies (VCD and ROA), however, were found to be significantly more sensitive than the unpolarized (IR, Raman) ones. Optimization of the geometry and the character of the amino acid side chain was relatively unimportant for the transfer. On the other hand, intramolecular hydrogen bonds in the helix required larger fragments for the same accuracy than in an unfolded peptide. Nevertheless, with reasonable fragmentation, all the spectra (IR, VCD, Raman, and ROA) of the target structures could be reconstructed to an accuracy sufficient for a full interpretation of the experiment, with substantial savings of computer time as an added benefit. PMID- 26593360 TI - Analytical Gradients for the MSINDO-sCIS and MSINDO-UCIS Method: Theory, Implementation, Benchmarks, and Examples. AB - Analytical expressions for the sCIS (scaled configuration interaction singles) and UCIS (unrestricted CIS) energy gradients are presented for the semiempirical method MSINDO. The theoretical background of the derivation of the analytical gradients is presented, and the implementation into the MSINDO program package is described. The computational efficiency of the underlying Z-vector method is greatly enhanced by making use of the transpose-free quasiminimal residual (TFQMR) algorithm. Benchmark timing tests are compared to the widely used TD B3LYP approach. For a statistical evaluation of the accuracy of MSINDO-sCIS, geometry optimizations are performed for a small set of organic molecules in selected excited states. The obtained results are compared to CASPT2 and TD B3LYP/TZVP. In order to demonstrate the applicability of the present approach to periodic systems within the cyclic cluster model, we present first calculations of the excited state structure of ethyne adsorbed on the NaCl (100) surface. PMID- 26593361 TI - Excited States of Dicyanovinyl-Substituted Oligothiophenes from Many-Body Green's Functions Theory. AB - Excited states of dicyanovinyl-substituted oligothiophenes are studied using many body Green's functions theory within the GW approximation and the Bethe-Salpeter equation. By varying the number of oligomer repeat units, we investigate the effects of resonant-antiresonant transition coupling, dynamical screening, and molecular conformations on calculated excitations. We find that the full dynamically screened Bethe-Salpeter equation yields absorption and emission energies in good agreement with experimental data. The effect of resonant antiresonant coupling on the first singlet pi -> pi* excitation monotonically decreases with increasing size of the molecule, while dynamical screening effects uniformly lower the excitation energies. PMID- 26593362 TI - Dimerization of Amino Acid Side Chains: Lessons from the Comparison of Different Force Fields. AB - The interactions between amino acid side chains govern protein secondary, tertiary, and quaternary structure formation. For molecular modeling approaches to be able to realistically describe these phenomena, the underlying force fields have to represent these interactions as accurately as possible. Here, we compare the side chain-side chain interactions for a number of commonly used force fields, namely the all-atom OPLS, the united-atom GROMOS, and the coarse-grain MARTINI force field. We do so by calculating the dimerization free energies between selected pairs of side chains and structural characterization of their binding modes. To mimic both polar and nonpolar environments, the simulations are performed in water, n-octanol, and decane. In general, reasonable correlations are found between all three force fields, with deviations on the order of 1 kT in aqueous solvent. In apolar solvent, however, significantly larger differences are found, especially for charged amino acid pairs between the OPLS and GROMOS force fields, and for polar interactions in the MARTINI force field in comparison to the higher resolution models. Interestingly, even in cases where the dimerization free energies are similar, the binding mode may differ substantially between the force fields. This was found to be especially the case for aromatic residues. In addition to the inter-force-field comparison, we compared the various force fields to a knowledge-based potential. The two independent approaches show good correlation in aqueous solvent with an exception of aromatic residues for which the interaction strength is lower in the knowledge-based potentials. PMID- 26593363 TI - General Perturbative Approach for Spectroscopy, Thermodynamics, and Kinetics: Methodological Background and Benchmark Studies. AB - A general second-order perturbative approach based on resonance- and threshold free computations of vibrational properties is introduced and validated. It starts from the evaluation of accurate anharmonic zero-point vibrational energies for semirigid molecular systems, in a way that avoids any singularity. Next, the degeneracy corrected second-order perturbation theory (DCPT2) is extended to a hybrid version (HDCPT2), allowing for reliable computations even in cases where the original formulation faces against severe problems, including also an automatic treatment of internal rotations through the hindered-rotor model. These approaches, in conjunction with the so-called simple perturbation theory (SPT) reformulated to treat consistently both energy minima and transition states, allow one to evaluate degeneracy-corrected partition functions further used to obtain vibrational contributions to properties like enthalpy, entropy, or specific heat. The spectroscopic accuracy of the HDCPT2 model has been also validated by computing anharmonic vibrational frequencies for a number of small to-medium size, closed- and open-shell, molecular systems, within an accuracy close to that of well established but threshold-dependent perturbative variational models. The reliability of the B3LYP/aug-N07D model for anharmonic computations is also highlighted, with possible improvements provided by the B2PLYP/aug-cc-pVTZ models or by hybrid schemes. On a general grounds, the overall approach proposed in the present work is able to provide the proper accuracy to support experimental investigations even for large molecular systems of biotechnological interest in a fully automated manner, without any ad hoc scaling procedure. This means a fully ab initio evaluation of thermodynamic and spectroscopic properties with an overall accuracy of about, or better than, 1 kJ mol(-1), 1 J mol(-1) K(-1) and 10 cm(-1) for enthalpies, entropies, and vibrational frequencies, respectively. PMID- 26593364 TI - The Silica-Water Interface: How the Silanols Determine the Surface Acidity and Modulate the Water Properties. AB - Silica is the most abundant metal oxide and the main component of the Earth's crust. Its behavior in contact with water plays a critical role in a variety of geochemical and environmental processes. Despite its key role, the details of the aqueous silica interface at the microscopic molecular level are still elusive. Here we provide such a detailed understanding of the molecular behavior of the silica-water interface, using density functional theory based molecular dynamics (DFTMD) simulations, where a consistent treatment of the electronic structure of solvent and surface is provided. We have calculated the acidity of the silanol groups at the interface directly from the DFTMD simulations, without any fitting of parameters to the experimental data. We find two types of silanol groups at the surface of quartz: out-of-plane silanols with a strong acidic character (pKa = 5.6), which consequently results in the formation of strong and short hydrogen bonds with water molecules at the interface, and in-plane silanols with a pKa of 8.5, forming weak hydrogen bonds with the interfacial water molecules. Our estimate of the quartz point of zero charge (1.0) is found in good agreement with the experimental value of 1.9. We have also shown how the silanols orientation and their hydrogen bond properties are responsible for an amphoteric behavior of the surface. A detailed analysis has identified two species of adsorbed water molecules at the solid-liquid interface, which using the language of vibrational spectroscopy can be identified as "liquid-like" and "ice-like" water or, in other words, water molecules forming respectively weak and strong H-bonds with the oxide surface. These two populations of water are in turn responsible for two distinct peaks in the infrared spectrum of interfacial water and thus provide a molecular explanation of the experimental sum frequency generation spectrum recorded in the literature. In the specific case of quartz, we show that the liquid-/ice-like behavior is the result of the silanol groups ability to donate or accept hydrogen bonds with different strengths, which consequently modulates the vibrational properties of the adsorbed water layer. PMID- 26593365 TI - A New Kinetic Monte Carlo Algorithm for Heteroepitactical Growth: Case Study of C60 Growth on Pentacene. AB - A novel multilattice kinetic Monte Carlo algorithm is developed for heteroepitactical growth of a hexagonal lattice material (C60) on an oblique lattice material (pentacene). This algorithm captures the behavior of single molecule and small clusters of C60 molecules diffusing, clustering, and reorganizing as monolayers on the surface and switching lattices depending on their local environment. An extensive catalog of jump rates and energy barriers created from molecular dynamics simulations and molecular mechanics is used as the sole input to the method in order to follow the evolution of C60 growth on pentacene for time scales approaching a millisecond that are unattainable using molecular dynamics alone. PMID- 26593366 TI - Curvature Effect on the Capacitance of Electric Double Layers at Ionic Liquid/Onion-Like Carbon Interfaces. AB - Recent experiments have revealed that onion-like carbons (OLCs) offer high energy density and charging/discharging rates when used as the electrodes in supercapacitors. To understand the physical origin of this phenomenon, molecular dynamics simulations were performed for a room-temperature ionic liquid near idealized spherical OLCs with radii ranging from 0.356 to 1.223 nm. We find that the surface charge density increases almost linearly with the potential applied on electric double layers (EDLs) near OLCs. This leads to a nearly flat shape of the differential capacitance versus the potential, unlike the bell or camel shape observed on planar electrodes. Moreover, our simulations reveal that the capacitance of EDLs on OLCs increases with the curvature or as the OLC size decreases, in agreement with experimental observations. The curvature effect is explained by dominance of charge overscreening over a wide potential range and increased ion density per unit area of electrode surface as the OLC becomes smaller. PMID- 26593367 TI - Lithium Adsorption on Graphene: From Isolated Adatoms to Metallic Sheets. AB - We have studied Li adsorption on graphene for Li concentrations ranging from about 1% to 50% by means of density functional theory calculations. At low adsorbant densities, we observe a strong ionic interaction characterized by a substantial charge transfer from the adatoms to the substrate. In this low concentration regime, the electronic density around the Li adatoms is well localized and does not contribute to the electronic behavior in the vicinity of the Fermi level. For larger concentrations, we observe the formation of a chemically bound Li layer characterized by a stronger binding energy as well as a significant density of states above the Fermi level coming from both graphene and the two-dimensional Li sheet. PMID- 26593368 TI - A Molecular Dynamics Technique to Extract Forces in Soft Matter Systems Under Compression With Constant Solvent Chemical Potential. AB - Molecular dynamics simulations of opposing polymer brushes at varying surface separation distances were performed to develop a method for conducting a static compression of soft matter. As all separation distances were represented by independent simulations, the proper solvent density for every level of compression needed to be determined to acquire realistic data. This was accomplished by maintaining a constant solvent chemical potential for each separation distance. In doing so, each independent simulation is equilibrated with all others, reproducing conditions encountered experimentally in force spectroscopy measurements. Chemical potential was determined using the Widom test particle insertion method. Force information was extracted from pressure profiles, such that unphysical forces occurring within the surface layers were not accounted for in the calculation. Each individual simulation was a canonical ensemble molecular dynamics simulation, but taken together they approximate a grand canonical ensemble for the solvent particles by holding their chemical potential constant. PMID- 26593369 TI - The Protonation States of the Active-Site Histidines in (6-4) Photolyase. AB - The active sites of the (6-4) photolyases contain two conserved histidine residues, which, in the Drosophila melanogaster enzyme, correspond to His365 and His369. While there are nine combinations in which the three possible protonation states of the two histidines (with protons on Ndelta (HID), Nepsilon (HIE), or both Ndelta and Nepsilon (HIP)) can be paired, there is presently no consensus as to which of these states is present, let alone mechanistically relevant. EPR hyperfine couplings for selected protons of the FADH(*) radical have previously been used to address this issue. Our QM/MM calculations show, however, that the experimental couplings are equally well reproduced by each of the nine combinations. Since the EPR results seemingly cannot be used to unequivocally assign the protonation states, the pKa values of the two histidines were calculated using the popular PROPKA, H++, and APBS approaches, in various environments and for several lesions. These techniques consistently indicate that, at pH = 7, both His365 and His369 should be neutral, although His369 is found to be more prone to becoming protonated. In a comparative approach, a series of molecular dynamics simulations was performed with all nine combinations, employing various reference crystal structures and different oxidation states of the FAD cofactor. The overall result of this approach is in agreement with our pKa results. Consequently, although the introduction of the reduced cofactor results in an increased stability for selected protonated states, particularly the His365?HID and His369?HIP combination, the neutral combination His365?HID and His365?HIE stands out as the most relevant state for the activity of the enzyme. PMID- 26593370 TI - Efficient Construction of Mesostate Networks from Molecular Dynamics Trajectories. AB - The coarse-graining of data from molecular simulations yields conformational space networks that may be used for predicting the system's long time scale behavior, to discover structural pathways connecting free energy basins in the system, or simply to represent accessible phase space regions of interest and their connectivities in a two-dimensional plot. In this contribution, we present a tree-based algorithm to partition conformations of biomolecules into sets of similar microstates, i.e., to coarse-grain trajectory data into mesostates. On account of utilizing an architecture similar to that of established tree-based algorithms, the proposed scheme operates in near-linear time with data set size. We derive expressions needed for the fast evaluation of mesostate properties and distances when employing typical choices for measures of similarity between microstates. Using both a pedagogically useful and a real-word application, the algorithm is shown to be robust with respect to tree height, which in addition to mesostate threshold size is the main adjustable parameter. It is demonstrated that the derived mesostate networks can preserve information regarding the free energy basins and barriers by which the system is characterized. PMID- 26593371 TI - Designing Short Peptides with High Affinity for Organic Molecules: A Combined Docking, Molecular Dynamics, And Monte Carlo Approach. AB - We present a method for designing artificial receptors capable of binding with high affinity to a chosen target organic molecule. The primary sequence of the peptide is optimized to maximize its binding affinity. Our algorithm builds on a combination of molecular dynamics, semiflexible docking, and replica exchange Monte Carlo and performs simultaneous sampling in sequence and conformational spaces carefully selecting the degree of flexibility in the mutated peptides. The approach is used to design a decapeptide able to bind efavirenz. The calculated binding energy of the designed peptide (approximately -12 kcal/mol) was confirmed experimentally by fluorescence measurements. NMR spectroscopy confirmed the interactions between the peptide and the efavirenz molecule predicted by the algorithm. PMID- 26593372 TI - Dynamic Fingerprints of Protein Thermostability Revealed by Long Molecular Dynamics. AB - The dynamical requirements for protein thermostability are a subject of intense debate since different techniques are sensitive to different dynamical processes. The present investigation arises from a neutron scattering experiment pointing to the lower temperature dependence of the flexibility of thermophilic proteins as a mechanism of enhanced thermostability. By means of 200 ns molecular dynamics simulations at different temperatures, we have investigated the differences in internal dynamics of the thermo-mesophilic pair of proteins studied in the experiment. The present work exceeds the time scales explored by the experiment and former studies on other thermo-mesophilic pairs by several orders of magnitude. Our simulations confirm the different thermal behavior observed in the experiment and suggest that both reduced coil segments and salt bridge interactions contribute to lowering the increase in flexibility with temperature. Moreover, the mesophilic protein exhibits a more heterogeneous distribution of residue mobilities involving more local motions. We suggest that the more collective motions of the thermophilic protein underlie a broader energy landscape. PMID- 26593373 TI - SCC-DFTB Parametrization for Boron and Boranes. AB - We present the results of our recent parametrization of the boron-boron and boron hydrogen interactions for the self-consistent charge density-functional-based tight-binding (SCC-DFTB) method. To evaluate the performance, we compare SCC-DFTB to full density functional theory (DFT) and wave-function-based semiempirical methods (AM1 and MNDO). Since the advantages of SCC-DFTB emerge especially for large systems, we calculated molecular systems of boranes and pure boron nanostructures. Computed bond lengths, bond angles, and vibrational frequencies are close to DFT predictions. We find that the proposed parametrization provides a transferable and balanced description of both finite and periodic systems. PMID- 26593374 TI - Cu(II) complexation does not affect oxytocin action on pregnant human myometrium in vitro. AB - OBJECTIVE: Copper may influence the in vivo and in vitro uterine activity. Recent evidence shows that cupric ions can easily form complexes with oligopeptides like oxytocin (OXT). The high complex stability in vitro suggests a possibility of complex formation in vivo. STUDY DESIGN: In vitro isometric contractions were recorded in uterine tissues from pregnant women undergoing caesarean sections and the effect of OXT and the Cu-OXT complex on isolated human pregnant myometrium was investigated. RESULTS: In the concentration range from 10(-14) to 10(-6)M of OXT alone, pre-formed Cu-OXT complex, and OXT following sample preincubation with Cu(II) salt, nosignificant differences were observed for the following parameters of pregnant uterine smooth muscle contraction: the area under the curve, frequency and amplitude of contraction. CONCLUSION: The binding of Cu(2+) ions does not abolish the ability of OXT to interact with oxytocin receptors and stimulate myometrial contraction in vitro. PMID- 26593375 TI - Aqueous Rechargeable Alkaline CoxNi2-xS2/TiO2 Battery. AB - An electrochemical energy storage system with high energy density, stringent safety, and reliability is highly desirable for next-generation energy storage devices. Here an aqueous rechargeable alkaline CoxNi2-xS2 // TiO2 battery system is designed by integrating two reversible electrode processes associated with OH( ) insertion/extraction in the cathode part and Li ion insertion/extraction in the anode part, respectively. The prototype CoxNi2-xS2 // TiO2 battery is able to deliver high energy/power densities of 83.7 Wh/kg at 609 W/kg (based on the total mass of active materials) and good cycling stabilities (capacity retention 75.2% after 1000 charge/discharge cycles). A maximum volumetric energy density of 21 Wh/l (based on the whole packaged cell) has been achieved, which is comparable to that of a thin-film battery and better than that of typical commercial supercapacitors, benefiting from the unique battery and hierarchical electrode design. This hybrid system would enrich the existing aqueous rechargeable LIB chemistry and be a promising battery technology for large-scale energy storage. PMID- 26593376 TI - The triumph of chemically enhanced cellular reprogramming: a patent review. AB - INTRODUCTION: The revolutionary discovery of induced pluripotent stem cells (iPSCs) by Shinya Yamanaka has exposed science to new horizons. However, genetic modifications render reprogrammed cells unstable; for that reason, non-genetic modification approaches are actively under investigation. Among these, the use of small molecules is safe, and these molecules minimally affect the genome. Although iPSCs are ready for clinical trials there are many caveats hindering successful therapy, and small molecules are the best alternative to overcome those caveats. AREAS COVERED: Small molecules are playing an active role in generating and improving the quality of iPSCs. In this review, we will highlight the imperative role of small molecules in accelerating the successful translation of basic research into clinical use. Particularly, those ligands that replace the need for reprogramming factors will be discussed. EXPERT OPINION: Stem cell research is promising for harvesting medical benefits in near future. The invention of new techniques, mechanisms elucidation, and identification of novel compounds for stem cell creation has certainly established a solid foundation for regenerative medicine. This is the beginning of a new era for the cure of most disabling diseases, and small molecules will have a definite role in successful therapeutic use of iPSCs. PMID- 26593378 TI - Dual purpose recovered coagulant from drinking water treatment residuals for adjustment of initial pH and coagulation aid in electrocoagulation process. AB - The present study is focused on the application of recovered coagulant (RC) by acidification from drinking water treatment residuals for both adjusting the initial pH and aiding coagulant in electrocoagulation. To do this, real cotton textile wastewater was used as a target pollutant, and decolorization and chemical oxygen demand (COD) removal efficiency were monitored. A preliminary test indicated that a stainless steel electrode combined with RC significantly accelerated decolorization and COD removal efficiencies, by about 52% and 56%, respectively, even at an operating time of 5 min. A single electrocoagulation system meanwhile requires at least 40 min to attain the similar removal performances. Subsequently, the interactive effect of three independent variables (applied voltage, initial pH, and reaction time) on the response variables (decolorization and COD removal) was evaluated, and these parameters were statistically optimized using the response surface methodology. Analysis of variance showed a high coefficient of determination values (decolorization, R(2) = 0.9925 and COD removal, R(2) = 0.9973) and satisfactory prediction second-order polynomial quadratic regression models. Average decolorization and COD removal of 89.52% and 94.14%, respectively, were achieved, corresponding to 97.8% and 98.1% of the predicted values under statistically optimized conditions. The results suggest that the RC effectively played a dual role of both adjusting the initial pH and aiding coagulant in the electrocoagulation process. PMID- 26593377 TI - Modular PROTAC Design for the Degradation of Oncogenic BCR-ABL. AB - Proteolysis Targeting Chimera (PROTAC) technology is a rapidly emerging alternative therapeutic strategy with the potential to address many of the challenges currently faced in modern drug development programs. PROTAC technology employs small molecules that recruit target proteins for ubiquitination and removal by the proteasome. The synthesis of PROTAC compounds that mediate the degradation of c-ABL and BCR-ABL by recruiting either Cereblon or Von Hippel Lindau E3 ligases is reported. During the course of their development, we discovered that the capacity of a PROTAC to induce degradation involves more than just target binding: the identity of the inhibitor warhead and the recruited E3 ligase largely determine the degradation profiles of the compounds; thus, as a starting point for PROTAC development, both the target ligand and the recruited E3 ligase should be varied to rapidly generate a PROTAC with the desired degradation profile. PMID- 26593379 TI - Right Atrial Mechanics Long-Term after Biventricular Repair of Pulmonary Atresia or Stenosis with Intact Ventricular Septum. AB - BACKGROUND: This study tested the hypothesis that right atrial (RA) mechanics are altered in patients after repair of pulmonary atresia with intact ventricular septum (PAIVS) and pulmonary stenosis (PS) and to explore their relationships with right ventricular (RV) diastolic function and P-wave indices. METHODS: Thirty-six adult patients, 16 with PAIVS and 20 with PS patients, and 20 age matched healthy subjects were studied. Right atrial mechanics were assessed using speckle tracking echocardiography (STE) with quantification of positive, negative, and total strain, and strain rates at ventricular systole (aSRs ), early diastole (aSRed ), and atrial contraction (aSRac ). Right ventricular diastolic function was assessed by Doppler interrogation and STE. Maximum P-wave duration and P-wave dispersion were measured. RESULTS: Compared with controls, PAIVS and PS patients had significantly lower RA positive and total strain, aSRs and aSRed (all P < 0.05). Parameters of RV diastolic function including transtricuspid early (E) and late (A) diastolic inflow velocities, E/A ratio, early diastolic tricuspid annular velocity (e), early to late diastolic annular velocity ratio, E/e ratio, and RV early diastolic strain rate were found to correlate significantly with RA positive and total strain and aSRed (all P < 0.05). Maximum P-wave duration and P-wave dispersion increased progressively across control, PS, and PAIVS groups (P for trend <0.001). Both P-wave indices correlated negatively with RA positive strain, total strain, and aSRed (all P < 0.05). CONCLUSION: Impairment of RA mechanics occurs in patients long term after repair of PAIVS and PS and is associated with RV diastolic dysfunction, longer P wave duration, and greater P-wave dispersion. PMID- 26593380 TI - Thermal Conductivity of Ultrahigh Molecular Weight Polyethylene Crystal: Defect Effect Uncovered by 0 K Limit Phonon Diffusion. AB - Crystalline ultrahigh molecular weight polyethylene (UHMWPE) has the highest reported thermal conductivity at room temperature: 104 W/(m.K), while theoretical predictions proposed an even higher value of 300 W/(m.K). Defects and amorphous fraction in practical UHMWPE fibers significantly reduces the thermal conductivity from the ideal value. Although the amorphous effect can be readily analyzed based on the effective medium theory, the defect effects are poorly understood. This work reports on the temperature-dependent behavior (down to 22 K) of thermal diffusivity and conductivity of UHMWPE fibers in anticipation of observing the reduction in phonon density and scattering rate against temperature and of freezing out high-momentum phonons to clearly observe the defect effects. By studying the temperature-dependent behavior of thermal reffusivity (Theta, inverse of thermal diffusivity) of UHMWPE fibers, we are able to quantify the defect effects on thermal conductivity. After taking out the amorphous region's effect, the residual thermal reffusivities (Theta0) for the studied two samples at the 0 K limit are determined as 3.45 * 10(4) and 2.95 * 10(4) s/m(2), respectively. For rare-/no-defects crystalline materials, Theta0 should be close to zero at the 0 K limit. The defect-induced low-momentum phonon mean free paths are determined as 8.06 and 9.42 nm for the two samples. They are smaller than the crystallite size in the (002) direction (19.7 nm) determined by X-ray diffraction. This strongly demonstrates the diffuse phonon scattering at the grain boundaries. The grain boundary thermal conductance (G) can be evaluated as G ~ betarhoc(p)v with sound accuracy. At room temperature, G is around 3.73 GW/(m(2).K) for S2, comparable to that of interfaces with tight atomic bonding. PMID- 26593381 TI - Downregulation of prostaglandin E2 is involved in hindgut mucosal damage in lactating goats fed a high-concentrate diet. AB - NEW FINDINGS: What is the central question of this study? A high-concentrate (HC) diet results in damage to the hindgut mucosa. The aim of the study was to investigate the status of epithelial proliferation in the hindgut mucosa of goats with subacute ruminal acidosis and, simultaneously, to evaluate prostaglandin E2 synthesis and the downstream signalling pathways. What is the main finding and its importance? The downregulation of local prostaglandin E2 synthesis and its downstream signalling pathway are involved in the process of inhibiting epithelial proliferation in the hindgut epithelium of HC-fed goats. Our results provide new insight into the relationship between abnormal fermentation in the hindgut and damage to the intestinal mucosal barrier. Our previous data demonstrated that feeding a high-concentrate (HC) diet to lactating goats for a long time causes severe damage to the hindgut mucosa and parallels the activation of cell apoptosis and local oxidative stress. In the present study, changes in production of prostaglandin E2 (PGE2 ) and its signalling pathway were evaluated in the process of epithelial barrier disruption in the hindgut. Twelve goats in mid-lactation were randomly assigned to either a HC diet group or a low concentrate (LC) diet group for 10 weeks. Cell proliferation markers, cyclooxygenase-2 activity, PGE2 content and the relative signalling pathway, including CREB and AKT, were analysed by enzyme-linked immunosorbent assay and Western blot, respectively. The mRNA and protein expressions of MKI67 and CCND2 (two proliferation markers) were significantly decreased in the caecal mucosa of HC- compared with LC-fed goats (P < 0.05). The protein content of interleukin-10 and beta-defensin in the caecal mucosa was also downregulated in HC-fed goats (P < 0.05). The HC-fed goats showed a tendency to a decrease in cyclooxygenase-2 enzyme activity (P = 0.081) and a significant decrease of local PGE2 content and EP4 (PGE2 receptor) protein expression in caecal mucosa (P < 0.05). Moreover, the protein abundance of p-CREB (P = 0.069) and p-AKT (P < 0.05) and the mRNA expression of epidermal growth factor receptor (P < 0.05) were downregulated in caecal mucosa of HC- compared with LC-fed goats. These results indicate that a reduction in epithelial cell proliferation was partly responsible for the damage to the epithelial barrier, which might be associated with the downregulation of PGE2 synthesis and its downstream signalling pathway. PMID- 26593382 TI - Simulated Aeromedical Evacuation Exacerbates Experimental Brain Injury. AB - Aeromedical evacuation, an important component in the care of many patients with traumatic brain injury (TBI), particularly in war zones, exposes them to prolonged periods of hypobaria. The effects of such exposure on pathophysiological changes and outcome after TBI are largely unexplored. The objective of this study was to investigate whether prolonged hypobaria in rats subjected to TBI alters behavioral and histological outcomes. Adult male Sprague Dawley rats underwent fluid percussion induced injury at 1.5-1.9 atmospheres of pressure. The effects of hypobaric exposure (6 h duration; equivalent to 0.75 atmospheres) at 6, 24, and 72 h, or 7 days after TBI were evaluated with regard to sensorimotor, cognitive, and histological changes. Additional groups were evaluated to determine the effects of two hypobaric exposures after TBI, representing primary simulated aeromedical evacuation (6 h duration at 24 h after injury) and secondary evacuation (10 h duration at 72 h after injury), as well as the effects of 100% inspired oxygen concentrations during simulated evacuation. Hypobaric exposure up to 7 days after injury significantly worsened cognitive deficits, hippocampal neuronal loss, and microglial/astrocyte activation in comparison with injured controls not exposed to hypobaria. Hyperoxia during hypobaric exposure or two exposures to prolonged hypobaric conditions further exacerbated spatial memory deficits. These findings indicate that exposure to prolonged hypobaria up to 7 days after TBI, even while maintaining physiological oxygen concentration, worsens long-term cognitive function and neuroinflammation. Multiple exposures or use of 100% oxygen further exacerbates these pathophysiological effects. PMID- 26593383 TI - New electron-donor and -acceptor architectures from benzofurazans and sym triaminobenzenes: intermediates, products and an unusual nitro group shift. AB - New all-conjugated C-C coupling products bearing both an electron-poor and an electron-rich aromatic moiety have been obtained from the reaction between sym triaminobenzene derivatives and a series of isomeric chloro-nitrobenzofurazans. The reactions occur under mild reaction conditions, and in some cases a different behaviour depending on the presence, or not, of triethylamine was observed. From 1,3,5-tris(N-morpholinyl)benzene and 5-chloro-4-nitrobenzofurazan in the presence of triethylamine an unexpected product derived from the shift of the nitro group from C-4 to C-5 of the electrophile and bearing the nucleophile at position 4 was obtained. Moreover, from the coupling between 1,3,5-tris(N-pyrrolidinyl)benzene and 4-chloro-7-nitrobenzofurazan a highly stable Wheland intermediate was isolated. PMID- 26593385 TI - Correction: Electronic vs. structural ordering in a manganese(III) spin crossover complex. AB - Correction for 'Electronic vs. structural ordering in a manganese(III) spin crossover complex' by Anthony J. Fitzpatrick et al., Chem. Commun., 2015, DOI: 10.1039/c5cc05129k. PMID- 26593384 TI - Obstructive sleep apnea risk and psychological health among non-Hispanic blacks in the Metabolic Syndrome Outcome (MetSO) cohort study. AB - INTRODUCTION: This study assessed associations of depression and anxiety with risk of obstructive sleep apnea (OSA) among non-Hispanic blacks in the Metabolic Syndrome Outcome (MetSO) study. METHOD: A total of 1,035 patients participated. ARESTM score >=6 defined high OSA risk. Moderate depression was defined by a CES D score >=16. Moderate anxiety was measured by a BAI score >=16. RESULTS: The mean age was 62 +/- 14 years; 70% were female. A total of 93% were diagnosed with hypertension; 61%, diabetes; and 72%, dyslipidemia; 90% were overweight/obese; 33% had a history of heart disease; and 10% had a stroke. Logistic regression analysis, adjusting for age and gender, showed that patients with depression had nearly two-fold increased odds of being at risk for OSA (OR 1.75, 95% CI 1.02 2.98, p < 0.05). Patients with anxiety had three-fold increased odds of being at risk for OSA (OR 3.30, 95% CI 2.11-5.15, p < 0.01). After adjusting for marital status and income, patients with anxiety had a 6% increase in OSA risk (OR 1.06, 95% CI 1.04-1.09, p < 0.05), but depression was no longer significant. CONCLUSION: Our results suggest that non-Hispanic blacks with metabolic syndrome who experience anxiety and/or depression should be screened for OSA. PMID- 26593386 TI - Whole animal HTS of small molecules for antifungal compounds. AB - INTRODUCTION: The high morbidity and mortality among patients with invasive fungal infections and the growing problem of fungal resistance have resulted in an urgent need for new antifungal agents. AREAS COVERED: This review covers the importance of antifungal drug discovery with an emphasis on whole-animal high throughput techniques. More specifically, the authors focus on Caenorhabditis elegans, as a substitute model host and discuss C. elegans as an alternative model host for the study of microbial pathogenesis and the identification of novel antifungal compounds. EXPERT OPINION: There are significant advantages from using the substitute model host C. elegans in high-throughput drug discovery. The C. elegans-microbe model provides a whole animal system where host-pathogen interactions can be studied along with the evaluation of antimicrobial efficacy of compounds. This approach allows the study of compound characteristics, such as toxicity and solubility, during the initial screen and compounds discovered using C. elegans are affective in mammalian models. PMID- 26593387 TI - Metal-free oxidative cyclization of acetophenones with diamines: a facile access to phenylpyridines. AB - An efficient metal-free access to 2- and 3-phenylpyridines via oxidative coupling of acetophenones or phenylacetones with 1,3-diaminopropane has been described. The reaction involves shorter reaction time, excellent yields and a broad substrate scope. The reaction proceeds via the formation of imine, which further undergoes oxidative C-N bond cleavage, C-C bond formation and oxidation to give a pyridine skeleton. The quantum chemical calculations identified the transition state for the reaction and helped in tracing the reaction mechanism. PMID- 26593388 TI - Antihypertensive effects of oleuropein-enriched olive leaf extract in spontaneously hypertensive rats. AB - The effects of chronic consumption of oleuropein-enriched (15% w/w) olive leaf extract (OLE) on blood pressure, endothelial function, and vascular oxidative and inflammatory status in spontaneously hypertensive rats (SHR) were evaluated. Ten Wistar Kyoto rats (WKY) and twenty SHR were randomly assigned to three groups: a control WKY group, a control SHR group and a SHR group treated with OLE (30 mg kg(-1)) for 5 weeks. Long-term administration of OLE reduced systolic blood pressure, heart rate, and cardiac and renal hypertrophy. OLE treatment reversed the impaired aortic endothelium-dependent relaxation to acetylcholine observed in SHR. OLE restored aortic eNOS phosphorylation at Ser-1177 and Thr-495 and increased eNOS activity. OLE eliminated the increased aortic superoxide levels, and reduced the elevated NADPH oxidase activity, as a result of reduced NOX-1 and NOX-2 mRNA levels in SHR. OLE reduced the enhanced vascular TLR4 expression by inhibition of mitogen-activated protein kinase (MAPK) signaling with the subsequent reduction of proinflammatory cytokines. In conclusion, OLE exerts antihypertensive effects on genetic hypertension related to the improvement of vascular function as a result of reduced pro-oxidative and pro-inflammatory status. PMID- 26593389 TI - Supramolecular Packing Controls H2 Photocatalysis in Chromophore Amphiphile Hydrogels. AB - Light harvesting supramolecular assemblies are potentially useful structures as components of solar-to-fuel conversion materials. The development of these functional constructs requires an understanding of optimal packing modes for chromophores. We investigated here assembly in water and the photocatalytic function of perylene monoimide chromophore amphiphiles with different alkyl linker lengths separating their hydrophobic core and the hydrophilic carboxylate headgroup. We found that these chromophore amphiphiles (CAs) self-assemble into charged nanostructures of increasing aspect ratio as the linker length is increased. The addition of salt to screen the charged nanostructures induced the formation of hydrogels and led to internal crystallization within some of the nanostructures. For linker lengths up to seven methylenes, the CAs were found to pack into 2D crystalline unit cells within ribbon-shaped nanostructures, whereas the nine methylene CAs assembled into long nanofibers without crystalline molecular packing. At the same time, the different molecular packing arrangements after charge screening led to different absorbance spectra, despite the identical electronic properties of all PMI amphiphiles. While the crystalline CAs formed electronically coupled H-aggregates, only CAs with intermediate linker lengths showed evidence of high intermolecular orbital overlap. Photocatalytic hydrogen production using a nickel-based catalyst was observed in all hydrogels, with the highest turnovers observed for CA gels having intermediate linker lengths. We conclude that the improved photocatalytic performance of the hydrogels formed by supramolecular assemblies of the intermediate linker CA molecules likely arises from improved exciton splitting efficiencies due to their higher orbital overlap. PMID- 26593390 TI - Nanocrystal size distribution analysis from transmission electron microscopy images. AB - We propose a method, with minimal bias caused by user input, to quickly detect and measure the nanocrystal size distribution from transmission electron microscopy (TEM) images using a combination of Laplacian of Gaussian filters and non-maximum suppression. We demonstrate the proposed method on bright-field TEM images of an a-SiC:H sample containing embedded silicon nanocrystals with varying magnifications and we compare the accuracy and speed with size distributions obtained by manual measurements, a thresholding method and PEBBLES. Finally, we analytically consider the error induced by slicing nanocrystals during TEM sample preparation on the measured nanocrystal size distribution and formulate an equation to correct this effect. PMID- 26593391 TI - Correcting Acidosis during Hemodialysis: Current Limitations and a Potential Solution. AB - The deleterious catabolic and pro-inflammatory effects of acidosis in hemodialysis (HD) patients and the importance of its correction for limiting mineral bone disease (MBD) are well known. Although oral base therapy could be a solution for correcting acidosis in HD patients, it increases their already enormous medication load and sodium intake; this approach is not used commonly. Therefore, we need to rely more on correcting acidosis during the HD procedure, which is difficult to achieve, in part, because HD is an intermittent therapy. The currently used fixed dialysate bicarbonate concentrations are associated with pre-HD acidosis and intra-dialytic alkalosis. We suggest that a decreasing dialysate bicarbonate concentration from an initially high concentration be considered as a means of correcting acidosis with limited intra-dialytic alkalosis. Some evidence, as well as theoretical considerations, supports such an approach. PMID- 26593392 TI - Cancer-related fatigue and depression in breast cancer patients postchemotherapy: Different associations with optimism and stress appraisals-CORRIGENDUM. PMID- 26593393 TI - Testing nanoeffect onto model bacteria: Impact of speciation and genotypes. AB - The gram-negative bacteria Escherichia coli (E. coli) is a very useful prokaryotic model for testing the toxicity of ZnO nanoparticles (nano-ZnO). This toxicity is often linked to Zn(2+) released from nanoparticles in the culture medium, and nano-ZnO dissolution in different media is clearly established. Here, two model E. coli strains MG1655 and W3110 both descendant from the original K-12 showing slight differences in their genome were submitted to nano-ZnO or Zn(2+) in order 1 > to refine the nano-ZnO toxicity mechanisms to E. coli, and 2 > to investigate whether toxicity resulted from a real "nanoparticle" effect or from the release of Zn(2+) in solution. To do so, both strains were submitted to various concentrations (i.e., 0.1-1 mM) of nano-ZnO or Zn(2+) in Luria Bertani (LB) medium. These toxicity studies take into account the nano-ZnO solubility in the culture medium by specifically monitoring the Zn(2+) release in our experimental systems. In our experimental conditions, differences in tolerance to nano-ZnO or Zn(2+) between both strains were clearly evidenced. W3110 is generally more tolerant to metal than MG1655, the latter showing no real difference in its sensitivity to the two zinc added forms unlike W3110. The differences in behavior between both strains could be attributed to differences in the two genomes as a mutation named "amber" in W3110. Moreover, by using these two closely E. coli strains, a real "nano" effect is here clearly demonstrated providing a model to study the toxicity of ZnO nanoparticles. PMID- 26593395 TI - Revealing photofragmentation dynamics through interactions between Rydberg states: REMPI of HI as a case study. AB - High energy regions of molecular electronic states are largely characterized by the nature and involvement of Rydberg states. Whereas there are a number of observed dynamical processes that are due to interactions between Rydberg and valence states, reports on the corresponding effect of Rydberg-Rydberg state interaction in the literature are scarce. Here we report a detailed characterization of the effects of interactions between two Rydberg states on photofragmentation processes, for a hydrogen halide molecule. Perturbation effects, showing as rotational line shifts, intensity alterations and line broadenings in REMPI spectra of HI, for two-photon resonance excitations to the j(3)Sigma(-)(0(+); v' = 0) and k(3)Pi1(v' = 2) Rydberg states, are analyzed. The data reveal pathways of further photofragmentation processes involving photodissociation, autoionization and photoionization affected by the Rydberg Rydberg state interactions as well as the involvement of other states, close in energy. Detailed mechanisms of the involved processes are proposed. PMID- 26593394 TI - CUL4A facilitates hepatocarcinogenesis by promoting cell cycle progression and epithelial-mesenchymal transition. AB - CUL4A, a member of the CULLIN family, functions as a scaffold protein for an E3 ubiquitin ligase. It was reported that the CUL4A gene showed amplification in some human primary hepatocellular carcinomas (HCC). However, the exact role of CUL4A in HCC remains unknown. Here, we aimed to investigate the expression and function of CUL4A in HCC development. Through immunohistochemistry study, we showed increased CUL4A expression in HCC tissues. Statistical analysis disclosed an inverse correlation between CUL4A expression and tumor differentiation grade, and patient survival, but a positive correlation with hepatocyte proliferation as well as lymphatic and venous invasion. CUL4A expression in HCC tissues was associated with HBeAg status in patients and upregulated by HBV in HCC cell lines. Further functional assay showed that CUL4A overexpression significantly promoted growth of H22 tumor homografts in BALB/c mice. Consistently, CUL4A knockdown inhibited the proliferation of established HCC cells, accompanied by S phase reduction and Cyclin A and Cyclin B1 repression. Furthermore, CUL4A siRNA ameliorated the motility of HCC cell lines with altered expression of epithelial mesenchymal transition (EMT)-associated molecules. Taken together, our findings indicate that CUL4A plays a pivotal role in HCC progression and may serve as a potential marker for clinical diagnosis and target for therapy. PMID- 26593397 TI - Structural insights into YfiR sequestering by YfiB in Pseudomonas aeruginosa PAO1. AB - YfiBNR is a tripartite signalling system in Pseudomonas aeruginosa that modulates intracellular c-di-GMP levels in response to signals received in the periplasm. YfiB is an outer membrane lipoprotein and presumed sensor protein that sequesters the repressor protein YfiR. To provide insights into YfiBNR function, we have determined three-dimensional crystal structures of YfiB and YfiR from P. aeruginosa PAO1 alone and as a 1:1 complex. A YfiB(27-168) construct is predominantly dimeric, whereas a YfiB(59-168) is monomeric, indicating that YfiB can dimerize via its N-terminal region. YfiR forms a stable complex with YfiB(59 168), while the YfiR binding interface is obstructed by the N-terminal region in YfiB(27-168). The YfiB-YfiR complex reveals a conserved interaction surface on YfiR that overlaps with residues predicted to interact with the periplasmic PAS domain of YfiN. Comparison of native and YfiR-bound structures of YfiB suggests unwinding of the N-terminal linker region for attachment to the outer membrane. A model is thus proposed for YfiR sequestration at the outer membrane by YfiB. Our work provides the first detailed insights into the interaction between YfiB and YfiR at the molecular level and is a valuable starting point for further functional and mechanistic studies of the YfiBNR signalling system. PMID- 26593399 TI - Photoinduced Isomerization and Hepatoxicities of Semaxanib, Sunitinib and Related 3-Substituted Indolin-2-ones. AB - 3-Substituted indolin-2-ones are an important class of compounds that display a wide range of biological activities. Sunitinib is an orally available multiple tyrosine kinase inhibitor that has been approved by the US Food and Drug Administration (FDA) for the treatment of renal cell cancer. Sunitinib and a related compound, semaxanib, exist as thermodynamically stable Z isomers, which photoisomerize to E isomers in solution. In this study, 17 3-substituted indolin 2-ones were synthesized, and the kinetics of their photoisomerization were studied by (1)H NMR spectroscopy. The rate constants for photoisomerization ranged from 0.009 to 0.048 h(-1). Selected compounds were tested for cytotoxicity in the TAMH liver cell line. E/Z mixtures of four compounds were also assessed for toxicity in the TAMH and HepG2 cell lines. In some cases, the stereochemically pure drug was more toxic than the E/Z mixtures, but a general statement cannot be made. Our studies show that each stereoisomer could contribute differently to toxicity, suggesting that stereochemical purity issues that could arise from isomerization cannot be ignored. PMID- 26593398 TI - EZH2 is highly expressed in pituitary adenomas and associated with proliferation. AB - Enhancer of zeste homolog 2 (EZH2) is a core epigenetic regulator, playing a crucial role in cell cycle regulation. The protein is known to be associated with proliferation and worse outcome in several tumor entities. In this study, we immunohistochemically investigated the expression pattern of EZH2 in a large cohort of pituitary tumors. These results were correlated with clinical features and double immunofluorescence stainings (DIS) were conducted to evaluate co expression of EZH2 and proliferation marker Ki-67. Furthermore, we analyzed the effect of EZH2 inhibition on cell proliferation in vitro using the pituitary cell line AtT-20. While in the normal anterior pituitary EZH2 was almost absent, the cohort of tumors showed enhanced expression levels (p <= 0.0005). This was positively associated with Ki-67 indices (r = 0.834, p <= 0.0005) and DIF confirmed a predominant co-expression of both markers. In vitro experiments revealed a significant (p <= 0.05) decrease of tumor cell proliferation using the EZH2 inhibitor GSK126. Our results further support that epigenetic events are involved in the pathogenesis and biology of pituitary adenomas (PA). Therefore, EZH2 may function as a new potential target for therapeutic interventions in PA. PMID- 26593401 TI - Therapeutic effect of astragaloside-IV on bradycardia is involved in up regulating klotho expression. AB - AIMS: In order to determine whether klotho is involved in the therapeutic effects of Astragaloside-IV on bradycardia, we evaluated the effect of ASG-IV on klotho and the effect of klotho on HCN4 and If. MAIN METHODS: Administrating isoproterenol (5 mg/kg) for 15 days to establish a rat bradycardia model randomized SD rats into control, model (ISO) and ASG-IV (5 mg/kg/day) groups to explore the effect of ASG-IV on klotho. Rats were sacrificed on day 15 after heart rate and heart function were measured; SAN tissues were collected to measure the expression of klotho and HCN4. In vitro, neonatal rat myocardial cells were incubated with LPS for 24 h to inhibit the expression of HCN4 and incubated with LPS+ klotho to explore the effect of klotho on HCN4 expression. We also adopted full-patch-clamp technique to explore the effect of klotho on If. KEY FINDINGS: Heart rate in model group was significantly decreased (356.6+/-19.7 vs. 428.9+/-19.9 in control group, P<0.01) and ASG-IV can increase heart rate (401.4+/-12.0 vs. 356.6+/-19.7 in model group, P<0.01). The expression of klotho was also up-regulated (P<0.05). In vitro, after incubation with LPS for 24h, HCN4 expression was significantly decreased in neonatal rat myocardial cells (0.6+/ 0.07 vs. 1.0, P<0.01) and If was significantly declined. Exogenous klotho showed protective effect on HCN4 expression (1.58+/-0.16 in ASG-IV group vs. 0.6+/-0.07 in LPS group, P<0.05) and If. SIGNIFICANCE: Klotho is involved in the treatment mechanism of ASG-IV. PMID- 26593400 TI - Targeted Nitric Oxide Delivery by Supramolecular Nanofibers for the Prevention of Restenosis After Arterial Injury. AB - AIMS: Cardiovascular interventions continue to fail as a result of arterial restenosis secondary to neointimal hyperplasia. We sought to develop and evaluate a systemically delivered nanostructure targeted to the site of arterial injury to prevent neointimal hyperplasia. Nanostructures were based on self-assembling biodegradable molecules known as peptide amphiphiles. The targeting motif was a collagen-binding peptide, and the therapeutic moiety was added by S-nitrosylation of cysteine residues. RESULTS: Structure of the nanofibers was characterized by transmission electron microscopy and small-angle X-ray scattering. S nitrosylation was confirmed by mass spectrometry, and nitric oxide (NO) release was assessed electrochemically and by chemiluminescent detection. The balloon carotid artery injury model was performed on 10-week-old male Sprague-Dawley rats. Immediately after injury, nanofibers were administered systemically via tail vein injection. S-nitrosylated (S-nitrosyl [SNO])-targeted nanofibers significantly reduced neointimal hyperplasia 2 weeks and 7 months following balloon angioplasty, with no change in inflammation. INNOVATION: This is the first time that an S-nitrosothiol (RSNO)-based therapeutic was shown to have targeted local effects after systemic administration. This approach, combining supramolecular nanostructures with a therapeutic NO-based payload and a targeting moiety, overcomes the limitations of delivering NO to a site of interest, avoiding undesirable systemic side effects. CONCLUSION: We successfully synthesized and characterized an RSNO-based therapy that when administered systemically, targets directly to the site of vascular injury. By integrating therapeutic and targeting chemistries, these targeted SNO nanofibers provided durable inhibition of neointimal hyperplasia in vivo and show great potential as a platform to treat cardiovascular diseases. PMID- 26593402 TI - Remote influence of Atlantic multidecadal variability on Siberian warm season precipitation. AB - The time series of 20th century Siberian warm season (May to October) precipitation (SWP) shows variations over decadal timescales, including a wetting trend since the 1970s. Here, it is shown that the Atlantic multidecadal variability (AMV) can be implicated as a remote driver of the decadal-scale variations in SWP. Observational analysis identifies a significant in-phase relationship between the AMV and SWP, and the SWP decadal variability can be largely explained by the AMV. The physical mechanism for this relationship is investigated using both observations and numerical simulations. The results suggest that North Atlantic sea surface temperature (SST) warming associated with the positive AMV phase can excite an eastward propagating wave train response across the entire Eurasian continent, which includes an east-west dipole structure over Siberia. The dipole then leads to anomalous southerly winds bringing moisture northward to Siberia; the precipitation increases correspondingly. The mechanism is further supported by linear barotropic modeling and Rossby wave ray tracing analysis. PMID- 26593405 TI - It's all about women: creating healthy, functional markets to address the unmet global need for contraception. PMID- 26593403 TI - Diversity and relatedness of Shiga toxin-producing Escherichia coli and Campylobacter jejuni between farms in a dairy catchment. AB - The aim of this study was to examine the population structure, transmission and spatial relationship between genotypes of Shiga toxin-producing Escherichia coli (STEC) and Campylobacter jejuni, on 20 dairy farms in a defined catchment. Pooled faecal samples (n = 72) obtained from 288 calves were analysed by real-time polymerase chain reaction (rtPCR) for E. coli serotypes O26, O103, O111, O145 and O157. The number of samples positive for E. coli O26 (30/72) was high compared to E. coli O103 (7/72), O145 (3/72), O157 (2/72) and O111 (0/72). Eighteen E. coli O26 and 53 C. jejuni isolates were recovered from samples by bacterial culture. E. coli O26 and C. jejuni isolates were genotyped using pulsed-field gel electrophoresis and multilocus sequence typing, respectively. All E. coli O26 isolates could be divided into four clusters and the results indicated that E. coli O26 isolates recovered from calves on the same farm were more similar than isolates recovered from different farms in the catchment. There were 11 different sequence types of C. jejuni isolated from the cattle and 22 from water. An analysis of the population structure of C. jejuni isolated from cattle provided evidence of clustering of genotypes within farms, and among groups of farms separated by road boundaries. PMID- 26593406 TI - Aiming for quality in Iran's national family planning program - two decades of sustained efforts. AB - The Iranian family planning program was relaunched in 1989 to improve maternal and child health. As coverage was extended throughout the country, it had the challenge to achieve harmonization and improve and maintain quality of care. Five strategies were put in place: (1) expand the method mix, (2) standardize provider training through the adoption of national norms and guidelines, (3) facilitate and harmonize service provision, (4) improve integration of family planning in family health services and (5) address myths and misconceptions surrounding contraception in the general population. This was supported by regular monitoring and evaluation. To date, this program is regarded as one of the most successful programs worldwide. While the direct impact of these quality improvements is difficult to evaluate, it is believed to have built the trust that family planning clients place in the program. Challenges remain, particularly facing a total fertility rate below replacement level nationally and providing quality services to an ever-growing peri-urban population. PMID- 26593408 TI - Magnetic phase diagram of superantiferromagnetic TbCu2 nanoparticles. AB - The structural state and static and dynamic magnetic properties of TbCu2 nanoparticles are reported to be produced by mechanical milling under inert atmosphere. The randomly dispersed nanoparticles as detected by TEM retain the bulk symmetry with an orthorhombic Imma lattice and Tb and Cu in the 4e and 8h positions, respectively. Rietveld refinements confirm that the milling produces a controlled reduction of particle sizes reaching ?6 nm and an increase of the microstrain up to ?0.6%. The electrical resistivity indicates a metallic behavior and the presence of a magnetic contribution to the electronic scattering which decreases with milling times. The dc-susceptibility shows a reduction of the Neel transition (from 49 K to 43 K) and a progressive increase of a peak (from 9 K to 15 K) in the zero-field-cooled magnetization with size reduction. The exchange anisotropy is very weak (a bias field of ?30 Oe) and is due to the presence of a disordered (thin) shell coupled to the antiferromagnetic core. The dynamic susceptibility evidences a critical slowing down in the spin-disordered state for the lowest temperature peak associated with a spin glass-like freezing with a tendency of zv and beta exponents to increase when the size becomes 6 nm (zv ? 6.6 and beta ? 0.85). A Rietveld analysis of the neutron diffraction patterns 1.8 <= T <= 60 K, including the magnetic structure determination, reveals that there is a reduction of the expected moment (?80%), which must be connected to the presence of the disordered particle shell. The core magnetic structure retains the bulk antiferromagnetic arrangement. The overall interpretation is based on a superantiferromagnetic behavior which at low temperatures coexists with a canting of surface moments and a mismatch of the antiferromagnetic sublattices of the nanoparticles. We propose a novel magnetic phase diagram where changes are provoked by a combination of the decrease of size and the increase of microstrain. PMID- 26593409 TI - A Method for Detection of Cholesterol Synthesis in the Placenta during Exacerbation of Cytomegalovirus Infection. AB - Histochemical analysis showed that exacerbation of cytomegalovirus infection even at early terms of gestation (weeks 5-6) suppresses synthesis of mevalonic acid, squalene, and 7alpha-dehydrocholesterol dehydrogenase in the placenta. Inhibition of cholesterol biosynthesis in the placenta at the early stages of gestation decreases production of sex hormones, reduces cholesterol concentration in the maternal peripheral blood, and impairs cholesterol supply to the fetus, which is associated with the risk of placental insufficiency. PMID- 26593407 TI - Isolation of a novel bio-peptide from walnut residual protein inducing apoptosis and autophagy on cancer cells. AB - BACKGROUND: Walnut is unique because they have a perfect balance of n-6 and n-3 polyunsaturated fatty acids. The increasing market demand of walnut lipids results in the large amount of the oil extraction residue. The walnut residue is rich in nutritional proteins, and the uneconomic use of the by-product discouraged the development of walnut industry. Anticancer peptides have recently received attention as alternative chemotherapeutic agents that overcome the limits of current drugs. The aim of this study was to investigate whether anticancer bioactive peptide is contained in walnut. METHODS: Walnut residual protein was hydrolyzed separately by five different proteases. The sequential purification of the hydrolysates was carried out by ultra-filtration, gel filtration chromatography and RP-HPLC to obtain a cancer cell growth inhibitory peptide. Cell cycle distribution, Annexin V-FITC/PI double staining, TUNEL assay, western blot and immunofluorescence for LC3-II assay were used to detect apoptosis and autophagy on cells. Cytokine production was measured by ELISA kits, macrophage phagocytosis was measured by neutral red uptake assay, nitric oxide production was measured by Griess reagent. RESULTS: The hydrolysates of walnut residual protein produced by papain under the optimal conditions (5 % substrate concentration and an enzyme-substrate ratio of 10 % at temperature 60 C for 3 h), showed significant growth inhibitory activity on MCF-7. The amino acid sequence of the purified peptide was identified as CTLEW with a molecular weight of 651.2795 Da. It is a novel bio-peptide with an amphiphilic structure. CTLEW induced both apoptosis and autophagy on MCF-7 cells, inhibited the cancer cells growth of Caco-2 and HeLa significantly, but did not show any cytotoxic activity against non-cancerous IEC-6 cells. Moreover, the bio-peptide enhanced proliferation and IL-2 secretion of spleen lymphocytes, promoted phagocytosis and NO production of macrophages. CONCLUSION: These results suggested that a novel bio-peptide, CTLEW inducing apoptosis and autophagy on MCF-7 cells can be released from walnut residual protein through papain hydrolyzing under the certain condition. The bio-peptide shows selective inhibition towards cancer cells growth and immunomodulatory activity. PMID- 26593410 TI - Effect of Hypoxanthine on Functional Activity of Nucleoside Transporters ENT1 and ENT2 in Caco-2 Polar Epithelial Intestinal Cells. AB - We studied regulation of hypoxanthine transport depending on its concentration in the culture medium. Caco-2 cells were differentiated on membrane filters to create a model of the intestine. Different hypoxanthine uptake on the apical and basolateral cell membranes was observed. The expression of SLC29 family genes encoding passive nucleoside transporters increased upon changes in hypoxanthine concentration in the medium Localization of the transporters and their influence on the effect of pharmacological preparations are discussed. PMID- 26593411 TI - Differentiation and Cell-Cell Interactions of Neural Progenitor Cells Transplanted into Intact Adult Brain. AB - We studied the behavior and cell-cell interactions of embryonic brain cell from GFP-reporter mice after their transplantation into the intact adult brain. Fragments or cell suspensions of fetal neocortical cells at different stages of development were transplanted into the neocortex and striatum of adult recipients. Even in intact brain, the processes of transplanted neurons formed extensive networks in the striatum and neocortical layers I and V-VI. Processes of transplanted cells at different stages of development attained the rostral areas of the frontal cortex and some of them reached the internal capsule. However, the cells transplanted in suspension had lower process growth potency than cells from tissue fragments. Tyrosine hydroxylase fibers penetrated from the recipient brain into grafts at both early and late stages of development. Our experiments demonstrated the formation of extensive reciprocal networks between the transplanted fetal neural cells and recipient brain neurons even in intact brain. PMID- 26593412 TI - Comparison of the Efficiency of Viral Transduction and Episomal Transfection in Human Fibroblast Reprogramming. AB - Induced pluripotent cells were derived from adult human skin fibroblast by using two methods of reprogramming. Episomal transfection with vectors containing oriP/EBNA-1 sequence for delivery of reprogramming genes Oct4, Sox2, Klf4, L-Myc, and Lin28 proved to be more effective than viral transduction with Sendai virus based vector: ~200 and 8 colonies per 10(5) cells were found on day 21 of culturing, respectively. Colonies of induced pluripotent cells obtained by these two methods expressed pluripotency marker Tra1-60. PMID- 26593413 TI - Differentiation of Cholinergic Neurons in Rat Spinal Cord Under Conditions of Allotransplantation into a Peripheral Nerve and In Situ Development. AB - The method of ectopic transplantation of embryonic anlages of CNS allows studying histoblastic potencies of progenitor cells developing under conditions of changed microenvironment. Some progenitor cells in the transplants of rat embryonic spinal cord retained their ability to express choline acetyltransferase after transplantation into the sciatic nerve of adult animals. Comparative analysis of cholinergic neurons in the neurotransplants and neurons formed in rat spinal cord during normal ontogeny showed that choline acetyltransferase-positive cells after transplantation into the nerve reached morphological differentiation of motor neurons at later terms than cells developing in situ. They were scattered one by one and did not form nuclear nerve centers. We did not fi nd structures similar to presynaptic cholinergic buds typical of intact spinal cord near these cells throughout the observation period. Solitary cholinergic neurons survived in the transplants for 19 months. PMID- 26593414 TI - Antitoxic Activity of Extract from Salix Viminalis Leaves under Conditions of 5 Fluorouracil Treatment. AB - Injection of 5-fluorouracil to animals caused a pronounced toxic effect. Therapeutic and preventive treatment with Salix viminalis leaf extract significantly reduced the negative effects of the antitumor drug: promoted recovery of the bone marrow, peripheral blood, and visceral parameters and prevented ulceration. Combined use of the cytostatic and Salix viminalis extract increased the efficiency of antitumor therapy. PMID- 26593415 TI - Regulation of the Melanocortin-Sensitive Adenylate Cyclase System by N-Acylated Peptide 71-82 of Type 4 Melanocortin Receptor. AB - The peptides structurally corresponding in to cytoplasmic loops of G protein coupled receptors (GPCR) are able to control functional activity of homologous receptors and the corresponding signaling pathways. Modification of these peptides with hydrophobic radicals enhances their biological activity due to penetration of lipophilic derivatives through the membrane and anchoring near their targets, GPCR. We synthesized an N-palmitoylated peptide Palm-Val-[Lys-Asn Lys-Asn-Leu-His-Ser-Pro-(Nle)-Tyr-Phe-Phe71-82]-amide-Palm-Val-(71-82) structurally corresponding to cytoplasmic loop 1 of melanocortin 4 receptor (M4R). We found that in micromolar concentrations it very effectively suppresses stimulation of basal adenylate cyclase activity and basal level of GppNHp binding of heterotrimeric G proteins produced by THIQ and alpha-melanocyte stimulating hormone (alpha-MSH), agonists of M4R homologous to the peptide, in synaptosomal membranes of rat brain. The peptide Palm-Val-(71-82) also reduced, albeit to a significantly less extent, stimulation of adenylate cyclase and G-proteins by M3R agonist of gamma-MSH, due to high homology of the peptide primary structure to M3R cytoplasmic loop 1. The synthesized peptide with activity of M4R/M3R antagonist can be used for the development of regulators of M4R and M3R and the corresponding biochemical and physiological processes. PMID- 26593416 TI - Study of Subchronic Toxicity of Relatox on Sexually Immature Animals. AB - Intramuscular injections of Relatox in therapeutic and toxic doses to young outbred laboratory rats for 14 days caused no changes in the peripheral blood and bone marrow parameters, serum biochemical parameters, and morphology of the major viscera. In the toxic dose, the drug caused local irritation (inflammation, atrophy, and sclerosis in muscle tissue). Regeneration processes started in muscle tissue 7 days after Relatox withdrawal. PMID- 26593417 TI - Morphological Criteria of Cell Differentiation Stages in Experimental Hepatocarcinoma and Evaluation of Antitumor Drug Efficiency. AB - Structural polymorphism of 5 cell differentiation stages of hepatocarcinoma-29 from ascitic fluid is detected and the morphological criteria for identification of these stages are defined on the base of optic and electron microscopy findings, cytofluorometry, and DNA cytometry. The percentage of cells at differentiation stages 4 and 5 in the tumor structure increases after hepatocarcinoma cell inoculation into the hip. Injection of a cell cycle modulating substance to animals with tumor growth shifts the proportion of cells with various differentiation stages. The morphological criteria of 5 stages of hepatocarcinoma-29 cell differentiation can be used for prospective drug testing. PMID- 26593418 TI - Gene regulation: Landscape and mechanisms of transcription factor cooperativity. PMID- 26593419 TI - Principle of proportionality in genomic data sharing. AB - We propose that a principle of proportionality be applied to genomic data that weighs the depth of data (what is shared) against the breadth of sharing (with whom). PMID- 26593420 TI - Disease genetics: SNP location helps predict disease aetiology. PMID- 26593422 TI - Molecular genetics: Through the cracked lens of cancer genomes. PMID- 26593421 TI - RNA mis-splicing in disease. AB - The human transcriptome is composed of a vast RNA population that undergoes further diversification by splicing. Detecting specific splice sites in this large sequence pool is the responsibility of the major and minor spliceosomes in collaboration with numerous splicing factors. This complexity makes splicing susceptible to sequence polymorphisms and deleterious mutations. Indeed, RNA mis splicing underlies a growing number of human diseases with substantial societal consequences. Here, we provide an overview of RNA splicing mechanisms followed by a discussion of disease-associated errors, with an emphasis on recently described mutations that have provided new insights into splicing regulation. We also discuss emerging strategies for splicing-modulating therapy. PMID- 26593423 TI - Chromosomal Loop Domains Direct the Recombination of Antigen Receptor Genes. AB - RAG initiates antibody V(D)J recombination in developing lymphocytes by generating "on-target" DNA breaks at matched pairs of bona fide recombination signal sequences (RSSs). We employ bait RAG-generated breaks in endogenous or ectopically inserted RSS pairs to identify huge numbers of RAG "off-target" breaks. Such breaks occur at the simple CAC motif that defines the RSS cleavage site and are largely confined within convergent CTCF-binding element (CBE) flanked loop domains containing bait RSS pairs. Marked orientation dependence of RAG off-target activity within loops spanning up to 2 megabases implies involvement of linear tracking. In this regard, major RAG off-targets in chromosomal translocations occur as convergent RSS pairs at enhancers within a loop. Finally, deletion of a CBE-based IgH locus element disrupts V(D)J recombination domains and, correspondingly, alters RAG on- and off-target distributions within IgH. Our findings reveal how RAG activity is developmentally focused and implicate mechanisms by which chromatin domains harness biological processes within them. PMID- 26593425 TI - The effects of female sexual hormones on the expression and function of alpha1A- and alpha1D-adrenoceptor subtypes in the late-pregnant rat myometrium. AB - The aim of the study was to investigate the roles of alpha1-adrenoceptor subtypes in the last-day pregnant rat uterus in vitro by the administration of subtype specific antagonists (the alpha1A-adrenoceptor antagonist WB 4101 and the alpha1D adrenoceptor antagonist BMY 7378) after 17beta-estradiol or progesterone pretreatment. In isolated organ bath studies, contractions were elicited with (-) noradrenaline (10(-8)-10(-5)M) in the presence of propranolol (10(-5)M) and yohimbine (10(-6)M) in order to avoid beta-, and alpha2-adrenergic action. The myometrial expressions of the alpha1-adrenoceptor subtypes were determined by means of the real time reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting techniques. The activated G protein levels were investigated through radiolabelled GTP binding assays. Both 17beta-estradiol and progesterone pretreatment changed the myometrial contracting effect of (-)-noradrenaline. In the presence of WB 4101, progesterone pretreatment decreased the (-) noradrenaline-induced myometrial contraction. In the presence of BMY 7378, both the 17beta-estradiol and the progesterone pretreatment reduced the effect of (-) noradrenaline. The mRNA and protein expressions of the alpha1A-adrenoceptors were decreased after 17beta-estradiol pretreatment. (-)-Noradrenaline increased the [(35)S]GTPgammaS binding of the alpha1-adrenoceptors, which was most markedly elevated by progesterone. Pertussis toxin inhibited the [(35)S]GTPgammaS binding stimulating effect of (-)-noradrenaline, indicating the role of Gi proteins in the signal mechanisms. 17beta-estradiol pretreatment blocks the expression of the alpha1A-adrenoceptors, whereas it does not influence the expression of the alpha1D-adrenoceptors. Progesterone pretreatment does not have any effect on the myometrial mRNA and protein expressions of the alpha1-adrenoceptors, but it alters the G protein coupling of these receptors, promoting a Gi-dependent pathway. PMID- 26593424 TI - 5' UTR m(6)A Promotes Cap-Independent Translation. AB - Protein translation typically begins with the recruitment of the 43S ribosomal complex to the 5' cap of mRNAs by a cap-binding complex. However, some transcripts are translated in a cap-independent manner through poorly understood mechanisms. Here, we show that mRNAs containing N(6)-methyladenosine (m(6)A) in their 5' UTR can be translated in a cap-independent manner. A single 5' UTR m(6)A directly binds eukaryotic initiation factor 3 (eIF3), which is sufficient to recruit the 43S complex to initiate translation in the absence of the cap-binding factor eIF4E. Inhibition of adenosine methylation selectively reduces translation of mRNAs containing 5'UTR m(6)A. Additionally, increased m(6)A levels in the Hsp70 mRNA regulate its cap-independent translation following heat shock. Notably, we find that diverse cellular stresses induce a transcriptome-wide redistribution of m(6)A, resulting in increased numbers of mRNAs with 5' UTR m(6)A. These data show that 5' UTR m(6)A bypasses 5' cap-binding proteins to promote translation under stresses. PMID- 26593426 TI - Epiberberine reduces serum cholesterol in diet-induced dyslipidemia Syrian golden hamsters via network pathways involving cholesterol metabolism. AB - This study aimed to evaluate the cholesterol-lowering effect of epiberberine in dyslipidemia Syrian golden hamsters induced by high fat and high cholesterol (HFHC) diet and its regulation mechanism on some key genes involved in cholesterol metabolism. Hamsters were divided into six groups: normal control group (NC), HFHC group, simvastatin (Sim) and three doses of epiberberine group. The body weight, organs weight and serum lipid levels, as well as total cholesterol (TC) and total bile acids (TBA) levels in liver and feces were determined. Furthermore, the antidyslipidemia effect of epiberberine on key genes involved in cholesterol biosynthesis, uptake, conversion and elimination such as 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), low density lipoprotein receptor (LDL receptor), 7-alpha-hydroxylase (CYP7A1) and apical sodium dependent bile acid transporter (ASBT) were investigated. The results showed that epiberberine at high dosage significantly reduced serum TC, low density lipoprotein cholesterol (LDL-c) and TBA levels by 20.2%, 22.3% and 43.8%, respectively, and increased TBA and TC levels in feces. Epiberberine inhibited HMGCR mRNA and protein expressions and slightly reduced the protein level of ASBT, as well as dramatically up-regulated mRNA and protein expressions of CYP7A1 and LDL receptor. These findings suggested that the antidyslipidemia effects of epiberberine can be achieved via inhibiting the synthesis of cholesterol, promoting the uptake and conversion of TC in liver and increasing the excretion of TC and TBA in feces. Thus, epiberberine should be considered as one of the promising natural drugs for the treatment of dyslipidemia. PMID- 26593427 TI - Determinants of conditioned reinforcing effectiveness: Dopamine D2-like receptor agonist-stimulated responding for cocaine-associated stimuli. AB - Environmental stimuli associated with drug use can take on conditioned properties capable of promoting drug-seeking behaviors during abstinence. This study investigated the relative importance of the amount of reinforced responding, number of cocaine-stimulus pairings, total cocaine intake, and reinforcing effectiveness of the self-administered dose of cocaine to the conditioned reinforcing effectiveness of cocaine-associated stimuli (CS). Male rats were trained to self-administer cocaine (0.1 [small] or 1.0mg/kg/inf [large]) under a fixed ratio schedule of reinforcement. A progressive ratio (PR) schedule was used to quantify the reinforcing effectiveness of each dose of cocaine, as well as the conditioned reinforcing effectiveness of the CS following treatment with saline or the dopamine D2-like receptor agonist pramipexole (0.1-3.2mg/kg). The large dose of cocaine maintained larger final ratios and greater levels of cocaine intake, whereas the small dose resulted in more cocaine-CS pairings. The total amount of responding was comparable between groups. During PR tests of conditioned reinforcement, pramipexole increased responding for CS presentations in both groups; however, the final ratio completed was significantly greater in large- as compared to small-dose group. In addition to highlighting a central role for dopamine D2-like receptors in modulating the effectiveness of cocaine paired stimuli to reinforce behavior, these results suggest that conditioned reinforcing effectiveness is primarily determined by the reinforcing effectiveness of the self-administered dose of cocaine and/or total cocaine intake, and not the total amount of responding or number cocaine-stimulus pairings. These findings have implications for understanding how different patterns of drug-taking might impact vulnerability to relapse. PMID- 26593428 TI - ATP is not involved in alpha1-adrenoceptor-mediated vasoconstriction in resistance arteries. AB - Recent publications suggest that alpha1-adrenoceptor stimulation by exogenous agonists such as phenylephrine in resistance arteries cause contraction through the release of ATP from within the vascular smooth muscle cells. This ATP exits the cell through pannexin-1 channels to act back "autocrine-like" on P2 receptors on the smooth muscle that cause the contraction. In this work we directly test this hypothesis by using a selective P2X1 purinoceptor antagonist NF449 (1-10uM) against phenylephrine and ATP concentration-response curves in small mesenteric arteries of the rat and thoracodorsal arteries of the mouse. We show that NF449 is a simple competitive antagonist of ATP with a pKB of 6.43 and 6.41 in rat and mouse arteries, respectively, but did not antagonise phenylephrine concentration response curves. This work cautions against the growing overstated role of the reputed pannexin-1/ATP release axis following alpha1-adrenoceptor activation in small resistance arteries. PMID- 26593429 TI - Biological profile and bioavailability of imidazoline compounds on morphine tolerance modulation. AB - Tolerance to opioid administration represents a serious medical alert in different chronic conditions. This study compares the effects of the imidazoline compounds 1, 2, and 3 on morphine tolerance in an animal model of inflammatory pain in the rat. 1, 2, and 3 have been selected in that, although bearing a common scaffold, preferentially bind to alpha2-adrenoceptors, imidazoline I2 receptors, or both systems, respectively. Such compounds have been tested in vivo by measuring the paw withdrawal threshold to mechanical pressure after complete Freund's adjuvant injection. To determine the ligand levels in rat plasma, an HPLC-mass spectrometry method has been developed. All the compounds significantly reduced the induction of morphine tolerance, showing different potency and duration of action. Indeed, the selective imidazoline I2 receptor interaction (2) restored the analgesic response by maintaining the same time-dependent profile observed after a single morphine administration. Differently, the selective alpha2C-adrenoceptor activation (1) or the combination between alpha2C adrenoceptor activation and imidazoline I2 receptor engagement (3) promoted a change in the temporal profile of morphine analgesia by maintaining a mild but long lasting analgesic effect. Interestingly, the kinetics of compounds in rat plasma supported the pharmacodynamic data. Therefore, this study highlights that both peculiar biological profile and bioavailability of such ligands complement each other to modulate the reduction of morphine tolerance. Based on these observations, 1-3 can be considered useful leads in the design of new drugs able to turn off the undesired tolerance induced by opioids. PMID- 26593430 TI - Farrerol can attenuate the aortic lesion in spontaneously hypertensive rats via the upregulation of eNOS and reduction of NAD(P)H oxidase activity. AB - Farrerol, a typical natural flavanone, is the major active component of Rhododendron dauricum L. The objective of this study was to evaluate the attenuation effect of farrerol against the aortic lesions in spontaneously hypertensive rats (SHR) for the first time. Twelve-week-old male SHR were orally administered with farrerol (50mg/kg/day), verapamil (50mg/kg/day, positive control), or vehicle for 8 weeks (n=10 in each group). Age-matched Wistar-Kyoto rats (WKY) served as normal controls (n=10). Our results revealed that farrerol significantly reduced the systolic blood pressure in SHR (from 177+/-4mmHg to 158+/-5mmHg) and also dramatically attenuated the aortic lesion, which is characterized by decreased media thickness, wall area, media-lumen ratio, nuclei size and an increased nuclei number (P<0.05). Moreover, the levels of O2(-) along with NAD(P)H oxidase activity were reduced (P<0.05), while the activity of endothelial nitric oxide synthase (eNOS) was elevated (P<0.05) in aortic homogenates after the intervention of farrerol. Furthermore, farrerol upregulated the expression of eNOS in both of mRNA and protein levels, accompanied by the downregulated mRNA and protein expression of p22(phox) (P<0.05), an essential subunit for NADPH oxidase activity. Our findings indicated that farrerol has a significant protective effect against the aortic lesion in SHR, which may be related to the enhanced eNOS activity and reduced NAD(P)H oxidase activity. PMID- 26593431 TI - Dopamine treatment attenuates acute kidney injury in a rat model of deep hypothermia and rewarming - The role of renal H2S-producing enzymes. AB - Hypothermia and rewarming produces organ injury through the production of reactive oxygen species. We previously found that dopamine prevents hypothermia and rewarming-induced apoptosis in cultured cells through increased expression of the H2S-producing enzyme cystathionine beta-Synthase (CBS). Here, we investigate whether dopamine protects the kidney in deep body cooling and explore the role of H2S-producing enzymes in an in vivo rat model of deep hypothermia and rewarming. In anesthetized Wistar rats, body temperature was decreased to 15 degrees C for 3h, followed by rewarming for 1h. Rats (n>=5 per group) were treated throughout the procedure with vehicle or dopamine infusion, and in the presence or absence of a non-specific inhibitor of H2S-producing enzymes, amino-oxyacetic acid (AOAA). Kidney damage and renal expression of three H2S-producing enzymes (CBS, CSE and 3-MST) was quantified and serum H2S level measured. Hypothermia and rewarming induced renal damage, evidenced by increased serum creatinine, renal reactive oxygen species production, KIM-1 expression and influx of immune cells, which was accompanied by substantially lowered renal expression of CBS, CSE, and 3-MST and lowered serum H2S levels. Infusion of dopamine fully attenuated renal damage and maintained expression of H2S-producing enzymes, while normalizing serum H2S. AOAA further decreased the expression of H2S-producing enzymes and serum H2S level, and aggravated renal damage. Hence, dopamine preserves renal integrity during deep hypothermia and rewarming likely by maintaining the expression of renal H2S-producing enzymes and serum H2S. PMID- 26593432 TI - Inhibitory effect of sesquiterpene lactones and the sesquiterpene alcohol aromadendrane-4beta,10alpha-diol on memory impairment in a mouse model of Alzheimer. AB - Alzheimer's disease (AD), a progressive neurodegenerative disorder of the aged brain with no known cause or cures, has become a major medical and social problem for industrialized countries. Cerebral deposition of amyloid-beta peptide (Abeta) is a critical feature of AD. The use of medicinal plants as an alternative form of prevention, or even as a possible treatment of AD, is therefore interesting areas of research. Sesquiterpene lactones and a sesquiterpene alcohol are compounds found in H. brasiliense that have several anti-oxidative and anti inflammatory effects. In the present study, we investigated whether these compounds have neuroprotective effects in an amyloid-beta peptide-induced Alzheimer's disease mouse model. Mice were injected with Abeta1-42 peptide intracerebroventricularly and were subsequently injected (i.c.v.) with 1ug/site of IGM-A (15-acetoxy-isogermafurenolide), IGM-H (15-hydroxy-isogermafurenolide), PDA (Podoandin), EHP (1,2-epoxy-10alpha-hydroxy-podoandin), HDS (13-hydroxy-8,9 dehydroshizukanolide), and ARD (aromadendrane-4beta,10alpha-diol). Seven days after treatments the animals had their memory tested in the inhibitory avoidance. After the behavioral testing of animals the brains were removed and subjected to biochemical tests for oxidative stress. The results showed that ARD, HDS and PDA significantly ameliorated the Abeta1-42 peptide-induced memory impairment in the passive avoidance task (P<0.05). In addition, GSH activity was increased while the TBARS levels were decreased by treatment with these compounds. These results suggest that these compounds inhibit the cognitive deficit of animals induced peptide amyloid and may be potential candidates for Alzheimer's disease therapy. PMID- 26593433 TI - Dual effect of curcumin targets reactive oxygen species, adenosine triphosphate contents and intermediate steps of mitochondria-mediated apoptosis in lung cancer cell lines. AB - Exposure to arsenic is one of the major causes of lung cancer due to production of Reactive Oxygen Species (ROS). Herbal medicine is a new approach used for prevention or treatment of cancers. Among various herbal compounds, a lot of attention has been paid to curcumin, as antioxidant, anti-proliferative, anti carcinogenic and anti-tumor and pro-apoptotic properties of curcumin have been well studied. In the present study, we investigated the effects of curcumin on lung cancer cell lines and arsenic-treated lung cancer cell lines, originated from different stages of lung cancer development. Here, we measured ROS generation and caspase 3/7 activity for both curcumin-treated cell lines and those co-treated with arsenic and curcumin. Then, we studied lipid peroxidation, intracellular ATP content, and cytochrome c release to further investigate how ROS generation and curcumin exert synergistic effects and direct cells toward apoptosis. According to our data, curcumin has a dual effect on ROS generation which is dependent on specific concentration as a threshold and seems to induce apoptosis by two different mechanisms. Moreover, for the first time we report that curcumin delays the drop in ATP levels in these cell lines and hence provides required energy for apoptosis process. Furthermore, western blot analysis reveals that release of cytochrome c is highest when ATP begins to drop in the presence of curcumin. To sum it up, it seems that curcumin is strong candidate for prevention or treatment of lung cancer, especially at stage 2. PMID- 26593434 TI - Protective role of autophagy in methionine-choline deficient diet-induced advanced nonalcoholic steatohepatitis in mice. AB - The methionine choline-deficient (MCD) diet leads to severe liver injury similar to human nonalcoholic steatohepatitis (NASH). Autophagy has emerged as a critical lysosomal pathway that maintains cell function and survival through the degradation of cellular components such as organelles and proteins. The goal of this study was to elucidate the role of autophagy in MCD-induced steatosis, fibrosis, inflammation, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress in mice. Mice were fed with MCD diet and treated with rapamycin (an autophagy enhancer) or chloroquine (an autophagy inhibitor) for 10 weeks. Liver injury was evaluated biochemically and histologically together with hepatic gene expression analysis. Autophagic flux was impaired in livers of mice fed with MCD diet, evidenced by reduced ratio of LC3-II/LC3-I and increased protein expression of p62. It was found that autophagy activation by rapamycin attenuated MCD induced steatosis, fibrosis, inflammation, mitochondrial dysfunction, and ER stress. By contrast, MCD mice treated with chloroquine developed more liver injury. In conclusions, the autophagic pathway plays an important protective role in MCD-induced advanced NASH. Thus, pharmacological promotion of autophagy may provide a novel therapeutic strategy for treatment of NASH. PMID- 26593435 TI - Ellagic acid in Emblica officinalis exerts anti-diabetic activity through the action on beta-cells of pancreas. AB - PURPOSE: The present study was undertaken to explore the possible anti-diabetic mechanism(s) of Emblica officinalis (EO) and its active constituent, ellagic acid (EA), in vitro and in vivo. METHOD: Neonatal streptozotocin-induced non-obese type 2 diabetic rats were treated with a methanolic extract of EO (250 or 500 mg/kg) for 28 days, and blood glucose, serum insulin, and plasma antioxidant status were measured. Insulin and glucagon immunostaining and morphometry were performed in pancreatic section, and liver TBARS and GSH levels were measured. Additionally, EA was tested for glucose-stimulated insulin secretion and glucose tolerance test. RESULTS: Treatment with EO extract resulted in a significant decrease in the fasting blood glucose in a dose- and time-dependent manner in the diabetic rats. It significantly increased serum insulin in the diabetic rats in a dose-dependent manner. Insulin-to-glucose ratio was also increased by EO treatment. Immunostaining of pancreas showed that EO250 increased beta-cell size, but EO500 increased beta-cells number in diabetic rats. EO significantly increased plasma total antioxidants and liver GSH and decreased liver TBARS. EA stimulated glucose-stimulated insulin secretion from isolated islets and decreased glucose intolerance in diabetic rats. CONCLUSION: Ellagic acid in EO exerts anti-diabetic activity through the action on beta-cells of pancreas that stimulates insulin secretion and decreases glucose intolerance. PMID- 26593437 TI - 3,5-diiodo-L-thyronine: A Possible Pharmacological Agent? AB - Overweight and obesity related metabolic disorders, commonly sharing a pathogenic excess of body adiposity, are world-wide epidemic leading to increasing morbidity and mortality. The related conditions include, among the others, liver steatosis, insulin resistance, and cardiovascular risk. Effective and safe anti-obesity drugs are still needed. Likely without undesirable side effects, an ideal treatment should be able to counteract the numerous causes associated with excess of body adiposity putatively modulating the delicate balance between feeding and energy expenditure, untimely controlling the adipose mass. In the past, thyroid hormones have been tested in reducing weight and lipid accumulation, however, the concomitant induction of a thyrotoxicosis state limited their use. Recent studies in rodents revealed that 3,5- diiodo-L-thyronine (T2), an endogenous metabolite of thyroid hormones, exhibits interesting metabolic activities. Specifically, when exogenously administered, T2 increases the resting metabolic rate and elicits short-term beneficial hypolipidemic effects, without being thyrotoxic, at lest in high fat diet fed rats. Now, a matter of interest is whether T2 can be considered or not a potential anti-obesity pharmacological agent. Actually, very few studies have been performed as far as it concerns the effects of T2 in humans and further analyses on larger cohorts to test time of use- and dose-dependent actions as well as the putative occurrence of T2 induced undesirable side effects, are needed. Here, an updated overview of the current literature on T2 bioactivity is furnished with a particular focus on those effects which may be defined "beneficial" vs. "deleterious" ones above all in view of its putative pharmacological use. PMID- 26593436 TI - Isoliquiritigenin in licorice functions as a hepatic protectant by induction of antioxidant genes through extracellular signal-regulated kinase-mediated NF-E2 related factor-2 signaling pathway. AB - PURPOSE: Liver is the major site of biotransformation for exogenous toxins, in having a defense system against oxidative stress as well as cytochrome P450 system. Isoliquiritigenin (isoLQ) is an active component present in Glycyrrhizae radix and has been shown to have various biological activities. This study investigated the effect of isoLQ as a liver protectant against oxidative stress, both in vivo and in vitro, and also its molecular mechanisms. METHODS: We used tert-butylhydroperoxide-induced hepatocyte damage model and cadmium (Cd) stimulated liver toxicity animal model, which are assessed by immunoblot and flow cytometry as well as plasma and histopathological parameters. RESULTS: In HepG2 cells, pretreatment of 10 and 30 uM isoLQ significantly inhibited the induction of apoptosis and mitochondrial damage, and production of reactive oxygen species. Moreover, isoLQ induced the activation of nuclear factor erythroid 2-related factor-2 (Nrf2), as indicated by an increase in its nuclear translocation and antioxidant response element-luciferase activity. IsoLQ also induced the expression of Nrf2 target phase II enzymes, such as heme oxygenase-1, glutamate cysteine ligase catalytic subunit and NAD(P)H:quinone oxidoreductase 1. IsoLQ also induced phosphorylation of extracellular stimuli-regulated kinase (ERK), and its activation of Nrf2 was mediated with ERK-dependent phosphorylation of Nrf2, as determined by its chemical inhibitor. In rats, oral treatment of 5 and 20 mg/kg isoLQ prevented Cd-induced acute hepatic damage, as assessed by plasma parameters and semiquantative histology, such as the modified HAI grading scores and the degenerative regions in hepatic parenchyma. CONCLUSION: These findings are considered as scientific evidence that isoLQ in licorice has the function of being a hepatic protectant against oxidative damages through ERK-mediated Nrf2 activation. PMID- 26593438 TI - A Comparative Summary on Antioxidant-like Actions of Timolol with Other Antioxidants in Diabetic Cardiomyopathy. AB - Cellular signaling associated with cardiac beta-adrenergic receptors (beta-AR) is composed of coupled mechanism among beta 1-/beta2-AR and Gs proteins with contribution of constitutive beta3-AR coupling to Gi proteins. However, down regulation of beta-ARs in the heart under pathological conditions is mediated with a signaling G proteins-included mechanism. Additionally, there are serious conflicting data on this field in literature yet. Although some of these conflictions are generally related with either experimental protocols for different approaches or different animal models. To treat cardiovascular disorders, generally, various types of beta-blockers are used while their action mechanisms are not fully known yet. Furthermore, although beta-blockers are generally used to block the activated beta-ARs, they can be used to scavenge free radicals under oxidative stress. Studies, in whole-system, organ or cellular levels, showed that some beta-blockers, including timolol, have protective actions against increased oxidative stress in diseased heart via ROSscavenging. Additionally, it has been mentioned that some beta-blockers nicely prevented the development of heart failure in both experimental and clinical studies by restoring sarcoplasmic reticulum (SR) Ca(2+) release channels, RyR2. Since diabetic cardiomyopathy is recognized due to its diminished responsiveness to beta1-AR agonist stimulation in the heart with an up-regulation of beta 3-AR, inducing a strong negative inotropic effect on left ventricular function, it has been shown that treatment of streptozotocin-diabetic rats with timolol provided a marked cardio-protection. Importantly, it has been also documented that timolol treatment-dependent cardio-protection in diabetic rats includes basically prevention of RyR2- hyperphosphorylation, which, in turn, block Ca(2+)-leakage from SR via scavenging oxidative agents to control redox-state of cardiomyocytes. This action of timolol in diabetic heart is very similar to other known antioxidants, such as N-acetylcysteine or selenium compounds. In this review article, antioxidant-like action of timolol in diabetic cardiomyopathy was summarized in way of comparison with the benefits obtained with other antioxidants in the similar animal model. PMID- 26593439 TI - High-throughput transcriptome sequencing of the cold seep mussel Bathymodiolus platifrons. AB - Bathymodiolid mussels dominate hydrothermal vents, cold methane/sulfide hydrocarbon seeps, and other sites of organic enrichment. Here, we aimed to explore the innate immune system and detoxification mechanism of the deep sea mussel Bathymodiolus platifrons collected from a methane seep in the South China Sea. We sequenced the transcriptome of the mussels' gill, foot and mantle tissues and generated a transcriptomic database containing 96,683 transcript sequences. Based on GO and KEGG annotations, we reported transcripts that were related to the innate immune system, heavy metal detoxification and sulfide metabolic genes. Our in-depth analysis on the isoforms of peptidoglycan recognition protein (PGRP) that have different cellular location and potentially differential selectivity towards peptidoglycan (PGN) from gram-positive and gram-negative bacteria were differentially expressed in different tissues. We also reported a potentially novel form of metallothionein and the production of phytochelatin in B. platifrons, which has not been reported in any of its coastal relative Mytilus mussel species. Overall, the present study provided new insights into heavy metal and sulfide metabolism in B. platifrons and can be served as the basis for future molecular studies on host-symbiont interactions in cold seep mussels. PMID- 26593440 TI - The evolution of gene expression and binding specificity of the largest transcription factor family in primates. AB - The KRAB-containing zinc finger (KRAB-ZF) proteins represent the largest family of transcription factors (TFs) in humans, yet for the great majority, their function and specific genomic target remain unknown. However, it has been shown that a large fraction of these genes arose from segmental duplications, and that they have expanded in gene and zinc finger number throughout vertebrate evolution. To determine whether this expansion is linked to selective pressures acting on different domains, we have manually curated all KRAB-ZF genes present in the human genome together with their orthologous genes in three closely related species and assessed the evolutionary forces acting at the sequence level as well as on their expression profiles. We provide evidence that KRAB-ZFs can be separated into two categories according to the polymorphism present in their DNA contacting residues. Those carrying a nonsynonymous single nucleotide polymorphism (SNP) in their DNA-contacting amino acids exhibit significantly reduced expression in all tissues, have emerged in a recent lineage, and seem to be less strongly constrained evolutionarily than those without such a polymorphism. This work provides evidence for a link between age of the TF, as well as polymorphism in their DNA-contacting residues and expression levels-both of which may be jointly affected by selection. PMID- 26593442 TI - A new Leishmania-specific hypothetical protein, LiHyT, used as a vaccine antigen against visceral leishmaniasis. AB - The present study aimed to evaluate a new Leishmania-specific hypothetical protein, LiHyT, as a vaccine candidate against VL. The immunogenicity of the recombinant protein (rLiHyT) plus saponin was evaluated in BALB/c mice. In the results, it is shown that rLiHyT plus saponin vaccinated mice produced high levels of IFN-gamma, IL-12, and GM-CSF after in vitro stimulation of spleen cells using both rLiHyT and Leishmania infantum SLA. The protective efficacy was evaluated after subcutaneous challenge with stationary promastigotes of L. infantum. Immunized and infected mice, when compared to the controls, showed significant reductions in the number of parasites in the liver, spleen, bone marrow, and in the paws' draining lymph nodes. Protection was associated with an IL-12-dependent production of IFN-gamma, mainly by CD4(+) T cells, with a minor contribution of CD8(+) T cells. In these mice, a decrease in the parasite mediated IL-4 and IL-10 responses, as well as a predominance of LiHyT- and parasite-specific IgG2a isotype antibodies, were also observed. The present study showed that a new Leishmania-specific protein, when combined with a Th1-type adjuvant, presents potential to be used as a vaccine against VL. PMID- 26593441 TI - Characterizing the fecal microbiota of infants with botulism. AB - BACKGROUND: Infant botulism is the most prevalent form of botulism in the USA, representing 68.5 % of cases reported from 2001-2012. Infant botulism results when botulinum toxin-producing clostridia (BTPC) colonize the infant gut with concomitant in vivo production of the highly potent botulinum neurotoxin (BoNT). The gut microbiota of infants with botulism is largely uncharacterized; therefore, it remains unclear whether the microbiota profile of these patients are distinct in composition, abundance, or diversity. To address this uncertainty, we employed 16S rRNA gene profiling to characterize the fecal microbiota in 14 stool samples among laboratory-confirmed and non-confirmed infant botulism cases. RESULTS: Seven bacterial phyla were identified among all 14 infant stool samples examined. Compared to samples from non-confirmed cases, the fecal microbiota of infant botulism patients displayed significantly higher Proteobacteria abundance. Of the 20 bacterial families identified, Enterobacteriaceae was significantly more abundant in samples from infants with botulism. Firmicutes abundance and the abundance ratio of Firmicutes/Proteobacteria was significantly lower in samples from infants with botulism. Lactobacillus spp. abundance was notably reduced in 12 of the 14 samples. Clostridium botulinum and Clostridium baratii were identified in low relative abundances in confirmed and non-confirmed samples based on their 16S rRNA gene profiles, although their toxigenicity remained undetermined. No significant differences were observed in the number of operational taxonomic units (OTUs) observed or in fecal microbiota diversity between laboratory confirmed and non-confirmed samples. Correlations between individual phylum abundances and infant age were variable, and no significant differences were shown in number of OTUs observed or in fecal microbiota diversity between samples delineated by overall mean age. CONCLUSIONS: Significant differences in Proteobacteria, Firmicutes, and Enterobacteriaceae abundances were identified in the fecal microbiota of infants with botulism when compared to samples from non confirmed cases. Fecal microbiota diversity was not significantly altered in infants with botulism, and a limited presence of BTPC was shown. It could not be determined whether the fecal microbiota profiles shown here were comparable prior to patient illness, or whether they were the direct result of infant botulism. The results of this study do, however, provide a detailed and descriptive observation into the infant gut microbiota after intestinal colonization by BTPC. PMID- 26593444 TI - The estrogenic effect of trigonelline and 3,3-diindolymethane on cell growth in non-malignant colonocytes. AB - Epidemiological and animal data have demonstrated the protective effects of estrogen signaling on colon carcinogenesis. Nonetheless, studies have suggested that estrogen replacement therapy is positively correlated to increased risk of breast cancer. Therefore, there is considerable interest in investigating novel phytoestrogens that mimic the protective actions of estrogen in the colon. Trigonelline (Trig) and 3,3-diindolylmethane (DIM) have been reported as phytoestrogens in spite of their distinct chemical structures from other phytoestrogens. Both compounds elicit estrogenic responses without directly interacting with the binding domain of the estrogen receptor (ER). We examined the influence of Trig and DIM on non-malignant colonocytes. Both compounds reduced cell growth of young adult mouse colonocytes (YAMCs). Trig and DIM induced cell cycle arrest in the G0/G1 phase and enhanced apoptosis in YAMCs. The inhibitory effect of Trig on cell growth was disrupted by co-treatment of ICI 182,780, an ER antagonist. DIM elevated ER mediated transcriptional activity. Both compounds changed gene expression related to apoptosis and cell proliferation in unique ways. In conclusion, Trig and DIM impact cell physiology and gene expression in YAMCs via novel estrogenic actions and these data suggest that intake of novel phytoestrogens may activate protective effects of estrogen signaling in the colon. PMID- 26593443 TI - AF4 uses the SL1 components of RNAP1 machinery to initiate MLL fusion- and AEP dependent transcription. AB - Gene rearrangements generate MLL fusion genes, which can lead to aggressive leukemia. In most cases, MLL fuses with a gene encoding a component of the AEP (AF4 family/ENL family/P-TEFb) coactivator complex. MLL-AEP fusion proteins constitutively activate their target genes to immortalize haematopoietic progenitors. Here we show that AEP and MLL-AEP fusion proteins activate transcription through selectivity factor 1 (SL1), a core component of the pre initiation complex (PIC) of RNA polymerase I (RNAP1). The pSER domain of AF4 family proteins associates with SL1 on chromatin and loads TATA-binding protein (TBP) onto the promoter to initiate RNA polymerase II (RNAP2)-dependent transcription. These results reveal a previously unknown transcription initiation mechanism involving AEP and a role for SL1 as a TBP-loading factor in RNAP2 dependent gene activation. PMID- 26593445 TI - Non-hormonal male contraception: A review and development of an Eppin based contraceptive. AB - Developing a non-hormonal male contraceptive requires identifying and characterizing an appropriate target and demonstrating its essential role in reproduction. Here we review the development of male contraceptive targets and the current therapeutic agents under consideration. In addition, the development of EPPIN as a target for contraception is reviewed. EPPIN is a well characterized surface protein on human spermatozoa that has an essential function in primate reproduction. EPPIN is discussed as an example of target development, testing in non-human primates, and the search for small organic compounds that mimic contraceptive antibodies; binding EPPIN and blocking sperm motility. Although many hurdles remain before the success of a non-hormonal male contraceptive, continued persistence should yield a marketable product. PMID- 26593446 TI - Early perception of stink bug damage in developing seeds of field-grown soybean induces chemical defences and reduces bug attack. AB - BACKGROUND: Southern green stink bugs (Nezara viridula L.) invade field-grown soybean crops, where they feed on developing seeds and inject phytotoxic saliva, which causes yield reduction. Although leaf responses to herbivory are well studied, no information is available about the regulation of defences in seeds. RESULTS: This study demonstrated that mitogen-activated protein kinases MPK3, MPK4 and MPK6 are expressed and activated in developing seeds of field-grown soybean and regulate a defensive response after stink bug damage. Although 10-20 min after stink bug feeding on seeds induced the expression of MPK3, MPK6 and MPK4, only MPK6 was phosphorylated after damage. Herbivory induced an early peak of jasmonic acid (JA) accumulation and ethylene (ET) emission after 3 h in developing seeds, whereas salicylic acid (SA) was also induced early, and at increasing levels up to 72 h after damage. Damaged seeds upregulated defensive genes typically modulated by JA/ET or SA, which in turn reduced the activity of digestive enzymes in the gut of stink bugs. Induced seeds were less preferred by stink bugs. CONCLUSION: This study shows that stink bug damage induces seed defences, which is perceived early by MPKs that may activate defence metabolic pathways in developing seeds of field-grown soybean. (c) 2015 Society of Chemical Industry. PMID- 26593447 TI - Potential involvement of placental AhR in unexplained recurrent spontaneous abortion. AB - Recurrent spontaneous abortion (RSA) is a common complication of pregnancy. Recent studies have demonstrated that the aryl hydrocarbon receptor (AhR) might play important roles in establishing and maintaining early pregnancy. In this study, we found that placental AhR protein levels were significantly lower and placental CYP1A1 mRNA levels were higher in unexplained RSA (URSA) patients than in control subjects. The results of immunohistochemical analyzes showed that placental AhR was expressed in syncytiotrophoblast cells and that the level of AhR was markedly lower in these cells in URSA subjects than in control subjects. beta-Naphthoflavone (beta-NF, an AhR ligand) at 5MUM significantly inhibited proliferation and migration in HTR-8/SVneo cells and was associated with the activation of AhR. Moreover, overexpressing AhR in JAR cells significantly increased CYP1A1 mRNA levels and inhibited cell migration. These results indicate that AhR is highly activated in URSA placentas and that the activation of AhR in the placenta might impair trophoblast cell proliferation and migration, possibly leading to the occurrence of URSA. PMID- 26593448 TI - Three supplementary methods for analyzing cytotoxicity of Escherichia coli O157:H7. AB - Escherichia coli O157:H7 is an enterohemorrhagic E. coli (EHEC) strain and a major food-borne pathogen, causing severe disease in humans worldwide. Multiple sensitive, accurate, and quantitative methods are needed to provide a comprehensive analysis of cell damage caused by O157:H7. However, the current, universally adopted methods for O157:H7 virulence assessment fail to investigate the interactive effects of O157:H7 and its host cells, neglect the effects of infection of host cells by O157:H7, and fail to comprehensively and accurately reflect the true pathogenicity of O157:H7. In this study, three different accurate, sensitive, and quantifiable methods were supplementary to provide standard operating procedures to analyze the cytotoxicity of O157:H7. This set of methods can be applied to toxicity studies of newly discovered O157:H7 clinical isolates and used to study how a clinical isolate's toxicity correlates with its pathogenicity. These methods can also be used in future studies of latent virulence factors and to explore the pathogenic mechanisms of O157:H7. PMID- 26593449 TI - Comparison of lipid and detergent enzyme environments for identifying inhibitors of membrane-bound energy-transducing proteins. AB - This study compared detergent-solubilised (soluble) and lipid-reconstituted (proteoliposome) protein to establish a high-throughput method for identifying membrane protein inhibitors. We identified inhibitors of the membrane-bound type II NADH dehydrogenase with lower lipophilicity and better potency, suggesting proteoliposome systems may be advantageous over detergent-solubilised systems for respiratory membrane proteins. PMID- 26593450 TI - Plasmon-Induced Water Splitting Using Metallic-Nanoparticle-Loaded Photocatalysts and Photoelectrodes. AB - Visible- and near-infrared-light-driven water splitting, which splits water molecules to generate hydrogen and oxygen gases, is a significant subject in artificial photosynthesis with the goal of achieving a low-carbon society. In recent years, considerable attention has been paid to studies on the development of a plasmon-induced water-splitting system responding to visible light. In this review, we categorized water-splitting systems as gold-nanoparticle-loaded semiconductor photocatalytic particles system and metallic-nanoparticles-loaded semiconductor photoelectrode systems, and introduce the latest studies according to these categories. Especially, we describe the studies that optimize a material or a structural design of metallic-nanoparticle-loaded semiconductor photoelectrodes and consider a whole water-splitting system, including a cathode design. Furthermore, we discuss important points when studying plasmon-induced water splitting, and we describe a methodology that enhances plasmon-induced water-splitting efficiency. PMID- 26593451 TI - Standard loading controls are not reliable for Western blot quantification across brain development or in pathological conditions. AB - A frequently utilized method of data quantification in Western blot analysis is comparison of the protein of interest with a house keeping gene or control protein. Commonly used proteins include beta-actin, glyceraldehyde 3 phosphate dehydrogenase (GAPDH), and alpha-tubulin. Various reliability issues have been raised when using this technique for data analysis-particularly when investigating protein expression changes during development and in disease states. In this study, we have demonstrated that beta-actin, GAPDH, and alpha tubulin are not appropriate controls in the study of development and hypoxic ischemic induced damage in the piglet brain. We have also shown that using an in house pooled standard, loaded on all blots is a reliable method for controlling interassay variability and data normalization in protein expression analysis. PMID- 26593452 TI - The history of efforts to regulate dietary supplements in the USA. AB - This review examines the emergence of dietary supplements and how the Food and Drug Administration (FDA) attempted to regulate these, beginning with the arrival of vitamins and how these were managed under the 1906 Food and Drugs Act, and ending with the seismic influence of the 1994 Dietary Supplement Health and Education Act (DSHEA). Included are the impact of major laws, key court decisions, and the construction of the FDA's supplement actions and rules from the 1920s to the 1990s for products that were neither drugs nor typical foods. Stiff resistance to the regulations by supplement manufacturers, trade associations, politicians, and especially the public at large is an important part of this story. The paper closes with the passage of DSHEA and how it literally changed the definition and parameters of control of dietary supplements. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26593454 TI - Many congratulations to Professor Angus Deaton. PMID- 26593453 TI - The effects of household wealth on HIV prevalence in Manicaland, Zimbabwe - a prospective household census and population-based open cohort study. AB - INTRODUCTION: Intensified poverty arising from economic decline and crisis may have contributed to reductions in HIV prevalence in Zimbabwe. OBJECTIVES: To assess the impact of the economic decline on household wealth and prevalent HIV infection using data from a population-based open cohort. METHODS: Household wealth was estimated using data from a prospective household census in Manicaland Province (1998 to 2011). Temporal trends in summed asset ownership indices for sellable, non-sellable and all assets combined were compared for households in four socio-economic strata (small towns, agricultural estates, roadside settlements and subsistence farming areas). Multivariate logistic random-effects models were used to measure differences in individual-level associations between prevalent HIV infection and place of residence, absolute wealth group and occupation. RESULTS: Household mean asset scores remained similar at around 0.37 (on a scale of 0 to 1) up to 2007 but decreased to below 0.35 thereafter. Sellable assets fell substantially from 2004 while non-sellable assets continued increasing until 2008. Small-town households had the highest wealth scores but the gap to other locations decreased over time, especially for sellable assets. Concurrently, adult HIV prevalence fell from 22.3 to 14.3%. HIV prevalence was highest in better-off locations (small towns) but differed little by household wealth or occupation. Initially, HIV prevalence was elevated in women from poorer households and lower in men in professional occupations. However, most recently (2009 to 2011), men and women in the poorest households had lower HIV prevalence and men in professional occupations had similar prevalence to unemployed men. CONCLUSIONS: The economic crisis drove more households into extreme poverty. However, HIV prevalence fell in all socio-economic locations and sub-groups, and there was limited evidence that increased poverty contributed to HIV prevalence decline. PMID- 26593455 TI - Comparing perioperative processes of care in high and low mortality centers performing pancreatic surgery. AB - BACKGROUND: Pancreatic surgery outcomes vary widely. We hypothesize that by comparing high and low mortality hospitals, we may identify differences in patient care impacting safety. METHODS: We sampled hospitals with very-low and very-high mortality (LMH; HMH) and conducted on-site chart reviews evaluating perioperative care practices for pancreatic operations. RESULTS: HMHs had an 11.6% mortality rate; LMHs 1.5%. Patients in HMHs had worse ASA classification (20.9% ASA Class 4/5 vs. 2.0%, P < 0.001) and comorbidity burden (55.3% with >= 1 comorbidity vs. 39.6%, P = 0.037). At HMHs, operations took longer (353.9 min vs. 313.7 min, P = 0.05), had higher blood loss (1,203.7 ml vs. 881.6 ml, P = 0.04), and patients underwent more transfusions (70.2% vs. 41.1%, P < 0.001). There were differences in anesthetic care: less invasive monitoring (76.1% vs. 93.1%, P < 0.001) and epidural pain management (22.5% vs. 62.9%, P < 0.001). Both cohorts had similar rates of VTE prophylaxis and SSI prevention compliance. CONCLUSION: High and low mortality hospitals both have high compliance with common quality measures; however, HMHs performed worse in other areas of perioperative care, indicating possible targets for quality improvement efforts. PMID- 26593456 TI - Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis. AB - BACKGROUND: Pouchitis occurs in approximately 50% of patients following ileal pouch-anal anastomosis (IPAA) for chronic ulcerative colitis. OBJECTIVES: The primary objective was to determine the efficacy and safety of medical therapies (including antibiotics, probiotics, and other agents) for prevention or treatment of acute or chronic pouchitis. SEARCH METHODS: We searched MEDLINE, EMBASE and the Cochrane Library from inception to October 2014. SELECTION CRITERIA: Randomized controlled trials of prevention or treatment of acute or chronic pouchitis in adults who underwent IPAA for ulcerative colitis were considered for inclusion. DATA COLLECTION AND ANALYSIS: Two authors independently screened studies for eligibility, extracted data and assessed study quality. Methodological quality was assessed using the Cochrane risk of bias tool. The overall quality of the evidence supporting the outcomes was evaluated using the GRADE criteria. The primary outcome was the proportion of patients with clinical improvement or remission of pouchitis in patients with acute or chronic pouchitis, or the proportion of patients with no episodes of pouchitis after IPAA. The proportion of patients who developed at least one adverse event was a secondary outcome. We calculated the risk ratio (RR) and corresponding 95% confidence interval (CI) for each dichotomous outcome. MAIN RESULTS: Thirteen studies (517 participants) were included in the review. Four studies assessed treatment of acute pouchitis. One study (16 participants) compared ciprofloxacin and metronidazole; another (26 participants) compared metronidazole to budesonide enemas; another (18 participants) compared rifaximin to placebo; and the fourth study (20 participants) compared Lactobacillus GG to placebo. Four studies assessed treatment of chronic pouchitis. One study (19 participants) compared glutamine to butyrate suppositories; another (40 participants) compared bismuth enemas to placebo; and two studies (76 participants) compared VSL#3 to placebo. Five studies assessed prevention of pouchitis. One study (40 participants) compared VSL#3 to placebo; another (28 participants) compared VLS#3 to no treatment; one study (184 participants) compared allopurinol to placebo; another (12 participants) compared the probiotic Bifidobacterium longum to placebo; and one study (38 participants) compared tinidazole to placebo. Three studies were judged to be of high quality. Two studies were judged to be low quality and the quality of the other studies was unclear. Treatment of acute pouchitis: The results of one small study (16 participants) suggest that ciprofloxacin may be more effective than metronidazole for the treatment of acute pouchitis. One hundred per cent (7/7) of ciprofloxacin patients achieved remission at two weeks compared to 33% (3/9) of metronidazole patients. A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was very low due to high risk of bias (no blinding) and very sparse data (10 events). There was no difference in the proportion of patients who had at least one adverse event (RR 0.18, 95% CI 0.01 to 2.98). Adverse events included vomiting, dysgeusia or transient peripheral neuropathy. There were no differences between metronidazole and budesonide enemas in terms of clinical remission, clinical improvement or adverse events. Adverse events included anorexia, nausea, headache, asthenia, metallic taste, vomiting, paraesthesia, and depression. There were no differences between rifaximin and placebo in terms of clinical remission, clinical improvement, or adverse events. Adverse events included diarrhea, flatulence, nausea, proctalgia, vomiting, thirst, candida, upper respiratory tract infection, increased hepatic enzyme, and cluster headache. There was no difference in clinical improvement between Lactobacillus GG and placebo. The results of these studies are uncertain due to very low quality evidence. Treatment of chronic pouchitis: A pooled analysis of two studies (76 participants) suggests that VSL#3 may be more effective than placebo for maintenance of remission. Eighty-five per cent (34/40) of VLS#3 patients maintained remission at 9 to 12 months compared to 3% (1/36) of placebo patients (RR 20.24, 95% CI 4.28 to 95.81). A GRADE analysis indicated that the quality of evidence supporting this outcome was low due to very sparse data (35 events). Adverse events included abdominal cramps, vomiting and diarrhea. There was no difference in effectiveness between glutamine and butyrate suppositories for maintenance of remission. There was no difference in clinical improvement or adverse event rates between bismuth carbomer foam enemas and placebo. Adverse events included diarrhea, worsening symptoms, cramping, sinusitis, and abdominal pain. The results of these studies are uncertain due to very low quality evidence. Prevention of pouchitis: The results of one small study (40 participants) suggest that VSL#3 may be more effective than placebo for prevention of pouchitis. Ninety per cent (18/20) of VSL#3 patients had no episodes of acute pouchitis during the 12 month study compared to 60% (12/20) of placebo patients (RR 1.50, 95% CI 1.02 to 2.21). A GRADE analysis indicated that the quality of evidence supporting this outcome was low due to very sparse data (30 events). Another small study (28 participants) found that VLS#3 was not more effective than no treatment for prevention of pouchitis. Bifidobacterium longum, allopurinol and tinidazole were not more effective than placebo for prevention of pouchitis. The results of these studies are uncertain due to very low quality evidence. AUTHORS' CONCLUSIONS: For acute pouchitis, very low quality evidence suggests that ciprofloxacin may be more effective than metronidazole. For chronic pouchitis, low quality evidence suggests that VSL#3 may be more effective than placebo for maintenance of remission. For the prevention of pouchitis, low quality evidence suggests that VSL#3 may be more effective than placebo. Well designed, adequately powered studies are needed to determine the optimal therapy for the treatment and prevention of pouchitis. PMID- 26593457 TI - Successful eradication of helical rim keloids with surgical excision followed by pressure therapy using a combination of magnets and silicone gel sheeting. AB - Extremely limited data are available for the treatment of helical rim keloids. The purpose of the present study was to demonstrate the successful treatment of helical rim keloids using surgical exicison followed by a newly designed pressure therapy device. We treated 40 pure helical rim keloids in 36 patients with surgical excisions followed by pressure therapy using a combination of magnets and silicone gel sheeting for 12 hours over a period of 2 years, from May 2012 to February 2014, at tertiary medical centre. The follow-up period was 18 months. Primary outcome was recurrence of keloids. Secondary outcome was patient satisfaction as assessed by the Patient Observer Scar Assessment Scale (POSAS). The overall recurrence-free rate was 95.0% after a follow-up period of 18 months. Scores obtained from the POSAS showed that most items were reported to be improved. This adjuvant therapy protocol resulted in excellent outcomes in cases of helical rim keloids compared to previously published protocols. PMID- 26593458 TI - Multiresidue analysis of multiclass pesticides and polyaromatic hydrocarbons in fatty fish by gas chromatography tandem mass spectrometry and evaluation of matrix effect. AB - This paper reports a selective and sensitive method for multiresidue determination of 119 chemical residues including pesticides and polyaromatic hydrocarbons (PAH) in high fatty fish matrix. The novel sample preparation method involved extraction of the target analytes from homogenized fish meat (5 g) in acetonitrile (15 mL, 1% acetic acid) after three-phase partitioning with hexane (2 mL) and the remaining aqueous layer. An aliquot (1.5 mL) of the acetonitrile layer was aspirated and subjected to two-stage dispersive solid phase extraction (dSPE) cleanup and the residues were finally estimated by gas chromatography mass spectrometry with selected reaction monitoring (GC-MS/MS). The co-eluted matrix components were identified on the basis of their accurate mass by GC with quadrupole time of flight MS. Addition of hexane during extraction and optimized dSPE cleanup significantly minimized the matrix effects. Recoveries at 10, 25 and 50 MUg/kg were within 60-120% with associated precision, RSD<11%. PMID- 26593459 TI - The ability of peptide extracts obtained at different dry cured ham ripening stages to bind aroma compounds. AB - The ability of peptide extracts, obtained at different dry-cured ham ripening stages, to bind volatile compounds has been examined using solid-phase microextraction and gas-chromatography. The peptide extracts from dry-cured ham were previously defatted and deodorised in order to be able to study peptide volatile interactions. The binding effect of each peptide extracts to volatile compounds was analysed at different concentrations. In the presence of peptide extracts, a release was observed for ethyl butyrate, ethyl 2-methylbutyrate, ethyl 3-methylbutyrate and 3-methylthiopropanal. On the other hand, retention of about 20% and 30% was observed for 2-methylpropanal, hexanal and ethyl acetate while the highest interaction was observed for trimethylpyrazine. All peptide extracts did not exert any binding effect on 2-methylbutanal. No significant differences in binding-ability were detected for the peptides obtained at different ripening-stages; therefore, the binding-ability of peptide extracts was mainly based on volatile chemical characteristics and not on the type of peptide extract obtained. PMID- 26593460 TI - Heat-denaturation and aggregation of quinoa (Chenopodium quinoa) globulins as affected by the pH value. AB - The influence of heating (100 degrees C; 0-15 min) on the relative molecular mass, protein unfolding and secondary structure of quinoa globulins was studied at pH 6.5 (low solubility), 8.5 and 10.5 (high solubility). The patterns of denaturation and aggregation varied with pH. Heating triggered the disruption of the disulfide bonds connecting the acidic and basic chains of the chenopodin subunits at pH 8.5 and 10.5, but not at pH 6.5. Large aggregates unable to enter a 4% SDS-PAGE gel were formed at pH 6.5 and 8.5, which became soluble under reducing conditions. Heating at pH 10.5 lead to a rapid dissociation of the native chenopodin and to the disruption of the subunits, but no SDS-insoluble aggregates were formed. No major changes in secondary structure occurred during a 15 min heating, but an increase in hydrophobicity indicated unfolding of the tertiary structure in all samples. PMID- 26593461 TI - Optimization of a QuEChERS based method by means of central composite design for pesticide multiresidue determination in orange juice by UHPLC-MS/MS. AB - In this study, different extraction procedures based on the QuEChERS method were compared for the multiresidue determination of pesticides in orange juice by ultra high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS). After choosing preliminary conditions, an experimental design was carried out with the variables C18, PSA, NaOH and CH3COONa to optimize the sample preparation step. The validation results of the validation were satisfactory, since the method presented recoveries between 70% and 118%, with RSD lower than 19% for spike levels between 10 and 100 MUg L(-1). The method limit of detection (LOD) and limit of quantification (LOQ) ranged from 3.0 to 7.6 MUg L(-1) and from 4.9 to 26 MUg L(-1), respectively. The method developed was adequate for the determination of 74 pesticide residues in orange juice. PMID- 26593462 TI - Influence of microwave parameters and water activity on radical generation in rice starch. AB - Radical generation in rice starch under microwave treatment as well as the related chemical bond changes were investigated by electron paramagnetic resonance (EPR) and Raman spectroscopy. Samples with water activity of 0.4 and 0.7 have been treated and analyzed. It was found that microwave power level and water content could influence the amount of radicals along with the radical components and their contribution. Raman spectra showed corresponding changes in vibrational features of chemical bonds. During storage the signal intensity started to drop after a short period of increase. Rice starch radicals were relatively stable and could exist a long time in room temperature. Through signal simulation, 3 main components were separated from the original spectra and the evolving process was investigated. The main component was the radical located on C1 position in the glucose ring. PMID- 26593463 TI - Solubilisation of myosin in a solution of low ionic strength L-histidine: Significance of the imidazole ring. AB - Myosin, a major muscle protein, can be solubilised in a low ionic strength solution containing L-histidine (His). To elucidate which chemical constituents in His are responsible for this solubilisation, we investigated the effects of 5mM His, imidazole (Imi), L-alpha-alanine (Ala), 1-methyl-L-histidine (M-his) and L-carnosine (Car) on particle properties of myosin suspensions and conformational characteristics of soluble myosin at low ionic strength (1 mM KCl, pH 7.5). His, Imi and Car, each containing an imidazole ring, were able to induce a myosin suspension, which had small particle size species and high absolute zeta potential, thus increasing the solubility of myosin. His, Imi and Car affected the tertiary structure and decreased the alpha-helix content of soluble myosin. Therefore, the imidazole ring of His appeared to be the significant chemical constituent in solubilising myosin at low ionic strength solution, presumably by affecting its secondary structure. PMID- 26593464 TI - Microwave assisted saponification (MAS) followed by on-line liquid chromatography (LC)-gas chromatography (GC) for high-throughput and high-sensitivity determination of mineral oil in different cereal-based foodstuffs. AB - A high throughput, high-sensitivity procedure, involving simultaneous microwave assisted extraction (MAS) and unsaponifiable extraction, followed by on-line liquid chromatography (LC)-gas chromatography (GC), has been optimised for rapid and efficient extraction and analytical determination of mineral oil saturated hydrocarbons (MOSH) and mineral oil aromatic hydrocarbons (MOAH) in cereal-based products of different composition. MAS has the advantage of eliminating fat before LC-GC analysis, allowing an increase in the amount of sample extract injected, and hence in sensitivity. The proposed method gave practically quantitative recoveries and good repeatability. Among the different cereal-based products analysed (dry semolina and egg pasta, bread, biscuits, and cakes), egg pasta packed in direct contact with recycled paperboard had on average the highest total MOSH level (15.9 mg kg(-1)), followed by cakes (10.4 mg kg(-1)) and bread (7.5 mg kg(-1)). About 50% of the pasta and bread samples and 20% of the biscuits and cake samples had detectable MOAH amounts. The highest concentrations were found in an egg pasta in direct contact with recycled paperboard (3.6 mg kg( 1)) and in a milk bread (3.6 mg kg(-1)). PMID- 26593465 TI - A new QRT-PCR assay designed for the differentiation between elements provided from Agrobacterium sp. in GMOs plant events and natural Agrobacterium sp. bacteria. AB - The question asked in the present work was how to differentiate between contamination of field samples with and GM plants contained sequences provided from this bacterium in order to avoid false positives in the frame of the detection and the quantification of GMO. For this, new set of primers and corresponding TaqMan Minor Groove Binder (MGB) probes were designed to target Agrobacterium sp. using the tumor-morphology-shooty gene (TMS1). Final standard curves were calculated for each pathogen by plotting the threshold cycle value against the bacterial number (log (colony forming units) per milliliter) via linear regression. The method designed was highly specific and sensitive, with a detection limit of 10CFU/ml. No significant cross-reaction was observed. Results from this study showed that TaqMan real-time PCR, is potentially an effective method for the rapid and reliable quantification of Agrobacterium sp. in samples containing GMO or non GMO samples. PMID- 26593466 TI - Encapsulation of folic acid in different silica porous supports: A comparative study. AB - Although folic acid is essential to numerous bodily functions, recent research indicates that a massive exposition to the vitamin could be a double-edged sword. In this study, the capacity of different caped mesoporous silica particles (i.e. Hollow Silica Shells, MCM-41, SBA-15 and UVM-7) to dose FA during its passage through the gastrointestinal tract has been evaluated. Results confirmed that the four capped materials were capable to hinder the delivery of FA at low pH (i.e. stomach) as well as able to deliver great amounts of the vitamin at neutral pH (i.e. intestine). Nevertheless, the encapsulation efficiency and the deliver kinetics differed among supports. While supports with large pore entrance exhibited an initial fast release, MCM-41, showed a sustained release along the time. This correlation between textural properties and release kinetics for each of the supports reveals the importance of a proper support selection as a strategy to control the delivery of active molecules. PMID- 26593467 TI - Low intramuscular fat (but high in PUFA) content in cooked cured pork ham decreased Maillard reaction volatiles and pleasing aroma attributes. AB - The influence of intramuscular fat content (high - HI versus low - LI) and fatty acid composition on pork cooked cured ham flavour was analysed by gas chromatography-olfactometry using nasal impact frequency (GC-O/NIF) and quantitative descriptive analysis (QDA). Potential relationships were studied by principal component analysis (PCA). Sixteen and fourteen odourants were identified by GC-O/NIF in LI and HI cooked hams, respectively. The two ham types differed in lipid oxidation odourants: polyunsaturated fatty acid (PUFA) derivatives hexanal, 1-octen-3-one and (E,E)-2,4-decadienal were higher in LI ham; while monounsaturated fatty acid (MUFA) derivative decanal was higher in HI. HI samples resulted in higher values for odour-active aroma compounds from Maillard reaction, which are related to roast flavour and a higher overall flavour liking. In summary, our results suggest that Maillard derived odour active aroma compounds were partially inhibited in LI samples (high in PUFA), resulting in lower positive sensory ratings. PMID- 26593468 TI - Simultaneous determination of residues of dipyrone metabolites in goat tissues by hydrophilic interaction liquid chromatography tandem mass spectrometry. AB - A reliable LC-MS/MS method with high sensitivity was developed and validated for the determination of dipyrone (DIP) metabolites in goat muscle, fat, liver, and kidney samples. Analytes were extracted using acetonitrile mixed with ammonia solution. After dehydration and evaporation to dryness, extracts were purified using an Oasis MAX cartridge. Chromatographic separation was performed on a hydrophilic interaction liquid chromatography column. The analytes were then detected using triple-quadrupole mass spectrometry in positive electrospray ionization and multiple reaction monitoring mode. Calibration plots were constructed using matrix-matched standards and showed good linearity. Limits of quantification for 4-methylaminoantipyrine (MAA), 4-formylaminoantipyrine (FAA), and 4-acetylaminoantipyrone (AAA) ranged from 0.4 MUg kg(-1) to 6 MUg kg(-1), while those for 4-aminoantipyrone (AA) ranged from 10 MUg kg(-1) to 125 MUg kg( 1) in all tissues. The developed method was successfully applied in the determination of DIP metabolite residues in actual goat tissues. PMID- 26593469 TI - Antioxidant properties of diverse cereal grains: A review on in vitro and in vivo studies. AB - Cereal grains and products have gained popularity in contributing to healthy eating behavior because of their antioxidant properties associated with protection against chronic diseases. In this review, notable studies on the in vitro and in vivo antioxidant activity of commonly consumed cereal grains are summarized. Cereals contain phytochemicals or certain minor components with antioxidant properties. The antioxidant potential of cereals depends on their bioaccessibility, absorption in the gastrointestinal and their bioavailability utilization in vivo. The in vitro gastrointestinal digestion and fermentation of cereals increased their antioxidant potentials which are significantly correlated with their total phenolic contents. Most studies performed in vivo have been concerned with the antioxidant properties of colored rice, wheat bran and rye products. There are inadequate in vitro and in vivo studies on antioxidative potentials of fermented versus unfermented cereals. Therefore, further studies are necessary to maximize possible health benefits of cereal antioxidative phytochemicals. PMID- 26593471 TI - Niosome-loaded cold-set whey protein hydrogels. AB - The alpha-tocopherol-carrying niosomes with mean diameter of 5.7 MUm were fabricated and charged into a transglutaminase-cross-linked whey protein solution that was subsequently gelled with glucono delta-lactone. Encapsulation efficiency of alpha-tocopherol within niosomes was ~80% and encapsulation did not influence the radical scavenging activity of alpha-tocopherol. Fourier transform infrared (FTIR) spectroscopy suggested formation of epsilon-(gamma-glutamyl) lysine cross linkages by transglutaminase and that enzymatic cross-linking increased proteins hydrophobicity. FTIR also proposed hydrogen bonding between niosomes and proteins. Dynamic rheometry indicated that transglutaminase cross-linking and niosomes charging of the protein solution enhanced the gelation process. However, charging the cross-linked protein solution with niosomal suspension resulted in lower elastic modulus (G') of the subsequently formed gel compared with both non cross-linked niosome-loaded and cross-linked niosome-free counterparts. Electron microscopy indicated a discontinuous network for the niosome-loaded cross-linked sample. Niosome loading into the protein gel matrix increased its swelling extent in the enzyme-free simulated gastric fluid. PMID- 26593470 TI - The use of IRMS, (1)H NMR and chemical analysis to characterise Italian and imported Tunisian olive oils. AB - Isotope Ratio Mass Spectrometry (IRMS), (1)H Nuclear Magnetic Resonance ((1)H NMR), conventional chemical analysis and chemometric elaboration were used to assess quality and to define and confirm the geographical origin of 177 Italian PDO (Protected Denomination of Origin) olive oils and 86 samples imported from Tunisia. Italian olive oils were richer in squalene and unsaturated fatty acids, whereas Tunisian olive oils showed higher delta(18)O, delta(2)H, linoleic acid, saturated fatty acids beta-sitosterol, sn-1 and 3 diglyceride values. Furthermore, all the Tunisian samples imported were of poor quality, with a K232 and/or acidity values above the limits established for extra virgin olive oils. By combining isotopic composition with (1)H NMR data using a multivariate statistical approach, a statistical model able to discriminate olive oil from Italy and those imported from Tunisia was obtained, with an optimal differentiation ability arriving at around 98%. PMID- 26593472 TI - Study on dietary fibre by Fourier transform-infrared spectroscopy and chemometric methods. AB - Fresh fruit is an important part of the diet of people all over the world as a significant source of water, vitamins and natural sugars. Nowadays it is also one of the main sources of dietary fibre. In fruit the dietary fibre is simply cell wall consisting essentially of polysaccharides. The aim of present study was to predict the contents of pectins, cellulose and hemicelluloses by partial least squares regression (PLS) analysis on the basis of Fourier transform-infrared (FT IR) spectra of fruit cell wall residue. The second purpose was to analyse the composition of dietary fibre from fruit based on FT-IR spectral information in combination with chemometric methods (principle components analysis (PCA) and hierarchical cluster analysis (HCA)). Additionally the contents of polysaccharides in studied fruits were determined by analytical methods. It has been shown that the analysis of infrared spectra and the use of multivariate statistical methods can be useful for studying the composition of dietary fibre. PMID- 26593473 TI - Effect of end of season water deficit on phenolic compounds in peanut genotypes with different levels of resistance to drought. AB - Terminal drought reduces pod yield and affected the phenolic content of leaves, stems and seed of peanut (Arachis hypogaea L.). The aim of this study was to investigate the effects of end of season water deficit on phenolic content in drought tolerant and sensitive genotypes of peanuts. Five peanut genotypes were planted under two water regimes, field capacity and 1/3 available water. Phenolic content was analyzed in seeds, leaves, and stems. The results revealed that terminal drought decreased phenolic content in seeds of both tolerant and sensitive genotypes. Phenolic content in leaves and stems increased under terminal drought stress in both years. This study provides basic information on changes in phenolic content in several parts of peanut plants when subjected to drought stress. Future studies to define the effect of terminal drought stress on specific phenolic compounds and antioxidant properties in peanut are warranted. PMID- 26593475 TI - Effects of milk type, production month, and brand on fatty acid composition: A case study in Korea. AB - The aim of this study was to examine the difference in fatty acid (FA) composition of organic and conventional milk at the retail market level in Korea for different milk production months and brands. The essential FA contents of the milk vary significantly under the combined effects of milk type, production month, and brand. Chemometric analysis reveals a greater difference between milk types than between production months and identifies significantly different levels of nutritionally desirable FAs-notably C18:3 n-3, C18:2 n-6 c and t-in the organic and conventional milks. Notwithstanding the limited sampling size and period, the results from this study may provide a better understanding of the nutritional quality of organic milk to consumers who are interested in organic milk intake. PMID- 26593474 TI - Validation of a liquid chromatography-electrospray ionization tandem mass spectrometric method to determine six polyether ionophores in raw, UHT, pasteurized and powdered milk. AB - This study aimed to validate a method developed for the determination of six antibiotics from the polyether ionophore class (lasalocid, maduramicin, monensin, narasin, salinomycin and semduramicin) at residue levels in raw, UHT, pasteurized and powdered milk using QuEChERS extraction and high performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS). The validation was conducted under an in-house laboratory protocol that is primarily based on 2002/657/EC Decision, but takes in account the variability of matrix sources. Overall recoveries between 93% and 113% with relative standard deviations up to 16% were obtained under intermediate precision conditions. CCalpha calculated values did not exceed 20% the Maximum Residue Limit for monensin and 25% the Maximum Levels for all other substances. The method showed to be simple, fast and suitable for verifying the compliance of raw and processed milk samples regarding the limits recommended by Codex Alimentarius and those adopted in European Community for polyether ionophores. PMID- 26593476 TI - Improved stability of (+)-catechin and (-)-epicatechin by complexing with hydroxypropyl-beta-cyclodextrin: Effect of pH, temperature and configuration. AB - The stability and bioavailability of catechins, a kind of tea polyphenols with health benefit, could be improved by complexing with cyclodextrins. The aim of this study was to investigate the complexation of two geometrical isomers, (+) catechin and (-)-epicatechin, with hydroxypropyl-beta-cyclodextrin (HP-beta-CD) in tris-HCl buffer solutions at pH 6.8-8.0 using isothermal titration calorimetry, fluorescence and proton nuclear magnetic resonance spectroscopy. Experimental results showed that these inclusion interactions are primarily enthalpy-driven processes. The complexation constant (KC) of EC+HP-beta-CD complex was less than that of CA+HP-beta-CD at the same temperature and pH value. Temperature and pH studies showed that the KC value decreased with the rise of temperature and pH. Stability study indicated that HP-beta-CD showed a stronger protection effect on CA than that on EC. The different inclusion modes between CA and EC were discussed in terms of the discrepancy in their molecular structures. PMID- 26593477 TI - Production of a bioactive sweetener steviolbioside via specific hydrolyzing ester linkage of stevioside with a beta-galactosidase. AB - A beta-galactosidase from Kluyveromyces lactis was found to specifically catalyze hydrolysis of the glycosyl ester linkage of stevioside to yield steviolbioside, a rare sweetener that also exists in Stevia rebaudiana leaves. In a packed bed reactor, a reaction coupling separation was realized and a production yield of steviolbioside reached 90% in 6 h. The hydrolysis product steviolbioside presented higher cytoxicity on human normal cells (hepatocytes cell L02 and intestinal epithelial cell T84) than stevioside did. Comparing to the typical chemotherapy agent, 5-fluorouracil (5-FU), steviolbioside presents much lower cytotoxicity on all assayed human normal cells; it presented notable inhibition on human hepatocarcinoma cell Hep3B, human breast cancer cell MDA-MB-231 and human pancreatic cancer cell BxPC-3. The remarkable inhibition on MDA-MB-231 cells makes steviolbioside a potential remedy for human breast cancer, when steviolbioside is served as a natural sweetener. PMID- 26593478 TI - Influence of home cooking conditions on Maillard reaction products in beef. AB - The influence of home cooking methods on the generation of Maillard reaction products (MRP) in beef was investigated. Grilling and frying hamburgers to an internal temperature below 90 degrees C mainly generated furosine. When the temperature reached 90 degrees C and 100 degrees C, furosine content decreased by 36% and fluorescent compounds increased by up to 98%. Baking meat at 300 degrees C, the most severe heat treatment studied, resulted in the formation of carboxymethyllysine. Boiling in water caused very low MRP formation. Acrylamide concentrations in grilled, fried or baked meat were extremely low. Home cooking conditions leading to low MRP generation and pleasant colours were obtained and could be used to guide diabetic and chronic renal patients on how to reduce their carboxymethyllysine intake. PMID- 26593479 TI - Determination of metrafenone in bitter gourd and soil by GC with ECD. AB - A method for determination of metrafenone residues in bitter gourd and soil was developed. All samples were extracted with ethyl acetate, purified with the glass column of florisil and NH2-SPE column, analyzed by gas chromatography with electronic capture detector (GC-ECD). The results showed that it had good linearity in the range of 0.01-2 mg/L and the correlation coefficient (r) was 0.9999. The average recoveries of metrafenone in bitter gourd and soil were 83.51 91.75% and 84.76-91.72% with the relative standard deviation of 3.48-9.18% and 4.23-7.25%, respectively. The limit of detection was estimated to be 0.005 mg/kg, the minimum concentration of detection in bitter gourd and soil was 1 * 10(-2) mg/kg. PMID- 26593480 TI - Antioxidant activities of distiller dried grains with solubles as protein films containing tea extracts and their application in the packaging of pork meat. AB - Distiller dried grains with solubles (DDGS) as protein (DP) films were prepared. Additionally, to prepare anti-oxidant films, green tea extract (GTE), oolong tea extract (OTE), and black tea extract (BTE) were incorporated into the DP films. Consequently, the incorporation of the tea extracts did not alter the physical properties of the films much, whereas the antioxidant activities, such as ABTS and DPPH radical scavenging activities were observed. To apply the DP films containing tea extracts to food packaging, pork meat was wrapped with the films and stored at 4 degrees C for 10 d. During storage, the pork meat wrapped with the DP films containing GTE, OTE, and BTE had less lipid oxidation than did the control. Among the tea extracts, the DP film containing GTE had the greatest antioxidant activity. These results indicate that the DP films containing green tea extracts can be utilized as an anti-oxidative packaging material for pork meat. PMID- 26593481 TI - Shear, heat and pH induced conformational changes of wheat gluten - Impact on antigenicity. AB - Processing can induce conformational changes of food proteins depending on the conditions used that may affect their antigenicity. This study investigated the effect of pH (3,5,7) temperature (80,90,100 degrees C) and shear (500,1000,1500 s(-1)) on the conformational changes (surface hydrophobicity, FTIR, SDS-PAGE and thiol content) of gluten in relation to its antigenicity (determined by Enzyme linked Immunosorbent Assay). Overall, at pH 3, up to 90 degrees C, conformational changes and possible burial of some antigenic hydrophobic residues resulted in reduction of antigenicity to one-third that of control. Further heating to 100 degrees C caused increase in antigenicity due to exposure of some hidden epitopes. However, at pH 5 and 7, the antigenicity declined only at 100 degrees C due to modification in thiol content and related structural changes causing destruction and/or masking of some epitopes. Shear alone had no effect on antigenicity of gluten but could have a synergistic influence at pH 7 and 100 degrees C. PMID- 26593482 TI - Redox cycling and generation of reactive oxygen species in commercial infant formulas. AB - Three nationally prominent commercial powdered infant formulas generated hydrogen peroxide, ranging from 10.46 to 11.62 MUM, when prepared according to the manufacturer's instructions. Treating infant formulas with the chelating agent diethylene triamine pentaacetic acid (DTPA) significantly reduced H2O2 generation. In contrast, the addition of disodium ethylenediaminetetraacetic acid (EDTA) elevated the level of H2O2 generated in the same infant formulas by approximately 3- to 4-fold above the untreated infant formulas. The infant formulas contained ascorbate radicals ranging from about 138 nM to 40 nM. Treatment with catalase reduced the ascorbate radical contents by as much as 67%. Treatment with DTPA further reduced ascorbate radical signals to below quantifiable levels in most samples, further implicating the involvement of transition metal redox cycling in reactive oxygen species (ROS) formation. Supportive evidence of the generation of ROS is provided using luminol-enhanced luminescence (LEL) in both model mixtures of ascorbic acid and in commercial infant formulas. PMID- 26593483 TI - Chemical data as markers of the geographical origins of sugarcane spirits. AB - In an attempt to classify sugarcane spirits according to their geographic region of origin, chemical data for 24 analytes were evaluated in 50 cachacas produced using a similar procedure in selected regions of Brazil: Sao Paulo - SP (15), Minas Gerais - MG (11), Rio de Janeiro - RJ (11), Paraiba -PB (9), and Ceara - CE (4). Multivariate analysis was applied to the analytical results, and the predictive abilities of different classification methods were evaluated. Principal component analysis identified five groups, and chemical similarities were observed between MG and SP samples and between RJ and PB samples. CE samples presented a distinct chemical profile. Among the samples, partial linear square discriminant analysis (PLS-DA) classified 50.2% of the samples correctly, K nearest neighbor (KNN) 86%, and soft independent modeling of class analogy (SIMCA) 56.2%. Therefore, in this proof of concept demonstration, the proposed approach based on chemical data satisfactorily predicted the cachacas' geographic origins. PMID- 26593484 TI - In vivo effects of Maillard reaction products derived from biscuits. AB - The antioxidant activity, antihypertensive effect and prebiotic activity of Maillard reaction products (MRPs) derived from biscuits were investigated in Wistar rats. Animals were fed the following diets for 6 weeks: control (AIN-93 diet); Asc-diet (AIN-93 diet with ascorbic acid in the drinking water); HT-B diet (containing high amount of MRP derived from biscuits) and LT-B diet (containing negligible amounts of biscuit MRP). Serum antioxidant activity (FRAP, ABTS), as well as lipid peroxidation (TBARS) were determined at the end of the experiment. Results showed that dietary MRP reduced the food efficiency, increased the antioxidant activity of serum, increased the ratio between lactic and total aerobic bacteria, increased water-holding capacity of faeces and reduced blood pressure, but did not reduce mineral absorption. Therefore, the biscuit MRP functional claims could be demonstrated by an in vivo study. PMID- 26593485 TI - Measurement of phthalates diesters in food using gas chromatography-tandem mass spectrometry. AB - An analytical strategy dedicated to 4 major phthalate diesters (DiBP, DnBP, BBzP and DEHP) monitoring in food items has been developed and validated according to normalized guidelines. The method has been applied to a wide range of foodstuffs (n=54) to generate first-ever occurrence data at the French level. This method involves separation and detection using gas chromatography coupled to tandem mass spectrometry, in electron ionisation with highly specific selected reaction monitoring, quantification being performed according to the isotope dilution principle. A particular attention has been paid to background contamination management at any stage of the analytical process, from the sampling to the expression of the results. Limits of reporting, defined as statistically different from background contamination, were found to be 2.7, 0.53, 0.18 and 3.4 MUg kg(-1), and relative combined uncertainties were finally found to be 7.6%, 12.2%, 12.0% and 14.1%, for DiBP, DnBP, BBzP and DEHP, respectively. PMID- 26593486 TI - Pigment and color stability of beetroot betalains in cow milk during thermal treatment. AB - Thermal stability of beetroot betalains in cow milk was determined during heating at 70-90 degrees C. Changes in color values of colored milk were also investigated. Degradation of betalains followed first order kinetics while changes of L(*), Hue angle and Chroma values fitted zero order and first order kinetic, respectively. Reaction rate for degradation of betalains, L(*), Hue angle and Chroma values ranged between 1.588-30.975 * 10(-3) min(-1), 90.50 379.75 L(*)min(-1), 0.581-5.008 Hue anglemin(-1) and 3.250-19.750 * 10(-3) min( 1), respectively. Between 70 and 90 degrees C, activation energy for the degradation of betalains was 42.449 kJ mol(-1). L(*) values was more stable than Hue angle and Chroma color values in colored milk during heating. 74.150 kJ mol( 1), 111.174 kJ mol(-1) and 93.311 kJ mol(-1) of activation energy values were found for L(*), Hue angle and Chroma values of milk, respectively. Significant positive and negative linear correlations were determined between betalains and color values. Multiple regression models were also established to predict the content of betalains in milk during thermal process by using color values. PMID- 26593487 TI - Growth temperature affects sensory quality and contents of glucosinolates, vitamin C and sugars in swede roots (Brassica napus L. ssp. rapifera Metzg.). AB - Swede is a root vegetable grown under a range of growth conditions that may influence the product quality. The objective of this controlled climate study was to find the effect of growth temperature on sensory quality and the contents of glucosinolates, vitamin C and soluble sugars. High temperature (21 degrees C) enhanced the intensities of sensory attributes like pungent odour, bitterness, astringency and fibrousness, while low temperature (9 degrees C) was associated with acidic odour, sweet taste, crispiness and juiciness. Ten glucosinolates were quantified, with progoitrin as the dominant component followed by glucoberteroin, both with highest content at 21 degrees C. Vitamin C also had its highest content at 21 degrees C, while the total sugar content was lowest at this temperature. In conclusion, the study demonstrated clear effects of growth temperature on sensory quality and some chemical properties of swede and indicated a good eating quality of swedes grown at low temperatures. PMID- 26593488 TI - Comparative analysis of chemical compositions between non-transgenic soybean seeds and those from plants over-expressing AtJMT, the gene for jasmonic acid carboxyl methyltransferase. AB - Transgenic overexpression of the Arabidopsis gene for jasmonic acid carboxyl methyltransferase (AtJMT) is involved in regulating jasmonate-related plant responses. To examine its role in the compositional profile of soybean (Glycine max), we compared the seeds from field-grown plants that over-express AtJMT with those of the non-transgenic, wild-type (WT) counterpart. Our analysis of chemical compositions included proximates, amino acids, fatty acids, isoflavones, and antinutrients. Overexpression of AtJMT in the seeds resulted in decreased amounts of tryptophan, palmitic acid, linolenic acid, and stachyose, but increased levels of gadoleic acid and genistein. In particular, seeds from the transgenic soybeans contained 120.0-130.5% more genistein and 60.5-82.1% less stachyose than the WT. A separate evaluation of ingredient values showed that all were within the reference ranges reported for commercially available soybeans, thereby demonstrating the substantial equivalence of these transgenic and non-transgenic seeds. PMID- 26593489 TI - Monoterpenes: Novel insights into their biological effects and roles on glucose uptake and lipid metabolism in 3T3-L1 adipocytes. AB - Various strategies have been adopted to combat complications caused by Type 2 diabetes mellitus and controlled diet is one of them. Monoterpenes, major constituents of essential oils, are synthesized and widely used as artificial food flavors. A series of twelve monoterpenes were assessed in the present study. Monoterpenes, exhibited low 2,2-diphenyl-2-picrylhydrazyl hydrate (DPPH) and 2,2' azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging activity even at high concentrations. Some monoterpenes inhibited alpha-amylase and alpha-glucosidase activity and stimulated glucose uptake and lipolysis. Monoterpenes such as (R)-(+)-limonene stimulated both glucose uptake (17.4%) and lipolysis (17.7%); the mRNA expression of glucose transporter 1 (GLUT1) was upregulated but glucose transporter 4 (GLUT4) was unaffected, and adipose triglyceride lipase (ATGL) was suppressed. Taken together, the selected monoterpenes may not confer strong protection against free radicals but nevertheless, their positive influence on lipid and glucose metabolism may have potential in the control of obesity and Type 2 diabetes mellitus. PMID- 26593490 TI - In vitro fermentation of jucara pulp (Euterpe edulis) by human colonic microbiota. AB - This study was carried out to investigate the potential fermentation properties of jucara pulp, using pH-controlled anaerobic batch cultures reflective of the distal region of the human large intestine. Effects upon major groups of the microbiota were monitored over 24h incubations by fluorescence in situ hybridisation (FISH). Short-chain fatty acids (SCFA) were measured by HPLC. Phenolic compounds, during an in vitro simulated digestion and fermentation, were also analysed. Jucara pulp can modulate the intestinal microbiota in vitro, promoting changes in the relevant microbial populations and shifts in the production of SCFA. Fermentation of jucara pulp resulted in a significant increase in numbers of bifidobacteria after a 24h fermentation compared to a negative control. After in vitro digestion, 46% of total phenolic content still remained. This is the first study reporting the potential prebiotic effect of jucara pulp; however, human studies are necessary to prove its efficacy. PMID- 26593491 TI - Germinated brown rice and its bio-functional compounds. AB - Brown rice (BR) contains bran layers and embryo, where a variety of nutritional and biofunctional components, such as dietary fibers, gamma-oryzanol, vitamins, and minerals, exist. However, BR is consumed less than white rice because it has an inferior eating texture when cooked. Germination is one of the techniques used to improve the texture of the cooked BR. In addition, it induces numerous changes in the composition and chemical structure of the bioactive components. Moreover, many studies reported that the germination could induce the formation of new bioactive compounds, such as gamma-aminobutyric acid (GABA). The consumption of germinated brown rice (GBR) is increasing in many Asian countries because of its improved eating quality and potential health-promoting functions. However, there is still a lack of studies on the compositional and functional changes of the bioactive components during germination. This review contains recent research findings, especially on the bioactive components in GBR. PMID- 26593492 TI - Adaptation of Volvariella volvacea metabolism in high carbon to nitrogen ratio media. AB - Increasing glucose concentration (up to 46%) in the culture medium of Volvariella volvacea resulted in a noticeable biomass increase (63.82%) and intracellular polysaccharide (IPS) production (32.84% in absolute and 51.34% in relative values). In high glucose concentrations, decreased biomass yields on glucose consumed were recorded. A non-negligible lipid was synthesized (up to 32.22%, w/w) in the first growth steps. Lipids and IPS were decreased as fermentation proceeded. Fatty acid composition of lipids was not remarkably affected by the C/N ratio imposed, whereas the concentration of neutral lipids increased in the high C/N ratio media. Phospholipid was the richest in saturated fatty acids lipid fraction. The major phospholipid classes, i.e. phosphatidyl-choline and phosphatidyl-inositol, were differentially affected by the high glucose concentrations, as the former increased its proportion and the latter decreased. Linoleic was the predominate fatty acid. C/N ratio and fermentation time affected IPS composition, as glucose increased in a high C/N ratio, while fructose and mannitol decreased. PMID- 26593493 TI - Bioactivity and nutritional properties of hardy kiwi fruit Actinidia arguta in comparison with Actinidia deliciosa 'Hayward' and Actinidia eriantha 'Bidan'. AB - The aim of this research is to identify and compare the bioactive compounds, antioxidant capacities and binding potentials to human protein in different varieties of hardy kiwi (Actinidia (A.) arguta), 'Hayward' (Actinidia deliciosa) and less - known 'Bidan' (Actinidia eriantha). Polyphenols, flavonoids, flavanols, tannins, vitamin C, lutein, zeaxanthin and dietary fibers were significantly higher in cultivar 'M1' among the A. arguta than in 'Hayward'. The binding properties of studied kiwi fruits were determined by interaction of polyphenols with human serum albumin (HSA). An internal standard FTIR technique allowed the quantitative comparison of specific IR absorption bands (Amides I, II, III) of different kiwi fruit samples after interaction with HSA. It was shown that the antioxidant and binding capacities and FTIR quantitative estimations of A. arguta fruits were significantly higher than in 'Hayward', but lower than the 'Bidan'. In MS spectra were found some slight differences in A. arguta kiwis in comparison with 'Hayward' and 'Bidan'. Two A. arguta cultivars were similar to 'Bidan'. The interaction of polyphenols with HSA, evaluated by fluorometry/FTIR, made it possible to compare the bioactivity of different cultivars and families. In conclusion, for the first time fruits A. arguta, cultivated in Poland, were compared with widely consumed kiwi fruits, using advanced analytical methods. The high bioactivity and nutritional value of A. arguta fruits from Polish ecological plantation enables us to recommend them for marketing and consumption. PMID- 26593494 TI - Novel analytical procedure using a combination of hollow fiber supported liquid membrane and dispersive liquid-liquid microextraction for the determination of aflatoxins in soybean juice by high performance liquid chromatography - Fluorescence detector. AB - This study describes a combination between hollow fiber membrane and dispersive liquid-liquid microextraction for determination of aflatoxins in soybean juice by HPLC. The main advantage of this approach is the use of non-chlorinated solvent and small amounts of organic solvents. The optimum extraction conditions were 1 octanol as immobilized solvent; toluene and acetone at 1:5 ratio as extraction and disperser solvents (100 MUL), NaCl at 2% of the sample volume and extraction time of 60 min. The optimal condition for the liquid desorption was 150 MUL acetonitrile:water (50:50 v/v) and desorption time of 20 min. The linear range varied from 0.03 to 21 MUg L(-1), with R(2) coefficients ranging from 0.9940 to 0.9995. The limits of detection and quantification ranged from 0.01 MUg L(-1) to 0.03 MUg L(-1) and from 0.03 MUg L(-1) to 0.1 MUg L(-1), respectively. Recovery tests ranged from 72% to 117% and accuracy between 12% and 18%. PMID- 26593495 TI - Generation of reactive oxidative species from thermal treatment of sugar solutions. AB - Sugars, prominently fructose, have been shown to accelerate the degradation of food components during thermal treatment. Yet, the mechanism by which this occurs is not well understood. Fructose and glucose have been reported to undergo autoxidation to generate reactive oxidative species (ROS) under physiological conditions; however, information on ROS generation during thermal treatment is limited. We observed that hydrogen peroxide was generated during thermal treatment (up to 70 degrees C) of aqueous solutions of fructose and glucose (up to 10% w/v), with significantly higher concentrations observed in fructose solutions. The rate of generation of hydrogen peroxide increased with temperature, pH, oxygen concentration and the presence of phosphate buffer. Singlet oxygen was also detected in fructose and glucose solutions prepared in phosphate buffer. Results of this study indicated that fructose and glucose undergo oxidation during thermal treatment resulting in generation of ROS that may have deleterious effects on food components. PMID- 26593496 TI - Honey: Chemical composition, stability and authenticity. AB - The aim of this review is to describe the chemical characteristics of compounds present in honey, their stability when heated or stored for long periods of time and the parameters of identity and quality. Therefore, the chemical characteristics of these compounds were examined, such as sugars, proteins, amino acids, enzymes, organic acids, vitamins, minerals, phenolic and volatile compounds present in honey. The stability of these compounds in relation to the chemical reactions that occur by heating or prolonged storage were also discussed, with increased understanding of the behavior regarding the common processing of honey that may compromise its quality. In addition, the identity and quality standards were described, such as sugars, moisture, acidity, ash and electrical conductivity, color, 5-HMF and diastase activity, along with the minimum and maximum limits established by the Codex Alimentarius. PMID- 26593497 TI - An inclusion complex of eugenol into beta-cyclodextrin: Preparation, and physicochemical and antifungal characterization. AB - The inclusion of eugenol (EG) into beta-cyclodextrin (betaCD), its structural characterization and antifungal activity, and mode of action for control of Peronophythora litchii in postharvest fresh litchi fruits is described. Nuclear magnetic resonance spectra revealed chemical shifts in H-3 and H-5 protons of betaCD, indicating EG inclusion into the lipophilic cavity of betaCD. In vitro assays showed betaCD-EG significantly inhibited P. litchii colony growth in a concentration- and time-dependent manner (MIC100=0.2g). In vivo assays showed betaCD-EG significantly (p<0.05) reduced the decay index of treated fresh litchi fruits. After exposure to betaCD-EG, the surface of P. litchii hyphae and/or sporangiophores became wrinkled, with folds and breakage observed by scanning electron microscopy. Damage to hyphal and/or sporangiophore cell walls and membrane structures post-treatment with betaCD-EG was confirmed by transmission electron microscopy. Therefore, betaCD-EG shows great potential as a controlled release agent against P. litchii. PMID- 26593498 TI - Evaluation of inorganic elements in cat's claw teas using ICP OES and GF AAS. AB - The determination of Ba, Ca, Cu, Fe, Mg, Mn, P, Pb, and Zn by inductively coupled plasma optical emission spectrometry (ICP OES), and Se by graphite furnace atomic absorption spectrometry (GF AAS), has been carried out in dry matter and teas from 11 samples of the cat's claw plant. The accuracy and precision values were verified against GBW 07604 (Poplar leaves) certified reference material and by the recovery test. Results showed a high content of Ca in the medicinal plant studied, followed by Mg and P. The values obtained showed that the elements studied have different concentrations depending on the method of tea preparation. The highest levels were observed in Ca and Mg, and the lowest for Se and Pb, by both infusion and decoction. Teas prepared from this plant were found to be at safe levels for human consumption, and may be suitable as sources of these elements in the human diet. PMID- 26593499 TI - Physicochemical properties of beta-carotene emulsions stabilized by chlorogenic acid-lactoferrin-glucose/polydextrose conjugates. AB - In this study, the influence of chlorogenic acid (CA)-lactoferrin (LF)-glucose (Glc) conjugate and CA-LF-polydextrose (PD) conjugate on the physicochemical characteristics of beta-carotene emulsions was investigated. Novel emulsifiers were formed during Maillard reaction between CA-LF conjugate and Glc/PD. The physicochemical properties of beta-carotene emulsions were characterized by droplet size, zeta-potential, rheological behavior, transmission changes during centrifugal sedimentation and beta-carotene degradation. Results showed that the covalent attachment of Glc or PD to CA-LF conjugate effectively increased the hydrophilicity of the oil droplets surfaces and strengthened the steric repulsion between the oil droplets. Glucose was better than polydextrose for the conjugation with CA-LF conjugate to stabilize beta-carotene emulsions. In comparison with LF and CA-LF-Glc/PD mixtures, CA-LF-Glc/PD ternary conjugates exhibited better emulsifying properties and improved physical stability of beta carotene emulsions during the freeze-thaw treatment. In addition, CA-LF-Glc/PD conjugates significantly enhanced chemical stability of beta-carotene in the emulsions against ultraviolet light exposure. PMID- 26593500 TI - Differential behaviors of tea catechins under thermal processing: Formation of non-enzymatic oligomers. AB - Tea catechins as a member of flavan-3-ols subclass with the same skeleton may behave differentially. This study investigated the chemical conversions of 8 catechins under heat treatment with the involvement of epimerization, hydrolysis and oxidation/condensation reactions. Three reactions were enhanced as temperature increased from 30 degrees C to 90 degrees C. The epimerization of non-gallated catechins was favored by epi-configuration but hindered by pyrogallol moiety, and the hydrolysis reaction of gallated catechins was facilitated by pyrogallol moiety. Epicatechin and epigallocatechin had the lowest thermostabilities due to epimerization and oxidation/condensation reactions respectively. Sufficient O2 was not a precondition for the occurrence of chemical conversions of catechins under heat treatment. Non-enzymatic oligomerization occurred to epi type catechins and catechin under heat treatment, and dehydrodicatechins A were mainly responsible for the browning of epicatechin and catechin solutions. The evidence of generation of catechin oligomers provides a novel way to explain sensory change of tea and relevant products during thermal processing. PMID- 26593501 TI - Effect of roasting time of buckwheat groats on the formation of Maillard reaction products and antioxidant capacity. AB - Changes in the formation of Maillard reaction products and antioxidant capacity of buckwheat, induced by roasting at 160 degrees C for 30, 40 and 50 min, were evaluated in the study. Furozine, was detected after roasting, in all buckwheat samples. Increase of FIC, the presence of significant amounts of CML and enhanced browning were observed, along with increasing times of roasting. The formation of acrylamide in the obtained buckwheat products was also significantly connected with the time of roasting. A significant degradation was observed in natural antioxidants, as affected by heat treatment time. The colour parameter changed significantly with the increasing of roasting time. Overall, 30min of roasting was beneficial from a nutritional point of view for the obtained buckwheat product. PMID- 26593502 TI - Proteolysis in goat "coalho" cheese supplemented with probiotic lactic acid bacteria. AB - This study aimed to analyse the proteolytic effects of adding isolated and combined probiotic strains to goat "coalho" cheese. The cheeses were: QS - with culture Start, composed by Lactococcus lactis subsp. lactis and L. lactis subsp. cremoris (R704); QLA - with Lactobacillus acidophilus (LA-5); QLP - with Lactobacillus paracasei subsp. paracasei (L. casei 01); QB - with Bifidobacterium animalis subsp. lactis (BB 12); and QC, co-culture with the three probiotic microorganisms. The cheeses were analysed during 28 days of storage at 10 degrees C. The probiotic cell count was higher than 6.5 and 7 log colony-forming units (CFU) g(-1) of cheese at the 1st and 28th days of storage, respectively. The addition of co-culture influenced (p<0.01) proteolysis in the cheese and resulted in a higher content of soluble protein and release of amino acids at the 1st day after processing. However, over all 28 days, the cheese supplemented with Bifidobacterium lactis in its isolated form showed the highest proteolytic activity, particularly in the hydrolysis of the alpha-s2 and kappa-casein fractions. PMID- 26593503 TI - Vitamin E analysis by ultra-performance convergence chromatography and structural elucidation of novel alpha-tocodienol by high-resolution mass spectrometry. AB - We have developed a method for analysing vitamin E using ultra-performance convergence chromatography with a chromatographic runtime of 5.5 min. A well resolved chromatogram with excellent precision in retention time revealed seven vitamin E components in the palm oil derived tocotrienol-rich fraction. The major vitamin E components were alpha-tocopherol, alpha-tocotrienol, gamma-tocotrienol and delta-tocotrienol whereas the minor vitamin E components were alpha tocomonoenol, beta-tocotrienol and an unreported trace component. The new component was positively identified by high-resolution mass spectrometry as 2 methyl-2(4',8',12'-trimethyltrideca-7',11'-dienyl)5,7,8-trimethylchroman-6-ol or alpha-tocodienol. PMID- 26593504 TI - Modulation of flavanone and furocoumarin levels in grapefruits (Citrus paradisi Macfad.) by production and storage conditions. AB - Grapefruits grown under organic or conventional systems were analyzed for 6,7 dihydroxybergamottin (DHB) and flavanones using HPLC, and DPPH activity and ORAC using a micro-plate reader. Grapefruits harvested in November 2008 (E-1) and February 2010 (E-2) were stored at room temperature (RT) and 9 degrees C for four weeks. Higher levels of DHB were observed in conventional grapefruits during the second (4.7 +/- 0.2 MUg/g), third (1.5 +/- 0.2 MUg/g) and fourth (2.5 +/- 0.2 MUg/g) week of storage at room temperature in E2. Among flavonoids analyzed, narirutin (666.7 +/- 33.9 MUg/g), neohesperidin (17.5 +/- 1.3 MUg/g), didymin (75.5 +/- 5.6 MUg/g) and poncirin (130.8 +/- 10.4 MUg/g) levels were significantly higher (P?0.05) in organic grapefruits over conventional grapefruits at harvest and storage in E-1. Although DPPH levels were moderately correlated with grapefruit flavanone content, variability in the individual flavanone activity was pronounced, resulting in non-significant differences in antioxidant activity between organic and conventional grapefruits. PMID- 26593505 TI - Pyridine-grafted chitosan derivative as an antifungal agent. AB - Pyridine moieties were introduced into chitosan by nucleophilic substitution to afford N-(1-carboxybutyl-4-pyridinium) chitosan chloride (pyridine chitosan). The resulting chitosan derivative was well characterized, and its antifungal activity was examined, based on the inhibition of mycelial growth and spore germination. The results indicated that pyridine chitosan exhibited enhanced antifungal activity by comparison with pristine chitosan. The values of the minimum inhibitory concentration and the minimal fungicidal concentration of pyridine chitosan against Fulvia fulva were 0.13 mg/ml and 1 mg/ml, respectively, while the corresponding values against Botrytis cinerea were 0.13 mg/ml and 4 mg/ml, respectively. Severe morphological changes of pyridine chitosan-treated B. cinerea were observed, indicative that pyridine chitosan could damage and deform the structure of fungal hyphae and subsequently inhibit strain growth. Non toxicity of pyridine chitosan was demonstrated by an acute toxicity study. These results are beneficial for assessing the potential utilization of this chitosan derivative and for exploring new functional antifungal agents with chitosan in the food industry. PMID- 26593506 TI - Evaluation of protein structural changes and water mobility in chicken liver paste batters prepared with plant oil substituting pork back-fat combined with pre-emulsification. AB - Protein structural changes and water mobility properties in chicken liver paste batters prepared with plant oil (sunflower and canola oil combinations) substituting 0-40% pork back-fat combined with pre-emulsification were studied by Raman spectroscopy and low-field nuclear magnetic resonance (NMR). Results showed that pre-emulsifying back-fat and plant oil, including substituting higher than 20% back-fat with plant oil increased the water- and fat-binding (p<0.05) properties, formed more even and fine microstructures, and gradually decreased the NMR relaxation times (T21a, T21b and T22), which was related to the lower fluid losses in chicken liver paste batters. Raman spectroscopy revealed that compared with a control, there was a decrease (p<0.05) in alpha-helix content accompanied by an increase (p<0.05) in beta-sheet structure when substituting 20 40% back-fat with plant oil combined with pre-emulsification. Pre-emulsification and plant oil substitution changed tryptophan and tyrosine doublet hydrophobic residues in chicken liver paste batters. PMID- 26593507 TI - Environmental stress stability of microencapsules based on liposomes decorated with chitosan and sodium alginate. AB - In this study, liposomes (LPs), chitosan (CH) coated LPs, sodium alginate (AL) and CH multilayered LPs (AL-CH-LPs) were developed based on the electrostatic interaction between charged polysaccharides at a certain pH. The increase of polymer layers on LPs led to a monotonic increase in size from ~600 (LPs) to ~1810 nm (AL-CH-LPs) and negative charge from -12.5 to -25.2 mV, regarded as a consequence of the formation of gradually expanded structures by cationic CH and anionic AL. The environmental stress including pH, storage and ionic strength (10 200 mM NaCl) had significant impact on the appearance and the particle size of the double-layered liposome (AL-CH-LPs). Furthermore, LPs showed the highest release rate of hydrophilic model ingredient (vitamin C) under gastrointestinal conditions, while the polymers had a capacity to reduce the vitamin C release in simulated intestinal fluid. This work provided useful information on the potential application of CH and AL based delivery systems. PMID- 26593508 TI - Chronocoulometry of wine on multi-walled carbon nanotube modified electrode: Antioxidant capacity assay. AB - Phenolic antioxidants of wine were electrochemically oxidized on multi-walled carbon nanotubes modified glassy carbon electrode (MWNT/GCE) in phosphate buffer solution. Three oxidation peaks were observed at 0.39, 0.61 and 0.83V for red dry wine and 0.39, 0.80 and 1.18 V for white dry wine, respectively, using differential pulse voltammetry at pH 4.0. The oxidation potentials for individual phenolic antioxidants confirmed the integral nature of the analytical signals for the wines examined. A one-step chronocoulometric method at 0.83 and 1.18 V for red and white wines, respectively, has been developed for the evaluation of wine antioxidant capacity (AOC). The AOC is expressed in gallic acid equivalents per 1L of wine. The AOC of white wine was significantly less than red wine (386 +/- 112 vs. 1224 +/- 184, p<0.0001), as might be expected. Positive correlations were observed between gallic acid equivalent AOC of wine and total antioxidant capacity, based on coulometric titration with electrogenerated bromine (r=0.8957 at n=5 and r=0.8986 at n=4 for red and white wines, respectively). PMID- 26593509 TI - Simultaneous imaging of fat crystallinity and crystal polymorphic types by Raman microspectroscopy. AB - The crystalline states of fats, i.e., the crystallinity and crystal polymorphic types, strongly influence their physical properties in fat-based foods. Imaging of fat crystalline states has thus been a subject of abiding interest, but conventional techniques cannot image crystallinity and polymorphic types all at once. This article demonstrates a new technique using Raman microspectroscopy for simultaneously imaging the crystallinity and polymorphic types of fats. The crystallinity and beta' crystal polymorph, which contribute to the hardness of fat-based food products, were quantitatively visualized in a model fat (porcine adipose tissue) by analyzing several key Raman bands. The emergence of the beta crystal polymorph, which generally results in food product deterioration, was successfully imaged by analyzing the whole fingerprint regions of Raman spectra using multivariate curve resolution alternating least squares analysis. The results demonstrate that the crystalline states of fats can be nondestructively visualized and analyzed at the molecular level, in situ, without laborious sample pretreatments. PMID- 26593510 TI - Boosting effect of ortho-propenyl substituent on the antioxidant activity of natural phenols. AB - Seven new antioxidants derived from natural or synthetic phenols have been designed as alternatives to BHT and BHA antioxidants. Influence of various substituents at the ortho, meta and para positions of the aromatic core of phenols on the bond dissociation enthalpy of the ArO-H bond was evaluated using a DFT method B3LYP/6-311++G(2d,2p)//B3LYP/6-311G(d,p). This prediction highlighted the ortho-propenyl group as the best substituent to decrease the bond dissociation enthalpy (BDE) value. The rate constants of hydrogen transfer from these phenols to DPPH radical in a non-polar and non-protic solvent have been measured and were found to be in agreement with the BDE calculations. For o propenyl derivatives from 2-tert-butyl-4-methylphenol, BHA, creosol, isoeugenol and di-o-propenyl p-cresol, fewer radicals were trapped by a single phenol molecule, i.e. a lower stoichiometric number. Reaction mechanisms involving the evolution of the primary phenoxyl radical ArO are proposed to rationalise these effects. PMID- 26593511 TI - Fabric phase sorptive extraction for the fast isolation of sulfonamides residues from raw milk followed by high performance liquid chromatography with ultraviolet detection. AB - Fabric phase sorptive extraction (FPSE) is a novel sample preparation technique which utilizes advanced material properties of sol-gel derived microextraction sorbents and the hydrophilic property of the cellulose fabric substrate, resulting in a highly sensitive and fast microextraction device, capable of extracting target analyte(s) from any complex aqueous sample matrices. Due to the low organic solvent consumption, FPSE meets all green analytical chemistry (GAC) criteria. This technique was applied, for the first time, for the determination of sulfonamides residues in milk using a highly polar sol-gel poly(ethylene glycol) (sol-gel PEG) coated FPSE media. The developed HPLC method was validated according to the European Union Decision 2002/657/EC. Decision limit (CCalpha) values were 116.5 MUg kg(-1) for sulfamethazine, 114.4 MUg kg(-1) for sulfisoxazole and 94.7 MUg kg(-1) for sulfadimethoxine, whereas the corresponding results for detection capability (CCbeta) were 120.4 MUg kg(-1) for sulfamethazine, 118.5 MUg kg(-1) for sulfisoxazole and 104.1 MUg kg(-1) for sulfadimethoxine. PMID- 26593512 TI - The use of label-free mass spectrometry for relative quantification of sarcoplasmic proteins during the processing of dry-cured ham. AB - The aim of this work was to quantify changes in the abundance of the major sarcoplasmic proteins throughout the ham dry-curing process by using a label-free mass spectrometry methodology based on the measurement of mass spectral peak intensities obtained from the extracted ion chromatogram. For this purpose, extraction of sarcoplasmic proteins was followed by trypsin digestion and analysis by nanoliquid chromatography coupled to tandem mass spectrometry (Q/TOF) for the identification and relative quantification of sarcoplasmic proteins through individual quantification of trypsinised peptides. In total, 20 proteins, including 12 glycolytic enzymes, were identified and quantified. The accuracy of the protocol was based on MS/MS replicates, and beta-lactoglobulin protein was used to normalise data and correct possible variations during sample preparation or LC-MS/MS analysis. Mass spectrometry-based proteomics provides precise identification and quantification of proteins in comparison with traditional methodologies based on gel electrophoresis, especially in the case of overlapping proteins. Moreover, the label-free approach used in this study proved to be a simple, fast, reliable method for evaluating proteolytic degradation of sarcoplasmic proteins during the processing of dry-cured ham. PMID- 26593513 TI - Fungal diversity and natural occurrence of deoxynivalenol and zearalenone in freshly harvested wheat grains from Brazil. AB - This study investigated the fungal diversity and presence of deoxynivalenol and zearalenone in 150 samples of freshly harvested wheat grains collected in three regions of Brazil (Sao Paulo, Parana, and Rio Grande do Sul). Analysis of the mycobiota showed a predominance of Alternaria sp., Fusarium sp. and Epicoccum sp. Microdochium nivale (23%), a fungus rarely found in Brazilian crops, was detected in Sao Paulo. Four members of the Fusarium graminearum species complex were isolated: F. graminearum s.s. (37%), Fusarium meridionale (46%), Fusarium cortaderiae (13%), and Fusarium austroamericanum (3%). Toxin analysis revealed 99% contamination with deoxynivalenol (mean 706 MUg/kg). The frequency of zearalenone varied greatly across regions: wheat grains from Rio Grande do Sul (84%) and Sao Paulo (12%) had median concentrations of 70.9 and 57.9 MUg/kg, respectively. ZEA was not detected in the samples from Parana. A total of six samples were above the maximum tolerated level recommended by the European Commission for ZEA in wheat grains. This study provided new insights into the natural mycobiota of Brazilian wheat, demonstrating contamination of most samples with deoxynivalenol and high frequency of zearalenone in samples from Rio Grande do Sul. PMID- 26593514 TI - Unsaturated lipid matrices protect plant sterols from degradation during heating treatment. AB - The interest in plant sterols enriched foods has recently enhanced due to their healthy properties. The influence of the unsaturation degree of different fatty acids methyl esters (FAME: stearate, oleate, linoletate and linolenate) on a mixture of three plant sterols (PS: campesterol, stigmasterol and beta sitosterol) was evaluated at 180 degrees C for up to 180 min. Sterols degraded slower in the presence of unsaturated FAME. Both PS and FAME degradation fit a first order kinetic model (R(2)>0.9). Maximum oxysterols concentrations were achieved at 20 min in neat PS and 120 min in lipid mixtures and this maximum amount decreased with increasing their unsaturation degree. In conclusion, the presence of FAME delayed PS degradation and postponed oxysterols formation. This protective effect was further promoted by increasing the unsaturation degree of FAME. This evidence could help industries to optimize the formulation of sterol enriched products, so that they could maintain their healthy properties during cooking or processing. PMID- 26593515 TI - Allergen composition analysis and allergenicity assessment of Chinese peanut cultivars. AB - Peanut (Arachis hypogaea) is among the eight major food allergens in the world. Several attempts have been made to decrease or eliminate the allergenicity of peanut. Systemic screening of thousands of peanut cultivars may identify peanut with low allergenicity. In this study, the allergen compositions of 53 Chinese peanut cultivars were characterized, and their allergenicity to sera IgE of Chinese patients and in a mouse model was assessed. Contents of total protein and allergens were quantified by SDS-PAGE and densitometry analysis on gel. Although the contents of allergens broadly varied among cultivars, they were related to one another. The IgE binding capacity of cultivars was tested by ELISA, and their allergenicity was further evaluated in a mouse model by oral sensitization. Results showed that the allergenicity of peanut was affected by allergen composition rather than a single allergen. Peanut cultivars with low allergenicity may contain more Ara h 3/4 (24 kDa), Ara h 2 and less Ara h 3/4 (43, 38, and 36 kDa), Ara h 6. Screening based on allergen composition would facilitate the identification of low-allergenic peanut. PMID- 26593516 TI - Effect of resveratrol or ascorbic acid on the stability of alpha-tocopherol in O/W emulsions stabilized by whey protein isolate: Simultaneous encapsulation of the vitamin and the protective antioxidant. AB - Food proteins have been widely used as carrier materials due to their multiple functional properties. Hydrophobic bioactives are generally dissolved in the oil phase of O/W emulsions. Ligand-binding properties provide the possibility of binding bioactives to the protein membrane of oil droplets. In this study, the influence of whey protein isolate (WPI) concentration and amphiphilic resveratrol or hydrophilic ascorbic acid on the decomposition of alpha-tocopherol in the oil phase of WPI emulsions is considered. Impact of ascorbic acid, in the continuous phase, on the decomposition depended on the vitamin concentration. Resveratrol partitioned into the oil-water interface and the cis-isomer contributed most of the protective effect of this polyphenol. About 94% of alpha-tocopherol and 50% of resveratrol were found in the oil droplets stabilized by 0.01% WPI. These results suggest the feasibility of using the emulsifying and ligand-binding properties of WPI to produce carriers for simultaneous encapsulation of bioactives with different physicochemical properties. PMID- 26593517 TI - Impact of pH, freeze-thaw and thermal sterilization on physicochemical stability of walnut beverage emulsion. AB - The effects of environment stresses on the stability of walnut emulsion were investigated. The physical stability of walnut emulsion was characterized by droplet size, zeta potential and chemical stability of walnut oil in the emulsion was evaluated by determining the peroxide concentration during the storage. The results showed that emulsion in the presence of xanthan gum and mixed emulsifiers exhibited better stability after 4 freeze-thaw cycles. At pH 3-10, the mixed emulsifiers could improve the stability through their absorption on the oil-water interface. However, xanthan gum couldn't protect the droplets against the aggregation in high acid environment, but greatly enhanced the physical stability at pH 6-10. During the thermal sterilization process, the physical stability of walnut emulsion was decreased with a rise of sterilization temperature and the extension of sterilization time. The sterilization temperature above 121 degrees C and time over 25 min led to the poor physical and oxidative stability. PMID- 26593518 TI - Production of natural edible melanin by Auricularia auricula and its physicochemical properties. AB - Fermentation conditions of natural edible melanin by Auricularia auricula were optimized to obtain a high melanin yield and physicochemical properties of melanin were firstly investigated. The results indicated that yeast extract, tyrosine and lactose have significant effects on melanin production. Under the proposed optimized conditions, the melanin experimental yield (2.97 g/L) closely matched the value (3.04 g/L) predicted by the second-order model, which provided a statistically prediction of media in submerged fermentation of A. auricula. The yield achieved was 2.14-fold higher compared to the control. It was firstly revealed that tyrosine could stimulate melanin synthesis in A. auricula. The results showed that this melanin had better thermostability and light resistance, and its solubility was relatively high under alkaline conditions. Zn(2+) and Cu(2+) could result in melanin precipitation. The results should be useful for the efficient production of melanin and enable numerous applications in food, cosmetics, pharmacology, medicines and other fields. PMID- 26593519 TI - Evaluation of the nutraceutical, antioxidant and cytoprotective properties of ripe pistachio (Pistacia vera L., variety Bronte) hulls. AB - Every year tons of pistachio hulls are separated and eliminated, as waste products, from pistachio seeds. In this study the hulls of ripe pistachios were extracted with two organic solvents (ethanol and methanol) and characterized for phenolic composition, antioxidant power and cytoprotective activity. RP-HPLC-DAD FLU separation enabled us to identify 20 derivatives, including and by far the most abundant gallic acid, 4-hydroxybenzoic acid, protocatechuic acid, naringin, eriodictyol-7-O-glucoside, isorhamnetin-7-O-glucoside, quercetin-3-O-rutinoside, isorhamnetin-3-O-glucoside and catechin. Methanol extraction gave the highest yields for all classes of compounds and presented a higher scavenging activity in all the antioxidant assays performed. The same was found for cytoprotective activity on lymphocytes, lipid peroxidation and protein degradation. These findings highlight the strong antioxidant and cytoprotective activity of the extract components, and illustrate how a waste product can be used as a source of nutraceuticals to employ in manufacturing industry. PMID- 26593520 TI - Effect of pH on the stability and molecular structure of nitrosyl hemochromogen. AB - This study explored the effect of pH on the stability and molecular structure of nitrosyl hemochromogen (NO-Heme) using ultraviolet (UV), electron paramagnetic resonance (EPR) and Fourier transform infrared (FT-IR) spectroscopy. The NO-Heme was extracted from pre-cooked cured beef and was dissolved in an 80% acetone solution pre-adjusted to different pH values with 2 mol/L HCl and 2 mol/L NaOH. The results show that pH significantly influences the optical properties and stability of NO-Heme. Strong acidic and weak basic conditions favor the red stability of NO-Heme. The conjugate structure of NO-Heme changed under strong basic conditions, as the NO(-) group was shown to be still associated with the iron porphyrin, but the color of NO-Heme changed from pink to yellow. NO-Heme is extremely unstable at weakly acidic pH, and this may be the why pH affects the apparent color of cured meat products during storage. PMID- 26593521 TI - Structural characterization of phenolic compounds and antioxidant activity of the phenolic-rich fraction from defatted adlay (Coix lachryma-jobi L. var. ma-yuen Stapf) seed meal. AB - The current study aims to investigate the antioxidant activities of various extracts from defatted adlay seed meal (DASM) based on the oxygen radical absorbance capacity (ORAC) assay, peroxyl radical scavenging capacity (PSC) assay and cellular antioxidant activity (CAA) assay. Of all the fractions, the n butanol fraction exhibited the highest antioxidant activity, followed by crude acetone extract and aqueous fractions. Of the three sub-fractions obtained by Sephadex LH-20 chromatography, sub-fraction 3 possessed the highest antioxidant activity and total phenolic content. There was a strong positive correlation between the total phenolic content and the antioxidant activity. Based on HPLC DAD-ESI-MS/MS analysis, the most abundant phenolic acid in sub-fraction 3 of DASM was ferulic acid at 67.28 mg/g, whereas the predominant flavonoid was rutin at 41.11 mg/g. Of the major individual compounds in sub-fraction 3, p-coumaric acid exhibited the highest ORAC values, and quercetin exhibited the highest PSC values and CAA values. PMID- 26593522 TI - Solubility, photostability and antifungal activity of phenylpropanoids encapsulated in cyclodextrins. AB - Effects of the encapsulation in cyclodextrins (CDs) on the solubility, photostability and antifungal activities of some phenylpropanoids (PPs) were investigated. Solubility experiments were carried out to evaluate the effect of CDs on PPs aqueous solubility. Loading capacities and encapsulation efficiencies of freeze-dried inclusion complexes were determined. Moreover, photostability assays for both inclusion complexes in solution and solid state were performed. Finally, two of the most widespread phytopathogenic fungi, Fusarium oxysporum and Botrytis cinerea, were chosen to examine the antifungal activity of free and encapsulated PPs. Results showed that encapsulation in CDs significantly increased the solubility and photostability of studied PPs (by 2 to 17-fold and 2 to 44-fold, respectively). Free PPs revealed remarkable antifungal properties with isoeugenol showing the lowest half-maximal inhibitory concentration (IC50) values of mycelium growth and spore germination inhibition. Encapsulated PPs, despite their reduced antifungal activity, could be helpful to solve drawbacks such as solubility and stability. PMID- 26593523 TI - Role of cell wall deconstructing enzymes in the proanthocyanidin-cell wall adsorption-desorption phenomena. AB - The transference of proanthocyanidins from grapes to wine is quite low. This could be due, among other causes, to proanthocyanidins being bound to grape cell wall polysaccharides, which are present in high concentrations in the must. Therefore, the effective extraction of proanthocyanidins from grapes will depend on the ability to disrupt these associations, and, in this respect, enzymes that degrade these polysaccharides could play an important role. The main objective of this work was to test the behavior of proanthocyanidin-cell wall interactions when commercial maceration enzymes are present in the solution. The results showed that cell wall polysaccharides adsorbed a high amount of proanthocyanidins and only a limited quantity of proanthocyanidins could be desorbed from the cell walls after washing with a model solution. The presence of enzymes in the solution reduced the proanthocyanidin-cell wall interaction, probably through the elimination of pectins from the cell wall network. PMID- 26593524 TI - Stability of aspartame and neotame in pasteurized and in-bottle sterilized flavoured milk. AB - Analytical high performance liquid chromatography (HPLC) conditions were standardized along with the isolation procedure for separation of aspartame and neotame in flavoured milk (pasteurized and in-bottle sterilized flavoured milk). The recovery of the method was approximately 98% for both aspartame and neotame. The proposed HPLC method can be successfully used for the routine determination of aspartame and neotame in flavoured milk. Pasteurization (90 degrees C/20 min) resulted in approximately 40% loss of aspartame and only 8% of neotame was degraded. On storage (4-7 degrees C/7 days) aspartame and neotame content decreased significantly (P<0.05) from 59.70% to 44.61% and 91.78% to 87.18%, respectively. Sterilization (121 degrees C/15 min) resulted in complete degradation of aspartame; however, 50.50% of neotame remained intact. During storage (30 degrees C/60 days) neotame content decreased significantly (P<0.05) from 50.36% to 8.67%. Results indicated that neotame exhibited better stability than aspartame in both pasteurized and in-bottle sterilized flavoured milk. PMID- 26593525 TI - Using near infrared spectroscopy to classify soybean oil according to expiration date. AB - A rapid and non-destructive methodology is proposed for the screening of edible vegetable oils according to conservation state expiration date employing near infrared (NIR) spectroscopy and chemometric tools. A total of fifty samples of soybean vegetable oil, of different brands andlots, were used in this study; these included thirty expired and twenty non-expired samples. The oil oxidation was measured by peroxide index. NIR spectra were employed in raw form and preprocessed by offset baseline correction and Savitzky-Golay derivative procedure, followed by PCA exploratory analysis, which showed that NIR spectra would be suitable for the classification task of soybean oil samples. The classification models were based in SPA-LDA (Linear Discriminant Analysis coupled with Successive Projection Algorithm) and PLS-DA (Discriminant Analysis by Partial Least Squares). The set of samples (50) was partitioned into two groups of training (35 samples: 15 non-expired and 20 expired) and test samples (15 samples 5 non-expired and 10 expired) using sample-selection approaches: (i) Kennard-Stone, (ii) Duplex, and (iii) Random, in order to evaluate the robustness of the models. The obtained results for the independent test set (in terms of correct classification rate) were 96% and 98% for SPA-LDA and PLS-DA, respectively, indicating that the NIR spectra can be used as an alternative to evaluate the degree of oxidation of soybean oil samples. PMID- 26593526 TI - Comparative carotenoid compositions during maturation and their antioxidative capacities of three citrus varieties. AB - This study investigated total carotenoid content, comparative carotenoid composition, vitamin C content, and total antioxidant capacity of three citrus varieties which are Yuza (Citrus junos Sieb ex Tabaka), Kjool (Citrus unshiu Marcow), and Dangyooja (Citrus grandis Osbeck). Seven carotenoids were identified, with beta-cryptoxanthin, astaxanthin, and zeaxanthin being predominant in citrus varieties. Ripening increased the total carotenoid in three citrus varieties. Individual carotenoid of canthaxanthin, astaxanthin, and alpha carotene in citrus varieties decreased with maturation, whereas the others increased with ripening. Yuza exhibited the highest total antioxidant capacity in 2,2'-azino-bis-3-ethylbenzthiazoline-6-sulfonic acid (ABTS) and 1,1-diphenyl-2 picrylhydrazyl (DPPH) assays, with VCEAC values of 582.9 mg/100 g and 451.5 mg/100g, respectively. The relative VCEAC values were vitamin C (1.00)>lycopene (0.375), alpha-carotene (0.304), beta-carotene (0.289), beta-cryptoxanthin (0.242), and zeaxanthin (0.099). These results indicate that Yuza contains higher amounts of total carotenoids, individual carotenoids, and vitamin C than other Korean citrus varieties. PMID- 26593527 TI - Interaction of cyanidin-3-O-glucoside with three proteins. AB - We studied the binding of cyanidin-3-O-glucoside (C3G) with bovine serum albumin (BSA), hemoglobin (Hb) and myoglobin (Mb), using multi-spectral techniques and molecular modeling. Fluorescence and time-resolved fluorescence studies suggested that C3G quenched BSA, Hb or Mb fluorescence in a static mode with binding constants of 4.159, 0.695 and 1.545 * 10(4) L mol(-1) at 308K, respectively. The thermodynamic parameters represented hydrogen bonds and van der Waals forces dominated the binding. Furthermore, CD, UV-vis, and three-dimensional fluorescence spectra results indicated the secondary structures of BSA, Hb and Mb were partially destroyed by C3G with the alpha-helix percentage of C3G-Hb and C3G Mb decreased while that of C3G-BSA was increased. UV-vis spectral results showed these binding interactions partially affected the heme bands of Hb and Mb. In addition, molecular modeling analysis supported the experimental results well. The calculated results of equilibrium fraction showed that the concentration of free C3G in plasma was high enough to be stored and transported from the circulatory system to reach their target sites to provide their therapeutic effects. PMID- 26593528 TI - Effect of equilibrium moisture content on barrier, mechanical and thermal properties of chitosan films. AB - Water molecules modify the properties of biodegradable films obtained from hydrophilic materials. Most studies dealing with thermal, mechanical and barrier properties of hydrophilic films are carried out under one relative humidity (RH) condition. The objective of this work was to evaluate the effect of the moisture content on the thermal, mechanical and barrier properties of chitosan films under several RH conditions. Microclimates, obtained with saturated salt solutions were used for conditioning samples and the properties of the films were evaluated under each RH condition. Chitosan films absorbed up to 40% of moisture at the higher RH studied. The percentage of elongation and the water vapour permeability increased while tensile strength, Young's modulus and glass transition temperature decreased, when the moisture content increased. The results suggest that the water molecules plasticized the polymer matrix, changing the properties when the films were in contact with high RH environments. PMID- 26593529 TI - Oxidative stability of a heme iron-fortified bakery product: Effectiveness of ascorbyl palmitate and co-spray-drying of heme iron with calcium caseinate. AB - Fortification of food products with iron is a common strategy to prevent or overcome iron deficiency. However, any form of iron is a pro-oxidant and its addition will cause off-flavours and reduce a product's shelf life. A highly bioavailable heme iron ingredient was selected to fortify a chocolate cream used to fill sandwich-type cookies. Two different strategies were assessed for avoiding the heme iron catalytic effect on lipid oxidation: ascorbyl palmitate addition and co-spray-drying of heme iron with calcium caseinate. Oxidation development and sensory acceptability were monitored in the cookies over one-year of storage at room temperature in the dark. The addition of ascorbyl palmitate provided protection against oxidation and loss of tocopherols and tocotrienols during the preparation of cookies. In general, ascorbyl palmitate, either alone or in combination with the co-spray-dried heme iron, prevented primary oxidation and hexanal formation during storage. The combination of both strategies resulted in cookies that were acceptable from a sensory point of view after 1year of storage. PMID- 26593530 TI - Umami compounds enhance the intensity of retronasal sensation of aromas from model chicken soups. AB - We examined the influence of taste compounds on retronasal aroma sensation using a model chicken soup. The aroma intensity of a reconstituted flavour solution from which glutamic acid (Glu), inosine 5'-monophosphate (IMP), or phosphate was omitted was significantly lower (p<0.05) than that of the model soup. The aroma intensity of 0.4% NaCl solution containing the aroma chicken model (ACM) with added Glu and IMP was significantly higher (p<0.05) than that of 0.4% NaCl solution containing only ACM. The quantitative analyses showed that adding monosodium glutamate (MSG) to aqueous aroma solution containing only ACM enhanced the intensity of retronasal aroma sensation by 2.5-folds with increasing MSG concentration from 0% to 0.3%. Sensation intensity using an umami solution with added MSG and IMP was significantly higher than that with only MSG when the MSG concentration was 0.05%, 0.075%, or 0.1%. However, it plateaued when MSG concentration was beyond 0.3%. PMID- 26593531 TI - FT-Raman and chemometric tools for rapid determination of quality parameters in milk powder: Classification of samples for the presence of lactose and fraud detection by addition of maltodextrin. AB - FT-Raman spectroscopy has been explored as a quick screening method to evaluate the presence of lactose and identify milk powder samples adulterated with maltodextrin (2.5-50% w/w). Raman measurements can easily differentiate samples of milk powder, without the need for sample preparation, while traditional quality control methods, including high performance liquid chromatography, are cumbersome and slow. FT-Raman spectra were obtained from samples of whole lactose and low-lactose milk powder, both without and with addition of maltodextrin. Differences were observed between the spectra involved in identifying samples with low lactose content, as well as adulterated samples. Exploratory data analysis using Raman spectroscopy and multivariate analysis was also developed to classify samples with PCA and PLS-DA. The PLS-DA models obtained allowed to correctly classify all samples. These results demonstrate the utility of FT-Raman spectroscopy in combination with chemometrics to infer about the quality of milk powder. PMID- 26593532 TI - Understanding genistein in cancer: The "good" and the "bad" effects: A review. AB - Nowadays, diet and specific dietary supplements are seen as potential adjuvants to prevent different chronic diseases, including cancer, or to ameliorate pharmacological therapies. Soybean is one of the most important food components in Asian diet. A plethora of evidence supports the in vitro and in vivo anticancer effects of genistein, a soybean isoflavone. Major tumors affected by genistein here reviewed are breast, prostate, colon, liver, ovarian, bladder, gastric, brain cancers, neuroblastoma and chronic lymphocytic leukemia. However, it is not always clear if and when genistein is beneficial against tumors (the "good" effects), or the opposite, when the same molecule exerts adverse effects (the "bad" effects), favouring cancer cell proliferation. This review will critically evaluate this concept in the light of the different molecular mechanisms of genistein which occur when the molecule is administered at low doses (chemopreventive effects), or at high doses (pharmacological effects). PMID- 26593533 TI - (1)H NMR metabolomic profiling of the blue crab (Callinectes sapidus) from the Adriatic Sea (SE Italy): A comparison with warty crab (Eriphia verrucosa), and edible crab (Cancer pagurus). AB - The metabolomic profile of blue crab (Callinectes sapidus) captured in the Acquatina lagoon (SE Italy) was compared to an autochthonous (Eriphia verrucosa) and to a commercial crab species (Cancer pagurus). Both lipid and aqueous extracts of raw claw muscle were analyzed by (1)H NMR spectroscopy and MVA (multivariate data analysis). Aqueous extracts were characterized by a higher inter-specific discriminating power compared to lipid fractions. Specifically, higher levels of glutamate, alanine and glycine characterized the aqueous extract of C. sapidus, while homarine, lactate, betaine and taurine characterized E. verrucosa and C. pagurus. On the other hand, only the signals of monounsaturated fatty acids distinguished the lipid profiles of the three crab species. These results support the commercial exploitation and the integration of the blue crab in human diet of European countries as an healthy and valuable seafood. PMID- 26593534 TI - Use of active extracts of poplar buds against Penicillium italicum and possible modes of action. AB - Antifungal components, from poplar buds active fraction (PBAF) against Penicillium italicum, the causal agent of blue mold in citrus fruits, were identified and possible action modes were investigated. Pinocembrin, chrysin and galangin were determined as active components in PBAF, using HPLC and HPLC-MS analysis. The antifungal activity is stable at temperatures ranging from 4 degrees C to 100 degrees C and pH levels ranging from 4 to 8. In the presence of PBAF, the hyphae become shriveled, wrinkled and the cell membrane became seriously disrupted. Further investigation on cell permeability, nucleic acid content and alkaline phosphatase suggest that the cell membrane might be the target. Mycelial oxygen consumption and the respiration-related enzymatic activity of succinate dehydrogenase, malate dehydrogenase and ATPase were all inhibited by PBAF. We propose that PBAF is a potentially useful alternative for blue mold control and may act against P. italicum by interfering with respiration and disrupting the cell membrane. PMID- 26593535 TI - C- and O-glycosyl flavonoids in Sanguinello and Tarocco blood orange (Citrus sinensis (L.) Osbeck) juice: Identification and influence on antioxidant properties and acetylcholinesterase activity. AB - Sanguinello and Tarocco are the blood orange (Citrus sinensis (L.) Osbeck) cultivars most diffused worldwide. Reversed phase liquid chromatography coupled with MS-MS analysis showed that these two varieties have a similar chromatographic pattern, characterised by the presence of C- and O-glycosyl flavonoids. Of the two, Sanguinello was found to be far richer in flavonoids than Tarocco. In the juices, twelve individual components were identified for the first time, namely, four C-glycosyl flavones (lucenin-2, vicenin-2, stellarin-2, lucenin-2 4'-methyl ether and scoparin), three flavonol derivatives (quercetin-3 O-(2-rhamnosyl)-rutinoside, quercetin-3-O-hexoside, quercetin 3-hydroxy-3 methylglutaryl-glycoside), an O-triglycosyl flavanone (narirutin 4'-O-glucoside) and a flavone O-glycosides (chrysoeriol 7-O-neoesperidoside). Moreover, the influence of the identified C- and O-glycosyl flavonoids on the antioxidant and acetylcholinesterase activity of these juices has been evaluated. PMID- 26593536 TI - Physico-chemical changes during storage and sensory acceptance of low sodium probiotic Minas cheese added with arginine. AB - The partial substitution of sodium chloride by potassium chloride (0%, 25%, and 50%) and addition of arginine (1% w/w) in probiotic Minas cheese was investigated. Microbiological (Lactococcus lactis and Lactobacillus acidophilus counts, and functionality of the prebiotics L. acidophilus), physicochemical (pH, proteolysis, organic acids, fatty acids, and volatile profiles), rheological (uniaxial compression) and sensory (hedonic test with 100 consumers) characterizations were carried out. The sodium reduction and addition of arginine did not constitute a hurdle to lactic and probiotic bacteria survival, with presented values of about 9 log CFU/g, ranging from 7.11 to 9.21 log CFU/g, respectively. In addition, lower pH values, higher proteolysis, and a decrease in toughness, elasticity and firmness were observed, as well as an increase in lactic, citric, and acetic acid contents. In contrast, no change was observed in the fatty acid profile. With respect to the sensory acceptance, the probiotic low sodium Minas cheese presented scores above 6.00 (liked slightly) for the attributes flavor and overall acceptance. The addition of arginine can be a potential alternative for the development of probiotic dairy products with reduced sodium content. PMID- 26593537 TI - Antioxidant and antiproliferative activities in immature and mature wheat kernels. AB - The purpose of this study was to investigate health benefit-related parameters such as antioxidant contents and antiproliferative activities in immature wheat compared to mature wheat. Immature and mature wheats were harvested 35 and 45 days after the heading date, respectively; steamed immature wheat was also tested. The phenolic, flavonoid and vitamin E contents of immature and steamed immature wheat were compared with those of mature wheat. Additionally, antiproliferative activities against colon cancer cells (HT-29 and Caco-2) and cervical cancer cells (HeLa) were evaluated in three samples. The immature wheat contained higher phenolic and flavonoid contents but lower vitamin E contents than mature wheat. The antioxidant capacity, as measured by oxygen radical absorbance capacity (ORAC), was higher in immature wheat than in other samples. In the antiproliferation assays, immature wheat had the lowest EC50 values in HT 29 (39.3 mg/mL) and HeLa (31.4 mg/mL) cells, indicating stronger antiproliferative activity. PMID- 26593538 TI - Redox agents and N-ethylmaleimide affect protein polymerization during laboratory scale dry pasta production and cooking. AB - Durum wheat (Triticum durum Desf.) semolina gluten proteins consist of monomeric gliadin and polymeric glutenin and determine the quality of pasta products made therefrom. During pasta drying, glutenin starts polymerizing already below 60 degrees C (65% relative humidity (RH)), whereas gliadin only is incorporated in the protein network at temperatures exceeding 68 degrees C (68% RH) through thiol (SH)/disulfide (SS) exchange reactions. Removal of free SH groups in glutenin by adding 2.3 MUmol KBrO3 or KIO3 per g dry matter semolina protein (g protein) or 13.8 MUmol N-ethylmaleimide/g protein reduces gliadin-glutenin cross linking during pasta drying and/or cooking and yields cooked pasta of high quality. Introducing free SH groups by adding 13.8 MUmol glutathione/g protein increases gliadin-glutenin cross-linking during pasta processing, resulting in cooked pasta of lower quality. We hypothesize that too much gliadin incorporation in the glutenin network during pasta processing tightens the protein network and results in lower cooking quality. PMID- 26593539 TI - Pulsed electric field improves the bioprotective capacity of purees for different coloured carrot cultivars against H2O2-induced oxidative damage. AB - This research aimed to study the effect of pulsed electric field (PEF) processing on the bioprotective capacity of carrot puree for White Belgian, Yellow Solar, Nantes, Nutri Red and Purple Haze cultivars against H2O2-induced oxidative damage. The bioprotective capacity was determined using cell viability, membrane integrity and nitric oxide (NO) production in a human Caco-2 cell culture assay. Total carotenoids, total anthocyanins, total vitamin C and total phenolics were also evaluated. Compared to the untreated puree, Purple Haze and Nutri Red processed at 303 kJ/kg completely increased Caco-2 cells resistance towards oxidative damage by recovering the cell viability and inhibiting NO production. For cultivar with low carotenoid levels, i.e. Yellow Solar, the application of 0.8 kV/cm resulted in a higher total carotenoid content in the puree than its untreated counterpart, leading to an improved bioprotective effect. This study clearly shows that PEF could add value to carrots by maximising bioprotective effects. PMID- 26593540 TI - Comparative proteomics of milk fat globule membrane in different species reveals variations in lactation and nutrition. AB - In present study, 312, 554, 175 and 143 proteins were identified and quantified by label-free quantitative proteomics in human, cow, goat and yak milk fat globule membrane (MFGM), respectively. Fifty proteins involved in vesicle mediate transport and milk fat globule secretion were conserved among species. Moreover, proteins involved in lipid synthesis and secretion (xanthine dehydrogenase/oxidase, stomatin and CD36), showed different expression pattern and the host defense proteins exhibited various profiles within species. Notably, the content and activity of lipid catabolic enzymes were significantly higher in human MFGM, which could be indicative of the superior fat utilization in breast fed infants. Our findings unraveled the significant differences in protein composition of human milk and conventionally used substitutes of it. The in-depth study of lipid metabolic enzymes in human MFGM will probably contribute to the improvement of the fat utilization through modulation of lipid catabolic enzymes in infant formula. PMID- 26593541 TI - Ultra-performance liquid chromatography tandem mass spectrometry for the rapid simultaneous analysis of nine organophosphate esters in milk powder. AB - Organophosphate esters (OPEs) are common flame retardants that are used in a wide variety of products. These compounds might migrate into and pollute food products. An analytical method involving an improved approach called the "quick, easy, cheap, effective, rugged, and safe" (QuEChERS) method and ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was developed to simultaneously measure trace levels of nine OPEs in milk powder. Separation of the nine OPEs was optimized on a reversed-phase column within 7 min. The stable isotope tri-n-butyl phosphate-d27 (TBP-d27) was used as an internal standard. This method was validated in terms of its linearity, sensitivity, precision, accuracy and matrix effects. Matrix-matched calibration curves were constructed with 1/x(2) as the weighting factor for all of the target compounds resulting in coefficients of regression lines between 0.9938 and 0.9999. The average accuracy was between 73.5% and 110.2%. Intra- and inter-assay precisions for six replicates ranged from 3.9% to 8.9% or below 11%, respectively. The limits of detection (LODs) were in the range of 0.1-0.25 MUg/kg, and the limits of quantification (LOQs) were below 1.5 MUg/kg. Significant matrix effects have been observed, but suppression or enhancement of the signal was compensated for by the use of an isotopically labeled internal standard. This validated method was successfully applied to determine the concentrations of the OPEs in milk powder. PMID- 26593542 TI - Chemical and sensory profiles of rose wines from Australia. AB - The appeal of rose wine is attributable to its sensory profiles and underlying chemical composition, which are determined by viticultural and oenological inputs. This study provided the first insight into the sensory attributes and volatile profiles of Australian rose wines. An HS-SPME-GC-MS method and a recently developed HPLC-MS/MS method were used to quantify 51 volatile compounds, including 4 potent sulfur compounds, in 26 commercial rose wines. Descriptive analysis on all wines was undertaken and the sensory results were correlated with quantitative chemical data to explore relationships between wine composition and sensory profiles. Based on odour activity values, esters were prominent aroma volatiles, and beta-damascenone, 3-methylbutyl acetate, ethyl hexanoate and 3-MHA were deemed to be important, in accord with other studies. Wines were described with terms ranging from developed, spicy and savoury to fresh green, citrus, tropical fruit, floral and confectionery. PMID- 26593543 TI - Variation in accumulation of isoflavonoids in Phaseoleae seedlings elicited by Rhizopus. AB - Seeds from seven species of tribe Phaseoleae, i.e. Phaseolus, Vigna, Lablab and Psophocarpus, were investigated for inducibility of isoflavonoids by germination with or without subsequent elicitation with Rhizopus oryzae. Germination alone poorly induced isoflavonoid production (in the range of 0.2-0.7 mg representative compound equivalents (RCE)/g DW), whereas application of Rhizopus onto the seedlings increased the isoflavonoid content considerably (in the range of 0.5 3.3 mg RCE/g DW). The inducibility of different isoflavonoid subclasses in seedlings with Rhizopus varied per species. Isoflavones and isoflavanones were mainly found in elicited seedlings of Phaseolus, Vigna and Lablab, whereas pterocarpans were mainly observed in those of Psophocarpus. Despite their phylogenetic relatedness, the seeds of various species within Phaseoleae appeared to respond differently towards elicitation by Rhizopus during germination. The kind of molecules induced followed the phylogenetic relationship of the various species, but their amounts induced during germination, alone or combined with elicitation, did not. PMID- 26593544 TI - The importance of amylose and amylopectin fine structure for textural properties of cooked rice grains. AB - Statistically and causally meaningful relationships are established between starch molecular structure (the molecular distribution of branched starch and the chain length distribution of debranched starch) and texture (hardness and stickiness) of cooked rice grains. The amounts of amylose chains with degree of polymerization (DP) 100-20,000, and of long amylopectin chains, positively correlated with hardness, while amylopectin chains with DP<70 and amylose molecular size both showed negative correlations with hardness (p<0.05). There was also a significant negative correlation between stickiness and the amounts of long amylopectin chains (p<0.01). For rices with similar amylose content, the amount of amylose chains with DP 1000-2000 positively correlated with hardness while size negatively correlated with hardness (p<0.05). This indicates for the first time that, regardless of amylose content, rice varieties with smaller amylose molecular sizes and with higher proportions of long amylose chains have a harder texture after cooking. PMID- 26593545 TI - Compositional and functional dynamics of dried papaya as affected by storage time and packaging material. AB - Papaya has been identified as a valuable source of nutrients and antioxidants, which are beneficial for human health. To preserve the nutritional properties after drying, appropriate storage specifications should be considered. This study aimed to investigate the quality and stability of air-dried papaya in terms of quality dynamics and behavior of bio-active compounds during storage for up to 9 months in two packaging materials: aluminum laminated polyethylene and polyamide/polyethylene. Samples with moisture content (MC) of 0.1328 g g(-1) and water activity (aw) of 0.5 were stored at 30 degrees C and relative humidity (RH) of 40-50%. The MC, aw, degree of browning (DB) and 5-hydroxymethylfurfural (HMF) content were found to notably increase as storage progressed. On the contrary, there was a significant decrease in antioxidant capacity (DPPH, FRAP and ABTS), total phenolic (TP) and ascorbic acid (AA) contents. Packaging in aluminum laminated polyethylene under ambient conditions was found to better preserve bio-active compounds and retard increases in MC, aw and DB, when compared to polyamide/polyethylene. PMID- 26593546 TI - Effect of acetic acid on physical properties of pregelatinized wheat and corn starch gels. AB - Pregelatinized starches are physically modified starches with ability to absorb water and increase viscosity at ambient temperature. The main purpose of this study was to determine how different concentrations of acetic acid (0, 500, 1000, 10,000 mg/kg) can affect functional properties of pregelatinized wheat and corn starches (PGWS and PGCS, respectively) produced by a twin drum drier. With increasing acetic acid following changes occurred for both samples; cold water solubility (at 25 degrees C) increased, water absorption and apparent cold water viscosity (at 25 degrees C) reduced, the smooth surface of the starch particles converted to an uneven surface as confirmed by scanning electron microscopy, cohesiveness, consistency and turbidity of the starch gels reduced while their syneresis increased. It was found that in presence of acetic acid, PGWS resulted in higher water absorption and apparent cold water viscosity and produced more cohesive and turbid gels with less syneresis compared to PGCS. PMID- 26593547 TI - New antiinflammatory sucrose esters in the natural sticky coating of tomatillo (Physalis philadelphica), an important culinary fruit. AB - Tomatillo is a popular culinary fruit. The sticky material on its surface, consumed as part of the fruit, has never been investigated. Chemical characterization of sticky material on tomatillo fruits yielded five new sucrose esters, as confirmed by spectroscopic methods. The solvent extract of the sticky material from the whole fresh fruit and pure isolates showed antiinflammatory activity as confirmed by in vitro cyclooxygenase enzymes inhibitory assays. Five sucrose esters isolated at 100 MUg/mL (153.8, 138.8, 136.2, 141.6 and 138.8 MUM, respectively) inhibited cyclooxygenase-1 and -2 enzymes by 50%. The cyclooxygenase enzyme inhibitory activity of extract and isolates at 100 MUg/mL was similar to non-steroidal antiinflammatory drugs aspirin, ibuprofen and naproxen, used as positive controls in the assay at 108, 12 and 15 MUg/mL (600, 60 and 60 MUM), respectively. PMID- 26593548 TI - The effect of proteins from animal source foods on heme iron bioavailability in humans. AB - Forty-five women (35-45 year) were randomly assigned to three iron (Fe) absorption sub-studies, which measured the effects of dietary animal proteins on the absorption of heme Fe. Study 1 was focused on heme, red blood cell concentrate (RBCC), hemoglobin (Hb), RBCC+beef meat; study 2 on heme, heme+fish, chicken, and beef; and study 3 on heme and heme+purified animal protein (casein, collagen, albumin). Study 1: the bioavailability of heme Fe from Hb was similar to heme only (~13.0%). RBCC (25.0%) and RBCC+beef (21.3%) were found to be increased 2- and 1.6-fold, respectively, when compared with heme alone (p<0.05). Study 2: the bioavailability from heme alone (10.3%) was reduced (p<0.05) when it was blended with fish (7.1%) and chicken (4.9%), however it was unaffected by beef. Study 3: casein, collagen, and albumin did not affect the bioavailability of Fe. Proteins from animal source foods and their digestion products did not enhance heme Fe absorption. PMID- 26593549 TI - Orange proteomic fingerprinting: From fruit to commercial juices. AB - Combinatorial peptide ligand library technology, coupled to mass spectrometry, has been applied to extensively map the proteome of orange pulp and peel and, via this fingerprinting, to detect its presence in commercial orange juices and drinks. The native and denaturing extraction protocols have captured 1109 orange proteins, as identified by LC-MS/MS. This proteomic map has been searched in an orange concentrate, from a Spanish juice manufacturer, as well as in commercial orange juices and soft drinks. The presence of numerous orange proteins in commercial juices has demonstrated the genuineness of these products, prepared by using orange fruits as original ingredients. However, the low number of identified proteins in sparkling beverages has suggested that they were prepared with scarce amounts of fruit extract, thus imparting lower quality to the final products. These findings not only increase the knowledge of the orange proteome but also present a reliable analytical method to assess quality and genuineness of commercial products. PMID- 26593550 TI - Origin of haloacetic acids in milk and dairy products. AB - Haloacetic acids (HAAs) are formed during the process of water disinfection. Therefore their presence in foods can be correlated with the addition of or contact with treated water. To determine the origin of HAAs in milk and dairy products, firstly a chromatographic method was developed for their determination. The sample treatment involves deproteination of milk followed by derivatization/extraction of the HAAs in the supernatant. About 20% of the foods analyzed contained two HAAs - which in no case exceeded 2 MUg L(-1), that can be ascribed to contamination from sanitizers usually employed in the dairy industry. The process of boiling tap water (containing HAAs) for the preparation of powdered infant formula did not remove them; therefore it would be advisable to prepare this type of milk with mineral water (free of HAAs). In addition, it is possible to establish if the milk has been adulterated with treated water through the determination of HAAs. PMID- 26593551 TI - Further comments on ''Solubility and thermodynamic behavior of vanillin in propane-1,2-diol+water cosolvent mixtures at different temperatures''. PMID- 26593552 TI - NMR metabolic fingerprinting and chemometrics driven authentication of Greek grape marc spirits. AB - NMR metabolomics was used to investigate 57 Greek spirits of four indigenous and four international varieties from Macedonia (tsipouro) and Crete (tsikoudia) to establish their authenticity. The metabolic profile of Romeiko, Malvasia, Xinomavro, Sangiovese and Nebbiolo varieties was assessed for the first time. The WET1D sequence was used to improve sensitivity and unveil minor metabolites. PCA was applied to delineate the provenance of samples and associate metabolites with distinct varietal characteristics, such as the acidity of Sangiovese, the overripe grapes harvesting of Romeiko, the intense body of Cabernet Sauvignon, the light body of Xinomavro and the glutamic acid for Malvasia. The migration of Cabernet Sauvignon from north Greece to Crete was framed. Monitoring multi varietal spirits introduced 2-vinylethanol as a marker for yeast selection. OPLS DA was applied to samples from the same vineyard, thus highlighting genotypic markers. Consequently, the findings address the concepts of typicity and traceability in grape marc spirits. PMID- 26593553 TI - Conformational changes in proteins recovered from jumbo squid (Dosidicus gigas) muscle through pH shift washing treatments. AB - Conformational and thermal-rheological properties of acidic (APC) and neutral (NPC) protein concentrates were evaluated and compared to those of squid (Dosidicus gigas) muscle proteins (SM). Surface hydrophobicity, sulfhydryl status, secondary structure profile, differential scanning calorimetry and oscillatory dynamic rheology were used to evaluate the effect of treatments on protein properties. Acidic condition during the washing process (APC) promoted structural and conformational changes in the protein present in the concentrate produced. These changes were enhanced during the heat setting of the corresponding sol. Results demonstrate that washing squid muscle under the proposed acidic conditions is a feasible technological alternative for squid based surimi production improving its yield and gel-forming ability. PMID- 26593554 TI - Profiling and relationship of water-soluble sugar and protein compositions in soybean seeds. AB - Sugar and protein are important quality traits in soybean seeds for making soy based food products. However, the investigations on both compositions and their relationship have rarely been reported. In this study, a total of 35 soybean germplasms collected from Zhejiang province of China, were evaluated for both water-soluble sugar and protein. The total water-soluble sugar (TWSS) content of the germplasms studied ranged from 84.70 to 140.91 mg/g and the water-soluble protein (WSP) content varied from 26.5% to 36.0%. The WSP content showed positive correlations with the TWSS and sucrose contents but negative correlations with the fructose and glucose contents. The clustering showed the 35 germplasms could be divided into four groups with specific contents of sugar and protein. The combination of water-soluble sugar and protein profiles provides useful information for future breeding and genetic research. This investigation will facilitate future work for seed quality improvement. PMID- 26593555 TI - Classification of plum spirit drinks by synchronous fluorescence spectroscopy. AB - Synchronous fluorescence spectroscopy was used in combination with principal component analysis (PCA) and linear discriminant analysis (LDA) for the differentiation of plum spirits according to their geographical origin. A total of 14 Czech, 12 Hungarian and 18 Slovak plum spirit samples were used. The samples were divided in two categories: colorless (22 samples) and colored (22 samples). Synchronous fluorescence spectra (SFS) obtained at a wavelength difference of 60 nm provided the best results. Considering the PCA-LDA applied to the SFS of all samples, Czech, Hungarian and Slovak colorless samples were properly classified in both the calibration and prediction sets. 100% of correct classification was also obtained for Czech and Hungarian colored samples. However, one group of Slovak colored samples was classified as belonging to the Hungarian group in the calibration set. Thus, the total correct classifications obtained were 94% and 100% for the calibration and prediction steps, respectively. The results were compared with those obtained using near-infrared (NIR) spectroscopy. Applying PCA-LDA to NIR spectra (5500-6000 cm(-1)), the total correct classifications were 91% and 92% for the calibration and prediction steps, respectively, which were slightly lower than those obtained using SFS. PMID- 26593556 TI - Different additives to enhance the gelation of surimi gel with reduced sodium content. AB - This study tested the effect of adding tetra-sodium pyrophosphate, cystine and lysine as surimi gelation enhancers (Alaska Pollock) in order to reduce the sodium content of gels up to 0.3%. These gels were compared with others that contained 3% NaCl content (the amount typically used for surimi processing). To induce protein gelation, gels were first heated and then set at 5 degrees C/24 h. Once the physicochemical and rheological properties of the gels were determined, cystine and lysine were found to be the most effective additives improving the characteristics of low NaCl surimi gels. The action of these additives is mainly based on the induction of myofibrillar protein unfolding thus facilitating the formation of the types of bonds needed to establish an appropriate network. It was found that a setting period was needed for gel processing to maximize the effect of the additives. PMID- 26593557 TI - Preparation of iron bound succinylated milk protein concentrate and evaluation of its stability. AB - Major problems associated with the fortification of soluble iron salts include chemical reactivity and incompatibility with other components. Milk protein concentrate (MPC) are able to bind significant amount of iron due to the presence of both casein and whey protein. MPC in its native state possess very poor solubility, therefore, succinylated derivatives of MPC (succ. MPC) were also used for the preparation of protein-iron complex. Preparation of the complex involved centrifugation (to remove insoluble iron), ultrafiltration (to remove unbound iron) and lyophilisation (to attain in dry form). Iron binding ability of MPC enhanced significantly (P<0.05) upon succinylation. Stability of bound iron from both varieties of complexes was monitored under different conditions encountered during processing. Higher stability (P<0.05) of bound iron was observed in succ. MPC-iron complex than native protein complex. This method could be adopted for the production of stable iron enriched protein, an organic iron source. PMID- 26593558 TI - Identification and characterization of a novel chitinase with antifungal activity from 'Baozhu' pear (Pyrus ussuriensis Maxim.). AB - A novel chitinase from the 'Baozhu' pear was found, purified, and characterized in this report. This chitinase was a monomer with a molecular mass of 28.9 kDa. Results of the internal peptide sequence analyses classify this chitinase as a class III chitinase. In the enzymatic hydrolytic assay, this chitinase could hydrolyze chitin derivatives into di-N-acetylchitobiose (GlcNAc2) as a major product in the initial phase, as well as hydrolyze GlcNAc2 into N acetylglucosamine (GlcNAc), which represents both chitobiosidase and beta-N acetylglucosaminase activity. Biological analyses showed that this chitinase exhibits strong antifungal activity toward agricultural pathogenic fungi. In total, chitinase from 'Baozhu' pear is a novel bifunctional chitinase that could be a potential fungicide in the biological control of plant diseases. PMID- 26593559 TI - Application of a dye-binding method for the determination of available lysine in skim milk powders. AB - A dye-binding method using Acid Orange 12 was investigated regarding its suitability for the quantification of available lysine, as a means of monitoring the Maillard reaction in skim milk powders. The method was evaluated by analyzing a wide range of milk powders produced by three different drying methods and stored under various conditions. A pilot-scale freeze-dryer, spray-dryer and drum dryer were used to produce skim milk powders and the samples were stored at two temperatures (20 degrees C and 30 degrees C) and two relative humidities (33% and 52%) under strictly controlled conditions. Moreover to validate the method, two protein isolates; bovine serum albumin and casein were investigated for their available lysine content. The results demonstrate the suitability of this method for measuring the available lysine in skim milk powders with good precision and high reproducibility. The relative standard deviations obtained from the 125 freeze-dried powders were 1.8%, and those from the 100 drum-dried samples were all 1.9%. The highest variation was found for the spray-dried powders, which showed relative standard deviations between 0.9% and 6.7%. PMID- 26593560 TI - Lutein-enriched emulsion-based delivery systems: Influence of pH and temperature on physical and chemical stability. AB - Lutein may be utilized in foods as a natural pigment or nutraceutical ingredient to improve eye health. Nevertheless, its use is limited by its poor water solubility and chemical instability. We evaluated the effect of storage temperature and pH on the physical and chemical stability of lutein-enriched emulsions prepared using caseinate. The emulsions (initial droplet diameter=232 nm) remained physically stable at all incubation temperatures (5-70 degrees C); however the chemical degradation of lutein increased with increasing temperature (activation energy=38 kJ/mol). Solution pH had a major impact on the physical stability of the emulsions, causing droplet aggregation at pH 4 and 5. Conversely, the chemical stability of lutein was largely independent of the pH, with only a slight decrease in degradation at pH 8. This work provides important information for the rational design of emulsion-based delivery systems for a lipophilic natural dye and nutraceutical. PMID- 26593561 TI - Minimizing geometric isomerization of alpha-cypermethrin in the residue analysis. AB - Isomerization of chiral pesticides in residue analysis has not drawn much attention which can cause wrong decisions on the enantioselective environmental behavior. A residue analysis method for alpha-cypermethrin and its three acid metabolites, cis/trans-3-(2,2-dichlorovinyl)-2,2-dimethyl cyclopropanecarboxylic acid (cis/trans-DCVA) and 3-phenoxybenzoic acid (3-PBA), in foods such as chicken, honey, milk and pork has been established, in which the isomerization of alpha-cypermethrin was minimized. The target compounds were determined by GC-ECD after a derivatization reaction with 1,1,1,3,3,3-hexafluoroisopropanol. The conditions of the method were optimized by Taguchi orthogonal experiment. Under the optimized conditions, good linearity was obtained with correlation coefficients ranging from 0.9964 to 0.9998. The limits of detection were 0.001 0.005 mg kg(-1). The recoveries were 70.9-114.9% with relative standard deviations of 0.6-15%. In addition, ratios of isomerization ranged only from 2.3% to 7.0%. This method was applied in commercial animal food products. PMID- 26593562 TI - Evaluation of the anthocyanin release and health-promoting properties of Pinot Noir grape juices after pulsed electric fields. AB - This study evaluated the health-promoting properties of Pinot Noir juices (Vitis vinifera L.) obtained at different maceration times after pulsed electric fields (PEF) using 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging and human intestinal Caco-2 cells assays. Juice quality, anthocyanins, total phenolics and vitamin C were also determined. The evaluation of bioprotective capacity of the juice against H2O2-induced oxidative stress in Caco-2 cells was determined using biomarkers for cellular health and integrity: cell viability and lactate dehydrogenase (LDH) leakage. Compared to untreated grape juice, PEF pre-treatment on grapes enhanced the release of the major anthocyanin found in Pinot Noir, i.e. malvidin-3-O-glucoside (+224%). Increase in the content of total phenolic (+61%) and vitamin C (+19%) as well as improvement in the DPPH scavenging activity (+31%) and bioprotective capacity (+25% for cell viability and +30% for LDH leakage) were observed in grape juices following PEF treatment. Bioprotective capacity determined by the cellular biomarkers had significant linear correlations with malvidin-3-O-glucoside content (0.71?r?0.73) whereas DPPH scavenging activity was not well correlated with malvidin-3-O-glucoside (r=0.30) and total phenolics (r=0.30). Therefore, evaluation of the bioprotective capacities using Caco-2 cell assay performed in this study makes a novel contribution to the current knowledge that demonstrates the capability of PEF technology to produce plant-based foods with better phytochemical composition and exhibiting the capacity to protect cells from oxidative stress. PMID- 26593563 TI - Iron chelating active packaging: Influence of competing ions and pH value on effectiveness of soluble and immobilized hydroxamate chelators. AB - Many packaged foods utilize synthetic chelators (e.g. ethylenediaminetetraacetic acid, EDTA) to inhibit iron-promoted oxidation or microbial growth which would result in quality loss. To address consumer demands for all natural products, we have previously developed a non-migratory iron chelating active packaging material by covalent immobilization of polyhydroxamate and demonstrated its efficacy in delaying lipid oxidation. Herein, we demonstrate the ability of this hydroxamate-functionalized iron chelating active packaging to retain iron chelating capacity; even in the presence of competing ions common in food. Both immobilized and soluble hydroxamate chelators retained iron chelating capacity in the presence of calcium, magnesium, and sodium competing ions, although at pH 5.0 the presence of calcium reduced immobilized hydroxamate iron chelation. A strong correlation was found between colorimetric and mass spectral analysis of iron chelation by the chelating packaging material. Such chelating active packaging may support reducing additive use in product formulations, while retaining quality and shelf life. PMID- 26593564 TI - The impact of cooking and delivery modes of thymol and carvacrol on retention and bioaccessibility in starchy foods. AB - Oregano and thyme possess beneficial properties for human health, mainly attributable to monoterpenes such as thymol and carvacrol. The main objective of this research was to assess, on starchy food, the impact of cooking (boiling and baking) and delivery (ground leaves and essential oil) modes on retention and bioaccessibility of thymol and carvacrol. Retention was assessed after cooking, while bioaccessibility was estimated in cooked samples using an in vitro digestion model. Our results indicate that bioaccessibility was weakly dependent on cooking and delivery modes (27-33%). Boil cooking presented 20% more retention than baking for both compounds. When essential oil was added to the food matrix, thymol was retained almost 25% more when compared with ground leaves' addition. Conversely, carvacrol was retained 39% more when ground leaves were added. PMID- 26593565 TI - Influence of PEGylation on the ability of carboxymethyl-dextran to form complexes with alpha-lactalbumin. AB - Electrostatic interactions between alpha-lactalbumin (alpha-lac) and carboxymethyldextran (CMD) in acidic solutions lead to phase-separated complexes. By adding a non-ionic poly(ethylene glycol) (PEG) chain onto the reducing end of CMD, forming carboxymethyl-dextran-block-poly(ethylene glycol) (CMD-b-PEG), the PEG block was hypothesized to reduce interactions with alpha-lac and promote formation of a micelle-like complex structure. Formation of complexes between alpha-lac and CMD-b-PEG or alpha-lac and CMD was determined following acidification by light scattering and electrophoretic mobility. Phase separation, size, and structure of alpha-lac/CMD-b-PEG complexes were characterized by turbidimetry, dynamic light scattering, and electron microscopy, respectively. Complexes of alpha-lac/CMD-b-PEG formed at pH values near pH 6, while alpha lac/CMD complexes formed at pH 5.5. Both CMD and CMD-b-PEG decreased the charge of alpha-lac below pH 5.5 and led to phase separation below pH 5. Shift in charge and the critical pH of phase separation were both sensitive to the alpha-lac to CMD ratio, while the relative amount of CMD-b-PEG did not significantly influence either. Hydrodynamic radii of alpha-lac/CMD-b-PEG complexes was between 11 and 20 nm, which increased with increasing alpha-lac to CMD-b-PEG ratio and with decreasing pH. Spheroidal structures of ~10 nm were also observed in micrographs that were attributed to alpha-lac/CMD-b-PEG complexes. PMID- 26593566 TI - Effect of hot air drying on volatile compounds of Flammulina velutipes detected by HS-SPME-GC-MS and electronic nose. AB - Volatile compounds are important factors that affect the flavor quality of Flammulina velutipes, but the changes occurring during hot air drying is still unclear. To clarify the dynamic changes of flavor components during hot air drying, comprehensive flavor characterization and volatile compounds of F. velutipes were evaluated using electronic nose technology and headspace solid phase micro-extraction combined with gas chromatography-mass spectrometry (HS SPME-GC-MS), respectively. Results showed that volatile components in F. velutipes significantly changed during hot air drying according to the principal component analysis and radar fingerprint chart of electronic nose. Volatile compounds of fresh F. velutipes consisted mainly of ketones, aldehydes and alcohols, and 3-octanone was the dominant compound. Drying process could significantly decrease the relative content of ketones and promoted the generation of alcohols, acids, and esters, which became the main volatile compounds of dried F. velutipes. These may provide a theoretical basis for the formation mechanism of flavor substances in dried F. velutipes. PMID- 26593567 TI - Vortex-assisted matrix solid-liquid dispersive microextraction for the analysis of triazole fungicides in cotton seed and honeysuckle by gas chromatography. AB - A one-step analytical method termed vortex-assisted matrix solid-liquid dispersive microextraction (VA-MSLDME) was developed for the determination of seven triazole fungicides from cotton seed and honeysuckle prior to gas chromatography with electron capture detection. The VA-MSLDME was performed by mixing the matrix, primary secondary amine, acetonitrile, toluene, and water in one single system. The target fungicides in the sample were extracted, cleaned up and preconcentrated simultaneously in the matrix/acetonitrile/water/toluene system. Meanwhile, the interferences were adsorbed by the cleanup adsorbent. The extraction recoveries of the fungicides from the samples varied from 82.9% to 97.8% with relative standard deviations of 4.4-8.5%. The enrichment factors of the analytes ranged from 22 to 47, and the limits of detection were in the range of 0.05-20 MUg/kg. The results demonstrated the significant predominance of VA MSLDME in the analysis of pesticide residues in cotton seed and honeysuckle samples. PMID- 26593568 TI - Vibrational spectroscopy used in milk products analysis: A review. AB - Milk is a fluid containing several substances, and its composition depends on several factors. Vibrational spectroscopy is a powerful tool to determine the constituent concentrations and qualitative characteristics of dairy products. Vibrational spectrometry covers a series of well-established analytical methodologies suitable to be employed for both qualitative and quantitative purposes. In the first part of this review, theoretical aspects on vibrational techniques are presented; in the second part, the most important papers, published during the period 2009-2015, related to milk analysis are discussed. PMID- 26593569 TI - Antioxidant activity of Citrus fruits. AB - Citrus is well-known for its nutrition and health-promotion values. This reputation is derived from the studies on the biological functions of phytochemicals in Citrus fruits and their derived products in the past decades. In recent years, the antioxidant activity of Citrus fruits and their roles in the prevention and treatment of various human chronic and degenerative diseases have attracted more and more attention. Citrus fruits are suggested to be a good source of dietary antioxidants. To have a better understanding of the mechanism underlying the antioxidant activity of Citrus fruits, we reviewed a study on the antioxidant activity of the phytochemicals in Citrus fruits, introduced methods for antioxidant activity evaluation, discussed the factors which influence the antioxidant activity of Citrus fruits, and summarized the underlying mechanism of action. Some suggestions for future study were also presented. PMID- 26593570 TI - Antioxidant activity of low molecular weight alginate produced by thermal treatment. AB - By definition, antioxidants are molecules that inhibit the oxidation of other molecules. Therefore, such compounds have very important clinical roles. In this study alginate polymer was depolymerized by heat treatment. The resulting low molecular weight alginates were investigated by UV-visible spectroscopy, Viscometry, Dynamic light scattering and FT-IR spectroscopy techniques. Antioxidant properties of these heat products were studied by ABTS and superoxide radical scavenging assays. Results showed that heating caused breaks in the polymer chain and so generation of low molecular weight alginates. Antioxidant measurements confirmed antioxidant activity of alginate increased upon a decrease in molecular weight. Therefore, low molecular weight alginate produced by heating could be considered as a stronger antioxidant than alginate polymer. These products could be useful for industrial and biomedical applications. PMID- 26593571 TI - Techno-functional properties and in vitro bile acid-binding capacities of tamarillo (Solanum betaceum Cav.) hydrocolloids. AB - Hydrocolloids were extracted from seed mucilage and the pulp fractions from red tamarillo (Solanum betaceum Cav.) mesocarp, and characterisation of their techno functional properties and in vitro bile acid-binding capacities was performed. The seed mucilage hydrocolloids that were extracted, using either 1% citric acid (THC) or water (THW), had a good foaming capacity (32-36%), whereas the pulp hydrocolloids that were extracted, using 72% ethanol (THE) or 20mM HEPES buffer (THH), had no foaming capacity. The pulp hydrocolloid, however, possessed high oil-holding and water-holding capacities in the range of 3.3-3.6 g oil/g dry sample and 25-27 g water/g dry sample, respectively. This enabled the pulp hydrocolloid to entrap more bile acids (35-38% at a hydrocolloid concentration of 2%) in its gelatinous network in comparison to commercial oat fibre and other hydrocolloids studied. The exceptional emulsifying properties (80-96%) of both hydrocolloids suggest their potential applications as food emulsifiers and bile acid binders. PMID- 26593572 TI - Bread fortified with anthocyanin-rich extract from black rice as nutraceutical sources: Its quality attributes and in vitro digestibility. AB - Anthocyanin-rich black rice extract powder (ABREP) as a nutraceutical source was fortified into bread. The quality and digestibility behaviors of bread with ABREP were evaluated through instrumental and in vitro digestion studies. The quality of bread with 2% of ABREP was not significantly (p>0.05) different from the control bread; however, increasing the ABREP level to 4% caused less elasticity and higher density of bread. A mathematical model was further developed to systemically describe the trajectory of bread digestion. The digestion rates of bread with ABREP were found to be reduced by 12.8%, 14.1%, and 20.5% for bread with 1%, 2%, and 4% of ABREP, respectively. Results of the study suggest that the fortification of anthocyanins into bread could be an alternative way to produce functional bread with a lower digestion rate and extra health benefits. PMID- 26593573 TI - Antioxidant phenolic extracts obtained from secondary Tunisian date varieties (Phoenix dactylifera L.) by hydrothermal treatments. AB - Three common non-commercial Tunisian date varieties were treated by two thermal systems, obtaining a liquid fraction which was characterized and its antioxidant capacity determined. The concentration of total phenols in the three varieties (Smeti, Garen Gazel, and Eguwa) was increased by steam explosion treatment up to 5311, 4680, and 3832 mg/kg of fresh dates, and their antioxidant activity up to 62.5, 46.5 and 43.1 mmol Trolox/kg of fresh date, respectively. Both thermal treatments increased the content of phenolic acids. Additionally, a long scale study was carried out in a pilot plant, with steam treatment at 140 degrees C and 160 degrees C for 30 min. The liquid phase was extracted and fractionated chromatographically using adsorbent or ionic resins. The phenolic profiles were determined for each fraction, yielding fractions with interesting antioxidant activities with EC50 values of up to 0.08 mg/L or values of TEAC of 0.67 mmol Trolox/g of extract. PMID- 26593574 TI - Stability of phenolic compounds, antioxidant activity and colour through natural sweeteners addition during storage of sour cherry puree. AB - The aim of this study was to describe the changes in phenolic compounds, antioxidant activity and colour of sour cherry puree supplemented with different natural sweeteners (sucrose, palm sugar, erythritol, xylitol, steviol glycoside, Luo Han Kuo), and natural prebiotic (inulin). A total of 18 types of polyphenolic compounds were assessed in the following sour cherry puree by LC-MS-QTof analysis, before and after 6 months of storage at 4 degrees C and 30 degrees C. Total phenolics determined by UPLC-PDA-FL was 1179.6 mg/100 g dm. In samples with addition of sweeteners the content of phenolic compounds ranged from 1133.1 (puree with steviol glycoside) to 725.6 mg/100 g dm (puree with erythritol), and the content of these compounds strongly affected on antioxidant activity. After 6 month storage, protective effects of some additives (palm sugar, erythritol, steviol glycoside, xylitol and inulin) on the polyphenol content, especially on anthocyanins and consequently on colour, and antioxidant activity were noticed. The results showed that some natural sweeteners might be interesting from a nutritional as well as commercial and pharmaceutical perspective. PMID- 26593575 TI - An integrated approach with experimental and computational tools outlining the cooperative binding between 2-phenylchromone and human serum albumin. AB - 2-Phenylchromone (2PHE) is a flavone, found in cereals and herbs, indispensable in the human diet. Its chemical structure is the basis of all flavonoids present in black and green tea, soybean, red fruits and so on. Although offering such nutritional value, it still requires a molecular approach to understand its interactions with a specific target. The combination of experimental and computational techniques makes it possible to describe the interaction between 2PHE and human serum albumin (HSA). Fluorescence spectroscopy results show that the quenching mechanism is static, and thermodynamic analysis points to an entropically driven complex. The binding density function method provides information about a positive cooperative interaction, while drug displacement experiments indicate Sites 1 and 2 of HSA as the most probable binding sites. From the molecular dynamic study, it appears that the molecular docking is in agreement with experimental data and thus more realistic. PMID- 26593576 TI - Protective effect of wild raspberry (Rubus hirsutus Thunb.) extract against acrylamide-induced oxidative damage is potentiated after simulated gastrointestinal digestion. AB - Raspberry is well known as rich source of antioxidants, such as polyphenols and flavonoids. However, after consumption, the antioxidants are subjected to digestive conditions within the gastrointestinal tract that may result in structural and functional alterations. Our previous study indicated that acrylamide (AA)-induced cytotoxicity was associated with oxidative stress. However, the protective effect of wild raspberry extract produced before and after in vitro gastrointestinal digestion against AA-induced oxidative damage is unclear. In the present study, we found that wild raspberry extract produced after digestion (RD) had a pronounced protective effect against AA-induced cytotoxicity compared with that produced before digestion (RE). Further investigation indicated that RD significantly inhibited AA-induced intracellular reactive oxygen species (ROS) generation, mitochondrial membrane potential (MMP) collapse and glutathione (GSH) depletion. Moreover, LC-MS analysis revealed that wild raspberry underwent gastrointestinal digestion significantly increased the contents of esculin, kaempferol hexoside and pelargonidin hexoside. PMID- 26593577 TI - Nutritional composition and total collagen content of three commercially important edible jellyfish. AB - The study aimed to evaluate nutraceutical potential of three commercially significant edible jellyfish species (Acromitus hardenbergi, Rhopilema hispidum and Rhopilema esculentum). The bell and oral arms of these jellyfishes were analyzed for their proximate composition, calorific value, collagen content, amino acid profile, chemical score and elemental constituent. In general, all jellyfish possessed low calorific values (1.0-4.9 kcal/g D.W.) and negligible fat contents (0.4-1.8 g/100 g D.W.), while protein (20.0-53.9 g/100 g D.W.) and minerals (15.9-57.2g/100g D.W.) were found to be the richest components. Total collagen content of edible jellyfish varied from 122.64 to 693.92 mg/g D.W., accounting for approximately half its total protein content. The dominant amino acids in both bell and oral arms of all jellyfish studied includes glycine, glutamate, threonine, proline, aspartate and arginine, while the major elements were sodium, potassium, chlorine, magnesium, sulfur, zinc and silicon. Among the jellyfish, A. hardenbergi exhibited significantly higher total amino acids, chemical scores and collagen content (p<0.05) compared to R. hispidum and R. esculentum. Having good protein quality and low calories, edible jellyfish is an appealing source of nutritive ingredients for the development of oral formulations, nutricosmetics and functional food. PMID- 26593578 TI - Applicability of PTR-MS in the quality control of saffron. AB - The applicability of the emerging non-destructive technique, proton transfer reaction mass spectrometry (PTR-MS), was explored for the first time in the quality control of saffron. Monitoring of volatile organic compounds (VOCs) was achieved using a minute sample (35 mg). Fresh saffron was stored under selected conditions (25 and 40 degrees C, aw=0.64) over a five weeks period to produce lower quality material, which was used to prepare mixtures with fresh saffron. Analysis showed that the VOCs fingerprint changed upon storage, and the concentration of initially dominant VOC safranal decreased progressively. Examination of calculated and recorded fingerprints for various admixtures showed that PTR-MS VOCs analysis, in combination with chemometrics, could be used to screen for the presence of lower quality saffron in a commercial product in a few minutes. The technique can be used in a complementary fashion, adding to the battery of advanced analytical techniques available to address the quality and authenticity issues of saffron. PMID- 26593579 TI - Characterization of beta-cyclodextrin inclusion complexes containing an essential oil component. AB - An important issue in food technology is that antimicrobial compounds can be used for various applications, such as the development of antimicrobial active packaging materials. Yet most antimicrobial compounds are volatile and require protection. In the present study, the inclusion complexes of 2-nonanone (2-NN) with beta-cyclodextrin (beta-CD), were prepared by a co-precipitation method. Entrapment efficiency (EE), thermal analysis (DSC and TGA), X-ray diffractometry (XRD), Fourier transform infrared spectroscopy (FT-IR), sorption isotherms and antifungal activity were evaluated for the characterization of the inclusion complex (beta-CD:2-NN). A higher EE was obtained (34.8%) for the inclusion complex 1:0.5 than for other molar rates. Both DSC and TGA of the inclusion complexes showed the presence of endothermic peaks between 80 degrees C and 150 degrees C, attributed to a complexation phenomenon. Antimicrobial tests for mycelial growth reduction under atmospheric conditions proved the fungistatic behaviour of the inclusion complexes against Botrytis cinerea. PMID- 26593580 TI - Triacylglycerol biosynthesis in developing Ribes nigrum and Ribes rubrum seeds from gene expression to oil composition. AB - Oils with sufficient contents of fatty acids, which can be metabolized into precursors of anti-inflammatory eicosanoids, have potential health effects. Ribes sp. seed oil is rich in alpha-linolenic, gamma-linolenic and stearidonic acids belonging to this fatty acid group. Only a few previous studies exist on Ribes sp. gene expression. We followed the seed oil biosynthesis of four Ribes nigrum and two Ribes rubrum cultivars at different developmental stages over 2 years in Southern and Northern Finland with a 686 km latitudinal difference. The species and the developmental stage were the most important factors causing differences in gene expression levels and oil composition. Differences between cultivars were detected in some cases, but year and location had only small effects. However, expression of the gene encoding Delta(9)-desaturase in R. nigrum was affected by location. Triacylglycerol biosynthesis in Ribes sp. was distinctly buffered and typically followed a certain path, regardless of growth environment. PMID- 26593581 TI - Transformation of chemical constituents of lychee wine by simultaneous alcoholic and malolactic fermentations. AB - This work examined for the first time the impact of malolactic fermentation (MLF) on the chemical constituents of lychee wine. Oenococcus oeni Viniflora Oenos (MLF inducer) and Saccharomyces cerevisiae MERIT.ferm were co-inoculated into lychee juice to induce simultaneous alcoholic fermentation (AF) and MLF. MLF did not affect sugar utilisation and ethanol production statistically (8.54% v/v for MLF and 9.27% v/v for AF). However, MLF resulted in dramatic degradation of malic and citric acids with concomitant increases of lactic acid, ethyl lactate and pH. The final concentrations of acetic and succinic acids between AF and MLF wines had no significant difference. The MLF wine contained significantly higher amounts of amino acids than the AF wine. More importantly, MLF significantly elevated the levels of potent aroma-active compounds including isoamyl acetate, linalool, geraniol and cis-rose oxide (to levels above or near respective detection thresholds), suggesting that MLF is an effective way of retaining the original lychee flavour. PMID- 26593582 TI - Fabrication of electrospun polylactic acid nanofilm incorporating cinnamon essential oil/beta-cyclodextrin inclusion complex for antimicrobial packaging. AB - A novel antimicrobial packaging material was obtained by incorporating cinnamon essential oil/beta-cyclodextrin inclusion complex (CEO/beta-CD-IC) into polylacticacid (PLA) nanofibers via electrospinning technique. The CEO/beta-CD-IC was prepared by the co-precipitation method and SEM and FT-IR spectroscopy analysis indicated the successful formation of CEO/beta-CD-IC, which improved the thermal stability of CEO. The CEO/beta-CD-IC was then incorporated into PLA nanofibers by electrospinning and the resulting PLA/CEO/beta-CD nanofilm showed better antimicrobial activity compared to PLA/CEO nanofilm. The minimum inhibitory concentration (MIC) of PLA/CEO/beta-CD nanofilm against Escherichia coli and Staphylococcus aureus was approximately 1 mg/ml (corresponding CEO concentration 11.35 MUg/ml) and minimum bactericidal concentration (MBC) was approximately 7 mg/ml (corresponding CEO concentration 79.45 MUg/ml). Furthermore, compared with the casting method, the mild electrospinning process was more favorable for maintaining greater CEO in the obtained film. The PLA/CEO/beta-CD nanofilm can effectively prolong the shelf life of pork, suggesting it has potential application in active food packaging. PMID- 26593583 TI - The effect of high pressure on the functional properties of pork myofibrillar proteins. AB - Complementary methodologies were used to analyse the pressure-induced modification and functionality of myofibrillar proteins from pork meat pressurised at 200, 400, 600, or 800 MPa (10 min, 5 or 20 degrees C). Pressure at 400 MPa was found to be the threshold for loss of solubility, and the structural proteins, myosin and actin, lost their native solubility due to aggregation. The results from the extraction of proteins with different reagents targeting the disruption of specific molecular interactions suggested that pressure-induced aggregation was caused mainly by hydrogen bonding during pressurisation and not hydrophobic interactions nor disulphide cross-links. Furthermore, the soluble proteins were exposed to remarkable structural changes already at 200 MPa and lost their native functionality. The modification of the proteins in pressurised meat affected the water binding sites of the myofibrillar proteins and, thereby, the interactions between proteins and water molecules, and distribution between myofibrillar and extra-myofibrillar compartments. PMID- 26593584 TI - Whey protein aerogel as blended with cellulose crystalline particles or loaded with fish oil. AB - Whey protein hydrogels blended with nanocrystalline and microcrystalline cellulose particles (NCC and MCC, respectively) were prepared, followed by freeze drying, to produce aerogels. NCC blending increased the Young's modulus, and elastic character, of the protein aerogel. Aerogels were microporous and mesoporous materials, as characterized by the pores sizing 1.2 nm and 12.2 nm, respectively. Blending with NCC decreased the count of both microporous and mesoporous-classified pores at the sub-100 nm pore size range investigated. In contrast, MCC blending augmented the specific surface area and pores volume of the aerogel. It also increased moisture sorption affinity of aerogel. The feasibility of conveying hydrophobic nutraceuticals by aerogels was evaluated through loading fish oil into the non-blended aerogel. Oil loading altered its microstructure, corresponding to a peak displacement in Fourier-transform infra red spectra, which was ascribed to increased hydrophobic interactions. Surface coating of aerogel with zein decreased the oxidation susceptibility of the loaded oil during subsequent storage. PMID- 26593585 TI - Green direct determination of mineral elements in artichokes by infrared spectroscopy and X-ray fluorescence. AB - Near infrared (NIR) and X-ray fluorescence (XRF) spectroscopy were investigated to predict the concentration of calcium, potassium, iron, magnesium, manganese and zinc in artichoke samples. Sixty artichokes were purchased from different Spanish areas (Benicarlo, Valencia and Murcia). NIR and XRF spectra, combined with partial least squares (PLS) data treatment, were used to develop chemometric models for the prediction of mineral concentration. To obtain reference data, samples were mineralised and analysed by inductively coupled plasma optical emission spectrometry (ICP-OES). Coefficients of determination obtained for the regression between predicted values and reference ones for calcium, potassium, magnesium, iron, manganese and zinc were 0.61, 0.79, 0.53, 0.77, 0.54 and 0.60 for NIR and 0.96, 0.93, 0.80, 0.79, 0.76 and 0.90 for XRF, respectively. Both assayed methodologies, offer green alternatives to classical mineral analysis, but XRF provided the best results in order to be used as a quantitative screening method. PMID- 26593586 TI - Quantitative determination of carboxylic acids, amino acids, carbohydrates, ethanol and hydroxymethylfurfural in honey by (1)H NMR. AB - A method using (1)H NMR spectroscopy has been developed to quantify simultaneously thirteen analytes in honeys without previous separation or pre concentration steps. The method has been successfully applied to determine carboxylic acids (acetic, formic, lactic, malic and succinic acids), amino acids (alanine, phenylalanine, proline and tyrosine), carbohydrates (alpha- and beta glucose and fructose), ethanol and hydroxymethylfurfural in eucalyptus, heather, lavender, orange blossom, thyme and rosemary honeys. Quantification was performed by using the area of the signal of each analyte in the honey spectra, together with external standards. The regression analysis of the signal area against concentration plots, used for the calibration of each analyte, indicates a good linearity over the concentration ranges found in honeys, with correlation coefficients higher than 0.985 for the thirteen quantified analytes. The recovery studies give values over the 93.7-105.4% range with relative standard deviations lower than 7.4%. Good precision, with relative standard deviations over the range of 0.78-5.21% is obtained. PMID- 26593587 TI - Pre-harvest application of polyamines enhances antioxidants and table grape (Vitis vinifera L.) quality during postharvest period. AB - Pre-harvest foliar spraying of grapevines with putrescine (Put) and spermidine (Spd) (0, 1, 2mM) was evaluated for determining the fruit quality at harvest and improving postharvest characteristics of table grapes during cold storage. Fruit parameters in terms of firmness, fungal infection, weight loss, total phenol concentration, antioxidant activity, skin color, total anthocyanin concentration, total soluble solids (TSS) and titratable acidity (TA) were evaluated after 0, 25 and 55 days of storage at 1.5 +/- 1 degrees C and 90 +/- 5% R.H. Softening, fungal infection and weight loss increased during cold storage but the rate of changes significantly was delayed in Put- and Spd-treated fruits. Besides these, the application of Put and Spd maintained higher values of phenolics content, antioxidant activity and anthocyanins at the end of storage in compare to control. Furthermore, after 55 days of storage all treated fruits with Put and Spd showed lower changes in L(*), TSS and TA and also higher value of chroma in berries. PMID- 26593588 TI - Changes in physico-chemical and volatile aroma compound composition of Gewurztraminer wine as a result of late and ice harvest. AB - To investigate the changes in physico-chemical and aroma composition after late and ice harvest, Gewurztraminer wines were subjected to standard, enzymatic and GC/MS analysis. Late harvest (LHGW) and ice wines (IHGW) contained more sugars, extract and volatile acidity than standard wines (SGW). IHGW had elevated glycerol and gluconic acid amounts. LHGW was richer in monoterpenol oxides, beta damascenone, 1-octen-3-ol, acetates, ethyl cinnamate and 4-vinylguaiacol than SGW. IHGW contained even higher amounts, with increased citronellol, acetaldehyde, ethyl acetate, dicarboxylic acids esters, benzenoids, furans and acetals, and reduced fermentation aroma compounds. Based on odour activity values, the strongest odorants in SGW were fruity esters. In LHGW the impact of esters increased, while in IHGW cis-rose oxide, beta-damascenone and 1,1 diethoxyethane emerged as the most potent. Fruity and sweet were the dominant aroma compound series in SGW and LHGW, but in IHGW declined, while terpenic, floral, chemical, pungent and ripe fruit aroma compound series increased. PMID- 26593589 TI - Fluorescence properties of flavonoid compounds. Quantification in paprika samples using spectrofluorimetry coupled to second order chemometric tools. AB - The influence of pH on the fluorescence of flavonoid compounds was investigated and the highest fluorescence emission was obtained in basic medium. Selected conditions to improve this signal were: pH 9.5, 0.14 M Britton Robinson buffer and methanol between 5% and 10%. The excitation-emission fluorescence matrices of a set of 36 samples of Spanish paprika were analyzed by means of parallel factor analysis (PARAFAC). Thus, the profiles of possible fluorescence components (PARAFAC loadings) were obtained. One of these profiles was identified by matching PARAFAC scores with LC analysis on the same samples. Two clusters of samples were obtained when score values were plotted against each other. Spectrofluorimetry coupled to second order multivariate calibration methods, as unfolded-partial least squares with residual bilinearization (U-PLS/RBL) and multidimensional-partial least-squares with residual bilinearization (N-PLS/RBL), was investigated to quantify quercetin and kaempferol in those samples. Good results were obtained for quercetin by this approach. PMID- 26593590 TI - In vitro evaluation of anti-diabetic activity and cytotoxicity of chemically analysed Ocimum basilicum extracts. AB - The aim of this study was to evaluate the role of glucose transporter-4 (GLUT4) in the anti-diabetic effects of methanol, hexane and dichloromethane extracts of the aerial parts of Ocimum basilicum (OB) and to analyze their phytochemical composition. Phytochemical analysis of the three extracts by GC/MS using the silylation derivatization technique revealed 53 compounds, 17 of them were found for the first time in OB. Cytotoxic and anti-diabetic properties of the extracts were evaluated using L6-GLUT4myc muscle cells stably expressing myc epitope at the exofacial loop (GLUT4). No cytotoxic effects were observed in treated cells up to 0.25 mg/ml extract as measured with MTT and LDH-leakage assays. GLUT4 translocation to the plasma membrane was elevated by 3.5 and 7 folds (-/+ insulin) after treatment with OB extracts for 20 h. Our findings suggest that the observed anti-diabetic properties of OB extracts are possibly mediated in part through one or more of the 17 new identified compound. PMID- 26593591 TI - Influence of processing and in vitro digestion on the allergic cross-reactivity of three mealworm species. AB - Edible insects are currently being evaluated as an alternative and more sustainable protein source for humans. The introduction of new food sources can lead to development of novel allergies. Because in the Western world, insects are unlikely to be consumed raw, it is important to know how processing and in vitro digestion might influence their allergenicity. Three edible mealworm species (Tenebrio molitor, Zophobas atratus and Alphitobius diaperinus) subjected to processing and in vitro digestion were analysed for IgE cross-reactivity. Immunoblot and MALDI-MS/MS analyses revealed that IgE from crustaceans or House dust mite (HDM) allergic patients showed cross-reactivity to mealworm tropomyosin or alpha-amylase, hexamerin 1B precursor and muscle myosin, respectively. Heat processing as well as in vitro digestion did diminish, but not eliminate, HDM or tropomyosin IgE cross-reactivity. Results show that individuals allergic to HDM or crustaceans might be at risk when consuming mealworms, even after heat processing. PMID- 26593592 TI - Parsimonious model development for real-time monitoring of moisture in red meat using hyperspectral imaging. AB - A hyperspectral imaging system in the spectral range of 400-1000 nm was investigated to develop a multispectral real-time imaging system allowing the meat industry to determine moisture content in red meat including beef, lamb, and pork. Multivariate calibration models were developed using partial least-squares regression (PLSR) and least-squares support vector machines (LS-SVM) in the full spectral range. Instead of selection of different sets of feature wavelengths for beef, lamb, and pork, a set of 10 feature wavelengths was selected for convenient industrial application for the determination of moisture content in red meat. A quantitative linear function was then established using MLR based on these key feature wavelengths for predicting moisture content of red meat in an online system and creating moisture distribution maps. The results reveal that the combination of hyperspectral imaging and multivariate has great potential in the meat industry for real-time determination of moisture content. PMID- 26593593 TI - Toughening and its association with the postharvest quality of king oyster mushroom (Pleurotus eryngii) stored at low temperature. AB - Toughening-induced textural decay easily occurs in stored mushrooms. The objective of this study was to investigate the textural alteration caused by toughening in relation to other quality attributes of king oyster mushroom (Pleurotus eryngii). Fresh king oyster mushrooms, packed in low-density polyethylene bags, were stored at different low temperatures for 18 days to measure textural and other quality attributes. It was found that toughening occurred twice during the entire storage time. Highly associated change profiles were observed for the lignin content and activities of three important enzymes involved in lignin synthesis. The chitin and cellulose contents exhibited low correlation with toughening. Malondialdehyde content, electrolyte leakage rate and total phenolics content appeared to be related to toughening, but the browning index showed a negative correlation with toughening. Our results suggested that toughening may be mainly caused by lignification and can affect the postharvest quality of the tested mushrooms. PMID- 26593594 TI - Cooking techniques improve the levels of bioactive compounds and antioxidant activity in kale and red cabbage. AB - The aim of this study is to investigate the effects of different home cooking techniques (boiling, steaming, and stir-frying) in kale and red cabbage, on the levels of bioactive compounds (carotenoids, anthocyanins and phenolic compounds) determined by high-performance liquid chromatography coupled with photodiode array and mass spectrometry detectors (HPLC-DAD-MS(n)), and on the antioxidant activity evaluated by ABTS, ORAC and cellular antioxidant activity (CAA) assays. The steaming technique resulted in a significant increase in phenolic content in kale (86.1%; p<0.001) whereas in red cabbage it was significantly reduced (34.6%; p<0.001). In the kale, steaming resulted in significant increases in antioxidant activity levels in all of the evaluation methods. In the red cabbage, boiling resulted in a significant increase in antioxidant activity using the ABTS assay but resulted in a significant decrease using the ORAC assay. According to the CAA assay, the stir-fried sample displayed the highest levels of antioxidant activity. PMID- 26593595 TI - Dissipation dynamic, residue distribution and processing factor of hexythiazox in strawberry fruits under open field condition. AB - Two independent field trials were performed to investigate the dissipation and residue levels of hexythiazox in strawberry. The study presents a method validation for extraction and quantitative analysis of hexythiazox residues in strawberry using HPLC-DAD. The results shown that the mean recoveries ranged from 85% to 93%, furthermore the intra- and inter-day relative standard deviations were less than 10%. The results suggest that the hexythiazox dissipation curves followed the first-order kinetic and its half-life ranged from 3.43 to 3.81 days. The final residues in strawberry were below the Codex maximum residue limit (MRL) (6 mg/kg) after three days of the application. The effects of household processing and storage on the levels of hexythiazox residues were quantified, and it's useful for reducing the dietary exposure. The processing factor after each stage were generally less than 1, indicating that the whole process can reduce the residues of hexythiazox in strawberry. The results could provide guidance to safe and reasonable use of hexythiazox in agriculture. PMID- 26593596 TI - Kinetic evaluation of the inhibition of protein glycation during heating. AB - This study aimed to investigate the kinetics of early stage of the Maillard reaction by a reversible bimolecular reaction mechanism and also to evaluate the compatibility of enzyme inhibition kinetics for calculating the inhibitory activity of protein anti-glycation agents. Model systems composed of ovalbumin, glucose, and anti-glycation agents (tannic acid or calcium ion) at different molar ratios were heated at 90 degrees C for different times in dry state or in solution. Heated samples were analysed for furosine, acid derivative of N-epsilon fructoselysine (FL), to monitor the progression of the early glycation stage. Compared to a control, presence of calcium ions and tannic acid decreased FL formation significantly (p<0.05) during heating in dry state. Evaluation of the kinetic data revealed that calcium inhibited glycation of ovalbumin by a mixed non-competitive mechanism in both dry and in solution conditions; while the mode of inhibition by tannic acid was found to be purely non-competitive in the dry state. PMID- 26593597 TI - Characterization of fig achenes' oil of Ficus carica grown in Tunisia. AB - This work investigated the composition of the oil extract from achenes of "Kholi" variety of Ficus carica, grown in Tunisia. Fatty acid and sterol compositions were analyzed by gas chromatography (GC) coupled to flame ionization detector (FID). Furthermore, the antioxidant capacity in fig achenes' oil was assessed by employing two different in vitro assays such as DPPH, ABTS(+) radical scavenging capacities. Our results indicated that the fig achenes' oil is a rich source of bioactive molecules. The soxhlet n-hexane extraction of these achenes produced a total oil yield of 16.24%. The predominant fatty acid was linolenic acid. Concerning phytosterols, the total amount reached 1061.45 mg/100 g with a predominance of Delta(5,23)-stigmastadienol (73.78%). Regarding antioxidant activities, the half maximal inhibitory concentration (IC50) was 215.86 MUg/ml and Trolox equivalent antioxidant capacity (TEAC) was 95.25 mM. These data indicate that fig achenes oil of F. carica could be potentially useful in food and pharmaceutical applications. PMID- 26593598 TI - Gas chromatography/mass spectrometry for the determination of nitrosamines in red wine. AB - N-nitrosamines (NAms) are highly active carcinogens that have been detected in food and beverages. Currently certain studies report their presence in red wine, while others fail to detect their presence. In this study the head space solid phase micro-extraction technique coupled to gas chromatography-mass spectrometry (HS-SPME-GC-MS) was applied to quantify four NAms in different types of red wine. The technique was found to be a simple, precise, fast and environmentally friendly alternative for the quantification of volatile NAms. A factorial analysis was carried out to evaluate the influence of the parameters on the HS SPME technique. This is the first study that such analysis has been reported and where NAms in red wine have been quantified using HS-SPME-GC-MS. The method was validated by calculating the linearity, limit of detection and quantification. Two of the four NAms analyzed were found to be present in red wine samples. PMID- 26593599 TI - Cranberries (Oxycoccus quadripetalus) inhibit pro-inflammatory cytokine and chemokine expression in 3T3-L1 adipocytes. AB - Oxidative stress and inflammation are involved in the development of obesity, type 2 diabetes and vascular complications. Systemic inflammation, as seen in obesity, is associated with high plasmatic levels of pro-inflammatory, pro atherogenic and pro-thrombotic adipokines. Here we studied the effects of lyophilized cranberries (LCB) on the secretion and expression of PAI-1, IL-6, MCP 1 and leptin in mature 3T3-L1 adipocytes under baseline conditions and excessive inflammatory response elicitation by stimulation with H2O2. Our data demonstrated that LCB significantly reduced the expression and secretion of IL-6, MCP-1 and leptin, as well as suppressed the overexpression of PAI-1 induced by H2O2. Our findings suggested that LCB counteracted the stimulatory effect of H2O2 on secretion and expression of pro-inflammatory adipokines, implying a potential anti-inflammatory effect during the inflammatory process induced via oxidative stress in adipose tissue. PMID- 26593600 TI - Development of an immunoaffinity chromatography and HPLC-UV method for determination of 16 sulfonamides in feed. AB - A novel and simple method for detecting 16 sulfonamides (SAs) in animal feed using high performance liquid chromatography equipped with a photo-diode array detector (HPLC/PDA) and immunoaffinity chromatography was developed. The chromatographic peaks of the 16 SAs were successfully identified by comparing their retention times and UV spectra with reference standards. Method validation was performed with linearity, sensitivity, selectivity, accuracy and precision. The limits of detection (LODs) for the instrument used to study sulfonamides ranged from 14.1 to 45.0 MUg/kg, and the limits of quantification (LOQs) ranged from 46.9 to 150.0 MUg/kg. Average recoveries of the 16 SAs ranged from 78.2% to 105.2%. Method replication resulted in intraday and interday peak area variation of <5.5%. The developed method was specific and reliable and is suited for the routine analysis of SAs in animal feed. PMID- 26593601 TI - Discovering metabolic indices for early detection of squash (Cucurbita maxima) storage quality using GC-MS-based metabolite profiling. AB - Squash (Cucubita maxima) cultivars with good storage qualities are needed for breeding to improve poor crop supply during winter in Japan. We measured changes in squash constituents during different storage periods to identify compounds that were suitable to be used as indices of storage quality. Principal components analysis of compounds at 1-5 months after harvest showed that PC1 scores were lower for cultivars with a higher rather than lower SQ (storage quality) ranks. Partial least-squares regression analysis was performed using the peak areas of all compounds identified from the 15 cultivars at 1 month after harvest as explanation variables and SQ as the target variable. Variable influence on projection scores and rank correlation coefficients were higher for arabinose and xylose, which showed less temporal change during the storage period; hence, they were considered to be suitable indicators for storage evaluation. These data will be useful for future studies aiming to improve storage quality of squash. PMID- 26593602 TI - Extraction of bioactive carbohydrates from artichoke (Cynara scolymus L.) external bracts using microwave assisted extraction and pressurized liquid extraction. AB - Microwave assisted extraction (MAE) and pressurized liquid extraction (PLE) methods using water as solvent have been optimized by means of a Box-Behnken and 3(2) composite experimental designs, respectively, for the effective extraction of bioactive carbohydrates (inositols and inulin) from artichoke (Cynara scolymus L.) external bracts. MAE at 60 degrees C for 3 min of 0.3 g of sample allowed the extraction of slightly higher concentrations of inositol than PLE at 75 degrees C for 26.7 min (11.6 mg/g dry sample vs. 7.6 mg/g dry sample). On the contrary, under these conditions, higher concentrations of inulin were extracted with the latter technique (185.4 mg/g vs. 96.4 mg/g dry sample), considering two successive extraction cycles for both techniques. Both methodologies can be considered appropriate for the simultaneous extraction of these bioactive carbohydrates from this particular industrial by-product. To the best of our knowledge this is the first time that these techniques are applied for this purpose. PMID- 26593603 TI - Characterisation of Australian Verdelho wines from the Queensland Granite Belt region. AB - Verdelho is a white-grape-vine, growing well in the Granite Belt region of Queensland. Despite its traditional use in Madeira wine production, there is scant literature on the flavour characteristics of this variety as a dry wine. In this work, for the first time, volatile compounds of Verdelho wines from the Granite Belt have been isolated by solid phase extraction (SPE), and analysed using gas chromatography-mass spectrometry (GC-MS). A corresponding sensory characterisation of this distinctive wine style has also been investigated, using sensory descriptive analysis. Chemical compounds that mostly contribute to the flavour of these wines were related to fruity sweet notes (ethyl esters and acetates), grassy notes (3-hexenol), floral aromas (2-phenylethanol and beta linalool) and cheesy aromas (fatty acids). Sensory analysis confirmed that the Verdelho wines were characterised by fruity aroma attributes, especially "tree fruit" and "rockmelon", together with "herbaceous", while significant differences in the other attributes were found. PMID- 26593604 TI - Optimised method for the analysis of phenolic compounds from caper (Capparis spinosa L.) berries and monitoring of their changes during fermentation. AB - In this work, an ad hoc method to identify and quantify polyphenols from caper berries was developed on high-performance liquid chromatography/electrospray ionisation source/mass spectrometry (HPLC-ESI-MS). The method was applied during fermentation carried out with Lactobacillus pentosus OM13 (Trial S) and without starter (Trial C). A total of five polyphenols were identified. All samples contained high concentrations of rutin. Epicatechin was found in untreated fruits, on the contrary quercetin was detected during fermentation. Trial S was characterised by a more rapid acidification and lower levels of spoilage microorganisms than Trial C. L. pentosus dominated among the microbial community of both trials and the highest biodiversity, in terms of strains, was displayed by Trial C. Aureobasidium pullulans was the only yeast species found. The analytical method proposed allowed a high polyphenolic compound recovery from untreated and processed caper berries in short time. The starter culture reduced the bitter taste of the final product. PMID- 26593606 TI - The influence of microwave-assisted drying techniques on the rehydration behavior of blueberries (Vaccinium corymbosum L.). AB - The aim of this study was to determine the effect of: (a) different drying methods, (b) hot air temperature in a convection oven, and (c) the moisture content of fruits dehydrated by multi-stage drying which involves a transition between different stages of drying, on the rehydration kinetics of dry blueberries. Models describing rehydration kinetics were also studied. Blueberries dehydrated by multi-stage microwave-assisted drying, which involved a hot air pre-drying step at 80 degrees C until the achievement of a moisture content of 1.95 kg H2O kg(-1)DM, were characterized by significantly higher rates of initial and successive rehydration as well as smaller initial loss of soluble solids in comparison with the samples dried by other methods. The highest initial rehydration rate and the smallest loss of soluble solids after 30 min of soaking were determined at 0.46 min(-1) and 0.29 kg DM kg(-1)DM, respectively. The Peleg model and the first-order-kinetic model fit the experimental data well. PMID- 26593605 TI - Chemical interactions and gel properties of black carp actomyosin affected by MTGase and their relationships. AB - Partial least squares regression (PLSR) was applied to evaluate and correlate chemical interactions (-NH2 content, S-S bonds, four non-covalent interactions) with gel properties (dynamic rheological properties and cooking loss (CL)) of black carp actomyosin affected by microbial transglutaminase (MTGase) at suwari and kamaboko stages. The G' and CL were significantly enhanced by MTGase and their values in kamaboko gels were higher than those in suwari gels at the same MTGase concentration. The gamma-carboxyamide and amino cross-links, catalyzed by MTGase, were constructed at suwari stage and contributed to the network formation, while disulfide bonds were formed not only in suwari gels but also in kamaboko gels, further enhancing the gel network. PLSR analysis revealed that 86.6-90.3% of the variation of G' and 91.8-94.4% of the variation of CL were best explained by chemical interactions. G' mainly depended on covalent cross-links and gave positive correlation. CL was positively correlated with covalent cross links, but negatively related to non-covalent bonds, indicating that covalent bonds promoted water extrusion, whereas non-covalent bonds were beneficial for water-holding. PMID- 26593607 TI - Altering the phenolics profile of a green tea leaves extract using exogenous oxidases. AB - Transformation from green tea leaves into black tea involves oxidation of catechins into theaflavins and other complex phenolics by endogenous enzymes in tea leaves. By employing tyrosinase and laccase, both from Agaricus bisporus, on green tea catechins, the oxidation process was directed towards a higher theaflavins content, which is considered an important quality parameter in tea. The main tea catechins were incubated with tyrosinase and laccase, and product formation was monitored by RP-UHPLC-PDA-ESI-MS. The kind of catechin, their substitution with a galloyl group, and the type of oxidase used were important factors determining theaflavin concentrations. In particular, incubation of epicatechin with epigallocatechin with tyrosinase gave a high, stable theaflavin content. In a green tea extract, tyrosinase increased the proportion of theaflavins by twofold compared to black tea. Laccase mainly formed insoluble complexes. Our results indicate that the phenolic profile of tea can be modulated by using commercially available exogenous oxidases. PMID- 26593608 TI - A novel liquid chromatography-mass spectrometric method for the simultaneous determination of trimethylamine, dimethylamine and methylamine in fishery products. AB - A novel multianalyte method has been developed to determine the concentration of trimethylamine (TMA), dimethylamine (DMA) and methylamine (MA) in fish. The optimal points of the key parameters (pH 8, 60 degrees C and 60 min of reaction time) were determined for the reaction with tert-butyl bromoacetate. An HILIC column was used to elute all the compounds in only 12 min and selective quantitation of the compounds was achieved. The methodology was validated in trout, hake and Atlantic horse mackerel and was used to study the shelf life of fish under refrigeration. A good correlation with the picrate method was obtained and the proposed methodology has been proved to be robust, specific and sensible with a limit of detection of 0.08 mg N-TMA kg(-1) in freshwater fish and 1 mg N TMA kg(-1) in marine fish. In addition, TMA has been proved to be a good spoilage indicator also in freshwater fish. PMID- 26593609 TI - Bioactive properties of honey with propolis. AB - Nowadays, propolis is used as an innovative preservative and as a bioactive food supplement. Due to its bitter and astringent flavour, propolis is hardly accepted by consumers. The aim of this study was to obtain a likeable food product made with honey and propolis, whose antimicrobial, antioxidant and anti-inflammatory properties were enhanced in comparison with those of the base honeys used. 0.1%, 0.3% and 0.5% soft propolis extracts were added to honeys and the products that most appealed to the users were subjected to further research. Total phenolics, flavonoids, ABTS free radical and hydroxyl radicals scavenging and anti inflammatory activities increased in all mixtures. Antimicrobial activity of the combined products showed synergic effects, resulting in higher results than those of the base honeys and propolis extracts. Therefore, honeys enriched with small amounts of propolis extracts are promising functional foods. PMID- 26593610 TI - A comprehensive study of red wine properties according to variety. AB - More than 80 properties have been studied in 250 commercial red wines to obtain a reliable description of the characteristics of each variety. Such a large set of data allows the testing of previous assumptions and a thorough investigation about whether varietal discrimination is possible despite the strong influences of ageing and environment. Even though several studies have been performed regarding how variety influences wine phenolics or colour, only a few count on a large data set. Most studies are performed by applying only one technology or on a limited number of wines. In this work, a heterogeneous wine population is thoroughly analysed by using diverse analytical techniques. Therefore, analysis of variance can be applied and patterns are observable in different parameters like flavonols or anthocyanins in spite of the high heterogeneity of the samples. The study confirms that discriminant analysis can be successful in distinguishing wines according to variety in spite of the influences of winemaking techniques and vintage. PMID- 26593611 TI - Effects of light quality on main health-promoting compounds and antioxidant capacity of Chinese kale sprouts. AB - The effects of different light qualities, including white, red and blue lights, on main health-promoting compounds and antioxidant capacity of Chinese kale sprouts were investigated using light-emitting diodes (LEDs) as a light source. Our results showed that blue light treatment significantly decreased the content of gluconapin, the primary compound for bitter flavor in shoots, while increased the glucoraphanin content in roots. Moreover, the maximum content of vitamin C was detected in the white-light grown sprouts and the highest levels of total phenolic and anthocyanins, as well as the strongest antioxidant capacity were observed in blue-light grown sprouts. Taken together, the application of a colorful light source is a good practice for improvement of the consumers' acceptance and the nutritional phtyochemicals of Chinese kale sprouts. PMID- 26593612 TI - Characterization of fruit development and potential health benefits of arrayan (Luma apiculata), a native berry of South America. AB - The arrayan berry (Luma apiculata) is a native fruit from South America that belongs to the Myrtaceae family. To elucidate and characterize the developmental process and the potential health benefits of this edible fruit, quality and physiological parameters, along with antioxidant capacity, were evaluated during four clearly defined developmental stages of the fruit in two seasons. Fruit firmness slowly decreases during fruit development, whereas the solid soluble content/titratable acidity ratio (SSC/TA) increases significantly in the final stages of development. The measurement of low respiration rates and low ethylene production during growth and ripening suggested that the arrayan berry should be classified as a non-climacteric fruit. Arrayan berries show a significant increase in their antioxidant capacity from small green to black ripe fruit. FRAP and TEAC assays showed high correlations with total polyphenolic content (TPC) during ripening and high antioxidant capacity at all fruit stages, showing greater values in ripe fruit (FRAP: 24 +/- 2 and 28 +/- 3 MUM FeSO4/gFW; TEAC: 18 +/- 2 and 20 +/- 1 Eq. Trolox/gFW for each season, respectively) than those observed in the blueberry (FRAP: 10 +/- 2 and 19 +/- 3 MUM FeSO4/gFW; TEAC: 10 +/ 2 and 17 +/- 3). In addition, bioactive assays using ripe fruit extracts show presence of flavonol and anthocyanins, a high ORAC value (62,500 +/- 7000 MUmol/gDW) and a concentration-dependent vascular protection under high glucose conditions. The results obtained show that these endemic berry fruits have a promising potential as functional food. PMID- 26593613 TI - Wide-scope screening and quantification of 50 pesticides in wine by liquid chromatography/quadrupole time-of-flight mass spectrometry combined with liquid chromatography/quadrupole linear ion trap mass spectrometry. AB - In this paper, a wide scope screening method of pesticides in wine was established using liquid chromatography/quadrupole time-of-flight mass spectrometry (LC-QTOF MS) and liquid chromatography/quadrupole linear ion trap mass spectrometry (LC-QqLIT MS). Information dependent acquisition (IDA) experiments are used to obtain both MS and MS/MS information for LC-QTOF MS analysis. For LC-QqLIT MS analysis, MS/MS spectra of target pesticides were simultaneously acquired using Enhanced Product Ion (EPI) mode at very low concentrations to increase the confidence in analytical results of multiple reaction monitoring (MRM) by library searching. Method validation was carried out using 50 pesticides commonly used in vineyards. The LOQs, linearity, repeatability were determined and good enough for quantification. The screening and quantification results obtained using LC-QTOF MS and LC-QqLIT MS were compared. Contaminants were screened against libraries containing over 2800 compounds based on accurate mass, isotopic patterns, and MS/MS spectra searching to extend the scope of this methodology to non-target screening. PMID- 26593614 TI - Degradation of C-hordein by metal-catalysed oxidation. AB - C-hordein is a monomeric prolamin protein in barley. The unusual primary structure of C-hordein has highly repetitive sequences and forms a secondary structure of beta-turns. C-hordein structure is similar to that of collagen protein, whose degradation by metal-catalysed oxidation has been intensively studied. No information exists on the metal catalysed oxidation of C-hordein, however. In this study, copper-catalysed hydrogen peroxide induced oxidation of C hordein caused substantial degradation and formed some insoluble compounds. The use of a gliadin standard in R5 ELISA determinations causes an overestimation of hordeins in a sample. A C-hordein standard was therefore directly used as a standard, thus allowing the C-hordein to be analysed as its oxidised prolamin product. After 48 h of oxidation, the prolamin concentration of oxidised C hordein decreased to 20% of its original amount for competitive ELISA, and to 3% for sandwich ELISA methods. Carbonyl groups were formed during the oxidation. Backbone fragmentation and side-chain modification suggested structural changes of R5 epitopes in C-hordein. Oxidation is an alternative to enzymatic hydrolysis when degrading and modifying C-hordein. PMID- 26593615 TI - Fractionation and characterization of soy beta-conglycinin-dextran conjugates via macromolecular crowding environment and dry heating. AB - Conjugates of beta-conglycinin and dextran were prepared by heating in solution under macromolecular crowding environment and dry-heating methods, and then fractionated by solubility at pH 4.8 and pH 6.5 and characterized. The results showed that the degree of glycation of the conjugates extracted from pH 4.8 were higher than the conjugates extracted from pH 6.5. Corresponding to the higher degree of glycation, it was supposed that the beta-conglycinin of groups 4.8 of macromolecular crowding environment was completely surrounded by the dextran molecular while that of groups 6.5 were encircled partially with a lower degree of glycation. Compared to beta-conglycinin, groups 4.8 demonstrated a decreasing surface hydrophobicity and sulfhydryl group content while groups 6.5 increased. The secondary structure of beta-conglycinin soluble at pH 4.8 after conjugating under macromolecular crowding environment tended to stretch out and the highly ordered structure turn to random structures. The differences between the extraction of pH 4.8 and pH 6.5 conjugated by dry-heating methods were not as remarkable as the difference between the extraction conjugated by macromolecular crowding environment. PMID- 26593616 TI - Efficient immobilization of a fungal laccase and its exploitation in fruit juice clarification. AB - The clarification step represents, in fruit juices industries, a bottleneck process because residual phenols cause severe haze formation affecting juice quality and impairing customers acceptance. An enzymatic step can be efficiently integrated in the process, and use of immobilized enzymes entails an economical advantage. In this work, covalent immobilization of recombinant POXA1b laccase from Pleurotus ostreatus on epoxy activated poly(methacrylate) beads was optimized thanks to a Response Surface Methodologies approach. Through regression analysis the process was well fitted by a quadratic polynomial equation (R(2)=0.9367, adjusted R(2)=0.8226) under which laccase activity reached 2000 +/- 100 Ug(-1) of beads, with an immobilization efficiency of 98%. The immobilized biocatalyst was characterized and then tested in fruit juice clarification reaching up to 45% phenol reduction, without affecting health-effective flavanones content. Furthermore, laccase treated juice displays an improved sensory profile, due to the reduction of vinyl guaiacol, a potent off-flavor possessing a peppery/spicy aroma. PMID- 26593617 TI - Fungicide multiresidue monitoring in international wines by immunoassays. AB - Azoxystrobin, boscalid, cyprodinil, fenhexamid, and pyrimethanil are new generation fungicides extensively employed in order to combat diseases affecting vineyards worldwide. Owing to their physico-chemical characteristics, residues of these compounds on grapes are transferred to must and wine. In this study, a survey of the occurrence of these fungicides in international wines was carried out by using rapid antibody-based assays. Results are discussed as a function of wine type and sample geographical origin. 44.4% of the samples contained at least one of the targets (>10 MUg L(-1)). Fungicide residue occurrences were 22.4%, 19.2%, 18.8%, 6.8%, and 1.2% for pyrimethanil, boscalid, fenhexamid, cyprodinil, and azoxystrobin, respectively, while residue contents higher than 100 MUg L(-1) were found in 8.4% of the samples. This study shows that contamination of commercial wines with pesticides is an issue of worldwide relevance with potential implications for consumer health and international trade. PMID- 26593618 TI - Ultrasound-assisted extraction for the determination of Cu, Mn, Ca, and Mg in alternative oilseed crops using flame atomic absorption spectrometry. AB - An ultrasound-assisted extraction procedure was evaluated for the multi-element determination of Cu, Mn, Ca, and Mg in alternative oilseed crops using flame atomic absorption spectrometry. The best results were obtained when 0.3g of samples were used to extract the mineral content using 10 mL of a 1.40 mol L(-1) HNO3 solution for 10 min at 25 degrees C. The accuracy and precision of the analysis were evaluated using two oilseed reference materials, and the results were in agreement with reference values at 95% confidence level (paired t-test). The method was used to analyze five oilseed samples and the results were in agreement with those obtained using a closed-vessel microwave-assisted acid digestion system for sample preparation. The relative standard deviations were 0.52-6.13% for all of the standard and sample measurements, and the limits of detection were 666.7, 416.7, 333.4 MUg g(-1), and 3.5 mg g(-1) for Cu, Mn, Ca, and Mg, respectively. PMID- 26593619 TI - Carnauba wax p-methoxycinnamic diesters: Characterisation, antioxidant activity and simulated gastrointestinal digestion followed by in vitro bioaccessibility. AB - The beneficial biological effects of cinnamic acid derivatives and the lack of studies on the antioxidant activity and bioavailability of cinnamic esters from carnauba wax, diesters were extracted from carnauba wax powder. Their structural, physical and morphological characteristics, antioxidant activity and in vitro bioaccessibility were measured. p-Methoxycinnamic diester (PCO-C) was identified, which has a crystalline, apolar structure and exhibited significant antioxidant activity (107.27 +/- 3.92 MUM Trolox/g of dry weight) before and after simulated in vitro gastrointestinal digestion and 32.46% bioaccessibility. In human cells, PCO-C (250 MUg/mL) inhibited the production of intracellular reactive oxygen species, with an effect similar to that of Trolox (80 MUM). Thermogravimetric analysis showed that PCO-C had high thermal stability and high UV absorption between 250 and 350 nm. These results indicate that this compound is promising as an antioxidant for pharmaceutical and food industry applications, such as the development of active packaging and functional foods. PMID- 26593620 TI - Betaines and related ammonium compounds in chestnut (Castanea sativa Mill.). AB - Chestnut fruits, being poor of simple sugars and consisting mainly of fibers and starch, are among the constituents of Mediterranean diet. While numerous studies report on content of proteins and amino acids in chestnut, no one has appeared so far on betaines, an important class of nitrogen compounds ubiquitous in plants for their protective action in response to abiotic stress. In this study, we analyzed by HPLC-ESI-tandem mass spectrometry, in fruits and flours of varieties of chestnut cultivated in Italy, the composition of betaines and ammonium compounds intermediates of their biosynthesis. Besides the parent amino acids, the compounds quantified were choline, glycerophosphocholine, phosphocholine, glycine betaine, N-methylproline, proline betaine (stachydrine), beta-alanine betaine, 4-guanidinobutyric acid, trigonelline, N,N,N-trimethyllysine. Interestingly, some uncommon derivatives of pipecolic acid, such as N methylpipecolic acid, 4-hydroxypipecolic acid and 4-hydroxy-N-methylpipecolic acid were identified for the first time in chestnut samples and characterized by MS(n) tandem mass spectrometry. PMID- 26593621 TI - Effect of protein oxidation on the impaired quality of dry-cured loins produced from frozen pork meat. AB - Dry-cured loins elaborated from frozen (-20 degrees C/20 weeks)/thawed longissimus dorsi muscles (F) were compared with counterparts elaborated from fresh (unfrozen) muscles (UF) for the extent of protein oxidation (carbonylation and Schiff base formation) and their sensory profile (quantitative-descriptive analysis). All samples had similar moisture, fat and protein contents (p>0.05). In accordance with previous studies, freezing meat prior to processing affected the oxidative stability of meat proteins. This chemical change occurred concomitantly with modifications of the sensory profile of the loins as F-samples received significantly (p<0.05) higher scores for rancid and salty flavor, hardness and fibrousness than UF-counterparts. The formation of cross-links (assessed as Schiff bases) during freezing and the subsequent processing may have contributed to strengthening the meat structure and hence, impairing the texture properties of dry-cured loins. PMID- 26593622 TI - Provitamin A potential of landrace orange maize variety (Zea mays L.) grown in different geographical locations of central Malawi. AB - The provitamin A potential of landrace orange maize from different locations (A, B, C and D) of central Malawi has been evaluated. Physicochemical compositions, color, total carotenoid content (TCC), carotenoid profiles, and oxygen radical absorbance capacity (ORAC) and 2,2-diphenyl-1-picryhydrazyl (DPPH) free radical scavenging activity as antioxidant capacities of maize were determined. Color values of orange maize had correlations with beta-cryptoxanthin (r>0.36). TCC of white and orange maize averaged 2.12 and 59.5 mg/kg, respectively. Lutein was the most abundant carotenoid (47.8%) in orange maize, followed by zeaxanthin (24.2%), beta-carotene (16.4%) and beta-cryptoxanthin (11.6%). Location D showed the highest levels of lutein, zeaxanthin and antioxidant capacity. Provitamin A content of orange maize met the target level (15 MUg/g) of biofortification. Retinol activity equivalent (RAE) from beta-cryptoxanthin and beta-carotene in orange maize averaged 81.73 MUg/100g. In conclusion, orange maize has the potential to be a natural source of provitamin A. PMID- 26593623 TI - Plant stanol content remains stable during storage of cholesterol-lowering functional foods. AB - Plant stanols reduce the absorption of both dietary and biliary cholesterol. The aim of this study was to examine the stability of plant stanols in the form of plant stanol esters in spreads and biscuits stored under typical storage conditions. The plant stanol content of two commercial margarine-type spreads, containing 35% and 60% absorbable fat, was 6.5 and 6.4 g/100 g after production and remained unaltered when stored at 6 degrees C for a shelf life of 18 and 22 weeks, respectively. Comparable results were obtained for plant stanol ester ingredient stored under the same conditions and for plant stanol ester-containing biscuits stored at room temperature for up to 74 weeks. Furthermore, the peroxide value and free fatty acids showed that the quality of the food products remained good. The present study demonstrated that plant stanol esters as an ingredient and when added in food products, are stable whilst stored under the appropriate conditions. PMID- 26593624 TI - Development of a high-performance liquid chromatography with fluorescence detection method for quantification of piperazine in animal products by using precolumn derivatization. AB - A new high-performance liquid chromatography with fluorescence detection (HPLC FLD) method was developed for determination of piperazine residues in food animal products. Samples were extracted with formic acid in water and purified using the PCX cartridge. Following purification, the samples were derivatized using dansyl chloride, and the analyte was separated using water/acetonitrile as a mobile phase. The calibration curves showed good linearity over a concentration range of 20-120 ng/g with coefficient of determination (R(2))?0.996. The intra-day accuracy (presented as recovery %) and precision (presented as relative standard deviation, RSD %) were 81-97.3% and 0.83-6.87%, whereas, the inter-day values were 80.5-96.8% and 1.7-6.8%, respectively. The limit of quantification (LOQ) was 20 ng/g, which was considerably lower than the maximum residue limit (MRL). The developed method was used to monitor market samples, and piperazine was not detected in any of the samples. To our knowledge, this is the first study in which the detection of piperazine in various food and animal products by using a sensitive and reliable analytical method has been described. PMID- 26593625 TI - The potential of papain and alcalase enzymes and process optimizations to reduce allergenic gliadins in wheat flour. AB - The objectives of this study were to select effective enzymes that catalyze the hydrolysis of allergenic proteins, gliadins, in wheat flour and to optimize the enzymatic treatment conditions. Six proteases were tested. Hydrolyzed samples were tested for residual gliadin concentrations and in vitro allergenicity. The hydrolysis conditions of wheat protein by the effective enzymes were optimized by central composite design. Results showed that alcalase from Bacillus licheniformis, and papain from latex of papaya fruit had greater ability to reduce gliadin content of wheat flour than flavourzyme, pepsin, trypsin or alpha chymotrypsin. The sequential-treatment of wheat flour by alcalase-papain was more effective in reducing gliadin content than single enzyme treatment. Under the optimal conditions of sequential enzymatic treatment, gliadin was almost completely removed, resulting in the flour extract showing lowest IgE-binding. Therefore, this could be a promising biotechnology for preparing low allergenic wheat products. PMID- 26593626 TI - Biochemical and molecular characterisation of a new alkaline trypsin from Liza aurata: Structural features explaining thermal stability. AB - This study investigated the fine structure and biochemical characterization of trypsin from the viscera of Liza aurata. The purified enzyme displayed an apparent molecular weight of 23 kDa as determined by sodium dodecyl sulphate polyaccrylamide gel electrophoresis (SDS-PAGE). The optimum pH and temperature for the proteolytic activity were 10.0 and 50 degrees C, respectively. Trypsin was strongly inhibited by serine protease inhibitor. The cDNA of the mature trypsin was cloned and sequenced. It encodes a protein of 222 amino acids, having only 86% of identity with its most homologous trypsin II of the Salmo salar. A phylogenic analysis showed that L. aurata trypsin (LAT) is close to fish enzymes. Given the high amino acid sequence homology between fish enzymes, a 3-D structure model was built using the structure of S. salar as a template. According to this model, structural features common with warm-active trypsins would explain why LAT acts at high temperatures, unlike cold adapted enzymes. PMID- 26593627 TI - Quantification of aroma constituents of mango sap from different Pakistan mango cultivars using gas chromatography triple quadrupole mass spectrometry. AB - In this study, a quantitative method was developed based on gas chromatography triple quadrupole mass spectrometry (GC-QQQ-MS) for the analysis of aroma component of mango sap (latex) in nine Pakistani varieties that are Anmol, Began pali, Badami, Caroba, Chaunsa, Lal patra, Neelum, Sohnara and Tota pari. The non aqueous phase of sap was studied and a total seven selected terpenes that are alpha-pinene, alpha-phellandrene, (+)-3-carene, sabinene, gamma-terpinene, (-) trans-caryophyllene and alpha-humulene were quantified using GC-QQQ-MS in MRM (multiple reaction mode) mode. Calibration curves were generated and R(2)>0.99 was found for all analytes. Intra-day and inter-day precision (% R.S.D.) of the developed method was less than 4% while % accuracy was in the range of 95.3-105.1 for all analytes. Among all the varieties, Neelum contains the highest amount of four terpenes out of seven quantified terpenes. PMID- 26593628 TI - Oxygen dependency of one-electron reactions generating ascorbate radicals and hydrogen peroxide from ascorbic acid. AB - The effect of oxygen on the two separate one-electron reactions involved in the oxidation of ascorbic acid was investigated. The rate of ascorbate radical (Asc( )) formation (and stability) was strongly dependent on the presence of oxygen. A product of ascorbic acid oxidation was measurable levels of hydrogen peroxide, as high as 32.5 MUM from 100 MUM ascorbic acid. Evidence for a feedback mechanism where hydrogen peroxide generated during the oxidation of ascorbic acid accelerates further oxidation of ascorbic acid is also presented. The second one electron oxidation reaction of ascorbic acid leading to the disappearance of Asc( ) was also strongly inhibited in samples flushed with argon. In the range of 0.05 1.2 mM ascorbic acid, maximum levels of measurable hydrogen peroxide were achieved with an initial concentration of 0.2 mM ascorbic acid. Hydrogen peroxide generation was greatly diminished at ascorbic acid levels of 0.8 mM or above. PMID- 26593630 TI - A Biphasic Transversely Isotropic Poroviscoelastic Model for the Unconfined Compression of Hydrated Soft Tissue. AB - The unconfined compression experiments are commonly used for characterizing the mechanical behavior of hydrated soft tissues such as articular cartilage. Several analytical constitutive models have been proposed over the years to analyze the unconfined compression experimental data and subsequently estimate the material parameters. Nevertheless, new mathematical models are still required to obtain more accurate numerical estimates. The present study aims at developing a linear transversely isotropic poroviscoelastic theory by combining a viscoelastic material law with the transversely isotropic biphasic model. In particular, an integral type viscoelastic model is used to describe the intrinsic viscoelastic properties of a transversely isotropic solid matrix. The proposed constitutive theory incorporates viscoelastic contributions from both the fluid flow and the intrinsic viscoelasticity to the overall stress-relaxation behavior. Moreover, this new material model allows investigating the biomechanical properties of tissues whose extracellular matrix exhibits transverse isotropy. In the present work, a comprehensive parametric study was conducted to determine the influence of various material parameters on the stress-relaxation history. Furthermore, the efficacy of the proposed theory in representing the unconfined compression experiments was assessed by comparing its theoretical predictions with those obtained from other versions of the biphasic theory such as the isotropic, transversely isotropic, and viscoelastic models. The unconfined compression behavior of articular cartilage as well as corneal stroma was used for this purpose. It is concluded that while the proposed model is capable of accurately representing the viscoelastic behavior of any hydrated soft tissue in unconfined compression, it is particularly useful in modeling the behavior of those with a transversely isotropic skeleton. PMID- 26593629 TI - Brain Imaging Using Mobile CT: Current Status and Future Prospects. AB - Computed tomography (CT) is an invaluable tool in the diagnosis of many clinical conditions. Several advancements in biomedical engineering have achieved increase in speed, improvements in low-contrast detectability and image quality, and lower radiation. Portable or mobile CT constituted one such important advancement. It is especially useful in evaluating critically ill, intensive care unit patients by scanning them at bedside. A paradigm shift in utilization of mobile CT was its installation in ambulances for the management of acute stroke. Given the time sensitive nature of acute ischemic stroke, Mobile stroke units (MSU) were developed in Germany consisting of an ambulance equipped with a CT scanner, point of care laboratory system, along with teleradiological support. In a radical reconfiguration of stroke care, the MSU would bring the CT scanner to the stroke patient, without waiting for the patient at the emergency room. Two separate MSU projects in Saarland and Berlin demonstrated the safety and feasibility of this concept for prehospital stroke care, showing increased rate of intravenous thrombolysis and significant reduction in time to treatment compared to conventional care. MSU also improved the triage of patients to appropriate and specialized hospitals. Although multiple issues remain yet unanswered with the MSU concept including clinical outcome and cost-effectiveness, the MSU venture is visionary and enables delivery of life-saving and enhancing treatment for ischemic and hemorrhagic stroke. In this review, we discuss the development of mobile CT and its applications, with specific focus on its use in MSUs along with our institution's MSU experience. PMID- 26593632 TI - Bayesian evidence synthesis for exploring generalizability of treatment effects: a case study of combining randomized and non-randomized results in diabetes. AB - In this paper, we present a unified modeling framework to combine aggregated data from randomized controlled trials (RCTs) with individual participant data (IPD) from observational studies. Rather than simply pooling the available evidence into an overall treatment effect, adjusted for potential confounding, the intention of this work is to explore treatment effects in specific patient populations reflected by the IPD. In this way, by collecting IPD, we can potentially gain new insights from RCTs' results, which cannot be seen using only a meta-analysis of RCTs. We present a new Bayesian hierarchical meta-regression model, which combines submodels, representing different types of data into a coherent analysis. Predictors of baseline risk are estimated from the individual data. Simultaneously, a bivariate random effects distribution of baseline risk and treatment effects is estimated from the combined individual and aggregate data. Therefore, given a subgroup of interest, the estimated treatment effect can be calculated through its correlation with baseline risk. We highlight different types of model parameters: those that are the focus of inference (e.g., treatment effect in a subgroup of patients) and those that are used to adjust for biases introduced by data collection processes (e.g., internal or external validity). The model is applied to a case study where RCTs' results, investigating efficacy in the treatment of diabetic foot problems, are extrapolated to groups of patients treated in medical routine and who were enrolled in a prospective cohort study. PMID- 26593631 TI - RNAi pathways in Mucor: A tale of proteins, small RNAs and functional diversity. AB - The existence of an RNA-mediated silencing mechanism in the opportunistic fungal pathogen Mucor circinelloides was first described in the early 2000. Since then, Mucor has reached an outstanding position within the fungal kingdom as a model system to achieve a deeper understanding of regulation of endogenous functions by the RNA interference (RNAi) machinery. M. circinelloides combines diverse components of its RNAi machinery to carry out functions not only limited to the defense against invasive nucleic acids, but also to regulate expression of its own genes by producing different classes of endogenous small RNA molecules (esRNAs). The recent discovery of a novel RNase that participates in a new RNA degradation pathway adds more elements to the gene silencing-mediated regulation. This review focuses on esRNAs in M. circinelloides, the different pathways involved in their biogenesis, and their roles in regulating specific physiological and developmental processes in response to environmental signals, highlighting the complexity of silencing-mediated regulation in fungi. PMID- 26593633 TI - Bottom-Up Fabrication of Single-Layered Nitrogen-Doped Graphene Quantum Dots through Intermolecular Carbonization Arrayed in a 2D Plane. AB - A single-layered intermolecular carbonization method was applied to synthesize single-layered nitrogen-doped graphene quantum dots (N-GQDs) by using 1,3,5 triamino-2,4,6-trinitrobenzene (TATB) as the only precursor. In this method, the gas produced in the pyrolysis of TATB assists with speeding up of the reactions and expanding the layered distance, so that it facilitates the formation of single-layered N-GQDs (about 80 %). The symmetric intermolecular carbonizations of TATB arrayed in a plane and six nitrogen-containing groups ensure small, uniform sizes (2-5 nm) of the resulting products, and provide high nitrogen doping concentrations (N/C atomic ratio ca. 10.6 %). In addition to release of the produced gas, TATB is almost completely converted into aggregated N-GQDs; thus, relatively higher production rates are possible with this approach. Investigations show that the as-produced N-GQDs have superior fluorescent characteristics; high water solubility, biocompatibility, and low toxicity; and are ready for potential applications, such as biomedical imaging and optoelectronic devices. PMID- 26593634 TI - Characterization of Nanoparticles by Solvent Infrared Spectroscopy. AB - The characterization of the surface chemistry of nanoparticles using infrared spectroscopy of adsorbed solvents is proposed. In conventional IR spectroscopy of nanomaterials the capability of characterizing the chemistry of the surface is limited. To overcome these limitations, we record IR spectra of different solvents inside a fixed bed of the nanopowder to be tested. Using water and different alcohols as solvents enables the characterization of the nanomaterial's surface chemistry via the molecular interactions affecting the hydrogen-bonding network in the solvent. Different ceramic nanopowders (titania, two different iron oxides, and iron oxide nanocrystallites embedded in a closed silica matrix) are studied using water, ethanol, and n-butanol as solvents. The OH stretching region of the IR spectra reveals characteristic differences in the surface chemistry of the nanoparticles. The proposed method is fast and straightforward, and hence, it can be a versatile tool for rapid screening. PMID- 26593635 TI - The Electronic Spectrum of the Fulvenallenyl Radical. AB - The fulvenallenyl radical was produced in 6 K neon matrices after mass-selective deposition of C7H5(-) and C7H5(+) generated from organic precursors in a hot cathode ion source. Absorption bands commencing at lambda=401.3 nm were detected as a result of photodetachment of electrons from the deposited C7H5(-) and also by neutralization of C7H5(+) in the matrix. The absorption system is assigned to the 1 (2)B1 <-X (2)B1 transition of the fulvenallenyl radical on the basis of electronic excitation energies calculated with the MS-CASPT2 method. The vibrational excitation bands detected in the spectrum concur with the structure of the fulvenallenyl radical. Employing DFT calculations, it is found that the fulvenallenyl anion and its radical are the global minima on the potential energy surface among plausible structures of C7H5. PMID- 26593636 TI - Pancreatic islet autotransplantation for nonmalignant and malignant indications. AB - The standard therapy for patients with chronic pancreatitis (CP) and severe abdominal pain is total pancreatectomy (TP) followed by islet autotransplantation (IAT) to prevent the development of brittle diabetes. In adult patients, narcotic independence is achieved in up to 73% of patients 1 to 5 years after transplantation whereas insulin independence is achieved in up to 40% of patients 1 to 2 years after transplantation. Pediatric patients have shown similar outcomes for narcotic independence (up to 79%) but better outcomes for insulin independence (up to 56% 1 year after transplantation). The quality of life of both adult and pediatric patients improved significantly after TP-IAT using the Medical Outcomes Study SF-36 survey. IAT after pancreatectomy is also performed for patients with benign and malignant disease of the pancreas. The limited studies in this patient population suggest that IAT may be potentially beneficial for carefully selected patients when sufficient numbers of islet cells can be isolated. Further studies involving a larger number of patients are needed to determine the risks and benefits of IAT in patients with malignancy. The feasibility of IAT depends on the availability of a laboratory that can isolate the pancreatic islet cells. An on-site laboratory is the traditional model; however, remote processing of pancreatic islets has been reported to result in successful outcomes. This review discusses the outcomes of adult and pediatric autologous pancreatic islet cell transplantation for CP and pancreatic tumors as well as laboratory processing of pancreatic islet cells. PMID- 26593637 TI - Comment on Patel et al; "Protein transfer-mediated surface engineering to adjuvantate virus-like nanoparticles for enhanced anti-viral immune responses" Nanomedicine, 2015. 11(5): p. 1097-107. PMID- 26593638 TI - Acyclic Cucurbit[n]uril Dendrimers. AB - The synthesis of acyclic cucurbit[n]uril dendrimers G1-G3 that bear four dendrons on their aromatic sidewalls via thiolate S(N)2 chemistry is reported. G1-G3 are polycationic and can bind to pEGFP plasmid DNA as shown by dynamic light scattering (DLS), gel electrophoresis, and scanning electron microscopy (SEM). The gene delivery ability of G1-G3 is presented. PMID- 26593639 TI - Breathing pattern in a phase I clinical trial of intraspinal injection of autologous bone marrow mononuclear cells in patients with amyotrophic lateral sclerosis. AB - The safety of autologous bone marrow mononuclear cells (ABMNC) intraspinal infusion in amyotrophic lateral sclerosis (ALS) patients was evaluated considering breathing and sleep patterns. Patients between 20 and 65 years old were eligible if they had definite ALS, spinal onset, a disease duration between 6 and 36 months, FVC>50%, and a below 90% oxygen saturation (T90) <2% of sleep time. The transplant was performed 6 months after enrollment. ABMNC were infused at thoracic 3-4 level. Eleven patients were included. The REM sleep decreased slightly one year after the cell transplant but not significantly. There were no differences in apnea-hipopnea index, mean oxygen saturation and nadir desaturation evolution. An increase of T90 was observed 180 and 360 days after injection (2.95+/-1.51% and 4.30+/-4.10% respectively), although it was not statistically significant. The central drive determined by occlusion pressure (P01) and inspiratory flow showed non-significant differences after one year. Intramedullary injection of ABMNC did not worsen the cortico medullar diaphragmatic pathways. PMID- 26593640 TI - Aerobic exercise training without weight loss reduces dyspnea on exertion in obese women. AB - Dyspnea on exertion (DOE) is a common symptom in obesity. We investigated whether aerobic exercise training without weight loss could reduce DOE. Twenty-two otherwise healthy obese women participated in a 12-week supervised aerobic exercise training program, exercising 30 min/day at 70-80% heart rate reserve, 4 days/week. Subjects were grouped based on their Ratings of Perceived Breathlessness (RPB) during constant load 60 W cycling: +DOE (n=12, RPB>=4, 37+/ 7 years, 34+/-4 kg/m(2)) and -DOE (n=10, RPB<=2, 32+/-6 years, 33+/-3 kg/m(2)). No significant differences between the groups in body composition, pulmonary function, or cardiorespiratory fitness were observed pre-training. Post training,peak was improved significantly in both groups (+DOE: 12+/-7, -DOE: 14+/ 8%). RPB was significantly decreased in the +DOE (4.7+/-1.0-2.5+/-1.0) and remained low in the -DOE group (1.2+/-0.6-1.3+/-1.0) (interaction p<0.001). The reduction in RPB was not significantly correlated with the improvement in cardiorespiratory fitness. Aerobic exercise training improved cardiorespiratory fitness and DOE and thus appears to be an effective treatment for DOE in obese women. PMID- 26593641 TI - The in vivo respiratory phenotype of the adenosine A1 receptor knockout mouse. AB - The nucleoside adenosine has been implicated in the regulation of respiration, especially during hypoxia in the newborn. In this study the role of adenosine A1 receptors for the control of respiration was investigated in vivo. To this end, respiration of unrestrained adult and neonatal adenosine A1 receptor knockout mice (A1R(-/-)) was measured in a plethysmographic device. Under control conditions (21% O2) and mild hypoxia (12-15% O2) no difference of respiratory parameters was observed between adult wildtype (A1R(+/+)) and A1R(-/-) mice. Under more severe hypoxia (6-10% O2) A1R(+/+) mice showed, after a transient increase of respiration, a decrease of respiration frequency (fR) and tidal volume (VT) leading to a decrease of minute volume (MV). This depression of respiration during severe hypoxia was absent in A1R(-/-) mice which displayed a stimulated respiration as indicated by the enhancement of MV by some 50-60%. During hypercapnia-hyperoxia (3-10% CO2/97-90 % O2), no obvious differences in respiration of A1R(-/-) and A1R(+/+) was observed. In neonatal mice, the respiratory response to hypoxia was surprisingly similar in both genotypes. However, neonatal A1R(-/-) mice appeared to have more frequently periods of apnea during hypoxia and in the post-hypoxic control period. In conclusion, these data indicate that the adenosine A1 receptor is an important molecular component mediating hypoxic depression in adult mice and it appears to stabilize respiration of neonatal mice. PMID- 26593642 TI - Respiratory modulation of sympathetic nerve activity is enhanced in male rat offspring following uteroplacental insufficiency. AB - Sympathetic nerve activity to the cardiovascular system displays prominent respiratory-related modulation which leads to the generation of rhythmic oscillations in blood pressure called Traube-Hering waves. An amplification of this respiratory modulation of sympathetic activity is observed in hypertension of both genetic, the spontaneously hypertensive rat, and induced, chronic intermittent hypoxia or maternal protein restriction during gestation, origin. Male offspring of mothers with uteroplacental insufficiency, induced by bilateral uterine vessel ligation at 18 days of gestation, are also hypertensive in adulthood. In this study we examined whether these male offspring display altered respiratory modulation of sympathetic activity at pre-hypertensive ages compared to controls. Respiratory, cardiovascular and sympathetic parameters were examined using the working heart-brainstem preparation in 35 day old male rats that had reduced birth weight due to uteroplacental insufficiency. Whilst all respiratory parameters were not different between groups, we observed an enhanced respiratory related burst of thoracic sympathetic nerve activity and amplified Traube-Hering waves in the growth-restricted group. This group also showed an increased sympathetic and bradycardic response to activation of peripheral chemoreceptors. The observations add support to the view that altered respiratory modulation of sympathetic activity represents a common mechanism involved in the development of several forms of hypertension. PMID- 26593643 TI - Hydrophilic Magnetochromatic Nanoparticles with Controllable Sizes and Super-high Magnetization for Visualization of Magnetic Field Intensity. AB - Hydrophilic Fe3O4 nanoparticles with controllable size and shape have been fabricated using a facile solvothermal approach followed by surface modification with polyacrylic acid (PAA). The nanoparticles form one-dimension photonic crystal structure under external magnetic field ranging from 29.6 to 459 G. The reflection peaks of formed photonic crystals cover the entire visible spectrum, which indicates a good magnetochromatic property and prospect of wide applications. The size and shape of Fe3O4 nanoparticles are controlled by changing the ratio between ethylene glycol and diethylene glycol. In the process of surface modification, PAA synthesized by free radical polymerization was chemisorbed onto the surface of Fe3O4 particles with the aid of Fe(3+) cations, which renders the particles well dispersed in aqueous solution with high thermo stability. The Fe3O4 particles exhibit ferrimagnetism with a high saturation magnetization value of 88.0 emu/g. Both the high magnetization and the wide reflection spectrum under magnetic field make the magnetochromatic nanoparticles a promising material for visualization of the distribution of magnetic field intensity on microfluidic chips. PMID- 26593644 TI - [Raw-meat-based diets (RMBD) as a feeding principle for dogs]. AB - BARF (Bone And Raw Food) is an increasing trend for feeding dogs in Germany. This article provides an overview of the history and principles of this type of feeding. Risks of feeding raw-meat diets include infections of dogs with parasites, bacteria and viruses. Some of these pathogenic organisms also have zoonotic potential. Additionally, raw-meat diets often show nutritional imbalances. Over-supplementation and deficiencies of nutrients are frequently found, especially regarding calcium, the trace elements copper, zinc and iodine, vitamins A and D and the calcium : phosphorus ratio. This malnutrition can cause clinical symptoms. Therefore, checking and optimising the diet by a specialized veterinarian is strongly recommended. PMID- 26593645 TI - Water Lubrication of Stainless Steel using Reduced Graphene Oxide Coating. AB - Lubrication of mechanical systems using water instead of conventional oil lubricants is extremely attractive from the view of resource conservation and environmental protection. However, insufficient film thickness of water due to low viscosity and chemical reaction of water with metallic materials have been a great obstacle in utilization of water as an effective lubricant. Herein, the friction between a 440 C stainless steel (SS) ball and a 440 C stainless steel (SS) plate in water lubrication could be reduced by as much as 6-times by coating the ball with reduced graphene oxide (rGO). The friction coefficient with rGO coated ball in water lubrication was comparable to the value obtained with the uncoated ball in oil lubrication. Moreover, the wear rate of the SS plate slid against the rGO coated ball in water lubrication was 3-times lower than that of the SS plate slid against the uncoated ball in oil lubrication. These results clearly demonstrated that water can be effectively utilized as a lubricant instead of oil to lower the friction and wear of SS components by coating one side with rGO. Implementation of this technology in mechanical systems is expected to aid in significant reduction of environmental pollution caused by the extensive use of oil lubricants. PMID- 26593646 TI - Excitation Gaps of Finite-Sized Systems from Optimally Tuned Range-Separated Hybrid Functionals. AB - Excitation gaps are of considerable significance in electronic structure theory. Two different gaps are of particular interest. The fundamental gap is defined by charged excitations, as the difference between the first ionization potential and the first electron affinity. The optical gap is defined by a neutral excitation, as the difference between the energies of the lowest dipole-allowed excited state and the ground state. Within many-body perturbation theory, the fundamental gap is the difference between the corresponding lowest quasi-hole and quasi-electron excitation energies, and the optical gap is addressed by including the interaction between a quasi-electron and a quasi-hole. A long-standing challenge has been the attainment of a similar description within density functional theory (DFT), with much debate on whether this is an achievable goal even in principle. Recently, we have constructed and applied a new approach to this problem. Anchored in the rigorous theoretical framework of the generalized Kohn-Sham equation, our method is based on a range-split hybrid functional that uses exact long-range exchange. Its main novel feature is that the range-splitting parameter is not a universal constant but rather is determined from first principles, per system, based on satisfaction of the ionization potential theorem. For finite sized objects, this DFT approach mimics successfully, to the best of our knowledge for the first time, the quasi-particle picture of many-body theory. Specifically, it allows for the extraction of both the fundamental and the optical gap from one underlying functional, based on the HOMO-LUMO gap of a ground-state DFT calculation and the lowest excitation energy of a linear response time-dependent DFT calculation, respectively. In particular, it produces the correct optical gap for the difficult case of charge-transfer and charge transfer-like scenarios, where conventional functionals are known to fail. In this perspective, we overview the formal and practical challenges associated with gap calculations, explain our new approach and how it overcomes previous difficulties, and survey its application to a variety of systems. PMID- 26593647 TI - A Novel Strategy to Study Electrostatic Effects in Chemical Reactions: Differences between the Role of Solvent and the Active Site of Chalcone Isomerase in a Michael Addition. AB - The electrostatic behavior of active site residues in enzyme catalysis is quite different from that of water molecules in solution. To highlight the electrostatic differences between both environments, we propose a QM/MM strategy to study the role of the environment in chemical reactions. The novelty of the present communication is that free energy surfaces are generated by means of two distinguished reaction coordinates: a solute coordinate and the electrostatic potential created by the environment. This is applied to analyze the origin of catalysis in the transformation of a chalcone into a flavanone, a Michael addition that requires the desolvation of the nucleophile. PMID- 26593648 TI - Improved Treatment of Surrounding Effects: UV/vis Absorption Properties of a Solvated Ru(II) Complex. AB - The UV/vis and circular-dichroism spectra of a bis-bipyridinyl ruthenium complex are computed at the density functional theory level and the time dependent density functional level of theory. The effects of the solvent, here water, have been taken into account, by polarizable continuum methods and by a hybrid quantum mechanics/molecular-mechanics approach combined with molecular dynamics. The effects of the solvent have been decomposed in geometric, electrostatic, and polarization of the environment. The principal transitions have been analyzed by means of natural transition orbitals. PMID- 26593649 TI - Modeling the Self-Assembly and Stability of DHPC Micelles Using Atomic Resolution and Coarse Grained MD Simulations. AB - Membrane mimics such as micelles and bicelles are widely used in experiments involving membrane proteins. With the aim of being able to carry out molecular dynamics simulations in environments comparable to experimental conditions, we set out to test the ability of both coarse grained and atomistic resolution force fields to model the experimentally observed behavior of the lipid 1,2-dihexanoyl sn-glycero-3-phosphocholine (DHPC), which is a widely used lipid for biophysical characterization of membrane proteins. It becomes clear from our results that a satisfactory modeling of DHPC aggregates in solution poses different demands to the force field than do the modeling of bilayers. First, the representation of the short tailed lipid DHPC in the coarse grained force field MARTINI is assessed with the intend of successfully self-assemble micelles with structural characteristics comparable to experimental data. Then, the use of the recently presented polarizable water model in MARTINI is shown to be essential for producing micelles that are structurally in accordance with experiments. For the atomistic representations of DHPC micelles in solution the GROMOS96 force field with lipid parameters by A. Kukol fails to maintain stable micelles, whereas the most recent CHARMM36 lipid parameters and GROMOS96 with the so-called Berger lipid parameters both succeed in this regard. PMID- 26593650 TI - Short Time Dynamics of Ionic Liquids in AIMD-Based Power Spectra. AB - Power spectra of several imidazolium-based ionic liquids, 1,3-dimethylimidazolium chloride, 1-ethyl-3-methylimidazolium thiocyanate, 1-ethyl-3-methylimidazolium dicyanamide 5, 1-butyl-3-methylimidazolium chloride, 1-butyl-3-methylimidazolium thiocyanate, and 1-butyl-3-methylimidazolium dicyanamide, are presented based on ab initio molecular dynamics simulations. They provide an alternative tool of analysis of several electronic structure-based properties, in particular, those related to the strength of hydrogen bonding in liquids. Moreover, they can be employed to interpret experimental IR or Raman spectra, avoiding the additional calculations required for theoretical IR or Raman spectra. The obtained power spectra are shown to be in good agreement with experimental spectra, and electronic structure properties related to them are analyzed. Further, there are indications for a locality of the power spectra on a relatively short time scale of ~10 ps or system size of about 8 ion pairs as already speculated in previous work. PMID- 26593651 TI - Ultrametricity in Protein Folding Dynamics. AB - The free energy of the transition state (TS) between two nodes of an ergodic Markov state model (MSM) can be obtained from the minimum cut, which is the set of edges that has the smallest sum of the flow capacities among all the possible cuts separating the two nodes. Here, we first show that the free energy of the TS is an ultrametric distance. The ultrametric property offers a way to simplify the MSM in a small number of states and, as a consequence, meaningful rate constants (free energy barriers) for the simplified MSM can be defined. We also present a new definition of the cut-based free energy profile (cbFEP), which is useful to check for the existence of a state for which the equilibration is much faster than the time to escape from it. From our analysis, a parallelism emerges between the minimum cut (maximum flow), and transition state theory (TST) or Kramers' theory. PMID- 26593652 TI - Accelerating the Convergence and Reducing the Variance of Path Integral Calculations of Quantum Mechanical Free Energies by Using Local Reference Potentials. AB - We present two new methods to accelerate the convergence of Feynman path integral calculations of thermodynamic partition functions. The first enhancement uses information from instantaneous normal mode (INM) calculations to decrease the number of discretized points necessary to represent the Feynman paths and is denoted the local generalized Pitzer-Gwinn (LGPG) scheme. The second enhancement, denoted harmonically guided variance reduction (HGVR), reduces the variance in Monte Carlo (MC) calculations by exploiting the correlation between the sampling error associated with the sum over paths at a particular centroid location for the accurate potential and for the INM approximation of a model potential, the latter of which can be exactly calculated. The LGPG scheme can reduce the number of quadrature points required along the paths by nearly an order of magnitude, and the HGVR scheme can reduce the number of MC samples needed to achieve a target accuracy by more than an order of magnitude. Numerical calculations are presented for H2O2, a very anharmonic system where torsional motion is important, and H2O, a system more amenable to harmonic reference treatment. PMID- 26593653 TI - Incremental Scheme for Intermolecular Interactions: Benchmarking the Accuracy and the Efficiency. PMID- 26593655 TI - Asymmetric-Lanczos-Chain-Driven Implementation of Electronic Resonance Convergent Coupled-Cluster Linear Response Theory. AB - We present an implementation of the damped coupled-cluster linear response function based on an asymmetric Lanczos chain algorithm for the hierarchy of coupled-cluster approximations CCS (coupled-cluster singles), CC2 (coupled cluster singles and approximate doubles), and CCSD (coupled-cluster singles and doubles). Triple corrections to the excitation energies can be included via the CCSDR(3) (coupled-cluster singles and doubles with noniterative-triples-corrected excitation energies) approximation. The performance and some of the potentialities of the approach are investigated in calculations of the visible/ultraviolet absorption spectrum and the dispersion of the real polarizability in near-resonant regions of pyrimidine, the near-edge absorption fine structure (NEXAFS) of ammonia, and the direct determination of the C6 dipole dipole dispersion coefficient of the benzene dimer. PMID- 26593654 TI - DFVB: A Density-Functional-Based Valence Bond Method. AB - A new ab initio valence bond method with density-functional-based correlation correction, so-called DFVB, is presented. In the DFVB method, the dynamic correlation energy is taken into account by use of density correlation functional(s), while the static correlation energy is covered by the VBSCF wave function. Owing to incorporation of DFT methods, DFVB provides an economic route to improving the accuracy of ab initio VB theory. Various tests of the method are presented, including the spectroscopic parameters of a series of diatomic molecules, the dipole moments of the NF molecule for different electronic states, and the singlet-triplet gaps of the diradical species, chemical reactions barriers, and total charge-shift resonance energies. These tests show that DFVB is capable of providing high accuracy with relatively low computational cost by comparison to the currently existing post-VBSCF methods. PMID- 26593656 TI - Why are the Interaction Energies of Charge-Transfer Complexes Challenging for DFT? AB - The description of ground state charge-transfer complexes is highly challenging. Illustrative examples include large overestimations of charge-transfer by local and semilocal density functional approximations as well as inaccurate binding energies. It is demonstrated here that standard density functionals fail to accurately describe interaction energies of charge-transfer complexes not only because of the missing long-range exchange as generally assumed but also as a result of the neglect of weak interactions. Thus, accounting for the missing van der Waals interactions is of key importance. These assertions, based on the evaluation of the extent of stabilization due to dispersion using both DFT coupled with our recent density-dependent dispersion correction (dDsC) and high level ab initio computations, reflect the imperfect error-cancellation between the overestimation of charge-transfer and the missing long-range interactions. An in-depth energy decomposition analysis of an illustrative series of four small ambidentate molecules (HCN, HNC, HF, and ClF) bound together with NF3 provides the main conclusions, which are validated on a prototypical organic charge transfer complex (i.e., tetrathiafulvalene-tetracyanoquinodimethane, TTF-TCNQ). We establish that the interaction energies for charge-transfer complexes can only be properly described when using well-balanced functionals such as PBE0-dDsC, M06 2X, and LC-BOP-LRD. PMID- 26593657 TI - Spin-Orbit Coupling and Outer-Core Correlation Effects in Ir- and Pt-Catalyzed C H Activation. AB - The transition metal-dependent spin-orbit coupling (SOC) and outer-core (5s5p) correlation effects in Ir- and Pt-catalyzed C-H activation processes are studied here using high level ab initio computations. The catalysts involve complexes with oxidation states: Ir(I), Ir(III), Pt(0), and Pt(II). It is demonstrated that for these heavy 5d transition metal-containing systems, the SOC effect and outer core correlation effect on C-H activation are up to the order of ~1 kcal/mol, and should be included if chemical accuracy is aimed. The interesting trends in our studied systems are: (1) the SOC effect consistently increases the C-H activation barriers and is apparently larger in higher oxidation states (Pt(II) and Ir(III)) than in low-oxidation states (Pt(0) and Ir(I)); and (2) the magnitude of outer core (5s5p) correlation effects is larger in less coordinate-saturated system. The effect of basis set on the outer-core correlation correction is significant; larger basis sets tend to increase the C-H activation barriers. PMID- 26593658 TI - Hydrocarbon/Water Interactions: Encouraging Energetics and Structures from DFT but Disconcerting Discrepancies for Hessian Indices. AB - In this work, ab initio electronic structure computations have been used to systematically examine the structures and energetics of nine small hydrocarbon molecules interacting with water. Full geometry optimizations and harmonic vibrational frequency calculations were performed on 30 unique dimer configurations with the MP2 method and a triple-zeta correlation consistent basis set (cc-pVTZ for H and aug-cc-pVTZ for C and O, denoted haTZ). Three different estimates of the CCSD(T) complete basis set (CBS) limit interaction energies were determined for all 30 MP2 optimized hydrocarbon/water structures, and they never deviate from their mean by more than 0.07 kcal mol(-1). MP2 and CCSD(T) interaction energies are virtually identical (within 0.05 kcal mol(-1)) for dimer configurations primarily exhibiting CH...O and OH...C type interactions, but MP2 overbinds appreciably in some dimers that exhibited OH...pi type interactions, by as much as 0.3 to 0.4 kcal mol(-1) (or ~10%) for the unsaturated cyclic hydrocarbons examined (1,3-cyclobutadiene, 1,3-cyclopentadiene, and benzene). Four density functional theory (DFT) methods (B3LYP, B97-D, omegaB97X-D, and M06 2X) were also applied to all 30 systems with the haTZ basis set to compare optimized structures, energetics, and numbers of imaginary vibrational frequencies (ni). The B97-D, omegaB97X-D, and M06-2X functionals provide quite reasonable structures and energetics, which is consistent with other studies. This work, however, finds that all 4 DFT methods examined struggle to reliably characterize these potential energy surfaces (PESs). For example, the values of ni from the DFT frequency calculations differed from the corresponding MP2 results for approximately one-third of the stationary points located. PMID- 26593659 TI - Distributions of r1.r2 and p1.p2 in Atoms. AB - We consider the two-electron position and momentum dot products, alpha = r1.r2 and beta = p1.p2, and present a method for extracting their distributions, A(alpha) and B(beta), from molecular wave functions built on Gaussian basis functions. The characteristics of the Hartree-Fock AHF(alpha) and BHF(beta) for He and the first-row atoms are investigated, with particular attention to the effects of Pauli exchange. The effects of electron correlation are studied via the holes, DeltaA(alpha) = A(alpha) - AHF(alpha) and DeltaB(beta) = B(beta) - BHF(beta), and the hole structures are rationalized in terms of radial and angular correlation effects. Correlation effects are also examined through an analysis of the first moments of A(alpha), AHF(alpha), B(beta), and BHF(beta). PMID- 26593660 TI - Reducing and Reversing the Diphosphene-Diphosphinylidene Energy Separation. AB - The dependence of the relative energies of 116 diphosphene and diphosphinylidene compounds on the modification of their structures is studied theoretically. Optimized geometries and relative energies are reported for all structures. With the purpose of investigating the effects of various substituents on the parent PPH2 and HPPH molecules, isodesmic reaction energies were obtained for single and double substitution. In the case of the substitution of both H atoms by lithoxy (OLi) or ONa groups is the diphosphinylidene type structure found to be lower in energy. For the lithoxy group, the energy difference amounts to 33 kcal/mol at CCSD(T) cc-pVTZ level of theory. This result is explained through the natural population analyses, where a very favorable Coulombic attraction is found in the OLi substituted diphosphinylidene structure. The order of the effectiveness of the substituents in lowering the relative energy of the diphosphinylidene structure is OLi > ONa > OH > OSiH3 > OCH3 > OPh > NH2 > N(CH3)2 > F > ONH2 > OBH2 > CH3 > OOH > Ph > BF2 > PH2 > SiH3 > SH > HC?O > Cl > CF3 > Br > SiF3 > NF2 > NO2 > C=CH > OF > CN. Natural bond orbital (NBO) analysis explains other qualitative bonding features, for example, phosphorus-phosphorus bond orders as large as 2.5 for R2PP structures and as small as 1.6 for RPPR structures. PMID- 26593661 TI - The Frozen Cage Model: A Computationally Low-Cost Tool for Predicting the Exohedral Regioselectivity of Cycloaddition Reactions Involving Endohedral Metallofullerenes. AB - Functionalization of endohedral metallofullerenes (EMFs) is an active line of research that is important for obtaining nanomaterials with unique properties that might be used in a variety of fields, ranging from molecular electronics to biomedical applications. Such functionalization is commonly achieved by means of cycloaddition reactions. The scarcity of both experimental and theoretical studies analyzing the exohedral regioselectivity of cycloaddition reactions involving EMFs translates into a poor understanding of the EMF reactivity. From a theoretical point of view, the main obstacle is the high computational cost associated with this kind of studies. To alleviate the situation, we propose an approach named the frozen cage model (FCM) based on single point energy calculations at the optimized geometries of the empty cage products. The FCM represents a fast and computationally inexpensive way to perform accurate qualitative predictions of the exohedral regioselectivity of cycloaddition reactions in EMFs. Analysis of the Dimroth approximation, the activation strain or distortion/interaction model, and the noncluster energies in the Diels-Alder cycloaddition of s-cis-1,3-butadiene to X@D3h-C78 (X = Ti2C2, Sc3N, and Y3N) EMFs provides a justification of the method. PMID- 26593662 TI - High-Throughput Characterization of Porous Materials Using Graphics Processing Units. AB - We have developed a high-throughput graphics processing unit (GPU) code that can characterize a large database of crystalline porous materials. In our algorithm, the GPU is utilized to accelerate energy grid calculations, where the grid values represent interactions (i.e., Lennard-Jones + Coulomb potentials) between gas molecules (i.e., CH4 and CO2) and materials' framework atoms. Using a parallel flood fill central processing unit (CPU) algorithm, inaccessible regions inside the framework structures are identified and blocked, based on their energy profiles. Finally, we compute the Henry coefficients and heats of adsorption through statistical Widom insertion Monte Carlo moves in the domain restricted to the accessible space. The code offers significant speedup over a single core CPU code and allows us to characterize a set of porous materials at least an order of magnitude larger than those considered in earlier studies. For structures selected from such a prescreening algorithm, full adsorption isotherms can be calculated by conducting multiple Grand Canonical Monte Carlo (GCMC) simulations concurrently within the GPU. PMID- 26593663 TI - Calculation of the CD Spectrum of a Peptide from Its Conformational Phase Space: The Case of Met-enkephalin and Its Unnatural Analogue. AB - We have investigated the conformational phase spaces of both Met-enkephalin and Ada-enkephalin in 2,2,2-trifluoroethanol in order to connect them to their respective CD spectra. To this end, we have characterized the conformational preferences of the zwitterionic and neutral forms of Met-enkephalin and of both the R- and the S-epimers of Ada-enkephalin, as obtained by classical molecular dynamics. The CD spectrum for each peptide was subsequently obtained with a procedure of successive averaging, which accounts for the behavior of the solvent, the side chains, and the backbone variations of the peptides. To make an appropriate comparison with experimental results, we have produced composite spectra that account for the appropriate contributions of the zwitterionic and neutral forms of the peptides as well as the expected epimeric ratio. Such a procedure results in theoretically obtained CD spectra that show significant promise in terms of reproducing their experimentally measured counterparts. PMID- 26593664 TI - An Efficient N(3)-Scaling Propagation Scheme for Simulating Two-Dimensional Infrared and Visible Spectra. AB - In this paper, we develop and test a new approximate propagation scheme for calculating two-dimensional infrared and visible spectra. The new scheme scales one order more efficiently with the system size than the existing schemes. A Trotter type of approximation is used for the matrix exponent that describes the time evolution of the quantum system. This is needed for calculating the third order response functions governing the two-dimensional infrared and visible spectra. The method is tested on a model dimer system, the amide I spectrum of the Gramicidin A antimicrobial peptide, the spectrum of the OH stretching vibration of bulk water, and a homogeneous J-aggregate. Errors due to the approximation are hardly observable in the calculated spectra. Scaling simulations with different system sizes are used to demonstrate that the new scheme is indeed scaling with the system size to the third power, one order faster than the existing methods. PMID- 26593665 TI - Theoretical Modeling of the Surface-Enhanced Raman Optical Activity. AB - Surface-enhanced Raman optical activity (SEROA) is a new technique combining the sensitivity of the surface-enhanced Raman scattering (SERS) with the detailed information about molecular structure provided by the chiral spectroscopies. So far, experimental SEROA spectra have been reported in several studies, but the interpretation and theoretical background are rather limited. In this work, general expressions for the electromagnetic contribution to SEROA are derived using the matrix polarization theory and used to investigate the enhancement in model systems. The results not only reveal a strong dependence of the enhancement on the distance between the molecule and a metal part but also the dependence of the ratio of ROA and Raman intensities (circular intensity difference, CID) on the distance and rotational averaging. For a ribose model, an optimal molecule colloid distance was predicted which provided the highest CIDs. However, the CID maximum disappeared after a rotational averaging. For cysteine zwitterion, the simulated SEROA and SERS spectra provided a qualitative agreement with previous experiments. PMID- 26593666 TI - On the Need for Spin Polarization in Heterogeneously Catalyzed Reactions on Nonmagnetic Metallic Surfaces. AB - A series of reactions including water, oxygen, hydrogen and nitric oxide dissociation and carbon monoxide or nitric oxide oxidations catalyzed by metallic surfaces have been investigated by means of periodic density functional calculations with the main aim of establishing the importance of spin polarization when the substrate is nonmagnetic. Numerical differences in the calculated total energies and bond lengths of the breaking/forming bonds corresponding to spin restricted or spin unrestricted formalisms are usually smaller than the inherent error of density functional theory based methods. Nevertheless, it is important to insist on the fact that the spin polarized solution exists and is lower in energy than the one corresponding to the spin restricted formalism, as one would expect, and from a practical point of view, results obtained without taking spin polarization into account lead to the same description of the potential energy surface. PMID- 26593667 TI - A Straightforward Approach for the Determination of the Maximum Time Step for the Simulation of Nanometric Metallic Systems. AB - In the present work, we report on a systematic analysis to determine the maximum time step allowed in molecular dynamics simulations applied to study metal systems of current interest in nanoscience. Using the velocity Verlet integration scheme, we have found that it is possible to use a 20 fs time step for the simulation of gold nanosystems. This is roughly an order of magnitude greater than the usually employed integration step (2 to 5 fs). We also propose a general criterion to select this maximum time step for other metallic nanosystems, even in the case of bimetallic nanosystems. PMID- 26593668 TI - Insight into the Properties of Cardiolipin Containing Bilayers from Molecular Dynamics Simulations, Using a Hybrid All-Atom/United-Atom Force Field. AB - Simulation of three models of cardiolipin (CL) containing membranes using a new set of parameters for tetramyristoyl and tetraoleoyl CLs has been developed in the framework of the united-atom CHARMM27-UA and the all-atom CHARMM36 force fields with the aim of performing molecular dynamics (MD) simulations of cardiolipin-containing mixed-lipid membranes. The new parameters use a hybrid representation of all-atom head groups in conjunction with implicit-hydrogen united-atom (UA) to describe the oleoyl and myristoyl chains of the CLs, in lieu of the fully atomistic description, thereby allowing longer simulations to be undertaken. The physicochemical properties of the bilayers were determined and compared with previously reported data. Furthermore, using tetramyristoyl CL mixed with POPG and POPE lipids, a mitochondrial membrane was simulated. The results presented here show the different behavior of the bilayers as a result of the lipid composition, where the length of the acyl chain and the conformation of the headgroup can be associated with the mitochondrial membrane properties. The new hybrid CL parameters prove to be well suited for the simulation of the molecular structure of CL-containing bilayers and can be extended to other lipid bilayers composed of CLs with different acyl chains or alternate head groups. PMID- 26593669 TI - How Does Darunavir Prevent HIV-1 Protease Dimerization? AB - The drug Darunavir (DRV) is a potent inhibitor of HIV-1 protease (PR), a homodimeric essential enzyme of the AIDS virus. Recent experimental data suggest that DRV is able to prevent dimerization of HIV-1 PR, which, together with its high affinity for the mature enzyme, has been linked to the high genetic barrier to the development of viral resistance. The mechanism of dimerization inhibition and the binding mode(s) of DRV to monomeric HIV-1 PR are unknown. Here, multiple molecular dynamics simulations with explicit solvent (for a total of 11 MUs with the CHARMM force field and 1 MUs with the Amber force field) show that the monomer of HIV-1 PR is structurally stable and reveal a major binding mode of DRV. This binding mode is stabilized by favorable interactions between the apolar groups of DRV and the hydrophobic residues Ile32, Ile47, Ile50, Ile54, Pro79, Val82, and Ile84. The binding mode to monomeric HIV-1 PR identified by molecular dynamics is different from the two binding modes observed in the crystal structure of the complex with dimeric HIV-1 PR. As an example, there are no interactions between DRV and the catalytic Asp25 in the binding mode to monomeric HIV-1 PR revelead by the simulations. In contrast, the simulations show extensive and stable interactions between DRV and the flap (residues 46-55), which are likely to sterically hinder the formation of the flap interface as observed in the dimeric structure. Which of the two mechanisms of inhibition (dimerization inhibition by association with the flap or binding to the active site of the mature enzyme) dominates might depend on the HIV-1 PR mutations, and it is likely that dimerization inhibition is predominant for multiple mutations at the active site in multidrug resistant strains. PMID- 26593670 TI - A Collective Coordinate to Obtain Free Energy Profiles for Complex Reactions in Condensed Phases. AB - Exploration of chemical reactions in complex explicit environments has become an affordable task with the use of hybrid quantum mechanics/molecular mechanics potentials which allow calculating free energy profiles of chemical reactions under the influence of the surroundings. Tracing these free energy profiles requires the selection of a reaction coordinate, which can be cumbersome for those processes involving more than a single chemical event in a concerted step. We here propose a collective coordinate to be used in the calculation of free energy profiles for complex reactions in condensed phases. This coordinate is based in the definition of the advance along a path introduced by Branduardi et al. (J. Chem. Phys.2007, 126, 054103) but modified to use internal coordinates which are more adequate for the description of chemical reactions. The coordinate is tested with the analysis of the isochorismate transformation to pyruvate and salycilate in aqueous solution and in the active site of PchB, a reaction that involves a CO bond breaking simultaneously with a proton transfer between two carbon atoms. The coordinate introduced here allows obtaining smooth and meaningful free energy profiles of the reaction. PMID- 26593671 TI - Kirkwood-Buff Coarse-Grained Force Fields for Aqueous Solutions. AB - We present an approach to systematically coarse-grain liquid mixtures using the fluctuation solution theory of Kirkwood and Buff in conjunction with the iterative Boltzmann inversion method. The approach preserves both the liquid structure at pair level and the dependence of solvation free energies on solvent composition within a unified coarse-graining framework. To test the robustness of our approach, we simulated urea-water and benzene-water systems at different concentrations. For urea-water, three different coarse-grained potentials were developed at different urea concentrations, in order to extend the simulations of urea-water mixtures up to 8 molar urea concentration. In spite of their inherent state point dependence, we find that the single-site models for urea and water are transferable in concentration windows of approximately 2 M. We discuss the development and application of these solvent models in coarse-grained biomolecular simulations. PMID- 26593672 TI - A Multilevel Strategy for the Exploration of the Conformational Flexibility of Small Molecules. AB - Predicting the conformational preferences of flexible compounds is still a challenging problem with important implications in areas such as molecular recognition and drug design. In this work, we describe a multilevel strategy to explore the conformational preferences of molecules. The method relies on the predominant-state approximation, which partitions the conformational space into distinct conformational wells. Moreover, it combines low-level (LL) methods for sampling the conformational minima and high-level (HL) techniques for calibrating their relative stability. In the implementation used in this study, the LL sampling is performed with the semiempirical RM1 Hamiltonian, and solvent effects are included using the RM1 version of the MST continuum solvation model. The HL refinement of the conformational wells is performed by combining geometry optimizations of the minima at the B3LYP (gas phase) or MST-B3LYP (solution) level, followed by single point MP2 computations using Dunning's augmented basis sets. Then, the effective free energy of a conformational well is estimated by combining the MP2 energy, supplemented with the MST-B3LYP solvation free energy for a conformational search in solution, with the local curvature of the well sampled at the semiempirical level. Applications of this strategy involve the exploration of the conformational preferences of 1,2-dichloroethane and neutral histamine in both the gas phase and water solution. Finally, the multilevel strategy is used to estimate the reorganization cost required for selecting the bioactive conformation of HIV reverse transcriptase inhibitors, which is estimated to be at most 1.3 kcal/mol. PMID- 26593673 TI - Protein Loop Modeling with Optimized Backbone Potential Functions. AB - We represented protein backbone potential as a Fourier series. The parameters of the backbone dihedral potential were initialized to random values and optimized by Monte Carlo simulations so that generated native-like loop decoys had a lower energy than non-native decoys. The low energy regions of the optimized backbone potential were consistent with observed Ramachandran plots derived from crystal structures. The backbone potential was then used for the prediction of loop conformations (OSCAR-loop) combining with the previously described OSCAR force field, which has been shown to be very accurate in side chain modeling. As a result, the accuracy of OSCAR-loop was improved by local energy minimization based on the complete force field. The average accuracies were 0.40, 0.70, 1.10, 2.08, and 3.58 A for 4, 6, 8, 10, and 12-residue loops, respectively, with each size being represented by 325 to 2809 targets. The accuracy was better than that of other loop modeling algorithms for short loops (<10 residues). For longer loops, the prediction accuracy was improved by concurrently sampling with a fragment-based method, Spanner. OSCAR-loop is available for download at http://sysimm.ifrec.osaka-u.ac.jp/OSCAR/ . PMID- 26593674 TI - Coarse-Grained Potential Model for Structural Prediction of Confined Water. AB - We propose a coarse-grained potential model to predict the concentration and potential profiles of confined water. In this model, we represent one water molecule with one coarse-grained bead, such that the interactions between the coarse-grained beads are given by isotropic two-body potentials. Due to the inherent inhomogeneity of the confined water microstructure, we find that a single spatially uniform coarse-grained water-water potential may not be sufficient to accurately predict the structure of water near the surface. To accurately capture surface effects on the water structure, we add a coarse grained correction potential between wall atoms and water coarse-grained beads. We use an empirical potential-based quasi-continuum theory (EQT) (J. Chem. Phys.2007, 127, 174701) to derive and evaluate optimal parameters for the coarse grained potential model. We evaluate the ability of our model to predict the structure of confined water for two different types of surfaces-a silicon slit channel and a graphite slit channel-and show that the results predicted by EQT are in good agreement with all-atom molecular dynamics results across multiple length scales. We also demonstrate that the coarse-grained potential parameters optimized using EQT work well even in the coarse-grained molecular dynamics simulations. PMID- 26593675 TI - Optimization of a Genetic Algorithm for the Functionalization of Fullerenes. AB - We present the optimization of a genetic algorithm (GA) that is designed to predict the most stable structural isomers of hydrogenated and hydroxylated fullerene cages. Density functional theory (DFT) and density functional tight binding (DFTB) methods are both employed to compute isomer energies. We show that DFTB and DFT levels of theory are in good agreement with each other and that therefore both sets of optimized GA parameters are very similar. As a prototypical fullerene cage, we consider the functionalization of the C20 species, since for this smallest possible fullerene cage it is possible to compute all possible isomer energies for evaluation of the GA performance. An energy decomposition analysis for both C20Hn and C20(OH)n systems reveals that, for only few functional groups, the relative stabilities of different structural isomers may be rationalized simply with recourse to pi-Huckel theory. However, upon a greater degree of functionalization, pi-electronic effects alone are incapable of describing the interaction between the functional groups and the distorted cage, and both sigma- and pi-electronic structure must be taken into account in order to understand the relative isomer stabilities. PMID- 26593677 TI - Size-Controlled Intercalation-to-Conversion Transition in Lithiation of Transition-Metal Chalcogenides-NbSe3. AB - Transition-metal chalcogenides (TMCs) can be used either as intercalation cathodes or as conversion-type anodes for lithium ion batteries, for which two distinctively different lithiation reaction mechanisms govern the electrochemical performance of TMCs. However, the factors that control the transition of lithiation mechanisms remain elusive. In this work, we investigated the lithiation process of NbSe3 ribbons using in situ transmission electron microscopy and observed a size-dependent transition from intercalation to the conversion reaction. Large NbSe3 ribbons can accommodate high concentrations of Li(+) through intercalation by relaxing their internal spacing, while lithiation of small NbSe3 ribbons proceeds readily to full conversion. We found that the size-dependent variation of the lithiation mechanism is associated with both Li(+) diffusion in NbSe3 and the accommodation of newly formed phases. For large NbSe3 ribbons, the intercalation-to-conversion transition is impeded by both long range Li(+) diffusion and large-scale accommodation of volume expansion induced by the formation of new phases. These results demonstrate the inherent structural instability of NbSe3 as an intercalation cathode and its high lithiation rate as a promising conversion-type anode. PMID- 26593676 TI - Citron Rho-interacting kinase mediates arsenite-induced decrease in endothelial nitric oxide synthase activity by increasing phosphorylation at threonine 497: Mechanism underlying arsenite-induced vascular dysfunction. AB - We reported that arsenite causes an acute decrease in nitric oxide (NO) production by increasing phosphorylation of endothelial NO synthase at threonine 497 (eNOS-Thr(497)); however, the detailed mechanism has not yet been clarified. Here, we investigated the kinase involving in arsenite-stimulated eNOS-Thr(497) phosphorylation. Although treatment with H-89, a known protein kinase A (PKA) inhibitor, inhibited arsenite-stimulated eNOS-Thr(497) phosphorylation, no inhibition was found in cells treated with other PKA inhibitors, including Rp-8 Br-cAMPS or PKI. Based on previous reports, we also tested whether RhoA mediates arsenite-stimulated eNOS-Thr(497) phosphorylation and found that arsenite causes an acute increase in RhoA activity. Ectopic expression of dominant negative (DN) RhoA significantly reversed arsenite-stimulated eNOS-Thr(497) phosphorylation. An in vitro phosphorylation assay also revealed that the well-known Rho effectors, Rho-associated protein kinase 1/2 (ROCK1/2), directly phosphorylate eNOS Thr(497). Y27632, a selective ROCK inhibitor, reversed arsenite-stimulated eNOS Thr(497) phosphorylation. However, overexpression of a small interfering RNA (siRNA) against ROCK1/2 or DN-ROCK did not reverse arsenite-stimulated eNOS Thr(497) phosphorylation, thereby providing no conclusive evidence of a role for ROCK1/2. Knockdown of PKC-related protein kinase 1/2, another Rho effector, also did not reverse arsenite-stimulated eNOS-Thr(497) phosphorylation. In contrast, we found that transfection with an siRNA against citron Rho-interacting kinase (CRIK), the other downstream effector of Rho, significantly reversed the arsenite induced eNOS-Thr(497) phosphorylation that was accompanied by restoration of eNOS enzymatic activity repressed by arsenite. Moreover, CRIK directly phosphorylated eNOS-Thr(497)in vitro. Finally, we also found that arsenite increased eNOS Thr(497) phosphorylation and decreased acetylcholine-induced vessel relaxation in rat aortas. In conclusion, we demonstrate that arsenite acutely inhibits eNOS enzymatic activity and vessel relaxation in part by increasing the RhoA/CRIK/eNOS Thr(497) phosphorylation signaling axis, which provides a molecular mechanism underlying arsenite-induced impaired vascular diseases. PMID- 26593678 TI - Novel N-pyrimidin-4-yl-3-amino-pyrrolo [3, 4-C] pyrazole derivatives as PKC kinase inhibitors: a patent evaluation of US2015099743 (A1). AB - INTRODUCTION: Protein kinase Cbeta (PKCbeta) is a member of the PKC family of serine/threonine kinases that has been implicated in the pathophysiology of diabetic complications. Developing small molecule drugs targeting this PKC isozyme is a rational approach for treating these disease states. PKCbeta belongs to the conventional class of PKC and contains both regulatory and kinase domain. Numerous compounds of different chemical classes were designed targeting the kinase domain, but achieved very limited success in clinical trials. AREAS COVERED: This patent application reports the synthesis of about 100 new N pyrimidin-4-yl-3-amino-pyrolo [3, 4-C] pyrazole derivatives and their competitive inhibition constant (Ki) for protein kinase C betaII (PKCbetaII), one of the two splice variants of PKCbeta. The compounds compete with ATP at the kinase domain of PKCbetaII, and inhibit with high potency having Ki values in the 0.1-181 nM range. The compounds are claimed to be selective towards PKCbetaI, PKCbetaII and PKCalpha over other protein kinases. Several routes of administration of these compounds are discussed for possible treatment of diabetes and related diseases. EXPERT OPINION: This is an important effort toward developing PKC-based drugs for diabetic complications. Further biological evaluations of these compounds are required before proceeding toward clinical trails. PMID- 26593679 TI - Mass-Spectrometry-Based Proteomics Reveals Organ-Specific Expression Patterns To Be Used as Forensic Evidence. AB - Standard forensic procedures to examine bullets after an exchange of fire include a mechanical or ballistic reconstruction of the event. While this is routine to identify which projectile hit a subject by DNA analysis of biological material on the surface of the projectile, it is rather difficult to determine which projectile caused the lethal injury--often the crucial point with regard to legal proceedings. With respect to fundamental law it is the duty of the public authority to make every endeavor to solve every homicide case. To improve forensic examinations, we present a forensic proteomic method to investigate biological material from a projectile's surface and determine the tissues traversed by it. To obtain a range of relevant samples, different major bovine organs were penetrated with projectiles experimentally. After tryptic "on surface" digestion, mass-spectrometry-based proteome analysis, and statistical data analysis, we were able to achieve a cross-validated organ classification accuracy of >99%. Different types of anticipated external variables exhibited no prominent influence on the findings. In addition, shooting experiments were performed to validate the results. Finally, we show that these concepts could be applied to a real case of murder to substantially improve the forensic reconstruction. PMID- 26593680 TI - Cethrene: A Helically Chiral Biradicaloid Isomer of Heptazethrene. AB - We report the synthesis and properties of "cethrene", the only helically chiral isomer of heptazethrene with a biradicaloid singlet ground state. Cethrene gives a well-resolved EPR spectrum at room temperature and its structure was confirmed by 2D NMR and absorption spectroscopies. Our experiments and calculations show that the helical twist affects its electronic properties and decreases the singlet-triplet energy gap when compared to that of planar heptazethrene. Cethrene undergoes an intramolecular cyclization within several hours at room temperature. PMID- 26593681 TI - Removal of caffeine from pharmaceutical wastewater by adsorption: influence of NOM, textural and chemical properties of the adsorbent. AB - This work involves the study of the influence of textural and chemical adsorbent properties on natural organic matter (NOM) removal and the simultaneous adsorption of caffeine and NOM in pharmaceutical wastewater. The performance of a microporous activated carbon, Calgon F400, a synthesized mesoporous carbon from peach stones and a commercial sepiolite in the removal of NOM of a WWTP effluent, and the competitive adsorption of caffeine/NOM were evaluated. It was evidenced that the microporous structure of the adsorbents significantly conditioned the removal of NOM, finding that F400 activated carbon (microporous volume of 0.46 cm(3) g(-1)) led to a NOM removal of 45%. The presence of NOM in the aqueous medium led to worse adsorption parameters, including adsorption capacity at breakthrough time, mass transfer zone length and fractional bed utilization. Additionally, an overshooting in the Total Organic Carbon concentration (TOC/TOC0 = 1.05) was observed in the sepiolite adsorption fixed-bed experiment, due to the displacement of the background NOM. The tested adsorbents were efficient in the removal of caffeine from a pharmaceutical wastewater, finding a competitive effect between the target compound and the background NOM for the active sites. PMID- 26593682 TI - The Strange Case of the Infarcted Myxoma. AB - In the setting of an acute coronary syndrome, the differential diagnosis between a thrombus and a myxoma may be cumbersome. We describe the case of a patient presenting with an acute coronary syndrome associated with an aneurysmatic apical left ventricular myxoma. PMID- 26593683 TI - Hierarchical Fe3O4@Fe2O3 Core-Shell Nanorod Arrays as High-Performance Anodes for Asymmetric Supercapacitors. AB - Anode materials with relatively low capacitance remain a great challenge for asymmetric supercapacitors (ASCs) to pursue high energy density. Hematite (alpha Fe2O3) has attracted intensive attention as anode material for ASCs, because of its suitable reversible redox reactions in a negative potential window (from 0 V to -1 V vs Ag/AgCl), high theoretical capacitance, rich abundance, and nontoxic features. Nevertheless, the Fe2O3 electrode cannot deliver large volumetric capacitance at a high rate, because of its poor electrical conductivity (~10(-14) S/cm), resulting in low power density and low energy density. In this work, a hierarchical heterostructure comprising Fe3O4@Fe2O3 core-shell nanorod arrays (NRAs) is presented and investigated as the negative electrode for ASCs. Consequently, the Fe3O4@Fe2O3 electrode exhibits superior supercapacitive performance, compared to the bare Fe2O3 and Fe3O4 NRAs electrodes, demonstrating large volumetric capacitance (up to 1206 F/cm(3) with a mass loading of 1.25 mg/cm(2)), as well as good rate capability and cycling stability. The hybrid electrode design is also adopted to prepare Fe3O4@MnO2 core-shell NRAs as the positive electrode for ASCs. Significantly, the as-assembled 2 V ASC device delivered a high energy density of 0.83 mWh/cm(3) at a power density of 15.6 mW/cm(3). This work constitutes the first demonstration of Fe3O4 as the conductive supports for Fe2O3 to address the concerns about its poor electronic and ionic transport. PMID- 26593684 TI - Sample acceptance time criteria, electronic issue and alloimmunisation in thalassaemia. AB - OBJECTIVES: To determine the safety of a 1-week acceptance criteria of sample receipt in laboratory to transfusion commencement in transfusion dependent thalassaemia with respect to alloimmunisation. To determine the safety of electronic issue of blood components in such a setting. METHODS: Retrospective audit of alloimmunisation (1999-2012) and blood exposure in registered thalassaemia patients at a central London thalassaemia centre where the acceptance criteria for the group and save sample from arrival in the laboratory to the time of issue of blood for transfusion for someone who has been transfused in the last 28 days was 1 week, and there was electronic issue protocol for patients who have always had a negative antibody screen (other than temporary positivity in pregnant women receiving prophylactic anti-D or anti Le-a, Anti Le b and Anti P1 that are no longer detectable). RESULTS: There were 133 patients with thalassemia variants regularly attending UCLH for review. A total of 105 patients had transfusion dependent thalassaemia (TDT) (7 E-beta thalassaemia, 98 beta thalassaemia major). Ten of the 84 patients who received their transfusions at UCLH were alloimmunised. Seven of them had been alloimmunised prior to arrival at UCLH. Only two patients developed antibodies at UCLH during this period. CONCLUSION: The prevalence of alloantibody formation of 2% in UCLH transfused patients, with presumptive incidence of 0.01 alloantibodies per 100 units or 0.001 immunisations per person per year compares favourably with other reported series and suggests that 1 week interval with appropriate electronic issue is acceptable practice. PMID- 26593685 TI - Teaching and learning of medical biochemistry according to clinical realities: A case study. AB - To foster medical students to become physicians who will be lifelong independent learners and critical thinkers with healthy skepticism and provide high-quality patient care guided by the best evidence, teaching of evidence-based medicine (EBM) has become an important component of medical education. Currently, the teaching and learning of biochemistry in medical schools incorporates its medical relevance and applications. However, to our knowledge there have been no reports on integrating EBM with teaching and learning medical biochemistry. Here, we present a case study to illustrate the significance of this approach. This case study was based on a biochemistry/nutrition question in a popular board review book about whether a homeless alcoholic man is at risk of developing a deficiency of vitamin E. The possible answers and explanation provided in the book raised a question about the correct answer, which provided us with an opportunity to adapt the philosophy and certain basic EBM principles to find evidence for the clinical applicability of a commonly taught biochemistry topic. The outcome of this case study not only taught us how to conduct an EBM exercise to answer a specific patient question, but also provided us with an opportunity for in-depth teaching and learning of the medical relevance of a specific biochemistry topic based on the best clinical evidence obtained from a systematic research of medical literature. PMID- 26593686 TI - Differential Diagnosis of Genetic Disorders Associated with Moderate to Severe Refractory Eczema and Elevated Immunoglobulin E. AB - The association of moderate to severe eczema and elevated plasma levels of immunoglobulin E is a characteristic not only of atopic dermatitis but also of various genodermatoses: hyperimmunoglobulin E syndromes, Omenn syndrome, Netherton syndrome, peeling skin syndrome type B, severe dermatitis, multiple allergies, and metabolic wasting syndrome, Wiskott-Aldrich syndrome, prolidase deficiency, Loeys-Dietz syndrome, IPEX syndrome, STAT5B deficiency, and pentasomy X. The clinical presentation of these genodermatoses -typically in children- is consistent with severe atopic dermatitis. Immunoglobulin E is elevated from birth and response to conventional treatments is poor. Diagnosis is further complicated by the fact that these genodermatoses often share other clinical manifestations and laboratory findings. We present practical guidelines for differentiating among these various entities, with the aim of helping physicians decide what type of genetic test should be carried out -and when- in order to establish a definitive diagnosis. PMID- 26593688 TI - The resurgence of phenotypic screening in drug discovery and development. PMID- 26593687 TI - Erythema Multiforme Associated With Phenytoin and Cranial Radiation Therapy (EMPACT syndrome) in a Patient With Lung Cancer. PMID- 26593689 TI - Ab initio electronic structure study of a model water splitting dimer complex. AB - A model manganese dimer electrocatalyst bridged by MU-OH ligands is used to investigate changes in spin states that may occur during water oxidation. We have employed restricted open-shell Hartree-Fock (ROHF), second-order Moller-Plesset perturbation theory (MP2), complete active space self-consistent field (CASSCF), and multireference second-order Moller-Plesset perturbation theory (MRMP2) calculations to investigate this system. Multiconfigurational methods like CASSCF and MRMP2 are appropriate methods to study these systems with antiferromagnetically-coupled electrons. Orbital occupations and distributions have been closely analyzed to understand the electronic details and contributions to the water splitting from manganese and oxygen atoms. The presence of Mn(IV)O radical moieties has been observed in this catalytic pathway. Multiple nearly degenerate excited states were found close to the ground state in all structures. This suggests competing potential energy landscapes near the ground state may influence the reactivity of manganese complexes such as the dimers studied in this work. PMID- 26593690 TI - Conversion of nitroalkanes into carboxylic acids via iodide catalysis in water. AB - We report a new method for the conversion of nitroalkanes into carboxylic acids that achieves this transformation under very mild conditions. Catalytic amounts of iodide in combination with a simple zinc catalyst are needed to give good conversions into the corresponding carboxylic acids. PMID- 26593691 TI - Fusion of genomic, proteomic and phenotypic data: the case of potyviruses. AB - Data fusion has been widely applied to analyse different sources of information, combining all of them in a single multivariate model. This methodology is mandatory when different omic data sets must be integrated to fully understand an organism using a systems biology approach. Here, a data fusion procedure is presented to combine genomic, proteomic and phenotypic data sets gathered for Tobacco etch virus (TEV). The genomic data correspond to random mutations inserted in most viral genes. The proteomic data represent both the effect of these mutations on the encoded proteins and the perturbation induced by the mutated proteins to their neighbours in the protein-protein interaction network (PPIN). Finally, the phenotypic trait evaluated for each mutant virus is replicative fitness. To analyse these three sources of information a Partial Least Squares (PLS) regression model is fitted in order to extract the latent variables from data that explain (and relate) the significant variables to the fitness of TEV. The final output of this methodology is a set of functional modules of the PPIN relating topology and mutations with fitness. Throughout the re-analysis of these diverse TEV data, we generated valuable information on the mechanism of action of certain mutations and how they translate into organismal fitness. Results show that the effect of some mutations goes beyond the protein they directly affect and spreads on the PPIN to neighbour proteins, thus defining functional modules. PMID- 26593692 TI - Water Oxidation by the [Co4O4(OAc)4(py)4](+) Cubium is Initiated by OH(-) Addition. AB - The cobalt cubium Co4O4(OAc)4(py)4(ClO4) (1A(+)) containing the mixed valence [Co4O4](5+) core is shown by multiple spectroscopic methods to react with hydroxide (OH(-)) but not with water molecules to produce O2. The yield of reaction products is stoichiometric (>99.5%): 41A(+) + 4OH(-) -> O2 + 2H2O + 41A. By contrast, the structurally homologous cubium Co4O4(trans-OAc)2(bpy)4(ClO4)3, 1B(ClO4)3, produces no O2. EPR/NMR spectroscopies show clean conversion to cubane 1A during O2 evolution with no Co(2+) or Co3O4 side products. Mass spectrometry of the reaction between isotopically labeled MU-(16)O(bridging-oxo) 1A(+) and (18)O-bicarbonate/water shows (1) no exchange of (18)O into the bridging oxos of 1A(+), and (2) (36)O2 is the major product, thus requiring two OH(-) in the reactive intermediate. DFT calculations of solvated intermediates suggest that addition of two OH(-) to 1A(+) via OH(-) insertion into Co-OAc bonds is energetically favored, followed by outer-sphere oxidation to intermediate [1A(OH)2](0). The absence of O2 production by cubium 1B(3+) indicates the reactive intermediate derived from 1A(+) requires gem-1,1-dihydoxo stereochemistry to perform O-O bond formation. Outer-sphere oxidation of this intermediate by 2 equiv of 1A(+) accounts for the final stoichiometry. Collectively, these results and recent literature (Faraday Discuss., doi:10.1039/C5FD00076A and J. Am. Chem. Soc. 2015, 137, 12865-12872) validate the [Co4O4](4+/5+) cubane core as an intrinsic catalyst for oxidation of hydroxide by an inner-sphere mechanism. PMID- 26593693 TI - Estimation of the maintenance energy requirements, methane emissions and nitrogen utilization efficiency of two suckler cow genotypes. AB - Seventeen non-lactating dairy-bred suckler cows (LF; Limousin*Holstein-Friesian) and 17 non-lactating beef composite breed suckler cows (ST; Stabiliser) were used to study enteric methane emissions and energy and nitrogen (N) utilization from grass silage diets. Cows were housed in cubicle accommodation for 17 days, and then moved to individual tie-stalls for an 8-day digestibility balance including a 2-day adaption followed by immediate transfer to an indirect, open-circuit, respiration calorimeters for 3 days with gaseous exchange recorded over the last two of these days. Grass silage was offered ad libitum once daily at 0900 h throughout the study. There were no significant differences (P>0.05) between the genotypes for energy intakes, energy outputs or energy use efficiency, or for methane emission rates (methane emissions per unit of dry matter intake or energy intake), or for N metabolism characteristics (N intake or N output in faeces or urine). Accordingly, the data for both cow genotypes were pooled and used to develop relationships between inputs and outputs. Regression of energy retention against ME intake (r 2=0.52; P<0.001) indicated values for net energy requirements for maintenance of 0.386, 0.392 and 0.375 MJ/kg0.75 for LF+ST, LF and ST respectively. Methane energy output was 0.066 of gross energy intake when the intercept was omitted from the linear equation (r 2=0.59; P<0.001). There were positive linear relationships between N intake and N outputs in manure, and manure N accounted for 0.923 of the N intake. The present results provide approaches to predict maintenance energy requirement, methane emission and manure N output for suckler cows and further information is required to evaluate their application in a wide range of suckler production systems. PMID- 26593694 TI - Unexpected electronic perturbation effects of simple PEG environments on the optical properties of small cadmium chalcogenide clusters. AB - Poly(ethylene glycol) (PEG) has been widely used for the surface protection of inorganic nanoobjects because of its virtually 'inert' nature, but little attention has been paid to its inherent electronic impacts on inorganic cores. Herein, we definitively show, through studies on optical properties of a series of PEG-modified Cd(10)Se(4)(SR)(10) clusters, that the surrounding PEG environments can electronically affect the properties of the inorganic core. For the clusters with PEG units directly attached to an inorganic core (R = (CH(2)CH(2)O)nOCH(3), 1-PEGn, n = 3, ~7, ~17, ~46), the absorption bands, associated with the low-energy transitions, continuously blue-shifted with the increasing PEG chain length. The chain length dependencies were also observed in the photoluminescence properties, particularly in the excitation spectral profiles. By combining the spectral features of several PEG17-modified clusters (2-C(m)-PEG17 and 3) whose PEG and core units are separated by various alkyl chain-based spacers, it was demonstrated that sufficiently long PEG units, including PEG17 and PEG46, cause electronic perturbations in the cluster properties when they are arranged near the inorganic core. These unique effects of the long-PEG environments could be correlated with their large dipole moments, suggesting that the polarity of the proximal chemical environment is critical when affecting the electronic properties of the inorganic cluster core. PMID- 26593695 TI - Azathioprine is effective for oral involvement in Crohn's disease but not for orofacial granulomatosis alone. AB - BACKGROUND: There have been no previous reports assessing the effectiveness of azathioprine (AZA) in the treatment of orofacial granulomatosis (OFG). This report is a review of patients receiving AZA for active OFG with or without concomitant gut Crohn's disease (CD) in a specialist tertiary referral centre. METHODS: Clinical response was defined by Global Physician Assessment at 4-, 12- and 24-month follow-up and a standardised oral disease activity score (ODAS). RESULTS: Sixty of 215 patients seen with OFG in our clinic over a 12-year period were treated with AZA. Of these, 22 had concomitant CD. The proportion of patients responding to AZA with a diagnosis of CD/OFG vs. OFG only at 4, 12 and 24 months were 54% vs. 21% (P = 0.03), 59% vs. 21% (P = 0.003) and 41% vs. 24% (P = 0.16), respectively. A statistically significant difference was seen between starting and follow-up ODAS scores at 4 months in the CD/OFG group which was not observed in the OFG only group. Factors predicting a need for AZA included a diagnosis of intestinal CD, sulcal swelling, sulcal ulcers and upper lip involvement. The factor predicting response to treatment was a diagnosis of CD at 12 months of follow-up. No difference in the number of adverse effects was observed between the two groups of patients. CONCLUSIONS: AZA is significantly more effective in the treatment of oral disease with a concurrent diagnosis of CD rather than in the treatment of OFG alone. PMID- 26593696 TI - In vitro screening of metal oxide nanoparticles for effects on neural function using cortical networks on microelectrode arrays. AB - Nanoparticles (NPs) may translocate to the brain following inhalation or oral exposures, yet higher throughput methods to screen NPs for potential neurotoxicity are lacking. The present study examined effects of 5 CeO2 (5- 1288 nm), and 4 TiO2 (6-142 nm) NPs and microparticles (MP) on network function in primary cultures of rat cortex on 12 well microelectrode array (MEA) plates. Particles were without cytotoxicity at concentrations <=50 ug/ml. After recording 1 h of baseline activity prior to particle (3-50 ug/ml) exposure, changes in the total number of spikes (TS) and # of active electrodes (#AEs) were assessed 1, 24, and 48 h later. Following the 48 h recording, the response to a challenge with the GABAA antagonist bicuculline (BIC; 25 uM) was assessed. In all, particles effects were subtle, but 69 nm CeO2 and 25 nm TiO2 NPs caused concentration-related decreases in TS following 1 h exposure. At 48 h, 5 and 69 nm CeO2 and 25 and 31 nm TiO2 decreased #AE, while the two MPs increased #AEs. Following BIC, only 31 nm TiO2 produced concentration-related decreases in #AEs, while 1288 nm CeO2 caused concentration-related increases in both TS and #AE. The results indicate that some metal oxide particles cause subtle concentration related changes in spontaneous and/or GABAA receptor-mediated neuronal activity in vitro at times when cytotoxicity is absent, and that MEAs can be used to screen and prioritize nanoparticles for neurotoxicity hazard. PMID- 26593697 TI - Influence of additives on the structure of surfactant-free microemulsions. AB - We study the addition of electrolytes to surfactant-free microemulsions in the domain where polydisperse pre-Ouzo aggregates are present. As in previous studies, the microemulsion is the ternary system water/ethanol/1-octanol, where ethanol acts as co-solvent. Addition of electrolytes modifies the static X-ray and neutron scattering, and dynamic light scattering patterns, as well as the position of the miscibility gap, where spontaneous emulsification occurs upon dilution with water. All observations can be rationalized considering that electrolytes are either "salting out" the ethanol, which is the main component of the interface stabilizing the aggregates, or producing charge separation via the antagonistic ion effect discovered by Onuki et al. Amphiphilic electrolytes, such as sodium dodecylsulfate or sodium dietheylhexylphosphate, induce a gradual transition towards monodisperse ionic micelles with their characteristic broad scattering "peak". In these micelles the ethanol plays then the role of a cosurfactant. Dynamic light scattering can only be understood by combination of fluctuations of aggregate concentration due to the vicinity of a critical point and in-out fluctuations of ethanol. PMID- 26593698 TI - Evidence of discrete yellowfin tuna (Thunnus albacares) populations demands rethink of management for this globally important resource. AB - Tropical tuna fisheries are central to food security and economic development of many regions of the world. Contemporary population assessment and management generally assume these fisheries exploit a single mixed spawning population, within ocean basins. To date population genetics has lacked the required power to conclusively test this assumption. Here we demonstrate heterogeneous population structure among yellowfin tuna sampled at three locations across the Pacific Ocean (western, central, and eastern) via analysis of double digest restriction site associated DNA using Next Generation Sequencing technology. The differences among locations are such that individuals sampled from one of the three regions examined can be assigned with close to 100% accuracy demonstrating the power of this approach for providing practical markers for fishery independent verification of catch provenance in a way not achieved by previous techniques. Given these results, an extended pan-tropical survey of yellowfin tuna using this approach will not only help combat the largest threat to sustainable fisheries (i.e. illegal, unreported, and unregulated fishing) but will also provide a basis to transform current monitoring, assessment, and management approaches for this globally significant species. PMID- 26593699 TI - Characterizing the transplanar and in-plane water transport properties of fabrics under different sweat rate: Forced Flow Water Transport Tester. AB - The water absorption and transport properties of fabrics are critical to wear comfort, especially for sportswear and protective clothing. A new testing apparatus, namely Forced Flow Water Transport Tester (FFWTT), was developed for characterizing the transplanar and in-plane wicking properties of fabrics based on gravimetric and image analysis technique. The uniqueness of this instrument is that the rate of water supply is adjustable to simulate varying sweat rates with reference to the specific end-use conditions ranging from sitting, walking, running to other strenuous activities. This instrument is versatile in terms of the types of fabrics that can be tested. Twenty four types of fabrics with varying constructions and surface finishes were tested. The results showed that FFWTT was highly sensitive and reproducible in differentiating these fabrics and it suggests that water absorption and transport properties of fabrics are sweat rate-dependent. Additionally, two graphic methods were proposed to map the direction of liquid transport and its relation to skin wetness, which provides easy and direct comparison among different fabrics. Correlation analysis showed that FFWTT results have strong correlation with subjective wetness sensation, implying validity and usefulness of the instrument. PMID- 26593702 TI - The Acceptability Limit in Food Shelf Life Studies. AB - Despite its apparently intuitive nature, the acceptability limit is probably the most difficult parameter to be defined when developing a shelf life test. Although it dramatically affects the final shelf life value, it is surprising that discussion on its nature has been largely neglected in the literature and only rare indications about the possible methodologies for its determination are available in the literature. This is due to the fact that the definition of this parameter is a consumer- and market-oriented issue, requiring a rational evaluation of the potential negative consequences of food unacceptability in the actual market scenario. This paper critically analyzes the features of the acceptability limit and the role of the decision maker. The methodologies supporting the choice of the acceptability limit as well as acceptability limit values proposed in the literature to calculate shelf life of different foods are reviewed. PMID- 26593700 TI - The Molecular Basis for Dual Fatty Acid Amide Hydrolase (FAAH)/Cyclooxygenase (COX) Inhibition. AB - The design of multitarget-directed ligands is a promising strategy for discovering innovative drugs. Here, we report a mechanistic study that clarifies key aspects of the dual inhibition of the fatty acid amide hydrolase (FAAH) and the cyclooxygenase (COX) enzymes by a new multitarget-directed ligand named ARN2508 (2-[3-fluoro-4-[3-(hexylcarbamoyloxy)phenyl]phenyl]propanoic acid). This potent dual inhibitor combines, in a single scaffold, the pharmacophoric elements often needed to block FAAH and COX, that is, a carbamate moiety and the 2 arylpropionic acid functionality, respectively. Molecular modeling and molecular dynamics simulations suggest that ARN2508 uses a noncovalent mechanism of inhibition to block COXs, while inhibiting FAAH via the acetylation of the catalytic Ser241, in line with previous experimental evidence for covalent FAAH inhibition. This study proposes the molecular basis for the dual FAAH/COX inhibition by this novel hybrid scaffold, stimulating further experimental studies and offering new insights for the rational design of novel anti inflammatory agents that simultaneously act on FAAH and COX. PMID- 26593703 TI - Selection of best-performing reference gene products for investigating transcriptional regulation across silvering in the European eel (Anguilla anguilla). AB - The focus of the present study was to set a methodological approach for evaluating molecular mechanisms underlying silvering transformation in the European eel, Anguilla anguilla. Silvering is a tightly controlled process during which eels undergo significant morphological, physiological and behavioral changes, pre-adapting for the oceanic spawning migration. Female eels showing different silver indexes were caught in different seasons in the Comacchio Lagoon (North Adriatic Sea, Italy). Isolated hepatocytes from these eels were selected as the experimental model given the relevant role of these cells in metabolic functions potentially altered during silvering. Expression profiles of 7 candidate reference transcripts were analyzed seeking the most viable and robust strategies for accurate qPCR data normalization during silvering. Stability analysis and further statistical validation identified transcripts encoding the ribosomal proteins L13 and ARP as the appropriate reference genes in studies on A. anguilla through silvering. The identified reference transcripts were further used to evaluate expression profiles of target transcripts encoding the thyroid hormone receptor beta (THRbeta) and vitellogenin (vtg), known to be involved in silvering processes. To the best of our knowledge, this is the first study comparing THRbeta expression in European eels across silvering. PMID- 26593704 TI - Modeling the spread and control of dengue with limited public health resources. AB - A deterministic model for the transmission dynamics of dengue fever is formulated to study, with a nonlinear recovery rate, the impact of available resources of the health system on the spread and control of the disease. Model results indicate the existence of multiple endemic equilibria, as well as coexistence of an endemic equilibrium with a periodic solution. Additionally, our model exhibits the phenomenon of backward bifurcation. The results of this study could be helpful for public health authorities in their planning of a proper resource allocation for the control of dengue transmission. PMID- 26593706 TI - Diagnostic uncertainty of herpangina and hand-foot-and-mouth disease and its impact on national enterovirus syndromic monitoring. AB - The community burden of enterovirus is often monitored through syndromic monitoring systems based on reported cases of enterovirus-related infection (EVI) diagnoses. The extent to which this is affected by under- and over-diagnosis has not been reported. In Taiwan, children often make more than one healthcare visit during an episode of infection. We used change of diagnosis within an episode of infection as a guide of diagnostic uncertainty in a nationally representative cohort of Taiwanese children (n = 13 284) followed from birth to the 9th birthday through electronic health records. We conducted a nested case-control analysis and estimated cross-diagnosis ratios (CDRs) as the observed proportion of acute respiratory infection (ARI) diagnoses following an EVI diagnosis in excess of background ARI burdens. With 19 357 EVI diagnoses in this cohort, the CDR within 7 days was 1.51 (95% confidence interval 1.45-1.57), confirming a significant excess of ARI diagnoses within the week following an EVI diagnosis. We used age specific CDRs to calibrate the weekly EVI burden in children aged 3-5 years in 2008, and the difference between observed and calibrated weekly EVI burdens was small. Therefore, there was evidence suggesting a small uncertainty in EVI diagnosis, but the observed EVI burdens through syndromic monitoring were not substantially affected by the small uncertainty. PMID- 26593705 TI - HdeB chaperone activity is coupled to its intrinsic dynamic properties. AB - Enteric bacteria encounter extreme acidity when passing through hosts' stomach. Since the bacterial periplasmic space quickly equilibrates with outer environment, an efficient acid resistance mechanism is essential in preventing irreversible protein denaturation/aggregation and maintaining bacteria viability. HdeB, along with its homolog HdeA, was identified as a periplasmic acid-resistant chaperone. Both proteins exist as homodimers and share similar monomeric structures under neutral pH, while showing different dimeric packing interfaces. Previous investigations show that HdeA functions through an acid-induced dimer-to monomer transition and partial unfolding at low pH (pH 2-3), resulting in exposure of hydrophobic surfaces that bind substrate proteins. In contrast, HdeB appears to have a much higher optimal activation pH (pH 4-5), under which condition the protein maintains a well-folded dimer and the mechanism for its chaperone activity remains elusive. Herein, we present an NMR study of HdeB to investigate its dynamic properties. Our results reveal that HdeB undergoes significant micro- to milli-second timescale conformational exchanges at neutral to near-neutral pH, under the later condition it exhibits optimal activity. The current study indicates that HdeB activation is coupled to its intrinsic dynamics instead of structural changes, and therefore its functional mechanism is apparently different from HdeA. PMID- 26593707 TI - Betaine prevented fructose-induced NAFLD by regulating LXRalpha/PPARalpha pathway and alleviating ER stress in rats. AB - Betaine has been proven effective in treating nonalcoholic fatty liver disease (NAFLD) in animal models, however, its molecular mechanisms remain elusive. The aims of this study were to explore the mechanisms mediating the anti-inflammatory and anti-lipogenic actions of betaine in fructose-fed rats. In this study, betaine improved insulin resistance, reduced body weight gain and serum lipid levels, and prevented hepatic lipid accumulation in fructose-fed rats. It up regulated hepatic expression of liver X receptor-alpha (LXRalpha) and peroxisome proliferator-activated receptor-alpha (PPARalpha), with the attenuation of the changes of their target genes, including hepatic carnitine palmitoyl transferase (CPT) 1alpha, glycosylphosphatidylinositol anchored high density lipoprotein binding protein 1, apolipoprotein B, sterol regulatory element-binding protein 1c and adipocyte differentiation-related protein, involved in fatty acid oxidation and lipid storage in these model rats. Furthermore, betaine alleviated ER stress and inhibited acetyl-CoA carboxylase alpha, CPT II, stearoyl-CoA desaturase 1 and fatty acid synthase expression involved in fatty acid synthesis in the liver of fructose-fed rats. Betaine suppressed hepatic gluconeogenesis in fructose-fed rats by moderating protein kinase B -forkhead box protein O1 pathway, as well as p38 mitogen-activated protein kinase and mammalian target of rapamycin activity. Moreover, betaine inhibited hepatic nuclear factor kappa B /nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 inflammasome activation-mediated inflammation in this animal model. These results demonstrated that betaine ameliorated hepatic lipid accumulation, gluconeogenesis, and inflammation through restoring LXRalpha and PPARalpha expression and alleviating ER stress in fructose-fed rats. This study provides the potential mechanisms of betaine involved in the treatment of NAFLD. PMID- 26593708 TI - Involvement of nitric oxide in anticompulsive-like effect of agmatine on marble burying behaviour in mice. AB - In view of the reports that nitric oxide modulates the neurotransmitters implicated in obsessive-compulsive disorder (OCD), patients with OCD exhibit higher plasma nitrate levels, and drugs useful in OCD influence nitric oxide. Agmatine is a polyamine and widely distributed in mammalian brain which interacts with nitrergic systems. Hence, the present study was carried out to understand the involvement of nitrergic systems in the anticompulsive-like effect of agmatine. We used marble-burying behaviour (MBB) of mice as the animal model of OCD, and nitric oxide levels in hippocampus (HC) and cortex homogenate were measured. Results revealed that, agmatine (20 and 40mg/kg, i.p) significantly inhibited the MBB. Intraperitoneal administration of nitric oxide enhancers viz. nitric oxide precursor - l-arginine (l-ARG) (400mg/kg and 800mg/kg) increased MBB as well as brain nitrites levels, whereas treatment with N(G)-nitro-l-arginine methyl ester (l-NAME) neuronal nitric oxide synthase inhibitor (30mg/kg and 50mg/kg, i.p.) and 7-nitroindazole (7-NI) (20mg/kg and 40mg/kg) attenuated MBB and nitrites levels in brain. Further, in combination studies, the anticompulsive like effect of agmatine (20mg/kg, ip) was exacerbated by prior administration of l-ARG (400mg/kg) and conversely l-NAME (15mg/kg) or 7-NI (10.0mg/kg) attenuated OCD-like behaviour with HC and cortex changes in the levels of NO. None of the above treatment had any significant influence on locomotor activity. In conclusion, Agmatine is effective in ameliorating the compulsive-like behaviour in mice which appears to be related to nitric oxide in brain. PMID- 26593709 TI - Pro-Nuclear Environmentalism: Should We Learn to Stop Worrying and Love Nuclear Energy? AB - In light of repeated failures to reach political agreement on effective policies to combat climate change, pro-nuclear environmentalists have set out to reverse the traditionally anti-nuclear inclinations of environmentalists. This essay examines the ideological commitments and assumptions of pro-nuclear environmentalism by performing a critical, historical analysis of the nuclear environment nexus through the prism of documentary film. We focus on the work and career of documentary filmmaker Rob Stone, whose most recent production, Pandora's Promise (PP) (2013), has emerged as a central statement of this creed. PP actively forges a new political imaginary that replaces the apocalyptic image of nuclear fallout with that of catastrophic climate change. In terms of its rhetorical and visual strategies, however, PP also reveals that pro-nuclear environmentalist arguments have a long lineage. A close study of such continuities reveals a number of political implications that call for reflection as well as caution. PMID- 26593710 TI - Simulation and Spacecraft Design: Engineering Mars Landings. AB - A key issue in history of technology that has received little attention is the use of simulation in engineering design. This article explores the use of both mechanical and numerical simulation in the design of the Mars atmospheric entry phases of the Viking and Mars Pathfinder missions to argue that engineers used both kinds of simulation to develop knowledge of their designs' likely behavior in the poorly known environment of Mars. Each kind of simulation could be used as a warrant of the other's fidelity, in an iterative process of knowledge construction. PMID- 26593711 TI - Networking Biology: The Origins of Sequence-Sharing Practices in Genomics. AB - The wide sharing of biological data, especially nucleotide sequences, is now considered to be a key feature of genomics. Historians and sociologists have attempted to account for the rise of this sharing by pointing to precedents in model organism communities and in natural history. This article supplements these approaches by examining the role that electronic networking technologies played in generating the specific forms of sharing that emerged in genomics. The links between early computer users at the Stanford Artificial Intelligence Laboratory in the 1960s, biologists using local computer networks in the 1970s, and GenBank in the 1980s, show how networking technologies carried particular practices of communication, circulation, and data distribution from computing into biology. In particular, networking practices helped to transform sequences themselves into objects that had value as a community resource. PMID- 26593712 TI - Designing to the Test: Performance Standards and Technological Change in the U.S. Automobile after 1966. AB - Performance standards have played an important part in the regulation of technology for many years, yet they have received little attention from historians. This article presents a three-part framework of analysis for examining the role of regulatory performance standards in technological change. Parts one and two of the framework focus on how regulatory agencies construct and enforce standards for technological risks, or "negative externalities." The final part addresses the important question of whether and how firms choose to internalize these standards in their design procedures and other organizational routines. The article provides examples from the history of automotive regulation in the United States to illustrate each part of the framework, and it gives some thoughts on how regulatory performance standards fit within the voluminous literature on standardization, including other work on de facto and voluntary consensus standards. PMID- 26593713 TI - A Hard Sell: Factors Influencing the Interwar Adoption of Tungsten Carbide Cutting Tools in Germany, Britain, and the United States. AB - Cemented tungsten carbide cutting tools-virtually unknown to historians-came on the market in the late 1920s. Although existing literature alleges that their adoption was rapid and universal, contemporary data indicate that the rate of adoption in fact took many decades and varied greatly between the world's three leading industrialized economies of the time: Germany, England, and the United States. This article suggests that the explanation lies in differing national environments for innovation in the interwar period. It looks at many features that influence adoption by users and argues that the feature emphasized in the literature, increased cutting speed, was not the primary consideration behind adoption, but rather metal shortages. It thereby casts doubt on what measures of national productivity show. The case raises important questions about the use of production efficiency to make international comparisons and about the role of patent monopolies in introducing production innovations. PMID- 26593714 TI - Prophets of Progress: Authority in the Scientific Projections and Religious Realizations of the Great Eastern Steamship. AB - Naval architect John Scott Russell heralded the Great Eastern steamship as a beacon of modern science and used it to promote his own approaches to shipbuilding among Britain's science elites. While Russell defined the project through a rhetoric of science, to popular audiences the ship was analogous to biblical teachings, embodying profound moral lessons. This article places Russell's projections within this wider cultural context of religious interpretation and argues that in Victorian Britain the right to define the meaning of engineering spectacles was not the exclusive privilege of men of science, but open to broader cultural understandings. Religious, as much as scientific, values shaped social constructions of the project. PMID- 26593716 TI - Social accountability for maternal health services in Muanda and Bolenge Health Zones, Democratic Republic of Congo: a situation analysis. AB - BACKGROUND: The Democratic Republic of the Congo is one of the countries in Sub Saharan Africa with the highest maternal mortality ratio estimated at 846 deaths per 100,000 live births. Innovative strategies such as social accountability are needed to improve both health service delivery and utilization. Indeed, social accountability is a form of citizen engagement defined as the 'extent and capability of citizens to hold politicians, policy makers and providers accountable and make them responsive to their needs.' This study explores existing social accountability mechanisms through which women's concerns are expressed and responded to by health providers in local settings. METHODS: An exploratory study was conducted in two health zones with purposively sampled respondents including twenty-five women, five men, five health providers, two health zone officers and eleven community stakeholders. Data on women's voice and oversight and health providers' responsiveness were collected using semi structured interviews and analysed using thematic analysis. RESULTS: In the two health zones, women rarely voiced their concerns and expectations about health services. This reluctance was due to: the absence of procedures to express them, to the lack of knowledge thereof, fear of reprisals, of being misunderstood as well as factors such as age-related power, ethnicity backgrounds, and women's status. The means most often mentioned by women for expressing their concerns were as individuals rather than as a collective. They did not use them instead; instead they looked to intermediaries, mostly, trusted health providers, community health workers and local leaders. Their perceptions of health providers' responsiveness varied. For women, there were no mechanisms for oversight in place. Individual discontent with malpractice was not shown to health providers. In contrast, health providers mentioned community health workers, health committee, and community based organizations as formal oversight mechanisms. All respondents recognized the lack of coalition around maternal health despite the many local associations and groups. CONCLUSIONS: Social accountability is relatively inexistent in the maternal health services in the two health zones. For social accountability to be promoted, efforts need to be made to create its mechanisms and to open the local context settings to dialogue, which appears structurally absent. PMID- 26593717 TI - IL-17 receptor composition. PMID- 26593718 TI - The Fanconi Anemia Pathway Maintains Genome Stability by Coordinating Replication and Transcription. AB - DNA replication stress can cause chromosomal instability and tumor progression. One key pathway that counteracts replication stress and promotes faithful DNA replication consists of the Fanconi anemia (FA) proteins. However, how these proteins limit replication stress remains largely elusive. Here we show that conflicts between replication and transcription activate the FA pathway. Inhibition of transcription or enzymatic degradation of transcription-associated R-loops (DNA:RNA hybrids) suppresses replication fork arrest and DNA damage occurring in the absence of a functional FA pathway. Furthermore, we show that simple aldehydes, known to cause leukemia in FA-deficient mice, induce DNA:RNA hybrids in FA-depleted cells. Finally, we demonstrate that the molecular mechanism by which the FA pathway limits R-loop accumulation requires FANCM translocase activity. Failure to activate a response to physiologically occurring DNA:RNA hybrids may critically contribute to the heightened cancer predisposition and bone marrow failure of individuals with mutated FA proteins. PMID- 26593720 TI - Transcription of Mammalian cis-Regulatory Elements Is Restrained by Actively Enforced Early Termination. AB - Upon recruitment to active enhancers and promoters, RNA polymerase II (Pol II) generates short non-coding transcripts of unclear function. The mechanisms that control the length and the amount of ncRNAs generated by cis-regulatory elements are largely unknown. Here, we show that the adaptor protein WDR82 and its associated complexes actively limit such non-coding transcription. WDR82 targets the SET1 H3K4 methyltransferases and the nuclear protein phosphatase 1 (PP1) complexes to the initiating Pol II. WDR82 and PP1 also interact with components of the transcriptional termination and RNA processing machineries. Depletion of WDR82, SET1, or the PP1 subunit required for its nuclear import caused distinct but overlapping transcription termination defects at highly expressed genes and active enhancers and promoters, thus enabling the increased synthesis of unusually long ncRNAs. These data indicate that transcription initiated from cis regulatory elements is tightly coordinated with termination mechanisms that impose the synthesis of short RNAs. PMID- 26593719 TI - Discovery and Functional Characterization of Diverse Class 2 CRISPR-Cas Systems. AB - Microbial CRISPR-Cas systems are divided into Class 1, with multisubunit effector complexes, and Class 2, with single protein effectors. Currently, only two Class 2 effectors, Cas9 and Cpf1, are known. We describe here three distinct Class 2 CRISPR-Cas systems. The effectors of two of the identified systems, C2c1 and C2c3, contain RuvC-like endonuclease domains distantly related to Cpf1. The third system, C2c2, contains an effector with two predicted HEPN RNase domains. Whereas production of mature CRISPR RNA (crRNA) by C2c1 depends on tracrRNA, C2c2 crRNA maturation is tracrRNA independent. We found that C2c1 systems can mediate DNA interference in a 5'-PAM-dependent fashion analogous to Cpf1. However, unlike Cpf1, which is a single-RNA-guided nuclease, C2c1 depends on both crRNA and tracrRNA for DNA cleavage. Finally, comparative analysis indicates that Class 2 CRISPR-Cas systems evolved on multiple occasions through recombination of Class 1 adaptation modules with effector proteins acquired from distinct mobile elements. PMID- 26593721 TI - Functional Dynamics within the Human Ribosome Regulate the Rate of Active Protein Synthesis. AB - The regulation of protein synthesis contributes to gene expression in both normal physiology and disease, yet kinetic investigations of the human translation mechanism are currently lacking. Using single-molecule fluorescence imaging methods, we have quantified the nature and timing of structural processes in human ribosomes during single-turnover and processive translation reactions. These measurements reveal that functional complexes exhibit dynamic behaviors and thermodynamic stabilities distinct from those observed for bacterial systems. Structurally defined sub-states of pre- and post-translocation complexes were sensitive to specific inhibitors of the eukaryotic ribosome, demonstrating the utility of this platform to probe drug mechanism. The application of three-color single-molecule fluorescence resonance energy transfer (smFRET) methods further revealed a long-distance allosteric coupling between distal tRNA binding sites within ribosomes bearing three tRNAs, which contributed to the rate of processive translation. PMID- 26593722 TI - Monocyte and macrophage contributions to cardiac remodeling. AB - The mammalian heart contains a population of resident macrophages that expands in response to myocardial infarction and hemodynamic stress. This expansion occurs likely through both local macrophage proliferation and monocyte recruitment. Given the role of macrophages in tissue remodeling, their contribution to adaptive processes in the heart is conceivable but currently poorly understood. In this review, we discuss monocyte and macrophage heterogeneity associated with cardiac stress, the cell's potential contribution to the pathogenesis of cardiac fibrosis, and describe different tools to study and characterize these innate immune cells. Finally, we highlight their potential role as therapeutic targets. PMID- 26593723 TI - Role of inflammatory cells in fibroblast activation. AB - Although fibrosis is an essential response to acute cardiac tissue injury, prolonged myofibroblast activation and progressive fibrosis lead to further distortion of tissue architecture and worsened cardiac function. Thus, optimal tissue repair following injury requires tight control over myofibroblast activation. It is now recognized that inflammation plays a critical role in regulating fibrosis. In this review we will highlight how advances in the field of innate immunity have led to a better understanding of the role of inflammation in cardiovascular disease and, in particular, in the regulation of fibrosis. Specifically, we will discuss how the innate immune system recognizes tissue damage in settings of acute injury and chronic cardiovascular disease. We will also review the role of different cell populations in this response, particularly the unique role of different macrophage subsets and mast cells. PMID- 26593724 TI - Bacterial community composition of an urban river in the North West Province, South Africa, in relation to physico-chemical water quality. AB - The aim of this study was to determine the impacts of anthropogenic disturbances on bacterial community composition in an urban river (Mooi River). Physico chemical analysis, bacterial enumeration and 454-pyrosequencing were conducted on the Mooi River system upstream and downstream of an urban settlement in the North West Province, South Africa. Pyrosequencing and multivariate analysis showed that nutrient inputs and faecal pollution strongly impacted the physico-chemical and microbiological quality at the downstream sites. Also, bacterial communities showed higher richness and evenness at the downstream sites. Multivariate analysis suggested that the abundances of Betaproteobacteria, Epsilonproteobacteria, Acidobacteria, Bacteroidetes and Verrucomicrobia are related to temperature, pH, dissolved oxygen (DO), sulphate and chlorophyll-a levels. These results suggest that urbanisation caused the overall water quality of this river to deteriorate, which in turn affected the bacterial community composition. In addition, our work identified potential indicator groups that may be used to track faecal and organic pollution in freshwater systems. PMID- 26593725 TI - Pesticide and trace metals in surface waters and sediments of rivers entering the Corner Inlet Marine National Park, Victoria, Australia. AB - Water and sediment samples were collected from up to 17 sites in waterways entering the Corner Inlet Marine National Park monthly between November 2009 and April 2010, with the Chemcatcher passive sampler system deployed at these sites in November 2009 and March 2010. Trace metal concentrations were low, with none occurring at concentrations with the potential for adverse ecological effects. The agrochemical residues data showed the presence of a small number of pesticides at very low concentration (ng/L) in the surface waters of streams entering the Corner Inlet, and as widespread, but still limited contamination of sediments. Concentrations of pesticides detected were relatively low and several orders of magnitude below reported ecotoxicological effect and hazardous concentration values. The low levels of pesticides detected in this study indicate that agricultural industries were responsible agrochemical users. This research project is a rarity in aligning both agrochemical usage data obtained from chemical resellers in the target catchment with residue analysis of environmental samples. Based on frequency of detection and concentrations, prometryn is the priority chemical of concern for both the water and sediments studied, but this chemical was not listed in reseller data. Consequently, the risks may be greater than the field data would suggest, and priorities for monitoring different since some commonly used herbicides (such as glyphosate, phenoxy acid herbicides, and sulfonyl urea herbicides) were not screened. Therefore, researchers, academia, industry, and government need to identify ways to achieve a more coordinated land use approach for obtaining information on the use of chemicals in a catchment, their presence in waterways, and the longer term performance of chemicals, particularly where they are used multiple times in a year. PMID- 26593726 TI - Distribution and factors affecting adsorption of sterols in the surface sediments of Bosten Lake and Manas Lake, Xinjiang. AB - This study investigated the concentrations and distribution of eight sterol compounds in the surface sediments of Bosten Lake and Manas Lake, Xinjiang, China. The ratios of sterols as diagnostic indices were used to identify pollution sources. The sediment of the two lakes was selected as an adsorbent to investigate the adsorption behaviour of sterols. Results showed that the sterols were widely distributed in the sediments of the lakes in the study areas. The total concentrations of the detected sterols in Bosten Lake and in Manas Lake were 1.584-27.897 and 2.048-18.373 MUg g(-1)?dw, respectively. In all of the sampling sites, the amount of faecal sterols was less than that of plant sterols. beta-sitosterol was the dominant plant sterol with a mean concentration of 2.378 +/- 2.234 MUg g(-1)?dw; cholesterol was the most abundant faecal sterol with a mean concentration of 1.060 +/- 1.402 MUg g(-1)?dw. The pollution level was higher in Bosten Lake than in Manas Lake. Majority of the ratios clearly demonstrated that the contamination by human faecal sources was occurring at stations which are adjacent to residential areas and water inlets. The adsorption behaviour of sterols to sediment suggested that the sterol adsorption coefficients were reduced as temperature increased. As salinity increased, the adsorption quantity also increased. As pH increased, the sediment adsorption of sterol slightly increased because the strong alkaline solution is not conducive to the adsorption of sterols. The ratios between sterols did not change largely with the change in external factors. PMID- 26593727 TI - Macronutrient composition of nickel-treated wheat under different sulfur concentrations in the nutrient solution. AB - The effect of different sulfate(VI) sulfur (2, 6, and 9 mM S) levels and nickel(II) chloride (0, 0.0004, 0.04 and 0.08 mM Ni) in the nutrient solution on productivity and macronutrient (N, P, K, Ca, Mg, S) status and accumulation in spring wheat (Triticum aestivum L.) Zebra cv. was studied. Ni treatment reduced the biomass and disturbed the balance and accumulation of macronutrients in wheat. Intensive S nutrition, especially with 6 mM S, at least partially increased the biomass, improved ionic equilibrium, and enhanced nutrient accumulation in Ni-exposed plants in spite of increased Ni accumulation. Admittedly, the dose 9 mM S reduced Ni accumulation in shoots but increased accumulation thereof in roots. Compared to 6 mM, the dose 9 mM was less effective in improving the mineral status of Ni-treated wheat. PMID- 26593728 TI - Assessment of the environmental significance of nutrients and heavy metal pollution in the river network of Serbia. AB - In this paper, the data for ten water quality variables collected during 2009 at 75 monitoring sites along the river network of Serbia are considered. The results are alarming because 48% of the studied sites were contaminated by Ni, Mn, Pb, As, and nutrients, which are key factors impairing the water quality of the rivers in Serbia. Special attention should be paid to Zn and Cu, listed in the priority toxic pollutants of US EPA for aquatic life protection. The employed Q model cluster analysis grouped the data into three major pollution zones (low, moderate, and high). Most sites classified as "low pollution zones" (LP) were in the main rivers, whereas those classified as "moderate and high pollution zones" (MP and HP, respectively) were in the large and small tributaries/hydro-system. Principal component analysis/factor analysis (PCA/FA) showed that the dissolved metals and nutrients in the Serbian rivers varied depending on the river, the heterogeneity of the anthropogenic activities in the basins (influenced primarily by industrial wastewater, agricultural activities, and urban runoff pollution), and natural environmental variability, such as geological characteristics. In LP dominated non-point source pollution, such as agricultural and urban runoff, whereas mixed source pollution dominated in the MP and HP zones. These results provide information to be used for developing better pollution control strategies for the river network of Serbia. PMID- 26593729 TI - Assessment of factors limiting algal growth in acidic pit lakes--a case study from Western Australia, Australia. AB - Open-cut mining operations can form pit lakes on mine closure. These new water bodies typically have low nutrient concentrations and may have acidic and metal contaminated waters from acid mine drainage (AMD) causing low algal biomass and algal biodiversity. A preliminary study was carried out on an acidic coal pit lake, Lake Kepwari, in Western Australia to determine which factors limited algal biomass. Water quality was monitored to obtain baseline data. pH ranged between 3.7 and 4.1, and solute concentrations were slightly elevated to levels of brackish water. Concentrations of N were highly relative to natural lakes, although concentrations of FRP (<0.01 mg/L) and C (total C 0.7-3.7 and DOC 0.7 3.5 mg/L) were very low, and as a result, algal growth was also extremely low. Microcosm experiment was conducted to test the hypothesis that nutrient enrichment will be able to stimulate algal growth regardless of water quality. Microcosms of Lake Kepwari water were amended with N, P and C nutrients with and without sediment. Nutrient amendments under microcosm conditions could not show any significant phytoplankton growth but was able to promote benthic algal growth. P amendments without sediment showed a statistically higher mean algal biomass concentration than controls or microcosms amended with phosphorus but with sediment did. Results indicated that algal biomass in acidic pit lake (Lake Kepwari) may be limited primarily by low nutrient concentrations (especially phosphorus) and not by low pH or elevated metal concentrations. Furthermore, sediment processes may also reduce the nutrient availability. PMID- 26593730 TI - Prevent the degradation of algicidal ability in Scenedesmus-lysing bacteria using optimized cryopreservation. AB - With the anthropogenic nutrient loading increasing, the frequency and impacts of harmful algal blooms (HABs) have intensified in recent years. To biocontrol HABs, many corresponding algal-lysing bacteria have been exploited successively. However, there are few studies on an effective algal-lysing culture collection to prevent cells from death and particularly the degradation of algicidal ability to their hosts. An optimized cryopreservation was developed and experiments on the validation of this method on preventing algicidal degradation and effects of this optimized cryopreservation on the survival rate of Scenedesmus-lysing bacterium, Enterobacter NP23, isolated from Scenedesmus sp. community, China, on the algicidal dynamic of Scenedesmus wuhanensis was investigated. The optimized cryoprotectant composition consists of 30.0 g/L gelatin, 48.5 g/L sucrose, and 28.4 g/L glycerol, respectively. Using this approach, the survival rate of NP23 cells can still maintain above 90 % and the algal-lysing rate only decline 4 % after the 18-month cryoprotection. Moreover, the 16 generations' passage experiment showed a significant (p < 0.05) genetic stability of algicidal capacity after 18 months. The growth dynamic of S. wuhanensis was investigated in a 5-L bioreactor during 132 h in the absence or presence of NP23. As a result, NP23 has a significant (p < 0.05) inhibition to S. wuhanensis growth when injected into algal culture in the exponential phase at 60th hour. In addition, S. wuhanensis culture initially with NP23 exhibited a slow growth, performing a prolonged lag phase without a clear stationary phase and then rapidly decreased. Our findings, combined with the capacity of preventing the degradation of algicidal ability collectively suggest that the use of this opitimized cryopreservation may be a promising strategy for maintaining algicidal cells. PMID- 26593731 TI - Nanofluid heat transfer under mixed convection flow in a tube for solar thermal energy applications. AB - The solar flat plate collector operating under different convective modes has low efficiency for energy conversion. The energy absorbed by the working fluid in the collector system and its heat transfer characteristics vary with solar insolation and mass flow rate. The performance of the system is improved by reducing the losses from the collector. Various passive methods have been devised to aid energy absorption by the working fluid. Also, working fluids are modified using nanoparticles to improve the thermal properties of the fluid. In the present work, simulation and experimental studies are undertaken for pipe flow at constant heat flux boundary condition in the mixed convection mode. The working fluid at low Reynolds number in the mixed laminar flow range is undertaken with water in thermosyphon mode for different inclination angles of the tube. Local and average coefficients are determined experimentally and compared with theoretical values for water-based Al2O3 nanofluids. The results show an enhancement in heat transfer in the experimental range with Rayleigh number at higher inclinations of the collector tube for water and nanofluids. PMID- 26593733 TI - Newton and scholastic philosophy. AB - This article examines Isaac Newton's engagement with scholastic natural philosophy. In doing so, it makes two major historiographical interventions. First of all, the recent claim that Newton's use of the concepts of analysis and synthesis was derived from the Aristotelian regressus tradition is challenged on the basis of bibliographical, palaeographical and intellectual evidence. Consequently, a new, contextual explanation is offered for Newton's use of these concepts. Second, it will be shown that some of Newton's most famous pronouncements - from the General Scholium appended to the second edition of the Principia (1713) and from elsewhere - are simply incomprehensible without an understanding of specific scholastic terminology and its later reception, and that this impacts in quite significant ways on how we understand Newton's natural philosophy more generally. Contrary to the recent historiographical near consensus, Newton did not hold an elaborate metaphysics, and his seemingly 'metaphysical' statements were in fact anti-scholastic polemical salvoes. The whole investigation will permit us a brief reconsideration of the relationship between the self-proclaimed 'new' natural philosophy and its scholastic predecessors. PMID- 26593732 TI - Oral iron acutely elevates bacterial growth in human serum. AB - Iron deficiency is the most common nutrient deficiency worldwide and routine supplementation is standard policy for pregnant mothers and children in most low income countries. However, iron lies at the center of host-pathogen competition for nutritional resources and recent trials of iron administration in African and Asian children have resulted in significant excesses of serious adverse events including hospitalizations and deaths. Increased rates of malaria, respiratory infections, severe diarrhea and febrile illnesses of unknown origin have all been reported, but the mechanisms are unclear. We here investigated the ex vivo growth characteristics of exemplar sentinel bacteria in adult sera collected before and 4 h after oral supplementation with 2 mg/kg iron as ferrous sulfate. Escherichia coli, Yersinia enterocolitica and Salmonella enterica serovar Typhimurium (all gram-negative bacteria) and Staphylococcus epidermidis (gram-positive) showed markedly elevated growth in serum collected after iron supplementation. Growth rates were very strongly correlated with transferrin saturation (p < 0.0001 in all cases). Growth of Staphylococcus aureus, which preferentially scavenges heme iron, was unaffected. These data suggest that even modest oral supplements with highly soluble (non-physiological) iron, as typically used in low-income settings, could promote bacteremia by accelerating early phase bacterial growth prior to the induction of immune defenses. PMID- 26593734 TI - Challenges in the estimation of extinction from molecular phylogenies: A response to Beaulieu and O'Meara. AB - Time-calibrated phylogenies that contain only living species have been widely used to study the dynamics of speciation and extinction. Concerns about the reliability of phylogenetic extinction estimates were raised by Rabosky (2010), where I suggested that unaccommodated heterogeneity in speciation rate could lead to positively biased extinction estimates. In a recent article, Beaulieu and O'Meara (2015a) correctly point out several technical errors in the execution of my 2010 study and concluded that phylogenetic extinction estimates are robust to speciation rate heterogeneity under a range of model parameters. I demonstrate that Beaulieu and O'Meara underestimated the magnitude of speciation rate variation in real phylogenies and consequently did not incorporate biologically meaningful levels of rate heterogeneity into their simulations. Using parameter values drawn from the recent literature, I find that modest levels of heterogeneity in speciation rate result in a consistent, positive bias in extinction estimates that are exacerbated by phylogenetic tree size. This bias, combined with the inherent lack of information about extinction in molecular phylogenies, suggests that extinction rate estimates from phylogenies of extant taxa only should be treated with caution. PMID- 26593735 TI - Ecological and epidemiological status of species of the Phlebotomus perniciosus complex (Diptera: Psychodidae, Phlebotominae) in Morocco. AB - Leishmania infantum (Kinetoplastida: Trypanosomatidae) infection is transmitted by an infected female sand fly (Diptera: Psychodidae, Phlebotominae) of the subgenus Larroussius: Phlebotomus ariasi, Phlebotomus perniciosus, and Phlebotomus longicuspis in the Mediterranean basin. In Morocco, the vectorial role of P. ariasi was demonstrated, while that of P. longicuspis and P. perniciosus is not elucidated. In addition, Moroccan P. longicuspis and P. perniciosus populations present a higher morphologic and genetic variability. It was classified as P. perniciosus complex, including typical (PN) and atypical (PNA) morphs of P. perniciosus, P. longicuspis sensu stricto (LCss), and a sibling species of P. longicuspis (LCx). With the aim to study the ecological and epidemiological status of P. perniciosus complex species in Morocco, entomological surveys were carried out during three entomological seasons (2012, 2013, and 2014). We collected a total of 6298 specimens from 81 localities of northern, central, and southern Morocco. After describing the geographical distribution of P. perniciosus complex trough Morocco according to many variables (altitude, latitude, and longitude), we discuss the resulting epidemiological implications of its species. Our results highlight the geographical distribution of the two morphs of P. perniciosus through Morocco: PN is limited to the north, while PNA is widespread in northern, central, and southern Morocco. In terms of vectorial role, we hypothesize the potential involvement of PN, LCss, and LCx, at least, with P. ariasi, in the epidemiological cycle of L. infantum in Morocco. PMID- 26593738 TI - Phthalocyanine-Biomolecule Conjugated Photosensitizers for Targeted Photodynamic Therapy and Imaging. AB - Photodynamic therapy (PDT) is now in clinical practice in many European and American countries as a minimally invasive therapeutic technique to treat oncologic malignancies and other nononcologic conditions. Phthalocyanines (Pcs) are gathering importance as effective photosensitizers in targeted PDT and imaging of tumors. The possibility of modification around the Pc macrocycle led the researchers to the synthesis of a diversity of photosensitizers with varied cell specificity, cellular internalization and localization, photodynamic cytotoxicity and excretion. Cellular targeting is the primary aspect of an ideal photosensitizer for targeting PDT. Therefore, Pcs have been structurally modified with a variety of biomolecules capable of recognizing the specific lesions. This review emphasizes the photocytotoxicity and the cellular uptakes of phthalocyanine photosensitizers conjugated with biomolecules including carbohydrates, nucleotides and protein constituents such as amino acids and peptides. In addition, the role of the Pc-biomolecule conjugates in imaging and antimicrobial chemotherapy has been discussed. PMID- 26593736 TI - Endoparasite survey of free-swimming baleen whales (Balaenoptera musculus, B. physalus, B. borealis) and sperm whales (Physeter macrocephalus) using non/minimally invasive methods. AB - A number of parasitic diseases have gained importance as neozoan opportunistic infections in the marine environment. Here, we report on the gastrointestinal endoparasite fauna of three baleen whale species and one toothed whale: blue (Balaenoptera musculus), fin (Balaenoptera physalus), and sei whales (Balaenoptera borealis) and sperm whales (Physeter macrocephalus) from the Azores Islands, Portugal. In total, 17 individual whale fecal samples [n = 10 (B. physalus); n = 4 (P. macrocephalus); n = 2 (B. musculus); n = 1 (B. borealis)] were collected from free-swimming animals as part of ongoing studies on behavioral ecology. Furthermore, skin biopsies were collected from sperm whales (n = 5) using minimally invasive biopsy darting and tested for the presence of Toxoplasma gondii, Neospora caninum, and Besnoitia besnoiti DNA via PCR. Overall, more than ten taxa were detected in whale fecal samples. Within protozoan parasites, Entamoeba spp. occurred most frequently (64.7%), followed by Giardia spp. (17.6%) and Balantidium spp. (5.9%). The most prevalent metazoan parasites were Ascaridida indet. spp. (41.2%), followed by trematodes (17.7%), acanthocephalan spp., strongyles (11.8%), Diphyllobotrium spp. (5.9%), and spirurids (5.9%). Helminths were mainly found in sperm whales, while enteric protozoan parasites were exclusively detected in baleen whales, which might be related to dietary differences. No T. gondii, N. caninum, or B. besnoiti DNA was detected in any skin sample. This is the first record on Giardia and Balantidium infections in large baleen whales. PMID- 26593737 TI - Dynamics of Th17 associating cytokines in Cryptosporidium parvum-infected mice. AB - Cryptosporidium parvum commonly inhabits the intestinal tract of animals and humans and can cause acute watery diarrhea and weight loss. However, host immune responses to Cryptosporidium infections are not fully understood. IL-17 (also called IL-17A) is a pro-inflammatory cytokine of Th17 cells that plays a role in the host response to Cryptosporidium baileyi infection. The present study examined levels of IL-17-specific messenger RNA (mRNA) and Th17 associating cytokines in C. parvum-infected immune-suppressed BALB/c mice using real-time quantitative PCR (qPCR). Levels of IL-17 protein were determined by ELISA. The results showed that levels of IL-17 mRNA and Th17 cell-related cytokines, namely TGF-beta, IL-6, STAT-3, RORgammat, IL-22, TNF-alpha, and IL-23, were significantly increased (P < 0.05) in gut-associated lymphoid tissue (GALT) and spleen. IL-17 protein levels in GALT were also significantly increased (P < 0.05) after infection. The present study suggested that Th17 cells play a role in host C. parvum interaction. These results could inform future studies of the immune response against C. parvum infection in transient immunosuppressed populations. PMID- 26593739 TI - Clinical Characteristics and Outcomes of Patients with Myocardial Infarction, Myocardial Injury, and Nonelevated Troponins. AB - BACKGROUND: Cardiac troponins have emerged as the preferred biomarkers for detecting myocardial necrosis and diagnosing myocardial infarction. However, current cardiac troponin assays do not discriminate between ischemic and nonischemic causes of myocardial cell death. Thus, when an increased troponin value is encountered in the absence of obvious myocardial ischemia, a careful search for other clinical conditions is crucial. METHODS: In 2010 to 2011, we prospectively studied hospitalized patients who had cardiac troponin I measured on clinical indication. An acute myocardial infarction was diagnosed in cases of a cardiac troponin I increase or decrease pattern with at least 1 value >30 ng/L (99th percentile) together with myocardial ischemia. Myocardial injury was defined as cardiac troponin I values >30 ng/L, but without signs or symptoms indicating overt cardiac ischemia. Patients with peak values <=30 ng/L were classified as nonelevated cardiac troponin I. Follow-up was at least 3 years with all-cause mortality as the sole clinical end point. RESULTS: A total of 3762 patients were included. Of these, 488 (13%) had acute myocardial infarction, 1089 (29%) had myocardial injury, and 2185 (58%) had nonelevated cardiac troponin I values. Patients with myocardial injury frequently presented with dyspnea, were older, and had more comorbidity than patients in the 2 other groups. During a median follow-up of 3.2 years, 1342 patients died. Mortality differed significantly between groups: 39% in those with myocardial infarction, 59% in those with myocardial injury, and 23% in those with nonelevated cardiac troponin I (log-rank test; P < .0001). No significant difference in mortality between patients with type 2 myocardial infarction and patients with myocardial injury was observed (63% and 59%, respectively). CONCLUSIONS: Patients with myocardial injury are older and have more comorbidity than those with acute myocardial infarction. Both groups exhibit a poorer prognosis than patients with nonelevated cardiac troponin I values. Of note, a very high long-term mortality is observed in patients with type 2 myocardial infarction and patients with myocardial injury. PMID- 26593740 TI - Bipolar Host Materials for Organic Light-Emitting Diodes. AB - It is important to balance holes and electrons in the emitting layer of organic light-emitting diodes to maximize recombination efficiency and the accompanying external quantum efficiency. Therefore, the host materials of the emitting layer should transport both holes and electrons for the charge balance. From this perspective, bipolar hosts have been popular as the host materials of thermally activated delayed fluorescent devices and phosphorescent organic light-emitting diodes. In this review, we have summarized recent developments of bipolar hosts and suggested perspectives of host materials for organic light-emitting diodes. PMID- 26593741 TI - Effect of a broad-spectrum LED curing light on the Knoop microhardness of four posterior resin based composites at 2, 4 and 6-mm depths. AB - OBJECTIVE: To measure the Knoop microhardness at the bottom of four posterior resin-based composites (RBCs): Tetric EvoCeram Bulk Fill (Ivoclar Vivadent), SureFil SDR flow (DENTSPLY), SonicFill (Kerr), and x-tra fil (Voco). METHODS: The RBCs were expressed into metal rings that were 2, 4, or 6-mm thick with a 4-mm internal diameter at 30 degrees C. The uncured specimens were covered by a Mylar strip and a Bluephase 20i (Ivoclar Vivadent) polywave((r)) LED light-curing unit was used in high power setting for 20s. The specimens were then removed and placed immediately on a Knoop microhardness-testing device and the microhardness was measured at 9 points across top and bottom surfaces of each specimen. Five specimens were made for each condition. RESULTS: As expected, for each RBC there was no significant difference in the microhardness values at the top of the 2, 4 and 6-mm thick specimens. SureFil SDR Flow was the softest resin, but was the only resin that had no significant difference between the KHN values at the bottom of the 2 and 4-mm (Mixed Model ANOVA p<0.05). Although the KHN of SureFil SDR Flow was only marginally significantly different between the 2 and 6-mm thickness, the bottom at 6-mm was only 59% of the hardness measured at the top. CLINICAL SIGNIFICANCE: This study highlights that clinicians need to consider how the depth of cure was evaluated when determining the depth of cure. SureFil SDR Flow was the softest material and, in accordance with manufacturer's instructions, this RBC should be overlaid with a conventional resin. PMID- 26593742 TI - Extremely stretchable and conductive water-repellent coatings for low-cost ultra flexible electronics. AB - Rapid advances in modern electronics place ever-accelerating demands on innovation towards more robust and versatile functional components. In the flexible electronics domain, novel material solutions often involve creative uses of common materials to reduce cost, while maintaining uncompromised performance. Here we combine a commercially available paraffin wax-polyolefin thermoplastic blend (elastomer matrix binder) with bulk-produced carbon nanofibres (charge percolation network for electron transport, and for imparting nanoscale roughness) to fabricate adherent thin-film composite electrodes. The simple wet based process produces composite films capable of sustained ultra-high strain (500%) with resilient electrical performance (resistances of the order of 10(1) 10(2) Omega sq(-1)). The composites are also designed to be superhydrophobic for long-term corrosion protection, even maintaining extreme liquid repellency at severe strain. Comprised of inexpensive common materials applied in a single step, the present scalable approach eliminates manufacturing obstacles for commercially viable wearable electronics, flexible power storage devices and corrosion-resistant circuits. PMID- 26593743 TI - The Effect of Humidity upon the Crystallization Process of Two-Step Spin-Coated Organic-Inorganic Perovskites. AB - Moisture is shown to activate the reaction between PbI2 and methylammonium halides. In addition, two activating mechanisms are proposed for the formation of CH3 NH3 PbI3 and CH3 NH3 PbI3-x Clx films from a series of carefully controlled experiments. When these rapidly formed perovskite films are directly fabricated into the devices, poor photovoltaic properties are found, due to heavy surface charge recombination. However, the cell performance can be significantly enhanced to 13.63 % and to over 12 % in the steady state for CH3 NH3 PbI3 and to 15.50 % and over 14 % in the steady state for CH3 NH3 PbI3-x Clx , if the rapidly formed perovskite film is annealed. Thus, it is believed that moisture (below 60 % RH) is not a problem for the fabrication of highly efficient perovskite solar cells. PMID- 26593744 TI - Newspaper coverage of mental illness in Hong Kong between 2002 and 2012: impact of introduction of a new Chinese name of psychosis. AB - AIM: In Hong Kong, 'si-jue-shi-tiao' () was officially adopted as the Chinese translation of psychosis in 2001. The new term covered a broader aspect of psychosis, compared with the original term, 'jing-shen-fen-lie' (), which gave a negative stereotype as a 'mental split-mind disorder'. The current study compared the usage of the two terms, and added evidence to the name changing as anti stigma strategy. METHODS: The usage and themes of the new Chinese name of psychosis 'si-jue-shi-tiao' was examined in 1217 local newspaper articles in comparison with the traditional Chinese name of schizophrenia 'jing-shen-fen lie'. RESULTS: Results show that an increase use of 'si-jue-shi-tiao' was found equally across themes, whereas 'jing-shen-fen-lie' was decreasingly used in positive/neutral themes over time. The association of 'jing-shen-fen-lie' with dangerous wordings increased over time, but no change was found with the new name. CONCLUSIONS: Our finding adds to literature on effects of changing new name on public stigma. PMID- 26593745 TI - Isolation of human anti-serum albumin Fab antibodies with an extended serum-half life. AB - The serum albumin (SA) has been exploited to generate long-acting biotherapeutics by taking advantage of the FcRn-mediated recycling mechanism in a direct or an indirect way. Since Fab fragments have been proven to be clinically safe for human usage, we assumed that human anti-SA Fab antibodies could have a great potential as a carrier molecule to extend the serum half-life of therapeutic proteins. We, herein, had attempted to isolate anti-SA Fab antibodies from HuDVFab-8L antibody library via a phage display technology, and identified eight discrete human Fab antibodies. One of the Fab antibodies, SL335, showed the strongest binding reactivity to human SA with nM range of affinity at both pH 6 and pH 7.4, and cross-reacted to SAs from various species including rat, mouse, canine and monkey. The in vivo pharmacokinetic assay using a rat model indicated that SL335 has approximately 10 fold longer serum half-life and 26 to 44-fold increase in AUC0 -> infinity compared to the negative control Fab molecule in both intravenous and subcutaneous administrations. Knowing that Fabs have proven to be safe in clinics for a long time, SL335 seems to have a great potential in generating long-acting protein drugs by tagging effector molecules with either chemical conjugation or genetic fusion. PMID- 26593746 TI - Recycling of osmotic solutions in microwave-osmotic dehydration: product quality and potential for creation of a novel product. AB - BACKGROUND: Despite osmotic dehydration being a cost effective process for moisture removal, the cost implications of making, regenerating, and properly disposing of the spent osmotic solutions contributes greatly to the economic feasibility of the drying operation. The potential for recycling of osmotic solutions and their use for creation of a novel product was explored using microwave-osmotic dehydration under continuous flow spray (MWODS) conditions. RESULTS: Identical runs were repeated 10 times to determine the progressive physical and compositional effects of the thermal treatment and leaching from the cranberry samples. The microbiological stability and constant drying performance indicated that MWODS would be well suited for employing recycled solutions. While the anthocyanin content of the solution never approached that of cranberry juice concentrate, it is demonstrated that the spent syrup can infuse these health positive components into another product (apple). CONCLUSION: This study found that re-using osmotic solutions is a viable option to reduce cost in future MWODS applications, with no detriment to product quality and potential to use the spent solution for novel products. (c) 2015 Society of Chemical Industry. PMID- 26593747 TI - Task-related dissociation of EEG beta enhancement and suppression. AB - Previous investigations of EEG beta processes can be divided into two categories: one in which beta enhancement is obtained and one in which beta suppression is obtained. The current study investigated the beta band range (14-30Hz) by subdividing the signal into 2Hz sub-bands. We presented participants with photographs of faces expressing happy, angry, sad or neutral expressions under two primary tasks in which participants judged the emotion the individual was expressing, or how the way the other person feels makes the participant feel. Results revealed a pattern of both beta suppression and enhancement that appeared to depend on whether the task required first-person emotional experience (self task) or perspective-taking (other-task). Specifically, the self-task was associated with enhancement while the other-task was associated with suppression. While some previous research has reported beta enhancement to emotion-inducing stimuli, other research has reported beta suppression in tasks also associated with mu suppression. To our knowledge, the current data are the first to reveal both beta enhancement and suppression within a single experiment and suggests a neurocognitive dissociation of enhancement and suppression within the beta band range. PMID- 26593748 TI - Momordin Ic couples apoptosis with autophagy in human hepatoblastoma cancer cells by reactive oxygen species (ROS)-mediated PI3K/Akt and MAPK signaling pathways. AB - Momordin Ic is a principal saponin constituent of Fructus Kochiae, which acts as an edible and pharmaceutical product more than 2000 years in China. Our previous research found momordin Ic induced apoptosis by PI3K/Akt and MAPK signaling pathways in HepG2 cells. While the role of autophagy in momordin Ic induced cell death has not been discussed, and the connection between the apoptosis and autophagy is not clear yet. In this work, we reported momordin Ic promoted the formation of autophagic vacuole and expression of Beclin 1 and LC-3 in a dose- and time-dependent manner. Compared with momordin Ic treatment alone, the autophagy inhibitor 3-methyladenine (3-MA) also can inhibit apoptosis, while autophagy activator rapamycin (RAP) has the opposite effect, and the apoptosis inhibitor ZVAD-fmk also inhibited autophagy induced by momordin Ic. Momordin Ic simultaneously induces autophagy and apoptosis by suppressing the ROS-mediated PI3K/Akt and activating the ROS-related JNK and P38 pathways. Additionally, momordin Ic induces apoptosis by suppressing PI3K/Akt-dependent NF-kappaB pathways and promotes autophagy by ROS-mediated Erk signaling pathway. Those results suggest that momordin Ic has great potential as a nutritional preventive strategy in cancer therapy. PMID- 26593749 TI - Characterization and origin of the 'B' and 'C' compounds in the acid/neutral forensic signatures of heroin - products from the acylation of porphyroxine and subsequent hydrolysis. AB - Two significant compounds often found in the gas chromatographic analysis of the acid/neutral extracts from illicit heroin have remained uncharacterized for 30 years. The unknown compounds are referred to as the 'B' and 'C' compounds. It has been postulated that these compounds arise from acetylation of porphyroxine, a rhoeadine alkaloid found at trace levels in the opium poppy, Papaver somniferum. Porphyroxine was isolated from opium and acetylated to produce N,O8 diacetylporphyroxine. Mild hydrolysis produced N,O8 -diacetyl-O14 -desmethyl-epi porphyroxine (the C compound) and N-acetyl-O14 -desmethyl-epi-porphyroxine (the B compound). Both N,O8 -diacetyl-O14 -desmethyl-epi-porphyroxine and N-acetyl-O14 desmethyl-epi-porphyroxine were determined to be C-14 epimers of porphyroxine and N,O8 -diacetylporphyroxine. The non-epimerized isomers of the B and C compounds were also detected in illicit heroin, but at much lower levels. Chromatographic and spectroscopic data are presented for the aforementioned compounds. The presence/absence and relative concentrations of these compounds is presented for the four types of heroin (Southwest Asian, South American, Southeast Asian, and Mexican). The prevalence of detection for the B and C compounds are Southwest Asian = 92-93%, South American = 64-72%, Southeast Asian = 45-49%, and Mexican <= 3%. When detected, the overall trend of relative concentrations of dicaetylporhyroxine, the B-compound, and C-compound is Southwest Asian > South American > Southeast Asian, each by an order of magnitude. These compounds were rarely detected in Mexican heroin. The presence/absence and relative concentrations of these compounds provide pertinent forensic signature characteristics that significantly enhance the final regional classifications. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26593751 TI - Changes to Tissue Antigens. PMID- 26593750 TI - Neuromyelitis optica spectrum disorders: comparison of clinical and magnetic resonance imaging characteristics of AQP4-IgG versus MOG-IgG seropositive cases in the Netherlands. AB - BACKGROUND AND PURPOSE: Neuromyelitis optica spectrum disorders (NMOSDs) are a group of rare inflammatory demyelinating disorders of the central nervous system. The identification of specific antibodies directed to aquaporin 4 (AQP4-IgG) led to the distinction from multiple sclerosis. However, up to 25% of the clinically diagnosed NMO patients are seronegative for AQP4-IgG. A subgroup of these patients might be identified by antibodies directed to myelin oligodendrocyte glycoprotein (MOG-IgG). Our objective was to investigate whether the clinical characteristics of these patients differ. METHODS: Using a cell-based assay, samples of 61 AQP4-IgG seronegative patients and 41 AQP4-IgG seropositive patients with clinically NMOSD were analysed for the presence of MOG-IgG. Clinical characteristics of the AQP4-IgG, MOG-IgG seropositive and double seronegative NMOSD patients were compared. RESULTS: Twenty of the 61 AQP4-IgG seronegative patients tested MOG-IgG seropositive (33%). MOG-IgG seropositive patients were more frequently males in contrast to AQP4-IgG seropositive patients (55% vs. 15%, P < 0.01) and Caucasians (90% vs. 63%, P = 0.03). They more frequently presented with coincident optic neuritis and transverse myelitis (40% vs. 12%, P = 0.02) and had a monophasic disease course (70% vs. 29%, P < 0.01). AQP4-IgG seropositive patients were 2.4 times more likely to suffer from relapses compared with MOG-IgG seropositive patients (relative risk 2.4, 95% confidence interval 1.2-4.7). AQP4-IgG seropositive patients had higher Expanded Disability Status Scale levels at last follow-up (P < 0.01). CONCLUSION: Antibodies directed to MOG identify a subgroup of AQP4-IgG seronegative NMO patients with generally a favourable monophasic disease course. PMID- 26593752 TI - Genetic variation of the MHC class II DRB genes in the Japanese weasel, Mustela itatsi, endemic to Japan, compared with the Siberian weasel, Mustela sibirica. AB - Major histocompatibility complex (MHC) genes encode proteins that play a critical role in vertebrate immune system and are highly polymorphic. To further understand the molecular evolution of the MHC genes, we compared MHC class II DRB genes between the Japanese weasel (Mustela itatsi), a species endemic to Japan, and the Siberian weasel (Mustela sibirica), a closely related species on the continent. We sequenced a 242-bp region of DRB exon 2, which encodes antigen binding sites (ABS), and found 24 alleles from 31 M. itatsi individuals and 17 alleles from 21 M. sibirica individuals, including broadly distributed, species specific and/or geographically restricted alleles. Our results suggest that pathogen-driven balancing selection have acted to maintain the diversity in the DRB genes. For predicted ABS, nonsynonymous substitutions exceeded synonymous substitutions, also indicating positive selection, which was not seen at non-ABS. In a Bayesian phylogenetic tree, two M. sibirica DRB alleles were basal to the rest of the sequences from mustelid species and may represent ancestral alleles. Trans-species polymorphism was evident between many mustelid DRB alleles, especially between M. itatsi and M. sibirica. These two Mustela species divided about 1.7 million years ago, but still share many MHC alleles, indicative of their close phylogenetic relationship. PMID- 26593753 TI - Identification of a novel HLA-A*02:06:01:02 allele in a Chinese individual by sequence-based typing. AB - The new HLA-A*02:06:01:02 allele differs from HLA-A*02:06:01 by a C->G substitution in Intron 1. PMID- 26593754 TI - A novel HLA-A*02 variant, HLA-A*02:575, detected in a Taiwanese bone marrow hematopoietic stem cell donor. AB - One nucleotide substitution at residue 410 of HLA-A*02:07:01 results in a new allele, HLA-A*02:575. PMID- 26593755 TI - Four amino acid exchanges located in the alpha-2 domain specify the novel HLA B*50:20 allele. AB - HLA-B*50:20 contains seven nucleotide substitutions leading to four amino acid changes in the alpha-2 domain. PMID- 26593756 TI - Nomenclature for factors of the HLA system, update July 2015. PMID- 26593757 TI - Nomenclature for factors of the HLA system, update August 2015. PMID- 26593759 TI - Corrigendum. PMID- 26593758 TI - Nomenclature for factors of the HLA system, update September 2015. PMID- 26593760 TI - Wild type HBx and truncated HBx: Pleiotropic regulators driving sequential genetic and epigenetic steps of hepatocarcinogenesis and progression of HBV associated neoplasms. AB - Hepatitis B virus (HBV) is one of the causative agents of hepatocellular carcinoma. The molecular mechanisms of tumorigenesis are complex. One of the host factors involved is apparently the long-lasting inflammatory reaction which accompanies chronic HBV infection. Although HBV lacks a typical viral oncogene, the HBx gene encoding a pleiotropic regulatory protein emerged as a major player in liver carcinogenesis. Here we review the tumorigenic functions of HBx with an emphasis on wild type and truncated HBx variants, and their role in the transcriptional dysregulation and epigenetic reprogramming of the host cell genome. We suggest that HBx acquired by the HBV genome during evolution acts like a cellular proto-onc gene that is activated by deletion during hepatocarcinogenesis. The resulting viral oncogene (v-onc gene) codes for a truncated HBx protein that facilitates tumor progression. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26593761 TI - Role of initial cell density of algal bioassay of toxic chemicals. AB - A variety of toxicants such as, metal ions, pesticides, dyes, etc. are continuously being introduced anthropogenically in the environment and adversely affect to the biotic component of the ecosystem. Therefore, the assessment of negative effects of these toxicants is required. However, toxicity assessment anticipated by chemical analysis are extremely poor, therefore the application of the living systems for the same is an excellent approach. Concentration of toxicant as well as cell density both influenced the result of the algal toxicity assay. Here, Scenedesmus sp, a very fast growing green microalgae was selected for study the effects of initial cell densities on the toxicity of Cu(II), Cd(II), Zn(II), paraquat and 2,4-D. Results demonstrated concentration dependent decrease in biomass and specific growth rate of Scenedesmus sp. on exposure of abovesaid toxicants. Paraquat and 2,4-D emerged as extremely toxic to the test alga which reflected from the lowest EC value and very steep decline in biomass was evident with increasing concentration of paraquat and 2,4-D in the medium. Result also demonstrated that initial cell density is a very important parameter than specific growth rate for algal bioassay of various toxicants. Present study clearly illustrated that the use of smaller cell density is always recommended for assaying toxicity of chemicals in algal assays. PMID- 26593762 TI - [In process citation]. PMID- 26593763 TI - [In Process Citation]. PMID- 26593764 TI - [Infectious diseases as a clinical specialty in Germany and Europe]. AB - Clinical infectious diseases have only slowly been established as a medical specialty in Germany. The density of infectious diseases (ID) specialists and the number of ID divisions in general hospitals is still limited when compared with the situation in many other European countries, and there is also a lack of hospital-based medical microbiologists and infection control doctors for many reasons. Often, there is a lack of understanding of the roles and the performance of ID specialists versus microbiologists. Experience in other countries shows that ID specialists are important as clinical experts at the bedside, can help ascertain healthcare quality and patient safety, and are perfectly suited for undertaking strategic tasks in the field of cost-effective antimicrobial therapy algorithms and antibiotic stewardship (ABS) in hospitals. ID specialists are responsible for infection control in several countries, can improve the utility of diagnostic microbiology and are key partners in translational research. We estimate that more than 1,000 additional ID specialists are needed in this country, and believe that specially trained ABS experts can take over parts of their responsibilities and tasks in smaller hospitals. More capacity and flexibility in postgraduate training in infectious diseases, antibiotic stewardship and infection control in Germany will be critical to address the problem of antimicrobial resistance. (As supplied by publisher). PMID- 26593765 TI - [Impact of an infectious diseases consultation service on the quality of care and the survival of patients with infectious diseases]. AB - While trained infectious diseases (ID) specialists are regularly involved in inpatient and outpatient care in the United States and Canada, these specialized services are only rarely established in Germany. This article aims to summarize the findings of numerous studies that investigated the impact of ID consultation services on patient care and outcome in patients suffering from infectious diseases. The strongest evidence for a clinical benefit is found in the context of Staphylococcus aureus bacteremia (SAB), where in-hospital- and day-30 mortality was significantly and consistently reduced by about 40% in patients that were evaluated and treated in cooperation with an ID physician. Furthermore, studies revealed that this effect was associated with an improved adherence to standards of care. Newer studies show a reduced length of hospital stay due to ID consultations, especially if patients are evaluated early in the course of their hospital stay. Of note, informal or curbside consultations do not seem to be equivalent to a formal ID consultation with bedside patient evaluation. Studies in other patient groups (solid organ transplant recipients or intensive care unit patients) or in the context of other infections (infective endocarditis, pneumonia, other bloodstream infections) also revealed positive effects of ID consultations. Higher rates of appropriate empirical and targeted antimicrobial treatments and de-escalation strategies due to successful pathogen identification were documented. These modifications resulted in lower treatment costs and decreased antimicrobial resistance development. Although there are methodological limitations in single studies, we consider the consistent and reproducible positive effects of ID consultations shown in studies in different countries and health care systems as convincing evidence for the improved quality of care and treatment outcomes in patients with infectious diseases. Thus, strong consideration should be given to establish ID consultation services in small and medium sized hospitals as well. PMID- 26593766 TI - [In Process Citation]. PMID- 26593767 TI - [Antibiotic Stewardship (ABS) im Krankenhaus: Voraussetzungen und Empfehlungen zur Gestaltung von ABS-Programmen]. PMID- 26593768 TI - [Impact of an |A|B|S|-training initiative on |A|B|S|-structural quality of participating hospitals]. AB - The "ABS-training initiative" was funded by the German Ministry of Health as part of the German Antimicrobial Resistance Strategy (Deutsche Antibiotika-Resistenz Strategie, DART) from 2009 until early 2014. The initiative was designed for clinicians and clinical pharmacists and contains several training units covering antiinfectives, infectious diseases and ABS strategies including the conduction of a research project at the participants' hospital. Participants who complete the four-weeks training initiative will become a certified "ABS Expert". 281 ABS Experts were asked to take part in a survey (staff for ABS, surveillance data about agents and consumption, ABS activity) to estimate the influence of the ABS training initiative on the ABS-structural quality. The evaluation was performed using GrafStat (V 4.255), statistical software package for the evaluation of surveys. Ninety-two ABS Experts representing 92 hospitals participated in a questionnaire-based survey before and after completing the training initiative. Forty (44 %) hospitals appointed an ABS representative (+22 %) after completing the training initiative. Antibiotic surveillance data available as a report increased from 34 (40 %) to 54 (60 %) and correct data presentation (DDD or RDD/100 days) from 7 (8 %) to 40 (43 %). Proactive auditing of antiinfective prescribing improved from 54 (60 %) to 71 (78 %) in intensive care units, and from 28 (31 %) to 53 (58 %) on normal wards. Availability of local guidelines increased from 36 (39 %) to 52 (57 %). The "ABS Training Initiative" had a positive impact on ABS-structural quality regarding nomination of ABS-teams, surveillance data of antibiotic consumption, implementation of proactive auditing of antiinfective prescribing and availability of local guidelines. However, there is optimization potential in many sectors. The short time period between pre- and post-assessment and the ongoing personnel or time constraints need to be taken into account. PMID- 26593769 TI - [Documentation of Antibiotic Stewardship (ABS)-interventions during proactive audit of antibiotic use]. AB - Proactive audit of antibiotic use ensures quality of prescribing and can improve outcome in patients with infections. A rational, individualized therapy is being defined in interdisciplinary cooperation on the basis of clinical, laboratory, radiological and microbiological examination findings. By fostering targeted antibiotic therapy proactive audit reduces adverse effects and contributes to drug therapy safety and subsequently to patient safety. A proactive audit of antibiotic use is performed weekly on four intensive care units at the University Hospital Dresden by a infectious disease specialist a pharmacist and the attending physicians. Patient-related therapy adjustments were systematically documented over a 4-month period; antibiotic use before and after audit as well as ABS strategies (de-escalation, oral switch, duration of treatment, dose and administration optimization) were analyzed. Both targeted therapy and interventions regarding the duration of treatment led to a reduction in the prescribing of broad spectrum antibiotics by 20%. Routine interdisciplinary proactive audit of antibiotic use with intervention and feedback increases guideline-adherent therapy and process quality. PMID- 26593770 TI - [In Process Citation]. AB - INTRODUCTION: One of the core strategies to optimize antiinfective therapy is to review antibiotic prescriptions. Therefore, Antibiotic Stewardship (ABS) team members either attend ward rounds or perform a chart review to provide feedback to and discuss with the attending physician. Acceptance and effectiveness of both options are discussed in this article. METHODS: Attending physicians were asked to complete a questionnaire evaluating ABS activities. The modality of the reviewing process and its effectiveness, as well as the feasibility of recommendations was assessed. As the degree of implementation of ABS recommendations decreased on a trauma ward, the reviewing process was changed from chart review to attending the daily ward rounds. In this setting, the duration of the reviewing process and the consumption of antiinfectives in recommended daily doses/100 patient days (RDD/100PT) were assessed, comparing the two intervention modalities. RESULTS: Attending physicians predominantly appreciated the modality and extent of ABS currently offered to them by the ABS team, rating it relevant and effective. Implementation of ABS recommendations was increased on the trauma ward by academic detailing during the daily ward round; the consumption of broad spectrum antibiotics was reduced. DISCUSSION: ABS team members with formal authority and dedicated time for antibiotic stewardship activities effectively optimize antiinfective therapies by reviewing antibiotic prescriptions. The interaction of ABS experts and attending physicians contributes fundamentally to the effectiveness and degree of implementation of ABS interventions. PMID- 26593771 TI - Characterization and expression of cyp19a gene in the Chinese giant salamander Andrias davidianus. AB - We cloned the full length cyp19a of Chinese giant salamander Andrias davidianus, determined its distribution in tissues and developing gonads, and analyzed the CpG methylation pattern of the cyp19a promoter. The results revealed isoforms of 1706 bp (G arom) and 1698 bp (B arom) in length, differing in the 5' flanking region, both encoding 502 amino acids. The G arom gene was observed mainly in the ovary and kidney, with little in other investigated tissues, while B arom expression was high in the brain, ovary, testis, and pituitary, with low or undetected expression in other examined tissues. Total aromatase expression was high in the ovary; moderate in the kidney, brain, testis, and pituitary; and low in the remaining tissues. G arom expression was significantly higher in the ovary than in the testis and gradually decreased with maturation of the salamander. A single injection of methyltestosterone or letrozole resulted in ovarian G arom expression decreasing over a 12-96 h period. A 1366 bp sequence of the cyp19a promoter was cloned and shown to be conserved in selected species. CpG methylation level was negatively correlated with cyp19a expression in the examined tissues and developing ovaries. Five and three CpG methylation sites positively correlated with DNA methylation levels in tissues and developing ovary, suggesting that they play an important role in regulating cyp19a expression. The aromatase gene showed two isoforms with distinct expression patterns, and the promoter methylation level at specific CpG sites was associated with variation in expression profiles of tissues and developing ovaries. PMID- 26593772 TI - Methods to adjust for misclassification in the quantiles for the generalized linear model with measurement error in continuous exposures. AB - In many biomedical studies, covariates of interest may be measured with errors. However, frequently in a regression analysis, the quantiles of the exposure variable are often used as the covariates in the regression analysis. Because of measurement errors in the continuous exposure variable, there could be misclassification in the quantiles for the exposure variable. Misclassification in the quantiles could lead to bias estimation in the association between the exposure variable and the outcome variable. Adjustment for misclassification will be challenging when the gold standard variables are not available. In this paper, we develop two regression calibration estimators to reduce bias in effect estimation. The first estimator is normal likelihood-based. The second estimator is linearization-based, and it provides a simple and practical correction. Finite sample performance is examined via a simulation study. We apply the methods to a four-arm randomized clinical trial that tested exercise and weight loss interventions in women aged 50-75 years. PMID- 26593773 TI - Computationally Optimizing the Compliance of a Biopolymer Based Tissue Engineered Vascular Graft. AB - Coronary heart disease is a leading cause of death among Americans for which coronary artery bypass graft (CABG) surgery is a standard surgical treatment. The success of CABG surgery is impaired by a compliance mismatch between vascular grafts and native vessels. Tissue engineered vascular grafts (TEVGs) have the potential to be compliance matched and thereby reduce the risk of graft failure. Glutaraldehyde (GLUT) vapor-crosslinked gelatin/fibrinogen constructs were fabricated and mechanically tested in a previous study by our research group at 2, 8, and 24 hrs of GLUT vapor exposure. The current study details a computational method that was developed to predict the material properties of our constructs for crosslinking times between 2 and 24 hrs by interpolating the 2, 8, and 24 hrs crosslinking time data. matlab and abaqus were used to determine the optimal combination of fabrication parameters to produce a compliance matched construct. The validity of the method was tested by creating a 16-hr crosslinked construct of 130 MUm thickness and comparing its compliance to that predicted by the optimization algorithm. The predicted compliance of the 16-hr construct was 0.00059 mm Hg-1 while the experimentally determined compliance was 0.00065 mm Hg 1, a relative difference of 9.2%. Prior data in our laboratory has shown the compliance of the left anterior descending porcine coronary (LADC) artery to be 0.00071 +/- 0.0003 mm Hg-1. Our optimization algorithm predicts that a 258-MUm thick construct that is GLUT vapor crosslinked for 8.1 hrs would match LADC compliance. This result is consistent with our previous work demonstrating that an 8-hr GLUT vapor crosslinked construct produces a compliance that is not significantly different from a porcine coronary LADC. PMID- 26593774 TI - Identification and Validation of Atypical N-Glycosylation Sites. AB - It is well-known that N-linked glycans usually attach to asparagine residues in the N-X-S/T motifs of proteins. However, accumulating evidence indicates that N glycosylation could also possibly occur at other atypical motifs. In this study, we tried to identify atypical N-glycosylation sites using our recently developed solid-phase extraction of the N-linked Glycans And Glycosite-containing peptides (NGAG) method. Peptides with deamidation sites at asparagine residues but lacking a typical asparagine-X-serine/threonine sequons (N-X-S/T, X is any amino acid except proline) motif were identified from deglycosylated peptide data as potentially atypical glycosite-containing peptides. These atypical glycosites were verified by the presence of glycans on their intact glycopeptides and further confirmed by specific inhibition of cells with an N-linked glycosylation inhibitor, tunicamycin. From this study, two atypical N-linked glycosylation sites with N-X-C and N-X-V motifs were identified and validated from an ovarian cancer cell line (OVCAR-3). PMID- 26593775 TI - Potential Biomarker of Myofibrillar Protein Oxidation in Raw and Cooked Ham: 3 Nitrotyrosine Formed by Nitrosation. AB - The stability of cured meat products is increased by the protection of its proteins from oxidation by sodium nitrite (NaNO2) during processing. This study investigated the effects of NaNO2 (0, 50, 100, 200, and 400 mg/kg) on the physiochemical and structural characteristics of myofibrillar protein (MP) in raw and cooked ham. The NaNO2 showed a dose-dependent antioxidant effect, by inhibiting carbonyl formation, dityrosine formation, and denaturation of MP, and a nitrosative effect, through the formation of 3-Nitrotyrosine (3-NT). The 3-NT content within MP of raw ham had distinct negative correlations with sulfhydryl content and surface hydrophobicity. The 3-NT content within MP of cooked ham had significantly negative correlations with carbonyl, sulfhydryl content and turbidity and had significantly positive correlations with disulfide content. These results indicated that 3-NT may be a potential marker for protein oxidation in raw and cooked cured meat products. PMID- 26593776 TI - A new era in psoriasis and psoriatic arthritis therapy: new mechanisms of action and the introduction of biogeneric drugs. PMID- 26593777 TI - Methanol Conversion into Dimethyl Ether on the Anatase TiO2(001) Surface. AB - Exploring reactions of methanol on TiO2 surfaces is of great importance in both C1 chemistry and photocatalysis. Reported herein is a combined experimental and theoretical calculation study of methanol adsorption and reaction on a mineral anatase TiO2(001)-(1*4) surface. The methanol-to-dimethyl ether (DME) reaction was unambiguously identified to occur by the dehydration coupling of methoxy species at the fourfold-coordinated Ti(4+) sites (Ti(4c)), and for the first time confirms the predicted higher reactivity of this facet compared to other reported TiO2 facets. Surface chemistry of methanol on the anatase TiO2(001)-(1*4) surface is seldom affected by co-chemisorbed water. These results not only greatly deepen the fundamental understanding of elementary surface reactions of methanol on TiO2 surfaces but also show that TiO2 with a high density of Ti(4c) sites is a potentially active and selective catalyst for the important methanol-to-DME reaction. PMID- 26593778 TI - Tuning the Electron Acceptor in Phthalocyanine-Based Electron Donor-Acceptor Conjugates. AB - Zinc phthalocyanines (ZnPc) have been attached to the peri-position of a perylenemonoimide (PMI) and a perylenemonoanhydride (PMA), affording electron donor-acceptor conjugates 1 and 2, respectively. In addition, a perylene monoimide-monoanhydride (PMIMA) has been connected to a ZnPc through its imido position to yield the ZnPc-PMIMA conjugate 10. The three conjugates have been studied for photoinduced electron transfer. For ZnPc-PMIMA 10, electron transfer occurs upon both ZnPc and PMIMA excitation, giving rise to a long-lived (340 ps) charge-separated state. For ZnPc-PMI 1 and ZnPc-PMA 2, stabilization of the radical ion pair states by using polar media is necessary. In THF, photoexcitation of either ZnPc or PMI/PMA produces charge-separated states with lifetimes of 375 and 163 ps, respectively. PMID- 26593779 TI - High mortality among children with sickle cell anemia and overt stroke who discontinue blood transfusion after transition to an adult program. AB - BACKGROUND: Chronic blood transfusion is the standard of care in the management of overt stroke due to sickle cell anemia (SS) to prevent recurrence of stroke. The problem arises when children are transitioned to adult care where blood transfusion may be discontinued. The purpose of this study was to report the outcome of 22 patients with SS and overt stroke who were transitioned to our adult program between 1993 and 2009. STUDY DESIGN AND METHODS: Transitioned patients were kept on chronic blood transfusion they had as children. Blood bank data were performed and computerized according to FDA and AABB regulations. Records were kept prospectively. Blood counts and percent hemoglobin (Hb)S were obtained before and after transfusion. HbS was kept below 30% after transfusion. Metabolic profiles were obtained every 6 months or more often if needed. Statistical analysis was by the two-tailed t-test. RESULTS: Patients who were compliant with blood transfusion were rarely hospitalized for painful crises. Alloimmunization and iron overload were the major complications of blood transfusion. Eight patients who refused to be maintained on chronic blood transfusion or who were noncompliant died within 1 to 5 years after transition. Causes of death included stroke in two, sudden in three, and multiorgan failure in three. The overall rate of death after transition was 36% and the major cause was discontinuation of blood transfusion. CONCLUSION: Efforts must be made to maintain adequate chronic simple or exchange blood transfusion for children with SS and stroke after transition to adult care. PMID- 26593780 TI - Is chlorhexidine-methacrylate as effective as chlorhexidine digluconate in preserving resin dentin interfaces? AB - OBJECTIVES: The aim of the current study was to evaluate the effect of 2% CHX and 2% CHX-methacrylate compared to the resin-dentin bonds created by a two-step etch and-rinse adhesive system after 24h, 6min and 12min. METHODS: Microtensile bond strengths and interfacial nanoleakage within resin-dentin interfaces created by Adper Single Bond 2, with or without CHX or CHX-methacrylate pre-treatment for 30s on acid-etched dentin surfaces, were evaluated after 24h, 6min and 12min of storage in distilled water at 37 degrees C. RESULTS: Twelve months of storage resulted in a significant decrease in microtensile bond strength in the control group, and significant increases in silver nanoleakage. In contrast, Single Bond 2+CHX, and to a greater extent CHX-methacrylate, significantly reduced the rate of deterioration of resin-dentin interfaces over the 12min water storage period, in terms of bond strength. CONCLUSIONS: Similar to Single Bond 2+CHX, Single Bond+CHX-methacrylates reduced the degradation of resin-bonded interfaces over a 12 month storage period. Thus it can be concluded that Single Bond 2+CHX methacrylate may be important to improve durability of bonded interfaces and therefore, prolong the life span of adhesive restorations. CLINICAL SIGNIFICANCE: Although CHX primers have been shown to enhance the durability of etch-and-rinse adhesives, that protection is lost after 2h. The use of CHX-methacrylate should last much longer since it may copolymerize with adhesive monomers, unlike CHX. PMID- 26593782 TI - Influence of Humic Acid Complexation with Metal Ions on Extracellular Electron Transfer Activity. AB - Humic acids (HAs) can act as electron shuttles and mediate biogeochemical cycles, thereby influencing the transformation of nutrients and environmental pollutants. HAs commonly complex with metals in the environment, but few studies have focused on how these metals affect the roles of HAs in extracellular electron transfer (EET). In this study, HA-metal (HA-M) complexes (HA-Fe, HA-Cu, and HA-Al) were prepared and characterized. The electron shuttle capacities of HA-M complexes were experimentally evaluated through microbial Fe(III) reduction, biocurrent generation, and microbial azoreduction. The results show that the electron shuttle capacities of HAs were enhanced after complexation with Fe but were weakened when using Cu or Al. Density functional theory calculations were performed to explore the structural geometry of the HA-M complexes and revealed the best binding sites of the HAs to metals and the varied charge transfer rate constants (k). The EET activity of the HA-M complexes were in the order HA-Fe > HA-Cu > HA-Al. These findings have important implications for biogeochemical redox processes given the ubiquitous nature of both HAs and various metals in the environment. PMID- 26593781 TI - Rationale, design, samples, and baseline sun protection in a randomized trial on a skin cancer prevention intervention in resort environments. AB - INTRODUCTION: Exposure to solar ultraviolet radiation during recreation is a risk factor for skin cancer. A trial evaluated an intervention to promote advanced sun protection (sunscreen pre-application/reapplication; protective hats and clothing; use of shade) during vacations. MATERIALS AND METHODS: Adult visitors to hotels/resorts with outdoor recreation (i.e., vacationers) participated in a group-randomized pretest-posttest controlled quasi-experimental design in 2012 14. Hotels/resorts were pair-matched and randomly assigned to the intervention or untreated control group. Sun. protection (e.g., clothing, hats, shade and sunscreen) was measured in cross-sectional samples by observation and a face-to face intercept survey during two-day visits. RESULTS: Initially, 41 hotel/resorts (11%) participated but 4 dropped out before posttest. Hotel/resorts were diverse (employees=30 to 900; latitude=24 degrees 78' N to 50 degrees 52' N; elevation=2ft. to 9726ft. above sea level), and had a variety of outdoor venues (beaches/pools, court/lawn games, golf courses, common areas, and chairlifts). At pretest, 4347 vacationers were observed and 3531 surveyed. More females were surveyed (61%) than observed (50%). Vacationers were mostly 35-60years old, highly educated (college education=68%) and non-Hispanic white (93%), with high risk skin types (22%). Vacationers reported covering 60% of their skin with clothing. Also, 40% of vacationers used shade; 60% applied sunscreen; and 42% had been sunburned. CONCLUSIONS: The trial faced challenges recruiting resorts but result showed that the large, multi-state sample of vacationers were at high risk for solar UV exposure. PMID- 26593783 TI - The mechanism and modulation of complement activation on polymer grafted cells. AB - Cell surface engineering using polymers is a promising approach to address unmet needs and adverse immune reactions in the fields of transfusion, transplantation, and cell-based therapies. Furthermore, cell surface modification may minimize or prevent adverse immune reactions to homologous incompatible cells as the interface between the host immune system and the cell surface is modified. In this report, we investigate the immune system reaction, precisely the complement binding and activation on cell surfaces modified with a functional polymer, hyperbranched polyglycerol (HPG). We used red blood cells (RBCs) as a model system to investigate the mechanism of complement activation on cell surfaces modified with various forms of HPG. Using a battery of in vitro assays including: traditional diagnostic hemolytic assays involving sheep and rabbit erythrocytes, ELISAs and flow cytometry, we show that HPG modified RBCs at certain concentrations and molecular weights activate complement via the alternative pathway. We show that by varying the grafting concentration, molecular weight and the number of cell surface reactive groups of HPG, the complement activity on the cell surface can be modulated. HPGs with molecular weights greater than 28kDa and grafting concentrations greater than 1.0mM, as well as a high degree of HPG functionalization with cell surface reactive groups result in the activation of the complement system via the alternative pathway. No complement activation observed when these threshold levels are not exceeded. These insights may have an impact on devising key strategies in developing novel next generation cell surface engineered therapeutic products for applications in the fields of cell therapy, transfusion and drug delivery. STATEMENT OF SIGNIFICANCE: Cell-surface engineering using functional polymers is a fast emerging area of research. Importantly modified cells are used in many experimental therapeutics, transplantation and in transfusion. The success of such therapies depend on the ability of modified products to avoid immune detection and subsequent rejection or removal. Polymer grafting has been shown to modulate immune response, however, there is limited knowledge available. Thus in this manuscript, we investigated the interaction of human complement, part of our innate immune system, by polymer modified cells. Our results provide important evidences on the mechanism of complement activation by the modified cells and also found ways to modulate the innate immune response. These results will have implications in development of next generation cell-based therapies. PMID- 26593784 TI - Strategy towards independent electrical stimulation from cochlear implants: Guided auditory neuron growth on topographically modified nanocrystalline diamond. AB - Cochlear implants (CI) have been used for several decades to treat patients with profound hearing loss. Nevertheless, results vary between individuals, and fine hearing is generally poor due to the lack of discrete neural stimulation from the individual receptor hair cells. A major problem is the deliverance of independent stimulation signals to individual auditory neurons. Fine hearing requires significantly more stimulation contacts with intimate neuron/electrode interphases from ordered axonal re-growth, something current CI technology cannot provide. Here, we demonstrate the potential application of micro-textured nanocrystalline diamond (NCD) surfaces on CI electrode arrays. Such textured NCD surfaces consist of micrometer-sized nail-head-shaped pillars (size 5*5MUm(2)) made with sequences of micro/nano-fabrication processes, including sputtering, photolithography and plasma etching. The results show that human and murine inner ear ganglion neurites and, potentially, neural progenitor cells can attach to patterned NCD surfaces without an extracellular matrix coating. Microscopic methods revealed adhesion and neural growth, specifically along the nail-head shaped NCD pillars in an ordered manner, rather than in non-textured areas. This pattern was established when the inter-NCD pillar distance varied between 4 and 9MUm. The findings demonstrate that regenerating auditory neurons show a strong affinity to the NCD pillars, and the technique could be used for neural guidance and the creation of new neural networks. Together with the NCD's unique anti bacterial and electrical properties, patterned NCD surfaces could provide designed neural/electrode interfaces to create independent electrical stimulation signals in CI electrode arrays for the neural population. STATEMENT OF SIGNIFICANCE: Cochlear implant is currently a successful way to treat sensorineural hearing loss and deafness especially in children. Although clinically successful, patients' fine hearing cannot be completely restored. One problem is the amount of the electrodes; 12-20 electrodes are used to replace the function of 3400 inner hair cells. Intense research is ongoing aiming to increase the number of electrodes. This study demonstrates the use of nanocrystalline diamond as a potential nerve-electrode interface. Micrometer-sized nanocrystalline diamond pillars showed high affinity to regenerated human neurons, which grew into a pre-defined network based on the pillar design. Our findings are of particular interest since they can be applied on any silicon based implant to increase electrode count and to achieve individual neuron stimulation patterns. PMID- 26593786 TI - Functionalized collagen scaffold implantation and cAMP administration collectively facilitate spinal cord regeneration. AB - Previous studies have demonstrated that several mechanisms, including numerous inhibitory molecules, weak neurotrophic stimulation and deficient intrinsic regenerative responses, collectively contribute to the failure of mature spinal cord axon regeneration. Thus, combinatorial therapies targeting multiple mechanisms have attracted much attention. In the present study, a porous collagen scaffold was used to support neuronal attachment and bridge axonal regeneration. The scaffold was specifically functionalized using neutralizing proteins (CBD EphA4LBD, CBD-PlexinB1LBD and NEP1-40) and collagen-binding neurotrophic factors (CBD-BDNF and CBD-NT3) to simultaneously antagonize myelin inhibitory molecules (ephrinB3, Sema4D and Nogo) and exert neurotrophic protection and stimulation. Cerebellar granular neurons cultured on the functionalized collagen scaffold promoted neurite outgrowth in the presence of myelin. Furthermore, a full combinatorial treatment comprising functionalized scaffold implantation and cAMP administration was developed to evaluate the synergistic repair ability in a rat T10 complete removal spinal cord injury model. The results showed that full combinatorial therapy exhibited the greatest advantage in reducing the volume of cavitation, facilitating axonal regeneration, and promoting neuronal generation. The newborn neurons generated in the lesion area could form the neuronal relay and enhance the locomotion recovery after severe spinal cord injury. STATEMENT OF SIGNIFICANCE: A porous collagen scaffold was specifically functionalized with neutralizing proteins and neurotrophic factors to antagonize the myelin inhibitory molecules and exert neurotrophic protection and stimulation for spinal cord regeneration. Cerebellar granular neurons seeded on the functionalized collagen scaffold showed enhanced neurite outgrowth ability in vitro. The functionalized scaffold implantation combined with cAMP administration exhibited synergistic repair ability for rat T10 complete spinal cord transection injury. PMID- 26593787 TI - [Late-preterm infants, a growing challenge in both the short and long term]. PMID- 26593785 TI - PolySTAT-modified chitosan gauzes for improved hemostasis in external hemorrhage. AB - Positively-charged chitosan gauzes stop bleeding from wounds by electrostatically interacting with negatively-charged cell membranes of erythrocytes to cause erythrocyte agglutination and by sealing wounds through tissue adhesion. In the following work, nonwoven chitosan gauze was impregnated with PolySTAT, a synthetic polymer that enhances coagulation by cross-linking fibrin, to generate PolySTAT/chitosan gauzes with improved hemostatic efficacy. When comparing nonwoven chitosan and PolySTAT/chitosan to a commercially-available chitosan containing gauze (Celox(r) Rapid), no appreciable differences were observed in fiber size, morphology, and pore size. However, PolySTAT/chitosan demonstrated more rapid blood absorption compared to Celox(r) Rapid. In a rat model of femoral artery injury, PolySTAT/chitosan gauzes reduced blood loss and improved survival rate compared to non-hemostatic controls and Celox(r) Rapid. While Celox(r) Rapid had stronger adherence to tissues compared to PolySTAT/chitosan gauzes, blood loss was greater due to hematoma formation under the Celox(r) dressing. Animals treated with PolySTAT/chitosan gauzes required less saline infusion to restore and maintain blood pressure above the target blood pressure (60mmHg) while other treatment groups required more saline due to continued bleeding from the wound. These results suggest that PolySTAT/chitosan gauzes are able to improve blood clotting and withstand increasing arterial pressure with the addition of a fibrin cross-linking hemostatic mechanism. STATEMENT OF SIGNIFICANCE: Blood loss remains one of the leading causes of death after traumatic injury in civilian populations and on the battlefield. Advanced biomaterials that interact with blood components and/or accelerate the clotting process to form a hemostatic plug are necessary to staunch bleeding after injury. Chitosan-based gauzes, which stop bleeding by causing red blood cell aggregation, are currently used on the battlefield and have shown variable performance under high pressure arterial blood flow in animal studies, suggesting that red blood cell aggregates require further mechanical stabilization for more reliable performance. In this work, we investigate the binding and cross-linking of fibrin, a major component in blood clots, on chitosan gauze fiber surfaces to structurally reinforce red blood cell aggregates. PMID- 26593788 TI - [Electronic publishing brings good news to Archivos Argentinos de Pediatria]. PMID- 26593789 TI - [Art as an instrument to learn how to overcome uncertainty]. PMID- 26593790 TI - [Humanism and scientific rigor: twins separated at birth]. PMID- 26593792 TI - [Dr. Carlos Gianantonio]. PMID- 26593791 TI - [Lung development in children and its relationship to environmental pollution]. PMID- 26593793 TI - [Comparison of the predictive ability of two scoring systems for the diagnosis of tuberculosis in children]. AB - Diagnosing childhood tuberculosis requires a strong diagnostic suspicion due to its paucibacillary manifestation. Different scoring systems and algorithms have been developed to deal with such challenge skillfully. These include the Keith Edwards diagnostic score and Stegen's criteria modified by Toledo (Stegen Toledo). OBJECTIVES: To compare the predictive ability of the Keith Edwards diagnostic score to that of the Stegen-Toledo scoring system. To estimate the predictive diagnostic ability of chest X-rays individually. POPULATION, MATERIAL AND METHODS: Patients seen at the Department of Pediatric Pulmonology of the City of Buenos Aires between 2009 and 2012. A2 test was used to analyze the predictive diagnostic ability, and performance was compared using the extended McNemar test. RESULTS: Keith Edwards: 19.62% sensitivity, 97.62% specificity (p < 0.0001). Stegen-Toledo: 43.54% sensitivity, 97.82% specificity (p < 0.0001). Sensitivity was significantly different between both scoring systems (p < 0.05), but no differences were observed in terms of specificity. Chest X-ray: 91.15% sensitivity, 87.72% specificity (p < 0.0001). CONCLUSION: The Keith Edwards scoring system showed a lower diagnostic sensitivity than the Stegen-Toledo score in this group of patients, with no differences observed in terms of specificity. The chest X-ray showed a 91.15% sensitivity to diagnose tuberculosis in this group of patients. PMID- 26593794 TI - [Prevalence of neural tube defects and estimation of cases averted in the post fortification period in Argentina]. AB - Periconceptional intake of folic acid has demonstrated to be effective to reduce the frequency of neural tube defects, and food fortification has been one of the strategies implemented to increase it. An update is herein presented on the reduced prevalence of neural tube defect cases in the post-fortification period in Argentina and an estimation of cases averted in the 2005-2013 period as a result of this intervention. When comparing the prevalence observed in the post fortification period to that reported in the pre-fortification period, anencephaly and encephalocele decreased by 66%, and spina bifida, by 47%, which were significant reductions. The estimated number of cases averted was higher for anencephaly, followed by spina bifida; encephalocele showed the lowest number of cases averted given that the prevalence of this defect was smaller. The decrease observed in the prevalence supports findings from previous studies on the impact of fortification. PMID- 26593795 TI - [Impact of the 13-valent pneumococcal conjugate vaccine on the incidence of consolidated pneumonia in children younger than 5 years old in Pilar, Buenos Aires: A population-based study]. AB - INTRODUCTION: In January 2012, Argentina introduced the 13-valent pneumococcal conjugate vaccine (PCV13) in its immunization schedule for children younger than 2 years old. Coverage in Pilar in 2012 reached>90% for the first two doses and 60% for the third dose. OBJECTIVE: To measure the effectiveness of PCV13 to reduce the incidence of consolidated pneumonia (CP)in the two-year period following its introduction in the immunization schedule. METHODS: Prospective, population-based study conducted in Pilar. All children younger than 5 year sold with clinical signs of pneumonia assisted at the reference hospitals (both inpatients and outpatients) in the first two years since the vaccine introduction (2012-2013) were included. The annual incidence of CP was compared to the 2003 2005 baseline period. Clinical and radiological assessments were done as per the World Health Organization's criteria. RESULTS: Six hundred and sixty-six patients with clinical suspicion of pneumonia were included. CP was diagnosed in 309 patients; 52.1% were girls, 70.2% were younger than 2 years old, and 56.4% had been immunized with the PCV13; 4.5% (14/309) had bacteriological confirmation (S. pneumoniae: 4; N. meningitidis: 4; S. aureus: 2; others: 4). A significant reduction in the incidence of CP (per 100 000 children younger than 5 years old) was observed between the pre- and postimmunization periods, from 750 (204/27209) to 561 (171/30 475) in 2012 and to 453 (138/30 475) in 2013; effectiveness accounted for 25.2% and 39.6%, respectively. Reduction in infants younger than 1 year old: 33.9% in 2012 and 44.6% in 2013; and in children aged 12-23 months old: 57.9% in 2013. No significant differences were observed in the incidence of CP at an older age. CONCLUSIONS: Following the introduction of PCV13 in Argentina's immunization schedule, a fast and significant reduction in the incidence of CP was observed, mainly in infants younger than 1 year old in 2012 and in children younger than 2 years old in 2013. PMID- 26593796 TI - [Safe and family-centered maternity hospitals: organizational culture of maternity hospitals in the province of Buenos Aires]. AB - INTRODUCTION: In 2010, the Safe and Family-Centered Maternity Hospitals initiative was launched in order to transform large public maternity centers into settings where safe practices are implemented and the rights of women, newborn infants and families are warranted. As a result, the paradigm of perinatal care was modified. This article reports on the findings of organizational culture as a component for the implementation of the initiative. POPULATION AND METHODS: The sample was selected in a non-probabilistic way and was made up of 29 public hospitals located in the province of Buenos Aires that participated in the initiative. During 2011 and 2012, an anonymous, self-administered survey was completed by members of the Department of Neonatology and the Department of Obstetrics. The survey collected information on three dimensions of the organizational culture: organizational environment, safe practices, and facilitation of change. RESULTS: A total of 1828 surveys were collected; 51% of survey respondents stated that there is a need to improve communication by having more meetings, while 60% made a positive assessment of various aspects of leadership. Work overload was described as the main cause of conflicts by 60%. Approximately 25% agreed and showed commitment with the initiative of transforming maternity centers. Adherence to practices was dissimilar depending on the practice, but half of survey respondents reported that there were genuine reasons for change. CONCLUSIONS: The assessment of the organizational culture showed that commitment to the Safe and Family-Centered Maternity Hospitals initiative is yet to be consolidated, and the evaluation of leadership is not comprehensive. Work overload and communication failures are the main reasons for conflict. PMID- 26593797 TI - [Mass media influence and risk of developing eating disorders in female students from Lima, Peru]. AB - INTRODUCTION: Eating disorders (EDs) are a public health problem, and their relationship to mass media is still controversial. OBJECTIVE: To assess whether there is an association between models of body image shown in mass media and the risk of developing EDs among female adolescent students from Lima, Peru. METHODOLOGY: Cross-sectional study conducted in three schools located in the district of La Victoria, Lima, Peru. The risk of developing EDs was measured using the Eating Attitudes Test-26 (EAT-26), while mass media influence was measured using the Sociocultural Attitudes Towards Appearance Questionnaire-3 (SATAQ-3), which was categorized into tertiles both in the overall score and its subscales (information, pressure, general internalization, and athletic internalization). Adjusted prevalence ratios (aPR) for EDs were estimated. RESULTS: Four hundred and eighty-three students were included, their median age was 14 ? 3 years old. A risk of developing an ED was observed in 13.9% of them. Students who are more influenced by mass media (upper tertile of the SATAQ-3) have a higher probability of having a risk of developing an ED (aPR: 4.24; 95% confidence interval |-CI-|: 2.10-8.56), as well as those who have a greater access to information (PR: 1.89; 95% CI: 1.09-3.25), suffer more pressure (PR: 4.97; 95% CI: 2.31-10.69), show a greater general internalization (PR: 5.00; 95% CI: 2.39-10.43), and show a greater level of athletic internalization (PR: 4.35; 95% CI: 2.19-8-66). CONCLUSION: The greater the influence of mass media, the greater the probability of having a risk of developing an ED among female students from Lima, Peru. PMID- 26593798 TI - [Perceived health and academic performance among adolescents from public schools in the city of Cordoba]. AB - INTRODUCTION: During adolescence, school performance may be related to health, and academic achievements at this age can have an impact on the future. Our objective was to assess the relationship between academic performance and perceived health among adolescents, considering sociodemographic characteristics of their families. POPULATION AND METHODS: Cross-sectional pilot study conducted in a sample of adolescents attending common basic courses of three public secondary schools in the city of Cordoba (Argentina). Academic performance was calculated as the average grade in all subjects; performance was considered satisfactory if equal to or higher than 6. Perceived health was assessed using the KIDSCREEN-52 questionnaire, which scores ten dimensions. In addition, age, sex, maternal education level, socioeconomic level and household composition were also recorded. Univariate and bivariate analyses and multivariate logistic regression models were conducted. RESULTS: Five hundred fifty-four adolescents participated, 52% of them were girls. Unsatisfactory academic performance (27.6%) was more common among adolescents who evidenced a worse relationship with parents (OR: 2.68, 95% CI: 1.22-5.85) and a better relationship with peers (OR: 0.46, 95% CI: 0.26-0.82). Stratification by socioeconomic level showed differences: among those with a high socioeconomic level, an unsatisfactory performance was more common among adolescents who perceived themselves as having a low autonomy, while it was more common among those who perceived a worse school environment in the middle-low socioeconomic level. CONCLUSION: Academic performance was associated with psychosocial dimensions of health, such as relationship with family members, peers, autonomy and school environment. PMID- 26593799 TI - [The role of serum interleukin-6 and C-reactive protein levels for differentiating aetiology of neonatal sepsis]. AB - INTRODUCTION: In our clinical practice, we observed high interleukin-6 (IL-6) levels in gram-negative sepsis. OBJECTIVE: To investigate the relationship between IL-6 and C-reactive protein (CRP) levels and early determination of neonatal sepsis of gram-negative or gram-positive aetiology. POPULATION AND METHODS: White blood cell count, IL-6 and CRP levels were compared among different groups. RESULTS: Gram-negative, gram-positive and fungal infection groups consisted of 73, 82 and 15 patients, respectively. The optimal cut-off levels of IL-6 between gram-negative and gram-positive fungal infection groups were 202 and 57 pg/ml. The fungal infection group had higher CRP levels than gram negative and positive infection groups. CONCLUSIONS: To our knowledge, this is the largest reported study aiming at determining of IL-6 cut-off levels to differentiate neonatal sepsis aetiology. Gram-negative microorganisms led to 10 fold higher IL-6 production. The evaluation of IL-6 and CRP is useful to diagnose and also differentiate neonatal sepsis aetiology. PMID- 26593800 TI - [Use of component-resolved diagnosis in the follow-up of children with plant food allergy]. AB - Food allergy poses a major problem during childhood. Component-resolved diagnosis detects allergy to proteins isolated in food. This descriptive study analyzes the use of customized and standardized recommendations in a sample made up of 22 children aged 2 to 16 years old with plant food allergy and assesses sensitivity to four plant panallergens. According to component-resolved diagnosis results, therapy was personalized, guidelines on what foods or components to avoid were provided, and co-factors that may favor food allergic reactions were explained. No new reactions were referred by 20/22 cases. Oral allergy syndrome developed in 2/22 patients with allergy to profilin because they did not follow the recommendations. Component-resolved diagnosis was useful for the diagnosis and management of these children. Standardized recommendations, based on each patient's component-resolved diagnosis, prevented severe food allergic reactions. PMID- 26593801 TI - [Lumbar puncture training using simulation-based educational strategies: Experience in a clinical pediatric residency]. AB - Pediatricians should acquire multiple skills during their professional training, including procedural skills. Skill acquisition requires knowledge on theoretical bases, direct observation and, lastly, supervised repetitive practice. Training using simulators allows to learn procedures in a controlled setting, ensuring patients' safety, integrating this as a learning stage prior to the actual contact with patients. Here we report on the teaching experience of a simulated lumbar puncture procedure. Training was provided to 112 first year pediatric residents who entered Hospital Prof. Dr. Juan P. Garrahan in the 2013-2014 period. Educational contents included communication with parents regarding the procedure, material preparation, compliance with biosafety standards, sepsis and general patient care, puncture and subsequent cerebrospinal fluid collection, and specimen collection. Strategies included, in a sequential order, the introduction of theoretical aspects using the bibliography and audiovisual resources available at the hospital's online campus and subsequent practice of lumbar puncture in a 3 month-old infant phantom on a lateral recumbent position that allowed to make a puncture and collect cerebrospinal fluid. At each training session, the level of confidence was measured before and after the procedure, and a checklist was developed to verify an adequate compliance with each step of the procedure. The simulated lumbar puncture training model has been introduced as an educational strategy of our Pediatric Residency Program. PMID- 26593803 TI - [Child maltreatment prevention: the pediatrician's function. Part 1: Overview, evidence, risk factors, protective factors and triggers]. AB - Child maltreatment is a common and serious problem. It harms children in the short and long term, affecting their future health and their offspring. Primary, secondary, tertiary and quaternary preventing interventions target on child abuse are described. Evidence-based recommendations on child abuse prevention and examples of researches with proven efficacy are detailed. Risk factors, protective factors and triggers of child abuse and their relationships are described. PMID- 26593802 TI - [Development and assessment of EPInfant: a rating scale of perceived exertion for the pediatric population]. PMID- 26593804 TI - [Management of the most frequent functional gastrointestinal dis orders in healthy infants]. AB - Healthy infants during the first year of life often have multiple functional gastrointestinal symptoms such as colic, regurgitation and constipation. The usual fuzziness and/or crying at this stage of life is interpreted as digestive discomfort or pain, and the corresponding concerns result in unsuitable behaviors as overeating, interruption of breastfeeding, multiple changes of formulas, innumerable queries and unnecessary medications. The aim of this paper is to update knowledge on the pathophysiology of the most common functional gastrointestinal dis orders, in order to avoid over diagnosis and select the most appropriate therapeutic approach and convenient nutritional interventions. PMID- 26593805 TI - [New recommendations against the current controversies in urinary tract infection: Executive summary]. PMID- 26593806 TI - [Intraductal metachronic papilloma: Clinical case]. AB - INTRODUCTION: The association of gynecomastia and bloody nipple discharge (thelorragia) leads us to the diagnosis of intraductal papilloma. This is a very rare benign tumor in children. CLINICAL CASE: A 2 year old male child was referred due to gynecomastia and bloody nipple discharge of the left breast. A mastectomy was performed. At the age of 4 he returned with identical symptoms but in the right breast. A right mastectomy was also required. An excellent clinical outcome was present in the follow up. The pathology reported intraductal papilloma with no evidence of malignancy or atypia. CONCLUSION: The intraductal papilloma rarely affects children, there are 15 reported cases. Ultrasound is the most useful diagnostic method. In male patients, mastectomy is recommended to ensure definitive diagnosis and treatment. PMID- 26593807 TI - [Anomalous mitral arcade: a disguised and silent lesion leading to a recurrent wheezing in children. A case report]. AB - Recurrent wheezing is a very common clinical ailment throughout infancy and childhood. The most common diagnosis in children with wheezing is asthma. However, some other causes should be considered in the differential diagnosis such as a congenital cardiac defect. We present a case of a four year old boy presenting with recurrent wheezing who was referred to our institution for cardiac evaluation. Severe mitral stenosis secondary to an anomalous mitral arcade was diagnosed by physical examination, chest X-ray, electrocardiogram and mainly transthoracic and transesophageal echocardiography. Anomalous mitral arcade is a rare congenital malformation of the mitral tensor apparatus which comprises the chordae tendineae and papillary muscles. This abnormal anatomy leads to increased filling pressure of the left ventricle, a retrograde post capillary pulmonary hypertension and interstitial aedema. The patient was referred to cardiac surgery and underwent a successful procedure with complete removal of the obstructive mitral lesion. PMID- 26593808 TI - [Hypothalamyc hamartomas: different ways of clinical debut. Cases report]. AB - Hypothalamic hamartomas are benign tumors of gray substance composed by hyperplasic neurons. They are usually asymptomatic small masses with extensions into the third ventricular cavity. In some instances they can cause cognitive behavioral alterations, seizures and/or central precocious puberty depending on the location. Here we present two cases of central precocious puberty due to hypothalamic hamartomas at 2(8/12) and 7 years of age. The younger patient also presents gelastic seizures, typically associated with hypothalamic hamartomas. After the clinical and radiological findings, they started treatment with GnRH analogues and a regression of the puberty signs without progression in the hamartomas size was observed. PMID- 26593809 TI - [Rosai-Dorfman disease: Case report]. AB - Rosai-Dorfman disease, also known as sinus histiocytosis with massive lymphadenopathy, is a rare dis order of unknown etiology, generally associated with enlargement of superficial and/or deep lymph nodes. Most patients do not require treatment. We report the case of a 10 month old infant who was admitted with a left cervical tumor of 25 days duration. PMID- 26593810 TI - [Meconium periorchitis: A case report]. AB - Meconium periorchitis is uncommon. In the unborn child the peritoneum vaginal canal is open and, secondary to intestinal perforation due to any cause (intestinal atresia, volvulus, and others), meconium peritonitis occurs. The intestinal content reaches the scrotal vaginal cavity. Meconium peritonitis can heal spontaneously and without consequences. Calcified remnants of this event may remain in the peritoneal cavity and/or scrotum. In the newborn, a hydrocele and scrotal mass can be observed; the ultrasound will show a heterogeneous image with calcifications. Meconium periorchitis or meconium vaginalitis resolves spontaneously. The lack of awareness of this disease could lead to unnecessary surgery in the newborn. We present a 33 days old patient with a scrotal mass in whom surgery was performed with the pathological diagnosis of meconium periorchitis. PMID- 26593811 TI - [Colorectal adenocarcinoma in a 5 year old girl]. AB - Colorectal adenocarcinoma is exceptional in children, generally diagnosed in advanced stages, with worse prognosis. We report the case of a 5 year old girl with isolated hematochezia lasting two months without other findings, in whom a colorectal adenocarcinoma was confirmed by colonoscopy. Staging revealed localized disease, extending to perisigmoid fat and a few adjacent ganglia. She was treated by laparoscopic resection and adjuvant chemotherapy, being free of disease at 21 moths of follow-up. PMID- 26593812 TI - [Pediatric-onset adult type sarcoidosis: A case report]. PMID- 26593813 TI - [Clinical and molecular study in a child with X-linked hypohidrotic ectodermal dysplasia]. AB - Ectodermal dysplasia encompasses more than 200 clinically distinct entities, which affect at least two structures derived from the ectoderm, including the skin, hair, nails, teeth, sweat glands, and sebaceous glands. X-linked hypohidrotic ectodermal dysplasia is the most common type and is caused by mutation of the EDA gene that encodes Ectodysplasin-A. It occurs in less than 1 in 100 000 individuals and is clinically characterized by hypodontia, hypohidrosis, hypotrichosis, and eye dis orders. We present a child evaluated in a multidisciplinary manner with clinical and molecular diagnosis of X-linked hypohidrotic ectodermal dysplasia with type missense mutation c.1133C> T; p.T378M in EDA gene. PMID- 26593814 TI - [Thoracic actinomycosis: report of a case]. AB - Actinomycosis is a disease produced by bacteria of the genus Actinomyces. The thoracic form represents 30% of the cases. Signs and symptoms are generally unspecific. A previously healthy 11 year old girl was admitted with a chest mass of a month of evolution associated with fever, hyporexia and weight loss. Thoracic actinomycosis was diagnosed with the isolation of Actinomyces meyeri in the mass drainage. She received antibiotic treatment for a year with complete resolution. Although rare, it should be taken into account as a differential diagnosis in long evolution thoracic tumor affecting the general condition. The microbiologist must be warned about the suspected diagnosis because it is difficult to find it in routinely used culture media. PMID- 26593815 TI - [Brucella melitensis is an agent in pediatric arthritis: Case series]. PMID- 26593816 TI - [Fractured tracheostomy tube: a rare cause of respiratory distress in the tracheotomized child. Case report]. AB - Fracture and migration of the tracheotomy tube in the tracheobronchial tree is an uncommon complication of tracheotomy. Early diagnosis and proper treatment are essential because of the potential risk of fatal respiratory obstruction. Diagnosis should be suspected in all tracheotomized children undergoing breathing difficulties. It is confirmed by chest x-ray and endoscopic examination. The recommended treatment includes the endoscopic removal of the aspirated cannula through the tracheal stoma. We describe the clinical presentation and the management of a broken tracheotomy tube which was presented as a foreign body in the airway of a 18-month-old child. Recommendations for tracheostomy care are listed. PMID- 26593817 TI - [Clinical, radiological and auxologic long-term evolution of 8 children with asphyxiating thoracic dysplasia]. AB - Asphyxiating thoracic dysplasia is an uncommon condition with multiple organ affectation and high neonatal mortality. It presents with short stature, short extremities, narrow thorax. With growth, there is respiratory improvement, but emergence of renal, hepatic, pancreatic and/or retinal impairment. OBJECTIVE: to describe the long-term evolution of 8 patients of a pediatric hospital. METHODS: we retrospectively evaluated age at diagnosis, sex, anthropometric variables, complications and radiology. RESULTS: male/female 6/2. Median age at diagnosis: 2.54 years. EVOLUTION: 8/8 respiratory compromise, 3/8 kidney, liver 2/8, 1/8 ophthalmologic, cardiac 1/8. Median height at diagnosis -1.76 DS, normal postnatal growth and body proportions. Radiology: 8/8 narrow chest and brachyphalangia in hands. 5/8 acetabular abnormalities. DISCUSSION: for surveillance it is recommended to monitor renal, liver and eye function. The pediatrician should suspect this entity in a newborn with narrow thorax and respiratory distress. PMID- 26593820 TI - Insights on P-Glycoprotein's Efflux Mechanism Obtained by Molecular Dynamics Simulations. AB - P-Glycoprotein (P-gp) is often involved in multidrug resistance (MDR) to the pharmacological action of a wide number of anticancer agents. In this article, a series of molecular dynamics simulations of murine's P-gp were developed, elucidating the importance of the lipid membrane and linker sequence in the protein structure stability. The behavior of several molecules inside the drug binding pocket revealed a striking difference between substrates or modulators, and motion patterns were identified that could be correlated with conformational alterations due to substrate binding, corresponding to the initial step in the efflux mechanism. Only one "entrance gate" to the drug-binding pocket was found and, in the presence of a substrate, leads to changes in the motion patterns of the transporter into an efflux-like movement. PMID- 26593819 TI - Enteral siRNA delivery technique for therapeutic gene silencing in the liver via the lymphatic route. AB - An efficient targeting delivery technology is needed for functional oligonucleotides to exert their potential effect on the target gene without an adverse effect in vivo. Development of enteral delivery systems for nucleic acids is a major challenge because of their large molecular size and instability. Here, we describe a new enteral delivery technique that enables small interfering RNA (siRNA) selectively delivered to the liver to silence its target Apolipoprotein B gene expression. A nuclease-resistant synthetic siRNA was conjugated with alpha tochopherol and administered as lipid nanoparticle to the large intestine of the mice in a postprandial state. The selective transport into the liver, effective gene silence, and consequently significant reduction in serum low density lipoprotein-cholesterol level, were demonstrated. The chylomicron-mediated pathway via the lymphatic route was suggested as major mechanism. This unique approach may provide a basis for developing oral and rectal delivery systems for nucleic acids targeting liver. PMID- 26593821 TI - Establishing Uniform Acceptance in Force Biased Monte Carlo Simulations. AB - Uniform acceptance force biased Monte Carlo (UFMC) simulations have previously been shown to be a powerful tool to simulate atomic scale processes, enabling one to follow the dynamical path during the simulation. In this contribution, we present a simple proof to demonstrate that this uniform acceptance still complies with the condition of detailed balance, on the condition that the characteristic parameter lambda = 1/2 and that the maximum allowed step size is chosen to be sufficiently small. Furthermore, the relation to Metropolis Monte Carlo (MMC) is also established, and it is shown that UFMC reduces to MMC by choosing the characteristic parameter lambda = 0 [Rao, M. et al. Mol. Phys.1979, 37, 1773]. Finally, a simple example compares the UFMC and MMC methods. PMID- 26593822 TI - The Cobalt-Methyl Bond Dissociation in Methylcobalamin: New Benchmark Analysis Based on Density Functional Theory and Completely Renormalized Coupled-Cluster Calculations. AB - The Co-CMe bond dissociation in methylcobalamin (MeCbl), modeled by the Im [Co(III)corrin]-Me(+) system consisting of 58 atoms, is examined using the coupled-cluster (CC), density-functional theory (DFT), complete-active-space self consistent-field (CASSCF), and CASSCF-based second-order perturbation theory (CASPT2) approaches. The multilevel variant of the local cluster-in-molecule framework, employing the completely renormalized (CR) CC method with singles, doubles, and noniterative triples, termed CR-CC(2,3), to describe higher-order electron correlation effects in the region where the Co-CMe bond breaking takes place, and the canonical CC approach with singles and doubles (CCSD) to capture the remaining correlation effects, abbreviated as CR-CC(2,3)/CCSD, is used to obtain the benchmark potential energy curve characterizing the Co-CMe dissociation in the MeCbl cofactor. The Co-CMe bond dissociation energy (BDE) resulting from the CR-CC(2,3)/CCSD calculations for the Im-[Co(III)corrin]-Me(+) system using the 6-31G* basis set, corrected for the zero-point energies (ZPEs) and the effect of replacing the 6-31G* basis by 6-311++G**, is about 38 kcal/mol, in excellent agreement with the experimental values characterizing MeCbl of 37 +/ 3 and 36 +/- 4 kcal/mol. Of all DFT functionals examined, the best dissociation energies and the most accurate description of the Co-CMe bond breaking in the Im [Co(III)corrin]-Me(+) system are provided by B97-D and BP86 corrected for dispersion using the D3 correction of Grimme et al., which give 35 and 40 kcal/mol, respectively, when the 6-311++G** basis set is employed and when the results are corrected for ZPEs and basis set superposition error. None of the other DFT approaches examined provide results that fall into the experimental range of the Co-CMe dissociation energies in MeCbl of 32-40 kcal/mol. The hybrid DFT functionals with a substantial amount of the Hartree-Fock (HF) exchange, such as B3LYP, considerably underestimate the calculated dissociation energies, with the magnitude of the error being proportional to the percentage of the HF exchange in the functional. It is argued that the overstabilization of diradical structures that emerge as the Co-CMe bond is broken and, to some extent, the neglect of dispersion interactions at shorter Co-CMe distances, postulated in previous studies, are the main factors that explain the substantial underestimation of the Co-CMe BDE by B3LYP and other hybrid functionals. Our calculations suggest that CASSCF and CASPT2 may have difficulties with providing a reliable description of the Co-CMe bond breaking in MeCbl, since using adequate active spaces is prohibitively expensive. PMID- 26593823 TI - NOx Catalyzed Pathway of Stratospheric Ozone Depletion: A Coupled Cluster Investigation. AB - We report a theoretical investigation on the NOx catalyzed pathways of stratospheric ozone depletion using highly accurate coupled cluster methods. These catalytic reactions represent a great challenge to state-of-the-art ab initio methods, while their mechanisms remain unclear to both experimentalists and theoreticians. In this work, we have used the so-called "gold standard of quantum chemistry," the CCSD(T) method, to identify the saddle points on NOx based reaction pathways of ozone hole formation. Energies of the saddle points are calculated using the multireference variants of coupled cluster methods. The calculated activation energies and rate constants show good agreement with available experimental results. Tropospheric precursors to stratospheric NOx radicals have been identified, and their potential importance in stratospheric chemistry has been discussed. Our calculations resolve previous conflicts between ab initio and experimental results for a trans nitro peroxide intermediate, in the NOx catalyzed pathway of ozone depletion. PMID- 26593824 TI - Generalization of Natural Bond Orbital Analysis to Periodic Systems: Applications to Solids and Surfaces via Plane-Wave Density Functional Theory. AB - Natural bond orbital (NBO) analysis is a powerful analysis technique capable of generating intuitive chemical representations of otherwise complex quantum mechanical electronic structure results, yielding a localized "Lewis-like" description of bonding and reactivity. We generalize this algorithm to periodic systems, thus expanding the scope of NBO analysis to bulk materials and/or periodic surface models. We employ a projection scheme to further expand the algorithm's applicability to ubiquitous plane-wave density functional theory (PW DFT) calculations. We also present a variety of example applications: examining bulk bonding and surface reconstruction and elucidating fundamental aspects of heterogeneous catalysis-all derived from rigorous underlying PW DFT calculations. PMID- 26593825 TI - Toward Molecular-Level Characterization of Photoinduced Decarboxylation of the Green Fluorescent Protein: Accessibility of the Charge-Transfer States. AB - Irradiation of the green fluorescent protein (GFP) by intense violet or UV light leads to decarboxylation of the Glu222 side chain in the vicinity of the chromophore (Chro). This phenomenon is utilized in optical highlighters, such as photoactivatable GFP (PA-GFP). Using state-of-the-art quantum chemical calculations, we investigate the feasibility of the mechanism proposed in the experimental studies [van Thor et al. Nature Struct. Biol.2002, 9, 37-41; Bell et al. J. Am. Chem. Soc.2003, 125, 37-41]. It was hypothesized that a primary event of this photoconversion involves population of a charge-transfer (CT) state via either the first excited state S1 when using longer wavelength (404 and 476 nm) or a higher excited state when using higher energy radiation (254 and 280 nm). Based on the results of electronic structure calculations, we identify these critical CT states (produced by electron transfer from Glu to electronically excited Chro) and show that they are accessible via different routes, i.e., either directly, by one-photon absorption, or through a two-step excitation via S1. The calculations are performed for model systems representing the chromophore and the key nearby residues using two complementary approaches: (i) the multiconfigurational quasidegenerate perturbation theory of second order with the occupation restricted multiple active space scheme for configuration selection in the multiconfigurational self-consistent field reference; and (ii) the single reference configuration interaction singles method with perturbative doubles that does not involve active space selection. We examined electronic transitions with nonzero oscillator strengths in the UV and visible range between the electronic states involving the Chro and Glu residues. Both methods predict the existence of CT states with nonzero oscillator strength in the UV range and a local excited state of the chromophore accessible via S1 that may lead to the target CT state. The results suggest several possible scenarios for the primary photoconversion event. We also demonstrate that the point mutation Thr203His exploited in PA-GFP results in shifting the light wavelength to access the CT up to 20 nm, which suggests a possibility of a rational design of photoactivatable proteins in silico. PMID- 26593826 TI - Coupled Cluster and Moller-Plesset Perturbation Theory Calculations of Noncovalent Intermolecular Interactions using Density Fitting with Auxiliary Basis Sets from Cholesky Decompositions. AB - We compute noncovalent intermolecular interaction energies for the S22 test set [Phys. Chem. Chem. Phys.2006, 8, 1985-1993] of molecules at the Moller-Plesset and coupled cluster levels of supermolecular theory using density fitting (DF) to approximate all two-electron integrals. The error due to the DF approximation is analyzed for a range of auxiliary basis sets derived from Cholesky decomposition (CD) in conjunction with correlation consistent and atomic natural orbital valence basis sets. A Cholesky decomposition threshold of 10(-4)Eh for full molecular CD and its one-center approximation (1C-CD) generally yields errors below 0.03 kcal/mol, whereas 10(-3)Eh is sufficient to obtain the same level of accuracy or better with the atomic CD (aCD) and atomic compact CD (acCD) auxiliary basis sets. Comparing to commonly used predefined auxiliary basis sets, we find that while the aCD and acCD sets are larger by a factor of 2-4 with triple-zeta AO basis sets, they provide results 1-2 orders of magnitude more accurate. PMID- 26593827 TI - Benchmark Assessment of the Accuracy of Several van der Waals Density Functionals. AB - The nonlocal correlation functional VV10, developed recently in our group, describes the whole range of dispersion interactions in a seamless and general fashion using only the electron density as input. The VV10 functional has a simple analytic form that can be adjusted for pairing with the exchange functional of choice. In this paper, we use several benchmark data sets of weakly interacting molecular complexes to test the accuracy of two VV10 variants, differing in their treatment of the exchange component. For the sake of comparison, several other density functionals suitable for noncovalent interactions were also tested against the same benchmarks. We find that the "default'' version of VV10 with semilocal exchange gives very accurate geometries and binding energies for most van der Waals complexes but systematically overbinds hydrogen-bonded complexes. The alternative variant of VV10 with long range corrected hybrid exchange performs exceptionally well for all types of weak bonding sampled in this study, including hydrogen bonds. PMID- 26593828 TI - Tuning the C-H...pi Interaction by Different Substitutions in Benzene-Acetylene Complexes. AB - The influence of substitutions in aromatic moieties on the binding strength of their complexes is a subject of broad importance. Using a set of various substituted benzenes, Sherrill and co-workers ( J. Am. Chem. Soc. 2011 , 133 , 13244 ; J. Phys. Chem. A 2003 , 107 , 8377 ) recently showed that the strength of a stacking interaction (pi...pi interaction) is enhanced by adding substituents regardless of their nature. Although the binding strength of an activated C H...pi interaction is comparable to that of a stacking interaction, a similar systematic study is hitherto unknown in the literature. We have computed the stabilization energies of the C-H...pi complex of acetylene and multiple fluoro /methyl-substituted benzenes at the coupled-cluster single and double (triple) excitation [CCSD(T)]/complete basis set (CBS) limit. The trend for interaction energies was found to be hexafluorobenzene-acetylene < sym-tetrafluorobenzene acetylene < sym-trifluorobenzene-acetylene < sym-difluorobenzene-acetylene < benzene-acetylene < sym-dimethylbenzene-acetylene < sym-trimethylbenzene acetylene < sym-tetramethylbenzene-acetylene < hexamethylbenzene-acetylene. Therefore, contrary to the case of stacking interaction ( Hohenstein et al. J. Am. Chem. Soc. 2011 , 133 , 13244 ), we show here that electron-withdrawing groups weaken the dimer while electron-donating groups strengthen the interaction energy of the dimer. Various recently developed density functional theoretic (DFT) methods were assessed for their performance and the M05-2X, M06-2X, and omegaB97X-D methods were found to be the best performers. These best DFT performers were employed in determining the influence of other representative substituents (-NO2, -CN, -COOH, -Br, -Cl, -OH, and -NH2) as an extension to the above work. The results for the complex of acetylene and various para disubstituted benzenes revealed a trend in binding energies that is in accordance with the ring-activating/deactivating capacity of each of these groups. The stabilization energy was partitioned via the DFT symmetry-adapted perturbation theory (SAPT) method, and both dispersion and electrostatic interactions were seen to be major driving forces for the complex stabilization. Interestingly, the sum of the energy contributors such as dispersion, exchange, induction, etc., is close to zero and the total energy follows the trend of the electrostatic energy. We observe an excellent linear correlation between the optimized intermolecular separation of the different complexes and the exchange/dispersion interaction. PMID- 26593829 TI - Size-Extensive Wave Functions for Quantum Monte Carlo: A Linear Scaling Generalized Valence Bond Approach. AB - We propose a new class of multideterminantal Jastrow-Slater wave functions constructed with localized orbitals and designed to describe complex potential energy surfaces of molecular systems for use in quantum Monte Carlo (QMC). Inspired by the generalized valence bond formalism, we elaborate a coupling scheme between electron pairs which progressively includes new classes of excitations in the determinantal component of the wave function. In this scheme, we exploit the local nature of the orbitals to construct wave functions which have increasing complexity but scale linearly. The resulting wave functions are compact, can correlate all valence electrons, and are size extensive. We assess the performance of our wave functions in QMC calculations of the homolytic fragmentation of N-N, N-O, C-O, and C-N bonds, very common in molecules of biological interest. We find excellent agreement with experiments, and, even with the simplest forms of our wave functions, we satisfy chemical accuracy and obtain dissociation energies of equivalent quality to the CCSD(T) results computed with the large cc-pV5Z basis set. PMID- 26593830 TI - Molecular Electrical Properties from Quantum Monte Carlo Calculations: Application to Ethyne. AB - We used Quantum Monte Carlo (QMC) methods to study the polarizability and the quadrupole moment of the ethyne molecule using the Jastrow-Antisymmetrised Geminal Power (JAGP) wave function, a compact and strongly correlated variational ansatz. The compactness of the functional form and the full optimization of all its variational parameters, including linear and exponential coefficients in atomic orbitals, allow us to observe a fast convergence of the electrical properties with the size of the atomic and Jastrow basis sets. Both variational results on isotropic polarizability and quadrupole moment based on Gaussian type and Slater type basis sets are very close to the Lattice Regularized Diffusion Monte Carlo values and in very good agreement with experimental data and with other quantum chemistry calculations. We also study the electronic density along the C=C and C-H bonds by introducing a generalization for molecular systems of the small-variance improved estimator of the electronic density proposed by Assaraf et al. (Assaraf, R.; Caffarel, M.; Scemama, A. Phys. Rev. E, 2007, 75, 035701). PMID- 26593831 TI - Efficient Calculations of Dispersion Energies for Nanoscale Systems from Coupled Density Response Functions. AB - Dispersion energies computed from coupled Kohn-Sham (CKS) dynamic density-density response functions are known to be highly accurate. At the same time, the computational algorithm is of only modest complexity compared to other accurate methods of dispersion energy calculation. We present a new implementation of this algorithm that removes several computational barriers present in current implementations and enables calculations of dispersion energies for systems with more than 200 atoms using more than 5000 basis functions. The improvements were mainly achieved by reorganizing the algorithm to minimize memory and disk usage. We present applications to two systems: the buckycatcher complex with fullerene and the vancomycin complex with a diacetyl-Lys-d-Ala-d-Ala bacterial wall precursor, both calculations performed with triple-zeta-quality basis sets. Our implementation makes it possible to use ab initio computed dispersion energies in popular "density functional theory plus dispersion" approaches. PMID- 26593832 TI - Design of Carbene-Based Organocatalysts for Nitrogen Fixation: Theoretical Study. AB - Nitrogen fixation is a great challenge in solving the food supply of mankind. However N2 activation is extremely hard. Up until recently, the investigated catalysts for N2 fixation were based on metallic reducing agents. They are generally not environment friendly. We designed organocatalysts (carbenes) for nitrogen fixation using density functional theory (DFT) and ab initio theory. The reactivity of the carbene catalysts is mainly related to the electrostatic properties of the side chains. We compared the binding affinity to N2 with various carbenes (:CF2, :CCl2, :CBr2, and :CI2). We revealed that the electron donating ability of the central carbene carbon is the most important factor for trapping N2. Among heterocyclic carbenes, the cyclic diphospinocarbenes (PHC) represented a good candidate moiety for an efficient catalyst. We further designed the carbene based catalyst which has two carbene moieties to chelate N2 and investigated the whole catalytic mechanism. The highest energy barrier of the entire catalytic cycle is 28.5 kcal/mol, which is comparable to the previously reported metallic catalysts. This demonstrates the possibility of novel organic catalysts for nitrogen fixation. PMID- 26593833 TI - Partial Atomic Charges and Screened Charge Models of the Electrostatic Potential. AB - We propose a new screened charge method for calculating partial atomic charges in molecules by electrostatic potential (ESP) fitting. The model, called full density screening (FDS), is used to approximate the screening effect of full charge densities of atoms in molecules. The results are compared to the conventional ESP fitting method based on point charges and to our previously proposed outer density screening (ODS) method, in which the parameters are reoptimized for the present purpose. In ODS, the charge density of an atom is represented by the sum of a point charge and a smeared negative charge distributed in a Slater-type orbital (STO). In FDS, the charge density of an atom is taken to be the sum of the charge density of the neutral atom and a partial atomic charge (of either sign) distributed in an STO. The zeta values of the STOs used in these two models are optimized in the present study to best reproduce the electrostatic potentials. The quality of the fit to the electrostatics is improved in the screened charge methods, especially for the regions that are within one van der Waals radius of the centers of atoms. It is also found that the charges derived by fitting electrostatic potentials with screened charges are less sensitive to the positions of the fitting points than are those derived with conventional electrostatic fitting. Moreover, we found that the electrostatic potential-fitted (ESP) charges from the screened charge methods are similar to those from the point-charge method except for molecules containing the methyl group, where we have explored the use of restraints on nonpolar H atoms. We recommend the FDS model if the only goal is ESP fitting to obtain partial atomic charges or a fit to the ESP field. However, the ODS model is more accurate for electronic embedding in combined quantum mechanical and molecular mechanical (QM/MM) modeling and is more accurate than point-charge models for ESP fitting, and it is recommended for applications involving QM/MM methods. Since the screened charges describe the electrostatic potentials more accurately than point charges, since they asymptotically act as point charges at long distances, and since the electrostatic potential in terms of the screened charges is still a sum of functions centered at the atoms, the screened-charge representation of the electrostatic potential can be used in the same way as the conventional point charge representation to model the electrostatic interactions, but it is more realistic. For the H atom and p block elements, the error in the fit to the electrostatic potential is reduced by about a factor of 3, and the sensitivity of the derived partial atomic charges to the choice of fitting points is reduced by about a factor of 2. For s and d block elements, there are also improvements in the inner regions but not necessarily in the outer regions. PMID- 26593834 TI - Improving Generalized Born Models by Exploiting Connections to Polarizable Continuum Models. I. An Improved Effective Coulomb Operator. AB - We investigate the generalized Born (GB) implicit solvation model in comparison with polarizable continuum models (PCMs). We show that the GB model is intimately connected to the conductor-like PCM (C-PCM), a method that is accurate for high dielectric solvents but less so for weakly polar and nonpolar solvents. The formal connection between C-PCM and the GB model suggests that C-PCM calculations place a limit on the accuracy that one should expect from GB models but also demonstrates that comparison of GB and C-PCM calculations directly interrogates the accuracy of the effective Coulomb operator that is used in the pairwise GB energy expression. We introduce a simple alternative to the "canonical" pairwise interaction operator first proposed by Still et al. and show that this alternative reduces the cost of the pairwise GB energy summation by as much as a factor of 3. At the same time, the new operator reduces statistical errors in solvation energies (as compared to C-PCM benchmarks) by 0.3% with respect to the canonical operator that exhibits an error of roughly 1.0%. PMID- 26593835 TI - Highlights on Anthocyanin Pigmentation and Copigmentation: A Matter of Flavonoid pi-Stacking Complexation To Be Described by DFT-D. AB - Anthocyanidins are a class of pi-conjugated systems responsible for red, blue, and purple colors of plants. They exhibit the capacity of aggregation in the presence of other natural compounds including flavonols. Such complexations induce color modulation in plants, which is known as copigmentation. It is largely driven by pi-interactions existing between pigments and copigments. In this work, the energies of copigmentation-complexation and self-association are systematically evaluated for an anthocyanidin/flavonol couple prototype (3-O methylcyanidin/quercetin). To describe noncovalent interactions, DFT-D appears mandatory to reach a large accuracy. Due to the chemical complexity of this phenomenon, we also aim at assessing the relevance of both B3P86-D2 and omegaB97X D functionals. The benchmarking has shown that B3P86-D2 possesses enough accuracy when dealing with pi-pi interactions with respect to both spin component scaled Moller-Plesset second-order perturbation theory post Hartree-Fock method and experimental data. UV-vis absorption properties are then evaluated with time dependent DFT for the different complexes. The use of range-separated hybrid functionals, such as omegaB97X-D, helped to correctly disentangle and interpret the origin of the UV-vis experimental shifts attributed to the subtle copigmentation phenomenon. PMID- 26593836 TI - Assessment of DFT Exchange-Correlation Functionals for Evaluating the Multipolar Contributions to the Quadratic Nonlinear Optical Responses of Small Reference Molecules. AB - The hyper-Rayleigh scattering responses as well as the multipolar contributions to the first hyperpolarizabilities are calculated by means of density functional theory for a series of reference molecules (acetonitrile, dichloromethane, trichloroacetonitrile, chloroform, carbon tetrachloride), covering the whole range of dipolar/octupolar character. The performance of various exchange correlation functionals is addressed by comparison to CCSD(T) calculations. The best functionals turn out to be LC-BLYP, M05-2X, and M06-2X. PMID- 26593837 TI - Parameterized Bases for Calculating Vibrational Spectra Directly from ab Initio Data Using Rectangular Collocation. AB - We compared different parametrized bases for computing anharmonic vibrational spectra using a new version of the rectangular collocation-optimization method of Manzhos and Carrington (Can. J. Chem. 2009, 87, 864; Chem. Phys. Lett. 2011, 511, 434). The method enables one to compute a small number of vibrational levels with an ultrasmall basis set without a potential function. To test the ideas, parametrized uncoupled and coupled Gaussian functions as well as direct-product and coupled Hermite basis sets are used to compute four low-lying vibrational energy levels of H2O on model harmonic and anharmonic uncoupled (polynomial) potential energy surfaces. In addition, we compute levels directly from ab initio points and thereby include all coupling and anharmonicity. We conclude that uncoupled parametrized Gaussian and Hermite functions are a good choice for anharmonic and coupled problems. PMID- 26593838 TI - 3DRISM Multigrid Algorithm for Fast Solvation Free Energy Calculations. AB - In this paper we present a fast and accurate method for modeling solvation properties of organic molecules in water with a main focus on predicting solvation (hydration) free energies of small organic compounds. The method is based on a combination of (i) a molecular theory, three-dimensional reference interaction sites model (3DRISM); (ii) a fast multigrid algorithm for solving the high-dimensional 3DRISM integral equations; and (iii) a recently introduced universal correction (UC) for the 3DRISM solvation free energies by properly scaled molecular partial volume (3DRISM-UC, Palmer et al., J. Phys.: Condens. Matter2010, 22, 492101). A fast multigrid algorithm is the core of the method because it helps to reduce the high computational costs associated with solving the 3DRISM equations. To facilitate future applications of the method, we performed benchmarking of the algorithm on a set of several model solutes in order to find optimal grid parameters and to test the performance and accuracy of the algorithm. We have shown that the proposed new multigrid algorithm is on average 24 times faster than the simple Picard method and at least 3.5 times faster than the MDIIS method which is currently actively used by the 3DRISM community (e.g., the MDIIS method has been recently implemented in a new 3DRISM implicit solvent routine in the recent release of the AmberTools 1.4 molecular modeling package (Luchko et al. J. Chem. Theory Comput. 2010, 6, 607-624). Then we have benchmarked the multigrid algorithm with chosen optimal parameters on a set of 99 organic compounds. We show that average computational time required for one 3DRISM calculation is 3.5 min per a small organic molecule (10-20 atoms) on a standard personal computer. We also benchmarked predicted solvation free energy values for all of the compounds in the set against the corresponding experimental data. We show that by using the proposed multigrid algorithm and the 3DRISM-UC model, it is possible to obtain good correlation between calculated and experimental results for solvation free energies of aqueous solutions of small organic compounds (correlation coefficient 0.97, root-mean-square deviation <1 kcal/mol). PMID- 26593839 TI - Assessment of Density Functional Theory in Predicting Structures and Free Energies of Reaction of Atmospheric Prenucleation Clusters. AB - This work assesses different computational strategies for predicting structures and Gibb's free energies of reaction of atmospheric prenucleation clusters. The performance of 22 Density Functional Theory functionals in predicting equilibrium structures of molecules and water prenucleation clusters of atmospheric relevance is evaluated against experimental data using a test set of eight molecules and prenucleation clusters: SO2, H2SO4, CO2.H2O, CS2.H2O, OCS.H2O, SO2.H2O, SO3.H2O, and H2SO4.H2O. Furthermore, the functionals are tested and compared for their ability to predict the free energy of reaction for the formation of five benchmark atmospheric prenucleation clusters: H2SO4.H2O, H2SO4.(H2O)2, H2SO4.NH3, HSO4(-).H2O, and HSO4(-).(H2O)2. The performance is evaluated against experimental data, coupled cluster, and complete basis set extrapolation procedure methods. Our investigation shows that the utilization of the M06-2X functional with the 6-311++G(3df,3pd) basis set represents an improved approach compared to the conventionally used PW91 functional, yielding mean absolute errors of 0.48 kcal/mol and maximum errors of 0.67 kcal/mol compared to experimental results. PMID- 26593840 TI - A meta-GGA Made Free of the Order of Limits Anomaly. AB - We have improved the revised Tao-Perdew-Staroverov-Scuseria (revTPSS) meta generalized gradient approximation (GGA) in order to remove the order of limits anomaly in its exchange energy. The revTPSS meta-GGA recovers the second-order gradient expansion for a wide range of densities and therefore provides excellent atomization energies and lattice constants. For other properties of materials, however, even the revTPSS does not give the desired accuracy. The revTPSS does not perform as well as expected for the energy differences between different geometries for the same molecular formula and for the related nonbarrier height chemical reaction energies. The same order of limits problem might lead to inaccurate energy differences between different crystal structures and to inaccurate cohesive energies of insulating solids. Here we show a possible way to remove the order of limits anomaly with a weighted difference of the revTPSS exchange between the slowly varying and iso-orbitals (one- or two-electron) limits. We show that the new regularized (regTPSS) gives atomization energies comparable to revTPSS and preserves the accurate lattice constants as well. For other properties, the regTPSS gives at least the same performance as the revTPSS or TPSS meta-GGAs. PMID- 26593841 TI - Electron-Deficiency Aromaticity in Silicon Nanoclusters. AB - Aromaticity in silicon-containing molecules has been a controversy for more than a century. Combining molecular dynamics simulations with ab initio calculations, we show here that it is possible to obtain aromatic-like behavior with pure hydrogenated silicon clusters without the need for multiple bonds. To this end, we exploit the natural tendency of silicon toward overcoordination to construct electron-deficient molecules with ring structures. Even without the incorporation of any protective bulky substituents the resulting structures are more stable than any other known hydrogenated silicon nanoparticles of this size and exhibit aromatic-like properties due to strong electron delocalization. PMID- 26593842 TI - Force-Field Development and Molecular Dynamics of [NiFe] Hydrogenase. AB - Classical molecular force-field parameters describing the structure and motion of metal clusters in [NiFe] hydrogenase enzymes can be used to compare the dynamics and thermodynamics of [NiFe] under different oxidation, protonation, and ligation circumstances. Using density functional theory (DFT) calculations of small model clusters representative of the active site and the proximal, medial, and distal Fe/S metal centers and their attached protein side chains, we have calculated classical force-field parameters for [NiFe] in reduced and oxidized states, including internal coordinates, force constants, and atom-centered charges. Derived force constants revealed that cysteinate ligands bound to the metal ions are more flexible in the Ni-B active site, which has a bridging hydroxide ligand, than in the Ni-C active site, which has a bridging hydride. Ten nanosecond all atom, explicit-solvent MD simulations of [NiFe] hydrogenase in oxidized and reduced catalytic states established the stability of the derived force-field parameters in terms of Calpha and metal cluster fluctuations. Average active site structures from the protein MD simulations are consistent with [NiFe] structures from the Protein Data Bank, suggesting that the derived force-field parameters are transferrable to other hydrogenases beyond the structure used for testing. A comparison of experimental H2-production rates demonstrated a relationship between cysteinate side chain rotation and activity, justifying the use of a fully dynamic model of [NiFe] metal cluster motion. PMID- 26593843 TI - Free Energy Guided Sampling. AB - A free energy-guided sampling (FEGS) method is proposed for accelerating exploration of conformational space in unbiased molecular dynamics. Using the cut based free energy profile and Markov state models, FEGS speeds up sampling of the canonical ensemble by iteratively restarting multiple short simulations in parallel from regions of the free energy surface visited rarely. This exploration stage is followed by a refinement stage in which multiple independent runs are initiated from Boltzmann distributed conformations. Notably, FEGS does not require either collective variables or reaction coordinates and can control the kinetic distance from the starting conformation. We applied FEGS to the alanine dipeptide, which has a human-comprehensible two-dimensional free energy landscape, and a three-stranded antiparallel beta-sheet peptide of 20 residues whose folding/unfolding process is governed by a delicate interplay of enthalpy and entropy. For these two systems, FEGS speeds up the exploration of conformational space by 1 to 2 orders of magnitude with respect to conventional sampling and preserves the basins and barriers on the free energy profile. PMID- 26593844 TI - A Protein Solvation Model Based on Residue Burial. AB - The influence of solvent on the individual amino acids of a protein depends not simply on their surface exposure but rather on the degree of their burial within the structure. This property can be related to a simple geometrical measure termed circular variance. Circular variance depends on the spatial distribution of neighboring residues and varies from zero to one as a residue becomes buried. Its only adjustable parameter is a cutoff distance for selecting neighbors. Here, we show that circular variance can be used to build a fast and effective model of protein solvation energies. For this, we combine a coarse-grain protein representation with statistical potentials derived by Boltzmann inversion of circular variance probability distributions for different classes of pseudoatom within a large protein structure database. The method is shown to work well for distinguishing native protein structures from decoy structures generated in a variety of ways. It can also be used to detect specific residues in unfavorable solvent environments. Compared to surface accessibility, circular variance calculations are faster, less sensitive to small conformational changes, and able to account for the longer-range interactions that characterize the electrostatic component of solvent effects. The resulting solvation energies can be used alone or as part of a more general coarse-grain protein model. PMID- 26593845 TI - DNA Bending through Large Angles Is Aided by Ionic Screening. AB - We used adaptive umbrella sampling on a modified version of the roll angle to simulate the bending of DNA dodecamers. Simulations were carried out with the AMBER and CHARMM force fields for 10 sequences in which the central base pair step was varied. On long length scales, the DNA behavior was found to be consistent with the worm-like chain model. Persistence lengths calculated directly from the simulated structures and indirectly through the use of sequence independent coarse-grained models based on simulation data were similar to literature values. On short length scales, the free energy cost of bending DNA was found to be consistent with the worm-like chain model for small and intermediate bending angles. At large angles, the bending free energy as a function of the roll angle became linear, suggesting a relative increase in flexibility at larger roll angles. Counterions congregated on the concave side of the highly bent DNA and screened the repulsion of the phosphate groups, facilitating the bending. PMID- 26593846 TI - Studying the Effect of Site-Specific Hydrophobicity and Polarization on Hydrogen Bond Energy of Protein Using a Polarizable Method. AB - Quantification of backbone hydrogen bond energies in protein folding has remained elusive despite extensive theoretical and experimental investigations over the past 70 years. This is due to difficulties in experimental mutagenesis study as well as the lack of quantitatively reliable methods in theoretical calculation. Recent advance in experiment has enabled accurate measurement of site-specific backbone hydrogen bond energy in protein. In the present work, we developed an accurate and practical polarizable method to study site-specific hydrogen bond energies in the PIN WW domain. Excellent quantitative agreement between our calculated hydrogen bonding energy and recent experimental measurement is obtained. The direct comparison between theory and experiment helps uncover the microscopic mechanism of experimentally observed context dependent hydrogen bond contribution to protein stability in beta-sheet. In particular, our study reveals two effects that act in a cooperative manner to impact the strength of a hydrogen bond. One is the dynamic stability of the hydrogen bond determined by nearby solvent molecules, and the other is the polarization state of the hydrogen bond influenced by local electrostatic environment. The polar character of the hydrogen bond results in strong coupling between hydrophobic and polarization interactions in a cooperative manner. This nonadditive character in hydrogen bonding should help us better understand the microscopic mechanism in protein folding. Our study also investigated the possible structural effect of backbone amide to ester mutation which should be helpful to experimentalists using this technique in mutagenesis study. PMID- 26593847 TI - Geometries and Vibrational Frequencies of Small Radicals: Performance of Coupled Cluster and More Approximate Methods. AB - We generated a new set of reference geometries of small radicals using experimental equilibrium structures, as well as a benchmark-quality coupled cluster additivity scheme including up to quadruples excitations (CCSDTQ). Using these geometries and a set of experimental vibrational frequencies of open shell diatomics, we evaluated the performance of various coupled cluster methods based mainly on unrestricted references, using Dunning basis sets both with and without core correlation. Contrary to previous results, we found that UCCSD(T) and ROCCSD(T) perform equally well for geometries, better than CCSD, and close to their performances for closed shell systems. No improvement over CCSD(T) was achieved by using a Brueckner reference (BD(T)) or full triples (CCSDT). For frequencies, ROCCSD(T), BD(T), and CCSDT improve upon UCCSD(T), especially for the troublesome NO and CO(+) cases. EOMIP-CCSD yields geometries and harmonic frequencies similar to CCSD, and qualitatively correct anharmonic (VPT2) contributions in all cases, like the RO-CC methods. The double hybrid DFT functional B2PLYP-D yields geometries and frequencies of similar quality to that of CCSD but at a much reduced cost. The meta hybrid functionals M06-2X, M06-HF, and BMK perform worse than CCSD, and worse than B3LYP, on average. PMID- 26593850 TI - Risk factors for accidental dural puncture during epidural anesthesia for laboring women. AB - BACKGROUND AND OBJECTIVES: Accidental dural puncture (ADP) during epidural analgesia is a debilitating complication. Symptoms of ADP post-dural puncture headache (PDPH) are headache while rising from supine to upright position, nausea, and neck stiffness. While age, gender and needle characteristics are established risk factors for ADP, little is known about risk factors in laboring women. METHODS: All cases of ADP during epidural analgesia treated with blood patching during a 3-years period were retrospectively reviewed. Each case was matched to two controls according to delivery period. RESULTS: Forty-nine cases of blood patches after ADP out 17 977 epidural anesthesia procedures were identified (0.27%). No differences were found between cases and controls with regards to body mass index, labor stage at time of epidural, length of second stage, location of epidural along the lumbar vertebrae, anesthesiologist's experience or time when epidural was done. In cases of ADP, significantly lower doses of local anesthetics were injected (10.9 versus 13.5 cc, p < 0.001); anesthesiologists reported significantly more trials of epidurals (70 versus 2.8% more than one trial, p < 0.001), more patient movement during the procedure (13 versus 0%, p < 0.001), more intra-procedure suspicion of ADP (69 versus 0%, p < 0.001) and more cases where CSF/blood was drawn with the syringe (57 versus 2.4%, p < 0.001). CONCLUSION: ADP during labor is a rare but debilitating complication. Risk factors for this iatrogenic complication include patient movement and repeated epidural trials. Intra-procedure identification of ADP is common, allowing early intervention with blood patching where indicated. PMID- 26593849 TI - Cerebrovascular contributions to aging and Alzheimer's disease in Down syndrome. AB - Down syndrome (DS) is a common cause of intellectual disability and is also associated with early age of onset of Alzheimer's disease (AD). Due to an extra copy of chromosome 21, most adults over 40years old with DS have beta-amyloid plaques as a result of overexpression of the amyloid precursor protein. Cerebrovascular pathology may also be a significant contributor to neuropathology observed in the brains of adults with DS. This review describes the features of cardiovascular dysfunction and cerebrovascular pathology in DS that may be modifiable risk factors and thus targets for interventions. We will describe cerebrovascular pathology, the role of co-morbidities, imaging studies indicating vascular pathology and the possible consequences. It is clear that our understanding of aging and AD in people with DS will benefit from further studies to determine the role that cerebrovascular dysfunction contributes to cognitive health. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock. PMID- 26593851 TI - Gold-Coated M13 Bacteriophage as a Template for Glucose Oxidase Biofuel Cells with Direct Electron Transfer. AB - Glucose oxidase-based biofuel cells are a promising source of alternative energy for small device applications, but still face the challenge of achieving robust electrical contact between the redox enzymes and the current collector. This paper reports on the design of an electrode consisting of glucose oxidase covalently attached to gold nanoparticles that are assembled onto a genetically engineered M13 bacteriophage using EDC-NHS chemistry. The engineered phage is modified at the pIII protein to attach onto a gold substrate and serves as a high surface-area template. The resulting "nanomesh" architecture exhibits direct electron transfer (DET) and achieves a higher peak current per unit area of 1.2 mA/cm(2) compared to most other DET attachment schemes. The final enzyme surface coverage on the electrode was calculated to be approximately 4.74 * 10(-8) mol/cm(2), which is a significant improvement over most current glucose oxidase (GOx) DET attachment methods. PMID- 26593853 TI - Microwave Plasma-Activated Chemical Vapor Deposition of Nitrogen-Doped Diamond. I. N2/H2 and NH3/H2 Plasmas. AB - We report a combined experimental/modeling study of microwave activated dilute N2/H2 and NH3/H2 plasmas as a precursor to diagnosis of the CH4/N2/H2 plasmas used for the chemical vapor deposition (CVD) of N-doped diamond. Absolute column densities of H(n = 2) atoms and NH(X(3)Sigma(-), v = 0) radicals have been determined by cavity ring down spectroscopy, as a function of height (z) above a molybdenum substrate and of the plasma process conditions, i.e., total gas pressure p, input power P, and the nitrogen/hydrogen atom ratio in the source gas. Optical emission spectroscopy has been used to investigate variations in the relative number densities of H(n = 3) atoms, NH(A(3)Pi) radicals, and N2(C(3)Piu) molecules as functions of the same process conditions. These experimental data are complemented by 2-D (r, z) coupled kinetic and transport modeling for the same process conditions, which consider variations in both the overall chemistry and plasma parameters, including the electron (Te) and gas (T) temperatures, the electron density (ne), and the plasma power density (Q). Comparisons between experiment and theory allow refinement of prior understanding of N/H plasma chemical reactivity, and its variation with process conditions and with location within the CVD reactor, and serve to highlight the essential role of metastable N2(A(3)Sigma(+)u) molecules (formed by electron impact excitation) and their hitherto underappreciated reactivity with H atoms, in converting N2 process gas into reactive NHx (x = 0-3) radical species. PMID- 26593854 TI - Catalytic Electrophilic C-H Silylation of Pyridines Enabled by Temporary Dearomatization. AB - A C?H silylation of pyridines that seemingly proceeds through electrophilic aromatic substitution (SE Ar) is reported. Reactions of 2- and 3-substituted pyridines with hydrosilanes in the presence of a catalyst that splits the Si?H bond into a hydride and a silicon electrophile yield the corresponding 5 silylated pyridines. This formal silylation of an aromatic C?H bond is the result of a three-step sequence, consisting of a pyridine hydrosilylation, a dehydrogenative C?H silylation of the intermediate enamine, and a 1,4 dihydropyridine retro-hydrosilylation. The key intermediates were detected by (1) H NMR spectroscopy and prepared through the individual steps. This complex interplay of electrophilic silylation, hydride transfer, and proton abstraction is promoted by a single catalyst. PMID- 26593852 TI - Comprehensive Characterization of Glycosylation and Hydroxylation of Basement Membrane Collagen IV by High-Resolution Mass Spectrometry. AB - Collagen IV is the main structural protein that provides a scaffold for assembly of basement membrane proteins. Posttranslational modifications such as hydroxylation of proline and lysine and glycosylation of lysine are essential for the functioning of collagen IV triple-helical molecules. These modifications are highly abundant posing a difficult challenge for in-depth characterization of collagen IV using conventional proteomics approaches. Herein, we implemented an integrated pipeline combining high-resolution mass spectrometry with different fragmentation techniques and an optimized bioinformatics workflow to study posttranslational modifications in mouse collagen IV. We achieved 82% sequence coverage for the alpha1 chain, mapping 39 glycosylated hydroxylysine, 148 4 hydroxyproline, and seven 3-hydroxyproline residues. Further, we employed our pipeline to map the modifications on human collagen IV and achieved 85% sequence coverage for the alpha1 chain, mapping 35 glycosylated hydroxylysine, 163 4 hydroxyproline, and 14 3-hydroxyproline residues. Although lysine glycosylation heterogeneity was observed in both mouse and human, 21 conserved sites were identified. Likewise, five 3-hydroxyproline residues were conserved between mouse and human, suggesting that these modification sites are important for collagen IV function. Collectively, these are the first comprehensive maps of hydroxylation and glycosylation sites in collagen IV, which lay the foundation for dissecting the key role of these modifications in health and disease. PMID- 26593855 TI - Detection of hypoglycin A in the seeds of sycamore (Acer pseudoplatanus) and box elder (A. negundo) in New Zealand; the toxin associated with cases of equine atypical myopathy. AB - CASE HISTORY AND CLINICAL FINDINGS: During April and May 2014 four horses aged between 5 months and 9 years, located in the Canterbury, Marlborough and Southland regions, presented with a variety of clinical signs including recumbency, stiffness, lethargy, dehydration, depression, and myoglobinuria suggestive of acute muscle damage. Two horses were subjected to euthanasia and two recovered. In all cases seeds of sycamore maple (Acer pseudoplatanus) or box elder (A. negundo) were present in the area where the horse had been grazing. LABORATORY INVESTIGATION: The samaras (seeds) of some Acer spp. may contain hypoglycin A, that has been associated with cases of atypical myopathy in Europe and North America. To determine if hypoglycin A is present in the samaras of Acer spp. in New Zealand, samples were collected from trees throughout the country that were associated with historical and/or current cases of atypical myopathy, and analysed for hypoglycin A. Serum samples from the four cases and four unaffected horses were analysed for the presence of hypoglycin A, profiles of acylcarnitines (the definitive diagnosis for atypical myopathy) and activities of creatine kinase and aspartate aminotransferase.Markedly elevated serum activities of creatine kinase and aspartate aminotransferase, and increased concentrations of selected acylcarnitines were found in the case horses. Hypoglycin A was detected in the serum of those horses but not in the healthy controls. Hypoglycin A was detected in 10/15 samples of samaras from sycamore maple and box elder from throughout New Zealand. DIAGNOSIS: Cases of atypical myopathy were diagnosed on properties where samaras containing hypoglycin A were also found. CLINICAL RELEVANCE: Sycamore and box elder trees in New Zealand are a source of hypoglycin A associated with the development of atypical myopathy. If pastured horses present with clinical and biochemical signs of severe muscle damage then the environment should be checked for the presence of these trees. Horses should be prevented from grazing samaras from Acer spp. in the autumn. PMID- 26593856 TI - Patients with Diabetes and Significant Epicardial Coronary Artery Disease Have Increased Systolic Left Ventricular Apical Rotation and Rotation Rate at Rest. AB - OBJECTIVE: The purpose of this study was to determine whether resting myocardial deformation and rotation may be altered in diabetic patients with significant epicardial coronary artery disease (CAD) with normal left ventricular ejection fraction. DESIGN: A prospective observational study. SETTING: Diagnosis of epicardial CAD in patients with diabetes. PATIENTS AND METHODS: Eighty-four patients with diabetes suspected of epicardial CAD scheduled for cardiac catheterization had a resting echocardiogram performed prior to their procedure. Echocardiographic measurements were compared between patients with and without significant epicardial CAD as determined by cardiac catheterization. MAIN OUTCOME MEASURES: Measurement of longitudinal strain, strain rate, apical rotation, and rotation rate, using speckle tracking echocardiography. RESULTS: Eighty-four patients were studied, 39 (46.4%) of whom had significant epicardial CAD. Global peak systolic apical rotation was significantly increased (14.9 +/- 5.1 vs. 11.0 +/- 4.8 degrees, P < 0.001) in patients with epicardial CAD along with faster peak systolic apical rotation rate (90.4 +/- 29 vs. 68.1 +/- 22.2 degrees/sec, P < 0.001). These findings were further confirmed through multivariate logistic regression analysis (global peak systolic apical rotation OR = 1.17, P = 0.004 and peak systolic apical rotation rate OR = 1.05, P < 0.001). CONCLUSIONS: Patients with diabetes with significant epicardial CAD and normal LVEF exhibit an increase in peak systolic apical counterclockwise rotation and rotation rate detected by echocardiography, suggesting that significant epicardial CAD and its associated myocardial effects in patients with diabetes may be detected noninvasively at rest. PMID- 26593857 TI - Fluorescent N-Doped Carbon Dots as in Vitro and in Vivo Nanothermometer. AB - The fluorescent N-doped carbon dots (N-CDs) obtained from C3N4 emit strong blue fluorescence, which is stable with different ionic strengths and time. The fluorescence intensity of N-CDs decreases with the temperature increasing, while it can recover to the initial one with the temperature decreasing. It is an accurate linear response of fluorescence intensity to temperature, which may be attributed to the synergistic effect of abundant oxygen-containing functional groups and hydrogen bonds. Further experiments also demonstrate that N-CDs can serve as effective in vitro and in vivo fluorescence-based nanothermometer. PMID- 26593858 TI - Resistance training improves fatigue and quality of life in previously sedentary breast cancer survivors: a randomised controlled trial. AB - The primary aim of this study was to evaluate the benefits of resistance training (RT) on quality of life (QOL) and fatigue in breast cancer survivors as an adjunct to usual care. We recruited 39 women who had survived breast cancer [mean age (y) 51.9 +/- 8.8; time since diagnosis (m) 11.6 +/- 13.2]. Primary outcomes were fatigue as assessed by the Functional Assessment of Chronic Illness Therapy Fatigue (FACIT) scale and QOL as assessed by the Functional Assessment of Cancer Therapy - General (FACT-G) scale. ANCOVA was used to assess the change in the primary outcomes while controlling for baseline values, with effect sizes (ES) displayed as partial Eta squared. The experimental group received supervised RT 3 days per week in a university clinic for 16 weeks. Perceptions of fatigue improved significantly in the RT group compared to controls [mean (SD) 6.7 (7.5) points vs. 1.5 (3.7) points], (P = 0.006, ES = 0.20) as did QOL [6.9 (8.5) points vs. 1.6 (4.4) points], (P = 0.015, ES = 0.16). We demonstrated both statistically and clinically important improvements in fatigue and QOL in response to RT in breast cancer survivors. PMID- 26593859 TI - Assessment of learning gains in a flipped biochemistry classroom. AB - The flipped classroom has become an increasingly popular pedagogical approach to teaching and learning. In this study, learning gains were assessed in a flipped biochemistry course and compared to gains in a traditional lecture. Although measured learning gains were not significantly different between the two courses, student perception of learning gains did differ and indicates a higher level of satisfaction with the flipped lecture format. PMID- 26593860 TI - Photosensitivity of reflection notch tuning and broadening in polymer stabilized cholesteric liquid crystals. AB - The position or bandwidth of the selective reflection of polymer stabilized cholesteric liquid crystals (PSCLCs) prepared from negative dielectric anisotropy ("-Deltaepsilon") liquid crystalline hosts can be shifted by applying a DC voltage. The underlying mechanism of the tuning or broadening of the reflection of PSCLCs detailed in these recent efforts is ion-facilitated, electromechanical deformation of the structurally chiral, polymer stabilizing network in the presence of a DC bias. Here, we show that these electro-optic responses can also be photosensitive. The photosensitivity is most directly related to the presence of photoinitiator, which is a known ionic contaminant to liquid crystal devices. Measurement of the ion density of a series of control compositions before, during, and after irradiation with UV light confirms that the ion density in compositions that exhibit photosensitivity is increased by irradiation and correlates to not only the concentration of the photoinitiator but also the type. Thus, the magnitude of the electrically tuned or broadened reflection of PSCLC of certain compositions when subjected to DC field is further increased in the presence of UV light. While interesting and potentially useful in applications such as architectural windows, the effect may be deleterious to some device implementations. Accordingly, compositions in which photosensitivity is not observed are identified. PMID- 26593861 TI - Analysis of FMR1 gene premutation and X chromosome cytogenetic abnormalities in 100 Tunisian patients presenting premature ovarian failure. AB - OBJECTIVE: To evaluate the prevalence of FMR1 premutations and X chromosome cytogenetic abnormalities in a large cohort of Tunisian women with premature ovarian failure (POF). PATIENTS AND METHODS: The cohort consisted of 127 Tunisian women with POF referred by endocrinologists and gynecologists for genetic investigation in the context of idiopathic POF and altered hormonal profiles. Clinical information concerning the reproductive function in the family, previous hormonal measurements and/or possible fertility treatment were collected. Karyotype, FISH analyses, FMR1 and FMR2 testing were performed for all patients. RESULTS: Fifteen patients (11.81%) presented structural or numerical X chromosomal abnormalities. Moreover, we detected in 12 patients (10.71%) a high level of X mosaicism. Analysis of FMR1 gene in the 100 patients without X chromosomal abnormalities showed that five percent of the patients carried a FMR1 premutation allele. On the other hand, the FMR2 screening did not reveal any deletion. CONCLUSION: Our study confirms the major role of X chromosome abnormalities in POF and highlights the importance of karyotype analyses and FMR1 screening. These investigations provide valuable information for diagnosis and genetic counseling for these women who still have a 5% chance of spontaneous conception. PMID- 26593862 TI - Upper gastrointestinal haemorrhage due to a small extra-papillary duodenal neuroendocrine tumour expressing somatostatin. PMID- 26593863 TI - Genetic susceptibility to autoimmune thyroid diseases in a Chinese Han population: Role of vitamin D receptor gene polymorphisms. AB - PURPOSE: Previous studies have found that some immune-related genes were associated with autoimmune thyroid diseases (AITDs). A couple of studies have explored the association between vitamin D (1,25-dihydroxyvitamin D3) receptor (VDR) gene polymorphisms and susceptibility to AITDs in different populations and found conflicting results. This case-control study was designed to evaluate the role of polymorphisms of VDR gene in the predisposition of AITDs in a Chinese Han population. METHODS: A total of 417 patients with Graves' disease (GD), 250 patients with Hashimoto's thyroiditis (HT) and 301 healthy subjects were enrolled. The Matrix Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometer (MALDI-TOF-MS) Platform was applied to detect four SNPs (rs1544410, rs2228570, rs731236 and rs7975232) in the VDR gene. RESULTS: In the rs7975232 allele A frequency showed a significant increase in GD patients (30.34% vs. 25.42% in controls; P=0.041, OR=1.278, 95%CI=1.010-1.617). However, no relationship was found between clinical phenotypes and the four SNPs. CONCLUSIONS: This result suggests that the VDR gene may be one susceptibility gene which contributes to the risk of GD. PMID- 26593864 TI - Sequence analysis of TMEM173 exon 5 in patients with systemic autoimmune diseases. AB - BACKGROUND: Overactivation of the interferon pathways has been demonstrated in patients suffering from different systemic autoimmune diseases (SADs). Genetic associations have been described for many genes involved in these pathways. Gain of-function mutations in the TMEM173 gene have recently been reported in patients with autoinflammatory diseases that share some clinical features with SADs. METHODS: We aimed at detecting the reported three mutations of transmembrane protein 173 (TMEM173) exon 5 in 100 patients suffering from: systemic lupus erythematosus (SLE) (n = 22), primary antiphospholipid syndrome (PAPS) (n = 20), systemic sclerosis (SSc) (n = 20), dermatomyositis (DM) (n = 20), and vasculitis (n = 18). Samples from 19 healthy controls were also included. Sequence analyses were performed from the derived TMEM173 exon 5 PCR fragment amplified from DNA obtained from whole blood. RESULTS: Neither mutations nor single nucleotide polymorphisms (SNPs) in the exon 5 of the TMEM173 gene were detected. Just the rs7380272 SNP, located in the intronic region upstream exon 5, was detected in some patients and controls. The allele frequency of this SNP, though, was not statistically different between the patients groups and the control group. CONCLUSIONS: Our study demonstrates the lack of association between the presence of SADs and mutations in exon 5 of the TMEM173 gene. SADs are complex multifactorial diseases in which not just one but probably many different genetic alterations may coexist. Although we cannot rule out the possibility that other variations may exist in other regions of this gene, we think that studies must be directed towards the analysis of other genes which, as TMEM173, also code for nucleic acid sensors that activate the nucleic-acid induced type I IFN pathway. PMID- 26593865 TI - Using hydrogen sulfide to design and develop drugs. AB - INTRODUCTION: Hydrogen sulfide (H2S) is an endogenous gasotransmitter, involved in the regulation of several biological functions. Conversely, impaired biosynthesis of H2S is associated with important diseases. This paves the way for exciting pharmacological perspectives for drugs acting on the 'H2S system'. AREAS COVERED: At the beginning of this manuscript, the authors present the biological roles and mechanisms of action of hydrogen sulfide. The authors then discuss the developments in the modulation of the H2S system via heterogeneous molecules, which behave as sources of exogenous H2S, and are promising drugs for a number of diseases. EXPERT OPINION: The rate of H2S generation, the physicochemical characteristics and the bioavailability greatly affect the overall pharmacological profile of each H2S-releasing compound. Therefore, the development of broad collections of original moieties endowed with heterogeneous rates/mechanisms of H2S release and a variety of physicochemical, biological and pharmacological features is the most timely and compelling issue in the field of H2S-based drug discovery. PMID- 26593866 TI - High thermoelectric performance from optimization of hole-doped CuInTe2. AB - We investigated the electronic structure, lattice dynamics and thermoelectric transport properties of CuInTe2 based on first-principles calculations. From the analysis of density of states and partial charge density, it can be expected that p-doping at the In-site or n-doping at the Cu-site will barely modify the electronic states near the valence or conduction band edge but increase the carrier concentration to achieve the highest thermoelectric efficiency. Lattice dynamics calculations suggest that the thermal conductivity of CuInTe2 can be effectively reduced by introducing structural defects at Cu, In and Te sites. p type CuInTe2 possesses better thermoelectric properties as compared to the n-type one, which mainly originates from the steeper density of states resulting from nearly degenerate valence bands near the band edge. The temperature dependence of the thermoelectric transport properties of p-type CuInTe2 at different carrier concentrations was studied in detail, which is found to be in good agreement with the experimental data. Our results of calculation showed that p-type CuInTe2 can achieve an upper-limit figure of merit value of 1.72 at 850 K and are promising thermoelectric materials for waste heat recovery at medium temperatures. PMID- 26593867 TI - Combining visible light catalysis and transfer hydrogenation for in situ efficient and selective semihydrogenation of alkynes under ambient conditions. AB - By combining visible light catalysis and transfer hydrogenation, we are able to convert a series of alkynes to their corresponding alkenes in high chemical yields. Then the visible light catalytic transfer hydrogenation reaction can couple photoisomerization to produce E-alkenes or Z-alkenes exclusively depending on the aryl or alkyl substituted alkynes. PMID- 26593868 TI - High resolution metabolomics technology reveals widespread pathway changes of alcoholic liver disease. AB - Alcoholic liver disease (ALD) is a significant cause of death and morbidity. However little is known regarding the widespread pathway changes of ALD disorder. This study utilized metabolomic profiling to examine the pathogenic mechanisms of ALD based on a rat model. A total of 21 metabolites with significant changes were identified, involving several key metabolic pathways such as pentose and glucuronate interconversions, starch and sucrose metabolism, cysteine and methionine metabolism. Furthermore, the differential proteins corresponding to alterations in metabolism across the metabolic network were identified using iTRAQ-based quantitative proteomics analysis. The proteins appear to be involved in protein binding, metabolism, immune response, and signal conduction. Interestingly, integrated omics profiling firstly reveals that p53 and Fc epsilon RI signaling pathways were closely related to ALD. Our study indicates that most of these proteins were found to play a pivotal role in the regulation of multiple metabolism pathways. Collectively, the current study provides insights into the molecular mechanisms of ALD from widespread pathway changes. PMID- 26593869 TI - A Concise Approach to Paxilline Indole Diterpenes. AB - A synthetic approach to paxilline indole diterpenes is described. The route to the pentacyclic core relies on a new regioselective alkenylation of ketones and a tandem radical addition-aldol reaction sequence to access vicinal quaternary stereocenters. Emindole SB, the simplest member of the family, is synthesized in 11 steps from commercially available material to demonstrate the application of this approach. PMID- 26593870 TI - Water-mediated and instantaneous transfer of graphene grown at 220 degrees C enabled by a plasma. AB - Atomically thin graphene holds exceptional promise to enable new functionalities and drastically improve performance of electronic, energy, sensing, and bio medical devices. One of the most promising approaches to device-compatible graphene synthesis is chemical vapour deposition on a copper catalyst; this technique however is limited by very high temperatures (~900 degrees C) and a lack of control as well as post-growth separation from the catalyst. We demonstrate and explain how, through the use of a plasma, a graphene film containing single layer graphene can be grown at temperature as low as 220 degrees C, the process can be controlled and an instant and water-mediated decoupling mechanism is realised. Potential use of our films in flexible transparent conductive films, electrical devices and magneto-electronics is demonstrated. Considering the benefits of catalyst reuse, energy efficiency, simplicity, and environmental friendliness, we present this versatile plasma process as a viable alternative to many existing graphene production approaches. PMID- 26593871 TI - Relationships between range access as monitored by radio frequency identification technology, fearfulness, and plumage damage in free-range laying hens. AB - Severe feather-pecking (SFP), a particularly injurious behaviour in laying hens (Gallus gallus domesticus), is thought to be negatively correlated with range use in free-range systems. In turn, range use is thought to be inversely associated with fearfulness, where fearful birds may be less likely to venture outside. However, very few experiments have investigated the proposed association between range use and fearfulness. This experiment investigated associations between range use (time spent outside), fearfulness, plumage damage, and BW. Two pens of 50 ISA Brown laying hens (n=100) were fitted with radio frequency identification (RFID) transponders (contained within silicone leg rings) at 26 weeks of age. Data were then collected over 13 days. A total of 95% of birds accessed the outdoor run more than once per day. Birds spent an average duration of 6.1 h outside each day over 11 visits per bird per day (51.5 min per visit). The top 15 and bottom 15 range users (n=30), as determined by the total time spent on the range over 13 days, were selected for study. These birds were tonic immobility (TI) tested at the end of the trial and were feather-scored and weighed after TI testing. Birds with longer TI durations spent less time outside (P=0.01). Plumage damage was not associated with range use (P=0.68). The small group sizes used in this experiment may have been conducive to the high numbers of birds utilising the outdoor range area. The RFID technology collected a large amount of data on range access in the tagged birds, and provides a potential means for quantitatively assessing range access in laying hens. The present findings indicate a negative association between fearfulness and range use. However, the proposed negative association between plumage damage and range use was not supported. The relationships between range use, fearfulness, and SFP warrant further research. PMID- 26593872 TI - Distribution and accumulation of 10 nm silver nanoparticles in maternal tissues and visceral yolk sac of pregnant mice, and a potential effect on embryo growth. AB - We examined the distribution of silver in pregnant mice and embryos/fetuses following intravenous injections of 10 nm silver nanoparticles (AgNPs) or soluble silver nitrate (AgNO3) at dose levels of 0 (citrate buffer control) or 66 ug Ag/mouse to pregnant mice on gestation days (GDs) 7, 8 and 9. Selected maternal tissues and all embryos/fetuses from control, AgNP- and AgNO3-treated groups on GD10 and control and AgNP-treated groups on GD16 were processed for the measurement of silver concentrations, intracellular AgNP localization, histopathology and gross examination of tissue morphology. Inductively-coupled plasma mass spectrometry revealed silver in all examined tissues following either AgNP or AgNO3 treatment, with highest concentrations of silver in maternal liver, spleen and visceral yolk sac (VYS), and lowest concentrations in embryos/fetuses. For VYS, mean silver concentration following AgNO3 treatment (4.87 ng Ag/mg tissue) was approximately two-fold that following AgNP treatment (2.31 ng Ag/mg tissue); for all other tissues examined, mean silver concentrations following either AgNP or AgNO3 treatment were not significantly different from each other (e.g. 2.57 or 2.84 ng Ag/mg tissue in maternal liver and 1.61 or 2.50 ng Ag/mg tissue in maternal spleen following AgNP or AgNO3 treatment, respectively). Hyperspectral imaging revealed AgNP aggregates in maternal liver, kidney, spleen and VYS from AgNP-treated mice, but not AgNO3-treated mice. Additionally, one or more embryos collected on GD10 from eight of ten AgNP-treated mice appeared small for their age (i.e. Theiler stage 13 [GD8.5] or younger). In the control group (N = 11), this effect was seen in embryos from only one mouse. In conclusion, intravenous injection of 10 nm AgNPs to pregnant mice resulted in notable silver accumulation in maternal liver, spleen and VYS, and may have affected embryonic growth. Silver accumulation in embryos/fetuses was negligible. PMID- 26593874 TI - Charge transport and mobility engineering in two-dimensional transition metal chalcogenide semiconductors. AB - Two-dimensional (2D) van der Waals semiconductors represent the thinnest, air stable semiconducting materials known. Their unique optical, electronic and mechanical properties hold great potential for harnessing them as key components in novel applications for electronics and optoelectronics. However, the charge transport behavior in 2D semiconductors is more susceptible to external surroundings (e.g. gaseous adsorbates from air and trapped charges in substrates) and their electronic performance is generally lower than corresponding bulk materials due to the fact that the surface and bulk coincide. In this article, we review recent progress on the charge transport properties and carrier mobility engineering of 2D transition metal chalcogenides, with a particular focus on the markedly high dependence of carrier mobility on thickness. We unveil the origin of this unique thickness dependence and elaborate the devised strategies to master it for carrier mobility optimization. Specifically, physical and chemical methods towards the optimization of the major factors influencing the extrinsic transport such as electrode/semiconductor contacts, interfacial Coulomb impurities and atomic defects are discussed. In particular, the use of ad hoc molecules makes it possible to engineer the interface with the dielectric and heal the vacancies in such materials. By casting fresh light on the theoretical and experimental studies, we provide a guide for improving the electronic performance of 2D semiconductors, with the ultimate goal of achieving technologically viable atomically thin (opto)electronics. PMID- 26593873 TI - Improving the safety of oral immunotherapy for food allergy. AB - Food allergy is a major public health problem in children, impacting upon the affected individual, their families and others charged with their care, for example educational establishments, and the food industry. In contrast to most other paediatric diseases, there is no established cure: current management is based upon dietary avoidance and the provision of rescue medication in the event of accidental reactions, which are common. This strategy has significant limitations and impacts adversely on health-related quality of life. In the last decade, research into disease-modifying treatments for food allergy has emerged, predominantly for peanut, egg and cow's milk. Most studies have used the oral route (oral immunotherapy, OIT), in which increasing amounts of allergen are given over weeks-months. OIT has proven effective to induce immune modulation and 'desensitization' - that is, an increase in the amount of food allergen that can be consumed, so long as regular (typically daily) doses are continued. However, its ability to induce permanent tolerance once ongoing exposure has stopped seems limited. Additionally, the short- and long-term safety of OIT is often poorly reported, raising concerns about its implementation in routine practice. Most patients experience allergic reactions and, although generally mild, severe reactions have occurred. Long-term adherence is unclear, which rises concerns given the low rates of long-term tolerance induction. Current research focuses on improving current limitations, especially safety. Strategies include alternative routes (sublingual, epicutaneous), modified hypoallergenic products and adjuvants (anti-IgE, pre-/probiotics). Biomarkers of safe/successful OIT are also under investigation. PMID- 26593876 TI - Scaling of decoherence for a system of uncoupled spin qubits. AB - Significant experimental progresses in recent years have generated continued interest in quantum computation. A practical quantum computer would employ thousands if not millions of coherent qubits, and maintaining coherence in such a large system would be imperative for its utility. As an attempt at understanding the quantum coherence of multiple qubits, here we study decoherence of a multi spin-qubit state under the influence of hyperfine interaction, and clearly demonstrate that the state structure is crucial to the scaling behavior of n-spin decoherence. Specifically, we find that coherence times of a multi-spin state at most scale with the number of qubits n as ?n, while some states with higher symmetries have scale-free coherence with respect to n. Statistically, convergence to these scaling behavior is generally determined by the size of the Hilbert space m, which is usually much larger than n (up to an exponential function of n), so that convergence rate is very fast as we increase the number of qubits. Our results can be extended to other decoherence mechanisms, including in the presence of dynamical decoupling, which allow meaningful discussions on the scalability of spin-based quantum coherent technology. PMID- 26593875 TI - Novel Mode of Defective Neural Tube Closure in the Non-Obese Diabetic (NOD) Mouse Strain. AB - Failure to close the neural tube results in birth defects, with severity ranging from spina bifida to lethal anencephaly. Few genetic risk factors for neural tube defects are known in humans, highlighting the critical role of environmental risk factors, such as maternal diabetes. Yet, it is not well understood how altered maternal metabolism interferes with embryonic development, and with neurulation in particular. We present evidence from two independent mouse models of diabetic pregnancy that identifies impaired migration of nascent mesodermal cells in the primitive streak as the morphogenetic basis underlying the pathogenesis of neural tube defects. We conclude that perturbed gastrulation not only explains the neurulation defects, but also provides a unifying etiology for the broad spectrum of congenital malformations in diabetic pregnancies. PMID- 26593877 TI - Three-dimensional Carbon Nitride/Graphene Framework as a High-Performance Cathode for Lithium-Ion Batteries. AB - A three-dimensional polymeric carbon nitride/graphene framework (CN/GF) was fabricated by the ionic self-assembly of graphene oxide and protonated polymeric carbon nitride nanosheets. As the cathode material in lithium-ion batteries, CN/GF showed an excellent reversible capacity of 184 mA h g(-1) at 0.05 A g(-1) for 150 cycles and maintained the capacity of 60 mA h g(-1) at 5 A g(-1) . PMID- 26593879 TI - Access to sanitation and violence against women: evidence from Demographic Health Survey (DHS) data in Kenya. AB - Violence against women (VAW) is a serious public health and human rights concern. Literature suggests sanitation conditions in developing countries may be potential neighborhood-level risk factors contributing to VAW, and that this association may be more important in highly socially disorganized neighborhoods. This study analyzed 2008 Kenya Demographic Health Survey's data and found women who primarily practice open defecation (OD), particularly in disorganized communities, had higher odds of experiencing recent non-partner violence. This study provides quantitative evidence of an association between sanitation and VAW that is attracting increasing attention in media and scholarly literature throughout Kenya and other developing countries. PMID- 26593880 TI - Intrahaplotypic Variants Differentiate Complex Linkage Disequilibrium within Human MHC Haplotypes. AB - Distinct regions of long-range genetic fixation in the human MHC region, known as conserved extended haplotypes (CEHs), possess unique genomic characteristics and are strongly associated with numerous diseases. While CEHs appear to be homogeneous by SNP analysis, the nature of fine variations within their genomic structure is unknown. Using multiple, MHC-homozygous cell lines, we demonstrate extensive sequence conservation in two common Asian MHC haplotypes: A33-B58-DR3 and A2-B46-DR9. However, characterization of phase-resolved MHC haplotypes revealed unique intra-CEH patterns of variation and uncovered 127 single nucleotide variants (SNVs) which are missing from public databases. We further show that the strong linkage disequilibrium structure within the human MHC that typically confounds precise identification of genetic features can be resolved using intra-CEH variants, as evidenced by rs3129063 and rs448489, which affect expression of ZFP57, a gene important in methylation and epigenetic regulation. This study demonstrates an improved strategy that can be used towards genetic dissection of diseases. PMID- 26593881 TI - Output order and variability in free recall are linked to cognitive ability and hippocampal volume in elderly individuals. AB - Adapted from the work of Kahana and colleagues (e.g., Kahana, 1996), we present two measures of order of recall in neuropsychological free recall tests. These are the position on the study list of the first recalled item, and the degree of variability in the order in which items are reported at test (i.e., the temporal distance across the first four recalled items). We tested two hypotheses in separate experiments: (1) whether these measures predicted generalized cognitive ability, and (2) whether they predicted gray matter hippocampal volume. To test hypothesis 1, we conducted ordinal regression analyses on data from a group of 452 participants, aged 60 or above. Memory performance was measured with Rey's AVLT and generalized cognitive ability was measured with the MMSE test. To test hypothesis 2, we conducted a linear regression analysis on data from a sample of 79 cognitively intact individuals aged 60 or over. Memory was measured with the BSRT and hippocampal volume was extracted from MRI images. Results of Experiment 1 showed that the position of the first item recalled and the degree of output order variability correlated with MMSE scores only in the delayed test, but not in the immediate test. In Experiment 2, the degree of variability in the recall sequence of the delayed trial correlated (negatively) with hippocampal size. These findings confirm the importance of delayed primacy as a marker of cognitive ability, and are consistent with the idea that the hippocampus is involved in coding the temporal context of learned episodes. PMID- 26593882 TI - Linking inter- and intra-sentential processes for narrative production following traumatic brain injury: Implications for a model of discourse processing. AB - Some suggest that traumatic brain injury (TBI) produces dissociation between the macrolinguistic and microlinguistic levels of discourse production. This assumption is based primarily on studies that have found preserved intersentential cohesion and/or intra-sentential processing in narratives produced by these individuals. However, few studies exist, if any, that have investigated the relationship between these processes in TBI speakers who do demonstrate such microlinguistic impairments. This study investigated the relationship between impairments of intersentential cohesion and intra-sentential processing in the discourse of 15 speakers with severe TBI. The results demonstrated a significant relationship between the production of cohesive ties and instances of intra-sentential impairment that suggests that utilization of resources for adequate cohesion appears to negatively affect intra-sentential processing following TBI. We propose that macrolinguistic and microlinguistic processes are not independent of one another, as has been proposed, but share cognitive resources that support the planning and production of both local (microlinguistic) and long-distance (macrolinguistic) relationships expressed through discourse. PMID- 26593884 TI - The Valeo stent: a pre-mounted, open-cell, large stent for use in small children with CHD. AB - OBJECTIVES: The aim of the present study was to determine the outcomes of using the Valeo stent (Bard Peripheral Vascular, Tempe, Arizona, United States of America) in small children with CHD. BACKGROUND: Stenting vascular stenoses is safe and effective in adults and older children with CHD but is limited in smaller children. The design of the Valeo stent addresses these limitations but has not been extensively described. METHODS: Bench testing was conducted to determine the maximum diameter of the stent, foreshortening, and side-cell diameter. A retrospective analysis of Valeo stents implanted between October, 2012 and October, 2014 was performed. Patient profile, pre-implant/post-implant catheterization data, and stent geometry were reviewed. RESULTS: Bench testing: medium and large Valeo stents can be dilated up to 13 mm and 20 mm diameters, respectively. Side-cells are dilatable up to 12 mm. Valeo stents are of low profile - delivered through 6- or 7-Fr sheaths - and show minimal foreshortening. Retrospective analysis: a total of 81 stents were implanted in 61 patients with CHD. The median weight was 15.3 kg, and the median age was 58.9 months. Stents were implanted in the pulmonary artery, systemic vein, aorta, and pulmonary vein. Overall, mean vessel diameters increased from 4.1 to 7.7 mm (121.7%). There was effective mean gradient reduction: 3.7-0.5 mmHg (63%) in the venous systems, 28.2 12.5 mmHg (63.7%) in the pulmonary arteries, and 17.4-4 mmHg (77.1%) in the aorta. The mean stent foreshortening was 2.5%, and the mean recoil was 5.9%. Side cells that crossed other vessels were dilated in four cases, and stents were re mounted onto different-sized balloons in seven cases. CONCLUSIONS: The features of the Valeo stent, such as low profile, large maximum diameter, open-cell design, minimal foreshortening, and recoil, make it suitable for treating vascular stenoses in small children with CHD. PMID- 26593883 TI - Flicker-assisted localization microscopy reveals altered mitochondrial architecture in hypertension. AB - Mitochondrial morphology is central to normal physiology and disease development. However, in many live cells and tissues, complex mitochondrial structures exist and morphology has been difficult to quantify. We have measured the shape of electrically-discrete mitochondria, imaging them individually to restore detail hidden in clusters and demarcate functional boundaries. Stochastic "flickers" of mitochondrial membrane potential were visualized with a rapidly-partitioning fluorophore and the pixel-by-pixel covariance of spatio-temporal fluorescence changes analyzed. This Flicker-assisted Localization Microscopy (FaLM) requires only an epifluorescence microscope and sensitive camera. In vascular myocytes, the apparent variation in mitochondrial size was partly explained by densely packed small mitochondria. In normotensive animals, mitochondria were small spheres or rods. In hypertension, mitochondria were larger, occupied more of the cell volume and were more densely clustered. FaLM provides a convenient tool for increased discrimination of mitochondrial architecture and has revealed mitochondrial alterations that may contribute to hypertension. PMID- 26593885 TI - Next-generation sequencing of ABCA4: High frequency of complex alleles and novel mutations in patients with retinal dystrophies from Central Europe. AB - Variation in the ABCA4 locus has emerged as the most prevalent cause of monogenic retinal diseases. The study aimed to discover causative ABCA4 mutations in a large but not previously investigated cohort with ABCA4-related diseases originating from Central Europe and to refine the genetic relevance of all identified variants based on population evidence. Comprehensive clinical studies were performed to identify patients with Stargardt disease (STGD, n = 76) and cone-rod dystrophy (CRD, n = 16). Next-generation sequencing targeting ABCA4 was applied for a widespread screening of the gene. The results were analyzed in the context of exome data from a corresponding population (n = 594) and other large genomic databases. Our data disprove the pathogenic status of p.V552I and provide more evidence against a causal role of four further ABCA4 variants as drivers of the phenotype under a recessive paradigm. The study identifies 12 novel potentially pathogenic mutations (four of them recurrent) and a novel complex allele p.[(R152*; V2050L)]. In one third (31/92) of our cohort we detected the p.[(L541P; A1038V)] complex allele, which represents an unusually high level of genetic homogeneity for ABCA4-related diseases. Causative ABCA4 mutations account for 79% of STGD and 31% of CRD cases. A combination of p.[(L541P; A1038V)] and/or a truncating ABCA4 mutation always resulted in an early disease onset. Identification of ABCA4 retinopathies provides a specific molecular diagnosis and justifies a prompt introduction of simple precautions that may slow disease progression. The comprehensive, population-specific study expands our knowledge on the genetic landscape of retinal diseases. PMID- 26593886 TI - From eyeless to neurological diseases. AB - Age-related cataracts are frequently associated with degenerative changes in the ocular lens including the aggregation of proteins - mainly crystallins, but also other proteins including amyloids (Abeta) leading to the hypothesis that cataracts could be used as "biomarkers" for Alzheimer disease. Even if this hypothesis was rejected by David Beebe's last paper (Bei et al., Exp. Eye Res., 2015), it is a fascinating aspect to look for commonalities between eye diseases and neurological disorders. In this review, I discuss such commonalities between eye and brain mainly from a developmental point of view. The finding of the functional homology of the Drosophila eyeless gene with the mammalian Pax6 gene marks a first highlight in the developmental genetics of the eye - this result destroyed the "dogma" of the different evolutionary routes of eye development in flies and mammals. The second highlight was the finding that Pax6 is also involved in the development of the forebrain supporting the pleiotropic role of many genes. These findings opened a new avenue for research showing that a broad variety of transcription factors, but also structural proteins are involved both, in eye and brain development as well as into the maintenance of the functional integrity of the corresponding tissue(s). In this review recent findings are summarized demonstrating that genes whose mutations have been identified first to be causative for congenital or juvenile eye disorders are also involved in regenerative processes and neurogenesis (Pax6), but also in neurodegenerative diseases like Parkinson (e.g. Pitx3) or in neurological disorders like Schizophrenia (e.g. Crybb1, Crybb2). PMID- 26593887 TI - [Developmental disorders in children and adolescents of the Los Rios region, Valdivia, Chile, 2006-2008]. AB - OBJECTIVES: To study possible findings of factors in the antenatal, perinatal or postnatal period, in the mother or the child that may have an influence on the appearance of a developmental disorder. PATIENTS AND METHOD: A Data Base of Clinical Histories from every patient with a developmental disorder (F80-F90 ICD10) was created. The patients attended the Child Psychiatric Unit at Hospital Regional of Valdivia, Chile, from August 2006 to December 2008. Total: 493 patientes (48.7% of the total of patients consulting); CONTROL GROUP: 32 healthy patients. STATISTICAL METHOD: odds ratio (95% confidence). RESULTS: The main risk factors for developing a developmental disorder (P<.005, 25% frequency in the consulting population) are: prematurity, male sex, mother with low education, early hospitalizations, and medical illnesses (all with a significant odds ratio). Also, having a mother with psychiatric illness doubles the risk of having a developmental disorder. CONCLUSION: It requires an interdisciplinary collaborative work between neonatologists, obstetricians, child psychiatrists and the primary care to detect early children at risk. PMID- 26593888 TI - [Impact of an educational program for parents of children with cancer on the increased knowledge of their children's disease and the decrease in anxiety]. AB - PURPOSE: To determine the impact of an educational program provided by a nurse to parents of children with cancer to improve the level of knowledge of the disease and to decrease the levels of anxiety. PATIENTS AND METHODS: A prospective randomized study was conducted on parents of children recently diagnosed with cancer and treated in the Hospital Luis Calvo Mackenna. After informed consent, parents were randomized in two groups: one receiving the educational program and another without intervention. Both groups completed a questionnaire on social risk, and three tests to assess the levels of knowledge and anxiety. RESULTS: A total of 96 parents were enrolled (July 2010-November 2011). When comparing the number of correct responses on day 10, and day 90 after the intervention, a significant increase was observed in the level of parental knowledge in the group that received the educational program (P<.0001). No significant differences were observed in the levels of anxiety (P=.06) between both groups. CONCLUSIONS: An educational program provided by nurses to parents of children recently diagnosed with cancer, increased the knowledge of their children's disease. However there was no effect on the levels of anxiety. A feasible educational intervention is proposed that could be implemented at other cancer centers for children. PMID- 26593889 TI - [Sleep bruxism in children and adolescents]. AB - Bruxism is a rhythmic masticatory muscle activity, characterized by teeth grinding and clenching. This is a phenomenon mainly regulated by the central nervous system and peripherally influenced. It has two circadian manifestations, during sleep (sleep bruxism) and awake states (awake bruxism). Bruxism is much more than just tooth wearing. It is currently linked to orofacial pain; headaches; sleep disorders; sleep breathing disorders, such as apnea and hypopnea sleep syndrome; behavior disorders, or those associated with the use of medications. It is also influenced by psycho-social and behavior factors, which means that oromandibular parafunctional activities, temporomandibular disorders, malocclusion, high levels of anxiety and stress, among others, may precipitate the occurrence of bruxism. Nowadays, its etiology is multifactorial. The dentist and the pediatrician are responsible for its early detection, diagnosis, management, and prevention of its possible consequences on the patients. The aim of this review is to update the concepts of this disease and to make health professionals aware of its early detection and its timely management. PMID- 26593890 TI - Optimization of Ultrasound-Assisted Extraction of Natural Antioxidants from Sugar Apple (Annona squamosa L.) Peel Using Response Surface Methodology. AB - Sugar apple (Annona squamosa L.) is a popular tropical fruit and its peel is a municipal waste. An ultrasound-assisted extraction method was developed for the recovery of natural antioxidants from sugar apple peel. Central composite design was used to optimize solvent concentration (13.2%-46.8%), ultrasonic time (33.2 66.8 min), and temperature (43.2-76.8 degrees C) for the recovery of natural antioxidants from sugar apple peel. The second-order polynomial models demonstrated a good fit of the quadratic models with the experimental results in respect to total phenolic content (TPC, R2=0.9524, p<0.0001), FRAP (R2=0.9743, p<0.0001), and TEAC (R2=0.9610, p<0.0001) values. The optimal extraction conditions were 20:1 (mL/g) of solvent-to-solid ratio, 32.68% acetone, and 67.23 degrees C for 42.54 min under ultrasonic irradiation. Under these conditions, the maximal yield of total phenolic content was 26.81 (mg GA/g FW). The experimental results obtained under optimal conditions agreed well with the predicted results. The application of ultrasound markedly decreased extraction time and improved the extraction efficiency, compared with the conventional methods. PMID- 26593891 TI - Variation in Phenolics, Flavanoids, Antioxidant and Tyrosinase Inhibitory Activity of Peach Blossoms at Different Developmental Stages. AB - Peach blossoms were harvested and classified into six developmental stages: (I) bud emerging stage; (II) middle bud stage; (III) large bud stage; (IV) initial flowering stage; (V) full-flowering stage; and (VI) end-flowering stage. The contents of total phenolics, flavanoids, individual phenolic compounds as well as antioxidant and tyrosinase inhibitory activity of peach blossoms at different developmental stages were investigated. The total phenolic contents varied from 149.80 to 74.80 mg chlorogenic acid equivalents/g dry weight (DW), and the total flavanoid contents ranged from 93.03 to 44.06 mg rutin equivalents/g DW. Both the contents of total phenolics and flavanoids decreased during blossom development. Chlorogenic acid was the predominant component, accounting for 62.08%-71.09% of the total amount of identified phenolic compounds in peach blossom. The antioxidant capacities determined by different assays and tyrosinase inhibitory activity also showed descending patterns during blossom development. Significant correlations were observed between antioxidant capacities with contents of total phenolics and total flavanoids as well as chlorogenic acid, cinnamic acid and kaempferol-3-O-galactoside, while the tyrosinase inhibitory activity had lower correlations with total phenolics and total flavanoids as well as chlorogenic acid, quercetin-3-O-rhamnoside, kaempferol-3-O-galactoside and cinnamic acid. The antioxidant activities of peach blossom seemed to be more dependent on the phenolic compounds than tyrosinase inhibitory activity. PMID- 26593892 TI - Relationship between Structure and Conformational Change of the Vitamin D Receptor Ligand Binding Domain in 1alpha,25-Dihydroxyvitamin D3 Signaling. AB - Vitamin D Receptor (VDR) belongs to the nuclear receptor (NR) superfamily. Whereas the structure of the ligand binding domain (LBD) of VDR has been determined in great detail, the role of its amino acid residues in stabilizing the structure and ligand triggering conformational change is still under debate. There are 13 alpha-helices and one beta-sheet in the VDR LBD and they form a three-layer sandwich structure stabilized by 10 residues. Thirty-six amino acid residues line the ligand binding pocket (LBP) and six of these residues have hydrogen-bonds linking with the ligand. In 1alpha,25-dihydroxyvitamin D3 signaling, H3 and H12 play an important role in the course of conformational change resulting in the provision of interfaces for dimerization, coactivator (CoA), corepressor (CoR), and hTAFII 28. In this paper we provide a detailed description of the amino acid residues stabilizing the structure and taking part in conformational change of VDR LBD according to functional domains. PMID- 26593893 TI - Chemical Composition and in-Vitro Evaluation of the Antimicrobial and Antioxidant Activities of Essential Oils Extracted from Seven Eucalyptus Species. AB - Eucalyptus is well reputed for its use as medicinal plant around the globe. The present study was planned to evaluate chemical composition, antimicrobial and antioxidant activity of the essential oils (EOs) extracted from seven Eucalyptus species frequently found in South East Asia (Pakistan). EOs from Eucalyptus citriodora, Eucalyptus melanophloia, Eucalyptus crebra, Eucalyptus tereticornis, Eucalyptus globulus, Eucalyptus camaldulensis and Eucalyptus microtheca were extracted from leaves through hydrodistillation. The chemical composition of the EOs was determined through GC-MS-FID analysis. The study revealed presence of 31 compounds in E. citriodora and E. melanophloia, 27 compounds in E. crebra, 24 compounds in E. tereticornis, 10 compounds in E. globulus, 13 compounds in E. camaldulensis and 12 compounds in E. microtheca. 1,8-Cineole (56.5%), alpha pinene (31.4%), citrinyl acetate (13.3%), eugenol (11.8%) and terpenene-4-ol (10.2%) were the highest principal components in these EOs. E. citriodora exhibited the highest antimicrobial activity against the five microbial species tested (Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Aspergillus niger and Rhizopus solani). Gram positive bacteria were found more sensitive than Gram negative bacteria to all EOs. The diphenyl-1-picrylhydazyl (DPPH) radical scavenging activity and percentage inhibition of linoleic acid oxidation were highest in E. citriodora (82.1% and 83.8%, respectively) followed by E. camaldulensis (81.9% and 83.3%, respectively). The great variation in chemical composition of EOs from Eucalyptus, highlight its potential for medicinal and nutraceutical applications. PMID- 26593894 TI - Redox Species of Redox Flow Batteries: A Review. AB - Due to the capricious nature of renewable energy resources, such as wind and solar, large-scale energy storage devices are increasingly required to make the best use of the renewable power. The redox flow battery is considered suitable for large-scale applications due to its modular design, good scalability and flexible operation. The biggest challenge of the redox flow battery is the low energy density. The redox active species is the most important component in redox flow batteries, and the redox potential and solubility of redox species dictate the system energy density. This review is focused on the recent development of redox species. Different categories of redox species, including simple inorganic ions, metal complexes, metal-free organic compounds, polysulfide/sulfur and lithium storage active materials, are reviewed. The future development of redox species towards higher energy density is also suggested. PMID- 26593895 TI - Analysis of the Constituents in "Zhu She Yong Xue Shuan Tong" by Ultra High Performance Liquid Chromatography with Quadrupole Time-of-Flight Mass Spectrometry Combined with Preparative High Performance Liquid Chromatography. AB - "Zhu She Yong Xue Shuan Tong" lyophilized powder (ZSYXST), consists of a series of saponins extracted from Panax notoginseng, which has been widely used in China for the treatment of strokes. In this study, an ultra-high performance liquid chromatography with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF/MS) combined with preparative high performance liquid chromatography (PHPLC) method was developed to rapidly identify both major and minor saponins in ZSYXST. Some high content components were removed through PHPLC in order to increase the sensitivity of the trace saponins. Then, specific characteristic fragment ions in both positive and negative mode were utilized to determine the types of aglycone, saccharide, as well as the saccharide chain linkages. As a result, 94 saponins, including 20 pairs of isomers and ten new compounds, which could represent higher than 98% components in ZSYXST, were identified or tentatively identified in commercial ZSYXST samples. PMID- 26593896 TI - Agrimonia eupatoria L. and Cynara cardunculus L. Water Infusions: Phenolic Profile and Comparison of Antioxidant Activities. AB - Reactive oxygen species (ROS) are highly considered in the ethiopathogenesis of different pathological conditions because they may cause significant damage to cells and tissues. In this paper, we focused on potential antioxidant properties of two medical plants such as the Agrimonia eupatoria L. and Cynara cardunculus L. Both plants have previously been studied for their pharmacological activities, especially as hepatoprotective and hypoglycemic activities. It has been suggested, that their effects are related to the antioxidant properties of polyphenols, which are dominant compounds of the plants' extracts. In the present study HPLC-MS analysis of water infusion was performed allowing the identification of several phenolic constituents. Furthermore, antioxidant effects of the two extracts were compared showing higher effects for agrimony extract compared to artichoke. Thus, agrimony was selected for the in vivo study using the skin flap viability model. In conclusion, our results provide evidence that the A. eupatoria extract may be a valuable source of polyphenols to be studied for the future development of supplements useful in the prevention of diseases linked to oxidative stress. PMID- 26593897 TI - A Quantitative Real-Time PCR-Based Strategy for Molecular Evaluation of Nicotine Conversion in Burley Tobacco. AB - Nornicotine production in Nicotiana tabacum is undesirable because it is the precursor of the carcinogen N'-nitrosonornicotine. In some individual burley tobacco plants, a large proportion of the nicotine can be converted to nornicotine, and this process of nicotine conversion is mediated primarily by enzymatic N-demethylation of nicotine which is controlled mainly by CYP82E4. Here we report a novel strategy based on quantitative real-time polymerase chain reaction (qPCR) method, which analyzed the ratio of nicotine conversion through examining the transcript level of CYP82E4 in burley leaves and do not need ethylene induction before detected. The assay was linear in a range from 1 * 101 to 1 * 105 copies/mL of serially diluted standards, and also showed high specificity and reproducibility (93%-99%). To assess its applicability, 55 plants of burley cultivar Ky8959 at leaf maturing stage were analyzed, and the results were in accordance with those from gas chromatograph-mass spectrometry (GC-MS) method. Moreover, a linear correlation existed between conversion level and CYP82E4 transcript abundance. Taken together, the quantitative real-time PCR assay is standardized, rapid and reproducible for estimation of nicotine conversion level in vivo, which is expected to shed new light on monitoring of burley tobacco converter. PMID- 26593899 TI - The Use of the Schizonticidal Agent Quinine Sulfate to Prevent Pond Crashes for Algal-Biofuel Production. AB - Algal biofuels are investigated as a promising alternative to petroleum fuel sources to satisfy transportation demand. Despite the high growth rate of algae, predation by rotifers, ciliates, golden algae, and other predators will cause an algae in open ponds to crash. In this study, Chlorella kessleri was used as a model alga and the freshwater rotifer, Brachionus calyciflorus, as a model predator. The goal of this study was to test the selective toxicity of the chemical, quinine sulfate (QS), on both the alga and the rotifer in order to fully inhibit the rotifer while minimizing its impact on algal growth. The QS LC50 for B. calyciflorus was 17 uM while C. kessleri growth was not inhibited at concentrations <25 uM. In co-culture, complete inhibition of rotifers was observed when the QS concentration was 7.7 uM, while algal growth was not affected. QS applications to produce 1 million gallons of biodiesel in one year are estimated to be $0.04/gallon or ~1% of Bioenergy Technologies Office's (BETO) projected cost of $5/gge (gallon gasoline equivalent). This provides algae farmers an important tool to manage grazing predators in algae mass cultures and avoid pond crashes. PMID- 26593900 TI - Protective Effects of Cardamom in Isoproterenol-Induced Myocardial Infarction in Rats. AB - Cardamom is a popular spice that has been commonly used in cuisines for flavor since ancient times. It has copious health benefits such as improving digestion, stimulating metabolism, and exhibits antioxidant and anti-inflammatory effects. The current study investigated the effect of cardamom on hemodynamic, biochemical, histopathological and ultrastructural changes in isoproterenol (ISO) induced myocardial infarction. Wistar male albino rats were randomly divided and treated with extract of cardamom (100 and 200 mg/kg per oral) or normal saline for 30 days with concomitant administration of ISO (85 mg/kg, subcutaneous) on 29th and 30th days, at 24 h interval. ISO injections to rats caused cardiac dysfunction evidenced by declined arterial pressure indices, heart rate, contractility and relaxation along with increased preload. ISO also caused a significant decrease in endogenous antioxidants, superoxide dismutase, catalase, glutathione peroxidase, depletion of cardiomyocytes enzymes, creatine kinase-MB, lactate dehydrogenase and increase in lipid peroxidation. All these changes in cardiac and left ventricular function as well as endogenous antioxidants, lipid peroxidation and myocyte enzymes were ameliorated when the rats were pretreated with cardamom. Additionally, the protective effects were strengthened by improved histopathology and ultrastructural changes, which specifies the salvage of cardiomyocytes from the deleterious effects of ISO. The present study findings demonstrate that cardamom significantly protects the myocardium and exerts cardioprotective effects by free radical scavenging and antioxidant activities. PMID- 26593898 TI - Prostate Cancer Stem Cells: Research Advances. AB - Cancer stem cells have been defined as cells within a tumor that possesses the capacity to self-renew and to cause the heterogeneous lineages of cancer cells that comprise the tumor. Experimental evidence showed that these highly tumorigenic cells might be responsible for initiation and progression of cancer into invasive and metastatic disease. Eradicating prostate cancer stem cells, the root of the problem, has been considered as a promising target in prostate cancer treatment to improve the prognosis for patients with advanced stages of the disease. PMID- 26593901 TI - Andrographolide Inhibits Ovariectomy-Induced Bone Loss via the Suppression of RANKL Signaling Pathways. AB - Osteoporosis is a debilitating skeletal disorder with an increased risk of low energy fracture, which commonly occurs among postmenopausal women. Andrographolide (AP), a natural product isolated from Andrographis paniculata, has been found to have anti-inflammatory, anti-cancer, anti-asthmatic, and neuro protective properties. However, its therapeutic effect on osteoporosis is unknown. In this study, an ovariectomy (OVX) mouse model was used to evaluate the therapeutic effects of AP on post-menopausal osteoporosis by using micro-computed tomography (micro-CT). Bone marrow-derived osteoclast culture was used to examine the inhibitory effect of AP on osteoclastogenesis. Real time PCR was employed to examine the effect of AP on the expression of osteoclast marker genes. The activities of transcriptional factors NF-kappaB and NFATc1 were evaluated using a luciferase reporter assay, and the IkappaBalpha protein level was analyzed by Western blot. We found that OVX mice treated with AP have greater bone volume (BV/TV), trabecular thickness (Tb.Th), and trabecular number (Tb.N) compared to vehicle-treated OVX mice. AP inhibited RANKL-induced osteoclastogenesis, the expression of osteoclast marker genes including cathepsin K (Ctsk), TRACP (Acp5), and NFATc1, as well as the transcriptional activities of NF-kappaB and NFATc1. In conclusion, our results suggest that AP inhibits estrogen deficiency-induced bone loss in mice via the suppression of RANKL-induced osteoclastogensis and NF-kappaB and NFATc1 activities and, thus, might have therapeutic potential for osteoporosis. PMID- 26593902 TI - Maternal Prenatal Mental Health and Placental 11beta-HSD2 Gene Expression: Initial Findings from the Mercy Pregnancy and Emotional Wellbeing Study. AB - High intrauterine cortisol exposure can inhibit fetal growth and have programming effects for the child's subsequent stress reactivity. Placental 11beta hydroxysteroid dehydrogenase (11beta-HSD2) limits the amount of maternal cortisol transferred to the fetus. However, the relationship between maternal psychopathology and 11beta-HSD2 remains poorly defined. This study examined the effect of maternal depressive disorder, antidepressant use and symptoms of depression and anxiety in pregnancy on placental 11beta-HSD2 gene (HSD11B2) expression. Drawing on data from the Mercy Pregnancy and Emotional Wellbeing Study, placental HSD11B2 expression was compared among 33 pregnant women, who were selected based on membership of three groups; depressed (untreated), taking antidepressants and controls. Furthermore, associations between placental HSD11B2 and scores on the State-Trait Anxiety Inventory (STAI) and Edinburgh Postnatal Depression Scale (EPDS) during 12-18 and 28-34 weeks gestation were examined. Findings revealed negative correlations between HSD11B2 and both the EPDS and STAI (r = -0.11 to -0.28), with associations being particularly prominent during late gestation. Depressed and antidepressant exposed groups also displayed markedly lower placental HSD11B2 expression levels than controls. These findings suggest that maternal depression and anxiety may impact on fetal programming by down-regulating HSD11B2, and antidepressant treatment alone is unlikely to protect against this effect. PMID- 26593903 TI - TriFabs--Trivalent IgG-Shaped Bispecific Antibody Derivatives: Design, Generation, Characterization and Application for Targeted Payload Delivery. AB - TriFabs are IgG-shaped bispecific antibodies (bsAbs) composed of two regular Fab arms fused via flexible linker peptides to one asymmetric third Fab-sized binding module. This third module replaces the IgG Fc region and is composed of the variable region of the heavy chain (VH) fused to CH3 with "knob"-mutations, and the variable region of the light chain (VL) fused to CH3 with matching "holes". The hinge region does not contain disulfides to facilitate antigen access to the third binding site. To compensate for the loss of hinge-disulfides between heavy chains, CH3 knob-hole heterodimers are linked by S354C-Y349C disulphides, and VH and VL of the stem region may be linked via VH44C-VL100C disulphides. TriFabs which bind one antigen bivalent in the same manner as IgGs and the second antigen monovalent "in between" these Fabs can be applied to simultaneously engage two antigens, or for targeted delivery of small and large (fluorescent or cytotoxic) payloads. PMID- 26593904 TI - Age-Dependent Changes in the Inflammatory Nociceptive Behavior of Mice. AB - The processing of pain undergoes several changes in aging that affect sensory nociceptive fibers and the endogenous neuronal inhibitory systems. So far, it is not completely clear whether age-induced modifications are associated with an increase or decrease in pain perception. In this study, we assessed the impact of age on inflammatory nociception in mice and the role of the hormonal inhibitory systems in this context. We investigated the nociceptive behavior of 12-month-old versus 6-8-week-old mice in two behavioral models of inflammatory nociception. Levels of TRP channels, and cortisol as well as cortisol targets, were measured by qPCR, ELISA, and Western blot in the differently aged mice. We observed an age related reduction in nociceptive behavior during inflammation as well as a higher level of cortisol in the spinal cord of aged mice compared to young mice, while TRP channels were not reduced. Among potential cortisol targets, the NF-kappaB inhibitor protein alpha (IkappaBalpha) was increased, which might contribute to inhibition of NF-kappaB and a decreased expression and activity of the inducible nitric oxide synthase (iNOS). In conclusion, our results reveal a reduced nociceptive response in aged mice, which might be at least partially mediated by an augmented inflammation-induced increase in the hormonal inhibitory system involving cortisol. PMID- 26593905 TI - Differentially-Expressed Genes Associated with Faster Growth of the Pacific Abalone, Haliotis discus hannai. AB - The Pacific abalone Haliotis discus hannai is used for commercial aquaculture in Korea. We examined the transcriptome of Pacific abalone Haliotis discus hannai siblings using NGS technology to identify genes associated with high growth rates. Pacific abalones grown for 200 days post-fertilization were divided into small-, medium-, and large-size groups with mean weights of 0.26 +/- 0.09 g, 1.43 +/- 0.405 g, and 5.24 +/- 1.09 g, respectively. RNA isolated from the soft tissues of each group was subjected to RNA sequencing. Approximately 1%-3% of the transcripts were differentially expressed in abalones, depending on the growth rate. RT-PCR was carried out on thirty four genes selected to confirm the relative differences in expression detected by RNA sequencing. Six differentially expressed genes were identified as associated with faster growth of the Pacific abalone. These include five up-regulated genes (including one specific to females) encoding transcripts homologous to incilarin A, perlucin, transforming growth factor-beta-induced protein immunoglobulin-heavy chain 3 (ig-h3), vitelline envelope zona pellucida domain 4, and defensin, and one down-regulated gene encoding tomoregulin in large abalones. Most of the transcripts were expressed predominantly in the hepatopancreas. The genes identified in this study will lead to development of markers for identification of high-growth-rate abalones and female abalones. PMID- 26593906 TI - DNA Repair--A Double-Edged Sword in the Genomic Stability of Cancer Cells--The Case of Chronic Myeloid Leukemia. AB - Genomic instability is a common feature of cancer cells, which can result from aberrant DNA damage reaction (DDR). We and others showed that the well-known BCR ABL1 fusion oncogene, the cause of chronic myeloid leukemia, induced an increased production of reactive oxygen species (ROS) and conferred therapeutic drug resistance by suppression of apoptotic signaling, prolonged G2/M arrest and stimulation of several pathways of DNA repair. However, to protect from apoptosis, cancer cells may tolerate some DNA lesions, which may increase genomic instability. Moreover, BCR/ABL1-stimulated DNA repair might be faulty, especially non-homologous end joining in its alternative forms. Normal DNA repair can remove DNA damage and prevent mutations, reducing genome instability, but on the other hand, due to its imprecise nature, it may increase genomic instability by increasing the ratio of mutagenic DNA lesions. The example of BCR-ABL1-expressing cells shows that DNA repair can both increase and decrease genomic instability of cancer cells and understanding the mechanism of the regulation of these opposite effects would be helpful in anticancer strategies. PMID- 26593907 TI - Improvement of Psychotic Symptoms and the Role of Tissue Plasminogen Activator. AB - Tissue plasminogen activator (tPA) mediates a number of processes that are pivotal for synaptogenesis and remodeling of synapses, including proteolysis of the brain extracellular matrix, degradation of adhesion molecules, activation of neurotrophins, and activation of the N-methyl-d-aspartate receptor. Abnormalities in these processes have been consistently described in psychotic disorders. In this paper, we review the physiological roles of tPA, focusing on conditions characterized by low tPA activity, which are prevalent in schizophrenia. We then describe how tPA activity is influenced by lifestyle interventions and nutritional supplements that may ameliorate psychotic symptoms. Next, we analyze the role of tPA in the mechanism of action of hormones and medications effective in mitigating psychotic symptoms, such as pregnenolone, estrogen, oxytocin, dopamine D3 receptor antagonists, retinoic acid, valproic acid, cannabidiol, sodium nitroprusside, N-acetyl cysteine, and warfarin. We also review evidence that tPA participates in the mechanism by which electroconvulsive therapy and cigarette smoking may reduce psychotic symptoms. PMID- 26593908 TI - A Mechanism of O-Demethylation of Aristolochic Acid I by Cytochromes P450 and Their Contributions to This Reaction in Human and Rat Livers: Experimental and Theoretical Approaches. AB - Aristolochic acid I (AAI) is a plant alkaloid causing aristolochic acid nephropathy, Balkan endemic nephropathy and their associated urothelial malignancies. AAI is detoxified by cytochrome P450 (CYP)-mediated O-demethylation to 8-hydroxyaristolochic acid I (aristolochic acid Ia, AAIa). We previously investigated the efficiencies of human and rat CYPs in the presence of two other components of the mixed-functions-oxidase system, NADPH:CYP oxidoreductase and cytochrome b5, to oxidize AAI. Human and rat CYP1A are the major enzymes oxidizing AAI. Other CYPs such as CYP2C, 3A4, 2D6, 2E1, and 1B1, also form AAIa, but with much lower efficiency than CYP1A. Based on velocities of AAIa formation by examined CYPs and their expression levels in human and rat livers, here we determined the contributions of individual CYPs to AAI oxidation in these organs. Human CYP1A2 followed by CYP2C9, 3A4 and 1A1 were the major enzymes contributing to AAI oxidation in human liver, while CYP2C and 1A were most important in rat liver. We employed flexible in silico docking methods to explain the differences in AAI oxidation in the liver by human CYP1A1, 1A2, 2C9, and 3A4, the enzymes that all O-demethylate AAI, but with different effectiveness. We found that the binding orientations of the methoxy group of AAI in binding centers of the CYP enzymes and the energies of AAI binding to the CYP active sites dictate the efficiency of AAI oxidation. Our results indicate that utilization of experimental and theoretical methods is an appropriate study design to examine the CYP-catalyzed reaction mechanisms of AAI oxidation and contributions of human hepatic CYPs to this metabolism. PMID- 26593909 TI - Borneol Depresses P-Glycoprotein Function by a NF-kappaB Signaling Mediated Mechanism in a Blood Brain Barrier in Vitro Model. AB - P-glycoprotein (P-gp) on brain microvascular endothelial cells (BMECs) that form the blood brain barrier (BBB), influences transportation of substances between blood and brain. The objective of this study was to characterize the effects of borneol on P-gp efflux function on BBB and explore the potential mechanisms. We established an in vitro BBB model comprised of rat BMECs and astrocytes to measure the effects of borneol on the known P-gp substrates transport across BBB, and examined the function and expression of P-gp in BMECs and the signaling pathways regulating P-gp expression. Borneol increased intracellular accumulation of Rhodamine 123, enhanced verapamil and digoxin across the BBB in vitro model, and depressed mdr1a mRNA and P-gp expression. Borneol could activate nuclear factor-kappaB (NF-kappaB) and inhibition of NF-kappaB with MG132 (carbobenzoxy Leu-Leu-leucinal) and SN50 (an inhibitory peptide) obscuring the P-gp decreases induced by borneol. These data suggested that borneol depresses P-gp function in BMECs by a NF-kappaB signaling medicated mechanism in a BBB in vitro model. PMID- 26593910 TI - Brazilein Suppresses Inflammation through Inactivation of IRAK4-NF-kappaB Pathway in LPS-Induced Raw264.7 Macrophage Cells. AB - The medicinal herbal plant has been commonly used for prevention and intervention of disease and health promotions worldwide. Brazilein is a bioactive compound extracted from Caesalpinia sappan Linn. Several studies have showed that brazilein exhibited the immune suppressive effect and anti-oxidative function. However, the molecular targets of brazilein for inflammation prevention have remained elusive. Here, we investigated the mechanism underlying the inhibitory effect of brazilein on LPS-induced inflammatory response in Raw264.7 macrophage cells. We demonstrated that brazilein decreased the expression of IRAK4 protein led to the suppression of MAPK signaling and IKKbeta, and subsequent inactivation of NF-kappaB and COX2 thus promoting the expression of the downstream target pro inflammatory cytokines such as IL-1beta, MCP-1, MIP-2, and IL-6 in LPS-induced Raw264.7 macrophage cells. Moreover, we observed that brazilein reduced the production of nitrite compared to the control in LPS-induced Raw264.7. Thus, we suggest that brazilein might be a useful bioactive compound for the prevention of IRAK-NF-kappaB pathway associated chronic diseases. PMID- 26593911 TI - A Critical Role for Cysteine 57 in the Biological Functions of Selenium Binding Protein-1. AB - The concentration of selenium-binding protein1 (SBP1) is often lower in tumors than in the corresponding tissue and lower levels have been associated with poor clinical outcomes. SBP1 binds tightly selenium although what role selenium plays in its biological functions remains unknown. Previous studies indicated that cysteine 57 is the most likely candidate amino acid for selenium binding. In order to investigate the role of cysteine 57 in SBP1, this amino acid was altered to a glycine and the mutated protein was expressed in human cancer cells. The SBP1 half-life, as well as the cellular response to selenite cytotoxicity, was altered by this change. The ectopic expression of SBP1(GLY) also caused mitochondrial damage in HCT116 cells. Taken together, these results indicated that cysteine 57 is a critical determinant of SBP1 function and may play a significant role in mitochondrial function. PMID- 26593912 TI - Leptin Genes in Blunt Snout Bream: Cloning, Phylogeny and Expression Correlated to Gonads Development. AB - To investigate the leptin related genes expression patterns and their possible function during the gonadal development in fish, the cDNA and genomic sequences of leptin, leptin receptor (leptinR), and leptin receptor overlapping transcript like-1 (leprotl1) were cloned and their expression levels were quantified in the different gonadal development stages of Megalobrama amblycephala. The results showed that the full length cDNA sequences of leptin, leptinR and leprotl1 were 953, 3432 and 1676 bp, coding 168, 1082, and 131 amino acid polypeptides, and the genomic sequences were 1836, 28,528 and 5480 bp, which respectively had 3, 15 and 4 exons, respectively. The phylogenetic analysis revealed that three genes were relatively conserved in fish species. Quantitative real-time PCR results showed that the three genes were ubiquitously expressed in all examined tissues during the different gonadal development stages. The leptin and leptinR took part in the onset of puberty, especially in female M. amblycephala, by increasing the expression levels in brain during the stage I to III of ovary. The expression levels of leptin and leptinR had significant differences between male and female in hypothalamic-pituitary-gonadal (HPG) axis tissues (p < 0.05). The leptinR had the same variation tendency with leptin, but the opposite changes of expression levels were found in leprotl1, which may resist the expression of leptinR for inhibiting the function of leptin in target organ. These findings revealed details about the possible role of these genes in regulating gonadal maturation in fish species. PMID- 26593913 TI - Gold-Coated Superparamagnetic Nanoparticles for Single Methyl Discrimination in DNA Aptamers. AB - Au- and iron-based magnetic nanoparticles (NPs) are promising NPs for biomedical applications due to their unique properties. The combination of a gold coating over a magnetic core puts together the benefits from adding the magnetic properties to the robust chemistry provided by the thiol functionalization of gold. Here, the use of Au-coated magnetic NPs for molecular detection of a single methylation in DNA aptamer is described. Binding of alpha-thrombin to two aptamers conjugated to these NPs causes aggregation, a phenomenon that can be observed by UV, DLS and MRI. These techniques discriminate a single methylation in one of the aptamers, preventing aggregation due to the inability of alpha thrombin to recognize it. A parallel study with gold and ferromagnetic NPs is detailed, concluding that the Au coating of FexOy NP does not affect their performance and that they are suitable as complex biosensors. These results prove the high detection potency of Au-coated SPIONs for biomedical applications especially for DNA repair detection. PMID- 26593915 TI - An Intrusion Detection System Based on Multi-Level Clustering for Hierarchical Wireless Sensor Networks. AB - In this work, an intrusion detection system (IDS) framework based on multi-level clustering for hierarchical wireless sensor networks is proposed. The framework employs two types of intrusion detection approaches: (1) "downward-IDS (D-IDS)" to detect the abnormal behavior (intrusion) of the subordinate (member) nodes; and (2) "upward-IDS (U-IDS)" to detect the abnormal behavior of the cluster heads. By using analytical calculations, the optimum parameters for the D-IDS (number of maximum hops) and U-IDS (monitoring group size) of the framework are evaluated and presented. PMID- 26593914 TI - Leptin Promotes cPLA2 Gene Expression through Activation of the MAPK/NF kappaB/p300 Cascade. AB - Hyperplasia or hypertrophy of adipose tissues plays a crucial role in obesity, which is accompanied by the release of leptin. Recently, obesity was determined to be associated with various pulmonary diseases including asthma, acute lung injury, and chronic obstructive pulmonary disease. However, how obesity contributes to pulmonary diseases and whether leptin directly regulates lung inflammation remains unclear. We used cell and animal models to study the mechanisms of leptin mediation of pulmonary inflammation. We found that leptin activated de novo synthesis of cytosolic phospholipase A2-alpha (cPLA2-alpha) in vitro in the lung alveolar type II cells, A549, and in vivo in ICR mice. Upregulated cPLA2-alpha protein was attenuated by pretreatment with an OB-R blocking antibody, U0126, SB202190, SP600125, Bay11-7086, garcinol, and p300 siRNA, suggesting roles of p42/p44 MAPK, p38 MAPK, JNK1/2, NF-kappaB, and p300 in leptin effects. Leptin enhanced the activities of p42/p44 MAPK, p38 MAPK, JNK1/2, and p65 NF-kappaB in a time-dependent manner. Additional studies have suggested the participation of OB-R, p42/p44 MAPK, and JNK1/2 in leptin-increased p65 phosphorylation. Furthermore, p300 phosphorylation and histone H4 acetylation were reduced by blockage of OB-R, p42/p44 MAPK, p38 MAPK, JNK1/2, and NF-kappaB in leptin-stimulated cells. Similarly, blockage of the MAPKs/NF-kappaB/p300 cascade significantly inhibited leptin-mediated cPLA2-alpha mRNA expression. Our data as a whole showed that leptin contributed to lung cPLA2-alpha expression through OB-R-dependent activation of the MAPKs/NF-kappaB/p300 cascade. PMID- 26593916 TI - A Mode Matched Triaxial Vibratory Wheel Gyroscope with Fully Decoupled Structure. AB - To avoid the oscillation of four unequal masses seen in previous triaxial linear gyroscopes, a modified silicon triaxial gyroscope with a rotary wheel is presented in this paper. To maintain a large sensitivity and suppress the coupling of different modes, this novel gyroscope structure is designed be perfectly symmetrical with a relatively large size of about 9.8 mm * 9.8 mm. It is available for differentially detecting three-axis angular rates simultaneously. To overcome the coupling between drive and sense modes, numerous necessary frames, beams, and anchors are delicately figured out and properly arranged. Besides, some frequency tuning and feedback mechanisms are addressed in the case of post processing after fabrication. To facilitate mode matched function, a new artificial fish swarm algorithm (AFSA) performed faster than particle swarm optimization (PSO) with a frequency split of 108 Hz. Then, by entrusting the post adjustment of the springs dimensions to the finite element method (FEM) software ANSYS, the final frequency splits can be below 3 Hz. The simulation results demonstrate that the modal frequencies in drive and different sense modes are respectively 8001.1, 8002.6, 8002.8 and 8003.3 Hz. Subsequently, different axis cross coupling effects and scale factors are also analyzed. The simulation results effectively validate the feasibility of the design and relevant theoretical calculation. PMID- 26593917 TI - Feasibility of Ultra-Thin Fiber-Optic Dosimeters for Radiotherapy Dosimetry. AB - In this study, prototype ultra-thin fiber-optic dosimeters were fabricated using organic scintillators, wavelength shifting fibers, and plastic optical fibers. The sensor probes of the ultra-thin fiber-optic dosimeters consisted of very thin organic scintillators with thicknesses of 100, 150 and 200 MUm. These types of sensors cannot only be used to measure skin or surface doses but also provide depth dose measurements with high spatial resolution. With the ultra-thin fiber optic dosimeters, surface doses for gamma rays generated from a Co-60 therapy machine were measured. Additionally, percentage depth doses in the build-up regions were obtained by using the ultra-thin fiber-optic dosimeters, and the results were compared with those of external beam therapy films and a conventional fiber-optic dosimeter. PMID- 26593919 TI - Capacity Model and Constraints Analysis for Integrated Remote Wireless Sensor and Satellite Network in Emergency Scenarios. AB - This article investigates the capacity problem of an integrated remote wireless sensor and satellite network (IWSSN) in emergency scenarios. We formulate a general model to evaluate the remote sensor and satellite network capacity. Compared to most existing works for ground networks, the proposed model is time varying and space oriented. To capture the characteristics of a practical network, we sift through major capacity-impacting constraints and analyze the influence of these constraints. Specifically, we combine the geometric satellite orbit model and satellite tool kit (STK) engineering software to quantify the trends of the capacity constraints. Our objective in analyzing these trends is to provide insights and design guidelines for optimizing the integrated remote wireless sensor and satellite network schedules. Simulation results validate the theoretical analysis of capacity trends and show the optimization opportunities of the IWSSN. PMID- 26593918 TI - Selection of Mother Wavelet Functions for Multi-Channel EEG Signal Analysis during a Working Memory Task. AB - We performed a comparative study to select the efficient mother wavelet (MWT) basis functions that optimally represent the signal characteristics of the electrical activity of the human brain during a working memory (WM) task recorded through electro-encephalography (EEG). Nineteen EEG electrodes were placed on the scalp following the 10-20 system. These electrodes were then grouped into five recording regions corresponding to the scalp area of the cerebral cortex. Sixty second WM task data were recorded from ten control subjects. Forty-five MWT basis functions from orthogonal families were investigated. These functions included Daubechies (db1-db20), Symlets (sym1-sym20), and Coiflets (coif1-coif5). Using ANOVA, we determined the MWT basis functions with the most significant differences in the ability of the five scalp regions to maximize their cross correlation with the EEG signals. The best results were obtained using "sym9" across the five scalp regions. Therefore, the most compatible MWT with the EEG signals should be selected to achieve wavelet denoising, decomposition, reconstruction, and sub-band feature extraction. This study provides a reference of the selection of efficient MWT basis functions. PMID- 26593920 TI - Self-Learning Embedded System for Object Identification in Intelligent Infrastructure Sensors. AB - The emergence of new horizons in the field of travel assistant management leads to the development of cutting-edge systems focused on improving the existing ones. Moreover, new opportunities are being also presented since systems trend to be more reliable and autonomous. In this paper, a self-learning embedded system for object identification based on adaptive-cooperative dynamic approaches is presented for intelligent sensor's infrastructures. The proposed system is able to detect and identify moving objects using a dynamic decision tree. Consequently, it combines machine learning algorithms and cooperative strategies in order to make the system more adaptive to changing environments. Therefore, the proposed system may be very useful for many applications like shadow tolls since several types of vehicles may be distinguished, parking optimization systems, improved traffic conditions systems, etc. PMID- 26593921 TI - Feasibility Study of EO SARs as Opportunity Illuminators in Passive Radars: PAZ Based Case Study. AB - Passive radars exploit the signal transmitted by other systems, known as opportunity illuminators (OIs), instead of using their own transmitter. Due to its almost total invulnerability to natural disasters or physical attacks, satellite OIs are of special interest. In this line, a feasibility study of Earth Observation Synthetic Aperture Radar (EO SAR) systems as OIs is carried out taking into consideration signal waveform, availability, bistatic geometry, instrumented coverage area and incident power density. A case study based on the use of PAZ, the first Spanish EO SAR, is presented. PAZ transmitted waveform, operation modes, orbit characteristics and antenna and transmitter parameters are analyzed to estimate potential coverages and resolutions. The study concludes that, due to its working in on-demand operating mode, passive radars based on PAZ type illuminators can be proposed as complementing tools during the sensor commissioning phase, for system maintenance and for improving its performance by providing additional information about the area of interest and/or increasing the data updating speed, exploiting other sensors during the time PAZ is not available. PMID- 26593922 TI - EFPC: An Environmentally Friendly Power Control Scheme for Underwater Sensor Networks. AB - In oceans, the limited acoustic spectrum resource is heavily shared by marine mammals and manmade systems including underwater sensor networks. In order to limit the negative impact of acoustic signal on marine mammals, we propose an environmentally friendly power control (EFPC) scheme for underwater sensor networks. EFPC allocates transmission power of sensor nodes with a consideration of the existence of marine mammals. By applying a Nash Equilibrium based utility function with a set of limitations to optimize transmission power, the proposed power control algorithm can conduct parallel transmissions to improve the network's goodput, while avoiding interference with marine mammals. Additionally, to localize marine mammals, which is a prerequisite of EFPC, we propose a novel passive hyperboloid localization algorithm (PHLA). PHLA passively localize marine mammals with the help of the acoustic characteristic of these targets. Simulation results show that PHLA can localize most of the target with a relatively small localization error and EFPC can achieve a close goodput performance compared with an existing power control algorithm while avoiding interfering with marine mammals. PMID- 26593923 TI - Hiding the Source Based on Limited Flooding for Sensor Networks. AB - Wireless sensor networks are widely used to monitor valuable objects such as rare animals or armies. Once an object is detected, the source, i.e., the sensor nearest to the object, generates and periodically sends a packet about the object to the base station. Since attackers can capture the object by localizing the source, many protocols have been proposed to protect source location. Instead of transmitting the packet to the base station directly, typical source location protection protocols first transmit packets randomly for a few hops to a phantom location, and then forward the packets to the base station. The problem with these protocols is that the generated phantom locations are usually not only near the true source but also close to each other. As a result, attackers can easily trace a route back to the source from the phantom locations. To address the above problem, we propose a new protocol for source location protection based on limited flooding, named SLP. Compared with existing protocols, SLP can generate phantom locations that are not only far away from the source, but also widely distributed. It improves source location security significantly with low communication cost. We further propose a protocol, namely SLP-E, to protect source location against more powerful attackers with wider fields of vision. The performance of our SLP and SLP-E are validated by both theoretical analysis and simulation results. PMID- 26593924 TI - An Efficient Data-Gathering Routing Protocol for Underwater Wireless Sensor Networks. AB - Most applications of underwater wireless sensor networks (UWSNs) demand reliable data delivery over a longer period in an efficient and timely manner. However, the harsh and unpredictable underwater environment makes routing more challenging as compared to terrestrial WSNs. Most of the existing schemes deploy mobile sensors or a mobile sink (MS) to maximize data gathering. However, the relatively high deployment cost prevents their usage in most applications. Thus, this paper presents an autonomous underwater vehicle (AUV)-aided efficient data-gathering (AEDG) routing protocol for reliable data delivery in UWSNs. To prolong the network lifetime, AEDG employs an AUV for data collection from gateways and uses a shortest path tree (SPT) algorithm while associating sensor nodes with the gateways. The AEDG protocol also limits the number of associated nodes with the gateway nodes to minimize the network energy consumption and to prevent the gateways from overloading. Moreover, gateways are rotated with the passage of time to balance the energy consumption of the network. To prevent data loss, AEDG allows dynamic data collection at the AUV depending on the limited number of member nodes that are associated with each gateway. We also develop a sub-optimal elliptical trajectory of AUV by using a connected dominating set (CDS) to further facilitate network throughput maximization. The performance of the AEDG is validated via simulations, which demonstrate the effectiveness of AEDG in comparison to two existing UWSN routing protocols in terms of the selected performance metrics. PMID- 26593925 TI - 29iemes Journees Franco-Belges de Pharmacochimie: Meeting Report. AB - The "Journees Franco-Belges de Pharmacochimie" is a recognized two-day annual meeting on Medicinal Chemistry that is renowned for the advanced science presented, conviviality, and outstanding opportunities for senior and young scientists to exchange knowledge. Abstracts of plenary lectures, oral communications, and posters presented during the meeting are collected in this report. PMID- 26593926 TI - Non-Monotonic Survival of Staphylococcus aureus with Respect to Ciprofloxacin Concentration Arises from Prophage-Dependent Killing of Persisters. AB - Staphylococcus aureus is a notorious pathogen with a propensity to cause chronic, non-healing wounds. Bacterial persisters have been implicated in the recalcitrance of S. aureus infections, and this motivated us to examine the persistence of S. aureus to ciprofloxacin, a quinolone antibiotic. Upon treatment of exponential phase S. aureus with ciprofloxacin, we observed that survival was a non-monotonic function of ciprofloxacin concentration. Maximal killing occurred at 1 ug/mL ciprofloxacin, which corresponded to survival that was up to ~40-fold lower than that obtained with concentrations >= 5 ug/mL. Investigation of this phenomenon revealed that the non-monotonic response was associated with prophage induction, which facilitated killing of S. aureus persisters. Elimination of prophage induction with tetracycline was found to prevent cell lysis and persister killing. We anticipate that these findings may be useful for the design of quinolone treatments. PMID- 26593927 TI - A New Analogue of Echinomycin and a New Cyclic Dipeptide from a Marine-Derived Streptomyces sp. LS298. AB - Quinomycin G (1), a new analogue of echinomycin, together with a new cyclic dipeptide, cyclo-(l-Pro-4-OH-l-Leu) (2), as well as three known antibiotic compounds tirandamycin A (3), tirandamycin B (4) and staurosporine (5), were isolated from Streptomyces sp. LS298 obtained from a marine sponge Gelliodes carnosa. The planar and absolute configurations of compounds 1 and 2 were established by MS, NMR spectral data analysis and Marfey's method. Furthermore, the differences in NMR data of keto-enol tautomers in tirandamycins were discussed for the first time. Antibacterial and anti-tumor activities of compound 1 were measured against 15 drug-sensitive/resistant strains and 12 tumor cell lines. Compound 1 exhibited moderate antibacterial activities against Staphylococcuse pidermidis, S. aureus, Enterococcus faecium, and E. faecalis with the minimum inhibitory concentration (MIC) values ranged from 16 to 64 MUg/mL. Moreover, it displayed remarkable anti-tumor activities; the highest activity was observed against the Jurkat cell line (human T-cell leukemia) with an IC50 value of 0.414 MUM. PMID- 26593928 TI - Induction of the Estrogenic Marker Calbindn-D9k by Octamethylcyclotetrasiloxane. AB - Interrupting the hormonal balance of an organism by interfering with hormones and their target receptors gives rise to various problems such as developmental disorders. Collectively, these reagents are known as endocrine disruptors (EDs). Cyclic volatile methyl siloxanes (cVMSs) are a group of silicone polymers that including octamethylcyclotetrasiloxane (D4). In the present study, we examined the estrogenicity of D4 through in vitro and in vivo assays that employed calcium binding protein 9K (calbindin-D9k; CaBP-9K) as a biomarker. For in vitro investigation, GH3 rat pituitary cells were exposed to vehicle, 17beta-estradiol (E2), or D4 with/without ICI 182 780 (ICI). CaBP-9K and progesterone receptor (PR) both were up-regulated by E2 and D4 which were completely blocked by ICI. Transcription of estrogen receptor alpha (ER alpha) was decreased by E2 and D4 but increased by ICI. D4 was also administered to immature female rats for an uterotrophic (UT) assay and detection of CaBP-9K. Ethinyl estradiol (EE) or D4 was administered subcutaneously with or without ICI. Although uterine weight was not significant altered by D4, an effect thought to be due to cytochrome P450 (CYP), it induced CaBP-9K and PR gene expression. Based on these results we reveal that D4 has estrogenic potential proven under in vitro and in vivo experimental conditions. PMID- 26593929 TI - Characterization of La/Fe/TiO2 and Its Photocatalytic Performance in Ammonia Nitrogen Wastewater. AB - La/Fe/TiO2 composite photocatalysts were synthesized by Sol-Gel method and well characterized by powder X-ray diffraction (XRD), scanning electron microscopy (SEM), nitrogen-physical adsorption, and UV-Vis diffuse reflectance spectra (UV Vis DRS). It is interesting that the doped catalysts were in anatase phase while the pure TiO2 was in rutile phase. In addition, the composites possessed better physical chemical properties in photocatalytic activity than pure TiO2: stronger visible-light-response ability, larger specific surface area, and more regular shape in morphology. The photodegradation results of ammonia nitrogen indicate that: the La/Fe/TiO2 had higher catalytic activity to ammonia nitrogen waste water compared pure TiO2 and the other single metal-doped TiO2. pH 10 and 2 mmol/L H2O2 were all beneficial to the removal of ammonia nitrogen by La/Fe/TiO2. However, the common inorganic ions of Cl(-), NO3(-), SO4(2-), HCO3(-)/CO32(-), Na+, K+, Ca(2+) and Mg(2+) in water all inhibited the degradation of ammonia nitrogen. By balance calculation, at least 20% of ammonia nitrogen was converted to N2 during the 64.6% removal efficiency of ammonia nitrogen. PMID- 26593930 TI - The Effects of Weight Perception on Adolescents' Weight-Loss Intentions and Behaviors: Evidence from the Youth Risk Behavior Surveillance Survey. AB - The objective of this study was to examine the correlation between self perception of being overweight and weight loss intentions, eating and exercise behaviors, as well as extreme weight-loss strategies for U.S. adolescents. This study uses 50,241 observations from the Youth Risk Behavior Surveillance Survey (YRBSS) 2001-2009, which were nationally representative sample of 9th- through 12th-grade students in both public and private schools in the US. This study finds that, irrespective of the weight status base on self-reported weight and height, adolescents who perceive themselves as overweight have a stronger intention to lose weight, but do not develop better eating and exercise habits, compared with their counterparts of same gender and reported weight status. Normal-weight adolescents, if they perceive themselves as overweight, are more likely to engage in health-compromising weight-loss methods. This study shows that it is critical to transform weight-loss intentions into actual behaviors among overweight/obese adolescents and improve the efficacy of behavioral interventions against childhood obesity. It also highlights the need of establishing a correct perception of body weight among normal weight adolescents to curb extreme weight-loss methods. PMID- 26593931 TI - Mercury Exposure in Healthy Korean Weaning-Age Infants: Association with Growth, Feeding and Fish Intake. AB - Low-level mercury (Hg) exposure in infancy might be harmful to the physical growth as well as neurodevelopment of children. The aim of this study was to investigate postnatal Hg exposure and its relationship with anthropometry and dietary factors in late infancy. We recruited 252 healthy Korean infants between six and 24 months of age from an outpatient clinic during the 2009/2010 and 2013/2014 seasons. We measured the weight and height of the infants and collected dietary information using questionnaires. The Hg content of the hair and blood was assessed using inductively coupled plasma mass spectroscopy. The geometric mean Hg concentration in the hair and blood was 0.22 (95% confidence interval: 0.20-0.24) ug/g and 0.94 (n = 109, 95% confidence interval: 0.89-0.99) ug/L, respectively. The hair Hg concentration showed a good correlation with the blood Hg concentration (median hair-to-blood Hg ratio: 202.7, r = 0.462, p < 0.001) and was >1 ug/g in five infants. The hair Hg concentration showed significant correlations with weight gain after birth (Z-score of the weight for age-Z-score of the birthweight; r = -0.156, p = 0.015), the duration (months) of breastfeeding as the dominant method of feeding (r = 0.274, p < 0.001), and the duration of fish intake more than once per week (r = 0.138, p = 0.033). In an ordinal logistic regression analysis with categorical hair Hg content (quartiles), dietary factors, including breastfeeding as the dominant method of feeding in late infancy (cumulative odds ratio: 6.235, 95% confidence interval: 3.086-12.597, p < 0.001) and the monthly duration of fish intake more than once per week (cumulative odds ratio: 1.203, 95% confidence interval: 1.034-1.401; p = 0.017), were significantly associated with higher hair Hg content. Weight gain after birth was not, however, significantly associated with hair Hg content after adjustment for the duration of breastfeeding as the dominant method of feeding. Low-level Hg exposure through breastfeeding and fish intake as a complementary food did not directly affect anthropometry in this population. If prolonged breastfeeding is expected, however, the Hg exposure through fish intake may need to be monitored for both mothers and infants. PMID- 26593932 TI - Caesarean Section--A Density-Equalizing Mapping Study to Depict Its Global Research Architecture. AB - Caesarean section (CS) is a common surgical procedure. Although it has been performed in a modern context for about 100 years, there is no concise analysis of the international architecture of caesarean section research output available so far. Therefore, the present study characterizes the global pattern of the related publications by using the NewQIS (New Quality and Quantity Indices in Science) platform, which combines scientometric methods with density equalizing mapping algorithms. The Web of Science was used as a database. 12,608 publications were identified that originated from 131 countries. The leading nations concerning research activity, overall citations and country-specific h Index were the USA and the United Kingdom. Relation of the research activity to epidemiologic data indicated that Scandinavian countries including Sweden and Finland were leading the field, whereas, in relation to economic data, countries such as Israel and Ireland led. Semi-qualitative indices such as country-specific citation rates ranked Sweden, Norway and Finland in the top positions. International caesarean section research output continues to grow annually in an era where caesarean section rates increased dramatically over the past decades. With regard to increasing employment of scientometric indicators in performance assessment, these findings should provide useful information for those tasked with the improvement of scientific achievements. PMID- 26593933 TI - Economic, Environmental and Health Implications of Enhanced Ventilation in Office Buildings. AB - INTRODUCTION: Current building ventilation standards are based on acceptable minimums. Three decades of research demonstrates the human health benefits of increased ventilation above these minimums. Recent research also shows the benefits on human decision-making performance in office workers, which translates to increased productivity. However, adoption of enhanced ventilation strategies is lagging. We sought to evaluate two of the perceived potential barriers to more widespread adoption-Economic and environmental costs. METHODS: We estimated the energy consumption and associated per building occupant costs for office buildings in seven U.S. cities, representing different climate zones for three ventilation scenarios (standard practice (20 cfm/person), 30% enhanced ventilation, and 40 cfm/person) and four different heating, ventilation and air conditioning (HVAC) system strategies (Variable Air Volume (VAV) with reheat and a Fan Coil Unit (FCU), both with and without an energy recovery ventilator). We also estimated emissions of greenhouse gases associated with this increased energy usage, and, for comparison, converted this to the equivalent number of vehicles using greenhouse gas equivalencies. Lastly, we paired results from our previous research on cognitive function and ventilation with labor statistics to estimate the economic benefit of increased productivity associated with increasing ventilation rates. RESULTS: Doubling the ventilation rate from the American Society of Heating, Refrigeration and Air-Conditioning Engineers minimum cost less than $40 per person per year in all climate zones investigated. Using an energy recovery ventilation system significantly reduced energy costs, and in some scenarios led to a net savings. At the highest ventilation rate, adding an ERV essentially neutralized the environmental impact of enhanced ventilation (0.03 additional cars on the road per building across all cities). The same change in ventilation improved the performance of workers by 8%, equivalent to a $6500 increase in employee productivity each year. Reduced absenteeism and improved health are also seen with enhanced ventilation. CONCLUSIONS: The health benefits associated with enhanced ventilation rates far exceed the per-person energy costs relative to salary costs. Environmental impacts can be mitigated at regional, building, and individual-level scales through the transition to renewable energy sources, adoption of energy efficient systems and ventilation strategies, and promotion of other sustainable policies. PMID- 26593934 TI - A Discriminant Function Approach to Adjust for Processing and Measurement Error When a Biomarker is Assayed in Pooled Samples. AB - Pooling biological specimens prior to performing expensive laboratory assays has been shown to be a cost effective approach for estimating parameters of interest. In addition to requiring specialized statistical techniques, however, the pooling of samples can introduce assay errors due to processing, possibly in addition to measurement error that may be present when the assay is applied to individual samples. Failure to account for these sources of error can result in biased parameter estimates and ultimately faulty inference. Prior research addressing biomarker mean and variance estimation advocates hybrid designs consisting of individual as well as pooled samples to account for measurement and processing (or pooling) error. We consider adapting this approach to the problem of estimating a covariate-adjusted odds ratio (OR) relating a binary outcome to a continuous exposure or biomarker level assessed in pools. In particular, we explore the applicability of a discriminant function-based analysis that assumes normal residual, processing, and measurement errors. A potential advantage of this method is that maximum likelihood estimation of the desired adjusted log OR is straightforward and computationally convenient. Moreover, in the absence of measurement and processing error, the method yields an efficient unbiased estimator for the parameter of interest assuming normal residual errors. We illustrate the approach using real data from an ancillary study of the Collaborative Perinatal Project, and we use simulations to demonstrate the ability of the proposed estimators to alleviate bias due to measurement and processing error. PMID- 26593935 TI - Travel Behavior Change in Older Travelers: Understanding Critical Reactions to Incidents Encountered in Public Transport. AB - Accessibility of travel may be better understood if psychological factors underlying change in travel behavior are known. This paper examines older (65+) travelers' motives for changing their travel behavior. These changes are grounded in critical incidents earlier encountered in public-transport travel. A scientific framework is developed based on cognitive and behavioral theory. In 29 individual interviews, travelers' critical reactions (i.e., cognitive, emotional, and/or behavioral) to 77 critical incidents were examined. By applying critical incident technique (CIT), five reaction themes were identified that had generated travel-behavior change: firm restrictions, unpredictability, unfair treatment, complicated trips, and earlier adverse experiences. To improve older travelers' access to public transport, key findings were: (a) service must be designed so as to strengthen the feeling of being in control throughout the journey; (b) extended personal service would increase predictability in the travel chain and decrease travel complexity; consequently, PMID- 26593936 TI - Chikungunya Virus Replication in Salivary Glands of the Mosquito Aedes albopictus. AB - Chikungunya virus (CHIKV) is an emerging arbovirus transmitted to humans by mosquitoes such as Aedes albopictus. To be transmitted, CHIKV must replicate in the mosquito midgut, then disseminate in the hemocele and infect the salivary glands before being released in saliva. We have developed a standardized protocol to visualize viral particles in the mosquito salivary glands using transmission electron microscopy. Here we provide direct evidence for CHIKV replication and storage in Ae. albopictus salivary glands. PMID- 26593937 TI - Antiviral Activity of Porcine Interferon Regulatory Factor 1 against Swine Viruses in Cell Culture. AB - Interferon regulatory factor 1 (IRF1), as an important transcription factor, is abundantly induced upon virus infections and participates in host antiviral immune responses. However, the roles of porcine IRF1 (poIRF1) in host antiviral defense remain poorly understood. In this study, we determined that poIRF1 was upregulated upon infection with viruses and distributed in nucleus in porcine PK 15 cells. Subsequently, we tested the antiviral activities of poIRF1 against several swine viruses in cells. Overexpression of poIRF1 can efficiently suppress the replication of viruses, and knockdown of poIRF1 promotes moderately viral replication. Interestingly, overexpression of poIRF1 enhances dsRNA-induced IFN beta and IFN-stimulated response element (ISRE) promoter activation, whereas knockdown of poIRF1 cannot significantly affect the activation of IFN-beta promoter induced by RNA viruses. This study suggests that poIRF1 plays a significant role in cellular antiviral response against swine viruses, but might be dispensable for IFN-beta induction triggered by RNA viruses in PK-15 cells. Given these results, poIRF1 plays potential roles in cellular antiviral responses against swine viruses. PMID- 26593938 TI - Efficacy of a Trivalent Hand, Foot, and Mouth Disease Vaccine against Enterovirus 71 and Coxsackieviruses A16 and A6 in Mice. AB - Hand, foot, and mouth disease (HFMD) has recently emerged as a major public health concern across the Asian-Pacific region. Enterovirus 71 (EV71) and Coxsackievirus A16 (CVA16) are the primary causative agents of HFMD, but other members of the Enterovirus A species, including Coxsackievirus A6 (CVA6), can cause disease. The lack of small animal models for these viruses have hampered the development of a licensed HFMD vaccine or antivirals. We have previously reported on the development of a mouse model for EV71 and demonstrated the protective efficacy of an inactivated EV71 vaccine candidate. Here, mouse-adapted strains of CVA16 and CVA6 were produced by sequential passage of the viruses through mice deficient in interferon (IFN) alpha/beta (A129) and alpha/beta and gamma (AG129) receptors. Adapted viruses were capable of infecting 3 week-old A129 (CVA6) and 12 week-old AG129 (CVA16) mice. Accordingly, these models were used in active and passive immunization studies to test the efficacy of a trivalent vaccine candidate containing inactivated EV71, CVA16, and CVA6. Full protection from lethal challenge against EV71 and CVA16 was observed in trivalent vaccinated groups. In contrast, monovalent vaccinated groups with non-homologous challenges failed to cross protect. Protection from CVA6 challenge was accomplished through a passive transfer study involving serum raised against the trivalent vaccine. These animal models will be useful for future studies on HFMD related pathogenesis and the efficacy of vaccine candidates. PMID- 26593939 TI - Insertion Process of Ceramic Nanoporous Microneedles by Means of a Novel Mechanical Applicator Design. AB - Arrays of microneedles (MNAs) are integrated in an out-of-plane fashion with a base plate and can serve as patches for the release of drugs and vaccines. We used soft-lithography and micromolding to manufacture ceramic nanoporous (np)MNAs. Failure modes of ceramic npMNAs are as yet poorly understood and the question remained: is our npMNA platform technology ready for microneedle (MN) assembly into patches? We investigated npMNAs by microindentation, yielding average crack fracture forces above the required insertion force for a single MN to penetrate human skin. We further developed a thumb pressure-actuated applicator-assisted npMNA insertion method, which enables anchoring of MNs in the skin by an adhesive in one handling step. Using a set of simple artificial skin models, we found a puncture efficiency of this insertion method a factor three times higher than by applying thumb pressure on the npMNA base plate directly. In addition, this new method facilitated zero MN-breakage due to a well-defined force distribution exerted onto the MNs and the closely surrounding area prior to bringing the adhesive into contact with the skin. Owing to the fact that such parameter space exists, we can conclude that npMNAs by soft lithography are a platform technology for MN assembly into a patch. PMID- 26593940 TI - Impact of Maternal Diet on the Epigenome during In Utero Life and the Developmental Programming of Diseases in Childhood and Adulthood. AB - Exposure to environmental factors in early life can influence developmental processes and long-term health in humans. Early life nutrition and maternal diet are well-known examples of conditions shown to influence the risk of developing metabolic diseases, including type 2 diabetes mellitus and cardiovascular diseases, in adulthood. It is increasingly accepted that environmental compounds, including nutrients, can produce changes in the genome activity that, in spite of not altering the DNA sequence, can produce important, stable and, in some instances, transgenerational alterations in the phenotype. Epigenetics refers to changes in gene function that cannot be explained by changes in the DNA sequence, with DNA methylation patterns/histone modifications that can make important contributions to epigenetic memory. The epigenome can be considered as an interface between the genome and the environment that is central to the generation of phenotypes and their stability throughout the life course. To better understand the role of maternal health and nutrition in the initiation and progression of diseases in childhood and adulthood, it is necessary to identify the physiological and/or pathological roles of specific nutrients on the epigenome and how dietary interventions in utero and early life could modulate disease risk through epigenomic alteration. PMID- 26593941 TI - Coleus forskohlii Extract Supplementation in Conjunction with a Hypocaloric Diet Reduces the Risk Factors of Metabolic Syndrome in Overweight and Obese Subjects: A Randomized Controlled Trial. AB - Limited studies have shown that Coleus forskohlii extract may aid in weight management. This randomized, double blind placebo-controlled clinical study assessed the effects of supplementation with C. forskohlii extract on key markers of obesity and metabolic parameters in overweight and obese individuals. Thirty participants completed the trial and they were randomly assigned to receive either 250 mg of C. forskohlii extract (n = 15) or a placebo twice daily for 12 weeks. All participants were advised to follow a hypocaloric diet throughout the study. Body weight, body mass index (BMI), waist and hip circumference, and waist to hip ratio, were monitored fortnightly. Dietary intake was assessed at the baseline and weeks 4, 8 and 12. Appetite was assessed using visual analogue scales and blood samples were analyzed for plasma lipids, ghrelin, leptin, glucose and insulin at the baseline and end of the intervention. Significant reductions to waist and hip circumference (p = 0.02; p = 0.01, respectively) were recorded in both experimental and placebo groups after the 12 week intervention. Furthermore, high density lipoprotein-cholesterol (HDL-C) was significantly increased (p = 0.01) in both groups. The experimental group showed a favorable improvement in insulin concentration and insulin resistance (p = 0.001; 0.01 respectively) compared to the placebo group. These findings suggest that C. forskohlii extract in conjunction with a hypocaloric diet may be useful in the management of metabolic risk factors. PMID- 26593942 TI - Analysis of Dietary Pattern Impact on Weight Status for Personalised Nutrition through On-Line Advice: The Food4Me Spanish Cohort. AB - Obesity prevalence is increasing. The management of this condition requires a detailed analysis of the global risk factors in order to develop personalised advice. This study is aimed to identify current dietary patterns and habits in Spanish population interested in personalised nutrition and investigate associations with weight status. Self-reported dietary and anthropometrical data from the Spanish participants in the Food4Me study, were used in a multidimensional exploratory analysis to define specific dietary profiles. Two opposing factors were obtained according to food groups' intake: Factor 1 characterised by a more frequent consumption of traditionally considered unhealthy foods; and Factor 2, where the consumption of "Mediterranean diet" foods was prevalent. Factor 1 showed a direct relationship with BMI (beta = 0.226; r2 = 0.259; p < 0.001), while the association with Factor 2 was inverse (beta = -0.037; r2 = 0.230; p = 0.348). A total of four categories were defined (Prudent, Healthy, Western, and Compensatory) through classification of the sample in higher or lower adherence to each factor and combining the possibilities. Western and Compensatory dietary patterns, which were characterized by high-density foods consumption, showed positive associations with overweight prevalence. Further analysis showed that prevention of overweight must focus on limiting the intake of known deleterious foods rather than exclusively enhance healthy products. PMID- 26593944 TI - Dietary Intake according to Gender and Education: A Twenty-Year Trend in a Swiss Adult Population. AB - We assessed trends in dietary intake according to gender and education using repeated cross-sectional, population-based surveys conducted between 1993 and 2012 in Geneva, Switzerland (17,263 participants, 52.0 +/- 10.6 years, 48% male). In 1993-1999, higher educated men had higher monounsaturated fatty acids (MUFA), carotene and vitamin D intakes than lower educated men, and the differences decreased in 2006-2012. In 1993-1999, higher educated women had higher fiber, iron, carotene, vitamin D and alcohol intakes than lower educated women, and the differences decreased in 2006-2012. Total energy, polyunsaturated fatty acids, retinol and alcohol intakes decreased, while mono/disaccharides, MUFA and carotene intake increased in both genders. Lower educated men had stronger decreases in saturated fatty acid (SFA) and calcium intakes than higher educated men: multivariate-adjusted slope and 95% confidence interval -0.11 (-0.15; -0.06) vs. -0.03 (-0.08; 0.02) g/day/year for SFA and -5.2 (-7.8; -2.7) vs. -1.03 (-3.8; 1.8) mg/day/year for calcium, p for interaction <0.05. Higher educated women had a greater decrease in iron intake than lower educated women: -0.03 (-0.04; -0.02) vs. -0.01 (-0.02; 0.00) mg/day/year, p for interaction = 0.002. We conclude that, in Switzerland, dietary intake evolved similarly between 1993 and 2012 in both educational groups. Educational differences present in 1993 persisted in 2012. PMID- 26593943 TI - New Insights into the Pros and Cons of the Clinical Use of Vitamin K Antagonists (VKAs) Versus Direct Oral Anticoagulants (DOACs). AB - Vitamin K-antagonists (VKA) are the most widely used anticoagulant drugs to treat patients at risk of arterial and venous thrombosis for the past 50 years. Due to unfavorable pharmacokinetics VKA have a small therapeutic window, require frequent monitoring, and are susceptible to drug and nutritional interactions. Additionally, the effect of VKA is not limited to coagulation, but affects all vitamin K-dependent proteins. As a consequence, VKA have detrimental side effects by enhancing medial and intimal calcification. These limitations stimulated the development of alternative anticoagulant drugs, resulting in direct oral anticoagulant (DOAC) drugs, which specifically target coagulation factor Xa and thrombin. DOACs also display non-hemostatic vascular effects via protease activated receptors (PARs). As atherosclerosis is characterized by a hypercoagulable state indicating the involvement of activated coagulation factors in the genesis of atherosclerosis, anticoagulation could have beneficial effects on atherosclerosis. Additionally, accumulating evidence demonstrates vascular benefit from high vitamin K intake. This review gives an update on oral anticoagulant treatment on the vasculature with a special focus on calcification and vitamin K interaction. PMID- 26593945 TI - The Ratio of Dietary Branched-Chain Amino Acids is Associated with a Lower Prevalence of Obesity in Young Northern Chinese Adults: An Internet-Based Cross Sectional Study. AB - This study aims to examine the association between the ratio of dietary branched chain amino acids (BCAA) and risk of obesity among young northern Chinese adults. A total of 948 randomly recruited participants were asked to finish our internet based dietary questionnaire for the Chinese (IDQC). Associations between dietary BCAA ratio and prevalence of overweight/obesity and abdominal obesity were analyzed. Furthermore, 90 subjects were randomly selected to explore the possible mechanism. Dietary BCAA ratio in obese participants was significantly lower than non-obese participants. We found negative correlations between the ratio of dietary BCAA and body mass index (BMI) (r = -0.197, p < 0.001) or waist circumference (r = -0.187, p < 0.001). Compared with those in the first quartile, the multivariable-adjusted OR (95% CI) of the 3rd and 4th quartiles of dietary BCAA ratio for overweight/obesity were 0.508 (0.265-0.972) and 0.389 (0.193 0.783), respectively (all p < 0.05). After stratification by gender, the significance still existed in the 3rd and 4th quartile in males and the 4th quartile in females. For abdominal obesity, the multivariable-adjusted OR (95% CI) of the 3rd and 4th quartile of dietary BCAA ratio were 0.351 (0.145-0.845) and 0.376 (0.161-0.876), respectively (all p < 0.05). This significance was stronger in males. Further studies indicated that dietary BCAA ratio was inversely associated with 2-h postprandial glucose (2 h-PG) and status of inflammation. In conclusion, a higher ratio of dietary BCAA is inversely associated with prevalence of obesity, postprandial glucose and status of inflammation in young northern Chinese adults. PMID- 26593946 TI - Diverse profiles of ricin-cell interactions in the lung following intranasal exposure to ricin. AB - Ricin, a plant-derived exotoxin, inhibits protein synthesis by ribosomal inactivation. Due to its wide availability and ease of preparation, ricin is considered a biothreat, foremost by respiratory exposure. We examined the in vivo interactions between ricin and cells of the lungs in mice intranasally exposed to the toxin and revealed multi-phasic cell-type-dependent binding profiles. While macrophages (MPhis) and dendritic cells (DCs) displayed biphasic binding to ricin, monophasic binding patterns were observed for other cell types; epithelial cells displayed early binding, while B cells and endothelial cells bound toxin late after intoxication. Neutrophils, which were massively recruited to the intoxicated lung, were refractive to toxin binding. Although epithelial cells bound ricin as early as MPhis and DCs, their rates of elimination differed considerably; a reduction in epithelial cell counts occurred late after intoxication and was restricted to alveolar type II cells only. The differential binding and cell-elimination patterns observed may stem from dissimilar accessibility of the toxin to different cells in the lung and may also reflect unequal interactions of the toxin with different cell-surface receptors. The multifaceted interactions observed in this study between ricin and the various cells of the target organ should be considered in the future development of efficient post-exposure countermeasures against ricin intoxication. PMID- 26593948 TI - Non-Surgical Breast-Conserving Treatment (KORTUC-BCT) Using a New Radiosensitization Method (KORTUC II) for Patients with Stage I or II Breast Cancer. AB - The purpose of the present study was to establish a non-surgical breast conserving treatment (BCT) using KORTUC II radiosensitization treatment. A new radiosensitizing agent containing 0.5% hydrogen peroxide and 0.83% sodium hyaluronate (a CD44 ligand) has been developed for intra-tumoral injection into various tumors. This new method, named KORTUC II, was approved by our local ethics committee for the treatment of breast cancer and metastatic lymph nodes. A total of 72 early-stage breast cancer patients (stage 0, 1 patient; stage I, 23; stage II, 48) were enrolled in the KORTUC II trial after providing fully informed consent. The mean age of the patients was 59.7 years. A maximum of 6 mL (usually 3 mL for tumors of less than approximately 3 cm in diameter) of the agent was injected into breast tumor tissue twice a week under ultrasonographic guidance. For radiotherapy, hypofraction radiotherapy was administered using a tangential fields approach including an ipsilateral axillary region and field-in-field method; the energy level was 4 MV, and the total radiation dose was 44 Gy administered as 2.75 Gy/fraction. An electron boost of 3 Gy was added three times. Treatment was well tolerated with minimal adverse effects in all 72 patients. No patients showed any significant complications other than mild dermatitis. A total of 24 patients under 75 years old with stage II breast cancer underwent induction chemotherapy (EC and/or taxane) prior to KORTUC II treatment, and 58 patients with estrogen receptor-positive tumors also received hormonal therapy following KORTUC II. The mean duration of follow-up as of the end of September 2014 was 51.1 months, at which time 68 patients were alive without any distant metastases. Only one patient had local recurrence and died of cardiac failure at 6.5 years. Another one patient had bone metastases. For two of the 72 patients, follow-up ended after several months following KORTUC II treatment. In conclusion, non-surgical BCT can be performed using KORTUC II, which has three major characteristics: imaging guidance; enzyme-targeting; and targeting of breast cancer stem cells via the CD44 receptor. PMID- 26593947 TI - Centipede venoms and their components: resources for potential therapeutic applications. AB - Venomous animals have evolved with sophisticated bio-chemical strategies to arrest prey and defend themselves from natural predators. In recent years, peptide toxins from venomous animals have drawn considerable attention from researchers due to their surprising chemical, biochemical, and pharmacological diversity. Similar to other venomous animals, centipedes are one of the crucial venomous arthropods that have been used in traditional medicine for hundreds of years in China. Despite signifying pharmacological importance, very little is known about the active components of centipede venoms. More than 500 peptide sequences have been reported in centipede venomous glands by transcriptome analysis, but only a small number of peptide toxins from centipede has been functionally described. Like other venomous animals such as snakes, scorpions, and spiders, the venom of centipedes could be an excellent source of peptides for developing drugs for treatments as well as bio-insecticides for agrochemical applications. Although centipede venoms are yet to be adequately studied, the venom of centipedes as well as their components described to date, should be compiled to help further research. Therefore, based on previous reports, this review focusses on findings and possible therapeutic applications of centipede venoms as well as their components. PMID- 26593950 TI - Identification of Candidate Genes for Seed Glucosinolate Content Using Association Mapping in Brassica napus L. AB - Rapeseed contains glucosinolates, a toxic group of sulfur-containing glucosides, which play critical roles in defense against herbivores and microbes. However, the presence of glucosinolates in rapeseed reduces the value of the meal as feed for livestock. We performed association mapping of seed glucosinolate (GS) content using the 60K Brassica Infinium single nucleotide polymorphism (SNP) array in 520 oilseed rape accessions. A total of 11 peak SNPs significantly associated with GS content were detected in growing seasons of 2013 and 2014 and were located on B. napus chromosomes A08, A09, C03, and C09, respectively. Two associated regions of GS content covered by these markers were further verified, and three B. napus homologous genes involved in the biosynthesis and accumulation of GS were identified. These genes were multigene family members and were distributed on different chromosomes. Moreover, two genes (BnGRT2 and BnMYB28) associated with GS content were validated by the qRT-PCR analysis of their expression profiles. The further identification and functionalization of these genes will provide useful insight into the mechanism underlying GS biosynthesis and allocation in B. napus, and the associated SNPs markers could be helpful for molecular maker-assisted breeding for low seed GS in B. napus. PMID- 26593949 TI - Prostate Cancer Stem-like Cells Contribute to the Development of Castration Resistant Prostate Cancer. AB - Androgen deprivation therapy (ADT) has been the standard care for patients with advanced prostate cancer (PC) since the 1940s. Although ADT shows clear benefits for many patients, castration-resistant prostate cancer (CRPC) inevitably occurs. In fact, with the two recent FDA-approved second-generation anti-androgens abiraterone and enzalutamide, resistance develops rapidly in patients with CRPC, despite their initial effectiveness. The lack of effective therapeutic solutions towards CRPC largely reflects our limited understanding of the underlying mechanisms responsible for CRPC development. While persistent androgen receptor (AR) signaling under castration levels of serum testosterone (<50 ng/mL) contributes to resistance to ADT, it is also clear that CRPC evolves via complex mechanisms. Nevertheless, the physiological impact of individual mechanisms and whether these mechanisms function in a cohesive manner in promoting CRPC are elusive. In spite of these uncertainties, emerging evidence supports a critical role of prostate cancer stem-like cells (PCSLCs) in stimulating CRPC evolution and resistance to abiraterone and enzalutamide. In this review, we will discuss the recent evidence supporting the involvement of PCSLC in CRPC acquisition as well as the pathways and factors contributing to PCSLC expansion in response to ADT. PMID- 26593951 TI - Evaluation of an mHealth Medication Regimen Self-Management Program for African American and Hispanic Uncontrolled Hypertensives. AB - African Americans and Hispanics have disproportionate rates of uncontrolled essential hypertension (EH) compared to Non-Hispanic Whites. Medication non adherence (MNA) is the leading modifiable behavior to improved blood pressure (BP) control. The Smartphone Medication Adherence Stops Hypertension (SMASH) program was developed using a patient-centered, theory-guided, iterative design process. Electronic medication trays provided reminder signals, and Short Message Service [SMS] messaging reminded subjects to monitor BP with Bluetooth-enabled monitors. Motivational and reinforcement text messages were sent to participants based upon levels of adherence. Thirty-eight African-American (18) and Hispanic (20) uncontrolled hypertensives completed clinic-based anthropometric and resting BP evaluations prior to randomization, and again at months 1, 3 and 6. Generalized linear mixed modeling (GLMM) revealed statistically significant time by-treatment interactions (p < 0.0001) indicating significant reductions in resting systolic blood pressure (SBP) and diastolic blood pressure (DBP) for the SMASH group vs. the standard care (SC) control group across all time points. 70.6% of SMASH subjects vs. 15.8% of the SC group reached BP control (< 140/90 mmH) at month 1 (p < 0.001). At month 6, 94.4% of the SMASH vs. 41.2% of the SC group exhibited controlled BP (p < 0.003). Our findings provide encouraging evidence that efficacious mHealth, chronic disease, medical regimen, self management programs can be developed following principles of patient-centered, theory-guided design. PMID- 26593952 TI - Salivary Biomarkers in the Control of Mosquito-Borne Diseases. AB - Vector control remains the most effective measure to prevent the transmission of mosquito-borne diseases. However, the classical entomo-parasitological methods used to evaluate the human exposure to mosquito bites and the effectiveness of control strategies are indirect, labor intensive, and lack sensitivity in low exposure/transmission areas. Therefore, they are limited in their accuracy and widespread use. Studying the human antibody response against the mosquito salivary proteins has provided new biomarkers for a direct and accurate evaluation of the human exposure to mosquito bites, at community and individual levels. In this review, we discuss the development, applications and limits of these biomarkers applied to Aedes- and Anopheles-borne diseases. PMID- 26593953 TI - Objectifying "Pain" in the Modern Neurosciences: A Historical Account of the Visualization Technologies Used in the Development of an "Algesiogenic Pathology", 1850 to 2000. AB - Particularly with the fundamental works of the Leipzig school of experimental psychophysiology (between the 1850s and 1880s), the modern neurosciences witnessed an increasing interest in attempts to objectify "pain" as a bodily signal and physiological value. This development has led to refined psychological test repertoires and new clinical measurement techniques, which became progressively paired with imaging approaches and sophisticated theories about neuropathological pain etiology. With the advent of electroencephalography since the middle of the 20th century, and through the use of brain stimulation technologies and modern neuroimaging, the chosen scientific route towards an ever more refined "objectification" of pain phenomena took firm root in Western medicine. This article provides a broad overview of landmark events and key imaging technologies, which represent the long developmental path of a field that could be called "algesiogenic pathology." PMID- 26593955 TI - Chromosome biology: Moving a TAD closer to unravelling chromosome architecture. PMID- 26593959 TI - Regeneration of Thyroid Function by Transplantation of Differentiated Pluripotent Stem Cells. AB - Differentiation of functional thyroid epithelia from pluripotent stem cells (PSCs) holds the potential for application in regenerative medicine. However, progress toward this goal is hampered by incomplete understanding of the signaling pathways needed for directed differentiation without forced overexpression of exogenous transgenes. Here we use mouse PSCs to identify key conserved roles for BMP and FGF signaling in regulating thyroid lineage specification from foregut endoderm in mouse and Xenopus. Thyroid progenitors derived from mouse PSCs can be matured into thyroid follicular organoids that provide functional secretion of thyroid hormones in vivo and rescue hypothyroid mice after transplantation. Moreover, by stimulating the same pathways, we were also able to derive human thyroid progenitors from normal and disease-specific iPSCs generated from patients with hypothyroidism resulting from NKX2-1 haploinsufficiency. Our studies have therefore uncovered the regulatory mechanisms that underlie early thyroid organogenesis and provide a significant step toward cell-based regenerative therapy for hypothyroidism. PMID- 26593961 TI - Neuroanatomical correlates of attitudes toward suicide in a large healthy sample: A voxel-based morphometric analysis. AB - Previous studies have indicated that permissive attitudes toward suicide are positively associated with mental illness (e.g., depression and loneliness). Evidence suggests that there are abnormalities in the cognitive and brain functioning of suicidal patients. Nevertheless, there has been no evidence of the correlation between attitudes toward suicide and abnormal brain structure variations in healthy people. Therefore, in this study, we seek to investigate the neuroanatomical differences in healthy participants with regard to attitudes toward suicide. The results show that permissive attitudes toward suicide were significantly correlated with gray matter volume (GMV) in the left dorsolateral prefrontal cortex (DLPFC) and the left cerebellum in the large sample (n=405), which may be related to inefficient inhibitory control of negative emotion. Then, in a subset of healthy individuals with permissive attitudes (n=113), we also observed that stronger permissive attitudes toward suicide were positively related to the larger GMV in the left DLPFC and the left middle temporal gyrus (MTG), which may be associated with sensitivity of emotional feeling. Furthermore, loneliness had a mediating effect on the relation between the DLPFC volume and attitudes toward suicide. Taken together, neuroanatomical differences in healthy participants with permissive attitudes toward suicide may provide a better understanding of permissive attitudes toward suicide as a likely risk factor for suicidal behavior. PMID- 26593960 TI - Impairments in precision, rather than spatial strategy, characterize performance on the virtual Morris Water Maze: A case study. AB - Damage to the medial temporal lobes produces profound amnesia, greatly impairing the ability of patients to learn about new associations and events. While studies in rodents suggest a strong link between damage to the hippocampus and the ability to navigate using distal landmarks in a spatial environment, the connection between navigation and memory in humans remains less clear. Past studies on human navigation have provided mixed findings about whether patients with damage to the medial temporal lobes can successfully acquire and navigate new spatial environments, possibly due, in part, to issues related to patient demographics and characterization of medial temporal lobe damage. Here, we report findings from a young, high functioning patient who suffered severe medial temporal lobe damage. Although the patient is densely amnestic, her ability to acquire and utilize new, but coarse, spatial "maps" appears largely intact. Specifically, a novel computational analysis focused on the precision of her spatial search revealed a significant deficit in spatial precision rather than spatial search strategy. These findings argue that an intact hippocampus in humans is not necessary for representing multiple external landmarks during spatial navigation of new environments. We suggest instead that the human hippocampus may store and represent complex high-resolution bindings of features in the environment as part of a larger role in perception, memory, and navigation. PMID- 26593964 TI - SEX DIFFERENCES IN DIGIT RATIO (2D:4D) AMONG MILITARY AND CIVIL COHORTS AT A MILITARY ACADEMY IN WROCLAW, POLAND. AB - The ratio of second-to-fourth digit length (2D:4D), which is generally higher in women compared with men, is a putative marker of prenatal testosterone (PT) exposure. Lower 2D:4D is linked with greater physical ability and strength, better sporting performance and a propensity towards jobs demanding greater physical ability. The objectives of this paper were to examine the sexual dimorphism in 2D:4D in both hands 1and compare this dimorphism in the students of military and civil courses at the General Kusciuszko Military Academy of Land Forces in Wroclaw. The cross-sectional study compared 59 female and 118 male students from the military courses and 53 females and 64 male students from the civil courses. Besides calculating 2D:4D (2D/4D) for each hand, height and weight were also recorded. Physical fitness and endurance were assessed using Eurofit tests. Handgrip strength was measured using a standardized isometric dynamometer. In almost all physical tests, students in the military cohort showed highly significant greater physical ability and strength (e.g. handgrip strength) when compared with the civil cohort. Male participants had a significantly lower 2D:4D than females for each hand, as well as for the average value for both hands. The sexual dimorphism was, however, a little more pronounced in the right hand than in the left. Both sex and course type were significant predictors of 2D:4D. There were significant interactions between sex and the student type. Among females, but not in males, the military cohort had a significantly lower, i.e. more 'masculine', 2D:4D for the left hand and right hand and average for both hands (t=3.290, p<0.001) than the civil cohort. This was not the case in males. However, the sex difference in 2D:4D was only significant among the civil students, and not among the military cadets. In conclusion, higher PT exposure, as represented by a lower 2D:4D, among the Polish females might be an indicator of relatively increased physical ability and motivation to choose professions that require higher strength and endurance. PMID- 26593954 TI - Along the Axis between Type 1 and Type 2 Immunity; Principles Conserved in Evolution from Fish to Mammals. AB - A phenomenon already discovered more than 25 years ago is the possibility of naive helper T cells to polarize into TH1 or TH2 populations. In a simplified model, these polarizations occur at opposite ends of an "immune 1-2 axis" (i1-i2 axis) of possible conditions. Additional polarizations of helper/regulatory T cells were discovered later, such as for example TH17 and Treg phenotypes; although these polarizations are not selected by the axis-end conditions, they are affected by i1-i2 axis factors, and may retain more potential for change than the relatively stable TH1 and TH2 phenotypes. I1-i2 axis conditions are also relevant for polarizations of other types of leukocytes, such as for example macrophages. Tissue milieus with "type 1 immunity" ("i1") are biased towards cell mediated cytotoxicity, while the term "type 2 immunity" ("i2") is used for a variety of conditions which have in common that they inhibit type 1 immunity. The immune milieus of some tissues, like the gills in fish and the uterus in pregnant mammals, probably are skewed towards type 2 immunity. An i2-skewed milieu is also created by many tumors, which allows them to escape eradication by type 1 immunity. In this review we compare a number of i1-i2 axis factors between fish and mammals, and conclude that several principles of the i1-i2 axis system seem to be ancient and shared between all classes of jawed vertebrates. Furthermore, the present study is the first to identify a canonical TH2 cytokine locus in a bony fish, namely spotted gar, in the sense that it includes RAD50 and bona fide genes of both IL-4/13 and IL-3/ IL-5/GM-CSF families. PMID- 26593963 TI - Epstein-Barr virus from Burkitt Lymphoma biopsies from Africa and South America share novel LMP-1 promoter and gene variations. AB - Epstein Barr virus (EBV) sequence variation is thought to contribute to Burkitt lymphoma (BL), but lack of data from primary BL tumors hampers efforts to test this hypothesis. We directly sequenced EBV from 12 BL biopsies from Ghana, Brazil, and Argentina, aligned the obtained reads to the wild-type (WT) EBV reference sequence, and compared them with 100 published EBV genomes from normal and diseased people from around the world. The 12 BL EBVs were Type 1. Eleven clustered close to each other and to EBV from Raji BL cell line, but away from 12 EBVs reported from other BL-derived cell lines and away from EBV from NPC and healthy people from Asia. We discovered 23 shared novel nucleotide-base changes in the latent membrane protein (LMP)-1 promoter and gene (associated with 9 novel amino acid changes in the LMP-1 protein) of the 11 BL EBVs. Alignment of this region for the 112 EBV genomes revealed four distinct patterns, tentatively termed patterns A to D. The distribution of BL EBVs was 48%, 8%, 24% and 20% for patterns A to D, respectively; the NPC EBV's were Pattern B, and EBV-WT was pattern D. Further work is needed to investigate the association between EBV LMP 1 patterns with BL. PMID- 26593962 TI - Activated hepatic stellate cells promote angiogenesis via interleukin-8 in hepatocellular carcinoma. AB - BACKGROUND: Chemokines have been recognized as important modulators of angiogenesis, and they play critical roles in the development and metastasis of hepatocellular carcinoma (HCC), although their origins and latent molecular mechanisms remain elusive. The aim of this study was to investigate how activated hepatic stellate cells (a-HSCs) promote angiogenesis in HCC. METHODS: A total of 22 HCC patients were enrolled randomly. We used immunohistochemistry, western blotting, and enzyme-linked immunosorbent assay (ELISA) to analyse the production of interleukin-8 (IL-8) in a-HSCs derived from HCC tissues. The angiogenic effects of IL-8 in vitro and in vivo were assessed by ELISA, real-time quantitative polymerase chain reaction, capillary tube formation assay, and chick embryo chorioallantoic membrane assay. RESULTS: The present study showed that IL 8 was enriched predominantly in the tumour stroma of HCC tissues and was mainly derived from a-HSCs, rather than from hepatoma cells, in vivo and in vitro. Angiogenesis was most active at the invading edge, which was close to the a-HSCs. The angiogenic effect was dramatically attenuated by an IL-8 neutralizing antibody both in vitro and in vivo. Moreover, the IL-8 neutralizing antibody down regulated Ser727-phosphorylated STAT3 levels in hepatoma cells treated with a HSCs conditioned medium. CONCLUSIONS: These findings reveal that a-HSCs within the stroma of HCC contribute to tumour angiogenesis via IL-8. PMID- 26593965 TI - Floral trait evolution associated with shifts between insect and wind pollination in the dioecious genus Leucadendron (Proteaceae). AB - Transitions between animal and wind pollination have occurred in many lineages and have been linked to various floral modifications, but these have seldom been assessed in a phylogenetic framework. In the dioecious genus Leucadendron (Proteaceae), transitions from insect to wind pollination have occurred at least four times. Using analyses that controlled for relatedness among Leucadendron species, we investigated how these transitions shaped the evolution of floral structural and signaling traits, including the degree of sexual dimorphism in these traits. Pollen grains of wind-pollinated species were found to be smaller, more numerous, and dispersed more efficiently in wind than were those of insect pollinated species. Wind-pollinated species also exhibited a reduction in spectral contrast between showy subtending leaves and background foliage, reduced volatile emissions, and a greater degree of sexual dimorphism in color and scent. Uniovulate flowers and inflorescence condensation are conserved ancestral features in Leucadendron and likely served as exaptations in shifts to wind pollination. These results offer insights into the key modifications of male and female floral traits involved in transitions between insect and wind pollination. PMID- 26593966 TI - Simplified dead-time compensator for multiple delay SISO systems. AB - This paper presents a dead-time compensation structure able to deal with stable and unstable multiple delay single input single output (SISO) systems. The proposed method aims to simplify the primary controller by replacing it for FIR filters placed at the feedback path. Such modification reduces the total number of parameters to be tuned which facilitates the overall design in comparison with other primary controllers normally considered. Simulation results show a better performance for the proposed control approach compared with other dead-time compensator (DTC) recently proposed in the literature. PMID- 26593967 TI - Robust absolute stability criteria for uncertain Lurie interval time-varying delay systems of neutral type. AB - This study investigates the delay-dependent robust absolute stability analysis for uncertain Lurie systems with interval time-varying delays of neutral type. First, we divide the whole delay interval into two segmentations with an unequal width and checking the variation of the Lyapunov-Krasovskii functional (LKF) for each subinterval of delay, much less conservative delay-dependent absolute and robust stability criteria are derived. Second, a new delay-dependent robust stability condition for uncertain Lurie neutral systems with interval time varying delays, which expressed in terms of quadratic forms of linear matrix inequalities (LMIs), and has been derived by constructing the LKF from the delayed decomposition approach (DDA) and integral inequality approach (IIA). Finally, three numerical examples are given to show the effectiveness of the proposed stability criteria. PMID- 26593968 TI - On robust control of continuous-time systems with state-dependent uncertainties and its application to mechanical systems. AB - This paper revisits the problems of robust stability analysis and control of continuous-time systems with state-dependent uncertainties. First, a more general polytopic model describing systems with state-dependent uncertain parameters is proposed, and such a system model is more applicable in practice. A low conservative stability condition is obtained for the system by introducing the Lagrange multiplier term and adding some weight matrix variables. Then, based on our proposed idea, the output-feedback controllers will be designed in two cases: (1) the system matrices share the same polytopic parameters; (2) the system matrices do not share the same polytopic parameters. The controllers are designed in a model-dependent manner, which can provide more flexibilities in control synthesis. Besides, a decay rate can be set in advance to achieve better system performances. Finally, a numerical example together with a classic mechanical system is used to demonstrate the effectiveness and applicability of our theoretical findings. PMID- 26593969 TI - Resting Energy Expenditure and Body Composition of Women with Weight Regain 24 Months After Bariatric Surgery. AB - BACKGROUND: Weight regain 24 months after Roux-en-Y gastric bypass (RYGB) and low protein intake in patients without protein supplementation can favor fat-free mass loss and reduce resting energy expenditure (REE). We aimed to assess REE and its association with the body composition of women with weight regain and no protein supplementation in the late postoperative period of RYGB. METHODS: We determined the body mass index (BMI), REE by indirect calorimetry, body composition by tetrapolar bioelectrical impedance analysis, and energy intake by two 24-h recalls of 34 patients with at least 5 % of weight regain and no protein supplementation. The software SPSS v.17 analyzed the data calculating measures of central tendency and dispersion and using Pearson's correlation to test the association between the variables and the multivariate linear regression model at a p < 0.05 significance level. RESULTS: Postoperative period was positively associated with weight regain (r = 0.39; p = 0.023). The mean percentages of fat and fat-free masses were 45.1 +/- 8.3 % and 54.3 +/- 8.1 %, respectively. The mean REE was 1424.7 +/- 187.2 kcal (14 kcal/kg of the current weight), mean energy intake was 1258.6 +/- 454.3 kcal, and mean protein intake was 0.9 g/kg of the ideal weight +/- 0.3. Fat-free mass was positively associated with REE regardless of protein intake and postoperative period. CONCLUSIONS: Female bariatric patients with weight regain and no protein supplementation lose fat free mass, lowering their REE. Health practices that promote maintenance of BMI and body composition may lead to improved outcomes of bariatric surgery. PMID- 26593970 TI - Comparing variation in hospital rates of cesarean delivery among low-risk women using 3 different measures. AB - This report describes the development of a measure of low-risk cesarean delivery by the Society for Maternal-Fetal Medicine (SMFM). Safely lowering the cesarean delivery rate is a priority for maternity care clinicians and health care delivery systems. Therefore, hospital quality assurance programs are increasingly tracking cesarean delivery rates among low-risk pregnancies. Two commonly used definitions of "low risk" are available, the Joint Commission (JC) and the Agency for Healthcare Research and Quality (AHRQ) measures, but these measures are not clinically comprehensive. We sought to refine the definition of the low-risk cesarean delivery rate to enhance the validity of the metric for quality measurement. We created this refined definition-called the SMFM definition-and compared it to the JC and AHRQ measures using claims-based data from the 2011 Nationwide Inpatient Sample of >863,000 births in 612 hospitals. Using these definitions, we calculated means and interquartile ranges (25th-75th percentile range) for hospital low-risk cesarean delivery rates, stratified by hospital size, teaching status, urban/rural location, and payer mix. Across all hospitals, the mean low-risk cesarean delivery rate was lowest for the SMFM definition (12.65%), but not substantially different from the JC and AHRQ measures (13.12% and 13.29%, respectively). We empirically examined the SMFM definition to ensure its validity and utility. This refined definition performs similarly to existing measures and has the added advantage of clinical perspective, enhanced face validity, and ease of use. PMID- 26593971 TI - Telomere longitudinal shortening as a biomarker for dementia status of adults with Down syndrome. AB - Previous studies have suggested that Alzheimer's disease (AD) causes an accelerated shortening of telomeres, the ends of chromosomes consisting of highly conserved TTAGGG repeats that, because of unidirectional 5'-3' DNA synthesis, lose end point material with each cell division. Our own previous work suggested that telomere length of T-lymphocytes might be a remarkably accurate biomarker for "mild cognitive impairment" in adults with Down syndrome (MCI-DS), a population at dramatically high risk for AD. To verify that the progression of cognitive and functional losses due to AD produced this observed telomere shortening, we have now examined sequential changes in telomere length in five individuals with Down syndrome (3F, 2M) as they transitioned from preclinical AD to MCI-DS (N = 4) or dementia (N = 1). As in our previous studies, we used PNA (peptide nucleic acid) probes for telomeres and the chromosome 2 centromere (as an "internal standard" expected to be unaffected by aging or dementia status), with samples from the same individuals now collected prior to and following development of MCI-DS or dementia. Consistent shortening of telomere length was observed over time. Further comparisons with our previous cross-sectional findings indicated that telomere lengths prior to clinical decline were similar to those of other adults with Down syndrome (DS) who have not experienced clinical decline while telomere lengths following transition to MCI-DS or dementia in the current study were comparable to those of other adults with DS who have developed MCI-DS or dementia. Taken together, findings indicate that telomere length has significant promise as a biomarker of clinical progression of AD for adults with DS, and further longitudinal studies of a larger sample of individuals with DS are clearly warranted to validate these findings and determine if and how factors affecting AD risk also influence these measures of telomere length. PMID- 26593972 TI - Dietary supplementation of a mixture of Lactobacillus strains enhances performance of broiler chickens raised under heat stress conditions. AB - High ambient temperature is a major problem in commercial broiler production in the humid tropics because high producing broiler birds consume more feed, have higher metabolic activity, and thus higher body heat production. To evaluate the effects of two previously isolated potential probiotic strains (Lactobacillus pentosus ITA23 and Lactobacillus acidophilus ITA44) on broilers growing under heat stress condition, a total of 192 chicks were randomly allocated into four treatment groups of 48 chickens each as follows: CL, birds fed with basal diet raised in 24 degrees C; PL, birds fed with basal diet plus 0.1 % probiotic mixture raised in 24 degrees C; CH, birds fed with basal diet raised in 35 degrees C; and PH, birds fed with basal diet plus 0.1 % probiotic mixture raised in 35 degrees C. The effects of probiotic mixture on the performance, expression of nutrient absorption genes of the small intestine, volatile fatty acids (VFA) and microbial population of cecal contents, antioxidant capacity of liver, and fatty acid composition of breast muscle were investigated. Results showed that probiotic positively affected the final body weight under both temperature conditions (PL and PH groups) compared to their respective control groups (CL and CH). Probiotic supplementation numerically improved the average daily gain (ADG) under lower temperature, but significantly improved ADG under the higher temperature (P < 0.05) by sustaining high feed intake. Under the lower temperature environment, supplementation of the two Lactobacillus strains significantly increased the expression of the four sugar transporter genes tested (GLUT2, GLUT5, SGLT1, and SGLT4) indicating probiotic enhances the absorption of this nutrient. Similar but less pronounced effect was also observed under higher temperature (35 degrees C) condition. In addition, the probiotic mixture improved bacterial population of the cecal contents, by increasing beneficial bacteria and decreasing Escherichia coli population, which could be because of higher production of VFA in the cecum, especially at heat stress condition. The two Lactobacillus strains also improved the fatty acid profile of meat, including at heat stress. Generally, the two Lactobacillus strains can be considered as good potential probiotics for chickens due to their good probiotic properties and remarkable efficacy on broiler chickens. PMID- 26593973 TI - Changes in coagulation during therapeutic hypothermia in cardiac arrest patients. AB - AIM: Therapeutic hypothermia improves neurological outcome in patients resuscitated after out-of-hospital cardiac arrest. The aim was to investigate whether therapeutic hypothermia induced impaired coagulation. METHODS: Changes in coagulation were investigated in 22 out-of-hospital cardiac arrest patients treated with therapeutic hypothermia (33 +/- 1 degrees C). Blood samples were obtained after 22 +/- 2h of hypothermia and compared with normothermic samples drawn 48 h later. The coagulation was evaluated with thromboelastometry (ROTEM((r))) using a sensitive low-tissue-factor assay. Leukocytes, haemoglobin, haematocrit, platelet count, activated partial thromboplastin time (aPTT), thrombin time, international normalised ratio (INR) and fibrinogen were also measured. Clinical information including use of anti thrombotic drugs was systematically collected. RESULTS: No significant changes were found in clotting time (p=0.21), clot formation time (p=0.26), time to maximum velocity (p=0.52) or maximum velocity (p=0.17) when results obtained at hypothermia were compared with results obtained at normothermia. Maximum clot firmness (p<0.01) and fibrinogen levels (p<0.01) were significantly higher in patients at normothermia. However, the fibrinogen levels were within the reference interval for all patients at both hypothermia and normothermia. Values of aPTT, thrombin time and INR at hypothermia and normothermia were not significantly different. CONCLUSIONS: No substantial difference in coagulation was found in hypothermia compared with normothermia in out-of-hospital cardiac arrest patients. The results indicate that treatment with hypothermia does not impair coagulation. CLINICALTRIALS IDENTIFIER: NCT02179021. PMID- 26593975 TI - Reversible Photoisomerization of Spiropyran on the Surfaces of Au25 Nanoclusters. AB - Au25 nanoclusters functionalized with a spiropyran molecular switch are synthesized via a ligand-exchange reaction at low temperature. The resulting nanoclusters are characterized by optical and NMR spectroscopies as well as by mass spectrometry. Spiropyran bound to nanoclusters isomerizes in a reversible fashion when exposed to UV and visible light, and its properties are similar to those of free spiropyran molecules in solution. The reversible photoisomerization entails the modulation of fluorescence as well as the light-controlled self assembly of nanoclusters. PMID- 26593974 TI - Control of developmentally primed erythroid genes by combinatorial co-repressor actions. AB - How transcription factors (TFs) cooperate within large protein complexes to allow rapid modulation of gene expression during development is still largely unknown. Here we show that the key haematopoietic LIM-domain-binding protein-1 (LDB1) TF complex contains several activator and repressor components that together maintain an erythroid-specific gene expression programme primed for rapid activation until differentiation is induced. A combination of proteomics, functional genomics and in vivo studies presented here identifies known and novel co-repressors, most notably the ETO2 and IRF2BP2 proteins, involved in maintaining this primed state. The ETO2-IRF2BP2 axis, interacting with the NCOR1/SMRT co-repressor complex, suppresses the expression of the vast majority of archetypical erythroid genes and pathways until its decommissioning at the onset of terminal erythroid differentiation. Our experiments demonstrate that multimeric regulatory complexes feature a dynamic interplay between activating and repressing components that determines lineage-specific gene expression and cellular differentiation. PMID- 26593976 TI - The Clinic for Assessment of Youth at Risk (CAYR): 10 years of service delivery and research targeting the prevention of psychosis in Montreal, Canada. AB - AIM: In the context of an increasing focus on indicated prevention of psychotic disorders, we describe the operation of the Clinic for Assessment of Youth at Risk (CAYR) over 10 years, a specialized service for identification, monitoring and treatment of young individuals who meet ultra-high risk (UHR) criteria for psychosis, and its integration within the Prevention and Early Intervention Program for Psychosis (PEPP) in Montreal, Canada. METHODS: We outline rationale, development, inclusion and exclusion criteria, assessment, services offered, community outreach and liaison with potential referral sites, and our research focus on risk and protective factors related to the neural diathesis-stress model of psychosis. RESULTS: Between January 2005 and December 2014, CAYR has received 370 referrals and accepted 177 patients who met UHR criteria based on the Comprehensive Assessment for At Risk Mental States. Conversion rates to a first episode of psychosis were 11%. Our research findings point to high subjective stress levels, poor self-esteem, social support and coping skills, and a dysregulation of the hypothalamus-pituitary-adrenal axis during the high-risk phase. CONCLUSIONS: Our efforts at community outreach have resulted in increasing numbers of referrals and patients accepted to CAYR, highlighting the relevance of and need for a high-risk programme in the Montreal area. Patients with psychotic symptoms can be immediately assigned to the first-episode psychosis clinic within PEPP, which has likely contributed to the low conversion rates observed in the UHR group. Our research findings on stress and protective factors emphasize the importance of psychosocial interventions for high-risk patients. PMID- 26593977 TI - Assessment of the activity of directly acting antivirals and other products against different genotypes of hepatitis C virus prevalent in resource-poor countries. AB - Certain food additives and drugs used for other indications have been shown to inhibit in vitro replication of HCV and have been proposed as cheap options for the treatment of HCV infections in resource-poor countries. We here report that the in vitro anti-HCV (genotypes 1a, 1b, 2a and 4b) activity of nitazoxanide, silymarin, silibinin and the green tea extract EGCG is very weak when compared to directly acting antivirals. HCV-infected patients in resource-poor countries should receive the best possible treatment (if possible via expanded access programs); it is therefore advisable not to plan clinical studies with drugs/compounds with weak anti-HCV activity. PMID- 26593978 TI - Respiratory syncytial virus infection in macaques is not suppressed by intranasal sprays of pyrimidine biosynthesis inhibitors. AB - There is imperious need for efficient therapies against ubiquitous and life threatening respiratory viruses, foremost among them being the human respiratory syncytial virus (hRSV). Several research groups who performed functional screens for broad-spectrum antivirals identified compounds targeting the de novo pyrimidine biosynthesis pathway. Despite their strong antiviral activity in vitro, whether such antimetabolites are effective in vivo remains highly controversial. Here, we evaluated two potent pyrimidine biosynthesis inhibitors developed in our laboratory, IPPA17-A04 and GAC50, in a model of mild hRSV infection in cynomolgus macaques. In this model, hRSV replication is restricted to the epithelium of the upper respiratory tract, and is compatible with a topical treatment by intranasal sprays. The local administration of palivizumab, a neutralizing anti-hRSV antibody used in clinics, significantly reduced virus replication. In contrast, pyrimidine biosynthesis inhibitors did not show any inhibitory effect on hRSV growth when delivered topically as experimented in our model. Our results should help to better define the potential applications of this class of antimetabolites in the treatment of viral infections. PMID- 26593979 TI - Identification of a small-molecule inhibitor of influenza virus via disrupting the subunits interaction of the viral polymerase. AB - Assembly of the heterotrimeric influenza virus polymerase complex from the individual subunits PB1, PA, and PB2 is a prerequisite for viral replication, in which the interaction between the C terminal of PA (PAC) and the N-terminal of PB1 (PB1N) may be a desired target for antiviral development. In this study, we compared the feasibility of high throughput screening by enzyme-linked immunosorbent assay (ELISA) and fluorescence polarization assay. Among the two, ELISA was demonstrated to own broader dynamic range so that it was used for screening inhibitors that blocked PAC and PB1N interaction. Several binding inhibitors of PAC-PB1N were identified and subsequently tested for the antiviral efficacy. Apparently, 3-(2-chlorophenyl)-6-ethyl-7-methyl[1,2,4]triazolo[4,3 a]pyrimidin-5-ol, designated ANA-1, was found to be a strong inhibitor of viral polymerase activity and act as a potent antiviral agent against the infections of multiple subtypes of influenza A virus, including H1N1, H3N2, H5N1, H7N7, H7N9 and H9N2 subtypes, in cell cultures. Intranasal administration of ANA-1 protected mice from lethal challenge and reduced lung viral loads in H1N1 virus infected BALB/c mice. Docking analyses predicted that ANA-1 bound to an allosteric site of PAC, which might cause conformational changes thereby disrupting the PAC-PB1N interaction. Overall, our study has identified a novel compound with potential to be developed as an anti-influenza drug. PMID- 26593980 TI - A novel H6N1 virus-like particle vaccine induces long-lasting cross-clade antibody immunity against human and avian H6N1 viruses. AB - Avian influenza A(H6N1) virus is one of the most common viruses isolated from migrating birds and domestic poultry in many countries. The first and only known case of human infection by H6N1 virus in the world was reported in Taiwan in 2013. This led to concern that H6N1 virus may cause a threat to public health. In this study, we engineered a recombinant H6N1 virus-like particle (VLP) and investigated its vaccine effectiveness compared to the traditional egg-based whole inactivated virus (WIV) vaccine. The H6N1-VLPs exhibited similar morphology and functional characteristics to influenza viruses. Prime-boost intramuscular immunization in mice with unadjuvanted H6N1-VLPs were highly immunogenic and induced long-lasting antibody immunity. The functional activity of the VLP elicited IgG antibodies was proved by in vitro seroprotective hemagglutination inhibition and microneutralization titers against the homologous human H6N1 virus, as well as in vivo viral challenge analyses which showed H6N1-VLP immunization significantly reduced viral load in the lung, and protected against human H6N1 virus infection. Of particular note, the H6N1-VLPs but not the H6N1 WIVs were able to confer cross-reactive humoral immunity; antibodies induced by H6N1-VLP vaccine robustly inhibited the hemagglutination activities and in vitro replication of distantly-related heterologous avian H6N1 viruses. Furthermore, the H6N1-VLPs were found to elicit significantly greater anti-HA2 antibody responses in immunized mice than H6N1-WIVs. Collectively, we demonstrated for the first time a novel H6N1-VLP vaccine that effectively provides broadly protective immunity against both human and avian H6N1 viruses. These results, which uncover the underlying mechanisms for induction of wide-range immunity against influenza viruses, may be useful for future influenza vaccine development. PMID- 26593981 TI - Generating a long DNA fragment of the target ncRNA for quantitative polymerase chain reaction by combining ncRNA-oligos hybridization and oligos ligation. AB - The poor reproducibility of the reverse transcription combined with quantitative polymerase chain reaction (RT-qPCR) results in an unacceptable reliability of publications based on these data. We established a novel method, in which two short complementary DNA oligos were hybridized with target ncRNA molecules and linked by DNA ligase to obtain a long DNA strand (HL-DNA) replacing cDNA for qPCR detection (HL-qPCR). A series of diluted samples prepared from the same total RNA resource were measured by HL-qPCR and RT-qPCR respectively to acquire their relative concentration of RNU4-1, AK026510 and SNORA73B. For every tested sample, the relative concentration of RNU4-1, AK026510 and SNORA73B obtained by HL-qPCR instead of RT-qPCR is closer to its corresponding true value without significant difference, demonstrating that HL-qPCR exhibits higher accuracy compared with RT qPCR. With three independent repeats, no significant difference was observed among AK026510/RNU4-1 values of four samples diluted from the same RNA resource, by employing HL-qPCR but not RT-qPCR. It strongly suggests that the good reproducibility of HL-qPCR results from the stable efficiency of HL-DNA production regardless of the concentration and individual features of ncRNA. The novel HL-qPCR could be applied for the regular relative ncRNA concentration detection in the future. PMID- 26593982 TI - Carbon monoxide stunning of Atlantic salmon (Salmo salar L.) modifies rigor mortis and sensory traits as revealed by NIRS and other instruments. AB - BACKGROUND: Methods of stunning used in salmon slaughter are still the subject of research. Fish quality can be influenced by pre-, ante- and post-mortem conditions, including handling before slaughter, slaughter methods and storage conditions. Carbon monoxide (CO) is known to improve colour stability in red muscle and to reduce microbial growth and lipid oxidation in live fish exposed to CO. Quality differences in Atlantic salmon, Salmo salar L., stunned by CO or percussion, were evaluated and compared by different techniques [near infrared reflectance spectroscopy (NIRS), electronic nose (EN), electronic tongue (ET)] and sensory analysis. RESULTS: Thawed samples, freeze-dried preparates and NIRS devices proved to be the most efficient combinations for discriminating the treatments applied to salmon, i.e. first the stunning methods adopted, then the back-prediction of the maximum time to reach rigor mortis and finally to correlate some sensory attributes. A trained panel found significant differences between control and CO-stunned salmon: reduced tactile crumbliness, reduced odour and aroma intensities, and reduced tenderness of CO-treated fillets. CO stunning reduced radiation absorbance in spectra of thawed and freeze-dried fillets, but not fillet samples stored in ethanol, where it may have interacted with myoglobin and myosin. CONCLUSIONS: The good results in a rapid discrimination of thawed samples detected by NIRS suggest suitable applications in the fish industry. CO treatment could mitigate sensory perception, but consumer tests are needed to confirm our findings. (c) 2015 Society of Chemical Industry. PMID- 26593983 TI - Genetic, Epigenetic and Biological Effects of Zinc Transporter (SLC30A8) in Type 1 and Type 2 Diabetes. AB - Zinc is essential for the proper storage, secretion and action of insulin, while solute carrier family 30 members (SLC30A8) transports Zinc from cytoplasm to insulin secretory granules in the pancreatic beta-cells. Accumulating genetic studies have demonstrated that the common single nucleotide polymorphisms in the SLC30A8 gene confer the risk susceptibility to type 2 diabetes. The rare loss-of function variants in the gene, however, may have protective effects in the disease. SLC30A8 is highly expressed in the pancreas, particularly in the islets of Langerhans. Clinical investigations have implicated that SLC30A8 acts as a new antigenic target in the patients with type 1 diabetes. Biological experimental evidence has indicated that this gene expression at both mRNA and protein levels is down-regulated in diabetic pancreatic islets. Furthermore, epigenetic analysis showed that DNA methylation levels in the SLC30A8 gene are increased in type 2 diabetes patients, which complies with the decreased gene expression. In this review, biological relevance and bioinformatics of Zinc transport SLC30A8 are described. Genetic and epigenetic effects of the SLC30A8 gene in type 1 and type 2 diabetes are summarized. Further investigation of SLC30A8 interactions with Zinc and other functional partners is discussed. PMID- 26593984 TI - Molecular Links Between Diabetes and Osteoarthritis: The Role of Physical Activity. AB - BACKGROUND: Diabetes mellitus (DM) and osteoarthritis (OA) are two of the most relevant and common chronic diseases affecting older people. Both DM and OA are considered metabolic diseases due to their high correlation with the capacity of the body to metabolize some nutritive substances such as glucose, fat, vitamins and also the response to oxidative molecules. METHODS: We searched PubMed, Scopus, Google Scholar, and authors' bibliographies in order to extract articles regarding the relationship between DM and OA. OBJECTIVE: The main purpose of this review is to investigate the molecules involved in the onset and progression of both DM and OA and the beneficial role of physical activity. RESULTS: The main focus is on the importance of glucose metabolism and its derivatives in the pathogenesis of OA and DM. Advanced glycation end-product (AGEs), sorbitol and diacylglycerol (DAG) are glucose derivatives which promote the activation of several pathways, most of them involved in the activation of inflammatory processes. The possible link between DM and OA is represented by the inflammatory process deriving from the increased expression of pro-inflammatory cytokines. Moreover, we investigated the biological mechanisms and the clinical findings that confirm a beneficial effect of physical activity in both DM and OA. CONCLUSION: Thus a tailored and adapted physical activity can be used in the treatment of both diseases as a part of a correct and healthy lifestyle. For this reason we strongly suggest the scientific community to introduce mild physical activity as part of our lifestyle to prevent metabolism diseases and osteoarthritis. PMID- 26593985 TI - Efficient anti-tumor effect of photodynamic treatment with polymeric nanoparticles composed of polyethylene glycol and polylactic acid block copolymer encapsulating hydrophobic porphyrin derivative. AB - To develop potent and safer formulation of photosensitizer for cancer photodynamic therapy (PDT), we tried to formulate hydrophobic porphyrin derivative, photoprotoporphyrin IX dimethyl ester (PppIX-DME), into polymeric nanoparticles composed of polyethylene glycol and polylactic acid block copolymer (PN-Por). The mean particle size of PN-Por prepared was around 80nm and the zeta potential was determined to be weakly negative. In vitro phototoxicity study for PN-Por clearly indicated the significant phototoxicity of PN-Por for three types of tumor cells tested (Colon-26 carcinoma (C26), B16BL6 melanoma and Lewis lung cancer cells) in the PppIX-DME concentration-dependent fashion. Furthermore, it was suggested that the release of PppIX-DME from PN-Por would gradually occur to provide the sustained release of PppIX-DME. In vivo pharmacokinetics of PN-Por after intravenous administration was evaluated in C26 tumor-bearing mice, and PN Por exhibited low affinity to the liver and spleen and was therefore retained in the blood circulation for a long time, leading to the efficient tumor disposition of PN-Por. Furthermore, significant and highly effective anti-tumor effect was confirmed in C26 tumor-bearing mice with the local light irradiation onto C26 tumor tissues after PN-Por injection. These findings indicate the potency of PN Por for the development of more efficient PDT-based cancer treatments. PMID- 26593986 TI - Morphological and histological changes in eye lens: Possible application for estimating postmortem interval. AB - Establishing the postmortem interval is a very complex problem in Forensic Science despite the existence of several macro- and microscopic methods. In the case of ocular methods, most are based on an evaluation of the biochemical components of the vitreous humour 24-36h after death, but, to our knowledge, there are no studies on the relationship between lens and the postmortem interval. Since the lens is protected between the vitreous humour and the aqueous humour inside the eyeball, postmortem changes are assumed to start later in the lens. To evaluate the usefulness of using the lens to establish the postmortem interval, we examined 80 rabbit lens enucleated 24, 48, 72 and 96h after death, assessing changes in sphericity and absorbance at different wavelengths and any histological alterations. Both sphericity and absorbance were seen to decrease to a statistically significant extent, and there was a gradual loss of structure and organisation of the lens components as a function of the postmortem interval. Modifications in the lens were seen to be useful for determining the postmortem interval between 24 and 96h. PMID- 26593987 TI - Epithelioid hemangiomas arising in the coronary artery and right ventricle: A case report. AB - Epithelioid hemangioma (EH) is a benign vascular lesion. It is generally found in the dermis, subcutis, and rarely in visceral organs. We identified incidental EHs of the right coronary artery and right ventricle during an autopsy of Japanese female whose cause of death was liver cirrhosis. The tumor of the coronary artery originated from the tunica media of the artery and proliferated into the intima and out of the vascular wall. It resulted in marked luminal narrowing of approximately 50%-75% stenosis. However, no evidence of myocardial ischemia was found. Cardiac EH is rare and this is the first report of EH arising in the coronary artery, to our knowledge. PMID- 26593988 TI - Evaluating the genetic impact of South and Southeast Asia on the peopling of Bangladesh. AB - Despite rapidly growing understandings and dependency on single nucleotide polymorphisms (SNPs), highly variable autosomal short tandem repeats (STRs) are still regarded as the most established method to differentiate individuals at forensic level. Here with large number of various ethnic groups we undertook this study to reveal the genetic structure of the most densely populated part of South Asia i.e. the Bangladesh. The purpose of this work was to estimate population parameters based on the allele frequencies obtained for 15 polymorphic autosomal STR loci investigated in caste and tribal populations from Bangladesh (n=706). We compared the results in a broader context by merging 24 different populations of Asia to pertain their affinity. Various statistical analyses suggested a clear cut demarcation of tribal and non-tribal in Bangladesh. Moreover, beside the phylogenetic structure of the studied populations, it is found that the mean heterozygosity value was highest among the populations of Bangladesh, likely because of gene flow from different directions. However, Tonchangya, Adi and Khumi showed sign of genetic isolation and reduced diversity, possibly as a result of genetic drift and/or strong founder effects working on small endogamous populations. PMID- 26593989 TI - An objective approach using three indexes for determining fatal hypothermia due to cold exposure; statistical analysis of oxyhemoglobin saturation data. AB - Analysis of oxyhemoglobin (O2-Hb) saturation levels in the left and right heart blood is useful in the assessment of exposure to cold surroundings before death. We quantified conventional subjective visual evaluation of O2-Hb saturation levels and developed useful diagnostic criteria for fatal hypothermia: O2-Hb saturation in the left heart blood (L-O2Hb) was ?36%, the O2-Hb saturation gap between the left and right heart blood (L-R gap) was ?13%, and the O2-Hb saturation ratio of the left to right heart blood (L/R ratio) was ?1.8. When we used L-O2Hb of ?36% as a basic criterion and applied a further criterion of an L R gap of ?13% or an L/R ratio of ?1.8, these criteria registered a sensitivity level of ?86% and specificity level of ?93% for the diagnosis of fatal hypothermia. This method can be useful for determining fatal hypothermia in connection with conventional autopsy findings, as well as histological and biochemical markers. PMID- 26593990 TI - Variations of midline facial soft tissue thicknesses among three skeletal classes in Central Anatolian adults. AB - Facial reconstruction is a technique employed in a forensic investigation as a last resort to recreate an individual's facial appearance from his/her skull. Forensic anthropologists or artists use facial soft tissue thickness (FSTT) measurements as a guide in facial reconstructions. The aim of this study was to develop FSTT values for Central Anatolian adults, taking into consideration sex and skeletal classes; first, to achieve better results obtaining the likenesses of deceased individuals in two or three-dimensional forensic facial reconstructions and, second, to compare these values to existing databases. Lateral cephalograms were used to determine FSTT values at 10 midline facial landmarks of 167 adults. Descriptive statistics were calculated for these facial soft tissue thickness values, and these values were compared to those reported in two other comparable databases. The majority of the landmarks showed sex-based differences. Males were found to have significantly larger landmark values than female subjects. These results point not only to the necessity to present data in accordance with sexual dimorphism, but also the need to consider that individuals from different geographical areas have unique facial features and that, as a result, geographical population-specific FSTT values are required. PMID- 26593991 TI - Analysis of 30 insertion-deletion polymorphisms in the Japanese population using the Investigator DIPplex(r) kit. AB - Allele frequencies and forensic parameters for 30 insertion-deletion polymorphisms (INDELs) were investigated in a sample of 251 unrelated Japanese individuals using the Investigator DIPplex(r) kit (QIAGEN). The frequency distributions showed no deviations from Hardy-Weinberg equilibrium expectations. The combined powers of discrimination and match probability for the 30 INDELs were 0.9999999998 and 2.67*10(-11), respectively. To assess the effectiveness of the kit in typing degraded DNA, an ancient bone sample of a Jomon skeleton was analyzed; most of 30 INDELs and amelogenin were typed successfully. We concluded that the kit offers considerable potential for personal identification from degraded DNA samples due to the small amplicon length and high degree of polymorphisms. PMID- 26593992 TI - Characterization of cellular and extracellular DNA in saliva. AB - Although the presence of extracellular DNA in various body fluids was discovered long ago, only recently has it begun to attract attention for examining the genetic profiles of individuals in forensics studies. However, information on extracellular DNA is scarce. Among human body fluids, saliva is known to be rich in extracellular DNA. In this study, to analyze the possibility of identifying individuals and body fluids by using only extracellular DNA of saliva, we investigated the amount, size distribution, short tandem repeat (STR) profile, and methylation pattern of extracellular DNA from saliva and compared these with those of cellular DNA. The amount and size distribution of extracellular DNA was different from that of cellular DNA. However, their respective STR profiles were the same. The methylation patterns of the BCAS4 gene were different among donors, but no significant difference was observed between cellular and extracellular DNA. The results of our study suggest that identification of individuals and body fluids from saliva may be possible without the need for cells. PMID- 26593993 TI - Comprehensive investigation of postmortem glucose levels in blood and body fluids with regard to the cause of death in forensic autopsy cases. AB - The serum glucose level is regulated within a narrow range by multiple factors under physiological conditions, but is greatly modified in the death process and after death. The present study comprehensively investigated glucose levels in blood and body fluids, including pericardial fluid (PCF), cerebrospinal fluid (CSF) and vitreous humor, reviewing forensic autopsy cases (n=672). Right heart blood glucose level was often higher than at other sites, and the CSF glucose level was the lowest, showing greater dissociation in acute/subacute death cases. The glucose level was higher in the diabetic (high HbA1c) than in the non diabetic (low HbA1c) group at each site (p<0.01-0.0001). Fatal diabetic ketoacidosis cases had evidently high glucose levels at each site; whereas in the non-diabetic group, blood glucose level was higher in fatal alcohol abuse, saltwater drowning, electrocution, cerebrovascular disease and sudden cardiac death due to ischemic heart disease. Fatal methamphetamine (MA) abuse, sepsis, malnutrition (starvation) and hypoglycemia due to antidiabetics showed markedly lower blood glucose levels. Ketones in bilateral cardiac blood and PCF were increased in diabetic ketoacidosis and fatal alcohol abuse as well as in most cases of hyperthermia (heatstroke), hypothermia (cold exposure) and malnutrition. These findings suggest that combined analysis of glucose, HbA1c and ketones in blood and body fluids is useful to investigate not only fatal diabetic metabolic disorders but also death processes due to other causes, including alcohol and MA abuse, as well as thermal disorders, sepsis and malnutrition. PMID- 26593994 TI - Estimation of stature from radiologic anthropometry of the lumbar vertebral dimensions in Chinese. AB - The recent study was to assess the relationship between the radiologic anthropometry of the lumbar vertebral dimensions and stature in Chinese and to develop regression formulae to estimate stature from these dimensions. A total of 412 normal, healthy volunteers, comprising 206 males and 206 females, were recruited. The linear regression analysis were performed to assess the correlation between the stature and lengths of various segments of the lumbar vertebral column. Among the regression equations created for single variable, the predictive value was greatest for the reconstruction of stature from the lumbar segment in both sexes and subgroup analysis. When individual vertebral body was used, the heights of posterior vertebral body of L3 gave the most accurate results for male group, the heights of central vertebral body of L1 provided the most accurate results for female group and female group with age above 45 years, the heights of central vertebral body of L3 gave the most accurate results for the groups with age from 20-45 years for both sexes and the male group with age above 45 years. The heights of anterior vertebral body of L5 gave the less accurate results except for the heights of anterior vertebral body of L4 provided the less accurate result for the male group with age above 45 years. As expected, multiple regression equations were more successful than equations derived from a single variable. The research observations suggest lumbar vertebral dimensions to be useful in stature estimation among Chinese population. PMID- 26593995 TI - Polymorphism analysis of 15 STR loci in a large sample of Guangdong (Southern China) Han population. AB - AmpFlSTR Sinofiler PCR Amplification Kit is specially developed for Chinese forensic laboratories, but there are little population-genetic data about this kit for Southern China. This kit contains 15 STR loci: D8S1179, D21S11, D7S820, CSF1PO, D3S1358, D13S317, D16S539, D2S1338, D19S433, vWA, D18S51, D6S1043, D12S391, D5S818 and FGA. We have conducted genotyping experiments on the 15 STR loci in 5234 unrelated individuals from Guangdong (Southern China). We observed a total of 243 alleles in the group with the allelic frequency values ranging from less than 0.0001 to 0.3686. Our statistic analysis indicates that the 15 STR loci conform to the Hardy-Weinberg's equilibrium (p>0.05). The highest polymorphism was found at D6S1043 locus and the lowest was found at D3S1358. The combined power of discrimination reached 0.99999999999999999977431 and the combined probability of paternity exclusion reached 0.999999721 for 15 STR loci. Guangdong Han population had significant differences compared with Shaanxi, Shandong and Henan province of Northern China. A Neighbor-joining tree indicates that the Guangdong Han has a close genetic relationship with the Yunnan population. Significant differences were found between Guangdong Han population and other reported populations (Japanese, Philippine, African American, Caucasian, Hispanic and Western Romanian) at 2-11 STR loci. The results may provide useful information for forensic sciences and population genetics studies. The present findings indicate that all the 15 STR loci are highly genetically polymorphic in the Han population of Guangdong. PMID- 26593996 TI - Postmortem magnetic resonance imaging: Reproducing typical autopsy heart measurements. AB - PURPOSE: The aim of this study was to evaluate the utility of cardiac postmortem magnetic resonance (PMMR) to perform routine measurements of the ventricular wall thicknesses and the heart valves and to assess if imaging measurements are consistent with traditional autopsy measurements. METHODS: In this retrospective study, 25 cases with cardiac PMMR and subsequent autopsy were included. The thicknesses of the myocardial walls as well as the circumferences of all heart valves were measured on cardiac PMMR and compared to autopsy measurements. Paired samples T-test and the Wilcoxon-Signed rank test, were used to compare autopsy and cardiac PMMR measurements. For exploring correlations, the Pearson's Correlation coefficient and the Spearman's Rho test were used. RESULTS: Cardiac PMMR measurements of the aortic and pulmonary valve circumferences showed no significant differences from autopsy measurements. The mitral and tricuspid valves circumferences differed significantly from autopsy measurements. Left myocardial and right myocardial wall thickness also differed significantly from autopsy measurements. Left and right myocardial wall thickness, and tricuspid valve circumference measurements on cardiac PMMR and autopsy, correlated strongly and significantly. CONCLUSION: Several PMMR measurements of cardiac parameters differ significantly from corresponding autopsy measurements. However, there is a strong correlation between cardiac PMMR measurements and autopsy measurements in the majority of these parameters. It is important to note that myocardial walls are thicker when measured in situ on cardiac PMMR than when measured at autopsy. Investigators using post-mortem MR should be aware of these differences in order to avoid false diagnoses of cardiac pathology based on cardiac PMMR. PMID- 26593997 TI - Evaluation of the on-site immunoassay drug-screening device Triage-TOX in routine forensic autopsy. AB - Instrumental identification of drugs with quantification is essential in forensic toxicology, while on-site immunoassay urinalysis drug-screening devices conveniently provide preliminary information when adequately used. However, suitable or sufficient urine specimens are not always available. The present study evaluated the efficacy of a new on-site immunoassay drug-screening device Triage-TOX (Alere Inc., San Diego, CA, USA), which has recently been developed to provide objective data on the one-step automated processor, using 51 urine and 19 pericardial fluid samples from 66 forensic autopsy cases, compared with Triage Drug of Abuse (DOA) and Monitect-9. For benzodiazepines, the positive predictive value and specificity of Triage-TOX were higher than those of Triage-DOA; however, sensitivity was higher with Monitect-9, despite frequent false positives. The results for the other drugs with the three devices also included a few false-negatives and false-positives. These observations indicate the applicability of Triage-TOX in preliminary drug screening using urine or alternative materials in routine forensic autopsy, when a possible false-negative is considered, especially for benzodiazepines, providing objective information; however, the combined use of another device such as Monitect-9 can help minimize misinterpretation prior to instrumental analysis. PMID- 26593998 TI - The effects of acid and alkaline solutions on cut marks and on the structure of bone: An experimental study on porcine ribs. AB - Among taphonomical modifications during decomposition processes, little is known about the action of high or low pH to human tissues and bones. Moreover, acid or basic solutions are seldom used to ease decomposition and wrecking of the body. In this study a total of 60 samples of porcine bones on which two cut marks were produced before the beginning of the experiment, were put in six different solutions with different pH (1, 3, 5, 9, 12, 14) and analyzed every five days over a period of 70 days. Surveys were carried out macroscopically, with stereomicroscopy and with light microscopy on thin sections. Only the specimens exposed to extremely acid (<1) or basic (>12) pH showed evident modifications of the bone's structure, as witnessed by the analyses with stereomicroscopy as well. Many samples showed a detachment of the periosteum; cut marks became soon unrecognizable with pH 14 but still detectable in all the other samples. The information gained from the present study can be of great help in detecting the exposure of human tissues to high or low environmental pH and in understanding the effects that these solutions can exert on human bones. PMID- 26593999 TI - A silent allele in the locus D5S818 contained within the PowerPlex(r)21 PCR Amplification Kit. AB - Three paternity tests cases were found with a single locus mismatch at the locus D5S818 with PowerPlex(r)21 PCR Amplification Kit (Promega). Forward and reverse primers were redesigned to type the samples again and to evaluate if there were alleles dropped out. The results showed the existence of a silent allele 12 in all the three families, due to a point mutation that changed cytosine to adenine at 90 nucleotides upstream from the 5' end of the AGAT repeat sequences in all the six individuals. A single locus mismatch due to a silent allele may occur in any locus using any kit. Therefore, we recommend using multiple kits to confirm the results in paternity testing cases with mismatches, especially when there is a single locus mismatch with homozygote involved. PMID- 26594000 TI - Strangulation--Suicide at the wheel. AB - In cases of suicide at the wheel mostly velocity is used to cause death by a single occupant vehicle crash against a fixed roadside object or collision with other vehicles. A further well known mode of death is e.g. carbon monoxide poisoning. In the recent years several cases of vehicle assisted ligature strangulation resulting even in decapitation have been reported. However, cars are also used in rare cases just as places for a suicide by hanging or ligature strangulation. Not only forensic pathologists but also police officers have to be aware of this rare type of suicide to avoid unnecessary investigations. PMID- 26594001 TI - Multiple infectious pseudoaneurysms: An autopsy case. AB - A 47-year-old Japanese woman died unexpectedly 11 days after admission due to acute cerebellar infarction. The patient had a history of Sjogren syndrome with long-term steroid therapy, hypertension, thalamic infarction and amphetamine psychosis. Multiple pseudoaneurysms in both the aorta and coronary artery were found at autopsy, and one located in the aortic root had ruptured into the pericardium resulting in sudden unexpected death. The detailed examination suggested that the pseudoaneurysms resulted from microbial infection to the arterial wall via the vasa vasorum. Immunosuppression induced by the long-term steroid therapy and abused drug injection could have influenced the formation of pseudoaneurysms. PMID- 26594002 TI - Possibility of visualization of gastrothorax based on unenhanced postmortem computed tomography/PMCT. AB - We present a fatal case of a gastrothorax due to an acute gastric volvulus resulting from a Bochdalek hernia. A 5-year-old boy without previous medical history was brought to our institution in a state of cardiopulmonary arrest and was subsequently pronounced dead. Postmortem computed tomography (PMCT) of the torso showed abdominal organs involving the lower section of the esophagus up to the entire stomach, the left side of the transverse colon, the entire spleen, and the tail of the pancreas herniated into the left thoracic cavity. The stomach was markedly expanded and a mesentero-axial (rotation along the short axis) volvulus was observed, displacing mediastinal structures to the right side and depressing the diaphragmatic contour. A PMCT of the thorax at the lung window setting revealed displacement of bilateral lungs. The bilateral lungs were severely atelectatic and congested. The PMCT findings mentioned above were consistent with the autopsy findings. PMCT can provide useful information for the diagnosis in cases we initially cannot predict any significant changes, for example, organ displacement. PMID- 26594003 TI - Right ventricular free wall dissection as a rupture tract in left ventricular rupture during acute myocardial infarction. AB - Three rare cases of cardiac rupture with right ventricular wall dissection during acute myocardial infarction (AMI) were reported. The cases comprised 2% among our 148 previously reported postinfarction cardiac ruptures with sudden death. The dissections occurred in hearts with biventricular inferior wall AMI and developed between the superficial layers and the deeper layers of inferior wall of the right ventricle. All had an endocardial tear at the basal septum where it meets the inferior free wall of the left ventricle, and had an epicardial tear on the middle inferior wall of the right ventricle. Based on the evidence of the ages of the thrombi of the rupture tracts, delayed epicardial rupture was found besides that soon after the right ventricular dissection. PMID- 26594004 TI - An autopsy case of death due to metabolic acidosis after citric acid ingestion. AB - A man in his 40s was found unconscious on a sofa in a communal residence for people with various disabilities. He appeared to have drunk 800 ml of undiluted citric acid from a commercial plastic bottle. The instructions on the label of the beverage specified that the beverage be diluted 20- to 30-fold before consumption. The patient was admitted to an emergency hospital with severe metabolic acidosis (pH, 6.70; HCO3(-), 3.6 mEq/L) and a low ionized calcium level (0.73 mmol/L). Although ionized calcium and catecholamines were continuously administered intravenously to correct the acidosis, the state of acidemia and low blood pressure did not improve, and he died 20 h later. Citric acid concentrations in the patient's serum drawn shortly after treatment in the hospital and from the heart at autopsy were 80.6 mg/ml and 39.8 mg/dl, respectively (normal range: 1.3-2.6 mg/dl). Autopsy revealed black discoloration of the mucosal surface of the esophagus. Microscopically, degenerated epithelium and neutrophilic infiltration in the muscle layer were observed. In daily life, drinking a large amount of concentrated citric acid beverage is rare as a cause of lethal poisoning. However, persons with mental disorders such as dementia may mistakenly drink detergent or concentrated fluids, as in our case. Family members or facility staff in the home or nursing facility must bear in mind that they should not leave such bottles in places where they are easily accessible to mentally handicapped persons. PMID- 26594005 TI - Non specific drug distribution in an autopsy case report of fatal caffeine intoxication. AB - Caffeine has long been recognized as an addictive substance that causes autonomic nerve effect, and is known to increase catecholamine secretion from the adrenal glands. In recent years, the risk of ingesting toxic levels of caffeine has increased because of the easy availability of analgesics, CNS (Central Nervous System) stimulant medicine and dietary supplements at shops, health stores and through online purchases. We report the death of a young female resulting from the ingestion for suicide of an online purchased sleepiness-preventing medicine containing caffeine. The autopsy findings included pulmonary edema and congestion plus cutaneous emphysema. The stomach contents included a dark-brown viscous fluid without tablet or food residue. Toxicological examination revealed the presence of caffeine in the right heart blood (154.2 MUg/mL) and stomach contents (197.5 MUg/mL) (lethal blood level, >80 MUg/mL). The highest caffeine content was in the bile (852.3 MUg/mL). Biochemical findings showed that catecholamine concentration in the peripheral blood in the iliac vein was elevated. Immunostaining of catecholamine was weak in the adrenal medulla. We recommend highlighting the toxicity risk of ingesting substances with a high caffeine concentration, and we propose that caffeine concentrations should be included in the comprehensive routine forensic toxicological tests for all cases. PMID- 26594006 TI - Should states and local governments regulate dietary supplements? AB - Federal regulation of dietary supplements in the United States is governed by the Dietary Supplement Health and Education Act of 1994. The law has been criticized as weak and ineffective. Alarming research has emerged demonstrating that supplements may be mislabelled, contaminated, adulterated with dangerous or unknown compounds, or sold at toxic doses. As a result, the health community has raised concerns about the safety and quality of dietary supplements. Increased federal oversight is an important avenue for improving supplement safety; however, states and local governments may also pursue strategies to strengthen the overall regulatory control of dietary supplements. States and local governments have substantial experience in regulating other products that pose a risk to public health, such as tobacco. Additionally, much has been learned about the tactics the tobacco industry has employed to protect its interests. Lessons learned may be applied to new regulatory efforts aimed at improving the safety of dietary supplements at the state and local levels. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26594007 TI - Differential gene expression patterns between smokers and non-smokers: cause or consequence? AB - The molecular mechanisms causing smoking-induced health decline are largely unknown. To elucidate the molecular pathways involved in cause and consequences of smoking behavior, we conducted a genome-wide gene expression study in peripheral blood samples targeting 18 238 genes. Data of 743 smokers, 1686 never smokers and 890 ex-smokers were available from two population-based cohorts from the Netherlands. In addition, data of 56 monozygotic twin pairs discordant for ever smoking were used. One hundred thirty-two genes were differentially expressed between current smokers and never smokers (P < 1.2 * 10-6 , Bonferroni correction). The most significant genes were G protein-coupled receptor 15 (P < 1 * 10-150 ) and leucine-rich repeat neuronal 3 (P < 1 * 10-44 ). The smoking related genes were enriched for immune system, blood coagulation, natural killer cell and cancer pathways. By taking the data of ex-smokers into account, expression of these 132 genes was classified into reversible (94 genes), slowly reversible (31 genes), irreversible (6 genes) or inconclusive (1 gene). Expression of 6 of the 132 genes (three reversible and three slowly reversible) was confirmed to be reactive to smoking as they were differentially expressed in monozygotic pairs discordant for smoking. Cis-expression quantitative trait loci for GPR56 and RARRES3 (downregulated in smokers) were associated with increased number of cigarettes smoked per day in a large genome-wide association meta analysis, suggesting a causative effect of GPR56 and RARRES3 expression on smoking behavior. In conclusion, differential gene expression patterns in smokers are extensive and cluster in several underlying disease pathways. Gene expression differences seem mainly direct consequences of smoking, and largely reversible after smoking cessation. However, we also identified DNA variants that may influence smoking behavior via the mediating gene expression. PMID- 26594009 TI - Copper nanoclusters trigger muscle cell apoptosis and atrophy in vitro and in vivo. AB - Copper nanoclusters (CuNCs) are increasingly being used in nanomedicine owing to their utility in cellular imaging and as catalysts. Additionally, nanotoxicology research of CuNCs is gaining attention. We report here the synthesis and characterization of CuNCs and their cytotoxic impact on muscle cells. A simple protein-directed synthesis of stable CuNCs was prepared, using bovine serum albumin as the stabling agent. Physicochemical characterization of the synthesized CuNCs was performed using transmission electron microscopy. To evaluate the in vitro cytotoxicity, C2C12 cells were exposed to increasing doses (from 0.1 to 50 ug ml(-1)) of CuNCs. CuNCs affected the viability of C2C12 cells in a dose-dependent manner, as detected by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide and a lactate dehydrogenase release assay. Further studies indicated that CuNCs induced the formation of reactive oxygen species and decreased the activities of catalase and glutathione. CuNC treatment decreased the mitochondrial membrane potential and induced apoptosis, accompanied by an increase in the protein expression ratio of Bax/Bcl-2 and caspase-3/9 activity in C2C12 cells. CuNCs treatment resulted in atrophy of the C2C12 myotubes, which was characterized by the increased expression of atrophy-related genes, such as atrogin-1 and MuRF1. Finally, CuNCs induce morphological atrophy of primary muscle cells and mouse gastrocnemius muscle. Taken together, these results suggest that exposure to CuNCs may be a risk factor for the skeletal muscle system. PMID- 26594010 TI - Cancer-related hair loss: a selective review of the alopecia research literature. AB - OBJECTIVE: Alopecia is a common side effect of cancer treatment, affecting approximately 65% of patients. Healthcare providers and allied staff recognize that alopecia is distressing for people with cancer; however, they are often unaware of the extent of distress or the great efforts expended by patients to cope with hair loss. This study reviews the existing literature regarding the psychosocial impact of alopecia on cancer survivors and the coping strategies they use to manage hair loss. METHODS: We searched for studies examining the psychosocial effects of alopecia on cancer survivors using PubMed and PsycInfo databases and Google Scholar. RESULTS: A total of 36 peer-reviewed articles were deemed relevant to be included in this review. In this review, alopecia was consistently ranked as one of the most distressing side effects of cancer treatment. Survivors report that hair loss disrupts how they experience their bodies, interact with others, and conceptualize their body image beyond treatment. Although upsetting for both genders, the scarce literature that exists suggests that there may be some gender-specific aspects of experiencing cancer related hair loss. Cancer survivors cope with alopecia in numerous ways and often rely on strategies such as concealment, social support, social avoidance, information seeking, and behavioral rehearsal. CONCLUSIONS: Treatment-induced alopecia negatively affects millions of survivors each year in unique and nuanced ways. We hope that survivors' healthcare providers and loved ones may better appreciate the psychosocial challenges they experience related to hair loss, as well as the strategies they use to cope. Further research is much needed to better understand cancer-related alopecia. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26594011 TI - A seventeen-year observation of the antimicrobial susceptibility of clinical Campylobacter jejuni and the molecular mechanisms of erythromycin-resistant isolates in Beijing, China. AB - OBJECTIVES: To investigate the dynamic development of the antimicrobial resistance of Campylobacter jejuni isolated from human diarrhea in Beijing, China, between 1994 and 2010, and to further analyze the molecular mechanisms of erythromycin-resistant strains. METHODS: Susceptibility tests were performed on 203 non-duplicate clinical C. jejuni strains against eight common antibiotics using the standard agar dilution method. The molecular determinants were further studied in the erythromycin (ERY) non-susceptible strains. The analysis focused on the 23S rRNA gene, the rplD and rplV ribosomal genes, the ermB gene, and the regulatory region of the CmeABC efflux pump. RESULTS: The rates of resistance of C. jejuni to ciprofloxacin (CIP), nalidixic acid (NAL), doxycycline (DOX), tetracycline (TET), florfenicol (FFC), and chloramphenicol (CHL) increased significantly over the period studied (all p<0.05). Similarly, the proportions of resistant patterns (CIP-NAL-DOX-TET, CIP-NAL-DOX-TET-FFC, and CIP-NAL-DOX-TET CHL) increased remarkably. In this study, 4.4% (9/203) of C. jejuni strains were ERY non-susceptible. The A2075G mutation in the 23S rRNA was found in all of the resistant strains except cj8091, which harbored the ermB gene. Interestingly, the ermB gene was also detected in intermediately resistant isolates, and the earliest ermB-positive strain cj94473 was derived in 1994. Moreover, none of the ribosomal rplD or rplV genes harbored mutations that have been described to confer resistance to macrolides. Different mutations affecting the regulatory region of the CmeABC efflux pump were also found. CONCLUSIONS: This is the first comprehensive study on the recent trend in antimicrobial resistance and the molecular mechanisms of macrolide resistance in clinical C. jejuni strains isolated in China. More stringent monitoring and regulation of human and animal antimicrobial use are warranted. PMID- 26594012 TI - Impacts of neglected tropical disease on incidence and progression of HIV/AIDS, tuberculosis, and malaria: scientific links. AB - The neglected tropical diseases (NTDs) are the most common infections of humans in Sub-Saharan Africa. Virtually all of the population living below the World Bank poverty figure is affected by one or more NTDs. New evidence indicates a high degree of geographic overlap between the highest-prevalence NTDs (soil transmitted helminths, schistosomiasis, onchocerciasis, lymphatic filariasis, and trachoma) and malaria and HIV, exhibiting a high degree of co-infection. Recent research suggests that NTDs can affect HIV and AIDS, tuberculosis (TB), and malaria disease progression. A combination of immunological, epidemiological, and clinical factors can contribute to these interactions and add to a worsening prognosis for people affected by HIV/AIDS, TB, and malaria. Together these results point to the impacts of the highest-prevalence NTDs on the health outcomes of malaria, HIV/AIDS, and TB and present new opportunities to design innovative public health interventions and strategies for these 'big three' diseases. This analysis describes the current findings of research and what research is still needed to strengthen the knowledge base of the impacts NTDs have on the big three. PMID- 26594013 TI - Why is Pakistan a threat to "The Polio Eradication and Endgame Strategic Plan 2013-2018"? A look into the past decade. PMID- 26594014 TI - The rest of the story of the patient described in the letter to the editors: 'Hypersensitivity to amoxicillin after... (DRESS) to carbamazepine...: a possible co-sensitization'. PMID- 26594015 TI - Plasmonic Surfaces for Cell Growth and Retrieval Triggered by Near-Infrared Light. AB - Methods for efficient detachment of cells avoiding damage are required in tissue engineering and regenerative medicine. We introduce a bottom-up approach to build plasmonic substrates using micellar block copolymer nanolithography to generate a 2D array of Au seeds, followed by chemical growth leading to anisotropic nanoparticles. The resulting plasmonic substrates show a broad plasmon band covering a wide part of the visible and near-infrared (NIR) spectral ranges. Both human and murine cells were successfully grown on the substrates. A simple functionalization step of the plasmonic substrates with the cyclic arginylglycylaspartic acid (c-RGD) peptide allowed us to tune the morphology of integrin-rich human umbilical vein endothelial cells (HUVEC). Subsequent irradiation with a NIR laser led to highly efficient detachment of the cells with cell viability confirmed using the MTT assay. We thus propose the use of such plasmonic substrates for cell growth and controlled detachment using remote near IR irradiation, as a general method for cell culture in biomedical applications. PMID- 26594016 TI - Gold- or Silver-Catalyzed Syntheses of Pyrones and Pyridine Derivatives: Mechanistic and Synthetic Aspects. AB - 3-Oxo-5-alkynoic acid esters, on treatment with a carbophilic catalyst, undergo 6 endo-dig cyclization reactions to furnish either 2-pyrones or 4-pyrones in high yields. The regiochemical course can be dialed in by the proper choice of the alcohol part of the ester and the pi-acid. This transformation is compatible with a variety of acid-sensitive groups as witnessed by a number of exigent applications to the total synthesis of natural products, including pseudopyronine A, hispidine, phellinin A, the radininol family, neurymenolide, violapyrone, wailupemycin and an unnamed brominated 4-pyrone of marine origin. Although the reaction proceeds well in neutral medium, the rate is largely increased when HOAc is used as solvent or co-solvent, which is thought to favor the protodeauration of the reactive alkenyl-gold intermediates as the likely rate-determining step of the catalytic cycle. Such intermediates are prone to undergo diauration as an off cycle event that sequesters the catalyst; this notion is consistent with literature data and supported by the isolation of the gem-diaurated complexes 12 and 15. Furthermore, silver catalysis allowed access to be gained to 2 alkoxypyridine and 2-alkoxyisoquinoline derivatives starting from readily available imidate precursors. PMID- 26594017 TI - Blood transmission studies of prion infectivity in the squirrel monkey (Saimiri sciureus): the Baxter study. AB - BACKGROUND: Four secondary transmissions of variant Creutzfeldt-Jakob disease (vCJD) infectivity have been associated with the transfusion of nonleukoreduced red blood cells collected from vCJD patients during the asymptomatic phase of the disease. Establishing efficient experimental models for assessing the risk of future transmissions of vCJD infectivity via blood transfusion is of paramount importance in view of a study of archived appendix samples in which the prevalence of asymptomatic vCJD infection in the United Kingdom was estimated at approximately 1 in 2000 of the population. In this study, we investigated transmission of vCJD and sporadic CJD (sCJD) infectivity from blood using the squirrel monkey, which is highly susceptible to experimental challenge with human prion disease. STUDY DESIGN AND METHODS: Whole blood collected from vCJD- and sCJD-infected squirrel monkeys was transfused at multiple time points into recipient squirrel monkeys. Blood recipients were euthanized approximately 7 years after their first blood transfusion. RESULTS: No clinical or pathologic signs of a prion disease were observed in either the sCJD- or the vCJD-transfused monkeys, and immunohistochemistry and biochemical investigations showed no PrP(TSE) in central nervous system or lymphoreticular tissues. Similarly, monkeys inoculated intracerebrally (IC) and intravenously (IV) with either buffy coat or plasma from vCJD and sCJD patients failed to develop disease. However, white blood cells from a chimpanzee-passaged strain of human Gerstmann-Straussler Scheinker (GSS) disease transmitted autopsy-proven disease to two IC-inoculated monkeys after incubation periods of 34 and 39 months. CONCLUSION: Blood transmits GSS but not sCJD or vCJD infectivity to IC- or IV-inoculated squirrel monkeys within a 7-year observation period. PMID- 26594019 TI - A Theoretical review of cognitive biases and deficits in obsessive-compulsive disorder. AB - During the past 30 years, experimental psychopathologists have conducted many studies aiming to elucidate the cognitive abnormalities that may figure in the etiology and maintenance of OCD. In this paper, we review research on both dysfunctional beliefs and cognitive deficits in OCD, as findings from both traditional self-report and information-processing approaches provide distinct sources of information concerning cognitive abnormalities. First, we discuss dysfunctional beliefs and metacognitive beliefs implicated in the disorder. Research has identified a number of maladaptive appraisals (e.g., heightened responsibility) and metacognitive beliefs (e.g., need to control one's thoughts) that are associated with the disorder, yet these are not invariably present in all cases of OCD. Next, we review the literature on memory and attentional deficits and biases in OCD. This line of research shows inconsistent evidence for deficits in memorial and attentional processes, but does indicate that people with the disorder have memory and attention biases that may be related to metacognitive beliefs about their ability to remember and attend to stimuli. Finally, we discuss recent work that suggests that people with OCD have reduced access to internal states, thus causing them to engage in rituals to resolve persistent uncertainty. Implications and future directions are discussed. PMID- 26594018 TI - Ixodes scapularis dystroglycan-like protein promotes Borrelia burgdorferi migration from the gut. AB - The causative agent of Lyme borreliosis, Borrelia burgdorferi, is transmitted by Ixodes ticks. During tick feeding, B. burgdorferi migrates from the tick gut to the salivary glands from where transmission to the host occurs. B. burgdorferi interacting tick proteins might serve as vaccine targets to thwart B. burgdorferi transmission. A previous screening for B. burgdorferi-interacting Ixodes scapularis gut proteins identified an I. scapularis putative dystroglycan protein (ISCW015049). Here, we describe the ISCW015049's protein structure and its cellular location in the tick gut in relation to B. burgdorferi migration. Secondly, in vivo B. burgdorferi-tick attachment murine models were performed to study the role of ISCW015049 during B. burgdorferi migration and transmission. In silico analysis confirmed that ISCW015049 is similar to dystroglycan and was named I. scapularis dystroglycan-like protein (ISDLP). Confocal microscopy of gut tissue showed that ISDLP is expressed on the surface of gut cells, is upregulated during tick feeding, and is expressed significantly higher in infected ticks compared to uninfected ticks. Inhibition of ISDLP by RNA interference (RNAi) resulted in lower B. burgdorferi transmission to mice. In conclusion, we have identified a dystroglycan-like protein in I. scapularis gut that can bind to B. burgdorferi and promotes B. burgdorferi migration from the tick gut. Key messages: B. burgdorferi exploits tick proteins to orchestrate its transmission to the host. B. burgdorferi is able bind to an I. scapularis dystroglycan-like protein (ISDLP). Inhibition of ISDLP in ticks results in lower B. burgdorferi transmission to mice. ISDLP is a potential target to prevent Lyme borreliosis. PMID- 26594020 TI - Mitochondrial genome of Ogmocotyle sikae and implications for phylogenetic studies of the Notocotylidae trematodes. AB - Ogmocotyle spp. (Trematoda: Digenea: Notocotylidae) are neglected but important trematodes that can infect numerous mammal species, causing significant economic losses to livestock industries. However, there have been few studies on the molecular ecology of these trematodes. We amplified and sequenced the complete mitochondrial (mt) genome of Ogmocotyle sikae (14,307 bp). The gene content and gene arrangement of O. sikae mt genome was similar to that of Dicrocoelium chinensis, except that trnE and trnG were reversed. Phylogenetic analysis of O. sikae and selected parasites using Bayesian inference was performed based on concatenated amino acid sequence datasets conceptually translated from the 12 protein-coding genes. The results indicated that the family Notocotylidae is related to the family Paramphistomatidae. Our description of O. sikae mt genome provides a significant resource of molecular markers for future comparative studies of the Notocotylidae and other trematodes. PMID- 26594021 TI - Substrate specificities of cutinases on aliphatic-aromatic polyesters and on their model substrates. AB - The enzymatic hydrolysis of the biodegradable polyester ecoflex and of a variety of oligomeric and polymeric ecoflex model substrates was investigated. For this purpose, substrate specificities of two enzymes of typical compost inhabitants, namely a fungal cutinase from Humicola insolens (HiC) and a bacterial cutinase from Thermobifida cellulosilytica (Thc_Cut1) were compared. Model substrates were systematically designed with variations of the chain length of the alcohol and the acid as well as with varying content of the aromatic constituent terephthalic acid (Ta). HPLC/MS identification and quantification of the hydrolysis products terephthalic acid (Ta), benzoic acid (Ba), adipic acid (Ada), mono(4 hydroxybutyl) terephthalate (BTa), mono-(2-hydroxyethyl) terephthalate (ETa), mono-(6-hydroxyhexyl) terephthalate (HTa) and bis(4-hydroxybutyl) terephthalate (BTaB) indicated that these enzymes indeed hydrolyze the tested esters. Shorter terminal chain length acids but longer chain length alcohols in oligomeric model substrates were generally hydrolyzed more efficiently. Thc_Cut1 hydrolyzed aromatic ester bonds more efficiently than HiC resulting in up to 3-fold higher concentrations of the monomeric hydrolysis product Ta. Nevertheless, HiC exhibited a higher overall hydrolytic activity on the tested polyesters, resulting in 2-fold higher concentration of released molecules. Thermogravimetry and differential scanning calorimetry (TG-DSC) of the polymeric model substrates revealed a general trend that a lower difference between melting temperature (Tm) and the temperature at which the enzymatic degradation takes place resulted in higher susceptibility to enzymatic hydrolysis. PMID- 26594022 TI - Enhancing the sensitivity of a micro-diaphragm resonating sensor by effectively positioning the mass on the membrane. AB - The detection of biomarkers in the liquid phase using mechanical sensors is difficult because of noise caused by the liquid. To reduce and verify the side effects of liquid loading, we performed calculations and experiments to determine the shift in resonant frequency according to the loading conditions. A 2-MUm thick piezoelectric rectangular micro-diaphragm with a 500 * 500 MUm membrane was used. These dimensions were determined such that there would be an analogous resonant frequency shift ratio in both (1, 1) and (2, 2) modes. By calculating and measuring the resonant frequency, we verified that the resonant frequency of the sensor would change only through contact with the liquid, even the resonant frequency change by only liquid much higher than the changes caused by the nanoparticles. The real signal constituted only 0.017% of the initial resonant frequency. To enhance the sensitivity by reducing the unexpected surface stress in the liquid, the liquid was dropped onto the surface of the micro-diaphragm. This resulted in an improvement of more than 10 times the sensitivity in both modes. In addition, by controlling the position in the micro-diaphragm resonating sensor, more sensitive positions with large displacements were determined according to each mode. PMID- 26594023 TI - Evaluation of Anatomical and Functional Hip Joint Center Methods: The Effects of Activity Type, Gender, and Proximal Reference Segment. AB - Accurate hip joint center (HJC) location is critical when studying hip joint biomechanics. The HJC is often determined from anatomical methods, but functional methods are becoming increasingly popular. Several studies have examined these methods using simulations and in vivo gait data, but none has studied high-range of motion activities, such a chair rise, nor has HJC prediction been compared between males and females. Furthermore, anterior superior iliac spine (ASIS) marker visibility during chair rise can be problematic, requiring a sacral cluster as an alternative proximal segment; but functional HJC has not been explored using this approach. For this study, the quality of HJC measurement was based on the joint gap error (JGE), which is the difference in global HJC between proximal and distal reference segments. The aims of the present study were to: (1) determine if JGE varies between pelvic and sacral referenced HJC for functional and anatomical methods, (2) investigate which functional calibration motion results in the lowest JGE and if the JGE varies depending on movement type (gait versus chair rise) and gender, and (3) assess whether the functional HJC calibration results in lower JGE than commonly used anatomical approaches and if it varies with movement type and gender. Data were collected on 39 healthy adults (19 males and 20 females) aged 14-50 yr old. Participants performed four hip "calibration" tests (arc, cross, star, and star-arc), as well as gait and chair rise (activities of daily living (ADL)). Two common anatomical methods were used to estimate HJC and were compared to HJC computed using a published functional method with the calibration motions above, when using pelvis or sacral cluster as the proximal reference. For ADL trials, functional methods resulted in lower JGE (12-19 mm) compared to anatomical methods (13-34 mm). It was also found that women had significantly higher JGE compared to men and JGE was significantly higher for chair rise compared to gait, across all methods. JGE for sacrum referenced HJC was consistently higher than for the pelvis, but only by 2.5 mm. The results indicate that dynamic hip range of movement and gender are significant factors in HJC quality. The findings also suggest that a rigid sacral cluster for HJC estimation is an acceptable alternative for relying solely on traditional pelvis markers. PMID- 26594025 TI - The impact of new generic formulations of imatinib mesylate on general quality of life in chronic phase chronic myeloid leukaemia patients. AB - Treatment with tyrosine kinase inhibitors (TKIs) has dramatically changed the life expectancy of chronic myeloid leukaemia (CML) patients. Although the impact of first-generation TKIs on quality of life (QoL) was shown in CML, the effects of new generic formulations of imatinib mesylate (IM) are unclear. We evaluated differences in QoL under treatment with first- or second-generation TKIs. Fifty two patients diagnosed with CP-CML completed the European Organization for Research and Treatment of Cancer Quality of Life Questionaire-C30, Hospital Anxiety and Depression Scale, and General Health Questionnaire. General QoL scores were similar between groups. There was a significant difference in the frequency of diarrhoea between IM group and the group using new generic formulations of IM (P = 0.012). General QoL score tended to be higher in patients with disease duration longer than 3 years (P = 0.052). GHQ, anxiety and depression scores correlated positively with symptom scales and negatively with functional subscales.CML patients using new generic formulations of IM reported a higher frequency of diarrhoea than patients using original IM and second generation TKIs that could result in more drug discontinuation. PMID- 26594024 TI - Bone marrow mesenchymal stem cell aggregate: an optimal cell therapy for full layer cutaneous wound vascularization and regeneration. AB - Cutaneous wounds are among the most common soft tissue injuries. Wounds involving dermis suffer more from outside influence and higher risk of chronic inflammation. Therefore the appearance and function restoration has become an imperative in tissue engineering research. In this study, cell-aggregates constructed with green fluorescent protein-expressing (GFP(+)) rat bone marrow mesenchymal stem cells (BMMSCs) were applied to rat acute full-layer cutaneous wound model to confirm its pro-regeneration ability and compare its regenerative efficacy with the currently thriving subcutaneous and intravenous stem cell administration strategy, with a view to sensing the advantages, disadvantages and the mechanism behind. According to results, cell-aggregates cultured in vitro enjoyed higher expression of several pro-healing genes than adherent cultured cells. Animal experiments showed better vascularization along with more regular dermal collagen deposition for cell-aggregate transplanted models. Immunofluorescence staining on inflammatory cells indicated a shorter inflammatory phase for cell-aggregate group, which was backed up by further RT PCR. The in situ immunofluorescence staining manifested a higher GFP(+)-cell engraftment for cell-aggregate transplanted models versus cell administered ones. Thus it is safe to say the BMMSCs aggregate could bring superior cutaneous regeneration for full layer cutaneous wound to BMMSCs administration, both intravenous and subcutaneous. PMID- 26594026 TI - An in vitro biorelevant gastrointestinal transfer (BioGIT) system for forecasting concentrations in the fasted upper small intestine: Design, implementation, and evaluation. AB - PURPOSE: Design an in vitro methodology for studying gastrointestinal transfer in the fasted state and implement the methodology in vitro by using a biorelevant gastrointestinal transfer system(BioGIT); evaluate the usefulness of BioGIT in predicting luminal concentrations of lipophilic weak bases in the fasted upper small intestine. METHODS: The methodology was designed after modeling existing luminal data. Its implementation in vitro was based on a three compartment setup. Reproducibility of the transfer process was evaluated under conditions where solutions and/or suspensions were present in gastric and/or duodenal compartment and by using ranitidine, dipyridamole, ketoconazole, and posaconazole as model drugs. The transfer process as well as concentrations of dipyridamole, ketoconazole and posaconazole measured in the duodenal compartment were compared with data previously collected in the upper small intestine, after administration of identical preparations/dosage forms to fasted adults. RESULTS: Using BioGIT, the transfer process was performed reproducibly in all cases (RSD b 12.9%); data with dipyridamole and ketoconazole were in line with luminal data in humans. Dipyridamole, ketoconazole and posaconazole concentrations in duodenal compartment were also in line with previously measured concentrations in the fasted upper small intestine of healthy adults. CONCLUSIONS: BioGIT system could be useful for the evaluation of the impact of gastrointestinal transfer on concentrations in the upper intestinal lumen during the first hour, after oral administration of dispersing/solution dosage forms of lipophilic weak bases. PMID- 26594027 TI - Enteric-coated tablet of risedronate sodium in combination with phytic acid, a natural chelating agent, for improved oral bioavailability. AB - The oral bioavailability (BA) of risedronate sodium (RS), an antiresorptive agent, is less than 1% due to its low membrane permeability as well as the formation of non-absorbable complexes with multivalent cations such as calcium ion (Ca(2+)) in the gastrointestinal tract. In the present study, to increase oral BA of the bisphosphonate, a novel enteric-coated tablet (ECT) dosage form of RS in combination with phytic acid (IP6), a natural chelating agent recognized as safe, was formulated. The chelating behavior of IP6 against Ca(2+), including a stability constant for complex formulation was characterized using the continuous variation method. Subsequently, in vitro dissolution profile and in vivo pharmacokinetic profile of the novel ECT were evaluated comparatively with that of the marketed product (Altevia, Sanofi, US), an ECT containing ethylenediaminetetraacetic acid (EDTA) as a chelating agent, in beagle dogs. The logarithm of stability constant for Ca(2+)-IP6 complex, an equilibrium constant approximating the strength of the interaction between two chemicals to form complex, was 19.05, which was 3.9-fold (p<0.05) and 1.7-fold (p<0.05) higher than those of Ca(2+)-RS and Ca(2+)-EDTA complexes. The release profile of RS from both enteric-coated dosage forms was equivalent, regardless of the type of chelating agent. An in vivo absorption study in beagle dogs revealed that the maximum plasma concentration and area under the curve of RS after oral administration of IP6-containing ECT were approximately 7.9- (p<0.05) and 5.0-fold (p<0.05) higher than those of the marketed product at the same dose (35mg as RS). Therefore, our study demonstrates the potential usefulness of the ECT system in combination with IP6 for an oral therapy with the bisphosphonate for improved BA. PMID- 26594029 TI - Reaction between HN and SN: a possible channel for the interstellar formation of N2 and SH in the cold interstellar clouds. AB - Using computational calculations the potential energy surface (PES) of the reaction between NH and NS has been analysed. The PES of the reaction shows the formation of two very stable species, HNSN and HNNS. Out of these two, HNNS which has the signature N-N linkage was found to be the most stable species in the PES. In view of the highly exothermic nature of the reaction surface, it has been proposed that these two species can possibly be detected in the interstellar space. For the first time it has also been shown that the reaction between the NH and NS can lead to the possible formation of N2via the isomer HNNS, and how the effect of tunnelling can make this reaction very much feasible, even under the extremely low temperature conditions prevailing in the interstellar medium. Based on the already reported results, a similar kind of behaviour for the NH + NO reaction surface has also been proposed. These dissociation reactions leading to the formation of N2 can be considered as potential secondary contributing channels while accounting for the total estimates of N2 in the interstellar medium, and thus HNNS as well as HNNO can be considered as stable reservoir molecules for interstellar N2. Besides the formation of N2, the formation of another astronomically important radical, SH in the cold interstellar clouds, has also been proposed. PMID- 26594028 TI - Probing the Lipid Annular Belt by Gas-Phase Dissociation of Membrane Proteins in Nanodiscs. AB - Interactions between membrane proteins and lipids are often crucial for structure and function yet difficult to define because of their dynamic and heterogeneous nature. Here, we use mass spectrometry to demonstrate that membrane protein oligomers ejected from nanodiscs in the gas phase retain large numbers of lipid interactions. The complex mass spectra that result from gas-phase dissociation were assigned using a Bayesian deconvolution algorithm together with mass defect analysis, allowing us to count individual lipid molecules bound to membrane proteins. Comparison of the lipid distributions measured by mass spectrometry with molecular dynamics simulations reveals that the distributions correspond to distinct lipid shells that vary according to the type of protein-lipid interactions. Our results demonstrate that nanodiscs offer the potential for native mass spectrometry to probe interactions between membrane proteins and the wider lipid environment. PMID- 26594030 TI - To counteract or to clear high-mobility group box-1 protein in influenza A (H1N1) infection? That may become the question. PMID- 26594031 TI - Topologically diverse shape-persistent bis-(Zn-salphen) catalysts: efficient cyclic carbonate formation under mild conditions. AB - By adopting a shape-persistent bimetallic design approach, high initial molecular turnover frequencies (up to 14,800 h(-1)) for coupling of CO2 with epoxides in conjunction with (n)Bu4NI, plus excellent yields under mild conditions (1 bar of CO2, 45 degrees C) have been achieved for catalysts containing cofacial Zn salphen units. PMID- 26594033 TI - Silver(I)-mediated three-component annulation reaction of [60]fullerene, sulfonylhydrazones, and nitriles: leading to diverse disubstituted [60]fullerene fused dihydropyrroles. AB - A novel Ag(I)-induced three-component annulation reaction of [60]fullerene with sulfonylhydrazones and nitriles has been developed for the efficient synthesis of diverse disubstituted [60]fullerene-fused dihydropyrroles. The reaction exhibits a broad substrate scope and excellent functional-group tolerance, and also allows for the synthesis of fullerene-bound macromolecules. PMID- 26594032 TI - DNA methylation age is associated with mortality in a longitudinal Danish twin study. AB - An epigenetic profile defining the DNA methylation age (DNAm age) of an individual has been suggested to be a biomarker of aging, and thus possibly providing a tool for assessment of health and mortality. In this study, we estimated the DNAm age of 378 Danish twins, age 30-82 years, and furthermore included a 10-year longitudinal study of the 86 oldest-old twins (mean age of 86.1 at follow-up), which subsequently were followed for mortality for 8 years. We found that the DNAm age is highly correlated with chronological age across all age groups (r = 0.97), but that the rate of change of DNAm age decreases with age. The results may in part be explained by selective mortality of those with a high DNAm age. This hypothesis was supported by a classical survival analysis showing a 35% (4-77%) increased mortality risk for each 5-year increase in the DNAm age vs. chronological age. Furthermore, the intrapair twin analysis revealed a more-than-double mortality risk for the DNAm oldest twin compared to the co twin and a 'dose-response pattern' with the odds of dying first increasing 3.2 (1.05-10.1) times per 5-year DNAm age difference within twin pairs, thus showing a stronger association of DNAm age with mortality in the oldest-old when controlling for familial factors. In conclusion, our results support that DNAm age qualifies as a biomarker of aging. PMID- 26594034 TI - Effects of Aluminum Exposure on the Bone Stimulatory Growth Factors in Rats. AB - Aluminum (Al) is considered to be a potentially toxic metal and inhibits bone formation. Transforming growth factor beta1 (TGF-beta1) and bone morphogenetic protein 2 (BMP-2) play an important role in regulating the bone formation. Therefore, this study aimed to investigate the effects of Al on the TGF-beta1 and BMP-2 in rats. In this study, Wistar rats were randomly divided into Al-treated group and control group. The Al-treated rats were provided with drinking water containing 100 mg/L AlCl3, and the control rats were given distilled water for 30, 60, and 90 days, respectively. Ten rats were sacrificed in each group every 30 days. The Al-treated rats showed lower body weight and higher serum and bone levels of Al compared with the control rats. The expression levels of TGF-beta1 and BMP-2 were also significantly decreased in the Al-treated rats. Serum levels of bone gamma-carboxyglutamic acid protein (BGP), carboxy-terminal propeptide of type I procollagen (PICP), and bone alkaline phosphatase (B-ALP) were markedly lower in the Al-treated groups than in the control group. These results indicate that Al inhibits the expression of TGF-beta1 and BMP-2 in bone, which inhibits the activity of osteoblasts and reduces the synthesis of BGP, B-ALP, and type I collagen, thereby inhibiting bone formation. PMID- 26594035 TI - Mode of prostate cancer detection is associated with the psychological wellbeing of survivors: results from the PiCTure study. AB - PURPOSE: Many men with prostate cancer are asymptomatic, diagnosed following prostate specific antigen (PSA) testing. We investigate whether mode of detection, i.e. 'PSA detected' or 'clinically detected', was associated with psychological wellbeing among prostate cancer survivors. METHODS: A cross sectional postal questionnaire was administered in 2012 to 6559 prostate cancer (ICD10 C61) survivors up to 18 years post-diagnosis, identified through population-based cancer registries in Ireland. Psychological wellbeing was assessed using the Depression Anxiety Stress Scale-21. Logistic regression was used to investigate associations between mode of detection and depression, anxiety and stress, adjusting for socio-demographic and clinical confounders. RESULTS: The response rate was 54 % (3348/6262). Fifty-nine percent of survivors were diagnosed with asymptomatic PSA-tested disease. Prevalence of depression (13.8 vs 20.7 %; p < 0.001), anxiety (13.6 vs 20.9 %; p < 0.001) and stress (8.7 vs 13.8 %; p < 0.001) were significantly lower among survivors diagnosed with PSA detected, than clinically detected disease. After adjusting for clinical and socio-demographic factors, survivors with clinically detected disease had significantly higher risk of depression (odds ratio (OR) = 1.46 95 % CI 1.18, 1.80; p = 0.001), anxiety (OR = 1.36 95 % CI 1.09, 1.68; p = 0.006) and stress (OR = 1.43 95 % CI 1.11, 1.85; p = 0.006) than survivors with PSA-detected disease. CONCLUSIONS: These findings contribute to the ongoing debate on benefits and risks of PSA testing and may be considered by policy makers formulating population-based prostate cancer screening policies. The relatively high prevalence of negative psychological states among survivors means that a 'risk adapted approach' should be implemented to screen survivors most at risk of psychological morbidity for psychological health, and mode of detection could be considered as a risk stratum. PMID- 26594037 TI - Copper binding to naturally occurring, lactam form of angiogenin differs from that to recombinant protein, affecting their activity. AB - Angiogenin is a member of the ribonuclease family and a normal constituent of human plasma. It is one of the most potent angiogenic factors known and is overexpressed in different types of cancers. Copper is also an essential cofactor in angiogenesis and, during this process, it is mobilized from inside to outside of the cell. To date, contrasting results have been reported about copper(ii) influencing angiogenin activity. However, in these studies, the recombinant form of the protein was used. Unlike recombinant angiogenin, that contains an extra methionine with a free terminal amino group, the naturally occurring protein present in human plasma starts with a glutamine residue that spontaneously cyclizes to pyroglutamate, a lactam derivative. Herein, we report spectroscopic evidence indicating that copper(ii) experiences different coordination environments in the two protein isoforms, and affects their RNase and angiogenic activity differently. These results show how relatively small differences between recombinant and wild type proteins can result in markedly different behaviours. PMID- 26594036 TI - Identification of novel, therapy-responsive protein biomarkers in a mouse model of Duchenne muscular dystrophy by aptamer-based serum proteomics. AB - There is currently an urgent need for biomarkers that can be used to monitor the efficacy of experimental therapies for Duchenne Muscular Dystrophy (DMD) in clinical trials. Identification of novel protein biomarkers has been limited due to the massive complexity of the serum proteome and the presence of a small number of very highly abundant proteins. Here we have utilised an aptamer-based proteomics approach to profile 1,129 proteins in the serum of wild-type and mdx (dystrophin deficient) mice. The serum levels of 96 proteins were found to be significantly altered (P < 0.001, q < 0.01) in mdx mice. Additionally, systemic treatment with a peptide-antisense oligonucleotide conjugate designed to induce Dmd exon skipping and recover dystrophin protein expression caused many of the differentially abundant serum proteins to be restored towards wild-type levels. Results for five leading candidate protein biomarkers (Pgam1, Tnni3, Camk2b, Cycs and Adamts5) were validated by ELISA in the mouse samples. Furthermore, ADAMTS5 was found to be significantly elevated in human DMD patient serum. This study has identified multiple novel, therapy-responsive protein biomarkers in the serum of the mdx mouse with potential utility in DMD patients. PMID- 26594038 TI - (1) H and (13) C NMR spectral assignments of novel flavonoids bearing benzothiazepine. PMID- 26594039 TI - Excess vibrational density of states and the brittle to ductile transition in crystalline and amorphous solids. AB - The conditions which determine whether a material behaves in a brittle or ductile fashion on mechanical loading are still elusive and comprise a topic of active research among materials physicists and engineers. In this study, we present the results of in silico mechanical deformation experiments from two very different model solids in two and three dimensions. The first consists of particles interacting with isotropic potentials and the other has strongly direction dependent interactions. We show that in both cases, the excess vibrational density of states is one of the fundamental quantities which characterizes the ductility of the material. Our results can be checked using careful experiments on colloidal solids. PMID- 26594040 TI - Filaggrin genotype and skin diseases independent of atopic dermatitis in childhood. AB - BACKGROUND: Filaggrin gene (FLG) mutations compromise skin barrier functions and increase risk of atopic dermatitis. We aimed to study effects on other skin diseases using unique data from the Danish registers. METHODS: FLG genotyping of a population-based sample of 1547 children with extracted DNA and information on skin diseases from the Danish National Birth Cohort and Health Register, with 18 years follow-up during years 1996-2013. Odds ratios (OR) and hazard ratios (HR) were estimated using logistic regression and Cox regression, respectively, and adjusted for physician-diagnosed atopic dermatitis. RESULTS: FLG mutations were associated with increased risk of dry skin (OR 1.9, CI 1.1-3.1), and a decreased risk of fungal skin infections at age <18 months (OR 0.2, CI 0.1-0.8). There was no association with wart treatments (HR 1.0, CI 0.6-1.7). FLG mutations were associated with an increased risk of atopic dermatitis (OR 3.3, CI 2.1-5.3), dermatology consultations for allergy or rash (HR 2.2, CI 1.4-3.5), basic dermatology consultations at age <5 years (HR 2.2, CI 1.7-2.9), urticaria at age <18 months (OR 2.9, CI 1.0-7.9), and other rash at age <18 months (OR 2.1, CI 1.2 3.8). CONCLUSIONS: FLG mutations may predispose to skin disease in young children including urticaria, and rash not recognized as atopic dermatitis although equally frequent. In clinical practice, FLG genotyping may help indicate the use of moisturizers to reduce skin problems. PMID- 26594041 TI - Engineering microencapsulation of highly catalytic gold nanoclusters for an extreme thermal stability. AB - A synthetic strategy for the microencapsulation of ultra-small gold nanoparticles toward the development of a novel nanoreactor is reported. In this case, it is shown that the catalytic activity of Au nanoclusters as small as 0.8 nm remains unaffected after a thermal treatment up to 800 degrees C in air. This is accomplished through the deposition and further coating of the gold nanoparticles in a void/silica/Au/silica configuration where the nature of the alternate shells can be tuned regardless of each other's porosity and the size of the embedded metal nanoparticles. Such spatial confinement suppresses the growth of the gold nanoclusters and thus preserves their catalytic properties. In this way, a remarkable compromise between the immobilization and the accessibility to the metal nanocatalyst can be met. Furthermore, these nanoreactors are found to be colloidally stable in simulated body fluids which also makes them suitable for biomedical applications. The implementation of hollow nanoreactors containing highly dispersed and immobilized but accessible ultra-small metal nanoparticles constitutes a promising alternative in the search for model catalysts stable under realistic technical conditions. PMID- 26594042 TI - Extreme lithium isotopic fractionation in three zircon standards (Plesovice, Qinghu and Temora). AB - To understand the behavior of Li in zircon, we have analyzed the abundance and isotopic composition of Li in three zircon standards (Plesovice, Qinghu and Temora) widely used for microbeam analysis of U-Pb ages and O-Hf isotopes. We have mapped Li concentration ([Li]) on large grains, using a Cameca 1280HR Secondary Ion Mass Spectrometer (SIMS). All zircons have a rim 5-20 MUm wide in which [Li] is 5 to 20 times higher than in the core. Up to ~200/00 isotopic fractionation is observed on a small scale in the rims of a single zircon grain. The measured delta(7)Li values range from -14.3 to 3.70/00 for Plesovice, -22.8 to 1.40/00 for Qinghu and -4.7 to 16.10/00 for Temora zircon. The [Li] and delta(7)Li are highly variable at the rims, but relatively homogenous in the cores of the grains. From zircon rim to core, [Li] decreases rapidly, while delta(7)Li increases, suggesting that the large isotopic variation of Li in zircons could be caused by diffusion. Our data demonstrate that homogeneous delta(7)Li in the cores of zircon can retain the original isotopic signatures of the magmas, while the bulk analysis of Li isotopes in mineral separates and in bulk-rock samples may produce misleading data. PMID- 26594044 TI - Covariability of western tropical Pacific-North Pacific atmospheric circulation during summer. AB - North Pacific subtropical high (NPSH) is permanent high-pressure system over the Northern Pacific Ocean and it extends to the western North Pacific during the boreal summer (June-July-August), which is so called the western North Pacific subtropical high (WNPSH). Here, we examine the covariability of the NPSH-WNPSH during summer using both observation and Coupled Model Intercomparison Project phase 5 (CMIP5) model data. The statistical analyses indicate that the NPSH-WNPSH covariability shows significant decadal variability in the observations, in addition, the in-phase relationship of NPSH-WNPSH is enhanced after the mid-to late 1990s. A dipole-like sea surface temperature (SST) pattern, i.e., a warming in the western Pacific and a cooling in the eastern Pacific, is dominant after the mid-to-late 1990s, which acts to enhance the covariability of NPSH-WNPSH by modulating the atmospheric teleconnections. However, the covariability of NPSH WNPSH in the future climate is not much influenced by the anthropogenic forcing but it is largely characterized by the natural decadal-to-interdecadal variability, implying that the enhancement of NPSH-WNPSH covariability after the mid-to-late 1990s could be considered as part of decadal-to-interdecadal variability. PMID- 26594045 TI - A highly durable fuel cell electrocatalyst based on double-polymer-coated carbon nanotubes. AB - Driven by the demand for the commercialization of fuel cell (FC) technology, we describe the design and fabrication of a highly durable FC electrocatalyst based on double-polymer-coated carbon nanotubes for use in polymer electrolyte membrane fuel cells. The fabricated electrocatalyst is composed of Pt-deposited polybenzimidazole-coated carbon nanotubes, which are further coated with Nafion. By using this electrocatalyst, a high FC performance with a power density of 375 mW/cm(2) (at 70 C, 50% relative humidity using air (cathode)/H2(anode)) was obtained, and a remarkable durability of 500,000 accelerated potential cycles was recorded with only a 5% loss of the initial FC potential and 20% loss of the maximum power density, which were far superior properties compared to those of the membrane electrode assembly prepared using carbon black in place of the carbon nanotubes. The present study indicates that the prepared highly durable fuel cell electrocatalyst is a promising material for the next generation of PEMFCs. PMID- 26594043 TI - Targeting of host organelles by pathogenic bacteria: a sophisticated subversion strategy. AB - Many bacterial pathogens have evolved the ability to subvert and exploit host functions in order to enter and replicate in eukaryotic cells. For example, bacteria have developed specific mechanisms to target eukaryotic organelles such as the nucleus, the mitochondria, the endoplasmic reticulum and the Golgi apparatus. In this Review, we highlight the most recent advances in our understanding of the mechanisms that bacterial pathogens use to target these organelles. We also discuss how these strategies allow bacteria to manipulate host functions and to ultimately enable bacterial infection. PMID- 26594046 TI - European junior neurologists perceive various shortcomings in current residency curricula. AB - BACKGROUND: Whether residency programs in Europe and neighboring countries appropriately prepare one for clinical practice is a matter of discussion. AIMS OF THE STUDY: To assess perceived satisfaction and preparedness for clinical practice among residents and junior neurologists from Europe and neighboring countries. MATERIAL AND METHODS: We inquired about the level of satisfaction with the quality of teaching, rotations and research opportunities of their residency program with an anonymous paper-based questionnaire. We assessed different aspects of practical training including clinical examination, diagnostic procedures, and patient management. RESULTS: The survey revealed limited satisfaction with the overall training (47%). The quality of teaching was frequently perceived as good or excellent (73%), whereas supervision for patient care and diagnostic procedures was rated as improvable. Discontent related often to poor proficiency for neurological emergencies, diagnostic considerations, and therapeutic decisions. Whether the working time directive introduced by the European Union (EU) affected patient care or resident education or residents' quality of life remained ambiguous. CONCLUSIONS: This cross-sectional survey disclosed shortcomings in current residency curricula. These concerned diagnostic and therapeutic procedures as well as practical skills, regardless of country, region, or institutional background. Initiatives aimed to harmonize postgraduate neurology training across Europe will need to consider these findings. PMID- 26594047 TI - Silane-coated magnetic nanoparticles with surface thiol functions for conjugation with gold nanostars. AB - Small (d~ 8 nm) magnetite nanoparticles, Fe3O4NP, are prepared and coated with mercaptopropyl trimethoxysilane (MPTS) to form Fe3O4NP@MPTS. In the coating step controlled MPTS/Fe3O4NP molar ratios are used, ranging from 1 to 7.8 * 10(4). The total quantity of MPTS per Fe3O4NP is determined by SEM-EDS analysis and the average number of free, reactive -SH groups per Fe3O4NP is calculated by a colorimetric method. At very low molar ratios MPTS forms a submonolayer on the Fe3O4NP surface with all -SH free to react, while on increasing the MPTS/Fe3O4NP molar ratio the (CH3O)3Si- groups of MPTS polymerize, forming a progressively thicker shell, in which only a small fraction of the -SH groups, positioned on the shell surface, is available for further reaction. The MPTS shell reduces the magnetic interactions occurring between the magnetite cores, lowering the occurrence and strength of collective magnetic states, with Fe3O4NP@MPTS showing the typical behaviour expected for a sample with a mono-modal size distribution of superparamagnetic nanoparticles. Interaction of Fe3O4NP@MPTS with gold nanostars (GNS) was tested, using both Fe3O4NP@MPTS with a MPTS submonolayer and with increasing shell thickness. Provided that a good balance is used between the number of available -SH and the overall size of Fe3O4NP@MPTS, the free thiols of such nanoparticles bind GNS decorating their surface, as shown by UV-Vis spectroscopy and TEM imaging. PMID- 26594048 TI - Dengue: an update on treatment options. AB - Dengue is the most important mosquito-borne viral pathogen globally, with approximately 100 million cases of acute dengue annually. Infection can result in severe, life-threatening disease. Currently, there is no effective vaccine or licensed antiviral. Management is primarily supportive with fluids. Direct antiviral therapies that reduce dengue severity could be useful although these would need to inhibit all four viral serotypes effectively. This review focuses on the interventions that currently considered the gold standard in case management as well as exploratory therapies that have been studied in clinical trials. Although antiviral drug and therapeutic antibodies for dengue remain a work in progress, these studies have produced some promising results and may have the potential to be future drugs. PMID- 26594049 TI - MicroRNA-155-IFN-gamma Feedback Loop in CD4(+)T Cells of Erosive type Oral Lichen Planus. AB - Oral lichen planus (OLP) is a T cell-mediated immune disorder, and we have indicated a Th1-dominated immune response in OLP. MicroRNA-155 (miR-155) could promote Th1 cells polarization. The present study aims to determine the role of miR-155 in immune response of OLP. The expression of miR-155 and the target mRNA was tested by Real-Time PCR. The serum levels of IL-2, 4, 10 and IFN-gamma were examined with ELISA. Furthermore, in vitro study was built to observe the function of miR-155 in erosive-type OLP (EOLP). Finally, we determined the expression and correlation of miR-155 and SOCS1 in EOLP CD4(+) T cells. The results showed miR-155 was high related with the disease severities. Besides, serum IFN-gamma was specifically increased in EOLP group, while IL-4 was decreased. In vitro studies showed miR-155 could reinforce IFN-gamma signal transducer, and the induction of IFN-gamma could also promote miR-155 expression in EOLP CD4(+) T cells. In addition, miR-155 levels were negatively related with SOCS1 mRNA expression in EOLP CD4(+) T cells. Our study revealed a positive miR 155- IFN-gamma feedback loop in EOLP CD4(+) T cell, which might contribute to the Th1-dominated immune response. Furthermore, miR-155 could be used for the evaluation and treatment of OLP. PMID- 26594050 TI - A combination approach to treating fungal infections. AB - Azoles are antifungal drugs used to treat fungal infections such as candidiasis in humans. Their extensive use has led to the emergence of drug resistance, complicating antifungal therapy for yeast infections in critically ill patients. Combination therapy has become popular in clinical practice as a potential strategy to fight resistant fungal isolates. Recently, amphiphilic tobramycin analogues, C12 and C14, were shown to display antifungal activities. Herein, the antifungal synergy of C12 and C14 with four azoles, fluconazole (FLC), itraconazole (ITC), posaconazole (POS), and voriconazole (VOR), was examined against seven Candida albicans strains. All tested strains were synergistically inhibited by C12 when combined with azoles, with the exception of C. albicans 64124 and MYA-2876 by FLC and VOR. Likewise, when combined with POS and ITC, C14 exhibited synergistic growth inhibition of all C. albicans strains, except C. albicans MYA-2876 by ITC. The combinations of FLC-C14 and VOR-C14 showed synergistic antifungal effect against three C. albicans and four C. albicans strains, respectively. Finally, synergism between C12/C14 and POS were confirmed by time-kill and disk diffusion assays. These results suggest the possibility of combining C12 or C14 with azoles to treat invasive fungal infections at lower administration doses or with a higher efficiency. PMID- 26594052 TI - Europe's Tired, Poor, Huddled Masses: Self-Selection and Economic Outcomes in the Age of Mass Migration. AB - During the age of mass migration (1850-1913), one of the largest migration episodes in history, the United States maintained a nearly open border, allowing the study of migrant decisions unhindered by entry restrictions. We estimate the return to migration while accounting for migrant selection by comparing Norway-to US migrants with their brothers who stayed in Norway in the late nineteenth century. We also compare fathers of migrants and nonmigrants by wealth and occupation. We find that the return to migration was relatively low (70 percent) and that migrants from urban areas were negatively selected from the sending population. "Keep, ancient lands, your storied pomp!" cries she With silent lips. "Give me your tired, your poor, Your huddled masses yearning to breathe free, The wretched refuse of your teeming shore. Send these, the homeless, tempest-tost to me, I lift my lamp beside the golden door!"--Emma Lazarus (1883). PMID- 26594051 TI - Beta diversity determinants in Badagongshan, a subtropical forest in central China. AB - Niche and neutral theories emphasize different processes contributing to the maintenance of species diversity. In this study, we calculated the local contribution to beta diversity (LCBD) of every cell, using variation partitioning in combination with spatial distance and environmental variables of the 25-ha Badagongshan plot (BDGS), to determine the contribution of environmentally related variation versus pure spatial variation. We used topography and soil characteristics as environmental variables, distance-based Moran's eigenvectors maps (dbMEM) to describe spatial relationships among cells and redundancy analysis (RDA) to apportion the variation in beta diversity into three components: pure environmental, spatially-structured environmental, and pure spatial. Results showed LCBD values were negatively related to number of common species and positively related to number of rare species. Environment and space jointly explained ~60% of the variation in species composition; soil variables alone explained 21.6%, slightly more than the topographic variables that explained 15.7%; topography and soil together explained 27%, slightly inferior to spatial variables that explained 34%. The BDGS forest was controlled both by the spatial and environmental variables, and the results were consistent across different life forms and life stages. PMID- 26594053 TI - Mixed aliphatic and aromatic composition of evaporating very small grains in NGC 7023 revealed by the 3.4/3.3 MUm ratio. AB - CONTEXT: A chemical scenario was proposed for photon-dominated regions (PDRs) according to which UV photons from nearby stars lead to the evaporation of very small grains (VSGs) and the production of gas-phase polycyclic aromatic hydrocarbons (PAHs). AIMS: Our goal is to achieve better insight into the composition and evolution of evaporating very small grains (eVSGs) and PAHs through analyzing the infrared (IR) aliphatic and aromatic emission bands. METHODS: We combined spectro-imagery in the near- and mid-IR to study the spatial evolution of the emission bands in the prototypical PDR NGC 7023. We used near-IR spectra obtained with the IRC instrument onboard AKARI to trace the evolution of the 3.3 MUm and 3.4 MUm bands, which are associated with aromatic and aliphatic C H bonds on PAHs. The spectral fitting involved an additional broad feature centered at 3.45 MUm that is often referred to as the plateau. Mid-IR observations obtained with the IRS instrument onboard the Spitzer Space Telescope were used to distinguish the signatures of eVSGs and neutral and cationic PAHs. We correlated the spatial evolution of all these bands with the intensity of the UV field given in units of the Habing field G0 to explore how their carriers are processed. RESULTS: The intensity of the 3.45 MUm plateau shows an excellent correlation with that of the 3.3 MUm aromatic band (correlation coefficient R = 0.95) and a relatively poor correlation with the aliphatic 3.4 MUm band (R=0.77). This indicates that the 3.45 MUm feature is dominated by the emission from aromatic bonds. We show that the ratio of the 3.4 MUm and 3.3 MUm band intensity (I3.4/I3.3) decreases by a factor of 4 at the PDR interface from the more UV shielded layers (G0 ~ 150, I3.4/I3.3 = 0.13) to the more exposed layers (G0 > 1 * 104, I3.4/I3.3 = 0.03). The intensity of the 3.3 MUm band relative to the total neutral PAH intensity shows an overall increase with G0, associated with an increase of both the hardness of the UV field and the H abundance. In contrast, the intensity of the 3.4 MUm band relative to the total neutral PAH intensity decreases with G0, showing that their carriers are actively destroyed by UV irradiation and are not efficiently regenerated. The transition region between the aliphatic and aromatic material is found to correspond spatially with the transition zone between neutral PAHs and eVSGs. CONCLUSIONS: We conclude that the photo-processing of eVSGs leads to the production of PAHs with attached aliphatic sidegroups that are revealed by the 3.4 MUm emission band. Our analysis provides evidence for the presence of very small grains of mixed aromatic and aliphatic composition in PDRs. PMID- 26594054 TI - Detailed mechanistic investigation into the S-nitrosation of cysteamine. AB - The nitrosation of cysteamine (H2NCH2CH2SH) to produce cysteamine-S-nitrosothiol (CANO) was studied in slightly acidic medium by using nitrous acid prepared in situ. The stoichiometry of the reaction was H2NCH2CH2SH + HNO2 -> H2NCH2CH2SNO + H2O. On prolonged standing, the nitrosothiol decomposed quantitatively to yield the disulfide, cystamine: 2H2NCH2CH2SNO -> H2NCH2CH2S-SCH2CH2NH2 + 2NO. NO2 and N2O3 are not the primary nitrosating agents, since their precursor (NO) was not detected during the nitrosation process. The reaction is first order in nitrous acid, thus implicating it as the major nitrosating agent in mildly acidic pH conditions. Acid catalyzes nitrosation after nitrous acid has saturated, implicating the protonated nitrous acid species, the nitrosonium cation (NO+) as a contributing nitrosating species in highly acidic environments. The acid catalysis at constant nitrous acid concentrations suggests that the nitrosonium cation nitrosates at a much higher rate than nitrous acid. Bimolecular rate constants for the nitrosation of cysteamine by nitrous acid and by the nitrosonium cation were deduced to be 17.9 +/- 1.5 (mol/L)-1 s-1 and 6.7 * 104 (mol/L)-1 s-1, respectively. Both Cu(I) and Cu(II) ions were effective catalysts for the formation and decomposition of the cysteamine nitrosothiol. Cu(II) ions could catalyze the nitrosation of cysteamine in neutral conditions, whereas Cu(I) could only catalyze in acidic conditions. Transnitrosation kinetics of CANO with glutathione showed the formation of cystamine and the mixed disulfide with no formation of oxidized glutathione (GSSG). The nitrosation reaction was satisfactorily simulated by a simple reaction scheme involving eight reactions. PMID- 26594055 TI - Identification of quantitative trait loci for yield and yield related traits in groundnut (Arachis hypogaea L.) under different water regimes in Niger and Senegal. AB - Yield under drought stress is a highly complex trait with large influence to even a minor fluctuation in the environmental conditions. Genomics-assisted breeding holds great promise for improving such complex traits more efficiently in less time, but requires markers associated with the trait of interest. In this context, a recombinant inbred line mapping population (TAG 24 * ICGV 86031) was used to identify markers associated with quantitative trait loci (QTLs) for yield and yield related traits at two important locations of West Africa under well watered and water stress conditions. Among the traits analyzed under WS condition, the harvest index (HI) and the haulm yield (HYLD) were positively correlated with the pod yield (PYLD) and showed intermediate broad sense heritability. QTL analysis using phenotyping and genotyping data resulted in identification of 52 QTLs. These QTLs had low phenotypic variance (<12 %) for all the nine traits namely plant height, primary branching, SPAD chlorophyll meter reading, percentage of sound mature kernels, 100 kernel weight, shelling percentage, HI, HYLD and PYLD. Interestingly, few QTLs identified in this study were also overlapped with previously reported QTLs detected for drought tolerance related traits identified earlier in Indian environmental conditions using the same mapping population. Accumulating these many small-effect QTLs into a single genetic background is nearly impossible through marker-assisted backcrossing and even marker-assisted recurrent selection. Under such circumstances, the deployment of genomic selection is the most appropriate approach for improving such complex traits with more precision and in less time. PMID- 26594057 TI - Performance of the Tachyon Time-of-Flight PET Camera. AB - We have constructed and characterized a time-of-flight Positron Emission Tomography (TOF PET) camera called the Tachyon. The Tachyon is a single-ring Lutetium Oxyorthosilicate (LSO) based camera designed to obtain significantly better timing resolution than the ~ 550 ps found in present commercial TOF cameras, in order to quantify the benefit of improved TOF resolution for clinically relevant tasks. The Tachyon's detector module is optimized for timing by coupling the 6.15 * 25 mm2 side of 6.15 * 6.15 * 25 mm3 LSO scintillator crystals onto a 1-inch diameter Hamamatsu R-9800 PMT with a super-bialkali photocathode. We characterized the camera according to the NEMA NU 2-2012 standard, measuring the energy resolution, timing resolution, spatial resolution, noise equivalent count rates and sensitivity. The Tachyon achieved a coincidence timing resolution of 314 ps +/- ps FWHM over all crystal-crystal combinations. Experiments were performed with the NEMA body phantom to assess the imaging performance improvement over non-TOF PET. The results show that at a matched contrast, incorporating 314 ps TOF reduces the standard deviation of the contrast by a factor of about 2.3. PMID- 26594058 TI - Methamphetamine Use and Violent Behavior: User Perceptions and Predictors. AB - This study describes the extent to which methamphetamine users perceive that their methamphetamine use has resulted in violent behavior, and describes the level of self-reported prevalence of specific violent criminal behaviors irrespective of methamphetamine use. Predictors of these two violence-related indicators, in terms of potential correlates from substance use history, criminal history, and health risk domains are examined. Data are from extensive interviews of 350 methamphetamine users who received substance use treatment in a large California county. A majority (56%) perceived that their methamphetamine use resulted in violent behavior; 59% reported specific violent criminal behaviors. For more than half of those reporting violent criminal behavior, this behavior pattern began before methamphetamine initiation. Thus, for a subsample of methamphetamine users, violence may be related to factors other than methamphetamine use. Users' perceptions that their methamphetamine use resulted in violence appears strongest for those with the most severe methamphetamine related problems, particularly paranoia. PMID- 26594056 TI - Hydrogel microparticles for biosensing. AB - Due to their hydrophilic, biocompatible, and highly tunable nature, hydrogel materials have attracted strong interest in the recent years for numerous biotechnological applications. In particular, their solution-like environment and non-fouling nature in complex biological samples render hydrogels as ideal substrates for biosensing applications. Hydrogel coatings, and later, gel dot surface microarrays, were successfully used in sensitive nucleic acid assays and immunoassays. More recently, new microfabrication techniques for synthesizing encoded particles from hydrogel materials have enabled the development of hydrogel-based suspension arrays. Lithography processes and droplet-based microfluidic techniques enable generation of libraries of particles with unique spectral or graphical codes, for multiplexed sensing in biological samples. In this review, we discuss the key questions arising when designing hydrogel particles dedicated to biosensing. How can the hydrogel material be engineered in order to tune its properties and immobilize bioprobes inside? What are the strategies to fabricate and encode gel particles, and how can particles be processed and decoded after the assay? Finally, we review the bioassays reported so far in the literature that have used hydrogel particle arrays and give an outlook of further developments of the field. PMID- 26594059 TI - Participation in Team Sports and Alcohol and Marijuana Use Initiation Trajectories. AB - A parallel-process latent growth curve model was used to model alcohol and marijuana use (vs. nonuse). Participation in team sports and gender were considered to be time-invariant covariates. The sample consisted of 8,179 youth from the National Survey of Parents and Youth. Data were collected over four yearly rounds. Analysis revealed that being part of a competitive sports team was related to a lower probability of marijuana initiation, but to increased rates of alcohol use over time. Males had significantly higher levels of marijuana initiation and decreases in rates of alcohol use over time; females had significantly greater rate of increase in alcohol use over time. Analysis suggests that youth involved in sports are less likely to use marijuana over time. This information may help to uncover other predictors of use over time and to inform policy making as well design as effective prevention. PMID- 26594060 TI - Longitudinal analysis in Plantago: strength of selection and reverse-age analysis reveal age-indeterminate senescence. AB - : 1. Senescence is usually viewed as increased age-specific mortality or decreased age-specific fecundity due to the declining ability of natural selection to remove deleterious age-specific mutations with age. In herbaceous perennial plants, trends in age-specific mortality are often confounded by size. Age-indeterminate senescence, where accumulated physiological damage varies strongly with environment, may be a better model of senescence in these species. 2. We analysed trends in size and fertility in Plantago lanceolata, using a long term demographic census involving >10 years and >8,000 individuals in 4 cohorts. We used elasticity and pairwise invasion analysis of life history function parameterized age * stage matrices to assess whether the force of natural selection declined with age. Then, we used reverse age analysis of size and fertility to assess whether age-indeterminate senescence occurred. Reverse age analysis uses longitudinal data for individuals that have died to look at trait patterns as a function of both age and remaining time to death. We hypothesized that i) the strength of natural selection would decline strongly with age, and ii) physiological condition would deteriorate for several years prior to death. 3. Both elasticity and invasion analyses suggested that the strength of natural selection through mortality declined strongly with age once size was accounted for. Further, reverse age analyses showed that individuals shrank for ~3yrs prior to death, suggesting physiological decline. Inflorescence production declined with age, and also declined in the 3 years prior to death regardless of overall age. 4 SYNTHESIS: The hypothesis that plants escape senescence generally assumes that plants can continue to grow larger and increase reproduction as they get older. The results here show that size and reproduction decline with age and the rates of these declines toward death are lifespan- and age-dependent. Further research is needed to delineate the importance of age-determinate vs. age indeterminate factors in senescence patterns across species. PMID- 26594061 TI - Effect of Quencher, Denaturants, Temperature and pH on the Fluorescent Properties of BSA Protected Gold Nanoclusters. AB - In this paper, we have synthesized BSA protected gold nanoclusters (BSA Au nanocluster) and studied the effect of quencher, protein denaturant, pH and temperature on the fluorescence properties of the tryptophan molecule of the BSA Au nanocluster and native BSA. We have also studied their effect on the peak emission of BSA Au nanoclusters (650 nm). The phtophysical characterization of a newly developed fluorophore in different environments is absolutely necessary to futher develop their biomedical and analytical applications. It was observed from our experiments that the tryptophan in BSA Au nanoclusters is better shielded from the polar environment. Tryptophan in native BSA showed a red shift in its peak emission wavelength position. Tryptophan is a highly polarity sensitive dye and a minimal change in its microenvironment can be easily observed in its photophysical properties. PMID- 26594062 TI - Can Food Processing Enhance Cancer Protection? PMID- 26594063 TI - Desire Resistance and Desire Reduction in Public Health Approaches to Obesity. PMID- 26594064 TI - Social Support, Negative Social Interactions, and Psychological Well-Being. AB - Research examining the relationship between social support and psychological well being has largely ignored the negative side of social interactions. However, empirical evidence suggests that negative interactions can potentially be more harmful than social support is helpful. This article critically reviews the literature investigating the relationship between social support and negative social interactions and their simultaneous effect on psychological well-being. A review of 28 studies revealed that there are conceptual, theoretical, and methodological limitations associated with this body of research. In order to unravel some of these limitations, studies are grouped according to three conceptual models: the additive effects model, the moderator model, and the domain-specific model. Finally, the article discusses directions social work practice research should take to tackle and fully appreciate the complexities of the relationship between social support and psychological well-being. PMID- 26594065 TI - Preparation of a 1,2-isoxazolidine synthon for the synthesis of zetekitoxin AB. AB - A synthesis of the 1,2-isoxazolidine fragment of the potent voltage gated sodium channel blocker, zetekitoxin AB is described. The synthesis utilizes an intramolecular nitrone -olefin 1,3-dipolar cycloaddition to establish the stereochemistry of the cis-1,2-isoxazolidine. The oxidative cleavage of an all anti-triol with the excision of the central carbon is central to using alpha-D glucopyranoside as a traceless stereochemical template. This route furnishes a suitably protected synthon for the synthesis of zetekitoxin AB. PMID- 26594066 TI - Preparation of a conjugation-ready thiol responsive molecular switch. AB - In this work we synthesize molecular switches that are responsive to cysteine, homocysteine, and glutathione; three redox systems that make up the majority of the body's antioxidant defenses. Synthesized spiropyran isomers with conjugation ready linkages showed good selectivity of response to these major antioxidant thiols over nucleophilic amino acids; however the position of the linking group can affect selectivity and reversibility of the switching response. An isomer with selectivity for cysteine against GSH and Hcy was identified. PMID- 26594067 TI - Epidemiology, Comorbidity, and Behavioral Genetics of Antisocial Personality Disorder and Psychopathy. AB - Psychopathy is theorized as a disorder of personality and affective deficits while antisocial personality disorder (ASPD) diagnosis is primarily behaviorally based. While ASPD and psychopathy are similar and are highly comorbid with each other, they are not synonymous. ASPD has been well studied in community samples with estimates of its lifetime prevalence ranging from 1-4% of the general population.4,5 In contrast, psychopathy is almost exclusively investigated within criminal populations so that its prevalence in the general population has been inferred by psychopathic traits rather than disorder (1%). Differences in etiology and comorbidity with each other and other psychiatric disorders of these two disorders are also evident. The current article will briefly review the epidemiology, etiology, and comorbidity of ASPD and psychopathy, focusing predominately on research completed in community and clinical populations. This paper aims to highlight ASPD and psychopathy as related, but distinct disorders. PMID- 26594068 TI - Green Algae as Model Organisms for Biological Fluid Dynamics. AB - In the past decade the volvocine green algae, spanning from the unicellular Chlamydomonas to multicellular Volvox, have emerged as model organisms for a number of problems in biological fluid dynamics. These include flagellar propulsion, nutrient uptake by swimming organisms, hydrodynamic interactions mediated by walls, collective dynamics and transport within suspensions of microswimmers, the mechanism of phototaxis, and the stochastic dynamics of flagellar synchronization. Green algae are well suited to the study of such problems because of their range of sizes (from 10 MUm to several millimetres), their geometric regularity, the ease with which they can be cultured and the availability of many mutants that allow for connections between molecular details and organism-level behavior. This review summarizes these recent developments and highlights promising future directions in the study of biological fluid dynamics, especially in the context of evolutionary biology, that can take advantage of these remarkable organisms. PMID- 26594069 TI - Pathways to Pain: Racial Discrimination and Relations Between Parental Functioning and Child Psychosocial Well-Being. AB - The relationship between racial discrimination, parental functioning, and child adjustment is not well understood. The goal of the present study was to assess parental reports of discrimination in relation to depression and parenting practices, as well as on subsequent child internalizing and externalizing problems in low-income Black families. Data include a subsample of the Early Steps project, a multisite longitudinal study of financial and behaviorally at risk families. Structural equation modeling was used to analyze our hypothesized model. Excellent model fit was established after removing externalizing problems from the model. As predicted, indirect associations were found from discrimination to parental depression, parenting, and child internalizing problems; and direct associations were found from discrimination to child internalizing problems. The results are consistent with findings suggesting that discrimination is negatively associated with adult well-being; moreover, contribute to the sparse literature on the effects of discrimination beyond the direct recipient. Finally, that parent discrimination was directly associated with child emotional problems suggests the continued need to address and treat discriminatory practices more generally. PMID- 26594070 TI - C1 finite elements on non-tensor-product 2d and 3d manifolds. AB - Geometrically continuous (Gk ) constructions naturally yield families of finite elements for isogeometric analysis (IGA) that are Ck also for non-tensor-product layout. This paper describes and analyzes one such concrete C1 geometrically generalized IGA element (short: gIGA element) that generalizes bi-quadratic splines to quad meshes with irregularities. The new gIGA element is based on a recently-developed G1 surface construction that recommends itself by its a B spline-like control net, low (least) polynomial degree, good shape properties and reproduction of quadratics at irregular (extraordinary) points. Remarkably, for Poisson's equation on the disk using interior vertices of valence 3 and symmetric layout, we observe O(h3) convergence in the Linfinity norm for this family of elements. Numerical experiments confirm the elements to be effective for solving the trivariate Poisson equation on the solid cylinder, deformations thereof (a turbine blade), modeling and computing geodesics on smooth free-form surfaces via the heat equation, for solving the biharmonic equation on the disk and for Koiter type thin-shell analysis. PMID- 26594071 TI - Competing Demands from Aging Parents and Adult Children in Two Cohorts of American Women. AB - In late middle age, individuals may face competing demands on their time and financial resources from elderly parents and young adult children. This study uses the Panel Study of Income Dynamics to examine changes over time in the probability of having children and living parents for women age 45 to 64. We compare two cohorts: those born in the 1920s and 1930s and those born in the 1940s and 1950s. We find that there has been a dramatic increase in the probability of having children and living parents and that this increase has been driven mainly by changes in life expectancy of the parent generation. We further examine transfers of money and co-residence for women in the later cohort. We find that while women may not give to parents and children concurrently, approximately thirty percent of them have provided support to both parents and children at some point in the past. PMID- 26594072 TI - Can technology life-cycles be indicated by diversity in patent classifications? The crucial role of variety. AB - In a previous study of patent classifications in nine material technologies for photovoltaic cells, Leydesdorff et al. (Scientometrics 102(1):629-651, 2015) reported cyclical patterns in the longitudinal development of Rao-Stirling diversity. We suggested that these cyclical patterns can be used to indicate technological life-cycles. Upon decomposition, however, the cycles are exclusively due to increases and decreases in the variety of the classifications, and not to disparity or technological distance, measured as (1 - cosine). A single frequency component can accordingly be shown in the periodogram. Furthermore, the cyclical patterns are associated with the numbers of inventors in the respective technologies. Sometimes increased variety leads to a boost in the number of inventors, but in early phases-when the technology is still under construction-it can also be the other way round. Since the development of the cycles thus seems independent of technological distances among the patents, the visualization in terms of patent maps, can be considered as addressing an analytically different set of research questions. PMID- 26594073 TI - The bibliometric analysis of scholarly production: How great is the impact? AB - Bibliometric methods or "analysis" are now firmly established as scientific specialties and are an integral part of research evaluation methodology especially within the scientific and applied fields. The methods are used increasingly when studying various aspects of science and also in the way institutions and universities are ranked worldwide. A sufficient number of studies have been completed, and with the resulting literature, it is now possible to analyse the bibliometric method by using its own methodology. The bibliometric literature in this study, which was extracted from Web of Science, is divided into two parts using a method comparable to the method of Jonkers et al. (Characteristics of bibliometrics articles in library and information sciences (LIS) and other journals, pp. 449-551, 2012: The publications either lie within the Information and Library Science (ILS) category or within the non-ILS category which includes more applied, "subject" based studies. The impact in the different groupings is judged by means of citation analysis using normalized data and an almost linear increase can be observed from 1994 onwards in the non-ILS category. The implication for the dissemination and use of the bibliometric methods in the different contexts is discussed. A keyword analysis identifies the most popular subjects covered by bibliometric analysis, and multidisciplinary articles are shown to have the highest impact. A noticeable shift is observed in those countries which contribute to the pool of bibliometric analysis, as well as a self-perpetuating effect in giving and taking references. PMID- 26594074 TI - Can intellectual processes in the sciences also be simulated? The anticipation and visualization of possible future states. AB - Socio-cognitive action reproduces and changes both social and cognitive structures. The analytical distinction between these dimensions of structure provides us with richer models of scientific development. In this study, I assume that (1) social structures organize expectations into belief structures that can be attributed to individuals and communities; (2) expectations are specified in scholarly literature; and (3) intellectually the sciences (disciplines, specialties) tend to self-organize as systems of rationalized expectations. Whereas social organizations remain localized, academic writings can circulate, and expectations can be stabilized and globalized using symbolically generalized codes of communication. The intellectual restructuring, however, remains latent as a second-order dynamics that can be accessed by participants only reflexively. Yet, the emerging "horizons of meaning" provide feedback to the historically developing organizations by constraining the possible future states as boundary conditions. I propose to model these possible future states using incursive and hyper-incursive equations from the computation of anticipatory systems. Simulations of these equations enable us to visualize the couplings among the historical-i.e., recursive-progression of social structures along trajectories, the evolutionary-i.e., hyper-incursive-development of systems of expectations at the regime level, and the incursive instantiations of expectations in actions, organizations, and texts. PMID- 26594075 TI - Steady State and Time Resolved Fluorescence Studies of Azadioxatriangulenium (ADOTA) Fluorophore in Silica and PVA Thin Films. AB - A cationic azadioxatriangulenium (ADOTA) dye was entrapped in silica thin films obtained by the sol-gel process and in poly (vinyl) alcohol (PVA) thin films. Azadioxatriangulenium is a red emitting fluorophore with a long fluorescence lifetime of ~20 ns. The fluorescent properties of azadioxatriangulenium in silica thin films and PVA films were studied by means of steady-state and time resolved fluorescence techniques. We have found that the azadioxatriangulenium entrapped in silica thin film has a wider fluorescence lifetime distribution (Lorentzian distribution), lower fluorescence efficiencies, shorter lifetimes compared to Azadioxatriangulenium in a PVA film. The local environment of azadioxatriangulenium molecules in the silica thin film is rich with water and ethanol, which creates the possibility of forming excited state aggregates due to high concentration of dye within a small confined area. In contrast to the PVA matrices, the porous silica films allow restricted rotations of Azadioxatriangulenium molecules, which result in faster and complex fluorescence anisotropy decays suggesting energy migration among dye molecules. PMID- 26594076 TI - Intersecting Sexual and Reproductive Health and Disability in Humanitarian Settings: Risks, Needs, and Capacities of Refugees with Disabilities in Kenya, Nepal, and Uganda. AB - The current literature recognizes the fact that persons with disabilities have historically been deprived of their sexual and reproductive health (SRH) rights. Little is known, however, about the situation for women, men, and adolescents with disabilities in humanitarian settings. The Women's Refugee Commission led a participatory research project with partners to explore the risks, needs, and barriers for refugees with disabilities to access SRH services, and the practical ways in which these challenges could be addressed. The study gathered information from refugee women, men, and adolescents aged 15-19 with physical, intellectual, sensory, and mental impairments in refugee settings in Kenya, Nepal, and Uganda. Findings showed that refugees with disabilities demonstrated varying degrees of awareness around SRH, especially regarding the reproductive anatomy, family planning, and sexually transmitted infections. Among barriers to accessing services, lack of respect by providers was reported as the most hurtful. Pregnant women with disabilities were often discriminated against by providers and scolded by caregivers for becoming pregnant and bearing children; marital status was a large factor that determined if a pregnancy was accepted. Risks of sexual violence prevailed across sites, especially for persons with intellectual impairments. The ability of women with disabilities to exercise their SRH rights was mixed. Refugees with disabilities showed a mixed understanding of their own rights in relationships and in the pursuit of opportunities. Findings speak to the need to realize the SRH rights of refugees with disabilities and build their longer-term SRH capacities. PMID- 26594077 TI - British Attitudes Towards Sexuality in Men and Women with Intellectual Disabilities: A Comparison Between White Westerners and South Asians. AB - Although sexuality is a fundamental aspect of human existence, public attitudes towards the sexuality of people with intellectual disabilities may vary. In particular, different ethnic communities may have different perspectives. These differing perspectives may impact on the opportunities and support available for people with intellectual disabilities to express sexuality within 'normalized' life experiences. Despite the South Asian population being one of the largest minority ethnic groups residing within the UK, few studies have aimed to understand how South Asian attitudes towards the sexuality of people with intellectual disabilities may differ from White Western perspectives. This study used an online questionnaire to investigate public attitudes towards the sexuality of people with intellectual disabilities within a UK sample (n = 331). Attitudes between people from White Western (n = 184) and South Asian backgrounds (n = 147) were compared with the use of five scales measuring attitudes towards sexuality. Whilst overall attitudes appeared to be generally positive, South Asian participants were found to have significantly more negative attitudes towards the sexual control and sexual rights of people with intellectual disabilities compared to White Westerners. These differences remained significant even after factors known to influence such attitudes were taken into consideration. These findings implicate the need to develop culturally sensitive interventions to improve knowledge and awareness of sexual needs of people with intellectual disabilities. This paper discusses these implications further, the limitations of the present study and suggested directions for future research. PMID- 26594078 TI - Alternating skew deviation in association with anti-glutamic acid decarboxylase antibodies. AB - The presence of an elevated anti-glutamic acid decarboxylase (GAD) antibody level has been associated with a number of eye movement abnormalities, as well as other findings including cerebellar ataxia and insulin dependent diabetes mellitus. Skew deviation in association with anti-GAD antibodies has not been previously reported. Here we report a case of alternating skew deviation along with cerebellar-brainstem signs in a patient with an elevated anti-GAD antibody titer. Follow-up neurologic evaluation after treatment with intravenous immunoglobulin revealed improvement in cerebellar-brainstem signs, while ophthalmic evaluation was stable. PMID- 26594079 TI - Comparison of eigensolvers for symmetric band matrices. AB - We compare different algorithms for computing eigenvalues and eigenvectors of a symmetric band matrix across a wide range of synthetic test problems. Of particular interest is a comparison of state-of-the-art tridiagonalization-based methods as implemented in Lapack or Plasma on the one hand, and the block divide and-conquer (BD&C) algorithm as well as the block twisted factorization (BTF) method on the other hand. The BD&C algorithm does not require tridiagonalization of the original band matrix at all, and the current version of the BTF method tridiagonalizes the original band matrix only for computing the eigenvalues. Avoiding the tridiagonalization process sidesteps the cost of backtransformation of the eigenvectors. Beyond that, we discovered another disadvantage of the backtransformation process for band matrices: In several scenarios, a lot of gradual underflow is observed in the (optional) accumulation of the transformation matrix and in the (obligatory) backtransformation step. According to the IEEE 754 standard for floating-point arithmetic, this implies many operations with subnormal (denormalized) numbers, which causes severe slowdowns compared to the other algorithms without backtransformation of the eigenvectors. We illustrate that in these cases the performance of existing methods from Lapack and Plasma reaches a competitive level only if subnormal numbers are disabled (and thus the IEEE standard is violated). Overall, our performance studies illustrate that if the problem size is large enough relative to the bandwidth, BD&C tends to achieve the highest performance of all methods if the spectrum to be computed is clustered. For test problems with well separated eigenvalues, the BTF method tends to become the fastest algorithm with growing problem size. PMID- 26594080 TI - Hydrothermal alteration and Cu-Ni-PGE mobilization in the charnockitic rocks of the footwall of the South Kawishiwi intrusion, Duluth Complex, USA. AB - In the Neoarchean (~ 2.7 Ga) contact metamorphosed charnockitic footwall of the Mesoproterosoic (1.1 Ga) South Kawishiwi intrusion of the Duluth Complex, the primary metamorphic mineral assemblage and Cu-Ni-PGE sulfide mineralization is overprinted by an actinolite + chlorite + cummingtonite + prehnite + pumpellyite + quartz + calcite hydrothermal mineral assemblage along 2-3 cm thick veins. In calcite, hosted by the hydrothermal alteration zones and in a single recrystallized quartz porphyroblast, four different fluid inclusion assemblages are documented; the composition of these fluid inclusions provide p-T conditions of the fluid flow, and helps to define the origin of the fluids and evaluate their role in the remobilization and reprecipitation of the primary metamorphic sulfide assemblage. Pure CO2 fluid inclusions were found as early inclusions in recrystallized quartz porphyroblast. These inclusions may have been trapped during the recrystallization of the quartz during the contact metamorphism of the footwall charnockite in the footwall of the SKI. The estimated trapping pressure (1.6-2.0 kbar) and temperature (810-920 degrees C) conditions correspond to estimates based on felsic veins in the basal zones of the South Kawishiwi intrusion. Fluid inclusion assemblages with CO2-H2O-NaCl and CH4-N2-H2O-NaCl compositions found in this study along healed microfractures in the recrystallized quartz porphyroblast establish the heterogeneous state of the fluids during entrapment. The estimated trapping pressure and temperature conditions (240-650 bar and 120-150 degrees C for CO2-H2O-NaCl inclusions and 315-360 bar and 145-165 degrees C for CH4-N2-H2O-NaCl inclusions) are significantly lower than the p-T conditions (> 700 degrees C and 1.6-2 kbar) during the contact metamorphism, indicating that this fluid flow might not be related to the cooling of the Duluth Complex and its contact aureole. The presence of chalcopyrite inclusions in these fluid inclusions and in the trails of these fluid inclusion assemblages confirms that at least on local scale these fluids played a role in base metal remobilization. No evidences have been observed for PGE remobilization and transport in the samples. The source of the carbonic phase in the carbonic assemblages (CO2; CH4) could be the graphite, present in the metasedimentary hornfelsed inclusions in the basal zones of the South Kawishiwi intrusion. The hydrothermal veins in the charnockite can be characterized by an actinolite + cummingtonite + chlorite + prehnite + pumpellyite + calcite (I-II) + quartz mineral assemblage. Chlorite thermometry yields temperatures around 276-308 degrees C during the earliest phase of the fluid flow. In the late calcite (II) phase, high salinity (21.6-28.8 NaCl + CaCl2 equiv. wt.%), low temperature (90-160 degrees C), primary aqueous inclusions were found. Chalcopyrite (+/- sphalerite +/- millerite), replacing and intersecting the early hydrothermal phases, are associated to the late calcite (II) phase. The composition of the formational fluids in the Canadian Shield is comparable with the composition of the studied fluid inclusions. This suggests that the composition of the fluids did not change in the past 2 Ga and base metal remobilization by formational fluids could have taken place any time after the formation of the South Kawishiwi intrusion. Sulfur isotope studies carried out on the primary metamorphic (delta34S = 7.4-8.90/00) and the hydrothermal sulfide mineral assemblage (delta34S = 5.5-5.70/00) proves, that during the hydrothermal fluid flow the primary metamorphic ores were remobilized. PMID- 26594081 TI - Thermodynamic Limits of Spatial Resolution in Active Thermography. AB - Thermal waves are caused by pure diffusion: their amplitude is decreased by more than a factor of 500 within a propagation distance of one wavelength. The diffusion equation, which describes the temperature as a function of space and time, is linear. For every linear equation the superposition principle is valid, which is known as Huygens principle for optical or mechanical wave fields. This limits the spatial resolution, like the Abbe diffraction limit in optics. The resolution is the minimal size of a structure which can be detected at a certain depth. If an embedded structure at a certain depth in a sample is suddenly heated, e.g., by eddy current or absorbed light, an image of the structure can be reconstructed from the measured temperature at the sample surface. To get the resolution the image reconstruction can be considered as the time reversal of the thermal wave. This inverse problem is ill-conditioned and therefore regularization methods have to be used taking additional assumptions like smoothness of the solutions into account. In the present work for the first time, methods of non-equilibrium statistical physics are used to solve this inverse problem without the need of such additional assumptions and without the necessity to choose a regularization parameter. For reconstructing such an embedded structure by thermal waves the resolution turns out to be proportional to the depth and inversely proportional to the natural logarithm of the signal-to-noise ratio. This result could be derived from the diffusion equation by using a delta source at a certain depth and setting the entropy production caused by thermal diffusion equal to the information loss. No specific model about the stochastic process of the fluctuations and about the distribution densities around the mean values was necessary to get this result. PMID- 26594082 TI - Comparison of median frequency between traditional and functional sensor placements during activity monitoring. AB - Long-term monitoring is of great clinical relevance. Accelerometers are often used to provide information about activities of daily living. The median frequency (fm) of acceleration has recently been suggested as a powerful parameter for activity recognition. However, compliance issues arise when people need to integrate activity recognition sensors into their daily lives. More functional placements should provide higher levels of conformity, but may also affect the quality and generalizability of the signals. How fm changes as a result of a more functional sensor placement remains unclear. This study investigates the agreement in fm for a sensor placed on the back with one in the pocket across a range of daily activities. The translational and gravitational accelerations are also computed to determine if the accelerometer should be fused with additional sensors to improve agreement. Twelve subjects were tested over four tasks and only the "vertical" x-axis showed a moderate agreement (Intraclass Correlation Coefficient of 0.54) after correction for outliers. Generalizability across traditional and functional sensor locations might therefore be limited. Differentiation of the signal into a translational and gravitational component decreased the level of agreement further, suggesting that combined information streams are more robust to changing locations then singular data streams. Integrating multiple sensor modalities to obtain specific components is unlikely to improve agreement across sensor locations. More research is needed to explore measurement signals of more user friendly sensor configurations that will lead to a greater clinical acceptance of body worn sensor systems. PMID- 26594083 TI - Modeling defects and plasticity in MgSiO3 post-perovskite: Part 1-generalized stacking faults. AB - In this work, we examine the transferability of a pairwise potential model (derived for MgSiO3 perovskite) to accurately compute the excess energies of the generalized stacking faults (GSF, also called gamma-surfaces) in MgSiO3 post perovskite. All calculations have been performed at 120 GPa, a pressure relevant to the D" layer. Taking into account an important aspect of crystal chemistry for complex materials, we consider in detail all possible locations of slip planes in the post-perovskite structure. The gamma-surface calculations emphasize the easiness of glide of slip systems with the smallest shear vector [100] and of the [001](010) slip system. Our results are in agreement with previous ab initio calculations. This validates the use the chosen potential model for further full atomistic modeling of dislocations in MgSiO3 post-perovskite. PMID- 26594084 TI - Modeling defects and plasticity in MgSiO3 post-perovskite: Part 2-screw and edge [100] dislocations. AB - In this study, we propose a full atomistic study of [100] dislocations in MgSiO3 post-perovskite based on the pairwise potential parameterized by Oganov et al. (Phys Earth Planet Inter 122:277-288, 2000) for MgSiO3 perovskite. We model screw dislocations to identify planes where they glide easier. We show that despite a small tendency to core spreading in {011}, [100] screw dislocations glide very easily (Peierls stress of 1 GPa) in (010) where only Mg-O bonds are to be sheared. Crossing the Si-layers results in a higher lattice friction as shown by the Peierls stress of [100](001): 17.5 GPa. Glide of [100] screw dislocations in {011} appears also to be highly unfavorable. Whatever the planes, (010), (001) or {011}, edge dislocations are characterized by a wider core (of the order of 2b). Contrary to screw character, they bear negligible lattice friction (0.1 GPa) for each slip system. The layered structure of post-perovskite results in a drastic reduction in lattice friction opposed to the easiest slip systems compared to perovskite. PMID- 26594085 TI - Objectification in Virtual Romantic Contexts: Perceived Discrepancies between Self and Partner Ideals Differentially affect Body Consciousness in Women and Men. AB - The current study examined whether exposure to sexually objectifying images in a potential romantic partner's virtual apartment affects discrepancies between people's perception of their own appearance (i.e., self-perceptions) and their perception of the body ideal that is considered desirable to a romantic partner (i.e., partner-ideals). Participants were 114 heterosexual undergraduate students (57 women and 57 men) from a northeastern U.S. university. The study used a 2 (Participant Gender) x 2 (Virtual Environment: Sexualized vs. Non-Sexualized) between-subjects design. We predicted that women exposed to sexually objectifying images in a virtual environment would report greater discrepancies between their self-perceptions and partner-ideals than men, which in turn would contribute to women's body consciousness. Findings support this hypothesis and show that perceived discrepancies account for the relationship between exposure to sexually objectifying images and body consciousness for women but not men. We also found gender asymmetries in objectification responses when each component of perceived discrepancies, i.e., self-perceptions versus perceptions of a romantic partner's body ideal, were examined separately. For men, exposure to muscular sexualized images was significantly associated with their self-perceptions but not their perceptions of the body size that is considered desirable to a romantic partner. For women, exposure to thin sexualized images was significantly associated with their perceptions that a romantic partner preferred a woman with a smaller body size. However, exposure to these images did not affect women's self-perceptions. Implications for gender asymmetries in objectification responses and perceived discrepancies that include a romantic partner's perceptions are discussed. PMID- 26594086 TI - ULTRASONIC PROPAGATION VELOCITY IN KTaO3. AB - Ultrasonic velocity measurements in KTaO3 between 2 degrees and 300 degrees K are reported. No evidence for a phase transition was observed. PMID- 26594087 TI - Stochastic diffusion processes on Cartesian meshes. AB - Diffusion of molecules is simulated stochastically by letting them jump between voxels in a Cartesian mesh. The jump coefficients are first derived using finite difference, finite element, and finite volume approximations of the Laplacian on the mesh. An alternative is to let the first exit time for a molecule in random walk in a voxel define the jump coefficient. Such coefficients have the advantage of always being non-negative. These four different ways of obtaining the diffusion propensities are compared theoretically and in numerical experiments. A finite difference and a finite volume approximation generate the most accurate coefficients. PMID- 26594088 TI - Asymptotic correlation functions and FFLO signature for the one-dimensional attractive spin-1/2 Fermi gas. AB - We investigate the long distance asymptotics of various correlation functions for the one-dimensional spin-1/2 Fermi gas with attractive interactions using the dressed charge formalism. In the spin polarized phase, these correlation functions exhibit spatial oscillations with a power-law decay whereby their critical exponents are found through conformal field theory. We show that spatial oscillations of the leading terms in the pair correlation function and the spin correlation function solely depend on [Formula: see text] and [Formula: see text], respectively. Here [Formula: see text] denotes the mismatch between the Fermi surfaces of spin-up and spin-down fermions. Such spatial modulations are characteristics of a Fulde-Ferrell-Larkin-Ovchinnikov (FFLO) state. Our key observation is that backscattering among the Fermi points of bound pairs and unpaired fermions results in a one-dimensional analog of the FFLO state and displays a microscopic origin of the FFLO nature. Furthermore, we show that the pair correlation function in momentum space has a peak at the point of mismatch between both Fermi surfaces [Formula: see text], which has recently been observed in numerous numerical studies. PMID- 26594089 TI - Wideband Electrically-Pumped 1050 nm MEMS-Tunable VCSEL for Ophthalmic Imaging. AB - In this paper, we present a 1050 nm electrically-pumped micro-electro mechanically-tunable vertical-cavity-surface-emitting-laser (MEMS-VCSEL) with a record dynamic tuning bandwidth of 63.8 nm, suitable for swept source optical coherence tomography (SS-OCT) imaging. These devices provide reduced cost & complexity relative to previously demonstrated optically pumped devices by obviating the need for a pump laser and associated hardware. We demonstrate ophthalmic SS-OCT imaging with the electrically-pumped MEMS-VCSEL at a 400 kHz axial scan rate for wide field imaging of the in vivo human retina over a 12 mm * 12 mm field and for OCT angiography of the macula over 6 mm * 6 mm & 3 mm * 3 mm fields to show retinal vasculature and capillary structure near the fovea. These results demonstrate the feasibility of electrically pumped MEMS-VCSELs in ophthalmic instrumentation, the largest clinical application of OCT. In addition, we estimate that the 3 dB coherence length in air is 225 meters +/- 51 meters, far greater than required for ophthalmic SS-OCT and suggestive of other distance ranging applications. PMID- 26594090 TI - General spline filters for discontinuous Galerkin solutions. AB - The discontinuous Galerkin (dG) method outputs a sequence of polynomial pieces. Post-processing the sequence by Smoothness-Increasing Accuracy-Conserving (SIAC) convolution not only increases the smoothness of the sequence but can also improve its accuracy and yield superconvergence. SIAC convolution is considered optimal if the SIAC kernels, in the form of a linear combination of B-splines of degree d, reproduce polynomials of degree 2d. This paper derives simple formulas for computing the optimal SIAC spline coefficients for the general case including non-uniform knots. PMID- 26594091 TI - Single serum cortisol values at 09:00 h can be indices of adrenocortical function in children with Kawasaki disease treated with intravenous immunoglobulin plus prednisolone. AB - Combination treatment with intravenous immunoglobulin (IVIG) plus prednisolone is effective for prevention of cardiovascular complications in children with Kawasaki disease (KD). However, administration of prednisolone for approximately 20 d in this regimen causes adrenocortical suppression in a high proportion of treated children. To establish a simple method to screen for this suppression, we performed a prospective study on 72 children with KD treated with this regimen in our institution from February 2012 to March 2014. By performing ROC analysis of 21 initial patients treated between February and June 2012, a serum cortisol value at 09:00 h of 5 mcg/dL was established as a threshold for intact adrenocortical function, which is equivalent to a peak serum cortisol value of higher than 15 mcg/dL in the CRH stimulation test. Then, we applied this screening test to 51 subsequent patients treated between July 2012 and March 2014. Approximately 90% of the patients with morning serum cortisol values above 5 mcg/dL 2 to 6 mo after the cessation of initial prednisolone treatment had peak serum cortisol values exceeding 15 mcg/dL, suggesting the efficacy of this approach. PMID- 26594094 TI - Two Japanese patients with the renal form of pseudohypoaldosteronism type 1 caused by mutations of NR3C2. AB - Pseudohypoaldosteronism type 1 (PHA1) is a disease characterized by neonatal salt loss due to aldosterone resistance. Two types of PHA1 are known: an autosomal recessive systemic form and an autosomal dominant renal form. The cause of the renal form of PHA1 is heterozygous mutations in NR3C2, which encodes the mineralocorticoid receptor (MR). We encountered two female Japanese infants with the renal form of PHA1 and analyzed NR3C2. The two patients had poor weight gain, and one was developmentally delayed. Genetic analysis identified one novel mutation (c.492_493insTT, p.Met166LeufsX8) and one previously reported mutation (p.R861X). The two produced a premature stop codon, resulting in haploinsufficiency of the MR. In conclusion, genetic analysis of NR3C2 is useful for diagnosis and planning therapeutic strategies. PMID- 26594092 TI - Guidelines for diagnosis and treatment of 21-hydroxylase deficiency (2014 revision). AB - Purpose of developing the guidelines: The first guidelines for diagnosis and treatment of 21-hydroxylase deficiency (21-OHD) were published as a diagnostic handbook in Japan in 1989, with a focus on patients with severe disease. The "Guidelines for Treatment of Congenital Adrenal Hyperplasia (21-Hydroxylase Deficiency) Found in Neonatal Mass Screening (1999 revision)" published in 1999 were revised to include 21-OHD patients with very mild or no clinical symptoms. Accumulation of cases and experience has subsequently improved diagnosis and treatment of the disease. Based on these findings, the Mass Screening Committee of the Japanese Society for Pediatric Endocrinology further revised the guidelines for diagnosis and treatment. Target disease/conditions: 21-hydroxylase deficiency. Users of the guidelines: Physician specialists in pediatric endocrinology, pediatric specialists, referring pediatric practitioners, general physicians; and patients. PMID- 26594095 TI - A case of spondyloepiphyseal dysplasia tarda caused by a novel intragenic deletion of TRAPPC2. PMID- 26594093 TI - Guidelines for Mass Screening of Congenital Hypothyroidism (2014 revision). AB - Purpose of developing the guidelines: Mass screening for congenital hypothyroidism started in 1979 in Japan, and the prognosis for intelligence has been improved by early diagnosis and treatment. The incidence was about 1/4000 of the birth population, but it has increased due to diagnosis of subclinical congenital hypothyroidism. The disease requires continuous treatment, and specialized medical facilities should make a differential diagnosis and treat subjects who are positive in mass screening to avoid unnecessary treatment. The Guidelines for Mass Screening of Congenital Hypothyroidism (1998 version) were developed by the Mass Screening Committee of the Japanese Society for Pediatric Endocrinology in 1998. Subsequently, new findings on prognosis and problems in the adult phase have emerged. Based on these new findings, the 1998 guidelines were revised in the current document (hereinafter referred to as the Guidelines). Target disease/conditions: Primary congenital hypothyroidism. Users of the Guidelines: Physician specialists in pediatric endocrinology, pediatric specialists, physicians referring patients to pediatric practitioners, general physicians, laboratory technicians in charge of mass screening, and patients. PMID- 26594096 TI - Comparison of oil removal in surfactant alternating gas with water alternating gas, water flooding and gas flooding in secondary oil recovery process. AB - Growing oil prices coupled with large amounts of residual oil after operating common enhanced oil recovery methods has made using methods with higher operational cost economically feasible. Nitrogen is one of the gases used in both miscible and immiscible gas injection process in oil reservoir. In heterogeneous formations gas tends to breakthrough early in production wells due to overriding, fingering and channeling. Surfactant alternating gas (SAG) injection is one of the methods commonly used to decrease this problem. Foam which is formed on the contact of nitrogen and surfactant increases viscosity of injected gas. This increases the oil-gas contact and sweep efficiency, although adsorption of surfactant on rock surface can causes difficulties and increases costs of process. Many parameters must be considered in design of SAG process. One of the most important parameters is SAG ratio that should be in optimum value to improve the flooding efficiency. In this study, initially the concentration of surfactant was optimized due to minimization of adsorption on rock surface which results in lower cost of surfactant. So, different sodium dodecyl sulfate (SDS) concentrations of 100, 500, 1000, 2000, 3000 and 4000 ppm were used to obtain the optimum concentration at 70 degrees C and 144.74*105 Pa. A simple, clean and relatively fast spectrophotometric method was used for determination of surfactant which is based on the formation of an ion-pair. Then the effect of surfactant to gas volume ratio on oil recovery in secondary oil recovery process during execution of immiscible surfactant alternating gas injection was examined experimentally. The experiments were performed with sand pack under certain temperature, pressure and constant rate. Experiments were performed with surfactant to gas ratio of 1:1, 1:2, 1:3, 2:1 and 3:1 and 1.2 pore volume injected. Then, comparisons were made between obtained results (SAG) with water flooding, gas flooding and water alternating gas (WAG) processes. This study shows that using the concentration of 1500 ppm of surfactant solution is practical and economical. Results also show that the SAG ratio of 1:1 with 0.2 cm3/min at temperature and pressure of 70 degrees C and 144.74*105 Pa, has the maximum oil removal efficiency. In this SAG ratio, stable foam was formed and viscous fingering delayed in comparison to other ratios. Finally, the results demonstrated that SAG injection has higher oil recovery in comparison to other displacement methods (water flooding, gas flooding and WAG). PMID- 26594097 TI - Ethylene Oxide and Hydrogen Peroxide Gas Plasma Sterilization: Precautionary Practices in U.S. Hospitals. AB - OBJECTIVE: Evaluate precautionary practices and extent of use of ethylene oxide (EtO) and hydrogen peroxide gas plasma (HPGP) sterilization systems, including use of single chamber EtO units. DESIGN: Modular, web-based survey. PARTICIPANTS: Members of professional practice organizations who reported using EtO or HPGP in the past week to sterilize medical instruments and supplies. Participating organizations invited members via email which included a hyperlink to the survey. METHODS: Descriptive analyses were conducted including simple frequencies and prevalences. RESULTS: A total of 428 respondents completed the module on chemical sterilants. Because most respondents worked in hospitals (87%, n=373) analysis focused on these workers. Most used HPGP sterilizers (84%, n=373), 38% used EtO sterilizers, with 22% using both. Nearly all respondents using EtO operated single chamber units (94%, n=120); most of them reported that the units employed single use cartridges (83%, n=115). Examples of where engineering and administrative controls were lacking for EtO include: operational local exhaust ventilation (7%; n=114); continuous air monitoring (6%; n=113); safe handling training (6%; n=142); and standard operating procedures (4%; n=142). Examples of practices which may increase HPGP exposure risk included lack of standard operating procedures (9%; n=311) and safe handling training (8%; n=312). CONCLUSIONS: Use of precautionary practices was good but not universal. EtO use appears to have diminished in favor of HPGP which affords higher throughput and minimal regulatory constraints. Separate EtO sterilization and aeration units were still being used nearly one year after U.S. EPA prohibited their use. PMID- 26594098 TI - What Eye Movements Reveal about Deaf Readers. AB - Levels of illiteracy in the deaf populations around the world have been extremely high for decades and much higher than the illiteracy levels found in the general population. Research has mostly focused on deaf readers' difficulties rather than on their strengths, which can then inform reading education. Deaf readers are a unique population. They process language and the world surrounding them mostly via the visual channel and this greatly affects how they read or might learn to read. The study of eye movements in reading provides highly sophisticated information about how words and sentences are processed and our research with deaf readers reveals the importance of their uniqueness. PMID- 26594099 TI - Educating Intuition: Reducing Risky Decisions Using Fuzzy-Trace Theory. AB - Risky decision-making, especially in adolescence, is a major public health problem. However, fuzzy-trace theory suggests that bad outcomes are preventable by changing thinking, and, therefore, feelings, about risks. The theory aligns with new findings and has been shown to be effective in experiments on sexual risk-taking, medication adherence, and genetic testing. Despite the vulnerabilities of the adolescent brain, decision processes can be modified by applying evidence-based theory. PMID- 26594100 TI - Does paedomorphosis contribute to prairie vole monogamy? AB - We examined skull morphology in prairie voles (Microtus ochrogaster) and meadow voles (M. pennsylvanicus), two closely related species with fundamentally different mating systems, to test the hypothesis that paedomorphosis contributes to the evolution of monogamous mating systems. Using several skull measurements, we found that the overall length:width ratio of meadow vole skulls was greater than that of prairie voles suggesting that meadow vole have longer narrower skulls. We then examined which aspects of skull morphology differed between the species and found that the ratio difference was attributable primarily to longer snout length in meadow voles. Finally, we compared adult morphology in both species to that of pups and found the prairie vole, a monogamous species, displays a more juvenile-like skull morphology than does the meadow vole, a promiscuous species. These results suggest that monogamous vole species retain more juvenile-like morphology than do promiscuous species, and thus possibly retain juvenile-like behaviors that may contribute to a monogamous mating system. PMID- 26594101 TI - Measuring the Parenting Practices of Custodial Grandmothers. AB - Despite increased interest in parenting among custodial grandmothers (CGM), there is scant research on assessing their parenting practices. With CGMs as informants we examined the factor structure for five self-report scales developed as measures of parental nurturance and discipline with birth parents, and then tested for measurement invariance by grandchildren's age (4 - <7 versus >=7 - 12). We also examined concurrent validity for these scales according to the Family Stress Model. Data were from 343 CGMs (M = 58.45, SD = 8.22) enrolled in a randomized clinical trial caring for grandchildren (GC) aged 4 to 12 (M = 7.81, SD = 2.56). Discipline was assessed by three scales from the Parental Behavior Inventory (Consistency, Effective, and Punitive). Nurturance was assessed by the Positive Affect Index and the Supportive Engaged Behavior scale of the Parenting Practice Interview. Confirmatory factor analysis (CFA) revealed that these scales were best represented as five distinct yet covarying factors (RMSEA = .055; SRMR = .07). Follow-up CFAs within each GC age group supported this model, with only few changes suggested by the corresponding diagnostic tests. A model with these changes was then examined for measurement invariance by CG age group, with complete measurement invariance found and all items loading onto their respective factors significantly. The five scales also correlated as expected with indices of CGM psychological distress and GC adjustment. We conclude that the scales examined here can be used meaningfully with CGM as respondents. PMID- 26594102 TI - Male marriage squeeze and inter-provincial marriage in central China: evidence from Anhui. AB - Since the 1990s, inter-provincial female migration for marriage has become important in central and eastern rural China. Using survey data from X County in rural Anhui Province, we explore the arrangement of inter-provincial marriages, as well as the characteristics of husbands and wives, marital satisfaction, and marital stability for these marriages. We find that inter-provincial marriage is an important option for local men to respond to the marriage squeeze and the increasing expense of marriage. It helps to relieve the shortage of marriageable women in the local marriage market. Because this kind of marriage is based on economic exchange, but not affection, it is often subject to a higher risk of marriage instability, and can lead to such illegal behaviors as marriage fraud and mercenary marriage. PMID- 26594104 TI - Land and Law in Marijuana Country: Clean Capital, Dirty Money, and the Drug War's Rentier Nexus. AB - Despite its ongoing federal illegality, marijuana production has become a licit, or socially accepted, feature of northern California's real estate market. As such, marijuana is a key component of land values and the laundering of "illegal" wealth into legitimate circulation. By following land transaction practices, relations, and instruments, this article shows how formally equal property transactions become substantively unequal in light of the "il/legal" dynamics of marijuana land use. As marijuana becomes licit, prohibitionist policies have enabled the capture of ground rent by landed interests from the marijuana industry at a time when the price of marijuana is declining (in part due to its increasing licitness). The resulting "drug war rentier nexus," a state-land finance complex, is becoming a key, if obscured, component within marijuana's contemporary political economy. PMID- 26594103 TI - Coexisting Frailty, Cognitive Impairment, and Heart Failure: Implications for Clinical Care. AB - OBJECTIVE: To review some of the proposed pathways that increase frailty risk in older persons with heart failure and to discuss tools that may be used to assess for changes in physical and cognitive functioning in this population in order to assist with appropriate and timely intervention. METHODS: Review of the literature. RESULTS: Heart failure is the only cardiovascular disease that is increasing by epidemic proportions, largely due to an aging society and therapeutic advances in disease management. Because heart failure is largely a cardiogeriatric syndrome, age-related syndromes such as frailty and cognitive impairment are common in heart failure patients. Compared with age-matched counterparts, older adults with heart failure 4 to 6 times more likely to be frail or cognitively impaired. The reason for the high prevalence of frailty and cognitive impairment in this population is not well known but may likely reflect the synergistic effects of heart failure and aging, which may heighten vulnerability to stressors and accelerate loss of physiologic reserve. Despite the high prevalence of frailty and cognitive impairment in the heart failure population, these conditions are not routinely screened for in clinical practice settings and guidelines on optimal assessment strategies are lacking. CONCLUSION: Persons with heart failure are at an increased risk for frailty, which may worsen symptoms, impair self-management, and lead to worse heart failure outcomes. Early detection of frailty and cognitive impairment may be an opportunity for intervention and a key strategy for improving clinical outcomes in older adults with heart failure. PMID- 26594105 TI - Female-Paced Mating does not Affect Pair-Bond Expression by Male Prairie Voles (Microtus ochrogaster). AB - Prairie vole males typically display robust preferences for affiliation with their respective mates that indicate the expression of a pair-bond. However, it recently has been shown that the strength of a male vole's pair-bond can differ depending on the reproductive status of his mate. In the present study, we examined the possibility that female-controlled pacing of the mating sequence could alter males' affiliative behaviors in a partner-preference test by affecting reproductive success. We expected an earlier onset of mating and thus earlier onset of pregnancy would occur if females controlled the pace of mating, in turn, reinforcing males' preference for their familiar mates vs for a stranger. We found that female-pacing did not affect latency to mating, mating duration, or any of our other measures of social or mating behaviors. Further, female paced-mating did not alter reproductive success as indicated by litter size. We conclude that female-paced mating in prairie voles does not impact the formation, consolidation and/or expression of a pair-bond, either directly or indirectly, by their male partners. PMID- 26594107 TI - We want what's best for our baby: Prenatal Parenting of Babies with Lethal Conditions. AB - This article reports on qualitative research into the experience of couples who chose to continue their pregnancies after receiving a lethal fetal diagnosis, and to embrace the parenting of their baby in the shortened time they have. This analysis of interview data is part of a larger research project describing parents' experiences of continuing pregnancy with a known lethal fetal diagnosis (LFD). PMID- 26594106 TI - Lysophospholipids and their G protein-coupled receptors in atherosclerosis. AB - Lysophospholipids (LPLs) are bioactive lipid-derived signaling molecules generated by the enzymatic and chemical processes of regiospecific phospholipases on substrates such as membrane phospholipids (PLs) and sphingolipids (SLs). They play a major role as extracellular mediators by activating G-protein coupled receptors (GPCRs) and stimulating diverse cellular responses from their signaling pathways. LPLs are involved in various pathologies of the vasculature system including coronary heart disease and hypertension. Many studies suggest the importance of LPLs in their association with the development of atherosclerosis, a chronic and severe vascular disease. This paper focuses on the pathophysiological effects of different lysophospholipids on atherosclerosis, which may promote the pathogenesis of myocardial infarction and strokes. Their atherogenic biological activities take place in vascular endothelial cells, vascular smooth muscle cells, fibroblasts, monocytes and macrophages, dendritic cells, T-lymphocytes, platelets, etc. PMID- 26594108 TI - AIM for Allostery: Using the Ising Model to Understand Information Processing and Transmission in Allosteric Biomolecular Systems. AB - In performing their biological functions, molecular machines must process and transmit information with high fidelity. Information transmission requires dynamic coupling between the conformations of discrete structural components within the protein positioned far from one another on the molecular scale. This type of biomolecular "action at a distance" is termed allostery. Although allostery is ubiquitous in biological regulation and signal transduction, its treatment in theoretical models has mostly eschewed quantitative descriptions involving the system's underlying structural components and their interactions. Here, we show how Ising models can be used to formulate an approach to allostery in a structural context of interactions between the constitutive components by building simple allosteric constructs we termed Allosteric Ising Models (AIMs). We introduce the use of AIMs in analytical and numerical calculations that relate thermodynamic descriptions of allostery to the structural context, and then show that many fundamental properties of allostery, such as the multiplicative property of parallel allosteric channels, are revealed from the analysis of such models. The power of exploring mechanistic structural models of allosteric function in more complex systems by using AIMs is demonstrated by building a model of allosteric signaling for an experimentally well-characterized asymmetric homodimer of the dopamine D2 receptor. PMID- 26594110 TI - Quality in the pharmaceutical industry - A literature review. AB - OBJECTIVES: The aim of this study is to:a.Highlight the most important guidelines and practices of quality in the pharmaceutical industry.b.Organize such guidelines and practices to create a guide to pave the way for other researchers who would like to dig deeper into these guidelines and practices. DESIGN: A review was conducted of 102 publications; 56 publications were concerned with the pharmaceutical quality directly while 46 publications were concerned with the general quality practices. The content of those sources was analyzed and the following themes were identified:a.Research theme 1: Guidelines of the pharmaceutical quality.b.Research theme 2: General practices recently applied in the pharmaceutical industry. MAIN OUTCOME MEASURES: The following guidelines were identified and reviewed: WHO guidelines, FDA guidelines, EU guidelines and ICH guidelines in the research theme I. In research theme II; the following topics were identified and reviewed: quality risk management, quality by design, corrective actions and preventive actions, process capability analysis, Six Sigma, process analytical technology, lean manufacturing, total quality management, ISO series and HACCP. RESULTS: Upon reviewing the previously highlighted guidelines and the practices that are widely applied in the pharmaceutical industry, it was noticed that there is an abundant number of papers and articles that explain the general guidelines and practices but the literature lack those describing application; case studies of the pharmaceutical factories applying those guidelines and significance of those guidelines and practices. CONCLUSIONS: It is recommended that the literature would invest more in the area of application and significance of guidelines and practices. New case studies should be done to prove the feasibility of such practices. PMID- 26594109 TI - Dietary Intake among American Indians with Metabolic Syndrome - Comparison to Dietary Recommendations: the Balance Study. AB - BACKGROUND: American Indians have a very high prevalence of metabolic syndrome that increases their risk of developing cardiovascular disease and type 2 diabetes. Dietary habits are of central importance in the prevention and treatment of metabolic syndrome. OBJECTIVE: The main objective of this article was to describe dietary intake among American Indians with metabolic syndrome and compare it to several dietary recommendations. A secondary objective was to identify certain barriers to dietary adherence experienced by this population. METHODS: A total of 213 participants with metabolic syndrome were enrolled in the Balance Study, a randomized controlled trial with two intervention groups: Guided Group and Self-Managed Group. Dietary intake was assessed using the Block Food Frequency questionnaire. Dietary intakes were evaluated against the Dietary Guidelines for Americans. RESULTS: Intakes of saturated fats, cholesterol, and sodium were higher and intakes of dietary fiber, calcium, magnesium, potassium, vitamin A, vitamin D, and vitamin E were lower than recommended. Additionally, intake of many food groups was noticeably low. Economic factors seem to be related to low adherence to dietary recommendations. CONCLUSION: Results showed low adherence by the participants to dietary recommendations for key nutrients and food groups related to risk factors for metabolic syndrome, type 2 diabetes, and cardiovascular disease. Economic factors are related to this low adherence. These findings illustrate a need to develop innovative, focused, and perhaps individualized health promotion strategies that can improve dietary habits of American Indians with metabolic syndrome. PMID- 26594111 TI - The role of pharmacists in developing countries: The current scenario in the United Arab Emirates. AB - Pharmacy practice has passed several rounds of advancements over the past few years. It had changed the traditional positioning criteria of pharmacists as business people into patient-centered healthcare professionals. This worldwide shift is increasingly accumulating pressure on UAE pharmacists to turn up into better level of service providing accompanied with higher demand of inter personal skills and intellectual capabilities. This can be accomplished through stressing the significance of continuing pharmacy education in basic sciences as well as social and administrative pharmacy techniques and its collaboration in elevating the quality of pharmacy practice in the UAE. PMID- 26594112 TI - Synthesis and oral hypoglycemic effect of novel thiazine containing trisubstituted benzenesulfonylurea derivatives. AB - A new series of 3-(4-substituted phenyl)-1-(4-(4,6-dimethyl-6H-1,3-thiazin-2 yl)phenylsulfonyl)-1-substituted urea (5a-o) was synthesized by an effectual route via sulfonylcarbamates and explores the novel site for substitution in sulfonylurea as well as the way of thiazine can be prepared. The molecules were established by elemental analysis and spectroscopic viz. IR, (1)H NMR, (13)C NMR and MS techniques. All the fifteen derivatives were shown very prominent oral hypoglycemic effect at the dose of 40 mg/kg body weight (p.o.) in respect of standard drug glibenclamide and control. The hypoglycemic effect was studied using oral glucose tolerance test in normal and NIDDM in STZ-rat model. The compounds 5a, 5d, 5f, 5i, 5k and 5n were dominant out of fifteen derivatives for blood glucose lowering activity (more than 80%) when comparing with NIDDM control. These derivatives were either containing simply phenyl ring (5a, 5f and 5k) on to the second amine of sulfonylurea (R' = H) or nitro group at the para position in compound 5d, 5i and 5n (R' = NO2 ) to produce significant oral hypoglycemic effect. Other structural activity relationship is also observed regarding the heteroaromatic and substituted aromatic group at R and R' position respectively. PMID- 26594113 TI - Antiproliferative effects of aspirin and diclofenac against the growth of cancer and fibroblast cells: In vitro comparative study. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the growth of several cancer cell lines. The aim of this study is to compare the cytotoxic effect of aspirin with diclofenac on the growth of HeLa cell, mammary cell carcinoma, rhabdomyosarcoma and fibroblast cell lines in the culture media. The cells are cultured in RPMI-1640 culture media supplemented with 5% fetal calf serum and antibiotics. Aspirin (5 mg/well) and diclofenac (0.625 mg/well) significantly inhibit the growth of HeLa, rhabdomyosarcoma and fibroblast cells. The cytotoxic effect of aspirin against rhabdomyosarcoma is significantly (p < 0.001) higher than that of diclofenac with a potency approximated 2.6. It concludes that aspirin and diclofenac inhibit the growth of fibroblast and cancer cell by inhibiting the up-regulation of cyclooxygenases enzymes in cancer cells. Aspirin is more effective than diclofenac against the growth of rhabdomyosarcoma cell line. PMID- 26594115 TI - Validation of the knowledge, attitude and perceived practice of asthma instrument among community pharmacists using Rasch analysis. AB - There is no instrument which collectively assesses the knowledge, attitude and perceived practice of asthma among community pharmacists. Therefore, this study aimed to validate the instrument which measured the knowledge, attitude and perceived practice of asthma among community pharmacists by producing empirical evidence of validity and reliability of the items using Rasch model (Bond & Fox software(r)) for dichotomous and polytomous data. This baseline study recruited 33 community pharmacists from Penang, Malaysia. The results showed that all PTMEA Corr were in positive values, where an item was able to distinguish between the ability of respondents. Based on the MNSQ infit and outfit range (0.60-1.40), out of 55 items, 2 items from the instrument were suggested to be removed. The findings indicated that the instrument fitted with Rasch measurement model and showed the acceptable reliability values of 0.88 and 0.83 and 0.79 for knowledge, attitude and perceived practice respectively. PMID- 26594114 TI - The possible antianginal effect of allopurinol in vasopressin-induced ischemic model in rats. AB - The anti-anginal effects of allopurinol were assessed in experimental model rats of angina and their effects were evaluated with amlodipine. In the vasopressin induced angina model, oral administration of allopurinol in dose of 10 mg/kg revealed remarkably analogous effects in comparison with amlodipine such as dose dependent suppression of vasopressin-triggered time, duration and severity of ST depression. In addition, allopurinol produced dose dependent suppression of plasma Malondialdehyde (MDA) level, systolic blood pressure, cardiac contractility and cardiac oxygen consumption; while in contrast, amlodipine minimally suppressed the elevation of plasma MDA level. Endothelial NO synthase (eNOS) expression, serum nitrate were strikingly increased, however lipid profile was significantly reduced. Seemingly, allopurinol was found to be more potent than amlodipine - a calcium channel antagonist. To conclude, it was explicitly observed and verified that on the ischemic electrocardiography (ECG) changes in angina pectoris model in rats, allopurinol exerts a significant protective effects, reminiscent of enhancement of vascular oxidative stress, function of endothelial cells, improved coronary blood flow in addition to the potential enhancement in myocardial stress. Moreover, our findings were in conformity with several human studies. PMID- 26594116 TI - Why sildenafil and sildenafil citrate monohydrate crystals are not stable? AB - Sildenafil citrate was crystallized by various techniques aiming to determine the behavior and factors affecting the crystal growth. There are only 2 types of sildenafil obtaining from crystallization: sildenafil (1) and sildenafil citrate monohydrate (2). The used techniques were (i) crystallization from saturated solutions, (ii) addition of an antisolvent, (iii) reflux and (iv) slow solvent evaporation method. By pursuing these various methods, our work pointed that the best formation of crystal (1) was obtained from technique no. (i). Surprisingly, the obtained crystals (1) were perfected if the process was an acidic pH at a cold temperature then perfect crystals occurred within a day. Crystals of compound (2) grew easily using technique no. (ii) which are various polar solvents over a wide range of pH and temperature preparation processes. The infrared spectroscopy and nuclear magnetic resonance spectra fit well with these two X-ray crystal structures. The crystal structures of sildenafil free base and salt forms were different from their different growing conditions leading to stability difference. PMID- 26594117 TI - Detection of adverse drug reactions by medication antidote signals and comparison of their sensitivity with common methods of ADR detection. AB - OBJECTIVE: To determine the PPVs of selected ten medication antidote signals in recognizing potential ADRs and comparison of their sensitivity with manual chart analysis, and voluntary reporting recognizing the same ADRs. METHOD: The inpatient EMR database of internal medicine department was utilized for a period of one year, adult patients prescribed at least one of the ten signals, were included in the study, recipient patients of antidote signals were assessed for the occurrence of an ADR by Naranjo's tool of ADR evaluation. PPVs of each antidote signal were verified. RESULT: PPV of Methylprednisolone and Phytonadione was 0.28, Metoclopramide and Potassium Chloride - 0.29, Dextrose 50%, Promethazine, Sodium Polystyrene and Loperamide - 0.30, Protamine and Acetylcysteine - 0.33. In comparison of confirmed ADRs of antidote signals with other methods, Dextrose 50%, Metoclopramide, Sodium Polystyrene, Potassium Chloride, Methylprednisolone and Promethazine seem to be extremely significant (P value > 0.0001), while ADRs of Phytonadione, Protamine, Acetylcysteine and Loperamide were insignificant. CONCLUSION: Antidote medication signals have definitive discerning evaluation value of ADRs over routine methods of ADR detection with a high detection rate with a minimum cost; Their integration with hospital EMR database and routine patient safety surveillance enhances transparency, time-saving and facilitates ADR detection. PMID- 26594118 TI - Attitude of future healthcare provider towards vitamin D significance in relation to sunlight exposure. AB - OBJECTIVE: Nature is the kindest of all to provide man with all the necessary components for a healthy life at easily accessible lengths. The deprivation arises with unawareness and lack of correct measures to extract the benefits. Medical education makes the youth aware of the numerous disorders and diseases, as well as their preventions and treatments. This awareness needs to be realized and implemented in the society, and it is not possible without the advisers acting on the same lines. Since doctors are the most trusted and their advice is adopted without much thought, it is extremely inevitable to analyze the attitude of medical students of various levels to understand the cause of their negligence toward their own deficiencies, the focus for this study being vitamin D (VD). METHOD: A cross sectional descriptive study was done on undergraduate medical students of health profession from different universities of Pakistan to access the awareness regarding VD deficiency associated with sunlight. Informed consent was duly signed by each participant after which self-constructed questionnaire was provided to them and data are collected. SPSS 17 was used for Statistical analysis. RESULTS: Final students are well aware of VD significance, take food rich in VD but still suffer from fatigue and muscular pain. No treatment was taken for fatigue and muscular pain by majority of these sufferers and those who took treatment were VD supplement. The health sufferers were mostly those who avoided sunlight highlighting the role of VD in maintaining an active lifestyle as well as the significance of sunlight in maintaining VD levels. CONCLUSION: It can be concluded that in spite of awareness, the role of sunlight exposure and the proper time and duration of exposure cannot be ignored to create a healthy and active society. PMID- 26594119 TI - Design, optimization and evaluation of glipizide solid self-nanoemulsifying drug delivery for enhanced solubility and dissolution. AB - A solid self-nanoemulsifying drug-delivery system (solid SNEDDS) has been explored to improve the solubility and dissolution profile of glipizide. SNEDDS preconcentrate was systematically optimized using a circumscribed central composite design by varying Captex 355 (Oil), Solutol HS15 (Surfactant) and Imwitor 988 (Co-surfactant). The optimized SNEDDS preconcentrate consisted of Captex 355 (30% w/w), Solutol HS15 (45% w/w) and Imwitor 988 (25% w/w). The saturation solubility (SS) of glipizide in optimized SNEDDS preconcentrate was found to be 45.12 +/- 1.36 mg/ml, indicating an improvement (1367 times) of glipizide solubility as compared to its aqueous solubility (0.033 +/- 0.0021 mg/ml). At 90% SS, glipizide was loaded to the optimized SNEDDS. In-vitro dilution of liquid SNEDDS resulted in a nanoemulsion with a mean droplet size of 29.4 nm. TEM studies of diluted liquid SNEDDS confirmed the uniform shape and size of the globules. The liquid SNEDDS was adsorbed onto calcium carbonate and talc to form solid SNEDDS. PXRD, DSC, and SEM results indicated that, the presence of glipizide as an amorphous and as a molecular dispersion state within solid SNEDDS. Glipizide dissolution improved significantly (p < 0.001) from the solid SNEDDS (~100% in 15 min) as compared to the pure drug (18.37%) and commercial product (65.82) respectively. PMID- 26594120 TI - Akathisia with Erythromycin: Induced or precipitated? AB - OBJECTIVE: A 28-year-old male diagnosed with schizophrenia, maintaining well on Olanzapine, developed akathisia soon after addition of Erythromycin for Pityriasis Rosea. This prompted us to evaluate the relationship of Erythromycin and akathisia. METHOD: We report the case and the literature focusing on akathisia as a possible adverse event of Erythromycin. RESULTS: Akathisia resolved after Erythromycin was stopped following 5 days of treatment. Akathisia was possibly induced or precipitated with use of Erythromycin. Possible etiological reasons of this clinically significant association are discussed. CONCLUSION: Erythromycin, by itself, may induce akathisia or precipitate akathisia in individuals by interfering with metabolism of other culprit drugs. PMID- 26594121 TI - Evaluation of a biosimilar recombinant alpha epoetin in the management of anemia in hemodialysis patients. AB - BACKGROUND: The efficacy of human recombinant erythropoietins (rHuEPOs) in the treatment of anemia with different etiologies is proven. Development of biosimilar rHuEPO products with lower cost and wider availability is important for the care of anemic patients. OBJECTIVE: The aim of the present study was to determine the bioequivalence and safety of a biosimilar rHuEPO (Pastopoitin((r))) and compare it with the innovator product Eprex((r)), as a standard rHuEPO. METHODS: One hundred and seven anemic patients on stable hemodialysis were recruited to this randomized double-blind comparative trial and assigned to either subcutaneous Pastopoitin (n = 50) or Eprex (n = 57). Each study group received rHuEPO at a dose of 80-120 IU/kg/week in 2-3 divided doses for a period of 3 months. Hematologic parameters including Hemoglobin, hematocrit, RBC, EBC, platelet, MCV, MCH and MCHC were checked every 2 weeks. Blood iron, ferritin, TIBC, creatinine, BUN and electrolytes (Na, K, Ca and P) were evaluated monthly over the 3 months. RESULTS: A significant increase in hemoglobin, hematocrit and RBC was observed by the end of study in both Pastopoitin and Eprex groups (p < 0.001). However, these factors were not significantly different between the groups, neither at baseline nor at the end of study (p > 0.05). Likewise, the groups were comparable regarding MCV, MCH, MCHC, iron, ferritin, TIBC, creatinine, BUN and electrolytes at baseline as well as at the end of trial. Adverse events were not serious and occurred with the same frequency in the study groups. CONCLUSION: Pastopoitin showed comparable efficacy and safety profile with Eprex in anemic patients on hemodialysis. Hence, Pastopoitin may be considered as a rHuEPO with a lower cost and wider availability compared with the innovator product Eprex. PMID- 26594122 TI - Full factorial design for optimization, development and validation of HPLC method to determine valsartan in nanoparticles. AB - High performance liquid chromatographic method was optimized, developed and validated as per the ICH guidelines. In this study the 20 mM ammonium formate and acetonitrile in the 57:43 ratio were used as mobile phase for the analysis of valsartan. Full factorial design was used to optimize the effect of variable factors. The responses were peak area, tailing factor and number of theoretical plates. The quadratic effect of flow rate and wavelength individually as well as in interaction were most significant (p < 0.0001 and p < 0.0086, respectively) on peak area; the quadratic effect of pH of buffer was also most significant effect (p < 0.0001) on tailing factor (5%) whereas the quadratic effect of flow rate and wavelength individually was significant (p = 0.0006 and p = 0.0265, respectively) on the number of theoretical plates. The high-performance liquid chromatographic separation was performed at the flow rate 1.0 min/mL, UV detector wavelength 250 nm and pH of the buffer 3.0 as optimized parameters using design of experiments. The retention time values of valsartan were found to be 10.177 min. Percent recovery in terms of accuracy for the prepared valsartan nanoparticles was found in the range of 98.57-100.27%. PMID- 26594123 TI - Safety of lacosamide in children with refractory partial epilepsy. AB - OBJECTIVES: The study was carried out to investigate the safety of lacosamide on children with refractory partial epilepsy. MATERIALS & METHODS: The study was carried out at a tertiary care hospital after obtaining approval from the institutional ethics committee. Patients aged between 5 and 15 years taking oral lacosamide (LCM) tablets that were given orally as an adjunctive anti-epileptic drug were enrolled for assessing safety, tolerability and its effect on the behavioural life at every visit of titration, during the treatment period (3 months) and at 2 follow up visits that were done at monthly intervals. Adverse events reported by caregiver or by investigator were recorded. Patients/caregivers also completed a 25 items on Connor's behavioural rating clinical scale at every visit. RESULTS: Out of 531 screened patients, 79 patients with refractory partial epilepsy were enrolled after they fulfilled the inclusion and exclusion criteria. Mean age of the children was 8.84 +/- 3.09 years (5-15 years), of which 53 were males and 26 females. The mean age at onset of seizures in males was 6.46 +/- 3.57 and in females, 6.38 +/- 3.39 years. Seventy-six children of 79, completed 3 months of treatment period showed significant (p < 0.001) decrease in the frequency of seizures, significant improvement in behaviour and showed good tolerability. Three (3.79%) patients dropped out of the study due to hyperactive behaviour, vomiting and lack of seizure control respectively. CONCLUSIONS: Lacosamide is a well-tolerated newer antiepileptic drug that is effective in refractory partial epilepsy paediatric patients and concurrently improved patient's behaviour. PMID- 26594124 TI - Microsponges based novel drug delivery system for augmented arthritis therapy. AB - The motive behind present work was to formulate and evaluate gel containing microsponges of diclofenac diethylamine to provide prolonged release for proficient arthritis therapy. Quasi-emulsion solvent diffusion method was implied using Eudragit RS-100 and microsponges with varied drug-polymer ratios were prepared. For the sake of optimization, diverse factors affecting microparticles physical properties were too investigated. Microsponges were characterized by SEM, DSC, FT-IR, XRPD and particle size analysis, and evaluated for morphology, drug loading, in vitro drug release and ex vivo diffusion as well. There were no chemical interactions between drug and polymers used as revealed by compatibility studies outcomes. The drug polymer ratio reflected notable effect on drug content, encapsulation efficiency and particle size. SEM results revealed spherical microsponges with porous surface, and had 7.21 MUm mean particle size. The microsponges were then incorporated in gel; which exhibited viscous modulus along with pseudoplastic behavior. In vitro drug release results depicted that microsponges with 1:2 drug-polymer ratio were more efficient to give extended drug release of 75.88% at the end of 8 h; while conventional formulation get exhausted incredibly earlier by releasing 81.11% drug at the end of 4 h only. Thus the formulated microsponge-based gel of diclofenac diethylamine would be a promising alternative to conventional therapy for safer and efficient treatment of arthritis and musculoskeletal disorders. PMID- 26594125 TI - Pharmacist, the pharmaceutical industry and pharmacy education in Saudi Arabia: A questionnaire-based study. AB - BACKGROUND: In Saudi Arabia there is an estimated need of more than 100,000 pharmacy graduates to cover all present sectors. The shortage of pharmacists has affected many of these sectors especially the pharmaceutical industry. The contribution of Saudi pharmacists to local pharmaceuticals industry would be extremely beneficial and important for shaping the future of the drug industry within the Kingdom. It is not clear whether future Saudi pharmacists are willing to contribute to local pharmaco-industrial fields. METHODS: A cross-sectional, questionnaire-based survey was conducted on all final-year pharmacy students in King Saud University (KSU), Riyadh, Kingdom of Saudi Arabia (KSA). RESULTS: Out of a total of 130 students registered in the final-year of the pharmacy program in KSU, 122 (93.8%) were able to complete the questionnaire. The results showed that the majority (83%) of Saudi pharmacy students indicated that they had not received practical training in the pharmaceutical companies, while only 17.2% of the students felt that they had the knowledge and the skills to work in the pharmaceutical industry after graduation. The majority of the students (66.7%) chose clinical pharmacy as their future career field while only 10.9% indicated willingness to work in a pharmaceutical industry career. Only 8.2% selected working in the pharmaceutical industry. The significant predictor of possibly choosing a career in the local drug industry is a student with a bachelor's degree (compared to Pharm D degree) in pharmacy (OR = 2.7 [95% CI 1.1-6.3]). CONCLUSION: Pharmacy students who are enrolled in the capital city of Riyadh are not properly trained to play an influential role in local drug companies. As a result, their level of willingness to have a career in such important business is not promising (more among Pharm D program). Future research in other pharmacy colleges within Saudi Arabia is needed to confirm such results. PMID- 26594126 TI - Preparation and in vitro evaluation of enteric-coated tablets of rosiglitazone sodium. AB - The aim of this study was to prepare the rosiglitazone sodium enteric-coated tablets and investigate its release rate. The rosiglitazone sodium enteric-coated tablet was prepared by single punch tablet press using substituted hydroxypropyl cellulose and polyvinylpyrrolidone (PVP). The release rate from the enteric coated tablet of rosiglitazone sodium was evaluated. The release rate study showed that few rosiglitazone sodium was released from enteric coated formulation within 2 h in simulated gastric juice, while it released more than 80% of the labeled amount in 30 min in simulated intestinal juice. The preparing method of rosiglitazone sodium enteric-coated tablets was simple and had a good reproducibility. The release condition and determined methods could be used for the routine determinations of rosiglitazone sodium enteric-coated tablets. PMID- 26594127 TI - Atmospheric dispersion of PCB from a contaminated Lake Michigan harbor. AB - Indiana Harbor and Ship Canal (IHSC) in East Chicago is an industrial waterway on Lake Michigan and a source of PCBs to Lake Michigan and the overlying air. We hypothesized that IHSC is an important source of airborne PCBs to surrounding communities. We used AERMOD to model hourly PCB concentrations, utilizing emission fluxes from a prior study and hourly meteorology provided by the State of Indiana. We also assessed dispersion using hourly observed meteorology from a local airport and high resolution profiles simulated by the Weather Research and Forecasting model. We found that emissions from IHSC waters contributed about 15% of the observed SigmaPCB concentrations close to IHSC when compared on an hourly basis and about 10% of observed annual concentrations at a nearby school. Concentrations at the school due to emissions from IHSC ranged from 0 to 18,000 pg m-3, up to 20 times higher than observed background levels, with an annual geometric mean (GSD) of 19 (31) pg m-3. Our findings indicate that IHSC is an important source of PCBs to East Chicago, but not the only source. Four observed enriched PCB3 samples suggest a nearby non-Aroclor source. PMID- 26594128 TI - Pulmonary toxicity of well-dispersed cerium oxide nanoparticles following intratracheal instillation and inhalation. AB - We performed inhalation and intratracheal instillation studies of cerium dioxide (CeO2) nanoparticles in order to investigate their pulmonary toxicity, and observed pulmonary inflammation not only in the acute and but also in the chronic phases. In the intratracheal instillation study, F344 rats were exposed to 0.2 mg or 1 mg of CeO2 nanoparticles. Cell analysis and chemokines in bronchoalveolar lavage fluid (BALF) were analyzed from 3 days to 6 months following the instillation. In the inhalation study, rats were exposed to the maximum concentration of inhaled CeO2 nanoparticles (2, 10 mg/m3, respectively) for 4 weeks (6 h/day, 5 days/week). The same endpoints as in the intratracheal instillation study were examined from 3 days to 3 months after the end of the exposure. The intratracheal instillation of CeO2 nanoparticles caused a persistent increase in the total and neutrophil number in BALF and in the concentration of cytokine-induced neutrophil chemoattractant (CINC)-1, CINC-2, chemokine for neutrophil, and heme oxygenase-1 (HO-1), an oxidative stress marker, in BALF during the observation time. The inhalation of CeO2 nanoparticles also induced a persistent influx of neutrophils and expression of CINC-1, CINC-2, and HO-1 in BALF. Pathological features revealed that inflammatory cells, including macrophages and neutrophils, invaded the alveolar space in both studies. Taken together, the CeO2 nanoparticles induced not only acute but also chronic inflammation in the lung, suggesting that CeO2 nanoparticles have a pulmonary toxicity that can lead to irreversible lesions. PMID- 26594129 TI - The partitioning of nanoparticles to endothelium or interstitium during ultrasound-microbubble-targeted delivery depends on peak-negative pressure. AB - Patients diagnosed with advanced peripheral arterial disease often face poor prognoses and have limited treatment options. For some patient populations, the therapeutic growth of collateral arteries (i.e. arteriogenesis) that bypass regions affected by vascular disease may become a viable treatment option. Our group and others are developing therapeutic approaches centered on the ability of ultrasound-activated microbubbles to permeabilize skeletal muscle capillaries and facilitate the targeted delivery of pro-arteriogenic growth factor-bearing nanoparticles. The development of such approaches would benefit significantly from a better understanding of how nanoparticle diameter and ultrasound peak negative pressure affect both total nanoparticle delivery and the partitioning of nanoparticles to endothelial or interstitial compartments. Toward this goal, using Balb/C mice that had undergone unilateral femoral artery ligation, we intra arterially co-injected nanoparticles (50 and 100 nm) with microbubbles, applied 1 MHz ultrasound to the gracilis adductor muscle at peak-negative pressures of 0.7, 0.55, 0.4, and 0.2 MPa, and analyzed nanoparticle delivery and distribution. As expected, total nanoparticle (50 and 100 nm) delivery increased with increasing peak-negative pressure, with 50 nm nanoparticles exhibiting greater tissue coverage than 100 nm nanoparticles. Of particular interest, increasing peak negative pressure resulted in increased delivery to the interstitium for both nanoparticle sizes, but had little influence on nanoparticle delivery to the endothelium. Thus, we conclude that alterations to peak-negative pressure may be used to adjust the fraction of nanoparticles delivered to the interstitial compartment. This information will be useful when designing ultrasound protocols for delivering pro-arteriogenic nanoparticles to skeletal muscle. PMID- 26594131 TI - A randomised wait-list controlled clinical trial of the effects of acceptance and commitment therapy in patients with type 1 diabetes: a study protocol. AB - BACKGROUND: In order to manage the acute and long-term effects of living with a chronic disease such as diabetes, both medical treatment and good psychosocial support are needed. In this study, we wish to examine whether a psychological group intervention targeting people with poorly controlled type 1 diabetes can be helpful in augmenting quality of life while also lowering participants' HbA1c level. The group intervention will consist of a brief treatment developed from a branch of cognitive behavioural therapy called acceptance and commitment therapy, which is part of the so-called third wave of cognitive behavioural therapy. Common for these third-wave therapies, the focus is less on the content and restructuring of thoughts and more on the function of behaviour. Here, we describe the protocol and plans for study enrolment. METHODS/DESIGN: This on going study is designed as a randomised wait-list controlled trial. Eighty patients aged 26-55 years and with an HbA1c level >70 mmol/mol at the time of enrolment will be included. DISCUSSION: In this study, we will assess the effect of starting acceptance and commitment therapy group treatment for patients with type 1 diabetes and its effect on glycaemic control and well-being. TRIAL REGISTRATION: Current controlled trials: ISRCTN17006837, registered 12(th) January 2015. PMID- 26594130 TI - Genetically modified whole-cell bioreporters for environmental assessment. AB - Living whole-cell bioreporters serve as environmental biosentinels that survey their ecosystems for harmful pollutants and chemical toxicants, and in the process act as human and other higher animal proxies to pre-alert for unfavorable, damaging, or toxic conditions. Endowed with bioluminescent, fluorescent, or colorimetric signaling elements, bioreporters can provide a fast, easily measured link to chemical contaminant presence, bioavailability, and toxicity relative to a living system. Though well tested in the confines of the laboratory, real-world applications of bioreporters are limited. In this review, we will consider bioreporter technologies that have evolved from the laboratory towards true environmental applications, and discuss their merits as well as crucial advancements that still require adoption for more widespread utilization. Although the vast majority of environmental monitoring strategies rely upon bioreporters constructed from bacteria, we will also examine environmental biosensing through the use of less conventional eukaryotic-based bioreporters, whose chemical signaling capacity facilitates a more human-relevant link to toxicity and health-related consequences. PMID- 26594132 TI - Choosing wisely in Allergology: a Slow Medicine approach to the discipline promoted by the Italian Society of Allergy, Asthma and Clinical Immunology (SIAAIC). AB - BACKGROUND: One of the main problem health care systems are facis is the mis-use and over-use of medical resources (including useless exams, surgical interventions, medical treatments, screening procedures...) which may lead to high health care related costs without increased patients' benefit and possible harm to the patients themselves. The "Choosing wisely" campaign, in Italy denominated "Doing more does not mean doing better", tries to educate doctors and citizens at a correct use of medical resources. METHODS: the Italian Society of Allergy, Asthma and Clinical Immunology (SIAAIC) adhered to the "Doing more does not mean doing better" campaing and made a list of the 5 allergological procedures with the highest evidence of inappropriateness. RESULTS: the 5 recommendations were: "Do not perform allergy tests for drugs (including anhestetics) and/or foods when there are neither clinical history nor symptoms suggestive of hypersensitivity reactions"; "Do not perform the so-called "food intolerance tests" (apart from those which are validated for suspect celiac disease or lactose enzymatic intolerance)"; "Do not perform serological allergy tests (i.e.: total IgE, specific IgE, ISAC) as first-line tests or as "screening" assays"; "Do not treat patients sensitized to allergens or aptens if there is not a clear correlation between exposure to that specific allergen/apten and symptoms suggestive of allergic reaction"; "Do not diagnose asthma without having performed lung function tests". CONCLUSIONS: An important role scientific societies should play is to advise on correct diagnostic and therapeutical pathways. For this reason SIAAIC decided to adhere to the Slow Medicine Italy campaign "Doing more does not mean doing better" with the aim of warning the scientific community and the citizens/patients about some allergological procedures, which, when performed in the wrong clinical setting, may be not only useless, but unnecessarily expensive and even harmful for patients' health. PMID- 26594133 TI - Scatter Matters: Regularities and Implications for the Scatter of Healthcare Information on the Web. AB - Despite the development of huge healthcare Web sites and powerful search engines, many searchers end their searches prematurely with incomplete information. Recent studies suggest that users often retrieve incomplete information because of the complex scatter of relevant facts about a topic across Web pages. However, little is understood about regularities underlying such information scatter. To probe regularities within the scatter of facts across Web pages, this article presents the results of two analyses: (a) a cluster analysis of Web pages that reveals the existence of three page clusters that vary in information density and (b) a content analysis that suggests the role each of the above-mentioned page clusters play in providing comprehensive information. These results provide implications for the design of Web sites, search tools, and training to help users find comprehensive information about a topic and for a hypothesis describing the underlying mechanisms causing the scatter. We conclude by briefly discussing how the analysis of information scatter, at the granularity of facts, complements existing theories of information-seeking behavior. PMID- 26594134 TI - Access to Adequate Healthcare for Hmong Women: A Patient Navigation Program to Increase Pap Test Screening. AB - This paper describes the development and implementation of a Hmong Cervical Cancer Intervention Program utilizing a patient navigation model to raise cervical cancer awareness for Hmong women through educational workshops and to assist Hmong women in obtaining a Pap test. Out of 402 women who participated in a baseline survey, the Patient Navigation Program was able to enroll 109 participants who had not had a Pap test in the past 3 years and had never had a Pap test. Through utilization of outreach, an awareness campaign and patient navigation support, at least 38 percent of 109 participants obtained a Pap test. Overall, 21 workshops and 43 outreach activities were conducted by the Hmong Women's Heritage Association, leading to 63 percent of those enrolled in the Patient Navigation Program who could be contacted to obtain a Pap test. PMID- 26594135 TI - Optimizing Nanoplasmonic Biosensor Sensitivity with Orientated Single Domain Antibodies. AB - Localized surface plasmon resonance (LSPR) spectroscopy and imaging are emerging biosensor technologies which tout label-free biomolecule detection at the nanoscale and ease of integration with standard microscopy setups. The applicability of these techniques can be limited by the restrictions that surface conjugated ligands must be both sufficiently small and orientated to meet analyte sensitivity requirements. We demonstrate that orientated single domain antibodies (sdAb) can optimize nanoplasmonic sensitivity by comparing three anti-ricin sdAb constructs to biotin-neutravidin, a model system for small and highly orientated ligand studies. LSPR imaging of electrostatically orientated sdAb exhibited a ricin sensitivity equivalent to that of the biotinylated LSPR biosensors for neutravidin. These results, combined with the facts that sdAb are highly stable and readily produced in bacteria and yeast, build a compelling case for the increased utilization of sdAbs in nanoplasmonic applications. PMID- 26594136 TI - High-throughput metabolic screening of microalgae genetic variation in response to nutrient limitation. AB - Microalgae produce metabolites that could be useful for applications in food, biofuel or fine chemical production. The identification and development of suitable strains require analytical methods that are accurate and allow rapid screening of strains or cultivation conditions. We demonstrate the use of Fourier transform infrared (FT-IR) spectroscopy to screen mutant strains of Chlamydomonas reinhardtii. These mutants have knockdowns for one or more nutrient starvation response genes, namely PSR1, SNRK2.1 and SNRK2.2. Limitation of nutrients including nitrogen and phosphorus can induce metabolic changes in microalgae, including the accumulation of glycerolipids and starch. By performing multivariate statistical analysis of FT-IR spectra, metabolic variation between different nutrient limitation and non-stressed conditions could be differentiated. A number of mutant strains with similar genetic backgrounds could be distinguished from wild type when grown under specific nutrient limited and replete conditions, demonstrating the sensitivity of FT-IR spectroscopy to detect specific genetic traits. Changes in lipid and carbohydrate between strains and specific nutrient stress treatments were validated by other analytical methods, including liquid chromatography-mass spectrometry for lipidomics. These results demonstrate that the PSR1 gene is an important determinant of lipid and starch accumulation in response to phosphorus starvation but not nitrogen starvation. However, the SNRK2.1 and SNRK2.2 genes are not as important for determining the metabolic response to either nutrient stress. We conclude that FT-IR spectroscopy and chemometric approaches provide a robust method for microalgae screening. PMID- 26594137 TI - Molecular and neuronal plasticity mechanisms in the amygdala-prefrontal cortical circuit: implications for opiate addiction memory formation. AB - The persistence of associative memories linked to the rewarding properties of drugs of abuse is a core underlying feature of the addiction process. Opiate class drugs in particular, possess potent euphorigenic effects which, when linked to environmental cues, can produce drug-related "trigger" memories that may persist for lengthy periods of time, even during abstinence, in both humans, and other animals. Furthermore, the transitional switch from the drug-naive, non dependent state to states of dependence and withdrawal, represents a critical boundary between distinct neuronal and molecular substrates associated with opiate-reward memory formation. Identifying the functional molecular and neuronal mechanisms related to the acquisition, consolidation, recall, and extinction phases of opiate-related reward memories is critical for understanding, and potentially reversing, addiction-related memory plasticity characteristic of compulsive drug-seeking behaviors. The mammalian prefrontal cortex (PFC) and basolateral nucleus of the amygdala (BLA) share important functional and anatomical connections that are involved importantly in the processing of associative memories linked to drug reward. In addition, both regions share interconnections with the mesolimbic pathway's ventral tegmental area (VTA) and nucleus accumbens (NAc) and can modulate dopamine (DA) transmission and neuronal activity associated with drug-related DAergic signaling dynamics. In this review, we will summarize research from both human and animal modeling studies highlighting the importance of neuronal and molecular plasticity mechanisms within this circuitry during critical phases of opiate addiction-related learning and memory processing. Specifically, we will focus on two molecular signaling pathways known to be involved in both drug-related neuroadaptations and in memory related plasticity mechanisms; the extracellular-signal-regulated kinase system (ERK) and the Ca(2+)/calmodulin-dependent protein kinases (CaMK). Evidence will be reviewed that points to the importance of critical molecular memory switches within the mammalian brain that might mediate the neuropathological adaptations resulting from chronic opiate exposure, dependence, and withdrawal. PMID- 26594138 TI - Dominant spinal muscular atrophy is caused by mutations in BICD2, an important golgin protein. AB - Spinal muscular atrophies (SMAs) are characterized by degeneration of spinal motor neurons and muscle weakness. Autosomal recessive SMA is the most common form and is caused by homozygous deletions/mutations of the SMN1 gene. However, families with dominant inherited SMA have been reported, for most of them the causal gene remains unknown. Recently, we and others have identified heterozygous mutations in BICD2 as causative for autosomal dominant SMA, lower extremity predominant, 2 (SMALED2) and hereditary spastic paraplegia (HSP). BICD2 encodes the Bicaudal D2 protein, which is considered to be a golgin, due to its coiled coil (CC) structure and interaction with the small GTPase RAB6A located at the Golgi apparatus. Golgins are resident proteins in the Golgi apparatus and form a matrix that helps to maintain the structure of this organelle. Golgins are also involved in the regulation of vesicle transport. In vitro overexpression experiments and studies of fibroblast cell lines derived from patients, showed fragmentation of the Golgi apparatus. In the current review, we will discuss possible causes for this disruption, and the consequences at cellular level, with a view to better understand the pathomechanism of this disease. PMID- 26594142 TI - The Golgi complex in stress and death. AB - The Golgi complex is a central organelle of the secretory pathway where sorting and processing of cargo occurs. While Golgi structure is important for the efficient processing of secretory cargo, the unusual organization suggests additional potential functions. The Golgi is disassembled after various cellular stresses, and we hypothesize that Golgi disassembly activates a stress signaling pathway. This pathway would function to correct the stress if possible, with irreparable stress resulting in apoptosis. Neurons appear to be particularly sensitive to Golgi stress; early disassembly of the organelle correlates with many neurodegenerative diseases. Here, Golgi stress and potential signaling pathways to the nucleus are reviewed. PMID- 26594140 TI - Cerebro-cerebellar circuits in autism spectrum disorder. AB - The cerebellum is one of the most consistent sites of abnormality in autism spectrum disorder (ASD) and cerebellar damage is associated with an increased risk of ASD symptoms, suggesting that cerebellar dysfunction may play a crucial role in the etiology of ASD. The cerebellum forms multiple closed-loop circuits with cerebral cortical regions that underpin movement, language, and social processing. Through these circuits, cerebellar dysfunction could impact the core ASD symptoms of social and communication deficits and repetitive and stereotyped behaviors. The emerging topography of sensorimotor, cognitive, and affective subregions in the cerebellum provides a new framework for interpreting the significance of regional cerebellar findings in ASD and their relationship to broader cerebro-cerebellar circuits. Further, recent research supports the idea that the integrity of cerebro-cerebellar loops might be important for early cortical development; disruptions in specific cerebro-cerebellar loops in ASD might impede the specialization of cortical regions involved in motor control, language, and social interaction, leading to impairments in these domains. Consistent with this concept, structural, and functional differences in sensorimotor regions of the cerebellum and sensorimotor cerebro-cerebellar circuits are associated with deficits in motor control and increased repetitive and stereotyped behaviors in ASD. Further, communication and social impairments are associated with atypical activation and structure in cerebro-cerebellar loops underpinning language and social cognition. Finally, there is converging evidence from structural, functional, and connectivity neuroimaging studies that cerebellar right Crus I/II abnormalities are related to more severe ASD impairments in all domains. We propose that cerebellar abnormalities may disrupt optimization of both structure and function in specific cerebro-cerebellar circuits in ASD. PMID- 26594141 TI - Autism spectrum disorders and neuropathology of the cerebellum. AB - The cerebellum contains the largest number of neurons and synapses of any structure in the central nervous system. The concept that the cerebellum is solely involved in fine motor function has become outdated; substantial evidence has accumulated linking the cerebellum with higher cognitive functions including language. Cerebellar deficits have been implicated in autism for more than two decades. The computational power of the cerebellum is essential for many, if not most of the processes that are perturbed in autism including language and communication, social interactions, stereotyped behavior, motor activity and motor coordination, and higher cognitive functions. The link between autism and cerebellar dysfunction should not be surprising to those who study its cellular, physiological, and functional properties. Postmortem studies have revealed neuropathological abnormalities in cerebellar cellular architecture while studies on mouse lines with cell loss or mutations in single genes restricted to cerebellar Purkinje cells have also strongly implicated this brain structure in contributing to the autistic phenotype. This connection has been further substantiated by studies investigating brain damage in humans restricted to the cerebellum. In this review, we summarize advances in research on idiopathic autism and three genetic forms of autism that highlight the key roles that the cerebellum plays in this spectrum of neurodevelopmental disorders. PMID- 26594139 TI - Glutamatergic transmission in drug reward: implications for drug addiction. AB - Individuals addicted to drugs of abuse such as alcohol, nicotine, cocaine, and heroin are a significant burden on healthcare systems all over the world. The positive reinforcing (rewarding) effects of the above mentioned drugs play a major role in the initiation and maintenance of the drug-taking habit. Thus, understanding the neurochemical mechanisms underlying the reinforcing effects of drugs of abuse is critical to reducing the burden of drug addiction in society. Over the last two decades, there has been an increasing focus on the role of the excitatory neurotransmitter glutamate in drug addiction. In this review, pharmacological and genetic evidence supporting the role of glutamate in mediating the rewarding effects of the above described drugs of abuse will be discussed. Further, the review will discuss the role of glutamate transmission in two complex heterogeneous brain regions, namely the nucleus accumbens (NAcc) and the ventral tegmental area (VTA), which mediate the rewarding effects of drugs of abuse. In addition, several medications approved by the Food and Drug Administration that act by blocking glutamate transmission will be discussed in the context of drug reward. Finally, this review will discuss future studies needed to address currently unanswered gaps in knowledge, which will further elucidate the role of glutamate in the rewarding effects of drugs of abuse. PMID- 26594143 TI - Supplier-dependent differences in intermittent voluntary alcohol intake and response to naltrexone in Wistar rats. AB - Alcohol use disorder (AUD) is a worldwide public health problem and a polygenetic disorder displaying substantial individual variation. This work aimed to study individual differences in behavior and its association to voluntary alcohol intake and subsequent response to naltrexone in a seamless heterogenic group of animals. Thus, by this approach the aim was to more accurately recapitulate the existing heterogeneity within the human population. Male Wistar rats from three different suppliers (Harlan Laboratories B.V., RccHanTM:WI; Taconic Farms A/S, HanTac:WH; and Charles River GmbH, Crl:WI) were used to create a heterogenic group for studies of individual differences in behavior, associations to intermittent voluntary alcohol intake and subsequent response to naltrexone. The rats were tested in the open field prior to the Y-maze and then given voluntary intermittent access to alcohol or water in the home cage for 6 weeks, where after, naltrexone in three different doses or saline was administered in a Latin square design over 4 weeks and alcohol intake and preference was measured. However, supplier-dependent differences and concomitant skew subgroup formations, primarily in open field behavior and intermittent alcohol intake, resulted in a shifted focus to instead study voluntary alcohol intake and preference, and the ensuing response to naltrexone in Wistar rats from three different suppliers. The results showed that outbred Wistar rats are diverse with regard to voluntary alcohol intake and preference in a supplier-dependent manner; higher in RccHanTM:WI relative to HanTac:WH and Crl:WI. The results also revealed supplier dependent differences in the effect of naltrexone that were dose- and time dependent; evident differences in high-drinking RccHanTM:WI rats relative to HanTac:WH and Crl:WI rats. Overall these findings render RccHanTM:WI rats more suitable for studies of individual differences in voluntary alcohol intake and response to naltrexone and further highlight the inherent heterogeneity of the Wistar strain. The overall results put focus on the importance of thoroughly considering the animals used to aid in study design and for comparison of reported results. PMID- 26594144 TI - A novel versatile hybrid infusion-multielectrode recording (HIME) system for acute drug delivery and multisite acquisition of neuronal activity in freely moving mice. AB - To characterize information transfer in defined brain circuits involving multiple brain regions and to evaluate underlying molecular mechanisms and their dysregulation in major brain diseases, a simple and reliable system is ultimately required for electrophysiological recording of local field potentials (LFPs, or local EEG) in combination with local delivery of drugs, enzymes and gene expression-controlling viruses near the place of recording. Here we provide a new design of a versatile reusable hybrid infusion-recording (HIME) system which can be utilized in freely moving mice performing cognitive tasks. The HIME system allows monitoring neuronal activity in multiple layers in several brain structures. Here, we provide examples of bilateral injection and recordings of full spectrum of learning and memory related oscillations, i.e., theta (4-12 Hz), gamma (40-100) and ripple activity (130-150 Hz), in five hippocampal layers as well as in the CA1 and CA2 regions. Furthermore, the system is designed to be used for parallel recordings in the amygdala, cortex and other brain areas, before and after infusion of reagents of interest, either in or off a cognitive test. We anticipate that the HIME system can be particularly convenient to advance functional neuroglycobiological studies and molecular deciphering of mechanisms governing long-term memory consolidation. PMID- 26594145 TI - Soluble beta amyloid evokes alteration in brain norepinephrine levels: role of nitric oxide and interleukin-1. AB - Strong evidence showed neurotoxic properties of beta amyloid (Abeta) and its pivotal role in the Alzheimer's disease (AD) pathogenesis. Beside, experimental data suggest that Abeta may have physiological roles considering that such soluble peptide is produced and secreted during normal cellular activity. There is now suggestive evidence that neurodegenerative conditions, like AD, involve nitric oxide (NO) in their pathogenesis. Nitric oxide also possess potent neuromodulatory actions in brain regions, such as prefrontal cortex (PFC), hippocampus (HIPP), and nucleus accumbens (NAC). In the present study, we evaluated the effect of acute Abeta injection on norepinephrine (NE) content before and after pharmacological manipulations of nitrergic system in above mentioned areas. Moreover, effects of the peptide on NOS activity were evaluated. Our data showed that 2 h after i.c.v. soluble Abeta administration, NE concentrations were significantly increased in the considered areas along with increased iNOS activity. Pre-treatment with NOS inhibitors, 7-Nitroindazole (7 NI), and N6-(1-iminoethyl)-L-lysine-dihydrochloride (L-NIL), reversed Abeta induced changes. Ultimately, pharmacological block of interleukin1 (IL-1) receptors prevented NE increase in all brain regions. Taken together our findings suggest that NO and IL-1 are critically involved in regional noradrenergic alterations induced by soluble Abeta injection. PMID- 26594146 TI - Evidence for a neuroprotective microRNA pathway in amnestic mild cognitive impairment. AB - MicroRNAs (miRNAs) that regulate mRNA stability have been linked to amyloid production, tau phosphorylation, and inflammation in Alzheimer's disease (AD). However, whether cerebral miRNA networks are dysregulated during the earliest stages of AD remains underexplored. We performed miRNA expression analysis using frontal cortex tissue harvested from subjects who died with a clinical diagnosis of no cognitive impairment (NCI), amnestic mild cognitive impairment (aMCI, a putative prodromal AD stage), or mild AD. Analysis revealed that the miRNA clusters miR-212/132 and miR-23a/23b were down-regulated in the frontal cortex of aMCI subjects. Both miR-212/132 and miR23a/b are predicted to destabilize the message for sirtuin 1 (sirt1); hence, down-regulation of either miR-212/132 or miR-23a/b in frontal cortex should promote sirt1 mRNA expression in this region. qPCR studies revealed that frontal cortex levels of sirt1 were increased in aMCI. Given the ability of frontal cortex to respond to the onset of dementia by neuronal reorganization, these data suggest that miRNA-mediated up-regulation of the sirt1 pathway represents a compensatory response to the onset of the disease. By contrast, qPCR analysis of inferior temporal cortex, an area affected early in the progression of AD, showed no changes in miR-212/132, miR-23a/b, or sirt1 transcripts in the same aMCI subjects. In vitro mechanistic studies showed that coordinated down-regulation of miR-212 and miR-23a increased sirt1 protein expression and provided neuroprotection from beta-amyloid toxicity in human neuronal cells. Taken together, these data suggest a novel miRNA-mediated neuroprotective pathway activated during the progression of AD that may be amenable to therapeutic manipulation. PMID- 26594147 TI - Editorial: Biosignal processing and computational methods to enhance sensory motor neuroprosthetics. PMID- 26594148 TI - Non-linear leak currents affect mammalian neuron physiology. AB - In their seminal works on squid giant axons, Hodgkin, and Huxley approximated the membrane leak current as Ohmic, i.e., linear, since in their preparation, sub threshold current rectification due to the influence of ionic concentration is negligible. Most studies on mammalian neurons have made the same, largely untested, assumption. Here we show that the membrane time constant and input resistance of mammalian neurons (when other major voltage-sensitive and ligand gated ionic currents are discounted) varies non-linearly with membrane voltage, following the prediction of a Goldman-Hodgkin-Katz-based passive membrane model. The model predicts that under such conditions, the time constant/input resistance voltage relationship will linearize if the concentration differences across the cell membrane are reduced. These properties were observed in patch-clamp recordings of cerebellar Purkinje neurons (in the presence of pharmacological blockers of other background ionic currents) and were more prominent in the sub threshold region of the membrane potential. Model simulations showed that the non linear leak affects voltage-clamp recordings and reduces temporal summation of excitatory synaptic input. Together, our results demonstrate the importance of trans-membrane ionic concentration in defining the functional properties of the passive membrane in mammalian neurons as well as other excitable cells. PMID- 26594150 TI - Compartment-dependent mitochondrial alterations in experimental ALS, the effects of mitophagy and mitochondriogenesis. AB - Amyotrophic lateral sclerosis (ALS) is characterized by massive loss of motor neurons. Data from ALS patients and experimental models indicate that mitochondria are severely damaged within dying or spared motor neurons. Nonetheless, recent data indicate that mitochondrial preservation, although preventing motor neuron loss, fails to prolong lifespan. On the other hand, the damage to motor axons plays a pivotal role in determining both lethality and disease course. Thus, in the present article each motor neuron compartment (cell body, central, and peripheral axons) of G93A SOD-1 mice was studied concerning mitochondrial alterations as well as other intracellular structures. We could confirm the occurrence of ALS-related mitochondrial damage encompassing total swelling, matrix dilution and cristae derangement along with non-pathological variations of mitochondrial size and number. However, these alterations occur to a different extent depending on motor neuron compartment. Lithium, a well-known autophagy inducer, prevents most pathological changes. However, the efficacy of lithium varies depending on which motor neuron compartment is considered. Remarkably, some effects of lithium are also evident in wild type mice. Lithium is effective also in vitro, both in cell lines and primary cell cultures from the ventral spinal cord. In these latter cells autophagy inhibition within motor neurons in vitro reproduced ALS pathology which was reversed by lithium. Muscle and glial cells were analyzed as well. Cell pathology was mostly severe within peripheral axons and muscles of ALS mice. Remarkably, when analyzing motor axons of ALS mice a subtotal clogging of axoplasm was described for the first time, which was modified under the effects of lithium. The effects induced by lithium depend on several mechanisms such as direct mitochondrial protection, induction of mitophagy and mitochondriogenesis. In this study, mitochondriogenesis induced by lithium was confirmed in situ by a novel approach using [2-(3)H]-adenosine. PMID- 26594149 TI - Estrogen administration modulates hippocampal GABAergic subpopulations in the hippocampus of trimethyltin-treated rats. AB - Given the well-documented involvement of estrogens in the modulation of hippocampal functions in both physiological and pathological conditions, the present study investigates the effects of 17-beta estradiol (E2) administration in the rat model of hippocampal neurodegeneration induced by trimethyltin (TMT) administration (8 mg/kg), characterized by loss of pyramidal neurons in CA1, CA3/hilus hippocampal subfields, associated with astroglial and microglial activation, seizures and cognitive impairment. After TMT/saline treatment, ovariectomized animals received two doses of E2 (0.2 mg/kg intra-peritoneal) or vehicle, and were sacrificed 48 h or 7 days after TMT-treatment. Our results indicate that in TMT-treated animals E2 administration induces the early (48 h) upregulation of genes involved in neuroprotection and synaptogenesis, namely Bcl2, trkB, cadherin 2 and cyclin-dependent-kinase-5. Increased expression levels of glutamic acid decarboxylase (gad) 67, neuropeptide Y (Npy), parvalbumin, Pgc 1alpha and Sirtuin 1 genes, the latter involved in parvalbumin (PV) synthesis, were also evident. Unbiased stereology performed on rats sacrificed 7 days after TMT treatment showed that although E2 does not significantly influence the extent of TMT-induced neuronal death, significantly enhances the TMT-induced modulation of GABAergic interneuron population size in selected hippocampal subfields. In particular, E2 administration causes, in TMT-treated rats, a significant increase in the number of GAD67-expressing interneurons in CA1 stratum oriens, CA3 pyramidal layer, hilus and dentate gyrus, accompanied by a parallel increase in NPY-expressing cells, essentially in the same regions, and of PV-positive cells in CA1 pyramidal layer. The present results add information concerning the role of in vivo E2 administration on mechanisms involved in cellular plasticity in the adult brain. PMID- 26594152 TI - On the function of object cells in the claustrum-key components in information processing in the visual system? PMID- 26594151 TI - Distinct and synergistic feedforward inhibition of pyramidal cells by basket and bistratified interneurons. AB - Feedforward inhibition (FFI) enables pyramidal cells in area CA1 of the hippocampus (CA1PCs) to remain easily excitable while faithfully representing a broad range of excitatory inputs without quickly saturating. Despite the cortical ubiquity of FFI, its specific function is not completely understood. FFI in CA1PCs is mediated by two physiologically and morphologically distinct GABAergic interneurons: fast-spiking, perisomatic-targeting basket cells and regular spiking, dendritic-targeting bistratified cells. These two FFI pathways might create layer-specific computational sub-domains within the same CA1PC, but teasing apart their specific contributions remains experimentally challenging. We implemented a biophysically realistic model of CA1PCs using 40 digitally reconstructed morphologies and constraining synaptic numbers, locations, amplitude, and kinetics with available experimental data. First, we validated the model by reproducing the known combined basket and bistratified FFI of CA1PCs at the population level. We then analyzed how the two interneuron types independently affected the CA1PC spike probability and timing as a function of inhibitory strength. Separate FFI by basket and bistratified respectively modulated CA1PC threshold and gain. Concomitant FFI by both interneuron types synergistically extended the dynamic range of CA1PCs by buffering their spiking response to excitatory stimulation. These results suggest testable hypotheses on the precise effects of GABAergic diversity on cortical computation. PMID- 26594153 TI - High-Speed imaging reveals opposing effects of chronic stress and antidepressants on neuronal activity propagation through the hippocampal trisynaptic circuit. AB - Antidepressants (ADs) are used as first-line treatment for most stress-related psychiatric disorders. The alterations in brain circuit dynamics that can arise from stress exposure and underlie therapeutic actions of ADs remain, however, poorly understood. Here, enabled by a recently developed voltage-sensitive dye imaging (VSDI) assay in mouse brain slices, we examined the impact of chronic stress and concentration-dependent effects of eight clinically used ADs (belonging to different chemical/functional classes) on evoked neuronal activity propagations through the hippocampal trisynaptic circuitry (HTC: perforant path > dentate gyrus (DG) -> area CA3 -> area CA1). Exposure of mice to chronic social defeat stress led to markedly weakened activity propagations ("HTC-Waves"). In contrast, at concentrations in the low micromolar range, all ADs, which were bath applied to slices, caused an amplification of HTC-Waves in CA regions (invariably in area CA1). The fast-acting "antidepressant" ketamine, the mood stabilizer lithium, and brain-derived neurotrophic factor (BDNF) exerted comparable enhancing effects, whereas the antipsychotic haloperidol and the anxiolytic diazepam attenuated HTC-Waves. Collectively, we provide direct experimental evidence that chronic stress can depress neuronal signal flow through the HTC and demonstrate shared opposing effects of ADs. Thus, our study points to a circuit level mechanism of ADs to counteract stress-induced impairment of hippocampal network function. However, the observed effects of ADs are impossible to depend on enhanced neurogenesis. PMID- 26594154 TI - Bulk regional viral injection in neonatal mice enables structural and functional interrogation of defined neuronal populations throughout targeted brain areas. AB - The ability to label and manipulate specific cell types is central to understanding the structure and function of neuronal circuits. Here, we have developed a simple, affordable strategy for labeling of genetically defined populations of neurons throughout a targeted brain region: Bulk Regional Viral Injection (BReVI). Our strategy involves a large volume adeno-associated virus (AAV) injection in the targeted brain region of neonatal Cre driver mice. Using the mouse olfactory bulb (OB) as a model system, we tested the ability of BReVI to broadly and selectively label tufted cells, one of the two principal neuron populations of the OB, in CCK-IRES-Cre mice. BReVI resulted in labeling of neurons throughout the injected OB, with no spatial bias toward the injection site and no evidence of damage. The specificity of BReVI labeling was strikingly similar to that seen previously using immunohistochemical staining for cholecystokinin (CCK), an established tufted cell marker. Hence, the CCK-IRES-Cre line in combination with BReVI can provide an important tool for targeting and manipulation of OB tufted cells. We also found robust Cre-dependent reporter expression within three days of BReVI, which enabled us to assess developmental changes in the number and laminar distribution of OB tufted cells during the first three postnatal weeks. Furthermore, we demonstrate that BReVI permits structural and functional imaging in vivo, and can be combined with transgenic strategies to facilitate multi-color labeling of neuronal circuit components. BReVI is broadly applicable to different Cre driver lines and can be used to regionally manipulate genetically defined populations of neurons in any accessible brain region. PMID- 26594155 TI - Forebrain neuroanatomy of the neonatal and juvenile dolphin (T. truncatus and S. coeruloalba). AB - Knowledge of dolphin functional neuroanatomy mostly derives from post-mortem studies and non-invasive approaches (i.e., magnetic resonance imaging), due to limitations in experimentation on cetaceans. As a consequence the availability of well-preserved tissues for histology is scarce, and detailed histological analyses are referred mainly to adults. Here we studied the neonatal/juvenile brain in two species of dolphins, the bottlenose dolphin (Tursiops truncatus) and the striped dolphin (Stenella coeruleoalba), with special reference to forebrain regions. We analyzed cell density in subcortical nuclei, white/gray matter ratio, and myelination in selected regions at different anterior-posterior levels of the whole dolphin brain at different ages, to better define forebrain neuroanatomy and the developmental stage of the dolphin brain around birth. The analyses were extended to the periventricular germinal layer and the cerebellum, whose delayed genesis of the granule cell layer is a hallmark of postnatal development in the mammalian nervous system. Our results establish an atlas of the young dolphin forebrain and, on the basis of occurrence/absence of delayed neurogenic layers, confirm the stage of advanced brain maturation in these animals with respect to most terrestrial mammals. PMID- 26594156 TI - Crowdsourcing the creation of image segmentation algorithms for connectomics. AB - To stimulate progress in automating the reconstruction of neural circuits, we organized the first international challenge on 2D segmentation of electron microscopic (EM) images of the brain. Participants submitted boundary maps predicted for a test set of images, and were scored based on their agreement with a consensus of human expert annotations. The winning team had no prior experience with EM images, and employed a convolutional network. This "deep learning" approach has since become accepted as a standard for segmentation of EM images. The challenge has continued to accept submissions, and the best so far has resulted from cooperation between two teams. The challenge has probably saturated, as algorithms cannot progress beyond limits set by ambiguities inherent in 2D scoring and the size of the test dataset. Retrospective evaluation of the challenge scoring system reveals that it was not sufficiently robust to variations in the widths of neurite borders. We propose a solution to this problem, which should be useful for a future 3D segmentation challenge. PMID- 26594157 TI - ERP markers of target selection discriminate children with high vs. low working memory capacity. AB - Selective attention enables enhancing a subset out of multiple competing items to maximize the capacity of our limited visual working memory (VWM) system. Multiple behavioral and electrophysiological studies have revealed the cognitive and neural mechanisms supporting adults' selective attention of visual percepts for encoding in VWM. However, research on children is more limited. What are the neural mechanisms involved in children's selection of incoming percepts in service of VWM? Do these differ from the ones subserving adults' selection? Ten year-olds and adults used a spatial arrow cue to select a colored item for later recognition from an array of four colored items. The temporal dynamics of selection were investigated through EEG signals locked to the onset of the memory array. Both children and adults elicited significantly more negative activity over posterior scalp locations contralateral to the item to-be-selected for encoding (N2pc). However, this activity was elicited later and for longer in children compared to adults. Furthermore, although children as a group did not elicit a significant N2pc during the time-window in which N2pc was elicited in adults, the magnitude of N2pc during the "adult time-window" related to their behavioral performance during the later recognition phase of the task. This in turn highlights how children's neural activity subserving attention during encoding relates to better subsequent VWM performance. Significant differences were observed when children were divided into groups of high vs. low VWM capacity as a function of cueing benefit. Children with large cue benefits in VWM capacity elicited an adult-like contralateral negativity following attentional selection of the to-be-encoded item, whereas children with low VWM capacity did not. These results corroborate the close coupling between selective attention and VWM from childhood and elucidate further the attentional mechanisms constraining VWM performance in children. PMID- 26594158 TI - The cognitive basis of social behavior: cognitive reflection overrides antisocial but not always prosocial motives. AB - Even though human social behavior has received considerable scientific attention in the last decades, its cognitive underpinnings are still poorly understood. Applying a dual-process framework to the study of social preferences, we show in two studies that individuals with a more reflective/deliberative cognitive style, as measured by scores on the Cognitive Reflection Test (CRT), are more likely to make choices consistent with "mild" altruism in simple non-strategic decisions. Such choices increase social welfare by increasing the other person's payoff at very low or no cost for the individual. The choices of less reflective individuals (i.e., those who rely more heavily on intuition), on the other hand, are more likely to be associated with either egalitarian or spiteful motives. We also identify a negative link between reflection and choices characterized by "strong" altruism, but this result holds only in Study 2. Moreover, we provide evidence that the relationship between social preferences and CRT scores is not driven by general intelligence. We discuss how our results can reconcile some previous conflicting findings on the cognitive basis of social behavior. PMID- 26594159 TI - Emotional susceptibility trait modulates insula responses and functional connectivity in flavor processing. AB - The present study aimed at investigating the relationship between Emotional Susceptibility (ES), an aspect of the personality trait Neuroticism, and individual differences in the neural responses in anterior insula to primary sensory stimuli colored by affective valence, i.e., distasting or pleasantly tasting oral stimuli. In addition, it was studied whether intrinsic functional connectivity patterns of brain regions characterized by such differential responses could be related to ES. To this purpose 25 female participants underwent functional magnetic resonance imaging scanning, while being involved in a flavor experiment. During the experiment, flavor stimuli were administered consisting of small amounts of liquid with a different affective valence: neutral, pleasant, unpleasant. The results showed that individual differences in ES trait predicted distinct neural activity patterns to the different stimulus conditions in a region of left anterior insula that a previous meta-analysis revealed to be linked with olfacto-gustatory processing. Specifically, low ES was associated with enhanced neural responses to both pleasant and unpleasant stimuli, compared to neutral stimuli. By contrast, high ES participants showed equally strong neural responses to all types of stimuli without differentiating between the neutral and affective stimuli. Finally, during a task-free state, high ES trait appeared also to be related to decreased intrinsic functional connectivity between left anterior insula and left cerebellum. Our findings show that individual differences in ES are associated with differential anterior insula responses to primary sensory (flavor) stimuli as well as to intrinsic functional cortico-cerebellar connectivity, the latter suggesting a basis in the brain intrinsic functional architecture of the regulation of emotional experiences. PMID- 26594160 TI - "I didn't want to do it!" The detection of past intentions. AB - In daily life and in courtrooms, people regularly analyze the minds of others to understand intentions. Specifically, the detection of intentions behind prior events is one of the main issues dealt with in courtrooms. To our knowledge, there are no experimental works focused on the use of memory detection techniques to detect past intentions. This study aims at investigating whether reaction times (RTs) could be used for this purpose, by evaluating the accuracy of the autobiographical Implicit Association Test (aIAT) in the detection of past intentions. Sixty healthy volunteers took part in the experiment (mean age: 36.5 y; range: 18-55; 30 males). Participants were asked to recall and report information about a meeting with a person that had occurred at least 1 month before. Half of the participants were required to report about an intentional meeting, whereas the other half reported on a chance meeting. Based on the conveyed information, participants performed a tailored aIAT in which they had to categorize real reported information contrasted with counterfeit information. Results demonstrated that RTs can be a useful measure for the detection of past intentions and that aIAT can detect real past intentions with an accuracy of 95%. PMID- 26594162 TI - Editorial: Physical activity, self-regulation, and executive control across the lifespan. PMID- 26594161 TI - Loss of regional accent after damage to the speech production network. AB - Lesion-symptom mapping studies reveal that selective damage to one or more components of the speech production network can be associated with foreign accent syndrome, changes in regional accent (e.g., from Parisian accent to Alsatian accent), stronger regional accent, or re-emergence of a previously learned and dormant regional accent. Here, we report loss of regional accent after rapidly regressive Broca's aphasia in three Argentinean patients who had suffered unilateral or bilateral focal lesions in components of the speech production network. All patients were monolingual speakers with three different native Spanish accents (Cordobes or central, Guaranitico or northeast, and Bonaerense). Samples of speech production from the patient with native Cordoba accent were compared with previous recordings of his voice, whereas data from the patient with native Guaranitico accent were compared with speech samples from one healthy control matched for age, gender, and native accent. Speech samples from the patient with native Buenos Aires's accent were compared with data obtained from four healthy control subjects with the same accent. Analysis of speech production revealed discrete slowing in speech rate, inappropriate long pauses, and monotonous intonation. Phonemic production remained similar to those of healthy Spanish speakers, but phonetic variants peculiar to each accent (e.g., intervocalic aspiration of /s/ in Cordoba accent) were absent. While basic normal prosodic features of Spanish prosody were preserved, features intrinsic to melody of certain geographical areas (e.g., rising end F0 excursion in declarative sentences intoned with Cordoba accent) were absent. All patients were also unable to produce sentences with different emotional prosody. Brain imaging disclosed focal left hemisphere lesions involving the middle part of the motor cortex, the post-central cortex, the posterior inferior and/or middle frontal cortices, insula, anterior putamen and supplementary motor area. Our findings suggest that lesions affecting the middle part of the left motor cortex and other components of the speech production network disrupt neural processes involved in the production of regional accent features. PMID- 26594163 TI - Learning to push and learning to move: the adaptive control of contact forces. AB - To be successful at manipulating objects one needs to apply simultaneously well controlled movements and contact forces. We present a computational theory of how the brain may successfully generate a vast spectrum of interactive behaviors by combining two independent processes. One process is competent to control movements in free space and the other is competent to control contact forces against rigid constraints. Free space and rigid constraints are singularities at the boundaries of a continuum of mechanical impedance. Within this continuum, forces and motions occur in "compatible pairs" connected by the equations of Newtonian dynamics. The force applied to an object determines its motion. Conversely, inverse dynamics determine a unique force trajectory from a movement trajectory. In this perspective, we describe motor learning as a process leading to the discovery of compatible force/motion pairs. The learned compatible pairs constitute a local representation of the environment's mechanics. Experiments on force field adaptation have already provided us with evidence that the brain is able to predict and compensate the forces encountered when one is attempting to generate a motion. Here, we tested the theory in the dual case, i.e., when one attempts at applying a desired contact force against a simulated rigid surface. If the surface becomes unexpectedly compliant, the contact point moves as a function of the applied force and this causes the applied force to deviate from its desired value. We found that, through repeated attempts at generating the desired contact force, subjects discovered the unique compatible hand motion. When, after learning, the rigid contact was unexpectedly restored, subjects displayed after effects of learning, consistent with the concurrent operation of a motion control system and a force control system. Together, theory and experiment support a new and broader view of modularity in the coordinated control of forces and motions. PMID- 26594164 TI - Fourier power, subjective distance, and object categories all provide plausible models of BOLD responses in scene-selective visual areas. AB - Perception of natural visual scenes activates several functional areas in the human brain, including the Parahippocampal Place Area (PPA), Retrosplenial Complex (RSC), and the Occipital Place Area (OPA). It is currently unclear what specific scene-related features are represented in these areas. Previous studies have suggested that PPA, RSC, and/or OPA might represent at least three qualitatively different classes of features: (1) 2D features related to Fourier power; (2) 3D spatial features such as the distance to objects in a scene; or (3) abstract features such as the categories of objects in a scene. To determine which of these hypotheses best describes the visual representation in scene selective areas, we applied voxel-wise modeling (VM) to BOLD fMRI responses elicited by a set of 1386 images of natural scenes. VM provides an efficient method for testing competing hypotheses by comparing predictions of brain activity based on encoding models that instantiate each hypothesis. Here we evaluated three different encoding models that instantiate each of the three hypotheses listed above. We used linear regression to fit each encoding model to the fMRI data recorded from each voxel, and we evaluated each fit model by estimating the amount of variance it predicted in a withheld portion of the data set. We found that voxel-wise models based on Fourier power or the subjective distance to objects in each scene predicted much of the variance predicted by a model based on object categories. Furthermore, the response variance explained by these three models is largely shared, and the individual models explain little unique variance in responses. Based on an evaluation of previous studies and the data we present here, we conclude that there is currently no good basis to favor any one of the three alternative hypotheses about visual representation in scene selective areas. We offer suggestions for further studies that may help resolve this issue. PMID- 26594165 TI - Distinguishing Parkinson's disease from atypical parkinsonian syndromes using PET data and a computer system based on support vector machines and Bayesian networks. AB - Differentiating between Parkinson's disease (PD) and atypical parkinsonian syndromes (APS) is still a challenge, specially at early stages when the patients show similar symptoms. During last years, several computer systems have been proposed in order to improve the diagnosis of PD, but their accuracy is still limited. In this work we demonstrate a full automatic computer system to assist the diagnosis of PD using (18)F-DMFP PET data. First, a few regions of interest are selected by means of a two-sample t-test. The accuracy of the selected regions to separate PD from APS patients is then computed using a support vector machine classifier. The accuracy values are finally used to train a Bayesian network that can be used to predict the class of new unseen data. This methodology was evaluated using a database with 87 neuroimages, achieving accuracy rates over 78%. A fair comparison with other similar approaches is also provided. PMID- 26594166 TI - Primary Amelanotic Rhabdoid Melanoma: A Case Report with Review of the Literature. AB - Primary rhabdoid melanoma (PRM) is a rare variant of melanoma. Herein, we describe a case of primary amelanotic rhabdoid melanoma and review the clinicopathological features of previously reported cases of PRMs. A 63-year-old Japanese man presented with a nonpigmented red granular tumor without peripheral pigmented macules on the left heel measuring 21 * 18 mm in size. Light microscopic examination revealed a tumor mass composed entirely of polygonal neoplastic cells resembling pulmonary alveoli. Tumor cells were also discohesive with bizarre nuclei, prominent nucleoli and large hyaline cytoplasmic inclusions. No melanin pigment was present. Tumor cells were strongly and diffusely positive for S-100, MART-1, HMB-45 and vimentin, while negative for desmin, alphaSMA and synaptophysin. According to previous reviews, PRM tends to be amelanotic and nodular. S-100 protein and vimentin stained in all cases contrary to low stainability for HMB-45, which was, by contrast, positive in our case. Prognosis of PRM remains controversial due to the very rare occurrence of this tumor and the small number of confirmed cases that have been reported. Recognition of this rare entity is important in clinical practice even for skillful dermatologists to avoid misdiagnosis with the other tumors and to determinate the subsequent treatment principles. PMID- 26594167 TI - Large Papillomatous and Pedunculated Nevus Sebaceous. AB - We present a 6-week-old female infant from the Lao People's Democratic Republic with a large, red, exophytic scalp mass and numerous flesh-colored verrucous plaques on her face and the right half of her body since birth. The clinical and pathological findings are consistent with the new phenotype of the large, polypoid types of nevus sebaceous. PMID- 26594168 TI - Fifty-Three Years after a Pencil Puncture Wound. AB - A pencil core with an intact pencil tip was excised from the thigh of a 60-year old male 53 years after a puncture wound. Histologic examination of the excised pencil core and the surrounding tissue revealed a foreign body reaction with abundant entrapped dark black pigment and chronic reparative changes, including dense sclerosis and focal granulation tissue formation. PMID- 26594169 TI - Bilateral Tinea Nigra Plantaris with Good Response to Isoconazole Cream: A Case Report. AB - Tinea nigra is a superficial fungal infection caused by Hortaea werneckii. It typically affects young individuals as an asymptomatic unilateral macule, from light brown to black on the palms and soles, mainly in tropical and subtropical regions. In 1997, Gupta et al. [Br J Dermatol 1997;137:483-484] described the dermoscopic characteristics of tinea nigra. Topical antifungals with or without keratolytic agents can be used for the treatment. The authors report a case of a 47-year-old man with asymptomatic light brown macules bilaterally on the plantar regions. Dermoscopic examination revealed brownish spicules consistent with the pattern described in the literature. Treatment with isoconazole cream was effective with complete resolution. PMID- 26594170 TI - Extensive Darier Disease Successfully Treated with Doxycycline Monotherapy. AB - Darier disease (DD) is a rare dominantly inherited genodermatosis characterized by loss of intercellular adhesion (acantholysis) and abnormal keratinization. DD is often difficult to manage. Numerous treatments have reportedly been used for the treatment of DD, with limited success. Systemic retinoids are considered the drug of choice for treating DD. However, their use is limited by potential deleterious side effects. Considering the recently reported efficacy of doxycycline for Hailey-Hailey disease, an inherited acantholytic skin disorder pathogenetically similar to DD, we report the case of a patient with extensive DD who showed a dramatic response to oral doxycycline monotherapy. PMID- 26594171 TI - Multiple Primary Merkel Cell Carcinomas Presenting as Pruritic, Painful Lower Leg Tumors. AB - Merkel cell carcinoma (MCC) is a rare and highly aggressive neuroendocrine tumor of the skin which almost exclusively presents as a solitary tumor. It is most often seen on sun-exposed regions, historically almost exclusively on the head and neck, with only rare case reports on the extremities. Although recent studies have shown increased incidence with up to 20% on the extremities, here we present one of these rare emerging presentations, with the addition of a unique treatment option. Our patient is an 80-year-old male with a 3-month history of multiple raised, rapidly enlarging tumors on the right ankle. Two separate biopsies were performed and demonstrated sheets and clusters of small blue cells filling the dermis with scant cytoplasm, dusty chromatin, and nuclear molding. Subsequent immunohistochemical stains confirmed the diagnosis of multiple primary MCC. Despite the characteristic immunohistochemical profile of primary MCC, the possibility of a metastatic neuroendocrine carcinoma from an alternate primary site was entertained, given his unusual clinical presentation. A complete clinical workup including CT scans of the chest, abdomen, and pelvis showed no evidence of disease elsewhere. Instead of amputation, the patient opted for nonsurgical treatment with radiation therapy alone, resulting in a rapid and complete response. This case represents an unusual presentation of primary MCC and demonstrates further evidence that radiation as monotherapy is an effective local treatment option for inoperable MCC. PMID- 26594172 TI - Multifocal BRAF(V600E)-Mutated Melanoma in situ on the Foot. AB - Melanoma is an aggressive skin cancer that originates from melanocytes, and about one half of melanoma cases possess a BRAF mutation. Together with PD-L1 expression, the BRAF(V600E) mutation is one of the optimal therapeutic targets for the treatment of melanoma. In this report, we describe a case of multifocal melanoma in situ on the foot, which carried the p.V600E mutation in the BRAF gene. Interestingly, the spotted melanoma lesion is demarcated by normal skin, and in all spotted pigmented lesions, there were no signs of dermal invasion of melanoma cells or spontaneous regression. Our case presented atypical clinical features, which might correlate with the local mutations of BRAF gene and the immunological expression of PD-L1. PMID- 26594173 TI - MicroRNAs as potential targets for progressive pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and devastating disorder. It is characterized by alveolar epithelial cell injury and activation, infiltration of inflammatory cells, initiation of epithelial mesenchymal transition (EMT), aberrant proliferation and activation of fibroblasts, exaggerated deposition of extracellular matrix (ECM) proteins, and finally leading to the destruction of lung parenchyma. MicroRNAs (miRNAs) are endogenous small non-coding RNA molecules that post-transcriptionally regulate gene expression in diverse biological and pathological processes, including cell proliferation, differentiation, apoptosis and metastasis. As a result, miRNAs have emerged as a major area of biomedical research with relevance to pulmonary fibrosis. In this context, the present review discusses specific patterns of dysregulated miRNAs in patients with IPF. Further, we discuss the current understanding of miRNAs involvement in regulating lung inflammation, TGF-beta1 mediated EMT and fibroblast differentiation processes, ECM genes expression, and in the progression of lung fibrosis. The possible future directions that might lead to novel therapeutic strategies for the treatment of pulmonary fibrosis are also reviewed. PMID- 26594174 TI - NLRP3 inflammasome and its inhibitors: a review. AB - Inflammasomes are newly recognized, vital players in innate immunity. The best characterized is the NLRP3 inflammasome, so-called because the NLRP3 protein in the complex belongs to the family of nucleotide-binding and oligomerization domain-like receptors (NLRs) and is also known as "pyrin domain-containing protein 3". The NLRP3 inflammasome is associated with onset and progression of various diseases, including metabolic disorders, multiple sclerosis, inflammatory bowel disease, cryopyrin-associated periodic fever syndrome, as well as other auto-immune and auto-inflammatory diseases. Several NLRP3 inflammasome inhibitors have been described, some of which show promise in the clinic. The present review will describe the structure and mechanisms of activation of the NLRP3 inflammasome, its association with various auto-immune and auto-inflammatory diseases, and the state of research into NLRP3 inflammasome inhibitors. PMID- 26594177 TI - Neck-cooling improves repeated sprint performance in the heat. AB - The present study evaluated the effect of neck-cooling during exercise on repeated sprint ability in a hot environment. Seven team-sport playing males completed two experimental trials involving repeated sprint exercise (5 * 6 s) before and after two 45 min bouts of a football specific intermittent treadmill protocol in the heat (33.0 +/- 0.2 degrees C; 53 +/- 2% relative humidity). Participants wore a neck-cooling collar in one of the trials (CC). Mean power output and peak power output declined over time in both trials but were higher in CC (540 +/- 99 v 507 +/- 122 W, d = 0.32; 719 +/- 158 v 680 +/- 182 W, d = 0.24 respectively). The improved power output was particularly pronounced (d = 0.51 0.88) after the 2nd 45 min bout but the CC had no effect on % fatigue. The collar lowered neck temperature and the thermal sensation of the neck (P < 0.001) but had no effect on heart rate, fluid loss, fluid consumption, lactate, glucose, plasma volume change, cortisol, or thermal sensation (P > 0.05). There were no trial differences but interaction effects were demonstrated for prolactin concentration and rating of perceived exertion (RPE). Prolactin concentration was initially higher in the collar cold trial and then was lower from 45 min onwards (interaction trial * time P = 0.04). RPE was lower during the football intermittent treadmill protocol in the collar cold trial (interaction trial * time P = 0.01). Neck-cooling during exercise improves repeated sprint performance in a hot environment without altering physiological or neuroendocrinological responses. RPE is reduced and may partially explain the performance improvement. PMID- 26594178 TI - An antennal carboxylesterase from Drosophila melanogaster, esterase 6, is a candidate odorant-degrading enzyme toward food odorants. AB - Reception of odorant molecules within insect olfactory organs involves several sequential steps, including their transport through the sensillar lymph, interaction with the respective sensory receptors, and subsequent inactivation. Odorant-degrading enzymes (ODEs) putatively play a role in signal dynamics by rapid degradation of odorants in the vicinity of the receptors, but this hypothesis is mainly supported by in vitro results. We have recently shown that an extracellular carboxylesterase, esterase-6 (EST-6), is involved in the physiological and behavioral dynamics of the response of Drosophila melanogaster to its volatile pheromone ester, cis-vaccenyl acetate. However, as the expression pattern of the Est-6 gene in the antennae is not restricted to the pheromone responding sensilla, we tested here if EST-6 could play a broader function in the antennae. We found that recombinant EST-6 is able to efficiently hydrolyse several volatile esters that would be emitted by its natural food in vitro. Electrophysiological comparisons of mutant Est-6 null flies and a control strain (on the same genetic background) showed that the dynamics of the antennal response to these compounds is influenced by EST-6, with the antennae of the null mutants showing prolonged activity in response to them. Antennal responses to the strongest odorant, pentyl acetate, were then studied in more detail, showing that the repolarization dynamics were modified even at low doses but without modification of the detection threshold. Behavioral choice experiments with pentyl acetate also showed differences between genotypes; attraction to this compound was observed at a lower dose among the null than control flies. As EST-6 is able to degrade various bioactive odorants emitted by food and plays a role in the response to these compounds, we hypothesize a role as an ODE for this enzyme toward food volatiles. PMID- 26594176 TI - Transmembrane signal transduction by peptide hormones via family B G protein coupled receptors. AB - Although family B G protein-coupled receptors (GPCRs) contain only 15 members, they play key roles in transmembrane signal transduction of hormones. Family B GPCRs are drug targets for developing therapeutics for diseases ranging from metabolic to neurological disorders. Despite their importance, the molecular mechanism of activation of family B GPCRs remains largely unexplored due to the challenges in expression and purification of functional receptors to the quantity for biophysical characterization. Currently, there is no crystal structure available of a full-length family B GPCR. However, structures of key domains, including the extracellular ligand binding regions and seven-helical transmembrane regions, have been solved by X-ray crystallography and NMR, providing insights into the mechanisms of ligand recognition and selectivity, and helical arrangements within the cell membrane. Moreover, biophysical and biochemical methods have been used to explore functions, key residues for signaling, and the kinetics and dynamics of signaling processes. This review summarizes the current knowledge of the signal transduction mechanism of family B GPCRs at the molecular level and comments on the challenges and outlook for mechanistic studies of family B GPCRs. PMID- 26594179 TI - Building SuperModels: emerging patient avatars for use in precision and systems medicine. PMID- 26594175 TI - Post-translational modifications of voltage-gated sodium channels in chronic pain syndromes. AB - In the peripheral sensory nervous system the neuronal expression of voltage-gated sodium channels (Navs) is very important for the transmission of nociceptive information since they give rise to the upstroke of the action potential (AP). Navs are composed of nine different isoforms with distinct biophysical properties. Studying the mutations associated with the increase or absence of pain sensitivity in humans, as well as other expression studies, have highlighted Nav1.7, Nav1.8, and Nav1.9 as being the most important contributors to the control of nociceptive neuronal electrogenesis. Modulating their expression and/or function can impact the shape of the AP and consequently modify nociceptive transmission, a process that is observed in persistent pain conditions. Post-translational modification (PTM) of Navs is a well-known process that modifies their expression and function. In chronic pain syndromes, the release of inflammatory molecules into the direct environment of dorsal root ganglia (DRG) sensory neurons leads to an abnormal activation of enzymes that induce Navs PTM. The addition of small molecules, i.e., peptides, phosphoryl groups, ubiquitin moieties and/or carbohydrates, can modify the function of Navs in two different ways: via direct physical interference with Nav gating, or via the control of Nav trafficking. Both mechanisms have a profound impact on neuronal excitability. In this review we will discuss the role of Protein Kinase A, B, and C, Mitogen Activated Protein Kinases and Ca++/Calmodulin-dependent Kinase II in peripheral chronic pain syndromes. We will also discuss more recent findings that the ubiquitination of Nav1.7 by Nedd4-2 and the effect of methylglyoxal on Nav1.8 are also implicated in the development of experimental neuropathic pain. We will address the potential roles of other PTMs in chronic pain and highlight the need for further investigation of PTMs of Navs in order to develop new pharmacological tools to alleviate pain. PMID- 26594180 TI - Bone resorption: an actor of dental and periodontal development? AB - Dental and periodontal tissue development is a complex process involving various cell-types. A finely orchestrated network of communications between these cells is implicated. During early development, communications between cells from the oral epithelium and the underlying mesenchyme govern the dental morphogenesis with successive bud, cap and bell stages. Later, interactions between epithelial and mesenchymal cells occur during dental root elongation. Root elongation and tooth eruption require resorption of surrounding alveolar bone to occur. For years, it was postulated that signaling molecules secreted by dental and periodontal cells control bone resorbing osteoclast precursor recruitment and differentiation. Reverse signaling originating from bone cells (osteoclasts and osteoblasts) toward dental cells was not suspected. Dental defects reported in osteopetrosis were associated with mechanical stress secondary to defective bone resorption. In the last decade, consequences of bone resorption over-activation on dental and periodontal tissue formation have been analyzed with transgenic animals (RANK (Tg) and Opg (-/-) mice). Results suggest the existence of signals originating from osteoclasts toward dental and periodontal cells. Meanwhile, experiments consisting in transitory inhibition of bone resorption during root elongation, achieved with bone resorption inhibitors having different mechanisms of action (bisphosphonates and RANKL blocking antibodies), have evidenced dental and periodontal defects that support the presence of signals originating bone cells toward dental cells. The aim of the present manuscript is to present the data we have collected in the last years that support the hypothesis of a role of bone resorption in dental and periodontal development. PMID- 26594181 TI - Performance changes and relationship between vertical jump measures and actual sprint performance in elite sprinters with visual impairment throughout a Parapan American games training season. AB - The aims of this study were to estimate the magnitude of variability and progression in actual competitive and field vertical jump test performances in elite Paralympic sprinters with visual impairment in the year leading up to the 2015 Parapan American Games, and to investigate the relationships between loaded and unloaded vertical jumping test results and actual competitive sprinting performance. Fifteen Brazilian Paralympic sprinters with visual impairment attended seven official competitions (four national, two international and the Parapan American Games 2015) between April 2014 and August 2015, in the 100- and 200-m dash. In addition, they were tested in five different periods using loaded (mean propulsive power [MPP] in jump squat [JS] exercise) and unloaded (squat jump [SJ] height) vertical jumps within the 3 weeks immediately prior to the main competitions. The smallest important effect on performances was calculated as half of the within-athlete race-to-race (or test-to-test) variability and a multiple regression analysis was performed to predict the 100- and 200-m dash performances using the vertical jump test results. Competitive performance was enhanced during the Parapan American Games in comparison to the previous competition averages, overcoming the smallest worthwhile enhancement in both the 100- (0.9%) and 200-m dash (1.43%). In addition, The SJ and JS explained 66% of the performance variance in the competitive results. This study showed that vertical jump tests, in loaded and unloaded conditions, could be good predictors of the athletes' sprinting performance, and that during the Parapan American Games the Brazilian team reached its peak competitive performance. PMID- 26594182 TI - Investigating conceptions of intentional action by analyzing participant generated scenarios. AB - We describe and report on results of employing a new method for analyzing lay conceptions of intentional and unintentional action. Instead of asking people for their conceptual intuitions with regard to construed scenarios, we asked our participants to come up with their own scenarios and to explain why these are examples of intentional or unintentional actions. By way of content analysis, we extracted contexts and components that people associated with these action types. Our participants associated unintentional actions predominantly with bad outcomes for all persons involved and linked intentional actions more strongly to positive outcomes, especially concerning the agent. People's conceptions of intentional action seem to involve more aspects than commonly assumed in philosophical models of intentional action that solely stress the importance of intentions, desires, and beliefs. The additional aspects include decisions and thoughts about the action. In addition, we found that the criteria that participants generated for unintentional actions are not a mere inversion of those used in explanations for intentional actions. Associations between involuntariness and unintentional action seem to be stronger than associations between aspects of voluntariness and intentional action. PMID- 26594184 TI - Complex problem solving-single ability or complex phenomenon? PMID- 26594183 TI - Neural processing of emotions in traumatized children treated with Eye Movement Desensitization and Reprocessing therapy: a hdEEG study. AB - Eye Movement Desensitization and Reprocessing (EMDR) therapy has been proven efficacious in restoring affective regulation in post-traumatic stress disorder (PTSD) patients. However, its effectiveness on emotion processing in children with complex trauma has yet to be explored. High density electroencephalography (hdEEG) was used to investigate the effects of EMDR on brain responses to adults' emotions on children with histories of early maltreatment. Ten school-aged children were examined before (T0) and within one month after the conclusion of EMDR (T1). hdEEGs were recorded while children passively viewed angry, afraid, happy, and neutral faces. Clinical scales were administered at the same time. Correlation analyses were performed to detect brain regions whose activity was linked to children's traumatic symptom-related and emotional-adaptive problem scores. In all four conditions, hdEEG showed similar significantly higher activity on the right medial prefrontal and fronto-temporal limbic regions at T0, shifting toward the left medial and superior temporal regions at T1. Moreover, significant correlations were found between clinical scales and the same regions whose activity significantly differed between pre- and post-treatment. These preliminary results demonstrate that, after EMDR, children suffering from complex trauma show increased activity in areas implicated in high-order cognitive processing when passively viewing pictures of emotional expressions. These changes are associated with the decrease of depressive and traumatic symptoms, and with the improvement of emotional-adaptive functioning over time. PMID- 26594185 TI - Processing of pitch and location in human auditory cortex during visual and auditory tasks. AB - The relationship between stimulus-dependent and task-dependent activations in human auditory cortex (AC) during pitch and location processing is not well understood. In the present functional magnetic resonance imaging study, we investigated the processing of task-irrelevant and task-relevant pitch and location during discrimination, n-back, and visual tasks. We tested three hypotheses: (1) According to prevailing auditory models, stimulus-dependent processing of pitch and location should be associated with enhanced activations in distinct areas of the anterior and posterior superior temporal gyrus (STG), respectively. (2) Based on our previous studies, task-dependent activation patterns during discrimination and n-back tasks should be similar when these tasks are performed on sounds varying in pitch or location. (3) Previous studies in humans and animals suggest that pitch and location tasks should enhance activations especially in those areas that also show activation enhancements associated with stimulus-dependent pitch and location processing, respectively. Consistent with our hypotheses, we found stimulus-dependent sensitivity to pitch and location in anterolateral STG and anterior planum temporale (PT), respectively, in line with the view that these features are processed in separate parallel pathways. Further, task-dependent activations during discrimination and n-back tasks were associated with enhanced activations in anterior/posterior STG and posterior STG/inferior parietal lobule (IPL) irrespective of stimulus features. However, direct comparisons between pitch and location tasks performed on identical sounds revealed no significant activation differences. These results suggest that activations during pitch and location tasks are not strongly affected by enhanced stimulus-dependent activations to pitch or location. We also found that activations in PT were strongly modulated by task requirements and that areas in the inferior parietal lobule (IPL) showed task-dependent activation modulations, but no systematic activations to pitch or location. Based on these results, we argue that activations during pitch and location tasks cannot be explained by enhanced stimulus-specific processing alone, but rather that activations in human AC depend in a complex manner on the requirements of the task at hand. PMID- 26594186 TI - Multimodal retrieval of autobiographical memories: sensory information contributes differently to the recollection of events. AB - Previous studies on autobiographical memory have focused on unimodal retrieval cues (i.e., cues pertaining to one modality). However, from an ecological perspective multimodal cues (i.e., cues pertaining to several modalities) are highly important to investigate. In the present study we investigated age distributions and experiential ratings of autobiographical memories retrieved with unimodal and multimodal cues. Sixty-two participants were randomized to one of four cue-conditions: visual, olfactory, auditory, or multimodal. The results showed that the peak of the distributions depends on the modality of the retrieval cue. The results indicated that multimodal retrieval seemed to be driven by visual and auditory information to a larger extent and to a lesser extent by olfactory information. Finally, no differences were observed in the number of retrieved memories or experiential ratings across the four cue conditions. PMID- 26594187 TI - Words as cultivators of others minds. AB - The embodied-grounded view of cognition and language holds that sensorimotor experiences in the form of 're-enactments' or 'simulations' are significant to the individual's development of concepts and competent language use. However, a typical objection to the explanatory force of this view is that, in everyday life, we engage in linguistic exchanges about much more than might be directly accessible to our senses. For instance, when knowledge-sharing occurs as part of deep conversations between a teacher and student, language is the salient tool by which to obtain understanding, through the unfolding of explanations. Here, the acquisition of knowledge is realized through language, and the constitution of knowledge seems entirely linguistic. In this paper, based on a review of selected studies within contemporary embodied cognitive science, I propose that such linguistic exchanges, though occurring independently of direct experience, are in fact disguised forms of embodied cognition, leading to the reconciliation of the opposing views. I suggest that, in conversation, interlocutors use Words as Cultivators (WAC) of other minds as a direct result of their embodied-grounded origin, rendering WAC a radical interpretation of the Words as social Tools (WAT) proposal. The WAC hypothesis endorses the view of language as dynamic, continuously integrating with, and negotiating, cognitive processes in the individual. One such dynamic feature results from the 'linguification process', a term by which I refer to the socially produced mapping of a word to its referent which, mediated by the interlocutor, turns words into cultivators of others minds. In support of the linguification process hypothesis and WAC, I review relevant embodied-grounded research, and selected studies of instructed fear conditioning and guided imagery. PMID- 26594188 TI - Composite body movements modulate numerical cognition: evidence from the motion numerical compatibility effect. AB - A recent hierarchical model of numerical processing, initiated by Fischer and Brugger (2011) and Fischer (2012), suggested that situated factors, such as different body postures and body movements, can influence the magnitude representation and bias numerical processing. Indeed, Loetscher et al. (2008) found that participants' behavior in a random number generation task was biased by head rotations. More small numbers were reported after leftward than rightward head turns, i.e., a motion-numerical compatibility effect. Here, by carrying out two experiments, we explored whether similar motion-numerical compatibility effects exist for movements of other important body components, e.g., arms, and for composite body movements as well, which are basis for complex human activities in many ecologically meaningful situations. In Experiment 1, a motion numerical compatibility effect was observed for lateral rotations of two body components, i.e., the head and arms. Relatively large numbers were reported after making rightward compared to leftward movements for both lateral head and arm turns. The motion-numerical compatibility effect was observed again in Experiment 2 when participants were asked to perform composite body movements of congruent movement directions, e.g., simultaneous head left turns and arm left turns. However, it disappeared when the movement directions were incongruent, e.g., simultaneous head left turns and arm right turns. Taken together, our results extended Loetscher et al.'s (2008) finding by demonstrating that their effect is effector-general and exists for arm movements. Moreover, our study reveals for the first time that the impact of spatial information on numerical processing induced by each of the two sensorimotor-based situated factors, e.g., a lateral head turn and a lateral arm turn, can cancel each other out. PMID- 26594189 TI - Investigating the importance of self-theories of intelligence and musicality for students' academic and musical achievement. AB - Musical abilities and active engagement with music have been shown to be positively associated with many cognitive abilities as well as social skills and academic performance in secondary school students. While there is evidence from intervention studies that musical training can be a cause of these positive relationships, recent findings in the literature have suggested that other factors, such as genetics, family background or personality traits, might also be contributing factors. In addition, there is mounting evidence that self-concepts and beliefs can affect academic performance independently of intellectual ability. Students who believe that intelligence is malleable are more likely to attribute poor academic performances to effort rather than ability, and are more likely to take remedial action to improve their performance. However, it is currently not known whether student's beliefs about the nature of musical talent also influence the development of musical abilities in a similar fashion. Therefore, this study introduces a short self-report measure termed "Musical Self Theories and Goals," closely modeled on validated measures for self-theories in academic scenarios. Using this measure the study investigates whether musical self-theories are related to students' musical development as indexed by their concurrent musical activities and their performance on a battery of listening tests. We use data from a cross-sectional sample of 313 secondary school students to construct a network model describing the relationships between self-theories and academic as well as musical outcome measures, while also assessing potential effects of intelligence and the Big Five personality dimensions. Results from the network model indicate that self-theories of intelligence and musicality are closely related. In addition, both kinds of self-theories are connected to the students' academic achievement through the personality dimension conscientiousness and academic effort. Finally, applying the do-calculus method to the network model we estimate that the size of the assumed causal effects between musical self-theories and academic achievement lie between 0.07 and 0.15 standard deviations. PMID- 26594190 TI - Overspecification of color, pattern, and size: salience, absoluteness, and consistency. AB - The rates of overspecification of color, pattern, and size are compared, to investigate how salience and absoluteness contribute to the production of overspecification. Color and pattern are absolute and salient attributes, whereas size is relative and less salient. Additionally, a tendency toward consistent responses is assessed. Using a within-participants design, we find similar rates of color and pattern overspecification, which are both higher than the rate of size overspecification. Using a between-participants design, however, we find similar rates of pattern and size overspecification, which are both lower than the rate of color overspecification. This indicates that although many speakers are more likely to include color than pattern (probably because color is more salient), they may also treat pattern like color due to a tendency toward consistency. We find no increase in size overspecification when the salience of size is increased, suggesting that speakers are more likely to include absolute than relative attributes. However, we do find an increase in size overspecification when mentioning the attributes is triggered, which again shows that speakers tend to refer in a consistent manner, and that there are circumstances in which even size overspecification is frequently produced. PMID- 26594192 TI - A cautionary note on testing latent variable models. AB - The article tackles the practice of testing latent variable models. The analysis covered recently published studies from 11 psychology journals varying in orientation and impact. Seventy-five studies that matched the criterion of applying some of the latent modeling techniques were reviewed. Results indicate the presence of a general tendency to ignore the model test (chi(2)) followed by the acceptance of approximate fit hypothesis without detailed model examination yielding relevant empirical evidence. Due to reduced sensitivity of such a procedure to confront theory with data, there is an almost invariable tendency to accept the theoretical model. This absence of model test consequences, manifested in frequently unsubstantiated neglect of evidence speaking against the model, thus implies the perilous question of whether such empirical testing of latent structures (the way it is widely applied) makes sense at all. PMID- 26594191 TI - Distinct representations of configural and part information across multiple face selective regions of the human brain. AB - Several regions of the human brain respond more strongly to faces than to other visual stimuli, such as regions in the amygdala (AMG), superior temporal sulcus (STS), and the fusiform face area (FFA). It is unclear if these brain regions are similar in representing the configuration or natural appearance of face parts. We used functional magnetic resonance imaging of healthy adults who viewed natural or schematic faces with internal parts that were either normally configured or randomly rearranged. Response amplitudes were reduced in the AMG and STS when subjects viewed stimuli whose configuration of parts were digitally rearranged, suggesting that these regions represent the 1st order configuration of face parts. In contrast, response amplitudes in the FFA showed little modulation whether face parts were rearranged or if the natural face parts were replaced with lines. Instead, FFA responses were reduced only when both configural and part information were reduced, revealing an interaction between these factors, suggesting distinct representation of 1st order face configuration and parts in the AMG and STS vs. the FFA. PMID- 26594193 TI - Modeling behavior dynamics using computational psychometrics within virtual worlds. AB - In case of fire in a building, how will people behave in the crowd? The behavior of each individual affects the behavior of others and, conversely, each one behaves considering the crowd as a whole and the individual others. In this article, I propose a three-step method to explore a brand new way to study behavior dynamics. The first step relies on the creation of specific situations with standard techniques (such as mental imagery, text, video, and audio) and an advanced technique [Virtual Reality (VR)] to manipulate experimental settings. The second step concerns the measurement of behavior in one, two, or many individuals focusing on parameters extractions to provide information about the behavior dynamics. Finally, the third step, which uses the parameters collected and measured in the previous two steps in order to simulate possible scenarios to forecast through computational models, understand, and explain behavior dynamics at the social level. An experimental study was also included to demonstrate the three-step method and a possible scenario. PMID- 26594194 TI - Commentary: Attentional control and the self: The Self-Attention Network (SAN). PMID- 26594195 TI - The development of a sense of control scale. AB - In the past decades, sense of control-the feeling that one is in control of one's actions has gained much scientific interests. Various scales have been used to measure sense of control in previous studies, yet no study has allowed participants to create a scale for rating their control experiences despite advances in the neighboring field of conscious vision has been linked to this approach. Here, we examined how participants preferred to rate sense of control during a simple motor control task by asking them to create a scale to be used to describe their sense of control experience during the task. Scale with six steps was most frequently created. Even though some variability was observed in the number of preferred scale steps, descriptions were highly similar across all participants when scales were converted to the same continuum. When we divided participants into groups based on their number of preferred scale steps, mean task performance and sense of control could be described as sigmoid functions of the noise level, and the function parameters were equivalent across groups. We also showed that task performance increased exponentially as a function of control rating, and that, again, function parameters were equivalent for all groups. In summary, the present study established a participant-generated 6-point sense of control rating scale for simple computerized motor control tasks that can be empirically tested against other measures of control in future studies. PMID- 26594199 TI - Editorial: Transcriptional Regulation in Cancers and Metabolic Diseases. PMID- 26594196 TI - Traumatic Brain Injury and Peripheral Immune Suppression: Primer and Prospectus. AB - Nosocomial infections are a common occurrence in patients following traumatic brain injury (TBI) and are associated with an increased risk of mortality, longer length of hospital stay, and poor neurological outcome. Systemic immune suppression arising as a direct result of injury to the central nervous system (CNS) is considered to be primarily responsible for this increased incidence of infection, a view strengthened by recent studies that have reported novel changes in the composition and function of the innate and adaptive arms of the immune system post-TBI. However, our knowledge of the mechanisms that underlie TBI induced immune suppression is equivocal at best. Here, after summarizing our current understanding of the impact of TBI on peripheral immunity and discussing CNS-mediated regulation of immune function, we propose roles for a series of novel mechanisms in driving the immune suppression that is observed post-TBI. These mechanisms, which have never been considered before in the context of TBI induced immune paresis, include the CNS-driven emergence into the circulation of myeloid-derived suppressor cells and suppressive neutrophil subsets, and the release from injured tissue of nuclear and mitochondria-derived damage associated molecular patterns. Moreover, in an effort to further our understanding of the mechanisms that underlie TBI-induced changes in immunity, we pose throughout the review a series of questions, which if answered would address a number of key issues, such as establishing whether manipulating peripheral immune function has potential as a future therapeutic strategy by which to treat and/or prevent infections in the hospitalized TBI patient. PMID- 26594197 TI - Fibroblast Growth Factor 21 Analogs for Treating Metabolic Disorders. AB - Fibroblast growth factor (FGF) 21 is a member of the endocrine FGF subfamily. FGF21 expression is induced under different disease conditions, such as type 2 diabetes, obesity, chronic kidney diseases, and cardiovascular diseases, and it has a broad spectrum of functions in regulating various metabolic parameters. Many different approaches have been pursued targeting FGF21 and its receptors to develop therapeutics for treating type 2 diabetes and other aspects of metabolic conditions. In this article, we summarize some of these key approaches and highlight the potential challenges in the development of these agents. PMID- 26594198 TI - Sexual Dimorphism of Adipose and Hepatic Aquaglyceroporins in Health and Metabolic Disorders. AB - Gender differences in the relative risk of developing metabolic complications, such as insulin resistance or non-alcoholic fatty liver disease (NAFLD), have been reported. The deregulation of glycerol metabolism partly contributes to the onset of these metabolic diseases, since glycerol constitutes a key substrate for the synthesis of triacylglycerols (TAGs) as well as for hepatic gluconeogenesis. The present mini-review covers the sex--related differences in glycerol metabolism and aquaglyceroporins (AQPs) and its impact in the control of adipose and hepatic fat accumulation as well as in whole-body glucose homeostasis. Plasma glycerol concentrations are increased in women compared to men probably due to the higher lipolytic rate and larger AQP7 amounts in visceral fat as well as the well-known sexual dimorphism in fat mass with women showing higher adiposity. AQP9 represents the primary route for glycerol uptake in hepatocytes, where glycerol is converted by the glycerol-kinase enzyme into glycerol-3-phosphate, a key substrate for de novo synthesis of glucose and TAG. In spite of showing similar hepatic AQP9 protein, women exhibit lower hepatocyte glycerol permeability than men, which might contribute to their lower prevalence of insulin resistance and NAFLD. PMID- 26594200 TI - Biosurveillance of avian influenza and Newcastle disease viruses in the Barda region of Azerbaijan using real time RT-PCR and hemagglutination inhibition. AB - The Azerbaijan State Veterinary Control Service (SVCS) has conducted active serological surveillance for avian influenza (AI) in poultry since 2006, when the first outbreak of AI H5N1 occurred in Azerbaijan. Samples are collected from September to May annually and tested using a hemagglutination inhibition (HI) assay to detect antibodies against H5 AI viruses. HI testing is also performed for Newcastle disease virus (NDV) upon request, but since this method cannot distinguish between natural infections and immune responses to vaccination, all positive results require follow-up epidemiological investigations. Furthermore, blood collection for the surveillance program is time-intensive and can be stressful to birds. In order to improve the national surveillance program, alternative sampling and testing methodologies were applied among a population of birds in the Barda region and compared with results of the national surveillance program. Tracheal and cloacal swabs were collected instead of blood. Rather than testing individual samples, RNA was pooled to conserve resources and time, and pools were tested by real-time reverse transcription polymerase chain reaction (rRT-PCR). Environmental sampling at a live bird market was also introduced as another surveillance mechanism. A total of 1,030 swabs were collected, comprising tracheal, and cloacal samples from 441 birds and 148 environmental surface samples from farms or the live bird market. During the same time, 3,890 blood samples were collected nationally for the surveillance program; 400 of these samples originated in the Barda region. Birds sampled for rRT-PCR were likely different than those tested as part of national surveillance. All swab samples tested negative by rRT-PCR for both AI and NDV. All blood samples tested negative for H5 by HI, while 6.2% of all samples and 5% of the Barda samples tested positive for exposure to NDV. Follow-up investigations found that positive samples were from birds vaccinated in the previous month. This study demonstrated that taking swabs was quicker and less invasive than blood collection. Results of rRT-PCR testing were similar to HI testing for H5 but also ruled out infection with all influenza type A viruses and not just H5. In addition, rRT-PCR testing was able to rule out active infections with NDV. PMID- 26594202 TI - The control of classical swine fever in wild boar. AB - Classical swine fever (CSF) is a viral disease with severe economic consequences for domestic pigs. Natural hosts for the CSF virus (CSFV) are members of the family Suidae, i.e., Eurasian wild boar (sus scrofa) are also susceptible. CSF in wild boar poses a serious threat to domestic pigs. CSFV is an enveloped RNA virus belonging to the pestivirus genus of the Flaviviridae family. Transmission of the infection is usually by direct contact or by feeding of contaminated meat products. In recent decades CSF has been successfully eradicated from Australia, North America, and the European Union. In areas with dense wild boar populations CSF tends to become endemic whereas it is often self-limiting in small, less dense populations. In recent decades eradication strategies of CSF in wild boar have been improved considerably. The reduction of the number of susceptible animals to a threshold level where the basic reproductive number is R 0 < 1 is the major goal of all control efforts. Depending on the epidemiological situation, hunting measures combined with strict hygiene may be effective in areas with a relatively low density of wild boar. Oral immunization was shown to be highly effective in endemic situations in areas with a high density of wild boar. PMID- 26594203 TI - Regulation of BolA abundance mediates morphogenesis in Fremyella diplosiphon. AB - Filamentous cyanobacterium Fremyella diplosiphon is known to alter its pigmentation and morphology during complementary chromatic acclimation (CCA) to efficiently harvest available radiant energy for photosynthesis. F. diplosiphon cells are rectangular and filaments are longer under green light (GL), whereas smaller, spherical cells and short filaments are prevalent under red light (RL). Light regulation of bolA morphogene expression is correlated with photoregulation of cellular morphology in F. diplosiphon. Here, we investigate a role for quantitative regulation of cellular BolA protein levels in morphology determination. Overexpression of bolA in WT was associated with induction of RL characteristic spherical morphology even when cultures were grown under GL. Overexpression of bolA in a DeltarcaE background, which lacks cyanobacteriochrome photosensor RcaE and accumulates lower levels of BolA than WT, partially reverted the cellular morphology of the strain to a WT-like state. Overexpression of BolA in WT and DeltarcaE backgrounds was associated with decreased cellular reactive oxygen species (ROS) levels and an increase in filament length under both GL and RL. Morphological defects and high ROS levels commonly observed in DeltarcaE could, thus, be in part due to low accumulation of BolA. Together, these findings support an emerging model for RcaE-dependent photoregulation of BolA in controlling the cellular morphology of F. diplosiphon during CCA. PMID- 26594201 TI - Extremely thermophilic microorganisms as metabolic engineering platforms for production of fuels and industrial chemicals. AB - Enzymes from extremely thermophilic microorganisms have been of technological interest for some time because of their ability to catalyze reactions of industrial significance at elevated temperatures. Thermophilic enzymes are now routinely produced in recombinant mesophilic hosts for use as discrete biocatalysts. Genome and metagenome sequence data for extreme thermophiles provide useful information for putative biocatalysts for a wide range of biotransformations, albeit involving at most a few enzymatic steps. However, in the past several years, unprecedented progress has been made in establishing molecular genetics tools for extreme thermophiles to the point that the use of these microorganisms as metabolic engineering platforms has become possible. While in its early days, complex metabolic pathways have been altered or engineered into recombinant extreme thermophiles, such that the production of fuels and chemicals at elevated temperatures has become possible. Not only does this expand the thermal range for industrial biotechnology, it also potentially provides biodiverse options for specific biotransformations unique to these microorganisms. The list of extreme thermophiles growing optimally between 70 and 100 degrees C with genetic toolkits currently available includes archaea and bacteria, aerobes and anaerobes, coming from genera such as Caldicellulosiruptor, Sulfolobus, Thermotoga, Thermococcus, and Pyrococcus. These organisms exhibit unusual and potentially useful native metabolic capabilities, including cellulose degradation, metal solubilization, and RuBisCO-free carbon fixation. Those looking to design a thermal bioprocess now have a host of potential candidates to choose from, each with its own advantages and challenges that will influence its appropriateness for specific applications. Here, the issues and opportunities for extremely thermophilic metabolic engineering platforms are considered with an eye toward potential technological advantages for high temperature industrial biotechnology. PMID- 26594204 TI - Maturation of molybdoenzymes and its influence on the pathogenesis of non typeable Haemophilus influenzae. AB - Mononuclear molybdenum enzymes of the dimethylsulfoxide (DMSO) reductase family occur exclusively in prokaryotes, and a loss of some these enzymes has been linked to a loss of bacterial virulence in several cases. The MobA protein catalyzes the final step in the synthesis of the molybdenum guanine dinucleotide (MGD) cofactor that is exclusive to enzymes of the DMSO reductase family. MobA has been proposed as a potential target for control of virulence since its inhibition would affect the activities of all molybdoenzymes dependent upon MGD. Here, we have studied the phenotype of a mobA mutant of the host-adapted human pathogen Haemophilus influenzae. H. influenzae causes and contributes to a variety of acute and chronic diseases of the respiratory tract, and several enzymes of the DMSO reductase family are conserved and highly expressed in this bacterium. The mobA mutation caused a significant decrease in the activities of all Mo-enzymes present, and also resulted in a small defect in anaerobic growth. However, we did not detect a defect in in vitro biofilm formation nor in invasion and adherence to human epithelial cells in tissue culture compared to the wild type. In a murine in vivo model, the mobA mutant showed only a mild attenuation compared to the wild-type. In summary, our data show that MobA is essential for the activities of molybdenum enzymes, but does not appear to affect the fitness of H. influenzae. These results suggest that MobA is unlikely to be a useful target for antimicrobials, at least for the purpose of treating H. influenzae infections. PMID- 26594205 TI - Discovery of an algicidal compound from Brevibacterium sp. BS01 and its effect on a harmful algal bloom-causing species, Alexandrium tamarense. AB - Blooms of the dinoflagellate Alexandrium tamarense have become worldwide phenomena and have detrimental impacts on aquatic ecosystems and human health. In this study, a culture supernatant of the marine actinomycete BS01 exerted a strong algicidal effect on A. tamarense (ATGD98-006). The target algicide from BS01 was separated by adsorption chromatography and identified by MALDI-TOF-MS and NMR analysis. The results suggested that the purified algicidal component corresponded to a hydrophobic compound (2-isobutoxyphenyl)amine (C10H15NO) with a molecular weight of 165 Da, which exhibited a significant algicidal effect (64.5%) on A. tamarense. After incubation in 5 MUg/mL of (2-isobutoxyphenyl)amine for 24 h, the algae lost mobility and sank to the bottom of the flasks, and 56.5% of the algae cells lost vitality at a concentration of 20 MUg/mL (p < 0.01) despite having intact cell profiles. Morphological analysis revealed that the cell structure of A. tamarense was altered by (2-isobutoxyphenyl)amine resulting in cytoplasm degradation and the loss of organelle integrity. The images following propidium iodide staining suggested that the algal nucleus was also severely damaged and eventually degraded due to exposure to the algicidal compound. All of the results indicate that (2-isobutoxyphenyl)amine from the actinomycete might be a candidate for the control of bloom-forming A. tamarense. PMID- 26594206 TI - Modeling the synergistic antibacterial effects of honey characteristics of different botanical origins from the Sahara Desert of Algeria. AB - BACKGROUND: Honey has multiple therapeutic properties due to its composition with diverse components. OBJECTIVES: This study aims to investigate the antimicrobial efficacy of Saharan honeys against bacterial pathogens, the variation of honey floral origins, and its physicochemical characteristics. MATERIALS AND METHODS: The antimicrobial activity of 32 samples of honey collected from the Algerian Sahara Desert was tested on four bacteria; Bacillus subtilis, Clostridium perfringens, Escherichia coli, and Staphylococcus aureus. The botanical origin of honeys and their physicochemical properties were determined and their combined antibacterial effects were modeled using a generalized linear mixed model (GLMM). RESULTS: Out of the 32 study samples, 14 were monofloral and 18 were multifloral. The pollen density was on average 7.86 * 10(6) grains/10 g of honey, water content was 14.6%, electrical conductivity (EC) was 0.5 MUS/cm, pH was 4.38 +/- 0 50, hydroxymethylfurfural (HMF) content was 82 mg/kg of honey, total sugars = 83%, reducing sugars = 71%, and the concentration of proline = 525.5 +/- 550.2 mg/kg of honey. GLMM revealed that the antibacterial effect of honey varied significantly between bacteria and floral origins. This effect increased with increasing of water content and reducing sugars in honey, but it significantly decreased with increase of honey EC. E. coli was the most sensitive species with an inhibition zone of 10.1 +/- 4.7 mm, while C. perfringens was the less sensitive. Honeys dominated by pollen of Fabaceae sp. were most effective with an overall antimicrobial activity equals to 13.5 +/- 4.7 mm. CONCLUSION: Saharan honeys, of certain botanical origins, have physicochemical and pollinic characteristics with relevant potential for antibacterial purposes. This encourages a more comprehensive characterization of honeys with in vivo and in vitro investigations. PMID- 26594207 TI - Antibacterial phage ORFans of Pseudomonas aeruginosa phage LUZ24 reveal a novel MvaT inhibiting protein. AB - The functional elucidation of small unknown phage proteins ('ORFans') presents itself as one of the major challenges of bacteriophage molecular biology. In this work, we mined the Pseudomonas aeruginosa-infecting phage LUZ24 proteome for antibacterial and antibiofilm proteins against its host. Subsequently, their putative host target was identified. In one example, we observed an interaction between LUZ24 gp4 and the host transcriptional regulator MvaT. The polymerization of MvaT across AT-rich DNA strands permits gene silencing of foreign DNA, thereby limiting any potentially adverse effects of such DNA. Gel shift assays proved the inhibitory effect of LUZ24 gp4 on MvaT DNA binding activity. Therefore, we termed this gene product as Mip, the MvaT inhibiting protein. We hypothesize Mip prevents the AT-rich LUZ24 DNA from being physically blocked by MvaT oligomers right after its injection in the host cell, thereby allowing phage transcription and thus completion of the phage infection cycle. PMID- 26594208 TI - Identification of Weissella species by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. AB - Although some Weissella species play beneficial roles in food fermentation and in probiotic products, others such as Weissella confusa are emerging Gram-positive pathogens in immunocompromised hosts. Weissella species are difficult to identify by conventional biochemical methods and commercial automated systems and are easily misidentified as Lactobacillus and Leuconostoc species. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) is increasingly being used for bacterial identification. Little, however, is known about the effectiveness of MALDI-TOF MS in identifying clinical isolates of Weissella to the species level. In this study, we evaluated whether the MALDI-TOF MS Bruker Biotyper system could accurately identify a total of 20 W. confusa and 2 W. cibaria blood isolates that had been confirmed by 16s rRNA sequencing analysis. The MALDI-TOF Biotyper system yielded no reliable identification results based on the current reference spectra for the two species (all score values <1.7). New W. confusa spectra were created by randomly selecting 3 W. confusa isolates and external validation was performed by testing the remaining 17 W. confusa isolates using the new spectra. The new main spectra projection (MSP) yielded reliable score values of >2 for all isolates with the exception of one (score value, 1.963). Our results showed that the MSPs in the current database are not sufficient for correctly identifying W. confusa or W. cibaria. Further studies including more Weissella isolates are warranted to further validate the performance of MALDI-TOF in identifying Weissella species. PMID- 26594209 TI - Corrigendum: Biochemistry and genetics of ACC deaminase: a weapon to "stress ethylene" produced in plants. AB - [This corrects the article on p. 937 in vol. 6, PMID: 26441873.]. PMID- 26594210 TI - Precision Subtypes of T Cell-Mediated Rejection Identified by Molecular Profiles. AB - Among kidney transplant recipients, the treatment of choice for acute T cell mediated rejection (TCMR) with pulse steroids or antibody protocols has variable outcomes. Some rejection episodes are resistant to an initial steroid pulse, but respond to subsequent antibody protocols. The biological mechanisms causing the different therapeutic responses are not currently understood. Histological examination of the renal allograft is considered the gold standard in the diagnosis of acute rejection. The Banff Classification System was established to standardize the histopathological diagnosis and to direct therapy. Although widely used, it shows variability among pathologists and lacks criteria to guide precision individualized therapy. The analysis of the transcriptome in allograft biopsies, which we analyzed in this study, provides a strategy to develop molecular diagnoses that would have increased diagnostic precision and assist the development of individualized treatment. Our hypothesis is that the histological classification of TCMR contains multiple subtypes of rejection. Using R language algorithms to determine statistical significance, multidimensional scaling, and hierarchical, we analyzed differential gene expression based on microarray data from biopsies classified as TCMR. Next, we identified KEGG functions, protein protein interaction networks, gene regulatory networks, and predicted therapeutic targets using the integrated database ConsesnsusPathDB (CPDB). Based on our analysis, two distinct clusters of biopsies termed TCMR01 and TCMR02 were identified. Despite having the same Banff classification, we identified 1933 differentially expressed genes between the two clusters. These genes were further divided into three major groups: a core group contained within both the TCMR01 and TCMR02 subtypes, as well as genes unique to TCMR01 or TCMR02. The subtypes of TCMR utilized different biological pathways, different regulatory networks and were predicted to respond to different therapeutic agents. Our results suggest approaches to identify more precise molecular diagnoses of TCMR, which could form the basis for personalized treatments. PMID- 26594211 TI - Introduction of a Framework for Dynamic Knowledge Representation of the Control Structure of Transplant Immunology: Employing the Power of Abstraction with a Solid Organ Transplant Agent-Based Model. AB - Agent-based modeling has been used to characterize the nested control loops and non-linear dynamics associated with inflammatory and immune responses, particularly as a means of visualizing putative mechanistic hypotheses. This process is termed dynamic knowledge representation and serves a critical role in facilitating the ability to test and potentially falsify hypotheses in the current data- and hypothesis-rich biomedical research environment. Importantly, dynamic computational modeling aids in identifying useful abstractions, a fundamental scientific principle that pervades the physical sciences. Recognizing the critical scientific role of abstraction provides an intellectual and methodological counterweight to the tendency in biology to emphasize comprehensive description as the primary manifestation of biological knowledge. Transplant immunology represents yet another example of the challenge of identifying sufficient understanding of the inflammatory/immune response in order to develop and refine clinically effective interventions. Advances in immunosuppressive therapies have greatly improved solid organ transplant (SOT) outcomes, most notably by reducing and treating acute rejection. The end goal of these transplant immune strategies is to facilitate effective control of the balance between regulatory T cells and the effector/cytotoxic T-cell populations in order to generate, and ideally maintain, a tolerant phenotype. Characterizing the dynamics of immune cell populations and the interactive feedback loops that lead to graft rejection or tolerance is extremely challenging, but is necessary if rational modulation to induce transplant tolerance is to be accomplished. Herein is presented the solid organ agent-based model (SOTABM) as an initial example of an agent-based model (ABM) that abstractly reproduces the cellular and molecular components of the immune response to SOT. Despite its abstract nature, the SOTABM is able to qualitatively reproduce acute rejection and the suppression of acute rejection by immunosuppression to generate transplant tolerance. The SOTABM is intended as an initial example of how ABMs can be used to dynamically represent mechanistic knowledge concerning transplant immunology in a scalable and expandable form and can thus potentially serve as useful adjuncts to the investigation and development of control strategies to induce transplant tolerance. PMID- 26594212 TI - PKC-Theta is a Novel SC35 Splicing Factor Regulator in Response to T Cell Activation. AB - Alternative splicing of nuclear pre-mRNA is essential for generating protein diversity and regulating gene expression. While many immunologically relevant genes undergo alternative splicing, the role of regulated splicing in T cell immune responses is largely unexplored, and the signaling pathways and splicing factors that regulate alternative splicing in T cells are poorly defined. Here, we show using a combination of Jurkat T cells, human primary T cells, and ex vivo naive and effector virus-specific T cells isolated after influenza A virus infection that SC35 phosphorylation is induced in response to stimulatory signals. We show that SC35 colocalizes with RNA polymerase II in activated T cells and spatially overlaps with H3K27ac and H3K4me3, which mark transcriptionally active genes. Interestingly, SC35 remains coupled to the active histone marks in the absence of continuing stimulatory signals. We show for the first time that nuclear PKC-theta co-exists with SC35 in the context of the chromatin template and is a key regulator of SC35 in T cells, directly phosphorylating SC35 peptide residues at RNA recognition motif and RS domains. Collectively, our findings suggest that nuclear PKC-theta is a novel regulator of the key splicing factor SC35 in T cells. PMID- 26594214 TI - Increased NK Cell Maturation in Patients with Acute Myeloid Leukemia. AB - Understanding immune alterations in cancer patients is a major challenge and requires precise phenotypic study of immune subsets. Improvement of knowledge regarding the biology of natural killer (NK) cells and technical advances leads to the generation of high dimensional dataset. High dimensional flow cytometry requires tools adapted to complex dataset analyses. This study presents an example of NK cell maturation analysis in Healthy Volunteers (HV) and patients with Acute Myeloid Leukemia (AML) with an automated procedure using the FLOCK algorithm. This procedure enabled to automatically identify NK cell subsets according to maturation profiles, with 2D mapping of a four-dimensional dataset. Differences were highlighted in AML patients compared to HV, with an overall increase of NK maturation. Among patients, a strong heterogeneity in NK cell maturation defined three distinct profiles. Overall, automatic gating with FLOCK algorithm is a recent procedure, which enables fast and reliable identification of cell populations from high-dimensional cytometry data. Such tools are necessary for immune subset characterization and standardization of data analyses. This tool is adapted to new immune cell subsets discovery, and may lead to a better knowledge of NK cell defects in cancer patients. Overall, 2D mapping of NK maturation profiles enabled fast and reliable identification of NK cell subsets. PMID- 26594213 TI - The Timing of T Cell Priming and Cycling. AB - The proliferation of specific lymphocytes is the central tenet of the clonal selection paradigm. Antigen recognition by T cells triggers a series of events that produces expanded clones of differentiated effector cells. TCR signaling events are detectable within seconds and minutes and are likely to continue for hours and days in vivo. Here, I review the work done on the importance of TCR signals in the later part of the expansion phase of the primary T cell response, primarily regarding the regulation of the cell cycle in CD4(+) and CD8(+) cells. The results suggest a degree of programing by early signals for effector differentiation, particularly in the CD8(+) T cell compartment, with optimal expansion supported by persistent antigen presentation later on. Differences to CD4(+) T cell expansion and new avenues toward a molecular understanding of cell cycle regulation in lymphocytes are discussed. PMID- 26594215 TI - The Ins and Outs of B Cells in Multiple Sclerosis. AB - B cells play a central role in multiple sclerosis (MS) pathology. B and plasma cells may contribute to disease activity through multiple mechanisms: antigen presentation, cytokine secretion, or antibody production. Molecular analyses of B cell populations in MS patients have revealed significant overlaps between peripheral lymphoid and clonally expanded central nervous system (CNS) B cell populations, indicating that B cell trafficking may play a critical role in driving MS exacerbations. In this review, we will assess our current knowledge of the mechanisms and pathways governing B cell migration into the CNS and examine evidence for and against a compartmentalized B cell response driving progressive MS pathology. PMID- 26594216 TI - Effector Functions of Natural Killer Cell Subsets in the Control of Hematological Malignancies. AB - Treatment of hematological malignant disorders has been improved over the last years, but high relapse rate mainly attributable to the presence of minimal residual disease still persists. Therefore, it is of great interest to explore novel therapeutic strategies to obtain long-term remission. Immune effector cells, and especially natural killer (NK) cells, play a crucial role in the control of hematological malignancies. In this regard, the efficiency of allogeneic stem cell transplantation clearly depends on the immune-mediated graft versus leukemia effect without the risk of inducing graft versus host disease. Alloreactive donor NK cells generated following hematopoietic stem cell transplantation ameliorate the outcome of leukemia patients; in addition, in vivo transfer of in vitro expanded NK cells represents a crucial tool for leukemia treatment. To improve NK cell effector functions against resistant leukemia cells, novel immunotherapeutic strategies are oriented to the identification, isolation, expansion, and administration of particular NK cell subsets endowed with multifunctional anti-tumor potential and tropism toward tumor sites. Moreover, the relationship between the emergence and persistence of distinct NK cell subsets during post-graft reconstitution and the maintenance of a remission state is still rather unclear. PMID- 26594217 TI - Cadmium affects microtubule organization and post-translational modifications of tubulin in seedlings of soybean (Glycine max L.). AB - Cadmium (Cd) is a non-essential heavy metal, toxic to all living organisms. The microtubule (MT) cytoskeleton appears to be one of the main targets of Cd action. In this study we present, with the use of various immunological approaches, the effect of Cd at moderate (85 MUM) and high (170 MUM) concentrations on the structure and functioning of the MT cytoskeleton in the root cells of soybean seedlings. As the result of heavy metal action, root growth was significantly diminished and was accompanied by a reduction in mitotic activity and disturbance in the structure of the MT arrays, including randomization of the cortical MT arrangement, distorted mitotic arrays and complete depolymerization of the MTs. Biochemical analysis revealed decreased levels of various alpha- and beta-tubulin isoforms with a parallel down-regulation of most examined alpha-tubulin genes. Simultaneously, Cd treatment led to differentiated changes in the level of tubulin post-translational modifications, including tyrosination, detyrosination, acetylation, and polyglutamylation. Decreased tyrosination and polyglutamylation of particular tubulin isoforms accompanied by increase in the level of specific detyrosinated and acetylated isoforms implies augmented stability and reduced turnover of the MTs during stress conditions. Taken together, the obtained results indicate the significant impact of Cd on gene expression levels and subsequent post-translational processing of tubulin, which may be related to the impairment of MT cytoskeleton functioning in root cells. PMID- 26594218 TI - A genome-wide identification of the miRNAome in response to salinity stress in date palm (Phoenix dactylifera L.). AB - Although date palm is relatively salt-tolerant, little is known about the underlying molecular mechanisms that contribute to its salt tolerance. Only recently, investigators have uncovered microRNA-mediated post-transcriptional gene regulation, which is critical for typical plant development and adaptation to stress conditions such as salinity. To identify conserved and novel miRNAs in date palm and to characterize miRNAs that could play a role in salt tolerance, we have generated sRNA libraries from the leaves and roots of NaCl-treated and untreated seedlings of date palm. Deep sequencing of these four sRNA libraries yielded approximately 251 million reads. The bioinformatics analysis has identified 153 homologs of conserved miRNAs, 89 miRNA variants, and 180 putative novel miRNAs in date palm. Expression profiles under salinity revealed differential regulation of some miRNAs in date palm. In leaves, 54 of the identified miRNAs were significantly affected and the majority (70%) of them were upregulated, whereas in roots, 25 of the identified miRNAs were significantly affected and 76% of them were upregulated by the salinity stress. The salt responsiveness of some of these miRNAs was further validated using semi quantitative PCR (qPCR). Some of the predicted targets for the identified miRNA include genes with known functions in plant salt tolerance, such as potassium channel AKT2-like proteins, vacuolar protein sorting-associated protein, calcium dependent and mitogen-activated proteins. As one of the first cultivated trees in the world that can tolerate a wide range of abiotic stresses, date palm contains a large population of conserved and non-conserved miRNAs that function at the post-transcriptional level. This study provided insights into miRNA-mediated gene expression that are important for adaptation to salinity in date palms. PMID- 26594219 TI - Endogenous target mimics down-regulate miR160 mediation of ARF10, -16, and -17 cleavage during somatic embryogenesis in Dimocarpus longan Lour. AB - MicroRNA160 plays a critical role in plant development by negatively regulating the auxin response factors ARF10, -16, and -17. However, the ways in which miR160 expression is regulated at the transcriptional level, and how miR160 interacts with its targets during plant embryo development, remain unknown. Here, we studied the regulatory relationships among endogenous target mimics (eTMs), and miR160 and its targets, and their involvement in hormone signaling and somatic embryogenesis (SE) in Dimocarpus longan. We identified miR160 family members and isolated the miR160 precursor, primary transcript, and promoter. The promoter contained cis-acting elements responsive to stimuli such as light, abscisic acid, salicylic acid (SA) and heat stress. The pri-miR160 was down-regulated in response to SA but up-regulated by gibberellic acid, ethylene, and methyl jasmonate treatment, suggesting that pri-miR160 was associated with hormone transduction. Dlo-miR160a, -a(*) and -d(*) reached expression peaks in torpedo shaped embryos, globular embryos and cotyledonary embryos, respectively, but were barely detectable in friable-embryogenic callus. This suggests that they have expression-related and functional diversity, especially during the middle and later developmental stages of SE. Four potential eTMs for miR160 were identified. Two of them, glucan endo-1,3-beta- glucosidase-like protein 2-like and calpain type cysteine protease DEK1, were confirmed to control the corresponding dlo miR160a(*) expression level. This suggests that they may function to abolish the binding between dlo-miR160a(*) and its targets. These two eTMs also participated in 2,4-D and ABA signal transduction. DlARF10, -16, and -17 targeting by dlo miR160a was confirmed; their expression levels were higher in friable-embryogenic callus and incomplete compact pro-embryogenic cultures and responded to 2,4-D, suggesting they may play a major role in the early stages of longan SE dependent on 2,4-D. The eTMs, miR160, and ARF10, -16, and -17 exhibited tissue specificity in 'Sijimi' longan vegetative and reproductive organs, but were not significant negatively correlated. These results provide insights into the possible role of the eTM-miR160-ARF10-16-17 pathway in longan somatic embryo development. PMID- 26594220 TI - Biosafety research for non-target organism risk assessment of RNAi-based GE plants. AB - RNA interference, or RNAi, refers to a set of biological processes that make use of conserved cellular machinery to silence genes. Although there are several variations in the source and mechanism, they are all triggered by double stranded RNA (dsRNA) which is processed by a protein complex into small, single stranded RNA, referred to as small interfering RNAs (siRNA) with complementarity to sequences in genes targeted for silencing. The use of the RNAi mechanism to develop new traits in plants has fueled a discussion about the environmental safety of the technology for these applications, and this was the subject of a symposium session at the 13th ISBGMO in Cape Town, South Africa. This paper continues that discussion by proposing research areas that may be beneficial for future environmental risk assessments of RNAi-based genetically modified plants, with a particular focus on non-target organism assessment. PMID- 26594221 TI - Crop epigenetics and the molecular hardware of genotype * environment interactions. AB - Crop plants encounter thermal environments which fluctuate on a diurnal and seasonal basis. Future climate resilient cultivars will need to respond to thermal profiles reflecting more variable conditions, and harness plasticity that involves regulation of epigenetic processes and complex genomic regulatory networks. Compartmentalization within plant cells insulates the genomic central processing unit within the interphase nucleus. This review addresses the properties of the chromatin hardware in which the genome is embedded, focusing on the biophysical and thermodynamic properties of DNA, histones and nucleosomes. It explores the consequences of thermal and ionic variation on the biophysical behavior of epigenetic marks such as DNA cytosine methylation (5mC), and histone variants such as H2A.Z, and how these contribute to maintenance of chromatin integrity in the nucleus, while enabling specific subsets of genes to be regulated. Information is drawn from theoretical molecular in vitro studies as well as model and crop plants and incorporates recent insights into the role epigenetic processes play in mediating between environmental signals and genomic regulation. A preliminary speculative framework is outlined, based on the evidence of what appears to be a cohesive set of interactions at molecular, biophysical and electrostatic level between the various components contributing to chromatin conformation and dynamics. It proposes that within plant nuclei, general and localized ionic homeostasis plays an important role in maintaining chromatin conformation, whilst maintaining complex genomic regulation that involves specific patterns of epigenetic marks. More generally, reversible changes in DNA methylation appear to be consistent with the ability of nuclear chromatin to manage variation in external ionic and temperature environment. Whilst tentative, this framework provides scope to develop experimental approaches to understand in greater detail the internal environment of plant nuclei. It is hoped that this will generate a deeper understanding of the molecular mechanisms underlying genotype * environment interactions that may be beneficial for long-term improvement of crop performance in less predictable climates. PMID- 26594223 TI - The role of promoter cis-element, mRNA capping, and ROS in the repression and salt-inducible expression of AtSOT12 in Arabidopsis. AB - Inducible gene expression is a gene regulatory mechanism central to plant response to environmental cues. The inducible genes are often repressed under normal growth conditions while their expression levels are significantly elevated by conditions such as abiotic stresses. Induction of gene expression requires both cis-acting DNA elements and trans-acting proteins that are modulated through signal transduction pathways. Here we report several molecular events that affect salt induced expression of the Arabidopsis AtSOT12 gene. Promoter deletion analysis revealed that DNA elements residing in the 5' UTR are required for the salt induced expression of AtSOT12. Cytosine methylation in the promoter was low and salt stress slightly increased the DNA methylation level, suggesting that DNA methylation may not contribute to AtSOT12 gene repression. Co-transcriptional processing of AtSOT12 mRNA including capping and polyadenylation site selection was also affected by salt stress. The percentage of capped mRNA increased by salt treatment, and the polyadenylation sites were significantly different before and after exposure to salt stress. The expression level of AtSOT12 under normal growth conditions was markedly higher in the oxi1 mutant defective of reactive oxygen species (ROS) signaling than in the wild type. Moreover, AtSOT12 transcript level was elevated by treatments with DPI and DMTU, two chemicals preventing ROS accumulation. These results suggest that repression of AtSOT12 expression may require physiological level of ROS and ROS signaling. PMID- 26594222 TI - Ferns: the missing link in shoot evolution and development. AB - Shoot development in land plants is a remarkably complex process that gives rise to an extreme diversity of forms. Our current understanding of shoot developmental mechanisms comes almost entirely from studies of angiosperms (flowering plants), the most recently diverged plant lineage. Shoot development in angiosperms is based around a layered multicellular apical meristem that produces lateral organs and/or secondary meristems from populations of founder cells at its periphery. In contrast, non-seed plant shoots develop from either single apical initials or from a small population of morphologically distinct apical cells. Although developmental and molecular information is becoming available for non-flowering plants, such as the model moss Physcomitrella patens, making valid comparisons between highly divergent lineages is extremely challenging. As sister group to the seed plants, the monilophytes (ferns and relatives) represent an excellent phylogenetic midpoint of comparison for unlocking the evolution of shoot developmental mechanisms, and recent technical advances have finally made transgenic analysis possible in the emerging model fern Ceratopteris richardii. This review compares and contrasts our current understanding of shoot development in different land plant lineages with the aim of highlighting the potential role that the fern C. richardii could play in shedding light on the evolution of underlying genetic regulatory mechanisms. PMID- 26594224 TI - Fibrillarin methylates H2A in RNA polymerase I trans-active promoters in Brassica oleracea. AB - Fibrillarin is a well conserved methyltransferase involved in several if not all of the more than 100 methylations sites in rRNA which are essential for proper ribosome function. It is mainly localized in the nucleoli and Cajal bodies inside the cell nucleus where it exerts most of its functions. In plants, fibrillarin binds directly the guide RNA together with Nop56, Nop58, and 15.5ka proteins to form a snoRNP complex that selects the sites to be methylated in pre-processing of ribosomal RNA. Recently, the yeast counterpart NOP1 was found to methylate histone H2A in the nucleolar regions. Here we show that plant fibrillarin can also methylate histone H2A. In Brassica floral meristem cells the methylated histone H2A is mainly localized in the nucleolus but unlike yeast or human cells it also localize in the periphery of the nucleus. In specialized transport cells the pattern is altered and it exhibits a more diffuse staining in the nucleus for methylated histone H2A as well as for fibrillarin. Here we also show that plant fibrillarin is capable of interacting with H2A and carry out its methylation in the rDNA promoter. PMID- 26594226 TI - Potential envenomation by the aglyphous pseudoxyrhophiine snake Leioheterodon madagascariensis and description of its dentition. AB - We report on a case of potential envenomation caused by multiple bites by the aglyphous opisthodont snake Leioheterodon madagascariensis in the left thumb of a healthy adult man, which is among the most serious snakebites hitherto reported from Madagascar. The adult snake (total length > 1 meter) was unusually aggressive before and during capture. The symptoms included extensive bleeding, severe local pain, and substantial swelling of the hand and the distal part of the lower arm. The swelling disappeared entirely after five days, but pain in the thumb (when moved) was recognizable even longer. Although L. madagascariensis is widespread and common in anthropogenic habitats in eastern and western Madagascar, this case report seems to be the first description of long-lasting symptoms of its bite. Since aglyphous snakes are relatively rarely involved in "envenomation" and because hemolytic activity has been recorded in the secretions of the Duvernoy's glands of Leioheterodon, we describe its dentition using microcomputed tomography and discuss the potential mode of envenomation in this case. PMID- 26594225 TI - Nitroxide pharmaceutical development for age-related degeneration and disease. AB - Nitroxide small molecule agents are in development as preventative or therapeutic pharmaceutical drugs for age-related macular degeneration (AMD) and cardiovascular disease, which are two major diseases of aging. These aging diseases are associated with patient genetics, smoking, diet, oxidative stress, and chronic inflammation. Nitroxide drugs preventing aging-, smoking-, high sugar or high fat diet-, or radiation- and other environmental-induced pathophysiological conditions in aging disease are reviewed. Tempol (TP), Tempol Hydroxylamine (TP-H), and TP-H prodrug (OT-551) are evaluated in (1) non-smokers versus smokers with cutaneous microvascular dysfunction, rapidly reversed by cutaneous TP; (2) elderly cancer patients at risk for radiation-induced skin burns or hair loss, prevented by topical TP; and (3) elderly smoker or non-smoker AMD patients at risk for vision loss, prevented by daily eye drops of OT-551. The human data indicates safety and efficacy for these nitroxide drugs. Both TP and TP-H topically penetrate and function in skin or mucosa, protecting and treating radiation burns and hair loss or smoking-induced cutaneous vascular dysfunction. TP and TP-H do not penetrate the cornea, while OT-551 does effectively penetrate and travels to the back of the eye, preserving visual acuity and preserving normal and low light luminance in dry AMD smokers and non-smoker patients. Topical, oral, or injectable drug formulations are discussed. PMID- 26594227 TI - T-cell phenotypes in chronic rhinosinusitis with nasal polyps in Japanese patients. AB - BACKGROUND: Chronic rhinosinusitis with nasal polyps is characterized by local inflammation and is categorized into two subtypes in Japan: eosinophilic chronic rhinosinusitis, and non-eosinophilic chronic rhinosinusitis. The objective of this study was to investigate the expression of key transcription factors for Treg and Th1/Th2/Th17 cells, in relation to the mRNA expression of representative cytokines in these two subtypes of chronic rhinosinusitis with nasal polyps. METHODS: The expression of forkhead box P3 (FOXP3), T-box transcription factor (T bet), GATA3, retinoid acid-related orphan receptor C (RORc), the suppressive cytokines TGF-beta1 and IL-10, and Th1/Th2/Th17 cytokines (IFN-gamma, IL-4, IL-5, IL-13, IL-17) were analyzed by means of RT-PCR in eosinophilic polyps. Eosinophilic polyps were defined as having an eosinophil count of more than 50 per microscopic field (*400 magnification) using five fields located in the subepithelial area of the polyps, while the non-eosinophilic polyps and controls did not fulfill this criteria. The numbers of T cells, CD4+ T cells, CD8+ T cells and Treg were histologically counted using sections that were immunostained for CD3, CD4, CD8, and FOXP3, respectively. RESULTS: In eosinophilic polyps, we observed significantly fewer CD4+ T cells and CD8+ T cells, and lower GATA3, RORc and IL-10 mRNA expression, but a significantly higher IL-5, and IL-13 mRNA expression compared with controls, whereas FOXP3 and T-bet mRNA expression were not significantly different compared with controls. In non-eosinophilic polyps, FOXP3, IL-10, IL-17A, TGFbeta1 and IFNgamma mRNA expression was significantly higher compared with controls, whereas IL-4, 5 and 13 expression was not significantly different from controls. CONCLUSION: We showed a reduction of GATA3 and RORc mRNA, low Treg-related cytokines and elevated Th2 cytokine levels in eosinophilic chronic rhinosinusitis, whereas we demonstrated the upregulation of Treg cells and increases of Th1 and Th17 cytokines in non-eosinophilic chronic rhinosinusitis in the Japanese population. The different mRNA expression profiles of Treg and Th1/Th2/Th17 signature transcription factors and cytokines between eosinophilic chronic rhinosinusitis and non-eosinophilic chronic rhinosinusitis suggests heterogeneity in the pathogenesis of chronic rhinosinusitis with nasal polyps. PMID- 26594228 TI - A retrospective comparison of false negative skin test rates in penicillin allergy, using pencilloyl-poly-lysine and minor determinants or Penicillin G, followed by open challenge. AB - BACKGROUND: A history of penicillin allergy in patients is common, but only 10-15 % are truly allergic. While the gold standard for diagnosing penicillin allergy is challenge, it is not recommended that this be done without first carrying out diagnostic skin testing. This is carried out with the major determinant benzylpenicilloyl (PPL) and the minor determinant mixture (MDM), consisting of penilloate, penicilloate and Penicillin G. However, since availability of the MDM is limited, Penicillin G alone has been used. METHODS: A retrospective chart review was carried out on patients tested for penicillin allergy in the Clinical Immunology and Allergy Clinic at the Health Sciences Centre, Winnipeg, Canada between 2005 and 2013. A total of 521 patients charts were reviewed, of whom 240 had skin testing, ImmunoCap((r)) for IgE to Penicillin G and V and had oral challenges with penicillin, amoxicillin or cloxacillin. RESULTS: 17/240 (7.5 %) were skin test positive, 8 to PPL, 4 to MDM and 5 to Penicillin G. One was also positive on ImmunoCap((r)) testing. Three patients had negative skin tests but weakly positive ImmunoCap((r)). 222 patients with negative skin tests and serological tests were challenged. Of these, 12 patients reacted to challenge. Three of the challenges were equivocal. Of the nine patients with definite positive challenges, three were tested with Penicillin G and six with MDM. Therefore the false negative rates for testing were 2.3 % with PPL and Penicillin G and 6.97 % for PPL and MDM. The difference was not significant (p = 0.0856). CONCLUSIONS: In this group of patients with a history of penicillin allergy tested with the major determinant of benzyl penicillin and either MDM or Penicillin G, there was no difference in the rate of false negative testing, based on oral penicillin challenges. Therefore, Penicillin G can be safely used as an alternative to MDM in diagnosing penicillin allergy. PMID- 26594229 TI - Evaluation of a new whole room indirect calorimeter specific for measurement of resting metabolic rate. AB - BACKGROUND: The most common methods for obtaining human resting metabolic rate (RMR) use either a ventilated hood connected to a metabolic cart (VH_MC) or calculation by many prediction equations utilizing the person's height and weight. These methods may be inherently inaccurate. The objective of this study is to compare the accuracy for the measurement of RMR by three methods: a new whole room indirect calorimeter specific for this purpose (RMR_WRIC), VH_MC and calculation by the Mifflin equation (ME). First, the VH_MC (Vmax Encore 2900, Carefusion Inc, San Diego, CA) and RMR_WRIC (Promethion GA-6/FG-1, Sable Systems Intl, Las Vegas, NV) were subjected to 10, one-hour ethanol (99.8 % purity) and propane (99.5 % purity) combustion tests, respectively, for simulated metabolic measurements. Thereafter, 40 healthy adults (22 M/18 F, 78.0 +/- 24.5 kg, BMI = 25.6 +/- 4.8, age 36.6 +/- 13.4 years) had one-hour RMR (kcal), ventilation (liters) rates of oxygen (VO2), carbon dioxide (VCO2) and RQ (VCO2/VO2) measured after a 12-h fast with both the VH_ MC and the RMR_WRIC in a randomized fashion. The resting state was documented by heart rate. The RMR was also calculated using the ME, which was compared to both the RMR_WRIC and the VH_MC. All simulated and human metabolic data were extrapolated to 24-h and analyzed (SPSS, Ver. 22). RESULTS: Comparing stoichiometry to actual combustion, the VH_MC underestimated simulated RMR (p < 0.05), VO2 (p < 0.05), VCO2 (p < 0.05) and the RQ. Similarly the RMR_WRIC underestimated simulated RMR (p < 0.05) and VO2 while overestimating VCO2 and the RQ. There was much greater variability in the simulated metabolic data between combustion and the VH_MC as compared to that of the RMR_WRIC. With regards to the volunteers, the RMR, RQ, VO2 and VCO2 determined by the VH_MC tended to be lower in comparison to these measurements determined by the RMR_WRIC. Finally, RMR calculated utilizing the ME was significantly (p < 0.05) less than the RMR_WRIC but similar to that obtained by the VH_MC. CONCLUSION: The RMR_WRIC was more accurate and precise than either the VH_MC or ME, which has implications for determining energy requirements for individuals participating in weight loss or nutrition rehabilitation programs. PMID- 26594230 TI - Longitudinal study on the association between three dietary indices, anthropometric parameters and blood lipids. AB - BACKGROUND: From a health promotion perspective, the use of dietary indices is preferred above single nutrients and foods to evaluate diet quality. Longitudinal research about the association between dietary indices and respectively anthropometric parameters and blood lipids is lacking. The aim of this study was to investigate the longitudinal association between three dietary indices (Healthy Eating Index-2010 (HEI), Mediterranean Diet Score (MDS) and Diet Quality Index (DQI)) and respectively anthropometric parameters and blood lipids. METHODS: A three day diet record was completed by 373 men and 197 women in 2002 2004 and 2012-2014. HEI, MDS and DQI were calculated. Waist circumference (WC) and Body Mass Index (BMI) were used as anthropometric parameters. A linear regression analysis was performed to investigate associations between changes in dietary indices and changes in respectively anthropometric parameters and blood lipids, adjusted for potential confounders. RESULTS: Only in men an increase in all three dietary indices was associated with a decrease in WC and BMI in the non adjusted analysis and for HEI and DQI also in the adjusted analysis. No longitudinal associations were found between dietary indices and blood lipids both in men and women. CONCLUSIONS: Only few associations were found between dietary indices and anthropometric parameters, whilst no associations were found with blood lipids. An increase in dietary indices was associated with an improvement in anthropometric parameters only in men. As this is the first study investigating associations between changes in dietary indices and changes in respectively anthropometric parameters and blood lipids, further research is needed to evaluate these possible associations. PMID- 26594231 TI - Effects of antenatal care and institutional delivery on exclusive breastfeeding practice in northwest Ethiopia: a nested case-control study. AB - BACKGROUND: For the first six months of life, breast milk is the ideal food to provide adequate quality and quantity of nutrients. Exclusive breastfeeding has a profound effect to reduce the risk of respiratory and gastrointestinal related morbidities as well as all-cause and infection-related neonatal mortalities. Despite the immense benefits of exclusive breastfeeding, the practice is suboptimal in Ethiopia. The aim of this study was to assess whether antenatal care and institutional delivery contributes to mothers' practice of exclusive breastfeeding in rural communities of northwest Ethiopia. METHODS: A community based nested case-control study was conducted in northwest Ethiopia from November 2009 to August 2011. About 1769 mother-infant pairs were included and followed for six months after birth. Interviews with mothers were conducted in the first week, at 1(st), 4(th), and 6(th) month. Bivariate and multivariate logistic regression were carried out to determine associations between independent variables and exclusive breastfeeding practice. RESULTS: Of the total respondents, 30.7 % (95 % CI: 27 %, 35 %) of mothers exclusively breastfed their infants. In multivariate analysis, own business activity (AOR= 3.06; 95 % CI: 1.29, 7.25), being a housewife (AOR= 3.41; 95 % CI: 1.28, 9.11), having antenatal care (AOR= 1.32; 95 % CI: 1.01, 1.73), giving birth in a health institution (AOR= 1.29; 95 % CI: 1.02, 1.62), and possessing a microfinance bank account (AOR= 2.35; 95 % CI: 1.80, 3.07) were positively associated with exclusive breastfeeding practice. CONCLUSIONS: Despite underutilization of maternal health services, these services contributed to mothers exclusive breastfeeding practice. Strengthening utilization of antenatal care and institutional delivery would have an added benefit in improving exclusive breastfeeding practice. Moreover involving mothers in business activities is important. PMID- 26594232 TI - Effect of breastfeeding on bone mass from childhood to adulthood: a systematic review of the literature. AB - BACKGROUND: Conflicting results exist about the short-and long-term effects of breastfeeding on bone mineral content (BMC) and bone mineral density (BMD). We conducted a systematic review to assess the relationship between method of infant feeding and bone mass in children, adolescents and adults. METHODS: The literature review was concluded in September 2014 in MEDLINE, Web of Science and LILACS databases and articles published between 1998 and 2013 were included. Studies using dual-energy X-ray absorptiometry (DXA) instrument to assess the bone mineral content and/or bone mineral density (BMD) of total body, lumbar spine, femoral neck, or at least one of these sites were included in the review. RESULTS: From the 648 references identified, eleven were selected, ten of which had a longitudinal design. All studies were conducted in high-income countries, six evaluated the outcome in children, four in adolescents and one in young adults (<35 years). Of the studies that assessed the outcome in childhood, two found a positive association and the others showed a negative effect of being breastfed on bone mass. In adolescence, three studies showed a positive association between being breastfed and bone outcomes. Among adults, a negative effect of being breastfed exclusively for a longer period of time on bone mass was observed only in men. In women, there was no effect of being breastfed on bone mass. CONCLUSIONS: There is no consensus on the effects of method of infant feeding on an individual's bone mass at different ages. PMID- 26594233 TI - The Association between Airborne PM2.5 Chemical Constituents and Birth Weight Implication of Buffer Exposure Assignment. AB - Several papers reported associations between airborne fine particulate matter (PM2.5) and birth weight, though findings are inconsistent across studies. Conflicting results might be due to (1) different PM2.5 chemical structure across locations, and (2) various exposure assignment methods across studies even among the studies that use ambient monitors to assess exposure. We investigated associations between birth weight and PM2.5 chemical constituents, considering issues arising from choice of buffer size (i.e. distance between residence and pollution monitor). We estimated the association between each pollutant and term birth weight applying buffers of 5 to 30km in Connecticut (2000-2006), in the New England region of the U.S. We also investigated the implication of the choice of buffer size in relation to population characteristics, such as socioeconomic status. Results indicate that some PM2.5 chemical constituents, such as nitrate, are associated with lower birth weight and appear more harmful than other constituents. However, associations vary with buffer size and the implications of different buffer sizes may differ by pollutant. A homogeneous pollutant level within a certain distance is a common assumption in many environmental epidemiology studies, but the validity of this assumption may vary by pollutant. Furthermore, we found that areas close to monitors reflect more minority and lower socio-economic populations, which implies that different exposure approaches may result in different types of study populations. Our findings demonstrate that choosing an exposure method involves key tradeoffs of the impacts of exposure misclassification, sample size, and population characteristics. PMID- 26594234 TI - Erratum to: caustic ingestion management: world society of emergency surgery preliminary survey of expert opinion. AB - [This corrects the article DOI: 10.1186/s13017-015-0043-4.]. PMID- 26594235 TI - Antifungal mode of action of macrocarpal C extracted from Eucalyptus globulus Labill (Lan An) towards the dermatophyte Trichophyton mentagrophytes. AB - BACKGROUND: The fresh leaves of Eucalyptus globulus Labill. (Lan An) have been used in Chinese medicine for many years to treat dermatomycosis. Macrocarpal C was isolated from this herb and identified as its major antifungal component by bioassay-guided purification. This study aims to investigate the antifungal activity of macrocarpal C against Trichophyton mentagrophytes, which can cause tinea pedis. METHODS: Fresh leaves of E. globulus were extracted with 95 % ethanol, and the resulting ethanolic extracts were dried before being partitioned with n-hexane. The n-hexane layer was then subjected to chromatographic purification to give macrocarpal C. The antifungal minimum inhibitory concentration (MIC) of macrocarpal C was determined using the standard M38-A2 method described by the Clinical Laboratory Standards Institute (CLSI). The mode of action of macrocarpal C was elucidated using three in vitro assays, including (1) a fungal membrane permeability test using SYTOX((r)) Green; (2) a reactive oxygen species (ROS) production test using 5-(and-6)-carboxy-2',7' dihydrodichlorofluorescein diacetate as a cell-permeable fluorogenic probe; and (3) a DNA fragmentation test based on terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) detection. Terbinafine hydrochloride and nystatin were used as positive controls. RESULTS: The suppression in the growth of T. mentagrophytes following its treatment with macrocarpal C was associated with an increase in the permeability of the fungal membrane (P = 0.0043 when compared to control); an increase in the production of intracellular ROS (P = 0.0063); and the induction of apoptosis as a consequence of DNA fragmentation (P = 0.0007). CONCLUSION: This study demonstrated that the antifungal action of macrocarpal C was associated with increases of membrane permeability, intracellular ROS and DNA fragmentation. PMID- 26594236 TI - A prospective randomized study on limits of colposcopy and histology: the skill of colposcopist and colposcopy-guided biopsy in diagnosis of cervical intraepithelial lesions. AB - BACKGROUND: The main objective of our study was to evaluate the colposcopist ability to correctly identify the worst area of a cervical lesion where biopsy should be performed; the secondary objective was to investigate the influence of the colposcopist skill in grading cervical preneoplastic lesions. METHODS: 296 patients referred for colposcopy were enrolled in a prospective study. All patients were randomized in two groups: in the first group, "senior group", the colposcopy was performed by an experienced colposcopist; in the second group, "junior group", the colposcopy was performed by a less experienced colposcopist. A detailed colposcopic description, including a grading of the lesion, was completed for each case. During the colposcopic exam patients underwent two direct biopsies; each biopsy was labeled with letter A (suspicious area with most severe grade) or B (suspicious area with less severe grade) according to the judgment of the colposcopist. An experienced pathologist reanalyzed the histological slides, after routine diagnosis. RESULTS: The senior group identify the worst area of the cervical lesion in statistical significant higher rates than junior group. Specimen A resulted representative of the higher-grade lesion (A > B) in 73.7 % (N = 28) in senior group and in 48.4 % (N = 15) in junior group; while in 26.3 % (N = 10) the higher-grade lesion corresponded to specimen B (A < B) in senior group and in 51.6 % (N = 16) in junior group (p < .05). CONCLUSION: The ability of a colposcopist in grading cervical lesion depends on his experience. PMID- 26594237 TI - Training frontline workforce on psychosis management: a prospective study of training effects. AB - BACKGROUND: The care situation for persons experiencing severe mental illness is often complex and demands good coordination, communication, and interpersonal relationships among those involved from the primary and specialized mental health care systems. For 15 years, professional care providers from different service levels within the same geographical areas in Norway have been trained together in a 2-year local onsite training program with the aim of increasing skills, joint understanding, and collaboration in their work with individuals experiencing severe mental illness. METHODS: The key aspects of competence addressed by the training program were measured at baseline, after 1 year, and at the end of the training period. Professional education and experience were also rated at baseline. Data were collected between 1999 and 2005 and were analyzed by estimating a linear mixed model. RESULTS: Results showed a significant increase in participants' experienced competence in all training goals, especially for the understanding of psychosis and relationship building. There was no significant variance at the program level, indicating consistent implementation of local programs. CONCLUSIONS: This prospective study indicates that the training program was successful in increasing perceived competence in the areas addressed, and training staff from different service levels together probably contributed to more collaboration. This training model still operates in Norway. PMID- 26594238 TI - Engineering dynamic cell cycle control with synthetic small molecule-responsive RNA devices. AB - BACKGROUND: The cell cycle plays a key role in human health and disease, including development and cancer. The ability to easily and reversibly control the mammalian cell cycle could mean improved cellular reprogramming, better tools for studying cancer, more efficient gene therapy, and improved heterologous protein production for medical or industrial applications. RESULTS: We engineered RNA-based control devices to provide specific and modular control of gene expression in response to exogenous inputs in living cells. Specifically, we identified key regulatory nodes that arrest U2-OS cells in the G0/1 or G2/M phases of the cycle. We then optimized the most promising key regulators and showed that, when these optimized regulators are placed under the control of a ribozyme switch, we can inducibly and reversibly arrest up to ~80 % of a cellular population in a chosen phase of the cell cycle. Characterization of the reliability of the final cell cycle controllers revealed that the G0/1 control device functions reproducibly over multiple experiments over several weeks. CONCLUSIONS: To our knowledge, this is the first time synthetic RNA devices have been used to control the mammalian cell cycle. This RNA platform represents a general class of synthetic biology tools for modular, dynamic, and multi-output control over mammalian cells. PMID- 26594239 TI - Lignin degradation in corn stalk by combined method of H2O2 hydrolysis and Aspergillus oryzae CGMCC5992 liquid-state fermentation. AB - BACKGROUND: Lignin peroxidase (LiP) is the primary enzyme responsible for lignin degradation. In our previous work, in order to shorten the pretreatment time and increase the lignin degradation, we have pretreated the corn stalk (CS) using a combination of Aspergillus oryzae CGMCC 5992 solid-state fermentation and H2O2 treatment. RESULTS: In the present study, one-factor-at-a-time design and response surface design were applied to optimize the nutritional constituents for LiP production in liquid-state fermentation by A. oryzae CGMCC 5992 and the conditions for CS degradation by A. oryzae CGMCC 5992. The optimal medium included CS of 30 g/L, glucose of 4.6 g/L, sodium nitrate of 1.2 g/L, corn steep liquor of 1 g/L, yeast extract of 1.2 g/L, and vitamin B1 of 0.15 g/L. Under these optimal conditions, the LiP production reached its maximum of 652.34 U/L. The optimal condition for CS degradation included CS of 20 g, A. oryzae CGMCC 5992 broth of 50 mL, 1.5 % H2O2 solution of 80 mL, H2O2 flow rate of 0.4 mL/min, water volume of 240 mL (water/material ratio of 12:1), hydrolysis temperature of 39 degrees C, and hydrolysis time of 8 h. Before hydrolysis, CS and water were pretreated at 113 degrees C for 11 min. Under these optimal conditions, the sugar yield reached its maximum of 46.28 %. CONCLUSIONS: Our newly developed method had great advantages in pretreatment of CS due to its quickness, convenience, safety, no special equipment and high sugar yield.Graphical abstractThe schematic diagram of corn straw hydrolysis. PMID- 26594240 TI - Combinatory strategy for characterizing and understanding the ethanol synthesis pathway in cyanobacteria cell factories. AB - BACKGROUND: Photosynthetic production of chemicals and fuels by recycling CO2 in cyanobacteria is a promising solution facing energy shortage and resource declination. Ethanol is an attractive and demonstrative biofuel product, and ethanol synthesis in cyanobacteria has been achieved by assembling of a pathway consisting of pyruvate decarboxylase (PDCzm) and alcohol dehydrogenase II (slr1192). For enabling more powerful ethanol photosynthetic production, an optimized and balanced catalyzing route was required. In this work, we provided a paradigm for systematically characterizing and optimizing the PDCzm-slr1192 pathway from engineered cyanobacteria strains, combining in vitro reconstitution, genetic engineering and feeding-cultivation. RESULTS: We reconstituted the PDCzm slr1192 pathway in vitro and performed specific titration assays for enzymes, substrates, cofactors, and metal ions. In the in vitro system, K 50 of PDCzm was 0.326 MUM, with a V max of 2.074 MUM/s; while for slr1192, the values were 0.109 MUM and 1.722 MUM/s, respectively. Titration response discrepancy indicated that PDCzm rather than slr1192 was the rate-limiting factor for ethanol synthesis. In addition, a 4:6 concentration ratio of PDCzm-slr1192 would endow the reaction with a maximal specific catalytic activity. Titration assays for other components were also performed. K m values for NADPH, pyruvate, TPP, Mg(2+) and acetaldehyde were 0.136, 6.496, 0.011, 0.104, and 0.393 mM, respectively. We further constructed Synechocystis mutant strains with diverse PDCzm-slr1192 concentrations and ratios, and compared the growth and ethanol synthesis performances. The results revealed that activities of PDCzm indeed held control over the ethanol generation capacities. We performed pyruvate-feeding treatment with the newly developed Syn-YQ4 strain, and confirmed that improvement of pyruvate supply would direct more carbon flow to ethanol formation. CONCLUSIONS: We systematically characterized and optimized the PDCzm-slr1192 pathway in engineered cyanobacteria for ethanol production. Information gained from in vitro monitoring and genetic engineering revealed that for further enhancing ethanol synthesis capacities, PDCzm activities needed enhancement, and the PDCzm-slr1192 ratio should be improved and held to about 1:1.5. Considering actual metabolites concentrations of cyanobacteria cells, enhancing pyruvate supply was also a promising strategy for further updating the current ethanol photosynthetic cell factories. PMID- 26594241 TI - Association between sister chromatid exchange and double minute chromosomes in human tumor cells. AB - BACKGROUND: Double minute chromosomes (DMs) are the cytogenetic hallmark of extra chromosomal genomic amplification. They can well represent the advanced stage of malignancy. However, the mechanisms of DM generation are still not fully understood. Here, the sister chromatid exchange (SCE) was used to determine whether the occurrence of DMs was related to the high genomic instability in human carcinoma cells. We analyzed SCE frequencies in two groups of cell lines: the first group contained DM-positive cell lines such as UACC-1598, SK-PN-DW, and NCI-N87 carcinomas, while the second group comprised DM-negative cell lines including HO-8910, U251, and MGC-803. RESULTS: The data showed that SCE was significantly increased in the DM-positive cells as compared to the DM-negative cells. In addition, there was a positive correlation between the incidence of DMs and the SCE frequency in the UACC-1598, SK-PN-DW, and NCI-N87 carcinoma cells. CONCLUSIONS: Because SCE can reflect general genome instability, it is suggested that the DMs are likely to be closely associated with genomic instability in carcinoma cells. Meanwhile, SCE may be involved in the malignant progression of DM-positive cancers. PMID- 26594242 TI - Recombinant chromosome with partial 14 q trisomy due to maternal pericentric inversion. AB - BACKGROUND: 14q duplications caused by parental pericentric inversion of chromosome 14 are rarely reported and no clear genotype-phenotype correlation has been determined yet. CASE PRESENTATION: Here we reported a 7 years old female patient with recombinant chromosome characterized by 14 q duplication and originated from maternal pericentric inversion of chromosome 14. Principal clinical findings of the child include developmental delay, microcephaly, hypertelorism, low set ears, clinodactyly of fifth fingers, hypotonia, telecanthus and cardiac malformation. CONCLUSIONS: Her final karyotype was 46,XX,rec(14)dup(14q)inv(14)(p11.2q24)mat,arr14q24.1-qter(64,800,000-108,350,000 bp)x3. PMID- 26594243 TI - gammaMAXT: a fast multiple-testing correction algorithm. AB - BACKGROUND: The purpose of the MaxT algorithm is to provide a significance test algorithm that controls the family-wise error rate (FWER) during simultaneous hypothesis testing. However, the requirements in terms of computing time and memory of this procedure are proportional to the number of investigated hypotheses. The memory issue has been solved in 2013 by Van Lishout's implementation of MaxT, which makes the memory usage independent from the size of the dataset. This algorithm is implemented in MBMDR-3.0.3, a software that is able to identify genetic interactions, for a variety of SNP-SNP based epistasis models effectively. On the other hand, that implementation turned out to be less suitable for genome-wide interaction analysis studies, due to the prohibitive computational burden. RESULTS: In this work we introduce gammaMAXT, a novel implementation of the maxT algorithm for multiple testing correction. The algorithm was implemented in software MBMDR-4.2.2, as part of the MB-MDR framework to screen for SNP-SNP, SNP-environment or SNP-SNP-environment interactions at a genome-wide level. We show that, in the absence of interaction effects, test-statistics produced by the MB-MDR methodology follow a mixture distribution with a point mass at zero and a shifted gamma distribution for the top 10 % of the strictly positive values. We show that the gammaMAXT algorithm has a power comparable to MaxT and maintains FWER, but requires less computational resources and time. We analyze a dataset composed of 10(6) SNPs and 1000 individuals within one day on a 256-core computer cluster. The same analysis would take about 10(4) times longer with MBMDR-3.0.3. CONCLUSIONS: These results are promising for future GWAIs. However, the proposed gammaMAXT algorithm offers a general significance assessment and multiple testing approach, applicable to any context that requires performing hundreds of thousands of tests. It offers new perspectives for fast and efficient permutation-based significance assessment in large-scale (integrated) omics studies. PMID- 26594244 TI - Description of Campylobacter jejuni Bf, an atypical aero-tolerant strain. AB - BACKGROUND: Campylobacter jejuni is a leading cause of bacterial enteritis worldwide. This microaerophilic bacterium can survive in aerobic environments, suggesting it has protective mechanisms against oxidative stress. The clinical C. jejuni Bf strain is characterized by an increased resistance to oxygen. This study aimed to characterize the behavior of the clinical C. jejuni Bf strain under an aerobic atmosphere and in response to ROS-promoter agents. METHODS: Growth was studied in both aerobic and microaerobic conditions using classic cultivable methods. Electronic microscopy and mreB gene expression were used to evaluate the morphology of this strain under aerobic conditions. The survival under oxidative stress was tested in the presence of different concentrations of hydrogen peroxide (H2O2) and paraquat (PQ). RESULTS: The results showed that C. jejuni Bf strain can grow aerobically, unlike other strains of C. jejuni tested. Cells of C. jejuni Bf exposed to oxidative stress presented changes in morphology and the gene mreB, responsible for maintaining the bacillary cell morphology, was down-expressed. In aerobically acclimated conditions, C. jejuni Bf exhibited a higher survival rate of 52 % in the presence of H2O2 (1 mM) compared to the reference strain NCTC 11168. Concentrations above 1 mM PQ were lethal for the reference strain but not for C. jejuni Bf. CONCLUSIONS: Taken together, these data highlight the resistance to oxidative stress conditions of C. jejuni Bf, indicating that this microorganism seems more adapted to survival in hostile environmental conditions. PMID- 26594245 TI - The Effect of Parental Divorce on the Health of Adult Children. AB - Decades of research have produced evidence that parental divorce is negatively associated with offspring outcomes from early childhood, through adolescence, and into the adult years. This study adds to the literature on the effects of parental divorce by examining how the timing of a parental divorce influences the total effect on adult health. Furthermore, we look at how this long-term effect of parental divorce depends on mediators such as the family's socioeconomic status, parental involvement, cognitive test scores, behavioural problems, smoking, and the offspring's own experience with divorce. The analyses use data from the National Child Development Study, which includes nine waves of data beginning at birth in 1958 and continuing through age 50. Results from a structural equation model suggest that a parental divorce experienced before age 7 does influence adult health by operating primarily through family socioeconomic status and smoking in adulthood. PMID- 26594246 TI - Metabolic syndrome related to cardiovascular events in a 10-year prospective study. AB - BACKGROUND: Metabolic syndrome (MetS) becomes a serious society health problem. The main risk factors of MetS are related to the increased risk of cardiovascular diseases, appearance of stroke, type 2 diabetes mellitus and the growing risk of mortality. MetS stimulates the appearance of early atherosclerosis, its progress and accelerates the frequency of cardiovascular complications related to atherosclerosis and diabetes mellitus. OBJECTIVE: To evaluate the risk of cardiovascular events (myocardial infarction, stroke) among the individuals with MetS in a 10 year prospective study; to identify MetS components that determine risk and character of cardiovascular events. METHODS: The study design was prospective. It was started in 2003 to assess the risk factors, clinical components, diagnostic criteria of MetS. At the second stage in 2013 the individuals were repeatedly invited to evaluate cardiovascular pathology that was confirmed by cardiologist and neurologist. The 45 years old and older citizens of Lithuanian district participated in the study. 1115 individuals (562 men and 553 women) were randomly selected in 2003. 538 respondents: 278 (51.70 %) men and 260 (48.30 %) women participated in the repeated study in 2013. RESULTS: During the study myocardial infarction (MI) was confirmed to 7.43 % individuals taken part in the study, stroke-to 4.28 % individuals. The odds' ratio (OR) of MI between individuals with MetS and without MetS was 1.80 (95 % CI 1.67-1.97), p < 0.05. The OR of stroke for individuals with MetS and without MetS was 2.05 (95 % CI 1.21-2.54), p < 0.05. The OR of MI between men with abdominal obesity and identified MetS was 3.12 (95 % CI 2.77-3.53), p < 0.05. The OR of stroke between men with low level of high density lipoprotein cholesterol and identified MetS was 4.98 (95 % CI 4.40-5.65), p < 0.05. The OR of stroke between men with hypertriglyceridemia and identified MetS was 8.43 (95 % CI 7.45-9.54), p < 0.05. CONCLUSIONS: Individuals with identified MetS have 1.80 and 2.05 times higher statistically significant probability, respectively, for MI and stroke events, than individuals without MetS. Separate components or MetS increase risk of cardiovascular events in men: abdominal obesity increases risk of MI, and low level of high density lipoprotein cholesterol and hypertriglyceridemia increase risk of stroke. PMID- 26594247 TI - Endothelin-1 gene polymorphisms and diabetic kidney disease in patients with type 2 diabetes mellitus. AB - BACKGROUND AND AIMS: Diabetic kidney disease (DKD) is the leading cause of end stage renal disease worldwide and is associated with increased cardiovascular mortality. The endothelin system has been implicated in the pathogenesis of arterial hypertension and renal dysfunction. In the present study, the association of DKD with polymorphisms in ET-1 (EDN1) and ETRA (EDNRA) genes was analyzed in patients with type 2 diabetes mellitus (T2DM). METHODS: A case control study was conducted in 548 white T2DM patients. Patients with proteinuria or on dialysis were considered cases and patients with normoalbuminuria were considered controls. Two polymorphisms in the EDN1 gene (rs1800541 and rs57072783) and five in EDNRA gene (rs6842241; rs4835083; rs4639051; rs5333 and rs5343) were genotyped and haplotype analyses were performed. RESULTS: The presence of rs57072783 T allele (TT/TG vs. GG) or rs1800541 G allele (GG/GT vs. TT) protected against DKD (OR = 0.69, 95 % CI 0.48-0.99, P = 0.049; and OR = 0.60, 95 % CI 0.41-0.88, P = 0.009, respectively). However in multivariate analyses, only the rs1800541 G allele remained independently associated with DKD (P = 0.046). CONCLUSIONS: The present study shows that ET-1 could be involved in the pathogenesis of DKD in patients with T2DM. PMID- 26594248 TI - Treatment with the SGLT2 inhibitor luseogliflozin improves nonalcoholic steatohepatitis in a rodent model with diabetes mellitus. AB - BACKGROUND: Insulin resistance with elevated glucose is a risk factor for non alcoholic steatohepatitis (NASH). We investigated the effects of the sodium glucose cotransporter 2 (SGLT2) inhibitor luseogliflozin on NASH development using a rodent model. METHODS: Mice were treated with both nicotinamide and streptozotocin (NA/STZ) to reduce insulin secretory capacity, and then fed a high fat diet containing trans fatty acids (HFDT) for 8 weeks. The NA/STZ HFDT-fed mice were divided into two groups, either treated with luseogliflozin or untreated, during this period. The glucose elevations in the NA/STZ-treated and HFDT-fed mice were significantly improved by luseogliflozin administration. While HFDT feeding induced NASH development as shown by liver weight gain with lipid accumulation and increased serum alanine aminotransferase, these changes were all attenuated in the group treated with luseogliflozin. In addition, fibrotic change and increases in collagen deposition with upregulations of collagen1 and smooth muscle actin and inflammatory cytokine expressions observed in the HFDT-fed mouse livers were also normalized by luseogliflozin administration. CONCLUSIONS: Taken together, these results obtained in mice demonstrate the favorable effects of administering SGLT2 inhibitors, for the treatment of NASH associated with diabetes mellitus. We anticipate that these agents would be applicable to humans. PMID- 26594249 TI - Prevalence of metabolic syndrome in the Brazilian Xavante indigenous population. AB - BACKGROUND: The raising prevalence of weight excess and of non-communicable diseases in indigenous populations, as well as changes in food consumption and reduction in the frequency and intensity of physical activity, suggest that the prevalence of metabolic syndrome (MS) is also elevated. The objective of this study was to evaluate the prevalence of MS and the frequency of its components in the Xavante adult population living in the Indian reservations of Sao Marcos and Sangradouro/Volta Grande, in the state of Mato Grosso, Brazil. A cross-sectional study was carried out among 932 Xavante Indians aged 20 years or more, in the 2008-2012 period. The variables analysed were gender, age, weight, height, waist circumference, blood pressure, initial and 2-h capillary glycemia in a 75 g OGTT, levels of triglycerides and HDL-cholesterol. The diagnostic criteria for MS proposed by the IDF and AHA/NHLBI were used. RESULTS: The prevalence of MS was 66.1 % (95 % CI 63.0-69.2), being 76.2 % (95 % CI 72.4-80.0) in women and 55.6 % (95 % CI 51.0-60.2) in men. Women had higher prevalence of MS in all age groups. Elevated waist circumference and lower levels of HDL-cholesterol were the more frequent components in those with MS, and elevated blood pressure was the less frequent. CONCLUSIONS: The high prevalence of MS in the Xavante Indians is mainly due to the increased prevalence of weight excess that resulted from an intense change in their life-style, in a short period of time in a population with a genetic predisposition. These findings highlight the magnitude of this health problem and make an alert about the necessity to implement specific preventive interventions. PMID- 26594250 TI - Evaluation of the efficacy and safety of lixisenatide add-on treatment to basal insulin therapy among T2DM patients with different body mass indices from GetGoal trials. AB - BACKGROUND: Using patient data from the GetGoal-Duo1, -L, and L-Asia trials, the objectives of this study were to evaluate and compare the impact of lixisenatide once-daily add-on treatment to basal insulin therapy +/-oral antidiabetic drugs (OADs) among type 2 diabetes (T2DM) patients subdivided into groups, based on their baseline body mass indices (BMI). METHODS: Data of patients treated with lixisenatide were extracted from the modified intent-to-treat populations of the trials. Patients were subdivided into 4 groups based on baseline BMI category (BMIs <25, 25-<30, 30-<35, and >=35 kg/m(2)). At the unadjusted data level, efficacy and safety endpoints were evaluated and compared among study cohorts. Additionally, multivariable regression analyses were used to specify key patient characteristics and then assess the adjusted outcomes. RESULTS: Of the 662 T2DM patients, the mean changes in HbA1c (-0.63 to -0.73 %, p = 0.88) and FPG levels ( 3.9 to 3.2 mg/dL, p = 0.60) were not significantly different among the different BMI groups. The proportions of T2DM patients that achieved HbA1c <7 % ranged between 34.7 and 46.8 %. After adjusted for patient characteristics, T2DM patients in the lowest BMI group relative to those in the highest BMI group had a smaller reduction in HbA1c during the trial periods (difference: 0.32 %, confidence interval: 0.10, 0.53, p = 0.005) and were less likely to achieve HbA1c <7 %. CONCLUSIONS: The findings of this analysis of the GetGoal clinical trials suggest that lixisenatide may be a good treatment option for optimizing glycemic control in patients unable to achieve their HbA1c target on basal insulin therapy +/-OADs, regardless of BMI category. PMID- 26594251 TI - Acceptability of a Mobile Smartphone Application Intervention to Improve Access to HIV Prevention and Care Services for Black Men Who Have Sex with Men in the District of Columbia. AB - Eliminating racial HIV disparities among men who have sex with men (MSM) will require a greater uptake of HIV prevention and care interventions among Black MSM (BMSM), yet such strategies generally require meaningful engagement in a health care system that often does not meet the unique needs of BMSM. This study assessed the acceptability of, and correlates of having favorable perceptions of, a mobile smartphone application (app) intervention for BMSM that aims to remove structural barriers and improve access to culturally relevant HIV prevention and care services. An Internet-based sample of 93 BMSM completed an online survey on their perceptions of the app using 14 items measured on a 100-point visual analogue scale that were validated in exploratory factor analysis (alpha=0.95). Among the sample, perceptions of two sample app modules were generally favorable and most BMSM agreed that they would use the modules (81.2% and 87.1%). Correlates of having favorable perceptions included trusting medical advice from social networks, lacking private health insurance, and not having accessed a primary care physician in the last year. Our findings warrant the further development of this app and point to subgroups of BMSM for which it may have the greatest impact. PMID- 26594252 TI - Addressing Barriers to the Development and Adoption of Rapid Diagnostic Tests in Global Health. AB - Immunochromatographic rapid diagnostic tests (RDTs) have demonstrated significant potential for use as point-of-care diagnostic tests in resource-limited settings. Most notably, RDTs for malaria have reached an unparalleled level of technological maturity and market penetration, and are now considered an important complement to standard microscopic methods of malaria diagnosis. However, the technical development of RDTs for other infectious diseases, and their uptake within the global health community as a core diagnostic modality, has been hindered by a number of extant challenges. These range from technical and biological issues, such as the need for better affinity agents and biomarkers of disease, to social, infrastructural, regulatory and economic barriers, which have all served to slow their adoption and diminish their impact. In order for the immunochromatographic RDT format to be successfully adapted to other disease targets, to see widespread distribution, and to improve clinical outcomes for patients on a global scale, these challenges must be identified and addressed, and the global health community must be engaged in championing the broader use of RDTs. PMID- 26594253 TI - EGF as a New Therapeutic Target for Medulloblastoma Metastasis. AB - Medulloblastoma (MB) is a malignant pediatric brain tumor known for its aggressive metastatic potential. Despite the well-documented migration of MB cells to other parts of the brain and spinal column, MB chemotaxis is poorly understood. Herein, we examined the in vitro migratory and cellular responses of MB-derived cells to external signaling of Epidermal Growth Factor (EGF), hepatocyte growth factor (HGF), platelet-derived growth factor (PDGF-BB), and the stromal cell-derived factors 1-alpha (SDF-1). Experiments utilized transwell assays and immunocytochemistry to identify receptor activation in MB migration, and used a microfluidic platform to examine directionality, trajectory, and gradient-dependence of motile cells. Data illustrates that MB-derived cells respond strongly to EGF in a dosage and gradient-dependent manner with increased EGF-R activation, and show that high EGF gradient fields cause an increased number of cells to migrate longer directed distances. Our results provide evidence that EGF and its receptor play an important role than previously documented in MB chemotactic migration than previously documented and should be considered for developing migration-target therapies against MB metastasis. PMID- 26594254 TI - Mindfulness-based Stress Reduction as a Promising Intervention for Amelioration of Premenstrual Dysphoric Disorder Symptoms. PMID- 26594255 TI - Analyses of Acceptability Judgments Made Toward the Use of Nanocarrier-Based Targeted Drug Delivery: Interviews with Researchers and Research Trainees in the Field of New Technologies. AB - The assessment of nanotechnology applications such as nanocarrier-based targeted drug delivery (TDD) has historically been based mostly on toxicological and safety aspects. The use of nanocarriers for TDD, a leading-edge nanomedical application, has received little study from the angle of experts' perceptions and acceptability, which may be reflected in how TDD applications are developed. In recent years, numerous authors have maintained that TDD assessment should also take into account impacts on ethical, environmental, economic, legal, and social (E3LS) issues in order to lead to socially responsible innovation. Semi structured interviews (n = 22) were conducted with French and Canadian researchers and research trainees with diverse disciplinary backgrounds and involved in research related to emerging technologies. The interviews focussed on scenarios presenting two types of TDD nanocarriers (carbon, synthetic DNA) in two contexts of use (lung cancer, seasonal flu). Content and inductive analyses of interviews showed how facets of perceived impacts such as health, environment, social cohabitation, economy, life and death, representations of the human being and nature, and technoscience were weighed in acceptability judgments. The analyses also revealed that contextual factors related to device (nature of the treatment), to use (gravity of the disease), and to user (culture) influenced the weighting assigned to perceived impacts and thus contributed to variability in interviewees' judgments of acceptability. Giving consideration to researchers' perspective could accompany first steps of implementation and development of nanomedicine by producing a first, but wide, picture of the acceptability of nanocarrier-based TDD. PMID- 26594256 TI - The Ethics of Deep Brain Stimulation for the Treatment of Anorexia Nervosa. AB - There is preliminary evidence, from case reports and investigational studies, to suggest that Deep Brain Stimulation (DBS) could be used to treat some patients with Anorexia Nervosa (AN). Although this research is at an early stage, the invasive nature of the intervention and the vulnerability of the potential patients are such that anticipatory ethical analysis is warranted. In this paper, we first show how different treatment mechanisms raise different philosophical and ethical questions. We distinguish three potential mechanisms alluded to in the neuroscientific literature, relating to desire, control, and emotion, respectively. We explain why the precise nature of the mechanism has important implications for the patient's autonomy and personal identity. In the second part of the paper, we consider practical dimensions of offering DBS to patients with AN in certain cases. We first discuss some limited circumstances where the mere offering of the intervention might be perceived as exerting a degree of coercive pressure that could serve to undermine the validity of the patient's consent. Finally, we consider the implications of potential effects of DBS for the authenticity of the patient's choice to continue using stimulation to ameliorate their condition. PMID- 26594257 TI - Moral Evaluations of Organ Transplantation Influence Judgments of Death and Causation. AB - Two experiments investigated whether moral evaluations of organ transplantation influence judgments of death and causation. Participants' beliefs about whether an unconscious organ donor was dead and whether organ removal caused death in a hypothetical vignette varied depending on the moral valence of the vignette. Those who were randomly assigned to the good condition (vs. bad) were more likely to believe that the donor was dead prior to organ removal and that organ removal did not cause death. Furthermore, attitudes toward euthanasia and organ donation independently predicted judgments of death and causation, regardless of experimental condition. The results are discussed in light of the framework of motivated reasoning, in which motivation influences the selection of cognitive processes and representations applied to a given domain, as well as Knobe's person-as-moralist model, in which many basic concepts are appropriately imbued with moral features. On either explanatory framework, these data cast doubt on the psychological legitimacy of the mainstream justification for vital organ procurement from heart-beating donors, which holds that neurological criteria for death are scientifically justified, independently of concerns about organ transplantation. These data suggest that, rather than concluding that organ removal is permissible because the donor is dead, people may believe that the donor is dead because they believe organ removal to be permissible. PMID- 26594258 TI - The Health of India's Elderly Population: A Comparative Assessment Using Subjective and Objective Health Outcomes. AB - This study examined relationships between and predictors of objective and subjective health measures among 766 individuals aged >= 45 years in India using the 2010 pilot wave of the Longitudinal Aging Study in India (LASI). Correlations between and gender differences in objective [grip strength, lung function] and subjective [self-rated health (SRH), dependence in activities of daily living (dADL)] health measures were examined. Multivariate logistic regression analyses, accounting for sample design, were conducted to identify predictors of poor health. Fewer individuals were classified as at risk according to subjective (SRH, 9 %; dADL, 12 %) than objective (lung function, 57 %; grip strength, 77 % women, 87 % men) indicators. Poor SRH was only weakly correlated with dADL (r = 0.103, p <= 0.05) and grip strength (r = -0.138, p <= 0.001). From this study we conclude that older Indians tend to report more positive perception of health than the objective measures of health indicates, and that subjective and objective health indicators capture different aspects of health and only weakly correlated. PMID- 26594259 TI - Exploring the impact of the 2008 global food crisis on food security among vulnerable households in rural South Africa. AB - Recurring food crises endanger the livelihoods of millions of households in developing countries around the globe. Owing to the importance of this issue, we explore recent changes in food security between the years 2004 and 2010 in a rural district in Northeastern South Africa. Our study window spans the time of the 2008 global food crises and allows the investigation of its impacts on rural South African populations. Grounded in the sustainable livelihood framework, we examine differences in food security trajectories among vulnerable sub populations. A unique panel data set of 8,147 households, provided by the Agincourt Health and Demographic Surveillance System (Agincourt HDSS), allows us to employ a longitudinal multilevel modeling approach to estimate adjusted growth curves for the differential change in food security across time. We observe an overall improvement in food security that leveled off after 2008, most likely resulting from the global food crisis. In addition, we discover significant differences in food security trajectories for various sub populations. For example, female-headed households and those living in areas with better access to natural resources differentially improved their food security situation, compared to male-headed households and those households with lower levels of natural resource access. However, former Mozambican refugees witnessed a decline in food security. Therefore, poverty alleviation programs for the Agincourt region should work to improve the food security of vulnerable households, such as former Mozambican refugees. PMID- 26594260 TI - The Importance of Research during Pharmacy Residency Training. AB - Practice-related projects and pharmacy practice research are requirements to complete postgraduate pharmacy residency programs. Many residents will complete residencies without fully developing the skills needed to perform research required for new clinical and academic positions. Many studies have quantified successes and identified characteristics that may be associated with successful resident publication. There are many benefits to gaining research and publication skills during residency training for the resident, preceptor/mentors, and the residency program. Published works have also suggested approaches than can be taken to improve research within a residency program. The aims of this article are to discuss the publication rates of resident research projects, suggest ways to improve residency research, review benefits of residency research, and briefly review research training alternatives. PMID- 26594261 TI - An optically transparent membrane supports shear stress studies in a three dimensional microfluidic neurovascular unit model. AB - We report a microfluidic blood-brain barrier model that enables both physiological shear stress and optical transparency throughout the device. Brain endothelial cells grown in an optically transparent membrane-integrated microfluidic device were able to withstand physiological fluid shear stress using a hydrophilized polytetrafluoroethylene nanoporous membrane instead of the more commonly used polyester membrane. A functional three-dimensional microfluidic co culture model of the neurovascular unit is presented that incorporates astrocytes in a 3D hydrogel and enables physiological shear stress on the membrane-supported endothelial cell layer. PMID- 26594262 TI - Multiscale modeling of droplet interface bilayer membrane networks. AB - Droplet interface bilayer (DIB) networks are considered for the development of stimuli-responsive membrane-based materials inspired by cellular mechanics. These DIB networks are often modeled as combinations of electrical circuit analogues, creating complex networks of capacitors and resistors that mimic the biomolecular structures. These empirical models are capable of replicating data from electrophysiology experiments, but these models do not accurately capture the underlying physical phenomena and consequently do not allow for simulations of material functionalities beyond the voltage-clamp or current-clamp conditions. The work presented here provides a more robust description of DIB network behavior through the development of a hierarchical multiscale model, recognizing that the macroscopic network properties are functions of their underlying molecular structure. The result of this research is a modeling methodology based on controlled exchanges across the interfaces of neighboring droplets. This methodology is validated against experimental data, and an extension case is provided to demonstrate possible future applications of droplet interface bilayer networks. PMID- 26594263 TI - Plug-in nanoliter pneumatic liquid dispenser with nozzle design flexibility. AB - This paper presents a novel plug-in nanoliter liquid dispensing system with a plug-and-play interface for simple and reversible, yet robust integration of the dispenser. A plug-in type dispenser was developed to facilitate assembly and disassembly with an actuating part through efficient modularization. The entire process for assembly and operation of the plug-in dispenser is performed via the plug-and-play interface in less than a minute without loss of dispensing quality. The minimum volume of droplets pneumatically dispensed using the plug-in dispenser was 124 nl with a coefficient of variation of 1.6%. The dispensed volume increased linearly with the nozzle size. Utilizing this linear relationship, two types of multinozzle dispensers consisting of six parallel channels (emerging from an inlet) and six nozzles were developed to demonstrate a novel strategy for volume gradient dispensing at a single operating condition. The droplet volume dispensed from each nozzle also increased linearly with nozzle size, demonstrating that nozzle size is a dominant factor on dispensed volume, even for multinozzle dispensing. Therefore, the proposed plug-in dispenser enables flexible design of nozzles and reversible integration to dispense droplets with different volumes, depending on the application. Furthermore, to demonstrate the practicality of the proposed dispensing system, we developed a pencil-type dispensing system as an alternative to a conventional pipette for rapid and reliable dispensing of minute volume droplets. PMID- 26594264 TI - Microstencils to generate defined, multi-species patterns of bacteria. AB - Microbial communities are complex heterogeneous systems that are influenced by physical and chemical interactions with their environment, host, and community members. Techniques that facilitate the quantitative evaluation of how microscale organization influences the morphogenesis of multispecies communities could provide valuable insights into the dynamic behavior and organization of natural communities, the design of synthetic environments for multispecies culture, and the engineering of artificial consortia. In this work, we demonstrate a method for patterning microbes into simple arrangements that allow the quantitative measurement of growth dynamics as a function of their proximity to one another. The method combines parylene-based liftoff techniques with microfluidic delivery to simultaneously pattern multiple bacterial species with high viability using low-cost, customizable methods. Quantitative measurements of bacterial growth for two competing isolates demonstrate that spatial coordination can play a critical role in multispecies growth and structure. PMID- 26594266 TI - USING SOMATIC MUTATION DATA TO TEST TUMORS FOR CLONAL RELATEDNESS. AB - A major challenge for cancer pathologists is to determine whether a new tumor in a patient with cancer is a metastasis or an independent occurrence of the disease. In recent years numerous studies have evaluated pairs of tumor specimens to examine the similarity of the somatic characteristics of the tumors and to test for clonal relatedness. As the landscape of mutation testing has evolved a number of statistical methods for determining clonality have developed, notably for comparing losses of heterozygosity at candidate markers, and for comparing copy number profiles. Increasingly tumors are being evaluated for point mutations in panels of candidate genes using gene sequencing technologies. Comparison of the mutational profiles of pairs of tumors presents unusual methodological challenges: mutations at some loci are much more common than others; knowledge of the marginal mutation probabilities is scanty for most loci at which mutations might occur; the sample space of potential mutational profiles is vast. In this article we examine this problem and propose a test for clonal relatedness of a pair of tumors from a single patient. Using simulations, its properties are shown to be promising. The method is illustrated using several examples from the literature. PMID- 26594265 TI - Label-free isolation of a prostate cancer cell among blood cells and the single cell measurement of drug accumulation using an integrated microfluidic chip. AB - Circulating tumor cells (CTCs) are found in the blood of patients with cancer. Although these cells are rare, they can provide useful information for chemotherapy. However, isolation of these rare cells from blood is technically challenging because they are small in numbers. An integrated microfluidic chip, dubbed CTC chip, was designed and fabricated for conducting tumor cell isolation. As CTCs usually show multidrug resistance (MDR), the effect of MDR inhibitors on chemotherapeutic drug accumulation in the isolated single tumor cell is measured. As a model of CTC isolation, human prostate cancer cells were mixed with mouse blood cells and the label-free isolation of the tumor cells was conducted based on cell size difference. The major advantages of the CTC chip are the ability for fast cell isolation, followed by multiple rounds of single-cell measurements, suggesting a potential assay for detecting the drug responses based on the liquid biopsy of cancer patients. PMID- 26594267 TI - The Experience of Older Women Living with Loneliness and Chronic Conditions in Appalachia. AB - This phenomenological qualitative study explored the experience of living with loneliness and multiple chronic conditions for rural older women in Appalachia. The study took place in 2012 in Northern West Virginia. Participants were 14 older women who were chronically ill, community dwelling, and lonely (Score of 40 or higher on the Revised 20-item UCLA Loneliness Scale). Thematic content analysis revealed four categories that contained thirteen themes: (a) negative emotions of loneliness, which included themes of sadness, disconnection, fear, anger, and worry; (b) positive emotions when not lonely, which included themes of joy with others and pride in self; (c) loss of independence and loneliness, which included themes of functional decline contributes to loneliness, burden, and gratitude for help; and (d) ways of managing loneliness, which included remembering holidays and happier moments, staying busy, and getting out. The study contributes new knowledge about the experience of anger, fear, and worry when lonely. These emotions have not extensively been identified as significant to loneliness. Future studies exploring the links between loneliness and anger, fear, worry, and negative physical health outcomes could enhance knowledge of mechanisms by which loneliness contributes to health decline. Additionally, knowing that positive emotions such as joy are described as being linked to less lonely times could inform future work that aims to diminish loneliness and enhance positive emotional states. Finally, understanding that functional impairment is described as contributing to loneliness in this population reinforces the need to assess for and address functional limitations. PMID- 26594268 TI - Growing a Specialty-Specific Community of Practice in Education Scholarship. PMID- 26594269 TI - Emergency Medicine: On the Frontlines of Medical Education Transformation. AB - Emergency medicine (EM) has always been on the frontlines of healthcare in the United States. I experienced this reality first hand as a young general medical officer assigned to an emergency department (ED) in a small naval hospital in the 1980s. For decades the ED has been the only site where patients could not be legally denied care. Despite increased insurance coverage for millions of Americans as a result of the Affordable Care Act, ED directors report an increase in patient volumes in a recent survey.1 EDs care for patients from across the socioeconomic spectrum suffering from a wide range of clinical conditions. As a result, the ED is still one of few components of the American healthcare system where social justice is enacted on a regular basis. Constant turbulence in the healthcare system, major changes in healthcare delivery, technological advances and shifting demographic trends necessitate that EM constantly adapt and evolve as a discipline in this complex environment. PMID- 26594270 TI - Education Scholarship and its Impact on Emergency Medicine Education. AB - Emergency medicine (EM) education is becoming increasingly challenging as a result of changes to North American medical education and the growing complexity of EM practice. Education scholarship (ES) provides a process to develop solutions to these challenges. ES includes both research and innovation. ES is informed by theory, principles and best practices, is peer reviewed, and is disseminated and archived for others to use. Digital technologies have improved the discovery of work that informs ES, broadened the scope and timing of peer review, and provided new platforms for the dissemination and archiving of innovations. This editorial reviews key steps in raising an education innovation to the level of scholarship. It also discusses important areas for EM education scholars to address, which include the following: the delivery of competency based medical education programs, the impact of social media on learning, and the redesign of continuing professional development. PMID- 26594271 TI - Morbidity and Mortality Conference in Emergency Medicine Residencies and the Culture of Safety. AB - INTRODUCTION: Morbidity and mortality conferences (M+M) are a traditional part of residency training and mandated by the Accreditation Counsel of Graduate Medical Education. This study's objective was to determine the goals, structure, and the prevalence of practices that foster strong safety cultures in the M+Ms of U.S. emergency medicine (EM) residency programs. METHODS: The authors conducted a national survey of U.S. EM residency program directors. The survey instrument evaluated five domains of M+M (Organization and Infrastructure; Case Finding; Case Selection; Presentation; and Follow up) based on the validated Agency for Healthcare Research & Quality Safety Culture survey. RESULTS: There was an 80% (151/188) response rate. The primary objectives of M+M were discussing adverse outcomes (53/151, 35%), identifying systems errors (47/151, 31%) and identifying cognitive errors (26/151, 17%). Fifty-six percent (84/151) of institutions have anonymous case submission, with 10% (15/151) maintaining complete anonymity during the presentation and 21% (31/151) maintaining partial anonymity. Forty seven percent (71/151) of programs report a formal process to follow up on systems issues identified at M+M. Forty-four percent (67/151) of programs report regular debriefing with residents who have had their cases presented. CONCLUSION: The structure and goals of M+Ms in EM residencies vary widely. Many programs lack features of M+M that promote a non-punitive response to error, such as anonymity. Other programs lack features that support strong safety cultures, such as following up on systems issues or reporting back to residents on improvements. Further research is warranted to determine if M+M structure is related to patient safety culture in residency programs. PMID- 26594272 TI - Are Live Ultrasound Models Replaceable? Traditional versus Simulated Education Module for FAST Exam. AB - INTRODUCTION: The focused assessment with sonography for trauma (FAST) is a commonly used and life-saving tool in the initial assessment of trauma patients. The recommended emergency medicine (EM) curriculum includes ultrasound and studies show the additional utility of ultrasound training for medical students. EM clerkships vary and often do not contain formal ultrasound instruction. Time constraints for facilitating lectures and hands-on learning of ultrasound are challenging. Limitations on didactics call for development and inclusion of novel educational strategies, such as simulation. The objective of this study was to compare the test, survey, and performance of ultrasound between medical students trained on an ultrasound simulator versus those trained via traditional, hands-on patient format. METHODS: This was a prospective, blinded, controlled educational study focused on EM clerkship medical students. After all received a standardized lecture with pictorial demonstration of image acquisition, students were randomized into two groups: control group receiving traditional training method via practice on a human model and intervention group training via practice on an ultrasound simulator. Participants were tested and surveyed on indications and interpretation of FAST and training and confidence with image interpretation and acquisition before and after this educational activity. Evaluation of FAST skills was performed on a human model to emulate patient care and practical skills were scored via objective structured clinical examination (OSCE) with critical action checklist. RESULTS: There was no significant difference between control group (N=54) and intervention group (N=39) on pretest scores, prior ultrasound training/education, or ultrasound comfort level in general or on FAST. All students (N=93) showed significant improvement from pre- to post-test scores and significant improvement in comfort level using ultrasound in general and on FAST (p<0.001). There was no significant difference between groups on OSCE scores of FAST on a live model. Overall, no differences were demonstrated between groups trained on human models versus simulator. DISCUSSION: There was no difference between groups in knowledge based ultrasound test scores, survey of comfort levels with ultrasound, and students' abilities to perform and interpret FAST on human models. CONCLUSION: These findings suggest that an ultrasound simulator is a suitable alternative method for ultrasound education. Additional uses of ultrasound simulation should be explored in the future. PMID- 26594273 TI - Teaching and Assessing ED Handoffs: A Qualitative Study Exploring Resident, Attending, and Nurse Perceptions. AB - INTRODUCTION: The Accreditation Council for Graduate Medical Education requires that residency programs ensure resident competency in performing safe, effective handoffs. Understanding resident, attending, and nurse perceptions of the key elements of a safe and effective emergency department (ED) handoff is a crucial step to developing feasible, acceptable educational interventions to teach and assess this fundamental competency. The aim of our study was to identify the essential themes of ED-based handoffs and to explore the key cultural and interprofessional themes that may be barriers to developing and implementing successful ED-based educational handoff interventions. METHODS: Using a grounded theory approach and constructivist/interpretivist research paradigm, we analyzed data from three primary and one confirmatory focus groups (FGs) at an urban, academic ED. FG protocols were developed using open-ended questions that sought to understand what participants felt were the crucial elements of ED handoffs. ED residents, attendings, a physician assistant, and nurses participated in the FGs. FGs were observed, hand-transcribed, audio-recorded and subsequently transcribed. We analyzed data using an iterative process of theme and subtheme identification. Saturation was reached during the third FG, and the fourth confirmatory group reinforced the identified themes. Two team members analyzed the transcripts separately and identified the same major themes. RESULTS: ED providers identified that crucial elements of ED handoff include the following: 1) Culture (provider buy-in, openness to change, shared expectations of sign-out goals); 2) Time (brevity, interruptions, waiting); 3) Environment (physical location, ED factors); 4) Process (standardization, information order, tools). CONCLUSION: Key participants in the ED handoff process perceive that the crucial elements of intershift handoffs involve the themes of culture, time, environment, and process. Attention to these themes may improve the feasibility and acceptance of educational interventions that aim to teach and assess handoff competency. PMID- 26594274 TI - The Impact of Medical Student Participation in Emergency Medicine Patient Care on Departmental Press Ganey Scores. AB - INTRODUCTION: Press Ganey (PG) scores are used by public entities to gauge the quality of patient care from medical facilities in the United States. Academic health centers (AHCs) are charged with educating the new generation of doctors, but rely heavily on PG scores for their business operation. AHCs need to know what impact medical student involvement has on patient care and their PG scores. PURPOSE: We sought to identify the impact students have on emergency department (ED) PG scores related to overall visit and the treating physician's performance. METHODS: This was a retrospective, observational cohort study of discharged ED patients who completed PG satisfaction surveys at one academic, and one community based ED. Outcomes were responses to questions about the overall visit assessment and doctor's care, measured on a five-point scale. We compared the distribution of responses for each question through proportions with 95% confidence intervals (CIs) stratified by medical student participation. For each question, we constructed a multivariable ordinal logistic regression model including medical student involvement and other independent variables known to affect PG scores. RESULTS: We analyzed 2,753 encounters, of which 259 (9.4%) had medical student involvement. For all questions, there were no appreciable differences in patient responses when stratifying by medical student involvement. In regression models, medical student involvement was not associated with PG score for any outcome, including overall rating of care (odds ratio [OR] 1.10, 95% CI [0.90-1.34]) or likelihood of recommending our EDs (OR 1.07, 95% CI [0.86-1.32]). Findings were similar when each ED was analyzed individually. CONCLUSION: We found that medical student involvement in patient care did not adversely impact ED PG scores in discharged patients. Neither overall scores nor physician-specific scores were impacted. Results were similar at both the academic medical center and the community teaching hospital at our institution. PMID- 26594275 TI - What is the Prevalence and Success of Remediation of Emergency Medicine Residents? AB - INTRODUCTION: The primary objective of this study was to determine the prevalence of remediation, competency domains for remediation, the length, and success rates of remediation in emergency medicine (EM). METHODS: We developed the survey in SurveymonkeyTM with attention to content and response process validity. EM program directors responded how many residents had been placed on remediation in the last three years. Details regarding the remediation were collected including indication, length and success. We reported descriptive data and estimated a multinomial logistic regression model. RESULTS: We obtained 126/158 responses (79.7%). Ninety percent of programs had at least one resident on remediation in the last three years. The prevalence of remediation was 4.4%. Indications for remediation ranged from difficulties with one core competency to all six competencies (mean 1.9). The most common were medical knowledge (MK) (63.1% of residents), patient care (46.6%) and professionalism (31.5%). Mean length of remediation was eight months (range 1-36 months). Successful remediation was 59.9% of remediated residents; 31.3% reported ongoing remediation. In 8.7%, remediation was deemed "unsuccessful." Training year at time of identification for remediation (post-graduate year [PGY] 1), longer time spent in remediation, and concerns with practice-based learning (PBLI) and professionalism were found to have statistically significant association with unsuccessful remediation. CONCLUSION: Remediation in EM residencies is common, with the most common areas being MK and patient care. The majority of residents are successfully remediated. PGY level, length of time spent in remediation, and the remediation of the competencies of PBLI and professionalism were associated with unsuccessful remediation. PMID- 26594276 TI - Results from the First Year of Implementation of CONSULT: Consultation with Novel Methods and Simulation for UME Longitudinal Training. AB - INTRODUCTION: An important area of communication in healthcare is the consultation. Existing literature suggests that formal training in consultation communication is lacking. We aimed to conduct a targeted needs assessment of third-year students on their experience calling consultations, and based on these results, develop, pilot, and evaluate the effectiveness of a consultation curriculum for different learner levels that can be implemented as a longitudinal curriculum. METHODS: Baseline needs assessment data were gathered using a survey completed by third-year students at the conclusion of the clinical clerkships. The survey assessed students' knowledge of the standardized consultation, experience and comfort calling consultations, and previous instruction received on consultation communication. Implementation of the consultation curriculum began the following academic year. Second-year students were introduced to Kessler's 5 Cs consultation model through a didactic session consisting of a lecture, viewing of "trigger" videos illustrating standardized and informal consults, followed by reflection and discussion. Curriculum effectiveness was assessed through pre- and post- curriculum surveys that assessed knowledge of and comfort with the consultation process. Fourth-year students participated in a consultation curriculum that provided instruction on the 5 Cs model and allowed for continued practice of consultation skills through simulation during the Emergency Medicine clerkship. Proficiency in consult communication in this cohort was assessed using two assessment tools, the Global Rating Scale and the 5 Cs Checklist. RESULTS: The targeted needs assessment of third-year students indicated that 93% of students have called a consultation during their clerkships, but only 24% received feedback. Post-curriculum, second-year students identified more components of the 5 Cs model (4.04 vs. 4.81, p<0.001) and reported greater comfort with the consultation process (0% vs. 69%, p<0.001). Post- curriculum, fourth-year students scored higher in all criteria measuring consultation effectiveness (p<0.001 for all) and included more necessary items in simulated consultations (62% vs. 77%, p<0.001). CONCLUSION: While third-year medical students reported calling consultations, few felt comfortable and formal training was lacking. A curriculum in consult communication for different levels of learners can improve knowledge and comfort prior to clinical clerkships and improve consultation skills prior to residency training. PMID- 26594277 TI - Does the Concept of the "Flipped Classroom" Extend to the Emergency Medicine Clinical Clerkship? AB - INTRODUCTION: Linking educational objectives and clinical learning during clerkships can be difficult. Clinical shifts during emergency medicine (EM) clerkships provide a wide variety of experiences, some of which may not be relevant to recommended educational objectives. Students can be directed to standardize their clinical experiences, and this improves performance on examinations. We hypothesized that applying a "flipped classroom" model to the clinical clerkship would improve performance on multiple-choice testing when compared to standard learning. METHODS: Students at two institutions were randomized to complete two of four selected EM clerkship topics in a "flipped fashion," and two others in a standard fashion. For flipped topics, students were directed to complete chief complaint-based asynchronous modules prior to a shift, during which they were directed to focus on the chief complaint. For the other two topics, modules were to be performed at the students' discretion, and shifts would not have a theme. At the end of the four-week clerkship, a 40-question multiple-choice examination was administered with 10 questions per topic. We compared performance on flipped topics with those performed in standard fashion. Students were surveyed on perceived effectiveness, ability to follow the protocol, and willingness of preceptors to allow a chief-complaint focus. RESULTS: Sixty-nine students participated; examination scores for 56 were available for analysis. For the primary outcome, no difference was seen between the flipped method and standard (p=0.494.) A mixed model approach showed no effect of flipped status, protocol adherence, or site of rotation on the primary outcome of exam scores. Students rated the concept of the flipped clerkship highly (3.48/5). Almost one third (31.1%) of students stated that they were unable to adhere to the protocol. CONCLUSION: Preparation for a clinical shift with pre-assigned, web-based learning modules followed by an attempt at chief complaint-focused learning during a shift did not result in improvements in performance on a multiple-choice assessment of knowledge; however, one third of participants did not adhere strictly to the protocol. Future investigations should ensure performance of pre-assigned learning as well as clinical experiences, and consider alternate measures of knowledge. PMID- 26594278 TI - Assessing the Impact of Video-based Training on Laceration Repair: A Comparison to the Traditional Workshop Method. PMID- 26594279 TI - Coordinating a Team Response to Behavioral Emergencies in the Emergency Department: A Simulation-Enhanced Interprofessional Curriculum. AB - INTRODUCTION: While treating potentially violent patients in the emergency department (ED), both patients and staff may be subject to unintentional injury. Emergency healthcare providers are at the greatest risk of experiencing physical and verbal assault from patients. Preliminary studies have shown that a team based approach with targeted staff training has significant positive outcomes in mitigating violence in healthcare settings. Staff attitudes toward patient aggression have also been linked to workplace safety, but current literature suggests that providers experience fear and anxiety while caring for potentially violent patients. The objectives of the study were (1) to develop an interprofessional curriculum focusing on improving teamwork and staff attitudes toward patient violence using simulation-enhanced education for ED staff, and (2) to assess attitudes towards patient aggression both at pre- and post-curriculum implementation stages using a survey-based study design. METHODS: Formal roles and responsibilities for each member of the care team, including positioning during restraint placement, were predefined in conjunction with ED leadership. Emergency medicine residents, nurses and hospital police officers were assigned to interprofessional teams. The curriculum started with an introductory lecture discussing de-escalation techniques and restraint placement as well as core tenets of interprofessional collaboration. Next, we conducted two simulation scenarios using standardized participants (SPs) and structured debriefing. The study consisted of a survey-based design comparing pre- and post-intervention responses via a paired Student t-test to assess changes in staff attitudes. We used the validated Management of Aggression and Violence Attitude Scale (MAVAS) consisting of 30 Likert-scale questions grouped into four themed constructs. RESULTS: One hundred sixty-two ED staff members completed the course with >95% staff participation, generating a total of 106 paired surveys. Constructs for internal/biomedical factors, external/staff factors and situational/interactional perspectives on patient aggression significantly improved (p<0.0001, p<0.002, p<0.0001 respectively). Staff attitudes toward management of patient aggression did not significantly change (p=0.542). Multiple quality improvement initiatives were successfully implemented, including the creation of an interprofessional crisis management alert and response protocol. Staff members described appreciation for our simulation-based curriculum and welcomed the interaction with SPs during their training. CONCLUSION: A structured simulation-enhanced interprofessional intervention was successful in improving multiple facets of ED staff attitudes toward behavioral emergency care. PMID- 26594280 TI - Development of an Objective Structured Clinical Examination for Assessment of Clinical Skills in an Emergency Medicine Clerkship. PMID- 26594281 TI - Direct Observation Assessment of Milestones: Problems with Reliability. AB - INTRODUCTION: Emergency medicine (EM) milestones are used to assess residents' progress. While some milestone validity evidence exists, there is a lack of standardized tools available to reliably assess residents. Inherent to this is a concern that we may not be truly measuring what we intend to assess. The purpose of this study was to design a direct observation milestone assessment instrument supported by validity and reliability evidence. In addition, such a tool would further lend validity evidence to the EM milestones by demonstrating their accurate measurement. METHODS: This was a multi-center, prospective, observational validity study conducted at eight institutions. The Critical Care Direct Observation Tool (CDOT) was created to assess EM residents during resuscitations. This tool was designed using a modified Delphi method focused on content, response process, and internal structure validity. Paying special attention to content validity, the CDOT was developed by an expert panel, maintaining the use of the EM milestone wording. We built response process and internal consistency by piloting and revising the instrument. Raters were faculty who routinely assess residents on the milestones. A brief training video on utilization of the instrument was completed by all. Raters used the CDOT to assess simulated videos of three residents at different stages of training in a critical care scenario. We measured reliability using Fleiss' kappa and interclass correlations. RESULTS: Two versions of the CDOT were used: one used the milestone levels as global rating scales with anchors, and the second reflected a current trend of a checklist response system. Although the raters who used the CDOT routinely rate residents in their practice, they did not score the residents' performances in the videos comparably, which led to poor reliability. The Fleiss' kappa of each of the items measured on both versions of the CDOT was near zero. CONCLUSION: The validity and reliability of the current EM milestone assessment tools have yet to be determined. This study is a rigorous attempt to collect validity evidence in the development of a direct observation assessment instrument. However, despite strict attention to validity evidence, inter-rater reliability was low. The potential sources of reducible variance include rater- and instrument-based error. Based on this study, there may be concerns for the reliability of other EM milestone assessment tools that are currently in use. PMID- 26594282 TI - Development and Implementation of an Emergency Medicine Podcast for Medical Students: EMIGcast. PMID- 26594283 TI - Ready for Discharge? A Survey of Discharge Transition-of-Care Education and Evaluation in Emergency Medicine Residency Programs. AB - This study aimed to assess current education and practices of emergency medicine (EM) residents as perceived by EM program directors to determine if there are deficits in resident discharge handoff training. This survey study was guided by the Kern model for medical curriculum development. A six-member Council of EM Residency Directors (CORD) Transitions of Care task force of EM physicians performed these steps and constructed a survey. The survey was distributed to program residency directors via the CORD listserve and/or direct contact. There were 119 responses to the survey, which were collected using an online survey tool. Over 71% of the 167 American College of Graduate Medical Education (ACGME) accredited EM residency programs were represented. Of those responding, 42.9% of programs reported formal training regarding discharges during initial orientation and 5.9% reported structured curriculum outside of orientation. A majority (73.9%) of programs reported that EM residents were not routinely evaluated on their discharge proficiency. Despite the ACGME requirements requiring formal handoff curriculum and evaluation, many programs do not provide formal curriculum on the discharge transition of care or evaluate EM residents on their discharge proficiency. PMID- 26594284 TI - Combined Versus Detailed Evaluation Components in Medical Student Global Rating Indexes. AB - INTRODUCTION: To determine if there is any correlation between any of the 10 individual components of a global rating index on an emergency medicine (EM) student clerkship evaluation form. If there is correlation, to determine if a weighted average of highly correlated components loses predictive value for the final clerkship grade. METHODS: This study reviewed medical student evaluations collected over two years of a required fourth-year rotation in EM. Evaluation cards, comprised of a detailed 10-part evaluation, were completed after each shift. We used a correlation matrix between evaluation category average scores, using Spearman's rho, to determine if there was any correlation of the grades between any of the 10 items on the evaluation form. RESULTS: A total of 233 students completed the rotation over the two-year period of the study. There were strong correlations (>0.80) between assessment components of medical knowledge, history taking, physical exam, and differential diagnosis. There were also strong correlations between assessment components of team rapport, patient rapport, and motivation. When these highly correlated were combined to produce a four component model, linear regression demonstrated similar predictive power in terms of final clerkship grade (R(2)=0.71, CI95=0.65-0.77 and R(2)=0.69, CI95=0.63-0.76 for the full and reduced models respectively). CONCLUSION: This study revealed that several components of the evaluation card had a high degree of correlation. Combining the correlated items, a reduced model containing four items (clinical skills, interpersonal skills, procedural skills, and documentation) was as predictive of the student's clinical grade as the full 10-item evaluation. Clerkship directors should be aware of the performance of their individual global rating scales when assessing medical student performance, especially if attempting to measure greater than four components. PMID- 26594285 TI - Effect of Doximity Residency Rankings on Residency Applicants' Program Choices. AB - INTRODUCTION: Choosing a residency program is a stressful and important decision. Doximity released residency program rankings by specialty in September 2014. This study sought to investigate the impact of those rankings on residency application choices made by fourth year medical students. METHODS: A 12-item survey was administered in October 2014 to fourth year medical students at three schools. Students indicated their specialty, awareness of and perceived accuracy of the rankings, and the rankings' impact on the programs to which they chose to apply. Descriptive statistics were reported for all students and those applying to Emergency Medicine (EM). RESULTS: A total of 461 (75.8%) students responded, with 425 applying in one of the 20 Doximity ranked specialties. Of the 425, 247 (58%) were aware of the rankings and 177 looked at them. On a 1-100 scale (100=very accurate), students reported a mean ranking accuracy rating of 56.7 (SD 20.3). Forty-five percent of students who looked at the rankings modified the number of programs to which they applied. The majority added programs. Of the 47 students applying to EM, 18 looked at the rankings and 33% changed their application list with most adding programs. CONCLUSION: The Doximity rankings had real effects on students applying to residencies as almost half of students who looked at the rankings modified their program list. Additionally, students found the rankings to be moderately accurate. Graduating students might benefit from emphasis on more objective characterization of programs to assess in light of their own interests and personal/career goals. PMID- 26594286 TI - Introducing Medical Students into the Emergency Department: The Impact upon Patient Satisfaction. AB - INTRODUCTION: Performance on patient satisfaction surveys is becoming increasingly important for practicing emergency physicians and the introduction of learners into a new clinical environment may impact such scores. This study aimed to quantify the impact of introducing fourth-year medical students on patient satisfaction in two university-affiliated community emergency departments (EDs). METHODS: Two community-based EDs in the Indiana University Health (IUH) system began hosting medical students in March 2011 and October 2013, respectively. We analyzed responses from patient satisfaction surveys at each site for seven months before and after the introduction of students. Two components of the survey, "Would you recommend this ED to your friends and family?" and "How would you rate this facility overall?" were selected for analysis, as they represent the primary questions reviewed by the Center for Medicare Services (CMS) as part of value-based purchasing. We evaluated the percentage of positive responses for adult, pediatric, and all patients combined. RESULTS: Analysis did not reveal a statistically significant difference in the percentage of positive response for the "would you recommend" question at both clinical sites with regards to the adult and pediatric subgroups, as well as the all-patient group. At one of the sites, there was significant improvement in the percentage of positive response to the "overall rating" question following the introduction of medical students when all patients were analyzed (60.3% to 68.2%, p=0.038). However, there was no statistically significant difference in the "overall rating" when the pediatric or adult subgroups were analyzed at this site and no significant difference was observed in any group at the second site. CONCLUSION: The introduction of medical students in two community-based EDs is not associated with a statistically significant difference in overall patient satisfaction, but was associated with a significant positive effect on the overall rating of the ED at one of the two clinical sites studied. Further study is needed to evaluate the effect of medical student learners upon patient satisfaction in settings outside of a single health system. PMID- 26594287 TI - Teaching Emotional Intelligence: A Control Group Study of a Brief Educational Intervention for Emergency Medicine Residents. AB - INTRODUCTION: Emotional Intelligence (EI) is defined as an ability to perceive another's emotional state combined with an ability to modify one's own. Physicians with this ability are at a distinct advantage, both in fostering teams and in making sound decisions. Studies have shown that higher physician EI's are associated with lower incidence of burn-out, longer careers, more positive patient-physician interactions, increased empathy, and improved communication skills. We explored the potential for EI to be learned as a skill (as opposed to being an innate ability) through a brief educational intervention with emergency medicine (EM) residents. METHODS: This study was conducted at a large urban EM residency program. Residents were randomized to either EI intervention or control groups. The intervention was a two-hour session focused on improving the skill of social perspective taking (SPT), a skill related to social awareness. Due to time limitations, we used a 10-item sample of the Hay 360 Emotional Competence Inventory to measure EI at three time points for the training group: before (pre) and after (post) training, and at six-months post training (follow up); and at two time points for the control group: pre- and follow up. The preliminary analysis was a four-way analysis of variance with one repeated measure: Group x Gender x Program Year over Time. We also completed post-hoc tests. RESULTS: Thirty-three EM residents participated in the study (33 of 36, 92%), 19 in the EI intervention group and 14 in the control group. We found a significant interaction effect between Group and Time (p<=0.05). Post-hoc tests revealed a significant increase in EI scores from Time 1 to 3 for the EI intervention group (62.6% to 74.2%), but no statistical change was observed for the controls (66.8% to 66.1%, p=0.77). We observed no main effects involving gender or level of training. CONCLUSION: Our brief EI training showed a delayed but statistically significant positive impact on EM residents six months after the intervention involving SPT. One possible explanation for this finding is that residents required time to process and apply the EI skills training in order for us to detect measurable change. More rigorous measurement will be needed in future studies to aid in the interpretation of our findings. PMID- 26594288 TI - Correlation of Simulation Examination to Written Test Scores for Advanced Cardiac Life Support Testing: Prospective Cohort Study. AB - INTRODUCTION: Traditional Advanced Cardiac Life Support (ACLS) courses are evaluated using written multiple-choice tests. High-fidelity simulation is a widely used adjunct to didactic content, and has been used in many specialties as a training resource as well as an evaluative tool. There are no data to our knowledge that compare simulation examination scores with written test scores for ACLS courses. OBJECTIVE: To compare and correlate a novel high-fidelity simulation-based evaluation with traditional written testing for senior medical students in an ACLS course. METHODS: We performed a prospective cohort study to determine the correlation between simulation-based evaluation and traditional written testing in a medical school simulation center. Students were tested on a standard acute coronary syndrome/ventricular fibrillation cardiac arrest scenario. Our primary outcome measure was correlation of exam results for 19 volunteer fourth-year medical students after a 32-hour ACLS-based Resuscitation Boot Camp course. Our secondary outcome was comparison of simulation-based vs. written outcome scores. RESULTS: The composite average score on the written evaluation was substantially higher (93.6%) than the simulation performance score (81.3%, absolute difference 12.3%, 95% CI [10.6-14.0%], p<0.00005). We found a statistically significant moderate correlation between simulation scenario test performance and traditional written testing (Pearson r=0.48, p=0.04), validating the new evaluation method. CONCLUSION: Simulation-based ACLS evaluation methods correlate with traditional written testing and demonstrate resuscitation knowledge and skills. Simulation may be a more discriminating and challenging testing method, as students scored higher on written evaluation methods compared to simulation. PMID- 26594289 TI - How Does Emergency Department Crowding Affect Medical Student Test Scores and Clerkship Evaluations? AB - INTRODUCTION: The effect of emergency department (ED) crowding has been recognized as a concern for more than 20 years; its effect on productivity, medical errors, and patient satisfaction has been studied extensively. Little research has reviewed the effect of ED crowding on medical education. Prior studies that have considered this effect have shown no correlation between ED crowding and resident perception of quality of medical education. OBJECTIVE: To determine whether ED crowding, as measured by the National ED Overcrowding Scale (NEDOCS) score, has a quantifiable effect on medical student objective and subjective experiences during emergency medicine (EM) clerkship rotations. METHODS: We collected end-of-rotation examinations and medical student evaluations for 21 EM rotation blocks between July 2010 and May 2012, with a total of 211 students. NEDOCS scores were calculated for each corresponding period. Weighted regression analyses examined the correlation between components of the medical student evaluation, student test scores, and the NEDOCS score for each period. RESULTS: When all 21 rotations are included in the analysis, NEDOCS scores showed a negative correlation with medical student tests scores (regression coefficient= -0.16, p=0.04) and three elements of the rotation evaluation (attending teaching, communication, and systems-based practice; p<0.05). We excluded an outlying NEDOCS score from the analysis and obtained similar results. When the data were controlled for effect of month of the year, only student test score remained significantly correlated with NEDOCS score (p=0.011). No part of the medical student rotation evaluation attained significant correlation with the NEDOCS score (p>=0.34 in all cases). CONCLUSION: ED overcrowding does demonstrate a small but negative association with medical student performance on end-of-rotation examinations. Additional studies are recommended to further evaluate this effect. PMID- 26594290 TI - Medical Student Performance on the National Board of Medical Examiners Emergency Medicine Advanced Clinical Examination and the National Emergency Medicine M4 Exams. AB - INTRODUCTION: In April 2013, the National Board of Medical Examiners (NBME) released an Advanced Clinical Examination (ACE) in emergency medicine (EM). In addition to this new resource, CDEM (Clerkship Directors in EM) provides two online, high-quality, internally validated examinations. National usage statistics are available for all three examinations, however, it is currently unknown how students entering an EM residency perform as compared to the entire national cohort. This information may help educators interpret examination scores of both EM-bound and non-EM-bound students. OBJECTIVES: The objective of this study was to compare EM clerkship examination performance between students who matched into an EM residency in 2014 to students who did not. We made comparisons were made using the EM-ACE and both versions of the National fourth year medical student (M4) EM examinations. METHOD: In this retrospective multi-institutional cohort study, the EM-ACE and either Version 1 (V1) or 2 (V2) of the National EM M4 examination was given to students taking a fourth-year EM rotation at five institutions between April 2013 to February 2014. We collected examination performance, including the scaled EM-ACE score, and percent correct on the EM M4 exams, and 2014 NRMP Match status. Student t-tests were performed on the examination averages of students who matched in EM as compared with those who did not. RESULTS: A total of 606 students from five different institutions took both the EM-ACE and one of the EM M4 exams; 94 (15.5%) students matched in EM in the 2014 Match. The mean score for EM-bound students on the EM-ACE, V1 and V2 of the EM M4 exams were 70.9 (n=47, SD=9.0), 84.4 (n=36, SD=5.2), and 83.3 (n=11, SD=6.9), respectively. Mean scores for non-EM-bound students were 68.0 (n=256, SD=9.7), 82.9 (n=243, SD=6.5), and 74.5 (n=13, SD=5.9). There was a significant difference in mean scores in EM-bound and non-EM-bound student for the EM-ACE (p=0.05) and V2 (p<0.01) but not V1 (p=0.18) of the National EM M4 examination. CONCLUSION: Students who successfully matched in EM performed better on all three exams at the end of their EM clerkship. PMID- 26594291 TI - Competency Assessment in Senior Emergency Medicine Residents for Core Ultrasound Skills. AB - INTRODUCTION: Quality resident education in point-of-care ultrasound (POC US) is becoming increasingly important in emergency medicine (EM); however, the best methods to evaluate competency in graduating residents has not been established. We sought to design and implement a rigorous assessment of image acquisition and interpretation in POC US in a cohort of graduating residents at our institution. METHODS: We evaluated nine senior residents in both image acquisition and image interpretation for five core US skills (focused assessment with sonography for trauma (FAST), aorta, echocardiogram (ECHO), pelvic, central line placement). Image acquisition, using an observed clinical skills exam (OSCE) directed assessment with a standardized patient model. Image interpretation was measured with a multiple-choice exam including normal and pathologic images. RESULTS: Residents performed well on image acquisition for core skills with an average score of 85.7% for core skills and 74% including advanced skills (ovaries, advanced ECHO, advanced aorta). Residents scored well but slightly lower on image interpretation with an average score of 76%. CONCLUSION: Senior residents performed well on core POC US skills as evaluated with a rigorous assessment tool. This tool may be developed further for other EM programs to use for graduating resident evaluation. PMID- 26594292 TI - Mentoring during Medical School and Match Outcome among Emergency Medicine Residents. AB - INTRODUCTION: Few studies have documented the value of mentoring for medical students, and research has been limited to more subjective (e.g., job satisfaction, perceived career preparation) rather than objective outcomes. This study examined whether having a mentor is associated with match outcome (where a student matched based on their rank order list [ROL]). METHODS: We sent a survey link to all emergency medicine (EM) program coordinators to distribute to their residents. EM residents were surveyed about whether they had a mentor during medical school. Match outcome was assessed by asking residents where they matched on their ROL (e.g., first choice, fifth choice). They were also asked about rank in medical school, type of degree (MD vs. DO), and performance on standardized tests. Residents who indicated having a mentor completed the Mentorship Effectiveness Scale (MES), which evaluates behavioral characteristics of the mentor and yields a total score. We assessed correlations among these variables using Pearson's correlation coefficient. Post-hoc analysis using independent sample t-test was conducted to compare differences in the MES score between those who matched to their first or second choice vs. third or higher choice. RESULTS: Participants were a convenience sample of 297 EM residents. Of those, 199 (67%) reported having a mentor during medical school. Contrary to our hypothesis, there was no significant correlation between having a mentor and match outcome (r=0.06, p=0.29). Match outcome was associated with class rank (r=0.13, p=0.03), satisfaction with match outcome (r= -0.37, p<0.001), and type of degree (r=0.12, p=0.04). Among those with mentors, a t-test revealed that the MES score was significantly higher among those who matched to their first or second choice (M=51.31, SD=10.13) compared to those who matched to their third or higher choice (M=43.59, SD=17.12), t(194)=3.65, p<0.001, d=0.55. CONCLUSION: Simply having a mentor during medical school does not impact match outcome, but having an effective mentor is associated with a more favorable match outcome among medical students applying to EM programs. PMID- 26594293 TI - Emergency Medicine Residents Consistently Rate Themselves Higher than Attending Assessments on ACGME Milestones. AB - INTRODUCTION: In 2012 the Accreditation Council for Graduate Medical Education (ACGME) introduced the Next Accreditation System (NAS), which implemented milestones to assess the competency of residents and fellows. While attending evaluation and feedback is crucial for resident development, perhaps equally important is a resident's self-assessment. If a resident does not accurately self assess, clinical and professional progress may be compromised. The objective of our study was to compare emergency medicine (EM) resident milestone evaluation by EM faculty with the same resident's self-assessment. METHODS: This is an observational, cross-sectional study that was performed at an academic, four-year EM residency program. Twenty-five randomly chosen residents completed milestone self-assessment using eight ACGME sub-competencies deemed by residency leadership as representative of core EM principles. These residents were also evaluated by 20 faculty members. The milestone levels were evaluated on a nine-point scale. We calculated the average difference between resident self-ratings and faculty ratings, and used sample t-tests to determine statistical significance of the difference in scores. RESULTS: Eighteen residents evaluated themselves. Each resident was assessed by an average of 16 attendings (min=10, max=20). Residents gave themselves statistically significant higher milestone ratings than attendings did for each sub-competency examined (p<0.0001). CONCLUSION: Residents over-estimated their abilities in every sub-competency assessed. This underscores the importance of feedback and assessment transparency. More attention needs to be paid to methods by which residency leadership can make residents' self perception of their clinical ability more congruent with that of their teachers and evaluators. The major limitation of our study is small sample size of both residents and attendings. PMID- 26594294 TI - Integration of a Blog into an Emergency Medicine Residency Curriculum. PMID- 26594295 TI - Ultrasound Training in the Emergency Medicine Clerkship. AB - INTRODUCTION: The curriculum in most emergency medicine (EM) clerkships includes very little formalized training in point-of-care ultrasound. Medical schools have begun to implement ultrasound training in the pre-clinical curriculum, and the EM clerkship is an appropriate place to build upon this training. The objectives are (1) to evaluate the effectiveness of implementing a focused ultrasound curriculum within an established EM clerkship and (2) to obtain feedback from medical students regarding the program. METHODS: We conducted a prospective cohort study of medical students during an EM clerkship year from July 1, 2011, to June 30, 2012. Participants included fourth-year medical students (n=45) enrolled in the EM clerkship at our institution. The students underwent a structured program focused on the focused assessment with sonography for trauma exam and ultrasound guided vascular access. At the conclusion of the rotation, they took a 10-item multiple choice test assessing knowledge and image interpretation skills. A cohort of EM residents (n=20) also took the multiple choice test but did not participate in the training with the students. We used an independent samples t test to examine differences in test scores between the groups. RESULTS: The medical students in the ultrasound training program scored significantly higher on the multiple-choice test than the EM residents, t(63)=2.3, p<0.05. The feedback from the students indicated that 82.8% were using ultrasound on their current rotations and the majority (55.2%) felt that the one-on-one scanning shift was the most valuable aspect of the curriculum. DISCUSSION: Our study demonstrates support for an ultrasound training program for medical students in the EM clerkship. After completing the training, students were able to perform similarly to EM residents on a knowledge-based exam. PMID- 26594296 TI - Assessing EM Patient Safety and Quality Improvement Milestones Using a Novel Debate Format. AB - Graduate medical education is increasingly focused on patient safety and quality improvement; training programs must adapt their curriculum to address these changes. We propose a novel curriculum for emergency medicine (EM) residency training programs specifically addressing patient safety, systems-based management, and practice-based performance improvement, called "EM Debates." Following implementation of this educational curriculum, we performed a cross sectional study to evaluate the curriculum through resident self-assessment. Additionally, a cross-sectional study to determine the ED clinical competency committee's (CCC) ability to assess residents on specific competencies was performed. Residents were overall very positive towards the implementation of the debates. Of those participating in a debate, 71% felt that it improved their individual performance within a specific topic, and 100% of those that led a debate felt that they could propose an evidence-based approach to a specific topic. The CCC found that it was easier to assess milestones in patient safety, systems-based management, and practice-based performance improvement (sub competencies 16, 17, and 19) compared to prior to the implementation of the debates. The debates have been a helpful venue to teach EM residents about patient safety concepts, identifying medical errors, and process improvement. PMID- 26594297 TI - Model for Developing Educational Research Productivity: The Medical Education Research Group. AB - INTRODUCTION: Education research and scholarship are essential for promotion of faculty as well as dissemination of new educational practices. Educational faculty frequently spend the majority of their time on administrative and educational commitments and as a result educators often fall behind on scholarship and research. The objective of this educational advance is to promote scholarly productivity as a template for others to follow. METHODS: We formed the Medical Education Research Group (MERG) of education leaders from our emergency medicine residency, fellowship, and clerkship programs, as well as residents with a focus on education. First, we incorporated scholarship into the required activities of our education missions by evaluating the impact of programmatic changes and then submitting the curricula or process as peer-reviewed work. Second, we worked as a team, sharing projects that led to improved motivation, accountability, and work completion. Third, our monthly meetings served as brainstorming sessions for new projects, research skill building, and tracking work completion. Lastly, we incorporated a work-study graduate student to assist with basic but time-consuming tasks of completing manuscripts. RESULTS: The MERG group has been highly productive, achieving the following scholarship over a three-year period: 102 abstract presentations, 46 journal article publications, 13 MedEd Portal publications, 35 national didactic presentations and five faculty promotions to the next academic level. CONCLUSION: An intentional focus on scholarship has led to a collaborative group of educators successfully improving their scholarship through team productivity, which ultimately leads to faculty promotions and dissemination of innovations in education. PMID- 26594298 TI - Implementation of an Education Value Unit (EVU) System to Recognize Faculty Contributions. AB - INTRODUCTION: Faculty educational contributions are hard to quantify, but in an era of limited resources it is essential to link funding with effort. The purpose of this study was to determine the feasibility of an educational value unit (EVU) system in an academic emergency department and to examine its effect on faculty behavior, particularly on conference attendance and completion of trainee evaluations. METHODS: A taskforce representing education, research, and clinical missions was convened to develop a method of incentivizing productivity for an academic emergency medicine faculty. Domains of educational contributions were defined and assigned a value based on time expended. A 30-hour EVU threshold for achievement was aligned with departmental goals. Targets included educational presentations, completion of trainee evaluations and attendance at didactic conferences. We analyzed comparisons of performance during the year preceding and after implementation. RESULTS: Faculty (N=50) attended significantly more didactic conferences (22.7 hours v. 34.5 hours, p<0.005) and completed more trainee evaluations (5.9 v. 8.8 months, p<0.005). During the pre-implementation year, 84% (42/50) met the 30-hour threshold with 94% (47/50) meeting post implementation (p=0.11). Mean total EVUs increased significantly (94.4 hours v. 109.8 hours, p=0.04) resulting from increased conference attendance and evaluation completion without a change in other categories. CONCLUSION: In a busy academic department there are many work allocation pressures. An EVU system integrated with an incentive structure to recognize faculty contributions increases the importance of educational responsibilities. We propose an EVU model that could be implemented and adjusted for differing departmental priorities at other academic departments. PMID- 26594299 TI - Correlation of the National Board of Medical Examiners Emergency Medicine Advanced Clinical Examination Given in July to Intern American Board of Emergency Medicine in-training Examination Scores: A Predictor of Performance? AB - INTRODUCTION: There is great variation in the knowledge base of Emergency Medicine (EM) interns in July. The first objective knowledge assessment during residency does not occur until eight months later, in February, when the American Board of EM (ABEM) administers the in-training examination (ITE). In 2013, the National Board of Medical Examiners (NBME) released the EM Advanced Clinical Examination (EM-ACE), an assessment intended for fourth-year medical students. Administration of the EM-ACE to interns at the start of residency may provide an earlier opportunity to assess the new EM residents' knowledge base. The primary objective of this study was to determine the correlation of the NBME EM-ACE, given early in residency, with the EM ITE. Secondary objectives included determination of the correlation of the United States Medical Licensing Examination (USMLE) Step 1 or 2 scores with early intern EM-ACE and ITE scores and the effect, if any, of clinical EM experience on examination correlation. METHODS: This was a multi-institutional, observational study. Entering EM interns at six residencies took the EM-ACE in July 2013 and the ABEM ITE in February 2014. We collected scores for the EM-ACE and ITE, age, gender, weeks of clinical EM experience in residency prior to the ITE, and USMLE Step 1 and 2 scores. Pearson's correlation and linear regression were performed. RESULTS: Sixty-two interns took the EM-ACE and the ITE. The Pearson's correlation coefficient between the ITE and the EM-ACE was 0.62. R-squared was 0.5 (adjusted 0.4). The coefficient of determination was 0.41 (95% CI [0.3-0.8]). For every increase of one in the scaled EM-ACE score, we observed a 0.4% increase in the EM in-training score. In a linear regression model using all available variables (EM-ACE, gender, age, clinical exposure to EM, and USMLE Step 1 and Step 2 scores), only the EM-ACE score was significantly associated with the ITE (p<0.05). We observed significant colinearity among the EM-ACE, ITE and USMLE scores. Gender, age and number of weeks of EM prior to the ITE had no effect on the relationship between EM-ACE and the ITE. CONCLUSION: Given early during intern year, the EM-ACE score showed positive correlation with ITE. Clinical EM experience prior to the in training exam did not affect the correlation. PMID- 26594300 TI - Effect of a Novel Engagement Strategy Using Twitter on Test Performance. AB - INTRODUCTION: Medical educators in recent years have been using social media for more penetrance to technologically-savvy learners. The utility of using Twitter for curriculum content delivery has not been studied. We sought to determine if participation in a social media-based educational supplement would improve student performance on a test of clinical images at the end of the semester. METHODS: 116 second-year medical students were enrolled in a lecture-based clinical medicine course, in which images of common clinical exam findings were presented. An additional, optional assessment was performed on Twitter. Each week, a clinical presentation and physical exam image (not covered in course lectures) were distributed via Twitter, and students were invited to guess the exam finding or diagnosis. After the completion of the course, students were asked to participate in a slideshow "quiz" with 24 clinical images, half from lecture and half from Twitter. RESULTS: We conducted a one-way analysis of variance to determine the effect Twitter participation had on total, Twitter only, and lecture-only scores. Twitter participation data was collected from the end-of-course survey and was defined as submitting answers to the Twitter-only questions "all or most of the time", "about half of the time", and "little or none of the time." We found a significant difference in overall scores (p<0.001) and in Twitter-only scores (p<0.001). There was not enough evidence to conclude a significant difference in lecture-only scores (p=0.124). Students who submitted answers to Twitter "all or most of the time" or "about half the time" had significantly higher overall scores and Twitter-only scores (p<0.001 and p<0.001, respectively) than those students who only submitted answers "little or none of the time." CONCLUSION: While students retained less information from Twitter than from traditional classroom lecture, some retention was noted. Future research on social media in medical education would benefit from clear control and experimental groups in settings where quantitative use of social media could be measured. Ultimately, it is unlikely for social media to replace lecture in medical curriculum; however, there is a reasonable role for social media as an adjunct to traditional medical education. PMID- 26594301 TI - Energy bagging tree. AB - This paper introduces Energy Bagging Tree (EBT) for multivariate nonparametric regression problems. The EBT makes use of a measure of dispersion constructed from a generalized Gini's mean difference as node impurity, and the tree split function therefore corresponds to the product of energy distance and descendants' proportions. As a non-parametric extension of the between-sample variation in the analysis of variance, this measure of dispersion serves well for EBT in understanding certain complex data. Extensive simulation studies indicate that EBT is highly competitive with existing regression tree methods. We also assess the performance of the EBT through a real data analysis on forest fires. PMID- 26594302 TI - Utilizing Exploratory Spatial Data Analysis to Examine Health and Environmental Disparities in Disadvantaged Neighborhoods. AB - Health disparities research has focused primarily on racial and socioeconomic differences in health outcomes. Although neighborhood characteristics and the concept of built environment have been shown to affect individual health, measuring the effects of environmental risks on health has been a less developed area of disparities research. To examine spatial associations and the distribution of geographic patterns of sociodemographic characteristics, environmental cancer risk, and cancer rates, we utilized existing data from multiple sources. The findings from our initial analysis, which concerned with proximity to environmental hazards and at-risk communities, were consistent with results of previous studies, which often reported mixed relationships between health disparity indicators and environmental burden. However, further analysis with refined models showed that several key demographic and subdomains of cancer risk measures were shown to have spatial components. With the application of exploratory spatial data analysis, we were able to identify areas with both high rates of poverty and racial minorities to further examine for possible associations to environmental cancer risk. Global spatial autocorrelation found spatial clustering with percent black, percent poverty, point and non-point cancer risks requiring further spatial analysis to determine relationship of significance based on geography. This methodology was based upon particular assumptions associated with data and applications, which needed to be met. We conclude that careful assessment of the data and applications were required to properly interpret the findings in understanding the relationship between vulnerable populations and environmental burden. PMID- 26594304 TI - Tensor sufficient dimension reduction. AB - Tensor is a multiway array. With the rapid development of science and technology in the past decades, large amount of tensor observations are routinely collected, processed, and stored in many scientific researches and commercial activities nowadays. The colorimetric sensor array (CSA) data is such an example. Driven by the need to address data analysis challenges that arise in CSA data, we propose a tensor dimension reduction model, a model assuming the nonlinear dependence between a response and a projection of all the tensor predictors. The tensor dimension reduction models are estimated in a sequential iterative fashion. The proposed method is applied to a CSA data collected for 150 pathogenic bacteria coming from 10 bacterial species and 14 bacteria from one control species. Empirical performance demonstrates that our proposed method can greatly improve the sensitivity and specificity of the CSA technique. PMID- 26594303 TI - Allergen Immunotherapy (AIT): a prototype of Precision Medicine. AB - Precision medicine is a medical model aiming to deliver customised healthcare - with medical decisions, practices, and/or products tailored to the individual patient informed but not directed by guidelines. Allergen immunotherapy has unique immunological rationale, since the approach is tailored to the specific IgE spectrum of an individual and modifies the natural course of the disease as it has a persistent efficacy after completion of treatment. In this perspective Allergen Immunotherapy - AIT has to be presently considered a prototype of Precision Medicine. Precise information and biomarkers provided by systems medicine and network medicine will address the discovery of Allergen immunotherapy biomarkers for (i) identification of the causes, (ii) stratification of eligible patients for AIT and (iii) the assessment of AIT efficacy. This area of medical technology is evolving rapidly and, compelemented by e-health, will change the way we practice medicine. It will help to monitor patients' disease control and data for (i) patient stratification, (ii) clinical trials, (iii) monitoring the efficacy and safety of targeted therapies which are critical for reaching an appropriate reimbursement. Biomarkers associated with e health combined with a clinical decision support system (CDSS) will change the scope of Allergen immunotherapy. The cost/effectiveness of Allergen immunotherapy is a key issue for successful implementation. It should include the long-term benefits in the pharmaco-economic evaluation, since no other allergy treatment has this specific characteristic. AIT is the prototype of current and future precision medicine. PMID- 26594305 TI - Effects of the Age-Education Structure of Female Workers on Male Earnings in Brazil. AB - The main concern of this study is the impact that an increase in female participation within the labor force has on the earnings of males in Brazil. Previous research considered these transitions for male workers, but did not include female workers when estimating various effects on earnings. The 1970, 1980, 1991, and 2000 Brazilian Demographic Censuses were used for this analysis. Results suggest a significant negative impact on male earnings in 1970 as a result of the share of female workers. This effect has been decreasing over time, as the coefficients from more recent years are positive. Changes in age and educational composition make a substantial difference on the estimation of male earnings in Brazil. The method developed in this study is not infallible, but it improves previous estimates by including the relationship among compositional changes, female labor force participation, and earnings, thus going beyond the direct impact of age and education. PMID- 26594306 TI - Complete genome sequence of Thioalkalivibrio paradoxus type strain ARh 1(T), an obligately chemolithoautotrophic haloalkaliphilic sulfur-oxidizing bacterium isolated from a Kenyan soda lake. AB - Thioalkalivibrio paradoxus strain ARh 1(T) is a chemolithoautotrophic, non motile, Gram-negative bacterium belonging to the Gammaproteobacteria that was isolated from samples of haloalkaline soda lakes. It derives energy from the oxidation of reduced sulfur compounds and is notable for its ability to grow on thiocyanate as its sole source of electrons, sulfur and nitrogen. The full genome consists of 3,756,729 bp and comprises 3,500 protein-coding and 57 RNA-coding genes. This organism was sequenced as part of the community science program at the DOE Joint Genome Institute. PMID- 26594307 TI - Genome sequence and description of the anaerobic lignin-degrading bacterium Tolumonas lignolytica sp. nov. AB - Tolumonas lignolytica BRL6-1(T) sp. nov. is the type strain of T. lignolytica sp. nov., a proposed novel species of the Tolumonas genus. This strain was isolated from tropical rainforest soils based on its ability to utilize lignin as a sole carbon source. Cells of Tolumonas lignolytica BRL6-1(T) are mesophilic, non-spore forming, Gram-negative rods that are oxidase and catalase negative. The genome for this isolate was sequenced and returned in seven unique contigs totaling 3.6Mbp, enabling the characterization of several putative pathways for lignin breakdown. Particularly, we found an extracellular peroxidase involved in lignin depolymerization, as well as several enzymes involved in beta-aryl ether bond cleavage, which is the most abundant linkage between lignin monomers. We also found genes for enzymes involved in ferulic acid metabolism, which is a common product of lignin breakdown. By characterizing pathways and enzymes employed in the bacterial breakdown of lignin in anaerobic environments, this work should assist in the efficient engineering of biofuel production from lignocellulosic material. PMID- 26594308 TI - Complete genome sequence of Novosphingobium pentaromativorans US6-1(T). AB - Novosphingobium pentaromativorans US6-1(T) is a species in the family Sphingomonadaceae. According to the phylogenetic analysis based on 16S rRNA gene sequence of the N. pentaromativorans US6-1(T) and nine genome-sequenced strains in the genus Novosphingobium, the similarity ranged from 93.9 to 99.9 % and the highest similarity was found with Novosphingobium sp. PP1Y (99.9 %), whereas the ANI value based on genomes ranged from 70.9 to 93 % and the highest value was 93 %. This microorganism was isolated from muddy coastal bay sediments where the environment is heavily polluted by polycyclic aromatic hydrocarbons (PAHs). It was previously shown to be capable of degrading multiple PAHs, including benzo[a]pyrene. To further understand the PAH biodegradation pathways the previous draft genome of this microorganism was revised to obtain a complete genome using Illumina MiSeq and PacBio platform. The genome of strain US6-1(T) consists of 5,457,578 bp, which includes the 3,979,506 bp chromosome and five megaplasmids. It comprises 5110 protein-coding genes and 82 RNA genes. Here, we provide an analysis of the complete genome sequence which enables the identification of new characteristics of this strain. PMID- 26594309 TI - Annotation inconsistencies beyond sequence similarity-based function prediction - phylogeny and genome structure. AB - The function annotation process in computational biology has increasingly shifted from the traditional characterization of individual biochemical roles of protein molecules to the system-wide detection of entire metabolic pathways and genomic structures. The so-called genome-aware methods broaden misannotation inconsistencies in genome sequences beyond protein function assignments, encompassing phylogenetic anomalies and artifactual genomic regions. We outline three categories of error propagation in databases by providing striking examples - at various levels of appreciation by the community from traditional to emerging, thus raising awareness for future solutions. PMID- 26594310 TI - Complete genome sequence of Staphylococcus aureus, strain ILRI_Eymole1/1, isolated from a Kenyan dromedary camel. AB - We report the genome of a Staphylococcus aureus strain (ILRI_Eymole1/1) isolated from a nasal swab of a dromedary camel (Camelus dromedarius) in North Kenya. The complete genome sequence of this strain consists of a circular chromosome of 2,874,302 bp with a GC-content of 32.88 %. In silico annotation predicted 2755 protein-encoding genes and 76 non-coding genes. This isolate belongs to MLST sequence type 30 (ST30). Phylogenetic analysis based on a subset of 283 core genes revealed that it falls within the human clonal complex 30 (CC30) S. aureus isolate cluster but is genetically distinct. About 79 % of the protein encoding genes are part of the CC30 core genome (genes common to all CC30 S. aureus isolates), ~18 % were within the variable genome (shared among multiple but not all isolates) and ~ 3 % were found only in the genome of the camel isolate. Among the 85 isolate-specific genes, 79 were located within putative phages and pathogenicity islands. Protein encoding genes associated with bacterial adhesion, and secretory proteins that are essential components of the type VII secretion system were also identified. The complete genome sequence of S. aureus strain ILRI_Eymole1/1 has been deposited in the European Nucleotide Archive under the accession no LN626917.1. PMID- 26594311 TI - Health, Height, Height Shrinkage, and SES at Older Ages: Evidence from China. AB - In this paper, we build on the literature that examines associations between height and health outcomes of the elderly. We investigate the associations of height shrinkage at older ages with socioeconomic status, finding that height shrinkage for both men and women is negatively associated with better schooling, current urban residence, and household per capita expenditures. We then investigate the relationships between pre-shrinkage height, height shrinkage, and a rich set of health outcomes of older respondents, finding that height shrinkage is positively associated with poor health outcomes across a variety of outcomes, being especially strong for cognition outcomes. PMID- 26594312 TI - Community Wise: A formative evaluation of a community based health intervention. AB - Individuals with histories of incarceration and substance abuse residing in distressed communities often receive suboptimal services partly due to a lack of empirically supported substance abuse treatments targeting this population. Grounded in community-engaged research, we developed Community Wise, a manualized, 12-week, group behavioral intervention. The intervention aims to reduce substance use frequency, HIV/HCV risk behaviors, and reoffending among individuals with histories of substance abuse and incarceration. Thirty six individuals were recruited to participate in a formative evaluation of Community Wise processes and outcomes. Analysis showed significantly lower post intervention number of cigarettes smoked per day, days using an illicit drug, money spent on illegal drugs, and rearrests. Based on the evaluation, the research team made the following changes: 1) added a session on sexuality; 2) increased the number of sessions from 12 to 15; and 3) modified strategies to help participants develop and implement capacity building projects. PMID- 26594313 TI - Usability Testing of an HPV Information Website for Parents and Adolescents. AB - OBJECTIVE: Parents make the decisions regarding their children's health care. Unfortunately, many parents are misinformed about HPV and HPV vaccines. In order to help parents make an informed decision regarding HPV vaccination for their daughter, the GoHealthyGirls website was created for parents and their adolescent daughters. Usability testing was conducted with members of the target population to refine the website prior to conducting an efficacy trial. METHODS: Parents with girls (n=9) between the ages of 11-13 and 11-13 year old adolescents (n=10) were recruited for usability testing. The testing consisted of completing twelve scenarios where participants were asked to find specific information on the GoHealthyGirls site. This was followed by a self-administered system usability scale-to determine ease of use and functionality of the website-and a user satisfaction survey. RESULTS: Both adult and adolescent participants were able to easily find the requested information and reported an increased positive opinion of HPV vaccines after visiting the website. Both groups of participants reported favorable evaluations of using the website. CONCLUSION: The GoHealthyGirls website has the potential to help parents of adolescent daughters make an informed decision about HPV vaccination. A large scale efficacy trial will determine its usefulness. PMID- 26594314 TI - Androgen receptor and immune inflammation in benign prostatic hyperplasia and prostate cancer. AB - Both benign prostatic hyperplasia (BPH) and prostate cancer (PCa) are frequent diseases in middle-aged to elderly men worldwide. While both diseases are linked to abnormal growth of the prostate, the epidemiological and pathological features of these two prostate diseases are different. BPH nodules typically arise from the transitional zone, and, in contrast, PCa arises from the peripheral zone. Androgen deprivation therapy alone may not be sufficient to cure these two prostatic diseases due to its undesirable side effects. The alteration of androgen receptor-mediated inflammatory signals from infiltrating immune cells and prostate stromal/epithelial cells may play key roles in those unwanted events. Herein, this review will focus on the roles of androgen/androgen receptor signals in the inflammation-induced progression of BPH and PCa. PMID- 26594315 TI - Understanding melanoma stem cells. AB - Tumors are incredibly diverse and contain many different subpopulations of cells. The cancer stem cell (CSC) subpopulation is responsible for many aspects of tumorigenesis and has been shown to play an important role in melanoma development, progression, drug resistance and metastasis. However, it is becoming clear that tumor cell populations are dynamic and can be influenced by many factors, such as signals from the tumor microenvironment and somatic evolution. This review will present the current understanding of CSCs and the challenges of identifying and characterizing this dynamic cell population. The known characteristics and functions of melanoma stem cells, and the potential for therapeutic targeting of these cells in melanoma, will be discussed. PMID- 26594317 TI - Role of primary care providers in a pandemic - conflicting views and future opportunities. AB - In pandemic situations, primary care providers may be involved in a variety of roles related to disease surveillance, diagnosis and treatment, prevention, and patient education. This commentary describes the contextual factors that may influence primary care providers' perspectives on their pandemic roles and responsibilities. These factors include the natural evolution of the pandemic situation, with early uncertainty affecting decision-making and communication; the variation in typical practice patterns and clinical expertise across and within primary care providers; and the lack of representation of practicing primary care providers in pandemic planning and decision-making bodies. PMID- 26594316 TI - Converting biology into clinical benefit: lessons learned from BRAF inhibitors. AB - The identification and pharmacological targeting of activating BRAF mutations in melanoma has led to significant improvements in patient outcomes. This perspective paper illustrates the lessons learned from the study of BRAF mutations and the development of BRAF inhibitors. The relevance of these lessons to the development of future targeted therapies is highlighted. PMID- 26594319 TI - A salp bloom (Tunicata, Thaliacea) along the Apulian coast and in the Otranto Channel between March-May 2013. AB - Between March-May 2013 a massive Salpa maxima bloom was recorded by a citizen science study along the Ionian and Adriatic coast of the Salento peninsula (Italy). Citizen records were substantiated with field inspections along the coast and during an oceanographic campaign in the Otranto Channel. Salps clogged nets, impairing fishing activities along the coast. Swimmers were scared by the gelatinous appearance of the salps, and thought they were jellyfish. At the end of the bloom the dead bodies of the colonies, that were up to 6-7 m long, were accumulated along the coast and stirred by the waves, forming foams along dozens of kilometers of coast. The bloom also occurred at the Tremiti Islands, north of the Gargano Peninsula. The possible impacts of such events on the functioning of pelagic systems are discussed. PMID- 26594320 TI - A pre-zygotic barrier to hybridization in two con-generic species of scleractinian corals. AB - Hybridization is often cited as a potential source of evolutionary novelty in the order Scleractinia. While hybrid embryos can be produced in vitro, it has been difficult to identify adult hybrids in the wild. Here, we tested the potential for hybridization between two closely related species in the family Fungiidae. We mixed approximately 5000 eggs of Ctenactis echinata with sperm from Ctenactis crass. No hybrid embryos were produced. This observation adds to a growing body of evidence for pre-zygotic barriers to hybridization in corals and challenges the claim that hybridization is a major source of evolutionary novelty in the order. PMID- 26594318 TI - Stem cell therapy for amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the loss of motor neurons. Currently, no effective therapy is available to treat ALS, except for Riluzole, which has only limited clinical benefits. Stem-cell-based therapy has been intensively and extensively studied as a potential novel treatment strategy for ALS and has been shown to be effective, at least to some extent. In this article, we will review the current state of research on the use of stem cell therapy in the treatment of ALS and discuss the most promising stem cells for the treatment of ALS. PMID- 24741439 TI - Fiberoptic monitoring of central venous oxygen saturation (PediaSat) in small children undergoing cardiac surgery: continuous is not continuous. AB - BACKGROUND: Monitoring of superior vena cava saturation (ScvO 2) has become routine in the management of pediatric patients undergoing cardiac surgery. The objective of our study was to evaluate the correlation between continuous ScvO 2 by the application of a fiber-optic oximetry catheter (PediaSat) and intermittent ScvO 2 by using standard blood gas measurements. These results were compared to those obtained by cerebral near infrared spectroscopy (cNIRS). SETTING: Tertiary pediatric cardiac intensive care unit (PCICU). METHODS AND MAIN RESULTS: A retrospective study was conducted in consecutive patients who were monitored with a 4.5 or 5.5 F PediaSat catheter into the right internal jugular vein. An in vivo calibration was performed once the patient was transferred to the PCICU and re-calibration took place every 24 hours thereafter. Each patient had a NIRS placed on the forehead. Saturations were collected every 4 hours until extubation. Ten patients with a median age of 2.2 (0.13-8.5) years and a weight of 12.4 (3.9-24) kg were enrolled. Median sampling time was 32 (19-44) hours: 64 pairs of PediaSat and ScVO2 saturations showed a poor correlation (r=0.62, 95% CI 44-75; p<0.0001) and Bland Altman analysis for repeated measures showed an average difference of 0.34 with a standard deviation of 7,9 and 95% limits of agreement from -15 to 16. Thirty-six pairs of cNIRS and ScVO2 saturations showed a fair correlation (r=0.79, 95% CI 0.60-0.89; p<0.0001) an average difference of 1.4 with a standard deviation of 6 and 95% limits of agreement from -13 to 10. Analysis of median percentage differences between PediaSat and ScvO2 saturation over time revealed that, although not statistically significant, the change in percentage saturation differences was clinically relevant after the 8th hour from calibration (from -100 to +100%). CONCLUSION: PediaSat catheters showed unreliable performance in our cohort. It should be further investigated whether repeating calibrations every 8 hours may improve the accuracy of this system. CNIRS may provide similar results with a lower invasiveness. PMID- 26594322 TI - Biological network analysis with CentiScaPe: centralities and experimental dataset integration. AB - The growing dimension and complexity of available experimental data generating biological networks has increased the need for tools allowing to categorize nodes by their topological relevance in biological networks. Here we present CentiScaPe, a Cytoscape app specifically designed to calculate centrality indexes for the identification of the most important nodes of a network. CentiScaPe is a comprehensive suite of algorithms dedicated to network nodes centrality analysis, computing several centralities for undirected, directed and weighted networks. The results of the topological analysis can be also integrated with data sets from lab experiments, such as expression or phosphorylation levels of the proteins represented in the network, using the graphical features of the tool. This opens a new perspective in the analysis of biological networks, since integration of topological analysis with lab experimental data can increase the predictive power of a bioinformatical analysis. PMID- 25653840 TI - Journal subscription expenditure of UK higher education institutions. AB - The academic libraries of higher education institutions (HEIs) pay significant amounts of money each year for access to academic journals. The amounts paid are often not transparent especially when it comes to knowing how much is paid to specific publishers. Therefore data on journal subscription expenditure were obtained for UK HEIs using a series of Freedom of Information requests. Data were obtained for 153 HEIs' expenditure with ten publishers over a five-year period. The majority of institutions have provided figures but some are still outstanding. The data will be of interest to those who wish to understand the economics of scholarly communication and see the scale of payments flowing within the system. Further research could replicate the data collection in other jurisdictions. PMID- 26401263 TI - Countries' Biomedical Publications and Attraction Scores. A PubMed-based assessment. AB - Studying publication volumes at the country level is key to understanding and improving a country's research system. PubMed is a public search engine of publications in all life sciences areas. Here, we show how this search engine can be used to assess the outputs of life science-related research by country. We have measured the numbers of publications during different time periods based on the country of affiliation of the first authors. Moreover, we have designed scores, which we have named Attraction Scores, to appraise the relative focus either toward particular types of studies, such as clinical trials or reviews, or toward specific research areas, such as public health and pharmacogenomics, or toward specific topics, for instance embryonic stem cells; we have also investigated a possible use of these Attraction Scores in connection with regulatory policies. We have weighed the statistics against general indicators such as country populations and gross domestic products (GDP). During the 5-year period 2008-2012, the United States was the country with the highest number of publications and Denmark the one with the highest number of publications per capita. Among the 40 countries with the highest GDPs, Israel had the highest publications-to-GDP ratio. Among the 20 countries with the most publications, Japan had the highest Attraction Score for induced pluripotent stem (iPS) cells and Italy the highest proportion of review publications. More than 50% of publications in English were from countries in which English is not the primary language. We show an assorted and extensive collection of rankings and charts that will inform scholars and policymakers in studying and improving the research systems both at the national and international level. PMID- 26594326 TI - Bias in peer review: a case study. AB - Peer review is the "gold standard" for evaluating journal and conference papers, research proposals, on-going projects and university departments. However, it is widely believed that current systems are expensive, conservative and prone to various forms of bias. One form of bias identified in the literature is "social bias" linked to the personal attributes of authors and reviewers. To quantify the importance of this form of bias in modern peer review, we analyze three datasets providing information on the attributes of authors and reviewers and review outcomes: one from Frontiers - an open access publishing house with a novel interactive review process, and two from Spanish and international computer science conferences, which use traditional peer review. We use a random intercept model in which review outcome is the dependent variable, author and reviewer attributes are the independent variables and bias is defined by the interaction between author and reviewer attributes. We find no evidence of bias in terms of gender, or the language or prestige of author and reviewer institutions in any of the three datasets, but some weak evidence of regional bias in all three. Reviewer gender and the language and prestige of reviewer institutions appear to have little effect on review outcomes, but author gender, and the characteristics of author institutions have large effects. The methodology used cannot determine whether these are due to objective differences in scientific merit or entrenched biases shared by all reviewers. PMID- 25469231 TI - Pandemic 2009 Influenza A (H1N1) virus infection in cancer and hematopoietic stem cell transplant recipients; a multicenter observational study. AB - BACKGROUND: During March 2009 a novel Influenza A virus emerged in Mexico. We describe the clinical picture of the pandemic Influenza A (H1N1) Influenza in cancer patients during the 2009 influenza season. METHODS: Twelve centers participated in a multicenter retrospective observational study of cancer patients with confirmed infection with the 2009 H1N1 Influenza A virus (influenza like illness or pneumonia plus positive PCR for the 2009 H1N1 Influenza A virus in respiratory secretions). Clinical data were obtained by retrospective chart review and analyzed. RESULTS: From May to August 2009, data of 65 patients were collected. Median age was 51 years, 57 % of the patients were female. Most patients (47) had onco-hematological cancers and 18 had solid tumors. Cancer treatment mainly consisted of chemotherapy (46), or stem cell transplantation (SCT) (16). Only 19 of 64 patients had received the 2009 seasonal Influenza vaccine. Clinical presentation included pneumonia (43) and upper respiratory tract infection (22). Forty five of 58 ambulatory patients were admitted. Mechanical ventilation was required in 12 patients (18%). Treatment included oseltamivir monotherapy or in combination with amantadine for a median of 7 days. The global 30-day mortality rate was 18%. All 12 deaths were among the non vaccinated patients. No deaths were observed among the 19 vaccinated patients. Oxygen saturation <96% at presentation was a predictor of mortality (OR 19.5; 95%CI: 2.28 to 165.9). CONCLUSIONS: In our cancer patient population, the pandemic 2009 Influenza A (H1N1) virus was associated with high incidence of pneumonia (66%), and 30-day mortality (18.5%). Saturation <96% was significantly associated with death. No deaths were observed among vaccinated patients. PMID- 26594327 TI - Interactive lectures: Clickers or personal devices? AB - Audience response systems ('clickers') are frequently used to promote participation in large lecture classes, and evidence suggests that they convey a number of benefits to students, including improved academic performance and student satisfaction. The limitations of these systems (such as limited access and cost) can be overcome using students' personal electronic devices, such as mobile phones, tablets and laptops together with text message, web- or app-based polling systems. Using questionnaires, we compare student perceptions of clicker and smartphone based polling systems. We find that students prefer interactive lectures generally, but those that used their own device preferred those lectures over lectures using clickers. However, device users were more likely to report using their devices for other purposes (checking email, social media etc.) when they were available to answer polling questions. These students did not feel that this distracted them from the lecture, instead, concerns over the use of smartphones centred around increased battery usage and inclusivity for students without access to suitable technology. Our results suggest that students generally preferred to use their own devices over clickers, and that this may be a sensible way to overcome some of the limitations associated with clickers, although issues surrounding levels of distraction and the implications for retention and recall of information need further investigation. PMID- 26594328 TI - Tweets from the forest: using Twitter to increase student engagement in an undergraduate field biology course. AB - Twitter is a cold medium that allows users to deliver content-rich but small packets of information to other users, and provides an opportunity for active and collaborative communication. In an education setting, this social media tool has potential to increase active learning opportunities, and increase student engagement with course content. The effects of Twitter on learning dynamics was tested in a field biology course offered by a large Canadian University: 29 students agreed to take part in the Twitter project and quantitative and qualitative data were collected, including survey data from 18 students. Students published 200% more public Tweets than what was required, and interacted frequently with the instructor and teaching assistant, their peers, and users external to the course. Almost 80% of students stated that Twitter increased opportunities for among-group communication, and 94% of students felt this kind of collaborative communication was beneficial to their learning. Although students did not think they would use Twitter after the course was over, 77% of the students still felt it was a good learning tool, and 67% of students felt Twitter had a positive impact on how they engaged with course content. These results suggest social media tools such as Twitter can help achieve active and collaborative learning in higher education. PMID- 26594329 TI - A bioinformatics insight to rhizobial globins: gene identification and mapping, polypeptide sequence and phenetic analysis, and protein modeling. AB - Globins (Glbs) are proteins widely distributed in organisms. Three evolutionary families have been identified in Glbs: the M, S and T Glb families. The M Glbs include flavohemoglobins (fHbs) and single-domain Glbs (SDgbs); the S Glbs include globin-coupled sensors (GCSs), protoglobins and sensor single domain globins, and the T Glbs include truncated Glbs (tHbs). Structurally, the M and S Glbs exhibit 3/3-folding whereas the T Glbs exhibit 2/2-folding. Glbs are widespread in bacteria, including several rhizobial genomes. However, only few rhizobial Glbs have been characterized. Hence, we characterized Glbs from 62 rhizobial genomes using bioinformatics methods such as data mining in databases, sequence alignment, phenogram construction and protein modeling. Also, we analyzed soluble extracts from Bradyrhizobium japonicum USDA38 and USDA58 by (reduced + carbon monoxide (CO) minus reduced) differential spectroscopy. Database searching showed that only fhb, sdgb, gcs and thb genes exist in the rhizobia analyzed in this work. Promoter analysis revealed that apparently several rhizobial glb genes are not regulated by a -10 promoter but might be regulated by -35 and Fnr (fumarate-nitrate reduction regulator)-like promoters. Mapping analysis revealed that rhizobial fhbs and thbs are flanked by a variety of genes whereas several rhizobial sdgbs and gcss are flanked by genes coding for proteins involved in the metabolism of nitrates and nitrites and chemotaxis, respectively. Phenetic analysis showed that rhizobial Glbs segregate into the M, S and T Glb families, while structural analysis showed that predicted rhizobial SDgbs and fHbs and GCSs globin domain and tHbs fold into the 3/3- and 2/2 folding, respectively. Spectra from B. japonicum USDA38 and USDA58 soluble extracts exhibited peaks and troughs characteristic of bacterial and vertebrate Glbs thus indicating that putative Glbs are synthesized in B. japonicum USDA38 and USDA58. PMID- 26594331 TI - Combining complexity measures of EEG data: multiplying measures reveal previously hidden information. AB - Many studies have noted significant differences among human electroencephalograph (EEG) results when participants or patients are exposed to different stimuli, undertaking different tasks, or being affected by conditions such as epilepsy or Alzheimer's disease. Such studies often use only one or two measures of complexity and do not regularly justify their choice of measure beyond the fact that it has been used in previous studies. If more measures were added to such studies, however, more complete information might be found about these reported differences. Such information might be useful in confirming the existence or extent of such differences, or in understanding their physiological bases. In this study we analysed publically-available EEG data using a range of complexity measures to determine how well the measures correlated with one another. The complexity measures did not all significantly correlate, suggesting that different measures were measuring unique features of the EEG signals and thus revealing information which other measures were unable to detect. Therefore, the results from this analysis suggests that combinations of complexity measures reveal unique information which is in addition to the information captured by other measures of complexity in EEG data. For this reason, researchers using individual complexity measures for EEG data should consider using combinations of measures to more completely account for any differences they observe and to ensure the robustness of any relationships identified. PMID- 26594330 TI - The Resource Identification Initiative: A cultural shift in publishing. AB - A central tenet in support of research reproducibility is the ability to uniquely identify research resources, i.e., reagents, tools, and materials that are used to perform experiments. However, current reporting practices for research resources are insufficient to allow humans and algorithms to identify the exact resources that are reported or answer basic questions such as "What other studies used resource X?" To address this issue, the Resource Identification Initiative was launched as a pilot project to improve the reporting standards for research resources in the methods sections of papers and thereby improve identifiability and reproducibility. The pilot engaged over 25 biomedical journal editors from most major publishers, as well as scientists and funding officials. Authors were asked to include Research Resource Identifiers (RRIDs) in their manuscripts prior to publication for three resource types: antibodies, model organisms, and tools (including software and databases). RRIDs represent accession numbers assigned by an authoritative database, e.g., the model organism databases, for each type of resource. To make it easier for authors to obtain RRIDs, resources were aggregated from the appropriate databases and their RRIDs made available in a central web portal ( www.scicrunch.org/resources). RRIDs meet three key criteria: they are machine readable, free to generate and access, and are consistent across publishers and journals. The pilot was launched in February of 2014 and over 300 papers have appeared that report RRIDs. The number of journals participating has expanded from the original 25 to more than 40. Here, we present an overview of the pilot project and its outcomes to date. We show that authors are generally accurate in performing the task of identifying resources and supportive of the goals of the project. We also show that identifiability of the resources pre- and post-pilot showed a dramatic improvement for all three resource types, suggesting that the project has had a significant impact on reproducibility relating to research resources. PMID- 26594332 TI - CPIRD: A successful Thai programme to produce clinically competent medical graduates. AB - The programme titled "Collaborative Project to Increase Production of Rural Doctors" (CPIRD) is a rural medical education project launched in 1994 in Thailand. This study aimed to compare the academic performances in medical study over five years and the pass rates in national medical license examinations (MLE) between students enrolled in CPIRD and two other tracks. Grade point average (GPA) over five years and results of MLEs for four cohorts of students enrolled from 2003 to 2006 in Prince of Songkla University were collected from the registration department. A longitudinal analysis was used to compare the GPA over time for medical students enrolled in CPIRD and those from the national and direct regional tracks through generalized estimating equation (GEE) models. The MLE pass rates were compared using chi-square and fisher's exact tests as appropriate. Female students dominated the CPIRD group. GPAs in the first three years in the CPIRD group were significantly lower than those of the other two groups, this disparity narrowed in the fourth and fifth years. For step one of the MLE (basic sciences), cohorts 2003 and 2006 of the CPIRD group had a significantly lower pass rate than the other two groups but there was no significant difference in cohort 2004 and cohort 2005. The CPIRD step two and three MLE pass rates were not significantly different from the national track in all cohorts and lower than the direct track only for step two in cohort 2003 and step three in cohort 2006. The step three pass rate of the CPIRD group in cohort 2004 was significantly higher than the other two tracks. Despite weaker competency in basic science, the CPIRD was successful in forming clinical competency. PMID- 26594333 TI - Constellation Map: Downstream visualization and interpretation of gene set enrichment results. AB - Gene set enrichment analysis (GSEA) approaches are widely used to identify coordinately regulated genes associated with phenotypes of interest. Here, we present Constellation Map, a tool to visualize and interpret the results when enrichment analyses yield a long list of significantly enriched gene sets. Constellation Map identifies commonalities that explain the enrichment of multiple top-scoring gene sets and maps the relationships between them. Constellation Map can help investigators take full advantage of GSEA and facilitates the biological interpretation of enrichment results. AVAILABILITY: Constellation Map is freely available as a GenePattern module at http://www.genepattern.org. PMID- 26594334 TI - An unexpected effect of TNF-alpha on F508del-CFTR maturation and function. AB - Cystic fibrosis (CF) is a multifactorial disease caused by mutations in the cystic fibrosis transmembrane conductance regulator gene ( CFTR), which encodes a cAMP-dependent Cl (-) channel. The most frequent mutation, F508del, leads to the synthesis of a prematurely degraded, otherwise partially functional protein. CFTR is expressed in many epithelia, with major consequences in the airways of patients with CF, characterized by both fluid transport abnormalities and persistent inflammatory responses. The relationship between the acute phase of inflammation and the expression of wild type (WT) CFTR or F508del-CFTR is poorly understood. The aim of the present study was to investigate this effect. The results show that 10 min exposure to TNF-alpha (0.5-50ng/ml) of F508del-CFTR transfected HeLa cells and human bronchial cells expressing F508del-CFTR in primary culture (HBE) leads to the maturation of F508del-CFTR and induces CFTR chloride currents. The enhanced CFTR expression and function upon TNFalpha is sustained, in HBE cells, for at least 24 h. The underlying mechanism of action involves a protein kinase C (PKC) signaling pathway, and occurs through insertion of vesicles containing F508del-CFTR to the plasma membrane, with TNFalpha behaving as a corrector molecule. In conclusion, a novel and unexpected action of TNFalpha has been discovered and points to the importance of systematic studies on the roles of inflammatory mediators in the maturation of abnormally folded proteins in general and in the context of CF in particular. PMID- 26594336 TI - The Inherent Drawbacks of the Pressure to Publish in Health Sciences: Good or Bad Science. AB - In recent years, there has been a significant increase in the number of scientific publications- it is the era of "hunting the article". This commentary discusses the drawbacks of the pressure to publish that certainly contribute to the 'dark side' of science. In fact, health science career progression greatly relies on the number of scientific publications a researcher has, and in many cases these may be more valorized than the health services provided. Of course, scientific publications help to develop the skills of health care professionals, but as Einstein highlighted " not everything that counts can be counted, and not everything that can be counted counts". PMID- 26594335 TI - A ChIP on the shoulder? Chromatin immunoprecipitation and validation strategies for ChIP antibodies. AB - Chromatin immunoprecipitation (ChIP) is a technique widely used in the study of epigenetics and transcriptional regulation of gene expression. However, its antibody-centric nature exposes it to similar challenges faced by other antibody based procedures, of which the most prominent are issues of specificity and affinity in antigen recognition. As with other techniques that make use of antibodies, recent studies have shown the need for validation of ChIP antibodies in order to be sure they recognize the advertised protein or epitope. We summarize here the issues surrounding ChIP antibody usage, and highlight the toolkit of validation methods that can be employed by investigators looking to appraise these reagents. PMID- 26594337 TI - Case Report: Whole exome sequencing helps in accurate molecular diagnosis in siblings with a rare co-occurrence of paternally inherited 22q12 duplication and autosomal recessive non-syndromic ichthyosis. AB - Lamellar ichthyosis (LI), considered an autosomal recessive monogenic genodermatosis, has an incidence of approximately 1 in 250,000. Usually associated with mutations in the transglutaminase gene ( TGM1), mutations in six other genes have, less frequently, been shown to be causative. Two siblings, born in a collodion membrane, presented with fish like scales all over the body. Karyotyping revealed duplication of the chromosome arm on 22q12+ in the father and two siblings. Whole exome sequencing revealed a homozygous p.Gly218Ser variation in TGM1; a variation reported earlier in an isolated Finnish population in association with autosomal recessive non-syndromic ichthyosis. This concurrence of a potentially benign 22q12+ duplication and LI, both rare individually, is reported here likely for the first time. PMID- 26594339 TI - Deep Sequencing of the T-cell Receptor Repertoire Demonstrates Polyclonal T-cell Infiltrates in Psoriasis. AB - It is well known that infiltration of pathogenic T-cells plays an important role in psoriasis pathogenesis. However, the antigen specificity of these activated T cells is relatively unknown. Previous studies using T-cell receptor polymerase chain reaction technology (TCR-PCR) have suggested there are expanded T-cell receptor (TCR) clones in psoriatic skin, suggesting a response to an unknown psoriatic antigen. Here we describe the results of high-throughput deep sequencing of the entire alphabeta- and gammadelta- TCR repertoire in normal healthy skin and psoriatic lesional and non-lesional skin. From this study, we were able to determine that there is a significant increase in the abundance of unique beta- and gamma- TCR sequences in psoriatic lesional skin compared to non lesional and normal skin, and that the entire T-cell repertoire in psoriasis is polyclonal, with similar diversity to normal and non-lesional skin. Comparison of the alphabeta- and gammadelta- TCR repertoire in paired non-lesional and lesional samples showed many common clones within a patient, and these close were often equally abundant in non-lesional and lesional skin, again suggesting a diverse T cell repertoire. Although there were similar (and low) amounts of shared beta chain sequences between different patient samples, there was significantly increased sequence sharing of the gamma-chain in psoriatic skin from different individuals compared to those without psoriasis. This suggests that although the T-cell response in psoriasis is highly polyclonal, particular gammadelta- T-cell subsets may be associated with this disease. Overall, our findings present the feasibility of this technology to determine the entire alphabeta- and gammadelta- T-cell repertoire in skin, and that psoriasis contains polyclonal and diverse alphabeta- and gammadelta- T-cell populations. PMID- 26594340 TI - Creating 3D visualizations of MRI data: A brief guide. AB - While magnetic resonance imaging (MRI) data is itself 3D, it is often difficult to adequately present the results papers and slides in 3D. As a result, findings of MRI studies are often presented in 2D instead. A solution is to create figures that include perspective and can convey 3D information; such figures can sometimes be produced by standard functional magnetic resonance imaging (fMRI) analysis packages and related specialty programs. However, many options cannot provide functionality such as visualizing activation clusters that are both cortical and subcortical (i.e., a 3D glass brain), the production of several statistical maps with an identical perspective in the 3D rendering, or animated renderings. Here I detail an approach for creating 3D visualizations of MRI data that satisfies all of these criteria. Though a 3D 'glass brain' rendering can sometimes be difficult to interpret, they are useful in showing a more overall representation of the results, whereas the traditional slices show a more local view. Combined, presenting both 2D and 3D representations of MR images can provide a more comprehensive view of the study's findings. PMID- 26594338 TI - Is suvorexant a better choice than alternative hypnotics? AB - Suvorexant is a novel dual orexin receptor antagonist (DORA) newly introduced in the U.S. as a hypnotic, but no claim of superiority over other hypnotics has been offered. The manufacturer argued that the 5 and 10 mg starting doses recommended by the FDA might be ineffective. The manufacturer's main Phase III trials had not even included the 10 mg dosage, and the 5 mg dosage had not been tested at all in registered clinical trials at the time of approval. Popular alternative hypnotics may be similarly ineffective, since the FDA has also reduced the recommended doses for zolpidem and eszopiclone. The "not to exceed" suvorexant dosage of 20 mg does slightly increase sleep. Because of slow absorption, suvorexant has little effect on latency to sleep onset but some small effect in suppressing wakening after sleep onset and in improving sleep efficiency. The FDA would not approve the manufacturer's preferred 40 mg suvorexant dosage, because of concern with daytime somnolence, driving impairment, and possible narcolepsy like symptoms. In its immediate benefits-to-risks ratio, suvorexant is unlikely to prove superior to currently available hypnotics-possibly worse-so there is little reason to prefer over the alternatives this likely more expensive hypnotic less-tested in practice. Associations are being increasingly documented relating hypnotic usage with incident cancer, with dementia risks, and with premature death. There is some basis to speculate that suvorexant might be safer than alternative hypnotics in terms of cancer, dementia, infections, and mortality. These safety considerations will remain unproven speculations unless adequate long-term trials can be done that demonstrate suvorexant advantages. PMID- 26594341 TI - NetMatchStar: an enhanced Cytoscape network querying app. AB - We present NetMatchStar, a Cytoscape app to find all the occurrences of a query graph in a network and check for its significance as a motif with respect to seven different random models. The query can be uploaded or built from scratch using Cytoscape facilities. The app significantly enhances the previous NetMatch in style, performance and functionality. Notably NetMatchStar allows queries with wildcards. PMID- 26594342 TI - An evolutionary perspective on signaling peptides: toxic peptides are selected to provide information regarding the processing of the propeptide, which represents the phenotypic state of the signaling cell. AB - Structurally similar short peptides often serve as signals in diverse signaling systems. Similar peptides affect diverse physiological pathways in different species or even within the same organism. Assuming that signals provide information, and that this information is tested by the structure of the signal, it is curious that highly similar signaling peptides appear to provide information relevant to very different metabolic processes. Here we suggest a solution to this problem: the synthesis of the propeptide, and its post translational modifications that are required for its cleavage and the production of the mature peptide, provide information on the phenotypic state of the signaling cell. The mature peptide, due to its chemical properties which render it harmful, serves as a stimulant that forces cells to respond to this information. To support this suggestion, we present cases of signaling peptides in which the sequence and structure of the mature peptide is similar yet provides diverse information. The sequence of the propeptide and its post-translational modifications, which represent the phenotypic state of the signaling cell, determine the quantity and specificity of the information. We also speculate on the evolution of signaling peptides. We hope that this perspective will encourage researchers to reevaluate pathological conditions in which the synthesis of the mature peptide is abnormal. PMID- 26594343 TI - Murine Cep290 phenotypes are modified by genetic backgrounds and provide an impetus for investigating disease modifier alleles. AB - The study of primary cilia is of broad interest both in terms of disease pathogenesis and the fundamental biological role of these structures. Murine models of ciliopathies provide valuable tools for the study of these diseases. However, it is important to consider the precise phenotype of murine models and how dependant it is upon genetic background. Here we compare and contrast murine models of Cep290, a frequent genetic cause of Joubert syndrome in order to refine our concept of genotype-phenotype correlations. PMID- 26594345 TI - Hippocampal development and the dissociation of cognitive-spatial mapping from motor performance. AB - The publication of a recent article in F1000Research has led to discussion of, and correspondence on a broader issue that has a long history in the fields of neuroscience and psychology. Namely, is it possible to separate the cognitive components of performance, in this case spatial behavior, from the motoric demands of a task? Early psychological experiments attempted such a dissociation by studying a form of spatial maze learning where initially rats were allowed to explore a complex maze, termed "latent learning," before reinforcement was introduced. Those rats afforded the latent learning experience solved the task faster than those that were not, implying that cognitive map learning during exploration aided in the performance of the task once a motivational component was introduced. This form of latent learning was interpreted as successfully demonstrating that an exploratory cognitive map component was acquired irrespective of performing a learned spatial response under deprivation/motivational conditions. The neural substrate for cognitive learning was hypothesized to depend on place cells within the hippocampus. Subsequent behavioral studies attempted to directly eliminate the motor component of spatial learning by allowing rats to passively view the distal environment before performing any motor response using a task that is widely considered to be hippocampal-dependent. Latent learning in the water maze, using a passive placement procedure has met with mixed results. One constraint on viewing cues before performing a learned swimming response to a hidden goal has been the act of dynamically viewing distal cues while moving through a part of the environment where an optimal learned spatial escape response would be observed. We briefly review these past findings obtained with adult animals to the recent efforts of establishing a "behavioral topology" separating cognitive-spatial learning from tasks differing in motoric demands in an attempt to define when cognitive-spatial behavior emerges during development. PMID- 26594344 TI - Viscoelastic Properties of Hyaluronan in Physiological Conditions. AB - Hyaluronan (HA) is a high molecular weight glycosaminoglycan of the extracellular matrix (ECM), which is particularly abundant in soft connective tissues. Solutions of HA can be highly viscous with non-Newtonian flow properties. These properties affect the movement of HA-containing fluid layers within and underlying the deep fascia. Changes in the concentration, molecular weight, or even covalent modification of HA in inflammatory conditions, as well as changes in binding interactions with other macromolecules, can have dramatic effects on the sliding movement of fascia. The high molecular weight and the semi-flexible chain of HA are key factors leading to the high viscosity of dilute solutions, and real HA solutions show additional nonideality and greatly increased viscosity due to mutual macromolecular crowding. The shear rate dependence of the viscosity, and the viscoelasticity of HA solutions, depend on the relaxation time of the molecule, which in turn depends on the HA concentration and molecular weight. Temperature can also have an effect on these properties. High viscosity can additionally affect the lubricating function of HA solutions. Immobility can increase the concentration of HA, increase the viscosity, and reduce lubrication and gliding of the layers of connective tissue and muscle. Over time, these changes can alter both muscle structure and function. Inflammation can further increase the viscosity of HA-containing fluids if the HA is modified via covalent attachment of heavy chains derived from Inter-alpha-Inhibitor. Hyaluronidase hydrolyzes HA, thus reducing its molecular weight, lowering the viscosity of the extracellular matrix fluid and making outflow easier. It can also disrupt any aggregates or gel-like structures that result from HA being modified. Hyaluronidase is used medically primarily as a dispersion agent, but may also be useful in conditions where altered viscosity of the fascia is desired, such as in the treatment of muscle stiffness. PMID- 26594346 TI - Repository of mutations from Oman: The entry point to a national mutation database. AB - The Sultanate of Oman is a rapidly developing Muslim country with well-organized government-funded health care services, and expanding medical genetic facilities. The preservation of tribal structures within the Omani population coupled with geographical isolation has produced unique patterns of rare mutations. In order to provide diagnosticians and researchers with access to an up-to-date resource that will assist them in their daily practice we collated and analyzed all of the Mendelian disease-associated mutations identified in the Omani population. By the 1 (st) of August 2015, the dataset contained 300 mutations detected in over 150 different genes. More than half of the data collected reflect novel genetic variations that were first described in the Omani population, and most disorders with known mutations are inherited in an autosomal recessive fashion. A number of novel Mendelian disease genes have been discovered in Omani nationals, and the corresponding mutations are included here. The current study provides a comprehensive resource of the mutations in the Omani population published in scientific literature or reported through service provision that will be useful for genetic care in Oman and will be a starting point for variation databases as next-generation sequencing technologies are introduced into genetic medicine in Oman. PMID- 26594347 TI - Impact of a structured review session on medical student psychiatry subject examination performance. AB - INTRODUCTION: The National Board of Medical Examiners (NBME) subject examinations are used as a standardized metric for performance in required clerkships for third-year medical students. While several medical schools have implemented a review session to help consolidate knowledge acquired during the clerkship, the effects of such an intervention are not yet well-established. One prior study reported an improvement in NBME psychiatry examination scores with a 1.5-hour review session, but this study was limited by a small sample size and the fact that attendance at the review session was optional, leading to likely selection bias. METHODS: A 1.5-hour structured review session was conducted for medical students in the last week of each 4-week psychiatry clerkship between September 2014 and July 2015. Students were required to attend unless excused due to scheduling conflicts. Scores on the NBME psychiatry subject exam were compared with those of students taking the examination in the corresponding time period in each of the previous two academic years. RESULTS: 83 students took the exam during the experimental period, while 176 took the exam during the control period. Statistically significant improvements were found in mean score (p=0.03), mean for the two lowest scores in each group (p<0.0007), and percentage of students scoring 70 or less (p=0.03). Percentage of students achieving the maximum possible score (99) was higher in the experimental group, but did not reach significance (p=0.06). CONCLUSIONS: An end-of-clerkship review session led to increased mean scores on the NBME psychiatry subject examination, particularly for students at the lower end of the score range. Future research should investigate the impact of such an intervention in other specialties and other institutions. PMID- 26594348 TI - Design for learning - a case study of blended learning in a science unit. AB - Making material available through learning management systems is standard practice in most universities, but this is generally seen as an adjunct to the 'real' teaching, that takes place in face-to-face classes. Lecture attendance is poor, and it is becoming increasingly difficult to engage students, both in the material being taught and campus life. This paper describes the redevelopment of a large course in scientific practice and communication that is compulsory for all science students studying at our Melbourne and Malaysian campuses, or by distance education. Working with an educational designer, a blended learning methodology was developed, converting the environment provided by the learning management system into a teaching space, rather than a filing system. To ensure focus, topics are clustered into themes with a 'question of the week', a pre class stimulus and follow up activities. The content of the course did not change, but by restructuring the delivery using educationally relevant design techniques, the content was contextualised resulting in an integrated learning experience. Students are more engaged intellectually, and lecture attendance has improved. The approach we describe here is a simple and effective approach to bringing this university's teaching and learning into the 21 (st) century. PMID- 26594350 TI - Hot topics in biodiversity and climate change research. AB - With scientific and societal interest in biodiversity impacts of climate change growing enormously over the last decade, we analysed directions and biases in the recent most highly cited data papers in this field of research (from 2012 to 2014). The majority of this work relied on leveraging large databases of already collected historical information (but not paleo- or genetic data), and coupled these to new methodologies for making forward projections of shifts in species' geographical ranges, with a focus on temperate and montane plants. A consistent finding was that the pace of climate-driven habitat change, along with increased frequency of extreme events, is outpacing the capacity of species or ecological communities to respond and adapt. PMID- 26594349 TI - Recent advances in echocardiography for valvular heart disease. AB - Echocardiography is the imaging modality of choice for the assessment of patients with valvular heart disease. Echocardiographic advancements may have particular impact on the assessment and management of patients with valvular heart disease. This review will summarize the current literature on advancements, such as three dimensional echocardiography, strain imaging, intracardiac echocardiography, and fusion imaging, in this patient population. PMID- 26594351 TI - Cytotoxic granule secretion by lymphocytes and its link to immune homeostasis. AB - The granule-dependent cytotoxic activity of T and natural killer lymphocytes has progressively emerged as an important effector pathway not only for host defence but also for immune regulation. The analysis of an early-onset, severe, primary immune dysregulatory syndrome known as hemophagocytic lymphohistiocytosis (HLH) has been decisive in highlighting this latter role and identifying key effectors on the basis of gene mutation analyses and mediators in the maturation and secretion of cytotoxic granules. Studies of cytotoxicity-deficient murine counterparts have helped to define primary HLH as a syndrome in which uncontrolled T-cell activation in response to lymphocytic choriomeningitis virus infection results in excessive macrophage activation and inflammation-associated cytopenia. Recent recognition of late-onset HLH, which occurs in a variety of settings, in association with hypomorphic, monoallelic mutations in genes encoding components of the granule-dependent cytotoxic pathway or even in the absence of such mutations has broadened our view about the mechanisms that underlie the perturbation of immune homeostasis. These findings have led to the development of a model in which disease occurs when a threshold is reached through the accumulation of genetic and environmental risk factors. Nevertheless, validation of this model will require further investigations. PMID- 26594353 TI - Anti-dsDNA Antibodies are one of the many autoantibodies in systemic lupus erythematosus. AB - Anti-dsDNA antibodies are the most studied antibodies of the lupus-related autoantibodies. The dogma is that these are the most important autoantibodies in systemic lupus erythematosus. In this review, evidence is presented to show that these antibodies (as measured by modern clinical laboratories) are not the most important autoantibodies in the diagnosis of systemic lupus erythematosus, and are of limited value in clinical correlation and in predicting disease flares. In addition, they are not likely to be the initiating autoantibodies in lupus nephritis. Thus, several pervasively held beliefs on anti-dsDNA antibodies are not valid. We suggest that anti-dsDNA antibodies should be considered as just one of the many autoantibodies associated with systemic lupus erythematosus. PMID- 26594352 TI - Leishmania carbon metabolism in the macrophage phagolysosome- feast or famine? AB - A number of medically important microbial pathogens target and proliferate within macrophages and other phagocytic cells in their mammalian hosts. While the majority of these pathogens replicate within the host cell cytosol or non hydrolytic vacuolar compartments, a few, including protists belonging to the genus Leishmania, proliferate long-term within mature lysosome compartments. How these parasites achieve this feat remains poorly defined. In this review, we highlight recent studies that suggest that Leishmania virulence is intimately linked to programmed changes in the growth rate and carbon metabolism of the obligate intra-macrophage stages. We propose that activation of a slow growth and a stringent metabolic response confers resistance to multiple stresses (oxidative, temperature, pH), as well as both nutrient limitation and nutrient excess within this niche. These studies highlight the importance of metabolic processes as key virulence determinants in Leishmania. PMID- 26594354 TI - A Microfluidic Device for Multiplex Single-Nucleotide Polymorphism Genotyping. AB - Single-nucleotide polymorphisms (SNPs) are the most abundant type of genetic variations; they provide the genetic fingerprint of individuals and are essential for genetic biomarker discoveries. Accurate detection of SNPs is of great significance for disease prevention, diagnosis and prognosis, and for prediction of drug response and clinical outcomes in patients. Nevertheless, conventional SNP genotyping methods are still limited by insufficient accuracy or labor-, time , and resource-intensive procedures. Microfluidics has been increasingly utilized to improve efficiency; however, the currently available microfluidic genotyping systems still have shortcomings in accuracy, sensitivity, throughput and multiplexing capability. To address these challenges, we developed a multi-step SNP genotyping microfluidic device, which performs single-base extension of SNP specific primers and solid-phase purification of the extension products on a temperature-controlled chip. The products are ready for immediate detection by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), providing identification of the alleles at the target loci. The integrated device enables efficient and automated operation, while maintaining the high accuracy and sensitivity provided by MS. The multiplex genotyping capability was validated by performing rapid, accurate and simultaneous detection of 4 loci on a synthetic template. The microfluidic device has the potential to perform automatic, accurate, quantitative and high-throughput assays covering a broad spectrum of applications in biological and clinical research, drug development and forensics. PMID- 26594355 TI - Synthesis of 1,5-Dioxocanes via the Two-Fold C-O Bond Forming Nucleophilic 4+4 Cyclodimerization of Cycloprop-2-en-1-ylmethanols. AB - An efficient [4+4] cyclodimerization of cyclopropenemethanols operating via a two fold strain release-driven addition of alkoxides across the double bond of cyclopropenes was investigated. This chemo- and diastereoselective transformation provided previously unknown 2,7-dioxatricyclo[7.1.0.04,6]decane scaffolds. PMID- 26594356 TI - Laparoscopic Nissen Rossetti fundoplication: Possibility towards day care anti reflux surgeries. AB - INTRODUCTION: As we proceed towards more and more day care surgeries we always need to choose patients and procedures within a great deal of safety margin. Anti reflux surgeries are gaining more popularity and awareness and Laparoscopic Nissen Rosetti fundoplication is a safe and effective method of performing them. METHODS AND OBSERVATIONS: Our case series of 25 patients who underwent day care Laparoscopic Nissen Rossetti fundoplication done over a period of 3 years suggests the feasibility and safety of performing day care anti reflux surgeries with no complications. DISCUSSION: Surgical outcomes of procedure are unaffected and the main challenge faced remains pain relief and which can be effectively tackled by local blocks or plain NSAIDs. RESULTS: Laparoscopic Nissen Rossetti fundoplication is a safe procedure to be offered as day care anti-reflux surgery. We encourage more studies in this regards with appropriate blinding to enforce its possibility as day care surgery and help patients with early recovery and decreasing cost of surgeries. PMID- 26594357 TI - A randomized controlled experimental study comparing chitosan coated polypropylene mesh and ProceedTM mesh for abdominal wall defect closure. AB - BACKGROUND: Abdominal wall defects and hernias are commonly repaired with synthetic or biological materials. Adhesions and recurrences are a common problem. A study was conducted to compare Chitosan coated polypropylene mesh and a polypropylene-polydioxanone composite with oxidized cellulose coating mesh (ProceedTM) in repair of abdominal wall defect in a Rabbit hernia model. METHODS: A randomized controlled experimental study was done on twelve New Zealand white rabbits. A ventral abdominal defect was created in each of the rabbits. The rabbits were divided into two groups. In one group the defect was repaired with Chitosan coated polypropylene mesh and Proceed meshTM in the other. The rabbits were operated in two phases. They were followed up at four weeks and twelve weeks respectively after which the rabbits were sacrificed. They were evaluated by open exploration and histopathological examination. Their efficacy in reducing adhesion and ability of remodeling and tissue integration were studied. RESULTS: There was no statistical significance in the area of adhesion, the force required to remove the adhesions, tissue integration and remodeling between Chitosan and ProceedTM group. Histological analysis revealed that the inflammatory response, fibrosis, material degradation and remodeling were similar in both the groups. There were no hernias, wound infection or dehiscence in any of the studied animals. CONCLUSION: Chitosan coated polypropylene mesh was found to have similar efficacy to ProceedTM mesh. Chitosan coated polypropylene mesh, can act as an anti adhesive barrier when used in the repair of incisional hernias and abdominal wall defects. PMID- 26594358 TI - Longitudinal Functional Data Analysis. AB - We consider dependent functional data that are correlated because of a longitudinal-based design: each subject is observed at repeated times and at each time a functional observation (curve) is recorded. We propose a novel parsimonious modeling framework for repeatedly observed functional observations that allows to extract low dimensional features. The proposed methodology accounts for the longitudinal design, is designed to study the dynamic behavior of the underlying process, allows prediction of full future trajectory, and is computationally fast. Theoretical properties of this framework are studied and numerical investigations confirm excellent behavior in finite samples. The proposed method is motivated by and applied to a diffusion tensor imaging study of multiple sclerosis. PMID- 26594359 TI - Schema modes in eating disorders compared to a community sample. AB - BACKGROUND: The aim of this study was to examine the association between eating disorders (ED) and schema modes, and identify which specific schema modes are associated with particular eating disorders, including anorexia nervosa (AN), bulimia nervosa (BN) and other specified feeding or eating disorder (OSFED). METHODS: A total of forty seven women with eating disorders and 89 women from the community participated in this study. Eating disorder diagnosis was determined by a clinician treating the eating disorder and was confirmed on the basis of Body Mass Index (BMI) and the Eating Disorder Examination Questionnaire (EDE-Q). The Schema Mode Inventory (SMI) was used to explore the association between schema modes and eating disorder diagnostic status. RESULTS: A series t-tests revealed that when compared to the community sample, the ED group scored significantly higher on 10 out of 12 maladaptive schema modes, and significantly lower on both adaptive schema modes. A series of planned contrasts revealed that the AN, BN, and OSFED groups each scored significantly higher than the community sample group in the majority of maladaptive schema modes, with slight variations between groups. Further, AN, BN, and OSFED groups each scored significantly lower than the community sample group for the two SMI scores categorized as adaptive. All Cohen's d that reached significance ranged 0.55-2.24. CONCLUSIONS: The current study shows a tendency for females with eating disorders to rely on maladaptive schema modes more frequently, and more adaptive schema modes less frequently compared to a community sample. These findings provide initial empirical support for a schema mode model of eating disorders. PMID- 26594362 TI - Prospective comparison of a PCR assay and a microbiological culture technique for identification of pathogens from blood and non-blood samples in septic patients. AB - BACKGROUND: Molecular amplification techniques are suggested to be a useful adjunct in early detection of pathogens in septic patients. The aim was to study the feasibility of a polymerase chain reaction (PCR) assay compared to the standard microbiological culture (MC) technique in identification of pathogenic microorganisms from blood and non-blood samples in septic patients. METHODS: Samples for pathogen identification were taken during febrile septic episodes (SE) in 54 patients with sepsis and analyzed using both MC and PCR. Semi automated multiplex PCR, provided by Philips Medical Systems, was able to detect nine different pathogens. The accuracy of pathogen identification using PCR vs. MC as well as the time-saving effect of PCR on the potential decision-making process for antimicrobial therapy was evaluated. RESULTS: In a total of 258 samples taken during 87 SE, both methods yielded more pathogens from the non blood than blood samples (87 % vs. 45 %; p = 0.002). PCR identified more pathogens than MC in the blood samples (98 vs. 21; p < 0.0001), but not in other body fluids. In 35 SE, the potential decision on appropriate antimicrobial therapy based on PCR results could have been made 50 (median; interquartile range 35-87) hours earlier than decisions based on standard MC. CONCLUSIONS: In septic patients, multiplex PCR identified more pathogenic microorganisms isolated from the blood samples than the standard MC technique. In the non-blood samples, PCR was comparable to that of MC. PMID- 26594363 TI - Erratum to: Smartphone apps for orthopaedic sports medicine - a smart move? AB - [This corrects the article DOI: 10.1186/s13102-015-0017-6.]. PMID- 26594361 TI - Fluid responsiveness in acute circulatory failure. AB - Although fluid resuscitation of patients having acute circulatory failure is essential, avoiding unnecessary administration of fluids in these patients is also important. Fluid responsiveness (FR) is defined as the ability of the left ventricle to increase its stroke volume (SV) in response to fluid administration. The objective of this review is to provide the recent advances in the detection of FR and simplify the physiological basis, advantages, disadvantages, and cut off values for each method. This review also highlights the present gaps in literature and provides future thoughts in the field of FR. Static methods are generally not recommended for the assessment of FR. Dynamic methods for the assessment of FR depend on heart-lung interactions. Pulse pressure variation (PPV) and stroke volume variation (SVV) are the most famous dynamic measures. Less-invasive dynamic parameters include plethysmographic-derived parameters, variation in blood flow in large arteries, and variation in the diameters of central veins. Dynamic methods for the assessment of FR have many limitations; the most important limitation is spontaneous breathing activity. Fluid challenge techniques were able to overcome most of the limitations of the dynamic methods. Passive leg raising is the most popular fluid challenge method. More simple techniques have been recently introduced such as the mini-fluid challenge and 10 s fluid challenge. The main limitation of fluid challenge techniques is the need to trace the effect of the fluid challenges on SV (or any of its derivatives) using a real-time monitor. More research is needed in the field of FR taking into consideration not only the accuracy of the method but also the ease of implementation, the applicability on a wider range of patients, the time needed to apply each method, and the feasibility of its application by acute care physicians with moderate and low experience. PMID- 26594364 TI - Crystallography in the 21st century. AB - The field of crystallography, which has had a major impact on the sciences in the last 100 years, is continuing to expand scientific horizons as technical and conceptual boundaries are overcome. Structure-function-dynamics will become an integrated theme for many studies as will obtaining structures without the 'benevolent tyranny' of crystals. PMID- 26594360 TI - PEG-b-AGE Polymer Coated Magnetic Nanoparticle Probes with Facile Functionalization and Anti-fouling Properties for Reducing Non-specific Uptake and Improving Biomarker Targeting. AB - Non-specific surface adsorption of bio-macromolecules (e.g. proteins) on nanoparticles, known as biofouling, and the uptake of nanoparticles by the mononuclear phagocyte system (MPS) and reticuloendothelial system (RES) lead to substantial reduction in the efficiency of target-directed imaging and delivery in biomedical applications of engineered nanomaterials in vitro and in vivo. In this work, a novel copolymer consisting of blocks of poly ethylene glycol and allyl glycidyl ether (PEG-b-AGE) was developed for coating magnetic iron oxide nanoparticles (IONPs) to reduce non-specific protein adhesion that leads to formation of "protein corona" and uptake by macrophages. The facile surface functionalization was demonstrated by using targeting ligands of a small peptide of RGD or a whole protein of transferrin (Tf). The PEG-b-AGE coated IONPs exhibited anti-biofouling properties with significantly reduced protein corona formation and non-specific uptake by macrophages before and after the surface functionalization, thus improving targeting of RGD-conjugated PEG-b-AGE coated IONPs to integrins in U87MG glioblastoma and MDA-MB-231 breast cancer cells that overexpress alphavbeta3 integrins, and Tf-conjugated PEG-b-AGE coated IONPs to transferrin receptor (TfR) in D556 and Daoy medulloblastoma cancer cells with high overexpression of transferrin receptor, compared to respective control cell lines. Magnetic resonance imaging (MRI) of cancer cells treated with targeted IONPs with or without anti-biofouling PEG-b-AGE coating polymers demonstrated the target specific MRI contrast change using anti-biofouling PEG-b-AGE coated IONP with minimal off-targeted background compared to the IONPs without anti biofouling coating, promising the highly efficient active targeting of nanoparticle imaging probes and drug delivery systems and potential applications of imaging quantification of targeted biomarkers. PMID- 26594365 TI - Are X-rays the key to integrated computational materials engineering? AB - An IUCrJ paper by Levine et al. highlights the promise and challenge of 3D X-ray structural microscopy as a unique tool to test predictive models of materials behavior. PMID- 26594366 TI - Will measuring mechanical properties help us understand solid-state reactions? AB - In the solid-state photodimerization of cinnamic acid polymorphs, can mechanical properties tell us whether Schmidt 'minimal molecular movement' or Kaupp 'molecular migration' is more important? PMID- 26594367 TI - Proteins: interaction at a distance. AB - How do the surface side chains of a protein behave when it binds to another protein? Do they optimize interactions by crumpling inwards or by extending outwards? PMID- 26594368 TI - Structure-mechanical property correlations in mechanochromic luminescent crystals of boron difluoride dibenzoylmethane derivatives. AB - The structure and mechanical properties of crystalline materials of three boron difluoride dibenzoylmethane (BF2dbm) derivatives were investigated to examine the correlation, if any, among mechanochromic luminescence (ML) behaviour, solid state structure, and the mechanical behaviour of single crystals. Qualitative mechanical deformation tests show that the crystals of BF2dbm( (t) Bu)2 can be bent permanently, whereas those of BF2dbm(OMe)2 exhibit an inhomogeneous shearing mode of deformation, and finally BF2dbmOMe crystals are brittle. Quantitative mechanical analysis by nano-indentation on the major facets of the crystals shows that BF2dbm( (t) Bu)2 is soft and compliant with low values of elastic modulus, E, and hardness, H, confirming its superior suceptibility for plastic deformation, which is attributed to the presence of a multitude of slip systems in the crystal structure. In contrast, both BF2dbm(OMe)2 and BF2dbmOMe are considerably stiffer and harder with comparable E and H, which are rationalized through analysis of the structural attributes such as the intermolecular interactions, slip systems and their relative orientation with respect to the indentation direction. As expected from the qualitative mechanical behaviour, prominent ML was observed in BF2dbm( (t) Bu)2, whereas BF2dbm(OMe)2 exhibits only a moderate ML and BF2dbmOMe shows no detectable ML, all examined under identical conditions. These results confirm that the extent of ML in crystalline organic solid-state fluorophore materials can be correlated positively with the extent of plasticity (low recovery). In turn, they offer opportunities to design new and improved efficient ML materials using crystal engineering principles. PMID- 26594369 TI - Characterizing transverse coherence of an ultra-intense focused X-ray free electron laser by an extended Young's experiment. AB - Characterization of transverse coherence is one of the most critical themes for advanced X-ray sources and their applications in many fields of science. However, for hard X-ray free-electron laser (XFEL) sources there is very little knowledge available on their transverse coherence characteristics, despite their extreme importance. This is because the unique characteristics of the sources, such as the ultra-intense nature of XFEL radiation and the shot-by-shot fluctuations in the intensity distribution, make it difficult to apply conventional techniques. Here, an extended Young's interference experiment using a stream of bimodal gold particles is shown to achieve a direct measurement of the modulus of the complex degree of coherence of XFEL pulses. The use of interference patterns from two differently sized particles enables analysis of the transverse coherence on a single-shot basis without a priori knowledge of the instantaneous intensity ratio at the particles. For a focused X-ray spot as small as 1.8 um (horizontal) * 1.3 um (vertical) with an ultrahigh intensity that exceeds 10(18) W cm(-2) from the SPring-8 Angstrom Compact free-electron LAser (SACLA), the coherence lengths were estimated to be 1.7 +/- 0.2 um (horizontal) and 1.3 +/- 0.1 um (vertical). The ratios between the coherence lengths and the focused beam sizes are almost the same in the horizontal and vertical directions, indicating that the transverse coherence properties of unfocused XFEL pulses are isotropic. The experiment presented here enables measurements free from radiation damage and will be readily applicable to the analysis of the transverse coherence of ultra-intense nanometre-sized focused XFEL beams. PMID- 26594370 TI - Towards phasing using high X-ray intensity. AB - X-ray free-electron lasers (XFELs) show great promise for macromolecular structure determination from sub-micrometre-sized crystals, using the emerging method of serial femtosecond crystallography. The extreme brightness of the XFEL radiation can multiply ionize most, if not all, atoms in a protein, causing their scattering factors to change during the pulse, with a preferential 'bleaching' of heavy atoms. This paper investigates the effects of electronic damage on experimental data collected from a Gd derivative of lysozyme microcrystals at different X-ray intensities, and the degree of ionization of Gd atoms is quantified from phased difference Fourier maps. A pattern sorting scheme is proposed to maximize the ionization contrast and the way in which the local electronic damage can be used for a new experimental phasing method is discussed. PMID- 26594371 TI - Full elastic strain and stress tensor measurements from individual dislocation cells in copper through-Si vias. AB - Nondestructive measurements of the full elastic strain and stress tensors from individual dislocation cells distributed along the full extent of a 50 um-long polycrystalline copper via in Si is reported. Determining all of the components of these tensors from sub-micrometre regions within deformed metals presents considerable challenges. The primary issues are ensuring that different diffraction peaks originate from the same sample volume and that accurate determination is made of the peak positions from plastically deformed samples. For these measurements, three widely separated reflections were examined from selected, individual grains along the via. The lattice spacings and peak positions were measured for multiple dislocation cell interiors within each grain and the cell-interior peaks were sorted out using the measured included angles. A comprehensive uncertainty analysis using a Monte Carlo uncertainty algorithm provided uncertainties for the elastic strain tensor and stress tensor components. PMID- 26594372 TI - Changes in protein structure at the interface accompanying complex formation. AB - Protein interactions are essential in all biological processes. The changes brought about in the structure when a free component forms a complex with another molecule need to be characterized for a proper understanding of molecular recognition as well as for the successful implementation of docking algorithms. Here, unbound (U) and bound (B) forms of protein structures from the Protein Protein Interaction Affinity Database are compared in order to enumerate the changes that occur at the interface atoms/residues in terms of the solvent accessible surface area (ASA), secondary structure, temperature factors (B factors) and disorder-to-order transitions. It is found that the interface atoms optimize contacts with the atoms in the partner protein, which leads to an increase in their ASA in the bound interface in the majority (69%) of the proteins when compared with the unbound interface, and this is independent of the root-mean-square deviation between the U and B forms. Changes in secondary structure during the transition indicate a likely extension of helices and strands at the expense of turns and coils. A reduction in flexibility during complex formation is reflected in the decrease in B factors of the interface residues on going from the U form to the B form. There is, however, no distinction in flexibility between the interface and the surface in the monomeric structure, thereby highlighting the potential problem of using B factors for the prediction of binding sites in the unbound form for docking another protein. 16% of the proteins have missing (disordered) residues in the U form which are observed (ordered) in the B form, mostly with an irregular conformation; the data set also shows differences in the composition of interface and non-interface residues in the disordered polypeptide segments as well as differences in their surface burial. PMID- 26594373 TI - Crystal chemistry and photomechanical behavior of 3,4-dimethoxycinnamic acid: correlation between maximum yield in the solid-state topochemical reaction and cooperative molecular motion. AB - A new monoclinic polymorph, form II (P21/c, Z = 4), has been isolated for 3,4 dimethoxycinnamic acid (DMCA). Its solid-state 2 + 2 photoreaction to the corresponding alpha-truxillic acid is different from that of the first polymorph, the triclinic form I ([Formula: see text], Z = 4) that was reported in 1984. The crystal structures of the two forms are rather different. The two polymorphs also exhibit different photomechanical properties. Form I exhibits photosalient behavior but this effect is absent in form II. These properties can be explained on the basis of the crystal packing in the two forms. The nanoindentation technique is used to shed further insights into these structure-property relationships. A faster photoreaction in form I and a higher yield in form II are rationalized on the basis of the mechanical properties of the individual crystal forms. It is suggested that both Schmidt-type and Kaupp-type topochemistry are applicable for the solid-state trans-cinnamic acid photodimerization reaction. Form I of DMCA is more plastic and seems to react under Kaupp-type conditions with maximum molecular movements. Form II is more brittle, and its interlocked structure seems to favor Schmidt-type topochemistry with minimum molecular movement. PMID- 26594374 TI - Single-molecule imaging with longer X-ray laser pulses. AB - During the last five years, serial femtosecond crystallography using X-ray laser pulses has been developed into a powerful technique for determining the atomic structures of protein molecules from micrometre- and sub-micrometre-sized crystals. One of the key reasons for this success is the 'self-gating' pulse effect, whereby the X-ray laser pulses do not need to outrun all radiation damage processes. Instead, X-ray-induced damage terminates the Bragg diffraction prior to the pulse completing its passage through the sample, as if the Bragg diffraction were generated by a shorter pulse of equal intensity. As a result, serial femtosecond crystallography does not need to be performed with pulses as short as 5-10 fs, but can succeed for pulses 50-100 fs in duration. It is shown here that a similar gating effect applies to single-molecule diffraction with respect to spatially uncorrelated damage processes like ionization and ion diffusion. The effect is clearly seen in calculations of the diffraction contrast, by calculating the diffraction of the average structure separately to the diffraction from statistical fluctuations of the structure due to damage ('damage noise'). The results suggest that sub-nanometre single-molecule imaging with 30-50 fs pulses, like those produced at currently operating facilities, should not yet be ruled out. The theory presented opens up new experimental avenues to measure the impact of damage on single-particle diffraction, which is needed to test damage models and to identify optimal imaging conditions. PMID- 26594375 TI - Supramolecular interactions in the solid state. AB - In the last few decades, supramolecular chemistry has been at the forefront of chemical research, with the aim of understanding chemistry beyond the covalent bond. Since the long-range periodicity in crystals is a product of the directionally specific short-range intermolecular interactions that are responsible for molecular assembly, analysis of crystalline solids provides a primary means to investigate intermolecular interactions and recognition phenomena. This article discusses some areas of contemporary research involving supramolecular interactions in the solid state. The topics covered are: (1) an overview and historical review of halogen bonding; (2) exploring non-ambient conditions to investigate intermolecular interactions in crystals; (3) the role of intermolecular interactions in morphotropy, being the link between isostructurality and polymorphism; (4) strategic realisation of kinetic coordination polymers by exploiting multi-interactive linker molecules. The discussion touches upon many of the prerequisites for controlled preparation and characterization of crystalline materials. PMID- 26594376 TI - Report on a transborder spread of carbapenemase-producing bacteria by a patient injured during Euromaidan, Ukraine. AB - Spread of carbapenemase-producing bacteria has been described all over the world. This phenomenon may be accelerated by many factors, including wars and natural disasters. In this report, we described an NDM-1-producing Klebsiella pneumonia ST11 recovered from a patient injured during the Maidan revolution in Ukraine. To our knowledge, this is the first report of a carbapenemase-producing Enterobacteriaceae in Ukraine and one of several reports describing wound colonization/infection of humans injured during war. PMID- 26594377 TI - Erratum to: Accrediting retail drug shops to strengthen Tanzania's public health system: an ADDO case study. AB - [This corrects the article DOI: 10.1186/s40545-015-0044-4.]. PMID- 26594378 TI - Multi-contrast submillimetric 3 Tesla hippocampal subfield segmentation protocol and dataset. AB - The hippocampus is composed of distinct anatomical subregions that participate in multiple cognitive processes and are differentially affected in prevalent neurological and psychiatric conditions. Advances in high-field MRI allow for the non-invasive identification of hippocampal substructure. These approaches, however, demand time-consuming manual segmentation that relies heavily on anatomical expertise. Here, we share manual labels and associated high-resolution MRI data (MNI-HISUB25; submillimetric T1- and T2-weighted images, detailed sequence information, and stereotaxic probabilistic anatomical maps) based on 25 healthy subjects. Data were acquired on a widely available 3 Tesla MRI system using a 32 phased-array head coil. The protocol divided the hippocampal formation into three subregions: subicular complex, merged Cornu Ammonis 1, 2 and 3 (CA1-3) subfields, and CA4-dentate gyrus (CA4-DG). Segmentation was guided by consistent intensity and morphology characteristics of the densely myelinated molecular layer together with few geometry-based boundaries flexible to overall mesiotemporal anatomy, and achieved excellent intra-/inter-rater reliability (Dice index >=90/87%). The dataset can inform neuroimaging assessments of the mesiotemporal lobe and help to develop segmentation algorithms relevant for basic and clinical neurosciences. PMID- 26594379 TI - Biological, ecological, conservation and legal information for all species and subspecies of Australian bird. AB - We introduce a dataset of biological, ecological, conservation and legal information for every species and subspecies of Australian bird, 2056 taxa or populations in total. Version 1 contains 230 fields grouped under the following headings: Taxonomy & nomenclature, Phylogeny, Australian population status, Conservation status, Legal status, Distribution, Morphology, Habitat, Food, Behaviour, Breeding, Mobility and Climate metrics. It is envisaged that the dataset will be updated periodically with new data for existing fields and the addition of new fields. The dataset has already had, and will continue to have applications in Australian and international ornithology, especially those that require standard information for a large number of taxa. PMID- 26594380 TI - Construction, complete sequence, and annotation of a BAC contig covering the silkworm chorion locus. AB - The silkmoth chorion was studied extensively by F.C. Kafatos' group for almost 40 years. However, the complete structure of the chorion locus was not obtained in the genome sequence of Bombyx mori published in 2008 due to repetitive sequences, resulting in gaps and an incomplete view of the locus. To obtain the complete sequence of the chorion locus, expressed sequence tags (ESTs) derived from follicular epithelium cells were used as probes to screen a bacterial artificial chromosome (BAC) library. Seven BACs were selected to construct a contig which covered the whole chorion locus. By Sanger sequencing, we successfully obtained complete sequences of the chorion locus spanning 871,711 base pairs on chromosome 2, where we annotated 127 chorion genes. The dataset reported here will recruit more researchers to revisit one of the oldest model systems which has been used to study developmentally regulated gene expression. It also provides insights into egg development and fertilization mechanisms and is relevant to applications related to improvements in breeding procedures and transgenesis. PMID- 26594381 TI - A resource of ribosomal RNA-depleted RNA-Seq data from different normal adult and fetal human tissues. AB - Gene expression is the most fundamental level at which the genotype leads to the phenotype of the organism. Enabled by ultra-high-throughput next-generation DNA sequencing, RNA-Seq involves shotgun sequencing of fragmented RNA transcripts by next-generation sequencing followed by in silico assembly, and is rapidly becoming the most popular method for gene expression analysis. Poly[A]+ RNA-Seq analyses of normal human adult tissue samples such as Illumina's Human BodyMap 2.0 Project and the RNA-Seq atlas have provided a useful global resource and framework for comparisons with diseased tissues such as cancer. However, these analyses have failed to provide information on poly[A]-RNA, which is abundant in our cells. The most recent advances in RNA-Seq analyses use ribosomal RNA depletion to provide information on both poly[A]+ and poly[A]-RNA. In this paper, we describe the use of Illumina's HiSeq 2000 to generate high quality rRNA depleted RNA-Seq datasets from human fetal and adult tissues. The datasets reported here will be useful in understanding the different expression profiles in different tissues. PMID- 26594382 TI - Recreation, transportation or labour saving? Examining the association between household asset ownership and body mass index among Ghanaian women. AB - BACKGROUND: In most of the developing world, ownership of modern household assets such as television sets, refrigerators, microwave ovens and washing machines is becoming common. Ownership of these household assets, however, promotes sedentary behaviour which has implications for obesity and non-communicable disease conditions such as hypertension, diabetes, stroke and other cardiovascular conditions. Additionally, increased household asset ownership is an indicator of socio-economic status and is also associated with obesity promoting dietary behaviours especially in urban areas. Very few studies have examined the relationship between household asset ownership and obesity in sub-Saharan Africa where asset ownership is becoming a norm. This paper examined the relationship between ownership of different types of household assets and Body Mass Index (BMI) among a nationally representative sample of Ghanaian women. METHODS: The study analysed secondary data from the 2008 Ghana Demographic and Health Survey (GDHS) involving a total of 4916 women aged 15-49 years. The analytical sample consist of 4010 (weighted sample) non-pregnant females who had valid data on all the variables used in the analyses. The BMI of the women was used as the dependent variable with three categories of normal weight, overweight and obese based on the standard World Health Organization (WHO) classifications. Multinomial logistic regression models were specified to examine the relationship between ownership of household assets and BMI. RESULTS: Obesity was more common among women whose household owned a television-15.60 %, DVD/VCD-18.58 %, computer 20.70 %, refrigerator-17.16 % and washing machine-27.43 %, but less common among women whose household owned a motorcycle/scooter-7.74 % and a bicycle-7.92 %. Household ownership of DVD was significantly associated with increased odds of obesity (OR = 1.59, P < 0.01) while ownership of a motor cycle/scooter (OR = 2.05, P <0.001), a refrigerator (OR = 1.33, P < 0.05), and a television set (OR = 1.27, P < 0.10) were associated with higher odds of overweight. Ownership of each additional household asset was also associated with 15 % and 25 % higher odds of overweight and obesity respectively. CONCLUSION: The findings indicate that at least one asset among the various domains of household assets examined is associated with either overweight or obesity among Ghanaian women. Also, increased household asset ownership is associated with increased odds of overweight and obesity. Interventions that aim at reducing sedentary and unhealthy dietary behaviours in the phase of increasing asset ownership maybe helpful in addressing the rising prevalence of obesity among Ghanaian women. PMID- 26594384 TI - The Mouse That Trolled: The Long and Tortuous History of a Gene Mutation Patent That Became an Expensive Impediment to Alzheimer's Research. PMID- 26594383 TI - Implied functional crossed cerebello-cerebral diaschisis and interhemispheric compensation during hand grasping more than 20 years after unilateral cerebellar injury in early childhood. AB - BACKGROUND: Crossed cerebello-cerebral diaschisis (CCCD) conventionally refers to decreased resting cerebral activity caused by injury to the contralateral cerebellum. We investigated whether functional activation of a contralesional cerebral cortical region controlling a specific task is reduced during task performance in a patient with a unilateral cerebellar lesion. We also examined functional compensation by the corresponding ipsilesional cerebral cortex. It was hypothesized that dysfunction of the primary sensorimotor cortex (SM1) contralateral to the cerebellar lesion would be detected together with a compensatory increase in neural activity of the ipsilesional SM1. To test these possibilities, we conducted non-invasive functional neuroimaging techniques for bilateral SM1 during hand grasping, a task known to activate predominantly the SM1 contralateral to the grasping hand. Activity in SM1 during hand grasping was measured electrophysiologically by magnetoencephalography and hemodynamically by near-infrared spectroscopy in an adult with mild right hemiataxia associated with a large injury of the right cerebellum due to resection of a tumor in early childhood. RESULTS: During left hand grasping, increased neural activity was detected predominantly in the right SM1, the typical developmental pattern. In contrast, neural activity increased in the bilateral SM1 with slight right-side dominance during right (ataxic) hand grasping. CONCLUSIONS: This study reported a case that implied functional CCCD and compensatory neural activity in the SM1 during performance of a simple hand motor task in an adult with unilateral cerebellar injury and mild hemiataxia 24 years prior to the study without rehabilitative interventions. This suggests that unilateral cerebellar injuries in early childhood may result in persistent functional abnormalities in the cerebrum into adulthood. Therapeutic treatments that target functional CCCD and interhemispheric compensation might be effective for treating ataxia due to unilateral cerebellar damage. PMID- 26594385 TI - Activation of peroxisome proliferator-activated receptor gamma induces anti inflammatory properties in the chicken free avian respiratory macrophages. AB - BACKGROUND: Activation of peroxisome proliferator activated receptor gamma (PPAR gamma) in the alveolar macrophages (AM) by selective synthetic PPAR gamma ligands, improves the ability of the cells to resolve inflammation. In birds, respiratory macrophages are known as free avian respiratory macrophages (FARM) and show distinct functional differences from AM. The effects of treating FARM with PPAR gamma ligands are unclear. METHODS: FARM were harvested by lavage of chicken respiratory tract and their morphology assessed at microscopic level. The effects of PPAR gamma agonists on the FARM in vitro viability, phagocytic capacity and proinflammatory cytokine (TNF-alpha) production were assessed. RESULTS: FARM had eccentric nucleus and plasma membrane ruffled with filopodial extensions. Ultrastructurally, numerous vesicular bodies presumed to be lysosomes were present. FARM treated with troglitazone, a selective PPAR gamma agonist, had similar in vitro viability with untreated FARM. However, treated FARM co-cultured with polystyrene particles, internalized more particles with a mean volume density of 41 % compared to that of untreated FARM of 21 %. Further, treated FARM significantly decreased LPS-induced TNF-alpha production in a dose dependent manner. CONCLUSION: Results from this study show that PPAR gamma synthetic ligands enhance phagocytic ability of FARM. Further the ligands attenuate production of proinflammatory cytokines in the FARM, suggesting potential therapeutic application of PPAR gamma ligands in the management of respiratory inflammatory disorders in the poultry industry. PMID- 26594386 TI - Crystal structures of two (+/-)-exo-N-isobornyl-acetamides. AB - The title compounds consist of a bornane skeleton with attached acetamide, C12H21NO (+/-)-(1) {systematic name: (+/-)-N-[(1RS,2RS,4RS)-1,7,7-tri-methylbi cyclo-[2.2.1]heptan-2-yl]acetamide}, and chloro-acetamide, C12H20ClNO (+/-)-(2) {systematic name: (+/-)-2-chloro-N-[(1RS,2RS,4RS)-1,7,7-tri-methylbi-cyclo [2.2.1]heptan-2-yl]-acetamide}, functionalities to the 2-exo-position. The crystal structure of the first monoclinic polymorph of (+/-)-(1) has been reported previously [Ung et al. (2014 ?). Monatsh. Chem. 145, 983-992]. Compound (+/-)-(1) crystallizes in the space group P21/n with two independent mol-ecules in the asymmetric unit, in contrast to the above-mentioned polymorph which crystallized in the space group C2/c with one mol-ecule in the asymmetric unit. In the title compounds, the bicyclic bornane moieties have normal geometries. In the crystals of both compounds, mol-ecules are linked by N-H?O hydrogen bonds, reinforced by C-H?O contacts, forming trans-amide chains propagating along the a axis direction. In the case of compound (+/-)-(1), neighbouring chains are linked by further C-H?O contacts, forming double-chain ribbons along [100]. PMID- 26594387 TI - A monoclinic polymorph of 4-(2H-1,3-benzodioxol-5-yl)-1-(4-methyl-phen-yl)-1H pyrazol-5-amine. AB - The title compound, C17H15N3O2, is a monoclinic polymorph (P21/c with Z' = 1) of the previously reported triclinic (P-1 with Z' = 2) form [Gajera et al. (2013 ?). Acta Cryst. E69, o736-o737]. The mol-ecule in the monoclinic polymorph features a central pyrazolyl ring with an N-bound p-tolyl group and a C-bound 1,3 benzodioxolyl fused-ring system on either side of the C atom bearing the amino group. The dihedral angles between the central ring and the N- and C-bound rings are 50.06 (5) and 27.27 (5) degrees , respectively. The angle between the pendent rings is 77.31 (4) degrees , indicating the mol-ecule has a twisted conformation. The five-membered dioxolyl ring has an envelope conformation with the methyl-ene C atom being the flap. The relative disposition of the amino and dioxolyl substituents is syn. One of the independent mol-ecules in the triclinic form has a similar syn disposition but the other has an anti arrangement of these substituents. In the crystal structure of the monoclinic form, mol-ecules assemble into supra-molecular helical chains via amino-pyrazolyl N-H?N hydrogen bonds. These are linked into layers via C-H?pi inter-actions, and layers stack along the a axis with no specific inter-actions between them. PMID- 26594388 TI - Crystal structures of 1-bromo-3,5-bis-(4,4-dimethyl-1,3-oxazolin-2-yl)benzene 0.15-hydrate and 3,5-bis-(4,4-dimethyl-1,3-oxazolin-2-yl)-1-iodo-benzene. AB - The bromo and iodo derivatives of a meta-bis-(1,3-oxazolin-2-yl)-substituted benzene, C16H19BrN2O2.0.15H2O (1) and C16H19IN2O2 (2), have been prepared and studied in terms of their mol-ecular and crystal structures. While the former crystallizes as a sub-hydrate, with 0.15 formula units of water and shows an almost all-planar arrangement of the three ring systems, the latter crystallizes solvate-free with the flanking heterocycles twisted considerably with respect to the central arene. Non-covalent contacts include parallel-displaced pi-pi inter actions and (non-classical) hydrogen bonding for both (1) and (2), as well as relatively short I?N contacts for (2). PMID- 26594389 TI - Comparison of the crystal structures of 4,4'-bis-[3-(4-methyl-piperidin-1-yl)prop 1-yn-1-yl]-1,1'-biphenyl and 4,4'-bis-[3-(2,2,6,6-tetra-methyl-piperidin-1 yl)prop-1-yn-1-yl]-1,1'-biphen-yl. AB - As part of a comprehensive program to discover alpha9alpha10 nicotinic acetyl choline receptor antagonists, the title compounds C30H36N2, (I), and C36H48N2, (II), were synthesized by coupling 4,4'-bis-(3-bromo-prop-1-yn-1-yl)-1,1' biphenyl with 4-methyl-piperidine and 2,2,6,6-tetra-methyl-piperidine, respectively, in aceto-nitrile at room temperature. In compound (I), the biphenyl system has a twisted conformation with a dihedral angle of 26.57 (6) degrees between the two phenyl rings of the biphenyl moiety, while in compound (II), the biphenyl moiety sits on a crystallographic inversion centre so the two phenyl rings are exactly coplanar. The terminal piperidine rings in both compound (I) and compound (II) are in the chair conformation. In compound (I), the dihedral angles about the ethynyl groups between the planes of the phenyl rings and the piperidine ring N atoms are 37.16 (16) and 14.20 (17) degrees . In compound (II), the corresponding dihedral angles are both 61.48 (17) degrees . There are no noteworthy inter-molecular inter-actions in (I), but in (II) there is a small pi overlap between inversion-related mol-ecules (1 - x, 1 - y, 1 - z), with an inter planar spacing of 3.553 (3) A and centroid-to-centroid separation of 3.859 (4) A. PMID- 26594390 TI - Structure and spectroscopic properties of N,S-coordinating 2-methyl-sulfanyl-N [(1H-pyrrol-2-yl)methyl-idene]aniline methanol monosolvate. AB - The reaction of pyrrole-2-carboxaldehyde and 2-(methyl-sulfan-yl)aniline in refluxing methanol gave an olive-green residue in which yellow crystals of the title compound, C12H12N2S.CH3OH, were grown from slow evaporation of methanol at 263 K. In the crystal, hydrogen-bonding inter-actions link the aniline mol-ecule and a nearby methanol solvent mol-ecule. These units are linked by a pair of weak C-H?Omethanol interactions, forming inversion dimers consisting of two main molecules and two solvent molecules. PMID- 26594391 TI - Crystal structure of dimethyl 3,3'-[(4-fluoro-phen-yl)methyl-ene]bis-(1H-indole-2 carboxyl-ate). AB - In the title compound, C27H21FN2O4, the mean planes of the indole ring systems (r.m.s. deviations = 0.0263 and 0.0160 A) are approximately perpendic-ular to one another, making a dihedral angle of 84.0 (5) degrees ; the fluoro-benzene ring is twisted with respect to the mean planes of the two indole ring systems at 89.5 (5) and 84.6 (3) degrees . In the crystal, pairs of N-H?O hydrogen bonds link the mol-ecules into inversion dimers, which are further linked by N-H?O hydrogen bonds into supra-molecular chains propagated along the b-axis direction. Weak C H?pi inter-actions are observed between neighbouring chains. PMID- 26594392 TI - Crystal structure of [MU2-1,1'-bis-(di-phenyl-phos-phanyl)ferrocene-kappa(2) P:P']bis-[(pyrrolidine-1-carbo-dithioato-kappaS)gold(I)]. AB - The asymmetric unit of the title compound, {(C34H28FeP2)[Au(C5H8NS2)]2}, comprises half a mol-ecule, with the full mol-ecule being generated by the application of a centre of inversion. The independent Au(I) atom is coordinated by thiol-ate S and phosphane P atoms that define an approximate linear geometry [S-Au-P = 169.35 (3) degrees ]. The deviation from the ideal linear is traced to the close approach of the (intra-molecular) non-coordinating thione S atom [Au?S = 3.1538 (8) A]. Supra-molecular layers parallel to (100) feature in the crystal packing, being sustained by phen-yl-thione C-H?S inter-actions, with the non coordinating thione S atom in the role of a dual acceptor. Layers stack with no specific inter-actions between them. PMID- 26594393 TI - Comparison crystal structure conformations of two structurally related biphenyl analogues: 4,4'-bis-[3-(pyrrolidin-1-yl)prop-1-yn-1-yl]-1,1'-biphenyl and 4,4' bis-{3-[(S)-2-methyl-pyrrolidin-1-yl]prop-1-yn-1-yl}-1,1'-biphen-yl. AB - The title compounds, C26H28N2, (I), and C28H32N2, (II), were designed based on the structure of the potent alpha9alpha10 nicotinic acetyl-choline receptor antagonist ZZ161C {1,1'-[[1,1'-biphen-yl]-4,4'-diylbis(prop-2-yne-3,1-di-yl)]bis (3,4-di-methyl-pyridin-1-ium) bromide}. In order to improve the druglikeness properties of ZZ161C for potential oral administration, the title compounds (I) and (II) were prepared by coupling 4,4'-bis-(3-bromo-prop-1-yn-1-yl)-1,1' biphenyl with pyrrol-idine, (I), and (S)-2-methyl-pyrrolidine, (II), respectively, in aceto-nitrile at room temperature. The asymmetric unit of (I) contains two half mol-ecules that each sit on sites of crystallographic inversion. As a result, the biphenyl ring systems in compound (I) are coplanar. The biphenyl ring system in compound (II), however, has a dihedral angle of 28.76 (11) degrees . In (I), the two independent mol-ecules differ in the orientation of the pyrrolidine ring (the nitro-gen lone pair points towards the biphenyl rings in one mol-ecule, but away from the rings in the other). The torsion angles about the ethynyl groups between the planes of the phenyl rings and the pyrrolidine ring N atoms are 84.15 (10) and -152.89 (10) degrees . In compound (II), the corresponding torsion angles are 122.0 (3) and 167.0 (3) degrees , with the nitro-gen lone pairs at both ends of the mol-ecule directed away from the central biphenyl rings. PMID- 26594394 TI - Crystal structure of 4-(meth-oxy-carbon-yl)phenyl-boronic acid. AB - In the title compound, C8H9BO4, the meth-oxy-carbonyl group is rotated out of the plane of the benzene ring by 7.70 (6) degrees . In the crystal, mol-ecules are linked via pairs of O-H?O hydrogen bonds, involving the boronic acid OH groups, forming inversion dimers. The dimers are linked via O-H?O hydrogen bonds, involving a boronic acid OH group and the carbonyl O atom, forming undulating sheets parallel to (10-2). Within the sheets there are also C-H?O hydrogen bonds present, also involving the carbonyl O atom. The sheets are linked via C-H?pi and offset face-to-face pi-inter-actions between inversion-related mol-ecules [inter centroid distance = 3.7843 (16) A, inter-planar distance = 3.3427 (4) A and offset = 1.744 A], forming a three-dimensional structure. PMID- 26594395 TI - Redetermination of the crystal structure of catena-poly[[[bis-(ethyl-enedi-amine) platinum(II)]-MU-iodido-[bis-(ethyl-enedi-amine)-platinum(IV)]-MU-iodido] tetra kis-(octane-1-sulfonate) dihydrate]. AB - The structure of the title compound, which represents a mixed-valence platinum(II,IV) complex, {[Pt(II)Pt(IV)I2(C2H8N2)4][CH3(CH2)7SO3]4.2H2O} n , has been redetermined in a different space group. In contrast to the previously reported determination in the space group P21 cn [Matsushita & Taira (1999 ?). Synth. Met. 102, 1787-1788], the current model was refined in the centrosymmetric space group Pmcn using the original diffraction data. The title compound has a linear chain structure composed of square-planar [Pt(en)2](2+) and elongated octa hedral trans-[PtI2(en)2](2+) cations (en is ethyl-enedi-amine) stacked alternately, bridged by the I atoms, parallel to the c axis. Inorganic layers aligned parallel to the bc plane, composed of the Pt-complex columns, the -SO3 ( ) part of the octane-1-sulfonate anion, and the water mol-ecule of crystallization, are stacked alternately with organic layers composed of the long chain alkyl groups along the a axis. The Pt and I sites are located on the same mirror plane whereby the I site is equally disordered over two positions. The Pt and I atoms form a slight zigzag ?I-Pt(IV)-I?Pt(II)? chain, with Pt(IV)-I bond lengths of 2.6888 (17) and 2.7239 (17) A, Pt(II)?I contacts of 3.2065 (17) and 3.1732 (16) A, and Pt(IV)-I?Pt(II) angles of 178.3 (3) and 176.7 (2) degrees . The mixed-valence state of the Pt site is expressed by the structural parameter delta = (Pt(IV)-I)/(Pt(II)?I), with values of 0.839 and 0.858 for the two independent I atoms. In the crystal, N-H?O hydrogen bonds involving the cationic chains, the sulfonate groups and water mol-ecules of crystallization, stabilize the columnar structure. PMID- 26594396 TI - Crystal structures of 5-amino-N-phenyl-3H-1,2,4-di-thia-zol-3-iminium chloride and 5-amino-N-(4-chloro-phen-yl)-3H-1,2,4-di-thia-zol-3-iminium chloride monohydrate. AB - The crystal and mol-ecular structures of the title salt, C8H8N3S2 (+).Cl(-), (I), and salt hydrate, C8H7ClN3S2 (+).Cl(-).H2O, (II), are described. The heterocyclic ring in (I) is statistically planar and forms a dihedral angle of 9.05 (12) degrees with the pendant phenyl ring. The comparable angle in (II) is 15.60 (12) degrees , indicating a greater twist in this cation. An evaluation of the bond lengths in the H2N-C-N-C-N sequence of each cation indicates significant delocalization of pi-electron density over these atoms. The common feature of the crystal packing in (I) and (II) is the formation of charge-assisted amino-N-H?Cl( ) hydrogen bonds, leading to helical chains in (I) and zigzag chains in (II). In (I), these are linked by chains mediated by charge-assisted iminium-N(+)-H?Cl(-) hydrogen bonds into a three-dimensional architecture. In (II), the chains are linked into a layer by charge-assisted water-O-H?Cl(-) and water-O-H?O(water) hydrogen bonds with charge-assisted iminium-N(+)-H?O(water) hydrogen bonds providing the connections between the layers to generate the three-dimensional packing. In (II), the chloride anion and water mol-ecules are resolved into two proximate sites with the major component being present with a site occupancy factor of 0.9327 (18). PMID- 26594397 TI - Crystal structure of bis-(acetyl-acetonato-kappa(2) O,O')(tetra-hydro-furan kappaO)(tri-fluoro-methane-sulfonato-kappaO)iron(III). AB - The mononuclear title complex, [Fe(CF3O3S)(C5H7O2)2(C4H8O)] or [Fe(acac)2(OTf)(THF)] (acac = acetyl-acetonate; OTf = tri-fluoro-methane-sulfon ate; THF = tetrahydrofuran), (I), consists of one six-coordinate Fe(3+) atom in a slightly distorted octa-hedral environment [Fe-O bond-length range = 1.9517 (11) 2.0781 (11) A]. The triflate ligand was found to be disordered over two sets of sites, with a site-occupancy ratio of 0.622 (16):0.378 (16). Weak inter-molecular C-H?O and C-H?F hydrogen-bonding inter-actions generate a two-dimensional supra molecular structure lying parallel to (100). This is only the second crystal structure reported of a mononuclear bis-(acetyl-acetonato)iron(III) complex. PMID- 26594398 TI - Crystal structures of three (trichloromethyl)(carbamoyl)disulfanes. AB - The present paper reports crystallographic studies on three related compounds that were of inter-est as precursors for synthetic and mechanistic work in organosulfur chemistry, as well as to model nitro-gen-protecting groups: (N methyl-carbamo-yl)(tri-chloro-meth-yl)disulfane, C3H4Cl3NOS2, (1), (N-benzyl carbamo-yl)(tri-chloro-meth-yl)disulfane, C9H8Cl3NOS2, (2), and (N-methyl-N phenyl-carbamo-yl)(tri-chloro-meth-yl)disulfane, C9H8Cl3NOS2, (3). Their mol ecular structures, with similar bond lengths and angles for the CCl3SS(C=O)N moieties, are confirmed. Compounds (1) and (3) both crystallized with two independent mol-ecules in the asymmetric unit. Classical hydrogen bonding, as well as chlorine-dense regions, are evident in the crystal packing for (1) and (2). In the crystal of (1), mol-ecules are linked via N-H?O hydrogen bonds forming chains along [110], which are linked by short Cl?Cl and S?O contacts forming sheets parallel to (001). In the crystal of (2), mol-ecules are linked via N-H?O hydrogen bonds forming chains along [001], which in turn are linked by pairs of short O?Cl contacts forming ribbons along the c-axis direction. In the crystal of (3), there are no classical hydrogen bonds present and the chlorine dense regions observed in (1) and (2) are lacking. PMID- 26594399 TI - Crystal structure of (MU-4-hy-droxy-benzene-thiol-ato-kappa(2) S:S)bis-(MU-phenyl methane-thiol-ato-kappa(2) S:S)bis-[(eta(6)-1-isopropyl-4-methyl-benzene) ruthenium(II)] tetra-fluorido-borate. AB - The crystal structure of the dinuclear arene ruthenium title complex, [Ru2(C6H5OS)(C7H7S)2(C10H14)2]BF4, shows the two Ru(II) atoms to be bridged by two benzyl-thio-pheno-late units and one 4-hy-droxy-thio-pheno-late unit, with the remaining three coordination sites of each Ru(II) atom being occupied by p cymene ligands, completing the typical piano-stool coordination geometry. The BF4 (-) counter-anion is surrounded by four cationic dinuclear complexes, showing an O-H?F hydrogen bond and several weak C-H?F inter-actions. This is the first example of an X-ray analysis of a mixed dinuclear tri-thiol-ate arene ruthenium(II) complex. PMID- 26594400 TI - Crystal structures of the potassium and rubidium salts of (3,5-di-chloro-phen oxy)acetic acid: two isotypic coordination polymers. AB - The two-dimensional coordination polymeric structures of the hydrated potassium and rubidium salts of (3,5-di-chloro-phen-oxy)acetic acid (3,5-D), namely, poly[MU-aqua-bis-[MU3-2-(3,5-di-chloro-phen-oxy)acetato]-dipotassium], [K2(C8H5Cl2O3)2(H2O)] n , and poly[MU-aqua-bis-[MU3-2-(3,5-di-chloro-phen oxy)acetato]-dirubidium], [Rb2(C8H5Cl2O3)2(H2O)] n , respectively, have been determined and are described. The two compounds are isotypic and the polymeric structure is based on centrosymmetric dinuclear bridged complex units. The irregular six-coordination about the alkali cations comprises a bridging water mol-ecule lying on a twofold rotation axis, the phen-oxy O-atom donor and a triple bridging carboxyl-ate O atom of the oxo-acetate side chain of the 3,5-D ligand, and the second carb-oxy-ate O-atom donor also bridging. The K-O and Rb-O bond-length ranges are 2.7238 (15)-2.9459 (14) and 2.832 (2)-3.050 (2) A, respectively, and the K?K and Rb?Rb separations in the dinuclear units are 4.0214 (7) and 4.1289 (6) A, respectively. Within the layers which lie parallel to (100), the coordinating water mol-ecule forms an O-H?O hydrogen bond to the single bridging carboxyl-ate O atom. PMID- 26594401 TI - Crystal structure of (+/-)-(7RS,8SR)-7-methyl-1,4-dioxa-spiro-[4.5]decane-7,8 diol. AB - In the title compound, C9H16O4, the five-membered dioxolane ring adopts a twist conformation; two adjacent C atoms deviate alternately from the mean plane of other atoms by -0.297 (4) and 0.288 (4) A. The spiro-fused cyclo-hexane ring shows a chair form. The hy-droxy group substituted in an axial position makes an intra-molecular O-H?O hydrogen bond with one of the O atoms in the cyclic ether, forming an S(6) ring motif. In the crystal, the O-H?O hydrogen bond involving the equatorial hy-droxy group connects the mol-ecules into a zigzag chain with a C(5) motif running along the c axis. PMID- 26594402 TI - Etude structurale et vibrationnelle d'un nouveau compose complexe de cobalt: [Co(imidazole)4Cl]Cl. AB - In the title complex, chlorido-tetra-kis-(1H-imidazole-kappaN (3))cobalt(II) chloride, [CoCl(C3H4N2)4]Cl, the Co(II) cation has a distorted square-pyramidal coordination environment. It is coordinated by four N atoms of four imidazole (Im) groups in the basal plane, and by a Cl atom in the apical position. It is isostructural with [Cu(Im)4Cl]Cl [Morzyk-Ociepa et al. (2012 ?). J. Mol. Struct. 1028, 49-56] and [Cu(Im)4Br]Br [Hossaini Sadr et al. (2004 ?). Acta Cryst. E60, m1324-m1326]. In the crystal, the [CoCl(C3H4N2)4](+) cations and Cl(-) anions are linked via N-H?Cl hydrogen bonds, forming layers parallel to (010). These layers are linked via C-H?Cl hydrogen bonds and C-H?pi and pi-pi [inter-centroid distance = 3.794 (2) A] inter-actions, forming a three-dimensional framework. The IR spectrum shows vibrational bands typical for imidazol groups. The monoclinic unit cell of the title compound emulates an ortho-rhom-bic cell as its beta angle is close to 90 degrees . The crystal is twinned, with the refined ratio of twin components being 0.569 (1):0.431 (1). PMID- 26594403 TI - Crystal structure of aceto-nitrile-[eta(6)-1-methyl-4-(1-methyl-eth-yl)benzene][1 (pyrimidin-2-yl)-3H-indol-1-ium-2-yl-kappa(2) N,C]ruthenium(II) bis-(hexa fluorido-anti-monate). AB - In the title compound, [Ru(C10H14)(C12H9N3)(CH3CN)][SbF6]2, the ruthenium(II) cation is eta (6)-coordinated by the para-cymene ligand with a Ru-centroid(eta (6)-benzene) distance of 1.746 (2) A. Furthermore, ruthenium coordinations to the C and N atoms of the pyrimidyl indole ligand are found to be 1.986 (4) and 2.082 (3) A, respectively. The typical piano-stool coordination environment is saturated with an aceto-nitrile solvent mol-ecule with a Ru-N distance of 2.044 (3) A. The indolyl ligand is protonated at the C3 position with the N=C imine bond length appropriate to that of related 3H-indole-based complexes. In the crystal, the complex cation is linked to the SbF6 (-) ions through weak C-H?F hydrogen bonds. PMID- 26594404 TI - Crystal structure of Boc-(S)-ABOC-(S)-Ala-(S)-ABOC-(S)-Phe-OBn chloro-form monosolvate. AB - In the title compound, phenyl (S)-2-[(S)-(1-{2-[(S)-(1-{[(tert-but-oxy)carbon yl]amino}-bicyclo-[2.2.2]octan-2-yl)formamido]-propanamido}-bicyclo-[2.2.2]octan 2-yl)formamido]-3-phenyl-propano-ate chloro-form monosolvate, C42H56N4O7.CHCl3, the alpha,beta-hybrid peptide contains two non-proteinogenic amino acid residues of (S)-1-amino-bicyclo-[2.2.2]octane-2-carb-oxy-lic acid [(S)-ABOC], two amino acid residues of (S)-2-amino-propanoic acid [(S)-Ala] and (S)-2-amino-3-phenyl propanoic acid [(S)-Phe], and protecting groups of tert-but-oxy-carbonyl (Boc) and benzyl ester (OBn). The tetra-mer folds into a right-handed mixed 11/9 helix stabilized by intra-molecular i,i + 3 and i,i - 1 C=O?H-N hydrogen bonds. In the crystal, the oligomers are linked by N-H?O=C hydrogen bonds into chains along the a-axis direction. The chloro-form solvent mol-ecules are inter-calated between the folded chains via C-H?O=C inter-actions. PMID- 26594405 TI - Crystal structure of 3-methyl-pyridinium picrate: a triclinic polymorph. AB - The title mol-ecular salt, C6H8N(+).C6H2N3O7 (-) (systematic name: 3-methyl pyridinium 2,4,6-tri-nitro-phenolate), crystallizes in the triclinic space group P-1. The crystal structure of the monoclinic polymorph (space group P21/n) has been reported [Stilinovic & Kaitner (2011 ?). Cryst. Growth Des. 11, 4110-4119]. In the crystal, the anion and cation are linked via bifurcated N-H?(O,O) hydrogen bonds, enclosing an R 1 (2)(6) graph-set motif. These units are linked via C-H?O hydrogen bonds, forming a three-dimensional framework. Within the framework there are pi-pi inter-actions present, involving inversion-related picrate anions and inversion-related pyridinium cations, with inter-centroid distances of 3.7389 (14) and 3.560 (2) A, respectively. PMID- 26594406 TI - Crystal structure of poly[[MU2-di-aqua-di-aqua-MU2-l-proline-kappa(2) O:O' strontium] dibromide]. AB - In the title coordination polymer, {[Sr(C5H9NO2)(H2O)4]Br2} n , the proline mol ecule exists in a zwitterionic form with one of the ring C atoms disordered over two sites [site-occupancy factors = 0.57 (6):0.43 (6)]. The Sr(II) ion is nine coordinated by six water O atoms, two monodentate and two MU2-bridging, and three carboxyl-ate O atoms of the proline ligands, with two bridging [Sr-O range = 2.524 (4)-2.800 (5) A]. In the crystal, there is no direct inter-action between the proline mol-ecules. However, the proline and water mol-ecules associate with the bromide counter-anions through a number of inter-molecular O-H?Br and N-H?Br hydrogen-bonding inter-actions, giving a three-dimensional supra-molecular structure. PMID- 26594407 TI - Crystal structure of tetra-kis-(MU3-2-{[1,1-bis-(hy-droxy-meth-yl)-2-oxidoeth yl]imino-meth-yl}-6-meth-oxy-phenolato)tetra-kis-[aqua-copper(II)]: a redetermination at 200 K. AB - The crystal structure of the tetra-nuclear title compound, [Cu4(C12H15NO5)4(H2O)4], has been previously reported by Back, Oliveira, Canabarro & Iglesias [Z. Anorg. Allg. Chem. (2015), 641, 941-947], based on room temperature data. In the previously published structure, no standard uncertainties are recorded for the deprotonated hy-droxy-methyl group and water mol-ecule O atoms coordinating to the metal atom indicating that they were not refined; furthermore, the H atoms of some OH groups and water mol-ecules have not been positioned accurately. Since the current structure was determined at a lower temperature, all atoms, including the H atoms of these hy-droxy groups and the water mol-ecule, have been determined more accurately resulting in improved standard uncertainties in the bond lengths and angles. Diffraction data were collected at 200 K, rather than the more usual 100 K, due to apparent disordering at lower temperatures. In addition, it is now possible to report intra- and inter molecular O-H?O inter-actions. In the title complex molecule, which has crystallographic -4 symmetry, the Cu(II) ions are coordinated by the tridentate Schiff base ligands and water mol-ecules, forming a tetra-nuclear Cu4O4 cubane like core. The Cu(II) ion adopts a CuNO5 elongated octa-hedral environment. The coordination environment of Cu(II) at 200 K displays a small contraction of the Cu-N/O bonds, compared with the room-temperature structure. In the crystal lattice, the neutral clusters are linked by inter-molecular O-H?O hydrogen bonds into a one-dimensional hydrogen-bonding network propagating along the b axis. PMID- 26594408 TI - Crystal structures of two chiral piperidine derivatives: 1-[(1R)-2-hy-droxy-1 phenyl-eth-yl]piperidin-4-one and 8-[(1S)-1-phenyl-eth-yl]-1,4-dioxa-8-aza-spiro [4.5]decane-7-thione. AB - The crystal structures of the two title piperidine derivatives show different conformations for the six-membered heterocycle. The N-substituted 4-piperidinone 1-[(1R)-2-hy-droxy-1-phenyl-eth-yl]piperidin-4-one, C13H17NO2, (I), has a chair conformation, while the piperidine substituted in position 2 with a thio-carbonyl group, 8-[(1S)-1-phenyl-eth-yl]-1,4-dioxa-8-aza-spiro-[4.5]decane-7-thione, C15H19NO2S, (II), features a half-chair conformation. Comparison of the two structures, and data retrieved from the literature, suggests that the conformational flexibility is mainly related to the hybridization state of the C atom alpha to the piperidinic N atom: a Csp (3) atom favours the chair conformer, while a Csp (2) atom distorts the ring towards a half-chair conformer. In the crystal structure of (I), weak C-H?O hydrogen bonds link the mol-ecules into supra-molecular chains propagating along the b-axis direction. In the crystal of (II), the mol-ecules are linked by weak C-H?S contacts into supra-molecular chains propagating along the b-axis direction. PMID- 26594409 TI - Crystal structure of 3-C-(N-benzyl-oxy-carbon-yl)amino-methyl-3-de-oxy-1,2:5,6-di O-iso-propyl-idene-alpha-d-allo-furan-ose. AB - The title compound, C21H29NO7 (1) [systematic name: benzyl ({(3aR,5S,6R,6aR)-5 [(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,2-di-methyl-tetrahydro-furo[2,3 d][1,3]dioxol-6-yl}meth-yl)carbamate], consists of a substituted 2,2-di-methyl tetra-hydro-furo[2,3-d][1,3]dioxolane skeleton. The furan-ose ring adopts an envelope conformation close to C 3-exo, where the C atom substituted by the benzyl carbamate group is the flap. The fused dioxolane ring also adopts an envelope conformation, as does the terminal dioxolane ring, with in each case an O atom as the flap. In the crystal, mol-ecules are linked by N-H?O and C-H?O hydrogen bonds, forming chains propagating along the b-axis direction. PMID- 26594410 TI - Crystal structure of bis-[MU-(4-meth-oxy-phen-yl)methane-thiol-ato-kappa(2) S:S]bis-[chlorido-(eta(6)-1-isopropyl-4-methyl-benzene)-ruthenium(II)] chloro form disolvate. AB - The mol-ecular structure of the title complex, [Ru2(C8H9OS)2Cl2(C10H14)2].2CHCl3 or (p-MeC6H4Pr (i) )2Ru2(SCH2-p-C6H5-OCH3)2Cl2.2CHCl3, shows inversion symmetry. The two symmetry-related Ru(II) atoms are bridged by two 4-meth-oxy-alpha-toluene thiol-ato [(4-meth-oxy-phen-yl)methane-thiol-ato] units. One chlorido ligand and the p-cymene ligand complete the typical piano-stool coordination environment of the Ru(II) atom. In the crystal, the CH moiety of the chloro-form mol-ecule inter acts with the chlorido ligand of the dinuclear complex, while one Cl atom of the solvent inter-acts more weakly with the methyl group of the bridging 4-meth-oxy alpha-toluene-thiol-ato unit. This assembly leads to the formation of supra molecular chains extending parallel to [021]. PMID- 26594411 TI - Crystal structure of di-MU-isobutyrato-kappa(4) O:O'-bis-[cis-di-chlorido (dimethyl sulfoxide-kappaS)rhenium(III)]. AB - The title compound, [Re2(C3H7COO)2Cl4{(CH3)2SO}2], comprises binuclear complex mol-ecules [Re-Re = 2.24502 (13) A] involving cis-oriented double carboxyl-ate bridges, four equatorial chloride ions and two weakly bonded O atoms from dimethyl sulfoxide ligands in the axial positions at the Re(III) atoms. In the crystal, mol-ecules are linked into corrugated layers parallel to (101) by very weak C-H?Cl and C-H?O hydrogen-bonding inter-actions. C-H?Cl hydrogen bonding provides the links between layers to consolidate a three-dimensional framework. PMID- 26594412 TI - Synthesis, characterization and crystal structure of a 2 (diethylaminomethyl)indole ligated dimethyl-aluminium complex. AB - The title compound, [Al(CH3)2(C13H17N2)] (systematic name; {2-[(di-ethyl-amino) meth-yl]indol-1-yl-kappa(2) N,N'}di-methyl-aluminium), was prepared by methane elimination from the reaction of 2-(di-ethyl-amino-meth-yl)indole and tri-methyl aluminium. The complex crystallizes readily from a concentrated toluene solution in high yield. The asymmetric unit contains two crystallographically independent mol-ecules. Each mol-ecule has a four-coordinate aluminium atom that has pseudo tetra-hedral geometry. C-H?pi inter-actions link the independent mol-ecules into chains extending along the b-axis direction. PMID- 26594413 TI - Crystal structures of morpholinium hydrogen bromanilate at 130, 145 and 180 K. AB - Crystal structures of the title compound (systematic name: morpholin-4-ium 2,5-di bromo-4-hy-droxy-3,6-dioxo-cyclo-hexa-1,4-dien-1-olate), C4H10NO(+).C6HBr2O4 (-), were determined at three temperatures, viz. 130, 145 and 180 K. The asymmetric unit comprises one morpholinium cation and two halves of crystallographically independent bromanilate monoanions, which are located on inversion centres. The conformations of the two independent bromanilate anions are different from each other with respect to the O-H orientation. In the crystal, the two different anions are linked alternately into a chain along [211] through a short O-H?O hydrogen bond, in which the H atom is disordered over two positions. The refined site-occupancy ratios, which are almost constant in the temperature range studied, are 0.49 (3):0.51 (3), 0.52 (3):0.48 (3) and 0.50 (3):0.50 (3), respectively, at 130, 145 and 180 K, and no significant difference in the mol ecular geometry and the mol-ecular packing is observed at the three temperatures. The morpholinium cation links adjacent chains of anions via N-H?O hydrogen bonds, forming a sheet structure parallel to (-111). PMID- 26594414 TI - Crystal structures of three new N-halo-methyl-ated quaternary ammonium salts. AB - In the crystals of the title N-halo-methyl-ated quaternary ammonium salts, C19H23IN(+).I(-), (I) [systematic name: N-(4,4-di-phenyl-but-3-en-1-yl)-N-iodo methyl-N,N-di-methyl-ammonium iodide], C20H25IN(+).I(-), (II) [systematic name: N (5,5-di-phenyl-pent-4-en-1-yl)-N-iodo-methyl-N,N-di-methyl-ammonium iodide], and C21H27IN(+).I(-), (III) [systematic name: N-(6,6-di-phenyl-hex-5-en-1-yl)-N-iodo methyl-N,N-di-methyl-ammonium iodide], there are short I?I(-) inter-actions of 3.564 (4), 3.506 (1) and 3.557 (1) A for compounds (I), (II) and (III), respectively. Compound (I) crystallizes in the Sohncke group P21 as an 'enanti opure' compound and is therefore a potential material for NLO properties. In the crystal of compound (I), mol-ecules are linked by C-H?I(-) and C-H?pi inter actions which, together with the I?I(-) inter-actions, lead to the formation of ribbons along [100]. In (II), there are only C-H?I(-) inter-actions which, together with the I?I(-) inter-actions, lead to the formation of helices along [010]. In (III), apart from the I?I(-) inter-actions, there are no significant inter-molecular inter-actions present. PMID- 26594415 TI - Crystal structure of 1-(4-methyl-phen-yl)-3-(propan-2-yl-idene-amino)-thio-urea. AB - In the title thio-semicarbazone, C11H15N3S, the p-tolyl-N-H and imino-N-H groups are anti and syn, respectively, to the central thione-S atom. This allows for the formation of an intra-molecular p-tolyl-N-H?N(imino) hydrogen bond. The mol-ecule is twisted with the dihedral angle between the p-tolyl ring and the non-hydrogen atoms of the N=CMe2 residue being 29.27 (8) degrees . The crystal packing features supra-molecular layers lying in the bc plane whereby centrosymmetric aggregates sustained by eight-membered thio-amide {?HNCS}2 synthons are linked by further N-H?S hydrogen bonds. Layers are connected via methyl-C-H?pi inter actions. The supra-molecular aggregation was further investigated by an analysis of the Hirshfeld surface and comparison made to related structures. PMID- 26594416 TI - Crystal structure of 5-[4-(di-ethyl-amino)-benzyl-idene]-2,2-dimethyl-1,3-dioxane 4,6-dione. AB - The title compound, C17H21NO4, consists of substituted Meldrum's acid with a [4 (di-ethyl-amino)-phen-yl]methyl-idene fragment attached to the fifth position. The heterocycle assumes a distorted boat conformation. The planar part of heterocycle is almost coplanar with the benzene ring due to the presence of a long conjugated system in the mol-ecule. This leads to the formation of C-H?O type intra-molecular contacts. As a result of the absence of hydrogen-bond donors in the structure, the crystal packing is controlled by van der Waals forces and weak C-H?O inter-actions, which associate the mol-ecules into inversion dimers. PMID- 26594417 TI - Crystal structure of 4'-{[4-(2,2':6',2''-terpyrid-yl-4'-yl)phen-yl]ethyn yl}biphenyl-4-yl (2,2,5,5-tetra-methyl-1-oxyl-3-pyrrolin-3-yl)formate benzene 2.5 solvate. AB - The title compound, C44H35N4O3.2.5C6H6 (1), consists of a terpyridine and a N oxylpyrroline-3-formate group separated by an aromatic spacer, viz. 4-(phenyl ethyn-yl)-1,1'-biphenyl. It crystallized in the triclinic space group P-1 with two and a half benzene solvate mol-ecules (one benzene mol-ecule is located about an inversion center), while the di-chloro-methane solvate (2) of the same mol ecule [Ackermann et al. (2015 ?). Chem. Commun. 51, 5257-5260] crystallized in the tetra-gonal space group P42/n, with considerable disorder in the mol-ecule. In (1), the terpyridine (terpy) group assumes an all-trans conformation typical for terpyridines. It is essentially planar with the two outer pyridine rings (B and C) inclined to the central pyridine ring (A) by 8.70 (15) and 14.55 (14) degrees , respectively. The planes of the aromatic spacer (D, E and F) are nearly coplanar with dihedral angles D/E, D/F and E/F being 3.42 (15), 5.80 (15) and 4.00 (16) degrees , respectively. It is twisted with respect to the terpy group with, for example, dihedral angle A/D being 24.48 (14) degrees . The mean plane of the N-oxylpyrroline is almost normal to the biphenyl ring F, making a dihedral angle of 86.57 (16) degrees , and it is inclined to pyridine ring A by 72.61 (15) degrees . The intra-molecular separation between the O atom of the nitroxyl group and the N atom of the central pyridine ring of the terpyridine group is 25.044 (3) A. In the crystal, mol-ecules are linked by pairs of C-H?O hydrogen bonds, forming inversion dimers. The dimers stack along the c axis forming columns. Within and between the columns, the spaces are occupied by benzene mol-ecules. The shortest oxygen-oxygen separation between nitroxyl groups is 4.004 (4) A. The details of the title compound are compared with those of the di-chloro-methane solvate (2) and with the structure of a related mol-ecule, 4'-{4-[(2,2,5,5-tetra methyl-N-oxyl-3-pyrrolin-3-yl)ethyn-yl]phen-yl}-2,2':6',2''-terpyridine (3), which has an ethynylphenyl spacer [Meyer et al. (2015). Acta Cryst. E71, 870 874]. PMID- 26594418 TI - Double salt crystal structure of hexa-sodium hemiundeca-hydrogen alpha-hexa molybdoplatinate(IV) heminona-hydrogen alpha-hexa-molybdoplatinate(IV) nona-cosa hydrate: di-hydrogen disordered-mixture double salt. AB - The title double salt containing two distinct, differently protonated hexa molybdoplatinate(IV) polyanions, Na6[H5.5 alpha-PtMo6O24][H4.5 alpha PtMo6O24].29H2O, has been synthesized by a hydro-thermal reaction at ca pH 1.80. The positions of the H atoms in the polyanions were established from difference Fourier maps and confirmed by the inter-polyanion hydrogen bonds, bond-distance elongation, and bond-valence sum (BVS) calculations. The fractional numbers of H atoms in each polyanion are required for charge balance and in order to avoid unrealistically short H?H distances in the inter-polyanion hydrogen bonds. Considering the disorder, the refined formula of the title polyanion, {[H5.5 alpha-PtMo6O24]; polyanion (A) and [H4.5 alpha-PtMo6O24]; polyanion (B)}(6-), can be rewritten as a set of real formula, viz. {[H6 alpha-PtMo6O24]; polyanion (A). [H4 alpha-PtMo6O24]; polyanion (B)}(6-) and {[H5 alpha-PtMo6O24]; polyanion (A). [H5 alpha-PtMo6O24]; polyanion (B)}(6-). The polyanion pairs both form dimers of the same formula, viz. {[H10 alpha-Pt2Mo12O48]}(6-) connected by seven inter polyanion O-H?O hydrogen bonds. PMID- 26594419 TI - Crystal structure of strontium dinickel iron orthophosphate. AB - The title compound, SrNi2Fe(PO4)3, synthesized by solid-state reaction, crystallizes in an ordered variant of the alpha-CrPO4 structure. In the asymmetric unit, two O atoms are in general positions, whereas all others atoms are in special positions of the space group Imma: the Sr cation and one P atom occupy the Wyckoff position 4e (mm2), Fe is on 4b (2/m), Ni and the other P atom are on 8g (2), one O atom is on 8h (m) and the other on 8i (m). The three dimensional framework of the crystal structure is built up by [PO4] tetra-hedra, [FeO6] octa-hedra and [Ni2O10] dimers of edge-sharing octa-hedra, linked through common corners or edges. This structure comprises two types of layers stacked alternately along the [100] direction. The first layer is formed by edge-sharing octa-hedra ([Ni2O10] dimer) linked to [PO4] tetra-hedra via common edges while the second layer is built up from a strontium row followed by infinite chains of alternating [PO4] tetra-hedra and FeO6 octa-hedra sharing apices. The layers are held together through vertices of [PO4] tetra-hedra and [FeO6] octa-hedra, leading to the appearance of two types of tunnels parallel to the a- and b-axis directions in which the Sr cations are located. Each Sr cation is surrounded by eight O atoms. PMID- 26594420 TI - Crystal structure of [5-bromo-2-(pyridin-2-yl-kappaN)phenyl-kappaC (1)](pentane 2,4-dionato-kappa (2) O,O')platinum(II). AB - The title cyclo-metalated platinum(II) complex with 2-(4-bromo-phen-yl)pyridinato and acetyl-acetonato ligands, [Pt(C11H7BrN)(C5H7O2)], consists of two crystallographically non-equivalent dimers, each stacked by pi-pi inter-actions with distances of ? 3.4 A. In both dimers, the platinum(II) complexes are arranged anti-parallel to each other. Each complex exhibits a slightly distorted square-planar coordination environment around the central Pt(II) atom. The dihedral angles between two chelate rings including the Pt(II) atom in these complexes are 0.08 (12) and 1.54 (9) degrees . PMID- 26594421 TI - Crystal structure of an unknown tetra-hydro-furan solvate of tetra-kis-(MU 3 cyanato-kappa(3) N:N:N)tetra-kis-[(triphenyl-phosphane-kappaP)-silver(I)]. AB - In the title compound, [{[(C6H5)3P]Ag}4{NCO}4], a distorted Ag4N4-heterocubane core is set up by four Ag(I) ions being coordinated by the N atoms of the cyanato anions in a MU 3-bridging mode. In addition, a tri-phenyl-phosphine ligand is datively bonded to each of the Ag(I) ions. Intra-molecular Ag?Ag distances as short as 3.133 (9) A suggest the presence of argentophilic (d (10)?d (10)) inter actions. Five moderate-to-weak C-H?O hydrogen-bonding inter-actions are observed in the crystal structure, spanning a three-dimensional network. A region of electron density was treated with the SQUEEZE procedure in PLATON [Spek (2015). Acta Cryst. C71, 9-18] following unsuccessful attempts to model it as being part of disordered tetra-hydro-furan solvent mol-ecules. The given chemical formula and other crystal data do not take into account these solvent mol-ecules. PMID- 26594422 TI - A co-crystal of nona-hydrated disodium(II) with mixed anions from m-chloro benzoic acid and furosemide. AB - In the title compound, [Na2(H2O)9](C7H4ClO2)(C12H10ClN2O5S) {systematic name: catena-poly[[[triaquasodium(I)]-di-MU-aqua-[triaquasodium(I)]-MU-aqua] 3 chlorobenzoate 4-chloro-2-[(furan-2-ylmethyl)amino]-5-sulfamoylbenzoate]}, both the original m-chloro-benzoic acid and furosemide exist with deprotonated carboxyl-ates, and the sodium cations and water mol-ecules exist in chains with stoichiometry [Na2(OH2)9](2+) that propagate in the [-110] direction. Each of the two independent Na(+) ions is coordinated by three monodentate water mol-ecules, two double-water bridges, and one single-water bridge. There is considerable cross-linking between the [Na2(OH2)9](2+) chains and to furosemide sulfonamide and carboxyl-ate by inter-molecular O-H?O hydrogen bonds. All hydrogen-bond donors participate in a complex two-dimensional array parallel to the ab plane. The furosemide NH group donates an intra-molecular hydrogen bond to the carboxyl ate group, and the furosemide NH2 group donates an intra-molecular hydrogen bond to the Cl atom and an inter-molecular one to the m-chloro-benzoate O atom. The plethora of hydrogen-bond donors on the cation/water chain leads to many large rings, up to graph set R 4 (4)(24), involving two chains and two furosemide anions. The chloro-benzoate is involved in only one R 2 (2)(8) ring, with two water mol-ecules cis-coordinated to Na. The furan O atom is not hydrogen bonded. PMID- 26594423 TI - Crystal structure of CdSO4(H2O): a redetermination. AB - The crystal structure of the title compound, cadmium sulfate monohydrate or poly[(MU2-aqua)(MU4-sulfato)-cadmium], was redetermined based on modern CMOS (complementary metal oxide silicon) data. In comparison with the previous study [Bregeault & Herpin (1970 ?). Bull. Soc. Fr. Mineral. Cristallogr. 93, 37-42], all non-H atoms were refined with anisotropic displacement parameters and the hydrogen-bonding pattern unambiguously established due to location of the hydrogen atoms. In addition, a significant improvement in terms of precision and accuracy was achieved. In the crystal, the Cd(2+) cation is coordinated by four O atoms of four sulfate anions and two O atoms of water mol-ecules, forming a distorted octa-hedral trans-[CdO6] polyhedron. Each sulfate anion bridges four Cd(2+) cations and each water mol-ecule bridges two Cd(2+) cations, leading to the formation of a three-dimensional framework, with Cd?Cd separations in the range 4.0757 (2)-6.4462 (3) A. O-H?O hydrogen-bonding inter-actions of medium strength between the coordinating water mol-ecules and sulfate anions consolidate the crystal packing. PMID- 26594424 TI - Crystal structure of tris-(1,3-dimesityl-4,5-di-hydro-1H-imidazol-3-ium) tetra bromido-cobaltate(II) bromide chloro-form hexa-solvate. AB - In the unit cell of the title compound, (C21H27N2)3[CoBr4]Br.6CHCl3, the tetrabromidocobaltate(II) anion and the bromide anion are located on a crystallographic threefold rotation axis. For the [CoBr4](2-) group, the axis runs through one of the Br ligands and the Co(II) atom. All other structure moieties lie on general sites. Various tris-(1,3-dimesityl-4,5-di-hydro-1H imidazol-3-ium) structures with different counter-ions have been reported. In the title compound, the N-C-N angle is 113.7 (5) degrees , with short C-N bond lengths of 1.297 (7) and 1.307 (7) A. The two mesityl planes make a dihedral angle of 34.6 (1) degrees and the dihedral angles between the mesityl and N-C-N planes are 82.0 (1) and 88.5 (1) degrees , respectively. The imidazoline ring is almost planar, with atom deviations in the range 0.003 (5)-0.017 (5) A from the best plane; the mean deviation is 0.012 (5) A. In the crystal, non-covalent inter actions of the C-H?Br type occur between the Br(-) anion and the cation, as well as between the [CoBr4](2-) anion and both the chloro-form solvent mol-ecules. These H?A distances are slightly shorter than the sum of van der Waals radii. PMID- 26594425 TI - Crystal structure of poly[(2,2'-bi-pyridine-kappa(2) N,N')tetra-MU2-cyanido kappa(4) C:N;kappa(4) N:C-manganese(II)disilver(I)]. AB - The title compound, [Ag2Mn(CN)4(C10H8N2)] n or Mn(bipy){Ag(CN)2}2 (bipy = 2,2'-bi pyridine) is isostructural with Cd(bipy){Au(CN)2}2 [Guo et al. (2009 ?). CrystEngComm, 11, 61-66]. The Mn(II) atom has crystallographically imposed twofold symmetry and a distorted octa-hedral coordination sphere consisting of six N atoms from one bi-pyridine ligand and four di-cyano-argentate(I) anions, [Ag(CN)2](-), while the Ag(I) atom of the complex anion displays the expected linear geometry. Each [Ag(CN)2](-) unit connects to two neighbouring [Mn(bipy)](2+) cations to give an threefold inter-penetrating quartz-like three dimensional framework. No directional inter-actions beyond van der Waals contacts are observed. PMID- 26594426 TI - Crystal structure of di-chlorido-[2-(di-phenyl-phosphan-yl)-3,4,5,6-tetra-fluoro benzene-1-thiol-ato-kappa(2) P,S]gold(III). AB - The title compound, [Au(C18H10F4PS)Cl2], crystallizes as neutral mol-ecules, with the Au(III) atom coordinated by two Cl atoms and by the P and S atoms of the bidentate phosphanyl thiol-ate ligand, in a slightly distorted square-planar environment. The mol-ecules are linked into centrosymmetric dimers via long axial Au-Cl bonds of 3.393 (4) A. This axial Au-Cl distance is longer than is usually seen, although one other example has been given. Dimer formation may explain the unexpectedly low solubility of the compound in common polar solvents. There is also a separate inter-molecular Au-F contact of 3.561 (6) A, but this distance seems too long to be regarded as a bond. Two putative C-H?F hydrogen bonds appear to link the dimers into sheets parallel to (110). There is a short inter molecular F?F contact of 2.695 (10) A between two dimers related by the twofold axis. PMID- 26594427 TI - Crystal structure of an unknown solvate of dodecakis-(MU2-alaninato-1:2kappa(2) O:N,O)cerium(III)hexa-nickel(II) aqua-tris-(hydroxido-kappaO)tris-(nitrato kappa(2) O,O')cerate(III). AB - The chiral title compound, [CeNi6(C3H6NO2)12][Ce(NO3)3(OH)3(H2O)], comprises a complex heterometallic Ni/Ce cation and a homonuclear Ce anion. Both the cation and anion exhibit point group symmetry 3. with the Ce(III) atom situated on the threefold rotation axis. The cation metal core consists of six Ni(II) atoms coordinated in a slightly distorted octa-hedral N2O4 configuration by N and O atoms of 12 deprotonated l-alaninate ligands exhibiting both bridging and chelating modes. This metal-organic coordination motif encapsulates one Ce(III) atom that shows an icosa-hedral coordination by the O-donor atoms of the l alaninate ligands, with Ce-O distances varying in the range 2.455 (5)-2.675 (3) A. In the anion, the central Ce(III) ion is bound to three bidentate nitrate ligands, to three hydroxide ligands and to one water mol-ecule, with Ce-O distances in the range 2.6808 (19)-2.741 (2) A. The H atoms of the coordinating water mol-ecule are disordered over three positions due to its location on a threefold rotation axis. Disorder is also observed in fragments of two l alaninate ligands, with occupancy ratios of 0.608 (14):0.392 (14) and 0.669 (8):0.331 (8), respectively, for the two sets of sites. In the crystal, the complex cations and anions assemble through O-H?O and N-H?O hydrogen bonds into a three-dimensional network with large voids of approximately 1020 A(3). The contributions of highly disordered ethanol and water solvent mol-ecules to the diffraction data were removed with the SQUEEZE procedure [Spek (2015 ?). Acta Cryst. C71, 9-18]. The given chemical formula and other crystal data do not take into account the unknown amount of these solvent mol-ecules. PMID- 26594428 TI - Crystal structure of [3-amino-2-(phenyl-diazenyl)-pyridine]chlorido-(eta(6)-p cymene)-ruthenium(II) chloride. AB - The title compound, [RuCl(C10H14)(C11H10N4)]Cl is an Ru(II) complex in which an eta (6) -p-cymene ligand, two N atoms of 3-amino-2-(phenyl-azo)pyridine and one Cl ion form a piano-stool coordination environment around the metal ion. In the crystal structure, N-H?Cl hydrogen bonds play an important role in the formation of the supramolecular zigzag chain along the a-axis direction. Disorder is observed for the isopropyl group with site-occupancy factors refined to 0.78 (5) and 0.22 (5). PMID- 26594429 TI - Crystal structure of 2-cyano-1-methyl-pyridinium tetra-fluoro-borate. AB - The asymmetric unit of the title salt, C7H7N2 (+).BF4 (-), comprises two independent but nearly identical formula units. The solid-state structure comprises corrugated layers of cations and anions, formed by C-H?F hydrogen bonding, that are approximately parallel to (010). Further C-H?F hydrogen bonding consolidates the three-dimensional architecture. The sample was refined as a two component non-merohedral twin. PMID- 26594430 TI - Crystal structure of ethyl 4-(2-fluoro-phen-yl)-6-methyl-2-sulfanyl-idene-1,2,3,4 tetra-hydro-pyrimidine-5-carboxyl-ate. AB - The title compound, C14H15FN2O2S, crystallizes with two mol-ecules in the asymmetric unit. In each mol-ecule, the pyrimidine ring adopts a sofa conformation with the sp (3)-hybridized C atom forming the flap and the fluoro substituted ring in an axial position. In the crystal, mol-ecules are linked via N-H?S hydrogen bonds, forming chains of R 2 (2)(8) rings along [100]. In one independent mol-ecule, an intra-molecular C-H?O hydrogen bond is observed. PMID- 26594431 TI - Crystal structure of 2-meth-oxy-1-nitro-naphthalene. AB - The asymmetric unit of the title compound, C11H9NO3, contains two mol-ecules, A and B. In mol-ecule A, the dihedral angle between the planes of the naphthalene ring system (r.m.s. deviation = 0.003 A) and the nitro group is 89.9 (2) degrees , and the C atom of the meth-oxy group deviates from the naphthyl plane by 0.022 (2) A. Equivalent data for mol-ecule B are 0.008 A, 65.9 (2) degrees and -0.198 (2) A, respectively. In the crystal, mol-ecules are linked by weak C-H?O inter actions, forming [100] chains of alternating A and B mol-ecules. Weak aromatic pi pi stacking contacts, with a range of centroid-centroid distances from 3.5863 (9) to 3.8048 (9) A, are also observed. PMID- 26594432 TI - Crystal structure of [4-(chloro-meth-yl)phen-yl](4-hy-droxy-piperidin-1 yl)methanone. AB - The title compound, C13H16ClNO2, crystallized with two independent mol-ecules in the asymmetric unit (A and B). The piperidinol ring in mol-ecule B is disordered over two positions with a site occupancy ratio of 0.667 (5):0.333 (5). In both mol-ecules these rings have a chair conformation, including the minor component in mol-ecule B. Their mean planes are inclined to the benzene ring by 45.57 (13) degrees in mol-ecule A, and by 50.5 (4) degrees for the major component of the piperidine ring in mol-ecule B. In the crystal, the individual mol-ecules are linked by O-H?O hydrogen bonds, forming chains of A and B mol-ecules along the [100] direction. The chains are inter-linked by C-H?O hydrogen bonds, forming ribbons. PMID- 26594433 TI - Crystal structure of 1'-ethyl-spiro[chroman-4,4'-imidazolidine]-2',5'-dione: a hydantoine derivative. AB - The title compound, C13H13N2O3, a hydantoin derivative, crystallized with two mol ecules (A and B) in an asymmetric unit. In mol-ecule A, the imidazolidine ring is twisted about the C-N bond involving the spiro C atom, while in mol-ecule B this ring is flat (r.m.s. deviation = 0.010 A). The pyran rings in both mol-ecules have distorted half-chair conformations. The mean plane of the imidazolidine ring is inclined to the aromatic ring of the chroman unit by 79.71 (11) degrees in mol-ecule A and 82.83 (12) degrees in mol-ecule B. In the crystal, pairs of N H?O hydrogen bonds link the individual mol-ecules to form A-A and B-B inversion dimers. The dimers are linked via N-H?O and C-H?O hydrogen bonds, forming sheets lying parallel to the bc plane, viz. (011). Within the sheets, the A and B mol ecules are linked by C-H?pi inter-actions. PMID- 26594434 TI - Crystal structure of (E)-1-(3-chloro-phen-yl)-3-(furan-2-yl)prop-2-en-1-one. AB - The title compound, C13H9ClO2, exhibits a non-planar geometry; the furan ring being inclined to the benzene ring by 50.52 (16) degrees . In the crystal, mol ecules stack along the a axis; however, there are no significant inter-molecular inter-actions present. PMID- 26594435 TI - Crystal structure of 3,5-dimeth-oxy-2-[5-(naphthalen-1-yl)-4,5-di-hydro-1H pyrazol-3-yl]phenol. AB - In the title compound, C21H20N2O3, the planes of the benzene ring and the naphthalene ring system are inclined to one another by 70.95 degrees , and by 4.99 (6) and 75.93 (5) degrees , respectively, to the mean plane of the pyrazoline ring. The latter has an envelope conformation with the methine (CH) C atom as the flap. There is an intra-molecular O-H?N hydrogen bond that forms an S(6) ring motif. In the crystal, mol-ecules are linked by C-H?O hydrogen bonds, forming chains along [100]. The chains are linked via C-H?N hydrogen bonds, forming sheets parallel to the ab plane. The sheets are linked by a series of N H?pi and C-H?pi inter-actions forming a three-dimensional structure. PMID- 26594436 TI - Crystal structure of 3a,6,6,9a-tetra-methyl-dodeca-hydro-naphtho-[2,1-b]furan-2 ol. AB - The title compound (common name: sclaral), C16H28O2, is a sclareolide derivative, which was synthesized from sclareolide itself. In the mol-ecule, the two six membered rings, A and B, of the labdane skeleton adopt chair conformations and the five-membered O-containing heterocyclic ring C displays an envelope conformation, with the methine C atom of the fused C-C bond as the flap. In the crystal, mol-ecules are linked by O-H?O hydrogen bonds, forming chains propagating along [100]. PMID- 26594437 TI - Crystal structure of 5-di-ethyl-amino-2-({[4-(di-ethyl-amino)-phen-yl]imino}-meth yl)phenol. AB - In the title compound, C21H29N3O, the dihedral angle between the planes of the aromatic rings is 8.1 (2) degrees . The ethyl groups at one terminal site of the compound are disordered over two sets of sites with occupancies of 0.775 (9) and 0.225 (9). The mol-ecule has an E conformation about the N=C bond. The mol-ecular structure features an intra-molecular O-H?N hydrogen bond, which closes an S(6) loop. In the crystal, weak C-H?pi inter-actions leads to the formation of a three dimensional network. PMID- 26594438 TI - Crystal structure of fenclorim. AB - In the title compound, C10H6Cl2N2 (systematic name: 4,6-di-chloro-2-phenyl pyrimidine), which is used commercially as the herbicide safener, fenclorim, the dihedral angle between the di-chloro-pyrimidyl and phenyl rings is 9.45 (10) degrees . In the crystal, C-H?N hydrogen bonds link adjacent mol-ecules, forming chains along the c-axis direction. In addition, weak inter-molecular C-Cl?pi [3.6185 (10) A] and pi-pi [3.8796 (11) A] inter-actions are present, forming a three-dimensional network. PMID- 26594439 TI - Crystal structure of 2-hy-droxy-2-(2-oxo-cyclo-hept-yl)-2,3-di-hydro-1H-indene 1,3-dione. AB - In the title compound, C16H16O4, the five-membered ring of the indene-1,3-dione unit adopts a twist conformation, whereas the seven-membered ring adopts a twist chair conformation. In the crystal, mol-ecules are linked by O-H?O hydrogen bonds, weak C-H?O hydrogen bonds and pi-pi stacking [centroid-to-centroid distance = 3.7373 (8) A] into a three-dimensional supra-molecular architecture. PMID- 26594440 TI - Crystal structure of ammonium (3,5-di-chloro-phen-oxy)acetate hemihydrate. AB - In the structure of the title hydrated salt, NH4 (+).C8H5Cl2O3 (-).0.5H2O, where the anion derives from (3,5-di-chloro-phen-oxy)acetic acid, the ammonium cation is involved in extensive N-H?O hydrogen bonding with both carboxyl-ate and ether O-atom acceptors giving sheet structures lying parallel to (100). The water mol ecule of solvation lies on a crystallographic twofold rotation axis and is involved in intra-sheet O-H?Ocarboxyl-ate hydrogen-bonding inter-actions. In the anion, the oxoacetate side chain assumes an antiperiplanar conformation with the defining C-O-C-C torsion angle = -171.33 (15) degrees . PMID- 26594441 TI - Crystal structure of beta-d,l-fructose. AB - The title compound, C6H12O6, was crystallized from an aqueous solution of equimolar mixture of d- and l-fructose (1,3,4,5,6-penta-hydroxy-hexan-2-one, arabino-hexulose or levu-lose), and it was confirmed that d-fructose (or l fructose) formed beta-pyran-ose with a (2) C 5 (or (5) C 2) conformation. In the crystal, two O-H?O hydrogen bonds between the hy-droxy groups at the C-1 and C-3 positions, and at the C-4 and C-5 positions connect homochiral mol-ecules into a column along the a axis. The columns are linked by other O-H?O hydrogen bonds between d- and l-fructose mol-ecules, forming a three-dimensional network. PMID- 26594448 TI - Crystal structure of (2R)-1-[(methyl-sulfon-yl)-oxy]propan-2-aminium chloride: a chiral mol-ecular salt. AB - In the title chiral mol-ecular salt, C4H12NO3S(+).Cl(-), the cation is protonated at the N atom, producing [RNH3](+), where R is CH3SO2OCH2C(H)CH3. The N atom in the cation is sp (3)-hybridized. In the crystal, cations and anions are connected by strong N-H?Cl hydrogen bonds to generate edge-shared 12-membered rings of the form {?Cl?HNH}3. This pattern of hydrogen bonding gives rise to zigzag supra molecular layers in the ab plane. The layers are connected into a three dimensional architecture by C-H?O hydrogen bonds. The structure was refined as an inversion twin. PMID- 26594450 TI - Crystal structure of 1,3-di-cyclo-hexyl-1-[3-(pyren-1-yl)prop-anoyl]urea. AB - In the title compound, C33H38N2O2, each of the cyclo-hexyl rings adopts a chair conformation. The two planes involving carbonyl groups, C-(C=O)-N and N-(C=O)-N, are oriented at a dihedral angle of 62.28 (10) degrees . In the crystal, two neighboring mol-ecules are linked by a pair of N-H?O inter-actions, generating an inversion dimer. The dimers are inter-connected by C-H?O hydrogen bonds into a supra-molecular chain along the a-axis direction. PMID- 26594445 TI - Crystal structure of mandipropamid. AB - In the title compound, C23H22ClNO4 (systematic name: (RS)-2-(4-chloro-phen-yl)-N {2-[3-meth-oxy-4-(prop-2-yn-1-yl-oxy)phen-yl]eth-yl}-2-(prop-2-yn yloxy)acetamide), an amide fungicide, the dihedral angle between the chloro benzene and benzene rings is 65.36 (6) degrees . In the crystal, N-H?O hydrogen bonds lead to zigzag supra-molecular chains along the c axis (glide symmetry). These are connected into layers by C-H?O and C-H?pi inter-actions; the layers stack along the a axis with no specific inter-molecular inter-actions between them. PMID- 26594442 TI - The crystal structure of 2-[5-(di-methyl-amino)-naphthalene-1-sulfonamido]-phenyl 5-(di-methyl-amino)-naphthalene-1-sulfonate. AB - The complete mol-ecule of the title compound, C30H29N3O5S2, is generated by a crystallographic twofold axis: the O atom and NH group attached to the central benzene ring are statistically disordered. The dihedral angle between the naphthalene ring system and the central benzene ring is 52.99 (6) degrees , while the pendant naphthalene ring systems subtend a dihedral angle of 68.17 (4) degrees . An intra-molecular C-H?O hydrogen bond closes an S(6) ring. In the crystal, the mol-ecules are linked by weak C-H?O hydrogen bonds. PMID- 26594447 TI - Crystal structure of (S)-2-amino-2-methyl-succinic acid. AB - The title compound, C5H9NO4, crystallized as a zwitterion. There is an intra molecular N-H?O hydrogen bond involving the trans-succinic acid and the ammonium group, forming an S(6) ring motif. In the crystal, mol-ecules are linked by O-H?O hydrogen bonds, forming C(7) chains along the c-axis direction. The chains are linked by N-H?O and C-H?O hydrogen bonds, forming sheets parallel to the bc plane. Further N-H?O hydrogen bonds link the sheets to form a three-dimensional framework. PMID- 26594444 TI - Crystal structure of ethyl 2-phenyl-9-phenyl-sulfonyl-9H-carbazole-3-carboxyl ate. AB - In the title compound, C27H21NO4S, the dihedral angles between the carbazole ring system (r.m.s. deviation = 0.015 A) and the sulfur-bonded and directly linked benzene rings are 79.98 (11) and 53.51 (18) degrees , respectively. The benzene rings subtend a dihedral angle of 48.4 (2) degrees . The ethyl side chain of the ester group has an extended conformation [C-O-C-C = -172.3 (3) degrees ]. In the crystal, inversion dimers linked by pairs of weak C-H?O hydrogen bonds generate R 2 (2)(22) loops. The dimers are linked by weak C-H?pi and pi-pi [centroid-to centroid distances ranging from 3.5042 (14) to 3.888 (2) A] inter-actions, thereby forming a three-dimensional supra-molecular network. PMID- 26594443 TI - Crystal structure of (E)-2-(4-meth-oxy-styr-yl)-3-methyl-1-phenyl-sulfonyl-1H indole. AB - In the title compound, C24H21NO3S, the dihedral angles between the indole ring system (r.m.s. deviation = 0.030 A) and the sulfur and ethyl-ene-bonded benzene rings are 80.2 (2) and 49.29 (15) degrees , respectively. The dihedral angle between the pendant benzene rings is 37.7 (2) degrees . In the crystal, mol ecules are linked by C-H?O hydrogen bonds and weak C-H?pi and pi-pi [centroid-to centroid distances = 3.549 (2) and 3.743 (3) A] inter-actions, forming a three dimensional network. PMID- 26594453 TI - Crystal structure of borated N,N,N',N'-tetra-methyldi-amino-methane. AB - In the title compound, {[(di-methyl-amino)-meth-yl]di-methyl-amine} trihydridoboron, C5H17BN2, the tetra-hedral geometry of the N-C-N unit is slightly disorted. As a result of the bulky amine substituents, a wider N-C-N angle of 113.6 (1) degrees is observed. The bond lengths between the N atom and methyl groups are slighly elongated to 1.481 (2) and 1.482 (2) A at the borated N atom, whereas the distances between the other N atom and its methyl groups are only 1.461 (2) and 1.462 (2) A. The studied crystal was twinned. The twin data refinement was subsequently carried out with a scale factor of 0.263 (1). The two lattices of the twin domains were rotated by 179.84 degrees . PMID- 26594457 TI - Crystal structure of 3-ethynyl-benzoic acid. AB - In the title compound, C9H6O2, the carb-oxy-lic acid group is almost in the plane of the benzene ring, making a dihedral angle of 2.49 (18) degrees . In the crystal, mol-ecules are linked by pairs of O-H?O hydrogen bonds, forming classical acid-acid inversion dimers, with an R 2 (2)(8) ring motif. The dimers are linked by pairs of C-H?O hydrogen bonds forming chains, enclosing R 2 (2)(16) ring motifs, propagating along the c-axis direction. PMID- 26594446 TI - Crystal structure of methyl (3RS,4SR,4aRS,11aRS,11bSR)-5-oxo 3,4,4a,5,7,8,9,10,11,11a-deca-hydro-3,11b-ep-oxy-azepino[2,1-a]iso-indole-4 carboxyl-ate. AB - The title compound, C15H19NO4, is the a product of the esterification of the corresponding carbonic acid with methanol. The mol-ecule comprises a fused tetra cyclic system containing three five-membered rings (2-pyrrolidinone, tetra-hydro furan and di-hydro-furan) and one seven-membered ring (azepane). The five membered rings have the usual envelope conformations, with the quaternary C atom being the flap atom for the 2-pyrrolidinone ring, and the ether O atom being the common flap atom for the remaining rings. The seven-membered azepane ring adopts a chair conformation with the methine and middle methyl-ene C atoms lying above and below the mean plane defined by the remaining five atoms. The carboxyl-ate substituent is rotated by 77.56 (5) degrees with respect to the base plane of the tetra-hydro-furan ring. In the crystal, the mol-ecules are bound by weak C H?O hydrogen-bonding inter-actions into puckered layers parallel to (001). PMID- 26594451 TI - Crystal structure of (3S*,4S*,4aS*,5R*,6R*,6aS*,7R*,11aS*,11bR*)-5,6-bis(benzo yloxy)-3,4a-dihy-droxy-4,7,11b-trimethyl-1,2,3,4,4a,5,6,6a,7,11,11a,11b-dodeca hydro-phenanthro[3,2-b]furan-4-carb-oxy-lic acid methanol monosolvate. AB - The title compound, C34H36O9.CH3OH, is a diterpenoid isolated from the roots of Caesalpinia pulcherrima (L.) Swartz. The three trans-fused six-membered rings are in chair, chair and half-chair conformations. The mean plane of this fused-ring system makes dihedral angles of 67.95 (15) and 83.72 (14) degrees with the two phenyl rings of the benzo-yloxy groups. An intra-molecular C-H?O hydrogen bond is observed. In the crystal, mol-ecules are linked via O-H?O hydrogen bonds, forming an infinite chain along the b-axis direction. PMID- 26594452 TI - Crystal structure of (E)-2-(4-chloro-benzyl-idene)-3,4-di-hydro-naphthalen-1(2H) one: a second monoclinic polymorph. AB - The title compound, C17H13ClO, is the second monoclinic polymorph to crystallize in the space group P21/c. The first polymorph crystallized with two independent mol-ecules in the asymmetric unit [Bolognesi et al. (1975 ?). Acta Cryst. A31, S119; Z' = 2; no atomic coordinates available], whereas the title compound has Z' = 1. In the title polymorph, the dihedral angle between the plane of the benzene ring of the tetra-lone moiety and that of the 4-chloro-benzyl ring is 52.21 (11) degrees . The cyclo-hex-2-en-1-one ring of the tetra-lone moiety has a screw-boat conformation. In the crystal, mol-ecules are liked by pairs of C-H?pi inter actions forming inversion dimers. There are no other significant inter-molecular inter-actions present. PMID- 26594449 TI - Crystal structure of 5-chloro-1,3-bis-[2-(2-oxo-1,3-oxazolidin-3-yl)eth-yl]-1H benz-imidazol-2(3H)-one. AB - In the title compound, C17H19ClN4O5, the benzimidazole fused-ring system is essentially planar, the maximum deviation from the mean plane being 0.06 (1) A. Both oxazolidine rings are nearly planar, the maximum deviations from the mean planes are 0.071 (13) and 0.070 (10) A. The dihedral angle between the mean planes of the oxazolidine rings is 69.9 (7) degrees . The benzimidazole mean plane makes the dihedral angles of 43.9 (6) and 45.6 (6) degrees with the two oxazolidine rings. In the crystal, the mol-ecules are linked together by weak C H?O hydrogen bonds building zigzag tapes running along the c axis. The Cl atom is split over two positions with an occupancy ratio of 0.567 (7):0.433 (7). This means that the reaction yields two isomers, A and B; the A component has the Cl atom substituent in the 5-position of the benzimidazolone ring and the B component has the Cl atom in the 6-position. The two isomers form the disordered co-crystal, with a nearly half Cl atom in each of them, as indicated by the occupancy ratio. The crystal structure was refined as an inversion twin. PMID- 26594455 TI - Crystal structure of bis-{2-[amino(iminium-yl)meth-yl]-1,1-di-methyl-guanidine} carbonate methanol disolvate. AB - In the title solvated mol-ecular salt, 2C4H12N5 (+).CO3 (2-).2CH3OH, the complete carbonate ion is generated by crystallographic twofold symmetry, with the C atom and one O atom lying on the rotation axis. The cation is twisted about the central C-N bond [C-N-C-N = -137.7 (6) degrees ]. In the crystal, the components are linked by N-H?O, N-H?N and O-H?O hydrogen bonds, generating a three dimensional supra-molecular network. PMID- 26594454 TI - Crystal structure of (2Z)-2-{(5Z)-5-[3-fluoro-2-(4-phenyl-piperidin-1-yl)benzyl idene]-4-oxo-3-(p-tol-yl)-1,3-thia-zolidin-2-yl-idene}-N-(p-tol-yl)ethane-thio amide dimethyl sulfoxide monosolvate. AB - The title compound, C37H34FN3OS2.C2H6OS, was obtained by the Knoevenagel condensation. The thia-zolidine ring is essentially planar (r.m.s. deviation = 0.025 A) and forms dihedral angles of 4.2 (3), 68.60 (14) and 39.57 (15) degrees with the attached thio-amide group, p-tolyl group benzene ring and fluoro substituted benzene ring, respectively. The exocyclic double bonds are in a Z configuration. In the crystal, the dimethyl sulfoxide solvent mol-ecule is connected to the main mol-ecule via an N-H?O hydrogen bond. Weak C-H?O hydrogen bonds link the components of the structure into a two-dimensional network parallel to (10-1). Weak intra-molecular C-H?S hydrogen bonds are also observed. The crystal is an inversion twin with a ratio of twin components 0.78 (2):0.22 (6). PMID- 26594456 TI - Crystal structure of 1-fluoro-1,3-di-hydro-benzo[c]thio-phene 2,2-dioxide. AB - In the title compound, C8H7FO2S, the thio-phene ring has an envelope conformation, with the S atom bearing the two O atoms being the flap. In the crystal, mol-ecules are linked by C-H?O and C-H?F inter-actions, generating a three-dimensional network structure. PMID- 26594458 TI - Crystal structure of 1,4,5,6,7,8,9,10,11,12,13-undeca-hydro-cyclo dodeca[c]pyrazol-3-ol. AB - The title compound, C13H22N2O, crystallized as a pyrazolol tautomer. The 12 membered macrocycle has a distorted chair conformation. In the crystal, mol ecules are linked via pairs of O-H?N hydrogen bonds, forming inversion dimers. The dimers are linked via N-H?pi and C-H?pi inter-actions, forming slabs parallel to the bc plane. PMID- 26594459 TI - Crystal structure of tetra-kis-(1-oxidopyridin-2-yl)methane methanol tetra solvate. AB - The asymmetric unit of the title compound, C21H16N4O4.4CH3OH, consists of a quarter mol-ecule of tetra-kis-(1-oxidopyridin-2-yl)methane and one methanol solvent mol-ecule. In the crystal, the pyridine N-oxide derivative is located about a fourfold rotoinversion axis and exhibits S 4 symmetry along the c axis. An inter-molecular O-H?O hydrogen bond is observed between the O atom of the pyridine N-oxide and the OH group of the methanol. An inter-molecular C-H?O bond is also observed between adjacent pyridine N-oxide rings. PMID- 26594460 TI - Crystal structure of N-{[3-bromo-1-(phenyl-sulfon-yl)-1H-indol-2-yl]meth yl}benzene-sulfonamide. AB - In the title compound, C21H17BrN2O4S2, the indole ring system subtends dihedral angles of 85.96 (13) and 9.62 (16) degrees with the planes of the N- and C bonded benzene rings, respectively. The dihedral angles between the benzene rings is 88.05 (17) degrees . The mol-ecular conformation is stabilized by intra molecular N-H?O and C-H?O hydrogen bonds and an aromatic pi-pi stacking [centroid to-centroid distance = 3.503 (2) A] inter-action. In the crystal, short Br?O [2.9888 (18) A] contacts link the mol-ecules into [010] chains. The chains are cross-linked by weak C-H?pi inter-actions, forming a three-dimensional network. PMID- 26594461 TI - Crystal structure of [(2S,3R)-3-hy-droxy-3-phenyl-butan-2-yl]pyrrolidinium chloride. AB - In the title mol-ecular salt, C14H22NO(+).Cl(-), the pyrrolidinium ring adopts a twisted conformation about one of the N-C bonds. It is oriented at a dihedral angle of 42.0 (1) degrees with respect to the benzene ring. The torsion angle for the central N-C-C-Car (ar = aromatic) linkage is 163.74 (15) degrees . In the crystal, the components are linked via N-H?Cl and O-H?Cl hydrogen bonds, forming zigzig chains along the b-axis direction. These chains are connected along the c axis by very weak C-H?pi inter-actions, forming a two-dimensional supra-molecular network. PMID- 26594462 TI - Crystal structure of benz-yl(meth-yl)phen-yl[(piperidin-1-ium-1-yl)meth-yl]silane bromide. AB - The title compound, C20H29NSi(+).Br(-), contains a chiral silicon atom but crystallizes as a racemate. The C-Si-C bond angles in the range of 103.64 (8) 111.59 (9) degrees are usual for tetra-hedral geometry. The piperidine ring shows a regular chair conformation with an equatorially positioned exocyclic N-C bond. In the crystal, there is a hydrogen bond between the ammonium cation and the bromide anion. The crystal packing shows the dominant inter-molecular inter action to be the electrostatic attraction between the ammonium cation and the bromide anion. PMID- 26594463 TI - Crystal structure of 4-nitro-N-[(pyridin-2-yl)methyl-idene]aniline. AB - The title compound, C12H9N3O2, adopts an E conformation at the imine double bond. The pyridyl ring makes a dihedral angle of 47.78 (5) degrees with the benzene ring, indicating the mol-ecule is twisted. In the crystal, mol-ecules are pi-pi stacked into columns parallel to [100], with an inter-planar separation of 3.8537 (8) A, corresponding to the length of the a axis. The chains are further linked via weak C-H?O and C-H?N hydrogen bonds, forming two-dimensional sheets parallel to (010). The sheets interact by van der Waals inter-actions. PMID- 26594464 TI - Crystal structure of (E)-N'-(3,4-di-fluoro-benzyl-idene)-4-methyl-benzene-sulfono hydrazide. AB - In the title compound, C14H12F2N2O2S, the dihedral angle between the aromatic rings is 70.23 (8) degrees and the S-N-N=C torsion angle is 172.11 (11) degrees . In the crystal, N-H?O hydrogen bonds link the mol-ecules into [100] C(4) chains, with adjacent mol-ecules in the chain related by translational symmetry. The chains are linked by weak C-H?F and C-H?O inter-actions, thereby forming a three-dimensional network. PMID- 26594465 TI - Crystal structure of ethyl 5-acetyl-2-{[(di-methyl-amino)-methyl-idene]amino}-4 methyl-thio-phene-3-carboxyl-ate. AB - In the title thio-phene derivative, C13H18N2O3S, the dihedral angles between the thio-phene ring and the [(di-methyl-amino)-methyl-idene]amino side chain (r.m.s. deviation = 0.009 A) and the -CO2 ester group are 3.01 (16) and 59.9 (3) degrees , respectively. In the crystal, inversion dimers linked by pairs of C-H?O hydrogen bonds generate R 2 (2)(16) loops. The dimers are linked by another weak C-H?O inter-action, forming chains along [001]. In addition, weak C-H?pi inter actions are observed, which link the chains into (001) layers. PMID- 26594467 TI - Crystal structure of 3-methyl-1-phenyl-6-propyl-amino-1H-pyrazolo[3,4-b]pyridine 5-carbo-nitrile. AB - In the title compound, C17H17N5, the dihedral angle between the 1H-pyrazolo-[3,4 b]pyridine ring system (r.m.s. deviation = 0.001 A) and the attached phenyl group is 2.56 (6) degrees . The propyl-amino side chain has a contorted conformation [Car-N-C-C = -77.97 (16) degrees and N-C-C-C = -57.37 (17) degrees ]. An intra molecular C-H?N inter-action closes an S(6) ring. In the crystal, inversion dimers linked by pairs of N-H?N hydrogen bonds generate R 2 (2)(12) loops. Aromatic pi-pi stacking inter-actions [centroid-centroid distance = 3.5726 (8) A] are also observed. PMID- 26594466 TI - Crystal structure of 2-acetyl-5-(3,4-di-meth-oxy-phen-yl)-6-eth-oxy-carbonyl-3,7 dimethyl-5H-thia-zolo[3,2-a]pyrimidin-8-ium chloride. AB - The title mol-ecular salt, C21H25N2O5S(+).Cl(-), crystallizes with two ion pairs in the asymmetric unit. The cations have similar conformations (r.m.s. overlay fit = 0.40 A), with one of them showing disorder of the terminal methyl group of the ester in a 0.72 (2):0.28 (2) ratio. In the first cation, the 3,4-dimeth-oxy substituted phenyl ring subtends a dihedral angle of 88.38 (7) degrees with the pyrimidine ring and 6.79 (8) degrees with the thia-zole ring. The equivalent data for the second cation are 89.97 (3) and 6.42 (7) degrees , respectively. The pyrimidine ring adopts a sofa conformation in each cation. In the crystal, the components are linked by N-H?Cl hydrogen bonds, generating isolated ion pairs. The ion pairs are are linked by C-H?O inter-actions, generating a three dimensional network. In addition, a weak C-H?pi inter-action is observed. PMID- 26594468 TI - Crystal structure of flumioxazin. AB - The title compound {systematic name: 2-[7-fluoro-3,4-di-hydro-3-oxo-4-(prop-2-yn 1-yl)-2H-1,4-benzoxazin-6-yl]-4,5,6,7-tetra-hydro-1H-iso-indole-1,3(2H)-dione}, C19H15FN2O4, is a dicarboximide herbicide. The dihedral angle between the male imide and benzene ring planes is 66.13 (5) degrees . In the crystal, C-H?O and C H?F hydrogen bonds and weak C-H?pi inter-actions [3.5601 (19) A] link adjacent mol-ecules, forming two-dimensional networks extending parallel to the (110) plane. PMID- 26594469 TI - Crystal structure of 1,5-diethyl-3',5'-di-phenyl-1,5-di-hydro-3'H-spiro-[pyra zolo[3,4-d]pyrimidine-4,2'-[1,3,4]thia-diazole]. AB - In the title compound, C22H22N6S, the pyrazolo-[3,4-d]pyrimidine rings system is almost planar, with the r.m.s. deviation for the fitted atoms being 0.011 A. The two phenyl groups linked to the thia-diazole ring are nearly perpendicular to the fused-ring system as indicated by the dihedral angles of 86.93 (10) and 83.35 (11) degrees . However, the phenyl rings are almost coplanar with the thia diazole ring (r.m.s. deviation = 0.015 A), forming dihedral angles of 10.44 (11) and 10.06 (12) degrees . In the crystal, mol-ecules are connected into a supra molecular layer in the ac plane via C-H?pi inter-actions. PMID- 26594470 TI - Crystal structure of (E)-4,6-dimeth-oxy-2-(4-meth-oxy-styr-yl)-3-methyl benzaldehyde. AB - In the title mol-ecule, C19H20O4, the central C=C double bond adopts an E configuration. The dihedral angle formed by the planes of the two benzene rings is 83.57 (12) degrees . The three meth-oxy groups are essentially coplanar with the benzene rings to which they are attached, with C C-O-C torsion angles of -0.2 (3), -2.3 (3) and -4.1 (3) degrees . PMID- 26594471 TI - Crystal structure of 4-[(E)-(2-carbamo-thio-ylhydrazinyl-idene)meth-yl]benzoic acid. AB - The title compound, C9H9N3O2S, is close to planar with an r.m.s. deviation of 0.032 A. An intra-molecular N-H?N hydrogen bond closes an S(5) ring. In the crystal, mol-ecules are connected into inversion dimers of the R 2 (2)(8) type by pairs of O-H?O inter-actions. The dimers are further connected by pairs of N-H?S inter-actions, which also complete R 2 (2)(8) ring motifs. The chains of dimers are cross-linked by N-H?O bonds and hence R 4 (2)(28) rings are completed. Taken together, these inter-actions lead to infinite sheets propagating in the (122) plane. PMID- 26594472 TI - Crystal structure of 1-(5-bromo-1-benzo-furan-2-yl)ethanone oxime. AB - The title compound, C10H8BrNO2, is almost planar (r.m.s. deviation for the non-H atoms = 0.031 A) and the conformation across the C=N bond is trans. Further, the O atom of the benzo-furan ring is syn to the N atom of the oxime group. In the crystal, inversion dimers linked by pairs of O-H?N hydrogen bonds generate R 2 (2)(6) loops. Very weak aromatic pi-pi stacking inter-actions [centroid-centroid separations = 3.9100 (12) and 3.9447 (12) A] are also observed. PMID- 26594473 TI - Crystal structure of 2,6-di-chloro-4-nitro-pyridine N-oxide. AB - In the title compound, C5H2Cl2N2O3, the nitro group is essentially coplanar with the aromatic ring, with a twist angle of 4.00 (6) degrees and a fold angle of 2.28 (17) degrees . The crystal structure exhibits a herringbone pattern with the zigzag running along the b axis. The herringbone layer-to-layer distance is 3.0075 (15) A, with a shift of 5.150 (4) A. Neighboring mol-ecules are tilted at a 57.83 (4) degrees (ring-to-ring) angle with each other. The nitro group on one mol-ecule points to the N-oxide group on the neighboring one, with an inter molecular O?N(nitro) distance of 3.1725 (13) A. PMID- 26594474 TI - Crystal structure of methyl (2Z)-2-[(2Z)-2-(2-cyclo-pentyl-idenehydrazin-1-yl idene)-4-oxo-3-phenyl-1,3-thia-zolidin-5-yl-idene]ethano-ate. AB - In the title compound, C17H17N3O3S, the cyclo-pentane ring is disordered over two sets of sites with an occupancy ratio of 0.775 (8):0.225 (8) for the affected atoms. The thia-zolidinyl ring is planar (r.m.s. deviation = 0.024 A) and forms a dihedral angle of 65.13 (8) degrees with the attached phenyl ring. The mol ecular packing is stabilized by C-H?O and C-H?pi inter-actions, forming a three dimensional structure. PMID- 26594475 TI - Crystal structure of tetra-ethyl 27,30-dioxo-7,12,20,25-tetra-tert-but-yl-3,16 dioxa-9,22,28,31-tetra-thia-hepta-cyclo [21.3.1.1(1,5).1(4,8).1(10,14).1(14,18).1(17,21)]dotriaconta 4,6,8(29),10,12,17,19,21(32),23,25-deca-ene-2,2,15,15-tetra-carboxyl-ate. AB - The asymmetric unit of the title compound, C54H64O12S4, consists of one half of the mol-ecule, which is located on an inversion centre. The heterocyclic six membered ring adopts a distorted envelope conformation with the spiro C atom as the flap. In the crystal, mol-ecules are linked by weak C-H?O hydrogen bonds with an R (2) 2(14) motif, forming a chain along the b-axis direction. PMID- 26594476 TI - Crystal structure of triethyl 2-(5-nitro-2H-indazol-2-yl)propane-1,2,3-tri carboxyl-ate. AB - In the title compound, C19H23N3O8, the 5-nitro-2H-indazol-2-yl unit is almost planar, with the maximum deviation from the mean plane being 0.024 (2) A. The fused-ring system is nearly perpendicular to the three carboxyl-ate groups, with dihedral angles of 90.0 (3), 83.8 (1) and 80.4 (1) degrees . The ethyl groups attached to both ends of the propane chain are each disordered over two sets of sites, with site-occupancy ratios of 0.425 (17):0.575 (17) and 0.302 (15):0.698 (15). In the crystal, mol-ecules are linked by pairs of C-H?N hydrogen bonds, forming inversion dimers. The dimers are further linked by C-H?O hydrogen bonds, forming a three-dimensional network. PMID- 26594477 TI - Crystal structure of O-ethyl N-(eth-oxy-carbon-yl)thio-carbamate. AB - The title compound, C6H11NO3S, provides entries to novel carbamoyl disulfanes and related compounds of inter-est to our laboratory. The atoms of the central O(C=S)N(C=O)O fragment have an r.m.s. deviation of 0.1077 A from the respective least-squares plane. While several conformational orientations are conceivable, the crystal structure shows only the one in which the carbonyl and the thio carbonyl moieties are anti to each other across the central conjugated C-N-C moiety. Pairs of 2.54 A N-H?S=C hydrogen bonds between adjacent mol-ecules form centrosymmetric dimers in the crystal. PMID- 26594478 TI - Crystal structure of dimethyl 9H-carbazole-2,7-di-carb-oxy-late. AB - In the title compound, C16H13NO4, the carbazole ring system is almost planar with non-H atoms possessing a mean deviation from planarity of 0.037 A. The two ester groups are orientated trans to one another and tilted slightly from the mean plane of the carbazole ring system, making dihedral angles of 8.12 (6) and 8.21 (5) degrees . In the crystal, mol-ecules are linked by pairs of N-H?O hydrogen bonds forming inversion dimers. The dimers are linked by parallel slipped pi-pi inter-actions, forming slabs propagating along the b-axis direction [inter centroid distance = 3.6042 (8) A, inter-planar distance = 3.3437 (5) A, slippage = 1.345 A]. PMID- 26594479 TI - Crystal structure of N,N,N-tris-[(1,3-benzo-thia-zol-2-yl)meth-yl]amine. AB - The title compound, C24H18N4S3, exhibits three near planar benzo-thia-zole systems in a pseudo-C 3 conformation. The dihedral angles between the planes of the benzo-thia-zole groups range from 112.56 (4) to 124.68 (4) degrees In the crystal, mol-ecules are connected to each other through three short C-H?N contacts, forming an infinite chain along [100]. The molecules are also linked by pi-pi interactions with each of the three five-membered thiazole rings. [inter centroid distance range: 3.614 (1)-4.074 (1) A, inter-planar distance range: 3.4806 (17)-3.6902 (15) A, slippage range: 0.759 (3)-1.887 (3) A]. PMID- 26594480 TI - Crystal structure of 2-[(1R,2R,4aS,8aS)-2-hy-droxy-2,5,5,8a-tetra-methyl-deca hydro-naphthalen-1-yl]-N-(o-tol-yl)acetamide. AB - The title compound, C23H35NO2, is an amide derivative of the lactone (+) sclareolide, and was synthesized from natural sclareol. In the mol-ecular structure, the two six-membered rings (A and B) of the labdane skeleton are trans fused, and adopt chair conformations. There is an intra-molecular N-H?O hydrogen bond present forming an S(7) ring motif. In the crystal, O-H?O hydrogen bonds link the mol-ecules into helical chains propagating along the b-axis direction. The chains are linked via C-H?pi inter-actions, forming a three-dimensional structure. PMID- 26594481 TI - Crystal structure of (4-hy-droxy-piperidin-1-yl)[4-(tri-fluoro-meth-yl)phen yl]methanone. AB - The title compound, C13H14NO2F3, crystallises with two mol-ecules, A and B, in the asymmetric unit, with similar conformations. The dihedral angles between the piperidine and phenyl rings are 83.76 (2) and 75.23 (2) degrees in mol-ecules A and B, respectively. The bond-angle sums around the N atoms [359.1 and 359.7 degrees for mol-ecules A and B, respectively] indicate sp (2) hybridization for these atoms. In the crystal, O-H?O hydrogen bonds link the mol-ecules into separate [100] chains of A and B mol-ecules. The chains are cross-linked by C-H?O inter-actions, generating alternating (001) sheets of A and B mol-ecules. PMID- 26594482 TI - Crystal structure of 2-(2,4-diphenyl-3-aza-bicyclo-[3.3.1]nonan-9-yl-idene)aceto nitrile. AB - In the title 3-aza-bicyclo-nonane derivative, C22H22N2, both the fused piperidine and cyclo-hexane rings adopt a chair conformation. The phenyl rings attached to the central aza-bicylononane fragment in an equatorial orientation are inclined to each other at 23.7 (1) degrees . The amino group is not involved in any hydrogen bonding, so the crystal packing is stabilized only by van der Waals forces. PMID- 26594483 TI - Crystal structure of benzimidazolium salicylate. AB - In the anion of the title mol-ecular salt, C7H7N2 (+).C7H5O3 (-) (systematic name: 1H-benzimidazol-3-ium 2-hy-droxy-ben-zo-ate), there is an intra-molecular O H?O hydrogen bond that generates an S(6) ring motif. The CO2 group makes a dihedral angle of 5.33 (15) degrees with its attached ring. In the crystal, the dihedral angle between the benzimidazolium ring and the anion benzene ring is 75.88 (5) degrees . Two cations bridge two anions via two pairs of N-H?O hydrogen bonds, enclosing an R (4) 4(16) ring motif, forming a four-membered centrosymmetric arrangement. These units are linked via C-H?O hydrogen bonds, forming chains propagating along the b-axis direction. The chains are linked by C H?pi and pi-pi inter-actions [inter-centroid distances = 3.4156 (7) and 3.8196 (8) A], forming a three-dimensional structure. PMID- 26594484 TI - Crystal structure of 2-[2-(hy-droxy-imino)-1-phenyl-propyl-idene]-N-phen ylhydrazinecarbo-thio-amide. AB - In the title compound, C16H16N4OS, an intra-molecular C-H?S hydrogen bond is observed. With the exception of the phenyl ring of the phenyl-propyl-idene unit, the remainder of the mol-ecule has an almost planar skeleton with an r.m.s. deviation of 0.121 (5) A from the plane through the remaining 16 atoms. In the crystal O-H?N hydrogen bonds are observed between the terminal hy-droxy-imino groups, forming inverson dimers with R 2 (2)(6) graph-set motifs. Additional C H?N contacts stack the dimers along [100]. While no pi-pi inter-actions are present, weak C-H?O and O-H?Cg inter-actions are also observed and help stabilize the crystal packing. PMID- 26594485 TI - Crystal structure of 1-meth-oxy-5-methyl-N-phenyl-1,2,3-triazole-4-carboxamide. AB - The title compound, C 11H12N4O2,was prepared via the transformation of sodium 4 acetyl-1-phenyl-1H-[1.2.3]triazolate under the action of meth-oxy-amine hydro chloride. The dihedral angle between the triazole and phenyl rings is 25.12 (16) degrees and the C atom of the meth-oxy group deviates from the triazole plane by 0.894 (4)A. The conformation of the CONHR-group is consolodated by an intra molecular N-H?N hydrogen bond to an N-atom of the triazole ring, which closes an S(5) ring. In the crystal, weak N-H?N hydrogen bonds link the mol-ecules into C(6) [010] chains. PMID- 26594486 TI - Redetermined structure of 4,4'-bi-pyridine-1,4-phenyl-enedi-acetic acid (1/1) co crystal. AB - The asymmetric unit of the title 1:1 co-crystal, C10H8N2.C10H10O4, consists of one half-mol-ecule each of 4,4'-bi-pyridine and 1,4-phenyl-enedi-acetic acid: the complete mol-ecules are generated by crystallographic inversion centres. The dihedral angle between the -CO2H group and the benzene ring in the diacid is 73.02 (7) degrees . In the crystal, the components are linked by O-H?N hydrogen bonds, generating [1-2-1] chains of alternating amine and carb-oxy-lic acid mol ecules. The chains are cross-linked by C-H?O inter-actions. This structure was previously incorrectly described as a (C10H10N2)(2+).(C10H8O4)(2-) mol-ecular salt [Jia et al. (2009 ?). Acta Cryst. E65, o2490-o2490]. PMID- 26594487 TI - Crystal structure of 7-isopropyl-1,4a,N-trimethyl-1,2,3,4,4a,4b,5,6,7,8,10,10a dodeca-hydro-phenanthrene-1-carb-ox-amide. AB - In the title compound, C26H37NO, a new derivative of di-hydro-abietic acid, the two cyclo-hexene rings adopt half chair conformations, whereas the cyclo-hexane ring has a chair conformation. Each of the methyl groups is in an axial position with respect to the tricyclic hydro-phenanthrene residue. In the crystal packing, methyl-ene-C-H?pi(phen-yl) inter-actions lead to supra-molecular helical chains along [010]; the amide-H atom does not form a significant inter-molecular inter action owing to steric pressure. PMID- 26594488 TI - Crystal structure of (E)-4-[N-(7-methyl-2-phenyl-imidazo[1,2-a]pyridin-3 yl)carboximido-yl]phenol. AB - The mol-ecule of the title compound, C21H17N3O, is built up from fused five- and six-membered rings connected to a methyl group, a phenyl ring and an (imino-meth yl)phenol group. The fused ring system is almost planar (r.m.s. deviation = 0.031 A) and forms dihedral angles of 64.97 (7) and 18.52 (6) degrees with the phenyl ring and the (imino-meth-yl)phenol group, respectively. In the crystal, centrosymmetric mol-ecules are linked by pairs of C-H?pi inter-actions into dimeric units, which are further connected by O-H?N hydrogen bonds to form layers parallel to (101). PMID- 26594489 TI - Crystal structure of 4-[(2,4-di-chloro-phen-yl)(5-hy-droxy-3-methyl-1-phenyl-1H pyrazol-4-yl)meth-yl]-5-methyl-2-phenyl-2,3-di-hydro-1H-pyrazol-3-one. AB - In the title compound C27H22Cl2N4O2, the pyrazol-5-ol ring makes a dihedral angle of 34.80 (11) degrees with the phenyl ring to which it is bound, while the pyrazolone ring is inclined at 34.34 (12) degrees to its attached phenyl ring. In the crystal, N-H?O and C-H?Cl hydrogen bonds link the mol-ecules into chains along [010]. Inter-molecular pi-pi inter-actions are observed between the pyrazolone ring and the phenyl ring bound to the pyrazol-5-ol ring system [centroid-centroid separation = 3.916 (2) A]. PMID- 26594490 TI - A comparison of the structures of some 2- and 3-substituted chromone derivatives: a structural study on the importance of the secondary carboxamide backbone for the inhibitory activity of MAO-B. AB - The crystal structures of the 3-substituted tertiary chromone carboxamide derivative, C17H13NO3, N-methyl-4-oxo-N-phenyl-4H-chromene-3-carboxamide (1), and the chromone carbonyl pyrrolidine derivatives, C14H13NO3, 3-(pyrrolidine-1-carbon yl)-4H-chromen-4-one (3) and 2-(pyrrolidine-1-carbon-yl)-4H-chromen-4-one (4) have been determined. Their structural features are discussed and compared with similar compounds namely with respect to their MAO-B inhibitory activities. The chromone carboxamide presents a -syn conformation with the aromatic rings twisted with respect to each other [the dihedral angle between the mean planes of the chromone system and the exocyclic phenyl ring is 58.48 (8) degrees ]. The pyrrolidine derivatives also display a significant twist: the dihedral angles between the chromone system and the best plane formed by the pyrrolidine atoms are 48.9 (2) and 23.97 (12) degrees in (3) and (4), respectively. Compound (3) shows a short C-H?O intra-molecular contact forming an S(7) ring. The supra molecular structures for each compound are defined by weak C-H?O hydrogen bonds, which link the mol-ecules into chains and sheets. The Cambridge Structural Database gave 45 hits for compounds with a pyrrolidinecarbonyl group. A simple statistical analysis of their geometric parameters is made in order to compare them with those of the mol-ecules determined in the present work. PMID- 26594491 TI - Crystal structure of 2alpha-(1,1-di-phenyl-eth-yl)-4-methyl-4alpha,5alpha diphenyl-1,3-dioxolane: the result of a non-acid pinacol rearrangement. AB - The title compound, C30H28O2, was obtained during recrystallization of (+/-)-1,2 diphenyl-1,2-propane-diol in 1-butanol, from an unexpected non-acid-catalyzed pinacol rearrangement followed by acetal formation of the newly formed aldehyde with the diol. The tri-substituted dioxolane ring has a twist conformation on the C-O bond opposite the methyl-substituted C atom. There is an intra-molecular C H?pi inter-action present involving one of the di-phenyl-ethyl rings and an H atom of the phenyl ring in position 4 of the dioxolane ring. In the crystal, mol ecules are linked by weak C-H?O hydrogen bonds, forming chains along [001]. The chains are linked by a second C-H?pi inter-action, forming sheets parallel to the bc plane. PMID- 26594492 TI - Crystal structure of benzene-1,3,5-tri-carb-oxy-lic acid-4-pyridone (1/3). AB - Slow co-crystallization of a solution of benzene-1,3,5-tri-carb-oxy-lic acid with a large excess of 4-hy-droxy-pyridine produces an inter-penetrating, three dimensional, hydrogen-bonded framework consisting of three 4-pyridone and one benzene-1,3,5-tri-carb-oxy-lic acid mol-ecules, C9H6O6.3C5H5NO. This structure represents an ortho-rhom-bic polymorph of the previously reported C-centered, monoclinic structure [Campos-Gaxiola et al. (2014 ?). Acta Cryst. E70, o453 o454]. PMID- 26594493 TI - Crystal structure of a helical silver(I) coordination polymer based on an unsymmetrical dipyridyl ligand: catena-poly[[silver(I)-MU-N-(pyridin-4-ylmeth yl)pyridine-3-amine-kappa (2) N:N'] tetra-fluorido-borate methanol hemisolvate]. AB - The asymmetric unit of the title compound, {[AgL].BF4.0.5CH3OH} n , L = N (pyridin-4-ylmeth-yl)pyridine-3-amine, C11H11N3, contains one Ag(I) ion, one ligand L, one tetra-fluorido-borate anion disordered over two orientations in a 0.669 (13):0.331 (13) ratio and one half of a methanol solvent mol-ecule situated on an inversion center. Each Ag(I) ion is coordinated by two N atoms from two L ligands in a distorted linear geometry [N-Ag-N = 174.70 (19) degrees ]. Each L ligand bridges two Ag(I) ions, thus forming polymeric helical chains propagating in [010]. In the crystal, Ag?Ag [3.3369 (10) A] and pi-pi inter-actions between the aromatic rings [centroid-to-centroid distance = 3.676 (4) A] link these chains into layers parallel to (10-1). Ag?F and weak N(C)-H?F inter-actions further consolidate the crystal packing. PMID- 26594494 TI - Crystal structures of three co-crystals of 4,4'-bipyridyl with 4-alk-oxy-benzoic acids: 4-eth-oxy-benzoic acid-4,4'-bipyridyl (2/1), 4-n-propoxybenzoic acid-4,4' bipyridyl (2/1) and 4-n-but-oxy-benzoic acid-4,4'-bipyridyl (2/1). AB - The crystal structures of three hydrogen-bonded co-crystals of 4-alk-oxy-benzoic acid-4,4'-bipyridyl (2/1), namely, 2C9H10O3.C10H8N2, (I), 2C10H12O3.C10H8N2, (II) and 2C11H14O3.C10H8N2, (III), have been determined at 93 K. Although the structure of (I) has been determined in the space group P21 with Z = 4 [Lai et al. (2008 ?). J. Struct. Chem. 49, 1137-1140], the present study shows that the space group is P21/n with Z = 4. In each crystal, the components are linked by O H?N hydrogen bonds, forming a linear hydrogen-bonded 2:1 unit of the acid and the base. The 2:1 unit of (I) adopts nearly pseudo-C 2 symmetry, viz. twofold rotation around an axis passing through the mid-point of the central C-C bond of 4,4'-bipyridyl, while the units of (II) and (III), except for the terminal alkyl chains, have pseudo-inversion symmetry. The 2:1 units of (I), (II) and (III) are linked via C-H?O hydrogen bonds, forming sheet, double-tape and tape structures, respectively. PMID- 26594495 TI - Crystal structure of [MU2-3,3-dimethyl-4-(propan-2-yl-idene)thietane-2,2-dithiol ato-kappa(4) S:S':S:S']bis[tricarbonyl-iron(I)](Fe-Fe). AB - The title complex, [Fe2(C8H12S3)(CO)6] or [{Fe(CO)3}2(MU-L)] [L = 3,3-dimethyl-4 (propan-2-yl-idene)thietane-2,2-bis-(thiol-ato)], consists of two Fe(CO)3 moieties double-bridged by a di-thiol-ate ligand. Each of the two Fe(I) atoms has a distorted anti-prismatic coordination environment consisting of three carbonyl groups, two S atoms of the di-thiol-ate ligand and the neighboring Fe(I) atom [Fe Fe = 2.4921 (4) A]. Weak C-H?O inter-molecular inter-actions result in the formation of dimers. This is the second crystal structure reported with the 3,3 dimethyl-4-(propan-2-yl-idene)thietane-2,2-bis-(thiol-ate) ligand and the first in which it bridges two metal atoms. PMID- 26594496 TI - Crystal structure of tetra-aqua-(di-methyl-formamide)-tetra-kis-(MU-N,2-dioxido benzene-1-carboximidato)tetra-kis-(MU-tri-methyl-acetato)-tetra manganese(III)sodiumyttrium-di-methyl-formamide-water (1/8.04/0.62). AB - The synthesis and crystal structure for the title compound, [YNaMn4(C7H4NO3)4(C5H9O2)4(H2O)3.76(C3H7NO)0.24].8.04C3H7NO.0.62H2O or [Y(III)Na(OTMA)4[12-MCMn(III)N(shi)-4](H2O)3.76(DMF)0.24.8.04DMF.0.62H2O, where OTMA is tri-methyl-acetate, MC is metallacrown, shi(3-) is salicyl-hydroximate, and DMF is N,N-di-methyl-formamide, is reported. The macrocyclic metallacrown consists of an -[Mn(III)-N-O]4- ring repeat unit, and the metallacrown captures one Y(III) ion and one Na(I) ion in the central cavity on opposite faces of the metallacrown. Overall the metallacrown is domed towards the side of the Na(I) ion. Both the Y(III) and Na(I) ions are eight-coordinate, and the tri-methyl acetate anions bridge the central Y(III) to each ring Mn(III) ion. The ring Mn(III) ions are six-coordinate with a tetra-gonally distorted octa-hedral geometry. PMID- 26594497 TI - Crystal structure of bis-(2-{[1,1-bis-(hy-droxy-meth-yl)-2-oxidoeth-yl]imino-meth yl}-6-meth-oxy-phenolato)manganese(IV) 0.39-hydrate. AB - The title compound, [Mn(C12H15NO5)2].0.39H2O, is a 0.39 hydrate of the isostructural complex bis-(2-{[1,1-bis-(hy-droxy-meth-yl)-2-oxidoeth-yl]imino meth-yl}-6-meth-oxy-phenolato)manganese(IV) that has previously been reported by Back, Oliveira, Canabarro & Iglesias [Z. Anorg. Allg. Chem. (2015), 641, 941 947], based on room-temperature data. The current structure that was determined at 100 K reveals a lengthening of the c cell parameter compared with the published one due to the incorporation of the partial occupancy water mol-ecule. The title compound crystallizes in the tetra-gonal chiral space group P41212; the neutral [Mn(IV)(C12H15NO5)2] mol-ecule is situated on a crystallographic C 2 axis. The overall geometry about the central manganese ion is octa-hedral with an N2O4 core; each ligand acts as a meridional ONO donor. The coordination environment of Mn(IV) at 100 K displays a difference in one of the two Mn-O bond lengths, compared with the room-temperature structure. In the crystal, the neutral mol-ecules are stacked in a helical fashion along the c-axis direction. PMID- 26594498 TI - Crystal structure of 5-hy-droxy-5-propyl-barbituric acid. AB - Mol-ecules of the title compound, C7H10N2O4, systematic name 5-hy-droxy-5-propyl pyrimidine-2,4,6(1H,3H,5H)-trione, form a hydrogen-bonded framework which is based on three independent hydrogen bonds, N-H?O(carbon-yl), N-H?O(hy-droxy) and O-H?O(carbon-yl). This framework has the topology of the 5-connected nov net. Each mol-ecule is linked to five other mol-ecules via six hydrogen bonds, and the descriptor of the hydrogen-bonded structure is F65[4(4).6(6)-nov]. The crystal packing is isostructural with that of the previously reported 5-hy-droxy-5-ethyl analogue. PMID- 26594500 TI - Crystal structure of (E)-2-amino-4-methyl-sulfanyl-6-oxo-1-{[(thiophen-2-yl) methyl-idene]-amino}-1,6-di-hydro-pyrimidine-5-carbo-nitrile. AB - The title compound, C11H9N5OS2, a 1-thio-phen-2-yl-methyl-ene-amino-pyrimidine derivative, displays an essentially planar C-NH2 group. The conformation across the N=C bond linking the pyrimidine and thienyl groups is E. The pyrimidine and thienyl ring systems subtend an inter-planar angle of 42.72 (5) degrees . In the crystal, mol-ecules are linked by N-H?Nnitrile and N-H?O=C hydrogen bonds, forming chains parallel to the b axis. PMID- 26594499 TI - Crystal structures of two unusual, high oxidation state, 16-electron irida benzenes. AB - Treatment of carbon-yl(1,2-diphenylpenta-1,3-dien-1-yl-5-yl-idene)bis-(tri-phenyl phosphane)iridium, [IrCO(-C(Ph)=C(Ph)-CH=CH-CH=)(PPh3)2], with either bromine or iodine produced di-bromido-(1,2-diphenylpenta-1,3-dien-1-yl-5-yl-idene)(tri phenyl-phosphine)iridium(III), [IrBr2{-C(Ph)=C(Ph)-CH=CH-CH=}(PPh3)], (I), and (1,2-diphenylpenta-1,3-dien-1-yl-5-yl-idene)di-iodido-(tri-phenyl phosphane)iridium(III), [IrI2{-C(Ph)=C(Ph)-CH=CH-CH=}(PPh3)], (II), respectively, which are two rare examples of 16-electron metalla-benzenes. Structural elucidation of (I) and (II) reveals that these isotypic irida-benzenes are unusual, not only in their electron count, but also in their coordination sphere of the Ir(III) atom where they contain an apparent open coordination site. The crystal structures of (I) and (II) confirm that the mol-ecules are complexes containing five-coordinated Ir(III) with only one tri-phenyl-phosphine group bound to the iridium atom, unambiguously proving that the mol-ecules are indeed 16-electron, high-oxidation-state irida-benzenes. The coordination geometry of the Ir(III) atom in both structures can be best described as a distorted square pyramid with the P, two Br (or I) and one C atom in the basal plane and another C atom in the apical position. PMID- 26594501 TI - Crystal structure of N-(2-amino-5-cyano-4-methyl-sulfanyl-6-oxo-1,6 dihydropyrimidin-1-yl)-4-bromo-benzene-sulfonamide di-methyl-formamide monosolvate. AB - The title compound, C12H10BrN5O3S2.C3H7NO, displays an almost planar amine group. The inter-planar angle between the rings is 31.72 (6) degrees . The residues are associated into ribbons parallel to [110] by three classical hydrogen bonds; one from each amine Hamine to ODMF and one from NHamide to Ooxo. Adjacent ribbons are connected by translation parallel to the c axis by a 'weak' hydrogen bond Hmeth yl?Osulfon-yl to form a layer structure parallel to (1-10), while a further contact Hbromo-phen-yl?Osulfon-yl connects the residues in the third dimension. PMID- 26594502 TI - Crystal structures of cristobalite-type and coesite-type PON redetermined on the basis of single-crystal X-ray diffraction data. AB - Hitherto, phospho-rus oxonitride (PON) could not be obtained in the form of single crystals and only powder diffraction experiments were feasible for structure studies. In the present work we have synthesized two polymorphs of phospho-rus oxonitride, cristobalite-type (cri-PON) and coesite-type (coe-PON), in the form of single crystals and reinvestigated their crystal structures by means of in house and synchrotron single-crystal X-ray diffraction. The crystal structures of cri-PON and coe-PON are built from PO2N2 tetra-hedral units, each with a statistical distribution of oxygen and nitro-gen atoms. The crystal structure of the coe-PON phase has the space group C2/c with seven atomic sites in the asymmetric unit [two P and three (N,O) sites on general positions, one (N,O) site on an inversion centre and one (N,O) site on a twofold rotation axis], while the cri-PON phase possesses tetra-gonal I-42d symmetry with two independent atoms in the asymmetric unit [the P atom on a fourfold inversion axis and the (N,O) site on a twofold rotation axis]. In comparison with previous structure determinations from powder data, all atoms were refined with anisotropic displacement parameters, leading to higher precision in terms of bond lengths and angles. PMID- 26594503 TI - Crystal structure of 2,4,6-tris-(cyclo-hex-yloxy)-1,3,5-triazine. AB - The title compound, C21H33N3O3, is a tri-substituted cyclo-hex-yloxy triazine. In the crystal, the triazine rings form (C3i-PU) Piedfort units. The inter-centroid distance of the pi-pi inter-action involving the triazine rings is 3.3914 (10) A. In the crystal, mol-ecules are linked by C-H?O hydrogen bonds, forming ribbons propagating along [1-10]. There are also weak C-H?N and C-H?O contacts present, linking inversion-related ribbons, forming a three-dimensional structure. PMID- 26594504 TI - Crystal structure of 2-amino-1,3-di-bromo-6-oxo-5,6-di-hydro-pyrido[1,2 a]quinoxalin-11-ium bromide monohydrate. AB - In the title hydrated salt, C12H8Br2N3O(+).Br(-).H2O, which was synthesized by the reaction of the pyridine derivative Schiff base N (1),N (4)-bis-(pyridine-2 yl-methyl-ene)benzene-1,4-di-amine with bromine, the asymmetric unit contains a 2 amino-1,3-di-bromo-6-oxo-5,6-di-hydro-pyrido[1,2-a]quinoxalin-11-ium cation, with a protonated pyridine moiety, a bromide anion and a water mol-ecule of solvation. The cation is non-planar with the di-bromo-substituted benzene ring, forming dihedral angles of 24.3 (4) and 11.5 (4) degrees with the fused pyridine and pyrazine ring moieties, respectively. In the crystal, the cations are linked through a centrosymmetric hydrogen-bonded cyclic R 4 (2)(8) Br2(H2O)2 unit by N H?Br, N-H?O and O-H?Br hydrogen bonds, forming one-dimensional ribbons extending along b, with the planes of the cations lying parallel to (100). PMID- 26594505 TI - Crystal structure of hexa-kis-(urea-kappaO)chromium(III) dichromate bromide monohydrate from synchrotron X-ray data. AB - The title bromide salt, [Cr{CO(NH2)2}6](Cr2O7)Br.H2O, is isotypic to the corresponding chloride salt. Within the complex cation, the Cr(III) atom is coordinated by six O atoms of six urea ligands, displaying a slightly distorted octa-hedral coordination environment. The Cr-O bond lengths involving the urea ligands are in the range 1.9534 (13)-1.9776 (12) A. The Cr2O7 (2-) anion has a nearly staggered conformation, with a bridging angle of 130.26 (10) degrees . The individual components are arranged in rows extending parallel to [100]. The Br(-) anion links the complex cation, as well as the solvent water mol-ecule, through N H?Br and O-H?Br hydrogen-bonding inter-actions. The supra-molecular architecture also includes N-H?O and O-H?O hydrogen bonding between urea N-H and water O-H donor groups and the O atoms of the Cr2O7 (2-) anion as acceptor atoms, leading to a three-dimensional network structure. PMID- 26594506 TI - Crystal structures of three co-crystals of 1,2-bis-(pyridin-4-yl)ethane with 4 alk-oxy-benzoic acids: 4-eth-oxy-benzoic acid-1,2-bis-(pyridin-4-yl)ethane (2/1), 4-n-propoxybenzoic acid-1,2-bis(pyridin-4-yl)ethane (2/1) and 4-n-but-oxy-benzoic acid-1,2-bis-(pyridin-4-yl)ethane (2/1). AB - The crystal structures of three hydrogen-bonded co-crystals of 4-alk-oxy-benzoic acid-1,2-bis-(pyridin-4-yl)ethane (2/1), namely, 2C9H10O3.C12H12N2, (I), 2C10H12O3.C12H12N2, (II), and 2C11H14O3.C12H12N2, (III), have been determined at 93, 290 and 93 K, respectively. In (I), the asymmetric unit consists of one 4-eth oxy-benzoic acid mol-ecule and one half-mol-ecule of 1,2-bis-(pyridin-4 yl)ethane, which lies on an inversion centre. In (II) and (III), the asymmetric units each comprise two crystallographically independent 4-alk-oxy-benzoic acid mol-ecules and one 1,2-bis-(pyridin-4-yl)ethane mol-ecule. In each crystal, the two components are linked by O-H?N hydrogen bonds, forming a linear hydrogen bonded 2:1unit of the acid and the base. Similar to the structure of 2:1 unit of (I), the units of (II) and (III) adopt nearly pseudo-inversion symmetry. The 2:1 units of (I), (II) and (III) are linked via C-H?O hydrogen bonds, forming tape structures. PMID- 26594507 TI - Crystal structure of an organic-inorganic hybrid compound based on morpholinium cations and a beta-type Anderson polyanion. AB - A new organic-inorganic hybrid compound, penta-morpholinium hexa-hydrogen hexa molybdoferrate(III) sulfate 3.5-hydrate, (C4H10NO)5[Fe(III)(OH)6Mo6O18](SO4).3.5H2O, was obtained from an aqueous solution. The polyoxidomolybdate (POM) anion is of the Anderson beta-type with a central Fe(III) ion. Three of five crystallographically independent morpholinium cations are disordered over two sets of sites. An intricate network of inter molecular N-H?O and O-H?O inter-actions between cations, POMs, sulfate anions and non-coordinating water mol-ecules creates a three-dimensional network structure. PMID- 26594508 TI - Crystal structure of [butane-2,3-dione bis-(4-methyl-thio-semicarbazonato) kappa(4) S,N (1),N (1'),S'](pyridine-kappaN)zinc(II). AB - In the structure of the title complex, [Zn(C8H14N6S2)(C5H5N)], the Zn(II) ion has a pseudo-square-pyramidal coordination environment and is displaced by 0.490 A from the plane of best fit defined by the bis-(thio-semicarbazonate) N2S2 donor atoms. Chains sustained by intermolecular N-H?N and N-H?S hydrogen-bonding interactions extend parallel to [10-1]. PMID- 26594509 TI - Synthesis and structural studies of a new complex of catena-poly[p-anisidinium [[diiodidobismu-thate(III)]-di-MU-iodido] dihydrate]. AB - A new organic-inorganic hybrid material, {(C7H10NO)[BiI4].2H2O} n , has been synthesized by slow evaporation of an aqueous solution at room temperature. The anionic sublattice of the crystal is built up by [BiI6] octa-hedra sharing edges. The resulting zigzag chains extend along the a-axis direction and are arranged in a distorted hexagonal rod packing. The p-anisidinium cations and the water mol ecules are located in the voids of the anionic sublattice. The cations are linked to each other through N-H?O hydrogen bonds with the water mol-ecules, and also through weaker N-H?I inter-actions to the anionic inorganic layers. PMID- 26594510 TI - Crystal structure of the 1,3,6,8-tetra-aza-tri-cyclo[4.3.1.1(3,8)]undecane (TATU) 4-nitro-phenol (1/2) adduct: the role of anomeric effect in the formation of a second hydrogen-bond inter-action. AB - In the title ternary co-crystalline adduct, C7H14N4.2C6H5NO3, mol-ecules are linked by two inter-molecular O-H?N hydrogen bonds, forming a tricomponent aggregates in the asymmetric unit. The hydrogen-bond formation to one of the N atoms is enough to induce structural stereoelectronic effects in the normal donor >acceptor direction. In the title adduct, the two independent nitro-phenol mol ecules are essentially planar, with maximum deviations of 0.0157 (13) and 0.0039 (13) A. The dihedral angles between the planes of the nitro group and the attached benzene rings are 4.04 (17) and 5.79 (17) degrees . In the crystal, aggregates are connected by C-H?O hydrogen bonds, forming a supra-molecular dimer enclosing an R 6 (6)(32) ring motif. Additional C-H?O inter-molecular hydrogen bonding inter-actions form a second supra-molecular inversion dimer with an R 2 (2)(10) motif. These units are linked via C-H?O and C-H?N hydrogen bonds, forming a three-dimensional network. PMID- 26594511 TI - Crystal structure of (4R,5S,6R)-6-azido-5-benz-yloxy-3,3,4-tri-fluoro-azepan-1 ium 2,2,2-tri-fluoro-acetate from synchrotron data. AB - The structure of the title compound, C15H16F6N4O3, was determined using synchrotron radiation on an extremely small crystal (0.015 * 0.01 * 0.01 mm). Although the diffraction was weak, leading to high residuals and a poor data-to parameter ratio, the data allowed ready solution and refinement to reveal the entire structure. The solid-state structure is in accordance with the absolute configuration assigned based on that of the known starting material. The compound comprises a highly substituted seven-membered N-heterocyclic cation and a tri fluoro-methane-sulfonate counter-anion. The title compound crystallizes with two independent cations (A and B) and anions (C and D) in the asymmetric unit. Two geminal F atoms, a single F atom, a benzyl ether and an azide group are substituted on consecutive C atoms between the NH2 and CH2 units of the azepan-1 ium ring system. The seven-membered rings adopt different conformations with the principal differences occurring in the CF2CHFCH2 segments of the ring systems. The geminal F atoms on the quaternary C atom exhibit essentially identical bond angles [109 (2) and 106 (2) degrees ] in the two independent mol-ecules. The two mol-ecules associate as a dimeric unit via two C-H?F inter-actions. An extensive series of N-H?O, N-H?F, C-H?O, C-H?N, C-H?F and C-H?pi contacts generate a three dimensional network with cations and anions linked into ABCD repeat columns along a. PMID- 26594512 TI - Two isostructural carbamates: the o-tolyl N-(pyridin-3-yl)carbamate and 2-bromo phenyl N-(pyridin-3-yl)carbamate monohydrates. AB - The title carbamate monohydrates, C13H12N2O2.H2O and C12H9BrN2O2.H2O, form isomorphous crystals that are isostructural in their primary hydrogen-bonding modes. In both carbamates, the primary hydrogen bonding and aggregation involves cyclic amide-water-pyridine moieties as (N-H?O-H?N)2 dimers about inversion centres [as R 4 (4)(14) rings], where the participation of strong hydrogen bonding donors and acceptors is maximized. The remaining water-carbonyl O-H?O=C inter-action extends the aggregation into two-dimensional planar sheets that stack parallel to the (100) plane. The Br derivative does not participate in halogen bonding. A weak intra-molecular C-H?O hydrogen bond is observed in each compound. PMID- 26594513 TI - Crystal structures of (N-methyl-N-phenyl-amino)(N-methyl-N-phenyl carbamoyl)sulfide and the corresponding disulfane. AB - The title compounds, (N-methyl-N-phenyl-amino)(N-methyl-N-phenyl-car-bam oyl)sulfide, C15H16N2OS, (I), and (N-methyl-N-phenyl-amino)-(N-methyl-N-phenyl carbamo-yl)disulfane, C15H16N2OS2, (II), are stable derivatives of (chloro-carbon yl)sulfenyl chloride and (chloro-carbon-yl)disulfanyl chloride, respectively. The torsion angle about the S-S bond in (II) is -92.62 (6) degrees , which is close to the theoretical value of 90 degrees . In the crystal of (II), non-classical inter-molecular C-H?O hydrogen bonds form centrosymmetric cyclic dimers [graph set R 2 (2)(10)], while inter-dimer C-H?S inter-actions generate chains extending along the b axis. PMID- 26594514 TI - Crystal structure of cyclo-tris-(MU-3,4,5,6-tetra-fluoro-o-phenyl-ene-kappa(2) C (1):C (2))trimercury-tetra-cyano-ethyl-ene (1/1). AB - The title compound, [Hg3(C6F4)3].C6N4, contains one mol-ecule of tetra-cyano ethyl-ene B per one mol-ecule of mercury macrocycle A, i.e., A*B, and crystallizes in the monoclinic space group C2/c. Macrocycle A and mol-ecule B both occupy special positions on a twofold rotation axis and the inversion centre, respectively. The supra-molecular unit [A*B] is built by the simultaneous coordination of one of the nitrile N atoms of B to the three mercury atoms of the macrocycle A. The Hg?N distances range from 2.990 (4) to 3.030 (4) A and are very close to those observed in the related adducts of the macrocycle A with other nitrile derivatives. The mol-ecule of B is almost perpendicular to the mean plane of the macrocycle A at the dihedral angle of 88.20 (5) degrees . The donor acceptor Hg?N inter-actions do not affect the C N bond lengths [1.136 (6) and 1.140 (6) A]. The trans nitrile group of B coordinates to another macrocycle A, forming an infinite mixed-stack [A*B]infinity architecture toward [101]. The remaining N atoms of two nitrile groups of B are not engaged in any donor acceptor inter-actions. In the crystal, the mixed stacks are held together by inter-molecular C-F?C N secondary inter-actions [2.846 (5)-2.925 (5) A]. PMID- 26594515 TI - Crystal structures of MU-oxalato-bis-[azido-(hista-mine)-copper(II)] and MU oxalato-bis-[(dicyan-amido)(hista-mine)-copper(II)]. AB - The title compounds, MU-oxalato-kappa(4) O (1),O (2):O (1'),O (2')-bis-[[4-(2 amino-eth-yl)-1H-imid-azole-kappa(2) N (3),N (4)](azido-kappaN (1))copper(II)], [Cu2(C2O4)(N3)2(C5H9N3)2], (I), and MU-ox-al-ato-kappa(4) O (1),O (2):O (1'),O (2')-bis-[[4-(2-amino-eth-yl)-1H-imidazole-kappa(2) N (3),N (4)](dicyanamido kappaN (1))copper(II)], [Cu2(C2O4)(C2N3)2(C5H9N3)2], (II), are two oxalate bridged dinuclear copper complexes. Each Cu(II) ion adopts a five-coordinate square-pyramidal coordination sphere where the basal N2O2 plane is formed by two O atoms of the oxalate ligand and two N atoms of a bidentate chelating histamine mol-ecule. The apical coordination site in compound (I) is occupied by a monodentate azide anion through one of its terminal N atoms. The apical coordination site in compound (II) is occupied by a monodentate dicyanamide anion through one of its terminal N atoms. The mol-ecules in both structures are centrosymmetric. In the crystals of compounds (I) and (II), the dinuclear complexes are linked through N-H?X and C-H?X (X = N, O) hydrogen bonds where the donors are provided by the histamine ligand and the acceptor atoms are provided by the azide, dicyanamide, and oxalate ligands. In compound (I), the coordinatively unsaturated copper ions inter-act with the histamine ligand via a C-H?Cu inter-action. The coordinatively unsaturated copper ions in compound (II) inter-act via a weak N?Cu inter-action with the dicyanamide ligand of a neighboring mol-ecule. The side chain of the histamine ligand is disordered over three sets of sites in (II). PMID- 26594516 TI - Crystal structure of the new hybrid material bis-(1,4-diazo-niabi-cyclo [2.2.2]octa-ne) di-MU-chlorido-bis-[tetra-chlorido-bis-muthate(III)] dihydrate. AB - The title compound bis-(1,4-diazo-niabi-cyclo-[2.2.2]octa-ne) di-MU-chlorido-bis [tetra-chlorido-bis-muthate(III)] dihydrate, (C6H14N2)2[Bi2Cl10].2H2O, was ob tain-ed by slow evaporation at room temperature of a hydro-chloric aqueous solution (pH = 1) containing bis-muth(III) nitrate and 1,4-di-aza-bicyclo [2.2.2]octane (DABCO) in a 1:2 molar ratio. The structure displays a two dimensional arrangement parallel to (100) of isolated [Bi2Cl10](4-) bi-octa-hedra (site symmetry -1) separated by layers of organic 1,4-diazo-niabi-cyclo [2.2.2]octane dications [(DABCOH2)(2+)] and water mol-ecules. O-H?Cl, N-H?O and N H?Cl hydrogen bonds lead to additional cohesion of the structure. PMID- 26594517 TI - Crystal structures of 4-meth-oxy-N-(4-methyl-phenyl)benzene-sulfonamide and N-(4 fluoro-phenyl)-4-meth-oxy-benzene-sulfonamide. AB - Crystal structures of two N-(ar-yl)aryl-sulfonamides, namely, 4-meth-oxy-N-(4 methyl-phen-yl)benzene-sulfonamide, C14H15NO3S, (I), and N-(4-fluoro-phen-yl)-4 meth-oxy-benzene-sulfonamide, C13H12FNO3S, (II), were determined and analyzed. In (I), the benzene-sulfonamide ring is disordered over two orientations, in a 0.516 (7):0.484 (7) ratio, which are inclined to each other at 28.0 (1) degrees . In (I), the major component of the sulfonyl benzene ring and the aniline ring form a dihedral angle of 63.36 (19) degrees , while in (II), the planes of the two benzene rings form a dihedral angle of 44.26 (13) degrees . In the crystal structure of (I), N-H?O hydrogen bonds form infinite C(4) chains extended in [010], and inter-molecular C-H?piar-yl inter-actions link these chains into layers parallel to the ab plane. The crystal structure of (II) features N-H?O hydrogen bonds forming infinite one dimensional C(4) chains along [001]. Further, a pair of C-H?O inter-molecular inter-actions consolidate the crystal packing of (II) into a three-dimensional supra-molecular architecture. PMID- 26594518 TI - Crystal structures and hydrogen bonding in the morpholinium salts of four phen oxy-acetic acid analogues. AB - The anhydrous salts morpholinium (tetra-hydro-2-H-1,4-oxazin-4-ium) phen-oxy acetate, C4H10NO(+).C8H7O3 (-), (I), morpholinium (4-fluoro-phen-oxy)acetate, C4H10NO(+).C8H6 FO3 (-), (II), and isomeric morpholinium (3,5-di-chloro-phen oxy)acetate (3,5-D), (III), and morpholinium (2,4-di-chloro-phen-oxy)acetic acid (2,4-D), C4H10NO(+).C8H5Cl2O3 (-), (IV), have been determined and their hydrogen bonded structures are described. In the crystals of (I), (III) and (IV), one of the the aminium H atoms is involved in a three-centre asymmetric cation-anion N H?O,O' R 1 (2)(4) hydrogen-bonding inter-action with the two carboxyl O-atom acceptors of the anion. With the structure of (II), the primary N-H?O inter action is linear. In the structures of (I), (II) and (III), the second N H?Ocarbox-yl hydrogen bond generates one-dimensional chain structures extending in all cases along [100]. With (IV), the ion pairs are linked though inversion related N-H?O hydrogen bonds [graph set R 4 (2)(8)], giving a cyclic hetero-tetra meric structure. PMID- 26594519 TI - Crystal structure of [5-n-butyl-10-(2,5-di-meth-oxy-phen-yl)-2,3,7,8,13,12,17,18 octa-ethyl-porphyrin-ato]nickel(II). AB - The asymmetric unit of the title nickel(II) porphyrin, [Ni(C48H60N4O2)], contains one independent mol-ecule. The average Ni-N bond length is 1.917 (13) A. The mol ecules are arranged in a closely spaced lattice structure in which neighbouring porphyrins are oriented in inversion-related dimers. The nickel(II) porphyrin is characterized by a significant degree of a ruffled (B 1u ) conformation with small contributions from saddle (B 2u ) and wave (y) [Eg (y)], as determined using normal structural decomposition. Disorder in the 2,5-di--meth-oxy-phenyl substituent was modelled over two positions with a 60% occupancy for the major moiety. One of the ethyl groups is also disordered over two positions and was modelled with the major moiety being present in 51.3% occupancy. PMID- 26594520 TI - Crystal structure and absolute configuration of (3S,4aS,8aS)-N-tert-butyl-2-[(S) 3-(2-chloro-4-nitro-benzamido)-2-hy-droxy-prop-yl]deca-hydro-isoquinoline-3 carboxamide and (3S,4aS,8aS)-N-tert-butyl-2-{(S)-2-[(S)-1-(2-chloro-4-nitro benzoyl)pyrrolidin-2-yl]-2-hy-droxy-eth-yl}deca-hydro-iso-quinoline-3 carboxamide. AB - The crystal structure and absolute configuration of the two new title nelfinavir analogs, C24H35ClN4O5, (I), and C27H39ClN4O5, (II), have been determined. Each of these mol-ecules exhibits a number of disordered moieties. There are intra molecular N-H?O hydrogen bonds in both (I) and (II). In (I) it involves the two carboxamide groups, while in (II) it involves the N-tert-butyl carboxamide group and the 2-hydroxyl O atom. The inter-molecular hydrogen bonding in (I) (O-H?O and N-H?O) leads to two-dimensional sheets that extend parallel to the ac plane. The inter-molecular hydrogen bonding in (II) (O-H?O) leads to chains that extend parallel to the a axis. PMID- 26594521 TI - Crystal structure of tris-[4-(di-methyl-amino)-pyridinium] tris-(oxalato-kappa(2) O,O')chromate(III) tetra-hydrate. AB - In the title hybrid salt, (C7H11N2)3[Cr(C2O4)3].4H2O, the central Cr(III) ion of the complex anion (point group symmetry 2) is coordinated by six O atoms from three chelating oxalate(2-) ligands in a slightly distorted octa-hedral coordination sphere. The Cr-O bond lengths vary from 1.9577 (11) to 1.9804 (11) A, while the chelate O-Cr-O angles range from 82.11 (6) to 93.41 (5) degrees . The 4-(di-methyl-amino)-pyridinium cations (one situated in a general position and one on a twofold rotation axis) are protonated at the pyridine N atoms. In the crystal, N-H?O and O-H?O hydrogen bonds link the cations and anions into a three-dimensional network. pi-pi inter-actions between the pyridine rings of adjacent cations provide additional stabilization of the crystal packing, with the closest centroid-to-centroid distances being 3.541 (1) and 3.575 (1) A. PMID- 26594522 TI - Crystal structure of 4-({(1E,2E)-3-[3-(4-fluoro-phen-yl)-1-isopropyl-1H-indol-2 yl]allyl-idene}amino)-5-methyl-1H-1,2,4-triazole-5(4H)-thione. AB - The title compound, C23H22FN5S, exists in a trans conformation with respect to the methene C=C and the acyclic N=C bonds. The 1,2,4-triazole-5(4H)-thione ring makes dihedral angles of 88.66 (9) and 84.51 (10) degrees , respectively, with the indole and benzene rings. In the crystal, mol-ecules are linked by pairs of N H?S hydrogen bonds, forming inversion dimers with an R 2 (2)(8) ring motif. The dimers are linked via C-H?pi inter-actions, forming chains along [1-10]. The chains are linked via pi-pi inter-actions involving inversion-related triazole rings [centroid-centroid distance = 3.4340 (13) A], forming layers parallel to the ab plane. PMID- 26594523 TI - Crystal structure of rac-3-[2,3-bis-(phenyl-sulfan-yl)-3H-indol-3-yl]propanoic acid. AB - The title compound, C23H19NO2S2, was obtained as an unexpected regioisomer from an attempted synthesis of an inter-mediate for a substituent-effect study on ergot alkaloids. This is the first report of a 1H-indole mono-thio-ating at the 2 and 3-positions to give a 3H-indole. In the crystal, the acid H atom is twisted roughly 180 degrees from the typical carb-oxy conformation and forms centrosymmetric O-H?N hydrogen-bonded dimers with the indole N atom of an inversion-related mol-ecule. Together with a weak C-H?O hydrogen bond involving the carbonyl O atom, chains are formed along [100]. PMID- 26594524 TI - Crystal structure of [Co(NH3)6][Co(CO)4]2. AB - Hexaamminecobalt(II) bis-[tetra-carbonyl-cobaltate(-I)], [Co(NH3)6][Co(CO)4]2, was synthesized by reaction of liquid ammonia with Co2(CO)8. The Co(II) atom is coordinated by six ammine ligands. The resulting polyhedron, the hexa amminecobalt(II) cation, exhibits point group symmetry -3. The Co(-I) atom is coordinated by four carbonyl ligands, leading to a tetra-carbonyl-cobaltate(-I) anion in the shape of a slightly distorted tetra-hedron, with point group symmetry 3. The crystal structure is related to that of high-pressure BaC2 (space group R-3m), with the [Co(NH3)6](2+) cations replacing the Ba sites and the [Co(CO)4](-) anions replacing the C sites. N-H?O hydrogen bonds between cations and anions stabilize the structural set-up in the title compound. PMID- 26594525 TI - Crystal structure of tris-(hydroxyl-ammonium) orthophosphate. AB - The crystal structure of the title salt, ([H3NOH](+))3.[PO4](3-), consists of discrete hydroxyl-ammonium cations and ortho-phos-phate anions. The atoms of the cation occupy general positions, whereas the anion is located on a threefold rotation axis that runs through the phospho-rus atom and one of the phosphate O atoms. In the crystal structure, cations and anions are linked by inter-molecular O-H?O and N-H?O hydrogen bonds into a three-dimensional network. Altogether, one very strong O-H?O, two N-H?O hydrogen bonds of medium strength and two weaker bifurcated N-H?O inter-actions are observed. PMID- 26594526 TI - Crystal structure of tris-[MU2-bis-(di-phenyl-phosphan-yl)methane-kappa(2) P:P']di-MU3-iodido-tris-ilver(I) iodide-N-phenyl-thio-urea (1/1). AB - The title complex, [Ag3I2(C25H22P2)3]I.C7H8N2S, comprises a trinuclear [Ag3I2(C25H22P2)3](+) unit, an I(-) anion and one N,N'-phenyl-thio-urea mol-ecule (ptu). Two MU3-bridging I(-) anions are linked by three Ag(I) ions, leading to the formation of a dicapped triangular motif with Ag?Ag separations in the range 3.0823 (5)-3.2999 (5) A. Each Ag(I) atom exhibits a distorted tetra-hedral geometry, with coordination to two I atoms and two P atoms from bis-(di-phenyl phosphan-yl)methane ligands. In the crystal, the I(-) anion is linked to the ptu mol-ecule through two N-H?I hydrogen bonds [graph-set motif R 2 (1)(6)]. These N H?I hydrogen bonds, in addition to weak C-H?S and C-H?I hydrogen bonds, form zigzag chains along [010]. Two of the phenyl rings of two dppm ligands are disordered over two sets of sites with refined occupancies of 0.557 (16) and 0.443 (16). PMID- 26594527 TI - Crystal structure of di-MU-iodido-bis-[bis(aceto-nitrile-kappaN)copper(I)]. AB - The title compound, [Cu2I2(CH3CN)4], exhibits a centrosymmetric Cu2I2 core [Cu?Cu distance = 2.7482 (11) A], the Cu(I) atoms of which are further coordinated by four mol-ecules of aceto-nitrile. The Cu(I) atom has an overall distorted tetra hedral coordination environment evidenced by L-Cu-L angles (L = N or I) ranging from 100.47 (10) to 117.06 (2) degrees . The coordination geometries of the aceto nitrile ligands deviate slightly from linearity as shown by Cu-N-C angles of 167.0 (2) and 172.7 (2) degrees . In the crystal, there are no significant hydrogen-bonding inter-actions present, so the crystal packing seems to be formed predominantly by van der Waals forces. PMID- 26594528 TI - Crystal structure of new organically templated copper sulfate with 2-amino pyridinium. AB - The title compound, (C5H7N2)2[Cu(H2O)6](SO4)2.4H2O [systematic name: bis(2 aminopyridinium) hexaaquacopper(II) bis(sulfate) tetrahydrate], comprises axially elongated hexa-aqua-coordinated octa-hedral Cu(II) ions located on an inversion centre, non-coordinating sulfate anions, 2-amino-pyridinium cations and lattice water mol-ecules. The crystal structure is built of successive inorganic and organic layers extending parallel to (001) that are connected by an extensive three-dimensional hydrogen-bonded network of the type O-H?O and N-H?O, as well as pi-pi inter-actions [centroid-centroid distance 3.4140 (14) A, offset 0.277 A]. PMID- 26594529 TI - Crystal structure of di-MU-iodido-bis{[bis(piperidin-1-yl)methane-kappa(2) N,N']copper(I)}. AB - The title compound, [Cu2I2(C11H22N2)2], crystallizes as a symmetric dimer with one quarter of the mol-ecule in the asymmetric unit. The copper(I) atom, the iodine atom and the central methyl-ene C atom of the di(piperidin-1-yl)methane ligand lie on a mirror plane and the complete molecule exhibits point group symmetry 2/m. To the best of our knowledge it is the first di-amine copper(I) complex containing a four-membered chelate ring. Compared to other di-amine copper(I) iodide dimers, the title compound has a short Cu?Cu distance of 2.5137 (11) A, but a long Cu-N bond length of 2.213 (3) A. The I-Cu-I angle [121.84 (2) degrees ] is large, and the N-Cu-N angle = 66.61 (13) degrees is the smallest one found for copper(I) di-amine complexes. As a result of the four-membered ring, the ligands around the copper(I) atom have an extremely distorted tetra hedral arrangement. In the crystal, there are no significant inter-molecular inter-actions present. PMID- 26594530 TI - Crystal structure of tetra-kis-(MU-caproato-kappa(2) O:O')bis-[(4-cyano-pyridine kappaN (1))copper(II)]. AB - The title dinuclear complex, [Cu2(C6H11O2)4(C6H4N2)2], has a paddle-wheel structure. The two crystallographically independent Cu(II) atoms are each in a distorted square-pyramidal environment, in which four O atoms from the four bridging caproate ligands form the basal plane and the pyridine N atom of the 4 cyano-pyridine ligand occupies the apical position. The Cu?Cu distance is 2.6055 (9) A. One of the alkyl chains of the caproate ligands is disordered over two sets of sites, with occupancies of 0.725 (5) and 0.275 (5). In the crystal, two pairs of C-H?N hydrogen bonds connect the mol-ecules into chains along [11-1] and C-H?O hydrogen bonds link the chains into a three-dimensional network. PMID- 26594531 TI - Crystal structure of catena-poly[[[tri-aqua-(4-cyano-benzoato-kappaO)nickel(II)] MU-4,4'-bi-pyridine-kappa(2) N:N'] 4-cyano-benzoate]. AB - In the title polymeric complex salt, {[Ni(C8H4NO2)(C10H8N2)(H2O)3](C8H4NO2)} n , the Ni(II) cation is coordinated by a 4-cyano-benzoate anion, two 4,4'-bi pyridine ligands and three water mol-ecules in a distorted N2O4 octa-hedral geometry. The 4,4'-bi-pyridine ligands bridge the Ni(II) cations to form polymeric chains of the title complex cations, propagating along the c-axis direction. The dihedral angle between the pyridine rings of the 4,4'-bi-pyridine ligand is 24.9 (6) degrees . In the crystal, the uncoordinating 4-cyano-benzoate anions link with the complex cations via O-H?O hydrogen bonds into a three dimensional supra-molecular architecture. Weak C-H?O, C-H?N inter-actions and pi pi stacking [centroid-to-centroid distances = 3.566 (4) and 3.885 (4) A] are also observed in the crystal. PMID- 26594532 TI - Crystal structure of bis-[N,N-bis-(2-hydroxy-eth-yl)glycinato-kappa(3) O (1),N,O (2)]cobalt(II) monohydrate. AB - The title compound, [Co(C6H12O4)2].H2O, was prepared by mild heating of an aqueous solution. The Co(II) ion has a slightly distorted octahedral coordination environment which is defined by two N atoms occupying the apical position, while the equatorial plane is furnished by two hy-droxy O atoms and two carboxyl-ate O atoms. The four hy-droxy O atoms from two distinct N,N-bis-(2-hy-droxy-eth yl)glycine (bicH2 (-)) ligands act as hydrogen-bond donors with two carboxyl-ate O atoms as acceptors to form O-H?O hydrogen-bonded layers extending parallel to (100). In addition, the guest water mol-ecule acts as both a hydrogen-bond donor and acceptor, so that each Co(bicH2)2 mol-ecule is connected simultaneously to six neighbouring Co(bicH2)2 and two guest water mol-ecules by hydrogen bonding. PMID- 26594533 TI - Crystal structure of di-chlorido-bis-[2-(phenyl-diazen-yl)pyridine-kappaN (1)]zinc. AB - The structure of the title complex, [ZnCl2(C11H9N3)2], comprises two 2-(phenyl diazen-yl)pyridine ligands coordin-ating to a central Zn(II) dichloride unit via the pyridyl N-atom donors, resulting in a slightly distorted tetra-hedral geometry. The complex exhibits twofold rotation symmetry, with the rotation axis bis-ecting the zinc cation. The structure is stabilized by weak inter-molecular C H?Cl inter-actions [C?Cl = 3.411 (2) and 3.675 (2) A], connecting neighbouring mol-ecules into layers perpendicular to the c axis. PMID- 26594535 TI - Crystal structure of {2-[({2-[(2-amino-ethyl)amino]-ethyl}imino)-meth-yl]-6-hy droxy-phenolato-kappa(4) N,N',N'',O (1)}(nitrato-kappaO)copper(II) ethanol 0.25 solvate. AB - In the crystal structure of the title mononuclear Cu(II) complex, [Cu(C11H16N3O2)(NO3)].0.25C2H5OH, the complex molecules are linked by N-H?O and O H?O hydrogen bonds, forming a dimer with an approximate non-crystallographic twofold rotation axis of symmetry. In the monomeric unit, the Cu(2+) ion exhibits a distorted square-pyramidal configuration, whereby the anionic [HL](-) Schiff base ligand binds in a tetradentate fashion via the O and the three N atoms which all are approximately coplanar. The O atom of a nitrate anion occupies the fifth coordination site, causing the Cu(II) atom to move slightly out of the approximate basal plane toward the bound nitrate group. The structure exhibits disorder of the ethanol solvent mol-ecule. PMID- 26594534 TI - Crystal structure of {6,6'-dihy-droxy-2,2'-[imino-bis-(propane-1,3-diyl-nitrilo methanylyl-idene)]diphenolato-kappa(5) O (1),N,N',N'',O (1')}copper(II). AB - The title compound, [Cu(C20H23N3O4)], crystallizes in the space group Cc with two independent mol-ecules in the asymmetric unit. The Cu(II) atoms are each coordinated by the penta-dentate Schiff base ligand in a distorted trigonal bipyramidal N3O2 geometry. The equatorial plane is formed by the two phenolic O atoms and the amine N atom, while the axial positions are occupied by the two imine N atoms. In the crystal, the two independent mol-ecules are each connected into a column along the b axis through inter-molecular O-H?O hydrogen bonds. The two independent columns are further linked through an N-H?O hydrogen bond, forming a double-column structure. PMID- 26594536 TI - Crystal structure of bis-{1-[(E)-(2-meth-oxy-phen-yl)diazen-yl]naphthalen-2-olato kappa(3) O,N (2),O'}copper(II) containing an unknown solvate. AB - The title complex, [Cu(C17H13N2O2)2], crystallizes with two independent mol ecules in the asymmetric unit. Each Cu(II) atom has a distorted ocahedral coordination environment defined by two N atoms and four O atoms from two tridentate 1-[(E)-(2-meth-oxy-phen-yl)diazen-yl]naphthalen-2-olate ligands. In the crystal, the two mol-ecules are linked via weak C-H?O hydrogen bonds which in turn stack parallel to [010]. A region of disordered electron density, most probably disordered methanol solvent molecules, was corrected for using the SQUEEZE routine in PLATON [Spek (2015). Acta Cryst. C71, 9-18]. Their formula mass and unit-cell characteristics were not taken into account during refinement. PMID- 26594537 TI - Crystal structure of 2-amino-N-(2-fluoro-phen-yl)-4,5,6,7-tetra-hydro-1-benzo thio-phene-3-carboxamide. AB - In the title compound, C15H15FN2OS, the dihedral angle between the planes of the benzo-thio-phene ring system and the fluoro-benzene ring is 3.74 (14) degrees . The six-membered ring of the benzo-thio-phene moiety adopts a half-chair conformation. The mol-ecular conformation is consolidated by intra-molecular N H?F and N-H?O hydrogen bonds. In the crystal, mol-ecules are linked by N-H?O hydrogen bonds, generating C(6) [001] chains. PMID- 26594538 TI - Crystal structure of 3-benzyl-sulfanyl-6-(5-methyl-1,2-oxazol-3-yl)-1,2,4 triazolo[3,4-b][1,3,4]thia-diazole. AB - In the title compound, C14H11N5OS2, the triazolo-thia-diazole system is essentially planar (r.m.s. deviation = 0.002 A) and makes dihedral angles of 6.33 (12) and 42.95 (14) degrees with the planes of the oxazole and phenyl rings, respectively. In the crystal, face-to-face pi-pi inter-actions are observed between the thia-diazole and oxazole rings [centroid-centroid distance = 3.4707 (18) A], leading to columns along [010]. PMID- 26594539 TI - The crystal structure of 1-(2-hydroxy-5-meth-oxy-phen-yl)ethanone 4,4-di-methyl thio-semicarbazone. AB - The asymmetric unit of the title compound, C12H17N3O2S, contains two independent mol-ecules, A and B. Both mol-ecules are nearly planar with the dihedral angle between the mean planes of the thio-amide group and benzene ring being 7.5 (1) degrees in A and 4.3 (2) degrees in B. In each mol-ecule, the hy-droxy group participates in intra-molecular O-H?N hydrogen bonding, while the amino H atom is not involved in hydrogen bonding because of the steric hinderence caused by two neighboring methyl groups. In the crystal, the individual molecules are linked by weak C-H?O hydrogen bonds, forming A-A and B-B inversion dimers. The dimers are linked via C-H?pi inter-actions which help stabilize the packing. PMID- 26594540 TI - Crystal structure of 2-bromo-4,6-di-nitroaniline. AB - In the title compound, C6H4BrN3O4, the dihedral angles between the nitro groups and the aniline ring are 2.04 (3) and 1.18 (4) degrees , respectively. In the crystal, N-H?O and C-H?O hydrogen bonds and weak side-on C-Br?pi inter-actions [3.5024 (12) A] link adjacent mol-ecules, forming a three-dimensional network. A close O?Br contact [3.259 (2) A] may also add additional stability. PMID- 26594541 TI - Crystal structure of 5''-(4-chloro-benzyl-idene)-4'-(4-chloro-phen-yl)-1' methyltri-spiro[acenapthylene-1,2'-pyrrolidine-3',1''-cyclo-hexane-3'',2''' [1,3]dioxane]-2(1H),6''-dione. AB - In the title compound, C36H29Cl2NO4, two spiro links connect the methyl substituted pyrrolidine ring to the ace-naphthyl-ene and cyclo-hexa-none rings. The cyclo-hexa-none ring is further connected to the dioxalane ring by a third spiro junction. The five-membered ring of the ace-naphthylen-1-one ring system adopts a flattened envelope conformation, with the ketonic C atom as the flap, whereas the dioxalane and pyrrolidine rings each have a twist conformation. The cyclo-hexenone ring assumes a boat conformation. An intra-molecular C-H?O hydrogen-bond inter-action is present. In the crystal, mol-ecules are linked by non-classical C-H?O hydrogen bonds, forming chains extending parallel to the a axis. PMID- 26594542 TI - Crystal structure of tris-(3-methyl-1H-pyrazol-1-yl)methane. AB - The title mol-ecule, C13H16N6, crystallizes from hexane as a mol-ecular crystal with no strong inter-molecular inter-actions (the shortest C-H?N contact is longer than 3.38 A). A relatively short intra-molecular contact (3.09 A) has a C H?N angle of 118 degrees which is quite small to be still considered a hydrogen bond. The three pyrazole rings form a propeller-like motif, with one methylpyrazole unit almost perpendicular to the mean plane of the three rings [82.20 (6) degrees ]. The other two methylpyrazole units, with nitrogen donor atoms oriented in opposite directions, are oriented at 67.26 (6) and 72.53 (6) degrees to the mean plane. PMID- 26594543 TI - Crystal structure of (4-hy-droxy-piperidin-1-yl)(4-methyl-phen-yl)methanone. AB - In the title compound, C13H17NO2, the dihedral angle between the planes of the piperidine and benzene rings is 51.7 (2) degrees . The bond-angle sum around the N atom [359.8 (3) degrees ] indicates sp (2) hybridization of the atom. In the crystal, O-H?O hydrogen bonds link the mol-ecules, forming chains along [001]. PMID- 26594544 TI - Crystal structure of (E)-4-meth-oxy-2-{[(5-methyl-pyridin-2-yl)imino]-meth yl}phenol. AB - The mol-ecule of the title Schiff base compound, C14H14N2O2, displays an E conformation with respect the imine C=N double bond. The mol-ecule is approximately planar, with the dihedral angle formed by the planes of the pyridine and benzene rings being 5.72 (6) degrees . There is an intra-molecular hydrogen bond involving the phenolic H and imine N atoms. PMID- 26594545 TI - Crystal structure of N-[(4-eth-oxy-phen-yl)carbamo-thio-yl]cyclo-hexa-ne carboxamide. AB - The asymmetric unit of the title compound, C16H22N2O2S, contains two crystallographically independent mol-ecules (A and B). In mol-ecule A, the cyclo hexane ring is disordered over two orientations [occupancy ratio 0.841 (10):0.159 (10)]. In each mol-ecule, the central carbonyl thio-urea unit is nearly planar (r.m.s. deviations for all non-H atoms of 0.034 A in mol-ecule A and 0.094 A in mol-ecule B). In both mol-ecules, the cyclo-hexane ring adopts a chair conformation. The mean plane of the cyclo-hexane ring makes dihedral angles of 35.8 (4) (mol-ecule A) and 20.7 (3) degrees (mol-ecule B) with that of the benzene ring. Each mol-ecule features an intra-molecular N-H?O hydrogen bond, which closes an S(6) ring motif. In the crystal, mol-ecules are linked via pairs of weak N-H?S inter-actions, forming inversion dimers with an R 2 (2)(8) ring motif for both mol-ecules. The crystal structure also features weak C-H?pi ring inter-actions. PMID- 26594546 TI - Crystal structure of 5-(5-chloro-2-hydroxy-benzo-yl)-2-(2-methyl-1H-indol-3 yl)nicotino-nitrile. AB - In the title compound, C22H14ClN3O2, the indole unit is essentially coplanar, with a maximum deviation of 0.035 A for the C atom bearing the methyl group. The central pyridine ring is inclined to the indole ring system by 43.7 (1) degrees . The dihedral angle between the phenyl ring and the indole ring system is 15.7 (2) degrees , while that between the phenyl ring and the central pyridine ring is 46.3 (1) degrees . The mol-ecular structure is stabilized by an intra-molecular O H?O hydrogen bonding, forming an S(6) ring motif. In the crystal, mol-ecules are linked via pairs of N-H?N hydrogen bonds, forming inversion dimers with an R 2 (2)(16) ring motif. The crystal structure also features C-H?pi and pi-pi inter actions [centroid-centroid separation = 3.688 (1) A]. PMID- 26594547 TI - Crystal structure of 1-methyl-2-methyl-amino-3-nitro-1H-chromeno[2,3-b]pyridin 5(10aH)-one. AB - In the title compound, C14H13N3O4, the pyran ring adopts an envelope conformation with the methine C atom as the flap. The dihedral angle between the benzene and hydro-pyridine rings is 29.33 (3) degrees . The methyl-amine C atom deviates from the plane of its attached ring by 0.380 (5) A and an intra-molecular N-H?O hydrogen bond closes an S(6) ring. In the crystal, weak C-H?O hydrogen bonds and aromatic pi-pi stacking inter-actions [centroid-centroid distances vary from 3.6529 (10) to 3.6872 (10) A] link the mol-ecules, generating a three-dimensional network. PMID- 26594548 TI - Crystal structure of N'-[(E)-3,5-di-chloro-2-hy-droxy-benzyl-idene]-4-nitro-benzo hydrazide di-methyl-formamide monosolvate. AB - In the title compound, C14H9Cl2N3O4.C3H7NO, the hydrazone mol-ecule adopts an E conformation with respect to azomethine bond, and the dihedral angle between the two aromatic rings [8.96 (11) degrees ] shows that the rings are almost co planar. The planar conformation of the mol-ecule is stabilized by the intra molecular O-H?N hydrogen bond involving the OH group and azomethine N atom. The azomethine and keto bond distances [1.269 (2) and 1.210 (2) A, respectively] are very close to the formal C=N and C=O bond lengths. The di-methyl-formamide solvent mol-ecule is connected to the hydrazone NH group via an N-H?O hydrogen bond. In the crystal, non-classical C-H?O and C-H?Cl hydrogen bonds link the mol ecules into chains along [322]. A supra-molecular three-dimensional architecture is created by weak C-Cl?pi [4.163 (3) A, 83.26 (9) degrees ] and pi-pi [centroid centroid distance = 4.0395 (14) A] inter-actions. PMID- 26594549 TI - Crystal structure of 3-meth-oxy-2-[5-(naphthalen-1-yl)-4,5-di-hydro-1H-pyrazol-3 yl]phenol. AB - In the title compound, C20H18N2O2, the central pyrazoline ring has an envelope conformation with the atom substituted by the naphthalene ring as the flap. It bridges a benzene ring and a naphthalene ring system which are almost normal to one another, making a dihedral angle of 82.03 (6) degrees . There is an intra molecular O-H?N hydrogen bond forming an S(6) ring motif. In the crystal, mol ecules are linked by pairs of N-H?pi inter-actions, forming inversion dimers. There are also C-H?pi inter-actions present and the dimers are linked via C-H?O hydrogen bonds, forming ribbons propagating along the a-axis direction. PMID- 26594550 TI - Crystal structure of the inclusion complex 25-benzo-ylmeth-oxy-5,11,17,23-tetra tert-butyl-26,27,28-trihy-droxy-2,8,14,20-tetra-thia-calix[4]arene-tetra-ethyl ammonium chloride (1/1). AB - The asymmetric unit of the title compound, C48H54O5S4.N(C2H5)4 (+).Cl(-), contains two tetra-tert-butyl-[(benzo-yl)meth-oxy]-trihy-droxy-tetra-thia calix[4]arene mol-ecules, two tetra-ethyl-ammonium cations and two chloride anions. The two calixarene molecules in the asymmetric unit each display a cone conformation. There are no significant differences between the two independent molecules. The guest species do not sit within the calixarene 'buckets'. In the crystal, extensive O-H?O, O-H?S and O-H?Cl hydrogen bonds and weak C-H?O, C-H?S and C-H?Cl inter-actions link the thia-calixarene mol-ecules, tetra-ethyl ammonium cations and chloride anions, forming a three-dimensional network encompassing channels running parallel to the a-axis direction. The structure contains a solvent-accessible void of 76 (3) A(3), but no solvent mol-ecule could reasonably be located. The crystal studied was an inversion twin with a 0.57 (8):0.43 (8) domain ratio. PMID- 26594551 TI - Crystal structure of 2-[4(E)-2,6-bis-(4-chloro-phen-yl)-3-ethyl-piperidin-4-yl idene]acetamide. AB - In the title piperidine derivative, C21H22Cl2N2O, the piperidine ring adopts a chair conformation. The chloro-phenyl rings are oriented at an angle of 45.59 (14) degrees with respect to each other. In the crystal, mol-ecules are linked via N-H?O hydrogen bonds, forming C(4) chains along [100]. The chains are linked by C-H?O hydrogen bonds, forming sheets parallel to the ab plane. Within the sheets, there are N-H?pi inter-actions present. The crystal studied was refined as an inversion twin. PMID- 26594552 TI - Crystal structure of 3-chloro-1-methyl-5-nitro-1H-indazole. AB - The mol-ecule of the title compound, C8H6ClN3O2, is built up from fused five- and six-membered rings connected to a chlorine atom and to nitro and methyl groups. The indazole system is essentially planar with the largest deviation from the mean plane being 0.007 (2) A. No classical hydrogen bonds are observed in the structure. Two mol-ecules form a dimer organised by a symmetry centre via a close contact between a nitro-O atom and the chlorine atom [at 3.066 (2) A this is shorter than the sum of their van der Waals radii]. PMID- 26594553 TI - Crystal structure of ethyl 2-phenyl-4-(prop-2-yn-1-yl-oxy)-5,6,7,8-tetra-hydro pyrido[4',3':4,5]thieno[2,3-d]pyrimidine-7-carboxyl-ate. AB - In the title compound, C21H19N3O3S, the 5,6,7,8-tetra-hydro-pyridine ring adopts a half-chair conformation. The fused-thieno[2,3-d]pyrimidine ring system is essentially planar (r.m.s. deviation = 0.001 A) and forms a dihedral angle of 2.66 (6) degrees with the attached phenyl ring. The three-dimensional crystal packing is stabilized by C-H?O and C-H?N hydrogen bonds and C-H?pi inter-actions. PMID- 26594554 TI - Crystal structure of methyl 4-(2-fluoro-phenyl)-6-methyl-2-sulfanylidene-1,2,3,4 tetra-hydro-pyrimidine-5-carb-oxy-late. AB - In the title compound, C13H13FN2O2S, the pyrimidine ring adopts a twist-boat conformation with the MeCN and methine-C atoms displaced by 0.0938 (6) and 0.2739 (3) A, respectively, from the mean plane through the other four atoms of the ring. The 2-fluoro-benzene ring is positioned axially and forms a dihedral angle of 89.13 (4) degrees with the mean plane through the pyrimidine ring. The crystal structure features N-H?O, N-H?S and C-H?O hydrogen bonds that link mol ecules into supra-molecular chains along the b axis. These chains are linked into a layer parallel to (10-1) by C-H?pi inter-actions; layers stack with no specific inter-actions between them. PMID- 26594555 TI - Crystal structure of (2E)-1-(1-benzo-furan-2-yl)-3-(2-bromo-phen-yl)prop-2-en-1 one monohydrate. AB - The title compound, C17H11BrO2.H2O, crystallizes as a monohydrate in the chiral ortho-rhom-bic space group P212121, and has non-linear optical (NLO) properties. The mol-ecule has an E conformation about the C=C bond and is relatively planar with the benzo-furan and bromo-phenyl rings being inclined to one another by 10.60 (14) degrees . In the crystal, the water mol-ecule is linked to the organic mol-ecule by O-H?O hydrogen bonds, forming an R (2) 2(7) ring motif while C-H?O hydrogen bonds lead to the formation of helices along the b-axis direction. PMID- 26594556 TI - Crystal structure of 2-(2,3-di-meth-oxy-naphthalen-1-yl)-3-hy-droxy-6-meth-oxy-4H chromen-4-one. AB - In the title compound, C22H18O6, the dimeth-oxy-substituted naphthalene ring system is twisted relative to the 4H-chromenon skeleton by 88.96 (3) degrees . The two meth-oxy substituents are tilted from the naphthalene ring system by 1.4 (4) and 113.0 (2) degrees , respectively. An intra-molecular O-H?O hydrogen bond closes an S(5) ring motif. In the crystal, pairs of O-H?O hydrogen bonds form inversion dimers with R (2) 2(10) loops and C-H?O inter-actions connect the dimers into [010] chains. PMID- 26594557 TI - Crystal structure of 2-(1H-imidazol-3-ium-4-yl)ethanaminium dichloride, a re determination. AB - The crystal structure of the title mol-ecular salt, C5H11N3 (+).2Cl(-), was redetermined. In comparison with the previous study [Bonnet et al. (1975 ?). Bull. Soc. Fr. Mineral. Crist. 98, 208-213.], the positions of some H atoms were corrected, allowing a more accurate description of the hydrogen-bonding scheme. In addition, the absolute structure was also determined. The maximum differences in terms of bond lengths and angles between the two determinations are 0.022 A and 1.43 degrees , respectively. The organic cation display a anti conformation of the protonated amine function and the imidazolium ring. The dihedral angle between the imidazolium plane and the plane through the C-C-N side chain is 29.58 (3) degrees . In the crystal, the organic cations and Cl(-) anions are stacked alternatively into layers parallel to (100). N-H?Cl hydrogen bonds between all H atoms of the ammonium group and both N-H groups of the imidazolium ring and the Cl(-) acceptor anions lead to the linkage of organic and inorganic layers into a three-dimensional network. PMID- 26594558 TI - Crystal structure of (E)-1-(2,4-di-nitro-phen-yl)-2-[(E)-5-phenyl-1-(p-tol yl)pent-2-en-4-yn-1-yl-idene]hydrazine. AB - In the title compound, C24H18N4O4, the plane of the phenyl ring is inclined to those of the toluene ring and the di-nitro-substituted benzene ring by 66.96 (19) and 47.06 (18) degrees , respectively, while the planes of the two benzene rings are inclined to one another by 36.26 (19) degrees . There is an intra-molecular N H?O hydrogen bond between the NH group and the O atom of a nitro group, forming an S(6) ring motif. In the crystal, mol-ecules are linked by C-H?O hydrogen bonds and C-H?pi inter-actions, forming a three-dimensional network. There are also weak pi-pi inter-actions present involving the phenyl ring and the di-nitro substituted benzene ring [inter-centroid distance = 3.741 (2) A]. PMID- 26594559 TI - Crystal structure of a second triclinic polymorph of 2-methyl-pyridinium picrate. AB - The title mol-ecular salt, C6H8N(+).C6H2N3O7 (-) (systematic name: 2-methyl pyridinium 2,4,6-tri-nitro-phenolate), crystallizes with two cations and two anions in the asymmetric unit. In the crystal, the cations are linked to the anions via bifurcated N-H?(O,O) hydrogen bonds, generating R 1 (2)(6) graph-set motifs. Numerous C-H?O hydrogen bonds are observed between these cation-anion pairs, which result in a three-dimensional network. In addition, weak aromatic pi pi stacking between the 2-methyl-pyridinium rings [inter-centroid distance = 3.8334 (19) A] and very weak stacking [inter-centroid distance = 4.0281 (16) A] between inversion-related pairs of picrate anions is observed. The title salt is a second triclinic polymorph of the structure (also with Z' = 2) reported earlier [Anita et al. (2006). Acta Cryst. C62, o567-o570; Chan et al. (2014 ?). CrystEngComm, 16, 4508-4538]. In the title compound, the cations and anions display a chequerboard arrangement when viewed down [100], whereas in the first polymorph, (010) layers of alternating cations and anions are apparent in a [100] view. It is inter-esting that the unit-cell lengths are almost identical for the two polymorphs, although the inter-axial angles are quite different. PMID- 26594560 TI - Crystal structure of morpholin-4-ium cinnamate. AB - In the anhydrous salt formed from the reaction of morpholine with cinnamic acid, C4H10NO(+).C9H7O2 (-), the acid side chain in the trans-cinnamate anion is significantly rotated out of the benzene plane [C-C-C- C torsion angle = 158.54 (17) degrees ]. In the crystal, one of the the aminium H atoms is involved in an asymmetric three-centre cation-anion N-H?(O,O') R 1 (2)(4) hydrogen-bonding inter action with the two carboxyl-ate O-atom acceptors of the anion. The second aminium-H atom forms an inter-species N-H?Ocarboxyl-ate hydrogen bond. The result of the hydrogen bonding is the formation of a chain structure extending along [100]. Chains are linked by C-H?O inter-actions, forming a supra-molecular layer parallel to (01-1). PMID- 26594561 TI - Crystal structure of 2-cyano-1-methyl-pyridinium perchlorate. AB - The asymmetric unit of the title salt, C7H7N2 (+).ClO4 (-), comprises two independent formula units. The solid-state structure comprises corrugated layers of cations and of anions, approximately parallel to (010). The supra-molecular layers are stabilized and connected by C-H?O hydrogen bonding to consolidate a three-dimensional architecture. A close pyridin-ium-perchlorate N?O contact [2.867 (5) A] is noted. The crystal was refined as an inversion twin. PMID- 26594562 TI - Crystal structure of 2-cyano-1-methyl-pyridinium bromide. AB - In the title mol-ecular salt, C7H7N2 (+).Br(-), all the non-H atoms lie on crystallographic mirror planes. The packing consists of (010) cation-anion layers, with the cations forming dimeric units via very weak pairwise C-H?N inter actions. Weak C-H?Br inter-actions link the cations to the anions. PMID- 26594563 TI - Crystal structure of 2-(4-chloro-benzamido)-benzoic acid. AB - In the title mol-ecule, C14H10ClNO3, the amide C=O bond is anti to the o-carb-oxy substituent in the adjacent benzene ring, a conformation that facilitates the formation of an intra-molecular amide-N-H?O(carbon-yl) hydrogen bond that closes an S(6) loop. The central amide segment is twisted away from the carb-oxy- and chloro-substituted benzene rings by 13.93 (17) and 15.26 (15) degrees , respectively. The most prominent supra-molecular inter-actions in the crystal packing are carb-oxy-lic acid-H?O(carbox-yl) hydrogen bonds that lead to centrosymmetric dimeric aggregates connected by eight-membered {?HOC=O}2 synthons. PMID- 26594564 TI - Crystal structure of 4,4',4''-(1,3,5-triazine-2,4,6-tri-yl)tripyridinium trichloride 2.5-hydrate. AB - The asymmetric unit of the title compound, C18H15N6 (3+).3Cl(-).2.5H2O, contains two independent (1,3,5-triazine-2,4,6-tri-yl)tripyridinium cations. Both cations are approximately planar, the r.m.s. deviations of fitted non-H atoms being 0.045 and 0.051 A. In the crystal, extensive O-H?Cl, O-H?O, N-H?Cl and N-H?O hydrogen bonds and weak C-H?Cl and C-H?O inter-actions link the organic cations, Cl(-) anions and water mol-ecules into a three-dimensional supra-molecular architecture. pi-pi stacking between the pyridine rings of adjacent cations is also observed, the centroid-to-centroid distance being 3.7578 (8) A. PMID- 26594565 TI - Crystal structure of 8-eth-oxy-3-(4-nitro-phen-yl)-2H-chromen-2-one. AB - In the title compound, C17H13NO5, the coumarin ring system is essentially planar (r.m.s. deviation = 0.008 A). The nitro-phenyl ring makes a dihedral angle of 25.27 (9) degrees with the coumarin ring plane. The nitro group is almost coplanar with the phenyl ring to which it is attached, making a dihedral angle of 4.3 (3) degrees . The eth-oxy group is inclined to the coumarin ring plane by 4.1 (2) degrees . Electron delocalization was found at the short bridging C-C bond with a bond length of 1.354 (2) A. In the crystal, mol-ecules are linked via C H?O hydrogen bonds, forming sheets in the bc plane. The sheets are linked via pi pi stacking [centroid-centroid distances = 3.5688 (13) and 3.7514 (13) A], forming a three-dimensional structure. PMID- 26594566 TI - Crystal structure of (Z)-2-benzyl-idene-4-methyl-2H-benzo[b][1,4]thia-zin-3(4H) one. AB - In the title compound, C16H13NOS, the 1,4-thia-zine ring displays a screw-boat conformation. The conformation about the ethene bond [1.344 (2) A] is Z. The plane of the fused benzene ring makes a dihedral angle of 58.95 (9) degrees with the pendent phenyl ring, indicating a twisted conformation in the mol-ecule. In the crystal, mol-ecules are linked by pairs of C-H?O hydrogen bonds, forming inversion dimers. PMID- 26594567 TI - Crystal structure of {[2-hy-droxy-2-(3-meth-oxy-phen-yl)cyclo-hex-yl]meth-yl}di methyl-ammonium benzoate. AB - The title compound, C16H26NO2 (+).C7H5O2 (-), is a benzoate salt of the painkiller Tramadol. The six-membered cyclo-hexane ring of the cation adopts a slightly distorted chair conformation and carries OH and 3-meth-oxy-phenyl substituents at the 2-position and a protonated methyl-aza-niumylmethyl group at the 3-position. In addition, a weak intra-molecular C-H?O hydrogen bond is observed in the cation. In the crystal, weak O-H?O, N-H?O and C-H?O hydrogen bonds link the components into chains along [010]. A C-H?pi contact is also observed. PMID- 26594568 TI - Crystal structure of 2-cyclo-hexyl-1,3-thia-zolo[4,5-b]pyridine. AB - In the title compound, C12H14N2S, the cyclo-hexane ring adopts a chair conformation with the exocyclic C-C bond in an equatorial orientation. The mean plane through the cyclo-hexane ring (all atoms) is twisted from the thia-zolo pyridine ring system (r.m.s. deviation = 0.013 A) by 39.57 (6) degrees . In the crystal, mol-ecules form (100) sheets, although there are no specific directional inter-actions between them. The crystal stucture was refined as a two-component perfect twin. PMID- 26594569 TI - Crystal and mol-ecular structure of aflatrem. AB - The crystal structure of the title compound, C32H39NO4, confirms the absolute configuration of the seven chiral centres in the mol-ecule. The molecule has a 1,1-dimethylprop-2-enyl substituent on the indole nucleus and this nucleus shares one edge with the five-membered ring which is, in turn, connected to a sequence of three edge-shared fused rings. The skeleton is completed by the 7,7-trimethyl 6,8-dioxabi-cyclo-[3.2.1]oct-3-en-2-one group connected to the terminal cyclohexene ring. The two cyclohexane rings adopt chair and half-chair conformations, while in the dioxabi-cyclo-[3.2.1]oct-3-en-2-one unit, the six membered ring has a half-chair conformation. The indole system of the mol-ecule exhibits a tilt of 2.02 (1) degrees between its two rings. In the crystal, O-H?O hydrogen bonds connect mol-ecules into chains along [010]. Weak N-H?pi inter actions connect these chains, forming sheets parallel to (10-1). PMID- 26594570 TI - Crystal structure of 3-bromo-pyridine N-oxide. AB - In the title compound, C5H4BrNO, there are two mol-ecules in the asymmetric unit that are related by a pseudo-inversion center. The two independent mol-ecules are approximately planar, with an observed (ring-ring) angle of 5.49 (13) degrees . The crystal structure exhibits a herringbone pattern with the zigzag running along the b-axis direction. The least-squares plane containing the rings of both asymmetric molecules and the plane containing the symmetrically related mol ecules make a plane-plane angle of 66.69 (10) degrees , which makes the bend of the herringbone pattern. The bromo group on one mol-ecule points to the bromo group on the neighboring mol-ecule, with a Br?Br inter-molecular distance of 4.0408 (16) A. The herringbone layer-to-layer distance is 3.431 (4) A with a shift of 1.742 (7) A. There are no short contacts, hydrogen bonds, or pi-pi inter actions. PMID- 26594571 TI - Crystal structure of (2E,4E)-5-[bis-(2-hy-droxy-eth-yl)amino]-1-(4-chloro-phen yl)-5-phenyl-penta-2,4-dien-1-one. AB - In the title compound, C21H22ClNO3, the penta-diene unit is nearly planar [maximum deviation = 0.023 (1) A], but the carbonyl O atom deviates significantly [by 0.304 (1) A] from its mean plane, which is twisted with respect to the phenyl and chloro-benzene rings by 71.34 (13) and 46.40 (13) degrees , respectively. In the crystal, inversion-related molecules are linked by two pairs of O-H?O hydrogen bonds, forming chains propagating along [01-1], enclosing R (2) 2(16) and R (2) 2(22) ring motifs. The chains are linked via C-H?O hydrogen bonds and C H?pi inter-actions into a three-dimensional supra-molecular architecture. PMID- 26594572 TI - Crystal structure of diethyl (E)-2-[(benzo-furan-2-yl)methyl-idene]succinate. AB - The title compound, C17H18O5, was synthesized by a base-free catalytic Wittig reaction. The mol-ecule consists of a diethyl itaconate unit, which is connected via the C=C double bond to a benzo-furan moiety. The benzo-furan ring system (r.m.s. deviation = 0.007 A) forms dihedral angles of 79.58 (4) and 12.12 (10) degrees with the mean planes through the cis and trans eth-oxy-carbonyl groups, respectively. An intra-molecular C-H?O hydrogen bond involving the O atom of the benzo-furan moiety is observed. In the crystal, mol-ecules are linked into ribbons running parallel to the b axis by C-H?O hydrogen bonds. PMID- 26594573 TI - Crystal structure of 3,4'-diphenyl-3'-p-tolyl-4'H-spiro-[indan-2,5'-[1,2]oxazol] 1-one. AB - In the title compound, C30H23NO2, the five-membered rings are both in envelope conformations with the same spiro C atom as the flap. The benzene ring and the two phenyl rings are inclined to the mean plane of the indene ring system by 83.98 (8), 81.46 (8) and 72.31 (7) degrees . In the crystal, mol-ecules are linked by pairs of C-H?O hydrogen bonds into inversion dimers. The dimers are further connected by C-H?N inter-actions, forming layers parallel to (10-1). PMID- 26594574 TI - Crystal structure of (5-chloro-2-hy-droxy-phen-yl)(3-methyl-isoxazolo[5,4 b]pyridin-5-yl)methanone. AB - In the title compound, C14H9ClN2O3, the fused pyridine and isoxazole rings are approximately planar, making a dihedral angle of 1.14 (16) degrees . The mol ecule is twisted with the benzene ring and the mean plane through the fused pyridine-isoxazole ring system being inclined to one another by 47.03 (13) degrees . There is an intra-molecular O-H?O hydrogen bond forming an S(6) ring motif. In the crystal, mol-ecules are linked by C-H?N hydrogen bonds, forming chains propagating along [001]. The chains are linked by slipped parallel pi-pi inter-actions, involving inversion-related benzene rings, forming slabs lying parallel to the bc plane {inter-centroid distance = 3.770 (2) A]. PMID- 26594575 TI - Crystal structure of 2-(3-nitro-phen-yl)-1,3-thia-zolo[4,5-b]pyridine. AB - In the title compound, C12H7N3O2S, the dihedral angle between the planes of the thia-zolo-pyridine ring system (r.m.s. deviation = 0.005 A) and the benzene ring is 3.94 (6) degrees . The nitro group is rotated by 7.6 (2) degrees from its attached ring. In the crystal, extensive aromatic pi-pi stacking [shortest centroid-centroid separation = 3.5295 (9) A] links the mol-ecules into (001) sheets. PMID- 26594576 TI - Crystal structure of di-cyclo-hexyl-ammonium nitrate(V). AB - In the title mol-ecular salt, C12H24N(+).NO3 (-), the cyclohexyl rings adopt chair conformations with the exocyclic C-N bonds in equatorial orientations. In the crystal, a bifurcated N-H?(O,O) hydrogen bond links the cation to the anion; the ion pairs are linked via C-H?O hydrogen bonds, forming layers in the ac plane. PMID- 26594577 TI - Crystal structure of 5-(furan-2-yl)-N-phenyl-1,3,4-oxa-diazol-2-amine. AB - The title compound, C12H9N3O2, was obtained as a cyclized oxa-diazole derivative from substituted thio-semicarbazide in the presence of manganese(II) acetate. The furan ring is disordered over two orientations, with occupancies of 0.76 (2) and 0.24 (2). The dihedral angles between the central oxa-diazole ring and the pendant phenyl ring and furan ring (major disorder component) are 3.34 (18) and 5.7 (6) degrees , respectively. A short intra-molecular C-H?O contact generates an S(6) ring. In the crystal, inversion dimers linked by pairs of N-H?N hydrogen bonds generate R 2 (2)[8] loops. The dimers are linked by C-H?pi and pi-pi inter actions [range of centroid-centroid distances = 3.291 (2)-3.460 (8) A], generating a three-dimensional network. PMID- 26594578 TI - Crystal structure of 2-fluoro-N-(1,3-thia-zol-2-yl)benzamide. AB - In the title compound, C10H7FN2OS, the mean plane of the central amide fragment (r.m.s. deviation = 0.048 A) makes dihedral angles of 35.28 (8) and 10.14 (12) degrees with those of the fluoro-benzene and thia-zole rings, respectively. The thia-zole S and amide O atoms lie to the same side of the mol-ecule. In the crystal, pairs of N-H?N hydrogen bonds connect the mol-ecules into inversion dimers with R 2 (2)(8) motifs, and weak C-H?O inter-actions connect the mol ecules into C(6) [001] chains. Together, the N-H?N and C-H?O hydrogen bonds generate (100) sheets. PMID- 26594579 TI - Crystal structure of (E)-1,3-bis-(6-methoxy-naphthalen-2-yl)prop-2-en-1-one. AB - In the title compound, C25H20O3, the central -C(=O)-C=C- chain is disordered over two positions about the central C atom, with an occupancy ratio of 0.848 (6):0.152 (6). The mol-ecule is twisted with the two naphthalene ring systems being inclined to one another by 52.91 (9) degrees . In the crystal, mol-ecules are linked by C-H?pi inter-actions, forming a three-dimensional structure. The structure was refined as a two-component twin with a 180 degrees rotation about the c* axis. PMID- 26594580 TI - Crystal structure of 2-{(R)-[1-(4-bromo-phen-yl)eth-yl]imino-meth-yl}-4-(phenyl diazen-yl)phenol, a chiral photochromic Schiff base. AB - The title chiral photochromic Schiff base compound, C21H18BrN3O, was synthesized from (R)-(+)-1-(4-bromo-phen-yl)ethyl-amine and the salicyl-aldehyde of an azo benzene derivative. The mol-ecule corresponds to the phenol-imine tautomer, the C=N and N-C bond distances being 1.285 (3) and 1.470 (3) A, respectively. The diazenyl group adopts a trans form, with an N=N distance of 1.256 (3) A. The hy droxy group is involved in intra-molecular O-H?N hydrogen bonding. In the crystal, C-H?pi inter-actions consolidate the crystal packing of one-dimensional chains, which exhibits short inter-molecular Br?C contacts of 3.400 (3) A. PMID- 26594581 TI - Crystal structure of 1,1,2,2-tetra-methyl-1,2-bis-(2,3,4,5-tetra-methyl-cyclo penta-2,4-dien-1-yl)disilane. AB - The mol-ecular structure of the title compound, C22H38Si2, features a trans arrangement of the cyclo-penta-dienyl rings to avoid steric strain [C-Si-Si-C torsion angle = -179.0 (5) degrees ]. The Si-Si bond length is 2.3444 (4) A. The most notable inter-molecular inter-actions in the mol-ecular packing are C-H?pi contacts that lead to the formation of wave-like supra-molecular chains along the b axis. PMID- 26594582 TI - Crystal structure of 1,2,3,5-di-O-methyl-ene-alpha-d-xylo-furan-ose. AB - The title compound, C7H10O5, was synthesized by reaction of d-xylose with paraformaldehyde. In the crystal, the central part of the mol-ecule consists of a five-membered C4O ring with an envelope conformation, with the methine C atom adjacent to the O atom being the flap. The protected O atoms of both cyclic acetal groups are oriented so that the four chiral C atoms of the furan-ose part show an R configuration. C-H?O hydrogen bonds are present between adjacent mol ecules, generating a three-dimensional network. PMID- 26594583 TI - Crystal structure of N'-di-phenyl-methyl-idene-5-methyl-1H-pyrazole-3-carbo hydrazide. AB - In the title compound, C18H16N4O, the planes of the phenyl rings are approximately perpendicular to each other [dihedral angle = 78.07 (8) degrees ] and form dihedral angles of 56.43 (8) and 24.59 (8) degrees with the pyrazole ring. In the crystal, mol-ecules are linked by N-H?O hydrogen bonds to form one dimensional chains parallel to the [010] direction. PMID- 26594584 TI - Crystal structure of 3-(2-nitro-phen-yl)-1-(1-phenyl-sulfonyl-1H-indol-3 yl)propan-1-one. AB - In the title compound, C23H18N2O5S, the phenyl and benzene rings subtend dihedral angles of 78.18 (10) and 30.18 (9) degrees , respectively, with the indole ring system (r.m.s. deviation = 0.022 A). The crystal structure features weak C-H?O and C-H?pi inter-actions, which link the mol-ecules into a three-dimensional network. PMID- 26594585 TI - Crystal structure of 2-di-methyl-amino-1-eth-oxy-carbonyl-3-methyl-3,4,5,6-tetra hydro-pyrimidin-1-ium tetra-phenyl-borate. AB - The asymmetric unit of the title salt, C10H20N3O2 (+).C24H20B(-), contains two cations and two tetra-phenyl-borate ions. The C-N bond lengths in the central CN3 unit of the guanidinium ions range between 1.323 (2) and 1.381 (2) A, indicating partial double-bond character. The central C atoms are bonded to the three N atoms in a nearly ideal trigonal-planar geometry and the positive charge is delocalized in the CN3 plane. The cationic six-membered rings are nonplanar, the dihedral angles between the N/C/N and C/C/C planes ranging from 45.8 (1) to 53.6 (1) degrees . In the crystal, C-H?pi inter-actions are present between the guanidinium H atoms and the phenyl rings of the tetra-phenyl-borate ions. The phenyl rings form aromatic pockets, in which the guanidinium ions are embedded. PMID- 26594586 TI - Crystal structure of the adduct (4-chloro-phen-yl)(4-hy-droxy-piperidin-1 yl)methanone-(4-chloro-phen-yl)(piperidin-1-yl)methanone (0.75/0.25). AB - In the title compound, 0.75C12H14ClNO2.0.25C12H14ClNO, which is an adduct comprising 0.75 4-hy-droxy-piperidin-1-yl or 0.25 4-piperidin-1-yl substituents on a common (4-chloro-phen-yl)methanone component; the dihedral angles between the benzene ring and the two piperidine rings are 51.6 (3) and 89.5 (7) degrees , respectively. The hy-droxy-piperidine ring is in a bis-ectional oriention (bi) with the phenyl ring. In the crystal, inter-molecular O-H?O hydrogen bonds between the hy-droxy-piperidine group and the keto O atom lead to the formation of chains extending along the c- axis direction. PMID- 26594587 TI - Crystal structure of 3'-(1H-indole-3-carbon-yl)-1'-methyl-2-oxo-4'-(4-oxo-4H chromen-3-yl)spiro-[indoline-3,2'-pyrrolidine]-3'-carbo-nitrile. AB - In the title compound, C31H22N4O4, the pyrrolidine ring adopts a twist conformation on the N-CH2 bond. The indolin-2-one and the 1H-indole rings are nearly planar (r.m.s. deviations = 0.06 and 0.011 A, respectively) and are inclined to one another by 34.19 (9) degrees . The chromene ring system is also nearly planar (r.m.s. deviation = 0.029 A). It is almost normal to the 1H-indole ring system, with a dihedral angle of 88.71 (8) degrees , and is inclined to the indolin-2-one ring system by 72.76 (8) degrees . In the crystal, mol-ecules are linked via N-H?O hydrogen bonds, forming slabs parallel to (10-1). The slabs are linked by C-H?O hydrogen bonds, forming a three-dimensional structure. PMID- 26594588 TI - Crystal structure of 2-(4-methyl-piperazin-1-yl)quinoline-3-carbaldehyde. AB - In the title compound, C15H17N3O, the aldehyde group is twisted relative to the quinoline group by17.6 (2) degrees due to the presence of a bulky piperazinyl group in the ortho position. The piperazine N atom attached to the aromatic ring is sp (3)-hybridized and the dihedral angle between the mean planes through the the six piperazine ring atoms and through the quinoline ring system is 40.59 (7) degrees . Both piperazine substituents are in equatorial positions. PMID- 26594589 TI - Crystal structure of 2-benzene-sulfon-amido-3-hy-droxy-propanoic acid. AB - In the title compound, C9H11NO5S, the O=S=O plane of the sulfonyl group is twisted at a dihedral angle of 52.54 (16) degrees with respect to the benzene ring. The dihedral angle between the carb-oxy-lic acid group and the benzene ring is 49.91 (16) degrees . In the crystal, C-H?O, N-H?O and O-H?O hydrogen bonds link the mol-ecules into (001) sheets. PMID- 26594590 TI - Crystal structure of trans-1-{2-[4-(di-methyl-amino)-phen-yl]eth-yl}-4-[2-(pyren 1-yl)eth-yl]cyclo-hexa-ne. AB - The title compound, C34H37N, is a pyrene derivative in which the pyrene ring system is linked to an ethyl-cyclo-hexane unit which, in turn, carries a [4-(di methyl-amino)-phen-yl]ethyl substituent in the para position. The central cyclo hexane ring has a chair conformation, with the exocyclic C-C bonds in equatorial orientations. The benzene ring is inclined to the mean plane of the pyrene ring system [maximum deviation = 0.038 (4) A] by 14.84 (15) degrees . In the crystal, mol-ecules are linked by C-H?pi inter-actions, forming chains propagating along [010]. The crystal was refined as a non-merohedral twin [domain ratio = 0.9989 (4):0.0011 (4)]. PMID- 26594591 TI - Pre-Chemoradiotherapy FDG PET/CT cannot Identify Residual Metabolically-Active Volumes within Individual Esophageal Tumors. AB - OBJECTIVE: To study whether subvolumes with a high pre-chemoradiotherapy (CRT) FDG uptake could identify residual metabolically-active volumes (MAVs) post-CRT within individual esophageal tumors. Accurate identification will allow simultaneous integrated boost to these subvolumes at higher risk to improve clinical outcomes. METHODS: Twenty patients with esophageal cancer were treated with CRT plus surgery and underwent FDG PET/CT scans before and after CRT. The two scans were rigidly registered. Seven MAVs pre-CRT and four MAVs post-CRT within a tumor were defined with various SUV thresholds. The similarity and proximity between the MAVs pre-CRT and post-CRT were quantified with three metrics: fraction of post-CRT MAV included in pre-CRT MAV, volume overlap and centroid distance. RESULTS: Eight patients had no residual MAV. Six patients had local residual MAV (SUV >=2.5 post-CRT) within or adjoining the original MAV (SUV >=2.5 pre-CRT). On average, less than 65% of any post-CRT MAVs was included in any pre-CRT MAVs, with a low volume overlap <45%, and large centroid distance >8.6 mm. In general, subvolumes with higher FDG-uptake pre-CRT or post-CRT had lower volume overlap and larger centroid distance. Six patients had new distant MAVs that were determined to be inflammation from radiation therapy. CONCLUSIONS: Pre-CRT PET/CT cannot reliably identify the residual MAVs within individual esophageal tumors. Simultaneous integrated boost to subvolumes with high FDG uptake pre-CRT may not be feasible. PMID- 26594592 TI - Grief and Women: Stillbirth in the Social Context of India. AB - INTRODUCTION: Few in Western society would argue the potentially devastating impact of stillbirth related grief; but in many developing countries where stillbirth remains the highest in the world, perinatal grief is barely recognized as an issue. The purpose of this study was to explore how poor, rural central Indian women perceive and cope with stillbirths. METHODS: Seventeen key informant interviews and two focus groups (N = 33) with local health care providers, family members, and women who experienced stillbirth were conducted over a 1-month period in 2011 and then systematically coded for emerging themes using grounded theory methods to explore how women experienced stillbirth. RESULTS: Although usually never talked about and not recognized as an issue, perinatal grief emerged as a significant shared experience by all. The perceptions of stillbirth related grief emerged in three major themes and bear evidence of gender and power issues and indicate that local social norms negatively factor heavily into their perinatal grief experiences. DISCUSSION: The findings in this richly textured study add to the limited literature regarding rural, central Indian women's experiences with stillbirth and factors influencing their resulting perinatal grief. In light of the void of recognition of this phenomenon in Indian society, a better understanding of the context in which poor Indian women experience perinatal grief will be a first step toward developing much needed culturally rooted interventions to positively impact the women's abilities to better cope with stillbirth in the context of their realities. PMID- 26594593 TI - Focal Task-specific Dystonia among Professional Musicians in Latin America. AB - In Response To: Frucht SJ. Focal task-specific dystonia-from early descriptions to a new, modern formulation. Tremor Other Hyperkinet Mov. 2014; 4. doi: 10.7916/D8VD6WHP. PMID- 26594594 TI - Identification of alpha1-Antitrypsin as a Potential Candidate for Internal Control for Human Synovial Fluid in Western Blot. AB - Western blot of synovial fluid has been widely used for osteoarthritis (OA) research and diagnosis, but there is no ideal loading control for this purpose. Although beta-actin is extensively used as loading control in western blot, it is not suitable for synovial fluid because it is not required in synovial fluid as a cytoskeletal protein. A good loading control for synovial fluid in OA studies should have unchanged content in synovial fluids from normal and OA groups, because synovial fluid protein content can vary with changes in synovial vascular permeability with OA onset. In this study, we explore the potential of using alpha1-antitripsin (A1AT) as loading control for OA synovial fluid in western blot. A1AT level is elevated in inflammatory conditions such as rheumatoid arthritis (RA). Unlike RA, OA is a non-inflammation disease, which does not induce A1AT. In this study, we identified A1AT as an abundant component of synovial fluid by Mass Spectrometry and confirmed that the level of A1AT is relative constant between human OA and normal synovial fluid by western blot and ELISA. Hence, we proposed that A1AT may be a good loading control for western blot in human OA synovial fluid studies provided that pathological conditions such as RA or A1AT deficiency associated liver or lung diseases are excluded. PMID- 26594595 TI - Converting Instance Checking to Subsumption: A Rethink for Object Queries over Practical Ontologies. AB - Efficiently querying Description Logic (DL) ontologies is becoming a vital task in various data-intensive DL applications. Considered as a basic service for answering object queries over DL ontologies, instance checking can be realized by using the most specific concept (MSC) method, which converts instance checking into subsumption problems. This method, however, loses its simplicity and efficiency when applied to large and complex ontologies, as it tends to generate very large MSCs that could lead to intractable reasoning. In this paper, we propose a revision to this MSC method for DL [Formula: see text], allowing it to generate much simpler and smaller concepts that are specific enough to answer a given query. With independence between computed MSCs, scalability for query answering can also be achieved by distributing and parallelizing the computations. An empirical evaluation shows the efficacy of our revised MSC method and the significant efficiency achieved when using it for answering object queries. PMID- 26594597 TI - Fabricating a high-resolution mask with improved line-edge roughness by using a nonchemically amplified resist and a postexposure bake. AB - The authors have developed a high-resolution technique for fabricating photomasks at the 10-nm half-pitch logic nodes and beyond. Current mask-manufacturing techniques use a chemically amplified resist (CAR) that has a complex mechanism of acid generation, complicating the criteria for selecting the polymer and the quencher for industrial purposes. Thus, it is important to study fabricating masks with non-CARs. The authors exposed a non-CAR, diluted ZEP520A, to variable shaped electron-beam lithography and used a postexposure bake (PEB) to modify the resist. Studying how the PEB temperature affected the non-CAR and resultant masks, the authors demonstrate that their technique can produce high-resolution structures. By measuring the critical dimensions (CDs), the authors show that the PEB shrunk, enlarged, and retained the size of 1:1 line-and-space, isolated space, and isolated line patterns, respectively. By optimizing the PEB temperature, the authors improved the line-edge roughness (LER) of the 1:1 line and-space and isolated space CDs by ~40%. To understand how the PEB affected the resultant structures, the authors measured the hardness of cured resists with and without a PEB at various temperatures. Optimizing the PEB temperature of the non CAR increased the resist contrast, annealing the resist and improving the LER. As such, their technique is capable of high resolutions on the order of 20 nm. The insights the authors gained from optimizing the PEB might be useful when fabricating next-generation masks. PMID- 26594596 TI - Melatonin Counteracts at a Transcriptional Level the Inflammatory and Apoptotic Response Secondary to Ischemic Brain Injury Induced by Middle Cerebral Artery Blockade in Aging Rats. AB - Aging increases oxidative stress and inflammation. Melatonin counteracts inflammation and apoptosis. This study investigated the possible protective effect of melatonin on the inflammatory and apoptotic response secondary to ischemia induced by blockade of the right middle cerebral artery (MCA) in aging male Wistar rats. Animals were subjected to MCA obstruction. After 24 h or 7 days of procedure, 14-month-old nontreated and treated rats with a daily dose of 10 mg/kg melatonin were sacrificed and right and left hippocampus and cortex were collected. Rats aged 2 and 6 months, respectively, were subjected to the same brain injury protocol, but they were not treated with melatonin. mRNA expression of interleukin-1 beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha), Bcl-2 associated death promoter (BAD), Bcl-2-associated X protein (BAX), glial fibrillary acidic protein (GFAP), B-cell lymphoma 2 (Bcl-2), and sirtuin 1 was measured by reverse transcription-polymerase chain reaction. In nontreated animals, a significant time-dependent increase in IL-1beta, TNF-alpha, BAD, and BAX was observed in the ischemic area of both hippocampus and cortex, and to a lesser extent in the contralateral hemisphere. Hippocampal GFAP was also significantly elevated, while Bcl-2 and sirtuin 1 decreased significantly in response to ischemia. Aging aggravated these changes. Melatonin administration was able to reverse significantly these alterations. In conclusion, melatonin may ameliorate the age-dependent inflammatory and apoptotic response secondary to ischemic cerebral injury. PMID- 26594600 TI - Initial Weight Loss after Restrictive Bariatric Procedures May Predict Mid-Term Weight Maintenance: Results From a 12-Month Pilot Trial. AB - Background: Bariatric procedures are effective options for weight loss (WL) in the morbidly obese. However, some patients fail to lose any weight after bariatric surgery, and mid-term weight maintenance is variable. The aim of this study was to investigate whether initial WL could predict mid-term weight maintenance. Methods: Eighty patients were enrolled, of whom 44 were treated with the BioEnterics Intragastric Balloon (BIB), 21 with laparoscopic adjustable gastric lap-banding (LAGB), and 15 with laparoscopic sleeve gastrectomy (LSG). Percentage of body WL and percentage of excess weight loss (EWL) were calculated at baseline and after 1, 3, 6, and 12 months. Successful WL was defined as EWL >20% for patients treated with BIB and >50% for patients treated with LAGB and SG. Results: Success in the 6th and 12th month was achieved in 80% and 58% of patients in the BIB group, 33% and 40% in the LAGB group, and 60% and 73% in the LSG group. In the BIB group, WL in the 1st month correlated positively with WL at the 6th and 12th month, and an initial WL >6.5% best predicted success (sensitivity 50%, specificity 80%). A similar association was observed in the LAGB group at the 6th and 12th month and an initial WL >9.4% best predicted success (sensitivity 90.0%, specificity 81.2%). In patients treated with LSG, WL in the 3rd month correlated positively with EWL at the 6th and 12th month, with a cutoff value of 17% (sensitivity 66.7%, specificity 100%). Conclusions: WL in the 1st month in patients treated with BIB and LAGB and WL in the 3rd month in patients treated with LSG could be used as a prognostic factor to predict mid term weight maintenance. PMID- 26594601 TI - Novel Tool for Complete Digitization of Paper Electrocardiography Data. AB - OBJECTIVE: We present a Matlab-based tool to convert electrocardiography (ECG) information from paper charts into digital ECG signals. The tool can be used for long-term retrospective studies of cardiac patients to study the evolving features with prognostic value. METHODS AND PROCEDURES: To perform the conversion, we: 1) detect the graphical grid on ECG charts using grayscale thresholding; 2) digitize the ECG signal based on its contour using a column-wise pixel scan; and 3) use template-based optical character recognition to extract patient demographic information from the paper ECG in order to interface the data with the patients' medical record. To validate the digitization technique: 1) correlation between the digital signals and signals digitized from paper ECG are performed and 2) clinically significant ECG parameters are measured and compared from both the paper-based ECG signals and the digitized ECG. RESULTS: The validation demonstrates a correlation value of 0.85-0.9 between the digital ECG signal and the signal digitized from the paper ECG. There is a high correlation in the clinical parameters between the ECG information from the paper charts and digitized signal, with intra-observer and inter-observer correlations of 0.8-0.9 (p < 0.05), and kappa statistics ranging from 0.85 (inter-observer) to 1.00 (intra-observer). CONCLUSION: The important features of the ECG signal, especially the QRST complex and the associated intervals, are preserved by obtaining the contour from the paper ECG. The differences between the measures of clinically important features extracted from the original signal and the reconstructed signal are insignificant, thus highlighting the accuracy of this technique. CLINICAL IMPACT: Using this type of ECG digitization tool to carry out retrospective studies on large databases, which rely on paper ECG records, studies of emerging ECG features can be performed. In addition, this tool can be used to potentially integrate digitized ECG information with digital ECG analysis programs and with the patient's electronic medical record. PMID- 26594598 TI - New Approaches for Studying Alcoholic Liver Disease. AB - Alcoholic liver disease (ALD) is major cause of chronic liver injury which results in liver fibrosis and cirrhosis. According to the surveillance report published by the National Institute on Alcohol Abuse and Alcoholism, liver cirrhosis is the 12th leading cause of death in the United States with 48 % of these deaths being attributed to excessive alcohol consumption. ALD includes a spectrum of disorders from simple steatosis to steatohepatitis, fibrosis, and hepatocellular carcinoma. Several mechanisms play a critical role in the pathogenesis of ALD. These include ethanol-induced oxidative stress and depletion of glutathione, pathological methionine metabolism, increased gut permeability and release of endotoxins into the portal blood, recruitment and activation of inflammatory cells including bone marrow-derived and liver resident macrophages (Kupffer cells). Chronic alcohol consumption results in liver damage and activation of hepatic stellate cells (HSCs) and myofibroblasts, leading to liver fibrosis. Here we discuss the current view on factors that are specific for different stages of ALD and those that regulate its progression, including cytokines and chemokines, alcohol-responsive intracellular signaling pathways, and transcriptional factors. We also review recent studies demonstrating that alcohol-mediated changes can be regulated on an epigenetic level, including microRNAs. Finally, we discuss the reversibility of liver fibrosis and inactivation of HSCs as a potential strategy for treating alcohol-induced liver damage. PMID- 26594599 TI - Gene Therapy for Duchenne muscular dystrophy. AB - INTRODUCTION: Duchenne muscular dystrophy (DMD) is a relatively common inherited disorder caused by defective expression of the protein dystrophin. The most direct approach to treating this disease would be to restore dystrophin production in muscle. Recent progress has greatly increased the prospects for successful gene therapy of DMD, and here we summarize the most promising developments. AREAS COVERED: Gene transfer using vectors derived from adeno associated virus (AAV) has emerged as a promising method to restore dystrophin production in muscles bodywide, and represents a treatment option applicable to all DMD patients. Using information gleaned from PubMed searches of the literature, attendance at scientific conferences and results from our own lab, we provide an overview of the potential for gene therapy of DMD using AAV vectors including a summary of promising developments and issues that need to be resolved prior to large-scale therapeutic implementation. EXPERT OPINION: Of the many approaches being pursued to treat DMD and BMD, gene therapy based on AAV-mediated delivery of microdystrophin is the most direct and promising method to treat the cause of the disorder. The major challenges to this approach are ensuring that microdystrophin can be delivered safely and efficiently without eliciting an immune response. PMID- 26594603 TI - Marble Bone Disease: A Rare Bone Disorder. AB - Osteopetrosis, or marble bone disease, is a rare skeletal disorder due to a defective function of the osteoclasts. This defect renders bones more susceptible to osteomyelitis due to decreased vascularity. This disorder is inherited as autosomal dominant and autosomal recessive. Healthcare professionals should urge these patients to maintain their oral health as well as general health, as this condition makes these patients more susceptible to frequent infections and fractures. This case report emphasizes the signs and symptoms of marble bone disease and presents clinical and radiographic findings. PMID- 26594604 TI - Autologous Peritoneum Graft Repair of a Superior Mesenteric Vein Defect During Pancreaticoduodenectomy. AB - Pancreatic cancers frequently invade the portomesenteric veins. Venous resection during pancreaticoduodenectomy with curative intent is more common now than it was in the past. Most venous resections can be repaired primarily, but some require vascular grafts. Here, we describe the use of an autologous parietal peritoneum graft instead of vascular grafts for repairing a superior mesenteric vein (SMV) defect. Pylorus-preserving pancreaticoduodenectomy combined with en bloc resection of the SMV lateral wall was performed in a 70-year-old woman with cancer of the pancreatic head. The SMV defect was 2 cm long and its width was half the SMV circumference. The defect was covered with a 3 * 2 cm parietal autologous peritoneum graft obtained from the left subcostal area and using running 6/0 polypropylene suture. Tension-free patching was performed, and we retained slight bulging of the graft. Her postoperative course was uneventful. She was discharged on Day 11 after computed tomography confirmed the patency of the SMV, despite slight narrowing. She was well after 10 months of follow-up. Autologous parietal peritoneum grafts can be used for repairing partial venous defects during pancreaticoduodenectomy. They are effective and are easy, fast, and cheap to obtain. PMID- 26594602 TI - Posterior Fixation Techniques in the Subaxial Cervical Spine. AB - This article reviews the historical context, indications, techniques, and complications of four posterior fixation techniques to stabilize the subaxial cervical spine. Specifically, posterior wiring, laminar screw fixation, lateral mass fixation, and pedicle screw fixation are among the common methods of operative fixation of the subaxial cervical spine. While wiring and laminar screw fixation are now rarely used, both lateral mass and pedicle screw fixation are technically challenging and present the risk of significant complications if performed incorrectly. With a sound understanding of anatomy and rigorous preoperative evaluation of bony structures, both lateral mass and pedicle screw fixation provide a safe and reliable method for subaxial cervical spine fixation. PMID- 26594605 TI - The Mathematics of Three N-Localizers Used Together for Stereotactic Neurosurgery. AB - The N-localizer enjoys widespread use in image-guided stereotactic neurosurgery and radiosurgery. This article derives the mathematical equations that are used with three N-localizers and provides analogies, explanations, and appendices in order to promote a deeper understanding of the mathematical principles that govern the N-localizer. PMID- 26594606 TI - Dietary lactosucrose suppresses influenza A (H1N1) virus infection in mice. AB - This study examined the effects of lactosucrose (4(G)-beta-D-galactosylsucrose) on influenza A virus infections in mice. First, the effects of lactosucrose on fermentation in the cecum and on immune function were investigated. In female BALB/c mice, lactosucrose supplementation for 6 weeks promoted cecal fermentation and increased both secretory IgA (SIgA) levels in feces and total IgA and IgG2a concentrations in serum. Both the percentage of CD4(+) T cells in Peyer's patches and the cytotoxic activity of splenic natural killer (NK) cells increased significantly in response to lactosucrose. Next, we examined the effects of lactosucrose on low-dose influenza A virus infection in mice. After 2 weeks of dietary supplementation with lactosucrose, the mice were infected with low-dose influenza A virus. At 7 days post infection, a comparison with control mice showed that weight loss was suppressed, as were viral titers in the lungs. In the spleens of lactosucrose-fed mice, there was an increase in the percentage of NK cells. Lastly, mice fed lactosucrose were challenged with a lethal dose of influenza A virus. The survival rate of these mice was significantly higher than that of mice fed a control diet. These results suggested that lactosucrose supplementation suppresses influenza A virus infection by augmenting innate immune responses and enhancing cellular and mucosal immunity. PMID- 26594607 TI - Short- and long-term dynamics in the intestinal microbiota following ingestion of Bifidobacterium animalis subsp. lactis GCL2505. AB - Bifidobacterium animalis subsp. lactis GCL2505 (B. lactis GCL2505) is able to survive passage through the intestines and proliferate. The daily dynamics of the intestinal bifidobacteria following ingestion of probiotics are not yet clear. Moreover, the effects of long-term ingestion of probiotics on the intestinal microbiota have not been well studied. Two experiments were performed in the present study. In Experiment 1, 53 healthy female volunteers received B. lactis GCL2505; B. bifidum GCL2080, which can survive but not proliferate in the intestine; or yogurt fermented with Lactobacillus delbrueckii subsp. bulgaricus and Streptococcus thermophilus for 2 weeks, and the daily dynamics of intestinal bifidobacteria were investigated. The number of fecal bifidobacteria significantly increased on day 1, and this was maintained until day 14 in the B. lactis GCL2505 ingestion group. However, no significant change in the number of fecal bifidobacteria was observed in the other groups throughout the ingestion period. In Experiment 2, 38 constipated volunteers received either B. lactis GCL2505 or a placebo for 8 weeks. Both the number of fecal bifidobacteria and the frequency of defecation significantly increased throughout the ingestion period in the B. lactis GCL2505 ingestion group. These results suggested that the proliferation of ingested bifidobacteria within the intestine contributed to a rapid increase in the amount of intestinal bifidobacteria and subsequent maintenance of these levels. Moreover, B. lactis GCL2505 improved the intestinal microbiota more effectively than non-proliferating bifidobacteria and lactic acid bacteria. PMID- 26594608 TI - Differences in folate production by bifidobacteria of different origins. AB - Bifidobacteria are known to produce folate, a vital nutrient for humans. Previous studies have suggested that the ability to produce folate is strain dependent, but further adequate evaluation is needed. In this study, a total of 44 strains, including 12 species and 7 subspecies, of bifidobacteria were investigated for the production of folate during cultivation in medium containing essential levels of folate for growth of the tested strains. An in vitro assay showed that all strains of human-residential bifidobacteria (HRB) were able to produce folate, whereas most strains of non-HRB were not, with the exception of the B. thermophilum and B. longum ssp. suis strains. The differences in the in vivo production of folate by HRB and non-HRB were confirmed using mono-associated mice. The fecal folate concentrations, blood levels of hemoglobin and mean corpuscular volumes were significantly higher in the mice colonized with a folate producer, B. longum subsp. longum, compared with mice colonized with a nonproducer, B. animalis subsp. lactis. Our results confirmed the differences in folate production between HRB and non-HRB strains and suggested the benefit of HRB to hosts from the perspective of potential folate delivery. PMID- 26594609 TI - Using publicly visible social media to build detailed forecasts of civil unrest. AB - We demonstrate how one can generate predictions for several thousand incidents of Latin American civil unrest, often many days in advance, by surfacing informative public posts available on Twitter and Tumblr. The data mining system presented here runs daily and requires no manual intervention. Identification of informative posts is accomplished by applying multiple textual and geographic filters to a high-volume data feed consisting of tens of millions of posts per day which have been flagged as public by their authors. Predictions are built by annotating the filtered posts, typically a few dozen per day, with demographic, spatial, and temporal information. Key to our textual filters is the fact that social media posts are necessarily short, making it possible to easily infer topic by simply searching for comentions of typically unrelated terms within the same post (e.g. a future date comentioned with an unrest keyword). Additional textual filters then proceed by applying a logistic regression classifier trained to recognize accounts belonging to organizations who are likely to announce civil unrest. Geographic filtering is accomplished despite sparsely available GPS information and without relying on sophisticated natural language processing. A geocoding technique which infers non-GPS-known user locations via the locations of their GPS-known friends provides us with location estimates for 91,984,163 Twitter users at a median error of 6.65km. We show that announcements of upcoming events tend to localize within a small geographic region, allowing us to forecast event locations which are not explicitly mentioned in text. We annotate our forecasts with demographic information by searching the collected posts for demographic specific keywords generated by hand as well as with the aid of DBpedia. Our system has been in production since December 2012 and, at the time of this writing, has produced 4,771 distinct forecasts for events across ten Latin American nations. Manual examination of 2,859 posts surfaced by our method revealed that only 108 were discussing topics unrelated to civil unrest. Examination of 2,596 forecasts generated between 2013-07-01 and 2013-11-30 found 1,192 (45.9%) matched exactly the date and within a 100 km radius of a civil unrest event reported in traditional news media. PMID- 26594610 TI - Failure time regression with continuous informative auxiliary covariates. AB - In this paper we use Cox's regression model to fit failure time data with continuous informative auxiliary variables in the presence of a validation subsample. We first estimate the induced relative risk function by kernel smoothing based on the validation subsample, and then improve the estimation by utilizing the information on the incomplete observations from non-validation subsample and the auxiliary observations from the primary sample. Asymptotic normality of the proposed estimator is derived. The proposed method allows one to robustly model the failure time data with an informative multivariate auxiliary covariate. Comparison of the proposed approach with several existing methods is made via simulations. Two real datasets are analyzed to illustrate the proposed method. PMID- 26594611 TI - Human Babesiosis: Pathogens, Prevalence, Diagnosis and Treatment. AB - Human babesiosis is a zoonotic disease caused by protozoan parasites of the Babesia genus, primarily in the Northeastern and Midwest United States due to B. microti, and Western Europe due to B. divergens. Parasites are transmitted by the bite of the ixodid tick when the vector takes a blood meal from the vertebrate host, and the economic importance of bovine babesiosis is well understood. The pathology of human disease is a direct result of the parasite's ability to invade host's red blood cells. The current understanding of human babesiosis epidemiology is that many infections remain asymptomatic, especially in younger or immune competent individuals, and the burden of severe pathology resides within older or immunocompromised individuals. However, transfusion-transmitted babesiosis is an emerging threat to public health as asymptomatic carriers donate blood and there are as yet no licensed or regulated tests to screen blood products for this pathogen. Reports of tick-borne cases within new geographical regions such as the Pacific Northwest of the US, through Eastern Europe, and into China are also on the rise. Further, new Babesia spp. have been identified globally as agents of severe human babesiosis, suggesting that the epidemiology of this disease is rapidly changing, and it is clear that human babesiosis is a serious public health concern that requires close monitoring and effective intervention measure. PMID- 26594612 TI - Black Men's Perceptions and Knowledge of Diabetes: A Church-Affiliated Barbershop Focus Group Study. AB - BACKGROUND: Diabetes is the seventh leading cause of death in the United States and disproportionately affects racial and ethnic minorities. These disparities persist despite educational efforts to reduce the prevalence of diabetes. Receptiveness of educational efforts for Black men needs to be studied. OBJECTIVE: This study assesses Black men's receptiveness to a barbershop-based program focused on diabetes prevention and awareness in a church-affiliated barbershop in Rochester, Minnesota. METHODS: The pastor and barber of a church affiliated barbershop and academic medical researchers designed a community engaged research study to determine Black men's perception of diabetes. Recruitment for the 90-minute focus group included flyers (n=60), email, and in person. Units of analysis included focus-group audio recording, transcripts, and field notes. Using traditional content analysis, we categorized data into themes and sub-themes. RESULTS: Thirteen Black men participated (Group 1, n=6; Group 2, n=7) having a mean age of 40.3 years (range 19 to 65), and employed full-time (77%). Themes included diabetes prevention, treatment, prevalence, risks, and health education. Participants identified diet and exercise as essential components of diabetes prevention. Additionally, participants mentioned that family history contributes to diabetes. Participants agreed that barbershops are an appropriate setting for data collection and health education on diabetes for Black men. DISCUSSION/CONCLUSION: Findings indicate that Black men are generally aware of diabetes. The community-engaged research process allowed for development of a culturally appropriate research study on diabetes. This study is the foundation for developing a culturally appropriate health education program on diabetes for Black men. PMID- 26594613 TI - Models for Predicting Drug Absorption From Oral Lipid-Based Formulations. AB - In this review, we describe the in vitro tools currently used to identify when a lipid-based formulation has the potential to deliver a poorly water-soluble drug via the oral route. We describe the extent to which these tools reflect the in vivo performance of the formulation and, more importantly, we present strategies that we foresee will improve the in vitro-in vivo correlations. We also present emerging computational methods that are likely to allow large parts of the formulation development to be carried out in the computer rather than in the test tube. We suggest that these computational tools will also improve the mechanistic understanding of in vivo formulation performance in the complex and dynamic environment of the gut. PMID- 26594614 TI - Medication Error Disclosure and Attitudes to Reporting by Healthcare Professionals in a Sub-Saharan African Setting: A Survey in Uganda. AB - BACKGROUND: Medication errors (MEs) are largely under-reported, which undermines quality improvement and medication risk management in healthcare. OBJECTIVES: To assess attitudes of Ugandan healthcare professionals (HCPs) towards ME reporting, and identify characteristics of HCPs who endorsed integration of ME and adverse drug reaction (ADR) reporting, valued patient involvement in ME reporting, disclosed having ever made potentially harmful MEs, or observed possibly harmful MEs committed by other HCPs. METHODS: Healthcare professionals self-completed a questionnaire on their attitudes towards the occurrence and reporting of MEs in purposively selected Ugandan health facilities (public/private) including the national referral and six regional referral hospitals representative of all regions. RESULTS: Response rate was 67 % (1345/2000). Most HCPs (91 %; 1174/1289) approved a national ME reporting system for Uganda and 58 % (734/1261) endorsed integration of ME and ADR reporting. Two-thirds (65 %; 819/1267) of HCPs valued patient involvement in ME reporting, one-fifth (18 %; 235/1310) disclosed that they had ever made potentially harmful MEs, while two-fifths (41 %; 542/1323) had ever identified possibly harmful MEs committed by other HCPs. Endorsing patient involvement in ME reporting was more likely by HCPs who valued root-cause analysis and reporting of both actual and potential MEs, or who conceded inadequate communication and lack of time. Self-disclosure of having ever committed potentially harmful MEs was more likely with the need for confidentiality, working in stressful conditions, and willingness to report ADRs. Identifying possibly harmful MEs committed by other HCPs was more likely by non nurses and those who reported blame culture, stressful conditions, ever encountered a fatal ADR, or attachment to hospital-level health facility. CONCLUSION: A non-punitive healthcare environment and patient involvement may promote ME disclosure and reporting in Uganda and possibly other African countries. PMID- 26594615 TI - Acute respiratory infection and bacteraemia as causes of non-malarial febrile illness in African children: a narrative review. AB - The replacement of "presumptive treatment for malaria" by "test before treat" strategies for the management of febrile illness is raising awareness of the importance of knowing more about the causes of illness in children who are suspected to have malaria but return a negative parasitological test. The most common cause of non-malarial febrile illness (NMFI) in African children is respiratory tract infection. Whilst the bacterial causes of NMFI are well known, the increasing use of sensitive techniques such as polymerase chain reaction (PCR) tests is revealing large numbers of viruses that are potential respiratory pathogens. However, many of these organisms are commonly present in the respiratory tract of healthy children so causality and risk factors for pneumonia remain poorly understood. Infection with a combination of viral and bacterial pathogens is increasingly recognised as important in the pathogenesis of pneumonia. Similarly, blood stream infections with organisms typically grown by aerobic culture are well known but a growing number of organisms that can be identified only by PCR, viral culture, or serology are now recognised to be common pathogens in African children. The high mortality of hospitalised children on the first or second day of admission suggests that, unless results are rapidly available, diagnostic tests to identify specific causes of illness will still be of limited use in guiding the potentially life saving decisions relating to initial treatment of children admitted to district hospitals in Africa with severe febrile illness and a negative test for malaria. Malaria control and the introduction of vaccines against Haemophilus influenzae type b and pneumococcal disease are contributing to improved child survival in Africa. However, increased parasitological testing for malaria is associated with increased use of antibiotics to which resistance is already high. PMID- 26594616 TI - Human Papillomavirus Vaccine Initiation among 9-13-Year-Olds in the United States. AB - OBJECTIVE: The quadrivalent and 9-valent human papillomavirus (HPV) vaccines are licensed for administration among 9-26-year-old males and females, with routine vaccination recommended for 11-12-year-olds. Despite the availability of the vaccine at younger ages, few studies have explored vaccine uptake prior to age 13, and national HPV vaccination surveillance data is limited to 13-17-year-olds. Our objective was to examine rates and predictors of HPV vaccine initiation among 9-13-year-olds in the United States. METHODS: A national sample of mothers of 9 13-year-olds in the United States (N=2,446) completed a 2014 Web-based survey assessing socio-demographic characteristics, child's HPV vaccination history, provider communication regarding the vaccine, and other attitudes and behaviors pertaining to vaccination and healthcare utilization. The main outcome measure was child's initiation of the HPV vaccine (i.e., receipt of one or more doses). RESULTS: Approximately 35% of the full sample and 27.5% of the 9-10-year-olds had initiated HPV vaccination. Females were more likely than males to have initiated HPV vaccination by the age of 13 but not by younger ages. Strength of health provider recommendation regarding HPV vaccination was a particularly salient predictor of vaccine initiation. CONCLUSIONS: Approximately a third of children may be initiating the HPV vaccine series before or during the targeted age range for routine administration of the vaccine. Because coverage remains below national targets, further research aimed at increasing vaccination during early adolescence is needed. Improving providers' communication with parents about the HPV vaccine may be one potential mechanism for increasing vaccine coverage. PMID- 26594617 TI - Detection of demyelination in multiple sclerosis by analysis of [Formula: see text] relaxation at 7 T. AB - Multiple sclerosis (MS) is a relatively common cause of inflammatory demyelinating lesions of the central nervous system. In an attempt to detect and characterize ongoing demyelination in MS patient brains, we used a novel magnetic resonance imaging (MRI) technique, involving the fitting of a three-component model to the [Formula: see text] relaxation behavior at high-field (7 T). This model allowed estimation of the amount of myelin water (and thus indirectly myelin content), axonal water, and interstitial water. In this study, 25 relapsing-remitting MS patients underwent a 7 T MRI from which 12 gadolinium enhancing lesions, 61 non-enhancing lesions, and their corresponding contralateral normal appearing white matter (NAWM) regions were analyzed. In both enhancing and non-enhancing lesions, the amplitude of myelin water was significantly decreased, and interstitial and axonal water were increased relative to the contralateral NAWM. Longer relaxation time [Formula: see text] of interstitial and axonal water, and lower frequency shift of axonal water, were also observed in both enhancing and non-enhancing lesions when compared to the contralateral NAWM. No significant difference was found between enhancing lesions and non-enhancing lesions. These findings suggest that the fitting of a three component model to the [Formula: see text] decay curve in MS lesions may help to quantify myelin loss. PMID- 26594618 TI - A preliminary evaluation of the correlation between regional energy phosphates and resting state functional connectivity in depression. AB - Impaired brain energy metabolism is among the leading hypotheses in the pathogenesis of affective disorders and linking energy phosphates with states of tissue-function activity is a novel and non-invasive approach to differentiate healthy from unhealthy states. Resting state functional MRI (fMRI) has been established as an important tool for mapping cerebral regional activity and phosphorous chemical shift imaging ((31)P CSI) has been applied to measure levels of energy phosphates and phospholipids non-invasively in order to gain insight into the possible etiology of affective disorders. This is an initial attempt to identify the existence of a correlation between regional energy phosphates and connectivity at nodes of the posterior default mode network (DMN). Resting state fMRI in conjunction with (31)P 2D CSI was applied to 11 healthy controls and 11 depressed patients at 3 T. We found that differences between the two groups exist in correlation of lateral posterior parietal cortex functional connectivity and regional Pi/PCr. Results of this study indicate that resting-state-fMRI-guided (31)P CSI can provide new insight into depression via regional energy phosphates and functional connectivity. PMID- 26594619 TI - Less efficient and costly processes of frontal cortex in childhood chronic fatigue syndrome. AB - The ability to divide one's attention deteriorates in patients with childhood chronic fatigue syndrome (CCFS). We conducted a study using a dual verbal task to assess allocation of attentional resources to two simultaneous activities (picking out vowels and reading for story comprehension) and functional magnetic resonance imaging. Patients exhibited a much larger area of activation, recruiting additional frontal areas. The right middle frontal gyrus (MFG), which is included in the dorsolateral prefrontal cortex, of CCFS patients was specifically activated in both the single and dual tasks; this activation level was positively correlated with motivation scores for the tasks and accuracy of story comprehension. In addition, in patients, the dorsal anterior cingulate gyrus (dACC) and left MFG were activated only in the dual task, and activation levels of the dACC and left MFG were positively associated with the motivation and fatigue scores, respectively. Patients with CCFS exhibited a wider area of activated frontal regions related to attentional resources in order to increase their poorer task performance with massive mental effort. This is likely to be less efficient and costly in terms of energy requirements. It seems to be related to the pathophysiology of patients with CCFS and to cause a vicious cycle of further increases in fatigue. PMID- 26594620 TI - Measuring longitudinal myelin water fraction in new multiple sclerosis lesions. AB - OBJECTIVES: Investigating the potential of myelin repair strategies in multiple sclerosis (MS) requires an understanding of myelin dynamics during lesion evolution. The objective of this study is to longitudinally measure myelin water fraction (MWF), an MRI biomarker of myelin, in new MS lesions and to identify factors that influence their subsequent myelin content. METHODS: Twenty-three MS patients were scanned with whole-brain Fast Acquisition with Spiral Trajectory and T2prep (FAST-T2) MWF mapping at baseline and median follow-up of 6 months. Eleven healthy controls (HC) confirmed the reproducibility of FAST-T2 in white matter regions of interests (ROIs) similar to a lesion size. A random-effect model was implemented to determine the association between baseline clinical and lesion variables and the subsequent MWF. RESULTS: ROI-based measurements in HCs were highly correlated between scans [mean r = 0.893 (.764-.967)]. In MS patients, 38 gadolinium enhancing (Gd+) and 25 new non-enhancing (Gd-) T2 hyperintense lesions (5.7 months, +/-3.8) were identified. Significant improvement in MWF was seen in Gd+ lesions (0.035 +/- 0.029, p < 0.001) as compared to Gd- lesions (0.006 +/- 0.017, p = 0.065). In the model, a higher baseline MWF (p < 0.001) and the presence of Gd (p < 0.001) were associated with higher subsequent MWF. CONCLUSIONS: FAST T2 provides a clinically feasible method to quantify MWF in new MS lesions. The observed influence of baseline MWF, which represents a combined effect of both resolving edema and myelin change within acute lesions, suggests that the extent of initial inflammation impacts final myelin recovery. PMID- 26594621 TI - Aberrant development of post-movement beta rebound in adolescents and young adults with fetal alcohol spectrum disorders. AB - Dependent on maternal (e.g. genetic, age) and exposure (frequency, quantity, and timing) variables, the effects of prenatal alcohol exposure on the developing fetus are known to vary widely, producing a broad range of morphological anomalies and neurocognitive deficits in offspring, referred to as fetal alcohol spectrum disorders (FASD). Maternal drinking during pregnancy remains a leading risk factor for the development of intellectual disabilities in the US. While few functional findings exist today that shed light on the mechanisms responsible for the observed impairments in individuals with FASD, animal models consistently report deleterious effects of early alcohol exposure on GABA-ergic inhibitory pathways. The post-motor beta rebound (PMBR), a transient increase of 15-30 Hz beta power in the motor cortex that follows the termination of movement, has been implicated as a neural signature of GABA-ergic inhibitory activity. Further, PMBR has been shown to be a reliable predictor of age in adolescents. The present study sought to investigate any differences in the development of PMBR between FASD and control groups. Beta event-related de-synchronization (ERD) and movement related gamma synchronization (MRGS), although not clearly linked to brain maturation, were also examined. Twenty-two participants with FASD and 22 age and sex-matched controls (12-22 years old) underwent magnetoencephalography scans while performing an auditory oddball task, which required a button press in response to select target stimuli. The data surrounding the button presses were localized to the participants' motor cortices, and the time courses from the locations of the maximally evoked PMBR were subjected to wavelet analyses. The subsequent analysis of PMBR, ERD, and MRGS revealed a significant interaction between group and age in their effects on PMBR. While age had a significant effect on PMBR in the controls, no simple effects of age were detected in the FASD group. The FASD group additionally displayed decreased overall ERD levels. No group or age effects on MRGS were detected. The described findings provide further evidence for broad impairments in inhibitory processes in adolescents with FASD, possibly related to aberrant development of GABA-ergic pathways. PMID- 26594622 TI - Olfactory training induces changes in regional functional connectivity in patients with long-term smell loss. AB - Recently, olfactory training has been introduced as a promising treatment for patients with olfactory dysfunction. However, less is known about the neuronal basis and the influence on functional networks of this training. Thus, we aimed to investigate the neuroplasticity of chemosensory perception through an olfactory training program in patients with smell loss. The experimental setup included functional MRI (fMRI) experiments with three different types of chemosensory stimuli. Ten anosmic patients (7f, 3m) and 14 healthy controls (7f, 7m) underwent the same testing sessions. After a 12-week olfactory training period, seven patients (4f, 3m) were invited for follow-up testing using the same fMRI protocol. Functional networks were identified using independent component analysis and were further examined in detail using functional connectivity analysis. We found that anosmic patients and healthy controls initially use the same three networks to process chemosensory input: the olfactory; the somatosensory; and the integrative network. Those networks did not differ between the two groups in their spatial extent, but in their functional connectivity. After the olfactory training, the sensitivity to detect odors significantly increased in the anosmic group, which was also manifested in modifications of functional connections in all three investigated networks. The results of this study indicate that an olfactory training program can reorganize functional networks, although, initially, no differences in the spatial distribution of neural activation were observed. PMID- 26594623 TI - Prefrontal cortex connectivity dysfunction in performing the Fist-Edge-Palm task in patients with first-episode schizophrenia and non-psychotic first-degree relatives. AB - Neurological soft signs have been considered one of the promising neurological endophenotypes for schizophrenia. However, most previous studies have employed clinical rating data only. The present study aimed to examine the neurobiological basis of one of the typical motor coordination signs, the Fist-Edge-Palm (FEP) task, in patients with first-episode schizophrenia and their non-psychotic first degree relatives. Thirteen patients with first-episode schizophrenia, 14 non psychotic first-degree relatives and 14 healthy controls were recruited. All of them were instructed to perform the FEP task in a 3 T GE Machine. Psychophysiological interaction (PPI) analysis was used to evaluate the functional connectivity between the sensorimotor cortex and frontal regions when participants performed the FEP task compared to simple motor tasks. In the contrast of palm-tapping (PT) vs. rest, activation of the left frontal-parietal region was lowest in the schizophrenia group, intermediate in the relative group and highest in the healthy control group. In the contrast of FEP vs. PT, patients with schizophrenia did not show areas of significant activation, while relatives and healthy controls showed significant activation of the left middle frontal gyrus. Moreover, with the increase in task complexity, significant functional connectivity was observed between the sensorimotor cortex and the right frontal gyrus in healthy controls but not in patients with first episode schizophrenia. These findings suggest that activity of the left frontal-parietal and frontal regions may be neurofunctional correlates of neurological soft signs, which in turn may be a potential endophenotype of schizophrenia. Moreover, the right frontal gyrus may play a specific role in the execution of the FEP task in schizophrenia spectrum disorders. PMID- 26594624 TI - Joint assessment of white matter integrity, cortical and subcortical atrophy to distinguish AD from behavioral variant FTD: A two-center study. AB - We investigated the ability of cortical and subcortical gray matter (GM) atrophy in combination with white matter (WM) integrity to distinguish behavioral variant frontotemporal dementia (bvFTD) from Alzheimer's disease (AD) and from controls using voxel-based morphometry, subcortical structure segmentation, and tract based spatial statistics. To determine which combination of MR markers differentiated the three groups with the highest accuracy, we conducted discriminant function analyses. Adjusted for age, sex and center, both types of dementia had more GM atrophy, lower fractional anisotropy (FA) and higher mean (MD), axial (L1) and radial diffusivity (L23) values than controls. BvFTD patients had more GM atrophy in orbitofrontal and inferior frontal areas than AD patients. In addition, caudate nucleus and nucleus accumbens were smaller in bvFTD than in AD. FA values were lower; MD, L1 and L23 values were higher, especially in frontal areas of the brain for bvFTD compared to AD patients. The combination of cortical GM, hippocampal volume and WM integrity measurements, classified 97-100% of controls, 81-100% of AD and 67-75% of bvFTD patients correctly. Our results suggest that WM integrity measures add complementary information to measures of GM atrophy, thereby improving the classification between AD and bvFTD. PMID- 26594625 TI - Repeated verum but not placebo acupuncture normalizes connectivity in brain regions dysregulated in chronic pain. AB - Acupuncture, an ancient East Asian therapy, is aimed at rectifying the imbalance within the body caused by disease. Studies evaluating the efficacy of acupuncture with neuroimaging tend to concentrate on brain regions within the pain matrix, associated with acute pain. We, however, focused on the effect of repeated acupuncture treatment specifically on brain regions known to support functions dysregulated in chronic pain disorders. Transition to chronic pain is associated with increased attention to pain, emotional rumination, nociceptive memory and avoidance learning, resulting in brain connectivity changes, specifically affecting the periaqueductal gray (PAG), medial frontal cortex (MFC) and bilateral hippocampus (Hpc). We demonstrate that the PAG-MFC and PAG-Hpc connectivity in patients with chronic pain due to knee osteoarthritis indeed correlates with clinical severity scores and further show that verum acupuncture induced improvement in pain scores (compared to sham) is related to the modulation of PAG-MFC and PAG-Hpc connectivity in the predicted direction. This study shows that repeated verum acupuncture might act by restoring the balance in the connectivity of the key pain brain regions, altering pain-related attention and memory. PMID- 26594626 TI - Predictive timing functions of cortical beta oscillations are impaired in Parkinson's disease and influenced by L-DOPA and deep brain stimulation of the subthalamic nucleus. AB - Cortex-basal ganglia circuits participate in motor timing and temporal perception, and are important for the dynamic configuration of sensorimotor networks in response to exogenous demands. In Parkinson's disease (PD) patients, rhythmic auditory stimulation (RAS) induces motor performance benefits. Hitherto, little is known concerning contributions of the basal ganglia to sensory facilitation and cortical responses to RAS in PD. Therefore, we conducted an EEG study in 12 PD patients before and after surgery for subthalamic nucleus deep brain stimulation (STN-DBS) and in 12 age-matched controls. Here we investigated the effects of levodopa and STN-DBS on resting-state EEG and on the cortical response profile to slow and fast RAS in a passive-listening paradigm focusing on beta-band oscillations, which are important for auditory-motor coupling. The beta modulation profile to RAS in healthy participants was characterized by local peaks preceding and following auditory stimuli. In PD patients RAS failed to induce pre-stimulus beta increases. The absence of pre-stimulus beta-band modulation may contribute to impaired rhythm perception in PD. Moreover, post stimulus beta-band responses were highly abnormal during fast RAS in PD patients. Treatment with levodopa and STN-DBS reinstated a post-stimulus beta-modulation profile similar to controls, while STN-DBS reduced beta-band power in the resting state. The treatment-sensitivity of beta oscillations suggests that STN-DBS may specifically improve timekeeping functions of cortical beta oscillations during fast auditory pacing. PMID- 26594627 TI - Adaptive grip force is modulated by subthalamic beta activity in Parkinson's disease patients. AB - INTRODUCTION: Healthy subjects scale grip force to match the load defined by physical object properties such as weight, or dynamic properties such as inertia. Patients with Parkinson's disease (PD) show an elevated grip force in dynamic object handling, but temporal aspects of anticipatory grip force control are relatively preserved. In PD patients, beta frequency oscillatory activity in the basal ganglia is suppressed prior to externally paced movements. However, the role of the subthalamic nucleus (STN) in anticipatory grip force control is not known. METHODS: After implantation of deep brain stimulation (DBS) electrodes in the STN, PD patients performed adaptive and voluntary grip force tasks, while we recorded subthalamic local field potentials (LFP) and scalp EEG. RESULTS: During adaptive grip force control (Shake), we found event related desynchronization (ERD) in the beta frequency band, which was time-locked to the grip force. In contrast, during voluntary grip force control (Press) we recorded a biphasic ERD, corresponding to peak grip force and grip force release. Beta synchronization between STN and cortical EEG was reduced during adaptive grip force control. CONCLUSION: The time-locked suppression of beta oscillatory activity in the STN is in line with previous reports of beta ERD prior to voluntary movements. Our results show that the STN is involved in anticipatory grip force control in PD patients. The difference in the phasic beta ERD between the two tasks and the reduction of cortico-subthalamic synchronization suggests that qualitatively different neuronal network states are involved in different grip force control tasks. PMID- 26594628 TI - Frontal gray matter abnormalities predict seizure outcome in refractory temporal lobe epilepsy patients. AB - Developing more reliable predictors of seizure outcome following temporal lobe surgery for intractable epilepsy is an important clinical goal. In this context, we investigated patients with refractory temporal lobe epilepsy (TLE) before and after temporal resection. In detail, we explored gray matter (GM) volume change in relation with seizure outcome, using a voxel-based morphometry (VBM) approach. To do so, this study was divided into two parts. The first one involved group analysis of differences in regional GM volume between the groups (good outcome (GO), e.g., no seizures after surgery; poor outcome (PO), e.g., persistent postoperative seizures; and controls, N = 24 in each group), pre- and post surgery. The second part of the study focused on pre-surgical data only (N = 61), determining whether the degree of GM abnormalities can predict surgical outcomes. For this second step, GM abnormalities were identified, within each lobe, in each patient when compared with an ad hoc sample of age-matched controls. For the first analysis, the results showed larger GM atrophy, mostly in the frontal lobe, in PO patients, relative to both GO patients and controls, pre-surgery. When comparing pre-to-post changes, we found relative GM gains in the GO but not in the PO patients, mostly in the non-resected hemisphere. For the second analysis, only the frontal lobe displayed reliable prediction of seizure outcome. 81% of the patients showing pre-surgical increased GM volume in the frontal lobe became seizure free, post-surgery; while 77% of the patients with pre-surgical reduced frontal GM volume had refractory seizures, post-surgery. A regression analysis revealed that the proportion of voxels with reduced frontal GM volume was a significant predictor of seizure outcome (p = 0.014). Importantly, having less than 1% of the frontal voxels with GM atrophy increased the likelihood of being seizure-free, post-surgery, by seven times. Overall, our results suggest that using pre-surgical GM abnormalities within the frontal lobe is a reliable predictor of seizure outcome post-surgery in TLE. We believe that this frontal GM atrophy captures seizure burden outside the pre-existing ictal temporal lobe, reflecting either the development of epileptogenesis or the loss of a protective, adaptive force helping to control or limit seizures. This study provides evidence of the potential of VBM-based approaches to predict surgical outcomes in refractory TLE candidates. PMID- 26594629 TI - Autistic fluid intelligence: Increased reliance on visual functional connectivity with diminished modulation of coupling by task difficulty. AB - Different test types lead to different intelligence estimates in autism, as illustrated by the fact that autistic individuals obtain higher scores on the Raven's Progressive Matrices (RSPM) test than they do on the Wechsler IQ, in contrast to relatively similar performance on both tests in non-autistic individuals. However, the cerebral processes underlying these differences are not well understood. This study investigated whether activity in the fluid "reasoning" network, which includes frontal, parietal, temporal and occipital regions, is differently modulated by task complexity in autistic and non-autistic individuals during the RSPM. In this purpose, we used fMRI to study autistic and non-autistic participants solving the 60 RSPM problems focussing on regions and networks involved in reasoning complexity. As complexity increased, activity in the left superior occipital gyrus and the left middle occipital gyrus increased for autistic participants, whereas non-autistic participants showed increased activity in the left middle frontal gyrus and bilateral precuneus. Using psychophysiological interaction analyses (PPI), we then verified in which regions did functional connectivity increase as a function of reasoning complexity. PPI analyses revealed greater connectivity in autistic, compared to non-autistic participants, between the left inferior occipital gyrus and areas in the left superior frontal gyrus, right superior parietal lobe, right middle occipital gyrus and right inferior temporal gyrus. We also observed generally less modulation of the reasoning network as complexity increased in autistic participants. These results suggest that autistic individuals, when confronted with increasing task complexity, rely mainly on visuospatial processes when solving more complex matrices. In addition to the now well-established enhanced activity observed in visual areas in a range of tasks, these results suggest that the enhanced reliance on visual perception has a central role in autistic cognition. PMID- 26594630 TI - Reduced binding of Pittsburgh Compound-B in areas of white matter hyperintensities. AB - The amyloid imaging agent, Pittsburgh Compound-B, binds with high affinity to beta-amyloid (Abeta) in the brain, and it is well established that PiB also shows non-specific retention in white matter (WM). However, little is known about retention of PiB in areas of white matter hyperintensities (WMH), abnormalities commonly seen in older adults. Further, it is hypothesized that WMH are related to both cognitive dysfunction and Abeta deposition. The goal of the present study was to explore PiB retention in both normal-appearing WM (NAWM) and WMH in a group of elderly, cognitively normal individuals. In a group of cognitively normal elderly (n = 64; 86.5 +/- 2.6 years) two analyses were applied: (1) ROIs were placed over periventricular areas in which WMH caps are commonly seen on all subjects, regardless of WMH burden or size. (2) Subject-specific maps of NAWM and WMH were co-registered with the PiB-PET images and mean SUVR values were calculated in these NAWM and WMH maps. PiB retention was significantly reduced in the ROIs of subjects with high WMH compared to subjects with low WMH. Additionally, in subjects with high WMH, there was significantly lower PiB retention in subject-specific maps of WMH compared to NAWM, which was not observed in subjects with low WMH, likely because of the small size of WMH maps in this group. These data suggest that WM in areas of WMH binds PiB less effectively than does normal WM. Further exploration of this phenomenon may lead to insights about the molecular basis of the non-specific retention of amyloid tracers in white matter. PMID- 26594632 TI - Evidence of multisensory plasticity: Asymmetrical medial geniculate body in people with one eye. AB - The medial geniculate body (MGB) plays a central role in auditory processing with both efferent and afferent tracts to primary auditory cortex. People who have lost one eye early in life have enhanced sound localization, lack visual over auditory dominance and integrate auditory and visual information optimally, similar to controls, despite taking longer to localize unimodal visual stimuli. Compared to controls, people with one eye have decreased lateral geniculate nuclei (LGN) volume as expected given the 50% deafferentation of the visual system. However, LGN volume is larger than predicted contralateral to the remaining eye, indicating altered structural development likely through recruitment of deafferented LGN cells. PURPOSE: the current study investigated whether structural MGB changes are also present in this group given the changes they exhibit in auditory processing. METHODS: MGB volumes were measured in adults who had undergone early unilateral eye enucleation and were compared to binocularly intact controls. RESULTS: unlike controls, people with one eye had a significant asymmetry with a larger left compared to right MGB, independent of eye of enucleation. MGB volume correlated positively with LGN volume in people with one eye. CONCLUSIONS: volume asymmetry in the MGB in people with one eye may represent increased interactions between the left MGB and primary auditory cortex. This interaction could contribute to increased auditory and other left hemisphere-dominant processing, including language, as compensation for the loss of one half of visual inputs early in life. The positive correlation between MGB and LGN volume is not due to space constraints but rather indicates increased plasticity in both auditory and visual sensory systems following early eye enucleation. PMID- 26594631 TI - Affective mentalizing and brain activity at rest in the behavioral variant of frontotemporal dementia. AB - BACKGROUND: bvFTD patients display an impairment in the attribution of cognitive and affective states to others, reflecting GM atrophy in brain regions associated with social cognition, such as amygdala, superior temporal cortex and posterior insula. Distinctive patterns of abnormal brain functioning at rest have been reported in bvFTD, but their relationship with defective attribution of affective states has not been investigated. OBJECTIVE: To investigate the relationship among resting-state brain activity, gray matter (GM) atrophy and the attribution of mental states in the behavioral variant of fronto-temporal degeneration (bvFTD). METHODS: We compared 12 bvFTD patients with 30 age- and education matched healthy controls on a) performance in a task requiring the attribution of affective vs. cognitive mental states; b) metrics of resting-state activity in known functional networks; and c) the relationship between task-performances and resting-state metrics. In addition, we assessed a connection between abnormal resting-state metrics and GM atrophy. RESULTS: Compared with controls, bvFTD patients showed a reduction of intra-network coherent activity in several components, as well as decreased strength of activation in networks related to attentional processing. Anomalous resting-state activity involved networks which also displayed a significant reduction of GM density. In patients, compared with controls, higher affective mentalizing performance correlated with stronger functional connectivity between medial prefrontal sectors of the default-mode and attentional/performance monitoring networks, as well as with increased coherent activity in components of the executive, sensorimotor and fronto-limbic networks. CONCLUSIONS: Some of the observed effects may reflect specific compensatory mechanisms for the atrophic changes involving regions in charge of affective mentalizing. The analysis of specific resting-state networks thus highlights an intermediate level of analysis between abnormal brain structure and impaired behavioral performance in bvFTD, reflecting both dysfunction and compensation mechanisms. PMID- 26594633 TI - Brain and cord myelin water imaging: a progressive multiple sclerosis biomarker. AB - OBJECTIVES: Conventional magnetic resonance imaging (MRI) is used to diagnose and monitor inflammatory disease in relapsing remitting (RR) multiple sclerosis (MS). In the less common primary progressive (PP) form of MS, in which focal inflammation is less evident, biomarkers are still needed to enable evaluation of novel therapies in clinical trials. Our objective was to characterize the association - across the brain and cervical spinal cord - between clinical disability measures in PPMS and two potential biomarkers (one for myelin, and one for atrophy, both resulting from the same imaging technique). METHODS: Multi component driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) MRI of the brain and cervical spinal cord were obtained for 15 PPMS patients and 11 matched controls. Data were analysed to estimate the signal related to myelin water (VFM), as well as volume measurements. MS disability was assessed using the Multiple Sclerosis Functional Composite score, which includes measures of cognitive processing (Paced Auditory Serial Addition Test), manual dexterity (9 Hole Peg Test) and ambulatory function (Timed 25-Foot Walk); and the Expanded Disability Status Scale. RESULTS: Brain and spinal cord volumes were different in PPMS compared to controls, particularly ventricular (+ 46%, p = 0.0006) and cervical spinal cord volume (- 16%, p = 0.0001). Brain and spinal cord myelin (VFM) were also reduced in PPMS (brain: - 11%, p = 0.01; spine: - 19%, p = 0.000004). Cognitive processing correlated with brain ventricular volume (p = 0.009). Manual dexterity correlated with brain ventricular volume (p = 0.007), and both brain and spinal cord VFM (p = 0.01 and 0.06, respectively). Ambulation correlated with spinal cord volume (p = 0.04) and spinal cord VFM (p = 0.04). INTERPRETATION: In this study we demonstrated that mcDESPOT can be used to measure myelin and atrophy in the brain and spinal cord. Results correlate well with clinical disability scores in PPMS representing cognitive, fine motor and ambulatory disability. PMID- 26594634 TI - Cryotherapy suppresses tendon inflammation in an animal model. AB - Cryotherapy (or cold treatment) has been a popular treatment to relieve pain caused by injuries to tissues such as tendons. However, the exact mechanisms behind the beneficial effects of cryotherapy in tendons remain largely unclear. As prostaglandin E2 (PGE2) is known to be a major mediator of acute inflammation in tissues, which is related to tissue pain, we hypothesized that the beneficial effects of cryotherapy in tendons are mediated by downregulation of PGE2 levels. To test this hypothesis, we applied cold treatment to mouse patellar and Achilles tendons using two animal models: exhaustive mouse treadmill running and acute mouse tendon injury by needle penetration. We then measured the levels of PGE2 and protein expression levels of COX-2, an enzyme responsible for PGE2 production in tissues, under both experimental conditions. We found that treadmill running increased PGE2 levels in both patellar and Achilles tendons compared to control mice without running. Cold treatment for 30 min after treadmill running was sufficient to reduce PGE2 levels to near baseline control levels in both tendons. An extension of cold treatment to 60 min resulted only in a marginal decrease in patellar tendons, but a marked decrease in Achilles tendons. Moreover, COX-2 protein levels in both tendons were also lowered by cold treatment, suggesting that the reduction of PGE2 levels in tendons by cold treatment is at least in part due to the decreased COX-2 expression. Similarly, in the acutely injured tendons, 30 min of cold treatment after needle penetration reduced PGE2 levels when compared to the controls at room temperature (22 degrees C). This decrease was sustained up to at least 3 h after the administration of cryotherapy. Given that PGE2 is a known pain sensitiser, the results of this study suggest that the ability of cold treatment to reduce pain may be attributable to its ability to decrease PGE2 production in tendons. PMID- 26594636 TI - Influence of Bioaerosol Source Location and Ceiling Fan Direction on Eggcrate Upper-room Ultraviolet Germicidal Irradiation. AB - BACKGROUND: Eggcrate upper-room ultraviolet germicidal irradiation (UVGI), an engineering control method for reducing the airborne transmission of infectious diseases, was recently developed as an alternative to conventional upper-room UVGI using conventional louvered fixtures. A UV screen, which is composed of open cell eggcrate panels supported in a frame designed for a conventional suspended ceiling, was used to minimize UV radiation in the lower room. A ceiling fan, which was blowing upward directly above the microbiological source, provided vertical air exchange between the upper and lower room. This system has been shown to be significantly more effective than conventional upper-room UVGI. STUDY DESIGN: In the present study, the microbiological source location and the airflow direction due to the ceiling fan were varied in order to evaluate their impact on germicidal efficacy. RESULTS: The test results clearly showed that placing an aerosol source directly underneath an upward blowing ceiling fan produces the maximum efficacy. CONCLUSIONS: The likely explanation for this outcome is that the fan sucks the microorganisms emitted by the source into the UV beam before being mixed with the air in the room. This is somewhat analogous to local exhaust ventilation in which the contaminant is removed prior to being mixed with the air in the room. Thus, when possible, the ceiling fan should be blowing upward and directly above the source. However, for experimental testing, the source location should be varied in order to access the range of germicidal efficacies that can be expected. PMID- 26594637 TI - Antifungal Susceptibility Patterns of Vulvovaginal Candida species among Women Attending Antenatal Clinic at Mbarara Regional Referral Hospital, South Western Uganda. AB - AIMS: To identify the Candida species that cause vulvovaginal candidiasis and determine their antifungal susceptibility patterns. STUDY DESIGN: This was a cross-sectional study. PLACE AND DURATION OF STUDY: The study was conducted at the antenatal clinic of Mbarara Regional Referral Hospital in Mbarara Municipality, between December 2012 and February 2013. METHODS: High vaginal swabs from 456 pregnant women were subjected to microscopy and culture on Sabouraud Dextrose Agar. Candida isolates were identified by the germ tube and Analytical profile index (API(r) Candida) tests. Susceptibility to fluconazole, itraconazole and voriconazole was determined by the Etest strips and for clotrimazole and nystatin by the disc diffusion method on Mueller Hinton agar supplemented with 2%w/v glucose and 0.5MUg/ml methylene blue dye. RESULTS: Of the 456 High vaginal swabs cultured, 207 grew Candida species. Species distribution was as follows: C. albicans (78.95%), C. glabrata (14.35%), C. krusei (3.35%), C. tropicalis (1.44%), C. famata (0.96%), C. parapsilosis (0.48%) and C. lusitaniae (0.48%). Resistance to nystatin was only observed in 0.61% of C.albicans. Resistance to clotrimazole was observed in 50%, 36.67% and 0.61% of C. famata, C. glabrata and C. albicans respectively. C. krusei showed a high resistance of 71.43% to fluconazole. C. glabrata, C. krusei, C. famata and C. lusitaniae exhibited 100% resistance to itraconazole. Resistance to voriconazole of less than 11% was exhibited by only C. albicans and C. glabrata. CONCLUSION: C.albicans was susceptible to most antifungal agents tested except itraconazole and voriconazole. All isolates were susceptible to nystatin except less than 1% of Candida albicans. Non-albicans demonstrated resistance to some drugs especially itraconazole. We recommend use of Nystatin for empirical management of vulvovaginal candidiasis among pregnant women. PMID- 26594635 TI - Characterization of the Contribution of Genetic Background and Gender to Disease Progression in the SOD1 G93A Mouse Model of Amyotrophic Lateral Sclerosis: A Meta Analysis. AB - BACKGROUND: The SOD1 G93A mouse model of amyotrophic lateral sclerosis (ALS) is the most frequently used model to examine ALS pathophysiology. There is a lack of homogeneity in usage of the SOD1 G93A mouse, including differences in genetic background and gender, which could confound the field's results. OBJECTIVE: In an analysis of 97 studies, we characterized the ALS progression for the high transgene copy control SOD1 G93A mouse on the basis of disease onset, overall lifespan, and disease duration for male and female mice on the B6SJL and C57BL/6J genetic backgrounds and quantified magnitudes of differences between groups. METHODS: Mean age at onset, onset assessment measure, disease duration, and overall lifespan data from each study were extracted and statistically modeled as the response of linear regression with the sex and genetic background factored as predictors. Additional examination was performed on differing experimental onset and endpoint assessment measures. RESULTS: C57BL/6 background mice show delayed onset of symptoms, increased lifespan, and an extended disease duration compared to their sex-matched B6SJL counterparts. Female B6SJL generally experience extended lifespan and delayed onset compared to their male counterparts, while female mice on the C57BL/6 background show delayed onset but no difference in survival compared to their male counterparts. Finally, different experimental protocols (tremor, rotarod, etc.) for onset determination result in notably different onset means. CONCLUSIONS: Overall, the observed effect of sex on disease endpoints was smaller than that which can be attributed to the genetic background. The often-reported increase in lifespan for female mice was observed only for mice on the B6SJL background, implicating a strain-dependent effect of sex on disease progression that manifests despite identical mutant SOD1 expression. PMID- 26594638 TI - Use of melatonin in oral health and as dental premedication. AB - Anxiety is a common problem in dentistry which could affect the correct treatment and involve failure. Oral premedication is needed to treat several anxious patients. Many people are so highly anxious that oral sedation is not effective and need to be under deep sedation or even general anaesthesia in order to receive dental care. In these patients, due to a high level of anxiety, even the insertion of an intravenous catheter can be difficult. Benzodiazepines have been the most commonly used anxiolytic in these cases, but many may be associated with paradoxical reactions. Melatonin has a good potential to be used in this field as alternative to benzodiazepines because it may induce a natural sleepiness and improve sedation. The purpose of this paper was to summarize what is known about the use of melatonin in oral health and as dental premedication in anxious dental patients. Databases were searched for the relevant published literature to 30 April 2015. The following search items were used in various combinations: melatonin, premedication, anxiety, dental, sedation and anaesthesia. Few articles were found about this aspect, and the use of melatonin is still a controversial aspect in dental field. More detailed/specific studies are necessary to extend the therapeutic possibilities of melatonin as premedication in dentistry. PMID- 26594640 TI - Manifestation and treatment in a cleidocranial dysplasia patient with a RUNX2 (T420I) mutation. AB - Cleidocranial dysplasia is an autosomal dominant heritable skeletal disorder. The characteristic features of cleidocranial dysplasia (CCD) may include hypoplasia of the clavicle, delayed closure of frontanelles, late tooth eruption, and other skeletal disorders. This case report describes clinical and radiographic manifestations at the age of 11 and 29 of a CCD patient, investigates the mutation of core-binding factor A1 (CBFA1) based on gene analysis, and illustrates successful oral reconstruction with fixed prosthesis and dental implant after the extraction of multiple teeth. PMID- 26594641 TI - Editorial: Perinatology in the Era of Big Data and Nanoparticles. PMID- 26594639 TI - MAPT STUDY: A MULTIDOMAIN APPROACH FOR PREVENTING ALZHEIMER'S DISEASE: DESIGN AND BASELINE DATA. AB - OBJECTIVE: The Multidomain Alzheimer Preventive Trial (MAPT study) was designed to assess the efficacy of isolated supplementation with omega-3 fatty acid, an isolated multidomain intervention (consisting of nutritional counseling, physical exercise, cognitive stimulation) or a combination of the two interventions on the change of cognitive functions in frail subjects aged 70 years and older for a period of 3 years. Ancillary neuroimaging studies were additionally implemented to evaluate the impact of interventions on cerebral metabolism (FDG PET scans) and atrophy rate (MRIs), as well as brain amyloid deposit (AV45 PET scans). DESIGN PATIENTS: 1680 subjects (mean age: 75.3 years; female: 64.8 %), enrolled by 13 memory clinics, were randomized into one of the following four groups: omega-3 supplementation alone, multidomain intervention alone, omega-3 plus multidomain intervention, or placebo. Participants underwent cognitive, functional and biological assessments at M6, M12, M24 and M36 visits. The primary endpoint is a change of memory function at 3 years, as assessed by the Free and Cued Selective Reminding test. All participants will be followed for 2 additional years after the 3-years intervention (MAPT PLUS extension study). INTERVENTIONS: 1/Omega-3 supplementation: two soft capsules daily as a single dose, containing a total of 400 mg docosahexaenoic acid (DHA), i.e., 800 mg docosahexaenoic acid per day, for 3 years. 2/ Multidomain intervention: collective training sessions conducted in small groups (6-8 participants) in twelve 120-minute sessions over the first 2 months (two sessions a week for the first month, and one session a week the second month) then a 60-minute session per month in the following three areas: nutrition, physical activity, and cognition until the end of the 3 years. In addition to the collective sessions, individualized preventive outpatient visits exploring possible risk factors for cognitive decline are performed at baseline, M12 and M24. BASELINE POPULATION: For cognition, the mean MMSE at baseline was 28.1 (+/- 1.6). About 58% and 42% of participants had a CDR score equal to 0 and 0.5, respectively. Regarding mobility status, 200 (11.9%) had a 4 m gait speed lower or equal to 0.8 m/s. According to the Fried criteria, 673 (42.1%) participants were considered pre frail, and 51 (3.2%) frail. The red blood cell DHA content was 26.1 +/- 8.1 ug/g. Five hundred and three participants underwent baseline MRI. AV45 PET scans were performed in 271 individuals and preliminary results showed that 38.0% had a cortical SUVR > 1.17, which gave an indication of significant brain amyloid deposit. DISCUSSION: The MAPT trial is presently the first largest and longest multidomain preventive trial relevant to cognitive decline in older adults with subjective memory complaints. The multidomain intervention designed for the MAPT trial is likely to be easily implemented within the general population. PMID- 26594642 TI - Uniform Surface Modification of 3D Bioglass((r))-Based Scaffolds with Mesoporous Silica Particles (MCM-41) for Enhancing Drug Delivery Capability. AB - The design and characterization of a new family of multifunctional scaffolds based on bioactive glass (BG) of 45S5 composition for bone tissue engineering and drug delivery applications are presented. These BG-based scaffolds are developed via a replication method of polyurethane packaging foam. In order to increase the therapeutic functionality, the scaffolds were coated with mesoporous silica particles (MCM-41), which act as an in situ drug delivery system. These sub micron spheres are characterized by large surface area and pore volume with a narrow pore diameter distribution. The solution used for the synthesis of the silica mesoporous particles was designed to obtain a high-ordered mesoporous structure and spherical shape - both are key factors for achieving the desired controlled drug release. The MCM-41 particles were synthesized directly inside the BG-based scaffolds, and the drug-release capability of this combined system was evaluated. Moreover, the effect of MCM-41 particle coating on the bioactivity of the BG-based scaffolds was assessed. The results indicate that it is possible to obtain a multifunctional scaffold system characterized by high and interconnected porosity, high bioactivity, and sustained drug delivery capability. PMID- 26594643 TI - Conformational selection and induced fit for RNA polymerase and RNA/DNA hybrid backtracked recognition. AB - RNA polymerase catalyzes transcription with a high fidelity. If DNA/RNA mismatch or DNA damage occurs downstream, a backtracked RNA polymerase can proofread this situation. However, the backtracked mechanism is still poorly understood. Here we have performed multiple explicit-solvent molecular dynamics (MD) simulations on bound and apo DNA/RNA hybrid to study backtracked recognition. MD simulations at room temperature suggest that specific electrostatic interactions play key roles in the backtracked recognition between the polymerase and DNA/RNA hybrid. Kinetics analysis at high temperature shows that bound and apo DNA/RNA hybrid unfold via a two-state process. Both kinetics and free energy landscape analyses indicate that bound DNA/RNA hybrid folds in the order of DNA/RNA contracting, the tertiary folding and polymerase binding. The predicted Phi-values suggest that C7, G9, dC12, dC15, and dT16 are key bases for the backtracked recognition of DNA/RNA hybrid. The average RMSD values between the bound structures and the corresponding apo ones and Kolmogorov-Smirnov (KS) P-test analyses indicate that the recognition between DNA/RNA hybrid and polymerase might follow an induced fit mechanism for DNA/RNA hybrid and conformation selection for polymerase. Furthermore, this method could be used to relative studies of specific recognition between nucleic acid and protein. PMID- 26594644 TI - MVP-Associated Filamin A Mutations Affect FlnA-PTPN12 (PTP-PEST) Interactions. AB - Although the genetic basis of mitral valve prolapse (MVP) has now been clearly established, the molecular and cellular mechanisms involved in the pathological processes associated to a specific mutation often remain to be determined. The FLNA gene (encoding Filamin A; FlnA) was the first gene associated to non syndromic X-linked myxomatous valvular dystrophy, but the impacts of the mutations on its function remain un-elucidated. Here, using the first repeats (1 8) of FlnA as a bait in a yeast two-hybrid screen, we identified the tyrosine phosphatase PTPN12 (PTP-PEST) as a specific binding partner of this region of FlnA protein. In addition, using yeast two-hybrid trap assay pull down and co immunoprecipitation experiments, we showed that the MVP-associated FlnA mutations (G288R, P637Q, H743P) abolished FlnA/PTPN12 interactions. PTPN12 is a key regulator of signaling pathways involved in cell-extracellular matrix (ECM) crosstalk, cellular responses to mechanical stress that involve integrins, focal adhesion transduction pathways, and actin cytoskeleton dynamics. Interestingly, we showed that the FlnA mutations impair the activation status of two PTPN12 substrates, the focal adhesion associated kinase Src, and the RhoA specific activating protein p190RhoGAP. Together, these data point to PTPN12/FlnA interaction and its weakening by FlnA mutations as a mechanism potentially involved in the physiopathology of FlnA-associated MVP. PMID- 26594645 TI - Medicinal Plants: Their Use in Anticancer Treatment. AB - Globally cancer is a disease which severely effects the human population. There is a constant demand for new therapies to treat and prevent this life-threatening disease. Scientific and research interest is drawing its attention towards naturally-derived compounds as they are considered to have less toxic side effects compared to current treatments such as chemotherapy. The Plant Kingdom produces naturally occurring secondary metabolites which are being investigated for their anticancer activities leading to the development of new clinical drugs. With the success of these compounds that have been developed into staple drugs for cancer treatment new technologies are emerging to develop the area further. New technologies include nanoparticles for nano-medicines which aim to enhance anticancer activities of plant-derived drugs by controlling the release of the compound and investigating new methods for administration. This review discusses the demand for naturally-derived compounds from medicinal plants and their properties which make them targets for potential anticancer treatments. PMID- 26594646 TI - Vitamin D Metabolites Inhibit Hepatitis C Virus and Modulate Cellular Gene Expression. AB - BACKGROUND AND AIMS: Previous studies suggest that low serum 25-hydroxyvitamin D [25(OH) D] levels are associated with reduced responsiveness to interferon and ribavirin therapy. We investigated the impact of vitamin D metabolites on HCV and cellular gene expression in cultured hepatoma cells. METHODS: HCV Replicon cell lines stably expressing luciferase reporter constructs (genotype 1b and 2a replicon) or JC1-Luc2a were incubated in the presence of vitamin D2, vitamin D3 or 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). Presence of HCV was quantified by a luciferase reporter assay and immunoblot of the Core protein. Synergy of interferon-alpha A/D (IFN-alpha) and 1,25(OH)2D3 was evaluated using the Chou Talalay method. Cellular gene expression by microarray analysis using Illumina Bead Chips and real-time quantitative PCR. RESULTS: Vitamin D2, D3 and 1,25(OH)2D3 each demonstrated anti-HCV activity at low micro molar concentrations. In vitro conversion from D3 to 25(OH)D3 was shown by LC/MS/MS. Combination indices of 1,25(OH)2D3 and IFN-alpha demonstrated a synergistic effect (0.23-0.46) and significantly reduced core expression by immunoblot. Differentially expressed genes were identified between Huh7.5.1 cells in the presence and absence of 1,25(OH)2D3 and HCV. Genes involved with classical effects of vitamin D metabolism and excretion were activated, along with genes linked to autophagy such as G-protein coupled receptor 37 (GPR37) and Hypoxia inducible factor 1-alpha (HIF1a). Additionally, additive effects of 1,25(OH)2D3 and IFN-alpha were seen on mRNA expression of chemokine motif ligand 20 (CCL20). CONCLUSIONS: This study shows that vitamin D reduces HCV protein production in cell culture synergistically with IFN-alpha. Vitamin D also activates gene expression independently and additively with IFN-alpha and this may explain its ability to aid in the clearance of HCV in vivo. PMID- 26594647 TI - Reduction in Prosodic Prominence Predicts Speakers' Recall: Implications for Theories of Prosody. AB - Repeated words are often reduced in prosodic prominence, but the underlying mechanisms remain unclear. The present study contrasted two theories: does prosodic reduction reflect the choice of a particular linguistic form, or does ease of retrieval within the language production system lead to facilitated, less prominent productions? One test of facilitation-based theories is suggested by findings on human memory: Whether a second presentation of an item benefits later memory is predicted by the item's availability at the time of the second presentation. If prosodic reduction partially reflects facilitated retrieval, it should predict later memory. One naive participant described to another participant routes on a map. Critical items were mentioned twice. Following the map task, the speaker attempted written recall of the mentioned items. As expected, acoustic intensity of the second mentions predicted later recall in the same way that difficulty of retrieval has in other tasks. This pattern suggests that one source of prosodic reduction is facilitation within the language production system. PMID- 26594648 TI - Exploring Institutional Research Ethics Systems: A Case Study From Uganda. AB - BACKGROUND: The increasing globalization of research drives a need for greater research ethics capacity in low resource countries. Several programs have attempted to expand research ethics capacity by training individuals, but few have focused on broader research ethics systems and institutions. This study describes and applies an institutional research ethics model to assess the institutional research ethics capacity of Makerere University College of Heath Sciences (MakCHS) in 2011. METHODS: Internal and external stakeholders conducted the assessment of MakCHS using the multidimensional Octagon framework. Five methods were used to collect data on current ethical processes and institutional relationships. RESULTS: MakCHS scored in the mid range on all Octagon domains, with some variation between external and internal assessments. The external Octagon scores suggest that MakCHS's areas of strengths are in identity, structure, relevance, target groups, and working environment; needs are greater in the areas of production, competence, and systems of finance and administration. Discrepancies in external and internal assessment can serve as a useful platform to shape ongoing discussions and strategic efforts. CONCLUSIONS: The assessment identified strengths, opportunities, and challenges for institutional research ethics capacity at MakCHS. We believe this systematic approach was helpful in evaluating research ethics needs and provides a benchmark for institutions to measure progress over time. PMID- 26594649 TI - Variations in Delivery and Exercise Content of Physical Therapy Rehabilitation Following Total Knee Replacement Surgery: A Cross-Sectional Observation Study. AB - OBJECTIVE: Prevalence of total knee replacement (TKR) is large and growing but functional outcomes are variable. Physical therapy (PT) is integral to functional recovery following TKR but little is known about the quantity or content of PT delivered. Purposes of this study were to describe the amount and exercise content of PT provided in the terminal episode of PT care following TKR and to examine factors associated with utilization and content. METHODS: Subjects included participants in a clinical trial of behavioral interventions for patients undergoing primary unilateral TKR who had completed the 6-month study evaluation. PT records were requested from 142 consecutive participants who had completed their post-TKR rehabilitation, 102 in/out patient care, and 40 in homecare. Information on utilization and exercises was extracted from a retrospective review of the PT records. RESULTS: We received 90 (88%) outpatient and 27 (68%) homecare PT records. Records showed variability in timing, amount and content of PT. Patients receiving outpatient PT had more visits and remained in PT longer (p<0.001). Exercises known in the TKR literature were utilized more frequently in the outpatient setting (p=0.001) than in home care. Records from both settings had limited documentation of strengthening progression. CONCLUSIONS: The study reveals considerable variability in timing, utilization and exercise content of PT following TKR and suggests sub-optimal exercise for strengthening. While methods we employed document variability, improved systematic PT documentation and in-depth research are needed to identify optimal timing, utilization and content of PT following TKR. PMID- 26594650 TI - The parasitic worm product ES-62 up-regulates IL-22 production by gammadelta T cells in the murine model of Collagen-Induced Arthritis. AB - ES-62 is a phosphorylcholine (PC)-containing glycoprotein secreted by the filarial nematode Acanthocheilonema viteae that acts to modulate the host immune response to promote the establishment of chronic helminth infection. Reflecting its anti-inflammatory actions, we have previously reported that ES-62 protects mice from developing Collagen-Induced Arthritis (CIA): thus, as this helminth derived product may exhibit therapeutic potential in Rheumatoid Arthritis (RA), it is important to understand the protective immunoregulatory mechanisms triggered by ES-62 in this model in vivo. We have established to date that ES-62 acts by downregulating pathogenic Th17/IL-17-mediated responses and upregulating the regulatory cytokine IL-10. In addition, our studies have identified that IL 22, another member of the IL-10 family of cytokines, exerts dual pathogenic and protective roles in this model of RA with ES-62 harnessing the cytokine's inflammation-resolving and tissue repair properties in the joint during the established phase of disease. Here, we discuss the counter-regulatory roles of IL 22 in the murine model of CIA and present additional novel data showing that ES 62 selectively induces gammadelta T cells with the capacity to induce IL-22 production and that gammadelta T cells with the capacity to produce IL-22, but not IL-17, induced during CIA can be identified by their expression of TLR4. Moreover, we also show that treatment of mice undergoing CIA with the active PC moiety of ES-62, in the form of PC conjugated to BSA, is not only sufficient to mimic the ES-62-dependent suppression of pathogenic IL-17 responses shown previously but also that of the IL-22 and IL-10 up-regulation observed with the parasitic worm product during CIA. These findings not only reinforce the potential of IL-22, firstly described as a Th17-related pro-inflammatory cytokine, as a protective factor in arthritis but also suggest that drugs based on the PC moiety found in ES-62 may be able to harness the joint-protecting activities of IL-22 therapeutically. PMID- 26594651 TI - Re-Search: The Missing Pieces in Investigating African-American Relationship Dynamics and Implications for HIV Risk. PMID- 26594652 TI - Editorial Commentary. PMID- 26594653 TI - Influence of temperature on the formation and encapsulation of gold nanoparticles using a temperature-sensitive template. AB - This data article describes the synthesis of temperature-sensitive and amine-rich microgel particle as a dual reductant and template to generate smart gold/polymer nanocomposite particle. TEM images illustrate the influence of reaction temperature on the formation and in-site encapsulation of gold nanoparticles using the temperature-sensitive microgel template. Thermal stability of the resultant gold/polymer composite particles was also examined. PMID- 26594654 TI - Data to establish the optimal standard regimen and predicting the response to docetaxel therapy. AB - This paper contains data to establish the optimal standard regimen and predicting the response to docetaxel therapy (Moawad, 2014) [1]. Docetaxel has been in use for over a decade without demonstrating data indicates a predictable response in the treatment of cancer. Data of puzzling response to docetaxel therapy was due to its cell cycle specific effect. Although several administered schedules were investigated, the relative therapeutic advantage of high versus low doses has not been identified yet. Also the antitumor target of docetaxel has not yet been identified to optimize therapy by predicting the response of patients prior to therapy to provide a protection against treatment failure. In the present paper, we demonstrate the data used to optimize docetaxel therapy and investigate the possibility of predicting for the first time the antitumor target of docetaxel. PMID- 26594655 TI - Identifying the effects of social media on health behavior: Data from a large scale online experiment. AB - Sedentary lifestyle is an escalating epidemic. Little is known about whether or how social media can be used to design a cost-effective solution for sedentary lifestyle. In this article we describe the data from a randomized controlled trial (RCT) that evaluated two prominent strategies for conducting exercise interventions using elements of social media: motivational media campaigns and online peer networks. The data file includes 217 participants' basic demographic information, number of exercise class enrollments over 13 weeks, and self reported number of days for exercise activities in the previous 7 days at baseline. Among the 217, 164 also have data on self-reported number of days for exercise activities at the post-program. Data are supplied with this article. The interpretation of these data can be found in the research article published by the authors in Preventive Medicine Reports in 2015 [1]. PMID- 26594656 TI - Data on Income inequality in Germany, France, Italy, Spain, the UK, and other affluent nations, 2012. AB - This data article contains information on the distribution of household incomes in the five most populous European countries as surveyed in 2012, with data released in 2014 and published here aggregated and so further anonymized in 2015. The underlying source data is the already anonymized EU Statistics on Income and Living Conditions (EUSILC) Microdata. The data include the annual household income required in each country to fall within the best-off 1% in that country, median and mean incomes, average (mean) incomes of the best off 1%, 0.1% and estimates for the 0.01%, 0.001% and so on for the UK, and of the 90% and worse off 10%, the best-off 10% and best-off 1% of households for all countries. Average income from the state is also calculated by these income categories and the number of people working in finance and receiving over ?1,000,000 a year in income is reported from other sources (the European Banking Authority). Finally income distribution data is provided from the USA and the rest of Europe in order to allow comparisons to be made. The data revealed the gross household (simple unweighted) median incomes in 2012 to have been (in order from best-off country by median to worse-off): France ?39,000, Germany: ?33,400, UK: ?36,300, Italy ?33,400 and Spain ?27,000. However the medians, once households are weighted to reflect the nation populations do differ although they are in the same order: France ?36,000, Germany: ?33,400, UK: ?31,300, Italy ?31,000 and Spain ?23,700. Thus weighting to increase representativeness of the medians reduces each by ?3000, ?0, ?5000, ?3300 and ?3300 respectively. In short, the middle (weighted median) French household is ?4700 a year better off than the middle UK family, and that is before housing costs are considered. This Data in Brief article accompanies Dorling, D. (2015) Income Inequality in the UK: Comparisons with five large Western European countries and the USA [1]. PMID- 26594657 TI - Structure and fabrication details of an integrated modularized microfluidic system. AB - This article contains schemes, original experimental data and figures for an integrated modularized microfluidic system described in "An integrated microfluidic system for bovine DNA purification and digital PCR detection [1]". In this data article, we described the structure and fabrication of the integrated modularized microfluidic system. This microfluidic system was applied to isolate DNA from ovine tissue lysate and detect the bovine DNA with digital PCR (dPCR). The DNA extraction efficiency of the microdevice was compared with the efficiency of benchtop protocol. PMID- 26594658 TI - Construction of a plasmid coding for green fluorescent protein tagged cathepsin L and data on expression in colorectal carcinoma cells. AB - The endo-lysosomal cysteine cathepsin L has recently been shown to have moonlighting activities in that its unexpected nuclear localization in colorectal carcinoma cells is involved in cell cycle progression (Tamhane et al., 2015) [1]. Here, we show data on the construction and sequence of a plasmid coding for human cathepsin L tagged with an enhanced green fluorescent protein (phCL-EGFP) in which the fluorescent protein is covalently attached to the C-terminus of the protease. The plasmid was used for transfection of HCT116 colorectal carcinoma cells, while data from non-transfected and pEGFP-N1-transfected cells is also shown. Immunoblotting data of lysates from non-transfected controls and HCT116 cells transfected with pEGFP-N1 and phCL-EGFP, showed stable expression of cathepsin L-enhanced green fluorescent protein chimeras, while endogenous cathepsin L protein amounts exceed those of hCL-EGFP chimeras. An effect of phCL EGFP expression on proliferation and metabolic states of HCT116 cells at 24 h post-transfection was observed. PMID- 26594659 TI - The Neuroprotective Aspects of Sleep. AB - Sleep is an important component of human life, yet many people do not understand the relationship between the brain and the process of sleeping. Sleep has been proven to improve memory recall, regulate metabolism, and reduce mental fatigue. A minimum of 7 hours of daily sleep seems to be necessary for proper cognitive and behavioral function. The emotional and mental handicaps associated with chronic sleep loss as well as the highly hazardous situations which can be contributed to the lack of sleep is a serious concern that people need to be aware of. When one sleeps, the brain reorganizes and recharges itself, and removes toxic waste byproducts which have accumulated throughout the day. This evidence demonstrates that sleeping can clear the brain and help maintain its normal functioning. Multiple studies have been done to determine the effects of total sleep deprivation; more recently some have been conducted to show the effects of sleep restriction, which is a much more common occurrence, have the same effects as total sleep deprivation. Each phase of the sleep cycle restores and rejuvenates the brain for optimal function. When sleep is deprived, the active process of the glymphatic system does not have time to perform that function, so toxins can build up, and the effects will become apparent in cognitive abilities, behavior, and judgment. As a background for this paper we have reviewed literature and research of sleep phases, effects of sleep deprivation, and the glymphatic system of the brain and its restorative effect during the sleep cycle. PMID- 26594660 TI - Diaza-anthracene Antibiotics from a Freshwater-Derived Actinomycete with Selective Antibacterial Activity toward Mycobacterium tuberculosis. AB - Multidrug- and extensively drug-resistant strains of Mycobacterium tuberculosis are resistant to first- and second-line drug regimens and resulted in 210,000 fatalities in 2013. In the current study, we screened a library of aquatic bacterial natural product fractions for their ability to inhibit this pathogen. A fraction from a Lake Michigan bacterium exhibited significant inhibitory activity, from which we characterized novel diazaquinomycins H and J. This antibiotic class displayed an in vitro activity profile similar or superior to clinically used anti-tuberculosis agents and maintained this potency against a panel of drug-resistant M. tuberculosis strains. Importantly, these are among the only freshwater-derived actinomycete bacterial metabolites described to date. Further in vitro profiling against a broad panel of bacteria indicated that this antibiotic class selectively targets M. tuberculosis. Additionally, in the case of this pathogen we present evidence counter to previous reports that claim the diazaquinomycins target thymidylate synthase in Gram-positive bacteria. Thus, we establish freshwater environments as potential sources for novel antibiotic leads and present the diazaquinomycins as potent and selective inhibitors of M. tuberculosis. PMID- 26594661 TI - Geographic Variation in Cold Ischemia Time: Kidney vs. Liver Transplantation in the United States, 2003-2011. AB - BACKGROUND: Regional variations in kidney and liver transplant outcomes have been reported, but their causes remain largely unknown. This study investigated variations in kidney and liver cold ischemia times (CITs) across Organ Procurement Organizations (OPO) as potential causes of variations in transplant outcomes. METHODS: This retrospective study analyzed the Standard Transplant Analysis and Research (STAR) data of deceased donor kidney (n=61,335) and liver (n=39,285) transplants performed between 2003 and 2011. CIT variations between the two types of organs were examined and compared. Factors associated with CIT were explored using multivariable regressions. Spearman's rank tests were used to associate CIT with graft failure at the OPO level. RESULTS: Significant CIT variations were found across OPOs for both organs (p < 0.05). The variation was particularly large for kidney CIT. Those OPOs with longer average kidney CIT were likely to have a lower graft survival rate (p=0.01). For liver, this association was insignificant (p=0.23). The regression analysis revealed sharp contrasts between the factors associated with kidney and liver CITs. High risk kidney transplant recipients and marginal kidneys were associated with longer average CIT. The reverse was true for liver transplants. CONCLUSIONS: Large variations in kidney CIT compared to liver CIT may indicate that there is a room to reduce kidney CIT. Reducing kidney CIT through managerial improvements could be a cost effective way to improve the current transplant system. PMID- 26594663 TI - NDEx, the Network Data Exchange. AB - Networks are a powerful and flexible methodology for expressing biological knowledge for computation and communication. Network-encoded information can include systematic screens for molecular interactions, biological relationships curated from literature, and outputs from analysis of Big Data. NDEx, the Network Data Exchange (www.ndexbio.org), is an online commons where scientists can upload, share, and publicly distribute networks. Networks in NDEx receive globally unique accession IDs and can be stored for private use, shared in pre publication collaboration, or released for public access. Standard and novel data formats are accommodated in a flexible storage model. Organizations can use NDEx as a distribution channel for networks they generate or curate. Developers of bioinformatic applications can store and query NDEx networks via a common programmatic interface. NDEx helps expand the role of networks in scientific discourse and facilitates the integration of networks as data in publications. It is a step towards an ecosystem in which networks bearing data, hypotheses, and findings flow easily between scientists. PMID- 26594664 TI - Understanding traditional African healing. AB - Traditional African healing has been in existence for many centuries yet many people still seem not to understand how it relates to God and religion/spirituality. Some people seem to believe that traditional healers worship the ancestors and not God. It is therefore the aim of this paper to clarify this relationship by discussing a chain of communication between the worshipers and the Almighty God. Other aspects of traditional healing namely types of traditional healers, training of traditional healers as well as the role of traditional healers in their communities are discussed. In conclusion, the services of traditional healers go far beyond the uses of herbs for physical illnesses. Traditional healers serve many roles which include but not limited to custodians of the traditional African religion and customs, educators about culture, counselors, social workers and psychologists. PMID- 26594662 TI - Geospatial Resolution of Human and Bacterial Diversity with City-Scale Metagenomics. AB - The panoply of microorganisms and other species present in our environment influence human health and disease, especially in cities, but have not been profiled with metagenomics at a city-wide scale. We sequenced DNA from surfaces across the entire New York City (NYC) subway system, the Gowanus Canal, and public parks. Nearly half of the DNA (48%) does not match any known organism; identified organisms spanned 1,688 bacterial, viral, archaeal, and eukaryotic taxa, which were enriched for harmless genera associated with skin (e.g., Acinetobacter). Predicted ancestry of human DNA left on subway surfaces can recapitulate U.S. Census demographic data, and bacterial signatures can reveal a station's history, such as marine-associated bacteria in a hurricane-flooded station. Some evidence of pathogens was found (Bacillus anthracis), but a lack of reported cases in NYC suggests that the pathogens represent a normal, urban microbiome. This baseline metagenomic map of NYC could help long-term disease surveillance, bioterrorism threat mitigation, and health management in the built environment of cities. PMID- 26594666 TI - 3D FFTs on a Single FPGA. AB - The 3D FFT is critical in many physical simulations and image processing applications. On FPGAs, however, the 3D FFT was thought to be inefficient relative to other methods such as convolution-based implementations of multi grid. We find the opposite: a simple design, operating at a conservative frequency, takes 4MUs for 163, 21MUs for 323, and 215MUs for 643 single precision data points. The first two of these compare favorably with the 25MUs and 29MUs obtained running on a current Nvidia GPU. Some broader significance is that this is a critical piece in implementing a large scale FPGA-based MD engine: even a single FPGA is capable of keeping the FFT off of the critical path for a large fraction of possible MD simulations. PMID- 26594665 TI - Towards integration of traditional healing and western healing: Is this a remote possibility? AB - There is a shortage of Western-trained health care personnel in state hospitals and clinics in South Africa. However, traditional healers are in abundance in both the urban and rural areas of South Africa. Some health care interest groups and individual researchers have called for integration of traditional healing and Western biomedicine in South Africa. The South African government seems to support the idea of integrating the two health care systems. The current paper offers a critical discussion of this issue. The paper discusses pertinent issues such as the demand for traditional healing, possible integration of traditional healing and Western healing as well as anticipated hindrances to integration of traditional healing and Western healing. Finally, the paper discusses dilemmas posed by non-integration of traditional healing and Western healing. In conclusion, the potential to integrate the two health care systems remains a complex possibility which might take years to achieve. PMID- 26594667 TI - GPU Optimizations for a Production Molecular Docking Code. AB - Modeling molecular docking is critical to both understanding life processes and designing new drugs. In previous work we created the first published GPU accelerated docking code (PIPER) which achieved a roughly 5* speed-up over a contemporaneous 4 core CPU. Advances in GPU architecture and in the CPU code, however, have since reduced this relalative performance by a factor of 10. In this paper we describe the upgrade of GPU PIPER. This required an entire rewrite, including algorithm changes and moving most remaining non-accelerated CPU code onto the GPU. The result is a 7* improvement in GPU performance and a 3.3* speedup over the CPU-only code. We find that this difference in time is almost entirely due to the difference in run times of the 3D FFT library functions on CPU (MKL) and GPU (cuFFT), respectively. The GPU code has been integrated into the ClusPro docking server which has over 4000 active users. PMID- 26594668 TI - An Investigation of Unified Memory Access Performance in CUDA. AB - Managing memory between the CPU and GPU is a major challenge in GPU computing. A programming model, Unified Memory Access (UMA), has been recently introduced by Nvidia to simplify the complexities of memory management while claiming good overall performance. In this paper, we investigate this programming model and evaluate its performance and programming model simplifications based on our experimental results. We find that beyond on-demand data transfers to the CPU, the GPU is also able to request subsets of data it requires on demand. This feature allows UMA to outperform full data transfer methods for certain parallel applications and small data sizes. We also find, however, that for the majority of applications and memory access patterns, the performance overheads associated with UMA are significant, while the simplifications to the programming model restrict flexibility for adding future optimizations. PMID- 26594669 TI - Demographic determinants of health care practitioners' intentions to work with traditional healers. AB - The aim of this study was to investigate the demographic determinants of health care practitioners' intentions to work with traditional healers in South Africa. The study sampled 319 health care practitioners from State hospitals and clinics in Limpopo and Gauteng provinces, South Africa. Participants completed the Views on Traditional Healing Questionnaire (VTHQ) which was designed for the purposes of this study. Results of multiple regression analyses indicated that health care practitioners' demographic variables (i.e. their designated roles, home language and hospital/clinic setting) did not yield significant variations in terms of their intentions to work with traditional healers in the future. Overall, health care practitioners' attitudes towards traditional healing explained their intentions to work with traditional healers in the future. For xiTsonga and Sesotho speaking health care practitioners, their experiences with traditional healing explained their intentions to work with traditional healers in the future. PMID- 26594670 TI - Presence of Octopamine and an Octopamine Receptor in Crassostrea virginica. AB - Octopamine is a biogenic amine first identified in octopus. It has been well studied in arthropods and a few gastropods, serving as a neurotransmitter and hormone. The presence of octopamine has rarely been reported in bivalves and has not been reported in Crassostrea virginica. We utilized HPLC to identify and measure octopamine in cerebral ganglia, visceral ganglia, gill, palps, mantle, heart and hemolymph of C. virginica. Endogenous octopamine levels increased when animals were treated with tyramine, an octopamine precursor. A preliminary study in our lab found that octopamine has a cardio-excitatory action on C. virginica heart. In the present study we also used immunoblotting techniques to identify an octopamine-like receptor (Pan TAAR, trace amine-associated receptor) in oyster heart. The study confirms the presence of octopamine in the nervous system, innervated organs and hemolymph of C. virginica and identifies the presence of an octopamine-like receptor in heart, strengthening the contention that octopamine is important in the physiology of C. virginica as it is in other invertebrates. PMID- 26594672 TI - Authors' reply. PMID- 26594674 TI - [Henry Hamard (1933-2015)]. PMID- 26594673 TI - Introduction to special issue on: the David Barker commemorative meeting, September 2014; the future of the science he inspired. PMID- 26594675 TI - Reflections: Neurology and the Humanities. Autism. PMID- 26594676 TI - Susceptibility-weighted MRI in mild traumatic brain injury. PMID- 26594677 TI - Patients test drive pacemaker before choosing permanent implant. PMID- 26594678 TI - Uninterrupted novel oral anticoagulant therapy during atrial fibrillation ablation is safe. PMID- 26594679 TI - A London cardiologist launches his research career by finding out how to find out what's been found out. PMID- 26594681 TI - Abstracts of the 7th Annual Meeting of the North American NeuroEndocrine Tumor Society. October 10-11, 2014. Nashville, Tennessee. PMID- 26594680 TI - Pregnancy-related spontaneous coronary artery dissection. PMID- 26594682 TI - In memoriam. Jeanne Elizabeth Dise-Lewis, PhD. PMID- 26594683 TI - Ragnar Granit--Sensory Structure of Retina and Vision. PMID- 26594684 TI - Baruch Blumberg: Discoverer of Hepatitis B Virus. PMID- 26594685 TI - DENTSPLY International and Sirona Dental Systems Announce Merger. PMID- 26594686 TI - Introducing MouthLab, a "Check-Engine" Light for Humans. PMID- 26594687 TI - Periodontitis and Heart Disease: Researchers Connect the Molecular Dots. PMID- 26594688 TI - Study Confirms Smoking's Link to Increased Risk of Tooth Loss. PMID- 26594689 TI - Blueberries Versus Periodontitis. PMID- 26594690 TI - Prevalence and strength of density-dependent tree recruitment. AB - Density dependence could maintain diversity in forests, but studies continue to disagree on its role. Part of the disagreement results from the fact that different studies have evaluated different responses (survival, recruitment, or growth) of different stages (seeds, seedlings, or adults) to different inputs (density of seedlings, density or distance to adults). Most studies are conducted on a single site and thus are difficult to generalize. Using USDA Forest Service's Forest Inventory and Analysis data, we analyzed over a million seedling to-sapling recruitment observations of 50 species from the eastern United States, controlling for the effects of climate. We focused on the per-seedling recruitment rate, because it is most likely to promote diversity and to be identified in observational or experimental data. To understand the prevalence of density dependence, we quantified the number of species with significant positive or negative effects. To understand the strength of density dependence, we determined the magnitude of effects among con- and heterospecifics, and how it changes with overall species abundance. We found that density dependence is pervasive among the 50 species, as the majority of them have significant effects and mostly negative. Density-dependence effects are stronger from conspecific than heterospecfic adult neighbors, consistent with the predictions of the Janzen Connell hypothesis. Contrary to recent reports, density-dependence effects are more negative for common than rare species, suggesting disproportionately stronger population regulation in common species. We conclude that density dependence is pervasive, and it is strongest from conspecific neighbors of common species. Our analysis provides direct evidence that density dependence reaulates opulation dynamics of tree species in eastern U.S. forests. PMID- 26594691 TI - Stoichiometric homeostasis predicts plant species dominance, temporal stability, and responses to global change. AB - Why some species are consistently more abundant than others, and predicting how species will respond to global change, are fundamental questions in ecology. Long term observations indicate that plant species with high stoichiometric homeostasis for nitrogen (HN), i.e., the ability to decouple foliar N levels from variation in soil N availability, were more common and stable through time than low-HN species in a central U.S. grassland. However, with nine years of nitrogen addition, species with high H(N) decreased in abundance, while those with low H(N) increased in abundance. In contrast, in climate change experiments simulating a range of forecast hydrologic changes, e.g., extreme drought (two years), increased rainfall variability (14 years), and chronic increases in rainfall (21 years), plant species with the highest H(N) were least responsive to changes in soil water availability. These results suggest that H(N) may be predictive of plant species success and stability, and how plant species and ecosystems will respond to global-change-driven alterations in resource availability. PMID- 26594692 TI - Mycorrhizal co-invasion and novel interactions depend on neighborhood context. AB - Biological invasions are a rapidly increasing driver of global change, yet fundamental gaps remain in our understanding of the factors determining the success or extent of invasions. For example, although most woody plant species depend on belowground mutualists such as mycorrhizal fungi and nitrogen-fixing bacteria, the relative importance of these mutualisms in conferring invasion success is unresolved. Here, we describe how neighborhood context (identity of nearby tree species) affects the formation of belowground ectomycorrhizal partnerships between fungi and seedlings of a widespread invasive tree species, Pseudotsuga menziesii (Douglas-fir), in New Zealand. We found that the formation of mycorrhizal partnerships, the composition of the fungal species involved in these partnerships, and the origin of the fungi (co-invading or native to New Zealand) all depend on neighborhood context. Our data suggest that nearby ectomycorrhizal host trees act as both a reservoir of fungal inoculum and a carbon source for late-successional and native fungi. By facilitating mycorrhization of P. menziesii seedlings, adult trees may alleviate mycorrhizal limitation at the P. menziesii invasion front. These results highlight the importance of studying biological invasions across multiple ecological settings to understand establishment success and invasion speed. PMID- 26594693 TI - Latitudinal variation in the response of tidepool copepods to mean and daily range in temperature. AB - Understanding the evolutionary potential of organisms to adapt to a changing climate, and the fitness consequences of temperature fluctuations, are critical to forecasting the future of biodiversity. Geographic variation among populations in life history response to temperature mean and variability offers one view of the potential for local adaptation to broaden the thermal niche. We used laboratory growth experiments to examine the effects of temperatures between 13 degrees C and 30 degrees C on five life history traits and the intrinsic rate of increase for 15 Tigriopus californicus populations distributed over 17 degrees of latitude. Different life history stages showed distinct latitudinal shifts in thermal response, while the temperature of peak population growth consistently declined with increasing latitude. In addition, high-latitude populations grew faster at optimal temperatures but showed steeper fitness declines at high temperature. To test geographic population variation in response to the amplitude of daily thermal fluctuations, we grew three northern and three southern populations and manipulated nightly low and daily high temperatures. We found the lowest fitness overall in the treatment with the highest mean temperature, and the treatment with the greatest variability showed high fitness despite an 80C greater daily range. Population responses to daily thermal variability were unrelated to latitude of origin. Our results indicate that trade-offs between adaptation to high vs. low temperature, and between growth and maturation vs. survival and fecundity, govern local adaptation along the latitudinal gradient. They also indicate that, T. californicus populations can maintain fitness over a wide range of daily variability but are more sensitive to small changes in the mean temperature. PMID- 26594694 TI - Quantifying nonadditive selection caused by indirect ecological effects. AB - In natural biological communities, species interact with many other species. Multiple species interactions can lead to indirect ecological effects that have important fitness consequences and can cause nonadditive patterns of natural selection. Given that indirect ecological effects are common in nature, nonadditive selection may also be quite common. As a result, quantifying nonadditive selection resulting from indirect ecological effects may be critical for understanding adaptation in natural communities composed of many interacting species. We describe how to quantify the relative strength of nonadditive selection resulting from indirect ecological effects compared to the strength of pairwise selection. We develop a clear method for testing for nonadditive selection caused by indirect ecological effects and consider how it might affect adaptation in multispecies communities. We use two case studies to illustrate how our method can be applied to empirical data sets. Our results suggest that nonadditive selection caused by indirect ecological effects may be common in nature. Our hope is that trait-based approaches, combined with multifactorial experiments, will result in more estimates of nonadditive selection that reveal the relative importance of indirect ecological effects for evolution in a community context. PMID- 26594695 TI - Model averaging and muddled multimodel inferences. AB - Three flawed practices associated with model averaging coefficients for predictor variables in regression models commonly occur when making multimodel inferences in analyses of ecological data. Model-averaged regression coefficients based on Akaike information criterion (AIC) weights have been recommended for addressing model uncertainty but they are not valid, interpretable estimates of partial effects for individual predictors when there is multicollinearity among the predictor variables. Multicollinearity implies that the scaling of units in the denominators of the regression coefficients may change across models such that neither the parameters nor their estimates have common scales, therefore averaging them makes no sense. The associated sums of AIC model weights recommended to assess relative importance of individual predictors are really a measure of relative importance of models, with little information about contributions by individual predictors compared to other measures of relative importance based on effects size or variance reduction. Sometimes the model averaged regression coefficients for predictor variables are incorrectly used to make model-averaged predictions of the response variable when the models are not linear in the parameters. I demonstrate the issues with the first two practices using the college grade point average example extensively analyzed by Burnham and Anderson. I show how partial standard deviations of the predictor variables can be used to detect changing scales of their estimates with multicollinearity. Standardizing estimates based on partial standard deviations for their variables can be used to make the scaling of the estimates commensurate across models, a necessary but not sufficient condition for model averaging of the estimates to be sensible. A unimodal distribution of estimates and valid interpretation of individual parameters are additional requisite conditions. The standardized estimates or equivalently the t statistics on unstandardized estimates also can be used to provide more informative measures of relative importance than sums of AIC weights. Finally, I illustrate how seriously compromised statistical interpretations and predictions can be for all three of these flawed practices by critiquing their use in a recent species distribution modeling technique developed for predicting Greater Sage-Grouse (Centrocercus urophasianus) distribution in Colorado, USA. These model averaging issues are common in other ecological literature and ought to be discontinued if we are to make effective scientific contributions to ecological knowledge and conservation of natural resources. PMID- 26594696 TI - Elk, sagebrush, and saprotrophs: indirect top-down control on microbial community composition and function. AB - Saprotrophic microbial communities in soil are primarily structured by the availability of growth-limiting resources (i.e., plant detritus), a bottom-up ecological force. However, foraging by native ungulates can alter plant community composition and the nature of detritus entering soil, plausibly exerting an indirect, top-down ecological force that shapes both the composition and function of soil microbial communities. To test this idea, we used physiological assays and molecular approaches to quantify microbial community composition and function inside and outside of replicate, long-term (60-80 yr) winter-foraging exclosures in sagebrush steppe of Wyoming, USA. Winter foraging exclusion substantially increased shrub biomass (2146 g/m2 vs. 87 g/m2), which, in turn, increased the abundance of bacterial and fungal genes with lignocellulolytic function; microbial respiration (+50%) and net N mineralization (+70%) also were greater in the absence of winter foraging. Our results reveal that winter foraging by native, migratory ungulates in sagebrush steppe exerts an indirect, top-down ecological force that shapes the composition and function of soil microbial communities. Because approximately 25% of the Earth's land surface is influenced by grazing animals, this indirect top-down ecological force could function to broadly shape the community membership and physiological capacity of saprotrophic microbial communities in shrub steppe. PMID- 26594697 TI - Lichen physiological traits and growth forms affect communities of associated invertebrates. AB - While there has been much interest in the relationships between traits of primary producers and composition of associated invertebrate consumer communities, our knowledge is largely based on studies from vascular plants, while other types of functionally important producers, such as lichens, have rarely been considered. To address how physiological traits of lichens drive community composition of invertebrates, we collected thalli from 27 lichen species from southern Norway and quantified the communities of associated springtails, mites, and nematodes. For each lichen species, we measured key physiological thallus traits and determined whether invertebrate communities were correlated with these traits. We also explored whether invertebrate communities differed among lichen groups, categorized according to nitrogen-fixing ability, growth form, and substratum. Lichen traits explained up to 39% of the variation in abundances of major invertebrate groups. For many invertebrate groups, abundance was positively correlated with lichen N and P concentrations, N:P ratio, and the percentage of water content on saturation (WC), but had few relationships with concentrations of carbon-based secondary compounds. Diversity and taxonomic richness of invertebrate groups were sometimes also correlated with lichen N and N:P ratios. Nitrogen-fixing lichens showed higher abundance and diversity of some invertebrate groups than did non-N-fixing lichens. However, this emerged in part because most N-fixing lichens have a foliose growth form that benefits invertebrates, through, improving the microclimate, independently of N concentration. Furthermore, invertebrate communities associated with terricolous lichens were determined more by their close proximity to the soil invertebrate pool than by lichen traits. Overall, our results reveal that differences between lichen species have a large impact on the invertebrate communities that live among the thalli. Different invertebrate groups show contrasting responses to traits that are indicative of thallus quality (nutrient concentrations), and thallus growth form is often an important determinant of the invertebrate community. Given the large diversity of lichen traits and growth forms that occur in many ecosystems, lichen-invertebrate communities may be an important contributor to overall community diversity in boreal forests. PMID- 26594698 TI - Hemiparasitic plant impacts animal and plant communities across four trophic levels. AB - Understanding the impact of species on community structure is a fundamental question in ecology. There is a growing body of evidence that suggests that both subdominant species and parasites can have disproportionately large effects on other organisms. Here we report those impacts for a species that is both subdominant and parasitic, the hemiparasite Rhinanthus minor. While the impact of parasitic angiosperms on their hosts and, to a lesser degree, coexisting plant species, has been well characterized, much less is known about their effects on higher trophic levels: We experimentally manipulated field densities of the hemiparasite Rhinanthus minor in a species-rich grassland, comparing the plant and invertebrate communities in plots where it was removed, present at natural densities, or present at enhanced densities. Plots with natural and enhanced densities of R. minor had lower plant biomass than plots without the hemiparasite, but enhanced densities almost doubled the abundance of invertebrates within the plots across all trophic levels, with effects evident in herbivores, predators, and detritivores. The hemiparasite R. minor, despite being a subdominant and transient component within plant communities that it inhabits, has profound effects on four different trophic levels. These effects persist beyond the life of the hemiparasite, emphasizing its role as a keystone species in grassland communities. PMID- 26594699 TI - Impacts of weather on long-term patterns of plant richness and diversity vary with location and management. AB - Better understanding the influence of precipitation and temperature on plant assemblages is needed to predict the effects of climate change. Many studies have examined the relationship between plant productivity and weather (primarily precipitation), but few have directly assessed the relationship between plant richness or diversity and weather despite their increased use as metrics of ecosystem condition. We focus on the grasslands of central North America, which are characterized by high temporal climatic variability. Over the next 100 years, these grasslands are predicted to experience further increased variability in growing season precipitation, as well as increased temperatures, due to global climate change. We assess the portion of interannual variability of richness and diversity explained by weather, how relationships between these metrics and weather vary among plant assemblages, and which aspects of weather best explain temporal variability. We used an information-theoretic approach to assess relationships between long-term plant richness and diversity patterns and a priori weather covariates using six data sets from four grasslands. Weather explained up to 49% and 63% of interannual variability in total plant species richness and diversity, respectively. However, richness and diversity responses to specific weather variables varied both among sites and among experimental treatments within sites. In general, we found many instances in which temperature was of equal or greater importance as precipitation, as well as evidence of the importance of lagged effects and precipitation or temperature variability. Although precipitation has been shown to be a key driver of productivity in grasslands, our results indicate that increasing temperatures alone, without substantial changes in precipitation patterns, could have measurable effects on Great Plains grassland plant assemblages and biodiversity metrics. Our results also suggest that richness and diversity will respond in unique ways to changing climate and management can affect these responses; additional research and monitoring will be essential for further understanding of these complex relationships. PMID- 26594701 TI - No release for the wicked: enemy release is dynamic and not associated with invasiveness. AB - The enemy release hypothesis predicts that invasive species will receive less damage from enemies, compared to co-occurring native and noninvasive exotic species in their introduced range. However, release operating early in invasion could be lost over time and with increased range size as introduced species acquire new enemies. We used three years of data, from 61 plant species planted into common gardens, to determine whether (1) invasive, noninvasive exotic, and native species experience differential damage from insect herbivores. and mammalian browsers, and (2) enemy release is lost with increased residence time and geographic spread in the introduced range. We find no evidence suggesting enemy release is a general mechanism contributing to invasiveness in this region. Invasive species received the most insect herbivory, and damage increased with longer residence times and larger range sizes at three spatial scales. Our results show that invasive and exotic species fail to escape enemies, particularly over longer temporal and larger spatial scales. PMID- 26594700 TI - The role of ecotypic variation and the environment on biomass and nitrogen in a dominant prairie grass. AB - Knowledge of the relative strength of evolution and the environment on a phenotype is required to predict species responses to environmental change and decide where to source plant material for ecological restoration. This information is critically needed for dominant species that largely determine the productivity of the central U.S. grassland. We established a reciprocal common garden experiment across a longitudinal gradient to test whether ecotypic variation interacts with the environment to affect growth and nitrogen (N) storage in a dominant grass. We predicted plant growth would increase from west to east, corresponding with increasing precipitation, but differentially among ecotypes due to local adaptation in all ecotypes and a greater range of growth response in ecotypes originating from west to east. We quantified aboveground biomass, root biomass, belowground net primary production (BNPP), root C:N ratio, and N storage in roots of three ecotypes of Andropogon gerardii collected from and reciprocally planted in central Kansas, eastern Kansas, and s6uthern Illinois. Only the ecotype from the most mesic region (southern Illinois) exhibited more growth from west to east. There was evidence for local adaptation in the southern Illinois ecotype by means of the local vs. foreign contrast within a site and the home vs. away contrast when growth in southern Illinois was compared to the most distant 'site in central Kansas. Root biomass of the eastern Kansas ecotype was higher at home than at either away site. The ecotype from the driest region, central Kansas, exhibited the least response across the environmental gradient, resulting in a positive relationship between the range of biomass response and precipitation in ecotype region of origin. Across all sites, ecotypes varied in root C:N ratio (highest in the driest-origin ecotype) and N storage in roots (highest in the most mesic-origin ecotype). The low and limited range of biomass, higher C:N ratio of roots, and lower N storage in the central Kansas ecotype relative to the southern Illinois ecotype suggests that introducing ecotypes of A. gerardii from much drier regions into highly mesic prairie would reduce productivity and alter belowground ecosystem processes under a wide range of conditions. PMID- 26594702 TI - Similarity in the difference: changes in community functional features along natural and anthropogenic stress gradients. AB - The effect of stressors on biodiversity can vary in relation to the degree to which biological communities have adapted over evolutionary time. We compared the responses of functional features of stream insect communities along chronic stress gradients with contrasting time persistence. Water salinity and land use intensification were used as examples of natural (long-term persistent) and anthropogenic (short-term persistent) stressors, respectively. A new trait-based approach was applied to quantify functional diversity components and functional redundancy within the same multidimensional space, using metrics at the taxon and community levels. We found similar functional responses along natural and anthropogenic stress gradients. In both cases, the mean taxon functional richness and functional similarity between taxa increased with stress, whereas community functional richness and functional redundancy decreased. Despite the differences in evolutionary persistence, both chronic stressors act as strong nonrandom environmental filters, producing convergent functional responses. These results can improve our ability to predict functional effects of novel stressors at ecoloiical and evolutionary scales. PMID- 26594703 TI - Interspecific competition in phytoplankton drives the availability of essential mineral and biochemical nutrients. AB - The underlying mechanisms and consequences of competition and diversity are central themes in ecology. A higher diversity of primary, producers often results in higher resource use efficiency in aquatic and terrestrial ecosystems. This may result in more food for consumers on one hand, while, on the other hand, it can also result in a decreased food quality for consumers; higher biomass combined with the same availability of the limiting compound directly reduces the dietary proportion of the limiting compound. Here we tested whether and how interspecific competition in phytoplankton communities leads to changes in resource use efficiency and cellular concentrations of nutrients and fatty acids. The measured particulate carbon: phosphorus ratios (C:P) and fatty acid concentrations in the communities were compared to the theoretically expected ratios and concentrations of measurements on simultaneously running monocultures. With interspecific competition, phytoplankton communities had higher concentrations of the monounsaturated fatty acid oleic acid and also much higher concentrations of the ecologically and physiologically relevant long-chain polyunsaturated fatty acid eicosapentaenoic acid than expected concentrations based on monocultures. Such higher availability of essential fatty acids may contribute to the positive relationship between phytoplankton diversity and zooplankton growth, and may compensate limitations by mineral nutrients in higher trophic levels. PMID- 26594704 TI - Net primary production of a temperate deciduous forest exhibits a threshold response to increasing disturbance severity. AB - The global carbon (C) balance is vulnerable to disturbances that alter terrestrial C storage. Disturbances to forests occur along a continuum of severity, from low-intensity disturbance causing the mortality or defoliation of only a subset of trees to severe stand- replacing disturbance that kills all trees; yet considerable uncertainty remains in how forest production changes across gradients of disturbance intensity. We used a gradient of tree mortality in an upper Great Lakes forest ecosystem to: (1) quantify how aboveground wood net primary production (ANPP,) responds to a range of disturbance severities; and (2) identify mechanisms supporting ANPPw resistance or resilience following moderate disturbance. We found that ANPPw declined nonlinearly with rising disturbance severity, remaining stable until >60% of the total tree basal area senesced. As upper canopy openness increased from disturbance, greater light availability to the subcanopy enhanced the leaf-level photosynthesis and growth of this formerly light-limited canopy stratum, compensating for upper canopy production losses and a reduction in total leaf area index (LAI). As a result, whole-ecosystem production efficiency (ANPPw/LAI) increased with rising disturbance severity, except in plots beyond the disturbance threshold. These findings provide a mechanistic explanation for a nonlinear relationship between ANPPw, and disturbance severity, in which the physiological and growth enhancement of undisturbed vegetation is proportional to the level of disturbance until a threshold is exceeded. Our results have important ecological and management implications, demonstrating that in some ecosystems moderate levels of disturbance minimally alter forest production. PMID- 26594705 TI - Soil nitrogen affects phosphorus recycling: foliar resorption and plant-soil feedbacks in a northern hardwood forest. AB - Previous studies have attempted to link foliar resorption of nitrogen and phosphorus to their. respective availabilities in soil, with mixed results. Based on resource optimization theory, we hypothesized that the foliar resorption of one element could be driven by the availability of another element. We tested various measures of soil N and P as predictors of N and P resorption in six tree species in 18 plots across six stands at the Bartlett Experimental Forest, New Hampshire, USA. Phosphorus resorption efficiency (P < 0.01) and proficiency (P = 0.01) increased with soil N content. to 30 cm depth, suggesting that trees conserve P based on the availability of soil N. Phosphorus resorption also increased with soil P content, which is difficult to explain basdd on single element limitation, butfollows from the correlation between soil N and soil P. The expected single-element relationships were evident only in the 0 horizon: P resorption was high where resin-available P was low in the Oe (P < 0.01 for efficiency, P < 0.001 for proficiency) and N resorption was high where potential N mineralization in the Oa was low (P < 0.01 for efficiency and 0.11 for proficiency). Since leaf litter is a principal source of N and P to the 0 horizon, low nutrient availability there could be a result rather than a cause of high resorption. The striking effect of soil N content on foliar P resorption is the first evidence of multiple-element control on nutrient resorption to be reported from an unmanipulated ecosystem. PMID- 26594706 TI - Maternal investment mediates offspring life history variation with context dependent fitness consequences. AB - Maternal effects, such as per capita maternal investment, often interact with environmental conditions to strongly affect traits expressed early in ontogeny. However, their impact on adult life history traits and fitness components is relatively unknown. Theory predicts that lower per capita maternal investment will have strong fitness costs when the offspring develop in unfavorable conditions, yet few studies have experimentally manipulated per capita maternal investment and followed offspring through adulthood. We used a surgical embryonic yolk removal technique to investigate how per capita maternal investment interacted with an important ecological factor, larval density, to mediate offspring life history traits through reproductive maturity in an amphibian, Ambystoma talpoideum. We predicted that increased larval density would reinforce the life history variation induced by differences in per capita investment (i.e., Controls vs. Reduced Yolk), with Reduced larvae ultimately expressing traits associated with lower fitness than Controls when raised at high densities. We found that Reduced individuals were initially smaller and more developed, caught up in size to Controls within the first month of the larval stage, but were smaller at the end of the larval stage in low densities. Reduced individuals also were more likely to undergo metamorphosis at high densities and mature 'females invested in more eggs for their body sizes than Controls. Together, our results do not support our hypothesis, but instead indicate that Reduced individuals express traits associated with higher fitness when they develop in high-density environments, but lower fitness in low-density environments. The observed life history and fitness patterns are consistent with the "maternal match" hypothesis, which predicts that when the maternal environment (e.g., high density) results in phenotypic variation that is transmitted to the offspring (e.g., reduced per capita yolk investment), and offspring face that same environment (e.g., high larval density), the fitness of both mother and offspring is maximized. PMID- 26594707 TI - The ghosts of trees past: savanna trees create enduring legacies in plant species composition. AB - Isolated trees in savannas worldwide are known to modify their local environment and interact directly with neighboring plants. Less is known about how related tree species differ in their impacts on surrounding communities, how the effects of trees vary between years, and how composition might change following loss of the tree. To address these knowledge gaps, we explored the following questions: How do savanna trees influence the surrounding composition of herbaceous plants? Is the influence of trees consistent across different species and years? How does this change following the death of the tree? We surveyed herbaceous species composition and environmental attributes surrounding living and dead evergreen and deciduous Quercus trees in California (USA) savannas across several years that differed in their total precipitation. Oak trees of all species created distinct, homogenous understory communities dominated by exotic grasses across several sites. The composition of the low-diversity understory communities showed less interannual variation than open grassland, despite a two-fold difference in precipitation between the driest and wettest year. Vegetation composition was correlated with variation in soil properties, which were strongly affected by trees. Oaks also influenced the communities beyond the edge of the crown, but this depended on site and oak species. Low-diversity understory communities persisted up to 43 years following the death of the tree. A gradual decline in the effect of trees on the physical, environment following death did not result in vegetation becoming more similar to open grassland over time. The presence of long-lasting legacies of past tree crowns highlights the difficulty of assigning control of the current distribution of herbaceous species in grassland to their contemporary environment. PMID- 26594708 TI - Plant-soil feedbacks shift from negative to positive with decreasing light in forest understory species. AB - Net pairwise plant-soil feedbacks (PSF) may be an important factor structuring plant communities, yet the influence of abiotic context on PSF is not yet understood. Abiotic factors such as light availability can alter plant-soil interactions, potentially resulting in strong context dependence of PSF. Here, we present an experiment in which we measured whole-soil net pairwise feedbacks amongst six common forest understory species across a gradient of light availability. Light treatments were imposed throughout both phases (the conditioning phase and the response phase) of the feedback experiment. Across the plant community, PSF shifted from negative at high light availability to weakly positive under low light (P = 0.0 13). Differences in the biomass of plants during the conditioning phase did not fully explain light-imposed differences in feedbacks, indicating that reduced light availability qualitatively changes the nature of PSF rather than simply weakening feedbacks by reducing plant growth. Results indicate that abiotic context can fundamentally alter the role of PSF in structuring plant communities. PMID- 26594709 TI - Prey size structure diminishes cascading effects by increasing interference competition and predation among prey. AB - The size of an organism can change by orders of magnitude during its lifespan. Size can determine whether an individual consumes, is consumed, competes, or avoids individuals of the same or different species. Two complementary mesocosm experiments with a tri-trophic food chain (top predator, toadfish, Opsanus tau; intermediate prey, mud crab, family Xanthidae; basal resource, oyster, Crassostrea virginica) were conducted to measure how the size of both the top predator and the intermediate prey affects consumptive and behavioral interactions in trophic cascades. In the first experiment, I systematically varied the sizes of predators and prey, respectively. The amount of crab biomass consumed was dependent on crab size and not toadfish size, but the effect of crab size did not cascade to alter oyster survival. Increased oyster survival from crab interference competition in the absence of toadfish was similar to oyster survival,from predator-avoidance behavior in the presence of a toadfish. When all crab size classes were present, crab mortality was similar in the presence and absence of toadfish, highlighting the importance of intraguild predation in food web dynamics. The second experiment separated crab mortality by other crabs from crab mortality by predatory toadfish and found that crab mortality generally switched from intra- to interguild predation when a toadfish was present. In addition, field surveys indicated mud crab abundance and size was primarily influenced by mud crab recruitment, but not by toadfish abundance, which supports our experimental results that interactions among mud crabs have similar effects to predator-prey interactions. These findings indicate that changes in size or abundance of intermediate prey may be comparable to changes in top predator abundance in terms of trophic interactions and their transmission to lower levels, which suggests that certain types of relatively simple food chains can be resilient to the loss of higher trophic levels. PMID- 26594710 TI - Invasive toads shift predator-prey densities in animal communities by removing top predators. AB - Although invasive species can have substantial impacts on animal communities, cases of invasive species facilitating native species by removing their predators have rarely been demonstrated across vertebrate trophic linkages. The predictable spread of the invasive cane toad (Rhinella marina), however, offered a unique opportunity to quantify cascading effects. In northern Australia, three species of predatory monitor lizards suffered severe population declines due to toad induced lethal toxic ingestion (yellow-spotted monitor (Varanus panoptes), Mertens' water monitor (V. mertensi), Mitchell's water monitor (V. mitchelli). We, thus, predicted subsequent increases in the abundance and recruitment of prey species due to the reduction of those predators. Toad-induced population-level declines in the water monitor species approached 50% over a five-year period spanning the toad invasion, apparently causing fledging success of the Crimson Finch (Neochmia.phaeton) to increase from 55% to 81%. The consensus of our original and published long-term data is that invasive cane toads are causing predators to lose a foothold on top-down regulation of their prey, triggering shifts in the relative densities of predator and prey in the Australian tropical savannah ecosystem. PMID- 26594711 TI - Protected areas mitigate diseases of reef-building corals by reducing damage from fishing. AB - Parks and protected areas have been instrumental in reducing anthropogenic sources of damage in terrestrial and aquatic environments. Pathogen invasion often succeeds physical wounding and injury, yet links between the reduction of damage and the moderation of disease have not been assessed. Here, we examine the utility of no-take marine reserves as tools for mitigating diseases that affect reef-building corals. We found that sites located within reserves had fourfold reductions in coral disease prevalence compared to non-reserve sites (80466 corals surveyed). Of 31 explanatory variables assessed, coral damage and the abundance of derelict fishing line best explained differences in disease assemblages between reserves and non-reserves. Unexpectedly, we recorded significantly higher levels of disease, coral damage, and derelict fishing line in non-reserves with fishing gear restrictions than in those without gear restrictions. Fishers targeting stocks perceived to be less depleted, coupled with enhanced site access from immediately adjacent boat moorings, may explain these unexpected patterns. Significant correlations between the distance from mooring sites and prevalence values for a ciliate disease known to infest wounded tissue (r = -0.65), coral damage (r = -0.64), and the abundance of derelict fishing line (r = -0.85) corroborate this interpretation. This is the first study to link disease with recreational use intensity in a park, emphasizing the need to evaluate the placement of closures and their direct relationship to ecosystem health. Since corals are modular, ecological processes that govern reproductive and competitive fitness are frequently related to colony surface area therefore, even low levels of cumulative tissue loss from progressing diseases pose significant threats to reef coral persistence. Disease mitigation through reductions in physical injury in areas where human activities are concentrated is another mechanism by which protected areas may improve ecosystem resilience in a changing climate. PMID- 26594712 TI - Cooperative Networks: Altruism, Group Solidarity, Reciprocity, and Sanctioning in Ugandan Producer Organizations. AB - Repeated interaction and social networks are commonly considered viable solutions to collective action problems. This article identifies and systematically measures four general mechanisms--that is, generalized altruism, group solidarity, reciprocity, and the threat of sanctioning--and tests which of them brings about cooperation in the context of Ugandan producer organizations. Using an innovative methodological framework that combines "lab-in-the-field" experiments with survey interviews and complete social networks data, the article goes beyond the assessment of a relationship between social networks and collective outcomes to study the mechanisms that favor cooperative behavior. The article first establishes a positive relationship between position in the network structure and propensity to cooperate in the producer organization and then uses farmers' behavior in dictator and public goods games to test different mechanisms that may account for such a relationship. Results show that cooperation is induced by patterns of reciprocity that emerge through repeated interaction rather than other-regarding preferences like altruism or group solidarity. PMID- 26594713 TI - The Cost of Color: Skin Color, Discrimination, and Health among African Americans. AB - In this study, the author uses a nationally representative survey to examine the relationship(s) between skin tone, discrimination, and health among African Americans. He finds that skin tone is a significant predictor of multiple forms of perceived discrimination (including perceived skin color discrimination from whites and blacks) and, in turn, these forms of perceived discrimination are significant predictors of key health outcomes, such as depression and self-rated mental and physical health. Intraracial health differences related to skin tone (and discrimination) often rival or even exceed disparities between blacks and whites as a whole. The author also finds that self-reported skin tone, conceptualized as a form of embodied social status, is a stronger predictor of perceived discrimination than interviewer-rated skin tone. He discusses the implications of these findings for the study of ethnoracial health disparities and highlights the utility of cognitive and multidimensional approaches to ethnoracial and social inequality. PMID- 26594714 TI - From Narcissism to Face Work: Two Views on the Self in Social Interaction. AB - Through the analysis of conversational interaction and clinical notes, this article develops conceptual linkages between the Goffmanian concept of face and the psychoanalytic and psychiatric understandings of narcissism. Self-cathexis- the investment of libidinal emotion to the image of self--is a key issue both for Goffman and in psychoanalytic studies of narcissism. For Goffman, the self and its cathexis are inherently fragile interactional achievements, whereas for psychoanalysts such as Kernberg and Kohut, they are relatively stable intrapsychic structures. An application of Goffman's theory to narcissistic personality disorders suggests that pathological narcissism involves the isolation of the person's self-image from interactional. practices and a consequent inability to benefit from face work in ordinary social encounters. Clinical experience suggests revisions to the theory of face work: there is a biographical continuity in a person's experience of face, and successful participation in face work is made possible by the psychic capacity of playful orientation to one's own and others' narcissistic illusions. Such playful orientation is manifested through the interactional practices of role distancing. PMID- 26594715 TI - Group Threat and Policy Change: The Spatial Dynamics of Prohibition Politics, 1890-1919. AB - The authors argue that group threat is a key driver of the adoption of new and controversial policies. Conceptualizing threat in spatial terms, they argue that group threat is activated through the joint occurrence of (1) proximity to threatening groups and (2) the population density of threatened groups. By analyzing the adoption of county and state "dry laws" banning alcohol from 1890 to 1919, they first show that prohibition victories were driven by the relative strength of supportive constituencies such as native whites and rural residents, vis-a-vis opponents such as Irish, Italian, or German immigrants or Catholics. Second, they show that threat contributed to prohibition victories: counties bordering large immigrant or urban populations, which did not themselves contain similar populations, were more likely to adopt dry laws. Threat arises primarily from interactions between spatially proximate units at the local level, and therefore higher-level policy change is not reducible to the variables driving local policy. PMID- 26594716 TI - The Making of a Good Woman: Extended Parental Leave Entitlements and Mothers' Work Commitment in Germany. AB - The authors investigate the relationship between family policy and women's attachment to the labor market, focusing specifically on policy feedback on women's subjective work commitment. They utilize a quasi-experimental design to identify normative policy effects from changes in mothers' work commitment in conjunction with two policy changes that significantly extended the length of statutory parental leave entitlements in Germany. Using unique survey data from the German Socio-Economic Panel and difference-in-differences, triple differenced, and instrumental variables estimators for panel data, they obtain consistent empirical evidence that increasing generosity of leave entitlements led to a decline in mothers' work commitment in both East and West Germany. They also probe potential mediating mechanisms and find strong evidence for role exposure and norm setting effects. Finally, they demonstrate that policy-induced shifts in mothers' preferences have contributed to. retarding women's labor force participation after childbirth in Germany, especially as far as mothers' return to full-time employment is concerned. PMID- 26594717 TI - Representing Human Rights Violations in Darfur: Global Justice, National Distinctions. AB - This article examines how international judicial interventions in mass atrocity influence representations of violence. It relies on content analysis of 3,387 articles and opinion pieces in leading newspapers from eight Western countries, compiled into the Darfur Media Dataset, as well as in-depth interviews to assess how media frame violence in the Darfur region of Sudan. Overall, it finds that UN Security Council and International Criminal Court interventions increase representations of mass violence as crime in all countries under investigation, although each country applies the crime frame at a different level. Reporting suffering and categorizing the violence as genocide also varies across countries. Comparative case studies identify country specific structural and cultural forces that appear to account for these differences. Multilevel multivariate analyses confirm the explanatory power of cultural sensitivities and policy practices, while individual-and organization-level factors, such as reporters' gender and the newspapers' ideological orientation, also have explanatory power. PMID- 26594718 TI - SWITCHING EHRs? HOW TO AVOID TAKING A HIT. PMID- 26594719 TI - Lab transitions: The bumpy road to relocation. PMID- 26594720 TI - Neurovascular Units: A New Cost Effective Model? PMID- 26594721 TI - WBRT plus SRS for Tumors in Eloquent Locations: But Why Give the WBRT? PMID- 26594722 TI - Subclinical ventricular dysfunction detected by speckle-tracking two years after use of anthracycline--reply. PMID- 26594723 TI - The imaging mirage. PMID- 26594724 TI - Naltrexone + bupropion (Mysimba). Too risky for only modest weight loss. AB - Weight loss and its long-term maintenance are mainly based on dietary measures and regular physical activity. There are currently no weight-loss medications with a favourable harm-benefit balance. Bupropion is chemically related to certain amphetamines, while naltrexone is an opioid receptor antagonist. A fixed dose combination of these two drugs has received marketing authorisation in the European Union for obese patients and for over-weight patients with other cardiovascular risk factors. In five placebo-controlled, randomised, double-blind trials, the patients, weighing on average between 100 kg and 105 kg (average body mass index 36 kg/m2), the naltrexone + bupropion combination was associated with an average weight loss of a few additional kilograms compared with placebo, after 6 months or one year of treatment. There are no post-trial follow-up data to show whether or not the patients regained their lost weight after treatment discontinuation. One trial including more than 8900 patients examined the effect of the naltrexone + bupropion combination on the freauency of maior cardiovascular events, but poor handling of an interim analysis undermined the validity of the final results. The known adverse effects of bupropion consist of potentially severe neuropsychiatric disorders such as aggressiveness, depression and suicidal ideation, and also allergic reactions, including Stevens-Johnson syndrome. Misuse and excessive consumption have been reported. In trials in obese or overweight patients, the naltrexone + bupropion combination caused sometimes severe neuropsychiatric disorders, including seizures, cognitive impairment, dizziness, anxiety, sleep disorders and psychotic symptoms. In clinical trials, the combination led to an increase in blood pressure compared with placebo, and also an excess of cardiac arrhythmias. About half of patients who took naltrexone + bupropion experienced gastrointestinal disorders such as nausea, vomiting and constipation. The naltrexone + bupropion combination is subject to many pharmacokinetic interactions, as well as pharmacodynamic interactions leading to additive convulsive or hypertensive effects, or undermining the action of antihypertensive drugs. A teratogenic effect of bupropion cannot be ruled out. In practice, given the limited effect of the naltrexone + bupropion combination on weight loss (a few kilograms), along with the lack of evidence supporting a persistent benefit or a decrease in the clinical complications of obesity, there is no reason to expose patients to its many potentially severe adverse effects. PMID- 26594725 TI - Regorafenib (Stivarga) and gastrointestinal stromal tumours after treatment failure. Radiological improvement but major adverse effects. AB - Regorafenib had no impact on overall survival in a placebo-controlled trial in 199 patients, but adverse effects were frequent and serious. Symptomatic care is a more reasonable choice. PMID- 26594727 TI - Treatment of childhood cancers: late effects. AB - In France, about 1 in 1000 young adults aged 20 to 30 years is a survivor of childhood cancer and is thus faced with late effects of their cancer and its treatment (radiation therapy and/or chemotherapy). What are the late effects of childhood cancer therapy? A systematic review by the Scottish Intercollegiate Guidelines Network (SIGN) provides useful information based on European and North American data. Cancer treatments can have many long-term consequences that depend on the drugs and doses used, radiation therapy protocols and irradiated organs, and age at the time of treatment. Cytotoxic drugs and radiation can both cause infertility. Abdominopelvic radiation therapy in girls has been linked to an increased risk of premature delivery and other complications of pregnancy. No increase in birth defects has been reported among children born to childhood cancer survivors. Anthracyclines and radiation therapy can cause cardiomyopathy. Neck irradiation can lead to thyroid disorders, and cranial irradiation to growth retardation. Chemotherapy can cause osteonecrosis and loss of bone density, but without an increased risk of fracture. The risk of cognitive impairment and structural abnormalities of the brain is higher when the child is younger or receives a high cumulative dose of cranial irradiation or total irradiation dosage. Some cytotoxic drugs can damage the kidneys. Cranial radiation therapy can cause long-term neuroendocrine disorders and growth disorders, especially when the dose exceeds 18 Gy. Cytotoxic drugs (alkylating agents, etoposide, etc.) and radiation therapy can cause second cancers of a different histological type. One analysis of second cancers showed a median time to onset of 7 years for solid tumours and 2.5 years for lymphoma and leukaemia. Better knowledge of the late effects of childhood cancer therapy can help orient the choice of treatment towards less harmful options or, if necessary, implement measures aimed at preventing late adverse effects. Childhood cancer survivors must be monitored into adulthood in order to detect such effects. PMID- 26594728 TI - HPV vaccines and pregnancy. AB - Occasionally, pregnant women are inadvertently vaccinated against human papillomavirus. Data are available able on pregnancy outcomes in over a thousand women exposed to the HPV 6/11/16/18 vaccine and several hundred exposed to the HPV 16/18 vaccine. No notable risks were identified. No specific safety signals have been identified with the aluminium- and lipid-containing adjuvant AS04 included in the HPV 16/18 vaccine, nor with the aluminium-based adjuvant used in the HPV 6/11/16/18 vaccine. PMID- 26594729 TI - High-strength venlafaxine: best avoided. PMID- 26594730 TI - Hypothyroidism in adults. Levothyroxine if warranted by clinical and laboratory findings, not for simple TSH elevation. AB - Hypothyroidism is a common disorder due to inadequate thyroid hormone secretion. When a patient has signs and symptoms suggestive of hypothyroidism, how is it determined whether thyroid hormone replacement therapy will have a favourable harm-benefit balance? How should treatment be managed? To answer these questions, we conducted a review of the literature using the standard Prescrire methodology. The symptoms of hypothyroidism are due to slow metabolism (constipation, fatigue, sensitivity to cold, weight gain, etc.) and to polysaccharide accumulation in certain tissues, leading to hoarseness, eyelid swelling, etc. A blood TSH concentration of less than 4 or 5 mlU/L rules out peripheral hypothyroidism. TSH levels increase with age. Between 30% and 60% of high TSH levels are not confirmed on a second blood test. In overt hypothyroidism, the TSH level is high and the free T4 (thyroxine) level is low. Most of these patients are symptomatic. So-called subclinical hypothyroidism, which is rarely symptomatic, is characterised by high blood TSH levels and normal free T4 levels. The natural history of hypothyroidism depends on its cause. In chronic autoimmune thyroiditis, the most common form seen in rich countries, hypothyroidism generally worsens over time. However, other situations can lead to transient hypothyroidism that may last several weeks or months. Subclinical hypothyroidism, as the name implies, is usually asymptomatic. The risk of progression to overt hypothyroidism is about 3% to 4% per year overall but increases with the initial TSH level. Treatment guidelines are mainly based on physiological and pharmacological considerations and generally recommend levothyroxine therapy. The adverse effects of levothyroxine are signs of thyrotoxicosis in case of overdose (tachycardia, tremor, sweating, etc.). Even a slight overdose carries a risk of osteoporotic fractures and atrial fibrillation, especially in the elderly. In young adults, levothyroxine is usually started at a dose of about 1.5 microg/kg per day, taken on an empty stomach. Elderly patients and those with coronary artery disease should start at a lower dose: 12.5 to 50 microg per day. Treatment monitoring is based mainly on blood TSH assay. Dose adjustment should only be considered after 6 to 12 weeks, given the long half-life of levothyroxine. Certain drugs, such as iron and calcium, reduce the gastrointestinal absorption of levothyroxine. Enzyme inducers reduce its efficacy. In 2015, there is no robust evidence that levothyroxine therapy has any tangible benefit in patients with subclinical hypothyroidism. Some practice guidelines recommend treatment when the TSH level is above 10 mIU/L, or sometimes trial treatment for a few months for patients with symptoms suggestive of hypothyroidism. In practice, replacement therapy is needed for patients with overt hypothyroidism and a blood TSH concentration above 10 mIU/L. The main challenge is to recognise transient hypothyroidism, which does not require life-long treatment. When the TSH is only slightly elevated, there is a risk of attributing non-specific symptoms to an abnormal laboratory result and prescribing unnecessary treatment. Watchful waiting is an alternative to routine levothyroxine prescription in case of TSH elevation. PMID- 26594731 TI - Lyme disease. Recognising and treating erythema migrans. AB - Lyme disease is a tick-borne bacterial infection caused by Borrelia spirochetes. The first stage of infection involves a characteristic skin lesion, erythema migrans. Erythema migrans is a ring-shaped skin lesion, centred on the bite, which expands outwards. It usually appears within two weeks after a bite from an infected tick. If left untreated, the infection sometimes extends or progresses over a period of months or years, leading to potentially severe neurological, articular, cutaneous and cardiac complications. How is erythema migrans associated with Lyme disease recognised and managed? We conducted a systematic review of the literature using the standard Prescrire methodology. This review does not address the complications of Lyme disease. Diagnosis of erythema migrans is based on clinical findings in a patient with a possible or confirmed recent tick bite. Serological tests are not useful at this stage of the infection. Antibiotics shown to be active in vitro also proved effective in non-comparative trials. In randomised trials, amoxicillin, doxycycline, cefuroxime and ceftriaxone had similar efficacy, clearing signs and symptoms in about 90% of patients, with a relapse rate of less than 5% at 6 months. Azithromycin, clarithromycin, erythromycin, three macrolide antibiotics, appear to have lower efficacy. Doxycycline should not be used to treat pregnant or breast-feeding women, or children under 8 years old, due to a risk of tooth and bone disorders in children. In practice, a diagnosis of erythema migrans should be borne in mind when a patient presents with recent history of a possible or confirmed tick bite and skin lesions suggestive of erythema migrans. Oral amoxicillin or doxycycline will prevent progression of the infection to the potentially severe, later stages of Lyme disease. Routine antibiotic prophylaxis is not justified after a tick bite, even in an endemic area, as the risk of infection is low. It is best to monitor the skin around the bite and to prescribe an antibiotic only if erythema migrans develops, thus avoiding unnecessary treatment and adverse effects. PMID- 26594732 TI - Tick bites: monitor closely, without routine antibiotic prophylaxis . PMID- 26594733 TI - Exorbitant drug prices harm research. PMID- 26594734 TI - Editorial: Investing in the Future Through Fostering Synergies Between Occupational Science and Occupational Therapy. PMID- 26594735 TI - "What Do You Think We Should Do?": Relationship and Reflexivity in Participant Observation. AB - This article uses three concepts as a framework by which to examine how the interrelational elements of ethnographic approaches to qualitative inquiry reflect dimensions of therapeutic engagement. Participant observation, reflexivity, and context are all widely and routinely included within research methods; however, they are less frequently attended to directly in their experiential capacity through the lens of the researcher, clinician turned investigator. A unique study design will be profiled to reflect the complicated juxtaposition between methods, questions, sample population, time, space, and identity. Studying occupational therapy students traveling abroad for a short term immersion experience, this narrative study called on a necessary and attentive awareness of locality as the researcher traveled with the group. Conducting ethnographic research where the researcher's therapeutic skills aided and constrained relationships resulted in rich, guarded, and relevant insights that parallel the therapeutic use of self in occupational therapy practice. PMID- 26594736 TI - Extending Beyond Qualitative Interviewing to Illuminate the Tacit Nature of Everyday Occupation: Occupational Mapping and Participatory Occupation Methods. AB - The study of human occupation requires a variety of methods to fully elucidate its complex, multifaceted nature. Although qualitative approaches have commonly been used within occupational therapy and occupational science, we contend that such qualitative research must extend beyond the sole use of interviews. Drawing on qualitative methodological literature, we discuss the limits of interview methods and outline other methods, particularly visual methods, as productive means to enhance qualitative research. We then provide an overview of our critical ethnographic study that used narrative, visual, and observational methods to explore the occupational transitions experienced by immigrants to Canada. We describe our use of occupational mapping and participatory occupation methods and the contributions of these combined methods. We conclude that adopting a variety of methods can enable a deeper understanding of the tacit nature of everyday occupation, and is key to advancing knowledge regarding occupation and to informing occupational therapy practice. PMID- 26594737 TI - Mixed-Method Exploration of Social Network Links to Participation. AB - The people who regularly interact with an adolescent form that youth's social network (SN), which may impact participation. We investigated the relationship of SNs to participation using personal network analysis and individual interviews. The sample included 36 youth, aged 11 to 16 years. Nineteen had diagnoses of learning disability, attention disorder, or high-functioning autism, and 17 were typically developing. Network analysis yielded 10 network variables, of which 8 measured network composition and 2 measured network structure, with significant links to at least I measure of participation using the Children's Assessment of Participation and Enjoyment (CAPE). Interviews from youth in the clinical group yielded description of strategies used to negotiate social interactions, as well as processes and reasoning used to remain engaged within SNs. Findings contribute to understanding the ways SNs are linked to youth participation and suggest the potential of SN factors for predicting rehabilitation outcomes. PMID- 26594738 TI - Physically Disabled Adults' Perceptions of Personal Autonomy: Impact on Occupational Engagement. AB - Despite the prominence of the concept of autonomy in the UN Convention on the Rights of Persons With Disabilities and within disability theory, the relevance of autonomy to occupational engagement is unclear. Using a qualitative, narrative approach, eight adults with significant physical disabilities engaged in iterative interviews exploring their life history and perception of autonomy in daily life. Interviews were transcribed verbatim and themed. Key themes that emerged were that participants valued autonomy differently; their perception of their own personal autonomy influenced both occupational choices and the meaning derived from occupational engagement. While some participants actively sought occupations in which they could make decisions, others preferred more supportive environments, yet all participants avoided situations in which their autonomy was undermined. Awareness of an individual's values regarding autonomy could assist occupational therapists to both select appropriate occupations for intervention and discuss the meaning derived from occupations, thereby enhancing client centered practice. PMID- 26594739 TI - The Distinctive Features of a Feasibility Study: Objectives and Guiding Questions. AB - In this article, we highlight the distinctive features of a feasibility study, identify the main objectives and guiding questions of a feasibility study, and illustrate the use of these objectives. We synthesized the research methods literature related to feasibility studies to identify five overarching objectives of feasibility studies that focus on social and behavioral interventions. Feasibility studies are designed to answer the overarching question: Can it work? The main objectives of feasibility include the assessment of recruitment capability and resulting sample characteristics, data collection procedures and outcome measures, acceptability of the intervention and study procedures, resources and ability to manage and implement the study and intervention, and preliminary evaluation of participant responses to the intervention. For each objective, we identified follow-up questions designed to assist the researchers to understand barriers to the ultimate success of the research. PMID- 26594740 TI - Toward Early Identification of Sensory Over-Responsivity (SOR): A Construct for Predicting Difficulties With Sleep and Feeding in Infants. AB - Sensory over-responsivity (SOR) is a type of sensory modulation disorder in which heightened sensitivity to non-noxious sensations interrupts daily life. In this preliminary study within a larger investigation, we used infants with sleep/feeding difficulties as a proxy for later development of SOR. We tested evidence for construct validity and internal reliability of preand perinatal factors that, together, could predict infant sleep/feeding difficulties. We obtained retrospective data on 360 mother-infant dyads on 38 pre- and perinatal variables and linked the data with infant referral for sleep/feeding difficulties. We analyzed the data with Rasch analysis to examine evidence for a unidimensional construct. Our results show good evidence for a construct comprising 18 of the 38 pre- and perinatal variables examined. This construct may represent a step toward early identification of SOR and provide therapists with evidence to support the use of pre- and perinatal information as predictors of infant sleep/feeding difficulties. PMID- 26594742 TI - Alarm Pheromone Activity of Nymph-specific Geraniol in Chrysanthemum Lace Bug Corythucha marmorata against Adults and Nymphs. AB - The exotic insect pest Corythucha marmorata (Uhler) is increasingly spreading in Japan using the weed Solidago canadensis L. as a major host plant. The nymphs form colonies on the backs of leaves where they crowd together; however, aggregation does not occur in the adults. When an individual nymph is crushed using a needle tip and further the needle tip covered with the nymph's bodily fluids is moved slowly toward the center of the crowd, the surrounding nymphs display an escape behavior and their aggregation is disrupted. We detected geraniol as a nymph-specific volatile component. Bioassay results indicated that geraniol was effective as an alarm pheromone on second to fifth instar nymphs. Furthermore, we found that male and female adults responded sensitively to the alarm pheromone produced by nymphs. These results suggest that although the adult insects do not secrete geraniol, they can detect it produced by nymphs, thereby retaining the ability to escape from danger while suppressing the cost of geraniol production. The present study is the first to demonstrate that an alarm pheromone secreted by nymphs is also effective in adults among Tingidae. PMID- 26594741 TI - Developing a Manualized Occupational Therapy Diabetes Management Intervention: Resilient, Empowered, Active Living With Diabetes. AB - This article reports on the development of a manualized occupational therapy intervention for diabetes management. An initial theoretical framework and core content areas for a Stage I intervention manual were developed based on an in depth needs assessment and review of existing literature. After evaluation by a panel of experts and completion of a feasibility study, the intervention was revised into a Stage 2 manual in preparation for a randomized study evaluating the intervention's efficacy. In developing the initial manual, we delineated core theoretical principles to allow for flexible application and tailoring of the intervention's content areas. Expert panel feedback and feasibility study results led to changes to the intervention structure and content as we developed the Stage 2 manual. Through describing this process, we illustrate the dynamic evolution of intervention manuals, which undergo revisions due to both theoretical and practical considerations at each stage of the research-to clinical practice pipeline. PMID- 26594743 TI - One New Conjugate of a Secoiridoid Glucoside with a Sesquiterpene Glucoside from the Flower Buds of Lonicera japonica. AB - Secosesquside (1), a new secoiridoid glucoside-sesquiterpene conjugate, together with three known secoiridoid derivatives, were isolated from flower buds of Lonicerajaponica. The isolated compounds were elucidated by extensive spectroscopic analyses, especially 2D NMR experiments. The anti-inflammatory activities of the new compound were also evaluated by enzyme-linked immunosorbent assay. PMID- 26594744 TI - Chemical Originalities of New Caledonian Liverworts from Lejeuneaceae Family. AB - Lejeuneaceae is the largest family of liverworts in the world. Through the analyses of the chemical composition of some species, it has been demonstrated that they may represent an important source of original and bioactive molecules. None of the 146 species that occur in New Caledonia has been studied yet. Here we describe the terpenoid content of twelve New Caledonian species, including two endemics. We describe here, for the first time, the presence of frullanolide in the Lejeuneaceae, occurring as a major compound in the extract from Colura leratii, and a rarely observed santalene derivative from Acrolejeunea securifolia subsp. caledonica. These analyses also highlight species that probably contain original structures, such as Schiffneriolejeunea tumida var. hasskarliana, Cheilolejeunea spp and Thysananthus retusus. The results obtained here also confirm several previous hypotheses about the chemosystematics of the Lejeuneaceae. For example, lepidozene can be considered as a chemosystematic marker of the Ptychantoideae subfamily, considering its abundance in many Ptychantoideae. On the other hand, some results are different from those described previously. For example, we detected no fusicoccane derivatives in any of the Lejeuneaceae species analyzed here, whereas they were previously described as a marker of the Ptychantoideae. This suggests that the available data toward the chemistry of the Lejeuneaceae are not sufficient to be confident with some of the previous chemosystematic conclusions. PMID- 26594745 TI - Antiproliferative Diterpenes from a Malleastrum sp. from the Madagascar dry forest. AB - An ethanol extract of leaves of the plant species Malleastrum sp. collected in northern Madagascar afforded the new clerodane diterpene 18-oxo-cleroda-3,13-dien 16,15-olide (1), together with the three known clerodane diterpenes 16,18 dihydroxykolavenic acid lactone (2), solidagolactone (3) and (-)-kolavenol (4), and the known labdane diterpene 3-oxo-ent-Iabda-8(17),13-dien-15,16-olide (5). Compounds 1, 3, and 4 showed moderate antiproliferative activities against the A2780 ovarian cancer cell line, with the IC50 values of 3.01 +/- 0.8, 7.84 +/- 0.2, and 17.9 +/- 3 uM, respectively. The structure elucidations of all compounds were carried out based on analysis of NMR and mass spectroscopic data. The relative stereochemistry of compound 1 was determined by NOESY NMR spectrum. PMID- 26594746 TI - Bio-guided Isolation of a New Sesterterpene from Serjania goniocarpa. AB - Serjania goniocarpa is a plant used in Mayan traditional medicine as a remedy for the treatment of cancer-like symptoms. Bio-guided fractionation of the methanol extract of the leaves led to the isolation of an alpha- and beta-amyrin mixture, palmitic acid, phytol and the new sesterterpene goniocarpic acid whose structure was elucidated by IR, GC-MS, and NMR spectroscopic analyses. Goniocarpic acid exhibited cytotoxic and antiproliferative activity against several cancer cell lines. PMID- 26594747 TI - Inhibitory Effects of seco-Triterpenoids from Acanthopanax sessiliflorus Fruits on HUVEC Invasion and ACE Activity. AB - This study was conducted to investigate the effects of the crude extract from Acanthopanax sessiliflorus fruits and the isolated seco-triterpenoids from the crude extract on blood flow in human umbilical vein endothelial cell (HUVEC) invasion assay and angiotensin converting enzyme (ACE) inhibitory activity assay. On the basis of DMSO, the extent of HUVECs' invasion was remarkably decreased with crude extract concentrations of 400 and 1000 pg/mL. Additionally, the extent of the HUVEC invasion inhibitory effect in 400 and 1000 ug/mL of acanthosessilioside F were 55.8% and 72.4%, respectively. In addition, the maximum extent of the HUVEC invasion inhibitory effect of 22-alpha hydroxychiisanoside was 88.9%. The IC50 value of the inhibitory effect on ACE activity in the crude extract was 4 ug/mL. The isolated seco-triterpenoids, 22alpha-hydroxychiisanogenin, 3,4-seco-lupan-20(30)-en-3,28-dioic acid, (lR)-1,4 epoxy-11alpha,22alpha-hydroxy-3,4-seco-lupan-20(30)-en-3,28-dioicacid, (+) divaroside, and chiisanosidehad showed very high inhibitory effects on ACE activity, ranging from 1.8 to 2.9 ug/mL, which is much higher than the 150.0 ug/mL effect of aspirin. These results suggest that the crude extract from Acanthopanax sessiliflorus fruits and the isolated seco-triterpenoids from the crude extract enhance the blood flow effect by decreasing ACE activity. PMID- 26594748 TI - A New Cucurbitane Glycoside from Siraitia grosvenorii. AB - A systematic phytochemical study of the commercial extract of Luo Han Guo (Siraitia grosvenorii) resulted in the isolation of an additional minor new cucurbitane glycoside, mogroside V Al (1). The structure of the new compound was characterized on the basis of 1D (1H and 13C NMR) and 2D (COSY, HMQC, HMBC and NOESY) NMR and high resolution mass spectral (HRMS) data, as well as hydrolysis studies. PMID- 26594749 TI - Triterpenoid Saponins from Clematis graveolens and Evaluation of their Insecticidal Activities. AB - A new hederagenin based triterpenoid saponin, clematograveolenoside A (1), along with three known saponins, tomentoside A (2), huzhangoside D (3) and clematoside S (4), were isolated from the roots and rhizomes of Clematis graveolens. The structure of new compound was elucidated on the basis of detailed analysis of chemical and spectroscopic data including 1D- and 2D NMR spectra. Compound 2 was found the most effective against aphid (Aphis craccivora) with an LC50 of 1.2 and 0.5 mg/mL after treatment for 72 and 96 h, respectively and was followed by compound 4 (LC50 = 2.3 and 1.9 mg/mL) and 1 (LC50 = 3.2 and 2.6 mg/mL). In case of termite (Coptotermis homii), compound 1 was found more toxic with an LC50 of 0.1 mg/L after 24 h of treatment followed by compound 2, 3 and 4 (LC50 = 0.1, 0.2 and 0.2 mg/mL, respectively). PMID- 26594750 TI - Rapid Determination of alpha-Hederin and Hederacoside C in Extracts of Hedera helix Leaves Available in the Czech Republic and Poland. AB - Leaf extracts of Hedera helix L. are widely used in the treatment of upper respiratory diseases. The saponins a-hederin and hederacoside C are considered to be the main compounds responsible for the biological activity. a-Hederin and hederacoside C were determined in H. helix leaf extracts using a fast, simple and validated HPLC method. An XTerra MS C18 column and mobile phase composed of 10 mM ammonium acetate at pH 8.5 (adjusted with triethylamine) and acetonitrile were used for the chromatography at 1.2 mL min(-1). The column was kept at 30 degrees C. Detection was performed at 220 nm. An approach utilizing a basic pH of the aqueous part of the mobile phase enabled analysis in 5 minutes in isocratic mode. The method was validated and used for the quality control of H. helix leaf ethanolic extracts. PMID- 26594751 TI - Antiinflammatory Steroidal Alkaloids from Sarcococca wallichii of Nepalese Origin. AB - Bio-assay guided isolation from the plant Sarcococca wallichii Staph. yielded two new steroidal alkaloids: wallichimine A (1) and wallichimine B (2), and five known ones: sarcodinine (3), N-methylpachysamine A (4), alkaloid C (5), dictyophlebine (6), and sarcorine (7). The structures of the compounds were determined using mass spectrometry and NMR spectroscopy techniques. The immunomodulatory potential of compounds was evaluated on different parameters including production of intracellular reactive oxygen species (ROS), nitric oxide (NO) and on proinflammatory cytokine TNF-alpha. All compounds were found to be potent inhibitors of intracellular ROS produced from isolated neutrophils, except compound 5, which showed a moderate level of inhibition. Compounds 2 and 4 potently inhibited the production of NO (67.9% and 62.5% respectively). Compound 2 showed potent suppression on production of proinflammatory cytokine TNF-alpha (76.7%). Among all the tested compounds the new compound 2 was found to be the most potent immunosuppressive agent. This study shows that steroidal alkaloids could be lead compounds for anti-inflammatory drug discovery. PMID- 26594752 TI - Antifungal and Antibacterial Activity of Extracts and Alkaloids of Selected Amaryllidaceae Species. AB - Alkaloidal extracts of six selected species of Amaryllidaceae were studied with respect to their antibacterial and anti-yeast activity and their alkaloidal fingerprint. Twenty-five alkaloids were determined by GC/MS, and sixteen of them identified from their mass spectra, retention times and retention indexes. In the antimicrobial assay, Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus were used, along with isolates of the human pathogenic yeasts Candida albicans, C. glabrata, C. dubliniensis and Lodderomyces elongiosporus. The six extracts, together with 19 Amaryllidaceae alkaloids isolated in our laboratory, showed almost no inhibitory activity against the bacteria tested. However, promising anti-yeast properties were detected; the most potent activity was shown by lycorine, which inhibited C. dubliniensis with a MIC of 32 ug/mL, C. albicans and L. elongiosporus, both with MICs of 64 ug/mL, followed by caranine inhibiting C. dubliniensis with a MIC of 128 ug/mL. Among the alkaloidal extracts, Narcissus jonquilla cv. Baby Moon showed the most potent anti-yeast activity, with minimal and average MIC values of 128 and 192 ug/mL, respectively, followed by Leucojum aestivum, Narcissus poeticus var. recurvus and N. canaliculatus (average MICs 256, 267 and 299 ug/mL, respectively). The lowest MIC value among extracts was obtained for N. canaliculatus against L. elongiosporus (MIC 64 ug/mL). PMID- 26594753 TI - Anti-malarial Activity of Isoquinoline Alkaloids from the Stem Bark of Actinodaphne macrophylla. AB - Seven isoquinoline alkaloids isolated from the bark of Actinodaphne macrophylla in this study demonstrated in vitro antiplasmodial activities against Plasmodium falciparum 3D7 with IC50 values of 0.08 uM, 0.05 uM, 1.18 uM, 3.11 uM, 0.65 uM, 0.26 uM, and 1.38 uM for cycleanine, 10-demethylxylopinine, reticuline, laurotetanine, bicuculine, alpha-hydrastine and anolobine, respectively, which are comparable with the reference standard, chloroquine. 10-Demethylxylopinine was found to be the most active of these compounds. PMID- 26594754 TI - Effects of Berberine on Adipose Tissues and Kidney Function in 3T3-L1 Cells and Spontaneously Hypertensive Rats. AB - We aimed to investigate the effect of berberine on adipose tissues, as well as its effect on renal injury in 3T3-L1 cells and spontaneously hypertensive rats. 3T3-L1 cells were cultured and treated with berberine (5-20 pM) from days 3 to 8. Berberine added to the cultured medium could significantly down-regulate transcription factors, including CCAAT/enhancer binding protein beta, CCAAT/enhancer binding protein a, and peroxisome pro liferator-activated receptor y, and suppress peroxisome proliferator-activated receptor target genes, such as adipocyte fatty acid binding protein and fatty acid synthase, and inhibit 3T3-Ll fibroblast differentiation to adipocytes. Male spontaneously hypertensive rats received either 150 mg/day of berberine or saline orally for 8 weeks. Compared with the control, berberine-treated rats exhibited significant reductions in body weight gain (p < 0.05), as well as retroperitoneal and mesenteric adipose tissues (p < 0.05). Berberine-treated rats significantly decreased urinary albumin excretion, a marker of renal injury (p < 0.05). Long-term treatment with berberine decreased the adipose tissues weight and attenuated renal injury in spontaneously hypertensive rats. Based on these results, berberine has an important role in regulating adipose tissues. These results suggest the protective effect of berberine on metabolic syndrome related diseases, such as renal injury. PMID- 26594755 TI - Sagitol D, a New Thiazole Containing Pyridoacridine Alkaloid from a Vietnamese Ascidian. AB - A new thiazole containing pyridoacridine alkaloid, named sagitol D (1), and five known alkaloids kuanoniaminesA (2), C (3), D (4), E (5), and F (6), have been isolated from an unidentified Vietnamese ascidian. The structure of the new compound was established from NMR spectroscopic data. Kuanoniamines C, D, E, and F showed moderate antioxidant activity in the DPPH (IC50 36 uM) and ABTS assays (TE = 0.5), while sagitol D showed weak activity (IC50 92 M;TE = 0.10), and kuanoniamine A was inactive. PMID- 26594756 TI - A New Terminal Cyano Group-containing Benzodiazepine Alkaloid from the Mangrove Endophytic Fungus Penicillium sp. . AB - A new benzodiazepine alkaloid containing terminal cyano group has been isolated from a mangrove endophytic fungus, Penicillium 299#. Structure elucidation was determined by 1D and 2D NMR spectroscopy and the absolute configuration was determined by electronic circular dichroism (ECD). The new compound showed no cytotoxic activities in vitro against human cancer lines MDA-MB-435, HepG2, HCT 116, and Calu-3. PMID- 26594757 TI - Tetramethylpyrazine from Pleurotus geesteranus. AB - For the first time, the bioactive compound tetramethylpyrazine (TMP) was isolated and identified from the culture of Pleurotus geesteranus Singer. Its identification was confirmed unambiguously by identical retention time and mass spectrum to those of a TMP standard. The TMP content in P. geesteranus from solid culture was up to 8.04 g.kg(-1)ds. This finding provides a novel natural way to produce TMP and will lead to new value added mushroom products with nutraceutical functions. PMID- 26594758 TI - A New Flavanone from the Leaves of Chromolaena odorata. AB - Chromolaena odorata (Syn: Eupatorium odoratum) is a perennial plant belonging to the Asteraceae family. Extracts of C. odorata have shown strong anti-oxidant and moderate anti-adipogenenesis activities. Detailed phytochemical investigation of C. odorata led to the isolation of 21 secondary metabolites, which include a new flavanone (3), and a chalcone, 3,2'-dihydroxy-4,4',5',6'-tetramethoxychalcone (2), reported for the first time from a natural source, besides three known compounds 1, 4 and 5, all of which are reported for the first time from C. odorata. Some of these compounds exhibited potent anti-oxidant and anti adipogenesis activities and these may be partly responsible for the activity of the extract. PMID- 26594759 TI - Antioxidant and alpha-Glucosidase Inhibitory Constituents from Hornstedtia Species of Malaysia. AB - Seven compounds were isolated from the n-hexane and chloroform extracts of the flowers and leaves of four Hornstedtia species and their structures were identified using spectroscopic techniques as 3,7,4'-trimethylkaempferol (1), 3,7 dimethylkaempferol (2), 7,4'-dimethylkaempferol (3), 3,5-dimethylkaempferol (4), 3-methylkaempferol (5), stigmast-4-en-3-one (6), and 6-hydroxy-stigmast-4-en-3 one (7). Compounds 1 to 7 were isolated from these species for the first time. They were assayed for free radical scavenging and alpha-glucosidase inhibition activities. The DPPH assay showed that 3-methylkaempferol (5) was the most potent antioxidant agent with an IC50 value 78.6 uM, followed by 7,4'-dimethylkaempferol (3) (IC50 = 86.1 uM). For alpha-glucosidase inhibition activity, 3 methylkaempferol (5) exhibited significant inhibitory activity with an IC50 value 21.0 uM. The present study revealed that Hornstedtia species have potential activities as antioxidant and alpha-glucosidase inhibitors. PMID- 26594760 TI - Synthesis and Antiviral Activity of Quercetin Brominated Derivatives. AB - Reaction of quercetin (QR) (1) with bromine under various conditions was studied. Interaction of QR with 2-3 equiv. of bromine in glacial acetic acid at 35-40 degrees C for 2-4 h and 20-22 degrees C for 24 h led to the formation of QR 6,8 dibromide (2) (52-54% yields, 96-98% purity by HPLC). Interaction of QR with 2-5 equiv. bromine in absolute ethanol at 0-5 degrees C and 20-22 degrees C for 24 h led to the formation of 3-O-ethyl-QR-2,3,6,8,5'-pentabromide (3) (95-97% purity by HPLC) the output of which depends on the quantity of bromine. It was shown in MDCK cell culture that compound 2 exhibits a moderate inhibitory activity against pandemic influenza virus A/H1N1/pdm09 (EC50 6.0 ug/mL, CTD50 97.7 ug/mL, SI 16). Compound 3 was inactive. PMID- 26594761 TI - Pharmacokinetic Profile of uSMIN PlusTM, a new Micronized Diosmin Formulation, after Oral Administration in Rats. AB - Diosmin is a naturally occurring flavonoid present in citrus fruits and other plants belonging to the Rutaceae family. It is used for the treatment of chronic venous insufficiency (CVI) for its pheblotonic and vaso-active properties, safety and tolerability as well. The aim of the current in vivo study was to investigate the pharmacokinetic profile of a branded micronized diosmin (uSMIN PlusTM) compared with plain micronized diosmin in male Sprague-Dawley rats. After oral administration by gastric gavage, blood samples were collected via jugular vein catheters at regular time intervals from baseline up to 24 hours. Plasma concentrations were assessed by LC/MS. For each animal, the following pharmacokinetic parameters were calculated using a non-compartmental analysis: maximum plasma drug concentration (Cmax), time to reach Cmax (Tmax), area under the plasma concentration-time curve (AUC0-last), elimination half-life (t1/2), and relative oral bioavailability (%F). The results of the current study clearly showed an improvement in the pharmacokinetic parameters in animals treated with uSMIN PlusTM compared with animals treated with micronized diosmin. In particular, uSMIN PlusTM showed a 4-fold increased bioavailability compared with micronized diosmin. In conclusion, the results from the current study provided a preliminary pharmacokinetic profile for uSMIN PlusTM, which may represent a new tool for CVI management. PMID- 26594762 TI - The Combinatory Effects of Glabridin and Tamoxifen on Ishikawa and MCF-7 Cell Lines. AB - Estrogen replacement therapy is commonly used to replace the loss of estrogen in post-menopausal women. However, it is not suitable to be used in women taking tamoxifen as both of the drugs increase the risk of endometrial cancer. This project aimed to study the potential of using the natural compound glabridin in combination with tamoxifen as a drug for estrogen replacement therapy. Ishikawa and MCF-7 cells were used to investigate the estrogenic activities stimulated by the combination of tamoxifen and glabridin through ALP and MTT assays. The expressions of the ESR1 and bcl-2 genes have also been determined using RT-PCR. The results indicated that the combination of 1 x 10(-5)M tamoxifen and 1 x 10( 6)M glabridin exhibited estrogenic activities and suppressed cell growth in both cell lines. The relative expressions of ESR1 and bcl-2 genes indicated that the estrogenicity expressed by the combinatory drug was regulated by estrogen receptor a; however, the reduction in cell proliferation was not modulated by bcl 2 anti-apoptotic proteins. These results suggested that the combination of tamoxifen and glabridin has potential to be used as an estrogen replacement drug with a reduced risk of endometrial cancer that has arisen from the intake of tamoxifen. PMID- 26594763 TI - Potential of Horse Apple Isoflavones in Targeting Inflammation and Tau Protein Fibrillization. AB - In our ongoing search for anti-inflammatory and neuroprotective agents of natural origin, the total methanolic extract (MPE) of horse apple (Maclura pomifera) and its two major prenylated isoflavones, osajin (OSA) and pomiferin (POM), were evaluated in vitro for their ability to affect four mediators of inflammation and to inhibit tau protein fibrillization. The two isoflavones were effective in enhancing the activity of NSAID activated gene (NAG-1) at 2.5 pg/mL (1.5-1.8 fold increase) and inhibiting iNOS and NF-kappaB activity with IC50 values in the range of 6-13 ug/mL. Pomiferin also inhibited intracellular oxidative stress with IC50 of 3.3 ug/mL, while osajin did not show any effect. The extract activated NAG-1 and inhibited iNOS and oxidative stress without affecting NF-kappaB. As observed by transmission electron microscopy (TEM), MPE, OSA and POM also inhibited arachidonic acid-induced tau fibrillization in a concentration dependent manner. PMID- 26594764 TI - Inhibitory Effect of Isoflavones from Erythrina poeppigiana on the Growth of HL 60 Human Leukemia Cells through Inhibition of Glyoxalase I. AB - It has been reported that many malignant human tissues, including breast, colon, and lung cancers, may show an elevated expression of glyoxalase I (GLO I). GLO I catalyzes the reaction to transform hemimercaptal, a compound formed from methylglyoxal (MG) and reduced glutathione, into S-D-lactoylglutathione, which is then converted to D-lactic acid by glyoxalase II. GLO I inhibitors are expected to be useful for inhibiting tumorigenesis through the accumulation of apoptosis inducible MG in tumor cells. Here, we investigated the anti-proliferative activity of eight kinds of isoflavone isolated from Erythrina poeppigiana against the growth of HL-60 human leukemia cells from the viewpoint of GLO I inhibition. Of the compounds tested, the diprenyl isoflavone, isolupalbigenin, was shown to exhibit the highest anti-proliferative activity against HL-60 cells. Upon the treatment of HL-60 cells with isolupalbigenin, MG was significantly accumulated in the culture medium, and the caspase 3 activity of the cell lysate was elevated in a time-dependent manner. Thus, it is suggested that isolupalbigenin inhibits the enzyme GLO I, resulting in MG accumulation in the medium, and leading to cell apoptosis. Isolupalbigenin, with two prenyl groups in its A- and B-rings, might be expected to become a potent leading compound for the development of anticancer agents. PMID- 26594765 TI - alpha-Glucosidase and 15-Lipoxygenase Inhibitory Activities of Phytochemicals from Calophyllum symingtonianum. AB - A phytochemical investigation of the crude extracts of the bark and leaves of Calophyllum symingtonianum has resulted in the isolation of inophyllum D, inophyllum H, calanone, isocordato-oblongic acid, amentoflavone, carpachromene and lupenone. Their chemical structures were elucidated and confirmed by spectroscopic analysis. All flavonoids and coumarins showed significant alpha glucosidase inhibitory activity, while amentoflavone gave a positive result against 15-lipoxygenase inhibition. PMID- 26594766 TI - Antifungal Activity of Pyranonaphthoquinones Obtained from Cipura paludosa Bulbs. AB - Previous studies with the bulbs of Cipura paludosa (Iridaceae) showed the presence of pyranonaphthoquinones, including eleutherine, isoeleutherine and eleutherol. The aim of this study was to evaluate the antifungal properties of these compounds. The activity was tested against the clinically relevant yeasts Candida albicans, C. tropicalis, Saccharomyces cerevisiae and Cryptococcus neoformans with the microbroth dilution method, following the guidelines of CLSI. Eleutherine, isoeleutherine and eleutherol all presented significant antifungal activity, especially the first two, the major components, with MIC values between 7.8 and 250 ug/mL. In conclusion, these results demonstrate that C. paludosa bulbs produce active principles with relevant antifungal potential, contributing, at least in part, to the antimicrobial effect evidenced for this plant and justifying its popular use against infections. PMID- 26594767 TI - Plant Extract (Bupleurum falcatum) as a Green Factory for Biofabrication of Gold Nanoparticles. AB - This work describes a biofabrication process for gold nanoparticles in which the plant extract (Bupleurum falcatum) is used as a reducing agent to convert gold ions to gold nanoparticles. Biofabricated gold nanoparticles with spherical shapes were observed with an average diameter of 10.5 +/- 2.3 nm. The color of the gold nanoparticles was purple, with a surface plasmon resonance peak at 542 nm. The face-centered cubic structure of crystalline gold was confirmed by high resolution X-ray diffraction patterns. The biofabricated gold nanoparticles demonstrated excellent catalytic activity towards the 4-nitrophenol reduction reaction. The current report suggests that plant extracts are valuable natural sources for the biofabrication of gold nanoparticles with excellent catalytic activities. PMID- 26594768 TI - OM-X(r), Fermented Vegetables Extract Suppresses Antigen-Stimulated Degranulation in Rat Basophilic Leukemia RBL-2H3 Cells and Passive Cutaneous Anaphylaxis Reaction in Mice. AB - OM-X(r) is a hand-made and naturally manufactured probiotic supplement. This fermented food product is made from vegetables, fruits, seaweeds and mushrooms, using 12 strains of lactic acid bacteria and bifidobacteria. OM-X(r) is also known to have beneficial health properties, and some of its components show effects on antigen (Ag)-stimulated degranulation activity, indicating that OM X(r) may be useful in the treatment of allergy responses and symptoms. In this study, we evaluated the inhibitory effects of OM-X(r) on Ag-stimulated degranulation in rat basophilic leukemia RBL-2H3 cells, clarified the underlying mechanisms, and determined the active compounds in OM-X(r) for suppression of degranulation. Treatment with OM-X(r) gradually suppressed Ag-stimulated degranulation throughout the maturation period. OM-X(r) also gradually produced melanoidins by lactic acid bacterial fermentation during the maturation process. There was a high correlation between the suppression levels of Ag-stimulated degranulation and the browning of OM-X(r). Furthermore, the inhibition of Ag stimulated degranulation by OM-X(r) was found to be partially due to the direct inactivation of NADPH oxidase. To elucidate the in vivo effects of OM- X(r), type I allergy model mice were orally administered with OM-X(r), and the passive cutaneous anaphylaxis (PCA) reaction was measured. OM-X(r) intake remarkably suppressed the PCA reaction. Taken together, our findings suggest that OMX(r) could be a beneficial food to ameliorate allergic reactions. PMID- 26594769 TI - Siomycin A Induces Apoptosis in Human Lung Adenocarcinoma A549 Cells by Suppressing the Expression of FoxM1. AB - Forkhead box M1 (FoxM1), a transcription factor of the Forkhead family, is demonstrated to be critical for proliferation, apoptosis, migration and invasion of lung cancer. In this study, we extensively investigated the anticancer effect of siomycin A, which was identified as an inhibitor of FoxM1 transcriptional activity, on human lung adenocarcinoma A549 cells. Our study indicated that treatment with siomycin A resulted in the suppression of FoxM1 expression, which consequently contributed to its effect of cell growth inhibition and cell apoptosis induction in A549 cells. Then the molecular mechanism of siomycin A's apoptotic action on A549 cells was further investigated. The results revealed that siomycin A induced apoptosis by influencing the downstream events of FoxM1, including inhibiting the expression of Bcl-2 and Mcl-1, as well as leading to caspase-3 cleavage. Taken together, our findings may be useful for understanding the mechanism of action of siomycin A on lung cancer cells and provide new insights into the possible application of such a compound in lung cancer therapy in the future. PMID- 26594770 TI - Novel Pharmacological Properties of Dinoponera quadriceps Giant Ant Venom. AB - The South American giant ant, Dinoponera quadriceps (Hymenoptera, Formicidae, Ponerinae), produces proteinaceous venom that has antinociceptive, neuroprotective and antimicrobial effects, thereby supporting the popular use of these ants to treat asthma, rheumatism, earache and back pain. Anticoagulant activity is another biological property that has been shown for the venom of other hymenopteran species, like wasps. The aim of this study was to assess the anti-inflammatory, anticoagulant and antiplatelet properties of D. quadriceps venom (DqV). DqV anti-inflammatory activity was assessed by intravenous administration in Swiss mice in the models of paw edema and peritonitis. In vitro, DqV was assessed in coagulation (activated partial thromboplastin time) and platelet aggregation tests. DqV inhibited (27-33%) the edema elicited by carrageenan and the leucocyte migration (43%) elicited by zymosan. DqV decreased by 57% and 42%, respectively, the content of malondialdehyde and nitrite in the peritoneal fluid. DqV prolonged (1.8x) the clotting time and decreased (27%) the platelet aggregation induced by adenosine diphosphate. The crude venom of D. quadriceps presents an anti-inflammatory effect in mice and in vitro anticoagulant and antiplatelet effects. PMID- 26594771 TI - The Leaf Essential Oil of Eugenia reinwardtiana Growing in Australia. AB - The leaf essential oils of the two chemotypes of Eugenia reinwardtiana (Blume) DC growing in Australia have been investigated. Chemotype 1, isolated in 0.2% yield, w/w, dry weight, contained major amounts of alpha-pinene (10-26%), limonene (1 15%), beta-caryophyllene (0.7-11%), alpha-humulene (0.9-16%) and bicyclogermacrene (1-23%). The second chemotype, found only on coastal dunes SW of Lockerbie Qld, and isolated in 0.4-0.6% (w/w, dry weight), contained alpha pinene (tr-8.5%) beta-caryophyllene (12-27%) and alpha-humulene (1-17%) as the major terpenes. This chemotype also contained the novel aliphatic diketone, 2 butyl-2,4,4-trimethyl-5-methoxycyclohex-5-en-1,3-dione (18-33%), whose structure determination is reported herein. PMID- 26594772 TI - Relationship Between Soil and Essential Oil Profiles in Salvia desoleana Populations: Preliminary Results. AB - Salvia desoleana is a herbaceous perennial shrub endemic of Sardinia (Italy). The leaves are a source of essential oil, used in pharmaceutical and cosmetic industries. The therapeutic function of this species has been associated to the presence of essential oils rich in alpha/beta-pinene, p-cimene, linalool, linalyl acetate and 1,8-cineole. Today.the industrial request of Salvia essential oils is increasing and most of the biomass is exploited from the natural populations which are under severe risk of genetic erosion. In order to improve the essential oil production, the study of the environmental parameters that influence composition, quality and quantity of the essential oils, turns out to be necessary. Soil physical and chemical structure represents one of the determinant factors in secondary metabolites production, and could also be involved in volatiles fraction composition in the same species. The main aim of this research was to explore the relationship between essential oil profiles and soil characteristics in S. desoleana populations. GC/MS analysis performed on the essential oil extracts identified 22 principal compounds, which were extremely variable among the five S. desoleana populations studied. The analysis of the essential oils revealed different compositions in the terpenes fractions: 68.2% of monoterpenes, 27.3% of sesquiterpenes and 4.5% of diterpenes. Analysis of chemical and physical soil parameters at the collection sites revealed that silt and sand contents were correlated with alpha-pinene and sclareol fractions and the total K20 was significantly correlated to several compounds belonging to the three terpene fractions identified. These results will provide guidelines for the in site conservation and for the improvement of the commercial value of the species. PMID- 26594773 TI - Simultaneous Determination of Essential Oil Components and Fatty Acids in Fennel using Gas Chromatography with a Polar Capillary Column. AB - Cultivated and wild growing samples of fennel (Foeniculum vulgare Mill., Apiaceae) from R. Macedonia were studied for their volatiles and fatty acid composition. The main essential oil components isolated via hydrodistillation were: trans-anethole (>80%), estragole (< 6%), limonene (< 6%), anisaldehyde (< 1%) and 0.5 % fenchone. An alternative method for characterization of both the non-polar volatile and non volatile fractions was developed using n-hexane and dichloromethane (3:1, v/v) in a Soxhlet extraction followed by transesterification. The obtained extracts were then characterized and the dominant fatty acid was 18:1 (petroselinic and oleic acid) 75.0-82.8%, followed by 18:2 (linoleic acid) 10.8-16.2% and other fatty acids: palmitic (4.3-6.9%), stearic (1.2-1.7%) and myristic (0-2.9%). The results for the volatile fraction after Soxhlet extraction and transesterification did not significantly differ from results obtained after hydrodistillation, especially for the main components (trans-anethole, estragole, fenchone and limonene), implying that the developed method can be used for simultaneous determination of volatiles and fatty acids. PMID- 26594774 TI - Antischistosomal and Cytotoxic Effects of the Essential Oil of Tetradenia riparia (Lamiaceae). AB - This paper reports on the antischistosomal and cytotoxic effects of the essential oil obtained from Tetradenia riparia leaves (TR-EO). At concentrations of 50 and 100 ug/mL, TR-EO killed all the worms after 120 and 24 h of incubation, respectively. At a concentration equal to or higher than 50 ug/mL, this oil also separated the coupled pairs and decreased the adult worm motor activity after incubation periods higher than 72 h. In addition, at 120 h of incubation, TR-EO slightly decreased the number of eggs produced by Schistosoma mansoni adult worms and significantly reduced the percentage of developed eggs, in a dose-dependent manner. XTT-colorimetric assays showed that the tested TR-EO concentrations were not considerably cytotoxic to V79 cells (IC50 = 253.5 ug/mL). The effects of TR EO on egg development were noteworthy; therefore, this essential oil deserves further investigation to identify the chemical constituents that elicit activity against S. mansoni. PMID- 26594775 TI - Biological Activity and Chemical Constituents of Essential Oil and Extracts of Murraya microphylla. AB - Murraya microphylla is the most closely related species to M. koenigii (Curry tree). Inspired by the traditional effects of M koenigii, the antioxidant, anti- inflammatory, and cytotoxic activities of the essential oil and extracts of M. microphylla were evaluated for the first time. The light petroleum and chloroform extracts were found to be able to scavenge DPPH free radicals, inhibit linoleic acid peroxidation, and nitric oxide production, as well as to present cytotoxicity to the human cancer cell lines HepG2, Bel7402, Bel7403, and Hela, but the essential oil only showed moderate activities. Chemical analysis of the active extracts by LC-DAD-MS" indicated that carbazole alkaloids were the main constituents. GC-MS analysis of the essential oil resulted in identification of 91 constituents, representing 96.9% of the total oil, with (E)-caryophyllene (18.4%) and terpinen-4-ol (12.6%) as the major constituents. These results demonstrate that M microphylla has similar biological activities, as well as chemical constituents to M. koenigii, and the carbazole alkaloids were disclosed to be the main potential active components. A promising development as a flavor and potential therapeutic agent could thus be predicated for this plant. PMID- 26594776 TI - Chemical Constituents and Activity of Murraya microphylla Essential Oil against Lasioderma serricorne. AB - The chemical composition, contact and repellent activities of the essential oil from Murraya microphylla branches and leaves against Lasioderma serricorne adults were determined and six compounds from the essential oil were isolated as well. The essential oil of M microphylla obtained by hydrodistillation was analyzed by gas chromatography-mass spectrometric (GC-MS) analysis; 22 compounds were identified. The main constituents of the essential oil included beta caryophyllene (18.0%), alpha-pinene (13.8%), spathulenol (9.5%), alpha-humulene (6.0%), gamma-elemene (5.1%) and zingiberene (4.6%), followed by alpha-cadinol (3.9%) and caryophyllene oxide (3.8%). Six of these compounds were isolated and fully identified as alpha-pinene, beta-caryophyllene, alpha-humulene, caryophyllene oxide, spathulenol and alpha-cadinol. L. serricorne adults had different sensitivities to the crude essential oil and isolated compounds. alpha Humulene exhibited the strongest contact activity against L. serricorne, showing an LD50 value of 13.1 ug adult(-1). However, spathulenol, the crude essential oil and alpha-cadinol showed stronger contact activity against L. serricorne than caryophyllene oxide and beta-caryophyllene. The essential oil, alpha-humulene and spathulenol showed comparable repellency against L. serricorne adults at 2 h after exposure, relative to the positive control, DEET. The results demonstrate that the essential oil and isolated compounds exhibited important contact and repellent activities against L. serricorne. Thus, they could become potential natural insecticides or repellents for control of insects in stored products. PMID- 26594777 TI - Suturing of the flexor digitorum profundus tendon to the entire volar plate in distal zone I injuries. AB - PURPOSE: The author conducted an anatomical and a prospective clinical study to address the technique and complications of using the entire volar plate (VP) as a distally-based flap for distal Zone I flexor digitorum profundus (FDP) tendon repair. METHODS: In the anatomical study, eight fresh finger specimens were dissected to study the anatomy of the VP as well as the stability of the distal interphalangeal joint (DIPJ) after raising the entire VP as a distally-based flap. In the clinical series, six patients underwent repair of distal Zone I FDP lacerations using the VP flap technique and were assessed at a mean of 9 months for range of motion as well as DIPJ deformities. RESULTS: The results of the anatomical study showed that the intact collateral ligaments can still maintain the stability of the DIPJ after loss of joint support from the VP. In the clinical series, none of the patients showed joint hyper-extension or flexion contracture at the DIPJ. Using Moiemen-Elliot criteria, the post-operative active range of motion at the DIPJ was rated as excellent in one, good in three, and fair in two patients. CONCLUSION: It was concluded that the use of the entire VP as a distally based flap is an acceptable technique to repair distal FDP injuries and the technique does not result in DIPJ instability or flexion contracture. PMID- 26594778 TI - Asymmetric Latent Carbocation Catalysis with Chiral Trityl Phosphate. AB - Stable carbocations such as tritylium ions have been widely explored as organic Lewis acid catalysts and reagents in organic synthesis. However, achieving asymmetric carbocation catalysis remains elusive ever since they were first identified over one century ago. The challenges mainly come from their limited compatibility, scarcity of chiral carbocations, as well as the extremely low barrier to racemization of chiral carbenium ions. We reported here a latent concept for asymmetric carbocation catalysis. In this strategy, chiral trityl phosphate is employed as the carbocation precursor, which undergoes facile ionic dissociation upon mild external stimulation (e.g., acid, H-bonding, polar substrates) to form a catalytically active chiral ion pair for substrate activation and chiral induction. The latent strategy provides a solution for the long sought-after asymmetric carbocation catalysis as illustrated in three different enantioselective transformations. PMID- 26594779 TI - A glass fiber-reinforced composite - bioactive glass cranioplasty implant: A case study of an early development stage implant removed due to a late infection. AB - This case study describes the properties of an early development stage bioactive glass containing fiber-reinforced composite calvarial implant with histology that has been in function for two years and three months. The patient is a 33-year old woman with a history of substance abuse, who sustained a severe traumatic brain injury later unsuccessfully treated with an autologous bone flap and a custom made porous polyethylene implant. She was thereafter treated with developmental stage glass fiber-reinforced composite - bioactive glass implant. After two years and three months, the implant was removed due to an implant site infection. The implant was analyzed histologically, mechanically, and in terms of chemistry and dissolution of bioactive glass. Mechanical integrity of the load bearing fiber reinforced composite part of the implant was not affected by the in vivo period. Bioactive glass particles demonstrated surface layers of hydroxyapatite like mineral and dissolution, and related increase of pH was considerably less after two and three months period than that for fresh bioactive glass. There was a difference in the histology of the tissues inside the implant areas near to the margin of the implant that absorbed blood during implant installation surgery, showed fibrous tissue with blood vessels, osteoblasts, collagenous fibers with osteoid formation, and tiny clusters of more mature hard tissue. In the center of the implant, where there was less absorbed blood, only fibrous tissue was observed. This finding is in line with the combined positron emission tomography computed tomography examination with (18F)-fluoride marker, which demonstrated activity of the mineralizing bone by osteoblasts especially at the area near to the margin of the implant 10 months after implantation. Based on these promising reactions found in the bioactive glass containing fiber-reinforced composite implant that has been implanted for two years and three months, calvarial reconstruction with the presented material appears to be a feasible method. PMID- 26594780 TI - Cold-rolling behavior of biomedical Ni-free Co-Cr-Mo alloys: Role of strain induced epsilon martensite and its intersecting phenomena. AB - Ni-free Co-Cr-Mo alloys are some of the most difficult-to-work metallic materials used commonly in biomedical applications. Since the difficulty in plastically deforming them limits their use, an in-depth understanding of their plastic deformability is of crucial importance for both academic and practical purposes. In this study, the microstructural evolution of a Co-29Cr-6Mo-0.2N (mass%) alloy during cold rolling was investigated. Further, its work-hardening behavior is discussed while focusing on the strain-induced face-centered cubic (fcc) gamma >hexagonal close-packed (hcp) epsilon martensitic transformation (SIMT). The planar dislocation slip and subsequent SIMT occurred even in the initial stage of the deformation process owing to the low stability of the gamma-phase and contributed to the work hardening behavior. However, the amount of the SIMTed epsilon-phase did not explain the overall variation in work hardening during cold rolling. It was found that the intersecting of the SIMTed epsilon-plates enhanced local strain evolution and then produced fine domain-like deformation microstructures at the intersections. Consequently, the degree of work hardening was reduced during subsequent plastic deformation, resulting in the alloy exhibiting a two-stage work hardening behavior. The results obtained in this study suggest that the interaction between epsilon-martensites, and ultimately its relaxation mechanism, is of significant importance; therefore, this aspect should be addressed in detail; the atomic structures of the gamma-matrix/epsilon martensite interfaces, the phenomenon of slip transfer at the interfaces, and the slipping behavior of the epsilon-phase itself are needed to be elucidated for further increasing the cold deformability of such alloys. PMID- 26594781 TI - Towards near-permanent CoCrMo prosthesis surface by combining micro-texturing and low temperature plasma carburising. AB - An advanced surface engineering process combining micro-texture with a plasma carburising process was produced on CoCrMo femoral head, and their tribological properties were evaluated by the cutting-edge pendulum hip joint simulator coupled with thin film colorimetric interferometry. FESEM and GDOES showed that precipitation-free C S-phase with a uniform case depth of 10MUm was formed across the micro-textures after duplex treatment. Hip simulator tests showed that the friction coefficient was reduced by 20% for micro-metre sized texture, and the long-term tribological property of microtexture was enhanced by the C supersaturated crystalline microstructure formed on the surface of duplex treated CoCrMo, thereby enhancing biotribological durability significantly. In-situ colorimetric interferometry confirmed that the maximum film thickness around texture area was 530nm, indicating that the additional lubricant during sliding motion might provide exceptional bearing life. PMID- 26594782 TI - Immediate postoperative changes in synthetic meshes - In vivo measurements. AB - BACKGROUND AND OBJECTIVE: Immediate post-operative structural changes in implanted synthetic meshes are believed to contribute to graft related complications. Our aim was to observe in vivo dimensional changes at the pore level. METHOD: Two different polyvinylidine fluoride (PVDF) meshes, CICAT and ENDOLAP (Dynamesh, FEG Textiltechnik) were implanted in 18 female Sprague Dawley (n=9/group). The meshes (30*25mm(2)) were overlaid on a full thickness incision (2*1cm(2)) and sutured on the abdominal wall. All animals underwent microCT imaging (res. 35um/px) at day 1 and 15 postsurgery. A customized procedure was developed to semi-automatically detect the pore centers from the microCT dataset. Horizontal (transverse) and vertical (cranio-caudal) inter-pore distances were then recorded. The overall mesh dimensions were also noted from 3D models generated from in vivo microCT datasets. Inter-pore distances and the overall dimensions from microCT images of the meshes set in agarose gel phantom were used as controls. Mann-Whitney U test was done to check for significant differences. RESULTS: Number of measurable vertical and horizontal inter-pore distances was 56.5(10.5) and 54.5(14.5) [median (IQR)] per animal. At day 1, we observed a 4.3% (CICAT) and 4.6% (ENDOLAP) increase in vertical inter-pore distance when compared to controls (p<0.001, p=0.003, respectively). Measurements fell back to phantom values by day 15 (3.7% and 4.9% decrease compared to day 1, p<0.001 for both). The horizontal inter-pore distances for ENDOLAP increased by 1.4% (p=0.003) during the two weeks period. The overall mesh dimensions did not change significantly day 1 and day 15. The in vivo measurement of the overall mesh dimensions demonstrated a 15.9% reduction in mesh area as compared to that in phantom controls. CONCLUSION: We report for the first time, in vivo changes in pore dimensions of a textile implant. This study clearly demonstrates the dynamic nature of a textile implant during the tissue integration process. For studied PVDF meshes, the process of tissue integration leads to limited but significant reduction over time as observed at the pore level. Remarkably the extent of this reduction does not account for the change in overall mesh dimensions. PMID- 26594783 TI - Multiaxial fatigue modeling for Nitinol shape memory alloys under in-phase loading. AB - The realistic loading condition for many components is multiaxial arising from multidirectional loading or geometry complexities. In this study, some multiaxial stress-based classical and critical plane fatigue models are briefly reviewed and their application for martensitic Nitinol under torsion and in-phase axial torsion loading is evaluated. These models include von Mises equivalent stress, Tresca, Findley, McDiarmid, and a proposed stress-based Fatemi-Socie-type model. As the fatigue cracks appear to be on the maximum shear plane for the martensitic Nitinol, all the models examined here consider the shear stress as the primary damage parameter. Among all the models considered in this study, the proposed Fatemi-Socie-type model provides a better prediction for fatigue lives when compared to torsion and in-phase multiaxial fatigue experimental data from literature. Analyses indicate that critical plane approaches are more appropriate for multiaxial fatigue prediction of Nitinol alloys, at least in martensitic phase. Finally, recommendations are made to calibrate more reliable multiaxial fatigue models for Nitinol. PMID- 26594784 TI - Development of soy lecithin based novel self-assembled emulsion hydrogels. AB - The current study reports the development and characterization of soy lecithin based novel self-assembled emulsion hydrogels. Sesame oil was used as the representative oil phase. Emulsion gels were formed when the concentration of soy lecithin was >40% w/w. Metronidazole was used as the model drug for the drug release and the antimicrobial tests. Microscopic study showed the apolar dispersed phase in an aqueous continuum phase, suggesting the formation of emulsion hydrogels. FTIR study indicated the formation of intermolecular hydrogen bonding, whereas, the XRD study indicated predominantly amorphous nature of the emulsion gels. Composition dependent mechanical and drug release properties of the emulsion gels were observed. In-depth analyses of the mechanical studies were done using Ostwald-de Waele power-law, Kohlrausch and Weichert models, whereas, the drug release profiles were modeled using Korsmeyer-Peppas and Peppas-Sahlin models. The mechanical analyses indicated viscoelastic nature of the emulsion gels. The release of the drug from the emulsion gels was diffusion mediated. The drug loaded emulsion gels showed good antimicrobial activity. The biocompatibility test using HaCaT cells (human keratinocytes) suggested biocompatibility of the emulsion gels. PMID- 26594785 TI - Potential biotechnological application of microalgae: a critical review. AB - Microalgae are diverse microorganisms inhabiting a wide range of habitats with only a small fraction being cultivated for human use. Recently, interest in microalgal research has increased in the quest for alternative renewable fuels due to possible depletion of fossil fuels in the near future. However, costly downstream processing has hampered the commercialization of biofuels derived from microalgae. Several value added products of industrial, pharmaceutical and agricultural relevance could be simultaneously derived from microalgae during bioenergy production. Despite these value-added products having the potential to offset the high cost of downstream processing of renewable fuels, their production has not been explored in-depth. This review presents a critical overview of the current state of biotechnological applications of microalgae for human benefit and highlights possible areas for further research and development. PMID- 26594786 TI - Revisiting the Criteria for Exchange Transfusion for Severe Neonatal Hyperbilirubinemia in Resource-Limited Settings. AB - BACKGROUND: Exchange transfusion (ET) for severe neonatal hyperbilirubinemia (SNH) is frequently undertaken in low- and middle-income countries (LMIC), in sharp contrast to the prevailing practice in high-income countries. However, the criteria for initiating this procedure in settings with limited resources for treating infants with SNH have not been systematically explored. OBJECTIVE: To identify key considerations for initiating ET in resource-poor countries to curtail its unnecessary use for the prevention of kernicterus. METHODS: A review of the existing guidelines and literature on the management of neonatal hyperbilirubinemia worldwide was conducted to identify criteria and underlying factors for initiating ET. RESULTS: There is a dearth of evidence from randomized clinical trials to support clear criteria for indicated ET worldwide. Because risk assessment for kernicterus based solely on the levels of total serum bilirubin (TSB) has often proved inadequate, a combination of plasma/serum bilirubin estimation and clinical evaluation for acute bilirubin encephalopathy (ABE) has been recommended for predicting the risk of kernicterus. However, there is a lack of consistency regarding the TSB levels for which ET should be initiated in relation to the clinical signs/symptoms of ABE and hemolytic disorders. CONCLUSIONS: A decision-making framework that combines TSB thresholds and evidence of neurotoxicity is needed for evaluating the risk of kernicterus and prioritising infants for ET in LMICs to curtail unnecessary interventions. PMID- 26594787 TI - Social influence on metacognitive evaluations: The power of nonverbal cues. AB - Metacognitive evaluations refer to the processes by which people assess their own cognitive operations with respect to their current goal. Little is known about whether this process is susceptible to social influence. Here we investigate whether nonverbal social signals spontaneously influence metacognitive evaluations. Participants performed a two-alternative forced-choice task, which was followed by a face randomly gazing towards or away from the response chosen by the participant. Participants then provided a metacognitive evaluation of their response by rating their confidence in their answer. In Experiment 1, the participants were told that the gaze direction was irrelevant to the task purpose and were advised to ignore it. The results revealed an effect of implicit social information on confidence ratings even though the gaze direction was random and therefore unreliable for task purposes. In addition, nonsocial cues (car) did not elicit this effect. In Experiment 2, the participants were led to believe that cue direction (face or car) reflected a previous participant's response to the same question-that is, the social information provided by the cue was made explicit, yet still objectively unreliable for the task. The results showed a similar social influence on confidence ratings, observed with both cues (car and face) but with an increased magnitude relative to Experiment 1. We additionally showed in Experiment 2 that social information impaired metacognitive accuracy. Together our results strongly suggest an involuntary susceptibility of metacognitive evaluations to nonverbal social information, even when it is implicit (Experiment 1) and unreliable (Experiments 1 and 2). PMID- 26594788 TI - Mitosis and Interphase of the Highly Polyploid Palm Voanioalagerardii (2n = 606 +/- 3). AB - The endemic, highly polyploid, monotypic Madagascan palm genus Voanioala (2n ~ 606) was studied with regard to mitotic stages and interphase. Features of the cell cycle, morphology and sizes of metaphase chromosomes, fluorochrome banding patterns, and silver staining of NORs of such an extremely high polyploid organism are reported for the first time. On a whole, karyokinesis appears to be stable and efficient. A comparison with closely related palm taxa reveals that V. gerardii is 38-ploid, and comparison with the closely related genera Butia, Cocos (coconut) and Jubaea shows that Voanioala has lost ~ 35% of its DNA amount subsequent to polyploidization and has suppressed between 74 and 88% of the original nucleolar organizers. About 10 active NORs are present in the nuclei. An auto- or allopolyploid origin of Voanioala is discussed with respect to currently available nuclear gene data. The biogeographic relations to Jubaeopsis, a closely related, monotypic, apparently likewise relict palm genus from eastern mainland South Africa are discussed. From a cytogenetic point of view, a common polyploid ancestor of both genera is most likely, but the available molecular phylogenetic data are not univocal. PMID- 26594789 TI - Long-Lifetime Luminescent Europium(III) Complex as an Acceptor in an Upconversion Resonance Energy Transfer Based Homogeneous Assay. AB - Long-lifetime luminescent Eu(III) complexes are widely used as donors in Forster resonance energy transfer to enable time-gated detection of sensitized emission from an intrinsically short-lived acceptor. Here we report a unique energy transfer system, where the sensitized acceptor emission has prolonged luminescence lifetime compared to the donor and the long lifetime is not cut short upon high energy-transfer efficiency. The infrared-excited, ultraviolet emitting, Tm(III)-doped upconverting nanoparticles were used as donors, and a luminescent Eu(III)-chelate was used as an acceptor. Upon excitation the sensitized acceptor emission, which is already spectrally resolved from the donor, can be measured even after the donor luminescence has decayed. Because of anti-Stokes characteristics, the time-gated detection is not needed to avoid the autofluorescence. Thus, the long luminescence lifetime can be further modulated and utilized, e.g., in background-free molecular sensing, rendering the system extremely attractive. PMID- 26594790 TI - Exoproteome analysis reveals higher abundance of proteins linked to alkaline stress in persistent Listeria monocytogenes strains. AB - The foodborne pathogen Listeria monocytogenes, responsible for listeriosis a rare but severe infection disease, can survive in the food processing environment for month or even years. So-called persistent L. monocytogenes strains greatly increase the risk of (re)contamination of food products, and are therefore a great challenge for food safety. However, our understanding of the mechanism underlying persistence is still fragmented. In this study we compared the exoproteome of three persistent strains with the reference strain EGDe under mild stress conditions using 2D differential gel electrophoresis. Principal component analysis including all differentially abundant protein spots showed that the exoproteome of strain EGDe (sequence type (ST) 35) is distinct from that of the persistent strain R479a (ST8) and the two closely related ST121 strains 4423 and 6179. Phylogenetic analyses based on multilocus ST genes showed similar grouping of the strains. Comparing the exoproteome of strain EGDe and the three persistent strains resulted in identification of 22 differentially expressed protein spots corresponding to 16 proteins. Six proteins were significantly increased in the persistent L. monocytogenes exoproteomes, among them proteins involved in alkaline stress response (e.g. the membrane anchored lipoprotein Lmo2637 and the NADPH dehydrogenase NamA). In parallel the persistent strains showed increased survival under alkaline stress, which is often provided during cleaning and disinfection in the food processing environments. In addition, gene expression of the proteins linked to stress response (Lmo2637, NamA, Fhs and QoxA) was higher in the persistent strain not only at 37 degrees C but also at 10 degrees C. Invasion efficiency of EGDe was higher in intestinal epithelial Caco2 and macrophage-like THP1 cells compared to the persistent strains. Concurrently we found higher expression of proteins involved in virulence in EGDe e.g. the actin assembly-inducing protein ActA and the surface virulence associated protein SvpA. Furthermore proteins involved in cell wall modification, such as the lipoteichonic acid primase LtaP and the N-acetylmuramoyl-l-alanine amidase (Lmo2591) are more abundant in EGDe than in the persistent strains and could indirectly contribute to virulence. In conclusion this study provides information about a set of proteins that could potentially support survival of L. monocytogenes in abiotic niches in food processing environments. Based on these data, a more detailed analysis of the role of the identified proteins under stresses mimicking conditions in food producing environment is essential for further elucidate the mechanism of the phenomenon of persistence of L. monocytogenes. PMID- 26594791 TI - Aroma compounds generation in citrate metabolism of Enterococcus faecium: Genetic characterization of type I citrate gene cluster. AB - Enterococcus is one of the most controversial genera belonging to Lactic Acid Bacteria. Research involving this microorganism reflects its dual behavior as regards its safety. Although it has also been associated to nosocomial infections, natural occurrence of Enterococcus faecium in food contributes to the final quality of cheese. This bacterium is capable of fermenting citrate, which is metabolized to pyruvate and finally derives in the production of the aroma compounds diacetyl, acetoin and 2,3 butanediol. Citrate metabolism was studied in E. faecium but no data about genes related to these pathways have been described. A bioinformatic approach allowed us to differentiate cit(-) (no citrate metabolism genes) from cit(+) strains in E. faecium. Furthermore, we could classify them according to genes encoding for the transcriptional regulator, the oxaloacetate decarboxylase and the citrate transporter. Thus we defined type I organization having CitI regulator (DeoR family), CitM cytoplasmic soluble oxaloacetate decarboxylase (Malic Enzyme family) and CitP citrate transporter (2 hydroxy-carboxylate transporter family) and type II organization with CitO regulator (GntR family), OAD membrane oxaloacetate decarboxylase complex (Na(+) transport decarboxylase enzyme family) and CitH citrate transporter (CitMHS family). We isolated and identified 17 E. faecium strains from regional cheeses. PCR analyses allowed us to classify them as cit(-) or cit(+). Within the latter classification we could differentiate type I but no type II organization. Remarkably, we came upon E. faecium GM75 strain which carries the insertion sequence IS256, involved in adaptative and evolution processes of bacteria related to Staphylococcus and Enterococcus genera. In this work we describe the differential behavior in citrate transport, metabolism and aroma generation of three strains and we present results that link citrate metabolism and genetic organizations in E. faecium for the first time. PMID- 26594792 TI - Single-cell sequencing in cancer research. AB - Genome-wide single-cell sequencing investigations have the potential to classify individual cells within a tumor mass. In recent years, various single-cell DNA and RNA quantification techniques have facilitated significant advances in our ability to classify subpopulations of cells within a heterogeneous population. These approaches provide the possibility of unraveling the complex variability in genetic, epigenetic and transcriptional interactions that occur within identical cells in a tumor. This should enhance our knowledge of the underlying biological phenotypes and could have a huge impact in designing more precise anticancer treatments in order to improve outcomes and avoid tumor resistance. In addition, single-cell sequencing analysis has the potential to allow the development of better diagnostic and prognostic biomarkers, and thus aid the delivery of more personalized targeted cancer therapy. Nevertheless, further research is still required to overcome technical, biological and computational problems before clinical application. PMID- 26594793 TI - Conducting a Peer Review: Novice or Expert. PMID- 26594795 TI - Recognizing Excellence in the Neonatal Nursing Profession. PMID- 26594798 TI - Decreased expression of PBLD correlates with poor prognosis and functions as a tumor suppressor in human hepatocellular carcinoma. AB - Recent accumulating genomic and proteomic data suggested that decreased expression of phenazine biosynthesis-like domain-containing protein (PBLD) was frequently involved in hepatocellular carcinoma (HCC). However, there is lack of systematical investigation focusing on its expression pattern, clinical relevance, and biological function. Here, we found that PBLD was frequently decreased in HCC tissues relative to adjacent non-tumorigenic liver tissues. This decreased expression was significantly associated with poor tumor differentiation and advanced tumor stage. Kaplan-Meier analysis further showed that recurrence free survival and overall survival were significantly worse among patients with low PBLD expression. Moreover, multivariate analyses revealed that PBLD was an independent predictor of OS and RFS. This prognostic value of PBLD was further validated in another independent cohort. We also found PBLD inhibited HCC cell growth and invasion in vitro and tumor growth in vivo. Furthermore, forced expression of PBLD influenced multiple downstream genes related to MAPK, NF kappaB, EMT, and angiogenesis signaling pathways. PBLD deletion was an independent predictor of poor prognosis in patients with HCC. Elevated PBLD expression may reduce HCC cell growth and invasion via inactivation of several tumorigenesis-related signaling pathways. PMID- 26594802 TI - View from the Summit reveals gaps in the landscape. PMID- 26594799 TI - Donor-derived stem-cells and epithelial mesenchymal transition in squamous cell carcinoma in transplant recipients. AB - BACKGROUND: Skin squamous-cell-carcinoma (SCC), is the main complication in long term kidney-transplant recipients, and it can include donor-derived cells. Preclinical models demonstrated the involvement of epithelial mesenchymal transition (EMT) in the progression of skin SCC, and the role of Snail, an EMT transcription factor, in cancer stem-cell survival and expansion.Here, we studied stem-cells and EMT expression in SCCs and concomitant actinic keratoses (AK) in kidney-transplant recipients. METHODS: In SCC and AK in 3 female recipients of male kidney-transplants, donor-derived Y chromosome in epidermal stem cells was assessed using combined XY-FISH/CD133 immunostaining, and digital-droplet-PCR on laser-microdissected CD133 expressing epidermal cells.For EMT study, double immunostainings of CD133 with vimentin or snail and slug, electron microscopy and immunostainings of keratinocytes junctions were performed. Digital droplet PCR was used to check CDH1 (E-cadherin) expression level in laser-microdissected cells co-expressing CD133 and vimentin or snail and slug.The numbers of Y chromosome were assessed using digital droplet PCR in laser-microdissected cells co-expressing CD133 and vimentin, or snail and slug, and in CD133 positive cells not expressing any EMT maker. RESULTS: We identified donor-derived stem-cells in basal layers and invasive areas in all skin SCCs and in concomitant AKs, but not in surrounding normal skin.The donor-derived stem-cells expressed the EMT markers, vimentin, snail and slug in SCCs but not in AKs. The expression of the EMT transcription factor, SNAI1, was higher in stem-cells when they expressed vimentin. They were located in invasive areas of SCCs. In these areas, the expressions of claudin-1 and desmoglein 1 were reduced or absent, and within the basal layer there were features of basal membrane disappearance.Donor-derived stem cells were in larger numbers in stem cells co-expressing vimentin or snail and slug than in stem cells not expressing any EMT marker. CONCLUSIONS: We identified here donor-derived stem cells within skin SCC in kidney-transplant recipients. They were located in invasive areas of SCC and had EMT characteristics. PMID- 26594800 TI - A PCA3 gene-based transcriptional amplification system targeting primary prostate cancer. AB - Targeting specifically primary prostate cancer (PCa) cells for immune therapy, gene therapy or molecular imaging is of high importance. The PCA3 long non-coding RNA is a unique PCa biomarker and oncogene that has been widely studied. This gene has been mainly exploited as an accurate diagnostic urine biomarker for PCa detection. In this study, the PCA3 promoter was introduced into a new transcriptional amplification system named the 3-Step Transcriptional Amplification System (PCA3-3STA) and cloned into type 5 adenovirus. PCA3-3STA activity was highly specific for PCa cells, ranging between 98.7- and 108.0-fold higher than that for benign primary prostate epithelial or non-PCa cells, respectively. In human PCa xenografts, PCA3-3STA displayed robust bioluminescent signals at levels that are sufficient to translate to positron emission tomography (PET)-based reporter imaging. Remarkably, when freshly isolated benign or cancerous prostate biopsies were infected with PCA3-3STA, the optical signal produced from primary PCa biopsies was significantly higher than from benign prostate biopsies (4.4-fold, p < 0.0001). PCA3-3STA therefore represents a PCa specific expression system with the potential to target, with high accuracy, primary or metastatic PCa epithelial cells for imaging, vaccines, or gene therapy. PMID- 26594803 TI - Searching for shelter. Veterinarians in Wisconsin fight homelessness while protecting the human-animal bond. PMID- 26594804 TI - Effects of diet on lower urinary tract signs in cats with nonobstructive idiopathic cystitis. PMID- 26594805 TI - What Is Your Diagnosis? Gastric dilatation-volvulus. PMID- 26594806 TI - What Is Your Diagnosis? Transmissible venereal tumor. PMID- 26594807 TI - What Is Your Neurologic Diagnosis? Intracranial cyst. PMID- 26594808 TI - ECG of the Month. Sinus arrhythmia. PMID- 26594809 TI - Pathology in Practice. Transitional cell carcinoma. PMID- 26594810 TI - Compendium of Veterinary Standard Precautions for Zoonotic Disease Prevention in Veterinary Personnel: National Association of State Public Health Veterinarians: Veterinary Infection Control Committee 2015. PMID- 26594811 TI - Comparison of the ability of veterinary medical students to perform laparoscopic versus conventional open ovariectomy on live dogs. AB - OBJECTIVE: To compare the feasibility of training veterinary medicine students to perform laparoscopic versus conventional open ovariectomy in live dogs. DESIGN: Randomized prospective parallel-group experiment. POPULATION: 25 students completing the second year of their veterinary curriculum. PROCEDURES: Students were randomly assigned to 2 groups to receive 14 hours of specific training in either open ovariectomy (n = 13) or laparoscopic ovariectomy (12). Confidence, basic surgical skills, and basic laparoscopic skills were evaluated before and after training, prior to live surgical procedures. RESULTS: Scores related to basic surgical skills were high in both groups and did not improve with either training program. Before live animal surgeries, student confidence and basic laparoscopic skills improved after training in laparoscopic ovariectomy and were higher than after training in open ovariectomy. Surgery time was higher for the students who received training in laparoscopic ovariectomy (129 minutes; range, 84 to 143 minutes), compared with students who received training in open ovariectomy (80 minutes; range, 62 to 117 minutes). On a 55-point scoring system, ovariectomy scores were similar between students who received training in open ovariectomy (34.5; range, 16.5 to 45) and students who received training in laparoscopic ovariectomy (34.5; range, 25 to 44.5). CONCLUSIONS AND CLINICAL RELEVANCE: The training programs were effective in improving student confidence and skills in laparoscopic ovariectomy. Results of this study suggested that veterinary medical students, with assistance from an instructor, may be taught to perform laparoscopic ovariectomies with performance equivalent to that for students performing open ovariectomies. PMID- 26594812 TI - Effects of repeated petting sessions on leukocyte counts, intestinal parasite prevalence, and plasma cortisol concentration of dogs housed in a county animal shelter. AB - OBJECTIVE: To describe changes in WBC counts, plasma cortisol concentration, and fecal parasite shedding of dogs housed in an animal shelter and determine the effects of daily petting sessions on these variables. DESIGN: Hybrid prospective observational and experimental study. ANIMALS: 92 healthy dogs newly arrived to an animal shelter and 15 healthy privately owned dogs (control group). PROCEDURES: Blood and fecal samples were collected from shelter dogs 1, 3, and 10 days after arrival and from control dogs once. A subset of shelter dogs (n = 15) was assigned to receive 30 minutes of petting daily. Plasma cortisol concentration was measured, CBCs were performed, and fecal samples were evaluated for parasite ova. RESULTS: For shelter dogs, total leukocyte, neutrophil, and lymphocyte counts increased significantly between days 1 and 10, with less consistent increases in monocyte count and neutrophil-to-lymphocyte count ratio. Parasite shedding was unaffected by duration of shelter stay but was greater for shelter versus control dogs. For shelter dogs, plasma cortisol concentration decreased with time and was higher than that of control dogs on each day. Total leukocyte, neutrophil, and monocyte counts and neutrophil-to-lymphocyte count ratios were also higher for shelter versus control dogs. Petting sessions resulted in a decrease in plasma cortisol concentration but in no other variables. CONCLUSIONS AND CLINICAL RELEVANCE: Large increasing immunologic responses, heavy parasite shedding, and high but decreasing plasma cortisol concentration were identified in shelter dogs. Daily 30-minute petting sessions affected only cortisol values, so the clinical importance of petting for immunologic and other health outcomes remains unclear. PMID- 26594813 TI - Transcatheter arterial embolization for treatment of hepatocellular carcinoma in a cat. AB - CASE DESCRIPTION: A 16-year-old 6.8-kg (15-lb) castrated male domestic shorthair cat was evaluated because of a 3 * 6-cm mass in the right medial lobe of the liver. CLINICAL FINDINGS: The cat had a history of frequent vomiting and anorexia along with 10% weight loss over the past year. TREATMENT AND OUTCOME: Transcatheter arterial embolization was selected because surgery (standard first line treatment) was declined and only 1 vessel feeding the tumor was apparent on contrast-enhanced CT. A 4F sheath was placed in the left carotid artery, and a 3.3F guide catheter was advanced into the celiac artery. A 0.014-inch guidewire and 1.7F microcatheter were inserted into the hepatic artery through the guiding catheter and advanced into the feeding vessel. A mixture of polyvinyl alcohol particles and contrast agent was injected for embolization. A hypoechoic area in the tumor was identified on ultrasonography on posttreatment day 6, and necrotic and degenerated cells in the area were identified cytologically. By posttreatment day 71, vomiting had resolved and CT revealed decreased tumor size, but altered attenuation suggested a more solid mass on day 205. No feeding vessel for embolization was found on contrast-enhanced CT, so ultrasonic emulsification to remove the tumor was performed on day 231. No recurrence was seen on contrast enhanced CT on day 420 or day 721. CLINICAL RELEVANCE: Findings suggested that transcatheter arterial embolization may be suitable for treating hepatic tumors in cats, but alternative approaches are needed in cats, compared with dogs, owing to anatomic differences. PMID- 26594814 TI - Endoscopic treatment of an intrathoracic tracheal osteochondroma in a dog. AB - CASE DESCRIPTION: A 1.5-year-old spayed female Bernese Mountain Dog was examined for a 6-month history of intermittent vomiting, regurgitation, wheezing, and coughing. Initially, a diagnosis of gastroesophageal reflux disease with secondary aspiration pneumonitis was made but clinical signs did not resolve with treatment. CLINICAL FINDINGS: Thoracic and cervical radiography and CT revealed a sessile, irregularly marginated soft tissue opacity at the level of the fourth rib. Results of a CBC, serum biochemical analysis, and urinalysis were within reference limits. Results of abdominal ultrasonography were normal. TREATMENT AND OUTCOME: Tracheoscopy revealed a firm, irregularly marginated mass apparently originating from the ventral aspect of the trachea, occluding approximately one half of the tracheal lumen, and located 2 cm cranial to the carina. Cytologic and histopathologic examination of fine-needle aspirate and biopsy samples suggested a benign etiology; therefore, endoscopic minimally invasive laser and electrocautery resection of the mass was scheduled. A total IV anesthetic protocol was administered with an oxygen-air mixture used to decrease the risk of fire during tracheal surgery. The mass was successfully resected, and histopathologic examination confirmed a diagnosis of osteochondroma. Clinical signs resolved, and at follow-up 32 months later, no regrowth of the mass was evident. CLINICAL RELEVANCE: Tracheoscopy-guided electrocautery and surgical diode laser resection was successful in removing an obstructive tracheal mass that was not resectable by means of a conventional open surgical approach. Minimally invasive procedures may decrease morbidity and mortality and improve outcome in appropriately selected small animal patients. PMID- 26594815 TI - Medical treatment of horses with deep digital flexor tendon injuries diagnosed with high-field-strength magnetic resonance imaging: 118 cases (2000-2010). AB - OBJECTIVE: To describe the location and severity of deep digital flexor tendon (DDFT) lesions diagnosed by means of high-field-strength MRI in horses and to identify variables associated with return to activity following medical treatment. DESIGN: Retrospective case series. ANIMALS: 118 horses. PROCEDURES: Medical records of horses with DDFT injury diagnosed with MRI over a 10-year period (2000-2010) and treated medically (intrasynovial administration of corticosteroids and sodium hyaluronan, rest and rehabilitation, or both) were reviewed. History, signalment, use, results of lameness examination and diagnostic local anesthesia, MRI findings, and treatment details were recorded. Outcome was obtained by telephone interview or follow-up examination. Horses were grouped by predictor variables and analyzed with logistic regression to identify significant effects. RESULTS: Overall, of 97 horses available for follow-up (median time to follow-up, 5 years; range, 1 to 12 years), 59 (61%) returned to activity for a mean duration of 22.6 months (median, 18 months; range, 3 to 72 months), with 25 (26%) still sound at follow-up. Of horses with mild, moderate, and severe injury, 21 of 29 (72%), 20 of 36 (56%), and 18 of 32 (56%), respectively, returned to use. Horses treated with intrasynovial corticosteroid injection and 6 months of rest and rehabilitation returned to use for a significantly longer duration than did horses treated without rest. Western performance horses returned to use for a significantly longer duration than did English performance horses. CONCLUSIONS AND CLINICAL RELEVANCE: Results of the present study suggested that outcome for horses with DDFT injuries treated medically depended on injury severity, presence of concurrent injury to other structures in the foot, type of activity, and owner compliance with specific treatment recommendations. Although some horses successfully returned to prior activity, additional treatment options are needed to improve outcome in horses with severe injuries and to improve long-term prognosis. PMID- 26594816 TI - Addition of long-acting beta2-agonists to inhaled corticosteroids for chronic asthma in children. AB - BACKGROUND: Long-acting beta2-agonists (LABA) in combination with inhaled corticosteroids (ICS) are increasingly prescribed for children with asthma. OBJECTIVES: To assess the safety and efficacy of adding a LABA to an ICS in children and adolescents with asthma. To determine whether the benefit of LABA was influenced by baseline severity of airway obstruction, the dose of ICS to which it was added or with which it was compared, the type of LABA used, the number of devices used to deliver combination therapy and trial duration. SEARCH METHODS: We searched the Cochrane Airways Group Asthma Trials Register until January 2015. SELECTION CRITERIA: We included randomised controlled trials testing the combination of LABA and ICS versus the same, or an increased, dose of ICS for at least four weeks in children and adolescents with asthma. The main outcome was the rate of exacerbations requiring rescue oral steroids. Secondary outcomes included markers of exacerbation, pulmonary function, symptoms, quality of life, adverse events and withdrawals. DATA COLLECTION AND ANALYSIS: Two review authors assessed studies independently for methodological quality and extracted data. We obtained confirmation from trialists when possible. MAIN RESULTS: We included in this review a total of 33 trials representing 39 control-intervention comparisons and randomly assigning 6381 children. Most participants were inadequately controlled on their current ICS dose. We assessed the addition of LABA to ICS (1) versus the same dose of ICS, and (2) versus an increased dose of ICS.LABA added to ICS was compared with the same dose of ICS in 28 studies. Mean age of participants was 11 years, and males accounted for 59% of the study population. Mean forced expiratory volume in one second (FEV1) at baseline was >= 80% of predicted in 18 studies, 61% to 79% of predicted in six studies and unreported in the remaining studies. Participants were inadequately controlled before randomisation in all but four studies.There was no significant group difference in exacerbations requiring oral steroids (risk ratio (RR) 0.95, 95% confidence interval (CI) 0.70 to 1.28, 12 studies, 1669 children; moderate quality evidence) with addition of LABA to ICS compared with ICS alone. There was no statistically significant group difference in hospital admissions (RR 1.74, 95% CI 0.90 to 3.36, seven studies, 1292 children; moderate-quality evidence)nor in serious adverse events (RR 1.17, 95% CI 0.75 to 1.85, 17 studies, N = 4021; moderate-quality evidence). Withdrawals occurred significantly less frequently with the addition of LABA (23 studies, 471 children, RR 0.80, 95% CI 0.67 to 0.94; low-quality evidence). Compared with ICS alone, addition of LABA led to significantly greater improvement in FEV1 (nine studies, 1942 children, inverse variance (IV) 0.08 L, 95% CI 0.06 to 0.10; mean difference (MD) 2.99%, 95% CI 0.86 to 5.11, seven studies, 534 children; low-quality evidence), morning peak expiratory flow (PEF) (16 studies, 3934 children, IV 10.20 L/min, 95% CI 8.14 to 12.26), reduction in use of daytime rescue inhalations (MD -0.07 puffs/d, 95% CI 0.11 to -0.02, seven studies; 1798 children) and reduction in use of nighttime rescue inhalations (MD -0.08 puffs/d, 95% CI -0.13 to -0.03, three studies, 672 children). No significant group difference was noted in exercise-induced % fall in FEV1, symptom-free days, asthma symptom score, quality of life, use of reliever medication and adverse events.A total of 11 studies assessed the addition of LABA to ICS therapy versus an increased dose of ICS with random assignment of 1628 children. Mean age of participants was 10 years, and 64% were male. Baseline mean FEV1 was >= 80% of predicted. All trials enrolled participants who were inadequately controlled on a baseline inhaled steroid dose equivalent to 400 ug/d of beclomethasone equivalent or less.There was no significant group differences in risk of exacerbation requiring oral steroids with the combination of LABA and ICS versus a double dose of ICS (RR 1.69, 95% CI 0.85 to 3.32, three studies, 581 children; moderate-quality evidence) nor in risk of hospital admission (RR 1.90, 95% CI 0.65 to 5.54, four studies, 1008 children; moderate-quality evidence).No statistical significant group difference was noted in serious adverse events (RR 1.54, 95% CI 0.81 to 2.94, seven studies, N = 1343; moderate-quality evidence) and no statistically significant differences in overall risk of all-cause withdrawals (RR 0.96, 95% CI 0.67 to 1.37, eight studies, 1491 children; moderate-quality evidence). Compared with double the dose of ICS, use of LABA was associated with significantly greater improvement in morning PEF (MD 8.73 L/min, 95% CI 5.15 to 12.31, five studies, 1283 children; moderate-quality evidence), but data were insufficient to aggregate on other markers of asthma symptoms, rescue medication use and nighttime awakening. There was no group difference in risk of overall adverse effects, A significant group difference was observed in linear growth over 12 months, clearly indicating lower growth velocity in the higher ICS dose group (two studies: MD 1.21 cm/y, 95% CI 0.72 to 1.70). AUTHORS' CONCLUSIONS: In children with persistent asthma, the addition of LABA to ICS was not associated with a significant reduction in the rate of exacerbations requiring systemic steroids, but it was superior for improving lung function compared with the same or higher doses of ICS. No differences in adverse effects were apparent, with the exception of greater growth with the use of ICS and LABA compared with a higher ICS dose. The trend towards increased risk of hospital admission with LABA, irrespective of the dose of ICS, is a matter of concern and requires further monitoring. PMID- 26594817 TI - Tannin-Rich Fraction from Pomegranate Rind Inhibits Quorum Sensing in Chromobacterium violaceum and Biofilm Formation in Escherichia coli. AB - Pomegranate rind has been found to inhibit numerous pathogens, mostly attributed to its tannin fraction. The present study was conducted to investigate the quorum sensing (QS) inhibition effect of tannin-rich fraction from pomegranate rind (TFPR) by using an indicator strain Chromobacterium violaceum. Meanwhile, its effect on biofilm formation and motility of Escherichia coli was evaluated. It was shown that TFPR inhibited QS-regulated violacein pigment production. Biofilm formation and motility of E. coli were also hindered by TFPR. Transcriptional analysis further showed that TFPR repressed expressions of curli genes (csgB and csgD) and various motility genes (fimA, fimH, flhD, motB, qseB, and qseC). Our findings indicated that TFPR has potential application for controlling E. coli contaminations or biofilms in the food industry. PMID- 26594818 TI - Improving Adherence to Therapy and Clinical Outcomes While Containing Costs: Opportunities From the Greater Use of Generic Medications: Best Practice Advice From the Clinical Guidelines Committee of the American College of Physicians. AB - DESCRIPTION: The discrepancy between health care spending and achieved outcomes in the United States has fueled efforts to identify and address situations where unnecessarily expensive therapies are used when less costly, equally effective options are available. The underuse of generic medications is an important example. METHODS: A literature review was conducted to answer 5 questions about generic medications: 1) How commonly are brand-name medications used when a generic version is available? 2) How does the use of generic medications influence adherence? 3) What is the evidence that brand-name and generic medications have similar clinical effects? 4) What are the barriers to increasing the use of generic medications? 5) What strategies can be used to promote cost savings through greater generic medication use? This article was reviewed and approved by the American College of Physicians Clinical Guidelines Committee. BEST PRACTICE ADVICE: Clinicians should prescribe generic medications, if possible, rather than more expensive brand-name medications. PMID- 26594819 TI - Estimated GFR for Living Kidney Donor Evaluation. AB - All living kidney donor candidates undergo evaluation of GFR. Guidelines recommend measured GFR (mGFR), using either an endogenous filtration marker or creatinine clearance, rather than estimated GFR (eGFR), but measurement methods are difficult, time consuming and costly. We investigated whether GFR estimated from serum creatinine (eGFRcr) with or without sequential cystatin C is sufficiently accurate to identify donor candidates with high probability that mGFR is above or below thresholds for clinical decision making. We combined the pretest probability for mGFR thresholds <60, <70, >=80, and >=90 mL/min per 1.73 m(2) based on demographic characteristics (from the National Health and Nutrition Examination Survey) with test performance of eGFR (categorical likelihood ratios from the Chronic Kidney Disease Epidemiology Collaboration) to compute posttest probabilities. Using data from the Scientific Registry of Transplant Recipients, 53% of recent living donors had predonation eGFRcr high enough to ensure >=95% probability that predonation mGFR was >=90 mL/min per 1.73 m(2) , suggesting that mGFR may not be necessary in a large proportion of donor candidates. We developed a Web-based application to compute the probability, based on eGFR, that mGFR for a donor candidate is above or below a range of thresholds useful in living donor evaluation and selection. PMID- 26594820 TI - Web-Based Behavioral Intervention Increases Maternal Exercise but Does Not Prevent Excessive Gestational Weight Gain in Previously Sedentary Women. AB - BACKGROUND: Innovative methods are warranted to optimize prenatal outcomes. This study's objective was to determine if a web-based behavioral intervention (BI) can prevent excessive gestational weight gain (GWG) by increasing physical activity (PA). METHODS: Participants were randomized to usual care (UC; n = 21) or BI (n = 24) between 10 to 14 weeks gestation. GWG, PA, and diet were assessed at baseline, mid-, and late pregnancy. RESULTS: No differences in GWG or adherence to GWG recommendations presented between groups. Total UC MET-minutes significantly decreased from baseline to late-pregnancy (1,234 +/- 372 MET minutes, P = .013). Mid-pregnancy sustained PA was greater for BI than UC (20 minute PA bouts: 122 +/- 106 vs. 46 +/- 48 minutes/week, P = .005; 30-minute PA bouts: 74 +/- 70 vs. 14 +/- 24 minutes/week, P < .001), and greater for BI at mid pregnancy compared with baseline (20-minute PA bouts: 61.3 +/- 21.9; 30-minute PA bouts: 39.6 +/- 14.8, both P < .05). BI energy intake at mid-pregnancy significantly increased from baseline (336 +/- 127 kcals, P = .04) and was significantly greater than UC (2,503 +/- 703 vs. 1,894 +/- 594, P = .005). CONCLUSIONS: Sedentary pregnant women should increase PA but may need additional dietary counseling to prevent excessive GWG. PMID- 26594822 TI - Influence of indoor microbial aerosol on the welfare of meat ducks. AB - The aim of the study was to evaluate the effects of microbial aerosols on ducks' welfare and provide information on which to establish microbial aerosol concentration standards for poultry. A total of 1800 1-d-old Cherry Valley ducks were randomly divided into 5 groups (A, B, C, D and E) with 360 ducks in each. To obtain objective data, each group had three replications. Different microbial aerosol concentrations in different groups were created by controlling ventilation and bedding cleaning frequency. Group A was the control group and hygienic conditions deteriorated progressively from group B to E. A 6-stage Andersen impactor was used to detect the aerosol concentration of aerobes, fungi, gram-negative bacteria and an AGI-30 microbial air sampler detected endotoxins. Physiological stress was evaluated in the ducks by adrenocorticotropic hormone (ACTH) values in serum. To assess the effects of bioaerosol factors, welfare indicators including fluctuating asymmetry (FA), appearance and gait as well as the Lactobacillus caecal concentration were evaluated. The data showed group D had already reached the highest limit of concentration of airborne aerobic bacteria, airborne fungi, airborne gram-negative bacteria and airborne endotoxin. The ducks in this group had significantly increased serum ACTH values and significantly decreased caecal lactobacilli concentration. Furthermore, appearance and gait scores, wing length and overall FA and caecal Lactobacillus concentration in this group were significantly increased at 6 and 8 weeks of age. In conclusion, high concentrations of microbial aerosol adversely affected the welfare of meat ducks. The microbial aerosol values in group D suggest a preliminary upper limit concentration of bioaerosols in ambient air for healthy meat ducks. PMID- 26594823 TI - Dalvelutinoside, a new isoflavone glycoside from the methanol extract of Dalbergia velutina roots. AB - A new isoflavone glycoside, dalvelutinoside (1), together with one known isoflavone (2) and five known isoflavone glycosides (3-7) were isolated from the methanol extract of the roots of Dalbergia velutina. Their structures were determined by spectroscopic analysis. All isolated compounds were evaluated for their cytotoxicity against KB and HeLa cell lines. PMID- 26594824 TI - Contribution of Electrostatics in the Fibril Stability of a Model Ionic Complementary Peptide. AB - In this work we quantified the role of electrostatic interactions in the self assembly of a model amphiphilic peptide (RADA 16-I) into fibrillar structures by a combination of size exclusion chromatography and molecular simulations. For the peptide under investigation, it is found that a net charge of +0.75 represents the ideal condition to promote the formation of regular amyloid fibrils. Lower net charges favor the formation of amorphous precipitates, while larger net charges destabilize the fibrillar aggregates and promote a reversible dissociation of monomers from the ends of the fibrils. By quantifying the dependence of the equilibrium constant of this reversible reaction on the pH value and the peptide net charge, we show that electrostatic interactions contribute largely to the free energy of fibril formation. The addition of both salt and a charged destabilizer (guanidinium hydrochloride) at moderate concentration (0.3-1 M) shifts the monomer-fibril equilibrium toward the fibrillar state. Whereas the first effect can be explained by charge screening of electrostatic repulsion only, the promotion of fibril formation in the presence of guanidinium hydrochloride is also attributed to modifications of the peptide conformation. The results of this work indicate that the global peptide net charge is a key property that correlates well with the fibril stability, although the peptide conformation and the surface charge distribution also contribute to the aggregation propensity. PMID- 26594825 TI - Letter from the Editor. PMID- 26594826 TI - Chiral Resolution of Racemic Environmental Pollutants by Capillary Electrophoresis. AB - The chiral resolution of environmental pollutants is an urgent need of today. Therefore, the chiral resolution of the environmental pollutants by capillary electrophoresis was reviewed. Various aspects of the chiral resolution by capillary electrophoresis such as chiral selectors, optimization of capillary electrophoresis conditions [composition of the back ground electrolyte (BGE), pH of the BGE, ionic strength of the BGE, structures and types of the chiral selectors, applied voltage, temperature, structures of the chiral pollutants, use of organic modifiers and other parameters, optimization by dependent variables], detection, sample treatment, validation of the methods and the chiral recognition mechanisms have been discussed. PMID- 26594827 TI - A More Rational Treatment of the Acid-Base Equilibria Applying the Proton Condition, or the Hydroxyl Condition, in Equilibrium. How the Hydroxyls are Additive in Equilibrium: Dissolutions of Bases, Salts and Mixtures. AB - The calculus of the acid-base equilibria can be rationalized by applying the proton condition or the hydroxyl condition in every case, on solutions of strong bases, mixtures of bases, mixtures of acids and bases, and different salts. Furthermore, applying the proton condition or the hydroxyl condition in equilibrium, it is clearly pointed out that the hydroxyls in equilibrium are additive in solutions of strong bases as well as in those of weak bases. PMID- 26594828 TI - Home-Based Screening for Biliary Atresia Using Infant Stool Color Cards in Canada: Quebec Feasibility Study. AB - OBJECTIVES: Biliary atresia (BA) is a leading cause of liver failure and liver transplantation in pediatrics. BA manifests by 3 weeks of life with jaundice and pale stools. Delayed diagnosis and surgical intervention with Kasai portoenterostomy after 3 months of age is significantly associated with poor prognosis for native liver survival. A national Taiwan infant stool color card (SCC) screening program has entirely eliminated late Kasai portoenterostomy >90 days of age and improved native liver survival. A recent large-scale prospective cohort study in British Columbia, Canada, indicated that distribution of SCC on the maternity ward was feasible, led to high utilization rate, and was cost effective. The aim of the present study was to assess the generalizability of this screening strategy in another Canadian jurisdiction with a different sociodemographic profile. METHODS: An SCC was distributed to families of newborns discharged at St Mary's Hospital Center, Montreal, Quebec. Families were instructed to monitor their infant's stool color for 21 days and then complete and mail the SCC to the study center. Phone surveys to families who did not return cards were used to estimate total card utilization rate. RESULTS: Two thousand two hundred forty-six infants were eligible for inclusion; 99.9% were enrolled. Mail SCC return rate was 63.3%. No cases of BA were identified. All of the 118 families who completed the phone survey reported that they had utilized the SCC. Conservative and optimistic estimates for total card utilization rates were 82% and 100%, respectively. CONCLUSIONS: The high enrollment and utilization rates in this screening study strongly support the feasibility of implementing a Canadian SCC screening program to improve outcomes of children with BA. PMID- 26594829 TI - Role of HLA-DQ Genotyping in Celiac Disease. PMID- 26594830 TI - Adverse Events Following Gastrointestinal Endoscopy in Children: Classifications, Characterizations, and Implications. AB - OBJECTIVE: To conduct a comprehensive study of postendoscopic adverse events (AEs) in children, categorizing them by the level of intervention required. BACKGROUND: Previous studies of endoscopic AE in children have focused on intraprocedural and short-term outcomes, such as bleeding, perforation, and infection, and may underestimate the incidence of AEs. DESIGN: Prospective observational study tracking AEs in pediatric patients within 72 hours of an endoscopic procedure. SETTING: Single-center study performed at an academic, tertiary care, free-standing children's hospital over a 48-month period, from July 2010 through June 2014. PATIENTS AND INTERVENTIONS: Of 9577 pediatric endoscopic procedures, cases identified as having an AE during or following endoscopy were subject to additional chart review for abstraction of relevant data. MAIN OUTCOME MEASUREMENTS: Type, severity, and subsequent interventions of AEs were the primary outcome measures. Events were categorized by severity grade, with grade 1, no intervention; grade 2, outpatient evaluation; grade 3, hospitalization or repeat endoscopy; grade 4, surgery or intensive care unit admission; and grade 5, death. RESULTS: In total, 249 endoscopic AEs were recognized of 9577 procedures performed, yielding a rate of 2.6%. Of these, 160 were identified to result in medical evaluation and costs (>=grade 2) for a rate of 1.7%. Rates of endoscopic AE after advanced or interventional endoscopic procedures were higher, with 65 of 1167 events, resulting in a total AE rate of 5.6% and a rate of 4.4% for AE >= grade 2. There were 10 cases of significant bleeding (0.1%), 9 cases of infection (0.09%), and 12 cases of perforation (0.13%), primarily occurring with advanced/interventional procedures. LIMITATIONS: Single-center study, lack of standardized criteria for ED referral. CONCLUSIONS: AEs presenting within 72 hours of endoscopy and resulting in medical intervention, occur more commonly than previously recognized in children. Standardized postendoscopy surveillance systems and definitions of AEs are needed. PMID- 26594831 TI - Liver Disease in Pediatric Patients With Ataxia Telangiectasia: A Novel Report. AB - OBJECTIVE: Ataxia telangiectasia (A-T) is a rare genetic multiorgan disease. Although gastrointestinal involvement is known, hepatic involvement in A-T has not been investigated. We aimed to study the hepatic involvement in a large cohort of patients with A-T. METHODS: A retrospective review of patients, studied from January 1986 to January 2015 at a National A-T Center. Clinical data including demographic, genetic, laboratory, nutritional, radiographic, and histological data were retrieved. RESULTS: Fifty-three patients, 27 (49%) boys, age 14.6 +/- 5.2 years (range 5.9-26.1 years), were included. Twenty-three patients (43.4%), age 9.9 +/- 5.1 years, had consistently abnormal liver enzymes. The mean enzyme levels were alanine aminotransferase 76.8 +/- 73.8 IU/L, aspartate aminotransferase 70 +/- 50 IU/L, alkaline phosphatase 331 +/- 134 IU/L, and gamma glutamyl transferase 114.7 +/- 8 IU/L. Evaluation of other etiology of liver disease was negative. Ultrasonography revealed fatty liver in 9 of them (39%). Liver biopsy was performed in 2 patients, revealing mild-to-moderate steatosis in both, and fibrosis in 1 patient. Progression to advanced liver disease occurred in 2 of 23 (9%) patients within 2 to 5 years. Dyslipidemia was significantly associated with abnormal liver enzymes: 3 of 30 (10%) patients without abnormal liver enzymes versus 10 of 23 (45.5%) patients with abnormal liver enzymes, respectively (P < 0.05, Fisher exact test). No correlation was found between hepatic involvement and HbA1C, sex, presence of malignancy, or type of mutation. CONCLUSIONS: Abnormal liver enzymes and fatty liver are common in patients with A-T and may progress to advanced liver disease at a young age. These findings are novel and implicate that patients with A-T with abnormal liver enzymes should be evaluated for the presence of liver disease. PMID- 26594833 TI - The Gut Is a Key Player in Cystic Fibrosis Malnutrition. PMID- 26594834 TI - Notice of Retraction: Ahimastos AA, et al. Effect of Perindopril on Large Artery Stiffness and Aortic Root Diameter in Patients With Marfan Syndrome: A Randomized Controlled Trial. JAMA. 2007;298(13):1539-1547. PMID- 26594832 TI - Toxic-metabolic Risk Factors in Pediatric Pancreatitis: Recommendations for Diagnosis, Management, and Future Research. AB - Pancreatitis in children can result from metabolic and toxic risk factors, but the evidence linking these factors is sparse. We review the evidence for association or causality of these risk factors in pancreatitis, discuss management strategies, and their rationale. We conducted a review of the pediatric pancreatitis literature with respect to the following risk factors: hyperlipidemia, hypercalcemia, chronic renal failure, smoking exposure, alcohol, and medications. Areas of additional research were identified. Hypertriglyceridemia of 1000 mg/dL or greater poses an absolute risk for pancreatitis; persistent elevations of calcium are predisposing. Further research is necessary to determine whether end-stage renal disease leads to increased pancreatitis in children similar to adults. It is unknown whether cigarette smoking exposure, which clearly increases risk in adults, also increases risk in children. The role of alcohol in pediatric pancreatitis, whether direct or modifying, needs to be elucidated. The evidence supporting most cases of medication-induced pancreatitis is poor. Drug structure, improper handling of drug by host, and bystander status may be implicated. Other pancreatitis risk factors must be sought in all cases. The quality of evidence supporting causative role of various toxic and metabolic factors in pediatric pancreatitis is variable. Careful phenotyping is essential, including search for other etiologic risk factors. Directed therapy includes correction/removal of any agent identified, and general supportive measures. Further research is necessary to improve our understanding of these pancreatitis risk factors in children. PMID- 26594835 TI - Multiparametric prostate magnetic resonance imaging in the evaluation of prostate cancer. AB - Imaging has traditionally played a minor role in the diagnosis and staging of prostate cancer. However, recent controversies generated by the use of prostate specific antigen (PSA) screening followed by random biopsy have encouraged the development of new imaging methods for prostate cancer. Multiparametric magnetic resonance imaging (mpMRI) has emerged as the imaging method best able to detect clinically significant prostate cancers and to guide biopsies. Here, the authors explain what mpMRI is and how it is used clinically, especially with regard to high-risk populations, and we discuss the impact of mpMRI on treatment decisions for men with prostate cancer. CA Cancer J Clin 2016;66:326-336. (c) 2015 American Cancer Society. PMID- 26594836 TI - Abscisic-acid-induced cellular apoptosis and differentiation in glioma via the retinoid acid signaling pathway. AB - Retinoid acid (RA) plays critical roles in regulating differentiation and apoptosis in a variety of cancer cells. Abscisic acid (ABA) and RA are direct derivatives of carotenoids and share structural similarities. Here we proposed that ABA may also play a role in cellular differentiation and apoptosis by sharing a similar signaling pathway with RA that may be involved in glioma pathogenesis. We reported for the first time that the ABA levels were twofold higher in low-grade gliomas compared with high-grade gliomas. In glioma tissues, there was a positive correlation between the ABA levels and the transcription of cellular retinoic acid-binding protein 2 (CRABP2) and a negative correlation between the ABA levels and transcription of fatty acid-binding protein 5 (FABP5). ABA treatment induced a significant increase in the expression of CRABP2 and a decrease in the expression of peroxisome proliferator-activated receptor (PPAR) in glioblastoma cells. Remarkably, both cellular apoptosis and differentiation were increased in the glioblastoma cells after ABA treatment. ABA-induced cellular apoptosis and differentiation were significantly reduced by selectively silencing RAR-alpha, while RAR-alpha overexpression exaggerated the ABA-induced effects. These results suggest that ABA may play a role in the pathogenesis of glioma by promoting cellular apoptosis and differentiation through the RA signaling pathway. PMID- 26594838 TI - Differentiation Potential of Adipose-Derived Stem Cells When Cocultured with Smooth Muscle Cells, and the Role of Low-Intensity Laser Irradiation. AB - OBJECTIVE: The aim of the study was to investigate the differentiation potential of adipose-derived stem cells (ADSCs) when cocultured with smooth muscle cells (SMCs), and to determine the role of low-intensity laser irradiation (LILI). BACKGROUND DATA: ADSCs isolated from adipose tissue are isolated with ease and in large amounts. SMCs constitute most parts of the intestinal, urinary, reproductive, and cardiovascular systems. LILI has been found to have positive effects on different cell types, including ADSCs. METHODS: The study used ADSCs (Stempro Adipose Derived Stem Cells-R7788-115) and SMCs (SKU-T-1 American Type Culture Collection HTB-114) cell lines. These cell lines were cocultured in a 1:1 ratio with and without growth factors and then exposed to LILI using 636 nm at 5 J/cm2. RESULTS: Cell viability and proliferation increased significantly in the cocultured groups that were exposed to LILI alone, as well as in combination with growth factors. Further, there was a significant decrease in the expression of stem cell markers with a concomitant increase in SMC markers. CONCLUSIONS: These results suggest that ADSCs have the ability to differentiate into SMCs when cocultured with SMCs, whereas LILI potentially augments the differentiation potential and need. This further highlights the significant role that LILI has to offer ADSC therapy in regenerative medicine. PMID- 26594837 TI - Efficacy and tolerability of pharmacotherapy for smoking cessation in adults with serious mental illness: a systematic review and network meta-analysis. AB - BACKGROUND AND AIMS: To assess the efficacy and tolerability of adjunctive pharmacotherapy for smoking cessation in adults with serious mental illness (SMI) by means of a systematic review and network meta-analysis. METHOD: We searched Embase, Medline, PsychINFO and the Cochrane Central Register of Controlled Trials from database inception to 1 December 2014 for randomized controlled trials (RCTs) published in English. We included all studies of smokers with SMI (including schizophrenia, schizoaffective disorder, bipolar disorder, delusional disorder and depressive psychoses) who were motivated to quit smoking. Pharmacotherapies included nicotine replacement therapy (NRT), bupropion and varenicline delivered as monotherapy or in combination compared with each other or placebo. The efficacy outcome was self-reported sustained smoking cessation, verified biochemically at the longest reported time-point. The tolerability outcome was number of patients discontinuing the trial due to any adverse event. RESULTS: Seventeen study reports were included, which represented 14 individual RCTs. No trials were found in patients with depressive psychoses, delusional disorder or that compared NRT monotherapy with placebo. A total of 356 and 423 participants were included in the efficacy and tolerability analyses, respectively. From the network meta-analysis, both bupropion and varenicline were more effective than placebo [odds ratio (OR) = 4.51, 95% credible interval (CrI) = 1.45-14.04 and OR = 5.17, 95% CrI = 1.78-15.06, respectively]. Data were insensitive to an assessment of varenicline versus bupropion (OR = 1.15, 95% CrI = 0.24-5.45). There were no significant differences in tolerability. All outcomes were rated by GRADE criteria as very low quality. CONCLUSIONS: The limited evidence available to date suggests that bupropion and varenicline are effective and tolerable for smoking cessation in adults with serious mental illnesses. PMID- 26594840 TI - Enhanced resistive switching in forming-free graphene oxide films embedded with gold nanoparticles deposited by electrophoresis. AB - Forming-free resistive random access memory (ReRAM) devices having low switching voltages are a prerequisite for their commercial applications. In this study, the forming-free resistive switching characteristics of graphene oxide (GO) films embedded with gold nanoparticles (Au Nps), having an enhanced on/off ratio at very low switching voltages, were investigated for non-volatile memories. The GOAu films were deposited by the electrophoresis method and as-grown films were found to be in the low resistance state; therefore no forming voltage was required to activate the devices for switching. The devices having an enlarged on/off ratio window of ~10(6) between two resistance states at low voltages (<1 V) for repetitive dc voltage sweeps showed excellent properties of endurance and retention. In these films Au Nps were uniformly dispersed over a large area that provided charge traps, which resulted in improved switching characteristics. Capacitance was also found to increase by a factor of ~10, when comparing high and low resistance states in GOAu and pristine GO devices. Charge trapping and de trapping by Au Nps was the mechanism responsible for the improved switching characteristics in the films. PMID- 26594839 TI - OBSESSIVE-COMPULSIVE PERSONALITY DISORDER: EVIDENCE FOR TWO DIMENSIONS. AB - BACKGROUND: To determine possible dimensions that underlie obsessive-compulsive personality disorder (OCPD) and to investigate their clinical correlates, familiality, and genetic linkage. METHODS: Participants were selected from 844 adults assessed with the Structured Instrument for the Diagnosis of DSM-IV Personality Disorders (SIDP) in the OCD Collaborative Genetics Study (OCGS) that targeted families with obsessive-compulsive disorder (OCD) affected sibling pairs. We conducted an exploratory factor analysis, which included the eight SIDP derived DSM-IV OCPD traits and the indecision trait from the DSM-III, assessed clinical correlates, and estimated sib-sib correlations to evaluate familiality of the factors. Using MERLIN and MINX, we performed genome-wide quantitative trait locus (QTL) linkage analysis to test for allele sharing among individuals. RESULTS: Two factors were identified: Factor 1: order/control (perfectionism, excessive devotion to work, overconscientiousness, reluctance to delegate, and rigidity); and Factor 2: hoarding/indecision (inability to discard and indecisiveness). Factor 1 score was associated with poor insight, whereas Factor 2 score was associated with task incompletion. A significant sib-sib correlation was found for Factor 2 (rICC = .354, P < .0001) but not Factor 1 (rICC = .129, P = .084). The linkage findings were different for the two factors. When Factor 2 was analyzed as a quantitative trait, a strong signal was detected on chromosome 10 at marker d10s1221: KAC LOD = 2.83, P = .0002; and marker d10s1225: KAC LOD = 1.35, P = .006. CONCLUSIONS: The results indicate two factors of OCPD, order/control and hoarding/indecision. The hoarding/indecision factor is familial and shows modest linkage to a region on chromosome 10. PMID- 26594841 TI - Ionic Liquid Coatings for Titanium Surfaces: Effect of IL Structure on Coating Profile. AB - Dicationic imidazolium-based ionic liquids (ILs) having bis(trifluoromethylsulfonyl)imide (NTf2) and amino acid-based (methionine and phenylalanine) anionic moieties were synthesized and used to coat titanium surfaces using a dip-coating technique. Dicationic moieties with varying alkyl chains (8 and 10 carbons) and anions with distinct characteristics were selected to understand the influence of IL structural features on deposition profile. X ray photoelectron spectroscopy (XPS) and atomic force microscopy (AFM) were used in this study to help elucidate intermolecular interactions within ILs as well as between ILs and TiO2 surfaces and to investigate IL coating morphology. Charge concentration on IL moieties, as well as the presence of functional groups that can interact via hydrogen bond, such as carboxylate and amino groups, were observed to influence the deposition profile. ILs containing amino acids as the anionic moiety were observed to interact strongly with TiO2, which resulted in more pronounced changes in Ti 2p binding energy. The higher hydrophobicity of the IL having NTf2 as the anionic moiety resulted in higher adhesion strength between the IL coating and TiO2. PMID- 26594842 TI - Optical characterization of temperature- and composition-dependent microstructure in asphalt binders. AB - We introduce noncontact optical microscopy and optical scattering to characterize asphalt binder microstructure at temperatures ranging from 15 degrees C to 85 degrees C for two compositionally different asphalt binders. We benchmark optical measurements against rheometric measurements of the magnitude of the temperature dependent bulk complex shear modulus |G*(T)|. The main findings are: (1) Elongated (~5 * 1 MUm), striped microstructures (known from AFM studies as 'bees' because they resemble bumble-bees) are resolved optically, found to reside primarily at the surface and do not reappear immediately after a single heating cooling cycle. (2) Smaller (~1 MUm(2) ) microstructures with no observable internal structure (hereafter dubbed 'ants'), are found to reside primarily in the bulk, to persist after multiple thermal cycles and to scatter light strongly. Optical scattering from 'ants' decreases to zero with heating from 15 degrees C to 65 degrees C, but recovers completely upon cooling back to 15 degrees C, albeit with distinct hysteresis. (3) Rheometric measurements of |G*(T)| reveal hysteresis that closely resembles that observed by optical scatter, suggesting that thermally driven changes in microstructure volume fraction cause corresponding changes in |G*(T)|. PMID- 26594843 TI - Synthetic lethal targeting of oncogenic transcription factors in acute leukemia by PARP inhibitors. AB - Acute myeloid leukemia (AML) is mostly driven by oncogenic transcription factors, which have been classically viewed as intractable targets using small-molecule inhibitor approaches. Here we demonstrate that AML driven by repressive transcription factors, including AML1-ETO (encoded by the fusion oncogene RUNX1 RUNX1T1) and PML-RARalpha fusion oncoproteins (encoded by PML-RARA) are extremely sensitive to poly (ADP-ribose) polymerase (PARP) inhibition, in part owing to their suppressed expression of key homologous recombination (HR)-associated genes and their compromised DNA-damage response (DDR). In contrast, leukemia driven by mixed-lineage leukemia (MLL, encoded by KMT2A) fusions with dominant transactivation ability is proficient in DDR and insensitive to PARP inhibition. Intriguingly, genetic or pharmacological inhibition of an MLL downstream target, HOXA9, which activates expression of various HR-associated genes, impairs DDR and sensitizes MLL leukemia to PARP inhibitors (PARPis). Conversely, HOXA9 overexpression confers PARPi resistance to AML1-ETO and PML-RARalpha transformed cells. Together, these studies describe a potential utility of PARPi-induced synthetic lethality for leukemia treatment and reveal a novel molecular mechanism governing PARPi sensitivity in AML. PMID- 26594844 TI - Treatment during a vulnerable developmental period rescues a genetic epilepsy. AB - The nervous system is vulnerable to perturbations during specific developmental periods. Insults during such susceptible time windows can have long-term consequences, including the development of neurological diseases such as epilepsy. Here we report that a pharmacological intervention timed during a vulnerable neonatal period of cortical development prevents pathology in a genetic epilepsy model. By using mice with dysfunctional Kv7 voltage-gated K(+) channels, which are mutated in human neonatal epilepsy syndromes, we demonstrate the safety and efficacy of the sodium-potassium-chloride cotransporter NKCC1 antagonist bumetanide, which was administered during the first two postnatal weeks. In Kv7 current-deficient mice, which normally display epilepsy, hyperactivity and stereotypies as adults, transient bumetanide treatment normalized neonatal in vivo cortical network and hippocampal neuronal activity, prevented structural damage in the hippocampus and restored wild-type adult behavioral phenotypes. Furthermore, bumetanide treatment did not adversely affect control mice. These results suggest that in individuals with disease susceptibility, timing prophylactically safe interventions to specific windows during development may prevent or arrest disease progression. PMID- 26594845 TI - A multilevel examination of affective job insecurity climate on safety outcomes. AB - Previous research has established a causal link between individual perceptions of job insecurity and safety outcomes. However, whether job insecurity climate is associated with safety outcomes has not been studied. The purpose of the current study was to explore the main and cross-level interaction effects of affective job insecurity climate on safety outcomes, including behavioral safety compliance, reporting attitudes, workplace injuries, experienced safety events, unreported safety events, and accident underreporting, beyond individual affective job insecurity. With 171 employees nested in 40 workgroups, multilevel analyses revealed that the negative impacts of individual affective job insecurity on safety outcomes are exacerbated when they occur in a climate of high affective job insecurity. These results are interpreted in light of safety management efforts and suggest that efforts to create a secure climate within one's workgroup may reap safety-related benefits. (PsycINFO Database Record PMID- 26594846 TI - Simplification of the standard three-bag intravenous acetylcysteine regimen for paracetamol poisoning results in a lower incidence of adverse drug reactions. AB - CONTEXT: Adverse reactions to intravenous (IV) acetylcysteine treatment in paracetamol overdose, are common. Previous studies suggest the incidence and severity of non-allergic anaphylactic reactions (NAARs) are influenced by the rate of acetylcysteine infusion. OBJECTIVE: We compared the incidence of adverse drug events of a two-bag IV acetylcysteine regimen with that of the traditional three-bag regimen. MATERIALS AND METHODS: This was a retrospective analysis of patients presenting with paracetamol overdose requiring treatment with acetylcysteine to three emergency departments. We prospectively identified all presentations where IV acetylcysteine was administered using a 20 h, two-bag regimen (200 mg/kg over 4 h followed by 100 mg/kg over 16 h) from February 2014 to June 2015. We compared this to an historical cohort treated with the 21 h three-bag IV regimen (150 mg/kg over 1 h, 50 mg/kg over 4 h and 100 mg/kg over 16 h) from October 2009 to October 2013. Medical and nursing notes were searched retrospectively for entries suggesting the presence of an adverse reaction. The primary outcome was incidence of NAARs and gastrointestinal reactions in each group. RESULTS: 389 presentations were treated with the three-bag regimen and 210 presentations received the two-bag regimen. NAARs were recorded more commonly with the three-bag acetylcysteine regimen than the two-bag regimen (10% vs 4.3%, p = 0.02, OR 2.5, 95% CI 1.1-5.8). There was no difference in reports of gastrointestinal reactions between cohorts (three-bag 39% vs two-bag 41%, p = 0.38, OR 1.17 95% CI (0.83-1.65)). DISCUSSION: The incidence of NAARs was significantly reduced by combining the first two bags of the traditional three bag regimen and infusing these over 4 h at 50 mg/kg/hr. Simplifying the administration of acetylcysteine may have other benefits such as better utilisation of nursing time and reduced infusion administration errors. CONCLUSIONS: A two-bag 20 h acetylcysteine regimen was well tolerated and resulted in significantly fewer and milder NAARs than the standard three-bag regimen. PMID- 26594848 TI - Binge eating disorder: from bench to bedside. PMID- 26594847 TI - The effect of recurrent seizures on cognitive, behavioral, and quality-of-life outcomes after 12 months of monotherapy in adults with newly diagnosed or previously untreated partial epilepsy. AB - PURPOSE: The purpose of this study was to determine whether seizure recurrence has a negative impact on cognition, psychological function, and health-related quality of life (HRQoL) over a 12-month period of monotherapy in adults with newly diagnosed or previously untreated partial epilepsy. METHODS: Seizure freedom (SF) was defined as no seizure recurrence during the 40-week maintenance period of medication. Neuropsychological tests, the Symptom Checklist-90 (SCL 90), and the Quality of Life in Epilepsy-31 (QOLIE-31) were administered at baseline and after 48 weeks of carbamazepine or lamotrigine monotherapy. Seventy three patients successfully continued treatment until the 48-week follow-up time point. Fifty patients (68.5%) had SF, and the remaining 23 were not seizure-free (NSF). A seizure outcome group-by-time interaction was analyzed using a linear mixed model. RESULTS: A group-by-time interaction was identified for the total QOLIE-31 score (p<0.05) and score on two QOLIE-31 subscales (social function: p<0.001 and seizure worry: p<0.001), with a significant improvement over time only present in the SF group (all p<0.001). There was no significant group-by time interaction for most cognitive function tests, with the exception of the serial clustering score (p<0.01) and number of recognition hits on the California Verbal Learning Test (p<0.05). Serial clustering did not differ between the SF and NSF groups at baseline, but was significantly more used in the NSF group than in the SF group at 48 weeks (p<0.01). There was no significant group-by-time interaction for any dimension of the SCL-90. CONCLUSION: Recurrent seizures had a significant effect on HRQoL, a subtle effect on cognitive performance, and no effect on psychological symptoms over one year in newly diagnosed or previously untreated adults with partial epilepsy. PMID- 26594849 TI - Overview of the treatment of binge eating disorder. AB - We performed a qualitative review of treatment studies of binge eating disorder (BED), focusing on randomized clinical trials (RCTs). Limited effectiveness has been demonstrated for self-help strategies, and substantial effectiveness has been shown for cognitive behavioral therapy (CBT) and interpersonal therapy (IPT). CBT and IPT may each be more effective than behavior weight loss therapy (BWLT) for reducing binge eating over the long term. The stimulant pro-drug lisdexamfetamine dimesylate (LDX) is the only drug approved by the FDA for the treatment of BED in adults based on 2 pivotal RCTs. Topiramate also decreases binge eating behavior, but its use is limited by its adverse event profile. Antidepressants may be modestly effective over the short term for reducing binge eating behavior and comorbid depressive symptoms, but are not associated with clinically significant weight loss. A RCT presented in abstract form suggests that intranasal naloxone may decrease time spent binge eating. There is no RCT of obesity surgery in BED, but many patients with BED seek and receive such surgery. While some studies suggest patients with BED and obesity do just as well as patients with obesity alone, other studies suggest that patients with BED have more post-operative complications, less weight loss, and more weight regain. This evidence suggests that patients with BED would benefit from receiving highly individualized treatment. PMID- 26594851 TI - Corrigendum. PMID- 26594850 TI - Cognitive biases in binge eating disorder: the hijacking of decision making. AB - Binge eating disorder (BED) is the most common of eating disorders and is characterized by excessive, out-of-control, rapid food intake. This review focuses on cognitive impairments in BED, which represent an endophenotype that mediates brain function and behavior. Here we focus on reviewing impulsivity, compulsivity, attentional biases to food cues, and executive function. Behavioral regulation in BED appears to be influenced by the context of motivationally salient food cues and the degree of obesity. Deficits in delay discounting and risk taking under ambiguity are impaired in obesity irrespective of BED status. However, in BED subjects with milder obesity, greater risk seeking under explicit probabilistic risk is observed to monetary rewards, whereas this shifts to risk aversion and enhanced delay discounting in more severe obesity. Relative to non BED obese subjects, BED is characterized by enhanced behavioral inflexibility or compulsivity across multiple domains, with subjects selecting the same choices despite change in relevance (set shifting), being no longer rewarding (habit formation), or irrespective of outcome (perseveration). The context of food cues was associated with multiple attentional and early and late inhibitory impairments and enhanced memory bias, although BED patients also have generalized cognitive interference in working memory. These findings may help explain the phenotype of binge eating. Motivationally salient food cues provoke attentional and memory biases along with impairing response inhibitory processes. Those with BED are also more susceptible to cognitive interference and have impaired decisional impulsivity, with the tendency to inflexibly stick with the same choices irrespective of changes in context. These findings suggest critical cognitive domains that may guide therapeutic interventions. PMID- 26594852 TI - Comprehensibility of Health-Related Documents for Older Adults with Different Levels of Health Literacy: A Systematic Review. AB - A systematic review was conducted to assess the available evidence for the effectiveness of interventions aiming to improve the comprehensibility of health related documents in older adults (>=50) with different levels of health literacy. Seven databases were searched (2005 forward), and references in relevant reviews were checked. The selection procedure was conducted by 2 independent reviewers. Data extraction and assessment of the quality of the resulting studies were conducted by 1 reviewer and checked for accuracy by a 2nd reviewer. A total of 38 intervention studies had a study population of older adults (n = 35) or made an explicit comparison between age groups, including older adults (n = 3). Inconsistent evidence was found for the importance of design features to enhance the comprehensibility of health-related documents. Only for narratives and multiple-feature revisions (e.g., combining revisions in textual and visual characteristics) did the included studies provide evidence that they may be effective for older adults. Using narrative formats and/or multiple-feature revisions of health-related documents seem to be promising strategies for enhancing the comprehensibility of health-related documents for older adults. The lack of consistent evidence for effective interventions stresses the importance of (a) replication and (b) the use of standardized research methodologies. PMID- 26594853 TI - Emotion regulation in adolescents with mental health problems. AB - INTRODUCTION: Current literature points to a clear and consistent association between poor emotion control and psychopathology in adolescence, a critical developmental period during which most adult mental health problems emerge. However, nearly all of the studies in this literature have assessed emotion regulation in nonclinical cohorts, or indexed this construct using only self report methodology. METHOD: The present study compared adolescents with a mental illness (n = 41) to demographically matched controls (n = 45) on an experimental task that required them to either suppress or amplify their emotion expressive behavior in response to images that were either negative or positive in affective valence. RESULTS: Clinical participants (like controls) showed evidence of being able to regulate their behavioral expression of emotion, indicating that the presence of mental health problems in adolescence does not prevent a basic level of control being exercised over the emotions that are expressed to others. However, the capacity to amplify expressive behavior was reduced, particularly for negative emotions. In addition, poorer emotion regulation in the clinical group was associated with reduced quality of life. CONCLUSIONS: These data indicate that specific aspects of emotion expressive behavior are disrupted in adolescents with mental illness and are discussed in the context of theoretical models that regard emotion dysregulation as a core, transdiagnostic feature of mental illness. PMID- 26594854 TI - Repatriations and 28-day mortality of ill and injured travellers: 12 years of experience in a Swiss emergency department. AB - QUESTIONS UNDER STUDY: Many persons are travelling all over the world; the elderly with pre-existing diseases also travel to places with less developed health systems. Reportedly, fewer than 0.5% of all travellers need repatriation. We aimed to analyse and examine people who are injured or ill while abroad, where they travelled to and by what means they were repatriated. METHODS: Retrospective cross-sectional study with adult patients repatriated to a single level 1 trauma centre in Switzerland (2000-2011). RESULTS: A total of 372 patients were repatriated, with an increasing trend per year. Of these, 67% were male; the median age was 56 years. Forty-nine percent sustained an injury, and 13% had surgical and 38% medical pathologies. Patients with medical conditions were older than those with injuries or surgical emergencies (p <0.001). Seventy-three percent were repatriated from Europe. For repatriation from Africa trauma was slightly more frequent (53%, n = 17) than illnesses, whereas for most other countries illnesses and trauma were equally distributed. Injured patients had a median Injury Severity Score of 8. The majority of illnesses involved the nervous system (38%), mainly stroke. Forty-five percent were repatriated by Swiss Air Ambulance, 26% by ground ambulance, 18% by scheduled flights with or without medical assistance and two patients injured near the Swiss boarder by helicopter. The 28-day mortality was 4%. CONCLUSIONS: The numbers of travellers repatriated increased from 2000 to 2011. About half were due to illnesses and half due to injuries. The largest group were elderly Swiss nationals repatriated from European countries. As mortality is relatively high, special consideration to this group of patients is warranted. PMID- 26594855 TI - Inflation Pressures for Ex Vivo Lung Biopsies After Application of Graduated Compression Staples. AB - OBJECTIVE: To compare 2 graduated compression staples (Tri-StapleTM, Covidien, Norwalk, CT) and standard staples (Endo GIATM, Covidien) for lung biopsy in dogs. STUDY DESIGN: Ex vivo experimental study, randomized, unblocked. ANIMALS: Lung lobes (n = 18) from 4 canine cadavers. METHODS: Eighteen lung lobes were harvested from 4 dogs immediately after euthanasia and randomized to 1 of 3 staples (n = 6 per stapler type). Each lung lobe was intubated and maintained inflated at 10 cmH2O. A biopsy of the periphery of each lung lobe was taken approximately 3 cm from the edge with a stapling device; the Tri-StapleTM medium/thick (TST), Tri-StapleTM vascular/medium (TSV), and Endo GIATM 45-2.5 (EG). Each lobe was inflated to a maximum of 45 cmH2O of water to determine the pressure at which air leakage occurred (leak pressure). RESULTS: The mean (95% confidence interval) leak pressure was 38.0 cmH2O (33.1-42.9) for EG, 29.2 (24.3 34.0) for TSV, and 26.0 (21.1-30.9) for TST. The mean leak pressure was significantly higher for EG than TSV (P = .016) and for EG than TST (P = .002), but was not different between TSV and TST (P = .344). One TSV leaked at 20 cmH2O and 1 TST leaked at 17 cmH2O. The surface area of the biopsy samples was not significantly different for staple types (P = .183). CONCLUSION: Both TST and TSV leaked at significantly lower airway pressures than EG and may not be suitable for canine lung biopsy as some specimens leaked at pressures of 20 cmH2O or less. PMID- 26594856 TI - Capture agents, conversion mechanisms, biotransformations and biomimetics: general discussion. PMID- 26594857 TI - Scald Burns From Hair Braiding. AB - Only one previous case report has described scald burns secondary to hair braiding in pediatric patients. The present case study is the largest to date of scald burns as a result of hair braiding in children and adults. Charts of all 1609 female patients seen at a single burn center from 2008 to 2014 were retrospectively reviewed to identify patients with scald burns attributed to hair braiding. Demographics, injury severity, injury patterns, and complications were analyzed. Twenty-six patients (1.6%) had scald burns secondary to hair braiding with median TBSA 3%. Eighty-five percent of patients were pediatric with median age 8 years. Injury patterns were as follows: back (62%), shoulder (31%), chest (15%), buttocks (15%), abdomen (12%), arms (12%), neck (12%), and legs (4%). No patients required operative intervention. Three patients were admitted to the hospital. Two patients required time off from school for 6 and 10 days post burn for recovery. Complications included functional limitations (n = 2), hypertrophic scarring (n = 1), cellulitis requiring antibiotics (n = 1), and anxiety requiring medical/psychological therapy (n = 2). This peculiar mechanism of injury not only carries inherent morbidity that includes the risks of functional limitations, infection, and psychological repercussions but also increases usage of resources through hospital admissions and multiple clinic visits. Further work in the form of targeted outreach programs is necessary to educate the community regarding this preventable mechanism of injury. PMID- 26594858 TI - Predicting Mechanical Ventilation and Mortality: Early and Late Indicators in Steven-Johnson Syndrome and Toxic Epidermal Necrolysis. AB - Steven-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are characterized by loss of the epidermis, often accompanied by sloughing of the oral mucosa and airway, which may be associated with the need for mechanical ventilation. We retrospectively examined our SJS and TEN population for factors predictive of the need for mechanical ventilation and mortality. Over more than a 7-year period, 74 subjects of >=18 years old with biopsy-confirmed SJS-TEN were identified. Variables within the first 3 days of admission and throughout the entire hospital stay were analyzed for their value in predicting the need for mechanical ventilation and mortality. Predictive variables were examined using univariate and multivariate logistic regression analyses. Of our 74 subjects, 28 (37.8%) required mechanical ventilation and 11 (13.9%) died, all of whom were intubated. Patients requiring ventilation had a significantly higher %TBSA loss of epidermis on admission and progressive epidermal loss after admission. On multivariate analysis, acute kidney injury within the first 3 days of admission and fewer days from symptom onset to admission were statistically significant in predicting need for mechanical ventilation. In addition, the early need for mechanical ventilation, early serum bicarbonate <20 mm/L, and older age were all associated with higher mortality on multivariate analysis. In conclusion, the need for mechanical ventilation in adult TEN subjects is associated with higher mortality. This is the first time that mechanical ventilation has been specifically examined in the recent U.S. SJS and TEN population. The early recognition of patients at risk for ventilation may help guide management, especially in those patients admitted early after symptom development with acute kidney injury and extensive, progressing epidermal loss. PMID- 26594859 TI - Does Bronchoscopic Evaluation of Inhalation Injury Severity Predict Outcome? AB - Although fiber-optic bronchoscopy is essential in the diagnosis of smoke inhalation injury (INH), controversy still exists over whether or not the visualized severity of the mucosal injury predicts clinically meaningful outcomes. The purpose of this study was to assess whether the grade of mucosal INH severity was associated with various outcomes among adult burn patients. We conducted a retrospective review of all patients requiring greater than or equal to 48 hours of mechanical ventilation who were admitted between January 1, 2007 and June 1, 2014 to an adult regional American Burn Association-verified burn center. Bronchoscopy was performed on all subjects at burn center admission and grading of severity was documented using the grades 0 to 4 abbreviated injury score (AIS). Subjects with grade 1 or 2 injury formed the low-grade INH group, whereas those with grade 3 or 4 injury formed the high-grade INH group. Values are shown as the median (first to third quartiles). A P value less than .05 was considered significant. The study population consisted of 160 subjects (age, 48 [35-60] years; %TBSA burn, 28 [19-39.9]; % full thickness burn, 12.8 [0-30]; and 61% with INH). There were no significant differences in age, %TBSA burn, or % full thickness burn between subjects with different individual INH severity grades. Oxygenation on the day of injury worsened significantly as the severity of INH increased, but otherwise there were no significant differences in 24 and 48-hour fluid requirements, duration of ventilation, ventilator free days, incidence of acute respiratory distress syndrome, or mortality between subjects with different individual grades of INH severity. Subjects with high-grade INH showed statistically insignificant trends toward larger 48-hour fluid volumes (P = .07), poorer oxygenation over the first 3 post burn days (P = .055), longer duration of ventilation (P = .08), and fewer ventilator free days (P = .047) than low-grade INH. High-grade and low-grade INH subjects did not differ significantly in the incidence of acute respiratory distress syndrome or mortality. The individual grades of the 0 to 4 AIS INH severity grading scale were not particularly robust in the prediction of various outcomes among a population of adult burn patients. However, clinically relevant trends toward worsened oxygenation over postburn days 0 to 3, longer duration of mechanical ventilation, and reduced ventilator-free days in association with more severe INH were identified when subjects were broadly stratified into low-grade (grades 1and 2) INH and high-grade (grades 3 and 4) INH. This suggests that there may clinically meaningful differences between patients with less and more severe INH, and that further refinement of the grades 0 to 4 AIS INH severity should be subjected to additional investigation. PMID- 26594860 TI - Development of a Burn Escharotomy Assessment Tool: A Pilot Study. AB - Severe burn injuries can require escharotomies which are urgent, infrequent, and relatively high-risk procedures necessary to preserve limb perfusion and sometimes ventilation. The American Burn Association Advanced Burn Life Support(c) course educates surgeons and emergency providers about escharotomy incisions but lacks a biomimetic trainer to demonstrate, practice, or provide assessment. The goal was to build an affordable biomimetic trainer with discrete points of failure and pilot a validation study. Fellowship-trained burn and plastic surgeons worked with special effect artists and anatomists to develop a biomimetic trainer with three discrete points of failure: median or ulnar nerve injury, fasciotomy, and failure to check distal pulse. Participants were divided between experienced and inexperienced, survey pre- and post-procedure on a biomimetic model while being timed. The trainer total cost per participant was less than $35. Eighteen participants were involved in the study. The inexperienced (0-1 prior escharotomies performed) had significantly more violations at the discrete points of failure relative to more experienced participants (P = .036). Face validity was assessed with 100% of participants agreement that the model appeared similar to real life and was valuable in their training. Given the advancements in biomimetic models and the need to train surgeons in how to perform infrequent, emergent surgical procedures, an escharotomy trainer is needed today. The authors developed an affordable model with a successful pilot study demonstrating discrimination between experienced and inexperienced surgeons. Additional research is needed to increase the reliability and assessment metrics. PMID- 26594861 TI - Lower Serum Albumin Shortly After Admission Predicts Prolonged Hospital Stay in Younger Burn Patients. AB - The purpose of this study was to assess whether albumin levels could be used to aid in the prediction of hospital stay in adult burn patients. A retrospective review of burn patients from 2009 to 2014 was used. Demographic, injury details, albumin levels within 72 hours of admission, and clinical outcomes were recorded. The abbreviated burn severity index (ABSI) was calculated for each patient. Hospital stay >3 weeks was defined as "prolonged stay." Since albumin showed a significant interaction with age, patients were divided into two groups based on a median age of 40 years. Albumin, total BSA, and ABSI were each used as predictors, and the area under the curve (AUC) of a receiver operating characteristic curve was calculated. A composite score was created for the <= 40 years age group using ABSI and albumin levels to predict an increased length of stay. Thirty-eight of 198 (19.2%) patients had a stay >3 weeks. The AUCs for albumin level, total BSA, and ABSI alone in younger patients were 0.97, 0.97, and 0.96, respectively. Among patients older than 40, the AUC values were substantially lower indicating lower predictive value. The probability of prolonged stay for patients with albumin level >= 2.4 g/dl was low (.8%) compared with those with albumin level <2.4 g/dl (96.5%). Adding ABSI to this model increased predictive accuracy. Albumin level obtained within 72 hours of admission was an effective predictor of prolonged hospital stay in adult burn patients <= 40 years. PMID- 26594862 TI - Socioeconomic Status and Outcomes After Burn Injury. AB - The objective of this article is to explore the impact of socioeconomic status on outcome metrics in post-burn injury patients. Retrospective review of patients with TBSA >15% between 2005 and 2012. Demographics and clinical course were recorded. Socioeconomics were approximated using census data of percent below poverty level at patient zip code, which was also used for calculating distance to regional burn center. Statistical analysis was performed using Statistical Analysis Software. Odds ratios and 95% confidence intervals were calculated followed by regression models for factors associated with graft loss and readmission. Two hundred and fifty subjects survived to discharge: 33% were of upper socioeconomic status, 32% were of middle status, and 35% were of lower status. Fourteen percentage of patients lived <99 miles from the burn center, 60% 100 to 249 miles away, and 26% >240 miles away. Eighty readmissions occurred among 39 patients; 43% were unplanned. Each percent increase in TBSA was associated with a 5% increase in likelihood of being readmitted. Thirty six percentage of readmission patients were covered under worker's compensation. Patients with worker's compensation were four times more likely to be readmitted than private insurance. Only worker's compensation had a majority of unplanned readmissions (58%). Graft loss occurred in 12% of patients. Those in the low socioeconomic group had five times the odds of having graft loss than those in the high socioeconomics. There was no correlation between graft loss and insurance status or distance. Findings indicate strong and statistically significant correlations between type of insurance and likelihood of readmission and between graft loss and poverty. PMID- 26594864 TI - Surgeon-Performed Hemodynamic Transesophageal Echocardiography in the Burn Intensive Care Unit. AB - The use of transesophageal echocardiography (TEE) for resuscitation after burn injury has been reported in small case studies. Conventional TEE is invasive and often requires a subspecialist with a high level of training. The authors report a series of surgeon-performed hemodynamic TEE with an indwelling, less bulky, user-friendly probe. Records of patients treated in a regional burn center who underwent hemodynamic TEE between October 1, 2012 and May 30, 2014 were reviewed. The clinical course of each patient was recorded. All bedside interpretations were retrospectively reviewed for accuracy by a cardiac anesthesiologist. Eleven patients were included in the study. Median age was 68.5 years (interquartile range, 49.5-79.5). Median burn size was 37% TBSA (interquartile range: 16.3-53%). Seven patients were male, and four suffered inhalation injury. The operator's interpretation matched that of the echocardiography technician and cardiac anesthesiologist in all instances. No complications occurred from probe placement. Four patients underwent hemodynamic TEE to determine volume status during resuscitation. Changes in volume status on echocardiography preceded the eventual changes in urine output and vital signs for one patient. Hemodynamic TEE diagnosed cardiogenic shock and was used to titrate inotropes and vasopressors in seven elderly patients. Hemodynamic TEE is a useful adjunct to manage the burn patient who deviates off the expected course, especially if there is a question of cardiac function or volume status. It is less invasive and can be accurately performed by surgical intensivists when transthoracic echo windows are limited. The role of echocardiography in optimizing routine burn resuscitations needs to be further studied. PMID- 26594863 TI - Multispectral and Photoplethysmography Optical Imaging Techniques Identify Important Tissue Characteristics in an Animal Model of Tangential Burn Excision. AB - Burn excision, a difficult technique owing to the training required to identify the extent and depth of injury, will benefit from a tool that can cue the surgeon as to where and how much to resect. We explored two rapid and noninvasive optical imaging techniques in their ability to identify burn tissue from the viable wound bed using an animal model of tangential burn excision. Photoplethysmography (PPG) imaging and multispectral imaging (MSI) were used to image the initial, intermediate, and final stages of burn excision of a deep partial-thickness burn. PPG imaging maps blood flow in the skin's microcirculation, and MSI collects the tissue reflectance spectrum in visible and infrared wavelengths of light to classify tissue based on a reference library. A porcine deep partial-thickness burn model was generated and serial tangential excision accomplished with an electric dermatome set to 1.0 mm depth. Excised eschar was stained with hematoxylin and eosin to determine the extent of burn remaining at each excision depth. We confirmed that the PPG imaging device showed significantly less blood flow where burn tissue was present, and the MSI method could delineate burn tissue in the wound bed from the viable wound bed. These results were confirmed independently by a histological analysis. We found these devices can identify the proper depth of excision, and their images could cue a surgeon as to the preparedness of the wound bed for grafting. These image outputs are expected to facilitate clinical judgment in the operating room. PMID- 26594865 TI - Not All Drugs Are Created Equal: The Importance of Causative Agent in Toxic Epidermal Necrolysis. AB - Toxic epidermal necrolysis (TEN), Steven-Johnson Syndrome (SJS), and SJS/TEN overlap make up a spectrum of severe mucocutaneous disease that is an adverse reaction to a large number of medications and various infectious agents. Little is known about the differences in acute course of illness depending on the inciting agent, which prompted the authors to further explore their experience with TEN. In a retrospective analysis, 88 patients >=18 years old were identified with biopsy-confirmed TEN and a variety of variables were analyzed. The authors evaluated for differences in presentation and hospital course between drug class and medication half-life using Kruskal-Wallis for continuous variables and chi or Fisher's exact test for categorical variables. Those subjects with the inciting agent of allopurinol had 100% incidence of acute kidney injury (AKI), significantly higher than other drug classes with antibiotics having the second highest incidence at 14%. Medications with a half-life of <6 hours were also associated with a higher incidence of AKI. Acutely there are significant clinical differences in TEN patients depending on the drug class and medication half-life of the inciting agent. Allopurinol, drugs with a short half-life, and a diagnosis of TEN were all associated with greater incidence of AKI. This is the first time that the relationship between clinical course and inciting agent has been examined in a United States population. PMID- 26594866 TI - Outcomes in Adult Survivors of Childhood Burn Injuries as Compared with Matched Controls. AB - Limited research exists examining long-term mental and physical health outcomes in adult survivors of pediatric burns. The authors examine the postinjury lifetime prevalence of common mental and physical disorders in a large pediatric burn cohort and compare the results with matched controls. Seven hundred and forty five survivors of childhood burns identified in the Burn Registry (<18 years old and total BSA >1% between April 1, 1988 and March 31, 2010) were matched 1:5 to the general population based on age at time of injury (index date), sex, and geographic residence. Postinjury rate ratio (RR) was used to compare burn cases and control cohorts for common mental and physical illnesses through physician billings, and hospital claims. RR was adjusted for sex, rural residence, and income. Compared with matched controls, postburn cases had significantly higher RR of all mental disorders, which remained significant (P < .05) after adjustment (major depression RR = 1.5 [confidence limit {CL}: 1.2 1.8], anxiety disorder RR = 1.5 [CL: 1.3-1.8), substance abuse RR = 2.3 [CL: 1.7 3.2], suicide attempt RR = 4.3 [CL: 1.6-12.1], or any mental disorder RR = 1.5 [CL: 1.3-1.8]). The relative rate of some physical illnesses was also significantly increased in burn survivors: arthritis RR = 1.2 (CL: 1.1-1.4), fractures RR = 1.4 (CL: 1.2-1.6), total respiratory morbidity RR = 1.1 (CL: 1.02 1.3), and any physical illness RR = 1.2 (CL: 1.1-1.3). Adult survivors of childhood burn injury have significantly increased rates of postburn mental and physical illnesses. Screening and appropriate management of these illnesses is essential when caring for this population. PMID- 26594867 TI - An Analysis of Inhalation Injury Diagnostic Methods and Patient Outcomes. AB - The purpose of this study was to compare patient outcomes according to the method of diagnosing burn inhalation injury. After approval from the American Burn Association, the National Burn Repository Dataset Version 8.0 was queried for patients with a diagnosis of burn inhalation injury. Subgroups were analyzed by diagnostic method as defined by the National Burn Repository. All diagnostic methods listed for each patient were included, comparing mortality, hospital days, intensive care unit (ICU) days, and ventilator days (VDs). Z-tests, t tests, and linear regression were used with a statistical significance of P value of less than .05. The database query yielded 9775 patients diagnosed with inhalation injury. The greatest increase in mortality was associated with diagnosis by bronchoscopy or carbon monoxide poisoning. A relative increase in hospital days was noted with diagnosis by bronchoscopy (9 days) or history (2 days). A relative increase in ICU days was associated with diagnosis according to bronchoscopy (8 days), clinical findings (2 days), or history (2 days). A relative increase in VDs was associated with diagnosis by bronchoscopy (6 days) or carbon monoxide poisoning (3 days). The combination of diagnosis by bronchoscopy and clinical findings increased the relative difference across all comparison measures. The combination of diagnosis by bronchoscopy and carbon monoxide poisoning exhibited decreased relative differences when compared with bronchoscopy alone. Diagnosis by laryngoscopy showed no mortality or association with poor outcomes. Bronchoscopic evidence of inhalation injury proved most useful, predicting increased mortality, hospital, ICU, and VDs. A combined diagnosis determined by clinical findings and bronchoscopy should be considered for clinical practice. PMID- 26594868 TI - Field Operators in Real Space. AB - Field operators are widely used in many-body theory of indistinguishable particles. In this work it is shown that these operators can be represented solely in position space. Explicit expressions for the field operators in position space are given. Using the derived expression, we further show how by generalizing operators in first quantization to arbitrary particle numbers, one can directly connect to the respective operators in second quantization. A few illustrative examples are also presented. PMID- 26594869 TI - The Impact of Endometriosis and Its Treatment on Ovarian Reserve. AB - Endometriosis is a chronic disease mostly affecting women at reproductive age. There is a clear association between endometriosis and infertility; however, exact mechanisms are unknown. Some evidence suggests an adverse effect on oocytes. Endometriosis and its surgical treatment can affect quantitative ovarian reserve as well. In the presence of endometriomas, serum level of anti-Mullerian hormone (AMH) seems a more reliable marker of ovarian reserve than antral follicle count. Women with endometrioma have decreased serum AMH levels as compared with healthy controls. This is further declined after surgical excision, and the decline seems permanent. Bipolar cauterization of the ovary seems to be playing a role on ovarian damage. Extraovarian endometriosis and its surgical treatment can also be associated with decreased ovarian reserve, but there is limited information. Patients with endometriosis should be informed about fertility preservation options, especially in the presence of bilateral endometriomas or prior to surgery. PMID- 26594870 TI - Identifying Non-Duchenne Muscular Dystrophy-Positive and False Negative Results in Prior Duchenne Muscular Dystrophy Newborn Screening Programs: A Review. AB - IMPORTANCE: Duchenne muscular dystrophy (DMD) is a candidate for the recommended universal screening panel based on evidence that early corticosteroid treatment improves outcomes and on new genetic therapies that require early diagnosis for effectiveness. Elevated creatine kinase levels in the neonatal period are the initial screening marker in DMD newborn screening programs but is found in inherited muscle disorders other than DMD. Data are needed to inform protocols for future screening and follow-up testing and care in these patients. OBJECTIVES: To review non-DMD muscle disorders identified by prior DMD screening programs and to investigate whether these programs failed to identify patients later diagnosed as having DMD (false-negative findings). EVIDENCE REVIEW: Since 1975, 10 DMD newborn screening programs have provided opportunities to study screening protocols, outcomes, and parental responses. These programs used elevated creatine kinase levels in dried blood spots for the initial screening, with the diagnosis of DMD based on findings of clinical follow-up, muscle biopsy, or direct mutational testing of the DMD gene. Literature regarding these prior programs was reviewed in PubMed, and the programs were discussed directly with the directors when possible to identify diagnoses of non-DMD disorders and false negative results from 1975 to July 12, 2015. Data were collected from screening programs, which were active between 1975 and December 2011. Data were analyzed from March 26, 2015, to August 24, 2015. FINDINGS: The 10 screening programs screened more than 1.8 million newborns between 1975 and 2011, and 344 were diagnosed with DMD. Of those screened, the majority were boys. Across all programs, 80 patients had positive results for non-DMD disorders, including Becker muscular dystrophy and forms of limb-girdle and congenital muscular dystrophies, and 21 patients had false-negative findings for DMD. CONCLUSIONS AND RELEVANCE: Screening for DMD will result in identification of other muscle diseases. Future screening protocols should include infants of both sexes and include follow-up testing algorithms to evaluate patients who do not have DMD gene mutations but may have another muscle disorder associated with elevated neonatal creatine kinase levels. These programs will need to be aware that false negative results are a possibility. PMID- 26594871 TI - Singlet-Oxygen Generation in Alkaline Periodate Solution. AB - A nonphotochemical generation of singlet oxygen ((1)O2) using potassium periodate (KIO4) in alkaline condition (pH > 8) was investigated for selective oxidation of aqueous organic pollutants. The generation of (1)O2 was initiated by the spontaneous reaction between IO4(-) and hydroxyl ions, along with a stoichiometric conversion of IO4(-) to iodate (IO3(-)). The reactivity of in-situ generated (1)O2 was monitored by using furfuryl alcohol (FFA) as a model substrate. The formation of (1)O2 in the KIO4/KOH system was experimentally confirmed using electron spin resonance (ESR) measurements in corroboration with quenching studies using azide as a selective (1)O2 scavenger. The reaction in the KIO4/KOH solution in both oxic and anoxic conditions initiated the generation of superoxide ion as a precursor of the singlet oxygen (confirmed by using superoxide scavengers), and the presence of molecular oxygen was not required as a precursor of (1)O2. Although hydrogen peroxide had no direct influence on the FFA oxidation process, the presence of natural organic matter, such as humic and fulvic acids, enhanced the oxidation efficiency. Using the oxidation of simple organic diols as model compounds, the enhanced (1)O2 formation is attributed to periodate-mediated oxidation of vicinal hydroxyl groups present in humic and fulvic constituent moieties. The efficient and simple generation of (1)O2 using the KIO4/KOH system without any light irradiation can be employed for the selective oxidation of aqueous organic compounds under neutral and near-alkaline conditions. PMID- 26594872 TI - ICS teaching module: Ambulatory urodynamic monitoring. AB - AIM: To present the ICS Teaching Module on ambulatory urodynamics monitoring (AUM). METHODS: This teaching module has been developed by the ICS Urodynamics Committee to assist ICS members in their routine clinical practice. A detailed literature search on studies published on the clinical role of AUM as well as expert opinions have been considered. A slide set on AUM has been developed, approved by all members of the ICS Urodynamics Committee and is available to the ICS membership on the ICS website. The final approved teaching module has been presented at the ICS Annual Scientific Meeting in Brazil 2014. RESULTS: The scientific evidence on the clinical role of AUM in patients with lower urinary tract symptoms is summarized. The catheters and recording systems used, the patient preparation for the test, the technique, the instructions to the patient, the analysis, interpretation, and quality control assessment of AUM trace as well as the contraindications for AUM are described. CONCLUSIONS: The clinical role of AUM is still controversial. The scientific evidence on the usefulness of AUM is still limited but the ICS Urodynamics Committee recommends its use as a second line diagnostic tool when office laboratory urodynamics have failed to achieve a diagnosis. AUM has been showed to be more sensitive than laboratory urodynamics in diagnosing detrusor overactivity but the level of evidence for this measurement is not high. This manuscript summarizes the evidence and provides practice recommendations on AUM for teaching purposes in the framework of an ICS teaching module. Neurourol. Urodynam. 36:364-367, 2017. (c) 2015 Wiley Periodicals, Inc. PMID- 26594873 TI - Combined Toxoplasma gondii seropositivity and high blood kynurenine--Linked with nonfatal suicidal self-directed violence in patients with schizophrenia. AB - Toxoplasma gondii (T. gondii) chronic infection and elevated kynurenine (KYN) levels have been individually associated with non-fatal suicidal self-directed violence (NF-SSDV). We aimed to test the hypothesis that the association between T. gondii seropositivity and history of NF-SSDV would be stronger in schizophrenia patients with high plasma KYN levels than in those with lower KYN levels. We measured anti-T. gondii IgG antibodies and plasma KYN in 950 patients with schizophrenia, and used logistic regression to evaluate the relationship between NF-SSDV and KYN in patients who were either seropositive or seronegative for T. gondii. For those with KYN levels in the upper 25th percentile, the unadjusted odds ratio for the association between NF-SSDV history and KYN in T. gondii seropositive patients was 1.63 (95% CI 1.01 to 2.66), p = 0.048; the adjusted odds ratio was 1.95 (95% CI 1.15 to 3.30), p = 0.014. Plasma KYN was not associated with a history of NF-SSDV in T. gondii seronegative patients. The results suggest that T. gondii and KYN may have a nonlinear cumulative effect on the risk of NF-SSDV among those with schizophrenia. If confirmed by future longitudinal studies, this result is expected to have both theoretical and clinical implications for the prevention and treatment of suicidal behavior. PMID- 26594874 TI - Cross-Linking Poly(lactic acid) Film Surface by Neutral Hyperthermal Hydrogen Molecule Bombardment. AB - Constructing a dense cross-linking layer on a polymer film surface is a good way to improve the water resistance of poly(lactic acid) (PLA). However, conventional plasma treatments have failed to achieve the aim as a result of the unavoidable surface damage arising from the charged species caused by the uncontrolled high energy coming from colliding ions and electrons. In this work, we report a modified plasma method called hyperthermal hydrogen-induced cross-linking (HHIC) technology to construct a dense cross-linking layer on PLA film surfaces. This method produces energy-controlled neutral hyperthermal hydrogen, which selectively cleaves C-H bonds by molecule collision from the PLA film without breaking other bonds (e.g., C-C bonds in the polymer backbone), and results in subsequent cross-linking of the carbon radicals generated from the organic molecules. The formation of a dense cross-linking layer can serve as a barrier layer to significantly improve both the hydrophobicity and water vapor barrier property of the PLA film. Because of the advantage of selective cleavage of C-H bonds by HHIC treatment, the original physical properties (e.g., mechanical strength and light transmittance) of the PLA films are well-preserved. PMID- 26594875 TI - Impact of Mitochondria-Mediated Apoptosis in U251 Cell Cycle Arrest in G1 Stage and Caspase Activation. AB - BACKGROUND Most mitochondria-mediated apoptosis has some relevance to the cell cycle, but there is still a lack of investigations about U251 cell cycle in human brain glioma cells. In this study, we aimed to clarify the correlation of mitochondria-mediated apoptosis with the U251 cell cycle and its influence on apoptosis, through observing the impact of mitochondria-mediated apoptosis in U251cell specificity cycle arrest and Caspase activation. MATERIAL AND METHODS AnnexinV/PI and API were used to label the brain glioma cells for flow cytometry analysis of U251 cell apoptosis and cell cycle. RT-PCR and Western blot were performed to detect Caspase-3 and Caspase-9 activation. RESULTS Peripheral blood in stationary phase is not sensitive to apoptosis induction, but U251 cells have obvious apoptosis. Mitochondria-mediated apoptosis mainly occurs in the G1 phase of the cell cycle. Caspase-3 and Caspase-9 mRNAs and proteins expression increased significantly after the cells were treated by mitochondrial apoptosis related gene Bax induction. CONCLUSIONS Mitochondria-mediated apoptosis is related to the U251 cell cycle with specific G1 stage arrest. Caspase activation occurs in the process of cell apoptosis. PMID- 26594876 TI - Computations underlying confidence in visual perception. AB - Humans intuitively evaluate their decisions by forming different levels of confidence. Despite being highly correlated, decisional confidence and sensitivity can be differentiated. The computational processes underlying this remain unknown. Here we find that, for visual judgments concerning global direction, signal range has a greater impact on confidence than it does sensitivity. We equated sensitivity for stimuli containing different degrees of directional variability. This failed, however, to equate confidence-participants were less confident when judging more variable signals despite constant sensitivity. When stimuli were instead calibrated to equate confidence, participants were more sensitive when judging more variable signals. Directional range had no impact on an unrelated judgment of brightness, helping to establish that these results cannot be attributed to a simple decisional confound. Our complementary results show that directional sensitivity and decisional confidence rely on independent transformations of sensory input. We propose that confidence will generally be shaped by the range of differently tuned neural mechanisms responsive to input during evidence accumulation, with this having a lesser impact on sensitivity. (PsycINFO Database Record PMID- 26594877 TI - A familiarity disadvantage for remembering specific images of faces. AB - Familiar faces are remembered better than unfamiliar faces. Furthermore, it is much easier to match images of familiar than unfamiliar faces. These findings could be accounted for by quantitative differences in the ease with which faces are encoded. However, it has been argued that there are also some qualitative differences in familiar and unfamiliar face processing. Unfamiliar faces are held to rely on superficial, pictorial representations, whereas familiar faces invoke more abstract representations. Here we present 2 studies that show, for 1 task, an advantage for unfamiliar faces. In recognition memory, viewers are better able to reject a new picture, if it depicts an unfamiliar face. This rare advantage for unfamiliar faces supports the notion that familiarity brings about some representational changes, and further emphasizes the idea that theoretical accounts of face processing should incorporate familiarity. (PsycINFO Database Record PMID- 26594878 TI - Exploring perception-action relations in music production: The asymmetric effect of tonal class. AB - When playing musical passages, performers integrate the pitch content of auditory feedback with current action plans. However, this process depends on the degree to which the musical structure of the feedback melody is perceived as similar to the structure of what is planned. Four experiments reported here explored the relationship between the tonal class of planned melodies (tonal or atonal) and the sequence of events formed by auditory feedback. Participants produced short melodies from memory that were either tonal (Experiments 1 and 3) or atonal (Experiments 2 and 4). Auditory feedback matched the planned melody with respect to contour but could vary in tonal class. The results showed that when participants planned a tonal melody, atonal feedback was treated as unrelated to the planned sequence. However, when planning an atonal melody, tonal feedback was still treated as similar to the planned sequence. This asymmetric similarity mirrors findings found within the music perception literature and implies that schematic musical knowledge is highly active in determining perception-action relations during music performance. PMID- 26594879 TI - Orientation and metacognition in virtual space. AB - Cognitive scientists increasingly use virtual reality scenarios to address spatial perception, orientation, and navigation. If based on desktops rather than mobile immersive environments, this involves a discrepancy between the physically experienced static position and the visually perceived dynamic scene, leading to cognitive challenges that users of virtual worlds may or may not be aware of. The frequently reported loss of orientation and worse performance in point-to-origin tasks relate to the difficulty of establishing a consistent reference system on an allocentric or egocentric basis. We address the verbalizability of spatial concepts relevant in this regard, along with the conscious strategies reported by participants. Behavioral and verbal data were collected using a perceptually sparse virtual tunnel scenario that has frequently been used to differentiate between humans' preferred reference systems. Surprisingly, the linguistic data we collected relate to reference system verbalizations known from the earlier literature only to a limited extent, but instead reveal complex cognitive mechanisms and strategies. Orientation in desktop virtual reality appears to pose considerable challenges, which participants react to by conceptualizing the task in individual ways that do not systematically relate to the generic concepts of egocentric and allocentric reference frames. PMID- 26594880 TI - Sequential modulation of backward crosstalk and task-shielding in dual-tasking. AB - In dual-task studies, Task 1 performance is often improved when Task 2 requires a spatially compatible response (i.e., 1 on the same side)-the backward crosstalk effect (BCE). This BCE is taken as evidence that at least some of the tasks' central processing related to response selection occurs in parallel, and the size of the BCE has been interpreted as an index of how well Task 1 is shielded against influences from the concurrent Task 2 processing. In 3 experiments, it is investigated whether the compatibility status of the previous trial influences the BCE similar to the Gratton effect observed for conflict tasks. In all experiments, the BCE was large after a compatible trial but absent (or reversed) after an incompatible trial, thus a Gratton-like sequential modulation of the BCE. This result suggests rapid bottom-up adjustments as a consequence of just experienced incompatibility of responses. One explanation is that the degree of allowed parallel processing during Task 1 response selection is adjusted according to recent experience. PMID- 26594881 TI - Linking melodic expectation to expressive performance timing and perceived musical tension. AB - This research explored the relations between the predictability of musical structure, expressive timing in performance, and listeners' perceived musical tension. Studies analyzing the influence of expressive timing on listeners' affective responses have been constrained by the fact that, in most pieces, the notated durations limit performers' interpretive freedom. To circumvent this issue, we focused on the unmeasured prelude, a semi-improvisatory genre without notated durations. In Experiment 1, 12 professional harpsichordists recorded an unmeasured prelude on a harpsichord equipped with a MIDI console. Melodic expectation was assessed using a probabilistic model (IDyOM [Information Dynamics of Music]) whose expectations have been previously shown to match closely those of human listeners. Performance timing information was extracted from the MIDI data using a score-performance matching algorithm. Time-series analyses showed that, in a piece with unspecified note durations, the predictability of melodic structure measurably influenced tempo fluctuations in performance. In Experiment 2, another 10 harpsichordists, 20 nonharpsichordist musicians, and 20 nonmusicians listened to the recordings from Experiment 1 and rated the perceived tension continuously. Granger causality analyses were conducted to investigate predictive relations among melodic expectation, expressive timing, and perceived tension. Although melodic expectation, as modeled by IDyOM, modestly predicted perceived tension for all participant groups, neither of its components, information content or entropy, was Granger causal. In contrast, expressive timing was a strong predictor and was Granger causal. However, because melodic expectation was also predictive of expressive timing, our results outline a complete chain of influence from predictability of melodic structure via expressive performance timing to perceived musical tension. (PsycINFO Database Record PMID- 26594882 TI - Distractor rejection in visual search breaks down with more than a single distractor feature. AB - Previous research has established that interference from irrelevant-but-salient color distractors occurs when observers search for variable-shape singletons among uniform shapes (singleton detection), but not when they look for a specific shape among mixed shapes (feature search). In the current study, we replicated this finding, and additionally, we introduced a random variation of color. Instead of always presenting the same target and distractor colors, colors were swapped randomly from trial to trial. With random color variation, interference from color distractors was generally stronger, and in particular, it also occurred in feature search mode, suggesting that observers were unable to focus on the relevant dimension (shape) even under the most favorable conditions. A second experiment showed that interference in feature search mode occurred with variable distractor color when target color was fixed, but not with variable target color when distractor color was fixed. Overall, the results question the view that interference in feature search is absent because observers monitor a single feature map (i.e., shape). Rather, random variation of an irrelevant feature induces participants to also monitor the irrelevant feature, which results in interference. Thus, complete distractor rejection is limited to situations with a single distractor feature. PMID- 26594883 TI - Distractor-relevance determines whether task-switching enhances or impairs distractor memory. AB - Richter and Yeung (2012) recently documented a novel task-switching effect, a switch-induced reduction in "memory selectivity," characterized by relatively enhanced memory for distractor stimuli and impaired memory for target stimuli encountered on switch trials compared with repeat trials. One interpretation of this finding argues that task-switching involves opening a "gate" to working memory, which promotes updating of the task-set, but at the same time allows for increased distraction from task-irrelevant information. However, in that study, the distractor category on a switch trial also represented the task-relevant target category from the previous trial. Thus, distractors were only intermittently task-irrelevant, such that switch-enhanced distractor memory could alternatively be because of remnant attention to the previously relevant stimuli, or "task-set inertia." Here we adjudicated between the open-gate and the task-set inertia accounts of switch-enhanced distractor memory by assessing incidental memory for distractors that were either intermittently or always task-irrelevant. While we replicated switch-enhanced distractor memory in the intermittently irrelevant distractor condition, this effect was reversed in the always irrelevant distractor condition. These results speak against the open-gate account, and instead indicate that switch-enhanced distractor memory arises from task-set inertia, and will not be observed for truly task-irrelevant stimuli presented during switching. PMID- 26594884 TI - Large perceptual distortions of locomotor action space occur in ground-based coordinates: Angular expansion and the large-scale horizontal-vertical illusion. AB - What is the natural reference frame for seeing large-scale spatial scenes in locomotor action space? Prior studies indicate an asymmetric angular expansion in perceived direction in large-scale environments: Angular elevation relative to the horizon is perceptually exaggerated by a factor of 1.5, whereas azimuthal direction is exaggerated by a factor of about 1.25. Here participants made angular and spatial judgments when upright or on their sides to dissociate egocentric from allocentric reference frames. In Experiment 1, it was found that body orientation did not affect the magnitude of the up-down exaggeration of direction, suggesting that the relevant orientation reference frame for this directional bias is allocentric rather than egocentric. In Experiment 2, the comparison of large-scale horizontal and vertical extents was somewhat affected by viewer orientation, but only to the extent necessitated by the classic (5%) horizontal-vertical illusion (HVI) that is known to be retinotopic. Large-scale vertical extents continued to appear much larger than horizontal ground extents when observers lay sideways. When the visual world was reoriented in Experiment 3, the bias remained tied to the ground-based allocentric reference frame. The allocentric HVI is quantitatively consistent with differential angular exaggerations previously measured for elevation and azimuth in locomotor space. (PsycINFO Database Record PMID- 26594885 TI - A self-powered glucose biosensing system. AB - A self-powered glucose biosensor (SPGS) system is fabricated and in vitro characterization of the power generation and charging frequency characteristics in glucose analyte are described. The bioelectrodes consist of compressed network of three-dimensional multi-walled carbon nanotubes with redox enzymes, pyroquinoline quinone glucose dehydrogenase (PQQ-GDH) and laccase functioning as the anodic and cathodic catalyst, respectively. When operated in 45 mM glucose, the biofuel cell exhibited an open circuit voltage and power density of 681.8 mV and 67.86 uW/cm(2) at 335 mV, respectively, with a current density of 202.2 uA/cm(2). Moreover, at physiological glucose concentration (5mM), the biofuel cell exhibits open circuit voltage and power density of 302.1 mV and 15.98 uW/cm(2) at 166.3 mV, respectively, with a current density of 100 uA/cm(2). The biofuel cell assembly produced a linear dynamic range of 0.5-45 mM glucose. These findings show that glucose biofuel cells can be further investigated in the development of a self-powered glucose biosensor by using a capacitor as the transducer element. By monitoring the capacitor charging frequencies, which are influenced by the concentration of the glucose analyte, a linear dynamic range of 0.5-35 mM glucose is observed. The operational stability of SPGS is monitored over a period of 63 days and is found to be stable with 15.38% and 11.76% drop in power density under continuous discharge in 10mM and 20mM glucose, respectively. These results demonstrate that SPGSs can simultaneously generate bioelectricity to power ultra-low powered devices and sense glucose. PMID- 26594886 TI - A sensitive electrochemical aptasensor for multiplex antibiotics detection based on high-capacity magnetic hollow porous nanotracers coupling exonuclease-assisted cascade target recycling. AB - A multiplex electrochemical aptasensor was developed for simultaneous detection of two antibiotics such as chloramphenicol (CAP) and oxytetracycline (OTC), and high-capacity magnetic hollow porous nanotracers coupling exonuclease-assisted target recycling was used to improve sensitivity. The cascade amplification process consists of the exonuclease-assisted target recycling amplification and metal ions encoded magnetic hollow porous nanoparticles (MHPs) to produce voltammetry signals. Upon the specific recognition of aptamers to targets (CAP and OTC), exonuclease I (Exo I) selectively digested the aptamers which were bound with CAP and OTC, then the released CAP and OTC participated new cycling to produce more single DNA, which can act as trigger strands to hybrid with nanotracers to generate further signal amplification. MHPs were used as carriers to load more amounts of metal ions and coupling with Exo I assisted cascade target recycling can amplify the signal for about 12 folds compared with silica based nanotracers. Owing to the dual signal amplification, the linear range between signals and the concentrations of CAP and OTC were obtained in the range of 0.0005-50 ng mL(-1). The detection limits of CAP and OTC were 0.15 and 0.10 ng mL(-1) (S/N=3) which is more than 2 orders lower than commercial enzyme-linked immunosorbent immunoassay (ELISA) method, respectively. The proposed method was successfully applied to simultaneously detection of CAP and OTC in milk samples. Besides, this aptasensor can be applied to other antibiotics detection by changing the corresponding aptamer. The whole scheme is facile, selective and sensitive enough for antibiotics screening in food safety. PMID- 26594887 TI - Investigation of the selectivity of thrombin-binding aptamers for thrombin titration in murine plasma. AB - Detection of thrombin in plasma raises timely challenges to enable therapeutic management of thrombosis in patients under vital threat. Thrombin binding aptamers represent promising candidates as sensing elements for the development of real-time thrombin biosensors; however implementation of such biosensor requires the clear understanding of thrombin-aptamer interaction properties in real-like environment. In this study, we used Surface Plasmon Resonance technique to answer the questions of specificity and sensitivity of thrombin detection by the thrombin-binding aptamers HD1, NU172 and HD22. We systematically characterized their properties in the presence of thrombin, as well as interfering molecular species such as the thrombin precursor prothrombin, thrombin in complex with some of its natural inhibitors, nonspecific serum proteins, and diluted plasma. Kinetic experiments show the multiple binding modes of HD1 and NU172, which both interact with multiple sites of thrombin with low nanomolar affinities and show little specificity of interaction for prothrombin vs. thrombin. HD22, on the other hand, binds specifically to thrombin exosite II and has no affinity to prothrombin at all. While thrombin in complex with some of its inhibitors could not be recognized by any aptamer, the binding of HD1 and NU172 properties is compromised by thrombin inhibitors alone, as well as with serum albumin. Finally, the complex nature of plasma was overwhelming for HD1, but we define conditions for the thrombin detection at 10nM range in 100-fold diluted plasma by HD22. Consequently HD22 showed key advantage over HD1 and NU172, and appears as the only alternative to design an aptasensor. PMID- 26594888 TI - Engineered "hot" core-shell nanostructures for patterned detection of chloramphenicol. AB - In this study, we described a novel method for highly sensitive and specific detection of chloramphenicol (CAP) based on engineered "hot" Au core-Ag shell nanostructures (Au@Ag NSs). Cy5-labeled DNA aptamer was embedded between the Au and Ag layers as a signal generator and target-recognition element, to fabricate uniform Au@Ag NSs with unexpected strong and stable SERS signals. The presented CAP can specifically bind to the DNA aptamer by forming an aptamer-CAP conjugate, and cause greatly decreased SERS signals of Au@Ag NSs. By using this method, we were able to detect as low as 0.19 pg mL(-1) of CAP with high selectivity, which is much lower than those previously reported biosensors. Compared with the other SERS sensors that attached a dye in the outer layer of nanoparticles, this method exhibits excellent sensitivity and has the potential to significantly improve stability and reproducibility of SERS-based detection techniques. PMID- 26594889 TI - Magnetic beads-based DNAzyme recognition and AuNPs-based enzymatic catalysis amplification for visual detection of trace uranyl ion in aqueous environment. AB - We herein developed a novel biosensor for the visual detection of trace uranyl ion (UO2(2+)) in aqueous environment with high sensitivity and specificity by using DNAzyme-functionalized magnetic beads (MBs) for UO2(2+) recognition and gold nano-particles (AuNPs)-based enzymatic catalysis oxidation of TMB (3,3',5,5' tetramethylbenzidine sulfate) for signal generation. The utilization of MBs facilitates the magnetic separation and collection of sensing system from complex sample solution, which leads to more convenient experimental operation and more strong resistibility of the biosensor to the matrix of sample, and the utilization of AuNPs-based enzymatic catalysis amplification greatly improved the sensitivity of the biosensor. Compared with the previous DNAzyme-based UO2(2+) sensors, the proposed biosensor has outstanding advantages such as relative high sensitivity and specificity, operation convenience, low cost and more strong resistibility to the matrix of sample. It can be used to detect as low as 0.02 ppb (74 pM) of UO2(2+) in aqueous environment by only naked-eye observation and 1.89 ppt (7.0 pM) of UO2(2+) by UV-visible spectrophotometer with a recovery of 93-99% and a RSD <= 5.0% (n=6) within 3h. Especially, the visual detection limit of 0.02 ppb (74 pM) is much lower than the maximum allowable level of UO2(2+) (130 nM) in the drinking water defined by the U.S. Environmental Protection Agency (EPA), indicating that our method meets the requirement of rapid and on site detection of UO2(2+) in the aqueous environment by only naked-eye observation. PMID- 26594890 TI - Detection of aquaporin-4 antibody using aquaporin-4 extracellular loop-based carbon nanotube biosensor for the diagnosis of neuromyelitis optica. AB - Here we propose a carbon nanotube (CNT) field-effect transistor (FET) functionalized with aquaporin-4 (AQP4) extracellular loop peptides for the rapid detection of AQP4 antibody without pretreatment. Neuromyelitis optica (NMO) is a rare disease of the central nerve system that affects the optic nerves and the spinal cord. NMO-IgG, a serum antibody in patients, is highly specific for NMO and targets AQP4. We synthesized AQP4 extracellular loop peptides, known as primary autoimmune target in NMO, and immobilized them onto CNT-FET. The sensor showed p-type FET characteristics after the functionalization of peptides. The sensor was able to detect antibody with a detection limit of 1 ng l(-1). Moreover, AQP4 antibody in human serum was detected without any pretreatment. These results indicate that the biosensor can be used for rapid and simple detection of NMO antibody. PMID- 26594891 TI - Acoustic wave biosensor for the detection of the breast and prostate cancer metastasis biomarker protein PTHrP. AB - There are currently no biosensors that are able to reliably detect the process of cancer metastasis. We describe the first label-free real-time ultra-high frequency acoustic wave biosensor prototype capable of detecting the breast and prostate cancer metastasis biomarker, parathyroid hormone-related peptide (PTHrP). Two different linkers - 11-trichlorosilyl-undecanoic acid pentafluorophenyl ester (PFP) and S-(11-trichlorosilyl-undecanyl) benzothiosulfonate (TUBTS) - were used to immobilize whole anti-PTHrP antibodies and Fab' fragments to surfaces as biorecognition elements. The biosensor surfaces were optimized using X-ray photoelectron spectroscopy (XPS) and the ultra-high frequency electromagnetic piezoelectric acoustic sensor (EMPAS). One optimized whole antibody-based surface (PFP/protein G'/whole antibodies/ethanolamine) and one optimized Fab' fragment-based surface (TUBTS/Fab' fragments) were tested as biosensors. It was determined that an in-line injection of bovine serum albumin prior to analyte injection yielded the most minimally fouling surfaces. Each surface was tested with no mass amplification and with sandwich-type secondary antibody mass amplification. The whole antibody-based mass-amplified biosensor yielded the lowest limit of detection (61 ng/mL), highest sensitivity, and a linear range from 61 ng/mL to 100 MUg/mL. However, the Fab' fragment-based biosensor displayed better regenerability as a loss of ~20% of the initial analyte signal intensity was observed with each subsequent injection. The whole antibody-based biosensor was only capable of producing an analyte signal in the first injection. PMID- 26594892 TI - Ambipolar Light-Emitting Transistors on Chemical Vapor Deposited Monolayer MoS2. AB - We realize and investigate ionic liquid gated field-effect transistors (FETs) on large-area MoS2 monolayers grown by chemical vapor deposition (CVD). Under electron accumulation, the performance of these devices is comparable to that of FETs based on exfoliated flakes. FETs on CVD-grown material, however, exhibit clear ambipolar transport, which for MoS2 monolayers had not been reported previously. We exploit this property to estimate the bandgap Delta of monolayer MoS2 directly from the device transfer curves and find Delta ~ 2.4-2.7 eV. In the ambipolar injection regime, we observe electroluminescence due to exciton recombination in MoS2, originating from the region close to the hole-injecting contact. Both the observed transport properties and the behavior of the electroluminescence can be consistently understood as due to the presence of defect states at an energy of 250-300 meV above the top of the valence band, acting as deep traps for holes. Our results are of technological relevance, as they show that devices with useful optoelectronic functionality can be realized on large-area MoS2 monolayers produced by controllable and scalable techniques. PMID- 26594894 TI - First trimester depression scores predict development of gestational diabetes mellitus in pregnant rural Appalachian women. AB - Gestational diabetes (GDM) occurs in up to 9% of pregnancies. Perinatal depression affects up to 20% of women during pregnancy, and can extend into the postpartum period. A number of studies have linked depression and diabetes, however, whether this applies to GDM or which might come first is less understood. The purpose of this study was to examine the potential relationship between depression identified in the first trimester of pregnancy and the subsequent development of GDM. Women without pre-existing Type I/II diabetes (n = 1021) were evaluated for depression during the first trimester of pregnancy, and medical records were reviewed to identify a positive history of diabetes. Women identified as depressed during the first trimester were more likely to have GDM compared to those not depressed. After controlling for demographic factors and weight-related variables level of depression in the first trimester still predicted later GDM development. Depression identified in early pregnancy may predict increased risk of subsequent GDM development. Due to the numerous maternal, fetal and neonatal complications associated with GDM, early recognition is essential to promote the best possible outcomes for mother and infant. Recognizing depression as a possible risk factor for GDM development could lead to earlier screening and preventative measures. PMID- 26594893 TI - Latent activity rhythm disturbance sub-groups and longitudinal change in depression symptoms among older men. AB - Activity rhythm disturbances and depression often co-occur among older adults. However, little is known about how activity rhythm disturbances themselves co occur, or how disturbances to multiple aspects of the activity rhythm relate to depression over time. In this study, we performed a Latent Class Analysis to derive sub-groups of older men [total n = 2933, mean age = 76.28, standard deviation (SD) = 5.48] who shared similar patterns of activity rhythm disturbances (defined as extreme values of modeled activity rhythm parameters). We found eight sub-groups with distinct combinations of activity rhythm disturbances: one had all normative activity rhythm parameters (32.09%), one had only lower activity (10.06%), three had earlier activity (totaling 26.96%) and three had later activity (totaling 30.89%). Groups with similar timing were distinguished depending on whether the relative length of the active period was shorter and/or if the activity rhythm had lesser amplitude/robustness. We next examined whether the derived activity rhythm sub-groups were associated with different rates of change in depression symptom levels over an average of 5.5 (0.52 SD) follow-up years. The sub-group with lower activity only had faster increases in depressive symptoms over time (compared with the group with normative rhythm parameters), but this association was accounted for by adjustments for concurrently assessed health status covariates. Independent of these covariates, we found that four activity rhythm disturbance sub-groups experienced faster depressive symptom increases (compared with the normative sub group): These included all three sub-groups that had later activity timing and one sub-group that had earlier activity timing plus a shorter active period and a dampened rhythm. Low activity rhythm height/robustness with normal timing therefore may mark depression risk that is attributable to co-occurring disease processes; in contrast, having late or combined early/compressed/dampened activity rhythms may independently contribute to depression symptom development. Our findings suggest that activity rhythm-related depression risk is heterogeneous, and may be detected when multiple aspects of rhythm timing are delayed or when early timing is accompanied by compressed/dampened activity rhythms. Future studies should consider how distinct combinations of altered activity rhythm timing and height/robustness develop and conjointly determine health risks. Further research is also needed to determine whether/how activity rhythms can be modified to improve depression outcomes. PMID- 26594895 TI - The role of working memory capacity and interference resolution mechanisms in task switching. AB - Theories of task switching have emphasized a number of control mechanisms that may support the ability to flexibly switch between tasks. The present study examined the extent to which individual differences in working memory (WM) capacity and two measures of interference resolution, response-distractor inhibition and resistance to proactive interference (PI), account for variability in task switching, including global costs, local costs, and N-2 repetition costs. A total of 102 young and 60 older adults were tested on a battery of tasks. Composite scores were created for WM capacity, response-distractor inhibition, and resistance to PI; shifting was indexed by rate residual scores, which combine response time and accuracy and account for individual differences in processing speed. Composite scores served as predictors of task switching. WM was significantly related to global switch costs. While resistance to PI and WM explained some variance in local costs, these effects did not reach significance. In contrast, none of the control measures explained variance in N-2 repetition costs. Furthermore, age effects were only evident for N-2 repetition costs, with older adults demonstrating larger costs than young adults. Results are discussed within the context of theoretical models of task switching. PMID- 26594897 TI - Patient-reported outcomes for US oncology labeling: review and discussion of score interpretation and analysis methods. AB - This paper describes ways to approach the conceptual and practical challenges associated with interpreting the clinical meaning of scores produced by patient reported outcome (PRO) questionnaires, particularly when used to inform efficacy decisions for regulatory approval for oncology products. Score interpretation estimates are not inherent to PRO questionnaires per se, instead, vary dependent upon sample and study design characteristics. Scores from PRO measures can be interpreted at the individual and group level, and each carries its own set of statistics for evaluating differences. Oncology researchers have a variety of methods and data analytic strategies available to support their score interpretation needs, which should be considered in the context of their a priori knowledge of the target patient population, the hypothesized effects of treatment, the study design and assessment schedule, and the inferences and decisions to be made from the PRO data. PMID- 26594896 TI - Evaluation of the Pulmonary Toxicity of Ambient Particulate Matter From Camp Victory, Iraq. AB - Anecdotal reports in the press and epidemiological studies suggest that deployment to Iraq and Afghanistan may be associated with respiratory diseases and symptoms in U.S. military personnel and veterans. Exposures during military operations were complex, but virtually all service members were exposed to high levels of respirable, geogenic dust. Inhalation of other dusts has been shown to be associated with adverse health effects, but the pulmonary toxicity of ambient dust from Iraq has not been previously studied. The relative toxicity of Camp Victory dust was evaluated by comparing it to particulate matter from northern Kuwait, a standard U.S. urban dust, and crystalline silica using a single intratracheal instillation in rats. Lung histology, protein levels, and cell counts were evaluated in the bronchoalveolar lavage fluid 1-150 d later. The Iraq dust provoked an early significant, acute inflammatory response. However, the level of inflammation in response to the Iraq dust, U.S. urban dust, and Kuwait dust rapidly declined and was nearly at control levels by the end of the study At later times, animals exposed to the Iraq, U.S. urban, or Kuwait dusts showed increased small airway remodeling and emphysema compared to silica-exposed and control animals without evidence of fibrosis or premalignant changes. The severity and persistence of pulmonary toxicity of these three dusts from the Middle East resemble those of a U.S. urban dust and are less than those of silica. Therefore, Iraq dust exposure is not highly toxic, but similar to other poorly soluble low-toxicity dusts. PMID- 26594898 TI - A Qualitative Examination of Exergame Motivations in Geocaching. AB - INTRODUCTION: Exergames are an innovative type of physical activity that engages participants through interactive gameplay. One exergame growing in popularity is geocaching. Geocaching is a high-tech treasure hunt that uses GPS-enabled technology to locate hidden caches. Caches are hidden all over the world, and their coordinates are listed in an online forum ( Geocaching.com ). Exergames like geocaching are widely endorsed; however, there is a lot of information that still needs to be learned about why people participate in these activities. MATERIALS AND METHODS: Thirty-four current geocachers were recruited from a larger geocaching study to learn about their motivations for engaging in the game. Individuals were asked to respond to a 30-minute phone interview, and 12 both consented and participated the interviews. Interviews assessed how individuals became involved in geocaching, how frequently they participated, who they went geocaching with, and their motivations behind geocaching. Interviews were recorded and then thematically coded. RESULTS: The majority of participants had geocached for more than 5 years and had learned about the activity through media. All 12 participants geocached at least once a week. The primary motivations behind geocaching were being outdoors, social interaction, physical activity, and relaxation. Individuals described geocaching as being part of a community. They typically made friends while geocaching or when they were on Geocaching.com and felt connected to other geocachers through their mutual interest. CONCLUSIONS: Geocaching and other exergames that use game-like properties to engage users, specifically though technology, have the potential to impact individual health through nontraditional methods of activity and socialization. PMID- 26594899 TI - Dynamic collagen changes in cervix during the first trimester and decreased collagen content in cervical insufficiency. AB - OBJECTIVE: To determine the changes in cervical collagen during the first trimester of pregnancy and to evaluate the collagen deficit in cases with a previous diagnosis of cervical insufficiency (CI). MATERIALS AND METHODS: Cervical punch biopsies were obtained from 66 patients divided into three groups: patients with recurrent abortions due to CI (CI group; n = 8); first-trimester abortion group (study group; n = 37), subdivided into three groups according their gestational week (<7, 7-9 and 9-12 weeks), and patients with cervical biopsy due to gynecologic reasons (control group; n = 12). Collagen quantity was determined by a biochemical method that measured the levels of hydroxyproline (HOP) in dry cervix tissue. RESULTS: The HOP concentrations were significantly higher at lower gestational ages (p = 0.001). Collagen quantity was lowest in the CI group compared with other groups (p < 0.001). CONCLUSION: This study shows collagen component of cervix decreases as pregnancy advances through the first trimester. Cervical collagen concentration is lower in women with a history of CI compared to controls who has not a history of CI. PMID- 26594900 TI - Total Lesion Glycolysis and Sequential (90)Y-Selective Internal Radiation Therapy in Breast Cancer Liver Metastases: Preliminary Results. AB - To assess the prognostic role of total lesion glycolysis (TLG) in patients with breast cancer liver metastases (BCLM) after sequential lobar (90)Y radioembolization ((90)Y-RE). Seventeen patients with bilobar BCLM underwent FDG PET/CT and TLG calculation before (90)Y-RE. The hepatic lobe with the highest TLG was treated in the first session. PET was performed 6 weeks postprocedure and decrease in TLG (DeltaTLG) in the treated lobe was calculated before the second (90)Y administration. Subjects were divided in two groups (group 1: DeltaTLG >50%, group 2: DeltaTLG <50%). After the two consecutive (90)Y-therapies, patients underwent follow-up until death. Statistical analysis was performed to identify prognostic factors on overall survival (OS). After the first (90)Y administration, 10 cases showed a DeltaTLG >50% and seven had a DeltaTLG value <50%. After the two consecutive procedures, the mean OS for all patients was 13.5 +/- 0.8 months. Subjects with a DeltaTLG >50% and DeltaTLG <50% had a mean OS of 16.4 +/- 0.6 and 10.3 +/- 0.4 months, respectively (p < 0.001). Cox regression analysis demonstrated hepatic tumor load (p = 0.048) and DeltaTLG as the only significant (p = 0.005) predictors of survival. DeltaTLG after the first (90)Y administration agrees with final outcome in BCLM patients after separate sequential lobar (90)Y-RE. PMID- 26594901 TI - Competing Effects Between Screen Media Time and Physical Activity in Adolescent Girls: Clustering a Self-Organizing Maps Analysis. AB - BACKGROUND: Previous research shows contradictory findings on potential competing effects between sedentary screen media usage (SMU) and physical activity (PA). This study examined these effects on adolescent girls via self-organizing maps analysis focusing on 3 target profiles. METHODS: A sample of 1,516 girls aged 12 to 18 years self-reported daily time engagement in PA (moderate and vigorous intensity) and in screen media activities (TV/video/DVD, computer, and videogames), separately and combined. RESULTS: Topological interrelationships from the 13 emerging maps indicated a moderate competing effect between physically active and sedentary SMU patterns. Higher SES and overweight status were linked to either active or inactive behaviors. Three target clusters were explored in more detail. Cluster 1, named temperate-media actives, showed capabilities of being active while engaging in a moderate level of SMU (TV/video/DVD mainly). In Cluster 2, named prudent-media inactives, and Cluster 3, compulsive-media inactives, a competing effect between SMU and PA emerged, being sedentary SMU behaviors responsible for a low involvement in active pursuits. CONCLUSION: SMU and PA emerge as both related and independent behaviors in girls, resulting in a moderate competing effect. Findings support the case for recommending the timing of PA and SMU for recreational purposes considering different profiles, sociodemographic factors and types of SMU. PMID- 26594902 TI - Site-Directed RNA Editing in Vivo Can Be Triggered by the Light-Driven Assembly of an Artificial Riboprotein. AB - Site-directed RNA editing allows for the manipulation of RNA and protein function by reprogramming genetic information at the RNA level. For this we assemble artificial RNA-guided editases and demonstrate their transcript repair activity in cells and in developing embryos of the annelid Platynereis dumerilii. A hallmark of our assembly strategy is the covalent attachment of guideRNA and editing enzyme by applying the SNAP-tag technology, a process that we demonstrate here to be readily triggered by light in vitro, in mammalian cell culture, and also in P. dumerilii. Lacking both sophisticated chemistry and extensive genetic engineering, this technology provides a convenient route for the light-dependent switching of protein isoforms. The presented strategy may also serve as a blue print for the engineering of addressable machineries that apply tailored nucleic acid analogues to manipulate RNA or DNA site-specifically in living organisms. PMID- 26594903 TI - Dynamic Nuclear Polarization as an Enabling Technology for Solid State Nuclear Magnetic Resonance Spectroscopy. PMID- 26594904 TI - Cytotoxic activity and molecular docking of a novel biflavonoid isolated from Jacaranda acutifolia (Bignoniaceae). AB - A novel biflavonoid [kaempferol (6->8") apigenin] was isolated from the leaves of Jacaranda acutifolia. The structure was elucidated based on chemical evidence, 1D and 2D spectroscopic analyses as well as spectrometric techniques. The compound showed promising cytotoxic activity against breast cancer cell line MCF-7. The anticancer activity was explained via virtual docking of the isolated compound to the main sites in the human cyclin-dependent kinase2 (CDK2) crystal structure. PMID- 26594905 TI - Correction to Bacterial Cellulose As a Support for the Growth of Retinal Pigment Epithelium. PMID- 26594906 TI - Increased Exclusivity of Breastfeeding Associated with Reduced Gut Inflammation in Infants. AB - INTRODUCTION: The development of the intestinal gut is largely influenced by early nutrition. Infant immunity is challenged by the exposure of the gut to foreign bodies, which mediate inflammation of the gut. This study assessed the levels of gut inflammation in relation to the percentage of breastmilk consumed/the exclusivity of breastfeeding in South African infants. This is the first study to examine markers of gut inflammation in infants in relation to exclusivity of breastfeeding measured by a gold standard method. METHODOLOGY: Twenty-four black South African infants were included in this study. The categorization of different degrees of exclusivity of breastfeeding was made using an objective gold standard method developed by the International Atomic Energy Agency (deuterium dilution method). Markers of gut inflammation were measured noninvasively by sampling stool from the infants averaging 6 months of age. Gut inflammation was investigated by running multiple Droplet DigitalTM (Bio Rad, Hercules, CA) polymerization chain reaction tests profiling a panel of five mRNA probes (interleukin-8 [IL-8], S100 calcium-binding protein A8 [S100A8], Toll like receptor-4, human leukocyte antigen on chromosome 6 region 6p21.31, and defensin alpha 8). These mRNA biomarkers expressions were tested in proportion to number of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) copies as GAPDH is constitutively expressed in most cells. RESULTS: Two previously described robust mRNA markers of gut inflammation (S100A8 and IL-8) were found to correlate significantly to the percentage of breastmilk intake (r(2) = 0.4302, p = 0.0004 and r(2) = 0.3633, p = 0.002, respectively) in the range of 75-100% in 22 samples analyzed. CONCLUSIONS: This study using objective methodology has shown that higher percentages of breastmilk intake are associated with significantly lower levels of gut inflammation. This further supports the health benefits observed in exclusively breastfed infants. PMID- 26594907 TI - Polymorphism of Metallothionein 2A Modifies Lead Body Burden in Workers Chronically Exposed to the Metal. AB - Lead (Pb) is a metal that accumulates in the human body, inducing several adverse health effects. One of the proteins responsible for the distribution of metal in the body is metallothionein (MT), which is expressed by different genes, and it is supposed that genetic variation in the genes that encode MTs may affect the Pb body burden. The present study aimed to evaluate the genetic effects of the polymorphism of MT2A (single nucleotide polymorphism rs10636; Cx2192;G) on blood Pb levels (BLL) of workers from car battery factories who are chronically exposed to the metal. In total, 221 men participated in the study; genomic DNA from whole blood was extracted, and genotyping of MT2A was performed by TaqMan assays; BLL were quantified by inductively coupled plasma mass spectrometry (ICP-MS). BLL were 25 +/- 14 ug/dl (range 1.9-68); BLL were positively correlated with duration of work and smoking status. Individuals who carried at least one C allele had higher BLL than those with the GG genotype (beta = -0.45; p = 0.025, multivariable linear regression analyses). Taken together, our data support the hypothesis that polymorphisms in genes related to the transport of Pb, such as MTs, may modulate the concentrations of the metal in the body and, consequently, adverse health effects induced by Pb exposure. PMID- 26594909 TI - Null Extinction of Ceria@silica Hybrid Particles: Transparent Polystyrene Composites. AB - Scattering of light in optical materials, particularly in composites based on transparent polymer and inorganic pigment nanoparticles, is a chronic problem. It might originate mainly from light scattering because of a refractive index mismatch between the particles and transparent polymer matrix. Thus, the intensity of light is rapidly diminished and optical transparency is reduced. Refractive index matching between the pigment core and the surrounding transparent matrix using a secondary component at the interface (shell) has recently appeared as a promising approach to alter light scattering. Here, CeO2 (ceria) nanoparticles with a diameter of 25 nm are coated with a SiO2 (silica) shell with various thicknesses in a range of 6.5-67.5 nm using the Stober method. When the hybrid core-shell particles are dispersed into transparent polystyrene (PS), the transmission of the freestanding PS composite films increases over both the ultraviolet (UV) and visible region as the shell thickness increases particularly at 37.5 nm. The increase of transmission can be attributed to the reduction in the scattering coefficient of the hybrid particles. On the other hand, the particles in tetrahydrofuran (THF) absorb over UV and the intensity of absorption shows a systematic decrease as the shell thickness increases. Thus, the silica shell suppresses not only the scattering coefficient but also the molar absorptivity of the core ceria particles. The experimental results regarding the target shell thickness to develop low extinction (scattering + absorption) composites show a qualitative agreement with the predictions of Effective Medium Theory. PMID- 26594908 TI - Noninvasive Detection of Early Metabolic Left Ventricular Remodeling in Systemic Hypertension. AB - OBJECTIVES: Hypertension (HTN) is a common cause of left ventricular hypertrophy (LVH). Sustained pressure overload induces a permanent myocardial switch from fatty-acid to glucose metabolism. In this study, we tested the hypothesis that metabolic remodeling, characterized by increased myocardial glucose uptake, precedes structural and functional remodeling in HTN-induced LVH. METHODS: We recruited 31 patients: 11 with HTN only, 9 with HTN and LVH and 11 normotensive controls without LVH. Transthoracic echocardiography was performed to assess the function, mass, wall thickness and diastolic function of the left ventricle. Positron emission tomography imaging was performed, and the rate of myocardial 2 deoxy-2-[18F]fluoro-D-glucose uptake, Ki, was determined using a 3-compartment kinetic model. RESULTS: The mean Ki values were significantly higher in HTN patients than in those with HTN and LVH (p < 0.001) and in controls (p = 0.003). The unexpected decrease in Ki with LVH may be secondary to a decreased Ki with diastolic dysfunction (DD), 0.039 +/- 0.032 versus 0.072 +/- 0.013 (p = 0.004). There was also a significant stepwise decrease in Ki with increasing DD grade (p = 0.04). CONCLUSION: Glucose metabolic remodeling is detectable in hypertensive patients before the development of LVH. Furthermore, lower glucose uptake rates are observed in patients with DD. The mechanism for this last finding requires further investigation. PMID- 26594910 TI - Effect of Solvent Molecule in Pore for Flexible Porous Coordination Polymer upon Gas Adsorption and Iodine Encapsulation. AB - Four new Zn(II)-coordination polymers, namely, [Zn2(MU6-ao2btc)(MU-obix)2]n (1), [Zn2(MU4-ao2btc)(MU-obix)2]n (2), [Zn2(MU4-ao2btc)(MU-mbix)2]n (3), and {[Zn2(MU4 ao2btc)(MU-pbix)2] . 2DMF . 8H2O}n (4), where ao2btc = dioxygenated form of 3,3',5,5'-azobenzenetetracarboxylate and obix, mbix, and pbix = 1,2-, 1,3-, and 1,4-bis(imidazol-1-ylmethyl)benzene, have been synthesized with azobenzenetetracarboxylic acid and isomeric bis(imidazole) ligands and characterized by elemental analyses, IR spectra, single-crystal X-ray diffraction, powder X-ray diffraction, and thermal analyses. X-ray results showed that 1, 2, and 4 had two-dimensional structures with 3,4L13 topology, while 3 was a three-dimensional coordination polymer with bbf topology. For 4, two types of activation strategies, solvent exchange + heating (which produced 4a) and direct heating (which produced 4b), were used to investigate the effect of a guest molecule in a flexible framework. Gas adsorption and iodine encapsulation properties of activated complexes were studied. The CO2 uptake capacities for 4a and 4b were 3.62% and 9.50%, respectively, and Langmuir surface areas calculated from CO2 isotherms were 167.4 and 350.7 m(2)/g, respectively. Moreover, 4b exhibited 19.65% and 15.27% iodine uptake in vapor phase and cyclohexane solution, respectively, which corresponded to 1.47 and 0.97 molecules of iodine/formula unit, respectively. Moreover, photoluminescence properties of the complexes were studied. PMID- 26594911 TI - Unique nano-domain structures in self-assembled BiFeO3 and Pb(Zr,Ti)O3 ferroelectric nanocapacitors. AB - In this work, self-assembled ferroelectric BiFeO3 (BFO) and Pb(Zr,Ti)O3 (PZT) nanocapacitors were fabricated by a one-step pulsed-laser deposition process. Each individual nanocapacitor consists of a SrRuO3 or LaSrMnO3 bottom electrode layer, an epitaxial ferroelectric middle layer and a self-assembled nanoisland of conductive Bi2O3 or PbO2 as the top nanoelectrode. The nanoelectrodes have a lateral size of 10-100 nm depending on various deposition equivalent thickness. The as-fabricated nanocapacitors exhibit unique so-called anti-domain structures, with opposite polarization orientation to that of the naked ferroelectric films, which can be understood by the different interface built-in-voltages between their neighboring layers. They also show apparent reduced coercive fields and enhanced piezoelectricity compared to the naked films, as revealed by the switching spectroscopy piezoresponse force microscopy (SSPFM) and band-excitation mapping. Besides that, individual addressable polarization writing and erasing properties were also observed in these nanocapacitors and the written domain can maintain stability up to 12 h, which is promising for data storage devices. PMID- 26594912 TI - Differential Opioid Tolerance and Opioid-induced Hyperalgesia: A Clinical Reality. PMID- 26594913 TI - Airway Command from 1700 to 1846: An Historical Review. PMID- 26594914 TI - Platelets Reflect Biologic Complexity. PMID- 26594915 TI - Mean platelet volume may predict histological severity of primary biliary cirrhosis, but drugs and comorbidities are major concerns. PMID- 26594916 TI - Thrombotic risk factors in nonmalignant and noncirrhotic patients with portal vein thrombosis: need for extensive investigation. PMID- 26594917 TI - Biliary atresia and stool: its consistency and fat content, another potentially useful clinical information. PMID- 26594919 TI - Assessment of anxiety among Northern Plains Indians. AB - This study is an examination of the reliability and validity of the Beck Anxiety Inventory (BAI; Beck, Epstein, Brown, & Steer, 1988) in a sample of NPIs (N = 529). Validity was assessed by comparing BAI scores among 3 different diagnostic categories in a clinical sample (anxiety disorder, mood disorder, and comorbid anxiety/mood disorder diagnostic groups) and a community sample of participants with no self-reported mental health diagnoses. The BAI was also compared with depression, quality of life, and anxiety measures to assess validity. Support toward the validity of the BAI was demonstrated through high correlations with similar measures of anxiety, as well as higher scores among the clinical samples compared to the control sample. The BAI also demonstrated strong internal consistency (alpha = .95). An exploratory factor analysis indicated the presence of 3 factors: (a) fear, (b) cardiorespiratory, and (c) body instability symptoms. The BAI was unable to accurately differentiate between mood disorder and anxiety disorder groups. Results of this study indicate that the BAI may be a useful instrument in the assessment of anxiety with NPIs; however, the BAI is potentially unsuited to differentiating between mood disorders and anxiety disorders with this population. (PsycINFO Database Record PMID- 26594920 TI - Responding to the mental health and substance abuse needs of youth in the juvenile justice system: Ohio's Behavioral Health/Juvenile Justice Initiative. AB - Nearly half a million inmates with mental health issues are housed in our country's jails and prisons. The majority of juvenile justice-involved (JJI) youth have a history of behavioral health (mental health or substance use) problems. Multiple studies estimate that between 65% to 75% of juvenile justice involved youth have at least one behavioral health disorder, and 20% to 30% report suffering from a serious behavioral disorder. With so many juveniles with behavioral health issues entering a system that was not designed to provide comprehensive treatment, communities are reevaluating their approach to juvenile justice. This article describes the origins and the results of Ohio's Behavioral Health Juvenile Justice Initiative (BHJJ), a diversion program for juvenile justice-involved youth with behavioral health issues. The authors also discuss the key components of program success, offer advice to other jurisdictions considering implementing similar programming, and identify ways to take diversion programs to scale. (PsycINFO Database Record (c) 2016 APA, all rights reserved) PMID- 26594921 TI - Are the risk and protective factors similar for gang-involved, pressured-to-join, and non-gang-involved youth? A social-ecological analysis. AB - This study examines the risk and protective factors for gang involvement among subgroups of youth (i.e., current or former gang members, youth who resisted gang membership, and non-gang-involved youth) using the social-ecological framework. Middle and high school students (N = 17,366) from school districts in a large Midwestern county participated. Results indicated that males were more likely than females to be involved in gangs. For the individual context, our findings indicate that racial and ethnic minorities, females, and youth with depression/suicidal ideation are likely to be at risk for gang involvement. For the family context, we found that having gang-involved family members and family dysfunction are related to youth gang involvement. For the peer context, peers' alcohol and drug use and bullying were significantly associated with gang involvement. For the school context, as our results demonstrate, youth who perceived fair treatment from teachers and other adults in school and those with a sense of belonging in school are more likely to avoid gang membership. For the neighborhood context, we found that presence of adult support in the neighborhood and perceived neighborhood safety are negatively associated with gang membership. Findings suggest that gang prevention efforts need to target multiple ecologies that surround and influence youth. (PsycINFO Database Record PMID- 26594922 TI - Ecology matters: Neighborhood differences in the protective role of self-control and social support for adolescent antisocial behavior. AB - Adolescence can be characterized as a time when aggression, delinquency, and violence (taken together as antisocial behavior) increase. Adolescents who engage in antisocial behavior increase local crime and can create unsafe conditions for families. Understanding the protective factors that mitigate antisocial behavior can help to inform prevention practices. Using data from the Project on Human Development in Chicago Neighborhoods (n = 1,072, 51.40% female, 39.18% Hispanic, 32.28% Black), we examined how self-control, social support, and neighborhood characteristics were associated with these behaviors. Using latent profile analyses, we categorized neighborhoods based on several dimensions, including violence, disadvantage, and collective efficacy. Then, we examined how self control and social support were associated with antisocial behavior within and across neighborhoods. Results suggested that self-control was a protective feature in only some types of disadvantaged and dangerous neighborhoods. We discuss findings in terms of implications for programs and policies to mitigate youth violence and delinquency. (PsycINFO Database Record PMID- 26594923 TI - Perceived racial/ethnic discrimination and psychological outcomes among adult international adoptees in Finland: Moderating effects of social support and sense of coherence. AB - Quantitative literature on international adoptees and racial/ethnic discrimination is lacking despite results in qualitative studies from Europe and the United States that have consistently indicated how racism constantly complicates adoptees' everyday lives. To advance the literature, the present study examined the prevalence of perceived racial/ethnic discrimination among 213 adult international adoptees in Finland (59.6% women and 40.4% men, mean age 24.1 years), and the association between perceived racial/ethnic discrimination and psychological well-being indicators, including psychological distress and sleeping problems. In addition, we examined social support and sense of coherence as moderators of the association between perceived racial/ethnic discrimination and psychological well-being. Our results showed that, on average, adult international adoptees perceived racial/ethnic discrimination occasionally. Hierarchical linear regression analyses indicated a significant association between perceived racial/ethnic discrimination and psychological distress and sleeping problems. Additionally, a significant 2-way interaction of perceived racial/ethnic discrimination and social support indicated that the availability of social support may moderate the association between perceived racial/ethnic discrimination and psychological distress such that adoptees with high levels of social support may be protected from the harmful effects of discrimination. These results highlight the potential significance of social support in reducing the harmful effects of racial/ethnic discrimination on international adoptees. (PsycINFO Database Record PMID- 26594924 TI - Arab youth involvement in delinquency and political violence and parental control: The mediating role of religiosity. AB - This study examines the involvement of Arab youth at risk from East Jerusalem in delinquent behaviors, such as crimes against a person, public disorder offenses, and political violence. The contribution of religiosity and parental control factors in explaining these different types of youth involvement in illegal behaviors is assessed. A total of 161 young males, aged 15-21, participated in the study. We found that the greater the parental control and the more religious the adolescent, the less likely they are to engage in delinquent behaviors and political violence. The relationship between parental control and youth involvement in delinquency and political violence was mediated by youth level of religiosity, after controlling for age and family socioeconomic status. (PsycINFO Database Record PMID- 26594925 TI - Bringing trauma-informed practice to domestic violence programs: A qualitative analysis of current approaches. AB - Three out of 10 women and 1 out of 10 men in the United States experience violence at the hands of an intimate partner-often with devastating costs. In response, hundreds of residential and community-based organizations have sprung up to support survivors. Over the last decade, many of these organizations have joined other human service systems in adopting trauma-informed care (TIC), an approach to working with survivors that responds directly to the effects of trauma. Although there have been various efforts to describe TIC in domestic violence (DV) programs, there is a need to further synthesize this discourse on trauma-informed approaches to better understand specific applications and practices for DV programs. This study aimed to address this gap. The authors of this study systematically identified key documents that describe trauma-informed approaches in DV services and then conducted a qualitative content analysis to identify core themes. Results yielded 6 principles (Establishing emotional safety, Restoring choice and control, Facilitating connection, Supporting coping, Responding to identity and context, and Building strengths), each of which comprised a set of concrete practices. Despite the common themes articulated across descriptions of DV-specific trauma-informed practices (TIP), we also found critical differences, with some publications focusing narrowly on individual healing and others emphasizing the broader community and social contexts of violence and oppression. Implications for future research and evaluation are discussed. (PsycINFO Database Record PMID- 26594926 TI - Identifying relevant components to include in a parenting intervention for homeless families in transitional housing: Using parent input to inform adaptation efforts. AB - Homeless families in transitional housing face a number of distinct challenges, yet there is little research seeking to guide prevention and intervention work with homeless parents. Informed by the tenets of community-based participatory research, the purpose of this study was to identify relevant components to include in a parenting intervention for this population. Data were gathered from 40 homeless parents through semistructured individual interviews and were analyzed using qualitative content analysis. The resulting 15 categories suggest several topics, approach considerations, and activities that can inform parenting intervention work with homeless families in transitional housing. Study findings are discussed within the context of intervention fidelity versus adaptation, and implications for practice, research, and policy are suggested. This study provides important insights for informing parenting intervention adaptation and implementation efforts with homeless families in transitional housing. (PsycINFO Database Record PMID- 26594927 TI - The role of the police in building community identity among young people. PMID- 26594928 TI - Creating conditions that promote trust and participation by young people.. And why it matters. PMID- 26594929 TI - Youth finding meaning through a larger sense of community. PMID- 26594930 TI - Does it matter if students experience school as a place of community? PMID- 26594931 TI - Listening to the voices of young people: Implications for working in diverse communities. PMID- 26594932 TI - Why trust matters with juveniles. PMID- 26594933 TI - The Journal of Public Health Management & Practice and the de Beaumont Foundation: A Partnership for the Public's Health. PMID- 26594934 TI - Amplifying Evidence Within and Beyond the Public Health Community. PMID- 26594935 TI - Smoking Isn't Cool Anymore: The Success and Continuing Challenge of Public Health Efforts to Reduce Smoking. PMID- 26594936 TI - A Cross-sectional Examination of What Smokers Perceive to be Important and Their Willingness to Pay for Tobacco Cessation Medications. AB - CONTEXT: Tobacco smoking is the leading cause of preventable morbidity and mortality in the United States, and smoking cessation has multiple health benefits. OBJECTIVE: The purpose of this study was to assess cigarette smokers' perceived importance toward characteristics of tobacco cessation medications using a willingness-to-pay approach. DESIGN, SETTING, AND PARTICIPANTS: Cross sectional analysis of data from the 2008 HealthStyles survey, a mail-based probability sample of 5399 adults aged 18 years and older.Point estimates and 95% confidence intervals were calculated overall and by sociodemographic and smoking behavior characteristics. Multivariate Probit regression analysis was used to evaluate smokers' willingness to pay in relation to perceived importance of 3 cessation medication characteristics: convenience of use, over-the-counter availability, and efficiency to help quit. All models controlled for sociodemographic characteristics, smoking behavior characteristics, and US regional fixed effects. A total of 914 current cigarette smokers. MAIN OUTCOME MEASURES: Interest in quitting, interest in using cessation medications, and willingness to pay for 6 types of cessation medications. RESULTS: Approximately 68.4% of current cigarette smokers were interested in quitting. Among these individuals, 45.6% indicated that they were interested in using cessation medications, and of these, 47.3% indicated that they were willing to pay $150 or more out-of-pocket for these medications. Convenience of use and the effectiveness of these medications to help quit were positively associated with current smokers' willingness to pay for $300 or more (P < .05); however, no association was observed for over-the-counter availability. Self-reported exposure to telephone quitline advertisements was also positively associated with the willingness to pay. CONCLUSIONS: Approximately 68% of current smokers are interested in quitting, and about half of those smokers interested in quitting are also interested in using cessation medications. Convenience of use and the medication's effectiveness are important characteristics of cessation medication for smokers with quit intentions. Understanding preferences for these cessation medication characteristics may help inform smoking cessation efforts. PMID- 26594937 TI - Adequacy of US Hospital Security Preparedness for Mass Casualty Incidents: Critical Lessons From the Israeli Experience. AB - CONTEXT: Due to Israel's threat environment, Israeli hospitals have developed effective and innovative security preparations for responding to all-hazards incidents. Although Israeli hospital preparedness has been the subject of international praise and attention, there has been a dearth of research focused specifically on applying Israeli hospital security measures to the US hospital setting to augment emergency planning. OBJECTIVE: This study examined practical and cost-effective lessons from the Israeli experience for improving US hospital security preparedness for a wide range of mass casualty incidents, both natural and man-made. DESIGN: Sixty semi-structured interviews were conducted with officials throughout Israel's and America's health, defense, and emergency response communities. Hospital preparedness was examined and disaster drills were evaluated in both countries, with San Francisco hospitals analyzed as a case study. Qualitative analysis was conducted and recommendations were made on the basis of an all-hazards approach to emergency preparedness. RESULTS: US hospitals examined in this study had not undertaken crucial preparations for managing the security consequences of a large-scale disaster. Recommendations from Israel included installing permanent emergency signage, improving security perimeter protocols and training, increasing defense against primary and secondary attacks, enhancing coordination with law enforcement, the National Guard, and other outside security agencies, and conducting more frequent and realistic lockdown exercises. CONCLUSIONS: A number of US hospitals have overlooked the important role of security in emergency preparedness. This study analyzed practical and cost-effective security recommendations from Israel to remedy this dangerous deficiency in some US hospitals' disaster planning. PMID- 26594938 TI - Mending Hearts and Building Bridges: The Save a Child's Heart Foundation. AB - CONTEXT: Save a Child's Heart addresses the challenges of heart care for children in underdeveloped countries. OBJECTIVE: Save a Child's Heart has created a center of excellence for pediatric cardiac care at the Wolfson Medical Center in Israel, helped develop partner sites for evaluation and referral, and trained medical teams to return and build their own capacity for local cardiac care. RESULTS: Save a Child's Heart has treated more than 3600 children from 48 countries, with 50% from Iraq, Jordan, the Palestinian Authority, and Syria. In cooperation with the Palestinian Authority, Save a Child's Heart has examined more than 6000 children and treated 1750 children, trained 21 medical personnel, and conducted seminars for Palestinian medical personnel. The "Heart of the Matter Project," funded by the European Union, US Agency for International Development, the Palestinian Ministry of Health, and the Israeli Ministry of Regional Cooperation, is currently training a team at the Wolfson Medical Center from the Palestine Medical Complex in Ramallah and provides funds for Palestinian children's care in Israel. CONCLUSIONS: Save a Child's Heart is a model of a global humanitarian health care initiative with a single focus on heart disease in children. The "Heart of the Matter Project" is a model of health care based on regional cooperation despite local political tensions. PMID- 26594939 TI - Working Together to Improve the Public Health Enterprise. PMID- 26594940 TI - Preparing for the Public Health Challenges of Climate Change: Perspectives From Local Public Health. PMID- 26594941 TI - Management of poisoning with ethylene glycol and methanol in the UK: a prospective study conducted by the National Poisons Information Service (NPIS). AB - BACKGROUND: Poisoning with methanol and ethylene glycol can cause serious morbidity and mortality. Specific treatment involves the use of antidotes (fomepizole or ethanol) with or without extracorporeal elimination techniques. METHODS: A prospective audit of patients with methanol or ethylene glycol poisoning reported by telephone to the National Poisons Information Service (NPIS) in the UK was conducted during the 2010 calendar year and repeated during the 2012 calendar year. The study was conducted to determine the frequency of clinically significant systemic toxicity and requirement for antidote use and to compare outcomes and rates of adverse reaction and other problems in use between ethanol and fomepizole. RESULTS: The NPIS received 1315 enquiries involving methanol or ethylene glycol, relating to 1070 individual exposures over the 2 year period. Of the 548 enquiries originating from hospitals, 329 involved systemic exposures (enteral or parenteral as opposed to topical exposure), of which 216 (66%) received an antidote (204 for ethylene glycol and 12 for methanol), and 90 (27%) extracorporeal treatment (86 for ethylene glycol and 4 for methanol). Comparing ethanol with fomepizole, adverse reactions (16/131 vs. 2/125, p < 0.001) and administration errors, lack of monitoring, or inappropriate use (45/131 vs. 6/125, p < 0.0001) were reported more commonly, whereas non availability and inadequate stocks were reported less commonly (6/125 vs. 33/131, p < 0.0001). Eight fatalities and complications or sequelae occurred in 21 patients. Poor outcome (death, complications, or sequelae) was significantly associated with older age, higher poisoning severity scores, and lower pH on admission (p < 0.001). CONCLUSIONS: Systemic poisoning with ethylene glycol or methanol results in hospitalisation at least 2-3 times per week on average in the UK. No difference in outcome was detected between ethanol and fomepizole-treated patients, but ethanol was associated with more frequent adverse reactions. PMID- 26594943 TI - Increased attentional load moves the left to the right. AB - INTRODUCTION: Unilateral brain damage can heterogeneously alter spatial processing. Very often brain-lesioned patients fail to report (neglect) items appearing within the contralesional space. Much less often patients mislocalize items' spatial position. We investigated whether a top-down attentional load manipulation (dual-tasking), known to result in contralesional omissions even in apparently unimpaired cases, might also induce spatial mislocalizations. METHOD: Nine right-hemisphere-damaged patients performed three computer-based tasks encompassing different levels of attentional load. The side of appearance of visual targets had to be reported either in isolation or while processing additional information (visual or auditory dual task). Spatial mislocalizations (from the contralesional hemispace towards the ipsilesional unaffected one) were then contrasted with omissions both within and across tasks, at individual as well as at group level. RESULTS: The representation of ipsilesional targets was accurate and not affected by dual-tasking requirements. Contralesional targets were instead often omitted and, under dual-task conditions, also mislocalized by four patients. Three cases reported a significant number of left targets as appearing on the right (alloesthesia). Two of these patients perceived more targets (albeit to a wrong spatial location) under dual- than under single-task load. In a fourth patient, increased visual load resulted in synchiria, the (mis)perception of single, contralesional targets as being two (one on each side). CONCLUSIONS: When the neural circuitry subtending spatial processing is damaged, an increase in task load can lead to either a disregard or a bias in the processing of contralesional hemispace. The spatial bias subtending mislocalizations seems to index a more severe deficit than neglect, as if contralesional space would be completely erased rather than merely ignored. PMID- 26594942 TI - Insights into ALS pathomechanisms: from flies to humans. AB - Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease causing the death of motor neurons with consequent muscle atrophy and paralysis. Several neurodegenerative diseases have been modeled in Drosophila and genetic studies on this model organism led to the elucidation of crucial aspects of disease mechanisms. ALS, however, has lagged somewhat behind possibly because of the lack of a suitable genetic model. We were the first to develop a fly model for ALS and over the last few years, we have implemented and used this model for a large scale, unbiased modifier screen. We also report an extensive bioinformatic analysis of the genetic modifiers and we show that most of them are associated in a network of interacting genes controlling known as well as novel cellular processes involved in ALS pathogenesis. A similar analysis for the human homologues of the Drosophila modifiers and the validation of a subset of them in human tissues confirm and expand the significance of the data for the human disease. Finally, we analyze a possible application of the model in the process of therapeutic discovery in ALS and we discuss the importance of novel "non obvious" models for the disease. PMID- 26594944 TI - Reflective functioning as predictor of working alliance and outcome in the treatment of depression. AB - AIMS: Although considerable attention has been paid to the concept of mentalization in psychotherapy, there is little research on mentalization as predictor of psychotherapy process and outcome. Using data from a randomized controlled trial of cognitive-behavioral therapy and interpersonal psychotherapy for depression, we studied mentalization in 85 outpatients with major depressive disorder (MDD) according to the Diagnostic and Statistical Manual of Mental Disorders. It was hypothesized that patients showing lower capacity for mentalization would experience poorer quality of alliance and worse outcome. METHOD: Depressive symptoms were measured each session using the Beck Depression Inventory-II. Mentalization was measured as reflective functioning (RF) on a slightly shortened version of the Adult Attachment Interview. A measure of depression-specific reflective functioning (DSRF), measuring mentalization about depressive symptoms, was also used. The Working Alliance Inventory-Short Form Revised was completed after each session by both therapist and patient. Longitudinal multilevel modeling was used to analyze data. RESULTS: The patients had on average very low RF (M = 2.62, SD = 1.22). Lower pretreatment RF/DSRF predicted significantly lower therapist-rated working alliance during treatment. RF did not affect patient-rated alliance, but lower DSRF predicted lower patient rated alliance across treatment. Patients with higher RF/DSRF had better outcomes on self-rated depression. CONCLUSIONS: The findings showed lower than normal capacity for mentalization in patients with MDD. Lower RF/DSRF predicted worse treatment outcome. More research is needed to understand how RF affects psychotherapy response and how RF is affected after recovery from depression. PMID- 26594945 TI - A prospective study of therapist facilitative interpersonal skills as a predictor of treatment outcome. AB - OBJECTIVE: This study examined whether therapists' facilitative interpersonal skills (FIS) would prospectively predict the outcomes of therapies that occurred more than one year later. METHOD: Therapists were 44 clinical psychology trainees who completed the FIS performance task and a self-reported measure of social skills in the initial weeks of their training. In the FIS task, prospective therapists were presented with a standard set of videos portraying clients in therapy. Verbal responses to these therapeutic simulations were recorded and then rated by trained coders. More than one year later, the therapists began providing psychotherapy to clients in a psychology clinic. Clients completed a symptom measure before each therapy session. RESULTS: Using multilevel modeling, it was found that therapist FIS significantly predicted client symptom change. That is, higher FIS therapists were more effective than lower FIS therapists. However, subsequent analyses showed that this FIS effect was not uniform across all therapy durations; specifically, higher FIS therapists were more effective than lower FIS therapists over shorter durations (e.g., <=8 sessions) but did not differ from lower FIS therapists in effectiveness for the small percentage of therapies that were longer-term (e.g., >16 sessions). CONCLUSIONS: Therapists' interpersonal characteristics may influence client progress in therapy. PMID- 26594946 TI - Resident-to-Resident Abuse. PMID- 26594950 TI - Managing Heroin Addiction in an Outpatient Setting: A Case Study. AB - Heroin use may be under-recognized among older adults. Baby Boomers are the largest age as well as the largest drug-using cohort in modern history. Although some drug users age out of their addiction, others do not. Nurses caring for older adults may come into contact with heroin users due to associated conditions or sequelae of their drug use that cause them to seek care. Few nurses are prepared to provide the care needed when heroin use accompanies other health problems. Using an individual example, the current article provides guidance for identifying heroin addiction, essential information about heroin use, and resources for guiding patients to experts for the comprehensive care needed for recovery. PMID- 26594951 TI - They Are Called Nursing Homes for a Reason: RN Staffing in Long-Term Care Facilities. AB - According to the Centers for Medicare and Medicaid Services (CMS), the Consolidated Medicare and Medicaid regulations have not been systematically reviewed and updated since 1991. Existing regulations require that, with certain exceptions, an RN provide services in a facility for 8 consecutive hours per day, 7 days per week; licensed practical nurses (LPNs) 24 hours per day; and sufficient staff to meet residents' needs. The requirements to determine "sufficient" staff remain undefined by CMS. Several national organizations support RN staffing 24 hours per day each day of the week (24/7). These organizations provided evidence refuting CMS' position that it does not have sufficient information at this time to require a specific number of staff or hours of nursing care per resident. Consideration should be given to the Institute of Medicine recommendation affrming the need for and requiring the presence of at least one RN within every nursing home facility at all times. Currently, there is a bill in the House of Representatives that supports 24/7 RN coverage in nursing homes, which must become both bipartisan and bicameral to be passed. PMID- 26594953 TI - Effects of the Patient-Centered Environment Program on Behavioral and Emotional Problems in Home-Dwelling Patients With Dementia. AB - The current pilot study examined the effects of the Patient-Centered Environment Program (PCEP) on agitation, cognition, stress, pain, sleep, and activities of daily living for home-dwelling patients with dementia. Nine individuals participated in the study. The PCEP included visual, auditory, olfactory, and tactile areas based on participants' preferences. PCEP sessions were held for 30 minutes twice per week and a total of 16 sessions were performed at participants' homes. Findings showed that agitation and pain improved with the PCEP (t = 2.91, p < 0.02; t = 4.51, p < 0.002, respectively). Findings suggested that a better study design, repeated with a reasonable sample size, must be considered for participants' health statuses to meet the PCEP contents. PMID- 26594955 TI - Slow Vis: Extending Opportunities for Insight and Understanding Over Time. AB - Andrea Polli has been working at the intersection of art, science, and technology since 1999. With degrees in both art and computing, she comes to collaborations with a solid art training and extensive practical experience. Her projects focus on creating opportunities for collaborators and student researchers to participate in public projects that express environmental data and information in new ways. In this interview with department editors Bruce Campbell and Francesca Samsel, Polli discusses how she has implemented a "slow vis" approach to real time visualization in large-scale public art installations. PMID- 26594954 TI - Impaired glucose metabolism and type 2 diabetes in apparently healthy senior citizens. AB - STUDY PRINCIPLE: To estimate the prevalence of unknown impaired glucose metabolism, also referred to as prediabetes (PreD), and unknown type 2 diabetes mellitus (T2DM) among subjectively healthy Swiss senior citizens. The fasting plasma glucose (FPG) and glycated haemoglobin A(1c) (HbA(1c)) levels were used for screening. A total of 1 362 subjects were included (613 men and 749 women; age range 60-99 years). Subjects with known T2DM were excluded. METHODS: The FPG was processed immediately for analysis under standardised preanalytical conditions in a cross-sectional cohort study; plasma glucose levels were measured by means of the hexokinase procedure, and HbA(1c) was measured chromatographically and classified using the current American Diabetes Association (ADA) criteria. RESULTS: The crude prevalence of individuals unaware of having prediabetic FPG or HbA(1c) levels, was 64.5% (n = 878). Analogously, unknown T2DM was found in 8.4% (n = 114) On the basis of HbA(1c) criteria alone, significantly more subjects with unknown fasting glucose impairment and laboratory T2DM could be identified than with the FPG. The prevalence of PreD as well as of T2DM increased with age. The mean HOMA indices (homeostasis model assessment) for the different age groups, between 2.12 and 2.59, are consistent with clinically hidden disease and are in agreement with the largely orderly Body Mass Indices found in the normal range. CONCLUSIONS: Laboratory evidence of impaired glucose metabolism and, to a lesser extent, unknown T2DM, has a high prevalence among subjectively healthy older Swiss individuals. Laboratory identification of people with unknown out-of-range glucose values and overt diabetic hyperglycaemia might improve the prognosis by delaying the emergence of overt disease. PMID- 26594956 TI - CraMs: Craniometric Analysis Application Using 3D Skull Models. AB - Craniometric analysis plays an important role in anthropology studies and forensics. This paper presents CraMs, an application using a new craniometric approach based on 3D models of the skull. The main objective is to obtain, through a process supervised by anthropologists, the main points of interest used to compute craniometric measurements. The application aids this process by analyzing the skull geometry and automatically providing points of interest. The application also allows for semiautomatic point detection, where the user provides an initial guess that might be refined based on the curvature of the skull, as well as the manual selection of any other points of interest. Moreover, results comparing measurements obtained with CraMs and traditional craniometry methods on eight skulls suggest that the application provides comparable craniometric measurements and lower inter-observer variability. This approach offers advantages such as an easier access to skulls with no risk of bone damage and the possibility of defining new measurements based on morphology or other skull characteristics, which are not possible using traditional methods. PMID- 26594957 TI - Visual Analytics for MOOC Data. AB - With the rise of massive open online courses (MOOCs), tens of millions of learners can now enroll in more than 1,000 courses via MOOC platforms such as Coursera and edX. As a result, a huge amount of data has been collected. Compared with traditional education records, the data from MOOCs has much finer granularity and also contains new pieces of information. It is the first time in history that such comprehensive data related to learning behavior has become available for analysis. What roles can visual analytics play in this MOOC movement? The authors survey the current practice and argue that MOOCs provide an opportunity for visualization researchers and that visual analytics systems for MOOCs can benefit a range of end users such as course instructors, education researchers, students, university administrators, and MOOC providers. PMID- 26594958 TI - Trends in Continuity and Interpolation for Computer Graphics. AB - In every computer graphics oriented application today, it is a common practice to texture 3D models as a way to obtain realistic material. As part of this process, mesh texturing, deformation, and visualization are all key parts of the computer graphics field. This PhD dissertation was completed in the context of these three important and related fields in computer graphics. The article presents techniques that improve on existing state-of-the-art approaches related to continuity and interpolation in texture space (texturing), object space (deformation), and screen space (rendering). PMID- 26594959 TI - Educational Virtual-Wear Trial: More Than a Virtual Try-On Experience. AB - Developments in computer capabilities, networks, mobile devices, and social media have enabled researchers and educators to increasingly employ blended strategies when developing new learning technologies. In addition, there is a growing need to develop discipline-specific learning technologies as result of expanding research in various domains. The study reported here was conducted in the context of a textile and clothing higher education course. The key aim was to develop a new learning technology for university students, specifically to help them learn about clothing thermal functional design (CTFD). PMID- 26594960 TI - Beautiful Math, Part 5: Colorful Archimedean Tilings from Dynamical Systems. AB - The art of tiling originated very early in the history of civilization. Almost every known human society has made use of tilings in some form or another. In particular, tilings using only regular polygons have great visual appeal. Decorated regular tilings with continuous and symmetrical patterns were widely used in decoration field, such as mosaics, pavements, and brick walls. In science, these tilings provide inspiration for synthetic organic chemistry. Building on previous CG&A “Beautiful Math” articles, the authors propose an invariant mapping method to create colorful patterns on Archimedean tilings (1-uniform tilings). The resulting patterns simultaneously have global crystallographic symmetry and local cyclic or dihedral symmetry. PMID- 26594961 TI - The Future Directions of the Educational Processes: Another Numbers Game. PMID- 26594962 TI - The Origins and Current State of Plastic Surgery Residency in the United States. AB - The history of plastic surgery residency training in the United States dates back to the establishment of plastic surgery as a specialty. The pivotal role played by the American Board of Plastic Surgery is outlined. The history of the early regulatory bodies leading to the formation of the Accreditation Council for Graduate Medical Education and the Residency Review Committees and the establishment of the American Council of Academic Plastic Surgeons gives context to our current training models. PMID- 26594963 TI - The Perfect Preceptor. AB - Every plastic surgeon can become a better teacher. One of the keys to improvement is to have a thoughtfully considered plan of what to teach and how to teach it. This article describes what any surgeon can do before, during, and after a rotation to create an excellent learning environment for a medical student, resident, or fellow. Before the rotation, the preceptor should collaborate with the program director to develop the goals and objectives. The defined content is then distributed by week so that each objective is consciously addressed. During the rotation, the resident and preceptor identify the critical clinical and surgical experiences germane to the week's topic and focus on those patients. After the rotation, giving and getting meaningful feedback is much easier as the assessment scope and tool is derived from the curriculum that the preceptor helped develop. PMID- 26594964 TI - All That You Can't Leave Behind: Professionalism as the Focus of Mentoring and Modeling. AB - Mentoring serves a critical and necessary role not only in the advancement of plastic surgery, but also in maintaining the health of our specialty. In addition to providing a driving force for innovation--which remains the core competency of plastic surgery--mentoring is a powerful, educational tool that helps us teach the critical skills of communication and model the tenets of professionalism. Our identity as innovators, healers, and providers of hope is dependent on conferring what it means to be a professional, from those who are just beginning their journey as surgeons, to those who are still on that odyssey. PMID- 26594965 TI - Midline Cleft Lip and Bifid Nose Deformity: Description, Classification, and Treatment. AB - BACKGROUND: Midline facial clefts are rare and challenging deformities caused by failure of fusion of the medial nasal prominences. These anomalies vary in severity, and may include microform lines or midline lip notching, incomplete or complete labial clefting, nasal bifidity, or severe craniofacial bony and soft tissue anomalies with orbital hypertelorism and frontoethmoidal encephaloceles. In this study, the authors present 4 cases, classify the spectrum of midline cleft anomalies, and review our technical approaches to the surgical correction of midline cleft lip and bifid nasal deformities. Embryology and associated anomalies are discussed. METHODS: The authors retrospectively reviewed our experience with 4 cases of midline cleft lip with and without nasal deformities of varied complexity. In addition, a comprehensive literature search was performed, identifying studies published relating to midline cleft lip and/or bifid nose deformities. Our assessment of the anomalies in our series, in conjunction with published reports, was used to establish a 5-tiered classification system. Technical approaches and clinical reports are described. RESULTS: Functional and aesthetic anatomic correction was successfully achieved in each case without complication. A classification and treatment strategy for the treatment of midline cleft lip and bifid nose deformity is presented. CONCLUSIONS: The successful treatment of midline cleft lip and bifid nose deformities first requires the identification and classification of the wide variety of anomalies. With exposure of abnormal nasolabial anatomy, the excision of redundant skin and soft tissue, anatomic approximation of cartilaginous elements, orbicularis oris muscle repair, and craniofacial osteotomy and reduction as indicated, a single-stage correction of midline cleft lip and bifid nasal deformity can be safely and effectively achieved. PMID- 26594966 TI - Health-Related Quality of Life Patients With a Cleft Lip and/or Palate. AB - BACKGROUND: The authors evaluated health-related quality of life (HRQoL) in patients with cleft lip and/or palate (CLP). METHODS: A descriptive, observational, cross-sectional study was conducted in the largest referral facility for treating individuals with CLP in Sergipe state. The authors created 3 groups with 97 subjects each: CLP, family, and control. An initial cognitive evaluation was performed with the Mini-Mental State Examination, and the Medical Outcomes Study 36 item Short-Form Health Survey (SF-36) was applied to evaluate HRQoL in individuals with sufficient cognitive capacity. RESULTS: Individuals with CLP usually had a primary education, were single, and had incomes between 1 and 2 minimum wages, and slightly more than half presented with a transforamen cleft (59.8%). No significant difference was observed in the overall HRQoL score among the 3 groups (cleft: 72.2; family: 70.6; control: 72.5). Individuals with CLP had a lower average on the Emotional Aspects domain of the SF-36 than that in the control group, whereas the CLP group had higher averages in the Vitality domain when compared with their relatives. Men had higher averages on the Physical Function (PF) and Mental Health (MH) domains. Patients operated on at the optimal time (<=12 months of age) had higher mean PF domain scores. CONCLUSIONS: Patients with CLP and their families often represent people with low purchasing power, strengthening the socioeconomic inequality. Although the global HRQoL was similar among all groups surveyed, the cleft influenced both the patients and their relatives. PMID- 26594967 TI - Bilateral Continuous Automated Distraction Osteogenesis: Proof of Principle. AB - The purpose of this study was to demonstrate that automated, continuous, curvilinear distraction osteogenesis (DO) in a minipig model is effective when performed bilaterally, at rates up to 3 mm/day, to achieve clinically relevant lengthening. A Yucatan minipig in the mixed dentition phase underwent bilaterally, at a continuous DO at a rate of 2 mm/day at the center of rotation; 1.0 and 3.0 mm/day at the superior and inferior regions, respectively. The distraction period was 13 days with no latency period. Vector and rate of distraction were remotely monitored without radiographs, using the device sensor. After fixation and euthanasia, the mandible and digastric muscles were harvested. The ex vivo appearance, stability, and radiodensity of the regenerate were evaluated using a semiquantitative scale. Percent surface area (PSA) occupied by bone, fibrous tissue, cartilage, and hematoma were calculated using histomorphometrics. The effects of DO on the digastric muscles and mandibular condyles were assessed via microscopy, and degenerative changes were quantified. The animal was distracted to 21 mm and 24 mm on the right and left sides, respectively. Clinical appearance, stability, and radiodensity were scored as "3" bilaterally indicating osseous union. The total PSA occupied by bone (right = 75.53 +/- 2.19%; left PSA = 73.11 +/- 2.18%) approached that of an unoperated mandible (84.67 +/- 0.86%). Digastric muscles and condyles showed negligible degenerative or abnormal histologic changes. This proof of principle study is the first report of osseous healing with no ill-effect on associated soft tissue and the mandibular condyle using bilateral, automated, continuous, and curvilinear DO at rates up to 3 mm/day. The model approximates potential human application of continuous automated distraction with a semiburied device. PMID- 26594968 TI - Postsurgical Relapse in Class III Patients Treated With Two-Jaw Surgery: Conventional Three-Stage Method Versus Surgery-First Approach. AB - The aim of this study was to investigate the pattern, amount, and distribution of postsurgical relapse in skeletal Class III patients treated with two-jaw surgery (TJS) using conventional three-stage method (CTM) and surgery-first approach (SFA). A total of 38 patients who underwent the nonextraction approach and TJS (LeFort I posterior impaction and mandibular setback) were divided into CTM and SFA groups (all n = 19/group). Lateral cephalograms were taken before treatment (T0), at 1 month before surgery (T1), immediately after surgery (T2), and at debonding (T3) for CTM patients and at T0, T2, and T3 stages for SFA patients. Cephalometric measurements and statistical analyses were performed. There were no significant differences in the cephalometric variables at all stages except maxillary incisor inclination (U1-UOP) and overbite at T0 between 2 groups. They also did not exhibit significant differences in the amounts of surgical movement except for advancement of the maxilla. The mandible in both groups was rotated slightly clockwise by surgery and counterclockwise during T2-T3 without a significant difference. Distribution of cases with "high relapse" (>30%) and "low relapse" (<30%) of the mandible differed for 2 groups (P < 0.05). SFA group had more "high relapse" cases than CTM group (57.9% versus 26.3%). Postsurgical relapse of the mandible had a positive relationship with the amount of mandibular setback in SFA group (P < 0.01) and clockwise rotation of the proximal segment of the mandible in both groups (P < 0.05 and P < 0.01). The results suggest that SFA might be an effective alternative to CTM if the cause of "high relapse" including amounts of mandibular setback and clockwise rotation of the proximal segment of the mandible during surgery can be controlled. PMID- 26594969 TI - Surgical Treatment of Pediatric Craniofacial Fractures: A National Perspective. AB - INTRODUCTION: Head trauma is the most common cause of death because of injury in children, and trauma alone is the leading cause of morbidity and mortality in pediatrics. This study aimed to characterize the demographics and economic burden associated with the surgical and nonsurgical repair of craniofacial fractures in the pediatric inpatient population in the United States. METHODS: A retrospective cohort study was performed using the 2012 Kids' Inpatient Database which identified 20,070 patients who had a skull or facial fracture, of whom 6395 (31.9%) were treated surgically. Epidemiologic patient and hospital data were analyzed as potential determinants of surgical treatment, prolonged hospitalizations, and higher charges. RESULTS: Pediatric craniofacial fractures are estimated to represent $1.2 billion of national healthcare expenditures annually. The average patient charge for surgical treatment of a craniofacial fracture in the pediatric population is $84,849 compared with $52,490 for nonsurgical management (P < 0.001), and the average length of stay was longer for surgical repair when compared with nonsurgical management for craniofacial fractures (5.3 days versus 4.6 days, P < 0.001). Patients who were older, African American, had nonprivate insurance, whose fracture was caused by external trauma, and who were treated in an urban hospital had an independently increased likelihood of surgical repair of craniofacial fractures. Patients who were older, female, insured, of lower income brackets, whose fracture was caused by a motor vehicle accident, who had surgical treatment of their craniofacial fracture, and who were treated in hospitals in the South, Midwest, or West, teaching hospitals, and government-owned hospitals had an independent risk for a prolonged hospitalization. Patients who were older, Caucasian, insured, whose fracture was caused by a motor vehicle accident, and who were treated in hospitals in the South, teaching hospitals, pediatric hospitals, larger hospitals, and government owned hospitals had an independent risk for increased patient charges. CONCLUSIONS: Craniofacial fractures in the pediatric population represent a large economic burden to the patient and family, as well as the healthcare system as a whole. The identified patient and hospital demographics that are associated with prolonged hospital stays and higher patient charges may represent potential barriers to care, and additional research to elucidate these factors is warranted. PMID- 26594970 TI - Reconstruction of Inferior Orbital Wall Fractures Using Bone Fragments. AB - INTRODUCTION: Various materials have been used as implants in orbital floor fractures. The fractured bone fragments, however, are not usually used because of their small size and delicate characteristics. To overcome this limitation, the authors used autologous bone fragments combined with fibrin glue and an absorbable plate to repair inferior orbital wall fractures. METHODS: Thirty-four patients with orbital floor fractures treated in a single center from January 2013 to September 2014 were prospectively evaluated. Patients' demographic characteristics, clinical signs and symptoms, physical examination findings, postoperative complications, and preoperative and postoperative computed tomography findings were assessed. Fracture repair by a transconjunctival approach in which bone fragments were merged with fibrin glue and an absorbable plate was performed in all the patients. RESULTS: Postoperative computed tomography showed good orbital fracture reduction and soft tissue restoration in all the patients. Five patients developed postoperative diplopia; however, this symptom resolved spontaneously. Exophthalmometry showed that the degree of enophthalmos had improved significantly. CONCLUSION: Based on the results of this study, the combination of autologous bone fragments and absorbable mesh appears to be a safe and feasible option for the reconstruction of orbital floor fractures. PMID- 26594971 TI - Maxillary Segmental Micro Osteotomy: A Human Cadaver Study on the Efficacy of the Technique. AB - PURPOSE: Ultrasonic bone cutting was recently introduced as a feasible alternative to the conventional tools of cranio-maxillofacial surgery because it offers improved precision and safety.This study examined the feasibility of minimally invasive orthodontic or preprosthetic surgery using a piezosurgery device for latero-posterior maxillary segmental osteotomy. MATERIALS AND METHODS: Four fresh cadaveric heads were obtained for this study. Maxillary posterior osteotomy was performed using piezoelectric surgery. To preserve the vascular supply, only 1 vestibular incision was made during surgery. The Mectron Piezosurgery unit is a multipurpose device that uses micrometric ultrasonic piezoelectric vibrations with a variable frequency and cutting energy. The strategy for maxillary osteotomy included 1 horizontal osteotomy, 2 vertical osteotomies, and 1 palatal osteotomy performed transantrally without incision of the mucoperiosteum. The osteotomies were performed using a piezodevice (OT7-type inserts: 0.55 and 0.35 mm). In total, 1 horizontal cut (3 mm above the roots of the teeth), 2 vertical bone cuts, and 1 palatal osteotomy were made without incision of the palatal mucoperiosteum.Gentle dissection of the buccal fat pad was used to promote the healing of hard and soft tissues in the osteotomized zone. RESULTS: No damage to soft tissues, including the palatal mucosa, occurred. The buccal fat pad was mobilized easily without requiring an additional incision. The osteotomic sites were linear and clean in the palatal aspect. The integrity of the vascular network was maintained because of the lack of damage to the palatal mucosa. No chisels were used during the osteotomies. DISCUSSION: This cadaveric study shows the feasibility of using piezosurgery for segmental maxillary osteotomy. This report outlines a new and simple application of segmental maxillary micro-osteotomy. PMID- 26594972 TI - Anatomic Study of Posterior Communicating Artery in Computed Tomographic Image. AB - PURPOSE: This study aims to provide an anatomic data of posterior communicating artery (PComA) and its anatomic relationship to the adjacent structures, so as to guide surgeons in the surgery of internal carotid artery-posterior communicating artery aneurysm clipping and sellar tumors resection without injuring the PComA. METHODS: Computer topographic angiography images of 123 individuals were reviewed, and the measurements were done on coronal, sagittal, axial, and other user-defined planes after multiplanar reconstruction. Posterior communicating artery was classified in the reconstructed three-dimensional image, measured in proper planes, and located by the structures such as anterior clinoid process (ACP), posterior clinoid process (PCP), and sagittal midline. RESULTS: Six types of PComA were identified in this study based on its existence and origin. The initial part of PComA can be located by ACP, PCP, and sagittal midline based on some particular angles and distances. CONCLUSIONS: Posterior communicating artery varies in different individuals, and the radiologic study of it is an optimal way to analyze the variances. The anatomic relations between PComA and basic skull structures such as the ACP and PCP are especially important for neurosurgeons. PMID- 26594973 TI - The Public Recognizes Plastic Surgeons as Leading Experts in the Treatment of Congenital Cleft and Craniofacial Anomalies. AB - OBJECTIVE: The aim of this study is to assess the public perception of plastic surgeons (PS) as craniofacial surgery specialists. METHODS: Members of the public (N = 1514) were asked to choose 1 or 2 specialists that they perceived to be an expert for 13 craniofacial surgery-related scenarios. Response patterns were distributed as "plastic surgeon alone" (PS alone), "PS combined with other specialists", or "no plastic surgeon" (No PS). Sociodemographic data, previous plastic surgery contact, and source of reported information were also collected. RESULTS: "Plastic surgeon alone" was significantly (all P < 0.05) more recognized as experts than all other response patterns particularly in congenital anomalies related scenarios (83.33%). There was a significantly (all P < 0.05) poor understanding of the role of PSs in head/neck infection management, chronic facial palsy management, dental disease management, head and neck cancer surgery, vascular malformation surgery, and facial fracture surgery. Sex, age, education level, health care professional, prior plastic surgery contact, and source of reported information were not significant (all P < 0.05) determinants of "PS" as the response in bivariate and multivariate analyses. CONCLUSIONS: Public recognized PSs as experts primarily in treatment of congenital cleft and craniofacial anomalies, but as the overall scope of craniofacial surgery practice was poorly understood and known, improved public education is needed. PMID- 26594974 TI - A Case of Aggravated Medial Orbital Wall Fracture After Reduction of Orbital Floor Fracture. AB - Concomitant fractures of the inferior and medial orbital wall can cause more severe orbital symptoms and lead to incomplete reduction postoperatively. This report presents the case of a 17-year-old boy, presenting with persistent diplopia and enophthalmos after floor reduction for concomitant fractures. At the time of the fracture, surgery was performed for only the orbital floor by a plastic surgeon, because the medial wall fracture was minimal. However, he presented with persistent orbital symptoms after surgery. An aggravated medial wall fracture was discovered via computed tomography (CT) examination. It was treated with a minimal-invasive method using an endoscopic approach. PMID- 26594975 TI - Leproma Presenting as a Nasal Cavity Mass. AB - Leprosy is a rare disease and unfamiliar to many people. A 55-year-old woman was presented to our hospital complaining of nasal obstruction and anosmia. Nasal endoscopic examination revealed reddish-colored exophytic, nonulcerative masses in both nasal cavities. The authors performed endoscopic sinus surgery which involved endoscopic mass removal and synechiolysis. A biopsy sample stained with acid-fast stain and a rapid silver stain showed numerous filamentous organisms infiltrating macrophages, consistent with lepromatous leprosy. The patient was treated with a triple drug regimen of rifampin and dapsone with clofazimine. Herein, the authors present a case of nasal leproma as a differential diagnosis of a nasal cavity mass. PMID- 26594976 TI - Juxta-articular Myxoma of the Temporomandibular Joint. AB - The juxta-articular myxoma represents a benign mesenchymal neoplasm that arises from tissue within or adjacent to a joint space. There have been a number of reported cases involving myxomas of the knee, shoulder, elbow, wrist, and hip. To our knowledge there, however, have been no reported cases of juxta-articular myxomas of the temporomandibular joint (TMJ). This report describes the case of a 57-year-old woman with a juxta-articular myxoma of the left TMJ extending into the infratemporal fossa (ITF). Access to the tumor was accomplished via a preauricular incision and low condylar osteotomy which allowed for displacement of the condyle for direct visualization and excision of the tumor. The postoperative course was benign and the patient demonstrated no cosmetic or functional limitation. Likewise, follow-up at 30 months showed no evidence of recurrence. Benign encapsulated tumors of the ITF can be effectively accessed by means of a modified preauricular incision, low condylar osteotomy, and anterior meniscal release. This direct approach allows for excellent surgical exposure, minimal surgical site morbidity, and maintenance of physiologic joint function and occlusion. PMID- 26594977 TI - Congenital Sialolipoma in an Infant. AB - Sialolipoma is a newly recognized tumor of the major and minor salivary glands and represents only 0.3% of all salivary gland tumors. Only 3 cases of congenital sialolipoma are available in the literature. In the current case, we performed a total parotidectomy with facial nerve preservation on a 12-week-old infant exhibiting huge mass in the parotid region. Histopathology results showed sialolipoma. There was no recurrence at the 18-month follow-up. Although it is a very rare disease in infants, congenital sialolipoma should be kept in mind in patients with parotid mass. The primary treatment is parotidectomy with facial nerve preservation. PMID- 26594978 TI - A Different Approach to the Reconstruction of Nasal Septum Perforations: Alar Winged Flap. AB - PURPOSE: Nasal septal perforations (NSPs) are one of the major complications among the nose surgery that the surgeon has to solve it. There are many reasons on the etiology of septal perforation such as iatrogenic and idiopathic. All the surgical procedures are based on 2 main principles, namely repair using an intranasal flaps: mucosal, mucoperichondrial, mucoperiosteal flaps within the nasal cavity; and extranasal flaps. Operation can be carried out using either the "closed technique" or "open technique." The author presents a different or additional method, namely alar winged flaps (AWFs). PATIENTS AND METHODS: Between 2010 and 2014, a total of 13 patients with medium-large NSP were treated with this approach. Of these 13 patients, 9 were male (69%) and 4 female (31%). Average age was 40.13 years. In 13 cases, average diameter of the perforation was between 1.5 and 2.4 cm; in 1 case, it was >3 cm; in 2 cases, it was <2 cm. RESULTS: Alar winged flaps was used for better exposure in all patients. Etiology of the NSP was detected as previous septal surgery in 5 cases (38%), over septal tissue resection in 3 cases (23%), and infection at septal surgery, blunt trauma, >1 blunt trauma, nasal corticosteroid using, respectively. There was no preoperative and postoperative complication. At the early follow-up, AWF flap incision scar was cosmetically satisfactory. DISCUSSION: As can be seen from the senior authors' description, especially large NSPs are difficult problems to solve. The proposed surgical techniques are still offered the highest recurrence rates. To address this problem, the authors developed the AWF method. The operation time before using AWF was so long in our previous NSP surgeries. After AWF, the authors saved an average of 14 to 25 minutes in each operation. No visible scar is seen on the AWF donor areas at the early follow-up. The authors suggest this flap method bilaterally and/or unilaterally for the medium or large perforations. PMID- 26594979 TI - Three-Dimensional Soft Tissue Assessment Following Mandibular Bilateral Sagittal Split Osteotomy. AB - PURPOSE: The purpose of the study is to quantify anteroposterior and transverse facial soft tissue changes with respect to underlying skeletal movements after bilateral sagittal split osteotomy by using cone beam computed tomography (CBCT). PATIENTS AND METHODS: The study was conducted on 6 patients who required bilateral sagittal split osteotomy for correction of mandibular retrognathism. The patients were scanned using CBCT 1 week preoperatively, and 6 months postoperatively. The differences between pre- and postoperative images were measured and the ratios of different hard to soft tissue movements were calculated. RESULTS: There was a statistically significant difference in the mean measurements postoperatively. The ratio of the mean hard to soft tissue movement after mandibular advancement was 1:0.97 in the chin region and 1:0.80 in the lower lip area. The mean decrease in the mentolabial fold (MLF) depth was 1.4 mm and the mean increase in the mentolabial angle (MLA) was (27.7). CONCLUSIONS: The soft tissue changes related to mandibular advancement would appear to be fairly predictable and follow their underlying skeletal structures in 1:0.97 ratio in the chin area. Also, increase in facial convexity has an important influence on changes in the position of the lower lip as well as on changes in MLF depth and MLA. PMID- 26594980 TI - Albumin Levels in Patients With Chronic Rhinosinusitis With Nasal Polyp. AB - OBJECTIVES: We aim to provide useful evidence on the relationship between the albumin levels and chronic rhinosinusitis with nasal polyp (CRSwNP) and its potential use as an inexpensive, reliable, and independent prognostic marker of CRSwNP. MATERIALS AND METHODS: Forty-five patients with CRSwNP and 45 healthy individuals were included in the study. Serum albumin levels were determined. The serum albumin levels of the study and control groups were compared to determine whether there is a statistically significant difference. RESULTS: The mean albumin level of the study group was 4.65 +/- 0.38, the median value was 4.70. The mean albumin level of the control group was 4.84 +/- 0.39, the median value was 4.90. There was a statistically significant difference between the albumin levels of the study and control groups (P = 0.045, P < 0.05). CONCLUSION: The albumin levels were found to be statistically significantly lower in patients with CRSwNP. This result may contribute to the diagnosis of CRSwNP and identifying its prognosis. PMID- 26594982 TI - A Novel Method to Attain Highly Symmetric Oblique Mandibular Chin-Body Osteotomy. AB - Oblique mandibular chin-body osteotomy is a widely used narrowing genioplasty. However, the historic challenge is how to achieve a highly symmetric result of oblique mandibular chin-body osteotomy. Here, we present a novel and simple method to achieve a highly symmetrical mandibular chin-body osteotomy. METHOD: Ten consecutive patients underwent mandibular chinbody osteotomy used silicone triangle template technique. Patient and surgeon's satisfaction of the surgery and surgeon's confidence improvement with template during the surgery were measured. RESULT: All patients and surgeons were satisfied with the outcome. The operator's confidence was significantly improved during the operation. CONCLUSIONS: Silicone triangle template technique is an effective method to achieve highly symmetrical mandibular chin-body osteotomy and boost surgeon's confidence. PMID- 26594981 TI - The Future of Plastic Surgery: Surgeon's Perspective. AB - Since the days of Sushruta, innovation has shaped the history of plastic surgery. Plastic surgeons have always been known as innovators or close followers of innovations. With this descriptive international survey study, the authors aimed to evaluate the future of plastic surgeons by analyzing how plastic surgery and plastic surgeons will be affected by new trends in medicine. Aesthetic surgery is the main subclass of plastic surgery thought to be the one that will change the most in the future. Stem cell therapy is considered by plastic surgeons to be the most likely "game changer." Along with changes in surgery, plastic surgeons also expect changes in plastic surgery education. The most approved assumption for the future of plastic surgery is, "The number of cosmetic nonsurgical procedures will increase in the future." If surgeons want to have better outcomes in their practice, they must at least be open minded for innovations if they do not become innovators themselves. Besides the individual effort of each surgeon, international and local plastic surgery associations should develop new strategies to adopt these innovations in surgical practice and education. PMID- 26594983 TI - Surgical Outcomes Comparison Between Endoscopic and Conventional Open Thyroidectomy for Benign Thyroid Nodules. AB - BACKGROUND: The aim of this study was to compare the surgical outcomes of endoscopic thyroidectomy (ET) and conventional open thyroidectomy (COT) for benign thyroid nodules. METHODS: Between March 2001 and November 2014, 224 patients underwent ET via the breast approach and 218 patients underwent COT. Clinicopathological characteristics and surgical outcomes were retrospectively compared. RESULTS: The operation time was significantly longer in the ET group than in the COT group (P = 0.000). However, the ET group had less intraoperative blood loss (P = 0.000), less amount of drainage (P = 0.000), and shorter duration of drainage (P = 0.000). The cosmetic satisfaction was more excellent in the ET group than in the COT group (P = 0.000). CONCLUSIONS: ET via the breast approach is a safe and effective procedure with excellent cosmetic results for patients with benign thyroid nodules. PMID- 26594984 TI - Up-and-Coming Mandibular Reconstruction Technique With Autologous Human Bone Marrow Stem Cells and Iliac Bone Graft in Patients With Large Bony Defect. AB - Large bony defects followed by resection of the mandible need to be reconstructed by various surgical techniques such as the fibular flap. In this article, we report the case of mandibular reconstruction with autologous human bone marrow mesenchymal stem cells and autogenous bone graft, followed by placement of dental implants and prosthodontic treatment in a patient who has been failed to reconstruct mandibular bone defect after resection of mandible. PMID- 26594985 TI - Frontorbital Fibrous Dysplasia Resection and Reconstruction With Custom Polyetherlatone Alloplast. AB - Fibrous dysplasia (FD) is a benign, pathological development of bone. Craniofacial bones are the most commonly involved and can potentially cause visual disturbance, proptosis, orbital dystopia, and facial deformity. This case involves a 13-year-old girl with significant proptosis (20 mm left, 17.5 mm right) and downward displacement of the left globe (1.5 mm) due to fibrous dysplasia. Reconstruction was performed with computed tomography-derived and 3D printed custom polyetheretherketone (PEEK) implantation. PEEK is a nonabsorbable, nonporous thermoplastic polymer notable for its ability to be modified intraoperatively and ideal imaging properties postoperatively. Never, to our knowledge, has PEEK been used for primary reconstruction of the frontal orbital region in fibrous dysplasia in a child. The lesion was successfully repaired with excellent aesthetic and no apparent damage to neurovascular or ocular structures. PMID- 26594986 TI - Is the Maxillary Sinus Really Suitable in Sex Determination? A Three-Dimensional Analysis of Maxillary Sinus Volume and Surface Depending on Sex and Dentition. AB - The morphometric analysis of maxillary sinus was recently presented as a helpful instrument for sex determination. The aim of the present study was to examine the volume and surface of the fully dentate, partial, and complete edentulous maxillary sinus depending on the sex. Computed tomography data from 276 patients were imported in DICOM format via special virtual planning software, and surfaces (mm) and volumes (mm) of maxillary sinuses were measured. In sex-specific comparisons (women vs men), statistically significant differences for the mean maxillary sinus volume and surface were found between fully dentate (volume, 13,267.77 mm vs 16,623.17 mm, P < 0.0001; surface, 3480.05 mm vs 4100.83 mm, P < 0.0001) and partially edentulous (volume, 10,577.35 mm vs 14,608.10 mm, P = 0.0002; surface, 2980.11 mm vs 3797.42 mm, P < 0.0001) or complete edentulous sinuses (volume, 11,200.99 mm vs 15,382.29 mm, P < 0.0001; surface, 3118.32 mm vs 3877.25 mm, P < 0.0001). For males, the statistically different mean values were calculated between fully dentate and partially edentulous (volume, P = 0.0022; surface, P = 0.0048) maxillary sinuses. Between the sexes, no differences were only measured for female and male partially dentate fully edentulous sinuses (2 teeth missing) and between partially edentulous sinuses in women and men (1 teeth vs 2 teeth missing). With a corresponding software program, it is possible to analyze the maxillary sinus precisely. The dentition influences the volume and surface of the pneumatic maxillary sinus. Therefore, sex determination is possible by analysis of the maxillary sinus event through the increase in pneumatization. PMID- 26594987 TI - Surgery Versus Nonsurgery Option for Scissors Bite Treatment. AB - BACKGROUND: This article compared the use of temporary skeletal anchorage devices (TSADs) and orthognathic surgery for scissors bite correction. METHODS: To correct the scissors bite without orthognathic surgery, a cross-type titanium miniplate was placed with 3 miniscrews (1.5 mm in diameter and 5 mm in length) in the midpalatal area, without a surgical incision and under local anesthesia. In addition, a 1 miniscrew was placed on the buccal alveolar bone to avoid molar extrusion during uprighting. In the surgical case, a 3-piece Le Fort osteotomy was performed to decrease maxillary arch width for transverse correction, and to close the extraction space by anterior retraction. The maxilla was stabilized with 4 L-shaped plates at the zygomatic buttresses and the pyriform aperture, as well as 2 straight plates between the 3 segments. RESULTS: After 15 months of treatment in the nonsurgery case, the scissors bite was successfully resolved by decreasing maxillary arch width and uprighting the molars. In the mandibular arch, correction of the crowding was aided by extraction of # 41. In the surgery case, after 24 months of treatment in the orthognathic surgery case, the bilateral scissors bite was successfully resolved and the facial asymmetry was corrected. The molar occlusion finished in Class II and the facial profile was improved. CONCLUSIONS: In scissors bite cases, a good diagnosis will help the clinician to decide whether treatment should involve orthognathic surgery. The authors have shown a case that was corrected with surgery and a case that was corrected using TSAD anchors. Treatment planning must include evaluation of the basal arch width of maxilla and mandible in class I occlusion, any skeletal asymmetry concomitant with a mandibular shift, the inclinations or atypical eruption degree of the posterior teeth, and the number of teeth involved in the scissors bite. PMID- 26594988 TI - Is Three-Dimensional Soft Tissue Prediction by Software Accurate? AB - The authors assessed whether virtual surgery, performed with a soft tissue prediction program, could correctly simulate the actual surgical outcome, focusing on soft tissue movement. Preoperative and postoperative computed tomography (CT) data for 29 patients, who had undergone orthognathic surgery, were obtained and analyzed using the Simplant Pro software. The program made a predicted soft tissue image (A) based on presurgical CT data. After the operation, we obtained actual postoperative CT data and an actual soft tissue image (B) was generated. Finally, the 2 images (A and B) were superimposed and analyzed differences between the A and B. Results were grouped in 2 classes: absolute values and vector values. In the absolute values, the left mouth corner was the most significant error point (2.36 mm). The right mouth corner (2.28 mm), labrale inferius (2.08 mm), and the pogonion (2.03 mm) also had significant errors. In vector values, prediction of the right-left side had a left-sided tendency, the superior-inferior had a superior tendency, and the anterior posterior showed an anterior tendency. As a result, with this program, the position of points tended to be located more left, anterior, and superior than the "real" situation. There is a need to improve the prediction accuracy for soft tissue images. Such software is particularly valuable in predicting craniofacial soft tissues landmarks, such as the pronasale. With this software, landmark positions were most inaccurate in terms of anterior-posterior predictions. PMID- 26594989 TI - Comparative Analysis Between Computed and Conventional Inferior Alveolar Nerve Block Techniques. AB - OBJECTIVE: The aim of this randomized, double-blind, controlled trial was to compare the computed and conventional inferior alveolar nerve block techniques in symmetrically positioned inferior third molars. PATIENTS AND METHODS: Both computed and conventional anesthetic techniques were performed in 29 healthy patients (58 surgeries) aged between 18 and 40 years. The anesthetic of choice was 2% lidocaine with 1: 200,000 epinephrine. The Visual Analogue Scale assessed the pain variable after anesthetic infiltration. Patient satisfaction was evaluated using the Likert Scale. Heart and respiratory rates, mean time to perform technique, and the need for additional anesthesia were also evaluated. RESULTS: Pain variable means were higher for the conventional technique as compared with computed, 3.45 +/- 2.73 and 2.86 +/- 1.96, respectively, but no statistically significant differences were found (P > 0.05). Patient satisfaction showed no statistically significant differences. The average computed technique runtime and the conventional were 3.85 and 1.61 minutes, respectively, showing statistically significant differences (P <0.001). CONCLUSIONS: The computed anesthetic technique showed lower mean pain perception, but did not show statistically significant differences when contrasted to the conventional technique. PMID- 26594990 TI - Triple V-Y Vermilion Augmentation of the Upper Lip. AB - Lip enhancement is one of the most common procedures in the facial cosmetic surgery. The most important reason for that is the fact that fullness of lips symbolizes youth and sensuality. The authors present 2 patients whose upper lip vermilion dimension was increased using the triple V-Y augmentation surgical technique. The main request for both was augmentation of the upper lip without dermal fillers and implants into the lip. Treatment and postrecovery were routine. After 1 month both upper lips had satisfactory look with the preservation of curvature of the Cupid's bow and natural appearance.The V-Y lip augmentation technique can be a method of choice for lip enhancement in adequately selected patients. PMID- 26594991 TI - Foreign Body Mimicking a Dental Implant Radiographically. AB - Foreign bodies are often encountered in the maxillofacial region and can present in several ways. They frequently occur as a result of accidents, explosions, and gunshot injuries or because of iatrogenic factors in therapeutic interventions in daily dental practice. This report describes an unusual case of a broken elevator blade mimicking a dental implant embedded in alveolar bone radiographically, within the maxillary palatal mucosa during a traumatic maxillary right first molar extraction. PMID- 26594992 TI - Arteriovenous Hemangioma of the Ear Lobule. AB - Primary tumors arising from the ear lobule are uncommon, and hemangiomas in this region are extremely rare. The authors report a case of an arteriovenous hemangioma in the left ear lobule. The mass was reddish-colored, soft, mobile, nonpulsatile, and not tender on palpation. There was no recurrence 22 months after surgical excision. PMID- 26594993 TI - A Novel Technique Using Customized Headgear for Fixation of Rigid External Distraction Device in an Infant With Crouzon Syndrome. AB - Rigid external distraction device is often indicated for superior midfacial advancement in pediatric syndromic craniosynostosis patients. Even though the technique is proven reliable to treat the functional issues related to the craniofacial deformity, major complications associated with its fixation, such as intracranial pin perforation and migration have been reported. We report a novel technique of using a customized headgear to prevent intracranial pin perforation over a very thin temporal bone region in an 8-month-old infant with Crouzon syndrome who underwent monobloc Le Fort III distraction osteogenesis using a combination of bilateral internal and a rigid external distraction device. The customized headgear provides a protective platform at the temporal region thus preventing intracranial pin perforation and allows stable fixation during the early phase of consolidation period to prevent central component relapse. The headgear can be used short term when rigid external distractor is indicated in infant patient but requires close monitoring because of risks of skin necrosis and temporal region indentation. PMID- 26594994 TI - Evaluation of the Trephine Method in Harvesting Bone Graft From the Anterior Iliac Crest for Oral and Maxillofacial Reconstructive Surgery. AB - Autogenous bone graft is the gold standard for maxillofacial reconstruction. Although there are many donor sites, the ilium is favored. Open iliac bone harvesting techniques can result in significant complications, which are to be reduced; a minimally invasive technique using trephine burs was used. The aim of the study was to evaluate the intra- and postoperative complications, the size of bone harvested, and the time of the procedure. Eighteen consecutive patients were conducted. The trephine bur makes holes of 10 mm diameter in the iliac crest from which a bone graft can be harvested. No major long-term morbidity was found; all patients were discharged on the first postoperative day. The trephine technique is generally a safe procedure, can provide enough corticocancellous bone for osseous defects in maxillofacial region up to 10 cc. In addition to that, the technique is easy to learn and allows early discharge of patients from the hospital. PMID- 26594995 TI - A Novel System for Navigation-and Robot-Assisted Craniofacial Surgery: Establishment of the Principle Prototype. AB - PURPOSE: The authors aimed to develop 1 novel navigation-guided robotic system for craniofacial surgery to improve accuracy during operation. MATERIALS AND METHODS: A new 7-DOF (7-degree-of-freedom) robotic arm was designed and manufactured. Based on our self-developed navigation system TBNAVIS-CMFS, the key technique of integration was studied. A phantom skull model was manufactured based on computed tomography image data and used for the preexperimental study. Firstly, virtual planning was achieved through the TBNAVIS-CMFS, where the Le Fort I procedure was executed through simulation. Then, the actual Le Fort 1 osteotomy was expected to perform with the use of the robotic arm following the instructions from the navigation system. RESULTS: The theoretical prototype of navigation-guided robotic system for craniofacial surgery was established successfully, which performed the planned Le Fort I procedure with the whole process visible on the screen. CONCLUSIONS: The technical method of navigation guided robotics system, allowing the operator to practice the virtual planning procedure through navigation system as well as perform the actual operation thru the robotic arm, could be regarded as a valuable option for benefiting craniofacial surgeons. PMID- 26594996 TI - Salvaging the Exposed Cochlear Implant. AB - Cochlear implant exposure is an uncommon occurrence that may imperil the fate of the implant. Insertion of this costly device is a delicate procedure, and reimplantation with another implant after removal is expensive and emotionally stressful for patients. Salvage of the original implant can be quite successful with a fully vascularized scalp-nape of the neck rotation flap. The authors review the literature and report their experience in salvaging exposed implants in 2 patients, who had risk factors that compromised healing. PMID- 26594997 TI - The Paradoxical Predominance of Medial Wall Injuries in Blowout Fracture. AB - PURPOSE: To evaluate the type and cause of orbital blowout fractures in Korea. DESIGN: Retrospective, observational case series. METHODS: Patients who underwent reconstruction for blowout fracture from March 2004 to April 2013 at Korea University Guro and Ansan Hospitals were included in this study. Patient demographics and orbital computed tomography (CT) scans were reviewed. On CT, ethmoid air cell septa, blowout fracture type, and other combined fractures were analyzed. Blowout fracture was classified as affecting up to 4 areas: the floor lateral to the infraorbital canal, the floor medial to the canal, the maxilla ethmoidal strut ("inferomedial" strut), and the medial wall. Furthermore, trauma type and associated injury were reviewed. The results of adolescent patients and adult patients were compared, as were those of males and females. RESULTS: The study included 659 eyes of 659 patients; mean patient age was 31.01 +/- 14.27 years. In total, 513 (77.85%) patients were male and 146 (22.15%) were female. The most common blowout fracture type was medial wall fracture, followed by floor wall, floor and medial wall without inferomedial strut, and floor and medial wall fracture with inferomedial strut, in that order. Interestingly, patients with floor wall blowout fracture were younger (26.87 +/- 12.90 y) than other groups: medial wall fracture (32.35 +/- 14.64 y, P < 0.0001), floor and medial wall fracture (35.22 +/- 14.49 y, P < 0.0001), and floor and medial wall fracture involving the maxillaethmoidal strut (32.62 +/- 13.75 y, P = 0.002). The number of ethmoidal air cell septa was lowest in the medial wall fracture group (3.62 +/ 0.67): floor wall fracture (4.07 +/- 0.69, P < 0.0001), floor and medial wall fracture (3.90 +/- 0.78, P < 0.0001), and floor and medial wall fracture involving the maxilla-ethmoidal strut (4.05 +/- 0.72, P = 0.001). CONCLUSIONS: Our study demonstrated that the blowout fracture type distribution in Korea varied from the results of many other studies. Medial wall fracture is the most common among the 4 types, and anatomic variance, such as number of ethmoid air cell septa, could influence blowout fracture type, especially in medial wall fracture. PMID- 26594998 TI - Reverse Distraction Cranioplasty for Treatment of Hydrocephalic Megalocephaly. AB - Macrocephaly resulting from untreated hydrocephalus is a rare but difficult condition to treat. The patient presented is a 6-year-old boy who had progressively increasing head size since birth secondary to untreated hydrocephalus with associated developmental delay. His initial head circumference was 69 cm, and computed tomography scan showed evidence of obstructive hydrocephalus. For the first stage of the procedure, bicoronal and circumferential strip craniectomies were performed, 5 fully open 3.5 mm midface distractors were placed to facilitate vault reduction, and absorbable plates were placed in the frontoorbital region. Neurosurgery also performed an endoscopic third ventriculostomy and placed an external ventricular drain. Reverse distraction was completed over 5 days and tolerated well by the patient. Three months after the first procedure, the distractors were removed and frontoorbital reduction and additional cranial vault reduction and reshaping were performed. At 1 month following this operation he was noted to have excellent forehead contour and dramatic improvement of his macrocephaly with some remaining mid-vault asymmetry. His head circumference was measured at 61.5 cm with bicoronal distance of 39.5 cm. He demonstrated improvement in head control and ability to sit. This patient demonstrates a new technique for reduction cranioplasty involving the use of reverse distraction to facilitate gradual and controlled reduction prior to extensive cranial vault remodeling. The challenges associated with managing hydrocephalus in cranial vault reduction patients are also addressed. PMID- 26594999 TI - Customized Titanium Mesh for Repairing Cranial Defects: A Method With Comprehensive Evaluation. AB - Titanium cranioplasty is one of the well-established and widely used techniques for repairing cranial defects. In this paper, we present an improved way to design and create titanium meshes with more evaluation process. Computed tomography scan data of patients were used to create three-dimensional virtual models. Implants were designed with NX ImageWare 13.2 (Siemens PLM Software, Plano, TX). Final titanium meshes were assessed by Geomagic Studio 12 (Geomagic, Inc., Morrisville, NC) and NX ImageWare 13.2.Titanium meshes were designed and applied to cranioplasty surgery on 8 patients. Postoperative results were evaluated by computed tomography scanning and further analyzed with rainbow difference tomography. All patients were satisfied with the outcome. With this method, surgeons, engineers, and patients work together to evaluate and edit implant design. Our method provides better communication and comprehensive evaluation, which result in a satisfying outcome. PMID- 26595000 TI - Orbital Wall Restoring Surgery for Inferomedial Blowout Fracture. AB - Repairing a large inferomedial blowout fracture remains a challenge to orbital surgeon. The authors restored the fracture using combined transnasal and transorbital approaches using support of both paranasal sinuses. The authors compared surgical results of this novel method with those of the traditional procedure. Of 106 inferomedial blowout fracture patients who underwent surgical treatment between March 2007 and July 2013, 50 patients were selected in our study: 25 patients underwent the traditional procedure as controls, and the other 25 patients underwent orbital wall restoring surgery by our combined approach. Outcomes were evaluated in terms of the orbital volume ratio (OVR) and changes in Hertel scale. The OVR in the experimental group (7.19%) decreased more significantly than in the control group (2.71%) (P < 0.05). In conclusion, the orbit was restored more successfully following orbital wall restoring surgery with dual support than by using the traditional inferomedial blowout fracture procedure. PMID- 26595001 TI - Change in the Upper Airway of Patients With Obstructive Sleep Apnea Syndrome Using Computational Fluid Dynamics Analysis: Conventional Maxillomandibular Advancement Versus Modified Maxillomandibular Advancement With Anterior Segmental Setback Osteotomy. AB - OBJECTIVE: The aim of the study was to compare the effect of conventional maxillomandibular advancement (MMA) and modified MMA with anterior segmental setback osteotomy (MMA-ASSO) on the airway changes in patients with obstructive sleep apnea syndrome (OSAS) using three-dimensional computational fluid dynamics (3D-CFD) analysis. METHODS: Two adult male patients with Class I malocclusion, lip protrusion, acute nasolabial angle, and OSAS were treated with conventional MMA (Case 1) and modified MMA-ASSO (Case 2). Individualized 3D airway models were fabricated using computed tomography data obtained 1 month before (T0) and at least 6 months after surgery (T1). A total of 7 cross-sectional areas of the airway were established, starting just above the hard palate (plane 1) with interval of 1 mm caudally. Airflow velocity and negative pressure were investigated using CFD analysis, and polysomnography studies were performed at T0 and T1. RESULTS: There were improvement of apnea-hypoapnea index and the lowest O2 level (T0 versus T1; 43.2 versus 15.2, 79% versus 90% in Case 1; 61.0 versus 6, 89% versus 92% in Case 2). At plane 2 (retropalatal area) in Cases 1 and 2, there were increase in the smallest cross-sectional areas (57.9% versus 28.4%), decrease in the airflow velocity and increase in the negative pressure at the peak of expiration (49.5% versus 31.7%; 88.4% versus 54.3%), end after expiration (53.2% versus 32.2%; 83.2% versus 47.9%), and peak of inspiration (53.1% versus 29.2%; 75.3% versus 48.2%). CONCLUSION: Modified MMA-ASSO method might be an effective treatment option for OSAS patients with improvement of airway problems and esthetic facial profile. PMID- 26595002 TI - Prevalence and Consequences of Positional Plagiocephaly and Brachycephaly. AB - The incidence of positional plagiocephaly and brachycephaly in infants has increased. Treatment options include physiotherapy and helmet therapy.No information exists on the prevalence, cosmetic, and psychological consequences of plagiocephaly and brachycephaly later in life. This study was performed to assess the prevalence and cosmetic relevance of plagiocephaly and brachycephaly, as well as its influence on quality of life in adolescence.The authors performed plagiocephalomety to assess cranial shape and used a questionnaire that included question about educational level, medical history, cosmetic appearance, and cranial shape. To evaluate quality of life, the authors used the KIDSCREEN-27 questionnaire.All data were analyzed using SPSS version 19.0 2010. The authors included 87 adolescents. The prevalence of plagiocephaly, defined as an oblique diameter difference index (ODDI) higher than 106%, was 10.3%; the prevalence of brachycephaly, defined as a cranial proportional index (CPI) higher than 95%, was 0%.There was no significant correlation between the level of the ODDI or CPI and the cosmetic assessment of cranial shape (P = 0.128/0.541). There was no significant correlation with the level of the ODDI (P = 0.428).There was no significant correlation between the level of the ODDI or CPI and the average T value for quality of life using the KIDSCREEN quality-of-life questionnaire (P = 0.461/0.713). The prevalence of positional deformities in our population of adolescents, born after the "back to sleep" campaign, is low. There was no significant correlation between the presence of a cranial deformity and the cosmetic judgement and quality of life. PMID- 26595003 TI - Comparative Analysis of Bilateral Temporomandibular Joints in Patients With Unilateral Temporomandibular Joint Complaints Using Cone Beam Computed Tomography. AB - OBJECTIVE: This study was to determine if there was any temporomandibular joint (TMJ) indicator that was not statistically different in the controls but was with statistical difference between the bilateral sides in patients with unilateral TMJ complaints using cone beam computed tomography (CBCT). METHODS: TMJ CBCT images of 123 patients were used to preliminarily determine the indicators suitable for the measuring method. TMJ CBCT image reconstruction was performed and 19 indicators were measured. Thirty-six patients without TMJ complaint were used as controls. These bilateral TMJs were analyzed by paired t test to find out the indicators without statistical significance in the control group. Fifty patients with TMJ complaints unilaterally were used to determine the indicators that showed no statistical difference in the control group and showed statistical difference in the unilateral TMJ complaints group. RESULTS: All measured values showed no difference statistically in the control group, except the radius value. In the group of unilateral TMJ complaints, sagittal 60 degrees joint space was statistically different (P < 0.05); parallel 120 degrees and sagittal 90 degrees joint space were significantly different (P < 0.01); the rest of the measured values proved to be of no statistical difference. CONCLUSIONS: Sagittal 60 degrees joint space, parallel 120 degrees , and sagittal 90 degrees joint space were suggested to be the indicators with statistical difference between symptomatic side and asymptomatic side in patients with unilateral TMJ complaints. Comparing with the asymptomatic side, there is a significant joint space increase in symptomatic side in the patients with unilateral TMJ complaint. PMID- 26595004 TI - The Application of Surgical Navigation in the Treatment of Temporomandibular Joint Ankylosis. AB - OBJECTIVE: The purpose of this study was to assess the safety and the accuracy of surgical navigation technology in the resection of severe ankylosis of the mandibular condyle with the middle cranial fossa. METHODS: The computed tomography scan data were transferred to a Windows-based computer workstation, and the patient's individual anatomy was assessed in multiplanar views at the workstation. In the operation, the patient and the virtual image were matched by individual registration with the reference points which were set on the skull bone surface and the teeth. Then, the real-time navigation can be performed. RESULTS: The acquisition of the data sets was uncomplicated, and image quality was sufficient to assess the operative result in 2 cases. Both of the operations were performed successfully with the guidance of real-time navigation. The application of surgical navigation has enhanced the safety and the accuracy of the surgery for bony ankylosis of temporomandibular joint. CONCLUSIONS: The use of surgical navigation resulted in the promotion of accurate and safe surgical excision of the ankylosed skull base tissue. PMID- 26595005 TI - Deep Venous Thrombosis in Teen With Crouzon Syndrome Post-Le Fort III Osteotomy With Rigid External Distraction. AB - Venous thromboembolic events are rare in pediatric patients. Risk factors associated with the development of venous thromboembolic events in pediatric patients include the use of central venous catheters, hospitalization, cancer, sepsis, trauma, surgery, and congenital prothrombotic disorders.The authors present the case of a 14-year-old man with Crouzon syndrome who required Le Fort III osteotomy with rigid external distraction for significant midface hypoplasia who presented postoperatively with an extensive deep venous thrombosis. This is the first reported case of symptomatic venous thrombosis post-Le Fort III osteotomy and rigid external distraction. Although rare, surgeons should be aware of this potential complication. PMID- 26595006 TI - Characteristics of Maxillofacial Trauma Among Alcohol and Drug Users. AB - The aim of the current study was to identify and compare the characteristics of maxillofacial trauma in alcohol and drug users with those of nonusers. A retrospective study was conducted using the medical records of patients treated for facial trauma between April 1999 and March 2012 at the Maxillofacial Surgery Division of the Piracicaba Dental School. The data were analyzed by descriptive analysis, binary logistic regression, and correlational analysis using SPSS 18.0 software. The results were considered relevant at P < 0.05. Medical records of 3724 patients with facial trauma were analyzed, of which 173 were illicit drug users and 19.36% reported alcohol intake. The use of illicit drugs was reported by 4.64%. The prevalent etiological factor among drug and alcohol users was interpersonal violence. The mandible was the face part most affected by fractures. Male patients exhibited increased odds of experiencing fractures (OR = 1.43), as did users of illicit drugs (OR = 1.62), when compared with nonusers. When faced with maxillofacial trauma, male drug users exhibited an increased chance of experiencing fractures. This knowledge should be used as a baseline to implement more efficient prevention strategies for this population. PMID- 26595007 TI - Reconstruction of Facial Defect Using Deltopectoral Flap. AB - Reconstruction of the head and neck is a challenge for otolarygology surgeons, maxillofacial surgeons as well as plastic surgeons. Defects caused by the resection and/or trauma should be closed with flaps which match in color, texture and hair bearing characteristics with the face. Deltopectoral flap is a one such flap from chest and neck skin mainly used to cover the facial defects. This study report a patient presenting with tragic Road Traffic Accident (RTA) admitted to maxillofacial surgery department at Ramadi Teaching Hospital, Anbar province, Iraq. An incision, medially based, was done and deltopectoral fascio-cutaneous flap was used for surgical exposure and closure of defects after RTA. There was no major complication. Good aesthetic and functional results were achieved. Deltopectoral flap is an excellent alternative for the reconstruction of head and neck. Harvesting and application of the flap is rapid and safe. Only a single incision is sufficient for dissection and flap elevation. PMID- 26595008 TI - Total Airway Reconstruction in the Neonate: Combined Mandibular Distraction and Slide Tracheoplasty for Multiple Level Airway Obstruction. AB - BACKGROUND: Long-segment congenital tracheal stenosis (CTS) is characterized by segmental tracheal stenosis, complete tracheal rings, and absent posterior pars membranosa for >50% of tracheal length. Slide tracheoplasty on cardiopulmonary bypass (CPB) has traditionally been the procedure of choice for airway reconstruction. Pierre Robin sequence (PRS) is characterized by the triad of micrognathia, glossoptosis, and airway obstruction. The authors and others, have demonstrated the efficacy of mandibular distraction osteogenesis (MDO) to avoid tracheostomy in severe cases of PRS. METHODS: The authors present a unique case of the multidisciplinary management of long-segment CTS and concomitant PRS via total airway reconstruction off CPB, involving our otolaryngology, cardiothoracic, and plastic surgery teams. RESULTS: This 36-week baby girl, prenatally diagnosed with PRS and polyhydramnios concerning for airway obstruction, was delivered via planned ex utero intrapartum treatment (EXIT). Tracheostomy was aborted because of long-segment CTS. A 2.5-French endotracheal tube (ETT) was temporarily sutured in before transfer to our facility for definitive airway management.Bilateral MDO was performed without complication at 2 weeks old (distraction to 20mm by postoperative day 25). At 6 weeks old, delayed slide tracheoplasty avoiding cardiopulmonary bypass was followed by an uneventful recovery. Most recent follow-up demonstrates airway patency without signs of obstruction. CONCLUSIONS: This patient's case is the first reporting combined MDO and slide tracheoplasty to relieve multilevel neonatal airway obstruction. Unique and challenging, it demonstrates the importance of multidisciplinary management of complex neonatal airway obstruction. PMID- 26595009 TI - Image-Guided Endoscopic Combined With Deep Lateral Orbitotomy Removal of a Small Foreign Body at the Deep Lateral Orbital Apex. AB - To remove a small foreign body located at the deep orbit apex presents an extremely challenging problem. Small foreign bodies located in shallow lateral orbital and nasal orbital apex have been reported successfully removing in endoscopic surgery with the help of surgical navigation system. Here, the authors first describe successfully removal of a small foreign body at the deep lateral orbital apex with the help of image-guided endoscopic. A 56-year-old man presented with blurred vision and eye movement pain of the left eye while grinding metal 4 days prior to admission. A computed tomography scan showed a small metallic foreign body lodged in the deep lateral orbital apex. The foreign body was smoothly removed without any complications by endoscopic surgery under the help of surgical navigation system combined with deep lateral orbitotomy. Eye movement pain was disappeared and visual acuity was improved after surgery. PMID- 26595010 TI - Nasopharyngeal Mass Diagnosed as Transsphenoidal Encephalocele in an Adult Patient. AB - Transsphenoidal encephalocele, a rare congenital malformation, is generally diagnosed during childhood when investigating the reason for complaints such as nasal obstruction and recurring cerebrospinal fluid fistula. In this adult patient, the authors identified an asymptomatic transsphenoidal encephalocele after requested monitoring of a pedunculated mass detected in the nasopharynx during nasal endoscopy. After evaluation, the authors decided to follow the patient. Few cases of transsphenoidal encephalocele have been reported, and even fewer have been reported in older patients, with no other anomaly or symptoms. The success of surgical treatment for these masses is debatable. The authors did not consider surgery for this asymptomatic case. With this case presentation, the authors wish to emphasize that without making radiologic assessments of any masses identified in a nasopharyngeal examination, it would be inappropriate to perform a biopsy or any intervention. PMID- 26595011 TI - Corpus Callosotomy for Patients With Intractable Seizures: An Insight Into the Rapid Relapse. AB - It is well known that corpus callosotomy (CC) can bring a favorable seizure control outcome for disabling generalized seizures, but the complete remission rate achieved by CC is rarely reported, and the postoperative relapse pattern is still not clear. In this study, the authors reviewed patients with medically refractory epilepsy who were suffering disabling seizures, including drop attacks, generalized tonic-clonic seizures (GTCS), tonic seizures, atonic seizures, atypical absences, and complex partial seizures. The patients underwent anterior two third or complete CC in our hospital. Seizure control outcome was evaluated postoperatively at 2 weeks, 1 month, 3 months, 6 months, thereafter, at yearly intervals. Seizure-free or >90% reduction was considered to be satisfactory. There were 14 patients with mean age 11.00 +/- 6.34 at surgery. Of all the patients, 6 patients underwent anterior two third CC, and the other 8 patients underwent complete CC. All the patients were postoperatively followed up for at least 1 year. Four patients (28.57%) were free of all seizure types in the first year after surgery. Among the 9 patients with follow-up longer than 3 years, 2 patients (22.22%) were free of all seizure types. In the first 3 months after surgery, more than half of the seizure free patients (55.56%) relapsed with the same seizure types as preoperatively. Although after that, there was only 1 patient relapsed. Of all the seizure types, CC achieved the most favorable seizure outcome in drop attacks. In conclusion, CC could achieve complete seizure remission in a small portion of selected candidates. Exploration of the relapse mechanism will contribute to improve the seizure outcome following CC. PMID- 26595012 TI - Etymology of the Eyelid Muscles. PMID- 26595013 TI - A Systematic Review and Head-to-Head Meta-Analysis of Outcomes following Direct to-Implant versus Conventional Two-Stage Implant Reconstruction. AB - BACKGROUND: Innovative approaches to reconstruction have ushered in an era of breast reconstruction in which direct-to-implant procedures can provide an immediately reconstructed breast. Balancing the benefits against its technical challenges is vital. The authors evaluated the safety and efficacy of using direct-to-implant versus conventional two-stage reconstruction through a systematic meta-analysis. METHODS: A literature search identified all articles published after 1999 involving prosthetic-based breast reconstruction as a two stage tissue expander/implant or direct-to-implant technique. The primary outcomes of interest, including implant loss, capsular contracture, reoperation, and infection, were analyzed by means of head-to-head meta-analysis. RESULTS: Thirteen studies involving 5216 breast reconstructions were included. The average patient age was 47.2 +/- 1.0 years, the average body mass index was 24.9 +/- 0.8 mg/k2, and the average follow-up was 40.8 months. Wound infection, seroma, and capsular contracture risk were similar between groups. However, direct-to-implant reconstruction was associated with a higher risk for skin flap necrosis (OR, 1.43; p = 0.01; I2 = 51 percent) and reoperation (OR, 1.25; p = 0.04; I2 = 43 percent). Ultimately, the risk for implant loss was nearly two-fold higher with direct-to-implant reconstruction compared with tissue expander/implant reconstruction (OR, 1.87; p = 0.04; I2 = 33 percent). CONCLUSIONS: Although direct-to-implant and two-stage tissue expander/implant reconstruction are successful approaches, this meta-analysis demonstrates significantly greater risk of flap necrosis and implant failure with direct-to-implant reconstruction. The authors' findings suggest that the critical component of patient selection is judgment of mastectomy flap tissue quality. These findings can enhance the risk counseling process and highlight the need for additional investigations to optimize outcomes. PMID- 26595014 TI - Dynamics of Gluteal Cleft Morphology in Lower Body Lift: Predictors of Unfavorable Outcomes. AB - BACKGROUND: The number of lower body lifts is increasing with the increase in post-bariatric surgery patients. An undesirable result of the lower body lift is elongation of the gluteal cleft. The authors assessed their patients for gluteal cleft elongation to determine predictors of this unfavorable result. METHODS: Lower body lift excision patterns were classified based on their relationship to the gluteal cleft. Type I patterns were superior to the gluteal cleft; type II were central, partially incorporating the superior portion of the cleft; and type III were characterized by the cleft spanning the entire height of the pattern. Postoperative deformities were classified as cleft unchanged (grade 1), moderate cleft lengthening (grade 2), or severe cleft lengthening (grade 3). Gluteal autoaugmentation was also determined. RESULTS: Eighty-six patients were included (average age, 46.4 +/- 9.0 years). Thirty-two patients (37 percent) had type I excision patterns, 30 (35 percent) had type II, and 24 (28 percent) had type III. Seventeen (19.8 percent) had grade 1 clefts, 43 (50 percent) had grade 2 clefts, and 26 (29.9 percent) had grade 3 clefts. Age, sex, change in body mass index, and gluteal autoaugmentation were not significantly associated with postoperative cleft grade. Type I patterns were significantly less likely to cause postoperative cleft elongation (p = 0.001). Two patients (2.3 percent) desired correction achieved by excision and direct closure. CONCLUSIONS: Although lower body lift patterns may be based lower for better contour of the buttocks, there is an increased propensity for gluteal cleft elongation. This often occurs in patients with significant horizontal length discrepancy between the upper and lower incisions. Careful planning and markings can reduce the risk of this unfavorable result. Excision and direct closure provides a reliable solution. PMID- 26595015 TI - Technical Refinements in Autologous Hand Rejuvenation. AB - The aging hand is characterized by skin changes and soft-tissue deflation, which leads to rhytides, dermal atrophy, and distinct anatomical structures. Soft tissue deflation and prominent hand anatomy can be corrected with volume augmentation using dermal fillers or lipofilling. Fat transfer volumizes the hand with prolonged durability and efficacy, autologous tissue replacement, and possible dermal regeneration. The senior author's (R.J.R.) technique for hand rejuvenation is described, which uses minimal access and blunt dissection to effectively augment the soft-tissue compartments of the hand. This approach addresses the prominent aged anatomy of the hand, providing excellent contour and aesthetic outcomes. PMID- 26595016 TI - Morphologic and Histologic Comparison of Hypertrophic Scar in Nude Mice, T-Cell Receptor, and Recombination Activating Gene Knockout Mice. AB - BACKGROUND: Proliferative scars in nude mice have demonstrated morphologic and histologic similarities to human hypertrophic scar. Gene knockout technology provides the opportunity to study the effect of deleting immune cells in various disease processes. The authors' objective was to test whether grafting human skin onto T-cell receptor (TCR) alphabeta-/-gammadelta-/-, recombination activating gene (RAG)-1-/-, and RAG-2gamma-/-c-/- mice results in proliferative scars consistent with human hypertrophic scar and to characterize the morphologic, histologic, and cellular changes that occur after removing immune cells. METHODS: Nude TCRalphabeta-/-gammadelta-/-, RAG-1-/-, and RAG-2-/-gammac-/- mice (n = 20 per strain) were grafted with human skin and euthanized at 30, 60, 120, and 180 days. Controls (n = 5 per strain) were autografted with mouse skin. Scars and normal skin were harvested at each time point. Sections were stained with hematoxylin and eosin, Masson's trichrome, and immunohistochemistry for anti human leukocyte antigen-ABC, alpha-smooth muscle actin, decorin, and biglycan. RESULTS: TCRalphabeta-/-gammadelta-/-, RAG-1-/-, and RAG-2-/-gammac-/- mice grafted with human skin developed firm, elevated scars with histologic and immunohistochemical similarities to human hypertrophic scar. Autografted controls showed no evidence of pathologic scarring. Knockout animals demonstrated a capacity for scar remodeling not observed in nude mice where reductions in alpha smooth muscle actin staining pattern and scar thickness occurred over time. CONCLUSIONS: Human skin transplanted onto TCRalphabeta-/-gammadelta-/-, RAG-1-/-, and RAG-2-/-gammac-/- mice results in proliferative scars with morphologic and histologic features of human hypertrophic scar. Remodeling of proliferative scars generated in knockout animals is analogous to changes in human hypertrophic scar. These animal models may better represent the natural history of human hypertrophic scar. PMID- 26595017 TI - Imaging the Stromal Vascular Fraction during Soft-Tissue Reconstruction. AB - BACKGROUND: Although fat grafting is an increasingly popular practice, suboptimal volume retention remains an obstacle. Graft enrichment with the stromal vascular fraction has gained attention as a method of increasing graft retention. However, few studies have assessed the fate and impact of transplanted stromal vascular fraction on fat grafts. In vivo imaging techniques can be used to help determine the influence stromal vascular fraction has on transplanted fat. METHODS: Stromal vascular fraction was labeled with 1,1'-dioctadecyl-3,3,3',3' tetramethylindotricarbocyanine iodide (DiR), a near-infrared dye, and tracked in vivo. Proliferation and differentiation of labeled cells were assessed to confirm that labeling did not adversely affect cellular function. Different doses of labeled stromal vascular fraction were tracked within fat grafts over time using the in vivo imaging system. RESULTS: No significant differences in differentiation and proliferation were observed in labeled versus unlabeled cells (p > 0.05). A pilot study confirmed that stromal vascular fraction fluorescence was localized to fat grafts and different cell doses could be distinguished. A larger-scale in vivo study revealed that stromal vascular fraction fluorescence was statistically significant (p < 0.05) between different cell dose groups and this significance was maintained in higher doses (3 * 10(6) and 2 * 10(6) cells/ml of fat graft) for up to 41 days in vivo. CONCLUSIONS: DiR labeling allowed the authors to differentiate between cell doses and confirm localization. This article supports the use of DiR labeling in conjunction with in vivo imaging as a tool for imaging stromal vascular fraction within fat grafts. PMID- 26595018 TI - Selective Neurotization of the Infraspinatus Muscle in Brachial Plexus Birth Injury Patients Using the Accessory Nerve. AB - The authors present a new technique to improve active shoulder external rotation in patients with brachial plexus birth injury. Eight brachial plexus birth injury patients (aged 1.5 to 4.7 years) lacking active external rotation in adduction (<10 degrees) with congruent glenohumeral joints and no significant internal rotation contracture (passive external rotation >45 degrees) underwent neurotization of the infraspinatus branch of the suprascapular nerve with the spinal accessory nerve. Active and passive range of shoulder motion was measured postoperatively (3, 6, and 12 months). Parents' satisfaction was assessed. At 1 year follow-up, mean improvement for active external rotation was 47 degrees (range, 20 to 85 degrees) in adduction and 49 degrees (range, 5 to 85 degrees) in abduction. All but one patient's parents were satisfied. Functionally significant active external rotation can be restored in brachial plexus birth injury by direct neurotization of the infraspinatus muscle. PMID- 26595019 TI - A Comparative Cost Analysis of Cleft Lip Adhesion and Nasoalveolar Molding before Formal Cleft Lip Repair. AB - BACKGROUND: Patients with complete cleft lip and palate may benefit from cleft lip adhesion or nasoalveolar molding before formal cleft lip repair. The authors compared the relative costs to insurers of these two treatment modalities and the burden of care to families. METHODS: A retrospective analysis was performed of cleft lip and palate patients treated with nasoalveolar molding or cleft lip adhesion at The Children's Hospital of Philadelphia between January of 2007 and June of 2012. Demographic, appointment, and surgical data were reviewed; surgical, inpatient hospital, and orthodontic charges and costs were obtained. Multivariate linear regression and two-sample, two-tailed independent t tests were performed to compare cost and appointment data between groups. RESULTS: Forty-two cleft adhesion and 35 nasoalveolar molding patients met inclusion criteria. Mean costs for nasoalveolar molding were $3550.24 +/- $667.27. Cleft adhesion costs, consisting of both hospital and surgical costs, were $9370.55 +/- $1691.79. Analysis of log costs demonstrated a significant difference between the groups, with the mean total cost for nasoalveolar molding significantly lower than that for adhesion (p < 0.0001). Nasoalveolar molding patients had significantly more made, cancelled, no-show, and missed visits and a higher missed percentage than adhesion patients (p < 0.0001) for all except no-show appointments, (p = 0.0199), indicating a higher burden of care to families. CONCLUSIONS: Nasoalveolar molding may cost less before formal cleft lip repair treatment than cleft lip adhesion. Third-party payers who cover adhesion and not nasoalveolar molding may not be acting in their own best interest. Nasoalveolar molding places a higher burden of care on families, and this fact should be considered in planning treatment. PMID- 26595020 TI - Reconstruction of Philtrum Using Partial Splitting and Folding of Orbicularis Oris Muscle in Secondary Unilateral Cleft Lip. AB - BACKGROUND: The reconstruction of the philtrum during unilateral cleft lip repair remains a surgical challenge. The authors introduce a modified surgical technique for the reconstruction of the philtrum that allows for both the deepening of the philtral dimple and augmentation of the philtral ridge. METHODS: Between January of 2011 and June of 2012, 37 patients, including 22 male and 15 female patients (mean age, 25.6 years), underwent secondary unilateral cleft lip repair. The philtrum was reconstructed by the partial splitting and folding of the orbicularis oris muscle. The aesthetic outcome of the philtrum and the scar after the operation was scored to evaluate the effectiveness of the procedure. RESULTS: The patients were evaluated for the appearance of the philtrum and scar at 12 to 18 months (mean, 14.6 months). Good symmetry of the bilateral philtral ridges was achieved in 35 of the 37 patients, with the postoperative scores for aesthetic outcome being 2 to 4. The postoperative appearance of the scar in almost all cases was also significantly better than that before the operation. Only two patients showed widening of the philtral ridges and less prominent philtral ridges on the reconstructed side than on the normal side. CONCLUSIONS: The authors presented a new technique for the repair of the philtrum in patients with secondary unilateral cleft lip; the technique afforded good aesthetic outcomes in almost all cases. PMID- 26595021 TI - Treatment of Pediatric Condylar Fractures: A 20-Year Experience. AB - BACKGROUND: The purpose of this study was to define patterns of injury and treatment for condylar and subcondylar fractures and evaluate short-term outcomes in the pediatric population. METHODS: A retrospective chart review was performed on pediatric patients with mandibular condylar fractures who presented between 1990 and 2010. Computed tomographic imaging was reviewed for all patients to assess fracture characteristics. Mandibular fractures were codified using the Strasbourg Osteosynthesis Research Group and Lindahl classification methods. RESULTS: Sixty-four patients with 92 condylar fractures were identified. Of these patients, 29 had isolated condylar fracture and 35 had a condylar fracture associated with an additional mandibular arch fracture. The most common fracture patterns were diacapitular fracture in the Strasbourg Osteosynthesis Research Group system (n = 46) and vertical condylar head fracture in the Lindahl system (n = 14). Condylar fracture with additional mandibular arch fractures were treated with maxillomandibular fixation more often than patients with condylar fracture [n = 40 (74.1 percent) versus n = 14 (25.9 percent); p = 0.004]. No condylar fracture was treated in an open fashion. Forty-three patients returned for follow-up. The median follow-up period was 81 days (interquartile range, 35 to 294 days). Ten patients had complications (23.3 percent). The most common complication was malocclusion (n = 5). Nine of 10 patients with complications had condylar fracture with an additional mandibular arch fracture. CONCLUSIONS: Closed treatment of condylar fractures yields satisfactory results in pediatric patients. Pediatric patients with condylar fractures combined with additional arch fractures experience a higher rate of unfavorable outcomes. PMID- 26595022 TI - Epidemiologic Overview of Synkinesis in 353 Patients with Longstanding Facial Paralysis under Treatment with Botulinum Toxin for 11 Years. AB - BACKGROUND: Patients with longstanding facial paralysis often exhibit synkinesis. Few reports describe the prevalence and factors related to the development of synkinesis after facial paralysis. Botulinum toxin type A injection is an important adjunct treatment for facial paralysis-induced asymmetry and synkinesis. The authors assessed the clinical and epidemiologic characteristics of patients with sequelae of facial paralysis treated with botulinum toxin type A injections to evaluate the prevalence of synkinesis and related factors. METHODS: A total of 353 patients (age, 4 to 84 years; 245 female patients) with longstanding facial paralysis underwent 2312 botulinum toxin type A injections during an 11-year follow-up. Doses used over the years, previous treatments (electrical stimulation, operations), and how they correlated to postparalysis and postreanimation synkinesis were analyzed. RESULTS: There was a significant association between cause and surgery. Most patients with facial paralysis caused by a congenital defect, trauma, or a tumor underwent reanimation. There were no sex- or synkinesis-related differences in the doses used, but the doses were higher in the reanimation group than in the no-surgery group. Synkinesis was found in 196 patients; 148 (41.9 percent) presented with postparalysis synkinesis (oro-ocular, oculo-oral) and 58 (16.4 percent) presented with postreanimation synkinesis. Ten patients presented with both types. CONCLUSIONS: This study determined the high prevalence (55.5 percent) of synkinesis in patients with longstanding facial paralysis. Postparalysis synkinesis was positively associated with infectious and idiopathic causes, electrical stimulation, facial nerve decompression, and no requirement for surgery. Postreanimation synkinesis was present in 28.2 percent of reanimated patients and was significantly associated with microsurgical flaps, transfacial nerve grafting, masseteric-facial anastomosis, and temporalis muscle transfers. PMID- 26595023 TI - A Systematic Review and Meta-Analysis of Double Venous Anastomosis in Free Flaps. AB - BACKGROUND: Venous problems are the most frequent causes of flap failure and surgical revision in free flap surgery. Double venous anastomosis can be used to improve flap drainage, but this procedure has not been adopted universally and remains controversial. The authors evaluated the benefits of double venous anastomosis in terms of venous thrombosis rate, surgical revision of flaps, and flap failure rate. METHODS: A systematic literature review was conducted searching the MEDLINE, PubMed Central, Cochrane, and Embase databases for articles published between 1996 and July of 2014. Data analysis consisted of evaluating the pooled relative risks of single and double venous anastomoses in fixed and random-effects models. RESULTS: The final analysis included 27 articles involving 6842 flaps. The overall success rate was 97.48 percent. Single venous anastomosis was performed in 4591 flaps versus two anastomoses in 2251 flaps. The failure rate was 3.1 percent for single anastomosis versus 1.3 percent for double anastomosis (OR, 0.511; 95 percent CI, 0.349 to 0.747; p = 0.001). The respective thrombosis rates were 3.1 percent versus 2.3 percent (OR, 0.586; 95 percent CI, 0.390 to 0.880; p = 0.010). In addition, more single venous anastomoses were revised: 7.7 percent versus 6 percent (OR, 0.601; 95 percent CI, 0.469 to 0.770; p < 0.0001). Stratified analysis by flap type did not show any significant differences. CONCLUSIONS: Although the physiologic mechanisms remain poorly understood, the data strongly support double venous anastomosis, considering the reduction in flap failure, microsurgical venous thrombosis, and surgical revision. The authors recommend double anastomosis whenever it is feasible in free flap surgery. PMID- 26595024 TI - Discussion: Evidence-Based Abdominal Wall Reconstruction: The Maxi-Mini Approach. PMID- 26595025 TI - Implications of Rheumatic Disease and Biological Response-Modifying Agents in Plastic Surgery. AB - The preoperative evaluation for any reconstructive or aesthetic procedure requires a detailed history of existing medical conditions and current home medications. The prevalence of rheumatic diseases such as rheumatoid arthritis, gout, and psoriasis is high, but the impact of these chronic illnesses on surgical outcome and the side effects of the powerful medications used for treatment are often underappreciated. In this review, the authors highlight key perioperative considerations specific to rheumatologic diseases and their associated pharmacologic therapies. In particular, the authors discuss the perioperative management of biological response-modifying agents, which have largely become the new standard of therapy for many rheumatic diseases. The literature reveals three key perioperative concerns with biological therapy for rheumatic disease: infection, wound healing delays, and disease flare. However, data on specific perioperative complications are lacking, and it remains controversial whether withholding biological therapy before surgery is of benefit. The risk of these adverse events is influenced by several factors: age, sex, class of biological agent, duration of exposure, dosage, onset and severity of disease, and type of surgical procedure. Overall, it remains best to develop an individualized plan. In younger patients with recent onset of biological therapy, it is reasonable to withhold therapy based on 3 to 5 half-lives of the specific agent. In older patients with a substantial history of rheumatic disease, the decision to discontinue therapy must be weighed and decided carefully in conjunction with the rheumatologist. PMID- 26595026 TI - Tissue-Engineered Skin Substitutes. AB - BACKGROUND: Skin substitutes are frequently used by plastic surgeons today to treat a wide variety of cutaneous defects. They provide methods to heal wounds while minimizing donor sites. They are commonly used in burns, acute wounds, and chronic wounds. METHODS: The authors reviewed the literature on both the development of skin substitutes and their use today. The authors focused their work on what are currently the more commonly used types of skin substitutes in the United States. There is a wide interest in human-derived placental products, which will be the subject of a future publication. RESULTS: Commonly used skin substitutes include semisynthetic dermal scaffolds, allogenic cell constructs, and cellular and decellularized allogenic or xenogenic sources. For semisynthetic dermal scaffolds and allogenic cell constructs, there have been large clinical trials demonstrating their efficacy. CONCLUSIONS: Skin substitutes represent great progress for plastic surgery and provide several advances and options with which to heal wounds. More studies are needed to guide surgeons into the most appropriate use of these materials. Future developments, including advances in scaffolds, stem cells, and tissue processing, are likely to produce even more clinical options for our patients. PMID- 26595028 TI - Lifetime Costs of Prophylactic Mastectomies and Reconstruction versus Surveillance. AB - BACKGROUND: The past decade has seen an increasing prevalence of prophylactic mastectomy with decreasing ages of patients treated for breast cancer. Data are limited on the fiscal impacts of contralateral prophylactic mastectomy trends, and no study has compared bilateral prophylactic mastectomy with reconstruction to surveillance in high-risk patients. METHODS: Lifetime third-party payer costs over 30 years were estimated with 2013 Medicare reimbursement rates. Costs were estimated for patients choosing contralateral or bilateral prophylactic mastectomy versus surveillance, with immediate reconstructions using a single stage implant, tissue expander, or perforator-based free flap approach. Published cancer incidence rates predicted the percentage of surveillance patients that would require mastectomies. Sensitivity analyses were conducted that varied cost growth, discount rate, cancer incidence rate, and other variables. Lifetime costs and present values (3 percent discount rate) were estimated. RESULTS: Lifetime prophylactic mastectomy costs were lower than surveillance costs, $1292 to $1993 lower for contralateral prophylactic mastectomy and $15,668 to $21,342 lower for bilateral prophylactic mastectomy, depending on the reconstruction. Present value estimates were slightly higher for contralateral prophylactic mastectomy over contralateral surveillance but still cost saving for bilateral prophylactic mastectomy compared with bilateral surveillance. Present value estimates are also cost saving for contralateral prophylactic mastectomy when the modeled contralateral breast cancer incidence rate is increased to at least 0.6 percent per year. CONCLUSIONS: These findings are consistent with contralateral and bilateral prophylactic mastectomy being cost saving in many scenarios, regardless of the reconstructive option chosen. They suggest that physicians and patients should continue to receive flexibility in deciding how best to proceed clinically in each case. PMID- 26595029 TI - Abdominoplasty with Customized Transverse Musculoaponeurotic Plications. AB - BACKGROUND: The standard abdominoplasty technique uses a wide, vertically oriented plication of the rectus sheath to narrow the waistline. However, this plication is not always enough to achieve good cosmetic and functional results. This is also the case with other plication techniques. To strengthen the abdominal wall at the points of greatest weakness in each particular patient, the authors have developed a personal technique consisting of customized transverse plications at the points of maximum protrusion in the musculoaponeurotic layer, in addition to the classic vertical plication. METHODS: Ninety-eight women were divided randomly into two groups: the control group (group A) comprised 44 patients (44.9 percent) who underwent classic vertical plication; the experimental group (group B) comprised 54 patients (55.1 percent) in whom vertical plication was associated with one or more customized horizontal plications. Results were rated on a scale of 0 to 10 by external observers and the patients. Complications and recurrences were recorded. RESULTS: In group A, the mean global rating scores were 8.5 of 10 for external raters and 8.3 of 10 for patients. In group B, they were 9.5 of 10 and 9.8 of 10, respectively. In group B, there were no recurrences of prominences, whereas three were recorded in group A. Five cases of seroma were registered in each group and resolved by closed suction. CONCLUSION: In some cases, vertical plication with customized transverse plications produces results that are aesthetically superior to those of the classic approach, achieves long-lasting effects, and does not increase the rate of recurrences or the risk of complications. PMID- 26595030 TI - The Effect of Abdominoplasty and Outcome of Rectus Fascia Plication on Health Related Quality of Life in Post-Bariatric Surgery Patients. AB - BACKGROUND: The authors prospectively evaluated the effect of isolated abdominoplasty with or without rectus fascia plication on the physical, functional, and psychosocial dimensions of health-related quality of life in post bariatric surgery patients. They also evaluated whether the objectively measured amount of abdominal excess skin affects the discomfort of excess abdominal skin and changes in health-related quality of life after abdominoplasty. METHODS: Ninety-four post-bariatric surgery patients answered questionnaires regarding their experience of excess skin and health-related quality of life before and 1 year after isolated abdominoplasty. An objective assessment of the amount of abdominal excess skin was also performed. All study participants were assigned randomly to either undergo or not undergo rectus fascia plication. RESULTS: Significant improvements were reported at the follow-up concerning physical, functional, and psychosocial dimensions of health-related quality of life. A significant decrease was observed for the general health subscale of the 36-Item Short-Form Health Survey for the nonplicated group (p = 0.039). No significant differences were observed between the plicated and nonplicated groups. A significant low correlation was identified between the change in the Short-Form physical function subscale after abdominoplasty and measured amount of excess abdominal skin (rs = 0.26, p = 0.033) or resection weight (rs = 0.20, p = 0.10). CONCLUSIONS: Isolated abdominoplasty in post-bariatric surgery patients seems to improve both physical and psychosocial dimensions of health-related quality of life. However, rectus fascia plication does not appear to influence health related quality of life. In addition, the correlation between the objectively measured amount of abdominal excess skin and improvements in health-related quality of life after abdominoplasty in post-bariatric surgery patients appears to be low. PMID- 26595031 TI - Relationship between Patient Expectations and Clinical Measures in Patients Undergoing Rheumatoid Hand Surgery from the Silicone Arthroplasty in Rheumatoid Arthritis (SARA) Study. AB - BACKGROUND: The purpose of this study was to evaluate the relationship between preoperative patient expectations and clinical measures in patients undergoing rheumatoid hand surgery. METHODS: Patients were recruited as a part of a larger prospective multicenter study to evaluate outcomes of silicone metacarpophalangeal joint arthroplasty (SMPA). Patients in the surgical cohort completed a baseline expectation questionnaire asking about expectations for function, work, pain, and aesthetics after SMPA. Responses were categorized into groups of low, middle, and high expectations for each domain and for cumulative expectations across all domains. Other study measurements were taken at baseline and 1 year, including the Michigan Hand Outcomes Questionnaire (MHQ) and objective clinical measurements (i.e., grip strength, pinch strength, the Jebsen Taylor Hand Function Test, ulnar drift, and extensor lag). RESULTS: Preoperative expectations and clinical measures were complete for 59 patients at baseline and 45 patients at 1-year follow-up. Preoperative expectation level was related to baseline patient-reported domains of activities of daily living and hand satisfaction measured by the MHQ (p = 0.04 and p = 0.07, respectively). Patients had relatively similar satisfaction with hand function postoperatively regardless of preoperative expectation level. No consistent relationship was seen between preoperative expectations and objective measures at baseline and 1-year follow up. CONCLUSIONS: High preoperative expectations were not a risk factor for dissatisfaction postoperatively. Preoperative expectation level may be considered for stratifying baseline patient-reported hand function in patients with similar objective hand function. PMID- 26595032 TI - Treatment Type Is Associated with Population Hand Preferences in Patients with Unilateral Coronal Synostosis: Implications for Functional Cerebral Lateralization. AB - BACKGROUND: Left-handedness is a highly conserved marker of cerebral functional laterality in the human population; elevated rates of left-handedness have been documented in patients with unilateral coronal synostosis treated with fronto orbital advancement. The purpose of this study was to determine whether the prevalence of left-handedness in patients with nonsyndromic unilateral coronal synostosis is related to treatment. METHODS: The incidence of left-handedness was compared among three groups: patients who were previously treated for unilateral coronal synostosis with endoscopic suturectomy and postoperative helmet therapy (group I); patients with unilateral coronal synostosis managed with fronto orbital advancement (group II); and healthy, unaffected controls (group III). RESULTS: Group I was composed of 19 patients; the side of synostosis was equally distributed (nine right and 10 left), and female gender was more common (n = 13). Mean age at endoscopic suturectomy and helmet therapy was 85.3 days, and the determination of handedness was performed at a mean age of 89.3 months. The rate of left-handedness in group I was 5.3 percent, not significantly different from that of the controls (group III) (11.5 percent) (p = 0.69) but significantly less than that observed in the fronto-orbital advancement patients (group II) (30.2 percent) (p = 0.023). CONCLUSIONS: Patients who underwent endoscopic suturectomy and helmet therapy for nonsyndromic unilateral coronal synostosis and healthy controls demonstrated functional cerebral lateralization with respect to handedness that differed from patients who underwent fronto-orbital advancement. The reason may be related to the type of procedure, secondary effects of general anesthesia, or age at which the procedure was performed. PMID- 26595033 TI - Gender and Satisfaction with Appearance in Children with Craniofacial Anomalies. AB - BACKGROUND: Although children with craniofacial anomalies appear to have relatively high self-esteem, research has identified gender differences in psychosocial outcomes, including self-concept, suggesting that girls with craniofacial anomalies may be at an increased risk. In addition, though parents make important medical and aesthetic decisions for their children, it is unclear whether they are attuned to their children's perceptions of their appearance. METHODS: The current study assessed self-ratings and parent proxy ratings of child satisfaction with the appearance of both the face and the body among 74 children with craniofacial anomalies (50 percent boys). Data were collected in a multidisciplinary clinic setting. RESULTS: The authors identified that ratings provided by parents and children, and particularly parents and daughters, were uncorrelated. Furthermore, whereas girls' dissatisfaction with the appearance of their faces was associated with negative psychosocial outcomes, these associations were not significant among boys. Finally, results obtained for satisfaction with the appearance of the face were largely replicated for satisfaction with appearance of the body, suggesting that children with craniofacial anomalies and their parents may apply more holistic criteria to evaluating their appearance. CONCLUSION: Considered together, the findings of this study highlight the importance of engaging both parents and children in discussions about craniofacial anomalies and possible reconstruction and suggest the need for future research on the intersection of gender and craniofacial anomalies in child psychosocial functioning. PMID- 26595034 TI - Large Contaminated Ventral Hernia Repair Using Component Separation Technique with Synthetic Mesh. AB - BACKGROUND: Large ventral hernia repair represents a major reconstructive surgical challenge, especially under contaminated conditions. Synthetic mesh is usually avoided in these circumstances because of fear of mesh infection, although evidence is outdated and does not regard new materials and techniques. The authors evaluated the safety of synthetic mesh in large contaminated ventral hernia repair. METHODS: All large ventral hernias repaired with the components separation technique and polypropylene mesh were included in analysis. Primary outcomes were wound and medical complications, with a focus on surgical-site infection and mesh removal. For risk analysis, patients were stratified by surgical wound class, Ventral Hernia Working Group grade, and modified Ventral Hernia Working Group grade. RESULTS: One hundred thirty-seven patients were included, with a mean age of 58.6 years, mean body mass index of 26.6 cm2, and mean defect size of 235.6 cm2. Surgical-site infection and total wound complication rates were 16.1 and 48.9 percent, respectively. The surgical wound class distribution of surgical-site infections was as follows: clean, five of 56 (9.1 percent); clean-contaminated, five of 34 (14.7 percent); contaminated, three of 19 (15.8 percent); and dirty/infected, nine of 28 (32.1 percent). Seven meshes (5.1 percent) needed removal, two after clean repairs, three after clean contaminated repairs, and two after dirty/infected repairs. Surgical wound class (OR, 1.77; 95 percent CI, 1.20 to 2.61) and Ventral Hernia Working Group grade (OR, 2.31; 95 percent CI, 1.24 to 4.28) were predictors of surgical-site infection. CONCLUSION: Rate of surgical-site infection after large contaminated ventral hernia repair with synthetic mesh is considerable but with a low mesh removal rate. PMID- 26595035 TI - Discussion: Large Contaminated Ventral Hernia Repair Using Component Separation Technique with Synthetic Mesh. PMID- 26595036 TI - Heterotopic Ossification following Tissue Transfer for Combat-Casualty Complex Periarticular Injuries. AB - BACKGROUND: Although mechanisms underlying heterotopic ossification remain unknown, certain risk factors can influence heterotopic bone formation. The purpose of this study was to determine whether flaps used in periarticular reconstruction had any effect on heterotopic ossification formation. METHODS: A retrospective review of periarticular injuries requiring flap coverage from 2003 through 2014 was performed. Flap types, Injury Severity Scores, functional outcomes, and complications were reviewed. Radiology findings were assessed to determine heterotopic ossification rates and grades. RESULTS: Three hundred eighty-nine flaps were performed for traumatic extremity coverage over the 13 year study period. Sixty-nine of these flaps were used for periarticular coverage. The rate of periarticular heterotopic ossification was 47 percent for fasciocutaneous versus 54 percent for muscle-based flap coverage (p = 0.88). There were no significant differences in Injury Severity Score (p = 0.44) or overall heterotopic ossification formation (p = 0.97) between groups; however, the grade of heterotopic ossification within muscle-based flap cohort was significantly higher (1.70 for muscle versus 1.06 for the fasciocutaneous cohort; p = 0.002). CONCLUSIONS: Combat-related trauma is associated with high rates of heterotopic ossification, with an overall formation rate exceeding 85 percent for our patients requiring periarticular flap coverage. Although no difference in the rate of heterotopic ossification formation was found between fasciocutaneous and muscle flap coverages, a significantly increased severity of heterotopic ossification was seen in periarticular muscle-based flaps. These findings suggest that flap composition might not affect the rate of heterotopic ossification formation but may have an effect on ectopic bone formation severity. PMID- 26595037 TI - Current Concepts in Lower Extremity Reconstruction. AB - LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Understand the existing principles for lower extremity reconstruction for both traumatic and ablative defects. 2. Understand the important factors for lower extremity reconstruction-based anatomical regions. 3. Discuss perforator flaps and their application in lower extremity reconstruction. SUMMARY: The Gustilo-Anderson open fracture classification is briefly reviewed. A comprehensive overview of the available flaps and methods for lower extremity reconstruction is provided. PMID- 26595038 TI - Reply: Cadaveric Study of Breast Measurements during Augmentation with Implants. PMID- 26595039 TI - Unilateral Cleft Lip Repair Using the Anatomical Subunit Approximation: Modifications and Analysis of Early Results in 100 Consecutive Cases. PMID- 26595040 TI - Controversies and Evolving Concepts in Critical Care. Preface. PMID- 26595041 TI - Personalized Critical Care Medicine: How Far Away Are We? AB - Personalized medicine has typically referred to the use of genomics in clinical care. However, the concept more broadly refers to recognizing the heterogeneity of each individual patient, particularly their unique risk factors for developing disease or having poor outcomes, and using this to inform treatment decisions. Pharmacogenomics was perhaps the first major clinical application that came out of the Human Genome Project, but its translation to the critical care arena has been limited by numerous factors. Biomarkers have been widely studied in critical illnesses such as sepsis and acute respiratory distress syndrome in an attempt to aid in accurate diagnostic classification, to predict outcomes, and to assess response to therapy. Clinical use of such biomarkers has remained limited, but multi-biomarker panels have attempted to better reflect the complex physiology of critical illness, and to assist in design and recruitment for clinical trials. Genetic association and gene expression studies have been aimed at classifying risk for and severity in disease, as well as in predicting outcomes. While our understanding of the pathogenesis of critical illness has progressed significantly, the clinical utility of genetic markers remains limited. Novel methods are reaching closer to clinically applicable platforms, both for use in clinical trials and in direct patient care. Although we are not yet living in an era of personalized and precise medical care in the intensive care unit, the future is promising. PMID- 26595042 TI - Controversies in the Management of Severe ARDS: Optimal Ventilator Management and Use of Rescue Therapies. AB - Groundbreaking research into the pathophysiology of the adult acute respiratory distress syndrome (ARDS) and the prevention of ventilator-induced lung injury has led to dramatic improvements in survival. Investigations over the last two decades have revolved around the development of rescue therapies that can be used for patients with severe ARDS and refractory hypoxemia. To date, the techniques of using high levels of positive end-expiratory pressure (PEEP), prompt institution of neuromuscular blockade, and early prolonged prone positioning have been shown to reduce mortality in patients with severe ARDS. PEEP titration using transpulmonary pressure estimations assisted by esophageal manometry has been shown to result in a substantial improvement in oxygenation. Extracorporeal membrane oxygenation (ECMO) has been used increasingly since the mid-2000s in part due to the H1N1 epidemic. A major randomized controlled trial conducted during this period showed a significant mortality benefit for patients with severe ARDS who were referred to a center with ECMO capabilities. The routine use of inhaled nitric oxide for patients with severe ARDS has not been shown to lead to more than a transient and limited improvement in oxygenation, which may hinder its use as a sole rescue therapy. Finally, recent studies have found that the routine use of high-frequency oscillatory ventilation in severe ARDS does not result in decreased mortality, although the technique has not been specifically investigated as rescue therapy for severe refractory hypoxemia. PMID- 26595043 TI - Controversies in the Management of Life-Threatening Pulmonary Embolism. AB - Patients with life-threatening pulmonary embolism (PE) offer clinicians a unique opportunity to intervene effectively on the patient's behalf. Hemodynamic status remains the most important short-term prognostic factor for patients with acute PE. Although the evidence is limited, the use of thrombolytic therapy is recommended for patients with acute symptomatic PE and associated hypotension or shock (i.e., high-risk PE) because these patients have a high short-term mortality risk (i.e., >15%) even when receiving anticoagulant treatment. In this setting, the hemodynamic benefits of thrombolytic treatment far outweigh its bleeding risk. For hemodynamically stable patients with PE, the identification of a subgroup of patients with a risk of PE-related complications similar to patients with PE and cardiovascular instability (i.e., intermediate-risk group) may assist with decision making regarding therapy. Given the lack of clear mortality benefit and increased bleeding risk, guidelines do not recommend routine use of systemic thrombolysis for this subgroup of patients. Careful monitoring and rescue fibrinolysis for intermediate-risk PE patients who experience hemodynamic compromise or deterioration while receiving standard anticoagulant therapy can minimize deaths from PE. For patients with life threatening PE at high risk of bleeding, clinicians might consider the use of low dose thrombolytic therapy, catheter-directed thrombolysis, or surgical embolectomy, if they have access to the required expertise and resources. The evidence does not support the use of inferior vena cava filters in patients with life-threatening PE unless there is a contraindication to anticoagulation. Since various medical and surgical specialties offer different perspectives and expertise, a multidisciplinary approach to patients with intermediate- and high risk PE might improve patient outcomes. PMID- 26595044 TI - Intensivist Staffing: Evolving Challenges and Solutions. AB - Increases in critical care utilization related to aging of our population, static supplies of critical care specialists, and reduced availability of physicians in training to staff intensive care units (ICUs) have led many institutions to reevaluate their ICU prescribing provider staffing plans. The epidemiology of critical care staffing needs, regulations, requirements, standards, and professional society staffing recommendations are reviewed and the components of a prescribing provider staffing plan are described along with their costs. Factors that impact staffing costs including the availability of intensivist extenders, electronic support, and telemedicine tools that impact the efficiency of care delivery are evaluated in the context of staffing plan evaluation. Financial modeling is used to compare the costs of common prescribing provider staffing plans for typical referral medical center ICUs, community hospital ICUs, and rural health centers that care for the critically ill. PMID- 26595046 TI - Metabolic Management during Critical Illness: Glycemic Control in the ICU. AB - Hyperglycemia is a commonly encountered metabolic derangement in the ICU. Important cellular pathways, such as those related to oxidant stress, immunity, and cellular homeostasis, can become deranged with prolonged and uncontrolled hyperglycemia. There is additionally a complex interplay between nutritional status, ambient glucose concentrations, and protein catabolism. While the nuances of glucose management in the ICU have been debated, results from landmark studies support the notion that for most critically ill patients moderate glycemic control is appropriate, as reflected by recent guidelines. Beyond the target population and optimal glucose range, additional factors such as hypoglycemia and glucose variability are important metrics to follow. In this regard, new technologies such as continuous glucose sensors may help alleviate the risks associated with such glucose fluctuations in the ICU. In this review, we will explore the impact of hyperglycemia upon critical cellular pathways and how nutrition provided in the ICU affects blood glucose. Additionally, important clinical trials to date will be summarized. A practical and comprehensive approach to glucose management in the ICU will be outlined, touching upon important issues such as glucose variability, target population, and hypoglycemia. PMID- 26595045 TI - To Trach or Not to Trach: Uncertainty in the Care of the Chronically Critically Ill. AB - The number of chronically critically ill patients requiring prolonged mechanical ventilation and receiving a tracheostomy is steadily increasing. Early tracheostomy in patients requiring prolonged mechanical ventilation has been proposed to decrease duration of mechanical ventilation and intensive care unit stay, reduce mortality, and improve patient comfort. However, these benefits have been difficult to demonstrate in clinical trials. So how does one determine the appropriate timing for tracheostomy placement in your patient? Here we review the potential benefits and consequences of tracheostomy, the available evidence for tracheostomy timing, communication surrounding the tracheostomy decision, and a patient-centered approach to tracheostomy. Patients requiring > 10 days of mechanical ventilation who are expected to survive their hospitalization likely benefit from tracheostomy, but protocols involving routine early tracheostomy placement do not improve patient outcomes. However, patients with neurologic injury, provided they have a good prognosis for meaningful recovery, may benefit from early tracheostomy. In chronically critically ill patients with poor prognosis, tracheostomy is unlikely to provide benefit and should only be pursued if it is consistent with the patient's values, goals, and preferences. In this setting, communication with patients and surrogates regarding tracheostomy and prognosis becomes paramount. For the foreseeable future, decisions surrounding tracheostomy will remain relevant and challenging. PMID- 26595047 TI - Protocol-Based Care versus Individualized Management of Patients in the Intensive Care Unit. AB - The delivery of evidence-based care in the high-acuity environment of the intensive care unit can be challenging. In an effort to help turn guidelines and standards of care into consistent and uniform practice, physicians and hospitals turn toward protocol-based medical care. A protocol can help guide a practitioner to make correct interventions, at the right time, and in the proper order when managing a given disease. But to be considered a success, a protocol must meet several standards. A protocol must facilitate consistent practice, guiding the practitioner to deliver care more consistently than without the protocol. A good protocol must also be in alignment with the provider's general practice and beliefs to assure wide adoption and complete penetrance. Finally, the protocol must deliver the most medically correct care-neither simplifying nor overcomplicating health care delivery. In addition to the care the protocol delivers, it must overcome other barriers to gain acceptance. These include concerns about protocol usage among medical trainees, physician concern regarding loss of autonomy, and the ceiling effect protocol-driven care places on expert practitioners, among other concerns. The aim of this article is to critically appraise what it means for a protocol to be considered successful with an aim toward improving protocol design and implementation in the future. PMID- 26595048 TI - Bedside Ultrasound in the Intensive Care Unit: Where Is the Evidence? AB - Interest in bedside ultrasound in the intensive care unit and emergency department has exploded in recent years. This interest is driven in part by the utility of ultrasound for procedural guidance. In most cases, enthusiasm outstrips current evidence. While ultrasound is often felt to be risk-free, the important risk of ultrasound is the chance of false diagnosis. The vividness of visual images may make practitioners especially prone to cognitive errors in interpretation. Possible applications of ultrasound include management of shock and respiratory failure, two complex syndromes with multiple aspects. Reasonable evidence supports use of ultrasound to guide volume expansion, although its value remains to be demonstrated in an explicit protocol. Other possibilities include ventilator titration and guidance of diuresis. While the literature is more complicated, there is some early evidence that lung ultrasound may improve the diagnosis of dyspnea, although these results have not been well validated. Centers should avoid premature loss of equipoise and participate in studies of explicit protocols that incorporate ultrasound. PMID- 26595049 TI - Hemodynamic Monitoring for the Evaluation and Treatment of Shock: What Is the Current State of the Art? AB - Hemodynamic monitoring has become a fundamental and ubiquitous, if not defining, aspect of critical care medicine practice. Modern monitoring techniques have changed significantly over the past few years and are now able to rapidly identify shock states earlier, define the etiology, and monitor the response to therapies. Many of these techniques are now minimally invasive or noninvasive. Basic hemodynamic monitoring and evaluation usually includes a focused physical examination and static hemodynamic vital signs: temperature, heart rate, respiratory rate, mean arterial pressure, and arterial hemoglobin oxygen saturation, typically measured with pulse photoplethysmography. When available, measurement of urinary output is often included. Advanced hemodynamic monitoring incorporates both noninvasive and invasive continuous hemodynamic monitoring. Noninvasive ultrasound has emerged as a fundamental hemodynamic evaluation tool and its use is now rapidly increasing. Invasive monitoring from arterial and central venous catheters, and occasionally pulmonary artery catheters, provides measurement of arterial pressure, intracardiac filling pressures, arterial and venous blood gases, and cardiac index. Minimally invasive and noninvasive measure of arterial pressure and cardiac output are also possible and often remain as accurate as invasive measures. Importantly, such advanced monitoring provides the foundation for goal-directed therapies for the treatment of shock. When coupled with functional hemodynamic monitoring analyses, these measures markedly extend the diagnostic and therapeutic potential of all monitoring modalities by defining preload reserve, vasomotor tone, cardiac performance, and tissue perfusion. PMID- 26595050 TI - Awake or Sedated: Trends in the Evaluation and Management of Agitation in the Intensive Care Unit. AB - Critically ill intensive care unit (ICU) patients often require sedation to tolerate life-saving interventions such as mechanical ventilation. Pain, anxiety, and delirium all contribute to patient distress and agitation which can interfere with ICU medical care if not addressed and treated appropriately. Sedation practices to treat pain, anxiety, and delirium that deviate from established practice guidelines affect mechanical ventilation duration, ICU and hospital length of stay, functional impairment, and mortality. Historically patients were kept deeply sedated in the ICU. However, considerable research has demonstrated that minimizing sedation with the goal to achieve comfortable wakefulness is preferred in most ICU patients and is associated with improved clinical outcomes. This review will focus on changes in sedation practice in the ICU over the past three decades. With the implementation of validated sedation assessment scales, a multidisciplinary treatment model, and development of daily awakening protocols, no or minimal sedation can be achieved in the majority of ICU patients. Frequent, careful consideration of the environmental stimuli that contribute to patient discomfort and agitation and judicious use of sedative medications individualized to each patient are important in achieving this goal. PMID- 26595051 TI - Critical Care Beds and Resource Utilization: Current Trends and Controversies. AB - Recent studies have shown a dramatic increase in the number of intensive care unit (ICU) beds in recent decades. As technologies have become more complex, ICUs continue to grow in size and in specialization. The driving forces behind ICU bed expansion include not only the incorporation of advanced technologies but also other factors such as the increased utilization of ICU beds for patients who previously were not offered ICU care--those who may be terminally ill and those who are not critically ill. This expansion of ICU care in the United States sets it apart from other industrialized nations with comparably fewer ICU beds in relation to other hospital beds. The consequences of this expansion are now being felt in the form of unused beds, workforce shortages, and overuse of ICUs for patients who previously were not cared for in ICUs. ICUs are also now commonly used in the care of dying patients. In coming decades it is likely that changes will need to take place to forestall exorbitant costs and labor shortages. In addition to bringing in new forms of medical staff such as hospitalists and physician assistants, recent opinion papers have suggested that a de-escalation of ICU growth and a new tiered system of ICU care will be necessary in the United States. PMID- 26595052 TI - The Assessment of the Right Heart Failure Syndrome. AB - The right heart failure (RHF) syndrome is a pathophysiologically complex state commonly associated with dysfunction of the right ventricle (RV). The normal RV is suited for its purposes of distributing venous blood to the low-resistance pulmonary circulation. Myriad stresses imposed upon it, though, can ultimately result in its failure, with the threat of cardiovascular collapse being the most dreaded outcome. Decreased cardiac output with increased central venous pressures are hemodynamic hallmarks of this highly morbid condition. Proper management of RHF is predicated on the accurate assessment of the key hemodynamic and clinical components signaling the syndrome that is the result of the failing RV. Appropriate use of diagnostic tools is paramount for understanding the key components of RV function: the preload state of the RV, its contractility, and the afterload burden placed on it. In making these assessments, it remains crucial to understand the limitations of these tools when managing RHF in the intensive care unit. An understanding of each of these components allows for the understanding of the physiology and the clinical presentation which can guide the use of therapies appropriately tailored to manage the condition. PMID- 26595053 TI - Physical, Cognitive, and Psychological Disability Following Critical Illness: What Is the Risk? AB - Critical illnesses affect millions of individuals annually in the United States. As advances in patient care continue to improve, the number of survivors is rapidly growing. Critical illness survivors endure profoundly severe illnesses and live through often frightening experiences throughout the course of ICU hospitalization, resulting in a variety of "survivorship" challenges, expressed through a condition known as post-intensive care syndrome (PICS). Questions abound regarding the ideal protocols for ensuring the best physical, cognitive, and psychological outcomes for these survivors. Organizational change is likely to be a key factor, though the specific components have not yet been established. Throughout this article, we highlight some of the barriers and facilitators to enhancing patient care across the spectrum of critical care environments, while also highlighting the challenges inherent to studying a complex patient population. We address each of the areas potentially affected by critical illness and ICU hospitalization--physical, cognitive, and psychological functional domains--experienced by patients as well as their family caregivers. PMID- 26595054 TI - Inhibition of mitogen-activated protein kinase 1/2 in the acute phase of stroke improves long-term neurological outcome and promotes recovery processes in rats. AB - AIM: Extracellular signal-regulated kinase (ERK) 1/2 is activated during acute phase of stroke and contributes to stroke pathology. We have found that acute treatment with MEK1/2 inhibitors decreases infarct size and neurological deficits 2 days after experimental stroke. However, it is not known whether benefits of this inhibition persist long-term. Therefore, the aim of this study was to assess neurological function, infarct size and recovery processes 14 days after stroke in male rats to determine long-term outcome following acute treatment with the MEK1/2 inhibitor U0126. METHODS: Transient middle cerebral artery occlusion was induced in male rats. U0126 or vehicle was given at 0 and 24 h of reperfusion. Neurological function was assessed by staircase, 6-point and 28-point neuroscore tests up to 14 days after induction of stroke. At day 14, infarct volumes were determined and recovery processes were evaluated by measuring protein expression of the tyrosine kinase receptor Tie-2 and nestin. Levels of p-ERK1/2 protein were determined. RESULTS: Acute treatment with U0126 significantly improved long-term functional recovery, reduced infarct size, and enhanced Tie-2 and nestin protein expression at 14 days post-stroke. There was no residual blockade of p-ERK1/2 at this time point. CONCLUSION: It is demonstrated that benefits of early treatment with U0126 persist beyond subacute phase of ischaemic stroke in male rats. Prevention of ERK1/2 activation in the acute phase results in improved long-term functional outcome and enhances later-stage recovery processes. These results expand our understanding of the benefits and promise of using MEK1/2 inhibitors in stroke recovery. PMID- 26595055 TI - New York Citywide Colon Cancer Control Coalition: A public health effort to increase colon cancer screening and address health disparities. AB - BACKGROUND: Although screening for colorectal cancer (CRC) is a widely accepted concept nationally and screening rates are increasing, there are differences in screening rates between states and within states. METHODS: In an effort to increase screening rates and ensure equal access with respect to race/ethnicity, the New York City Department of Health and Mental Hygiene formed a coalition of stakeholders in 2003, with its primary focus on colonoscopy, to develop and implement strategies across the city to achieve this goal. RESULTS: From a screening colonoscopy rate of only 42% in 2003, these concerted efforts contributed to achieving a screening rate of 62% by 2007 and a screening rate of almost 70% in 2014 with the elimination of racial and ethnic disparities. CONCLUSIONS: This article provides details of how this program was successfully conceived, implemented, and sustained in the large urban population of New York City. The authors hope that by sharing the many elements involved and the lessons learned, they may help other communities to adapt these experiences to their own environments so that CRC screening rates can be maximized. Cancer 2016;122:269 277. (c) 2015 American Cancer Society. PMID- 26595056 TI - Image-enhanced endoscopy for detection of second primary neoplasm in patients with esophageal and head and neck cancer: A systematic review and meta-analysis. AB - Image-enhanced endoscopy is helpful for screening of a second primary neoplasm in patients with esophageal and head and neck cancer. The purpose of this meta analysis was to determine the diagnostic efficacy of white-light imaging (WLI), narrow band imaging (NBI), and Lugol chromoendoscopy for second primary neoplasm detection. A review of the PubMed/Cochrane databases up to May 2014 was performed. Meta-analysis was done by Meta-DiSc software and the Quality Assessment of Diagnostic Accuracy Studies-2 tool. A total of 4918 patients from 16 prospective and randomized trials were enrolled. For WLI, NBI, and Lugol chromoendoscopy, the pooled sensitivities were 53% (95% confidence interval [CI] = 48% to 59%), 87% (95% CI = 83% to 90%), and 88% (95% CI = 85% to 91%), respectively; the pooled specificities were 99% (95% CI = 98% to 99%), 95% (95% CI = 94% to 96%), and 63% (95% CI = 61% to 66%), respectively; and the areas under the receiver-operating characteristic (ROC) curve were 66%, 97%, and 82%, respectively. NBI endoscopy has the most highly accurate diagnostic performance for detection of second primary neoplasms in high-risk patients. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E2343-E2349, 2016. PMID- 26595057 TI - Clinical, biophysical and immunohistochemical analysis of skin reactions to acute skin barrier disruption - a comparative trial between participants with sensitive skin and those with nonsensitive skin. PMID- 26595058 TI - Hepatitis B Virus Reactivation and Prophylaxis During Solid Tumor Chemotherapy: A Systematic Review and Meta-analysis. AB - BACKGROUND: Solid tumor chemotherapy regimens pose a risk for hepatitis B virus (HBV) reactivation, but screening and antiviral prophylaxis remains controversial because of insufficient evidence. PURPOSE: To determine the risk for HBV reactivation with and without antiviral prophylaxis and the effectiveness of prophylaxis in adults with solid tumors and chronic or resolved HBV infection. DATA SOURCES: MEDLINE through 1 July 2015 and Web of Science, Cochrane Central Register of Controlled Trials, TOXNET, and Scopus through 1 March 2015. STUDY SELECTION: 26 English-language observational studies and randomized, controlled trials in patients with chronic or resolved HBV receiving chemotherapy for solid tumors. DATA EXTRACTION: Study characteristics, quality, and risk of bias were assessed by 1 researcher and verified by another independent researcher. DATA SYNTHESIS: Random-effects model meta-analyses were used to estimate the risk and odds ratio (OR) of reactivation with versus without antiviral prophylaxis. Reactivation in chronic HBV without prophylaxis ranged from 4% to 68% (median, 25%) with substantial heterogeneity. Prophylaxis reduced the risk for HBV reactivation (OR, 0.12 [95% CI, 0.06 to 0.22]), HBV-related hepatitis (OR, 0.18 [CI, 0.10 to 0.32]), and chemotherapy interruption (OR, 0.10 [CI, 0.04 to 0.27]). In 3 studies of patients with resolved HBV infection, none received HBV prophylaxis and reactivation risk ranged from 0.3% to 9.0%. LIMITATIONS: Significant heterogeneity in underlying study populations and treatment regimens, incomplete baseline data, possibility of publication bias, and limited study quality. Most studies were observational and from Asia. CONCLUSION: In patients with chronic HBV receiving solid tumor chemotherapy, the risk for HBV reactivation is similar to the risk with other types of immunosuppressive therapy. Results support HBV screening and antiviral prophylaxis before initiation of chemotherapy for solid tumors. PRIMARY FUNDING SOURCE: National Center for Advancing Translational Sciences and National Institutes of Health. PMID- 26595059 TI - Stakeholder-Driven Comparative Effectiveness Research: An Update From PCORI. PMID- 26595060 TI - Serum folate receptor alpha as a biomarker for ovarian cancer: Implications for diagnosis, prognosis and predicting its local tumor expression. AB - Folate receptor alpha (FRA) is a GPI-anchored glycoprotein and encoded by the FOLR1 gene. High expression of FRA is observed in specific malignant tumors of epithelial origin, including ovarian cancer, but exhibits very limited normal tissue expression, making it as an attractive target for the ovarian cancer therapy. FRA is known to shed from the cell surface into the circulation which allows for its measurement in the serum of patients. Recently, methods to detect the soluble form of FRA have been developed and serum FRA (sFRA) is considered a highly promising biomarker for ovarian cancer. We prospectively investigated the levels of sFRA in patients clinically suspected of having malignant ovarian tumors. A total of 231 patients were enrolled in this study and analyzed for sFRA as well as tumor expression of FRA by immunohistochemistry. High sFRA was predominantly observed in epithelial ovarian cancer patients, but not in patients with benign or borderline gynecological disease or metastatic ovarian tumors from advanced colorectal cancers. Levels of sFRA were highly correlated to clinical stage, tumor grade and histological type and demonstrated superior accuracy for the detection of ovarian cancer than did serum CA125. High sFRA was significantly associated with shorter progression-free survival in both early and advanced ovarian cancer patients. Finally, tumor FRA expression status was strongly correlated with sFRA levels. Taken together, these data suggest that sFRA might be a useful noninvasive serum biomarkers for future clinical trials assessing FRA targeted therapy. PMID- 26595061 TI - New-Onset Heart Failure in a Patient With a Pacemaker: An Unusual Cause. PMID- 26595062 TI - Idiopathic pulmonary fibrosis: Diagnosis, epidemiology and natural history. AB - Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing lung disorder of unknown aetiology whose diagnosis involves the careful exclusion of secondary causes for pulmonary fibrosis and the presence of a pattern of usual interstitial pneumonia (UIP) at either high-resolution computed tomography (HRCT) scan or surgical lung biopsy. Despite great efforts made in establishing precise, universally acknowledged diagnostic criteria for IPF, its ascertainment remains a challenge, especially in those individuals presenting with atypical HRCT patterns. With new drugs emerging, establishing a precise diagnosis is becoming a clinically relevant issue. Although regarded as a rare disease, IPF epidemiology is controversial due to studies relying on old data and adopting mixed, incomparable methodologies for cases definition. Overall, the prevalence and incidence appear to be increasing over the last decades, suggesting that in earlier studies they might have been underestimated because of diagnostic uncertainty. IPF is invariably progressive, although its clinical course might greatly vary on an individual basis, with episodes of severe acute respiratory deterioration (acute exacerbations) being unpredictable. A deeper understanding of the mechanisms responsible for an accelerated course of the disease and the identification of biomarkers of progression would lead to a better stratification of the disease, essential for delivering individualized therapeutic strategies. PMID- 26595063 TI - Canaliculosinostomy as a Long-Term Treatment of Seven Horses for Permanent Obstruction of the Nasolacrimal Duct. AB - OBJECTIVE: To describe canaliculosinostomy performed to resolve epiphora caused by nasolacrimal duct obstruction and to report the outcome of horses undergoing this procedure. STUDY DESIGN: Case series. ANIMALS: Seven horses with uni- or bilateral nasolacrimal duct obstruction. METHODS: The ventral lacrimal punctum and canaliculus were expanded with catheters of increasing diameter until a 14 gauge, Jamshedi needle could be passed into and through the lacrimal sac into the caudal maxillary sinus. One end of a plastic tube was inserted through the needle into the sinus, and the needle was withdrawn over the tubing. Using a hubless needle, the other end of the tube was passed through the lower eyelid leaving a segment of tubing exposed ventral to the eyelid. The end of the tubing within the sinus was exteriorized through a trephine hole in the frontal sinus and then tunneled beneath the skin adjacent to the osteotomy using a hubless needle, leaving a segment of tubing exposed on the forehead. Exposed tubing was sutured to the skin. The tubing was removed at 5-6 weeks. RESULTS: Canaliculosinostomy was easily performed with the horses sedated. Five horses had resolution of epiphora, and 2 had improvement. CONCLUSION: Canaliculosinostomy to divert lacrimal secretions into the sinuses resolves or improves epiphora caused by nasolacrimal duct obstruction and provides a good functional and cosmetic outcome. Canaliculosinostomy can be performed in the sedated horse. PMID- 26595064 TI - Multi-allergen Quantitation and the Impact of Thermal Treatment in Industry Processed Baked Goods by ELISA and Liquid Chromatography-Tandem Mass Spectrometry. AB - Undeclared food allergens account for 30-40% of food recalls in the United States. Compliance with ingredient labeling regulations and the implementation of effective manufacturing allergen control plans require the use of reliable methods for allergen detection and quantitation in complex food products. The objectives of this work were to (1) produce industry-processed model foods incurred with egg, milk, and peanut allergens, (2) compare analytical method performance for allergen quantitation in thermally processed bakery products, and (3) determine the effects of thermal treatment on allergen detection. Control and allergen-incurred cereal bars and muffins were formulated in a pilot-scale industry processing facility. Quantitation of egg, milk, and peanut in incurred baked goods was compared at various processing stages using commercial enzyme linked immunosorbent assay (ELISA) kits and a novel multi-allergen liquid chromatography (LC)-tandem mass spectrometry (MS/MS) multiple-reaction monitoring (MRM) method. Thermal processing was determined to negatively affect the recovery and quantitation of egg, milk, and peanut to different extents depending on the allergen, matrix, and analytical test method. The Morinaga ELISA and LC-MS/MS quantitative methods reported the highest recovery across all monitored allergens, whereas the ELISA Systems, Neogen BioKits, Neogen Veratox, and R Biopharm ELISA Kits underperformed in the determination of allergen content of industry-processed bakery products. PMID- 26595065 TI - How do (some) people make a cognitive map? Routes, places, and working memory. AB - Research on the existence of cognitive maps and on the cognitive processes that support effective navigation has often focused on functioning across individuals. However, there are pronounced individual differences in navigation proficiency, which need to be explained and which can illuminate our understanding of cognitive maps and effective navigation. Using a virtual environment involving 2 routes (Virtual Silcton, a desktop virtual environment; Weisberg, Schinazi, Newcombe, Shipley, & Epstein, 2014), we divided people into 3 groups based on their within-route and between-route pointing accuracy: integrators, non integrators, and imprecise navigators. In Study 1, we found that imprecise navigators have lower spatial and verbal working memory, which may limit their ability to build accurate within-route representations. We also found that integrators maintain excellent memories of buildings as categorized by route membership, possibly supporting the idea of hierarchical representations of the environment. In Study 2, we assessed preferences regarding place and route learning using a virtual version of the rodent T-maze (Marchette, Bakker, & Shelton, 2011). Integrators found more goals overall, and although they did not have an overall preference for a place-based strategy, integrators who did choose a place-based strategy found more goals. The opposite was true for imprecise navigators. In Study 3, we added a monetary incentive for accuracy to evaluate whether increased motivation leads to fewer participants classified as imprecise, but found no significant change in the distribution of performance. These data have theoretical implications for the cognitive map hypothesis, and practical implications for improving navigational functioning. A one-size-fits-all approach may fit none. (PsycINFO Database Record PMID- 26595066 TI - Negative priming in free recall reconsidered. AB - Negative priming in free recall is the finding of impaired memory performance when previously ignored auditory distracters become targets of encoding and retrieval. This negative priming has been attributed to an aftereffect of deploying inhibitory mechanisms that serve to suppress auditory distraction and minimize interference with learning and retrieval of task-relevant information. In 6 experiments, we tested the inhibitory account of the effect of negative priming in free recall against alternative accounts. We found that ignoring auditory distracters is neither sufficient nor necessary to produce the effect of negative priming in free recall. Instead, the effect is more readily accounted for by a buildup of proactive interference occurring whenever 2 successively presented lists of words are drawn from the same semantic category. (PsycINFO Database Record PMID- 26595067 TI - When enough is not enough: Information overload and metacognitive decisions to stop studying information. AB - People are often exposed to more information than they can actually remember. Despite this frequent form of information overload, little is known about how much information people choose to remember. Using a novel "stop" paradigm, the current research examined whether and how people choose to stop receiving new possibly overwhelming-information with the intent to maximize memory performance. Participants were presented with a long list of items and were rewarded for the number of correctly remembered words in a following free recall test. Critically, participants in a stop condition were provided with the option to stop the presentation of the remaining words at any time during the list, whereas participants in a control condition were presented with all items. Across 5 experiments, the authors found that participants tended to stop the presentation of the items to maximize the number of recalled items, but this decision ironically led to decreased memory performance relative to the control group. This pattern was consistent even after controlling for possible confounding factors (e.g., task demands). The results indicated a general, false belief that we can remember a larger number of items if we restrict the quantity of learning materials. These findings suggest people have an incomplete understanding of how we remember excessive amounts of information. (PsycINFO Database Record PMID- 26595068 TI - Do judgments of learning predict automatic influences of memory? AB - Current memory theories generally assume that memory performance reflects both recollection and automatic influences of memory. Research on people's predictions about the likelihood of remembering recently studied information on a memory test, that is, on judgments of learning (JOLs), suggests that both magnitude and resolution of JOLs are linked to recollection. However, it has remained unresolved whether JOLs are also predictive of automatic influences of memory. This issue was addressed in 3 experiments. Using the process-dissociation procedure, we assessed the predictive accuracy of immediate and delayed JOLs (Experiment 1) and of immediate JOLs from a first and from a second study-test cycle (Experiments 2 and 3) for recollection and automatic influences. Results showed that each type of JOLs was predictive of both recollection and automatic influences. Moreover, we found that a delay between study and JOL improved the predictive accuracy of JOLs for recollection, while study-test experience improved the predictive accuracy of JOLs for both recollection and automatic influences. These findings demonstrate that JOLs predict not only recollection, but also automatic influences of memory. (PsycINFO Database Record PMID- 26595069 TI - The response dynamics of recognition memory: Sensitivity and bias. AB - Advances in theories of memory are hampered by insufficient metrics for measuring memory. The goal of this paper is to further the development of model independent, sensitive empirical measures of the recognition decision process. We evaluate whether metrics from continuous mouse tracking, or response dynamics, uniquely identify response bias and mnemonic evidence, and demonstrate 1 application of these metrics to the strength-based mirror-effect paradigm. In 4 studies, we show that response dynamics can augment our current analytic repertoire in a way that speaks to the psychological mechanisms underlying recognition memory. We manipulated familiarity and response bias via encoding strength and the proportion of targets at test (Experiment 1) and found that the initial degree of deviation of the mouse movement toward a response is a robust indicator of response bias. In order to better isolate measures of memory strength, we next minimized response bias through the use of 2-alternative forced choice tests (Experiments 2 and 3). Changes in the direction of movement along the x-axis provided an indication of encoding strength. We conclude by applying these metrics to the typical strength-based mirror effect design (Experiment 4) in an attempt to further discriminate between differentiation and criterion-shift accounts. (PsycINFO Database Record PMID- 26595070 TI - Semantic preview benefit in English: Individual differences in the extraction and use of parafoveal semantic information. AB - Although there is robust evidence that skilled readers of English extract and use orthographic and phonological information from the parafovea to facilitate word identification, semantic preview benefits have been elusive. We sought to establish whether individual differences in the extraction and/or use of parafoveal semantic information could account for this discrepancy. Ninety-nine adult readers who were assessed on measures of reading and spelling ability read sentences while their eye movements were recorded. The gaze-contingent boundary paradigm was used to manipulate the availability of relevant semantic and orthographic information in the parafovea. On average, readers showed a benefit from previews high in semantic feature overlap with the target. However, reading and spelling ability yielded opposite effects on semantic preview benefit. High reading ability was associated with a semantic preview benefit that was equivalent to an identical preview on first-pass reading. High spelling ability was associated with a reduced semantic preview benefit despite an overall higher rate of skipping. These results suggest that differences in the magnitude of semantic preview benefits in English reflect constraints on extracting semantic information from the parafovea and competition between the orthographic features of the preview and the target. (PsycINFO Database Record PMID- 26595071 TI - Intrathecal rituximab for EBV-associated post-transplant lymphoproliferative disorder with central nervous system involvement unresponsive to intravenous rituximab-based treatments: a prospective study. PMID- 26595072 TI - At-home autologous stem cell transplantation in multiple myeloma with and without G-CSF administration: a comparative study. PMID- 26595074 TI - Acute pericarditis before engraftment in hematopoietic stem cell transplantation. PMID- 26595073 TI - Long-term outcomes of fludarabine, melphalan and antithymocyte globulin as reduced-intensity conditioning regimen for allogeneic hematopoietic stem cell transplantation in children with primary immunodeficiency disorders: a prospective single center study. AB - Reduced-intensity conditioning (RIC) has offered many primary immunodeficiency disorder (PID) patients who are ineligible for myeloablative regimens a chance of cure. However, the beneficial role of RIC was questioned following reports suggesting higher chance of rejection and lower symptom resolution rate in mixed chimerism settings. Forty-five children affected by PIDs with a median age of 21 months underwent allogeneic hematopoietic stem cell transplantation in our institute from 2007 to 2013. All patients received an identical RIC regimen. Forty-one patients had successful primary engraftment (91%). Of the successful engraftments, 80% (n=33) had stable full donor chimerism at last contact. Overall, eleven transplant-related mortalities were reported including five patients due to sepsis, three children due to grade IV acute GvHD, two due to chronic GvHD and one patient due to sepsis after primary graft failure. The median post-transplantation follow-up of deceased patients was 55 days. Five-year overall survival and disease-free survival was 75.6% and 68.89%, respectively. All surviving patients with successful engraftment became disease free, regardless of having full or mixed chimerism. Our study suggests that RIC regimen provides satisfactory rates of successful engraftment and full chimerism. Furthermore, patients with mixed chimerism were stable in long-term follow-up and this chimerism status offered the potential to resolve symptoms of immunodeficiency. PMID- 26595075 TI - The gender gap: discrepant human T-cell reconstitution after cord blood stem cell transplantation in humanized female and male mice. PMID- 26595076 TI - Effect of immune modulation in relapsed peripheral T-cell lymphomas after post allogeneic stem cell transplantation: a study by the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire (SFGM-TC). AB - Peripheral T-cell lymphoma carries a poor prognosis. To document a possible graft versus-lymphoma effect in this setting, we evaluated the impact of immunomodulation in 63 patients with peripheral T-cell lymphoma who relapsed after allogeneic transplant in 27 SFGM-TC centers. Relapse occurred after a median of 2.8 months. Patients were then treated with non-immunologic strategies (chemotherapy, radiotherapy) and/or immune modulation (donor lymphocyte infusions (DLI) and/or discontinuation of immunosuppressive therapy). Median overall survival (OS) after relapse was 6.1 months (DLI group: 23.6 months, non-DLI group: 3.6 months). Among the 14 patients who received DLI, 9 responded and 2 had stable disease. Among the remaining 49 patients, a complete response accompanied by extensive chronic GvHD was achieved in two patients after tapering of immunosuppressive drugs. Thirty patients received radio-chemotherapy, with an overall response rate of 50%. In multivariate analysis, chronic GvHD (odds ratio: 11.25 (2.68-48.21), P=0.0009) and skin relapse (odds ratio: 4.15 (1.04-16.50), P=0.043) were associated with a better response to treatment at relapse. In a time-dependent analysis, the only factor predictive of OS was the time from transplantation to relapse (hazards ratio: 0.33 (0.17-0.640), P=0.0009). This large series provides encouraging evidence of a true GvL effect in this disease. PMID- 26595077 TI - New strategies of DLI in the management of relapse of hematological malignancies after allogeneic hematopoietic SCT. AB - DLI is an effective strategy for patients with recurrent hematological malignancies after allogeneic hematopoietic SCT (allo-HSCT). DLI has been widely applied to boost the graft vs tumor (GVT) or GVL effects. However, given the potentially severe complications associated with conventional DLI and transient GVL effect, new strategies for DLI are emerging. In this review, we have discussed the recent important studies on DLI as a prophylactic or therapeutic modality for relapsed hematological disorders after allo-HSCT. The strategies to separate GVL from GVHD have also been discussed. Leukemia-targeting therapy and lymphodepletion combined with DLI, and prophylactic DLI after allo-HSCT are often employed for patients with high risk of relapse, which has been reviewed as well. In addition, we have also discussed the issues on DLI to be further addressed, such as the doses, timing and frequency of DLI in different clinical settings, leukemic antigen-specific DLI as well as how to augment GVL effect while attenuating GVHD. PMID- 26595078 TI - Tacrolimus compared with cyclosporine A after haploidentical T-cell replete transplantation with post-infusion cyclophosphamide. PMID- 26595079 TI - Tumorablative haploidentical hematopoietic cell transplantation for treatment of hematologic malignancy in children. PMID- 26595080 TI - Novel disease burden assessment predicts allogeneic transplantation outcomes in myelodysplastic syndrome. AB - Among patients with myelodysplastic syndrome (MDS) undergoing hematopoietic cell transplantation (HCT), the impact of residual pretransplant cytogenetically abnormal cells on outcomes remains uncertain. We analyzed HCT outcomes by time of transplant disease variables, including (1) blast percentage, (2) percentage of cytogenetically abnormal cells and (3) Revised International Prognostic Scoring System (R-IPSS) cytogenetic classification. We included 82 MDS patients (median age 51 years (range 18-71)) transplanted between 1995 and 2013 with abnormal diagnostic cytogenetics. Patients with higher percentages of cytogenetically abnormal cells experienced inferior 5-year survival (37-76% abnormal cells: relative risk (RR) 2.9; 95% confidence interval (CI) 1.2-7.2; P=0.02; and 77-100% abnormal cells: RR 5.6; 95% CI 1.9-19.6; P<0.01). Patients with >10% blasts also had inferior 5-year survival (RR 2.9; 95% CI 1.1-7.2; P=0.02) versus patients with ?2% blasts. Even among patients with ?2% blasts, patients with 77-100% cytogenetically abnormal cells had poor survival (RR 4.4; 95% CI 1.1-18.3; P=0.04). Increased non-relapse mortality (NRM) was observed with both increasing blast percentages (P<0.01) and cytogenetically abnormal cells at transplant (P=0.01) in multivariate analysis. We observed no impact of disease burden characteristics on relapse outcomes due to high 1-year NRM. In conclusion, both blast percentage and percentage of cytogenetically abnormal cells reflect MDS disease burden and predict post-HCT outcomes. PMID- 26595081 TI - A preclinical acute GVHD mouse model based on chemotherapy conditioning and MHC matched transplantation. AB - Animal disease models have been criticized for lack of resemblance to human illnesses, hampering transfer of knowledge from preclinical research to clinical medicine. In the field of allogeneic hematopoietic stem cell transplantation (allo-HSCT), it is standard practice to study GVHD in lethal TBI-based murine models. Frequently, MHC-mismatched donors are used in GVHD models. In contrast, in clinical allo-HSCT conditioning with chemotherapy (+/-TBI) is common and donors are often MHC-matched. Aiming at a more clinically oriented situation, we established and characterized a murine MHC-matched, minor histocompatibility antigen mismatched GVHD model (LP/J [H2k(b)]-->C57BL/6 [H2k(b)]) using busulfan and cyclophosphamide conditioning. We found typical clinical and histological features of acute GVHD. T-cell infiltration, GVHD-specific damage and systemic inflammation were similar to observations made in patients after allo-HSCT. In survivors of acute GVHD, we found expansion of CD4+ T cells and the development of scleroderma-like chronic GVHD. The use of chemotherapy-based, minor histocompatibility antigen (miHA)-mismatched GVHD animal models may be a good option when studying clinically relevant questions in the field of allo-HSCT. PMID- 26595082 TI - Sinusoidal obstruction syndrome after allogeneic hematopoietic stem cell transplantation: Incidence, risk factors and outcomes. AB - This retrospective study was conducted in Japan to determine the incidence, risk factors and outcomes of sinusoidal obstruction syndrome (SOS) after allogeneic hematopoietic stem cell transplantation (HSCT). Among 4290 patients undergoing allogeneic HSCT between 1999 and 2010, 462 were diagnosed with SOS according to the Seattle criteria (cumulative incidence, 10.8%). The cumulative incidence of SOS diagnosed by the modified Seattle criteria was 9.3%. Of 462 patients, 107 met the Baltimore criteria and 168 had severe SOS with renal and/or respiratory failure. The median onset for SOS was 12 days after HSCT (range, -2-30). Overall survival at day 100 was 32% for SOS and 15% for severe SOS. Multivariate analyses showed that significant independent risk factors for SOS were the number of HSCTs, age, performance status, hepatitis C virus-seropositivity, advanced disease status and myeloablative regimen. SOS was highly associated with overall mortality (hazard ratio, 2.09; P<0.001). Our retrospective survey showed that the cumulative incidence of SOS in Japan was 10.8%, similar to that previously reported in Western countries, and that the overall survival of patients who developed SOS was low. Furthermore, several risk factors were identified. Preventive and therapeutic strategies for high-risk SOS patients must be established to improve overall survival. PMID- 26595083 TI - Impact of pre-transplant diffusion lung capacity for nitric oxide (DLNO) and of DLNO/pre-transplant diffusion lung capacity for carbon monoxide (DLNO/DLCO) ratio on pulmonary outcomes in adults receiving allogeneic stem cell transplantation for hematological diseases. PMID- 26595084 TI - Changes in microgaps, micromotion, and trabecular strain from interlocked cement trabecular bone interfaces in total knee replacements with in vivo service. AB - The initial fixation of cemented Total Knee Replacements (TKRs) relies on mechanical interlock between cement and bone, but loss of interlock occurs with in vivo service. In this study, cement-trabeculae gap morphology and micromechanics were measured for lab prepared (representing post-operative state) and postmortem retrieval (with in vivo remodeling) TKRs to determine how changes in fixation affect local micromechanics. Small specimens taken from beneath the tibial tray were loaded with 1 MPa axial compression and the local micromechanics of the trabeculae-cement interface was quantified using digital image correlation. Lab prepared trabeculae that initially interlock with cement had small gaps (ave:14 MUm) and limited micromotion (ave:1 MUm) which were larger near the cement border. Trabecular resorption was prevalent following in vivo service; interface gaps became larger (ave:40 MUm) and micromotion increased (ave:6 MUm), particularly near the cement border. Interlocked trabeculae from lab prepared specimens exhibited strains that were 20% of the supporting bone strain, indicating the trabeculae were initially strain shielded. The spatial and temporal progression of gaps, micromotion, and bone strain was complex and much more variable for post-mortem retrievals compared to the lab prepared specimens. From a clinical perspective, attaining more initial interlock results in cement bone interfaces that are better fixed with less micromotion. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1019-1025, 2016. PMID- 26595085 TI - Daily rhythms of lipid metabolic gene expression in zebra fish liver: Response to light/dark and feeding cycles. AB - Despite numerous studies about fish nutrition and lipid metabolism, very little is known about the daily rhythm expression of lipogenesis and lipolysis genes. This research aimed to investigate the existence of daily rhythm expressions of the genes involved in lipid metabolism and their synchronization to different light/dark (LD) and feeding cycles in zebra fish liver. For this purpose, three groups of zebra fish were submitted to a 12:12 h LD cycle. A single daily meal was provided to each group at various times: in the middle of the light phase (ML); in the middle of the dark phase (MD); at random times. After 20 days of acclimation to these experimental conditions, liver samples were collected every 4 h in one 24-h cycle. The results revealed that most genes displayed a significant daily rhythm with an acrophase of expression in the dark phase. The acrophase of lipolytic genes (lipoprotein lipase - lpl, peroxisome proliferator activated receptor - pparalpha and hydroxyacil CoA dehydrogenase - hadh) was displayed between ZT 02:17 h and ZT 18:31 h. That of lipogenic genes (leptin-a - lepa, peroxisome proliferator-activated receptor - ppargamma, liver X receptor - lxr, insulin-like growth factor - igf1, sterol regulatory element-binding protein - srebp and fatty acid synthase - fas) was displayed between ZT 15:25 h and 20:06 h (dark phase). Feeding time barely influenced daily expression rhythms, except for lxr in the MD group, whose acrophase shifted by about 14 h compared with the ML group (ZT 04:31 h versus ZT 18:29 h, respectively). These results evidence a strong synchronization to the LD cycle, but not to feeding time, and most genes showed a nocturnal acrophase. These findings highlight the importance of considering light and feeding time to optimize lipid metabolism and feeding protocols in fish farming. PMID- 26595086 TI - Thermal Rectification by Design in Telescopic Si Nanowires. AB - We show that thermal rectification by design is possible by joining/growing Si nanowires (SiNWs) with sections of appropriately selected diameters (i.e., telescopic nanowires). This is done, first, by showing that the heat equation can be applied at the nanoscale (NW diameters down to 5 nm). We (a) obtain thermal conductivity versus temperature, kappa(T), curves from molecular dynamics (MD) simulations for SiNWs of three different diameters, then (b) we conduct MD simulations of a telescopic NW built as the junction of two segments with different diameters, and afterward (c) we verify that the MD results for thermal rectification in telescopic NWs are very well reproduced by the heat equation with kappa(T) of the segments from MD. Second, we apply the heat equation to predict the amount of thermal rectification in a variety of telescopic SiNWs with segments made from SiNWs where kappa(T) has been experimentally measured, obtaining r values up to 50%. This methodology can be applied to predict the thermal rectification of arbitrary heterojunctions as long as the kappa(T) data of the constituents are available. PMID- 26595087 TI - Can deaths in police cells be prevented? Experience from Norway and death rates in other countries. AB - PURPOSE: To describe the changes in death rates and causes of deaths in Norwegian police cells during the last 2 decades. To review reports on death rates in police cells that have been published in medical journals and elsewhere, and discuss the difficulties of comparing death rates between countries. METHODS: Data on deaths in Norwegian police cells were collected retrospectively in 2002 and 2012 for two time periods: 1993-2001 (period 1) and 2003-2012 (period 2). Several databases were searched to find reports on deaths in police cells from as many countries as possible. RESULTS: The death rates in Norwegian police cells reduced significantly from 0.83 deaths per year per million inhabitants (DYM) in period 1 to 0.22 DYM in period 2 (p < 0.05). The most common cause of death in period 1 was alcohol intoxication including intracranial bleeding in persons with high blood alcohol levels, and the number declined from 16 persons in period 1 to 1 person in period 2 (p = 0.032). The median death rate in the surveyed Western countries was 0.44 DYM (range: 0.14-1.46 DYM). CONCLUSION: The number of deaths in Norwegian police cells reduced by about 75% over a period of approximately 10 years. This is probably mainly due to individuals with severe alcohol intoxication no longer being placed in police cells. However, there remain large methodology difficulties in comparing deaths rates between countries. PMID- 26595088 TI - Client perspectives of midwifery care in the transition from subfertility to parenthood: a qualitative study in the Netherlands. AB - BACKGROUND: Pregnancy, childbirth and the postpartum period after fertility treatment are considered "normal" in the Netherlands, with no indication of an increased obstetric risk, and can therefore be monitored by a primary care midwife. However, there is little evidence on the experiences of couples and women who finally get pregnant after fertility treatment and a lack of training for midwives exists on this subject. The aim of this study was to map the midwifery care needs of the subfertile client with past fertility problems. METHODS: In 2011, we interviewed two couples and seven women who conceived through fertility treatment and received primary midwifery care at some point during their pregnancies. This explorative, qualitative study was based on the interpretivist/constructivist paradigm. RESULTS: Although the participants are not representative of all subfertile clients, the findings of our qualitative study highlight the needs of women and their partners who have become pregnant through fertility treatment including help from the primary care midwife in understanding the likely course of their pregnancy, more psychosocial support and acknowledgement of the fertility treatment history, and more consultations and frequent ultrasound scans than usual to confirm pregnancy. CONCLUSIONS: Our study points out that the women who have become pregnant through fertility treatment and their partners communicate seemingly paradoxical prenatal care needs. It can help maternity care providers to optimally meet the care needs of subfertile clients and empower them during their transition from subfertility to parenthood. PMID- 26595089 TI - Mortality among immigrants in England and Wales by major causes of death, 1971 2012: A longitudinal analysis of register-based data. AB - Recent research has found a migrant mortality advantage among immigrants relative to the UK-born population living in England and Wales. However, while all-cause mortality is useful to show differences in mortality between immigrants and the host population, it can mask variation in mortality patterns from specific causes of death. This study analyses differences in the causes of death among immigrants living in England and Wales. We extend previous research by applying competing risks survival analysis to study a large-scale longitudinal dataset from 1971 to 2012 to directly compare causes of death. We confirm low all-cause mortality among nearly all immigrants, except immigrants from Scotland, Northern Ireland and the Republic of Ireland (who have high mortality). In most cases, low all cause mortality among immigrants is driven by lower mortality from chronic diseases (in nearly all cases by lower cancer mortality and in some cases by lower mortality from cardiovascular diseases (CVD)). This low all-cause mortality often coexists with low respiratory disease mortality and among non-western immigrants, coexists with high mortality from infectious diseases; however, these two causes of death contribute little to mortality among immigrants. For men, CVD is the leading cause of death (particularly among South Asians). For women, cancer is the leading cause of death (except among South Asians, for whom CVD is also the leading cause). Differences in CVD mortality over time remain constant between immigrants relative to UK-born, but immigrant cancer patterns shows signs of some convergence to the cancer mortality among the UK-born (though cancer mortality is still low among immigrants by age 80). The study provides the most up-to-date, reliable UK-based analysis of immigrant mortality. PMID- 26595090 TI - Overexpression of Crocus carotenoid cleavage dioxygenase, CsCCD4b, in Arabidopsis imparts tolerance to dehydration, salt and oxidative stresses by modulating ROS machinery. AB - Apocarotenoids modulate vital physiological and developmental processes in plants. These molecules are formed by the cleavage of carotenoids, a reaction catalyzed by a family of enzymes called carotenoid cleavage dioxygenases (CCDs). Apocarotenoids like beta-ionone and beta-cyclocitral have been reported to act as stress signal molecules during high light stress in many plant species. In Crocus sativus, these two apocarotenoids are formed by enzymatic cleavage of beta carotene at 9, 10 and 7, 8 bonds by CsCCD4 enzymes. In the present study three isoforms of CsCCD4 were subjected to molecular modeling and docking analysis to determine their substrate specificity and all the three isoforms displayed high substrate specificity for beta-carotene. Further, expression of these three CsCCD4 isoforms investigated in response to various stresses revealed that CsCCD4a and CsCCD4b exhibit enhanced expression in response to dehydration, salt and methylviologen, providing a clue towards their role in mediating plant defense response. This was confirmed by overexpressing CsCCD4b in Arabidopsis. The transgenic plants developed longer roots and possessed higher number of lateral roots. Further, overexpression of CsCCD4b imparted enhanced tolerance to salt, dehydration and oxidative stresses as was evidenced by higher survival rate, increased relative root length and biomass in transgenic plants as compared to wild type. Transgenic plants also displayed higher activity and expression of reactive oxygen species (ROS) metabolizing enzymes. This indicates that beta ionone and beta-cyclocitral which are enzymatic products of CsCCD4b may act as stress signals and mediate reprogramming of stress responsive genes which ultimately leads to plant defense. PMID- 26595091 TI - The role of secukinumab in the treatment of ankylosing spondylitis. AB - Ankylosing spondylitis is a chronic inflammatory disorder involving the sacroiliac joint, spine and less frequently the peripheral joints. Nonsteroidal anti-inflammatory drugs and TNF-alpha inhibitors are utilized to reduce signs and symptoms. Whether these agents slow disease progression, is still debatable. Secukinumab is a fully human monoclonal antibody against IL-17 that has been studied in patients with ankylosing spondylitis with promising results. It has demonstrated improvement in signs, symptoms, patient reported outcomes and functional status and has been well tolerated. The clinical improvement is also mirrored in the improvement in sacroiliac joint magnetic resonance imaging scans. PMID- 26595092 TI - "Proactive" in many ways: Developmental evidence for a dynamic pluralistic approach to prediction. AB - The anticipation of the forthcoming behaviour of social interaction partners is a useful ability supporting interaction and communication between social partners. Associations and prediction based on the production system (in line with views that listeners use the production system covertly to anticipate what the other person might be likely to say) are two potential factors, which have been proposed to be involved in anticipatory language processing. We examined the influence of both factors on the degree to which listeners predict upcoming linguistic input. Are listeners more likely to predict book as an appropriate continuation of the sentence "The boy reads a", based on the strength of the association between the words read and book (strong association) and read and letter (weak association)? Do more proficient producers predict more? What is the interplay of these two influences on prediction? The results suggest that associations influence language-mediated anticipatory eye gaze in two-year-olds and adults only when two thematically appropriate target objects compete for overt attention but not when these objects are presented separately. Furthermore, children's prediction abilities are strongly related to their language production skills when appropriate target objects are presented separately but not when presented together. Both influences on prediction in language processing thus appear to be context dependent. We conclude that multiple factors simultaneously influence listeners' anticipation of upcoming linguistic input and that only such a dynamic approach to prediction can capture listeners' prowess at predictive language processing. PMID- 26595094 TI - Managing Helicobacter pylori in college health, with special considerations for international students. AB - OBJECTIVE: Helicobacter pylori infection is the major cause of dyspepsia, peptic ulcer disease, and gastric cancer. This paper will make specific recommendations for a diagnostic and treatment strategy tailored to the international student population. PARTICIPANTS/METHODS: This paper is a case report and narrative review based on recent international epidemiologic studies and consensus conference recommendations identified in MEDLINE. RESULTS: In the nations (mostly Asian) that send the largest number of students to the United States, the prevalence of H. pylori is generally 60% to 80%, whereas the prevalence in the United States is about 25%. The patterns of antibiotic resistance in those countries are also different than that in the general US population. CONCLUSIONS: Health care providers should have a higher index of suspicion for Helicobacter infection among international students with dyspepsia and need to use a different treatment regimen than is standard for the general US population. PMID- 26595093 TI - Leishmania vaccine development: exploiting the host-vector-parasite interface. AB - Visceral leishmaniasis (VL) is a disease transmitted by phlebotomine sand flies, fatal if untreated, and with no available human vaccine. In rodents, cellular immunity to Leishmania parasite proteins as well as salivary proteins of the sand fly is associated with protection, making them worthy targets for further exploration as vaccines. This review discusses the notion that a combination vaccine including Leishmania and vector salivary antigens may improve vaccine efficacy by targeting the parasite at its most vulnerable stage just after transmission. Furthermore, we put forward the notion that better modeling of natural transmission is needed to test efficacy of vaccines. For example, the fact that individuals living in endemic areas are exposed to sand fly bites and will mount an immune response to salivary proteins should be considered in pre clinical and clinical evaluation of leishmaniasis vaccines. Nevertheless, despite remaining obstacles there is good reason to be optimistic that safe and effective vaccines against leishmaniasis can be developed. PMID- 26595095 TI - Change in ATP-binding cassette B1/19, glutamine synthetase and alcohol dehydrogenase gene expression during root elongation in Betula pendula Roth and Alnus glutinosa L. Gaertn in response to leachate and leonardite humic substances. AB - Humic substances (HS) are complex and heterogeneous compounds of humified organic matter resulting from the chemical and microbiological decomposition of organic residues. HS have a positive effect on plant growth and development by improving soil structure and fertility. They have long been recognized as plant growth promoting substances, particularly with regard to influencing nutrient uptake, root growth and architecture. The biochemical and molecular mechanisms through which HS influence plant physiology are not well understood. This study evaluated the bioactivity of landfill leachate and leonardite HS on alder (Alnus glutinosa L. Gaertn) and birch (Betula pendula Roth) during root elongation in vitro. Changes in root development were studied in relation to auxin, carbon and nitrogen metabolisms, as well as to the stress adaptive response. The cDNA fragments of putative genes encoding two ATP-binding cassette (ABC) transporters (ABCB1 and ABCB19) belonging to the B subfamily of plant ABC auxin transporters were cloned and sequenced. Molecular data indicate that HS and their humic acid (HA) fractions induce root growth by influencing polar auxin transport (PAT), as illustrated by the modulation of the ABCB transporter transcript levels (ABCB1 and ABCB19). There were also changes in alcohol dehydrogenase (ADH) and glutamine synthetase (GS) gene transcript levels in response to HS exposure. These findings confirmed that humic matter affects plant growth and development through various metabolic pathways, including hormonal, carbon and nitrogen metabolisms and stress response or signalization. PMID- 26595096 TI - Effect of pressure relaxation and membrane backwash on adenovirus removal in a membrane bioreactor. AB - Pressure relaxation and permeate backwash are two commonly used physical methods for membrane fouling mitigation in membrane bioreactor (MBR) systems. In order to assess the impact of these methods on virus removal by MBRs, experiments were conducted in a bench-scale submerged MBR treating synthetic wastewater. The membranes employed were hollow fibers with the nominal pore size of 0.45 MUm. The experimental variables included durations of the filtration (tTMP>0), pressure relaxation (tTMP=0) and backwash (tTMP<0) steps. Both pressure relaxation and permeate backwash led to significant reductions in removal of human adenovirus (HAdV). For the same value of tTMP>0/tTMP=0, longer filtration/relaxation cycles (i.e. larger tTMP+tTMP=0) led to higher transmembrane pressure (TMP) but did not have a significant impact on HAdV removal. A shorter backwash (tTMP<0 = 10 min) at a higher flow rate (Q = 40 mL/min) resulted in more substantial decreases in TMP and HAdV removal than a longer backwash (tTMP<0 = 20 min) at a lower flow rate (Q = 20 mL/min) even though the backwash volume (QtTMP<0) was the same. HAdV removal returned to pre-cleaning levels within 16 h after backwash was applied. Moderate to strong correlations (R(2) = 0.63 to 0.94) were found between TMP and HAdV removal. PMID- 26595097 TI - Effect of self-alkalization on nitrite accumulation in a high-rate denitrification system: Performance, microflora and enzymatic activities. AB - The self-alkalization of denitrifying automatic circulation (DAC) reactor resulted in a large increase of pH up to 9.20 and caused a tremendous accumulation of nitrite up to 451.1 +/- 49.0 mgN L(-1) at nitrate loading rate (NLR) from 35 kgN m(-3) d(-1) to 55 kgN m(-3) d(-1). The nitrite accumulation was greatly relieved even at the same NLR once the pH was maintained at 7.6 +/- 0.2 in the system. Enzymatic assays indicated that the long-term bacterial exposure to high pH significantly inhibited the activity of copper type nitrite reductase (NirK) rather than the cytochrome cd1 type nitrite reductase (NirS). The terminal restriction fragment length polymorphism (T-RFLP) analysis revealed that the dominant denitrifying bacteria shifted from the NirS-containing Thauear sp. 27 to the NirK-containing Hyphomicrobium nitrativorans strain NL23 during the self alkalization. The significant nitrite accumulation in the high-rate denitrification system could be therefore, due to the inhibition of Cu-containing NirK by high pH from the self-alkalization. The results suggest that the NirK containing H. nitrativorans strain NL23 could be an ideal functional bacterium for the conversion of nitrate to nitrite, i.e. denitritation, which could be combined with anaerobic ammonium oxidation (Anammox) to develop a new process for nitrogen removal from wastewater. PMID- 26595098 TI - Mathematical modelling and reactor design for multi-cycle bioregeneration of nitrate exhausted ion exchange resin. AB - Nitrate contamination is one of the largest issues facing communities worldwide. One of the most common methods for nitrate removal from water is ion exchange using nitrate selective resin. Although these resins have a great capacity for nitrate removal, they are considered non regenerable. The sustainability of nitrate-contaminated water treatment processes can be achieved by regenerating the exhausted resin several times rather than replacing and incineration of exhausted resin. The use of multi-cycle exhaustion/bioregeneration of resin enclosed in a membrane has been shown to be an effective and innovative regeneration method. In this research, the mechanisms for bioregeneration of resin were studied and a mathematical model which incorporated physical desorption process with biological removal kinetics was developed. Regardless of the salt concentration of the solution, this specific resin is a pore-diffusion controlled process (XdeltaD -CDr0(5+2alpha)<<1). Also, Thiele modulus was calculated to be between 4 and 12 depending on the temperature and salt concentration. High Thiele modulus (>3) shows that the bioregeneration process is controlled by reaction kinetics and is governed by biological removal of nitrate. The model was validated by comparison to experimental data; the average of R squared values for cycle 1 to 5 of regeneration was 0.94 +/- 0.06 which shows that the developed model predicted the experimental results very well. The model sensitivity for different parameters was evaluated and a model bioreactor design for bioregeneration of highly selective resins was also presented. PMID- 26595099 TI - A comparative assessment of intensive and extensive wastewater treatment technologies for removing emerging contaminants in small communities. AB - Ecosystem pollution due to the lack of or inefficient wastewater treatment coverage in small communities is still a matter of great concern, even in developed countries. This study assesses the seasonal performance of 4 different full-scale wastewater technologies that have been used in small communities (<2000 population equivalent) for more than 10 years in terms of emerging contaminant (EC), chemical oxygen demand (COD), total suspended solids (TSS) and NH4-N removal efficiency. The studied technologies, which were selected due to their widespread use, included two intensive treatment systems (an extended aeration system (AS) and a rotating biological contactor (RBC)) and two extensive treatment systems (a constructed wetland (CW) and a waste stabilization pond (WSP)), all located in north-eastern Spain. The studied compounds belonged to the groups of pharmaceuticals, sunscreen compounds, fragrances, antiseptics, flame retardants, surfactants, pesticides and plasticizers. The 25 ECs occurred in wastewater at concentrations ranging from undetectable to 80 MUg L(-1). The average removal efficiency was 42% for the CW, 62% for the AS, 63% for the RBC and 82% for the WSP. All the technologies except the WSP system showed seasonal variability in the removal of ECs. The ecotoxicological assessment study revealed that, whilst all the technologies were capable of decreasing the aquatic risk, only the WSP yielded no risk in both seasons. PMID- 26595100 TI - Factors Associated With Cardiovascular Events in Patients With Type 2 Diabetes and Acute Myocardial Infarction. AB - CONTEXT: Decreasing risk of cardiovascular (CV) disease remains a challenge to survival in type 2 diabetes. OBJECTIVE: The objective was to assess the association between demographic, glycemic, and other clinical factors and CV risk in the Hyperglycemia and Its Effect After Acute Myocardial Infarction on Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus trial. DESIGN, SETTINGS, PARTICIPANTS, AND INTERVENTION: We used discrete-time survival tree analysis to examine data collected for up to 4.6 years in 1115 patients with type 2 diabetes mellitus experiencing acute myocardial infarction (MI) less than or equal to 18 days before enrollment. MAIN OUTCOME MEASURES: The primary objective was to identify demographic, glycemic, and CV risk factors best separating survival curves over time for a composite end point: CV death, nonfatal MI, nonfatal stroke, hospitalization for acute coronary syndromes, or coronary revascularization planned after randomization. RESULTS: Average change across visits in mean 2-hour blood glucose level after meals was associated with the greatest difference in event-free survival probability for the primary end point: mean time to 75% event-free survival for an average change across visits less than or equal to -0.14 mmol/L, 73.48 weeks; for visits with average change more 0.14 mmol/L, 29.10 weeks. An average change across visits in the hemoglobin A1c level less than or equal to -0.92% (-10.06 mmol/mol) and the absence of a history of stroke or acute MI increased CV event-free survival time further. Fasting blood glucose and randomized insulin treatment strategy were weak predicting factors of event-free survival. CONCLUSIONS: Postprandial glycemia should be considered a potential target in trials to reduce CV morbidity and mortality in type 2 diabetes mellitus. PMID- 26595102 TI - C14-polyacetylenol glycosides from the roots of Codonopsis pilosula. AB - Eight new C14-polyacetylenol glycosides, containing ene-diyne and ene-yn-ene chromophores named codonopilodiynosides H-M (1-6) and codonopiloenynenosides A and B (7 and 8), respectively, together with three known analogs lobetyolinin, pratialin B, and lobetyolin (9-11), were isolated from an aqueous extract of the roots of Codonopsis pilosula. Their structures were determined by spectroscopic and chemical methods including 2D NMR data analysis and enzymatic hydrolysis. The absolute configurations of aglycones in 1-10 were assigned by application of the methoxyphenylacetic acid (MPA) determination rule of Deltadelta(RS) values and/or the empirical rule of Mo2(OAc)4-induced circular dichroism for the vicinal diols, or by comparison of specific rotation values with those of reported compounds. Compounds 4-6 are the first polyacetylenol glycosides possessing a cis-ene-diyne chromophore from the genus Codonopsis, while 8 has a rear trans-ene-yn-cis-ene chromophore and a (6S,7S)-6,7-diol unit against a (6R,7R)-6,7-diol unit in the others. The absolute configurations of lobetyolinin (9) and pratialin B (10) were determined for the first time. PMID- 26595103 TI - EEG-based decoding of error-related brain activity in a real-world driving task. AB - OBJECTIVES: Recent studies have started to explore the implementation of brain computer interfaces (BCI) as part of driving assistant systems. The current study presents an EEG-based BCI that decodes error-related brain activity. Such information can be used, e.g., to predict driver's intended turning direction before reaching road intersections. APPROACH: We executed experiments in a car simulator (N = 22) and a real car (N = 8). While subject was driving, a directional cue was shown before reaching an intersection, and we classified the presence or not of an error-related potentials from EEG to infer whether the cued direction coincided with the subject's intention. In this protocol, the directional cue can correspond to an estimation of the driving direction provided by a driving assistance system. We analyzed ERPs elicited during normal driving and evaluated the classification performance in both offline and online tests. RESULTS: An average classification accuracy of 0.698 +/- 0.065 was obtained in offline experiments in the car simulator, while tests in the real car yielded a performance of 0.682 +/- 0.059. The results were significantly higher than chance level for all cases. Online experiments led to equivalent performances in both simulated and real car driving experiments. These results support the feasibility of decoding these signals to help estimating whether the driver's intention coincides with the advice provided by the driving assistant in a real car. SIGNIFICANCE: The study demonstrates a BCI system in real-world driving, extending the work from previous simulated studies. As far as we know, this is the first online study in real car decoding driver's error-related brain activity. Given the encouraging results, the paradigm could be further improved by using more sophisticated machine learning approaches and possibly be combined with applications in intelligent vehicles. PMID- 26595101 TI - Paradoxical Relationship Between Body Mass Index and Thyroid Hormone Levels: A Study Using Mendelian Randomization. AB - CONTEXT: Free T3 (FT3) has been positively associated with body mass index (BMI) in cross-sectional studies in healthy individuals. This is difficult to reconcile with clinical findings in pathological thyroid dysfunction. OBJECTIVE: We aimed to investigate whether childhood adiposity influences FT3 levels. DESIGN: Mendelian randomization using genetic variants robustly associated with BMI. SETTING: Avon Longitudinal Study of Parents and Children, a population-based birth cohort. PARTICIPANTS: A total of 3014 children who had thyroid function measured at age 7, who also underwent dual x-ray absorptiometry scans at ages 9.9 and 15.5 years and have genetic data available. MAIN OUTCOME MEASURES: FT3. RESULTS: Observationally at age 7 years, BMI was positively associated with FT3: beta-standardized (beta-[std]) = 0.12 (95% confidence interval [CI]: 0.08, 0.16), P = 4.02 * 10(-10); whereas FT4 was negatively associated with BMI: beta-(std) = 0.08 (95% CI: -0.12, -0.04), P = 3.00 * 10(-5). These differences persisted after adjustment for age, sex, and early life environment. Genetic analysis indicated 1 allele change in BMI allelic score was associated with a 0.04 (95% CI: 0.03, 0.04) SD increase in BMI (P = 6.41 * 10(-17)). At age 7, a genetically determined increase in BMI of 1.89 kg/m(2) was associated with a 0.22 pmol/L (95% CI: 0.07, 0.36) increase in FT3 (P = .004) but no substantial change in FT4 0.01 mmol/L, (95% CI: -0.37, 0.40), P = .96. CONCLUSION: Our analysis shows that children with a genetically higher BMI had higher FT3 but not FT4 levels, indicating that higher BMI/fat mass has a causal role in increasing FT3 levels. This may explain the paradoxical associations observed in observational analyses. Given rising childhood obesity levels, this relationship merits closer scrutiny. PMID- 26595104 TI - Beyond Oblivobesity: Seven Myths About Parental Misperception of Children's Weight. PMID- 26595105 TI - Effects of Unilateral Muscle Fatigue on Performance and Force Coordination in Bimanual Manipulation Tasks. AB - We examined the effects of unilateral muscle fatigue on the performance and coordination of grip (GF; normal component acting between the hand and object) and load force (LF; tangential component) in bimanual manipulation tasks, as well as the associated lateral differences. Eleven participants performed various symmetric bimanual tasks either without fatigue, or after fatiguing the GF producing muscles of either the nondominant or dominant hand. The GF/LF ratio of the fatigued and nonfatigued hand decreased and increased, respectively, while the neither the effects of fatigue on the task performance and GF-LF coordination, nor the lateral differences were revealed. The lack of the fatigue associated effects on most of the tested variables typically observed from unimanual tasks could be explained by bimanual assimilation. The findings also suggest that in daily life switching to bimanual tasks when one hand becomes fatigued could be beneficial regarding preserving the high level of both the manipulation performance and force coordination. PMID- 26595107 TI - Evaluation of the Kinetic Performance Differences between Hydrophilic-Interaction Liquid Chromatography and Reversed-Phase Liquid Chromatography under Conditions of Identical Packing Structure. AB - A protocol using trifluoroacetic acid at a temperature of 60 degrees C is developed for the adequate removal of the stationary phase of reversed-phase liquid chromatography (RPLC) columns. This procedure allows for studying the same column first under RPLC and subsequently under hydrophilic-interaction liquid chromatography (HILIC) conditions to isolate intrinsic differences between mass transfer properties in HILIC and RPLC from differences in packing quality. The established procedure allows for a complete removal of the stationary phase (confirmed by retention studies and thermogravimetry analyses) while leaving the structure of the packing unaffected (witnessed by an unchanged external porosity and pressure drop). Accurate plate height analysis comparing compounds at the same zone retention factor indicates a significant difference in reduced c-term (typically 40-80% larger under HILIC conditions), despite the columns otherwise being identical. Correcting for the known contributions of longitudinal diffusion (b-term) and mass transfer (cm- and cs-term) to focus on band broadening originating from eddy dispersion, similar strong differences are observed (differences of some h = 0.3 up to 1.2). These findings show that the interior structure and retention mechanism of the particles have a very strong effect on the observed eddy dispersion, a factor typically ascribed to phenomena occurring outside the particles. This also implies that comparing the quality of packings of different particle types is virtually impossible without the availability of a sound model to correct for the intraparticle effect on the observed eddy dispersion. PMID- 26595108 TI - Natural antifungal compounds from the peels of Ipomoea batatas Lam. AB - Three antifungal compounds have been isolated for the first time from the peels of Ipomoea batatas Lam. Their structures were established on the basis of 1D and 2D NMR spectra data as well as ESI-MS and IR analysis. Urs-13(18)-ene-3beta-yl acetate was found to possess a weak activity against Sporothrix schenckii and Trichophyton metagrophytes fungi with an MIC value of 50 MUg/mL each. Stigmasterol and 3-friedelanol were equally active against T. metagrophytes. PMID- 26595111 TI - General Surgery Resident Vascular Operative Experience in the Era of Endovascular Surgery and Vascular Fellowships. AB - Advances in endovascular surgery have resulted in a decline in major open arterial reconstructions nationwide. Our objective is to investigate the effect of endovascular surgery on general surgery resident experience with open vascular surgery. Between 2004 and 2014, 112 residents graduated from two academic institutions in Southern California. Residents were separated into those who graduated in 2004 to 2008 (period 1) and in 2009 to 2014 (period 2). Case volumes of vascular procedures were compared using two-sample t test. A total of 43 residents were in period 1 and 59 residents were in period 2. In aggregate, there was no significant difference in open cases recorded between the two periods (84 vs 87, P = 0.194). Subgroup analysis showed period 2 recorded significantly fewer cases of open aneurysm repair (5 vs 3, P < 0.001), cerebrovascular (14 vs 10, P = 0.007), and peripheral obstructive procedures (16 vs 13, P = 0.017). Dialysis access procedures constituted the largest group of procedures and remained similar between the two periods (35 vs 42, P = 0.582). General surgery residents experienced a significant decline in several index open major arterial reconstruction cases. This decline was offset by maintenance of dialysis access procedures. If the trend continues, future general surgeons will not be proficient in open vascular procedures. PMID- 26595112 TI - A Physically Based Theoretical Model of Spore Deposition for Predicting Spread of Plant Diseases. AB - A physically based theory for predicting spore deposition downwind from an area source of inoculum is presented. The modeling framework is based on theories of turbulence dispersion in the atmospheric boundary layer and applies only to spores that escape from plant canopies. A "disease resistance" coefficient is introduced to convert the theoretical spore deposition model into a simple tool for predicting disease spread at the field scale. Results from the model agree well with published measurements of Uromyces phaseoli spore deposition and measurements of wheat leaf rust disease severity. The theoretical model has the advantage over empirical models in that it can be used to assess the influence of source distribution and geometry, spore characteristics, and meteorological conditions on spore deposition and disease spread. The modeling framework is refined to predict the detailed two-dimensional spatial pattern of disease spread from an infection focus. Accounting for the time variations of wind speed and direction in the refined modeling procedure improves predictions, especially near the inoculum source, and enables application of the theoretical modeling framework to field experiment design. PMID- 26595106 TI - Mimicking Ribosomal Unfolding of RNA Pseudoknot in a Protein Channel. AB - Pseudoknots are a fundamental RNA tertiary structure with important roles in regulation of mRNA translation. Molecular force spectroscopic approaches such as optical tweezers can track the pseudoknot's unfolding intermediate states by pulling the RNA chain from both ends, but the kinetic unfolding pathway induced by this method may be different from that in vivo, which occurs during translation and proceeds from the 5' to 3' end. Here we developed a ribosome mimicking, nanopore pulling assay for dissecting the vectorial unfolding mechanism of pseudoknots. The pseudoknot unfolding pathway in the nanopore, either from the 5' to 3' end or in the reverse direction, can be controlled by a DNA leader that is attached to the pseudoknot at the 5' or 3' ends. The different nanopore conductance between DNA and RNA translocation serves as a marker for the position and structure of the unfolding RNA in the pore. With this design, we provided evidence that the pseudoknot unfolding is a two-step, multistate, metal ion-regulated process depending on the pulling direction. Most notably, unfolding in both directions is rate-limited by the unzipping of the first helix domain (first step), which is Helix-1 in the 5' -> 3' direction and Helix-2 in the 3' -> 5' direction, suggesting that the initial unfolding step in either pulling direction needs to overcome an energy barrier contributed by the noncanonical triplex base-pairs and coaxial stacking interactions for the tertiary structure stabilization. These findings provide new insights into RNA vectorial unfolding mechanisms, which play an important role in biological functions including frameshifting. PMID- 26595113 TI - Detection of Goss's Wilt Pathogen Clavibacter michiganensis subsp. nebraskensis in Maize by Loop-Mediated Amplification. AB - The Goss's wilt pathogen, Clavibacter michiganensis subsp. nebraskensis, can cause considerable losses in maize (Zea mays) production. Diagnosis of Goss's wilt currently is based on symptomology and identification of C. michiganensis subsp. nebraskensis, following isolation on a semiselective medium and/or serological testing. In an effort to provide a more efficient identification method, a loop-mediated amplification (LAMP) assay was developed to detect the tripartite ATP-independent periplasmic (TRAP)-type C4-dicarboxylate transport system large permease component and tested using strains of C. michiganensis subsp. nebraskensis, all other C. michiganensis subspecies and several genera of nontarget bacteria. Only strains of C. michiganensis subsp. nebraskensis reacted positively with the LAMP assay. The LAMP assay was then used to identify bacterial isolates from diseased maize. 16S rDNA and dnaA sequence analyses were used to confirm the identity of the maize isolates and validate assay specificity. The Cmm ImmunoStrip assay was included as a presumptive identification test of C. michiganensis subsp. nebraskensis at the species level. The Cmn-LAMP assay was further tested using symptomatic leaf tissue. The Cmn-LAMP assay was run in a hand-held real-time monitoring device (SMART-DART) and performed equally to in-lab quantitative polymerase chain reaction equipment. The Cmn-LAMP assay accurately identified C. michiganensis subsp. nebraskensis and has potential as a field test. The targeted sequence also has potential application in other molecular detection platforms. PMID- 26595114 TI - Highly Stretchable and Ultrasensitive Strain Sensor Based on Reduced Graphene Oxide Microtubes-Elastomer Composite. AB - Strain sensors with excellent flexibility, stretchability, and sensitivity have attracted increasing interests. In this paper, a highly stretchable and ultrasensitive strain sensor based on reduced graphene oxide microtubes-elastomer is fabricated by a template induced assembly and followed a polymer coating process. The sensors can be stretched in excess of 50% of its original length, showing long-term durability and excellent selectivity to a specific strain under various disturbances. The sensitivity of this sensor is as high as 630 of gauge factor under 21.3% applied strain; more importantly, it can be easily modulated to accommodate diverse requirements. Implementation of the device for gauging muscle-induced strain in several biological systems shows reproducibility and different responses in the form of resistance or current change. The developed strain sensors show great application potential in fields of biomechanical systems, communications, and other related areas. PMID- 26595115 TI - Multistate and Multicolor Photochromism through Selective Cycloreversion in Asymmetric Platinum(II) Complexes with Two Different Dithienylethene-Acetylides. AB - Four asymmetric bis(dithienylethene-acetylide) platinum(II) complexes trans Pt(PEt3)2(L1o)(L5o) (1oo), trans-Pt(PEt3)2(L2o)(L5o) (2oo), trans Pt(PEt3)2(L3o)(L5o) (3oo), and trans-Pt(PEt3)2(L4o)(L5o) (4oo) with two different dithienylethene-acetylides (L1o-L5o) were designed to modulate stepwise, multistate, and multicolor photochromism by modifying ring-closure absorption wavelengths. Upon irradiation under UV light, 1oo converts only to 1oc without the observation of 1co and dually ring-closed species 1cc. In contrast, both mixed ring-open/closed species oc and co as well as dually ring-closed species cc are observed upon UV light irradiation of 2oo-4oo, implying that a substantial stepwise photochromic process occurs following 2oo-4oo -> 2oc-4oc/2co-4co -> 2cc 4cc. The conversion percentage of dually ring-closed species at the photostationary state (PSS) is progressively increased following 1cc (0%) -> 2cc (40%) -> 3cc (86%) -> 4cc (>95%), coinciding with the progressive red-shift of ring-closure absorption bands in free L1c (441 nm) -> L2c (510 nm) -> L3c (556 nm) -> L4c (591 nm). Particularly, compound 2 affords four states (2oo, 2co, 2oc, and 2cc) with different colors (colorless, purple, blue, and dark blue, respectively) through a selective photochemical cycloreversion process upon irradiation with appropriate wavelengths of light. Although stepwise photocyclization reactions 3oo -> 3co/3oc -> 3cc and 4oo -> 4co/4oc -> 4cc are observed, multicolor photochromism of 3oo and 4oo could not be achieved because ring-closure absorption bands between L3c/L4c and L5c are significantly overlapped. The stepwise photochemical processes are well demonstrated by NMR, UV vis, and infrared (IR) spectroscopy and time-dependent density functional theory (TD-DFT) computational studies. PMID- 26595116 TI - The Filum Terminale Revisited: A Histological Study in Human Fetuses. AB - Previous studies have suggested that secondary neurulation provides no functional neurons but only the filum terminale. However, no studies have confirmed that the coccygeal and lower sacral nerves do not originate from the secondary neural tube but only from the primary tube. To obtain a better understanding of these relationships, we examined sagittal or frontal sections from 20 embryonic and fetal specimens ranging from 6 to 14 weeks of gestation. During the growth of the vertebral column as well as the subsequent upward migration of the caudal end of the dural sac, the secondary neural tube was stretched to maintain the original attachment to the coccyx or the lower sacral vertebra. The filum-like structure showed much individual variability but in all cases appeared to be derived from the stretched neural tube. Intermediate age morphology revealed that the secondary neural tube itself provided an initial filum terminale before the ascent of the dural sac. Given that the coccygeal and lower sacral nerves are likely to originate from the secondary neural tube, these parts of the tube persisted and differentiated into spinal neurons to form the anococcygeal nerves. Likewise, the filum terminale was also most likely to contain some neurons that persisted postnatally. Depending on the timing and site of degeneration of the secondary neural tube, individual variations could occur in proportion to the amount of sensory and motor elements in the anococcygeal nerve supply. PMID- 26595117 TI - Sexual Dysfunction in Men Receiving Methadone Maintenance Treatment: Clinical History and Psychobiological Correlates. AB - A variety of studies evidenced a relationship between drug use disorders and sexual dysfunction. In particular, heroin and opioid agonist medications to treat heroin dependence have been found to be associated with erectile dysfunction and reduced libido. Controversial findings also indicate the possibility of factors other than the pharmacological effects of opioid drugs concurring to sexual dysfunction. With the present study, we investigated the link between sexual dysfunction and long-term exposure to opioid receptor stimulation (heroin dependence, methadone maintenance treatment, methadone dosage), the potentially related hormonal changes reflecting hypothalamus-pituitary-gonadal axis function and prolactin (PRL) pituitary release, the role of adverse childhood experiences in the clinical history and the concomitant symptoms of comorbid mental health disorders in contributing to sexual problems. Forty male patients participating in a long-term methadone treatment program were included in the present study and compared with 40 healthy control subjects who never used drugs nor abused alcohol. All patients and controls were submitted to the Arizona Sexual Experiences Scale (ASEX), Child Experiences of Care and Abuse-Questionnaire (CECA Q) and the Symptom Check List-90 Scale. A blood sample for testosterone and PRL assays was collected. Methadone dosages were recorded among heroin-dependent patients on maintenance treatment. Methadone patients scored significantly higher than controls on the 5-item rating ASEX scale, on CECA-Q and on Symptoms Check List 90 (SCL 90) scale. Testosterone plasma levels were significantly lower and PRL levels significantly higher in methadone patients with respect to the healthy control group. ASEX scores reflecting sexual dysfunction were directly and significantly correlated with CECA-Q neglect scores and SCL 90 psychiatric symptoms total score. The linear regression model, when applied only to addicted patients, showed that methadone dosages were not significantly correlated with sexual dysfunction scores except for 'erectile dysfunction', for which an inverse association was evidenced. Testosterone values showed a significant inverse correlation with ASEX sexual dysfunction scores, CECA-Q neglect scores and psychiatric symptom at SCL 90 among methadone patients. PRL levels were directly and significantly correlated with sexual dysfunction scores, psychiatric symptoms at SCL 90 and CECA-Q neglect scores. Both testosterone and PRL did not correlate with methadone dosages. The present findings appear to support the view of childhood adversities and comorbid psychiatric symptoms contributing to sexual dysfunction and related hormonal changes among methadone patients, challenging the assumption that attributes sexual problems entirely to the direct pharmacological effects of opioid agonist medications. PMID- 26595118 TI - Fast growth of inch-sized single-crystalline graphene from a controlled single nucleus on Cu-Ni alloys. AB - Wafer-scale single-crystalline graphene monolayers are highly sought after as an ideal platform for electronic and other applications. At present, state-of-the art growth methods based on chemical vapour deposition allow the synthesis of one centimetre-sized single-crystalline graphene domains in ~12 h, by suppressing nucleation events on the growth substrate. Here we demonstrate an efficient strategy for achieving large-area single-crystalline graphene by letting a single nucleus evolve into a monolayer at a fast rate. By locally feeding carbon precursors to a desired position of a substrate composed of an optimized Cu-Ni alloy, we synthesized an ~1.5-inch-large graphene monolayer in 2.5 h. Localized feeding induces the formation of a single nucleus on the entire substrate, and the optimized alloy activates an isothermal segregation mechanism that greatly expedites the growth rate. This approach may also prove effective for the synthesis of wafer-scale single-crystalline monolayers of other two-dimensional materials. PMID- 26595120 TI - Graphene synthesis: On-the-spot growth. PMID- 26595119 TI - A small-molecule dye for NIR-II imaging. AB - Fluorescent imaging of biological systems in the second near-infrared window (NIR II) can probe tissue at centimetre depths and achieve micrometre-scale resolution at depths of millimetres. Unfortunately, all current NIR-II fluorophores are excreted slowly and are largely retained within the reticuloendothelial system, making clinical translation nearly impossible. Here, we report a rapidly excreted NIR-II fluorophore (~90% excreted through the kidneys within 24 h) based on a synthetic 970-Da organic molecule (CH1055). The fluorophore outperformed indocyanine green (ICG)-a clinically approved NIR-I dye-in resolving mouse lymphatic vasculature and sentinel lymphatic mapping near a tumour. High levels of uptake of PEGylated-CH1055 dye were observed in brain tumours in mice, suggesting that the dye was detected at a depth of ~4 mm. The CH1055 dye also allowed targeted molecular imaging of tumours in vivo when conjugated with anti EGFR Affibody. Moreover, a superior tumour-to-background signal ratio allowed precise image-guided tumour-removal surgery. PMID- 26595122 TI - A new active Li-Mn-O compound for high energy density Li-ion batteries. AB - The search for new materials that could improve the energy density of Li-ion batteries is one of today's most challenging issues. Many families of transition metal oxides as well as transition metal polyanionic frameworks have been proposed during the past twenty years. Among them, manganese oxides, such as the LiMn2O4 spinel or the overlithiated oxide Li[Li1/3Mn2/3]O2, have been intensively studied owing to the low toxicity of manganese-based materials and the high redox potential of the Mn(3+)/Mn(4+) couple. In this work, we report on a new electrochemically active compound with the 'Li4Mn2O5' composition, prepared by direct mechanochemical synthesis at room temperature. This rock-salt-type nanostructured material shows a discharge capacity of 355 mAh g(-1), which is the highest yet reported among the known lithium manganese oxide electrode materials. According to the magnetic measurements, this exceptional capacity results from the electrochemical activity of the Mn(3+)/Mn(4+) and O(2-)/O(-) redox couples, and, importantly, of the Mn(4+)/Mn(5+) couple also. PMID- 26595121 TI - A three-dimensional engineered tumour for spatial snapshot analysis of cell metabolism and phenotype in hypoxic gradients. AB - The profound metabolic reprogramming that occurs in cancer cells has been investigated primarily in two-dimensional cell cultures, which fail to recapitulate spatial aspects of cell-to-cell interactions as well as tissue gradients present in three-dimensional tumours. Here, we describe an engineered model to assemble three-dimensional tumours by rolling a scaffold-tumour composite strip. By unrolling the strip, the model can be rapidly disassembled for snapshot analysis, allowing spatial mapping of cell metabolism in concert with cell phenotype. We also show that the establishment of oxygen gradients within samples that are shaped by oxygen-dependent signalling pathways, as well as the consequential variations in cell growth, response to hypoxic gradients extending from normoxia to severe hypoxia, and therapy responsiveness, are consistent with those of tumours in vivo. Moreover, by using liquid chromatography tandem mass spectrometry, we mapped cellular metabolism and identified spatially defined metabolic signatures of cancer cells to reveal both known and novel metabolic responses to hypoxia. PMID- 26595123 TI - Single file diffusion into a semi-infinite tube. AB - We investigate single file diffusion (SFD) of large particles entering a semi infinite tube, such as luminal diffusion of proteins into microtubules or flagella. While single-file effects have no impact on the evolution of particle density, we report significant single-file effects for individually tracked tracer particle motion. Both exact and approximate ordering statistics of particles entering semi-infinite tubes agree well with our stochastic simulations. Considering initially empty semi-infinite tubes, with particles entering at one end starting from an initial time t = 0, tracked particles are initially super-diffusive after entering the system, but asymptotically diffusive at later times. For finite time intervals, the ratio of the net displacement of individual single-file particles to the average displacement of untracked particles is reduced at early times and enhanced at later times. When each particle is numbered, from the first to enter (n = 1) to the most recent (n = N), we find good scaling collapse of this distance ratio for all n. Experimental techniques that track individual particles, or local groups of particles, such as photo-activation or photobleaching of fluorescently tagged proteins, should be able to observe these single-file effects. However, biological phenomena that depend on local concentration, such as flagellar extension or luminal enzymatic activity, should not exhibit single-file effects. PMID- 26595124 TI - An Experimental Study on the Relationship Among Airway Pressure, Pneumoperitoneum Pressure, and Central Venous Pressure in Pure Laparoscopic Hepatectomy. AB - OBJECTIVES: To determine optimal settings for airway pressure (AWP), pneumoperitoneum pressure (PPP), and central venous pressure (CVP) in pure laparoscopic hepatectomy. BACKGROUND: High PPP is often employed to control bleeding from the hepatic vein during pure laparoscopic hepatectomy; however, there is a risk of pulmonary gas embolism. We noted that decreases in AWP were often effective. METHODS: After establishing carbon dioxide pneumoperitoneum in 6 male piglets and maintaining PPP at 25 mmHg, CVP was measured 3 times at each of 9 levels of airway pressure, which was increased in increments of 5 cmH2O from 0 to 40 cmH2O. CVP was measured in the same manner by maintaining PPP at 20, 15, 10, 5, and 0 mmHg, and in laparotomy. Correlation and regression analyses were performed among airway pressure, CVP, and pneumoperitoneum pressure. RESULTS: Positive correlations were observed between AWP and CVP and between PPP and CVP (P < 0.001). Under high airway pressure, CVP was persistently higher than pneumoperitoneum pressure. Under low airway pressure, CVP did not increase or often decreased when PPP was higher than CVP. CONCLUSIONS: By increasing pneumoperitoneum pressure, bleeding from the hepatic vein cannot be controlled under high airway pressure, but can be controlled under low airway pressure. However, under low airway pressure, the risk of pulmonary gas embolism increases when PPP is higher than CVP. We consider that reducing AWP is also effective for controlling bleeding from the hepatic vein and safer than increasing pneumoperitoneum pressure. PMID- 26595126 TI - The Aging of Scientific Material: Datagism. PMID- 26595125 TI - PM2.5 and Diabetes and Hypertension Incidence in the Black Women's Health Study. AB - BACKGROUND: Clinical studies have shown that exposure to fine particulate matter (PM2.5) can increase insulin resistance and blood pressure. The epidemiologic evidence for an association of PM2.5 exposure with the incidence of type 2 diabetes or hypertension is inconsistent. Even a modest association would have great public health importance given the ubiquity of exposure and high prevalence of the conditions. METHODS: We used Cox proportional hazards models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident type 2 diabetes and hypertension associated with exposure to PM2.5 in a large cohort of African American women living in 56 metropolitan areas across the US, using data from the Black Women's Health Study. Pollutant levels were estimated at all residential locations over follow-up with a hybrid model incorporating land use regression and Bayesian Maximum Entropy techniques. RESULTS: During 1995 to 2011, 4,387 cases of diabetes and 9,570 cases of hypertension occurred. In models controlling for age, questionnaire cycle, and metro area, there were positive associations with diabetes (HR = 1.13, 95% CI = 1.04, 1.24) and hypertension (HR = 1.06, 95% CI = 1.00, 1.12) per interquartile range of PM2.5 (2.9 MUg/m). Multivariable HRs, however, were 0.99 (95% CI = 0.90, 1.09) for diabetes and 0.99 (95% CI = 0.93, 1.06) for hypertension. CONCLUSIONS: Our results provide little support for an association of PM2.5 with diabetes or hypertension incidence. PMID- 26595127 TI - Regioselective Copper-Catalyzed Dicarbonylation of Imidazo[1,2-a]pyridines with N,N-Disubstituted Acetamide or Acetone: An Approach to 1,2-Diketones Using Molecular Oxygen. AB - A novel copper-catalyzed regioselective double carbonylation of imidazo[1,2 a]pyridines with N,N-disubstituted acetamide or acetone using molecular oxygen has been described. It has provided a new approach to synthesize 1,2-carbonyl imidazo[1,2-a]pyridines, which are important substrates and intermediates in preparation of fine chemicals. The product shares a skeleton similar to that of Zolpidem, one of the most prescribed drugs in the world. (18)O-labeling experiments unambiguously established that the oxygen source of products originated from O2 rather than H2O. PMID- 26595128 TI - Rating of Perceived Exertion During Circuit Weight Training: A Concurrent Validation Study. AB - The aim of this study was to determine whether rating of perceived exertion (RPE) is a valid method to control the effort during the circuit weight training (CWT) in trained men. Ten men (21.3 +/- 3.3 years) with previous experience in resistance training (13.1 +/- 6.3 months) performed 3 sessions: 1 orientation session and 2 experimental sessions. The subjects were randomly counterbalanced to 2 experimental sessions: CWT or multiple-set resistance training (control). In both sessions, 8 exercises (bench press, leg press 45 degrees , seated row, leg curl, triceps pulley, leg extension, biceps curl, and adductor chair) were performed with the same work: 60% of 1 repetition maximum, 24 stations (3 circuits) or 24 sets (3 sets/exercise), 10 repetitions, 1 second in the concentric and eccentric phases, and rest intervals between sets and exercise of 60 seconds. Active muscle RPEs were measured after each 3 station/sets using the OMNI-Resistance Exercise Scale (OMNI-RES). In this same time, blood lactate was collected. Compared with baseline, both levels of blood lactate and RPE increased during whole workout in both sessions, the RPE at third, 23rd, and 27th minute and the blood lactate at third, seventh, 11th, 15th, 27th, and 31st minute were higher in multiple set compared with CWT. Positive correlation between blood lactate and RPE was observed in both experimental sessions. The results indicated that the RPE is a valid method to control the effort during the CWT in trained men and can be used to manipulate the intensity without the need to perform invasive assessments. PMID- 26595129 TI - The Effect of Altitude and Travel on Rugby Union Performance: Analysis of the 2012 Super Rugby Competition. AB - The aim of this study was to investigate whether playing rugby at altitude or after travel (domestic and international) disadvantaged teams. In a retrospective longitudinal study, all matches (N = 125) played in the 2012 Super Rugby Competition were analyzed for key performance indicators (KPI) from coded game data provided by OPTA sports data company. Matches were played in a home-away format in New Zealand, South Africa, and Australia. Teams based at sea level but playing at altitude (1,271-1,753 m) were more likely to miss tackles (mean +/- 90% confidence interval, 1.4 +/- 1.7) and score fewer points in the first half compared with games at sea level. In the second half of games, sea level teams at altitude were very likely to make fewer gain lines (-4.0 +/- 2.7) compared with the second half of games at sea level. The decreased ability to break the defensive line, which may be the result of altitude-induced fatigue, could reduce the likelihood of scoring points and winning a game. Travel also had an effect on KPI, where international travel resulted in more missed tackles (1.7 +/- 1.3) and less frequent gain lines (-3.0 +/- 1.9) in the first half relative to matches at home; overall, away teams (domestic and international) scored 4 less points in the second half compared with home teams. In conclusion, playing away from home in another country, particularly at altitude, can have a detrimental effect on KPI, which may affect the overall performance and the chances of winning matches. PMID- 26595130 TI - Physiological and Technical Demands of No Dribble Game Drill in Young Basketball Players. AB - This study assessed the physiological and technical demands of no dribble game drill (NDGD) in comparison with a regular drill (RD). Twenty-three young basketball players performed RDs and NDGDs in a random order. All basketball rules were followed for RDs, whereas dribbling was not permitted for NDGDs. The independent variable was the drill condition, and the dependent variables were percentage of maximal heart rate (%HRmax), rate of perceived exertion (RPE), Edwards training load (TL), and the following technical actions (TAs): pass (total, correct, wrong, and percent of correct passes), shot (total, scored, missed, and percent of made shots), interception, steal, turnover, and rebound. Wilcoxon signed-rank tests were applied to assess differences between NDGD and RD conditions for each dependent variable, and the level of statistical significance was set at p <= 0.05. Results showed higher values for %HRmax (p = 0.007), Edwards TL (p = 0.006), and RPE (p = 0.027) in NDGD compared with RD condition. Technical action analysis revealed higher values in NDGD than RD for total (p = 0.000), correct (p = 0.000), and wrong pass (p = 0.005), and interception (p = 0.001), whereas no significant differences were found for the other TAs. The main finding of this study was that NDGD condition elicited a greater physiological demand and a higher number of passes and interceptions than the RD one. Basketball coaches should consider the NDGD as a viable method to increase the physiological load of their training sessions and to teach passing skills in a game-based situation. PMID- 26595131 TI - Testosterone Concentration and Lower Limb Power Over an Entire Competitive Season in Elite Young Soccer Players. AB - The aim of this study was to investigate salivary T changes and its relationship with power performance over a 1-year competitive season in elite under 15 (U15) and under 17 (U17) soccer players. Soccer players were recruited from 1 soccer club that has been participated in the main state and national leagues for these age groups. The soccer players were divided into 2 age categories (U15, n = 16 and U17, n = 23). A resting saliva sample was taken to determine T level, and power was assessed using the countermovement jump test with a bar of 30% of body mass on the athletes' shoulders on 3 occasions (T1: beginning of the competitive season, T2: end of the regular season, and T3: end of the playoffs). There was a decrease in T concentration at the end of the competitive season (T3) as compared with the beginning of the season (T1) for both age categories (p <= 0.05). Conversely, power performance parameters were increased for both age groups (U15: mean power and relative mean power and U17: peak power, mean power, relative peak power, and relative mean power; p <= 0.05). No significant correlation was identified between the relative changes in T concentration and power performance in both groups. The findings of this study suggest that T changes and power changes are not related. PMID- 26595132 TI - Physical Demands in Competitive Ultimate Frisbee. AB - The objective was to study game demands in competitive ultimate Frisbee by performing match analysis during a game. Thirteen moderately trained (Yo-Yo intermittent recovery test levels 1 and 2 [Yo-Yo IR1 and IR2] performance: 1790 +/- 382 m and 657 +/- 225 m, respectively) competitive male ultimate Frisbee athletes played a game in which activity profile using Global Positioning System (GPS) technology and heart rate (HR) were recorded. Game HRmean and HRpeak were 82 +/- 2% and 99 +/- 1% of maximum heart rate, respectively. Total game distance was 4.70 +/- 0.47 km, of which 0.63 +/- 0.14 km was high-intensity running and 0.21 +/- 0.11 km was sprinting. In the second half, 10% less (p <= 0.05) ground was covered with high-intensity running compared with the first half (0.28 +/- 0.08 km vs. 0.31 +/- 0.07 km). Less (43-47%; p <= 0.05) high-intensity running was performed in the third 9-minute period of each half compared with the first two 9-minute periods of the same half. Players performed 17.4 +/- 5.7 sprints during the match. Yo-Yo IR2 performance correlated to the amount of high intensity running in the last 9 minutes of both halves (r = 0.69, p <= 0.05), whereas Yo-Yo IR1 performance correlated with total sprint distance (r = 0.74, p <= 0.05). Ultimate Frisbee is an intense intermittent team sport with high cardiovascular loading and clear indications of fatigue toward the end of each half. Yo-Yo IR test performances correlate with physical match performance. PMID- 26595133 TI - Kinematics and Kinetics of Multiple Sets Using Lifting Straps During Deadlift Training. AB - The deadlift is a fundamental exercise used in the development of whole body strength and a common element in resistance training programs for all levels. However, many practitioners report the fatigue of forearm muscles and possibly a lack of grip strength as obstacles to exercise performance, which may lead to the use of ergogenic aids, such as lifting straps. The objective of this study was to evaluate kinematic variables during the execution of multiple sets of deadlift with (WS) and without (NS) lifting straps. Eleven subjects (25 +/- 3.3 years) with an average of 4 +/- 2.6 years of resistance training experience were enrolled in the study. After the 1 repetition maximum (1RM) test WS and NS, subjects performed separate trials of 3 sets to failure at 90% of 1RM in a counterbalanced fashion. With straps resulted in lower speed (0 to -25%) (-3 to 10%) and greater force (20-28%) and duration (concentric phase: 0-13%) when compared with NS. Therefore, it is concluded that the use of straps directly influences exercise performance that requires manual grip strength, increasing the amount of work performed by the target muscles. PMID- 26595134 TI - Application of Session Rating of Perceived Exertion Among Different Models of Resistance Training in Older Adults. AB - The aim of this study was to assess the relationship between external measures of resistance training (RT) workload and intensity, volume load (VL) and training intensity (TI), and related internal measures, session load and session rating of perceived exertion (sRPE), across a chronic RT intervention and between different models of RT in older adults. Forty-one healthy, untrained older adults (female, 21; male, 20; age, 70.9 +/- 5.1 years; height, 166.3 +/- 8.2 cm; weight, 72.9 +/- 13.4 kg) were randomly stratified into 3 RT groups: nonperiodized (NP), block periodized (BP), or daily undulating periodized (DUP). They completed a 22-week RT intervention at a frequency of 3 d.wk. All training was executed on RT machines, and training volume was equalized between training groups based on total repetitions. Session RPE was measured 10-15 minutes after each training session. There were no meaningful relationships between VL and session load or TI and sRPE. Also, no significant differences were detected between training groups for mean sRPE across the training intervention. Based on these results, session load and sRPE do not appear to be valid markers of RT workload and intensity when compared with established external measures in healthy untrained older adults. However, sRPE and session load may hold promise as monitoring tools in RT that do not involve training to muscular failure. Furthermore, sRPE does not significantly differ between NP, BP, and DUP RT models, highlighting that this measure is not sensitive to such periodization as evident in the present study. PMID- 26595135 TI - Impact of Four Weeks of a Multi-Ingredient Performance Supplement on Muscular Strength, Body Composition, and Anabolic Hormones in Resistance-Trained Young Men. AB - Although multi-ingredient performance supplements (MIPS) have increased in popularity because of their array of ergogenic ingredients, their efficacy and safety remain in question. The objective of this study was to determine the impact of supplementation with T+ (SUP; Onnit Labs, Austin, TX, USA), an MIPS containing long jack root, beta-alanine, and branched-chain amino acids, and other proprietary blends, on strength, body composition, and hormones in young resistance-trained men. Subjects were randomized to consume either T+ (SUP; n = 14; age, 21 +/- 3 years; body fat, 18.3 +/- 4.7%) or an isocaloric placebo (PL; n = 13; age, 21 +/- 3 years; body fat, 21.5 +/- 6.2%) for 4 weeks. Both groups underwent a progressive, 4-week high-intensity resistance training protocol. Before and after the training protocol, mood state, body composition, blood hormones (also collected at midpoint), and maximal strength were measured. SUP had significantly greater increases in bench press (SUP, 102 +/- 16 kg to 108 +/- 16 kg vs. PL, 96 +/- 22 kg to 101 +/- 22 kg; p < 0.001) and total weight lifted (SUP, 379 +/- 59 kg to 413 +/- 60 kg vs. PL, 376 +/- 70 kg to 400 +/- 75 kg; p < 0.001) compared with PL. Additionally, deadlift strength relative to total body mass (calculated as weight lifted/body mass; kg:kg) (2.08 +/- 0.18 to 2.23 +/- 0.16; p = 0.036) and lean mass (2.55 +/- 0.19 to 2.72 +/- 0.16; p = 0.021) increased significantly in SUP but not PL (2.02 +/- 0.30 to 2.15 +/- 0.36 and 2.56 +/- 0.31 to 2.70 +/- 0.36, respectively). No other significant differences were detected between groups for the remaining variables. Supplementing with SUP enhanced resistance training adaptations independent of hormonal status, and thus SUP use may warrant inclusion into peri-workout nutrition regimens. This study was registered with clinicaltrials.gov (identifier: NCT01971723). PMID- 26595136 TI - Variants of the Solute Carrier SLC16A1 Gene (MCT1) Associated With Metabolic Responses During a Long-Graded Test in Road Cyclists. AB - Variants of the solute carrier SLC16A1 gene have been associated with alterations in MCT1 expression, because of a lactate (La) transport deficiency across the cell membrane and a blood La accumulation. The aim of this study was to associate the allelic and genotypic frequencies of 1470T>A, 2917(1414) C>T, and IVS3-17A>C variants relative to the blood La kinetics and metabolic responses to a progressive effort until exhaustion. Twenty-five well-trained road cyclists performed a long-graded laboratory test: 10 minutes at 2.0 W.kg, first step at 2.5 W.kg with increments of 0.5 W.kg every 10 minutes until exhaustion. Blood La, nonesterified fatty acids (NEFAS), and glucose levels were measured; fat and carbohydrate oxidation rates were estimated through stoichiometric equations. Three variants of SLC16A1 gene were determined for each subject, which were divided in two groups: wt (wild type)/mt (mutated type) and mt/mt genotype group versus wt/wt genotype group. Metabolic responses were compared between both groups with an unpaired Student's t-test; Friedman and Wilcoxon tests were performed for nonparametric data. The statistical significance was set at p <= 0.05. For 1470TA polymorphism, no significant blood La differences were found between groups. 2197(1414)C>T allele carriers and IVS3-17A>C carriers showed significantly higher blood La levels, lower blood NEFAS, and glucose levels at submaximal intensities. These findings open a new perspective to investigate SLC16A1 variants (1470TA and IVS3-17A>C) on La deficiency transport and its regulation/interaction with other metabolic pathways. Future studies would be needed to clarify whether 1470T>A, 2917(1414)C>T, and IVS3-17A>C allelic/genotypic distribution benefit performance in endurance athletes. PMID- 26595137 TI - Current Scientific Evidence for a Polarized Cardiovascular Endurance Training Model. AB - Recent publications have provided new scientific evidence for a modern aerobic or cardiovascular endurance exercise prescription that optimizes the periodization cycle and maximizes potential endurance performance gains in highly trained individuals. The traditional threshold, high volume, and high-intensity training models have displayed limited improvement in actual race pace in (highly) trained individuals while frequently resulting in overreaching or overtraining (physical injury and psychological burnout). A review of evidence for replacing these models with the proven polarized training model seems warranted. This review provides a short history of the training models, summarizes 5 key studies, and provides example training programs for both the pre- and in-season periods. A polarized training program is characterized by an undulating nonlinear periodization model with nearly all the training time spent at a "light" (<=13) and "very hard" (>=17) pace with very limited time at "hard" (14-16) or race pace (6-20 Rating of Perceived Exertion [RPE] scale). To accomplish this, the polarization training model has specific high-intensity workouts separated by one or more long slow distance workouts, with the exercise intensity remaining below ventilatory threshold (VT) 1 and/or blood lactate of less than 2 mM (A.K.A. below race pace). Effect sizes for increasing aerobic endurance performance for the polarized training model are consistently superior to that of the threshold training model. Performing a polarized training program may be best accomplished by: going easy on long slow distance workouts, avoiding "race pace" and getting after it during interval workouts. PMID- 26595138 TI - The Astronaut-Athlete: Optimizing Human Performance in Space. AB - It is well known that long-duration spaceflight results in deconditioning of neuromuscular and cardiovascular systems, leading to a decline in physical fitness. On reloading in gravitational environments, reduced fitness (e.g., aerobic capacity, muscular strength, and endurance) could impair human performance, mission success, and crew safety. The level of fitness necessary for the performance of routine and off-nominal terrestrial mission tasks remains an unanswered and pressing question for scientists and flight physicians. To mitigate fitness loss during spaceflight, resistance and aerobic exercise are the most effective countermeasure available to astronauts. Currently, 2.5 h.d, 6-7 d.wk is allotted in crew schedules for exercise to be performed on highly specialized hardware on the International Space Station (ISS). Exercise hardware provides up to 273 kg of loading capability for resistance exercise, treadmill speeds between 0.44 and 5.5 m.s, and cycle workloads from 0 and 350 W. Compared to ISS missions, future missions beyond low earth orbit will likely be accomplished with less vehicle volume and power allocated for exercise hardware. Concomitant factors, such as diet and age, will also affect the physiologic responses to exercise training (e.g., anabolic resistance) in the space environment. Research into the potential optimization of exercise countermeasures through use of dietary supplementation, and pharmaceuticals may assist in reducing physiological deconditioning during long-duration spaceflight and have the potential to enhance performance of occupationally related astronaut tasks (e.g., extravehicular activity, habitat construction, equipment repairs, planetary exploration, and emergency response). PMID- 26595139 TI - Worldwide interethnic variability and geographical distribution of CYP2C9 genotypes and phenotypes. AB - INTRODUCTION: Notably differences in CYP2C9 allele frequencies among worldwide populations have been reported, with an interesting low frequency of the CYP2C9*2 allele in Amerindians compared with Admixed and European populations. AREAS COVERED: Literature was searched using the PubMed database and was focused on worldwide original research papers on CYP2C9 alleles and CYP2C9 phenotypes ("predicted" from CYP2C9 genotypes and "measured" metabolic phenotype with a probe drug) among healthy volunteers according to their ethnicity and geographical distribution. Seventy-eight original research articles including a total of 31,978 subjects were identified. EXPERT OPINION: CYP2C9*2 allele is the most frequent in Caucasian populations (average 14%), with the lowest frequencies for Africans (0.46%), East Asians (0.56%) and Native Americans (1.25%), which is in agreement with the hypothesis about the low prevalence in Amerindians. CYP2C9*3 shows the highest frequency among South Asians (11.7%), while CYP2C9*5 (1.56%) and *8 (4.70%) in African Americans. The predicted poor metabolizers (gPMs) were found overall in a low frequency, with the highest frequency detected for South Asians, in accordance with the CYP2C9*3 frequency in these populations. This study shows the worldwide variability in the CYP2C9 allele frequencies across different ethnic and geographic groups. Data about CYP2C9 "measured" metabolic phenotypes is still limited. PMID- 26595140 TI - Self-Medication of Somatic and Psychiatric Conditions Using Botanical Marijuana. AB - As a complement to research evaluating botanical marijuana as a medical therapy for various somatic and psychiatric conditions, there is a growing body of research assessing marijuana users' self-reports of the symptoms and conditions for which they use marijuana without a physician's recommendation. As part of two larger web-based surveys and one in-situ survey at an outdoor marijuana festival, we asked regular marijuana users if they consumed the drug without a physician's recommendation and, if so, to describe (or select from a checklist) the conditions for which they used marijuana as a medication. Participants reported using marijuana to self-medicate a wide variety of both somatic conditions (such as pain, diabetes, and irritable bowel syndrome) and psychiatric conditions (such as depression, anxiety, and insomnia). Because fewer than half of the American states, and only a few countries, allow physicians to recommend medicinal marijuana, these findings may be of interest to clinicians as they treat patients, to lawmakers and policymakers as they consider legislation allowing physicians to recommend botanical marijuana for somatic and psychiatric conditions, and to researchers evaluating conditions that individuals elect to self-medicate using botanical marijuana. PMID- 26595141 TI - Evidence of motor-control difficulties in children with attention deficit hyperactivity disorder, explored through a hierarchical motor-systems perspective. AB - INTRODUCTION: Attention deficit hyperactivity disorder (ADHD) may reflect a disorder of neural systems that regulate motor control. The current study investigates motor dysfunction in children with ADHD using a hierarchical motor systems perspective where frontal-striatal/"medial" brain systems are viewed as regulating parietal/"lateral" brain systems in a top down manner, to inhibit automatic environmentally driven responses in favor of goal-directed behavior. It was hypothesized that due to frontal-striatal hypoactivation, children with ADHD would have difficulty with higher order motor control tasks felt to be dependent on these systems, yet have preserved general motor function. METHOD: A total of 63 children-ADHD and matched controls-completed experimental motor tasks that required maintenance of internal motor representations and the ability to inhibit visually driven responses. Children also completed a measure of motor inhibition, and a portion of the sample completed general motor function tasks. RESULTS: On motor tasks that required them to maintain internal motor representations and to inhibit automatic motor responses, children with ADHD had significantly greater difficulty than controls, yet on measures of general motor dexterity, their performance was comparable. Children with ADHD displayed significantly greater intraindividual (subject) variability than controls. Intraindividual variability (IIV) contributed to variations in performance across the motor tasks, but did not account for all of the variance on all tasks. CONCLUSIONS: These findings suggest that children with ADHD may be more controlled by external stimuli than by internally represented information, possibly due to dysfunction of the medial motor system. However, it is likely that children with ADHD also display general motor-execution problems (as evidenced by IIV findings), suggesting that atypicalities may extend to both medial and lateral motor systems. Findings are interpreted within the context of contemporary theories regarding motor dysfunction in ADHD, and implications for understanding externalizing behaviors in ADHD are discussed. PMID- 26595142 TI - Clinical Q & A: Translating Therapeutic Temperature Management from Theory to Practice. PMID- 26595143 TI - Does Time of Delivery Influence the Risk of Neonatal Morbidity? AB - OBJECTIVE: To examine whether time of delivery influences the risk of neonatal morbidity among women with singleton pregnancies. STUDY DESIGN: Secondary analysis of data from the Maternal Fetal Medicine Units Network Factor V Leiden Mutation study. We categorized time of delivery as day (07:00-16:59), evening (17:00-23:59), and overnight (midnight-06:59). Severe neonatal morbidity was defined by at least one of the following: respiratory distress syndrome, transient tachypnea of the newborn, sepsis, seizures, neonatal intensive care admission, or a 5-minute APGAR <=3. We calculated frequencies of severe neonatal morbidity by time of delivery. Multivariate analysis was performed to determine whether time of delivery was independently associated with severe neonatal morbidity. RESULTS: Among 4,087 women, 1,917 (46.9%) delivered during the day, 1,140 (27.9%) delivered in the evening, and 1,030 (25.2%) delivered overnight. We observed no significant differences in the rates of neonatal morbidity between delivery time periods (day: 12.3%; evening: 12.8%; overnight: 12.6%; p = 0.9). No significant association was observed between time of delivery and neonatal morbidity after adjustment for maternal, obstetric, and peripartum factors. CONCLUSION: Our findings suggest that time of delivery is not associated with severe neonatal morbidity. PMID- 26595144 TI - Chemogenomic analysis of neuronal differentiation with pathway changes in PC12 cells. AB - The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database creates networks from interrelations between molecular biology and underlying chemical elements. This allows for analysis of biologic networks, genomic information, and higher-order functional information at a system level. Through high throughput experiments and system biology analysis, we investigated the genes and pathways associated with NGF induced neuronal differentiation. We performed microarray experiments and used the KEGG database, system biology analysis, and annotation of pathway functions to study NGF-induced differentiation in PC12 cells. We identified 2020 NGF-induced genes with altered expressions over time. Cross matching with the KEGG database revealed 830 genes; among which, 395 altered genes were found to have a 2-fold increase in gene expression over a two-hour period. We then identified 191 associated biologic pathways in the KEGG database; the top 15 pathways showed correlation with neural differentiation. These included the neurotrophin pathways, mitogen-activated protein kinase (MAPK) pathways, genes associated with axonal guidance and the Wnt pathways. The activation of these pathways synchronized with nerve growth factor (NGF)-induced differentiation in PC12 cells. In summary, we have established a model system that allows one to systematically characterize the functional pathway changes in a group of neuronal population after an external stimulus. PMID- 26595145 TI - Desorption Kinetics of Ar, Kr, Xe, N2, O2, CO, Methane, Ethane, and Propane from Graphene and Amorphous Solid Water Surfaces. AB - The desorption kinetics for Ar, Kr, Xe, N2, O2, CO, methane, ethane, and propane from graphene-covered Pt(111) and amorphous solid water (ASW) surfaces are investigated using temperature-programmed desorption (TPD). The TPD spectra for all of the adsorbates from graphene have well-resolved first, second, third, and multilayer desorption peaks. The alignment of the leading edges is consistent the zero-order desorption for all of the adsorbates. An Arrhenius analysis is used to obtain desorption energies and prefactors for desorption from graphene for all of the adsorbates. In contrast, the leading desorption edges for the adsorbates from ASW do not align (for coverages < 2 ML). The nonalignment of TPD leading edges suggests that there are multiple desorption binding sites on the ASW surface. Inversion analysis is used to obtain the coverage dependent desorption energies and prefactors for desorption from ASW for all of the adsorbates. PMID- 26595146 TI - Behavioral Problems and Service Utilization in Children with Chronic Illnesses Referred for Trauma-Related Mental Health Services. AB - OBJECTIVE: Given its prevalence and impact on health and well-being, children's exposure to traumatic experiences is of growing importance to pediatricians and other medical providers. Little is known, however, about the traumatic experiences profiles, trauma-related sequelae, and service use patterns of youth with chronic or recurrent medical problems/disabilities. This study aimed to fill this research gap. METHOD: Participants were children less than 18 years of age who were referred for assessment and/or treatment services at one of the 56 National Child Traumatic Stress Network centers from 2004 to 2010 across the United States and had experienced at least one of 13 types of traumatic experience(s) (n = 9885; mean = 11 years, SD = 4.3; 52.3% girls). Generalized linear mixed models were used to examine associations among types of trauma, emotional and behavioral problems, and rates of service utilization adjusting for treatment center-level random effects, demographic characteristics, and the total number of types of trauma exposures. RESULTS: Among children seeking treatment for traumatic stress, those with comorbid medical problems/disabilities had different demographic characteristics, different types of trauma exposure, and more service utilization in multiple sectors before trauma treatment entry than those without comorbid medical problems/disabilities. Those without comorbid medical problems/disabilities had higher levels of some types of traumatic exposures, associated symptoms, and higher levels of behavioral problems at home, school, or day care. Those with medical disorders/disabilities were at 30% to 40% higher odds of meeting clinical criteria for hyperarousal and re-experiencing posttraumatic stress disorder symptoms, used more medical and mental health services for trauma, and had more emotional and behavioral concerns. CONCLUSION: Given that pediatricians are more likely to see children with medical disabilities and concerns than those without, there is an opportunity to ask directly about traumatic exposures and associated symptoms and provide support and interventions to promote resilience. Integrating trauma screening and mental health services into medical care could be especially beneficial for children with chronic medical conditions. PMID- 26595147 TI - Caregiver Preferences for the Treatment of Males with Fragile X Syndrome. AB - OBJECTIVE: Fragile X syndrome (FXS) is the most common inherited form of intellectual disability. The objective of this study was to determine the relative importance that caregivers place on improving different phenotypic traits observed in males with FXS to better understand the greatest medical needs for developing and evaluating FXS treatments. METHOD: Fragile X syndrome caregivers (n = 614) compared hypothetical treatments in a discrete-choice experiment. The treatments varied in their effects on 6 outcomes associated with FXS: learning and applying new skills, explaining needs, controlling behavior, taking part in new social activities, caring for oneself, and paying attention. The relative importance was calculated for improving severe or moderate levels of disability and transformed to a 10-point scale. Relative importance was also quantified by patient age group (child, adolescent, and adult). RESULTS: Most important to caregivers were controlling behavior (10.0) and caring for oneself (9.9). Least important was taking part in new social activities (4.2). A partial improvement in controlling behavior or self-care was more important than full resolution of the least important disabilities. This was consistent across age groups. Improvements from severe to moderate disability were more important than from moderate to no disability. CONCLUSION: Caregivers expressed strong preferences for improvement in self-care and behavioral control, independent of the age of the individual with FXS. These data may be helpful when designing studies to test the efficacy of FXS treatments because small treatment effects on very important outcomes may be valued more than large treatment effects on less valued outcomes. PMID- 26595148 TI - CHOROIDAL MORPHOLOGY IN A PATIENT WITH HELLP SYNDROME. AB - PURPOSE: We report here, the morphological characteristics of the retina and choroid in a patient with hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome, who was not aware of her pregnancy before visiting our hospital. METHODS: Case report. RESULTS: The patient complained of visual disturbances in both eyes for a few days. Extensive serous retinal detachment and hyperreflective foci were observed in both eyes on spectral domain optical coherence tomography (SDOCT). Enhanced depth imaging technique using SDOCT revealed choroidal thickening and unclear choroidal vessel contour. Her blood pressure was 230/168 mmHg. Laboratory data showed hemolysis and liver dysfunction. Obstetrical examination disclosed her pregnancy. She was diagnosed as having HELLP syndrome. Because her general condition improved after prompt Cesarean delivery, the fundus lesions were rapidly resolved with choroidal thinning. CONCLUSION: The eyes in a patient with HELLP syndrome showed characteristic choroidal morphology. The choroidal morphology shown with SDOCT might be one of the pathognomonic signs for a diagnosis of HELLP syndrome. PMID- 26595149 TI - Diagnostic Performance of a New Rapid Lateral Flow Immunoassay in Patients Suspected of Heparin-Induced Thrombocytopenia and Its Clinical Consequences. AB - We prospectively evaluated the diagnostic accuracy of a new rapid assay (STic Expert HIT) alone or in combination with a clinical score in 90 HIT-suspected patients. The 4Ts score was calculated, and ELISA and serotonin-release assay (SRA) were performed; the average time taken for test results were 2 and 5 days for ELISA and SRA, respectively. The STic test was performed in our laboratory as an evaluation exercise and the result was available in 1 hour, but results were not communicated to the clinicians so as to not influence management. Diagnostic performance of STic test was assessed, alone and in combination with 4Ts score. HIT was diagnosed in 19 patients. The sensitivity, specificity, and positive and negative predictive values for the STic test alone were 95%, 92%, 75%, and 98%, respectively, with an accuracy of 92%. The likelihood ratio for positive and negative results with the STic test was 11.2 and 0.06. The combination of the 4Ts score and the STic test results had a negative predictive value of 100% and a negative likelihood ratio of 0. The favorable performance of the STic test may allow for the rapid exclusion of HIT in combination with a low to intermediate pretest clinical probability. During the subsequent year, using the STic test in real time to rapidly exclude the diagnosis, we observed a 50% reduction in danaparoid administration in HIT-suspected patients. PMID- 26595150 TI - Comprehensive Assessment of the Hemostatic System in Polycystic Ovarian Syndrome. AB - Polycystic ovarian syndrome (PCOS) affects 12 to 19% of women and has reproductive and metabolic features (endothelial dysfunction, increased diabetes, and cardiovascular risk factors). It also appears to have altered coagulation and fibrinolysis with a prothrombotic state with epidemiological evidence of increased venous thromboembolism. We aimed to comprehensively assess hemostasis in women with PCOS versus control women. In an established case-control cohort of lean, overweight, and obese women with (n = 107) and without PCOS (n = 67), with existing measures of plasminogen activator inhibitor 1 (PAI-1), asymmetric dimethylarginine (ADMA), hormonal, and metabolic markers, we also assessed prothrombin fragments 1 and 2 (PF1 & 2), plasminogen, tissue plasminogen activator (tPA), and thrombin generation (TG). Higher levels of ADMA (0.70 vs. 0.39 umol/L, p < 0.01), PAI-1 (4.80 vs. 3.66 U/mL, p < 0.01), and plasminogen (118.39 vs. 108.46%, p < 0.01) were seen in PCOS versus controls, and persisted after adjustment for age and body mass index (BMI). PF1 & 2 was marginally lower (180.0 vs. 236.0 pmol/L, p = 0.05), whereas tPA and TG were not different between groups, after adjustment for age and BMI. Significant relationships were observed between hormonal and metabolic factors with ADMA and PAI-1. We demonstrate impaired fibrinolysis in PCOS. In the context of abnormal endothelial function and known hormonal and metabolic abnormalities, this finding may underpin an increased risk of cardiovascular disease and venous thrombosis in PCOS. PMID- 26595151 TI - Cancers in Patients with von Willebrand Disease: A Survey from the Italian Association of Haemophilia Centres. AB - Besides its essential role in hemostasis, there is growing evidence that von Willebrand factor (VWF) has an additional antitumor effect. To elucidate the clinical significance of this biological activity we conducted a retrospective study on cancers among Italian patients with von Willebrand disease (VWD) on behalf of the Italian Association of Haemophilia Centres (AICE). A questionnaire to collect demographic, clinical, and treatment data of VWD patients with cancer was sent to all the 54 Italian Haemophilia Treatment Centres (HTCs) members of AICE. Overall, 18 HTCs (33%) provided information on 92 VWD patients (61 alive and 31 deceased) with 106 cancers collected during the period 1981 to 2014. Of them, 19 (18%) were hematological cancers and 87 (82%) were solid cancers. A total of 61% of patients had type 1, 36% type 2 (12% type 2A, 14% type 2B, 9% type 2M, and 1% type 2N), and 3% type 3 VWD: this distribution was significantly different from that observed in the whole VWD population (79% type 1, 16% type 2 [8% type 2A, 4% type 2B, 2% type 2M, 2% type 2N], and 5% type 3; type 2 vs. non type 2: p < 0.001). Overall, VWD patients with cancer underwent 52 invasive and 72 surgical procedures, were treated with VWF/factor VIII (FVIII) concentrates in 77 cases, with desmopressin (DDAVP) alone in 24 cases and with DDAVP and VWF/FVIII concentrates in 7 cases. Hemorrhagic complications were observed only rarely (2% of invasive procedures and radiotherapy and 6% of surgical interventions). The data collected by this survey document that a substantial number of cancers are recorded among VWD patients and that these patients are safely managed by HTC physicians through a multidisciplinary approach. PMID- 26595152 TI - Correlation between ABO Blood Group, and Conventional Hematological and Metabolic Parameters in Blood Donors. AB - BACKGROUND: Although several studies have investigated and confirmed the existence of an association between ABO blood type and several human disorders, especially with cardiovascular disease, little is known on the physiological influence or association of ABO blood groups on basal levels of some conventional hematological and metabolic parameters. STUDY DESIGN AND METHODS: A total number of 7,723 consecutive healthy blood donors underwent laboratory testing at the time of their first blood donation, which apart from ABO typing included assessment of alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, total bilirubin, total cholesterol, high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), triglycerides, creatinine, iron, ferritin, uric acid, glucose, hemoglobin, and platelet count. RESULTS: The most relevant finding was the identification of significantly higher values of total cholesterol and HDL-c in subjects with blood group A compared with those with O blood type, with the highest levels being observed in A1 subtype. CONCLUSIONS: The positive association between A blood type and plasma lipid levels supports its potential role in the pathogenesis of atherosclerosis and the clinical observations of increased vulnerability to cardiovascular disease of individuals with non-O blood groups. PMID- 26595153 TI - Thrombin Generation Assay as a Laboratory Monitoring Tool during Bypassing Therapy in Patients with Hemophilia and Inhibitors. AB - Hemophilia treatment relies upon replacement of the deficient factor to restore physiological levels in plasma. The development of inhibitors is the main complication of replacement therapy, which renders replacement therapy ineffective and requires the use of alternative hemostatic drugs known as bypassing agents. The hemostatic response to bypassing agents is different from patient to patient and even in the same patient during different bleeding episodes. Up to now, no routine laboratory test has been found suitable to monitor efficacy and safety of these drugs. The unpredictable clinical response to bypassing therapy and the lack of a monitoring laboratory tool renders surgery in inhibitor patients a big challenge for the risk of both bleeding and thromboembolic complications. The thrombin generation assay (TGA) has been proposed as a monitoring tool in this patient population on the basis of the results obtained both in vitro and ex vivo. This review aims to summarize the current published evidence on the use of TGA as a laboratory monitoring tool in patients with hemophilia complicated by inhibitors. PMID- 26595154 TI - Keeping von Willebrand Factor under Control: Alternatives for ADAMTS13. AB - Von Willebrand factor (VWF) is one of the most important proteins of the hemostatic system. Its multimeric state is essential for its natural function to guide platelets to sites of injury. ADAMTS13 is the key protease that regulates the multimeric state of VWF. Without ADAMTS13, VWF multimers can grow to pathologically large sizes. This is a risk factor for the life-threatening condition thrombotic thrombocytopenic purpura (TTP). In this condition, VWF-rich thrombi occlude the microvasculature of various tissues. Intriguingly, a complete ADAMTS13 deficiency does not cause continuous TTP, either in patients or genetically targeted mice. Instead, TTP occurs in episodes of disease, separated by extended periods of remission. This indicates that regulating factors beyond ADAMTS13 are likely involved in this pathologic cascade of events. This raises the question of what really happens when ADAMTS13 is (temporarily) unavailable. In this review, we explore the possible role of complementary mechanisms that are capable of modifying the thrombogenic potential of VWF. PMID- 26595155 TI - Can Transportation Emission Reductions Be Achieved Autonomously? PMID- 26595156 TI - The role of endoscopy in inflammatory bowel disease. AB - Inflammatory bowel disease (IBD) is a group of chronic immune-mediated disorders of the gastrointestinal tract. It is often the result of the interaction of genetic and environmental factors. The role of endoscopy in disease surveillance is unprecedented. However, there is considerable debate in therapeutic goals in IBD patients, ranging from the resolution of clinical symptoms to mucosal healing. Furthermore, deep remission has recently been advocated for altering disease course in these patients. Additionally, neoplasia continues to be a significant cause of morbidity and mortality in IBD patients. This review discussed the role of several endoscopic techniques in assessing mucosal healing and neoplasia with emphasis on novel non-invasive endoscopic techniques. PMID- 26595157 TI - Comparison of systemic therapies used concurrently with radiation for the treatment of human papillomavirus-associated oropharyngeal cancer. AB - BACKGROUND: This was a retrospective study of patients with human papillomavirus (HPV)-associated oropharyngeal cancer treated with concurrent systemic therapy and radiation. METHODS: Data were extracted through chart review, and statistical analyses included frequency tabulation, chi-square, and Kaplan-Meier tests. RESULTS: Three hundred thirty-nine patients were analyzed; 166 received neoadjuvant chemotherapy. One hundred thirty-six patients were treated with cisplatin, 123 with cetuximab, and 59 with carboplatin. The 2-, 3-, and 5-year actuarial overall survival rates were 92%, 88%, and 78%, respectively. There were no significant differences in survival or disease control when analyzed by systemic agent. Platin-treated patients had greater hematologic toxicity, and required more intravenous hydration. The incidence of confluent mucositis was highest among patients treated with cetuximab. CONCLUSION: Platin and cetuximab seem to have similar efficacy when delivered concurrently with radiation in our retrospective population study. Although platin did cause greater hematologic toxicity, radiation-specific side effects seemed relatively comparable. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E1554-E1561, 2016. PMID- 26595159 TI - Mohs micrographic surgery for basal cell carcinoma: evaluation of the indication criteria and predictive factors for extensive subclinical spread. AB - BACKGROUND: The incidence of basal cell carcinoma (BCC) is rising and BCC treatment has an important impact on healthcare budget. Mohs micrographic surgery (MMS) has the highest 5-year cure rate but is an expensive technique. OBJECTIVES: To study the indication criteria for MMS, using a series of 1062 patients treated for facial BCCs between 1998 and 2011. METHODS: The accuracy of the indication criteria was evaluated by comparing the characteristics of BCC requiring one vs. more than one round of MMS. Predictors for extensive subclinical spread (three or more rounds) were examined using the preoperative patient and all tumour characteristics. RESULTS: BCCs with a surface > 1 cm(2) and aggressive histology (morphoeaform and micronodular), and a patient age > 80 years are strong predictors for two or more rounds of MMS being required. Extensive subclinical spread was present in recurrent tumours, morphoeaform BCC or BCC with mixed histology. CONCLUSIONS: We found that tumour size and aggressive histology are the strongest indication criteria for MMS. Recurrence and aggressive histology are predictors for extensive subclinical spread but not for two or more rounds of MMS. Evidence-based indications for MMS are necessary to ensure cost-effective management of BCC. PMID- 26595160 TI - Summaries for Patients. Improving Adherence to Therapy and Clinical Outcomes While Containing Costs: Opportunities From the Greater Use of Generic Medications. PMID- 26595158 TI - Immunosuppressive evidence of Tityus serrulatus toxins Ts6 and Ts15: insights of a novel K(+) channel pattern in T cells. AB - The voltage-gated potassium channel Kv1.3 is a novel target for immunomodulation of autoreactive effector memory T cells, which play a major role in the pathogenesis of autoimmune diseases. In this study, the Ts6 and Ts15 toxins isolated from Tityus serrulatus (Ts) were investigated for their immunosuppressant roles on CD4(+) cell subsets: naive, effector (TEF ), central memory (TCM) and effector memory (TEM). The electrophysiological assays confirmed that both toxins were able to block Kv1.3 channels. Interestingly, an extended Kv channel screening shows that Ts15 blocks Kv2.1 channels. Ts6 and Ts15 significantly inhibit the proliferation of TEM cells and interferon-gamma production; however, Ts15 also inhibits other CD4(+) cell subsets (naive, TEF and TCM). Based on the Ts15 inhibitory effect of proliferation of all CD4(+) cell subsets, and based on its blocking effect on Kv2.1, we investigated the Kv2.1 expression in T cells. The assays showed that CD4(+) and CD8(+) cells express the Kv2.1 channels mainly extracellularly with TCM cells expressing the highest number of Kv2.1 channels. We also provide in vivo experimental evidence to the protective effect of Ts6 and Ts15 on delayed-type hypersensitivity reaction. Altogether, this study presents the immunosuppressive behaviour of Ts6 and Ts15 toxins, indicating that these toxins could be promising candidates for autoimmune disease therapy. Moreover, this is the first report illustrating the involvement of a novel K(+) channel subtype, Kv2.1, and its distribution in T-cell subsets. PMID- 26595161 TI - Role of Serum Procalcitonin in Identifying Young Febrile Infants With Invasive Bacterial Infections: One Step Closer to the Holy Grail? PMID- 26595162 TI - Dietary total fat and fatty acids intake, serum fatty acids and risk of breast cancer: A meta-analysis of prospective cohort studies. AB - Results from prospective cohort studies on the association between dietary total fat and fatty acids intake and risk of breast cancer remain controversial. Pertinent prospective cohort studies were identified by a search of Embase and PubMed from inception to September 2015. Study-specific relative risks (RRs) with 95% confidence intervals were pooled using a random-effect model. Between-study heterogeneity and publication bias were assessed, and sensitivity analysis was conducted. Twenty-four independent studies on dietary total fat and fatty acids intake and seven studies on serum fatty acids were included. The pooled RR of breast cancer for the highest vs. lowest category of dietary total fat intake was 1.10 (1.02-1.19); however, no association was observed in studies adjusting for traditional risk factors of breast cancer. No association was observed between animal fat, vegetable fat, saturated fatty acids (SFA), monounsaturated fatty acids (MUFA), polyunsaturated fatty acids (PUFA), n-3 PUFA, n-6 PUFA, eicosapentaenoic acid, docosahexaenoic acid, alpha-linolenic acid, oleic acid, linoleic acid and arachidonic acid and risk of breast cancer. The pooled RRs of breast cancer for the highest vs. lowest category of serum SFA, MUFA, PUFA, n-3 PUFA and n-6 PUFA were 1.00 (0.78-1.28), 1.41 (0.99-2.03), 0.59 (0.27-1.30), 0.81 (0.60-1.10) and 0.84 (0.60-1.18), respectively. Results from this meta-analysis suggested that dietary total fat and fatty acids might be not associated with risk of breast cancer. PMID- 26595163 TI - Extrapolation of acute toxicity across bee species. AB - In applying cross-species extrapolation safety factors from honeybees to other bee species, some basic principles of toxicity have not been included, for example, the importance of body mass in determining a toxic dose. The present study re-analyzed published toxicity data, taking into account the reported mass of the individuals in the identified species. The analysis demonstrated a shift to the left in the distribution of sensitivity of honeybees relative to 20 other bee species when body size is taken into account, with the 95(th) percentile for contact and oral toxicity reducing from 10.7 (based on MUg/individual bee) to 5.0 (based on MUg/g bodyweight). Such an approach results in the real drivers of species differences in sensitivity-such as variability in absorption, distribution, metabolism, and excretion in and target-receptor binding-being more realistically reflected in the revised safety factor. Body mass can also be used to underpin the other parameter of first-tier risk assessment, that is, exposure. However, the key exposure factors that cannot be predicted from bodyweight are the effects of ecology and behavior of the different species on exposure to a treated crop. Further data are required to understand the biology of species associated with agricultural crops and the potential consequences of effects on individuals at the levels of the colony or bee populations. This information will allow the development of appropriate higher-tier refinement of risk assessments and testing strategies rather than extensive additional toxicity testing at Tier 1. Integr Environ Assess Manag 2016;12:622-626. (c) 2015 SETAC. PMID- 26595164 TI - Treatment of Hepatitis C Virus Infection in Real Life. PMID- 26595165 TI - Historical changes in flowering phenology are governed by temperature * precipitation interactions in a widespread perennial herb in western North America. AB - For most species, a precise understanding of how climatic parameters determine the timing of seasonal life cycle stages is constrained by limited long-term data. Further, most long-term studies of plant phenology that have examined relationships between phenological timing and climate have been local in scale or have focused on single climatic parameters. Herbarium specimens, however, can expand the temporal and spatial coverage of phenological datasets. Using Trillium ovatum specimens collected over > 100 yr across its native range, we analyzed how seasonal climatic conditions (mean minimum temperature (Tmin ), mean maximum temperature and total precipitation (PPT)) affect flowering phenology. We then examined long-term changes in climatic conditions and in the timing of flowering across T. ovatum's range. Warmer Tmin advanced flowering, whereas higher PPT delayed flowering. However, Tmin and PPT were shown to interact: the advancing effect of warmer Tmin was strongest where PPT was highest, and the delaying effect of higher PPT was strongest where Tmin was coldest. The direction of temporal change in climatic parameters and in the timing of flowering was dependent on geographic location. Tmin , for example, decreased across the observation period in coastal regions, but increased in inland areas. Our results highlight the complex effects of climate and geographic location on phenology. PMID- 26595166 TI - The influence of ABCB1 polymorphism C3435T on the pharmacokinetics of silibinin. AB - WHAT IS KNOWN AND OBJECTIVE: Silibinin (Silybin), a major constituent of the milk thistle, is commonly used to treat chronic liver disease in some countries. It has been reported to inhibit the transport activity of ABCB1. This study was carried out to determine whether ABCB1 C3435T polymorphism influenced the pharmacokinetics of silibinin contained in silymarin capsules. METHODS: Twenty three healthy volunteers (10 ABCB1 CC, 8 CT and 5 TT genotypes) were enrolled in this clinical trial. Each volunteer was given a single dose of 140 mg Silymarin Capsule. Blood samples were then collected up to 12 h. HPLC-MS/MS was used to detect serial blood concentration of silybin. RESULTS AND DISCUSSION: The peak plasma concentration (Cmax) in subjects of CC (144.8 +/- 60.1 ng/mL) and CT (129.3 +/- 50.3 ng/mL) genotypes were 2-fold higher than in subjects of TT genotype (60.1 +/- 18.3 ng/mL) (with P = 0.0007 and P = 0.0115 respectively). The area under the concentration-time curve (AUC) extrapolated to infinity [AUC(0 infinity)] of CC carriers (347.1 +/- 133.8 ng/mL h) was significantly higher than that of TT carriers (228.3 +/- 52.9 ng/mL h) (P = 0.0115). WHAT IS NEW AND CONCLUSION: The pharmacokinetics of silibinin was significantly influenced by ABCB1 C3435T polymorphism. Dosage adjustment may be necessary for subjects of different genotypes to ensure comparative exposures. A dose-ranging clinical trial should be undertaken to determine whether the observed differences are clinically significant. PMID- 26595167 TI - When the wind blows: The changing role for the airborne particulate matter in respiratory disease. PMID- 26595168 TI - pi-Extended rigid triptycene-trisaroylenimidazoles as electron acceptors. AB - Two soluble isomeric acceptor molecules based on a triptycene core, which is connected to three aroylenimidazole units are described. Due to the inherent threefold axis, the molecules are soluble and thus could be fully photophysically characterized in solution and film. Additionally, the preliminary results of these acceptors in organic photovoltaic devices with two different donor materials are reported. PMID- 26595169 TI - Development and Application of a Gel-Based Immunoassay for the Rapid Screening of Salbutamol and Ractopamine Residues in Pork. AB - Salbutamol (SAL) and ractopamine (RAC) have been illegally used to promote protein synthesis and to increase the feed conversion rate in livestock. However, the residues of SAL and RAC could cause potential hazards for human health. The Ministry of Agriculture of China banned the use of SAL and RAC as growth promoters. In this paper, we provide detailed information on developing a rapid and sensitive gel-based immunoassay for on-site screening of SAL and RAC residues in pork. The detection time was shortened to 20 min. The limits of detection were 0.5 MUg/kg for both SAL and RAC by visual detection, whereas the quantitative gel based immunoassay enabled the detection of SAL (0.051 MUg/kg) and RAC (0.020 MUg/kg) in spiked pork samples. The gel-based immunoassay showed promise as a multiplexed immunoassay for on-site surveilling of SAL and RAC residues in pork. PMID- 26595170 TI - Integrative Healthcare: An Exploration of Students Who Choose This Undergraduate Major. AB - OBJECTIVE: Given the dearth of literature on this topic, the aim of this study was to understand who chooses to study integrative healthcare at an academic institution and why they choose to do so, the demographic characteristics of the student population, their background, and postgraduate plans. DESIGN: A cross sectional survey design. SETTING: Data were collected at a large, urban, public university with a well-established undergraduate bachelor of science program in integrative healthcare. PARTICIPANTS: A total of 105 declared integrative health undergraduate majors. MEASUREMENTS: Online research software collected anonymous survey responses during a 2-month period. RESULTS: Survey participants were more likely to be white and full-time students compared with the general undergraduate population. Many respondents discovered the integrative health major and then decided to enroll at the university. Most had used complementary and alternative medicine modalities, such as massage, yoga, and meditation. More than half of the survey participants were dissatisfied with conventional/Western medicine and its providers. Most respondents had a personal interest in complementary and alternative medicine and holistic health that influenced their decision to declare the major. Additionally, more than half of the respondents want to become a complementary and alternative medicine provider. Most survey participants plan to pursue postgraduate training/education in an integrative healthcare-related field. CONCLUSION: Students who choose to study integrative healthcare in an undergraduate academic institution may mirror the patient population of complementary and alternative medicine practitioners. Their profile, rationale, exposures, intentions, and directions may be helpful to universities considering adding this type of program or postgraduate education programs in attracting new students to integrative health fields. It also informs existing integrative healthcare programs regarding program enhancement. A larger sample involving more integrative health academic institutions would be useful for a future study. PMID- 26595173 TI - Role of oxygen as a regulator of stem cell fate during the spontaneous repair of osteochondral defects. AB - The complexity of the in vivo environment makes it is difficult to isolate the effects of specific cues on regulating cell fate during regenerative events such as osteochondral defect repair. The objective of this study was to develop a computational model to explore how joint specific environmental factors regulate mesenchymal stem cell (MSC) fate during osteochondral defect repair. To this end, the spontaneous repair process within an osteochondral defect was simulated using a tissue differentiation algorithm which assumed that MSC fate was regulated by local oxygen levels and substrate stiffness. The developed model was able to predict the main stages of tissue formation observed by a number of in vivo studies. Following this, a parametric study was conducted to better understand why interventions that modulate angiogenesis dramatically impact the outcome of osteochondral defect healing. In the simulations where angiogenesis was reduced, by week 12, the subchondral plate was predicted to remain below the native tidemark, although the chondral region was composed entirely of cartilage and fibrous tissue. In the simulations where angiogenesis was increased, more robust cell proliferation and cartilage formation were observed during the first 4 weeks, however, by week 12 the subchondral plate had advanced above the native tidemark although any remaining tissue was either hypertrophic cartilage or fibrous tissue. These results suggest that osteochondral defect repair could be enhanced by interventions where angiogenesis is promoted but confined to within the subchondral region of the defect. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1026-1036, 2016. PMID- 26595172 TI - Nuclear hormone receptor LXRalpha inhibits adipocyte differentiation of mesenchymal stem cells with Wnt/beta-catenin signaling. AB - Nuclear hormone receptor liver X receptor-alpha (LXRalpha) has a vital role in cholesterol homeostasis and is reported to have a role in adipose function and obesity although this is controversial. Conversely, mesenchymal stem cells (MSCs) are suggested to be a major source of adipocyte generation. Accordingly, we examined the role of LXRalpha in adipogenesis of MSCs. Adult murine MSCs (mMSCs) were isolated from wild-type (WT) and LXR-null mice. Using WT mMSCs, we further generated cell lines stably overexpressing GFP-LXRalpha (mMSC/LXRalpha/GFP) or GFP alone (mMSC/GFP) by retroviral infection. Confluent mMSCs were differentiated into adipocytes by the established protocol. Compared with MSCs isolated from WT mice, MSCs from LXR-null mice showed significantly increased adipogenesis, as determined by lipid droplet accumulation and adipogenesis-related gene expression. Moreover, mMSCs stably overexpressing GFP-LXRalpha (mMSC/LXRalpha/GFP) exhibited significantly decreased adipogenesis compared with mMSCs overexpressing GFP alone (mMSC/GFP). Since Wnt/beta-catenin signaling is reported to inhibit adipogenesis, we further examined it. The LXR-null group showed significantly decreased Wnt expression accompanied by a decrease of cellular beta-catenin (vs WT). The mMSC/LXRalpha/GFP group exhibited significantly increased Wnt expression accompanied by an increase of cellular beta-catenin (vs mMSC/GFP). These data demonstrate that LXRalpha has an inhibitory effect on adipogenic differentiation in mMSCs with Wnt/beta-catenin signaling. These results provide important insights into the pathophysiology of obesity and obesity-related consequences such as metabolic syndrome and may identify potential therapeutic targets. PMID- 26595174 TI - III-V Nanowire Complementary Metal-Oxide Semiconductor Transistors Monolithically Integrated on Si. AB - III-V semiconductors have attractive transport properties suitable for low-power, high-speed complementary metal-oxide-semiconductor (CMOS) implementation, but major challenges related to cointegration of III-V n- and p-type metal-oxide semiconductor field-effect transistors (MOSFETs) on low-cost Si substrates have so far hindered their use for large scale logic circuits. By using a novel approach to grow both InAs and InAs/GaSb vertical nanowires of equal length simultaneously in one single growth step, we here demonstrate n- and p-type III-V MOSFETs monolithically integrated on a Si substrate with high I(on)/I(off) ratios using a dual channel, single gate-stack design processed simultaneously for both types of transistors. In addition, we demonstrate fundamental CMOS logic gates, such as inverters and NAND gates, which illustrate the viability of our approach for large scale III-V MOSFET circuits on Si. PMID- 26595171 TI - Take the Wnt out of the inflammatory sails: modulatory effects of Wnt in airway diseases. AB - Bronchial asthma and chronic obstructive pulmonary disease (COPD) are chronic diseases that are associated with inflammation and structural changes in the airways and lungs. Recent findings have implicated Wnt pathways in critically regulating inflammatory responses, especially in asthma. Furthermore, canonical and noncanonical Wnt pathways are involved in structural changes such as airway remodeling, goblet cell metaplasia, and airway smooth muscle (ASM) proliferation. In COPD, Wnt pathways are not only associated with structural changes in the airways but also involved in the development of emphysema. The present review summarizes the role and function of the canonical and noncanonical Wnt pathway with regard to airway inflammation and structural changes in asthma and COPD. Further identification of the role and function of different Wnt molecules and pathways could help to develop novel therapeutic options for these diseases. PMID- 26595175 TI - Late emergence chronotypes of fruit flies Drosophila melanogaster exhibit higher accuracy of entrainment. AB - Inter-individual variation in phase-of-entrainment (chronotype) is widely observed in many species, but the underlying mechanisms and its consequences remain largely unexplored. In light of considerable limitations of previous studies proposing that the late chronotypes exhibit weakly stable rhythms, we employed outbred Drosophila populations exhibiting early and late emergence chronotypes to re-visit such associations. Contrary to previous reports, we observed that the late chronotypes consistently exhibit higher stability in emergence and activity-rest rhythms as compared to the early chronotypes, both under laboratory and semi-natural conditions, which is not associated with higher precision of circadian clocks, thus demonstrating the existence of genetic correlations between accuracy of entrainment and chronotype. Our results, along with the previously reported clock property differences between the early and the late emergence chronotypes highlights a possible complex interplay of clock period, phase response curve and accuracy in determining phase-of-entrainment. PMID- 26595176 TI - Impact of ingredient replacers on the physicochemical properties and sensory quality of reduced salt and fat black puddings. AB - Twenty-two black puddings possessing different fat (10%, 5%) and sodium (0.6%, 0.4%) levels were used as base formulations for 11 different salt and fat replacers. Compositional, physicochemical and sensory analyses were conducted. Black pudding samples with 5% fat and 0.6% sodium containing potassium chloride (KCl), potassium chloride and glycine mixture (KClG), and seaweed, respectively, and 10% fat and 0.4% sodium containing carrageen were rated higher (P<0.05) for spiciness and saltiness. Samples with 10% fat and 0.4% sodium containing KClG were rated positively (P<0.05) to fatness. Samples with 5% fat and 0.6% sodium containing pectin and a combination of potassium citrate, potassium phosphate and potassium chloride (KCPCl), as well as samples containing 10% fat and 0.4% sodium with waxy maize starch (WMS) were liked (P<0.05) for flavor and overall acceptance. The Food Safety Authority of Ireland (FSAI) recommends a sodium target level of 0.6% and an even lower sodium level (0.4%) was achieved. PMID- 26595177 TI - Analysis of fatal train-pedestrian collisions in metropolitan Chicago 2004-2012. AB - The paper analyzes spatial and temporal data on fatal train-pedestrian collisions in the Chicago metropolitan area between 2004 and 2012. In comparing different municipalities within the region, the density of grade crossings and stations is found to increase the frequency of unintentional deaths. However, unintentional deaths do not increase with train volume suggesting that pedestrians may exercise more care around busier lines. The distribution of apparent intentional deaths is less strongly related to the density of crossings and stations suggesting that those intending self-harm will seek out a point of access. Apparent intentional deaths are more prevalent on lines with frequent passenger trains, and in municipalities with higher incomes and lower population densities. While most of the apparent intentional deaths (about 70%) are not associated with any copycat activities, the dataset contains possible clusters of intentional deaths that are proximate in both time and space. There was also a highly publicized suicide that led to a 95% increase in apparent intentional deaths throughout the region in the 18 weeks following the incident. PMID- 26595178 TI - Activated carbon doped with biogenic manganese oxides for the removal of indigo carmine. AB - Indigo carmine (IC) is one of the oldest, most important, and highly toxic dyes which is released from the effluents of many industries and results in serious pollution in water. In this study, the biogenic Mn oxides were activated by NaOH and then heated for 3 h at 350 degrees C to produce activated carbon doped with Mn oxide (Bio-MnOx-C), which were produced by culturing Mn (II)-oxidizing bacterial strain MnI7-9 in liquid A medium at 28 degrees C with 10 mmol/L MnCl2. Bio-MnOx-C was characterized by SEM, TEM, IR, XPS, XRD, etc. It contained C, O, and Mn which comprised Mn (IV) and Mn (III) valence states at a ratio of 3.81:1. It had poorly crystalline epsilon-MnO2 with a specific surface area of 130.94 m(2)/g. A total of 0.1 g Bio-MnOx-C could remove 45.95 g IC from 500 mg/L IC solution after 0.5 h contact time. IC removal by Bio-MnOx-C included a rapid oxidation reaction and the removal reaction followed second-order kinetic equation. These results confirmed that Bio-MnOx-C could be a potential material for wastewater remediation. PMID- 26595179 TI - Influence of COD/N ratio and carbon source on nitrogen removal in a structured bed reactor subjected to recirculation and intermittent aeration (SBRRIA). AB - This study aimed to evaluate the influence of COD/N ratio and carbon source on simultaneous nitrogen and carbon removal processes. A continuous up-flow structured-bed reactor subjected to recirculation and intermittent aeration (SBRRIA) was operated with hydraulic retention time (HRT) of 11.2 +/- 0.6 h. The carbon sources were meat peptone and sucrose. The COD/N ratio varied by maintaining the organic loading rate fixed at 1.07 kg COD m(-3) d(-1) and changing the total-N concentration. The COD/N ratios tested were 9.7 +/- 1 (sucrose); 7.6 +/- 1 (meat peptone); 2.9 +/- 1 (meat peptone) and 2.9 +/- 0.4 (sucrose). COD removal efficiencies remained above 90% in all experimental phases. At lower COD/N ratios, NH4(+)-N oxidation efficiencies were higher than 90%. An autotrophic metabolism by anammox process was observed in Phases III and IV, which was responsible for 35% and 27% of total-N loading removal rates, respectively. Therefore, the system achieved total nitrogen removal efficiencies of 84.6 +/- 10.1 and 81.5 +/- 5.3%, under low availability of organic electron donors. PMID- 26595181 TI - Estimating group size from human speech: Three's a conversation, but four's a crowd. AB - Much previous research has examined various aspects of auditory processing, including the localization of sounds, and the influence of lexical and indexical information on language processing. In the present set of experiments we explored the ability of listeners to estimate the number of speakers in a group solely from the information in an auditory signal. The bound on accurately estimating the number of simultaneous speakers is 3. We suggest that subitization-the ability to estimate numerosity of visual and auditory elements without explicitly counting these elements-rather than the capacity of short-term memory, may underlie this limitation. The cognitive constraint on estimating the number of simultaneous speakers may have implications for a wide variety of seemingly unrelated psychological phenomena. PMID- 26595182 TI - Use of computational and recombinant technologies for developing novel influenza vaccines. AB - Influenza vaccine design has changed considerably with advancements in bioinformatics and computational biology. Improved surveillance efforts provide up-to-date information about influenza sequence diversity and assist with monitoring the spread of epidemics and vaccine efficacy rates. The advent of next generation sequencing, epitope scanning and high-throughput analysis all help decipher influenza-associated protein interactions as well as predict immune responsiveness based on host genetic diversity. Computational approaches are utilized in nearly all aspects of vaccine design, from modeling, compatibility predictions, and optimization of antigens in various platforms. This overview discusses how computational techniques strengthen vaccine efforts against highly diverse influenza species. PMID- 26595180 TI - Vaccinia virus, a promising new therapeutic agent for pancreatic cancer. AB - The poor prognosis of pancreatic cancer patients signifies a need for radically new therapeutic strategies. Tumor-targeted oncolytic viruses have emerged as attractive therapeutic candidates for cancer treatment due to their inherent ability to specifically target and lyse tumor cells as well as induce antitumor effects by multiple action mechanisms. Vaccinia virus has several inherent features that make it particularly suitable for use as an oncolytic agent. In this review, we will discuss the potential of vaccinia virus in the management of pancreatic cancer in light of our increased understanding of cellular and immunological mechanisms involved in the disease process as well as our extending knowledge in the biology of vaccinia virus. PMID- 26595183 TI - Homology modeling of parasite histone deacetylases to guide the structure-based design of selective inhibitors. AB - Histone deacetylases (HDACs) are promising epigenetic targets for the treatment of various diseases, including cancer and neurodegenerative disorders. There is evidence that they can also be addressed to treat parasitic infections. Recently, the first X-ray structure of a parasite HDAC was published, Schistosoma mansoni HDAC8, giving structural insights into its inhibition. However, most of the targets from parasites of interest still lack this structural information. Therefore, we prepared homology models of relevant parasitic HDACs and compared them to human and S. mansoni HDACs. The information about known S. mansoni HDAC8 inhibitors and compounds that affect the growth of Trypanosoma, Leishmania and Plasmodium species was used to validate the models by docking and molecular dynamics studies. Our results provide analysis of structural features of parasitic HDACs and should be helpful for selecting promising candidates for biological testing and for structure-based optimisation of parasite-specific inhibitors. PMID- 26595184 TI - Synthesis and in vitro antitumor evaluation of dihydroartemisinin-cinnamic acid ester derivatives. AB - To explore novel high efficiency and low toxicity antitumor agents, a series of dihydroartemisinin-cinnamic acid ester derivatives modified on C-12 and/or C-9 position (s) were synthesized and the in vitro antitumor activities against PC-3, SGC-7901, A549 and MDA-MB-435s cancer cell lines were assessed. The hybrids (3 36) were prepared by esterification of 9alpha-hydroxyl-dihydroartemisinin (9alpha OH DHA), the biotransformation product of dihydroartemisinin (DHA), and cinnamic acid derivatives. Compound 17 (IC50 = 0.20 MUM) was the most potent anti proliferative agent against the human lung carcinoma A549 cells, although it displayed low cytotoxicity on normal hepatic L-02 cells. The mechanism of action of compound 17 was further investigated by analysis of cell apoptosis and intracellular ROS generation. The results indicated that both ROS and ferrous ion contributed to the compound 17-induced cell death. Meanwhile, high intracellular ferrous ion and endogenous oxidative stress in A549 cells made them easier to suffer to compound 17-induced apoptosis. Our promising findings indicated the compound 17 could stand as drug candidate against lung cancer for further investigation. PMID- 26595185 TI - Novel biphenyl bis-sulfonamides as acetyl and butyrylcholinesterase inhibitors: Synthesis, biological evaluation and molecular modeling studies. AB - A series of new biphenyl bis-sulfonamide derivatives 2a-3p were synthesized in good to excellent yield (76-98%). The inhibitory potential of the synthesized compounds on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) was investigated. Most of the screened compounds showed modest in vitro inhibition for both AChE and BChE. Compared to the reference compound eserine (IC50 0.04 +/- 0.0001 MUM for AChE) and (IC50 0.85 +/- 0.0001 MUM for BChE), the IC50 values of these compounds were ranged from 2.27 +/- 0.01 to 123.11 +/- 0.04 MUM for AChE and 7.74 +/- 0.07 to <400 MUM for BuChE. Among the tested compounds, 3p was found to be the most potent against AChE (IC50 2.27 +/- 0.01 MUM), whereas 3g exhibited the highest inhibition for BChE (IC50 7.74 +/- 0.07 MUM). Structure-activity relationship (SAR) of these compounds was developed and elaborated with the help of molecular docking studies. PMID- 26595186 TI - Dead Nano-Sized Lactobacillus plantarum Inhibits Azoxymethane/Dextran Sulfate Sodium-Induced Colon Cancer in Balb/c Mice. AB - The chemopreventive effects of dead nano-sized Lactobacillus plantarum (nLp) on colon carcinogenesis, induced by dextran sulfate sodium and azoxymethane, were evaluated using Balb/c mice and compared with the effects of pure live L. plantarum (pLp). nLp is a dead shrunken form of L. plantarum derived from kimchi and has a particle size of 0.5-1.0 MUm. Animals fed nLp showed less weight loss, longer colons, lower colon weight/length ratios, and fewer colonic tumors compared with pLp. In addition, the administration of nLp significantly reduced the expression of inflammatory markers, mediated the expression of cell cycle and apoptotic markers in colon tissues, and elevated fecal IgA levels more than pLp. Accordingly, the present study shows that the anticolorectal cancer activities of nLp are greater than those of pLp and suggests this is due to the suppression of inflammation, the induction of cell cycle arrest and apoptosis, and enhanced IgA secretion. PMID- 26595187 TI - Dietary intakes and lifestyle patterns of Korean children and adolescents with atopic dermatitis: Using the fourth and fifth Korean National Health and Nutrition Examination Survey (KNHANES IV,V), 2007-11. AB - We investigate dietary intake and lifestyle patterns of atopic children and adolescents (N = 539) by obesity level using a national survey of South Korea. Intakes of calcium, iron, and vitamin C in the underweight group were less than those of other groups. The frequency of drinking milk of the overweight group was higher than that of the normal weight group. Majority of the subjects had not applied nutrition labeling in food choices, had no experience of nutrition education, and were vitamin D deficient. In conclusion, most of the atopic subjects had little knowledge of nutrition and were vitamin D deficient. PMID- 26595188 TI - In vitro extracellular recording and stimulation performance of nanoporous gold modified multi-electrode arrays. AB - OBJECTIVE: Nanoporous gold (Au) structures can reduce the impedance and enhance the charge injection capability of multi-electrode arrays (MEAs) used for interfacing neuronal networks. Even though there are various nanoporous Au preparation techniques, fabrication of MEA based on low-cost electro-codeposition of Ag:Au has not been performed. In this work, we have modified a Au MEA via the electro-codeposition of Ag:Au alloy, followed by the chemical etching of Ag, and report on the in vitro extracellular recording and stimulation performance of the nanoporous Au-modified MEA. APPROACH: Ag:Au alloy was electro-codeposited on a bilayer lift-off resist sputter-deposition passivated Au MEA followed by chemical etching of Ag to form a porous Au structure. MAIN RESULTS: The porous Au structure was analyzed by scanning electron microscopy and tunneling electron microscopy and found to have an interconnected nanoporous Au structure. The impedance value of the nanoporous Au-modified MEA is 15.4 +/- 0.55 kOmega at 1 kHz, accompanied by the base noise V rms of 2.4 +/- 0.3 MUV. The charge injection limit of the nanoporous Au-modified electrode estimated from voltage transient measurement is approximately 1 mC cm(-2), which is comparable to roughened platinum and carbon nanotube electrodes. The charge injection capability of the nanoporous Au-modified MEA was confirmed by observing stimulus-induced spikes at above 0.2 V. The nanoporous Au-modified MEA showed mechanical durability upon ultrasonic treatment for up to an hour. SIGNIFICANCE: Electro-codeposition of Ag:Au alloy combined with chemical etching Ag is a low-cost process for fabricating nanoporous Au-modified MEA suitable for establishing the stimulus response relationship of cultured neuronal networks. PMID- 26595190 TI - The Effect of Blocked, Random and Mixed Practice Schedules on Speech Motor Learning of Tongue Twisters in Unimpaired Speakers. AB - There are few investigations comparing practice schedules in speech motor learning, despite certain schedules being recommended for the clinical treatment of speech motor disorders. This study compared effects of random, blocked and mixed practice on tongue twister accuracy in unimpaired speakers. We hypothesized that blocked practice would benefit acquisition of learning, but that random practice and mixed blocked-then-random practice would yield superior retention of learning. We found that the random and blocked-random practice schedules yielded superior accuracy at the end of the acquisition phase of learning and at a 1-week retention test. Exploratory post hoc analyses raised the possibility that the retention effects were most evident when tongue twisters were elicited in a random schedule. Theoretical accounts of these results are discussed. PMID- 26595191 TI - Fluorinated Boronic Acid-Appended Bipyridinium Salts for Diol Recognition and Discrimination via (19)F NMR Barcodes. AB - Fluorinated boronic acid-appended benzyl bipyridinium salts, derived from 4,4'-, 3,4'-, and 3,3'-bipyridines, were synthesized and used to detect and differentiate diol-containing analytes at physiological conditions via (19)F NMR spectroscopy. An array of three water-soluble boronic acid receptors in combination with (19)F NMR spectroscopy discriminates nine diol-containing bioanalytes--catechol, dopamine, fructose, glucose, glucose-1-phosphate, glucose 6-phosphate, galactose, lactose, and sucrose--at low mM concentrations. Characteristic (19)F NMR fingerprints are interpreted as two-dimensional barcodes without the need of multivariate analysis techniques. PMID- 26595192 TI - Two-Step Bipolar Electrochemistry: Generation of Composition Gradient and Visual Screening of Electrocatalytic Activity. AB - Bipolar electrochemistry (BE) is employed for both creating electrocatalysts composition gradient and visual screening of the prepared composition on a single substrate in just two experiment runs. In a series of proof-of-principle experiments, we demonstrate gradient electrodeposition of Ni-Cu using BE; then the electrocatalytic activity of the prepared composition gradient toward the hydrogen evolution reaction (HER) is visually screened in the BE system using array of BPEs. Moreover, the morphology and the chemical composition of the Ni-Cu gradient are screened along the length of the bipolar electrode (BPE). By measuring the potential gradient over the BPE, it is also demonstrated that by controlling the concentration of the metals precursor and the supporting electrolyte, the length of the bipolar electrodeposited gradient can be controlled. PMID- 26595193 TI - Self-Propelled Enzyme-Based Motors for Smart Mobile Electrochemical and Optical Biosensing. AB - A millimeter-sized tubular motor for mobile biosensing of H2O2 in environmental and relevant clinical samples is reported. The concept relies on the self propelled motion by the Marangoni effect, where the asymmetric release of SDS surfactant induces fluid convection and rapid dispersion of horseradish peroxidase (HRP) enzyme into the sample solution. This efficient movement together with the continuous release of fresh enzyme leads to greatly accelerated enzymatic reaction processes without the need of external stirring or chemical and physical attachment of the enzyme as in common classical biosensing approaches. In this strategy, the use of a single millimeter-sized tubular motor during 120 s allows the reliable and accurate quantification of hydrogen peroxide in a set of different matrices such as tap and mineral waters, urine, plasma, and tumor cell cultures treated with antineoplasic Cisplatin without any previous sample preparation. Furthermore, detection can be performed electrochemically, optically, and via visual detection, which makes this approach a clear candidate as a point-of-care analytical tool. PMID- 26595194 TI - Protic vs Aprotic Solvent Effect on Proton Transfer in 3-Hydroxyisoquinoline: A Theoretical Study. AB - In this work, the structures, energetics, and tautomerizations in 3 hydroxyisoquinoline (3HIQ) in both the ground state and the excited state have been theoretically investigated by the MP2, TDDFT, and CASPT2 methods, respectively. The solvent effect including the implicit solvent and explicit solvent on the structures, energetics, and tautomeizations are revealed. We found that the explicit solvent plays a more important role in the structures, energetics, and tautomerizations in 3HIQ than implicit solvent in both the ground state and the excited state. The proton transfer is more facilitated in explicit solvent (water or methanol) compared to that in the gas phase and in the implicit solvent in the excited state, and the reactive role of the molecular solvent is found to be related with the two linear hydrogen bonds. PMID- 26595189 TI - Thyroglobulin From Molecular and Cellular Biology to Clinical Endocrinology. AB - Thyroglobulin (Tg) is a vertebrate secretory protein synthesized in the thyrocyte endoplasmic reticulum (ER), where it acquires N-linked glycosylation and conformational maturation (including formation of many disulfide bonds), leading to homodimerization. Its primary functions include iodide storage and thyroid hormonogenesis. Tg consists largely of repeating domains, and many tyrosyl residues in these domains become iodinated to form monoiodo- and diiodotyrosine, whereas only a small portion of Tg structure is dedicated to hormone formation. Interestingly, evolutionary ancestors, dependent upon thyroid hormone for development, synthesize thyroid hormones without the complete Tg protein architecture. Nevertheless, in all vertebrates, Tg follows a strict pattern of region I, II-III, and the cholinesterase-like (ChEL) domain. In vertebrates, Tg first undergoes intracellular transport through the secretory pathway, which requires the assistance of thyrocyte ER chaperones and oxidoreductases, as well as coordination of distinct regions of Tg, to achieve a native conformation. Curiously, regions II-III and ChEL behave as fully independent folding units that could function as successful secretory proteins by themselves. However, the large Tg region I (bearing the primary T4-forming site) is incompetent by itself for intracellular transport, requiring the downstream regions II-III and ChEL to complete its folding. A combination of nonsense mutations, frameshift mutations, splice site mutations, and missense mutations in Tg occurs spontaneously to cause congenital hypothyroidism and thyroidal ER stress. These Tg mutants are unable to achieve a native conformation within the ER, interfering with the efficiency of Tg maturation and export to the thyroid follicle lumen for iodide storage and hormonogenesis. PMID- 26595198 TI - Metal-Metal Quadruple Bonds (M = Mo or W) Supported by 4-[2-(4-Pyridinyl)ethenyl] Benzoates and their Complexes with Tris(pentafluorophenyl)boron. AB - From the reactions between M2(T(i)PB)4 and two equivalents of the acids LH, the compounds trans-M2(T(i)PB)2L2 were isolated where M = Mo, compound I, and M = W, II, T(i)PB = 2,4,6-triisopropylbenzoate, and LH = 4-[2-(4 Pyridinyl)ethenyl]benzoic acid. In related reactions when tris(pentafluorophenyl)boron, A, was added, the Lewis acid-Lewis base complexes Mo2(T(i)PB)2(LA)2, IB, and W2(T(i)PB)2(LA)2, IIB, were isolated. Compounds I and IB are red and purple, respectively, while II and IIB are green. The new compounds have been characterized by (1)H NMR, UV-visible-NIR absorption spectroscopy, and electrochemical studies, which are tied together with density functional theory, DFT, and time-dependent DFT calculations. Chemical reduction of IB and IIB yields anions where the single electron occupies a ligand-based orbital as indicated by EPR spectroscopy. The LUMO and LUMO+1 are ligand-based, and are close in energy, and upon reduction, no IVCT is observed. PMID- 26595199 TI - MOTOR IMAGERY, PHYSICAL PRACTICE, AND MEMORY: THE EFFECTS ON PERFORMANCE AND WORKLOAD. AB - -The theoretical explanations used to explain changes in performance during motor imagery and physical practice conditions are inconsistent when memory retrieval is and is not required. This study measured performance time and workload during acquisition, a retention test requiring memory retrieval, and a retention test not requiring memory retrieval using a key-pressing task. The participants were assigned to physical practice with or without instructions to learn or motor imagery with or without instructions to learn. A diagram of the keys was presented during the practice trials and the first retention test, but was not presented during the second test. The results revealed no effect for the learning instructions or performance changes during the practice phases. However, during both retention tests participants in the physical practice conditions performed significantly faster than those in the motor imagery conditions. Also, higher levels of workload were reported for the motor imagery conditions when the retention test required memory retrieval compared to the other phases. A discussion of the implications of workload on performance is presented with respect to varying practice conditions. PMID- 26595195 TI - Rapid Exchange Between Free and Bound States in RNA-Dendrimer Polyplexes: Implications on the Mechanism of Delivery and Release. AB - A combination of solution NMR, dynamic light scattering (DLS), and fluorescence quenching assays were employed to obtain insights into the dynamics and structural features of a polyplex system consisting of HIV-1 transactivation response element (TAR) and PEGylated generation 5 poly(amidoamine) dendrimer (G5 PEG). NMR chemical shift mapping and (13)C spin relaxation based dynamics measurements depict the polyplex system as a highly dynamic assembly where the RNA, with its local structure and dynamics preserved, rapidly exchanges (=3) and tumor depth (>=3 mm) and these were associated with lymph node metastasis. Moreover, both budding and tumor depth significantly correlated with relapse-free survival; however, evaluating biopsy specimens often proved inaccurate for predicting true tumor depth of cancer invasion. CONCLUSION: Tumor budding using immunohistochemistry for cytokeratin should be added to routine histologic assessments as a new criterion factoring into the decision as to whether neck dissection is indicated. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E1582-E1590, 2016. PMID- 26595241 TI - Why Can't We Be Friends? A Case-Based Analysis of Ethical Issues with Social Media in Health Care. PMID- 26595239 TI - Extracellular 2'5'-oligoadenylate synthetase 2 mediates T-cell receptor CD3-zeta chain down-regulation via caspase-3 activation in oral cancer. AB - Decreased expression of CD3-zeta chain, an adaptor protein associated with T-cell signalling, is well documented in patients with oral cancer, but the mechanistic justifications are fragmentary. Previous studies in patients with oral cancer have shown that decreased expression of CD3-zeta chain was associated with decreased responsiveness of T cells. Tumours are known to induce localized as well as systemic immune suppression. This study provides evidence that oral tumour-derived factors promote immune suppression by down-regulating CD3-zeta chain expression. 2'5'-Oligoadenylate synthetase 2 (OAS2) was identified by the proteomic approach and our results established a causative link between CD3-zeta chain down-regulation and OAS2 stimulation. The surrogate situation was established by over-expressing OAS2 in a HEK293 cell line and cell-free supernatant was collected. These supernatants when incubated with T cells resulted in down-regulation of CD3-zeta chain, which shows that the secreted OAS2 is capable of regulating CD3-zeta chain expression. Incubation of T cells with cell-free supernatants of oral tumours or recombinant human OAS2 (rh-OAS2) induced caspase-3 activation, which resulted in CD3-zeta chain down-regulation. Caspase-3 inhibition/down-regulation using pharmacological inhibitor or small interfering RNA restored down-regulated CD3-zeta chain expression in T cells induced by cell-free tumour supernatant or rh-OAS2. Collectively these results show that OAS2 leads to impairment in CD3-zeta chain expression, so offering an explanation that might be applicable to the CD3-zeta chain deficiency observed in cancer and diverse disease conditions. PMID- 26595240 TI - Neutrophilic panniculitis associated with alpha-1-antitrypsin deficiency: an update. AB - Neutrophilic panniculitis associated with alpha-1-antitrypsin deficiency (AATD) is a very rare disease. Its estimated prevalence is 1 in 1000 subjects with severe AATD (usually white individuals with a Pi*ZZ genotype). It is manifested clinically by painful recurrent ulcerating subcutaneous nodules, and characterized histologically by dense infiltrates of neutrophils in the deep dermis and connective-tissue septae, with secondary lobular panniculitis. It may be the only clinical manifestation of AATD, although it can also occur together with the classical pulmonary or hepatic manifestations of the disease. AATD associated panniculitis is not only very rare but may also be significantly underdiagnosed. The physician managing a case of panniculitis with a clinical presentation suggestive of AATD and a compatible skin biopsy should measure serum AAT concentration and, if low, determine the AAT phenotype by isoelectric focusing. If uncertainty remains, the SERPINA1 gene should be sequenced to identify the genotype. If AATD is diagnosed, AATD testing of first-degree family members should be performed in order to take appropriate preventive and therapeutic measures, including genetic counselling, education on inheritance, risk arising from tobacco smoke, occupational exposure to pollutants and hepatotoxic substances, and the provision of information on clinical management. Cases of panniculitis in which conventional therapy with dapsone has failed may be managed with intravenous augmentative therapy using human AAT. The current manuscript addresses the fundamental concepts of the pathogenesis of AATD associated panniculitis and describes the clinical presentation and management of cases in order to reduce underdiagnosis and improve outcomes. PMID- 26595242 TI - The High-Value Care Considerations of Inpatient versus Outpatient Testing. PMID- 26595243 TI - Grow a Spine, Have a Heart: Responding to Patient Requests for Marginally Beneficial Care. PMID- 26595244 TI - Cost-Consciousness in Teaching Hospitals. PMID- 26595245 TI - Teaching High-Value Care. PMID- 26595246 TI - The Challenge of Understanding Health Care Costs and Charges. PMID- 26595247 TI - Repeal of the Medicare Sustainable Growth Rate: Direct and Indirect Consequences. PMID- 26595248 TI - Increasing Cost Efficiency in Health Care without Sacrificing the Human Touch. PMID- 26595249 TI - High-Value Palliative Care for Cancer Patients. PMID- 26595250 TI - Promoting Cost Transparency to Reduce Financial Harm to Patients. PMID- 26595251 TI - Countering Medicine's Culture of More. PMID- 26595252 TI - Prevention of Hepatitis C by Screening and Treatment in U.S. Prisons. AB - BACKGROUND: The prevalence of hepatitis C virus (HCV) in U.S. prisoners is high; however, HCV testing and treatment are rare. Infected inmates released back into society contribute to the spread of HCV in the general population. Routine hepatitis screening of inmates followed by new therapies may reduce ongoing HCV transmission. OBJECTIVE: To evaluate the health and economic effect of HCV screening and treatment in prisons on the HCV epidemic in society. DESIGN: Agent based microsimulation model of HCV transmission and progression of HCV disease. DATA SOURCES: Published literature. TARGET POPULATION: Population in U.S. prisons and general community. TIME HORIZON: 30 years. PERSPECTIVE: Societal. INTERVENTIONS: Risk-based and universal opt-out hepatitis C screening in prisons, followed by treatment in a portion of patients. OUTCOME MEASURES: Prevention of HCV transmission and associated disease in prisons and society, costs, quality adjusted life-years (QALYs), incremental cost-effectiveness ratio (ICER), and total prison budget. RESULTS OF BASE-CASE ANALYSIS: Implementing risk-based and opt-out screening could diagnose 41,900 to 122,700 new HCV cases in prisons in the next 30 years. Compared with no screening, these scenarios could prevent 5500 to 12,700 new HCV infections caused by released inmates, wherein about 90% of averted infections would have occurred outside of prisons. Screening could also prevent 4200 to 11,700 liver-related deaths. The ICERs of screening scenarios were $19,600 to $29,200 per QALY, and the respective first-year prison budget was $900 to $1150 million. Prisons would require an additional 12.4% of their current health care budget to implement such interventions. RESULTS OF SENSITIVITY ANALYSIS: Results were sensitive to the time horizon, and ICERs otherwise remained less than $50,000 per QALY. LIMITATION: Data on transmission network, reinfection rate, and opt-out HCV screening rate are lacking. CONCLUSION: Universal opt-out HCV screening in prisons is highly cost-effective and would reduce HCV transmission and HCV-associated diseases primarily in the outside community. Investing in U.S. prisons to manage hepatitis C is a strategic approach to address the current epidemic. PRIMARY FUNDING SOURCE: National Institutes of Health. PMID- 26595253 TI - Use of Procalcitonin Assays to Predict Serious Bacterial Infection in Young Febrile Infants. AB - IMPORTANCE: The procalcitonin (PCT) assay is an accurate screening test for identifying invasive bacterial infection (IBI); however, data on the PCT assay in very young infants are insufficient. OBJECTIVE: To assess the diagnostic characteristics of the PCT assay for detecting serious bacterial infection (SBI) and IBI in febrile infants aged 7 to 91 days. DESIGN, SETTING, AND PARTICIPANTS: A prospective cohort study that included infants aged 7 to 91 days admitted for fever to 15 French pediatric emergency departments was conducted for a period of 30 months (October 1, 2008, through March 31, 2011). The data management and analysis were performed from October 1, 2011, through October 31, 2014. MAIN OUTCOMES AND MEASURES: The diagnostic characteristics of the PCT assay, C reactive protein (CRP) concentration, white blood cell (WBC) count, and absolute neutrophil cell (ANC) count for detecting SBI and IBI were described and compared for the overall population and subgroups of infants according to the age and the duration of fever. Laboratory test cutoff values were calculated based on receiver operating characteristic (ROC) curve analysis. The SBIs were defined as a pathogenic bacteria in positive culture of blood, cerebrospinal fluid, urine, or stool samples, including bacteremia and bacterial meningitis classified as IBIs. RESULTS: Among the 2047 infants included, 139 (6.8%) were diagnosed as having an SBI and 21 (1.0%) as having an IBI (11.0% and 1.7% of those with blood culture (n = 1258), respectively). The PCT assay offered an area under the curve (AUC) of ROC curve similar to that for CRP concentration for the detection of SBI (AUC, 0.81; 95% CI, 0.75-0.86; vs AUC, 0.80; 95% CI, 0.75-0.85; P = .70). The AUC ROC curve for the detection of IBI for the PCT assay was significantly higher than that for the CRP concentration (AUC, 0.91; 95% CI, 0.83-0.99; vs AUC, 0.77; 95% CI, 0.65-0.89; P = .002). Using a cutoff value of 0.3 ng/mL for PCT and 20 mg/L for CRP, negative likelihood ratios were 0.3 (95% CI, 0.2-0.5) for identifying SBI and 0.1 (95% CI, 0.03-0.4) and 0.3 (95% CI, 0.2-0.7) for identifying IBI, respectively. Similar results were obtained for the subgroup of infants younger than 1 month and for those with fever lasting less than 6 hours. CONCLUSIONS AND RELEVANCE: The PCT assay has better diagnostic accuracy than CRP measurement for detecting IBI; the 2 tests perform similarly for identifying SBI in febrile infants aged 7 to 91 days. PMID- 26595255 TI - Enhanced bioactivity and osseointegration of PEEK with accelerated neutral atom beam technology. AB - Polyetheretherketone (PEEK) is growing in popularity for orthopedic, spinal, and trauma applications but has potential significant limitations in use. PEEK is biocompatible, similar in elasticity to bone, and radiolucent, but is inert and therefore does not integrate well with bone. Current efforts are focusing on increasing the bioactivity of PEEK with surface modifications to improve the bone implant interface. We used a novel Accelerated Neutral Atom Beam (ANAB) technology to enhance the bioactivity of PEEK. Human osteoblast-like cells seeded on ANAB-treated PEEK result in significantly enhanced proliferation compared with control PEEK. Cells grown on ANAB-treated PEEK increase osteogenic expression of ALPL (1.98-fold, p < 0.002), RUNX2 (3.20-fold, p < 0.002), COL1A (1.94-fold, p < 0.015), IBSP (2.78-fold, p < 0.003), and BMP2 (1.89-fold, p < 0.004). Cells grown on these treated surfaces also lead to an increased mineralization (6.4-fold at 21 days, p < 0.0005). In an ovine study, ANAB-treated PEEK implants resulted in enhanced bone-in-contact by 3.09-fold (p < 0.014), increased push-out strength (control 1959 +/- 1445 kPa; ANAB 4068 +/- 1197 kPa, p < 0.05), and evidence of bone ingrowth at both the early (4 weeks) and later (12 weeks) time points. Taken together, these data suggest that ANAB treatment of PEEK has the potential to enhance its bioactivity, leading to bone formation and significantly decreasing osseointegration time of orthopedic and spinal implants. ANAB treatment, therefore, may significantly enhance the performance of PEEK medical implants and lead to improved clinical outcomes. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 531-543, 2017. PMID- 26595254 TI - CD90(+) stromal cells are the major source of IL-6, which supports cancer stem like cells and inflammation in colorectal cancer. AB - IL-6 is a pleiotropic cytokine increased in CRC and known to directly promote tumor growth. Colonic myofibroblasts/fibroblasts (CMFs or stromal cells) are CD90(+) innate immune cells representing up to 30% of normal colonic mucosal lamina propria cells. They are expanded in CRC tumor stroma, where they also known as a cancer associated fibroblasts (CAFs). Cells of mesenchymal origin, such as normal myofibroblasts/fibroblasts, are known to secrete IL-6; however, their contribution to the increase in IL-6 in CRC and to tumor-promoting inflammation is not well defined. Using in situ, ex vivo and coculture analyses we have demonstrated that the number of IL-6 producing CMFs is increased in CRC (C-CMFs) and they represent the major source of IL-6 in T2-T3 CRC tumors. Activity/expression of stem cell markers-aldehyde dehydrogenase and LGR5- was significantly up-regulated in colon cancer cells (SW480, Caco-2 or HT29) cultured in the presence of conditioned medium from tumor isolated C-CMFs in an IL-6 dependent manner. C-CMF and its derived condition medium, but not normal CMF isolated from syngeneic normal colons, induced differentiation of tumor promoting inflammatory T helper 17 cells (Th17) cell responses in an IL-6 dependent manner. Our study suggests that CD90(+) fibroblasts/myofibroblasts may be the major source of IL-6 in T2-T3 CRC tumors, which supports the stemness of tumor cells and induces an immune adaptive inflammatory response (a.k.a. Th17) favoring tumor growth. Taken together our data supports the notion that IL-6 producing CAFs (a.k.a. C-CMFs) may provide a useful target for treating or preventing CRCs. PMID- 26595256 TI - Accountability of Hospitals for Medicare Beneficiaries' Postacute Care Discharge Disposition. PMID- 26595257 TI - Testing the large genome constraint hypothesis: plant traits, habitat and climate seasonality in Liliaceae. AB - The factors driving genome size evolution in Liliaceae were examined. In particular, we investigated whether species with larger genomes are confined to less stressful environments with a longer vegetative season. We tested our hypotheses by correlating the genome size with other plant traits and environmental variables. To determine the adaptive nature of the genome size, we also compared the performances of Brownian motion (BM) processes with those inferred by Ornstein-Uhlenbeck (OU) models of trait evolution. A positive correlation of genome size with plant size, mean temperature and habitat moisture and a negative correlation with altitude and precipitation seasonality were found. Models of trait evolution revealed a deviation from a drift process or BM. Instead, changes in genome size were significantly associated with precipitation regimes according to an OU process. Specifically, the evolutionary optima towards which the genome size evolves were higher for humid climates and lower for drier ones. Taken together, our results indicate that the genome size increase in Liliaceae is constrained by climate seasonality. PMID- 26595258 TI - The role of abuse-deterrent formulations in countering opioid misuse and abuse. AB - WHAT IS KNOWN AND OBJECTIVE: Pain is a prevalent, and due to the ageing population, increasing medical problem. Opioids are frequently prescribed to meet the unmet medical need. Unfortunately, with the increase in the legitimate use of opioids, there has been a corresponding increase in abuse. A practical way to retain the pain relief afforded by opioids while decreasing opportunities for abuse is to make it more difficult to extract the opioid from the product or to make it less desirable to do so by designing an abuse-deterrent formulation (ADF). We provide a brief overview of the strategies and early evidence related to opioid ADFs. METHODS: Published and unpublished literature, websites, and other sources were searched for current opioid formulation options, including immediate-release and extended-release products. Each was summarized, reviewed and assessed. RESULTS: The strategies that have been used to design the current opioid ADFs involve one or more of four approaches: a physical barrier; incorporation of an opioid receptor antagonist (e.g. naloxone) that self-limits opioid action when taken in excess amount; inclusion of a noxious agent that is released during inappropriate use; or a pro-drug. WHAT IS NEW AND CONCLUSIONS: Legitimate use of opioid analgesics carries with it certain risks, including the risk of abuse. The new ADFs utilize four major strategies and provide innovative additions to the armamentarium. They likely will become an important part of a comprehensive approach to limiting, although not eliminating, opioid misuse and abuse. PMID- 26595259 TI - Optimal dose of gemcitabine for the treatment of biliary tract or pancreatic cancer in patients with liver dysfunction. AB - A clear consensus does not exist about whether the initial dose of gemcitabine, an essential anticancer antimetabolite, should be reduced in patients with liver dysfunction. Adult patients with biliary tract or pancreatic cancer were divided into three groups according to whether they had mild, moderate, or severe liver dysfunction, evaluated on the basis of serum bilirubin and liver transaminase levels at baseline. As anticancer treatment, gemcitabine at a dose of 800 or 1000 mg/m(2) was given as an i.v. infusion once weekly for 3 weeks of a 4-week cycle. The patients were prospectively evaluated for adverse events during the first cycle, and the pharmacokinetics of gemcitabine and its inactive metabolite, difluorodeoxyuridine, were studied to determine the optimal initial dose of gemcitabine as monotherapy according to the severity of liver dysfunction. A total of 15 patients were studied. Liver dysfunction was mild in one patient, moderate in six, and severe in eight. All 15 patients had been undergoing biliary drainage for obstructive jaundice when they received gemcitabine. Grade 3 cholangitis developed in one patient with moderate liver dysfunction who received gemcitabine at the dose level of 1000 mg/m(2). No other patients had severe treatment-related adverse events resulting in the omission or discontinuation of gemcitabine treatment. The plasma concentrations of gemcitabine and difluorodeoxyuridine were similar among the groups. An initial dose reduction of gemcitabine as monotherapy for the treatment of biliary tract or pancreatic cancers is not necessary for patients with hyperbilirubinemia, provided that obstructive jaundice is well managed. (Clinical trial registration no. UMIN000005363.) PMID- 26595260 TI - In situ monitoring of catalytic process variations in a single nanowire by dark field-assisted surface-enhanced Raman spectroscopy. AB - In this communication, we provide a new method for characterizing the kinetics of a catalytic process on multiple sites of a single nanowire by dark-field-assisted surface-enhanced Raman spectroscopy (DFSERS). The differences in the reaction rate and the extent of the photocatalysis between sites of a single nanowire were observed. PMID- 26595261 TI - A New Method for Navigating Optimal Direction for Pulling Ligand from Binding Pocket: Application to Ranking Binding Affinity by Steered Molecular Dynamics. AB - In this paper we present a new method for finding the optimal path for pulling a ligand from the binding pocket using steered molecular dynamics (SMD). Scoring function is defined as the steric hindrance caused by a receptor to ligand movement. Then the optimal path corresponds to the minimum of this scoring function. We call the new method MSH (Minimal Steric Hindrance). Contrary to existing navigation methods, our approach takes into account the geometry of the ligand while other methods including CAVER only consider the ligand as a sphere with a given radius. Using three different target + receptor sets, we have shown that the rupture force Fmax and nonequilibrium work Wpull obtained based on the MSH method show a much higher correlation with experimental data on binding free energies compared to CAVER. Furthermore, Wpull was found to be a better indicator for binding affinity than Fmax. Thus, the new MSH method is a reliable tool for obtaining the best direction for ligand exiting from the binding site. Its combination with the standard SMD technique can provide reasonable results for ranking binding affinities using Wpull as a scoring function. PMID- 26595262 TI - Photoconjugation of Molecularly Imprinted Polymer Nanoparticles for Surface Enhanced Raman Detection of Propranolol. AB - We report a simple and versatile method to covalently immobilize molecularly imprinted polymer (MIP) nanoparticles on a Raman active substrate (Klarite) using a disulfide-derivatized perfluorophenylazide (PFPA-disulfide). Gold-coated Klarite was functionalized with PFPA-disulfide via a gold-sulfur bond. Upon light radiation, the available azido groups were converted to highly reactive singlet perfluorophenyl nitrene that undergoes a CH insertion reaction and form covalent bonds with the MIP nanoparticles. The resulting surfaces were characterized using scanning electron microscopy and surface enhanced Raman spectroscopy to study the morphology and template affinity of the surfaces, respectively. The Raman measurements clearly show a dose-responsive signal when propranolol binds to the MIP surface. Because the MIP particles were covalently attached to the Raman active substrate, the sensing surface was stable and could be reused after regeneration in acetic acid solution. The MIP-based Raman sensor was used successfully to detect propranolol in urine samples (7.7 * 10(-4) M). Our results show that the high selectivity of MIPs and the fingerprint Raman identification can be integrated into a compact sensing unit using high-efficiency photoconjugation. Thus, the method proposed is reliable, efficient and fast for fabricating label-free chemical sensors. PMID- 26595263 TI - A State-Level Analysis of Social and Structural Factors and HIV Outcomes Among Men Who Have Sex With Men in the United States. AB - We apply a social determinants of health model to examine the association of select social and structural influences on AIDS diagnosis rates among men who have sex with men (MSM) in the U.S. states. Secondary data for key social and structural variables were acquired and analyzed. Standard descriptive and inferential statistics were used to examine bivariate and multivariate associations of selected social and structural variables with estimated rate of Stage 3 HIV infection (AIDS) per 100,000 MSM in 2010. We found that living in states with a higher demographic density of lesbian, gay, bisexual, and transgender persons is independently associated with lower AIDS diagnosis rates among MSM. In addition, we found that greater income inequality and higher syphilis rates among men were associated with greater AIDS diagnosis rates among MSM, which may be attributable to state policy environments that underinvest in social goods that benefit population health, and to the fact that ulcerative sexually-transmitted infections increase biological risk of HIV transmission and acquisition. To end the epidemic in the U.S., it will be critical to identify and address state-level social and structural factors that may be associated with adverse HIV outcomes for MSM. PMID- 26595264 TI - The Development of a Counseling-Based HIV Prevention Intervention for African American Men Who Have Sex With Men and Women: The Bruthas Project. AB - African American men who have sex with both men and women (AAMSMW) are at high risk for acquiring and transmitting HIV, yet few interventions exist to address their unique prevention needs. We conducted 3 focus groups, 21 in-depth interviews, and a pilot test of our intervention with = 61 AAMSMW, which showed significant reductions in sexual risk behavior after 6 months. The intervention is currently being tested in a randomized controlled trial (RCT). We discuss the development of a culturally tailored, theoretically grounded counseling intervention for AAMSMW, presenting findings from our formative research, intervention development process, pilot study, and the implementation of our RCT. We describe the content of each session, our protocol for merging Bruthas with HIV testing, and best practices for recruiting AAMSMW. If Bruthas is found to be efficacious, the intervention will reach a vulnerable population to encourage uptake of regular HIV testing and reduced sexual risk taking. PMID- 26595265 TI - Using the Information-Motivation-Behavioral Skills Model to Guide the Development of an HIV Prevention Smartphone Application for High-Risk MSM. AB - HIV remains a significant public health problem among men who have sex with men (MSM). MSM comprise 2% of the U.S. population, but constitute 56% of persons living with HIV. Mobile health technology is a promising tool for HIV prevention. The purpose of this study was to identify the desired content, features and functions of a mobile application (app) for HIV prevention in high-risk MSM. We conducted five focus group sessions with 33 MSM. Focus group recordings were transcribed and coded using themes informed by the information-motivation behavioral (IMB) skills model. Participants identified information needs related to HIV prevention: HIV testing and prophylaxis distribution centers, support groups/peers, and HIV/STI disease/treatment information. Areas of motivation to target for the app included: attitudes and intentions. Participants identified behavioral skills to address with an app: using condoms correctly, negotiating safer sex, recognizing signs of HIV/STI. Findings from this work provide insight into the desired content of a mobile app for HIV prevention in high-risk MSM. PMID- 26595266 TI - Migration and HIV Risk Among Men Who Have Sex With Men, San Francisco, 2011. AB - In San Francisco, MSM account for nearly 90% of HIV infections. Studies have postulated increased risk for HIV faced by MSM who migrate, particularly to urban environments, yet empirical data are lacking. In this study we analyzed data from the National HIV Behavioral Surveillance System collected in 2011 to ascertain whether nativity (U.S. versus foreign born) was associated with HIV prevalence, risk behavior, and service use. Among 510 MSM enrolled, HIV prevalence was 23.0%. Multivariable analyses demonstrate that while nativity was not associated with increased risk for HIV infection, those who had lived in San Francisco for more than five years had higher HIV prevalence compared to those who had lived for less than a year even after adjusting for age, race, income, education, and location of birth. PMID- 26595267 TI - HIV Prevention Among Mexican Migrants at Different Migration Phases: Exposure to Prevention Messages and Association With Testing Behaviors. AB - Mobile populations are at increased risk for HIV infection. Exposure to HIV prevention messages at all phases of the migration process may help decrease im/migrants' HIV risk. We investigated levels of exposure to HIV prevention messages, factors associated with message exposure, and the association between exposure to prevention messages and HIV testing behavior among Mexican im/migrants at different phases of the migration process. We conducted a cross sectional, probability survey of Mexican im/migrants (N = 3,149) traveling through the border city of Tijuana, Mexico. The results indicate limited exposure to prevention messages (57-75%) and suboptimal last 12-month HIV testing rates (14-25%) across five migration phases. Compared to pre-departure levels (75%), exposure to messages decreases at all post-departure migration phases (57-63%, p < .001). In general, exposure to prevention messages is positively associated with greater odds of HIV testing at the pre-departure, destination, and interception phases. Binational efforts need to be intensified to reach and deliver HIV prevention to Mexican im/migrants across the migration continuum. PMID- 26595270 TI - Decline in Bone Mass During Weight Loss: A Cause for Concern? PMID- 26595268 TI - Facilitators of HIV Medical Care Engagement Among Former Prisoners. AB - Linkage to and retention in medical care is a concern for HIV-positive individuals leaving custody settings in the United States. The minimal existing research points to low rates of entry into care in the months following release and lapsed viral control among releasees who are subsequently reincarcerated. We conducted seven small focus group discussions with 27 HIVpositive individuals who were recently incarcerated in a California State prison to understand those factors that facilitated linkage to and retention in HIV care following their release. We used a consensual approach to code and analyze the focus group transcripts. Four main themes emerged from the analysis: (1) interpersonal relationships, (2) professional relationships, (3) coping strategies and resources, and (4) individual attitudes. Improving HIV-related outcomes among individuals after their release from prison requires strengthening supportive relationships, fostering the appropriate attitudes and skills, and ensuring access to resources that stabilize daily living and facilitate the process of accessing care. PMID- 26595271 TI - The contentious nature of soil organic matter. AB - The exchange of nutrients, energy and carbon between soil organic matter, the soil environment, aquatic systems and the atmosphere is important for agricultural productivity, water quality and climate. Long-standing theory suggests that soil organic matter is composed of inherently stable and chemically unique compounds. Here we argue that the available evidence does not support the formation of large-molecular-size and persistent 'humic substances' in soils. Instead, soil organic matter is a continuum of progressively decomposing organic compounds. We discuss implications of this view of the nature of soil organic matter for aquatic health, soil carbon-climate interactions and land management. PMID- 26595272 TI - FGF signalling regulates bone growth through autophagy. AB - Skeletal growth relies on both biosynthetic and catabolic processes. While the role of the former is clearly established, how the latter contributes to growth promoting pathways is less understood. Macroautophagy, hereafter referred to as autophagy, is a catabolic process that plays a fundamental part in tissue homeostasis. We investigated the role of autophagy during bone growth, which is mediated by chondrocyte rate of proliferation, hypertrophic differentiation and extracellular matrix (ECM) deposition in growth plates. Here we show that autophagy is induced in growth-plate chondrocytes during post-natal development and regulates the secretion of type II collagen (Col2), the major component of cartilage ECM. Mice lacking the autophagy related gene 7 (Atg7) in chondrocytes experience endoplasmic reticulum storage of type II procollagen (PC2) and defective formation of the Col2 fibrillary network in the ECM. Surprisingly, post natal induction of chondrocyte autophagy is mediated by the growth factor FGF18 through FGFR4 and JNK-dependent activation of the autophagy initiation complex VPS34-beclin-1. Autophagy is completely suppressed in growth plates from Fgf18(-/ ) embryos, while Fgf18(+/-) heterozygous and Fgfr4(-/-) mice fail to induce autophagy during post-natal development and show decreased Col2 levels in the growth plate. Strikingly, the Fgf18(+/-) and Fgfr4(-/-) phenotypes can be rescued in vivo by pharmacological activation of autophagy, pointing to autophagy as a novel effector of FGF signalling in bone. These data demonstrate that autophagy is a developmentally regulated process necessary for bone growth, and identify FGF signalling as a crucial regulator of autophagy in chondrocytes. PMID- 26595273 TI - Managing nitrogen for sustainable development. AB - Improvements in nitrogen use efficiency in crop production are critical for addressing the triple challenges of food security, environmental degradation and climate change. Such improvements are conditional not only on technological innovation, but also on socio-economic factors that are at present poorly understood. Here we examine historical patterns of agricultural nitrogen-use efficiency and find a broad range of national approaches to agricultural development and related pollution. We analyse examples of nitrogen use and propose targets, by geographic region and crop type, to meet the 2050 global food demand projected by the Food and Agriculture Organization while also meeting the Sustainable Development Goals pertaining to agriculture recently adopted by the United Nations General Assembly. Furthermore, we discuss socio-economic policies and technological innovations that may help achieve them. PMID- 26595275 TI - Death from drought in tropical forests is triggered by hydraulics not carbon starvation. AB - Drought threatens tropical rainforests over seasonal to decadal timescales, but the drivers of tree mortality following drought remain poorly understood. It has been suggested that reduced availability of non-structural carbohydrates (NSC) critically increases mortality risk through insufficient carbon supply to metabolism ('carbon starvation'). However, little is known about how NSC stores are affected by drought, especially over the long term, and whether they are more important than hydraulic processes in determining drought-induced mortality. Using data from the world's longest-running experimental drought study in tropical rainforest (in the Brazilian Amazon), we test whether carbon starvation or deterioration of the water-conducting pathways from soil to leaf trigger tree mortality. Biomass loss from mortality in the experimentally droughted forest increased substantially after >10 years of reduced soil moisture availability. The mortality signal was dominated by the death of large trees, which were at a much greater risk of hydraulic deterioration than smaller trees. However, we find no evidence that the droughted trees suffered carbon starvation, as their NSC concentrations were similar to those of non-droughted trees, and growth rates did not decline in either living or dying trees. Our results indicate that hydraulics, rather than carbon starvation, triggers tree death from drought in tropical rainforest. PMID- 26595276 TI - Soil biodiversity and human health. AB - Soil biodiversity is increasingly recognized as providing benefits to human health because it can suppress disease-causing soil organisms and provide clean air, water and food. Poor land-management practices and environmental change are, however, affecting belowground communities globally, and the resulting declines in soil biodiversity reduce and impair these benefits. Importantly, current research indicates that soil biodiversity can be maintained and partially restored if managed sustainably. Promoting the ecological complexity and robustness of soil biodiversity through improved management practices represents an underutilized resource with the ability to improve human health. PMID- 26595277 TI - High Ionic Conductivity of Composite Solid Polymer Electrolyte via In Situ Synthesis of Monodispersed SiO2 Nanospheres in Poly(ethylene oxide). AB - High ionic conductivity solid polymer electrolyte (SPE) has long been desired for the next generation high energy and safe rechargeable lithium batteries. Among all of the SPEs, composite polymer electrolyte (CPE) with ceramic fillers has garnered great interest due to the enhancement of ionic conductivity. However, the high degree of polymer crystallinity, agglomeration of ceramic fillers, and weak polymer-ceramic interaction limit the further improvement of ionic conductivity. Different from the existing methods of blending preformed ceramic particles with polymers, here we introduce an in situ synthesis of ceramic filler particles in polymer electrolyte. Much stronger chemical/mechanical interactions between monodispersed 12 nm diameter SiO2 nanospheres and poly(ethylene oxide) (PEO) chains were produced by in situ hydrolysis, which significantly suppresses the crystallization of PEO and thus facilitates polymer segmental motion for ionic conduction. In addition, an improved degree of LiClO4 dissociation can also be achieved. All of these lead to good ionic conductivity (1.2 * 10(-3) S cm(-1) at 60 degrees C, 4.4 * 10(-5) S cm(-1) at 30 degrees C). At the same time, largely extended electrochemical stability window up to 5.5 V can be observed. We further demonstrated all-solid-state lithium batteries showing excellent rate capability as well as good cycling performance. PMID- 26595278 TI - Influence of circadian disruption on neurotransmitter levels, physiological indexes, and behaviour in rats. AB - Brain monoamines - such as noradrenaline (NA), dopamine (DA) and serotonin (5-HT) - regulate several important physiological functions, including the circadian rhythm. The purpose of this study was to examine changes in NA, DA and 5-HT levels in various brain regions and their effect on core body temperature (Tc), heart rate (HR) and locomotor activity (Act) in rats following exposure to an artificial light/dark (LD) cycle. For this, male Wistar rats were housed at an ambient temperature (Ta) of 23 degrees C and 50% relative humidity with free access to food and water. Rats were exposed to either natural (12 h:12 h) or artificial (6 h:6 h) LD cycles for 1 month, after which each brain region was immediately extracted and homogenized to quantify the amounts of NA, DA and 5-HT by high-performance liquid chromatography. Behavioural changes were also monitored by the ambulatory activity test (AAT). Notably, we found that artificial LD cycles disrupted the physiological circadian rhythms of Tc, HR and Act. Although the 5-HT levels of rats with a disrupted circadian rhythm decreased in cell bodies (dorsal and median raphe nuclei) and projection areas (frontal cortex, caudate putamen, preoptic area and suprachiasmatic nucleus) relative to the control group, NA levels increased both in the cell body (locus coeruleus) and projection area (paraventricular hypothalamus). No significant changes were found with respect to DA. Moreover, circadian rhythm-disrupted rats also showed anxious behaviours in AAT. Collectively, the results of this study suggest that the serotonergic and noradrenergic systems, but not the dopaminergic system, are affected by artificial LD cycles in brain regions that control several neural and physiological functions, including the regulation of physiological circadian rhythms, stress responses and behaviour. PMID- 26595279 TI - Initiation Stories: An Examination of the Narratives of People Who Assist With a First Injection. AB - BACKGROUND: Research in the area of initiation to injection drug use that focuses on the perspective of initiators, or those who help with a first injection, is rare. OBJECTIVE: To explore the process of initiation to injection drug use from the point of view of initiators. METHODS: Semi-structured, in-depth qualitative interviews were conducted at a harm reduction program in Toronto, Canada. Twenty participants who had injected drugs in the last 30 days and who reported ever having initiated another person to injection drug use were recruited. A narrative analytic approach was used to explore the spectrum of narratives surrounding their experiences initiating others to injection drug use. RESULTS: Initiation events arise in a complex interplay of individual circumstances and social contexts. People who inject may assist with a first injection for a variety of reasons, from conceding to social pressure, to wanting to help reduce a perceived risk of harm, to assisting because it provides a sense of pride at possessing a skill or of having helped someone achieve a desired state, to assisting to obtain drugs or to cope with withdrawal, or a mix of several of these reasons at once. CONCLUSIONS/IMPORTANCE: Narratives reveal that preventing all instances of initiation is unrealistic. Combining elements from existing interventions that focus on enhancing reluctance to assist with initiation with safer injection training has the potential to reduce initiations and perhaps reduce injection related harm for novices if initiation occurs. PMID- 26595274 TI - Genome-wide patterns of selection in 230 ancient Eurasians. AB - Ancient DNA makes it possible to observe natural selection directly by analysing samples from populations before, during and after adaptation events. Here we report a genome-wide scan for selection using ancient DNA, capitalizing on the largest ancient DNA data set yet assembled: 230 West Eurasians who lived between 6500 and 300 bc, including 163 with newly reported data. The new samples include, to our knowledge, the first genome-wide ancient DNA from Anatolian Neolithic farmers, whose genetic material we obtained by extracting from petrous bones, and who we show were members of the population that was the source of Europe's first farmers. We also report a transect of the steppe region in Samara between 5600 and 300 bc, which allows us to identify admixture into the steppe from at least two external sources. We detect selection at loci associated with diet, pigmentation and immunity, and two independent episodes of selection on height. PMID- 26595280 TI - Methionine synthase A2756G variation is associated with the risk of retinoblastoma in Iranian children. AB - Association of epigenetic modifications with cancer has been widely studied. Gene specific hypermethylation and global DNA hypomethylation are the most frequently observed patterns in great number of tumors. The methionine synthase (MTR) gene plays key role in maintaining adequate intracellular folate, methionine and normal homocysteine concentrations and, its polymorphism have been associated with the risk of retinoblastoma and other neoplasms. We evaluated the association of MTR A2756G polymorphism with the risk of retinoblastoma in an Iranian population. Totally, 150 retinoblastoma patients and 300 individuals with no family history of cancer as control were included in this study. Genotyping of the A2756G polymorphism was performed by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) using the restriction enzymes HaeIII. Our results showed that the "G" was the minor allele with a frequency of 31.7% and 20.3% in both retinoblastoma and control groups, respectively. The frequency of the 2756GG genotype (P=0.023) and 2756G allele (P=0.0001) were significantly higher in the patients than control group, respectively. Individual with the 2756GG genotype had a 2.99 fold increased risk for retinoblastoma. According to our results, the MTR A2756G polymorphism was associated with the risk of retinoblastoma in Iranian patients. PMID- 26595281 TI - Effects of presentation duration on measures of complexity in affective environmental scenes and representational paintings. AB - Complexity constitutes an integral part of humans' environment and is inherent to information processing. However, little is known about the dynamics of visual complexity perception of affective environmental scenes (IAPS pictures) and artworks, such as affective representational paintings. In three experiments, we studied the time course of visual complexity perception by varying presentation duration and comparing subjective ratings with objective measures of complexity. In Experiment 1, 60 females rated 96 IAPS pictures, presented either for 1, 5, or 25s, for familiarity, complexity, pleasantness and arousal. In Experiment 2, another 60 females rated 96 representational paintings. Mean ratings of complexity and pleasantness changed according to presentation duration in a similar vein in both experiments, suggesting an inverted U-shape. No common pattern of results was observed for arousal and familiarity ratings across the two picture sets. The correlations between subjective and objective measures of complexity increased with longer exposure durations for IAPS pictures, but results were more ambiguous for paintings. Experiment 3 explored the time course of the multidimensionality of visual complexity perception. Another 109 females rated the number of objects, their disorganization and the differentiation between a figure-ground vs. complex scene composition of pictures presented for 1 and 5s. The multidimensionality of visual complexity only clearly emerged in the 5-s condition. In both picture sets, the strength of the correlations with objective measures depended on the type of subdimension of complexity and was less affected by presentation duration than correlations with general complexity in Experiments 1 and 2. These results have clear implications for perceptual and cognitive theories, especially for those of esthetic experiences, in which the dynamical changes of complexity perception need to be integrated. PMID- 26595282 TI - (1)H NMR based metabolomic profiling revealed doxorubicin-induced systematic alterations in a rat model. AB - Doxorubicin (DOX) is used as a chemotherapy drug with severe carditoxicity. In this study, an integrated echocardiography along with pathological examination and (1)H NMR analysis of multiple biological matrices (urine, serum, heart, and kidney) was employed to systemically assess the toxicity of DOX. Echocardiographic results showed that impaired left ventricular contractility and degenerative pathology lesions in DOX group, which were in consistent with pathology. The endogenous metabolites in the urine, serum, heart and kidney was identified by comparison with the data from the literature and databases. Multivariate analysis, including PCA and OPLS, revealed 8 metabolites in urine, including succinate, 2-ketoglutarate, citrate, hippurate, methylamine, benzoate, allantion, and acetate were the potential changed biomarkers. In serum, perturbed metabolites include elevation of leucine, beta-glucose, O-acetyl-glycoprotein, creatine, lysine, glycerin, dimethylglycine, trimethylamine-N-oxide, myo inositol, and N-acetyl-glycoprotein, together with level decreases of acetone, lipid, lactate, glutamate, phosphocholine, acetoacetate and pyruvate. For heart, DOX exposure caused decline of lipid, lactate, leucine, alanine, glutamate, choline, xanthine, glycerin, carnitine, and fumarate, together with elevation of glutamine, creatine, inosine, taurine and malate. Metabolic changes of kidney were mainly involved in the accumulation of alpha-glucose, lactate, phosphocholine, betaine, threonine, choline, taurine, glycine, urea, hypoxanthine, glutamate, and nicotinamide, coupled with reduction of asparagine, valine, methionine, tyrosine, lysine, alanine, leucine, ornithine, creatine, lipid, and acetate. In addition, alterations of urinary metabolites exhibited a time-dependent manner. Complementary evidences by multiple matrices revealed disturbed pathways concerning energy metabolism, fatty acids oxidation, amino acids and purine metabolism, choline metabolism, and gut microbiota-related metabolism. In addition, the change of endogenous metabolites in rats urine, serum, heart and kidney were correlated with the echocardiography parameters. This integrative study should help to develop a systematic understanding of cardiomyopathy-related diseases and their metabolic events. PMID- 26595283 TI - Tissue amino acid profile could be used to differentiate advanced adenoma from colorectal cancer. AB - Advanced adenomas are of higher risk to progress to colorectal cancer (CRC), the third leading cause of cancerous death worldwide. Endoscopy-based adenoma removal greatly contributes to arresting the progression of adenoma to CRC. Precise diagnosis, post-polypectomy surveillance and the follow-up clinical decisions predominantly depend on histopathologic inspection of the resected tissues. The common artificial histological inspection is not fully reliable and is only compatible with the en bloc removed tissues. An alternative measure ensuring more objective tissue malignance appraisal, which is applicable to various endoscopically acquired sample types are highly appreciated. In this study, we firstly employed capillary electrophoresis-mass spectrometry-based untargeted metabolomic technique to analyze CRC and corresponding paracancerous tissues to narrow the scope of malignancy-related metabolite changes. The primary results implied the most perturbated metabolites by CRC onset were amino acids. Subsequently, a targeted amino acid analysis by ultra-performance liquid chromatography-mass spectrometry indicated 9 amino acids were of different content between advanced adenoma and CRC tissues. Finally, regression analysis of the 9 differential amino acids exhibited that methionine, tyrosine, valine and isoleucine could be used to differentiate CRC from advanced adenomas with good sensitivity and specificity (p<0.001). Area under the receiver operating characteristic curve was 0.991. This study demonstrated the utility of metabolomic analysis in assisting malignance evaluation of colorectal neoplasia and the potential value of amino acids analysis in clinical pathology practice. PMID- 26595285 TI - COMPULSIVE BUYING TENDENCIES. AB - Compulsive buying behavior is typically viewed as pathological, but recent research has shown that compulsive buying tendencies are associated with attitudes toward money, personal financial behavior, and having materialistic values, suggesting that compulsive buyers are manifesting an extreme form of habits shown by people in general. In a study of 240 community residents, scores on the Compulsive Buying Scale were associated positively with scores on the Material Values Scale and the Canadian Problem Gambling Index, and negatively with scores on the Executive Personal Finance Scale and Ardelt's wisdom scale. These results suggest that, as is the case for many abnormal behaviors, tendencies toward compulsive buying may not be pathological, but are associated with attitudes toward money in general, financial management behavior, and materialistic values. PMID- 26595284 TI - Checkpoint inhibitors in bladder and renal cancers: results and perspectives. AB - The field of immunotherapy in urinary malignancy is expanding in several directions and checkpoint inhibitors are leading the way. The aim of this report is to highlight the efficacy and safety profile of the two classes of molecules, anti-cytotoxic T-lymphocyte antigen-4 and anti-programmed death receptor 1/programmed death ligand type 1, that are under investigation and represent potential candidates to be used in the near future for the management of bladder and renal cell cancer. The preliminary results as well as the future perspectives of this novel immunotherapy are analyzed. Novel immune checkpoint targets are reviewed as well. PMID- 26595286 TI - INTEREST IN ASTROLOGY AND PHRENOLOGY OVER TWO CENTURIES: A GOOGLE NGRAM STUDY. AB - The Google Ngram Viewer shows the frequency of words in a large corpus of books over two centuries. In this study, the names of two pseudosciences, astrology and phrenology, were compared. An interesting pattern emerged. While the level of interest in astrology remained relatively stable over the course of two centuries, interest in phrenology rose rapidly in the early 1800s but then declined. Reasons for this pattern are discussed. PMID- 26595287 TI - SPECIFIC EFFECTS OF ANGER RUMINATION ON PARTICULAR EXECUTIVE FUNCTIONS (.). AB - The effects of two types of rumination on different kinds of executive functions were investigated. Fifty-nine participants (M age = 22.8 yr., SD = 2.5) were assigned to one of three conditions and instructed either to: (1) ruminate in a self-distanced way, (2) ruminate in a self-immersed way, or (3) think about the layout of their campus following anger induction. Afterward, the participants were directed to finish tasks designed to assess three kinds of executive functions: shifting, inhibition, and updating. Results showed that self-immersed rumination impaired shifting ability the most, while participants engaged in self distanced rumination showed the worst performance on the inhibition task. No significant difference was found in the updating task. These results suggest that rumination influenced particular executive functions in different ways. PMID- 26595288 TI - FACTOR STRUCTURE AND PSYCHOMETRIC PROPERTIES OF THE INDEX OF TEACHING STRESS SHORT FORM (ITS-SF). AB - This study analyses factor structure and psychometric properties of the Italian short version of the Index of Teaching Stress-Short Form (ITS-SF). The original version of the ITS (90 items) was submitted to 567 teachers randomly drawn from a cross-section of school levels. Confirmatory factor analysis to check the factor structure was unsatisfactory, and Cronbach's alpha (.98) indicated a redundancy of items. Exploratory factor analysis was conducted for each section of the test and cross-loading items were eliminated. The resulting ITS-SF consists of 43 items, tapping eight meaningful and adequately reliable dimensions substantially corresponding to all dimensions measured by the original version of the ITS. The Italian short version of the Index of Teaching Stress constitutes a reliable measure of teacher stress in educative interactions. PMID- 26595289 TI - THREE STUDIES OF THE STANDARD PROGRESSIVE MATRICES IN MOROCCO (.). AB - Results are given for three studies of samples tested with the Standard Progressive Matrices (SPM) in Morocco. The first consisted of 85 children (boys, girls; M age = 8.5 yr.) in the town of Kenitra and obtained a British IQ of 74. The second consisted of 202 adults (92 men, 110 women; M age = 26 yr.) in four cities and obtained a British IQ of 81. The third consisted of 1,177 secondary school children (723 boys, 454 girls; ages 12-17 yr.) in a rural area and obtained a British IQ of 73.3. It is proposed that the best estimate of the Moroccan IQ can be obtained as the average of the three results, giving an IQ of 76. PMID- 26595290 TI - MOTIVATION INTERNALIZATION AND SIMPLEX STRUCTURE IN SELF-DETERMINATION THEORY. AB - Self-determination theory, as proposed by Deci and Ryan, postulated different types of motivation regulation. As to the introjected and identified regulation of extrinsic motivation, their internalizations were described as "somewhat external" and "somewhat internal" and remained undetermined in the theory. This paper introduces a constrained regression analysis that allows these vaguely expressed motivations to be estimated in an "optimal" manner, in any given empirical context. The approach was even generalized and applied for simplex structure analysis in self-determination theory. The technique was exemplified with an empirical study comparing science teaching in a classical school class versus an expeditionary outdoor program. Based on a sample of 84 German pupils (43 girls, 41 boys, 10 to 12 years old), data were collected using the German version of the Academic Self-Regulation Questionnaire. The science-teaching format was seen to not influence the pupils' internalization of identified regulation. The internalization of introjected regulation differed and shifted more toward the external pole in the outdoor teaching format. The quantification approach supported the simplex structure of self-determination theory, whereas correlations may disconfirm the simplex structure. PMID- 26595291 TI - THE EFFECT OF SELF-SET GRADE GOALS AND CORE SELF-EVALUATIONS ON ACADEMIC PERFORMANCE: A DIARY STUDY. AB - The aim of this diary study was to examine the effect of self-set grade goals and core self-evaluations on academic performance. Data were collected among 59 university students (M age = 18.4 yr., SD = 0.8) in a 2-wk. exam period on up to five exam days. Multilevel analyses revealed that the individual grade goals students set for their exams were positively related to the grades they obtained for these exams. However, the goal-performance relationship only applied to students scoring high on core self-evaluations. The results of this study contribute to the understanding of the effect of self-set grade goals and core self-evaluations on academic performance and imply important practical applications to enhance academic performance. PMID- 26595292 TI - EFFECTS OF MESSAGE FRAMING AND EXEMPLARS ON PROMOTING ORGAN DONATION. AB - People in many countries are unwilling to donate organs. Drawing on previous research regarding the use of message framing and the theory of exemplification promoting intentions to donate organs, this study examined messaging strategies. This study used a 2 * 2 between-subjects factorial design to examine the joint effects of gain/loss frames and statistical/exemplar appeals on the intentions of 189 Taiwanese college students (108 women, 81 men; age range = 19-24 yr., M = 21.6, SD = 2.9) regarding organ donation. Each participant was randomly assigned to read one of four versions of an organ donation promotional message and then to complete a questionnaire. The analysis of variance showed a significant interaction between the two factors. Loss-exemplar messages elicited significantly more positive intentions toward donation than did loss-statistical messages. There was no significant difference between the statistical and exemplar appeals observed under the gain-framed condition. The practical implications of developing effective organ donation promotional materials and the limitations of this study are discussed. PMID- 26595293 TI - THE INFLUENCE OF SOCIAL SUPPORT ON PSYCHOLOGICAL DISTRESS IN OLDER PERSONS: AN EXAMINATION OF INTERACTION PROCESSES IN AUSTRALIA. AB - Social support is proposed as a coping mechanism against anxiety and depression amongst older persons, but few data have examined how this occurs. This study assessed the contributions of two sub-components of social support as mediators against psychological distress-broadly defined as anxiety and depression. 1,560 men and 1,758 women from the Hunter Community Study (Australia) completed the Duke Social Support Scale and the Kessler Psychological Distress Scale. The Duke Social Support Scale examined the amount of social interaction and satisfaction with social interactions. Significant mediating effects of social support were found in the Kessler Psychological Distress Scale items measuring depression but not anxiety. Satisfaction with social support was a significant predictor of Kessler Psychological Distress Scale total score and Sadness items, but the amount of social support was not a predictor of stress. Social support may assist with symptoms of depression, i.e., specific sadness/depressed mood, but not necessarily with anxiety. Implications for policy and service delivery were discussed. PMID- 26595294 TI - SOURCES OF STRESS AND RECOVERY AS CONCURRENT PREDICTORS OF THE AFFECT BALANCE OF PATIENTS WITH FIBROMYALGIA. AB - This study examined sources of stress and recovery in a group of 107 patients with fibromyalgia (M age = 50.4 yr., SD = 11.8), in comparison to a control group of 68 healthy participants (M age = 47.8 yr., SD = 8.1) of equivalent age and marital status. Between-group differences in sources of stress and recovery were examined by means of an independent samples t test. In addition, between-groups differences in the relationship between sources of stress and recovery and affect balance were explored through a multi-group SEM analysis. The results provided evidence in support of the hypothesis that fibromyalgia patients find fewer sources of recovery and that the contribution of such sources for improving their affective well-being is lower than in healthy individuals. Relevant clinical implications were discussed. PMID- 26595295 TI - SELF-REPORT OF EMPATHY: A SHORTENED FRENCH ADAPTATION OF THE INTERPERSONAL REACTIVITY INDEX (IRI) USING TWO LARGE BELGIAN SAMPLES. AB - For more than 30 years, the Interpersonal Reactivity Index (IRI) has been used to measure the multidimensional aspects of empathy. But the 28-item, 4-factor model of Davis (1980 ) is currently contested because of methodological issues and for theoretical reasons. Confirmatory (CFA) and exploratory factor analyses (EFA) were applied in two French-speaking Belgian student samples (1,244 participants in the first and 729 in the second study) to test this model and to propose a shortened version. A non-optimal fit was found with respect to the CFI value (Study 1). By splitting the student group into two random subsamples, EFA and then CFA were used to propose a 15-item, 4-factor model with good fit indices. A CFA on the second student group (Study 2) replicated this model. Results are discussed considering the influence of social desirability response bias, an absence of strong invariance across sex and the usefulness of self-report scales to measure empathy. PMID- 26595296 TI - SEX DIFFERENCES ON THE WECHSLER INTELLIGENCE SCALE FOR CHILDREN-III IN BAHRAIN AND THE UNITED STATES. AB - Sex differences on the Wechsler Intelligence Scale for Children-III (WISC-III) are reported for children in Bahrain and the United States. The results for the two samples were consistent in showing no significant differences in Verbal, Performance, and Full Scale IQs, higher average scores by boys on the Block design and Mazes subtests of spatial ability, and higher average scores by girls on Coding. There was also greater variability in boys than in girls. PMID- 26595297 TI - PSYCHOMETRIC PROPERTIES OF THE OBSESSIVE-COMPULSIVE INVENTORY-REVISED IN A TURKISH ANALOGUE SAMPLE. AB - The Obsessive-Compulsive Inventory-Revised (OCI-R) assesses distress associated with the symptoms of obsessive-compulsive disorder (OCD). This study reports on the psychometric properties of the Turkish version of the OCI-R as a widely known measure. The sample consisted of 319 Turkish university students (67.1% women; M age = 21.5, SD = 2.0). The questionnaire battery included measures of OCD symptoms, specific cognitions, thought control, and personality characteristics. A target rotation analysis supported the factorial validity of the Turkish OCI-R as indicated by its replicability with the original factor structure (i.e., checking, washing, obsessing, hoarding, ordering, and mental neutralizing). High scoring OCD symptom groups also significantly differed on the Turkish OCI-R and thus presented preliminary evidence for its criterion validity. Correlational analysis supported convergent and divergent validity of the measure, with significant correlations between the Turkish OCI-R and OCD symptoms, OCD-specific beliefs, two thought control strategies (e.g., worry and punishment), and neuroticism, but not with psychoticism or extraversion. The current findings provide initial evidence of sound psychometric properties for the Turkish OCI-R in a nonclinical sample. PMID- 26595298 TI - SATISFACTION WITH LIFE AMONG YOUNG ADULTS IN FOUR ARAB COUNTRIES. AB - This study sought to explore the sex and cultural differences in satisfaction with life between undergraduate men and women recruited from four Arab countries, i.e., Egypt, Kuwait, Lebanon, and Qatar (N = 1,322); ages ranged from 18 to 27 years. The participants responded to the Arabic version of the Satisfaction with Life Scale. Egyptian and Lebanese women obtained significantly higher mean scores on satisfaction with life than did their male counterparts, whereas there were no significant sex differences in the Kuwaiti and Qatari samples. For men, the Qatari and Kuwaiti samples obtained the high mean scores on satisfaction with life, whereas the Egyptian and Lebanese samples obtained the low mean scores. For women, the Qatari sample had the higher mean score, whereas the Egyptian sample obtained the lowest mean score. The results were explained in light of the positive association between gross domestic product and satisfaction with life. PMID- 26595299 TI - SELF-REPORTS OF ILLEGAL ACTIVITY, SCL-90-R PERSONALITY SCALES, AND URINE TESTS IN METHADONE PATIENTS. AB - In routine work, medical staff usually has to rely on the patient's self-reports of criminal activity and of recent involvement in fights. This study examines how these self-reports of crime correlate with the patients' routine urine tests and personality measures. Pearson correlations of these self-reports by 55 methadone patients (M age = 34.1 yr., SD = 9.1; 35 men, 20 women) were calculated to their urine screening tests (those for opiates, benzodiazepines, and cocaine) and to personality scores on the Symptom Checklist 90-Revised (SCL-90-R). Patients who reported being involved in recent illegal activities to obtain drugs had significantly higher scores on the SCL-90-R scale assessing obsessive-compulsive symptoms (r = .28) and had more frequent positive urine tests for cocaine (r = .35). Those who reported having engaged in fights within the last 12 mo. had higher scores on SCL-90-R measures of somatic complaints (r = .32), anxiety (r = .31), and depression (r = .29), and of overall psychopathology (r = .29), and they also had more often positive urine tests for cocaine (r = .28) than other patients. Studies on larger samples are needed to help clinicians to predict criminal or hostile behavior during methadone treatment. PMID- 26595301 TI - PERSONALITY ASSESSMENT INVENTORY: PSYCHOMETRIC ANALYSES OF ITS ARGENTINEAN VERSION. AB - This psychometric analysis of the Argentinean version of the Personality Assessment Inventory employed a convenience sample of 998 non-clinical adults from Buenos Aires, Argentina, stratified by sex and age (50% men; M age = 40.4 yr., SD = 16.8; 50% women; M age = 40.7 yr., SD = 17.4; 69% were employed). For a criterion validity study, a second sample of 394 students at the University of Buenos Aires was selected (47% men; M age = 24 yr., SD = 3.7; 53% women; M age = 23.6 yr., SD = 3.4). Cronbach's alphas ranged from .60 to .86, indicating adequate internal consistency. Following American, German, and Spanish studies, a first analysis on the 22 scales obtained a five-factor solution (65.3% of total variance), and a second analysis on 11 clinical scales isolated a two-factor solution (69.3% of total variance). Correlations with the Symptom Checklist-90-R provided support for criterion validity. Most of the scales and subscales showed sex differences and differences between American and Argentinean samples. Future research must add other psychometric indicators. PMID- 26595300 TI - THE EFFECTS OF EXPRESSIVE WRITING ON POSTPARTUM DEPRESSION AND POSTTRAUMATIC STRESS SYMPTOMS. AB - This study investigated whether an Expressive Writing intervention decreased depression and posttraumatic stress symptoms after childbirth. 113 women (M age = 31.26 yr., SD = 4.42) were assessed at Time 1 for depression (Beck Depression Inventory) and PTS (Perinatal PTSD Questionnaire) in the first days after childbirth, then randomized to either expressive writing or neutral writing conditions and reassessed at Time 2, 3 months later. The results (ANCOVAs, regression models) show that at 3 mo. depressive and posttraumatic symptoms were lower in women who performed the expressive writing task than in the neutral writing group. Moreover, the intervention condition was associated significantly with decreased depression at the high and at the mean levels of baseline depression at Time 1. Regarding PTSD, the results showed that the intervention condition was linked significantly to reductions of the symptoms at all levels of baseline PTSD. Mainly, these outcomes suggest that Expressive Writing can be a helpful early and low-cost universal intervention to prevent postpartum distress for women. PMID- 26595302 TI - SUICIDE ON DEATH ROW. AB - For the period 1976-2011, the suicide rate on death rows in the United States was only weakly (and non-significantly) associated with the marriage, birth, divorce, and unemployment rates in the general population. Possible explanations for why social indicators in the larger society might be associated with the behavior of prisoners on death row were discussed. PMID- 26595303 TI - HUMOR STYLES, CREATIVE PERSONALITY TRAITS, AND CREATIVE THINKING IN A HONG KONG SAMPLE. AB - Humor is found to be an essential element of creative thinking in Western culture. In Eastern culture, however, the relationship between creativity and humor is ambivalent. This study examined the relationship among humor styles, creative personality traits, and creative thinking abilities. A sample of 118 Chinese undergraduates in Hong Kong was recruited to complete the Humor Styles Questionnaire, the three Creative Personality subscales of the Chinese Personality Assessment Inventory-2 (CPAI-2), and the Verbal Test of the Wallach Kogan Creativity Tests. Results show that humor styles are uncorrelated with creative thinking abilities of flexibility, fluency, and originality, but affiliative humor and aggressive humor are correlated with creative personality traits of novelty and diversity. A hierarchical multiple regression shows that both humor styles and creative personality traits of novelty and diversity account for non-significant variance on creative thinking abilities. These findings largely support a hypothesized non-association between humor styles and creative measures. They also pose a sharp contrast to findings obtained in the West, in which humor styles are typically correlated with both creative thinking abilities and creative personality traits. PMID- 26595304 TI - INFLUENCE OF PARENT-ADOLESCENT CONFLICT FREQUENCY ON ADOLESCENT FAMILY SATISFACTION AND SELF-SATISFACTION IN CHINA: CONFLICT COPING TACTICS AS MODERATORS. AB - Existing studies have found that parent-adolescent conflict frequency and conflict coping tactics influence adolescent family satisfaction and self satisfaction under the background of Western culture. However, due to differences between Eastern and Western cultures, it is unknown whether previous results of the Western population can be extended to Chinese adolescents. The present study investigated grade differences in parent-adolescent conflict frequency and conflict coping tactics and examined the moderating effects of conflict coping tactics on the relationships between conflict frequency and adolescent family satisfaction and between conflict frequency and adolescent self-satisfaction. Chinese adolescents in Grades 7, 8, 10, and 11 (N = 524) completed measures on conflict frequency, conflict coping tactics, family satisfaction, and self satisfaction. An analysis of variance (ANOVA) and structural equation model analyses found, first, that conflict frequency decreased with grade level. For coping tactics, conciliation, avoidance, and assertion behaviors increased with grade level. Second, conflict frequency was negatively related to family satisfaction regardless of conciliation and avoidance tactics. By contrast, conflict frequency was negatively related to self-satisfaction when high conciliation and high avoidance behaviors were practiced. In addition, at low conflict frequency conciliation was positively associated with self-satisfaction and was not significant at high conflict frequency. PMID- 26595305 TI - Differences of microbiota in small bowel and faeces between irritable bowel syndrome patients and healthy subjects. AB - OBJECTIVE: Several studies suggested that colonic microbiota have impacts on irritable bowel syndrome (IBS) patients. However, the knowledge about the association of small intestine (SI) microbiota with IBS is limited. We aimed to investigate the gut microbiota composition of SI and stool in IBS patients. MATERIALS AND METHODS: Biopsies of jejunum mucosa by balloon-assisted enteroscopy and faecal samples from 28 IBS patients and 19 healthy controls were analysed by next-generation sequencing method. RESULTS: The three major phyla in SI microbiota of case/control groups were Proteobacteria (32.8/47.7%), Bacteroidetes (25.2/15.3%), and Firmicutes (19.8/11.2%), and those of stool were Bacteroidetes (41.3/45.8%), Firmicutes (40.7/38.2%), and Proteobacteria (15.4/7.1%). Analysis based on the family level, IBS patients had a higher proportion of Veillonellaceae (mean proportion 6.49% versus 2.68%, p = 0.046) in stool than controls. Prevotellaceae was more abundant in IBS patients than in control group (14.27% versus 6.13%, p = 0.023), while Mycobacteriaceae (0.06% versus 0.17%, p = 0.024) and Neisseriaceae (6.40% versus 8.94%, p = 0.038) was less abundant in IBS patients' jejunal mucosa than those in controls. This less abundant jejunal Neisseriaceae was associated with more severe IBS (p = 0.03). The ratio of Firmicutes to Bacteroidetes in the stool of IBS-diarrhoea type patients was approximately three-fold higher, and the ratio of Firmicutes to Actinobacter in SI of IBS-mixed type patients was about nine-fold higher than healthy subjects. CONCLUSION: Higher abundance of colonic Veillonellaceae and SI Prevotellaceae, and lower amount of oral cavity normal flora in proximal SI were found in IBS patients. We may manipulate these bacteria in IBS patients in future studies (ClinicalTrial.gov Number NCT01679730). PMID- 26595306 TI - Neuro-immune dysfunction during brain aging: new insights in microglial cell regulation. AB - Microglia, the resident immune cells of the brain, are at the center of communication between the central nervous system and immune system. While these brain-immune interactions are balanced in healthy adulthood, the ability to maintain homeostasis during aging is impaired. Microglia develop a loss of integrated regulatory networks including aberrant signaling from other brain cells, immune sensors, and epigenetic modifiers. The low-grade chronic neuroinflammation associated with this dysfunctional activity likely contributes to cognitive deficits and susceptibility to age-related pathologies. A better understanding of the underlying mechanisms responsible for neuro-immune dysregulation with age is crucial for providing targeted therapeutic strategies to support brain repair and healthy aging. PMID- 26595307 TI - The prognostic value of p53 expression for patients with cervical cancer: a meta analysis. AB - OBJECTIVE: A number of studies have evaluated the association of p53 expression with the cervical cancer clinical outcome, but the results were inconsistent. STUDY DESIGN: Electronic search of PubMed was conducted to select studies. Studies which quantitatively evaluated the relationship between p53 expression and survival of the patients with cervical cancer were chosen, and hazard ratio (HR) with 95% confidence interval (CI) was used to assess the association. RESULTS: The final meta-analysis contained 11 published studies including 1105 patients. Combined HRs suggested that p53 overexpression has an unfavorable impact on overall survival(OS) [HR=1.672, 95% confidence interval (CI): 1.144 2.444, P=0.008], and Caucasian cervical cancer patients OS[HR=1.942, 95% CI: 1.162-3.245, P=0.011]. CONCLUSIONS: p53 expression indicates a poor prognosis for Caucasian people with cervical cancer. PMID- 26595308 TI - Integrated assessment of biochemical markers in premetamorphic tadpoles of three amphibian species exposed to glyphosate- and methidathion-based pesticides in single and combination forms. AB - In this study, we evaluated the toxic effects of a glyphosate-based herbicide (GBH) and a methidathion-based insecticide (MBI), individually and in combination, on premetamorphic tadpoles of three anuran species: Pelophylax ridibundus, Xenopus laevis, and Bufotes viridis. Based on the determined 96-h LC50 values of each species, the effects of a series of sublethal concentrations of single pesticides and their mixtures after 96-h exposure and also the time related effects of a high sublethal concentration of each pesticide were evaluated, with determination of changes in selected biomarkers: glutathione S transferase (GST), glutathione reductase (GR), acetylcholinesterase (AChE), carboxylesterase (CaE), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH). Also, the integrated biomarker response (IBR) was used to assess biomarker responses and quantitatively evaluate toxicological effects. Isozyme differences in CaE inhibition were assessed using native page electrophoresis; results showed that GBH to cause structural changes in the enzyme but not CaE inhibition in P. ridibundus. In general, single MBI and pesticide mixture exposures increased GST activity, while single GBH exposures decreased GST activity in exposed tadpoles. The AChE and CaE activities were inhibited after exposure to all single MBI and pesticide mixtures. Also, higher IBR values and GST, GR, AST, and LDH activities were determined for pesticide mixtures compared with single-pesticide exposure. This situation may be indicative of a synergistic interaction between pesticides and a sign of a more stressful condition. PMID- 26595309 TI - The role of selenium in insulin-like growth factor I receptor (IGF-IR) expression and regulation of apoptosis in mouse osteoblasts. AB - Selenium (Se) is an essential component for animals and human beings. The chemoprotective role of Se, via the regulation of the cell cycle, stimulation of apoptosis and activation of some cytokines among others, is well known; however, the comprehensive effects of Se on the expression of IGF-IR and its regulation of apoptosis have not been investigated. Thus the aim of this study was to report on the effects that different concentrations of Se extert on body weight, blood serum IGF-IR levels and histopathology in mice; and on IGF-IR expression, proliferation and apoptosis in mouse osteoblasts. In vivo experiments showed a significant decrease in body weight, serum levels of IGF-IR and prominent toxicant effects on the liver, kidney, heart and spleen following the administration of defined concentrations of Se for 30 d. However, moderate levels (0.1 mg/kg) of Se gradually improved weight and serum IGF-IR. In vitro osteoblast experiments revealed that at concentrations of 5 * 10(-6) and 10(-5) mol/L Se, MTT activity decreased in comparison with control cells. Cell cycle, TEM and caspase-3 activity supported these observations including an increase in the sub G1 phase and notable apoptosis in osteoblasts, along with a decrease in the expression of mRNA and protein levels of IGF-IR. Moreover, the MTT activity, mRNA and protein levels of IGF-IR in osteoblasts were decreased and caspase-3 activity was increased in siRNA groups as compared with non-siRNA groups. These data suggest that Se significantly affects IGF-IR expression, and that it contributes to the proliferation and regulation of apoptosis in osteoblasts. PMID- 26595310 TI - Bacterial regrowth in water reclamation and distribution systems revealed by viable bacterial detection assays. AB - Microbial regrowth needs to be managed during water reclamation and distribution. The aim of present study was to investigate the removal and regrowth of Escherichia coli (E. coli) and Salmonella in water reclamation and distribution system by using membrane integrity assay (PMA-qPCR), reverse transcriptional activity assay (Q-RT-PCR) and culture-based assay, and also to evaluate the relationships among bacterial regrowth, and environmental factors in the distribution system. The results showed that most of the water reclamation processes potentially induced bacteria into VBNC state. The culturable E. coli and Salmonella regrew 1.8 and 0.7 log10 in distribution system, which included reactivation of bacteria in the viable but non-culturable (VBNC) state and reproduction of culturable bacteria. The regrowth of culturable E. coli and Salmonella in the distribution system mainly depended on the residual chlorine levels, with correlations (R(2)) of -0.598 and -0.660. The abundances of membrane integrity and reverse transcriptional activity bacteria in reclamation effluents had significant correlations with the culturable bacteria at the end point of the distribution system, demonstrating that PMA-qPCR and Q-RT-PCR are sensitive and accurate tools to determine and predict bacterial regrowth in water distribution systems. This study has improved our understanding of microbial removal and regrowth in reclaimed water treatment and distribution systems. And the results also recommended that more processes should be equipped to remove viable bacteria in water reclamation plants for the sake of inhibition microbial regrowth during water distribution and usages. PMID- 26595312 TI - Comparison of species sensitivity distributions constructed with predicted acute toxicity data from interspecies correlation estimation models and measured acute data for benzo[a]pyrene. AB - Benzo[a]pyrene (BaP) is a priority Polycyclic Aromatic Hydrocarbon (PAH), which is toxic to aquatic organisms and has been widely detected in the environment. However, ecological risk assessment for BaP is hard to perform because of the absence of water quality criteria (WQC) and lack of toxicity data for this chemical. To fill in the data gaps, a interspecies correlation estimation (ICE) model was developed by USEPA to predict toxicity values for multiple species from the toxicity estimate for one species. In order to validate the applicability of the ICE model for BaP, measured-based-species sensitivity distributions (SSDs) generated using eight Chinese native aquatic species were compared with ICE-based SSDs generated using the data predicted from three surrogate species (Lepomis macrochirus, Cyprinus carpio and Daphnia magna). The results showed that there were no significant differences between the two SSD curves and the two hazardous concentrations for the 5% of species (HC5) derived from measured acute toxicity data and ICE-based predicted data. The ICE model was verified as a valid approach for generating SSDs with limited toxicity data. PMID- 26595311 TI - Use of passive samplers to detect organochlorine pesticides in air and water at wetland mountain region sites (S-SE Brazil). AB - Low-density polyethylene (LDPE) passive samplers were deployed in upland surface waters and the overlying atmosphere during May and June 2012, to determine the transport and trends of freely dissolved and gaseous organochlorine pesticides (OCPs) along altitudinal gradients in mountain regions in south and southeast Brazil. Gaseous OCP concentrations were dominated by hexachlorobenzene (3.0-29 pg m(-3)) and endosulfans (? = alpha-endosulfan + beta-endosulfan + endosulfan sulphate, 170-260 pg m(-3)), whereas freely dissolved endosulfans were significantly higher than all other OCPs (p < 0.001). The presence of some target pesticides at the highest elevation sites indicated their efficient high-altitude transport from regional sources. Air-water exchange gradients indicated net deposition of most volatile and recently banned OCPs (e.g., HCB, endosulfan) over Brazilian mountains. Moreover, the exposure of these sites to large-scale continental airflows with varying source contributions may partly explain the atmospheric deposition of selected OCPs over upland freshwaters at tropical and subtropical mountains sites in Brazil. These findings, coupled with LDPE passive air and water sampling measurements, point out the potential inputs from distant sources of semi-volatile chemicals to the two high-altitude sites. PMID- 26595313 TI - High As exposure induced substantial arsenite efflux in As-hyperaccumulator Pteris vittata. AB - Arsenite (AsIII) efflux is an important mechanism for arsenic (As) detoxification in plants. Low AsIII efflux has been observed in As-hyperaccumulator Pteris vittata, which may contribute to its highly efficient As translocation and accumulation; however, the results may be compromised by microbial AsIII oxidation, relatively low As concentration in the medium and short-term As exposure. Here, sterile P. vittata sporophytes were cultivated in sterile medium containing 10, 200 and 500 uM arsenate (AsV) for 28 d. Arsenite efflux to the growth medium and As speciation in P. vittata was investigated. Low AsIII efflux at 12% of AsV uptake was observed at 10 uM AsV, but high AsIII efflux (36-76%) was observed at 200 and 500 uM AsV, with 1987-2397 mg kg(-1) As being accumulated in the fronds. This is the first report to show efficient AsIII efflux in P. vittata. This study showed that P. vittata may use high AsIII efflux to cope with As toxicity under high As exposure, which may be necessary to sustain growth while accumulating As. PMID- 26595314 TI - Effects of beta-diketone antibiotic mixtures on behavior of zebrafish (Danio rerio). AB - To date, few data are available on neurotoxicity of beta-diketone antibiotics (DKAs) from the perspective of animal behavior. Herein, the effects of long-term DKAs exposure on zebrafish (Danio rerio) behavior were assessed for locomotor activity, anxiety, social interaction and their related molecular mechanisms. DKAs exposure to zebrafish consisted of six DKA species, including ofloxacin, ciprofloxacin, enrofloxacin, doxycycline, chlortetracycline and oxytetracycline, with equal weight concentration and equal volume. DKAs at 6.25 mg/L significantly increased the time spent in the upper portion of the test tank (+40%) and the number of line crossings (+/-42%), indicating occurrence of anxiolytic behavior. For conditioned place preference test, long-term DKAs exposure at 6.25 mg/L increased the number of motionless positions in the non-preferred white side (+31%), number of transitions to the white side (+221%) and time spent in the white side (+35%) in relation to the control. DKAs at 6.25 mg/L significantly increased zebrafish shoaling behavior (+38%) resulting from an anxiety-like state, but 25 mg/L DKAs exposure decreased zebrafish social cohesion (-41%) possibly due to an autism-like state. With increasing DKAs-exposure concentration, the signal intensity of (1)O2 gradually decreased, leading to insufficient energy supply and movement functional disorders. Based on GO functional annotation and metabolic pathway analysis, 11 genes closely associated with locomotor behavior were identified. Using qRT-PCR, we confirmed that DKAs exposure led to changes in the transcriptional levels of 11 locomotor-related genes. These results suggest that behavior is a potential strategy for evaluating mechanisms underlying the neurochemical basis triggered by stress in zebrafish. PMID- 26595315 TI - Country food sharing networks, household structure, and implications for understanding food insecurity in Arctic Canada. AB - We examine the cultural context of food insecurity among Inuit in Ulukhaktok, Northwest Territories, Canada. An analysis of the social network of country food exchanges among 122 households in the settlement reveals that a household's betweenness centrality-a measure of brokerage-in the country food network is predicted by the age of the household. The households of married couples were better positioned within the sharing network than were the households of single females or single males. Households with an active hunter or elder were also better positioned in the network. The households of single men and women appear to experience limited access to country food, a considerable problem given the increasing number of single-adult households over time. We conclude that the differences between how single women and single men experience constrained access to country foods may partially account for previous findings that single women in arctic settlements appear to be at particular risk for food insecurity. PMID- 26595316 TI - Placental morphology in pregnancies associated with pregravid obesity. AB - OBJECTIVE: Pre-gravid obesity is associated with increased morbidity and mortality for both mother and offspring. We aimed to investigate the changes in placental structure and to characterize the placental inflammatory status in obese women. METHODS: Placentas from 10 women with pregravid body mass index >= 30 kg/m(2) were analyzed histopathologically and compared with those from 10 normal weight women. The effect of pregravid obesity on placental structure was investigated by examining placental maturity, angiogenesis, inflammatory response, and vascular abnormalities. Hematoxylin and eosin stain, immunohistochemical analysis, and morphometric analysis were performed. RESULTS: Immaturity of the villous tree was demonstrated more often in the pregravid obesity group (p = 0.005). The villous tree was mainly represented by villi of larger diameter (p = 0.001) and lower number (p = 0.023) compared with controls. By contrast, the number of capillaries per villus was increased in the obese group (p = 0.001), while the global number of capillaries per surface unit did not differ in the studied groups (p = 1). There was no difference between the pre gravid obese group and controls in inflammatory status and vascular pathology. CONCLUSIONS: Pregravid obesity is associated with focal immaturity of the villous tree and angiogenetic abnormalities of the placenta. PMID- 26595317 TI - Use of probabilistic weights to enhance linear regression myoelectric control. AB - OBJECTIVE: Clinically available prostheses for transradial amputees do not allow simultaneous myoelectric control of degrees of freedom (DOFs). Linear regression methods can provide simultaneous myoelectric control, but frequently also result in difficulty with isolating individual DOFs when desired. This study evaluated the potential of using probabilistic estimates of categories of gross prosthesis movement, which are commonly used in classification-based myoelectric control, to enhance linear regression myoelectric control. APPROACH: Gaussian models were fit to electromyogram (EMG) feature distributions for three movement classes at each DOF (no movement, or movement in either direction) and used to weight the output of linear regression models by the probability that the user intended the movement. Eight able-bodied and two transradial amputee subjects worked in a virtual Fitts' law task to evaluate differences in controllability between linear regression and probability-weighted regression for an intramuscular EMG-based three-DOF wrist and hand system. MAIN RESULTS: Real-time and offline analyses in able-bodied subjects demonstrated that probability weighting improved performance during single-DOF tasks (p < 0.05) by preventing extraneous movement at additional DOFs. Similar results were seen in experiments with two transradial amputees. Though goodness-of-fit evaluations suggested that the EMG feature distributions showed some deviations from the Gaussian, equal-covariance assumptions used in this experiment, the assumptions were sufficiently met to provide improved performance compared to linear regression control. SIGNIFICANCE: Use of probability weights can improve the ability to isolate individual during linear regression myoelectric control, while maintaining the ability to simultaneously control multiple DOFs. PMID- 26595318 TI - Axial Segmental Coordination During Turning: Effects of Stroke and Attentional Loadings. AB - Attentional loadings deteriorate straight walking performance for individuals poststroke, but its effects on turning while walking remain to be determined. Here we compared turning kinematics under three attentional loading conditions (single, dual-motor, and dual-cognitive task) between stroke survivors and healthy controls. Nine chronic stroke survivors and 10 healthy controls performed the Timed Upand- Go test while their full-body kinematics were recorded. Onset times of yaw rotation of the head, thorax and pelvis segments and head anticipation distance were used to quantify turning coordination. Results showed that stroke survivors reoriented their body segments much earlier than the controls, but they preserved the similar segmental reorientation sequence under the single-task condition. For the healthy controls, attentional loading led to an earlier axial segment reorientation, but the reorientation sequence was preserved. In contrast, the dual-cognitive task condition led to a disrupted reorientation sequence in stroke. The results indicate that turning coordination was altered in individuals poststroke, especially under the dual-task interference. PMID- 26595319 TI - Molecular medicine and cancer. PMID- 26595320 TI - Bottom-Up Hierarchical Self-Assembly of Chiral Porphyrins through Coordination and Hydrogen Bonds. AB - A series of chiral synthetic compounds is reported that shows intricate but specific hierarchical assembly because of varying positions of coordination and hydrogen bonds. The evolution of the aggregates (followed by absorption spectroscopy and temperature-dependent circular dichroism studies in solution) reveal the influence of the proportion of stereogenic centers in the side groups connected to the chromophore ring in their optical activity and the important role of pyridyl groups in the self-assembly of these chiral macrocycles. The optical activity spans 2 orders of magnitude depending on composition and constitution. Two of the aggregates show very high optical activity even though the isolated chromophores barely give a circular dichroism signal. Molecular modeling of the aggregates, starting from the pyridine-zinc(II) porphyrin interaction and working up, and calculation of the circular dichroism signal confirm the origin of this optical activity as the chiral supramolecular organization of the molecules. The aggregates show a broad absorption range, between approximately 390 and 475 nm for the transitions associated with the Soret region alone, that spans wavelengths far more than the isolated chromophore. The supramolecular assemblies of the metalloporphyrins in solution were deposited onto highly oriented pyrolitic graphite in order to study their hierarchy in assembly by atomic force microscopy. Zero and one-dimensional aggregates were observed, and a clear dependence on deposition temperature was shown, indicating that the hierarchical assembly took place largely in solution. Moreover, scanning electron microscopy images of porphyrins and metalloporphyrins precipitated under out-of-equilibrium conditions showed the dependence of the number and position of chiral amide groups in the formation of a fibrillar nanomaterial. The combination of coordination and hydrogen bonding in the complicated assembly of these molecules-where there is a clear hierarchy for zinc(II)-pyridyl interaction followed by hydrogen-bonding between amide groups, and then van der Waals interactions-paves the way for the preparation of molecular materials with multiple chromophore environments. PMID- 26595321 TI - Histology-Guided High-Resolution Matrix-Assisted Laser Desorption Ionization Mass Spectrometry Imaging. AB - Mass spectrometry imaging (MSI) is widely used for clinical research because when combined with histopathological analysis the molecular signatures of specific cells/regions can be extracted from the often-complex histologies of pathological tissues. The ability of MSI to stratify patients according to disease, prognosis, and response is directly attributable to this cellular specificity. MSI developments are increasingly focused on further improving specificity, through higher spatial resolution to better localize the signals or higher mass resolution to better resolve molecular ions. Higher spatial/mass resolution leads to increased data size and longer data acquisition times. For clinical applications, which analyze large series of patient tissues, this poses a challenge to keep data load and acquisition time manageable. Here we report a new tool to perform histology guided MSI; instead of analyzing large parts of each tissue section the histology from adjacent tissue sections is used to focus the analysis on the areas of interest, e.g., comparable cell types in different patient tissues, thereby minimizing data acquisition time and data load. The histology tissue section is annotated and then automatically registered to the MSI-prepared tissue section; the registration transformation is then applied to the annotations, enabling them to be used to define the MSI measurement regions. Using a series of formalin-fixed, paraffin-embedded human myxoid liposarcoma tissues, we demonstrate an 80% reduction of data load and acquisition time, thereby enabling high resolution (mass or spatial) to be more readily applied to clinical research. The software is freely available for download. PMID- 26595322 TI - Investigating the Task Dependency of Viewing Time Effects. AB - The viewing time method (VT) is an indirect measure of sexual interest in which participants are usually asked to rate the sexual attractiveness of target stimuli while their response latencies are unobtrusively measured. Higher response latencies for a certain group of depicted individuals indicate sexual interest in that group. Contrary to the general assumption that the picture content accounts for this effect by eliciting affect- or attention-based response delays, we hypothesized that the attractiveness rating task might be responsible for the VT effect. To test this hypothesis, we used two different tasks. Our heterosexual and homosexual male participants (N = 50) were instructed to rate the attractiveness or the sex of the depicted individuals. As expected, VT effects only emerged in attractiveness rating trials. Based on these findings, we conclude that VT effects are task dependent and are unlikely to be caused by affective or attentional processes (at least when participants are instructed to rate the attractiveness of target stimuli). We argue that rating tasks in VT measures cause participants to use affect independent response strategies. These response strategies seem to undermine stimulus-driven processes (like increased attention directed toward salient stimuli) which were thought to cause VT effects according to previous hypotheses. PMID- 26595323 TI - Infrared and Visible Photodissociation Spectra of Rhodamine Ions at 3 K in the Gas Phase. AB - Helium-tagging predissociation spectroscopy in the visible spectral range (He@VisPD) is shown for Rhodamine 123, Rhodamine 110, and Rhodamine 110's silver salt (silver carboxylate). It is shown that the spectra reflect single-photon absorption. The helium-tagged ions are in the ground vibrational state, and the He@VisPD spectra feature the Franck-Condon envelopes for the excitation to the first excited singlet state that agree very well with theoretical simulations. The S0 -> S1 excitation energies are 2.712 +/- 0.006 eV for Rhodamine 123, 2.700 +/- 0.006 eV for Rhodamine 110, and 2.751 +/- 0.006 eV for the silver salt of Rhodamine 110. The determined energies can be slightly blue-shifted due to the binding energy of helium. The Rhodamine ions were also characterized by helium tagging infrared photodissociation spectroscopy. The distinctive spectral features of the individual derivatives are described and the spectra are compared to the classical solid-state IR spectra. PMID- 26595324 TI - LCST Behavior is Manifested in a Single Molecule: Elastin-Like polypeptide (VPGVG)n. AB - The physical origin of the lower critical solution temperature (LCST) behavior of a variety of fluids, including elastin-like polypeptides (ELPs), has been studied for the past few decades. As is the case for polymer solutions, LCST behavior of ELPs is invariably reported for large systems of molecules and is considered evidence for collective behavior. In contrast, we find evidence for properties changes associated with LCST behavior in a single molecule by performing long atomic-level molecular dynamics simulation on the ELP sequences (Val-Pro-Gly-Val Gly)n for four different length peptides over a wide range of temperatures. We observe a sharp transition in the number of hydrogen bonds between peptide and water and in the number of water molecules within the first hydration shell as temperature rises; this is used to locate the transition temperature. The dependence of the transition temperatures of ELPs on their lengths agrees well with experiments in that both have the same power law exponents. Our simulations reveal that the tendency for pentamers (VPGVG) in ELPs of all lengths to lose H bonds with water or to gain H-bonds with themselves as temperature rises is independent of the length of the chain in which they are embedded. Thus, the transition temperature of ELPs in pure water is determined by two factors: the hydrogen bonding tendency of the pentamers and the number of pentamers per ELP. Moreover, the hydrogen bonding tendency of pentamers depends only on their sequences, not on the ELP chain length. PMID- 26595327 TI - Shape-Dependent Nonlinear Optical Properties of Anisotropic Gold Nanoparticles. AB - This Letter reports the shape-dependent third-order nonlinear optical properties of anisotropic gold nanoparticles. We characterized the nonlinear absorption coefficients of nanorods, nanostars, and nanoshells using femtosecond Z-scan measurements. By comparing nanoparticle solutions with a similar linear extinction at the laser excitation wavelength, we separated shape effects from that of the localized surface plasmon wavelength. We found that the nonlinear response depended on particle shape. Using pump-probe spectroscopy, we measured the ultrafast transient response of nanoparticles, which supported the strong saturable absorption observed in nanorods and weak nonlinear response in nanoshells. We found that the magnitude of saturable absorption as well as the ultrafast spectral responses of nanoparticles were affected by the linear absorption of the nanoparticles. PMID- 26595328 TI - High-Nuclear Vanadoniobate {Nb48V8} Multiple-Strand Wheel. AB - An unprecedented octavanadium-substituted polyoxoniobate Na18[Nb48V8(OH)30O130] . 33H2O (1), with a multiple-strand wheel structure, was successfully synthesized via a conventional aqueous method, which represents the largest vanadoniobate cluster reported to date. Single-crystal X-ray diffraction, ESI-MS spectrum, IR spectra, and UV-vis spectra were investigated. In addition, photocatalytic H2 evolution activity for 1 under UV light was observed with TEA as a sacrificial electron donor. PMID- 26595329 TI - The "Fourth Mission": The Time Commitment of Anesthesiology Faculty for Management Is Comparable to Their Time Commitments to Education, Research, and Indirect Patient Care. AB - Academic anesthesia departments have management responsibilities (e.g., coordinating sedation, directing the operating rooms [ORs], informatics, ongoing professional performance evaluation, staff scheduling, and workroom inventory management). For each of the 64 faculty, a survey sampled 10 weekdays and 4 weekend days of professional activity over N=56 days. Faculty time in managerial activities was 126% of time spent on education, 107% of time spent in research, and 112% of time spent on mandatory indirect clinical support (e.g., fire safety training). The 95% lower confidence limits calculated using Fieller's theorem were 107%, 89%, and 91%, respectively. Corresponding bootstrap limits were 107%, 89%, and 90%, respectively. Thus, although our College of Medicine tripartite mission includes clinical care, education, and research, administrative activities constitute a "fourth mission" of our department. PMID- 26595330 TI - Molecular cavity optomechanics as a theory of plasmon-enhanced Raman scattering. AB - The exceptional enhancement of Raman scattering by localized plasmonic resonances in the near field of metallic nanoparticles, surfaces or tips (SERS, TERS) has enabled spectroscopic fingerprinting down to the single molecule level. The conventional explanation attributes the enhancement to the subwavelength confinement of the electromagnetic field near nanoantennas. Here, we introduce a new model that also accounts for the dynamical nature of the plasmon-molecule interaction. We thereby reveal an enhancement mechanism not considered before: dynamical backaction amplification of molecular vibrations. We first map the system onto the canonical Hamiltonian of cavity optomechanics, in which the molecular vibration and the plasmon are parametrically coupled. We express the vacuum optomechanical coupling rate for individual molecules in plasmonic 'hot spots' in terms of the vibrational mode's Raman activity and find it to be orders of magnitude larger than for microfabricated optomechanical systems. Remarkably, the frequency of commonly studied molecular vibrations can be comparable to or larger than the plasmon's decay rate. Together, these considerations predict that an excitation laser blue-detuned from the plasmon resonance can parametrically amplify the molecular vibration, leading to a nonlinear enhancement of Raman emission that is not predicted by the conventional theory. Our optomechanical approach recovers known results, provides a quantitative framework for the calculation of cross-sections, and enables the design of novel systems that leverage dynamical backaction to achieve additional, mode-selective enhancements. It also provides a quantum mechanical framework to analyse plasmon-vibrational interactions in terms of molecular quantum optomechanics. PMID- 26595331 TI - Revealing giant internal magnetic fields due to spin fluctuations in magnetically doped colloidal nanocrystals. AB - Strong quantum confinement in semiconductors can compress the wavefunctions of band electrons and holes to nanometre-scale volumes, significantly enhancing interactions between themselves and individual dopants. In magnetically doped semiconductors, where paramagnetic dopants (such as Mn(2+), Co(2+) and so on) couple to band carriers via strong sp-d spin exchange, giant magneto-optical effects can therefore be realized in confined geometries using few or even single impurity spins. Importantly, however, thermodynamic spin fluctuations become increasingly relevant in this few-spin limit. In nanoscale volumes, the statistical fluctuations of N spins are expected to generate giant effective magnetic fields Beff, which should dramatically impact carrier spin dynamics, even in the absence of any applied field. Here we directly and unambiguously reveal the large Beff that exist in Mn(2+)-doped CdSe colloidal nanocrystals using ultrafast optical spectroscopy. At zero applied magnetic field, extremely rapid (300-600 GHz) spin precession of photoinjected electrons is observed, indicating Beff ~ 15 -30 T for electrons. Precession frequencies exceed 2 THz in applied magnetic fields. These signals arise from electron precession about the random fields due to statistically incomplete cancellation of the embedded Mn(2+) moments, thereby revealing the initial coherent dynamics of magnetic polaron formation, and highlighting the importance of magnetization fluctuations on carrier spin dynamics in nanomaterials. PMID- 26595332 TI - Nanocavities: Optomechanics goes molecular. PMID- 26595333 TI - Nanoreactors: Chemistry in and out of nanoflasks. PMID- 26595334 TI - Harnessing the damping properties of materials for high-speed atomic force microscopy. AB - The success of high-speed atomic force microscopy in imaging molecular motors, enzymes and microbes in liquid environments suggests that the technique could be of significant value in a variety of areas of nanotechnology. However, the majority of atomic force microscopy experiments are performed in air, and the tapping-mode detection speed of current high-speed cantilevers is an order of magnitude lower in air than in liquids. Traditional approaches to increasing the imaging rate of atomic force microscopy have involved reducing the size of the cantilever, but further reductions in size will require a fundamental change in the detection method of the microscope. Here, we show that high-speed imaging in air can instead be achieved by changing the cantilever material. We use cantilevers fabricated from polymers, which can mimic the high damping environment of liquids. With this approach, SU-8 polymer cantilevers are developed that have an imaging-in-air detection bandwidth that is 19 times faster than those of conventional cantilevers of similar size, resonance frequency and spring constant. PMID- 26595335 TI - Reversible trapping and reaction acceleration within dynamically self-assembling nanoflasks. AB - The chemical behaviour of molecules can be significantly modified by confinement to volumes comparable to the dimensions of the molecules. Although such confined spaces can be found in various nanostructured materials, such as zeolites, nanoporous organic frameworks and colloidal nanocrystal assemblies, the slow diffusion of molecules in and out of these materials has greatly hampered studying the effect of confinement on their physicochemical properties. Here, we show that this diffusion limitation can be overcome by reversibly creating and destroying confined environments by means of ultraviolet and visible light irradiation. We use colloidal nanocrystals functionalized with light-responsive ligands that readily self-assemble and trap various molecules from the surrounding bulk solution. Once trapped, these molecules can undergo chemical reactions with increased rates and with stereoselectivities significantly different from those in bulk solution. Illumination with visible light disassembles these nanoflasks, releasing the product in solution and thereby establishes a catalytic cycle. These dynamic nanoflasks can be useful for studying chemical reactivities in confined environments and for synthesizing molecules that are otherwise hard to achieve in bulk solution. PMID- 26595336 TI - Nanoscopic exclusion between Rad51 and 53BP1 after ion irradiation in human HeLa cells. AB - Many proteins involved in detection, signalling and repair of DNA double-strand breaks (DSB) accumulate in large number in the vicinity of DSB sites, forming so called foci. Emerging evidence suggests that these foci are sub-divided in structural or functional domains. We use stimulated emission depletion (STED) microscopy to investigate localization of mediator protein 53BP1 and recombination factor Rad51 after irradiation of cells with low linear energy transfer (LET) protons or high LET carbon ions. With a resolution better than 100 nm, STED microscopy and image analysis using a newly developed analyzing algorithm, the reduced product of the differences from the mean, allowed us to demonstrate that with both irradiation types Rad51 occupies spherical regions of about 200 nm diameter. These foci locate within larger 53BP1 accumulations in regions of local 53BP1 depletion, similar to what has been described for the localization of Brca1, CtIP and RPA. Furthermore, localization relative to 53BP1 and size of Rad51 foci was not different after irradiation with low and high LET radiation. As expected, 53BP1 foci induced by low LET irradiation mostly contained one Rad51 focal structure, while after high LET irradiation, most foci contained >1 Rad51 accumulation. PMID- 26595337 TI - Molecular Analysis of Libyan Families with Allgrove Syndrome: Geographic Expansion of the Ancestral Mutation c.1331+1G>A in North Africa. AB - BACKGROUND/AIMS: Allgrove syndrome is a rare autosomal recessive disorder characterized by alacrima, achalasia, and adrenal insufficiency. It is caused by mutations of the AAAS gene located on chromosome 12q13 encoding the WD-repeat protein ALADIN. The c.1331+1G>A mutation is one of the most common mutations described in the literature and was identified in Tunisian and Algerian populations. Herein, we describe the clinical and genetic profile of two families from Libya in North Africa associated with Allgrove syndrome. METHODS: Two unrelated families clinically diagnosed with Allgrove syndrome were evaluated for sequence variations in the AAAS gene. Blood samples were collected, and isolated DNA derived from the subjects was amplified. The entire sequence of the AAAS gene was analyzed by PCR-RFLP and direct sequencing. RESULTS: Molecular analysis revealed the major homozygous mutation (c.1331+1G>A) in all patients. The presence of a major mutation in Tunisia, Algeria and, as discovered in this report, in Libya in patients with Allgrove syndrome suggests the existence of an ancestral mutation and a founder effect in North Africa. CONCLUSIONS: The findings allow for a fast genetic counseling in North African families with Allgrove syndrome. To the best of our knowledge, this is the first report of Allgrove syndrome in Libya. PMID- 26595338 TI - 111In-Pentetreotide Imaging in Diffuse Idiopathic Neuroendocrine Hyperplasia of the Lung. AB - Diffuse idiopathic endocrine neoplasia of the lung (DIPNECH) is a rare disease characterized by proliferation of neuroendocrine cells in the bronchial wall. Less than 20 cases of DIPNECH have been reported in imaging literature. We present here a case of histopathologically diagnosed DIPNECH with diffusely increased In-octreotide uptake in both lungs. PMID- 26595339 TI - Skeletal "Superscan" on 18F-Choline PET/CT: Cases of Myeloproliferative Disease. AB - We describe 2 cases of skeletal "superscan" with F-choline PET/CT in prostate cancer (PCa) patients. Both cases demonstrated diffuse skeletal involvement besides their primary prostate tumor. The first impression was that this presentation would be related to diffuse tumoral skeletal invasion by PCa as often seen in Tc-MDP bone scintigraphy. In both cases, the bone involvement was shown to be caused by hematological disease (polycythemia vera and chronic myelomonocytic leukemia), demonstrating the importance of also considering the presence of myeloproliferative syndromes when presented with diffuse bone disease on choline PET/CT performed in PCa patients. PMID- 26595340 TI - Intraoperative 3D Navigation for Single or Multiple 125I-Seed Localization in Breast-Preserving Cancer Surgery. AB - BACKGROUND: Mammographic screening has led to the identification of more women with nonpalpable breast cancer, many of them to be treated with breast-preserving surgery. To accomplish radical tumor excision, adequate localization techniques such as radioactive seed localization (RSL) are required. For RSL, a radioactive I-seed is implanted central in the tumor to enable intraoperative localization using a gamma-probe. In case of extensive tumor or multifocal carcinoma, multiple I-seeds can be used to delineate the involved area. Preoperative imaging is performed different from surgical positioning; therefore, exact I-seed depth remains unknown during surgery. PATIENTS AND METHODS: Twenty patients (mean age, 56.8 years) with 25 implanted I-seeds scheduled for RSL were included. Sixteen patients had 1 I-seed implanted in the primary lesion, 3 patients had 2 I-seeds, and 1 patient had 3 I-seeds. Freehand SPECT localized I-seeds by measuring gamma counts from different directions, all registered by an optical tracking system. A reconstruction and visualization algorithm enabled 3-dimensional (3D) navigation toward the I-seeds. RESULTS: Freehand SPECT visualized all I-seeds in primary tumors and provided preincision depth information. The deviation, mean (SD), between the freehand SPECT depth and the surgical depth estimation was 1.9 (2.1) mm (range, 0-7 mm). Three-dimensional freehand SPECT was especially useful identifying multiple implanted I-seeds because the conventional gamma-probe has more difficulty discriminating I-seeds transcutaneous. CONCLUSIONS: Freehand SPECT with 3D navigation is a valuable tool in RSL for both single and multiple implanted I-seeds in breast-preserving cancer surgery. Freehand SPECT provides continuous updating 3D imaging with information about depth and location of the I seeds contributing to adequate excision of nonpalpable breast cancer. PMID- 26595341 TI - MRI and FDG PET/CT Uncovered the Cause of a Paraneoplastic Leukemoid Reaction. AB - An 18-year-old man with progressive headache and vomiting for 2 weeks had significantly elevated levels of WBC count, which kept on rising over time during in-hospital evaluation. Exhaustive examinations did not reveal infection or any other explanations of increased WBC count. Instead, brain MRI and FDG PET/CT identified a malignant lesion in the brain without abnormality elsewhere. The pathological examination revealed a rhabdoid meningioma. The level of the WBC counts returned to normal promptly after surgical resection of the tumor, which confirmed the diagnosis of paraneoplastic leukemoid reaction. PMID- 26595342 TI - Reactivity of Cations and Zwitterions Formed in Photochemical and Acid-Catalyzed Reactions from m-Hydroxycycloalkyl-Substituted Phenol Derivatives. AB - Three m-substituted phenol derivatives, each with a labile benzylic alcohol group and bearing either protoadamantyl 4, homoadamantyl 5, or a cyclohexyl group 6, were synthesized and their thermal acid-catalyzed and photochemical solvolytic reactivity studied, using preparative irradiations, fluorescence measurements, nanosecond laser flash photolysis, and quantum chemical calculations. The choice of m-hydroxy-substitution was driven by the potential for these phenolic systems to generate m-quinone methides on photolysis, which could ultimately drive the excited-state pathway, as opposed to forming simple benzylic carbocations in the corresponding thermal route. Indeed, thermal acid-catalyzed reactions gave the corresponding cations, which undergo rearrangement and elimination from 4, only elimination from 5, and substitution and elimination from 6. On the other hand, upon photoexcitation of 4-6 to S1 in a polar protic solvent, proton dissociation from the phenol, coupled with elimination of the benzylic OH (as hydroxide ion) gave zwitterions (formal m-quinone methides). The zwitterions exhibit reactivity different from the corresponding cations due to a difference in charge distribution, as shown by DFT calculations. Thus, protoadamantyl zwitterion has a less nonclassical character than the corresponding cation, so it does not undergo 1,2-shift of the carbon atom, as observed in the acid-catalyzed reaction. PMID- 26595343 TI - Therapists' perspectives on optimal treatment for pathological narcissism. AB - This study used Q methodology to explore clinicians' perspectives regarding optimal psychotherapy process in the treatment of pathological narcissism, a syndrome of impaired self-regulation. Participants were 34 psychotherapists of various disciplines and theoretical orientations who reviewed 3 clinical vignettes portraying hypothetical cases of grandiose narcissism, vulnerable narcissism, and panic disorder without pathological narcissism. Participants then used the Psychotherapy Process Q set, a 100-item Q-sort instrument, to indicate their views regarding optimal therapy process for each hypothetical case. By person principal components analysis with varimax rotation was conducted on all 102 Q-sorts, revealing 4 components representing clinicians' perspectives on ideal therapy processes for narcissistic and non-narcissistic patients. These perspectives were then analyzed regarding their relationship to established therapy models. The first component represented an introspective, relationally oriented therapy process and was strongly correlated with established psychodynamic treatments. The second component, most frequently endorsed for the panic disorder vignette, consisted of a cognitive and alliance-building approach that correlated strongly with expert-rated cognitive-behavioral therapy. The third and fourth components involved therapy processes focused on the challenging interpersonal behaviors associated with narcissistic vulnerability and grandiosity, respectively. The perspectives on therapy processes that emerged in this study reflect different points of emphasis in the treatment of pathological narcissism, and may serve as prototypes of therapist-generated approaches to patients suffering from this issue. The findings suggest several areas for further empirical inquiry regarding psychotherapy with this population. (PsycINFO Database Record PMID- 26595344 TI - Development and Preliminary Psychometric Evaluation of a Brief Self-Report Questionnaire for the Assessment of the DSM-5 level of Personality Functioning Scale: The LPFS Brief Form (LPFS-BF). AB - The Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5; American Psychiatric Association, 2013) alternative model for personality disorders (PDs) introduced a new paradigm for the assessment of PDs that includes levels of personality functioning indexing the severity of personality pathology irrespective of diagnosis. In this study, we describe the development and preliminary psychometric evaluation of a newly developed brief self-report questionnaire to assess levels of personality functioning, the Level of Personality Functioning Scale-Brief Form (LPFS-BF; Bender, Morey, & Skodol, 2011). Patients (N = 240) referred to a specialized setting for the assessment and treatment of PDs completed the LPFS-BF, the Brief Symptom Inventory (BSI; Derogatis, 1975), the Severity Indices of Personality Problems (SIPP-118; Verheul et al., 2008), and were administered the Structured Clinical Interview for DSM-IV Axis I Personality Disorders (SCID-I; APA, 1994; First, Spitzer, Gibbon, & Williams, 1997) and the SCID Axis II Personality Disorders (SCID-II; First, Spitzer, Gibbon, Williams, & Benjamin, 1996). When constrained to a 2-factor oblique solution, the LPFS-BF yielded a structure that corresponded well to an interpretation of Self- and Interpersonal Functioning scales. The instrument demonstrated fair to satisfactory internal consistency and promising construct validity. The LPFS-BF constitutes a short, user-friendly instrument that provides a quick impression of the severity of personality pathology, specifically oriented to the DSM-5 model. Clearly, more research is needed to test its validity and clinical utility. PMID- 26595346 TI - Lumbar Disk Herniation in Children and Adolescents: The Significance of Configurations of the Lumbar Spine. AB - BACKGROUND: Lumbar disk herniation in adults is thought to be caused by repetitive overloading and age-rated degenerative changes. However, these causes are absent in children and adolescent patients. We assume that structural malformations in the lumbar spine could predispose intervertebral disks to early degeneration and hence need to be surgically fused. This issue has never been raised before. OBJECTIVE: To investigate the assumption that structural malformations in the lumbar spine could predispose intervertebral disks to early degeneration and hence need to be surgically fused. METHODS: Lumbar spine configurations, including the height of the intercrestal line, the length of L5 transverse processes, and the presence of transitional vertebrae, were recorded from anteroposterior radiographs taken from 63 consecutive pediatric patients with lumbar disk herniation admitted to our hospital over a period of 8 years. Each configuration was compared in relation to the level of disk herniation. Diskectomy alone was performed in 36 cases; arthrodesis was added in the remaining 27 cases. Patients' back and leg pain visual analog scale scores and frequency and their Oswestry Disability Index scores were recorded before surgery and at follow-up. The results were compared for assessment of outcome. RESULTS: Patients with high intercrestal lines and long L5 transverse processes had a significantly higher incidence of L4/5 disk herniation, whereas low intercrestal line and lumbarization were associated with L5/S1 disk herniation. Patients' visual analog scale scores, pain frequency, and Oswestry Disability Index score all improved significantly after surgery, but there was no significant difference with or without arthrodesis. CONCLUSION: Pediatric lumbar disk herniation is significantly associated with structural malformations of the lumbar spine, but arthrodesis does not improve the clinical outcome. ABBREVIATIONS: ICL, intercrestal lineLDH, lumbar disk herniationL5TP, L5 transverse processODI, Oswestry Disability IndexTV, transitional vertebraeVAS, visual analog scale. PMID- 26595347 TI - Endoscopic vs Open Decompression of the Ulnar Nerve in Cubital Tunnel Syndrome: A Prospective Randomized Double-Blind Study. AB - BACKGROUND: Prospective randomized data for comparison of endoscopic and open decompression methods are lacking. OBJECTIVE: To compare the long- and short-term results of endoscopic and open decompression in cubital tunnel syndrome. METHODS: In a prospective randomized double-blind study, 54 patients underwent ulnar nerve decompression for 56 cubital tunnel syndromes from October 2008 to April 2011. All patients presented with typical clinical and neurophysiological findings and underwent preoperative nerve ultrasonography. They were randomized for either endoscopic (n = 29) or open (n = 27) surgery. Both patients and the physician performing the follow-up examinations were blinded. The follow-up took place 3, 6, 12, and 24 months postoperatively. The severity of symptoms was measured by McGowan and Dellon Score, and the clinical outcome by modified Bishop Score. Additionally, the neurophysiological data were evaluated. RESULTS: No differences were found regarding clinical or neurophysiological outcome in both early and late follow-up between both groups. Hematomas were more frequent after endoscopic decompression (P = .05). The most frequent constrictions were found at the flexor carpi ulnaris (FCU) arch and the retrocondylar retinaculum. We found no compressing structures more than 4 cm distal from the sulcus in the endoscopic group. The outcome was classified as "good" or "excellent" in 46 out of 56 patients (82.1%). Eight patients did not improve sufficiently or had a relapse and underwent a second surgery. CONCLUSION: The endoscopic technique showed no additional benefits to open surgery. We could not detect relevant compressions distal to the FCU arch. Therefore, an extensive far distal endoscopic decompression is not routinely required. The open decompression remains the procedure of choice at our institution. ABBREVIATION: Dig, digitFCU, flexor carpi ulnarisNAS, numeric analog scale. PMID- 26595348 TI - New hepatitis C therapies for special patient populations. AB - INTRODUCTION: Chronic hepatitis C virus (HCV) infection has become a curable disease. More than 90% sustained virologic response rates have been obtained with 8-24 weeks of treatment with distinct combinations of direct-acting antivirals (DAA) in most registration trials. However, outcomes in real-world patients tend to be lower and treatment of special patient populations is often challenging. AREAS COVERED: We address the treatment of chronic hepatitis C with DAA in major special patient populations, such as HIV-positive persons, transplant recipients, patients with advanced cirrhosis, renal insufficiency, hepatitis B or D coinfection, injection drug users (IDUs) and prior DAA failures. EXPERT OPINION: Drug interactions between DAA and medications given to persons with HIV infection or transplant recipients can result in treatment failure and adverse events. Severe organ dysfunction as in kidney insufficiency or decompensated cirrhosis may lead to DAA overexposure and toxicities. Dysfunctional social circumstances and behavior are associated to poor drug adherence and increased risk for HCV re infection in active IDUs. Finally, DAA response might be impaired by viral interference in patients with hepatitis B or D coinfection or drug resistance in HCV either at baseline or after prior DAA failures. PMID- 26595349 TI - Indoleamine Hallucinogens in Cluster Headache: Results of the Clusterbusters Medication Use Survey. AB - Cluster headache is one of the most debilitating pain syndromes. A significant number of patients are refractory to conventional therapies. The Clusterbusters.org medication use survey sought to characterize the effects of both conventional and alternative medications used in cluster headache. Participants were recruited from cluster headache websites and headache clinics. The final analysis included responses from 496 participants. The survey was modeled after previously published surveys and was available online. Most responses were chosen from a list, though others were free-texted. Conventional abortive and preventative medications were identified and their efficacies agreed with those previously published. The indoleamine hallucinogens, psilocybin, lysergic acid diethylamide, and lysergic acid amide, were comparable to or more efficacious than most conventional medications. These agents were also perceived to shorten/abort a cluster period and bring chronic cluster headache into remission more so than conventional medications. Furthermore, infrequent and non hallucinogenic doses were reported to be efficacious. Findings provide additional evidence that several indoleamine hallucinogens are rated as effective in treating cluster headache. These data reinforce the need for further investigation of the effects of these and related compounds in cluster headache under experimentally controlled settings. PMID- 26595350 TI - tRNA acceptor-stem and anticodon bases embed separate features of amino acid chemistry. AB - The universal genetic code is a translation table by which nucleic acid sequences can be interpreted as polypeptides with a wide range of biological functions. That information is used by aminoacyl-tRNA synthetases to translate the code. Moreover, amino acid properties dictate protein folding. We recently reported that digital correlation techniques could identify patterns in tRNA identity elements that govern recognition by synthetases. Our analysis, and the functionality of truncated synthetases that cannot recognize the tRNA anticodon, support the conclusion that the tRNA acceptor stem houses an independent code for the same 20 amino acids that likely functioned earlier in the emergence of genetics. The acceptor-stem code, related to amino acid size, is distinct from a code in the anticodon that is related to amino acid polarity. Details of the acceptor-stem code suggest that it was useful in preserving key properties of stereochemically-encoded peptides that had developed the capacity to interact catalytically with RNA. The quantitative embedding of the chemical properties of amino acids into tRNA bases has implications for the origins of molecular biology. PMID- 26595351 TI - Multimodal assessment of visual attention using the Bethesda Eye & Attention Measure (BEAM). AB - INTRODUCTION: Computerized cognitive tests measuring manual response time (RT) and errors are often used in the assessment of visual attention. Evidence suggests that saccadic RT and errors may also provide valuable information about attention. This study was conducted to examine a novel approach to multimodal assessment of visual attention incorporating concurrent measurements of saccadic eye movements and manual responses. METHOD: A computerized cognitive task, the Bethesda Eye & Attention Measure (BEAM) v.34, was designed to evaluate key attention networks through concurrent measurement of saccadic and manual RT and inhibition errors. Results from a community sample of n = 54 adults were analyzed to examine effects of BEAM attention cues on manual and saccadic RT and inhibition errors, internal reliability of BEAM metrics, relationships between parallel saccadic and manual metrics, and relationships of BEAM metrics to demographic characteristics. RESULTS: Effects of BEAM attention cues (alerting, orienting, interference, gap, and no-go signals) were consistent with previous literature examining key attention processes. However, corresponding saccadic and manual measurements were weakly related to each other, and only manual measurements were related to estimated verbal intelligence or years of education. CONCLUSIONS: This study provides preliminary support for the feasibility of multimodal assessment of visual attention using the BEAM. Results suggest that BEAM saccadic and manual metrics provide divergent measurements. Additional research will be needed to obtain comprehensive normative data, to cross-validate BEAM measurements with other indicators of neural and cognitive function, and to evaluate the utility of these metrics within clinical populations of interest. PMID- 26595352 TI - Audiovisual speech perception in infancy: The influence of vowel identity and infants' productive abilities on sensitivity to (mis)matches between auditory and visual speech cues. AB - Recent studies suggest that infants' audiovisual speech perception is influenced by articulatory experience (Mugitani et al., 2008; Yeung & Werker, 2013). The current study extends these findings by testing if infants' emerging ability to produce native sounds in babbling impacts their audiovisual speech perception. We tested 44 6-month-olds on their ability to detect mismatches between concurrently presented auditory and visual vowels and related their performance to their productive abilities and later vocabulary size. Results show that infants' ability to detect mismatches between auditory and visually presented vowels differs depending on the vowels involved. Furthermore, infants' sensitivity to mismatches is modulated by their current articulatory knowledge and correlates with their vocabulary size at 12 months of age. This suggests that-aside from infants' ability to match nonnative audiovisual cues (Pons et al., 2009)-their ability to match native auditory and visual cues continues to develop during the first year of life. Our findings point to a potential role of salient vowel cues and productive abilities in the development of audiovisual speech perception, and further indicate a relation between infants' early sensitivity to audiovisual speech cues and their later language development. PMID- 26595353 TI - The development of stimulus and response interference control in midchildhood. AB - Interference control, the ability to overcome distraction from irrelevant information, undergoes considerable improvement during childhood, yet the mechanisms driving these changes remain unclear. The present study investigated the relative influence of interference at the level of the stimulus or the response. Seven-, 10-, and 20-year-olds completed a flanker paradigm in which stimulus and response interference was experimentally manipulated. The influence of stimulus interference decreased from 7 to 10 years, whereas there was no difference in response interference across age groups. The findings demonstrate that a range of processes contribute to the development of interference control and may influence performance to a greater or lesser extent depending on the task requirements and the age of the child. PMID- 26595354 TI - Effects of viewing relational aggression on television on aggressive behavior in adolescents: A three-year longitudinal study. AB - Most researchers on media and aggression have examined the behavioral effects of viewing physical aggression in the media. Conversely, in the current study, I examined longitudinal associations between viewing relational aggression on TV and subsequent aggressive behavior. Participants included 467 adolescents who completed a number of different questionnaires involving media and aggression at 3 different time points. Results revealed that viewing relational aggression on TV was longitudinally associated with future relational aggression. However, early levels of relational aggression did not predict future exposure to televised relational aggression. Conversely, there was a bidirectional relationship between TV violence and physical aggression over time. No longitudinal evidence was found for a general effect of viewing TV, as all significant media effects were specific to the type of aggression viewed. These results support the general aggression model and suggest that viewing relational aggression in the media can have a long-term effect on aggressive behavior during adolescence. PMID- 26595355 TI - The development of compulsive internet use and mental health: A four-year study of adolescence. AB - Is compulsive Internet use (CIU) an antecedent to poor mental health, a consequence, or both? Study 1 used a longitudinal design to track the development of CIU and mental health in Grade 8 (N = 1030 males, 1038 females, Mage = 13.7), 9, 10, and 11. Study 2 extended Study 1 by examining the kinds of Internet behaviors most strongly associated with CIU within males and females. Structural equation modeling revealed that CIU predicted the development of poor mental health, whereas poor mental health did not predict CIU development. Latent growth analyses showed that both females and males increased in CIU and mental health problems across the high school years. Females had higher CIU and worse mental health than males, and tended to engage in more social forms of Internet use. We discuss future directions for CIU intervention research. PMID- 26595357 TI - Flattened-Top Domical Water Drops Formed through Self-Organization of Hydrophobin Membranes: A Structural and Mechanistic Study Using Atomic Force Microscopy. AB - The Trichoderma reesei hydrophobin, HFBI, is a unique structural protein. This protein forms membranes by self-organization at air/water or water/solid interfaces. When HFBI forms a membrane at an air/water interface, the top of the water droplet is flattened. The mechanism underlying this phenomenon has not been explored. In this study, this unique phenomenon has been investigated. Self organized HFBI membranes form a hexagonal structured membrane on the surface of water droplets; the structure was confirmed by atomic force microscopy (AFM) measurement. Assembled hexagons can form a planar sheet or a tube. Self-organized HFBI membranes on water droplets form a sheet with an array of hexagonal structures or a honeycomb structure. This membrane, with its arrayed hexagonal structures, has very high buckling strength. We hypothesized that the high buckling strength is the reason that water droplets containing HFBI form flattened domes. To test this hypothesis, the strength of the self-organized HFBI membranes was analyzed using AFM. The buckling strength of HFBI membranes was measured to be 66.9 mN/m. In contrast, the surface tension of water droplets containing dissolved HFBI is 42 mN/m. Thus, the buckling strength of a self organized HFBI membrane is higher than the surface tension of water containing dissolved HFBI. This mechanistic study clarifies why the water droplets formed by self-organized HFBI membranes have a flattened top. PMID- 26595356 TI - Adolescent friend similarity on alcohol abuse as a function of participation in romantic relationships: Sometimes a new love comes between old friends. AB - This study tests the hypothesis that adolescents with romantic partners are less similar to their friends on rates of alcohol abuse than adolescents without romantic partners. Participants (662 girls, 574 boys) ranging in age from 12 to 19 years nominated friends and romantic partners, and completed a measure of alcohol abuse. In hierarchical linear models, friends with romantic partners were less similar on rates of alcohol abuse than friends without romantic partners, especially if they were older and less accepted. Follow-up longitudinal analyses were conducted on a subsample (266 boys, 374 girls) of adolescents who reported friendships that were stable across 2 consecutive years. Associations between friend reports of alcohol abuse declined after adolescents became involved in a romantic relationship, to the point at which they became more similar to their romantic partners than to their friends. (PsycINFO Database Record PMID- 26595358 TI - [Integrated Care for People with Dementia]. AB - The rising number of cases of people with dementia, the need for complex care and the insufficient care available call for innovative and sustainable solutions. The article presents a specialised dementia care model that has been developed to manage acute difficulties of care. The model implements comprehensive, patient oriented care across different sectors. The structure and requirements of successful cooperation and comprehensive care will be described. PMID- 26595359 TI - Dairy Consumption Lowers Systemic Inflammation and Liver Enzymes in Typically Low Dairy Consumers with Clinical Characteristics of Metabolic Syndrome. AB - OBJECTIVES: A 6-week cross-over study design was used to determine the effect of increased dairy consumption in typically low-dairy consumers (n = 37) with metabolic syndrome (MetS) on systemic inflammation and hepatic enzymes. METHODS: This was a randomized study in which participants consumed low-fat dairy (LFD) (10 oz 1% milk, 6 oz nonfat yogurt, 4 oz 2% cheese) or a carbohydrate-based control (CNT) (1.5 oz granola bar and 12 oz 100% juice) for 6 weeks. After a 4 week washout, they were allocated to the alternate dietary treatment. Inflammatory status was assessed by fasting plasma concentrations of C-reactive protein (CRP), tumor necrosis factor alpha (TNF-alpha), and monocyte chemoattractant -1 (MCP-1). In addition, gene expression of interleukin (IL)-1, IL-6, and TNF-alpha was evaluated in peripheral blood mononuclear cells isolated from a subset of 17 subjects (13 women, 3 men) at the end of each dietary period. Liver enzymes were also assessed to evaluate whether dairy components would affect hepatic function. RESULTS: Participants had lower concentrations of both hepatic alanine aminotransferase (p < 0.05) and aspartate aminotransferase (p < 0.005) after the LFD period. No significant changes in any of the plasma inflammatory compounds were found when all data were analyzed together. In contrast, expression of IL-1b and IL-6 were reduced by 46% and 63%, respectively, compared to the control period. When stratified by gender, women had lower TNF alpha, (p = 0.028) and MCP-1 (p = 0.001) following LFD consumption compared to CNT. In addition, hepatic steatosis index scores were significantly lower (p < 0.001) during the LFD period. CONCLUSIONS: We conclude that three dairy servings per day improved both liver function and systemic inflammation in subjects with MetS. PMID- 26595360 TI - Effect of 1-Butyl-3-methylimidazolium Halide on the Relative Stability between Sodium Dodecyl Sulfate Micelles and Sodium Dodecyl Sulfate-Poly(ethylene oxide) Nanoaggregates. AB - It is well-known that ionic liquids (ILs) alter the properties of aqueous systems containing only surfactants. However, the effect of ILs on polymer-surfactant systems is still unknown. Here, the effect of 1-butyl-3-methylimidazolium bromide (bmimBr) and chloride (bmimCl) on the micellization of sodium dodecyl sulfate (SDS) and its interaction with poly(ethylene oxide) (PEO) was evaluated using conductimetry, fluorimetry, and isothermal titration calorimetry. The ILs decreased the critical micellar concentration (cmc) of the surfactant, stabilizing the SDS micelles. A second critical concentration (c2thc) was verified at high SDS concentrations, due to the micelle size decrease. The stability of PEO/SDS aggregates was also affected by ILs, and the critical aggregation concentration (cac) of SDS increased. Integral aggregation enthalpy changed from -0.72 in water to 2.16 kJ mol(-1) in 4.00 mM bmimBr. IL anions did not affect the SDS micellization or the beginning of PEO/SDS aggregation. Nevertheless, when chloride was replaced with bromide, the amount of SDS bound to the polymer increased. At 100.0 mM IL, the PEO-SDS interaction vanished. We suggest that the effect of ILs comes from participating in the structure of the formed aggregates, interacting with the SDS monomers at the core/interface of the micelles, and promoting preferential solvation of the polymer. PMID- 26595361 TI - An Expanded Theoretical Framework of Care Coordination Across Transitions in Care Settings. AB - For many patients, high-quality, patient-centered, and cost-effective health care requires coordination among multiple clinicians and settings. Ensuring optimal care coordination requires a clear understanding of how clinician activities and continuity during transitions affect patient-centeredness and quality outcomes. This article describes an expanded theoretical framework to better understand care coordination. The framework provides clear articulation of concepts. Examples are provided of ways to measure the concepts. PMID- 26595363 TI - Posterolateral Instability of the Knee. PMID- 26595362 TI - EFFICACY OF INTRAVITREAL INJECTION OF CONBERCEPT IN POLYPOIDAL CHOROIDAL VASCULOPATHY: Subgroup Analysis of the Aurora Study. AB - PURPOSE: To evaluate the efficacy of different doses of conbercept in patients with polypoidal choroidal vasculopathy in the AURORA study. METHODS: Retrospective subgroup analyses of 12-month data from the AURORA study. Fifty three patients (32 in 0.5-mg group and 21 in 2.0-mg group) diagnosed with polypoidal choroidal vasculopathy in AURORA study were retrospectively evaluated. Efficacy outcomes were compared between the two dosage groups. RESULTS: At Month 12, mean changes in best-corrected visual acuity from baseline were 14.4 +/- 14.1 letter scores for the 0.5-mg group and 14.2 +/- 21.0 letter scores for the 2.0-mg group; mean central retinal thickness decreased by 104.5 +/- 127.3 MUm in the 0.5 mg group and 140.7 +/- 127.9 MUm in the 2.0-mg group; mean total macular volume decreased by 0.9 +/- 2.3 mm and 1.0 +/- 1.2 mm in the 0.5-mg and 2.0-mg groups, respectively. The mean subretinal fluid thickness decreased by 111.9 +/- 122.5 MUm and 76.3 +/- 112.6 MUm in the 0.5-mg and 2.0-mg groups, respectively. The mean pigment epithelial detachment height decreased by 79.3 +/- 217.8 MUm and 61.3 +/- 161.5 MUm in the 0.5-mg and 2.0-mg groups, respectively. The mean area of polyps decreased by 0.46 +/- 0.76 mm and 0.55 +/- 1.34 mm in the 0.5-mg and 2.0-mg groups, respectively. The mean total lesion area decreased by 2.51 +/- 5.94 mm (P = 0.088) and 4.62 +/- 5.51 mm in the 0.5-mg group and 2.0-mg groups, respectively. Complete regression of polyps was observed in 56.5% of patients in the 0.5-mg group and 52.9% of those in the 2.0-mg group, whereas partial regression was observed in 26.1% and 35.3% of patients in the 0.5-mg and 2.0-mg groups, respectively. CONCLUSION: Intravitreal injection of conbercept appears to significantly improve visual acuity and anatomical outcomes in patients with polypoidal choroidal vasculopathy. PMID- 26595364 TI - Development of Hot Exhaust Emission Factors for Iranian-Made Euro-2 Certified Light-Duty Vehicles. AB - Emission factors (EFs) are fundamental, necessary data for air pollution research and scenario implementation. With the vision of generating national EFs of the Iranian transportation system, a portable emission measurement system (PEMS) was used to develop the basic EFs for a statistically significant sample of Iranian gasoline-fueled privately owned light duty vehicles (LDVs) operated in Tehran. A smaller sample size of the same fleet was examined by chassis dynamometer (CD) bag emission measurement tests to quantify the systematic differences between the PEMS and CD methods. The selected fleet was tested over four different routes of uphill highways, flat highways, uphill urban streets, and flat urban streets. Real driving emissions (RDEs) and fuel consumption (FC) rates were calculated by weighted averaging of the results from each route. The activity of the fleet over each route type was assumed as a weighting factor. The activity data were obtained from a Tehran traffic model. The RDEs of the selected fleet were considerably higher than the certified emission levels of all vehicles. Differences between Tehran real driving cycles and the New European Driving Cycle (NEDC) was attributed to the lower loading of NEDC. A table of EFs based on RDEs was developed for the sample fleet. PMID- 26595365 TI - Acute viral bronchiolitis: Physician perspectives on definition and clinically important outcomes. AB - BACKGROUND: Two key limitations hamper intervention research in bronchiolitis: the absence of a clear definition of disease, and the heterogeneous choice of outcome measures in current clinical trials. We assessed how paediatricians and general practitioners (GPs) perceived definition and clinically important outcomes in bronchiolitis. METHODS: A nationwide online survey (ABBA study) was conducted through the Portuguese Society of Paediatrics and GPs' mailing lists. We assessed agreement with statements on bronchiolitis definition, and participants were asked to score the relative importance of several outcomes. Principal component analysis (PCA) explored dimensions underlying disease definition. Outcomes were ranked by mean score and proportion given highest score. RESULTS: We included 514 paediatricians and 165 GPs (overall 59% were board-certified). Most paediatricians (76.5%) agreed with a definition based on coryza, wheezing and/or crackles/rales, compared to 38.1% GPs (P < 0.001). Less than 5% physicians agreed with a definition commonly used in clinical trials (<12 months, first episode of wheeze). We retained three dimensions on PCA: one based on coryza, rales/crepitations and no sudden onset; another on number of episodes and age; and a third on wheeze. Dimensions varied by physician specialization and training (P < 0.01). Hospital admission and respiratory distress were top rated outcomes by both groups of physicians. CONCLUSIONS: Physician definitions of bronchiolitis have considerable variability and often mismatch those of clinical trials. Rating of important outcomes was consistent. Our results highlight the need for a robust standardized definition of acute bronchiolitis in infants and support the development of a core outcome set for future clinical trials. Pediatr Pulmonol. 2016;51:724-732. (c) 2015 Wiley Periodicals, Inc. PMID- 26595366 TI - Longitudinal cerebellar growth following very preterm birth. AB - PURPOSE: To measure cerebellar growth in a longitudinal cohort of very preterm infants to identify early predictors of subsequent brain growth. Although the cerebellum grows rapidly during late gestation, the rate and variability of growth following premature birth, and the effects of associated injury, are largely unknown. MATERIALS AND METHODS: In all, 105 very-preterm born infants (24 32 weeks GA) were imaged using magnetic resonance imaging (MRI) at birth, term equivalent, 2, and 4 years of age. Cerebellar and total cerebral volumes were estimated from 1 mm isotropic T1 -weighted scans acquired at 1.5T and 3T, using an atlas-based approach. Linear models were used to analyze cerebellar volume as cross-sectional and longitudinal functions of age, clinical, and radiological correlates. Linear models were also used to test for associations between volume and cognitive outcome. RESULTS: Cerebellar volume increased rapidly with age-at scan during both the preterm (0.7 mL/wk, P < 0.001) and term periods (1.8 mL/wk, P < 0.001). Infants with grade 3 or 4 germinal matrix hemorrhage (GMH) had smaller cerebellar volumes as a percentage of total brain volume starting at birth and continuing to 4 years of age (-0.43%, -0.57%, -1.09% at preterm, term, and 4 years, respectively, P < 0.01). Irrespective of age-at-scan, early cerebellar volume was predictive of volume at 4 years of age (slope = 1.3, P < 0.001). Cerebellar volumes were not found to predict cognitive outcome at 4 years of age; P < 0.2. CONCLUSION: High-grade GMH and small perinatal cerebellar size is predictive of cerebellar development up to 4 years of age. These findings suggest that it is possible to identify individuals at high risk of reduced cerebellar volumes at an early age. J. Magn. Reson. Imaging 2016;43:1462-1473. PMID- 26595367 TI - Complete reversal of muscle wasting in experimental cancer cachexia: Additive effects of activin type II receptor inhibition and beta-2 agonist. AB - Formoterol is a highly potent beta2-adrenoceptor-selective agonist, which is a muscle growth promoter in many animal species. Myostatin/activin inhibition reverses skeletal muscle loss and prolongs survival of tumor-bearing animals. The aim of this investigation was to evaluate the effects of a combination of the soluble myostatin receptor ActRIIB (sActRIIB) and the beta2-agonist formoterol in the cachectic Lewis lung carcinoma model. The combination of formoterol and sActRIIB was extremely effective in reversing muscle wasting associated with experimental cancer cachexia in mice. Muscle weights from tumor-bearing animals were completely recovered following treatment and this was also reflected in the measured grip strength. This combination increased food intake in both control and tumor-bearing animals. The double treatment also prolonged survival significantly without affecting the weight and growth of the primary tumor. In addition, it significantly reduced the number of metastasis. Concerning the mechanisms for the preservation of muscle mass during cachexia, the effects of formoterol and sActRIIB seemed to be additive, since formoterol reduced the rate of protein degradation (as measured in vitro as tyrosine release, using incubated isolated individual muscles) while sActRIIB only affected protein synthesis (as measured in vivo using tritiated phenylalanine). Formoterol also increased the rate of protein synthesis and this seemed to be favored by the presence of sActRIIB. Combining formoterol and sActRIIB seemed to be a very promising treatment for experimental cancer cachexia. Further studies in human patients are necessary and may lead to a highly effective treatment option for muscle wasting associated with cancer. PMID- 26595368 TI - Do early-life exposures explain why more advantaged children get eczema? Findings from the U.K. Millennium Cohort Study. AB - BACKGROUND: Atopic dermatitis (eczema) in childhood is socially patterned, with higher incidence in more advantaged populations. However, it is unclear what factors explain the social differences. OBJECTIVES: To identify early-life risk factors for eczema, and to explore how early-life risk factors explain any differences in eczema. METHODS: We estimated odds ratios (ORs) for ever having had eczema by age 5 years in 14 499 children from the U.K. Millennium Cohort Study (MCS), with a focus on maternal, antenatal and early-life risk factors and socioeconomic circumstances (SECs). Risk factors were explored to assess whether they attenuated associations between SECs and eczema. RESULTS: Overall 35.1% of children had ever had eczema by age 5 years. Children of mothers with degree level qualifications vs. no educational qualifications were more likely to have eczema (OR 1.52, 95% confidence interval 1.31-1.76), and there was a gradient across the socioeconomic spectrum. Maternal atopy, breastfeeding (1-6 weeks and >= 6 months), introduction of solids under 4 months or cow's milk under 9 months, antibiotic exposure in the first year of life and grime exposure were associated with an increased odds of having eczema. Female sex, Pakistani and Bangladeshi ethnicity, smoking during pregnancy, exposure to environmental tobacco smoke and having more siblings were associated with reduced odds for eczema. Controlling for maternal, antenatal and early-life characteristics (particularly maternal smoking during pregnancy, breastfeeding and number of siblings) reduced the OR for eczema to 1.26 (95% confidence interval 1.03-1.50) in the group with the highest educational qualifications compared with the least. CONCLUSIONS: In a representative U.K. child cohort, eczema was more common in more advantaged children. This was explained partially by early-life factors including not smoking during pregnancy, breastfeeding and having fewer siblings. PMID- 26595369 TI - Cumulus cell-conditioned medium supports embryonic stem cell differentiation to germ cell-like cells. AB - Cumulus cells provide cellular interactions and growth factors required for oogenesis. In vitro studies of oogenesis are limited primarily because of the paucity of their source, first trimester fetal gonads, and the small number of germ lineage precursor cells present within these tissues. In order to understand this obscure but vitally important process, the present study was designed to direct differentiation of embryonic stem (ES) cells into germ lineage cells. For this purpose, buffalo ES cells were differentiated, as embryoid bodies (EBs) and monolayer adherent cultures, in the presence of different concentrations of cumulus-conditioned medium (CCM; 10%, 20% and 40%) for different periods of culture (4, 8 and 14 days) to identify the optimum differentiation-inducing concentration and time. Quantitative polymerase chain reaction analysis revealed that 20%-40% CCM induced the highest expression of primordial germ cell-specific (deleted in Azoospermia- like (Dazl), dead (Asp-Glu-Ala-Asp) box polypeptide 4 (Vasa also known as DDX4) and promyelocytic leukemia zinc finger protein (Plzf)); meiotic (synaptonemal complex protein 3 (Sycp3), mutl homolog I (Mlh1), transition protein 1/2 (Tnp1/2) and protamine 2 (Prm2); spermatocyte-specific boule-like RNA binding protein (Boule) and tektin 1 (Tekt1)) and oocyte-specific growth differentiation factor 9 (Gdf9) and zona pellucida 2 /3 (Zp2/3)) genes over 8-14 days in culture. Immunocytochemical analysis revealed expression of primordial germ cell (c-KIT, DAZL and VASA), meiotic (SYCP3, MLH1 and PROTAMINE 1), spermatocyte (ACROSIN and HAPRIN) and oocyte (GDF9 and ZP4) markers in both EBs and monolayer differentiation cultures. Western blotting revealed germ lineage-specific protein expression in Day 14 EBs. The significantly lower (P<0.05) concentration of 5-methyl-2-deoxycytidine in differentiated EBs compared to undifferentiated EBs suggests that methylation erasure may have occurred. Oocyte-like structures obtained in monolayer differentiation stained positive for ZONA PELLUCIDA protein 4 and progressed through various embryo-like developmental stages in extended cultures. PMID- 26595370 TI - Using Behavioral Economics to Design Physician Incentives That Deliver High-Value Care. AB - Behavioral economics provides insights about the development of effective incentives for physicians to deliver high-value care. It suggests that the structure and delivery of incentives can shape behavior, as can thoughtful design of the decision-making environment. This article discusses several principles of behavioral economics, including inertia, loss aversion, choice overload, and relative social ranking. Whereas these principles have been applied to motivate personal health decisions, retirement planning, and savings behavior, they have been largely ignored in the design of physician incentive programs. Applying these principles to physician incentives can improve their effectiveness through better alignment with performance goals. Anecdotal examples of successful incentive programs that apply behavioral economics principles are provided, even as the authors recognize that its application to the design of physician incentives is largely untested, and many outstanding questions exist. Application and rigorous evaluation of infrastructure changes and incentives are needed to design payment systems that incentivize high-quality, cost-conscious care. PMID- 26595371 TI - Precision Treatment and Precision Prevention: Integrating "Below and Above the Skin". PMID- 26595373 TI - Punnoose, A.M., Elamparithi, A., and Kuruvilla, S. (2015), Electrospun Type 1 Collagen Matrices Using a Novel Benign Solvent for Cardiac Tissue Engineering. J. Cell. Physiol. doi: 10.1002/jcp.25035. PMID- 26595374 TI - In response to "National cohort study of opioid analgesic dose and risk of future hospitalization". PMID- 26595375 TI - Association of Postdischarge Spending and Performance on New Episode-Based Spending Measure. PMID- 26595376 TI - The attention habit: how reward learning shapes attentional selection. AB - There is growing consensus that reward plays an important role in the control of attention. Until recently, reward was thought to influence attention indirectly by modulating task-specific motivation and its effects on voluntary control over selection. Such an account was consistent with the goal-directed (endogenous) versus stimulus-driven (exogenous) framework that had long dominated the field of attention research. Now, a different perspective is emerging. Demonstrations that previously reward-associated stimuli can automatically capture attention even when physically inconspicuous and task-irrelevant challenge previously held assumptions about attentional control. The idea that attentional selection can be value driven, reflecting a distinct and previously unrecognized control mechanism, has gained traction. Since these early demonstrations, the influence of reward learning on attention has rapidly become an area of intense investigation, sparking many new insights. The result is an emerging picture of how the reward system of the brain automatically biases information processing. Here, I review the progress that has been made in this area, synthesizing a wealth of recent evidence to provide an integrated, up-to-date account of value driven attention and some of its broader implications. PMID- 26595377 TI - A Protocol for the Global Sensitivity Analysis of Impact Assessment Models in Life Cycle Assessment. AB - The life cycle assessment (LCA) framework has established itself as the leading tool for the assessment of the environmental impact of products. Several works have established the need of integrating the LCA and risk analysis methodologies, due to the several common aspects. One of the ways to reach such integration is through guaranteeing that uncertainties in LCA modeling are carefully treated. It has been claimed that more attention should be paid to quantifying the uncertainties present in the various phases of LCA. Though the topic has been attracting increasing attention of practitioners and experts in LCA, there is still a lack of understanding and a limited use of the available statistical tools. In this work, we introduce a protocol to conduct global sensitivity analysis in LCA. The article focuses on the life cycle impact assessment (LCIA), and particularly on the relevance of global techniques for the development of trustable impact assessment models. We use a novel characterization model developed for the quantification of the impacts of noise on humans as a test case. We show that global SA is fundamental to guarantee that the modeler has a complete understanding of: (i) the structure of the model and (ii) the importance of uncertain model inputs and the interaction among them. PMID- 26595378 TI - Timosaponin AIII inhibits melanoma cell migration by suppressing COX-2 and in vivo tumor metastasis. AB - Melanoma is the leading cause of death from skin disease, due in large part to its propensity to metastasize. We examined the effects of timosaponin AIII, a compound isolated from Anemarrhena asphodeloides Bunge, on melanoma cancer cell migration and the molecular mechanisms underlying these effects using B16-F10 and WM-115 melanoma cells lines. Overexpression of COX-2, its metabolite prostaglandin E2 (PGE2), and PGE2 receptors (EP2 and EP4) promoted cell migration in vitro. Exposure to timosaponin AIII resulted in concentration-dependent inhibition of cell migration, which was associated with reduced levels of COX-2, PGE2, and PGE2 receptors. Transient transfection of COX-2 siRNA also inhibited cell migration. Exposure to 12-O-tetradecanoylphorbal-13-acetate enhanced cell migration, whereas timosaponin AIII inhibited 12-O-tetradecanoylphorbal-13 acetate-induced cell migration and reduced basal levels of EP2 and EP4. Moreover, timosaponin AIII inhibited activation of nuclear factor-kappa B (NF-kappaB), an upstream regulator of COX-2 in B16-F10 cells. Consistent with our in vitro findings, in vivo studies showed that timosaponin AIII treatment significantly reduced the total number of metastatic nodules in the mouse lung and improved histological alterations in B16-F10-injected C57BL/6 mice. In addition, C57BL/6 mice treated with timosaponin AIII showed reduced expression of COX-2 and NF kappaB in the lung. Together, these results indicate that timosaponin AIII has the capacity to inhibit melanoma cell migration, an essential step in the process of metastasis, by inhibiting expression of COX-2, NF-kappaB, PGE2, and PGE2 receptors. PMID- 26595379 TI - Chalcogenization-Derived Band Gap Grading in Solution-Processed CuIn(x)Ga(1 x)(Se,S)2 Thin-Film Solar Cells. AB - Significant enhancement of solution-processed CuIn(x)Ga(1-x)(Se,S)2 (CIGSSe) thin film solar cell performance was achieved by inducing a band gap gradient in the film thickness, which was triggered by the chalcogenization process. Specifically, after the preparation of an amorphous mixed oxide film of Cu, In, and Ga by a simple paste coating method chalcogenization under Se vapor, along with the flow of dilute H2S gas, resulted in the formation of CIGSSe films with graded composition distribution: S-rich top, In- and Se-rich middle, and Ga- and S-rich bottom. This uneven compositional distribution was confirmed to lead to a band gap gradient in the film, which may also be responsible for enhancement in the open circuit voltage and reduction in photocurrent loss, thus increasing the overall efficiency. The highest power conversion efficiency of 11.7% was achieved with J(sc) of 28.3 mA/cm(2), V(oc) of 601 mV, and FF of 68.6%. PMID- 26595380 TI - Central Sleep-disordered Breathing Predicts Incident Atrial Fibrillation in Older Men. AB - RATIONALE: Although research supports a sleep-disordered breathing and atrial fibrillation association, prospective data examining sleep-disordered breathing predicting incident atrial fibrillation are lacking. OBJECTIVES: To investigate sleep-disordered breathing indices as predictors of incident atrial fibrillation. METHODS: A cohort (n = 843) of ambulatory older men without prevalent atrial fibrillation was assessed for baseline sleep indices: apnea-hypopnea index, central sleep apnea (central apnea index, >=5 vs. <5), central sleep apnea or Cheyne-Stokes respiration, obstructive apnea-hypopnea index, and percentage of sleep time with less than 90% oxygen saturation. Incident clinically symptomatic adjudicated or self-reported atrial fibrillation outcome was ascertained (mean follow-up, 6.5 +/- 0.7 yr). We used logistic regression models adjusted for age, race, body mass index, cardiopulmonary disease, alcohol use, pacemaker, cholesterol, cardiac medications, and alternate apnea type for obstructive and central apnea. Age interaction terms and median age-stratified analyses were performed. MEASUREMENTS AND MAIN RESULTS: Central sleep apnea (odds ratio [OR], 2.58; 95% confidence interval [CI], 1.18-5.66) and Cheyne-Stokes respiration with central sleep apnea (OR, 2.27; 95% CI, 1.13-4.56), but not obstructive apnea or hypoxemia, predicted incident atrial fibrillation. Central apnea, Cheyne-Stokes respiration, and sleep-disordered breathing-age interaction terms were significant (P < 0.05). Unlike the case with younger participants, among participants aged 76 years or older (albeit with small atrial fibrillation counts), atrial fibrillation was related to central apnea (OR, 9.97; 95% CI, 2.72 36.50), Cheyne-Stokes respiration with central apnea (OR, 6.31; 95% CI, 1.94 20.51), and apnea-hypopnea index (OR, 1.22; 95% CI, 1.08-1.39 [per 5-unit increase]). CONCLUSIONS: In older men, central apnea and Cheyne-Stokes respiration predicted increased atrial fibrillation risk, with findings being strongest in older participants in whom overall sleep-disordered breathing also increased atrial fibrillation risk. PMID- 26595381 TI - TMEM107 recruits ciliopathy proteins to subdomains of the ciliary transition zone and causes Joubert syndrome. AB - The transition zone (TZ) ciliary subcompartment is thought to control cilium composition and signalling by facilitating a protein diffusion barrier at the ciliary base. TZ defects cause ciliopathies such as Meckel-Gruber syndrome (MKS), nephronophthisis (NPHP) and Joubert syndrome (JBTS). However, the molecular composition and mechanisms underpinning TZ organization and barrier regulation are poorly understood. To uncover candidate TZ genes, we employed bioinformatics (coexpression and co-evolution) and identified TMEM107 as a TZ protein mutated in oral-facial-digital syndrome and JBTS patients. Mechanistic studies in Caenorhabditis elegans showed that TMEM-107 controls ciliary composition and functions redundantly with NPHP-4 to regulate cilium integrity, TZ docking and assembly of membrane to microtubule Y-link connectors. Furthermore, nematode TMEM 107 occupies an intermediate layer of the TZ-localized MKS module by organizing recruitment of the ciliopathy proteins MKS-1, TMEM-231 (JBTS20) and JBTS-14 (TMEM237). Finally, MKS module membrane proteins are immobile and super resolution microscopy in worms and mammalian cells reveals periodic localizations within the TZ. This work expands the MKS module of ciliopathy-causing TZ proteins associated with diffusion barrier formation and provides insight into TZ subdomain architecture. PMID- 26595382 TI - Conserved molecular interactions in centriole-to-centrosome conversion. AB - Centrioles are required to assemble centrosomes for cell division and cilia for motility and signalling. New centrioles assemble perpendicularly to pre-existing ones in G1-S and elongate throughout S and G2. Fully elongated daughter centrioles are converted into centrosomes during mitosis to be able to duplicate and organize pericentriolar material in the next cell cycle. Here we show that centriole-to-centrosome conversion requires sequential loading of Cep135, Ana1 (Cep295) and Asterless (Cep152) onto daughter centrioles during mitotic progression in both Drosophila melanogaster and human. This generates a molecular network spanning from the inner- to outermost parts of the centriole. Ana1 forms a molecular strut within the network, and its essential role can be substituted by an engineered fragment providing an alternative linkage between Asterless and Cep135. This conserved architectural framework is essential for loading Asterless or Cep152, the partner of the master regulator of centriole duplication, Plk4. Our study thus uncovers the molecular basis for centriole-to-centrosome conversion that renders daughter centrioles competent for motherhood. PMID- 26595384 TI - Transient PLK4 overexpression accelerates tumorigenesis in p53-deficient epidermis. AB - Aneuploidy is found in most solid tumours, but it remains unclear whether it is the cause or the consequence of tumorigenesis. Using Plk4 overexpression (PLK4OE) during epidermal development, we assess the impact of centrosome amplification and aneuploidy on skin development and tumorigenesis. PLK4OE in the developing epidermis induced centrosome amplification and multipolar divisions, leading to p53 stabilization and apoptosis of epidermal progenitors. The resulting delayed epidermal stratification led to skin barrier defects. Plk4 transgene expression was shut down postnatally in the surviving mice and PLK4OE mice never developed skin tumours. Concomitant PLK4OE and p53 deletion (PLK4OE/p53cKO) rescued the differentiation defects, but did not prevent the apoptosis of PLK4OE cells. Remarkably, the short-term presence of cells with supernumerary centrosomes in PLK4OE/p53cKO mice was sufficient to generate aneuploidy in the adult epidermis and triggered spontaneous skin cancers with complete penetrance. These results reveal that aneuploidy induced by transient centrosome amplification can accelerate tumorigenesis in p53-deficient cells. PMID- 26595383 TI - Glutamine synthetase activity fuels nucleotide biosynthesis and supports growth of glutamine-restricted glioblastoma. AB - L-Glutamine (Gln) functions physiologically to balance the carbon and nitrogen requirements of tissues. It has been proposed that in cancer cells undergoing aerobic glycolysis, accelerated anabolism is sustained by Gln-derived carbons, which replenish the tricarboxylic acid (TCA) cycle (anaplerosis). However, it is shown here that in glioblastoma (GBM) cells, almost half of the Gln-derived glutamate (Glu) is secreted and does not enter the TCA cycle, and that inhibiting glutaminolysis does not affect cell proliferation. Moreover, Gln-starved cells are not rescued by TCA cycle replenishment. Instead, the conversion of Glu to Gln by glutamine synthetase (GS; cataplerosis) confers Gln prototrophy, and fuels de novo purine biosynthesis. In both orthotopic GBM models and in patients, (13)C glucose tracing showed that GS produces Gln from TCA-cycle-derived carbons. Finally, the Gln required for the growth of GBM tumours is contributed only marginally by the circulation, and is mainly either autonomously synthesized by GS-positive glioma cells, or supplied by astrocytes. PMID- 26595385 TI - Facilitated physiological adaptation to prolonged circadian disruption through dietary supplementation with essence of chicken. AB - Synchrony between circadian and metabolic processes is critical to the maintenance of energy homeostasis. Studies on essence of chicken (EC), a chicken meat extract rich in proteins, amino acids and peptides, showed its effectiveness in alleviating fatigue and promoting metabolism. A recent study revealed that it facilitated the re-entrainment of clock genes (Bmal1, Cry1, Dec1, Per1 and Per2) in the pineal gland and liver in a rat model of circadian disruption. Here, we investigated the role of EC-facilitated circadian synchrony in the maintenance of the energy homeostasis using a mouse model of prolonged circadian disruption. Prolonged circadian disruption (12 weeks) resulted in hepatic maladaptation, manifested by a mild but significant (p < 0.05) hepatomegaly, accompanied by disturbed hepatic lipid metabolism and liver injury (indicated by increased circulating hepatic enzymes). Evidently, there was marked elevations of hepatic inflammatory mediators (interleukin-1beta and interleukin-6), suggesting an underlying inflammation leading to the hepatic injury and functional impairment. Importantly, the disruption paradigm caused the decoupling between key metabolic regulators (e.g. mTOR and AMPK) and hepatic clock genes (Per1, Cry1, Dec1, Bmal1). Further, we showed that the loss of circadian synchrony between the master and hepatic clock genes (Per1, Cry1, Dec1, Bmal1) could be the underlying cause of the maladaptation. When supplemented with EC, the functional impairment and inflammation were abolished. The protective effects could be linked to its effectiveness in maintaining the synchrony between the master and hepatic clocks, and the resultant improved coupling of the circadian oscillators (Per1, Cry1, Dec1, Bmal1) and metabolic regulators (mTOR, AMPK). Overall, EC supplementation promoted the physiological adaptation to the prolonged circadian disruption through facilitation of endogenous circadian synchrony and the coupling of circadian oscillators and metabolic regulators. This forms an important basis for further elucidation of the physiological benefits of EC-facilitated circadian synchrony. PMID- 26595386 TI - Mortality Risk Among Heroin Abusers: Clients and Non-clients of Public Treatment Centers for Drug Addiction. AB - In Europe, the prevalence of problematic heroin consumption is declining but, in spite of the constant rise in the number of treated patients, many of them do not turn to a public treatment center (PTC) for their drug addiction. The aim of this study is to study the mortality risk separately for heroin abusers PTC clients and non-PTC clients (i.e., those never treated at a PTC). METHODS: Cohort study on 959 subjects resident in the metropolitan area of Bologna who went to a health service (i.e., hospital, emergency unit) or to a PTC following problems due to heroin abuse for the first time between 01/01/2004 and 31/12/2009. Standardized mortality ratios (SMRs) were calculated, and regression analysis using the Poisson method was used. RESULTS: Elevated and statistically significant SMRs were found in both genders, irrespective of the contact facility, being higher for PTC clients. Among non-PTC clients 28% of deaths overall were from AIDS or infectious diseases (6% PTC clients), 17% from opiate overdose (6% PTC clients) and 14% from violent causes (6% PTC clients). Multivariate analysis showed a higher mortality risk for patients who used both heroin and cocaine and for concomitant abuse of benzodiazepines. CONCLUSIONS: The characteristics of patients never before treated for addiction prompts a reflection on the presence of a hidden group of patients who are hard to reach, who have a high mortality risk and who turn to health care treatment facilities only in the event of an emergency. PMID- 26595387 TI - Core-shell-corona doxorubicin-loaded superparamagnetic Fe3O4 nanoparticles for cancer theranostics. AB - Superparamagnetic iron oxide magnetic nanoparticles (MNPs) are successfully used as contrast agents in magnetic-resonance imaging. They can be easily functionalized for drug delivery functions, demonstrating great potential for both imaging and therapeutic applications. Here we developed new pH-responsive theranostic core-shell-corona nanoparticles consisting of superparamagentic Fe3O4 core that displays high T2 relaxivity, bovine serum albumin (BSA) shell that binds anticancer drug, doxorubicin (Dox) and poly(ethylene glycol) (PEG) corona that increases stability and biocompatibility. The nanoparticles were produced by adsorption of the BSA shell onto the Fe3O4 core followed by crosslinking of the protein layer and subsequent grafting of the PEG corona using monoamino terminated PEG via carbodiimide chemistry. The hydrodynamic diameter, zeta potential, composition and T2 relaxivity of the resulting nanoparticles were characterized using transmission electron microscopy, dynamic light scattering, thermogravimetric analysis and T2-relaxometry. Nanoparticles were shown to absorb Dox molecules, possibly through a combination of electrostatic and hydrophobic interactions. The loading capacity (LC) of the nanoparticles was 8 wt.%. The Dox loaded nanoparticles release the drug at a higher rate at pH 5.5 compared to pH 7.4 and display similar cytotoxicity against C6 and HEK293 cells as the free Dox. PMID- 26595388 TI - Catanionic drug-derivative nano-objects constructed by chlorambucil and its derivative for efficient leukaemia therapy. AB - A new carrier-free catanionic drug-derivative nano-object strategy is developed for leukaemia therapy. The as-prepared drug-derivative nano-objects are formed by ionic pairs of hydrophobic anticancer drug chlorambucil (CLB) and its derivative N-(2-Amino-ethyl)-4-{4-[bis-(2-chloro-ethyl)-amino]-phenyl}-butyramide (CLBM). The designed drug delivery system has the advantage of 100% drug content without additional carrier materials. The ionic pairs are formed by proton exchange between CLB and CLBM. Due to the amphiphilicity of the ionic pairs, they can assemble into well-defined drug-derivative (CLB-CLBM) nano-objects. Series of techniques such as transmission electron microscopy (TEM), dynamic light scattering (DLS) and electrical conductivity are used to investigate the property of the solution and aggregation behaviour of as-prepared drug-derivative ionic pairs. In vitro drug release study of the as-prepared nano-objects shows their prolonged drug release behavior. Specifically, in vitro cytotoxicity results of these nano-objects show obviously higher cytotoxicity, which is promising for clinical efficacy. This study may pave the way for the fabrication of carrier free drug delivery system with efficient cancer therapy. PMID- 26595389 TI - Multifunctional nano manganese ferrite ferrofluid for efficient theranostic application. AB - Ferrofluid-based manganese (Mn(2+)) substituted superparamagnetic iron oxide nanoparticles stabilized by surface coating with trisodium citrate (MnIOTCs) were synthesized for enhanced hyperthermic activity and use as negative magnetic resonance imaging (MRI) contrast media intended for applications in theranostics. The synthesized MnIOTC materials were characterized based on their physicochemical and biological features. The crystal size and the particle size at the nano level were studied using XRD and TEM. The presence of citrate molecules on the crystal surface of the iron oxide was established by FTIR, TGA, DLS and zeta potential measurements. The superparamagnetic property of MnIOTCs was measured using a vibrating sample magnetometer. Superparamagnetic iron oxide substituted with Mn(2+) with a 3:1 molar concentration of Mn(2+) to Fe(2+) and surface modified with trisodium citrate (MnIO75TC) that exhibited a high T2 relaxivity of 184.6mM(-1)s(-1) and showed excellent signal intensity variation in vitro. Hyperthermia via application of an alternating magnetic field to MnIO75TC in a HeLa cell population induced apoptosis, which was further confirmed by FACS and cLSM observations. The morphological features of the cells were highly disrupted after the hyperthermia experiment, as evidenced from E-SEM images. Biocompatibility evaluation was performed using an alamar blue assay and hemolysis studies, and the results indicated good cytocompatibility and hemocompatibility for the synthesized particles. In the current study, the potential of MnIO75TC as a negative MRI contrast agent and a hyperthermia agent was demonstrated to confirm its utility in the burgeoning field of theranostics. PMID- 26595390 TI - Immunomodulatory effects of Lactobacillus strains: emphasis on their effects on cancer cells. AB - Lactobacilli are a group of normal microbiota whose immunomodulatory effects have been known for a long time. Recently, they have gained more attention for their direct and indirect effects on cancer cells. Several cell line experiments, animal model studies as well as clinical trials have indicated their inhibitory effects on cancer initiation and progression. Different lactobacilli strains could modulate innate and adoptive immune system. Such effects have been documented in modulation of function of T cells, dendritic cells and macrophages as well as cytokine production. In this review, the various immunomodulatory effects of lactobacilli on tumor cells as well as their direct cytotoxic effects on cancer cells are discussed. PMID- 26595391 TI - Usefulness of a rapid faecal calprotectin test to predict relapse in Crohn's disease patients on maintenance treatment with adalimumab. AB - BACKGROUND AND AIM: Predicting relapse in Crohn's disease (CD) patients by measuring non-invasive biomarkers could allow for early changes of treatment. Data are scarce regarding the utility of monitoring calprotectin to predict relapse. The aim of the study was to evaluate the predictive value of a rapid test of faecal calprotectin (FC) to predict for flares in CD patients on maintenance treatment with adalimumab (ADA). METHODS: A prospective, observational cohort study was designed. Inclusion criteria were CD patients in clinical remission on a standard dose of ADA therapy. Fresh FC was measured using a rapid test. RESULTS: Thirty patients were included (median age 38 years, 56.7% female). After the 4 months follow-up, 70.0% patients remained in clinical remission and 30.0% had a relapse. FC concentration at inclusion was significantly higher in those patients who relapsed during the follow-up (625 MUg/g) compared to those who stayed in remission (45 MUg/g). The optimal cut-off for FC to predict relapse was 204 MUg/g. The area under the receiver-operating characteristic curve was 0.968. Sensitivity, specificity, positive, and negative predictive value of FC to predict relapse were 100%, 85.7%, 74.1%, and 100%, respectively. CONCLUSION: In CD patients on ADA maintenance therapy, FC levels measured with a rapid test allow relapse over the following months to be predicted with high accuracy. Low FC levels exclude relapse within at least 4 months after testing, whereas high levels are associated with relapse in three out of every four patients. PMID- 26595392 TI - Biogenic acidification reduces sea urchin gonad growth and increases susceptibility of aquaculture to ocean acidification. AB - Decreasing oceanic pH (ocean acidification) has emphasised the influence of carbonate chemistry on growth of calcifying marine organisms. However, calcifiers can also change carbonate chemistry of surrounding seawater through respiration and calcification, a potential limitation for aquaculture. This study examined how seawater exchange rate and stocking density of the sea urchin Tripneustes gratilla that were reproductively mature affected carbonate system parameters of their culture water, which in turn influenced growth, gonad production and gonad condition. Growth, relative spine length, gonad production and consumption rates were reduced by up to 67% by increased density (9-43 individuals.m(-2)) and reduced exchange rates (3.0-0.3 exchanges.hr(-1)), but survival and food conversion efficiency were unaffected. Analysis of the influence of seawater parameters indicated that reduced pH and calcite saturation state (OmegaCa) were the primary factors limiting gonad production and growth. Uptake of bicarbonate and release of respiratory CO2 by T. gratilla changed the carbonate chemistry of surrounding water. Importantly total alkalinity (AT) was reduced, likely due to calcification by the urchins. Low AT limits the capacity of culture water to buffer against acidification. Direct management to counter biogenic acidification will be required to maintain productivity and reproductive output of marine calcifiers, especially as the ocean carbonate system is altered by climate driven ocean acidification. PMID- 26595395 TI - Retraction. PMID- 26595394 TI - Chemical composition and evaluation of the antimicrobial activity of the essential oil from leaves of Eugenia platysema. AB - This study describes the qualitative and quantitative chemical composition and evaluates the antibacterial activity of essential oil from Eugenia platysema leaves. Analysis by GC-FID and GC-MS allowed the identification of 22 compounds. Different from the other species of the Eugenia genus, the major compound found in the essential oil was the diterpene phytol (66.05%), being this the first report of the presence of this compound in the essential oils from Eugenia genus. The sesquiterpene elixene was the second most concentrated compound in the studied essential oil (9.16%). The essential oil from E. platysema was tested for its antibacterial activity against cell-walled bacteria and mollicute strains of clinical interest using the microdilution broth assay. The results showed that the essential oil of E. platysema was inactive until 1000 MUg mL(-1) against tested bacteria. PMID- 26595396 TI - Trace metals partitioning among different sedimentary mineral phases and the deposit-feeding polychaete Armandia brevis. AB - Trace metals (Cd, Co, Cu, Fe, Mn, Ni, Pb, Zn) were determined in two operationally defined fractions (HCl and pyrite) in sediments from Ensenada and El Sauzal harbors (Mexico). The HCl fraction had significantly higher metal concentrations relative to the pyrite fraction in both harbors, underlining the weak tendency of most trace metals to associate with pyrite. Exceptionally, Cu was highly pyritized, with degrees of trace metal pyritization (DTMP) >80% in both harbors. Dissolved Fe flux measurements combined with solid phase Fe sulfide data indicated that 98 mt of Fe are precipitated as iron sulfides every year in Ensenada Harbor. These Fe sulfides (and associated trace metals) will remain preserved in the sediments, unless they are perturbed by dredging or sediment resuspension. Calculations indicate that dredging activities could export to the open ocean 0.20+/-0.13 to (0.30+/-0.56)*10(3) mt of Cd and Cu, respectively, creating a potential threat to marine benthic organisms. Degrees of pyritization (DOP) values in Ensenada and El Sauzal harbors were relatively low (<25%) while degrees of sulfidization (DOS) were high (~50%) because of the contribution of acid volatile sulfide. DOP values correlated with DTMP values (p<=0.001), indicating that metals are gradually incorporated into pyrite as this mineral is formed. Significant correlations were also found between DTMP values and log(Ksp(MeS)/Ksp(pyr)) for both harbors, indicating that incorporation of trace metals into the pyrite phase is a function of the solubility product of the corresponding metal sulfide. The order in which elements were pyritized in both harbors was Zn~Mn infinity, we find that control diminishes rapidly as soon as sigma exceeds the bandwidth of the pulse. However, we also find that control can be regained by reducing tauc. We attribute this trend to motional narrowing, whereby decreasing tauc narrows down the effective bandwidth of the solvent-induced fluctuations. The results suggest that the choice of methanol as a solvent in the actual experimental demonstration of chirp control by Cerullo et al. [ Chem. Phys. Lett. 1996 , 262 , 362 - 368 ] may have contributed to its success, due to the particularly short tauc (~20 fs) that the rapid librations of this hydrogen bonded liquid give rise to. The results also give rise to the rather surprising prediction that coherent control in liquid solution can be strongly dependent on the choice of solvent and be improved upon by choosing solvents that correspond to lower values of sigmatauc. PMID- 26595413 TI - Phytoremediation efficiency of Eichhornia crassipes in fly ash pond. AB - The present study was focused on field research to examine the phytoremediation potential of naturally grown Eichhornia crassipes in fly ash (FA) pond. Field results indicate the efficiency of E. crassipes for remediation of heavy metals from FA pond. The bioconcentration factor trend was Cr (3.75) > Cu (2.62) > Cd (1.05), and Cu (1.35) in root and stem, respectively. The survival and abundance growth of E. crassipes in the circumstance of heavy metal enriched FA pond is another highlight of the present research that reveals its toxitolerant characteristics. Thus, this lesson on phytoremediation proved that E. crassipes is a potential accumulator of Cu, Cr, and Cd from FA ponds and is a promising species for FA pond's remediation globally. PMID- 26595411 TI - Cancer chemoprevention research with selenium in the post-SELECT era: Promises and challenges. AB - The negative efficacy outcomes of double-blinded, randomized, placebo-controlled Phase III human clinical trials with selenomethionine (SeMet) and SeMet-rich selenized-yeast (Se-yeast) for prostate cancer prevention and Se-yeast for prevention of nonsmall cell lung cancer (NSCLC) in North America lead to rejection of SeMet/Se-yeast for cancer prevention in Se-adequate populations. We identify 2 major lessons from the outcomes of these trials: 1) the antioxidant hypothesis was tested in wrong subjects or patient populations, and 2) the selection of Se agents was not supported by cell culture and preclinical animal efficacy data as is common in drug development. We propose that next-generation forms of Se (next-gen Se), such as methylselenol precursors, offer biologically appropriate approaches for cancer chemoprevention but these are faced with formidable challenges. Solid mechanism-based preclinical efficacy assessments and comprehensive safety studies with next-gen Se will be essential to revitalize the idea of cancer chemoprevention with Se in the post-SELECT era. We advocate smaller mechanism-driven Phase I/II trials with these next-gen Se to guide and justify future decisions for definitive Phase III chemoprevention efficacy trials. PMID- 26595414 TI - Clinical Neurochemistry of Subarachnoid Hemorrhage: Toward Predicting Individual Outcomes via Biomarkers of Brain Energy Metabolism. AB - The functional outcome of patients with subarachnoid hemorrhage is difficult to predict at the individual level. The monitoring of brain energy metabolism has proven to be useful in improving the pathophysiological understanding of subarachnoid hemorrhage. Nonetheless, brain energy monitoring has not yet clearly been included in official guidelines for the management of subarachnoid hemorrhage patients, likely because previous studies compared only biological data between two groups of patients (unfavorable vs favorable outcomes) and did not determine decision thresholds that could be useful in clinical practice. Therefore, this Viewpoint discusses recent findings suggesting that monitoring biomarkers of brain energy metabolism at the level of individuals can be used to predict the outcomes of subarachnoid hemorrhage patients. Indeed, by taking into account specific neurochemical patterns obtained by local or global monitoring of brain energy metabolism, it may become possible to predict routinely, and with sufficient sensitivity and specificity, the individual outcomes of subarachnoid hemorrhage patients. Moreover, combining both local and global monitoring improves the overall performance of individual outcome prediction. Such a combined neurochemical monitoring approach may become, after prospective clinical validation, an important component in the management of subarachnoid hemorrhage patients to adapt individualized therapeutic interventions. PMID- 26595415 TI - Exome Variant Mining in Familial Parkinson Disease: Will Replication Find the Gold? PMID- 26595416 TI - Stimuli-responsive smart gating membranes. AB - Membranes are playing paramount roles in the sustainable development of myriad fields such as energy, environmental and resource management, and human health. However, the unalterable pore size and surface properties of traditional porous membranes restrict their efficient applications. The performances of traditional membranes will be weakened upon unavoidable membrane fouling, and they cannot be applied to cases where self-regulated permeability and selectivity are required. Inspired by natural cell membranes with stimuli-responsive channels, artificial stimuli-responsive smart gating membranes are developed by chemically/physically incorporating stimuli-responsive materials as functional gates into traditional porous membranes, to provide advanced functions and enhanced performances for breaking the bottlenecks of traditional membrane technologies. Smart gating membranes, integrating the advantages of traditional porous membrane substrates and smart functional gates, can self-regulate their permeability and selectivity via the flexible adjustment of pore sizes and surface properties based on the "open/close" switch of the smart gates in response to environmental stimuli. This tutorial review summarizes the recent developments in stimuli-responsive smart gating membranes, including the design strategies and the fabrication strategies that are based on the introduction of the stimuli-responsive gates after or during membrane formation, and the positively and negatively responsive gating models of versatile stimuli-responsive smart gating membranes, as well as the advanced applications of smart gating membranes for regulating substance concentration in reactors, controlling the release rate of drugs, separating active molecules based on size or affinity, and the self-cleaning of membrane surfaces. With self-regulated membrane performances, smart gating membranes show great power for use in global sustainable development. PMID- 26595417 TI - Supervised Learning Using Spike-Timing-Dependent Plasticity of Memristive Synapses. AB - We propose a supervised learning model that enables error backpropagation for spiking neural network hardware. The method is modeled by modifying an existing model to suit the hardware implementation. An example of a network circuit for the model is also presented. In this circuit, a three-terminal ferroelectric memristor (3T-FeMEM), which is a field-effect transistor with a gate insulator composed of ferroelectric materials, is used as an electric synapse device to store the analog synaptic weight. Our model can be implemented by reflecting the network error to the write voltage of the 3T-FeMEMs and introducing a spike timing-dependent learning function to the device. An XOR problem was successfully demonstrated as a benchmark learning by numerical simulations using the circuit properties to estimate the learning performance. In principle, the learning time per step of this supervised learning model and the circuit is independent of the number of neurons in each layer, promising a high-speed and low-power calculation in large-scale neural networks. PMID- 26595418 TI - Pinning Synchronization of Directed Networks With Switching Topologies: A Multiple Lyapunov Functions Approach. AB - This paper studies the global pinning synchronization problem for a class of complex networks with switching directed topologies. The common assumption in the existing related literature that each possible network topology contains a directed spanning tree is removed in this paper. Using tools from M -matrix theory and stability analysis of the switched nonlinear systems, a new kind of network topology-dependent multiple Lyapunov functions is proposed for analyzing the synchronization behavior of the whole network. It is theoretically shown that the global pinning synchronization in switched complex networks can be ensured if some nodes are appropriately pinned and the coupling is carefully selected. Interesting issues of how many and which nodes should be pinned for possibly realizing global synchronization are further addressed. Finally, some numerical simulations on coupled neural networks are provided to verify the theoretical results. PMID- 26595419 TI - Conserved mRNA-binding proteomes in eukaryotic organisms. AB - RNA-binding proteins (RBPs) are essential for post-transcriptional regulation of gene expression. Recent high-throughput screens have dramatically increased the number of experimentally identified RBPs; however, comprehensive identification of RBPs within living organisms is elusive. Here we describe the repertoire of 765 and 594 proteins that reproducibly interact with polyadenylated mRNAs in Saccharomyces cerevisiae and Caenorhabditis elegans, respectively. Furthermore, we report the differential association of mRNA-binding proteins (mRPBs) upon induction of apoptosis in C. elegans L4-stage larvae. Strikingly, most proteins composing mRBPomes, including components of early metabolic pathways and the proteasome, are evolutionarily conserved between yeast and C. elegans. We speculate, on the basis of our evidence that glycolytic enzymes bind distinct glycolytic mRNAs, that enzyme-mRNA interactions relate to an ancient mechanism for post-transcriptional coordination of metabolic pathways that perhaps was established during the transition from the early 'RNA world' to the 'protein world'. PMID- 26595420 TI - Structure of full-length human anti-PD1 therapeutic IgG4 antibody pembrolizumab. AB - Immunoglobulin G4 antibodies exhibit unusual properties with important biological consequences. We report the structure of the human full-length IgG4 S228P anti PD1 antibody pembrolizumab, solved to 2.3-A resolution. Pembrolizumab is a compact molecule, consistent with the presence of a short hinge region. The Fc domain is glycosylated at the CH2 domain on both chains, but one CH2 domain is rotated 120 degrees with respect to the conformation observed in all reported structures to date, and its glycan chain faces the solvent. We speculate that this new conformation is driven by the shorter hinge. The structure suggests a role for the S228P mutation in preventing the IgG4 arm exchange. In addition, this unusual Fc conformation suggests possible structural diversity between IgG subclasses and shows that use of isolated antibody fragments could mask potentially important interactions, owing to molecular flexibility. PMID- 26595421 TI - Step detection using multi- versus single tri-axial accelerometer-based systems. AB - Multiple sensors are often considered necessary for increased step count accuracy. However, subject adherence to device-wear increases using a minimal number of activity monitors (AMs). The study aims were to determine and compare the validity of using multiple AMs versus a single AM to detect steps by comparison to video using a modification of an algorithm previously developed for a four-accelerometer AM system capable, unlike other algorithms, of accurate step detection for gait velocities as low as 0.1 m s(-1). Twelve healthy adults wore ankle, thigh and waist AMs while performing walking/jogging trials at gait velocities from 0.1-4.8 m s(-1) and a simulated free-living dynamic activities protocol. Nineteen older adults wore ankle and waist AMs while walking at velocities from 0.5-2.0 m s(-1). As little as one AM (thigh or waist) accurately detected steps for velocities >0.5 m s(-1). A single ankle AM accurately detected steps for velocities ?0.1 m s(-1). Only the thigh AM could not accurately detect steps during the dynamic activities. Only the thigh-ankle combination or single waist AM could accurately distinguish between walking and jogging steps. These laboratory-based results suggest that the presented algorithm can accurately detect steps in a free-living environment using only one ankle or waist AM. PMID- 26595423 TI - Navigating the Affordable Care Act and the Patient with Inflammatory Bowel Disease. AB - The Patient Protection and Affordable Care Act of 2010 (ACA) is a critically important yet complex piece of legislation with far reaching impacts on patient care especially for those with chronic diseases such as inflammatory bowel disease. The tenets of the Affordable Care Act affect not only those purchasing new plans through the marketplaces but also Americans across the country as it sets baseline standards for many aspects of coverage. This review will address the fundamental goals that drove the inception of the legislation, the impact of the Affordable Care Act on day-to-day patient care, and the key components of the marketplace plans and potential subsidies. PMID- 26595424 TI - Biosimilars in allergic diseases. AB - PURPOSE OF REVIEW: This article realizes an overview on the world of biological and biosimilar drugs in allergic and immunologic diseases' treatment strategies. We started talking about the history of asthma treatment's progresses, continuing to daily biological therapies, concluding with the economic point of view. RECENT FINDINGS: Nowadays, the only pharmacological-biological approach approved for allergic diseases is omalizumab. Several other monoclonal antibodies are currently running premarketing studies but the costs of these therapies are difficult to be sustained by healthcare systems. SUMMARY: Several biological treatments have gone or are going off-patent, opening the drug market to biosimilars. In this way, in future, it will be possible to reduce health costs and increase accessibility to therapies that currently are not affordable to all patients. PMID- 26595422 TI - Mechanisms Underlying Dysregulation of Electrolyte Absorption in Inflammatory Bowel Disease-Associated Diarrhea. AB - Inflammatory bowel diseases (IBDs), including Crohn's disease and ulcerative colitis, are chronic relapsing inflammatory disorders of the gastrointestinal tract. Chronic inflammation of the intestine affects the normal fluid and electrolyte absorption leading to diarrhea, the hallmark symptom of IBD. The management of IBD-associated diarrhea still remains to be a challenge, and extensive studies over the last 2 decades have focused on investigating the molecular mechanisms underlying IBD-associated diarrhea. These studies have shown that the predominant mechanism of diarrhea in IBD involves impairment of electroneutral NaCl absorption, with very little role if any played by anion secretion. The electroneutral NaCl absorption involves coupled operation of Na/H exchanger 3 (NHE3 or SLC9A3) and Cl/HCO3 exchanger DRA (Down Regulated in Adenoma, or SLC26A3). Increasing evidence now supports the critical role of a marked decrease in NHE3 and DRA function and/or expression in IBD-associated diarrhea. This review provides a detailed analysis of the current knowledge related to alterations in NHE3 and DRA function and expression in IBD including the mechanisms underlying these observations and highlights the potential of these transporters as important and novel therapeutic targets. PMID- 26595425 TI - Rhodium(III)-Catalyzed C-H Activation and Annulation with 1-Alkynylphosphine Sulfides: A Mild and Regioselective Access for the Synthesis of Bulky Phosphine Ligands. AB - We reported herein rhodium(III)-catalyzed C-H activation and annulation reactions for the synthesis of bulky phosphine ligands by using 1-alkynylphosphine sulfides as key starting materials. In the presence of [Cp*RhCl2]2 (5 mol %) and CsOAc (2.0 equiv), various N-(pivaloyloxy)benzamides (3.0 equiv) could react smoothly with 1-alkynylphosphine sulfides at 40 degrees C in MeOH/CF3CH2OH cosolvent without external oxidant. Using [Cp(Ph)RhCl2]2 as catalyst, the reaction can be performed under less loading of benzamides (2.0 equiv) and milder reaction conditions (25 degrees C) with higher regioselectivity. In a sequential cyclization/desulfidation process, this new method provides a variety of bulky heteroarylphosphines with an isoquinolin-1(2H)-one motif. PMID- 26595426 TI - Heroin delay discounting: Modulation by pharmacological state, drug-use impulsivity, and intelligence. AB - Delay discounting (DD) refers to how rapidly an individual devalues goods based on delays to receipt. DD usually is considered a trait variable but can be state dependent, yet few studies have assessed commodity valuation at short, naturalistically relevant time intervals that might enable state-dependent analysis. This study aimed to determine whether drug-use impulsivity and intelligence influence heroin DD at short (ecologically relevant) delays during two pharmacological states (heroin satiation and withdrawal). Out-of-treatment, intensive heroin users (n = 170; 53.5% African American; 66.7% male) provided complete DD data during imagined heroin satiation and withdrawal. Delays were 3, 6, 12, 24, 48, 72, and 96 hours; maximum delayed heroin amount was thirty $10 bags. Indifference points were used to calculate area under the curve (AUC). We also assessed drug-use impulsivity (subscales from the Impulsive Relapse Questionnaire [IRQ]) and estimated intelligence (Shipley IQ) as predictors of DD. Heroin discounting was greater (smaller AUC) during withdrawal than satiation. In regression analyses, lower intelligence and IRQ Capacity for Delay as well as higher IRQ Speed (to return to drug use) predicted greater heroin discounting in the satiation condition. Lower intelligence and higher IRQ Speed predicted greater discounting in the withdrawal condition. Sex, race, substance use variables, and other IRQ subscales were not significantly related to the withdrawal or satiation DD behavior. In summary, heroin discounting was temporally rapid, pharmacologically state dependent, and predicted by drug-use impulsivity and estimated intelligence. These findings highlight a novel and sensitive measure of acute DD that is easy to administer. PMID- 26595427 TI - Complete Idiopathic Hypogonadotropic Hypogonadism due to Homozygous GNRH1 Mutations in the Mutational Hot Spots in the Region Encoding the Decapeptide. AB - INTRODUCTION: Mutations of the human GNRH1 gene are an extremely rare cause of normosmic idiopathic hypogonadotropic hypogonadism (nIHH), with only 6 mutations so far described. PATIENTS: As part of a larger study, families with IHH were screened for mutations in genes known to be associated with IHH. In family 1, a 15-year and 9-month-old boy first presented during infancy with micropenis and bilateral cryptorchidism. His pubic and axillary hair is at stage 4 and 2, respectively. His testes are 1 ml bilaterally, and his stretched penile length is 3.6 cm. In family 2, a 19-year and 2-month-old man was referred because of absence of secondary sexual characteristics. His 13-year and 8-month-old sister did not have any breast development. RESULTS: In 3 patients from 2 independent families we identified GNRH1 mutations. In the proband from family 1, a homozygous 1-base deletion (c.87delA) leading to a frameshift mutation (p.G29GfsX12) was identified. In family 2, the affected siblings had a novel homozygous mutation of c.G92A leading to p.R31H. CONCLUSION: Both mutations in these families are located in the region encoding the decapeptide and in the loci where the mutations have been described before. Therefore, these areas can be considered as mutational hot spots, indicating priority for routine diagnostic gene mutation analysis. PMID- 26595428 TI - Impact of Aneurysm Projection on Intraoperative Complications During Surgical Clipping of Ruptured Posterior Communicating Artery Aneurysms. AB - BACKGROUND: Surgical clipping of ruptured posterior communicating artery (PCoA) aneurysms is a well-established procedure to date. However, preoperative factors associated with procedure-related risk require further elucidation. OBJECTIVE: To investigate the impact of the direction of aneurysm projection on the incidence of procedure-related complications during surgical clipping of ruptured PCoA aneurysms. METHODS: A total of 65 patients with ruptured PCoA aneurysms who underwent surgical clipping were retrospectively analyzed from a single-center, prospective, observational cohort database in this study. The aneurysms were categorized into lateral and posterior projection groups, depending on direction of the dome. Characteristics and operative findings of each projection group were identified. We also evaluated any correlation of aneurysm projection with the incidence of procedure-related complications. RESULTS: Patients with ruptured PCoA aneurysms with posterior projection more likely presented with good admission-grade subarachnoid hemorrhage (P = .01, chi test) and were less to also have intracerebral hematoma (P = .01). These aneurysms were found to be associated with higher incidence of intraoperative rupture (P = .02), complex clipping with fenestrated clips (P = .02), and dense adherence to PCoA or its perforators (P = .04) by univariate analysis. Aneurysms with posterior projection were also correlated with procedure-related complications, including postoperative cerebral infarction or hematoma formation (odds ratio, 5.87; 95% confidence interval, 1.11-31.1; P = .04) by multivariable analysis. CONCLUSION: Ruptured PCoA aneurysms with posterior projection carried a higher risk of procedure-related complications of surgical clipping than those with lateral projection. PMID- 26595429 TI - Prospective Multicenter Assessment of Early Complication Rates Associated With Adult Cervical Deformity Surgery in 78 Patients. AB - BACKGROUND: Few reports have focused on treatment of adult cervical deformity (ACD). OBJECTIVE: To present early complication rates associated with ACD surgery. METHODS: A prospective multicenter database of consecutive operative ACD patients was reviewed for early (<=30 days from surgery) complications. Enrollment required at least 1 of the following: cervical kyphosis >10 degrees, cervical scoliosis >10 degrees, C2-7 sagittal vertical axis >4 cm, or chin-brow vertical angle >25 degrees. RESULTS: Seventy-eight patients underwent surgical treatment for ACD (mean age, 60.8 years). Surgical approaches included anterior only (14%), posterior-only (49%), anterior-posterior (35%), and posterior anterior-posterior (3%). Mean numbers of fused anterior and posterior vertebral levels were 4.7 and 9.4, respectively. A total of 52 early complications were reported, including 26 minor and 26 major. Twenty-two (28.2%) patients had at least 1 minor complication, and 19 (24.4%) had at least 1 major complication. Overall, 34 (43.6%) patients had at least 1 complication. The most common complications included dysphagia (11.5%), deep wound infection (6.4%), new C5 motor deficit (6.4%), and respiratory failure (5.1%). One (1.3%) mortality occurred. Early complication rates differed significantly by surgical approach: anterior-only (27.3%), posterior-only (68.4%), and anterior-posterior/posterior anterior-posterior (79.3%) (P = .007). CONCLUSION: This report provides benchmark rates for overall and specific ACD surgery complications. Although the surgical approach(es) used were likely driven by the type and complexity of deformity, there were significantly higher complication rates associated with combined and posterior-only approaches compared with anterior-only approaches. These findings may prove useful in treatment planning, patient counseling, and ongoing efforts to improve safety of care. ABBREVIATIONS: 3CO, 3-column osteotomiesACD, adult cervical deformityEBL, estimated blood lossISSG, International Spine Study groupSVA, sagittal vertical axis. PMID- 26595430 TI - Making Milestones: Development and Implementation of a Formal Socioeconomic Curriculum in a Neurosurgical Residency Training Program. AB - BACKGROUND: Improved training in the socioeconomic aspects of medicine is a priority of the Accreditation Council for Graduate Medical Education and the American Board of Neurological Surgeons. There is evidence that young neurosurgeons feel ill equipped in these areas and that additional education would improve patient care. OBJECTIVE: To present our experience with the introduction of a succinct but formal socioeconomic training course to the residency curriculum at our institution. METHODS: A monthly series of twelve 1 hour interactive modules was designed to address the pertinent Accreditation Council for Graduate Medical Education-American Board of Neurological Surgeons outcomes-based educational milestones. Slide-based lectures provided a comprehensive overview of social, legal, and business issues, and a monthly forum for open discussion allowed residents to draw on their applied experience. Residents took a 20-question pre- and postcourse knowledge assessment, as well as feedback surveys at 6 and 12 months. RESULTS: Residents were able to participate in the lectures, with an overall attendance rate of 91%. Residents felt that the course goals and objectives were well defined and communicated (4.88/5) and rated highly the content, quality, and relevance of the lectures (4.94/5). Performance on the knowledge assessment improved from 58% to 66%. CONCLUSION: Our experience demonstrates the feasibility of including a formal socioeconomic course in neurosurgical residency training with positive resident feedback and achievement of outcomes-based milestones. Extension to a 2-year curriculum cycle may allow the course to cover more material without compromising other residency training goals. Online modules should also be explored to allow for wider and more flexible participation. ABBREVIATIONS: ABNS, American Board of Neurological SurgeonsACGME, Accreditation Council for Graduate Medical Education. PMID- 26595431 TI - Letter: Industry Sponsorship of Spine Device Trials Is the Norm. PMID- 26595432 TI - Ferric maltol (ST10): a novel oral iron supplement for the treatment of iron deficiency anemia in inflammatory bowel disease. AB - INTRODUCTION: Iron deficiency anemia affects up to three quarters of patients with inflammatory bowel disease (IBD). It can significantly impact the quality of life and the ability to work by impairing physical, emotional, and cognitive functioning. The etiology of iron deficiency anemia is multifactorial and oral or intravenous iron replacement is necessary. However, oral iron supplements are often discontinued prematurely due to poor tolerability or insufficient efficacy. Moreover, intravenous supplementation is inconvenient, associated with potentially serious safety risks, and a burden on healthcare resources. AREAS COVERED: Ferric maltol is a novel ferric iron compound with potential use as an oral therapy for iron deficiency anemia. This overview explains how the molecule's design impacts clinical outcomes and summarizes available clinical data (ranging from early comparisons with ferrous sulfate to randomized, placebo controlled, Phase III data in patients with IBD known to be intolerant of oral ferrous products). EXPERT OPINION: Ferric maltol offers the ability to treat iron deficiency anemia in mild-to-moderate IBD without resorting to intravenous therapy, even in those who are intolerant of oral ferrous products. This clinical benefit has the potential to change treatment pathways and increase choice, not only in IBD but also perhaps in many areas beyond gastroenterology. PMID- 26595433 TI - Benefits of Exercise for the Quality of Life of Drug-Dependent Patients. AB - This study combined quantitative and qualitative research methods to evaluate quality-of-life changes in drug-dependent patients after participation in a group based exercise program. Quality of life (SF-36) and physical fitness (six-minute Walk Test, Timed Get Up and Go Test, and Chair Stand Test) were quantitatively determined in a group (n=37) of drug-dependent patients before and after a 12 week group exercise program (n=18) or routine care (n=19). Additionally, in-depth interviews were conducted at the end of the program with a subsample of 11 participants from the exercise group. Quantitative results showed improvements in fitness and different aspects of quality of life, such as physical function, mental health, vitality, social function, and general health perception. Qualitative results showed specific physical benefits (decreased injuries and muscle pain, decreased weight, and increased vitality with improvement in activities of daily living), psychological benefits (forgetting about everyday problems, improved mood, decreased stress and anxiety), social benefits, and a reduction in craving. The results of this study provide insight into the importance of exercise for the quality of life and recovery process of drug dependent patients. PMID- 26595434 TI - Every little piece counts: the many faces of tRNA transcripts. AB - For over half a century, tRNAs have been exclusively known as decoders of genomic information. However, recent reports evidenced that tRNA transcripts are also bearers of functional RNAs, which are able to execute various tasks through an array of mechanisms. Here, we succinctly review the diversity and functions of RNAs deriving from tRNA loci. PMID- 26595435 TI - Advanced Parkinson disease patients have impairment in prosody processing. AB - BACKGROUND: The ability to recognize and interpret emotions in others is a crucial prerequisite of adequate social behavior. Impairments in emotion processing have been reported from the early stages of Parkinson's disease (PD). This study aims to characterize emotion recognition in advanced Parkinson's disease (APD) candidates for deep-brain stimulation and to compare emotion recognition abilities in visual and auditory domains. METHOD: APD patients, defined as those with levodopa-induced motor complications (N = 42), and healthy controls (N = 43) matched by gender, age, and educational level, undertook the Comprehensive Affect Testing System (CATS), a battery that evaluates recognition of seven basic emotions (happiness, sadness, anger, fear, surprise, disgust, and neutral) on facial expressions and four emotions on prosody (happiness, sadness, anger, and fear). APD patients were assessed during the "ON" state. Group performance was compared with independent-samples t tests. RESULTS: Compared to controls, APD had significantly lower scores on the discrimination and naming of emotions in prosody, and visual discrimination of neutral faces, but no significant differences in visual emotional tasks. CONCLUSION: The contrasting performance in emotional processing between visual and auditory stimuli suggests that APD candidates for surgery have either a selective difficulty in recognizing emotions in prosody or a general defect in prosody processing. Studies investigating early-stage PD, and the effect of subcortical lesions in prosody processing, favor the latter interpretation. Further research is needed to understand these deficits in emotional prosody recognition and their possible contribution to later behavioral or neuropsychiatric manifestations of PD. PMID- 26595436 TI - Incidental fear cues increase monetary loss aversion. AB - In many everyday decisions, people exhibit loss aversion-a greater sensitivity to losses relative to gains of equal size. Loss aversion is thought to be (at least partly) mediated by emotional--in particular, fear-related--processes. Decision research has shown that even incidental emotions, which are unrelated to the decision at hand, can influence decision making. The effect of incidental fear on loss aversion, however, is thus far unclear. In two studies, we experimentally investigated how incidental fear cues, presented during (Study 1) or before (Study 2) choices to accept or reject mixed gambles over real monetary stakes, influence monetary loss aversion. We find that the presentation of fearful faces, relative to the presentation of neutral faces, increased risk aversion-an effect that could be attributed to increased loss aversion. The size of this effect was moderated by psychopathic personality: Fearless dominance, in particular its interpersonal facet, but not self-centered impulsivity, attenuated the effect of incidental fear cues on loss aversion, consistent with reduced fear reactivity. Together, these results highlight the sensitivity of loss aversion to the affective context. PMID- 26595437 TI - The word disgust may refer to more than one emotion. AB - Contrary to a common presupposition, the word disgust may refer to more than one emotion. From an array of 3 facial expressions (produced in our lab), participants (N = 44) in Study 1 selected the one that best matched 11 types of emotion-eliciting events: anger, sadness, and 9 types of disgust (7 types of physical disgust plus moral disgust and simply feeling ill). From an array of 4 facial expressions (two from Matsumoto & Ekman, 1988; two produced in lab), participants (N = 120) in Study 2 selected the one that best matched 14 types of disgust-eliciting events (8 physical and 6 moral). In both studies, the modal facial expression for physical disgust was the "sick face" developed by Widen, Pochedly, Pieloch, and Russell (2013), which shows someone about to vomit. The modal facial expression for the moral violations was the standard disgust face or, when available, an anger face. If facial expression is a constituent of an emotion, physical disgust and moral disgust are separate emotions. PMID- 26595438 TI - Differential effects of cognitive load on emotion: Emotion maintenance versus passive experience. AB - Two separate lines of research have examined the effects of cognitive load on emotional processing with similar tasks but seemingly contradictory results. Some research has shown that the emotions elicited by passive viewing of emotional images are reduced by subsequent cognitive load. Other research has shown that such emotions are not reduced by cognitive load if the emotions are actively maintained. The present study sought to compare and resolve these 2 lines of research. Participants either passively viewed negative emotional images or maintained the emotions elicited by the images, and after a delay rated the intensity of the emotion they were feeling. Half of trials included a math task during the delay to induce cognitive load, and the other half did not. Results showed that cognitive load reduced the intensity of negative emotions during passive-viewing of emotional images but not during emotion maintenance. The present study replicates the findings of both lines of research, and shows that the key factor is whether or not emotions are actively maintained. Also, in the context of previous emotion maintenance research, the present results support the theoretical idea of a separable emotion maintenance process. (PsycINFO Database Record PMID- 26595439 TI - I don't want to come back down: Undoing versus maintaining of reward recovery in older adolescents. AB - Adolescence is characterized by heightened and sometimes impairing reward sensitivity, yet less is known about how adolescents recover from highly arousing positive states. This is particularly important given high onset rates of psychopathology associated with reward sensitivity during late adolescence and early adulthood. The current study thus utilized a novel reward sensitivity task in order to examine potential ways in which older adolescent females (ages 18-21; N = 83) might recover from high arousal positive reward sensitive states. Participants underwent a fixed incentive reward sensitivity task and subsequently watched a neutral, sad, or a low approach-motivated positive emotional film clip during which subjective and physiological recovery was assessed. Results indicated that the positive and negative film conditions were associated with maintained physiological arousal while the neutral condition facilitated faster physiological recovery from the reward sensitivity task. It is interesting to note that individual differences in self-reported positive emotion during the reward task were associated with faster recovery in the neutral condition. Findings suggest elicited emotion (regardless of valence) may serve to maintain reward sensitivity whereas self-reported positive emotional experience may be a key ingredient facilitating physiological recovery or undoing. Understanding the nuances of reward recovery provides a critical step in understanding the etiology and persistence of reward dysregulation more generally. PMID- 26595441 TI - Mean-Field Approximation to the Hydrophobic Hydration in the Liquid-Vapor Interface of Water. AB - A mean-field approximation to the solvation of nonpolar solutes in the liquid vapor interface of aqueous solutions is proposed. It is first remarked with a numerical illustration that the solvation of a methane-like solute in bulk liquid water is accurately described by the mean-field theory of liquids, the main idea of which is that the probability (Pcav) of finding a cavity in the solvent that can accommodate the solute molecule and the attractive interaction energy (uatt) that the solute would feel if it is inserted in such a cavity are both functions of the solvent density alone. It is then assumed that the basic idea is still valid in the liquid-vapor interface, but Pcav and uatt are separately functions of different coarse-grained local densities, not functions of a common local density. Validity of the assumptions is confirmed for the solvation of the methane-like particle in the interface of model water at temperatures between 253 and 613 K. With the mean-field approximation extended to the inhomogeneous system the local solubility profiles across the interface at various temperatures are calculated from Pcav and uatt obtained at a single temperature. The predicted profiles are in excellent agreement with those obtained by the direct calculation of the excess chemical potential over an interfacial region where the solvent local density varies most rapidly. PMID- 26595440 TI - Ready-to-Eat Cereal Consumption with Total and Cause-Specific Mortality: Prospective Analysis of 367,442 Individuals. AB - BACKGROUND: Intakes of ready-to-eat cereal (RTEC) have been inversely associated with risk factors of chronic diseases such as cardiovascular disease (CVD), type 2 diabetes, and certain cancers; however, their relations with total and cause specific mortality remain unclear. OBJECTIVE: To prospectively assess the associations of RTEC intakes with all causes and disease-specific mortality risk. DESIGN: The study included 367,442 participants from the prospective National Institutes of Health (NIH)-AARP Diet and Health Study. Intakes of RTEC were assessed at baseline. RESULTS: Over an average of 14 years of follow-up, 46,067 deaths were documented. Consumption of RTEC was significantly associated with reduced risk of mortality from all-cause mortality and death from CVD, diabetes, all cancer, and digestive cancer (all p for trend < 0.05). In multivariate models, compared to nonconsumers of RTEC, those in the highest intake of RTEC had a 15% lower risk of all-cause mortality and 10%-30% lower risk of disease specific mortality. Within RTEC consumers, total fiber intakes were associated with reduced risk of mortality from all-cause mortality and deaths from CVD, all cancer, digestive cancer, and respiratory disease (all p for trend < 0.005). CONCLUSIONS: Consumption of RTEC was associated with reduced risk of all-cause mortality and mortality from specific diseases such as CVD, diabetes, and cancer. This association may be mediated via greater fiber intake. PMID- 26595443 TI - Do Patient Demographics and Patient-Reported Outcomes Predict 12-Month Loss to Follow-Up After Spine Surgery? AB - STUDY DESIGN: Analysis of patients in a prospective registry. OBJECTIVE: To determine the association between patient demographics, outcomes, and loss to follow-up 12 months after spine surgery. SUMMARY OF BACKGROUND DATA: Obtaining outcomes 12 months after spine surgery remains a challenge. Loss to follow-up is believed to introduce biases and portend poor outcomes. Associations between follow-up, patient demographics, and outcomes in the degenerative spine population have not been studied. METHODS: Patients undergoing surgery for degenerative spine disease at a single institution over a 2-year period were enrolled in a prospective registry. Patient demographics, comorbidities, treatment variables, readmissions/reoperations, and all 90-day surgical morbidity were collected. Patient-reported outcomes were recorded at baseline, 3-months, and 12-months after surgery. Multivariate logistic regression analysis was done to identify predictors of loss to follow-up. RESULTS: A total of 1484 patients with baseline and 3-month outcomes were included. Two hundred thirty-three (15.7%) patients were lost to follow-up at 12 months. There was no difference in the baseline demographics (Sex: P = 0.46) and comorbidities (American Society of Anesthesiologists Grade: P = 0.06) of patients who had follow-up at 12-months versus those who did not, except age and employment status. Patients lost to follow-up at 12 months were younger (51.0 vs. 57.1 years; P < 0.001) and a higher proportion were employed preoperatively (45.9% vs. 41.7%, P = 0.24). Preoperative pain, disability, and quality of life was similar between the two groups (P > 0.05). There was no difference in 90-day morbidity (17.2% vs. 16.2%; P = 0.70) and 3-month pain, disability, quality of life, and patient satisfaction (85.0% vs. 88.3%; P = 0.63) (P > 0.05). In multivariate model, only younger age (P < 0.001) was an independent predictor of loss to follow-up at 12 months. CONCLUSION: In our prospective spine registry the 12-month loss to follow-up rate is approximately 15%. The only independent predictor of loss to follow-up is younger age and preoperative employment. LEVEL OF EVIDENCE: 3. PMID- 26595444 TI - Linking Surface Urban Heat Islands with Groundwater Temperatures. AB - Urban temperatures are typically, but not necessarily, elevated compared to their rural surroundings. This phenomenon of urban heat islands (UHI) exists both above and below the ground. These zones are coupled through conductive heat transport. However, the precise process is not sufficiently understood. Using satellite derived land surface temperature and interpolated groundwater temperature measurements, we compare the spatial properties of both kinds of heat islands in four German cities and find correlations of up to 80%. The best correlation is found in older, mature cities such as Cologne and Berlin. However, in 95% of the analyzed areas, groundwater temperatures are higher than land surface temperatures due to additional subsurface heat sources such as buildings and their basements. Local groundwater hot spots under city centers and under industrial areas are not revealed by satellite-derived land surface temperatures. Hence, we propose an estimation method that relates groundwater temperatures to mean annual land-surface temperatures, building density, and elevated basement temperatures. Using this method, we are able to accurately estimate regional groundwater temperatures with a mean absolute error of 0.9 K. PMID- 26595445 TI - The development of brain network architecture. AB - Brain connectivity shows protracted development throughout childhood and adolescence, and, as such, the topology of brain networks changes during this period. The complexity of these changes with development is reflected by regional differences in maturation. This study explored age-related changes in network topology and regional developmental patterns during childhood and adolescence. We acquired two sets of Diffusion Weighted Imaging-scans and anatomical T1-weighted scans. The first dataset included 85 typically developing individuals (53 males; 32 females), aged between 7 and 23 years and was acquired on a Philips Achieva 1.5 Tesla scanner. A second dataset (N = 38) was acquired on a different (but identical) 1.5 T scanner and was used for independent replication of our results. We reconstructed whole brain networks using tractography. We operationalized fiber tract development as changes in mean diffusivity and radial diffusivity with age. Most fibers showed maturational changes in mean and radial diffusivity values throughout childhood and adolescence, likely reflecting increasing white matter integrity. The largest age-related changes were observed in association fibers within and between the frontal and parietal lobes. Furthermore, there was a simultaneous age-related decrease in average path length (P < 0.0001), increase in node strength (P < 0.0001) as well as network clustering (P = 0.001), which may reflect fine-tuning of topological organization. These results suggest a sequential maturational model where connections between unimodal regions strengthen in childhood, followed by connections from these unimodal regions to association regions, while adolescence is characterized by the strengthening of connections between association regions within the frontal and parietal cortex. Hum Brain Mapp 37:717-729, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26595446 TI - Five-year recurrence rate of lentigo maligna after treatment with imiquimod. AB - BACKGROUND: The current recommended treatment for lentigo maligna (LM) is surgical resection, which can cause significant scarring. The reported recurrence rate after Mohs micrographic surgery is 0-6.25%. There is little published data on long-term outcome after imiquimod therapy. Several reports record progression to LM melanoma during treatment. Clinical assessment of clearance is difficult. Histological confirmation is preferred but risks sampling error and missing areas of invasion. Confocal microscopy can be used to assess entire lesions. OBJECTIVES: To assess the 5-year recurrence rate of LM after imiquimod treatment. METHODS: Forty patients with LM were treated with imiquimod between 2002 and 2007. Their previous treatments included cryotherapy, incomplete surgical excision and radiotherapy. All applied imiquimod three times per week for 6 weeks; 25 (62.5%) experienced inflammation. The other 15 (37.5%) then applied imiquimod five times per week for a further 4 weeks; all experienced inflammation. All patients were subsequently examined and biopsied. Clinical clearance did not always correlate with histological clearance. Eleven patients (27.5%) had residual LM on histology and underwent surgical excision. At the time of this study, three patients had died (deaths were unrelated to LM). Eighteen of the 27 patients (66.7%) who were clear on biopsy after imiquimod attended for the study and were assessed using confocal microscopy (Vivascope 1500 and 3000). RESULTS: The recurrence rate of LM in patients who were clear on histology after imiquimod treatment who attended for this follow-up study was 0% (n = 18). CONCLUSIONS: Imiquimod is an effective long-term treatment for LM. Its use avoids potentially disfiguring surgical resection. PMID- 26595447 TI - A novel method for identifying settings for well-motivated ecologic studies of cancer. AB - A low within-country variability and a large between-country variability in cancer incidence may indicate that ecologic factors are involved in the etiology of the disease. The aim of this study is to explore the within- and between country variability of cancer incidence to motivate high-quality ecologic studies. We extracted age-standardized incidence rate estimates (world standard population) from 135 regions for the ten most frequent invasive cancers in Europe for non-Hispanic white populations from Cancer Incidence in Five Continents, Volume X. We fitted weighted multilevel Poisson regression models with random country effects for each cancer and sex. We estimated intraclass correlation coefficients (ICCs) and 95% confidence intervals (95% CIs). A high ICC indicates a low within- and a high between-country variability of rates. The two cancer sites with the highest ICC among men were prostate cancer (0.96, 95% CI: 0.92 0.99) and skin melanoma (0.78, 0.64-0.93). Among women, high ICCs were observed for lung cancer (0.84, 0.73-0.95) and breast cancer (0.80, 0.69-0.91). The two most prominent sex differences for ICC occurred for cancers of the head and neck (men: 0.70, 0.55-0.85, women: 0.19, 0.08-0.30) and breast cancer (men: 0.04, 0.01 0.07, women: 0.80, 0.69-0.91). ICCs were relatively low for pancreatic cancer (men: 0.23, 0.10-0.35; women: 0.13, 0.04-0.21) and leukemia (men: 0.12, 0.04 0.21; women: 0.08, 0.02-0.14). For cancers with high ICC for which systematic factors of the health care system, screening and diagnostic activities are not plausible explanations for between-country variations in incidence, cross-country sex-specific ecologic studies may be especially promising. PMID- 26595449 TI - Evaluating Hepatitis B Virus Reactivation During Solid Tumor Chemotherapy: Evidence to Guide Pretreatment Hepatitis B Screening and Prophylaxis. PMID- 26595448 TI - Quantitative H2S-mediated protein sulfhydration reveals metabolic reprogramming during the integrated stress response. AB - The sulfhydration of cysteine residues in proteins is an important mechanism involved in diverse biological processes. We have developed a proteomics approach to quantitatively profile the changes of sulfhydrated cysteines in biological systems. Bioinformatics analysis revealed that sulfhydrated cysteines are part of a wide range of biological functions. In pancreatic beta cells exposed to endoplasmic reticulum (ER) stress, elevated H2S promotes the sulfhydration of enzymes in energy metabolism and stimulates glycolytic flux. We propose that transcriptional and translational reprogramming by the integrated stress response (ISR) in pancreatic beta cells is coupled to metabolic alternations triggered by sulfhydration of key enzymes in intermediary metabolism. PMID- 26595450 TI - Four-Week Direct-Acting Antiviral Regimens in Noncirrhotic Patients With Hepatitis C Virus Genotype 1 Infection: An Open-Label, Nonrandomized Trial. AB - BACKGROUND: Treatment of chronic hepatitis C virus (HCV) infection with direct acting antivirals (DAAs) for 6 weeks achieves sustained virologic response (SVR) rates of 95% in some patients. If effective, shorter therapeutic courses could improve adherence and treatment costs. OBJECTIVE: To determine factors predictive of SVR to 4 weeks of DAA treatment in patients with stage F0 to F2 liver fibrosis. DESIGN: Open-label, nonrandomized, phase 2a trial. (Clinical Trials.gov: NCT01805882). SETTING: Single-center. PATIENTS: 50 treatment-naive and predominantly African American patients with HCV genotype 1 infection and early-stage liver fibrosis were sequentially enrolled into 2 treatment groups. INTERVENTION: 25 participants received a 3-drug regimen consisting of ledipasvir and sofosbuvir plus GS-9451 for 4 weeks, and 25 received a 4-drug regimen consisting of ledipasvir, sofosbuvir, GS-9451, and GS-9669 for 4 weeks. MEASUREMENTS: The primary efficacy end point was SVR12 (HCV RNA level below the lower limit of quantification at posttreatment week 12). RESULTS: Forty percent (10 of 25) (95% CI, 21% to 61%) of patients in the 3-drug group and 20% (5 of 25) (CI, 7% to 41%) of those in the 4-drug group achieved SVR12. Exploratory analysis suggested that lower baseline HCV viral load, younger age, and HCV genotype 1b were associated with SVR12. Ten patients had baseline HCV variants conferring greater than 20-fold resistance in vitro to at least 1 study DAA; all had viral relapse. Forty-eight percent (12 of 25) of patients receiving the 3-drug regimen and 72% (18 of 25) of those receiving the 4-drug regimen had adverse events, most of which were mild. One participant was lost to follow-up. LIMITATION: Nonrandomized study design and small sample of patients with early-stage fibrosis. CONCLUSION: Combination DAA therapy with 3 or 4 drugs for 4 weeks was well-tolerated but resulted in limited cure rates. PRIMARY FUNDING SOURCE: National Institute of Allergy and Infectious Diseases, National Cancer Institute, and Clinical Center Intramural Program; supported in part by a cooperative research and development agreement between the National Institutes of Health and Gilead Sciences. PMID- 26595451 TI - The LPV Motif Is Essential for the Efficient Export of Secretory DMP1 From the Endoplasmic Reticulum. AB - Dentin matrix protein 1 (DMP1) is found abundantly in the extracellular matrices of bone and dentin. Secretory DMP1 begins with a tripeptide of leucine-proline valine (LPV) after the endoplasmic reticulum (ER)-entry signal peptide is cleaved. The goal of this study was to determine the role of the LPV motif in the secretion of DMP1. A series of DNA constructs was generated to express various forms of DMP1 with or without the LPV motif. These constructs were transfected into a preosteoblast cell line, the MC3T3-E1 cells, and the subcellular localization and secretion of various forms of DMP1 were examined by immunofluorescent staining and Western-blotting analyses. Immunofluorescent staining showed that the LPV-containing DMP1 variants were primarily localized in the Golgi complex, whereas the LPV-lacking DMP1 variants were found abundantly within the ER. Western-blotting analyses demonstrated that the LPV-containing DMP1 variants were rapidly secreted from the transfected cells, as they did not accumulate within the cells, and the amounts increased in the conditioned media over time. In contrast, the LPV-lacking DMP1 variants were predominantly retained within the cells, and only small amounts were secreted out of the cells over time. These results suggest that the LPV motif is essential for the efficient export of secretory DMP1 from the ER to the Golgi complex. PMID- 26595452 TI - In reference to "National cohort study of opioid analgesic dose and risk of future hospitalization". PMID- 26595453 TI - Changes in Discharge Location and Readmission Rates Under Medicare Bundled Payment. PMID- 26595454 TI - Aggravation of airway inflammation and hyper-responsiveness following nasal challenge with Dermatophagoides pteronyssinus in perennial allergic rhinitis without symptoms of asthma. AB - BACKGROUND: House dust mites are the most prevalent allergen causing sensitizations in patients with rhinitis and asthma in China. We aimed to investigate the changes in both upper and lower airway inflammation and responsiveness following Dermatophagoides pteronyssinus (Der-p) nasal provocation test (NPT) in rhinitis patients. METHODS: Study subjects included 15 nonasthmatic Der-p-sensitized rhinitis (AR) patients with airway hyper-responsiveness (AHR) (AR+AHR+), 15 AR patients without AHR (AR+AHR-), 15 healthy controls (HCs) with Der-p sensitization (HC+DP+), and 15 HC without Der-p sensitization (HC+DP-). All subjects underwent Der-p NPT. Visual analogue scale (VAS) scores of nasal symptoms, nasal lavage and nasal airway resistance (NAR) measurement, sputum induction, and forced expiratory volume in 1 second (FEV1 ) were performed. Airway responsiveness to histamine bronchoprovocation (PD20 -FEV1 ) and exhaled nitric oxide (FeNO) was determined. RESULTS: NAR increased significantly in all subjects with the greatest effect seen in AR+AHR+ individuals. VAS increased in all subjects at 30 min and returned to baseline at 6 h, with significantly higher levels in AR+AHR+ and AR+AHR- subjects (P < 0.05). Eosinophils in nasal lavage fluid and sputum increased significantly after NPT in AR+AHR+ and AR+AHR- subjects (P < 0.001). FEV1 % and PD20 -FEV1 decreased and FeNO increased significantly after NPT only in AR+AHR+ subjects (P < 0.05). Nasal lavage eosinophil count was positively correlated with sputum eosinophil count and the level of FeNO and negatively correlated with FEV1 and PD20 . CONCLUSIONS: House dust mite nasal provocation test induces and aggravates both upper and lower airway inflammation and hyper-responsiveness in patients with persistent allergic rhinitis without asthmatic symptoms. PMID- 26595455 TI - Whither Risk Assessment: New Challenges and Opportunities a Third of a Century After the Red Book. AB - Six multi-decade-long members of SRA reflect on the 1983 Red Book in order to examine the evolving relationship between risk assessment and risk management; the diffusion of risk assessment practice to risk areas such as homeland security and transportation; the quality of chemical risk databases; challenges from other groups to elements at the core of risk assessment practice; and our collective efforts to communicate risk assessment to a diverse set of critical groups that do not understand risk, risk assessment, or many other risk-related issues. The authors reflect on the 10 recommendations in the Red Book and present several pressing challenges for risk assessment practitioners. PMID- 26595456 TI - Explaining public satisfaction with health-care systems: findings from a nationwide survey in China. AB - OBJECTIVE: To identify factors associated with health-care system satisfaction in China. CONTEXT: Recent research suggests that socio-demographic characteristics, self-reported health, income and insurance, ideological beliefs, health-care utilization, media use and perceptions of services may affect health-care system satisfaction, but the relative importance of these factors is poorly understood. New data from China offer the opportunity to test theories about the sources of health-care system satisfaction. DESIGN: Stratified nationwide survey sample analysed using multilevel logistic regression. SETTING AND PARTICIPANTS: 3680 Chinese adults residing in family dwellings between 1 November 2012 and 17 January 2013. MAIN OUTCOME MEASURE: Satisfaction with the way the health-care system in China is run. RESULTS: We find only weak associations between satisfaction and socio-demographic characteristics, self-reported health and income. We do, however, find that satisfaction is strongly associated with having insurance and belief in personal responsibility for meeting health-care costs. We also find it is negatively associated with utilization, social media use, perceptions of access as unequal and perceptions of service providers as unethical. CONCLUSIONS: To improve satisfaction, Chinese policymakers - and their counterparts in countries with similar health-care system characteristics - should improve insurance coverage and the quality of health services, and tackle unethical medical practices. PMID- 26595457 TI - High resolution absolute absorption cross sections of the B (1)A'-X (1)A' transition of the CH2OO biradical. AB - Carbonyl oxides, or Criegee intermediates, are formed from the gas phase ozonolysis of alkenes and play a pivotal role in night-time and urban area atmospheric chemistry. Significant discrepancies exist among measurements of the strong B (1)A'-X (1)A' electronic transition of the simplest Criegee intermediate, CH2OO in the visible/near-UV. We report room temperature spectra of the B (1)A'-X (1)A' electronic absorption band of CH2OO acquired at higher resolution using both single-pass broadband absorption and cavity ring-down spectroscopy. The new absorption spectra confirm the vibrational structure on the red edge of the band that is absent from ionization depletion measurements. The absolute absorption cross sections over the 362-470 nm range are in good agreement with those reported by Ting et al. Broadband absorption spectra recorded over the temperature range of 276-357 K were identical within their mutual uncertainties, confirming that the vibrational structure is not due to hot bands. PMID- 26595458 TI - Asymmetric Superhydrophobic/Superhydrophilic Cotton Fabrics Designed by Spraying Polymer and Nanoparticles. AB - Inspired by the special wettability of certain natural life forms, such as the high water repellency of lotus leaves, many researchers have attempted to impart superhydrophobic properties to fabrics in academic and industrial contexts. Recently, a new switching system of wettability has inspired a strong demand for advanced coatings, even though their fabrication remains complex and costly. Here, cotton fabrics with asymmetric wettability (one face with natural superhydrophilicity and one face with superhydrophobicity) were fabricated by one step spraying of a mixture of biocompatible commercial materials, hydrophobic SiO2 nanoparticles and ethyl-alpha-cyanoacrylate superglue. Our approach involves controlling the permeation of the fabric coatings by changing the distance between the fabric and the sprayer, to make one side superhydrophobic and the other side naturally superhydrophilic. As a result, the superhydrophobic side, with its high mechanical durability, exhibited a water contact angle of 154 degrees and sliding angle of 16 degrees , which meets the requirement for self cleaning ability of surfaces. The opposite side exhibited high water absorption ability owing to the natural superhydrophilic property of the fabric. In addition, the designed cotton fabrics had blood absorption and clotting abilities on the superhydrophilic side, while the superhydrophobic side prevented water and blood permeation without losing the natural breathability of the cotton. These functions may be useful in the design of multifunctional fabrics for medical applications. PMID- 26595459 TI - Huntingtin-Interacting Protein-1 Is an Early-Stage Prognostic Biomarker of Lung Adenocarcinoma and Suppresses Metastasis via Akt-mediated Epithelial-Mesenchymal Transition. AB - RATIONALE: Non-small cell lung cancer (NSCLC) carries a poor survival rate mainly because of metastasis. However, the molecular mechanisms that govern NSCLC metastasis have not been described. Because huntingtin-interacting protein-1 (HIP1) is known to play a role in tumorigenesis, we tested the involvement of HIP1 in NSCLC progression and metastasis. OBJECTIVES: HIP1 expression was measured in human NSCLC tumors, and correlation with survival outcome was evaluated. Furthermore, we investigated the ability of HIP1 to suppress metastasis. The molecular mechanism by which HIP1 contributes to suppress metastasis was investigated. METHODS: We used tissue arrays containing samples from 121 patients with NSCLC to analyze HIP1 expression by immunohistochemistry. To investigate the role of HIP1 expression on metastasis, we evaluated cellular mobility, migration, and invasion using lung adenocarcinoma (AdCA) cells with modified HIP1 expression levels. The human disease mouse models with the same cells were applied to evaluate the HIP1 suppressing metastasis and its mechanism in vivo. MEASUREMENTS AND MAIN RESULTS: HIP1 expression in AdCA progression was found to be an early-stage prognostic biomarker, with low expression correlated to poor prognosis. We also found HIP1 to be a metastatic suppressor in AdCA. HIP1 significantly repressed the mobility of lung cancer cells in vitro and in vivo and regulated the epithelial-mesenchymal transition by repressing AKT/glycogen synthase kinase-3beta/beta-catenin signaling. CONCLUSIONS: HIP1 serves as an early-stage prognostic biomarker and a metastatic suppressor. Reduced expression during AdCA progression can relieve HIP1 suppression of Akt-mediated epithelial mesenchymal transition and thereby lead to development of late metastases and poor prognosis. PMID- 26595460 TI - Operational Stress and Correlates of Mental Health Among Joint Task Force Guantanamo Bay Military Personnel. AB - Military personnel deployed to Joint Task Force Guantanamo Bay (JTF-GTMO) faced numerous occupational stressors. As part of a program evaluation, personnel working at JTF-GTMO completed several validated self-report measures. Personnel were at the beginning, middle, or end of their deployment phase. This study presents data regarding symptoms of posttraumatic stress disorder, alcohol abuse, depression, and resilience among 498 U.S. military personnel deployed to JTF-GTMO in 2009. We also investigated individual and organizational correlates of mental health among these personnel. Findings indicated that tenure at JTF-GTMO was positively related to adverse mental health outcomes. Regression models including these variables had R2 values ranging from .02 to .11. Occupation at JTF-GTMO also related to mental health such that guards reported poorer mental health than medical staff. Reluctance to seek out mental health care was also related to mental health outcomes. Those who reported being most reluctant to seek out care tended to report poorer mental health than those who were more willing to seek out care. Results suggested that the JTF-GTMO deployment was associated with significant psychological stress, and that both job-related and attitude-related variables were important to understanding mental health symptoms in this sample. PMID- 26595461 TI - CRISPR-Cas9-based target validation for p53-reactivating model compounds. AB - Inactivation of the p53 tumor suppressor by Mdm2 is one of the most frequent events in cancer, so compounds targeting the p53-Mdm2 interaction are promising for cancer therapy. Mechanisms conferring resistance to p53-reactivating compounds are largely unknown. Here we show using CRISPR-Cas9-based target validation in lung and colorectal cancer that the activity of nutlin, which blocks the p53-binding pocket of Mdm2, strictly depends on functional p53. In contrast, sensitivity to the drug RITA, which binds the Mdm2-interacting N terminus of p53, correlates with induction of DNA damage. Cells with primary or acquired RITA resistance display cross-resistance to DNA crosslinking compounds such as cisplatin and show increased DNA cross-link repair. Inhibition of FancD2 by RNA interference or pharmacological mTOR inhibitors restores RITA sensitivity. The therapeutic response to p53-reactivating compounds is therefore limited by compound-specific resistance mechanisms that can be resolved by CRISPR-Cas9-based target validation and should be considered when allocating patients to p53 reactivating treatments. PMID- 26595462 TI - De novo design of a four-fold symmetric TIM-barrel protein with atomic-level accuracy. AB - Despite efforts for over 25 years, de novo protein design has not succeeded in achieving the TIM-barrel fold. Here we describe the computational design of four fold symmetrical (beta/alpha)8 barrels guided by geometrical and chemical principles. Experimental characterization of 33 designs revealed the importance of side chain-backbone hydrogen bonds for defining the strand register between repeat units. The X-ray crystal structure of a designed thermostable 184-residue protein is nearly identical to that of the designed TIM-barrel model. PSI-BLAST searches do not identify sequence similarities to known TIM-barrel proteins, and sensitive profile-profile searches indicate that the design sequence is distant from other naturally occurring TIM-barrel superfamilies, suggesting that Nature has sampled only a subset of the sequence space available to the TIM-barrel fold. The ability to design TIM barrels de novo opens new possibilities for custom-made enzymes. PMID- 26595463 TI - From anxious youth to depressed adolescents: Prospective prediction of 2-year depression symptoms via attentional bias measures. AB - Anxious youth are at heightened risk for subsequent development of depression; however, little is known regarding which anxious youth are at the highest prospective risk. Biased attentional patterns (e.g., vigilance and avoidance of negative cues) are implicated as key mechanisms in both anxiety and depression. Aberrant attentional patterns may disrupt opportunities to effectively engage with, and learn from, threatening aspects of the environment during development and/or treatment, compounding risk over time. Sixty-seven anxious youth (ages 9 14; 36 female) completed a dot-probe task to assess baseline attentional patterns provoked by fearful-neutral face pairs. The time course of attentional patterns both during and after threat was assessed via eye-tracking and pupilometry. Self reported depressive and anxiety symptoms were assessed 2 years after the conclusion of a larger psychotherapy treatment trial. Eye-tracking patterns indicating threat avoidance predicted greater 2-year depression scores, over and above baseline and posttreatment symptoms. Sustained, postthreat pupillary avoidance (reflecting preferential neural engagement with the neutral relative to the previously threatening location) predicted additional variance in depression scores, suggesting sustained avoidance in the wake of threat further exacerbated risk. Identical eye-tracking and pupil indices were not predictive of anxiety at 2 years. These biobehavioral markers imply that avoidant attentional processing in the context of anxiety may be a gateway to depression across a key maturational window. Excessive avoidance of threat could interfere with acquisition of adaptive emotion regulation skills during development, culminating in the broad behavioral deactivation that typifies depression. Prevention efforts explicitly targeting avoidant attentional patterns may be warranted. PMID- 26595465 TI - Chronic environmental stress and the temporal course of depression and panic disorder: A trait-state-occasion modeling approach. AB - Both acute stressful life events and ongoing strains are thought to confer vulnerability to emotional disorders. Unremitting stressful conditions may be particularly pathogenic, but prior research has struggled to delimit chronic versus transient stressful experiences. We aimed to isolate stable stressors theorized to be indicators of a latent stress proneness trait-and to examine their effects on the temporal course of depression and panic disorder. We recruited 677 patients diagnosed with an emotional disorder and administered interviews for psychopathology and life stress 3 times over 12-month intervals. Trait-state-occasion modeling revealed that 74% of the variance in life stress was stable over the follow-up period. These stable stressors were associated with a more refractory course of depression and, to a smaller degree, panic disorder over time. In addition, neither gender nor participation in cognitive-behavioral therapy affected the persistence of environmental stress over the study time frame. We discuss implications of these findings for explaining depression recurrence, improving psychological interventions for emotional disorders, and the measurement and evaluation of stress proneness. PMID- 26595464 TI - Altered subjective reward valuation among drug-deprived heavy marijuana users: Aversion to uncertainty. AB - Marijuana is the most commonly used illicit drug in the United States and its use is rising. Nonetheless, scientific efforts to clarify the risk for addiction and other harm associated with marijuana use have been lacking. Maladaptive decision making is a cardinal feature of addiction that is likely to emerge in heavy users. In particular, distorted subjective reward valuation related to homeostatic or allostatic processes has been implicated for many drugs of abuse. Selective changes in responses to uncertainty have been observed in response to intoxication and deprivation from various drugs of abuse. To assess for these potential neuroadaptive changes in reward valuation associated with marijuana deprivation, we examined the subjective value of uncertain and certain rewards among deprived and nondeprived heavy marijuana users in a behavioral economics decision-making task. Deprived users displayed reduced valuation of uncertain rewards, particularly when these rewards were more objectively valuable. This uncertainty aversion increased with increasing quantity of marijuana use. These results suggest comparable decision-making vulnerability from marijuana use as other drugs of abuse, and highlights targets for intervention. PMID- 26595466 TI - Developmental psychopathology, ontogenic process models, gene-environment interplay, and brain development: An emerging synthesis. AB - This article introduces the special section of the Journal of Abnormal Psychology. This Special Section exemplifies what are arguably the most current iterations of developmental psychopathology, which involve an intensive focus on both molecular genetics and brain architecture-and their interactions with crucial environmental features and forces-for elucidating processes of individual development, or ontogenesis, toward psychopathology. PMID- 26595468 TI - DRD4 and DRD2 genes, parenting, and adolescent delinquency: Longitudinal evidence for a gene by environment interaction. AB - Gene by environment (G * E) research has been increasingly appreciated as it relates to the development of psychopathology. In particular, interactions between dopaminergic genotypes and maladaptive parenting have been prominently in the spotlight. In this study, we investigated whether high parental psychological control and low support would be differentially related to the development of delinquency in adolescents based on their genetic background (i.e., DRD4 and DRD2 genotypes). Data were derived from a 5-wave longitudinal survey among adolescents (N = 308; Mage = 13.4 at Time 1). After accounting for possible passive genetic effects (i.e., parents' genotype, Parents' Genotype * Adolescents' Genotype, and Parents' Genotype * Parenting, cf. Keller, 2014), latent growth modeling revealed a significant interaction of DRD2 * Parental Support, indicating that adolescents with the DRD2 A2A2 genotype were more vulnerable for low parental support, developing more delinquent behavior as a consequence. No significant interactions emerged for DRD4 with parental support and psychological control, nor for DRD2 with parental psychological control. The observed effect size of the identified DRD2 * parental support interaction was modest, emphasizing that replication is essential to confirm the present evidence. PMID- 26595467 TI - Additive genetic risk from five serotonin system polymorphisms interacts with interpersonal stress to predict depression. AB - Behavioral genetic research supports polygenic models of depression in which many genetic variations each contribute a small amount of risk, and prevailing diathesis-stress models suggest gene-environment interactions (G*E). Multilocus profile scores of additive risk offer an approach that is consistent with polygenic models of depression risk. In a first demonstration of this approach in a G*E predicting depression, we created an additive multilocus profile score from 5 serotonin system polymorphisms (1 each in the genes HTR1A, HTR2A, HTR2C, and 2 in TPH2). Analyses focused on 2 forms of interpersonal stress as environmental risk factors. Using 5 years of longitudinal diagnostic and life stress interviews from 387 emerging young adults in the Youth Emotion Project, survival analyses show that this multilocus profile score interacts with major interpersonal stressful life events to predict major depressive episode onsets (hazard ratio [HR] = 1.815, p = .007). Simultaneously, there was a significant protective effect of the profile score without a recent event (HR = 0.83, p = .030). The G*E effect with interpersonal chronic stress was not significant (HR = 1.15, p = .165). Finally, effect sizes for genetic factors examined ignoring stress suggested such an approach could lead to overlooking or misinterpreting genetic effects. Both the G*E effect and the protective simple main effect were replicated in a sample of early adolescent girls (N = 105). We discuss potential benefits of the multilocus genetic profile score approach and caveats for future research. PMID- 26595469 TI - Depression from childhood into late adolescence: Influence of gender, development, genetic susceptibility, and peer stress. AB - Depression is a debilitating mental illness with clear developmental patterns from childhood through late adolescence. Here, we present data from the Gene Environment Mood (GEM) study, which used an accelerated longitudinal cohort design with youth (N = 665) starting in 3rd, 6th, and 9th grades, and a caretaker, who were recruited from the general community, and were then assessed repeatedly through semistructured diagnostic interviews every 6 months over 3 years (7 waves of data) to establish and then predict trajectories of depression from age 8 to 18. First, we demonstrated that overall prevalence rates of depression over time, by age, gender, and pubertal status, in the GEM study closely match those trajectories previously obtained in past developmental epidemiological research. Second, we tested whether a genetic vulnerability stress model involving 5-HTTLPR and chronic peer stress was moderated by developmental factors. Results showed that older aged adolescents with SS/SL genotype, who experienced higher peer chronic stress over 3 years, were the most likely to be diagnosed with a depressive episode over time. Girls experiencing greater peer chronic stress were the most likely to develop depression. This study used repeated assessments of diagnostic interviewing in a moderately large sample of youth over 3 years to show that depression rates increase in middle to late adolescence, or postpubertally, and that the gender difference in depression emerges earlier in adolescence (age 12.5), or postpubertally. Additionally, genetically susceptible older adolescents who experience chronic peer stress were the most likely to become depressed over time. PMID- 26595471 TI - Linking the serotonin transporter gene, family environments, hippocampal volume and depression onset: A prospective imaging gene * environment analysis. AB - A single imaging gene-environment (IGxE) framework that is able to simultaneously model genetic, neurobiological, and environmental influences on psychopathology outcomes is needed to improve understanding of how complex interrelationships between allelic variation, differences in neuroanatomy or neuroactivity, and environmental experience affect risk for psychiatric disorder. In a longitudinal study of adolescent development we demonstrate the utility of such an IGxE framework by testing whether variation in parental behavior at age 12 altered the strength of an imaging genetics pathway, involving an indirect association between allelic variation in the serotonin transporter gene to variation in hippocampal volume and consequent onset of major depressive disorder by age 18. Results were consistent with the presence of an indirect effect of the serotonin transporter S-allele on depression onset via smaller left and right hippocampal volumes that was significant only in family environments involving either higher levels of parental aggression or lower levels of positive parenting. The previously reported finding of S-allele carriers' increased risk of depression in adverse environments may, therefore, be partly because of the effects of these environments on a neurobiological pathway from the serotonin transporter gene to depression onset that proceeds through variation in hippocampal volume. PMID- 26595472 TI - Predicting first onset of depression in young girls: Interaction of diurnal cortisol and negative life events. AB - Interactions between biological vulnerability and environmental adversity are central to the pathophysiology of depression. Given evidence that the hypothalamic-pituitary-adrenal (HPA) axis influences biological responses to environmental events, in the current longitudinal study the authors examined HPA axis functioning, negative life events, and their interaction as predictors of the first onset of depression. At baseline, girls ages 9 to 14 years provided saliva samples to assess levels of diurnal cortisol production, quantified by total cortisol production (area under the curve with respect to ground; AUCg) and the cortisol awakening response (CAR). The authors then followed these participants until they reached age 18 in order to assess their subsequent experience of negative life events and the onset of a depressive episode. They found that the influence of negative life events on the subsequent onset of depression depended on HPA-axis functioning at baseline. Specifically, negative life events predicted the onset of depression in girls with higher levels of AUCg, but not in girls with lower levels of AUCg. In contrast, CAR did not predict the onset of depression either alone or in interaction with negative life events. These findings suggest that elevated total cortisol production in daily life potentiates susceptibility to environmental adversity and signals the need for early intervention. PMID- 26595470 TI - Amygdala functional connectivity, HPA axis genetic variation, and life stress in children and relations to anxiety and emotion regulation. AB - Internalizing pathology is related to alterations in amygdala resting state functional connectivity, potentially implicating altered emotional reactivity and/or emotion regulation in the etiological pathway. Importantly, there is accumulating evidence that stress exposure and genetic vulnerability impact amygdala structure/function and risk for internalizing pathology. The present study examined whether early life stress and genetic profile scores (10 single nucleotide polymorphisms within 4 hypothalamic-pituitary-adrenal axis genes: CRHR1, NR3C2, NR3C1, and FKBP5) predicted individual differences in amygdala functional connectivity in school-age children (9- to 14-year-olds; N = 120). Whole-brain regression analyses indicated that increasing genetic "risk" predicted alterations in amygdala connectivity to the caudate and postcentral gyrus. Experience of more stressful and traumatic life events predicted weakened amygdala-anterior cingulate cortex connectivity. Genetic "risk" and stress exposure interacted to predict weakened connectivity between the amygdala and the inferior and middle frontal gyri, caudate, and parahippocampal gyrus in those children with the greatest genetic and environmental risk load. Furthermore, amygdala connectivity longitudinally predicted anxiety symptoms and emotion regulation skills at a later follow-up. Amygdala connectivity mediated effects of life stress on anxiety and of genetic variants on emotion regulation. The current results suggest that considering the unique and interacting effects of biological vulnerability and environmental risk factors may be key to understanding the development of altered amygdala functional connectivity, a potential factor in the risk trajectory for internalizing pathology. PMID- 26595474 TI - Low social rhythm regularity predicts first onset of bipolar spectrum disorders among at-risk individuals with reward hypersensitivity. AB - The social zeitgeber model (Ehlers, Frank, & Kupfer, 1988) suggests that irregular daily schedules or social rhythms provide vulnerability to bipolar spectrum disorders. This study tested whether social rhythm regularity prospectively predicted first lifetime onset of bipolar spectrum disorders in adolescents already at risk for bipolar disorder based on exhibiting reward hypersensitivity. Adolescents (ages 14-19 years) previously screened to have high (n = 138) or moderate (n = 95) reward sensitivity, but no lifetime history of bipolar spectrum disorder, completed measures of depressive and manic symptoms, family history of bipolar disorder, and the Social Rhythm Metric. They were followed prospectively with semistructured diagnostic interviews every 6 months for an average of 31.7 (SD = 20.1) months. Hierarchical logistic regression indicated that low social rhythm regularity at baseline predicted greater likelihood of first onset of bipolar spectrum disorder over follow-up among high reward-sensitivity adolescents but not moderate-reward-sensitivity adolescents, controlling for follow-up time, gender, age, family history of bipolar disorder, and initial manic and depressive symptoms (beta = -.150, Wald = 4.365, p = .037, odds ratio = .861, 95% confidence interval [.748, .991]). Consistent with the social zeitgeber theory, low social rhythm regularity provides vulnerability to first onset of bipolar spectrum disorder among at-risk adolescents. It may be possible to identify adolescents at risk for developing a bipolar spectrum disorder based on exhibiting both reward hypersensitivity and social rhythm irregularity before onset occurs. PMID- 26595475 TI - Decision processes and the slowing of simple choices in schizophrenia. AB - Individuals diagnosed with schizophrenia have slowed response times (RT). We examined the role of decision processes in the slowing of simple choice responses. We updated Schatz's (1998) meta-analysis of deficits in speed and extend it to systematically examine the effects of schizophrenia on choice accuracy. We then report an experiment requiring decisions about motion direction, which we analyzed using an evidence accumulation model of choice, the linear ballistic accumulator (LBA; Brown & Heathcote, 2008). By simultaneously taking into account all aspects of behavior, the LBA was more sensitive to deficits than mean RT or accuracy alone. It also identified the 2 underlying causes of slowing: more cautious decisions (i.e., requiring more evidence before making a decision) and perceptual deficits. The schizophrenia group displayed strong sequential effects that were captured by the response on the previous trial affecting the relative amount of evidence required for choice in the LBA. These results illustrate that evidence accumulation models provide a sensitive tool that can be used to identify the cognitive mechanisms causing slowing in schizophrenia. PMID- 26595473 TI - Monoacylglycerol lipase (MGLL) polymorphism rs604300 interacts with childhood adversity to predict cannabis dependence symptoms and amygdala habituation: Evidence from an endocannabinoid system-level analysis. AB - Despite evidence for heritable variation in cannabis involvement and the discovery of cannabinoid receptors and their endogenous ligands, no consistent patterns have emerged from candidate endocannabinoid (eCB) genetic association studies of cannabis involvement. Given interactions between eCB and stress systems and associations between childhood stress and cannabis involvement, it may be important to consider childhood adversity in the context of eCB-related genetic variation. We employed a system-level gene-based analysis of data from the Comorbidity and Trauma Study (N = 1,558) to examine whether genetic variation in six eCB genes (anabolism: DAGLA, DAGLB, NAPEPLD; catabolism: MGLL, FAAH; binding: CNR1; SNPs N = 65) and childhood sexual abuse (CSA) predict cannabis dependence symptoms. Significant interactions with CSA emerged for MGLL at the gene level (p = .009), and for rs604300 within MGLL (DeltaR2 = .007, p < .001), the latter of which survived SNP-level Bonferroni correction and was significant in an additional sample with similar directional effects (N = 859; DeltaR2 = .005, p = .026). Furthermore, in a third sample (N = 312), there was evidence that rs604300 genotype interacts with early life adversity to predict threat related basolateral amygdala habituation, a neural phenotype linked to the eCB system and addiction (DeltaR2 = .013, p = .047). Rs604300 may be related to epigenetic modulation of MGLL expression. These results are consistent with rodent models implicating 2-arachidonoylglycerol (2-AG), an endogenous cannabinoid metabolized by the enzyme encoded by MGLL, in the etiology of stress adaptation related to cannabis dependence, but require further replication. PMID- 26595477 TI - Bulimic symptom onset in young girls: A longitudinal trajectory analysis. AB - To investigate whether there are different patterns of development for binge eating and purging behavior among preadolescent and early adolescent girls, we conducted trajectory analyses of those behaviors in 938 girls across 8 waves of data from the spring of 5th grade (the last year of elementary school) through the spring of 9th grade (the first year of high school). Analyses revealed 4 separate developmental trajectories for binge eating behavior (labeled none, increasing, decreasing, and high steady) and 3 separate developmental trajectories for purging behavior (labeled none, dabble, and increasing). Fifth grade scores on risk factors that were both transdiagnostic (negative affect and negative urgency) and eating disorder specific (expectancies for reinforcement from eating and from thinness) differentiated among the trajectory groups, in some cases before the groups differed in the target behaviors. These findings are the first, to our knowledge, to examine developmental trajectories for bulimic symptom onset in youth as young as elementary school. Clinical implications are discussed. PMID- 26595478 TI - Atypical working memory decline across the adult lifespan in autism spectrum disorder? AB - Whereas working memory (WM) performance in typical development increases across childhood and adolescence, and decreases during adulthood, WM development seems to be delayed in young individuals with autism spectrum disorder (ASD). How WM changes when individuals with ASD grow old is largely unknown. We bridge this gap with a cross-sectional study comparing age-related patterns in WM performance (n back task: 3 load levels) among a large sample of individuals with and without ASD (N = 275) over the entire adult life span (19-79 years) as well as interindividual differences therein. Results demonstrated that, despite longer RTs, adults with ASD showed similar WM performance to adults without ASD. Age related differences appeared to be different among adults with and without ASD as adults without ASD showed an age-related decline in WM performance, which was not so evident in adults with ASD. Moreover, only IQ scores reliably dissociated interindividual differences in age-gradients, but no evidence was found for a role of basic demographics, comorbidities, and executive functions. These findings provide initial insights into how ASD modulates cognitive aging, but also underline the need for further WM research into late adulthood in ASD and for analyzing individual change trajectories in longitudinal studies. PMID- 26595476 TI - A behavioral genetic analysis of callous-unemotional traits and Big Five personality in adolescence. AB - Callous-unemotional (CU) traits, such as lacking empathy and emotional insensitivity, predict the onset, severity, and persistence of antisocial behavior. CU traits are heritable, and genetic influences on CU traits contribute to antisocial behavior. This study examines genetic overlap between CU traits and general domains of personality. We measured CU traits using the Inventory of Callous-Unemotional Traits (ICU) and Big Five personality using the Big Five Inventory in a sample of adolescent twins from the Texas Twin Project. Genetic influences on the Big Five personality dimensions could account for the entirety of genetic influences on CU traits. Item Response Theory results indicate that the Inventory of Callous and Unemotional Traits is better at detecting clinically relevant personality variation at lower extremes of personality trait continua, particularly low agreeableness and low conscientiousness. The proximate biological mechanisms that mediate genetic liabilities for CU traits remain an open question. The results of the current study suggest that understanding the development of normal personality may inform understanding of the genetic underpinnings of callous and unemotional behavior. PMID- 26595479 TI - Developmental trajectories of aggression, prosocial behavior, and social cognitive problem solving in emerging adolescents with clinically elevated attention-deficit/hyperactivity disorder symptoms. AB - Middle school is a critical yet understudied period of social behavioral risks and opportunities that may be particularly difficult for emerging adolescents with attention-deficit/hyperactivity disorder (ADHD) given their childhood social difficulties. Relatively few ADHD studies have examined social behavior and social-cognitive problem solving beyond the elementary years, or examined aspects of positive (prosocial) behavior. The current study examined how middle school students with clinically elevated ADHD symptoms differ from their non-ADHD peers on baseline (6th grade) and age-related changes in prosocial and aggressive behavior, and the extent to which social-cognitive problem solving strategies mediate these relations. Emerging adolescents with (n = 178) and without (n = 3,806) clinically elevated, teacher-reported ADHD-combined symptoms were compared longitudinally across 6th through 8th grades using parallel process latent growth curve modeling, accounting for student demographic characteristics, oppositional defiant disorder (ODD) symptoms, deviant peer association, school climate, and parental monitoring. Sixth graders with elevated ADHD symptoms engaged in somewhat fewer prosocial behaviors (d = -0.44) and more aggressive behavior (d = 0.20) relative to their peers. These small social behavioral deficits decreased but were not normalized across the middle school years. Contrary to hypotheses, social-cognitive problem solving was not impaired in the ADHD group after accounting for co-occurring ODD symptoms and did not mediate the association between ADHD and social behavior during the middle school years. ADHD and social cognitive problem solving contributed independently to social behavior, both in 6th grade and across the middle school years; the influence of social-cognitive problem solving on social behavior was highly similar for the ADHD and non-ADHD groups. PMID- 26595480 TI - Interactions between DRD4 and developmentally specific environments in alcohol dependence symptoms. AB - Social experiences may moderate genetic influences on alcohol dependence (AD) symptoms. Consistent with this hypothesis, Park, Sher, Todorov, and Heath (2011) previously reported interactions between the dopamine D4 receptor gene (DRD4) and developmentally specific environments in the etiology of AD symptoms during emerging and young adulthood. Using a longitudinal cohort of n = 367 White participants followed from ages 18 to 27 years, we examine a series of similar interactions between DRD4 and developmentally sensitive contexts including childhood adversity and work and family roles. In contrast to previous results, we observed no significant interactions between DRD4 and childhood adversity. Overall, results further highlight the need for longitudinal studies of Gene * Environment interaction in the behavioral sciences and the difficulty of identifying candidate Gene * Environment interaction effects that are consistent across studies. PMID- 26595482 TI - The hierarchical structure of common mental disorders: Connecting multiple levels of comorbidity, bifactor models, and predictive validity. AB - Studies of mental disorder comorbidity have produced an unsynthesized literature with multiple competing transdiagnostic models. The current study attempted to (a) integrate these models into an overarching comorbidity hierarchy, (b) link the resulting transdiagnostic factors to the bifactor model of psychopathology, and (c) investigate predictive validity of transdiagnostic factors for important future outcomes. A series of exploratory structural equation models (ESEMs) was conducted on 12 common mental disorders from a large, 2-wave nationally representative sample, using the bass-ackwards method to explore the hierarchical structure of transdiagnostic comorbidity factors. These Wave 1 factors were then linked with the bifactor model and with mental disorders at Wave 2. Results indicated that common mental disorder comorbidity was structured into an interpretable hierarchy. Connections between the hierarchy's general factor of psychopathology (denoted p), internalizing, and distress were very strong; these factors also linked strongly with the bifactor model's p factor. Predictive validity analyses prospectively predicting subsequent diagnoses indicated that, overall: (a) transdiagnostic factors outperformed disorder-specific variance; (b) within hierarchy levels, transdiagnostic factors where disorders optimally loaded outperformed other transdiagnostic factors, but this differed by disorder type; and (c) between hierarchy levels, transdiagnostic factors where disorders optimally loaded showed similar predictive validity. We discuss implications for hierarchical structure modeling, the integration of multiple competing comorbidity models, and benefits of transdiagnostic factors for understanding the continuity of mental disorders over time. PMID- 26595481 TI - A multilevel structural equation model of within- and between-person associations among subjective responses to alcohol, craving, and laboratory alcohol self administration. AB - Subjective responses to alcohol are important determinants of drinking behavior and have been linked with risk for alcohol use disorders. However, few attempts have been made to examine proximal within-person associations among state changes in subjective responses and ongoing alcohol self-administration in the laboratory. This study disaggregated within- and between-person associations among subjective responses and alcohol self-administration, while also examining the mediating role of craving and the moderating role of trait impaired control over alcohol. Sixty young heavy drinkers (mean age = 19.90, SD = 0.86) completed self-report measures including the Impaired Control Scale, then participated in a 2-hr intravenous alcohol self-administration session using the Computer-Assisted Self-infusion of Ethanol (CASE) paradigm. Repeated assessments of subjective stimulation, subjective sedation, and craving were examined in relation to ongoing in-session self-administration, as indexed by breath alcohol concentration (BrAC) assessed 15 min later. Multilevel structural equation modeling was used to isolate within-person and between-person associations. The results showed few significant associations at the between-person level, except for a direct negative association between sedation and BrAC. At the within-person level, state fluctuations in stimulation were positively associated with both craving and subsequent BrAC, whereas state changes in sedation were negatively associated with craving and positively associated with BrAC. Within-person indirect associations from subjective stimulation and sedation to subsequent BrAC mediated via craving were statistically significant. Also, participants higher on impaired control showed stronger within-person associations between craving and greater subsequent BrAC. The results suggest that subjective responses to alcohol and craving have proximal associations with self-administration behavior, the strength of which is linked with trait impaired control over alcohol. PMID- 26595483 TI - Relationships among sleep timing, sleep duration and glycemic control in Type 2 diabetes in Thailand. AB - There is evidence that the sleep and circadian systems play a role in glucose metabolism. In addition to physiological factors, sleep is also affected by behavioral, environmental, cultural and social factors. In this study, we examined whether morning or evening preference, sleep timing and sleep duration are associated with glycemic control in patients with type 2 diabetes residing in Thailand. Two hundred and ten type 2 diabetes patients who were not shift workers completed an interview and questionnaires to collect information on diabetes history, habitual sleep duration and sleep timing. Chronotype, an individual's tendency for being a "morning" or "evening" person, was assessed using the Composite Score of Morningness (CSM), which reflects an individual's subjective preference for activities in the morning or evening, as well as mid-sleep time on weekend nights (MSF), which reflects their actual sleep behavior. Most recent hemoglobin A1c (HbA1c) values were retrieved from medical records. Evening preference (as indicated by lower CSM), later bedtime on weekends, and shorter sleep duration correlated with higher HbA1c (r = -0.18, p = 0.01; r = 0.17, p = 0.01 and r = -0.17, p = 0.01, respectively), while there was no association between MSF or wake up time and glycemic control. In addition, later bedtime on weekends significantly correlated with shorter sleep duration (r = -0.34, p < 0.001). Hierarchical regression analyses adjusting for age, sex, body mass index, insulin use and diabetes duration revealed that later bedtime on weekends was significantly associated with poorer glycemic control (B = 0.018, p = 0.02), while CSM was not. Mediation analysis revealed that this association was fully mediated by sleep duration. In summary, later bedtime on weekends was associated with shorter sleep duration and poorer glycemic control in patients with type 2 diabetes. It is likely that patients with later weekend bedtimes curtail their sleep by waking up earlier. Exploring the potential reasons for this phenomenon (e.g. cultural influences, metropolitan lifestyle, environmental factors, family and social obligations) specific to a Thai population may help identify behavioral modifications (i.e. earlier bedtime and/or sleep duration extension) that could possibly lead to improved glycemic control in this population. PMID- 26595484 TI - Stages and Processes of Change Utilized by Female Sex Workers Participating in an Alcohol-Reduction Intervention in Mombasa, Kenya. AB - BACKGROUND: According to the transtheoretical model (TTM) behavior change occurs through a series of steps when an individual becomes aware of a behavior, prepares to change, and executes those changes using certain processes. This model has not yet been used to describe alcohol-reduction behavior change processes in resource-limited settings. OBJECTIVE: This qualitative analysis aimed to describe and characterize the stages and processes of change employed by female sex workers in Mombasa, Kenya during the course of their participation in a 6-month alcohol reduction intervention. METHODS: In 2011-2012, clinical interviews were conducted with 45 female sex workers. One interview was conducted each month during the intervention period, resulting in a total of six transcripts per participant. During each interview, the counselor noted the participant's stage of change and recent alcohol use. The clinical notes were analyzed via qualitative coding techniques and organized into matrices to classify alcohol reduction strategies discussed by participants. RESULTS: Participants discussed using the stage-specific processes of change described by the TTM to reduce their alcohol use and maintain the behavior change. Participants who were HIV-positive at the start of the intervention seemed to progress to the action/maintenance stage more quickly than HIV-negative participants. CONCLUSIONS/IMPORTANCE: Results suggest that the TTM constructs may be relevant in understanding the alcohol reduction behavior change process of an at-risk population in a resource-limited setting. Future quantitative research should seek to validate the TTM's application internationally. Alcohol interventions should consider tailoring content to participants' stages of change and HIV-status for increased effectiveness. PMID- 26595485 TI - Use of liposomal amplifiers in total internal reflection fluorescence fiber-optic biosensors for protein detection. AB - Evanescent-wave excited fluorescence technology has been demonstrated to enhance sensitivity and reduce matrix effects, making it suitable for biosensor development. In this study, we developed a liposome-based, total internal reflection fluorescence, fiber-optic biosensor (TIRF-FOB) for protein detection, which integrates a liposomal amplifier and sandwich immunoassay format with TIRF FOB. In addition, the antibody-tagged and fluorophore-entrapped liposomes for heterogeneous detection of target molecules were designed and synthesized. This biosensor successfully detected the target protein (model analyzed here is IgG) with a limit of detection (LOD) of 2.0 attomoles for the target protein (equivalent to 2.0 pg/mL of protein presented in 150 MUL of sample solution). The features of this ultra-sensitive liposomal TIRF-FOB are (i) fluorescence is excited via evanescent waves and amplified via liposomes; (ii) the use of two polyclonal antibodies in the sandwich assay format increases the specificity and lowers the cost of our assay. Based on the exceptional detection sensitivity and cost-effectiveness, we believe that the proposed biosensor has great potential as a practical, clinical diagnostic tool in the near future. PMID- 26595488 TI - Courageous Dedicated Research. PMID- 26595486 TI - DNA methylation and hydroxymethylation in hematologic differentiation and transformation. AB - Maintenance of the balance of DNA methylation and demethylation is fundamental for normal cellular development and function. Members of the Ten-Eleven Translocation (TET) family proteins are Fe(II)-dependent and 2-oxoglutarate dependent dioxygenases that catalyze sequential oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and subsequent oxidized derivatives in DNA. In addition to their roles as intermediates in DNA demethylation, these oxidized methylcytosines are novel epigenetic modifications of DNA. DNA methylation and hydroxymethylation profiles are markedly disrupted in a wide range of cancers but how these changes are related to the pathogenesis of cancers is still ambiguous. In this review, we discuss the current understanding of TET protein functions in normal and malignant hematopoietic development and the ongoing questions to be resolved. PMID- 26595489 TI - Comparison of Functional Outcomes of Patients Who Underwent Hand-Sewn or Stapled Ileal Pouch-Anal Anastomosis for Ulcerative Colitis. AB - Total proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the standard surgical treatment for patients with ulcerative colitis (UC). The purpose of this study was to investigate the long-term functional outcomes and quality of life (QOL) associated with hand-sewn and stapled IPAA. Ninety-one patients with UC had undergone IPAA using hand-sewn anastomosis with mucosectomy (32 patients) or stapled anastomosis (59 patients) from January 1988 to May 2010. Patients were evaluated according to patient characteristics, postoperative complications, functional outcomes and QOL. The QOL of patients were evaluated using the Medical Outcomes Study Short Form 36 (SF-36) and the Inflammatory Bowel Disease Questionnaire (IBDQ). Numbers of patients with colorectal cancer or dysplasia were significantly greater in the hand-sewn IPAA group (P < 0.01). These patients had longer disease durations and were older (both P < 0.01). There was no difference in the incidence of complications between the groups, except for a greater incidence of postoperative anal fistula in the stapled group (P = 0.03). In the early postsurgery period, both the frequency of bowel movements and the rate of soiling were significantly higher in the hand-sewn group, but in a later period, there was no difference in these events >3 years after surgery. The SF-36 and IBDQ results were similar in the two groups, indicating that hand-sewn and stapled IPAA result in similar QOL in the late postoperative period. Postoperative complications, functional outcomes, and long-term QOL were similar in patients who had received hand-sewn or stapled IPAA. PMID- 26595490 TI - Retrorectal Tumors in Adults: A 10-Year Retrospective Study. AB - Due to the rarity and large diversity of the primary retrorectal tumors (RTs), the diagnoses are often difficult and they can be misdiagnosed. We present our experience in light of scarce information available on the clinical manifestations of RTs. The retrospective study included 17 patients diagnosed as RTs between January 2004 and January 2014. Demographic characteristics, length of symptoms, clinical findings, diagnostic methods, evaluations on the treatment procedures and postoperative periods, pathology, complications, and length of hospital stay were recorded. A mean of 1.7 of patients were diagnosed with RTs annually in our hospital. Patients comprised 12 females and 5 males. Pain and discomfort were the most common symptoms at presentation. All the lesions were evaluated by using magnetic resonance imaging (MRI) and computed tomography (CT), and all the patients were treated operatively. Based on the preoperative MRI or CT findings, an anterior approach was performed in 7 patients, a posterior approach in 6 patients, and combined approach in 4 patients. Mean size of tumors was 9.2 +/- 4.3 cm. Epidermoid cyst (n = 8) was the most common tumor. Except for 1 case of liposarcoma, 16 tumors were confirmed to be of benign nature in histologic examination. Mean length of hospital stay 12.4 +/- 6.8 days. Retrorectal tumors are heterogeneous and lead to diagnostic difficulties. A high index of clinical suspicion is needed for diagnosis. Preoperative imaging may be helpful in determining the course of treatment. Total excision of a retrorectal tumor may alleviate pressure symptoms and confirm the diagnosis. PMID- 26595491 TI - Relationship Between the Neutrophil to Lymphocyte Ratio and Parathyroid Adenoma Size in Patients With Primary Hyperparathyroidism. AB - The aim of our study was to evaluate the relationship between neutrophil to lymphocyte ratio (NLR) and adenoma size in parathyroidectomized patients who underwent a parathyroidectomy. The neutrophil to lymphocyte ratio has recently become popular as a biomarker for malignant diseases or for estimating tumor size preoperatively. This study aimed to estimate the relationship between adenoma size and NLR. Furthermore, we assessed whether a higher level of NLR is correlated with the presence of parathyroid carcinoma. A retrospective chart review was performed for patients with parathyroid adenoma who underwent parathyroidectomy between January 2012 and August 2014. Data related to age, sex, NLR, parathyroid hormone level (PTH), preoperative calcium, phosphorus, adenoma size, and pathology reports were collected. The neutrophil to lymphocyte ratio was significantly correlated with calcium levels, PTH levels, parathyroid adenoma size, and the presence of cancer. However, there was no correlation between NLR and age, sex, and phosphorus levels. This study is the first to document a positive correlation between NLR and parathyroid adenoma size, as well as the presence of cancer, in patients who underwent surgery as a result of primary hyperparathyroidism. PMID- 26595492 TI - Adrenocortical Carcinoma With Renal Vein Thrombus Extended to Inferior Vena Cava: A Case Report. AB - Adrenocortical carcinoma (ACC) is a rare aggressive tumor. Renal vein and inferior vena cava (IVC) thrombi have been found as uncommon presentations of ACC; however, the implementation of comprehensive therapy has remained controversial in such cases. We report a case of a 46-year-old woman with a large ACC associated with the invasion of tumor to IVC confirmed by imaging and immunohistochemistry examinations. The patient was treated successfully using aggressive surgery, including adrenalectomy and thrombectomy adjunct to an adrenocorticolytic agent. However, she died of metastasis complications at 3 month follow-up period. ACC is a rare malignancy, mostly presenting in advanced stages with poor prognosis. Implementing aggressive surgical therapy might be effective for the management of such cases; however, the short survival duration in our case underscores the need for defining the precise therapy of metastatic ACC associated with venous invasion. PMID- 26595493 TI - Intestinal Obstruction Caused by Persimmon Bezoar: A Case Report. AB - Owing to their rare occurrence, persimmon bezoars are often overlooked as a cause of small bowel obstruction. We herein report a small bowel obstruction in a 67 year-old Japanese female who regularly consumed persimmons in autumn. The patient presented to our hospital with typical complaints of abdominal distension with pain for 2 days. Based on the patient's history of a cesarean section 34 years ago, we initially diagnosed her with small bowel obstruction resulting from adhesions and placed an ileus tube. At first, the patient rejected the operation in spite of our recommendation. After 10 days, because the ileus tube was unable to relieve the obstruction, finally surgery was scheduled. Upon releasing the obstruction by partial resection of the small bowel, we found an impacted bezoar without any evidence of adhesions. After stone analysis, we first realized her regular persimmon intake. This case serves as an important reminder to obtain dietary history in order to investigate all possible causes of small bowel obstruction when intestinal obstruction is suspected. PMID- 26595494 TI - Stump Invagination Versus Simple Ligation in Open Appendicectomy: A Systematic Review and Meta-Analysis. AB - The aim of this meta-analysis was to compare the superiority of stump closure between stump invagination (SI) and simple ligation (SL) during open appendicectomy (OA). The literature searching was conducted in MEDLINE, EMBASE, the Cochrane Library, and http://scholar.google.com . Available data was extracted by 3 independent reviewers. The clinical outcomes were analyzed by meta analytic software to compare the difference between 2 methods during OA. The pooled odds ratios (ORs) and weighted mean differences (WMDs) with 95% confidence intervals (95% CIs) were obtained by using fixed effect model. Eleven randomized controlled trials (RCTs) were finally included in this study involving 2634 patients. Postoperative pyrexia and infections were similar between SL and SI groups, respectively, but the former group had a shorter operative time (WMD: 8.72; 95% CI: 6.87-10.56; P < 0.00001); less incidence of postoperative ileus (WMD: 2.02; 95% CI: 1.36-3.01; P = 0.0005); and quicker postoperative recovery (WMD: 0.30; 95% CI: 0.11-0.48; P = 0.002). The above results were based on 5, 11, 4, 11, and 9 articles, respectively. The clinical results revealed that SL was significantly superior to SI. SL should be suggested during OA. PMID- 26595495 TI - Diagnostic and Therapeutic Challenges of Intrahepatic Biliary Cystadenoma and Cystadenocarcinoma: A Report of 10 Cases and Review of the Literature. AB - The objective of this study was to present our experience with intrahepatic biliary cystadenomas and cystadenocarcinomas in 10 patients surgically managed in our department. Intrahepatic biliary cystadenomas and cystadenocarcinomas are rare cystic tumors that are often misdiagnosed preoperatively as simple cysts or hydatid cysts. They recur after incomplete resection and entail a risk of malignant transformation to cystadenocarcinoma. A retrospective review was conducted of patients with histologically confirmed intrahepatic biliary cystadenomas and cystadenocarcinomas between August 2004 and February 2013 who were surgically managed in our department. A total of 10 patients, 9 female and 1 male (mean age, 50 years), with cystic liver were reviewed. The size of the cysts ranged between 3.5 and 16 cm (mean, 10.6). Five patients had undergone previous interventions elsewhere and presented with recurrences. Liver resections included 6 hepatectomies, 2 bisegmentectomies, 1 extended right hepatectomy, and 1 enucleation due to the central position and the large size of the lesion. Pathology reports confirmed R0 resections in all cases. All patients were alive after a median follow-up of 6 years (range, 1-10 years), and no recurrence was detected. Intrahepatic biliary cystadenoma and cystadenocarcinoma should be considered in differential diagnosis in patients with liver cystic tumors. Because of the high recurrence rate and difficult accurate preoperative diagnosis, formal liver resection is mandatory. Enucleation with free margins is an option and is indicated where resection is impossible. PMID- 26595496 TI - Higher Level of Serum Heme Oxygenase-1 in Patients With Intracerebral Hemorrhage. AB - The objective of this paper was to investigate the association of the serum level of heme oxygenase-1 in patients with intracerebral hemorrhage (ICH) with the risk of ICH. Heme oxygenase-1(HO-1) metabolizes heme into biliverdin, bilirubin, carbon monoxide, and iron, our recent study showed that serum level of HO-1 was increased in stroke patients, yet the association of HO-1 level with risk of intracerebral hemorrhage (ICH) is poorly known. Forty patients with ICH and another 40 patients without ICH were recruited. The serum level of HO-1, total, and direct bilirubin were measured. The level of HO-1, serum total bilirubin, and direct bilirubin, as well as blood pressure were increased in ICH group than in control group (P < 0.001). The level of HO-1, both systolic and diastolic blood pressure had a significant difference between subgroups (P < 0.05). Multivariate regression analysis showed that poor compliance to medicine for hypertension, the serum level of HO-1, and systolic blood pressure were associated with the prevalence of ICH. Blood pressure, serum HO-1, serum total bilirubin, and direct bilirubin were raised in patients with ICH who did not take medicine for hypertension compared with those who did, and increased in ICH patients in comparison with control group. Further investigation in multiple medical centers with large number of cohorts is warranted to verify these results. PMID- 26595497 TI - Endoscopic Treatment of Esophago-Pleural Fistula Following Total Gastrectomy: A Case Report. AB - This paper is designed to report the endoscopic treatment for a rare esophagopleural fistula after total gastrectomy. Esophagopleural fistula is a rare complication following total gastrectomy. Nonoperative treatment using endoscopic injection of tissue glue is a less invasive and effective option. The history, treatment, and options for managing an esophagopleural fistula following gastrectomy are discussed. A 53-year-old female patient underwent total gastrectomy for advanced gastric cancer. An anastomotic leak with esophagopleural fistula formation developed at the esophagojejunostomy site. The fistula was successfully managed by endoscopic injection with n-butyl-2-cyanoacrylate into the fistula, chest tube drainage, systemic antibiotics, and total parenteral nutrition. This case report suggests that combing effective drainage and the use of n-butyl-2-cyanoacrylate of nonoperative treatment options for esophagopleural fistula. PMID- 26595498 TI - Assessment of Graft Selection Criteria in Living-Donor Liver Transplantation: The Jikei Experience. AB - In living-donor liver transplantation, graft selection is especially important for the safety of the live donor and an acceptable outcome for the recipient. The essential medical requirements for living liver donation at Jikei University Hospital are as follows: an adult aged 65 years or younger, in good general condition, with partial liver volume of more than 35% of the standard liver volume (SLV) for the recipient, and without severe liver steatosis. Based on our criteria, we performed 13 living-donor liver transplantations between 2007 and 2013, including 1 retransplantation. Three cases were outside our standard donor criteria, including age (18 and 66 years) and 33% graft volume (GV) to SLV ratio for the recipient on preoperative volumetry using computed tomography. In 2 cases, the actual GV to SLV ratio at transplantation was less than 35%. Median postoperative hospital stay was 11 days for the donors, and 29 days for the recipients. All donors returned to their preoperative status, and all recipients were discharged in good condition. Our medical requirements for living liver donation seem to be acceptable because of the good outcome. PMID- 26595499 TI - Application of the Ureteroscope for Diagnosis and Treatment of the Seminal Vesicle Diseases. AB - The objective of this paper is to apply the transurethral endoscopic technique with the ureteroscope for diagnosis and treatment of the seminal vesicle and ejaculatory duct disorders. At present there is no special equipment designed to enter directly into the seminal vesicle cavity under direct vision. Sixty patients with disorders of the seminal vesicle were included in this study. A 6.5 F rigid ureteroscope (Richard Wolf GmbH, Knittlingen, Germany) was inserted into the posterior urethra to find the verumontanum. Then a 3F catheter (Shanghai Kangge JJMC, Shanghai, China) was inserted into the verumontanum. After that the 6.5 F ureteroscope was introduced into the ejaculatory duct and seminal vesicle to examine them under direct observation. A total of 55 patients were diagnosed and cured successfully with the ureteroscope; 42 (76.4%) patients were discovered to have hemospermia. They were given an anti-inflammatory and seminal vesicle washing. Eight (14.5%) patients who had small stones in the seminal vesicle were offered the operation of the stones removal. Five (9.1%) patients were found to have seminal vesicle gland cysts. The orifices of ejaculatory duct were not found in 3 patients among 5 who were operated unsuccessfully. The ureteroscope failed to enter the seminal vesicle in 2 patients. Some diseases of the seminal vesicle and ejaculatory duct can be easily diagnosed and treated in the clinical practice using a ureteroscope. Transurethral endoscopy technique with the ureteroscope for diagnosis and therapy of the seminal vesicle and ejaculatory duct disorders is safe and practicable. PMID- 26595500 TI - Noninvasive Monitoring and Evaluation of the Renal Structure and Function in a Mouse Model of Unilateral Ureteral Occlusion Using Microcomputed Tomography. AB - Mouse unilateral ureteral occlusion (UUO) is widely used as a model of renal experimental obstructive nephropathy with interstitial fibrosis. Microcomputed tomography (micro-CT) imaging has the potential to produce quantitative images. The aim of this study was to establish standard images of micro-CT for renal anatomic and functional evaluations in a mouse model of UUO. UUO was induced in adult male mice BALB/c. In total, 27 mice were used in this study. Three mice per group (a total of 6 groups) were examined with contrast-enhanced micro-CT prior to UUO (day 0) and on days 1, 3, 5, 7, 10, and 14 after UUO. In order to determine the histopathologic correlations at each point in time, contrast enhanced micro-CT imaging was performed in the 18 remaining mice. All animals were sacrificed, and both kidneys were harvested after the final micro-CT examination. UUO resulted in hydronephrosis and changes in the renal parenchyma. The predominant alteration was substantial changes in the hemodynamics of the renal vascular system after ureteral obstruction for 24 hours or longer, which may be resulting from increased action of vasoconstrictors versus vasodilators. The renal parenchyma was significantly reduced after 1 week, and the features of the histologic changes supported the findings of the micro-CT images. In the contralateral unobstructed kidneys, the images showed a normal structure and function and the pathohistology revealed a normal histoarchitecture. Micro-CT is a useful tool for providing noninvasive monitoring and evaluating the renal structure and function. PMID- 26595501 TI - Giant Splenic Artery Pseudoaneurysm: A Case Report and Literature Review. AB - Splenic artery aneurysms (SAAs) are the third most frequent intra-abdominal aneurysm, following abdominal aorta and iliac artery aneurysms. SAAs are classified according to their involvement of arterial wall layers: true aneurysms involve all 3 layers (intima, media, and adventitia), and pseudoaneurysms involve only one or two. Herein we present a new case of giant pseudo SAA. A 65-year-old female patient with a pancreatic mass and iron deficiency was referred to our clinic for further investigation. Abdominal ultrasonography, contrast-enhanced CT and magnetic resonance imaging showed a lesion resembling a subcapsular hemangioma in the spleen, and aneurysmatic dilation of the splenic artery with a diameter of >5 cm. The large size of the aneurysm and the clinical findings were indications for surgical treatment. The patient underwent en bloc resection of the spleen, distal pancreas, and aneurysmatic segment of the splenic artery. The patient remains complication-free 2 months after the operation. Spontaneous rupture is the most important life-threatening complications of giant SAAs. Therefore, all symptomatic patients with SAA should be treated, as well as asymptomatic patients with lesions >=2 cm, who are pregnant or fertile, have portal hypertension, or are candidates for liver transplantation. Despite advances in endovascular techniques, conventional abdominal surgery remains the gold standard for treatment. PMID- 26595502 TI - Midterm Results Following Percutaneous Rotational Thrombectomy for Acute Thrombotic Occlusions of Prosthetic Arteriovenous Access Grafts. AB - Patent vascular access is critical for patients on regular hemodialysis. Prosthetic grafts are good alternatives when the superficial venous system is of poor quality. However, thrombosis is one of the main drawbacks of synthetic grafts, with reports of 59% to 90% patency rates for 1 year. In cases of thrombotic occlusion of prosthetic arteriovenous fistula grafts, percutaneous mechanical thrombectomy has recently gained clinical popularity as a potential alternative to surgical thrombectomy or pharmacologic thrombolysis. We reviewed our preliminary results from 30 percutaneous rotational thrombectomies performed in a total of 22 patients in the setting of acute dialysis-access prosthetic graft occlusion of the upper extremity. Among the 30 cases of acute occlusion of the arteriovenous graft, immediate success with angiographic flow restoration was observed in all patients except for 2 patients (both females; 6%), with de novo occlusion where reocclusion occurred within 12 hours despite apparent immediate angiographic patency. The mean duration between the initial presentation with acute arteriovenous graft occlusion and the thrombectomy procedure was 27.4 +/- 12.4 hours. The mean duration of graft patency was 10.45 +/- 0.6 months. A total of 75% of the arteriovenous grafts were patent at the end of 12 months of follow up. Female gender, diabetes mellitus, and diagnosis to intervention interval were reviewed for midterm graft failure, and the presence of diabetes mellitus yielded significance (P < 0.05). Percutaneous techniques play important roles in the treatment of failed or failing arteriovenous fistulae and grafts. Ongoing analysis of outcomes of both percutaneous and surgical intervention is necessary to continue to identify optimum treatment algorithms. PMID- 26595503 TI - Endoscopic naso-gallbladder drainage versus gallbladder stenting before cholecystectomy in patients with acute cholecystitis and a high suspicion of choledocholithiasis: a prospective randomised preliminary study. AB - OBJECTIVE: Endoscopic transpapillary gallbladder drainage using a nasocystic tube or plastic stent has been attempted as an alternative to percutaneous drainage for patients with acute cholecystitis who are not candidates for urgent cholecystectomy. We aimed to assess the efficacy of single-step endoscopic drainage of the common bile duct and gallbladder, and to evaluate which endoscopic transpapillary gallbladder drainage method is ideal as a bridge before elective cholecystectomy. MATERIALS AND METHODS: From July 2011 to December 2014, 35 patients with acute moderate-to-severe cholecystitis and a suspicion of choledocholithiasis were randomly assigned to the endoscopic naso-gallbladder drainage (ENGBD) (n = 17) or endoscopic gallbladder stenting (EGBS) (n = 18) group. RESULTS: Bile duct clearance was performed successfully in all cases. No significant differences were found between the ENGBD and EGBS groups in the technical success rates [82.4% (14/17) vs. 88.9% (16/18), p = 0.658] and clinical success rates [by intention-to-treat analysis: 70.6% (12/17) vs. 83.3% (15/18), p = 0.443; by per protocol analysis of technically feasible cases: 85.7% (12/14) vs. 93.8% (15/16), p = 0.586]. Three ENGBD patients and two EGBS patients experienced adverse events (p = 0.658). No significant differences were found in operation time or rate of conversion to open cholecystectomy. CONCLUSIONS: Single step endoscopic transpapillary drainage of the common bile duct and gallbladder seems to be an acceptable therapeutic modality in patients with acute cholecystitis and a suspicion of choledocholithiasis. There were no significant differences in the technical and clinical outcomes between ENGBD and EGBS as a bridge before cholecystectomy. PMID- 26595505 TI - Nano-cage-mediated refolding of insulin by PEG-PE micelle. AB - Insulin aggregation has pronounced pharmaceutical implications and biological importance. Deposition of insulin aggregates is associated with type II diabetes and instability of pharmaceutical formulations. We present in this study the renaturation effect of PEG-PE micelle on dithiothreitol (DTT)-denatured insulin revealed by techniques including turbidity assay, circular dichroism (CD), thioflavinT (ThT) binding assay, bis-ANS binding assay, agarose gel electrophoresis and MALDI-TOF MS. The obtained results show that PEG-PE micelle having a hydrophilic nano-cage-like structure in which with a negative charge layer, can capture DTT-induced insulin A and B chains, and block their hydrophobic interaction, thereby preventing aggregation. The reduced insulin A and B chain in the nano-cage are capable of recognizing each other and form the native insulin with yields of ~30% as measured by hypoglycemic activity analysis in mice. The observed insulin refolding assisted by PEG-PE micelle may be applicable to other proteins. PMID- 26595506 TI - Characteristics of Females Who Use Contraception at Coitarche: An Analysis of the National Survey of Family Growth 2006-2010 Database. AB - STUDY OBJECTIVE: To determine demographical and behavioral characteristics associated with contraceptive use at coitarche, or first sexual experience, to determine which populations are at greatest risk of contraceptive nonuse during early sexual experiences. DESIGN: Cross-sectional study. METHODS: We used the National Survey of Family Growth 2006-2010 database to abstract pertinent variables, including race, highest education, annual family income, parental living situation, importance of religion, age at coitarche, number of sexual partners, type of first contraception, and source of first contraception. Generalized linear models with logit link and binomial distribution were applied to examine the association between use of contraceptive methods at coitarche and the variables abstracted. RESULTS: Of the 5931 female participants included in the study, 1071 (18%) did not use contraceptive methods at coitarche. Only 199 (2%) of the female participants included in this study used the more reliable hormonal contraceptive methods at coitarche. Black females were significantly more likely than white females to use contraceptive methods at coitarche (p < 0.01). Females who initiated coitarche from 16 to 20 years of age were significantly more likely to use contraception at coitarche than females who had their first sexual experience at less than 16 years of age (p < 0.001). Females with greater educational background and greater family income were also significantly more likely to use contraception at coitarche (p < 0.001). Finally, females who obtained their first contraceptive methods from a spouse, partner, or friend were more likely to use contraception at coitarche than females who obtained their first method from a medical facility (p < 0.001). CONCLUSIONS: This study highlights several key differences between females who use contraceptive methods at coitarche versus those who do not. Greater effort needs to be focused on increasing access to more reliable contraceptive methods for young females, as females who obtain methods from nonmedical facilities are more likely to use contraceptive methods at coitarche. PMID- 26595507 TI - A new pregnane glycoside from Gomphocarpus fruticosus growing in Egypt. AB - Phytochemical investigation of Gomphocarpus fruticosus (L.) Ait. of Egyptian origin afforded the new pregnane glycoside lineolon-3-O-[beta-D-oleandropyranosyl (1-4)-beta-D-cymaropyranosyl-(1-4)-beta-D-cymaropyranoside], along with six known compounds. The structures of the isolated compounds were elucidated on the basis of extensive spectroscopic evidences derived from 1D, 2D NMR experiments, mass spectrometry and by comparing their physical and spectroscopic data to literature. These included the triterpenoids 3beta-taraxerol, 3beta-taraxerol acetate and betulinic acid, which are identified for the first time in G. fruticosus and the cardenolides uzarigenin, gomphoside and calotropin. PMID- 26595508 TI - Great enhancement in the excitonic recombination and light extraction of highly ordered InGaN/GaN elliptic nanorod arrays on a wafer scale. AB - A series of highly ordered c-plane InGaN/GaN elliptic nanorod (NR) arrays were fabricated by our developed soft UV-curing nanoimprint lithography on a wafer. The photoluminescence (PL) integral intensities of NR samples show a remarkable enhancement by a factor of up to two orders of magnitude compared with their corresponding as-grown samples at room temperature. The radiative recombination in NR samples is found to be greatly enhanced due to not only the suppressed non radiative recombination but also the strain relaxation and optical waveguide effects. It is demonstrated that elliptic NR arrays improve the light extraction greatly and have polarized emission, both of which possibly result from the broken structure symmetry. Green NR light-emitting diodes have been finally realized, with good current-voltage performance and uniform luminescence. PMID- 26595509 TI - Functional and transcript analysis of a novel metal transporter gene EpNramp from a dark septate endophyte (Exophiala pisciphila). AB - Various metal transporters mediate sub-cellular sequestration of diverse metal ions, contribute to cellular metal tolerance, and control metal partitioning, particularly under conditions of high rates of metal influx into organisms. In the current study, a ubiquitous and evolutionary conserved metal transporter gene, homology to natural resistance associated macrophage protein (Nramp), was cloned from a metal-tolerant isolate of dark septate endophyte (DSE, Exophiala pisciphila), and its functional and transcript characterization were analyzed. The full-length Nramp gene from E. pisciphila (named EpNramp) was 1716 bp and expected to encode a polypeptide of 571 amino acid residues. EpNramp fused to green fluorescent protein suggested that EpNramp was a plasma membrane metal transporter, which was consistent with the results of bioinformatics analysis with 11 transmembrane domains. Yeast functional complementation revealed that EpNramp could complement the growth defect of Fe-uptake yeast mutant (fet3fet4 double mutant) by mediating the transport of Fe(2+). Expression of EpNramp increased Cd(2+) sensitivity and Cd(2+) accumulation in yeast. In addition, qPCR data revealed that E. pisciphila significantly down-regulated EpNramp expression with elevated Cd(2+) exposure. Altogether, EpNramp is a bivalent cation transporter localized in cell membrane, which is necessary for efficient translocation of both Fe and Cd, and its activities partly attributed to the tolerance of DSE to toxic and excessive Cd(2+) supplements. PMID- 26595510 TI - Heavy metal speciation in various grain sizes of industrially contaminated street dust using multivariate statistical analysis. AB - A total of 36 street dust samples were collected from the streets of the Organised Industrial District in Kayseri, Turkey. This region includes a total of 818 work places in various industrial areas. The modified BCR (the European Community Bureau of Reference) sequential extraction procedure was applied to evaluate the mobility and bioavailability of trace elements (Cd, Co, Cr, Cu, Fe, Mn, Ni, Pb and Zn) in street dusts of the study area. The BCR was classified into three steps: water/acid soluble fraction, reducible and oxidisable fraction. The remaining residue was dissolved by using aqua regia. The concentrations of the metals in street dust samples were determined by flame atomic absorption spectrometry. Also the effect of the different grain sizes (<38um, 38-53um and 53 74um) of the 36 street dust samples on the mobility of the metals was investigated using the modified BCR procedure. The mobility sequence based on the sum of the first three phases (for <74um grain size) was: Cd (71.3)>Cu (48.9)>Pb (42.8)=Cr (42.1)>Ni (41.4)>Zn (40.9)>Co (36.6)=Mn (36.3)>Fe (3.1). No significant difference was observed among metal partitioning for the three particle sizes. Correlation, principal component and cluster analysis were applied to identify probable natural and anthropogenic sources in the region. The principal component analysis results showed that this industrial district was influenced by traffic, industrial activities, air-borne emissions and natural sources. The accuracy of the results was checked by analysis of both the BCR-701 certified reference material and by recovery studies in street dust samples. PMID- 26595511 TI - Oxidative stress and immunotoxic effects of bisphenol A on the larvae of rare minnow Gobiocypris rarus. AB - Bisphenol A (BPA), a known endocrine disrupting chemical, is ubiquitous in the aquatic environment and can pose risk to the health of aquatic organisms. Studies on immunotoxicity of BPA in aquatic organisms are limited. In this study, rare minnow (Gobiocypris rarus) larvae were exposed to 1, 225 and 1000MUg/L BPA for 7 days. Inflammatory effects of BPA exposure were assessed from the increased production of nitric oxide (NO) and reactive oxygen species (ROS), the change of iNOS mRNA and other TLRs-associated immune gene expression. Our findings provide evidences that different concentrations of BPA can induce a toxic response in fish to produce reactive free radicals which can affect the function of T lymphocytes and decrease the transcription levels of cytokine genes. The excess production of H2O2, induced oxidative stress and suppressed TLR4/NF-kappaB signaling, leading to immunosuppressive effects in fish larvae. The present results suggest that BPA has the potential to induce oxidative stress accompanied by immunosuppression in rare minnow larvae. PMID- 26595512 TI - COMMENTARY ON "STUDY OF THE PREVALENCE OF AUTOIMMUNE THYROID DISEASE IN WOMEN WITH BREAST CANCER". PMID- 26595513 TI - HIGHER SERUM OSTEOPROTEGERIN LEVELS IN SUBJECTS WITH THYROID NODULES. AB - OBJECTIVE: A recent study demonstrated that osteoprotegerin (OPG) could be expressed both in benign and malignant thyroid tissue. However, epidemiologic studies investigating the association between serum OPG and thyroid nodules are not available. The objective of this study was to determine whether serum OPG is associated with thyroid nodules. METHODS: We measured serum OPG, total triiodothyronine, total thyroxine, free triiodothyronine, free thyroxine, thyrotropin, antithyroid peroxidase antibodies, thyrotropin-receptor antibodies, antithyroglobulin antibodies, and thyroglobulin in 1,120 Chinese participants in a cross-sectional community-based study performed in downtown Shanghai. Thyroid nodule was diagnosed by thyroid ultrasonographic examination. RESULTS: The serum OPG levels were significantly increased in nodule-positive subjects compared to nodule-negative subjects (2.8 +/- 1.2 ng/mL versus 2.1 +/- 1.0 ng/mL; P<.001). After multiple adjustments, the odds ratios were substantially higher for thyroid nodule (odds ratio, 3.09; 95% confidence interval, 1.60 to 5.97) in the highest OPG quartile compared with those in the lowest quartile. These associations remained significant after further adjustment for potential confounders. Multivariate linear regression analysis demonstrated that age (P = .015) and OPG (P = .003) were independently associated with thyroid nodule. CONCLUSION: Serum OPG is elevated significantly in subjects with thyroid nodules among middle-aged and elderly individuals. PMID- 26595514 TI - SGLT-2 INHIBITORS AS ADJUNCT THERAPY IN TYPE 1 DIABETES: REASON FOR HOPE AND CAUTION. PMID- 26595515 TI - VARIATIONS IN CLINICAL AND IMAGING FINDINGS BY TIME OF DIAGNOSIS IN FEMALES WITH HYPOPITUITARISM ATTRIBUTED TO LYMPHOCYTIC HYPOPHYSITIS. AB - OBJECTIVE: To describe the various patterns of presentation, including assisting analyses, associated with the timing of diagnosis of females with hypopituitarism and suspected clinical diagnosis of lymphocytic hypophysitis. METHODS: A retrospective study of 9 consecutive females with pituitary dysfunction developed during or after pregnancy. All subjects were treated in our clinics between 2008 and 2014. Data were collected on clinical characteristics, pituitary hormone levels, and imaging findings. RESULTS: The study group included 9 patients with a mean age 33.7 +/- 7.8 years at delivery. The probable cause of disease was lymphocytic hypophysitis. Headache or specific symptoms/signs of hypopituitarism appeared within 1 year of delivery. Five patients had headache, and 8 had difficulty breastfeeding or amenorrhea. Laboratory findings included central hypocortisolism (8/9 patients), hypogonadotropic hypogonadism (8/9), and central hypothyroidism (6/7). Insulin-like growth factor-1 (IGF-1) levels were low in 8/8 patients. Prolactin levels were low in 3/9 patients, and 1 patient had diabetes insipidus. Seven patients were diagnosed less than 1 year from symptom onset; 4 (57%) complained of headaches, and 5 (71%) had panhypopituitarism. Two patients were diagnosed later. Both had difficulty breastfeeding and amenorrhea, and one also had headaches. Both had panhypopituitarism and reduced pituitary volume. None of the patients fully recovered pituitary function. Normalization of the thyrotroph axis occurred in 3 patients, gonadotroph function in 3, the corticotroph axis in 2, and IGF-1 normalized in 1 subject. CONCLUSION: Hypopituitarism attributed to lymphocytic hypophysitis may present during pregnancy or early postpartum period with a clear clinical picture, or later, with indolent and nonspecific symptoms and signs. PMID- 26595516 TI - A Case Presentation. PMID- 26595518 TI - The formation mechanism of iron oxide nanoparticles within the microwave-assisted solvothermal synthesis and its correlation with the structural and magnetic properties. AB - Magnetic nanoparticles based on Fe3O4 were prepared by a facile and rapid one-pot solvothermal synthesis using FeCl3.6H2O as a source of iron ions, ethylene glycol as a solvent and NH4Ac, (NH4)2CO3, NH4HCO3 or aqueous NH3 as precipitating and nucleating agents. In contrast to previous reports we reduce the synthesis time to 30 minutes using a pressurized microwave reactor without the requirement of further post-treatments such as calcination. Dramatically reduced synthesis time prevents particle growth via Ostwald ripening thus the obtained particles have dimensions in the range of 20 to 130 nm, they are uniform in shape and exhibit magnetic properties with saturation magnetization ranging from 8 to 76 emu g(-1). The suggested method allows simple particle size and crystallinity tuning resulting in improved magnetic properties by changing the synthesis parameters, i.e. temperature and nucleating agents. Moreover, efficiency of conversion of raw material into the product is almost 100%. PMID- 26595519 TI - Instability of Nano- and Microscale Liquid Metal Filaments: Transition from Single Droplet Collapse to Multidroplet Breakup. AB - We carry out experimental and numerical studies to investigate the collapse and breakup of finite size, nano- and microscale, liquid metal filaments supported on a substrate. We find the critical dimensions below which filaments do not break up but rather collapse to a single droplet. The transition from collapse to breakup can be described as a competition between two fluid dynamic phenomena: the capillary driven end retraction and the Rayleigh-Plateau type instability mechanism that drives the breakup. We focus on the unique spatial and temporal transition region between these two phenomena using patterned metallic thin film strips and pulsed-laser-induced dewetting. The experimental results are compared to an analytical model proposed by Driessen et al. and modified to include substrate interactions. In addition, we report the results of numerical simulations based on a volume-of-fluid method to provide additional insight and highlight the importance of liquid metal resolidification, which reduces inertial effects. PMID- 26595520 TI - Solvatochromic Dyes as pH-Independent Indicators for Ionophore Nanosphere-Based Complexometric Titrations. AB - For half a century, complexometric titrations of metal ions have been performed with water-soluble chelators and indicators that typically require careful pH control. Very recently, ion-selective nanosphere emulsions were introduced that exhibit ion-exchange properties and are doped with lipophilic ionophores originally developed for chemical ion sensors. They may serve as novel, highly selective and pH independent complexometric reagents. While ion optode emulsions have been demonstrated as useful indicators for such titrations, they exhibit a pH cross-response that unfortunately complicates the identification of the end point. Here, we present pH-independent optode nanospheres as indicators for complexometric titrations, with calcium as an initial example. The nanospheres incorporate an ionic solvatochromic dye (SD), ion exchanger and ionophore. The solvatochromic dye will be only expelled from the core of the nanosphere into the aqueous solution at the end point at which point it results in an optical signal change. The titration curves are demonstrated to be pH-independent and with sharper end points than with previously reported chromoionophore-based optical nanospheres as indicator. The calcium concentration in mineral water was successfully determined using this method. PMID- 26595521 TI - HSP90 inhibition blocks ERBB3 and RET phosphorylation in myxoid/round cell liposarcoma and causes massive cell death in vitro and in vivo. AB - Myxoid sarcoma (MLS) is one of the most common types of malignant soft tissue tumors. MLS is characterized by the FUS-DDIT3 or EWSR1-DDIT3 fusion oncogenes that encode abnormal transcription factors. The receptor tyrosine kinase (RTK) encoding RET was previously identified as a putative downstream target gene to FUS-DDIT3 and here we show that cultured MLS cells expressed phosphorylated RET together with its ligand Persephin. Treatment with RET specific kinase inhibitor Vandetanib failed to reduce RET phosphorylation and inhibit cell growth, suggesting that other RTKs may phosphorylate RET. A screening pointed out EGFR and ERBB3 as the strongest expressed phosphorylated RTKs in MLS cells. We show that ERBB3 formed nuclear and cytoplasmic complexes with RET and both RTKs were previously reported to form complexes with EGFR. The formation of RTK hetero complexes could explain the observed Vandetanib resistence in MLS. EGFR and ERBB3 are clients of HSP90 that help complex formation and RTK activation. Treatment of cultured MLS cells with HSP90 inhibitor 17-DMAG, caused loss of RET and ERBB3 phosphorylation and lead to rapid cell death. Treatment of MLS xenograft carrying Nude mice resulted in massive necrosis, rupture of capillaries and hemorrhages in tumor tissues. We conclude that complex formation between RET and other RTKs may cause RTK inhibitor resistance. HSP90 inhibitors can overcome this resistance and are thus promising drugs for treatment of MLS/RCLS. PMID- 26595522 TI - HBx sensitizes hepatocellular carcinoma cells to lapatinib by up-regulating ErbB3. AB - Poor prognosis of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) involves HBV X protein (HBx)-induced tumor progression. HBx also contributes to chemo-resistance via inducing the expressions of anti-apoptosis and multiple drug resistance genes. However, the impact of HBx expression on the therapeutic efficacy of various receptor tyrosine kinase inhibitors remains unknown. In this study, our data showed that HBx overexpression did not alter the cellular sensitivity of HCC cell lines to sorafenib but unexpectedly enhanced the cell death induced by EGFR family inhibitors, including gefitinib, erlotinib, and lapatinib due to ErbB3 up-regulation. Mechanistically, HBx transcriptionally up regulates ErbB3 expression in a NF-kappaB dependent manner. In addition, HBx also physically interacts with ErbB2 and ErbB3 proteins and enhances the formation of ErbB2/ErbB3 heterodimeric complex. The cell viability of HBx-overexpressing cells was decreased by silencing ErbB3 expression, further revealing the pivotal role of ErbB3 in HBx-mediated cell survival. Our data suggest that HBx shifts the oncogenic addiction of HCC cells to ErbB2/ErbB3 signaling pathway via inducing ErbB3 expression and thereby enhances their sensitivity to EGFR/ErbB2 inhibitors. PMID- 26595523 TI - MiR-630 suppresses breast cancer progression by targeting metadherin. AB - MicroRNAs have been integrated into tumorigenic programs as either oncogenes or tumor suppressor genes. The miR-630 was reported to be deregulated and involved in tumor progression of several human malignancies. However, its expression regulation shows diversity in different kinds of cancers and its potential roles remain greatly elusive. Herein, we demonstrate that miR-630 is significantly suppressed in human breast cancer specimens, as well as in various breast cancer cell lines. In aggressive MDA-MB-231-luc and BT549 breast cancer cells, ectopic expression of miR-630 strongly inhibits cell motility and invasive capacity in vitro. Moreover, lentivirus delivered miR-630 bestows MDA-MB-231-luc cells with the ability to suppress cell colony formation in vitro and pulmonary metastasis in vivo. Further studies identify metadherin (MTDH) as a direct target gene of miR-630. Functional studies shows that MTDH contributes to miR-630-endowed effects including cell migration and invasion as well as colony formation in vitro. Taken together, these findings highlight an important role for miR-630 in the regulation of metastatic potential of breast cancer and suggest a potential application of miR-630 in breast cancer treatment. PMID- 26595524 TI - Genomic binding and regulation of gene expression by the thyroid carcinoma associated PAX8-PPARG fusion protein. AB - A chromosomal translocation results in production of an oncogenic PAX8-PPARG fusion protein (PPFP) in thyroid carcinomas. PAX8 is a thyroid transcription factor, and PPARG is a transcription factor that plays important roles in adipocytes and macrophages. PPFP retains the DNA binding domains of both proteins; however, the genomic binding sites of PPFP have not been identified, and only limited data exist to characterize gene expression in PPFP thyroid carcinomas. Therefore, the oncogenic function of PPFP is poorly understood. We expressed PPFP in PCCL3 rat thyroid cells and used ChIP-seq to identify PPFP genomic binding sites (PPFP peaks) and RNA-seq to characterize PPFP-dependent gene expression. PPFP peaks (~20,000) include known PAX8 and PPARG binding sites and are enriched with both motifs, indicating that both DNA binding domains are functional. PPFP binds to and regulates many genes involved in cancer-related processes. In PCCL3 thyroid cells, PPFP binds to adipocyte PPARG target genes in preference to macrophage PPARG target genes, consistent with the pro-adipogenic nature of PPFP and its ligand pioglitazone in thyroid cells. PPFP induces oxidative stress in thyroid cells, and pioglitazone increases susceptibility to further oxidative stress. Our data highlight the complexity of PPFP as a transcription factor and the numerous ways that it regulates thyroid oncogenesis. PMID- 26595525 TI - Diverse in vivo effects of soluble and membrane-bound M-CSF on tumor-associated macrophages in lymphoma xenograft model. AB - Macrophage colony-stimulating factor (M-CSF) is an important cytokine for monocyte/macrophage lineage. Secretory M-CSF (sM-CSF) and membrane-bound M-CSF (mM-CSF) are two major alternative splicing isoforms. The functional diversity of these isoforms in the activation of tumor-associated macrophages (TAMs), especially in lymphoma microenvironment, has not been documented. Here, we studied the effects of M-CSF isoforms on TAMs in xenograft mouse model. More infiltrating TAMs were detected in microenvironment with mM-CSF and sM-CSF. TAMs could be divided into three subpopulations based on their expression of CD206 and Ly6C. While sM-CSF had greater potential to recruit and induce differentiation of TAMs and TAM subpopulations, mM-CSF had greater potential to induce proliferation of TAMs and TAM subpopulations. Though both isoforms educated TAMs and TAM subpopulations to M2-like macrophages, mM-CSF and sM-CSF induced different spectrums of phenotype-associated genes in TAMs and TAM subpopulations. These results suggested the diverse effects of M-CSF isoforms on the activation of TAMs and TAM subpopulations in lymphoma microenvironments. PMID- 26595526 TI - ERK8 is a novel HuR kinase that regulates tumour suppressor PDCD4 through a miR 21 dependent mechanism. AB - Programmed cell death 4 (PDCD4) is a tumour suppressor implicated in cancer development and progression and was recently identified as a repressor of cap independent translation of specific genes involved in the regulation of apoptosis. We show that the RNA-binding protein HuR binds to the PDCD4 3'UTR to protect it from miR-21-induced silencing. However, following H2O2 treatment, PDCD4 mRNA is degraded via miR-21 binding. Importantly, we identify HuR as a novel substrate of the ERK8 kinase pathway in response to H2O2 treatment. We show that phosphorylation of HuR by ERK8 prevents it from binding to PDCD4 mRNA and allows miR-21-mediated degradation of PDCD4. PMID- 26595530 TI - Correlated Pair States Formed by Singlet Fission and Exciton-Exciton Annihilation. AB - Singlet fission to form a pair of triplet excitations on two neighboring molecules and the reverse process, triplet-triplet annihilation to upconvert excitation, have been extensively studied. Comparatively little work has sought to examine the properties of the intermediate state in both of these processes the bimolecular pair state. Here, the eigenstates constituting the manifold of 16 bimolecular pair excitations and their relative energies in the weak-coupling regime are reported. The lowest-energy states obtained from the branching diagram method are the triplet pairs with overall singlet spin |X1? ~ (1)[TT] and quintet spin |Q? ~ (5)[TT]. It is shown that triplet pair states can be separated by a triplet-triplet energy-transfer mechanism to give a separated, yet entangled triplet pair (1)[T...T]. Independent triplets are produced by decoherence of the separated triplet pair. Recombination of independent triplets by exciton-exciton annihilation to form the correlated triplet pair (i.e., nongeminate recombination) happens with 1/3 of the rate of either triplet migration or recombination of the separated correlated triplet pair (geminate recombination). PMID- 26595532 TI - Mono-cadmium vs Mono-mercury Doping of Au25 Nanoclusters. AB - Controlling the dopant type, number, and position in doped metal nanoclusters (nanoparticles) is crucial but challenging. In the work described herein, we successfully achieved the mono-cadmium doping of Au25 nanoclusters, and revealed using X-ray crystallography in combination with theoretical calculations that one of the inner-shell gold atoms of Au25 was replaced by a Cd atom. The doping mode is distinctly different from that of mono-mercury doping, where one of the outer shell Au atoms was replaced by a Hg atom. Au24Cd is readily transformed to Au24Hg, while the reverse (transformation from Au24Hg to Au24Cd) is forbidden under the investigated conditions. PMID- 26595527 TI - A subset of cancer cell lines is acutely sensitive to the Chk1 inhibitor MK-8776 as monotherapy due to CDK2 activation in S phase. AB - DNA damage activates Checkpoint kinase 1 (Chk1) to halt cell cycle progression thereby preventing further DNA replication and mitosis until the damage has been repaired. Consequently, Chk1 inhibitors have emerged as promising anticancer therapeutics in combination with DNA damaging drugs, but their single agent activity also provides a novel approach that may be particularly effective in a subset of patients. From analysis of a large panel of cell lines, we demonstrate that 15% are very sensitive to the Chk1 inhibitor MK-8776. Upon inhibition of Chk1, sensitive cells rapidly accumulate DNA double-strand breaks in S phase in a CDK2- and cyclin A-dependent manner. In contrast, resistant cells can continue to grow for at least 7 days despite continued inhibition of Chk1. Resistance can be circumvented by inhibiting Wee1 kinase and thereby directly activating CDK2. Hence, sensitivity to Chk1 inhibition is regulated upstream of CDK2 and correlates with accumulation of CDC25A. We conclude that cells poorly tolerate CDK2 activity in S phase and that a major function of Chk1 is to ensure it remains inactive. Indeed, inhibitors of CDK1 and CDK2 arrest cells in G1 or G2, respectively, but do not prevent progression through S phase demonstrating that neither kinase is required for S phase progression. Inappropriate activation of CDK2 in S phase underlies the sensitivity of a subset of cell lines to Chk1 inhibitors, and this may provide a novel therapeutic opportunity for appropriately stratified patients. PMID- 26595533 TI - Attentional effects on orientation judgements are dependent on memory consolidation processes. AB - Are the effects of memory and attention on perception synergistic, antagonistic, or independent? Tested separately, memory and attention have been shown to affect the accuracy of orientation judgements. When multiple stimuli are presented sequentially versus simultaneously, error variance is reduced. When a target is validly cued, precision is increased. What if they are manipulated together? We combined memory and attention manipulations in an orientation judgement task to answer this question. Two circular gratings were presented sequentially or simultaneously. On some trials a brief luminance cue preceded the stimuli. Participants were cued to report the orientation of one of the two gratings by rotating a response grating. We replicated the finding that error variance is reduced on sequential trials. Critically, we found interacting effects of memory and attention. Valid cueing reduced the median, absolute error only when two stimuli appeared together and improved it to the level of performance on uncued sequential trials, whereas invalid cueing always increased error. This effect was not mediated by cue predictiveness; however, predictive cues reduced the standard deviation of the error distribution, whereas nonpredictive cues reduced "guessing". Our results suggest that, when the demand on memory is greater than a single stimulus, attention is a bottom-up process that prioritizes stimuli for consolidation. Thus attention and memory are synergistic. PMID- 26595531 TI - Mass Spectrometry and Antibody-Based Characterization of Blood Vessels from Brachylophosaurus canadensis. AB - Structures similar to blood vessels in location, morphology, flexibility, and transparency have been recovered after demineralization of multiple dinosaur cortical bone fragments from multiple specimens, some of which are as old as 80 Ma. These structures were hypothesized to be either endogenous to the bone (i.e., of vascular origin) or the result of biofilm colonizing the empty osteonal network after degradation of original organic components. Here, we test the hypothesis that these structures are endogenous and thus retain proteins in common with extant archosaur blood vessels that can be detected with high resolution mass spectrometry and confirmed by immunofluorescence. Two lines of evidence support this hypothesis. First, peptide sequencing of Brachylophosaurus canadensis blood vessel extracts is consistent with peptides comprising extant archosaurian blood vessels and is not consistent with a bacterial, cellular slime mold, or fungal origin. Second, proteins identified by mass spectrometry can be localized to the tissues using antibodies specific to these proteins, validating their identity. Data are available via ProteomeXchange with identifier PXD001738. PMID- 26595534 TI - A Case of Rapid Eye Movement Sleep Behavior Disorder in Parkinson Disease Treated With Sodium Oxybate. PMID- 26595535 TI - Strategies to improve the understanding of long-term renal consequences after neonatal acute kidney injury. PMID- 26595536 TI - Inherited disorders of bilirubin clearance. AB - Inherited disorders of hyperbilirubinemia may be caused by increased bilirubin production or decreased bilirubin clearance. Reduced hepatic bilirubin clearance can be due to defective (i) unconjugated bilirubin uptake and intrahepatic storage, (ii) conjugation of glucuronic acid to bilirubin (e.g., Gilbert syndrome, Crigler-Najjar syndrome, Lucey-Driscoll syndrome, breast milk jaundice), (iii) bilirubin excretion into bile (Dubin-Johnson syndrome), or (iv) conjugated bilirubin re-uptake (Rotor syndrome). In this review, the molecular mechanisms and clinical manifestations of these conditions are described, as well as current approaches to diagnosis and therapy. PMID- 26595538 TI - Co-delivery of HIV-1 entry inhibitor and nonnucleoside reverse transcriptase inhibitor shuttled by nanoparticles: cocktail therapeutic strategy for antiviral therapy. AB - OBJECTIVES: Traditionally, the antiviral efficacy of classic cocktail therapy is significantly limited by the distinct pharmacokinetic profiles of partner therapeutics that lead to inconsistent in-vivo biodistribution. Here we developed a new cocktail-like drug delivery vehicle using biodegradable polymeric nanoparticles (NP) encapsulating nonnucleoside reverse transcriptase inhibitor (NNRTI) DAAN-14f (14f), surface-conjugated with HIV-1 fusion inhibitor T1144, designated T1144-NP-DAAN-14f (T1144-NP-14f), and aiming to achieve enhanced cellular uptake, improved antiviral activity and prolonged blood circulation time. METHODS: T1144-NP-14f was prepared through the emulsion/solvent evaporation technique and a maleimide-thiol coupling reaction. Particle size and morphology were determined by dynamic light scattering detection and transmission electron microscopy. Anti-HIV-1 activity was assessed by HIV-1 Env-mediated cell-cell fusion and infection by laboratory-adapted, primary, and resistant HIV-1 isolates, respectively. The in-vitro release of 14f was investigated using the equilibrium dialysis method, and the pharmacokinetic study of T1144-NP-14f was performed on Sprague-Dawley rats. RESULTS: T1144-NP-14f displayed a spherical shape under transmission electron microscopy observation and had a size of 117 +/ 19 nm. T1144-NP-14f exhibited the strongest antiviral activity against a broad spectrum of HIV-1 strains, including NNRTI-, T1144-, or T20-resistant isolates, respectively. Both in-vitro release and in-vivo pharmacokinetic profile showed that T1144-NP-14f exhibited a sustained controlled release behavior. CONCLUSION: Our results demonstrated that the combination of entry inhibitor with NNRTI encapsulated in nanoparticles (T1144-NP-14f) was highly effective in inhibiting HIV-1 infection. This new cocktail-like drug delivery platform could serve as an effective anti-HIV-1 regimen by taking advantage of the extrinsic and intrinsic antiviral activity of individual drugs. PMID- 26595539 TI - A strong association of human leukocyte antigen-associated Pol and Gag mutations with clinical parameters in HIV-1 subtype A/E infection. AB - OBJECTIVES: Identification of human leukocyte antigen-associated HIV-1 polymorphisms (HLA-APs) in different global populations furthers our understanding of HIV-1 pathogenesis and may help identify candidate immunogens for HIV vaccines targeted to these populations. Although numerous population based studies identifying HLA-APs have been conducted in HIV-1 subtype B- and subtype C-infected cohorts, few have focused on subtype A/E. DESIGN: We investigated HLA-APs in a cohort of chronically HIV-1 subtype A/E-infected Vietnamese individuals. METHODS: HLA-APs in HIV-1 Gag, Pol, and Nef regions from 388 treatment-naive individuals chronically infected with HIV-1 subtype A/E were analyzed using phylogenetically informed approaches. RESULTS: A total of 303 HLA APs were identified. HLA-APs occurring at six positions in Gag and six positions in Pol were significantly associated with higher plasma viral load (pVL), whereas HLA-APs occurring at two positions in Gag and 13 positions in Pol were significantly associated with lower CD4 T-cell counts. Furthermore, the proportion of Pol codons harboring an HLA-AP specific to the host's HLA correlated positively with HIV-1 pVL (R = 0.22; P < 0.0001) and inversely with CD4 T-cell counts (R = -0.32; P < 0.0001). Similarly, the proportion of HLA associated Gag codons harboring host-specific HLA-AP correlated inversely with CD4 T-cell counts (R = -0.13; P = 0.01). CONCLUSION: These significant associations between HIV-1 amino acids adapted to Vietnamese HLA alleles and higher pVL and lower CD4 T-cell counts suggests that accumulation of cytotoxic T cells escape mutations may influence clinical outcomes in HIV-1 subtype A/E infected Vietnamese individuals. PMID- 26595537 TI - Prospective immunotherapies in childhood sarcomas: PD1/PDL1 blockade in combination with tumor vaccines. AB - Progress has slowed substantially in improving survival rates for pediatric sarcomas, particularly in refractory and metastatic disease. Significant progress has been made in the field of tumor vaccines for such malignancies, which target established tumor antigens. While tumor vaccines have demonstrated safety and improved survival rates, they are inadequate in mediating the regression of established tumor masses and metastases. Programmed cell death ligand 1 (PDL1) is a cell-surface protein induced in a number of adult malignancies. By acting on the corresponding T-cell receptor PD1, PDL1 is able to suppress cytotoxic T-cell mediated tumor responses. Recent therapeutics blocking this interaction have shown promise in various adult cancers by restoring a functional T-cell response and by directing this response toward an activated, rather than regulatory, T cell phenotype. We shall discuss the current state of tumor vaccines targeting pediatric sarcomas, review PD1-PDL1 interactions and current therapies targeting these interactions in adult malignancies, and discuss recent studies in which tumor vaccines, combined with PDL1 blockades, produced superior tumor regression compared with the vaccine alone. These studies provide a compelling case for investigation of PDL1 expression and its inhibition in pediatric sarcomas, while continuing to utilize tumor vaccines in tandem to achieve superior clinical outcomes. PMID- 26595540 TI - A fully human antibody to gp41 selectively eliminates HIV-infected cells that transmigrated across a model human blood brain barrier. AB - OBJECTIVE: Many HIV patients on combined antiretroviral therapy exhibit HIV associated neurocognitive disorders because the brain becomes a viral reservoir. There is a need for therapeutics that can enter the central nervous system (CNS) and eradicate the virus. DESIGN: Radiolabeled human mAb 2556 to HIV gp41 selectively kills HIV-infected cells in vivo and in vitro. Here we tested the ability of 213Bi-2556 to cross a tissue culture model of the human blood brain barrier and kill HIV-infected peripheral blood mononuclear cells (PBMCs) and monocytes on the CNS side of the barrier. METHODS: 2556 mAb isoelectric point was determined with isoelectric focusing. The ability of radiolabeled 2556 to penetrate through the barrier was studied by adding it to the upper chamber of the barriers and its penetration into the CNS side was followed for 5 h. To assess the ability of Bi-2556 to kill the HIV-infected cells on the CNS side of barrier, the HIV-infected and uninfected PBMCs and monocytes were allowed to transmigrate across the barriers overnight followed by application of Bi-2556 or control mAb Bi-1418 to the top of the barrier. Killing of cells was measured by TUNEL and Trypan blue assays. The barriers were examined by confocal microscopy for overt damage. RESULTS: The isoelectric point of Bi-2556 was 9.6 enabling its penetration through the barrier by transcytosis. Bi-2556 killed significantly more transmigrated HIV-infected cells in comparison to Bi-1418 and uninfected cells. No overt damage to barriers was observed. CONCLUSION: We demonstrated that Bi-2556 mAb crossed an in-vitro human blood brain barrier and specifically killed transmigrated HIV-infected PBMCs and monocytes without overt damage to the barrier. PMID- 26595541 TI - HIV-1 transcriptional activity during frequent longitudinal sampling in aviremic patients on antiretroviral therapy. AB - BACKGROUND: HIV-1 transcription during suppressive antiretroviral therapy (ART) is not well understood. This is problematic as latency-reactivating agent-based HIV-1 eradication trials utilize changes in viral transcription as an efficacy biomarker. METHODS: We conducted an observational cohort study enrolling aviremic, HIV-1-infected adults on long-term ART. Cell-associated unspliced (CA US) HIV-1 RNA and total HIV-1 DNA were quantified in unfractionated CD4 T cells monthly for a total of six consecutive visits. Random-effects models were used to determine the following: (i) proportion of variation attributable to intra individual versus inter-individual changes; (ii) range estimate for random samples from any participant or cohort-matched individual (95% prediction interval); and (iii) range estimate for random samples from the same person (95% variation intervals expressed as fold change). RESULTS: Among our cohort of 26 HIV-1 patients, 10.4% of variation in CA-US HIV-1 RNA was attributable to intra individual fluctuations. Similarly, intra-individual changes also accounted for minor proportions of the variation in total HIV-1 DNA (5.1%) and RNA/DNA (28.3%). The 95% prediction interval (per 10 CD4 T cells) for CA-US HIV-1 RNA and HIV-1 DNA were each approximately 2 log10. Finally, model-derived 95% variation intervals indicate that spontaneous changes above 2.11-fold in CA-US HIV-1 RNA would occur in less than 5% of repeated measurements in an individual on long term ART. CONCLUSION: The individual CA-US HIV-1 RNA levels are remarkably stable during ART. Importantly, the observed variations were less than the reported changes for latency-reactivating agent trials. These data will serve as a foundation for planning and interpreting future eradication trials. PMID- 26595542 TI - Enhanced liver fibrosis marker as a noninvasive predictor of mortality in HIV/hepatitis C virus-coinfected women from a multicenter study of women with or at risk for HIV. AB - OBJECTIVE: Coinfection with hepatitis C virus (HCV) is a major cause of morbidity and mortality among individuals with HIV. Our objective was to assess the prognostic performance of noninvasive measures of liver fibrosis in predicting all-cause mortality in women with HIV/HCV coinfection. DESIGN: We studied HCV/HIV coinfected women enrolled in the prospective, multicenter Women's Interagency HIV Study. Aspartate aminotransferase to platelet ratio and FIB-4 were used to identify women without fibrosis at all visits and women who progressed to severe fibrosis. METHODS: Enhanced liver fibrosis (ELF), which utilizes direct measures of fibrosis, hyaluronic acid, procollagen III aminoterminal peptide and tissue inhibitor of matrix metalloproteinase was performed. RESULTS: Included were 381 women with 2296 ELF measurements, with mean follow-up 8.3 +/- 3.3 years. There were 134 deaths (60% with severe liver fibrosis). Receiver operator characteristic curves at fixed time windows prior to death or at end of follow-up showed that ELF was best at predicting mortality when tested within a year of death (area under the curve for ELF 0.85 vs. APRI 0.69, P < 0.0001 and vs. FIB-4 0.75, P = 0.0036); and 1-3 years prior (ELF 0.71 vs. APRI 0.61, P = 0.005 and vs. FIB-4 0.65, P = 0.06). Use of all three measures did not improve on ELF alone. In multivariate logistic regression models controlling for CD4 cell count, HIV viral load, antiretroviral use and age, ELF continued to perform better than APRI and FIB-4. CONCLUSION: ELF predicted all-cause mortality and was superior to APRI and FIB-4 in HIV/HCV coinfected women. PMID- 26595544 TI - Comment on: 'Resting mechanomyographic amplitude for the erector spinae and trapezius muscles following resistance exercise in a healthy population'. PMID- 26595543 TI - Impact of HIV-1 tropism on the emergence of non-AIDS events in HIV-infected patients receiving fully suppressive antiretroviral therapy. AB - OBJECTIVE: The impact of HIV-1 tropism on the emergence of non-AIDS events was evaluated in a cohort of 116 antiretroviral therapy (ART) responder patients. METHODS: The patients were followed for the emergence of hypertension, renal impairment, metabolic and bone disorders (defined as non-AIDS events) each 8 weeks at standard visits. A V3 plasma sequence genotype analysis was performed at the time of ART initiation and the geno2pheno algorithm with the results that defines the false-positive rate (FPR) was used to infer HIV tropism. The associations between the non-AIDS events and the FPR at baseline were evaluated using the chi test for trend. A Cox-regression analysis using the counting process formulation of Andersen and Gill was performed to define whether the emergence of non-AIDS events was correlated to FPR. RESULTS: The prevalence of at least one non-AIDS event resulted higher in patients with a FPR below 10% than in patients with a R5 virus (P = 0.033). Patients with a FPR below 5.0% most frequently developed non-AIDS events during ART (P = 0.01). A higher prevalence of patients with at least two AIDS events was found in the group of patients with a FPR below 5.0% with respect to the others (P < 0.001). At multivariate Cox regression analysis, having an X4 virus and age were independently associated with a higher probability of non-AIDS event development. CONCLUSION: This study shows that an X4 virus, particularly a FPR less than 5%, is related to non-AIDS events development. Further studies are warranted to understand the mechanisms underlying this phenomenon. PMID- 26595545 TI - Echophysiology: the transesophageal echo probe as a noninvasive Swan-Ganz catheter. AB - PURPOSE OF REVIEW: In an attempt to make cardiovascular monitoring less invasive and more effective, transesophageal echocardiography is progressively being used in critically ill patients suffering from hemodynamic instability. This review analyses the capacity of transesophageal echocardiography to fully replace the pulmonary artery catheter in the management of hemodynamic impairment, as transesophageal echocardiography similarly allows for the measurement of central venous pressure, pulmonary arterial pressure, pulmonary capillary wedge pressure, pulmonary vascular resistance, stroke volume and cardiac output, and systemic vascular resistance. RECENT FINDINGS: Recently, the accuracy and clinical applicability of transthoracic echocardiography to establish the entire hemodynamic profile in patients with decompensated heart failure has convincingly been demonstrated. Because many principles are similar in transthoracic and transesophageal echocardiography, it has been hypothesized that the latter modality is also qualified to quantitatively determine intracardiac hemodynamics, including pressure and flow. SUMMARY: Transesophageal echocardiography has the potential to offer a noninvasive, valid alternative to Swan-Ganz catheters in the hemodynamic assessment of patients in the perioperative period. PMID- 26595546 TI - Perioperative opioids aggravate obstructive breathing in sleep apnea syndrome: mechanisms and alternative anesthesia strategies. AB - PURPOSE OF REVIEW: Opioids induce and increase the severity of most sleep disordered breathing in all patients, but especially in morbidly obese patients. Discussed herein are the direct impact and mechanisms of opioids on inducing and exacerbating obstructive sleep apnea syndrome in normal and morbidly obese patients. RECENT FINDINGS: Respiratory depression is a larger problem than obstructive sleep apnea syndrome during the first night after an opioid anesthesia because of the reduced amount of deep sleep and rapid-eye-movement sleep. Acute tolerance to the analgesic effects of opioids can be observed after one anesthetic opioid dose, although tolerance to the side-effects of opioids develops more slowly. Therefore, it makes sense to avoid all opioids intraoperatively. A recently developed multimodal nonopioid anesthesia method may prevent development of acute tolerance and facilitate postoperative pain management with less opioids and sleep-disordered breathing. SUMMARY: A multimodal nonopioid anesthesia method avoids the necessity for intraoperative opioids, reduces the need for postoperative opioid use, and improves analgesia with less narcotic. PMID- 26595547 TI - Morbid obesity and perioperative complications. AB - PURPOSE OF REVIEW: Approximately 30% of the general surgical population presents with obesity, and the perioperative implications remain concerning. This review provides recent insights regarding morbid obesity and perioperative complications. RECENT FINDINGS: Cardiovascular risk including cardiac arrest and myocardial infarction varies by type of surgery and is not always correlated with BMI. Functional status rather than associated comorbidities is an important component for risk assessment of obese patients undergoing noncardiac surgery. Just as for cardiac complications, pulmonary outcomes are influenced by the concurrence of obesity and the metabolic syndrome and/or sleep apnea rather than by BMI alone. New evidence suggests that continuous positive airway pressure treatment before surgery may reduce postoperative complications. Clinical Practice Guidelines for thromboembolic prophylaxis in bariatric patients are available. A comprehensive understanding of the obesity survival paradox has remained elusive. Postoperative surgical infections remain a leading problem related to obesity. SUMMARY: Further research and evidence are needed for the development of accepted perioperative pathways to address obesity and related comorbidities including sleep disordered breathing and metabolic syndrome as well as evidence-based strategies to reduce surgical infections. Rather than BMI alone, an improved index for obesity risk assessment is needed. PMID- 26595548 TI - Fixed ratio versus goal-directed therapy in trauma. AB - PURPOSE OF REVIEW: This article compares the strategy of a fixed transfusion ratio of plasma and platelet concentrates to red blood cells to reconstitute 'whole blood' with the concept of individualized goal-directed coagulation therapy (GDCT). RECENT FINDINGS: Current data suggest that an early and high ratio of plasma and platelet concentrate transfusion, predominantly in a fixed 1 : 1 : 1 ratio with red blood cells, is associated with improved outcome. However, the optimal ratio is still under discussion. Moreover, storage time considerably affects the hemostatic competence of these products and no universal standard for the composition of these 'transfusion packages' has been established. Some European trauma centers instituted the concept of GDCT in trauma patients, which is based on early diagnosis of the coagulation deficit using point-of-care viscoelastic tests (VETs). These tests provide rapid information about the underlying hemostatic deficiencies, allowing targeted coagulation therapy according to the individual deficits of the patient. Treatment algorithms have been established for the administration of coagulation factor concentrates, and plasma and platelet concentrate based on VET results. SUMMARY: Individualized GDCT, guided by VET, offers several advantages over fixed ratio coagulation therapy. Studies comparing both hemostatic strategies are warranted. PMID- 26595549 TI - Assessing Colonic Exposure, Safety, and Clinical Activity of SRT2104, a Novel Oral SIRT1 Activator, in Patients with Mild to Moderate Ulcerative Colitis. AB - BACKGROUND: Sirtuins are a class of proteins with important physiologic roles in metabolism and inflammation. Sirtuin (silent mating type information regulation 2 homolog) 1, or SIRT1, activation is an unexplored therapeutic approach for the treatment of ulcerative colitis (UC). METHODS: Patients with mild to moderately active UC were blindly randomized to 50 mg or 500 mg daily of SRT2104, a selective activator of SIRT1, for 8 weeks. Colonic exposure and safety were assessed, as well as blinded endoscopic scoring and disease activity by Mayo score, Simple Clinical Colitis Activity Index and fecal calprotectin. RESULTS: Across both SRT2104 groups, only 3 of 26 evaluable subjects achieved remission on blinded endoscopic assessment. Clinical remission (Mayo score <=2, no subscore >1) was achieved in 4 patients (2 of 13 evaluable patients in each dose group). Fecal calprotectin levels declined with treatment in both groups, but after 56 days of treatment subjects were still found to have levels approximately 4-fold elevated above normal. One subject experienced an SAE requiring study withdrawal and another was withdrawn for a severe UC flare; 19 subjects (61%) across both treatment groups experienced at least 1 treatment emergent adverse event. Average drug exposure increased in a dose-dependent manner for escalating doses of SRT2104, and colonic exposure was 140 to 160 times higher than plasma exposures. CONCLUSIONS: SRT2104 did not demonstrate significant clinical activity in mild to moderately active UC. This suggests that further evaluation of SRT2104 as a therapeutic strategy for the treatment of UC is not warranted. PMID- 26595550 TI - Changes in the Abundance of Faecalibacterium prausnitzii Phylogroups I and II in the Intestinal Mucosa of Inflammatory Bowel Disease and Patients with Colorectal Cancer. AB - BACKGROUND: Faecalibacterium prausnitzii comprises 2 phylogroups, whose abundance in healthy and diseased gut and in conjunction with Escherichia coli has not yet been studied. This work aims to determine the contribution of F. prausnitzii phylogroups I and II in intestinal disease and to assess their potential diagnostic usefulness as biomarkers for gut diseases. METHODS: Total F. prausnitzii, its phylogroups, and E. coli loads were determined by quantitative polymerase chain reaction targeting the 16S rRNA gene on biopsies from 31 healthy controls (H), 45 patients with Crohn's disease (CD), 25 patients with ulcerative colitis, 10 patients with irritable bowel syndrome, and 20 patients with colorectal cancer. Data were normalized to total bacterial counts and analyzed according to patients' disease location and clinical characteristics. RESULTS: Lower levels of both total F. prausnitzii and phylogroup I were found in subjects with CD, ulcerative colitis, and colorectal cancer (P < 0.001) compared with H subjects. Phylogroup I load was a better biomarker than total F. prausnitzii to discriminate subjects with gut disorders from H. Phylogroup II depletion was observed only in patients with CD (P < 0.001) and can be potentially applied to differentiate ulcerative pancolitis from colonic CD. No statistically significant correlation between E. coli and any of the 2 F. prausnitzii phylogroups was found in any group of patients or by inflammatory bowel disease location. Phylogroup I was lower in active patients with CD, whereas those CD with intestinal resection showed a reduction in phylogroup II. Treatments with mesalazine and immunosuppressants did not result in the recovery of F. prausnitzii phylogroups abundance. CONCLUSIONS: F. prausnitzii phylogroup I was depleted in CD, ulcerative colitis, and colorectal cancer, whereas phylogroup II was specifically reduced in CD. Quantification of F. prausnitzii phylogroups and E. coli may help to identify gut disorders and to classify inflammatory bowel disease location. PMID- 26595551 TI - Immunogenicity of Influenza Vaccine for Patients with Inflammatory Bowel Disease on Maintenance Infliximab Therapy: A Randomized Trial. AB - BACKGROUND: In patients with inflammatory bowel disease (IBD) on infliximab, data are limited on immune response to influenza vaccine and the impact of vaccine timing. The study aims were to evaluate immune responses to the influenza vaccine in IBD patients on infliximab and the impact of vaccine timing on immune responses. METHODS: In this randomized study, 137 subjects with IBD on maintenance infliximab therapy were allocated to receive the 2012/2013 inactivated influenza vaccine at the time of infliximab infusion (n = 69) or midway between infusions (n = 68). Serum was collected before and after vaccination for hemagglutination inhibition titers. Serologic protection was defined by postvaccine titer of >=1:40. RESULTS: Comparing subjects vaccinated at the time of infliximab with those vaccinated midway, serologic protection was achieved in 67% versus 66% to H1N1 (P = 0.8), in 43% versus 49% to H3N2 (P = 0.5), and in 69% versus 79% to influenza B (P = 0.2). Although solicited adverse events were common (60%), no subject experienced a serious adverse event requiring additional medical attention. Only 6% of subjects had a clinically significant increase in disease activity score, not impacted by vaccine timing. CONCLUSIONS: Serologic protection to influenza vaccine is achieved in only approximately 45% to 80% of IBD patients on maintenance infliximab therapy varying by antigen. Yet, importantly, vaccine timing relative to infliximab infusion does not affect the achievement of serologic protection, and the influenza vaccine is well tolerated. Therefore, influenza vaccination at any point during infliximab scheduling is recommended for patients with IBD and opportunities to broaden the availability and convenience of influenza vaccine to optimize coverage should be explored. PMID- 26595552 TI - Nonbloody Diarrhea but Not Significant Weight Loss at Diagnosis Is Associated with the Development of Denovo Crohn's Disease After Ileal Pouch-anal Anastomosis for Ulcerative Colitis. AB - BACKGROUND: Denovo Crohn's disease (CD) develops in 5% to 10% of patients after ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC) leading to increased morbidity and rates of pouch failure. Initial nonbloody diarrhea and weight loss at diagnosis are independent risk factors for a change in diagnosis from UC to CD in nonsurgical patients. We investigated whether these features were risk factors for denovo CD in a longitudinal cohort of patients with UC undergoing IPAA. METHODS: Prospective profiles of patients with UC undergoing IPAA followed over a 22-year period by 1 surgeon were analyzed. Denovo CD was diagnosed when mucosal inflammation (5 or more ulcers) involved the small bowel mucosa proximal to the ileal pouch any time after surgery and/or when a pouch fistula or other perianal complication developed more than 3 months after ileostomy closure. Patients with inflammatory bowel disease unclassified, acute pouchitis, chronic pouchitis, and those lost to follow-up were excluded from analysis. Cox regression analysis was performed for statistical significance. RESULTS: Of the 199 study patients included in the analysis, denovo CD developed in 42 patients (21%). Patients who developed denovo CD had an increased incidence of nonbloody diarrhea (n = 12; 29%) compared with patients who had no evidence of pouch inflammation (n = 25; 16%) (P = 0.03). In contrast, the incidence of weight loss was not significantly increased in patients with denovo CD (n = 7; 17%) compared with patients who never had pouch inflammation (n = 16; 10%) (P = 0.12). CONCLUSIONS: Initial nonbloody diarrhea is associated with denovo CD after IPAA. This association warrants close consideration before surgery. PMID- 26595553 TI - Genome-Wide Copy Number Variation Scan Identifies Complement Component C4 as Novel Susceptibility Gene for Crohn's Disease. AB - BACKGROUND: The genetic component of Crohn's disease (CD) is well known, with 140 susceptibility loci identified so far. In addition to single nucleotide polymorphisms typically studied in genome-wide scans, copy number variation is responsible for a large proportion of human genetic variation. METHODS: We performed a genome-wide search for copy number variants associated with CD using array comparative genomic hybridization. One of the found regions was validated independently through real-time PCR. Serum levels of the found gene were measured in patients and control subjects. RESULTS: We found copy number differences for the C4S and C4L gene variants of complement component C4 in the central major histocompatibility complex region on chromosome 6p21. Specifically, we saw that CD patients tend to have lower C4L and higher C4S copies than control subjects (P = 5.00 * 10 and P = 9.11 * 10), which was independent of known associated classical HLA I and II alleles (P = 7.68 * 10 and P = 6.29 * 10). Although C4 serum levels were not different between patients and control subjects, the relationship between C4 copy number and serum level was different for patients and control subjects with higher copy numbers leading to higher serum concentrations in control subjects, compared with CD patients (P < 0.001). CONCLUSIONS: C4 is part of the classical activation pathway of the complement system, which is important for (auto)immunity. Low C4L or high C4S copy number, and corresponding effects on C4 serum level, could lead to an exaggerated response against infections, possibly leading to (auto)immune disease. PMID- 26595554 TI - Understanding Health Literacy and its Impact on Delivering Care to Patients with Inflammatory Bowel Disease. AB - Health literacy (HL) is the extent to which individuals have the capacity to obtain, process, and understand basic health information that is needed to make appropriate health decisions. As adults with inflammatory bowel disease engage in complex health decisions throughout their lives, attention is needed regarding the influence of HL on the lives of people with inflammatory bowel disease. About one-third of adults in the United States have limited HL. Limited HL is a potentially modifiable risk factor that has been associated with barriers to patient-provider communication and worse health outcomes for people with a range of chronic diseases. Gastroenterologists must recognize the role of HL in their practice. Limited HL can affect a patient's ability to understand the purpose of a screening test for colorectal cancer, understand the concept of an asymptomatic yet chronic disease, ask questions in an office visit and engage in shared decision making. Gastroenterologists must approach each patient as potentially having limited HL and use clear communication strategies in all encounters. Currently, there is a lack of training, education, and support for health care providers to meet the needs of patients with limited HL. More research is needed in inflammatory bowel disease to understand the impact of limited health literacy on health outcomes in this population and develop effective systems-based interventions to reduce the health literacy burden on patients. PMID- 26595555 TI - Reply to: Food Additives Should Not be Ruled Out as the Possible Causative Factors of Inflammatory Bowel Disease in Korea. PMID- 26595556 TI - Exosomes Released from Cells Infected with Crohn's Disease-associated Adherent Invasive Escherichia coli Activate Host Innate Immune Responses and Enhance Bacterial Intracellular Replication. AB - BACKGROUND: Crohn's disease is a chronic inflammatory bowel disease, of which the etiology involves environmental, genetic, and microbial factors. A high prevalence of adherent-invasive Escherichia coli, named AIEC, has been reported in the intestinal mucosa of patients with Crohn's disease. Exosomes are extracellular vesicles that function in intercellular communication and have been implicated in host responses to intracellular pathogens. We investigated the potential involvement of exosomes in host response to AIEC infection. METHODS: Human intestinal epithelial T84 cells, THP-1 macrophages, and CEABAC10 transgenic mice were infected with the AIEC reference strain LF82 or the nonpathogenic E. coli K-12 MG1655 strain. Exosomes were purified using the ExoQuick reagent. RESULTS: LF82 infection induced the release of exosomes by T84 and THP-1 cells. Compared with exosomes released from the uninfected or MG1655-infected T84 cells, those released from LF82-infected cells activated nuclear factor-kappa B, mitogen activated protein kinases p38, and c-Jun N-terminal kinase and increased the secretion of proinflammatory cytokines in naive THP-1 macrophages. LF82 infection of THP-1 macrophages also induced the release of exosomes that triggered a proinflammatory response in recipient THP-1 cells. Importantly, stimulation of T84 or THP-1 cells with exosomes released from LF82-infected cells increased LF82 intracellular replication compared with stimulation with exosomes secreted by uninfected cells. Exosomes purified from intestinal lumen of CEABAC10 transgenic mice infected with LF82 increased proinflammatory responses in murine RAW 264.7 macrophages compared with those from uninfected or MG1655-infected mice. CONCLUSIONS: Exosomes are new mediators of host-AIEC interaction with their capacity to activate innate immune responses and subvert the control of AIEC replication. PMID- 26595557 TI - Photosensitivity to Ultraviolet Light in Patients with Inflammatory Bowel Disease Newly Initiating Immunosuppressive Therapy. PMID- 26595558 TI - Role of Vitamin D in Infliximab-induced Remission in Adult Patients with Crohn's Disease. PMID- 26595559 TI - Biased Perception of Mean Emotion in Abstinent Heroin Abusers. AB - Although evidence suggests that drug abusers exhibit biases when coding individual emotional facial expressions, little is known about how they process multiple expressions simultaneously. The present study evaluated the mean emotions perceived by abstinent heroin abusers. Male abstinent heroin abusers (AHs) and healthy controls (HCs) were randomly assigned into three emotional conditions (happy, sad, or angry), viewed sets of four faces (Experiment 1) or individual faces (Experiment 2) that varied in emotionality (neutral to happy/sad/angry), and judged whether a test face presented later was more/less emotional than the preceding stimuli. Average points of subjective equality were calculated to reflect participants' biases in perceiving emotions of sets or single faces. Relative to HCs, AHs overestimated mean emotions for sad and angry faces in Experiment 1; however, no such biases were found in Experiment 2. This suggests biased ensemble coding towards negative emotional facial expressions in AHs. Furthermore, when controlling for depression and anxiety, AHs' enhanced perception of mean emotion for angry or sad faces in Experiment 1 decreased, indicating a possible mediating effect of these psychopathological variables in the relationship between drug addiction history and abnormal ensemble processing for sets of emotional expressions. PMID- 26595560 TI - Sofosbuvir plus ledipasvir in combination for the treatment of hepatitis C infection. AB - Sofsobuvir is the first-in-class NS5B nucleotide inhibitor to be launched as a treatment for the hepatitis C virus (HCV). Its viral potency, pan genotypic activity and high barrier to resistance make it the ideal candidate to become a backbone for several IFN-free regimens. Ledipasvir is a NS5A inhibitor with multi genotypic activity but modest barrier to resistance. The once-daily fixed-dose combination of sofosbuvir plus ledipasvir is the first-in-market single-tablet regimen for the treatment of hepatitis C infection. Recent data demonstrated that this FDC alone, or in combination with ribavirin, is able to achieve HCV cure of at least 90% or more among genotype 1,4, 5 and 6 patients. This combination appears to be suboptimal in genotype 3 patients and other direct acting antiviral combinations with sofosbuvir will help to fulfill this gap in the near future. The safety profile of the fixed dose combination is good. Resistance is not an issue with sofosbuvir but may be a significant issue with regards to ledipasvir for those rare individuals who harbor baseline HCV NS5A resistance-associated variants that conferred a high resistance level. The rational for using FDCs and the available clinical data are reviewed. PMID- 26595561 TI - Association of the U.S. Food and Drug Administration Morcellation Warning With Rates of Minimally Invasive Hysterectomy and Myomectomy. AB - OBJECTIVE: To evaluate whether there was a change in surgical practice immediately after the U.S. Food and Drug Administration (FDA) warning statement discouraging the use of power morcellation in the surgical treatment of uterine leiomyomas. METHODS: We performed a time-series analysis. Surgical case logs from the Florida Hospital operating room documentation system were used to retrospectively identify patients who underwent a hysterectomy or myomectomy between August 1, 2013, and December 31, 2014. Cases performed during the 8 months before the FDA announcement on April 17, 2014, were compared with cases performed during the 8 months after the FDA announcement. Six hospitals and 98 surgeons were included. We compared the proportion of minimally invasive surgery cases (vaginal, laparoscopic, or robotic-assisted) for each study period. RESULTS: There was a 5.8% decrease in minimally invasive hysterectomies after the FDA warning statement (85.7% [1,451/1,694] compared with 79.9% [1,350/1,690]; P<.001) and an 8.7% decrease when oncologist cases were excluded (90.2% [985/1,092] compared with 81.5% [834/1,023]; P<.001). There was a 19% decrease in minimally invasive myomectomies (62.7% [64/102] compared with 43.7% [38/87]; P=.009). Analysis by subspecialty showed a significant decrease in minimally invasive hysterectomies by obstetrician-gynecologists (ob-gyns) and minimally invasive gynecologic specialists but not urogynecologists or oncologists and a significant decrease in minimally invasive myomectomies by reproductive endocrinologists and minimally invasive gynecologic specialists but not ob-gyns. CONCLUSION: There was a significant decrease in the proportion of minimally invasive hysterectomies and myomectomies performed during the 8 months after the FDA warning statement on the use of power morcellation. LEVEL OF EVIDENCE: II. PMID- 26595562 TI - Bowel Injury in Gynecologic Laparoscopy: A Systematic Review. PMID- 26595563 TI - In Reply. PMID- 26595564 TI - Management of Persistent Postpartum Hemorrhage Caused by Inner Myometrial Lacerations. PMID- 26595565 TI - In Reply. PMID- 26595566 TI - Four Residents' Narratives on Abortion Training: A Residency Climate of Reflection, Support, and Mutual Respect. PMID- 26595567 TI - In Reply. PMID- 26595568 TI - Four Residents' Narratives on Abortion Training: A Residency Climate of Reflection, Support, and Mutual Respect. PMID- 26595569 TI - Adverse Outcomes and Potential Targets for Intervention in Gestational Diabetes and Obesity. PMID- 26595570 TI - In Reply. PMID- 26595571 TI - The Anachronistic Terminology of Gestational Hypertension: Time for a Change. PMID- 26595572 TI - In Reply. PMID- 26595578 TI - Committee Opinion No. 648 Summary: Umbilical Cord Blood Banking. AB - Once considered a waste product that was discarded with the placenta, umbilical cord blood is now known to contain potentially life-saving hematopoietic stem cells. When used in hematopoietic stem cell transplantation, umbilical cord blood offers several distinct advantages over bone marrow or peripheral stem cells. However, umbilical cord blood collection is not part of routine obstetric care and is not medically indicated. Umbilical cord blood collection should not compromise obstetric or neonatal care or alter routine practice for the timing of umbilical cord clamping. If a patient requests information on umbilical cord blood banking, balanced and accurate information regarding the advantages and disadvantages of public and private umbilical cord blood banking should be provided. The routine storage of umbilical cord blood as "biologic insurance" against future disease is not recommended. PMID- 26595579 TI - Committee Opinion No. 649 Summary: Racial and Ethnic Disparities in Obstetrics and Gynecology. AB - Projections suggest that people of color will represent most of the U.S. population by 2050, and yet significant racial and ethnic disparities persist in women's health and health care. Although socioeconomic status accounts for some of these disparities, factors at the patient, practitioner, and health care system levels contribute to existing and evolving disparities in women's health outcomes. The American College of Obstetricians and Gynecologists is committed to the elimination of racial and ethnic disparities in the health and health care of women and encourages obstetrician-gynecologists and other health care providers to engage in activities to help achieve this goal. PMID- 26595580 TI - Committee Opinion No. 650 Summary: Physical Activity and Exercise During Pregnancy and the Postpartum Period. AB - Physical activity in all stages of life maintains and improves cardiorespiratory fitness, reduces the risk of obesity and associated comorbidities, and results in greater longevity. Physical activity in pregnancy has minimal risks and has been shown to benefit most women, although some modification to exercise routines may be necessary because of normal anatomic and physiologic changes and fetal requirements. Women with uncomplicated pregnancies should be encouraged to engage in aerobic and strength-conditioning exercises before, during, and after pregnancy. Obstetrician-gynecologists and other obstetric care providers should carefully evaluate women with medical or obstetric complications before making recommendations on physical activity participation during pregnancy. Although frequently prescribed, bed rest is only rarely indicated and, in most cases, allowing ambulation should be considered. Regular physical activity during pregnancy improves or maintains physical fitness, helps with weight management, reduces the risk of gestational diabetes in obese women, and enhances psychologic well-being. An exercise program that leads to an eventual goal of moderate intensity exercise for at least 20-30 minutes per day on most or all days of the week should be developed with the patient and adjusted as medically indicated. Additional research is needed to study the effects of exercise on pregnancy specific outcomes and to clarify the most effective behavioral counseling methods, and the optimal intensity and frequency of exercise. Similar work is needed to create an improved evidence base concerning the effects of occupational physical activity on maternal-fetal health. PMID- 26595581 TI - Committee Opinion No. 651 Summary: Menstruation in Girls and Adolescents: Using the Menstrual Cycle as a Vital Sign. AB - Despite variations worldwide and within the U.S. population, median age at menarche has remained relatively stable-between 12 years and 13 years-across well nourished populations in developed countries. Environmental factors, including socioeconomic conditions, nutrition, and access to preventive health care, may influence the timing and progression of puberty. A number of medical conditions can cause abnormal uterine bleeding, characterized by unpredictable timing and variable amount of flow. Clinicians should educate girls and their caretakers (eg, parents or guardians) about what to expect of a first menstrual period and the range for normal cycle length of subsequent menses. Identification of abnormal menstrual patterns in adolescence may improve early identification of potential health concerns for adulthood. It is important for clinicians to have an understanding of the menstrual patterns of adolescent girls, the ability to differentiate between normal and abnormal menstruation, and the skill to know how to evaluate the adolescent girl patient. By including an evaluation of the menstrual cycle as an additional vital sign, clinicians reinforce its importance in assessing overall health status for patients and caretakers. PMID- 26595582 TI - ACOG Practice Bulletin No 156: Obesity in Pregnancy. PMID- 26595583 TI - ACOG Committee Opinion No. 648: Umbilical Cord Blood Banking. AB - Once considered a waste product that was discarded with the placenta, umbilical cord blood is now known to contain potentially life-saving hematopoietic stem cells. When used in hematopoietic stem cell transplantation, umbilical cord blood offers several distinct advantages over bone marrow or peripheral stem cells. However, umbilical cord blood collection is not part of routine obstetric care and is not medically indicated. Umbilical cord blood collection should not compromise obstetric or neonatal care or alter routine practice for the timing of umbilical cord clamping. If a patient requests information on umbilical cord blood banking, balanced and accurate information regarding the advantages and disadvantages of public and private umbilical cord blood banking should be provided. The routine storage of umbilical cord blood as "biologic insurance" against future disease is not recommended. PMID- 26595584 TI - ACOG Committee Opinion No. 649: Racial and Ethnic Disparities in Obstetrics and Gynecology. AB - Projections suggest that people of color will represent most of the U.S. population by 2050, and yet significant racial and ethnic disparities persist in women's health and health care. Although socioeconomic status accounts for some of these disparities, factors at the patient, practitioner, and health care system levels contribute to existing and evolving disparities in women's health outcomes. The American College of Obstetricians and Gynecologists is committed to the elimination of racial and ethnic disparities in the health and health care of women and encourages obstetrician-gynecologists and other health care providers to engage in activities to help achieve this goal. PMID- 26595585 TI - ACOG Committee Opinion No. 650: Physical Activity and Exercise During Pregnancy and the Postpartum Period. AB - Physical activity in all stages of life maintains and improves cardiorespiratory fitness, reduces the risk of obesity and associated comorbidities, and results in greater longevity. Physical activity in pregnancy has minimal risks and has been shown to benefit most women, although some modification to exercise routines may be necessary because of normal anatomic and physiologic changes and fetal requirements. Women with uncomplicated pregnancies should be encouraged to engage in aerobic and strength-conditioning exercises before, during, and after pregnancy. Obstetrician-gynecologists and other obstetric care providers should carefully evaluate women with medical or obstetric complications before making recommendations on physical activity participation during pregnancy. Although frequently prescribed, bed rest is only rarely indicated and, in most cases, allowing ambulation should be considered. Regular physical activity during pregnancy improves or maintains physical fitness, helps with weight management, reduces the risk of gestational diabetes in obese women, and enhances psychologic well-being. An exercise program that leads to an eventual goal of moderate intensity exercise for at least 20-30 minutes per day on most or all days of the week should be developed with the patient and adjusted as medically indicated. Additional research is needed to study the effects of exercise on pregnancy specific outcomes and to clarify the most effective behavioral counseling methods, and the optimal intensity and frequency of exercise. Similar work is needed to create an improved evidence base concerning the effects of occupational physical activity on maternal-fetal health. PMID- 26595586 TI - ACOG Committee Opinion No. 651: Menstruation in Girls and Adolescents: Using the Menstrual Cycle as a Vital Sign. AB - Despite variations worldwide and within the U.S. population, median age at menarche has remained relatively stable-between 12 years and 13 years-across well nourished populations in developed countries. Environmental factors, including socioeconomic conditions, nutrition, and access to preventive health care, may influence the timing and progression of puberty. A number of medical conditions can cause abnormal uterine bleeding, characterized by unpredictable timing and variable amount of flow. Clinicians should educate girls and their caretakers (eg, parents or guardians) about what to expect of a first menstrual period and the range for normal cycle length of subsequent menses. Identification of abnormal menstrual patterns in adolescence may improve early identification of potential health concerns for adulthood. It is important for clinicians to have an understanding of the menstrual patterns of adolescent girls, the ability to differentiate between normal and abnormal menstruation, and the skill to know how to evaluate the adolescent girl patient. By including an evaluation of the menstrual cycle as an additional vital sign, clinicians reinforce its importance in assessing overall health status for patients and caretakers. PMID- 26595587 TI - Computational Examination of (4 + 3) versus (3 + 2) Cycloaddition in the Interception of Nazarov Reactions of Allenyl Vinyl Ketones by Dienes. AB - A computational examination of the tandem Nazarov/cycloaddition process involving an allenyl vinyl ketone with a diene has been carried out using the omegaB97X-D/6 311++G(d,p)//omegaB97X-D/6-31+G(d,p) method with solvation modeled by SMD-PCM. The barrier for the initial Lewis acid mediated Nazarov reaction, which provided the intermediate cyclic oxylallyl cation, was higher than that for any subsequent cycloaddition. The barrier for the first step of a subsequent stepwise reaction did not vary much with the diene, and the lowest barrier was with the diene in its s-trans conformation. Stepwise formation of a (4 + 3) cycloaddition product was not energetically feasible, but (3 + 2) cycloaddition products could have been produced through low energy pathways. The barrier for a concerted (4 + 3) cycloaddition did depend upon the diene, which was always in an s-cis geometry. The barriers for the compact and the extended geometries for the transition states of (4 + 3) cycloadditions were not much different. PMID- 26595588 TI - Direct and indirect effects of commitment on interdependence and satisfaction in married couples. AB - This study tested the prediction that an individual's marital commitment would be positively associated with their own and their partner's marital satisfaction, and that one's own marital interdependence would be associated with one's own marital satisfaction. It also tested the prediction that there would be an indirect effect of marital commitment on marital satisfaction through higher marital interdependence for both the individual and the partner. Predictions were tested on 628 married couples. Overall, results were consistent with predictions. Tests of actor-partner interdependence mediation models revealed direct effects of marital commitment on marital satisfaction for both husbands and wives. Wives' commitment was also directly associated with husbands' marital interdependence and marital satisfaction, but husbands' commitment was not significantly associated with wives' interdependence or satisfaction. For both husbands and wives, their own marital interdependence was significantly associated with their own marital satisfaction. These same tests revealed indirect effects of marital commitment on marital satisfaction through higher marital interdependence for both husbands and wives individually. There was also an indirect effect of wives' commitment on husbands' marital satisfaction through wives' higher marital interdependence. These results are consistent with interdependence theory and the investment model of commitment. PMID- 26595589 TI - Asthma: Hospitalization Trends and Predictors of In-Hospital Mortality and Hospitalization Costs in the USA (2001-2010). AB - BACKGROUND: In the last decade, the proportion of people with asthma in the USA grew by nearly 15%, with 479,300 hospitalizations and 1.9 million emergency department visits in 2009 alone. The primary objective of our study was to evaluate in-hospital outcomes in patients admitted with asthma exacerbation in terms of mortality, length of stay (LOS) and hospitalization costs. METHODS: We queried the HCUP's Nationwide Inpatient Sample (NIS) between 2001 and 2010 using the ICD9-CM diagnosis code 493 for asthma (n = 760,418 patients). The NIS represents 20% of all hospitals in the USA. Multivariate logistic regression analysis was used to evaluate predictors of in-hospital mortality. LOS and hospitalization costs were also analyzed. RESULTS: The overall LOS was 3.9 days and as high as 8.3 days in patients requiring mechanical ventilation. LOS has decreased in recent years, though it continues to be higher than in 2001. The hospitalization cost increased steadily over the study period. The overall in hospital mortality was 1% and as high as 9.8% in patients requiring mechanical ventilation. Multivariate predictors of longer LOS, higher hospitalization costs and in-hospital mortality included increasing age and hospitalizations during the winter months. Private insurance was predictive of lower hospitalization costs and LOS as well as lower in-hospital mortality. CONCLUSION: Asthma continues to account for significant in-hospital mortality and resource utilization, especially in mechanically ventilated patients. Age, admissions during winter months and the type of insurance are independent predictors of in-hospital outcomes. PMID- 26595590 TI - Management and Outcome of Mucosal Injury During Pyloromyotomy--An Analytical Survey Study. AB - BACKGROUND: Different approaches of dealing with mucosal injury during pyloromyotomy for hypertrophic pyloric stenosis have been described. There is, however, no consensus on the best technique to use. We conducted a survey among International Pediatric Endosurgery Group (IPEG) members on their experience of mucosal injuries during pyloromyotomy, the way in which these were handled, any modification in subsequent postoperative care, and impact on outcome. MATERIALS AND METHODS: A confidential survey was sent to IPEG members querying demographic data, number of pyloromyotomies performed, operative approach, incidence of mucosal injury, intraoperative management, and postoperative consequences. Statistical analysis was performed to determine factors associated with complications and outcome. RESULTS: In total, 231 mucosa injuries were included in the study. Of these, 93% were noticed intraoperatively. Cases were nearly equally distributed between laparoscopic (49%) and open (51%) procedures, and the risk of mucosal injuries was no different between the two. Most surgeons addressed mucosal perforation with primary mucosal repair (70%), whereas a minority (27%) performed full-thickness closure, rotation, and repyloromyotomy in a different quadrant. Common alterations in management included delay in feeding (84%), longer hospital stay (30%), and contrast study before feeding (12%). The vast majority of patients had no adverse sequelae after a mucosal injury (96%), but three patients underwent re-operation. No correlations were found between repair method and complications. CONCLUSIONS: Mucosal injuries that are noticed and addressed intraoperatively resulted in few complications, regardless of the repair method. Among the queried surgeons, primary mucosal repair is the current standard of care. Primary mucosal repair is equivalent to full-thickness closure in terms of complications and outcome. PMID- 26595591 TI - Snacking Behavior and Obesity among Female Adolescents in Isfahan, Iran. AB - BACKGROUND AND OBJECTIVE: The high prevalence of obesity in the pediatric age groups draws attention to lifestyle factors including diet and physical activity. Data on obesity in adolescents and their snacking behavior are conflicting. This study aimed to assess the association of snacking behavior and obesity among female adolescents in Isfahan, Iran. SUBJECTS AND DESIGN: This cross-sectional study was carried out on 265 female Isfahanian students who were chosen by systematic cluster random sampling. Dietary intake was assessed using a validated self-administered semiquantitative food frequency questionnaire that included 53 food items. Snacking behavior was defined by healthy snack score in combination with the frequency of snack intake. RESULTS: Individuals who consumed more healthy snacks and those with snacking frequency of 4 times a day or more had significantly lower weight, body mass index (BMI), and waist circumference (p < 0.001). Decreased consumption of healthy snacks was significantly associated with a greater chance of being overweight, generally obese, and abdominally obese among adolescents (odds ratio [OR] = 1.98; 95% confidence interval [CI], 1.00 3.14, ptrend = 0.04 and OR = 2.10; 95% CI, 1.01-3.13, ptrend = 0.04, respectively). Frequency of snack intake was inversely related to overweight, general obesity, and abdominal obesity (OR = 3.23; 95% CI, 1.73-5.61, ptrend = 0.03 and OR = 1.84; 95% CI, 1.05-3.20, ptrend = 0.04, respectively). Healthy snack score in combination with frequency of snacking showed that those in the lowest tertile of snacking who consumed snacks less than 4 times/day had the highest risk of obesity compared to other categories (OR = 2.09, 95% CI, 1.11 3.20, p < 0.001). CONCLUSION: More frequent consumption of healthy snacks is associated with decreased prevalence of overweight, general obesity, and abdominal obesity in adolescents. Further studies, in particular of a prospective nature, are required to examine this association in other populations. PMID- 26595592 TI - Making Food Protein Gels via an Arrested Spinodal Decomposition. AB - We report an investigation of the structural and dynamic properties of mixtures of food colloid casein micelles and low molecular weight poly(ethylene oxide). A combination of visual observations, confocal laser scanning microscopy, diffusing wave spectroscopy, and oscillatory shear rheometry is used to characterize the state diagram of the mixtures and describe the structural and dynamic properties of the resulting fluid and solid-like structures. We demonstrate the formation of gel-like structures through an arrested spinodal decomposition mechanism. We discuss our observations in view of previous experimental and theoretical studies with synthetic and food colloids, and comment on the potential of such a route toward gels for food processing. PMID- 26595593 TI - Ganz Surgical Dislocation of the Hip Is a Safe Technique for Operative Treatment of Pipkin Fractures. Results of a Prospective Trial. AB - OBJECTIVES: The primary objective was to study the incidence of femoral head osteonecrosis after Ganz approach for Pipkin fracture dislocations. Clinico radiological and functional outcomes were also studied. DESIGN: Prospective, nonrandomised. SETTING: Tertiary care trauma center. PATIENTS: Twenty-eight patients with type I/II Pipkin fracture dislocation reduced within 6 hours of injury. INTERVENTION: The displaced head fracture was addressed through safe surgical dislocation after urgent closed reduction of the hip. OUTCOME MEASUREMENTS: Incidence of osteonecrosis using radiographs and functional outcome using modified Merle d'Aubigne and Oxford scores were studied. RESULTS: Twenty six fractures were fixed, and 2 type I fractures were excised. Twenty-six of 28 patients were followed up for a mean of 36 months. There was no osteonecrosis. All fractures and osteotomies had united. The mean modified Merle d'Aubigne score was 16.5 (14-18), and the mean Oxford score was 42.65 (38-48). CONCLUSIONS: Safe surgical dislocation provides satisfactory results in Pipkin fracture dislocations. The incidence of osteonecrosis is not increased in patients undergoing early joint reduction. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 26595594 TI - Anatomical Variations of the Lateral Femoral Cutaneous Nerve and Iatrogenic Injury After Autologous Bone Grafting From the Iliac Crest. AB - OBJECTIVE: We describe 2 patients with surgical injury to the lateral femoral cutaneous nerve (LFCN) after bone harvesting from the iliac crest for autologous bone grafting. DESIGN: A case-series of 2 patients and literature study of all anatomical variants of the LFCN in relation to the anterior superior iliac spine and inguinal ligament. SETTING: A teaching hospital in The Hague, the Netherlands. PATIENTS: Two patients with surgical injury to the LFCN after bone harvesting from the iliac crest for autologous bone grafting. RESULTS: All 9 known anatomical variations of the LFCN in the literature are reviewed, and the importance of these anatomical variations for surgeons and anesthetists is stressed. CONCLUSIONS: For every trauma, orthopedic, plastic, and cranio maxillofacial surgeon and anesthesiologist it is important to know the anatomy of the LFCN and its known variations. To prevent injury of the LFCN during bone harvesting, the bone should be harvested 4-5 cm posterior to the anterior superior iliac spine and the incision should be parallel to the iliac crest. LEVEL OF EVIDENCE: Therapeutic Level V. See Instructions for Authors for a complete description of levels of evidence. PMID- 26595595 TI - Dynamizations and Exchanges: Success Rates and Indications. AB - OBJECTIVE: To characterize the timing, indications, and "success rates of secondary interventions, dynamization and exchange nailing, in a large series of tibial nonunions" (dynamization and exchange nailing are types of secondary interventions). SETTING: Retrospective multicenter analysis from level 1 trauma hospitals. PATIENTS: A total of 194 tibia fractures that underwent dynamization or exchange nailing for delayed/nonunion. INTERVENTION: Records and radiographs to characterize demographic data, fracture type, and cortical contact after tibial nailing were gathered. The radiographic union score for tibias (RUST) and the timing of intervention and time to union were calculated. MAIN OUTCOME MEASURES: The primary outcome was success of either intervention, defined as achieving union, with the need for further intervention defining failure. Other outcomes included RUST scores at intervention and union, and timing to intervention and union for both techniques. Two-tailed t tests and Fisher exact with P set at <0.05 for significance were used as indicated. RESULTS: A total of 194 tibia fractures underwent dynamization (97) or exchange nailing (97). No statistical differences were found between groups with demographic characteristics. The presence of a fracture gap (P = 0.01) and comminuted fractures (P = 0.002) was more common in the exchange group. The success rates of the interventions and RUST scores were not different when performed before versus after 6 months; therefore, data were pooled. The RUST scores at the time of intervention were not different for successful or failed dynamizations (7.13 vs. 7.07, P = 0.83) or exchanges (6.8 vs. 7.3, P = 0.37). Likewise, the time to successful versus failed dynamization (165 vs. 158 days, P = 0.91) or exchange nailing (224 vs. 201 days, P = 0.48) was not different. No cortical contact or a gap was a statistically negative factor for both exchange nails (P = 0.09) and dynamizations (P = 0.06). When combined, the success in the face of a gap was 78% versus 92% when no gap was present (P = 0.02). CONCLUSIONS: Previous literature has few reports of the success rates of secondary interventions for tibial nonunions. The indications for dynamization and exchange were similar. Comminuted fractures, and fractures with no cortical contact or "gap" present after intramedullary nailing, favored having an exchange nail performed over dynamization. Fracture gap was also found to be a negative prognostic factor for both procedures. Overall, this study demonstrates high rates of union for both interventions, making them both viable options. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 26595596 TI - Correlation Between the Lauge-Hansen Classification and Ligament Injuries in Ankle Fractures. AB - OBJECTIVE: To evaluate the ability of the Lauge-Hansen classification to predict ligament injuries in ankle fractures using magnetic resonance imaging (MRI) and intraoperative findings. DESIGN: Prospective evaluation in consecutive patients. SETTING: Academic level 1 trauma center. PATIENTS: Three-hundred patients with an operatively treated ankle fracture who met the inclusion and exclusion criteria. INTERVENTION: Injury ankle radiographs were assigned to a Lauge-Hansen classification. MRI scans were obtained to evaluate the syndesmotic and deltoid ligaments. A Lauge-Hansen classification for each patient was recorded based on intraoperative findings. MAIN OUTCOME MEASUREMENTS: Comparisons were made between the predicted ankle ligamentous injuries based on radiographic Lauge-Hansen classifications, preoperative MRI analyses, and intraoperative findings. RESULTS: On the basis of the Lauge-Hansen system and injury radiographs, 77% (231/300) were classified as supination external rotation, 13% (40/300) were pronation external rotation, 4% (11/300) were supination adduction, <1% (1/300) was pronation abduction, and 6% (17/300) were not classifiable. Of the 283 fractures that were classified into Lauge-Hansen classes, 266 (94%) had MRI readings of ligamentous injuries consistent with the Lauge-Hansen predictions. Intraoperative findings also highly correlated with the Lauge-Hansen class of ankle fractures, with nearly complete agreement. Comparing MRI and intraoperative findings revealed discrepancies in 6% (16/283) of ankle fracture classifications. CONCLUSIONS: In our large cohort of patients, comparisons between injury radiographs, preoperative MRI, and intraoperative findings suggest that the Lauge Hansen system is an accurate predictor of ligamentous injuries. The predictions based on the Lauge-Hansen system can be useful for fracture reduction maneuvers and operative planning. LEVEL OF EVIDENCE: Diagnostic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 26595597 TI - Management of Distal Tibial Metaphyseal Fractures With the SIGN Intramedullary Nail in 3 Developing Countries. AB - OBJECTIVES: To evaluate the effectiveness of the Surgical Implant Generation Network (SIGN) intramedullary (IM) nail in distal tibial metaphyseal fractures. DESIGN: Retrospective Case Series. SETTING: Three Level I trauma centers in 3 different developing countries from 2009 to 2013. PATIENT/PARTICIPANTS: One hundred sixty patients with 162 distal tibial metaphyseal fractures (AO/OTA 43 A). INTERVENTION: SIGN IM nailing was performed using hand reaming and without the use of an image intensifier. MAIN OUTCOME MEASUREMENTS: The primary outcome measures were the rate of union and complications. The secondary outcome measures were the effect of open fractures on outcomes, effectiveness and safety of open reduction of closed fractures, and risk factors for the development of malalignment and possible solutions. RESULTS: The average age of patients was 35.3 years. Seventy-nine percent were male. Sixty percent of the fractures were closed. The mean time to surgery was 4.1 days. Fracture union occurred in 97.3% of fractures with an average time to union of 105 days. Open reduction of closed fractures was performed in 51 fractures. Nonunion occurred in 3 patients (1.8%). Acceptable alignment (<5 degrees deformity) was found in 134 fractures (83%). Infection occurred in 14 patients (8.6%). Revision surgery was required in 10 fractures (6.2%). CONCLUSIONS: In developing settings, distal metaphyseal tibial fractures can be managed successfully with the SIGN IM nail. There is an increased risk for complications (P = 0.001) and infection (P = 0.0004) in open fractures. Open reduction of closed distal tibia fractures is safe and effective. Malalignment can be improved with fibula stabilization but indications remain unclear. For surgeons interested in international mission work, the SIGN IM nail is an effective tool in managing distal tibial fractures. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 26595598 TI - Impact of Diabetes Mellitus on Surgical Quality Measures After Ankle Fracture Surgery: Implications for "Value-Based" Compensation and "Pay for Performance". AB - OBJECTIVES: To evaluate the impact of diabetes mellitus (DM) and associated complications on cost, length of stay, and inpatient mortality after open reduction internal fixation (ORIF) of an ankle fracture, and the implications of these variables during a time of health care payment reform. DESIGN: Retrospective study. SETTING: The Statewide Planning and Research Cooperative System database, which includes all admissions to New York State hospitals from 2000 to 2011. PATIENTS/PARTICIPANTS: A total of 58,748 patients were identified as having undergone the primary procedure of ORIF of the ankle (ICD-9-CM procedure code 79.36). INTERVENTION: ORIF of the ankle. MAIN OUTCOME MEASURE: Cost, length of stay, and inpatient mortality. RESULTS: Of the 58,748 patients evaluated, 7501 (12.8%) had DM. Mean length of stay and total hospital charges were significantly greater for the DM cohort compared to the without DM cohort (P < 0.01). Patients with DM had greater Charlson Comorbidity Index scores and greater in-hospital mortality than patients without DM (both P < 0.01). Of the patients with diabetes, 1098/7501 had complicated diabetes mellitus (C-DM). Patients with C-DM stayed 2.4 days longer and were $6895 more costly than those with diabetes alone (both P < 0.01). Patients with C-DM also had a significantly higher in-hospital mortality rate than those with diabetes alone. CONCLUSIONS: Patients with diabetes admitted to the hospital for ankle ORIF have more expensive hospital stays and higher in-hospital mortality rates than patients without diabetes. The presence of diabetic complications further increases these risks. These data will help provide risk-adjustment for future health care payment reform initiatives. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 26595599 TI - Combat-Related Hemipelvectomy: 14 Cases, a Review of the Literature and Lessons Learned. AB - OBJECTIVES: Trauma-related hemipelvectomy is a rare and often fatal injury that poses a number of challenges to the treating surgeon. Our objective was to identify patient and injury characteristics that have proven difficult to treat, and to describe management techniques. DESIGN: Retrospective review. SETTING: Level II trauma center. PATIENTS: Thirteen consecutive patients who underwent 14 combat-related hemipelvectomies between 2001 and 2013. INTERVENTION: We reviewed our prospective trauma registry, along with the patients' medical records, radiographs, and clinical photographs. MAIN OUTCOME MEASUREMENTS: Injury severity scores, required surgical procedures, ambulatory status, and bowel and bladder function. RESULTS: Hemipelvectomy was indicated for insufficient soft tissue coverage, complicated by life-threatening local infection and/or a dysvascular hemipelvis. Five patients underwent resection for angioinvasive fungal infections. All patients sustained a genitourinary injury, with 7 requiring suprapubic catheters and all undergoing diverting colostomy. After a median of 2 years of follow-up, 2 patients had normal urinary continence and 3 regained fecal continence. The surviving patients required a mean of 44 operations. One patient returned to community ambulation. CONCLUSIONS: This is the largest published series of trauma-related hemipelvectomies. Our lessons learned may benefit civilian surgeons who are confronted with high-energy open injuries to the pelvic girdle. Although the decision to perform hemipelvectomy should not be taken lightly, this procedure can be lifesaving and should be performed in a timely fashion when indicated. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 26595601 TI - Evaluating Cellular Instrumentation on Rural Handpumps to Improve Service Delivery-A Longitudinal Study in Rural Rwanda. AB - In rural sub-Saharan Africa, where handpumps are common, 10-67% are nonfunctional at any one time, and many never get repaired. Increased reliability requires improved monitoring and responsiveness of maintenance providers. In 2014, 181 cellular enabled water pump use sensors were installed in three provinces of Rwanda. In three arms, the nominal maintenance model was compared against a "best practice" circuit rider model, and an "ambulance" service model. In only the ambulance model was the sensor data available to the implementer, and used to dispatch technicians. The study ran for seven months in 2014-2015. In the study period, the nominal maintenance group had a median time to successful repair of approximately 152 days, with a mean per-pump functionality of about 68%. In the circuit rider group, the median time to successful repair was nearly 57 days, with a per-pump functionality mean of nearly 73%. In the ambulance service group, the successful repair interval was nearly 21 days with a functionality mean of nearly 91%. An indicative cost analysis suggests that the cost per functional pump per year is approximately similar between the three models. However, the benefits of reliable water service may justify greater focus on servicing models over installation models. PMID- 26595600 TI - Immobilization of Metal-Organic Framework Copper(II) Benzene-1,3,5-tricarboxylate (CuBTC) onto Cotton Fabric as a Nitric Oxide Release Catalyst. AB - Immobilization of metal-organic frameworks (MOFs) onto flexible polymeric substrates as secondary supports expands the versatility of MOFs for surface coatings for the development of functional materials. In this work, we demonstrate the deposition of copper(II) benzene-1,3,5-tricarboxylate (CuBTC) crystals directly onto the surface of carboxyl-functionalized cotton capable of generating the therapeutic bioagent nitric oxide (NO) from endogenous sources. Characterization of the CuBTC-cotton material by XRD, ATR-IR, and UV-vis indicate that CuBTC is successfully immobilized on the cotton fabric. In addition, SEM imaging reveals excellent surface coverage with well-defined CuBTC crystals. Subsequently, the CuBTC-cotton material was evaluated as a supported heterogeneous catalyst for the generation of NO using S-nitrosocysteamine as the substrate. The resulting reactivity is consistent with the activity observed for unsupported CuBTC particles. Overall, this work demonstrates deposition of MOFs onto a flexible polymeric material with excellent coverage as well as catalytic NO release from S-nitrosocysteamine at therapeutic levels. PMID- 26595602 TI - Implicitly strengthened task-irrelevant stimulus-response associations modulate cognitive control: Evidence from an fMRI study. AB - The dynamics of cognitive control have been investigated by the proportion congruency effect. However, the theory that this effect is due to attentional modulation has been challenged by contingency learning accounts. This raises the question of how the cognitive control system operates during and after increasing the strength of task-irrelevant stimulus-response (S-R) associations. We employed a novel paradigm that elicits positive and reversed Simon effects via task rule manipulations, and combined it with a between subjects proportion congruency manipulation. The pattern of enhancement and reversal of the positive and reversed Simon effects across conditions suggested that participants used strengthened task-irrelevant S-R associations to predict responses. Functional neuroimaging identified proportion congruency effects that interacted with task S R associations, showing greater activity when strengthened task-irrelevant S-R associations conflicted with task-defined S-R associations in frontoparietal regions, including bilateral superior parietal lobule (SPL) and dorsal premotor cortex (dPMC), presupplementary motor area/anterior midcingulate cortex (Pre SMA/aMCC), and left dorsolateral prefrontal cortex (DLPFC). These results suggest that the aMCC and DLPFC shifted to responding mainly to the conflict induced by the strengthened irrelevant S-R associations. The SPL and dPMC might represent the strengthened irrelevant S-R associations. Hum Brain Mapp 37:756-772, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26595603 TI - Marked intrafamilial phenotypic heterogeneity in dystrophic epidermolysis bullosa caused by inheritance of a mild dominant glycine substitution and a novel deep intronic recessive COL7A1 mutation. PMID- 26595605 TI - Outcomes of Multidisciplinary Low Vision Rehabilitation in Adults. AB - PURPOSE: To evaluate the outcomes of multidisciplinary low vision rehabilitation (LVR) in adults with low vision (LV) in India using the Veterans Affairs Low Vision Visual Functioning Questionnaire (VA LV VFQ-48) and the Impact of Vision Impairment (IVI) questionnaire. METHODS: Consecutive adults with LV referred for the first time to the Centre for Sight Enhancement were administered the 28-item IVI and VA LV VFQ-48 before and after LVR (4 months). Rasch-scaled scores were generated for the IVI and the VA LV VFQ-48 along with each of their subscales at both the time points. Effect size (ES) was calculated using Cohen's d coefficient. RESULTS: Two hundred fifty-five patients completed the LVR program. Following LVR, the linear measures revealed significant improvements in vision related quality of life (VRQoL) using the IVI at follow-up (P < 0.0001), with large ES for reading and accessing information (ES = 1.0) and relatively moderate ES for overall IVI (ES = 0.63) and mobility subscale (ES = 0.53). No significant improvement was found on emotional well-being subscale (ES = 0.18; P = 0.06). Similarly, significant improvements in VRQoL (P < 0.0001) were found for the VA LV VFQ-48 at follow-up, albeit moderate ES for the overall visual ability (ES = 0.67) and its subscales (reading [ES = -0.72], mobility [ES = -0.45], visual information [ES = -0.47), visual motor [ES = -0.54]). CONCLUSIONS: Regardless of the instrument used for assessment, our multidisciplinary LVR program resulted in statistically significant improvements in visual functioning and VRQoL of those adults with LV deemed appropriate for intervention (dropout rates were high); however, the improvements were modest, and the clinical relevance of these small improvements may be limited. Nonetheless, further studies should attempt to increase the completion rates in order to draw strong inferences. PMID- 26595604 TI - Non-invasive in vivo imaging of early metabolic tumor response to therapies targeting choline metabolism. AB - The cholinic phenotype, characterized by elevated phosphocholine and a high production of total-choline (tCho)-containing metabolites, is a metabolic hallmark of cancer. It can be exploited for targeted therapy. Non-invasive imaging biomarkers are required to evaluate an individual's response to targeted anticancer agents that usually do not rapidly cause tumor shrinkage. Because metabolic changes can manifest at earlier stages of therapy than changes in tumor size, the aim of the current study was to evaluate (1)H-MRS and diffusion weighted MRI (DW-MRI) as markers of tumor response to the modulation of the choline pathway in mammary tumor xenografts. Inhibition of choline kinase activity was achieved with the direct pharmacological inhibitor H-89, indirect inhibitor sorafenib and down-regulation of choline-kinase alpha (ChKA) expression using specific short-hairpin RNA (shRNA). While all three strategies significantly decreased tCho tumor content in vivo, only sorafenib and anti-ChKA shRNA significantly repressed tumor growth. The increase of apparent-diffusion coefficient of water (ADCw) measured by DW-MRI, was predictive of the induced necrosis and inhibition of the tumor growth in sorafenib treated mice, while the absence of change in ADC values in H89 treated mice predicted the absence of effect in terms of tumor necrosis and tumor growth. In conclusion, (1)H-choline spectroscopy can be useful as a pharmacodynamic biomarker for choline targeted agents, while DW-MRI can be used as an early marker of effective tumor response to choline targeted therapies. DW-MRI combined to choline spectroscopy may provide a useful non-invasive marker for the early clinical assessment of tumor response to therapies targeting choline signaling. PMID- 26595606 TI - Melanin Pigmentation in Rat Eyes: In Vivo Imaging by Polarization-Sensitive Optical Coherence Tomography and Comparison to Histology. AB - PURPOSE: The purpose of this study was to demonstrate polarization-sensitive optical coherence tomography (PS-OCT) for imaging pigmented structures in the posterior eye segments of albino and pigmented rats and to correlate depolarization contrast of the retinal pigment epithelium (RPE) and choroid in in vivo PS-OCT to melanin pigmentation detected in postmortem histologic serial sections. METHODS: In vivo three-dimensional PS-OCT imaging was performed in adult albino and pigmented rat eyes at 70-kHz A-line rate. Degree of polarization uniformity (DOPU) fundus maps and radial DOPU profiles were generated. Postmortem histomorphologic analysis was performed in order to investigate melanin pigmentation of the RPE and choroid. Fundus pigmentation maps were extracted from histologic serial sections. Pigmentation profiles were correlated to DOPU profiles of the same eyes. RESULTS: Strong depolarization was found in the RPE/choroid complex of pigmented rats, whereas the same structures exhibited uniform polarization in albino rats. The difference between the depolarization characteristics between albino and pigmented animals was statistically significant. In the fundus pigmentation maps, optical pigment density was zero in albino rat eyes. In pigmented rat eyes, a strong negative correlation between optical pigment density and DOPU was observed. CONCLUSIONS: This in vivo and ex vivo investigation of posterior rat eyes indicates that melanin is the cause of depolarization in retinal PS-OCT images. It further demonstrates that melanin pigmentation in the RPE and choroid can be quantified via depolarization imaging and therefore suggests that PS-OCT is a useful tool for the noninvasive quantitative assessment of pigmentary changes in vision-threatening diseases such as age-related macular degeneration. PMID- 26595607 TI - The Associations of Dietary Intake of Polyunsaturated Fatty Acids With Diabetic Retinopathy in Well-Controlled Diabetes. AB - PURPOSE: To assess the associations between dietary intake of polyunsaturated fatty acids (PUFAs) and diabetic retinopathy (DR). METHODS: This was a cross sectional study of 379 patients (median age: 66.0 years) with diabetes attending a diabetes eye clinic. Daily fatty acid intake was assessed by using a validated Food Frequency Questionnaire and adjusted for energy intake. Diabetic retinopathy was graded from fundus photographs as no DR, nonproliferative DR, or proliferative DR. Patients were categorized as "well-controlled diabetes" (n = 123) and "poorly controlled diabetes" (n = 256), defined as glycated hemoglobin (HbA1c) level < 7.0% or >= 7.0%, respectively. RESULTS: There were no associations between any fatty acid intake and DR. However, among patients with well-controlled diabetes, increasing daily intake of PUFAs was associated with a reduced likelihood of the presence (odds ratio [OR]: 0.18; 95% confidence interval [CI]: 0.06-0.59) and severity of DR after adjusting for age, sex, HbA1c, mean arterial blood pressure, and duration of diabetes. Moreover, an increased saturated fatty acid (SFA) intake was associated with increased likelihood of the presence (OR: 2.37; 95% CI: 1.15-4.88) and severity of DR. No association was found among those with poorly controlled diabetes. CONCLUSIONS: Increasing PUFA intake was associated with a reduced likelihood of the presence and severity of DR in well-controlled diabetes, whereas increasing SFA intake was associated with an increased likelihood of the presence and severity of DR. Further studies to confirm this observation are warranted to elucidate the underlying mechanisms and potential role of dietary PUFA and SFA intake in the management of DR. PMID- 26595608 TI - Modeling the Dynamic AMD-Associated Chronic Oxidative Stress Changes in Human ESC and iPSC-Derived RPE Cells. AB - PURPOSE: Here we use human embryonic stem cells (hESCs) and human-induced pluripotent stem cell (hiPSC)-derived retinal pigment epithelium (RPE) cells to model chronic oxidative stress in vitro. This model allows us to understand the evolution of chronic stress response in RPE in vivo, as well as to monitor microRNAs changes. Finally, we use this in vitro model to identify a partial agonist of NRF2 that is protective against reactive oxygen species (ROS)-induced cytotoxicity. METHODS: The hESCs and hiPSCs were differentiated toward an RPE fate. Upon maturation, RPE cells were subjected to chronic oxidative stress using Paraquat (PQ). The cells were then analyzed using immunocytochemistry and quantitative RT-PCR to look for changes in gene expression and microRNA changes. Small molecules targeting NRF2 pathways were utilized to look for protection against oxidative stress-induced apoptosis. RESULTS: We show that 160 MUM PQ can be used to generate a model of chronic oxidative stress in RPE cells derived from hESCs and hiPSCs. Using this model, we characterize the NRF2 pathway effectors during the early and late stages of chronic oxidative stress and identify microRNAs changes during oxidative stress. We find that hsa-miR144 modulates NRF2 activity during ROS stress. Lastly, we found a small molecule modulator of NRF2 that plays a protective role against oxidative stress-induced RPE apoptosis. CONCLUSIONS: In summary, pluripotent stem cell-derived retinal cells can be used to model retinal diseases in a dish. This can provide an unprecedented opportunity to understand the evolution of disease processes and allow us to identify novel therapeutics. PMID- 26595609 TI - Sex Differences in the Relationship Between Obesity and Choroidal Nevus in US Adults. AB - PURPOSE: To investigate sex differences and the effect of other variables on the association between obesity and choroidal nevus in the US adult population. METHODS: The study population of this cross-sectional study included 5575 subjects aged >=40 years from the 2005 to 2008 National Health and Nutrition Examination Survey (NHANES) who underwent retinal imaging. Primary predictor variables were body mass index (BMI) when the subject was 25 years old ("former BMI") and BMI at time of NHANES participation ("current BMI"). Body mass index was classified "elevated" (>=25 kg/m2) versus "normal" (<25 kg/m2). The main outcome measure was choroidal nevus in either eye on retinal imaging. Subgroup analysis was stratified by sex and race. RESULTS: The mean age of the study population was 56.4 years, with 47.3% male and 52.7% female subjects. The prevalence of choroidal nevus was 4.7% overall. Former elevated BMI was associated with choroidal nevus in the overall population (odds ratio [OR]: 1.35, 95% confidence interval [CI]: 1.06-1.71, P = 0.01) and males (OR: 1.43, CI: 1.03 1.99, P = 0.03). Current elevated BMI was associated with choroidal nevus in the overall population (OR: 1.37, CI: 1.02-1.85, P = 0.04); females (OR: 1.72, CI: 1.11-2.68, P = 0.02), and postmenopausal females (OR: 1.94, CI: 1.23-3.06, P = 0.006). CONCLUSIONS: Choroidal nevus is associated with former and current obesity. Sex and postmenopausal status differences in this association could provide insight into the demographics of patients at risk for developing choroidal nevus. PMID- 26595610 TI - Distinct Profiles of Soluble Cytokine Receptors Between B-Cell Vitreoretinal Lymphoma and Uveitis. AB - PURPOSE: To determine the profiles of soluble cytokine receptors and cytokines, including mostly their ligands, in the vitreous humor of patients with B-cell vitreoretinal lymphoma (VRL) and uveitis. METHODS: Vitreous samples were collected from immunocompetent patients with VRL (n = 21), uveitis (n = 20), and idiopathic epiretinal membrane (n = 21) as controls. Cytometric beads assay were used to determine the vitreous concentrations of soluble receptors and cytokines. RESULTS: Vitreous levels of soluble IL-2 receptor alpha (sIL-2Ralpha), sIL-6R, soluble tumor necrosis factor receptor (TNFR) 1, sTNFR2, soluble vascular endothelial growth factor receptor (sVEGFR) 1, sVEGFR2, and IL-10 were higher in patients with VRL than in those with uveitis and controls, whereas those of sIL 1R1, sIL-1R2, and sIL-4R were higher in patients with uveitis than those with VRL and controls. In analyses in patients with VRL, elevation of sVEGFR1 and sVEGFR2 levels was more prominent in patients with systemic metastatic retinal lymphoma (SMRL) than in those with primary VRL/primary central nervous system lymphoma (PVRL/PCNSL). Furthermore, sIL-2Ralpha levels were increased in patients with VRL who developed subretinal lesions compared with in those who mainly had vitreous cavity opacity, positively correlated with the density of CD3+ cells in the vitrectomy cell blocks. CONCLUSIONS: The profiles of soluble cytokine receptors and cytokines in patients with VRL were different from those with uveitis. In addition, sVEGFR1 and sVEGFR2 levels may be differential diagnostic markers between PVRL/PCNSL and SMRL, and sIL-2Ralpha levels can anticipate infiltration of VRL cells into the subretina and/or retina. PMID- 26595612 TI - Recurrence and Mortality in Young Women With Myocardial Infarction or Ischemic Stroke: Long-term Follow-up of the Risk of Arterial Thrombosis in Relation to Oral Contraceptives (RATIO) Study. PMID- 26595613 TI - The great balancing act of the Affordable Care Act. PMID- 26595614 TI - Ebola: forgotten but not gone? PMID- 26595611 TI - Lactation and Progression to Type 2 Diabetes Mellitus After Gestational Diabetes Mellitus: A Prospective Cohort Study. AB - BACKGROUND: Lactation improves glucose metabolism, but its role in preventing type 2 diabetes mellitus (DM) after gestational diabetes mellitus (GDM) remains uncertain. OBJECTIVE: To evaluate lactation and the 2-year incidence of DM after GDM pregnancy. DESIGN: Prospective, observational cohort of women with recent GDM. (ClinicalTrials.gov: NCT01967030). SETTING: Integrated health care system. PARTICIPANTS: 1035 women diagnosed with GDM who delivered singletons at 35 weeks' gestation or later and enrolled in the Study of Women, Infant Feeding and Type 2 Diabetes After GDM Pregnancy from 2008 to 2011. MEASUREMENTS: Three in-person research examinations from 6 to 9 weeks after delivery (baseline) and annual follow-up for 2 years that included 2-hour, 75-g oral glucose tolerance testing; anthropometry; and interviews. Multivariable Weibull regression models evaluated independent associations of lactation measures with incident DM adjusted for potential confounders. RESULTS: Of 1010 women without diabetes at baseline, 959 (95%) were evaluated up to 2 years later; 113 (11.8%) developed incident DM. There were graded inverse associations for lactation intensity at baseline with incident DM and adjusted hazard ratios of 0.64, 0.54, and 0.46 for mostly formula or mixed/inconsistent, mostly lactation, and exclusive lactation versus exclusive formula feeding, respectively (P trend = 0.016). Time-dependent lactation duration showed graded inverse associations with incident DM and adjusted hazard ratios of 0.55, 0.50, and 0.43 for greater than 2 to 5 months, greater than 5 to 10 months, and greater than 10 months, respectively, versus 0 to 2 months (P trend = 0.007). Weight change slightly attenuated hazard ratios. LIMITATION: Randomized design is not feasible or desirable for clinical studies of lactation. CONCLUSION: Higher lactation intensity and longer duration were independently associated with lower 2-year incidences of DM after GDM pregnancy. Lactation may prevent DM after GDM delivery. PRIMARY FUNDING SOURCE: National Institute of Child Health and Human Development. PMID- 26595615 TI - Dementia--not all about Alzheimer's. PMID- 26595616 TI - Essential medicines are still essential. PMID- 26595617 TI - Medicine Unboxed: frontiers and mortality. PMID- 26595619 TI - USA gears up for next round of enrolment under the ACA. PMID- 26595620 TI - Momentum grows for medical use of cannabis. PMID- 26595621 TI - Christopher Plowe: a leader in malaria elimination. PMID- 26595622 TI - Examining empathy. PMID- 26595625 TI - The given world. PMID- 26595626 TI - Alan Jon Magill. PMID- 26595627 TI - Dementia prevention: call to action. PMID- 26595628 TI - Pointing the FINGER at multimodal dementia prevention. PMID- 26595629 TI - Pointing the FINGER at multimodal dementia prevention. PMID- 26595630 TI - Gestational hypertension and advanced maternal age. PMID- 26595631 TI - Pointing the FINGER at multimodal dementia prevention - Authors' reply. PMID- 26595632 TI - Gestational hypertension and advanced maternal age - Authors' reply. PMID- 26595633 TI - Fetal macrosomia: induction of labour or expectant management? PMID- 26595634 TI - Fetal macrosomia: induction of labour or expectant management? - Authors' reply. PMID- 26595635 TI - Fetal macrosomia: induction of labour or expectant management? PMID- 26595637 TI - Department of Error. PMID- 26595638 TI - Department of Error. PMID- 26595636 TI - Fetal macrosomia: induction of labour or expectant management? PMID- 26595639 TI - Department of Error. PMID- 26595640 TI - Safeguarding children and improving their care in the UK. PMID- 26595641 TI - Frontotemporal dementia. AB - Frontotemporal dementia is an umbrella clinical term that encompasses a group of neurodegenerative diseases characterised by progressive deficits in behaviour, executive function, or language. Frontotemporal dementia is a common type of dementia, particularly in patients younger than 65 years. The disease can mimic many psychiatric disorders because of the prominent behavioural features. Various underlying neuropathological entities lead to the frontotemporal dementia clinical phenotype, all of which are characterised by the selective degeneration of the frontal and temporal cortices. Genetics is an important risk factor for frontotemporal dementia. Advances in clinical, imaging, and molecular characterisation have increased the accuracy of frontotemporal dementia diagnosis, thus allowing for the accurate differentiation of these syndromes from psychiatric disorders. As the understanding of the molecular basis for frontotemporal dementia improves, rational therapies are beginning to emerge. PMID- 26595643 TI - Vascular dementia. AB - Vascular dementia is one of the most common causes of dementia after Alzheimer's disease, causing around 15% of cases. However, unlike Alzheimer's disease, there are no licensed treatments for vascular dementia. Progress in the specialty has been difficult because of uncertainties over disease classification and diagnostic criteria, controversy over the exact nature of the relation between cerebrovascular pathology and cognitive impairment, and the paucity of identifiable tractable treatment targets. Although there is an established relation between vascular and degenerative Alzheimer's pathology, the mechanistic link between the two has not yet been identified. This Series paper critiques some of the key areas and controversies, summarises treatment trials so far, and makes suggestions for what progress is needed to advance our understanding of pathogenesis and thus maximise opportunities for the search for new and effective management approaches. PMID- 26595642 TI - Lewy body dementias. AB - The broad importance of dementia is undisputed, with Alzheimer's disease justifiably getting the most attention. However, dementia with Lewy bodies and Parkinson's disease dementia, now called Lewy body dementias, are the second most common type of degenerative dementia in patients older than 65 years. Despite this, Lewy body dementias receive little attention and patients are often misdiagnosed, leading to less than ideal management. Over the past 10 years, considerable effort has gone into improving diagnostic accuracy by refining diagnostic criteria and using imaging and other biomarkers. Dementia with Lewy bodies and Parkinson's disease dementia share the same pathophysiology, and effective treatments will depend not only on successful treatment of symptoms but also on targeting the pathological mechanisms of disease, ideally before symptoms and clinical signs develop. We summarise the most pertinent progress from the past 10 years, outlining some of the challenges for the future, which will require refinement of diagnosis and clarification of the pathogenesis, leading to disease-modifying treatments. PMID- 26595644 TI - Exogenous Lipocalin 2 Ameliorates Acute Rejection in a Mouse Model of Renal Transplantation. AB - Lipocalin 2 (Lcn2) is rapidly produced by damaged nephron epithelia and is one of the most promising new markers of renal injury, delayed graft function and acute allograft rejection (AR); however, the functional importance of Lcn2 in renal transplantation is largely unknown. To understand the role of Lcn2 in renal AR, kidneys from Balb/c mice were transplanted into C57Bl/6 mice and vice versa and analyzed for morphological and physiological outcomes of AR at posttransplantation days 3, 5, and 7. The allografts showed a steady increase in intensity of interstitial infiltration, tubulitis and periarterial aggregation of lymphocytes associated with a substantial elevation in serum levels of creatinine, urea and Lcn2. Perioperative administration of recombinant Lcn2:siderophore:Fe complex (rLcn2) to recipients resulted in functional and morphological amelioration of the allograft at day 7 almost as efficiently as daily immunosuppression with cyclosporine A (CsA). No significant differences were observed in various donor-recipient combinations (C57Bl/6 wild-type and Lcn2(-/-) , Balb/c donors and recipients). Histochemical analyses of the allografts showed reduced cell death in recipients treated with rLcn2 or CsA. These results demonstrate that Lcn2 plays an important role in reducing the extent of kidney AR and indicate the therapeutic potential of Lcn2 in transplantation. PMID- 26595645 TI - ASVCP quality assurance guidelines: external quality assessment and comparative testing for reference and in-clinic laboratories. AB - The purpose of this document is to educate providers of veterinary laboratory diagnostic testing in any setting about comparative testing. These guidelines will define, explain, and illustrate the importance of a multi-faceted laboratory quality management program which includes comparative testing. The guidelines will provide suggestions for implementation of such testing, including which samples should be tested, frequency of testing, and recommendations for result interpretation. Examples and a list of vendors and manufacturers supplying control materials and services to veterinary laboratories are also included. PMID- 26595647 TI - alpha-Hemolysin enhances Staphylococcus aureus internalization and survival within mast cells by modulating the expression of beta1 integrin. AB - Mast cells (MCs) are important sentinels of the host defence against invading pathogens. We previously reported that Staphylococcus aureus evaded the extracellular antimicrobial activities of MCs by promoting its internalization within these cells via beta1 integrins. Here, we investigated the molecular mechanisms governing this process. We found that S. aureus responded to the antimicrobial mediators released by MCs by up-regulating the expression of alpha hemolysin (Hla), fibronectin-binding protein A and several regulatory systems. We also found that S. aureus induced the up-regulation of beta1 integrin expression on MCs and that this effect was mediated by Hla-ADAM10 (a disintegrin and metalloproteinase 10) interaction. Thus, deletion of Hla or inhibition of Hla ADAM10 interaction significantly impaired S. aureus internalization within MCs. Furthermore, purified Hla but not the inactive HlaH35L induced up-regulation of beta1 integrin expression in MCs in a dose-dependent manner. Our data support a model in which S. aureus counter-reacts the extracellular microbicidal mechanisms of MCs by increasing expression of fibronectin-binding proteins and by inducing Hla-ADAM10-mediated up-regulation of beta1 integrin in MCs. The up-regulation of bacterial fibronectin-binding proteins, concomitantly with the increased expression of its receptor beta1 integrin on the MCs, resulted in enhanced S. aureus internalization through the binding of fibronectin-binding proteins to integrin beta1 via fibronectin. PMID- 26595646 TI - Establishment of Immortalized BMP2/4 Double Knock-Out Osteoblastic Cells Is Essential for Study of Osteoblast Growth, Differentiation, and Osteogenesis. AB - Bone morphogenetic proteins 2 and 4 (BMP2/4) are essential for osteoblast differentiation and osteogenesis. Generation of a BMP2/4 dual knock-out ((ko/ko)) osteoblastic cell line is a valuable asset for studying effects of BMP2/4 on skeletal development. In this study, our goal was to create immortalized mouse deleted BMP2/4 osteoblasts by infecting adenoviruses with Cre recombinase and green fluorescent protein genes into immortalized murine floxed BMP2/4 osteoblasts. Transduced BMP2/4(ko/ko) cells were verified by green immunofluorescence and PCR. BMP2/4(ko/ko) osteoblasts exhibited small size, slow cell proliferation rate and cell growth was arrested in G1 and G2 phases. Expression of bone-relate genes was reduced in the BMP2/4(ko/ko) cells, resulting in delay of cell differentiation and mineralization. Importantly, extracellular matrix remodeling was impaired in the BMP2/4(ko/ko) osteoblasts as reflected by decreased Mmp-2 and Mmp-9 expressions. Cell differentiation and mineralization were rescued by exogenous BMP2 and/or BMP4. Therefore, we for the first time described establishment of an immortalized deleted BMP2/4 osteoblast line useful for study of mechanisms in regulating osteoblast lineages. PMID- 26595648 TI - Surface Stiffness--a Parameter for Sensing the Chirality of Saccharides. AB - Surface stiffness is considered a key parameter for designing high-performance implantable materials and artificial extracellular matrices because of its substantial effects on cell behavior. How to transform biomolecule recognition events, particularly chiral recognition, into stiffness change on material surfaces is biologically essential but very challenging for chemists. Here, we report a chirality-triggered stiffness transition on a smart polymer film, which consists of flexible polyethylenimine (PEI) main chains grafted with dipeptide units capable of discriminating chiral monosaccharides. The polymer film became substantially softer after interacting with L-ribose and became more rigid after interacting with D-ribose (the basic building block of DNA and RNA). This chiral effect provides a new method for determining the enantiomeric purity of an L/D ribose mixture and facilitates the chiral separation of deoxyribose racemates as well as the separation of diverse mono-, di-, and oligosaccharides. These are three puzzle problems in carbohydrate chemistry. Furthermore, taking advantage of the significant differences in the surface stiffness, the proliferation of fibroblast cells on the polymeric surfaces can also be regulated by chiral biomolecules. PMID- 26595649 TI - Rhodium(I) N-Heterocyclic Carbene Bioorganometallics as in Vitro Antiproliferative Agents with Distinct Effects on Cellular Signaling. AB - Organometallics with N-heterocyclic carbene (NHC) ligands have triggered major interest in inorganic medicinal chemistry. Complexes of the type Rh(I)(NHC)(COD)X (where X is Cl or I, COD is cyclooctadiene, and NHC is a dimethylbenzimidazolylidene) represent a promising type of new metallodrugs that have been explored by advanced biomedical methods only recently. In this work, we have synthesized and characterized several complexes of this type. As observed by mass spectrometry, these complexes remained stable over at least 3 h in aqueous solution, after which hydrolysis of the halido ligands occurred and release of the NHC ligand was evident. Effects against mitochondria and general cell tumor metabolism were noted at higher concentrations, whereas phosphorylation of HSP27, p38, ERK1/2, FAK, and p70S6K was induced substantially already at lower exposure levels. Regarding the antiproliferative activity in tumor cells, a clear preference for iodido over chlorido secondary ligands was noted, as well as effects of the substituents of the NHC ligand. PMID- 26595650 TI - Epidemiology of 11 respiratory RNA viruses in a cohort of hospitalized children in Riyadh, Saudi Arabia. AB - Respiratory tract infections are a principal cause of illness and mortality in children worldwide and mostly caused by viruses. In this study, the epidemiology of 11 respiratory RNA viruses was investigated in a cohort of hospitalized children at a tertiary referral center in Riyadh from February 2008 to March 2009 using conventional and real-time monoplex RT-PCR assays. Among 174 nasopharyngeal aspirates, respiratory syncytial virus (RSV) was detected in 39 samples (22.41%), influenza A virus in 34 (19.54%), metapneumovirus (MPV) in 19 (10.92%), coronaviruses in 14 (8.05%), and parainfluenza viruses (PIVs) in 11 (6.32%). RSV, PIVs and coronaviruses were most prevalent in infants less than 6 months old, whereas MPV and influenza A virus were more prominent in children aged 7-24 and 25-60 months, respectively. The majority of the viruses were identified during winter with two peaks observed in March 2008 and January 2009. The presented data warrants further investigation to understand the epidemiology of respiratory viruses in Saudi Arabia on spatial and temporal basis. PMID- 26595651 TI - Mesolimbic dopamine signals the value of work. AB - Dopamine cell firing can encode errors in reward prediction, providing a learning signal to guide future behavior. Yet dopamine is also a key modulator of motivation, invigorating current behavior. Existing theories propose that fast (phasic) dopamine fluctuations support learning, whereas much slower (tonic) dopamine changes are involved in motivation. We examined dopamine release in the nucleus accumbens across multiple time scales, using complementary microdialysis and voltammetric methods during adaptive decision-making. We found that minute-by minute dopamine levels covaried with reward rate and motivational vigor. Second by-second dopamine release encoded an estimate of temporally discounted future reward (a value function). Changing dopamine immediately altered willingness to work and reinforced preceding action choices by encoding temporal-difference reward prediction errors. Our results indicate that dopamine conveys a single, rapidly evolving decision variable, the available reward for investment of effort, which is employed for both learning and motivational functions. PMID- 26595652 TI - Task-specific versus generalized mnemonic representations in parietal and prefrontal cortices. AB - Our ability to learn a wide range of behavioral tasks is essential for responding appropriately to sensory stimuli according to behavioral demands, but the underlying neural mechanism has been rarely examined by neurophysiological recordings in the same subjects across learning. To understand how learning new behavioral tasks affects neuronal representations, we recorded from posterior parietal cortex (PPC) before and after training on a visual motion categorization task. We found that categorization training influenced cognitive encoding in PPC, with a marked enhancement of memory-related delay-period encoding during the categorization task that was absent during a motion discrimination task before categorization training. In contrast, the prefrontal cortex (PFC) exhibited strong delay-period encoding during both discrimination and categorization tasks. This reveals a dissociation between PFC's and PPC's roles in working memory, with general engagement of PFC across multiple tasks, in contrast with more task specific mnemonic encoding in PPC. PMID- 26595653 TI - A neuromarker of sustained attention from whole-brain functional connectivity. AB - Although attention plays a ubiquitous role in perception and cognition, researchers lack a simple way to measure a person's overall attentional abilities. Because behavioral measures are diverse and difficult to standardize, we pursued a neuromarker of an important aspect of attention, sustained attention, using functional magnetic resonance imaging. To this end, we identified functional brain networks whose strength during a sustained attention task predicted individual differences in performance. Models based on these networks generalized to previously unseen individuals, even predicting performance from resting-state connectivity alone. Furthermore, these same models predicted a clinical measure of attention--symptoms of attention deficit hyperactivity disorder--from resting-state connectivity in an independent sample of children and adolescents. These results demonstrate that whole-brain functional network strength provides a broadly applicable neuromarker of sustained attention. PMID- 26595654 TI - Decoding the content of visual short-term memory under distraction in occipital and parietal areas. AB - Recent studies have provided conflicting accounts regarding where in the human brain visual short-term memory (VSTM) content is stored, with strong univariate fMRI responses being reported in superior intraparietal sulcus (IPS), but robust multivariate decoding being reported in occipital cortex. Given the continuous influx of information in everyday vision, VSTM storage under distraction is often required. We found that neither distractor presence nor predictability during the memory delay affected behavioral performance. Similarly, superior IPS exhibited consistent decoding of VSTM content across all distractor manipulations and had multivariate responses that closely tracked behavioral VSTM performance. However, occipital decoding of VSTM content was substantially modulated by distractor presence and predictability. Furthermore, we found no effect of target-distractor similarity on VSTM behavioral performance, further challenging the role of sensory regions in VSTM storage. Overall, consistent with previous univariate findings, our results indicate that superior IPS, but not occipital cortex, has a central role in VSTM storage. PMID- 26595657 TI - Comparison of the effects of micro-osteoperforation and corticision on the rate of orthodontic tooth movement in rats. AB - OBJECTIVE: To investigate the effects of flapless micro-osteoperforation and corticision on the rate of orthodontic tooth movement in rats. MATERIALS AND METHODS: Forty-five 8-week-old male Sprague-Dawley rats were divided into the following groups: micro-osteoperforation and orthodontic force (MOP + F), corticision and orthodontic force (C + F), and orthodontic force only (F, control). The left maxillary first molars were pulled forward with a force of 50 g. Flapless surgical interventions were conducted in the MOP + F and C + F groups. The total duration of the experiment was 6 weeks. Alveolar bone density and the number of osteoclasts were evaluated using microcomputed tomography and histologic examination, respectively. RESULTS: The tooth movement distance was significantly higher in both experimental groups than in the control group. Bone density and bone mineral density decreased in the MOP + F and C + F groups. The number of osteoclasts in the MOP + F and C + F groups was significantly higher than in the control group F. CONCLUSION: The two minimally invasive flapless surgical interventions increased bone remodeling and osteoclast activity and induced faster orthodontic tooth movement for at least 2 weeks in rats. No differences were observed between the outcome of flapless micro-osteoperforation and corticision in the rats. PMID- 26595656 TI - Stimulus-specific combinatorial functionality of neuronal c-fos enhancers. AB - The c-fos gene (also known as Fos) is induced by a broad range of stimuli and is a reliable marker for neural activity. Its induction mechanism and available reporter mouse lines are based exclusively on c-fos promoter activity. Here we demonstrate that multiple enhancers surrounding the c-fos gene are crucial for ensuring robust c-fos response to various stimuli. Membrane depolarization, brain derived neurotrophic factor (BDNF) and forskolin activate distinct subsets of the enhancers to induce c-fos transcription in neurons, suggesting that stimulus specific combinatorial activation of multiple enhancers underlies the broad inducibility of the c-fos gene. Accordingly, the functional requirement of key transcription factors varies depending on the type of stimulation. Combinatorial enhancer activation also occurs in the brain. Providing a comprehensive picture of the c-fos induction mechanism beyond the minimal promoter, our study should help in understanding the physiological nature of c-fos induction in relation to neural activity and plasticity. PMID- 26595658 TI - Upper airway assessment using four different maxillary expanders in cleft patients: A cone-beam computed tomography study. AB - OBJECTIVE: To evaluate the anterior and posterior maxillary width, the nasal passage volume, the oropharyngeal minimum axial area, and volume changes in unilateral cleft lip and palate patients treated with one of the following four expanders: Hyrax, Fan-Type, inverted mini-hyrax supported on the first permanent molars (iMini-M), or inverted mini-hyrax supported on the first premolars (iMini B). MATERIALS AND METHODS: A total of 40 patients with transverse maxillary deficiency who were submitted for rapid maxillary expansion were divided in four groups according to type of expander used. Cone-beam computed tomography images were taken before and 3 months after expansion. One-way analysis of variance was used to analyze the differences among the groups, and paired t-tests were used to evaluate the changes in each group. RESULTS: All groups showed a significant increase in the anterior maxillary width, with no intergroup differences. The iMini-B was the only group that did not show a significant increase in the posterior maxillary width. The intergroup comparison demonstrated differences among all groups except between Hyrax and iMini-M, which showed the greatest posterior expansions. The intragroup analysis showed a significant increase in the nasal passage volume in hyrax and inverted mini-hyrax on the molar groups, but the intergroup comparison revealed a significant difference only between Fan Type and inverted mini-hyrax on the molars. None of the expanders caused significant changes in the oropharyngeal measurements. CONCLUSIONS: Only the Hyrax and inverted mini-hyrax on the molar expanders effectively increased the nasal passage volume, and none of the expanders evaluated in this study modified the oropharyngeal airway. PMID- 26595655 TI - Synaptic adhesion molecule IgSF11 regulates synaptic transmission and plasticity. AB - Synaptic adhesion molecules regulate synapse development and plasticity through mechanisms that include trans-synaptic adhesion and recruitment of diverse synaptic proteins. We found that the immunoglobulin superfamily member 11 (IgSF11), a homophilic adhesion molecule that preferentially expressed in the brain, is a dual-binding partner of the postsynaptic scaffolding protein PSD-95 and AMPA glutamate receptors (AMPARs). IgSF11 required PSD-95 binding for its excitatory synaptic localization. In addition, IgSF11 stabilized synaptic AMPARs, as determined by IgSF11 knockdown-induced suppression of AMPAR-mediated synaptic transmission and increased surface mobility of AMPARs, measured by high throughput, single-molecule tracking. IgSF11 deletion in mice led to the suppression of AMPAR-mediated synaptic transmission in the dentate gyrus and long term potentiation in the CA1 region of the hippocampus. IgSF11 did not regulate the functional characteristics of AMPARs, including desensitization, deactivation or recovery. These results suggest that IgSF11 regulates excitatory synaptic transmission and plasticity through its tripartite interactions with PSD-95 and AMPARs. PMID- 26595659 TI - Mechanism-based candidate inhibitors of uridine diphosphate galactopyranose mutase (UGM). AB - Uridine diphosphate-galactopyranose mutase (UGM), an enzyme found in many eukaryotic and prokaryotic human pathogens, catalyzes the interconversion of UDP galactopyranose (UDP-Galp) and UDP-galactofuranose (UDP-Galf), the latter being used as the biosynthetic precursor of the galactofuranose polymer portion of the mycobacterium cell wall. We report here the synthesis of a sulfonium and selenonium ion with an appended polyhydroxylated side chain. These compounds were designed as transition state mimics of the UGM-catalyzed reaction, where the head groups carrying a permanent positive charge were designed to mimic both the shape and positive charge of the proposed galactopyranosyl cation-like transition state. An HPLC-based UGM inhibition assay indicated that the compounds inhibited about 25% of UGM activity at 500 uM concentration. PMID- 26595660 TI - Synthesis of 3-aminopropyl glycosides of linear beta-(1 -> 3)-D glucooligosaccharides. AB - 3-Aminopropyl glycosides of a series of linear beta-(1 -> 3)-linked D glucooligosaccharides containing from 3 to 13 monosaccharide units were efficiently prepared. The synthetic scheme featured highly regioselective glycosylation of 4,6-O-benzylidene-protected 2,3-diol glycosyl acceptors with a disaccharide thioglycoside donor bearing chloroacetyl groups at O-2' and -3' as a temporary protection of the diol system. Iteration of the deprotection and glycosylation steps afforded the series of the title oligoglucosides differing in length by two monosaccharide units. A novel procedure for selective removal of acetyl groups in the presence of benzoyl ones consisting in a brief treatment with a large excess of hydrazine hydrate has been proposed. PMID- 26595661 TI - Comparison of Diabetes Risk Following Smoking Cessation Treatment Using Varenicline Versus Bupropion Among Obese Smokers. AB - BACKGROUND: Recent literature suggests an initial increased risk of diabetes following smoking cessation. OBJECTIVES: To compare the risk of developing diabetes among obese smokers who tried to quit smoking using bupropion versus varenicline. METHODS: A population-based retrospective cohort study was conducted using the General Electric (GE) electronic medical record database (2006-2011). The cohort consisted of obese adult smokers without a diabetes diagnosis at baseline and newly initiating use of either bupropion or varenicline. This cohort was then followed for 1 year to observe the risk of developing diabetes. The relative risk of bupropion versus varenicline on developing diabetes was assessed using Cox Proportional Hazards regression model after controlling for covariates. RESULTS: The sample comprised of 78,002 obese smokers of which 1,937 (2.36%) developed diabetes during 1 year follow-up. Diabetes incidence rate was relatively comparable who used varenicline and bupropion (23.50 versus 25.80 per 1,000 person-years). Obese smokers who were prescribed bupropion had a statistically significant higher risk of developing diabetes during 1 year following cessation treatment than those who were prescribed varenicline. ([HR]: 1.58, 95% CI: 1.09-2.27) in the multivariate model. CONCLUSIONS/IMPORTANCE: Obese smokers who were prescribed bupropion might have a higher risk of developing diabetes during 1 year follow up compared to those who were prescribed varenicline. The clinical significance of the finding that bupropion had a higher risk of developing diabetes may need further investigation. PMID- 26595662 TI - Posttraumatic Stress among Victimized Latino Women: Evaluating the Role of Cultural Factors. AB - Research examining victimization and posttraumatic symptomatology among Latinos is lacking in the extant literature. This analysis used the victimized subsample (N = 752) of the Sexual Assault Among Latinas Study. The aim was to evaluate victimization prevalence and test the following hypotheses: (a) that victimization would be associated with higher levels of posttraumatic symptoms, (b) that cultural factors that move away from traditional Latino culture would be associated with higher levels of posttraumatic symptomatology, and (c) that cultural factors associated with traditional Latino culture would be related to lower posttraumatic symptomatology. Average age of the sample was 44.57 years, with three fourths having a high school education or higher, and two thirds having a household income below $30,000. Of exposure types, adulthood threats were most likely to result in Criterion A traumatic events (23.4%). Using the Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; American Psychiatric Association, 2000) based PTSD Checklist, between 8.8% and 45.5% of individuals met presumed PTSD diagnosis based on various PCL cut scores or algorithm criteria. Regression analyses indicated that the combined different types of adult and childhood victimizations, masculine gender role, and negative religious coping were associated with increased symptoms (betas ranging from .16 to .27). The results suggested a role of culture in posttraumatic symptoms for Latinas. PMID- 26595663 TI - Front-crawl stroke descriptors variability assessment for skill characterisation. AB - The goal of this article is to characterise front-crawl swimming skill based on variability pattern of technique descriptors. Nine national level and nine recreational swimmers performed three 300 m trials in a 50 m outdoor pool, at 70%, 80% and 90% of their front-crawl 400 m personal best time. Using wearable inertial measurement units (IMUs) and validated algorithms we assessed the variability of technique descriptors at each arm cycle (139 +/- 17 per trial). We calculated the duration of pull, push and non-propulsive phases, index of coordination (IdC), stroke length, stroke rate and intra-cyclic velocity variation. To track intra-trial technique variability, we calculated the Cauchy index to quantify the stability of multidimensional technique descriptors in space-time. Skilled swimmers, having access to divers motor solutions, achieved significantly higher velocities at similar intensities and similar IdC (P < 0.01) with more stable motor pattern (smaller Cauchy index). Besides, the similarity of intra-cyclic velocity variation at different intensities denotes that skilled swimmers used a wider dynamic range of velocity. We also introduced cycle velocity variation as a new metric of propulsive pattern repeatability and showed cycle velocity variation changes is correlated to the Cauchy index (rx,y = 0.72, P < 0.01). These findings indicate that IdC can be used as a predictor of performance only when swimmers of homogeneous expertise level are studied and suggest the scrutiny of both intra-cyclic velocity variation and cycle velocity variation as a requisite to study the motor adaptations of the swimmer in facing new constraints. PMID- 26595664 TI - Can upper airway surgery for OSA protect against cardiovascular sequelae via effects on coagulation? AB - CONCLUSION: Upper airway surgery is associated with salutary effects on the blood coagulation characteristics of OSA patients, a benefit that may be protective against cardiac and cerebrovascular morbidity and mortality. OBJECTIVE: Increased blood coagulation is an important factor linking OSA and cardiovascular complications. Surgery is an important method to treat OSA, but the effect of surgery on blood coagulation in OSA patients is unknown. METHODS: the authors performed a prospective clinical trial of adult OSA patients who underwent surgery from 2012-2014. Pre-operative and post-operative blood coagulation parameters and polysomnography (PSG) results were compared. RESULT: There were 61 subjects. The total rate of success in curing OSA was 11.5%. The rate of response after surgery was 40.8%. Overall, the Apnea-Hypopnea Index (AHI) improved after surgery (from 39.8 3 +/- 24.49 to 25.9 7 +/- 18.53, p < 0.01). After surgery, serum platelet counts (PLT) decreased (from 242.5 +/- 52.6 to 230.9 +/- 40.7, p=0.01), and Fibrinogen (FIB) levels declined (from 262.5 +/- 52.5 to 247.3 +/- 44.4, p = 0.02). Other blood coagulation parameters also improved: prothrombin time (PT) (from 10.6 2 +/- 0.62 to 10.8 6 +/- 0.70, p=0.01), activated partial thromboplastin time (APTT) (from 26.9 8 +/- 4.94 to 27.7 8 +/- 3.02, p = 0.06), and Thrombin time (TT) (from 19.5 3 +/- 0.84 to 20.1 1 +/- 1.31, p < 0.01). PMID- 26595665 TI - Profiling of lipid and glycogen accumulations under different growth conditions in the sulfothermophilic red alga Galdieria sulphuraria. AB - The unicellular red alga Galdieria sulphuraria grows efficiently and produces a large amount of biomass in acidic conditions at high temperatures. It has great potential to produce biofuels and other beneficial compounds without becoming contaminated with other organisms. In G. sulphuraria, biomass measurements and glycogen and lipid analyses demonstrated that the amounts and compositions of glycogen and lipids differed when cells were grown under autotrophic, mixotrophic, and heterotrophic conditions. Maximum biomass production was obtained in the mixotrophic culture. High amounts of glycogen were obtained in the mixotrophic cultures, while the amounts of neutral lipids were similar between mixotrophic and heterotrophic cultures. The amounts of neutral lipids were highest in red algae, including thermophiles. Glycogen structure and fatty acids compositions largely depended on the growth conditions. PMID- 26595666 TI - Two-phase photoperiodic cultivation of algal-bacterial consortia for high biomass production and efficient nutrient removal from municipal wastewater. AB - This study investigated the photoperiodic effects on the biomass production and nutrient removal in the algal-bacterial wastewater treatment, under the following three conditions: (1) a natural 12h:12h LD cycle, (2) a dark-elongated 12h:60h LD cycle, and (3) a two-phase photoperiodic 12h:60h LD, followed by 12h:12h LD cycles. The two-phase photoperiodic operation showed the highest dry cell weight and lipid productivity (282.6mgL(-1)day(-1), 71.4mgL(-1)day(-1)) and most efficient nutrient removals (92.3% COD, 95.8% TN, 98.1% TP). The genetic markers and sequencing analyses indicated rapid increments of bacteria, subsequent growths of Scenedesmus, and stabilized population balances between algae and bacteria. In addition, the two-phase photoperiod provided a higher potential for the algal-bacterial consortia to utilize various organic carbon substrates. PMID- 26595667 TI - Sexual Safety Planning as an HIV Prevention Strategy for Survivors of Domestic Violence. AB - Victims of domestic violence (DV) are not only subject to physical and emotional abuse but may also be at increased risk for less recognized dangers from infection with human immunodeficiency virus (HIV) and other sexually transmitted pathogens. Because of the close link between DV and sexual risk, women need to be educated about the consequences of acquiring a life-threatening sexually transmitted infection, risk reduction measures, and how to access appropriate HIV services for diagnosis and treatment. It is therefore critical for DV workers to receive sufficient training about the link between DV and HIV risk so that sexual safety planning can be incorporated into activities with their clients in the same way as physical safety plans. In this article, we discuss how the Many Hands Working Together project provides interactive training for workers in DV and DV affiliated agencies to increase their knowledge about HIV and teach sexual safety planning skills to achieve HIV risk reduction. PMID- 26595669 TI - The effect of carbon nanofillers on the performance of electromechanical polyaniline-based composite actuators. AB - Different types of crystalline carbon nanomaterials were used to reinforce polyaniline for use in electromechanical bilayer bending actuators. The objective is to analyze how the different graphitic structures of the nanocarbons affect and improve the in situ polymerized polyaniline composites and their subsequent actuator behavior. The nanocarbons investigated were multiwalled carbon nanotubes, nitrogen-doped carbon nanotubes, helical-ribbon carbon nanofibers and graphene oxide, each one presenting different shape and structural characteristics. Films of nanocarbon-PAni composite were tested in a liquid electrolyte cell system. Experimental design was used to select the type of nanocarbon filler and composite loadings, and yielded a good balance of electromechanical properties. Raman spectroscopy suggests good interaction between PAni and the nanocarbon fillers. Electron microscopy showed that graphene oxide dispersed the best, followed by multiwall carbon nanotubes, while nitrogen doped nanotube composites showed dispersion problems and thus poor performance. Multiwall carbon nanotube composite actuators showed the best performance based on the combination of bending angle, bending velocity and maximum working cycles, while graphene oxide attained similarly good performance due to its best dispersion. This parallel testing of a broad set of nanocarbon fillers on PAni composite actuators is unprecedented to the best of our knowledge and shows that the type and properties of the carbon nanomaterial are critical to the performance of electromechanical devices with other conditions remaining equal. PMID- 26595668 TI - Two new simple iridoids from the ant-plant Myrmecodia tuberosa and their antimicrobial effects. AB - Six iridoid derivatives (1-6), including two new compounds myrmecodoides A and B (1 and 2), were isolated from the ant-plant Myrmecodia tuberosa. Their structures were determined on the basis of spectroscopic data ((1)H and (13)C NMR, HSQC, HMBC, (1)H-(1)H COSY, NOESY and HR-ESI-MS) and by comparison with the literature values. Among isolates, 3 and 4 exhibit weak antibacterial effect against Staphylococcus aureus subsp. aureus with MIC value of 100.0 MUg/mL. PMID- 26595670 TI - Review on recent progress in observations, source identifications and countermeasures of PM2.5. AB - Recently, PM2.5 (atmospheric fine particulate matter with aerodynamic diameter <= 2.5 MUm) have received so much attention that the observations, source appointment and countermeasures of it have been widely studied due to its harmful impacts on visibility, mood (mental health), physical health, traffic safety, construction, economy and nature, as well as its complex interaction with climate. A review on the PM2.5 related research is necessary. We start with summary of chemical composition and characteristics of PM2.5 that contains both macro and micro observation results and analysis, wherein the temporal variability of concentrations of PM2.5 and major components in many recent reports is embraced. This is closely followed by an overview of source appointment, including the composition and sources of PM2.5 in different countries in the six inhabitable continents based on the best available results. Besides summarizing PM2.5 pollution countermeasures by policy, planning, technology and ideology, the World Air Day is proposed to be established to inspire and promote the crucial social action in energy-saving and emission reduction. Some updated knowledge of the important topics (such as formation and evolution mechanisms of hazes, secondary aerosols, aerosol mass spectrometer, organic tracers, radiocarbon, emissions, solutions for air pollution problems, etc.) is also included in the present review by logically synthesizing the studies. In addition, the key research challenges and future directions are put forward. Despite our efforts, our understanding of the recent reported observations, source identifications and countermeasures of PM2.5 is limited, and subsequent efforts both of the authors and readers are needed. PMID- 26595671 TI - Atom efficiency in small molecule and macromolecule synthesis: general discussion. PMID- 26595672 TI - Large-Scale Glycomics of Livestock: Discovery of Highly Sensitive Serum Biomarkers Indicating an Environmental Stress Affecting Immune Responses and Productivity of Holstein Dairy Cows. AB - Because various stresses strongly influence the food productivity of livestock, biomarkers to indicate unmeasurable environmental stress in domestic animals are of increasing importance. Thermal comfort is one of the basic principles of dairy cow welfare that enhances productivity. To discover sensitive biomarkers that monitor such environmental stresses in dairy cows, we herein performed, for the first time, large-scale glycomics on 336 lactating Holstein cow serum samples over 9 months between February and October. Glycoblotting combined with MALDI TOF/MS and DMB/HPLC allowed for comprehensive glycomics of whole serum glycoproteins. The results obtained revealed seasonal alterations in serum N glycan levels and their structural characteristics, such as an increase in high mannose type N-glycans in spring, the occurrence of di/triantennary complex type N-glycans terminating with two or three Neu5Gc residues in summer and autumn, and N-glycans in winter dominantly displaying Neu5Ac. A multivariate analysis revealed a correlation between the serum expression levels of these season specific glycoforms and productivity. PMID- 26595673 TI - Driving Adsorbed Gold Nanoparticle Assembly by Merging Lipid Gel/Fluid Interfaces. AB - Surface forces between inorganic nanoparticles and lipid bilayer is of great relevance to biophysics, medicine, and nanobiotechnology. Adsorbed nanoparticles may influence the fluidity of the underlying lipids, which may in turn influence nanoparticle assembly. Herein three types of lipids (DOPC, Tc = -20 degrees C; DMPC, Tc = 23 degrees C; and DPPC, Tc = 41 degrees C) are used, all with the same phosphocholine (PC) headgroup. Gold nanoparticle (AuNP) color change is monitored as a function of lipid phase transition temperature (Tc), surface ligands on AuNPs, and temperature. Liposomes with higher fluidity induce much faster aggregation of AuNPs. Aside from the kinetic aspect of faster diffusion on fluid bilayers, this faster color change is attributed to the local lipid gelation and merging of gelled regions to eliminate the interface between different lipid phases. PMID- 26595674 TI - Synthesis of a Liposomal MUC1 Glycopeptide-Based Immunotherapeutic and Evaluation of the Effect of l-Rhamnose Targeting on Cellular Immune Responses. AB - Generation of a CD8(+) response to extracellular antigen requires processing of the antigen by antigen presenting cells (APC) and cross-presentation to CD8(+) T cell receptors via MHC class I molecules. Cross-presentation is facilitated by efficient antigen uptake followed by immune-complex-mediated maturation of the APCs. We hypothesize that improved antigen uptake of a glycopeptide sequence containing a CD8(+) T cell epitope could be achieved by delivering it on a liposome surface decorated with an immune complex-targeting ligand, an l-Rhamnose (Rha) epitope. We synthesized a 20-amino-acid glycopeptide TSAPDT(GalNAc)RPAPGSTAPPAHGV from the variable number tandem repeat region of the tumor marker MUC1 containing an N-terminal azido moiety and a tumor-associated alpha-N-acetyl galactosamine (GalNAc) at the immunogenic DTR motif. The MUC1 antigen was attached to Pam3Cys, a Toll-like receptor-2 ligand via copper(I) catalyzed azido-alkyne cycloaddition (CuAAc) chemistry. The Rha-decorated liposomal Pam3Cys-MUC1-Tn 4 vaccine was evaluated in groups of C57BL/6 mice. Some groups were previously immunized to generate anti-Rha antibodies. Anti-Rha antibody expressing mice that received the Rha liposomal vaccine showed higher cellular immunogenicity compared to the control group while maintaining a strong humoral response. PMID- 26595677 TI - Immune evasion mechanisms of arenaviruses. PMID- 26595679 TI - Multistate-Mediated Rearrangements and FeCl2 Elimination in Dinuclear FePd Complexes. AB - Mass spectrometric, spectroscopic, and computational characterization of a novel bifunctional iron-palladium complex proves a change of coordination upon solvation. Collisional excitation reveals FeCl2 and HCl elimination in a solvent modulated competition. Hereby, syn and anti isomers, identified by theoretical calculations, favor and disfavor FeCl2 elimination, respectively. The FeCl2 elimination likely proceeds by chlorido and Cp ligand exchange among the metallic centers in a concerted, ballet-like manner. A multitude of stationary points were identified along the computed multistep reaction coordinates of the three conceivable spin states. The quintet state shows a static Jahn-Teller type relaxation by a tilt away of the Cp ligand at the iron center. The direct singlet quintet spin crossover is an unprecedented assumption, leaving behind the triplet state as a spectator without involvement. The FeCl2 elimination would decrease catalytic activity. It is kinetically hindered within a range of applicable temperatures in conceivable technical applications. PMID- 26595678 TI - Effects of electromagnetic fields from mobile phones on depression and anxiety after titanium mesh cranioplasty among patients with traumatic brain injury. AB - OBJECTIVE: To explore the effects of radiofrequency-electromagnetic fields (RF EMFs) from mobile phones on depression and anxiety after titanium mesh cranioplasty among patients with traumatic brain injury (TBI). METHODS: Two hundred and twenty patients with TBI and titanium mesh cranioplasty who were hospitalized from 2008-2012 were recruited in this study. From November-December 2012, the relevant information was surveyed including socio-demographic characteristics, lifestyle variables, injury-related information, RF-EMF exposure of mobile phone, Self-rating Depression Scale (SDS) and Self-rating Anxiety Scale (SAS). Associations of RF-EMFs exposure after titanium mesh cranioplasty with SAS and SDS were respectively estimated by multivariable linear regression models. RESULTS: The patients with long durations of mobile phone use (beta = -6.6, p = 0.002), long individual call duration (beta = -5.3, p = 0.012), more daily calls (beta = -3.6, p = 0.027), invariably answer call immediately (beta = -3.9, p = 0.022) and high comprehensive exposure level (beta = -4.8, p = 0.003) had a lower score of depression compared with those without a mobile phone. Moreover, an ipsilateral and contralateral answering phone enhanced the protective effect on depression. Individuals with a long duration of mobile phone use had a lower score of anxiety (beta = -4.2, p = 0.008), while those with a bilateral answering phone had higher anxiety (beta = 3.9, p = 0.012) in comparison to those without a mobile phone. CONCLUSION: RF-EMFs after cranioplasty were significantly associated with the lower risk of depression and anxiety status among patients with TBI. Chronic and frequent RF-EMFs exposure may improve psychiatric disorders among patients with TBI. PMID- 26595675 TI - Indirect p53-dependent transcriptional repression of Survivin, CDC25C, and PLK1 genes requires the cyclin-dependent kinase inhibitor p21/CDKN1A and CDE/CHR promoter sites binding the DREAM complex. AB - The transcription factor p53 is central to cell cycle control by downregulation of cell cycle-promoting genes upon cell stress such as DNA damage. Survivin (BIRC5), CDC25C, and PLK1 encode important cell cycle regulators that are repressed following p53 activation. Here, we provide evidence that p53-dependent repression of these genes requires activation of p21 (CDKN1A, WAF1, CIP1). Chromatin immunoprecipitation (ChIP) data indicate that promoter binding of B-MYB switches to binding of E2F4 and p130 resulting in a replacement of the MMB (Myb MuvB) by the DREAM complex. We demonstrate that this replacement depends on p21. Furthermore, transcriptional repression by p53 requires intact DREAM binding sites in the target promoters. The CDE and CHR cell cycle promoter elements are the sites for DREAM binding. These elements as well as the p53 response of Survivin, CDC25C, and PLK1 are evolutionarily conserved. No binding of p53 to these genes is detected by ChIP and mutation of proposed p53 binding sites does not alter the p53 response. Thus, a mechanism for direct p53-dependent transcriptional repression is not supported by the data. In contrast, repression by DREAM is consistent with most previous findings and unifies models based on p21-, E2F4-, p130-, and CDE/CHR-dependent repression by p53. In conclusion, the presented data suggest that the p53-p21-DREAM-CDE/CHR pathway regulates p53 dependent repression of Survivin, CDC25C, and PLK1. PMID- 26595676 TI - Down-regulation of oxidative phosphorylation in the liver by expression of the ATPase inhibitory factor 1 induces a tumor-promoter metabolic state. AB - The ATPase Inhibitory Factor 1 (IF1) is an inhibitor of the mitochondrial H+-ATP synthase that regulates the activity of both oxidative phosphorylation (OXPHOS) and cell death. Here, we have developed transgenic Tet-On and Tet-Off mice that express a mutant active form of hIF1 in the hepatocytes to restrain OXPHOS in the liver to investigate the relevance of mitochondrial activity in hepatocarcinogenesis. The expression of hIF1 promotes the inhibition of OXPHOS in both Tet-On and Tet-Off mouse models and induces a state of metabolic preconditioning guided by the activation of the stress kinases AMPK and p38 MAPK. Expression of the transgene significantly augmented proliferation and apoptotic resistance of carcinoma cells, which contributed to an enhanced diethylnitrosamine-induced liver carcinogenesis. Moreover, the expression of hIF1 also diminished acetaminophen-induced apoptosis, which is unrelated to differences in permeability transition pore opening. Mechanistically, cell survival in hIF1-preconditioned hepatocytes results from a nuclear factor erythroid 2-related factor (Nrf2)-guided antioxidant response. The results emphasize in vivo that a metabolic phenotype with a restrained OXPHOS in the liver is prone to the development of cancer. PMID- 26595680 TI - Hepcidin determination in dried blood by microfluidic LC-MS/MS: comparison of DBS and volumetric absorptive microsampling for matrix effect and recovery. AB - BACKGROUND: Dried blood analysis experiences a growing interest due to practical, ethical and financial advantages compared with classical wet plasma or serum analysis. Besides classical DBS, new alternatives are commercialized as volumetric absorptive microsampling (VAMS) that are expected to overcome hematocrit influence. RESULTS: The feasibility of hepcidin (a peptide hormone) extraction and determination from DBS and VAMS blood sampling was investigated. Experimental design was used to determine the optimal extraction conditions. Matrix effect and extraction recovery were studied and a special attention was paid to phospholipid removal. CONCLUSION: The data suggest that the combination of VAMS and phospholipid removal plates provides low matrix effect and high sensitivity, and constitutes an easy and promising protocol for hepcidin analysis. PMID- 26595681 TI - Three-Dimensional Metal-Catecholate Frameworks and Their Ultrahigh Proton Conductivity. AB - A series of three-dimensional (3D) extended metal catecholates (M-CATs) was synthesized by combining the appropriate metal salt and the hexatopic catecholate linker, H6THO (THO(6-) = triphenylene-2,3,6,7,10,11-hexakis(olate)) to give Fe(THO).Fe(SO4) (DMA)3, Fe-CAT-5, Ti(THO).(DMA)2, Ti-CAT-5, and V(THO).(DMA)2, V CAT-5 (where DMA = dimethylammonium). Their structures are based on the srs topology and are either a 2-fold interpenetrated (Fe-CAT-5 and Ti-CAT-5) or noninterpenetrated (V-CAT-5) porous anionic framework. These examples are among the first catecholate-based 3D frameworks. The single crystal X-ray diffraction structure of the Fe-CAT-5 shows bound sulfate ligands with DMA guests residing in the pores as counterions, and thus ideally suited for proton conductivity. Accordingly, Fe-CAT-5 exhibits ultrahigh proton conductivity (5.0 * 10(-2) S cm( 1)) at 98% relative humidity (RH) and 25 degrees C. The coexistence of sulfate and DMA ions within the pores play an important role in proton conductivity as also evidenced by the lower conductivity values found for Ti-CAT-5 (8.2 * 10(-4) S cm(-1) at 98% RH and 25 degrees C), whose structure only contained DMA guests. PMID- 26595682 TI - An investigation of the role of some person and situation variables in multiple cue probability learning. AB - Making decisions using judgements of multiple non-deterministic indicators is an important task, both in everyday and professional life. Learning of such decision making has often been studied as the mapping of stimuli (cues) to an environmental variable (criterion); however, little attention has been paid to the effects of situation-by-person interactions on this learning. Accordingly, we manipulated cue and feedback presentation mode (graphic or numeric) and task difficulty, and measured individual differences in working memory capacity (WMC). We predicted that graphic presentation, fewer cues, and elevated WMC would facilitate learning, and that person and task characteristics would interact such that presentation mode compatible with the decision maker's cognitive capability (enhanced visual or verbal WMC) would assist learning, particularly for more difficult tasks. We found our predicted main effects, but no significant interactions, except that those with greater WMC benefited to a larger extent with graphic than with numeric presentation, regardless of which type of working memory was enhanced or number of cues. Our findings suggest that the conclusions of past research based predominantly on tasks using numeric presentation need to be reevaluated and cast light on how working memory helps us learn multiple cue criterion relationships, with implications for dual-process theories of cognition. PMID- 26595684 TI - The challenges for cancer chemoprevention. AB - The incidence of cancer is rising in parallel with an ageing populous thus increasing the strain on both treatment options and budgets for healthcare providers worldwide. New cancer therapies are being developed but at what cost? The new treatments are expensive and poor survival rates still exist for some cancers. What is needed now is to prevent or at least limit the disease occurring in the first place. This review evaluates the current situation and the progress in upcoming strategies as well as suggesting some areas for further research within the increasingly important field of cancer chemoprevention. The key principles of cancer chemoprevention are discussed and areas for improvement highlighted. Despite significant progress, chemoprevention has not been widely adopted. Cancer chemoprevention has many challenges to face but this only emphasises the size of the task. These hurdles include a lack of awareness of the benefits, a lack of interest and a lack of investment in taking prevention forward. Despite the huge potential importance of cancer prevention and clinical success stories such as the well-publicised HPV vaccine, the challenges remain significant. With cancer and its treatment being a global issue, the opportunities offered by chemoprevention must be re-evaluated and uptake of chemoprevention actively encouraged. If chemoprevention is to be adopted successfully, a holistic approach is required. This approach will involve multidisciplinary teams of healthcare providers and scientists with the big challenge particularly for medicinal chemists being to design and synthesise the ideal chemopreventative agent. PMID- 26595685 TI - Dose-Response Relationships for Meningioma Radiosurgery. AB - OBJECTIVE: Dose-response relationships for meningioma radiosurgery are poorly characterized. We evaluated determinants of local recurrence for meningiomas treated with Gamma Knife radiosurgery (GKRS), to guide future treatment approaches to optimize tumor control. MATERIALS AND METHODS: A total of 101 consecutive patients (108 tumors) who underwent GKRS for benign, atypical, or malignant meningiomas between 1998 and 2011 were studied. Local recurrence was assessed. Cox proportional hazards and logistic regression analyses were used to determine the association of patient-related, tumor-related, and treatment related characteristics with local recurrence. Acute and late toxicity was evaluated. RESULTS: World Health Organization (2007 classification) tumor grade was I (82%), II (11%), or III (7%). Median dose was 14 Gy (range, 10 to 18 Gy) for grade I tumors and 16 Gy (range, 12 to 20 Gy) for grade II and III tumors. Median follow-up was 25 months (maximum, 17 y). Two- /5-year actuarial local control rates were 100%/98% for grade I tumors and 76%/56% for grade II/III tumors. Higher tumor grade and lower GKRS dose were associated with local failure. In this cohort, there was a 42% relative reduction in local recurrence for each 1 Gy of dose escalation. CONCLUSIONS: Treatment was well tolerated with no moderate or severe toxicity. Tumor control was excellent in benign tumors and suboptimal in higher grade tumors. Because the main determinant of local recurrence was GKRS dose, we recommend dose escalation for atypical or malignant tumors to doses between 16 and 20 Gy where critical structures allow. PMID- 26595683 TI - Association of Elevated Amyloid Levels With Cognition and Biomarkers in Cognitively Normal People From the Community. AB - IMPORTANCE: The role of amyloid in the progression of Alzheimer disease (AD) pathophysiology is of central interest to the design of randomized clinical trials. The presence of amyloid has become a prerequisite for enrollment in several secondary prevention trials for AD, yet the precise effect of elevated amyloid levels on subsequent clinical and biomarker events is less certain. OBJECTIVE: To explore the effect of elevated amyloid levels on subsequent changes in cognition and biomarkers. DESIGN, SETTING, AND PARTICIPANTS: A total of 564 cognitively normal individuals (median age, 78 years) from the Mayo Clinic Study of Aging, a population-based longitudinal study in Olmsted County, Minnesota, with serial cognitive data were selected for this study. The data used in this study were collected from January 12, 2006, to January 9, 2014. Individuals included in this study had undergone magnetic resonance imaging, fluorodeoxyglucose positron emission tomography (FDG-PET), and Pittsburgh Compound B (PiB) PET at baseline were not cognitively impaired at baseline and had at least 1 clinical follow-up. A subset of 286 individuals also underwent serial imaging. Elevated amyloid level was defined as a standardized uptake value ratio of greater than 1.5 on PiB PET. Associations with baseline amyloid status and baseline and longitudinal change in clinical and imaging measures were evaluated after adjusting for age and hippocampal volume. APOE4 effects were also evaluated. MAIN OUTCOMES AND MEASURES: Cognitive measures of memory, language, attention/executive function, visuospatial skills, PiB levels, hippocampal and ventricular volumes, and FDG-PET measures. RESULTS: At baseline, 179 (31.7%) individuals with elevated amyloid levels had poorer cognition in all domains measured, reduced hippocampal volume, and greater FDG-PET hypometabolism. Elevated amyloid levels at baseline were associated with a greater rate of cognitive decline in all domains (0.04 to 0.09 z score units per year) except language and a greater rate of amyloid accumulation (1.6% per year), hippocampal atrophy (30 mm3 per year), and ventricular enlargement (565 mm3 per year). Elevated amyloid levels were also associated with an increased risk of mild cognitive impairment (hazard ratio, 2.9; 95% CI, 1.7-5.0, and hazard ratio, 1.6; 95% CI, 0.9-2.8, for PiB+ APOE4 carriers and PiB+ noncarriers, respectively, compared with PiB- noncarriers). These associations were largely independent of APOE4. CONCLUSIONS AND RELEVANCE: In persons selected from a population-based study, elevated amyloid levels at baseline were associated with worse cognition and imaging biomarkers at baseline and with greater clinical decline and neurodegeneration. These results have implications for the design of randomized clinical trials for AD. PMID- 26595686 TI - Method of quantifying 3D strain distribution in skeletal muscle using cine phase contrast MRI. AB - Intramuscular pressure (IMP), a correlate of muscle tension, may fill an important clinical testing void. A barrier to implementing this measure clinically is its non-uniform distribution, which is not fully understood. Pressure is generated by changes in fluid mass and volume, therefore 3D volumetric strain distribution may affect IMP distribution. The purpose of this study was to develop a method for quantifying 3D volumetric strain distribution in the human tibialis anterior (TA) during passive tension using cine phase contrast (CPC) MRI and to assess its accuracy and precision.Five healthy subjects each participated in three data collections. A custom MRI-compatible apparatus repeatedly rotated a subject's ankle between 0 degrees and 26 degrees plantarflexion while CPC MRI data were collected. Additionally, T2-weighted images of the lower leg were collected both before and after the CPC data collection with the ankle stationary at both 0 degrees and 26 degrees plantarflexion for TA muscle segmentation. A 3D hexahedral mesh was generated based on the TA surface before CPC data collection with the ankle at 0 degrees plantarflexion and the node trajectories were tracked using the CPC data. The volumetric strain of each element was quantified.Three tests were employed to assess the measure accuracy and precision. First, to quantify leg position drift, the TA segmentations were compared before and after CPC data collection. The Hawsdorff distance measure (error) was 1.5 +/- 0.7 mm. Second, to assess the surface node trajectory accuracy, the deformed mesh surface was compared to the TA segmented at 26 degrees of ankle plantarflexion. This error was 0.6 +/- 0.2 mm. Third, the standard deviation of volumetric strain across the three data collections was calculated for each element and subject. The median between-day variability across subjects and mesh elements was 0.06 mm3 mm(-3) (95% confidence interval 0.01 to 0.18 mm3 mm(-3)). Overall the results demonstrated excellent accuracy and precision. PMID- 26595687 TI - JC Virus Replication at the First Symptoms of Multiple Sclerosis: A Case Report. AB - Multiple sclerosis (MS) is an autoimmune, demyelinating disorder of unknown etiology, in which viruses have been suggested as etiological/triggering agents. The attention to the association between viruses and MS has been rekindled by the development of progressive multifocal leukoencephalopathy in natalizumab-treated MS patients. Here we report the case of a woman with JC virus (JCV) replication in the cerebrospinal fluid, blood and urine collected at the first symptoms of MS and during several follow-up visits. This observation shows that JCV can be associated with MS without a relation with natalizumab treatment, although the triggering role of JCV in some cases of MS will require further studies. PMID- 26595692 TI - What are the precautions with proton pump inhibitor use for reflux disease? AB - Gastroesophageal reflux disease (GERD) affects 10% to 20% of the western world's population. Current treatment guidelines recommend proton pump inhibitors (PPIs) as first-line therapy. Although PPIs cause mild adverse reactions, they pose risks, particularly for older adults with comorbidities. PMID- 26595693 TI - A case of familial syndactyly associated with eye and dental abnormalities. AB - Syndactyly occurs in 1 in 2,000 live births and is more common in white children. This article describes a patient with syndactyly and additional abnormalities indicating oculodentodigital dysplasia. PMID- 26595694 TI - Treatment of a complex thoracoabdominal aneurysm and dissection with a branched graft. AB - This article describes the management of a patient with a complex symptomatic thoracoabdominal aneurysm and discusses the branched graft approach to surgical repair of complex aortic aneurysms. The case highlights the importance of a team approach during a complex, high-risk surgery and the perioperative period. PMID- 26595695 TI - Caring for patients who are deaf or hard of hearing. AB - Patients who are deaf and hard of hearing often find the American healthcare system to be inaccessible due to communication barriers. This article describes facilities' and providers' requirements under the Americans with Disabilities Act to provide qualified interpreters and other assistive devices to patients who are deaf or hard of hearing. Removing communication barriers can protect healthcare providers from potential legal action and lets them deliver consistent, quality healthcare to all patients. PMID- 26595696 TI - The Interservice Physician Assistant Program: Education quantity and quality. AB - The Interservice Physician Assistant Program (IPAP) was formed in 1996 by the assimilation of three service programs (Army, Air Force, and Navy). Applicants are selected from each service and upon successful completion of the program become commissioned officers within their respective medical corps. Clinical training takes place within military treatment facilities across the United States. Located in San Antonio, Texas, the program graduates about 169 PAs a year. Graduates are deployed to attend to service personnel, refugees, civilians, and victims of epidemics. The IPAP is unique in that it is the largest PA program in the world and its applicant pool is restricted to military personnel. PMID- 26595697 TI - An unusual left ventricular mass. PMID- 26595699 TI - The simultaneous mass and energy evaporation (SM2E) model. AB - In this article, the Simultaneous Mass and Energy Evaporation (SM2E) model is presented. The SM2E model is based on theoretical models for mass and energy transfer. The theoretical models systematically under or over predicted at various flow conditions: laminar, transition, and turbulent. These models were harmonized with experimental measurements to eliminate systematic under or over predictions; a total of 113 measured evaporation rates were used. The SM2E model can be used to estimate evaporation rates for pure liquids as well as liquid mixtures at laminar, transition, and turbulent flow conditions. However, due to limited availability of evaporation data, the model has so far only been tested against data for pure liquids and binary mixtures. The model can take evaporative cooling into account and when the temperature of the evaporating liquid or liquid mixture is known (e.g., isothermal evaporation), the SM2E model reduces to a mass transfer-only model. PMID- 26595700 TI - Cardiovascular implantable electronic device lead extraction: evidence, techniques, results, and future directions. AB - PURPOSE OF REVIEW: Cardiovascular implantable electronic devices are widely used to treat symptomatic arrhythmias, prevent sudden cardiac death, and improve symptoms and cardiac function. Continued population growth and expanding indications have resulted in a progressive increase in the number of cardiovascular implantable electronic device implantations. Mirroring this growth, an increasing number of leads require removal because of a variety of indications. Transvenous lead extraction continues to evolve with better techniques and risk-management strategies. This review highlights the indications, techniques, procedural outcomes, and future directions of arrhythmia device management and extraction. RECENT FINDINGS: Indications for extractions are reviewed in light of newly published data. Same day contralateral reimplantation has been shown to be safe in patients with localized pocket infection. Alternative extraction techniques, utilizing the femoral and internal jugular veins, provide additional routes for device removal as stand-alone procedures or in cases of difficult extraction via the subclavian vein. Preprocedural imaging to identify adherence sites and cardiac perforation can help to reduce complications. Routine capsulectomy at generator change does not seem to reduce the risk of device infection, and multiple trials are underway to assess other methods of reducing infections as part of a lead management strategy. SUMMARY: Improvement in technology, alternative routes of extraction and preprocedural imaging continue to add to procedural efficacy and reduce complication rates of lead extraction. PMID- 26595701 TI - Salt in the diet in patients with heart failure: what to recommend. AB - PURPOSE OF REVIEW: Recognizing the relevance of sodium balance in heart failure, it has been presumed that patients with heart failure benefit from a low-sodium diet, though its efficacy and safety are unclear. The purpose of this review is to provide insight into the currently available evidence base for the effects of dietary sodium restriction in patients with chronic heart failure. RECENT FINDINGS: There has been an increasing body of evidence on the effects of sodium restriction in heart failure; however, both observational and experimental studies have shown mixed results. Recent randomized controlled trial data has even suggested that sodium restriction may have detrimental effects in patients with heart failure. Only a few randomized controlled trials have included clinical outcomes as a primary endpoint. These have been either unpowered to test the association between reduced sodium intake and outcomes, or conducted in the context of an aggressive diuretic treatment and fluid restriction. SUMMARY: The effects of a low-sodium diet on clinical outcomes in patients with heart failure remain unclear. Ongoing research into the effects of lowering sodium for patients with chronic or acute heart failure will shed light on the importance of holistic self-care and dietary strategies in heart failure. PMID- 26595702 TI - The role of peer arrests on the development of youths' attitudes towards the justice system. AB - During adolescence, youths develop attitudes about the justice system. Although there is consistent evidence that personal experiences with legal actors contribute to attitudes toward the justice system, adolescents' attitudes may also be influenced vicariously through their friends' experiences with the justice system. Using data from a sample of 1,216 first-time male adolescent offenders, the present study examines how attitudes toward the justice system develop over 24 months following the adolescent's first arrest. Even after accounting for personal justice system experiences, including self-reported offending, time on the streets, and contacts with the police, results indicate that adolescents with friends who were arrested report more negative attitudes toward the justice system than those without friends who were arrested. Further, experiencing a friend's arrest has a larger impact on the attitudes of youths who are experiencing it for the first time. We provide evidence that attitudes toward the justice system are a product of accumulated social experiences-both personal and vicarious-with the justice system. PMID- 26595703 TI - Recidivism following mental health court exit: Between and within-group comparisons. AB - Over the past decade, Mental Health Courts (MHCs) have spread rapidly across the U.S. These courts aim to reduce recidivism among adults with mental illnesses through diversion into community-based treatment. Extant research suggests that MHCs can be effective in reducing recidivism, but also demonstrates that effectiveness varies as a function of characteristics of the participants (e.g., criminal history) and the program (e.g., coercion). Less is known regarding the extent to which process-related factors (e.g., length of participation, time between referral and receipt of services) impact effectiveness. Prior research also is limited by a focus on recidivism during MHC as opposed to postexit. To address these knowledge gaps, we examined recidivism 1 year postexit for a group of MHC participants (n = 57) and offenders receiving treatment as usual (TAU; n = 40), total N = 97. We also investigated the influence of individual characteristics and process factors on changes in jail days 1 year preentry to 1 year postexit for MHC participants. Overall, results provide some evidence supporting the effectiveness of MHCs. MHC participants had significantly fewer jail days, but not charges or convictions, relative to TAU participants. Among MHC participants, graduation from the MHC, presence of co-occurring substance use, and longer length of MHC participation were associated with greater reductions in jail days. Other process factors were unrelated to reductions in recidivism. Findings suggest that MHCs may be particularly effective for high risk participants and that time spent in a MHC has positive effects on recidivism, regardless of graduation status. PMID- 26595704 TI - The grain-size lineup: A test of a novel eyewitness identification procedure. AB - When making a memorial judgment, respondents can regulate their accuracy by adjusting the precision, or grain size, of their responses. In many circumstances, coarse-grained responses are less informative, but more likely to be accurate, than fine-grained responses. This study describes a novel eyewitness identification procedure, the grain-size lineup, in which participants eliminated any number of individuals from the lineup, creating a choice set of variable size. A decision was considered to be fine-grained if no more than 1 individual was left in the choice set or coarse-grained if more than 1 individual was left in the choice set. Participants (N = 384) watched 2 high-quality or low-quality videotaped mock crimes and then completed 4 standard simultaneous lineups or 4 grain-size lineups (2 target-present and 2 target-absent). There was some evidence of strategic regulation of grain size, as the most difficult lineup was associated with a greater proportion of coarse-grained responses than the other lineups. However, the grain-size lineup did not outperform the standard simultaneous lineup. Fine-grained suspect identifications were no more diagnostic than suspect identifications from standard lineups, whereas coarse-grained suspect identifications carried little probative value. Participants were generally reluctant to provide coarse-grained responses, which may have hampered the utility of the procedure. For a grain-size approach to be useful, participants may need to be trained or instructed to use the coarse-grained option effectively. PMID- 26595705 TI - Re: Assessment of competence in focused assessment with sonography for trauma (FAST) examination. PMID- 26595706 TI - Assessment of competence in focused assessment with sonography for trauma (FAST) examination. PMID- 26595707 TI - A case of small bowel obstruction after large mesenteric hematoma in blunt abdominal trauma. PMID- 26595708 TI - Multicenter external validation of the Geriatric Trauma Outcome Score: A study by the Prognostic Assessment of Life and Limitations After Trauma in the Elderly (PALLIATE) consortium. AB - BACKGROUND: A prognostic tool for geriatric mortality after injury called the Geriatric Trauma Outcome Score (GTOS), where GTOS = [age] + [ISS * 2.5] + [22 if transfused any PRBCs by 24 hours after admission], was previously developed based on 13 years of data from geriatric trauma patients admitted to Parkland Hospital. We sought to validate this model. METHODS: Four Level I centers identified subjects who are 65 years or older for the period of the original study. The GTOS model was first specified using the formula [GTOS = age + (ISS * 2.5) + 22 (if given PRBC by 24 hours)] developed from the Parkland sample and then used as the sole predictor in a logistic mixed model estimating probability of mortality in the validation sample, accounting for site as a random effect. We estimated the misclassification (error) rate, Brier score, Tjur R, and the area under the curve in evaluating the predictive performance of the GTOS model. RESULTS: The original Parkland sample (n = 3,841) had a mean (SD) age of 76.6 (8.1) years, mean (SD) ISS of 12.4 (9.9), mortality of 10.8%, and 11.9% receiving PRBCs at 24 hours. The validation sample (n = 18,282) had a mean (SD) age of 77.0 (8.1) years, mean (SD) ISS of 12.3 (10.6), mortality of 11.0%, and 14.1% receiving PRBCs at 24 hours. Fitting the GTOS model to the validation sample revealed that the parameter estimates from the validation sample were similar to those of fitting it to the Parkland sample with highly overlapping 95% confidence limits. The misclassification (error) rate for the GTOS logistic model applied to the validation sample was 9.97%, similar to that of the Parkland sample (9.79%). Brier score, Tjur R, and the area under the curve for the GTOS logistic model when applied to the validation sample were 0.07, 0.25, and 0.86, respectively, compared with 0.08, 0.20, and 0.82, respectively, for the Parkland sample. CONCLUSION: With the use of the data available at 24 hours after injury, the GTOS accurately predicts in-hospital mortality for the injured elderly. LEVEL OF EVIDENCE: Prognostic study, level III. PMID- 26595709 TI - Use of endotracheal tubes with subglottic secretion drainage reduces ventilator associated pneumonia in trauma patients. AB - BACKGROUND: Patients sustaining traumatic injuries have a higher incidence of ventilator-associated pneumonia (VAP) compared with other critically ill patient populations. Previous studies of patients with predominantly medical diagnoses and use of endotracheal tubes allowing subglottic secretion drainage (ETT-SSD) have shown significant reduction in VAP rates. We hypothesized that the use of ETT-SSD would reduce VAP in trauma patients. METHODS: A retrospective review from 2010 to 2014 of adult trauma patients orotracheally intubated for more than 48 hours was performed at a Level 1 trauma center. Patients were compared based on standard endotracheal tube (ETT) versus ETT-SSD for the primary outcome VAP per 1,000 ventilator days. The diagnosis of VAP was made by quantitative bronchoalveolar lavage cultures as defined by Centers for Disease Control and Prevention criteria. Patients with ETT-SSD were matched to patients with ETT based on age group, sex, mechanism of injury, head and chest Abbreviated Injury Scale (AIS) score, and Injury Severity Score (ISS). RESULTS: Of 1,135 patients included in the study, 667 patients had ETT and 468 had ETT-SSD. Groups did not differ by demographics, mechanism of injury, Glasgow Coma Scale (GCS) score, alcohol intoxication, or ISS. Patients with ETT-SSD had significantly higher head AIS score but lower chest AIS score. In matched cohorts, ETT-SSD had a lower VAP rate (5.7 vs. 9.3 for ETT, p = 0.03), decreased ventilator days (12 vs. 14, p = 0.04), and decreased intensive care unit length of stay (13 days vs. 16 days, p = 0.003). CONCLUSION: After controlling for confounding factors, ETT-SSD decreased VAP rate, ventilator days, and intensive care unit length of stay in trauma patients. In this high-risk patient population, we recommend routine use of ETT SSD to decrease VAP. LEVEL OF EVIDENCE: Therapeutic/care management study, level III. PMID- 26595710 TI - A prospective, controlled clinical evaluation of surgical stabilization of severe rib fractures. AB - BACKGROUND: Previous studies of surgical stabilization of rib fractures (SSRF) have been limited by small sample sizes, retrospective methodology, and inclusion of only patients with flail chest. We performed a prospective, controlled evaluation of SSRF as compared with optimal medical management for severe rib fracture patterns among critically ill trauma patients. We hypothesized that SSRF improves acute outcomes. METHODS: We conducted a 2-year clinical evaluation of patients with any of the following rib fracture patterns: flail chest, three or more fractures with bicortical displacement, 30% or greater hemithorax volume loss, and either severe pain or respiratory failure despite optimal medical management. In the year 2013, all patients were managed nonoperatively. In the year 2014, all patients were managed operatively. Outcomes included respiratory failure, tracheostomy, pneumonia, ventilator days, tracheostomy, length of stay, daily maximum incentive spirometer volume, narcotic requirements, and mortality. Univariate and multivariable analyses were performed. RESULTS: Seventy patients were included, 35 in each group. For the operative group, time from injury to surgery was 2.4 day, operative time was 1.5 hours, and the ratio of ribs fixed to ribs fractured was 0.6. The operative group had a significantly higher RibScore (4 vs. 3, respectively, p < 0.01) and a significantly lower incidence of intracranial hemorrhage (5.7% vs. 28.6%, respectively, p = 0.01). After controlling for these differences, the operative group had a significantly lower likelihood of both respiratory failure (odds ratio, 0.24; 95% confidence interval, 0.06-0.93; p = 0.03) and tracheostomy (odds ratio, 0.18; 95% confidence interval, 0.04-0.78; p = 0.03). Duration of ventilation was significantly lower in the operative group (p < 0.01). The median daily spirometry value was 250 mL higher in the operative group (p = 0.04). Narcotic requirements were comparable between groups. There were no mortalities. CONCLUSION: In this evaluation, SSRF as compared with the best medical management improved acute outcomes among a group of critically ill trauma patients with a variety of severe fracture patterns. LEVEL OF EVIDENCE: Therapeutic study, level II. PMID- 26595711 TI - Timing of withdrawal of life-sustaining therapies in severe traumatic brain injury: Impact on overall mortality. AB - BACKGROUND: The care of patients with severe traumatic brain injury (TBI) is complex and confounded by uncertainty in prognoses. Studies have demonstrated significant unexplained variation in mortality between centers. Possible explanations include differences in the quality and intensity of care across centers, including the appropriateness and timing of withdrawal of life sustaining therapies. We postulated that centers with a preponderance of early deaths might have a more pessimistic approach to the TBI patient, which would be reflected in an increased hospital TBI-related mortality. METHODS: This is a retrospective cohort study. Time to death was used as a proxy for time to withdrawal of life-sustaining therapies. Centers were classified as early or late based on when the majority (75th percentile) of their TBI-related deaths occurred. We evaluated the association between adjusted mortality and center classification using a hierarchical multivariable model. Two hundred trauma centers contributing data to the American College of Surgeons Trauma Quality Improvement Program from 2010 through 2013 were involved. The cohort included 17,505 patients with severe isolated TBI. RESULTS: One hundred eight centers were classified as early centers. The 75th percentile for time to death was 4 days among early centers versus 7 days in late centers. Mortality was 34% and 33%, respectively. After adjustment for case mix, care in an early center was not associated with increased odds of death (adjusted odds ratio, 0.95; 95% confidence interval, 0.83-1.09). Higher odds of death were independently associated with age, Glasgow Coma Scale (GCS) score, head Abbreviated Injury Scale (AIS) score, multiple comorbidities, traumatic subarachnoid hemorrhage, intracerebral mass lesions, brainstem lesions, and signs of compressed or absent basal cisterns. CONCLUSION: Centers rendering early decisions related to withdrawal of life-sustaining therapies in TBI patients, as measured by time until death, do not have worse outcomes than those making later decisions. How and when these decisions are made requires further exploration to balance an opportunity for clinical improvement with appropriate resource use. LEVEL OF EVIDENCE: Prognostic and epidemiologic study, level III. PMID- 26595713 TI - Comparative Sensitivity of Trichophyton and Aspergillus Conidia to Inactivation by Violet-Blue Light Exposure. AB - OBJECTIVE: To investigate the use of 405 nm light for inhibiting the growth of selected species of dermatophytic and saprophytic fungi. BACKGROUND DATA: The increasing incidence and resilience of dermatophytic fungal infections is a major issue, and alternative treatment methods are being sought. METHODS: The sensitivity of the dermatophytic fungi Trichophyton rubrum and Trichophyton mentagrophytes to 405 nm violet-blue light exposure was investigated, and the results compared with those obtained with the saprophytic fungus Aspergillus niger. Microconidia of T. rubrum and T. mentagrophytes and conidia of A. niger were seeded onto Sabauroud dextrose agar plates and irradiated with 405 nm light from an indium-gallium-nitride 99-DIE light-emitting diode (LED) array and the extent of inhibition was measured. RESULTS: Germination of the microconidia of the Trichophyton species was completely inhibited using an irradiance of 35 mW/cm(2) for 4 h (dose of 504 J/cm(2)). A. niger conidia showed greater resistance, and colonial growth developed after light exposure. In liquid suspension tests, 405 nm light dose levels of 360, 720, and 1440 J/cm(2) resulted in complete inactivation of T. rubrum microconidia, whereas A. niger showed greater resistance, and at the highest dose level applied (1440 J/cm(2)) although A niger hyphae were completely inactivated, only a 3-log10 reduction of a 5-log10 conidial suspension was achieved. CONCLUSIONS: The study results demonstrate the relatively high sensitivity of Trichophyton microconidia to 405 nm violet-blue light, and this is may be of potential interest regarding the control and treatment of dermatophyte infections. PMID- 26595712 TI - Preinjury physical frailty and cognitive impairment among geriatric trauma patients determine postinjury functional recovery and survival. AB - BACKGROUND: Injury is an external stressor that often initiates a cycle of decline in many older adults. The influence of physical frailty and cognitive decline on 6-month and 1-year outcomes after injury is unreported. We hypothesized that physical frailty and cognitive impairment would be predictive of 6-month and 1-year postinjury function and overall mortality. METHODS: The sample involved patients who are 65 years or older admitted to a Level I trauma center between October 2013 and March 2014 with a primary injury diagnosis. Surrogates of 188 patients were interviewed within 48 hours of hospital admission to determine preinjury cognitive and physical frailty impairments using brief screening instruments. Follow-up was completed on 172 patients at 6 months and 176 patients at 1 year to determine posthospitalization status and outcomes. Data analysis involved frequencies, measures of central tendency, chi analyses, linear and logistic regression. RESULTS: The mean age of the patients was 77 years. The median Injury Severity Score (ISS) was 10. The mechanism of injury involved falls from standing (n = 101, 54%). Preinjury vulnerabilities included cognitive impairment (AD8 Dementia Screen [AD8] score >= 2, n = 93, 50%) and physical frailty (Vulnerable Elders Survey [VES-13] score >= 4, n = 94, 50%). Overall, median physical frailty scores did not return to baseline in the majority of survivors at 1 year. Multivariate regression analysis revealed that preinjury cognitive impairment (6 months, AD8, beta = -0.20, p = 0.002) and preinjury physical frailty (6 months, Barthel Index, beta = 0.60, p < 0.001; 1 year, Barthel Index, beta = 0.52, p < 0.001) are independently associated with physical function (frailty). Multivariate logistic regression analysis revealed that age (odds ratio [OR], 1.09; 95% confidence interval [CI], 1.04-1.14), injury severity (OR, 1.07; 95% CI, 1.02-1.12), and preinjury physical frailty (OR, 1.28; 95% CI, 1.14-1.47) are independently associated with overall mortality at 1 year. CONCLUSION: Preinjury physical frailty is the predominant predictor of postinjury functional status and mortality in geriatric trauma patients. Identification of frailty and appropriate follow-up are crucial for decision making by providers, patients, and family caregivers. LEVEL OF EVIDENCE: Prognostic study, level II. PMID- 26595714 TI - Me, us, and them: Testing sociometer theory in a socially diverse real-life context. AB - Although numerous studies have emphasized the role evaluations by others play for people's self-esteem, the perspective of others and the social diversity of real life contexts have largely been ignored. In a large-scale longitudinal study, we examined the link between adolescents' self-esteem and their self- and peer perceived popularity in socially diverse classrooms. First, we tested the competing directions of effects predicted by sociometer theory (i.e., peer perceived popularity affects self-esteem, mediated by self-perceived popularity) and the self-broadcasting perspective (i.e., self-esteem affects peer-perceived popularity). Second, we examined differential effects of popularity in the own social group ("us") versus others ("them") by using immigrant status groups (i.e., immigrants versus host-nationals). We examined 1,057 13-year-old students in 3 annual waves. Cross-lagged analyses revealed that popularity among peers of the in-group but not among peers of the out-group prospectively predicted self esteem, which was mediated by self-perceived popularity. Self-esteem in turn prospectively predicted self- but not peer-perceived popularity. In sum, the findings provide support for sociometer theory and a conscious sociometer mechanism but no support for the self-broadcasting perspective. The findings further demonstrate that the sociometer was more responsive to popularity in immigrant status in- than out-groups. In conclusion, the findings underscore the need to consider the perspective of others and their social group memberships to better understand the complexities of the link between self-esteem and popularity. (PsycINFO Database Record PMID- 26595715 TI - Don't aim too high for your kids: Parental overaspiration undermines students' learning in mathematics. AB - Previous research has suggested that parents' aspirations for their children's academic attainment can have a positive influence on children's actual academic performance. Possible negative effects of parental overaspiration, however, have found little attention in the psychological literature. Employing a dual-change score model with longitudinal data from a representative sample of German school children and their parents (N = 3,530; Grades 5 to 10), we showed that parental aspiration and children's mathematical achievement were linked by positive reciprocal relations over time. Importantly, we also found that parental aspiration that exceeded their expectation (i.e., overaspiration) had negative reciprocal relations with children's mathematical achievement. These results were fairly robust after controlling for a variety of demographic and cognitive variables such as children's gender, age, intelligence, school type, and family socioeconomic status. The results were also replicated with an independent sample of U.S. parents and their children. These findings suggest that unrealistically high parental aspiration can be detrimental for children's achievement. (PsycINFO Database Record PMID- 26595716 TI - Treatment Effectiveness for Symptoms of Patulous Eustachian Tube: A Systematic Review. AB - OBJECTIVES: To determine the effectiveness of currently available medical and surgical interventions for treating symptoms of Patulous Eustachian Tube (PET). DATA SOURCES: A comprehensive search of MEDLINE (January 1948 to July 8, 2015), EMBASE (January 1974 to July 8, 2015), gray literature, hand searches, and cross reference checking. STUDY SELECTION: Original published reports evaluating an intervention to treat the symptoms of patulous eustachian tube in patients 18 years and older. DATA EXTRACTION: Quality-of-case reviews were assessed with the National Institute of Health (NIH) Quality Assessment Tool for Case Series Studies. DATA SYNTHESIS: The search strategy identified 1,104 unique titles; 39 articles with 533 patients are included. The available evidence consists of small case series and case reports. The most common medical treatment was nasal instillation of normal saline. Surgical treatments were categorized as mass loading of the tympanic membrane, eustachian tube plugging, and manipulation of eustachian tube musculature. CONCLUSIONS: The available evidence for management of patients with PET is poor in quality and consists predominantly of small case series. Further research is needed to determine the comparative efficacy of the current treatments. PMID- 26595717 TI - Altered Contralateral Auditory Cortical Morphology in Unilateral Sudden Sensorineural Hearing Loss. AB - OBJECTIVE: To investigate the cerebral gray matter volume alterations in unilateral sudden sensorineural hearing loss patients within the acute period by the voxel-based morphometry method, and to determine if hearing impairment is associated with regional gray matter alterations in unilateral sudden sensorineural hearing loss patients. STUDY DESIGN: Prospective case study. SETTING: Tertiary class A teaching hospital. PATIENTS: Thirty-nine patients with left-side unilateral sudden sensorineural hearing loss and 47 patients with right side unilateral sudden sensorineural hearing loss. INTERVENTION: Diagnostic. MAIN OUTCOME MEASURE: To compare the regional gray matter of unilateral sudden sensorineural hearing loss patients and healthy control participants. RESULTS: Compared with control groups, patients with left side unilateral sudden sensorineural hearing loss had significant gray matter reductions in the right middle temporal gyrus and right superior temporal gyrus, whereas patients with right side unilateral sudden sensorineural hearing loss showed gray matter decreases in the left superior temporal gyrus and left middle temporal gyrus. A significant negative correlation with the duration of the sudden sensorineural hearing loss (R = -0.427, p = 0.012 for left-side unilateral SSNHL and R = 0.412, p = 0.013 for right-side unilateral SSNHL) was also found in these brain areas. There was no region with increased gray matter found in both groups of unilateral sudden sensorineural hearing loss patients. CONCLUSIONS: This study confirms that detectable decreased contralateral auditory cortical morphological changes have occurred in unilateral SSNHL patients within the acute period by voxel-based morphometry methods. The gray matter volumes of these brain areas also perform a negative correlation with the duration of the disease, which suggests a gradual brain structural impairment after the progression of the disease. PMID- 26595718 TI - Ossiculoplasty With Titanium Prostheses in Patients With Intact Stapes: Comparison of TORP Versus PORP. AB - OBJECTIVES: Inferior rotation of the stapes or a small middle ear cleft can make placement of partial ossicular replacement prostheses (PORP) challenging. This study examines outcomes of total titanium prosthesis (TORP) ossiculoplasty in such patients and compares the results to PORPs. STUDY DESIGN: Review of prospective database. SETTING: Tertiary hospital. PATIENTS: Patients with an intact/mobile stapes undergoing titanium ossicular chain reconstruction from 2002 to 2014. INTERVENTION: Ossicular chain reconstruction. OUTCOMES: Hearing outcomes included ABG, closure of ABG(DeltaABG), SRT, improvement in SRT(DeltaSRT), achievement of ABG <=20 dB, and stability over time. RESULTS: Eighty-three patients were included; 56 were PORPs and 27 were TORPs. At initial follow-up (<6 mo), mean ABG and DeltaABG in the TORP group were 20.6 and 11.7 dB, respectively. Postoperative ABG<=20 dB was achieved in 60.0% of TORPs. At longer-term follow-up (mean 54.0 mo), hearing remained stable in TORPs. Specifically, the mean ABG and DeltaABG were 17.7 and 13.3 dB, respectively. Sixty-three percent of TORPs achieved ABG <=20 dB at later follow-up. When compared PORPs at both short and longer-term follow-ups, no differences in hearing outcomes were noted. A small, but statistically significant, deterioration in both ABG and SRT was observed within the PORP group (p = 0.02 and <0.01, respectively). CONCLUSION: TORP reconstruction in patients with an intact stapes is associated with good short and longer-term hearing results. Furthermore, hearing outcomes within TORPs remain stable at follow-up >12 months postoperatively. Results did not differ when compared with traditional PORP reconstruction, suggesting that TORP through an intact stapes arch is an acceptable alternative to PORP reconstruction in patients with challenging anatomy. PMID- 26595719 TI - Canal Paresis in Benign Paroxysmal Positional Vertigo Secondary to Sudden Sensorineural Hearing Loss. AB - OBJECTIVES: To review the clinical features of benign paroxysmal positional vertigo (BPPV) secondary to sudden sensorineural hearing loss (SNHL) and to analyze the correlation between canal paresis and the effectiveness of canalith repositioning procedures (CRPs) for the treatment. DESIGN: Study case series with chart review. SETTING: Academic university hospital. PATIENTS: We retrospectively reviewed 277 patients with BPPV. For sudden SNHL with a recent vertigo, patients underwent electronystagmography and bithermal caloric tests. We investigated the clinical characteristics including causes, type of involved semicircular canal, frequency of CRPs, treatment results, and canal paresis (CP). INTERVENTIONS: The diagnosis of BPPV accompanied by same-sided sudden SNHL was based on the results of head roll and Dix-Hallpike tests. RESULTS: Of 277 patients with BPPV, 24 (8.7%) had sudden SNHL. Multiple-canal involvement most commonly developed in post-sudden SNHL BPPV (p < 0.01). Patients with post-sudden SNHL BPPV received a greater number of CRPs (2.95) than those with idiopathic BPPV (1.58) (p = 0.043). In patients with post-sudden SNHL BPPV, the average number of CRPs was 3.31 in the presence of CP and 2.1 sessions in the absence of CP (p = 0.030); the CP value was correlated with the frequency of CRPs (p = 0.020). CONCLUSIONS: In post sudden SNHL BPPV, the worse the canal paresis becomes, the greater the number of CRPs will be needed for treatment; the simultaneous involvement of the posterior semicircular canal and horizontal semicircular canal is most common. PMID- 26595720 TI - Approach to Monobactams and Nocardicins via Diastereoselective Kinugasa Reaction. AB - A Kinugasa reaction between copper(I) acetylides and cyclic nitrones derived from chiral amino alcohols and glyoxylic acid is reported. The stereochemical preferences observed in this reaction are discussed. The alkyne molecule approaches the nitrone exclusively anti to the large substituent next to the nitrogen atom to provide the cis-substituted beta-lactam ring preferentially. The six-membered oxazinone ring can be opened by reduction with lithium borohydride. Deprotection of the beta-lactam nitrogen atom can be achieved by lithium in liquid ammonia reduction or by CAN oxidation, depending on the substituents attached to the four-membered azetidinone ring. The adducts obtained by the Kinugasa reaction provide an attractive entry to a variety of monocyclic beta lactam structures related to monobactams and nocardicins. PMID- 26595721 TI - A High-Throughput Method for Direct Detection of Therapeutic Oligonucleotide Induced Gene Silencing In Vivo. AB - Preclinical development of RNA interference (RNAi)-based therapeutics requires a rapid, accurate, and robust method of simultaneously quantifying mRNA knockdown in hundreds of samples. The most well-established method to achieve this is quantitative real-time polymerase chain reaction (qRT-PCR), a labor-intensive methodology that requires sample purification, which increases the potential to introduce additional bias. Here, we describe that the QuantiGene((r)) branched DNA (bDNA) assay linked to a 96-well Qiagen TissueLyser II is a quick and reproducible alternative to qRT-PCR for quantitative analysis of mRNA expression in vivo directly from tissue biopsies. The bDNA assay is a high-throughput, plate based, luminescence technique, capable of directly measuring mRNA levels from tissue lysates derived from various biological samples. We have performed a systematic evaluation of this technique for in vivo detection of RNAi-based silencing. We show that similar quality data is obtained from purified RNA and tissue lysates. In general, we observe low intra- and inter-animal variability (around 10% for control samples), and high intermediate precision. This allows minimization of sample size for evaluation of oligonucleotide efficacy in vivo. PMID- 26595722 TI - Phylogenetic Position and Molecular Chronology of a Colonial Green Flagellate, Stephanosphaera pluvialis (Volvocales, Chlorophyceae), among Unicellular Algae. AB - The genus Balticola comprises a group of unicellular green flagellate algae and is composed of four species formerly classified in the genus Haematococcus. Balticola is closely related to a colonial green flagellate, Stephanosphaera pluvialis. Although the phylogeny among these genera was previously investigated based on two nuclear gene sequences, the phylogenetic sister of S. pluvialis has yet to be determined. In the present study, the species diversity of Balticola and Stephanosphaera was investigated using 18S rRNA gene sequences, and phylogenetic analyses of combined nuclear and chloroplast gene sequences were performed to understand the evolutionary origin of coloniality in Stephanosphaera. The divergence times of four colonial volvocalean flagellates from their respective unicellular sisters were also estimated. Six Balticola genotypes and a single Stephanosphaera genotype were recognized, and one Balticola genotype was resolved as the sister of S. pluvialis, showing that Balticola is a nonmonophyletic genus. The divergence time of Stephanosphaera from its nearest Balticola relative was estimated to be 4-63 million years ago, and these genera represent the most recently diverged pair of unicellular and colonial flagellates among the Volvocales. PMID- 26595723 TI - No Change in 24-Hour Hydration Status Following a Moderate Increase in Fluid Consumption. AB - PURPOSE: To investigate changes in 24-hour hydration status when increasing fluid intake. METHODS: Thirty-five healthy males (age 23.8 +/- 4.7 years; mass 74.0 +/- 9.4 kg) were divided into 4 treatment groups for 2 weeks of testing. Volumes of 24-hour fluid ingestion (including water from food) for weeks 1 and 2 was 35 and 40 ml/kg body mass, respectively. Each treatment group was given the same proportion of beverages in each week of testing: water only (n = 10), water + caloric cola (n = 7), water + noncaloric cola (n = 10), or water + caloric cola + noncaloric cola + orange juice (n = 8). Serum osmolality (Sosm), total body water (TBW) via bioelectrical impedance, 24-hour urine osmolality (Uosm), and volume (Uvol) were analyzed at the end of each 24-hour intervention. RESULTS: Independent of treatment, total beverage consumption increased 22% from week 1 to 2 (1685 +/- 320 to 2054 +/- 363 ml; p < 0.001). Independent of beverage assignment, the increase in fluid consumption between weeks 1 and 2 did not change TBW (43.4 +/- 5.2 vs 43.0 +/- 4.8 kg), Sosm (292 +/- 5 vs 292 +/- 5 mOsm/kg), 24-hour Uosm (600 +/- 224 vs 571 +/- 212 mOsm/kg), or 24-hour Uvol (1569 +/- 607 vs 1580 +/- 554 ml; all p > 0.05). CONCLUSIONS: Regardless of fluid volume or beverage type consumed, measures of 24-hour hydration status did not differ, suggesting that standard measures of hydration status are not sensitive enough to detect a 22% increase in beverage consumption. PMID- 26595725 TI - Purpose of the Conference: 2015 Transatlantic Airway Conference. PMID- 26595724 TI - Cost-effectiveness of Early Treatment of Hepatitis C Virus Genotype 1 by Stage of Liver Fibrosis in a US Treatment-Naive Population. AB - IMPORTANCE: Novel treatments for hepatitis C virus (HCV) infection are highly efficacious but costly. Thus, many insurers cover therapy only in advanced fibrosis stages. The added health benefits and costs of early treatment are unknown. OBJECTIVE: To assess the cost-effectiveness of (1) treating all patients with HCV vs only those with advanced fibrosis and (2) treating each stage of fibrosis. DESIGN, SETTING, AND PARTICIPANTS: This study used a decision-analytic model for the treatment of HCV genotype 1. The model used a lifetime horizon and societal perspective and was representative of all US patients with HCV genotype 1 who had not received previous treatment. Comparisons in the model included antiviral treatment of all fibrosis stages (METAVIR [Meta-analysis of Histological Data in Virial Hepatitis] stages F0 [no fibrosis] to F4 [cirrhosis]) vs treatment of stages F3 (numerous septa without cirrhosis) and F4 only and by specific fibrosis stage. Data were collected from March 1 to September 1, 2014, and analyzed from September 1, 2014, to June 30, 2015. INTERVENTIONS: Six HCV therapy options (particularly combined sofosbuvir and ledipasvir therapy) or no treatment. MAIN OUTCOMES AND MEASURES: Cost and health outcomes were measured using total medical costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs), calculated as the difference in costs between strategies divided by the difference in QALYs. RESULTS: We simulated 1000 individuals, but present the results normalized to a single HCV-infected person. In the base-case analysis, among patients receiving 8 or 12 weeks of sofosbuvir ledipasvir treatment, treating all fibrosis stages compared with treating stages F3 and F4 adds 0.73 QALYs and $28,899, for an ICER of $39,475 per QALY gained. Treating at stage F2 (portal fibrosis with rare septa) costs $19,833 per QALY gained vs waiting until stage F3; treating at stage F1 (portal fibrosis without septa), $81,165 per QALY gained compared with waiting until stage F2; and treating at stage F0, $187,065 per QALY gained compared with waiting until stage F1. Results for other regimens show a similar pattern. At base-case drug prices, treating 50% of all eligible US patients with HCV genotype 1 would cost $53 billion. In sensitivity analyses, the ICER for treating all stages vs treating stages F3 and F4 was most sensitive to cohort age, drug costs, utility values in stages F1 and F2, and percentage of patients eligible for 8-week therapy. Except for patients aged 70 years, the ICER remains less than $100,000 per QALY gained. A 46% reduction in cost of sofosbuvir-ledipasvir therapy decreases the ICER for treating at all fibrosis stages by 48%. CONCLUSIONS AND RELEVANCE: In this simulated model, treating HCV infection at early stages of fibrosis appeared to improve health outcomes and to be cost-effective but incurred substantial aggregate costs. The findings may have implications for health care coverage policies and clinical decision making. PMID- 26595726 TI - Chair's Summary: Mechanisms of Exacerbation of Lung Diseases. AB - This year's conference focused on the origins of exacerbations in chronic lung diseases, such as asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and cystic fibrosis. Common themes emerged, with the role of viral infections being key. In addition, there were data presented supporting the role of the microbiota and microbial dysbiosis either in the gut or in the lung contributing to disease progression and the susceptibility to disease exacerbation. These effects can be amplified by the triggering of biologic cascades that include alterations in oxidative stress and inflammatory mediator release, which can be driven by epithelial cell injury or activation. PMID- 26595727 TI - Pathogenesis of Viral Infection in Exacerbations of Airway Disease. AB - Chronic airway diseases are a significant cause of morbidity and mortality worldwide, and their prevalence is predicted to increase in the future. Respiratory viruses are the most common cause of acute pulmonary infection, and there is clear evidence of their role in acute exacerbations of inflammatory airway diseases such as asthma and chronic obstructive pulmonary disease. Studies have reported impaired host responses to virus infection in these diseases, and a better understanding of the mechanisms of these abnormal immune responses has the potential to lead to the development of novel therapeutic targets for virus induced exacerbations. The aim of this article is to review the current knowledge regarding the role of viruses and immune modulation in acute exacerbations of chronic pulmonary diseases and to discuss exciting areas for future research and novel treatments. PMID- 26595728 TI - Reduced Antioxidant and Cytoprotective Capacity in Allergy and Asthma. AB - In asthma, reactive oxygen species induce damage to biomolecules like proteins. This oxidative stress can promote inflammation, but its contribution to asthma pathology is controversial, not in the least because antioxidant interventions have proven rather unsuccessful. Recent studies indicate that the oxidative stress at baseline can be predictive of the fall in FEV1 upon an allergen challenge and of sensitization to an allergen. Interestingly, this baseline oxidative stress correlated with the capacity of antioxidant and cytoprotective responses to deal with reactive oxygen species, but not with inflammatory parameters. These findings have led to several considerations in relation to antioxidant trials that are discussed. Trials should be complemented by in-depth analyses of the failing antioxidant and cytoprotective responses and their consequences for cellular function in asthma. PMID- 26595729 TI - Virus/Allergen Interaction in Asthma Exacerbation. AB - Allergy and viral respiratory infections have long been recognized as two of the most important risk factors for exacerbations of asthma. These observations have raised questions regarding potential interactions between these two important risk factors. For example, does allergy diminish the antiviral response, thereby promoting exacerbations of asthma? Alternately, do viral respiratory infections potentiate ongoing allergic inflammation in the airway? The answers to these questions are likely to have implications regarding the prevention and treatment of exacerbations of asthma. This article reviews that clinical evidence linking viral infections and allergy to exacerbations of asthma, reviews potential interactions between these two risk factors, and discusses possible application of new insights in virus/allergen interactions to the prevention and treatment of exacerbations of asthma. PMID- 26595730 TI - The Role of Type 2 Inflammation in the Pathogenesis of Asthma Exacerbations. AB - Asthma exacerbations are an important cause of asthma morbidity. Although viral infection of the upper airway is a common cause of asthma exacerbations, the reasons why some patients with asthma are exacerbation prone and others are exacerbation resistant are not fully understood. In this review, we examine whether Type 2 inflammation modifies airway function to make patients more susceptible to asthma exacerbations. The best data supporting a role for Type 2 inflammation in asthma exacerbations come from clinical trials of inhibitors of Type 2 inflammation in asthma. These trials include studies with omalizumab (an inhibitor of IgE) and others with inhibitors of Type 2 cytokines (IL-4, IL-5, and IL-13). All of these trials consistently show that inhibiting the Type 2 pathway causes a clinically significant reduction in asthma exacerbations. Thus, it is now clear that Type 2 inflammation is an important mechanism of susceptibility to asthma exacerbation. PMID- 26595731 TI - The Gut-Lung Axis in Respiratory Disease. AB - Host-microorganism interactions shape local cell functionality, immune responses, and can influence disease development. Evidence indicates that the impact of host microbe interactions reaches far beyond the local environment, thus influencing responses in peripheral tissues. There is a vital cross-talk between the mucosal tissues of our body, as exemplified by intestinal complications during respiratory disease and vice versa. Although, mechanistically, this phenomenon remains poorly defined, the existence of the gut-lung axis and its implications in both health and disease could be profoundly important for both disease etiology and treatment. In this review, we highlight how changes in the intestinal microenvironment, with a particular focus on the intestinal microbiota, impact upon respiratory disease. PMID- 26595732 TI - Mechanisms of Chronic Obstructive Pulmonary Disease Exacerbations. AB - Chronic obstructive pulmonary disease (COPD) exacerbations are important events that contribute to worsening health status, disease progression, and mortality. They are mainly triggered by respiratory viruses (especially rhinovirus, the cause of the common cold), but airway bacteria are also involved in their pathogenesis. Exacerbations are associated with both airway and systemic inflammation and, this is mainly neutrophilic in origin. Some patients are especially prone to develop exacerbations, and these have been identified as a high-risk group with increased airway inflammation and greater disease progression. Management of acute exacerbations involves therapy with oral corticosteroids and/or antibiotics, and new therapies are needed. A number of interventions may prevent exacerbations, including vaccination, long-acting bronchodilators, antiinflammatory agents, and long-term antibiotic therapy. Understanding of the pathophysiological mechanisms of COPD exacerbations is important to develop novel therapies. PMID- 26595733 TI - On the Pathogenesis of Acute Exacerbations of Mucoobstructive Lung Diseases. AB - Mucoobstructive lung diseases have highlighted the importance of a proper description of the normal mucus clearance system. A useful description of the normal mucus clearance apparatus requires the presence of two gels on the airway surface (i.e., a mucus layer gel and a periciliary gel). Importantly, most mucoobstructive lung diseases are distributed heterogeneously in the lung, and exacerbations may reflect spread of the disease to previously normal areas. The spread may reflect disturbances in the balance of water between the two gel layers, producing heterogeneous mucus adhesion and infection within the lung. Ultimately, spread can produce losses of lung function that may be associated with acute exacerbation frequency. PMID- 26595734 TI - Loss of Peripheral Tolerance in Emphysema. Phenotypes, Exacerbations, and Disease Progression. AB - Heterogeneity in the development and progression of cigarette smoke-induced lung diseases strongly argues for a need to improve the clinical and phenotypic characterization of patients with chronic obstructive lung disease and emphysema. Smokers with emphysema are at a much higher risk for accelerated loss of lung function, increased cardiovascular morbidity, and development of lung cancer. Recent evidence in human translational studies and animal models suggests that emphysema is associated with activation of specialized antigen-presenting cells and that cigarette smoke can disrupt the induction of immune tolerance in the lungs. Quantitative assessment of cytokines expressed by autoreactive T lymphocytes in response to human lung elastin fragments has shown a strong positive correlation between T helper Type 1 (Th1) and Th17 cells' immune responses and emphysema. In search of factors that could reduce the threshold for induction of autoimmune inflammation, we have discovered that cleavage of complement protein 3 (C3) generates bioactive molecules (e.g., C3a) and activates lung antigen-presenting cells. The autocrine and paracrine function of C3a and its receptor are required in T cell-mediated inflammatory responses to cigarette smoke in both human and preclinical models of emphysema. Targeting upstream molecules that reduce the potential for generation of autoreactive T cells could lead to the development of novel therapeutics to prevent progression of emphysema in smokers. PMID- 26595736 TI - The Sputum Microbiome in Chronic Obstructive Pulmonary Disease Exacerbations. AB - Acute exacerbations of chronic obstructive pulmonary disease (COPD) are thought to be associated with--and perhaps to mediate--accelerated loss of lung function in COPD. Although the application of culture-independent methods for detection of bacteria have shown COPD to be associated with marked differences in the burden, diversity, and composition of the bronchial bacterial microbiome, few studies have examined the changes associated with community-acquired exacerbations of the disease. In a longitudinal cohort study of COPD, the availability of sputum samples from subjects obtained at the onset of an exacerbation and during periods of clinical stability before and after the event enabled us to recently address this gap in knowledge, using culture-independent, 16S rRNA-based analysis methods combined with in silico inference of metagenomic functions. We observed sputum bacterial composition to be generally stable over the preexacerbation period of clinical stability, but to change at the time of exacerbation, with specific enrichment in not only typical COPD-associated bacterial species (e.g., Haemophilus influenzae) but also other phylogenetically related species with pathogenic potential. Concurrently, we observed depleted abundance of other bacteria whose predicted metagenomes suggest functional capacities to produce a variety of antiinflammatory compounds. Most strikingly, we found that resolution of these exacerbation-related changes in sputum microbiota composition differed significantly, depending on the exacerbation treatments prescribed. Treatment with corticosteroids resulted in microbiome enrichment for a number of bacterial communities, mostly members of the Proteobacteria phylum, whereas prolonged suppression of microbiota was seen in those treated with antibiotics alone. Taken together, our findings suggest that exacerbations of COPD are associated with heterogeneous changes in the bronchial microbiome, with increases in the abundance of species related to typical COPD pathogens and decreases in microbiota members that contribute to compositional and functional homeostasis. The findings further suggest that exacerbation treatments may have very different impacts on the bronchial microbiome's rate of return toward baseline composition. PMID- 26595735 TI - Immune Dysfunction in Patients with Chronic Obstructive Pulmonary Disease. AB - Chronic obstructive pulmonary disease (COPD) is a complex chronic disease. Chronic inflammation is the hallmark of COPD, involving the interplay of a wide variety of cells in the lung microenvironment. Cigarette smoke (CS) induces chronic lung inflammation and is considered a key etiological factor in the development and pathogenesis of COPD. Structural and inflammatory cells in the lung respond to CS exposure by releasing proinflammatory mediators that recruit additional inflammatory immune cells, which collectively contribute to the establishment of a chronic inflammatory microenvironment. Chronic inflammation contributes to lung damage, compromises innate and adaptive immune responses, and facilitates the recurrent episodes of respiratory infection that punctuate and further contribute to the pathological manifestations of the stable disease. A number of studies support the conclusion that immune dysfunction leads to exacerbations and disease severity in COPD. Our group has clearly demonstrated that CS exacerbates lung inflammation and compromises immunity to respiratory pathogens in a mouse model of COPD. We have also investigated the phenotype of immune cells in patients with COPD compared with healthy control subjects and found extensive immune dysfunction due to the presence and functional activity of T regulatory cells, CD4(+)PD-1(+) exhausted effector T cells and myeloid-derived suppressor cells. Manipulation of these immunosuppressive networks in COPD could provide a rational strategy to restore functional immune responses, reduce exacerbations, and improve lung function. In this review, we discuss the role of immune dysfunction in COPD that may contribute to recurrent respiratory infections and disease severity. PMID- 26595737 TI - Time for Prevention of Idiopathic Pulmonary Fibrosis Exacerbation. AB - Acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF), with an annual incidence up to 20% and a short-term mortality around 50%, are the more frequent cause of death in patients with IPF. These unpredictable and clinically relevant events are more frequent in patients with advanced disease, as measured by a lower lung function. In the absence of an evidence-based, approved treatment of AE-IPF, patients with IPF with acute respiratory worsening are usually treated with systemic high-dose corticosteroids according to current guideline recommendations. Part of the reason for the lack of a treatment for AE-IPF with proven safety and efficacy is the difficulty in designing clinical trials addressing this specific clinical endpoint. Another part of the problem is represented by the current definition of AE-IPF, until now based on clinical and radiological features, and the absence of an identifiable etiology. Because a number of studies have shown that the features and prognosis of AE-IPF are similar to other causes of acute respiratory worsening, recently a change in the definition of AE-IPF has been proposed, focusing more on clinical and radiological findings consistent with an underlying pathobiology of diffuse alveolar damage and placing less emphasis on the search for the etiological cause. It is hoped that the international scientific community will soon be able to reach a consensus on a new definition of AE-IPF, thus speeding up research for an effective and safe treatment. PMID- 26595738 TI - Viruses in Idiopathic Pulmonary Fibrosis. Etiology and Exacerbation. AB - Viral infections are important contributors to exacerbation of asthma and chronic obstructive pulmonary disease; however, the role of viruses in the pathogenesis of idiopathic pulmonary fibrosis (IPF) is less clear. This likely reflects that fact that IPF acute exacerbations are defined clinically as "noninfectious," and little attention has been paid to the outcomes of patients with IPF with diagnosed infections. However, accumulating evidence suggests that infections (both bacterial and viral) may influence disease outcomes either as exacerbating agents or initiators of disease. Support for a viral role in disease initiation comes from studies demonstrating the presence of herpesviral DNA and epithelial cell stress in the lungs of asymptomatic relatives at risk for developing familial IPF. In addition, the number of studies that can associate viral (especially herpesviral) signatures in the lung with the development of IPF is steadily growing, and activated leukocyte signatures in patients with IPF provide further support for infectious processes driving IPF progression. Animal modeling has been used to better understand how a gamma herpesvirus infection can modulate the pathogenesis of lung fibrosis and has demonstrated that preceding infections appear to reprogram lung epithelial cells during latency to produce profibrotic factors, making the lung more susceptible to subsequent fibrotic insult, whereas exacerbations of existing fibrosis, or infections in susceptible hosts, involve active viral replication and are influenced by antiviral therapy. In addition, there is new evidence that bacterial burden in the lungs of patients with IPF may predict a poor prognosis. PMID- 26595740 TI - Pulmonary Exacerbations in Children with Cystic Fibrosis. AB - Pulmonary exacerbations treated with intravenous antibiotics have significant, well-characterized negative consequences on clinical outcomes in cystic fibrosis (CF). The impact of milder exacerbations in children with CF, commonly treated with oral antibiotics, are less well defined. Pulmonary exacerbations have multiple triggers, but viral infections are particularly common in children. Children with CF and healthy control subjects have similar frequencies of viral respiratory infections, but there is evidence of greater virus-related morbidity in patients with CF, likely due to a combination of increased viral load, more pronounced inflammatory response, and more pronounced impairment in mucociliary clearance. In recent clinical trials in children, definitions have been used that are more symptom based rather than intervention based. These studies have demonstrated differences in the spectrum of symptoms between children and older patients but have also shown that, despite low threshold definitions, a considerable number of patients receive treatment for events not fulfilling the pulmonary exacerbation criteria. Additional research is needed to determine the impact of these milder exacerbations on lung function recovery and time to subsequent exacerbation as well as long-term outcomes such as mortality. PMID- 26595741 TI - Clinical Insights into Pulmonary Exacerbations in Cystic Fibrosis from the Microbiome. What Are We Missing? AB - Pulmonary exacerbations account for much of the decrease in lung function and consequently most of the morbidity and mortality in patients with cystic fibrosis. These events are driven by an acute inflammatory response to infection. Recent technological advancements in molecular profiling techniques have allowed for a proliferation of microbiome studies of the lower airways of patients with cystic fibrosis. But these methods may not provide a comprehensive and unbiased measure of the lung microbiota in these patients and molecular profiles do not always translate to quantitative microbiology. Furthermore, these studies have not yet been able to provide much in the way of mechanistic insights into exacerbations or to guide patient therapy. We propose a model in which pulmonary exacerbations may be driven by an active subpopulation of the lung microbiota, which may represent only a small portion of the microbiota measured in a clinical sample. Methodology should be focused on the ultimate goal, which is to use the best available approaches to provide accurate quantitative measures of the microbiome to inform clinical decisions and provide rapid assessment of treatment efficacy. These strategies would be relevant to other chronic lung diseases such as chronic obstructive pulmonary disease and neutrophilic asthma. PMID- 26595739 TI - MUC5B and Idiopathic Pulmonary Fibrosis. AB - Idiopathic pulmonary fibrosis (IPF), a fatal disease that is a result of complex interactions between genetics and the environment, has limited treatment options. We have identified the MUC5B promoter polymorphism and other common genetic variants that in aggregate explain roughly one-third of disease risk. The MUC5B promoter polymorphism is the strongest and the most replicated genetic risk factor for IPF, appears to be protective and predictive in this disease, and is likely involved in disease pathogenesis through an increase in MUC5B expression in terminal bronchi and honeycombed cysts. Expression of MUC5B is also highly correlated with expression of cilium genes in IPF lung. Our work suggests that mucociliary dysfunction in the distal airway may play a role in the development of progressive fibroproliferative lung disease. In addition, our work has important implications for secondary prevention, early detection, and future early and personalized treatment based on genetic profiles. PMID- 26595742 TI - The modulating effect of ATM, ATR, DNA-PK inhibitors on the cytotoxicity and genotoxicity of benzo[a]pyrene in human hepatocellular cancer cell line HepG2. AB - The effect of inhibitors of phosphatidylinositol-3-kinase-related kinases (PIKK): ataxia-telangiectasia mutated (ATM), ATM- and Rad3-related (ATR) and DNA dependent protein kinase (DNA-PK) on response of HepG2 human liver cancer cells to benzo[a]pyrene (BaP) was investigated. PIKK inhibitors: KU55933 (5 MUM), NU7026 (10 MUM) or caffeine (1 and 2mM) when used as single agents or in combinations (KU55933/NU7026 and caffeine/NU7026) did not significantly influence the BaP (3 MUM) cytotoxicity (MTT reduction test). BaP induced a weak proapoptotic effect which was moderately enhanced by both inhibitor combinations. HepG2 cells exposed to BaP showed a strong S-phase arrest which was considerably diminished by both inhibitor combinations. The DNA damage (comet assay) induced after continuous 24h exposure to BaP was significantly diminished by both inhibitor combinations. Weak induction of reactive oxygen species by BaP was observed, which was not modulated by the inhibitor combinations. Similarly, no modulation of the glutathione levels was observed. PMID- 26595743 TI - Rubratoxin-B-induced secretion of chemokine ligands of cysteine-cysteine motif chemokine receptor 5 (CCR5) and its dependence on heat shock protein 90 in HL60 cells. AB - To elucidate the mechanism underlying rubratoxin B toxicity, the effects of rubratoxin B on the secretion of CCR5 chemokines, CCL3, CCL4, and CCL5, in a human promyelocytic leukemia cell line, HL60, were investigated. In addition, to examine whether the molecular chaperone 90-kDa heat shock protein (Hsp90) contributes to rubratoxin B toxicity, the effects of Hsp90-specific inhibitors, radicicol and geldanamycin, were investigated. Exposure to rubratoxin B for 24h induced secretion of each CCR5 chemokine, although the effect on CCL5 secretion was modest, and it enhanced secretion of proinflammatory cytokines tumor necrosis factor-alpha, CXCL8, and CCL2. Concomitant treatment with radicicol abolished the rubratoxin-induced secretion of all cytokines investigated. Geldanamycin antagonized the rubratoxin B-induced effects on CCL3 and CCL5, but not CCL4; the effects of geldanamycin were less than that of radicicol. Taken together, the results suggest that rubratoxin B, with the contribution of Hsp90, induces secretion of CCR5 chemokines. PMID- 26595745 TI - Superhydrophobic SERS Substrates Based on Silver-Coated Reduced Graphene Oxide Gratings Prepared by Two-Beam Laser Interference. AB - Reported here is the fabrication of reduced graphene oxide (RGO) grating structures by two-beam laser interference (TBLI) for the development of highly efficient SERS substrates via simple physical vapor deposition (PVD) coating of silver. TBLI has been utilized to make hierarchical RGO grating structures with microscale gratings and nanoscale folders through a laser treatment induced ablation and photoreduction process. The hierarchical structures contribute to the formation of plasmonic structures after silver coating, giving rise to the formation of plenty of SERS "hot spots", while the RGO substrate would provide chemical enhancement of Raman signal through interaction with analytes molecules. The significantly increased roughness with respect to the hierarchical structures in combination with the removal of hydrophilic oxygen-containing groups endow the resultant substrates with unique superhydrophobicity, which leads to the enrichment of analytes and further lowers the detection limit. The synergistic effects make the silver coated RGO gratings a highly efficient SERS substrate; in the detection of Rhodamine B, our SERS substrates showed high SERS enhancement and good reproducibility, a detection limit of 10(-10) M has been achieved. PMID- 26595744 TI - A pilot study of low-moderate drinking water arsenic contamination and chronic diseases among reproductive age women in Timis County, Romania. AB - We conducted a pilot study of associations between drinking water contaminated by inorganic arsenic (iAs), mostly <10 MUg/L, and self-reported chronic diseases in 297 pregnant women. Adjusted for confounding variables, we identified a positive association between iAs and heart disease (OR = 1.63, 95%CI 0.81-3.04, p = 0.094), which was stronger for women living at their current residence >= 10 years (OR = 2.47, 95%CI 0.87-10.43, p = 0.058). Confounder-adjusted associations were also suggested for iAs with kidney disease (OR = 1.32, 95%CI 0.77-2.21, p = 0.265) and with high blood pressure (OR = 1.36, 95%CI 0.68-2.39, p = 0.300). A post hoc power analysis indicated the need for a larger study with more statistical power. PMID- 26595746 TI - Arsenic Relative Bioavailability in Contaminated Soils: Comparison of Animal Models, Dosing Schemes, and Biological End Points. AB - Different animals and biomarkers have been used to measure the relative bioavailability of arsenic (As-RBA) in contaminated soils. However, there is a lack of As-RBA comparison based on different animals (i.e., swine and mouse) and biomarkers [area under blood As concentration curve (AUC) after a single gavaged dose vs steady-state As urinary excretion (SSUE) and As accumulation in liver or kidney after multiple doses via diet]. In this study, As-RBA in 12 As contaminated soils with known As-RBA via swine blood AUC model were measured by mouse blood AUC, SSUE, and liver and kidney analyses. As-RBA ranges for the four mouse assays were 2.8-61%, 3.6-64%, 3.9-74%, and 3.4-61%. Compared to swine blood AUC assay (7.0-81%), though well correlated (R(2) = 0.83), the mouse blood AUC assay yielded lower values (2.8-61%). Similarly, strong correlations of As-RBA were observed between mouse blood AUC and mouse SSUE (R(2) = 0.86) and between urine, liver, and kidney (R(2) = 0.75-0.89), suggesting As-RBA was congruent among different animals and end points. Different animals and biomarkers had little impact on the outcome of in vivo assays to validate in vitro assays. On the basis of its simplicity, mouse liver or kidney assay following repeated doses of soil-amended diet is recommended for future As-RBA studies. PMID- 26595747 TI - Factors Affecting Steady-state Plasma Concentrations of Enantiomeric Mirtazapine and its Desmethylated Metabolites in Japanese Psychiatric Patients. AB - INTRODUCTION: This study evaluated the effects of the CYP2D6*10 genotype on steady-state plasma concentrations of enantiomeric mirtazapine (MIR) and N desmethylmirtazapine (DMIR) in Japanese patients. METHODS: Subjects were 77 Japanese patients treated with racemic MIR. Steady-state plasma concentrations of MIR and DMIR enantiomers were measured using stereoselective liquid chromatography. Polymerase chain reaction was used to determine the CYP2D6 genotypes. RESULTS: After correcting for dose and body weight, smokers (n=15) had significantly lower S-(+)-MIR than nonsmokers (n=55) (15.1+/-17.8 vs. 23.9+/-17.8 ng/mL/mg/kg, Kruskal-Wallis test, p=0.034). One-way analysis of variance revealed that CYP2D6*10 homozygotes had significantly higher corrected plasma concentrations of S-(+)-MIR than the no-variant allele group (p=0.034). Multiple regression analysis revealed a significant positive correlation between the number of CYP2D6*10 alleles and corrected plasma concentrations of S-(+)-MIR. These results yielded the following final model: corrected plasma concentration of S-(+)-MIR=15.9+7.30*(number of CYP2D6*10 alleles) (R=0.279, p=0.023, coefficient of determination (R(2))=0.078). CONCLUSION: Homozygous CYP2D6*10 alleles and smoking have a significant impact on the metabolism of S-(+)-MIR in Japanese patients. PMID- 26595748 TI - HIV Salvage Therapy Does Not Require Nucleoside Reverse Transcriptase Inhibitors: A Randomized, Controlled Trial. AB - BACKGROUND: Nucleoside reverse transcriptase inhibitors (NRTIs) are often included in antiretroviral regimens in treatment-experienced patients in the absence of data from randomized trials. OBJECTIVE: To compare treatment success between participants who omit versus those who add NRTIs to an optimized antiretroviral regimen of 3 or more agents. DESIGN: Multicenter, randomized, controlled trial. (ClinicalTrials.gov: NCT00537394). SETTING: Outpatient HIV clinics. PARTICIPANTS: Treatment-experienced patients with HIV infection and viral resistance. INTERVENTION: Open-label optimized regimens (not including NRTIs) were selected on the basis of treatment history and susceptibility testing. Participants were randomly assigned to omit or add NRTIs. MEASUREMENTS: The primary efficacy outcome was regimen failure through 48 weeks using a noninferiority margin of 15%. The primary safety outcome was time to initial episode of a severe sign, symptom, or laboratory abnormality before discontinuation of NRTI assignment. RESULTS: 360 participants were randomly assigned, and 93% completed a 48-week visit. The cumulative probability of regimen failure was 29.8% in the omit-NRTIs group versus 25.9% in the add-NRTIs group (difference, 3.2 percentage points [95% CI, -6.1 to 12.5 percentage points]). No significant between-group differences were found in the primary safety end points or the proportion of participants with HIV RNA level less than 50 copies/mL. No deaths occurred in the omit-NRTIs group compared with 7 deaths in the add-NRTIs group. LIMITATION: Unblinded study design, and the study may not be applicable to resource-poor settings. CONCLUSION: Treatment-experienced patients with HIV infection starting a new optimized regimen can safely omit NRTIs without compromising virologic efficacy. Omitting NRTIs will reduce pill burden, cost, and toxicity in this patient population. PRIMARY FUNDING SOURCES: National Institute of Allergy and Infectious Diseases, Boehringer Ingelheim, Janssen, Merck, ViiV Healthcare, Roche, and Monogram Biosciences (LabCorp). PMID- 26595749 TI - N-Benzylbenzamides: A Novel Merged Scaffold for Orally Available Dual Soluble Epoxide Hydrolase/Peroxisome Proliferator-Activated Receptor gamma Modulators. AB - Metabolic syndrome (MetS) is a multifactorial disease cluster that consists of dyslipidemia, cardiovascular disease, type 2 diabetes mellitus, and obesity. MetS patients are strongly exposed to polypharmacy; however, the number of pharmacological compounds required for MetS treatment can be reduced by the application of multitarget compounds. This study describes the design of dual target ligands that target soluble epoxide hydrolase (sEH) and the peroxisome proliferator-activated receptor type gamma (PPARgamma). Simultaneous modulation of sEH and PPARgamma can improve diabetic conditions and hypertension at once. N Benzylbenzamide derivatives were determined to fit a merged sEH/PPARgamma pharmacophore, and structure-activity relationship studies were performed on both targets, resulting in a submicromolar (sEH IC50 = 0.3 MUM/PPARgamma EC50 = 0.3 MUM) modulator 14c. In vitro and in vivo evaluations revealed good ADME properties qualifying 14c as a pharmacological tool compound for long-term animal models of MetS. PMID- 26595750 TI - Targeting of heme oxygenase-1 as a novel immune regulator of neuroblastoma. AB - Heme oxygenase (HO)-1 catalyzes the degradation of cytotoxic heme into biliverdin and blocks antitumor immune responses, thus protecting cancer against host defense. Whether this scenario also applies to neuroblastoma (NB), the most common extracranial solid childhood tumor, is not known. Here, we demonstrate for the first time a prognostic relevance of HO-1 expression in samples from NB patients and show that targeting of HO-1 prevents both cancer resistance against cellular stress and immune escape in the syngeneic NXS2 A/J mouse model of NB. High HO-1 RNA expression in NB tissues emerged as unfavorable prognostic marker, in particular for patients older than 18 months as indicated by univariate as well as multivariate survival probability analyses including disease stage and MYCN status. On the basis of this observation we aimed to target HO-1 by systemic as well as tumor-specific zinc protoporphyrin-mediated HO-1 suppression in a syngeneic immunocompetent NB mouse model. This resulted in 50% reduction of primary tumor growth and a suppression of spontaneous liver metastases. Importantly, HO-1 inhibition abrogated immune cell paralysis affecting CD4 and CD8 T-effector cells. This in turn reverted HO-1-dependent immune escape mechanisms in NB by increasing NB apoptosis and improved DC maturation. In summary, HO-1 emerges as a novel immune regulator in NB and emerges as a promising target for the development of therapeutic approaches. PMID- 26595751 TI - The importance of needle gauge for pain during injection of lidocaine. AB - BACKGROUND: Local anaesthetics such as lidocaine are used both in minor and major surgical procedures, and can be painful. Different methods have been investigated to reduce the discomfort of the injections. This study investigated if different needle gauges can influence the pain experienced during injection of lidocaine. METHODS: A randomised study was performed on 36 healthy volunteers. Each participant received three injections of 3 ml 1% lidocaine subcutaneously on the abdomen using needles of different gauges. Following each injection, the participants evaluated the pain experienced on a visual analogue scale (VAS). After the session, they were asked to evaluate verbally which injection they found least and most painful. The VAS and verbal reports were used and compared to evaluate the difference between the two types of clinically reported pain scales. RESULTS: Twenty-one participants verbally reported the thinnest needle (27 gauge (G)) as least painful, compared to the intermediate (23 gauge; p = 0.013) and the thickest needle (21 gauge, p = 0.004). The mean VAS scores were 19 (SD = 13) for the 21 gauge, 18 (SD = 13) for the 23 gauge, and 16 (SD = 14) for the 27 gauge needles. CONCLUSION: A significant preponderance of respondents stated that there had been less pain using the thinnest needle. Mean VAS responses showed the same trend, but the differences between them were not statistically significant. PMID- 26595753 TI - Dark clouds or silver linings? A stigma threat perspective on the implications of an autism diagnosis for workplace well-being. AB - This article unpacks the stigma associated with a developmental disability at work, specifically autism spectrum disorders (ASD), by presenting findings from 2 studies-one interview-based and the other survey-based. Drawing on in-depth interviews with individuals on the autism spectrum, the first study showed that a clinical diagnosis of autism is a milestone event that triggered both positive (silver linings) and negative (dark clouds) responses to work. These positive and negative responses were shaped by the age at which the diagnosis occurred as well as specific work-related contingencies-identity management (disclosing or not disclosing), the importance of the social demands imposed by the job, and organizational support policies for autism. The second study developed and tested propositions derived from the qualitative data by using survey data gathered from working adults with ASD. Results showed that, compared with individuals diagnosed later in life, individuals who were diagnosed at an earlier age experienced greater organization-based self-esteem and lower perceived discrimination when they disclosed their disability, worked in jobs that placed lower social demands on them, or were employed in organizations that offered policies to support workers with ASD. We conclude that, depending on the age of diagnosis, attributes of the employment context can trigger stigma-related threat in different ways and we outline important practical implications of these findings. PMID- 26595754 TI - Who withdraws? Psychological individual differences and employee withdrawal behaviors. AB - Psychological individual differences, such as personality, affectivity, and general mental ability, have been shown to predict numerous work-related behaviors. Although there is substantial research demonstrating relationships between psychological individual differences and withdrawal behaviors (i.e., lateness, absenteeism, and turnover), there is no integrative framework providing scholars and practitioners a guide for conceptualizing how, why, and under what circumstances we observe such relationships. In this integrative conceptual review we: (a) utilize the Cognitive-Affective Processing System framework (Mischel & Shoda, 1995) to provide an overarching theoretical basis for how psychological individual differences affect withdrawal behaviors; (b) create a theoretical model of the situated person that summarizes the existing empirical literature examining the effect of psychological differences on withdrawal behavior; and (c) identify future research opportunities based on our review and integrative framework. PMID- 26595752 TI - The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the treatment of adolescent sexual offenders with paraphilic disorders. AB - The primary aim of these guidelines was to evaluate the role of pharmacological agents in the treatment of adolescents with paraphilic disorders who are also sexual offenders or at-risk of sexual offending. Psychotherapeutic and psychosocial treatments were also reviewed. Adolescents with paraphilic disorders specifically present a different therapeutic challenge as compared to adults. In part, the challenge relates to adolescents being in various stages of puberty and development, which may limit the use of certain pharmacological agents due to their potential side effects. In addition, most of the published treatment programmes have used cognitive behavioural interventions, family therapies and psychoeducational interventions. Psychological treatment is predicated in adolescents on the notion that sexually deviant behaviour can be controlled by the offender, and that more adaptive behaviours can be learned. The main purposes of these guidelines are to improve the quality of care and to aid physicians in their clinical decisions. These guidelines brought together different expert views and involved an extensive literature research. Each treatment recommendation was evaluated and discussed with respect to the strength of evidence for efficacy, safety, tolerability and feasibility. An algorithm is proposed for the treatment of paraphilic disorders in adolescent sexual offenders or those who are at risk. PMID- 26595755 TI - The right friends in the right places: Understanding network structure as a predictor of voluntary turnover. AB - Research examining the relationship between social networks and employee retention has focused almost exclusively on the number of direct links and generally found that having more ties decreases the likelihood of turnover. The present research moves beyond simple measures of network centrality to investigate the relationship between 2 additional, and theoretically distinct, facets of social capital and voluntary turnover. In 2 organizations, we found consistent evidence of a negative relationship between reputation, as measured by relationships with highly sought-out others (incoming eigenvector centrality) and voluntary turnover. Further, we found that the negative relationship between brokerage (structural holes) and turnover is significant, but only for higher level employees. The theoretical and practical implications of expanding the suite of social capital measures to understand voluntary turnover are discussed. PMID- 26595756 TI - Going the extra mile and feeling energized: An enrichment perspective of organizational citizenship behaviors. AB - Scholars have voiced concerns about the potential dark side of Organizational Citizenship Behavior (OCB), arguing that OCB consumes energy, which contributes to a depletion of personal resources and results in poorer well-being. Drawing from research on the meaningfulness of work, we propose a pattern opposite to depletion: that OCB enhances energy, which contributes to an enrichment of personal resources and results in better well-being. This idea was tested over the course of a workweek with 224 day-level ratings from 67 employees and 30 managers working in a service management firm. Three-level hierarchical linear modeling indicated that supervisor-rated daily OCB was positively associated with employees' vigor at the end of the workday, and multilevel structural equation modeling analyses showed that this relationship was mediated by meaningfulness of work. Moreover, we found that the association between OCB and work meaningfulness was stronger for employees with greater role ambiguity. Exploratory analyses revealed that daily in-role performance and daily OCB interacted to predict meaningfulness of work, such that the association between daily OCB and meaningfulness of work was more prominent among those who exhibited high levels of daily in-role performance. We discuss implications of these findings, limitations, and directions for future research. PMID- 26595757 TI - The role of self-determined motivation in job search: A dynamic approach. AB - Job search is a dynamic self-regulated process during which job seekers need to stay motivated to secure a job. However, past research has taken a relatively static approach to examining motivation during the job search, in addition to ignoring how the quality of one's motivation--ranging from autonomous to controlled--can influence job search processes. Adopting a within-person perspective, the current study extends self-determination theory (SDT) to the job search context to investigate (a) when autonomous and controlled motivations are more or less prevalent and (b) whether they influence job search effort through metacognitive strategies in differing ways depending upon the amount of time elapsed in the search. In a weekly study of new labor market entrants (Level-2 n = 149; Level-1 n = 691), results indicated that autonomous motivation decreased until the midpoint of the job search and then plateaued, whereas controlled motivation remained stable. Results also showed that autonomous motivation had a consistent, positive relation with metacognitive strategies, whereas the relation between controlled motivation and such strategies was negative early in the job search, but became positive as the job search progressed. Finally, the effects of motivation on job search effort occurred via metacognitive strategies differentially depending upon the time elapsed in the search. Combined, we provide a first glimpse into the dynamics of self-determined motivation on job search processes. PMID- 26595758 TI - Selecting team players: Considering the impact of contextual performance and workplace deviance on selection decisions in the National Football League. AB - Contextual performance and workplace deviance likely influence team functioning and effectiveness and should therefore be considered when evaluating job candidates for team-based roles. However, obtaining this information is difficult given a lack of reliable sources and the desire of job applicants to present themselves in a favorable light. Thus, it is unknown whether those selecting employees for teams incorporate prior contextual performance and workplace deviance into their evaluations, or whether doing so improves the quality of selection decisions. To address these issues, we examined the impact of prior task performance, contextual performance, and workplace deviance on National Football League (NFL) decision maker (organizational insider) and external expert (organizational outsider) evaluations of college football players in the NFL draft, using a content analysis methodology to generate measures of contextual performance and workplace deviance. Our findings indicate that insiders value contextual performance more than outsiders, which is likely because of differing interests and goals that lead to different levels of motivation and/or ability to acquire information about prior contextual performance. We also propose that prior task performance, contextual performance, and workplace deviance will predict player performance in the NFL. Our results support this prediction for task and contextual performance. In addition, we investigated the quality of insider and outsider judgments using Brunswik's (1952) lens model. Implications of our findings for the team selection, contextual performance, and workplace deviance literatures are discussed. PMID- 26595759 TI - Off-duty deviance: Organizational policies and evidence for two prevention strategies. AB - Anecdotal evidence suggests that organizations are increasingly concerned with employee off-duty deviance (ODD), yet management research has rarely investigated this type of deviant behavior. We define ODD as behaviors committed outside the workplace or when off-duty that are deviant by organizational and/or societal standards, jeopardize the employee's status within the organization, and threaten the interests and well-being of the organization and its stakeholders. Three studies are presented to better understand the relevance of ODD to modern organizations and then to understand potential approaches to reduce the incidence of ODD. The first study provides a qualitative review of publicly available ODD policies within the Fortune 500; the results showed that 13.4% of the Fortune 500 had a publicly available ODD policy, with the majority prohibiting criminal forms of ODD to protect the firm's reputation. The next 2 studies examine the efficacy of different approaches to reduce criminal ODD: policy adoption and personnel selection. In the second study, a longitudinal, quasi-experimental design showed a significant-albeit modest-reduction in criminal ODD following the adoption of a conduct policy. In the third and final study, a criterion-related validity design supported the predictive validity of general mental ability and prior deviance in predicting criminal ODD. This compendium of studies provides an initial empirical investigation into ODD and offers implications relevant to the deviance literature, policy development, and personnel selection. PMID- 26595760 TI - Liquid chromatography-tandem mass spectrometry (LC-MS/MS) for analysis of endogenous steroids in the luteal phase and early pregnancy in dogs: a pilot study. AB - BACKGROUND: Blood samples from dogs are often limited in volume, only allowing few steroids to be quantified with immunoassays. In addition, immunoassays may be compromised by interferences such as anti-reagent antibodies. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) can be used for the simultaneous quantitation of several steroids. This has not been described in dogs before. OBJECTIVES: The aims were to use LC-MS/MS to study steroid profiles in early pregnancy and luteal phase in dogs, and to determine if differences exist between pregnant (P) and nonpregnant (NP) dogs. METHODS: Nine female dogs were included, 4 during a NP luteal phase, 4 during a P luteal phase, and one during one NP and one P luteal phase. Blood samples were collected around the time of the LH surge (Day 0) and on Day 26. Serum was analyzed for 5 classes of steroids, including glucocorticoids, androgens, estrogens, pregnanes, and progestins, using LC-MS/MS methods. RESULTS: The concentration of progesterone was significantly higher on Day 26 in P than in NP bitches. Distribution of concentrations of glucocorticoids, androgens, estrogens, or pregnanes in P and NP dogs were not statistically different. The predominating glucocorticoid was cortisol, and dihydroepiandrosterone (DHEA) was the predominating androgen. Concentration of estrone was comparable to oestradiol, whereas concentrations of pregnenolone were higher than those of 17-OH pregnenolone. CONCLUSIONS: Only concentration of progesterone differed between P and NP bitches, being significantly higher on Day 26 in P than in NP bitches. LC-MS/MS offers interesting possibilities for studies of canine reproductive endocrinology. PMID- 26595761 TI - Hard is Normal: Military Families' Transitions Within the Process of Deployment. AB - US military deployments have become more frequent and lengthier in duration since 2003. Over half of US military members are married, and many also have children. The authors sought to understand the process of deployment from the perspective of the military family. After a thorough search of the literature, 21 primary research reports of 19 studies with an aggregate sample of 874 were analyzed using qualitative metasynthesis. The deployment process was experienced in four temporal domains. The military family as a whole shared the pre-deployment transition: all family members felt uncertain about the future, needed to complete tasks to "get ready" for deployment, and experienced a sense of distancing in preparation for the upcoming separation. The AD member went through the deployment transition independently, needing to "stay engaged" with the military mission, building a surrogate family and simultaneously trying to maintain connection with the family at home. In parallel, the home front family was going through a transposement transition, moving forward as an altered family unit, taking on new roles and responsibilities, and trying to simultaneously connect with the deployed member and find support from other military families. In post-deployment, the family went through the "reintegration" transition together, managing expectations, and readjusting family roles, all needing understanding and appreciation for their sacrifices during the recent separation. Effective family communication was important for military family well-being after deployment but unexpectedly challenging for many. Clinical, research, and policy recommendations are discussed. PMID- 26595762 TI - Identification and Characterization of Lineage(-)CD45(-)Sca-1(+) VSEL Phenotypic Cells Residing in Adult Mouse Bone Tissue. AB - Murine bone marrow (BM)-derived very small embryonic-like stem cells (BM VSELs), defined by a lineage-negative (Lin(-)), CD45-negative (CD45(-)), Sca-1-positive (Sca-1(+)) immunophenotype, were previously reported as postnatal pluripotent stem cells (SCs). We developed a highly efficient method for isolating Lin( )CD45(-)Sca-1(+) small cells using enzymatic treatment of murine bone. We designated these cells as bone-derived VSELs (BD VSELs). The incidences of BM VSELs in the BM-derived nucleated cells and that of BD VSELs in bone-derived nucleated cells were 0.002% and 0.15%, respectively. These BD VSELs expressed a variety of hematopoietic stem cell (HSC), mesenchymal stem cell (MSC), and endothelial cell markers. The gene expression profile of the BD VSELs was clearly distinct from those of HSCs, MSCs, and ES cells. In the steady state, the BD VSELs proliferated slowly, however, the number of BD VSELs significantly increased in the bone after acute liver injury. Moreover, green fluorescent protein-mouse derived BD VSELs transplanted via tail vein injection after acute liver injury were detected in the liver parenchyma of recipient mice. Immunohistological analyses suggested that these BD VSELs might transdifferentiate into hepatocytes. This study demonstrated that the majority of the Lin(-)CD45(-)Sca-1(+) VSEL phenotypic cells reside in the bone rather than the BM. However, the immunophenotype and the gene expression profile of BD VSELs were clearly different from those of other types of SCs, including BM VSELs, MSCs, HSCs, and ES cells. Further studies will therefore be required to elucidate their cellular and/or SC characteristics and the potential relationship between BD VSELs and BM VSELs. PMID- 26595763 TI - Food Allergy in childhood: phenotypes, prevention and treatment. AB - The prevalence of food allergy in childhood increased in the last decades, especially in Westernized countries where this phenomenon has been indicated as a second wave of the allergic epidemic. In parallel, scientific interest also increased with the effort to explain the reasons of this sudden rise and to identify potential protective and risk factors. A great attention has been focused on early exposures to allergenic foods, as well as on other nutritional factors or supplements that may influence the immune system in a positive direction. Both interventions on maternal diet before birth or during breastfeeding and then directly on infant nutrition have been investigated. Furthermore, the natural history of food allergy also seems to be changing over time; IgE-mediated cow's milk allergy and egg allergy seem to be more frequently a persistent rather than a transient disease in childhood, as described in the last years. Food avoidance and the emergency drugs in case of an adverse event, such as epinephrine self-injector, are currently the first-line treatment in patients with food allergies, with a resulting impairment in the quality of life and social behaviour. During the last decade, oral immunotherapy emerged as an optional treatment with remarkable results, offering a novel perspective in the treatment for and management of food allergy. PMID- 26595764 TI - The effect of speaking context on spectral- and cepstral-based acoustic features of normal voice. AB - The effect of speaking context on four cepstral- and spectral-based acoustic measures was investigated in 20 participants with normal voice. Speakers produced three different continuous speaking tasks that varied in duration and phonemic content. Cepstral and spectral measures that can be validly derived from continuous speech were computed across the three speaking contexts. Cepstral peak prominence (CPP), low/high spectral ratio, and the standard deviation (SD) of the low/high spectral ratio did not significantly differ across speaking contexts, and correlations for the first two measures were strong among the three speaking tasks. The SD of the CPP showed significant task differences, and relationships between the speaking contexts were generally moderate. These findings suggest that in speakers with normal voice, the differing phonemic content across several frequently used speaking stimuli minimally impacted group means for three clinically relevant cepstral- and spectral-based acoustic measures. PMID- 26595765 TI - Hypokalemia and suspected renal tubular acidosis associated with topical carbonic anhydrase inhibitor therapy in a cat. AB - OBJECTIVE: To describe the occurrence of hypokalemia, metabolic acidosis, and suspected renal tubular acidosis associated with the administration of topical ophthalmic carbonic anhydrase inhibitor (CAI) in a cat. CASE SUMMARY: A 2-year old, 5.3 kg, male, castrated, domestic short-haired cat developed hyporexia 6 weeks after starting topical ophthalmic dorzolamide 2% therapy for treatment of ocular hypertension. Two weeks later, the cat was evaluated for severe weakness, cervical ventroflexion, and anorexia. Plasma electrolyte and acid-base measurement revealed hypokalemia (K+ = 2.9 mmol/L; reference interval 3.8-5.4 mmol/L) and metabolic acidosis (plasma HCO3- = 9.8 mmol/L; reference interval 15 23 mmol/L) in the presence of a urine pH of 7.5 (reference interval 6.5-7.5). The pH abnormalities were consistent with a renal tubular acidosis. Clinical and biochemical abnormalities resolved with short-term supportive care, potassium supplementation, and discontinuation of dorzolamide therapy. NEW OR UNIQUE INFORMATION PROVIDED: This is the first report of hypokalemia and metabolic acidosis associated with topical CAI therapy in a cat. PMID- 26595766 TI - Direct Interface between Digital Microfluidics and High Performance Liquid Chromatography-Mass Spectrometry. AB - We introduce an automated method to facilitate in-line coupling of digital microfluidics (DMF) with HPLC-MS, using a custom, 3D-printed manifold and a custom plugin to the popular open-source control system, DropBot. The method was designed to interface directly with commercial autosamplers (with no prior modification), suggesting that it will be widely accessible for end-users. The system was demonstrated to be compatible with samples dissolved in aqueous buffers and neat methanol and was validated by application to a common steroid labeling derivatization reaction. We propose that the methods described here will be useful for a wide range of applications, combining the automated sample processing power of DMF with the resolving and analytical capacity of HPLC-MS. PMID- 26595767 TI - A Comparative Analysis of the Safety, Efficacy, and Cost of Islet Versus Pancreas Transplantation in Nonuremic Patients With Type 1 Diabetes. AB - Few current studies compare the outcomes of islet transplantation alone (ITA) and pancreas transplantation alone (PTA) for type 1 diabetes (T1D). We examined these two beta cell replacement therapies in nonuremic patients with T1D with respect to safety, graft function and cost. Sequential patients received PTA (n = 15) or ITA (n = 10) at our institution. Assessments of graft function included duration of insulin independence; glycemic control, as measured by hemoglobin A1c; and elimination of severe hypoglycemia. Cost analysis included all normalized costs associated with transplantation and inpatient management. ITA patients received one (n = 6) or two (n = 4) islet transplants. Mean duration of insulin independence in this group was 35 mo; 90% were independent at 1 year, and 70% were independent at 3 years. Mean duration of insulin independence in PTA was 55 mo; 93% were insulin independent at 1 year, and 64% were independent at 3 years. Glycemic control was comparable in all patients with functioning grafts, as were overall costs ($138 872 for ITA, $134 748 for PTA). We conclude that with advances in islet isolation and posttransplant management, ITA can produce outcomes similar to PTA and represents a clinically viable option to achieve long term insulin independence in selected patients with T1D. PMID- 26595768 TI - The primate-specific noncoding RNA HPAT5 regulates pluripotency during human preimplantation development and nuclear reprogramming. AB - Long intergenic noncoding RNAs (lincRNAs) are derived from thousands of loci in mammalian genomes and are frequently enriched in transposable elements (TEs). Although families of TE-derived lincRNAs have recently been implicated in the regulation of pluripotency, little is known of the specific functions of individual family members. Here we characterize three new individual TE-derived human lincRNAs, human pluripotency-associated transcripts 2, 3 and 5 (HPAT2, HPAT3 and HPAT5). Loss-of-function experiments indicate that HPAT2, HPAT3 and HPAT5 function in preimplantation embryo development to modulate the acquisition of pluripotency and the formation of the inner cell mass. CRISPR-mediated disruption of the genes for these lincRNAs in pluripotent stem cells, followed by whole-transcriptome analysis, identifies HPAT5 as a key component of the pluripotency network. Protein binding and reporter-based assays further demonstrate that HPAT5 interacts with the let-7 microRNA family. Our results indicate that unique individual members of large primate-specific lincRNA families modulate gene expression during development and differentiation to reinforce cell fate. PMID- 26595771 TI - Chemical and Sensory Quality Preservation in Coated Almonds with the Addition of Antioxidants. AB - Almonds provide many benefits such as preventing heart disease due to their high content of oleic fatty acid-rich oil and other important nutrients. However, they are susceptible to oxidation reactions causing rancidity during storage. The objective of this work was to evaluate the chemical and sensory quality preservation of almonds coated with carboxymethyl cellulose and with the addition of natural and synthetic antioxidants during storage. Four samples were prepared: almonds without coating (C), almonds coated with carboxymethyl cellulose (CMC), almonds coated with CMC supplemented with peanut skins extract (E), and almonds coated with CMC and supplemented with butylhydroxytoluene (BHT). Proximate composition and fatty acid profile were determined on raw almonds. Almond samples (C, CMC, E and BHT) were stored at 40 degrees C for 126 d. Lipid oxidation indicators: peroxide value (PV), conjugated dienes (CD), volatile compounds (hexanal and nonanal), and sensory attributes were determined for the stored samples. Samples showed small but significant increases in PV, CD, hexanal and nonanal contents, and intensity ratings of negative sensory attributes (oxidized and cardboard). C had the highest tendency to deterioration during storage. At the end of storage (126 d), C had the highest PV (3.90 meqO2 /kg), and BHT had the lowest PV (2.00 meqO2 /kg). CMC and E samples had similar intermediate PV values (2.69 and 2.57 meqO2 /kg, respectively). CMC coating and the addition of natural (peanut skin extract) and synthetic (BHT) antioxidants provide protection to the roasted almond product. PMID- 26595772 TI - Earlier adjuvant therapy is beneficial in patients with breast and colon cancer. PMID- 26595773 TI - "Hot background" of the mobile inelastic neutron scattering system for soil carbon analysis. AB - The problem of gamma spectrum peak identification arises when conducting soil carbon analysis using the inelastic neutron scattering (INS) system. Some spectral peaks could be associated with radioisotopes appearing due to neutron activation of both the measurement system and soil samples. The investigation of "hot background" gamma spectra from the construction materials, whole measurement system, and soil samples over time showed that activation of (28)Al isotope can contribute noticeable additions to the soil neutron stimulated gamma spectra. PMID- 26595770 TI - The noncoding RNAs SNORD50A and SNORD50B bind K-Ras and are recurrently deleted in human cancer. AB - Small nucleolar RNAs (snoRNAs) are conserved noncoding RNAs best studied as ribonucleoprotein (RNP) guides in RNA modification. To explore their role in cancer, we compared 5,473 tumor-normal genome pairs to identify snoRNAs with frequent copy number loss. The SNORD50A-SNORD50B snoRNA locus was deleted in 10 40% of 12 common cancers, where its loss was associated with reduced survival. A human protein microarray screen identified direct SNORD50A and SNORD50B RNA binding to K-Ras. Loss of SNORD50A and SNORD50B increased the amount of GTP bound, active K-Ras and hyperactivated Ras-ERK1/ERK2 signaling. Loss of these snoRNAs also increased binding by farnesyltransferase to K-Ras and increased K Ras prenylation, suggesting that KRAS mutation might synergize with SNORD50A and SNORD50B loss in cancer. In agreement with this hypothesis, CRISPR-mediated deletion of SNORD50A and SNORD50B in KRAS-mutant tumor cells enhanced tumorigenesis, and SNORD50A and SNORD50B deletion and oncogenic KRAS mutation co occurred significantly in multiple human tumor types. SNORD50A and SNORD50B snoRNAs thus directly bind and inhibit K-Ras and are recurrently deleted in human cancer. PMID- 26595774 TI - Demonstration of the importance of a dedicated neutron beam monitoring system for BNCT facility. AB - The neutron beam monitoring system is indispensable to BNCT facility in order to achieve an accurate patient dose delivery. The neutron beam monitoring of a reactor-based BNCT (RB-BNCT) facility can be implemented through the instrumentation and control system of a reactor provided that the reactor power level remains constant during reactor operation. However, since the neutron flux in reactor core is highly correlative to complicated reactor kinetics resulting from such as fuel depletion, poison production, and control blade movement, some extent of variation may occur in the spatial distribution of neutron flux in reactor core. Therefore, a dedicated neutron beam monitoring system is needed to be installed in the vicinity of the beam path close to the beam exit of the RB BNCT facility, where it can measure the BNCT beam intensity as closely as possible and be free from the influence of the objects present around the beam exit. In this study, in order to demonstrate the importance of a dedicated BNCT neutron beam monitoring system, the signals originating from the two in-core neutron detectors installed at THOR were extracted and compared with the three dedicated neutron beam monitors of the THOR BNCT facility. The correlation of the readings between the in-core neutron detectors and the BNCT neutron beam monitors was established to evaluate the improvable quality of the beam intensity measurement inferred by the in-core neutron detectors. In 29 sampled intervals within 16 days of measurement, the fluctuations in the mean value of the normalized ratios between readings of the three BNCT neutron beam monitors lay within 0.2%. However, the normalized ratios of readings of the two in-core neutron detectors to one of the BNCT neutron beam monitors show great fluctuations of 5.9% and 17.5%, respectively. PMID- 26595769 TI - TRAIP promotes DNA damage response during genome replication and is mutated in primordial dwarfism. AB - DNA lesions encountered by replicative polymerases threaten genome stability and cell cycle progression. Here we report the identification of mutations in TRAIP, encoding an E3 RING ubiquitin ligase, in patients with microcephalic primordial dwarfism. We establish that TRAIP relocalizes to sites of DNA damage, where it is required for optimal phosphorylation of H2AX and RPA2 during S-phase in response to ultraviolet (UV) irradiation, as well as fork progression through UV-induced DNA lesions. TRAIP is necessary for efficient cell cycle progression and mutations in TRAIP therefore limit cellular proliferation, providing a potential mechanism for microcephaly and dwarfism phenotypes. Human genetics thus identifies TRAIP as a component of the DNA damage response to replication blocking DNA lesions. PMID- 26595775 TI - Semi-automated production of 89Zr-oxalate/89Zr-chloride and the potential of 89Zr chloride in radiopharmaceutical compounding. AB - Interest in using (89)Zr is rapidly increasing for immuno-PET applications due to its unique characteristics and increased availability. The focus of this study was to develop an optimized semi-automated methodology for producing (89)Zr oxalate/(89)Zr-chloride, and evaluate the potential application of (89)Zr chloride for radiopharmaceutical compounding. The data presented herein will be useful for the production of (89)Zr-labeled radiopharmaceuticals and their compliance with regulatory issues for both preclinical and clinical use. PMID- 26595776 TI - Assessing rare earth elements in quartz rich geological samples. AB - Sodium peroxide (Na2O2) fusion coupled to Inductively Coupled Plasma Tandem Mass Spectrometry (ICP-MS/MS) measurements was used to rapidly screen quartz-rich geological samples for rare earth element (REE) content. The method accuracy was checked with a geological reference material and Instrumental Neutron Activation Analysis (INAA) measurements. The used mass-mode combinations presented accurate results (only exception being (157)Gd in He gas mode) with recovery of the geological reference material QLO-1 between 80% and 98% (lower values for Lu, Nd and Sm) and in general comparable to INAA measurements. Low limits of detection for all elements were achieved, generally below 10 pg g(-1), as well as measurement repeatability below 15%. Overall, the Na2O2/ICP-MS/MS method proved to be a suitable lab-based method to quickly and accurately screen rock samples originating from quartz-rich geological areas for rare earth element content; particularly useful if checking commercial viability. PMID- 26595777 TI - Using a Tandem Pelletron accelerator to produce a thermal neutron beam for detector testing purposes. AB - Active thermal neutron detectors are used in a wide range of measuring devices in medicine, industry and research. For many applications, the long-term stability of these devices is crucial, so that very well controlled neutron fields are needed to perform calibrations and repeatability tests. A way to achieve such reference neutron fields, relying on a 3 MV Tandem Pelletron accelerator available at the CNA (Seville, Spain), is reported here. This paper shows thermal neutron field production and reproducibility characteristics over few days. PMID- 26595778 TI - Multi-components determination by single reference standard and HPLC fingerprint analysis for Lamiophlomis rotata Pill. AB - A validated HPLC method was developed to evaluate the quality of Lamiophlomis rotata Pill combining the multi-components analysis by single reference standard with HPLC fingerprint analysis. Five bioactive components (shanzhiside methyl ester, loganin, 8-O-acetylshanzhiside methyl ester, forsythoside B and luteolin-7 O-beta-D-glucopyranoside) were selected as markers to control the quality of L. rotata Pill. The results revealed that the chromatographic fingerprint method coupled with multi-components analysis provides an effective and feasible way to determine the components in L. rotata Pill. PMID- 26595779 TI - Circulating nucleosomes in chronic heart failure. PMID- 26595780 TI - Cheyne-Stokes respiration in patients with heart failure. PMID- 26595781 TI - ERS-PERK signaling pathway-mediated Nrf2/ARE-HO-1 axis: A novel therapeutic target for attenuating myocardial ischemia and reperfusion injury. PMID- 26595782 TI - Which child catheter should we choose to deliver a bulky bioresorbable vascular scaffold? PMID- 26595783 TI - Do we need MIBG in the evaluation of patients with suspected Takotsubo syndrome? Diagnostic, prognostic, and pathophysiologic connotations. PMID- 26595784 TI - A decisional model to individualize warfarin recommendations: Expected impact on treatment and outcome rates in a real-world population with atrial fibrillation. AB - BACKGROUND: How the adoption of prediction models to decide which patient with atrial fibrillation (AF) to anticoagulate can affect prescription rates and outcomes is unclear. METHODS: We retrospectively analyzed data from Danish registries on patients with a first-time recorded AF from 2005 to 2010. We simulated the adoption of a decisional model based on the individual absolute risk reduction of stroke and absolute risk increase of bleeding with warfarin, as expected from the patient CHA2DS2-VASc and HAS-BLED, adjusted for a 0.6 relative value for bleeding versus stroke. We studied 3 different model versions and calculated for each of them the net benefit associated with its adoption, measured as the value-adjusted reduction in stroke and bleeding events at 1 year, compared with i) the actual practice, or ii) recommending warfarin consistently with the European Society of Cardiology (ESC) guidelines, irrespective of HAS BLED. RESULTS: We included 41,455 patients; 31.9% actually received warfarin. The expected treatment rate with the model ranged from 21% to 87% according to the version used. The model version resulting into the highest treatment rate (i.e. treating any patient with CHA2DS2-VASc >= 1) was associated with the greatest net benefit (0.98; 95% credible interval 0.72-1.23), compared with the actual practice, with a 1/3 reduction in overall mortality, as with the adoption of ESC guidelines. CONCLUSIONS: Preliminarily to a randomized impact study, our analysis suggests that individualizing anticoagulation for AF using a decisional model might have a clinical advantage over actual practice, and no added advantage over following ESC guidelines. PMID- 26595785 TI - The right Marginal Vessel Bypass Emerging After Right Coronary Artery Stenting. PMID- 26595786 TI - Metabolic syndrome and the risk of sudden cardiac death in middle-aged men. AB - BACKGROUND: Little is known about the relationship between metabolic syndrome and sudden cardiac death (SCD). We examined the association of metabolic syndrome, as defined by World Health Organization (WHO), International Diabetes Federation (IDF), National Cholesterol Education Program (NCEP) and American Heart Association (AHA)--IDF interim criteria, with incident SCD. We also assessed the association of a continuous metabolic risk score with SCD. METHODS: A total of 1466 middle-aged men participating in a prospective population-based cohort study from eastern Finland with no history of coronary heart disease or diabetes at baseline were included. RESULTS: During the average follow-up of 21 years 85 SCDs occurred. Men with the metabolic syndrome as defined by the WHO, NCEP, IDF and interim criteria had a 2.2-2.6 fold, increased risk for SCD, after adjusting for lifestyle and traditional cardiovascular risk factors not included in the metabolic syndrome definition (P<0.001-0.011). A one-standard deviation increase in the metabolic risk score (composed of the sum of Z-scores for waist circumference, insulin, glucose, high-density lipoprotein (HDL) cholesterol, triglycerides, and blood pressure) was associated with a 1.68-fold higher (95% CI 1.33-2.11) risk of SCD. Even when adjusting further for systolic blood pressure, HDL cholesterol and body mass index, the association remained significant for the interim criteria and the metabolic risk score, but not for WHO, NCEP, or IDF definitions. CONCLUSIONS: Men with metabolic syndrome are at increased risk for SCD. Incident SCD associated with the IDF/AHA interim criteria and metabolic risk clustering estimated by a score is not explained by obesity or traditional cardiovascular risk factors. KEY MESSAGES: Men with metabolic syndrome are at increased risk for sudden cardiac death. Incident sudden cardiac death associated with metabolic risk clustering estimated by a score in not explained by obesity or traditional cardiovascular risk factors. Prevention of the metabolic syndrome may help reduce the health burden of SCD. PMID- 26595788 TI - Six-minute walk test in moderate to severe heart failure with preserved ejection fraction: Useful for functional capacity assessment? PMID- 26595787 TI - Forced expiratory volume in one second: Predicting return to work within 3 months after chronic heart failure diagnosis. PMID- 26595789 TI - Diamond-Forrester and Morise risk models perform poorly in predicting obstructive coronary disease in Middle Eastern Cohort. PMID- 26595790 TI - Galectin-3 and Kawasaki disease patients with special reference to coronary artery aneurysm. PMID- 26595791 TI - A multi-artery Fractional Flow Reserve (FFR) approach for handling coronary stenosis-stenosis interaction in the multi-vessel disease (MVD) arena. AB - BACKGROUND: FFR is a widely accepted 'gold standard' of coronary stenosis severity indices in MVD cases. Contrary to this conception, reality shows that true FFR values that are equal to the real fractional remnant blood flow exist only in single vessel disease (SVD) cases and in those MVD cases that are decomposable into independent SVD cases. OBJECTIVES: The article is firstly aimed at defining the limits of validity of the basic single-artery FFR index. It is then intended to devise an FFR method for handling MVD cases in the presence of stenosis-stenosis interaction. METHODS: The boundaries of the frame of validity of single-artery true FFR are determined. A detailed multi-artery FFR analysis of the effect of stenosis-stenosis interaction in an MVD scenario consisting of stenotic LM and LAD arteries and a non-stenotic LCx artery is subsequently developed. RESULTS: The multi-artery FFR approach developed in the article demonstrates handling a 3-artery configuration like LM-LAD-LCx. The method takes into account the effect of all the stenoses and yields quantitative guidelines for the practitioner that lead to optimal treatment that accommodates each artery. Calculations are also in agreement with the effect of stenosis-stenosis interaction on FFR(LM) reported in the literature. CONCLUSIONS: It turns out that the basic single-artery FFR approach cannot handle MVD cases that involve stenosis-stenosis interaction like concomitantly stenotic LM artery and LAD (or LCx) artery. In the multi-artery FFR approach the various ratios of intracoronary pressures lose their original single-artery FFR meaning and the revascularization criteria change. PMID- 26595792 TI - Left ventricle diastolic function and cognitive performance in adults with Down syndrome. PMID- 26595793 TI - Association between socioeconomic factors and depression among cardiovascular patients living in rich resourced Middle Eastern country. PMID- 26595794 TI - The progressed atrioventricular block associated with ticagrelor therapy may not require permanent pacemaker after acute coronary syndrome; it may be reversible. PMID- 26595795 TI - Combined analysis of N'-nitrosonornicotine and 4-(methylnitrosamino)-1-(3 pyridyl)-1-butanol in the urine of cigarette smokers and e-cigarette users. AB - A liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC ESI(+)-MS/MS) method for the analysis of the tobacco-specific carcinogens N' nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and their glucuronides (total NNN and total NNAL) in human urine was developed. The method has excellent accuracy and intra-day and inter-day precision, and limits of quantitation of 0.015 and 0.075pmol/mL urine, respectively, for total NNN and total NNAL. A unique aspect of this method is internal assessment of possible artifactual formation of NNN by inclusion of the monitor amine [pyridine D4]nornicotine. We found that artifactual formation of NNN comprised only 2.5% of the measured amounts of total NNN in urine of cigarette smokers, under our conditions using ammonium sulfamate as an inhibitor of nitrosation. The method was applied to urine samples from cigarette smokers and e-cigarette users. Levels of total NNN and total NNAL in the urine of cigarette smokers averaged 0.060+/ 0.035pmol/mL and 2.41+/-1.41pmol/mL urine, (N=38), respectively, which were both significantly greater than in the urine of 27 e-cigarette users. PMID- 26595796 TI - Synthesis of monodisperse molecularly imprinted microspheres with multi recognition ability via precipitation polymerization for the selective extraction of cyromazine, melamine, triamterene and trimethoprim. AB - Through precipitation polymerization, three monodisperse molecularly imprinted polymers (MIPs) containing imprints of 2,4-diamino-6-methyl-1,3,5-triazine (DM), cyromazine (CY) or trimethoprim (TM), were synthesized using methacrylic acid as functional monomer, divinylbenzene as cross-linker, and a mixture of acetonitrile toluene (90/10, v/v) as porogen. The morphology and selectivity of the MIPs were characterized and compared systematically. The MIPs had the best specific binding in pure acetonitrile, and the data of adsorption experiment were fitted well with Langmuir and Freundlich model. In addition, DM-MIPs showed the excellent binding and multi-recognition capability for CY, melamine (ME), triamterene (TA) and TM, and the binding capacity were 7.18, 7.56, 5.66 and 5.45MUmol/g, respectively. Due to the pseudo template and the ability of multi-recognition, DM-MIPs as sorbent material could avoid the effect of template leakage on quantitative analysis. Therefore, DM-MIPs were used as a solid-phase extraction material to enrich ME, CY, TA and TM from different bio-matrix samples for high performance liquid chromatography analysis. Under the optimized conditions, the recoveries of three spiked levels in different bio-matrix samples were ranged from 80.9% to 91.5% with RSD<=4.2 (n=3). PMID- 26595797 TI - Estimating back to front ratio of wire screen for measurement of thoron decay products. AB - Wire screens are widely used for measuring the fine fraction of radon/thoron decay products. Their capture efficiencies are generally defined at low aerosol concentration conditions as well as at low sampling flow rates. Effect of changes in sampling flow rate and aerosol concentration on wire screen capture efficiencies and counting correction factor has been studied in this work. Controlled experiments have been conducted using two different mesh sizes at two different aerosol concentration conditions. Experimental results were compared with the existing theories for capture efficiencies of wire screens given by Cheng and Yeh (1980) and Alonso et al. (2001); and semi empirical relation for the front to total ratio given by Solomon and Ren (1992). Theoretical predictions have been found to be relatively close to the experimental findings for moderate aerosol conditions but disagreement was observed in case of high aerosol concentration. The possible reasons for these differences have been discussed in this work. PMID- 26595798 TI - The Relationship Between Cardiorespiratory Fitness and Aortic Stiffness in Women with Central Obesity. AB - PURPOSE: To examine the association between cardiorespiratory fitness and aortic stiffness in women with central obesity. The secondary purpose was to examine whether traditional and nontraditional cardiovascular risk factors mediate the relationship between cardiorespiratory fitness and aortic stiffness. MATERIALS AND METHODS: Eighty-seven centrally obese women (age, 42 +/- 9 years, [body mass index (BMI)] 28 +/- 3 kg/m(2)) participated in this cross-sectional study. Central obesity was defined as a waist circumference >85 cm. Pulse wave velocity (PWV) was obtained from the carotid and femoral pulse sites using applanation tonometry to measure aortic stiffness. Maximal aerobic capacity (VO2 Max) was estimated using a submaximal walk test and taken as a measure of cardiorespiratory fitness. Potential correlates of both cardiorespiratory fitness and aortic stiffness examined in this study included the following: triglycerides (TG), C-reactive protein (CRP), homeostasis model assessment of insulin resistance index (HOMA-IR), and pulsatile load (i.e., heart rate * aortic pulse pressure [aPP]). RESULTS: Pearson's bivariate correlations indicated that estimated VO2 Max was inversely associated with PWV (r = -0.330, p < 0.05). Using hierarchical multiple regression, the association between estimated VO2 Max and PWV was no longer significant after controlling for traditional and nontraditional cardiovascular risk factors, age, BMI, TG, CRP, HOMA-IR, and pulsatile load (beta = 0.121, p > 0.05). CONCLUSION: In centrally obese women, cardiorespiratory fitness was inversely associated with aortic stiffness. Associations were not independent of traditional and nontraditional cardiovascular disease (CVD) risk factors. This suggests that higher levels of cardiorespiratory fitness may indirectly reduce aortic stiffness through its beneficial effects on traditional and nontraditional CVD risk factors in women with central obesity. PMID- 26595799 TI - Characterization of Heme-DNA Complexes Composed of Some Chemically Modified Hemes and Parallel G-Quadruplex DNAs. AB - Heme {Fe(II)- or Fe(III)-protoporphyrin IX complex [heme(Fe(2+)) or heme(Fe(3+)), respectively]} binds selectively to the 3'-terminal G-quartet of a parallel G quadruplex DNA formed from a single repeat sequence of the human telomere, d(TTAGGG), through a pi-pi stacking interaction between the porphyrin moiety of the heme and the G-quartet. The binding affinities of some chemically modified hemes(Fe(3+)) for DNA and the structures of complexes between the modified hemes(Fe(2+)) and DNA, with carbon monoxide (CO) coordinated to the heme Fe atom on the side of the heme opposite the G6 G-quartet, have been characterized to elucidate the interaction between the heme and G-quartet in the complexes through analysis of the effects of the heme modification on the structural properties of the complex. The study revealed that the binding affinities and structures of the complexes were barely affected by the heme modification performed in the study. Such plasticity in the binding of heme to the G-quartet is useful for the versatile design of the complex through heme chemical modification and DNA sequence alteration. Furthermore, exchangeable proton signals exhibiting two proton intensity were observed at approximately -3.5 ppm in the (1)H nuclear magnetic resonance (NMR) spectra of the CO adducts of the complexes. Through analysis of the NMR results, together with theoretical consideration, we concluded that the heme(Fe(2+)) axial ligand trans to CO in the complex is a water molecule (H2O). Identification of the Fe-bound H2O accommodated between the heme and G-quartet planes in the complex provides new insights into the structure function relationship of the complex. PMID- 26595800 TI - Dual effects of heme oxygenase-1 on astrocyte injury induced by hemin in vitro. AB - PRIMARY OBJECTIVE: The purpose of this study was to investigate the effects of heme oxygenase-1 (HO-1) on astrocyte injury induced by hemin. RESEARCH DESIGN: Primary astrocytes were isolated from Sprague Dawley rat pups and cultured in vitro. The expression of HO-1 was induced by hemin in a quantitative fashion and the effects of HO-1 on hemin-induced astrocyte injury were estimated by cell viability, cell membrane permeability and apoptosis. METHODS AND PROCEDURES: Astrocytes were divided into control group, hemin 5 MUM group, hemin 5 MUM + Zn PPIX group, hemin 30 MUM group and hemin 30 MUM + Zn-PPIX group. Survival quality of astrocyte was measured by WST-8 assay, LDH assay, Hoechst 33258 Staining and annexin V-FITC/PI assay and apoptotic-related proteins were measured using Western blotting. MAIN OUTCOME AND RESULTS: Hemin could dose-dependently up regulate the expression of HO-1. HO-1 exerted a protective role on astrocyte damage induced by 5 MUM hemin, including increased cell survival rate and anti apoptotic proteins expression (Bcl-2 and p-AKT), as well as decreased LDH release, apoptosis ratio and apoptotic protein expression (Bax, p-ERK and cleaved caspase3). However, the effect of HO-1 on astrocyte injury between 30 MUM hemin treated groups was opposite of the protective role in 5 MUM hemin-treated groups. CONCLUSIONS: There were dual effects of HO-1 in 5 MUM and 30 MUM hemin-induced astrocyte injuries. PMID- 26595801 TI - Prolonged latency of preterm premature rupture of membranes and risk of cerebral palsy (.). AB - OBJECTIVE: To determine whether prolonged latency after preterm premature rupture of membranes (PPROM) is associated with an increased risk of death or moderate-to severe cerebral palsy (CP). STUDY DESIGN: This secondary analysis of the randomized controlled trial of magnesium sulfate for the prevention of CP evaluated whether the time interval between diagnosis of PPROM and delivery was associated with increased risk for CP. Prolonged latency was defined as an interval of >=4 weeks, latency time was also categorized by week of latency for further analysis. The primary outcome was death or moderate-to-severe CP at 2 years of age. Logistic regression was used to control for confounders. RESULTS: In all, 1522 patients with PPROM were analyzed; of whom, 1328 had a <4-week interval and 194 had an interval of >=4 weeks. In the unadjusted analysis, the primary outcome was less likely in the PPROM >=4 weeks group 4.1% versus 8.4%, RR: 0.49, 95% CI: 0.24-0.98. After adjusting for possible confounders, there was no statistical difference associated with PPROM latency >=4 weeks versus <4 weeks for death or moderate-to-severe CP. CONCLUSION: Prolonged exposure to an intrauterine environment of PPROM does not increase risk for CP. PMID- 26595802 TI - Taxanes enhance trastuzumab-mediated ADCC on tumor cells through NKG2D-mediated NK cell recognition. AB - Recent clinical data indicate a synergistic therapeutic effect between trastuzumab and taxanes in neoadjuvantly treated HER2-positive breast cancer (BC) patients. In HER2+ BC experimental models and patients, we investigated whether this synergy depends on the ability of drug-induced stress to improve NK cell effectiveness and thus trastuzumab-mediated ADCC. HER2+ BC cell lines BT474 and MDAMB361 treated with docetaxel showed up-modulation of NK activator ligands both in vitro and in vivo, accompanied by a 15-40% increase in in vitro trastuzumab mediated ADCC; antibodies blocking the NKG2D receptor significantly reduced this enhancement. NKG2D receptor expression was increased by docetaxel treatment in circulating and splenic NK cells from mice xenografted with tumor cells, an increase related to expansion of the CD11b+Ly6G+ cell population. Accordingly, NK cells derived from HER2+ BC patients after treatment with taxane-containing therapy expressed higher levels of NKG2D receptor than before treatment. Moreover, plasma obtained from these patients recapitulated the modulation of NKG2D on healthy donors' NK cells, improving their trastuzumab-mediated activity in vitro. This enhancement occurred mainly using plasma from patients with low NKG2D basal expression. Our results indicate that taxanes increase tumor susceptibility to ADCC by acting on tumor and NK cells, and suggest that taxanes concomitantly administered with trastuzumab could maximize the antibody effect, especially in patients with low basal immune effector cytotoxic activity. PMID- 26595803 TI - An integrated genomic approach identifies that the PI3K/AKT/FOXO pathway is involved in breast cancer tumor initiation. AB - Therapy resistance is one of the major impediments to successful cancer treatment. In breast cancer, a small subpopulation of cells with stem cell features, named breast cancer stem cells (BCSC), is responsible for metastasis and recurrence of the tumor. BCSC have the unique ability to grow under non adherent conditions in "mammospheres". To prevent breast cancer recurrence and metastasis it will be crucial to eradicate BCSC.We used shRNA genetic screening to identify genes that upon knockdown enhance mammosphere formation in breast cancer cells. By integration of these results with gene expression profiles of mammospheres and NOTCH-activated cells, we identified FOXO3A. Modulation of FOXO3A activity results in a change in mammosphere formation, expression of mammary stem cell markers and breast cancer initiating potential. Importantly, lack of FOXO3A expression in breast cancer patients is associated with increased recurrence rate. Our findings provide evidence for a role for FOXO3A downstream of NOTCH and AKT that may have implications for therapies targeting BCSCs. PMID- 26595806 TI - Surface Structure of Silver Nanoparticles as a Model for Understanding the Oxidative Dissolution of Silver Ions. AB - The toxicity of silver nanoparticles (AgNPs) has been related to the release of ionic silver. This process is influenced by a large variety of factors and is poorly understood. The key to understanding Ag(+) release by AgNPs is its subvalency. This is a fundamental property of Ag that can be elucidated by analyzing the crystal structures of a specific class of Ag materials as well as MO/DFT (molecular orbital/density functional theory)-optimized Ag13(OH)4 clusters, being precursors of AgNPs. Semimetallic silver at the (111) faces of AgNPs has a subvalency of +(1)/3 v.u., forming =Ag3OH(0) surface groups with a maximum site density of 4.7 sites/nm(2). Oxidative dissolution may remove these groups with the simultaneous formation of oxygen radicals that may further interact with the surface via different pathways. Reactive oxygen species (ROS) can create a circular process with the dissolution of =Ag3OH(0), exposure of new metallic sites at the underlying lattice, and subsequent oxidation to =Ag3OH(0). This regeneration process is interrupted by the penetration of O(*) radicals into the lattice, forming highly stable Ag6O octahedra with subvalent silver that protects the AgNP from further oxidation. A thermodynamic model has been developed that quantitatively describes the equilibrium condition between =Ag3OH(0) and =Ag6O(0) and explains a large variety of collectively observed phenomena. PMID- 26595804 TI - ASPP1/2-PP1 complexes are required for chromosome segregation and kinetochore microtubule attachments. AB - Regulated interactions between kinetochores and spindle microtubules are critical for maintaining genomic stability during chromosome segregation. Defects in chromosome segregation are widespread phenomenon in human cancers that are thought to serve as the fuel for tumorigenic progression. Tumor suppressor proteins ASPP1 and ASPP2, two members of the apoptosis stimulating proteins of p53 (ASPP) family, are frequently down-regulated in human cancers. Here we report that ASPP1/2 are required for proper mitotic progression. In ASPP1/2 co-depleted cells, the persistence of unaligned chromosomes and the reduction of tension across sister kinetochores on aligned chromosomes resulted in persistent spindle assembly checkpoint (SAC) activation. Using protein affinity purification methods, we searched for functional partners of ASPP1/2, and found that ASPP1/2 were associated with a subset of kinetochore proteins (Hec1, KNL-1, and CENP-F). It was found that ASPP1/2 act as PP1-targeting subunits to facilitate the interaction between PP1 and Hec1, and catalyze Hec1 (Ser165) dephosphorylation during late mitosis. These observations revealed a previously unrecognized function of ASPP1/2 in chromosome segregation and kinetochore-microtubule attachments that likely contributes to their roles in chromosome stability and tumor suppression. PMID- 26595805 TI - Mechanisms for autophagy modulation by isoprenoid biosynthetic pathway inhibitors in multiple myeloma cells. AB - Multiple myeloma (MM) is characterized by the production of monoclonal protein (MP). We have shown previously that disruption of the isoprenoid biosynthetic pathway (IBP) causes a block in MP secretion through a disruption of Rab GTPase activity, leading to an enhanced unfolded protein response and subsequent apoptosis in MM cells. Autophagy is induced by cellular stressors including nutrient deprivation and ER stress. IBP inhibitors have been shown to have disparate effects on autophagy. Here we define the mechanisms underlying the differential effects of IBP inhibitors on autophagic flux in MM cells utilizing specific pharmacological inhibitors. We demonstrate that IBP inhibition induces a net increase in autophagy as a consequence of disruption of isoprenoid biosynthesis which is not recapitulated by direct geranylgeranyl transferase inhibition. IBP inhibitor-induced autophagy is a cellular defense mechanism as treatment with the autophagy inhibitor bafilomycin A1 enhances the cytotoxic effects of GGPP depletion, but not geranylgeranyl transferase inhibition. Immunofluorescence microscopy studies revealed that IBP inhibitors disrupt ER to Golgi trafficking of monoclonal light chain protein and that this protein is not a substrate for alternative degradative pathways such as aggresomes and autophagosomes. These studies support further development of specific GGTase II inhibitors as anti-myeloma agents. PMID- 26595807 TI - Multifunctional hyaluronic acid modified graphene oxide loaded with mitoxantrone for overcoming drug resistance in cancer. AB - Multifunctional nanosheets (HA-GO/Pluronic) with targeted chemo-photothermal properties were successfully developed for controlled delivery of mitoxantrone (MIT) to overcome multidrug resistance (MDR). In vitro release profiles displayed that both an acidic environment and a NIR laser could trigger and accelerate the release of a drug, which ensured nanosheets were stable in blood circulation and released MIT within tumor cells under laser irradiation. HA-GO/Pluronic nanosheets were taken up into MCF-7/ADR cells via receptor-mediated endocytosis, which further facilitated escapement of P-gp efflux. Compared with MIT solution, MIT/HA-GO/Pluronic showed greater cytotoxicity and increase in cellular MIT accumulation in MCF-7/ADR cells. Cell apoptosis and cell cycle arrest studies also revealed that MIT/HA-GO/Pluronic was more potent than MIT/GO/Pluronic and MIT solution. The anticancer efficacy in vivo was evaluated in MCF-7 and MCF 7/ADR-bearing mice, and inhibition of tumors by MIT/HA-GO/Pluronic with NIR laser irradiation was the most effective among all MIT formulations. In summary, the MIT/HA-GO/Pluronic system had striking functions such as P-gp reversible inhibitor and anticancer efficacy, and could present a promising platform for drug-resistant cancer treatment. PMID- 26595810 TI - Host immunity contributes to the anti-melanoma activity of BRAF inhibitors. PMID- 26595808 TI - Whole-Exome Sequencing in Familial Parkinson Disease. AB - IMPORTANCE: Parkinson disease (PD) is a progressive neurodegenerative disease for which susceptibility is linked to genetic and environmental risk factors. OBJECTIVE: To identify genetic variants contributing to disease risk in familial PD. DESIGN, SETTING, AND PARTICIPANTS: A 2-stage study design that included a discovery cohort of families with PD and a replication cohort of familial probands was used. In the discovery cohort, rare exonic variants that segregated in multiple affected individuals in a family and were predicted to be conserved or damaging were retained. Genes with retained variants were prioritized if expressed in the brain and located within PD-relevant pathways. Genes in which prioritized variants were observed in at least 4 families were selected as candidate genes for replication in the replication cohort. The setting was among individuals with familial PD enrolled from academic movement disorder specialty clinics across the United States. All participants had a family history of PD. MAIN OUTCOMES AND MEASURES: Identification of genes containing rare, likely deleterious, genetic variants in individuals with familial PD using a 2-stage exome sequencing study design. RESULTS: The 93 individuals from 32 families in the discovery cohort (49.5% [46 of 93] female) had a mean (SD) age at onset of 61.8 (10.0) years. The 49 individuals with familial PD in the replication cohort (32.6% [16 of 49] female) had a mean (SD) age at onset of 50.1 (15.7) years. Discovery cohort recruitment dates were 1999 to 2009, and replication cohort recruitment dates were 2003 to 2014. Data analysis dates were 2011 to 2015. Three genes containing a total of 13 rare and potentially damaging variants were prioritized in the discovery cohort. Two of these genes (TNK2 and TNR) also had rare variants that were predicted to be damaging in the replication cohort. All 9 variants identified in the 2 replicated genes in 12 families across the discovery and replication cohorts were confirmed via Sanger sequencing. CONCLUSIONS AND RELEVANCE: TNK2 and TNR harbored rare, likely deleterious, variants in individuals having familial PD, with similar findings in an independent cohort. To our knowledge, these genes have not been previously associated with PD, although they have been linked to critical neuronal functions. Further studies are required to confirm a potential role for these genes in the pathogenesis of PD. PMID- 26595809 TI - Aberrant sodium influx causes cardiomyopathy and atrial fibrillation in mice. AB - Increased sodium influx via incomplete inactivation of the major cardiac sodium channel Na(V)1.5 is correlated with an increased incidence of atrial fibrillation (AF) in humans. Here, we sought to determine whether increased sodium entry is sufficient to cause the structural and electrophysiological perturbations that are required to initiate and sustain AF. We used mice expressing a human Na(V)1.5 variant with a mutation in the anesthetic-binding site (F1759A-Na(V)1.5) and demonstrated that incomplete Na+ channel inactivation is sufficient to drive structural alterations, including atrial and ventricular enlargement, myofibril disarray, fibrosis and mitochondrial injury, and electrophysiological dysfunctions that together lead to spontaneous and prolonged episodes of AF in these mice. Using this model, we determined that the increase in a persistent sodium current causes heterogeneously prolonged action potential duration and rotors, as well as wave and wavelets in the atria, and thereby mimics mechanistic theories that have been proposed for AF in humans. Acute inhibition of the sodium calcium exchanger, which targets the downstream effects of enhanced sodium entry, markedly reduced the burden of AF and ventricular arrhythmias in this model, suggesting a potential therapeutic approach for AF. Together, our results indicate that these mice will be important for assessing the cellular mechanisms and potential effectiveness of antiarrhythmic therapies. PMID- 26595811 TI - G(q/11)alpha and G(s)alpha mediate distinct physiological responses to central melanocortins. AB - Activation of brain melanocortin 4 receptors (MC4Rs) leads to reduced food intake, increased energy expenditure, increased insulin sensitivity, and reduced linear growth. MC4R effects on energy expenditure and glucose metabolism are primarily mediated by the G protein G(s)alpha in brain regions outside of the paraventricular nucleus of the hypothalamus (PVN). However, the G protein(s) that is involved in MC4R-mediated suppression of food intake and linear growth, which are believed to be regulated primarily though action in the PVN, is unknown. Here, we show that PVN-specific loss of G(q)alpha and G11alpha, which stimulate PLC, leads to severe hyperphagic obesity, increased linear growth, and inactivation of the hypothalamic-pituitary-adrenal axis, without affecting energy expenditure or glucose metabolism. Moreover, we demonstrate that the ability of an MC4R agonist delivered to PVN to inhibit food intake is lost in mice lacking G(q/11)alpha in the PVN but not in animals deficient for G(s)alpha. The blood pressure response to the same MC4R agonist was only lost in animals lacking G(s)alpha specifically in the PVN. Together, our results exemplify how different physiological effects of GPCRs may be mediated by different G proteins and identify a pathway for appetite regulation that could be selectively targeted by G(q/11)alpha-biased MC4R agonists as a potential treatment for obesity. PMID- 26595812 TI - Immune activation caused by vascular oxidation promotes fibrosis and hypertension. AB - Vascular oxidative injury accompanies many common conditions associated with hypertension. In the present study, we employed mouse models with excessive vascular production of ROS (tg(sm/p22phox) mice, which overexpress the NADPH oxidase subunit p22(phox) in smooth muscle, and mice with vascular-specific deletion of extracellular SOD) and have shown that these animals develop vascular collagen deposition, aortic stiffening, renal dysfunction, and hypertension with age. T cells from tg(sm/p22phox) mice produced high levels of IL-17A and IFN gamma. Crossing tg(sm/p22phox) mice with lymphocyte-deficient Rag1(-/-) mice eliminated vascular inflammation, aortic stiffening, renal dysfunction, and hypertension; however, adoptive transfer of T cells restored these processes. Isoketal-protein adducts, which are immunogenic, were increased in aortas, DCs, and macrophages of tg(sm/p22phox) mice. Autologous pulsing with tg(sm/p22phox) aortic homogenates promoted DCs of tg(sm/p22phox) mice to stimulate T cell proliferation and production of IFN-gamma, IL-17A, and TNF-alpha. Treatment with the superoxide scavenger tempol or the isoketal scavenger 2-hydroxybenzylamine (2 HOBA) normalized blood pressure; prevented vascular inflammation, aortic stiffening, and hypertension; and prevented DC and T cell activation. Moreover, in human aortas, the aortic content of isoketal adducts correlated with fibrosis and inflammation severity. Together, these results define a pathway linking vascular oxidant stress to immune activation and aortic stiffening and provide insight into the systemic inflammation encountered in common vascular diseases. PMID- 26595813 TI - PML-RARA requires DNA methyltransferase 3A to initiate acute promyelocytic leukemia. AB - The DNA methyltransferases DNMT3A and DNMT3B are primarily responsible for de novo methylation of specific cytosine residues in CpG dinucleotides during mammalian development. While loss-of-function mutations in DNMT3A are highly recurrent in acute myeloid leukemia (AML), DNMT3A mutations are almost never found in AML patients with translocations that create oncogenic fusion genes such as PML-RARA, RUNX1-RUNX1T1, and MLL-AF9. Here, we explored how DNMT3A is involved in the function of these fusion genes. We used retroviral vectors to express PML RARA, RUNX1-RUNX1T1, or MLL-AF9 in bone marrow cells derived from WT or DNMT3A deficient mice. Additionally, we examined the phenotypes of hematopoietic cells from Ctsg-PML-RARA mice, which express PML-RARA in early hematopoietic progenitors and myeloid precursors, with or without DNMT3A. We determined that the methyltransferase activity of DNMT3A, but not DNMT3B, is required for aberrant PML-RARA-driven self-renewal ex vivo and that DNMT3A is dispensable for RUNX1-RUNX1T1- and MLL-AF9-driven self-renewal. Furthermore, both the PML-RARA driven competitive transplantation advantage and development of acute promyelocytic leukemia (APL) required DNMT3A. Together, these findings suggest that PML-RARA requires DNMT3A to initiate APL in mice. PMID- 26595814 TI - Antisense oligonucleotide-mediated MDM4 exon 6 skipping impairs tumor growth. AB - MDM4 is a promising target for cancer therapy, as it is undetectable in most normal adult tissues but often upregulated in cancer cells to dampen p53 tumor suppressor function. The mechanisms that underlie MDM4 upregulation in cancer cells are largely unknown. Here, we have shown that this key oncogenic event mainly depends on a specific alternative splicing switch. We determined that while a nonsense-mediated, decay-targeted isoform of MDM4 (MDM4-S) is produced in normal adult tissues as a result of exon 6 skipping, enhanced exon 6 inclusion leads to expression of full-length MDM4 in a large number of human cancers. Although this alternative splicing event is likely regulated by multiple splicing factors, we identified the SRSF3 oncoprotein as a key enhancer of exon 6 inclusion. In multiple human melanoma cell lines and in melanoma patient-derived xenograft (PDX) mouse models, antisense oligonucleotide-mediated (ASO-mediated) skipping of exon 6 decreased MDM4 abundance, inhibited melanoma growth, and enhanced sensitivity to MAPK-targeting therapeutics. Additionally, ASO-based MDM4 targeting reduced diffuse large B cell lymphoma PDX growth. As full-length MDM4 is enhanced in multiple human tumors, our data indicate that this strategy is applicable to a wide range of tumor types. We conclude that enhanced MDM4 exon 6 inclusion is a common oncogenic event and has potential as a clinically compatible therapeutic target. PMID- 26595815 TI - Ultrasound ablation enhances drug accumulation and survival in mammary carcinoma models. AB - Magnetic resonance-guided focused ultrasound (MRgFUS) facilitates noninvasive image-guided conformal thermal therapy of cancer. Yet in many scenarios, the sensitive tissues surrounding the tumor constrain the margins of ablation; therefore, augmentation of MRgFUS with chemotherapy may be required to destroy remaining tumor. Here, we used 64Cu-PET-CT, MRI, autoradiography, and fluorescence imaging to track the kinetics of long-circulating liposomes in immunocompetent mammary carcinoma-bearing FVB/n and BALB/c mice. We observed a 5 fold and 50-fold enhancement of liposome and drug concentration, respectively, within MRgFUS thermal ablation-treated tumors along with dense accumulation within the surrounding tissue rim. Ultrasound-enhanced drug accumulation was rapid and durable and greatly increased total tumor drug exposure over time. In addition, we found that the small molecule gadoteridol accumulates around and within ablated tissue. We further demonstrated that dilated vasculature, loss of vascular integrity resulting in extravasation of blood cells, stromal inflammation, and loss of cell-cell adhesion and tissue architecture all contribute to the enhanced accumulation of the liposomes and small molecule probe. The locally enhanced liposome accumulation was preserved even after a multiweek protocol of doxorubicin-loaded liposomes and partial ablation. Finally, by supplementing ablation with concurrent liposomal drug therapy, a complete and durable response was obtained using protocols for which a sub-mm rim of tumor remained after ablation. PMID- 26595816 TI - Health Services for Management of Chronic Non-Cancer Pain in Kuwait: A Case Study Review. AB - The experience of chronic pain is universal, yet pain management services delivered by health professionals vary substantially, depending on the context and patient. This review is a part of a series that has examined the issue of chronic non-cancer pain services and management in different global cities. The review is structured as a case study of the availability of management services for people living with chronic non-cancer pain within the context of the Kuwaiti health systems, and the cases are built from evidence in the published literature identified through a comprehensive review process. The evolution of the organizational structure of the public and private health systems in Kuwait is described. These are discussed in terms of their impact on the delivery of comprehensive chronic pain management service by health professionals in Kuwait. This review also includes a description of chronic pain patient personas to highlight expected barriers as well as compliance issues with services likely to be encountered in Kuwait. The case study analysis and persona descriptions illustrate a need to move beyond pain symptom management towards considering the entire person and his/her individual experience of pain such that health care success is judged by enhancement of patient well-being rather than access to services. A road map for improving integrative chronic pain management in Kuwait is discussed. PMID- 26595817 TI - Combination of Silver Nanoparticles and Curcumin Nanoparticles for Enhanced Anti biofilm Activities. AB - Biofilm tolerance has become a serious clinical concern in the treatment of nosocomial pneumonia owing to the resistance to various antibiotics. There is an urgent need to develop alternative antimicrobial agents or combination drug therapies that are effective via different mechanisms. Silver nanoparticles (AgNPs) have been developed as an anti-biofilm agent for the treatment of infections associated with the use of mechanical ventilations, such as endotracheal intubation. Meanwhile curcumin, a phenolic plant extract, has displayed natural anti-biofilm properties through the inhibition of bacterial quorum sensing systems. The aim of this study was to investigate the possible synergistic/additive interactions of AgNPs and curcumin nanoparticles (Cur-NPs) against both Gram-negative (Pseudomonas aeruginosa) and Gram-positive (Staphylococcus aureus) microorganisms. The combination of AgNPs and Cur-NPs (termed Cur-SNPs) at 100 MUg/mL disrupted 50% of established bacterial biofilms (formed on microtiter plates). However, further increase in the concentration of Cur-SNPs failed to effectively eliminate the biofilms. To achieve the same effect, at least 500 MUg/mL Cur-NP alone was needed. Scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM) revealed that combination therapy (Cur-SNPs) was the most potent to eradicate preformed biofilm compared to monodrug therapy. These agents are also nontoxic to healthy human bronchial epithelial cells (BEAS2B). PMID- 26595818 TI - The propositional basis of cue-controlled reward seeking. AB - Two experiments examined the role of propositional and automatic (ideomotor) processes in cue-elicited responding for rewarding outcomes (beer and chocolate). In a training phase, participants earned either chocolate or beer points by making one of two button-press responses. Rewards were indicated by the presentation of chocolate and beer pictures. On test, each trial began with a picture of beer or chocolate, or a blank screen, and choice of the beer versus chocolate response was assessed in the presence of these three pictures. Participants tended to choose the beer and chocolate response in the presence of the beer and chocolate pictures, respectively. In Experiment 1, instructions signalling that the pictures did not indicate which response would be rewarded significantly reduced the priming effect. In Experiment 2, instructions indicating that the pictures signified which response would not be rewarded resulted in a reversed priming effect. Finally, in both experiments, the priming effect correlated with self-reported beliefs that the cues signalled which response was more likely to be reinforced. These results suggest that cue elicited response selection is mediated by a propositional belief regarding the efficacy of the response-outcome relationship, rather than an automatic ideomotor mechanism. PMID- 26595819 TI - Total Synthesis of Linckosides A and B, the Representative Starfish Polyhydroxysteroid Glycosides with Neuritogenic Activities. AB - Linckosides A and B, two starfish metabolites with promising neuritogenic activities, are synthesized in a longest linear sequence of 32 steps and 0.5% overall yield; this represents the first synthesis of members of the polyhydroxysteroid glycoside family, which occur widely in starfishes. PMID- 26595820 TI - Effect of dietary supplementation of thymol, synbiotic and their combination on performance, egg quality and serum metabolic profile of Hy-Line Brown hens. AB - An experiment was conducted to determine the effects of dietary supplementation of thymol, synbiotic (Biomin, IMBO) and their combination in laying hen diets on laying performance, egg quality and serum metabolic profile from 24 to 36 weeks of age. Treatment groups were fed on a control diet, the control diet supplemented with thymol (250 mg/kg), the control diet supplemented with synbiotic (250 mg/kg) or the control diet supplemented with a combination of thymol (250 mg/kg) and synbiotic (250 mg/kg). Supplementation of thymol and synbiotic, separately as well as combined, improved egg weight, egg production, egg mass and feed conversion ratio from 24 to 36 weeks of age. The eggs obtained from thymol, synbiotic or their combination treatments displayed higher values of shell thickness, Haugh unit and shell percentage compared to the control. Serum cholesterol significantly decreased in the single or combined form of thymol and synbiotic supplementation treatments. PMID- 26595821 TI - GATA3 Expression in Normal Skin and in Benign and Malignant Epidermal and Cutaneous Adnexal Neoplasms. AB - Initial investigations reported GATA3 to be a sensitive and relatively specific marker for mammary and urothelial carcinomas. Recently, GATA3 expression has been described in several other epithelial tumors. However, there has been only limited investigation of GATA3 expression in cutaneous epithelial tumors. The objective of this study was to examine the immunohistochemical expression of GATA3 in a wide variety of cutaneous epithelial neoplasms. GATA3 expression was evaluated in 99 benign and 63 malignant cutaneous epithelial tumors. GATA3 was consistently and usually strongly expressed in clear cell acanthoma, trichofolliculoma, trichoepithelioma, trichilemmoma, sebaceous adenoma, sebaceoma, apocrine hidrocystoma, apocrine tubular papillary adenoma, hidradenoma papilliferum, and syringocystadenoma papilliferum. Hidradenomas exhibited variable positive staining. Most poromas, syringomas, chondroid syringomas, cylindromas, and spiradenomas were negative or only focally and weakly positive. Focal staining was present in all pilomatrixomas. Thirteen of 14 basal cell carcinomas, 21 of 24 squamous carcinomas, and all 6 sebaceous carcinomas exhibited positive staining. The 1 apocrine carcinoma, both mucinous carcinomas, and 2 of 3 microcystic adnexal carcinomas also exhibited positive staining, whereas the 1 eccrine porocarcinoma and the 1 adenoid cystic carcinoma were negative. One of 11 Merkel cell carcinomas exhibited focal weak staining. Our findings demonstrate that GATA3 is expressed in a wide variety of benign and malignant cutaneous epithelial neoplasms. In addition to carcinomas of breast and urothelial origin and other more recently described GATA3-positive tumors, the differential diagnosis of a metastatic tumor of unknown primary origin that expresses GATA3 should also include a carcinoma of cutaneous epithelial origin. PMID- 26595822 TI - CO2 reduction reactions: general discussion. PMID- 26595823 TI - Improvement in Laser-Irradiation Efficiency of Robot-Assisted Laser Hair Removal Through Pose Measurement of Skin Surface. AB - OBJECTIVE: This study aims to improve the performance of an automatic laser hair removal (LHR) system by applying an algorithm that considers the curve and slant of the skin surface. BACKGROUND DATA: In an earlier research, a robot-assisted LHR system has been developed and validated for an almost flat skin or a relatively smooth curved part of the skin. For practical clinical applications, the feature of the robot-assisted LHR system is extended for real curved skins. METHODS: A novel pose-measurement algorithm is developed and applied to the LHR system. This system detects a six-degree of freedom (DOF) pose of the skin surface using the pose-measurement algorithm. The main principle of this algorithm is finding the equation of a plane using three noncollinear points, which are obtained by sequential movement of a one dimensional laser sensor. RESULTS: Evaluation of the proposed system was conducted. During the test, we demonstrated that the LHR device automatically and completely contacted the targets along the curved surface. The contact-accuracy test produced satisfactory outcome. The averages of the root mean square (RMS) of the position error and the RMS of the rotation were 1.4437 mm and 1.0982 degrees, respectively. The curvature measurement test produced a satisfactory average result of 0.0006 mm RMS error. CONCLUSIONS: Using the proposed six-DOF pose-measurement algorithm, the performance of the robot-assisted LHR system could be significantly improved from the clinical point of view because most real skins have curved shapes. PMID- 26595824 TI - CD3 Deformation Modes as Preferential Promoters of Methylamine-d3 to the First Electronic State. AB - The room-temperature photoacoustic Raman and jet-cooled H action spectra, measured in the region of the fundamental CD3 stretches and the almost isoenergetic overtones or combinations of CD3 deformations in the methylamine-d3 (CD3NH2) isotopologue, show different relative intensities of the vibrational bands. The observed difference and the vibrational assignment point to favored ultraviolet excitation due to larger Franck-Condon (FC) factors from the deformation modes, leading to more effective N-H bond cleavage in CD3NH2 predissociation. The comparable measured two-color reduced-Doppler ion images and total kinetic energy distributions resulting from the predissociation of molecules promoted from vibrationally excited and vibrationless ground states confirmed that the FC factors and not the ensuing dynamics are the main reason for the mode specificity in this molecule. PMID- 26595825 TI - Amphotericin B deoxycholate versus liposomal amphotericin B: effects on kidney function. AB - BACKGROUND: The incidence of invasive fungal infections has increased globally as a result of several factors. Conventional amphotericin B (sodium deoxycholate) has been used as standard therapy for the treatment of invasive fungal infections; however, it is associated with adverse drug reactions, including acute kidney injury (AKI). New formulations of amphotericin B have aimed to improve the safety profile of the conventional formulation. OBJECTIVES: This review aimed to assess the effects of amphotericin B deoxycholate versus liposomal amphotericin B on kidney function. SEARCH METHODS: We searched Cochrane Kidney and Transplant's Specialised Register to 10 March 2015 through contact with the Trials' Search Co-ordinator using search terms relevant to this review. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared amphotericin B sodium deoxycholate with liposomal amphotericin B. DATA COLLECTION AND ANALYSIS: Two authors independently assessed studies for eligibility and conducted risk of bias evaluation. MAIN RESULTS: We included 12 studies (2298 participants) in this review. Of these, 10 were meta-analysed (2172 participants). Liposomal amphotericin B was found to be significantly safer than conventional amphotericin B in terms of serum creatinine increase (RR 0.49, 95% CI 0.40 to 0.59). There was significant decrease in all infusion-related reactions in the liposomal group compared with the conventional group: fever (4 studies, 1092 participants): RR 0.39, 95% CI 0.28 to 0.55; I(2) = 32%); chills and/or rigours (5 studies, 1081 participants): RR 0.27, 95% CI 0.15 to 0.48; I(2) = 75%); fever and/or rigours (2 studies, 720 participants): RR 0.68, 95% CI 0.52 to 0.90; I(2) = 58%); nausea (6 studies, 1187 participants): RR 0.50, 95% CI 0.35 to 0.72; I(2) = 0%); and vomiting (3 studies, 1019 participants): RR 0.51, 95% CI 0.27 to 0.95; I(2) = 61%). Overall, risk of bias in included studies was low or unclear for most domains. However, blinding of participants and personnel, blinding of outcome assessment and other bias (funding) tended to have a high risk of bias. The sensitivity analysis performed did not change the significance of difference in favour of the liposomal formulation. Assessment for publication bias found that review results were robust. AUTHORS' CONCLUSIONS: Current evidence suggests that liposomal amphotericin B is less nephrotoxic than conventional amphotericin B (when the effect on kidney function is measured as an increase in serum creatinine level equal to or greater than two-fold from the baseline level). We also found that there were fewer infusion-related reactions associated with the liposomal formulation. PMID- 26595827 TI - Environment and cognitive aging: A cross-sectional study of place of residence and cognitive performance in the Irish longitudinal study on aging. AB - OBJECTIVE: Stimulating environments foster cognitive vitality in older age. However, it is not known whether and how geographical and physical characteristics of lived environments contribute to cognitive aging. Evidence of higher prevalence of dementia in rural rather than urban contexts suggests that urban environments may be more stimulating either cognitively, socially, or in terms of lifestyle. The present study explored urban/rural differences in cognition for healthy community-dwelling older people while controlling for a comprehensive spectrum of confounding factors. METHOD: Cognitive performance of 3,765 healthy Irish people aged 50+ years participating in Wave 1 of The Irish Longitudinal Study on Aging was analyzed in relation to current location of residence-urban, other settlements, or rural areas-and its interaction with childhood residence. Regression models controlled for sociodemographic, health, and lifestyle factors. RESULTS: Urban residents showed better performance than the other 2 residence groups for global cognition and executive functions after controlling for covariates. Childhood urban residence was associated with a cognitive advantage especially for currently rural participants. CONCLUSION: Our findings suggest higher cognitive functioning for urban residents, although childhood residence modulates this association. Suggestions for further developments of these results are discussed. (PsycINFO Database Record PMID- 26595826 TI - Biomarker validation of a decline in semantic processing in preclinical Alzheimer's disease. AB - OBJECTIVE: Differentially worse performance on category versus letter fluency suggests greater semantic versus retrieval difficulties. This discrepancy, combined with reduced episodic memory, has widespread clinical utility in diagnosing Alzheimer's disease (AD). Our objective was to investigate whether changes in semantic processing, as measured by the discrepancy between category and letter fluency, was detectable in preclinical AD: in clinically normal older adults with abnormal beta-amyloid (Abeta) deposition on positron emission tomography (PET) neuroimaging. METHOD: Clinically normal older adults (mean Mini Mental State Exam (MMSE) score = 29) were classified as Abeta+ (n = 70) or Abeta- (n = 205) using Pittsburgh Compound B-(PET) imaging. Participants completed letter fluency (FAS; word generation to letters F-A-S) and category fluency (CAT; word generation to animals, vegetables, fruits) annually (mean follow-up = 2.42 years). The effect of Abeta status on fluency over time was examined using linear mixed models controlling for age, sex, and education. To dissociate effects related to semantic (CAT) versus retrieval processes (CAT and FAS), we repeated models predicting CAT over time, controlling for FAS and likewise for CAT controlling for FAS. RESULTS: At baseline, the Abeta+ group performed better on FAS compared with the Abeta- group but comparably on CAT. Longitudinally, the Abeta+ group demonstrated greater decline on CAT compared with the Abeta- group (p = .0011). This finding remained significant even when covarying for FAS (p = .0107). Abeta+ participants similarly declined compared with Abeta- participants on FAS (p = .0112), but this effect became insignificant when covarying for CAT (p = .1607). CONCLUSION: These findings provide biomarker validation for the greater specificity of declines in category versus letter fluency to underlying AD pathology. Our results also suggest that changes in semantic processing occur earlier in the AD trajectory than previously hypothesized. (PsycINFO Database Record PMID- 26595828 TI - Relation between diagnosis of atheromatous plaque from orthopantomographs and cardiovascular risk factors. A study of cases and control subjects. AB - BACKGROUND: In recent years the use of orthopantomography has been proposed as a low-cost, reliable and non-invasive diagnostic medium for detecting atheromatous plaque. The purpose of this study was to correlate the presence of carotid calcifications (atheroma) in orthopantomographs with specific risk factors for cerebrovascular accidents (previous cerebrovascular accidents, arterial hypertension, and diabetes). PATIENT AND METHODS: The methods used in this observational study of cases and control subjects followed STROBE (Strengthening the Reporting of Observational studies in Epidemiology) recommendations. The study analyzed a total of 1,602 panoramic radiographs taken for dental diagnostic purposes between January 2010 and February 2014. The main variables analyzed were the incidence of atheromatous plaque and other cardiovascular risk factors. Epidat 3.1 statistical software was used to determine minimum sample sizes and the results were analyzed using PASW (Predictive Analytics Software) Statistics 10.0.0. RESULTS: For all the variables analyzed, the correlation between radiographic detection of atheromatous plaque and the presence of cardiovascular disease risk factors was found to be statistically significant (RR>1.5). CONCLUSIONS: The presence of cardiovascular risk factors is related to the incidence of radiopaque lesions at the carotid artery bifurcation, indicating the presence of atheromatous plaque. PMID- 26595829 TI - Evaluation of Xerostomia and salivary flow rate in Hashimoto's Thyroiditis. AB - BACKGROUND: One of the most common causes of hypothyroidism is Hashimoto's Thyroiditis (HT). Early detection of dry mouth is critical in preserving and promoting systemic and oral health. In this study we have assessed, for the first time, salivary function and xerostomia in HT patients who have not been involved with Sjogren's syndrome. MATERIAL AND METHODS: HT was diagnosed in 40 patients based on clinical findings and positive anti-thyroid peroxidase antibodies (anti TPO). Controls, matched by sex, age and body mass index (BMI), and with no history of thyroid disease, were selected. A questionnaire was used for diagnosis of xerostomia. Saliva samples were taken between 8 a.m. and 9 a.m., and at least 2 hours after the last intake of food or drink. The flow rate was calculated in milliliters per minute. RESULTS: Xerostomia was significantly higher in patients with HT. Unstimulated salivary flow rate was significantly lower in the HT group. Stimulated salivary flow rate was lower in HT group, but the difference was not significant. CONCLUSIONS: The patients with HT experienced xerostomia, and their salivary flow rate was diminished. Spitting the saliva then assessing salivary flow rate based on milliliter per minute is non-invasive, fast, and simple for chair-side diagnosis of dry mouth. Autoimmune diseases can be accompanied by salivary gland dysfunction. This may be due to the effect of cytokines in the autoimmune process or because of thyroid hormone dysfunctions. PMID- 26595830 TI - Expression of NF-kappaB and IL-6 in oral precancerous and cancerous lesions: An immunohistochemical study. AB - BACKGROUND: The purpose of this study was to evaluate the immunohistochemical expression of NF-kappaB and IL-6 in oral premalignant and malignant lesions and to investigate their possible correlation with the presence of subepithelial inflammation. MATERIAL AND METHODS: Thirty two oral premalignant lesions, clinically compatible with leukoplakia or erythroplakia, were investigated. Microscopically, 11 of them showed hyperkeratosis and acanthosis (epithelial hyperplasia) and 21 showed dysplasia of varying degrees. Nine cases of OSCC and four control cases of normal oral mucosa were also included in the study. Immunohistochemical staining with NF-kappaB (p65) and IL-6 was performed. IL-6 and nuclear NF-kappaB staining were assessed as positive or negative. For cytoplasmic localization of NF-kappaB, a total score combining intensity and percentage of positive epithelial cells was additionally calculated. The presence of inflammation was also recorded. RESULTS: Intensity and total scores for NF kappaBeta cytoplasmic immunostaining showed a statistically significant gradual increase from normal mucosa to OSCC (p=0.012 and p=0.026 respectively). Non statistically significant increased NF-kappaBeta nuclear localization was detected in dysplasias and OSCCs. Positive statistical correlation was detected between the presence of inflammation and IL-6 expression (p=0.015). No correlation between NF-kappaBeta and IL-6 was detected. CONCLUSIONS: NF-kappaBeta is activated in the early stages of oral carcinogenesis. IL-6 may have an NF kappaBeta-independent role, possibly through regulation of the inflammatory response. PMID- 26595831 TI - Association of susceptible genotypes to periodontal disease with the clinical outcome and tooth survival after non-surgical periodontal therapy: A systematic review and meta-analysis. AB - BACKGROUND: The real clinical utility of genetic testing is the prognostic value of genetic factors in the clinical outcome of periodontal treatment and the tooth survival. A meta-analysis was undertaken to estimate the effect of a susceptible genotype to periodontitis on the clinical outcomes of non-surgical periodontal therapy and the tooth survival. MATERIAL AND METHODS: A systematic search of MEDLINE-Pubmed, Cochrane Library and Scopus was performed. Additionally, a hand search was done in three journals. No specific language restriction was applied. Two reviewers screened independently titles and abstracts or full text copies. Quality assessment of all the included studies was held. RESULTS: Initial screening of electronic databases resulted in 283 articles. Ten studies met the inclusion criteria, nine of them examined the clinical outcome, while the other one investigated the tooth survival in susceptible individuals after non-surgical periodontal therapy. Eight of included studies were selected for the meta analysis. IL-1 positive genotypes increase the risk of tooth loss, while no association found between the bleeding on probing (BOP), clinical attachment loss (CAL) and plaque index (PI) with the genotype status. Probing pocket depth (PPD) reduction in the first three months and in long-term results found to have a significant association with the genotype. CONCLUSIONS: There is no difference in the clinical measurements after non-surgical periodontal treatment, apart from PPD. More publications are needed to identify a cause-effect relationship. PMID- 26595832 TI - Multidisciplinary management of ankyloglossia in childhood. Treatment of 101 cases. A protocol. AB - BACKGROUND: Partial ankyloglossia is a limitation which restricts the possibility of protrusion and elevation of the tip of the tongue due to the shortness of either the lingual frenulum or the genioglossus muscles or both. The principal objective of this paper is to present our protocol of action for the treatment of ankyloglossia. The specific objectives are to study patients with ankyloglossia treated by the Service of Maxillofacial Surgery and the Service of Speech Therapy of our pediatric Hospital, describe the diagnostic procedures, the pre-surgical intervention, the surgical technique undertaken and the post-surgical rehabilitation taking into account the level of collaboration of the patients, and finally, describe the surgical complications and the referral of patients. MATERIAL AND METHODS: This is a descriptive study of healthy patients, without any diagnosis of syndrome, ranging between 4 and 14 years that have been surgically treated and rehabilitated post-surgery within a period of 2 years. RESULTS: 101 frenectomies and lingual plasties have been performed and patients have been treated following the protocol of action that we hereby present. After the surgical intervention, the degree of ankyloglossia has been improved, considering correction in 29 (28%) of the patients (95% CI: 20%, 38%), reaching, with the post-surgical orofacial rehabilitation, a correction of 97 (96%) of the participants (95% CI: 90%, 98%). CONCLUSIONS: The chosen surgical technique for moderate-severe ankyloglossia in our centre is the frenectomy and lingual plasty. The myofunctional training begins one week before the surgical intervention so that the patients learn the exercises without pain. PMID- 26595833 TI - The isolated orbital floor fracture from a transconjunctival or subciliary perspective-A standardized anthropometric evaluation. AB - BACKGROUND: The influence of orbital fractures and their repair on the rate of deformities of the lower eyelid is an ongoing source of discussion in the literature. Most of the present studies include isolated blow-out as well as combined orbital fractures. MATERIAL AND METHODS: We present a retrospective evaluation of a series of 100 patients after isolated blow-out fracture repair using reference anthropometric data on standardized photographs. Analysis included eye fissure width and height, lid sulcus height, upper lid height, upper and lower iris coverage, position of cornea to palpebra inferior, canthal tilt, scleral show, ectropion and entropion. It was clearly distinguished between operated and contralateral eyelid, whether a transconjunctival or a subciliary approach was performed and amount of fracture. Our main interests were changes of the aforementioned parameters with regards to eyelid deformities. RESULTS: Surgery per se did not significantly influence eyelid deformities. However, the surgical approach selected significantly affected eye fissure index, lower iris coverage and rate of scleral show, indicating retraction of the lower eyelid. CONCLUSIONS: The standardized measurements described here are accurate and objective to evaluate postoperative results. The subciliary approach included the highest risk of lower lid retraction as compared to transconjunctival approaches. PMID- 26595834 TI - Bacterial inactivation/sterilization by argon plasma treatment on contaminated titanium implant surfaces: In vitro study. AB - BACKGROUND: Surface treatment by argon plasma is widely used as the last step of the manufacturing process of titanium implant fixtures before their sterilization by gamma rays. The possibility of using such a technology in the daily clinical practice is particularly fascinating. The aim of the present study was to assess the effects of the argon plasma treatment on different titanium implant surfaces previously exposed in vitro to bacterial contamination. MATERIAL AND METHODS: Sterile c.p. titanium implant discs with turned (T, Sa: 0.8MUm), sandblasted/acid etched (SAE, Sa: 1.3MUm) and titanium plasma sprayed (TPS, Sa: 3.0MUm) surface were used in this study. A strain of Aggregatibacter actinomycetemcomitans ATCC3718 was grown at 37 degrees C under anaerobic conditions for 24 h and then transferred on six discs for each of the three surface types. After 24 hours, a half of the contaminated discs (control group) were directly used to evaluate the colony forming units (CFUs). The other half of the contaminated discs (test group) were treated in an argon plasma chamber for 12 minutes at room temperature prior to be analyzed for CFU counting. All assays were performed using triplicate samples of each material in 3 different experiments. RESULTS: When the CFU counting was carried out on control discs, a total of 1.50x106+/-1.4x105, 1.55x106+/-7.07x104 and 3.15x106+/-2.12x105 CFU was respectively assessed for T, SAE and TPS discs, without statistically significant differences among the three surfaces. On the contrary, any trace of bacterial contamination was assessed for titanium discs treated in the argon plasma chamber prior to be analyzed, irrespectively to the implant surface tested. CONCLUSIONS: Within the limit of this study, reported data suggested that the argon plasma technology could be efficiently used to decontaminate/sterilize previously infected titanium implant surfaces. PMID- 26595835 TI - Melatonin enhances vertical bone augmentation in rat calvaria secluded spaces. AB - BACKGROUND: Melatonin has many roles, including bone remodeling and osseointegration of dental implants. The topical application of melatonin facilitated bone regeneration in bone defects. We evaluated the effects of topical application of melatonin on vertical bone augmentation in rat calvaria secluded spaces. MATERIAL AND METHODS: In total, 12 male Fischer rats were used and two plastic caps were fixed in the calvarium. One plastic cap was filled with melatonin powder and the other was left empty. RESULTS: Newly generated bone at bone defects and within the plastic caps was evaluated using micro-CT and histological sections. New bone regeneration within the plastic cap was increased significantly in the melatonin versus the control group. CONCLUSIONS: Melatonin promoted vertical bone regeneration in rat calvaria in the secluded space within the plastic cap. PMID- 26595836 TI - Surgical treatment of localized gingival recessions using coronally advanced flaps with or without subepithelial connective tissue graft. AB - BACKGROUND: A coronally advanced flap with subepithelial connective tissue graft is the gold standard surgical treatment of gingival recessions, since it offers a higher probability of achieving complete root coverage compared with other techniques. However, optimum short- and middle-term clinical results have also been obtained with coronally advanced flaps alone. The aim of the present study was to evaluate the results obtained by the surgical treatment of localized gingival recessions using coronally advanced flaps with or without subepithelial connective tissue graft. MATERIAL AND METHODS: The reduction of recession height was assessed, together with the gain in gingival attachment apical to the recession, and total reduction of recession, in a comparative study of two techniques. Twenty-two gingival recessions were operated upon: 13 in the control group (coronally advanced flap) and 9 in the test group (coronally advanced flap associated to subepithelial connective tissue graft). RESULTS: After 18 months, the mean reduction of recession height was 2.2 +/- 0.8 mm in the control group and 2.3 +/- 0.7 mm in the test group, with a mean gain in gingival attachment of 1.3 +/- 0.9 mm and 2.3 +/- 1.3 mm, respectively. In percentage terms, the mean reduction of recession height was 84.6 +/- 19.6% in the control group and 81.7 +/ 17.8% in the test group, with a mean gain in gingival attachment of 20.5 +/- 37.4% and 184.4 +/- 135.5%, respectively. CONCLUSIONS: Significant reduction of gingival recession was achieved with both techniques, though the mean gain in gingival attachment (in mm and as a %) was greater in test group. PMID- 26595837 TI - Photodynamic therapy in the treatment of aggressive periodontitis: A systematic review. AB - BACKGROUND: Aggressive periodontitis (AgP) is a severe form of periodontal diseases with rapid destruction of the supporting bone around teeth. The efficacy of PDT in suppressing periodontal pathogens may be crucial in adopting new protocols for the treatment of AgP. Thus, the aim of this systematic review was to investigate the possible role of PDT in the treatment of AgP as an adjunctive therapy or monotherapy. MATERIAL AND METHODS: A systematic search of the literature was performed. Additionally, the references from all the selected full text studies were searched for relevant articles. Two reviewers screened independently titles and abstracts or full text copies. Quality assessment of all the included studies was held. RESULTS: Initial screening of electronic databases yielded 418 potentially relevant publications. After screening of the titles and full-text examination, five studies were included in the systematic review. Four publications evaluated the effects of PDT adjunctive to SRP in patients with AgP: two of them compared the clinical outcomes of SRP and PDT with a control group that received therapy with SRP and antibiotics (metronidazole and amoxicillin); two publications included SRP and PDT in the test group, and SRP alone in the control group. In one study, PDT was tested as a monotherapy compared with SRP alone. CONCLUSIONS: Within the limitations of this review, PDT may exhibit a beneficial role in the therapy of aggressive periodontitis after repeated applications. In the future, more methodologically sound, long-term randomized clinical trials are needed to be conducted. PMID- 26595838 TI - One step ahead: The perceived kinematics of others' actions are biased toward expected goals. AB - Action observation is often conceptualized in a bottom-up manner, where sensory information activates conceptual (or motor) representations. In contrast, here we show that expectations about an actor's goal have a top-down predictive effect on action perception, biasing it toward these goals. In 3 experiments, participants observed hands reach for or withdraw from objects and judged whether a probe stimulus corresponded to the hand's final position. Before action onset, participants generated action expectations on the basis of either object types (safe or painful, Experiments 1 and 2) or abstract color cues (Experiment 3). Participants more readily mistook probes displaced in a predicted position (relative to unpredicted positions) for the hand's final position, and this predictive bias was larger when the movement and expectation were aligned. These effects were evident for low-level movement and high-level goal expectancies. Expectations bias action observation toward the predicted goals. These results challenge current bottom-up views and support recent predictive models of action observation. PMID- 26595839 TI - Freezing promotes perception of coarse visual features. AB - Freezing is an evolutionarily preserved defensive behavior, characterized by immobility and heart rate deceleration, which is thought to promote visual perception. Rapid perceptual assessment of threat is crucial in life-threatening situations; for example, when policemen need to make split-second decisions about the use of deadly force. Here, we hypothesized that freezing is specifically associated with better perception of rapidly processed coarse, low-spatial frequency (LSF) features. We used a visual discrimination task in which participants determined the orientation of LSF and high-spatial frequency (HSF) gratings under threat of shock and safe conditions. As predicted, threat anticipation improved perception of LSF at the expense of HSF gratings. Crucially, stronger decrease in heart rate, a parasympathetic physiological index of freezing, was linked to better perception of LSF. These results provide empirical evidence for the comobilization of physiological and perceptual processes, which may play an important role in decision making under acute stress. PMID- 26595840 TI - Informing others is associated with behavioral and neural signatures of value. AB - One of the many proclivities of our species is the drive to share information with others. What drives this unusual proclivity for propagating knowledge? Here, we test a common prediction made by recent theories in this domain: that individuals value opportunities to inform others. Two sets of studies supported this hypothesis. Behaviorally, individuals gave up money to inform others, even in "minimalistic" settings under which informing neither improved participants' reputation nor provided material benefits to information recipients. Neurally, opportunities to inform others engaged brain regions associated with motivation and reward, including the nucleus accumbens and ventromedial prefrontal cortex. Together, these findings suggest that people place intrinsic value on sharing information with others. PMID- 26595841 TI - p-hacking by post hoc selection with multiple opportunities: Detectability by skewness test?: Comment on Simonsohn, Nelson, and Simmons (2014). AB - Simonsohn, Nelson, and Simmons (2014) have suggested a novel test to detect p hacking in research, that is, when researchers report excessive rates of "significant effects" that are truly false positives. Although this test is very useful for identifying true effects in some cases, it fails to identify false positives in several situations when researchers conduct multiple statistical tests (e.g., reporting the most significant result). In these cases, p-curves are right-skewed, thereby mimicking the existence of real effects even if no effect is actually present. PMID- 26595842 TI - Better P-curves: Making P-curve analysis more robust to errors, fraud, and ambitious P-hacking, a Reply to Ulrich and Miller (2015). AB - When studies examine true effects, they generate right-skewed p-curves, distributions of statistically significant results with more low (.01 s) than high (.04 s) p values. What else can cause a right-skewed p-curve? First, we consider the possibility that researchers report only the smallest significant p value (as conjectured by Ulrich & Miller, 2015), concluding that it is a very uncommon problem. We then consider more common problems, including (a) p-curvers selecting the wrong p values, (b) fake data, (c) honest errors, and (d) ambitiously p-hacked (beyond p < .05) results. We evaluate the impact of these common problems on the validity of p-curve analysis, and provide practical solutions that substantially increase its robustness. PMID- 26595843 TI - A question of reliability or of boundary conditions? Comment on Gomes and McCullough (2015). AB - Gomes and McCullough (2015) are to be commended on their high-powered attempt to replicate our earlier research (Shariff & Norenzayan, 2007). We suggest that notable differences between the two studies indicate that Gomes and McCullough were testing a different question. Here we place Gomes and McCullough's results in context with other studies and discuss how their findings may point to an interesting boundary condition of the original effect. PMID- 26595844 TI - Just out of reach: On the reliability of the action-sentence compatibility effect. AB - The action-sentence compatibility effect (ACE; Glenberg & Kaschak, 2002), a hallmark finding in Embodied Cognition, implicates the motor system in language comprehension. In the ACE, people process sentences implying movement toward or away from themselves, responding with actions toward or away from their bodies. These processes interact, implying a linkage between linguistic and motor systems. From a theoretical perspective, the ACE has been extremely influential, being widely cited evidence in favor of embodied cognition. The present study began as an attempt to extend the ACE in a new direction, but eventually became a series of attempts to simply replicate the effect. Across 8 experiments, I tested whether the ACE extends to a novel mouse-tracking method and/or is susceptible to higher-order cognitive influences. In 3 experiments, attempts were made to "disembody" the ACE by presenting participants' names on the computer screen (as in Markman & Brendl, 2005). In each experiment, the ACE could not be disembodied, because the ACE did not occur. In further experiments, the ACE was not observed in reading times, regardless of response mode (mouse movements vs. button presses) or stimuli, including those from the original research. Similarly, no ACE was observed in physical movement times. Bayes Factor analyses of the current experiments, and the previous ACE literature, suggest that the evidence for the ACE is generally weak: Many studies considered as positive evidence actually support the null hypothesis, and very few published results offer strong evidence for the ACE. Implications for the embodiment hypothesis are discussed. PMID- 26595845 TI - Current management of glaucoma and vascular occlusive disease. AB - PURPOSE OF REVIEW: This article summarizes recent findings pertaining to advancements in the treatment of glaucomas secondary to vascular occlusive disease to maximize visual outcomes. RECENT FINDINGS: Retinal ischemia leads to a local increase in transcription of proteins responsible for aberrant angiogenesis and subsequent neovascular glaucoma. Antivascular endothelial growth factor (VEGF) therapy is helpful in the management of this condition. Although bevacizumab and ranibizumab offer relatively short-term effects, preliminary studies suggest that aflibercept may allow for longer term treatment. Preoperative anti-VEGF injection therapy improves outcomes after trabeculectomy and glaucoma drainage implant surgeries. The treatments for vascular occlusive disease may lead to intraocular pressure elevation and subsequent glaucoma. Aflibercept appears to be a safer agent in this regard. SUMMARY: Prompt diagnosis and management of glaucomas associated with vascular occlusive disease are required to allow for the best possible outcome. Novel anti-VEGF agents, particularly aflibercept, should be strongly considered in the management of these conditions. PMID- 26595846 TI - Resident surgical training in glaucoma. AB - PURPOSE OF REVIEW: The review provides an overview of the training of ophthalmology residents to perform glaucoma surgery. RECENT FINDINGS: Data from the Accreditation Council for Graduate Medical Education indicate that the average number of glaucoma surgeries performed by graduating ophthalmology residents has remained stable over the past 5 years. However, a proportional increase in shunting procedures and decrease in filtering procedures has occurred during this time period. The existing medical literature has not identified any differences in the safety and efficacy of glaucoma procedures performed by residents compared with those performed by glaucoma specialists. A structured curriculum for glaucoma is designed to help residents transition from the wet laboratory to live surgery, and it serves to maximize resident learning and patient safety. SUMMARY: Tube shunts are being used with greater frequency in the surgical management of glaucoma as an alternative to trabeculectomy, and this shift in practice patterns is reflected in the surgical experience of ophthalmology residents. Patients should be reassured by the outcomes of resident performed glaucoma surgery, which compare favorably with those reported by experienced glaucoma surgeons. A structured curriculum can assist in introducing residents to glaucoma surgery. PMID- 26595849 TI - Innovations and adaptations in trabeculectomy. AB - PURPOSE OF REVIEW: This article examines the current literature reporting updates on trabeculectomy techniques, complications, and cost-effectiveness. RECENT FINDINGS: Trabeculectomy continues to be the standard for glaucoma surgery when a low intraocular pressure is required. Recent publications describe technique modifications that successfully increase efficacy and lower complications. There is also an ongoing effort to define the role of trabeculectomy in the management of glaucoma from a cost and public health standpoint. SUMMARY: The current literature continues to support the use of trabeculectomy as a method of lowering intraocular pressure in glaucoma management. Efficacy has been improved by ongoing surgical innovation, and reported complication rates are lower than those previously noted. Trabeculectomy has a favorable cost-benefit profile when compared with medical therapy or other surgical techniques. In spite of these ongoing changes, trabeculectomy appears to be decreasing in frequency in favor of newer surgeries and medications. PMID- 26595848 TI - Glaucoma management after vitreoretinal surgeries. AB - PURPOSE OF REVIEW: The surgical management of retinal disorders, including scleral buckling procedures, pars plana vitrectomy, and intravitreal injections of gas or silicone oil, can lead to short-term elevations in intraocular pressure (IOP) and ultimately long-term glaucomatous damage if not treated in a timely manner. Glaucoma in these cases is commonly refractory to conventional therapies. This review highlights the treatment strategies for glaucoma in eyes that have previously undergone vitreoretinal surgery. RECENT FINDINGS: Although medical therapy is often used initially to control a temporary rise in IOP, laser and surgical therapy may be required to treat sustained IOP elevation and subsequent glaucomatous damage in eyes that have undergone intraocular surgery for retinal disorders. Glaucoma drainage devices are an important treatment modality, particularly when there is high risk of failure with filtering surgery. SUMMARY: Previous vitreoretinal surgery is a known risk factor for the development of glaucoma. Treatment is usually initiated with medical therapy, however, surgical intervention is frequently required to control IOP and prevent progressive glaucomatous damage in patients with refractory glaucoma. PMID- 26595847 TI - Glaucoma management after corneal transplantation surgeries. AB - PURPOSE OF REVIEW: Intraocular pressure (IOP) elevation and glaucoma progression following corneal transplantation, specifically, penetrating keratoplasty, Descemet's stripping endothelial keratoplasty, and Boston keratoprosthesis, are well described causes of ocular morbidity. Depending on the procedure performed, the incidence of glaucoma is highly variable. Several etiologic factors have been identified, the most common being synechial angle closure and corticosteroid induced IOP elevation. The purpose of this review is to describe the various treatment strategies for glaucoma following corneal transplantation. RECENT FINDINGS: Medications and laser treatments are usually first-line therapies for postoperative IOP elevation. Surgical intervention, including filtering surgery and glaucoma drainage devices, may be necessary to control IOP and prevent progressive glaucomatous damage. SUMMARY: Glaucoma is a common complication of corneal transplantation, and the degree of aggressiveness is often related to the indication for corneal surgery. Although postoperative IOP elevation may be controlled with medical therapy alone, refractory cases may require glaucoma surgery. In all cases, early detection and intervention are necessary to optimize patient outcomes. PMID- 26595850 TI - Ferric Perchlorate Promoted Reaction of [60]Fullerene with N-Sulfonyl Aldimines: Synthesis and Functionalization of Fulleroxazolidines. AB - The rare fulleroxazolidines 2 were successfully synthesized by the facile ferric perchlorate promoted reaction of [60]fullerene with various N-sulfonyl aldimines 1. Further functionalization of fulleroxazolidines by arenes in the presence of boron trifluoride afforded 1,4-bisarylation products 4. A possible reaction mechanism for the formation of the fulleroxazolidines is proposed. PMID- 26595851 TI - Morphology, Cell Division, and Phylogeny of Uroleptus longicaudatus (Ciliophora, Hypotricha), a Species of the Uroleptus limnetis Complex. AB - A Chinese population of the little-known freshwater hypotrich Uroleptus longicaudatus was investigated with emphasis on its living morphology and infraciliature. The characteristic, tripartite body consists of a narrowed (cephalized) anterior portion, a slender trunk, and a long, slender, and strongly contractile tail occupying up to 30% of body length. Contracted specimens with a tail length of about 12% closely resemble Uroleptus limnetis which has, like U. longicaudatus, its type locality on the East Coast of the United States so that it cannot be excluded that these two species are synonymous. Thus, we propose to subsume these and few other little-known species, which are not clearly distinguishable at the present state of knowledge, as U. limnetis complex. The morphogenesis of U. longicaudatus proceeds as in most congeners. The phylogenetic analyses reveal that Uroleptus is a monophyletic group, but due to the lack of detailed morphological data of the populations sequenced so far, the relationships within this taxon remain obscure. For the objective determination of the tail length of hypotrichs, we propose the "1/3-method", which says that the tail commences at that body width which corresponds one-third of the maximum width. Paruroleptus ophryoglena Gelei, 1954 is transferred to Uroleptus: Uroleptus ophryoglena (Gelei, 1954) comb. nov. PMID- 26595852 TI - Effect of Octreotide on Colonic Motility in Pediatric Patients With Chronic Recalcitrant Constipation. AB - OBJECTIVE: The aim of the present study was to study the effect of octreotide on colonic motility in pediatric patients with recalcitrant chronic constipation/encopresis and other suspected colonic motility disorders. METHODS: This was a nonrandomized, single-center, open-label, prospective study evaluating the effect of a single subcutaneous dose of octreotide on colonic motility. RESULTS: Thirteen patients (5 boys) were enrolled in the study. The age range was 4.6 to 16.2 years. Eleven patients (84%) had normal colonic manometry and 2 patients (16%) had colonic neuropathy. Motility Index (MI) (mmHg) for the 15 minutes before and after octreotide infusion was 6.03 +/- 1.26 (95% confidence interval [CI] 5.35-6.72) and 5.32 +/- 1.66 (95% CI 4.42-6.23), respectively, with P value of 0.08. MI for the 30 minutes before and after octreotide infusion was 6.89 +/- 1.37 (95% CI 6.14-7.64) and 6.71 +/- 1.47 (95% CI 5.91-7.52), respectively, with P value of 0.55. MI for the 45 minutes before and after octreotide infusion was 7.73 +/- 1.32 (95% CI 7.01-8.45) and 7.53 +/- 1.38 (95% CI 6.78-8.28), respectively, with P value of 0.8. CONCLUSION: Our study showed that the administration of octreotide resulted in no significant changes in colonic MI in pediatric patients with chronic recalcitrant constipation. PMID- 26595853 TI - Intermittent Bolus or Semicontinuous Feeding for Preterm Infants? AB - OBJECTIVES: The aim of the present study was to assess the clinical benefits and risks of semicontinuous (CON) versus intermittent nasogastric tube feeding in low birth-weight infants. METHODS: Infants with a birth weight <1750 g and gestational age <32 weeks were stratified according to birth weight and assigned to either CON or intermittent bolus (BOL) feeding. The primary endpoint was days to full enteral feeding (defined as 120 mL(-1) . kg(-1) . day(-1)). We also collected data on feeding tolerance, weight gain, respiratory support, and complications (sepsis, necrotising enterocolitis, and death). RESULTS: There was no difference between the 2 groups (CON n = 121, BOL n = 125) in days to reach full enteral feeding--7 (5-10) versus 6 (5-8) days, respectively, with a difference 1 (-0.05 to 2.1). Mean daily gastric residual volumes, however, were significantly lower in the BOL group (4.8 vs 3.9 mL/day, difference 0.9 mL/day [0.1-1.7]), as was the total number of patients with feeding interruptions (76 vs 59, difference 16% [3%-28%]). CONCLUSIONS: Bolus and continuous feeding are equally suitable feeding strategies for preterm neonates. BOL feeding, however, may be preferable. PMID- 26595854 TI - Omega-3 Fatty Acid Consumption and Prostate Cancer: A Review of Exposure Measures and Results of Epidemiological Studies. AB - Animal studies have shown that dietary omega-3 polyunsaturated fatty acids (n-3) may play a role in the development of prostate cancer, but the results of epidemiologic studies have been equivocal. Associations in humans may vary depending on study design, measurement methodology of fatty acid intake, intake ranges, and stage of cancer development. To address this, we identified 36 published studies through PubMed (Medline) from 1993 through 2013 on long-chain n 3s and prostate cancer. Exposure measurements included dietary assessment and biomarker levels. Associations for total, early, and late stage prostate cancer were examined by subgroup of study design and exposure measure type and by using forest plots to illustrate the relative strength of associations within each subgroup. We also tested for potential threshold effects by considering studies that included measurement cut-points that met intake levels recommended by the American Heart Association. We found no consistent evidence supporting a role of n-3s in either the causation or prevention of prostate cancer at any stage or grade. Results did not vary appreciably by study design, exposure measurement, intake level, or stage of cancer development. PMID- 26595855 TI - Corporate Funding of Food and Nutrition Research: Science or Marketing? PMID- 26595856 TI - Boosting the Boron Dopant Level in Monolayer Doping by Carboranes. AB - Monolayer doping (MLD) presents an alternative method to achieve silicon doping without causing crystal damage, and it has the capability of ultrashallow doping and the doping of nonplanar surfaces. MLD utilizes dopant-containing alkene molecules that form a monolayer on the silicon surface using the well-established hydrosilylation process. Here, we demonstrate that MLD can be extended to high doping levels by designing alkenes with a high content of dopant atoms. Concretely, carborane derivatives, which have 10 B atoms per molecule, were functionalized with an alkene group. MLD using a monolayer of such a derivative yielded up to ten times higher doping levels, as measured by X-ray photoelectron spectroscopy and dynamic secondary mass spectroscopy, compared to an alkene with a single B atom. Sheet resistance measurements showed comparably increased conductivities of the Si substrates. Thermal budget analyses indicate that the doping level can be further optimized by changing the annealing conditions. PMID- 26595857 TI - Body image inflexibility mediates the relationship between body image evaluation and maladaptive body image coping strategies. AB - Body image inflexibility, the unwillingness to experience negative appearance related thoughts and emotions, is associated with negative body image and eating disorder symptoms. The present study investigated whether body image inflexibility mediated the relationship between body image evaluation and maladaptive body image coping strategies (appearance-fixing and experiential avoidance) in a college and community sample comprising 156 females aged 18-51 years (M=22.76, SD=6.96). Controlling for recruitment source (college vs. community), body image inflexibility fully mediated the relationship between body image evaluation and maladaptive body image coping strategies. Results indicated that an unwillingness to experience negative appearance-related thoughts and emotions is likely responsible for negative body image evaluation's relationship to appearance-fixing behaviours and experiential avoidance. Findings support extant evidence that interventions that explicitly target body image inflexibility, such as Acceptance and Commitment Therapy, may have utility in treating body dissatisfaction in nonclinical populations. PMID- 26595860 TI - Hospitalist Neurology. PMID- 26595858 TI - Stabilizing Alginate Confinement and Polymer Coating of CO-Releasing Molecules Supported on Iron Oxide Nanoparticles To Trigger the CO Release by Magnetic Heating. AB - Maghemite (Fe2O3) iron oxide nanoparticles (IONPs) were synthesized, modified with covalent surface-bound CO-releasing molecules of a tri(carbonyl)-chlorido phenylalaninato-ruthenium(II) complex (CORM), and coated with a dextran polymer. The time- and temperature-dependent CO release from this CORM-3 analogue was followed by a myoglobin assay. A new measurement method for the myoglobin assay was developed, based on confining "water-soluble" polymer-coated Dextran500k@CORM@IONP particles in hollow spheres of nontoxic and easily prepared calcium alginate. Dropping a mixture of Dextran500k@CORM@IONP and sodium alginate into a CaCl2 solution leads to stable hollow spheres of Ca(2+) cross-linked alginate which contain the Dextran500k@CORM@IONP particles. This "alginate method" (i) protects CORM-3 analogues from rapid CO-displacement reactions with a protein, (ii) enables a spatial separation of the CORM from its surrounding myoglobin assay with the alginate acting as a CO-permeable membrane, and (iii) allows the use of substances with high absorptivity (such as iron oxide nanoparticles) in the myoglobin assay without interference in the optical path of the UV cell. Embedding the CORM@IONP nanoparticles in the alginate vessel represents a compartmentation of the reactive component and allows for close contact with, yet facile separation from, the surrounding myoglobin assay. The half-life of the CO release from Dextran500k@CORM@IONP particles surrounded by alginate was determined to be 890 +/- 70 min at 20 degrees C. An acceleration of the CO release occurs at higher temperature with a half-life of 172 +/- 27 min at 37 degrees C and 45 +/- 7 min at 50 degrees C. The CO release can be triggered in an alternating current magnetic field (31.7 kA m(-1), 247 kHz, 39.9 mT) through local magnetic heating of the susceptible iron oxide nanoparticles. With magnetic heating at 20 degrees C in the bulk solution, the half-life of CO release from Dextran500k@CORM@IONP particles decreased to 155 +/- 18 min without a noticeable temperature increase in the dispersion. At 37 and 50 degrees C, the half-life for the CO release triggered by local magnetic heating was 65 +/- 5 min and 30 +/- 3 min, respectively. Thus, at a physiological temperature of 37 degrees C, magnetic heating accelerates the CO release of the IONP-bound CORM by a factor of ~ 2.6. The activation energy for CO release from a CORM-3 analogue was determined to be EA = 78 kJ/mol. PMID- 26595861 TI - A Practical Approach to Meningitis and Encephalitis. AB - Meningitis is an inflammatory syndrome involving the meninges that classically manifests with headache and nuchal rigidity and is diagnosed by cerebrospinal fluid examination. In contrast, encephalitis refers to inflammation of the brain parenchyma itself and often results in focal neurologic deficits or seizures. In this article, the authors review the differential diagnosis of meningitis and encephalitis, with an emphasis on infectious etiologies. The recommended practical clinical approach focuses on early high-yield diagnostic testing and empiric antimicrobial administration, given the high morbidity associated with these diseases and the time-sensitive nature of treatment initiation. If the initial workup does not yield a diagnosis, further etiology-specific testing based upon risk factors and clinical characteristics should be pursued. Effective treatment is available for many causes of meningitis and encephalitis, and when possible should address both the primary disease process as well as potential complications. PMID- 26595862 TI - Current Trends in Treatment of Status Epilepticus and Refractory Status Epilepticus. AB - Status epilepticus is a heterogeneous disorder with varied definitions and presentations. Taken together, all forms of status epilepticus carry significant morbidity and mortality, much of which is dictated by the underlying etiology. Generalized convulsive status epilepticus, which represents a common form, is a true neurologic emergency that requires emergent management. Treatment focuses on stabilizing the patient and aggressive medical management to achieve the timely termination of seizures. For other forms of status epilepticus including nonconvulsive and focal status epilepticus, the goal remains early seizure termination, but the use of intravenous medications should be weighed against the risks associated with these therapies. The diagnostic evaluation of status epilepticus is guided by the patient's history and should be broad, including a screen for toxins, electrolytes, structural abnormalities, and central nervous system infectious and autoimmune/inflammatory etiologies. Considerable research is still needed to improve our understanding of the mechanisms, consequences, and therapy of status epilepticus. PMID- 26595863 TI - Acute Care of Ischemic Stroke Patients in the Hospital. AB - Ischemic stroke is a leading cause of death and disability worldwide. Recent advances in acute treatment provide hope that the impact of this disease will be reduced. Rapid assessment for large vessel occlusion is now a key element in acute stroke care given advances in endovascular therapy. Because access to acute therapies is limited, development of systems of care to triage appropriate patients to specialized centers is essential. Acute hospitalization management requires multiple strategies including initiation of secondary prevention measures. In addition to preventing further stroke, physicians can also improve long-term survival by preventing the complications of stroke in the hospital and ensuring longitudinal poststroke care and rehabilitation following discharge. PMID- 26595864 TI - The Evaluation and Management of Adult Intracerebral Hemorrhage. AB - Intracerebral hemorrhage (ICH) is the most disabling and deadly form of stroke. Although mortality remains high, new data suggest that outcomes can be improved with standardized medical care. In this review, the authors outline the most up to-date knowledge, including the results of the latest phase III clinical trials on the specialized care needed to treat patients with ICH. They provide an overview on how to achieve rapid diagnosis and the initial steps of intervention to reduce hematoma volume or prevent expansion by modifying potentially treatable conditions, such as underlying vascular etiologies, blood pressure control, and coagulopathies. Grading scales can help identify patients at risk for hematoma expansion and functional disabilities and guide clinical decision making. Other medical management topics important to recovery and prevention of secondary brain injury include seizure prevention and treatment, glycemic control, temperature control, and deep venous thrombosis prophylaxis and treatment. Treatment options in surgery are also possible in select patients; there are emerging studies regarding minimally invasive surgery for the management of ICH. These aggressive therapies are essential to lower the morbidity and mortality of patients presenting with ICH. PMID- 26595865 TI - Moving Beyond Metabolic Encephalopathy: An Update on Delirium Prevention, Workup, and Management. AB - Delirium is a condition that frequently complicates hospitalization and consists of an acute decline in orientation and attention, often accompanied by other cognitive changes. Delirium is tied to multiple detrimental outcomes both in the short and long term, including cognitive and functional decline, inpatient complications, and mortality. Postoperative, elderly medical, and critical care patients have been identified as populations at particular risk. In this review, the authors discuss current theories on pathophysiology, recommended workup, and evidence-based prevention and management of inpatient delirium. In general, instituting a system of active screening of at-risk populations and nonpharmacologic interventions for prevention and treatment seems to be the most effective method of addressing delirium. More research is needed to clarify the etiology of delirium and develop safe therapeutic options that address the underlying pathophysiology. PMID- 26595866 TI - Fulminant Demyelinating Diseases of the Central Nervous System. AB - Fulminant demyelinating diseases of the central nervous system include acute disseminated encephalomyelitis, the related acute hemorrhagic leukoencephalitis, multiple sclerosis variants, neuromyelitis optica spectrum disorders, and idiopathic transverse myelitis. These syndromes are often managed with similar acute treatments including high-dose corticosteroids and plasmapheresis; however, long-term management varies. Although the prognosis of fulminant demyelinating disease was historically poor, outcomes today may be improved due to earlier diagnosis, rapid implementation of anti-inflammatory therapies such as high-dose corticosteroids and plasmapheresis, and improved supportive care. PMID- 26595867 TI - Approach to the Workup and Management of Headache in the Emergency Department and Inpatient Settings. AB - The challenge of headache management in the hospital can be divided into the diagnostic and management issues encountered in the emergency department, and the issues involved in the inpatient management of chronic refractory headaches. The two endeavors are different but linked because of overlapping diagnostic and treatment options. In addition, the problem of the intractable acute headache encountered in the emergency department can evolve into inpatient care of the same patient who has failed to respond to acute treatment. Here the author presents an approach to the patient with severe acute headache in the emergency department and explores the options available for managing intractable headaches in the inpatient setting. PMID- 26595868 TI - Neuro-Oncologic Emergencies. AB - Cancer can have diverse and widespread effects on the nervous system. Knowledge of the most common characteristic mechanisms by which cancer impacts the nervous system enables prompt diagnosis and appropriate management. Here, a variety of neuro-oncologic emergencies are reviewed. Mass effect, status epilepticus, pituitary apoplexy, and metastatic epidural spinal cord compression are emergencies that arise from direct effects of central nervous system neoplasms. Limbic encephalitis may result in hospitalization and at times critical illness, and is usually caused by antibody-mediated reactions to neoplasms. Treatment related neuro-oncologic emergencies from the effects of radiation and chemotherapy in severe cases may also result in medical emergencies. PMID- 26595869 TI - Neuromuscular Emergencies. AB - Although most neuromuscular disorders are recognized and treated in the outpatient clinic, a subset can present with rapidly advancing or severe weakness and constitute true emergencies by threatening respiratory and bulbar function. This review focuses on the recognition, diagnosis, and management of neuromuscular diseases most likely to present in the inpatient setting: infectious motor neuronopathies, inflammatory polyradiculopathies, and disorders of neuromuscular transmission. In each, the prompt recognition, diagnosis, and institution of specific therapies or supportive care can prevent mortality and mitigate morbidity. PMID- 26595870 TI - Perioperative Consultation for Patients with Preexisting Neurologic Disorders. AB - As the population ages, the prevalence of many neurologic diseases is increasing. At the same time, older patients are undergoing more surgical procedures. This confluence of events puts neurohospitalists in a unique position to provide both pre- and postoperative guidance to minimize complications, improve clinical outcomes, and decrease health care costs in patients with neurologic comorbidities. Early preoperative consultation is recommended for patients with severe, poorly controlled, or decompensated neurologic disease, a recent stroke, or those undergoing procedures with a high risk of neurologic complications. The neurohospitalist's role includes optimizing management of preexisting diseases, such as epilepsy, neuromuscular disorders, Parkinson's disease, dementia, and cerebrovascular disease, as well as providing guidance for perioperative management and clarification of risks. In the postoperative period, the neurohospitalist will frequently be consulted to mitigate any negative impact of neurologic complications that do occur. PMID- 26595871 TI - Inpatient Neurologic Consultation in Solid Organ Transplant Patients. AB - A third of solid organ transplant recipients experience neurologic complications after transplantation. In this article the author reviews common and uncommon complications of the perioperative period including stroke and peripheral neuropathy, neurotoxicity associated with immunosuppressant medications such as calcineurin inhibitors, and opportunistic infections that target the nervous system. A careful clinical history, neurologic examination, and medication review are vital in generating a differential diagnosis that will guide diagnostic testing and decisions regarding treatment and management, and early recognition of many disorders is imperative to prevent irreversible neurologic morbidity and death. PMID- 26595872 TI - Quality Metrics in Inpatient Neurology. AB - Quality of care in the context of inpatient neurology is the standard of performance by neurologists and the hospital system as measured against ideal models of care. There are growing regulatory pressures to define health care value through concrete quantifiable metrics linked to reimbursement. Theoretical models of quality acknowledge its multimodal character with quantitative and qualitative dimensions. For example, the Donabedian model distils quality as a phenomenon of three interconnected domains, structure-process-outcome, with each domain mutually influential. The actual measurement of quality may be implicit, as in peer review in morbidity and mortality rounds, or explicit, in which criteria are prespecified and systemized before assessment. As a practical contribution, in this article a set of candidate quality indicators for inpatient neurology based on an updated review of treatment guidelines is proposed. These quality indicators may serve as an initial blueprint for explicit quality metrics long overdue for inpatient neurology. PMID- 26595873 TI - Models of Inpatient Neurologic Care. AB - The rapid ascension of the neurohospitalist model has been a response to national pressures implemented around local practicalities. As such, there is no uniform or ideal neurohospitalist model; there remains tremendous variation nationally. Over time, several dominant models have emerged, each of which raises distinct issues, both clinical and financial. As the field continues to grow, neurohospitalists in both hospital-owned and private practices are developing models that are reshaping the practice of inpatient neurology. A thoughtful approach to developing and maintaining programs is critical to success. PMID- 26595874 TI - Sustainable employability--definition, conceptualization, and implications: A perspective based on the capability approach. AB - OBJECTIVES: The aim of this paper is to propose a new model of sustainable employability based on the capability approach, encompassing the complexity of contemporary work, and placing particular emphasis on work-related values. METHODS: Having evaluated existing conceptual models of work, health, and employability, we concluded that prevailing models lack an emphasis on important work-related values. Amartya Sen's capability approach (CA) provides a framework that incorporates a focus on values and reflects the complexity of sustainable employability. RESULTS: We developed a model of sustainable employability based on the CA. This model can be used as starting point for developing an assessment tool to investigate sustainable employability. CONCLUSIONS: A fundamental premise of the CA is that work should create value for the organization as well as for the worker. This approach challenges researchers, policy-makers, and practitioners to investigate what people find important and valuable--what they would like to achieve in a given (work) context--and moreover to ascertain whether people are able and enabled to do so. According to this approach, it is not only the individual who is responsible for achieving this; the work context is also important. Rather than merely describing relationships between variables, as existing descriptive models often do, the CA depicts a valuable goal: a set of capabilities that constitute valuable work. Moreover, the CA fits well with recent conceptions of health and modern insights into work, in which the individual works towards his or her own goals that s/he has to achieve within the broader goals of the organization. PMID- 26595875 TI - Antitumor Activity of Americanin A Isolated from the Seeds of Phytolacca americana by Regulating the ATM/ATR Signaling Pathway and the Skp2-p27 Axis in Human Colon Cancer Cells. AB - The antiproliferative and antitumor activities of americanin A (1), a neolignan isolated from the seeds of Phytolacca americana, were investigated in human colon cancer cells. Compound 1 inhibited the proliferation of HCT116 human colon cancer cells both in vitro and in vivo. The induction of G2/M cell-cycle arrest by 1 was concomitant with regulation of the ataxia telangiectasia-mutated/ATM and Rad3 related (ATM/ATR) signaling pathway. Treatment with 1 activated ATM and ATR, initiating the subsequent signal transduction cascades that include checkpoint kinase 1 (Chk1), checkpoint kinase 2 (Chk2), and tumor suppressor p53. Another line of evidence underlined the significance of 1 in regulation of the S phase kinase-associated protein 2 (Skp2)-p27 axis. Compound 1 targeted selectively Skp2 for degradation and thereby stabilized p27. Therefore, compound 1 suppressed the activity of cyclin B1 and its partner cell division cycle 2 (cdc2) to prevent entry into mitosis. Furthermore, prolonged treatment with 1 induced apoptosis by producing excessive reactive oxygen species. The intraperitoneal administration of 1 inhibited the growth of HCT116 tumor xenografts in nude mice without any overt toxicity. Modulation of the ATM/ATR signaling pathway and the Skp2-p27 axis might be plausible mechanisms of action for the antiproliferative and antitumor activities of 1 in human colon cancer cells. PMID- 26595876 TI - Hodgkin and Reed-Sternberg cells of classical Hodgkin lymphoma are highly dependent on oxidative phosphorylation. AB - The metabolic properties of lymphomas derived from germinal center (GC) B cells have important implications for therapeutic strategies. In this study, we have compared metabolic features of Hodgkin-Reed-Sternberg (HRS) cells, the tumor cells of classical Hodgkin's lymphoma (cHL), one of the most frequent (post-)GC derived B-cell lymphomas, with their normal GC B cell counterparts. We found that the ratio of oxidative to nonoxidative energy conversion was clearly shifted toward oxidative phosphorylation (OXPHOS)-linked ATP synthesis in HRS cells as compared to GC B cells. Mitochondrial mass, the expression of numerous key proteins of oxidative metabolism and markers of mitochondrial biogenesis were markedly upregulated in cHL cell lines and in primary cHL cases. NFkappaB promoted this shift to OXPHOS. Functional analysis indicated that both cell growth and viability of HRS cells depended on OXPHOS. The high rates of OXPHOS correlated with an almost complete lack of lactate production in HRS cells not observed in other GC B-cell lymphoma cell lines. Overall, we conclude that OXPHOS dominates energy conversion in HRS cells, while nonoxidative ATP production plays a subordinate role. Our results suggest that OXPHOS could be a new therapeutic target and may provide an avenue toward new treatment strategies in cHL. PMID- 26595877 TI - Summaries for patients. Lactation and Progression to Type 2 Diabetes After Gestational Diabetes. PMID- 26595878 TI - Western diets induce blood-brain barrier leakage and alter spatial strategies in rats. AB - Western diet (WD) intake induces obesity and metabolic dysfunction. The present study examined the effects of WD on hippocampal-dependent cognitive functioning and blood-brain barrier (BBB) permeability as a function of exposure duration, obesity phenotype, and peripheral markers of energy regulation. The use of hippocampal-dependent "place" or hippocampal-independent "response" strategies in a Y maze was assessed in male rats following 10, 40, and 90 days of WD exposure in diet-induced obese (DIO) rats, in diet resistant (DR) rats that are relatively insensitive to the obesogenic properties of WD, and in chow-fed controls. Insulin, glucose, and BBB permeability throughout several loci in the hippocampus, striatum, and cerebellum were evaluated in relation to duration of WD exposure, obesity phenotype, and type of strategy used. DIO rats had increased body weight and adiposity throughout the study, and elevated 10-day glucose and 90-day insulin levels. Throughout the study, chow-fed and DR rats reliably relied on a place strategy. DIO rats, in contrast, favored a response strategy at the 10 and 90-day time points. BBB leakage was observed in the dorsal striatum and multiple subregions of the hippocampus of DIO, but not DR or chow-fed rats. Increased ventral hippocampal BBB permeability and blood glucose levels were associated with reduced place strategy use. These data indicate that WD-induced BBB leakage is dependent on duration of diet exposure as well as obesity phenotype, and implicates BBB leakage and impaired glucoregulation in behavioral strategy and cognitive performance. PMID- 26595879 TI - Effects of methylphenidate and atomoxetine on impulsivity and motor activity in preadolescent rats prenatally-treated with alcohol. AB - Prenatal alcohol treatment (PA) produces a decrease in dopaminergic neuron activity in the ventral tegmental area, an alteration that is alleviated with methylphenidate treatment. Evidence exists that PA also produces hyperactivity, inattention and enhanced impulsivity, behavioral alterations that have been related to dopaminergic and noradrenergic functions. The purpose of this work was to study the effects of methylphenidate and atomoxetine on impulsivity and motor activity in preadolescent male rats prenatally exposed to alcohol. Pregnant Wistar rats were exposed to either alcohol or an isocaloric solution from Days 8 to 20 of gestation. Starting at 24 postnatal days, male offspring were tested for motor activity and trained in a delay-discounting task for impulsivity assessment before, and during, treatment with either 3 mg/kg i.p. of methylphenidate, 2 mg/kg i.p. of atomoxetine, or saline i.p. The group prenatally exposed to alcohol showed higher motor activity and more frequent choices of immediate, but small, rewards than the control group; a finding indicative of higher impulsivity. Atomoxetine reduced both motor activity and impulsivity. In contrast, methylphenidate had only a mild effect on impulsivity. Results suggest an important participation of noradrenergic transmission in cognitive impulsivity and hyperactivity in preadolescent rats with previous alterations in these behaviors. Dopaminergic participation in these behaviors is partially supported by the present findings on the basis of the effects of methylphenidate. PMID- 26595880 TI - Heterozygous deletion of alpha-neurexin I or alpha-neurexin II results in behaviors relevant to autism and schizophrenia. AB - The neurexins are a family of presynaptic cell adhesion molecules. Human genetic studies have found heterozygous deletions affecting NRXN1 and NRXN2, encoding alpha-neurexin I (Nrxn1alpha) and alpha-neurexin II (Nrxn2alpha), in individuals with autism spectrum disorders and schizophrenia. However, the link between alpha neurexin deficiency and the manifestation of psychiatric disorders remain unclear. To assess whether the heterozygous loss of neurexins results in behaviors relevant to autism or schizophrenia, we used mice with heterozygous (HET) deletion of Nrxn1alpha or Nrxn2alpha. We found that in a test of social approach, Nrxn1alpha HET mice show no social memory for familiar versus novel conspecifics. In a passive avoidance test, female Nrxn1alpha HET mice cross to the conditioned chamber sooner than female wild-type and Nrxn2alpha HET mice. Nrxn2alpha HET mice also express a lack of long-term object discrimination, indicating a deficit in cognition. The observed Nrxn1alpha and Nrxn2alpha genotypic effects were specific, as neither HET deletion had effects on a wide range of other behavioral measures, including several measures of anxiety. Our findings demonstrate that the heterozygous loss of alpha-neurexin I and alpha neurexin II in mice leads to phenotypes relevant to autism and schizophrenia. PMID- 26595881 TI - Acid base imbalances in ill neonatal foals and their association with survival. AB - REASONS FOR PERFORMING STUDY: Acid-base imbalances observed in human paediatric patients are associated with outcome. Likewise, neonatal foals may have different acid-base imbalances associated with diagnosis or prognosis. OBJECTIVES: To determine acid-base imbalances by the quantitative method in ill neonatal foals and assess their association with diagnosis and prognosis. STUDY DESIGN: Observational prospective clinical study. METHODS: This study included 65 ill neonatal foals (32 septic, 33 nonseptic) admitted to an equine referral hospital from 2005 to 2011with acid-base parameters determined on admission and a control group of 33 healthy neonatal foals. Blood pH, pCO2 , sodium, potassium, chloride, L-lactate, albumin and phosphate concentrations were determined. Bicarbonate, globulin, measured strong ion difference (SIDm ), nonvolatile weak buffer concentrations (Atot ), base excess and its components were calculated. Analysis of covariance (ANCOVA) and multiple linear regression statistical analyses were performed. Results are summarised as mean +/- s.d. for normally distributed variables and median [25-75th percentiles] for non-normally distributed ones. RESULTS: A total of 63% of ill foals had respiratory alkalosis and 58.5% had SIDm acidosis. The combination of both alterations was detected in 21 of 65 ill foals and abnormal pH was found in 24 of 65. Compared with healthy foals, ill foals had significantly lower SIDm (nonseptic 31.6 +/- 6.3 [P<0.01] and septic 32.0 +/- 6.4 [P<0.01] vs. control 40.3 +/- 3.1 mmol/l), potassium (nonseptic 3.5 [3.3-3.8; P<0.01] and septic 3.6 [3.2-4.3; P = 0.01] vs. control 4.2 [3.8-4.5] mEq/l) and higher L-lactate (nonseptic 5.1 +/- 4.2 [P = 0.01] and septic 5.0 +/- 3.7 [P = 0.03] vs. control 2.5 +/- 1.3 mmol/l). Significantly higher L-lactate and venous pCO2 were found in nonsurviving (6.4 +/- 3.5 mmol/l [P = 0.04] and 51 +/- 13 mmHg [P<0.01]) compared with surviving foals. CONCLUSIONS: The most common acid-base imbalances observed in ill foals were respiratory alkalosis, SIDm acidosis or mixed respiratory alkalosis with strong ion acidosis. Increased venous pCO2 and blood L-lactate concentration were associated with poor outcome. PMID- 26595882 TI - Risk of Osteosarcoma in Dogs After Open Fracture Fixation. AB - OBJECTIVE: To critically evaluate whether open fracture fixation is a significant risk factor for latent osteosarcoma development. STUDY DESIGN: Case-control study. SAMPLE POPULATION: Dogs undergoing open fracture repair and dogs diagnosed with osteosarcoma. METHODS: Records were retrieved from the Veterinary Medical Database VMDB (1970-2000) for dogs undergoing surgical repair of a fracture and dogs diagnosed with osteosarcoma. Dogs with open reduction of joint luxation, dogs diagnosed with bacterial cystitis, and dogs diagnosed with urinary bladder transitional cell carcinoma (UBTCC) were queried as comparison populations. Relative risk for osteosarcoma development was determined. RESULTS: From a population of 19,041 fractures treated surgically, 15 of those dogs subsequently appeared in the VMDB with osteosarcoma affecting the same bone. The relative risk of a fracture repair and associated orthopedic implants and osteosarcoma occurrence was equivalent to the relative risk of open joint reduction and osteosarcoma occurrence (95% confidence interval; 0.998-1.00). The relative risk of having bacterial cystitis and appearing again in the VMDB with UBTCC was higher than the risk of open fracture repair and a subsequent diagnosis of osteosarcoma (P < .02). CONCLUSION: The incidence of fracture-related osteosarcoma may be significantly less than previously estimated based on cases queried from the VMDB. Although possible cases of implant-associated osteosarcoma were identified, their occurrence was rare. Elective implant removal for the purpose of reducing the risk of osteosarcoma after fracture repair may not be warranted and merits further investigation. PMID- 26595883 TI - Colorectal cancer screening of the general population in East Asia. AB - In recent years, the incidence of colorectal cancer (CRC) has been increasing, and CRC has been becoming the major cause of cancer deaths in Asian countries. Therefore, an organized screening program to reduce CRC incidence and mortality is currently implemented in each country. In the present review, we summarize the current status and future perspectives of CRC screening of the general population in East Asian and South-East Asian countries. The fecal occult blood test is widely used for CRC screening in these countries, and its effectiveness in reducing CRC incidence and mortality has been demonstrated; however, the low participation rate in CRC screening programs is a problem to be solved in every country. Improvement in the public awareness of CRC and promotion of CRC screening by physicians will help to raise the participation rate and reduce the number of deaths caused by CRC. Regarding screening colonoscopy, several studies have recently demonstrated its effectiveness in reducing CRC incidence and mortality. However, at present, CRC screening colonoscopy is not adopted as a primary population-based screening tool because of staffing constraints in relation to large population sizes, increased medical costs, and potential adverse events (e.g., perforation and drug-induced anaphylaxis). Further study is required to consider colonoscopy as CRC screening that is established in Western countries. PMID- 26595884 TI - The area under the curve of L-lactate in neonatal foals from birth to 14 days of age. AB - BACKGROUND: Prior studies have shown the prognostic utility of measuring L lactate in critically ill neonatal foals, both as single (at admission) and serial measurements. Greater prognostic sensitivity and specificity may be achieved by use of the area under the L-lactate versus time curve (LACArea ) over the first 24 hours of hospitalization, which captures both severity and duration of hyperlactatemia. Prior to application of this concept in sick equine neonates, a reference interval for LACArea should be determined. METHODS: The concentration of lactate [LAC] was measured in blood obtained via direct jugular venipuncture from clinically normal foals on Days 1 (birth-24 h of age), 3, 7, and 14 following birth at 6-hour intervals for each 24-hour period. LACArea was calculated using the trapezoidal method. Differences in LACArea by Day were determined by MANOVA with a priori Bonferroni correction, P <= 0.05. RESULTS: LACArea differed by Day (P = 0.001), being largest on Day 1, followed by Day 3. Days 7 and 14 were smallest and not different from each other. CONCLUSION: LACArea decreases substantially and predictably over the first week of life in normal neonatal foals. Knowing how LACArea normally changes over the first 2 weeks of life will aid in future study of LACArea as it applies to sick neonatal foals, allowing for consideration of maturational changes potentially unrelated to disease. PMID- 26595885 TI - Isolated Pancreatic Islet Transplantation: A Coming of Age. PMID- 26595886 TI - Group 3 innate lymphoid cells continuously require the transcription factor GATA 3 after commitment. AB - The transcription factor GATA-3 is indispensable for the development of all innate lymphoid cells (ILCs) that express the interleukin 7 receptor alpha-chain (IL-7Ralpha). However, the function of low GATA-3 expression in committed group 3 ILCs (ILC3 cells) has not been identified. We found that GATA-3 regulated the homeostasis of ILC3 cells by controlling IL-7Ralpha expression. In addition, GATA 3 served a critical function in the development of the NKp46(+) ILC3 subset by regulating the balance between the transcription factors T-bet and RORgammat. Among NKp46(+) ILC3 cells, although GATA-3 positively regulated genes specific to the NKp46(+) ILC3 subset, it negatively regulated genes specific to lymphoid tissue-inducer (LTi) or LTi-like ILC3 cells. Furthermore, GATA-3 was required for IL-22 production in both ILC3 subsets. Thus, despite its low expression, GATA-3 was critical for the homeostasis, development and function of ILC3 subsets. PMID- 26595888 TI - Interferon and IL-27 antagonize the function of group 2 innate lymphoid cells and type 2 innate immune responses. AB - Group 2 innate lymphoid cells (ILC2 cells) are type 2 cytokine-producing cells of the innate immune system with important roles in helminth infection and allergic inflammation. Here we found that tissue-resident ILC2 cells proliferated in situ without migrating during inflammatory responses. Both type I and type II interferons and interleukin 27 (IL-27) suppressed ILC2 function in a manner dependent on the transcription factor STAT1. ILC2-mediated lung inflammation was enhanced in the absence of the interferon-gamma (IFN-gamma) receptor on ILC2 cells in vivo. IFN-gamma effectively suppressed the function of tissue-resident ILC2 cells but not that of inflammatory ILC2 cells, and IL-27 suppressed tissue resident ILC2 cells but not tissue-resident TH2 cells during lung inflammation induced by Alternaria alternata. Our results demonstrate that suppression mediated by interferon and IL-27 is a negative feedback mechanism for ILC2 function in vivo. PMID- 26595887 TI - Type I interferon restricts type 2 immunopathology through the regulation of group 2 innate lymphoid cells. AB - Viral respiratory tract infections are the main causative agents of the onset of infection-induced asthma and asthma exacerbations that remain mechanistically unexplained. Here we found that deficiency in signaling via type I interferon receptor led to deregulated activation of group 2 innate lymphoid cells (ILC2 cells) and infection-associated type 2 immunopathology. Type I interferons directly and negatively regulated mouse and human ILC2 cells in a manner dependent on the transcriptional activator ISGF3 that led to altered cytokine production, cell proliferation and increased cell death. In addition, interferon gamma (IFN-gamma) and interleukin 27 (IL-27) altered ILC2 function dependent on the transcription factor STAT1. These results demonstrate that type I and type II interferons, together with IL-27, regulate ILC2 cells to restrict type 2 immunopathology. PMID- 26595889 TI - Complementarity and redundancy of IL-22-producing innate lymphoid cells. AB - Intestinal T cells and group 3 innate lymphoid cells (ILC3 cells) control the composition of the microbiota and gut immune responses. Within the gut, ILC3 subsets coexist that either express or lack the natural cytoxicity receptor (NCR) NKp46. We identified here the transcriptional signature associated with the transcription factor T-bet-dependent differentiation of NCR(-) ILC3 cells into NCR(+) ILC3 cells. Contrary to the prevailing view, we found by conditional deletion of the key ILC3 genes Stat3, Il22, Tbx21 and Mcl1 that NCR(+) ILC3 cells were redundant for the control of mouse colonic infection with Citrobacter rodentium in the presence of T cells. However, NCR(+) ILC3 cells were essential for cecal homeostasis. Our data show that interplay between intestinal ILC3 cells and adaptive lymphocytes results in robust complementary failsafe mechanisms that ensure gut homeostasis. PMID- 26595891 TI - High-fat Diet-induced Intestinal Hyperpermeability is Associated with Increased Bile Acids in the Large Intestine of Mice. AB - Metabolic syndrome is characterized by low-grade chronic systemic inflammation, which is associated with intestinal hyperpermeability. This study examined the effects of 3 high-fat diets (HFDs) composed of different fat sources (soybean oil and lard) on the intestinal permeability, tight junction (TJ) protein expression, and cecal bile acid (BA) concentrations in mice, and then analyzed their interrelations. C57/BL6 mice were fed the control diet, HFD (soybean oil), HFD (lard), and HFD (mix; containing equal concentrations of soybean oil and lard) for 8 wk. Glucose tolerance, intestinal permeability, TJ protein expression, and cecal BA concentration were evaluated. Feeding with the 3 HDFs similarly increased body weight, liver weight, and fat pad weight, and induced glucose intolerance and intestinal hyperpermeability. The expression of TJ proteins, zonula occludens-2 and junctional adhesion molecule-A, were lower in the colons of the 3 HFD groups than in the control group (P < 0.05), and these changes appeared to be related to intestinal hyperpermeability. Feeding with HFDs increased total secondary BA (SBA) and total BA concentrations along with increases in some individual BAs in the cecum. Significant positive correlations between intestinal permeability and the concentrations of most SBAs, such as deoxycholic acid and omega-muricholic acids, were detected (P < 0.05). These results suggest that the HFD-induced intestinal hyperpermeability is associated with increased BA secretion. The abundance of SBAs in the large intestine may be responsible for the hyperpermeability. PMID- 26595892 TI - Structured palliative care program found to be helpful for caregivers of patients with lung cancer. PMID- 26595890 TI - An innate antiviral pathway acting before interferons at epithelial surfaces. AB - Mucosal surfaces are exposed to environmental substances and represent a major portal of entry for microorganisms. The innate immune system is responsible for early defense against infections and it is believed that the interferons (IFNs) constitute the first line of defense against viruses. Here we identify an innate antiviral pathway that works at epithelial surfaces before the IFNs. The pathway is activated independently of known innate sensors of viral infections through a mechanism dependent on viral O-linked glycans, which induce CXCR3 chemokines and stimulate antiviral activity in a manner dependent on neutrophils. This study therefore identifies a previously unknown layer of antiviral defense that exerts its action on epithelial surfaces before the classical IFN response is operative. PMID- 26595893 TI - 279(Val->Phe) Polymorphism of lipoprotein-associated phospholipase A(2) resulted in changes of folding kinetics and recognition to substrate. AB - INTRODUCTION: PLA2G7 encodes Lp-PLA2 having role in the formation of atherosclerotic plaques by catalyzing its substrate, phosphatydilcholine (PC), to be pro-inflammatory substances. The increased risk for coronary artery disease (CAD) in Asian population has been related with this enzyme. 279(Val->Phe) variant was reported to have a protective role against CAD due to, in part, secretion defect or loss of enzymatic function. Therefore, We study folding kinetics and enzyme-substrate interaction in 279(Val->Phe) by using clinical and computational biology approach. METHODS: Polymorphisms were detected by genotyping among 103 acute myocardial infarction patients and 37 controls. Folding Lp-PLA2 was simulated using GROMACS software by assessing helicity, hydrogen bond formation and stability. The interactions of Lp-PLA2 and its substrate were simulated using Pyrx software followed by molecular dynamics simulation using YASARA software. RESULT: Polymorphism of 279(Val->Phe) was represented by the change of nucleotide from G to T of 994th PLA2G7 gene. The folding simulation suggested a decreased percentage of alpha-helix, hydrogen bond formation, hydrogen bond stability and hydrophobicity in 279(Val->Phe). The PC did not interact with active site of 279(Val->Phe) as paradoxically observed in 279 valine. 279(Val->Phe) polymorphism is likely to cause unstable binding to the substrate and decrease the enzymatic activity as observed in molecular dynamics simulations. The results of our computational biology study supported a protected effect of 279(Val->Phe) Polymorphism showed by the odd ratio for MI of 0.22 (CI 95% 0.035-1.37) in this study. CONCLUSION: 279(Val->Phe) Polymorphism of Lp-PLA2 may lead to decrease the enzymatic activity via changes of folding kinetics and recognition to its substrate. PMID- 26595894 TI - Comparing the effectiveness of individualistic, altruistic, and competitive incentives in motivating completion of mental exercises. AB - This study examines the impact of individually oriented, purely altruistic, and a hybrid of competitive and cooperative monetary reward incentives on older adults' completion of cognitive exercises and cognitive function. We find that all three incentive structures approximately double the number of exercises completed during the six-week active experimental period relative to a no incentive control condition. However, the altruistic and cooperative/competitive incentives led to different patterns of participation, with significantly higher inter-partner correlations in utilization of the software, as well as greater persistence once incentives were removed. Provision of all incentives significantly improved performance on the incentivized exercises. However, results of an independent cognitive testing battery suggest no generalizable gains in cognitive function resulted from the training. PMID- 26595895 TI - Craniotomy for cerebellar hemangioblastoma excision in a patient with von Hippel Lindau disease complicated by uncontrolled hypertension due to pheochromocytoma. AB - INTRODUCTION: This report describes a patient with Von Hippel-Lindau (VHL) syndrome and uncontrolled hypertension due to pheochromocytoma who underwent craniotomy for the excision of a cerebellar hemangioblastoma combined with a laparoscopic adrenalectomy. CASE REPORT: A 31-year-old man presented with severe headache. MRI showed areas of abnormal enhancement in the left cerebellum that were determined to be hemangioblastoma with mass effect and obstructive hydrocephalus. His blood pressure rose abruptly and could not be controlled. CT of the abdomen revealed bilateral suprarenal tumors, and the patient was diagnosed as having VHL syndrome.On the third day, he presented with increasing headache, a decreased level of consciousness, and hemiparesis. We were not able to perform an craniotomy because abdominal compression in the prone or sitting position resulted in severe hypertension. We performed ventricular drainage to control his ICP. On the fifth day, we first performed a bilateral laparoscopic adrenalectomy to control ICP and then moved the patient to the prone position before performing a craniotomy to remove the left cerebellar hemangioblastoma. DISCU: ssion & conclusion In patients with pheochromocytoma, the effects of catecholamine oversecretion can cause significant perioperative morbidity and mortality, but these can be prevented by appropriate preoperative medical management. When carrying out an excision of cerebellar hemangioblastomas in patients with intracranial hypertension complicated by abnormal hypertension due to pheochromocytoma whose blood pressure is not sufficiently controlled, tumor resection of the pheochromocytoma prior to cerebellar hemangioblastoma excision in the same surgery may prevent increased ICP and reduce perioperative risk. PMID- 26595896 TI - Bilateral avascular necrosis of the femoral head due to the use of heroin: A case report. AB - INTRODUCTION: Femoral head avascular necrosis is caused by disruption of the blood supply of the femoral head, which finally results in hip dysfunction. Non traumatic osteonecrosis may related with corticosteroid use, alcohol abuse, SLE, hemoglobinopathies or exposure to cytotoxic agents. But avascular necrosis of the femoral head (ANFH) due to heroin use is a rare condition. We report a patient with bilateral ANFH due to heroin use treated by simultaneous bilateral hip arthroplasty. PRESENTATION OF CASE: 37 year-old male patient presented with bilateral hip pain that had been occurring for four years. The patient had no history of smoking, excessive drinking, using corticosteroid and the other drugs or trauma but used heroin for 10 years. In clinic and radiologic examination indicated advanced degenerative changes on both hip due to femoral head avascular necrosis. The patient was treated with simultaneous bilateral total hip arthroplasty. After 6 months postoperatively the active hip range of motion was painless. DISCUSSION: Avascular femoral head necrosis caused by the using of heroin is rare. Ultimately, osteonecrosis of the femoral head occurs through one final common pathway, which is decreased blood flow to the femoral head that leads bone ischemia and death. But it is still unknown that heroin's systemic effects. Intravenous drug use more as a serious problem for today. There is a need for comprehensive studies to demonstrate effects of heroin on bone and vascularity metabolism. CONCLUSION: Heroin use will be important problem for population. That's why is crucial to understand the effect of heroin. PMID- 26595897 TI - Surgical management of complicated intra-mural duodenal hematoma: A case-report and review of literature. AB - INTRODUCTION: Intramural duodenal hematoma (IDH) is a rare pathological entity that occurs as a complication of trauma, pancreatitis, peptic ulcer disease or endoscopic biopsy procedures. In this report, we present a case of IDH related to a duodenal diverticulum that was complicated by intra-abdominal bleeding and peritonitis. PRESENTATION OF CASE: We report a 31-year old male who presented with pancreatitis that was complicated with IDH, as diagnosed using endoscopy and CT scan of the abdomen. The condition was related to a duodenal diverticulum as appears on imaging. The patient was treated conservatively over a course of 1 week when he started to have intra-abdominal bleeding and developed peritonitis. The patient was successfully treated with laparotomy, drainage of intra-abdominal abscess, evacuation of IDH and repair of duodenal perforation. We discuss this case in the context of the current indications of surgery in cases of IDH. CONCLUSION: Despite shift towards conservative management of IDH cases over last few decades, these cases should be handled carefully as they might develop life threatening complications. PMID- 26595898 TI - The biofilm property and its correlationship with high-molecular-weight polyacrylamide degradation in a water injection pipeline of Daqing oilfield. AB - Biofilms increase dragging force for liquid transportation, cause power consumption, and result in equipment corrosion in polymer-flooding oilfields. To reveal the responsible microorganisms for biofilm formation and stability of high molecular-weight polyacrylamide (PAM), a biofilm, developed on the sieve of a piston plunger pump in a water transport and injection pipeline with partial hydrolyzed polyacrylamide (HPAM) in Daqing Oilfield, was collected and analyzed by molecular microbiology, chemical and physical methods. Diverse bacterial groups (11 families) were detected in the biofilm, including Pseudomonadaceae, Rhodocyclaceae, Desulfobulbaceae, Alcaligenaceae, Comamonadaceae, Oxalobacteraceae, Bacteriovoracaceae, Campylobacteraceae, Flavobacteriaceae, Clostridiales Incertae Sedis XIII and Moraxellaceae. Three archaeal orders of methanogens including Methanomicrobiales, Methanosarcinales and Thermoplasmatales were also detected separately. HPAM was degraded into lower molecular weight polymers and organic fragments with its amide groups hydrolyzed into carboxylic groups by the microorganisms. The microenvironment of the biofilm contained diverse bacterial and archaeal communities, correlating with the extracellular polymeric substance (EPS) and HPAM biodegradation. The results are helpful to provide information for biofilm control in oil fields. PMID- 26595899 TI - Utilization of reduced graphene oxide/cadmium sulfide-modified carbon cloth for visible-light-prompt photoelectrochemical sensor for copper (II) ions. AB - A newly developed CdS/rGO/CC electrode was prepared based on a flexible carbon cloth (CC) substrate with cadmium sulfide (CdS) nanoparticles and reduced graphene oxide (rGO). The CdS was synthesized using an aerosol-assisted chemical vapor deposition (AACVD) method, and the graphene oxide was thermally reduced on the modified electrode surface. The existence of rGO in the CdS-modified electrode increased the photocurrent intensity of the CdS/rGO/CC-modified electrode by three orders of magnitude, compared to that of the CdS/ITO electrode and two orders of magnitude higher than the CdS/CC electrode. A new visible-light prompt photoelectrochemical sensor was developed based on the competitive binding reaction of Cu(2+) and CdS on the electrode surface. The results showed that the effect of the Cu(2+) on the photocurrent response was concentration-dependent over the linear ranges of 0.1-1.0 MUM and 1.0-40.0 MUM with a detection limit of 0.05 MUM. The results of a selectivity test showed that this modified electrode has a high response toward Cu(2+) compared to other heavy metal ions. The proposed CdS/rGO/CC electrode provided a significantly high potential current compared to other reported values, and could be a practical tool for the fast, sensitive, and selective determination of Cu(2+). PMID- 26595900 TI - A new membrane electro-deposition based process for tin recovery from waste printed circuit boards. AB - The current research investigated a process combining leaching, purification and membrane electrodeposition to recover tin from the metal components of WPCBs. Experimental results showed that with a solid liquid ratio of 1:4, applying 1.1 times of stoichiometric SnCl4 dosage and HCl concentration of 3.5-4.0 mol/L at a temperature of 60-90 degrees C, 99% of tin can be leached from the metal components of WPCBs. The suitable purification conditions were obtained in the temperature range of 30-45 degrees C with the addition of 1.3-1.4 times of the stoichiometric quantity of tin metal and stirring for a period of 1-2h; followed by adding 1.3 times of the stoichiometric quantity of Na2S for sulfide precipitation about 20-30 min at room temperature. The purified solution was subjected to membrane electrowinning for tin electrodeposition. Under the condition of catholyte Sn(2+) 60 g/L, HCl 3 mol/L and NaCl 20 g/L, current density 200 A/m(2) and temperature 35 degrees C, a compact and smooth cathode tin layer can be obtained. The obtained cathode tin purity exceeded 99% and the electric consumption was less than 1200 kW h/t. The resultant SnCl4 solution generated in anode compartment can be reused as leaching agent for leaching tin again. PMID- 26595901 TI - Wider Impacts: general discussion. PMID- 26595903 TI - Visit-to-visit variability in LDL- and HDL-cholesterol is associated with adverse events after ST-segment elevation myocardial infarction: A 5-year follow-up study. AB - INTRODUCTION: We evaluated the relationship between visit-to-visit low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) variability and 5-year clinical outcomes in patients who presented with ST segment elevation myocardial infarction (STEMI). METHODS: 130 patients presenting with STEMI and surviving to discharge were analyzed. Visit-to-visit LDL-C and HDL C variability was evaluated from 2 months after discharge on the basis of corrected variation independent of mean (cVIM, primary measure), coefficient of variation and standard deviation. Major adverse cardiac event (MACE) included death, myocardial infarction, stroke, unplanned revascularization, and heart failure admission. RESULTS: After an average of 62.4 +/- 30.5 months follow-up, 41 patients (31.5%) had experienced MACE. Compared with the non-MACE group, the MACE group had a higher visit-to-visit LDL-C variability (cVIM: 0.23 +/- 0.11 vs. 0.19 +/- 0.08; p = 0.049; coefficient of variation: 0.24 +/- 0.12 vs. 0.19 +/- 0.00; p = 0.019; standard deviation: 24.1 +/- 14.5 vs. 17.6 +/- 10.0; p = 0.006), mean follow-up LDL-C (p = 0.033) and a higher prevalence of diabetes mellitus (p = 0.012). After adjusting for mean follow-up cholesterol levels and diabetes mellitus, each 0.01 cVIM increase in LDL-C and HDL-C variability increased the risk of MACE by 3.4% (HR: 1.034; 95% CI: 1.004 to 1.065; p = 0.025) and 6.8% (HR: 1.068; 95% CI: 1.003 to 1.137; p = 0.04), respectively. Results derived from coefficient of variation and standard deviation as measures of cholesterol variability were similar. CONCLUSION: This is the first report to show an independent association between visit-to-visit LDL-C and HDL-C variability and long-term MACE in patients presenting with STEMI. PMID- 26595902 TI - Impact of heart rate variability on C-reactive protein concentrations in Japanese adult nonsmokers: The Toon Health Study. AB - OBJECTIVE: Lower heart rate variability (HRV) is associated with the inflammation that is linked with the progression of atherosclerosis. We examined this association, taking insulin sensitivity into consideration, as it is related to both HRV and inflammation. METHODS: Subjects were 1728 individuals ages 30-79 years who did not smoke between 2009 and 2012. C-reactive protein (CRP) concentrations and white blood cell (WBC) counts were assessed as markers of inflammation. The homeostasis model assessment index for insulin resistance (HOMA IR) and Gutt's insulin sensitivity index (ISI) were calculated based on fasting and 2h-post-load glucose and insulin concentrations in a 75-g oral glucose tolerance test. Pulse was recorded for 5 min, and time-domain HRV indices of standard deviation of NN intervals (SDNN) and root mean square of successive differences (RMSSD) were calculated. Power spectral analysis provided frequency domain measures of HRV: high frequency (HF) power, low frequency (LF) power and LF/HF. RESULTS: Sex and age-adjusted logistic models presented quartiles of SDNN, RMSSD, LF, and HF significantly associated with the highest quartile of CRP or WBC. After adjustment for body mass index and ISI, the associations were attenuated for WBC; however, even after further adjustment for several variables, SDNN, RMSSD, LF, and HF remained significantly associated with elevated CRP concentrations. When results were stratified by weight, the associations appeared more evident among non-overweight individuals. CONCLUSION: Lowered HRV, primarily due to parasympathetic dysfunction, was associated with elevated inflammation, independent of weight, insulin sensitivity, and other related factors. PMID- 26595904 TI - Feasibility Study of Respiratory Motion Modeling Based Correction for MRI-Guided Intracardiac Interventional Procedures. AB - GOAL: The purpose of this study is to improve the accuracy of interventional catheter guidance during intracardiac procedures. Specifically, the use of preprocedural magnetic resonance roadmap images for interventional guidance has limited anatomical accuracy due to intraprocedural respiratory motion of the heart. Therefore, we propose to build a novel respiratory motion model to compensate for this motion-induced error during magnetic resonance imaging (MRI) guided procedures. METHODS: We acquire 2-D real-time free-breathing images to characterize the respiratory motion, and build a smooth motion model via registration of 3-D prior roadmap images to the real-time images within a novel principal axes frame of reference. The model is subsequently used to correct the interventional catheter positions with respect to the anatomy of the heart. RESULTS: We demonstrate that the proposed modeling framework can lead to smoother motion models, and potentially lead to more accurate motion estimates. Specifically, MRI-guided intracardiac ablations were performed in six preclinical animal experiments. Then, from retrospective analysis, the proposed motion modeling technique showed the potential to achieve a 27% improvement in ablation targeting accuracy. CONCLUSION: The feasibility of a respiratory motion model based correction framework has been successfully demonstrated. SIGNIFICANCE: The improvement in ablation accuracy may lead to significant improvements in success rate and patient outcomes for MRI-guided intracardiac procedures. PMID- 26595905 TI - A Novel Analysis Technique for Transcutaneous Measurement of Glomerular Filtration Rate With Ultralow Dose Marker Concentrations. AB - OBJECTIVE: A novel high-precision approach [lifetime-decomposition measurement (LTDM)] for the assessment of the glomerular filtration rate (GFR) based on clearance measurements of exogenous filtration marker. METHODS: The time correlated single photon counting (TCSPC) acquisition in combination with a new decomposition method allows the separation of signal and background from transcutaneous measurements of GFR. RESULTS: The performance of LTDM is compared versus the commercially available NIC-kidney patch-based system for transcutaneous GFR measurement. Measurements are performed in awake Sprague Dawley (SD) rats. Using the standard concentration required for the NIC-kidney system [7-mg/100-g body weight (b.w.) FITC-Sinistrin] as reference, the mean difference (bias) of the elimination curves GFR between LTDM and NIC-kidney was 4.8%. On the same animal and same day, the capability of LTDM to measure GFR with a FITC-Sinistrin dose reduced by a factor of 200 (35-MUg/100-g b.w.) was tested as well. The mean differences (half lives with low dose using LTDM compared with those using first, the NIC-Kidney system and its standard concentration, and second, LTDM with the same concentration as for the NIC-Kidney system) were 3.4% and 4.5%, respectively. CONCLUSION: We demonstrate that with the LTDM strategy substantial reductions in marker concentrations are possible at the same level of accuracy. SIGNIFICANCE: LTDM aims to resolve the issue of the currently necessary large doses of fluorescence tracer required for transcutaneous GFR measurement. Due to substantially less influences from autofluorescence and artifacts, the proposed method outperforms other existing techniques for accurate percutaneous organ function measurement. PMID- 26595906 TI - A Bioimpedance Analysis Platform for Amputee Residual Limb Assessment. AB - OBJECTIVE: The objective of this research was to develop a bioimpedance platform for monitoring fluid volume in residual limbs of people with trans-tibial limb loss using prostheses. METHODS: A customized multifrequency current stimulus profile was sent to thin flat electrodes positioned on the thigh and distal residual limb. The applied current signal and sensed voltage signals from four pairs of electrodes located on the anterior and posterior surfaces were demodulated into resistive and reactive components. An established electrical model (Cole) and segmental limb geometry model were used to convert results to extracellular and intracellular fluid volumes. Bench tests and testing on amputee participants were conducted to optimize the stimulus profile and electrode design and layout. RESULTS: The proximal current injection electrode needed to be at least 25 cm from the proximal voltage sensing electrode. A thin layer of hydrogel needed to be present during testing to ensure good electrical coupling. Using a burst duration of 2.0 ms, intermission interval of 100 MUs, and sampling delay of 10 MUs at each of 24 frequencies except 5 kHz, which required a 200-MUs sampling delay, the system achieved a sampling rate of 19.7 Hz. CONCLUSION: The designed bioimpedance platform allowed system settings and electrode layouts and positions to be optimized for amputee limb fluid volume measurement. SIGNIFICANCE: The system will be useful toward identifying and ranking prosthetic design features and participant characteristics that impact residual limb fluid volume. PMID- 26595908 TI - Simultaneous Electromagnetic Tracking and Calibration for Dynamic Field Distortion Compensation. AB - Electromagnetic (EM) tracking systems are highly susceptible to field distortion. The interference can cause measurement errors up to a few centimeters in clinical environments, which limits the reliability of these systems. Unless corrected for, this measurement error imperils the success of clinical procedures. It is therefore fundamental to dynamically calibrate EM tracking systems and compensate for measurement error caused by field distorting objects commonly present in clinical environments. We propose to combine a motion model with observations of redundant EM sensors and compensate for field distortions in real time. We employ a simultaneous localization and mapping technique to accurately estimate the pose of the tracked instrument while creating the field distortion map. We conducted experiments with six degrees-of-freedom motions in the presence of field distorting objects in research and clinical environments. We applied our approach to improve the EM tracking accuracy and compared our results to a conventional sensor fusion technique. Using our approach, the maximum tracking error was reduced by 67% for position measurements and by 64% for orientation measurements. Currently, clinical applications of EM trackers are hampered by the adverse distortion effects. Our approach introduces a novel method for dynamic field distortion compensation, independent from preoperative calibrations or external tracking devices, and enables reliable EM navigation for potential applications. PMID- 26595909 TI - Factorized Graph Matching. AB - Graph matching (GM) is a fundamental problem in computer science, and it plays a central role to solve correspondence problems in computer vision. GM problems that incorporate pairwise constraints can be formulated as a quadratic assignment problem (QAP). Although widely used, solving the correspondence problem through GM has two main limitations: (1) the QAP is NP-hard and difficult to approximate; (2) GM algorithms do not incorporate geometric constraints between nodes that are natural in computer vision problems. To address aforementioned problems, this paper proposes factorized graph matching (FGM). FGM factorizes the large pairwise affinity matrix into smaller matrices that encode the local structure of each graph and the pairwise affinity between edges. Four are the benefits that follow from this factorization: (1) There is no need to compute the costly (in space and time) pairwise affinity matrix; (2) The factorization allows the use of a path following optimization algorithm, that leads to improved optimization strategies and matching performance; (3) Given the factorization, it becomes straight forward to incorporate geometric transformations (rigid and non-rigid) to the GM problem. (4) Using a matrix formulation for the GM problem and the factorization, it is easy to reveal commonalities and differences between different GM methods. The factorization also provides a clean connection with other matching algorithms such as iterative closest point; Experimental results on synthetic and real databases illustrate how FGM outperforms state-of-the-art algorithms for GM. The code is available at http://humansensing.cs.cmu.edu/fgm. PMID- 26595907 TI - Characterization of Electrophysiological Propagation by Multichannel Sensors. AB - OBJECTIVE: The propagation of electrophysiological activity measured by multichannel devices could have significant clinical implications. Gastric slow waves normally propagate along longitudinal paths that are evident in recordings of serosal potentials and transcutaneous magnetic fields. We employed a realistic model of gastric slow wave activity to simulate the transabdominal magnetogastrogram (MGG) recorded in a multichannel biomagnetometer and to determine characteristics of electrophysiological propagation from MGG measurements. METHODS: Using MGG simulations of slow wave sources in a realistic abdomen (both superficial and deep sources) and in a horizontally-layered volume conductor, we compared two analytic methods (second-order blind identification, SOBI and surface current density, SCD) that allow quantitative characterization of slow wave propagation. We also evaluated the performance of the methods with simulated experimental noise. The methods were also validated in an experimental animal model. RESULTS: Mean square errors in position estimates were within 2 cm of the correct position, and average propagation velocities within 2 mm/s of the actual velocities. SOBI propagation analysis outperformed the SCD method for dipoles in the superficial and horizontal layer models with and without additive noise. The SCD method gave better estimates for deep sources, but did not handle additive noise as well as SOBI. CONCLUSION: SOBI-MGG and SCD-MGG were used to quantify slow wave propagation in a realistic abdomen model of gastric electrical activity. SIGNIFICANCE: These methods could be generalized to any propagating electrophysiological activity detected by multichannel sensor arrays. PMID- 26595910 TI - Two-Dimensional Whitening Reconstruction for Enhancing Robustness of Principal Component Analysis. AB - Principal component analysis (PCA) is widely applied in various areas, one of the typical applications is in face. Many versions of PCA have been developed for face recognition. However, most of these approaches are sensitive to grossly corrupted entries in a 2D matrix representing a face image. In this paper, we try to reduce the influence of grosses like variations in lighting, facial expressions and occlusions to improve the robustness of PCA. In order to achieve this goal, we present a simple but effective unsupervised preprocessing method, two-dimensional whitening reconstruction (TWR), which includes two stages: 1) A whitening process on a 2D face image matrix rather than a concatenated 1D vector; 2) 2D face image matrix reconstruction. TWR reduces the pixel redundancy of the internal image, meanwhile maintains important intrinsic features. In this way, negative effects introduced by gross-like variations are greatly reduced. Furthermore, the face image with TWR preprocessing could be approximate to a Gaussian signal, on which PCA is more effective. Experiments on benchmark face databases demonstrate that the proposed method could significantly improve the robustness of PCA methods on classification and clustering, especially for the faces with severe illumination changes. PMID- 26595911 TI - Doubly Sparse Relevance Vector Machine for Continuous Facial Behavior Estimation. AB - Certain inner feelings and physiological states like pain are subjective states that cannot be directly measured, but can be estimated from spontaneous facial expressions. Since they are typically characterized by subtle movements of facial parts, analysis of the facial details is required. To this end, we formulate a new regression method for continuous estimation of the intensity of facial behavior interpretation, called Doubly Sparse Relevance Vector Machine (DSRVM). DSRVM enforces double sparsity by jointly selecting the most relevant training examples (a.k.a. relevance vectors) and the most important kernels associated with facial parts relevant for interpretation of observed facial expressions. This advances prior work on multi-kernel learning, where sparsity of relevant kernels is typically ignored. Empirical evaluation on challenging Shoulder Pain videos, and the benchmark DISFA and SEMAINE datasets demonstrate that DSRVM outperforms competing approaches with a multi-fold reduction of running times in training and testing. PMID- 26595912 TI - Carotid Artery Wall Segmentation in Multispectral MRI by Coupled Optimal Surface Graph Cuts. AB - We present a new three-dimensional coupled optimal surface graph-cut algorithm to segment the wall of the carotid artery bifurcation from Magnetic Resonance (MR) images. The method combines the search for both inner and outer borders into a single graph cut and uses cost functions that integrate information from multiple sequences. Our approach requires manual localization of only three seed points indicating the start and end points of the segmentation in the internal, external, and common carotid artery. We performed a quantitative validation using images of 57 carotid arteries. Dice overlap of 0.86 +/- 0.06 for the complete vessel and 0.89 +/- 0.05 for the lumen compared to manual annotation were obtained. Reproducibility tests were performed in 60 scans acquired with an interval of 15 +/- 9 days, showing good agreement between baseline and follow-up segmentations with intraclass correlations of 0.96 and 0.74 for the lumen and complete vessel volumes respectively. PMID- 26595914 TI - Detection and Tracking of Multiple Microbubbles in Ultrasound B-Mode Images. AB - The imaging of microvessels and the quantification of their blood flow is of particular interest in the characterization of tumor vasculature. The imaging resolution (50-200 MUm) of high-frequency ultrasound (US) (20-50 MHz) is not sufficient to image microvessels (~10 MUm) and Doppler sensitivity is not high enough to measure capillary blood flow (~1 mm/s). For imaging of blood flow in microvessels, our approach is to detect single microbubbles (MBs), track them over several frames, and to estimate their velocity. First, positions of MBs will be detected by separating B-mode frames in a moving foreground and a static background. For the crucial task of association of these positions to tracks, we implemented a modified Markov chain Monte Carlo data association (MCMCDA) algorithm, which can handle a high number of MBs. False alarms, the detection, initiation, and termination of MBs tracks are incorporated in the underlying model. To test the performance of algorithms, a US imaging simulation of a vessel tree with flowing MBs was set up (resolution 148 MUm). The trajectories and flow velocity in the vessels with a lateral distance of 100 MUm were reconstructed with super-resolution. In a phantom experiment, a suspension of MBs was pumped through a tube (diameter 0.4 mm) at speeds of 2.2, 4.2, 6.3, and 10.5 mm/s and was imaged with a Vevo2100 system (Visualsonics). Estimated mean speeds of the MBs were 2.1, 4.7, 7, and 10.5 mm/s. To demonstrate the applicability for in vivo measurements, a tumor xenograft-bearing mouse was imaged by this approach. The tumor vasculature was visualized with higher resolution than in a maximum intensity persistence image and the velocity values were in the expected range 0 1 mm/s. PMID- 26595913 TI - Development of Real-Time Magnetic Resonance Imaging of Mouse Hearts at 9.4 Tesla- Simulations and First Application. AB - A novel method for real-time magnetic resonance imaging for the assessment of cardiac function in mice at 9.4 T is proposed. The technique combines a highly undersampled radial gradient echo acquisition with an image reconstruction utilizing both parallel imaging and compressed sensing. Simulations on an in silico phantom were performed to determine the achievable acceleration factor and to optimize regularization parameters. Several parameters characterizing the quality of the reconstructed images (such as spatial and temporal image sharpness or compartment areas) were calculated for this purpose. Subsequently, double gated segmented cine data as well as non-gated undersampled real-time data using only six projections per timeframe (temporal resolution ~ 10 ms) were acquired in a mid-ventricular slice of four normal mouse hearts in vivo. The highly accelerated data sets were then subjected to the introduced reconstruction technique and results were validated against the fully sampled references. Functional parameters obtained from real-time and fully sampled data agreed well with a comparable accuracy for left-ventricular volumes and a slightly larger scatter for mass. This study introduces and validates a real-time cine-MRI technique, which significantly reduces scan time in preclinical cardiac functional imaging and has the potential to investigate mouse models with abnormal heart rhythm. PMID- 26595915 TI - Bismuth Titanate Fabricated by Spray-on Deposition and Microwave Sintering For High-Temperature Ultrasonic Transducers. AB - Thick films of ferroelectric bismuth titanate (Bi4Ti3O12) have been fabricated by spray-on deposition in conjunction with microwave sintering for use as high temperature ultrasonic transducers. The elastic modulus, density, permittivity, and conductivity of the films were characterized. Electro-mechanical properties of the films were estimated with a commercial d33 meter which gave 16 pC/N. This value is higher than typically reported for bulk bismuth titanate; however, these films withstand higher field strengths during poling which is correlated with higher d33 values. Films were capable of operating at 650 degrees C for roughly 5 min before depoling and can operate at 600 degrees C for at least 7 days. PMID- 26595916 TI - Code-Phase Clock Bias and Frequency Offset in PPP Clock Solutions. AB - Precise point positioning (PPP) is a zero-difference single-station technique that has proved to be very effective for time and frequency transfer, enabling the comparison of atomic clocks with a precision of a hundred picoseconds and a one-day stability below the 1e-15 level. It was, however, noted that for some receivers, a frequency difference is observed between the clock solution based on the code measurements and the clock solution based on the carrier-phase measurements. These observations reveal some inconsistency either between the code and carrier phases measured by the receiver or between the data analysis strategy of codes and carrier phases. One explanation for this discrepancy is the time offset that can exist for some receivers between the code and the carrier phase latching. This paper explains how a code-phase bias in the receiver hardware can induce a frequency difference between the code and the carrier-phase clock solutions. The impact on PPP is then quantified. Finally, the possibility to determine this code-phase bias in the PPP modeling is investigated, and the first results are shown to be inappropriate due to the high level of code noise. PMID- 26595917 TI - Fast and Scalable Computation of the Forward and Inverse Discrete Periodic Radon Transform. AB - The discrete periodic radon transform (DPRT) has extensively been used in applications that involve image reconstructions from projections. Beyond classic applications, the DPRT can also be used to compute fast convolutions that avoids the use of floating-point arithmetic associated with the use of the fast Fourier transform. Unfortunately, the use of the DPRT has been limited by the need to compute a large number of additions and the need for a large number of memory accesses. This paper introduces a fast and scalable approach for computing the forward and inverse DPRT that is based on the use of: a parallel array of fixed point adder trees; circular shift registers to remove the need for accessing external memory components when selecting the input data for the adder trees; an image block-based approach to DPRT computation that can fit the proposed architecture to available resources; and fast transpositions that are computed in one or a few clock cycles that do not depend on the size of the input image. As a result, for an N * N image (N prime), the proposed approach can compute up to N(2) additions per clock cycle. Compared with the previous approaches, the scalable approach provides the fastest known implementations for different amounts of computational resources. For example, for a 251*251 image, for approximately 25% fewer flip-flops than required for a systolic implementation, we have that the scalable DPRT is computed 36 times faster. For the fastest case, we introduce optimized just 2N + ?log(2) N? + 1 and 2N + 3 ?log(2) N? + B + 2 cycles, architectures that can compute the DPRT and its inverse in respectively, where B is the number of bits used to represent each input pixel. On the other hand, the scalable DPRT approach requires more 1-b additions than for the systolic implementation and provides a tradeoff between speed and additional 1-b additions. All of the proposed DPRT architectures were implemented in VHSIC Hardware Description Language (VHDL) and validated using an Field-Programmable Gate Array (FPGA) implementation. PMID- 26595918 TI - 2D Orthogonal Locality Preserving Projection for Image Denoising. AB - Sparse representations using transform-domain techniques are widely used for better interpretation of the raw data. Orthogonal locality preserving projection (OLPP) is a linear technique that tries to preserve local structure of data in the transform domain as well. Vectorized nature of OLPP requires high-dimensional data to be converted to vector format, hence may lose spatial neighborhood information of raw data. On the other hand, processing 2D data directly, not only preserves spatial information, but also improves the computational efficiency considerably. The 2D OLPP is expected to learn the transformation from 2D data itself. This paper derives mathematical foundation for 2D OLPP. The proposed technique is used for image denoising task. Recent state-of-the-art approaches for image denoising work on two major hypotheses, i.e., non-local self-similarity and sparse linear approximations of the data. Locality preserving nature of the proposed approach automatically takes care of self-similarity present in the image while inferring sparse basis. A global basis is adequate for the entire image. The proposed approach outperforms several state-of-the-art image denoising approaches for gray-scale, color, and texture images. PMID- 26595919 TI - Robust Face Sketch Style Synthesis. AB - Heterogeneous image conversion is a critical issue in many computer vision tasks, among which example-based face sketch style synthesis provides a convenient way to make artistic effects for photos. However, existing face sketch style synthesis methods generate stylistic sketches depending on many photo-sketch pairs. This requirement limits the generalization ability of these methods to produce arbitrarily stylistic sketches. To handle such a drawback, we propose a robust face sketch style synthesis method, which can convert photos to arbitrarily stylistic sketches based on only one corresponding template sketch. In the proposed method, a sparse representation-based greedy search strategy is first applied to estimate an initial sketch. Then, multi-scale features and Euclidean distance are employed to select candidate image patches from the initial estimated sketch and the template sketch. In order to further refine the obtained candidate image patches, a multi-feature-based optimization model is introduced. Finally, by assembling the refined candidate image patches, the completed face sketch is obtained. To further enhance the quality of synthesized sketches, a cascaded regression strategy is adopted. Compared with the state-of the-art face sketch synthesis methods, experimental results on several commonly used face sketch databases and celebrity photos demonstrate the effectiveness of the proposed method. PMID- 26595920 TI - Constrained Metric Learning by Permutation Inducing Isometries. AB - The choice of metric critically affects the performance of classification and clustering algorithms. Metric learning algorithms attempt to improve performance, by learning a more appropriate metric. Unfortunately, most of the current algorithms learn a distance function which is not invariant to rigid transformations of images. Therefore, the distances between two images and their rigidly transformed pair may differ, leading to inconsistent classification or clustering results. We propose to constrain the learned metric to be invariant to the geometry preserving transformations of images that induce permutations in the feature space. The constraint that these transformations are isometries of the metric ensures consistent results and improves accuracy. Our second contribution is a dimension reduction technique that is consistent with the isometry constraints. Our third contribution is the formulation of the isometry constrained logistic discriminant metric learning (IC-LDML) algorithm, by incorporating the isometry constraints within the objective function of the LDML algorithm. The proposed algorithm is compared with the existing techniques on the publicly available labeled faces in the wild, viewpoint-invariant pedestrian recognition, and Toy Cars data sets. The IC-LDML algorithm has outperformed existing techniques for the tasks of face recognition, person identification, and object classification by a significant margin. PMID- 26595921 TI - Detecting Densely Distributed Graph Patterns for Fine-Grained Image Categorization. AB - Fine-grained image categorization is a challenging task aiming at distinguishing objects belonging to the same basic-level category, e.g., leaf or mushroom. It is a useful technique that can be applied for species recognition, face verification, and so on. Most of the existing methods either have difficulties to detect discriminative object components automatically, or suffer from the limited amount of training data in each sub-category. To solve these problems, this paper proposes a new fine-grained image categorization model. The key is a dense graph mining algorithm that hierarchically localizes discriminative object parts in each image. More specifically, to mimic the human hierarchical perception mechanism, a superpixel pyramid is generated for each image. Thereby, graphlets from each layer are constructed to seamlessly capture object components. Intuitively, graphlets representative to each super-/sub-category is densely distributed in their feature space. Thus, a dense graph mining algorithm is developed to discover graphlets representative to each super-/sub-category. Finally, the discovered graphlets from pairwise images are integrated into an image kernel for fine-grained recognition. Theoretically, the learned kernel can generalize several state-of-the-art image kernels. Experiments on nine image sets demonstrate the advantage of our method. Moreover, the discovered graphlets from each sub-category accurately capture those tiny discriminative object components, e.g., bird claws, heads, and bodies. PMID- 26595922 TI - Psychological Parameters for Crowd Simulation: From Audiences to Mobs. AB - In the social psychology literature, crowds are classified as audiences and mobs. Audiences are passive crowds, whereas mobs are active crowds with emotional, irrational and seemingly homogeneous behavior. In this study, we aim to create a system that enables the specification of different crowd types ranging from audiences to mobs. In order to achieve this goal we parametrize the common properties of mobs to create collective misbehavior. Because mobs are characterized by emotionality, we describe a framework that associates psychological components with individual agents comprising a crowd and yields emergent behaviors in the crowd as a whole. To explore the effectiveness of our framework we demonstrate two scenarios simulating the behavior of distinct mob types. PMID- 26595923 TI - Comparative Local Quality Assessment of 3D Medical Image Segmentations with Focus on Statistical Shape Model-Based Algorithms. AB - The quality of automatic 3D medical segmentation algorithms needs to be assessed on test datasets comprising several 3D images (i.e., instances of an organ). The experts need to compare the segmentation quality across the dataset in order to detect systematic segmentation problems. However, such comparative evaluation is not supported well by current methods. We present a novel system for assessing and comparing segmentation quality in a dataset with multiple 3D images. The data is analyzed and visualized in several views. We detect and show regions with systematic segmentation quality characteristics. For this purpose, we extended a hierarchical clustering algorithm with a connectivity criterion. We combine quality values across the dataset for determining regions with characteristic segmentation quality across instances. Using our system, the experts can also identify 3D segmentations with extraordinary quality characteristics. While we focus on algorithms based on statistical shape models, our approach can also be applied to cases, where landmark correspondences among instances can be established. We applied our approach to three real datasets: liver, cochlea and facial nerve. The segmentation experts were able to identify organ regions with systematic segmentation characteristics as well as to detect outlier instances. PMID- 26595924 TI - A Visual Attention Monitor Based on Steady-State Visual Evoked Potential. AB - Attention detection is important for many applications. Automatic determination of users' visual attention state is challenging because attention involves numerous complex and internal human cognitive functions. Behavioral observations, such as eye gaze or response to external stimuli, can provide clues for users' visual attention state; however, users' cognitive state cannot be easily known. Conventional electroencephalography-based methods detect attention by observing the dynamic changes in the frontal lobe of the brain, especially in the anterior cingulate cortex (ACC). However, that area in the brain is associated with many functions, some of which correlate with conscious experience but are not directly related to attention. In this paper, we design an attention monitoring system to detect whether the brain experiences a visual stimulus consciously. Our experiments verified the feasibility of our design, and the average classification rate ranged from 72% to 82%. PMID- 26595925 TI - Hand Rehabilitation Learning System With an Exoskeleton Robotic Glove. AB - This paper presents a hand rehabilitation learning system, the SAFE Glove, a device that can be utilized to enhance the rehabilitation of subjects with disabilities. This system is able to learn fingertip motion and force for grasping different objects and then record and analyze the common movements of hand function including grip and release patterns. The glove is then able to reproduce these movement patterns in playback fashion to assist a weakened hand to accomplish these movements, or to modulate the assistive level based on the user's or therapist's intent for the purpose of hand rehabilitation therapy. Preliminary data have been collected from healthy hands. To demonstrate the glove's ability to manipulate the hand, the glove has been fitted on a wooden hand and the grasping of various objects was performed. To further prove that hands can be safely driven by this haptic mechanism, force sensor readings placed between each finger and the mechanism are plotted. These experimental results demonstrate the potential of the proposed system in rehabilitation therapy. PMID- 26595926 TI - A Graphene and Aptamer Based Liquid Gated FET-Like Electrochemical Biosensor to Detect Adenosine Triphosphate. AB - Here we report successful demonstration of a FET-like electrochemical nano biosensor to accurately detect ultralow concentrations of adenosine triphosphate. As a 2D material, graphene is a promising candidate due to its large surface area, biocompatibility, and demonstrated surface binding chemistries and has been employed as the conducting channel. A short 20-base DNA aptamer is used as the sensing element to ensure that the interaction between the analyte and the aptamer occurs within the Debye length of the electrolyte (PBS). Significant increase in the drain current with progressive addition of ATP is observed whereas for control experiments, no distinct change in the drain current occurs. The sensor is found to be highly sensitive in the nanomolar (nM) to micromolar ( MUM) range with a high sensitivity of 2.55 MUA (mM) (-1), a detection limit as low as 10 pM, and it has potential application in medical and biological settings to detect low traces of ATP. This simplistic design strategy can be further extended to efficiently detect a broad range of other target analytes. PMID- 26595927 TI - A Hybrid Semi-Digital Transimpedance Amplifier With Noise Cancellation Technique for Nanopore-Based DNA Sequencing. AB - Over the past two decades, nanopores have been a promising technology for next generation deoxyribonucleic acid (DNA) sequencing. Here, we present a hybrid semi digital transimpedance amplifier (HSD-TIA) to sense the minute current signatures introduced by single-stranded DNA (ssDNA) translocating through a nanopore, while discharging the baseline current using a semi-digital feedback loop. The amplifier achieves fast settling by adaptively tuning a DC compensation current when a step input is detected. A noise cancellation technique reduces the total input-referred current noise caused by the parasitic input capacitance. Measurement results show the performance of the amplifier with 31.6 M Omega mid band gain, 950 kHz bandwidth, and 8.5 fA/ ?Hz input-referred current noise, a 2* noise reduction due to the noise cancellation technique. The settling response is demonstrated by observing the insertion of a protein nanopore in a lipid bilayer. Using the nanopore, the HSD-TIA was able to measure ssDNA translocation events. PMID- 26595928 TI - Learning to Perceive the World as Probabilistic or Deterministic via Interaction With Others: A Neuro-Robotics Experiment. AB - We suggest that different behavior generation schemes, such as sensory reflex behavior and intentional proactive behavior, can be developed by a newly proposed dynamic neural network model, named stochastic multiple timescale recurrent neural network (S-MTRNN). The model learns to predict subsequent sensory inputs, generating both their means and their uncertainty levels in terms of variance (or inverse precision) by utilizing its multiple timescale property. This model was employed in robotics learning experiments in which one robot controlled by the S MTRNN was required to interact with another robot under the condition of uncertainty about the other's behavior. The experimental results show that self organized and sensory reflex behavior-based on probabilistic prediction-emerges when learning proceeds without a precise specification of initial conditions. In contrast, intentional proactive behavior with deterministic predictions emerges when precise initial conditions are available. The results also showed that, in situations where unanticipated behavior of the other robot was perceived, the behavioral context was revised adequately by adaptation of the internal neural dynamics to respond to sensory inputs during sensory reflex behavior generation. On the other hand, during intentional proactive behavior generation, an error regression scheme by which the internal neural activity was modified in the direction of minimizing prediction errors was needed for adequately revising the behavioral context. These results indicate that two different ways of treating uncertainty about perceptual events in learning, namely, probabilistic modeling and deterministic modeling, contribute to the development of different dynamic neuronal structures governing the two types of behavior generation schemes. PMID- 26595929 TI - Brain Dynamics in Predicting Driving Fatigue Using a Recurrent Self-Evolving Fuzzy Neural Network. AB - This paper proposes a generalized prediction system called a recurrent self evolving fuzzy neural network (RSEFNN) that employs an on-line gradient descent learning rule to address the electroencephalography (EEG) regression problem in brain dynamics for driving fatigue. The cognitive states of drivers significantly affect driving safety; in particular, fatigue driving, or drowsy driving, endangers both the individual and the public. For this reason, the development of brain-computer interfaces (BCIs) that can identify drowsy driving states is a crucial and urgent topic of study. Many EEG-based BCIs have been developed as artificial auxiliary systems for use in various practical applications because of the benefits of measuring EEG signals. In the literature, the efficacy of EEG based BCIs in recognition tasks has been limited by low resolutions. The system proposed in this paper represents the first attempt to use the recurrent fuzzy neural network (RFNN) architecture to increase adaptability in realistic EEG applications to overcome this bottleneck. This paper further analyzes brain dynamics in a simulated car driving task in a virtual-reality environment. The proposed RSEFNN model is evaluated using the generalized cross-subject approach, and the results indicate that the RSEFNN is superior to competing models regardless of the use of recurrent or nonrecurrent structures. PMID- 26595930 TI - Dynamic Learning From Neural Control for Strict-Feedback Systems With Guaranteed Predefined Performance. AB - This paper focuses on dynamic learning from neural control for a class of nonlinear strict-feedback systems with predefined tracking performance attributes. To reduce the number of neural network (NN) approximators used and make the convergence of neural weights verified easily, state variables are introduced to transform the state-feedback control of the original strict feedback systems into the output-feedback control of the system in the normal form. Then, using the output error transformation based on performance functions, the constrained tracking control problem of the normal systems is transformed into the stabilization problem of an equivalent unconstrained one. By combining the backstepping method, a high-gain observer with radial basis function (RBF) NNs, a novel adaptive neural control (ANC) scheme is proposed to guarantee the predefined tracking error performance as well as the ultimate boundedness of all other closed-loop signals. In particular, only one NN is employed to approximate the lumped unknown system dynamics during the controller design. Under the satisfaction of the partial persistent excitation condition for RBF NNs, the proposed stable ANC scheme is shown to be capable of achieving knowledge acquisition, expression, and storage of unknown system dynamics. The stored knowledge is reused to develop a neural learning controller for improving the control performance of the closed-loop system. When the initial condition satisfies the predefined performance, the proposed neural learning control can still guarantee the predefined tracking performance. Simulation results on a third-order one-link robot are given to show the effectiveness of the proposed method. PMID- 26595931 TI - A Generalized Hopfield Network for Nonsmooth Constrained Convex Optimization: Lie Derivative Approach. AB - This paper proposes a generalized Hopfield network for solving general constrained convex optimization problems. First, the existence and the uniqueness of solutions to the generalized Hopfield network in the Filippov sense are proved. Then, the Lie derivative is introduced to analyze the stability of the network using a differential inclusion. The optimality of the solution to the nonsmooth constrained optimization problems is shown to be guaranteed by the enhanced Fritz John conditions. The convergence rate of the generalized Hopfield network can be estimated by the second-order derivative of the energy function. The effectiveness of the proposed network is evaluated on several typical nonsmooth optimization problems and used to solve the hierarchical and distributed model predictive control four-tank benchmark. PMID- 26595932 TI - Generalized Higher Order Orthogonal Iteration for Tensor Learning and Decomposition. AB - Low-rank tensor completion (LRTC) has successfully been applied to a wide range of real-world problems. Despite the broad, successful applications, existing LRTC methods may become very slow or even not applicable for large-scale problems. To address this issue, a novel core tensor trace-norm minimization (CTNM) method is proposed for simultaneous tensor learning and decomposition, and has a much lower computational complexity. In our solution, first, the equivalence relation of trace norm of a low-rank tensor and its core tensor is induced. Second, the trace norm of the core tensor is used to replace that of the whole tensor, which leads to two much smaller scale matrix TNM problems. Finally, an efficient alternating direction augmented Lagrangian method is developed to solve our problems. Our CTNM formulation needs only O((RN+NRI)log(?{IN})) observations to reliably recover an N th-order I*I*...*I tensor of n -rank (r,r,...,r) , compared with O(rIN-1) observations required by those tensor TNM methods ( I >> R >= r ). Extensive experimental results show that CTNM is usually more accurate than them, and is orders of magnitude faster. PMID- 26595933 TI - L1-Norm Low-Rank Matrix Decomposition by Neural Networks and Mollifiers. AB - The L1-norm cost function of the low-rank approximation of the matrix with missing entries is not smooth, and also cannot be transformed into a standard linear or quadratic programming problem, and thus, the optimization of this cost function is still not well solved. To tackle this problem, first, a mollifier is used to smooth the cost function. High closeness of the smoothed function to the original one can be obtained by tuning the parameters contained in the mollifier. Next, a recurrent neural network is proposed to optimize the mollified function, which will converge to a local minimum. In addition, to boost the speed of the system, the mollifying process is implemented by a filtering procedure. The influence of two mollifier parameters is theoretically analyzed and experimentally confirmed, showing that one of the parameters is critical to computational efficiency and accuracy, while the other not. A large number of experiments on synthetic data show that the proposed method is competitive to the state-of-the-art methods. In particular, the experiments on large matrices and a real application in the structure from motion indicate that the memory requirement of the proposed algorithm is mild, making it suitable for real applications that often involve large-scale matrix decomposition. PMID- 26595934 TI - Chair Rise Peak Power in Daily Life Measured With a Pendant Sensor Associates With Mobility, Limitation in Activities, and Frailty in Old People. AB - The aim of this study was to analyze the clinical relevance of sensor-based daily life chair rise performance measured in old people. A pendant-sensor was worn during standardized tests and in daily life to detect chair rise transfers and analyze transfer peak power. Linear correlations between mean, median, 25th, and 75th percentile transfer peak powers in daily life and mean peak power in standardized tests were evaluated with Pearson correlation ( r). Associations between transfer peak powers in different experiments and outcomes of a clinical mobility test [timed-up-and-go (TUG)], a test of limitation in activities [Groningen activity restriction scale (GARS)], and a frailty test [Groningen frailty indicator (GFI)] were evaluated with Spearman correlation (rho). Twenty five old people (70-85 years) participated in the study. The results showed that chair rise peak powers assessed based upon one-week of daily life activities significantly correlated with peak power measured in standardized tests (r: [0.66, 0.74], p < 0.01). Chair rise peak power in daily life significantly associated with TUG scores (rho: [-0.71, -0.58], ), GARS (rho: [-0.62, -0.48], ), and GFI (rho: [-0.52, -0.43], ). Chair rise peak powers in daily life had stronger associations with clinical measurements than standardized tests. In addition, chair rise peak powers measured in old people using assistive devices was significantly lower compared to those not using assistive devices. These results indicate usefulness of the pendant-sensor-based chair rise performance analysis in continuous monitoring and assessment of mobility, limitations in activities and frailty associated variables in old people's daily life. PMID- 26595935 TI - Distributed Adaptive Fuzzy Control for Nonlinear Multiagent Systems Via Sliding Mode Observers. AB - In this paper, the problem of distributed adaptive fuzzy control is investigated for high-order uncertain nonlinear multiagent systems on directed graph with a fixed topology. It is assumed that only the outputs of each follower and its neighbors are available in the design of its distributed controllers. Equivalent output injection sliding mode observers are proposed for each follower to estimate the states of itself and its neighbors, and an observer-based distributed adaptive controller is designed for each follower to guarantee that it asymptotically synchronizes to a leader with tracking errors being semi globally uniform ultimate bounded, in which fuzzy logic systems are utilized to approximate unknown functions. Based on algebraic graph theory and Lyapunov function approach, using Filippov-framework, the closed-loop system stability analysis is conducted. Finally, numerical simulations are provided to illustrate the effectiveness and potential of the developed design techniques. PMID- 26595936 TI - Exploring Representativeness and Informativeness for Active Learning. AB - How can we find a general way to choose the most suitable samples for training a classifier? Even with very limited prior information? Active learning, which can be regarded as an iterative optimization procedure, plays a key role to construct a refined training set to improve the classification performance in a variety of applications, such as text analysis, image recognition, social network modeling, etc. Although combining representativeness and informativeness of samples has been proven promising for active sampling, state-of-the-art methods perform well under certain data structures. Then can we find a way to fuse the two active sampling criteria without any assumption on data? This paper proposes a general active learning framework that effectively fuses the two criteria. Inspired by a two-sample discrepancy problem, triple measures are elaborately designed to guarantee that the query samples not only possess the representativeness of the unlabeled data but also reveal the diversity of the labeled data. Any appropriate similarity measure can be employed to construct the triple measures. Meanwhile, an uncertain measure is leveraged to generate the informativeness criterion, which can be carried out in different ways. Rooted in this framework, a practical active learning algorithm is proposed, which exploits a radial basis function together with the estimated probabilities to construct the triple measures and a modified best-versus-second-best strategy to construct the uncertain measure, respectively. Experimental results on benchmark datasets demonstrate that our algorithm consistently achieves superior performance over the state-of-the-art active learning algorithms. PMID- 26595937 TI - Effects of a DVD-Delivered Exercise Intervention on Maintenance of Physical Activity in Older Adults. AB - BACKGROUND: Previous research supports the efficacy of a 6-month DVD-delivered program for enhancing physical activity (PA) in older adults. In the current study, we examined the degree to which intervention-related increases in PA were maintained after a 6-month, no-contact follow-up. METHODS: Follow-up assessments of PA via accelerometry and the Godin Leisure-Time Exercise Questionnaire (GLTEQ) were collected in a sample of older adults (N = 238). Repeated measures analyses of variance were conducted to examine changes in PA over the course of the follow up period. RESULTS: For accelerometer measured PA, there was a significant time * treatment * age group interaction, F1,203 =11.319, P = .001, eta2 = .053, such that younger (<=70 years) intervention participants maintained high levels of PA across the follow-up period, while PA in older intervention and young control participants declined significantly. Rates of PA in older control participants remained low over the course of the follow-up period. Analyses of GLTEQ scores revealed similar, though less significant patterns. CONCLUSIONS: DVD-based exercise programs may be effective for maintaining PA in younger members of the older adult population; however, there remains a need to develop better strategies for promoting PA maintenance in older individuals when using home based designs. PMID- 26595938 TI - The Feasibility of Using Questionnaires and Accelerometers to Measure Physical Activity and Sedentary Behavior Among Inpatient Adults With Mental Illness. AB - BACKGROUND: The aim of this study was to assess the feasibility of using questionnaires and accelerometers to measure physical activity and sedentary behavior among inpatient adults with mental illness. METHODS: Participants completed a physical activity and sitting time questionnaire and wore an accelerometer for 7 consecutive days. Feasibility was assessed in terms of participant engagement, self-reported ease/ difficulty of completing study components, extreme self-report data values and adherence to accelerometer wear time criteria. Ease/difficulty ratings were examined by level of distress. RESULTS: 177 inpatients were invited to the study, 101 completed the questionnaires and 36 provided valid accelerometry data. Participants found it more difficult to complete sitting time and physical activity questionnaires than to wear the accelerometer during waking hours (z = 3.787, P < .001; z = 2.824, P = .005 respectively). No significant differences were found in ease/ difficulty ratings by level of distress for any of the study components. Extreme values for self-reported sitting time were identified in 27% of participants. CONCLUSION: Inpatient adults with mental illness can engage with self-report and objective methods of measuring physical activity and sedentary behavior. They were initially less willing to participate in objective measurement, which may however be more feasible than self-report measures. PMID- 26595939 TI - Rate of Physical Activity and Community Health: Evidence From U.S. Counties. AB - BACKGROUND: Although previous studies supported the health benefits of physical activity, these studies were limited to individual-level research designs. Building upon a social-ecological model, we examined the relationship between physical activity and community health-the health status of a defined group of people-while accounting for the potential endogeneity of physical activity to health. METHODS: We obtained U.S. county-level data from the 2012 Behavioral Risk Factor Surveillance System survey and the 2014 County Health Ranking Database. We first conducted an ordinary least squares (OLS) regression analysis to examine the relationship between the rate of physical activity and community health measured by the average perceived health score for each county. We then conducted a 2-stage least squares (2SLS) regression analysis to investigate this relationship after accounting for potential endogeneity. RESULTS: Results from the OLS analysis indicated that the rate of physical activity was positively associated with community health. Results from the 2SLS analysis confirmed that the physical activity rate remained positively associated with community health. CONCLUSIONS: In line with the social-ecological model, our findings provide the first evidence for the health benefits of county-level physical activity. Our results support extant research that has shown relationships between physical activity and individual-level, health-related outcomes. PMID- 26595940 TI - [Effects of Yili dark bee propolis on oral cariogenic biofilm in vitro]. AB - OBJECTIVE: To evaluate the effects of Yili dark bee propolis on the main cariogenic biofilm and mechanisms. METHODS: Susceptibilities to the ethanolic extract of propolis against Streptococcus mutans (S. mutans), Streptococcus sobrinus (S. sobrinus), Streptococcus sanguis (S. sanguis), Actinomyces viscosus (A. viscosus), and Actinomyces naeslundii (A. naeslundii) were analyzed by crystal violet stain method to determine the minimum biofilm eradication concentration (MBEC). The biofilm was initially cultivated for 24 h. Subsequently, the propolis groups with different concentration MBEC and initial pH 7.0 were cultured for 24 h. Moreover, the pH value was measured to evaluate the acid-producing ability of the tested plaque biofilm. The effects of propolis on the insoluble extracellular polysaccharide synthesis of S. mutans biofilm were evaluated by anthrone method. RESULTS: The MBEC of Yili propolis on S. mutans, S. sobrinus, S. sanguis, A. viscosus, and A. naeslundii were 6.25, 1.56, 3.13, 0.78, and 0.78 mg.mL-1, respectively. Propolis could decrease the DeltapH of the tested plaque biofilm, and the differences between the control and propolis groups were statistically significant (P<0.05). At MBEC, propolis could reduce the ability of S. mutans in synthesizing insoluble extracellular polysaccharides. CONCLUSION: Yili propolis demonstrate remarkable eradicative effects on the cariogenic plaque biofilm, showing inhibition of the synthesis of biofilm-produced acids and insoluble extracellular polysaccharides. PMID- 26595942 TI - Dental Devices; Reclassification of Electrical Salivary Stimulator System. Final order. AB - The Food and Drug Administration (FDA) is issuing a final order to reclassify the salivary stimulator system, a postamendments Class III device, into class II (special controls) and to rename the device the "electrical salivary stimulator system." The Agency is classifying the device into class II (special controls) in order to provide a reasonable assurance of safety and effectiveness of the device. PMID- 26595941 TI - Final Rules for Grandfathered Plans, Preexisting Condition Exclusions, Lifetime and Annual Limits, Rescissions, Dependent Coverage, Appeals, and Patient Protections Under the Affordable Care Act. Final rules. AB - This document contains final regulations regarding grandfathered health plans, preexisting condition exclusions, lifetime and annual dollar limits on benefits, rescissions, coverage of dependent children to age 26, internal claims and appeal and external review processes, and patient protections under the Affordable Care Act. It finalizes changes to the proposed and interim final rules based on comments and incorporates subregulatory guidance issued since publication of the proposed and interim final rules. PMID- 26595943 TI - Medical Devices; General Hospital and Personal Use Devices; Classification of the Ultraviolet Radiation Chamber Disinfection Device. Final order. AB - The Food and Drug Administration (FDA or the Agency) is classifying the ultraviolet (UV) radiation chamber disinfection device into class II (special controls). The special controls that will apply to the device are identified in this order and will be part of the codified language for the UV radiation chamber disinfection device classification. The Agency is classifying the device into class II (special controls) in order to provide a reasonable assurance of safety and effectiveness of the device. PMID- 26595944 TI - Medical Devices; Exemption From Premarket Notification; Class II Devices; Electric Positioning Chair. Final order. AB - The Food and Drug Administration (FDA or the Agency) is publishing an order granting a petition requesting exemption from premarket notification requirements for electric positioning chair devices. An electric positioning chair is a device with a motorized positioning control that is intended for medical purposes and that can be adjusted to various positions. These devices are used to provide stability for patients with athetosis (involuntary spasms) and to alter postural positions. This order exempts electric positioning chairs, class II devices, from premarket notification, subject to certain conditions for exemption. This exemption from premarket notification, subject to these conditions (and the limitations in the physical medicine devices limitations of exemptions from premarket notification section of the device regulations), is immediately in effect for electric positioning chairs. FDA is publishing this order in accordance with the exemption from class II premarket notification section of the Federal Food, Drug, and Cosmetic Act (the FD&C Act). PMID- 26595945 TI - Medical Devices; Gastroenterology-Urology Devices; Classification of the Prostate Lesion Documentation System. Final order. AB - The Food and Drug Administration (FDA) is classifying the prostate lesion documentation system into class II (special controls). The special controls that will apply to the device are identified in this order and will be part of the codified language for the prostate lesion documentation system classification. The Agency is classifying the device into class II (special controls) in order to provide a reasonable assurance of safety and effectiveness of the device. PMID- 26595946 TI - Response: Re: Magnesium Intake and Depression in Adults. PMID- 26595947 TI - Response: Re: The Use of Medical Scribes in Health Care Settings: A Systematic Review and Future Directions. PMID- 26595948 TI - Introduction to Vestibular Cognition Special Issue: Progress in Vestibular Cognition. PMID- 26595949 TI - Gravity in the Brain as a Reference for Space and Time Perception. AB - Moving and interacting with the environment require a reference for orientation and a scale for calibration in space and time. There is a wide variety of environmental clues and calibrated frames at different locales, but the reference of gravity is ubiquitous on Earth. The pull of gravity on static objects provides a plummet which, together with the horizontal plane, defines a three-dimensional Cartesian frame for visual images. On the other hand, the gravitational acceleration of falling objects can provide a time-stamp on events, because the motion duration of an object accelerated by gravity over a given path is fixed. Indeed, since ancient times, man has been using plumb bobs for spatial surveying, and water clocks or pendulum clocks for time keeping. Here we review behavioral evidence in favor of the hypothesis that the brain is endowed with mechanisms that exploit the presence of gravity to estimate the spatial orientation and the passage of time. Several visual and non-visual (vestibular, haptic, visceral) cues are merged to estimate the orientation of the visual vertical. However, the relative weight of each cue is not fixed, but depends on the specific task. Next, we show that an internal model of the effects of gravity is combined with multisensory signals to time the interception of falling objects, to time the passage through spatial landmarks during virtual navigation, to assess the duration of a gravitational motion, and to judge the naturalness of periodic motion under gravity. PMID- 26595950 TI - Contribution of Bodily and Gravitational Orientation Cues to Face and Letter Recognition. AB - Sensory information provided by the vestibular system is crucial in cognitive processes such as the ability to recognize objects. The orientation at which objects are most easily recognized--the perceptual upright (PU)--is influenced by body orientation with respect to gravity as detected from the somatosensory and vestibular systems. To date, the influence of these sensory cues on the PU has been measured using a letter recognition task. Here we assessed whether gravitational influences on letter recognition also extend to human face recognition. 13 right-handed observers were positioned in four body orientations (upright, left-side-down, right-side-down, supine) and visually discriminated ambiguous characters ('p'-from-'d'; 'i'-from-'!') and ambiguous faces used in popular visual illusions ('young woman'-from-'old woman'; 'grinning man'-from 'frowning man') in a forced-choice paradigm. The two transition points (e.g., 'p to-d' and 'd-to-p'; 'young woman-to-old woman' and 'old woman-to-young woman') were fit with a sigmoidal psychometric function and the average of these transitions was taken as the PU for each stimulus category. The results show that both faces and letters are more influenced by body orientation than gravity. However, faces are more optimally recognized when closer in alignment with body orientation than letters--which are more influenced by gravity. Our results indicate that the brain does not utilize a common representation of upright that governs recognition of all object categories. Distinct areas of ventro-temporal cortex that represent faces and letters may weight bodily and gravitational cues differently--possibly to facilitate the specific demands of face and letter recognition. PMID- 26595951 TI - Internal Models, Vestibular Cognition, and Mental Imagery: Conceptual Considerations. AB - Vestibular cognition has recently gained attention. Despite numerous experimental and clinical demonstrations, it is not yet clear what vestibular cognition really is. For future research in vestibular cognition, adopting a computational approach will make it easier to explore the underlying mechanisms. Indeed, most modeling approaches in vestibular science include a top-down or a priori component. We review recent Bayesian optimal observer models, and discuss in detail the conceptual value of prior assumptions, likelihood and posterior estimates for research in vestibular cognition. We then consider forward models in vestibular processing, which are required in order to distinguish between sensory input that is induced by active self-motion, and sensory input that is due to passive self-motion. We suggest that forward models are used not only in the service of estimating sensory states but they can also be drawn upon in an offline mode (e.g., spatial perspective transformations), in which interaction with sensory input is not desired. A computational approach to vestibular cognition will help to discover connections across studies, and it will provide a more coherent framework for investigating vestibular cognition. PMID- 26595952 TI - The Effects of Complete Vestibular Deafferentation on Spatial Memory and the Hippocampus in the Rat: The Dunedin Experience. AB - Our studies conducted over the last 14 years have demonstrated that a complete bilateral vestibular deafferentation (BVD) in rats results in spatial memory deficits in a variety of behavioural tasks, such as the radial arm maze, the foraging task and the spatial T maze, as well as deficits in other tasks such as the five-choice serial reaction time task (5-CSRT task) and object recognition memory task. These deficits persist long after the BVD, and are not simply attributable to ataxia, anxiety, hearing loss or hyperactivity. In tasks such as the foraging task, the spatial memory deficits are evident in darkness when vision is not required to perform the task. The deficits in the radial arm maze, the foraging task and the spatial T maze, in particular, suggest hippocampal dysfunction following BVD, and this is supported by the finding that both hippocampal place cells and theta rhythm are dysfunctional in BVD rats. Now that it is clear that the hippocampus is adversely affected by BVD, the next challenge is to determine what vestibular information is transmitted to it and how that information is used by the hippocampus and the other brain structures with which it interacts. PMID- 26595953 TI - Prediction in the Vestibular Control of Arm Movements. AB - The contribution of vestibular signals to motor control has been evidenced in postural, locomotor, and oculomotor studies. Here, we review studies showing that vestibular information also contributes to the control of arm movements during whole-body motion. The data reviewed suggest that vestibular information is used by the arm motor system to maintain the initial hand position or the planned hand trajectory unaltered during body motion. This requires integration of vestibular and cervical inputs to determine the trunk motion dynamics. These studies further suggest that the vestibular control of arm movement relies on rapid and efficient vestibulomotor transformations that cannot be considered automatic. We also reviewed evidence suggesting that the vestibular afferents can be used by the brain to predict and counteract body-rotation-induced torques (e.g., Coriolis) acting on the arm when reaching for a target while turning the trunk. PMID- 26595954 TI - The Components of Vestibular Cognition--Motion Versus Spatial Perception. AB - Vestibular cognition can be divided into two main functions--a primary vestibular sensation of self-motion and a derived sensation of spatial orientation. Although the vestibular system requires calibration from other senses for optimal functioning, both vestibular spatial and vestibular motion perception are typically employed when navigating without vision. A recent important finding is the cerebellar mediation of the uncoupling of reflex (i.e., the vestibular-ocular reflex) from vestibular motion perception (Perceptuo-Reflex Uncoupling). The brain regions that mediate vestibular motion and vestibular spatial perception is an area of on-going research activity. However, there is data to support the notion that vestibular motion perception is mediated by multiple brain regions. In contrast, vestibular spatial perception appears to be mediated by posterior brain areas although currently the exact locus is unclear. I will discuss the experimental evidence that support this functional dichotomy in vestibular cognition (i.e., motion processing vs. spatial orientation). Along the way I will highlight relevant practical technical tips in testing vestibular cognition. PMID- 26595955 TI - Making Sense of the Body: the Role of Vestibular Signals. AB - The role of the vestibular system in posture and eye movement control has been extensively described. By contrast, how vestibular signals contribute to bodily perceptions is a more recent research area in the field of cognitive neuroscience. In the present review article, I will summarize recent findings showing that vestibular signals play a crucial role in making sense of the body. First, data will be presented showing that vestibular signals contribute to bodily perceptions ranging from low-level bodily perceptions, such as touch, pain, and the processing of the body's metric properties, to higher level bodily perceptions, such as the sense of owning a body, the sense of being located within this body (embodiment), and the anchoring of the visuo-spatial perspective to this body. In the second part of the review article, I will show that vestibular information seems to be crucially involved in the visual perception of biological motion and in the visual perception of human body structure. Reciprocally, observing human bodies in motion influences vestibular self-motion perception, presumably due to sensorimotor resonance between the self and others. I will argue that recent advances in the mapping of the human vestibular cortex afford neuroscientific models of the vestibular contributions to human bodily self-consciousness. PMID- 26595956 TI - Vestibular-Somatosensory Interactions: A Mechanism in Search of a Function? AB - No unimodal vestibular cortex has been identified in the human brain. Rather, vestibular inputs are strongly integrated with signals from other sensory modalities, such as vision, touch and proprioception. This convergence could reflect an important mechanism for maintaining a perception of the body, including individual body parts, relative to the rest of the environment. Neuroimaging, electrophysiological and psychophysical studies showed evidence for multisensory interactions between vestibular and somatosensory signals. However, no convincing overall theoretical framework has been proposed for vestibular somatosensory interactions, and it remains unclear whether such percepts are by products of neural convergence, or a functional multimodal integration. Here we review the current literature on vestibular-multisensory interactions in order to develop a framework for understanding the functions of such multimodal interaction. We propose that the target of vestibular-somatosensory interactions is a form of self-representation. PMID- 26595957 TI - Disrupting Vestibular Activity Disrupts Body Ownership. AB - People are more sensitive at detecting asynchrony between a self-generated movement and visual feedback concerning that movement when the movement is viewed from a first-person perspective. We call this the 'self-advantage' and interpret it as an objective measure of self. Here we ask if disruption of the vestibular system in healthy individuals affects the self-advantage. Participants performed finger movements while viewing their hand in a first-person ('self') or third person ('other') perspective and indicated which of two periods (one with minimum delay and the other with an added delay of 33-264 ms) was delayed. Their sensitivity to the delay was calculated from the psychometric functions obtained. During the testing, disruptive galvanic vestibular stimulation (GVS) was applied in five-minute blocks interleaved with five minutes of no stimulation for a total of 40 min. We confirmed the self-advantage under no stimulation (31 ms). In the presence of disruptive GVS this advantage disappeared and there was no longer a difference in performance between perspectives. The threshold delay for the 'other' perspective was not affected by the GVS. These results suggest that an intact vestibular signal is required to distinguish 'self' from 'other' and to maintain a sense of body ownership. PMID- 26595958 TI - Beyond the Non-Specific Attentional Effect of Caloric Vestibular Stimulation: Evidence from Healthy Subjects and Patients. AB - Caloric vestibular stimulation (CVS) is a simple physiological manipulation that has been used for a long time in different clinical fields due to its rapid and relevant effects on behaviour. One of the most debated issues in this research field concerns the degree of specificity of such stimulation, namely whether the effects of CVS can be, and to what extent are, independent of the mere influence of non-specific factors such as general arousal, ocular movements or attentional shift towards the stimulated side. The hypothesis that CVS might cause a shift of attention towards the side of the stimulation has been largely supported; moreover, a large amount of evidence is available nowadays to corroborate the specific effect of CVS, providing behavioural and neurophysiological data in both patients and normal subjects. These data converge in indicating that the effects of CVS can be independent of eye deviation and general arousal, can modulate different symptoms in different directions, and do not merely depend on a general shift of attention. The present article is divided into three main sections. In the first section, we describe classical studies that investigate the effects of CVS on neglect and related symptoms. In the second and third parts, we provide an overview of the modulatory effects of CVS on somatosensory processes and body representation in both brain-damaged patients and healthy subjects. Finally, we conclude by discussing the relevance of these new findings for the understanding of the neural mechanisms underlying the modulatory effects of CVS. PMID- 26595959 TI - Out-of-Body Experiences and Other Complex Dissociation Experiences in a Patient with Unilateral Peripheral Vestibular Damage and Deficient Multisensory Integration. AB - Out-of-body experiences (OBEs) are illusory perceptions of one's body from an elevated disembodied perspective. Recent theories postulate a double disintegration process in the personal (visual, proprioceptive and tactile disintegration) and extrapersonal (visual and vestibular disintegration) space as the basis of OBEs. Here we describe a case which corroborates and extends this hypothesis. The patient suffered from peripheral vestibular damage and presented with OBEs and lucid dreams. Analysis of the patient's behaviour revealed a failure of visuo-vestibular integration and abnormal sensitivity to visuo-tactile conflicts that have previously been shown to experimentally induce out-of-body illusions (in healthy subjects). In light of these experimental findings and the patient's symptomatology we extend an earlier model of the role of vestibular signals in OBEs. Our results advocate the involvement of subcortical bodily mechanisms in the occurrence of OBEs. PMID- 26595960 TI - Vestibular Function and Depersonalization/Derealization Symptoms. AB - Patients with an acquired sensory dysfunction may experience symptoms of detachment from self or from the environment, which are related primarily to nonspecific symptoms of common mental disorders and secondarily, to the specific sensory dysfunction. This is consistent with the proposal that sensory dysfunction could provoke distress and a discrepancy between the multi-sensory frame given by experience and the actual perception. Both vestibular stimuli and vestibular dysfunction can underlie unreal experiences. Vestibular afferents provide a frame of reference (linear and angular head acceleration) within which spatial information from other senses is interpreted. This paper reviews evidence that symptoms of depersonalization/derealization associated with vestibular dysfunction are a consequence of a sensory mismatch between disordered vestibular input and other sensory signals of orientation. PMID- 26595961 TI - The Moving History of Vestibular Stimulation as a Therapeutic Intervention. AB - Although the discovery and understanding of the function of the vestibular system date back only to the 19th century, strategies that involve vestibular stimulation were used long before to calm, soothe and even cure people. While such stimulation was classically achieved with various motion devices, like Cox's chair or Hallaran's swing, the development of caloric and galvanic vestibular stimulation has opened up new possibilities in the 20th century. With the increasing knowledge and recognition of vestibular contributions to various perceptual, motor, cognitive, and emotional processes, vestibular stimulation has been suggested as a powerful and non-invasive treatment for a range of psychiatric, neurological and neurodevelopmental conditions. Yet, the therapeutic interventions were, and still are, often not hypothesis-driven as broader theories remain scarce and underlying neurophysiological mechanisms are often vague. We aim to critically review the literature on vestibular stimulation as a form of therapy in various selected disorders and present its successes, expectations, and drawbacks from a historical perspective. PMID- 26595962 TI - [Approaches to the clinical classification of the functional status in patients with stroke]. AB - The article presents the results of original investigation that included a detailed clinical analysis of 203 patients with stroke undergoing rehabilitation. The significance of pathogenic type of stroke and localization of the lesion in the brain are demonstrated. <> are distinguished among the patients with ischemic stroke of hemispheric and stem localization, and hemorrhagic hemispheric stroke. For each ((rehabilitation subgroup) a detailed description of the key indicators of the neurological status, results of cognitive and psychological tests based on general and local rehabilitation scales are presented. The prognostic value of the (rehabilitation activities profile) scale for stroke patients is estimated. PMID- 26595963 TI - [The combined application of yellow turpentine bathtubs and bronchodilators inhalations for the treatment of the patients presenting with chronic obstructive pulmonary disease]. AB - This paper was designed to report the results of comparative clinical and functional studies involving 89 patients who presented with moderately severe chronic obstructive pulmonary disease and were given the combined treatment with yellow turpentine bathtubs and bronchodilators inhalations with the use of a nebulizer. The patients comprising group 1 (n=29) were treated with yellow turpentine bathtubs and bronchodilators inhalations, those making up group 2 (n=30) received monotherapy with yellow turpentine bathtubs alone, and the patients included in group 3 (n=3) served as controls treated with the use of therapeutic physical exercises and symptomatic medications analogous to those given to the patients of the two former groups. The results of the study give evidence of the advantages of the rehabilitative complex including yellow turpentine bathtubs and atrovent inhalations over two alternative therapeutic modalities attributable to its pronounced anti-inflammatory and immune-corrective activity that resulted in the generalized improvement of bronchial patency, reduction of lung hypertension, and enhancement of physical tolerance; taken together, these effects ensured the best clinical results. PMID- 26595964 TI - [Muscular disorders associated with ankylosing spondylitis and their correction with the help of whole body cryotherapy]. AB - AIM: The objective of the present study was to evaluate the possibilities for the correction of muscular disorders associated with ankylosing spondylitis and their correction with the help of whole body cryotherapy. MATERIAL AND METHODS: The study included 55 patients randomly allocated to two groups. Group 1 was comprised of the patients treated with the use of the common mineral baths, physiotherapy, therapeutic physical exercises, spinal massage, and whole body air cryotherapy. Group 2 contained the patients who were treated in a similar way with the exception of whole body cryotherapy; they served as controls. Muscular disorders were diagnosed by means of functional muscular testing. RESULTS: The study has demonstrated the high prevalence of muscular disorders in the patients suffering from ankylosing spondylitis. Moreover, it revealed the profile of such disorders associated with ankylosing spondylitis and showed significant correlation between the results of functional muscular testing, BASMI and BASFI indices as well as characteristics of chest excursions (p<0.01). The analysis of the results of the treatment gave evidence of the higher effectiveness of the combined treatment including whole body cryotherapy in comparison with the alternative therapeutic modalities employed in the present study. This therapeutic modality ensured the statistically more pronounced improvement of functional muscular testing parameters (p<0.05), muscle strength and extensibility, as well as certain other clinical and functional characteristics. The groups of muscles most susceptible to cryogenic therapy have been identified. CONCLUSION: The data obtained in the present study shed light on some specific features of the action of whole body cryotherapy accounting for its corrective influence on the muscular disorders in the patients presenting with ankylosing spondylitis. It is concluded that the proposed approach can be recommended for the introduction in the combined therapeutic and rehabilitative treatment of muscular disorders associated with ankylosing spondylitis. PMID- 26595965 TI - [The influence of the low-frequency laser radiation on microcirculatory disorders in the patients presenting with chronic viral hepatitis]. AB - AIM: The objective of the present study was to elucidate the character of microcirculatory disorders in the patients presenting with chronic viral hepatitis and to evaluate the possibilities for the correction of the associated disorders with the use of laser irradiation. Material and methods. All the patients were divided into three groups. Group 1 was comprised of 30 patients who were treated by means of traditional medicamental therapy alone; they served as controls. Group 2 consisted of 45 patients treated by intravenous laser irradiation in addition to traditional medicamental therapy. The patients of group 3 (n=45) received a course of laser skin treatment. The state of microcirculation was assessed by the laser Doppler flowmetry (LDF) technique with the help of a LAKK-02 apparatus (<> Research and Manufacturing Complex, Moscow, Russia). RESULTS: The study has demonstrated heterogeneity of the types of microcirculation with the statistically significant increase in the frequency of its pathological cases. All the patients treated with the use of low-intensity laser therapy exhibited a significant improvement of the blood flow characteristics regardless of the initial hemodynamic type of microcirculation. CONCLUSION: It is concluded that the application of laser irradiation as a component of the combined treatment of the patients presenting with chronic viral hepatitis facilitates correction of microcirculatory disorders. PMID- 26595966 TI - [The application of the pulsed low-frequency electrostatic field for the combined treatment of the children presenting with bronchial asthma]. AB - The objective of the present study was to develop a scientifically sound rationale for the application of the pulsed low-frequency electrostatic fields (PLIESF) for the combined treatment of the children presenting with bronchial asthma and the comparative assessment of the effectiveness of the use of this method either as monotherapy or together with therapeutic physical exercises based on the immediate and long-term results of the treatment. The dynamic clinical observations and special investigations were carried out on 101 children at the age varying from 5 to 15 years who suffered from bronchial asthma. PLIESF were shown to produce the beneficial effect on dynamics of clinical symptoms in the children manifested as the disappearance or reduced frequency of episodes of laborious respiration and the improvement of sputum discharge, auscultation picture, bronchial patency, and respiratory excursions of the chest. The application of PLIESF significantly increased the level of the general physical performance in the children with bronchial asthma, improved the functional conditions of the cardiovascular system, normalized both the cardiac rhythm and the heart rate. It was shown based on the analysis of the short-term and long term outcomes of the treatment that the combined therapy with the use of the two physical factors, i.e. the pulsed low-frequency electrostatic fields and therapeutic physical exercises, ensures the significantly higher effectiveness of the treatment than the separate application of either of them. PMID- 26595969 TI - [Certain results of the investigations into the anti-tumour action of the magnetic field under experimental conditions]. AB - This paper summarizes the results of the application of thr magnetic fields for the treatment of experimental tumours, such as sarcoma M-1, alveolar liver cancer PC-1, and Erlich's carcinoma. The evidence of the anti-tumour action of both strong (1200 mTI) and weak (5 to 100 mTI) magnetic fields has been obtained. The author describes the modulating effect of the magnetic fields on the anti-tumour potency of photodynamic therapy and chemotherapy. The data concerning the impact of ferromagnetic hyperthermal therapy on the tumour growth and the survival rate among the tumour-bearing animals are presented. PMID- 26595967 TI - [The role of non-medicamental technologies in the rehabilitation of the children presenting with acute rhinosinusitis]. AB - Despite the recent achievements in diagnostics and pharmacotherapy of acute rhinosinusitis in the children, the problem of management of this pathology, thus far remains a serious challenge for practical medicine. The objective of the present study was to develop a scientifically sound rationale for the application of halotherapy (HT) and magnetic therapy (MT) or their combination for the treatment of acute rhinosinusitis in the children. The clinical observations and special investigations were carried out in the comparative aspect and encompassed 120 children at the age varying from 5 to 15 years suffering from acute rhinosinusitis. The therapeutic effectiveness of the rehabilitative treatment was evaluated based on the results of the endoscopic study of the nasal cavity, analysis of the X-ray images of paranasal sinuses, rhinomanometry, investigations into the ciliary activity, and assessment of the mucosal immunity. The results of the present study gave evidence of the feasibility of incorporating HT and MT in the combined treatment of the children presenting with acute rhinosinusitis. The integrated use of the two methods proved to have the advantage over the separate application of either of them. The specific effects of HT and MT on the clinical course of acute sinusitis and the functional state of intranasal mucosa are described. The optimal methods of the treatment are proposed. PMID- 26595968 TI - [The influence of electrical stimulation on the peripheral immune system under the experimental and clinical conditions]. AB - The authors for the first time provide the scientifically-grounded substantiation for the application of electrical stimulation with bipolar pulsed currents for the combined treatment of the patents presenting with acne vulgaris. Experiments on the rabbits have demonstrated the influence of bipolar pulsed currents on the cellular composition of lymph nodes and thereby facilitated the better understanding of certain theoretical aspects of the application of electrical stimulation at large. The clinical study on the application of multi-channel electrical stimulation and microcurrent therapy showed that these physical factors may cause remodeling of immunogenesis in the patents presenting with acne vulgaris manifested as the normalization of the cellular composition of peripheral blood (leukocyte, lymphocyte, T- and B-lymphocyte counts and immunoglobulin levels). These findings confirm the effectiveness of the proposed integrated treatment responsible for the enhancement of the overall resistance of the patents with acne vulgaris. Moreover, this therapeutic modality proved to exert the immunocorrective action and promote the restoration of the adaptive capacity at large. As a result, 80.9% of the patients presenting with acne vulgaris enjoyed prolonged remission of the disease. PMID- 26595970 TI - [The modern applications of radon therapy for the medical rehabilitation of the patients]. AB - Radon therapy is one of the methods of physiobalneotherapy the mechanism of action of which is believed to consist of the influence of the small radiation doses of radon and its daughter products on the nervous, vascular, and immune apparatuses of the skin and mucosal membranes that eventually enhances the protective and adaptive potential of the body and thereby its ability to resist pathological impacts. At present, the high effectiveness of radon therapy is universally recognized and this method is widely applied for the combined treatment of various diseases in different fields of medicine. These include (1) diseases of the musculoskeletal system and locomotor disorders in the patients presenting with recurrent rheumatic fever, reactive arthritis, ankylosing spondylitis, post-traumatic osteoarthrosis and knee joint synovitis, the sympathico-tonic course of vegetative dystonia associated with connective tissue dysplasia, etc.; (2) neurological disorders in the patients presenting with cervical dorsopathy, neurological manifedstations of degenerative lesions of the cervical and lumbar spine, etc.; (3) cardiological disorders in the patients presenting with hypertensive disease, coronary heart disease, atherosclerosis of different localization, etc.; (4) gastrointestinal disorders in the patients presenting with gastric and duodenal ulcers, irritated bowel syndrome, etc.; (5) gynecological problems in the patients presenting with primary and secondary dysmenorrhea, genital endometriosis, uterine myoma, dysregulated reproductive function, polycystic ovary - syndrome, polycystic ovary syndrome and ovulatory disorders of proinflammatory origin, etc. PMID- 26595971 TI - [The specific features of the psycho-emotional state and psychotherapy in the patients suffering from dorsopathies]. AB - The present article presents a review of the premorbid personality traits with special reference to the psychic state and pain-related behaviour characteristics of the patients presenting with dorsopathies. Also discussed is the relationship between the psychoemotional disorders and the intensity of pain syndrome. The psychodiagnostic approaches and techniques most commonly applied for the examination of this group of the patients are considered together with the psychotherapeutic methods used for their combined treatment and follow-up rehabilitative care. PMID- 26595972 TI - A prescription for change. PMID- 26595973 TI - Rethinking Revenue Cycle Management: Moving Toward Enterprise-Wide Operations. PMID- 26595974 TI - Preparing for the costs of XR-29 a new standard for CT radiation dose monitoring. AB - A new standard for computed tomography (CT) scanners, established by the Medical Imaging and Technology Alliance, is aimed at ensuring CT studies are performed on safe equipment that delivers high-quality images at the lowest possible radiation dose to patients. Starting in January, the Centers for Medicare & Medicaid Services will implement a new payment incentive, authorized by Congress in 2014, aimed at promoting healthcare providers' adoption of the new standard for all outpatient CT studies. Organizations that perform CT studies on an outpatient basis will need to develop a process to comply with the standards or face a reduction in payment per study. PMID- 26595975 TI - Moving beyond the EHR: a scenario-based approach to IDS design. AB - When seeking to establish an integrated delivery system, provider organizations can use the following broad steps to map out IT solutions: Identify high-level focus areas for integrated care. Analyze care gaps in those areas using hypothetical scenarios Project how patients would interact with newly implemented integrated-care elements. Translate this projection-i.e., a target-state scenario into technical design. PMID- 26595976 TI - Guidance for Capital Strategies on Mergers & Acquisitions. PMID- 26595977 TI - Mandatory bundled payment getting into formation for value-based care. AB - Succeeding under Medicare's enterprise Comprehensive Care for Joint Replacement Model will require collaboration among caregivers and financial arrangements to align incentives Priorities for most organization's transition to becoming a value-based hospitals will be care redesign, supply-purchasing strategy, and post acute care provider partnering. Pursuing value for your joint replacement program will chart a path for other service lines and lead your organization's transition to becoming a value-based enterprise. PMID- 26595978 TI - Mandated bundled payments compel hospitals to rethink post-acute care. AB - Health care is on the brink of an industrywide shift to a bundled payment model in which payment covers episodes of care extending from prehospitalization into post-acute care. Hospitals and health systems should begin development of a post acute care network strategy in preparation for bundled payments. The strategic effort will require four broad phases: Defining the value proposition. Developing the post-acute care network. Building the bundle. Executing smartly from the start with new delivery models that reduce clinical variation and real-time performance monitoring. PMID- 26595979 TI - Pricing commodity outpatient procedures assessing the impact. AB - Hospitals should carefully consider all relevant factors before choosing to lower prices and payments for certain outpatient commodity services in an effort to remain competitive in their market. Key steps to take in the evaluation process include: Determining current profitability. Assessing profitability by payer class. Understanding overall cost positions. Assessing the relative payment terms of current commercial contracts. Determining the net revenue effect of proposed changes. PMID- 26595980 TI - Built for the road ahead. AB - Henry Ford Health System in Detroit is seeking new ways to lower and cover costs for the large, low-income population it serves in southeastern Michigan. Employing a strategy that couples the federal 340B Drug Pricing Program with a prescription assistance program of its own creation, Henry Ford has seen improvement in the following areas: Increased medication adherence. Reduced readmissions. Cost savings that are sufficient to expand services where expansion otherwise would not have been feasible. PMID- 26595981 TI - Health care's patient safety crisis. PMID- 26595982 TI - A new role for health insurers. PMID- 26595983 TI - Patterns in bad debt expense. PMID- 26595984 TI - [Editorial]. PMID- 26595985 TI - [Convention in memory of the psychoanalyst Herbert Rosenfeld, Nurnberg 1910 - London 1986]. PMID- 26595986 TI - [My father Herbert Rosenfeld]. PMID- 26595987 TI - [Rosenfeld in Italy (1978 to 1985)]. AB - In this paper I try to throw some light on Rosenfeld's thought and his way of working when he came to Italy. I would like to show, in a sketchy way, the evolution of his thought and in particular the new way he looked at clinical practice at that time. My point is that the Rosenfeld we met in Italy was able to open new horizons in clinical practice, implicitly questioning some of his own or his circle's previous viewpoints. PMID- 26595988 TI - [Herbert Rosenfeld in Germany: on the seducibility/corruptibility by the idealization of destructive elements then and now]. AB - In connection with a conference in memory of Herbert Rosenfeld in 2014 in his home town Nuremberg, from which he had to flee in 1935, the author did some research on this outstanding, later British, psychoanalyst in Germany. The first results are presented here. How the first contacts came about remains unclear but a few of his articles were published in German from 1955 and in the 70's he held occasional seminars in Munich. His contacts with colleagues from the DPV at the end of the 70's and the beginning of the 80's (until his death in 1986) seem however to have been the most influential, especially through a supervision group he led. Rosenfeld transmitted a particularly experience-near approach to the patient, which also acknowledged and took seriously (self) destructive elements in the transference and countertransference. In the following years and decades a number of colleagues wished to deepen this approach. How this line was further developed is illustrated in outlining G. Appy's clinical description of intrusive speechlessness. Rosenfeld's ideas on the pernicious effect of idealizing destructive elements are especially stressed as they contributed to thinking about the entanglements with Nazi Germany, and in addition are still useful in analytical practice, out of which they developed. PMID- 26595989 TI - [A Rosenfeld seminar in Heidelberg 1981 to 1986. A retrospect]. AB - Rosenfeld led a clinical study group in Heidelberg from 1981 until his death in 1986. His influence on the German psychoanalytic community spread rapidly and widely. The authors, who had been members of the study group, describe their personal experience of Rosenfeld's supervision and how it impacted their own clinical work. They go on to give their personal view of Rosenfeld's great effect on the psychoanalytic community of that time, a time when psychoanalysts eagerly sought help for their treatment of severely disturbed patients in a traumatized post-war nation. PMID- 26595990 TI - [Edith Jacobson and Herbert Rosenfeld, an implicit clinical dialog]. AB - In the 1950's and 1960's Edith Jacobson and Herbert Rosenfeld commented critically on one another's work. Beginning with Jacobson's paper on psychotic identifications this controversial but very respectful dialogue continued for over twenty years. At the core of the controversy lay questions of technique. Although Rosenfeld and Jacobson agreed on the central importance of projective identification Jacobson regarded its interpretation in the clinical situation as a mistake. In contrast to Rosenfeld she emphasizes the defensive character of projective identification against psychosis whereas Rosenfeld always understands projective identification as a symptom and therefore considers its interpretation as essential for the modification of concretistic projections. In addition I understand this clinical dialogue as an implicit discussion of the rise and success of National Socialism and the power of destructive projection that flourished in the extermination of European Jewry. PMID- 26595991 TI - ["Long and difficult years followed". The situation of Freud's family after their arrival in Vienna in 1859]. AB - New documents--notes in Viennese newspapers--have shed new light on the social circumstances of Freud's childhood. His father's arrival in Vienna can now be dated to the 23rd of December 1859. In a "reminder", issued by the commercial court of Vienna in the gazette of the Wiener Zeitung in February 1860, Jakob Freud was ordered to repay a debt to his creditor Benjamin Leisorowitz, and liquidation proceedings were initiated against him in the same month. Jakob was nevertheless able to carry on doing business, as is evidenced by further records in the gazette where he is mentioned as taking part in a salt and draft business. This information contributes to clarifying the question of how Jakob Freud managed to feed his growing family, maintain a middle class life style and finance the education of his children in Vienna. Furthermore the article provides a list of all known addresses of the family from 1859 to 1896. PMID- 26595992 TI - ["Signs for the whole rest of the life". The house as symbol and autobiographical substrate in letters, dreams and literary texts by by Anna Freud]. AB - The house as object and symbol preoccupied Anna Freud from childhood onwards. This article traces these ideas in letters, autobiographical documents and literary texts. It focuses on the phantasmal construction of a dream house; on the organisation, loss and later efforts to recover Hochrotherd; on casual birthday poems dedicated to Anna, praising the country house, as well as on the purchase of a weekend cottage in Walberswick reflected in dreams related to the process of inner detachment from the dead father. A fluent interchange between reality and imagination comes into focus, high- lighting the dimension of inwardness rather than that of biographical reality. PMID- 26595993 TI - [Questions and worries. On the correspondence of Grete Bibring and Anna Freud 1949-1975]. AB - Grete Bibring (1899 - 1977) was a representative of the second generation of analysts. Having emigrated from Vienna to London in 1938, she left for Boston in 1942 where she made a remarkable career. 1946 she became head of the department of psychiatry at the Beth-Israel hospital in Harvard and from 1961 the first woman professor of medicine there. She maintained a connection with European psychoanalysis in the person of Anna Freud with whom she corresponded regularly. Their letters contain an interesting exchange of ideas about psychoanalytic institutions (e.g. the American Psychoanalytical Association) and papers (e.g. on pregnancy). It is also the testimony of an exceptional friendship. PMID- 26595994 TI - [Biography of a book: the history of Freud, Bullitt and Woodrow Wilson]. PMID- 26595995 TI - [Psychoanalysis and social work. Two books about the Vienna social worker Rosa Dworschak]. PMID- 26595996 TI - [Clinical analysis of labyrinthine fistula caused by choleseatoma otitis media]. AB - OBJECTIVE: To investigate the clinical features of labyrinthine fistula and obtain the diagnosis, treatment and prognosis of different types of fistula. METHOD: A retrospective analysis of 42 cases (43 ears) with labyrinthine fistula in our hospital from January 2007 to November 2014 was conducted. Data of preoperative clinical manifestation, auditory function, CT image, operative findings, treatment and postoperative recovery were collected and statistically analysed. RESULT: Thirty-nine cases (40 ears) of the 42 cases (43 ears) which were diagnosed as labyrinthine fistula according to operative findings occurred in the lateral semicircular canal, 1 case occurred in the posterior semicircular canal, 1 case occurred in the superior semicircular canal, and 1 case occurred both in lateral and posterior semicircular canal. Before operation, 24 ears (55.8% ) experienced vertigo and 14 ears (32.6%) showed impaired bone conduction hearing threshold. According to Dornhoffer classification standard, 22 cases (23 ears) were diagnosed as type I fistula, 9 cases as type II fistula and 11 cases as type III fistula. There was no statistical difference among the 3 groups on type of hearing loss, vertigo, CT, facial nerve canal damage before operation and bone conduction hearing threshold, vertigo after operation. CONCLUSION: An accurate diagnosis of labyrinthine fistula relies on the operative findings rather than preoperative clinical manifestation, auditory function or CT The surgical intervention should be individualized. There is no significant difference on postoperative recovery among different types of labyrinthine fistula. PMID- 26595997 TI - [Clinical analysis of Mondini dysplasia with cerebrospinal fluid leakage and preliminary genetic research of it]. AB - OBJECTIVE: To summarize and analyze the clinical characteristics of Mondini dysplasia with cerebrospinal fluid leakage, as well as preliminarily investigate the genetic mechanism of the disease. METHOD: The clinical data of 2 patients diagnosed as Mondini dysplasia with cerebrospinal fluid leakage treated in our hospital were analyzed. Blood samples of these two patients were obtained to extract DNA. We screened DNA samples for gene SLC26A4 mutations by using polymerase chain reaction and direct sequencing. The sequencing results were analyzed in DNASTAR software. RESULT: Both patients came to our hospital because of recurrent meningitis, and the fistula were both located in vestibular window. Patients were cured one-time after surgical closure of the leakages with temporalis + temporalis fascia + temporalis through the mastoid approach. No pathogenic mutations of gene SLC26A4 with exome sequencing were found. CONCLUSION: Mondini dysplasia with cerebrospinal fluid leakage should be considered in patients with recurrent meningitis and hearing disorder. Temporal bone HRCT is helpful to the diagnosis. Surgical closure is an effective therapeutic method and may prevent recurrent meningitis. The molecular mechanism of simple Mondini dysplasia needs further study. PMID- 26595998 TI - [The application of multi-slice CT three-dimensioned reconstruction in the cochlear implantation]. AB - OBJECTIVE: To evaluate the instructional effect of Multi-slice (MSCT) in the cochlear implantation pre- and post-operatively, and to contrast the image feature between the X-ray and the MSCT three-dimensional reconstruction of inner ear with implanted electrode. METHOD: Twenty-four cochlear implant (MEDEL Combi 40+) recipients,in No. 1 Hospital of China Medical University from January to October 2014, were involved in this study. Among them, 18 were male and 6 female,with an average age of 4 years. MSCT and three dimensional reconstruction of inner ear were performed in all of the 24 implanted inner ears pre- and post operatively. And X-ray plain film were examined by using 60 degrees lateral oblique position postoperatively. All data of the spiral CT scan with axial 1 mm image slices were transferred to workstation for three-dimensional reconstruction (direct volume rendering) of the inner ear. RESULT: In 1 of the 24 cases, preoperative three-dimensional reconstruction CT scan reveal that the length of the cochlear was shorter than the electrode. And this was confirmed by MSCT postoperatively that the electrode couldn't be inserted by full length. The insertion depth of the electrode can be evaluated directly by MSCT. Moreover, each of the electrode pairs can be identified clearly. CONCLUSION: MSCT plays an indispensable role in the preoperative evaluation of cochlear implantation. Postoperative evaluation by three-dimensional reconstruction of inner ear provide more accurate image to show the electrode insertion depth in the cochlea. MSCT combined with curved planar reformation to measure cochlear length could provide guidance in choosing the more adaptive electrode. And MSCT is superior to DR in demonstration of electrode postoperatively. PMID- 26595999 TI - [The features of high and low-frequency function of horizontal, semicircular canal in Meniere's disease]. AB - OBJECTIVE: To analyze the feature of horizontal semicircular canal function at high and low-frequencies in Meniere's disease. METHOD: Thirty patients suffering from unilateral Meniere's disease were included in the research from 2013 June to 2014 June. Caloric test and video head impulse test were performed to evaluate the high low-frequency function of horizontal semicircular canal. RESULT: these patients were devided by the severity of unilateral weakness in caloric test. The gain value in video head impulse test, which reflects the high-frequency function of semicircular canal, were not different between the normal and mild abnormal group (P > 0.05), but were obviously different between the normal and mild-severe abnormal group, slight abnormal and mild-severe abnormal group (P < 0.05). Gain asymmetry, which reflects the high-frequency function of both side, has no difference between three groups (P > 0.05). CONCLUSION: A part of Meniere's disease may have normal high, low-frequency function of horizontal semicircular canal. As patient suffering slight injury of low-frequency function, the high frequency function keeps normal. As the injury of low-frequency function become mildly to severely, the damage of high-frequency function appears, but the symmetry still keeps balance. PMID- 26596000 TI - [Comparison and analysis of ASSR test in sensorineural hearing loss children with cochlear lesion and retrocochlear lesion]. AB - OBJECTIVE: To compare the auditory steady-state response (ASSR) test data of severe sensorineural hearing loss children with cochlear lesion and those with retrocochlear lesion and find some specific phenomena of retrocochlear lesion in ASSR, then to improve diagnostic accuracy in clinical practice. METHOD: Between 2008 to 2012. 96 children (179 ears) were diagnosed with "retrocochlear auditory nerve lesion" and recieved ASSR test (" retrocochlear lesion" group). Eighty-one (143 ears) the same age children (143 ears) were diagnosed as "cochlear auditory nerve lesion" and selected them as the "cochlear lesion" group. Twenty-six (50 ears) normal hearing children at the same age who had ASSR test records selected from the pediatric hearing center database of our hospital were selected as "normal control" group. Compare the difference of ASSR threshold, ASSR elicit rate and ASSR audiogram among the three groups. RESULT: (1) ASSR threshold: Compared each frequency threshold in ASSR test with cochlear.lesion group, the retrocochlear lesion group with wave V and wave I had no significant difference in 500 Hz and 1000 Hz but had significant difference in 2000 Hz and 4000 Hz. As for the retrocochlear lesion group without wave V and wave I, there was a decline in 500 Hz, 1000 Hz, 2000 Hz and 4000 Hz compared with cochlear lesion group. (1) ASSR elicit rate: When compared to retrocochlear lesion group, the cochlear lesion group had a significance lower elicit rate in the four frequency. (3) Number of elicit reactions in ASSR test . In the retrocochlear lesion group, the elicit reactions in all the four frequency in ASSR test was significantly higher than ochlear lesion group. (4) ASSR audiogram type. The proportion of rising curve audiogram in retrocochlear lesion group was 26.83% (with wave I and wave V), 40% (with wave I and without wave V ) and 33.80% (without wave I and wave V). CONCLUTION: (1) Children with a severe hearing loss in ABR test and a rise type audiogram in ASSR test should be most possibly considered as retrocochlear lesion. (2) ASSR threshold cannot be used in determinate the severity of hearing loss in children with retrocochlear lesion. PMID- 26596001 TI - [Clinical characteristics of tinnitus complaint: an analysis of 453 patients]. AB - OBJECTIVE: To evaluate the clinical characteristics of tinnitus complaint. METHOD: The information of 628 patients with subjective tinnitus was collected using questionnaires from October, 2013 to June, 2014. Among them, 453 cases were included in this study, whose quality of life and sleep were significantly affected. Then we elucidated the features of tinnitus, tinnitus incentives and systemic diseases and analyzed their relationship. RESULT: The proportion of the patients complaint was highest in gruop <= 30 y. The patients with tinnitus complaint were more likely to have persistent tinnitus with higher loudness VAS scores than their counterparts. 65.4% of the total patients had at least one treatment (52.2% of patients can tolerate, and only 13. 2% can not tolerate). More patients had cranial Ming on the left than on the right ear. The proportion of patients with polyphony in bilateral tinnitus was higher than those with unilateral tinnitus (P < 0.05). Moreover, 59% patients had tinnitus inducing factors, and 44% patients had systemic comorbidities (The three most frequently involved systems were otolaryngologic, cardiovascular and digestive system). There was no significantly statistical difference of the tinnitus severity between patients with other systematic diseases and those without. CONCLUSION: Patients with tinnitus complaint were younger in age (<= 30 y) and more likely to have persistent tinnitus with higher loudness VAS scores Predisposing factors are closely associated with mental or physical trauma. The accompanied diseases can be classified by organ system. PMID- 26596002 TI - [Correlation between risk factors of hearing lose and results of initial hearing screening in 1021 neonates]. AB - OBJECTIVE: To explore the risk factors of the newborns who failed initial hearing screening by analysing the distortion production otoacoustic emission (DPOAE) results of 1021 newborns with potential risk factors of hearing loss. METHOD: All newborns, who were born in obstetrical department and admitted in the neonatal department of the Nanfang Hospital during June 2009 to January 2012 and underwent initial hearing screening, were included in this study. Their clinical data and DPOAE results were analyzed retrospectively in order to identify the risk factors for failure of initial hearing screening in infants; cases who failed the DPOAE test were followed up by telephone interviews. RESULT: (1) One hundred and thirty seven cases (13.42%) of the 1021 newborns did not pass the hearing screening. 51 cases (5.00%) did not pass the test in both ears. Meanwhile, left ear in 47 cases (4.60%) and right ear in another 39 cases (3.82%) failed the test respectively. (2) Univariate analysis showed that 14 factors had significant influence on the hearing screening results, such as birth weight, small for gestational age, multiple pregnancy, gestational age, delivery mode, oligohydramnion, oxytocin, blood sugar level of newborn, Apgar scores at 1 min, exposed prenatally to glucocorticoid, maxillofacial deformity, hypoxic-ischemic encephalopathy, neonatal respiratory distress syndrome and neonatal asphyxia (P < 0.01). (3) Multivariate Logistic regression analysis suggested that birthweight less than 1500 g, multiple pregnancy, Apgar scores of 0-4 at 1 min, exposed prenatally to glucocorticoid and maxillofacial deformity were risk factors for failure of initial hearing screening (OR were 3.132, 1.808, 2.615, 1.827 and 12.174 respectively; 95% CI were 1.466-6.691, 1.120-2.917, 1.317-5.336, 1.130-2.953 and 1.986-74.632 respectively). (4) Results of telephone interviews revealed that Apgar scores of 0-4 at 1 min would be a risk factor of language development. CONCLUSION: Birthweight less than 1500 g, multiple pregnancy, Apgar scores of 0-4 at 1 min, exposed prenatally to glucocorticoid and maxillofacial deformity are risk factors of failure of initial hearing screening among newborns with potential hearing loss. Monitoring of the hearing condition of the infants at risk should be strengthened. PMID- 26596003 TI - [Fungus culture of the ear discharge and therapeutic effects in 60 outpatients with otitis externa]. AB - OBJECTIVE: To assess the diagnosis and therapeutic effects for fungal otitis externa by clinical symptoms, endoscopic findings, and fungus culture of the ear discharge. METHOD: Sixty outpatients diagnosed with otitis externa were enrolled in the study. All patients were treated with a thorough debridement of the ear and one antifungal medication regimens (compound resorcinol solution) in case of a positive fungus culture. One subgroup of patients treated with daub glycerol during 2 weeks of follow-up. RESULT: Positive cultures were found in 42 cases. The efficacy was observed in all patients even in those who received only ear endoscopy. CONCLUSION: Fungal otitis externa could be easily diagnosed by ear endoscopy. A thorough debridement of the ear and utility of compound resorcinol solution is an easy and effective approach for treatment of fungal otitis externa. PMID- 26596004 TI - [Clinical analysis of otogenic extracranial and intracranial complications]. AB - OBJECTIVE: To study the clinical feature and treatment of extracranial and intracranial complications caused by otitis media. METHOD: Three hundred and twenty patients of acute and chronic otitis media were admitted to our department between 2005 and 2014. Among them, 34 patients were diagnosed with extracranial and intracranial complications. The clinical features and treatment outcome were retrospectively studied. Of the 34 patients associated with complications, 25 had a single complication,8 had two complications and 1 had three complications. Complications included labyrinthitis in 14 cases, facial paralysis in 11, postauricular subperiosteal abscess in 6, Bezold abscess in 1, thrombophlebitis of sigmoid sinus in 2, otitis meningitis in land otogenic brain abscess in 8. RESULT: Thirty-three patients were cured or improved and 1 patient died. CONCLUSION: Due to the widespread use of antibiotics, the clinical manifestations of extracranial and intracranial complications of otitis media become more hidden and atypical. The surgery is the primary treatment method. PMID- 26596005 TI - [The application of Tb-ABR and ASSR in pediatric hearing assessment]. AB - OBJECTIVE: To observe the correlation between the threshold of tone burst auditory brain stem response (Tb-ABR) and ASSR (auditory steady-state response) and the threshold of BA (behavioral audiometry). To investigate the accuracy and clinical value of Tb-ABR and ASSR in pediatric hearing assessment. METHOD: From January, 2014 to December, 2014, 76 children (123 ears) recieved hearing examination in the First Affiliated Hospital of Zhengzhou University. They were classified into three groups according to the hearing level: 23 children (46 ears) with normal hearing ability in group A, 27 children (32 ears) with slightly moderate sensorineural deafness in group B and 26 children (45 ears) with severe profound sensorineural deafness in group C. Tb-ABR, ASSR, BA in 4 frequencies (0.5, 1.0, 2.0, 4.0 kHz) were tested and the results were statistically analyzed. RESULT: (1) At the 4 frequencies (0.5-4.0 kHz), we obtained 132 thresholds of Tb ABR, 144 of ASSR, 152of BA. And 166 thresholds were obtained in Tb-ABR+ASSR+BA in total . (2) The thresholds of Tb-ABR, ASSR and those of BA in all 3 groups had linear relations at 0.5-4.0 kHz. The correlation coefficients of group A were 0.76, 0.82, 0.87 and 0.91; 0.52, 0.57, 0.67 and 0.64. Those of Group B were 0.89, 0.95, 0.98 and 0.95; 0.74, 0.82, 0.87 and 0.90. Those of Group C were 0.91, 0.90, 0.92 and 0.89; 0.93, 0.95, 0.95 and 0.91. CONCLUSION: (1) Both ASSR and Tb-ABR can allow reasonably accurate predictions for the pediatric hearing assessment. The correlation between Tb-ABR threshold and BA threshold is higher in normal hearing children and slightly-moderate sensorineural deafness children. The correlation between ASSR threshold and BA threshold is higher in severe-profound sensorineural deafness children. (2) The hearing test combination can evaluate the residual hearing ability for children with severe hearing loss. PMID- 26596006 TI - [Character of early tinnitus about sudden deafness]. AB - OBJECTIVE: To study the clinical characteristics of early tinnitus in patients with sudden deafness. METHOD: Forty-seven patients with sudden deafness and early tinnitus recieved subjective review and filled out classified questionnaire of tinnitus. By pure tone audiometry and tinnitus matching test, we obtain the distribution, quantity and matching loudness of tinnitus patients. RESULT: (1) Objective examination: the most common frequencies of tinnitus were 8000 Hz and 4000 Hz. The most common numbers were two frequencies. The matching loudness was (16.63 +/- 8.37) dB. (2) Subjective examination: the tinnitus was monotone (74.0%), sustained (89.0%), third level loudness (45.0%), third level annoying (60.0%), high frequency (83.0%), sound of cicadas (66.7%). The most influencing factors were hearing (28.2%) and mood (29.5%). (3) Relationship between tinnitus and pure tone hearing threshold curve: there was a significant correlation between the frequency of pure tone audiometry and the matching loudness of tinnitus (r = -0. 370, P < 0.01). There was no significant correlation between the frequency of pure tone tinnitus and the matching loudness of tinnitus (r = 0.083, P > 0.05). CONCLUSION: (1) The results of subjective examination were consistent with those of objective examination. (2) The tinnitus should be considered in the early treatment of sudden deafness. PMID- 26596007 TI - [The treatment effects analysis of 164 patients with sudden sensorineural hearing loss]. AB - OBJECTIVE: To explore the effective treatment of sudden sensorineural hearing loss and factors affecting its prognosis. METHOD: The clinical data and follow-up results of 164 patients with sudden sensorineural hearing loss were analyzed retrospectively. All the 164 patients were given intravenous vasodilator, neurotrophic drugs treatment, oral prednisone treatment, and intratympanic dexamethasone injection. All patients were divided into low frequency hearing loss type,intermediate frequency hearing loss, high frequency hearing loss, all frequency hearing loss and total deafness group. Pure tone hearing threshold test were performed before and 3 months after treatment. All patients and different groups were compared before and after treatment damage frequency of average air conduction and various frequency air conduction hearing. Analysis of gender, age, process and hearing curve type, frequency hearing of impaired before treatment, the symptoms with or without vertigo. RESULT: All the patients' hearing improved after treatment. The treatment efficiency was 46.3%, and low frequency hearing improvements were better than the high frequency hearing. Including age, process, frequency hearing of impaired before treatment, with or without vertigo isindependent factors influencing its prognosis. CONCLUSION: Based on the regular treatment,oral and intratympanic injection glucocorticoid therapy are safe and effective for sudden hearing loss,The prognosis and age, course, impaired hearing before curve type, treatment frequency hearing level is closely related, with or without vertigo. PMID- 26596008 TI - [Efficacy and safety of harmonic scalpel in neck dissection: a Meta-analysis]. AB - OBJECTIVE: To systematically evaluate the efficacy and safety of harmonic scalpel in neck dissection. METHOD: Available literatures of PubMed, EMBASE, Cochrane Library, Google Scholar, CBM, CNKI, WangFang and VIP published before June 2014 were searched. Inclusion criteria and quality assessment were performed. All data were analyzed by using RevMan 5.2 software. RESULT: Fourteen studies including 632 cases were enrolled. Among them, 319 cases were in harmonic scalpel group and 313 cases in conventional resection group. Compared with conventional resection group, the harmonic scalpel group showed shorter surgery time(weighted mean difference [95% confidence intetval]: -28.01 [-36.83, -19.19], Z = 6.22, P < 0.01)and less intra-operative blood loss (weighted mean difference [95% confidence intetval]: -46.68 [-57.25, -36.12], Z = 8.66, P < 0.01). The number of cervical lymph nodes dissected and the incidence of postoperative chylous leakage were similar in both groups. CONCLUSION: Using the harmonic scalpel in neck dissection was as efficient and safe as that of the conventional technique with the advantage of shorter time of surgery and less intraoperative blood loss. PMID- 26596009 TI - [Estrogen receptor-beta expression in laryngeal carcinoma: correlation with the expression of epithelial-mesenchymal transition specific biomarkers]. AB - OBJECTIVE: To detect the expression of ERbeta in laryngeal carcinoma and the its correlation with the expression of epithelial-mesenchymal transition(EMT) specific biomarkers. METHOD: Picture MT-Pv9000 was used to detect ERbeta and EMT in 72 cases of human aqueous laryngeal carcinoma and 8 cases of adjacent non neoplastic laryngeal mucosa by immunohistochemistry. RESULT: The positive rates of ERbeta in tumors and adjacent non-neoplastic laryngeal mucosa were 27.78% and 25.00%, respectively. The differences were not significant (P > 0.05). The abnormal expression rates of E-cadherin and beta-catenin were 61.11% and 76.39% respectively. The expression of ERbeta correlated negatively with the loss of E cadherin, nuclear translocation of beta-catenin and increased TNM stage. The differences were significant (P < 0.05). CONCLUSION: The positive expressions of ERbeta suggest a good prognosis in the differentiation, clinical stages and lymphatic metastasis of the laryngeal carcinoma. The underlying mechanism may be related with the abnormal expressions of E-cadherin and beta-catenin. PMID- 26596010 TI - [Benign paroxysmal positional vertigo associated with Meniere's disease: analysis of 36 cases]. AB - OBJECTIVE: To compare the clinical features and outcomes of benign paroxysmal positional vertigo (BPPV) associated with Meniere's disease and idiopathic BPPV. METHOD: Reviewing the clinical records of 372 patients with BPPV, 289 patients with idiopathic BPPV and 36 patients with BPPV accompanied by Meniere's disease and were enrolled in this study. All patients were diagnosed by using the Dix Hallpike test or roll test and treated with the canalith repositioning procedure. The outcomes were compared between the two groups. RESULT: The patients with BPPV associated with Meniere's disease presented the following features, in which they differed from the patients with idiopathic BPPV (P < 0.05): (1) a higher percentage of female patients; (2) a longer duration of symptoms; (3) frequent involvement of the horizontal semicircular canal; (4) a greater incidence of canal paresis; (5) more therapeutic sessions needed for cure and a higher rate of recurrence. CONCLUSION: The BPPV associated with Meniere's disease differs from idiopathic BPPV in clinical features, treatment response recurrence tendency. PMID- 26596011 TI - [Clinical effect on the treatment of the low-middle frequency sudden hearing loss with postaurical injection of methylprednisolone]. AB - OBJECTIVE: To evaluate the clinical efficacy on the treatment of the low-middle frequency sudden hearing loss with postaurical injection of methylprednisolone. METHOD: The 80 cases of the low-middle frequency sudden hearing loss were randomly divided into postaurical injection and oral hormone groups. The postaurical injection group (42 cases) received the postaurical injection of methylprednisolone, 40 mg/2 d, combined with the treatment of Ginkgo dipyidamolum and Alprostadil for 14 d; The oral hormone group (38 cases) received the oral prednisone, 1 mg/kg/d, administrated once on the morning for 3 d, if effective, prolonging for another 2 d, as mentioned above for Ginkgo dipyidamolum and Alprostadil. RESULT: The total effective rate was 88.10% in postaurical injection group and 86. 4o%in oral hormone group. There was no significant difference between the twbogroups( P> 0. 5). CONCLUSION: Postaurical injection of methylprednisolone for the low-middle frequency sudden hearing loss is effective, safe and simple, which may be an alternative for systemic administration of gulcocorticoid. PMID- 26596012 TI - [Clinical observation of the gamma-globulin levels when Benign paroxysmal positional vertigo is attacking]. AB - OBJECTIVE: To observe the characteristics of serum protein in patients with benign paroxysmal positional vertigo (BPPV) during the symptomatic period. METHOD: Fifty-five patients with BPPV and 58 control subjects were enrolled in the study. All the patients underwent the Dixe-Hallpike and Roll maneuver to confirm the type of BPPV. The average time of onset was (1.0 +/- 0.8)days in the group of BPPV. The clinical features and the laboratory tests of serum protein electrophoresis, blood counts, and liver and kidney function were performed in both groups. RESULT: The levels of serum albumin (Alb), alpha1 globulin, alpha2 globulin and beta globulin of BPPV group did not differ statistically in the two groups (P > 0.05); The gamma-globulin levels were significantly higher in patients with BPPV than in controls (P < 0.05). CONCLUSION: The gamma-globulin levels are increased when BPPV is attacking. PMID- 26596013 TI - [The efficacy of intratympanic dexamethasone injection for the moderate and severe sudden deafness with BPPV]. AB - OBJECTIVE: To evaluate the efficacy of intratympanic dexamethasone injection for the moderate and severe sudden deafness with BPPV. METHOD: A total of 63 patients diagnosed with sudden sensorineural hearing loss with BPPV were treated through OPD. Patients were divided into three groups: 20 cases in intratympanic dexamethasone injection as initial treatment (group A); 18 cases in systemic hormone therapy group (group B); 25 cases in intratympanic dexamethasone injection as salvage treatment (group C). In addition, routine drugs were used to all patients. RESULT: The overall effective rate of group A, B and C in hearing recovery was 60.0%, 38.9% and 48.0%, respectively: (1) No significant difference of hearing recovery was observed among three groups (P > 0.05); (2) A significant difference of hearing recovery was evidenced between group A and C (P < 0.05); (3) A significant difference of hearing recovery was evidenced between group A and C (P < 0.05); (4) No statistically significant difference was found in the hearing recovery between group B and C (P > 0.05). CONCLUSION: Our data showed that intratympanic dexamethasone should be used as initial therapy for treating the moderate and severe sudden deafness with BPPV. PMID- 26596014 TI - [Multivariate analysis of prognostic makers in patients with nasopharyngeal carcinoma intreatment of radiotherapy combined with induction chemotherapy]. AB - OBJECTIVE: To observe the therapeutic effect of radiotherapy combined with TPF in patients with nasopharyngeal carcinoma (NPC) and to explore the influencing factors on prognosis of NPC. METHOD: A retrospective analysis of 144 patients with nasopharyngeal carcinoma receiving radiotherapy combined with chemotherapy, from January 2006 to December 2011, was conducted. The survival analysis in patients with nasopharyngeal carcinoma were performed. The impact of age, sex, clinical stage, alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), lactate dehydrogenase (LDH), homocysteine (Hcy), uric acid, NK cell proportion, T cell proportion, Carbohydrate antigen on survival time was observed with univariate and multivariate methods. RESULT: By the last follow-up, 9 cases were lost . The follow-up rate was 93.75 percent and the average follow-up time were 54.67 +/ 17.17 (37-88) months. The age, clinical stage, LDH, proportion of T cells and NK cells were independent factor in patients with NPC with univariate analysis (P < 0.01). COX regression multivariate analysis revealed that age, clinical stage and LDH were strong risk factor affecting prognosis (P < 0.01) and the proportion of NK cells and T cells were protective factors (P < 0.01). CONCLUSION: Radiotherapy combined with TPF is more effective than radiotherapy alone in patients with nasopharyngeal carcinoma . Age, clinical stage and LDH may adversely influence the disease prognosis, and NK cells and T cell proportion may act as protective factors. PMID- 26596015 TI - [Effect of gene silencing of Bmi-1 on proliferation regulation of CD44+ nasopharyngeal carcinoma cancer stem-like cells]. AB - OBJECTIVE: To investigate the effect of gene silencing of Bmi-1 on proliferation regulation of CD44+ nasopharyngeal carcinoma cancer stem-like cells (CSC-LCs). METHOD: The sequence-specific short hairpin RNA lentivirus targeting at human Bmi 1 gene (LV-Bmi-1shRNA) was constructed and was used to infect CD44+ nasopharyngeal carcinoma cells which were sorted by flow cytometry. A lentiviral which included a random sequence was also designed to serve as a negative control. We employed fluorescence microscope and flow cytometry to detect infection efficiency; real-time PCR was used to detect Bmi-1 and its downstream gene while each protein expression level was confirmed by western blotting protocol; CCK-8 proliferation assay was applied to measure proliferation capacity; tumor spheroid assay was used to evaluate the self-renewal capacity. Colony formation assay was used to measure cell colony formation capability; flow cytometry analyzed cell cycle distribution. RESULT: The constructed LV-Bmi-1shRNA successfully infected into the CD44+ nasopharyngeal carcinoma cells. The infection efficiency could reach above 95%; LV-Bmi-lshRNA effectively inhibited Bmi-1 mRNA and protein expression, while the downstream gene p16INK4a and p14ARF mRNA as well as protein expression level were upregulated (P < 0.05). Notablely, the proliferation, colony formation, self-renewal capabilities of the experimental group decreased significantly (P < 0.05). In addition, the cell cycle arrested at the G0-G1 phase. CONCLUSION: Gene silencing of Bmi-1 inhibited the proliferation, colony formation and self-renewal capabilities of the CD44+ nasopharyngeal carcinoma CSC-LCs, inhibited the cell cycle processes, which may mediate through Bmi1-p16INK4a/p14ARF-p53 pathway. Our experimental results indicated that Bmi-1 gene may play an important role in the maintenance of the stem cell-like characteristics of CD44+ nasopharyngeal carcinoma cells. Bmi-1 gene may be a potential new target for the treatment of nasopharyng al carcinoma in the future. PMID- 26596016 TI - [Clinical observation the effect resection surgery by transferring the skin flap to repair the earlobe keloid]. PMID- 26596017 TI - [Denucleated elevation treats auricle keloids]. PMID- 26596018 TI - [Tuberculous granuloa of left auricle: case report]. AB - A femail patient was presented to our department for a dark red painless mass in the left auricle, which has progressively enlarged for one year. Pathological examination revealed granuloma change. Mycobacterium tuberculosis DNA test was positive. Tuberculin test revealed strong positive reaction. This case was diagnosed as tuberculous granuloma. PMID- 26596019 TI - [Sudden deafness as the initial manifestation of chronic myelogenous leukemia: case report]. AB - To study the pathogenesis of hearing loss in chronic myelogenous leukemia (CML). To report one case with CML whose first sign was sudden unilateral hearing loss. Sudden hearing loss in CML was presented with dramatic high white blood cell count in peripheral blood. Some cases of sudden hearing loss in CML may be improved or even cured by leukapheresis and intrathecal chemotherapy. The proposed pathogenesis for deafness in leukemia is due to hyperleukocytosis, hyperviscosity syndrome, leukemic infiltration and the inner ear hemorrhage. In treatment, clinicians should quickly reduce the number of white blood cells to lighten the tumor burden. Intrathecal injection of MTX and plasmapheresis is commonly used. PMID- 26596020 TI - [A case of huge extramedullary plasmacytoma in the retropharyngeal space]. AB - Extramedullary plasmacytoma (EMP) are often located in the head and neck region, commonly affecting the nasal cavity, tonsillar fossa and oral cavity but rarely the retropharyngeal space. In this report, a 60-year-old woman with large EMP in the retropharyngeal space is presented, who was diagnosed by pathology, bone marrow aspirate and computed tomography scan. The patient received operation and postoperative radiotherapy with dose of 50 Gy. At sixteen months follow-up, the patient was doing well with no signs of recurrence. PMID- 26596021 TI - [Treatment research progress on the treatment of neurofibromatosis type 2 associated vestibular schwannoma]. AB - Neurofibromatosis type 2 (NF2) is a dominantly inherited genetic condition. Bilateral vestibular schwannoma, which are benign tumors, composed of neoplastic Schwann cells that arise from the eighth cranial nerve, are the hallmark of NF2. Standard approaches for treatment of growing vestibular schwannoma include observation, surgical removal and radiation therapy. Molecular targeted therapies also present great prosperity in recent years. In this review, we summarize the latest progresses on the treatment of NF2-associated vestibular schwannoma. PMID- 26596022 TI - [The relationship between the latency-intensity function of click ABR wave V and the audiogram configuration]. AB - OBJECTIVE: The latency-intensity function (LIF) of wave V from click ABR of some deaf children showed great variation. We attempted to find out the intrinsic reasons. METHOD: The children recieved tone-burst ABR test. RESULT: Frequencies from 0.5-4.0 kHz have been tested and the thresholds of tone-burst ABR were recorded. The average thresholds of steeply LIF children at 0.5-4.0 kHz were (93.13 +/- 7.04), (79.37 +/- 7.72), (69.38 +/- 8.54) (66.25 +/- 8.06) dB respectively, while the average thresholds of shallower LIF children at these 4 frequencies were (65.00 +/- 7.32) (68.13 +/- 6.55) (70.63 +/- 6.80) (78.12 +/- 8.34) dB respectively. CONCLUSION: The results imply that the child with steeply LIF may have more hearing loss at frequencies 0.5 and 1 kHz than those with shallower LIF. LIF may predict the audiogram configuration. PMID- 26596023 TI - [AWAKE CRANIOTOMY: IN SEARCH FOR OPTIMAL SEDATION]. AB - Awake craniotomy is a "gold standard"for intraoperative brain language mapping. One of the main anesthetic challenge of awake craniotomy is providing of optimal sedation for initial stages of intervention. The goal of this study was comparison of different technics of anesthesia for awake craniotomy. Materials and methods: 162 operations were divided in 4 groups: 76 cases with propofol sedation (2-4mg/kg/h) without airway protection; 11 cases with propofol sedation (4-5 mg/kg/h) with MV via LMA; 36 cases of xenon anesthesia; and 39 cases with dexmedetomidine sedation without airway protection. Results and discussion: brain language mapping was successful in 90% of cases. There was no difference between groups in successfulness of brain mapping. However in the first group respiratory complications were more frequent. Three other technics were more safer Xenon anesthesia was associated with ultrafast awakening for mapping (5+/-1 min). Dexmedetomidine sedation provided high hemodynamic and respiratory stability during the procedure. PMID- 26596024 TI - [VEGETATIVE REACTIONS AS PROGNOSTIC FACTOR IN POSTERIOR FOSSA SURGERY]. AB - Mortality rate related to posterior fossa tumors resection varies from 1 to 8 percent, according to various authors. It depends on tumor size and its growth characteristics. To determine the physiological acceptability of surgery, physiological significance of vegetative reactions associated with tumors resection has to be assessed. We divide these reactions (centrogenic reactions - CR) into 2 main groups. The first group has a relatively precise morphofunctional structure, similar to the classic reflex arc. They appear due to irritation of local centers or cranial nerves nuclei with mixed motor-vegetative structure. In most cases they are not connected with anatomic damage of CNS structures. The second group of CR is correlated with dysfunction of brain and represents brain s attempt to turn into a new functional state. Their presence should be considered as a functional degradation symptom, which might be even irreversible. Emergence from anesthesia in the operative room is not recommended in this clinical situation. Neurovegetative stabilization should be provided for a period of 6 to 24 hours after tumor resection. PMID- 26596025 TI - [ANESTHESIA FOR AIRWAY ENDOSCOPIC RECANALISATION WITH SELFEXPANDED STENTS]. AB - Tracheal and bronchial endoscopic stenting can give a quick therapeutic result or delay surgiCal treatment of patients with stenosis. It also can improve quality of life, create conditions for palliative therapy and increase survival of incur- able oncological patients. This paper contains description of our experience in anesthesia for tracheal stenting with re- spiratory support. MATERIALS AND METHODS: 23 patients were investigated retrospectively (15 males, 8females). They had 28 interventions under general anesthesia. 14 patients had malignant and 9 had non-malignant lesions. Complicated somatic status, stenosis extention and localization, type of laryngoscope. unprotected airways determined choice of in- travenous anesthesia with high-frequency ventilation and muscle relaxation. RESULTS: Improvement (dyspnea decreasing) was mentioned in 78,3% (18/23) cases after stenting, in 8,7% (2/23) cases improvement was slight; in 4,3% (1/23) cases - no change; in 8,7% (2/23) cases patients died complications after stenting occurred in 10 cases (43,5%). In 4 cases (17,4%) - stent displacement; in 2 cases (8,7%) - purulent tracheobronchitis; in 1 case (4,35%) - paroxysmal cough with pain. In 1 case loss of stent during paroxysmal cough and vocal cords edema occurred. In 2 cases (8,7%) operation was failed and patients died due to the lesion progression and respiratory insufficiency. CONCLUSIONS: Anesthetic pro- tection is an important component at endoscopic recanalization with selfexpanded stents. Management is difficult due to complicated somatic status, and unprotected airways. Significant health enhancement, dyspnea decreasing even by exercise stress justified high anesthetics risks. PMID- 26596026 TI - [GOAL-TARGET INFUSION THERAPY BASED ON NONINVASIVE HEMODYNAMIC MONITORING ESCOO]. AB - We described our experience in using the new noninvasive hemodynamic monitoring (esCCO), which allowed recording most important parameters of heart capacity. Infusion therapy during laparoscopic operations might be based on dynamic of systolic blood volume. This functional approach can be used for evaluation of heart reaction on bolus fluid load, to optimike volemic status in situations associated with dynamical blood circulation changes. We compared intraoperative infused fluid volumes, calculated by traditional approach and by target approach. The obtained results had significant differences among groups, and didn't correspond with "liberal" and "restrictive" strategy for infusion therapy. PMID- 26596027 TI - [N-TERMINAL PRO-BRAIN NATRIURETIC PEPTIDE AS BIOMARKER OF ACUTE BRAIN INJURY]. AB - Laboratory diagnostic is very important in treatment of acute brain injury, together with neurophysiology and neurovisualisation methods. Biomarkers measurements can provide early brain injury diagnostic, monitoring of treatment as well as outcome prediction. We studied dynamic of N-terminal pro-brain natriuretic peptide (n-proBNP) level in patients with acute brain injury (intracranial hemorrage, traumatic brain injury, tumors). All patients were divided into 3 groups (by etiology of injury), each group consist of 2 subgroups: a - survivors with good outcome (I-II group in Glasgow outcome scale (GOS)); b - dead or severe morbidity (III-V group in GOS). High level of n-proBNP was mentioned in all groups. N-proBNP level was not correlated with etiology of injury. In cases of n-proBNB increasing more than 700pg/ml outcome was poor - severe morbidity or death. We suppose N-proBNP can be significant acute brain injury biomarker, useful to outcome prediction. PMID- 26596028 TI - [PERIOPERATIVE ANALGESIA INFLUENCE ON MOTHER REHABILITATION PERIOD AFTER CESAREAN SECTION]. AB - Early breast-feeding is a standard of perinatal care currently. After cesarean section it can be possible in case of early mother activation (verticalization). Assessment of perioperative analgesia influence on activation timing was the aim of our research. We included 120 parturient women. It was proved, that local analgesia using in postoperative period promotes early mother verticaliration, and optimal breast-feeding starting. PMID- 26596029 TI - [BLOOD AND CEREBROSPINAL FLUID PURINES IN PREGNANT]. AB - The research includes 88 pregnant women, that had their purine basis and malondialdehyde in water thermocoagulate extract of venous blood and cerebrospinal fluid examined (along with common standards clinical-laboratory tests) before the spinal anesthesia for the caesarian section was provided It was detected that preeclampsy and HELLP-syndine feature the increased adenine guanine hypoxantine and uric acid levels in cerebrospinal fluid, as well as increased concentrations of blood malondyaldehyde (higher than upper normal level), accompany with the increased hemotaencephalic barrier permeability for adenine, guanine and hypoxantine. It's demonstrated that level of guanine in blood serum can be used as a prognostic factor of spinal anesthesia quality in obstetrics. It is supposed to examine purine levels in pregnant women not only in blood but also in cere brospinal fluid. PMID- 26596030 TI - [SYSTEMIC INFLAMMATORY RESPONSE ON NOSOCOMIAL BACTEREMIA]. AB - GOAL: study of special aspects in system inflammatory reaction caused by nosocomial bacteremia in dependence of the pathogen Gram-origin. The study included 85 patients with nosocomial bacteremia in ICU from 2010 till 2012. The main inclusion criteria was bacteria identification in blood, which was taken more than 48 hours from arrival to ICU within the appearance of system inflammatory response signs. Key options for clinical rating of system inflammatory response was dynamic of patients condition according APACHE II, SOFA, SAPS-III/PIRO, Pitt scales and its correlation with durations of mechanical ventilation, length of staying in ICU, total hospital period and outcome. RESULTS: Gram-negative microorganisms are definitely leading in the modern ethiological structure of nosocomial bacteremia in ICU patients (64,4%). The main origin of Gram(+) agents is central venous catheter infections. The main reason of Gram(-) infections is ventilation-associated pneumonia. Appearance or persistence of system inflammatory response is associated with the rise of scale indexes (SOFA and Pitt from 5 scores and higher and SAPS-PIRO higher than 18 scores) and high risk of possible bacteremia. PMID- 26596031 TI - [INTENSIVE CARE OF COMPLICATED ACUTE PORPHYRIA]. AB - The experience of anesthesia and intensive care departments of Hematological center Russia for intensive care management in 13 patients with acute porphyria, from 1996 till 2013 was summarized ion this pape4: Main causes of life threatening complications of acute porphyria and its frequency were revealed Advantages of mechanical lung ventilation in respiratory failure, algorithms of clinical nutrition, correction of water-electrolyte disorders were represented. Importance of kinesiotherapy in successful treatment in these category of patients was revealed. It is shown that the whole complex of intensive care methods with the specific pathogenetical therapy brings success in 84,6 % of patients. PMID- 26596032 TI - [PHARMACOLOGICAL NEUROPROTECTION IN CARDIOSURGERY (Part 1): DRUGS FOR GENERAL ANESTHESIA]. AB - This literature review is devoted to modern condition of pharmacological neuroprotection. Aeuroprotection as a complex method of brain protection and reduction of neurological complications is a relevant trend in practical anesthesia and intensive care. The following data represents frequency of neurological complications in different types of surgery and its main classifications. In the first part of the review potential neuroprotectional abilities of modern anesthesia medications are discussed Mechanisms of neuronal destruction and possible ways of impact on the pathophysiological processes via pharmacological agents are observed. The most promising drugs with neuroprotectional effects are selected. In the second part of the review we are going to examine neuroprotection effects of non-anesthetic drugs. PMID- 26596033 TI - [CONTROVERSIAL ISSUES OF THE ANESTHESIOLOGICAL MAINTENANCE OF DELIVERY IN OBESE PATIENTS]. AB - The review represents debatable issues of the anesthesia management of the surgical delivery and postoperative period in patients with obese: the choice of anesthesia methods, anesthesia as a risk factor of maternal and perinatal morbidity and mortality and methods of intraoperative pain management. Authors made an attempt to reveal preventable risk factors of complications in obese patients: professional skills, technical equipment, standards compliance, period of time from the decision till delivery itself selection of an adequate dose of local anesthetic during spinal anesthesia, necessity of monitoring and correction of intra-abdominal hypertension. The article discusses the variety of problems, and in case offurther researches they will help to decrease frequency of the anesthetic complications, that determine obstetric and perinatal outcomes in obese patients. PMID- 26596034 TI - [INHALED ANTIBIOTICS IN TREATMENT OF NOSOCOMIAL PNEUMONIA]. AB - Nosocomial pneumonia is the most common infection in intensive care units. Currently the problem of resistance of noso-comial pathogens to miost of antibiotics is crucial. Using of inhaled antibiotics in combination with intravenous drugs is eff ective and safe method for treatment of nosocomial pneumonia. The literature review describes current opportunities of ihhaled antibiotic therapy of nosocomial pneumonia, descriptions of drugs, the advantages and disadvantages of this treatment. Special attention is paid for using inhaled aminoglycosides for nosocomial pneumonia. PMID- 26596035 TI - [CORRECTION OF HEMOSTASIS DISORDER IN HEMORRHAGIC SHOCK]. AB - It is a clinical case of successful correction of hemostasis disorder in hemorrhagic shock. This case demonstrates the need to perform advanced tests that assess hemostatic system in patients with ongoing bleeding. Using of thromboelastography helped us to make a comprehensive assessment of hemostatic system that allowed to detect the point of application of drugs and substitution therapy. Coagulation disorder was treated by intravenous injection of Ca2+. In this case the cause of hypocalcemia was combination offactors such as electrolytes losing during massive bleeding and progressing metabolic acidosis. Therefore, monitoring the level of ionized calcium is especially important in patients undergoing massive blood loss and receiving large doses of donor blood components. PMID- 26596036 TI - [SEPTIC SHOCK IN PATIENT WITH SEVERE HEAD TRAUMA]. AB - The clinical observation illustrates the role of screening of inflammatory markers and advanced hemodynamic monitoring in optimization of the treatment of the patient with severe traumatic brain injury (sTBI). The level of consciousness by the Glasgow Coma Scale at admission was 5 points. From the first day of stay the patient suffered hyperthermia to 39,0 degrees C degrees The diagnosis of the aspiration pneumonia was determined by radiological signs, bronchoscopy and inflammatory blood markers, C-reactive protein, leukocytosis. From the second day the constant infusion of norepinephrine was necessary to maintain mean ABP above 80 mmHg. On the 10th day the patient's condition deteriorated sharply. Developed hyperthermia to 40, 2 degrees and cardiovascular collapse (in spite of the high level of norepinephrine support a sharp decline in ABP up to 49/20 mmHg). Invasive advanced hemodynamic PiCCO monitoring (transpulmonary thermodilution) was started Septic shock was suspected. Standard laboratory tests did not meet the criteria for septic shock. Witnessed a slight increase in CRP and procalcitonin (PCT) was within normal limits. Diagnostic search was supplemented by a study of interleukins (IL-6 and IL-2R) in the blood plasma. The significant increase in their values, was regarded as the initial manifestations of the systemic inflammatory response. Sepsis was confirmed. The extended antibiotic therapy started Continuous Veno-Venous hemofiltration was used as part of treatment of the inflammatory-toxic condition. In two days of the therapy the patient's condition has stabilized, the patient recovered consciousness in the form of opening the eyes, simple instructions. At discharge, the patient's condition according to the Glasgow outcome scale was estimated at 4 points. PMID- 26596037 TI - [MASSIVE ARTERIAL BLEEDING FROM TRACHEOSTOMY: ANALYSIS OF TWO CASES]. AB - In article described two cases of severe complication of tracheostomy - massive arterial bleedingfrom tracheal stoma. Both patients died. The causes of this complication, time of development and predictors of tracheo - arterial fistula formation, life-saving measures, and possible surgical treatment discussed. PMID- 26596038 TI - [THE 105-ANNIVERSARY OF THE DISCOVERY INTRAVENOUS ANESTHESIA]. AB - The article shows the role off Jeremic Alexander in the discovery and development of the first methods of intravenous anesthesia in the world. PMID- 26596040 TI - [THE FATTY CELL. THE VISCERAL FATTY TISSUE, EFFECT OF HUMORAL MEDIATOR LEPTIN IN AUTOCRINE WAY AND IN PARACRIN CENOSISES OF CELLS. TWO PHYLOGENETICALLY, FUNCTIONALLY AND REGULATORY DIFFERENT POOLS OF FATTY TISSUE IN VIVO]. AB - Every cell reserves fatty acids in cytozol in drops of lipids in the form of non polar triglycerides for itself andfor oxidation in mitochondria. The specialized visceral fatty cells ofomentum and adipocytes ofsubcutaneous fat are the cells absorbing saturated and mono unsaturated fatty acids in form of triglycerides in apoB-48 chylomicrons, apoB-100 lipoproteins of low and very low density. They deposit their physiological time and liberate fatty acids in intercellular medium in the form ofpolar unesterified fatty acids bound by albumin. According phylogenetic theory of general pathology, in biological function of trophology (nutrition) fatty cells sequentially implement biological reaction of exotrophy (external nutrition), deposition and endotrophy (internal nutrition). The humoral regulator offeedback in visceral fatty cells is leptin acting in autocrine way, in paracrin cenosises of cells and on the level of organism. The biological role of leptin is in preventing a) deposition of surplus amount of non-polar triglycerides in fatty cells; b) formation of endoplasmic "stress"; c) death of fatty cells in apoptosis way, formation of corpuscles of apoptosis and failure of biological function of endoecology; d) formation of biological reaction of inflammation in visceral fatty tissue; e) high level of unsaturated fatty acids in intercellular medium and f) development of metabolic syndrome. The leptin prevents aphysiological deposit ofnon-polar triglycerides in insulin-dependent cells that are not intended to deposit non-polar triglycerides and also in beta cells of islands. The main cause of high level ofleptin in blood plasma is overeating offood physiological by content of nutrients. PMID- 26596041 TI - [THE BIOLOGICAL FUNCTION OF NUTRITION, BIOLOGICAL REACTION OF EXOTROPHY, DEPOSITING AND ENDOTROPHY. THE VISCERAL FATTY CELLS AND ADIPOCYTES - PHYLOGENETICALLY, FUNCTIONALLY AND REGULATORY DIFFERENT POOLS OF FATTY TISSUE]. AB - For billions years, two phylogenetically, functionally and regulatory different pools of fatty cells - visceral fatty acids and adipocytes coexist in vivo. Their becoming occurred at different degrees of phylogenesis. The phylogenetically earlier pool of visceral fatty acids is meant to supply with fatty acids substrates for gaining energy by those cells which implement biological function of nutrition (trophology), homeostasis, endoecology biological function of adaptation and continuation of species. They have no receptors to phylogenetically later insulin. The adipocytes, later in phylogenesis, implement one biological function - the function of locomotion and they are as insulin dependent as skeletal myocytes, cardiomyocytes, adipocytes and periportal hepatocytes. The difference in regulation is traced on all levels of "biological perfection " - autocrine (cellular) level, in humoral regulated paracrin cenosises of cells and on the level of organism. In biological function of trophology, paracrin cenosises of visceral fatty acids and adipocytes implement subsequently three biological reactions: exotrophy, deposit of fatty acids and endotrophy. In conditions of humoral regulation of three functionally different biological reactions in paracrin cenosises synthesis of so many humoral mediators is required. The humoral mediators of mechanism of feedback at autocrine level, in paracrin cenosises and at the level of organism are leptin of visceral fatty acids and adiponectin of adipocytes. At the level of organism, phylogenetically earlier paracrin cenosises of fatty cells are regulated by endocrine system. The phylogenetically later paracrin cenosises are regulated by insulin and nuclei of hypothalamus. The metabolic syndrome is a pathology of phylogenetically earlier insulin-independent visceral fatty acids. The obesity is a pathology of phylogenetically later pool of insulin-dependent adipocytes. PMID- 26596042 TI - [THE SIMULTANEOUS ANALYSIS OF FREE CATECHOLAMINES AND METANEPHRTNES IN URINE USING TECHNIQUE OF HIGHLY EFFECTIVE LIQUID CHROMATOGRAPHY WITH FLUORIMETRIC DETECTION AND SOLID PHASE EXTRACTION ON POLYMERIC SORBENT (PUROSEP-200)]. AB - The article considers the technique of simultaneous detection of free catecholamines and free metanephrines in urine using inverse phase highly effective liquid chromatography with fluorimetric detection. The solid phase extraction was implemented on cartridges with 30 mg of hyper cross-linked polystyrene (Purosep-200). The simplicity, reproducibility and sufficient sensitivity of technique permit applying it in clinical practice to diagnose pheochromocytoma. PMID- 26596043 TI - [THE CHOLINESTERASE OF BLOOD SERUM IN WORKERS OF INDUSTRIAL ENTERPRISE]. AB - The biochemical study of activity of serum cholinesterase in workers of industrial enterprise was carried out on the example of petrochemical industry. The indicators of average activity of enzyme and prevalence of indicators going beyond limits of reference values were analyzed depending on manufacturing-labor experience, profession and diseases established in workers. The main diseases, professional and labor experience groups were identified where activity of cholinesterase significantly changes. The impact of labor experience and profession on level of activity ofenzyme in blood serum is demonstrated. PMID- 26596044 TI - [THE VIRTUAL CYTOLOGIC SLIDES FOR EXTERNAL EVALUATION OF QUALITY OF IMPLEMENTATION OF CYTOLOGIC ANALYSES IN CLINICAL DIAGNOSTIC LABORATORIES: POSSIBILITIES AND PERSPECTIVES]. AB - The article considers application of technology of analysis of cytological slides in external quality control of clinical diagnostic laboratories. The advantages of virtual slides are demonstrated against other applied technologies of external evaluation of quality i.e. slide plate and digital micro-photography. The conditions of formation of virtual slides for external evaluation of quality of clinical diagnostic laboratories. The technology of their application is described. The success of practical application of considered technology in the Federal system of external evaluation of quality is emphasized. PMID- 26596045 TI - [THE MORPHOMETRY IN CYTOLOGICAL ANALYSIS OF EXUDATIVE FLUIDS]. AB - The cytological technique takes a leading position in diagnostic of tumor processes according exudative fluids. However, its results depend on large number of subjective factors. The morphometry is one of techniques by virtue of which objectification of data of cytological analysis is possible. The study was carried out to establish differences of morphometric parameters of benign and malignant cells of pleural effusion. The morphometric analysis of cells of mesothelium, breast cancer, adenocarcinoma of lung and adenocarcinoma of stomach was implemented. The parameters characterizing size (area, perimeter) and form (form factor) of nucleus and cell, nucleus-cytoplasm ratio. The results demonstrated that in pleural effusion between cells of proliferating mesothelium and malignant neoplasms exist significant differences in morphometric parameters (p<0.001). The differences between area of nuclei and cells are especially significant. The comparison of data of morphometry of cells of breast cancer; adenocarcinoma of lung and adenocarcinoma of stomach demonstrated that despite of some morphological similarities, analysis of morphometric parameters can provide important data for proper establishment of cytological diagnosis. PMID- 26596046 TI - [THE TECHNOLOGY "CELL BLOCK" IN CYTOLOGICAL PRACTICE]. AB - The article presents summary information concerning application of "cell block" technology in cytological practice. The possibilities of implementation of various modern techniques (immune cytochemnical analysis. FISH, CISH, polymerase chain reaction) with application of "cell block" method are demonstrated. The original results of study of "cell block" technology made with gelatin, AgarCyto and Shadon Cyoblock set are presented. The diagnostic effectiveness of "cell block" technology and common cytological smear and also immune cytochemical analysis on samples of "cell block" technology and fluid cytology were compared. Actually application of "cell block" technology is necessary for ensuring preservation of cell elements for subsequent immune cytochemical and molecular genetic analysis. PMID- 26596047 TI - [THE MODERN CONCEPTS OF HEMOSTASIS SYSTEM UNDER CHRONIC DISEASES OF LIVER: THE PUBLICATIONS REVIEW]. AB - The disorder of system of hemostasis under chronic diseases of liver results in coagulation imbalance affecting both primary and secondary hemostasis. The shifting of hemostasis balance beyond the limits of physiological standards in such patients can result either in bleeding or thrombosis. For a long time already it is considered that in patients with chronic diseases of liver alterations in hemostasis system and occurrence of bleeding are very often interrelated. However results of such screening coagulation tests as prothrombin time and activated partial thromboplastin time poorly correlate with onset and duration of bleeding, for example after liver biopsy and also with occurrence of gastro-intestinal bleeding in patients with terminal stage of diseases of liver The foreign publications of last decade contest concept of cause and effect relationship between changes of indicators of screening coagulation tests and risk of development of bleeding in patients with chronic diseases of liver The publications also dispute both usefulness of the given tests in evaluation of hemorrhages and expediency of therapeutic strategies in the case of correction of anomalous results of mentioned tests. This issue in patients with rare diseases is factually unexplored. For example, there are single publications concerning patients with glycogenous disease type. The bleeding in such patients begin in early childhood They are related to dysfunction of thrombocytes and decreasing of particular oligomers of von Willebrand factor Hence, disorders in various chains of hemostasis system in patients with chronic diseases of liver are characterized by many unresolved issues that hinder furthering of development of diagnostic biomarkers. At that, diagnostic of coagulopathies and correction of pathological conditions in such patients the new tests are to be developed to monitor states of hemostasis system in patients with chronic diseases of liver, rare nosologic forms included. PMID- 26596048 TI - [THE ROLE OF CYTOKINES AND CHEMOKINES IN LABORATORY DIAGNOSTIC OF CHRONIC VIRAL HEPATITIS C]. AB - The chronic viral hepatitis C is widely prevalent disease with prolonged persistence of virus and obliterated clinical picture. The present techniques of diagnostic of degree of fibrosis of liver and prognosis of course of disease have particular shortcomings. Hence, search of safe low invasive methods based on blood biomarkers is an actual task. The cytokines/chemokines (mediators of chronic inflammation) directly involved into immunopathogenesis of chronic viral hepatitis C can act in the capacity of biomarkers. The study was carried out to comprehensively analyze content of cytokines/chemokines in peripheral blood of patients with chronic viral hepatitis C at various stages of disease and infected by different genotypes of virus of hepatitis C. The concentration of cytokines/chemokines was identified in blood plasma of patients with chronic viral hepatitis C (n = 73) and conditionally healthy donors (n =3 7): IFNalpha, IFNgamma, IFNlambda/IL28alpha, TNFalpha, CCL2/MCP-1, CCL3/MIP-lalpha, CCL4/MIP lbeta, CCL5/RANTES, CCL8/MCP-2, CCL20/AIP-3alpha, CXCL9/MIG, CXCL10/P-10, CXCLII/ITAC. The multiplex analysis using technology xMAP was applied. The increasing of level of TNFalpha, CCL2/MCP-1, CCL4/ MIP-l, CCL8/ACP-2, CCL20/MIP 3alpha, CXCL9/MIG, CXCL10/IP-10, CXCL11/ITA C was established in blood plasma of patients with chronic viral hepatitis C as compared with control group. The levels of analyzed interferons IFNalpha, IFNgamma, IFNlambda/IL28alpha had no difference in studied groups. As far as chronic viral hepatitis C progresses and fibrosis of hepatic tissue develops the concentrations of TNFalpha, CCL2/MCP-1, CCL20/MIP-3alpha, CXCL9/MIG, CXCL10/IP-l0, CXCL11/ITAC increased significantly. The concentrations of chemokine CXCL11/IT4 C can be used as informative indicator for differentiating diagnostic of early stages of liver fibrosis. Depending on genotype of virus of hepatitis C, in patients with chronic viral hepatitis C change in content of CCL8/MCP-2 was established. Hence, detection in blood plasma of patients with chronic viral hepatitis C concentration of particular cytokines/chemokines using multiplex analysis technique permit analyzing additional information concerning degree of liver fibrosis, activity of process of damage of hepatic tissue under chronic viral hepatitis C that indicates indirectly on genotype of virus of hepatitis C. PMID- 26596049 TI - [THE IMMUNOLOGIC INDICATORS IN PATIENTS WITH CARIES OF CONTACT SURFACES OF LATERAL TEETH]. AB - The samplings of patients aged 18-45 years with caries of contact surfaces of lateral teeth (n=18) and healthy adults aged 18-20 years with intact teeth (n=18) were examined The saliva taken in rotary vial on empty stomach in amount of 3-4 mi served as assay for analysis. To identify secretory immunoglobulin A, interleukin lbeta, interleukin-4 and interferon y saliva was centrifuged during 15 min under 1500 rpm. The supernatant fluid was analyzed using enzymoimmunoassay (test-systems "Vector-Best", Novosibirsk). The registration of reaction was implemented using multiscan Labsystem under wavelength 450 nm. The content of secretory immunoglobulin A was expressed in mg/l, cytokines - in pg/ml. It is demonstrated that in patients with caries average level of interleukin lbeta was almost two times higher (p<0.05) than analogous indicator in healthy examined patients. In healthy patients average level of interferon gamma significantly (more than in 10 times) exceeded upper limit of allowable standard and was higher (p<0.05) in comparison with such in patients with caries of contact surfaces. The analysis of content of secretory immunoglobulin A in saliva established that in healthy patients average values of the given indicator were higher (p<0.05) than in patients with caries of contact surfaces of lateral teeth. The lower content of secretory immunoglobulin A and interferon y against the background of increased level of interleukin lbeta was detected in saliva of patients with caries of contact surfaces of lateral teeth. This occurrence can be considered as factor predisposing to development of caries process. PMID- 26596050 TI - [THE TRUE OR FALSE BACTERIEMIA: THE SIGNIFICANCE OF EVALUATION CRITERIA OF CLINICAL SIGNIFICANCE OF POSITIVE HEMOCULTURE]. AB - The diagnostic of infections of blood flow using technique of hemofermentation (blood inoculation) is one of the most significant functions of laboratory of clinical microbiology. The effectiveness of the given technique depends on many factors, including criteria of evaluation of clinical significance of episode of bacteriemia and isolated microorganism applied by physician-microbiologist. The intelligent analysis of received results is needed. The physician-microbiologist has to determine if microorganism isolated from given blood sample, is a genuine agent of infections of bloodflow or it is only effect of contamination of analyzed sample at certain stage. The article presents data concerning taxonomic structure of microorganisms isolated under episodes of bacteriemia of adult oncologic hematologic patients during 2005-2013. The criteria of evaluation of clinical significance of episode of bacteriemia and isolated microorganism are described. The given criteria are developed in the N.N. Blokhin Russian oncological research center and are applied since 1977. The cases of contamination and genuine bacteriemia are established. The comparative analysis of international data and results of one's own study are carried out. PMID- 26596051 TI - [THE CONDITION AND TENDENCIES OF DEVELOPMENT OF CLINICAL AND SANITARY MICROBIOLOGY IN THE RUSSIAN FEDERATION AND PROBLEM OF IMPORT SUBSTITUTION]. AB - The import substitution becomes one of the strategic tasks of national economy as a result of prolongation of economic sanctions concerning the Russian Federation of part of the USA, EU countries, Japan and number of other countries. It is not proper to be limited in import substitution only by goods because in conditions ofsanctions when access toforeign technologies is complicated Russia is needed to substitute foreign technologies by national designs in faster manner One of directions of effective import substitution is localization of production of laboratory equipment and consumables for clinical and sanitary microbiology on the territory ofthe Russian Federation and countries of Customs union. In Russia, in the field ofdiagnostic of dangerous and socially significant infections, all components for import substitution to implement gene diagnostic, immune diagnostic. bio-sensory and biochip approaches, isolation and storage of live microbial cultures, implementation of high-tech methods of diagnostic are available. At the same time, national diagnostic instrument-making industry for microbiology is factually absent. The few devices of national production more than on 50% consist of import components. The microbiological laboratories are to be equipped only with import devices of open type for applying national components. The most perspective national designs to be implemented are multiplex polimerase chain reaction test-systems and biochips on the basis of national plotters and readers. The modern development of diagnostic equipment and diagnostic instruments requires supplement of national collections of bacterial and viral pathogens and working-through of organizational schemes of supplying collections with strains. The presented data concerning justification of nomenclature of laboratory equipment and consumables permits to satisfy in fill scope the needs of clinical and sanitary microbiology in devices, growth mediums, consumables of national production and to refuse import deliveries without decreasing quality of microbiological analysis. This approach will ensure appropriate response to occurring challenges and new biological dangers and maintenance of biosecurity of the Russian Federation at proper level. PMID- 26596052 TI - [PRIMARY BILIARY LIVER CIRRHOSIS: MODERN CONCEPTS]. AB - Modern data on primary biliary liver cirrhosis are presented including the definition, prevalence, possible etiological factors, and detailed description of pathogenesis (autoimmune mechanisms, intrahepatic cholestasis, hereditary predisposition, environmental factors) and clinical picture. Also considered are complications and concomitant diseases, methods of laboratory, instrumental and morphological diagnostics, approaches to medicamental treatment and its effectiveness, indications for liver transplantation. PMID- 26596053 TI - [THE ROLE OF INFLAMMATION IN THE DEVELOPMENT OF PROLIFERATIVE VITREORETINOPATHY]. AB - This paper focuses on the risk factors of primay and secondary proliferative vitreoretinopathy, modern views of pathophysiology of this disease, and the role of inflammation in its development. Special attention is given to the involvement of pigment epithelial cells, macrophages, hyalocytes, gliocytes, supporting fibers (Muller's cells), mediators of inflammation, such as cytokines, chemokines, and growth factors, with reference to their interaction in the processes of proliferation and development of retinal membranes. PMID- 26596054 TI - [MICROSCOPIC COLITIS: CURRENT STATE-OF-THE-ART]. AB - The aim of the study was to analyse publications on practical aspects of the management of microscopic colitis (MC) as a common manifestation of diarrheic syndrome in aged subjects. Many etiopathogenetic issues remain debatable. Major difficulties are encountered in differential diagnostics. Of special importance is the relationship between MC, autoimmune and inflammatory intestinal diseases. Approaches to MC therapy vary from the use of antidiarrheal agents to comprehensive immunosuppressive treatment. PMID- 26596055 TI - [MARKERS OF SYSTEMIC INFLAMMATORY RESPONSE IN PATIENTS OPERATED FOR COMPLICATIONS OF INFECTIOUS ENDOCARDITIS]. AB - The study of markers of systemic inflammatory response in patients with infectious endocarditis showed that at admittance they had elevated blood C reactive protein and ferritin levels while leukocyte count and fibrinogen content remained normal. C-reactive protein and ferritin levels increased on day 1 of the postoperative period and tended to grow further on day 3 when both parameters reached maximum values; they started to decrease on day 6 These data indicate that C-reactive protein and ferritin levels can be used to characterise the postoperative conditions of the patients including manifestations of systemic inflammation and outcome of surgical treatment. PMID- 26596056 TI - [COMPARATIVE EFFECTIVENESS AND SAFETY OF NEW ORAL ANTICOAGULANTS AND WARFARIN IN PATIENTS WITH AGE-SPECIFIC NON-VALVULAR ATRIAL FIBRILLATION]. AB - This study was designed to compare effectiveness and safety of warfarin, direct thrombin inhibitor dabigatran, Xa factor inhibitors rivaroxaban and apixaban used to prevent stroke in 280 elderly patients in patients with age-specific non valvular atrial fibrillation. The treatment of patients aged 65-74 and 75-80 yearsfor 2 years with dab itragan (110 mg b.i.d), apixaban (5 mg b. i. d), and rivaroxaban (20 mg once daily) prevented stroke as effectively as warfarin therapy but less frequently caused severe intracranial hemorrhage. It is concluded that these new anticoagulants can be used as alternative medication for antithrombotic therapy of elderly patients with age-specific non-valvular atrialfibrillation. PMID- 26596057 TI - [ANTIBIOTIC RESISTANCE OF ESCHERICHIA COLI OF THE INTESTINAL MICROBIOTA IN PATIENTS WITH FAMILIAL MEDITERRANEAN FEVER]. AB - We used clinical bacteriological analysis and high-density DNA-microchips (PhyloChip) to study the quality and the quantity of commensal bacteria of the genus Escherichia in patients with familial mediterraneanfever (periodic disease). The intestinal microbiota of these patients contained a large number of operational taxonomic units of these bacteria. The study of antibiotic resistance of Escherichia coli from the intestinal microbiota in patients with familial mediterranean fever reveald a large number of resistant and multiresistant isolates. Therapy with commercial probiotic Narine (Vitamax-E, Armenia) reduced the number of operational taxonomic units of commensal bacteria and the frequency of multiresistant isiolates. The mechanism of action of Narine probiotic on intestinal bacteria and their resistance to antibiotics is discussed PMID- 26596058 TI - [POSSIBILITIES FOR THE SURGICAL TREATMENT OF PATIENTS WITH EXTENSIVE MALIGNANT CHEST WALL NEOPLASMS]. AB - The authors consider possibilities for the surgical treatment of patients with extensive malignant chest wall neoplasms. It is argued that combinedsugical interventions and resection of the affected parts of the chest wall together with the tumour and the use of plastic procedures allow to arrest further development of severe complications in the majority of patients and create conditions for the continuation of the anti-tumour treatment. Plastic and reconstructive surgery permits to extend operability limits and thereby improve the quality of the treatment and increase life expectancy of the patients with extensive tumorigenic process. PMID- 26596059 TI - [SMOKING AS A TRIGGER FACTOR IN THE DEVELOPMENT OF DIABETIC ANGIOPATHY OF LOWER EXTREMITIES IN MEN WITH METHYLENETETRAHYDROFOLATEREDUCTASE 677TT GENOTYPE]. AB - Enhanced thrombogenesis in patients with diabetes mellitus (D) is related to genetically determined disorders of the blood coagulation system analogous to those associated with hereditary thrombophilia. The aim of this work was to elucidate the relationship between the functionally significant methylenetetrahydroxyfolatereductase (MTHFR) C677T (rs1801133) gene polymorphism and the development of diabetic angiopathy of lower extremities (DALE) in ethnic Russian men residing in Central Russia (mostly Kursk region). The study involved 434 subjects including 50 with DALE and 384 healthy volunteers. All of them were genotypedfor the MTHFR C677T gene polimorphim by real-time PCR with allele discrimination using TaqMan-probes. No significant differences in the frequency of alleles of MTHFR C677T gene polymorphism were documented between the general samples and sex-matched groups. Stratified sex-specific analysis showed that 677TT genotype is associated with increased risk of DALE in smoking men (OR 4.2; 95% CI 1.28-13.79, p=0.01). In non-smoking men the 677TTgenotype was unrelated to the development of this complication. It is concluded that the risk of DALE is determined by the close relationship between genetic (UTHFR gene) and exogenous (smoking) factors which suggests the multifactorial nature of this pathology. PMID- 26596060 TI - [ACUTE KIDNEY INJURY AND IN-HOSPITAL MORTALITY IN PATIENTS WITH STROKE]. AB - AIM: to estimate the frequency and severity of acute kidney injury (AKI) in patients with stroke and the influence of AKI on intra-hospital lethality. MATERIALS AND METHODS: 180 patients with stroke. 8 (4.4%) of them died within 24 hr after admission. It was impossible to diagnose AKI in these patients from serum creatinine dynamics. The development of AKI was followed up in the remaining 80 (47.1%) men and 91 (52.9%) women (mean age 66.6 +/- 11.2 yr). AKI was diagnosed and classified as recommended by KDIGO (2012). RESULTS: AKI was documented in 47 (27.3%) patients including 13 (41.9%) and 34 (24.1%) with hemorrhagic and ischemic stroke respectively. Logistic regressive analysis revealed association of in-hospital lethality with AKI (relative risk 2.5; 95%, CI 1.7-3.8) regardless of sex, age, stroke type, duration of the disease prior to hospitalisation, arterial hypertension, and diabetes. CONCLUSION: stroke is complicated by AKI in every fourth patient; in combination, they significantly increase intra-hospital lethality. PMID- 26596061 TI - [NEWLY-DIAGNOSED CHRONIC KIDNEY DISEASE IN PATIENTS OF A THERAPEUTIC CLINIC: THE ROLE OF GFR CALCULATION BY THE CKD-EPI FORMULA]. AB - AIM: to estimate the prevalence of newly-diagnosed chronic kidney disease (CKD) and its risk factors in patients of a therapeutic clinic, to evaluate the importance of GFR calculation using the CKD-EPI formula. Materials and methods: the study included 275 patients (275 (31.1%) men and 610 (68.9%) women) aged 18 89 (mean 59.5 13.95) years. GFR of 60ml/min/l.73 m3 or signs of kidney lesions were diagnosed as CKD. Possible risk factors of CKD were elucidated based on the results of a questionnaire that provided information on complaints, metabolic disorders, family histoty compliance with a healthy lifestyle. Arterial pressure and serum creatinine level were measured, BMI and GFR calculated in all patients. RESULTS: Medical histories of 58% of the 885 patients contained signs of CKD. Among the remaining 372 (42%) ones, 7.2% had proteinuria and 20.1% GFR of 60ml/min/1. 73/m3. The prevalence of newly diagnosed CKD was 27.3%. The use of the CKD-EPI formula allowed to diagnose CKD in 18% of the patients having the serum creatinine level within normal values. The overall prevalence of CKD in the study group was 14%. CONCLUSION: the prevalence of newly diagnosed CKD in patients of a therapeutic clinic was 2 7.3%. The use of the CKD-EPI formula facilitates diagnostics of CKD. PMID- 26596062 TI - [EFFECTIVENESS OF FIXED COMBINATION OF PERINDOPRILARGININE AND AMLODIPINE FOR THE TREATMENT OF ARTERIAL HYPERTENSION WITH CONCOMITANT CHRONIC CARDIAC INSUFFICIENCY AND SIGNS OF CHRONIC KIDNEY DISEASE]. AB - AIM: to study effectiveness of a fixed combination of perindopril arginine and amlodipine besylate for the treatment of arterial hypertension with concomitant chronic cardiac insufficiency and signs of chronic kidney disease Materials and methods: 53 (44.9%) patients aged 64.5+/-8.2 yr with signs of chronic kidney disease (CKD) were selected from 118 subjects with grade II-III essential AH and chronic cardiac insufficiency They had an increased blood cystatin C level (mean 1.4+/-0.3 mg/l) and/or decreased glomerular filtration rate (GFR) calculated by 3 formulas: 77.6+/-15.9 (MDRD), 79.3+/-17.1 (CKD-EPI) and 57.7+/-15.2 ml/min/1. 73 m3 (from cystatin C level). Fixed combinations of perindopril arginine and amlodipine besylate (5/5, 5/10, 10/10 mg) were used to treat the patients. Their effectiveness was evaluated 2 months after the onset of therapy based on results of AP measurement, 24 hr AP monitoring, assessment of clinical conditions and 6 min walk test. Blood creatinine, urea and cystatin C levels and GFR were measured. RESULTS: Target AP was achieved in 82.6% of the patients. Systolic AP (SAP) decreased significantly from 172+/-11.2 to 135.7+/-8.2 mmHg (p<0.01), diastolic AP (DAP)from 110+/-6.9 to 85.3+/-7.2 mm Hg (p<0.5). Mean daily SAP and DAP decreased by 14.7 and 14.4% respectively. SAP and DAP load also decreased Clinical conditions estimated in terms of the CCI functional class improved (a decrease from 6.2+/-1.1 to 4.2+/-1.3 scores (p<0.01)). Tolerance of physical activity increased from 157.2+/-12.6 to 320.4+/-32.2 m (p<0.05). Blood cystatin C level decreased and GFR increased. CONCLUSION: The fixed combination of perindopril arginine and amlodipine besylate ensures high therapeutic effect in patients with arterial hypertension and concomitant chronic cardiac insufficiency having signs of chronic kidney disease. PMID- 26596063 TI - [THE INFLUENCE OF ABDOMINAL OBESITY ON LEFT VENTRICULAR MYOCARDIALREMODELING IN PATIENTS WITH ARTERIAL HYPERTENSION]. AB - The obesity dependence of selected clinical and instrumental characteristics of 10 male patients with arterial hypertension (AH) was evaluated Group I included 79 patients with grade II hypertensive disease (HD), normal body weight and waist circumference. Group 2 comprised 61 patients with grade II HD and abdominal obesity. Patients of both groups showed high frequency of left ventricular (LV) hypertrophy (59.2 and 73.8% respectively). Concentric LV hypertrophy prevailed in group I and eccentric hypertrophy in group 2. 24 hr ECG monitoring showed that signs of relative coronary insufficiency were recorded more frequently in group 2 and cardiac rhythm disturbances in group I. PMID- 26596066 TI - Beneath the surface. PMID- 26596065 TI - [Evgen'evich Votchal - innovator domestic therapy]. PMID- 26596064 TI - [INFECTIOUS ENDOCARDITIS IN PREGNANT WOMEN]. AB - A case of primary infectious endocarditis with the lesion of mitral valve in a pregnant woman is reported The diseases was caused by meticillin-resistant Staphylococcus aureus. Special attention is given to inefficiency of beta-lactame antibiotics against this infection and beneficial effect of daptomycin therapy. This observation confirms literature data about high frequency of thromboembolic complications of S aureus-induced infectious endocarditis due to the production of various coagulases and von Willebrand factor-binding protein by these microorganisms. An increase of coagulation caused by S. aureus is mediated through activation of prothrombin, factor XIII, and fibrin-binding fibronectin. It requires prescription of direct thrombin inhibitor pradax that proved to yield good results in the treatment of our patient. It is concluded that infectious endocarditis in pregnant women is characterized by an atypical clinical picture due to impaired immunity associated with rapid progression of the process after delivery, high frequency of thromboembolic and DIC syndromes. PMID- 26596067 TI - Tested triathlete. PMID- 26596068 TI - Equity advocate. PMID- 26596069 TI - Toward better health for all. PMID- 26596070 TI - Caring for hearts and souls. PMID- 26596071 TI - Toward more equitable research. PMID- 26596072 TI - Equity Rx. PMID- 26596073 TI - Tools of the trade. When listening is the best medicine. PMID- 26596074 TI - The scariest moment. PMID- 26596075 TI - We need a Triple Aim for Health Equity. PMID- 26596076 TI - The Clinician's Role in Addressing Disparities in Tobacco Use. AB - Although the overall smoking rate in Minnesota is now less than 15%, the rates among certain populations are much higher. For example, 60% of American Indian adults smoke. The rates are also higher for people with low incomes and little education, those who have a mental illness or are substance abusers, and those who are transgender or identify as lesbian, gay, bisexual, transgender or queer. With more people covered by health insurance and smoking-cessation treatment now included in insurance plans thanks to recent health care reforms, physicians and other members of the health care team have a new opportunity to address tobacco use This article discusses ways they can tailor the discussion as they seek to help patients in populations with the highest smoking rates. PMID- 26596077 TI - Addressing MMR Vaccine Resistance in Minnesota's Somali Community. AB - Over the past 10 years, Minnesota clinicians have noticed increased resistance to MMR vaccination among Somali Minnesotans. Misinformation about a discredited study asserting a link between the MMR vaccine and autism has permeated this community as parents have increasingly become concerned about the prevalence of autism spectrum disorder among their children. As a result, MMR vaccination rates among U.S.-born children of Somali descent are declining. This article reports findings from an investigation by the Minnesota Department of Health, which was undertaken to better understand vaccine hesitancy among Somali Minnesotans. Based on these and other findings, we propose a multi-pronged approach for increasing vaccination rates in this population. PMID- 26596078 TI - The Unequal Burden of Suicide among Minnesotans: Three Strategies for Prevention. AB - Minnesota's suicide rate has been increasing for more than 10 years. This article describes the demographic groups at highest risk for suicide and suicide attempts in the state. It also highlights prevention strategies outlined in the Minnesota State Suicide Prevention Plan 2015-2020. PMID- 26596079 TI - Health Disparities between Rural and Urban Women in Minnesota. AB - With much discussion about health disparities in Minnesota in recent years, there has been growing awareness about the inequities between rich and poor and between majority and minority groups. Attention also needs to be paid to the disparities between women who live in rural areas and those who live in urban parts of the state. Rural women are poorer, older and less likely to have adequate health insurance than their urban counterparts, which can compromise their health status. They also fare worse on a number of health indicators and face barriers to adequate health care that can exacerbate disparities. This article describes the root causes of health disparities between women living in rural and urban parts of the state and explores strategies to mitigate them that include increasing the rural physician workforce, improving access to primary and specialty care through telehealth services, and expanding health insurance options. PMID- 26596080 TI - [Bacterial Outer Membrane Nanovesicles: Structure, Biogenesis, Functions, and Application in Biotechnology and Medicine (Review)]. AB - The review summarizes the comprehensive biochemical and physicochemical characteristics of extracellular membrane nanovesicles (EMN) derived from different kinds of bacteria. The EMN structure, composition, biogenesis, secretion mechanisms, formation conditions, functions, involvement in pathogenesis, and application in biotechnology and medicine are discussed. PMID- 26596081 TI - [Signaling Systems of Rhizobia (Rhizobiaceae) and Leguminous Plants (Fabaceae) upon the Formation of a Legume-Rhizobium Symbiosis (Review)]. AB - Data from the literature and our own data on the participation and interrelation of bacterial signaling Nod-factors and components of the calcium, NADPH-oxidase, and NO-synthase signaling systems of a plant at the preinfection and infectious stages of the formation of a legume-rhizobium symbiosis are summarized in this review. The physiological role of Nod-factors, reactive oxygen species (ROS), calcium (Ca2+), NADPH-oxidase, nitric oxide (NO), and their cross influence on the processes determining the formation of symbiotic structures on the roots of the host plant is discussed. PMID- 26596082 TI - [Cephalosporin-Acid Synthetase of Escherichia coli Strain VKPM B-10182: Genomic Context, Gene Identification, Producer Strain Production]. AB - An enzyme of cephalosporin-acid synthetase produced by the E. coli strain VKPM B 10182 has specificity for the synthesis of beta-lactam antibiotics of the cephalosporin acids class (cefazolin, cefalotin, cefezole etc.). A comparison of the previously determined genomic sequence of E. coli VKPM B-10182 with a genome of the parent E. coli strain ATCC 9637 was performed. Multiple mutations indicating the long selection history of the strain were detected, including mutations in the genes of RNase and beta-lactamases that could enhance the level of enzyme synthesis and reduce the degree of degradation of the synthesized cephalosporin acids. The CASA gene--a direct homolog of the penicillin G-acylase gene--was identified by bioinformatics methods. The homology of the gene was confirmed by gene cloning and the expression and determination of its enzymatic activity in the reaction of cefazolin synthesis. The CASA gene was isolated and cloned into the original expression vector, resulting in an effective E. coli BL2l(DE3) pMD0107 strain producing CASA. PMID- 26596083 TI - [Novel Immobilized Biocatalyst for Microbiological Synthesis of Pharmaceutical Steroids]. AB - The steroid-transforming activity of free and immobilized cells of Pimelobacter simplex VKPM As-1632 entrapped in an operationally stable macroporous polyvinyl alcohol cryogel was studied. It was shown that the macroporous matrix of the carrier did not create any diffusional limitations for steroid access to the cells or the removal of the transformation products from them. The optimal conditions for the hydrocortisone 1,2-dehydration into prednisolone by free and immobilized cells were elucidated. The immobilized biocatalyst was obtained in a granulated form and used in 32 successive cycles of steroid transformation. The average cycle duration was 45 min, and the prednisolone yield of during the first 20 cycles was 98%. It was established that the immobilized cells of the actinobacteria P. simplex retained high steroid-transforming activity over all of the transformation cycles. The physicochemical and diffusion characteristics of the polyvinyl alcohol gels and its granules were determined, and their high stability during repeated cycles of steroid transformation was shown. The results indicated that P. simplex immobilized cells represent an effective catalyst suitable for multiple use. Biomass consumption decreased upon its use, and product isolation, as well as culture storage, was much easier. PMID- 26596084 TI - [Catalytic and Stereoselective Properties of the Immobilized Amidase of Rhodococcus rhodochrous 4-1]. AB - The amidase of Rhodococcus rhodochrous 4-1 was immobilized by covalent attachment to activated chitosan by physical sorption on carbon adsorbents and by the formation of crosslinked aggregates in the absence of carrier material. Comparative analysis of particular catalytic properties of the free and chitosan immobilized amidase was performed. It was shown that the enzyme retained 50-60% of its initial activity after covalent immobilization on chitosan and was characterized by increased temperature stability as compared to soluble amidase. Moreover, the immobilized enzyme retained more than 20% of its activity after five 24-h cycles of acrylamide deamination. The effects of different types of immobilization on amidase stereose-lective properties were studied by the model reaction of racemic lactamide hydrolysis to D-lactic acid and L-lactic acid. It was shown that crosslinked amidase aggregates possessed high D-stereoselectivity (up to 77-94%). The immobilized enzyme showed the highest enantioselectivity at 60 degrees C. PMID- 26596085 TI - [The Influence of Rifampicin Resistant Mutations on the Biosynthesis of Exopolysaccharides by Strain Escherichia coli K-12 lon]. AB - The influence of RNA polymerase (rif) mutations on the yield of capsular exopolysaccharide--colanic acid (CA) of Escherichia coli K-12 lon strain was studied. Five colanic acid isogenic producing strains were created by transduction transfer of rif alleles possessing pleiotropic effects. The obtained isogenic strains differed by specific growth rate, size and mucoidness of colonies, the dependence of growth on the medium composition and cultivation temperature, as well as by the adsorption rate of virulent bacteriophage M59, specifically lysing E. coli cells producing CA. Direct correlation between the yield of exopolysaccharides, growth rate and adsorption of bacteriophage M59 was revealed. Among rif recombinants strain AH203, which synthesized twice as much CA compared with the parental strain in submerged cultivation was selected. PMID- 26596086 TI - [Distiller Yeasts Producing Antibacterial Peptides]. AB - A new method of controlling lactic acid bacteria contamination was developed with the use of recombinant Saccharomyces cerevisiae strains producing antibacterial peptides. Genes encoding the antibacterial peptides pediocin and plantaricin with codons preferable for S. cerevisiae were synthesized, and a system was constructed for their secretory expression. Recombinant S. cerevisiae strains producing antibacterial peptides effectively inhibit the growth of Lactobacillus sakei, Pediacoccus pentasaceus, Pediacoccus acidilactici, etc. The application of distiller yeasts producing antibacterial peptides enhances the ethanol yield in cases of bacterial contamination. Recombinant yeasts producing the antibacterial peptides pediocin and plantaricin can successfully substitute the available industrial yeast strains upon ethanol production. PMID- 26596087 TI - [Novel Enzyme Preparations with High Pectinase and Hemicellulase Activity Based on Penicillium canescens Strains]. AB - Recombinant strains of Penicillium canescens producing homologous pectin lyase A and heterologous endo- 1,5-alpha-arabinase A and endo- 1,4-alpha polygalacturonase, as well as enzymes of the host strain (alpha-L arabinofuranosidases, xylanases, and others), were obtained by genetic engineering. The enzyme preparations (EPs) obtained from the cultural medium of recombinant P. canescens strains efficiently hydrolyzed raw plant material with a high content of pectin compounds. It was shown that the yield of reducing sugars and arabinose increased 16 and 22% in comparison with the control EP based on the host strain when one of the obtained EPs was used for beet pulp hydrolysis. It was established that the most active EP consisted of pectin lyase (10%), endo-1,5 arabinase (26%), alpha-L-arabinofuranosidase and arabinoxylan arabinofuranohydrolase (12%), and xylanase (10%). The activities of pectin lyase, polygalacturonase, and arabinase of the EP in reactions with various substrates were determined. The specificity, pH and T-optima, and thermal stability of the homogenous recombinant endo- 1,5-alpha-arabinase were investigated. The kinetic parameters (K(m), K(cat)) of the linear arabinan hydrolysis were determined. PMID- 26596088 TI - [State of Fungal Lipases of Rhizopus microsporus, Penicillium sp. and Oospora lactis in Border Layers Water-Solid Phase and Factors Affecting Catalytic Properties of Enzymes]. AB - We demonstrated that a change in the catalytic activity of fungal lipases synthesized by Rhizopus microsporus, Penicillium sp. and Oospora lactis and their ability to absorb on different sorbents depended on the nature of groups on the solid phase surface in the model systems water: lipid and water: solid phase. Thus, the stability of Penicillium sp. lipases increased 85% in the presence ofsorsilen or DEAE-cellulose, and 55% of their initial activity respectively was preserved. In the presence of silica gel and CM-cellulose, a decreased rate of lipid hydrolysis by Pseudomonas sp. enzymes was observed in water medium, and the hydrolysis rate increased by 2.4 and 1.5 times respectively in the presence of aminoaerosil and polykefamid. In an aqueous-alcohol medium, aminoaerosil and polykefamid decreased the rate of substrate hydrolysis by more than 30 times. The addition of aerosil to aqueous and aqueous-alcohol media resulted in an increase in the hydrolysis rate by 1.2-1.3 times. Sorsilen stabilized Penicillium sp. lipase activity at 40, 45, 50 and 55 degrees C. Either stabilization or inactivation of lipases was observed depending on the pH of the medium and the nature of chemical groups localized on the surface of solid phase. The synthetizing activity of lipases also changed depending on the conditions. PMID- 26596092 TI - PPS proposed rule: A re-mix of the case-mix--or take them out of the recipe. PMID- 26596089 TI - [Development of an Immunochromatographic Test System for the Detection of Helicobacter pylori Antigens]. AB - A test system based on immunochromatography in the sandwich format and intended for express detection of Helicobacter pylori antigens has been developed. Contact of a sample with a test strip coated with immunochemical reagents triggers the movement of the liquid along the membrane components of the test strip, immunochemical interactions, and the formation of detection zones stained by gold nanoparticles. The concentration and kinetic dependences of the immunochemical interactions have been characterized. The reagent and membrane composition of the test system has been selected to provide a minimal detection limit. The detection of H. pylori cell wall antigens at concentrations as low as 0.3 MUg/mL in aqueous solution and a suspension of a clinical sample of feces has been demonstrated; the assay duration was 10 minutes. Staining enhancement by the addition of silver salts allowed for a further reduction of the detection limit to 0.03 MUg/mL. The developed test system can be used for field diagnostics. PMID- 26596090 TI - [Effect of the Hydrogel Carrier Structure on the Activity of Immobilized Trypsin]. AB - The dependence of the activity of trypsin immobilized in polyacrylamide hydrogel on the hydrogel swelling ratio, the size distribution of its pores, and the means of enzyme binding has been studied. It has been shown that the most favorable conditions for immobilized trypsin are provided upon its binding to hydrogel via trypsin macromonomer copolymerization with acrylamide and a linking agent in the presence of a modifier that limits polymer chain growth. PMID- 26596093 TI - Renal anemia treatment: An evolving market. PMID- 26596091 TI - [Aniline Polymerization on Multiwall Carbon Nanotubes with Immobilized Laccase]. AB - A composite material consisting of electrically conductive polyaniline deposited on the surface of multiwall carbon nanotubes has been synthesized. Enzymatic synthesis was carried out in the presence of Trametes hirsuta laccase immobilized on the nanotube surface. The obtained composite was morphologically uniform, and its electrochemical capacity and stability were much higher than those of a composite synthesized according to the conventional chemical procedure. PMID- 26596094 TI - Identifying the physician's role in an EHR rebuild. PMID- 26596095 TI - Nurse Nancy doesn't work here anymore: The dilemma in dialysis nurse retention. AB - Summary Without an increase in base pay rates for both staff and travel nurses and rethinking some hard and fast practices, there will be no improvement in the dialysis nursing landscape in the foreseeable future. PMID- 26596096 TI - Options for nutritional intervention during pre-dialysis care. PMID- 26596097 TI - Using transitional care coordinators to reduce hospital readmissions. PMID- 26596099 TI - Multitasking the Art and Science of Dentistry. PMID- 26596098 TI - Building Relationships. PMID- 26596100 TI - Mercy, Mercy, Mercy. PMID- 26596101 TI - First Voice: Twenty Years of the MDA Student District Dental Society. PMID- 26596102 TI - Back Here on the Ground: The Brainerd Lakes Megastorm of 2015. PMID- 26596103 TI - Dens Evaginatus: Just Another Cusp? PMID- 26596104 TI - Amalgam Restorations: To Bond or Not. AB - This article will review the use of various liners used to eliminate microleakage in amalgam restorations. It will review the literature about whether amalgam restorations are improved by using a bonding process and if so specifically how it improves the patient outcome. PMID- 26596105 TI - Dollars and Sense: Mouth Guards in a General Dental Practice Philosophy. PMID- 26596106 TI - Recognize the Warning Signs of Opioid Misuse and Diversion. PMID- 26596107 TI - [On risk-oriented model of sanitary epidemiologic surveillance in occupational hygiene]. AB - In 2015, Federal Service on surveillance in consumers rights protection and public well-being set a task to organize planned work of regional agencies on basis of risk-oriented model of control and supervision. Based on results of pilot project in Rospotrebnadzor Department of Perm area and St-Petersburg, the article covers methodic approaches to classification of objects liable to surveillance in occupational hygiene. The classification considers possibility of sanitary law violation, severity of this violation consequences and number of workers exposed to risk factors including hazardous work conditions. The authors specified recommendations on periodicity and forms of planned inspections considering evaluation of potential risk for human health, determined problems that require solution in implementation of risk-oriented model of surveillance. PMID- 26596108 TI - [Occupational risk of cardiovascular diseases in workers engaged into underground mining]. AB - The article presents results of evaluation of a priori and a posteriori occupational risks for workers engaged into underground mining. Evidence is that work conditions of major occupational groups of workers engaged into underground mining, according to workplace certification, correspond to 3 class 3 jeopardy degree. A priori risk of diseases development corresponds to high (unbearable). Evaluation of cause-effect relationship between health disorders and work conditions revealed a medium degree of occupational conditionality for vascular regulation disorders and metabolic disorders, that can be considered as cardiorisk indicators. PMID- 26596109 TI - [Analysis of changes in characteristics of arterial hypertension occupational risk in workers of nonferrous metallurgy]. AB - The article covers changes in occupational cardiovascular risk for workers of nonferrous,metallurgy. Findings are that exposure to noise up to 94 dB with length of service increases possible atherosclerosis and metabolic syndrome. With 5 years of service, risk of the predicted conditions increases by 40.5%. When occupational exposure lasts over 5 years, risk of arterial hypertension increases. A group of workers without exposure to occupational factors appeared to have no connection between length of service and metabolic syndrome and arterial hypertension. Risk evolution modelling proved that risk of functional disorders in nonferrous metallurgy workers becomes unacceptable after 5 years of service (cardiovascular disorders are critical). PMID- 26596110 TI - [Prevalence and risk of endometriosis in industrial territories]. AB - The study covered prevalence of endometriosis under various levels of exposure to chemical environmental factors and chemical risk factors for immune and reproductive female systems, identified as exposure markers in sanitary epidemiologic studies. Findings are that a part of inhabited area neighbouring to industrial territory is characterized by unacceptable risk of immune disorders and reproductive system diseases due to chronic exposure to formaldehyde, nickel, lead, benzene, that can result in increased prevalence of endometriosis. PMID- 26596111 TI - [Possibilities of submicron objects study in blood of workers]. AB - The article contains results of studies characterizing nanoparticles in blood and serum of exposed workers engaged into titanium and magnesium production and workers outside coverage of occupational factors. Comparative study of the workers' serum included dynamic light dispersion, scanning electronic microscopy, transmission electronic microscopy. Measuring despersion characteristic of blood serumin the workers exposed to nanomaterial revealed increased percentage of particles with hydrodynamic diameter within 60-100 nm and over 100 nm. PMID- 26596112 TI - [Genetically determined lipid metabolism disorders due to oral intake of technogenic hyperchlorination products]. AB - The study covered genetically determined lipid metabolism disorders due to oral intake of technogenic hyperchlorination drinkable water products. Findings are that overweight and obese children in a main group appeared to have serum chloroform level 2.3 times higher than that in a reference group. In oral intake of hyperchlorination drinkable water products, the study revealed main genes having polymorphism associated with endocrine disorders: overweight and obesity- APOE, PPARG, HTR2A, characterizing antioxidant system state--SOD2 and detoxication--SULTA. Polymorphism of candidate genes HTR2A and SOD2 was characterized by increased occurrence of mutant homo-- and heterozygous genotype, relative risk of pathologic allele presence in population exceeded the refrence group values. Probability of increased serum serotonin and lower Cu/Zn in children with mutant homozygous genotype HTR2A and SOD2 is 1.2-1.3 times higher than in those with heterozygous and normal homozygous genotypes. PMID- 26596113 TI - [Risk communication in analysis of occupational health risk for industrial workers]. AB - The article covers problems of risk communication system function on industrial enterprise. Sociologic study in machinery construction enterprise of Perm area helped to consider main procedures of informing on occupational risk for health of workers exposed to occupational hazards, to describe features and mechanisms of risk communication, to specify its model. The authors proved that main obstacles for efficient system of occupational risks communication are insufficiently thorough legal basis, low corporative social responsibility of the enterprise and low social value of health for workers. This article was prepared with the support of the Russian Humanitarian Science Foundation (Project No. 14 16-59011). PMID- 26596114 TI - [Clinical and laboratory diagnostic criteria of chronic glomerular and tubulointerstitial kidney disorders associated with exposure to metals and oxygen organic compounds of technogenic origin]. AB - Complex clinical, functional an laboratory examination of children living under unacceptable risk conditions due to aerogenous exposure to cadmium, chromium, lead and phenol revealed that kidney diseases associated with exposure to metals and phenol develop in children with genetic predisposition to disordered biotransformation of chemicals--polymorphism of genes CYPOX, RCYT 450, SULTA1 in homozygous and heterozygous variants. Increased levels of chemicals in blood causes microcirculation disorders in renal cortex, direct toxic effect in nephrons, suppresses activity of anitoxidant defense on cellular and systemic levels. The authors specified pathogenetically based complex of clinical and laboratory diagnostic markers of chronic kidney diseases associated with exposure to metals (cadmium, chromium, lead) and oxygen-containing (phenol) organic compounds. PMID- 26596115 TI - [Endothelial dysfunction and nonspecific immune reactions in development and progression of osteoarthrosis in women engaged into manual work]. AB - The article considers mechanisms of development and progression of osteoarthrosis as an occupationally conditioned disease in women of manual work. Women working in physical overstrain conditions are under occupational risk with dysfunction of many body systems. The authors set a hypothesis on association of endothelial dysfunction markers dysbalance and structural remodelling of cartilage matrix as a proof of degenerative changes. PMID- 26596117 TI - [For jubilee of Ylianovsk regional center of occupational diseases: scientific and practical conference and meeting of Chief occupational therapists of Privolzhsky Federal District]. PMID- 26596116 TI - [Topical problems and prospects of industrial medicine nowadays (according to materials of scientific and practical conferences of 2014)]. AB - The article presents results of scientific and practical conferences on occupational medicine problems, that were held in Moscow, St-Petersburg, Rostov na-Donu, Nizhny Novgorod, Sochi, Irkutsk, Angarsk. Prospective trends of research work and practical implementation in occupational medicine and industrial ecology are set. PMID- 26596118 TI - Homework setting in cognitive behavioral therapy: A study of discursive strategies. AB - In recent years cognitive behavioral therapy (CBT), a form ofpsychotherapy, has risen to prominence due to a large number of studies attesting to its efficacy. A crucial part of the model of CBT is the use of the therapeutic strategy, homework, in which the client undertakes therapeutic tasks between sessions. The focus of this study is on how homework is implemented in sessions of CBT. This is undertaken through an analysis utilizing theme-orientated discourse analysis of video recorded sessions of CBT of one therapist and a client. Through tracking the focal theme of homework, the analysis focuses on homework as a face threatening act (Brown and Levinson 1987) and how discursive strategies are employed to manage this issue. Other analytic themes include the use of frames (Goffman 1974) and constructed dialogue (Tannen 2007). It is the expertise of the therapist in putting into practice the therapeutic task of homework that is the subject of this study. PMID- 26596119 TI - Key components of effective collaborative goal setting in the chronic care encounter. AB - Collaborative goal setting in patient-provider communication with chronic patients is the phase in which--after collecting the data regarding the patient's health--it is necessary to make a decision regarding the best therapy and behaviors the patient should adopt until the next encounter. Although it is considered a pivotal phase of shared decision making, there remain a few open questions regarding its components and its efficacy: What are the factors that improve or impede agreement on treatment goals and strategies?; What are the 'success conditions' of collaborative goal setting?; How can physicians effectively help patients make their preferences explicit and then co-construct with them informed preferences to help them reach their therapeutic goals? Using the theoretical framework of dialogue types, an approach developed in the field of Argumentation Theory, it will be possible to formulate hypotheses on the success conditions' and effects on patient commitment of collaborative goal setting. PMID- 26596120 TI - Using SurveyMonkey(r) to teach safe social media strategies to medical students in their clinical years. AB - Social media is a valuable tool in the practice of medicine, but it can also be an area of 'treacherous waters' for medical students. Those in their upper years of study are off-site and scattered broadly, undertaking clinical rotations; thus, in-house (university lecture) sessions are impractical. Nonetheless, during these clinical years students are generally high users of social media technology, putting them at risk of harm if they lack appropriate ethical awareness. We created a compulsory session in social media ethics (Doctoring and Social Media) offered in two online modes (narrated PowerPoint file or YouTube video) to fourth- and fifth-year undergraduate medical students. The novelty of our work was the use of SurveyMonkey(r) to deliver the file links, as well as to take attendance and deliver a post-session performance assessment. All 167 students completed the course and provided feedback. Overall, 73% Agreed or Strongly Agreed the course session would aid their professionalism skills and behaviours, and 95% supported delivery of the curriculum online. The most frequent areas of learning occurred in the following topics: email correspondence with patients, medical photography, and awareness of medical apps. SurveyMonkey(r) is a valuable and efficient tool for curriculum delivery, attendance taking, and assessment activities. PMID- 26596121 TI - Utilization of patient resources in physiotherapy interventions: Analysis of the interaction concerning non-specific low back pain. AB - This paper reports on an empirical study in Sweden of how patient resources come into play in physiotherapy interventions. A qualitative analysis was conducted of five video-recorded first encounters between patients with non-specific low back pain (NSLBP) and physiotherapists in primary care, using Conservation of Resource Theory (COR) to identify and focus on how physiotherapists made use of patients' resources (objects, conditions, personal characteristics and energies). The findings reveal variations in how these resources are utilized during the intervention. Resources with implications for what happens in the examination room during the ongoing encounter and resources characterized by professional familiarity were both employed in the intervention. However, underutilized resources were featured in the broader lifeworld perspective of laypeople and of other professional frames. The findings raise questions about professional challenges that go beyond professional skills. This implies that professionals need to improve skills in understanding and integrating patient resources into interventions. PMID- 26596122 TI - Autism itself actually isn't a disability': Negotiating a 'normal' versus 'abnormal' autistic identity. AB - The opposing positions of the social model of disability and the biomedical framework of impairment have created tensions regarding what constitutes 'normality'. In this article, we drew upon focus group data of parents, professionals, and people with autism, to explore how the dilemmatic tensions of normality and abnormality and of disability and ability were managed. Our findings illustrate how the boundaries of normality in relation to autism are blurred, as well as how the autistic identity is fluid. The members of the focus group invoked their epistemic rights to assert their positions and delicately considered the limitations of the rhetoric of cure. Our findings have implications for professionals working with families of children with autism, specifically as they aim to maintain a balance between providing sufficient support and not being intrusive, and we show how a medical sociology can facilitate an understanding of autism as a social category. PMID- 26596123 TI - Engaging death: Narrative and constructed dialogue in Advance Care Planning discussions. AB - Advance Care Planning (ACP) remains extremely low in the US, due to numerous institutional and cultural barriers and discomfort in discussing death. There is a need for guidance about how patient and healthcare providers can effectively engage in ACP discussion. Here we analyze the linguistic strategies that focus group participants use when discussing ACP in detailed ways. Prevalent linguistic structures in effective ACP discussions were loved ones' end-of-life narratives, hypothetical narratives, and constructed dialogue. In elucidating spontaneous, unprompted approaches to effective discussion of end-of-life issues, such research can help to dislodge communicative barriers to ACP so that more people are prepared to engage the process. PMID- 26596124 TI - The collective voice: Legitimation strategies in focus group discussions with nurses in municipal palliative care for older people in Sweden. AB - This paper explores focus group discussions of registered nurses in municipal palliative care for older people, using data collected by researchers with an interest in health sciences. The linguistically based discourse analyis builds on a combination of Bakhtinian notions of dialogicity, the Other and addressivity, the use of quotations, and also van Leeuwen's framework for legitimation in discourse. The aim is to investigate strategies of addressing and legitimizing palliative care. Three types of narrative are discerned: the cautionary tale, fictionalization of professional experiences and the enactment of a fictive dialogue. The other professions involved (physicians, assistant nurses) are positioned as the Other as a means of legitimizing the perspectives of the registered nurses. As the patients and their next of kin are the objects of professional activities, the notion of the Third (connecting to the Other) is proposed. The objectification is a manifestation of commitment with routinized and professional distance to the patients. PMID- 26596125 TI - Data sharing for public health research: A qualitative study of industry and academia. AB - Data sharing is a key biomedical research theme for the 21st century. Biomedical data sharing is the exchange of data among (non)affiliated parties under mutually agreeable terms to promote scientific advancement and the development of safe and effective medical products. Wide sharing of research data is important for scientific discovery, medical product development, and public health. Data sharing enables improvements in development of medical products, more attention to rare diseases, and cost-efficiencies in biomedical research. We interviewed 11 participants about their attitudes and beliefs about data sharing. Using a qualitative, thematic analysis approach, our analysis revealed a number of themes including: experiences, approaches, perceived challenges, and opportunities for sharing data. PMID- 26596126 TI - Disclosure of mental health problems in general practice: The gradual emergence of latent topics and resources for achieving their consideration. AB - Common mental disorders often go undetected in primary care. Sharpening general practitioners' (GPs') attention to potential signs thereof is therefore crucial. This conversation-analytic study arises from the observation that the consideration of psychological problems in new-concern visits can be achieved by way of 'gradual topic emergence'. This entails that the problem is not presented directly, but adjunct to somatic symptoms, and is hinted at by way of generic, ambiguous complaints, and furthermore by expressions of frustration and uncertainty and talk about lifeworld problems. It is argued that these materials are 'trouble-premonitory, alerting the GP to the presence of an underlying problem that can then be addressed throughfurther inquiry. The patient logic behind this approach is to assure the GP's recipiency and thus ratification of the problem's medical legitimacy. It allows the patient to introduce a potentially delicate problem 'off the record, thus guarding the patient against the loss of face that could resultfrom no uptake by the GP. The results of the study point to the importance of GPs being receptive to such interactional clues to psychological problems provided by patients. PMID- 26596127 TI - Revalidation in the spotlight. PMID- 26596128 TI - If you fail to prepare for revalidation you put your NMC registration at risk! PMID- 26596129 TI - Perinatal Care: reflections on dads' engagement. PMID- 26596130 TI - Infant Mental Health: Health visitors as key partners. PMID- 26596131 TI - Dysphagia: prevalence, management and the community nurse. AB - Swallowing problems are common and may occur in non neurological conditions. Swallowing problems are often insidious and ignored in older people; dysphagia should be recognized as a geriatric syndrome. It is important to identify this to ensure appropriate intervention and management is put into place. A Community Nurse is ideally placed to do this. PMID- 26596132 TI - Empowering health visitors: a multi-faceted approach. AB - Health visitors working in Tower Hamlets, a deprived inner London borough, face a large and growing under-5 population, and caseloads with disproportionate numbers of vulnerable families and child protection concerns. This paper reports and evaluation of a project to empower health visitors. Baseline data about their activity (primarily derived from observation and interviews) showed that health visitors would benefit from improved resources (e.g. leaflets, books, training packs); enhanced knowledge of local borough and third sector services; and support for their own wellbeing and morale. After the programme that was implemented to provide these, seven health visitors were interviewed for evaluation purposes. They reported feeling empowered by the project: the training had been invaluable in providing affirmation, reassurance, and the opportunity to reflect; the new sleep information packs were very helpful for families, as was the new leaflet explaining their role; and restorative supervision had been useful in helping individuals think through how to deal with particular challenges in life or work. The project was thus successful in helping the health visitors interviewed to feel more supported and thus empowered in their work with families. PMID- 26596133 TI - Exploring the support mechanisms health visitors use in safeguarding and child protection practice. AB - Health visitors lead the Healthy Child Programme (HCP), a universal public health service designed to give children the best start in life. Running through the HCP are responsibilities to safeguard and protect children. Supporting the role of the health visitor is essential to ensure quality interventions and improved outcomes for children. This article describes an empirical study. It explores the experiences and views of health visitors on the mechanisms of support they use for working in child protection and safeguarding. A qualitative approach was used to collect data from two focus groups. The data produced was transcribed and a thematic analysis used to produce the results. The results demonstrate that health visitors gain the majority of their support from their colleagues and from supervision processes. Also identified from the data analysis were three factors which health visitors felt supported their role. These were support for managing the emotions associated with child protection work, feeling safe and effective in practice and having time to reflect and evaluate casework. PMID- 26596134 TI - A Preceptorship Model for Health Visiting. AB - Many new qualified health visitors may find the transition from being a student to an accountable individual practitioner a daunting prospect. Although competent and knowledgeable, they may feel the need for support and guidance of more experienced professional colleagues as they find their feet in professional practice. The same may apply to those who have returned to practice after a break of five years or more. It may also apply to those who move registerable qualification, for example a registered nurse who subsequently qualifies as a health visitor. Feeling valued and invested in by the employing organisation does have benefits to the children, families and communities with whom we work. Building professional resilience and developing and maintaining up-to-date knowledge will inevitably provide a high quality delivery of equitable services. pilot of the HEE/iHV (2014) National Preceptorh Framework for health visitors, exploring the impact of the implementation of the health visitor Preceptorship framework. Whilst the pilot lasted just six months, early indications suggests a positive impact on the staff and the children, families and communities we serve. PMID- 26596135 TI - Last word with ... Dr CRYSTAL OLDHAM. PMID- 26596136 TI - Gold-Catalyzed Synthesis of Tropone and Its Analogues via Oxidative Ring Expansion of Alkynyl Quinols. AB - A new and convenient strategy for the synthesis of functionalized tropone derivatives based on the gold-catalyzed oxidative ring expansion of alkynyl quinols has been developed. The reaction proceeds via gold-catalyzed highly regioselective oxidation followed by 1,2-migration of a vinyl or phenyl group. Extension of this chemistry allows ready access to various seven- or six-membered ring systems such as benzotropones, benzooxepines, phenanthrenes, and quinolin 2(1H)-ones. PMID- 26596148 TI - Assessment and Validation of the Electrostatically Embedded Many-Body Expansion for Metal-Ligand Bonding. AB - The electrostatically embedded many-body method has been very successful for calculating cohesive energies and relative conformational energies of clusters, and here we extend it to calculate bond breaking energies for metal-ligand bonds in inorganic coordination chemistry. We find that, on average, the electrostatically embedded pairwise additive method is able to predict bond energies yielded by conventional full-system calculations done at the same level of theory to within 2.5 kcal/mol and that the electrostatically embedded three body method consistently yields energies within 1.0 kcal/mol of the full-system calculations. PMID- 26596149 TI - Shannon Entropy Based Time-Dependent Deterministic Sampling for Efficient "On-the Fly" Quantum Dynamics and Electronic Structure. AB - A new set of time-dependent deterministic sampling (TDDS) measures, based on local Shannon entropy, are presented to adaptively gauge the importance of various regions on a potential energy surface and to be employed in "on-the-fly" quantum dynamics. Shannon sampling and Shannon entropy are known constructs that have been used to analyze the information content in functions: for example, time series data and discrete data sets such as amino acid sequences in a protein structure. Here the Shannon entropy, when combined with dynamical parameters such as the instantaneous potential, gradient and wavepacket density provides a reliable probe on active regions of a quantum mechanical potential surface. Numerical benchmarks indicate that the methods proposed are highly effective in locating regions of the potential that are both classically allowed as well as those that are classically forbidden, such as regions beyond the classical turning points which may be sampled during a quantum mechanical tunneling process. The approaches described here are utilized to improve computational efficiency in two different settings: (a) It is shown that the number of potential energy calculations required to be performed during on-the-fly quantum dynamics is fewer when the Shannon entropy based sampling functions are used. (b) Shannon entropy based TDDS functions are utilized to define a new family of grid based electronic structure basis functions that reduce the computational complexity while maintaining accuracy. The role of both results for on-the-fly quantum/classical dynamics of electrons and nuclei is discussed. PMID- 26596150 TI - Reaction Ensemble Monte Carlo Simulation of Complex Molecular Systems. AB - Acceptance rules for reaction ensemble Monte Carlo (RxMC) simulations containing classically modeled atomistic degrees of freedom are derived for complex molecular systems where insertions and deletions are achieved gradually by utilizing the continuous fractional component (CFC) method. A self-consistent manner in which to utilize statistical mechanical data contained in ideal gas free energy parameters during RxMC moves is presented. The method is tested by applying it to two previously studied systems containing intramolecular degrees of freedom: the propene metathesis reaction and methyl-tert-butyl-ether (MTBE) synthesis. Quantitative agreement is found between the current results and those of Keil et al. (J. Chem. Phys. 2005, 122, 164705) for the propene metathesis reaction. Differences are observed between the equilibrium concentrations of the present study and those of Lisal et al. (AIChE J. 2000, 46, 866-875) for the MTBE reaction. It is shown that most of this difference can be attributed to an incorrect formulation of the Monte Carlo acceptance rule. Efficiency gains using CFC MC as opposed to single stage molecule insertions are presented. PMID- 26596151 TI - Estimation and Inference of Diffusion Coefficients in Complex Biomolecular Environments. AB - The 1-D diffusion coefficient associated with a charged atom fluctuating in an ion-channel binding pocket is statistically analyzed. More specifically, unconstrained and constrained molecular dynamics simulations of potassium in gramicidin A are studied. Time domain transition density based inference methods are used to fit simple stochastic differential equations and also to carry out frequentist goodness of fit tests. Particular attention is paid to varying the time between adjacent time series observations due to the well-known "non Markovian noise" that can appear in this system due to inertia and other unresolved coordinates influencing the dynamics. Different types of non-Markovian noise are shown by the goodness of fit tests to be statistically significant on vastly different time scales. On intermediate scales, a Markovian model is not rejected by the tests; models calibrated at these intermediate scales demonstrate a predictive capability for some physical quantities. However, in this intermediate regime, ergodic sampling does not occur over the length of a time series, but a local diffusion coefficient is deemed statistically acceptable for the observed raw data. It is demonstrated that a linear mixed effects model can be used to summarize the variation induced by slow unresolved degrees of freedom acting as a non-Markovian noise source. The utility of quantitative criteria for assessing low-dimensional stochastic models calibrated from time series generated by high-dimensional biomolecular systems is briefly discussed. Less coarse grained data summaries of this type show promise for better understanding the kinetic signature of unresolved degrees of freedom in time series coming from simulations and single-molecule experiments. PMID- 26596152 TI - Efficient and Accurate Double-Hybrid-Meta-GGA Density Functionals-Evaluation with the Extended GMTKN30 Database for General Main Group Thermochemistry, Kinetics, and Noncovalent Interactions. AB - We present an extended and improved version of our recently published database for general main group thermochemistry, kinetics, and noncovalent interactions [J. Chem. Theory Comput. 2010, 6, 107], which is dubbed GMTKN30. Furthermore, we suggest and investigate two new double-hybrid-meta-GGA density functionals called PTPSS-D3 and PWPB95-D3. PTPSS-D3 is based on reparameterized TPSS exchange and correlation contributions; PWPB95-D3 contains reparameterized PW exchange and B95 parts. Both functionals contain fixed amounts of 50% Fock-exchange. Furthermore, they include a spin-opposite scaled perturbative contribution and are combined with our latest atom-pairwise London-dispersion correction [J. Chem. Phys. 2010, 132, 154104]. When evaluated with the help of the Laplace transformation algorithm, both methods scale as N(4) with system size. The functionals are compared with the double hybrids B2PLYP-D3, B2GPPLYP-D3, DSD-BLYP-D3, and XYG3 for GMTKN30 with a quadruple-zeta basis set. PWPB95-D3 and DSD-BLYP-D3 are the best functionals in our study and turned out to be more robust than B2PLYP-D3 and XYG3. Furthermore, PWPB95-D3 is the least basis set dependent and the best functional at the triple-zeta level. For the example of transition metal carbonyls, it is shown that, mainly due to the lower amount of Fock-exchange, PWPB95-D3 and PTPSS-D3 are better applicable than the other double hybrids. Finally, we discuss in some detail the XYG3 functional [Proc. Nat. Acad. Sci. U.S.A. 2009, 106, 4963], which makes use of B3LYP orbitals and electron densities. We show that it is basically a highly nonlocal variant of B2PLYP and that its partially good performance is mainly due to a larger effective amount of perturbative correlation compared to other double hybrids. We finally recommend the PWPB95-D3 functional in general chemistry applications. PMID- 26596153 TI - A CASPT2 Description of the Electronic Structures of FeO3(-/0) in Relevance to the Anion Photoelectron Spectrum. AB - DFT and multireference methods were used to investigate the electronic structure of FeO3 and FeO3(-) clusters. Geometries of different spin multiplicities and conformations were optimized without any symmetry restrictions at the BP/QZVP level and further refined with the CASPT2 method. Although the latter type of calculations were performed by using the C2v point group, all low-lying states relevant to the photoelectron spectrum were found to correspond to or to resemble closely a planar D3h iron trioxide with no bonds between the oxygen atoms. Depending on the computational method used, the ground state of the FeO3(-) anion can be either (2)E'' or (4)A1'. The two lowest binding energy bands of the photoelectron spectrum of FeO3(-) can only be ascribed to electron detachments from the (2)E'' state. The first band is the result of a transition to the (1)A1' ground state of FeO3, whereas the second band originates from the first excited (3)E'' state. A harmonic vibrational analysis of the symmetric stretch shows that the observed vibrational progressions of these two bands in the photoelectron spectrum of FeO3(-) are also in line with the assignment. A molecular orbital analysis led to the conclusion that the electronic structures of the anionic and neutral clusters can formally be described by an oxidation state of iron of +5 and +6, respectively. A population analysis, on the contrary, points to an ionization that takes place on the oxygen atoms. PMID- 26596154 TI - Accurate Quantum Chemistry in Single Precision Arithmetic: Correlation Energy. AB - In the present work, we show the feasibility of using single precision in quantum chemistry, especially regarding the computation of electron correlation energy. On the example of the MP2 method, we clearly demonstrate that single precision arithmetic is sufficient for evaluating the molecular two-electron integrals by the use of the Cholesky decomposition method. The evaluation of integrals with single precision arithmetic introduces a negligible error into the computed MP2 correlation energy. In particular, the corresponding error in the MP2 correlation energy amounts to only 10(-7)Eh for the 113-atom taxol molecule in double-valence basis set (1099 basis functions). The practical relevance of our result is that 50% performance gain and 50% reduction in memory demands can be achieved by only minor changes in the existing codes. Our finding opens intriguing perspectives for doing accurate correlated quantum chemistry on specialized floating-point mathematical coprocessors. PMID- 26596155 TI - Trends in Aromatic Oxidation Reactions Catalyzed by Cytochrome P450 Enzymes: A Valence Bond Modeling. AB - The mixed density functional theory (DFT) and valence bond study described herein focuses on the activation of 17 benzene derivatives by the active species of Cytochrome P450, so-called Compound I (Cpd I), as well as by the methoxy radical, as a potentially simple model of Cpd I (Jones, J. P.; Mysinger, M.; Korzekwa, K. R. Drug Metab. Dispos. 2002, 30, 7-12). Valence bond modeling is employed to rationalize the P450 mechanism and its spin-state selectivity from first principles of electronic structure and to predict activation energies independently, using easily accessible properties of the reactants: the singlet triplet excitation energies, the ionization potentials of the aromatics, and the electron affinity of Cpd I and/or of the methoxy radical. It is shown that the valence bond model rationalizes all the mechanistic aspects and predicts activation barriers (for 35 reactions) with reasonable accuracy compared to the DFT barriers with an average deviation of +/-1.0 kcal.mol(-1) (for DFT barriers, see: Bathelt, C. M.; Ridder, L.; Mulholland, A. J.; Harvey, J. N. Org. Biomol. Chem. 2004, 2, 2998-3005). The valence bond modeling also reveals the mechanistic similarities between the P450 Cpd I and methoxy reactions and enables one to make predictions of barriers for reactions from other studies. PMID- 26596156 TI - Kohn-Sham Density Functional Theory Electronic Structure Calculations with Linearly Scaling Computational Time and Memory Usage. AB - We present a complete linear scaling method for hybrid Kohn-Sham density functional theory electronic structure calculations and demonstrate its performance. Particular attention is given to the linear scaling computation of the Kohn-Sham exchange-correlation matrix directly in sparse form within the generalized gradient approximation. The described method makes efficient use of sparse data structures at all times and scales linearly with respect to both computational time and memory usage. Benchmark calculations at the BHandHLYP/3 21G level of theory are presented for polypeptide helix molecules with up to 53 250 atoms. Threshold values for computational approximations were chosen on the basis of their impact on the occupied subspace so that the different parts of the calculations were carried out at balanced levels of accuracy. The largest calculation used 307 204 Gaussian basis functions on a single computer with 72 GB of memory. Benchmarks for three-dimensional water clusters are also included, as well as results using the 6-31G** basis set. PMID- 26596157 TI - Fast Sparse Cholesky Decomposition and Inversion using Nested Dissection Matrix Reordering. AB - Here we present an efficient, yet nonlinear scaling, algorithm for the computation of Cholesky factors of sparse symmetric positive definite matrices and their inverses. The key feature of this implementation is the separation of the task into an algebraic and a numeric part. The algebraic part of the algorithm attempts to find a reordering of the rows and columns which preserves at least some degree of sparsity and afterward determines the exact nonzero structure of both the Cholesky factor and its corresponding inverse. It is based on graph theory and does not involve any kind of numerical thresholding. This preprocessing then allows for a very efficient implementation of the numerical factorization step. Furthermore this approach even allows use of highly optimized dense linear algebra kernels which leads to yet another performance boost. We will show some illustrative timings of our sparse code and compare it to the standard library implementation and a recent sparse implementation using thresholding. We conclude with some comments on how to deal with positive semidefinite matrices. PMID- 26596158 TI - Bond Length Alternation of Conjugated Oligomers: Wave Function and DFT Benchmarks. AB - We have computed the bond length alternation (BLA) in a series of pi-conjugated quasilinear chains containing from two to six unit cells. Several structures (eight oligomeric sets including three conformers of polyacetylene, polymethineimine, polysilaacetylene, etc.) have been considered to cover the possible evolutions of the BLA with increasing chain length. Three objectives have been tackled: (1) the computation of accurate reference values using the CCSD(T) theory; (2) an evaluation of the performances of other electron correlated wave function approaches (MPn, SCS-MP2, CCSD, etc.); (3) the benchmarking of several DFT functionals, including global, range-separated, and double hybrids. It turns out that the SCS-MP2 approach is, on average, an efficient scheme in terms of its accuracy/cost ratio. Among the selected DFT approaches, no single functional emerges as uniformly accurate for all oligomeric series and chain lengths, but BHHLYP, M06-2X, and CAM-B3LYP could be reasonable choices for long oligomers. PMID- 26596159 TI - Average Local Ionization Energies as a Route to Intrinsic Atomic Electronegativities. AB - Historically, two important approaches to the concept of electronegativity have been in terms of: (a) an atom in a molecule (e.g., Pauling) and (b) the chemical potential. An approximate form of the latter is now widely used for this purpose, although it includes a number of deviations from chemical experience. More recently, Allen introduced an atomic electronegativity scale based upon the spectroscopic average ionization energies of the valence electrons. This has gained considerable acceptance. However it does not take into account the interpenetration of valence and low-lying subshells, and it also involves some ambiguity in enumerating d valence electrons. In this paper, we analyze and characterize a formulation of relative atomic electronegativities that is conceptually the same as Allen's but avoids the aforementioned problems. It involves the property known as the average local ionization energy, I(r), defined as [Formula: see text], where rhoi(r) is the electronic density of the i(th) orbital, having energy epsiloni, and rho(r) is the total electronic density. I(r) is interpreted as the average energy required to remove an electron at the point r. When I(r) is averaged over the outer surfaces of atoms, taken to be the 0.001 au contours of their electronic densities, a chemically meaningful scale of relative atomic electronegativities is obtained. Since the summation giving I(r) is over all occupied orbitals, the issues of subshell interpenetration and enumeration of valence electrons do not arise. The procedure is purely computational, and all of the atoms are treated in the same straightforward manner. The results of several different Hartree-Fock and density functional methods are compared and evaluated; those produced by the Perdew-Burke-Ernzerhof functional are chemically the most realistic. PMID- 26596160 TI - Highly Fluxional [Y(C(SiH(CH3)2)3)3]: A DFT Characterization of Structure and NMR Spectra. AB - The structure and NMR spectroscopic properties of [Y(C(SiH(CH3)2)3)3] are investigated with density functional theory calculations. The existence of a C3 principal axis that was found experimentally is reproduced, but the calculations also find that the symmetry of the equilibrium structure of [Y(C(SiH(CH3)2)3)3] has to be reduced from the experimentally suggested C3v or C3h to C3 in order to explain the observed SiH NMR chemical shifts. We show that the apparent mirror plane relating two agostic SiH(CH3)2 groups on each ligand is caused by the rapid interchange of the position of the third ligand, which could only be observed at much lower temperatures than used previously in the experiments. PMID- 26596161 TI - Protein Free Energy Corrections in ONIOM QM:MM Modeling: A Case Study for Isopenicillin N Synthase (IPNS). AB - The protein environment can have significant effects on the enzyme catalysis even though the reaction occurs locally at the reaction center. In this paper, we describe an efficient scheme that includes a classical molecular dynamics (MD) free-energy perturbation (FEP) correction to the reaction energy diagram, as a complement to the protein effect obtained from static ONIOM (QM:MM) calculations. The method is applied to eight different reaction steps, from the O2-bound reactant to formation of a high-valent ferryl-oxo intermediate, in the nonheme iron enzyme isopenicillin N synthase (IPNS), for which the QM:MM energy diagram has previously been computed [ Lundberg , M. et al. J. Chem. Theory Comput. 2009 , 5 , 220 - 234 ]. This large span of the reaction coordinate is covered by dividing each reaction step into microsteps using a virtual reaction coordinate, thus only requiring ONIOM information about the stationary points themselves. Protein effects are important for C-H bond activation and heterolytic O-O bond cleavage because both these two steps involve charge transfer, and compared to a static QM:MM energies, the dynamics of the protein environment changes the barrier for O-O bond cleavage by several kcal/mol. The origin of the dynamical contribution is analyzed in two terms, the geometrical effect caused by the change in average protein geometry (compared to the optimized geometry) in the room temperature MD simulation with the solvent, and the statistical (entropic) effect resulting from fluctuations in the interactions between the active site and the protein environment. These two effects give significant contributions in different steps of the reaction. PMID- 26596162 TI - Quantitative Assessment of Force Fields on Both Low-Energy Conformational Basins and Transition-State Regions of the (phi-psi) Space. AB - The free energy surfaces (FESs) of alanine dipeptide are studied to illustrate a new strategy to assess the performance of classical molecular mechanics force field on the full range of the (phi-psi) conformational space. The FES is obtained from metadynamics simulations with five commonly used force fields and from ab initio density functional theory calculations in both gas phase and aqueous solution. The FESs obtained at the B3LYP/6-311+G(2d,p)//B3LYP/6-31G(d,p) level of theory are validated by comparison with previously reported MP2 and LMP2 results as well as with experimentally obtained probability distribution between the C5-beta (or beta-PPII) and alphaR states. A quantitative assessment is made for each force field in three conformational basins, LeRI (C5-beta-C7eq), LeRII (beta2-alphaR), and LeRIII(alphaL-C7ax-alphaD) as well as three transition-state regions linking the above conformational basins. The performance of each force field is evaluated in terms of the average free energy of each region in comparison with that of the ab initio results. We quantify how well a force field FES matches the ab initio FES through the calculation of the standard deviation of a free energy difference map between the two FESs. The results indicate that the performance varies largely from region to region or from force field to force field. Although not one force field is able to outperform all others in all conformational areas, the OPLSAA/L force field gives the best performance overall, followed by OPLSAA and AMBER03. For the three top performers, the average free energies differ from the corresponding ab initio values from within the error range (<0.4 kcal/mol) to ~1.5 kcal/mol for the low-energy regions and up to ~2.0 kcal/mol for the transition-state regions. The strategy presented and the results obtained here should be useful for improving the parametrization of force fields targeting both accuracy in the energies of conformers and the transition-state barriers. PMID- 26596163 TI - Theoretical Investigations on the Conformation of the beta-d-Arabinofuranoside Ring. AB - A method for the conformational analysis of furanose rings that involves the prediction of (3)JH,H that can be compared directly to experimental values is investigated. This method, which differs from the traditional PSEUROT approach for conformational studies of furanose rings, was previously applied to a number of alpha-d-arabinofuranosides and enabled the direct comparison of (3)JH,H values to those obtained from NMR spectroscopy. In this paper, the use of this approach to study the conformational preferences of oligosaccharides containing beta linked arabinofuranose residues is reported. Density functional theory (DFT) calculations were carried out to derive Karplus relationships that are specifically tailored for these ring systems. In addition, probability distributions obtained from GLYCAM/AMBER molecular dynamics simulations were employed to calculate (3)JH,H values from these Karplus relationships. However, unlike the results obtained with alpha-arabinofuranosides, the (3)JH,H values computed for beta-arabinofuranosides agreed poorly with experimental values. This prompted the exploration of other methodologies including reevaluation and optimization of the initial MD protocol, use of various force field models, and recalculation of the DFT-derived coupling profiles using an optimized basis set. After extensive investigations, we established that the conformer distributions obtained from MD simulations with the GLYCAM force fields and the furanoside specific CHARMM force field in combination with the DFT Karplus equations, determined using an augmented basis set (B3LYP/aug-cc-pVTZ-J), produced the best agreement compared to experimental (3)JH,H values. Using these protocols, there is relatively good agreement in (3)JH,H for all coupling pathways with the exception of (3)J2,3 and (3)J3,4, which are underestimated. PMID- 26596164 TI - Electronic Excitations of Simple Cyanine Dyes: Reconciling Density Functional and Wave Function Methods. AB - The simplest cyanine dye series [H2N(CH)nNH2](+) with n = 1, 3, 5, 7, and 9 appears to be a challenge for all theoretical excited-state methods since the experimental spectra are difficult to predict and the observed deviations cannot be easily explained with standard arguments. We compute here the lowest vertical excitation energies of these dyes using a variety of approaches, namely, complete active space second-order perturbation theory (CASPT2), quantum Monte Carlo methods (QMC), coupled cluster linear response up to third approximate order (CC3), and various flavors of time-dependent density functional theory (TDDFT), including the recently proposed perturbative correction scheme (B2PLYP). In our calculations, all parameters such as basis set, active space, and geometry dependence are carefully analyzed. We find that all wave function methods give reasonably close excitation energies, with CASPT2 yielding the lowest values, and that the B2PLYP scheme gives excitations in satisfactory agreement with CC3 and DMC, significantly improving on the generalized gradient and hybrid approximations. Finally, to resolve the remaining discrepancy between predicted excitation energies and experimental absorption spectra, we also investigate the effect of excited-state relaxation. Our results indicate that a direct comparison of the experimental absorption maxima and the theoretical vertical excitations is not possible due to the presence of nonvertical transitions. The apparent agreement of earlier CASPT2 calculations with experiments was an artifact of the choice of active space and the use of an older definition of the zero-order Hamiltonian. PMID- 26596165 TI - Oscillator Strength: How Does TDDFT Compare to EOM-CCSD? AB - In this work, we compare a large variety of density functionals against the equation of motion coupled cluster singles and doubles (EOM-CCSD) method for the calculation of oscillator strengths. Valence and Rydberg states are considered for a test set composed of 11 small organic molecules. In our previous work, the same systems and methods were tested against experimental results for the excitation energies. The results from this investigation confirm our previous findings, i.e., that there is a large difference between the functionals. For the oscillator strength, the average best agreement with EOM-CCSD is provided by CAM B3LYP followed by LC-omegaPBE and, to a lesser extent, B3P86 and LC-BLYP. PMID- 26596166 TI - Anharmonicity and the Eigen-Zundel Dilemma in the IR Spectrum of the Protonated 21 Water Cluster. AB - The infrared anharmonic spectra for the H(+)(H2O)3, H(+)(H2O)4, and H(+)(H2O)21 water clusters have been reported using vibrational second-order perturbation theory at the B3LYP level with 6-31+G(d) and 6-311++G(3df,3pd) basis sets. The anharmonicity results crucial for the evaluation of the protonated water clusters and the anharmonic corrections can be larger than 500 cm(-1), resulting in a shift of the H3O(+) asymmetric stretchings near the region of 2000 cm(-1). PMID- 26596167 TI - A Classical Potential to Model the Adsorption of Biological Molecules on Oxidized Titanium Surfaces. AB - The behavior of titanium implants in physiological environments is governed by the thin oxide layer that forms spontaneously on the metal surface and mediates the interactions with adsorbate molecules. In order to study the adsorption of biomolecules on titanium in a realistic fashion, we first build up a model of an oxidized Ti surface in contact with liquid water by means of extensive first principles molecular dynamics simulations. Taking the obtained structure as reference, we then develop a classical potential to model the Ti/TiOx/water interface. This is based on the mapping with Coulomb and Lennard-Jones potentials of the adsorption energy landscape of single water and ammonia molecules on the rutile TiO2(110) surface. The interactions with arbitrary organic molecules are obtained via standard combination rules to established biomolecular force fields. The transferability of our potential to the case of organic molecules adsorbing on the oxidized Ti surface is checked by comparing the classical potential energy surfaces of representative systems to quantum mechanical results at the level of density functional theory. Moreover, we calculate the heat of immersion of the TiO2 rutile surface and the detachment force of a single tyrosine residue from steered molecular dynamics simulations, finding good agreement with experimental reference data in both cases. As a first application, we study the adsorption behavior of the Arg-Gly-Asp (RGD) peptide on the oxidized titanium surface, focusing particularly on the calculation of the free energy of desorption. PMID- 26596168 TI - First Principles Calculations of Atomic Nickel Redox Potentials and Dimerization Free Energies: A Study of Metal Nanoparticle Growth. AB - The redox potentials and dimerization free energies of transient transition metal cations in water shed light on the reactivity of species with unusual charge states and are particularly pertinent to understanding the mechanism and feasibility of radiolysis-assisted metal nanoparticle growth from salt solutions. A combination of quasi-chemical theory and ab initio molecular dynamics thermodynamic integration methods are applied to calculate these properties for nickel. The reduction potential for Ni(2+) (aq) is predicted to be between -1.05 to -1.28 V, which is substantially lower than previous estimates. This suggests that Ni(2+) reduction may possibly occur in the presence of organic radical anion electron scavengers and hydrogen atoms, not just hydrated electrons. In contrast, Ni(+) is found to be stable against disproportionation. The formation of dimers Ni2 and Ni2(+) from Ni and Ni(+) are predicted to be favorable in water. PMID- 26596169 TI - Efficient Calculation of QM/MM Frequencies with the Mobile Block Hessian. AB - The calculation of the analytical second derivative matrix (Hessian) is the bottleneck for vibrational analysis in QM/MM systems when an electrostatic embedding scheme is employed. Even with a small number of QM atoms in the system, the presence of MM atoms increases the computational cost dramatically: the long range Coulomb interactions require that additional coupled perturbed self consistent field (CPSCF) equations need to be solved for each MM atom displacement. This paper presents an extension to the Mobile Block Hessian (MBH) formalism for QM/MM calculations with blocks in the MM region and its implementation in a parallel version of the Q-Chem/CHARMM interface. MBH reduces both the CPU time and the memory requirements compared to the standard full Hessian QM/MM analysis, without the need to use a cutoff distance for the electrostatic interactions. Special attention is given to the treatment of link atoms which are usually present when the QM/MM border cuts through a covalent bond. Computational efficiency improvements are highlighted using a reduced chorismate mutase enzyme system, consisting of 24 QM atoms and 306 MM atoms, as a test example. In addition, the drug bortezomib, used for cancer treatment of myeloma, has been studied as a test case with multiple MBH block choices and both a QM and QM/MM description. The accuracy of the calculated Hessians is quantified by imposing Eckart constraints, which allows for the assessment of numerical errors in second derivative procedures. The results show that MBH within the QM/MM description not only is a computationally attractive method but also produces accurate results. PMID- 26596170 TI - Configurational Entropy Reallocation and Complex Loop Dynamics of the Mosquito Stage Pvs25 Protein Complexed with the Fab Fragment of the Malaria Transmission Blocking Antibody 2A8. AB - Pvs25 is a protein of unique 3D structure, and it is characterized by the presence of repeated EGF-like domains and 11 disulfide bonds. It is a very important candidate for the transmission-blocking malaria vaccine, as it plays an important role in mosquito infection by Plasmodium parasites. Recently, the X-ray structure of the protein complexed with the transmission blocking antibody 2A8 has been reported. In this study, we report the loop reorganization of the Pvs25 protein based on configurational entropy calculations and dihedral principal component analysis as revealed from the protein complex and free molecular dynamics simulations. While the total entropy of the protein was estimated to be almost the same in the free and complex trajectories, the partition of the entropy contribution in the loop fragments of the protein revealed interesting entropy reallocation after the 2A8 antibody binding. Interestingly, the 51-71 protein loop experienced a significant reduction in its configurational entropy, while other parts of the protein did not show any difference in it, or even showed an entropy increase. This trend in entropy redistribution was found to be in direct relationship with specific interactions with the antibody's binding site. Results from root-mean-square fluctuations/deviations and dihedral angle principal component analysis further support this finding. PMID- 26596171 TI - PROPKA3: Consistent Treatment of Internal and Surface Residues in Empirical pKa Predictions. AB - In this study, we have revised the rules and parameters for one of the most commonly used empirical pKa predictors, PROPKA, based on better physical description of the desolvation and dielectric response for the protein. We have introduced a new and consistent approach to interpolate the description between the previously distinct classifications into internal and surface residues, which otherwise is found to give rise to an erratic and discontinuous behavior. Since the goal of this study is to lay out the framework and validate the concept, it focuses on Asp and Glu residues where the protein pKa values and structures are assumed to be more reliable. The new and improved implementation is evaluated and discussed; it is found to agree better with experiment than the previous implementation (in parentheses): rmsd = 0.79 (0.91) for Asp and Glu, 0.75 (0.97) for Tyr, 0.65 (0.72) for Lys, and 1.00 (1.37) for His residues. The most significant advance, however, is in reducing the number of outliers and removing unreasonable sensitivity to small structural changes that arise from classifying residues as either internal or surface. PMID- 26596172 TI - Reliability of the hand held dynamometer in measuring muscle strength in people with interstitial lung disease. AB - OBJECTIVE: To evaluate the inter-rater and intra-rater reliability of the hand held dynamometer in measuring muscle strength in people with interstitial lung disease (ILD). DESIGN: Test retest reliability of hand-held dynamometry for elbow flexor and knee extensor strength between two independent raters and two testing sessions. SETTING: Physiotherapy department within a tertiary hospital. PARTICIPANTS: Thirty participants with ILD of varying aetiology were included. Twenty participants completed the inter-rater reliability protocol (10 idiopathic pulmonary fibrosis, mean (SD) age 73 (10) years, 11 male) and 21 participants completed the intra-rater reliability protocol (10 idiopathic pulmonary fibrosis, mean age 71 (10) years, 11 male). MAIN OUTCOME MEASURES: Mean muscle strength (kg). Agreement between the two raters and testing sessions was analyzed using Bland-Altman plots and reliability was estimated using intraclass correlation coefficients (ICC). RESULTS: For elbow flexor strength there was a mean difference between raters of -0.6kg (limits of agreement (LOA) -5.6 to 4.4kg) and within raters of -0.3kg (LOA -2.8 to 2.3kg). The ICCs were 0.95 and 0.98, respectively. For knee extensor strength there was a mean difference between raters of -1.5kg (LOA -6.9 to 3.9kg) and within raters of -0.7kg (LOA -3.9 to 2.4kg). The ICCs were 0.95 and 0.97, respectively. CONCLUSIONS: Hand-held dynamometry is reliable in measuring elbow flexor and knee extensor strength in people with ILD. PMID- 26596175 TI - Building a Better Box: Developing Reliable Models. PMID- 26596173 TI - The Notch ligand E3 ligase, Mind Bomb1, regulates glutamate receptor localization in Drosophila. AB - The postsynaptic density (PSD) is a protein-rich network important for the localization of postsynaptic glutamate receptors (GluRs) and for signaling downstream of these receptors. Although hundreds of PSD proteins have been identified, many are functionally uncharacterized. We conducted a reverse genetic screen for mutations that affected GluR localization using Drosophila genes that encode homologs of mammalian PSD proteins. 42.8% of the mutants analyzed exhibited a significant change in GluR localization at the third instar larval neuromuscular junction (NMJ), a model synapse that expresses homologs of AMPA receptors. We identified the E3 ubiquitin ligase, Mib1, which promotes Notch signaling, as a regulator of synaptic GluR localization. Mib1 positively regulates the localization of the GluR subunits GluRIIA, GluRIIB, and GluRIIC. Mutations in mib1 and ubiquitous expression of Mib1 that lacks its ubiquitin ligase activity result in the loss of synaptic GluRIIA-containing receptors. In contrast, overexpression of Mib1 in all tissues increases postsynaptic levels of GluRIIA. Cellular levels of Mib1 are also important for the structure of the presynaptic motor neuron. While deficient Mib1 signaling leads to overgrowth of the NMJ, ubiquitous overexpression of Mib1 results in a reduction in the number of presynaptic motor neuron boutons and branches. These synaptic changes may be secondary to attenuated glutamate release from the presynaptic motor neuron in mib1 mutants as mib1 mutants exhibit significant reductions in the vesicle associated protein cysteine string protein and in the frequency of spontaneous neurotransmission. PMID- 26596176 TI - Time-Driven Activity-Based Costing in IR. PMID- 26596174 TI - Epac activation sensitizes rat sensory neurons through activation of Ras. AB - Guanine nucleotide exchange factors directly activated by cAMP (Epacs) have emerged as important signaling molecules mediating persistent hypersensitivity in animal models of inflammation, by augmenting the excitability of sensory neurons. Although Epacs activate numerous downstream signaling cascades, the intracellular signaling which mediates Epac-induced sensitization of capsaicin-sensitive sensory neurons remains unknown. Here, we demonstrate that selective activation of Epacs with 8-CPT-2'-O-Me-cAMP-AM (8CPT-AM) increases the number of action potentials (APs) generated by a ramp of depolarizing current and augments the evoked release of calcitonin gene-related peptide (CGRP) from isolated rat sensory neurons. Internal perfusion of capsaicin-sensitive sensory neurons with GDP-betaS, substituted for GTP, blocks the ability of 8CPT-AM to increase AP firing, demonstrating that Epac-induced sensitization is G-protein dependent. Treatment with 8CPT-AM activates the small G-proteins Rap1 and Ras in cultures of sensory neurons. Inhibition of Rap1, by internal perfusion of a Rap1-neutralizing antibody or through a reduction in the expression of the protein using shRNA does not alter the Epac-induced enhancement of AP generation or CGRP release, despite the fact that in most other cell types, Epacs act as Rap-GEFs. In contrast, inhibition of Ras through expression of a dominant negative Ras (DN-Ras) or through internal perfusion of a Ras-neutralizing antibody blocks the increase in AP firing and attenuates the increase in the evoked release of CGRP induced by Epac activation. Thus, in this subpopulation of nociceptive sensory neurons, it is the novel interplay between Epacs and Ras, rather than the canonical Epacs and Rap1 pathway, that is critical for mediating Epac-induced sensitization. PMID- 26596177 TI - Intranodal Lymphangiography in Chyluria. PMID- 26596178 TI - Number of Blades-up Runs Using JetStream XC Atherectomy for Optimal Tissue Debulking in Patients with Femoropopliteal Artery In-Stent Restenosis. AB - Rotational atherectomy with the use of the JetStream XC device is indicated for treatment of infrainguinal arterial obstructive disease. The number of blades-up (BU) runs needed for optimal tissue debulking in femoropopliteal in-stent restenosis (ISR) is unknown. In the present series, 6 patients (15 lesions) were treated for femoropopliteal ISR with the JetStream XC device. Minimal luminal diameter or percent stenosis improved significantly from baseline after 2 BU runs, but no further gain was seen between 2 and 4 BU runs (P > .05). However, adjunctive balloon angioplasty reduced percent stenosis significantly following BU runs. In conclusion, the JetStream XC device achieved optimal acute angiographic results in treating femoropopliteal ISR following 2 BU runs and adjunctive balloon angioplasty. PMID- 26596179 TI - Percutaneous Placement of Permanent Metallic Stents in the Cystic Duct to Treat Obstructive Cholecystitis. AB - This report presents a series of five patients unsuitable for surgery who had nonretrievable self-expanding metallic stents deployed along the cystic duct as treatment for benign and malignant causes of gallbladder obstruction. Techniques are described for draining cholecystitis, removing gallstones, bypassing gallbladder obstructions, and inserting metallic stents across the cystic duct to restore permanent antegrade gallbladder drainage in acute and chronic cholecystitis. Symptoms resolved in all cases, and stents remained patent for as long as 22 months. This procedure may be an effective alternative to cholecystectomy or long-term gallbladder drainage for patients in inoperable condition. PMID- 26596180 TI - Transhepatic Management of a Migrated Intraductal Surgical Clip after Cholecystectomy and Gastrectomy. PMID- 26596181 TI - Percutaneous Cryoablation for Successful Treatment of a Persistent Urine Leak after Robotic-Assisted Partial Nephrectomy. AB - Urine leak after nephron-sparing surgery is a difficult and morbid situation that may delay recovery and necessitate additional hospitalization and intervention. The use of cryoablation to treat a 34-year-old woman with persistent urine leak after robotic-assisted partial nephrectomy is described. Surgery was performed to treat ureteral duplication that resulted in recurrent urinary tract infections and back pain. Cryoablation was performed with computed tomography guidance, targeting urine extravasation observed after the administration of intravenous contrast medium. Imaging performed after ablation confirmed resolution of the urine leak; renal function was preserved. PMID- 26596182 TI - A Coaxial Guide Wire-Catheter Technique to Facilitate Right Adrenal Vein Sampling: Evaluation in 76 Patients. AB - A technique to facilitate blood sampling from the right adrenal vein is described. Between May 2012 and February 2015, 148 adrenal vein sampling (AVS) procedures were attempted. In 72 procedures, a simple 5-F end-hole catheter was employed. In 76, a coaxial guide wire technique was used when blood could not be aspirated, whereby a 0.018-inch guide wire was passed through the catheter and into a branch of the right adrenal vein and the sample was drawn around the wire by using a side-arm adaptor. Successful sampling was achieved in 71 of the 72 catheter-only procedures (98.6%) and in 75 of the 76 coaxial wire-assisted procedures (98.7%). This simple technique may eliminate the need for multiple catheter exchanges during AVS. PMID- 26596183 TI - Gemcitabine and Oxaliplatin, but Not Sorafenib or Paclitaxel, Have a Synergistic Effect with Yttrium-90 in Reducing Hepatocellular Carcinoma and Cholangiocarcinoma Cell Line Viability. AB - Synergy between yttrium-90 (90Y) and antineoplastic drugs was investigated. Viability of HepaRG (hepatocellular carcinoma) and HuCCT1 (cholangiocarcinoma) cells was studied through a tetrazolium dye reduction assay. A combination index (CI) was calculated, with CI < 1 denoting synergy and CI > 1 denoting antagonism. In HepaRG cells, gemcitabine showed synergy with 90Y (CI = 0.70 [95% confidence interval = 0.65-0.75]), whereas oxaliplatin (CI = 1.15 [1.08-1.21]), paclitaxel (CI = 1.26 [1.15-1.37]), and sorafenib (CI = 1.77 [1.65-1.89]) showed antagonism. In HuCCT1 cells, gemcitabine (CI = 0.54 [0.50-0.58]) and oxaliplatin (CI = 0.86 [0.82-0.90]) showed synergy with 90Y, whereas paclitaxel (CI = 1.18 [1.09-1.27]) and sorafenib (CI = 1.21 [1.12-1.30]) showed antagonism. These results suggest that gemcitabine and oxaliplatin should be tested in combination with 90Y radioembolization for treatment of liver cancer. PMID- 26596184 TI - Bow-String Technique to Retrieve an Embolized Amplatzer Atrial Septal Occluder. PMID- 26596185 TI - Direct Percutaneous Access to the Cervical Portion of the Thoracic Duct, an Alternative to Traditional Access through the Cisterna Chyli. PMID- 26596187 TI - Vertebral Refracture after Unipedicular Kyphoplasty Resulting in Lateralized Cement Distribution. PMID- 26596186 TI - Long-Term Recurrence of Renal Angiomyolipoma Angiogenic Component after Ethylene Vinyl Alcohol Copolymer Embolization. PMID- 26596188 TI - How fluent is the fluent speech of people who stutter? A new approach to measuring kinematics with ultrasound. AB - We present a new approach to the investigation of dynamic ultrasound tongue imaging (UTI) data, applied here to analyse the subtle aspects of the fluency of people who stutter (PWS). Fluent productions of CV syllables (C = /k/; V = /alpha, i, e/) from three PWS and three control speakers (PNS) were analysed for duration and peak velocity relative to articulatory movement towards (onset) and away from (offset) the consonantal closure. The objective was to apply a replicable methodology for kinematic investigation to speech of PWS in order to test Wingate's Fault-Line hypothesis. As was hypothesised, results show comparable onset behaviours for both groups. Regarding offsets, groups differ in peak velocity. Results suggest that PWS do not struggle initiating consonantal closure (onset). In transition from consonantal closure into the vowel, however, groups appear to employ different strategies expressed in increased variation (PNS) versus decreased mean peak velocity (PWS). PMID- 26596189 TI - Childhood Adversity and Adult Reports of Food Insecurity Among Households With Children. AB - INTRODUCTION: Exposure to childhood adversity, including abuse, neglect, and household dysfunction, is associated with negative long-term health and economic outcomes. Little is known about how adversity exposure in parents' early lives may be related to later food insecurity for parents and their children. This study investigated the association between female caregivers' adverse childhood experiences (ACEs) and household and child food insecurity, taking into account depressive symptoms. METHODS: This study used cross-sectional data from 1,255 female caregivers of children aged <4 years surveyed in an urban clinical setting from March 2012 through June 2014. Measures included sociodemographic characteristics; caregivers' ACEs, including abuse, neglect, and household dysfunction; depressive symptoms; and household and child food insecurity. Multinomial and logistic regression analyses assessed the relationship among ACEs, depressive symptoms, and household and child food security status. RESULTS: Caregiver depressive symptoms modified associations between ACEs and food insecurity level. After adjusting for covariates, caregivers reporting both depressive symptoms and four or more ACEs were 12.3 times as likely to report low food security (95% CI=6.2, 24.7); 28.8 times as likely to report very low food security (95% CI=12.8, 64.8); and 17.6 times as likely to report child food insecurity (95% CI=7.3, 42.6) compared with those reporting no depressive symptoms and no ACEs. CONCLUSIONS: Depressive symptoms and ACEs were independently associated with household and child food insecurity, and depressive symptoms modified the association between ACEs and household and child food insecurity. Comprehensive policy interventions incorporating nutrition assistance and behavioral health may address intergenerational transmission of disadvantage. PMID- 26596190 TI - Sociodemographic Disparities in the Nonoperative Management of Small Renal Masses. AB - BACKGROUND: Local tumor ablation (LTA) and expectant management (EM) represent competing treatment modalities for patients with small renal masses (SRMs) who are unfit for surgery. We examined the potential social discrepancies in the access of LTA and EM. MATERIALS AND METHODS: A total of 1860 patients with cT1a kidney cancer who had undergone either LTA (n = 553) or EM (n = 1307) from 2000 to 2009 were selected from the Surveillance, Epidemiology, and End Results Medicare database. The baseline patient data (age, comorbidity status, defined as Charlson comorbidity index [CCI], and several sociodemographic variables) and tumor characteristics were examined. A multivariable analysis predicting access to LTA compared with EM was fitted. The subgroup analyses focused on patients aged >= 75 years with a CCI of >= 2. RESULTS: Compared with LTA patients, the EM patients were significantly older (median age, 78 vs. 77 years; P < .001), more frequently unmarried (43% vs. 37%; P = .02), more frequently of African-American ethnicity (14% vs. 8%; P = .005), and more frequently of low socioeconomic status (SES; 55% vs. 46%; P = .001). No differences were seen according to gender, population density, CCI, or tumor size. In a multivariable analysis predicting access to LTA over EM, older age, African-American ethnicity, male gender, low SES, and unmarried status were associated with lower access to LTA (P <= .04 for all). In the subgroup of older and sicker patients, none of the previous sociodemographic characteristics represented barriers to LTA access (P >= .1 for all). CONCLUSION: Sociodemographic characteristics might represent barriers to LTA access for patients with SRMs managed nonoperatively. However, these associations vanished when older and sicker patients were examined. PMID- 26596191 TI - Perceived support in parents of children with burns. AB - OBJECTIVE: Children sustaining burns that require treatment in a burn center have a need for multiprofessional aftercare services over a prolonged time. So far, there is little research into satisfaction with care and support after pediatric burns. The aim was to investigate parents' perception of support after pediatric burn and associations with parent, child and injury characteristics. METHOD: Parents (n=101) of children aged 0.4-17.8 years completed questionnaires on support, parent's psychological symptoms and health of the child. Time since injury was 0.1-9.0 years. RESULTS: Perceived lack of psychosocial, medical, societal or family support was reported by 21% of the parents. Lack of support was not associated with injury or sociodemographic characteristics, but it was significantly associated with parents' symptoms of general anxiety, depression and injury-related fear avoidance, as well as parents' ratings of their child's general health and heat sensitivity. CONCLUSION: Perceived support did not differ on account of burn severity or sociodemographic status. However, care providers should be more attentive to and supportive of parents signaling poorer general health in their child and cognitive beliefs that the child is at risk for harm when active and parents who themselves show signs of psychological symptoms. PMID- 26596192 TI - High prevalence of posttraumatic stress in patients with primary hypertension. AB - OBJECTIVE: Posttraumatic stress disorder (PTSD) is associated with a higher rate of arterial hypertension. However, data about prevalence rates of PTSD in patients suffering from arterial hypertension as well as the relation to blood pressure (BP) control are lacking. METHODS: We recruited 145 patients with primary hypertension from March to November 2012 at the cardiologic outpatient clinic at Ulm University Medical Center. Symptoms of PTSD (assessed with the Posttraumatic Diagnostic Scale), perceived stress (Perceived Stress Scale; Trier Inventory for Chronic Stress), depression and anxiety (Hospital Anxiety and Depression Scale) were assessed by self-report. Office BP was measured and medical data were collected. RESULTS: Criteria for a full PTSD syndrome were met by 13 patients (9%). Posttraumatic stress was higher in the group of patients with controlled (M=10.9, S.D.=9.8) than in those with uncontrolled hypertension (M=3.9, S.D.=5.4; P<.001). In linear regression, only status of hypertension control (beta=.39, P<.001) predicted posttraumatic stress significantly, even after controlling for important cofactors. CONCLUSIONS: PTSD is highly prevalent in hypertensive patients, especially in those with controlled hypertension. An explaining mechanism could be the higher use of health care by patients suffering from PTSD. The mental needs of these patients should be focused in addition to the well-established somatic care. PMID- 26596193 TI - Diagnosis of small fiber neuropathy: A comparative study of five neurophysiological tests. AB - The diagnosis of small fiber neuropathy (SFN) is a challenge for clinical neurophysiology. Conventional nerve conduction studies are inappropriate for this purpose and therefore various neurophysiological tests have been proposed. In this study, we compared the diagnostic value of five of these tests in 87 patients with clinically definite (n=33) or possible (n=54) SFN related to amyloid neuropathy secondary to transthyretin gene mutation or monoclonal gammopathy (n=30), primary Sjogren's syndrome (n=20), Fabry's disease (n=2), or unknown cause (n=35). Neurophysiological tests included quantitative sensory testing with determination of warm and cold detection thresholds (WDT, CDT), recording of laser-evoked potentials (LEP) and sympathetic skin responses (SSRs), and measurement of electrochemical skin conductance (ESC) using Sudoscan((r)) device. All tests were performed at the four extremities (hands and feet). All patients with clinically definite SFN and 70% of the patients with possible SFN had at least one abnormal test. The LEP was the most sensitive test (altered in 79% of the patients with at least one abnormal test), followed by ESC (61%), WDT (55%), SSR (41%), and CDT (32%). The combination of LEP, assessing A-delta sensory fibers, WDT, assessing sensory C fibers, and ESC, assessing autonomic C fibers, appears a relevant approach for the diagnosis of SFN. Compared to SSR and CDT, these three tests, LEP, WDT, and ESC, had a significantly better diagnostic sensitivity and their combination further improved diagnostic accuracy. PMID- 26596194 TI - Recent progress in the studies of structure and function of photosystems I and II. PMID- 26596196 TI - [Preface for Special Issue on the Image Reconstruction Technique]. PMID- 26596195 TI - Comparison of Fractional Flow Reserve Based on Computational Fluid Dynamics Modeling Using Coronary Angiographic Vessel Morphology Versus Invasively Measured Fractional Flow Reserve. AB - Invasive fractional flow reserve (FFRinvasive), although gold standard to identify hemodynamically relevant coronary stenoses, is time consuming and potentially associated with complications. We developed and evaluated a new approach to determine lesion-specific FFR on the basis of coronary anatomy as visualized by invasive coronary angiography (FFRangio): 100 coronary lesions (50% to 90% diameter stenosis) in 73 patients (48 men, 25 women; mean age 67 +/- 9 years) were studied. On the basis of coronary angiograms acquired at rest from 2 views at angulations at least 30 degrees apart, a PC-based computational fluid dynamics modeling software used personalized boundary conditions determined from 3-dimensional reconstructed angiography, heart rate, and blood pressure to derive FFRangio. The results were compared with FFRinvasive. Interobserver variability was determined in a subset of 25 narrowings. Twenty-nine of 100 coronary lesions were hemodynamically significant (FFRinvasive <= 0.80). FFRangio identified these with an accuracy of 90%, sensitivity of 79%, specificity of 94%, positive predictive value of 85%, and negative predictive value of 92%. The area under the receiver operating characteristic curve was 0.93. Correlation between FFRinvasive (mean: 0.84 +/- 0.11) and FFRangio (mean: 0.85 +/- 0.12) was r = 0.85. Interobserver variability of FFRangio was low, with a correlation of r = 0.88. In conclusion, estimation of coronary FFR with PC-based computational fluid dynamics modeling on the basis of lesion morphology as determined by invasive angiography is possible with high diagnostic accuracy compared to invasive measurements. PMID- 26596197 TI - [Examination of Visual Effect in Low-dose Cerebral CT Perfusion Phantom Image Using Iterative Reconstruction]. AB - CT perfusion (CTP) is obtained cerebrovascular circulation image for assessment of stroke patients; however, at the expense of increased radiation dose by dynamic scan. Iterative reconstruction (IR) method is possible to decrease image noise, it has the potential to reduce radiation dose. The purpose of this study is to assess the visual effect of IR method by using a digital perfusion phantom. The digital perfusion phantom was created by reconstructed filtered back projection (FBP) method and IR method CT images that had five exposure doses. Various exposure dose cerebral blood flow (CBF) images were derived from deconvolution algorithm. Contrast-to-noise ratio (CNR) and visual assessment were compared among the various exposure dose and each reconstructions. Result of low exposure dose with IR method showed, compared with FBP method, high CNR in severe ischemic area, and visual assessment was significantly improvement. IR method is useful for improving image quality of low-dose CTP. PMID- 26596198 TI - [Evaluation of Resolution Correction in Single Photon Emission Computed Tomography Reconstruction Method Using a Body Phantom: Study of Three Different Models]. AB - PURPOSE: The aim of this study was to evaluate the resolution recovery techniques of Flash3D, Astonish, and Evolution in single photon emission computed tomography(SPECT) using a body phantom. METHODS: We scanned a National Electrical Manufactures Association body phantom filled with 99mTc. The body of the phantom with radioactive sphere and background was filled with either water or radioactive solution. We investigated image quality using profile curves, recovery coefficient, and image contrast. RESULTS: The profile curve at the edge of the hot sphere showed artifact due to Gibbs oscillation for all techniques, and also over estimation of recovery coefficient was seen in the hot sphere, as had been previously reported in a simulation study. These phenomena were more remarkable than Evolution in the Flash3D and Astonish techniques. For the contrast between hot sphere and background, the contrast recover was enough for the <17-mm hot spheres. These results showed that the effect of contrast correction was less as the radius of rotation diameter became large. CONCLUSION: In the present study using the body phantom, overestimated counts and edge artifacts due to Gibbs oscillation were shown. These phenomena were different by each resolution correction algorithms. Also, there were limitation regarding image quality improvement by resolution correction depending on sphere size and length of radius of rotation. PMID- 26596199 TI - [Evaluation of Vessel Depictability in Compressed Sensing MR Angiography Using Numerical Phantom Model]. AB - As an acceleration technique for use with magnetic resonance imaging (MRI), compressed sensing MRI (CSMRI) was introduced recently to obtain MR images from under sampled k-space data. Images generated using a nonlinear iterative procedure based on sophisticated theory in informatics using data sparsity have complicated characteristics. Therefore, the factors affecting image quality (IQ) in CS-MRI must be elucidated. This article specifically describes the examination of the IQ of clinically important MR angiography (MRA). For MRA, the depictability of thin blood vessels is extremely important, but quantitative evaluation of thin blood vessel depictability is difficult. Therefore, we conducted numerical experiments using a simple numerical phantom model mimicking the cerebral arteries so that the experimental conditions, including the thin vessel positions, can be given. Results show that vessel depictability changed depending on the noise intensity when the wavelet transform was used as the sparsifying transform. Decreased vessel depictability might present difficulties at the clinical signal-to-noise ratio (SNR) level. Therefore, selecting data acquisition and reconstruction conditions carefully in terms of the SNR is crucially important for CS-MRI study. PMID- 26596200 TI - [Usefulness of Iterative Reconstruction Method in the Field of Acute Cerebral Infarction Computed Tomography Examination]. AB - We evaluated clinical images to investigate the usefulness of adaptive iterative dose reduction algorithm (AIDR) in the field of acute cerebral infarction. We did receiver operating characteristic (ROC) analysis by 4 radiologists using 50 clinical images (abnormal case=24, normal case=26) which were reconstructed by AIDR and filtered back projection (FBP). The area under the curve (AUC) value from average ROC curve of observers were 0.79 with the FBP and 0.87 with the AIDR (P=0.31). The standard deviation of AUC was 0.06 with the FBP and 0.03 with the AIDR. More in detail, the AUC value of Expert group (over 10 years of experience) increased to 0.06 by using AIDR compared with FBP method. On the other hand, in Beginner group (less than 10 years of experience) there was 0.09 increase. Therefore, there was some possibility to reduce the variation of diagnostic accuracy among observer and the diagnostic accuracy improvement of the doctor in a few Experience group, by using AIDR for acute cerebral infarction computed tomography (CT) examination. PMID- 26596201 TI - [Effect of Reconstruction Technique for Metal Artifact Reduction in Computed Tomography by Changing Display Field of View]. AB - We evaluated the effect of orthopedic-metal artifact reduction (O-MAR) for metal artifact in computed tomography with 73 simulated seeds for brachytherapy in different sizes of display field of view (DFOV) obtained by helical scan under the same clinical scan condition. The metal artifacts were analyzed with the Gumbel's method by changing DFOV sizes 80 mm, 160 mm, and 320 mm. Gumbel distribution, scale parameter (gamma), and location parameter (beta) of the metal artifacts with O-MAR were compared with that of the metal artifacts with filtered back projection (FBP). In conclusion, it was considered that the effect of metal artifact reduction with O-MAR was influenced by DFOV size in this study. The reduction rates of scale parameter (gamma) were 22.3%, 21.3%, and 10.0% in DFOV 80 mm, 160 mm, and 320 mm, respectively. The reduction rates of location parameter (beta) were 27.4%, 23.4 %, and 9.8%. Therefore, the effect of metal artifact reduction with O-MAR showed the tendency of increasing with decreasing DFOV size. PMID- 26596202 TI - [The Optimal Reconstruction Parameters by Scatter and Attenuation Corrections Using Multi-focus Collimator System in Thallium-201 Myocardial Perfusion SPECT Study]. AB - The aim of this study was to reveal the optimal reconstruction parameters of ordered subset conjugates gradient minimizer (OSCGM) by no correction (NC), attenuation correction (AC), and AC+scatter correction (ACSC) using IQ-single photon emission computed tomography (SPECT) system in thallium-201 myocardial perfusion SPECT. Myocardial phantom acquired two patterns, with or without defect. Myocardial images were performed 5-point scale visual score and quantitative evaluations using contrast, uptake, and uniformity about the subset and update (subset*iteration) of OSCGM and the full width at half maximum (FWHM) of Gaussian filter by three corrections. We decided on optimal reconstruction parameters of OSCGM by three corrections. The number of subsets to create suitable images were 3 or 5 for NC and AC, 2 or 3 for ACSC. The updates to create suitable images were 30 or 40 for NC, 40 or 60 for AC, and 30 for ACSC. Furthermore, the FWHM of Gaussian filters were 9.6 mm or 12 mm for NC and ACSC, 7.2 mm or 9.6 mm for AC. In conclusion, the following optimal reconstruction parameters of OSCGM were decided; NC: subset 5, iteration 8 and FWHM 9.6 mm, AC: subset 5, iteration 8 and FWHM 7.2 mm, ACSC: subset 3, iteration 10 and FWHM 9.6 mm. PMID- 26596203 TI - [Point-spread Function and Time-of-flight in PET Image Reconstruction]. PMID- 26596204 TI - [The Fundamental Principle in X-ray CT Scanner]. PMID- 26596206 TI - [Dose Management to Establish DRLs: Information Provided by CT Systems]. PMID- 26596205 TI - [The Report of the 2nd Educational Symposium on Radiation and Health by Young Scientists (ESRAH2015)]. PMID- 26596207 TI - [Eclectic: Viewpoint of DICOM on Radiological Technology and Informatics]. PMID- 26596208 TI - Therapy of the refractory ascites: Total paracentesis vs. TIPS. AB - This revision was aimed to report the evidences on the treatment of patients with cirrhosis and refractory ascites. Mainly, we wished to explore which of the predicting variables could be used to prefer large-volume paracentesis or TIPS. PMID- 26596209 TI - Contrast-enhanced magnetic resonance cholangiography with gadoxetic-acid-disodium for the detection of biliary-cyst communication in Caroli disease. PMID- 26596210 TI - Biceps electromyography in dialeptic and automotor seizures with and without secondary generalization. AB - OBJECTIVE: Localization of seizure onset during presurgical video-EEG monitoring is indispensable for successful epilepsy surgery. Sometimes analysis of ictal EEG and video fails to identify this zone. Therefore, this study explored the hypothesis that ictal EMG recordings contribute to the lateralization or localization of focal epilepsy. METHODS: All patients with automotor or dialeptic seizures with or without secondary generalization were prospectively included during presurgical video-EEG monitoring over a 5years study period. We analyzed characteristics of ictal biceps EMG and compared the results to EEG and video findings. RESULTS: 79 patients with 185 seizures were included (51.9% male; 73.5% automotor and 26.5% dialeptic seizures; 24.3% seizures secondarily generalized). Even in dialeptic seizures, muscle tone increased bilaterally within seconds after EEG seizure onset (66.7%) without clinical movements. Bilateral "spindle shaped" EMG activity during the automotor phase predicted secondary generalization in 88.7%. Increase of muscle activity in the contralateral side of the body in the beginning of the secondarily generalized tonic-clonic phase was detected in 78.1% after automotor seizures whereas this phenomenon was less pronounced after dialeptic seizures (69.2%). 38.5% of dialeptic seizures evolved into generalized tonic-unilateral clonic seizures. CONCLUSION: Ictal EMG recordings provide lateralizing signs especially in secondarily generalized automotor seizures. In addition, the study suggested that secondary generalization in automotor seizures is determined early already during the automotor phase. Dialeptic seizures can evolve only unilaterally into a tonic clonic seizure while the other side of the body remains tonic. SIGNIFICANCE: Ictal biceps EMG can provide further information regarding lateralization of epileptic seizures. PMID- 26596211 TI - Clinical Neurophysiology--From present to future. PMID- 26596213 TI - Modeling gene flow distribution within conventional fields and development of a simplified sampling method to quantify adventitious GM contents in maize. AB - Genetically modified (GM) crops have been commercially grown for two decades. GM maize is one of 3 species with the highest acreage and specific events. Many countries established a mandatory labeling of products containing GM material, with thresholds for adventitious presence, to support consumers' freedom of choice. In consequence, coexistence systems need to be introduced to facilitate commercial culture of GM and non-GM crops in the same agricultural area. On modeling adventitious GM cross-pollination distribution within maize fields, we deduced a simple equation to estimate overall GM contents (%GM) of conventional fields, irrespective of its shape and size, and with no previous information on possible GM pollen donor fields. A sampling strategy was designed and experimentally validated in 19 agricultural fields. With 9 samples, %GM quantification requires just one analytical GM determination while identification of the pollen source needs 9 additional analyses. A decision support tool is provided. PMID- 26596214 TI - Using human epithelial amnion cells in human de-epidermized dermis for skin regeneration. AB - BACKGROUND: Human amniotic epithelial cells (hAECs) is a desirable reserve of stem cells. Human de-epidermized dermis (DED) retains basic tissue structure and parts of the basement membrane (BM) components at the acelluIar dermal surface, and provides a potential tool for skin regeneration. OBJECTIVE: To evaluate the potential role of hAECs in skin regeneration, we used DED to perform organotypic culture of hAECs to develop organotypic skin. METHODS: HAECs were isolated and cultured. Biological characteristics of hAECs were determined by immunocytochemistry and flow cytometry. To prepare DED, the epidermis was removed and then repeated freeze-thaw cycles. HAECs and fibroblast were seeded onto DED to perform the submerged culture for 3 days and then to be maintained at the air liquid interface for 14 days to form organotypic culture. To identify whether the obtained DED retain the BM structure and components, the histological characteristics of DED and the BM were detected by immunohistochemistry. To evaluate whether the organotypic skin has similar histological characteristics with normal human skin, the marks of epidermal proliferation and differentiation and basement membrane component were detected by immunohistochemistry. Moreover, cell ultrastructure, cell-cell contact and ultrastructure of BM were examined under the transmission electron microscopy. RESULTS: HAECs has stem-cell characteristics with strong pluripotent Oct-4 and embryonic marker SSEA-4 expression. DED has effectively cleansed the cell components and continuous distributions of laminin and collagen IV. The histological appearance of tissue engineered skin in vitro has 4 to 9 continuous layers of stratified epithelium and is similar to normal human skin in morphology. Immunohistochemical studies revealed that proliferation and differentiation markers such as Ki67, CK19, CK14, CK10, filaggrin but not CK18 expressed similar pattern characteristics to normal human epidermis. In addition, Periodic acid-Schiff stain showed that a uniform red staining strip located at the epidermal-dermal junction. BM component proteins (type IV collagen and laminin) and cell adhesion protein (desmoglein) were detected by immunohistochemistry in organotypic skin. Ultrastructurally, desmosomes, hemidesmosomes and BM zone (BMZ) were observed in organotypic skin. CONCLUSIONS: Our studies indicate that the hAECs is a promising stem cell source for tissue-engineered skin, and DED with hAECs is a potential application prospects in regenerative medicine. PMID- 26596212 TI - Effects of partial sleep deprivation on slow waves during non-rapid eye movement sleep: A high density EEG investigation. AB - OBJECTIVE: Changes in slow waves during non-rapid eye movement (NREM) sleep in response to acute total sleep deprivation are well-established measures of sleep homeostasis. This investigation utilized high-density electroencephalography (hdEEG) to examine topographic changes in slow waves during repeated partial sleep deprivation. METHODS: Twenty-four participants underwent a 6-day sleep restriction protocol. Spectral and period-amplitude analyses of sleep hdEEG data were used to examine changes in slow wave energy, count, amplitude, and slope relative to baseline. RESULTS: Changes in slow wave energy were dependent on the quantity of NREM sleep utilized for analysis, with widespread increases during sleep restriction and recovery when comparing data from the first portion of the sleep period, but restricted to recovery sleep if the entire sleep episode was considered. Period-amplitude analysis was less dependent on the quantity of NREM sleep utilized, and demonstrated topographic changes in the count, amplitude, and distribution of slow waves, with frontal increases in slow wave amplitude, numbers of high-amplitude waves, and amplitude/slopes of low amplitude waves resulting from partial sleep deprivation. CONCLUSIONS: Topographic changes in slow waves occur across the course of partial sleep restriction and recovery. SIGNIFICANCE: These results demonstrate a homeostatic response to partial sleep loss in humans. PMID- 26596215 TI - Analysis of lncRNAs expression in UVB-induced stress responses of melanocytes. AB - BACKGROUND: Long non-coding RNAs (lncRNAs) have close relationships with oxidative stress, nutritional deficiency, DNA damage and other types of cellular stress responses. Previous studies have demonstrated that some non-coding RNAs in melanocytes such as microRNAs can change and contribute to the synthesis of melanin or the development of melanoma after stimulation with UV. However, as an important component of non-coding RNAs, it is unclear what changes occur in lncRNAs during UV-induced stress responses in melanocytes. OBJECTIVE: To explore changes in the expression of long non-coding RNAs (lncRNAs) in melanocytes following UVB-induced stress, and to explore if lncRNAs are involved in the synthesis of melanin. METHODS: Primary melanocytes were irradiated by 20mJ/cm(2) UVB. The MTT method was used to detect cell proliferation. Quantitative real-time PCR was carried out to analyze expression of tyrosinase (TYR) and lncRNAs. Dopa colorimetry was performed to analyze TYR activity. The expression profile of lncRNAs and mRNAs were confirmed using an Agilent Human lncRNA 4*180K chip. Intracellular ROS levels were detected by flow cytometry. ROS scavenger (NAC) was employed to inhibit the ROS level. TYR mRNA expression and activity were re analysed after transfecting of lnc-CD1D-2:1 siRNA and lnc-SGCG-5:4 siRNA in UVB irradiated melanocytes to confirm the roles of the two lncRNAs in the synthesis of melanin. phospho-ERK, phospho-p38, and phospho-JNK expressions were detected by Western Blot. RESULTS: Cell proliferation of the 20mJ/cm(2) UVB-irradiated melanocytes decreased to 91% of that of the control cells. Twenty-four hours after irradiation with 20mJ/cm(2) UVB, TYR mRNA expression and activity of the irradiated cells were significantly increased relative to the control group. Chip detection data showed that after irradiation with 20mJ/cm(2) UVB, the expression of 807 lncRNAs and 69 stress response-related genes had changed by more than two fold. Expression levels of Lnc-GKN2-1:1, lnc-CD1D-2:1, and lnc-SGCG-5:4 and ROS content were significantly increased after UVB irradiation. NAC reduced UVB induced ROS generation and inhibited UVB-induced upregulation of lnc-GKN2-1:1 and lnc-CD1D-2:1. Lnc-CD1D-2:1 siRNA significantly suppressed the UVB-induced TYR mRNA expression and tyrosinase activation. Lnc-CD1D-2:1 siRNA inhibited UVB induced p38 phosphorylation. CONCLUSIONS: LncRNAs in melanocytes undergo significant changes following irradiation with 20mJ/cm(2) UVB, suggestting that lncRNAs participate in the UVB-induced stress response. Some lncRNAs expression changes induced by UVB are dependent on ROS generation. ROS-mediated production of lnc-CD1D-2:1 may be involved in the melanogenesis induced by UVB. PMID- 26596216 TI - Prostaglandin E receptor 4 inhibition restores UVB-induced downregulation of ATP2A2/SERCA2 in cultured normal human keratinocytes. PMID- 26596217 TI - Reciprocal contribution of Th17 and regulatory T cells in severe drug allergy. PMID- 26596218 TI - Combination of retinoid and histone deacetylase inhibitor produced an anti-tumor effect in cutaneous T-cell lymphoma by restoring tumor suppressor gene, retinoic acid receptorbeta2, via histone acetylation. AB - BACKGROUND: Retinoids exert anti-proliferative, differentiative, and apoptosis inducing effects through their receptors. Retinoic acid receptor (RAR) beta2 behaves as a tumor suppressor gene, and its expression is suppressible by DNA methylation in many malignancies. OBJECTIVE: We aimed to determine whether combining a retinoid, Am 80, with a histone deacetylase inhibitor, MS-275, could suppress tumor growth in a RARbeta2-negative human cutaneous T cell lymphoma (CTCL) cell lines and freshly isolated primary CTCL cells, and to elucidate the epigenetic mechanism behind the phenomena. METHODS: SeAx cells were implanted subcutaneously in NOD-SCID mice which were randomly divided into four groups and treated with either Am80, MS-275 by oral gavage (five days/week), or a combination of the two agents. Cell proliferation assay, methylation-specific PCR, flow cytometric analysis of cell cycle and apoptosis and chromatin immunoprecipitation assay were employed. RESULTS: Quantitative PCR analysis revealed that RARbeta2 gene expression was restored only by this combination rather than by either of the agents singly. Restored retinoid sensitivity was observed in combining retinoid with a histone deacetylase inhibitor significantly inhibited cell growth in vitro, suppressed subcutaneously transplanted tumor growth, and prolonged survival of tumor-bearing mice in vivo by more strongly inducing apoptosis and p21 expression in CTCL cells than either agent alone. In the combination treatment, the histone H4 acetylation level at lysine 12 and 16 in the promoter region increased after restoration of RARbeta2 expression although the DNA methylation of RARbeta2 remained unchanged. CONCLUSION: This is the first report of histone acetylation as the primary event in the restoration of RARbeta2. Inducible RARbeta2 expression may serve as a reliable predictor for tumor response in patients undergoing 'epigenetic & differentiation' therapy. PMID- 26596219 TI - Novel p.Glu519Gln missense mutation in ST14 in a patient with ichthyosis, follicular atrophoderma and hypotrichosis and review of the literature. PMID- 26596220 TI - [Author's reply]. PMID- 26596221 TI - [Prone position ventilation for patients with severe ARDS and morbid obsity]. PMID- 26596222 TI - Atypical hemolytic uremic syndrome in intensive care: Case report in an adult. PMID- 26596223 TI - Green urine due to propofol infusion. PMID- 26596224 TI - Analysis of the first, third and last cycles of a sequence of two-minute cardiopulmonary resuscitation maneuvers on a mannequin. PMID- 26596225 TI - [Organ donation: An exception to consent futile treatments?]. PMID- 26596226 TI - Spanish Cardiac Catheterization and Coronary Intervention Registry. 24th Official Report of the Spanish Society of Cardiology Working Group on Cardiac Catheterization and Interventional Cardiology (1990-2014). AB - INTRODUCTION AND OBJECTIVES: The Working Group on Cardiac Catheterization and Interventional Cardiology presents its annual report on the data from the registry of the activity in Spain in 2014. METHODS: Data were voluntarily provided by participating centers. The information was introduced online and was analyzed by the Steering Committee of the Working Group on Cardiac Catheterization and Interventional Cardiology. RESULTS: Data were reported by 106 hospitals. A total of 140 461 diagnostic procedures (125 484 coronary angiograms) were performed, representing a rate of 3014 diagnostic studies per million population. This year, the number of percutaneous coronary interventions increased to 67 611, giving a rate of 1447 interventions per million population. A total of 94 458 stents were implanted, including 64 057 drug-eluting stents and 2424 biodegradable intracoronary devices. Of the total number of percutaneous coronary interventions, 17 825 were in acute myocardial infarction, representing 26.4% of all coronary interventions. A radial approach was used in 74% of diagnostic procedures and in 70.4% of interventional procedures. The use of renal denervation decreased, whereas over 125 mitral leak closures were performed. Transcatheter aortic valve implantation procedures exceeded 1300 implantations per year, a 27% increase from 2013. CONCLUSIONS: The registry for 2014 shows a slight increase in coronary disease activity despite no increase in the management of ST-segment elevation myocardial infarction. Drug-eluting intracoronary devices now comprise over 70% of all intracoronary devices. A continual increase is only seen in certain structural interventional techniques, such as transcatheter aortic valve implantation and perivalvular leak closure. PMID- 26596227 TI - Recent advances in the development of vaccines for Ebola virus disease. AB - Ebola virus is one of the most dangerous microorganisms in the world causing hemorrhagic fevers in humans and non-human primates. Ebola virus (EBOV) is a zoonotic infection, which emerges and re-emerges in human populations. The 2014 outbreak was caused by the Zaire strain, which has a kill rate of up to 90%, though 40% was recorded in the current outbreak. The 2014 outbreak is larger than all 20 outbreaks that have occurred since 1976, when the virus was first discovered. It is the first time that the virus was sustained in urban centers and spread beyond Africa into Europe and USA. Thus far, over 22,000 cases have been reported with about 50% mortality in one year. There are currently no approved therapeutics and preventive vaccines against Ebola virus disease (EVD). Responding to the devastating effe1cts of the 2014 outbreak and the potential risk of global spread, has spurred research for the development of therapeutics and vaccines. This review is therefore aimed at presenting the progress of vaccine development. Results showed that conventional inactivated vaccines produced from EBOV by heat, formalin or gamma irradiation appear to be ineffective. However, novel vaccines production techniques have emerged leading to the production of candidate vaccines that have been demonstrated to be effective in preclinical trials using small animal and non-human primates (NHP) models. Some of the promising vaccines have undergone phase 1 clinical trials, which demonstrated their safety and immunogenicity. Many of the candidate vaccines are vector based such as Vesicular Stomatitis Virus (VSV), Rabies Virus (RABV), Adenovirus (Ad), Modified Vaccinia Ankara (MVA), Cytomegalovirus (CMV), human parainfluenza virus type 3 (HPIV3) and Venezuelan Equine Encephalitis Virus (VEEV). Other platforms include virus like particle (VLP), DNA and subunit vaccines. PMID- 26596228 TI - [Unusual location of an intrathoracic mesothelial cyst in the posterior and upper mediastinum]. AB - BACKGROUND: Intrathoracic mesothelial cysts are congenital lesions due to an abnormal development of the pericardial coelom. They are usually asymptomatic and found incidentally on chest radiography or computed tomography. As their classic anatomical location is in the cardiophrenic angle, they are also referred to pleuropericardial cysts. CASE REPORT: A 50-year-old male presented with a history of chest pain. Physical examination and chest X-ray were normal. Computed tomography (CT) scan revealed a cystic lesion in the posterior and upper mediastinum. The cyst was surgically removed through a posterolateral thoracotomy. Histopathological examination confirmed that it was a mesothelial cyst. The surgical resection of the cyst lead to relief of the thoracic pain over a three-year follow-up period. CT-scan showed an aberrant right subclavian artery or arteria lusoria, which is an anomaly of the aortic arch secondary to abnormal embryogenesis. We know no other report of concurrent ectopic coelomic cyst and aberrant right subclavian artery. CONCLUSION: Although the majority of coelomic cysts needs only radiological and clinical follow-up, surgical resection should be performed when the patient is symptomatic or when the diagnosis is uncertain. PMID- 26596229 TI - [Delayed convulsion after lidocaine instillation for bronchoscopy]. AB - INTRODUCTION: Lidocaine toxicity usually appears rapidly and is directly correlated with plasma concentrations of the drug. CASE REPORT: We report a case of a late neurologic toxicity occurring after instillation of lidocaine during fibre-optic bronchoscopy. A patient with bronchiolitis obliterans underwent a diagnostic bronchoscopy. She received multiples instillations of Xylocaine((r)) 2% (lidocaine). Three and a half hours later, she had a tonic-clonic seizure. Seven hours later, this recurred. Lidocaine plasma levels were in the toxic range at the time of the first seizure (18.32MUg/mL) with a significant decrease in the concentration noted 24hours later. CONCLUSION: The slow absorption of lidocaine into the blood from the bronchial tree explains the delayed neurologic toxicity. Our observation is a reminder that complications can occur due to high doses of lidocaine administrated by instillation. Thus, if the recommended dose of lidocaine is exceeded, it is essential to monitor patients closely for a prolonged period, especially those with fibrosing lung disease in order to avoid possible late toxicity. PMID- 26596230 TI - Experimental study on thermophoresis of colloids in aqueous surfactant solutions. AB - Thermophoresis refers to the motion of particles under a temperature gradient and it is one of the particle manipulation techniques. Regarding the thermophoresis of particles in liquid media, however, many open questions still remain, especially the role of the interfacial effect. This work reports on a systematic experimental investigation of surfactant effects, especially the induced interfacial effect, on the thermophoresis of colloids in aqueous solutions via a microfluidic approach. Two kinds of commonly used surfactants, sodium dodecyl sulfate (SDS) and cetyltrimethylammonium bromide (CTAB), are selected and the results show that from relatively large concentrations, the two surfactants can greatly enhance the thermophilic mobilities. Specifically, it is found that the colloid-water interfaces modified with more polar end groups can potentially lead to a stronger thermophilic tendency. Due to the complex effects of surfactants, further theoretical model development is needed to quantitatively describe the dependence of thermophoresis on the interface characteristics. PMID- 26596231 TI - Subungual Hematoma in the Mountains. PMID- 26596232 TI - Estimated levator ani subtended volume: a novel assay for predicting surgical failure after uterosacral ligament suspension. AB - BACKGROUND: Levator ani muscle complex plays an important role in pelvic support and defects or laxity in this muscle complex contributes to pelvic organ prolapse and recurrence after surgical repair. OBJECTIVE: The purpose of this study was to determine whether estimated levator ani subtended volume can predict surgical outcomes for laparoscopic bilateral uterosacral ligament suspension. STUDY DESIGN: A retrospective cohort study was performed in patients who underwent laparoscopic uterosacral ligament suspension from 2010-2012. Only patients with a preoperative pelvic magnetic resonance image were included. Surgical failure was defined as a composite score that included the presence of anatomic bulge beyond the hymen with sensation of vaginal bulge or repeat treatment for prolapse via pessary or surgery by 1-year follow-up evaluation. Standard protocol pelvic magnetic resonance imaging measurements pubococcygeal line, H-line, and M-line were collected along with the calculation of the width of the levator ani hiatus. Estimated levator ani subtended volume was calculated for each subject. An optimal cutoff point was calculated and compared against categoric values of surgical success/failure. A Fisher exact test, an area under receiver operating characteristics curve, and logistic regression analysis were performed. A probability value of <.05 was considered statistically significant. RESULTS: Ninety-three women underwent laparoscopic bilateral uterosacral ligament suspension during study period. Of these, 66 women had a standardized preoperative pelvic magnetic resonance image per institutional protocol. Thirteen patients (19.6%) met the criteria for surgical failure by 1 year. An optimal cutoff point of 38.5 was calculated by Liu's method for optimization. Among the patients with defined surgical failures, 84.6% (11/13) had an estimated levator ani subtended volume above cutoff point of 38.5. Among the patients with defined surgical success, 39.6% (21/53) had an estimated levator ani subtended volume above the cutoff point (84.6% vs 39.6%; P = .0048) with a significant odds ratio of 8.38 (95% confidence interval, 1.69-41.68; P = .009). An area under receiver operating characteristics curve of 0.725 (95% confidence interval, 0.603-0.847), sensitivity of 84.6% (95% confidence interval, 54.6%-98.1%), and specificity of 60.4% (95% confidence interval, 46%-73.5%) at 38.5 were predictors of surgical success/failure by 1 year. Logistic regression analysis demonstrated no significant confounders among age, body mass index, stage, or parity. CONCLUSIONS: Estimated levator ani subtended volume may predict surgical failure for laparoscopic bilateral uterosacral ligament suspension. Patients with a calculated estimated levator ani subtended volume above 38.5 on a preoperative pelvic magnetic resonance imaging were associated with an increased risk for surgical failure by 1 year, regardless of age, body mass index, stage, or parity. Future investigation that will include repeatability, reliability analysis, and a prospective study is warranted. PMID- 26596233 TI - Does gestational diabetes affect fetal growth and pregnancy outcome in twin pregnancies? AB - BACKGROUND: Women with twin pregnancies are at increased risk for fetal growth restriction, which might be attributed to the limited maternal resources that are being shared by >1 fetus. Based on that, it may be hypothesized that the fetal effects of gestational diabetes mellitus (GDM) with respect to accelerated fetal growth may be less pronounced in twin gestations or alternatively may even have a beneficial role in decreasing the risk of fetal growth restriction in these pregnancies. However, available data are conflicting and are limited by the fact that many of the complications associated with GDM are less relevant for twin gestations, and that all women with GDM included in previous studies were monitored and treated to control maternal blood glucose levels. OBJECTIVE: We sought to assess the impact of GDM and milder degrees of glucose intolerance on fetal growth and pregnancy outcome in twin pregnancies. STUDY DESIGN: This was a retrospective cohort study of all women with twin pregnancies who underwent screening for GDM in a single tertiary referral center from October 2003 through December 2014. The diagnosis of GDM during the study period was based on the 2008 Canadian Diabetes Association (CDA) guidelines, which involve universal screening with a 50-g glucose challenge test (GCT) followed by a diagnostic 2-hour 75-g oral glucose tolerance test (OGTT). Fetal growth and pregnancy outcome were compared among 4 groups of women with increasing degree of glucose intolerance: (1) GCT-NEGATIVE, negative 50-g GCT; (2) OGTT-NEGATIVE, positive 50-g GCT followed by a negative 75-g OGTT; (3) GDM-IADPSG, positive 50-g GCT followed by a positive 75-g OGTT according to the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) criteria but not the 2008 CDA criteria-because these women were not considered to have GDM during the study period they were not subjected to any form of treatment; and (4) GDM-CDA, positive 50-g GCT followed by a positive 75-g OGTT according to the 2008 CDA criteria. RESULTS: Overall 1393 women were eligible for the study: 1021 (73.3%) in the GCT-NEGATIVE group, 184 (13.2%) in the OGTT-NEGATIVE group, 99 (7.1%) in the GDM-IADPSG group, and 89 (6.4%) in the GDM-CDA group. There was a continuous relationship between the degree of glucose intolerance and fetal growth as reflected by a right shift of the distribution curve of birthweight percentiles and a greater likelihood of high birthweight percentile: OGTT-NEGATIVE = odds ratio (OR), 1.5; 95% confidence interval (CI), 1.07-2.2; GDM-IADPSG = OR, 1.7; 95% CI, 1.1-2.6; and GDM-CDA = OR, 1.9, 95% CI, 1.3-3.1 (using the GCT-NEGATIVE group as reference). Fetuses of women with glucose intolerance were more likely to experience asymmetric growth as reflected by an elevated abdominal circumference to head circumference ratio. CONCLUSION: GDM and milder degrees of glucose intolerance in twin pregnancies are associated with an increased risk of asymmetric overgrowth in a manner that is related to the degree of glucose intolerance. PMID- 26596234 TI - Randomized controlled trial of minimal stimulation versus conventional in vitro fertilization. PMID- 26596235 TI - Reply. PMID- 26596237 TI - The ThRombolysis in UnconTrolled Hypertension (TRUTH) protocol: an observational study on treatment strategy of elevated blood pressure in stroke patients eligible for IVT. AB - BACKGROUND: Intravenous thrombolysis (IVT) with (recombinant) tissue plasminogen activator is an effective treatment in acute ischemic stroke. However, IVT is contraindicated when blood pressure is above 185/110 mmHg, because of an increased risk on symptomatic intracranial hemorrhage. In current Dutch clinical practice, two distinct strategies are used in this situation. The active strategy comprises lowering blood pressure with antihypertensive agents below these thresholds to allow start of IVT. In the conservative strategy, IVT is administered only when blood pressure drops spontaneously below protocolled thresholds. A retrospective analysis in two recent stroke trials showed a non significant signal towards better functional outcome in the active group; robust evidence for either strategy, however, is lacking. We hypothesize that (I) the active strategy leads to a better functional outcome three months after acute ischemic stroke. Secondary hypotheses are that this effect occurs despite (II) increasing the number of symptomatic intracranial hemorrhages, and could be attributable to (III) a higher rate of IVT treatments and (IV) a shorter door-to needle time. METHODS AND DESIGN: The TRUTH is a prospective, observational, cluster-based, parallel group follow-up study; in which participating centers continue their current local treatment guidelines. Outcomes of patients admitted to centers with an active will be compared to those admitted to centers with a conservative strategy. The primary outcome is functional outcome on the modified Rankin Scale at three months. Secondary outcomes are symptomatic intracranial hemorrhage, IVT treatment and door-to-needle time. We based our sample size estimate on an ordinal analysis of the mRS with the "proportional odds" model. With the aforementioned signal observed in a recent retrospective study in these patients as an estimate of the effect size and with alpha 0 . 05, this analysis would have an 80 % power with a total number of 600 patients. Corrections for expected imbalance in group size and clustering effects resulted in a sample size of 1235 patients. DISCUSSION: The TRUTH is the first large prospective study specifically studying IVT-candidates with elevated blood pressure, and has the potential to change clinical practice and optimize acute stroke care in these patients. PMID- 26596238 TI - Obesity and discrimination - a systematic review and meta-analysis of observational studies. AB - BACKGROUND: Research on obesity has shown that stigma often accompanies obesity and impacts many life domains. No previous research has systematically reviewed published literature about the prevalence and the nature of perceived weight discrimination in individuals with obesity. This systematic review and meta analysis aims to fill that gap. METHODS: A systematic literature search was conducted without time limits using the databases Medline, ISI Web of Knowledge and the Cochrane Library. Meta-analyses were performed using random effect models. Observational studies pertaining to (i) prevalence estimates and (ii) forms of perceived weight discrimination among individuals with obesity were included. RESULTS: Of 4393 citations retrieved, nine citations retrieved, nine studies met inclusion criteria. Pooled prevalence was 19.2% (95% confidence interval (CI) 11.7 to 29.8%) for individuals with class I obesity (Body mass index [BMI] = 30-35 kg m(-2) ) and 41.8% (95% CI 36.9 to 46.9%) for individuals with more extreme obesity (BMI > 35 kg m(-2) ). Findings from nationally representative US samples revealed higher prevalence estimates in individuals with higher BMI values (BMI > 35 kg m(-2) ) and in women. CONCLUSIONS: The results provide evidence that perceptions of weight discrimination by individuals with obesity were common, and its negative consequences are highly relevant issues within society and need to be the focus of potential interventions. (c) 2015 World Obesity. PMID- 26596239 TI - Single-molecule enzymology of steroid transforming enzymes: Transient kinetic studies and what they tell us. AB - Structure-function studies on steroid transforming enzymes often use site directed mutagenesis to inform mechanisms of catalysis and effects on steroid binding, and data are reported in terms of changes in steady state kinetic parameters kcat, Km and kcat/Km. However, this dissection of function is limited since kcat is governed by the rate-determining step and Km is a complex macroscopic kinetic constant. Often site-directed mutagenesis can lead to a change in the rate-determining step which cannot be revealed by just reporting a decrease in kcat alone. These issues are made more complex when it is considered that many steroid transforming enzymes have more than one substrate and product. We present the case for using transient-kinetics performed with stopped-flow spectrometry to assign rate constants to discrete steps in these multi-substrate reactions and their use to interpret enzyme mechanism and the effects of disease and engineered mutations. We demonstrate that fluorescence kinetic transients can be used to measure ligand binding that may be accompanied by isomerization steps, revealing the existence of new enzyme intermediates. We also demonstrate that single-turnover reactions can provide a klim for the chemical step and Ks for steroid-substrate binding and that when coupled with kinetic isotope effect measurements can provide information on transition state intermediates. We also demonstrate how multiple turnover experiments can provide evidence for either "burst-phase" kinetics, which can reveal a slow product release step, or linear phase kinetics, in which the chemical step can be rate-determining. With these assignments it becomes more straightforward to analyze the effects of mutations. We use examples from the hydroxysteroid dehydrogenases (AKR1Cs) and human steroid 5beta-reductase (AKR1D1) to illustrate the utility of the approach, which are members of the aldo-keto reductase (AKR) superfamily. PMID- 26596240 TI - The Great Earthquake in Nepal--A Personal View. PMID- 26596241 TI - Synergistic Substrate and Oxygen Activation in Salicylate Dioxygenase Revealed by QM/MM Simulations. AB - Salicylate 1,2-dioxygenase (SDO) is the first enzyme to be discovered to catalyze the oxidative cleavage of a monohydroxylated aromatic compound, namely salicylate, instead of the well-known electron-rich substrates. We have investigated the mechanism of dioxygen activation in SDO by QM/MM calculations. Our study reveals that the non-heme Fe(II) center in SDO activates salicylate and O2 synergistically through a strong covalent interaction to facilitate the reductive cleavage of O2. A covalent salicylate-Fe(II) -O2 complex is the reactive oxygen species in this case, and its electronic structure is best described as being between the two limiting cases, Fe(II)-O2 and Fe(II)-O2(-), with partial electron transfer from the activated salicylate to O2 via the Fe center. Thus SDO employs a synergistic strategy of substrate and oxygen activation to carry out the catalytic reaction, which is unprecedented in the family of iron dioxygenases. Moreover, O2 activation in SDO happens without the assistance of a proton source. Our study essentially shows a new mechanistic possibility for O2 activation. PMID- 26596236 TI - Evaluation of delivery options for second-stage events. AB - BACKGROUND: Cesarean delivery in the second stage of labor is common, whereas the frequency of operative vaginal delivery has been declining. However, data comparing outcomes for attempted operative vaginal delivery vs cesarean in the second stage are scant. Previous studies that examine operative vaginal delivery have compared it to a baseline risk of complications from a spontaneous vaginal delivery and cesarean delivery. However, when a woman has a need for intervention in the second stage, spontaneous vaginal delivery is not an option she or the provider can choose. Thus, the appropriate clinical comparison is cesarean vs operative vaginal delivery. OBJECTIVE: Our objective was to compare outcomes by the first attempted operative delivery (vacuum, forceps vs cesarean delivery) in patients needing second-stage assistance at a fetal station of +2 or below. STUDY DESIGN: We conducted secondary analysis of an observational obstetric cohort in 25 academically affiliated US hospitals over a 3-year period. A subset of >=37 weeks, nonanomalous, vertex, singletons, with no prior vaginal delivery who reached a station of +2 or below and underwent an attempt at an operative delivery were included. Indications included for operative delivery were: failure to descend, nonreassuring fetal status, labor dystocia, or maternal exhaustion. The primary outcomes included a composite neonatal outcome (death, fracture, length of stay >=3 days beyond mother's, low Apgar, subgaleal hemorrhage, ventilator support, hypoxic encephalopathy, brachial plexus injury, facial nerve palsy) and individual maternal outcomes (postpartum hemorrhage, third- and fourth degree tears [severe lacerations], and postpartum infection). Outcomes were examined by the 3 attempted modes of delivery. Odds ratios (OR) were calculated for primary outcomes adjusting for confounders. Final mode of delivery was quantified. RESULTS: In all, 2531 women met inclusion criteria. No difference in the neonatal composite outcome was observed between groups. Vacuum attempt was associated with the lowest frequency of maternal complications (postpartum infection 0.2% vs 0.9% forceps vs 5.3% cesarean, postpartum hemorrhage 1.4% vs 2.8% forceps vs 3.8% cesarean), except for severe lacerations (19.1% vs 33.8% forceps vs 0% cesarean). When confounders were taken into account, both forceps (OR, 0.16; 95% confidence interval, 0.05-0.49) and vacuum (OR, 0.04; 95% confidence interval, 0.01-0.17) were associated with a significantly lower odds of postpartum infection. The neonatal composite and postpartum hemorrhage were not significantly different between modes of attempted delivery. Cesarean occurred in 6.4% and 4.4% of attempted vacuum and forceps groups (P = .04). CONCLUSION: In patients needing second-stage delivery assistance with a station of +2 or below, attempted operative vaginal delivery was associated with a lower frequency of postpartum infection, but higher frequency of severe lacerations. PMID- 26596242 TI - Finite-time stochastic contractive boundedness of Markovian jump systems subject to input constraints. AB - This paper studies the finite-time stochastic contractive boundedness problem for a class of Markovian jump linear systems subject to input constraints. First of all, by employing exogenous disturbance, two novel concepts, namely finite-time stochastic contractive stability (FTSCS) and finite-time stochastic contractive boundedness (FTSCB) are introduced. Secondly, a relaxation scheme for incomplete (i.e., partly known, unknown, and uncertain) transition probability descriptions is introduced. Then, two kinds of design methodology of observer-based controllers are proposed. All the design conditions are established by employing a set of linear matrix inequalities (LMIs). At last, numerical examples are given to demonstrate the effectiveness of the proposed approach. PMID- 26596243 TI - Kill-painting of hypoxic tumours in charged particle therapy. AB - Solid tumours often present regions with severe oxygen deprivation (hypoxia), which are resistant to both chemotherapy and radiotherapy. Increased radiosensitivity as a function of the oxygen concentration is well described for X-rays. It has also been demonstrated that radioresistance in anoxia is reduced using high-LET radiation rather than conventional X-rays. However, the dependence of the oxygen enhancement ratio (OER) on radiation quality in the regions of intermediate oxygen concentrations, those normally found in tumours, had never been measured and biophysical models were based on extrapolations. Here we present a complete survival dataset of mammalian cells exposed to different ions in oxygen concentration ranging from normoxia (21%) to anoxia (0%). The data were used to generate a model of the dependence of the OER on oxygen concentration and particle energy. The model was implemented in the ion beam treatment planning system to prescribe uniform cell killing across volumes with heterogeneous radiosensitivity. The adaptive treatment plans have been validated in two different accelerator facilities, using a biological phantom where cells can be irradiated simultaneously at three different oxygen concentrations. We thus realized a hypoxia-adapted treatment plan, which will be used for painting by voxel of hypoxic tumours visualized by functional imaging. PMID- 26596244 TI - Biosimilars G-CSF versus originator G-CSF in post allotransplant recovery. A case control study. PMID- 26596245 TI - Structure-Tuned Lead Halide Perovskite Nanocrystals. AB - Colloidally stable suspensions of lead halide perovskite nanocrystals are prepared from high-quality lead halide nanocrystal seeds. Perovskite nanocrystals with different layered crystal structures are reported. These systems are well suited for investigations of the intrinsic photophysics and spectroscopy of organic-inorganic metal halide perovskites. PMID- 26596247 TI - Investigation of ZnCo2O4-Pt hybrids with different morphologies towards catalytic CO oxidation. AB - In this work, three kinds of ZnCo2O4 morphologies, that is, rod, plate and sphere, have been successfully prepared and further used to support Pt nanoparticles (NPs) via in situ deposition. The as-prepared ZnCo2O4-Pt hybrid nanomaterials were then carefully characterized by SEM, TEM, XRD, XPS, ICP EDX, and N2 adsorption measurement in great detail. Besides, the three catalysts were also evaluated by the model reaction of catalytic CO oxidation. After comparing the difference in the three kinds of morphologies, we have tried to clarify the reason for their different catalytic performances. As a result, the ZnCo2O4-Pt sphere was found to be the most active, attaining 100% CO conversion at a relatively low temperature of 140 degrees C, because more Pt NPs are prone to distribution on the surface of ZnCo2O4 spheres than the other ones. The following cycling tests confirm the excellent stability of the as-prepared ZnCo2O4-Pt samples. PMID- 26596246 TI - How well do WHO complementary feeding indicators relate to nutritional status of children aged 6-23 months in rural Northern Ghana? AB - BACKGROUND: Though the World Health Organization (WHO) recommended Infant and Young Child Feeding (IYCF) indicators have been in use, little is known about their association with child nutritional status. The objective of this study was to explore the relationship between IYCF indicators (timing of complementary feeding, minimum dietary diversity, minimum meal frequency and minimum acceptable diet) and child growth indicators. METHODS: A community-based cross-sectional survey was carried out in November 2013. The study population comprised mothers/primary caregivers and their children selected using a two-stage cluster sampling procedure. RESULTS: Of the 1984 children aged 6-23 months; 58.2 % met the minimum meal frequency, 34.8 % received minimum dietary diversity (>=4 food groups), 27.8 % had received minimum acceptable diet and only 15.7 % received appropriate complementary feeding. With respect to nutritional status, 20.5 %, 11.5 % and 21.1 % of the study population were stunted, wasted and underweight respectively. Multiple logistic regression analysis revealed that compared to children who were introduced to complementary feeding either late or early, children who started complementary feeding at six months of age were 25 % protected from chronic malnutrition (AOR = 0.75, CI = 0.50 - 0.95, P = 0.02). It was found that children whose mothers attended antenatal care (ANC) at least 4 times were 34 % protected [AOR 0.66; 95 % CI (0.50 - 0.88)] against stunted growth compared to children born to mothers who attended ANC less than 4 times. Children from households with high household wealth index were 51 % protected [AOR 0.49; 95 % CI (0.26 - 0.94)] against chronic malnutrition compared to children from households with low household wealth index. After adjusting for potential confounders, there was a significant positive association between appropriate complementary feeding index and mean WLZ (beta = 0.10, p = 0.005) but was not associated with mean LAZ. CONCLUSIONS: The WHO IYCF indicators better explain weight-for-length Z-scores than length-for-age Z-scores of young children in rural Northern Ghana. Furthermore, a composite indicator comprising timely introduction of solid, semi-solid or soft foods at 6 months, minimum meal frequency, and minimum dietary diversity better explains weight-for-length Z scores than each of the single indicators. PMID- 26596248 TI - Targeted cellular ablation based on the morphology of malignant cells. AB - Treatment of glioblastoma multiforme (GBM) is especially challenging due to a shortage of methods to preferentially target diffuse infiltrative cells, and therapy-resistant glioma stem cell populations. Here we report a physical treatment method based on electrical disruption of cells, whose action depends strongly on cellular morphology. Interestingly, numerical modeling suggests that while outer lipid bilayer disruption induced by long pulses (~100 MUs) is enhanced for larger cells, short pulses (~1 MUs) preferentially result in high fields within the cell interior, which scale in magnitude with nucleus size. Because enlarged nuclei represent a reliable indicator of malignancy, this suggested a means of preferentially targeting malignant cells. While we demonstrate killing of both normal and malignant cells using pulsed electric fields (PEFs) to treat spontaneous canine GBM, we proposed that properly tuned PEFs might provide targeted ablation based on nuclear size. Using 3D hydrogel models of normal and malignant brain tissues, which permit high-resolution interrogation during treatment testing, we confirmed that PEFs could be tuned to preferentially kill cancerous cells. Finally, we estimated the nuclear envelope electric potential disruption needed for cell death from PEFs. Our results may be useful in safely targeting the therapy-resistant cell niches that cause recurrence of GBM tumors. PMID- 26596250 TI - Children's thoughts and feelings related to visiting critically ill relatives in an adult ICU: A qualitative study. AB - OBJECTIVES: To describe and understand children's thoughts and feelings related to visiting critically ill relatives or family members in an adult intensive care unit. DESIGN: A qualitative descriptive study. METHOD: Twenty-eight children (14 girls; 14 boys) that had visited a critically ill relative or family member in an adult intensive care unit were invited to participate in an interview. The material was analysed inspired by Gadamer's hermeneutic philosophy and Doverborg and Pramling Samuelsson's method about interviews and dialogues with children. RESULTS: Children with a seriously ill/injured relative suffer. However, visiting seems to alleviate suffering. Visiting and being present as a part of the situation brought positive feelings of involvement and made it possible to show that they wanted to care for the relative. The sick relative was always on the child's mind and seeing and being with them in the intensive care unit resulted in relief and calmness, even if the relative's situation sometimes evoked feelings of despair and fear. CONCLUSION: Knowledge and awareness of the fact that children are affected by the relative's condition and for their wellbeing needs to visit, caring actions must focus on helping the child become involved in the relative's situation in order to alleviate suffering. PMID- 26596249 TI - A new live-cell reporter strategy to simultaneously monitor mitochondrial biogenesis and morphology. AB - Changes in mitochondrial amount and shape are intimately linked to maintenance of cell homeostasis via adaptation of vital functions. Here, we developed a new live cell reporter strategy to simultaneously monitor mitochondrial biogenesis and morphology. This was achieved by making a genetic reporter construct where a master regulator of mitochondrial biogenesis, nuclear respiratory factor 1 (NRF 1), controls expression of mitochondria targeted green fluorescent protein (mitoGFP). HeLa cells with the reporter construct demonstrated inducible expression of mitoGFP upon activation of AMP-dependent protein kinase (AMPK) with AICAR. We established stable reporter cells where the mitoGFP reporter activity corresponded with mitochondrial biogenesis both in magnitude and kinetics, as confirmed by biochemical markers and confocal microscopy. Quantitative 3D image analysis confirmed accordant increase in mitochondrial biomass, in addition to filament/network promoting and protecting effects on mitochondrial morphology, after treatment with AICAR. The level of mitoGFP reversed upon removal of AICAR, in parallel with decrease in mtDNA. In summary, we here present a new GFP-based genetic reporter strategy to study mitochondrial regulation and dynamics in living cells. This combinatorial reporter concept can readily be transferred to other cell models and contexts to address specific physiological mechanisms. PMID- 26596251 TI - Screening for coronary artery disease in asymptomatic individuals: Why and how? AB - Cardiovascular disease is still the main cause of death in the world, and coronary artery disease is the largest contributor. Screening asymptomatic individuals for coronary artery disease in view of preventive treatment is therefore of crucial interest. Apart from established risk scores based on traditional risk factors such as the Framingham or SCORE risk scores, new biomarkers and imaging methods have emerged (high-sensitivity C-reactive protein, lipoprotein-associated phospholipase A2 and secretory phospholipase A2, coronary artery calcium score, carotid intima-media thickness and ankle-brachial index). Their added value on top of the classic risk scores varies considerably and the most convincing evidence exists for coronary artery calcium score in intermediate risk asymptomatic individuals. PMID- 26596253 TI - Engineering the interlayer exchange coupling in magnetic trilayers. AB - When the thickness of metal film approaches the nanoscale, itinerant carriers resonate between its boundaries and form quantum well states (QWSs), which are crucial to account for the film's electrical, transport and magnetic properties. Besides the classic origin of particle-in-a-box, the QWSs are also susceptible to the crystal structures that affect the quantum resonance. Here we investigate the QWSs and the magnetic interlayer exchange coupling (IEC) in the Fe/Ag/Fe (001) trilayer from first-principles calculations. We find that the carriers at the Brillouin-zone center (belly) and edge (neck) separately form electron- and hole like QWSs that give rise to an oscillatory feature for the IEC as a function of the Ag-layer thickness with long and short periods. Since the QWS formation sensitively depends on boundary conditions, one can switch between these two IEC periods by changing the Fe-layer thickness. These features, which also occur in the magnetic trilayers with other noble-metal spacers, open a new degree of freedom to engineer the IEC in magnetoresistance devices. PMID- 26596252 TI - Quantitative proteomic analysis of anticancer drug RH1 resistance in liver carcinoma. AB - Acquired resistance of tumor cells to the therapeutic treatment is a major challenge in virtually any chemotherapy. A novel anticancer agent 2,5 diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone (RH1) is designed to be activated by NAD(P)H: quinone oxidoreductase, an enzyme expressed at high levels in many types of tumors. Here we investigated the potential mechanisms of acquired RH1 drug resistance in cancer cells by applying high-throughput differential quantitative proteomic analysis of the newly established RH1 resistant hepatoma cell lines. Over 400 proteins display significantly altered levels between drug-sensitive and drug-resistant cell lines. Differentially expressed proteins were clustered into more than 14 groups according to their functional annotation and protein-protein interactions. Bioinformatic analysis highlights the biological processes that might be responsible for acquired resistance to RH1. The level of several xenobiotic metabolism enzymes (total n=17) involved in RH1 activation and detoxification is decreased (Nqo1, catalase, Gst, Gsr), corresponding with the decrease in their catalytic activity. The altered biological processes also include the decrease of cell cycle positive regulators (n=15) and the increase of DNA repair proteins (n=5) as well as annexin family members (n=5) in the RH1-resistant cells. Drug-resistant hepatoma cell proteomes are also distinguished by the altered level of proteins involved in energy production and metabolism (n=55). Our data provide the basis for in depth study of molecular mechanisms of tumor cell resistance to the promising anticancer drug RH1 enabling the further validation of protein biomarkers for the drug insusceptibility and of potential secondary pharmacological targets of RH1 resistant cells. PMID- 26596254 TI - Inhaled drug treatment for tuberculosis: Past progress and future prospects. AB - Since the 1990s the rising incidence of multiple drug resistant TB, particularly in the context of human immunodeficiency virus co-infected patients, has threatened global TB control. At that time funding agencies began to support formal investigation of aerosol therapy which until then had been the subject of case reports of individual investigators. Over the last decade, proponents of aerosol therapy have increased in number within the TB research community as the incidence of multiple and extremely drug resistant TB has increased dramatically around the world. Aerosol therapy offers the potential to deliver drug at target concentrations directly into the lungs, use the alveolar-capillary interface to achieve systemic levels, while reducing the risk of systemic toxicity seen with parentally administered doses. In addition, there are insufficient new drugs in the pipeline to anticipate the appearance of a new regimen in time to assure future control of drug resistance. Consequently, alternative strategies are critical to achieving global TB control, and inhaled therapies should be considered as one such strategy. PMID- 26596255 TI - Liver anomalies as a phenotype parameter of Bardet-Biedl syndrome. PMID- 26596256 TI - Ethnobotanical survey of traditionally used medicinal plants for infections of skin, gastrointestinal tract, urinary tract and the oral cavity in Borabu sub county, Nyamira county, Kenya. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Different communities throughout the world have specialized and profound knowledge on the use medicinal plants for various diseases. However, the detailed information on the respective use may extinct in near future as this knowledge is passed only orally among generations in most of the communities. AIM OF THE STUDY: The present survey aimed to document the use of medicinal plants by traditional healers from the Kisii community, Borabu sub county in Nyamira county, Kenya, to treat infections of the urinary tract, oral cavity, gastrointestinal system and the skin and to evaluate the social context in which the healers work and practice. MATERIALS AND METHODS: Validated questionnaires were applied to 50 traditional healers in the study region, followed by interviews and structured conversations. Information on the relevant traditionally used medicinal plants and their use were documented, including sampling and identification of voucher specimens. RESULTS: The ethnopharmacological survey revealed 25 medicinal plant species belonging to 19 families. It got evident that most of these species will be extinct in the near future unless appropriate measures are taken, as it turned out difficult to collect some of the wild growing species. Elaeodendron buchananii Loes, Erlangea marginata S. Moore, Acacia gerrardii Benth., Balanites orbicularis Sprague, Solanum renschii Vatke and Orthosiphon hildebrandtii Vatke have not been described before for its medicinal use. Among the 25 species collected from the various regions of Borabu sub-county Urtica dioica L. was the only medicinal plant that was collected from all regions. In contrast Erythrina abyssinica and Rhus natalensis were found in only two regions of the study area. CONCLUSION: The traditional medicinal use of the reported plants for infections should be documented and a great need of awareness from scientists and local government for improved preservation or field cultivation of some species is obvious. PMID- 26596257 TI - Medicinal plants from Mali: Chemistry and biology. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Mali is one of the countries in West Africa where the health system rely the most on traditional medicine. The healers are mainly using medicinal plants for their treatments. The studies performed being the basis for this review is of importance as they will contribute to sustaining the traditional knowledge. They contribute to evaluate and improve locally produced herbal remedies, and the review gives also an overview of the plant preparations that will have the most potential to be evaluated for new Improved Traditional Medicines. AIM OF THE REVIEW: The aim of this review is to give an overview of the studies performed related to medicinal plants from Mali in the period 1995 2015. These studies include ethnopharmacology, chemistry and biological studies of the plants that were chosen based on our interviews with the healers in different regions of Mali, and contribute to sustainable knowledge on the medicinal plants. The Department of Traditional Medicine, Bamako, Mali, is responsible for registering the knowledge of the traditional healers on their use of medicinal plants and also identifying compounds in the plants responsible for the bioactivities claimed. The studies reported aimed at getting information from the healers on the use of medicinal plants, and study the biology and chemistry of selected plants for the purpose of verifying the traditional use of the plants. These studies should form the basis for necessary knowledge for the development of registered Improved Traditional Medicines in Mali. MATERIALS AND METHODS: The healers were the ethnopharmacological informants. Questions asked initially were related to wound healing. This was because the immune system is involved when wounds are healed, and additionally the immune system is involved in the majority of the illnesses common in Mali. Based on the results of the interviews the plant material for studies was selected. Studies were performed on the plant parts the healers were using when treating their patients. Conventional chromatographic and spectroscopic methods were used for the isolation and structural elucidation of compounds. The compounds to study were selected based on the bioassays performed concomitant with the fractionation. RESULTS: Our results show that plants traditionally used as wound healing agents contain polysaccharides basically of pectin nature with immunomodulating activities. These pectins all have different and new structures. Several of the plants also contain compounds with effects related to antioxidant properties. These compounds are mainly of polyphenolic nature. Three of these are new compounds from Nature, while 32 was for the first time described from the plant they were isolated from. This review gives an overview of the most important results obtained during the 20 year long collaboration between Department of Traditional Medicine, Bamako, Mali, and Department of Pharmacognosy, School of Pharmacy, University of Oslo, Norway. CONCLUSION: Our studies showed that ethnopharmacological information is important for the determination of screening and chemical methods to be used for studies of plants used in traditional medicine. PMID- 26596258 TI - Cytoplasmic polyadenylation in mammalian oocyte maturation. AB - Oocyte developmental competence is the ability of the mature oocyte to be fertilized and subsequently drive early embryo development. Developmental competence is acquired by completion of oocyte maturation, a process that includes nuclear (meiotic) and cytoplasmic (molecular) changes. Given that maturing oocytes are transcriptionally quiescent (as are early embryos), they depend on post-transcriptional regulation of stored transcripts for protein synthesis, which is largely mediated by translational repression and deadenylation of transcripts within the cytoplasm, followed by recruitment of specific transcripts in a spatiotemporal manner for translation during oocyte maturation and early development. Motifs within the 3' untranslated region (UTR) of messenger RNA (mRNA) are thought to mediate repression and downstream activation by their association with binding partners that form dynamic protein complexes that elicit differing effects on translation depending on cell stage and interacting proteins. The cytoplasmic polyadenylation (CP) element, Pumilio binding element, and hexanucleotide polyadenylation signal are among the best understood motifs involved in CP, and translational regulation of stored transcripts as their binding partners have been relatively well-characterized. Knowledge of CP in mammalian oocytes is discussed as well as novel approaches that can be used to enhance our understanding of the functional and contributing features to transcript CP and translational regulation during mammalian oocyte maturation. WIREs RNA 2016, 7:71-89. doi: 10.1002/wrna.1316 For further resources related to this article, please visit the WIREs website. PMID- 26596259 TI - Suspected thymic lymphoma with invasion of the gills in a gold crossback arowana (Scleropages formosus). PMID- 26596260 TI - Developing alerting thresholds for prospective drug safety monitoring. AB - BACKGROUND: Current methods for prospective drug safety monitoring focus on determining whether and when to generate safety alerts indicating that a new drug may be less safe than a comparator. Approaches are needed to develop safety thresholds that can be used to define whether a new drug is no less than or equally safe as the comparator. OBJECTIVES: Our aim is to develop a framework for determining which safety statements can be made about a new drug and when they can be made during prospective monitoring. METHODS: We developed a two-pronged approach to establish safety thresholds for active monitoring. First, we adapted concepts from setting margins in non-inferiority (NI) trials ("NI approach"). Second, we summarized NI margins used in published randomized trials and reviewed publicly available data from the US FDA's website to identify the type and magnitude of evidence used in regulatory decisions involving withdrawals and black box warnings between 2009 and 2013 ("benchmark approach"). We applied the framework to a case study of dabigatran versus warfarin and major bleed. RESULTS: We provide formulas on both risk ratio and risk difference scales for the NI approach that are analogous to threshold setting in NI trials but based on point estimates and using a maximum tolerable increase rather than a preservation factor. Using this approach, we established a safety threshold for the dabigatran case study that was within range of the findings from the benchmark approach (1.18 to 7.30). Comparing the safety threshold with post-approval studies of dabigatran versus warfarin indicated that no safety statement can be made. CONCLUSIONS: The proposed framework expands the safety statements that can be made in current prospective drug safety monitoring systems. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26596261 TI - Free-living stage of the unicellular algae Coccomyxa sp. parasite of the blue mussel (Mytilus edulis): Low-light adaptation, capacity for growth at a very wide salinity range and tolerance to low pH. AB - Coccomyxa parasitica and similar, unidentified Coccomyxa species infect the soft tissues of many bivalve species, giving them a conspicuous green coloration and leading to mantle and shell deformities. Very little information exists regarding the ecophysiology of parasitic Coccomyxa sp. and this limits our ability to understand how it can achieve its unusual life history. In the present study, the growth of Coccomyxa sp. Metis-sur-mer (KJ372210) in liquid culture was investigated. Coccomyxa sp. maximum growth rate was 0.75 day-1 (equivalent to a doubling time of 22 hours), growth saturated at ~100 MUmol quanta m-2 s-1 and was still ~20% of maximum at 13 MUmol quanta m-2 s-1, the lowest photosynthetically available radiation (PAR) intensity tested. Coccomyxa sp. showed a very wide tolerance to salinity, with growth rate practically invariable over the salinity range 15-35. Even in natural spring water enriched with f/2 media, the growth rate was nearly half of maximum. Unlike the closely related acid-tolerant Coccomyxa sp. CPCC 508, Coccomyxa sp. Metis-sur-mer could not grow in acidic waters. Considering the ability of Coccomyxa sp. to achieve a high growth rate at low irradiance and its relative insensitivity to the prevailing salinity, it is somewhat surprising it has not yet infected bivalves at a larger scale worldwide. PMID- 26596262 TI - From a pathologist's point of view: Histiocytic cells in Hodgkin lymphoma and T cell/histiocyte rich large B cell lymphoma. AB - While tumor cells were the focus of research for many years, only recently have attempts been made to understand the role of the reactive bystander cells in malignant lymphomas. In certain types of lymphomas, such as Hodgkin lymphoma and T cell/histiocyte rich large B cell lymphoma, more than 90% of the infiltrate represent non-neoplastic cells, and these have important functions for the development and progression of the tumor. Among the bystander cells are histiocytes of particular importance, which vary largely in number, shape and quality among different patients. In the present review, recent findings on the prognostic impact of histiocytic bystander cells in these lymphomas, as well as their molecular characteristics, are discussed. A better understanding of the role of these histiocytes may provide new concepts for diagnosis and treatment. PMID- 26596263 TI - Adenomyoepithelioma with carcinoma of the breast: A report of two cases and a review of the literature. AB - We herein described two cases of adenomyoepithelioma (AME) with carcinoma of the breast. Both of them were Japanese women, and they presented with a mass in their breast. Post-operative specimens revealed encapsulated and well-circumscribed tumors with local invasion, necrosis, cytological atypia, and a high mitotic rate. In immunohistochemistry, coincidentally with the loose adhesion pattern of myoepithelial cells in both cases, the intensities of E-cadherin and beta-catenin were much weaker in myoepithelial than luminal epithelial cells, with almost negative finding of beta-catenin in one case. We first found deletion of CDH1 and polysomy of CEP16 in myoepithelial cells by double color-fluorescence in situ hybridization. The two cases have been followed up for 5-8 years, and both remained free from local recurrence and distant metastases. We also presented an overview of 47 cases of AME with carcinoma in English-language literatures. PMID- 26596264 TI - Calcitonin gene-related peptide mediates an inflammatory response in Schwann cells via cAMP-dependent ERK signaling cascade. AB - AIMS: Calcitonin gene-related peptides (CGRP), an endogenous neuropeptide, play an important role in the development of neuroinflammation by acting upon its receptor. The CGRP receptor immunoreactivity was identified on Schwann cells. However the effects of CGRP on Schwann cells are unknown and the exact signaling mechanisms associated with CGRP receptor activation related to Schwann cells inflammatory responses are not well understood. We investigated the effect of CGRP on CGRP receptor activation mediates a proinflammatory signaling response in Schwann cells. MAIN METHODS: CGRP-induced ERK-MAPK phosphorylation and proinflammatory cytokines, interleukin-1 beta (IL-1beta), interleukin-6 (IL-6) and tumor necrosis factor (TNF-alpha) expressions were measured by immune blotting. We also used specific antagonist and inhibitors to confirm the exactly signaling pathway including CGRP (8-37), SQ 22536 and H-89. KEY FINDINGS: Treatment with CGRP demonstrated a significant generation of IL-1beta and IL-6 but not in the level of TNF-alpha. In addition, there was a temporal increase in the activated form of ERK caused by CGRP that was prevented after pretreatment with CGRP (8-37), SQ 22536 and H-89. Furthermore, use of the CGRP (8-37), ERK inhibitor PD 98059, SQ 22536 or H-89 abolished the CGRP mediated increase in IL 1beta. SIGNIFICANCE: This investigation provides evidence for a novel CGRP activation on Schwann cells that mediates inflammatory response by increasing of IL-1beta and IL-6 expression. CGRP activates the cAMP-PKA-ERK signaling cascade leading to IL-1beta production. These results support the notion that CGRP may play a direct role to initiate inflammatory processes in the peripheral nervous system. PMID- 26596265 TI - Down-regulation of antioxidant genes in human SH-SY5Y cells after treatment with morphine. AB - AIMS: Morphine strongly induces reactive oxygen species (ROS). The deleterious actions of morphine can be countered by antioxidant system. In the present study, we investigated the expression levels of nine antioxidant genes in human SH-SY5Y cells treated with morphine. MAIN METHODS: The cells were treated with three final concentrations of morphine (1, 5, and 10 MUmol) for four exposure times (1 h, 24 h, 72 h and 18 days). The mRNA levels were determined using quantitative real-time RCR. KEY FINDINGS: Based on the alterations of mRNA levels, the genes might be categorized into three different groups: In the first group, the mRNA levels of the CAT, SOD1 and GSTM3 genes were significantly down-regulated in all examined experimental conditions. In the second group, the mRNA levels of SOD2, NQO1, GSTM2 and GSTO1 were initially increased and then decreased. In the third group, the mRNA levels of NQO2 and GSTP1, were initially increased and then reached to the control levels. The number of down-regulated genes were significantly increased as a function of exposure time (chi(2)=7.52, P=0.006). We investigated the effect of morphine (10 MUmol) in the absence and presence of N acetyl-cysteine (NAC, 1 mmol). The mRNA levels revealed significant differences between cells exposed to morphine and cells co-treated with morphine plus NAC. In cases that morphine increased the level of mRNAs, morphine plus NAC, result in decreased mRNA levels and vice versa. SIGNIFICANCE: These findings suggested that there are different pathways for regulation of antioxidant genes after SH-SY5Y cells exposed to morphine and morphine might act through inducing ROS. PMID- 26596267 TI - The distal radial decompression osteotomy for ulnar impingement syndrome. AB - INTRODUCTION: The decompression of the distal radioulnar joint (DRUJ) is performed by ulnar translation of the radial shaft proximal to the sigmoid notch, i.e. detensioning of the distal part of the interosseous membrane (DIOM) while containment of the DRUJ is achieved by closed wedge osteotomy of the radius. The osteotomy shortens the radius which entails detensioning of the triangular fibrocartilage complex (TFCC). SURGICAL TECHNIQUE: Facilitating the modified Henry approach to the distal palmar radius a radial based wedge osteotomy is applied. The proximal osteotomy is proximal to the ulnar head and distal osteotomy is proximal to the sigmoid notch to prevent iatrogenic impingement. Ulnar translation of the radial shaft is performed to loosen the DIOM. The closed wedge osteotomy reduces radial inclination which will foster containment of the DRUJ. CONCLUSION: Distal radial decompression osteotomy of the DRUJ preserves DRUJ function while relieving painful impingement. Further surgical interventions are not compromised in case of failure. PMID- 26596266 TI - The autophagic response to polystyrene nanoparticles is mediated by transcription factor EB and depends on surface charge. AB - BACKGROUND: A number of engineered nanoparticles induce autophagy, the main catabolic pathway that regulates bulk degradation of cytoplasmic material by the lysosomes. Depending on the specific physico-chemical properties of the nanomaterial, however, nanoparticle-induced autophagy may have different effects on cell physiology, ranging from enhanced autophagic degradation to blockage of autophagic flux. To investigate the molecular mechanisms underlying the impact of nanoparticle charge on the nature of the autophagic response, we tested polystyrene nanoparticles (50 nm) with neutral, anionic, and cationic surface charges. RESULTS: We found all polystyrene nanoparticles investigated in this study to activate autophagy. We showed that internalization of polystyrene nanoparticles results in activation of the transcription factor EB, a master regulator of autophagy and lysosome biogenesis. Autophagic clearance, however, was observed to depend specifically on the charge of the nanoparticles. Particularly, we found that the autophagic response to polystyrene nanoparticles presenting a neutral or anionic surface involves enhanced clearance of autophagic cargo. Cell exposure to polystyrene nanoparticles presenting a cationic surface, on the other hand, results in transcriptional upregulation of the pathway, but also causes lysosomal dysfunction, ultimately resulting in blockage of autophagic flux. CONCLUSIONS: This study furthers our understanding of the molecular mechanisms that regulate the autophagic response to nanoparticles, thus contributing essential design criteria for engineering benign nanomaterials. PMID- 26596268 TI - Comparison between a chimeric lysin ClyH and other enzymes for extracting DNA to detect methicillin resistant Staphylococcus aureus by quantitative PCR. AB - Extracting DNA from Staphylococcus aureus cells is important for detecting MRSA by PCR. However, S. aureus cells are known to be difficult to disrupt due to their compact cell walls. Here, we systematically studied the efficiency of a highly active lysin ClyH for extracting DNA of S. aureus in comparison with commonly used enzymes, such as lysostaphin and achromopeptidase (ACP), and its compatibility in quantitative PCR (qPCR) detection of MRSA. qPCR analysis of S. aureus specific gene femB showed that ClyH was much faster than lysostaphin, ACP and lysozyme for releasing DNA. Five minutes disruption with ClyH at room temperature was enough to release all the DNA from S. aureus. Analysis of the spiked nasal swabs by a dual qPCR assay of the beta-lactam resistance mecA gene and the staphylococcal cassette chromosome (SCCmec)-open reading frame X (orfX) junction (SCCmec-orfX) after ClyH lysis showed 100% sensitivity and specificity to the commercial BD GeneOhmTM MRSA test with ACP lysis, but the lysis time was reduced from 20 min by ACP to 5 min by ClyH. Our research shows that ClyH could be a better option than the currently used enzymes for DNA extraction from S. aureus, which can provide simpler and faster PCR detection of MRSA. PMID- 26596269 TI - Effectiveness of probiotic in preventing and treating antibiotic-associated diarrhoea and/or Clostridium difficile-associated diarrhoea in patients with spinal cord injury: a protocol of systematic review of randomised controlled trials. AB - BACKGROUND: Probiotics may prevent antibiotic-associated and Clostridium difficile-associated diarrhoea (AAD/CDAD). Many spinal cord injury centre (SCIC) practitioners consider probiotics generically and may not realise that efficacy can be strain-, dose- and disease-specific. In order to confirm these effects and fully evaluate the extent of probiotic effectiveness in these patients, a systematic review and meta-analysis is indicated. METHODS: The following databases will be searched for relevant studies: Cochrane Library; Centre for Reviews and Dissemination (CRD) Database; CINAHL; PsycINFO; Embase; Medline; AMED; International Clinical Trials Registry Platform Search Portal and ISRCTN Registry and will hand search a list of conference proceedings. Any randomised controlled trials without restriction of publication status will be included with treatment of AAD/CDAD. Outcomes will include the effect of probiotic on the occurrence of AAD/CDAD and duration of diarrhoea, intensive care unit admission, hospital mortality and length of hospital stay. Two reviewers will independently screen the titles, abstracts or even full texts and extract data. Two other reviewers will assess study quality. Revman 5.1 software will be used to conduct meta-analysis and calculate the risk ratio for dichotomous data. Weighted mean difference or standard mean difference will be calculated for continuous data. The Cochrane Collaboration's tool will be used to assess the risk of bias. DISCUSSION: This systematic review protocol will provide information on probiotic therapy for AAD and CDAD in spinal cord injury (SCI) population. The results will be disseminated through peer-reviewed publication or conference presentation. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015016976. PMID- 26596270 TI - A parallel genome-wide RNAi screening strategy to identify host proteins important for entry of Marburg virus and H5N1 influenza virus. AB - BACKGROUND: Genome-wide RNAi screening has been widely used to identify host proteins involved in replication and infection of different viruses, and numerous host factors are implicated in the replication cycles of these viruses, demonstrating the power of this approach. However, discrepancies on target identification of the same viruses by different groups suggest that high throughput RNAi screening strategies need to be carefully designed, developed and optimized prior to the large scale screening. METHODS: Two genome-wide RNAi screens were performed in parallel against the entry of pseudotyped Marburg viruses and avian influenza virus H5N1 utilizing an HIV-1 based surrogate system, to identify host factors which are important for virus entry. A comparative analysis approach was employed in data analysis, which alleviated systematic positional effects and reduced the false positive number of virus-specific hits. RESULTS: The parallel nature of the strategy allows us to easily identify the host factors for a specific virus with a greatly reduced number of false positives in the initial screen, which is one of the major problems with high throughput screening. The power of this strategy is illustrated by a genome-wide RNAi screen for identifying the host factors important for Marburg virus and/or avian influenza virus H5N1 as described in this study. CONCLUSIONS: This strategy is particularly useful for highly pathogenic viruses since pseudotyping allows us to perform high throughput screens in the biosafety level 2 (BSL-2) containment instead of the BSL-3 or BSL-4 for the infectious viruses, with alleviated safety concerns. The screening strategy together with the unique comparative analysis approach makes the data more suitable for hit selection and enables us to identify virus-specific hits with a much lower false positive rate. PMID- 26596272 TI - Application of recent advances in hydrodynamic methods for characterising mucins in solution. AB - Mucins are the primary macromolecular component of mucus--nature's natural lubricant--although they are poorly characterised heterogeneous substances. Recent advances in hydrodynamic methodology now offer the opportunity for gaining a better understanding of their solution properties. In this study a combination of such methods was used to provide increased understanding of a preparation of porcine intestinal mucin (PIM), MUC2 mucin, in terms of both heterogeneity and quantification of conformational flexibility. The new sedimentation equilibrium algorithm SEDFIT-MSTAR is applied to yield a weight average (over the whole distribution) molar mass of 7.1 * 10(6) g mol(-1), in complete agreement with size exclusion chromatography coupled with multi-angle light scattering (SEC MALS), which yielded a value of 7.2 * 10(6) g mol(-1). Sedimentation velocity profiles show mucin to be very polydisperse, with a broad molar mass distribution obtained using the Extended Fujita algorithm, consistent with the elution profiles from SEC-MALS. On-line differential pressure viscometry coupled to the SEC-MALS was used to obtain the intrinsic viscosity [eta] as a function of molar mass. These data combined with sedimentation coefficient data into the global conformation algorithm HYDFIT show that PIM has a flexible linear structure, with persistence length L p ~10 nm and mass per unit length, M L ~2380 g mol(-1) nm( 1), consistent with a Wales-van Holde ratio of ~1.2 obtained from the concentration dependence of the sedimentation coefficient. PMID- 26596271 TI - Type 2 diabetes patients' and providers' differing perspectives on medication nonadherence: a qualitative meta-synthesis. AB - BACKGROUND: Poor adherence to medication regimens increases adverse outcomes for patients with Type 2 diabetes. Improving medication adherence is a growing priority for clinicians and health care systems. We examine the differences between patient and provider understandings of barriers to medication adherence for Type 2 diabetes patients. METHODS: We searched systematically for empirical qualitative studies on the topic of barriers to medication adherence among Type 2 diabetes patients published between 2002-2013; 86 empirical qualitative studies qualified for inclusion. Following qualitative meta-synthesis methods, we coded and analyzed thematically the findings from studies, integrating and comparing findings across studies to yield a synthetic interpretation and new insights from this body of research. RESULTS: We identify 7 categories of barriers: (1) emotional experiences as positive and negative motivators to adherence, (2) intentional non-compliance, (3) patient-provider relationship and communication, (4) information and knowledge, (5) medication administration, (6) social and cultural beliefs, and (7) financial issues. Patients and providers express different understandings of what patients require to improve adherence. Health beliefs, life context and lay understandings all inform patients' accounts. They describe barriers in terms of difficulties adapting medication regimens to their lifestyles and daily routines. In contrast, providers' understandings of patients poor medication adherence behaviors focus on patients' presumed needs for more information about the physiological and biomedical aspect of diabetes. CONCLUSIONS: This study highlights key discrepancies between patients' and providers' understandings of barriers to medication adherence. These misunderstandings span the many cultural and care contexts represented by 86 qualitative studies. Counseling and interventions aimed at improving medication adherence among Type 2 diabetes might become more effective through better integration of the patient's perspective and values concerning adherence difficulties and solutions. PMID- 26596273 TI - Predictors of mortality in patients with cardiogenic shock treated with primary percutaneous coronary intervention and intra-aortic balloon counterpulsation. AB - BACKGROUND: Cardiogenic shock remains the most serious complication of patients hospitalized with acute myocardial infarction (AMI). Early revascularization is the cornerstone of invasive therapy, while mechanical support with intra-aortic balloon pump (IABP) is debatable. From our institutional shock registry we sought to determine predictors of in-hospital mortality-including the aspect of IABP timing-and to develop a clinical risk score for shock patients with AMI. METHODS: From January 2005 till December 2010, 102 patients with cardiogenic shock due to AMI treated with primary percutaneous coronary intervention (PCI) and IABP were analyzed. Univariate and multivariate logistic regression analyses were used to identify independent predictors of in-hospital mortality. Logistic regression analysis and receiver-operating curves were used to generate a mortality risk score. RESULTS: The mean age of the cohort was 70.1 +/- 11.0 years and 70 % were men. One third of patients had a non-ST segment elevation myocardial infarction and 30 % had to be resuscitated before coronary intervention. Mean left ventricular ejection fraction was 25 %. After admission, 23 % of patients developed an acute renal failure and 10 % needed renal dialysis during hospital stay. In 52 % of patients IABP therapy was initiated after primary PCI, while the remaining patients had an IABP-assisted primary PCI. All-cause in-hospital mortality was 40.2 %. Using multivariate analysis, age (odds ratio [OR] 1.08, p = 0.006), resuscitation before PCI (OR 3.46, p = 0.045), vasopressor use (OR 7.88, p = 0.003), acute renal failure (OR 11.18, p = 0.001), and IABP implantation after PCI (OR 4.36, p = 0.011) were independently associated with in-hospital mortality. Based on these predictors, a mortality-risk score was calculated as follows: 1.5 * IABP timing before PCI + 0.1 * age + resuscitation before PCI + 2 * vasopressor use + 2.5 * acute renal failure. Using a cut-off value of 10.4, this score had a specificity of 83 % and a sensitivity of 82 % for prediction of in-hospital death. CONCLUSIONS: We identified age, vasopressor use, resuscitation before PCI, acute renal failure and IABP implantation after PCI as independent predictors of in-hospital mortality in patients with cardiogenic shock due to AMI. The timing of IABP insertion was the only modifiable factor predicting in hospital mortality in our cohort. Consequently, balloon pumping should be started before PCI to improve outcome of cardiogenic shock patients. PMID- 26596274 TI - [Specific aspects of pediatric emergencies in the prehospital setting]. AB - Life-threatening pediatric emergencies are relatively rare in the prehospital setting; therefore, the treating emergency physician may not always be familiar with and well trained in these situations. However, pediatric emergencies require early recognition and initiation of specific diagnostic and therapeutic interventions to prevent further complications. Treatment of pediatric emergencies follows current recommendations as detailed in published international guidelines. The aim of this review is to provide specific information with regard to respiratory, cardiac and neurological medical emergencies commnly encountered in children in the prehospital setting. It is not the aim of this review article to provide specific guidance with regard to a variety of surgical emergencies. Due to improved treatment modalities the emergency medical team may also be confronted with acutely ill children with very severe and complex underlying clinical syndromes (e.g. complex cardiac malformations and syndromic genetic disorders). This article also provides specific information with regard to treatment of this susceptible and vulnerable patient cohort. PMID- 26596275 TI - V. W. Fazio, "Vic the fighter". PMID- 26596276 TI - Genetic associations and shared environmental effects on the skin microbiome of Korean twins. AB - BACKGROUND: The skin is the outermost layer of the human body and one of the key sites for host-microbe interactions. Both environmental and host genetic factors influence microbial communities in distinct anatomical niches, but little is known about their interplay in shaping the skin microbiome. Here, we investigate the heritable components of the skin microbiome and their association with host genetic factors. RESULTS: Based on our analysis of the microbiota from 45 individuals including monozygotic and dizygotic twins aged 26-55 years and their mothers, we found that skin microbial diversity was significantly influenced by age and skin pigmentation. Heritability analysis revealed genetic and shared environmental impacts on the skin microbiome. Furthermore, we observed a strong association between the abundance of Corynebacterium jeikeium and single nucleotide polymorphisms (SNPs) in the host FLG gene related to epidermal barrier function. CONCLUSION: This study reveals an intimate association of the human skin microbiome and host genes, and increases our understanding of the role of human genetic factors in establishing a microbial ecosystem on the body surface. PMID- 26596277 TI - The Claim of Anti-Cataract Potential of Heliotropium indicum: A Myth or Reality? AB - INTRODUCTION: Heliotropium indicum has several uses in traditional medicine attributable to its numerous bioactive compounds. It is used as a traditional remedy for cataracts in Ghana without any scientific verification. This study aimed at verifying the anti-cataract properties of an aqueous whole plant extract of H. indicum. METHODS: The effect (cataract score) of 30, 100, and 300 mg kg(-1) extract (bid for 21 days, per os) on the development of 30 umol kg(-1) sodium selenite-induced cataract in 10-day-old rat pups was investigated. Soluble lens proteins alpha A and alpha B crystallins, total lens protein, total lens glutathione, and aquaporin 0 in enucleated lens homogenates were determined spectrophotometrically using commercially available kits. Histopathological studies on the lenses were also performed. The 2,2-diphenyl-1-picrylhydrazyl scavenging effect and linoleic acid autoxidation (antioxidant properties) of the extract (0.1-3.0 mg ml(-1)), compared to n-propyl gallate, were ascertained using standard procedures. RESULTS: Cataract scores showed that the extract, at all dose levels, significantly alleviated selenite-induced cataracts (P <= 0.001). Markers of lens transparency (aquaporin 0, alpha A and B crystallins), as well as total lens proteins and lens glutathione levels, were significantly preserved (P <= 0.01-0.001). The extract exhibited activity relevant for scavenging free radicals and inhibition of lipid peroxidation. Epithelial and lens fiber integrity in the histopathological assessment were maintained with HIE treatment. CONCLUSION: The aqueous whole plant extract of H. indicum significantly inhibited the development of cataracts in rats via multiple mechanisms. PMID- 26596278 TI - Impact of glucocorticoid receptor gene (NR3C1) polymorphisms in Turkish patients with metabolic syndrome. AB - BACKGROUND: The metabolic syndrome (MetS) is characterized by a cluster of metabolic factors, including insulin resistance and type-2 diabetes, abdominal obesity, dyslipidemia, hypertension and microalbuminuria. Impaired glucocorticoid receptor (GR) activity also plays an important role in the etiology of MetS. The objective of our study is to evaluate the effects of GR gene polymorphisms (BclI, N363S, TthIII1 and ER22/23EK) in Turkish patients with MetS. MATERIALS AND METHODS: Seventy subjects with MetS and 185 healthy controls were enrolled in the study. PCR-RFLP analysis was used for genotyping. Results for each polymorphism have been verified by allele-specific oligonucleotide analysis. RESULTS: BclI GG genotype was significantly associated with an increased risk of MetS (p = 0.02). Also, only in women, the G allele carriers were significantly associated with higher C-peptide. T allele carriers of TthIII1 polymorphism were significantly associated with higher C-peptide, triglyceride, insulin and C-reactive protein (CRP, p value 0.048, 0.022, 0.005 and 0.022, respectively), and lower fasting blood glucose (FBG, p = 0.02). The combined carriers of BclI polymorphism G allele and TthIII1 polymorphism T allele were significantly associated with higher diastolic blood pressure in all patients, and lower FBG and postprandial blood glucose in only men. All the ER22/23EK polymorphisms coexisted with polymorphic variant of TthIII1 (p = 0.0058). CONCLUSION: The presence of homozygote polymorphic variant of BclI might be good predictive markers for the disease susceptibility. The BclI and the TthIII1 polymorphism are associated with sex-specific clinical parameters. Our findings also suggest that the combination of BclI and TthIII1 polymorphisms may play a protective role in blood glucose. PMID- 26596279 TI - CORR Insights((r)): Risk of Post-TKA Acute Myocardial Infarction in Patients With a History of Myocardial Infarction or Coronary Stent. PMID- 26596280 TI - Characterization of Staphylococcus aureus Cas9: a smaller Cas9 for all-in-one adeno-associated virus delivery and paired nickase applications. AB - BACKGROUND: CRISPR-Cas systems have been broadly embraced as effective tools for genome engineering applications, with most studies to date utilizing the Streptococcus pyogenes Cas9. Here we characterize and manipulate the smaller, 1053 amino acid nuclease Staphylococcus aureus Cas9. RESULTS: We find that the S. aureus Cas9 recognizes an NNGRRT protospacer adjacent motif (PAM) and cleaves target DNA at high efficiency with a variety of guide RNA (gRNA) spacer lengths. When directed against genomic targets with mutually permissive NGGRRT PAMs, the S. pyogenes Cas9 and S. aureus Cas9 yield indels at comparable rates. We additionally show D10A and N580A paired nickase activity with S. aureus Cas9, and we further package it with two gRNAs in a single functional adeno-associated virus (AAV) vector. Finally, we assess comparative S. pyogenes and S. aureus Cas9 specificity using GUIDE-seq. CONCLUSION: Our results reveal an S. aureus Cas9 that is effective for a variety of genome engineering purposes, including paired nickase approaches and all-in-one delivery of Cas9 and multiple gRNA expression cassettes with AAV vectors. PMID- 26596281 TI - Characterization of the iron-binding properties of pyoverdine using electron capture dissociation-tandem mass spectrometry. AB - Pyoverdines (PVD) are a group of siderophores produced by fluorescent Pseudomonads. Identification of PVD variants mostly relies on liquid chromatography-tandem mass spectrometry (LC-MS/MS) using collision-induced dissociation (CID). Here, both CID and the novel dissociation technique electron capture dissociation (ECD) were applied to characterize PVD succinamide and its Fe(III)-chelated complex. The results clearly showed that ECD produced diagnostic side chain fragmentation of the PVD peptide chain and preserved the labile Fe(III) binding to the chromophore in contrast to CID. The ECD technique is therefore expected to support the understanding of strain-specific Fe(III) transport processes of PVDs. PMID- 26596282 TI - Effect of calcium ions on human calcitonin. Possible implications for bone resorption by osteoclasts. AB - Calcium ions (Ca(2+)) are indispensable for life and are involved in important physiological actions, which makes maintaining a constant level of blood Ca(2+) essential. Ca(2+) is mainly stored in bones which serve as a reservoir and its homeostasis is modulated by various hormones. Human calcitonin (hCt) is a small peptide hormone that exerts its physiological effect on Ca(2+) metabolism by means of osteoclast-mediated bone resorption inhibition. Most of these actions are mediated through peptide/receptor interaction that acts via a second messenger. However, in vitro studies have shown that hCt can interact with membrane lipids to form ion channels in membrane models. This ability is due to the peptide's secondary structure and aggregation state, that can be modulated by different molecules. In our study, we evaluated the effect of Ca(2+), at different concentrations, both on the hCt ion channel incorporated into a planar lipid membrane made up of phosphatidylcholine containing 15% phosphatidylglycerol and on the secondary structure of hCt in an aqueous environment. Ca(2+) is able to interact with the hCt peptide by acting on the channel incorporated into the membrane as well as on the peptide in solution, both by increasing hCt channel frequency and in solution promoting alpha-helix formation, that counteracts the fibrillating process. These experimental observations, suggesting that hCt senses Ca(2+) concentration variations, strengthen the hypothesis that channel formation represents an extra source of Ca(2+) entry into osteoclasts in addition to the well-known interaction of the monomer with the specific receptor. PMID- 26596285 TI - Prevalence and Correlates of Prehypertension Among Adults in Urban South India. AB - Prehypertension is one of the most common conditions affecting human beings worldwide. It is associated with several complications including hypertension. The blood pressure between normal and hypertension is prehypertension as per the Seventh Report Joint National Committee (JNC-7) classification. The current study was done to measure the magnitude of prehypertension and to study their sociodemographic correlates in the urban field practice area of Kasturba Medical College, Mangalore, India, among 624 people aged >=20 years. The measurements of blood pressure were done (JNC 7 criteria) with the anthropometric measurements and lifestyle factors. Data analysis was done using Statistical Package for Social Sciences version 16. Adjusted odds ratios were calculated. Overall, 55% subjects had prehypertension and 30% had hypertension. Prehypertension was higher among males. Those from the higher age groups, those from upper socioeconomic status, obese individuals, and those with lesser physical activity had significantly higher association with prehypertension, and it was least among those who never used tobacco and alcohol. PMID- 26596286 TI - UK should change law on surrogacy to help commissioning parents, report says. PMID- 26596284 TI - CDKN2B Regulates TGFbeta Signaling and Smooth Muscle Cell Investment of Hypoxic Neovessels. AB - RATIONALE: Genetic variation at the chromosome 9p21 cardiovascular risk locus has been associated with peripheral artery disease, but its mechanism remains unknown. OBJECTIVE: To determine whether this association is secondary to an increase in atherosclerosis, or it is the result of a separate angiogenesis related mechanism. METHODS AND RESULTS: Quantitative evaluation of human vascular samples revealed that carriers of the 9p21 risk allele possess a significantly higher burden of immature intraplaque microvessels than carriers of the ancestral allele, irrespective of lesion size or patient comorbidity. To determine whether aberrant angiogenesis also occurs under nonatherosclerotic conditions, we performed femoral artery ligation surgery in mice lacking the 9p21 candidate gene, Cdkn2b. These animals developed advanced hindlimb ischemia and digital autoamputation, secondary to a defect in the capacity of the Cdkn2b-deficient smooth muscle cell to support the developing neovessel. Microarray studies identified impaired transforming growth factor beta (TGFbeta) signaling in cultured cyclin-dependent kinase inhibitor 2B (CDKN2B)-deficient cells, as well as TGFbeta1 upregulation in the vasculature of 9p21 risk allele carriers. Molecular signaling studies indicated that loss of CDKN2B impairs the expression of the inhibitory factor, SMAD-7, which promotes downstream TGFbeta activation. Ultimately, this manifests in the upregulation of a poorly studied effector molecule, TGFbeta1-induced-1, which is a TGFbeta-rheostat known to have antagonistic effects on the endothelial cell and smooth muscle cell. Dual knockdown studies confirmed the reversibility of the proposed mechanism, in vitro. CONCLUSIONS: These results suggest that loss of CDKN2B may not only promote cardiovascular disease through the development of atherosclerosis but may also impair TGFbeta signaling and hypoxic neovessel maturation. PMID- 26596288 TI - Methyl Phosphate Dianion Hydrolysis in Solution Characterized by Path Collective Variables Coupled with DFT-Based Enhanced Sampling Simulations. AB - Herein, we propose a conceptually innovative approach to investigating reaction mechanisms. This study demonstrates the importance of considering explicitly the effects of large amplitude motions, aside from the intrinsic reaction coordinate, when tuning the free energy landscape of reaction pathways. We couple the path collective variables method with DFT-based enhanced sampling simulations to characterize the associative mechanism of the hydrolysis of the methyl phosphate dianion in solution. Importantly, energetics and mechanistic differences are observed when passing from the potential to the free energy surface. PMID- 26596287 TI - Dispositions of enrofloxacin and its major metabolite ciprofloxacin in Thai swamp buffaloes. AB - Given the limited information available in this species, the aim of this study was to investigate the pharmacokinetic characteristics of enrofloxacin (ER) and its major metabolite ciprofloxacin (CP) in buffaloes, Bubalus bubalis. ER was administered intravenously (i.v.) or subcutaneously (s.c.) to buffaloes at doses of 5.0 and 7.5 mg/kg BW, and plasma, urine and fecal samples were collected until 48 hr post-administration. The concentrations of ER and CP in the plasma, urine and feces were analyzed using high-performance liquid chromatography equipped with a fluorescence detector. The plasma concentrations of ER and CP could be determined up to 24 hr and 32 hr after i.v. and s.c. administrations at doses of 5.0 and 7.5 mg/kg BW, respectively. CP concentrations were always lower than those of parental drug. The s.c. bioavailability of ER was 52.36 +/- 4.24% and 72.12 +/- 5.39% at doses of 5.0 and 7.5 mg/kg BW, respectively. Both ER and CP were detectable in urine and feces up to 24 hr. ER and CP were mainly excreted via the urine. Based on the pharmacokinetic data and PK-PD indices, s.c. administration of ER at doses of 5.0 and 7.5 mg/kg BW might be appropriate for the treatment of susceptible bacterial diseases in Thai swamp buffaloes. PMID- 26596289 TI - An n log n Generalized Born Approximation. AB - Molecular dynamics (MD) simulations based on the generalized Born (GB) model of implicit solvation offer a number of important advantages over the traditional explicit solvent based simulations. Yet, in MD simulations, the GB model has not been able to reach its full potential partly due to its computational cost, which scales as ~n(2), where n is the number of solute atoms. We present here an ~n log n approximation for the generalized Born (GB) implicit solvent model. The approximation is based on the hierarchical charge partitioning (HCP) method (Anandakrishnan and Onufriev J. Comput. Chem. 2010 , 31 , 691 - 706 ) previously developed and tested for electrostatic computations in gas-phase and distant dependent dielectric models. The HCP uses the natural organization of biomolecular structures to partition the structures into multiple hierarchical levels of components. The charge distribution for each of these components is approximated by a much smaller number of charges. The approximate charges are then used for computing electrostatic interactions with distant components, while the full set of atomic charges are used for nearby components. To apply the HCP concept to the GB model, we define the equivalent of the effective Born radius for components. The component effective Born radius is then used in GB computations for points that are distant from the component. This HCP approximation for GB (HCP-GB) is implemented in the open source MD software, NAB in AmberTools, and tested on a set of representative biomolecular structures ranging in size from 632 atoms to ~3 million atoms. For this set of test structures, the HCP-GB method is 1.1-390 times faster than the GB computation without additional approximations (the reference GB computation), depending on the size of the structure. Similar to the spherical cutoff method with GB (cutoff GB), which also scales as ~n log n, the HCP-GB is relatively simple. However, for the structures considered here, we show that the HCP-GB method is more accurate than the cutoff-GB method as measured by relative RMS error in electrostatic force compared to the reference (no cutoff) GB computation. MD simulations of four biomolecular structures on 50 ns time scales show that the backbone RMS deviation for the HCP-GB method is in reasonable agreement with the reference GB simulation. A critical difference between the cutoff-GB and HCP-GB methods is that the cutoff-GB method completely ignores interactions due to atoms beyond the cutoff distance, whereas the HCP-GB method uses an approximation for interactions due to distant atoms. Our testing suggests that completely ignoring distant interactions, as the cutoff-GB does, can lead to qualitatively incorrect results. In general, we found that the HCP-GB method reproduces key characteristics of dynamics, such as residue fluctuation, chi1/chi2 flips, and DNA flexibility, more accurately than the cutoff-GB method. As a practical demonstration, the HCP-GB simulation of a 348 000 atom chromatin fiber was used to refine the starting structure. Our findings suggest that the HCP-GB method is preferable to the cutoff-GB method for molecular dynamics based on pairwise implicit solvent GB models. PMID- 26596290 TI - The Influence of Cholesterol on the Properties and Permeability of Hypericin Derivatives in Lipid Membranes. AB - The promising photosensitizing properties of hypericin, a natural quinine substituted with hydroxyl and alkyl groups, have led to the proposal that it can be utilized in photodynamic therapy. Neither the detailed mechanism behind the powerful action of hypericin, arising as a result of light excitation, nor the intracellular localization and transportation of the molecule is yet fully understood. The behavior of hypericin derivatives in a pure dipalmitoylphosphatidylcholine (DPPC) lipid membrane has recently been studied theoretically by means of molecular dynamics simulations. Natural membranes however contain many important constituents-cholesterol being one of the most essential-that influence the function and structure of the membrane, and thereby also the behavior of drug molecules therein. In the present study, we investigated hypericin and its brominated derivatives in membranes containing 9 and 25 mol % cholesterol. The results show that the presence of cholesterol in the membrane affects the permeability of the hypericin molecules and does so differently for the various molecules in the two membranes. Hypericin containing one bromine was found to exhibit the lowest free energy profile for the transport process into the lipids, and also the highest permeability coefficients, indicating that this molecule displays the fastest and easiest diffusion in the membranes. All three molecules were found to accumulate most preferably close to the polar headgroup region in both membranes. PMID- 26596291 TI - Extracting Realistic Kinetics of Rare Activated Processes from Accelerated Molecular Dynamics Using Kramers' Theory. AB - The cis-trans isomerization of peptide bonds is very slow, occurring in hundreds of seconds. Kinetic studies of such processes using straightforward molecular dynamics are currently not possible. Here, we use Kramers' rate theory in the high friction regime in combination with accelerated molecular dynamics in explicit solvent to successfully retrieve the normal rate of cis to trans switching in the glycyl-prolyl dipeptide. Our approach bypasses the time reweighting problem of the hyperdynamics scheme, wherein the addition of the bias potential alters the transition state regions and avoids an accurate estimation of kinetics. By performing accelerated molecular dynamics at a few different levels of acceleration, the rate of isomerization is enhanced as much as 10(10) to 10(11) times. Remarkably, the normal rates obtained by simply extrapolating to zero bias are within an order of experimental estimates. This provides validation from a kinetic standpoint of the omega torsional parameters of the AMBER force field that were recently revised by matching to experimentally measured equilibrium properties. We also provide a comparative analysis of the performance of the widely used water models, i.e., TIP3P and SPC/E, in estimating the kinetics of cis-trans isomerization. Furthermore, we show that the dynamic properties of bulk water can be corrected by adjusting the collision frequency in a Langevin thermostat, which then allows for better reproduction of cis-trans isomerization kinetics and a closer agreement of rates between experiments and simulations. PMID- 26596292 TI - Exploiting Configurational Freezing in Nonequilibrium Monte Carlo Simulations. AB - To achieve acceptable accuracy in fast-switching free energy estimates by Jarzynski equality [ Phys. Rev. Lett. 1997 , 78 , 2690 ] or Crooks fluctuation theorem [ J. Stat. Phys. 1998 , 90 , 1481 ], it is often necessary to realize a large number of externally driven trajectories. This is basically due to inefficient calculation of path-ensemble averages arising from the work dissipated during the nonequilibrium paths. We propose a computational technique, addressed to Monte Carlo simulations, to improve free energy estimates by lowering the dissipated work. The method is inspired by the dynamical freezing approach, recently developed in the context of molecular dynamics simulations [ Phys. Rev. E 2009 , 80 , 041124 ]. The idea is to limit the configurational sampling to particles of a well-established region of the sample (namely, the region where dissipation is supposed to occur), while leaving fixed (frozen) the other particles. Therefore, the method, called configurational freezing, is based on the reasonable assumption that dissipation is a local phenomenon in single molecule nonequilibrium processes, a statement which is satisfied by most processes, including folding of biopolymers, molecular docking, alchemical transformations, etc. At variance with standard simulations, in configurational freezing simulations the computational cost is not correlated with the size of the whole system, but rather with that of the reaction site. The method is illustrated in two examples, i.e., the calculation of the water to methane relative hydration free energy and the calculation of the potential of mean force of two methane molecules in water solution as a function of their distance. PMID- 26596293 TI - Exciton/Charge-Transfer Electronic Couplings in Organic Semiconductors. AB - Charge transfer (CT) states and excitons are important in energy conversion processes that occur in organic light emitting devices (OLEDS) and organic solar cells. An ab initio density functional theory (DFT) method for obtaining CT exciton electronic couplings between CT states and excitons is presented. This method is applied to two organic heterodimers to obtain their CT-exciton coupling and adiabatic energy surfaces near their CT-exciton diabatic surface crossings. The results show that the new method provides a new window into the role of CT states in exciton-exciton transitions within organic semiconductors. PMID- 26596294 TI - Evaluating the Performance of DFT Functionals in Assessing the Interaction Energy and Ground-State Charge Transfer of Donor/Acceptor Complexes: Tetrathiafulvalene Tetracyanoquinodimethane (TTF-TCNQ) as a Model Case. AB - We have evaluated the performance of several density functional theory (DFT) functionals for the description of the ground-state electronic structure and charge transfer in donor/acceptor complexes. The tetrathiafulvalene tetracyanoquinodimethane (TTF-TCNQ) complex has been considered as a model test case. Hybrid functionals have been chosen together with recently proposed long range corrected functionals (omegaB97X, omegaB97X-D, LRC-omegaPBEh, and LC omegaPBE) in order to assess the sensitivity of the results to the treatment and magnitude of exact exchange. The results show an approximately linear dependence of the ground-state charge transfer with the HOMOTTF-LUMOTCNQ energy gap, which in turn depends linearly on the percentage of exact exchange in the functional. The reliability of ground-state charge transfer values calculated in the framework of a monodeterminantal DFT approach was also examined. PMID- 26596295 TI - Self-Consistent Field and Polarizable Continuum Model: A New Strategy of Solution for the Coupled Equations. AB - We present a new strategy for the solution of the self-consistent field (SCF) equations when solvent effects are included by means of the polarizable continuum model (PCM). By exploiting the recently introduced variational formalism of the PCM (VPCM), we are able to recast the self-consistent reaction field problem as an energy functional of both electronic and polarization degrees of freedom. The variational minimization of such a functional leads to the free energy of the solvated molecule at a given geometry. In this contribution we describe an effective procedure and its implementation to achieve the solution of such a variational problem. Moreover, we present numerical evidence that the new approach is superior to the traditional one in terms of performance, especially when a relatively inexpensive semiempirical method is used to describe medium- and large-size solutes. PMID- 26596296 TI - Electron Pair Localization Function (EPLF) for Density Functional Theory and ab Initio Wave Function-Based Methods: A New Tool for Chemical Interpretation. AB - We present a modified definition of the Electron Pair Localization Function (EPLF), initially defined within the framework of quantum Monte Carlo approaches [ Scemama , A. ; Caffarel , M. ; Chaquin , P. J. Chem. Phys. 2004 , 121 , 1725 ] to be used in Density Functional Theories (DFT) and ab initio wave-function-based methods. This modified version of the EPLF-while keeping the same physical and chemical contents-is built to be analytically computable with standard wave functions or Kohn-Sham representations. It is illustrated that the EPLF defines a simple and powerful tool for chemical interpretation via selected applications including atomic and molecular closed-shell systems, sigma and pi bonds, radical and singlet open-shell systems, and molecules having a strong multiconfigurational character. Some applications of the EPLF are presented at various levels of theory and compared to Becke and Edgecombe's Electron Localization Function (ELF). Our open-source parallel software implementation of the EPLF opens the possibility of its use by a large community of chemists interested in the chemical interpretation of complex electronic structures. PMID- 26596297 TI - Electron Density Based Partitioning Scheme of Interaction Energies. AB - In this paper, a new partitioning of the complex interaction energy is proposed. This new partitioning is based on the decomposition of the one-electron and exchange-correlation densities into unperturbed and deformation densities. Thus, the proposed energy fragmentation can be applied at the SCF level and post-SCF levels as long as the corresponding density matrices have been evaluated previously. It provides the typical description of the complex interaction as a summation of electrostatic, exchange-repulsion, and polarization terms. However, the new method allows splitting up the exchange-repulsion into exchange and Pauli repulsion energies. A full theoretical description of the method is presented, and some examples of its application to small complexes are discussed. A comparison with results obtained using perturbation methods is also carried out, showing that the first order terms obtained from symmetry adapted perturbation theories are perfectly reproduced with the new method. A clear bridge between qualitative deformation density plots and quantitative measures of the interaction energy components can be established within the framework of this new partitioning scheme, giving rise to a graphical and very intuitive interpretation of the complex formation. PMID- 26596298 TI - Excited-State Tautomerization in the 7-Azaindole-(H2O)n (n = 1 and 2) Complexes in the Gas Phase and in Solution: A Theoretical Study. AB - A systematic study of the excited-state tautomerization of 7-azaindole-(H2O)n (n = 1 and 2) complexes in both gas and solution phases were investigated theoretically. Electronic structures and energies for the reactant, transition state (TS), and product were computed using the time-dependent density functional theory (TDDFT) and complete active space self-consistent field (CASSCF) levels with 6-31G (d,p), 6-311G(d,p), and 6-311+G(d,p) basis sets. Barrier heights and tautomerization energies were corrected by the second-order multireference perturbation theory (MRPT2) to consider the dynamic electron correlation. The solvent effect decreased the tautomerization barrier height in the 7-azaindole H2O complex. In the 7-azaindole-(H2O)2 complex, two transition states were found for two asynchronous but concerted paths: in the first, the pyrole ring proton moved first to water; in the second, the water proton moved first to the pyridine ring. The CASSCF level with the MRPT2 correction clearly showed that the former path was much preferable to the latter. The preferable barrier height was only 1.6 kcal/mol with a zero-point energy correction, which would make the excited state tautomerization possible. At all TDDFT levels, the TS structures and barrier heights depended on both the basis set used and the solvent effect. Most TDDFT methods failed to reproduce the CASSCF structures and MRPT2 energies. Only two methods, WB97XD/6-31G(d,p) and M062X/6-311+G(d,p), predicted two TSs for the two asynchronous paths in the 7AI-(H2O)2 complex but failed to reproduce the energetics. Further systematic study is necessary to test whether current TDDFT methods, including solvent effects, can be used to understand excited-state proton transfer reactions. PMID- 26596299 TI - Extrapolation and Scaling of the DFT-SAPT Interaction Energies toward the Basis Set Limit. AB - The dispersion energy term in the symmetry-adapted perturbation theory based on the density functional theory (DFT-SAPT) converges rather slowly with basis set size. Accurate results for large complexes, where only calculations in small basis sets are practical, can be obtained by extrapolation to the complete basis set limit (CBS). In this paper, we propose an extrapolation scheme with the variable exponent optimized specifically for the DFT-SAPT calculations in correlation-consistent basis sets with diffuse functions. Another way to improve the accuracy term at no additional cost is to scale the dispersion term by a fixed amount. We present the scaling factors averaged over a balanced set of 10 model complexes. The results of these schemes are compared to the high-quality DFT-SAPT/CBS interaction energies in small complexes obtained by fitting to a series of basis sets up to aug-cc-pV5Z and to the CCSD(T)/CBS interaction energies. It is shown that even the cheapest extrapolation scheme yields results that are limited by the accuracy of the DFT-SAPT approach rather than by the basis set convergence. Scaling the dispersion term allows accurate interaction energies as well as their components to be obtained using just the aug-cc-pVDZ basis set; such a calculation can be applied to complexes consisting of up to 50 first-row atoms. PMID- 26596300 TI - Locating Instantons in Many Degrees of Freedom. AB - We implemented and compared four algorithms to locate instantons, i.e., the most likely tunneling paths at a given temperature. These allow to calculate reaction rates, including atom tunneling, down to very low temperature. An instanton is a first-order saddle point of the Euclidean action in the space of closed Feynman paths. We compared the Newton-Raphson method to the partitioned rational function optimization (P-RFO) algorithm, the dimer method, and a newly proposed mode following algorithm, where the unstable mode is directly estimated from the instanton path. We tested the algorithms on three chemical systems, each including a hydrogen transfer, at different temperatures. Overall, the Newton Raphson turned out to be the most promising method, with our newly proposed mode following, being the fall-back option. PMID- 26596301 TI - An Integrated Protocol for the Accurate Calculation of Magnetic Interactions in Organic Magnets. AB - A new, fast, and efficient computational protocol for the accurate calculation of singlet-triplet magnetic splittings in organic diradicals is tested and validated. This procedure essentially consists of three steps: the adoption of modified virtual orbitals (MVO) and a mixed variational-perturbational approach (CSPA) are now combined with a third method that exploits the reduction of the configurational space dimensions achieved by fragmentation/localization criteria. This innovative approach is successfully tested on four different substituted m phenylene bis(tert-butyl) nitroxides, which show paramagnetic behavior, by computing singlet-triplet energy gaps and comparing them with their experimental counterparts. PMID- 26596302 TI - Electron Transport Suppression from Tip-pi State Interaction on Si(100)-2 * 1 Surfaces. AB - We investigate the electron transport between a scanning tunneling microscope tip and Si(100)-2 * 1 surfaces with four distinct configurations by performing calculations using density functional theory and the nonequilibrium Green's function method. Interestingly, we find that the conducting mechanism is altered when the tip-surface distance varies from large to small. At a distance larger than the critical value of 4.06 A, the conductance is increased with a reduction in distance owing to the pi state arising from the silicon dimers immediately under the tip; this in turn plays a key role in facilitating a large transmission probability. In contrast, when the tip is closer to the substrate, the conductance is substantially decreased because the pi state is suppressed by the interaction with the tip, and its contribution in the tunneling channels is considerably reduced. PMID- 26596303 TI - Silicon Nanocrystal Functionalization: Analytic Fitting of DFTB Parameters. AB - A density functional tight binding (DFTB) scheme has been applied to functionalized silicon nanocrystals. Using an analytic functional representation of DFTB parameters, the scheme has been used to compute the adsorption energies in the organic functionalization of reconstructed Si(100) and H-terminated Si(111) surfaces of hundreds-of-atoms nanocrystals. We adopt an ONIOM(QM:QM') approach that corrects the overbinding of DFTB, obtaining nice agreement with high-level reaction energies and structural configurations. PMID- 26596304 TI - Edge Stabilities of Hexagonal Boron Nitride Nanoribbons: A First-Principles Study. AB - We investigate the comparative stability of sp(2) bonded planar hexagonal boron nitride (h-BN) nanoribbon (BNNR) edges, using first principles calculations. We find that the pristine armchair edges have the highest degree of stability. Pristine zigzag edges are metastable, favoring planar reconstructions [in the form of 5-7 rings] that minimizes the energy. Our investigation further reveals that the pristine zigzag edges can be stabilized against 5-7 reconstructions by passivating the dangling bonds at the edges by other elements, such as hydrogen (H) atoms. Electronic and magnetic properties of nanoribbons depend on the edge shapes and are strongly affected by edge reconstructions. PMID- 26596305 TI - Molecular Dynamics Simulations of a Binding Intermediate between FKBP12 and a High-Affinity Ligand. AB - We characterized a binding intermediate between the protein FKBP12 and one of its high-affinity ligands by means of molecular dynamics simulations. In such an intermediate, which is expected to form at the end-point of the bimolecular diffusional search, short-range interactions between the molecular partners may play a role in the specificity of recognition as well as in the association rate. Langevin dynamics simulations were carried out to generate the intermediate by applying an external biasing force to unbind the ligand from the protein. The intermediate was then refined by seven independent molecular dynamics simulations performed with an explicit solvent model. We found consistent results both for the structure of the protein and for the position of the ligand in the intermediate. The two carbonyl oxygens O2 and O3 of the ligand core region act as two main anchors, making permanent contacts in the intermediate. The transient contacts with the protein are made by the ligand noncore moieties whose structures and mobilities enable many alternative contacts of different types to be formed: pi-pi molecular overlap and weak hydrogen bonds NH...pi, CH...pi, and CH...O. Hence, the stability of the ligand at the entrance of the protein binding pocket offers the possibility of fine-tuning a variety of short-range contacts that involve the ligand noncore moieties. Under the hypothesis that the stability of this intermediate is related to the affinity of the ligand, this binding intermediate model comes closest to explaining the role played by the noncore moieties in the affinity of this ligand. Moreover, this model also provides a plausible explanation for how structurally diverse core motifs that all share the carbonyl atoms O2 and O3 bind to FKBP12. PMID- 26596306 TI - Rubredoxin Function: Redox Behavior from Electrostatics. AB - Continuum electrostatic theory was applied to compute redox potentials of rubredoxin (Rd) proteins. We used multiple side chain conformers of Rd crystal structures, optimized geometries of salt bridges, mutated residues, and residues in the neighborhood of the iron-sulfur complex (FeS complex) self-consistently for given solvent pH and redox potential. The following contributions to Rd redox potentials are discussed: side chain conformations, H-bond geometries of the FeS complex, dielectric environment, charged residues, and salt bridges. We considered 15 different Rd's (of different species/strains and mutants) with available crystal structures whose redox potentials vary between -86 mV and +31 mV. The computed redox potentials deviated by less than 16 mV, root-mean-square deviation (RMSD), from measured values. The amide H-bond geometry is considered to be crucial for the variation of Rd redox potentials. To test this assumption, we considered 14 mutant Rd's for which we modeled the structures based on Rd from WT Clostridium pasterianum (Cp) leaving the amide H-bond geometry of the FeS complex invariant. Here, we obtained an RMSD of only 14 mV with measured values demonstrating that the amide H bond geometries cannot be a major factor determining Rd redox potentials. We analyzed the factors determining the Rd redox potentials of a mesophilic and a thermophilic Rd differing by nearly 90 mV. We found that half of the difference is due to sequence and half is due to backbone variations. Albeit salt-bridge networks vary considerably between these two Rd's and are considered to be responsible for differences in thermostability, their overall influence on Rd redox potentials is small. PMID- 26596307 TI - On the Convergence of QM/MM Energies. AB - We have studied the convergence of QM/MM calculations with respect to the size of the QM system. We study a proton transfer between a first-sphere cysteine ligand and a second-sphere histidine group in [Ni,Fe] hydrogenase and use a 446-atom model of the protein, treated purely with QM methods as a reference. We have tested 12 different ways to redistribute charges close to the junctions (to avoid overpolarization of the QM system), but once the junctions are moved away from the active site, there is little need to redistribute the charges. We have tested 13 different variants of QM/MM approaches, including two schemes to correct errors caused by the truncation of the QM system. However, we see little gain from such correction schemes; on the contrary, they are sensitive to the charge redistribution scheme and may cause large errors if charges are close to the junctions. In fact, the best results were obtained with a mechanical embedding approach that does not employ any correction scheme and ignores polarization. It gives a mean unsigned error for 40 QM systems of different sizes of 7 kJ/mol with a maximum error of 28 kJ/mol. The errors can be significantly decreased if bonds between the QM and MM system (junctions) are moved one residue away from all active-site residues. Then, most QM/MM variants give mean unsigned errors of 5-9 kJ/mol, maximum errors of 16-35 kJ/mol, and only five to seven residues give an error of over 5 kJ/mol. In general, QM/MM calculations converge faster with system size than pure QM calculations. PMID- 26596308 TI - On-the-Fly Identification of Conformational Substates from Molecular Dynamics Simulations. AB - We recently introduced a new method for discovering, characterizing, and monitoring spatiotemporal patterns in the conformational fluctuations in molecular dynamics simulation data ( J. Comput. Biol. 2010 , 17 ( 3 ), 309 - 324 ). Significantly, our method, called Dynamic Tensor Analysis (DTA), can be performed as the simulation is progressing. It is therefore well-suited to analyzing long timescale simulations, which are critical for studying biologically relevant motions but may be too large for traditional analysis methods. In this paper, we demonstrate that the patterns discovered by DTA often correspond to functionally important conformational substates. In particular, we apply DTA to a 150 ns simulation of ubiquitin and discover patterns that provide unique insights into ubiquitin's ability to bind multiple substrates. Moreover, we take advantage of DTA's ability to identify patterns on different timescales and investigate how fast positional fluctuations may modulate slower, large-scale motions in functionally important regions. Our findings here suggest that DTA is well-suited to organizing, visualizing, and analyzing very large trajectories and discovering conformational substates. PMID- 26596309 TI - Systematic Theoretical Investigation on the Light Emitter of Firefly. AB - This is a systematic theoretical investigation on all the possible light emitters of firefly using a multireference method. Six chemical forms of oxyluciferin (OxyLH2) molecules/anions were studied by a multistate complete active space second-order perturbation (MS-CASPT2) method in vacuum and dimethyl sulfoxide. The calculated results and subsequent analysis excluded enol-OxyLH2, keto-OxyLH2, and enolate-OxyLH(-) as possible light emitters. The remaining three candidates, phenolate-enol-OxyLH(-), phenolate-keto-OxyLH(-), and OxyL(2-), were further investigated in protein by a MS-CASPT2/molecular mechanics (MM) study to explain the natural bioluminescence of firefly. By comparison of the MS-CASPT2/MM calculated results of phenolate-enol-OxyLH(-), phenolate-keto-OxyLH(-), and OxyL(2-) with the experimental observation and detailed analysis, we concluded that the direct decomposition excited-state product of firefly dioxetanone in vivo and the only light emitter of firefly in natural bioluminescence is the first singlet excited state (S1) of phenolate-keto-OxyLH(-). PMID- 26596310 TI - Stability of Hydrocarbons of the Polyhedrane Family Containing Bridged CH Groups: A Case of Failure of the Colle-Salvetti Correlation Density Functionals. PMID- 26596311 TI - On the Structure and Geometry of Biomolecular Binding Motifs (Hydrogen-Bonding, Stacking, X-H...pi): WFT and DFT Calculations. PMID- 26596313 TI - Periodicity during hypercapnic and hypoxic stimulus is crucial in distinct aspects of phrenic nerve plasticity. AB - This study was undertaken to determine pattern sensitivity of phrenic nerve plasticity in respect to different respiratory challenges. We compared long-term effects of intermittent and continuous hypercapnic and hypoxic stimuli, and combined intermittent hypercapnia and hypoxia on phrenic nerve plasticity. Adult, male, urethane-anesthetized, vagotomized, paralyzed, mechanically ventilated Sprague-Dawley rats were exposed to: acute intermittent hypercapnia (AIHc or AIHc(O2)), acute intermittent hypoxia (AIH), combined intermittent hypercapnia and hypoxia (AIHcH), continuous hypercapnia (CHc), or continuous hypoxia (CH). Peak phrenic nerve activity (pPNA) and burst frequency were analyzed during baseline (T0), hypercapnia or hypoxia exposures, at 15, 30, and 60 min (T60) after the end of the stimulus. Exposure to acute intermittent hypercapnia elicited decrease of phrenic nerve frequency from 44.25+/-4.06 at T0 to 35.29+/ 5.21 at T60, (P=0.038, AIHc) and from 45.5+/-2.62 to 37.17+/-3.68 breaths/min (P=0.049, AIHc(O2)), i.e. frequency phrenic long term depression was induced. Exposure to AIH elicited increase of pPNA at T60 by 141.0+/-28.2 % compared to baseline (P=0.015), i.e. phrenic long-term facilitation was induced. Exposure to AIHcH, CHc, or CH protocols failed to induce long-term plasticity of the phrenic nerve. Thus, we conclude that intermittency of the hypercapnic or hypoxic stimuli is needed to evoke phrenic nerve plasticity. PMID- 26596312 TI - Adverse effects of AMP-activated protein kinase alpha2-subunit deletion and high fat diet on heart function and ischemic tolerance in aged female mice. AB - AMP-activated protein kinase (AMPK) plays a role in metabolic regulation under stress conditions, and inadequate AMPK signaling may be also involved in aging process. The aim was to find out whether AMPK alpha2-subunit deletion affects heart function and ischemic tolerance of adult and aged mice. AMPK alpha2(-/-) (KO) and wild type (WT) female mice were compared at the age of 6 and 18 months. KO mice exhibited subtle myocardial AMPK alpha2-subunit protein level, but no difference in AMPK alpha1-subunit was detected between the strains. Both alpha1- and alpha2-subunits of AMPK and their phosphorylation decreased with advanced age. Left ventricular fractional shortening was lower in KO than in WT mice of both age groups and this difference was maintained after high-fat feeding. Infarct size induced by global ischemia/reperfusion of isolated hearts was similar in both strains at 6 months of age. Aged WT but not KO mice exhibited improved ischemic tolerance compared with the younger group. High-fat feeding for 6 months during aging abolished the infarct size-reduction in WT without affecting KO animals; nevertheless, the extent of injury remained larger in KO mice. The results demonstrate that adverse effects of AMPK alpha2-subunit deletion and high-fat feeding on heart function and myocardial ischemic tolerance in aged female mice are not additive. PMID- 26596314 TI - Polycaprolactone foam functionalized with chitosan microparticles - a suitable scaffold for cartilage regeneration. AB - For biodegradable porous scaffolds to have a potential application in cartilage regeneration, they should enable cell growth and differentiation and should have adequate mechanical properties. In this study, our aim was to prepare biocompatible scaffolds with improved biomechanical properties. To this end, we have developed foam scaffolds from poly-epsilon-caprolactone (PCL) with incorporated chitosan microparticles. The scaffolds were prepared by a salt leaching technique from either 10 or 15 wt% PCL solutions containing 0, 10 and 20 wt% chitosan microparticles, where the same amount and size of NaCl was used as a porogen in all the cases. PCL scaffolds without and with low amounts of chitosan (0 and 10 wt% chitosan) showed higher DNA content than scaffolds with high amounts of chitosan during a 22-day experiment. 10 wt% PCL with 10 and 20 wt% chitosan showed significantly increased viscoelastic properties compared to 15 wt% PCL scaffolds with 0 and 10 wt% chitosan. Thus, 10 wt% PCL scaffolds with 0 wt% and 10 wt% chitosan are potential scaffolds for cartilage regeneration. PMID- 26596315 TI - Hypercalcemia. Pathophysiological aspects. AB - The metabolic pathways that contribute to maintain serum calcium concentration in narrow physiological range include the bone remodeling process, intestinal absorption and renal tubule resorption. Dysbalance in these regulations may lead to hyper- or hypocalcemia. Hypercalcemia is a potentionally life-threatening and relatively common clinical problem, which is mostly associated with hyperparathyroidism and/or malignant diseases (90 %). Scarce causes of hypercalcemia involve renal failure, kidney transplantation, endocrinopathies, granulomatous diseases, and the long-term treatment with some pharmaceuticals (vitamin D, retinoic acid, lithium). Genetic causes of hypercalcemia involve familial hypocalciuric hypercalcemia associated with an inactivation mutation in the calcium sensing receptor gene and/or a mutation in the CYP24A1 gene. Furthermore, hypercalcemia accompanying primary hyperparathyroidism, which develops as part of multiple endocrine neoplasia (MEN1 and MEN2), is also genetically determined. In this review mechanisms of hypercalcemia are discussed. The objective of this article is a review of hypercalcemia obtained from a Medline bibliographic search. PMID- 26596316 TI - Effect of sophoridine on Ca2+ induced Ca2+ release during heart failure. AB - Sophoridine is a type of alkaloid extract derived from the Chinese herb Sophora flavescens Ait (kushen) and possess a variety of pharmacological effects including anti-inflammation, anti-anaphylaxis, anti-cancer, anti-arrhythmic and so on. However, the effect of sophoridine on heart failure has not been known yet. In this study, the effect of sophoridine on heart failure was investigated using Sprague-Dawley (SD) rat model of chronic heart failure. Morphological results showed that in medium and high dose group, myofilaments were arranged orderly and closely, intermyofibrillar lysis disappeared and mitochondria contained tightly packed cristae compared with heart failure group. We investigated the Ca(2+) induced Ca(2+) transients and assessed the expression of ryanodine receptor (RyR2) and L-type Ca(2+) channel (dihydropyridine receptor, DHPR). We found that the cytosolic Ca(2+) transients were markedly increased in amplitude in medium (deltaF/F(0)=43.33+/-1.92) and high dose groups (deltaF/F(0)=47.21+/-1.25) compared with heart failure group (deltaF/F(0)=16.7+/ 1.29, P<0.01), Moreover, we demonstrated that the expression of cardiac DHPR was significantly increased in medium- and high dose-group compared with heart failure rats. Our results suggest that sophoridine could improve heart failure by ameliorating cardiac Ca(2+) induced Ca(2+) transients, and that this amelioration is associated with upregulation of DHPR. PMID- 26596318 TI - Characterization of calcium signals provoked by lysophosphatidylinositol in human microvascular endothelial cells. AB - The lipid molecule, lysophosphatidylinositol (LPI), is hypothesised to form part of a novel lipid signalling system that involves the G protein-coupled receptor GPR55 and distinct intracellular signalling cascades in endothelial cells. This work aimed to study the possible mechanisms involved in LPI-evoked cytosolic Ca(2+) mobilization in human brain microvascular endothelial cells. Changes in intracellular Ca(2+) concentrations were measured using cell population Ca(2+) assay. LPI evoked biphasic elevation of intracellular calcium concentration, a rapid phase and a sustained phase. The rapid phase was attenuated by the inhibitor of PLC (U 73122), inhibitor of IP(3) receptors, 2-APB and the depletor of endoplasmic reticulum Ca(2+) store, thapsigargin. The sustained phase, on the other hand, was enhanced by U 73122 and abolished by the RhoA kinase inhibitor, Y 27632. In conclusion, the Ca(2+) signal evoked by LPI is characterised by a rapid phase of Ca(2+) release from the endoplasmic reticulum, and requires activation of the PLC-IP(3) signalling pathway. The sustained phase mainly depends on RhoA kinase activation. LPI acts as novel lipid signalling molecule in endothelial cells, and elevation of cytosolic Ca(2+) triggered by it may present an important intracellular message required in gene expression and controlling of vascular tone. PMID- 26596317 TI - Blocking proteinase-activated receptor 2 alleviated neuropathic pain evoked by spinal cord injury. AB - Spinal cord injury (SCI) is an extremely serious type of physical trauma observed in clinics. Especially, neuropathic pain resulting from SCI has a lasting and significant impact on most aspects of daily life. Thus, a better understanding of the molecular pathways responsible for the cause of neuropathic pain observed in SCI is important to develop effectively therapeutic agents and treatment strategies. Proteinase-activated receptors (PARs) are a family member of G protein-coupled receptors and are activated by a proteolytic mechanism. One of its subtypes PAR2 has been reported to be engaged in mechanical and thermal hyperalgesia. Thus, in this study we specifically examined the underlying mechanisms responsible for SCI evoked-neuropathic pain in a rat model. Overall, we demonstrated that SCI increases PAR2 and its downstream pathways TRPV1 and TRPA1 expression in the superficial dorsal horn of the spinal cord. Also, we showed that blocking spinal PAR2 by intrathecal injection of FSLLRY-NH2 significantly inhibits neuropathic pain responses induced by mechanical and thermal stimulation whereas FSLLRY-NH2 decreases the protein expression of TRPV1 and TRPA1 as well as the levels of substance P and calcitonin gene-related peptide. Results of this study have important implications, i.e. targeting one or more of these signaling molecules involved in activation of PAR2 and TRPV1/TRPA1 evoked by SCI may present new opportunities for treatment and management of neuropathic pain often observed in patients with SCI. PMID- 26596319 TI - Minipig model of Huntington's disease: 1H magnetic resonance spectroscopy of the brain. AB - Huntington's disease (HD) is an inherited autosomal neurodegenerative disorder affecting predominantly the brain, characterized by motor dysfunctions, behavioral and cognitive disturbances. The aim of this study was to determine changes in the brain of transgenic minipigs before HD onset using (1)H magnetic resonance (MR) spectroscopy. Measurements were performed on a 3 T MR scanner using a single voxel spectroscopy sequence for spectra acquisition in the white matter and chemical shift imaging sequence for measurement in the striatum, hippocampus and thalamus. A decrease of (phospho)creatine (tCr) concentration was found only in the thalamus (p=0.002) of transgenic minipigs, nevertheless we found significant changes in metabolite ratios. Increase of the ratio choline compounds (tCho)/tCr was found in all examined areas: striatum (p=0.010), thalamus (p=0.011) as well as hippocampus (p=0.027). The ratio N acetylaspartate+N-acetylaspartylglutamate (tNAA)/tCr (p=0.043) and glutamate+glutamine (Glx)/tCr (p=0.039) was elevated in the thalamus, the ratio myo-inositol (Ins)/tCr (p=0.048) was significantly increased in the hippocampus. No significant differences were observed in the metabolite concentrations in the white matter, however we found significant increase of ratios tNAA/tCr (p=0.018) and tCho/tCr (p=0.003) ratios in transgenic boars. We suppose that the majority of the observed changes are predominantly related to changes in energy metabolism caused by decrease of tCr. PMID- 26596320 TI - Vascular stenosis asymmetry influences considerably pressure gradient and flow volume. AB - Vascular stenosis is often described only by its percentage in both clinical and scientific praxis. Previous studies gave inconclusive results regarding the effect of stenosis eccentricity on its hemodynamic effect. The aim of this experimental study was to investigate and quantify the effect of stenosis severity and eccentricity on the pressure drop. A combination of pressure and flow measurements by Particle Imaging Velocimetry (PIV) method was used. Models of the same stenosis significance but with different levels of eccentricity were studied in vitro by PIV. This study has shown that stenosis asymmetry is associated with more profound pressure drop and flow volume decrease. On the contrary, pressure drop and flow volume decrease were not further significantly influenced by the level of asymmetry. Hemodynamic changes associated with stenosis eccentricity must be taken into account in both clinical and scientific studies. PMID- 26596321 TI - The importance of the training-induced decrease in basal cortisol concentration in the improvement in muscular performance in humans. AB - Acute exercise-induced changes in cortisol concentration (C) and training related adaptation within hypothalamic-pituitary-adrenal (HPA) axis has been widely examined, but their influence on muscle strength performance is at best uncertain. Twenty four young healthy men were randomly assigned to an endurance training group (ET, n=12) or to a non-exercising controls (CON, n=12). ET performed supervised endurance training on cycle ergometer for 20 weeks. Endurance training program improved exercise capacity (14 % increase in power output generated at peak oxygen uptake - VO(2peak)), muscle strength performance (increase in MVC - maximal voluntary contraction - by 9 % and in TTF 50 % MVC - time to fatigue at 50 % MVC - by 21 %) and led to a decrease in basal serum C concentration (P=0.006) and an increase in basal testosterone to cortisol (T/C) and free testosterone to cortisol (fT/C) ratios (P=0.01 and P=0.02, respectively). It was found that the decrease in C concentration (deltaC) was positively correlated to the increase in local muscular endurance (deltaTTF 50 % MVC). No significant hormonal changes were seen in CON group. It is concluded that greater decrease in cortisol concentration after the endurance training is accompanied by poorer improvement in skeletal muscle performance in previously untrained subjects. PMID- 26596322 TI - Copper-induced changes in reproductive functions: in vivo and in vitro effects. AB - The goal of this study is to summarize the current knowledge on the effects of one of the essential metals, copper (Cu) on the reproductive system. The development of past four decades addressing effects of Cu on reproductive organs is reviewed. The most relevant data obtained from in vivo and in vitro experiments performed on humans and other mammals, including effects of copper nanoparticles (CuNPs) on the reproductive functions are presented. Short term Cu administration has been found to exert deleterious effect on intracellular organelles of rat ovarian cells in vivo. In vitro administration in porcine ovarian granulosa cells releases insulin-like growth factor (IGF-I), steroid hormone progesterone (P(4)), and induces expression of peptides related to proliferation and apoptosis. Adverse effect of Cu on male reproductive functions has been indicated by the decrease in spermatozoa parameters such as concentration, viability and motility. Copper nanoparticles are capable of generating oxidative stress in vitro thereby leading to reproductive toxicity. Toxic effect of CuNPs has been evident more in male mice than in females. Even though further investigations are necessary to arrive at a definitive conclusion, Cu notably influences the reproductive functions by interfering with both male and female reproductive systems and also hampers embryo development in dose dependent manner. PMID- 26596323 TI - The role of epicardial adipose tissue in heart disease. AB - Recent studies focused on epicardial fat, formerly relatively neglected component of the heart, have elucidated some of its key roles. It possesses several properties that can distinguish it from other adipose tissue depots. Its unique anatomical location in the heart predisposes the epicardial fat to be an important player in the physiological and biochemical regulation of cardiac homeostasis. Obesity is associated with an increase in epicardial fat mass. Excess of cardiac fat can contribute to greater left ventricular mass and work, diastolic dysfunction and attenuated septal wall thickening. Imbalance in adipokines levels secreted in autocrine or paracrine fashion by epicardial fat can contribute to the activation of the key atherogenic pathways in the setting of metabolic syndrome. Epicardial fat has also been identified as an important source of pro-inflammatory mediators worsening endothelial dysfunction, eventually leading to coronary artery disease. Increased production of pro inflammatory factors by epicardial fat can also contribute to systemic insulin resistance in patients undergoing cardiac surgery. Here we review the most important roles of epicardial fat with respect to heart disease in the context of other underlying pathologies such as obesity and type 2 diabetes mellitus. PMID- 26596324 TI - Influences of morphine on the spontaneous and evoked excitatory postsynaptic currents in lateral amygdala of rats. AB - Acute morphine exposure induces antinociceptive activity, but the underlying mechanisms in the central nervous system are unclear. Using whole-cell patch clamp recordings, we explore the role of morphine in the modulation of excitatory synaptic transmission in lateral amygdala neurons of rats. The results demonstrate that perfusion of 10 microM of morphine to the lateral amygdala inhibits the discharge frequency significantly. We further find that there are no significant influences of morphine on the amplitude of spontaneous excitatory postsynaptic currents (sEPSCs). Interestingly, morphine shows no marked influence on the evoked excitatory postsynaptic currents (eEPSCs) in the lateral amygdala neurons. These results indicate that acute morphine treatment plays an important role in the modulation on the excitatory synaptic transmission in lateral amygdala neurons of rats. PMID- 26596325 TI - Evaluation of cerebrovascular reserve in patients undergoing carotid artery stenting and its usefulness in predicting significant hemodynamic changes during temporary carotid occlusion. AB - We investigated the usefulness of cerebrovascular reserve (CVR) testing to predict severe hemodynamic changes during proximally protected carotid artery stenting. Of 90 patients referred, 63 eligible underwent complete evaluation of the extent of carotid artery disease and transcranial Doppler ultrasound (TCD) assessment of CVR by means of a breath-holding test and ophthalmic artery flow pattern evaluation. Periprocedural TCD monitoring of the ipsilateral middle cerebral artery flow was performed in 24 patients undergoing proximally protected procedure (requiring induction of flow arrest within internal carotid artery). Abnormal CVR was significantly less common in patients with unilateral compared to bilateral carotid artery disease (26.3 % vs. 76.9 %, p=0.02), while ophthalmic artery flow reversal was rare in patients with unilateral carotid artery disease (2.5 % vs. 42.9 %, p<0.01). During the induction of carotid flow arrest, the average mean flow velocity drop following external carotid artery occlusion was low (3.5 %, p=0.67) compared to the induction of complete flow arrest (32.8 %, p<0.01). Six patients had a total mean flow velocity drop >50 %, including 2 patients with normal pre-procedural CVR. Our results suggest that TCD evaluation of CVR is not a reliable predictor of hemodynamic changes induced during proximally protected carotid artery stenting in patients with unilateral carotid artery disease. PMID- 26596326 TI - Betaine increases the butyrylcholinesterase activity in rat plasma. AB - The physiological function of butyrylcholinesterase (EC 3.1.1.8, BChE) is not clearly understood, but a role was suggested in the fat utilization process, resulting in positive correlation between plasma triglyceride (TG) levels and BChE activity. Consequently we tested the hypothesis that regular intake of betaine, a natural compound intervening in the liver TG metabolism could influence the BChE activity. The BChE activity was estimated spectrophotometrically in plasma of rats fed with betaine enriched standard (B) or high-fat diet (HFB). The results confirmed decreased TG plasma levels after betaine treatment independently on the type of diet (0.15+/-0.03 (B) vs. 0.27+/ 0.08 (control) mmol/l; p=0.003 and 0.13+/-0.03 (HFB) vs. 0.27+/-0.08 (control) mmol/l; p=0.005). The BChE activity increased significantly with betaine administration, however the change was more distinct in the HFB group (0.84+/ 0.34 (HFB) vs. 0.22+/-0.04 (control) O.D./min/mg; p<0.001 and 0.41+/-0.11 (B) vs. 0.22+/-0.04 (control) O.D./min/mg; p=0.001). In conclusion, betaine intake led to elevated BChE activity in plasma and this effect was potentiated by the HF diet. Since betaine is in general used as a supplement in the treatment of liver diseases accompanied by TG overload, its impact on the BChE activity in the role of the liver function marker should be taken into account. PMID- 26596327 TI - Overtraining does not induce oxidative stress and inflammation in blood and heart of rats. AB - The aim of our research was to evaluate the changes in levels of cytokines and redox state parameters in blood and isolated heart of rats subjected to different swimming protocols. Rats were divided into 3 groups: 1) controls, 2) moderately trained rats that during all 12 weeks swam 1 h/day, 5 days/week, and 3) overtrained rats that in 10(th) week swam twice, 11(th) week 3 times, and in 12(th) week 4 times a day for 1 h. After sacrificing, blood from jugular vein was collected, and the heart excised and perfused on a Langendorff apparatus. Samples of the coronary effluent were collected during coronary autoregulation. Levels of superoxide anion radical (O(2)(-)), hydrogen peroxide (H(2)O(2)), nitric oxide (NO) and thiobarbituric acid reactive substances (TBARS) were measured in plasma and coronary effluent, while reduced glutathione (GSH), activities of superoxide dismutase (SOD) and catalase (CAT) were measured in erythrocytes. Venous blood was also used for interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF alpha) determination. Moderate training protocol induced the decrease of TBARS in plasma, while both training protocols induced the decrease of O(2)(-) and H(2)O(2) in coronary effluent. There was no significant difference in levels of cytokines between groups. The results of study add evidence about beneficial effects of moderate-intensity training on blood and cardiac redox state of rats, and furthermore, shows that exercising frequently, if the intensity stays within moderate range, may not have detrimental effects. PMID- 26596328 TI - Provision of a Medicines Information Service to Consumers on Facebook: An Australian Case Study. AB - BACKGROUND: Social networking sites (SNSs) have changed the way people communicate. They may also change the way people seek health advice. OBJECTIVE: This study describes the provision of a medicines information service on Facebook to individual consumers. It aimed to discuss the pros and cons, and inform health and pharmacy stakeholders and researchers about the opportunities and challenges of providing such a service. METHODS: We adopted an exploratory approach using a case study method. RESULTS: NPS MedicineWise, an independent, not-for-profit Australian organization, runs a public question-and-answer service on Facebook, dubbed Pharmacist Hour. Consumers following the organization's Facebook page are invited to post medication-related questions often with a suggested health topic. A wide range of questions and comments are posted related to medication usage. The pharmacist answers the queries, providing evidence-based medicines information and using consumer-friendly language, during the specific 1-hour period. The most popular questions in the past 12 months were related to adverse effects, treatment options for conditions, and drug interactions. The service had a mean number of engagements (defined as a like or share of the Pharmacy Hour post) of 38 (SD 19) people and a mean 5 (SD 3) questions per session. CONCLUSIONS: The Pharmacist Hour Facebook service addresses the medicines information needs of consumers and indirectly promotes other appropriate and relevant NPS MedicineWise products and services to further assist consumers. The service offers a new medium for a quality use of medicines organization committed to promoting awareness about the correct and safe use of medicines in Australia. PMID- 26596345 TI - Unconventional band structure for a periodically gated surface of a three dimensional topological insulator. AB - The surface states of the three-dimensional (3D) topological insulators are described by a two-dimensional (2D) massless dirac equation. A gate-voltage induced one-dimensional potential barrier on such surfaces creates a discrete bound state in the forbidden region outside the dirac cone. Even for a single barrier it is shown that such a bound state can create an electrostatic analogue of Shubnikov de Haas oscillation which can be experimentally observed for relatively smaller size samples. However, when these surface states are exposed to a periodic arrangement of such gate-voltage-induced potential barriers, the band structure of the same was significantly modified. This is expected to significantly alter the properties of the macroscopic system. We also suggest that, within suitable limits, the system may offer ways to control electron spin electrostatically, which may be practically useful. PMID- 26596346 TI - ESCRT-Dependent Cell Death in a Caenorhabditis elegans Model of the Lysosomal Storage Disorder Mucolipidosis Type IV. AB - Mutations in MCOLN1, which encodes the cation channel protein TRPML1, result in the neurodegenerative lysosomal storage disorder Mucolipidosis type IV. Mucolipidosis type IV patients show lysosomal dysfunction in many tissues and neuronal cell death. The ortholog of TRPML1 in Caenorhabditis elegans is CUP-5; loss of CUP-5 results in lysosomal dysfunction in many tissues and death of developing intestinal cells that results in embryonic lethality. We previously showed that a null mutation in the ATP-Binding Cassette transporter MRP-4 rescues the lysosomal defect and embryonic lethality of cup-5(null) worms. Here we show that reducing levels of the Endosomal Sorting Complex Required for Transport (ESCRT)-associated proteins DID-2, USP-50, and ALX-1/EGO-2, which mediate the final de-ubiquitination step of integral membrane proteins being sequestered into late endosomes, also almost fully suppresses cup-5(null) mutant lysosomal defects and embryonic lethality. Indeed, we show that MRP-4 protein is hypo-ubiquitinated in the absence of CUP-5 and that reducing levels of ESCRT-associated proteins suppresses this hypo-ubiquitination. Thus, increased ESCRT-associated de ubiquitinating activity mediates the lysosomal defects and corresponding cell death phenotypes in the absence of CUP-5. PMID- 26596347 TI - Testing for Ancient Selection Using Cross-population Allele Frequency Differentiation. AB - A powerful way to detect selection in a population is by modeling local allele frequency changes in a particular region of the genome under scenarios of selection and neutrality and finding which model is most compatible with the data. A previous method based on a cross-population composite likelihood ratio (XP-CLR) uses an outgroup population to detect departures from neutrality that could be compatible with hard or soft sweeps, at linked sites near a beneficial allele. However, this method is most sensitive to recent selection and may miss selective events that happened a long time ago. To overcome this, we developed an extension of XP-CLR that jointly models the behavior of a selected allele in a three-population tree. Our method - called "3-population composite likelihood ratio" (3P-CLR) - outperforms XP-CLR when testing for selection that occurred before two populations split from each other and can distinguish between those events and events that occurred specifically in each of the populations after the split. We applied our new test to population genomic data from the 1000 Genomes Project, to search for selective sweeps that occurred before the split of Yoruba and Eurasians, but after their split from Neanderthals, and that could have led to the spread of modern-human-specific phenotypes. We also searched for sweep events that occurred in East Asians, Europeans, and the ancestors of both populations, after their split from Yoruba. In both cases, we are able to confirm a number of regions identified by previous methods and find several new candidates for selection in recent and ancient times. For some of these, we also find suggestive functional mutations that may have driven the selective events. PMID- 26596348 TI - Accelerating Mutational Load Is Not Due to Synergistic Epistasis or Mutator Alleles in Mutation Accumulation Lines of Yeast. AB - Much of our knowledge about the fitness effects of new mutations has been gained from mutation accumulation (MA) experiments. Yet the fitness effect of single mutations is rarely measured in MA experiments. This raises several issues, notably for inferring epistasis for fitness. The acceleration of fitness decline in MA lines has been taken as evidence for synergistic epistasis, but establishing the role of epistasis requires measuring the fitness of genotypes carrying known numbers of mutations. Otherwise, accelerating fitness loss could be explained by increased genetic mutation rates. Here we segregated mutations accumulated over 4800 generations in haploid and diploid MA lines of the yeast Saccharomyces cerevisiae. We found no correspondence between an accelerated fitness decline and synergistic epistasis among deleterious mutations in haploid lines. Pairs of mutations showed no overall epistasis. Furthermore, several lines of evidence indicate that genetic mutation rates did not increase in the MA lines. Crucially, segregant fitness analyses revealed that MA accelerated in both haploid and diploid lines, even though the fitness of diploid lines was nearly constant during the MA experiment. This suggests that the accelerated fitness decline in haploids was caused by cryptic environmental factors that increased mutation rates in all lines during the last third of the lines' transfers. In addition, we provide new estimates of deleterious mutation rates, including lethal mutations, and highlight that nearly all the mutational load we observed was due to one or two mutations having a large effect on fitness. PMID- 26596349 TI - A generalized semiparametric mixed model for analysis of multivariate health care utilization data. AB - Health care utilization is an outcome of interest in health services research. Two frequently studied forms of utilization are counts of emergency department (ED) visits and hospital admissions. These counts collectively convey a sense of disease exacerbation and cost escalation. Different types of event counts from the same patient form a vector of correlated outcomes. Traditional analysis typically model such outcomes one at a time, ignoring the natural correlations between different events, and thus failing to provide a full picture of patient care utilization. In this research, we propose a multivariate semiparametric modeling framework for the analysis of multiple health care events following the exponential family of distributions in a longitudinal setting. Bivariate nonparametric functions are incorporated to assess the concurrent nonlinear influences of independent variables as well as their interaction effects on the outcomes. The smooth functions are estimated using the thin plate regression splines. A maximum penalized likelihood method is used for parameter estimation. The performance of the proposed method was evaluated through simulation studies. To illustrate the method, we analyzed data from a clinical trial in which ED visits and hospital admissions were considered as bivariate outcomes. PMID- 26596350 TI - Causal mediation analysis with multiple causally non-ordered mediators. AB - In many health studies, researchers are interested in estimating the treatment effects on the outcome around and through an intermediate variable. Such causal mediation analyses aim to understand the mechanisms that explain the treatment effect. Although multiple mediators are often involved in real studies, most of the literature considered mediation analyses with one mediator at a time. In this article, we consider mediation analyses when there are causally non-ordered multiple mediators. Even if the mediators do not affect each other, the sum of two indirect effects through the two mediators considered separately may diverge from the joint natural indirect effect when there are additive interactions between the effects of the two mediators on the outcome. Therefore, we derive an equation for the joint natural indirect effect based on the individual mediation effects and their interactive effect, which helps us understand how the mediation effect works through the two mediators and relative contributions of the mediators and their interaction. We also discuss an extension for three mediators. The proposed method is illustrated using data from a randomized trial on the prevention of dental caries. PMID- 26596351 TI - Influence diagnostics for count data under AB-BA crossover trials. AB - This paper aims to develop diagnostic measures to assess the influence of data perturbations on estimates in AB-BA crossover studies with a Poisson distributed response. Generalised mixed linear models with normally distributed random effects are utilised. We show that in this special case, the model can be decomposed into two independent sub-models which allow to derive closed-form expressions to evaluate the changes in the maximum likelihood estimates under several perturbation schemes. The performance of the new influence measures is illustrated by simulation studies and the analysis of a real dataset. PMID- 26596352 TI - The impact of covariate misclassification using generalized linear regression under covariate-adaptive randomization. AB - Under covariate adaptive randomization, the covariate is tied to both randomization and analysis. Misclassification of such covariate will impact the intended treatment assignment; further, it is unclear what the appropriate analysis strategy should be. We explore the impact of such misclassification on the trial's statistical operating characteristics. Simulation scenarios were created based on the misclassification rate and the covariate effect on the outcome. Models including unadjusted, adjusted for the misclassified, or adjusted for the corrected covariate were compared using logistic regression for a binary outcome and Poisson regression for a count outcome. For the binary outcome using logistic regression, type I error can be maintained in the adjusted model, but the test is conservative using an unadjusted model. Power decreased with both increasing covariate effect on the outcome as well as the misclassification rate. Treatment effect estimates were biased towards the null for both the misclassified and unadjusted models. For the count outcome using a Poisson model, covariate misclassification led to inflated type I error probabilities and reduced power in the misclassified and the unadjusted model. The impact of covariate misclassification under covariate-adaptive randomization differs depending on the underlying distribution of the outcome. PMID- 26596354 TI - Endovascular Approach to Transplant Renal Artery Stenosis. AB - BACKGROUND: The endovascular approach has shown high initial technical success rates, good patency rates, and minimal complications in treating transplant renal artery stenosis (TRAS). The objective of this study was to describe our experience with an endovascular approach to TRAS. MATERIAL AND METHODS: We performed a retrospective single-institutional review of all kidney transplant procedures performed at our institution from September 2009 to September 2014. All consecutive cases of TRAS were included. RESULTS: From a total of 183 kidney transplantations, 16 patients had TRAS. Mean time from transplantation to TRAS diagnosis was 201.8 days. Stenoses or hemodynamic significant kinkings were located at the anastomosis (7), proximal (5) and middle (4) portions of the transplant artery. All patients were treated with angioplasty and primary balloon expanding stenting. Early technical success was 93.75% and local complication rate was 12.5%. No deaths occurred. Mean serum creatinine level dropped from 3.87 mg/dL to 2.91 mg/dL after 24 hours; 1.85 mg/dL after one month; and 1.67 mg/dL after three months (P<0.05). Mean estimated glomerular filtration rate increased from 31.60 mL/min to 39.53 mL/min after 24 hours; 50.92 mL/min after one month; and 55.05 mL/min after three months (P<0.05). Doppler ultrasound criteria normalized after the procedure. Number of classes of antihypertensive drugs was not different before and after the procedure (P=0.38). Mean follow-up time was 9.75 months. One patient had a restenosis and required surgical intervention to restore graft function. CONCLUSIONS: The endovascular approach to TRAS with primary balloon-expanding stenting was safe and had a high rate of technical success. It was effective for restore and maintain the renal function in transplant kidney grafts with a low rate of restenosis. PMID- 26596353 TI - Direct observation of respectful maternity care in five countries: a cross sectional study of health facilities in East and Southern Africa. AB - BACKGROUND: Poor quality of care at health facilities is a barrier to pregnant women and their families accessing skilled care. Increasing evidence from low resource countries suggests care women receive during labor and childbirth is sometimes rude, disrespectful, abusive, and not responsive to their needs. However, little is known about how frequently women experience these behaviors. This study is one of the first to report prevalence of respectful maternity care and disrespectful and abusive behavior at facilities in multiple low resource countries. METHODS: Structured, standardized clinical observation checklists were used to directly observe quality of care at facilities in five countries: Ethiopia, Kenya, Madagascar, Rwanda, and the United Republic of Tanzania. Respectful care was represented by 10 items describing actions the provider should take to ensure the client was informed and able to make choices about her care, and that her dignity and privacy were respected. For each country, percentage of women receiving these practices and delivery room privacy conditions were calculated. Clinical observers' open-ended comments were also analyzed to identify examples of disrespect and abuse. RESULTS: A total of 2164 labor and delivery observations were conducted at hospitals and health centers. Encouragingly, women overall were treated with dignity and in a supportive manner by providers, but many women experienced poor interactions with providers and were not well-informed about their care. Both physical and verbal abuse of women were observed during the study. The most frequently mentioned form of disrespect and abuse in the open-ended comments was abandonment and neglect. CONCLUSIONS: Efforts to increase use of facility-based maternity care in low income countries are unlikely to achieve desired gains if there is no improvement in quality of care provided, especially elements of respectful care. This analysis identified insufficient communication and information sharing by providers as well as delays in care and abandonment of laboring women as deficiencies in respectful care. Failure to adopt a patient-centered approach and a lack of health system resources are contributing structural factors. Further research is needed to understand these barriers and develop effective interventions to promote respectful care in this context. PMID- 26596356 TI - Risk factors for granuloma formation in children induced by tracheobronchial foreign bodies. AB - OBJECTIVE: The aim of this study was to analyze the risk factors for granuloma formation caused by plant-based tracheobronchial foreign bodies in children, and investigate the underlying pathogenesis. METHOD: In this retrospective analysis of 153 cases with tracheobronchial foreign bodies (peanuts and watermelon seeds), 35 cases of granuloma formation as granulation group (G), and 118 cases of no granuloma formation as non-granulation group (NG) were studied. Clinical data pertaining to sex (S), age (A), foreign body surface smoothness (SF), foreign body shape (SH), foreign body oil release state (O), the location of foreign bodies (L), and foreign body retention time (T) were collected for statistical analysis. RESULTS: Univariate analysis showed no significant difference between the two groups (G and NG) with respect to S, A, SH and L. Significant factors based on univariate analysis included SF, O and T. Multivariate logistic regression analysis revealed that SF and T were independent risk factors associated with development of granuloma. CONCLUSIONS: SF, O and T had relationship with the granuloma formation. Local trauma caused by an irregular and sharp foreign body, and extended period of time represent the main factors causing granuloma formation. PMID- 26596355 TI - Profiles of sedentary and non-sedentary young men - a population-based MOPO study. AB - BACKGROUND: Sedentary behavior is associated with poor well-being in youth with adverse trajectories spanning to adulthood. Still, its determinants are poorly known. Our aim was to profile sedentary and non-sedentary young men and to clarify their differences in a population-based setting. METHODS: A total of 616 men (mean age 17.9, SD 0.6) attending compulsory conscription for military service completed a questionnaire on health, health behavior, socioeconomic situation and media use. They underwent a physical (body composition, muscle and aerobic fitness) and medical examination. Profiles were formed by principal component analysis (PCA). RESULTS: A total of 30.1 % men were sedentary (daily leisure-time sitting >=5 h) and 28.9 % non-sedentary (sitting <=2 h). The sedentary men had more body fat, more depressive symptoms, but lower fitness and life satisfaction than non-sedentary men. However, according to PCA, profiles of unhealthy eating, life-dissatisfaction, and gaming were detected both among sedentary and non-sedentary men, as well as high self-rated PA and motives to exercise. CONCLUSION: Determinants of sedentary and non-sedentary lifestyles were multiple and partially overlapping. Recognizing individual patterns and underlying factors of the sedentary lifestyle is essential for tailored health promotion and interventions. PMID- 26596357 TI - Radiation dose reduction in postoperative computed position control of cochlear implant electrodes in lambs - An experimental study. AB - OBJECTIVE: Cochlear implants (CI) are standard treatment for prelingually deafened children and postlingually deafened adults. Computed tomography (CT) is the standard method for postoperative imaging of the electrode position. CT scans accurately reflect electrode depth and position, which is essential prior to use. However, routine CT examinations expose patients to radiation, which is especially problematic in children. We examined whether new CT protocols could reduce radiation doses while preserving diagnostic accuracy. METHODS: To investigate whether electrode position can be assessed by low-dose CT protocols, a cadaveric lamb model was used because the inner ear morphology is similar to humans. The scans were performed at various volumetric CT dose-indexes CTDIvol)/kV combinations. For each constant CTDIvol the tube voltage was varied (i.e., 80, 100, 120 and 140kV). This procedure was repeated at different CTDIvol values (21mGy, 11mGy, 5.5mGy, 2.8mGy and 1.8mGy). To keep the CTDIvol constant at different tube voltages, the tube current values were adjusted. Independent evaluations of the images were performed by two experienced and blinded neuroradiologists. The criteria diagnostic usefulness, image quality and artifacts (scaled 1-4) were assessed in 14 cochlear-implanted cadaveric lamb heads with variable tube voltages. RESULTS: Results showed that the standard CT dose could be substantially reduced without sacrificing diagnostic accuracy of electrode position. The assessment of the CI electrode position was feasible in almost all cases up to a CTDIvol of 2-3mGy. The number of artifacts did not increase for images within this dose range as compared to higher dosages. The extent of the artifacts caused by the implanted metal-containing CI electrode does not depend on the radiation dose and is not perceptibly influenced by changes in the tube voltage. Summarizing the evaluation of the CI electrode position is possible even at a very low radiation dose. CONCLUSIONS: CT imaging of the temporal bone for postoperative electrode position control of the CI is possible with a very low and significantly radiation dose. The tube current-time product and voltage can be reduced by 50% without increasing artifacts. Low-dose postoperative CT scans are sufficient for localizing the CI electrode. PMID- 26596358 TI - Heterologous expression of a GH3 beta-glucosidase from Neurospora crassa in Pichia pastoris with high purity and its application in the hydrolysis of soybean isoflavone glycosides. AB - Previous studies have shown isoflavone aglycones to have more biological effects than their counterparts, isoflavone glycones. Some beta-glucosidases can hydrolyze isoflavone glucosides to release aglycones, and discovery of these has attracted great interest. A glycoside hydrolase (GH) family 3 beta-glucosidase (bgl2) gene from Neurospora crassa was heterologously expressed in Pichia pastoris with high purity. The recombinant BGL2 enzyme displayed its highest activity at pH 5.0 and 60 degrees C, and had its maximum activity against p nitrophenyl-beta-d-glucopyranoside (pNPG) (143.27 +/- 4.79 U/mg), followed by cellobiose (74.99 +/- 0.78 U/mg), gentiobiose (47.55 +/- 0.15 U/mg), p nitrophenyl-beta-d-cellobioside (pNPC) (40.07 +/- 0.87 U/mg), cellotriose (12.31 +/- 0.36 U/mg) and cellotetraose (9.04 +/- 0.14 U/mg). The kinetic parameters of Km and Vmax were 0.21 +/- 0.01 mM and 147.93 +/- 2.77 MUM/mg/min for pNPG. The purified enzyme showed a heightened ability to convert the major soybean isoflavone glycosides (daidzin, genistin and glycitin) into their corresponding aglycone forms (daidzien, genistein and glycitein). With this activity against soybean isoflavone glycosides, BGL2 shows great potential for applications in the food, animal feed, and pharmaceutical industries. PMID- 26596359 TI - [Comparative study of functional and structural changes produced in a porcine model of acute and chronic heart attack]. AB - INTRODUCTION AND OBJECTIVES: Animal models are a useful tool for the evaluation of disease mechanisms and also for technologies for diagnosis and treatment. In this study we performed a descriptive analysis of the functional and structural cardiac changes occurred as a result of acute coronary occlusion in pigs and its evolution during 5 weeks. METHODS: 19-Large White pigs, weighing 20kg, randomized into 3-experimental series were used. After sternotomy, anterior descending coronary artery was occluded. Duration of occlusion: Series 1 (n=6) 60min; series 2 (n=8) 90min; series 3 (n=5) 60min followed for 5 weeks. The following parameters where then analyzed: global cardiac function (ECG, left ventricular and atrium pressures, aortic flow and cardiac echocardiography), regional contractility, troponin T and CK-MB levels, macroscopic and histological analyzes. RESULTS: Coronary occlusion transiently altered the global cardiac function and produced increased cell damage markers, impaired regional contractility and produced histological changes. The increment of ischemic time (60 vs. 90min) increased infarct size (13.4+/-5.4% vs. 22.9+/-7.8 S1 S2%; P=.04). After 5 weeks, morphological remodelling changes were evident. In 79% of cases ischemia triggered ventricular fibrillation. CONCLUSION: The porcine open chest model of acute myocardial infarction and reperfusion is valid for studying the pathophysiology of coronary ischemia, allows direct analysis of regional myocardial function and is easily retrievable in the event of serious arrhythmias. PMID- 26596360 TI - Clinical relevance of cone beam computed tomography in mandibular third molar removal: A multicentre, randomised, controlled trial. AB - PURPOSE: The aims of this study were to investigate the effectiveness of cone beam computed tomography (CBCT) compared to panoramic radiography (PR), prior to mandibular third molar removal, in reducing patient morbidity, and to identify risk factors associated with inferior alveolar nerve (IAN) injury. MATERIAL AND METHODS: This multicentre, randomised, controlled trial was performed at three centres in the Netherlands. Adults with an increased risk for IAN injury, as diagnosed from PR, were included in the study. In one arm of the study, patients underwent an additional CBCT prior to third molar surgery. In a second arm of the study, no additional radiographs were acquired. The primary outcome measure was the number of patient-reported altered sensations 1 week after surgery. As secondary outcome measures, the number of patients with objective IAN injury, with long-term (>6 months) IAN injury, the occurrence of other postoperative complications, the Oral Health Related Quality of Life-14 (OHIP-14) questionnaire responses, postoperative pain (visual analogue scale score), duration of surgery, number of emergency visits, and number of missed days of work or study were scored. RESULTS: A total of 268 patients with 320 mandibular third molars were analysed according to the intention-to-treat principle. The overall incidence of IAN injury 1 week after surgery was 6.3%. No significant differences between CBCT and PR for temporary IAN injury (p = 0.64) and all other secondary outcomes were registered. A lingual position of the mandibular canal (MC) and narrowing, in which the diameter of the MC lumen was decreased at the contact area between the MC and the roots, were significant risk factors for temporary IAN injury. CONCLUSION: Although CBCT is a valuable diagnostic adjunct for identification of an increased risk for IAN injury, the use of CBCT does not translate into a reduction of IAN injury and other postoperative complications, after removal of the complete mandibular third molar. In these selected cases of a high risk for IAN injury, an alternative strategy, such as monitoring or a coronectomy, might be more appropriate. (http://clinicaltrials.gov, NCT02071030). PMID- 26596361 TI - The feasibility of a custom-made endoprosthesis in mandibular reconstruction: Implant design and finite element analysis. AB - This work studies the feasibility of custom-made endoprosthesis in the reconstruction of major mandibular defects. The natural anatomical and occlusal relations are used to accurately reconstruct a mandibular defect. The customized implant allows the accurate restoration of the facial profile and aesthetics. The biomechanical behaviour of mandibular endoprosthesis was validated with Finite Element Analysis for three masticatory tasks, namely incisal, right molar and left group clenching. The implanted mandible shows displacement fields and stress distributions very similar to the intact mandible. The strain fields observed along the bone-implant interface may promote bone maintenance and ingrowth. The preliminary results show that this implant may be a reliable alternative to other prosthetic mandibular reconstruction approaches. PMID- 26596362 TI - The Dutch Eating Behavior Questionnaire: Further psychometric validation and clinical implications of the French version in normal weight and obese persons. AB - OBJECTIVES: This study tested the psychometric properties of the French version of the Dutch Eating Behavior Questionnaire (DEBQ) for normal weight and obese patients; determined the factors associated with each DEBQ score: emotional eating (eating in response to emotional arousal states such as fear, anger or anxiety), externality (eating in response to external food cues such as sight and smell of food), and restrained eating behavior/cognitive restraint (conscious efforts to limit and control dietary intake); and determined how to interpret the results from this scale to guide clinical practice. METHODS: Between January 2009 and April 2009, we assessed non-paired normal weight persons (n=74) and all consecutive obese patients consulting in the Nutrition Ward of the University Hospital of Tours (n=75; including bariatric surgery patients) using the DEBQ. We tested the scale's factor structure using a factor analysis for ordinal data and internal consistency for each DEBQ dimension. RESULTS: Our results supported a three-factor structure for both normal weight and obese patients. The Cronbach's alpha coefficients were excellent for emotional eating and externality (alpha>=0.90) and good for cognitive restraint (alpha>=0.81). The emotional eating and cognitive restraint scores were higher for women (P<0.001) and obese patients (P<0.05). Higher cognitive restraint was associated with higher current and previous BMI (P<0.01). For patients who had bariatric surgery, higher length of time since surgery was significantly associated with higher externality (rho=0.359; P<=0.05) and marginally associated with higher cognitive restraint (rho=0.294; P=0.10) and higher emotional eating (rho=0.302; P=0.10). CONCLUSIONS: Our results support a three-dimensional factor structure for the French version of the DEBQ for normal weight and obese patients. We propose the chance to change hypothesis to explain results for bariatric surgery patients: patients experience a beneficial but transient decrease in externality, emotionality and cognitive restraint, and this period of time gives the patient a chance for cognitive, behavioral and emotional change. This critical period should be well prepared before surgery to improve the patient's postoperative success, by tackling each factor that could diminish the chances for success as soon as possible (e.g., early screening and treatment for psychiatric disorders). PMID- 26596363 TI - [The keys to success in French Medical National Ranking Examination: Integrated training activities in teaching hospital and medical school]. AB - INTRODUCTION: The National Ranking Examination (NRE) is the key to the choice of career and specialty for future physicians; it lets them choose their place of employment in a specialty and an hospital for their internship. It seems interesting to model the success factors to this exam for the medical students from Grenoble University. METHODS: For each of the medical students at Grenoble University who did apply to the NRE in 2012, data have been collected about their academic background and personal details from the administration of the University. A simple logistic regression with success set as being ranked in the first 2000 students, then a polytomous logistic regression, have been performed. RESULTS: The 191 students in the models are 59% female, 25 years old in average (SD 1.8). The factors associated to a ranking in the first 2000 are: not repeating the PCEM1 class (odds ratio [OR] 2.63, CI95: [1.26; 5.56]), performing nurse practice during internships (OR=1.27 [1.00; 1.62]), being ranked in the first half of the class for S3 pole (OR=6.04 [1.21; 30.20] for the first quarter, OR=5.65 [1.15; 27.74] for the second quarter) and being in the first quarter at T5 pole (OR=3.42 [1.08; 10.82]). CONCLUSION: Our study finds four factors independently contributing to the success at NRE: not repeating PCEM1, performing nurse practice and being ranked in the top of the class at certain academic fields. The AUC is 0.76 and student accuracy is more than 80%. However, some items, for example repeating DCEM4 or participating in NRE mock exams, have no influence on success. A different motivation should be a part of the explanation... As these analysed data are mainly institutional, they are accurate and reliable. The polytomic logistic model, sharing 3 factors with the simple logistic model, replace a performing nurse practice factor's by a grant recipient factor. PMID- 26596364 TI - Clinical features associated with an early onset in chronic tic disorders. AB - In chronic tic disorders such as Tourette syndrome (TS), tics often appear between 4 and 8 years but they can also appear in early childhood, a period in which symptom expression may be affected by early brain development. The present study examined whether symptom expression in early-onset TS was distinct from that observed in TS with a later onset. We compared the clinical characteristics in children with TS who developed tics before age 4 or after age 6. Early-onset TS was significantly associated with an increased rate of stuttering and other speech disfluencies as well as an increased rate of oppositional defiant disorder, symptoms that often appear before age 4. Early-onset TS was also linked to maternal transmission of tics. Early-onset TS was not significantly associated with tic severity, obsessive-compulsive behavior or attention-deficit hyperactivity disorder. The results suggest that an early onset affects symptom expression in tic disorders. PMID- 26596365 TI - Association of age-of-onset groups with GWAS significant schizophrenia and bipolar disorder loci in Romanian bipolar I patients. AB - We investigated the influence of the age-of-onset (AO) on the association of 45 loci conferring risk for bipolar disorder (BP) and schizophrenia with BP-type-I in a Romanian sample (461 patients, 436 controls). The AO-analysis implicated the EGFR gene, as well as loci in other genes, in the AO variation of BP-type-I and revealed for the first time the link between BP-type-I and risk variants considered specific to schizophrenia (polymorphisms in MMP16/RIPK2 and CNNM2 genes). PMID- 26596366 TI - Unique versus cumulative effects of physical and sexual assault on patterns of adolescent substance use. AB - The present study assessed the unique versus cumulative effects of physical and sexual assault, on patterns of substance-use in adolescents. It was hypothesized that experiencing a single assault (physical or sexual) when compared with exposure to both physical and sexual assault would be more strongly related to membership of polysubstance use classes. From the National Survey of Adolescents 1995 (N= 4023) 918 adolescents (age range=12-17 years, M=14.92, 49.6% female) with reports of physical assault and/or sexual assault were selected. Using information on alcohol-use, cigarette-smoking, chewing tobacco, non-prescribed use of medicines, and drug-use, latent class analysis indicated a three class solution for substance-use, namely, Experimental use, Light polysubstance-use, and Polysubstance-use. Multinomial logistic regression analyses indicated that as compared to adolescents exposed to a single type of assault those exposed to both physical and sexual assault were two-to-three times more likely to be in the heavier polysubstance-use class. Females were more likely to be members of the polysubstance-use class than of the experimental use class. Gender did not emerge as a significant moderator. It was concluded that assessing for single type or co occurring assault can facilitate identification of adolescents at elevated risk for polysubstance-use. PMID- 26596367 TI - Alagille syndrome associated with intestinal atresia. PMID- 26596368 TI - [Fulminant hepatitis caused by herpes virus 6 in immunocompetent adults]. PMID- 26596369 TI - Solitary rectal ulcer in a teenage patient. PMID- 26596370 TI - [Vitamin D deficiency in chronic liver disease, clinical-epidemiological analysis and report after vitamin d supplementation]. AB - INTRODUCTION: Vitamin D (VD) is known to have multiple extra-skeletal health functions. There is emerging interest in exploring the relationship between vitamin D and chronic liver disease (CLD). OBJECTIVES: To determine the prevalence of VD deficiency in patients with CLD in our setting and to assess whether VD supplementation influences plasma levels and is associated with improved liver function. MATERIAL AND METHODS: We conducted a study in 2 phases. First, we analysed clinical and epidemiological characteristics in 94 patients with CLD; second, different doses of calcifediol (25-OH-VD) were administered to patients with VD deficiency (<20ng/mL) and insufficiency (20-30ng/mL). Plasma concentrations and liver function (Child-Pugh and MELD) at the end of treatment were compared with baseline data. RESULTS: Deficient or insufficient VD levels were found in 87% of the patients, with an average concentration of 18.8ng/mL. Levels were lower in patients with cirrhosis (15.9ng/mL) (P=.002) and in alcoholic liver disease. VD levels were inversely proportional to the degree of liver function: Child A (16.52ng/mL) vs C (7.75ng/mL). After VD supplementation, optimal serum levels were achieved in 94% of patients and significant improvements were observed in platelet count, albumin levels (P<.05) and functional status assessed by the Child-Pugh scale (P<.05). CONCLUSION: Given the high prevalence of VD deficiency or insufficiency, the need for screening should be considered in the population with CLD. VD supplementation could be safe and effective. PMID- 26596373 TI - Exceptional hexose-fermenting ability of the xylitol-producing yeast Candida guilliermondii FTI 20037. AB - The yeast Candida guilliermondii FTI 20037 is well-known for its ability to produce xylitol from xylose. Recently, this strain was found to produce greater than 5% (w/v) ethanol from glucose. This level of ethanol is typically not exceeded by wild-type strains of other native pentose-fermenting yeasts. This prompted the current study to examine the ability of C. guilliermondii FTI 20037 to utilize and ferment high concentrations of each of the hexoses commonly found in lignocellulosic hydrolysates. In defined media, FTI 20037 fermented 14.4% 25.9% (w/v) of glucose, mannose or galactose individually to ethanol in concentrations ranging from 6% to 9.3% (w/v). Fermentation was completed within 36 h (for glucose) to 100 h (for galactose). In 25.9% (w/v) glucose, FTI 20037 produced 9.3% (w/v) ethanol within 40 h. FTI 20037 produced xylitol exclusively when xylose was given as the sole carbon source. The strain utilized arabinose poorly. Under the same fermentation conditions, an industrial Saccharomyces cerevisiae strain produced slightly higher levels of ethanol [9.9% (w/v)] from 25.0% (w/v) glucose. Another pentose-fermenting yeast Pachysolen tannophilus also fermented high concentrations of glucose and mannose to produce relatively high peak ethanol concentrations; however, this yeast required considerably longer to completely consume these hexoses. The ability of FTI 20037 to produce high level of ethanol rapidly from glucose is remarkable. To our knowledge, this is the first known instance of a non-modified native xylose-fermenting yeast strain able to produce such high levels of ethanol from glucose as rapidly as S. cerevisiae in a defined medium. PMID- 26596371 TI - Update of the human and mouse Fanconi anemia genes. AB - Fanconi anemia (FA) is a recessively inherited disease manifesting developmental abnormalities, bone marrow failure, and increased risk of malignancies. Whereas FA has been studied for nearly 90 years, only in the last 20 years have increasing numbers of genes been implicated in the pathogenesis associated with this genetic disease. To date, 19 genes have been identified that encode Fanconi anemia complementation group proteins, all of which are named or aliased, using the root symbol "FANC." Fanconi anemia subtype (FANC) proteins function in a common DNA repair pathway called "the FA pathway," which is essential for maintaining genomic integrity. The various FANC mutant proteins contribute to distinct steps associated with FA pathogenesis. Herein, we provide a review update of the 19 human FANC and their mouse orthologs, an evolutionary perspective on the FANC genes, and the functional significance of the FA DNA repair pathway in association with clinical disorders. This is an example of a set of genes--known to exist in vertebrates, invertebrates, plants, and yeast- that are grouped together on the basis of shared biochemical and physiological functions, rather than evolutionary phylogeny, and have been named on this basis by the HUGO Gene Nomenclature Committee (HGNC). PMID- 26596372 TI - Negative effects of diabetes-related distress on health-related quality of life: an evaluation among the adult patients with type 2 diabetes mellitus in three primary healthcare clinics in Malaysia. AB - BACKGROUND: Patients with type 2 diabetes mellitus (T2D) often experienced change in life, altered self-esteem and increased feelings of uncertainty about the future that challenge their present existence and their perception of quality of life (QoL). There was a dearth of data on the association between diabetes related distress (DRD) and health-related quality of life (HRQoL). This study examined the determinants of HRQoL, in particular the association between DRD and HRQoL by taking into account the socio-demographic-clinical variables, including depressive symptoms (DS) in adult patients with T2D. METHODS: This cross sectional study was conducted in 2012-2013 in three public health clinics in Malaysia. The World Health Organization Quality of Life-Brief (WHOQOL-BREF), 17 items Diabetes Distress Scale (DDS-17), and 9-items Patient Health Questionnaire (PHQ-9) were used to measure HRQoL, DRD and DS, respectively. The aim of this research was to examine the association between the socio-demographic-clinical variables and HRQoL as well as each of the WHOQOL-BREF domain score using multivariable regression analyses. RESULTS: The response rate was 93.1% (700/752). The mean (SD) for age was 56.9 (10.18). The majority of the patients were female (52.8%), Malay (53.1%) and married (79.1%). About 60% of the patients had good overall HRQoL. The mean (SD) for Overall QoL, Physical QoL, Psychological QoL, Social Relationship QoL and Environmental QoL were 61.7 (9.86), 56.7 (10.64), 57.9 (11.73), 66.8 (15.01) and 65.3 (13.02), respectively. The mean (SD) for the total DDS-17 score was 37.1 (15.98), with 19.6% (136/694) had moderate distress. DDS-17 had a negative association with HRQoL but religiosity had a positive influence on HRQoL (B ranged between 3.07 and 4.76). Women, especially younger Malays, who had diabetes for a shorter period of time experienced better HRQoL. However, patients who were not married, had dyslipidaemia, higher levels of total cholesterol and higher PHQ-9 scores had lower HRQoL. Macrovascular complications showed the largest negative effect on the overall HRQoL (adjusted B = -4.98, 95% CI -8.56 to -1.40). CONCLUSION: The majority of primary care adult with T2D had good overall HRQoL. Furthermore, the independent determinants for HRQoL had also concurred with many past studies. In addition, the researchers found that DRD had negative effects on HRQoL, but religiosity had positive influence on HRQoL. Appropriate support such as primary care is needed for adult patients with T2D to improve their life and their HRQoL. TRIAL REGISTRATION: NMRR-12-1167-14158. PMID- 26596375 TI - Stable isotope method to measure drug release from nanomedicines. AB - Existing methods to measure nanomedicine drug release in biological matrices are inadequate. A novel drug release method utilizing a stable isotope tracer has been developed. Stable isotope-labeled drug is spiked into plasma containing nanomedicine. The labeled drug equilibrates with plasma components identical to the normoisotopic drug released from the nanomedicine formulation. Therefore, the ultrafilterable fraction of the isotope-labeled drug represents a reliable measure of free normoisotopic drug fraction in plasma, and can be used to calculate nanomedicine encapsulated and unencapsulated drug fractions. To demonstrate the utility of this method, we performed a plasma drug release study with both a fast releasing commercial docetaxel formulation, Taxotere(r), and a delayed releasing nanomicellar formulation of a docetaxel prodrug, Procet 8. The instability of the unencapsulated prodrug in plasma allowed us to compare our calculated prodrug release and docetaxel conversion with the actual docetaxel concentration measured directly without fractionation. Drug release estimates for the fast releasing Taxotere formulation demonstrated accuracy deviation and precision (%CV) of <15%. For the controlled release Procet 8 formulation, we calculated a slow release and conversion of the prodrug in rat plasma that was highly correlated with the direct docetaxel measurement (R(2)=0.98). We believe that this method will have tremendous utility in the development and regulatory evaluation of nanomedicines, and aid in determination of generic bioequivalence. PMID- 26596374 TI - Pegvisomant treatment in patients with acromegaly in clinical practice: The French ACROSTUDY. AB - OBJECTIVE: To monitor long-term pegvisomant treatment of patients with acromegaly in routine clinical practice. PATIENTS AND METHODS: The French ACROSTUDY is part of the global ACROSTUDY, an observational post-authorization safety surveillance study of acromegaly treatment with pegvisomant. RESULTS: The median duration of follow-up of the 292 included patients was 5.2 years. Overall 272 (93%) patients received somatostatin analogues before initiation of pegvisomant. The most prescribed initial dose of pegvisomant (after possible administration of a loading dose) was 10mg/day and, starting from the 2nd year, the median dose was 20mg/day. Serum IGF-1 concentration decreased as soon as pegvisomant was started and after 5 years there was a 62% mean decrease in serum IGF-1 concentration. The percentage of patients with serum IGF-1 concentration within normal ranges (for age and sex) of the local laboratory shifted from 11% at start of pegvisomant to 43% at 6 months and 63% after 5 years. The last available imaging (242 patients) showed an increased or decreased tumor size in 4 and 10% of patients, respectively. Mean weight increased by 3 kg over the 5-year period (P<10(-3)). Mean fasting blood glucose significantly decreased over time (P<0.05), while HbA1c level remained unchanged. Tolerance profile was generally good and similar to that described in clinical studies. CONCLUSION: This analysis showed a significant decrease in IGF-1 levels throughout the follow-up period, and confirmed that pegvisomant treatment is safe in acromegaly. The results of this interim analysis remain to be confirmed by the final analysis. PMID- 26596376 TI - Molecular interplay between T-Antigen and splicing factor, arginine/serine-rich 1 (SRSF1) controls JC virus gene expression in glial cells. AB - BACKGROUND: Human polyomavirus JCV is the etiologic agent of progressive multifocal leukoencephalopathy (PML), a fatal demyelinating disease characterized by lytic infection of glial cells in the central nervous system. PML is seen primarily in immunosuppressed patients and is mainly classified as an AIDS defining disease. In addition to structural capsid proteins, JCV encodes multiple regulatory proteins, including T-antigen and agnoprotein, which are required for functional lytic infection. Previous studies have suggested that molecular interaction between viral proteins and host factors play an important role in reactivation of JCV and progression of the viral life cycle in glial cells. Recently, serine/arginine rich splicing factor 1 (SRSF1), a cellular alternative splicing factor, was identified as a strong negative regulator of JCV in glial cells. SRSF1 inhibits JCV gene expression and viral replication by directly interacting with viral promoter sequences. Here, we have investigated possible impact of JCV regulatory proteins, T-antigen and agnoprotein, on SRSF1-mediated suppression of JCV gene expression in glial cells. RESULTS: Reporter gene analysis has suggested that T-antigen rescues viral transcriptional suppression mediated by SRSF1. Further analyses have revealed that T-antigen promotes viral gene expression by suppressing SRSF1 gene transcription in glial cells. A subsequent ChIP analysis revealed that T-antigen associates with the promoter region of SRSF1 to induce the transcriptional suppression. CONCLUSIONS: These findings have revealed a molecular interplay between cellular SRSF1 and viral T antigen in controlling JCV gene expression, and may suggest a novel mechanism of JCV reactivation in patients who are at risk of developing PML. PMID- 26596377 TI - Electrocardiographic changes in adults living in a southern Brazilian city: A population-based study. AB - INTRODUCTION AND OBJECTIVES: Abnormalities on the resting electrocardiogram (ECG) are predictors of mortality and cardiovascular events among asymptomatic adults. The aim of this study was to estimate the prevalence of ECG abnormalities in adults and their association with cardiovascular risk factors. METHODS: We performed a cross-sectional analysis of ECGs in adults aged 19-59 years, living in Tubarao, Santa Catarina, Brazil. Data were collected between November 2011 and July 2012. Electrocardiographic findings were classified according to the guidelines of the Brazilian Society of Cardiology on analyzing and issuing electrocardiographic reports, and were divided into major abnormalities, minor abnormalities and no changes, as in previous studies. Pearson's chi-square test and ANOVA were used to analyze the association of ECG parameters with traditional cardiovascular risk factors. RESULTS: A total of 361 participants were studied. Mean age was 40.4+/-12.2 years; 232 (64.3%) were women. Minor abnormalities were found in 16.9% and major abnormalities in 3.3%. Among the risk factors examined, gender, smoking, alcohol consumption, systemic hypertension, diabetes, and high Framingham risk score were significantly associated with major and minor ECG changes. CONCLUSIONS: The prevalence of electrocardiographic changes was 20.2% in the population surveyed, the majority being minor. Both major and minor electrocardiographic abnormalities showed significant associations with risk of coronary artery disease, and may predict cardiovascular risk in asymptomatic adults. PMID- 26596379 TI - Precision Medicine-The New Reality. PMID- 26596378 TI - Transvenous removal of cardiac implantable electronic device leads. AB - INTRODUCTION AND OBJECTIVE: The number and complexity of cardiac implantable electronic devices (CIEDs) have increased, as has the number of related complications, often leading to removal of the implanted system. The aim of this study was to characterize transvenous explantation/extraction of CIED leads in a reference center. METHODS: This was a descriptive observational study of patients consecutively admitted from January 2009 to May 2014 for transvenous lead extraction. RESULTS: The sample consisted of 109 patients, with a mean age of 64.6+/-16.62 years, 73.1% male. The main indication for lead extraction was CIED infection. The mean time from first implantation to lead removal was 5.6+/-4.89 years. Blood cultures were positive in 32.8% of cases and 29% of patients had vegetations on echocardiography. A total of 228 cardiac leads were removed, of which 58.8% were ventricular, 32.4% atrial and 8.8% coronary sinus. Complete clinical success was achieved in 97.2% of cases, while procedural success was complete in 93.4% and partial in 5.3%. The complications reported were three cases of significant pocket hematoma, one of subclavian vein thrombosis and three of cardiac tamponade, effectively treated by pericardiocentesis. CONCLUSIONS: Transvenous explantion or extraction of CIED leads was highly effective. A high level of experience is an essential factor in the success and safety of the procedure. PMID- 26596380 TI - Tuning in Further to the Patient Experience: Ead H. How tuned in are you to the patient experience? J Perianesth Nurs. 2015;30(3):236-238. doi:10.1016/j.jopan.2015.03.003. PMID- 26596381 TI - Predicting Preoperative Hemodynamic Changes Using the Visual Analog Scale. AB - PURPOSE: This study aimed to investigate how both visual analog scale cutoff scores and State-Trait Anxiety Inventory scores relate to hemodynamic changes in patients entering the operating theater. DESIGN: A prospective observational study. METHODS: The study subjects included 130 prospectively enrolled patients who were scheduled for abdominal surgery under combined epidural-general anesthesia and who underwent preoperative anxiety level measurements using both scales. FINDINGS: The heart rate and systolic blood pressure on entering the operating theater were significantly higher than those at baseline in the high and low/moderate anxiety groups. Variations in heart rate and systolic blood pressure were significantly higher, whereas peripheral blood flow was significantly lower in the high anxiety group compared with the low/moderate anxiety group. CONCLUSIONS: Using the visual analog scale to measure anxiety can improve our understanding of the hemodynamic changes that occur when patients enter the operating theater. PMID- 26596382 TI - Swedish Nurse Anesthetists' Experiences of the WHO Surgical Safety Checklist. AB - PURPOSE: The World Health Organization (WHO) surgical safety checklist aims to increase communication, build teamwork, and standardize routines in clinical practice in an effort to reduce complications and improve patient safety. The checklist has been implemented in surgical departments both nationally and internationally. The purpose of this study was to describe the registered nurse anesthetists' (RNA) experience with the use of the WHO surgical safety checklist. DESIGN: This was a cross-sectional study with a descriptive mixed methods design, involving nurse anesthetists from two different hospitals in Sweden. METHODS: Data were collected using a study-specific questionnaire. FINDINGS: Forty-seven RNAs answered the questionnaire. There was a statistically significant lower compliance to "Sign-in" compared with the other two parts, "Timeout" and "Sign out." The RNAs expressed that the checklist was very important for anesthetic and perioperative care. They also expressed that by confirming their own area of expertise, they achieved an increased sense of being a team member. Thirty-four percent believed that the surgeon was responsible for the checklist, yet this was not the reality in clinical practice. Although 23% reported that they initiated use of the checklist, only one RNA believed that it was the responsibility of the RNA. Forty-three percent had received training about the checklist and its use. CONCLUSION: The WHO surgical checklist facilitates the nurse anesthetist's anesthetic and perioperative care. It allows the nurse anesthetist to better identify each patient's specific concerns and have an increased sense of being a team member. PMID- 26596383 TI - Bridging Protocol for Surgical Patients: One Clinic's Experience Facilitating a Safe Anticoagulation Intervention. AB - Surgical candidates often present with complex medical histories that necessitate an individualized approach to care to minimize surgical and anesthetic risk. Patients on warfarin require exceptionally careful clinical assessment, consideration, and consistency to reduce the risk of perioperative thromboembolism and bleeding complications. In response to this need, Victoria General Hospital in Winnipeg, Manitoba, Canada developed a bridging protocol based on evidence-based guidelines and a checklist tool to incorporate and communicate the necessary tasks among the interprofessional team. The purpose of this initiative was to create a patient-focused process to assist those at risk for a thromboembolic event to navigate through a clear, consistent, and collaborative surgical experience whenever cessation and resumption of warfarin administration was required. PMID- 26596384 TI - First Peripherally Inserted Central Catheter Under Ultrasound Guidance in a Greek Intensive Care Unit: A New Role for Greek Perianesthesia Nurses. AB - We present a case of a 67-year-old Caucasian female who was admitted to the pulmonary clinic of a general hospital in Athens with fever and respiratory symptoms. A lung biopsy was ordered because a clinical diagnosis of interstitial lung disease was suspected. The patient was then hospitalized in the intensive care unit. Because of the fact that peripheral catheterization was impossible and the prospect of further long-term hospitalization, the patient was referred to a vascular access nursing team composed of perianesthesia nurses to advance a peripherally inserted central catheter and support the line during treatment. The peripherally inserted central catheter line was advanced with no complications, and the position of the catheter was checked using the electrocardiography method. PMID- 26596385 TI - Examining the Relationship Among Ambulatory Surgical Settings Work Environment, Nurses' Characteristics, and Medication Errors Reporting. AB - PURPOSE: To describe work environment characteristics (leadership style and safety climate) of ambulatory surgical settings and to examine the relationship between work environment and nurses' willingness to report medication errors in ambulatory surgical settings. DESIGN: Descriptive correlational design using survey methodology. METHODS: The sample of this study consisted of 40 unit-based registered nurses, working as full time, part time, or as needed in four ambulatory surgical settings affiliated with one health care system located in Northeast Ohio. FINDINGS: The results of two separate regression analyses, one with three nurse manager's leadership styles and another with five safety climate dimensions as independent variables, explained 44% and 50%, respectively, on variance of nurses' willingness to report medication errors. CONCLUSION: To increase nurses' willingness to report medication errors, ambulatory surgical settings administrators should invest in nurse manager leadership training programs and focus on enhancing safety climate aspects, particularly errors feedback and organizational learning. PMID- 26596386 TI - Change Fatigue in Health Care Professionals--An Issue of Workload or Human Factors Engineering? AB - In the demanding and fast-paced world of health care, it is not uncommon for nurses and other health care professionals to have days where they are pushed to their limits. Despite these pressures, each year, new initiatives and practice recommendations are shared within organizations that the nurses must learn, embrace, and include in their practice. Each new initiative can be additive to the nurse's workload; most changes are not time neutral but require staff to expend an allotment of time from their day to complete. In our efforts to adopt new recommendations, is it realistic or possible to add on to workload and stretched resources in an ongoing manner? The following article provides an overview of how issues such as change fatigue and increased workload need to be addressed. Through use of workload measurement tools and guidance by the principles of human factors engineering, we can better support the provision of optimal patient care in a demanding environment. PMID- 26596387 TI - Pathophysiology and Prevention of Intraoperative Atelectasis: A Review of the Literature. AB - Atelectasis is a common problem in the perioperative setting, affecting a significant number of surgical patients receiving general anesthesia. Absorption, compression, and reduced surfactant are the three mechanisms implicated in the etiology of atelectasis. Interventions designed to minimize the risk of intraoperative atelectasis such as positioning, positive end-expiratory pressure, and administration of the least amount of fraction of inspired oxygen can be used to maintain patency of small airways and ultimately improve gas exchange in the surgical patient. PMID- 26596388 TI - Obstructive Sleep Apnea and the Adult Perioperative Patient. AB - Obstructive sleep apnea (OSA) is a chronic condition of upper airway obstruction during sleep. It is associated with significant morbidity and mortality and increases the perioperative risks of surgical patients. Thus, it is essential that perianesthesia nurses understand how to identify and manage patients with known or suspected OSA. This continuing education article will review the pathophysiology of OSA, discuss the effects of anesthesia and opioids on the sleep architecture of the OSA patients, describe the effects of OSA on postoperative complications, review the latest evidence on screening for undiagnosed OSA in the adult surgical patient, and review the perioperative management principles for patients with OSA. PMID- 26596389 TI - Taking Care of the Caregiver: Compassion Satisfaction and Compassion Fatigue. PMID- 26596390 TI - The Leader As Coach. AB - As a leader, you naturally influence other people. One of the most common ways you impact others is by being involved in their growth and improvement. We value people who have helped us grow and develop, and we are appreciated when we do the same in return. PMID- 26596392 TI - The Culture of Collaboration. PMID- 26596391 TI - Safety Culture--Just What Is It? PMID- 26596393 TI - Antifibrinolytic Use in the Perioperative Setting: Aminocaproic Acid and Tranexamic Acid. PMID- 26596394 TI - Endobronchial Procedures. PMID- 26596395 TI - Sleep-Disordered Breathing--Not Just for Grownups Anymore. AB - Previous research on SDB in children has focus edprimarily on OSA, whereas there is an increasing body of evidence to suggest that children with a spectrum of SDB symptoms may be at risk for perioperative and postoperative adverse events. To this end, it is imperative that these children are identified before surgery so that anesthesia and postoperative pain management plans can be optimized to mitigate risk. Although PSG remains the gold standard as a means to screen for SDB preoperatively,there are now clinically valid tools that can be used as part of the preanesthetic interview to identify children at risk. However, although recent work suggests that implementation of such screening tools may be important in identifying at-risk children and reducing perioperative adverse events through changes in anesthetic management, there is still much to be done with respect to changing the culture of standard postoperative opioid dosing. Perianesthesia nurses are thus in a unique position to help encourage a culture in which SDB in children is recognized asa significant risk for both perioperative and potentially deadly postoperative sequelae. PMID- 26596396 TI - "Knowing" as the Foundation of Clinical Competence. PMID- 26596397 TI - Results of Deep Anterior Lamellar Keratoplasty for Advanced Keratoconus in Children Less Than 18 Years. AB - PURPOSE: To evaluate the outcomes of deep anterior lamellar keratoplasty (DALK) in children with advanced keratoconus. DESIGN: Retrospective noncomparative interventional case series. METHODS: A retrospective analysis was conducted of 20 eyes of 16 patients who underwent deep anterior lamellar keratoplasty at a tertiary eye care center for advanced keratoconus. The main preoperative parameters measured were decimal uncorrected visual acuity (UCVA), decimal best corrected visual acuity (BCVA), and average keratometry. The average keratometry was taken as an average of the flat and steep keratometric readings. The follow up ranged from 24 to 105 months. The main outcome measures were UCVA, BCVA, steep and flat simulated keratometry, refraction, graft clarity, and complications. RESULTS: At the final follow-up, 18 patients had clear grafts in the visual axis area. Mean decimal UCVA changed from 0.06 +/- 0.08 to 0.24 +/- 0.09. Mean decimal BCVA changed from 0.12 +/- 0.19 to 0.45 +/- 0.24. The average keratometry decreased from 64.15 diopter (D) to 45.7 D after surgery. The complications noted in the patients were graft rejection (1), shield ulcers (2), graft infection (2), and interface vascularization (4). They were managed accordingly and only 1 patient needed penetrating keratoplasty. CONCLUSIONS: DALK is an effective therapeutic modality for the management of advanced keratoconus in children. PMID- 26596399 TI - Independent Prognostic Significance of Gene Expression Profile Class and Largest Basal Diameter of Posterior Uveal Melanomas. AB - PURPOSE: To determine whether any conventional clinical prognostic factors for metastasis from uveal melanoma retain prognostic significance in multivariate models incorporating gene expression profile (GEP) class of the tumor cells. DESIGN: Prospective, interventional case series with a prognostic model. METHODS: Single-institution study of GEP testing and other conventional prognostic factors for metastasis and metastatic death in 299 patients with posterior uveal melanoma evaluated by fine-needle aspiration biopsy (FNAB) at the time of or shortly prior to initial treatment. Univariate prognostic significance of all evaluated potential prognostic variables (patient age, largest linear basal diameter of tumor [LBD], tumor thickness, intraocular location of tumor, melanoma cytomorphologic subtype, and GEP class) was performed by comparison of Kaplan Meier event rate curves and univariate Cox proportional hazards modeling. Multivariate prognostic significance of combinations of significant prognostic factors identified by univariate analysis was performed using step-up and step down Cox proportional hazards modeling. RESULTS: GEP class was the strongest prognostic factor for metastatic death in this series. However, tumor LBD, tumor thickness, and intraocular tumor location also proved to be significant individual prognostic factors in this study. On multivariate analysis, a 2-term model that incorporated GEP class and largest basal diameter was associated with strong independent significance of each of the factors. CONCLUSION: Although GEP test is the most robust prognostic indicator in uveal melanoma and early studies of mostly larger tumors found that no clinicopathologic factors had significant prognostic value independent of GEP, our single-center study, which included a substantial proportion of smaller tumors, showed that both GEP and LBD of the tumor are independent prognostic factors for metastasis and metastatic death in multivariate analysis. PMID- 26596398 TI - Variation in Number of Doses, Bottle Volume, and Calculated Yearly Cost of Generic and Branded Latanoprost for Glaucoma. AB - PURPOSE: To evaluate discrepancies in doses per bottle, bottle fill volume, and cost among branded and generic formulations of latanoprost. DESIGN: Comparative economic analysis. METHODS: This study was conducted at the Ruiz Department of Ophthalmology and Visual Science at The University of Texas Health Science Center at Houston (UTHealth). Four regionally available latanoprost formulations were measured. Number of drops per bottle and actual bottle fill volume were measured for a calculated sample size (10 bottles). Annual cost (using average wholesale price), days use per bottle, drops per milliliter, and number of bottles used per year were calculated. Data were summarized using mean and standard deviation; 1 way analysis of variance and post hoc Tukey's studentized range test were used for comparing means among manufacturers. RESULTS: Pfizer's branded lantanoprost, Xalatan (New York, New York, USA), had the largest fill volume (P < .001). Pfizer had the highest yearly cost at $1198 (P < .001), whereas Akorn (Lake Forest, Illinois, USA) and Bausch & Lomb (Rochester, New York, USA) had the lowest ($184 and $201, respectively). Pfizer and Bausch & Lomb had the most drops per bottle (87.3 and 88.7, respectively), which was statistically more (P < .001) than either Akorn or Sandoz (Princeton, New Jersey, USA) (77.6 and 76.6, respectively), but there was no statistical difference among the standard deviation of drops per bottle (Levene 0.14). CONCLUSIONS: Annual cost and number of doses per bottle, factors important to patients, vary significantly depending on the manufacturer of latanoprost. Practitioners can better advise patients by being aware of these differences. PMID- 26596400 TI - Postoperative Complications in the Ahmed Baerveldt Comparison Study During Five Years of Follow-up. AB - PURPOSE: To compare the late complications in the Ahmed Baerveldt Comparison Study during 5 years of follow-up. DESIGN: Multicenter, prospective randomized clinical trial. METHODS: setting: Sixteen international clinical centers. STUDY POPULATION: Two hundred seventy-six subjects aged 18-85 years with previous intraocular surgery or refractory glaucoma with intraocular pressure of >18 mm Hg. INTERVENTIONS: Ahmed Glaucoma Valve FP7 or Baerveldt Glaucoma Implant BG 101 350. MAIN OUTCOME MEASURES: Late postoperative complications (beyond 3 months), reoperations for complications, and decreased vision from complications. RESULTS: Late complications developed in 56 subjects (46.8 +/- 4.8 5-year cumulative % +/- SE) in the Ahmed Glaucoma Valve group and 67 (56.3 +/- 4.7 5-year cumulative % +/ SE) in the Baerveldt Glaucoma Implant group (P = .082). The cumulative rates of serious complications were 15.9% and 24.7% in the Ahmed Glaucoma Valve and Baerveldt Glaucoma Implant groups, respectively (P = .034), although this was largely driven by subjects who had tube occlusions in the 2 groups (0.8% in the Ahmed Glaucoma Valve group and 5.7% in the Baerveldt Glaucoma Implant group, P = .037). Both groups had a relatively high incidence of persistent diplopia (12%) and corneal edema (20%), although half of the corneal edema cases were likely due to pre-existing causes other than the aqueous shunt. The incidence of tube erosion was 1% and 3% in the Ahmed Glaucoma Valve and Baerveldt Glaucoma Implant groups, respectively (P = .04). CONCLUSIONS: Long-term rates of vision threatening complications and complications resulting in reoperation were higher in the Baerveldt Glaucoma Implant than in the Ahmed Glaucoma Valve group over 5 years of follow-up. PMID- 26596401 TI - Clinical significance of blood supply to the internal capsule and basal ganglia. AB - Although the general vascular supply of the basal ganglia and internal capsule is well known, precise data are lacking regarding the variations of the vascular territories in the two regions. Twelve hemispheres were studied following an injection of coloured ink into the main cerebral arteries, namely the anterior cerebral (ACA), middle cerebral (MCA), anterior choroidal (AChA) and posterior cerebral artery (PCA). Serial sections of the injected hemispheres were taken in the axial or coronal plane. In 75% of the hemispheres, ACA perforators were seen to supply the inferomedial part of the head of the caudate nucleus and the anterior limb of the internal capsule, as well as the anterior and inferior portions of the putamen and globus pallidus. The MCA vessels perfused the superolateral part of the head and body of the caudate nucleus, the superior part of the entire internal capsule, most of the putamen and part of the globus pallidus. The AChA perforators perfused the medial segment of the globus pallidus, the inferior part of the posterior limb, the retrolenticular and sublenticular portions of the internal capsule, and occasionally its genu. The same segment of the globus pallidus and the inferior part of the genu of the internal capsule were most likely supplied by the perforators of the internal carotid artery. A predominance of ACA territory was noticed in one specimen (8.33%) and a predominance of MCA territory in two specimens (16.67%). The obtained anatomical data may help radiologic determination of perforators involved in ischemic events, as well as a better understanding of the neurological deficits in the same events. PMID- 26596402 TI - Intraoperative real-time MRI-guided stereotactic biopsy followed by laser thermal ablation for progressive brain metastases after radiosurgery. AB - Stereotactic radiosurgery is one of the treatment options for brain metastases. However, there are patients who will progress after radiosurgery. One of the potential treatments for this subset of patients is laser ablation. Image-guided stereotactic biopsy is important to determine the histopathological nature of the lesion. However, this is usually based on preoperative, static images, which may affect the target accuracy during the actual procedure as a result of brain shift. We therefore performed real-time intraoperative MRI-guided stereotactic aspiration and biopsies on two patients with symptomatic, progressive lesions after radiosurgery followed immediately by laser ablation. The patients tolerated the procedure well with no new neurologic deficits. Intraoperative MRI-guided stereotactic biopsy followed by laser ablation is safe and accurate, providing real-time updates and feedback during the procedure. PMID- 26596403 TI - Impaired mitochondrial degradation by autophagy in the skeletal muscle of the aged female interleukin 10 null mouse. AB - Mitochondrial dysfunction, chronic inflammation and muscle aging are closely linked. Mitochondrial clearance is a process to dampen inflammation and is a critical pre-requisite to mitobiogenesis. The combined effect of aging and chronic inflammation on mitochondrial degradation by autophagy is understudied. In interleukin 10 null mouse (IL-10(tm/tm)), a rodent model of chronic inflammation, we studied the effects of aging and inflammation on mitochondrial clearance. We show that aging in IL-10(tm/tm) is associated with reduced skeletal muscle mitochondrial death signaling and altered formation of autophagosomes, compared to age-matched C57BL/6 controls. Moreover, skeletal muscles of old IL 10(tm/tm) mice have the highest levels of damaged mitochondria with disrupted mitochondrial ultrastructure and autophagosomes compared to all other groups. These observations highlight the interface between chronic inflammation and aging on altered mitochondrial biology in skeletal muscles. PMID- 26596404 TI - Ischemia triggered ATP release through Pannexin-1 channel by myocardial cells activates sympathetic fibers. AB - The cardiovascular system is extensively innervated by the autonomic nervous system, and the autonomic modulation including sympathetic innervation is crucial to the function of heart during normal and ischemic conditions. Severe myocardial ischemia could cause acute myocardial infarction, which is one of the leading diseases in the world. Thus studying the sympathetic modulation during ischemia could reduce the probability of myocardial infarction and further heart failure. The neurotransmitter ATP is released by myocardial cells during ischemia; however, the effect of ATP release remains elusive. We examined whether ATP released during ischemia functions as a neurotransmitter that activates sympathetic nerve in the heart. A novel technique of recording the sympathetic fiber calcium imaging in mouse cardiac tissue slices was used. We have applied the Cre/loxP system to specifically express GCaMP3, a genetically encoded calcium indicator, in the sympathetic nerve. Using this technique, we found that ATP released by myocardial cells through Pannexin-1 channel during ischemia could evoke calcium responses in cardiac sympathetic nerve fibers. Our study provides a new approach to study the cell and nerve interaction in the cardiac system, as well as a new understanding of ATP function during ischemia. PMID- 26596405 TI - Initiating an online asthma management program in urban emergency departments: the recruitment experience. AB - BACKGROUND: The emergency department could represent a means of identifying patients with asthma who could benefit from asthma interventions. OBJECTIVE: To assess the initiation of a Web-based tailored asthma intervention in the emergency department of 2 urban tertiary care hospitals. METHODS: In addition to awareness strategies for emergency department staff (eg, attending nursing huddles, division meetings, etc), recruitment experiences are described for 2 strategies: (1) recruitment during an emergency department visit for acute asthma and (2) recruitment from patient listings (mail or telephone). Patient enrollment was defined as baseline completion, randomization, and completion of the first of 4 online sessions. RESULTS: Of 499 eligible patients 13 to 19 years old visiting the emergency department for asthma during the study period, 313 (63%) were contacted in the emergency department (n = 65) or by mail or telephone (n = 350). Of these, 121 (38.6%) were randomized. Mean age of the study sample was 15.4 years and 88.4% were African American. Refusal rates for emergency department recruitment and mail or telephone were 18.5% (12 of 65) and 16.6% (58 of 350), respectively. On average, emergency department enrollment took 44 to 67 minutes, including downtime. When surveyed, emergency department providers were more positive about awareness activities and emergency department recruitment than were research staff. CONCLUSION: Emergency department recruitment was feasible but labor intensive. Refusal rates were similar for the 2 strategies. Targeting patients with acute asthma in the emergency department is one way of connecting with youth at risk of future acute events. PMID- 26596406 TI - Dynamic airway collapse: a frequently misdiagnosed asthma mimicker. PMID- 26596407 TI - Hidden allergens: a challenge for allergists. PMID- 26596408 TI - Persistence of treatment with 5-grass pollen tablets in patients with allergic rhinitis: a real-life study. AB - BACKGROUND: In patients with allergic rhinitis, treatment adherence to allergen immunotherapy varies greatly in randomized and real-life studies. OBJECTIVE: To evaluate the use of a 5-grass pollen tablet as sublingual immunotherapy, its treatment persistence, and the reasons for discontinuation in a real-life clinical setting. METHODS: This multicenter, prospective, open-label, noncontrolled observational study evaluated the use of sublingual immunotherapy with a 5-grass pollen tablet in a cross-sectional population of patients (>=5 years old) with grass pollen-induced allergic rhinitis with or without asthma. The primary objective was to determine the percentage of patients persisting with treatment across 1 season in a pre-co-seasonal scheme. Secondary objectives included evaluation of reasons for treatment discontinuation, safety and adverse events; effectiveness (based on physician and patient assessments), and treatment compliance. RESULTS: The study included 196 patients (49.2% male, mean age 27.5 years, range 5.3-65.7 years), with treatment provided by 47 participating physicians. Sixty-seven percent of patients had polysensitivity and 32% had coexistent asthma. On average, patients were treated for 7 months with the 5 grass pollen tablet. After 1 month, 85% of all patients persisted with treatment, and 70% persisted after 7 months. Treatment discontinuation was due chiefly to known side effects (mild to moderate local allergic reactions). Most patients reported symptom improvement; 80% of all patients intended to continue treatment next season. CONCLUSION: Most patients with allergic rhinitis treated pre-co seasonally with a 5-grass pollen tablet persisted with treatment after the first pollen season. Patients were willing to continue their treatment in the following season owing to improvement of symptoms. PMID- 26596409 TI - Penicillin skin testing is a safe method to guide beta-lactam administration in the intensive care unit. PMID- 26596410 TI - Is the post-transplant survival the unique Holy Grail? PMID- 26596411 TI - Iron metabolism and related genetic diseases: A cleared land, keeping mysteries. AB - Body iron has a very close relationship with the liver. Physiologically, the liver synthesizes transferrin, in charge of blood iron transport; ceruloplasmin, acting through its ferroxidase activity; and hepcidin, the master regulator of systemic iron. It also stores iron inside ferritin and serves as an iron reservoir, both protecting the cell from free iron toxicity and ensuring iron delivery to the body whenever needed. The liver is first in line for receiving iron from the gut and the spleen, and is, therefore, highly exposed to iron overload when plasma iron is in excess, especially through its high affinity for plasma non-transferrin bound iron. The liver is strongly involved when iron excess is related either to hepcidin deficiency, as in HFE, hemojuvelin, hepcidin, and transferrin receptor 2 related haemochromatosis, or to hepcidin resistance, as in type B ferroportin disease. It is less involved in the usual (type A) form of ferroportin disease which targets primarily the macrophagic system. Hereditary aceruloplasminemia raises important pathophysiological issues in light of its peculiar organ iron distribution. PMID- 26596412 TI - Wnt5a, Ryk and Ror2 expression in glioblastoma subgroups. AB - BACKGROUND: Wnt5a, a non-canonical Wnt ligand, has been shown to play tumor promoting or tumor-suppressive roles in different neoplasms. Increased Wnt5a expression and Wnt5a-dependent invasive activity that is mediated by one of its receptors, Ryk, have been reported in glioblastomas. METHODS: We investigated the protein expression of Wnt5a, its receptors Ryk and Ror2, and the canonical Wnt pathway marker beta-catenin in 186 cases of glioblastoma and its variants. Associations with clinicopathological and molecular variables and prognosis were analyzed. RESULTS: All glioblastoma cases expressed Wnt5a, Ryk and Ror2 with a different grade. The expression of both Ryk and Ror2 correlated with that of Wnt5a in glioblastomas. The expression of beta-catenin did not correlate with any of Wnt5a, Ryk or Ror2. Wnt5a expression was significantly different among subgroups of the glioblastoma. However, none of Wnt5a, Ryk or Ror2 had a prognostic impact on glioblastoma. For beta-catenin, a shorter progression-free survival was noted in the glioblastoma with oligodendroglioma component (GBMO) subgroup. CONCLUSIONS: Our results corroborated previous findings of Ryk-mediated Wnt5a effect, and suggested a role for Ror2 in the Wnt5a machinery in glioblastoma. PMID- 26596414 TI - Analysis of biomechanical properties of patellar ligament graft and quadruple hamstring tendon graft. AB - INTRODUCTION: Two types of transplant are commonly used in the surgical management of anterior cruciate ligament lesions: the central part of the patellar ligament and quadruple tendons of the gracilis muscle and semitendinosus muscle. AIMS: The aim of this study was to determine the biomechanical characteristics of patellar ligament transplants and transplants of the quadruple tendons of the hamstring muscles under tensile force in the laboratory, and to compare the results in each group of samples. MATERIALS AND METHODS: The study comprised 160 specimens: 40 specimens of gracilis muscle tendons, 40 of semitendinosus muscle tendons, 40 of quadruple tendons and 40 of the patellar ligament, approximately equally distributed according to sex, age (50-70 years) and the side of the body from which the specimen had been taken. RESULTS: The working curve analysis of the specimens under tensile load of a maximum force of 30N showed the least elongation (0.31%) in the quadruple tendon, followed by the gracilis muscle tendon (1.48%) and patellar ligament tendon (3.91%). CONCLUSIONS: The quadruple tendon specimen showed greater strength and higher elasticity compared with the patellar ligament specimen, which proved the starting hypothesis. PMID- 26596413 TI - Volume overload induces autophagic degradation of procollagen in cardiac fibroblasts. AB - In a pure volume overloaded (VO) heart, interstitial collagen loss is degraded by matrix metalloproteinases (MMPs) that leads to left ventricular (LV) dilatation and heart failure. Cardiac fibroblasts are the primary source of extracellular matrix proteins that connect cardiomyocytes. The goal of this study was to determine how VO affects intracellular procollagen in cardiac fibroblasts. Using the aortocaval fistula (ACF) model in Sprague-Dawley rats, we demonstrate that cardiac fibroblasts isolated from 4 and 12 wk ACF animals have decreased intracellular procollagen I compared to the fibroblasts from age-matched shams. The reduction of procollagen I is associated with increased autophagy as demonstrated by increased autophagic vacuoles and LC3-II expression. To test the relationship between autophagy and procollagen degradation, we treated adult cardiac fibroblasts with either an autophagy inducer, rapamycin, or an inhibitor, wortmannin, and found that procollagen I protein levels were decreased in fibroblasts treated with rapamycin and elevated in wortmannin-treated cells. In addition, we demonstrated that VO induces oxidative stresses in cardiac fibroblasts from 4 and 12 wk ACF rats. Treatment of cultured cardiac fibroblasts with an oxidative stress-inducing agent (DMNQ) induces autophagy and intracellular procollagen I and fibronectin degradation, which is reversed by wortmannin but not by the global MMP inhibitor (PD166793). Mechanical stretch of cardiac fibroblasts also induces oxidative stress and autophagic degradation of procollagen I and fibronectin. Our results suggest that in addition to the well known effects of MMPs on extracellular collagen degradation in VO, there is a concurrent degradation of intracellular procollagen and fibronectin mediated by oxidative stress-induced autophagy in cardiac fibroblasts. PMID- 26596415 TI - Thermal changes during healing of distal radius fractures-Preliminary findings. AB - INTRODUCTION: The bone healing process is very complex. In simple terms, bone healing comprises three basic steps, the inflammation phase, the repair phase and the remodelling phase. The increase in blood flow around the fracture during the healing process increases the temperature of the surrounding tissue. Infrared thermography is a method of measuring body temperature that can detect temperature changes during bone healing. Studies on the application of thermography in traumatology are scarce, and there are no studies of thermal changes during normal bone healing. The authors have tried to determine the dynamics of thermal changes during bone healing. MATERIAL AND METHODS: The Flir ThermaCam B2 (FLIR Systems, Inc., Oregon, USA) was used for all measurements. Thermographic recordings were made one, three, five, 11 and 23 weeks after fracture. The contralateral, healthy, forearm was used for comparison. RESULTS: A total of 25 patients of mean age 65.9+/-10.4 years (range 50-80 years) with fracture of the distal radius were examined in this study. The mean temperature difference between healthy and fractured distal forearm one week after fracture was 1.20+/-0.48 degrees C, three weeks after fracture was 1.42+/-0.54 degrees C, five weeks after fracture was 1.04+/-0.53 degrees C, 11 weeks after fracture was 0.50+/-0.30 degrees C, and 23 weeks after fracture was 0.22+/-0.25 degrees C. CONCLUSION: Preliminary findings during this research showed significant temperature changes during healing of distal radius fractures. Infrared thermography is a simple and reliable method in clinical practice that could be used as a good follow-up method in traumatology, but further investigations on more patients are needed. PMID- 26596416 TI - Training effect of using Touch Surgery for intramedullary femoral nailing. AB - BACKGROUND: Simulation in orthopaedic training is becoming increasingly popular and has been widely used in formal curricula. However, these resources are expensive and not easily accessible to every trainee. Other means of disseminating surgical education through virtual reality (VR) multimedia can act as useful adjunct to traditional methods of teaching. One validated VR platform is Touch Surgery, a cognitive task simulation and rehearsal app. OBJECTIVES: The primary objective of this study was to identify the training effect of Touch Surgery intramedullary femoral nailing (IFN) modules using objective performance metrics over six consecutive attempts. Secondary objectives consisted of validated multiple choice questions (MCQ) testing before the first (pre) and after the sixth (post) attempts. METHODS: 27 medical undergraduates were recruited to complete the decision-making process six consecutive times for four modules on the procedural steps of IFN. The modules consisted of (i) preparing the patient and equipment, (ii) femoral canal preparation, (iii) nail insertion and proximal locking, and (iv) distal locking and closure. Real-time objective performance metrics were obtained, stored electronically and analysed using the median and Bonett-Price 95% confidence intervals from the participants' attempts to assess training effect. Significance was calculated using the Mann-Whitney U test for independent data whilst the Wilcoxon signed ranked test was used for paired data. Significance was set as 2-tailed p-value <0.05. RESULTS: Median performance scores per attempt for all four modules demonstrated a significant improvement ranging from 58 to 115%. Scoring variability and distribution was reduced and more predictable per attempt. Logarithmic learning curves elicited strong positive correlations between the number of attempts and scoring. Mean scores for pre and post-study MCQs tests significantly improved from 83 to 94% in all modules. CONCLUSION: IFN modules on Touch Surgery app demonstrated a significant training effect with practice. Novices demonstrated cognitive competencies to ensure patient safety prior to operating. The app is an effective adjunct to traditional learning methods and has the potential for curricular implementation. PMID- 26596417 TI - Nail patella syndrome: Knee symptoms and surgical outcomes. A questionnaire-based survey. AB - BACKGROUND: Patellofemoral instability and dysfunction are frequent symptoms in Nail patella syndrome (NPS). In this article, the first large series of NPS patients is presented in which these knee symptoms were assessed using validated outcome scores. Additionally, the need for surgical interventions, percentage of patients who received surgical treatment and patient reported outcomes are reported. METHODS: A questionnaire based survey was conducted in 139 Dutch NPS patients. Symptoms of the knees were assessed by the Knee injury and Osteoarthritis Outcome Score (KOOS) and Kujala knee score. The questionnaire addressed whether surgical intervention was currently considered, history of past surgeries, type of surgical procedures performed and results of these procedures. RESULTS: Response rate was 74%. Mean KOOS (73.04) and Kujala (74.01) scores showed a wide range and variability between patients. Patellofemoral instability was present in 48.5% of patients. Surgical intervention was currently considered by 12% of patients. Their KOOS and Kujala scores were significantly lower compared to those not considering surgery and they experienced more patellar instability. Surgery was performed on 31 knees in 23 patients. KOOS and Kujala scores were lower in surgically treated versus nonoperated patients but no difference in patellar instability was present. An improvement in pain in 87% and in function in 30% of knees was reported after surgery. Patient satisfaction with the surgical results was 61% and 10% was dissatisfied. Patellar realignment procedures showed similar results, although persistent patellar instability was reported in 40% of patients, not different from nonoperated patients. CONCLUSIONS: Knee symptoms in NPS patients vary widely, with patellar instability present in nearly half of the patients. Although surgical treatment appears unfavourable as surgically treated patients have lower KOOS and Kujala scores, the patient reported surgical results are generally good with a high patient satisfaction. LEVEL OF EVIDENCE: Level IV. PMID- 26596418 TI - Opening-wedge high tibial osteotomy with a secure bone allograft (OsteopureTM) and locked plate fixation: Retrospective clinical and radiological evaluation of 69 knees after 7.5years follow-up. AB - BACKGROUND: Medial opening-wedge high tibial osteotomy (OWHTO) provides reliable and long-lasting benefits, despite the wide range of wedge-filling and internal fixation techniques used. The purpose of this work was to assess the clinical and radiological outcomes in a case-series of OWHTO performed using a secure bone allograft and locked plate fixation. HYPOTHESIS: The clinical and radiological outcomes of OWHTO with a high-safety bone allograft and locked plate fixation are similar to those reported in previous case-series studies. MATERIALS AND METHODS: A single-centre retrospective design was used to study 69 knees in 64 patients with a mean age of 51.8years (31-53years) and a preoperative hip-knee-ankle (HKA) angle of 173 degrees (165 degrees -180 degrees ). The wedge was filled with secure OsteopureTM bone allograft and fixation was achieved using an Integra Surfix((r)) locked plate. Mean follow-up was 7.5years (5-9.3years). Clinical and functional outcomes were assessed by determining the IKS and KOOS-PS scores and recording complications related or unrelated to the allograft. The main criterion for assessing OWHTO survival was the time to revision surgery for symptom recurrence. Radiological assessment criteria were the HKA angle, tibial slope, patellar height, and osteoarthritis grade. GESTO criteria were used to evaluate the behaviour of the allograft. RESULTS: Of the 69 knees, 64 (92.8%) were re evaluated. The survival rate after 9.3years was 95%+/-2.7% (3 failures managed with arthroplasty). The functional IKS score improved significantly, by 20 points (P<0.001). Mean increases of 7.8 degrees for the HKA angle and 3.5 degrees for tibial slope were recorded. Bone healing without radiological abnormalities was consistently achieved within 6months. There were no complications related to the allograft (infections, allergies; local or systemic toxicity). DISCUSSION: The clinical, radiological, and safety outcomes documented in our study were similar to those reported in earlier work. LEVEL OF EVIDENCE: IV, retrospective case series study. PMID- 26596419 TI - MicroRNAs as potential biomarkers of eye diseases. PMID- 26596420 TI - Simulation of ultrasonic and EMAT arrays using FEM and FDTD. AB - This paper presents a method which combines electromagnetic simulation and ultrasonic simulation to build EMAT array models. For a specific sensor configuration, Lorentz forces are calculated using the finite element method (FEM), which then can feed through to ultrasonic simulations. The propagation of ultrasound waves is numerically simulated using finite-difference time-domain (FDTD) method to describe their propagation within homogenous medium and their scattering phenomenon by cracks. Radiation pattern obtained with Hilbert transform on time domain waveforms is proposed to characterise the sensor in terms of its beam directivity and field distribution along the steering angle. PMID- 26596421 TI - Toward cost-effective staffing mixes for Veterans Affairs substance use disorder treatment programs. AB - BACKGROUND: In fiscal year (FY) 2008, 133,658 patients were provided services within substance use disorders treatment programs (SUDTPs) in the U.S. Department of Veterans Affairs (VA) health care system. To improve the effectiveness and cost-effectiveness of SUDTPs, we analyze the impacts of staffing mix on the benefits and costs of specialty SUD services. This study demonstrates how cost effective staffing mixes for each type of VA SUDTPs can be defined empirically. METHODS: We used a stepwise method to derive prediction functions for benefits and costs based on patients' treatment outcomes at VA SUDTPs nationally from 2001 to 2003, and used them to formulate optimization problems to determine recommended staffing mixes that maximize net benefits per patient for four types of SUDTPs by using the solver function with the Generalized Reduced Gradient algorithm in Microsoft Excel 2010 while conforming to limits of current practice. We conducted sensitivity analyses by varying the baseline severity of addiction problems between lower (2.5 %) and higher (97.5 %) values derived from bootstrapping. RESULTS AND CONCLUSIONS: Compared to the actual staffing mixes in FY01-FY03, the recommended staffing mixes would lower treatment costs while improving patients' outcomes, and improved net benefits are estimated from $1472 to $17,743 per patient. PMID- 26596424 TI - Switchable asymmetric bio-epoxidation of alpha,beta-unsaturated ketones. AB - Efficient asymmetric bio-epoxidation of electron-deficient alpha,beta-unsaturated ketones was realized via a tandem reduction-epoxidation-dehydrogenation cascade, which proceeds in a switchable manner to afford either chiral epoxy ketones or allylic epoxy alcohols with up to >99% yield and >99%ee. PMID- 26596422 TI - Deciphering the molecular adaptation of the king scallop (Pecten maximus) to heat stress using transcriptomics and proteomics. AB - BACKGROUND: The capacity of marine species to survive chronic heat stress underpins their ability to survive warming oceans as a result of climate change. In this study RNA-Seq and 2-DE proteomics were employed to decipher the molecular response of the sub-tidal bivalve Pecten maximus, to elevated temperatures. RESULTS: Individuals were maintained at three different temperatures (15, 21 and 25 degrees C) for 56 days, representing control conditions, maximum environmental temperature and extreme warming, with individuals sampled at seven time points. The scallops thrived at 21 degrees C, but suffered a reduction in condition at 25 degrees C. RNA-Seq analyses produced 26,064 assembled contigs, of which 531 were differentially expressed, with putative annotation assigned to 177 transcripts. The proteomic approach identified 24 differentially expressed proteins, with nine identified by mass spectrometry. Network analysis of these results indicated a pivotal role for GAPDH and AP-1 signalling pathways. Data also suggested a remodelling of the cell structure, as revealed by the differential expression of genes involved in the cytoskeleton and cell membrane and a reduction in DNA repair. They also indicated the diversion of energetic metabolism towards the mobilization of lipid energy reserves to fuel the increased metabolic rate at the higher temperature. CONCLUSIONS: This work provides preliminary insights into the response of P. maximus to chronic heat stress and provides a basis for future studies examining the tipping points and energetic trade-offs of scallop culture in warming oceans. PMID- 26596423 TI - Annotation of pseudogenic gene segments by massively parallel sequencing of rearranged lymphocyte receptor loci. AB - BACKGROUND: The adaptive immune system generates a remarkable range of antigen specific T-cell receptors (TCRs), allowing the recognition of a diverse set of antigens. Most of this diversity is encoded in the complementarity determining region 3 (CDR3) of the beta chain of the alphabeta TCR, which is generated by somatic recombination of noncontiguous variable (V), diversity (D), and joining (J) gene segments. Deletion and non-templated insertion of nucleotides at the D-J and V-DJ junctions further increases diversity. Many of these gene segments are annotated as non-functional owing to defects in their primary sequence, the absence of motifs necessary for rearrangement, or chromosomal locations outside the TCR locus. METHODS: We sought to utilize a novel method, based on high throughput sequencing of rearranged TCR genes in a large cohort of individuals, to evaluate the use of functional and non-functional alleles. We amplified and sequenced genomic DNA from the peripheral blood of 587 healthy volunteers using a multiplexed polymerase chain reaction assay that targets the variable region of the rearranged TCRbeta locus, and we determined the presence and the proportion of productive rearrangements for each TCRbeta V gene segment in each individual. We then used this information to annotate the functional status of TCRbeta V gene segments in this cohort. RESULTS: For most TCRbeta V gene segments, our method agrees with previously reported functional annotations. However, we identified novel non-functional alleles for several gene segments, some of which were used exclusively in our cohort to the detriment of reported functional alleles. We also saw that some gene segments reported to have both functional and non functional alleles consistently behaved in our cohort as either functional or non functional, suggesting that some reported alleles were not present in the population studied. CONCLUSIONS: In this proof-of-principle study, we used high throughput sequencing of the TCRbeta locus of a large cohort of healthy volunteers to evaluate the use of functional and non-functional alleles of individual TCRbeta V gene segments. With some modifications, our method has the potential to be extended to gene segments in the alpha, gamma, and delta TCR loci, as well as the genes encoding for B-cell receptor chains. PMID- 26596425 TI - Estimation of Partial Charges in Small Zeolite Imidazolate Frameworks from Density Functional Theory Calculations. AB - Zeolitic Imidazolate Frameworks (ZIFs) are the new frontier in the field of metal organic materials. They incorporate the confining properties of the more traditional aluminosilicate zeolites together with the catalytic activity provided by transition metal ions and organic links. Computation of atomic point charges for these hybrid materials is important in the field of molecular simulations for substantial prediction of experimental results. However, due to the structural complexity of advanced materials in general, studies involving derivation of point charges for these materials are truly scarce. In this article, we have derived the atomic point charges of ZIF-8 through fitting of the quantum electrostatic potential obtained systematically from density functional theory (DFT) calculations both on finite clusters of increasing size and on the periodic system. For the periodic system, fluctuations on the atomic charges have been studied through ab initio molecular dynamics simulations. Using the latter approach, we have extended the study to ZIF-2 and ZIF-3, where it has been found that charge fluctuations are, as well as for ZIF-8, very narrow, therefore justifying the use of the point charge approximation for these materials. PMID- 26596426 TI - Use of Umbrella Sampling to Calculate the Entrance/Exit Pathway for Z-Pro Prolinal Inhibitor in Prolyl Oligopeptidase. AB - Prolyl oligopeptidase (POP), a member of the prolyl endopeptidase family, is known to play a role in several neurological disorders. Its primary function is to cleave a wide range of small oligopeptides, including neuroactive peptides. We have used force biased molecular dynamics simulation to study the binding mechanism of POP. We examined three possible binding pathways using Steered Molecular Dynamics (SMD) and Umbrella Sampling (US) on a crystal structure of porcine POP with bound Z-pro-prolinal (ZPP). Using SMD, an exit pathway between the first and seventh blade of the beta-propeller domain of POP was found to be a nonviable route. US on binding pathways through the beta-propeller tunnel and the TYR190-GLN208 flexible loop at the interface between both POP domains allowed us to isolate the flexible loop pathway as the most probable. Further analysis of that pathway suggests a long-range covariation of the interdomain H-bond network, which indicates the possibility of large-scale domain reorientation observed in bacterial homologues and hypothesized to also occur in human POP. PMID- 26596427 TI - Accelerating All-Atom Normal Mode Analysis with Graphics Processing Unit. AB - All-atom normal mode analysis (NMA) is an efficient way to predict the collective motions in a given macromolecule, which is essential for the understanding of protein biological function and drug design. However, the calculations are limited in time scale mainly because the required diagonalization of the Hessian matrix by Householder-QR transformation is a computationally exhausting task. In this paper, we demonstrate the parallel computing power of the graphics processing unit (GPU) in NMA by mapping Householder-QR transformation onto GPU using Compute Unified Device Architecture (CUDA). The results revealed that the GPU-accelerated all-atom NMA could reduce the runtime of diagonalization significantly and achieved over 20* speedup over CPU-based NMA. In addition, we analyzed the influence of precision on both the performance and the accuracy of GPU. Although the performance of GPU with double precision is weaker than that with single precision in theory, more accurate results and an acceptable speedup of double precision were obtained in our approach by reducing the data transfer time to a minimum. Finally, the inherent drawbacks of GPU and the corresponding solution to deal with the limitation in computational scale are also discussed in this study. PMID- 26596428 TI - Ab Initio Molecular Dynamics Simulations of (101) Surfaces of Potassium Dihydrogenphosphate. AB - We present an ab initio molecular dynamics study of bare and hydrated (101) surfaces of KDP. We examine the dynamical nature of the hydrogen bonding in the high and low temperature phases of bulk KDP and find evidence to support the theory that hydrogen atoms oscillate between two off-center positions in the high temperature phase. We report the translational relaxation of the surface species on the (101) surface and find good agreement with experimental results, particularly with reference to the direction of the relaxation. We find a strongly hydrogen bound water layer close to the KDP surface, comparing closely to a highly ordered water layer observed experimentally. Overall, there is good agreement with the results of nanoscale experimental studies, demonstrating the effectiveness of ab initio molecular dynamics calculations at simulating bulk and surface properties. PMID- 26596429 TI - On the Efficiency of Algorithms for Solving Hartree-Fock and Kohn-Sham Response Equations. AB - The response equations as occurring in the Hartree-Fock, multiconfigurational self-consistent field, and Kohn-Sham density functional theory have identical matrix structures. The algorithms that are used for solving these equations are discussed, and new algorithms are proposed where trial vectors are split into symmetric and antisymmetric components. Numerical examples are given to compare the performance of the algorithms. The calculations show that the standard response equation for frequencies smaller than the highest occupied molecular orbital-lowest unoccupied molecular orbital gap is best solved using the preconditioned conjugate gradient or conjugate residual algorithms where trial vectors are split into symmetric and antisymmetric components. For larger frequencies in the standard response equation as well as in the damped response equation in general, the preconditioned iterative subspace approach with symmetrized trial vectors should be used. For the response eigenvalue equation, the Davidson algorithm with either paired or symmetrized trial vectors constitutes equally good options. PMID- 26596430 TI - Complete vs Restricted Active Space Perturbation Theory Calculation of the Cr2 Potential Energy Surface. AB - In this paper, we calculate the potential energy surface (PES) and the spectroscopic constants of the chromium dimer using the recently developed restricted active space second-order perturbation (RASPT2) method. This approach is benchmarked against available experimental measurements and the complete active space second-order perturbation theory (CASPT2), which is nowadays established as one of the most accurate theoretical models available. Dissociation energies, vibrational frequencies, and bond distances are computed at the RASPT2 level using several reference spaces. The major advantage of the RASPT2 method is that with a limited number of configuration state functions, it can reproduce well the equilibrium bond length and the vibrational frequency of the Cr dimer. On the other hand, the PES is well described only at short distances, while at large distances, it compares very poorly with the CASPT2. The dissociation energy is also ill-behaved, but its value can be largely improved using a simple workaround that we explain in the text. In the paper, we also address the effect of the Ionization Potential Electron Affinity (IPEA) shift (a parameter introduced in the zeroth-order Hamiltonian in the CASPT2 method to include the effect of two-electron terms) and show how its default value of 0.25 is not suitable for a proper description of the PES and of the spectroscopic parameters and must be changed to a more sound value of 0.45. PMID- 26596431 TI - How Well Can Modern Density Functionals Predict Internuclear Distances at Transition States? AB - We introduce a new database called TSG48 containing 48 transition state geometrical data (in particular, internuclear distances in transition state structures) for 16 main group reactions. The 16 reactions are the 12 reactions in the previously published DBH24 database (which includes hydrogen transfer reactions, heavy-atom transfer reactions, nucleophilic substitution reactions, and association reactions plus one unimolecular isomerization) plus four H transfer reactions in which a hydrogen atom is abstracted by the methyl or hydroperoxyl radical from the two different positions in methanol. The data in TSG48 include data for four reactions that have previously been treated at a very high level in the literature. These data are used to test and validate methods that are affordable for the entire test suite, and the most accurate of these methods is found to be the multilevel BMC-CCSD method. The data that constitute the TSG48 database are therefore taken to consist of these very high level calculations for the four reactions where they are available and BMC-CCSD calculations for the other 12 reactions. The TSG48 database is used to assess the performance of the eight Minnesota density functionals from the M05-M08 families and 26 other high-performance and popular density functionals for locating transition state geometries. For comparison, the MP2 and QCISD wave function methods have also been tested for transition state geometries. The MC3BB and MC3MPW doubly hybrid functionals and the M08-HX and M06-2X hybrid meta-GGAs are found to have the best performance of all of the density functionals tested. M08 HX is the most highly recommended functional due to the excellent performance for all five subsets of TSG48, as well as having a lower cost when compared to doubly hybrid functionals. The mean absolute errors in transition state internuclear distances associated with breaking and forming bonds as calculated by the B2PLYP, MP2, and B3LYP methods are respectively about 2, 3, and 5 times larger than those calculated by MC3BB and M08-HX. PMID- 26596432 TI - A Locality Analysis of the Divide-Expand-Consolidate Coupled Cluster Amplitude Equations. AB - We present a thorough locality analysis of the divide-expand-consolidate amplitude equations for second-order Moller-Plesset perturbation theory and the coupled cluster singles doubles (CCSD) model, which demonstrates that the amplitude equations are local when expressed in terms of a set of local occupied and local unoccupied Hartree-Fock orbitals, such as the least-change molecular basis. The locality analysis thus shows that a CC calculation on a large molecular system may be carried out in terms of CC calculations on small orbital fragments of the total molecular system, where the sizes of the orbital fragment spaces are determined in a black box manner to ensure that the CC correlation energy is calculated to a preset energy threshold. A practical implementation of the locality analysis is described, and numerical results are presented, which demonstrate that both the orbital fragment sizes and the relative energy error compared to a full CC calculation are independent of the molecular system size. PMID- 26596433 TI - Selection and Validation of Charge and Lennard-Jones Parameters for QM/MM Simulations of Hydrocarbon Interactions with Zeolites. AB - Quantum mechanics/molecular mechanics (QM/MM) models are an appealing method for performing zeolite simulations. In QM/MM, a small cluster chosen to encompass the active center is described by QM, while the rest of the zeolite is described by MM. In the present study, we demonstrate that the charges and Lennard-Jones parameters on Si and O must be chosen properly for QM/MM calculations of adsorption energies and activation energies to agree closely with full QM calculations. The selection of parameters for Si and O is based on using the omegaB97X-D functional for DFT calculations of the QM region, which is effective in capturing the effects of van der Waals interactions. A comparison of the heats of adsorption for a variety of adsorbates and activation energies for the cracking of propane and butane reveals that energies derived from QM/MM calculation carried out with appropriately selected MM parameters agree to within an rms error of ~1.5 kcal/mol with QM calculations. To avoid reparametrization for new substrates, Lennard-Jones zeolite parameters are chosen to be compatible with existing CHARMM parameters. Transferability of these parameters is demonstrated by tests utilizing the B3LYP density functional and simulations of MFI and FAU zeolites. Moreover, the computational time for QM/MM calculations is considerably lower than that for QM calculations, and the ratio of computational times decreases rapidly with increasing size of the cluster used to represent the zeolite. PMID- 26596434 TI - Nature of Chemical Interactions from the Profiles of Electron Delocalization Indices. AB - We analyze the behavior of the profiles of delocalization indices (DIs) between relevant pairs of atoms along reaction coordinates for a set of model chemical processes. A relationship between the topology of the DI and the nature of the underlying chemical change is reported. As shown, exponential shapes correspond to the traditional category of repulsive/nonbonded interactions, while sigmoidal profiles signal the formation/breaking of chemical links. PMID- 26596435 TI - Nonorthogonality Problem and Effective Electronic Coupling Calculation: Application to Charge Transfer in pi-Stacks Relevant to Biochemistry and Molecular Electronics. AB - A recently proposed method for the calculation of the effective electronic coupling (or charge-transfer integral) in a two-state system is discussed and related to other methods in the literature. The theoretical expression of the coupling is exact within the two-state model and applies to the general case where the charge transfer (CT) process involves nonorthogonal initial and final diabatic (localized) states. In this work, it is shown how this effective electronic coupling is also the one to be used in a suitable extension of Rabi's formula to the nonorthogonal representation of two-state dynamical problems. The formula for the transfer integral is inspected in the regime of long-range CT and applied to CT reactions in redox molecular systems of interest to biochemistry and/or to molecular electronics: the guanine-thymine stack from regular B-DNA, the polyaromatic perylenediimide stack, and the quinol-semiquinone couple. The calculations are performed within the framework of the Density Functional Theory (DFT), using hybrid exchange-correlation (XC) density functionals, which also allowed investigation of the appropriateness of such hybrid-DFT methods for computing electronic couplings. The use of the recently developed M06-2X and M06 HF density functionals in appropriate ways is supported by the results of this work. PMID- 26596436 TI - Electron Attachment to Diselenides Revisited: Se-Se Bond Cleavage Is Neither Adiabatic nor the Most Favorable Process. AB - Up to now it has been generally assumed that the electron capture on diselenides XSeSeX' produces a fragmentation of the Se-Se bond. However, our high-level ab initio calculations indicate that this is the case only when the substituents X and X' attached to the diselenide bridge have low electronegativity. Also importantly, even when the two substituents are of similar electronegativity, the Se-Se bond cleavage rarely is an adiabatic process. For low-electronegative X substituents, the extra electron is placed in the sigma*(Se-Se) antibonding orbital, and the cleavage of the Se-Se bond is the most favorable process. However, the mechanism of this bond breaking is more intricate than previously assumed, and for asymmetric derivatives it proceeds through a conical intersection (CI). These findings emphasize the importance of using accurate ab initio calculations, rather than the usually employed density functional theory approaches, when dealing with reactions in biochemistry and organometallic chemistry, because the characterization of a CI requires the use of multireference methods to account for the mixing of states. When X is highly electronegative, the sigma*(Se-X) antibonding orbital becomes highly stabilized with respect to the sigma*(Se-Se) strongly favoring the cleavage of the Se-X bond, whereas the Se-Se remains practically unperturbed. Finally, when comparing the present results on diselenides with those of the disulfide analogues, it is apparent that the activation barriers and the final products of the different unimolecular reactions are higher in energy for the diselenides, in spite of the higher antioxidant strength of diselenides. This seems to indicate that the electron detachment process, less favorable for diselenides than for disulfides, competes with the electron-capture dissociation process and therefore should also be considered to explain the different antioxidant ability of these compounds. PMID- 26596437 TI - A Long-Range Electric Field Solver for Molecular Dynamics Based on Atomistic-to Continuum Modeling. AB - Understanding charge transport processes at a molecular level is currently hindered by a lack of appropriate models for incorporating nonperiodic, anisotropic electric fields in molecular dynamics (MD) simulations. In this work, we develop a model for including electric fields in MD using an atomistic-to continuum framework. This framework provides the mathematical and the algorithmic infrastructure to couple finite element (FE) representations of continuous data with atomic data. Our model represents the electric potential on a FE mesh satisfying a Poisson equation with source terms determined by the distribution of the atomic charges. Boundary conditions can be imposed naturally using the FE description of the potential, which then propagate to each atom through modified forces. The method is verified using simulations where analytical solutions are known or comparisons can be made to existing techniques. In addition, a calculation of a salt water solution in a silicon nanochannel is performed to demonstrate the method in a target scientific application in which ions are attracted to charged surfaces in the presence of electric fields and interfering media. PMID- 26596438 TI - The Significance of Parameters in Charge Equilibration Models. AB - Charge equilibration models such as the electronegativity equalization method (EEM) and the split charge equilibration (SQE) are extensively used in the literature for the efficient computation of accurate atomic charges in molecules. However, there is no consensus on a generic set of optimal parameters, even when one only considers parameters calibrated against atomic charges in organic molecules. In this work, the origin of the disagreement in the parameters is investigated by comparing and analyzing six sets of parameters based on two sets of molecules and three calibration procedures. The resulting statistical analysis clearly indicates that the conventional least-squares cost function based solely on atomic charges is in general ill-conditioned and not capable of fixing all parameters in a charge-equilibration model. Methodological guidelines are formulated to improve the stability of the parameters. Although in this case a simple interpretation of individual parameters is not possible, charge equilibration models remain of great practical use for the computation of atomic charges. PMID- 26596439 TI - Optimized Potential of Mean Force Calculations for Standard Binding Free Energies. AB - The prediction of protein-ligand binding free energies is an important goal of computational biochemistry, yet accuracy, reproducibility, and cost remain a problem. Nevertheless, these are essential requirements for computational methods to become standard binding prediction tools in discovery pipelines. Here, we present the results of an extensive search for an optimal method based on an ensemble of umbrella sampling all-atom molecular simulations tested on the phosphorylated tetrapeptide, pYEEI, binding to the SH2 domain, resulting in an accurate and converged binding free energy of -9.0 +/- 0.5 kcal/mol (compared to an experimental value of -8.0 +/- 0.1 kcal/mol). We find that a minimum of 300 ns of sampling is required for every prediction, a target easily achievable using new generation accelerated MD codes. Convergence is obtained by using an ensemble of simulations per window, each starting from different initial conformations, and by optimizing window-width, orthogonal restraints, reaction coordinate harmonic potentials, and window-sample time. The use of uncorrelated initial conformations in neighboring windows is important for correctly sampling conformational transitions from the unbound to bound states that affect significantly the precision of the calculations. This methodology thus provides a general recipe for reproducible and practical computations of binding free energies for a class of semirigid protein-ligand systems, within the limit of the accuracy of the force field used. PMID- 26596440 TI - Iterative Optimization of Molecular Mechanics Force Fields from NMR Data of Full Length Proteins. AB - High quality molecular mechanics force fields of proteins are key for the quantitative interpretation of experimental data and the predictive understanding of protein function based on computer simulations. A strategy is presented for the optimization of protein force fields based on full-length proteins in their native environment that is guided by experimental NMR chemical shifts and residual dipolar couplings (RDCs). An energy-based reweighting approach is applied to a long molecular dynamics trajectory, performed with a parent force field, to efficiently screen a large number of trial force fields. The force field that yields the best agreement with the experimental data is then used as the new parent force field, and the procedure is repeated until no further improvement is obtained. This method is demonstrated for the optimization of the backbone phi,psi dihedral angle potential of the Amber ff99SB force field using six trial proteins and another 17 proteins for cross-validation using (13)C chemical shifts with and without backbone RDCs. The phi,psi dihedral angle potential is systematically improved by the inclusion of correlation effects through the addition of up to 24 bivariate Gaussian functions of variable height, width, and tilt angle. The resulting force fields, termed ff99SB_phipsi(g24;CS) and ff99SB_phipsi(g8;CS,RDC), perform significantly better than their parent force field in terms of both NMR data reproduction and Cartesian coordinate root mean-square deviations between the MD trajectories and the X-ray crystal structures. The strategy introduced here represents a powerful addition to force field optimization approaches by overcoming shortcomings of methods that are solely based on quantum-chemical calculations of small molecules and protein fragments in the gas phase. PMID- 26596441 TI - Searching Peptide Conformational Space. AB - We have performed a near complete analysis of the conformational space in terms of minima and transition structures for four small peptide models with a force field energy function. There is a clear trend that minima having a large difference in structure, as measured by the distance in torsional space, are rarely connected by a single transition structure. There is a similar trend that activation energies for conformational transitions correlate with structure differences, such that small conformational changes occur with low energy barriers and vice versa. This suggests that a systematic search for low energy conformational transition structures should focus on pairs of minima that are structurally similar. Eigenvectors from diagonalization of force constant matrices at minima are better at describing conformational transitions than vibrational normal modes, as verified both by overlaps with geometry difference vectors and results from biased molecular dynamics simulations. PMID- 26596442 TI - Accurate Intermolecular Potentials with Physically Grounded Electrostatics. AB - A strategy is proposed to include the missing charge penetration energy term directly into a force field using a sum over pairwise electrostatic energies between spherical atoms as originally suggested by Spackman. This important contribution to the intermolecular potential can be further refined to reproduce the accurate electrostatic energy between monomers in a dimer by allowing for the radial contraction-expansion of atomic charge densities. The other components of a force field (exchange-repulsion and dispersion) are parametrized to reproduce the accurate data calculated by symmetry-adapted perturbation theory (SAPT). As a proof-of-concept, we have derived the force field parameters suitable for modeling intermolecular interactions between polycyclic aromatic hydrocarbons (PAH). It is shown that it is possible to have a balanced force field suitable for molecular simulations of large molecules avoiding error cancellation to a large extent. PMID- 26596443 TI - Exploring Anharmonic Nuclear Dynamics and Spectroscopy Using the Kratzer Oscillator. AB - The Kratzer oscillator is useful in modeling anharmonic molecular vibrations; therefore, its underlying theory is briefly explored in this study. The linear dipole moment time correlation function, within the Condon approximation, is analytically evaluated, and linear absorption lineshapes are calculated at different temperatures. An important integral formula of Landau and Liftshitz is, for the first time, utilized to evaluate the anharmonic Franck-Condon factor (FCF) resulting from modeling the initial and final states by Kratzer potentials. In addition, an exact closed-form expression of the FCF for the linearly displaced and shape-distorted final state energy curve, with respect to the ground state, is reported. Within the context of Mukamel formalism, nonlinear spectral/temporal lineshapes, such as hole-burning, photon echo, and pump-probe signals, may not be calculated without nonlinear response theory using the so called "four-point dipole moment time correlation function". The above FCFs will be employed to calculate optical linear and nonlinear spectra at different temperatures utilizing a previously developed formula [Toutounji, M. J. Phys. Chem. C2010, in press], whereby a hole-burned absorption lineshape may be found using a linear dipole moment time correlation function. PMID- 26596444 TI - Effective Time-Independent Calculations of Vibrational Resonance Raman Spectra of Isolated and Solvated Molecules Including Duschinsky and Herzberg-Teller Effects. AB - We present a method of modeling vibrational resonance Raman scattering (RRS) spectra of isolated and solvated systems with the inclusion of Franck-Condon (FC) and Herzberg-Teller (HT) effects and a full account for possible differences between the harmonic potential energy surfaces of the initial and resonant electronic states. It describes fundamentals, overtones, and combination bands and computes the RRS spectrum as a two-dimensional function of the incident and scattered frequencies. The theoretical foundations of the method are described and the differences with other currently available methodologies are outlined. Applications to the phenoxyl radical in the gas phase and indolinedimethine malononitrile (IDMN) in acetonitrile and cyclohexane solution are reported, as well as comparisons with available experimental data. PMID- 26596445 TI - Importance of Polarization and Charge Transfer Effects to Model the Infrared Spectra of Peptides in Solution. AB - We present a study of the infrared spectrum of N-methyl acetamide (NMA) performed by using molecular dynamics (MD) with a quantum electronic Hamiltonian. A recently developed method, based on the Born-Oppenheimer approximation and on a semiempirical level of quantum chemistry (SEBOMD), is employed. We focus on the solvent effect on the infrared spectrum of the solute, on its geometry, and on its electrostatic properties. We thus run simulations of NMA in the gas phase and in water (64 solvent molecules with periodic boundary conditions), taking into account its two different conformers-cis and trans. The use of a semiempirical electronic Hamiltonian allows us to explore much larger time scales compared to density functional theory based MD for systems of similar size. NMA represents a simple model system for peptide bonds: those infrared bands that are more significant as a signature of the peptide bond (amide I, II, and III and the N-H stretch) are identified, and the solvent shift is evaluated and compared to experiments. We find a satisfying agreement between our model and experimental measurements, not only for the solvent shift but also for the structural and electrostatic properties of the solute. On the other hand, when a molecular mechanics, nonpolarizable force field is used to run MD, very little or nil solvent effect is observed. By analyzing our results, we propose an explanation of this discrepancy by stressing the importance of mutual polarization and charge transfer in an accurate modeling of the solute-solvent interactions. PMID- 26596446 TI - Solvent Effects on the Structure and Spectroscopy of the Emitting States of 1 Phenylpyrrole. AB - Theoretical calculations of absorption and fluorescence properties of 1 phenylpyrrole have been performed, at the CASPT2//CASSCF level, in the gas phase and in acetonitrile solution, using in the latter case the ASEP/MD method. In addition to a locally excited state, it was also possible to identify a candidate intramolecular charge transfer state that could explain the second red-shifted fluorescence band that appears in polar solvents. In the gas phase, the charge transfer state is found to lie higher in energy than the locally excited state and the Franck-Condon absorption state, making it unlikely to be reached under these conditions. In acetonitrile solution, the charge transfer state is stabilized and lies much closer to the locally excited state, becoming accessible after absorption. The results indicate that the free-energy surface of the charge transfer state is very flat in solution, and several geometries are possible, ranging from almost planar to twisted and bent. Solvent caging and transition probabilities favor emission from structures with a small twist angle between the rings and without a pyramidal atom. PMID- 26596447 TI - Introduction of a New Theory for the Calculation of Magnetic Coupling Based on Spin-Flip Constricted Variational Density Functional Theory. Application to Trinuclear Copper Complexes which Model the Native Intermediate in Multicopper Oxidases. AB - We have introduced a new method for the calculation of spin-exchange between weakly interacting electron spins on different metal centers. The method is based on spin-flip constricted variational density functional theory (SF-CV-DFT). The application of SF-CV-DFT to two trinuclear systems [Cu3(L)(MU3-O)](4+) and [(L')3]Cu3(MU-OH)3](3+) revealed that SF-CV-DFT affords exchange coupling constants that are similar to the values obtained by the traditional broken symmetry (BS) scheme for the same functional. The BHandHLYP functional affords for both systems the best fit to experiment and results from high-level theory in the case of BS-DFT as well as SF-CV(2)-DFT. All methods and functionals predict [Cu(L)(MU3-O)](4+) to be ferromagnetic and the [(L')3Cu3(MU-OH)3](3+) system to be antiferromagnetic. The SF-CV(2)-DFT method is not only able to evaluate exchange coupling constants, it can in addition calculate the full multiplet spectrum with complete use of spatial symmetry. Further, in its restricted formulation, calculations can be carried out with use of full spin-symmetry without spin-contamination. PMID- 26596448 TI - Analysis of the Cartesian Tensor Transfer Method for Calculating Vibrational Spectra of Polypeptides. AB - The Cartesian Tensor Transfer Method (CTTM) was proposed as an efficient way to calculate infrared, Raman, and Raman Optical Activity (ROA) spectra for large molecules from the Hessian matrix and property tensor derivatives calculated for smaller molecular fragments. Although this approach has been widely used, its reliability has not been analyzed in depth yet. Especially for ROA spectra, such an analysis became only recently possible because of methodological advances that allow for the calculation of full ROA spectra of fairly large molecules with large basis sets. In this work, we investigate an alpha-helical polypeptide of 20 alanine amino acids, for which we reported the full ROA spectra earlier, in order to study the CTTM for protein subunits. By comparing the full first-principles calculation of the vibrational spectra with spectra reconstructed with the CTTM from different fragment sizes, we find that infrared and Raman spectra are mostly well reproduced. However, this is not the case for the ROA spectrum. This might have implications for peptide and protein CTTM ROA spectra that have already been published in the literature. PMID- 26596449 TI - TD-DFT Vibronic Couplings in Anthraquinones: From Basis Set and Functional Benchmarks to Applications for Industrial Dyes. AB - Vibrationally resolved absorption spectra of a series of anthraquinoidic dyes have been obtained with a polarizable continuum model time-dependent density functional theory approach. Firstly, we assessed the impact of the atomic basis set on both the transition energies and the vibronic shapes of 1,4-NH2 anthraquinone using a large panel of Pople's basis sets, up to the 6 311++G(3df,3pd). In a second stage, an extensive functional benchmark has been performed to determine an adequate approach for the same compound. In the third step, a complete analysis of the origin of the band shape was performed for the same derivative. In the fourth stage, a set of functionals has been applied to investigate the position isomers in the dihydroxy anthraquinone series. Finally, in a last phase, the methodology has been used for three dyes of technological interest. It turns out that the chosen basis set has a relatively limited impact on the computed transition energies as well as the topology of the vibronic shape, but both are significantly influenced by the selected functional. In the present case, no single functional simultaneously provides highly accurate positions and intensities of the different bands, but omegaB97XD appears to be a good compromise. This analysis allows to rationalize the difference in shapes experimentally noticed for the visible band of apparently similar anthraquinones. PMID- 26596450 TI - Absolute Entropy and Energy of Carbon Dioxide Using the Two-Phase Thermodynamic Model. AB - The two-phase thermodynamic (2PT) model is used to determine the absolute entropy and energy of carbon dioxide over a wide range of conditions from molecular dynamics trajectories. The 2PT method determines the thermodynamic properties by applying the proper statistical mechanical partition function to the normal modes of a fluid. The vibrational density of state (DoS), obtained from the Fourier transform of the velocity autocorrelation function, converges quickly, allowing the free energy, entropy, and other thermodynamic properties to be determined from short 20-ps MD trajectories. The anharmonic effects in the vibrations are accounted for by the broadening of the normal modes into bands from sampling the velocities over the trajectory. The low frequency diffusive modes, which lead to finite DoS at zero frequency, are accounted for by considering the DoS as a superposition of gas-phase and solid-phase components (two phases). The analytical decomposition of the DoS allows for an evaluation of properties contributed by different types of molecular motions. We show that this 2PT analysis leads to accurate predictions of entropy and energy of CO2 over a wide range of conditions (from the triple point to the critical point of both the vapor and the liquid phases along the saturation line). This allows the equation of state of CO2 to be determined, which is limited only by the accuracy of the force field. We also validated that the 2PT entropy agrees with that determined from thermodynamic integration, but 2PT requires only a fraction of the time. A complication for CO2 is that its equilibrium configuration is linear, which would have only two rotational modes, but during the dynamics it is never exactly linear, so that there is a third mode from rotational about the axis. In this work, we show how to treat such linear molecules in the 2PT framework. PMID- 26596451 TI - Development of a Polarizable Force Field for Molecular Dynamics Simulations of Poly (Ethylene Oxide) in Aqueous Solution. AB - We have developed a quantum chemistry-based polarizable potential for poly(ethylene oxide) (PEO) in aqueous solution based on the APPLE&P polarizable ether and the SWM4-DP polarizable water models. Ether-water interactions were parametrized to reproduce the binding energy of water with 1,2-dimethoxyethane (DME) determined from high-level quantum chemistry calculations. Simulations of DME-water and PEO-water solutions at room temperature using the new polarizable potentials yielded thermodynamic properties in good agreement with experimental results. The predicted miscibility of PEO and water as a function of the temperature was found to be strongly correlated with the predicted free energy of solvation of DME. The developed nonbonded force field parameters were found to be transferrable to poly(propylene oxide) (PPO), as confirmed by capturing, at least qualitatively, the miscibility of PPO in water as a function of the molecular weight. PMID- 26596452 TI - Transferability of Coarse Grained Potentials: Implicit Solvent Models for Hydrated Ions. AB - Understanding the relation between structural and thermodynamic quantities obtained with simplified-e.g., coarse-grained (CG) or implicit-solvent-models is an ongoing challenge in the field of multiscale simulation. Assessing the transferability of such models to state points that differ from the one where the model was parametrized is important if one wants to apply these models to complex systems, which, for example, exhibit spatially varying compositions. Here, we investigate the transferability of CG (in this case implicit-solvent) ion models with effective pair potentials derived at very low concentrations to different ion concentrations in aqueous solution. We evaluate both thermodynamic and structural properties of systems of NaCl in aqueous solution both in atomistic explicit-solvent and CG simulations. For the explicit solvent simulations, osmotic coefficients have been calculated at a wide range of salt concentrations and agree very well with experimental data. It had been shown previously that a concentration-dependent dielectric permittivity can be used to make effective implicit-solvent pair potentials transferable since it accounts for the effect of ion concentration on solvent properties, resulting in very good osmotic properties of these models for a certain range of salt concentrations. We investigate the explicit and implicit solvent models also in terms of structural properties, where we can show how with a concentration-dependent dielectric constant one obtains very good structural agreement at low and intermediate salt concentrations, while for larger salt concentrations, multibody ion-ion correlations put a limit to straightforward transferability. We show how-guided by this structural analysis-the transferability of the implicit-solvent model can be improved for high ion concentrations. Doing so, we obtain transferable implicit-solvent effective pair potentials which are both structurally and thermodynamically consistent with an explicit solvent reference model. PMID- 26596453 TI - Assessing the Quality of the OPEP Coarse-Grained Force Field. AB - A coarse-grained potential that could accurately describe the overall conformational landscape of proteins would be extremely valuable not only for structure prediction but also for studying protein dynamics, large conformational motions, and intrinsically disordered systems. Here, we assessed the quality of the OPEP coarse-grained potential by comparing the reconstructed free-energy surfaces (FESs) of two prototypical beta-hairpin and alpha-helix peptides to all atom calculations in explicit solvent. We found remarkable agreement between the OPEP FES and those obtained using atomistic models, despite a general overstabilization of alpha- and beta-structures by the coarse-grained potential. The use of advanced sampling techniques based on metadynamics and parallel tempering guaranteed a thorough exploration of the conformational space accessible to the two peptides studied. PMID- 26596454 TI - Analysis of Mammalian Histidine Decarboxylase Dimerization Interface Reveals an Electrostatic Hotspot Important for Catalytic Site Topology and Function. AB - Selective intervention of mammalian histidine decarboxylase (EC 4.1.1.22) could provide a useful antihistaminic strategy against many different pathologies. It is known that global conformational changes must occur during reaction that involves the monomer-monomer interface of the enzyme. Thus, the dimerization surface is a promising target for histidine decarboxylase inhibition. In this work, a rat apoenzyme structural model is used to analyze the interface of the dimeric active HDC. The dimerization surface mainly involves the fragments 1-213 and 308-371 from both subunits. Part of the overlapping surfaces conforms each catalytic site entrance and the substrate-binding sites. In addition, a cluster of charged residues is located in each overlapping surface, so that both electrostatic hotspots mediate in the interaction between the catalytic sites of the dimeric enzyme. It is experimentally demonstrated that the carboxyl group of aspartate 315 is critical for the proper conformation of the holoenzyme and the progression of the reaction. Comparison to the available information on other evolutionary related enzymes also provides new insights for characterization and intervention of homologous l-amino acid decarboxylases. PMID- 26596455 TI - A High-Throughput Steered Molecular Dynamics Study on the Free Energy Profile of Ion Permeation through Gramicidin A. AB - Steered molecular dynamics (SMD) simulations for the calculation of free energies are well suited for high-throughput molecular simulations on a distributed infrastructure due to the simplicity of the setup and parallel granularity of the runs. However, so far, the computational cost limited the estimation of the free energy typically over just a few pullings, thus impeding the evaluation of statistical uncertainties involved. In this work, we performed two thousand pulls for the permeation of a potassium ion in the gramicidin A pore by all-atom molecular dynamics in order to assess the bidirectional SMD protocol with a proper amount of sampling. The estimated free energy profile still shows a statistical error of several kcal/mol, while the work distributions are estimated to be non-Gaussian at pulling speeds of 10 A/ns. We discuss the methodology and the confidence intervals in relation to increasing amounts of computed trajectories and how different permeation pathways for the potassium ion, knock on and sideways, affect the sampling and the free energy estimation. PMID- 26596456 TI - Absolute pKa Values and Solvation Structure of Amino Acids from Density Functional Based Molecular Dynamics Simulation. AB - Absolute pKa values of the amino acid side chains of arginine, aspartate, cysteine, histidine, and tyrosine; the C- and N-terminal group of tyrosine; and the tryptophan radical cation are calculated using a revised density functional based molecular dynamics simulation technique introduced previously [ Cheng , J. ; Sulpizi , M. ; Sprik , M. J. Chem. Phys. 2009 , 131 , 154504 ]. In the revised scheme, acid deprotonation is considered as a dissociation rather than a proton transfer reaction, and a correction term for treating the proton as a hydronium ion is suggested. The acidity constants of the amino acids are obtained from the vertical energy gaps for removal or insertion of the acidic proton and the computed solvation free energy of the proton. The unsigned mean error relative to experimental results is 2.1 pKa units with a maximum error of 4.0 pKa units. The estimated mean statistical uncertainty due to the finite length of the trajectories is +/-1.1 pKa units. The solvation structures of the protonated and deprotonated amino acids are analyzed in terms of radial distribution functions, which can serve as reference data for future force field developments. PMID- 26596457 TI - CafeMol: A Coarse-Grained Biomolecular Simulator for Simulating Proteins at Work. AB - For simulating proteins at work in millisecond time scale or longer, we develop a coarse-grained (CG) molecular dynamics (MD) method and software, CafeMol. At the resolution of one-particle-per-residue, CafeMol equips four structure-based protein models: (1) the off-lattice Go model, (2) the atomic interaction based CG model for native state and folding dynamics, (3) the multiple-basin model for conformational change dynamics, and (4) the elastic network model for quasiharmonic fluctuations around the native structure. Ligands can be treated either explicitly or implicitly. For mimicking functional motions of proteins driven by some external force, CafeMol has various and flexible means to "switch" the energy functions that induce active motions of the proteins. CafeMol can do parallel computation with modest sized PC clusters. We describe CafeMol methods and illustrate it with several examples, such as rotary motions of F1-ATPase and drug exports from a transporter. The CafeMol source code is available at www.cafemol.org . PMID- 26596458 TI - Excited State Dynamics of the Green Fluorescent Protein on the Nanosecond Time Scale. AB - We have introduced a new algorithm in the parallel processing PMEMD module of the AMBER suite that allows MD simulations with a potential involving two coupled torsions. We have used this modified module to study the green fluorescent protein. A coupled torsional potential was adjusted on high accuracy quantum chemical calculations of the anionic chromophore in the first excited state, and several 15-ns-long MD simulations were performed. We have obtained an estimate of the fluorescence lifetime (2.2 ns) to be compared to the experimental value (3 ns), which is, to the best of our knowledge, the first theoretical estimate of that lifetime. PMID- 26596459 TI - Efficient Handling of Molecular Flexibility in Lattice Energy Minimization of Organic Crystals. AB - This paper presents a novel algorithm, CrystalOptimizer, for the minimization of the lattice energy of crystals formed by flexible molecules. The algorithm employs isolated-molecule quantum mechanical (QM) calculations of the intramolecular energy and conformation-dependent atomic multipoles in the course of the lattice energy minimization. The algorithm eliminates the need to perform QM calculations at each iteration of the minimization by using Local Approximate Models (LAMs), with a minimal impact on accuracy. Additional computational efficiencies are achieved by storing QM-derived components of the lattice energy model in a database and reusing them in subsequent calculations whenever possible. This makes the approach particularly well suited to applications that involve a sequence of lattice energy evaluations, such as crystal structure prediction. The algorithm is capable of handling efficiently complex systems with considerable conformational flexibility. The paper presents examples of the algorithm's application ranging from single-component crystals to cocrystals and salts of flexible molecules with tens of intramolecular degrees of freedom whose optimal values are determined by the interplay of conformational strain and packing forces. For any given molecule, the degree of flexibility to be considered can vary from a few torsional angles to relaxation of the entire set of torsion angles, bond angles, and bond lengths present in the molecule. PMID- 26596460 TI - Charge site assignment in native proteins by ultraviolet photodissociation (UVPD) mass spectrometry. AB - Characterization of all gas-phase charge sites of natively sprayed proteins and peptides is demonstrated using 193 nm UVPD. The high sequence coverage offered by UVPD is exploited for the accurate determination of charge sites in protein systems up to 18 kDa, allowing charge site to be studied as a function of protein conformation and the presence of disulfide bonds. Charging protons are found on both basic sidechains and on the amide backbone of less basic amino acids such as serine, glutamine, and proline. UVPD analysis was performed on the 3+ charge state of melittin, the 5+ to 8+ charge states of ubiquitin, and the 8+ charge state of reduced and oxidized beta-lactoglobulin. The location of charges in gas phase proteins is known to impact structure; molecular modeling of different charge site motifs of 3+ melittin demonstrates how placement of protons in simulations can dramatically impact the predicted structure of the molecule. The location of positive charge sites in ubiquitin and beta-lactoglobulin are additionally found to depend on the presence or absence of salt-bridges, columbic repulsion across the length of the peptide, and protein conformation. Charge site isomers are demonstrated for ubiquitin and beta-lactoglobulin but found to be much less numerous than previously predicted. PMID- 26596462 TI - Synthesis and structures of mononuclear and dinuclear gallium complexes with alpha-diimine ligands: reduction of the metal or ligand? AB - Reduction of the dichloro gallium(III) alpha-diimine complex [(L(ipr))(-)GaCl2] (1, L(ipr) = [(2,6-iPr2C6H3)NC(Me)]2) by different equivalents of sodium metal afforded the gallium complexes [(L(ipr))(2-)Ga(III)(MU2-Cl)2Na(THF)4] (2) and [(Na(THF)6)(+).((L(ipr))(2-)Ga-Ga(L(ipr))(2-))(-)] (3). Interestingly, in complex 2 a Na(+)Cl(-) ion pair is incorporated, while compound 3 is an anionic digallium complex. Moreover, a cationic gallium complex with a tetrachlorogallium(III) counter anion, [(LGaCl2)(+).(GaCl4)(-)] (4), was accessed from the reaction of GaCl3 with 0.5 equiv. of ligand L(ipr). In contrast, the reaction of GaCl3 with the doubly reduced anion (Na2L(2-)) of the smaller alpha-diimine ligands L(Me) ([(2,6-Me2C6H3)NC(Me)]2) or L(Et) ([(2,6-Et2C6H3)NC(Me)]2) yielded the Ga-Ga bonded complexes [(L(Et))(-)ClGa(II)-Ga(II)Cl(L(Et))(-)] (5) and [(L(Me))( )ClGa(II)-Ga(II)Cl(L(Me))(-)] (6). Here L is the neutral alpha-diimine ligand, L( ) represents the monoanion, and L(2-) is the dianionic form of the ligand. The complexes were characterized by X-ray diffraction and their electronic structures were studied by DFT computations. PMID- 26596461 TI - Diversification and evolution of the SDG gene family in Brassica rapa after the whole genome triplication. AB - Histone lysine methylation, controlled by the SET Domain Group (SDG) gene family, is part of the histone code that regulates chromatin function and epigenetic control of gene expression. Analyzing the SDG gene family in Brassica rapa for their gene structure, domain architecture, subcellular localization, rate of molecular evolution and gene expression pattern revealed common occurrences of subfunctionalization and neofunctionalization in BrSDGs. In comparison with Arabidopsis thaliana, the BrSDG gene family was found to be more divergent than AtSDGs, which might partly explain the rich variety of morphotypes in B. rapa. In addition, a new evolutionary pattern of the four main groups of SDGs was presented, in which the Trx group and the SUVR subgroup evolved faster than the E(z), Ash groups and the SUVH subgroup. These differences in evolutionary rate among the four main groups of SDGs are perhaps due to the complexity and variability of the regions that bind with biomacromolecules, which guide SDGs to their target loci. PMID- 26596464 TI - Canine IgA nephropathy: a case report. AB - Immunoglobulin (Ig) A nephropathy is a rare form of canine glomerular disease. This report describes a case of canine IgA nephropathy showing characteristics typical of human IgA nephropathy. An 8-year-old, spayed female Miniature Dachshund showed persistent severe proteinuria without azotemia. She was receiving long-term glucocorticoid therapy due to chronic gastritis and an intra abdominal suture granuloma. A renal biopsy demonstrated mesangial proliferative glomerulonephritis with predominantly mesangial IgA deposition and electron-dense deposits in the paramesangium. These findings closely resembled those of human IgA nephropathy. Glucocorticoid treatment was discontinued, and the angiotensin converting enzyme inhibitor enalapril was administrated as an antiproteinuric agent. The proteinuria subsequently went into remission, and the patient has maintained good condition without recurrence. PMID- 26596465 TI - Developmental morphology of Knemidokoptes pilae on an infested red-crowned parakeet (Cyanoramphus novaezelandiae). AB - A captive 4-year-old female red-crowned parakeet (Cyanoramphus novaezelandiae) presented with anorexia, diminished activity and thick, beige, crusted lesions over the cere, legs, wings and cloaca. Deep skin scrapings from various lesions identified Knemidokoptes pilae as the causative agent. For treatment, the crusts were debrided, and the lesions were topically treated with ivermectin, chlorhexidine and silver sulfadiazine. The parakeet died the day after treatment. Previous studies examining K. pilae have focused primarily on the morphologic characteristics of adult female mites. This study presents a more comprehensive morphologic analysis, with examination of K. pilae at different stages of development (eggs, larvae and adult males and females). PMID- 26596463 TI - Live detection and purification of cells based on the expression of a histone chaperone, HIRA, using a binding peptide. AB - Flow cytometry is a reliable method for identification and purification of live cells from a heterogeneous population. Since permeabilized cells cannot be sorted live in a FACS sorter, its application in isolation of functional cells largely depends on antibodies for surface markers. In various fields of biology we find intracellular markers that reveal subpopulations of biological significance. Cell cycle stage specific molecules, metastatic signature molecules, stemness associated proteins etc. are examples of potential markers that could improve the research and therapy enormously. Currently their use is restricted by lack of techniques that allow live detection. Even though a few methods like aptamers, droplet-based microfluidics and smartflares are reported, their application is limited. Here, for the first time we report a simple, cost-effective and efficient method of live sorting of cells based on the expression of an intracellular marker using a fluorophore-tagged binding peptide. The target molecule selected was a histone chaperone, HIRA, the expression of which can predict the fate of differentiating myoblast. Our results confirm that the peptide shows specific interaction with its target; and it can be used to separate cells with differential expression of HIRA. Further, this method offers high purity and viability for the isolated cells. PMID- 26596466 TI - Ultrasonographic evaluation of depth-width ratio (D/W) of benign and malignant mammary tumors in dogs. AB - Depth-width ratio (D/W) is the only quantitative item in the criteria recommended by the Japanese Ultrasound Society for the evaluation of breast tumors in humans. However, the usefulness of the D/W has not been evaluated in dogs. Eighty-six mammary masses in 34 female dogs underwent ultrasonographic examination to determine the D/W and other characteristics. Results of ultrasonographic and histopathologic examinations were compared. The D/W of malignant tumors was significantly greater than that of benign tumors, and it had a sensitivity of 56.3% and a specificity of 92.9% for the diagnosis of malignancy when the threshold of D/W was 0.7. In addition, irregular margin, polymorphous shape and heterogeneous internal echographic characteristics were correlated with malignancy. PMID- 26596467 TI - Ubiquitin-specific protease 9X in host cells interacts with herpes simplex virus 1 ICP0. AB - Herpes simplex virus 1 (HSV-1) expresses infected cell protein 0 (ICP0), a multi functional protein with E3 ubiquitin ligase activity and a critical regulator of the viral life cycle. To obtain novel insights into the molecular mechanism by which ICP0 regulates HSV-1 replication, we analyzed HEp-2 cells infected with HSV 1 by tandem affinity purification and mass spectrometry-based proteomics. This screen identified 50 host-cell proteins that potentially interact with ICP0, including ubiquitin-specific protease 9X (USP9X). The interaction between ICP0 and USP9X was confirmed by co-immunoprecipitation. Notably, USP9X depletion increased the ICP0 abundance and promoted viral replication. These results suggest that USP9X-dependent regulation of ICP0 expression is part of a complex feedback mechanism that facilitates optimal HSV-1 replication. PMID- 26596468 TI - Universal behavior of hydrogels confined to narrow capillaries. AB - Flow of soft matter objects through one-dimensional environments is important in industrial, biological and biomedical systems. Establishing the underlying principles of the behavior of soft matter in confinement can shed light on its performance in many man-made and biological systems. Here, we report an experimental and theoretical study of translocation of micrometer-size hydrogels (microgels) through microfluidic channels with a diameter smaller than an unperturbed microgel size. For microgels with different dimensions and mechanical properties, under a range of applied pressures, we established the universal principles of microgel entrance and passage through microchannels with different geometries, as well as the reduction in microgel volume in confinement. We also show a non-monotonic change in the flow rate of liquid through the constrained microgel, governed by its progressive confinement. The experimental results were in agreement with the theory developed for non-linear biaxial deformation of unentangled polymer gels. Our work has implications for a broad range of phenomena, including occlusion of blood vessels by thrombi and needle-assisted hydrogel injection in tissue engineering. PMID- 26596469 TI - Methionine Metabolism Alters Oxidative Stress Resistance via the Pentose Phosphate Pathway. AB - Nutrient uptake and metabolism have a significant impact on the way cells respond to stress. The amino acid methionine is, in particular, a key player in the oxidative stress response, and acting as a reactive oxygen species scavenger, methionine is implicated in caloric restriction phenotypes and aging. We here provide evidence that some effects of methionine in stress situations are indirect and caused by altered activity of the nicotinamide adenine dinucleotide phosphate (NADPH) producing oxidative part of the pentose phosphate pathway (PPP). In Saccharomyces cerevisiae, both methionine prototrophic (MET15) and auxotrophic (met15Delta) cells supplemented with methionine showed an increase in PPP metabolite concentrations downstream of the NADPH producing enzyme, 6 phosphogluconate dehydrogenase. Proteomics revealed this enzyme to also increase in expression compared to methionine self-synthesizing cells. Oxidant tolerance was increased in cells preincubated with methionine; however, this effect was abolished when flux through the oxidative PPP was prevented by deletion of its rate limiting enzyme, ZWF1. Stress resistance phenotypes that follow methionine supplementation hence involve the oxidative PPP. Effects of methionine on oxidative metabolism, stress signaling, and aging have thus to be seen in the context of an altered activity of this NADP reducing pathway. PMID- 26596470 TI - p53 dynamics upon response element recognition explored by molecular simulations. AB - p53 is a representative transcription factor that activates multiple target genes. To realize stimulus-dependent specificities, p53 has to recognize targets with structural variety, of which molecular mechanisms are largely unknown. Here, we conducted a series of long-time scale (totally more than 100-ms) coarse grained molecular dynamics simulations, uncovering structure and dynamics of full length p53 tetramer that recognizes its response element (RE). We obtained structures of a full-length p53 tetramer that binds to the RE, which is strikingly different from the structure of p53 at search. These structures are not only consistent with previous low-resolution or partial structural information, but also give access to previously unreachable detail, such as the preferential distribution of intrinsically disordered regions, the contacts between core domains, the DNA bending, and the connectivity of linker regions. We also explored how the RE variation affects the structure of the p53-RE complex. Further analysis of simulation trajectories revealed how p53 finds out the RE and how post-translational modifications affect the search mechanism. PMID- 26596472 TI - Berry phase mechanism of the anomalous Hall effect in a disordered two dimensional magnetic semiconductor structure. AB - The anomalous Hall effect (AHE) arises from the interplay of spin-orbit interactions and ferromagnetic order and is a potentially useful probe of electron spin polarization, especially in nanoscale systems where direct measurement is not feasible. While AHE is rather well-understood in metallic ferromagnets, much less is known about the relevance of different physical mechanisms governing AHE in insulators. As ferromagnetic insulators, but not metals, lend themselves to gate-control of electron spin polarization, understanding AHE in the insulating state is valuable from the point of view of spintronic applications. Among the mechanisms proposed in the literature for AHE in insulators, the one related to a geometric (Berry) phase effect has been elusive in past studies. The recent discovery of quantized AHE in magnetically doped topological insulators - essentially a Berry phase effect - provides strong additional motivation to undertake more careful search for geometric phase effects in AHE in the magnetic semiconductors. Here we report our experiments on the temperature and magnetic field dependences of AHE in insulating, strongly disordered two-dimensional Mn delta-doped semiconductor heterostructures in the hopping regime. In particular, it is shown that at sufficiently low temperatures, the mechanism of AHE related to the Berry phase is favoured. PMID- 26596497 TI - Controlled release of drugs from cellulose acetate matrices produced from sugarcane bagasse: monitoring by square-wave voltammetry. AB - In this paper, cellulose triacetate (CTA) was produced from sugarcane bagasse and used as matrices for controlled release of paracetamol. Symmetric and asymmetric membranes were obtained by formulations of CTA/dichloromethane/drug and CTA/dichloromethane/water/drug, respectively, and they were characterized by scanning electron microscopy (SEM) and differential scanning calorimetry (DSC). Different morphologies of membranes were observed by SEM, and the incorporation of paracetamol was confirmed by lowering of the glass transition temperature (Tg) in the DSC curves. This indicates the existence of interactions between the matrix and the drug. The evaluation of drug release was based on the electrochemical monitoring of paracetamol through its oxidation at a glassy carbon electrode surface using square-wave voltammetry (SWV), which provides fast, precise and accurate in situ measurements. The studies showed a content release of 27% and 45% by the symmetric and asymmetric membranes, respectively, during 8 h. PMID- 26596471 TI - SENP1-mediated NEMO deSUMOylation in adipocytes limits inflammatory responses and type-1 diabetes progression. AB - Adipocyte dysfunction correlates with the development of diabetes. Here we show that mice with a adipocyte-specific deletion of the SUMO-specific protease SENP1 gene develop symptoms of type-1 diabetes mellitus (T1DM), including hyperglycaemia and glucose intolerance with mild insulin resistance. Peri pancreatic adipocytes from SENP1-deficient mice exhibit heightened NF-kappaB activity and production of proinflammatory cytokines, which induce CCL5 expression in adjacent pancreatic islets and direct cytotoxic effects on pancreatic islets. Mechanistic studies show that SENP1 deletion in adipocytes enhances SUMOylation of the NF-kappaB essential molecule, NEMO, at lysine 277/309, leading to increased NF-kappaB activity, cytokine production and pancreatic inflammation. We further show that NF-kappaB inhibitors could inhibit pre-diabetic cytokine production, beta-cell damages and ameliorate the T1DM phenotype in SENP1-deficient mice. Feeding a high-fat diet augments both type-1 and type-2 diabetes phenotypes in SENP1-deficient mice, consistent with the effects on adipocyte-derived NF-kappaB and cytokine signalling. Our study reveals previously unrecognized mechanism regulating the onset and progression of T1DM associated with adipocyte dysfunction. PMID- 26596498 TI - Controlled Antibiotics Release System through Simple Blended Electrospun Fibers for Sustained Antibacterial Effects. AB - Implantation of sustained antibacterial system after abdominal surgery could effectively prevent complicated intra-abdominal infection. In this study, a simple blended electrospun membrane made of poly(D,L-lactic-co-glycolide) (PLGA)/poly(dioxanone) (PDO)/Ciprofloxacin hydrochloride (CiH) could easily result in approximately linear drug release profile and sustained antibacterial activity against both Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli). The addition of PDO changed the stack structure of PLGA, which in turn influenced the fiber swelling and created drug diffusion channels. It could be a good candidate for reducing postoperative infection or be associated with other implant to resist biofilm formation. PMID- 26596499 TI - Exploiting the locality of periodic subsystem density-functional theory: efficient sampling of the Brillouin zone. AB - In order to approximately satisfy the Bloch theorem, simulations of complex materials involving periodic systems are made n(k) times more complex by the need to sample the first Brillouin zone at n(k) points. By combining ideas from Kohn Sham density-functional theory (DFT) and orbital-free DFT, for which no sampling is needed due to the absence of waves, subsystem DFT offers an interesting middle ground capable of sizable theoretical speedups against Kohn-Sham DFT. By splitting the supersystem into interacting subsystems, and mapping their quantum problem onto separate auxiliary Kohn-Sham systems, subsystem DFT allows an optimal topical sampling of the Brillouin zone. We elucidate this concept with two proof of principle simulations: a water bilayer on Pt[1 1 1]; and a complex system relevant to catalysis-a thiophene molecule physisorbed on a molybdenum sulfide monolayer deposited on top of an alpha-alumina support. For the latter system, a speedup of 300% is achieved against the subsystem DTF reference by using an optimized Brillouin zone sampling (600% against KS-DFT). PMID- 26596500 TI - Renal Infarction Caused by Isolated Spontaneous Renal Artery Intramural Hematoma. AB - BACKGROUND: Acute renal infarction is an uncommon condition resulting from an obstruction or a decrease in renal arterial blood flow. Isolated spontaneous renal artery intramural hematoma is a rare cause of renal infarction. CASE REPORT: A 46-year-old healthy man presented to our emergency room because of sudden onset of severe right flank pain. An enhanced abdominal computed tomography scan showed a low-attenuated lesion in the lateral portion of the right kidney but no visible thromboembolisms in the main vessels. Computed tomography angiography revealed acute infarction resulting from intramural hematoma of the anterior segmental artery of the right kidney, with distal occlusion. CONCLUSIONS: The rarity and non-specific clinical presentation of renal infarction often lead to a delayed diagnosis that may result in impaired renal function. Clinical suspicion is important in the early diagnosis, and intramural hematoma of the renal artery should be considered the cause of renal infarction even in healthy patients without predisposing factors. PMID- 26596501 TI - Homeotic Transformations of Neuronal Cell Identities. AB - Homeosis is classically defined as the transformation of one body part into something that resembles another body part. We propose here to broaden the concept of homeosis to the many neuronal cell identity transformations that have been uncovered over the past few years upon removal of specific regulatory factors in organisms from Caenorhabditis elegans to Drosophila, zebrafish, and mice. The concept of homeosis provides a framework for the evolution of cell type diversity in the brain. PMID- 26596502 TI - Inactivation of C4orf26 in toothless placental mammals. AB - Previous studies have reported inactivated copies of six enamel-related genes (AMBN, AMEL, AMTN, ENAM, KLK4, MMP20) and one dentin-related gene (DSPP) in one or more toothless vertebrates and/or vertebrates with enamelless teeth, thereby providing evidence that these genes are enamel or tooth-specific with respect to their critical functions that are maintained by natural selection. Here, we employ available genome sequences for edentulous and enamelless mammals to evaluate the enamel specificity of four genes (WDR72, SLC24A4, FAM83H, C4orf26) that have been implicated in amelogenesis imperfecta, a condition in which proper enamel formation is abrogated during tooth development. Coding sequences for WDR72, SCL24A4, and FAM83H are intact in four edentulous taxa (Chinese pangolin, three baleen whales) and three taxa (aardvark, nine-banded armadillo, Hoffmann's two-toed sloth) with enamelless teeth, suggesting that these genes have critical functions beyond their involvement in tooth development. By contrast, genomic data for C4orf26 reveal inactivating mutations in pangolin and bowhead whale as well as evidence for deletion of this gene in two minke whale species. Hybridization capture of exonic regions and PCR screens provide evidence for inactivation of C4orf26 in eight additional baleen whale species. However, C4orf26 is intact in all three species with enamelless teeth that were surveyed, as well as in 95 additional mammalian species with enamel-capped teeth. Estimates of selection intensity suggest that dN/dS ratios on branches leading to taxa with enamelless teeth are similar to the dN/dS ratio on branches leading to taxa with enamel-capped teeth. Based on these results, we conclude that C4orf26 is tooth specific, but not enamel-specific, with respect to its essential functions that are maintained by natural selection. A caveat is that an alternative splice site variant, which translates exon 3 in a different reading frame, is putatively functional in Catarrhini and may have evolved an additional role in this primate clade. PMID- 26596503 TI - Current perspectives on the use of ancillary materials for the manufacture of cellular therapies. AB - Continued growth in the cell therapy industry and commercialization of cell therapies that successfully advance through clinical trials has led to increased awareness around the need for specialized and complex materials utilized in their manufacture. Ancillary materials (AMs) are components or reagents used during the manufacture of cell therapy products but are not intended to be part of the final products. Commonly, there are limitations in the availability of clinical-grade reagents used as AMs. Furthermore, AMs may affect the efficacy of the cell product and subsequent safety of the cell therapy for the patient. As such, AMs must be carefully selected and appropriately qualified during the cell therapy development process. However, the ongoing evolution of cell therapy research, limited number of clinical trials and registered cell therapy products results in the current absence of specific regulations governing the composition, compliance, and qualification of AMs often leads to confusion by suppliers and users in this field. Here we provide an overview and interpretation of the existing global framework surrounding AM use and investigate some common misunderstandings within the industry, with the aim of facilitating the appropriate selection and qualification of AMs. The key message we wish to emphasize is that in order to most effectively mitigate risk around cell therapy development and patient safety, users must work with their suppliers and regulators to qualify each AM to assess source, purity, identity, safety, and suitability in a given application. PMID- 26596504 TI - Kidney bioengineering in regenerative medicine: An emerging therapy for kidney disease. AB - The prevalence of end-stage renal disease is emerging as a serious worldwide public health problem because of the shortage of donor organs and the need to take lifelong immunosuppressive medication in patients who receive a transplanted kidney. Recently, tissue bioengineering of decellularization and recellularization scaffolds has emerged as a novel strategy for organ regeneration, and we review the critical technologies supporting these methods. We present a summary of factors associated with experimental protocols that may shed light on the future development of kidney bioengineering and we discuss the cell sources and bioreactor techniques applied to the recellularization process. Finally, we review some artificial renal engineering technologies and their future prospects, such as kidney on a chip and the application of three dimensional and four-dimensional printing in kidney tissue engineering. PMID- 26596505 TI - Chiral manganese (IV) complexes derived from Schiff base ligands: Synthesis, characterization, in vitro cytotoxicity and DNA/BSA interaction. AB - Two new couples of chiral manganese (IV) complexes with Schiff-base ligands, Lambda-[Mn(R-L(1))2].2(CH3OH) (Lambda-1) and Delta-[Mn(S-L(1))2].2(CH3OH) (Delta 1), Lambda-[Mn(R-L(2))2].(H2O)2 (Lambda-2) and Delta-[Mn(S-L(2))2].(H2O)2 (Delta 2), {H2L(1)=(R/S)-(+/-)-1-[(1-hydroxymethyl-propylimino)-methyl]-naphthalen-2-ol, H2L(2)=(R/S)-(+/-)-1-[(1-Hydroxymethyl-2-phenyl-ethylimino)-methyl]-naphthalen-2 ol} have been synthesized, and fully characterized by elemental analyses, UV-Vis spectrum, circular dichroism spectrum, FT-IR spectrum, mass spectrum, and single crystal X-ray diffraction (SXRD). The interaction of the four chiral Mn (IV) complexes with CT-DNA and BSA were also investigated by various spectroscopic techniques (UV-visible, fluorescence spectroscopic). The results show that the Delta-complexes exhibit more efficient CT-DNA interaction with respect to the Lambda-complexes. All the complexes could quench the intrinsic fluorescence of BSA by a static quenching process. In addition, the vitro cytotoxicity of these complexes toward four kinds of cancerous cell lines (A549, HeLa, HL-60, and Caco 2) was assayed by the MTT method, which exhibited to be selectively active against certain cell lines. PMID- 26596508 TI - Ultrasound assessment of optic nerve sheath diameter in healthy volunteers. AB - BACKGROUND: Ultrasound assessment of optic nerve sheath diameter (ONSD) has been suggested as a non-invasive measure of intracranial pressure. Numerous small studies suggest its validity; however, discrepancy exists around normal values for ONSD. In this study we sought to define a normal value range for ONSD in a population of healthy adult volunteers. METHODS: ONSD was measured in healthy adult volunteers and a normal range was defined using descriptive statistics. A regression analysis was used to determine relationship between ONSD measurements and sex, age, height and weight. RESULTS: One hundred twenty adults were recruited (age 18-65 [mean 29.3]) with 55 male and 65 female subjects. Mean ONSD was 3.68 mm (95% confidence interval [CI], 2.85-4.40). Upon regression analysis, mean ONSD did not vary with age, weight, or height but did vary with sex. Mean ONSD measurements for men were 3.78 mm (95% CI, 3.23-4.48) compared with 3.60 mm (95% CI, 2.83-4.11) for women. CONCLUSION: This study has defined the range of ONSD in a healthy cohort of volunteers. The lack of relationship to age, weight and height is similar to other studies but this is the first study to find a difference depending on sex suggesting the possible need for separate reference ranges for men and women. PMID- 26596507 TI - Using the health belief model to predict breast self examination among Saudi women. AB - BACKGROUND: In the Kingdom of Saudi Arabia, breast cancer (BC) usually presents at advanced stages and more frequently in young pre-menopausal women in comparison to western countries. There is controversy surrounding the efficacy of breast self examination (BSE) for early detection of BC in countries where other methods are available. This study aims to explore the perception towards breast cancer and towards BSE among Saudi women, using the Health Belief Model (HBM). METHODS: A convenient sample of adult Saudi female employees, working at King Abdulaziz Medical City, Riyadh, Saudi Arabia (n = 225), and their non-working adult female family members (n = 208), were subjected to the Arabic version of revised Champion's Health Belief Model Scale (CHBMS) and the Arabic version of Breast Cancer Awareness Measure (CAM), to assess their knowledge and attitude on BC respectively. Percentage mean score (PMS) for each HBM domain was calculated. Significant predictors of BSE practice were identified using logistic regression analysis and significance was considered at p < 0.05. RESULTS: The majority of women heard about BSE (91.2 %), only 41.6 % reported ever practicing BSE and 21 % performed it regularly. Reported reasons for not doing BSE were: not knowing how to examine their breast (54.9 %), or untrusting themselves able to do it (24.5 %). Women were less knowledgeable about BC in general, its risk factors, warning signs, nature and screening measures (PMS:54.2 %, 44.5 %, 61.4 %, 53.2 %, 57.6 % respectively). They reported low scores of; perceived susceptibility, seriousness, confidence and barriers (PMS: 44.8 %, 55.6 %, 56.5 % & 41.7 % respectively), and high scores of perceived benefits and motivation (PMS: 73 % & 73.2 % respectively) to perform BSE. Significant predictors of BSE performance were: levels of perceived barriers (p = 0.046) and perceived confidence (p = 0.001) to BSE, overall knowledge on BC (p < 0.001), work status (p = 0.032) and family history of BC (p = 0.011). CONCLUSIONS: Saudi women had poor knowledge on BC, reported negative attitude towards BSE and their practice was poor. Working women and those with family history of BC, higher perceived confidence and lower perceived barriers on HBM, and those with high level of knowledge on BC were more likely to perform BSE. Breast awareness as an alternative to BSE needs further investigations. HBM was shown as a valid tool to predict BSE practice among Saudi women. PMID- 26596506 TI - Sexual life and dysfunction after maternal morbidity: a systematic review. AB - BACKGROUND: Because there is a lack of knowledge on the long-term consequences of maternal morbidity/near miss episodes on women's sexual life and function we conducted a systematic review with the purpose of identifying the available evidence on any sexual impairment associated with complications from pregnancy and childbirth. METHODS: Systematic review on aspects of women sexual life after any maternal morbidity and/or maternal near miss, during different time periods after delivery. The search was carried out until May 22(nd), 2015 including studies published from 1995 to 2015. No language or study design restrictions were applied. Maternal morbidity as exposure was split into general or severe/near miss. Female sexual outcomes evaluated were dyspareunia, Female Sexual Function Index (FSFI) scores and time to resume sexual activity after childbirth. Qualitative syntheses for outcomes were provided whenever possible. RESULTS: A total of 2,573 studies were initially identified, and 14 were included for analysis after standard selection procedures for systematic review. General morbidity was mainly related to major perineal injury (3(rd) or 4(th) degree laceration, 12 studies). A clear pattern for severity evaluation of maternal morbidity could not be distinguished, unless when a maternal near miss concept was used. Women experiencing maternal morbidity had more frequently dyspareunia and resumed sexual activity later, when compared to women without morbidity. There were no differences in FSFI scores between groups. Meta-analysis could not be performed, since included studies were too heterogeneous regarding study design, evaluation of exposure and/or outcome and time span. CONCLUSION: Investigation of long-term repercussions on women's sexual life aspects after maternal morbidity has been scarcely performed, however indicating worse outcomes for those experiencing morbidity. Further standardized evaluation of these conditions among maternal morbidity survivors may provide relevant information for clinical follow-up and reproductive planning for women. PMID- 26596509 TI - The implementation of a nonpharmacologic protocol to prevent intensive care delirium. AB - PURPOSE: The purpose was to determine if the implementation of an evidence-based nonpharmacologic protocol reduced the percentage of time patients spent delirious in a medical intensive care unit (MICU) that already uses a sedation and mobility protocol. MATERIALS AND METHODS: This was a prospective, pre-post quality improvement project of MICU patients conducted from September 2013 to April 2014. Evidence-based effective nonpharmacologic interventions with nursing education were bundled into the project protocol: music, opening/closing of blinds, reorientation/cognitive stimulation, and eye/ear care. RESULTS: Patients were evaluated between September 2013 and April 2014, with 230 and 253 patients being included in the each phase. There was a 50.6% reduction (16.1% vs 9.6%, P < .001) in time spent delirious in the MICU. Incidence of delirium developed was decreased (15.7% vs 9.4%, P = .04). The protocol reduced the odds of developing delirium by 57% (odds ratio, 0.43; P = .005) after controlling for age, Acute Physiology and Chronic Health Evaluation II, mechanical ventilation, and dementia. CONCLUSIONS: The implementation of a nonpharmacologic delirium prevention protocol resulted in a significant decrease in the percentage of time spent delirious in the MICU while reducing the risk of delirium development. Additional studies with more rigorous study designs need to be completed to further the research of nonpharmacologic interventions with appropriate sedation and mobility protocols. PMID- 26596510 TI - Finding the red flags: Swallowing difficulties after cardiac surgery in patients with prolonged intubation. AB - PURPOSE: This retrospective audit set out to identify referral rates, swallowing characteristics, and risk factors for dysphagia and silent aspiration in at-risk patients after cardiac surgery. Dysphagia and silent aspiration are associated with poorer outcomes post cardiac surgery. METHODS: One hundred ninety patients who survived cardiac surgery and received more than 48 hours of intubation were included. Preoperative, perioperative, and postoperative information was collected. RESULTS: Forty-one patients (22%) were referred to speech-language pathology for a swallowing assessment. Twenty-four of these patients (13%) underwent instrumental swallowing assessment, and silent aspiration was observed in 17 (70% of patients diagnosed as having dysphagia via instrumental assessment). Multilogistic analysis revealed previous stroke (P < .05), postoperative stroke (P < .001), and tracheostomy (P < .001) independently associated with dysphagia. The odds ratio for being diagnosed as having pneumonia, if a patient was diagnosed as having dysphagia, was 3.3. CONCLUSIONS: Patients identified with dysphagia after cardiac surgery had a high incidence of silent aspiration and increased risk of pneumonia. However, referral rates were low in this at-risk patient group. Early identification and ongoing assessment and appropriate management of dysphagic patients by a speech-language pathologist are strongly recommended. PMID- 26596512 TI - A pilot study investigating the efficacy of botanical anti-inflammatory agents in an OTC eczema therapy. AB - BACKGROUND: Eczema is a frequently encountered dermatologic condition characterized by inflammation resulting in erythema, scaling, induration, and lichenification. AIMS: The objective of this research was to examine the roll of botanical anti-inflammatories in alleviating the signs and symptoms of mild-to moderate eczema. METHOD: A total of 25 subjects 18+ years of age with mild-to moderate eczema were asked to leave all oral medications and cleansers unchanged substituting the botanical study moisturizer for all topical treatment three times daily for 2 weeks. Investigator, subject, and noninvasive assessments were obtained at baseline and week 2. RESULTS: There was a highly statistically significant (P < 0.001) improvement in investigator-assessed irritation, erythema, desquamation, roughness, dryness, lichenification, itching, and overall skin appearance after 2 weeks of botanical anti-inflammatory moisturizer use. Overall, a 79% reduction in itching was noted. Skin hydration as measured by corneometry increased 44% increase (P < 0.001). CONCLUSIONS: The study moisturizer containing the occlusive ingredients of dimethicone and shea butter oil; the humectant ingredients of glycerin, vitamin B, sodium PCA, and sodium hyaluronate; the barrier repair ingredients of ceramide 3, cholesterol, phytosphingosine, ceramide 6 II, and ceramide 1; and the botanical anti inflammatories allantoin and bisabolol were helpful in reducing the signs and symptoms of mild-to-moderate eczema. PMID- 26596511 TI - Reprint of "Oxidant and environmental toxicant-induced effects compromise DNA ligation during base excision DNA repair". AB - DNA lesions arise from many endogenous and environmental agents, and such lesions can promote deleterious events leading to genomic instability and cell death. Base excision repair (BER) is the main DNA repair pathway responsible for repairing single strand breaks, base lesions and abasic sites in mammalian cells. During BER, DNA substrates and repair intermediates are channeled from one step to the next in a sequential fashion so that release of toxic repair intermediates is minimized. This includes handoff of the product of gap-filling DNA synthesis to the DNA ligation step. The conformational differences in DNA polymerase beta (pol beta) associated with incorrect or oxidized nucleotide (8-oxodGMP) insertion could impact channeling of the repair intermediate to the final step of BER, i.e., DNA ligation by DNA ligase I or the DNA Ligase III/XRCC1 complex. Thus, modified DNA ligase substrates produced by faulty pol beta gap-filling could impair coordination between pol beta and DNA ligase. Ligation failure is associated with 5'-AMP addition to the repair intermediate and accumulation of strand breaks that could be more toxic than the initial DNA lesions. Here, we provide an overview of the consequences of ligation failure in the last step of BER. We also discuss DNA-end processing mechanisms that could play roles in reversal of impaired BER. PMID- 26596514 TI - Postcranial osteogenesis of the helmeted water toad Calyptocephalella gayi (Neobatrachia: Calyptocephalellidae) with comments on the osteology of australobatrachians. AB - Calyptocephalella gayi is one of over 6,000 neobatrachians arranged into two main groups, Hyloides and Ranoides. Phylogenetically, C. gayi is placed in Australobatrachia, a Gondwanan clade that is either the most basal clade of Hyloides or the sister group of Hyloidea, depending on the cladistic hypothesis; as such, this species is a key taxon in the study of the early evolution of Neobatrachia. The ontogeny of the postcranial skeleton of C. gayi is described in this article. The description is based on pattern of chondrification and ossification of skeletal elements in a growth series of tadpoles, on juveniles and adult individuals. Particular attention was devoted to some developmental aspects and morphological traits of the adult skeleton. The body of Presacral Vertebra VIII is formed from three centers of ossification, in contrast to the usual two dorsolateral centers observed in the remaining vertebrae of C. gayi, as well as in most anuran taxa for which the development of the axial skeleton is known. Each half of the pelvic girdle arises from a single cartilaginous element. The early development of the autopodia of both the forelimb and hindlimb includes the presence of an additional chondral element, which occurs during the formation of Distal Carpal 5 and the transient formation of Distal Tarsal 4 before the latter is incorporated in the cartilaginous distal end of the fibular. Some osteological aspects of other australobatrachian anurans also are reviewed (e.g., presence of intervertebral discs) based on reports in the literature, as well as first hand observations. In the course of this study, it became evident that further osteological studies are needed to formulate a clear picture of the evolution of skeletal characters not only within Australobatrachia, but also within Neobatrachia. PMID- 26596513 TI - Structurally Defined Molecular Hypervalent Iodine Catalysts for Intermolecular Enantioselective Reactions. AB - Molecular structures of the most prominent chiral non-racemic hypervalent iodine(III) reagents to date have been elucidated for the first time. The formation of a chirally induced supramolecular scaffold based on a selective hydrogen-bonding arrangement provides an explanation for the consistently high asymmetric induction with these reagents. As an exploratory example, their scope as chiral catalysts was extended to the enantioselective dioxygenation of alkenes. A series of terminal styrenes are converted into the corresponding vicinal diacetoxylation products under mild conditions and provide the proof of principle for a truly intermolecular asymmetric alkene oxidation under iodine(I/III) catalysis. PMID- 26596516 TI - Long-Range Charge Transport in Adenine-Stacked RNA:DNA Hybrids. AB - An extremely important biological component, RNA:DNA can also be used to design nanoscale structures such as molecular wires. The conductance of single adenine stacked RNA:DNA hybrids is rapidly and reproducibly measured using the break junction approach. The conductance decreases slightly over a large range of molecular lengths, suggesting that RNA:DNA can be used as an oligonucleotide wire. PMID- 26596517 TI - SATB2-associated syndrome presenting with Rett-like phenotypes. AB - The SATB2-associated syndrome (SAS) was proposed recently, after the SATB2 gene was initially discovered to be associated with isolated cleft palate. This syndrome is characterized by intellectual disability with delayed speech development, facial dysmorphism, cleft or high-arched palate, and dentition problems. Here, we describe two novel SATB2 sequence variants in two unrelated patients presenting with Rett-like phenotypes. We performed trio-based whole exome sequencing in a 17-month-old girl presenting with severe retardation and Rett-like phenotypes, which revealed a de novo missense variant in SATB2 (p.Glu396Gln). Moreover, targeted sequencing of the SATB2 gene was performed in a 2-year-old girl with severe psychomotor retardation, facial hypotonia, and cleft palate who also exhibited some features of Rett syndrome. A nonsense variant in SATB2 was identified in this patient (p.Arg459*). This study expanded the clinical and genetic spectrum of SAS. SATB2 variants should be considered in cases with psychomotor retardation alone or in any cases with Rett-like phenotypes, regardless of the typical features of SAS such as cleft palate. PMID- 26596518 TI - Hybridization-Induced Carrier Localization at the C60 /ZnO Interface. AB - Electronic coupling and ground-state charge transfer at the C60 /ZnO hybrid interface is shown to localize carriers in the C60 phase. This effect, revealed by resonant X-ray photoemission, arises from interfacial hybridization between C60 and ZnO. Such localization at carrier-selective electrodes and interlayers may lead to severely reduced carrier harvesting efficiencies and increased recombination rates in organic electronic devices. PMID- 26596519 TI - IMAGING DIAGNOSIS-MULTIMODALITY FINDINGS IN AN ADULT DOG WITH PRIMARY SARCOMA OF THE PULMONARY ARTERY AND MYOCARDIAL METASTASES. AB - Intravascular pulmonary artery sarcomas in combination with myocardial metastasis are rare in dogs. We describe the radiographic, echocardiographic, and electrocardiographic-gated (ECG-gated) computed tomographic angiography (CTA) findings in a dog with pulmonary artery sarcoma. All imaging studies demonstrated severe main pulmonary artery enlargement. Echocardiography and ECG-gated CTA revealed a mass occluding the lumen of the right pulmonary artery. In addition, CTA revealed focal left ventricular myocardial contrast enhancement and parenchymal lung changes. Postmortem examination confirmed the presence of a large thrombus associated with arteriosclerosis and an intravascular sarcoma in the right pulmonary artery with metastases to the myocardium, lungs and brain. PMID- 26596520 TI - Altered sensitization patterns to sweet food stimuli in patients recovered from anorexia and bulimia nervosa. AB - Recent studies show that higher-order appetitive neural circuitry may contribute to restricted eating in anorexia nervosa (AN) and overeating in bulimia nervosa (BN). The purpose of this study was to determine whether sensitization effects might underlie pathologic eating behavior when a taste stimulus is administered repeatedly. Recovered AN (RAN, n=14) and BN (RBN, n=15) subjects were studied in order to avoid the confounding effects of altered nutritional state. Functional magnetic resonance imaging (fMRI) measured higher-order brain response to repeated tastes of sucrose (caloric) and sucralose (non-caloric). To test sensitization, the neuronal response to the first and second administration was compared. RAN patients demonstrated a decreased sensitization to sucrose in contrast to RBN patients who displayed the opposite pattern, increased sensitization to sucrose. However, the latter was not as pronounced as in healthy control women (n=13). While both eating disorder subgroups showed increased sensitization to sucralose, the healthy controls revealed decreased sensitization. These findings could reflect on a neuronal level the high caloric intake of RBN during binges and the low energy intake for RAN. RAN seem to distinguish between high energy and low energy sweet stimuli while RBN do not. PMID- 26596522 TI - [Meningiomas in the elderly]. PMID- 26596521 TI - Schizophrenia symptom and functional correlates of anterior cingulate cortex activation to emotion stimuli: An fMRI investigation. AB - Schizophrenia is a chronic mental illness characterized by distinct positive and negative symptoms and functional impairment. The anterior cingulate cortex (ACC) is a region of the brain's limbic system that is hypoactive during emotion processing in schizophrenia. Recent evidence suggests the hypoactive ACC in schizophrenia is due to negative (and not positive) symptoms. However, this finding has not been replicated and the functional significance of this relationship remains unclear. The present study examined the association between positive and negative symptoms, ACC activation to emotional images, and functional outcome in schizophrenia. Specifically, 16 schizophrenia/schizoaffective disorder (SZ/SZAF) and 15 control (CON) participants underwent an fMRI scan while completing an emotional picture-rating task. SZ/SZAF participants also completed clinician-rated measures of positive and negative symptoms and functional abilities. SZ/SZAF participants with high negative symptoms had reduced ACC activation to pleasant images relative to those with low negative symptoms and CON, who did not differ. Furthermore, amongst all SZ/SZAF participants poorer social functioning was associated with decreased ACC activation to pleasant images. Finally, ACC activation partially mediated the relationship between negative symptoms and social dysfunction. These results provide evidence of the functional significance of the relationship between negative symptoms and ACC dysfunction in schizophrenia. PMID- 26596523 TI - [Hyperglycaemia is associated with worse outcomes in Latin-American individuals with acute myocardial infarction]. AB - BACKGROUND: Alterations in glucose metabolism have been reported as risk and poor prognostic factors for acute myocardial infarction (AMI); however in Latin American population this information is limited. Thus, an evaluation was performed on the association between glycaemic status and short- and long-term outcomes in patients with a first AMI. METHODS: A multicentre, prospective, observational, cohort study was conducted in 8 hospitals from Colombia and Ecuador. RESULTS: A total of 439 patients with confirmed AMI were included, of which 305 (69.5%) had prediabetes or type2 diabetes mellitus (DM2). Compared with normal glycaemia group, patients with known DM2 had greater risk of prolonged hospital stay (HR: 2.60, 95%CI: 1.38-4.92, P=.003), Killip class iii/iv (HR: 9.46, 95%CI: 2.20-40.62, P=.002), and in-hospital heart failure (HR: 10.76, 95%CI: 3.37-34.31, P<.001). Patients with prediabetes, new DM2, and known DM2 showed higher rates of major adverse cardiovascular events after 3years follow up. CONCLUSION: Glucose metabolism abnormalities have an important significance in the short- and long-term prognosis in Latin-American patients that survive a first AMI. PMID- 26596524 TI - Next-Generation Sequencing and Fluorescence in Situ Hybridization Have Comparable Performance Characteristics in the Analysis of Pancreaticobiliary Brushings for Malignancy. AB - Cytological evaluation of pancreatic or biliary duct brushings is a specific, but insensitive, test for malignancy. We compared adjunctive molecular testing with next-generation sequencing (NGS) relative to fluorescence in situ hybridization (FISH) for detection of high-risk neoplasia or malignancy. Bile duct brushings from 81 specimens were subjected to cytological analysis, FISH using the UroVysion probe set, and targeted NGS. Specimens were placed into negative/atypical (negative) or suspicious/positive (positive) categories depending on cytology and negative or positive categories on the basis of FISH and NGS results. Performance characteristics for each diagnostic modality were calculated on the basis of clinicopathologic follow-up and compared in a receiver operating characteristic analysis. There were 33 high-risk neoplasia/malignant strictures (41%) and 48 benign (59%). NGS revealed driver mutations in 24 cases (30%), including KRAS (21 of 24 cases), TP53 (14 of 24 cases), SMAD4 (6 of 24 cases), and CDKN2A (4 of 24 cases). Cytology had a sensitivity of 67% (95% CI, 48%-82%) and a specificity of 98% (95% CI, 89%-100%). When added to cytology, NGS increased the sensitivity to 85% (95% CI, 68%-95%), leading to a significant increase in the area under the curve in a receiver operating characteristic analysis (P = 0.03). FISH increased the sensitivity to 76% (95% CI, 58%-89%), without significantly increasing the area under the curve. These results suggest that ancillary NGS testing offers advantages over FISH, although studies with larger cohorts are needed to verify these findings. PMID- 26596525 TI - Quantification of the Mutant CALR Allelic Burden by Digital PCR: Application to Minimal Residual Disease Evaluation after Bone Marrow Transplantation. AB - With the recent discovery of CALR mutations, >80% of patients with myeloproliferative neoplasms carry a phenotype-driving mutation. For JAK2 V617F, the most frequent mutation in myeloproliferative neoplasms, accurate determination of mutational loads is of interest at diagnosis, for phenotypic and prognostic purposes, and during follow-up for minimal residual disease assessment. We developed a digital PCR technique that allowed the accurate determination of CALR allelic burdens for the main mutations (types 1 and 2). Compared with the commonly used fluorescent PCR product analysis, digital PCR is more precise, reproducible, and accurate. Furthermore, this method reached a very high sensitivity. We detected at least 0.025% CALR mutants. It can thus be used for patient characterization at diagnosis and for minimal residual disease monitoring. When applied to patients with primary myelofibrosis who underwent hematopoietic stem cell transplant, the digital PCR detected low levels of minimal residual disease. After negativation of the mutational load in all patients, the disease reappeared at a low level in one patient, preceding hematologic relapse. In conclusion, digital PCR adapted to type 1 and 2 CALR mutations is an inexpensive, highly precise, and sensitive technique suitable for evaluation of myeloproliferative neoplasm patients during follow-up. PMID- 26596526 TI - Ultrasensitive Detection of Multiplexed Somatic Mutations Using MALDI-TOF Mass Spectrometry. AB - Multiplex detection of low-frequency mutations is becoming a necessary diagnostic tool for clinical laboratories interested in noninvasive prognosis and prediction. Challenges include the detection of minor alleles among abundant wild type alleles, the heterogeneous nature of tumors, and the limited amount of available tissue. A method that can reliably detect minor variants <1% in a multiplexed reaction using a platform amenable to a variety of throughputs would meet these requirements. We developed a novel approach, UltraSEEK, for high throughput, multiplexed, ultrasensitive mutation detection and used it for detection of mutant sequence mixtures as low as 0.1% minor allele frequency. The process consisted of multiplex PCR, followed by mutation-specific, single-base extension using chain terminators labeled with a moiety for solid phase capture. The captured and enriched products were then identified using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. For verification, we successfully analyzed ultralow fractions of mutations in a set of characterized cell lines, and included a direct comparison to droplet digital PCR. Finally, we verified the specificity in a set of 122 paired tumor and circulating cell-free DNA samples from melanoma patients. Our results show that the UltraSEEK chemistry is a particularly powerful approach for the detection of somatic variants, with the potential to be an invaluable resource to investigators in saving time and material without compromising analytical sensitivity and accuracy. PMID- 26596527 TI - Effects of Quadripulse Stimulation on Human Motor Cortex Excitability: A Replication Study. PMID- 26596528 TI - Life history trade-offs imposed by dragline use in two money spiders. AB - Trade-offs among life history traits are central to understanding the limits of adaptations to stress. In animals, virtually all decisions taken during life are expected to have downstream consequences. To what degree rare, but energy demanding, decisions carry over to individual performance is rarely studied in arthropods. We used spiders as a model system to test how single investments in silk use - for dispersal or predator escape - affect individual performance. Silk produced for safe lines and as threads for ballooning is of the strongest kind and is energetically costly, especially when resources are limited. We induced dragline spinning in two species of money spider at similar quantities to that under natural conditions and tested trade-offs with lifespan and egg sac production under unlimited prey availability and a dietary restriction treatment. We demonstrate strong trade-offs between dragline spinning and survival and fecundity. Survival trade-offs were additive to those imposed by the dietary treatment, but a reduction in eggs produced after silk use was only prevalent under conditions where food was restricted during the spider's life. Because draglines are not recycled after their use for dispersal or predator escape, their spinning incurs substantial fitness costs in dispersal, especially in environments with prey limitation. Rare but energetically costly decisions related to dispersal or predator escape may thus carry over to adult performance and explain phenotypic heterogeneity in natural populations. PMID- 26596529 TI - Convergence of joint mechanics in independently evolving, articulated coralline algae. AB - Flexible joints are a key innovation in the evolution of upright coralline algae. These structures have evolved in parallel at least three separate times, allowing the otherwise rigid, calcified thalli of upright corallines to achieve flexibility when subjected to hydrodynamic stress. As all bending occurs at the joints, stress is amplified, which necessitates that joints be made of material that is both extensible and strong. Data presented here indicate that coralline joints are in fact often stronger and more extensible, as well as tougher, than fleshy seaweed tissues. Corallinoids are particularly strong and tough, which is largely due to the presence of secondary cell walls that strengthen the joint tissue without adding bulk to the joint itself. Cell wall thickness is shown to be a large contributing factor to strength across all groups, with the exception of the corallinoid Cheilosporum sagittatum, which likely possesses distinct chemical composition in its walls to increase strength beyond that of all other species tested. PMID- 26596530 TI - Tail loss and narrow surfaces decrease locomotor stability in the arboreal green anole lizard (Anolis carolinensis). AB - Tails play an important role in dynamic stabilization during falling and jumping in lizards. Yet tail autotomy (the voluntary loss of an appendage) is a common mechanism used for predator evasion in these animals. How tail autotomy has an impact on locomotor performance and stability remains poorly understood. The goal of this study was to determine how tail loss affects running kinematics and performance in the arboreal green anole lizard, Anolis carolinensis. Lizards were run along four surface widths (9.5 mm, 15.9 mm, 19.0 mm and flat), before and following 75% tail autotomy. Results indicate that when perturbed with changes in surface breadth and tail condition, surface breadth tends to have greater impacts on locomotor performance than tail loss. Furthermore, while tail loss does have a destabilizing effect during regular running in these lizards, its function during steady locomotion is minimal. Instead, the tail probably plays a more active role during dynamic maneuvers that require dramatic changes in whole body orientation or center of mass trajectories. PMID- 26596531 TI - XROMM analysis of rib kinematics during lung ventilation in the green iguana, Iguana iguana. AB - The three-dimensional rotations of ribs during breathing are typically described as bucket-handle rotation about a dorsoventrally oriented axis, pump-handle rotation about a mediolateral axis, and caliper rotation about a rostrocaudal axis. In amniotes with double-headed ribs, rib motion is constrained primarily to one degree-of-freedom (DOF) rotation about an axis connecting the two rib articulations. However, in Squamata, the ribs are single headed and the hemispherical costovertebral joints permit rotations with three DOF. In this study, we used X-ray reconstruction of moving morphology (XROMM ) to quantify rib rotation during deep breathing in four green iguanas. We found that rib rotation was strongly dominated by bucket-handle rotation, thus exhibiting nearly hinge like motion, despite the potential for more complex motions. The vertebral and sternal segments of each rib did not deform measurably during breathing, but they did move relative to each other at a thin, cartilaginous intracostal joint. While standing still and breathing deeply, four individual iguanas showed variability in their rib postures, with two breathing around a highly inflated posture, and two breathing around a posture with the ribs folded halfway back. Bucket-handle rotations showed clear rostrocaudal gradients, with rotation increasing from the third cervical to the first or second dorsal rib, and then decreasing again caudally, a pattern that is consistent with the intercostal muscles in the rostral intercostal spaces being the primary drivers of inspiration. The constrained, primarily bucket-handle rotations observed here during breathing do not help to explain the evolution of permissive, hemispherical costovertebral joints in squamates from the more constrained, double-headed rib articulations of other amniotes. PMID- 26596532 TI - Accelerated behavioural development changes fine-scale search behaviour and spatial memory in honey bees (Apis mellifera L.). AB - Normally, worker honey bees (Apis mellifera) begin foraging when more than 2 weeks old as adults, but if individual bees or the colony is stressed, bees often begin foraging precociously. Here, we examined whether bees that accelerated their behavioural development to begin foraging precociously differed from normal aged foragers in cognitive performance. We used a social manipulation to generate precocious foragers from small experimental colonies and tested their performance in a free-flight visual reversal learning task, and a test of spatial memory. To assess spatial memory, bees were trained to learn the location of a small sucrose feeder within an array of three landmarks. In tests, the feeder and one landmark were removed and the search behaviour of the bees was recorded. Performance of precocious and normal-aged foragers did not differ in a visual reversal learning task, but the two groups showed a clear difference in spatial memory. Flight behaviour suggested normal-aged foragers were better able to infer the position of the removed landmark and feeder relative to the remaining landmarks than precocious foragers. Previous studies have documented the cognitive decline of old foragers, but this is the first suggestion of a cognitive deficit in young foragers. These data imply that worker honey bees continue their cognitive development during the adult stage. These findings may also help to explain why precocious foragers perform quite poorly as foragers and have a higher than normal loss rate. PMID- 26596533 TI - The effects of hypoxic bradycardia and extracellular HCO3(-)/CO2 on hypoxic performance in the eel heart. AB - During hypoxia, fishes exhibit a characteristic hypoxic bradycardia, the functional significance of which remains debated. Here, we investigated the hypothesis that hypoxic bradycardia primarily safeguards cardiac performance. In preparations from the European eel (Anguilla anguilla), a decrease in stimulation frequency from 40 to 15 beats min(-1), which replicates hypoxic bradycardia in vivo, vastly improved cardiac performance during hypoxia in vitro. As eels display dramatic shifts in extracellular HCO3(-)/CO2, we further investigated the effect this has upon hypoxic cardiac performance. Elevations from 10 mmol l(-1) HCO3(-)/1% CO2 to 40 mmol l(-1) HCO3(-)/4% CO2 had few effects on performance; however, further, but still physiologically relevant, increases to 70 mmol l(-1) HCO3(-)/7% CO2 compromised hypoxia tolerance. We revealed a four-way interaction between HCO3(-)/CO2, contraction frequency, hypoxia and performance over time, whereby the benefit of hypoxic bradycardia was most prolonged at 10 mmol l(-1) HCO3(-)/1% CO2. Together, our data suggest that hypoxic bradycardia greatly benefits cardiac performance, but its significance may be context specific. PMID- 26596534 TI - Body ram, not suction, is the primary axis of suction-feeding diversity in spiny rayed fishes. AB - Suction-feeding fishes exhibit diverse prey-capture strategies that vary in their relative use of suction and predator approach (ram), which is often referred to as the ram-suction continuum. Previous research has found that ram varies more than suction distance among species, such that ram accounts for most differences in prey-capture behaviors. To determine whether these findings hold at broad evolutionary scales, we collected high-speed videos of 40 species of spiny-rayed fishes (Acanthomorpha) feeding on live prey. For each strike, we calculated the contributions of suction, body ram (swimming) and jaw ram (mouth movement relative to the body) to closing the distance between predator and prey. We confirm that the contribution of suction distance is limited even in this phylogenetically and ecologically broad sample of species, with the extreme suction area of prey-capture space conspicuously unoccupied. Instead of a continuum from suction to ram, we find that variation in body ram is the major factor underlying the diversity of prey-capture strategies among suction-feeding fishes. Independent measurement of the contribution of jaw ram revealed that it is an important component of diversity among spiny-rayed fishes, with a number of ecomorphologies relying heavily on jaw ram, including pivot feeding in syngnathiforms, extreme jaw protruders and benthic sit-and-wait ambush predators. A combination of morphological and behavioral innovations has allowed fish to invade the extreme jaw ram area of prey-capture space. We caution that while two species comparisons may support a ram-suction trade-off, these patterns do not speak to broader patterns across spiny-rayed fishes. PMID- 26596535 TI - Comparative limb bone loading in the humerus and femur of the tiger salamander: testing the 'mixed-chain' hypothesis for skeletal safety factors. AB - Locomotion imposes some of the highest loads upon the skeleton, and diverse bone designs have evolved to withstand these demands. Excessive loads can fatally injure organisms; however, bones have a margin of extra protection, called a 'safety factor' (SF), to accommodate loads that are higher than normal. The extent to which SFs might vary amongst an animal's limb bones is unclear. If the limbs are likened to a chain composed of bones as 'links', then similar SFs might be expected for all limb bones because failure of the system would be determined by the weakest link, and extra protection in other links could waste energetic resources. However, Alexander proposed that a 'mixed-chain' of SFs might be found amongst bones if: (1) their energetic costs differ, (2) some elements face variable demands, or (3) SFs are generally high. To test whether such conditions contribute to diversity in limb bone SFs, we compared the biomechanical properties and locomotor loading of the humerus and femur in the tiger salamander (Ambystoma tigrinum). Despite high SFs in salamanders and similar sizes of the humerus and femur that would suggest similar energetic costs, the humerus had lower bone stresses, higher mechanical hardness and larger SFs. SFs were greatest in the anatomical regions where yield stresses were highest in the humerus and lowest in the femur. Such intraspecific variation between and within bones may relate to their different biomechanical functions, providing insight into the emergence of novel locomotor capabilities during the invasion of land by tetrapods. PMID- 26596536 TI - The association between parental life history and offspring phenotype in Atlantic salmon. AB - In many taxa there is considerable intraspecific variation in life history strategies from within a single population, reflecting alternative routes through which organisms can achieve successful reproduction. Atlantic salmon Salmo salar (Linnaeus) show some of the greatest within-population variability in life history strategies amongst vertebrates, with multiple discrete male and female life histories co-existing and interbreeding on many spawning grounds, although the effect of the various combinations of life histories on offspring traits remains unknown. Using crosses of wild fish we show here that the life history strategy of both parents was significantly associated with a range of offspring traits. Mothers that had spent longer at sea (2 versus 1 year) produced offspring that were heavier, longer and in better condition at the time of first feeding. However, these relationships disappeared shortly after fry had begun feeding exogenously. At this stage, the juvenile rearing environment (i.e. time spent in fresh water as juveniles) of the mother was a better predictor of offspring traits, with mothers that were faster to develop in fresh water (migrating to sea after two rather than three years of age) producing offspring that had higher maximal metabolic rates, aerobic scopes, and that grew faster. Faster developing fathers (1 year old sneaker males) tended to produce offspring that had higher maximal metabolic rates, were in better body condition and grew faster. The results suggest that both genetic effects and those related to parental early and late life history contribute to offspring traits. PMID- 26596537 TI - Big brown bats (Eptesicus fuscus) emit intense search calls and fly in stereotyped flight paths as they forage in the wild. AB - The big brown bat, Eptesicus fuscus, uses echolocation for orientation and foraging, and scans its surroundings by aiming its sonar beam at obstacles and prey. All call parameters are highly adaptable and determine the bat's acoustic field of view and hence its perception of the echo scene. The intensity (source level) and directionality of the emitted calls directly contribute to the bat's acoustic field of view; however, the source level and directionality of the big brown bat's sonar signals have not been measured in the field. In addition, for bats, navigation and prey capture require that they process several streams of acoustic information. By using stereotypic flight paths in known areas, bats may be able to reduce the sensory processing load for orientation and therefore allocate echo processing resources to prey. Here we recorded the echolocation calls from foraging E. fuscus in the field with a microphone array and estimated call intensity and directionality, based on reconstructed flight trajectories. The source levels were intense with an average maximum source level of 138 dB (root mean square re. 20 uPa at 0.1 m). Furthermore, measurements taken from a subset of calls indicate that the echolocation signals in the field may be more directional than estimated in the laboratory (half-amplitude angle 30 deg at 35 kHz). We also observed that E. fuscus appear to follow stereotypic flight paths, and propose that this could be a strategy to optimize foraging efficiency by minimizing the sensory processing load. PMID- 26596538 TI - Menthol-induced bleaching rapidly and effectively provides experimental aposymbiotic sea anemones (Aiptasia sp.) for symbiosis investigations. AB - Experimental manipulation of the symbiosis between cnidarians and photosynthetic dinoflagellates (Symbiodinium spp.) is crucial to advancing the understanding of the cellular mechanisms involved in host-symbiont interactions, and overall coral reef ecology. The anemone Aiptasia sp. is a model for cnidarian-dinoflagellate symbiosis, and notably it can be rendered aposymbiotic (i.e. dinoflagellate-free) and re-infected with a range of Symbiodinium types. Various methods exist for generating aposymbiotic hosts; however, they can be hugely time consuming and not wholly effective. Here, we optimise a method using menthol for production of aposymbiotic Aiptasia. The menthol treatment produced aposymbiotic hosts within just 4 weeks (97-100% symbiont loss), and the condition was maintained long after treatment when anemones were held under a standard light:dark cycle. The ability of Aiptasia to form a stable symbiosis appeared to be unaffected by menthol exposure, as demonstrated by successful re-establishment of the symbiosis when anemones were experimentally re-infected. Furthermore, there was no significant impact on photosynthetic or respiratory performance of re-infected anemones. PMID- 26596539 TI - Diffusion-weighted MR imaging of pancreatic cancer and inflammation: Prognostic significance of pancreatic inflammation in pancreatic cancer patients. AB - BACKGROUND: Pancreatic cancer often accompanies chronic obstructive pancreatitis (COP) due to obstruction of the main pancreatic duct, and the inflammatory environment may enhance cancer progression. The purpose of this study is to evaluate COP using the apparent diffusion coefficient (ADC) value measured by diffusion-weighted MR imaging (DWI), and to assess its prognostic significance in pancreatic cancer. METHODS: Twenty-eight patients (16 men, 12 women; mean age 67.1 years) with pancreatic cancers who underwent DWI followed by curative surgery were evaluated. The ADC value of pancreatic parenchyma upstream to the tumor (upstream pancreas) was measured and compared with the upstream pancreatic duct dilatation to assess whether DWI could reflect COP. The ADC values of tumor and upstream portion were compared with overall survival (OS) using Cox regression and Kaplan-Meier analysis. RESULTS: The ADC value of upstream pancreas was significantly lower in patients with greater dilated pancreatic duct than those with less (P = 0.03). In univariate Cox regression analysis, the ADC value of upstream pancreas showed a significant association with OS (P = 0.01), but that of tumor did not (P = 0.06). In Kaplan-Meier analysis, patients with lower ADC value of upstream pancreas (<1.36 * 10(-3) mm(2)/s) were significantly associated with poor OS (P = 0.0006). In multivariate analysis, the ADC value of upstream pancreas was identified as an independent prognostic factor (P = 0.01; hazards ratio, 0.05; 95% CI, 0.004-0.59). CONCLUSIONS: The ADC value of upstream pancreas was an independent prognostic factor for OS in pancreatic cancer patients. Inflammatory environment may play an important role in pancreatic cancer progression. PMID- 26596540 TI - Cognitive behaviour therapy for non-cardiac pain in the chest (COPIC): a multicentre randomized controlled trial with economic evaluation. AB - BACKGROUND: Most patients with chest pain have nothing wrong with their cardiac function. Psychological forms of treatment for this condition are more likely to be successful than others. METHODS/DESIGN: A two-arm parallel controlled randomized trial of standard care versus a modified form of cognitive behaviour therapy for chest pain (CBT-CP) in patients who have attended emergency hospital services. Inclusion criteria include (i) emergency attendance more than once in the previous year with chest pain when no physical pathology has been found, (ii) aged between 16 and 75, (iii) signed consent to take part in the study. Exclusion criteria are (i) under current psychiatric care, (ii) those who have had new psychotropic drugs prescribed within the last two months, (iii) are receiving or about to receive a formal psychological treatment. Those satisfying these criteria will be randomized to 4-10 sessions of CBT-CP or to continue with standard care. Participants are randomized using a remote web-based system using permuted stacked blocks stratified by study centre. Assessment is carried out at baseline by researchers subsequently masked to allocation and at 6 months and 1 year after randomization. The primary outcome is the Health Anxiety Inventory score at 6 months, and secondary outcomes are generalised anxiety and depressive symptoms, the Lucock Health Anxiety Questionnaire adapted for chest pain, visual analogue scales for chest pain and discomfort (Inskip Scale), the Schedule for Evaluating Persistent Symptoms (SEPS), health related quality of life, social functioning and medical resource usage. Intention to treat analyses will be carried out with clinical and functioning data, and a cost-utility analysis will compare differences in total costs and differences in quality of life using QALYs derived from the EQ-5D. The data will also be linked to another parallel study in New Zealand where 126 patients with the same inclusion criteria have been treated in a similar trial; the form of analysis of the combined data has yet to be determined. DISCUSSION: The morbidity and costs of non-cardiac chest pain are substantial and if a simple psychological treatment given by health professionals working in medical departments is beneficial it should prove to be of great value. Combining data with a similar study in New Zealand is an additional asset. TRIAL REGISTRATION: ISRCTN14711101 (registered 05/03/2015). PMID- 26596541 TI - Combined association of fitness and central adiposity with health-related quality of life in healthy Men: a cross-sectional study. AB - BACKGROUND: There is limited data examining the association of combined fitness and central obesity with health related quality of life (HRQoL) in adults. We examined the association of combined cardiorespiratory fitness (CRF) and waist-to height ratio (WHtR) in the form of a fit-fat index (FFI) with the Physical Component Summary (PCS) and Mental Component Summary (MCS) HRQoL scores in United States Navy servicemen. METHODS: As part of a health fitness assessment, a total of 709 healthy males aged 18-49 years completed a submaximal exercise test, WHtR measurement, and HRQoL survey (SF-12v2) between 2004 and 2006. FFI level was classified into thirds with the lowest FFI tertile serving as the referent group. PCS and MCS scores >=50 were taken to indicate average or better. Logistic regression was used to obtain odds ratios (OR) and 95% confidence intervals (CI). RESULTS: The prevalence of average or better HRQoL scores was lowest in the referent FFI tertile, PCS 60.2% and MCS 57.6%. Compared with the lowest FFI group in multivariate analyses, the OR (95% CI) of having average or better PCS was 1.63 (1.09-2.42) and 3.12 (1.95-4.99) for moderate and high FFI groups respectively; MCS was 1.70 (1.13-2.55) and 4.89 (3.03-7.89) for moderate and high FFI groups respectively (all P < 0.001). Consistent and progressive independent associations were observed between age and MCS, and also between CRF and MCS. CONCLUSION: Among males in the United States Navy, higher levels of FFI were independently and more consistently associated with having average or better HRQoL (physical and mental) than other known predictors of HRQoL. PMID- 26596542 TI - MERTK rs4374383 polymorphism affects the severity of fibrosis in non-alcoholic fatty liver disease. AB - BACKGROUND & AIM: Homozygosity for a common non-coding rs4374383 G>A polymorphism in MERTK (myeloid-epithelial-reproductive tyrosine kinase) has been associated with the protection against fibrosis progression in chronic hepatitis C. The main study objective was to assess whether MERTK AA genotype influences liver fibrosis, and secondarily MERTK expression in patients with non-alcoholic fatty liver disease (NAFLD). We also investigated whether MERTK is expressed in human hepatic stellate cells (HSC) and in murine models of fibrogenesis. METHODS: We considered 533 consecutive patients who underwent liver biopsy for suspected non alcoholic steatohepatitis (NASH) without severe obesity from two Italian cohorts. As controls, we evaluated 158 patients with normal liver enzymes and without metabolic disturbances. MERTK rs4374383 genotype was assessed by 5'-nuclease assays. MERTK expression was analysed in mouse models of fibrosis, and the effect of the MERTK ligand GAS6 were investigated in human HSC. RESULTS: Clinically significant fibrosis (stage F2-F4) was observed in 19% of patients with MERTK AA compared to 30% in those with MERTK GG/GA (OR 0.43, CI 0.21-0.88, p=0.02; adjusted for centre, and genetic, clinical-metabolic and histological variables). The protective rs4374383 AA genotype was associated with lower MERTK hepatic expression. MERTK was overexpressed in the liver of NAFLD patients with F2-F4 fibrosis and in in vivo models of fibrogenesis. Furthermore, exposure of cultured human HSC to the MERTK ligand GAS6, increased cell migration and induced procollagen expression. These effects were counteracted by inhibition of MERTK activity, which also resulted in apoptotic death of HSC. CONCLUSIONS: The rs4374383 AA genotype, associated with lower intrahepatic expression of MERTK, is protective against F2-F4 fibrosis in patients with NAFLD. The mechanism may involve modulation of HSC activation. PMID- 26596543 TI - Perioperative blood transfusion does not influence recurrence-free and overall survivals after curative resection for hepatocellular carcinoma: A Propensity Score Matching Analysis. AB - BACKGROUND & AIMS: Whether perioperative blood transfusions (PBTs) negatively impact oncologic outcomes after curative resection for HCC remains controversial. We aimed to identify the independent predictive factors of PBT for curative resection of hepatocellular carcinoma (HCC), and to investigate the impact of PBT on long-term recurrence and survivals after resection. METHODS: Of 1103 patients who underwent curative liver resection for HCC between 1999 and 2010, 285 (25.8%) patients received PBT. Univariable and multivariable regression analyses were used to identify independent predictive factors of PBT. Propensity scores and Cox regression analyses were used to compare the overall survival (OS) and recurrence free survival (RFS) between patients who did and did not receive PBT. RESULTS: Multivariable regression analysis revealed that performance status, preoperative hemoglobin, cirrhosis, portal hypertension, tumor rupture, tumor size, macroscopic vascular invasion, and intraoperative blood loss were independent predictive factors of PBT for HCC resection. Propensity score matching analysis created 234 pairs of patients. Before propensity matching, PBT was significantly associated with increased risks of OS (HR: 2.455, 95% CI: 2.077-2.901, p<0.001) and RFS (HR: 2.018, 95% CI: 1.718-2.370, p<0.001) in the entire cohort. After propensity matching, PBT was not significantly associated with increased risks of OS (HR: 1.229, 95% CI: 0.988-1.527, p=0.063) and RFS (HR: 1.188, 95% CI: 0.960 1.469, p=0.113). After adjustment for other prognostic variables in the propensity matched cohort, PBT was still found not to be associated with OS and RFS after HCC resection. CONCLUSIONS: The present study identified that PBT did not influence RFS and OS after curative resection of HCC. PMID- 26596544 TI - Persistent gammaH2AX: A promising molecular marker of DNA damage and aging. AB - One of the earliest cellular responses to DNA double strand breaks (DSBs) is the phosphorylation of the core histone protein H2AX (termed gammaH2AX). Persistent gammaH2AX is the level of gammaH2AX above baseline, measured at a given time point beyond which DNA DSBs are normally expected to be repaired (usually persist for days to months). This review summarizes the concept of persistent gammaH2AX in the context of exogenous source induced DNA DSBs (e.g. ionizing radiation (IR), chemotherapeutic drugs, genotoxic agents), and endogenous gammaH2AX levels in normal aging and accelerated aging disorders. Summary of the current literature demonstrates the following (i) gammaH2AX persistence is a common phenomenon that occurs in humans and animals; (ii) nuclei retain persistent gammaH2AX foci for up to several months after IR exposure, allowing for retrospective biodosimetry; (iii) the combination of various radiosensitizing drugs with ionizing radiation exposure leads to persistent gammaH2AX response, thus enabling the potential for monitoring cancer patients' response to chemotherapy and radiotherapy as well as tailoring cancer treatments; (iv) persistent gammaH2AX accumulates in telomeric DNA and in cells undergoing cellular senescence; and (v) increased endogenous gammaH2AX levels may be associated with diseases of accelerated aging. In summary, measurement of persistent gammaH2AX could potentially be used as a marker of radiation biodosimetry, evaluating sensitivity to therapeutic genotoxins and radiotherapy, and exploring the association of unrepaired DNA DSBs on telomeres with diseases of accelerated aging. PMID- 26596545 TI - Clinical application of micronucleus test in exfoliated buccal cells: A systematic review and metanalysis. AB - The micronucleus assay in uncultured exfoliated buccal mucosa cells, involving minimally invasive sampling, was successfully applied to evaluate inhalation and local exposure to genotoxic agents, impact of nutrition and lifestyle factors. The potential use of the assay in clinics to monitor the development of local oral lesions and as an early biomarker for tumors and different chronic disorders was also investigated. A systematic review of the literature was carried out focusing on the clinical application of the assay. The literature search updated to January 2015 allowed to retrieve 42 eligible articles. Fifty three percent of investigations are related to oral, head and neck cancer, and premalignant oral diseases. Our analysis evidences a potential usefulness of the MN assay applied in buccal exfoliated cells in the prescreening and in the follow up of precancerous oral lesions. A significant excess of MN, in patients compared with matched controls was observed for subgroups of oral and neck cancer (meta-MR of 2.40, 95% CI: 2.02-2.85) and leukoplakia (meta-MR 1.88, 95% CI: 1.51-2.35). The meta-analysis of studies available on other tumors (meta-MR 2.00; 95% CI:1.66 2.41) indicates that the MN frequency in buccal cells could reflect the chromosomal instability of other organs. Increased MN frequency was also observed in small size studies on patients with chronic diseases, with Alzheimer's disease and with Down syndrome. The application of the cytome approach providing information of genotoxic, cytotoxic and cytostatic effects is suggestive of the possibility of an improvement in the predictive value of the assay and this deserves further investigations. PMID- 26596546 TI - Dietary mycotoxins, co-exposure, and carcinogenesis in humans: Short review. AB - Mycotoxins, toxic secondary metabolites of fungi, affect global agriculture so prolifically that they are virtually ubiquitous at some concentration in the average human diet. Studies of in vitro and in vivo toxicity are discussed, leading to investigations of co-exposed mycotoxins, as well as carcinogenic effects. Some of the most common and toxicologically significant mycotoxins, such as the aflatoxins, ochratoxins, fumonisins, deoxynivalenol, T-2 toxin, HT-2 toxin, patulin, zearalenone, and some ergot alkaloids are outlined. The wide variety of pathogenic mechanisms these compounds employ are shown capable of inducing a complex set of interactions. Of particular note are potential synergisms between mycotoxins with regard to carcinogenic attributable risk, indicating an important field for future study. PMID- 26596547 TI - Genetic mutations strengthen functional association of LAP1 with DYT1 dystonia and muscular dystrophy. AB - Lamina-associated polypeptide 1 (LAP1) is a ubiquitously expressed integral protein of the inner nuclear membrane. It interacts physically with lamins, torsinA, emerin and protein phosphatase 1; potentially providing a pivotal mechanism for transducing signals across the inner nuclear membrane. In neurons a functional protein complex is formed, comprising LAP1 and torsinA and in skeletal muscle LAP1 and emerin likewise form a protein complex. Several isoforms of LAP1 have been reported across species. However, in humans only two isoforms have been described, LAP1B and LAP1C. The latter has only recently been reported, but its physiological function and mode of action are not clear. The first TOR1AIP1 (gene encoding LAP1) mutation identified is a single nucleotide deletion resulting in a frameshift and a putative truncated LAP1B protein (Turkish mutation). This has deleterious effects associated with a specific form of muscular dystrophy. A second point mutation, affecting both human LAP1 isoforms, was also recently described. This mutation involves the replacement of a single glutamic acid to alanine at position 482 (Moroccan Mutation), thereby causing severe dystonia, cerebellar atrophy and cardiomyopathy. This review focuses on the recently described human LAP1 isoform (LAP1C), the two recently reported LAP1 mutations and post-translational LAP1 modifications. The latter play an important role in regulating this protein. These scientific contributions strengthen the role of LAP1 in DYT1 dystonia and muscular dystrophy. PMID- 26596548 TI - Super DNAging-New insights into DNA integrity, genome stability and telomeres in the oldest old. AB - Reductions in DNA integrity, genome stability, and telomere length are strongly associated with the aging process, age-related diseases as well as the age related loss of muscle mass. However, in people reaching an age far beyond their statistical life expectancy the prevalence of diseases, such as cancer, cardiovascular disease, diabetes or dementia, is much lower compared to "averagely" aged humans. These inverse observations in nonagenarians (90-99 years), centenarians (100-109 years) and super-centenarians (110 years and older) require a closer look into dynamics underlying DNA damage within the oldest old of our society. Available data indicate improved DNA repair and antioxidant defense mechanisms in "super old" humans, which are comparable with much younger cohorts. Partly as a result of these enhanced endogenous repair and protective mechanisms, the oldest old humans appear to cope better with risk factors for DNA damage over their lifetime compared to subjects whose lifespan coincides with the statistical life expectancy. This model is supported by study results demonstrating superior chromosomal stability, telomere dynamics and DNA integrity in "successful agers". There is also compelling evidence suggesting that life style related factors including regular physical activity, a well-balanced diet and minimized psycho-social stress can reduce DNA damage and improve chromosomal stability. The most conclusive picture that emerges from reviewing the literature is that reaching "super old" age appears to be primarily determined by hereditary/genetic factors, while a healthy lifestyle additionally contributes to achieving the individual maximum lifespan in humans. More research is required in this rapidly growing population of super old people. In particular, there is need for more comprehensive investigations including short- and long-term lifestyle interventions as well as investigations focusing on the mechanisms causing DNA damage, mutations, and telomere shortening. PMID- 26596549 TI - The double-edged sword of long non-coding RNA: The role of human brain-specific BC200 RNA in translational control, neurodegenerative diseases, and cancer. AB - The complexity of eukaryotic organisms involves the regulation of gene expression through DNA-protein, RNA-DNA, RNA-RNA, and RNA-protein interactions. The role of RNA molecules in the regulation of genes in higher species has become even more evident with the discovery that about 97% of transcription products are represented by non-protein coding RNAs (ncRNAs) including short ncRNAs and long ncRNAs (lncRNAs). In addition to the well-characterized role of ncRNAs in different physiological cellular processes, numerous studies have also indicated the crucial roles of ncRNAs in neurological diseases and cancer. Although involvement of short ncRNA in those pathologies has already been well documented, there is only scarce evidence to show the participation of lncRNAs. One of the examples of lncRNAs is BC200 RNA, which plays an important role in the regulation of dendritic protein expression. Mislocalization and overexpression of BC200 RNA leads to inadequate RNA delivery to the synapses and results in neurodegenerative processes of Alzheimer's disease and neoplastic changes in various groups of tissues. In this review, we summarize the current state of art in the field of the biological significance of lncRNAs, with particular attention paid to the physiological and pathophysiological role of BC200 RNA. PMID- 26596550 TI - Interacting sources of interference during sensorimotor integration processes. AB - Every day, a multitude of interfering sensory inputs needs to be integrated and adequately processed using response selection processes. Interference effects are typically investigated using classical paradigms like the Flanker and Simon task. The sources of interference for Flanker and Simon effect are known to be different and according to dual process accounts, two distinct functional pathways are involved in resolving these types of interference. It is an open question how far these sources of interference are related to each other and interact. We investigated this question in a system neurophysiological study utilizing a hybrid paradigm combining both Flanker effect-like and Simon effect like features. We focus on event-related theta oscillations and use beamforming methods to examine functional neuroanatomical networks. The results show that Simon and Flanker interference interacted in a non-additive fashion by modulating theta band activity, probably reflecting the recruitment of cognitive control processes. Beamforming source reconstruction revealed that theta band activity was related to a broad neuronal network comprising prefrontal and cerebellar regions, including the MFG, SFG, IFG, and SMA. These regions were connected to interference processing and conflict resolution, but differed in the amount of specificity for different sources of interference. PMID- 26596551 TI - Validation of non-REM sleep stage decoding from resting state fMRI using linear support vector machines. AB - A growing body of literature suggests that changes in consciousness are reflected in specific connectivity patterns of the brain as obtained from resting state fMRI (rs-fMRI). As simultaneous electroencephalography (EEG) is often unavailable, decoding of potentially confounding sleep patterns from rs-fMRI itself might be useful and improve data interpretation. Linear support vector machine classifiers were trained on combined rs-fMRI/EEG recordings from 25 subjects to separate wakefulness (S0) from non-rapid eye movement (NREM) sleep stages 1 (S1), 2 (S2), slow wave sleep (SW) and all three sleep stages combined (SX). Classifier performance was quantified by a leave-one-subject-out cross validation (LOSO-CV) and on an independent validation dataset comprising 19 subjects. Results demonstrated excellent performance with areas under the receiver operating characteristics curve (AUCs) close to 1.0 for the discrimination of sleep from wakefulness (S0|SX), S0|S1, S0|S2 and S0|SW, and good to excellent performance for the classification between sleep stages (S1|S2:~0.9; S1|SW:~1.0; S2|SW:~0.8). Application windows of fMRI data from about 70 s were found as minimum to provide reliable classifications. Discrimination patterns pointed to subcortical-cortical connectivity and within-occipital lobe reorganization of connectivity as strongest carriers of discriminative information. In conclusion, we report that functional connectivity analysis allows valid classification of NREM sleep stages. PMID- 26596552 TI - Graphene oxide supported rhombic dodecahedral Cu2O nanocrystals for the detection of carcinoembryonic antigen. AB - In this work, a simple electrochemical immunosensor was developed for the detection of carcinoembryonic antigen (CEA) based on rhombic dodecahedral Cu2O nanocrystals-graphene oxide-gold nanoparticles (rCu2O-GO-AuNPs). GO as the template and surfactant resulting in rCu2O exhibit improved rhombic dodecahedral structure uniformity and excellent electrochemical performance. Moreover, GO was found to be able to effectively improve the long stability of rCu2O on the electrode response. Under optimal conditions, the immunosensor showed a low limit of detection (0.004 ng ml(-1)) and a large linear range (0.01-120 ng ml(-1)). This work presents a potential alternative for the diagnostic applications of GO supported special morphology materials in biomedicine and biosensors. PMID- 26596554 TI - Complications associated with opening wedge high tibial osteotomy--A review of the literature and of 15 years of experience. AB - BACKGROUND: Complication rates following opening wedge high tibial osteotomy (OWHTO) is an issue that has not been comprehensively addressed in current literature. METHODS: We performed a retrospective study of local patients who underwent OWHTO for isolated medial compartment knee osteoarthritis from 1997 to 2013. We analysed survivorship and complication rates and compared this to a literature review of previously reported data. RESULTS: One hundred and fifteen patients met the inclusion criteria. Mean follow-up=8.4 years. Mean age=47 (range 32 to 62). Mean Body Mass Index (BMI)=29.1 (range 20.3 to 40.2). Devices used consisted of Tomofix (72%), Puddu plate (21%) and Orthofix (seven percent) (no significant differences in age/sex/BMI). Wedge defects were filled with autologous graft (30%), Chronos (35%) or left empty (35%). Five years survival rate (without requiring conversion to arthroplasty)=80%. Overall complication rate=31%. Twenty five percent of patients suffered 36 complications including minor wound infections (9.6%), major wound infections (3.5%), metalwork irritation necessitating plate removal (seven percent), non-union requiring revision (4.3%), vascular injury (1.7%), compartment syndrome (0.9%), and other minor complications (four percent). No thromboembolic complications were observed. CONCLUSION: No significant differences existed in complication rates following OWHTO relative to BMI, implant type, type of bone graft used or patient age at surgery. When the complications from OWHTO were analysed closely they appear higher than previously reported in the literature; however serious complications appear rare. LEVEL OF EVIDENCE 3: Retrospective cohort study. PMID- 26596553 TI - Rapid detection of the common avian leukosis virus subgroups by real-time loop mediated isothermal amplification. AB - BACKGROUND: Subgroups A, B, E and J are the major subgroups of avian leukosis virus (ALV) infecting chickens. ALV infection has become endemic in China and has a significant negative effect on the poultry industry. Consequently, there is an urgent need for a specific, sensitive and rapid method for diagnosis and eradication of ALV. Therefore, we developed a simple and rapid real-time loop mediated isothermal amplification (LAMP) reaction for the timely detection of the common ALV subgroups, whereby the amplification can be obtained in 35 min under isothermal conditions at 63 degrees C, ability to specific, sensitive and rapid detect all the common ALV subgroups. METHODS: A set of four specific primers was designed to target the sequences of the pol gene of ALV, and the loop-mediated isothermal amplification (LAMP) assay were developed and compared with PCR and virus isolation methods. RESULTS: The results from specificity of the LAMP assay showed that only target ALVs DNA was amplified. The LAMP assay demonstrated a sensitivity of 20 copies/reaction of ALV DNA, which was 10 times higher than the conventional PCR measurement. To further evaluate the reliability of the method, the assay was evaluated with ALV DNA from a panel of 81 clinical samples suspected of ALV infection. The results verify that the LAMP method was more sensitive than the conventional PCR and virus isolation method. CONCLUSION: In conclusion, the developed LAMP assay was a simple, inexpensive, sensitive method for the rapid detection of the most common subgroups of ALV, and it provided a useful and practical tool in the eradication program for ALV in the poultry industry. PMID- 26596555 TI - A Bayesian approach for relaxation times estimation in MRI. AB - Relaxation time estimation in MRI field can be helpful in clinical diagnosis. In particular, T1 and T2 changes can be related to tissues modification, being an effective tool for detecting the presence of several pathologies and measure their development, thus their estimation is a useful research field. Currently, most techniques work pixel-wise, and transfer the noise reduction task to post processing filters. A novel method for estimating spin-spin and spin-lattice relaxation times is proposed. The approach exploits Markov Random Field theory for modeling the unknown data and implements an a posteriori estimator in the Bayesian framework. The effect is the joint parameters estimation and noise reduction. Proposed methodology, with respect to already existing techniques, is able to provide effective results while preserving details also in case of few acquisitions or severe signal to noise ratio. The algorithm has been tested on both simulated and real datasets. PMID- 26596556 TI - Antagonism of GABA-B but not GABA-A receptors in the VTA prevents stress- and intra-VTA CRF-induced reinstatement of extinguished cocaine seeking in rats. AB - Stress-induced reinstatement of cocaine seeking requires corticotropin releasing factor (CRF) actions in the ventral tegmental area (VTA). However the mechanisms through which CRF regulates VTA function to promote cocaine use are not fully understood. Here we examined the role of GABAergic neurotransmission in the VTA mediated by GABA-A or GABA-B receptors in the reinstatement of extinguished cocaine seeking by a stressor, uncontrollable intermittent footshock, or bilateral intra-VTA administration of CRF. Rats underwent repeated daily cocaine self-administration (1.0 mg/kg/ing; 14 * 6 h/day) and extinction and were tested for reinstatement in response to footshock (0.5 mA, 0.5" duration, average every 40 s; range 10-70 s) or intra-VTA CRF delivery (500 ng/side) following intra-VTA pretreatment with the GABA-A antagonist, bicuculline, the GABA-B antagonist, 2 hydroxysaclofen or vehicle. Intra-VTA bicuculline (1, 10 or 20 ng/side) failed to block footshock- or CRF-induced cocaine seeking at either dose tested. By contrast, 2-hydroxysaclofen (0.2 or 2 MUg/side) prevented reinstatement by both footshock and intra-VTA CRF at a concentration that failed to attenuate food reinforced lever pressing (45 mg sucrose-sweetened pellets; FR4 schedule) in a separate group of rats. These data suggest that GABA-B receptor-dependent CRF actions in the VTA mediate stress-induced cocaine seeking and that GABA-B receptor antagonists may have utility for the management of stress-induced relapse in cocaine addicts. PMID- 26596557 TI - Essential role of the NO signaling pathway in the hippocampal CA1 in morphine associated memory depends on glutaminergic receptors. AB - The nitric oxide (NO)/soluble guanylyl cyclase (sGC)/cGMP-dependent protein kinase (PKG) signaling pathway has been reported to play a key role in memory processing. However, little is known about its role in drug-associated reward memory. Here, we report the following. 1) The NO pathway in the CA1 is critical for the retrieval of morphine-associated reward memory. Specifically, the nNOS, sGC and PKG protein levels in the CA1 were increased after the expression of morphine conditioned place preference (CPP). Intra-CA1 injection of an NOS, sGC or PKG inhibitor prevented morphine CPP expression. 2) The involvement of the NO pathway in morphine CPP requires NR2B-containing NMDA receptors (NR2B-NMDARs). NR2B-NMDAR expression was elevated in the CA1 following morphine CPP expression, and intra-CA1 injection of the NR2B-NMDAR antagonist Ro25-6981 not only blocked morphine CPP expression but also inhibited the up-regulation of nNOS, sGC and PKG. Moreover, the Ro25-6981-induced blockade of morphine CPP was abolished by intra-CA1 injection of a NOS substrate or an sGC activator. 3) The NR2B-NMDAR stimulated the NO pathway by up-regulating the phosphorylation of Akt(Ser473). Morphine CPP expression enhanced the pAkt(Ser473) level, which has been corroborated to regulate nNOS activity, and this effect was reversed by intra-CA1 injection of Ro25-6981. 4) GluR1 acted downstream of the NO pathway. The membrane level of GluR1 in the CA1 was increased after morphine CPP expression, and this effect was prevented by pre-injection of a PKG inhibitor into the CA1. Additionally, co-immunoprecipitation revealed an interaction between PKG and GluR1; this result further indicated a role of PKG in regulating GluR1 trafficking. Collectively, the results of our study demonstrated that the activation of the NR2B-NMDAR/NO/sGC/PKG signaling pathway is necessary for the retrieval of morphine-associated reward memory. PMID- 26596559 TI - Integrating chemoradiation and molecularly targeted therapy. AB - While the advent of combined chemoradiation has improved outcomes for innumerable patients with locally advanced cancers, further improvements are urgently needed. Escalation of either chemotherapy or radiotherapy is associated with unacceptable toxicity. An alternative strategy is the integration of chemoradiation and molecularly targeted therapies, which exploits biological differences between cancer and normal tissue and should therefore increase efficacy while maintaining tolerable toxicity. Combining chemoradiation with agents that modulate tumor specific pathways such as cell cycle checkpoints, PARP signaling, EGFR signaling, the PI3K/AKT/mTOR axis and androgen signaling has shown immense promise in preclinical and clinical studies, as have combinations with environmentally targeted agents against the immune system and angiogenesis. The optimal application of these strategies will likely require consideration of molecular heterogeneity between patients and within individual tumors. PMID- 26596560 TI - The Radiologist Will See You Now: Patients' Perceptions of an Outpatient Interventional Clinic. AB - Patient satisfaction is becoming an increasingly important part of America's healthcare system. Patient satisfaction is now a metric assessed for value-based incentive payments by the Center for Medicare and Medicaid Services, and the healthcare market is becoming increasingly consumer-driven as patients are provided with more options regarding where they receive care as well as improved access to medical information. Radiologists, while less involved with direct patient care than other medical specialties, are not immune to the changing medical landscape and need to adapt to a progressively value- and patient oriented healthcare system. At our institution, first-year radiology residents take an active role in our outpatient interventional radiology clinic by performing clinical histories and physical exams in a dedicated radiology clinic examination rooms. Stressing the various opportunities for patient interaction and the potential benefits of patient- centered radiology in the evolving healthcare system may increase its perceived value among both radiology residents as well as practicing radiologists. Directly engaging patients may be unfamiliar territory for the practicing radiologist and an unexpected prospect for current residents, but available data suggests that patients do value direct interaction with radiologists during the course of their care. PMID- 26596558 TI - Novel adjuvant formulations for delivery of anti-tuberculosis vaccine candidates. AB - There is an urgent need for a new and improved vaccine against tuberculosis for controlling this disease that continues to pose a global health threat. The current research strategy is to replace the present BCG vaccine or boost BCG immunity with subunit vaccines such as viral vectored- or protein-based vaccines. The use of recombinant proteins holds a number of production advantages including ease of scalability, but requires an adjuvant inducing cell-mediated immune responses. A number of promising novel adjuvant formulations have recently been designed and show evidence of induction of cellular immune responses in humans. A common trait of effective TB adjuvants including those already in current clinical testing is a two-component approach combining a delivery system with an appropriate immunomodulator. This review summarizes the status of current TB adjuvant research with a focus on the division of labor between delivery systems and immunomodulators. PMID- 26596561 TI - Establishing a biomarker for postoperative ileus in humans - Results of the BiPOI trial. AB - AIMS: Postoperative ileus (POI) is a frequent complication after abdominal surgery, resulting from an inflammation of the muscularis externa (ME). So far no valid biomarker for occurrence, duration or intensity of POI exists. Extravasation of monocytes and neutrophils from blood circulating into the postoperative ME is well known as a hallmark of POI. In a previous study we demonstrated that a low abundant subset of TH1 cells, activated by IL-12, can be detected in the peripheral blood of a small subset of patients in response to abdominal surgery. The aim of the present study was to investigate if these specific TH1 cells, IL-12 or circulating leukocyte levels could act as a valid marker for POI occurrence. MAIN METHODS: At different time points, blood samples of patients undergoing abdominal or extraabdominal surgery were collected. Serum levels of IL-12 or TH1 cells as well as neutrophils and monocytes were analyzed. Data were compared between both groups and correlated with clinical signs of POI. KEY FINDINGS: Time until first flatus and defecation as well as solid food tolerances are delayed after abdominal compared to extraabdominal surgery. Circulating IL-12 levels and numbers of TH1 cells, neutrophils and monocytes did not differ between both groups. SIGNIFICANCE: While previous experiments indicated that specific TH1 cells play a crucial role in POI dissemination, our present data from a larger human cohort demonstrate that they do not seem to be suitable to distinguish between abdominal and extraabdominal surgery. Furthermore neither TH1 cells nor leukocytes or serum IL-12 levels are appropriate biomarkers for POI in a clinical setting. PMID- 26596563 TI - Men and mice: Relating their ages. AB - Since the late 18th century, the murine model has been widely used in biomedical research (about 59% of total animals used) as it is compact, cost-effective, and easily available, conserving almost 99% of human genes and physiologically resembling humans. Despite the similarities, mice have a diminutive lifespan compared to humans. In this study, we found that one human year is equivalent to nine mice days, although this is not the case when comparing the lifespan of mice versus humans taking the entire life at the same time without considering each phase separately. Therefore, the precise correlation of age at every point in their lifespan must be determined. Determining the age relation between mice and humans is necessary for setting up experimental murine models more analogous in age to humans. Thus, more accuracy can be obtained in the research outcome for humans of a specific age group, although current outcomes are based on mice of an approximate age. To fill this gap between approximation and accuracy, this review article is the first to establish a precise relation between mice age and human age, following our previous article, which explained the relation in ages of laboratory rats with humans in detail. PMID- 26596562 TI - Nephroprotective role of dipyridamole in diabetic nephropathy: Effect on inflammation and apoptosis. AB - AIMS: Inflammation plays significant roles in developing diabetic nephropathy (DN). Adenosine, natural purine nucleoside, acts as potent endogenous anti inflammatory agent. Extracellular adenosine usually disappears quickly due to rapid uptake into adjacent cells. In this regard; we investigated putative reno protective effects of dipyridamole, nucleoside transport inhibitor, by exploring its anti-inflammatory mechanisms in-vivo and in-vitro. MAIN METHODS: Daily 6mg/kg/day dipyridamole was given to six-weeks streptozotocin-induced diabetic rats over two-week period in presence/absence of 10mg/kg/day CGS15943, potent non selective adenosine receptors antagonist. Histological changes were assessed in kidney sections. Gene and protein expression of interleukin (IL)-1beta, IL-10, IL 18, tumor necrosis factor (TNF)-alpha and intercellular adhesion molecule (ICAM) 1 was measured. Activation of apoptotic pathway was demonstrated by measuring the activity of caspase-3/8/9 and activation of c-Jun NH2-terminal kinases (JNK) mitogen-activated-protein kinase (MAPK). In addition, all markers were measured in human mesangial cells cultured in high glucose. KEY FINDINGS: Diabetes induced marked changes in the glomerular and tubular structure including focal glomerulosclerosis with marked shrinkage of some glomerular tufts. Diabetes resulted in enhanced production of IL-1beta, IL-18, TNF-alpha and ICAM-1 associated with reduced IL-10 protein level, leading to activation of caspases 3/8/9 and pJNK/JNK in-vivo and in-vitro. Dipyridamole treatment restored diabetes induced reduction in adenosine levels and resulted in mild glomerular effects and vacuolation of tubular epithelium. Dipyridamole reduced the adhesion molecule, ICAM-1, and restored the normal balance between pro- and anti-inflammatory cytokines in-vivo and in-vitro. SIGNIFICANCE: Dipyridamole prevented the progression of DN by elevating endogenous levels of protecting adenosine, leading to reduction in inflammation and intrinsic apoptosis. PMID- 26596564 TI - Cytotoxic effect of galvanically coupled magnesium-titanium particles. AB - Recent work has shown that reduction reactions at metallic biomaterial surfaces can induce significant killing of cells in proximity to the surface. To exploit this phenomenon for therapeutic purposes, for example, for cancer tumor killing or antibacterial effects (amongst other applications), magnesium metal particles, galvanically coupled to titanium by sputtering, have been evaluated for their cell-killing capability (i.e. cytotoxicity). Magnesium (Mg) particles large enough to prevent particle phagocytosis were investigated, so that only electrochemical reactions, and not particle toxicity per se, caused cytotoxic effects. Titanium (Ti) coated magnesium particles, as well as magnesium-only particles were introduced into MC3T3-E1 mouse pre-osteoblast cell cultures over a range of particle concentrations, and cells were observed to die in a dosage dependent manner. Ti-coated magnesium particles killed more cells at lower particle concentration than magnesium alone (P<0.05), although the pH measured for magnesium and magnesium-titanium had no significant difference at similar particle concentrations. Complete cell killing occurred at 750MUg/ml and 1500MUg/ml for Mg-Ti and Mg, respectively. Thus, this work demonstrates that galvanically coupled Mg-Ti particles have a significant cell killing capability greater than Mg alone. In addition, when the pH associated with complete killing with particles was created using NaOH only (no particles), then the percentage of cells killed was significantly less (P<0.05). Together, these findings show that pH is not the sole factor associated with cell killing and that the electrochemical reactions, including the reduction reactions, play an important role. Reduction reactions on galvanically coupled Mg-Ti and Mg particles may generate reactive oxygen intermediates that are able to kill cells in close proximity to the particles and this approach may lead to potential therapies for infection and cancer. STATEMENT OF SIGNIFICANCE: This paper demonstrates that during active corrosion of both Mg and Mg-Ti particles cells cultured with the particles are killed in a dose-dependent particle concentration fashion. Additionally, galvanically-coupled magnesium-titanium microparticles kill cells more effectively than magnesium particles alone. The killing effect was shown to not be due to pH shifts since no differences were seen for different particle types and pH adjusted medium without particles did not exhibit the same level of killing. The significance of this work is the recognition of this killing effect with Mg particles and the potential therapeutic applications in infection control and cancer treatment that this process may provide. PMID- 26596565 TI - Copper-doped mesoporous silica nanospheres, a promising immunomodulatory agent for inducing osteogenesis. AB - The application of mesoporous silica nanospheres (MSNs) loaded with drugs/growth factors to induce osteogenic differentiation of stem cells has been trialed by a number of researchers recently. However, limitations such as high cost, complex fabrication and unintended side effects from supraphysiological concentrations of the drugs/growth factors represent major obstacles to any potential clinical application in the near term. In this study we reported an in situ one-pot synthesis strategy of MSNs doped with hypoxia-inducing copper ions and systematically evaluated the nanospheres by in vitro biological assessments. The Cu-containing mesoporous silica nanospheres (Cu-MSNs) had uniform spherical morphology (~100nm), ordered mesoporous channels (~2nm) and homogeneous Cu distribution. Cu-MSNs demonstrated sustained release of both silicon (Si) and Cu ions and controlled degradability. The Cu-MSNs were phagocytized by immune cells and appeared to modulate a favorable immune environment by initiating proper pro inflammatory cytokines, inducing osteogenic/angiogenic factors and suppressing osteoclastogenic factors by the immune cells. The immune microenvironment induced by the Cu-MSNs led to robust osteogenic differentiation of bone mesenchymal stem cells (BMSCs) via the activation of Oncostation M (OSM) pathway. These results suggest that the novel Cu-MSNs could be used as an immunomodulatory agent with osteostimulatory capacity for bone regeneration/therapy application. STATEMENT OF SIGNIFICANCE: In order to stimulate both osteogenesis and angiogenesis of stem cells for further bone regeneration, a new kind of hypoxia-inducing copper doped mesoporous silica nanospheres (Cu-MSNs) were prepared via one-pot synthesis. Biological assessments under immune environment which better reflect the in vivo response revealed that the nanospheres possessed osteostimulatory capacity and had potential as immunomodulatory agent for bone regeneration/therapy application. The strategy of introducing controllable amount of therapeutic ions instead of loading expensive drugs/growth factors in mesoporous silica nanosphere provides new options for bioactive nanomaterial functionalization. PMID- 26596566 TI - Controlled release kinetics of p-aminosalicylic acid from biodegradable crosslinked polyesters for enhanced anti-mycobacterial activity. AB - Unlike conventional polymeric drug delivery systems, where drugs are entrapped in polymers, this study focuses on the incorporation of the drug into the polymer backbone to achieve higher loading and sustained release. Crosslinked, biodegradable, xylitol based polyesters have been synthesized in this study. The bioactive drug moiety, p-aminosalicylic acid (PAS), was incorporated in xylitol based polyesters to impart its anti-mycobacterial activity. To understand the influence of the monomer chemistry on the incorporation of PAS and its subsequent release from the polymer, different diacids have been used. Controlled release profiles of the drug from these polyesters were studied under normal physiological conditions. The degradation of the polyesters varied from 48% to 76% and the release of PAS ranged from 54% to 65% of its initial loading in 7days. A new model was developed to explain the release kinetics of PAS from the polymer that accounted for the polymer degradation and drug concentration. The thermal, mechanical, drug release and cytocompatibility properties of the polymers indicate their suitability in biomedical applications. The released products from these polymers were observed to be pharmacologically active against Mycobacteria. The high drug loading and sustained release also ensured enhanced efficacy. These polymers form biocompatible, biodegradable polyesters where the sustained release of PAS may be tailored for potential treatment of mycobacterial infections. STATEMENT OF SIGNIFICANCE: In the present work, we report on novel polyesters with p-aminosalicylic acid (PAS) incorporated in the polymer backbone. The current work aims to achieve controlled release of PAS and ensures the delivered PAS is stable and pharmacologically active. The novelty of this work primarily involves the synthetic chemistry of polymerization and detailed analysis and efficacy of active PAS delivery. A new kinetic model has been developed to explain the PAS release profiles. These polymers are biodegradable, cytocompatible and anti-mycobacterial in nature. PMID- 26596568 TI - Cell sensing of physical properties at the nanoscale: Mechanisms and control of cell adhesion and phenotype. AB - The chemistry, geometry, topography and mechanical properties of biomaterials modulate biochemical signals (in particular ligand-receptor binding events) that control cells-matrix interactions. In turn, the regulation of cell adhesion by the biochemical and physical properties of the matrix controls cell phenotypes such as proliferation, motility and differentiation. In particular, nanoscale geometrical, topographical and mechanical properties of biomaterials are essential to achieve control of the cell-biomaterials interface. The design of such nanoscale architectures and platforms requires understanding the molecular mechanisms underlying adhesion formation and the assembly of the actin cytoskeleton. This review presents some of the important molecular mechanisms underlying cell adhesion to biomaterials mediated by integrins and discusses the nanoscale engineered platforms used to control these processes. Such nanoscale understanding of the cell-biomaterials interface offers exciting opportunities for the design of biomaterials and their application to the field of tissue engineering. STATEMENT OF SIGNIFICANCE: Biomaterials design is important in the fields of regenerative medicine and tissue engineering, in particular to allow the long term expansion of stem cells and the engineering of scaffolds for tissue regeneration. Cell adhesion to biomaterials often plays a central role in regulating cell phenotype. It is emerging that physical properties of biomaterials, and more generally the microenvironment, regulate such behaviour. In particular, cells respond to nanoscale physical properties of their matrix. Understanding how such nanoscale physical properties control cell adhesion is therefore essential for biomaterials design. To this aim, a deeper understanding of molecular processes controlling cell adhesion, but also a greater control of matrix engineering is required. Such multidisciplinary approaches shed light on some of the fundamental mechanisms via which cell adhesions sense their nanoscale physical environment. PMID- 26596567 TI - Repopulation of porcine kidney scaffold using porcine primary renal cells. AB - The only definitive treatment for end stage renal disease is renal transplantation, however the current shortage of organ donors has resulted in a long list of patients awaiting transplant. Whole organ engineering based on decellularization/recellularization techniques has provided the possibility of creating engineered kidney constructs as an alternative to donor organ transplantation. Previous studies have demonstrated that small units of engineered kidney are able to maintain function in vivo. However, an engineered kidney with sufficient functional capacity to replace normal renal function has not yet been developed. One obstacle in the generation of such an organ is the development of effective cell seeding methods for robust colonization of engineered kidney scaffolds. We have developed cell culture methods that allow primary porcine renal cells to be efficiently expanded while maintaining normal renal phenotype. We have also established an effective cell seeding method for the repopulation of acellular porcine renal scaffolds. Histological and immunohistochemical analyses demonstrate that a majority of the expanded cells are proximal tubular cells, and the seeded cells formed tubule-like structures that express normal renal tubule phenotypic markers. Functional analysis revealed that cells within the kidney construct demonstrated normal renal functions such as re-adsorption of sodium and protein, hydrolase activity, and production of erythropoietin. These structural and functional outcomes suggest that engineered kidney scaffolds may offer an alternative to donor organ transplant. STATEMENT OF SIGNIFICANCE: Kidney transplantation is the only definitive treatment for end stage renal disease, however the current shortage of organ donors has limited the treatment. Whole organ engineering based on decellularization/recellularization techniques has provided the possibility of creating engineered kidney constructs as an alternative to donor organ transplantation. While previous studies have shown that small units of engineered kidneys are able to maintain function in animal studies, engineering of kidneys with sufficient functional capacity to replace normal renal function is still challenging due to inefficient cell seeding methods. This study aims to establish an effective cell seeding method using pig kidney cells for the repopulation of acellular porcine kidney scaffolds, suggesting that engineered kidneys may offer an alternative to donor organ transplant. PMID- 26596569 TI - WHO "should focus on core activities" in light of problems over Ebola response. PMID- 26596570 TI - Assessment of radiation protection awareness and knowledge about radiological examination doses among Italian radiographers. AB - OBJECTIVES: To evaluate radiation protection basic knowledge and dose assessment for radiological procedures among Italian radiographers METHODS: A validated questionnaire was distributed to 780 participants with balanced demographic characteristics and geographic distribution. RESULTS: Only 12.1 % of participants attended radiation protection courses on a regular basis. Despite 90 % of radiographers stating to have sufficient awareness of radiation protection issues, most of them underestimated the radiation dose of almost all radiological procedures. About 5 % and 4 % of the participants, respectively, claimed that pelvis magnetic resonance imaging and abdominal ultrasound exposed patients to radiation. On the contrary, 7.0 % of the radiographers stated that mammography does not use ionising radiation. About half of participants believed that radiation-induced cancer is not dependent on age or gender and were not able to differentiate between deterministic and stochastic effects. Young radiographers (with less than 3 years of experience) showed a higher level of knowledge compared with the more experienced radiographers. CONCLUSIONS: There is a substantial need for radiographers to improve their awareness of radiation protection issues and their knowledge of radiological procedures. Specific actions such as regular training courses for both undergraduate and postgraduate students as well as for working radiographers must be considered in order to assure patient safety during radiological examinations. MAIN MESSAGES: * Radiographers should improve their knowledge on radiation protection issues. * Only 12.1 % of participants attended radiation protection courses on a regular basis. * Specific actions must be considered in order to increase knowledge and awareness. PMID- 26596572 TI - Unorthodox methods for enhancing solvent production in solventogenic Clostridium species. AB - While production of biofuels from renewable resources is currently receiving increased attention globally, concerns on availability and sustainability of cheap substrates for their production are growing as well. Lignocellulose-derived sugars (LDS) remain underutilized and merit consideration as a key feedstock. Among other obstacles such as low yield and low solvent titer, mitigation of stresses stemming from lignocellulose-derived microbial inhibitory compounds (LDMICs) that severely impair cell growth and solvent production is a major area of research interest. In addition to attempts at developing LDMIC-tolerant strains via metabolic engineering to enhance utilization of LDS, unconventional approaches that elicit different metabolic perturbations in microorganisms to relieve solvent- and LDMIC-mediated stresses have been explored to increase solvent production from LDS. In this review, the impacts of metabolic perturbations including medium supplementation with glycerol; furfural and 5 hydroxymethyl furfural; allopurinol, an inhibitor of xanthine dehydrogenase; calcium (Ca(2+)) and zinc (Zn(2+)) ions); and artificial electron carriers, methyl viologen and neutral red, on butanol production are discussed. Although these approaches have brought about considerable increases in butanol production, both from LDS and defined glucose-based media, the modes of action for most of these perturbations have yet to be fully characterized. Better understanding of these mechanisms would likely inform development of LDMIC-tolerant, butanol overproducing strains, as well as possible combinatorial application of these approaches for enhanced butanol production. Hence, delineating the underlying mechanisms of these perturbations deserves further attention. PMID- 26596571 TI - Preclinical Characterization of the Phosphodiesterase 10A PET Tracer [(11)C]MK 8193. AB - PURPOSE: A positron emission tomography (PET) tracer for the enzyme phosphodiesterase 10A (PDE10A) is desirable to guide the discovery and development of PDE10A inhibitors as potential therapeutics. The preclinical characterization of the PDE10A PET tracer [(11)C]MK-8193 is described. PROCEDURES: In vitro binding studies with [(3)H]MK-8193 were conducted in rat, monkey, and human brain tissue. PET studies with [(11)C]MK-8193 were conducted in rats and rhesus monkeys at baseline and following administration of a PDE10A inhibitor. RESULTS: [(3)H]MK-8193 is a high-affinity, selective PDE10A radioligand in rat, monkey, and human brain tissue. In vivo, [(11)C]MK-8193 displays rapid kinetics, low test-retest variability, and a large specific signal that is displaced by a structurally diverse PDE10A inhibitor, enabling the determination of pharmacokinetic/enzyme occupancy relationships. CONCLUSIONS: [(11)C]MK-8193 is a useful PET tracer for the preclinical characterization of PDE10A therapeutic candidates in rat and monkey. Further evaluation of [(11)C]MK 8193 in humans is warranted. PMID- 26596573 TI - New insights into the genetic and metabolic diversity of thiocyanate-degrading microbial consortia. AB - Thiocyanate is a common contaminant of the gold mining and coal coking industries for which biological degradation generally represents the most viable approach to remediation. Recent studies of thiocyanate-degrading bioreactor systems have revealed new information on the structure and metabolic activity of thiocyanate degrading microbial consortia. Previous knowledge was limited primarily to pure culture or co-culture studies in which the effects of linked carbon, sulfur and nitrogen cycling could not be fully understood. High throughput sequencing, DNA fingerprinting and targeted gene amplification have now elucidated the genetic and metabolic diversity of these complex microbial consortia. Specifically, this has highlighted the roles of key consortium members involved in sulfur oxidation and nitrification. New insights into the biogeochemical cycling of sulfur and nitrogen in bioreactor systems allow tailoring of the microbial metabolism towards meeting effluent composition requirements. Here we review these rapidly advancing studies and synthesize a conceptual model to inform new biotechnologies for thiocyanate remediation. PMID- 26596574 TI - Metabolic engineering and adaptive evolution for efficient production of D-lactic acid in Saccharomyces cerevisiae. AB - There is an increasing demand for microbial production of lactic acid (LA) as a monomer of biodegradable poly lactic acid (PLA). Both optical isomers, D-LA and L LA, are required to produce stereocomplex PLA with improved properties. In this study, we developed Saccharomyces cerevisiae strains for efficient production of D-LA. D-LA production was achieved by expressing highly stereospecific D-lactate dehydrogenase gene (ldhA, LEUM_1756) from Leuconostoc mesenteroides subsp. mesenteroides ATCC 8293 in S. cerevisiae lacking natural LA production activity. D-LA consumption after glucose depletion was inhibited by deleting DLD1 encoding D-lactate dehydrogenase and JEN1 encoding monocarboxylate transporter. In addition, ethanol production was reduced by deleting PDC1 and ADH1 genes encoding major pyruvate decarboxylase and alcohol dehydrogenase, respectively, and glycerol production was eliminated by deleting GPD1 and GPD2 genes encoding glycerol-3-phosphate dehydrogenase. LA tolerance of the engineered D-LA-producing strain was enhanced by adaptive evolution and overexpression of HAA1 encoding a transcriptional activator involved in weak acid stress response, resulting in effective D-LA production up to 48.9 g/L without neutralization. In a flask fed batch fermentation under neutralizing condition, our evolved strain produced 112.0 g/L D-LA with a yield of 0.80 g/g glucose and a productivity of 2.2 g/(L . h). PMID- 26596575 TI - Is anti-BP180 IgE associated with clinical phenotype? Reply to the letter to the editor. PMID- 26596576 TI - Investigation of antibacterial activity of aspidin BB against Propionibacterium acnes. AB - In the present study, antibacterial activity of four kinds of phloroglucinol derivatives extracted from Dryopteris fragrans (L.) Schott against S. aureus, S. epidermidis and P. acnes has been tested. Aspidin BB exerted the strongest antibacterial activity with minimal inhibition concentration (MIC) values ranging from 7.81 to 15.63 MUg/mL. The time-kill assay indicated that aspidin BB could kill P. acnes completely at 2 MIC (MBC) within 4 h. By using AFM, we demonstrated extensive cell surface alterations of aspidin BB-treated P. acnes. SDS-PAGE of supernatant proteins and lipid peroxidation results showed that aspidin BB dose dependently affected membrane permeability of P. acnes. DNA damage and protein degradation of P. acnes were also verified. SDS-PAGE of precipitated proteins revealed possible targets of aspidin BB, i.e., heat shock proteins (26 kDa) and lipase (33 kDa) which could all cause inflammation. Aspidin BB also seriously increased the inhibition rate of lipase activity from 10.20 to 65.20 % to possibly inhibit the inflammation. In conclusions, the effective constituents of D. fragrans (L.) Schott to treat acne might be phloroglucinol derivatives including aspidin BB, aspidin PB, aspidinol and dryofragin. Among this, aspidin BB inhibited the growth of P. acnes by disrupting their membrane, DNA and proteins and finally leaded to the cell death. The obtained data highlighted the potential of using aspidin BB as an alternative treatment for acne vulgaris. PMID- 26596577 TI - [Quality management in weight restitution in Anorexia nervosa--pathophysiology, evidence-based practice and prevention of the refeeding syndrome]. AB - During refeeding syndrome-a well-known and dreaded complication of weight restauration in anorexia nervosa-a shift of electrolytes and fluid can occur in malnourished patients and might therefore lead to-potentially fatal cardiovascular, respiratory and neurological symptoms. Causes of this are metabolic and hormonal changes during re-establishment of a carbohydrate-rich diet. This syndrome is most commonly associated with hypophosphatemia, which can however be accompanied by other chemical laboratory abnormalities. Standardized guidelines for the prevention and management of the refeeding syndrome have not yet been established. In case and cohort studies different low- and high-calorie diet protocols led to comparable results with similar complication rates. A focus should be placed on prevention of serious complications by careful monitoring. The pathophysiology, the main constituents in the development of the refeeding syndrome, recommendations for risk assessment and treatment, and current evidence are discussed. PMID- 26596578 TI - Acute fatal metabolic complications in alkaptonuria. AB - Alkaptonuria (AKU) is a rare inherited metabolic disorder of tyrosine metabolism that results from a defect in an enzyme called homogentisate 1,2-dioxygenase. The result of this is that homogentisic acid (HGA) accumulates in the body. HGA is central to the pathophysiology of this disease and the consequences observed; these include spondyloarthropathy, rupture of ligaments/muscle/tendons, valvular heart disease including aortic stenosis and renal stones. While AKU is considered to be a chronic progressive disorder, it is clear from published case reports that fatal acute metabolic complications can also occur. These include oxidative haemolysis and methaemoglobinaemia. The exact mechanisms underlying the latter are not clear, but it is proposed that disordered metabolism within the red blood cell is responsible for favouring a pro-oxidant environment that leads to the life threatening complications observed. Herein the role of red blood cell in maintaining the redox state of the body is reviewed in the context of AKU. In addition previously reported therapeutic strategies are discussed, specifically with respect to why reported treatments had little therapeutic effect. The potential use of nitisinone for the management of patients suffering from the acute metabolic decompensation in AKU is proposed as an alternative strategy. PMID- 26596580 TI - French adaptation and validation of the Osteoarthritis Quality of Life scale. AB - OBJECTIVE: The Osteoarthritis Quality of Life scale (OAQoL) is an osteoarthritis specific measure developed in the United Kingdom by a needs-based approach. This study describes the adaptation and validation of this English scale into French. METHODS: The OAQoL was translated into French by a dual-panel technique followed by cognitive debriefing interviews. Internal consistency was assessed by the Cronbach alpha. Construct validity was tested by exploratory and confirmatory factor analyses and by convergent and divergent correlations with other patient reported outcome measures by the Spearman rho (rho). Reliability was explored by Spearman rho as well as the Bland and Altman method for the total score and Cohen's kappa for each item score. RESULTS: Cognitive debriefing revealed the French OAQoL to be clear, relevant and comprehensive. The Cronbach alpha was 0.91. Exploratory factor analysis extracted 4 groups of items. After eliminating 4 items, confirmatory factor analysis of the remaining 18 items confirmed higher intra-factor than inter-factor correlations. The expected convergent and divergent correlations were observed. Test-retest reliability was good (rho 0.93) and was confirmed by Bland and Altman analysis; most items (12/18) had kappa values from 0.61 to 0.80. CONCLUSION: The French OAQoL is an easy-to-use 18-item questionnaire with good content and construct validity to assess the impact of osteoarthritis on quality of life for French-speaking patients. PMID- 26596579 TI - Dexmedetomidine-related polyuria in a pediatric patient. AB - Polyuria related to pharmacologic alpha2-adrenoreceptor agonism has been well described in vitro and in animal models and is thought to be the result of functional antagonism of arginine vasopressin. Despite its widespread use as a sedative and anesthetic adjunct, very few reports of dexmedetomidine-related polyuria in humans exist in the literature. We present the first description of a pediatric patient manifesting polyuria and hypernatremia in association with dexmedetomidine infusion for posterior spinal fusion. PMID- 26596582 TI - Assessment of Shock Pretreatment of Corn Stover Using the Carboxylate Platform. AB - Corn stover was pretreated with lime and shock, a mechanical process that uses a shockwave to alter the biomass structure. Two pretreatments (lime-only and lime + shock) were evaluated using enzymatic hydrolysis, batch mixed-culture fermentations, and continuous countercurrent mixed-culture fermentation. In a 120 h enzymatic hydrolysis, shock pretreatment increased the glucan digestibility of submerged lime pretreatment (SLP) corn stover by 3.5 % and oxidative lime pretreatment (OLP) corn stover by 2.5 %. The continuum particle distribution model (CPDM) was used to simulate a four-stage continuous countercurrent mixed culture fermentation using empirical rate models obtained from simple batch experiments. The CPDM model determined that lime + shock pretreatment increased the total carboxylic acids yield by 28.5 % over lime-only pretreatment in a countercurrent fermentation with a volatile solids loading rate (VSLR) of 12 g/(L/day) and liquid retention time (LRT) of 30 days. In a semi-continuous countercurrent fermentation performed in the laboratory for 112 days with a VSLR of 1.875 g/(L day) and LRT of 16 days, lime + shock pretreatment increased the total carboxylic acid yield by 14.8 %. The experimental results matched closely with CPDM model predictions (4.05 % error). PMID- 26596583 TI - Novel 24-h ovine model of brain death to study the profile of the endothelin axis during cardiopulmonary injury. AB - BACKGROUND: Upregulation of the endothelin axis has been observed in pulmonary tissue after brain death, contributing to primary graft dysfunction and ischaemia reperfusion injury. The current study aimed to develop a novel, 24-h, clinically relevant, ovine model of brain death to investigate the profile of the endothelin axis during brain death-associated cardiopulmonary injury. We hypothesised that brain death in sheep would also result in demonstrable injury to other transplantable organs. METHODS: Twelve merino cross ewes were randomised into two groups. Following induction of general anaesthesia and placement of invasive monitoring, brain death was induced in six animals by inflation of an extradural catheter. All animals were supported in an intensive care unit environment for 24 h. Animal management reflected current human donor management, including administration of vasopressors, inotropes and hormone resuscitation therapy. Activation of the endothelin axis and transplantable organ injury were assessed using ELISA, immunohistochemistry and standard biochemical markers. RESULTS: All animals were successfully supported for 24 h. ELISA suggested early endothelin-1 and big endothelin-1 release, peaking 1 and 6 h after BD, respectively, but there was no difference at 24 h. Immunohistochemistry confirmed the presence of the endothelin axis in pulmonary tissue. Brain dead animals demonstrated tachycardia and hypertension, followed by haemodynamic collapse, typified by a reduction in systemic vascular resistance to 46 +/- 1 % of baseline. Mean pulmonary artery pressure rose to 186 +/- 20 % of baseline at induction and remained elevated throughout the protocol, reaching 25 +/- 2.2 mmHg at 24 h. Right ventricular stroke work increased 25.9 % above baseline by 24 h. Systemic markers of cardiac and hepatocellular injury were significantly elevated, with no evidence of renal dysfunction. CONCLUSIONS: This novel, clinically relevant, ovine model of brain death demonstrated that increased pulmonary artery pressures are observed after brain death. This may contribute to right ventricular dysfunction and pulmonary injury. The development of this model will allow for further investigation of therapeutic strategies to minimise the deleterious effects of brain death on potentially transplantable organs. PMID- 26596584 TI - hASH1 is a specific immunohistochemical marker for lung neuroendocrine tumors. AB - Mammalian/human achaete-scute homolog 1 (hASH1) regulates neuroendocrine cell development. No detailed comparative study has been conducted to explore the immunohistochemical utility of hASH1 in distinguishing different types of lung cancers. We investigated the expression of hASH1, synaptophysin, chromogranin, and CD56 in 101 squamous cell carcinomas (SCCs), 183 adenocarcinomas (ADCs), 37 typical carcinoids (TCs), 14 atypical carcinoids (ACs), 11 large cell neuroendocrine carcinomas (LCNECs), and 24 small cell lung carcinomas (SCLCs) of the lung by immunohistochemical staining with a monoclonal antibody against hASH1. Staining intensity was graded from 0 to 3, and percentage of tumor cells in each grade was estimated. All cases of ADC and SCC were discreetly negative for hASH1 in contrast to their low percentage positivity for synaptophysin, chromogranin, and CD56. hASH1 positively stained TC (64.9%), AC (64.3%), LCNEC (72.7%), and SCLC (79.2%) as did chromogranin (TC, 100%; AC, 78.6%; LCNEC, 9.0%; and SCLC, 4.2%), synaptophysin (TC, 100%; AC, 78.6%; LCNEC, 81.8%; and SCLC, 83.3%), and CD56 (TC, 59.5%; AC, 57.1%; LCNEC, 36.4%; and SCLC, 79.2%). TC and AC often showed weaker intensity and lower percentage of tumor cells positive for hASH1 (median score, 5) than LCNEC and SCLC (median score, 40 and 170, respectively). There were statistically significant differences in mean intensity scores between SCLC (148.8 +/- 20.1) and other neuroendocrine tumors: TC (37.1 +/ 9.2) and AC (28.6 +/- 10.8) or LCNEC (51.8 +/- 18.0). Our findings indicate that hASH1 is a specific marker to distinguish neuroendocrine tumors from SCC and ADC. Additionally, hASH1 is a useful diagnostic marker for segregating SCLC from other neuroendocrine tumors. PMID- 26596585 TI - Vascular mesangial channels in human nodular diabetic glomerulopathy. AB - The presence of vascular mesangial channels has been reported in idiopathic nodular glomerulosclerosis and diabetic glomerulopathy. However, only limited information on the morphology and immunohistochemical phenotype of these channels is available. This study aims to describe the light and electron microscopic features of these channels and delineate their immunohistochemical phenotype. Thirty-eight cases of human nodular diabetic glomerulopathy with mesangial channels identified by light microscopy were prospectively selected (2010-2012). The cases were stained with CD31/periodic acid-Schiff combined stain. Selected cases were immunostained for CD34, podoplanin, ERG, and Ki-67. Frequent, small and peripheral vascular mesangial channels were seen in all cases, whereas larger and more centrally located vascular channels were also observed. Communication between peripheral capillary loops and peripheral vascular mesangial channels was seen as was communication between peripheral and central vascular mesangial channels. The vascular mesangial channel lining cells showed a typical endothelial phenotype with strong expression of CD31, CD34, and ERG by immunohistochemistry. The lymphatic channel marker podoplanin was negative in all channels, and the proliferation marker Ki-67 showed no evidence of increased proliferation. By electron microscopy, mesangial channels show angulated, irregular borders with lining cells compatible with endothelium and surrounded by mesangial matrix. No basement membranes were identified surrounding the mesangial channels. These findings support the existence of vascular mesangial channels in nodular diabetic glomerulopathy and suggest neovascularization and altered blood flow within these glomeruli. PMID- 26596586 TI - Molecular Characteristics, Clinical and Immunologic Manifestations of 11 Children with Omenn Syndrome in East Slavs (Russia, Belarus, Ukraine). AB - BACKGROUND: Omenn syndrome [Mendelian Inheritance (OMIM 603554)] is a genetic disease of the immune system, characterized by the presence of fatal generalized severe erythroderma, lymphoadenopathy, eosinophilia and profound immunodeficiency. OBJECTIVE: We studied clinical and immunologic presentation of the disease manifestation among East Slavs population with genetically confirmed Omenn syndrome. RESULTS: We collected clinical and immunologic data of 11 patients (1 from Belarus, 5--Ukraine, 5--Russia): 6 females, 5 males. The age of Omenn syndrome manifestation varied from the 1st day of life to 1 year and 1 month, the age of diagnosis--20 days to 1 year and 10 months. Nine out of 11 patients had classic immunologic phenotype T(+/-)B-NK+, 1 pt had TlowB + NK+ with CD3 + TCRgd + expansion and 1 had TlowB+/-NK+ phenotype. Eight out of 11 pts had mutation in RAG1 gene, 4 out of 8 had c.368-369delAA (p.K86fsX118) in homozygous state or heterozygous compound. In our cohort of patients, we also described two new mutations in RAG genes (p.E722Q in RAG1 and p.M459R in RAG2). At present, 7/11 were transplanted and 5 out of the transplanted are alive. CONCLUSION: This study demonstrates that the most popular genetic abnormality in East Slavs children with Omenn syndrome is c.368-369delAA (p.K86fs118) in RAG1 gene, which may be connected with more favorable prognosis because 4/4 patients survived after hematopoietic stem cells transplantation. PMID- 26596588 TI - Validation of the Generalized Anxiety Disorder-7 (GAD-7) and GAD-2 in patients with migraine. AB - BACKGROUND: Psychiatric problems have been commonly reported in patients with migraine. This study investigated the reliability and validity of the Generalized Anxiety Disorder-7 (GAD-7) and Generalized Anxiety Disorder-2 (GAD-2) in patients with migraine. METHODS: Subjects were recruited from a headache clinic and a neuropsychologist examined their GAD using the Mini International Neuropsychiatric Interview-Plus Version 5.0.0 (MINI). Subjects completed several instruments, including the GAD-7, the Beck Anxiety Inventory (BAI), the Migraine Disability Assessment Scale (MIDAS), the Headache Impact Test-6 (HIT-6), and the Migraine-Specific Quality of Life (MSQoL). RESULTS: Among 146 participants, 32 patients (21.9 %) had GAD as determined by the MINI. Cronbach's alpha for the GAD 7 and GAD-2 were 0.915 and 0.820, respectively. At a cutoff score of 5, the GAD-7 had a sensitivity of 78.1 %, a specificity of 74.6 %, a positive predictive value (PPV) of 46.3 %, and a negative predictive value (NPV) of 92.4 %. At a cutoff score of 1, the GAD-2 had a sensitivity of 84.4 %, a specificity of 72.8 %, a PPV of 46.6 %, and a NPV of 94.3 %. The scores of the GAD-7 and GAD-2 well correlated with the BAI score, the MIDAS score, the HIT-6 score, and the MSQoL score. CONCLUSIONS: The GAD-7 and GAD-2 are both reliable and valid screening instruments for GAD in patients with migraine. PMID- 26596589 TI - Kirkwood-Buff Analysis of Liquid Mixtures in an Open Boundary Simulation. AB - Using the adaptive resolution (AdResS) molecular dynamics scheme, we present a new approach to calculate the thermodynamic properties of liquid mixtures in an open boundary simulation. As a test case, we simulate methanol-water mixtures. We show that Kirkwood-Buff integrals (KBI), which directly connect global thermodynamic properties to microscopic molecular distributions, can be efficiently calculated over a wide range of methanol mole fractions by choosing only a very small (~3% of total simulation domain) open boundary explicit (all atom) region and a surrounding coarse-grained reservoir that takes care of correct particle fluctuations. PMID- 26596590 TI - Toward Predicting Full Catalytic Cycle Using Automatic Reaction Path Search Method: A Case Study on HCo(CO)3-Catalyzed Hydroformylation. AB - Toward systematic prediction of reaction pathways in complex chemical reaction systems by quantum chemical calculations, a new automatic reaction path search approach has been proposed on the basis of the artificial force induced reaction (AFIR) method [J. Chem. Theory Comput.2011, 7, 2335-2345.]. We demonstrate in this Letter that this approach enabled semiautomatic determination of the full catalytic cycle of the HCo(CO)3-catalyzed hydroformylation. The search was fully systematic; no initial guess was required concerning the entire reaction mechanism as well as each transition-state structure. This approach opens the door to nonempirical prediction of complex reaction mechanisms involving multiple steps in multiple pathways, such as full cycles of catalytic reactions. PMID- 26596591 TI - Structure Formation of Toluene around C60: Implementation of the Adaptive Resolution Scheme (AdResS) into GROMACS. AB - For the example of C60 solutes in toluene, we present the implementation of the adaptive resolutions scheme (AdResS) for molecular simulations into GROMACS. In AdResS a local, typically all-atom cavity is coupled to a surrounding of coarse grained, simplified molecules. This methodology can not only be used to reduce the CPU time demand of atomistic simulations but also to systematically investigate the relative influence of different interactions on structure formation. For this, we vary the thickness of the all atom layer of toluene around the C60 and analyze the first toluene layers in comparison to a full bulk simulation. PMID- 26596587 TI - Antagonism of triazolam self-administration in rhesus monkeys responding under a progressive-ratio schedule: In vivo apparent pA2 analysis. AB - BACKGROUND: Conventional benzodiazepines bind non-selectively to GABAA receptors containing alpha1, alpha2, alpha3, and alpha5 subunits (alpha1GABAA, alpha2GABAA, alpha3GABAA, and alpha5GABAA receptors, respectively), and the role of these different GABAA receptor subtypes in the reinforcing effects of benzodiazepines has not been characterized fully. We used a pharmacological antagonist approach with available subtype-selective ligands to evaluate the role of GABAA receptor subtypes in the reinforcing effects of the non-selective conventional benzodiazepine, triazolam. METHODS: Rhesus monkeys (n=4) were trained under a progressive-ratio schedule of intravenous midazolam delivery and dose-response functions were determined for triazolam, in the absence and presence of flumazenil (non-selective antagonist), betaCCT and 3-PBC (alpha1GABAA-preferring antagonists), and XLi-093 (alpha5GABAA-selective antagonist). RESULTS: Flumazenil, betaCCT and 3-PBC shifted the dose-response functions for triazolam to the right in a surmountable fashion, whereas XLi-093 was ineffective. Schild analyses revealed rank orders of potencies of flumazenil=betaCCT>3-PBC. Comparison of potencies between self-administration and previous binding studies with human cloned GABAA receptor subtypes suggested that the potencies for betaCCT and 3-PBC were most consistent with binding at alpha2GABAA and alpha3GABAA receptors, but not alpha1GABAA or alpha5GABAA receptor subtypes. CONCLUSIONS: Our findings were not entirely consistent with blockade of alpha1GABAA receptors and are consistent with the possibility of alpha2GABAA and/or alpha3GABAA subtype involvement in antagonism of the reinforcing effects of triazolam. The alpha5GABAA receptor subtype likely does not play a substantial role in self-administration under these conditions. PMID- 26596592 TI - On the Equivalence of Schemes for Simulating Bilayers at Constant Surface Tension. AB - Lipid bilayers are simulated using flexible simulation cells in order to allow for relaxations in area per lipid as bilayer content and temperature are varied. We develop a suite of Monte Carlo (MC) moves designed to generate constant surface tension gamma and constant pressure P and find that the NPT partition function proposed by Attard [J. Chem. Phys.1995, 103, 9884-9885] leads to an NPgammaT partition function with a form invariant to choice of independent shape variables. We then compare this suite of MC moves to NPgammaT MC moves previously employed in our group as well as a pair of MC moves designed to replicate the NP?P?T "ensemble" often used in molecular dynamics simulations to yield zero surface tension and constant pressure. A detailed analysis of shape fluctuations in a small bilayer system reveals that the two latter MC move sets are different from one another as well as from our new suite of MC moves, as justified by careful analysis of the partition functions. However, the study of a larger bilayer system reveals that, for practical purposes for this system, all six MC move sets are comparable to one another. PMID- 26596593 TI - Robust and Efficient Constrained DFT Molecular Dynamics Approach for Biochemical Modeling. AB - Constrained density functional theory (cDFT) is a powerful tool to investigate the dynamics of the electrons accompanying various physical-chemical processes. In this article we present our recent progresses in the implementation of the method in the parallelized version of the DFT program deMon2k. We take advantage of the possibility to express atomic densities in terms of linear combination of Hermite Gaussian functions to improve the computation of the cDFT integration weights within the Hirshfeld and Voronoi deformation density electronic population approaches. The efficiency of the method is illustrated on the computation of the average electronic coupling for an electron transfer (ET) through a glycine polypeptide of increasing length. The sampling is based on cDFT and hybrid cDFT/molecular mechanics molecular dynamics simulations. We also report the first estimations of quantum decoherence times from cDFT-based simulations for an ET reaction. PMID- 26596594 TI - Ab Initio Treatment of Bond-Breaking Reactions: Accurate Course of HO3 Dissociation and Revisit to Isomerization. AB - An efficient scheme is devised for accurate studies of bond-breaking/forming reactions and illustrated for HO3. It is suggested and numerically demonstrated that an accurate dissociation path for the title system can be obtained by defining the central OO bond as the reaction coordinate. The approach consists of optimizing the dissociation path at the full-valence-complete-active space level of theory followed by single-point multireference configuration interaction calculations along it. Using large diffusely augmented basis sets of the correlation consistent type, accurate dissociation curves are then obtained for both the cis- and trans-HO3 isomers by extrapolating the calculated raw energies to the complete basis set limit. The profiles show a weak van der Waals type minimum and a small barrier, both lying below the dissociation asymptote. It is shown that this barrier arises at the break-off of the central OO chemical bond and onset of the OH...O2 hydrogen bond. The calculated dissociation energies (De) are 4.5 +/- 0.1 and 4.7 +/- 0.1 kcal mol(-1) for the cis- and trans-HO3 isomers, respectively, with a very conservative estimate of the dissociation energy (D0) for trans-HO3 being 2.7 +/- 0.2 kcal mol(-1) and a more focused one being 2.8 +/- 0.1 kcal mol(-1). This result improves upon our previous estimate of this quantity while overlapping in the lower range of 2.9 +/- 0.1 kcal mol(-1), the commonly accepted value from the low-temperature CRESU experiments. Since the cis HO3 isomer is predicted to be 0.15 kcal mol(-1) less stable than trans-HO3, this may partly explain the failure to obtain a clear characterization of the former. The isomerization (torsional) potential is also revisited and a comparison presented with a curve inferred from spectroscopic measurements. Good agreement is observed, with the accuracy of the new calculated data commending its use for the reanalysis of the available vibrational-rotational spectroscopic data. PMID- 26596595 TI - Development of Accurate DFT Methods for Computing Redox Potentials of Transition Metal Complexes: Results for Model Complexes and Application to Cytochrome P450. AB - Single-electron reduction half potentials of 95 octahedral fourth-row transition metal complexes binding a diverse set of ligands have been calculated at the unrestricted pseudospectral B3LYP/LACV3P level of theory in a continuum solvent. Through systematic comparison of experimental and calculated potentials, it is determined that B3LYP strongly overbinds the d-manifold when the metal coordinates strongly interacting ligands and strongly underbinds the d-manifold when the metal coordinates weakly interacting ligands. These error patterns give rise to an extension of the localized orbital correction (LOC) scheme previously developed for organic molecules and which was recently extended to the spin splitting properties of organometallic complexes. Mean unsigned errors in B3LYP redox potentials are reduced from 0.40 +/- 0.20 V (0.88 V max error) to 0.12 +/- 0.09 V (0.34 V max error) using a simple seven-parameter model. Although the focus of this article is on redox properties of transition metal complexes, we have found that applying our previous spin-splitting LOC model to an independent test set of oxidized and reduced complexes that are also spin-crossover complexes correctly reverses the ordering of spin states obtained with B3LYP. Interesting connections are made between redox and spin-splitting parameters with regard to the spectrochemical series and in their combined predictive power for properly closing the thermodynamic cycle of d-electron transitions in a transition metal complex. Results obtained from our large and diverse databases of spin-splitting and redox properties suggest that, while the error introduced by single reference B3LYP for simple multireference systems, like mononuclear transition metal complexes, remains significant, at around 2-5 kcal/mol, the dominant error, at around 10-20 kcal/mol, is in B3LYP's prediction of metal-ligand binding. Application of the LOC scheme to the rate-determining hydrogen atom transfer step in substrate hydroxylation by cytochrome P450 shows that this approach is able to correct the B3LYP barriers in comparison to recent kinetics experiments. PMID- 26596596 TI - Multireference Character for 3d Transition-Metal-Containing Molecules. AB - Coupled cluster and configuration interaction diagnostics have been examined in order to assess the reliability of single reference quantum methods for a series of 3d transition metal species including hydrides, nitrides, chalcogenides, halides, small clusters, coordination complexes, and metal dimers. Several means of diagnostics have been considered including T1 and D1 diagnostics (the Frobenius norm and matrix 2-norm of coupled cluster amplitudes for single excitations, respectively), C0(2) (the weight of leading configuration of a complete active space wave function), and %TAE (percent total atomization energy). T1 and D1 diagnostics are strongly correlated for certain metal-ligand bonding types. The use of T1 and D1 together with %TAE can provide more reliable assessment of the severity of nondynamical correlation than a single indicator can provide. New criteria, namely T1 > 0.05, D1 > 0.15, and |%TAE| > 10, are suggested to identify inorganic species with substantial nondynamical correlation. For these systems, energies and spectroscopic properties computed using single reference electronic correlation methods may suffer from large errors and unpredictable behavior. Conversely, a computation where a molecule is below one or more of these thresholds does not always imply domination by a single reference. Some historically pathological molecules such as Mn2 and Cr2 show T1 < 0.05 and D1 < 0.15. Current implementations of coupled cluster diagnostics may still be insufficient for categorization of molecules that have pronounced nondynamical correlation. PMID- 26596597 TI - Combined Fragmentation Method: A Simple Method for Fragmentation of Large Molecules. AB - Here we present a new energy-based fragmentation method that is based on our previous work and combines the best elements of other energy-based fragmentation methods. Our new approach, termed "combined fragmentation method", is foremost simple to implement, robust, accurate, and produces small fragments, which are independent of conformation and size of the target molecule. Essentially small collections of bonded atoms in the target molecule are assigned to groups. Fragment molecules are formed by taking all bonded pairs of these groups. These fragments are then interacted with one another, and the interaction energy is simply added to the initial fragmentation energy. The method has been tested on numerous molecules of biological interest both in vacuum and in a continuum solvent. PMID- 26596598 TI - Benchmarking Experimental and Computational Thermochemical Data: A Case Study of the Butane Conformers. AB - Due to its crucial importance, numerous studies have been conducted to determine the enthalpy difference between the conformers of butane. However, it is shown here that the most reliable experimental values are biased due to the statistical model utilized during the evaluation of the raw experimental data. In this study, using the appropriate statistical model, both the experimental expectation values and the associated uncertainties are revised. For the 133-196 and 223-297 K temperature ranges, 668 +/- 20 and 653 +/- 125 cal mol(-1), respectively, are recommended as reference values. Furthermore, to show that present-day quantum chemistry is a favorable alternative to experimental techniques in the determination of enthalpy differences of conformers, a focal-point analysis, based on coupled-cluster electronic structure computations, has been performed that included contributions of up to perturbative quadruple excitations as well as small correction terms beyond the Born-Oppenheimer and nonrelativistic approximations. For the 133-196 and 223-297 K temperature ranges, in exceptional agreement with the corresponding revised experimental data, our computations yielded 668 +/- 3 and 650 +/- 6 cal mol(-1), respectively. The most reliable enthalpy difference values for 0 and 298.15 K are also provided by the computational approach, 680.9 +/- 2.5 and 647.4 +/- 7.0 cal mol(-1), respectively. PMID- 26596599 TI - Parallel Implementation of Multireference Coupled-Cluster Theories Based on the Reference-Level Parallelism. AB - A novel algorithm for implementing a general type of multireference coupled cluster (MRCC) theory based on the Jeziorski-Monkhorst exponential ansatz [Jeziorski, B.; Monkhorst, H. J. Phys. Rev. A1981, 24, 1668] is introduced. The proposed algorithm utilizes processor groups to calculate the equations for the MRCC amplitudes. In the basic formulation, each processor group constructs the equations related to a specific subset of references. By flexible choice of processor groups and subset of reference-specific sufficiency conditions designated to a given group, one can ensure optimum utilization of available computing resources. The performance of this algorithm is illustrated on the examples of the Brillouin-Wigner and Mukherjee MRCC methods with singles and doubles (BW-MRCCSD and Mk-MRCCSD). A significant improvement in scalability and in reduction of time to solution is reported with respect to recently reported parallel implementation of the BW-MRCCSD formalism [Brabec, J.; van Dam, H. J. J.; Kowalski, K.; Pittner, J. Chem. Phys. Lett.2011, 514, 347]. PMID- 26596600 TI - Modeling Molecular Crystals by QM/MM: Self-Consistent Electrostatic Embedding for Geometry Optimizations and Molecular Property Calculations in the Solid. AB - We present an approach to model molecular crystals using an adaptive quantum mechanics/molecular mechanics (QM/MM) based protocol. The molecule of interest (or a larger cluster thereof) is described at an appropriate QM level and is embedded in a large array of MM atoms built up from crystal structure information. The nonbonded MM force field consists of atom-centered point charges and Lennard-Jones potentials using van der Waals parameters from the UFF force field. The point charges are initially derived from a single molecule DFT calculation and are then updated self-consistently in the field of point charges. Additional charges are fitted around the MM cluster to correct for missing long range electrostatic effects. The geometry of the central complex can then be relaxed by quantum chemical calculations in the surrounding MM reaction field, hence capturing solid-state effects on the geometry. We demonstrate the accuracy of this approach for geometry optimization by successful modeling of the huge gas to-solid bond contraction of HCN-BF3, the ability to reproduce periodic-DFT quality local geometries of solid VOCl3, and the geometry of [Ru(eta(5) Cp*)(eta(3)-CH2CHCHC6H5)(NCCH3)2](2+), a difficult ruthenium allyl complex in the solid state. We further show that this protocol is well suited for subsequent molecular property calculations in the solid state (where accurate relaxed geometries are often required) as exemplified by transition metal NMR and EFG calculations of VOCl3 and a vanadium catechol complex in the solid state. PMID- 26596601 TI - High-Multiplicity Natural Orbitals in Multireference Configuration Interaction for Excited States. AB - Multireference configuration interaction (MRCI) is a very useful tool in studying excited states, dissociation of molecules, and chemical systems with multireference character. In many cases however, poor computational scaling limits its use to small systems. In the past, several different approaches have been taken in order to make MRCI and other multireference methods more accessible when dealing with larger systems. Here we propose the use of high-multiplicity natural orbitals (HMNO) in order to improve several aspects of the MRCI calculation. Natural orbitals, derived from a configuration interaction with single and double excitations calculation on a high-multiplicity reference state, were used in lieu of the standard complete active space self-consistent field (CASSCF) canonical molecular orbitals. This work examines the ability of the MRCI/HMNO approach to reliably reproduce vertical excitation energies for singlet states as well as energies for conical intersections. It is found that the MRCI/HMNO approach reliably reproduces vertical excitation energies obtained from a standard MRCI using CASSCF orbitals, with an average deviation of 0.12 and 0.15 eV for the uncorrected and Davidson corrected energies, respectively. We also explore some of the computational savings that the new method affords via systematic truncation of the virtual space. Overall, it is found that the HMNO approach is a reliable method for computing MRCI excited-state energies in a fraction of the time it would take to run a standard MRCI calculation. PMID- 26596602 TI - Charge Model 5: An Extension of Hirshfeld Population Analysis for the Accurate Description of Molecular Interactions in Gaseous and Condensed Phases. AB - We propose a novel approach to deriving partial atomic charges from population analysis. The new model, called Charge Model 5 (CM5), yields class IV partial atomic charges by mapping from those obtained by Hirshfeld population analysis of density functional electronic charge distributions. The CM5 model utilizes a single set of parameters derived by fitting to reference values of the gas-phase dipole moments of 614 molecular structures. An additional test set (not included in the CM5 parametrization) contained 107 singly charged ions with nonzero dipole moments, calculated from the accurate electronic charge density, with respect to the center of nuclear charges. The CM5 model is applicable to any charged or uncharged molecule composed of any element of the periodic table in the gas phase or in solution. The CM5 model predicts dipole moments for the tested molecules that are more accurate on average than those from the original Hirshfeld method or from many other popular schemes including atomic polar tensor and Lowdin, Mulliken, and natural population analyses. In addition, the CM5 charge model is essentially independent of a basis set. It can be used with larger basis sets, and thereby this model significantly improves on our previous charge models CMx (x = 1-4 or 4M) and other methods that are prone to basis set sensitivity. CM5 partial atomic charges are less conformationally dependent than those derived from electrostatic potentials. The CM5 model does not suffer from ill conditioning for buried atoms in larger molecules, as electrostatic fitting schemes sometimes do. The CM5 model can be used with any level of electronic structure theory (Hartree-Fock, post-Hartree-Fock, and other wave function correlated methods or density functional theory) as long as an accurate electronic charge distribution and a Hirshfeld analysis can be computed for that level of theory. PMID- 26596603 TI - Kinetic Isotope Effects from QM/MM Subset Hessians: "Cut-Off" Analysis for SN2 Methyl Transfer in Solution. AB - Isotopic partition-function ratios and kinetic isotope effects for reaction of S adenosylmethionine with catecholate in water are evaluated using a subset of 324 atoms within its surrounding aqueous environment at the AM1/TIP3P level. Two alternative methods for treating motion in the six librational degrees of freedom of the subset atoms relative to their environment are compared. A series of successively smaller subset Hessians are generated by cumulative deletion of rows and columns from the initial 972 * 972 Hessian. We find that it is better to treat these librations as vibrations than as translations and rotations and that there is no need to invoke the Teller-Redlich product rule. The validity of "cut off" procedures for computation of isotope effects with truncated atomic subsets is assessed: to ensure errors in ln(KIE) < 1% (or 2% for the quantum-corrected KIE) for all isotopic substitutions considered, it is necessary to use a less restrictive procedure than is suggested by the familiar two-bond cutoff rule. PMID- 26596604 TI - Automated Parametrization of AMBER Force Field Terms from Vibrational Analysis with a Focus on Functionalizing Dinuclear Zinc(II) Scaffolds. AB - A procedure for determining force constants that is independent of the internal redundant coordinate choice is presented. The procedure is based on solving each bond and angle term separately, using the Wilson B matrix. The method only requires a single ab initio frequency calculation at the minimum energy structure and is made available in the software "parafreq". The methodology is validated with a set of small molecules, by showing it can reproduce ab initio frequencies better than other methods such as taking the diagonal terms of the Hessian in internal coordinates or by using standard AMBER force fields. Finally, the utility of the method is demonstrated by parametrizing the dizinc scaffold of bis dipicolylamine (BDPA) bound to phosphotyrosine, which is then functionalized into promising antitumor drug proteomimetics. PMID- 26596605 TI - Detailed QM/MM study of the Electron Paramagnetic Resonance Parameters of Nitrosyl Myoglobin. AB - A number of popular density functionals are calibrated against high-resolution EPR data for low spin iron-nitrosyls present in nitric oxide bound myoglobin. The model incorporates both electrostatic and steric effects using a combined quantum mechanics/molecular mechanics (QM/MM) approach. Compared to the most recent experimental data, the calculated EPR parameters using GGA functionals are distinctly more accurate than those predicted by hybrid functionals. The latter is related to an erroneous spin distribution predicted with hybrid functionals in this particular case. However, owing to the inaccuracies in the prediction of spin state energetics, GGA functionals overestimate the binding energy of the nitric oxide ligand to the heme center. Using the calculated magnetic resonance parameters as well as the calculated rotational potential energy surface of the NO ligand over the heme plane, a possible geometric structure of elusive A-form if nitrosyl-myoglobin is proposed. PMID- 26596606 TI - (1)La and (1)Lb States of Indole and Azaindole: Is Density Functional Theory Inadequate? AB - The applicability of time-dependent density functional theory (TD-DFT) is tested in describing (1)La and (1)Lb pi-pi* states in indole, azaindole, indene, and benzimidazole. Several density functionals including popular three hybrid functionals (B3LYP, PBE0, and mPW1PW91), two meta-GGA functionals (M06-L and M06 2X), and four long-range corrected (CAM-B3LYP, omegaB97XD, LC-BLYP, and LC omegaPBE) density functionals have been considered for the present study. The 6 311+G(2d,p) basis set incorporated with two sets of Rydberg sp functions for carbon and nitrogen atoms is utilized. The range-separation parameters for the calculations with the long-range corrected density functionals were tuned by enforcing the DFT version of Koopmans' theorem, and the effect of this tuning on the accuracy of the results is also examined. Results show that all of the hybrid and meta-GGA functionals predict a wrong order of (1)La and (1)Lb pi-pi* states in indole and azaindole. Although all of the LC functionals correctly predict that (1)Lb is the lowest excited state in indole, the energy gap calculated between the (1)Lb and (1)La state is much smaller than the value observed in the experimental studies. In the case of azaindole, only LC-omegaPBE and LC-BLYP functionals could manage to reproduce the correct order of states; however, here too, the calculated energy gap between the two pi-pi* states is very small compared to the experimental value. Overall, the (1)Lb state excitation energies derived with all of the functionals are overestimated. In contrast, all of the nine selected functionals correctly reproduce the order of states in indene and benzimidazole. The origin of this differing performance is analyzed. Also in the study, oscillator strengths and dipole moments of the excited states are derived, and two other important states, pi-sigma* and n-pi* states, that could play important role in the photochemistry of these molecules are examined. PMID- 26596607 TI - Toward an Accurate Modeling of Optical Rotation for Solvated Systems: Anharmonic Vibrational Contributions Coupled to the Polarizable Continuum Model. AB - We present a newly implemented methodology to evaluate vibrational contributions (harmonic and anharmonic) to the optical rotation of solvated systems described by means of the polarizable continuum model (PCM). Proper account of an incomplete solvation regime in the treatment of both the electronic property and the molecular vibrations is considered, as well as the inclusion of cavity field effects. In order to assess the quality of our approach, test calculations on (R) methyloxirane in various solvents and (S)-N-acetylproline amide in cyclohexane and aqueous solution are presented. The comparison with experimental findings is also shown. PMID- 26596608 TI - Scalar Relativistic Computations and Localized Orbital Analyses of Nuclear Hyperfine Coupling and Paramagnetic NMR Chemical Shifts. AB - A method is reported by which calculated hyperfine coupling constants (HFCCs) and paramagnetic NMR (pNMR) chemical shifts can be analyzed in a chemically intuitive way by decomposition into contributions from localized molecular orbitals (LMOs). A new module for density functional calculations with nonhybrid functionals, global hybrids, and range-separated hybrids, utilizing the two-component relativistic zeroth-order regular approximation (ZORA), has been implemented in the parallel open-source NWChem quantum chemistry package. Benchmark results are reported for a test set of few-atom molecules with light and heavy elements. Finite nucleus effects on (199)Hg HFCCs are shown to be on the order of -11 to 15%. A proof of concept for the LMO analysis is provided for the metal and fluorine HFCCs of TiF3 and NpF6. Calculated pNMR chemical shifts are reported for the 2-methylphenyl-t-butylnitroxide radical and for five cyclopentadienyl (Cp) sandwich complexes with 3d metals. Nickelocene and vanadocene carbon pNMR shifts are analyzed in detail, demonstrating that the large carbon pNMR shifts calculated as +1540 for Ni (exptl.: +1514) and -443 for V (exptl.: -510) are caused by different spin-polarization mechanisms. For Ni, Cp to Ni pi back donation dominates the result, whereas for vanadocene, V to Cp sigma donation with relaxation of the carbon 1s shells can be identified as the dominant mechanism. PMID- 26596609 TI - A Polarizable QM/MM Explicit Solvent Model for Computational Electrochemistry in Water. AB - We present a quantum mechanical/molecular mechanical (QM/MM) explicit solvent model for the computation of standard reduction potentials E0. The QM/MM model uses density functional theory (DFT) to model the solute and a polarizable molecular mechanics (MM) force field to describe the solvent. The linear response approximation is applied to estimate E0 from the thermally averaged electron attachment/detachment energies computed in the oxidized and reduced states. Using the QM/MM model, we calculated one-electron E0 values for several aqueous transition-metal complexes and found substantially improved agreement with experiment compared to values obtained from implicit solvent models. A detailed breakdown of the physical effects in the QM/MM model indicates that hydrogen bonding effects are mainly responsible for the differences in computed values of E0 between the QM/MM and implicit models. Our results highlight the importance of including solute-solvent hydrogen-bonding effects in the theoretical modeling of redox processes. PMID- 26596610 TI - The Role of Atomic Polarization in the Thermodynamics of Chloroform Partitioning to Lipid Bilayers. AB - In spite of extensive research and use in medical practice, the precise molecular mechanism of volatile anesthetic action remains unknown. The distribution of anesthetics within lipid bilayers and potential targeting to membrane proteins is thought to be central to therapeutic function. Therefore, obtaining a molecular level understanding of volatile anesthetic partitioning into lipid bilayers is of vital importance to modern pharmacology. In this study we investigate the partitioning of the prototypical anesthetic, chloroform, into lipid bilayers and different organic solvents using molecular dynamics simulations with potential models ranging from simplified coarse-grained MARTINI to additive and polarizable CHARMM all-atom force fields. Many volatile anesthetics display significant inducible dipole moments, which correlate with their potency, yet the exact role of molecular polarizability in their stabilization within lipid bilayers remains unknown. We observe that explicit treatment of atomic polarizability makes it possible to accurately reproduce solvation free energies in solvents with different polarities, allowing for quantitative studies in heterogeneous molecular distributions, such as lipid bilayers. We calculate the free energy profiles for chloroform crossing lipid bilayers to reveal a role of polarizability in modulating chloroform partitioning thermodynamics via the chloroform-induced dipole moment and highlight competitive binding to the membrane core and toward the glycerol backbone that may have significant implications for understanding anesthetic action. PMID- 26596611 TI - Work Function of Oxide Ultrathin Films on the Ag(100) Surface. AB - Theoretical calculations of the work function of monolayer (ML) and bilayer (BL) oxide films on the Ag(100) surface are reported and analyzed as a function of the nature of the oxide for first-row transition metals. The contributions due to charge compression, charge transfer and rumpling are singled out. It is found that the presence of empty d-orbitals in the oxide metal can entail a charge flow from the Ag(100) surface to the oxide film which counteracts the decrease in the work function due to charge compression. This flow can also depend on the thickness of the film and be reduced in passing from ML to BL systems. A regular trend is observed along first-row transition metals, exhibiting a maximum for CuO, in which the charge flow to the oxide is so strong as to reverse the direction of rumpling. A simple protocol to estimate separately the contribution due to charge compression is discussed, and the difference between the work function of the bare metal surface and a Pauling-like electronegativity of the free oxide slabs is used as a descriptor quantity to predict the direction of charge transfer. PMID- 26596612 TI - Diatomics-in-Molecules Modeling of Many-Body Effects on the Structure and Thermodynamics of Mercury Clusters. AB - The stable structures and melting behavior of Hgn clusters, 2 <= n < 60, have been theoretically investigated using an updated diatomics-in-molecules (DIM) model initially proposed by Kitamura [Chem. Phys. Lett.2006, 425, 2056]. Global optimization and sampling at finite temperature are achieved on the basis of hierarchical and nested Markov chain Monte Carlo methods, respectively. The DIM model predicts highly symmetric icosahedral global minima that are generally similar to the standard van der Waals atomic clusters, without any indication of distorted or low-coordinated geometries, but also at variance with the global minima found with the pairwise Hg2 potential. The combined influences of surface and many-body effects due to s-p mixing are considerable on the melting point: although the model predicts a bulk melting temperature in fair agreement with experimental results, it is found to decrease with increasing cluster size. PMID- 26596613 TI - Unidirectional Mechanistic Valved Mechanisms for Ammonia Transport in GatCAB. AB - Glutamine amidotransferase CAB (GatCAB), a crucial enzyme involved in translational fidelity, catalyzes three reactions: (i) the glutaminase reaction to yield ammonia (NH3 or NH4(+)) from glutamine, (ii) the phosphorylation of Glu tRNA(Gln), and (iii) the transamidase reaction to convert the phosphorylated Glu tRNA(Gln) to Gln-tRNA(Gln). In the crystal structure of GatCAB, the two catalytic centers are far apart, and the presence of a hydrophilic channel to transport the molecules produced by the reaction (i) was proposed. We investigated the transport mechanisms of GatCAB by molecular dynamics (MD) simulations and free energy (PMF) calculations. In the MD simulations (in total ~1.1 MUs), the entrance of the previously proposed channel is closed, as observed in the crystal structure. Instead, a novel hydrophobic channel has been identified in this study: Since the newly identified entrance opened and closed repeatedly in the MD simulations, it may act as a gate. The calculated free energy difference revealed the significant preference of the newly identified gate/channel for NH3 transport (~10(4)-fold). In contrast, with respect to NH4(+), the free energy barriers are significantly increased for both channels due to tight hydrogen-bonding with hydrophilic residues, which hinders efficient transport. The opening of the newly identified gate is modulated by Phe206, which acts as a "valve". For the backward flow of NH3, our PMF calculation revealed that the opening of the gate is hindered by Ala207, which acts as a mechanistic "stopper" against the motion of the "valve" (Phe206). This is the first report to elucidate the detailed mechanisms of unidirectional mechanistic valved transport inside proteins. PMID- 26596614 TI - Assessment of Atomic Charge Models for Gas-Phase Computations on Polypeptides. AB - The concept of the atomic charge is extensively used to model the electrostatic properties of proteins. Atomic charges are not only the basis for the electrostatic energy term in biomolecular force fields but are also derived from quantum mechanical computations on protein fragments to get more insight into their electronic structure. Unfortunately there are many atomic charge schemes which lead to significantly different results, and it is not trivial to determine which scheme is most suitable for biomolecular studies. Therefore, we present an extensive methodological benchmark using a selection of atomic charge schemes [Mulliken, natural, restrained electrostatic potential, Hirshfeld-I, electronegativity equalization method (EEM), and split-charge equilibration (SQE)] applied to two sets of penta-alanine conformers. Our analysis clearly shows that Hirshfeld-I charges offer the best compromise between transferability (robustness with respect to conformational changes) and the ability to reproduce electrostatic properties of the penta-alanine. The benchmark also considers two charge equilibration models (EEM and SQE), which both clearly fail to describe the locally charged moieties in the zwitterionic form of penta-alanine. This issue is analyzed in detail because charge equilibration models are computationally much more attractive than the Hirshfeld-I scheme. Based on the latter analysis, a straightforward extension of the SQE model is proposed, SQE+Q(0), that is suitable to describe biological systems bearing many locally charged functional groups. PMID- 26596615 TI - Efficient Conformational Sampling in Explicit Solvent Using a Hybrid Replica Exchange Molecular Dynamics Method. AB - Temperature-based replica-exchange molecular dynamics (REMD), in which multiple simultaneous simulations, or replicas, are run at a range of temperatures, has become increasingly popular for exploring the energy landscape of biomolecular systems. The practical application of REMD toward systems of biomedical interest is often limited by the rapidly increasing number of replicas needed to model systems of larger size. Continuum solvent models, which replace the explicit modeling of solvent molecules with a mean-field approximation of solvation, decrease system size and correspondingly, the number of replicas, but can sometimes produce distortions of the free energy landscape. We present a hybrid implicit/explicit solvent REMD method in CHARMM in which replicas run in a purely explicit solvent regime while exchanges are implemented with a high-density GBMV2 implicit solvation model. Such a hybrid approach may be able to decrease the number of replicas needed to model larger systems while maintaining the accuracy of explicit solvent simulations. Toward that end, we run REMD using implicit solvent, explicit solvent, and our hybrid method, on three model systems: alanine dipeptide, a zwitterionic tetra-peptide, and a 10-residue beta-hairpin peptide. We compare free energy landscape in each system derived from a variety of metrics including dihedral torsion angles, salt-bridge distance, and folding stability, and perform clustering to characterize the resulting structural ensembles. Our results identify discrepancies in the free-energy landscape between implicit and explicit solvent and evaluate the capability of the hybrid approach to decrease the number of replicas needed for REMD while reproducing the energy landscape of explicit solvent simulations. PMID- 26596616 TI - Counterion Redistribution upon Binding of a Tat-Protein Mimic to HIV-1 TAR RNA. AB - Binding of proteins and small molecules to RNA involves many electrostatic interactions, which may alter the distribution of ions around the RNA molecule. Here, we use molecular dynamics simulations to investigate how binding of a cyclic peptide mimic of the HIV-1 Tat protein affects the ionic distribution around the HIV-1 TAR RNA element. The calculations reproduce the structural properties observed in NMR studies of TAR and its complex. They also provide insight into the rearrangement of counterions during the molecular recognition events leading to the formation of the protein/RNA complex. PMID- 26596617 TI - Subtle Monte Carlo Updates in Dense Molecular Systems. AB - Although Markov chain Monte Carlo (MC) simulation is a potentially powerful approach for exploring conformational space, it has been unable to compete with molecular dynamics (MD) in the analysis of high density structural states, such as the native state of globular proteins. Here, we introduce a kinetic algorithm, CRISP, that greatly enhances the sampling efficiency in all-atom MC simulations of dense systems. The algorithm is based on an exact analytical solution to the classic chain-closure problem, making it possible to express the interdependencies among degrees of freedom in the molecule as correlations in a multivariate Gaussian distribution. We demonstrate that our method reproduces structural variation in proteins with greater efficiency than current state-of the-art Monte Carlo methods and has real-time simulation performance on par with molecular dynamics simulations. The presented results suggest our method as a valuable tool in the study of molecules in atomic detail, offering a potential alternative to molecular dynamics for probing long time-scale conformational transitions. PMID- 26596618 TI - Internal Diffusion-Controlled Enzyme Reaction: The Acetylcholinesterase Kinetics. AB - Acetylcholinesterase is an enzyme with a very high turnover rate; it quenches the neurotransmitter, acetylcholine, at the synapse. We have investigated the kinetics of the enzyme reaction by calculating the diffusion rate of the substrate molecule along an active site channel inside the enzyme from atomic level molecular dynamics simulations. In contrast to the previous works, we have found that the internal substrate diffusion is the determinant of the acetylcholinesterase kinetics in the low substrate concentration limit. Our estimate of the overall bimolecular reaction rate constant for the enzyme is in good agreement with the experimental data. In addition, the present calculation provides a reasonable explanation for the effects of the ionic strength of solution and the mutation of surface residues of the enzyme. The study suggests that internal diffusion of the substrate could be a key factor in understanding the kinetics of enzymes of similar characteristics. PMID- 26596619 TI - Structural and Thermodynamic Characteristics That Seed Aggregation of Amyloid beta Protein in Water. AB - Amyloid-beta (Abeta) proteins undergo conformational transitions leading to aggregation-prone structures, which can initiate self-assembly to form soluble oligomers and eventually insoluble amyloid fibrils when transferred from the transmembrane phase to the physiological aqueous phase. Yet, how Abeta proteins acquire an aggregation-prone nature during the conformational transitions in water remains elusive. Here, we investigate key structural and thermodynamic features of a 42-residue Abeta (Abeta42) protein that seed aggregation based on the fully atomistic, explicit-water molecular dynamics simulations as well as on the integral-equation theory of liquids for solvation thermodynamic analysis. We performed a structure-based analysis on the solvation free energy, a major determinant of the protein hydrophobicity/solubility that influences the aggregation propensity of Abeta42 protein in water. In addition, the Gibbs free energy and its constituents including protein internal energy, protein configurational entropy, solvation enthalpy, and solvation entropy were computed to elucidate thermodynamic driving forces for the conformational transitions of Abeta42 protein in water. On the basis of the atomic-decomposition analysis of these thermodynamic functions, we demonstrate how N-terminal (residues 1-11) and C-terminal (39-42) regions as well as the central region (16-18) contribute significantly to decreasing the solubility of Abeta42 protein upon its conformational transitions in water. These results are consistent with the recent experimental and computational implications and further provide the molecular origin for why the C terminus may serve as an "internal seed" for aggregation and the N-terminal segment may act as a "catalyst" in inducing the Abeta42 self assembly. This work takes a step forward toward the identification of structural and thermodynamic features of the Abeta42 monomer that seed the aggregation process in water. PMID- 26596620 TI - Comparison of Cellulose Ibeta Simulations with Three Carbohydrate Force Fields. AB - Molecular dynamics simulations of cellulose have recently become more prevalent due to increased interest in renewable energy applications, and many atomistic and coarse-grained force fields exist that can be applied to cellulose. However, to date no systematic comparison between carbohydrate force fields has been conducted for this important system. To that end, we present a molecular dynamics simulation study of hydrated, 36-chain cellulose Ibeta microfibrils at room temperature with three carbohydrate force fields (CHARMM35, GLYCAM06, and Gromos 45a4) up to the near-microsecond time scale. Our results indicate that each of these simulated microfibrils diverge from the cellulose Ibeta crystal structure to varying degrees under the conditions tested. The CHARMM35 and GLYCAM06 force fields eventually result in structures similar to those observed at 500 K with the same force fields, which are consistent with the experimentally observed high temperature behavior of cellulose I. The third force field, Gromos 45a4, produces behavior significantly different from experiment, from the other two force fields, and from previously reported simulations with this force field using shorter simulation times and constrained periodic boundary conditions. For the GLYCAM06 force field, initial hydrogen-bond conformations and choice of electrostatic scaling factors significantly affect the rate of structural divergence. Our results suggest dramatically different time scales for convergence of properties of interest, which is important in the design of computational studies and comparisons to experimental data. This study highlights that further experimental and theoretical work is required to understand the structure of small diameter cellulose microfibrils typical of plant cellulose. PMID- 26596621 TI - Improving Upon String Methods for Transition State Discovery. AB - Transition state discovery via application of string methods has been researched on two fronts. The first front involves development of a new string method, named the Searching String method, while the second one aims at estimating transition states from a discretized reaction path. The Searching String method has been benchmarked against a number of previously existing string methods and the Nudged Elastic Band method. The developed methods have led to a reduction in the number of gradient calls required to optimize a transition state, as compared to existing methods. The Searching String method reported here places new beads on a reaction pathway at the midpoint between existing beads, such that the resolution of the path discretization in the region containing the transition state grows exponentially with the number of beads. This approach leads to favorable convergence behavior and generates more accurate estimates of transition states from which convergence to the final transition states occurs more readily. Several techniques for generating improved estimates of transition states from a converged string or nudged elastic band have been developed and benchmarked on 13 chemical test cases. Optimization approaches for string methods, and pitfalls therein, are discussed. PMID- 26596622 TI - A proteomic approach for the rapid, multi-informative and reliable identification of blood. AB - Blood evidence is frequently encountered at the scene of violent crimes and can provide valuable intelligence in the forensic investigation of serious offences. Because many of the current enhancement methods used by crime scene investigators are presumptive, the visualisation of blood is not always reliable nor does it bear additional information. In the work presented here, two methods employing a shotgun bottom up proteomic approach for the detection of blood are reported; the developed protocols employ both an in solution digestion method and a recently proposed procedure involving immobilization of trypsin on hydrophobin Vmh2 coated MALDI sample plate. The methods are complementary as whilst one yields more identifiable proteins (as biomolecular signatures), the other is extremely rapid (5 minutes). Additionally, data demonstrate the opportunity to discriminate blood provenance even when two different blood sources are present in a mixture. This approach is also suitable for old bloodstains which had been previously chemically enhanced, as experiments conducted on a 9-year-old bloodstain deposited on a ceramic tile demonstrate. PMID- 26596623 TI - Reclassification of Desulfurococcus mobilis as a synonym of Desulfurococcus mucosus, Desulfurococcus fermentans and Desulfurococcus kamchatkensis as synonyms of Desulfurococcus amylolyticus, and emendation of the D. mucosus and D. amylolyticus species descriptions. AB - Representatives of the crenarchaeal genus Desulfurococcus are strictly anaerobic hyperthermophiles with an organotrophic type of metabolism. Since 1982, five Desulfurococcus species names have been validly published: Desulfurococcus mucosus, D. mobilis, D. amylolyticus, D. fermentans and D. kamchatkensis. Recently, the genomic sequences of all five species became available, promoting the refinement of their taxonomic status. Analysis of full-length high-quality 16S rRNA gene sequences shows that the sequences of D. mobilis and D. mucosus are 100 % identical and differ by 2.2 % from those of D. amylolyticus, D. fermentans and D. kamchatkensis. The latter three sequences differ from each other by 0.1 0.3 % (99.9 % similarity in the D amylolyticus-D. kamchatkensis pair and 99.7 % in the pairs involving D. fermentans). In silico prediction of DNA-DNA hybridization (DDH) values by comparison of genomes using ggdc 2.0 blast+ at http://ggdc.dsmz.de/ produced results that correlated with the 16S rRNA gene sequence similarity values. In the D. mucosus-D. mobilis and D. amylolyticus-D. kamchatkensis pairs, the predicted DDH values were 99 and 92 %, respectively, much higher than the recommended 70 % species-delimiting DDH value. Between members of different pairs, these values were no higher than 20 %. For D. fermentans, its predicted DDH values were around 70 % with D. amylolyticus and D. kamchatkensis and no higher than 20 % with D. mobilis and D. mucosus. These results indicated that D. mobilis should be reclassified as a synonym of D. mucosus, whereas D. kamchatkensis and D. fermentans should be reclassified as synonyms of D. amylolyticus. PMID- 26596624 TI - Assessing feasibility and acceptability of study procedures: getting ready for implementation of national stroke guidelines in out-patient health care. AB - BACKGROUND: Even though Swedish national guidelines for stroke care (SNGSC) have been accessible for nearly a decade access to stroke rehabilitation in out patient health care vary considerably. In order to aid future interventions studies for implementation of SNGSC, this study assessed the feasibility and acceptability of study procedures including analysis of the context in out patient health care settings. METHODS: The feasibility and acceptability of recruitment, observations and interviews with managers, staff and patients were assessed, as well as the feasibility of surveying health care records. RESULTS: To identify patients from the the hospitals was feasible but not from out-patient care where a need to relieve clinical staff of the recruitment process was identified. Assessing adherence to guidelines and standardized evaluations of patient outcomes through health care records was found to be feasible and suitable assessment tools to evaluate patient outcome were identified. Interviews were found to be a feasible and acceptable tool to survey the context of the health care setting. CONCLUSION: In this feasibility study a variety of qualitative and quantitative data collection procedures and measures were tested. The results indicate what can be used as a set of feasible and acceptable data collection procedures and suitable measures for studying implementation of stroke guidelines in an out-patient health care context. PMID- 26596625 TI - Extracting phylogenetic signal and accounting for bias in whole-genome data sets supports the Ctenophora as sister to remaining Metazoa. AB - BACKGROUND: Understanding the phylogenetic relationships among major lineages of multicellular animals (the Metazoa) is a prerequisite for studying the evolution of complex traits such as nervous systems, muscle tissue, or sensory organs. Transcriptome-based phylogenies have dramatically improved our understanding of metazoan relationships in recent years, although several important questions remain. The branching order near the base of the tree, in particular the placement of the poriferan (sponges, phylum Porifera) and ctenophore (comb jellies, phylum Ctenophora) lineages is one outstanding issue. Recent analyses have suggested that the comb jellies are sister to all remaining metazoan phyla including sponges. This finding is surprising because it suggests that neurons and other complex traits, present in ctenophores and eumetazoans but absent in sponges or placozoans, either evolved twice in Metazoa or were independently, secondarily lost in the lineages leading to sponges and placozoans. RESULTS: To address the question of basal metazoan relationships we assembled a novel dataset comprised of 1080 orthologous loci derived from 36 publicly available genomes representing major lineages of animals. From this large dataset we procured an optimized set of partitions with high phylogenetic signal for resolving metazoan relationships. This optimized data set is amenable to the most appropriate and computationally intensive analyses using site-heterogeneous models of sequence evolution. We also employed several strategies to examine the potential for long branch attraction to bias our inferences. Our analyses strongly support the Ctenophora as the sister lineage to other Metazoa. We find no support for the traditional view uniting the ctenophores and Cnidaria. Our findings are supported by Bayesian comparisons of topological hypotheses and we find no evidence that they are biased by long-branch attraction. CONCLUSIONS: Our study further clarifies relationships among early branching metazoan lineages. Our phylogeny supports the still-controversial position of ctenophores as sister group to all other metazoans. This study also provides a workflow and computational tools for minimizing systematic bias in genome-based phylogenetic analyses. Future studies of metazoan phylogeny will benefit from ongoing efforts to sequence the genomes of additional invertebrate taxa that will continue to inform our view of the relationships among the major lineages of animals. PMID- 26596626 TI - M233I Mutation in the beta-Tubulin of Botrytis cinerea Confers Resistance to Zoxamide. AB - Three phenotypes were detected in 161 Botrytis cinerea field isolates, including Zox(S)Car(S) (sensitive to zoxamide and carbendazim), Zox(S)Car(R) (sensitive to zoxamide and resistant to carbendazim), and Zox(R)Car(R) (resistant to zoxamide and carbendazim), but not Zox(R)Car(S) (resistant to zoxamide and sensitive to carbendazim). The baseline sensitivity to zoxamide was determined with a mean EC50 of 0.76 MUg/ml. Two stable Zox(R)Car(S) isolates were obtained with a resistance factor of 13.28 and 20.43; there was a fitness penalty in mycelial growth rate, sporulation, virulence and sclerotium production. The results suggest that the resistance risk of B. cinerea to zoxamide is low where benzimidazoles have not been used. E198V, E198K and M233I, were detected in the beta-tubulin of Zox(S)Car(R), Zox(R)Car(R), Zox(R)Car(S), respectively. Molecular docking indicated that position 198 in beta-tubulin were targets for both zoxamide and carbendazim. The mutations at 198 prevented formation of hydrogen bonds between beta-tubulin and carbendazim (E198V/K), and changed the conformation of the binding pocket of zoxamide (E198K). M233I had no effect on the binding of carbendazim but resulted in loss of a hydrogen bond between zoxamide and F200. M233 is suggested to be a unique target site for zoxamide and be very important in the function of beta tubulin. PMID- 26596628 TI - Manganese coordination chemistry of bis(imino)phenoxide derived [2 + 2] Schiff base macrocyclic ligands. AB - The [2 + 2] Schiff-base macrocycles [2,2'-(CH2CH2)(C6H4N[double bond, length as m dash]CH)2-2,6-(4-RC6H2OH)]2 ((R)H2), upon reaction with MnCl2 (two equivalents) afforded the bimetallic complex [Cl3Mn(MU-Cl)Mn((Me)H2)] (1) or the salt complex [Cl3Mn(NCMe)][MnCl((tBu)H2)] (2). Under similar conditions, use of the related [2 + 2] oxy-bridged macrocycle [2,2'-O(C6H4N[double bond, length as m-dash]CH)2-4 RC6H2OH] (II(R)H2), afforded the bimetallic complexes [(MnCl)2II(R)] (R = Me 3, tBu 4), whilst the macrocycle derived from 1,2-diaminobenzene and 5,5'-di-tert butyl-2,2'-dihydroxy-3,3'-methylenedibenzaldehyde (H4) afforded the complex [(MnCl)2(III)].2MeCN (5.2MeCN). For comparative studies, the salt complexes [2,6 (ArNHCH)2-4-MeC6H2O][MnCl3(NCMe)] (Ar = 2,4-Me2C6H3, 6) and {[(2-ArN[double bond, length as m-dash]CH),6-(ArNHCH)-4-Me-C6H2O]MnCl}2[MnCl4]7.8CH2Cl2 (Ar = 4-MeC6H4, .8CH2Cl2) were prepared. The crystal structures of 1 - 7 are reported (synchrotron radiation was necessary for complexes 1, 3 and 5). Complexes 1 - 7 (not 5) were screened for their potential to act as pre-catalysts for the ring opening polymerization (ROP) of epsilon-caprolactone; 3, 4 and 6, 7 were inactive, whilst 1 and 2 exhibited only poor activity with low conversion (<15%) at temperatures above 60 degrees C. PMID- 26596629 TI - A novel biocompatible europium ligand for sensitive time-gated immunodetection. AB - We describe the synthesis of a novel hydrophilic derivative of a tetradentate beta-diketone europium ligand that was used to prepare an immunoconjugate probe against Giardia lamblia cysts. We used a Gated Autosynchronous Luminescence Detector (GALD) to obtain high quality delayed luminescence images of cells 30 fold faster than ever previously reported. PMID- 26596627 TI - Tumor necrosis factor-alpha blockade in recurrent and disabling chronic sciatica associated with post-operative peridural lumbar fibrosis: results of a double blind, placebo randomized controlled study. AB - INTRODUCTION: The aim of this study was to assess the efficacy and safety of tumor necrosis factor (TNF)-alpha inhibition with infliximab (IFX) in treating recurrent and disabling chronic sciatica pain associated with post-operative peridural lumbar fibrosis. METHOD: A double-blind, placebo-controlled study randomized 35 patients presenting with sciatica pain associated with post operative peridural lumbar fibrosis to two groups: IFX (n = 18), a single intravenous injection of 3 mg/kg IFX; and placebo (n = 17), a single saline serum injection. The primary outcome was a 50 % reduction in sciatica pain on a visual analog scale (VAS) at day 10. Secondary outcomes were radicular and lumbar VAS pain at day 0 and radicular and lumbar VAS pain, Quebec disability score, drug sparing effect and tolerance at days 10, 30, 90, and 180. RESULTS: At day 10, the placebo and IFX groups did not differ in the primary outcome (50 % reduction in sciatica pain observed in three (17.6 %) versus five (27.8 %) patients; p = 0.69). The number of patients reaching the patient acceptable symptom state for radicular pain was significantly higher in the placebo than IFX group after injection (12 (70.6 %) versus five (27.8 %) patients; p = 0.01). The two groups were comparable for all other secondary outcomes. CONCLUSION: Treatment with a single 3 mg/kg IFX injection for post-operative peridural lumbar fibrosis associated sciatica pain does not significantly reduce radicular symptoms at day 10 after injection. TRIAL REGISTRATION: ClinicalTrials.gov NCT00385086 ; registered 4 October 2006 (last updated 15 October 2015). PMID- 26596630 TI - The Diabetic Retinopathy Screening Workflow: Potential for Smartphone Imaging. AB - Complications of diabetes mellitus, namely diabetic retinopathy and diabetic maculopathy, are the leading cause of blindness in working aged people. Sufferers can avoid blindness if identified early via retinal imaging. Systematic screening of the diabetic population has been shown to greatly reduce the prevalence and incidence of blindness within the population. Many national screening programs have digital fundus photography as their basis. In the past 5 years several techniques and adapters have been developed that allow digital fundus photography to be performed using smartphones. We review recent progress in smartphone-based fundus imaging and discuss its potential for integration into national systematic diabetic retinopathy screening programs. Some systems have produced promising initial results with respect to their agreement with reference standards. However further multisite trialling of such systems' use within implementable screening workflows is required if an evidence base strong enough to affect policy change is to be established. If this were to occur national diabetic retinopathy screening would, for the first time, become possible in low- and middle-income settings where cost and availability of trained eye care personnel are currently key barriers to implementation. As diabetes prevalence and incidence is increasing sharply in these settings, the impact on global blindness could be profound. PMID- 26596631 TI - An accessory wall teichoic acid glycosyltransferase protects Staphylococcus aureus from the lytic activity of Podoviridae. AB - Many Staphylococcus aureus have lost a major genetic barrier against phage infection, termed clustered regularly interspaced palindromic repeats (CRISPR/cas). Hence, S. aureus strains frequently exchange genetic material via phage-mediated horizontal gene transfer events, but, in turn, are vulnerable in particular to lytic phages. Here, a novel strategy of S. aureus is described, which protects S. aureus against the lytic activity of Podoviridae, a unique family of staphylococcal lytic phages with short, non-contractile tails. Unlike most staphylococcal phages, Podoviridae require a precise wall teichoic acid (WTA) glycosylation pattern for infection. Notably, TarM-mediated WTA alpha-O GlcNAcylation prevents infection of Podoviridae while TarS-mediated WTA beta-O GlcNAcylation is required for S. aureus susceptibility to podoviruses. Tracking the evolution of TarM revealed an ancient origin in other staphylococci and vertical inheritance during S. aureus evolution. However, certain phylogenetic branches have lost tarM during evolution, which rendered them podovirus susceptible. Accordingly, lack of tarM correlates with podovirus susceptibility and can be converted into a podovirus-resistant phenotype upon ectopic expression of tarM indicating that a "glyco-switch" of WTA O-GlcNAcylation can prevent the infection by certain staphylococcal phages. Since lytic staphylococcal phages are considered as anti-S. aureus agents, these data may help to establish valuable strategies for treatment of infections. PMID- 26596633 TI - Impact of fatigue in patients with chronic obstructive pulmonary disease: results from an exploratory study. AB - INTRODUCTION: Fatigue, which is also present in the healthy population, is a common but understudied symptom in chronic obstructive pulmonary disease (COPD). We hypothesized that clinically significant fatigue is also frequent in COPD and can be associated with an increased disease burden. METHODS: An exploratory analysis derived from an ongoing cross-sectional study was carried out to evaluate levels of fatigue and impact on health-related quality of life/health status in patients with COPD (COPD group; n = 20) and healthy subjects (control group; n = 5). Health-related quality of life was measured using the Short Form Health Survey 36 (SF-36), health status with the Clinical COPD Questionnaire (CCQ), and airways obstruction with postbronchodilator forced expiratory volume in 1 s (FEV1 %predicted). Fatigue was measured with the vitality score of the SF 36, its clinical significance being defined by values of 50 or less. Fatigue was also measured using the Functional Assessment of Chronic Illness Therapy scale for fatigue (FACIT-F). RESULTS: Vitality scores were significantly worse in the COPD group (45.60 versus 76.25; p = 0.004). FACIT-F scores were significantly lower in the COPD group versus the control group (74.5 versus 95.0; p = 0.03). Clinically significant fatigue was detected in 60% of the COPD group, and was associated with a worse FEV1 %predicted (47.71 versus 65.82%; p = 0.016), worse symptoms burden (CCQ symptoms score 3.75 versus 2.43; p = 0.019), and worse overall health status (CCQ total score 3.30 versus 2.11; p = 0.011). Its link with systemic inflammation remains to be clarified further. CONCLUSIONS: Clinically significant fatigue is common among patients with COPD and is associated with an increased disease burden. It should therefore be integrated as a measure of disease prognosis and control in patients with COPD. PMID- 26596632 TI - Asthma and chronic obstructive pulmonary disease overlap: asthmatic chronic obstructive pulmonary disease or chronic obstructive asthma? AB - Asthma and chronic obstructive pulmonary disease (COPD) are different disease entities. They are both clinical diagnoses, with diagnostic tools to discriminate between one another. However, especially in older patients (>55 years) it seems more difficult to differentiate between asthma and COPD. This has led to the definition of a new phenotype called asthma COPD overlap syndrome (ACOS). However, our understanding of ACOS is at a very preliminary stage, as most research has involved subjects with existing diagnoses of asthma or COPD from studies with different definitions for ACOS. This has led to different and sometimes opposing results between studies on several features of ACOS, also depending on the comparison with COPD alone, asthma alone or both, which are summarized in this review.We suggest not using the term ACOS for a patient with features of both asthma and COPD, but to describe a patient with chronic obstructive airway disease as completely as possible, with regard to characteristics that determine treatment response (e.g. eosinophilic inflammation) and prognosis (such as smoking status, exacerbation rate, fixed airflow limitation, hyperresponsiveness, comorbidities). This will provide a far more clinically relevant diagnosis, and would aid in research on treatment in more homogenous groups of patients with chronic airways obstruction. More research is certainly needed to develop more evidence-based definitions for this patient group and to evaluate biomarkers, which will help to further classify these patients, treat them more adequately and unravel the underlying pathophysiological mechanism. PMID- 26596634 TI - Analyses of a satiety factor NUCB2/nesfatin-1; gene expressions and modulation by different dietary components in dogs. AB - Nesfatin-1 is an anorexic peptide derived from a precursor, nucleobindin-2 (NUCB2), which is distributed in various organs, coexists with ghrelin in the gastric X/A-like cells and closely relates to an appetite control in rodents and humans. Nesfatin-1 may be a significant factor addressing the satiety also in veterinary medicine, however, there are few reports about nesfatin-1 in dogs. In the present study, we detected canine NUCB2/nesfatin-1 mRNA in various tissues, especially abundant in pancreas, gastrointestinal tracts, testis and cerebellum. We examined circulating nesfatin-1 concentrations and NUCB2/nesfatin-1 mRNA expressions in upper gastrointestinal tracts (gastric corpus, pyloric antrum and duodenum) in dogs fed on different types of diets. Plasma nesfatin-1 concentrations in the dogs were approximately 4 ng/ml and they did not change after feeding through the study, however, NUCB2/nesfatin-1 mRNA expressions in pyloric antrum were 1.84-fold higher in the dogs fed on a High fiber/High protein diet (P<0.001), 1.48-fold higher in the dogs fed on a High fat/Low protein diet (P<0.05) and 1.02-fold higher in the dogs fed on a Low fat/High carbohydrate diet (not significant) comparing to those on a control diet. It was concluded that High fiber/High protein and High fat/Low protein diets increased NUCB2/nesfatin-1 production in canine gastrointestinal tracts. These results may set the stage for further investigations of canine NUCB2/nesfatin-1, which may relate to satiety effects in dogs. PMID- 26596635 TI - Positive correlation between patency and mRNA levels for cyclooxygenase-2 and prostaglandin E synthase in the uterine cervix of bitches with pyometra. AB - Factors involved in patency of uterine cervices in the bitch with pyometra remain to be clarified. This study examined relationship between patency and mRNA levels for inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-1, COX-2 and prostaglandin E synthase (PGES) in the uterine cervix of bitches with pyometra. Cervical patency was measured by inserting the stainless steel rods with different diameter into cervical canals. Levels of mRNA expression were determined by semi-quantitative reverse transcription-polymerase chain reaction. The cervical patency was positively correlated with mRNA levels for COX-2 and PGES, but not those for iNOS and COX-1. The results suggest that gene expression of COX-2 and PGES may be involved in the regulation of patency in the uterine cervix of bitches with pyometra. PMID- 26596636 TI - Occurrence and susceptibilities to disinfectants of Cryptococcus neoformans in fecal droppings from pigeons in Bangkok, Thailand. AB - Cryptococcus neoformans is an opportunistic pathogenic yeast that causes meningoencephalitis and deep skin dermatitis in humans and animals. A hygienic strategy using disinfectants on environmental samples can reduce the risk to the public. The objectives were to survey the distribution of C. neoformans in pigeon fecal droppings collected in 11 districts in Bangkok during 2011-2012 and to evaluate the efficacy of three commercial disinfectant products (based on potassium monopersulfate, sodium hypochlorite and quaternary ammonium compounds, respectively). These were evaluated against pure C. neoformans and yeasts resuspended in sterile pigeon feces using the dilution-neutralization method [Europaische NORM (EN) 1656]. In total, 18 of 164 (11%) samples were positive for C. neoformans. These came from only three of the 11 districts, with a prevalence of between 13-56%. Using multiplex PCR, serotype A was the sole group found. For all disinfectants, C. neoformans mixed in feces was tolerated at a higher dose and time exposure than pure isolates. The most effective disinfectant in this study was a 0.12% quaternary ammonium compound that could rapidly eradicate the yeasts mixed in feces. This finding highlights the occurrence and distribution of C. neoformans in the capital city of Thailand and the need to prolong the duration of exposure to disinfectants with pigeon feces. PMID- 26596637 TI - Drug-susceptibility of isolates of Brachyspira hyodysenteriae isolated from colonic mucosal specimens of pigs collected from slaughter houses in Japan in 2009. AB - Twenty nine isolates identified as Brachyspira hyodysenteriae were most susceptible to carbadox and metronidazole, whereas they were resistant to macrolides. The isolates showed intermediate susceptibility to tiamulin, lincomycin, penicillin G, ampicillin, chloramphenicol, tetracycline, enrofloxacin and valnemulin, with MIC50 values ranging from 0.39 to 3.13. PMID- 26596638 TI - Vibration mechanosignals superimposed to resistive exercise result in baseline skeletal muscle transcriptome profiles following chronic disuse in bed rest. AB - Disuse-induced muscle atrophy is a major concern in aging, in neuromuscular diseases, post-traumatic injury and in microgravity life sciences affecting health and fitness also of crew members in spaceflight. By using a laboratory analogue to body unloading we perform for the first time global gene expression profiling joined to specific proteomic analysis to map molecular adaptations in disused (60 days of bed rest) human soleus muscle (CTR) and in response to a resistive exercise (RE) countermeasure protocol without and with superimposed vibration mechanosignals (RVE). Adopting Affymetrix GeneChip technology we identified 235 differently transcribed genes in the CTR group (end- vs. pre-bed rest). RE comprised 206 differentially expressed genes, whereas only 51 changed gene transcripts were found in RVE. Most gene transcription and proteomic changes were linked to various key metabolic pathways (glycolysis, oxidative phosphorylation, tricarboxylic acid (TCA) cycle, lipid metabolism) and to functional contractile structures. Gene expression profiling in bed rest identified a novel set of genes explicitly responsive to vibration mechanosignals in human soleus. This new finding highlights the efficacy of RVE protocol in reducing key signs of disuse maladaptation and atrophy, and to maintain a close to-normal skeletal muscle quality outcome following chronic disuse in bed rest. PMID- 26596639 TI - Metabolic impact of 100% fruit juice consumption on antioxidant/oxidant status and lipid profiles of adults: An Evidence-Based review. AB - One hundred percent fruit juice (FJ) contains bioactive compounds with antioxidant activity. As such, this fruit form has the potential to improve antioxidant status and mediate outcomes influenced by redox status. A systematic review of the literature published between 1995 and 2013 was conducted using PubMed database to evaluate associations between intake of 100% FJ and markers of antioxidant/oxidant status and blood lipid levels in healthy, free-living adults >=18 years. Data extraction and analysis was conducted according to the Academy of Nutrition and Dietetics Evidence Analysis Process. Limited evidence from ten clinical trials meeting inclusion/exclusion criteria suggests potential improvements in a variety of antioxidant or oxidants biomarkers postconsumption of 100% FJ. Weak evidence from five studies suggests that one or more blood lipid measures may be positively influenced by consumption of 100% FJ. Heterogeneity in study methodology including biomarkers, 100% FJ type, dosage, and intervention duration precludes the ability to make evidence-based recommendations regarding a specific dose-duration-juice effect. Key characteristics in study designs were identified which must either be controlled or statistically adjusted for in future investigations in order to obtain a more accurate understanding of the complex relationship between metabolic outcomes and consumption of 100% FJ in context of a healthy dietary pattern. PMID- 26596641 TI - Three-dimensional magnetic cloak working from d.c. to 250 kHz. AB - Invisible cloaking is one of the major outcomes of the metamaterial research, but the practical potential, in particular for high frequencies (for example, microwave to visible light), is fatally challenged by the complex material properties they usually demand. On the other hand, it will be advantageous and also technologically instrumental to design cloaking devices for applications at low frequencies where electromagnetic components are favourably uncoupled. In this work, we vastly develop the bilayer approach to create a three-dimensional magnetic cloak able to work in both static and dynamic fields. Under the quasi static approximation, we demonstrate a perfect magnetic cloaking device with a large frequency band from 0 to 250 kHz. The practical potential of our device is experimentally verified by using a commercial metal detector, which may lead us to having a real cloaking application where the dynamic magnetic field can be manipulated in desired ways. PMID- 26596640 TI - Improving vagal activity ameliorates cardiac fibrosis induced by angiotensin II: in vivo and in vitro. AB - Cardiac remodeling is characterized by overactivity of the renin-angiotensin system (RAS) and withdrawal of vagal activity. We hypothesized that improving vagal activity could attenuate cardiac fibrosis induced by angiotensin II (Ang II) in vivo and in vitro. Rats were subjected to abdominal aorta constriction (AAC) with or without pyridostigmine (PYR) (31 mg/kg/d). After 8 weeks, PYR significantly decreased Ang II level, AT1 protein expression, and collagen deposition in cardiac tissue and improved heart rate variability, baroreflex sensitivity and cardiac function, which were abolished by atropine. In vitro, treatment of cardiac fibroblasts (CFs) with Ang II (10(-7) M) increased cell proliferation, migration, transformation, and secretory properties, which were significantly diminished by acetylcholine (ACh, 10(-6) M). Subsequently, Ang II significantly increased collagen type I expression as well as metalloproteinase (MMP)-2 expression and activity. Transforming growth factor (TGF)-beta1 expression and Smad3 phosphorylation presented a similar trend. Notably, the knockdown of the acetylcholine M2 receptor by siRNA could abolish ACh anti fibrotic action. These data implicated cholinesterase inhibitor can increase vagal activity and reduce local Ang II level, and ACh inhibit Ang II pro-fibrotic effects. Our findings suggested that the parasympathetic nervous system can serve as a promising target for cardiac remodeling treatment. PMID- 26596642 TI - Three-dimensional Reconstruction of Peripheral Nerve Internal Fascicular Groups. AB - Peripheral nerves are important pathways for receiving afferent sensory impulses and sending out efferent motor instructions, as carried out by sensory nerve fibers and motor nerve fibers. It has remained a great challenge to functionally reconnect nerve internal fiber bundles (or fascicles) in nerve repair. One possible solution may be to establish a 3D nerve fascicle visualization system. This study described the key technology of 3D peripheral nerve fascicle reconstruction. Firstly, fixed nerve segments were embedded with position lines, cryostat-sectioned continuously, stained and imaged histologically. Position line cross-sections were identified using a trained support vector machine method, and the coordinates of their central pixels were obtained. Then, nerve section images were registered using the bilinear method, and edges of fascicles were extracted using an improved gradient vector flow snake method. Subsequently, fascicle types were identified automatically using the multi-directional gradient and second order gradient method. Finally, a 3D virtual model of internal fascicles was obtained after section images were processed. This technique was successfully applied for 3D reconstruction for the median nerve of the hand-wrist and cubital fossa regions and the gastrocnemius nerve. This nerve internal fascicle 3D reconstruction technology would be helpful for aiding peripheral nerve repair and virtual surgery. PMID- 26596643 TI - Melanoma cell surface-expressed phosphatidylserine as a therapeutic target for cationic anticancer peptide, temporin-1CEa. AB - We have previously reported that temporin-1CEa, a cationic antimicrobial peptide, exerts preferential cytotoxicity toward cancer cells. However, the exact molecular mechanism for this cancer-selectivity is still largely unknown. Here, we found that the negatively charged phosphatidylserine (PS) expressed on cancer cell surface serves as a target for temporin-1CEa. Our results indicate that human A375 melanoma cells express 50-fold more PS than non-cancerous HaCaT cells. The expression of cell surface PS in various cancer cell lines closely correlated with their ability to be recognized, bound and killed by temporin-1CEa. Additionally, the cytotoxicity of temporin-1CEa against A375 cells can be ameliorated by annexin V, which binds to cell surface PS with high affinity. Moreover, the data of isothermal titration calorimetry assay further confirmed a direct binding of temporin-1CEa to PS, at a ratio of 1:5 (temporin-1CEa:PS). Interestingly, the circular dichroism spectra analysis using artificial biomembrane revealed that PS not only provides electrostatic attractive sites for temporin-1CEa but also confers the membrane-bound temporin-1CEa to form alpha helical structure, therefore, enhances the affinity and membrane disrupting ability of temporin-1CEa. In summary, these findings suggested that the melanoma cells expressed PS may serve as a promising target for temporin-1CEa or other cationic anticancer peptides. PMID- 26596644 TI - Self-Sterilizing, Self-Cleaning Mixed Polymeric Multifunctional Antimicrobial Surfaces. AB - Mitigation of bacterial adhesion and subsequent biofilm formation is quickly becoming a strategy for the prevention of hospital-acquired infections. We demonstrate a basic strategy for surface modification that combines the ability to control attachment by microbes with the ability to inactivate microbes. The surface consists of two active materials: poly(p-phenylene ethynylene)-based polymers, which can inactivate a wide range of microbes and pathogens, and poly(N isopropylacrylamide)-based polymers, which can switch between an hydrophobic "capture" state and a hydrophilic "release" state. The combination of these materials creates a surface that can both bind microbes in a switchable way and kill surface-bound microbes efficiently. Considerable earlier work with cationic poly(p-phenylene ethynylene) polyelectrolytes has demonstrated and characterized their antimicrobial properties, including the ability to efficiently destroy or deactivate Gram-negative and Gram-positive bacteria, fungi, and viruses. Similarly, much work has shown (1) that surface-polymerized films of poly(N isopropylacrylamide) are able to switch their surface thermodynamic properties from a swollen, relatively hydrophilic state at low temperature to a condensed, relatively hydrophobic state at higher temperature, and (2) that this switch can control the binding and/or release of microbes to poly(N-isopropylacrylamide) surfaces. The active surfaces described herein were fabricated by first creating a film of biocidal poly(p-phenylene ethynylene) using layer-by-layer methods, and then conferring switchable adhesion by growing poly(N-isopropylacrylamide) through the poly(p-phenylene ethynylene) layer, using surface-attached polymerization initiators. The resulting multifunctional, complex films were then characterized both physically and functionally. We demonstrate that such films kill and subsequently induce widespread release of Gram-negative and Gram positive bacteria. PMID- 26596645 TI - Hidden magnetism in the paramagnetic phase of EuTiO3. AB - EuTiO3 is investigated experimentally by temperature dependent conductivity and dielectric constant measurements. Both data sets evidence a crossover behavior in their temperature dependence around T * ~ 200 K indicating a change of the electrical and magnetic behavior of EuTiO3 as already observed by muon spin rotation (MUSR) measurements. Around T ' = 80 K an additional anomaly appears which is consistent with previous resonant ultrasound spectroscopy (RUS) data. By applying a magnetic field (1.2 T at room temperature) the bulk conductivity is anomalously enhanced by more than one order of magnitude. The bulk dielectric constant epsilon(r) decreases with increasing temperature and is enhanced by the magnetic field by up to 22%. All data reveal a substantial hysteresis which is diminished in a magnetic field. The unusual magnetic field dependence of all quantities is suggested to stem from magnetically active domain walls which are mobile between the structural phase transition temperature (T(S) = 282 K) and T * and are pinned below it. PMID- 26596646 TI - An Examination of Dynamic Gene Expression Changes in the Mouse Brain During Pregnancy and the Postpartum Period. AB - The developmental transition to motherhood requires gene expression changes that alter the brain to drive the female to perform maternal behaviors. We broadly examined the global transcriptional response in the mouse maternal brain, by examining four brain regions: hypothalamus, hippocampus, neocortex, and cerebellum, in virgin females, two pregnancy time points, and three postpartum time points. We find that overall there are hundreds of differentially expressed genes, but each brain region and time point shows a unique molecular signature, with only 49 genes differentially expressed in all four regions. Interestingly, a set of "early-response genes" is repressed in all brain regions during pregnancy and postpartum stages. Several genes previously implicated in underlying postpartum depression change expression. This study serves as an atlas of gene expression changes in the maternal brain, with the results demonstrating that pregnancy, parturition, and postpartum maternal experience substantially impact diverse brain regions. PMID- 26596647 TI - A RAB3GAP1 SINE Insertion in Alaskan Huskies with Polyneuropathy, Ocular Abnormalities, and Neuronal Vacuolation (POANV) Resembling Human Warburg Micro Syndrome 1 (WARBM1). AB - We observed a hereditary phenotype in Alaskan Huskies that was characterized by polyneuropathy with ocular abnormalities and neuronal vacuolation (POANV). The affected dogs developed a progressive severe ataxia, which led to euthanasia between 8 and 16 months of age. The pedigrees were consistent with a monogenic autosomal recessive inheritance. We localized the causative genetic defect to a 4 Mb interval on chromosome 19 by a combined linkage and homozygosity mapping approach. Whole genome sequencing of one affected dog, an obligate carrier, and an unrelated control revealed a 218-bp SINE insertion into exon 7 of the RAB3GAP1 gene. The SINE insertion was perfectly associated with the disease phenotype in a cohort of 43 Alaskan Huskies, and it was absent from 541 control dogs of diverse other breeds. The SINE insertion induced aberrant splicing and led to a transcript with a greatly altered exon 7. RAB3GAP1 loss-of-function variants in humans cause Warburg Micro Syndrome 1 (WARBM1), which is characterized by additional developmental defects compared to canine POANV, whereas Rab3gap1 deficient mice have a much milder phenotype than either humans or dogs. Thus, the RAB3GAP1 mutant Alaskan Huskies provide an interesting intermediate phenotype that may help to better understand the function of RAB3GAP1 in development. Furthermore, the identification of the presumed causative genetic variant will enable genetic testing to avoid the nonintentional breeding of affected dogs. PMID- 26596649 TI - Strong reflector-based beamforming in ultrasound medical imaging. AB - This paper investigates the use of sparse priors in creating original two dimensional beamforming methods for ultrasound imaging. The proposed approaches detect the strong reflectors from the scanned medium based on the well known Bayesian Information Criteria used in statistical modeling. Moreover, they allow a parametric selection of the level of speckle in the final beamformed image. These methods are applied on simulated data and on recorded experimental data. Their performance is evaluated considering the standard image quality metrics: contrast ratio (CR), contrast-to-noise ratio (CNR) and signal-to-noise ratio (SNR). A comparison is made with the classical delay-and-sum and minimum variance beamforming methods to confirm the ability of the proposed methods to precisely detect the number and the position of the strong reflectors in a sparse medium and to accurately reduce the speckle and highly enhance the contrast in a non sparse medium. We confirm that our methods improve the contrast of the final image for both simulated and experimental data. In all experiments, the proposed approaches tend to preserve the speckle, which can be of major interest in clinical examinations, as it can contain useful information. In sparse mediums we achieve a highly improvement in contrast compared with the classical methods. PMID- 26596648 TI - An RNAi-Based Candidate Screen for Modifiers of the CHD1 Chromatin Remodeler and Assembly Factor in Drosophila melanogaster. AB - The conserved chromatin remodeling and assembly factor CHD1 (chromodomains, helicase, DNA-binding domain) is present at active genes where it participates in histone turnover and recycling during transcription. In order to gain a more complete understanding of the mechanism of action of CHD1 during development, we created a novel genetic assay in Drosophila melanogaster to evaluate potential functional interactions between CHD1 and other chromatin factors. We found that overexpression of CHD1 results in defects in wing development and utilized this fully penetrant and reliable phenotype to conduct a small-scale RNAi-based candidate screen to identify genes that functionally interact with chd1 in vivo. Our results indicate that CHD1 may act in opposition to other remodeling factors, including INO80, and that the recruitment of CHD1 to active genes by RTF1 is conserved in flies. PMID- 26596650 TI - Design and prospective evaluation of a risk-based surveillance system for shrimp grow-out farms in northeast Brazil. AB - The farming of Pacific white shrimp Litopennaeus vannamei in northeast Brazil, has proven to be a promising sector. However, the farming of Pacific white shrimp in Brazil has been affected negatively by the occurrence of viral diseases, threatening this sector's expansion and sustainability. For this reason, the drafting of a surveillance system for early detection and definition of freedom from viral diseases, whose occurrence could result in high economic loses, is of the utmost importance. The stochastic model AquaVigil was implemented to prospectively evaluate different surveillance strategies to determine freedom from disease and identify the strategy with the lowest sampling efforts, making the best use of available resources through risk-based surveillance. The worked example presented was designed for regional application for the state of Ceara and can easily be applied to other Brazilian states. The AquaVigil model can analyse any risk-based surveillance system that considers a similar outline to the strategy here presented. PMID- 26596651 TI - The cost of clinical mastitis in the first 30 days of lactation: An economic modeling tool. AB - Clinical mastitis results in considerable economic losses for dairy producers and is most commonly diagnosed in early lactation. The objective of this research was to estimate the economic impact of clinical mastitis occurring during the first 30 days of lactation for a representative US dairy. A deterministic partial budget model was created to estimate direct and indirect costs per case of clinical mastitis occurring during the first 30 days of lactation. Model inputs were selected from the available literature, or when none were available, from herd data. The average case of clinical mastitis resulted in a total economic cost of $444, including $128 in direct costs and $316 in indirect costs. Direct costs included diagnostics ($10), therapeutics ($36), non-saleable milk ($25), veterinary service ($4), labor ($21), and death loss ($32). Indirect costs included future milk production loss ($125), premature culling and replacement loss ($182), and future reproductive loss ($9). Accurate decision making regarding mastitis control relies on understanding the economic impacts of clinical mastitis, especially the longer term indirect costs that represent 71% of the total cost per case of mastitis. Future milk production loss represents 28% of total cost, and future culling and replacement loss represents 41% of the total cost of a case of clinical mastitis. In contrast to older estimates, these values represent the current dairy economic climate, including milk price ($0.461/kg), feed price ($0.279/kg DM (dry matter)), and replacement costs ($2,094/head), along with the latest published estimates on the production and culling effects of clinical mastitis. This economic model is designed to be customized for specific dairy producers and their herd characteristics to better aid them in developing mastitis control strategies. PMID- 26596653 TI - Transitioning Care Across Various Health Care Organizations. AB - Health care is continuously undergoing evolutionary changes. These changes have been very dramatic for the end users. Instead of simple physician office visits and lengthy hospital stays, we are now faced with short hospital stays, office visits to different specialty providers, and an array of choices around them. With the present highway of choices between illness and wellness, it is important for transitions between these two to be affordable, advantageous to patients, and uncomplicated. This article discusses the choices patients and health care providers must make as the number of care options increase along with the risks and benefits. PMID- 26596652 TI - Experimental diabetes induced by alloxan and streptozotocin: The current state of the art. AB - Diabetes mellitus is a chronic metabolic disorder with a high prevalence worldwide. Animal models of diabetes represent an important tool in diabetes investigation that helps us to avoid unnecessary and ethically challenging studies in human subjects, as well as to obtain a comprehensive scientific viewpoint of this disease. Although there are several methods through which diabetes can be induced, chemical methods of alloxan- and streptozotocin-induced diabetes represent the most important and highly preferable experimental models for this pathological condition. Therefore, the aim of this article was to review the current knowledge related to quoted models of diabetes, including to this point available information about mechanism of action, particular time- and dose dependent protocols, frequent problems, as well as major limitations linked to laboratory application of alloxan and sterptozotocin in inducing diabetes. Given that diabetes is known to be closely associated with serious health consequences it is of fundamental importance that current animal models for induction of diabetes should be continuously upgraded in order to improve overall prevention, diagnosis and treatment of this pathological condition. PMID- 26596654 TI - Orthopedic Injuries: Protocols to Prevent and Manage Patient Falls. AB - Health care organizations must adopt a culture of safety and implement effective fall prevention protocols. The teach-back method is a useful strategy for health providers to determine patient understanding of information taught to maintain a safe environment and prevent falls. Purposeful rounding is a proactive approach to ensure that patient assessments are accurate and research supports that patients use the call light less when nurses participate in hourly rounding. This article provides the reader with evidence-based fall prevention interventions, tips for using the teach-back method, and fall prevention tools to safely care for patients of all ages. PMID- 26596655 TI - Technological Advances in Nursing Care Delivery. AB - Technology is rapidly changing the way nurses deliver patient care. The Health Information Technology for Economic and Clinical Health Act of 2009 encourages health care providers to implement electronic health records for meaningful use of patient information. This development has opened the door to many technologies that use this information to streamline patient care. This article explores current and new technologies that nurses will be working with either now or in the near future. PMID- 26596656 TI - Validation of the National Institutes of Health Patient-Reported Outcomes Measurement Information System Survey as a Quality-of-Life Instrument for Patients with Malignant Brain Tumors and Their Caregivers. AB - At present there is a lack of well-validated surveys used to measure quality of life in patients with malignant brain tumors and their caregivers. The main objective of this pilot study was to validate the National Institutes of Health Patient-Reported Outcomes Measurement Information System (NIH PROMIS) survey for use as a quality-of-life measure in this population. This article presents the rationale for using the NIH PROMIS instrument as a quality-of-life measure for patients with malignant brain tumors and their caregivers. PMID- 26596657 TI - Deep Brain Stimulation for Movement Disorders. AB - Disruption in the interaction between the central nervous system, nerves, and muscles cause movement disorders. These disorders can negatively affect quality of life. Deep brain stimulation (DBS) has been identified as a therapy for Parkinson disease and essential tremor that has significant advantages compared with medicinal therapies. Surgical intervention for these disorders before DBS included ablative therapies such as thalamotomy and pallidotomy. These procedures were not reversible and did not allow for treatment adjustments. The advent of DBS progressed therapies for significant movement disorders into the realm of being reversible and adjustable based on patient symptoms. PMID- 26596658 TI - Diabetes Mellitus Standards of Care. AB - Diabetes is a worldwide epidemic with a high cost regarding consumption of health care resources and is associated with high levels of morbidity and mortality. The complex nature of diabetes requires the use of evidence-based guidelines regarding diabetes management. These evidence-based guidelines are lengthy and do not readily translate into nursing care. As an integral component of the interprofessional team, the nurse must provide a thorough assessment of patients with diabetes and work to achieve individual patient treatment goals. Evaluation of patient progress toward treatment goals with regular/frequent follow-up is necessary to promote effective self-management of diabetes. PMID- 26596659 TI - Innovations in Cardiovascular Patient Care: Transcatheter Aortic Valve Replacement. AB - Aortic valve disease is a common and serious valvular disorder. Transcatheter aortic valve replacement is an option requiring nursing knowledge for the best patient outcome. PMID- 26596660 TI - Addressing Tobacco Dependence Through a Nurse-driven Tobacco Intervention Protocol. AB - Tobacco use contributes to the largest proportion of preventable disease, disability, and death. Use of tobacco products is at epidemic proportions in the United States. Estimates retrieved between 2012 and 2013 by the US Centers for Disease Control and Prevention reported that 1 in 5 adults used tobacco products. Tobacco use was greatest among men, young adults, those living in the Midwest and south, and those with less education. Cigarette smoking resulting in inhalation of tobacco and its by-products is the most common form of tobacco use. Tobacco use results in multiple diseases, including numerous cancers and chronic diseases. PMID- 26596661 TI - Bedside Reporting: Protocols for Improving Patient Care. AB - Bedside reporting continues to gain much attention and is being investigated to support the premise that "hand-off" communications enhance efficacy in delivery of patient care. Patient inclusion in shift reports enhances good patient outcomes, increased satisfaction with care delivery, enhanced accountability for nursing professionals, and improved communications between patients and their direct care providers. This article discusses the multiple benefits of dynamic dialogue between patients and the health care team, challenges often associated with bedside reporting, and protocols for managing bedside reporting with the major aim of improving patient care. Nursing research supporting the concept of bedside reporting is examined. PMID- 26596662 TI - Management of Travel-Related Illness Acquired in Haiti. AB - Management of travel-related diseases acquired in Haiti begins with the identification of tropical diseases that are prevalent in the region. Knowledge of various tropical disease incubation periods and presenting symptoms is crucial to ensure rapid triage and management of care. PMID- 26596663 TI - Pharmacology Update on Chronic Obstructive Pulmonary Disease, Rheumatoid Arthritis, and Major Depression. AB - This article presents a brief review and summarizes current therapies for the treatment of chronic obstructive pulmonary disease, major depression, and rheumatoid arthritis. One new pharmaceutical agent is highlighted for each of the topics. PMID- 26596664 TI - Implementing a Program for Ultrasound-Guided Peripheral Venous Access: Training, Policy and Procedure Development, Protocol Use, Competency, and Skill Tracking. AB - Peripheral intravenous (IV) access provides a means to administer medications, IV fluids, and blood products and allows for the sampling of blood for analysis. The traditional approach to obtaining peripheral IV access relies on vessel visualization in the arm and/or palpation of the blood vessel beneath the skin. However, the general population is aging, obesity is commonplace, and IV drug abuse is widespread, making peripheral IV access difficult. Use of ultrasound guided peripheral IV access fills a practice gap in safe patient care between traditional peripheral IV access methods of vein visualization and/or palpation and ultrasound-guided central venous access. PMID- 26596665 TI - Heart Failure: Pathophysiology, Diagnosis, Medical Treatment Guidelines, and Nursing Management. AB - Heart failure (HF) is a debilitating chronic disease and is expected to increase in upcoming years due to demographic changes. Nurses in all settings have an essential role in supporting patients in managing this disease. This article describes the pathophysiology of HF, diagnosis, medical management, and nursing interventions. It is crucial for nurses to understand the pathophysiology of HF and the importance that nursing actions have on enhancing medical management to alleviate symptoms and to deter the advancement of the pathophysiologic state. Such an understanding can ultimately reduce morbidity and mortality and optimize quality of life in patients with HF. PMID- 26596666 TI - Patient-Centered Care and Lifelong Learning. PMID- 26596667 TI - Clinical Updates in Pathophysiology and Care Protocols for Nursing Management. PMID- 26596668 TI - Autoimmune disease risk in survivors of childhood cancer. PMID- 26596669 TI - Continued role for ASCT in multiple myeloma. PMID- 26596671 TI - Type 1 and 2 papillary renal cancers are genetically distinct. PMID- 26596670 TI - Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a randomised, multicentre, phase 3 trial. AB - BACKGROUND: High-dose melphalan plus autologous stem-cell transplantation (ASCT) is the standard approach in transplant-eligible patients with newly diagnosed myeloma. Our aims were to compare consolidation with high-dose melphalan plus ASCT versus chemotherapy (cyclophosphamide and dexamethasone) plus lenalidomide, and maintenance with lenalidomide plus prednisone versus lenalidomide alone. METHODS: We did an open-label, randomised, multicentre, phase 3 study at 59 centres in Australia, Czech Republic, and Italy. We enrolled transplant-eligible patients with newly diagnosed myeloma aged 65 years or younger. Patients received a common induction with four 28-day cycles of lenalidomide (25 mg, days 1-21) and dexamethasone (40 mg, days 1, 8, 15, and 22) and subsequent chemotherapy with cyclophosphamide (3 g/m(2)) followed by granulocyte colony-stimulating factor for stem-cell mobilisation and collection. Using a 2 * 2 partial factorial design, we randomised patients to consolidation with either chemotherapy plus lenalidomide (six cycles of cyclophosphamide [300 mg/m(2), days 1, 8, and 15], dexamethasone [40 mg, days 1, 8, 15, and 22], and lenalidomide [25 mg, days 1-21]) or two courses of high-dose melphalan (200 mg/m(2)) and ASCT. We also randomised patients to maintenance with lenalidomide (10 mg, days 1-21) plus prednisone (50 mg, every other day) or lenalidomide alone. A simple randomisation sequence was used to assign patients at enrolment into one of the four groups (1:1:1:1 ratio), but the treatment allocation was disclosed only when the patient reached the end of the induction and confirmed their eligibility for consolidation. Both the patient and the treating clinician did not know the consolidation and maintenance arm until that time. The primary endpoint was progression-free survival assessed by intention-to-treat. The trial is ongoing and some patients are still receiving maintenance. This study is registered at ClinicalTrials.gov, number NCT01091831. FINDINGS: 389 patients were enrolled between July 6, 2009, and May 6, 2011, with 256 eligible for consolidation (127 high-dose melphalan and ASCT and 129 chemotherapy plus lenalidomide) and 223 eligible for maintenance (117 lenalidomide plus prednisone and 106 lenalidomide alone). Median follow-up was 52.0 months (IQR 30.4-57.6). Progression-free survival during consolidation was significantly shorter with chemotherapy plus lenalidomide compared with high-dose melphalan and ASCT (median 28.6 months [95% CI 20.6-36.7] vs 43.3 months [33.2 52.2]; hazard ratio [HR] for the first 24 months 2.51, 95% CI 1.60-3.94; p<0.0001). Progression-free survival did not differ between maintenance treatments (median 37.5 months [95% CI 27.8-not evaluable] with lenalidomide plus prednisone vs 28.5 months [22.5-46.5] with lenalidomide alone; HR 0.84, 95% CI 0.59-1.20; p=0.34). Fewer grade 3 or 4 adverse events were recorded with chemotherapy plus lenalidomide than with high-dose melphalan and ASCT; the most frequent were haematological (34 [26%] of 129 patients vs 107 [84%] of 127 patients), gastrointestinal (six [5%] vs 25 [20%]), and infection (seven [5%] vs 24 [19%]). Haematological serious adverse events were reported in two (2%) patients assigned chemotherapy plus lenalidomide and no patients allocated high dose melphalan and ASCT. Non-haematological serious adverse events were reported in 13 (10%) patients assigned chemotherapy plus lenalidomide and nine (7%) allocated high-dose melphalan and ASCT. During maintenance, adverse events did not differ between groups. The most frequent grade 3 or 4 adverse events were neutropenia (nine [8%] of 117 patients assigned lenalidomide plus prednisone vs 14 [13%] of 106 allocated lenalidomide alone), infection (eight [8%] vs five [5%]), and systemic toxicities (seven [6%] vs two [2%]). Non-haematological serious adverse events were reported in 13 (11%) patients assigned lenalidomide plus prednisone versus ten (9%) allocated lenalidomide alone. Four patients died because of adverse events, three from infections (two during induction and one during consolidation) and one because of cardiac toxic effects. INTERPRETATION: Consolidation with high-dose melphalan and ASCT remains the preferred option in transplant-eligible patients with multiple myeloma, despite a better toxicity profile with chemotherapy plus lenalidomide. FUNDING: Celgene. PMID- 26596673 TI - Better treatments needed for breast cancer brain metastases. PMID- 26596672 TI - Afatinib alone or afatinib plus vinorelbine versus investigator's choice of treatment for HER2-positive breast cancer with progressive brain metastases after trastuzumab, lapatinib, or both (LUX-Breast 3): a randomised, open-label, multicentre, phase 2 trial. AB - BACKGROUND: Patients with advanced HER2-positive breast cancer frequently develop CNS metastases. The metastases that progress after brain radiotherapy and HER2 targeted systemic therapy are a difficult therapeutic challenge. We aimed to assess the efficacy and safety of afatinib, an irreversible blocker of the ErbB protein family, alone or combined with vinorelbine, compared with treatment of the investigator's choice in women with HER2-positive breast cancer with progressive brain metastases during or after treatment with trastuzumab, lapatinib, or both. METHODS: We did this randomised, open-label, multicentre, phase 2 trial in 40 hospitals in Canada, Finland, France, Germany, Italy, Spain, South Korea, and the USA. Women older than 18 years with histologically confirmed HER2-overexpressing breast cancer and CNS recurrence or progression as determined by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) during or after treatment with trastuzumab, lapatinib, or both, were eligible. We randomly assigned patients (1:1:1) centrally to afatinib 40 mg orally once per day, afatinib 40 mg per day plus intravenous vinorelbine 25 mg/m(2) once per week, or investigator's choice of treatment in cycles of 3 weeks until disease progression, patient withdrawal, or unacceptable toxicity. Treatment assignment was not masked for clinicians or patients, but the trial team was masked until database lock to reduce bias. The primary endpoint, assessed in the intention-to treat population, was patient benefit at 12 weeks, defined by an absence of CNS or extra-CNS disease progression, no tumour-related worsening of neurological signs or symptoms, and no increase in corticosteroid dose. Safety was assessed in all patients who received at least one dose of a study drug. This completed trial is registered with ClinicalTrials.gov, number NCT01441596. FINDINGS: Between Dec 22, 2011, and Feb 12, 2013, we screened 132 patients, of whom 121 were eligible and randomly assigned to treatment: 40 to afatinib alone, 38 to afatinib plus vinorelbine, and 43 to investigator's choice. All patients discontinued study treatment before the data collection cutoff on Oct 16, 2014. Patient benefit was achieved in 12 (30.0%; 95% CI 16.6-46.5) patients given afatinib alone (difference vs investigator's choice: -11.9% [95% CI -32.9 to 9.7], p=0.37), 13 (34.2%; 19.6-51.4) given afatinib plus vinorelbine (difference vs investigator's choice: -7.6% [-28.9 to 14.2], p=0.63), and 18 (41.9%; 27.0-57.9) given investigator's choice. The most common treatment-related grade 3 or 4 adverse events were diarrhoea (seven [18%] of 40 patients in the afatinib only group vs nine [24%] of 37 patients in the afatinib plus vinorelbine group vs two [5%] of 42 patients in the investigator's choice group) and neutropenia (none vs 14 [38%] vs four [10%]). INTERPRETATION: Patient benefit with afatinib-containing treatments was not different from that in patients given investigator's choice of treatments; however, adverse events were frequent and afatinib-containing treatments seemed to be less well tolerated. No further development of afatinib for HER2-positive breast cancer is currently planned. FUNDING: Boehringer Ingelheim. PMID- 26596674 TI - GWAS as a Driver of Gene Discovery in Cardiometabolic Diseases. AB - Cardiometabolic diseases represent a common complex disorder with a strong genetic component. Currently, genome-wide association studies (GWAS) have yielded some 755 single-nucleotide polymorphisms (SNPs) encompassing 366 independent loci that may help to decipher the molecular basis of cardiometabolic diseases. Going from a disease SNP to the underlying disease mechanisms is a huge challenge because the associated SNPs rarely disrupt protein function. Many disease SNPs are located in noncoding regions, and therefore attention is now focused on linking genetic SNP variation to effects on gene expression levels. By integrating genetic information with large-scale gene expression data, and with data from epigenetic roadmaps revealing gene regulatory regions, we expect to be able to identify candidate disease genes and the regulatory potential of disease SNPs. PMID- 26596675 TI - Lessons Learned from Systems Approaches to Metabolism. PMID- 26596676 TI - Emerging Technologies and their Applications in Lipid Compartment Measurement. AB - Non-Communicable diseases (NCDs), including obesity, are emerging as the major health concern of the 21st century. Excess adiposity and related NCD metabolic disturbances have stimulated development of new lipid compartment measurement technologies to help us to understand cellular energy exchange, to refine phenotypes, and to develop predictive markers of adverse clinical outcomes. Recent advances now allow quantification of multiple intracellular lipid and adipose tissue compartments that can be evaluated across the human lifespan. With magnetic resonance methods leading the way, newer approaches will give molecular structural and metabolic information beyond the laboratory in real-world settings. The union between these new technologies and the growing NCD population is creating an exciting interface in advancing our understanding of chronic disease mechanisms. PMID- 26596678 TI - Protective effect of Edaravone against hypoxia-induced cytotoxicity in osteoblasts MC3T3-E1 cells. AB - Edaravone is a newly developed clinical medicine for the treatment of acute cerebral infarction. Reduced blood supply to bones (hypoxia) has been involved in the pathological development of osteoporosis. In this study, we investigated the effect of Edaravone and its latent mechanism on hypoxia-induced cell toxicity in MC3T3-E1 cells. Cell viability was determined by the 3-(4,5-dimethyl-thiazol-2yl) 2,5-diphenyl tetrazolium bromide (MTT) assay. Intracellular reactive oxygen species (ROS) and nitric oxide (NO) were determined by the fluorescence dyes 2',7'-dichlorofluorescein diacetate (DCFH-DA) and 4-amino-5-methylamino-2',7' difluorofluorescein diacetate (DAF-FM DA), respectively. mRNA and proteins were determined by real-time polymerase chain reaction and Western blot analysis, respectively. Edaravone significantly restored the hypoxia-induced reduction of MC3T3-E1 cell viability and inhibited lactate dehydrogenase release. In addition, we found that Edaravone inhibits the generation of ROS and NO. Hoechst staining results indicated that the nuclear condensation characteristic of apoptosis was increased in MC3T3-E1 cells after hypoxia exposure, which was significantly suppressed by Edaravone treatment. Mechanistically, we found that Edaravone markedly reduced the expression of cleaved caspase-3 and blunted the release of cytochrome c. These findings strongly suggested that Edaravone suppresses hypoxia induced cytotoxicity in MC3T3-E1 cells. The pleiotropic effects of Edaravone on hypoxia exposure in osteoblasts suggest potential antiosteoporosis mechanisms of Edaravone. PMID- 26596677 TI - Changes in detection of birth defects and perinatal mortality after introduction of prenatal ultrasound screening in the Kola Peninsula (North-West Russia): combination of two birth registries. AB - BACKGROUND: Prenatal diagnostics ultrasound was established in Russia in 2000 as a routine method of screening for birth defects. The aims of the current study were twofold: to assess changes in birth defects prevalence at birth and perinatal mortality after ultrasound screening was implemented and to estimate prenatal detection rates for congenital malformations in the city of Monchegorsk (Murmansk County, North-West Russia). METHODS: The Murmansk County Birth Registry and the Kola Birth Registry were the primary sources of information, and include 30 448 pregnancy outcomes in Monchegorsk for the period 1973-2011. Data from these registries were supplemented with information derived from hospital records about pregnancy terminations for 2000-2007. RESULTS: The total number of newborns with any kind of birth defects in Monchegorsk during 1973-2011 was 1099, of whom 816 were born in the 1973-2000 period. The prevalence of defects at birth increased from 34.2/1000 (95% CI = 31.9-36.5) to 42.8/1000 newborns (95% CI = 38.0-47.7) after prenatal ultrasound screening was formally implemented. We observed significant decreases (p < 0.05) in the birth prevalence of congenital malformations of the circulatory system, the musculoskeletal system (including deformations), and other (excluding multiple); those of the urinary system increased from 0.9/1000 to 17.1/1000 (p < 0.0001). The perinatal mortality among newborns with any kind of malformation decreased from 106.6 per 1000 newborns with birth defects (95% CI = 84.3-129.1) to 21.2 (95 % CI = 4.3-38.1). Mothers who had undergone at least one ultrasound examination during pregnancy (n = 9883) had a decreased risk of having a newborn die during the perinatal period [adjusted OR = 0.49 (95% CI = 0.27-0.89)]. The overall prenatal detection rate was 34.9% with the highest for malformations of the nervous system. CONCLUSION: Improved detection of severe malformations with subsequent pregnancy termination was likely the main contributor to the observed decrease in perinatal mortality in Murmansk County, Russia. PMID- 26596680 TI - Capture of CO2 by a Cationic Nickel(I) Complex in the Gas Phase and Characterization of the Bound, Activated CO2 Molecule by Cryogenic Ion Vibrational Predissociation Spectroscopy. AB - We describe a systematic method for the preparation and spectroscopic characterization of a CO2 molecule coordinated to an activated bisphenoidal nickel(I) compound containing a tetraazamacrocyclic ligand in the gas phase. The resulting complex was then structurally characterized by using mass-selected vibrational predissociation spectroscopy. The results indicate that a highly distorted CO2 molecule is bound to the metal center in an eta(2)-C,O coordination mode, thus establishing an efficient and rational method for the preparation of metal-activated CO2 for further studies using ion chemistry techniques. PMID- 26596679 TI - Awareness of risk factors for cancer: a comparative study of Sweden and Denmark. AB - BACKGROUND: Sweden and Denmark are neighbouring countries with similarities in culture, healthcare, and economics, yet notable differences in cancer statistics. A crucial component of primary prevention is high awareness of risk factors in the general public. We aimed to determine and compare awareness of risk factors for cancer between a Danish and a Swedish population sample, and to examine whether there are differences in awareness across age groups. METHODS: Data derive from Module 2 of the International Cancer Benchmarking Partnership. Telephone interviews were conducted with 3000 adults in Denmark and 3070 in Sweden using the Awareness and Beliefs about Cancer measure. Data reported here relate to awareness of 13 prompted risk factors for cancer. Prevalence ratios with 95 % confidence intervals were calculated to examine associations between country, age, and awareness of risk factors. RESULTS: Over 90 % of respondents in both countries recognized smoking, use of sunbeds and ionizing radiation as risk factors for cancer. Lowest awareness (<50 %) was found for HPV-infection, low fruit and vegetable intake and alcohol intake. Swedish respondents reported higher awareness than Danish respondents for ten of the 13 risk factors studied. Respondents from Denmark reported higher awareness only regarding low fruit and vegetable intake and use of sunbeds. Low physical activity was the only risk factor for which there was no difference in awareness between the countries. A decline in awareness was generally seen with increasing age in both countries, but deviating patterns were seen for alcohol intake, red/processed meat, obesity and age 70+. CONCLUSIONS: This study supports findings from other European studies that generally demonstrate modest public awareness of many established cancer risk factors. Efforts should be made to improve awareness of the cancer risk factors HPV-infection, low fruit and vegetable intake and alcohol intake, which showed particularly low awareness in both countries. Previous studies indicate that repeated, broad campaigns are successful, and suggest that a multimedia approach is used. PMID- 26596681 TI - Myoanatomy and anterior muscle regeneration of the fireworm Eurythoe cf. complanata (Annelida: Amphinomidae). AB - Amphinomidae or so-called "fireworms" are known for their inflammatory substances and their regeneration ability. Recent transcriptome-based molecular analyses revealed that these remarkable annelids are a basal branching taxon outside the annelid main radiation (Pleistoannelida). Although several studies dealing with analyses of the morphology of these annelids have been published, detailed investigations of the anterior muscle regeneration and the musculature in general are largely lacking for amphinomids. Using histology, phalloidin labeling together with subsequent confocal laser scanning microscopy (cLSM), and further light microscopic image acquisition of different regeneration stages, we here present the first morphological study describing the myoanatomy and muscular regeneration. During anterior muscular regeneration, longitudinal muscle bundles develop prior to transverse muscle fibers and segment boundaries. Additionally, Eurythoe cf. complanata develops an independent muscular ring surrounding the mouth opening in an early stage of regeneration. Detailed investigation of adult body wall musculature and the parapodial muscle complex in amphinomids show that E. cf. complanata bears well-developed dorsal and ventral longitudinal muscle bundles as well as outer transverse muscles comparable to the pattern described for several Pleistoannelida. Furthermore, the biramous parapodia possess a complex meshwork of distinct muscle fibers allowing detailed comparisons with other annelid families. PMID- 26596682 TI - Con-forming bodies: the interplay of machines and bodies and the implications of agency in medical imaging. AB - Attending to the material discursive constructions of the patient body within cone beam computed tomography (CBCT) imaging in radiotherapy treatments, in this paper I describe how bodies and machines co-create images. Using an analytical framework inspired by Science and Technology Studies and Feminist Technoscience, I describe the interplay between machines and bodies and the implications of materialities and agency. I argue that patients' bodies play a part in producing scans within acceptable limits of machines as set out through organisational arrangements. In doing so I argue that bodies are fabricated into the order of work prescribed and embedded within and around the CBCT system, becoming, not only the subject of resulting images, but part of that image. The scan is not therefore a representation of a passive subject (a body) but co-produced by the work of practitioners and patients who actively control (and contort) and discipline their body according to protocols and instructions and the CBCT system. In this way I suggest they are 'con-forming' the CBCT image. A Virtual Abstract of this paper can be found at: https://youtu.be/qysCcBGuNSM. PMID- 26596683 TI - Atomically Precise Prediction of 2D Self-Assembly of Weakly Bonded Nanostructures: STM Insight into Concentration-Dependent Architectures. AB - A joint experimental and computational study is reported on the concentration dependant self-assembly of a flat C3 -symmetric molecule on a graphite surface. As a model system a tripodal molecule, 1,3,5-tris(pyridin-3-ylethynyl)benzene, has been chosen, which can adopt either C3h or Cs symmetry when planar, as a result of pyridyl rotation along the alkynyl spacers. Density functional theory (DFT) simulations of 2D nanopatterns with different surface coverage reveal that the molecule can generate different types of self-assembled motifs. The stability of fourteen 2D patterns and the influence of concentration are analyzed. It is found that ordered, densely packed monolayers and 2D porous networks are obtained at high and low concentrations, respectively. A concentration-dependent scanning tunneling microscopy (STM) investigation of this molecular self-assembly system at a solution/graphite interface reveals four supramolecular motifs, which are in perfect agreement with those predicted by simulations. Therefore, this DFT method represents a key step forward toward the atomically precise prediction of molecular self-assembly on surfaces and at interfaces. PMID- 26596684 TI - Bet hedging via multiple mating: A meta-analysis. AB - Polyandry has been hypothesized to allow females to "bet hedge" against mating only with unsuitable mates, reducing variance in offspring fitness between members of a polyandrous lineage relative to a single-mating one. Theoretically, this reduction in fitness variance could select for polyandrous genotypes even when polyandry carries a direct cost, especially in small populations. However, this hypothesis is controversial and difficult to test empirically. Here, I apply a novel simulation model to 49 published empirical datasets, and quantify the potential selective advantage of multiple mating via reduced offspring fitness variance. For a wide range of assumptions, including those that most favor the evolution of bet hedging, I show that any fitness gains are meager. The variance in offspring quality caused by mate identity does not appear to be high enough for bet hedging to drive the evolution of polyandry. PMID- 26596685 TI - Giant Strains in Non-Textured (Bi1/2 Na1/2 )TiO3 -Based Lead-Free Ceramics. AB - Giant electric-field-induced strain of 0.70%, corresponding to a d33 * value of 1400 pm V(-1) , is observed in a lead-free (Bi1/2 Na1/2 )TiO3 -based polycrystalline ceramic. This is comparable to the properties of single crystals. An in situ transmission electron microscopy study indicates that the excellent performance originates from phase transitions under the applied electric fields. PMID- 26596686 TI - The "multiport airway adapter" in flexible bronchoscopy for peripheral bronchial foreign bodies in children. AB - Many children require emergency foreign body removal by bronchoscopy. Although a flexible bronchoscope is frequently used for removal of a bronchial foreign body in children, this procedure is difficult in children with a narrow tracheal lumen, even using a thin flexible bronchoscope. This report describes the use of a multiport airway adaptor to remove a bronchial foreign body with a flexible bronchoscope. The thicker forceps etc. were passed alongside the flexible bronchoscope through the adaptor. These findings suggest that this multiport airway adaptor will be useful as an advanced tool for foreign body removal in pediatric patients. PMID- 26596687 TI - Auditory perception of non-sense and familiar Bengali rhyming words in children with and without SLD. AB - BACKGROUND: Rhyming ability is among the earliest metaphonological skills to be acquired during the process of speech and language acquisition. Metalinguistic skills, particularly metaphonological skills, greatly influence language learning during early, school grades and reportedly children with learning disorders are poor at these skills. AIM AND OBJECTIVES: To develop and validate a Bengali rhyming checklist and study the auditory perception of non-sense and familiar Bengali rhyming words in children with and without specific learning disability (SLD). METHOD: 60 children, age range 8-11years, participated in two groups; group-A included children with SLD and group-B, typically developing children (TDC). All participants were native Bengali speakers, attending regular school, with hearing sensitivity less than 25dBHL, no history of ear discharge and middle socioeconomic background. A rhyming checklist was developed in Bengali, consisting of familiar (section-A) and non-sense (section-B) words. Test-retest reliability and validity measures were obtained. The items on the checklist were audio recorded and presented to the participants in a rhyming judgment task in one to one set up. Scores were obtained and statistically analyzed using SPSS software (version-11.0). RESULT: Children with SLD scored significantly low on the rhyming judgment task as against TDC (p<.05) for both familiar and non-sense words. Children with SLD performed significantly better on familiar word rhyming judgment task against non-sense words (p<.05). TDC showed no significant difference on familiar and non-sense words rhyming judgment tasks (p>.05). CONCLUSION: Semantic content influences rhyming perception in children with SLD but has no significant effect on TDC. The developed rhyming checklist may be used as a screening tool for children at risk of SLD at primary school grades. Rhyming activities may be utilized by teachers and parents, to promote language learning in young learners. PMID- 26596688 TI - Treatment of bisphosphonate-related osteonecrosis of the jaw with platelet-rich fibrin. PMID- 26596689 TI - Variation of current protocols for managing out-of-hospital cardiac arrest in prehospital settings among Asian countries. AB - BACKGROUND/PURPOSE: Protocols for managing patients with out-of-hospital cardiac arrest (OHCA) may vary due to legal, cultural, or socioeconomic concerns. We sought to assess international variation in policies and protocols related to OHCA. METHODS: A brief survey was developed by consensus. Elicited information included protocols for managing patients with nontraumatic OHCA or traumatic OHCA, policies for using automated external defibrillators (AEDs) during transportation of patients with ongoing resuscitation, and application of terminations of resuscitation (TOR) rules in prehospital settings in the respondent's city or country. The populations of interest were emergency physicians, medical directors of emergency medical services (EMS), and policy makers. RESULTS: Responses were obtained from eight cities in six Asian countries. Only one (12.5%) city applied TOR rules for OHCAs. Do-not-resuscitate (DNR) orders were valid in prehospital settings in five (62.5%) cities. All cities used AEDs for nontraumatic OHCAs; seven (87.5%) cities did not routinely use AEDs for traumatic OHCAs. For nontraumatic OHCAs, four (50%) cities performed 2 minutes of on-scene cardiopulmonary resuscitation (CPR) and then transported the patients with ongoing resuscitation to hospitals; three (37.5%) cities performed 4 minutes of on-scene CPR; one (12.5%) city allowed variation in the duration of on-scene CPR. CONCLUSION: International variation in practices and polices related to OHCAs do exist. Concerns regarding prehospital TOR rules include medical evidence, legal considerations, EMS manpower, public perception, medical oversight, education, EMS characteristics, and cost-effectiveness analysis. Further research is needed to achieve consensus regarding management protocols, especially for EMS that perform resuscitation during transportation of OHCA patients. PMID- 26596690 TI - Survival for haemodialysis vs. peritoneal dialysis and technique transference. Experience in Ourense, Spain, from 1976 to 2012. AB - OBJECTIVE: To assess SV in our RRT population in the period 1976-2012 as well as the influence of technique transference (TT). MATERIAL AND METHODS: The study included a retrospective cohort of 993 patients. Data were classified as transplant (Tx), change in technique, exitus or lost to follow-up. SV for TT was determined in patients with over 12 weeks of permanence. RESULTS: The mortality risk adjusted for age, sex, dialysis technique or diabetes mellitus (DM) showed that the estimated risk of death increased by 4.8% per year increase (HR=1.048; 95% CI: 1.04-1.06; P<.001) and was 44% higher in diabetics compared to non diabetics (HR=1.44; 95% CI 1.16-1.76; P<.01). Regarding SV for TT, patients who initiated HD had a shorter survival than those who initiated PD and transferred to HD (P=.00563). CONCLUSION: In our experience, SV in RRT is dependent on age and coexistence of DM. It would be beneficial to reinstate the concept of "comprehensive care", in which RRT would start with PD and later transfer to HD. PMID- 26596691 TI - [Cryptococcus where they are not expected: Five case reports of extra-cerebral and extra-pulmonary cryptococcosis]. AB - Cryptococcosis is a serious infection, possibly lethal, of worldwide distribution. It mainly affects immunosuppressed patients resulting with pulmonary and/or meningeal involvements or disseminated infections. Due to the rarity of visceral and osseous infections, and to the absence of specific clinical symptoms, this diagnosis is often deferred. Resulting of diagnostic errors, samples are often directed to the department of pathology and more rarely to the department of mycology. Histopathological examination appears crucial, highlighting encapsulated yeasts with alcian blue staining. Once the diagnosis is performed, an appropriate antifungal therapy must be quickly introduced because these infections are associated with a high mortality rate. The aim of our work was to report five extra-cerebral and extra-pulmonary cryptococcosis cases, to describe their histopathological features, to evoke diagnostic techniques and to discuss the differential diagnoses. PMID- 26596692 TI - [One aspect of tumor-like mass of inter-duodenopancreatic cephalic furrow]. PMID- 26596693 TI - [An IgG4-related pancreatitis mimicking an adenocarcinoma: A case report]. AB - Type 1 auto-immune pancreatitis (type 1 AIP) is the pancreatic manifestation of IgG4-related systemic disease (IgG4-RD). This disease has recently been individualized and is characterized by elevated serum IgG4 levels and extrapancreatic lesions with common histologic characteristic: dense infiltration of lymphocytes, IgG4-positive plasma cells and storiforme fibrosis. Obliterative phlebitis is frequently detected. The pancreas is frequently involved in this disease. As approach to the pancreas for histological examination is generally difficult, AIP is diagnosed using a combination of clinical, serological, morphological and histopathological features. In pseudotumoral cases, AIP can be misdiagnosed as pancreatic cancer. Since AIP responds dramatically to steroid therapy, accurate diagnosis of AIP can avoid unnecessary laparotomy or pancreatic resection. We report here a case of a patient who underwent surgery for presumed pancreatic cancer. The final diagnosis was type 1 AIP. PMID- 26596694 TI - A scoping review of end user involvement in disability research. AB - BACKGROUND: Involving clients and consumers of health care in research, policy and health service development has been widely advocated for across a number of different fields and disciplines. Despite some promising evidence, 'end users' have not been meaningfully involved in all stages of the research process in the area of disability research. OBJECTIVE: To conduct a scoping review on end user involvement in disability research, service and policy development. METHODS: Literature was searched using electronic databases, hand searching reference lists of papers and grey literature. Electronic databases searched included the Cochrane Database of Systematic Reviews, MEDLINE, EMBASE, CINAHL, PsycINFO and Google Scholar. The search was restricted to articles published in English between January 2000 and April 2013. RESULTS: Two clear themes emerged from a review of twenty-seven articles. Firstly, end users can benefit research as 'experts of experience' through their role as a co-researcher. Secondly, evidence suggests end users add value at different stages of the research process in this role. However, less is understood about end user involvement in the latter stages of the research process. CONCLUSIONS: This review suggests that end users can meaningfully contribute to the quality of disability research. End users are likely to engage in research with differing perspectives, desires to be involved at distinct stages of the process, differing roles and different abilities to participate in the research. Academic rigor, however, must be maintained by the researcher. PMID- 26596695 TI - Iodine status among pregnant women after mandatory salt iodisation. AB - I is essential for thyroid hormone synthesis and neurological development. Various changes occur in thyroid hormone metabolism during pregnancy and I requirements increase significantly. The purpose of this study was to investigate I status among pregnant women in Trabzon, formerly a severely I-deficient area but shown to have become I sufficient following mandatory iodisation of table salt based on monitoring studies among school-age children (SAC) in the area. A total of 864 healthy pregnant women with a median age of 28 (25th-75th percentile 17-47) years participated in the study. None of them were using I-containing supplement. All of them were screened for use of iodised salt, obstetric history, thyroid function tests and urinary I concentrations (UIC), and thyroid ultrasonography was performed. Median UIC was 102 (25th-75th percentile=62-143) MUg/l. Median UIC of the patients according to trimesters were 122 ug/l at the 1st, 97 ug/l at the 2nd and 87 ug/l at the 3rd trimester. UIC in the 1st trimester was higher compared with the 2nd and 3rd trimesters (P<0.017). Nodules were present in 17.7% of women (n 153). The rate of iodised salt usage among pregnant women was 90.7%. Our study demonstrates that, although the I status among SAC has been rectified, I deficiency (ID) is still prevalent among pregnant women. Current knowledge is in favour of I supplementation in this group. Until the effects of maternal I supplementation in mild ID have been clarified by large scale prospective controlled trials, pregnant women living in borderline defficient and I-sufficient areas, such as Trabzon city, should receive 100-200 ug/d of I-containing supplements in addition to iodised salt. PMID- 26596697 TI - Moral distress in intensive care unit professionals is associated with profession, age, and years of experience. AB - PURPOSE: To determine which demographic characteristics are associated with moral distress in intensive care unit (ICU) professionals. METHODS: We distributed a self-administered, validated survey to measure moral distress to all clinical personnel in 13 ICUs in British Columbia, Canada. Each respondent to the survey also reported their age, sex, and years of experience in the ICU where they were working. We used multivariate, hierarchical regression to analyze relationships between demographic characteristics and moral distress scores, and to analyze the relationship between moral distress and tendency to leave the workplace. RESULTS: Response rates to the surveys were the following: nurses--428/870 (49%); other health professionals (not nurses or physicians)--211/452 (47%); physicians--30/68 (44%). Nurses and other health professionals had higher moral distress scores than physicians. Highest ranked items associated with moral distress were related to cost constraints and end-of-life controversies. Multivariate analyses showed that age is inversely associated with moral distress, but only in other health professionals (rate ratio [95% confidence interval]: -7.3 [-13.4, -1.2]); years of experience is directly associated with moral distress, but only in nurses (rate ratio (95% confidence interval):10.8 [2.6, 18.9]). The moral distress score is directly related to the tendency to leave the ICU job, in both the past and present, but only for nurses and other non-physician health professionals. CONCLUSION: Moral distress is higher in ICU nurses and other non-physician professionals than in physicians, is lower with older age for other non-physician professionals but greater with more years of experience in nurses, and is associated with tendency to leave the job. PMID- 26596698 TI - Low total cholesterol and high total bilirubin are associated with prognosis in patients with prolonged sepsis. AB - PURPOSE: Nutritional biochemical indexes are generally used as markers for critically ill patients. However, they are easily influenced by acute phase changes after injury and are difficult to use as common and practical biomarkers. The objective of this study was to determine the most valuable prognostic markers among 15 common laboratory tests in patients with sepsis. METHODS: We included all sepsis patients who stayed in the intensive care unit for more than 2 weeks. We evaluated 15 biochemistry indexes including serum albumin, total protein, C reactive protein, cholinesterase, total cholesterol (T-Cho), triglyceride, sodium, potassium, blood urea nitrogen, creatinine, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, total bilirubin (T-Bil), and prothrombin time. The minimum and maximum values of these indexes during the first 14 days from admission were analyzed by classification and regression tree and multivariate logistic regression analyses. RESULTS: This study comprised 91 patients with sepsis. The primary split was the minimum value of serum T-Cho (T Cho (Min)), and the cutoff value was 73.5 mg/dL by classification and regression tree analysis. The second split was the maximum value of T-Bil (T-Bil (Max)), and the cutoff value was 1.35 mg/dL. The rate of mortality was 63% (17/27) in the group with T-Cho (Min) less than 73.5 mg/dL and T-Bil (Max) greater than 1.35 mg/dL. Multivariate logistic regression revealed that T-Cho (Min) and T-Bil (Max) were the biomarkers most closely associated with prognosis. CONCLUSIONS: Total cholesterol and T-Bil could be associated with prognosis in patients with sepsis. PMID- 26596696 TI - Non-affinity factors modulating vascular targeting of nano- and microcarriers. AB - Particles capable of homing and adhering to specific vascular biomarkers have potential as fundamental tools in drug delivery for mediation of a wide variety of pathologies, including inflammation, thrombosis, and pulmonary disorders. The presentation of affinity ligands on the surface of a particle provides a means of targeting the particle to sites of therapeutic interest, but a host of other factors come into play in determining the targeting capacity of the particle. This review presents a summary of several key considerations in nano- and microparticle design that modulate targeted delivery without directly altering epitope-specific affinity. Namely, we describe the effect of factors in definition of the base carrier (including shape, size, and flexibility) on the capacity of carriers to access, adhere to, and integrate in target biological milieus. Furthermore, we present a summary of fundamental dynamics of carrier behavior in circulation, taking into account interactions with cells in circulation and the role of hemodynamics in mediating the direction of carriers to target sites. Finally, we note non-affinity aspects to uptake and intracellular trafficking of carriers in target cells. In total, recent findings presented here may offer an opportunity to capitalize on mitigating factors in the behavior of ligand-targeted carriers in order to optimize targeting. PMID- 26596699 TI - Intraoperative ultrasound reduces the need for re-excision in breast-conserving surgery. AB - BACKGROUND: The purpose of this study was to evaluate ultrasound-guided surgery for palpable breast cancer by comparing the standard palpation-guided surgery in terms of the extent of healthy breast tissue resection, the percentage of tumor free margins, and cosmetic outcomes. METHODS: This was a prospective, observational cohort study conducted from January 2009 to July 2011. Breast cancer patients, diagnosed via biopsy, were operated in guidance with either ultrasound or palpation. Patient demographics, tumor features, intraoperative findings, pathologic and cosmetic results, intraoperative-measured ultrasound margins, and pathology margins were compared. RESULTS: Ultrasound (US)-guided lumpectomy was performed on 84 women and palpation-guided lumpectomy on 80 women. Patient demographics and tumor characteristics showed no differences. The rate of re-excision was 17 % for the palpation-guided surgery group, and 6 % for the US guided group (p = 0.03). There was good correlation between the closest margins recorded by US and pathology margins (r = 0.76, p = 0.01). Volume of resection was significantly larger in the palpation-guided group despite the similar size of tumors (p = 0.048). Cosmetic outcome of surgery was equivalent between groups. CONCLUSIONS: Intraoperative ultrasound guidance for excision of palpable breast cancers is feasible and gives results in terms of pathologic margins that are comparable with those achieved by standard palpation-guided excisions. PMID- 26596700 TI - Learning strategy refinement reverses early sensory cortical map expansion but not behavior: Support for a theory of directed cortical substrates of learning and memory. AB - Primary sensory cortical fields develop highly specific associative representational plasticity, notably enlarged area of representation of reinforced signal stimuli within their topographic maps. However, overtraining subjects after they have solved an instrumental task can reduce or eliminate the expansion while the successful behavior remains. As the development of this plasticity depends on the learning strategy used to solve a task, we asked whether the loss of expansion is due to the strategy used during overtraining. Adult male rats were trained in a three-tone auditory discrimination task to bar press to the CS+ for water reward and refrain from doing so during the CS- tones and silent intertrial intervals; errors were punished by a flashing light and time-out penalty. Groups acquired this task to a criterion within seven training sessions by relying on a strategy that was "bar-press from tone-onset-to-error signal" ("TOTE"). Three groups then received different levels of overtraining: Group ST, none; Group RT, one week; Group OT, three weeks. Post-training mapping of their primary auditory fields (A1) showed that Groups ST and RT had developed significantly expanded representational areas, specifically restricted to the frequency band of the CS+ tone. In contrast, the A1 of Group OT was no different from naive controls. Analysis of learning strategy revealed this group had shifted strategy to a refinement of TOTE in which they self-terminated bar presses before making an error ("iTOTE"). Across all animals, the greater the use of iTOTE, the smaller was the representation of the CS+ in A1. Thus, the loss of cortical expansion is attributable to a shift or refinement in strategy. This reversal of expansion was considered in light of a novel theoretical framework (CONCERTO) highlighting four basic principles of brain function that resolve anomalous findings and explaining why even a minor change in strategy would involve concomitant shifts of involved brain sites, including reversal of cortical expansion. PMID- 26596701 TI - epsilon-Viniferin, a resveratrol dimer, prevents diet-induced obesity in mice. AB - Red wines are thought to be one of the major dietary sources of trans resveratrol. The beneficial effects of t-resveratrol against metabolic disorders have been well characterized, however, red wines also contain various resveratrol derivatives whose health benefits have not been completely elucidated. In this report, we investigated epsilon-viniferin, a resveratrol dimer, which is present at comparable concentrations to t-resveratrol in red wines, and has higher anti adipogenesis activity in 3T3-L1 cells. In addition, epsilon-viniferin was more effective than t-resveratrol in its anti-obesity and anti-inflammatory effects in high-fat diet fed mice. These results suggested epsilon-viniferin may be one of the active ingredients against metabolic disorders in red wines, in addition to t resveratrol. PMID- 26596702 TI - Glucose metabolism and hepatic Igf1 DNA methylation are altered in the offspring of dams fed a low-salt diet during pregnancy. AB - A low-salt (LS) diet during pregnancy has been linked to insulin resistance in adult offspring, at least in the experimental setting. However, it remains unclear if this effect is due to salt restriction during early or late pregnancy. To better understand this phenomenon, 12-week-old female Wistar rats were fed a LS or normal-salt (NS) diet during gestation or a LS diet during either the first (LS10) or second (LS20) half of gestation. Glucose tolerance test, HOMA-IR, gene expression analysis and DNA methylation measurements were conducted for the Insr, Igf1, Igf1r, Ins1 and Ins2 genes in the livers of neonates and in the liver, white adipose tissue and muscle of 20-week-old male offspring. Birth weight was lower in the LS20 and LS animals compared with the NS and LS10 rats. In the liver, the Igf1 levels in the LS10, LS20 and LS neonates were lower than those in the NS neonates. Methylation of the Insr, Igf1r, Ins1 and Ins2 genes was influenced in a variable manner by low salt intake during pregnancy. Increased liver Igf1 methylation was observed in the LS and LS20 neonates compared with their NS and LS10 counterparts. Glucose intolerance was observed in adult offspring as an effect of low salt intake over the duration of pregnancy. Compared to the NS animals, the HOMA-IR was higher in the 12-week-old LS and 20 week-old LS-10 rats. Based on these results, it appears that the reason a LS diet during pregnancy induces a low birth weight is its negative correlation with Igf1 DNA methylation in neonates. PMID- 26596703 TI - Intermittent access to a sucrose solution impairs metabolism in obesity-prone but not obesity-resistant mice. AB - Consumption of sugar-sweetened beverages is associated with overweight and obesity. In this study, we hypothesized that obesity-prone (OP) mice fed a high fat high-sucrose diet (HFHS) are more sensitive to consumption of sucrose sweetened water (SSW) than obesity-resistant (OR) mice. After 3weeks of ad libitum access to the HFHS diet (7.5h/day), 180 male mice were classified as either OP (upper quartile of body weight gain, 5.2+/-0.1g, n=45) or OR (lower quartile, 3.2+/-0.1g, n=45). OP and OR mice were subsequently divided into 3 subgroups that had access to HFHS (7.5h/day) for 16weeks, supplemented with: i) water (OP/water and OR/water); ii) water and SSW (12.6% w/v), available for 2h/day randomly when access to HFHS was available and for 5 randomly-chosen days/week (OP/SSW and OR/SSW); or iii) water and SSW for 8weeks, then only water for 8weeks (OP/SSW-water and OR/SSW-water). OR/SSW mice decreased their food intake compared to OR/water mice, while OP/SSW mice exhibited an increase in food and total energy intake compared to OP/water mice. OP/SSW mice also gained more body weight and fat mass than OP/water mice, showed an increase in liver triglycerides and developed insulin resistance. These effects were fully reversed in OP/SSW-water mice. In the gut, OR/SSW mice, but not OP/SSW mice, had an increase GLP-1 and CCK response to a liquid meal compared to mice drinking only water. OP/SSW mice had a decreased expression of melanocortin receptor 4 in the hypothalamus and increased expression of delta opioid receptor in the nucleus accumbens compared to OP/water mice when fasted that could explain the hyperphagia in these mice. When access to the sucrose solution was removed for 8weeks, OP mice had increased dopaminergic and opioidergic response to a sucrose solution. Thus, intermittent access to a sucrose solution in mice fed a HFHS diet induces changes in the gut and brain signaling, leading to increased energy intake and adverse metabolic consequences only in mice prone to HFHS-induced obesity. PMID- 26596704 TI - Quantifying parental preferences for interventions designed to improve home food preparation and home food environments during early childhood. AB - Though preparing healthy food at home is a critical health promotion habit, few interventions have aimed to improve parental cooking skills and behaviors. We sought to understand parents' preferences and priorities regarding interventions to improve home food preparation practices and home food environments during early childhood. We administered a discrete choice experiment using maximum difference scaling. Eighty English-speaking parents of healthy 1-4 year-old children rated the relative importance of potential attributes of interventions to improve home food preparation practices and home food environments. We performed latent class analysis to identify subgroups of parents with similar preferences and tested for differences between the subgroups. Participants were mostly white or black 21-45 year-old women whose prevalence of overweight/obesity mirrored the general population. Latent class analysis revealed three distinct groups of parental preferences for intervention content: a healthy cooking group, focused on nutrition and cooking healthier food; a child persuasion group, focused on convincing toddlers to eat home-cooked food; and a creative cooking group, focused on cooking without recipes, meal planning, and time-saving strategies. Younger, lower income, 1-parent households comprised the healthy cooking group, while older, higher income, 2-parent households comprised the creative cooking group (p < 0.05). The child persuasion group was more varied with regard to age, income, and household structure but cooked dinner regularly, unlike the other two groups (p < 0.05). Discrete choice experiments using maximum difference scaling can be employed to design and tailor interventions to change health behaviors. Segmenting a diverse target population by needs and preferences enables the tailoring and optimization of future interventions to improve parental home food preparation practices. Such interventions are important for creating healthier home food environments and preventing obesity starting from early childhood. PMID- 26596705 TI - Undiagnosed Diseases Network International (UDNI): White paper for global actions to meet patient needs. AB - In 2008, the National Institutes of Health's (NIH) Undiagnosed Disease Program (UDP) was initiated to provide diagnoses for individuals who had long sought one without success. As a result of two international conferences (Rome 2014 and Budapest 2015), the Undiagnosed Diseases Network International (UDNI) was established, modeled in part after the NIH UDP. Undiagnosed diseases are a global health issue, calling for an international scientific and healthcare effort. To meet this demand, the UDNI has built a consensus framework of principles, best practices and governance; the Board of Directors reflects its international character, as it includes experts from Australia, Canada, Hungary, Italy, Japan and the USA. The UDNI involves centers with internationally recognized expertise, and its scientific resources and know-how aim to fill the knowledge gaps that impede diagnosis. Consequently, the UDNI fosters the translation of research into medical practice. Active patient involvement is critical; the Patient Advisory Group is expected to play an increasing role in UDNI activities. All information for physicians and patients will be available at the UDNI website. PMID- 26596706 TI - A novel gemycircularvirus in an unexplained case of child encephalitis. AB - BACKGROUND: Recently, a diverse group of viruses with circular, replication initiator protein(Rep) encoding, single stranded DNA (CRESS-DNA) genomes, were discovered from wide range of eukaryotic organisms ranging from mammals to fungi. Gemycircularvirus belongs to a distinct group of CRESS-DNA genomes and is classified under the genus name of Gemycircularvirus. FINDINGS: Here, a novel gemycircularvirus named GeTz1 from cerebrospinal fluid sample of a child with unexplainable encephalitis was characterized. The novel gemycircularvirus encodes two major proteins, including a capsid protein (Cap) and a replication-associated protein (Rep). Phylogenetic analysis based on the amino acid sequence of Rep indicated that GeTz1 clusters with one gemycircularvirus discovered from bird (KF371633), sharing 46.6 % amino acid sequence identity with each other. CONCLUSION: A novel gemycircularvirus was discovered from cerebrospinal fluid sample of a child with unexplainable encephalitis. Further studies, such as testing human sera for specific antibodies, should be performed to investigate whether gemycircularvirus infects human and is associated with encephalitis. PMID- 26596707 TI - Chemical composition and antibiofilm activity of Petroselinum crispum and Ocimum basilicum essential oils against Vibrio spp. strains. AB - In this study, we evaluated the antibacterial activity of parsley and basilic essential oils tested against Vibrio strains and their abilities to inhibit and eradicate the mature biofilm using the XTT assay. Petroselinum crispum essential oil was characterized by 1,3,8-p-menthatriene (24.2%), beta-phellandrene (22.8%), apiol (13.2%), myristicin (12.6%) and terpinolene (10.3%) as a major constituents. While, in the basilic oil, linalool (42.1%), (E)-methylcinnamate (16.9%) and 1-8 cineole (7.6%) were the main ones. These two essential oils exhibit high anti-Vibrio spp. activity with varying magnitudes. All microorganisms were strongly affected indicating an appreciable antimicrobial potential of basilic with a diameter of inhibition zones growth ranging from 8.67 to 23.33 mm and MIC and MBC values ranging from (0.023-0.047 mg/ml) and (>3->24 mg/ml), respectively. The two essential oils can inhibit and eradicate the mature biofilm formed on polystyrene surface even at low concentrations, with high magnitude for Ocimum basilicum essential oil. This study gives a better insight into the anti-Vibrio activity of parsley and basilc oils and the possibility of their use to prevent and eradicate contamination of sea products by these strains. PMID- 26596708 TI - HIV-1 Tat regulates the expression of the dcw operon and stimulates the proliferation of bacteria. AB - Infections of pathogenic bacteria are very common in acquired immunodeficiency syndrome (AIDS) patients. However, the biological effects of HIV-1 Tat on bacteria are incompletely understood. In this study, HIV-1 Tat was expressed in Escherichia coli and Pseudomonas aeruginosa (PA01) to investigate its biological effects on bacteria. Bacterial cells expressing either HIV-1 Tat1-86 (Tat1-86) or HIV-1 Tat1-72 (Tat1-72) grow significantly faster than those with either only an empty vector or an unrelated control (GFP or Rluc). Supplementation of purified HIV-1 Tat1-86 or Tat1-101 protein into bacterial culture medium stimulated the growth of both E. coli and PA01. The expression profile of certain cell division associated genes, such as those in the division cell wall (dcw) operon (ftsA, ftsQ, ftsW and ftsZ), yafO and zipA, was altered in HIV-1 Tat1-86 expressing E. coli BL21(DE3). Furthermore, the expression of firefly luciferase (Fluc) reporter gene, when engineered for control by the dcw promoter and terminator, was enhanced by HIV-1 Tat in E. coli, confirming that HIV-1 Tat transcriptionally regulates the expression of the dcw operon. The finding that HIV-1 Tat stimulates bacterial growth whether it is produced intracellularly or applied extracellularly may have relevance for HIV patients who are highly susceptible to opportunistic bacterial infections. Contents category: Viruses -Retroviruses. The GenBank accession number for the sequence of HIV-1 Tat1-86 is AF324439.1. PMID- 26596709 TI - Pleiotropic effects of temperature-regulated 2-OH-lauroytransferase (PA0011) on Pseudomonas aeruginosa antibiotic resistance, virulence and type III secretion system. AB - Pseudomonas aeruginosa is an important human pathogen which adapts to changing environment, such as temperature variations and entering host by regulating their gene expression. Here, we report that gene PA0011 in P. aeruginosa PAO1, which encodes a 2-OH-lauroytransferase participating in lipid A biosynthesis, is involved in carbapenem resistance and virulence in a temperature-regulated manner in PAO1. The expression of PA0011 was higher at an environment temperature (21 degrees C) than that at a body temperature (37 degrees C). The inactivation of PA0011 rendered increased antibiotic susceptibility and decreased virulence both in vivo and in vitro. The impaired integrity and the decreased stability of the outer membrane were the cause of the increased susceptibility of PAO1(Delta0011) to carbapenem and many other common antibiotics. The reduced endotoxic activity of lipopolysaccharide (LPS) contributed to the decreased virulence both at 21 degrees C and 37 degrees C in PAO1 (Delta0011). In addition, we have found that PA0011 repressed the expression of TTSS virulence factors both at transcriptional and translational levels, similar to the effect of O antigen of LPS but unlike any effect of its homologue reported in other bacteria. The effect of PA0011 on resistance to many antibiotics including carbapenem and virulence in P. aeruginosa makes it a target for novel antimicrobial therapies. PMID- 26596711 TI - Searching for novel applications of the benzohomoadamantane scaffold in medicinal chemistry: Synthesis of novel 11beta-HSD1 inhibitors. AB - The structural and physicochemical properties of the adamantane nucleus account for its use as a chemical scaffold in multiple drugs. In the last years, we have developed new polycyclic scaffolds as surrogates of the adamantane group with encouraging results in multiple targets. As adamantane is a common structural feature in several 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitors, we have explored the ability of the 6,7,8,9,10,11-hexahydro-5H 5,9:7,11-dimethanobenzo[9]annulen-7-yl scaffold to act as a surrogate of the adamantane nucleus in a novel series of 11beta-HSD1 inhibitors. Of note, within this family of compounds one derivative is endowed with submicromolar 11beta-HSD1 inhibitory activity. Molecular modeling studies support the binding of the compounds to the active site of the enzyme. However, a fine tuning of the hydrophobicity of the size-expanded nucleus may be beneficial for the inhibitory potency. PMID- 26596710 TI - Discovery of novel quinoline-based mTOR inhibitors via introducing intra molecular hydrogen bonding scaffold (iMHBS): The design, synthesis and biological evaluation. AB - A series of quinoline derivatives featuring the novelty of introducing intra molecular hydrogen bonding scaffold (iMHBS) were designed, synthesized and biologically evaluated for their mTOR inhibitory activity, as well as anti proliferative efficacies against HCT-116, PC-3 and MCF-7 cell lines. As a result, six compounds exhibited significant inhibition against mTOR with IC50 values below 35nM. Compound 15a, the most potent mTOR inhibitor reported herein (IC50=14nM), also displayed the most favorable cellular activities, with the IC50 values of 0.46, 0.61 and 0.24MUM against HCT-116, PC-3 and MCF-7, respectively. Besides, several compounds in this series were identified to be selective over class I PI3Ks. Further western blot analysis of 16b, a representative compound in this series, highlighted their advantage in surmounting the S6K/IRS1/PI3K negative feedback loop upon dual inhibition of mTORC1 and mTORC2. In addition to the remarkable activity, 15a demonstrated acceptable stability in simulated gastric fluid (SGF), simulated intestinal fluid (SIF) and liver microsome, thereby being valuable for extensive in vivo investigation. PMID- 26596712 TI - Location of the uncinate process with respect to the lacrimal fossa. PMID- 26596713 TI - Papilledema secondary to a superior sagittal sinus thrombosis. Mantle cell lymphoma paraneoplastic syndrome. AB - CLINICAL CASE: A 46 year old patient presented with visual loss in the left eye during the previous months. Ophthalmoscopic examination and magnetic resonance angiography found the presence of papilledema due to thrombosis in superior sagittal sinus. The examination findings revealed a mantle cell lymphoma. DISCUSSION: Cerebral venous thrombosis is an unusual cause of papilledema. This type of thrombosis may be secondary to hyper-viscosity within a context of a paraneoplastic syndrome. PMID- 26596714 TI - Modeling HIV-1 viral capsid nucleation by dynamical systems. AB - There are two stages generally recognized in the viral capsid assembly: nucleation and elongation. This paper focuses on the nucleation stage and develops mathematical models for HIV-1 viral capsid nucleation based on six species dynamical systems. The Particle Swarm Optimization (PSO) algorithm is used for parameter fitting to estimate the association and dissociation rates from biological experiment data. Numerical simulations of capsid protein (CA) multimer concentrations demonstrate a good agreement with experimental data. Sensitivity and elasticity analysis of CA multimer concentrations with respect to the association and dissociation rates further reveals the importance of CA trimer-of- dimers in the nucleation stage of viral capsid self- assembly. PMID- 26596715 TI - Mathematical analysis of a model for AVL-HIV co-endemicity. AB - A model for the transmission dynamics of Anthroponotic Visceral Leishmaniasis (AVL) and human immunodeficiency virus (HIV) in a population is developed and used to assess the impact of the spread of each disease on the overall transmission dynamics. As for other vector-borne disease models, the AVL component of the model undergoes backward bifurcation when the associated reproduction number of the AVL-only sub-model (denoted by RL) is less than unity. Uncertainty and sensitivity analyzes of the model, using data relevant to the dynamics of the two diseases in Ethiopia, show that the top three parameters that drive the AVL infection (with respect to the associated response function, RL) are the average number of times a sandfly bites humans per unit time (sigmaV), carrying capacity of vectors (KV) and transmission probability from infected humans to susceptible sandflies (beta2). The distribution of RL is RL?[0.06,3.94] with a mean of RL=1.08. Furthermore, the top three parameters that affect HIV dynamics (with respect to the response function RH) are the transmission rate of HIV (betaH), HIV-induced death rate (deltaH), and the modification parameter for the increase in infectiousness of AIDS individuals in comparison to HIV infected without clinical symptoms of AIDS (omegaH). The distribution of RH is RH?[0.88,2.79] with a mean of RH=1.46. The dominant parameters that affect the dynamics of the full VL-HIV model (with respect to the associated reproduction number, RLH, as the response function) are the transmission rate of HIV (betaH), the average number of times a sandfly bites humans per unit time (sigmaV), and HIV-induced death rate (deltaH) (the distribution of RLH is RLH?[0.88,3.94] with a mean of RLH=1.64). Numerical simulations of the model show that the two diseases co-exist (with AVL dominating, but not driving HIV to extinction) whenever the reproduction number of each disease exceeds unity. It is shown that AVL can invade a population at HIV-endemic state if a certain threshold quantity, known as invasion reproduction number, exceeds unity. PMID- 26596716 TI - Effect of alvimopan on accelerates gastrointestinal recovery after radical cystectomy: A systematic review and meta-analysis. AB - PURPOSE: The aim of the study was to evaluate the efficacy of alvimopan on accelerates gastrointestinal recovery after radical cystectomy. METHODS: We searched for all studies investigating alvimopan for bladder cancer patients undergoing radical cystectomy in Pubmed, Web of Knowledge, and the Cochrane Central Search Library. A systematic review and meta-analysis were performed. All studies that compared alvimopan with control group for patients undergoing radical cystectomy were included. Studies with overlapping or insufficient data were excluded. No language restrictions were made. Efficacy was assessed by the time to first toleration of clear liquids, first toleration of solid food, first bowel movement and length of stay. RESULTS: Our searches identified 5 studies, including 613 patients. A total of 294 (47%) patients took alvimopan. On meta analysis, alvimopan reduced time to first toleration of clear liquids (HR 1.34, 95% CI 1.19 to 1.51, p < 0.001), first toleration of solid food (HR 1.22, 95% CI 1.11 to 1.34, p < 0.001), first bowel movement (HR 1.27, 95% CI 1.12 to 1.43, p < 0.001) and length of stay (HR 1.17, 95% CI 1.10 to 1.25, p < 0.001). CONCLUSIONS: This meta-analysis has shown that alvimopan significantly accelerates recovery of gastrointestinal function and reduces the length of stay in patients performed radical cystectomy. More large scale, multicenter randomized controlled studies are needed before final clinical recommendations can be made. PMID- 26596717 TI - Morphometric and biomechanical remodeling of the small intestine during aging in rats. AB - The present study aimed to study the morphometric and biomechanical remodeling of the small intestine during aging in rats. Twenty-four male Wistar rats, aged from 6 to 22 months, were used in the study. The body weight and the wet weight per length of duodenal and ileal segments were measured at the termination of the experiments. Morphometry data was obtained by measuring the wall thickness and cross-sectional area. The mechanical test was done as a step-wise distension experiment. The intestinal diameter and length were obtained from digitized images of the segments at pre-selected pressure levels and at the no-load and zero-stress states. Circumferential and longitudinal stresses (force per area) and strains (deformation) were computed from the length, diameter and pressure data and from the zero-stress state geometry. The duodenal and ileal dimensions increased slightly from 6 to 22 months, e.g. the wall thickness and the wall cross-sectional area increased about 4% and 25% for duodenum and 5% and 8% for ileum. The opening angle gradually decreased from 154 to 117 degrees for duodenum and from 144 to 87 degrees for ileum during aging. The circumferential stress strain curves significantly shifted to the left after 22 months (p<0.05) whereas the longitudinal stress-strain curves significantly shifted to the left after 18 months (p<0.01) both for duodenum and ileum. The intestinal wall became stiffer circumferentially and longitudinally during the aging. Furthermore, the intestinal wall was stiffer longitudinally than circumferentially. In conclusion, pronounced morphometric and biomechanical remodeling occurred in the rat intestine during aging. PMID- 26596718 TI - The role of aortic compliance in determination of coarctation severity: Lumped parameter modeling, in vitro study and clinical evaluation. AB - Early detection and accurate estimation of the extent of coarctation of the aorta (COA) is critical to long-term outcome. Peak-to-peak trans-coarctation pressure gradient (PKdP) higher than 20mmHg is an indication for interventional/surgical repair. Patients with COA have reduced proximal and distal aortic compliances. A comprehensive study investigating the effects of variations of proximal COA and systemic compliances on PKdP, and consequently on the COA severity evaluation has never been done. This study evaluates the effect of aortic compliance on diagnostic accuracy of PKdP. Lumped parameter modeling and in vitro experiments were performed for COA severities of 50%, 75% and 90% by area. Modeling and in vitro results were validated against retrospective clinical data of PKdP, measured in 54 patients with COA. Modeling and in vitro. PKdP increases with reduced proximal COA compliance (+36%, +38% and +53% for COA severities of 50%, 75% and 90%, respectively; p<0.05), but decreases with reduced systemic compliance (-62%, -41% and -36% for COA severities of 50%, 75% and 90%, respectively; p<0.01). Clinical study. PKdP has a modest correlation with COA severity (R=0.29). The main determinants of PKdP are COA severity, stroke volume index and systemic compliance. Systemic compliance was found to be as influential as COA severity in PKdP determination (R=0.30 vs. R =0.34). In conclusion, PKdP is highly influenced by both stroke volume index and arterial compliance. Low values of PKdP cannot be used to exclude the severe COA presence since COA severity may be masked by reduced systemic compliance and/or low flow conditions. PMID- 26596720 TI - NHS should look to Alaska for model of reform, conference is told. PMID- 26596719 TI - Mechanical loading up-regulates early remodeling signals from osteocytes subjected to physical damage. AB - In the mineralized bone matrix, mechanical loading causes micrometer-sized cracks. These cracks trigger targeted remodeling along the micro-crack. Physical damage to osteocytes was shown to be involved in the initiation of this remodeling process. However, the role of subsequent mechanical loading osteocyte response to physical damage is unclear. In this study, we have designed and developed an in vitro cell model to study the impact of mechanical loading on osteocytes with physical damage. Specifically, a system was developed to create sub-cellular physical damage on MLO-Y4 osteocytes in vitro. This model re-created the spatial distribution of non-viable cells and VEGF expression around microdamage as reported in vivo. Using this system, the short term (24h) effects of fluid shear stress in regulation of osteocyte response to physical damage were investigated. We have observed that the mechanical stimuli had an additive effect in terms of COX-2, VEGF mRNA expressions, as well as PGE2, VEGF concentrations in the media. Interestingly, other inflammatory signals such as IL-6 and TNF-alpha did not change with these stimuli, at this time point. Moreover, fluid shear also had a modulating effect in regulation of osteoclast differentiation by osteocyte with physical damage. These results show that (1) subcellular physical damage upregulates remodeling signals in osteocytes at early time point, (2) mechanical loading substantially upregulates these signals for remodeling in osteocytes with physical damage. PMID- 26596721 TI - Item-focussed Trees for the Identification of Items in Differential Item Functioning. AB - A novel method for the identification of differential item functioning (DIF) by means of recursive partitioning techniques is proposed. We assume an extension of the Rasch model that allows for DIF being induced by an arbitrary number of covariates for each item. Recursive partitioning on the item level results in one tree for each item and leads to simultaneous selection of items and variables that induce DIF. For each item, it is possible to detect groups of subjects with different item difficulties, defined by combinations of characteristics that are not pre-specified. The way a DIF item is determined by covariates is visualized in a small tree and therefore easily accessible. An algorithm is proposed that is based on permutation tests. Various simulation studies, including the comparison with traditional approaches to identify items with DIF, show the applicability and the competitive performance of the method. Two applications illustrate the usefulness and the advantages of the new method. PMID- 26596722 TI - European Code against Cancer, 4th Edition: Cancer screening. AB - In order to update the previous version of the European Code against Cancer and formulate evidence-based recommendations, a systematic search of the literature was performed according to the methodology agreed by the Code Working Groups. Based on the review, the 4th edition of the European Code against Cancer recommends: "Take part in organized cancer screening programmes for: Bowel cancer (men and women); Breast cancer (women); Cervical cancer (women)." Organized screening programs are preferable because they provide better conditions to ensure that the Guidelines for Quality Assurance in Screening are followed in order to achieve the greatest benefit with the least harm. Screening is recommended only for those cancers where a demonstrated life-saving effect substantially outweighs the potential harm of examining very large numbers of people who may otherwise never have, or suffer from, these cancers, and when an adequate quality of the screening is achieved. EU citizens are recommended to participate in cancer screening each time an invitation from the national or regional screening program is received and after having read the information materials provided and carefully considered the potential benefits and harms of screening. Screening programs in the European Union vary with respect to the age groups invited and to the interval between invitations, depending on each country's cancer burden, local resources, and the type of screening test used For colorectal cancer, most programs in the EU invite men and women starting at the age of 50-60 years, and from then on every 2 years if the screening test is the guaiac-based fecal occult blood test or fecal immunochemical test, or every 10 years or more if the screening test is flexible sigmoidoscopy or total colonoscopy. Most programs continue sending invitations to screening up to the age of 70-75 years. For breast cancer, most programs in the EU invite women starting at the age of 50 years, and not before the age of 40 years, and from then on every 2 years until the age of 70-75 years. For cervical cancer, if cytology (Pap) testing is used for screening, most programs in the EU invite women starting at the age of 25-30 years and from then on every 3 or 5 years. If human papillomavirus testing is used for screening, most women are invited starting at the age of 35 years (usually not before age 30 years) and from then on every 5 years or more. Irrespective of the test used, women continue participating in screening until the age of 60 or 65 years, and continue beyond this age unless the most recent test results are normal. PMID- 26596723 TI - Measurement of circulating transcripts and gene cluster analysis predicts and defines therapeutic efficacy of peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumors. AB - BACKGROUND: Peptide receptor radionuclide therapy (PRRT) is an effective method for treating neuroendocrine tumors (NETs). It is limited, however, in the prediction of individual tumor response and the precise and early identification of changes in tumor size. Currently, response prediction is based on somatostatin receptor expression and efficacy by morphological imaging and/or chromogranin A (CgA) measurement. The aim of this study was to assess the accuracy of circulating NET transcripts as a measure of PRRT efficacy, and moreover to identify prognostic gene clusters in pretreatment blood that could be interpolated with relevant clinical features in order to define a biological index for the tumor and a predictive quotient for PRRT efficacy. METHODS: NET patients (n = 54), M: F 37:17, median age 66, bronchial: n = 13, GEP-NET: n = 35, CUP: n = 6 were treated with (177)Lu-based-PRRT (cumulative activity: 6.5-27.8 GBq, median 18.5). At baseline: 47/54 low-grade (G1/G2; bronchial typical/atypical), 31/49 (18)FDG positive and 39/54 progressive. Disease status was assessed by RECIST1.1. Transcripts were measured by real-time quantitative reverse transcription PCR (qRT-PCR) and multianalyte algorithmic analysis (NETest); CgA by enzyme-linked immunosorbent assay (ELISA). Gene cluster (GC) derivations: regulatory network, protein:protein interactome analyses. STATISTICAL ANALYSES: chi-square, non-parametric measurements, multiple regression, receiver operating characteristic and Kaplan-Meier survival. RESULTS: The disease control rate was 72 %. Median PFS was not achieved (follow-up: 1-33 months, median: 16). Only grading was associated with response (p < 0.01). At baseline, 94 % of patients were NETest-positive, while CgA was elevated in 59 %. NETest accurately (89 %, chi(2) = 27.4; p = 1.2 * 10(-7)) correlated with treatment response, while CgA was 24 % accurate. Gene cluster expression (growth factor signalome and metabolome) had an AUC of 0.74 +/- 0.08 (z-statistic = 2.92, p < 0.004) for predicting response (76 % accuracy). Combination with grading reached an AUC: 0.90 +/- 0.07, irrespective of tumor origin. Circulating transcripts correlated accurately (94 %) with PRRT responders (SD+PR+CR; 97 %) vs. non-responders (91 %). CONCLUSIONS: Blood NET transcript levels and the predictive quotient (circulating gene clusters+grading) accurately predicted PRRT efficacy. CgA was non-informative. PMID- 26596726 TI - Defining the Role of PCSK9 Inhibitors in the Treatment of Hyperlipidemia. AB - Statins remain the mainstay of medical cardiovascular risk reduction because of their effectiveness in decreasing low-density lipoprotein cholesterol (LDL-C) as well as some other potentially beneficial effects. The latest US 2013 lipid guidelines essentially recommend only the prescription of a high-dose statin for the high-risk patient. However, both quite old and quite new outcomes evidence, such as reported for ezetimibe, emphasize that LDL-C lowering is, in and of itself, quite important for cardiovascular risk reduction. It appears that the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors represent a major new contribution to this effort, especially for patients with severe familial hypercholesterolemia, proven clinical cardiovascular disease, statin intolerance, or failure to attain an acceptably low LDL-C goal despite maximum available medical management. Very recent clinical trials have proven overwhelmingly the effectiveness and safety of PCSK9 inhibitors for lowering LDL C. Both alirocumab and evolocumab have now been approved by the US FDA and there are some initial favorable outcomes data. This review is intended to summarize available evidence and emphasize the possible clinical role of these inhibitors following the approval of alirocumab and evolocumab. Understanding the negative receptor feedback of PCSK9 and the mechanism and beneficial effect of PCSK9 inhibitors for cardiovascular risk reduction is essential for the up-to-date practitioner of cardiovascular medicine. There is every reasonable hope for significant cardiovascular benefit from these new additions to our medical cardiovascular armamentarium. PMID- 26596725 TI - Embryologically based radical hysterectomy as peritoneal mesometrial resection (PMMR) with pelvic and para-aortic lymphadenectomy for loco-regional tumor control in endometrial cancer: first evidence for efficacy. AB - OBJECTIVE: To evaluate the feasibility and efficacy of embryologically based compartmental surgery for locoregional tumor control in intermediate and high risk endometrial cancer: peritoneal mesometrial resection with therapeutic pelvic and para-aortic lymphadenectomy by robotically assisted laparoscopy. METHODS: 75 consecutive surgically treated patients with uterine malignancies have been analyzed. 68 patients with histologically proven endometrial cancer and complete robotically assisted surgery have been included in this study on morbidity and oncological outcome. 56 % of the patients were at intermediate/high risk with either stage IAG3 or IB (n = 22) or stage II-IV (n = 16). Adjuvant EBRT was offered to three patients only (4 %), whereas five received isolated vaginal brachytherapy (7 %). Indocyanine-green (ICG) fluorescence lymphography is demonstrated being useful for additional intraoperative visualization of the compartment borders and lymphatic drainage to the postponed lymph compartments. RESULTS: After a mean follow-up of 32 months, there were only two loco-regional recurrences (2.9 %). Both recurrences were apparently cured by salvage therapy. 9 patients died; 6 (8.8 %) from metastatic disease (5) or unknown cause (1), 3 (4.4 %) from intercurrent disease without evidence of disease. One patient (1.4 %) experienced a peritoneal carcinosis and is alive. There were 8/68 perioperative complications (12 %). No perioperative mortality was observed. CONCLUSIONS: Embryologically defined compartmental surgery by robotically assisted laparoscopy seems to be feasible and safe in endometrial cancer. The low loco-regional recurrence rate of 2.9 % in spite of a very low percentage of adjuvant radiotherapy and 56 % of intermediate/high risk tumors should stimulate to initiate a multicentre trial to evaluate the value of compartmental surgery for prevention of locoregional recurrence in endometrial cancer. PMID- 26596727 TI - Overview and new results from large-scale excavations in Schoningen. AB - Archaeological finds including spears, other wooden artifacts, lithic artifacts, and bones with impact scars and cut marks document the repeated presence of hominins on the shoreline of an approximately 300,000 year old lake near Schoningen in Northern Germany. Continuing excavations have uncovered in the locality "Schoningen" at least 20 sites dating to the late Lower Paleolithic. Schoningen is therefore not only a singular archaeological site with remarkable finds; it is a vast locality that preserves a multifaceted archaeological landscape with numerous sites. Ongoing excavations have exposed several large surfaces with organic materials dating to MIS 9. In particular, recent excavations have uncovered new sections belonging to the original Spear Horizon from Schoningen 13 II-4 (the Horse Butchery Site). Current research in Schoningen places the exceptional artifacts within a spatial and environmental context, and provides a wealth of new information on the subsistence strategies and settlement dynamics of the inhabitants of these short-term lakeside occupations. Schoningen, with an overall excavated area of 9400 m(2), is one of the largest excavated archaeological localities from MIS 9. Here we present a summary of all the sites, as well as the most relevant excavated areas since 2008 (excavations Tubingen/NLD). PMID- 26596724 TI - Theranostic pretargeted radioimmunotherapy of colorectal cancer xenografts in mice using picomolar affinity 86Y- or 177Lu-DOTA-Bn binding scFv C825/GPA33 IgG bispecific immunoconjugates. AB - PURPOSE: GPA33 is a colorectal cancer (CRC) antigen with unique retention properties after huA33-mediated tumor targeting. We tested a pretargeted radioimmunotherapy (PRIT) approach for CRC using a tetravalent bispecific antibody with dual specificity for GPA33 tumor antigen and DOTA-Bn (radiolanthanide metal) complex. METHODS: PRIT was optimized in vivo by titrating sequential intravenous doses of huA33-C825, the dextran-based clearing agent, and the C825 haptens (177)Lu-or (86)Y-DOTA-Bn in mice bearing the SW1222 subcutaneous (s.c.) CRC xenograft model. RESULTS: Using optimized PRIT, therapeutic indices (TIs) for tumor radiation-absorbed dose of 73 (tumor/blood) and 12 (tumor/kidney) were achieved. Estimated absorbed doses (cGy/MBq) to tumor, blood, liver, spleen, and kidney for single-cycle PRIT were 65.8, 0.9 (TI 73), 6.3 (TI 10), 6.6 (TI 10), and 5.3 (TI 12), respectively. Two cycles of PRIT (66.6 or 111 MBq (177)Lu DOTA-Bn) were safe and effective, with a complete response of established s.c. tumors (100 - 700 mm(3)) in nine of nine mice, with two mice alive without recurrence at >140 days. Tumor log kill in this model was estimated to be 2.1 - 3.0 based on time to 500-mm(3) tumor recurrence. In addition, PRIT dosimetry/diagnosis was performed by PET imaging of the positron-emitting DOTA hapten (86)Y-DOTA-Bn. CONCLUSION: We have developed anti-GPA33 PRIT as a triple step theranostic strategy for preclinical detection, dosimetry, and safe targeted radiotherapy of established human colorectal mouse xenografts. PMID- 26596728 TI - Paleoenvironment and possibilities of plant exploitation in the Middle Pleistocene of Schoningen (Germany). Insights from botanical macro-remains and pollen. AB - Plant use is an elusive issue in Paleolithic archaeology. Due to poor organic preservation in many sites, botanical material is not always present. The sediments in Schoningen, however, contain abundant botanical macro-remains like wood, fruits, seeds, and other parts of plants which offer the opportunity to reconstruct the local vegetation. Combined with palynological results, it is possible to reveal the full potential of this environment to hominins. Ethnobotanical studies of hunter-gatherer societies living in similar environments illustrate the importance of plants for subsistence purposes. The identified taxa from the archaeological horizons at Schoningen include a broad spectrum of potentially exploitable species that could be sources of food, raw material, and firewood. PMID- 26596729 TI - The Michel Benoist and Robert Mulholland yearly European Spine Journal review: a survey of the "medical" articles in the European Spine Journal, 2015. PMID- 26596730 TI - Effectiveness of Riluzole as a pharmacotherapeutic treatment option for early cervical myelopathy: a double-blinded, placebo-controlled randomised controlled trial. AB - PURPOSE: To evaluate the effectiveness of Riluzole as a pharmacotherapeutic treatment option for early cervical myelopathy using clinical parameters and DTI analysis. METHODS: Early cervical myelopathy cases with MJOA scores >=13, were recruited for the double-blinded, placebo-controlled randomised control trial. Thirty cases with fifteen cases each in the test and placebo group were studied. Analysis was done using diffusion tensor imaging (DTI) and clinical evaluation, pre- and post-institution of sodium channel blocker Riluzole for a period of 1 month (50 mg twice daily). Placebo group was treated with Vitamin B complex tablets. Diffusion co-efficient fractional anisotrophy (FA), apparent diffusion co-efficient (ADC), volume ratio (VR), relative anisotrophy (RA) and Eigen vectors were calculated. Outcomes analysis was based on clinical scores of MJOA, Nurick grading, SF-12, NDI, and statistical analysis of DTI datametrics. RESULTS: The mean MJOA score was 15.6 (13-17) with no significant change in the test and control groups. The mean ADC, FA values were 1533.36 (1238-1779) and 494.36 (364 628) and changed to 1531.57 (1312-2091) and 484.86 (294-597), respectively, in the Riluzole group. However, the changes in the values of ADC, FA, and other co efficients including VR, RA and eigenvectors in the two groups were not statistically significant. The functional scores in the SF-12 and NDI questionnaires did not change significantly. CONCLUSIONS: Our study did not show a significant change in the clinical outcome and DTI Indices with the use of Riluzole as a standalone pharmacotherapeutic agent for early cervical myelopathy. More studies may be needed to confirm the usefulness of Riluzole as a treatment option for cervical myelopathy. PMID- 26596731 TI - Correlation between progression-free survival and overall survival in metastatic breast cancer patients receiving anthracyclines, taxanes, or targeted therapies: a trial-level meta-analysis. AB - Over the past decade, several new drugs have received regulatory approval for metastatic breast cancer (MBC). However, some of these approvals were based on improvement in progression-free survival (PFS), without a concomitant increase in overall survival (OS). This has led some to question the utility of using PFS as a measure for drug approval. To address the uncertainty of using PFS as a surrogate for OS in MBC, a systematic literature review followed by a trial-level correlative analysis was conducted in patients receiving anthracyclines, taxanes, or targeted therapies. Electronic databases were searched to identify randomized trials published between January 1990 and August 2015. Data extraction included hazard ratios for PFS (HRPFS) and OS (HROS) between comparative arms as well as trial-level parameters. Weighted multivariate regression analysis was then used to test the strength of the association between HRPFS and HROS. 72 trials providing 84 comparative arms met the inclusion criteria. HRPFS was a significant predictor of HROS (model coefficient = 0.18, p = 0.04). However, only 31% (i.e., model R (2)) of the variability between the PFS-OS association was accounted for. When trials were limited to >=2nd-line setting, the strength of the association improved (model coefficient = 0.40, p < 0.001) and the model R (2) increased to 55%. However, the HRPFS-HROS association was no longer significant when only 1st line trials were considered (p = 0.90). HRPFS is a predictor for HROS in MBC randomized trials. However, the effect was driven by trials in the >=2nd-line setting. Therefore, PFS can be a suitable surrogate for OS in trials evaluating new treatments in the 2nd setting and beyond. The use of PFS alone as a primary trial endpoint in the 1st-line setting is not recommended. PMID- 26596733 TI - Fucosyltransferase 8 expression in breast cancer patients: A high throughput tissue microarray analysis. AB - The aim of this study was to compare the expression of fucosyltransferase 8 (FUT8) in breast cancer tissue and to investigate the relationship between this marker with tumor progression and its applicability to differential diagnosis. An immunohistochemical study was performed for FUT8 using the tissue microarray technique. In addition, the mRNA and protein levels of FUT8 in the tissue were also tested by real-time PCR and Western blot. There was a significant difference in cytoplasmic expression of FUT8 between breast cancer tissue and matched normal tissue (p<0.001). The percent of FUT8 staining in breast cancer tissues ranging from negative, weak positive, positive and strong positive were 2.7%, 40.2%, 54% and 3.2%, respectively. High FUT8 protein expression correlated with lymphatic metastasis (p=0.008) and with stage status (p=0.039). We detected that reduced FUT8 expression correlated with disease-free survival (p=0.02) and overall survival (p=0.04) of breast cancer patients. Expression of FUT8 can stratify breast cancer tissue and may be considered a prognostic marker for breast cancer patients. PMID- 26596735 TI - Assessing the Performance of Metadynamics and Path Variables in Predicting the Binding Free Energies of p38 Inhibitors. AB - The accurate yet efficient evaluation of the free energy profiles of ligand target association is a long sought goal in rational drug design. Methods that calculate the free energy along realistic association pathways, such as metadynamics, have been shown to provide reliable profiles, while accounting properly for solvation and target flexibility. However, these approaches usually require prohibitive computational resources and expert human intervention. Here, we show how multiple walkers metadynamics, when performed with optimal path collective variables (PCV), provides in a predetermined amount of computer time an accurate set of free energy profiles for a series of p38 inhibitors. The chosen test set, spanning a wide range of activity, is a challenging benchmark, both for computational methods and for human intuition, as the correct order for the binding affinity cannot be easily guessed. An excellent ranking of the ligands was obtained with minimal human assistance, an important step toward a fully automated pharmaceutical work-flow. PMID- 26596734 TI - Synthesis, Luminescent Properties of aza-Boron-Diquinomethene Difluoride Complexes and Their Application for Fluorescent Security Inks. AB - Two aza-boron-diquinomethene (aza-BODIQU) complexes bearing phenyl and carbazyl substituents were synthesized and characterized. Their photophysical properties were investigated systematically via spectroscopic and theoretical methods. Both complexes exhibit strong (1)pi-pi* transition absorptions (lambda(abs) = 400-540 nm) and intense fluorescent emissions (lambda(em) = 440-600 nm, Phi(PL) = 0.93 and 0.78) in CH2Cl2 solution and in solid state at room temperature. Compared to the complex with phenyl groups, the complex bearing carbazyl groups shows significant bathochromic shift in both absorption and emission. This could be attributed to the larger pi-electron conjugation of the carbazole unit and intramolecular charge transfer feature from carbazole to aza-BODIQU component. In addition, the complexes exhibit intense photoluminescence and good stability on antacid, anti-alkali and stability in printing ink samples, which makes them potential dopants for the application of fluorescent security inks. PMID- 26596736 TI - Visualizing the Induced Binding of SH2-Phosphopeptide. AB - Approximately 100 proteins in the human genome contain an SH2 domain recognizing small flexible phosphopeptides. It is therefore important to understand in atomistic detail the way these peptides bind and the conformational changes that take place upon binding. Here, we obtained several spontaneous binding events between the p56 lck SH2 domain and the pYEEI peptide within 2 A RMSD from the crystal structure and with kinetic rates compatible with experiments using high throughput molecular dynamics simulations. Binding is achieved in two phases, fast contacts of the charged phospho-tyrosine and then rearrangement of the ligand involving the stabilization of two important loops in the SH2 domain. These observations provide insights into the binding pathways and induced conformations of the SH2-phosphopeptide complex which, due to the characteristics of SH2 domains, should be relevant for other SH2 recognition peptides. PMID- 26596737 TI - Dynamic Multiscale Quantum Mechanics/Electromagnetics Simulation Method. AB - A newly developed hybrid quantum mechanics and electromagnetics (QM/EM) method [Yam et al. Phys. Chem. Chem. Phys.2011, 13, 14365] is generalized to simulate the real time dynamics. Instead of the electric and magnetic fields, the scalar and vector potentials are used to integrate Maxwell's equations in the time domain. The TDDFT-NEGF-EOM method [Zheng et al. Phys. Rev. B2007, 75, 195127] is employed to simulate the electronic dynamics in the quantum mechanical region. By allowing the penetration of a classical electromagnetic wave into the quantum mechanical region, the electromagnetic wave for the entire simulating region can be determined consistently by solving Maxwell's equations. The transient potential distributions and current density at the interface between quantum mechanical and classical regions are employed as the boundary conditions for the quantum mechanical and electromagnetic simulations, respectively. Charge distribution, current density, and potentials at different temporal steps and spatial scales are integrated seamlessly within a unified computational framework. PMID- 26596738 TI - Gas-Phase Chemical Dynamics Simulations on the Bifurcating Pathway of the Pimaradienyl Cation Rearrangement: Role of Enzymatic Steering in Abietic Acid Biosynthesis. AB - The biosynthesis of abietadiene is the first biosynthetically relevant process shown to involve a potential energy surface with a bifurcating reaction pathway. Herein, we use gas-phase, enzyme-free direct dynamics simulations to study the behavior of the key reaction (bifurcating) step, which is conversion of the C20 pimaradienyl cation to the abietadienyl cation. In a previous study (J. Am. Chem. Soc.2011, 133, 8335), a truncated C10 model was used to investigate this reaction. The current work finds that the complete C20 pimaradienyl cation gives reaction dynamics similar to that reported for the truncated C10 model. We find that in the absence of the enzyme, the C20 abietadienyl cation is generated in almost equal quantity (1.3:1) as an unobserved (in nature) seven-membered ring product. These simulations allude to a need for abietadiene synthase to steer the reaction to avoid generation of the seven-membered ring product. The methodology of post-transition state chemical dynamics simulations is also considered. The trajectories are initiated at the rate-controlling transition state (TS) separating the pimaradienyl and abietadienyl cations. Accurate results are expected for the short-time direct motion from this TS toward the abietadienyl cation. However, the dynamics may be less accurate for describing the unimolecular reactions that occur in moving toward the pimaradienyl cation, due to the unphysical flow of zero-point energy. PMID- 26596739 TI - Momentum Distribution as a Fingerprint of Quantum Delocalization in Enzymatic Reactions: Open-Chain Path-Integral Simulations of Model Systems and the Hydride Transfer in Dihydrofolate Reductase. AB - The inclusion of nuclear quantum effects such as zero-point energy and tunneling is of great importance in studying condensed phase chemical reactions involving the transfer of protons, hydrogen atoms, and hydride ions. In the current work, we derive an efficient quantum simulation approach for the computation of the momentum distribution in condensed phase chemical reactions. The method is based on a quantum-classical approach wherein quantum and classical simulations are performed separately. The classical simulations use standard sampling techniques, whereas the quantum simulations employ an open polymer chain path integral formulation which is computed using an efficient Monte Carlo staging algorithm. The approach is validated by applying it to a one-dimensional harmonic oscillator and symmetric double-well potential. Subsequently, the method is applied to the dihydrofolate reductase (DHFR) catalyzed reduction of 7,8-dihydrofolate by nicotinamide adenine dinucleotide phosphate hydride (NADPH) to yield S-5,6,7,8 tetrahydrofolate and NADP(+). The key chemical step in the catalytic cycle of DHFR involves a stereospecific hydride transfer. In order to estimate the amount of quantum delocalization, we compute the position and momentum distributions for the transferring hydride ion in the reactant state (RS) and transition state (TS) using a recently developed hybrid semiempirical quantum mechanics-molecular mechanics potential energy surface. Additionally, we examine the effect of compression of the donor-acceptor distance (DAD) in the TS on the momentum distribution. The present results suggest differential quantum delocalization in the RS and TS, as well as reduced tunneling upon DAD compression. PMID- 26596740 TI - Balanced and Bias-Corrected Computation of Conformational Entropy Differences for Molecular Trajectories. AB - The mutual information (MI) expansion is applied to two molecular systems to probe algorithms that serve to estimate conformational entropy differences more precisely. The individual terms of the MI expansion are evaluated with a histogram method. Internal coordinates are used to avoid spurious correlations, which would require higher order terms in the MI expansion. Two approaches are applied that compensate for systematic errors that occur with a histogram method: (1) Simulation data are balanced by using the same number of coordinate sets (frames) for both conformer domains considered for the entropy difference computation. Balancing puts fluctuations of the histogram bin contents on the same level for both conformer domains, allowing efficient error cancellation. (2) Bias correction compensates for systematic deviations due to a finite number of frames per bin. Applying both corrections improves the precision of entropy differences drastically. Estimates of entropy differences are compared to thermodynamic benchmarks of a simple polymer model and trialanine, where excellent agreement was found. For trialanine, the average error for the estimated conformational entropy difference is only 0.3 J/(mol K), which is 100 times smaller than without applying the two corrections. Guidelines are provided for efficiently estimating conformational entropies. The program ENTROPICAL, used for the computations, is made available, which can be used for molecular dynamics or Monte Carlo simulation data on macromolecules like oligopeptides, polymers, proteins, and ligands. PMID- 26596741 TI - Integral Equation Theory of Molecular Solvation Coupled with Quantum Mechanical/Molecular Mechanics Method in NWChem Package. AB - We have developed a hybrid approach based on a combination of integral equation theory of molecular liquids and quantum mechanical/molecular mechanics (QM/MM) methodology in NorthWest computational Chemistry (NWChem) software package. We have split the evaluations into consequent QM/MM and statistical mechanics calculations based on the one-dimensional reference interaction site model, which allows us to reduce significantly the time of computation. The method complements QM/MM capabilities existing in the NWChem package. The accuracy of the presented method was tested through computation of the water structure around several organic solutes and their hydration free energies. We have also evaluated the solvent effect on the conformational equilibria. The applicability and limitations of the developed approach are discussed. PMID- 26596742 TI - Verdict: Time-Dependent Density Functional Theory "Not Guilty" of Large Errors for Cyanines. AB - We assess the accuracy of eight Minnesota density functionals (M05 through M08 SO) and two others (PBE and PBE0) for the prediction of electronic excitation energies of a family of four cyanine dyes. We find that time-dependent density functional theory (TDDFT) with the five most recent of these functionals (from M06-HF through M08-SO) is able to predict excitation energies for cyanine dyes within 0.10-0.36 eV accuracy with respect to the most accurate available Quantum Monte Carlo calculations, providing a comparable accuracy to the latest generation of CASPT2 calculations, which have errors of 0.16-0.34 eV. Therefore previous conclusions that TDDFT cannot treat cyanine dyes reasonably accurately must be revised. PMID- 26596743 TI - Toward a Unique Definition of the Local Spin. AB - In this work, we demonstrate that there is a continuum of different formulations for the decomposition of ?S(2)? that fulfills all physical requirements imposed to date. We introduce a new criterion based upon the behavior of single-electron systems to fix the value of the parameter defining that continuum, and thus we put forward a new general formula applicable for both single-determinant and correlated wave functions. The numerical implementation has been carried out in the three-dimensional physical space for several atomic definitions. A series of representative closed-shell and open-shell systems have been used to illustrate the performance of this new decomposition scheme against other existing approaches. Unlike other decompositions of ?S(2)?, the new scheme provides very small local-spin values for genuine diamagnetic molecules treated with correlated wave functions, in conformity with the physical expectations. PMID- 26596744 TI - Why Cyclooctatetraene Is Highly Stabilized: The Importance of "Two-Way" (Double) Hyperconjugation. AB - Despite its highly nonplanar geometry, the tub-shaped D2d cyclooctatetraene (COT) minimum is far from being an unconjugated polyene model devoid of important pi interactions. The warped skeleton of D2d COT results in the large stabilization (41.1 kcal/mol) revealed by its isodesmic bond separation energy (BSE). This originates largely from the "two-way" hyperconjugation, back and forth across the C-C single bonds, between the CC/CH sigma(sigma*) and the C?C (pi*)pi orbitals. These hyperconjugative effects compensate for the substantial, but not complete, loss of pi conjugation upon ring puckering. C-C single bond rotation of 1,3 butadiene involves a similar interplay between pi conjugation and "two-way" double hyperconjugation and serves as a simple model for the inversion of D2d to D4h COT. The perpendicular rotational transition states of many other systems, e.g., the allyl cation, styrene, biphenyl, and ethene, are stabilized similarly by "two-way" hyperconjugation. PMID- 26596745 TI - Physisorption, Diffusion, and Chemisorption Pathways of H2 Molecule on Graphene and on (2,2) Carbon Nanotube by First Principles Calculations. AB - We investigate the interaction of the H2 molecule with a graphene layer and with a small-radius carbon nanotube using ab initio density functional methods. H2 can interact with carbon materials like graphene, graphite, and nanotubes either through physisorption or chemisorption. The physisorption mechanism involves the binding of the hydrogen molecule on the material as a result of weak van der Waals forces, while the chemisorption mechanism involves the dissociation of the hydrogen molecule and the ensuing reaction of both hydrogen atoms with the unsatured C-C bonds to form C-H bonds. In our calculations, we take into account van der Waals interactions using a recently developed method based on the concept of maximally localized Wannier functions. We explore several adsorption sites and orientations of the hydrogen molecule relative to the carbon surface and compute the associated binding energies and adsorption potentials. The most stable physisorbed state on graphene is found to be the hollow site in the center of a carbon hexagon, with a binding energy of -48 meV, in good agreement with experimental results. The analysis of diffusion pathways between different physisorbed states on graphene shows that molecular hydrogen can easily diffuse at room temperature from one configuration to another, which are separated by energy barriers as small as 10 meV. We also compute the potential energy surfaces for the dissociative chemisorption of H2 on highly symmetric sites of graphene, the lowest activation barrier found being 2.67 eV. Much weaker adsorption characterizes instead the physisorption interaction of the H2 molecule with the small radius (2,2) CNT. The barriers for H2 dissociation on the nanotube external surface are significantly lowered with respect to the graphene case, showing the remarkable effect of the substrate curvature in promoting hydrogen dissociation. PMID- 26596746 TI - Formation Enthalpies Derived from Pairwise Interactions: A Step toward More Transferable Reactive Potentials for Organic Compounds. AB - A new approach to the development and parametrization of reactive potentials for organic compounds is put forward. As a byproduct of preliminary efforts in this direction, the performance of a simple representation of the energy of equilibrium structures in term of pairwise atom-atom and bond-bond contributions is investigated. For now, each contribution is assumed constant, given the multiplicity of covalent bonds, rather than computed on-the-fly from geometries and bond orders. In spite of this rough approximation, the approach performs remarkably well by comparison with semiempirical quantum chemical methods. Nevertheless, further refinement proves necessary for some unstable species involved in chemical reactions. As it stands, the present model appears as a promising basis in view of less empirical and more versatile alternatives to group contribution methods for the fast prediction of heats of formation, although much work remains to be done to demonstrate its value as a starting point toward better reactive potentials. PMID- 26596747 TI - Suitability of the MARTINI Force Field for Use with Gas-Phase Protein Complexes. AB - The MARTINI coarse-grained force field [Monticelli, L. et al. J. Chem. Theory Comput.2008, 4, 819-834] is examined for use in molecular dynamics simulations of the dissociation of gas-phase protein complexes. Coarse-grained force fields allow longer time scales and larger systems to be treated compared with all-atom force fields. In this work, results for the dissociation of the cytochrome c' dimer using MARTINI are compared with published studies using the OPLS-AA/L all atom force field. Several structural parameters such as the minimum distance between monomers, radius of gyration, and root-mean-square deviation as well as potential energy contributions (Lennard-Jones and Coulomb) are calculated as a function of the center of mass distance. The MARTINI force field semiquantitatively reproduces the results of previous all-atom studies but appears to be somewhat too attractive. PMID- 26596748 TI - On Extension of the Current Biomolecular Empirical Force Field for the Description of Halogen Bonds. AB - Until recently, the description of halogen bonding by standard molecular mechanics has been poor, owing to the lack of the so-called sigma hole localized at the halogen. This region of positive electrostatic potential located on top of a halogen atom explains the counterintuitive attraction of halogenated compounds interacting with Lewis bases. In molecular mechanics, the sigma hole is modeled by a massless point charge attached to the halogen atom and referred to as an explicit sigma hole (ESH). Here, we introduce and compare three methods of ESH construction, which differ in the complexity of the input needed. The molecular mechanical dissociation curves of three model complexes containing bromine are compared with accurate CCSD(T)/CBS data. Furthermore, the performance of the Amber force field enhanced by the ESH on geometry characteristics is tested on the casein kinase 2 protein complex with seven brominated inhibitors. It is shown how various schemes depend on the selection of the ESH parameters and to what extent the energies and geometries are reliable. The charge of 0.2e placed 1.5 A from the bromine atomic center is suggested as a universal model for the ESH. PMID- 26596749 TI - On the Origin of (35/37)Cl Isotope Effects on (195)Pt NMR Chemical Shifts. A Density Functional Study. AB - Zero-point vibrationally averaged (rg(0)) structures were computed at the PBE0/SDD/6-31G* level for [Pt(35)Cl6](2-) and [Pt(37)Cl6](2-), for the [Pt(35)Cln(37)Cl5-n(H2O)](-) (n = 0-5), cis-Pt(35)Cln(37)Cl(4-n)(H2O)2 (n = 0-4), and fac-[Pt(35)Cln(37)Cl(3-n)(H2O)3](+) (n = 0-3) isotopologues and isotopomers. Magnetic (195)Pt shielding constants, computed at the ZORA-SO/PW91/QZ4P/TZ2P level, were used to evaluate the corresponding (35/37)Cl isotope shifts in the experimental (195)Pt NMR spectra. While the observed effects are reproduced reasonably well computationally in terms of qualitative trends and the overall order of magnitude (ca. 1 ppm), quantitative agreement with experiment is not yet achieved. Only small changes in Pt-Cl and Pt-O bond lengths upon isotopic substitution, on the order of femtometers, are necessary to produce the observed isotope shifts. PMID- 26596750 TI - Photostability Mechanisms in Human gammaB-Crystallin: Role of the Tyrosine Corner Unveiled by Quantum Mechanics and Hybrid Quantum Mechanics/Molecular Mechanics Methodologies. AB - The tyrosine corner is proposed as a featured element to enhance photostability in human gammaB-crystallin when exposed to UV irradiation. Different ultrafast processes were studied by multiconfigurational quantum chemistry coupled to molecular mechanics: photoinduced singlet-singlet energy, electron and proton transfer, as well as population and evolution of triplet states. The minimum energy paths indicate two possible UV photoinduced events: forward-backward proton-coupled electron transfer providing to the system a mechanism for ultrafast internal conversion, and energy transfer, leading to fluorescence or phosphorescence. The obtained results are in agreement with the available experimental data, being in line with the proposed photoinduced processes for the different tyrosine environments within gammaB-crystallin. PMID- 26596751 TI - Graphite and Hexagonal Boron-Nitride have the Same Interlayer Distance. Why? AB - Graphite and hexagonal boron nitride (h-BN) are two prominent members of the family of layered materials possessing a hexagonal lattice structure. While graphite has nonpolar homonuclear C-C intralayer bonds, h-BN presents highly polar B-N bonds resulting in different optimal stacking modes of the two materials in the bulk form. Furthermore, the static polarizabilities of the constituent atoms considerably differ from each other, suggesting large differences in the dispersive component of the interlayer bonding. Despite these major differences, both materials present practically identical interlayer distances. To understand this finding, a comparative study of the nature of the interlayer bonding in both materials is presented. A full lattice sum of the interactions between the partially charged atomic centers in h-BN results in vanishingly small contributions to the interlayer binding energy. Higher order electrostatic multipoles, exchange, and short-range correlation Kohn-Sham contributions are found to be very similar in both materials and to almost completely cancel out by the kinetic energy term, which partly represents the effects of Pauli repulsions, at physically relevant interlayer distances, resulting in a marginal effective contribution to the interlayer binding. Further analysis of the dispersive energy term reveals that despite the large differences in the individual atomic polarizabilities, the heteroatomic B-N C6 coefficient is very similar to the homoatomic C-C coefficient in the hexagonal bulk form, resulting in very similar dispersive contribution to the interlayer binding. The overall binding energy curves of both materials are thus very similar, predicting practically the same interlayer distance and very similar binding energies. The conclusions drawn here regarding the role of electrostatic interactions between partially charged atomic centers for the interlayer binding of h-BN are of a general nature and are expected to hold true for many other polar layered systems. PMID- 26596752 TI - On Atomistic and Coarse-Grained Models for C60 Fullerene. AB - Many atomistic and coarse-grained simulations of fullerene and fullerene derivatives are reported in the literature, but validation of both atomistic and coarse-grained models has been very limited. Here, we report a thorough validation of several all-atom fullerene models and refinement of the MARTINI coarse-grained (CG) fullerene model. The all-atom model by Girifalco had been parametrized using only solid-state properties (lattice constant, heat of sublimation), but it performs well also in the liquid state in terms of partitioning between different solvents. The new MARTINI CG model is optimized by matching experimental free energies of transfer between different solvents (for fullerene-solvent interactions) and atomistic fullerene-fullerene potentials of mean force (PMF) in water and in octane (for fullerene-fullerene interactions). The model gives reasonable results for solid-state properties and also reproduces atomistic results on the PMF in a lipid membrane. We conclude that the new MARTINI model is suitable for large-scale simulations of the interaction of fullerene with water, organic solvents, and lipid membranes. PMID- 26596753 TI - Toward Quantitative Coarse-Grained Models of Lipids with Fluids Density Functional Theory. AB - We describe methods to determine optimal coarse-grained models of lipid bilayers for use in fluids density functional theory (fluids-DFT) calculations. Both coarse-grained lipid architecture and optimal parametrizations of the models based on experimental measures are discussed in the context of dipalmitoylphosphatidylcholine (DPPC) lipid bilayers in water. The calculations are based on a combination of the modified-iSAFT theory for bonded systems and an accurate fundamental measures theory (FMT) for hard sphere reference fluids. We furthermore discuss a novel approach for pressure control in the fluids-DFT calculations that facilitates both partitioning studies and zero tension control for the bilayer studies. A detailed discussion of the numerical implementations for both solvers and pressure control capabilities are provided. We show that it is possible to develop a coarse-grained lipid bilayer model that is consistent with experimental properties (thickness and area per lipid) of DPPC provided that the coarse-graining is not too extreme. As a final test of the model, we find that the predicted area compressibility moduli and lateral pressure profiles of the optimized models are in reasonable agreement with prior results. PMID- 26596754 TI - Reaction Event Counting Statistics of Biopolymer Reaction Systems with Dynamic Heterogeneity. AB - We investigate the reaction event counting statistics (RECS) of an elementary biopolymer reaction in which the rate coefficient is dependent on states of the biopolymer and the surrounding environment and discover a universal kinetic phase transition in the RECS of the reaction system with dynamic heterogeneity. From an exact analysis for a general model of elementary biopolymer reactions, we find that the variance in the number of reaction events is dependent on the square of the mean number of the reaction events when the size of measurement time is small on the relaxation time scale of rate coefficient fluctuations, which does not conform to renewal statistics. On the other hand, when the size of the measurement time interval is much greater than the relaxation time of rate coefficient fluctuations, the variance becomes linearly proportional to the mean reaction number in accordance with renewal statistics. Gillespie's stochastic simulation method is generalized for the reaction system with a rate coefficient fluctuation. The simulation results confirm the correctness of the analytic results for the time dependent mean and variance of the reaction event number distribution. On the basis of the obtained results, we propose a method of quantitative analysis for the reaction event counting statistics of reaction systems with rate coefficient fluctuations, which enables one to extract information about the magnitude and the relaxation times of the fluctuating reaction rate coefficient, without a bias that can be introduced by assuming a particular kinetic model of conformational dynamics and the conformation dependent reactivity. An exact relationship is established between a higher moment of the reaction event number distribution and the multitime correlation of the reaction rate for the reaction system with a nonequilibrium initial state distribution as well as for the system with the equilibrium initial state distribution. PMID- 26596755 TI - Improving the Efficiency of Protein-Ligand Binding Free-Energy Calculations by System Truncation. AB - We have studied whether the efficiency of alchemical free-energy calculations with the Bennett acceptance ratio method of protein-ligand binding energies can be improved by simulating only part of the protein. To this end, we solvated the full protein in a spherical droplet with a radius of 46 A, surrounded by a vacuum. Then, we systematically reduced the size of the droplet and at the same time ignored protein residues that were outside the droplet. Radii of 40-15 A were tested. Ten inhibitors of the blood clotting factor Xa were studied, and the results were compared to an earlier study in which the protein was solvated in a periodic box, showing complete agreement between the two sets of calculations within statistical uncertainty. We then show that the simulated system can be truncated down to 15 A, without changing the calculated affinities by more than 0.5 kJ/mol on average (maximum difference of 1.4 kJ/mol). Moreover, we show that reducing the number of intermediate states in the calculations from eleven to three gave deviations that, on average, were only 0.5 kJ/mol (maximum of 1.4 kJ/mol). Together, these results show that truncation is an appropriate way to improve the efficiency of free-energy calculations for small mutations that preserve the net charge of the ligand. In fact, each calculation of a relative binding affinity requires only six simulations, each of which takes ~15 CPU h of computation on a single processor. PMID- 26596756 TI - Optimization of the OPLS-AA Force Field for Long Hydrocarbons. AB - The all-atom optimized potentials for liquid simulations (OPLS-AA) force field is a popular force field for simulating biomolecules. However, the current OPLS parameters for hydrocarbons developed using short alkanes cannot reproduce the liquid properties of long alkanes in molecular dynamics simulations. Therefore, the extension of OPLS-AA to (phospho)lipid molecules required for the study of biological membranes was hampered in the past. Here, we optimized the OPLS-AA force field for both short and long hydrocarbons. Following the framework of the OPLS-AA parametrization, we refined the torsional parameters for hydrocarbons by fitting to the gas-phase ab initio energy profiles calculated at the accurate MP2/aug-cc-pVTZ theory level. Additionally, the depth of the Lennard-Jones potential for methylene hydrogen atoms was adjusted to reproduce the densities and the heats of vaporization of alkanes and alkenes of different lengths. Optimization of partial charges finally allowed to reproduce the gel-to-liquid phase transition temperature for pentadecane and solvation free energies. It is shown that the optimized parameter set (L-OPLS) yields improved hydrocarbon diffusion coefficients, viscosities, and gauche-trans ratios. Moreover, its applicability for lipid bilayer simulations is shown for a GMO bilayer in its liquid-crystalline phase. PMID- 26596757 TI - Construction of the Free Energy Landscape of Peptide Aggregation from Molecular Dynamics Simulations. AB - To describe the structure and dynamics of oligomers during peptide aggregation, a method is proposed that considers both the intramolecular and intermolecular structures of the multimolecule system and correctly accounts for its degeneracy. The approach is based on the "by-parts" strategy, which partitions a complex molecular system into parts, determines the metastable conformational states of each part, and describes the overall conformational state of the system in terms of a product basis of the states of the parts. Starting from a molecular dynamics simulation of n molecules, the method consists of three steps: (i) characterization of the intramolecular structure, that is, of the conformational states of a single molecule in the presence of the other molecules (e.g., beta strand or random coil); (ii) characterization of the intermolecular structure through the identification of all occurring aggregate states of the peptides (dimers, trimers, etc.); and (iii) construction of the overall conformational states of the system in terms of a product basis of the n "single-molecule" states and the aggregate states. Considering the Alzheimer beta-amyloid peptide fragment Abeta16-22 as a first application, about 700 overall conformational states of the trimer (Abeta16-22)3 were constructed from all-atom molecular dynamics simulation in explicit water. Based on these states, a transition network reflecting the free energy landscape of the aggregation process can be constructed that facilitates the identification of the aggregation pathways. PMID- 26596758 TI - Toward the Quantum Chemical Calculation of NMR Chemical Shifts of Proteins. 2. Level of Theory, Basis Set, and Solvents Model Dependence. AB - It has been demonstrated that the fragmentation scheme of our adjustable density matrix assembler (ADMA) approach for the quantum chemical calculations of very large systems is well-suited to calculate NMR chemical shifts of proteins [ Frank et al. Proteins2011, 79, 2189-2202 ]. The systematic investigation performed here on the influences of the level of theory, basis set size, inclusion or exclusion of an implicit solvent model, and the use of partial charges to describe additional parts of the macromolecule on the accuracy of NMR chemical shifts demonstrates that using a valence triple-zeta basis set leads to large improvement compared to the results given in the previous publication. Additionally, moving from the B3LYP to the mPW1PW91 density functional and including partial charges and implicit solvents gave the best results with mean absolute errors of 0.44 ppm for hydrogen atoms excluding H(N) atoms and between 1.53 and 3.44 ppm for carbon atoms depending on the size and also on the accuracy of the protein structure. Polar hydrogen and nitrogen atoms are more difficult to predict. For the first, explicit hydrogen bonds to the solvents need to be included and, for the latter, going beyond DFT to post-Hartree-Fock methods like MP2 is probably required. Even if empirical methods like SHIFTX+ show similar performance, our calculations give for the first time very reliable chemical shifts that can also be used for complexes of proteins with small-molecule ligands or DNA/RNA. Therefore, taking advantage of its ab initio nature, our approach opens new fields of application that would otherwise be largely inaccessible due to insufficient availability of data for empirical parametrization. PMID- 26596759 TI - Magnesium Ion-Water Coordination and Exchange in Biomolecular Simulations. AB - Magnesium ions have an important role in the structure and folding mechanism of ribonucleic acid systems. To properly simulate these biophysical processes, the applied molecular models should reproduce, among other things, the kinetic properties of the ions in water solution. Here, we have studied the kinetics of the binding of magnesium ions with water molecules and nucleic acid systems using molecular dynamics simulation in detail. We have validated the parameters used in biomolecular force fields, such as AMBER and CHARMM, for Mg(2+) ions and also for the biologically relevant ions Na(+), K(+), and Ca(2+) together with three different water models (TIP3P, SPC/E, and TIP5P). The results show that Mg(2+) ions have a slower exchange rate than Na(+), K(+), and Ca(2+) in agreement with the experimental trend, but the simulated value underestimates the experimentally observed Mg(2+)-water exchange rate by several orders of magnitude, irrespective of the force field and water model. A new set of parameters for Mg(2+) was developed to reproduce the experimental kinetic data. This set also leads to better reproduction of structural data than existing models. We have applied the new parameter set to Mg(2+) binding with a monophosphate model system and with the purine riboswitch, add A-riboswitch. In line with the Mg(2+)-water results, the newly developed parameters show a better description of the structure and kinetics of the Mg(2+)-phosphate binding than all other models. The characterization of the ion binding to the riboswitch system shows that the new parameter set does not affect the global structure of the ribonucleic acid system or the number of ions involved in direct or indirect binding. A slight decrease in the number of water-bridged contacts between A-riboswitch and the Mg(2+) ion is observed. The results support the ability of the newly developed parameters to improve the kinetic description of the Mg(2+) and phosphate ions and their applicability in nucleic acid simulation. PMID- 26596760 TI - An Assessment of the vdW-TS Method for Extended Systems. AB - The Tkatchenko-Scheffler vdW-TS method [Phys. Rev. Lett.2009, 102, 073005] has been implemented in a plane-wave DFT code and used to characterize several dispersion-dominated systems, including layered materials, noble-gas solids, and molecular crystals. Full optimizations of the structures, including relaxation of the stresses on the unit cells, were carried out. Internal geometrical parameters, lattice constants, bulk moduli, and cohesive energies are reported and compared to experimental results. PMID- 26596761 TI - An Improved meta-GGA Correlation Functional of the Lap Family. PMID- 26596762 TI - A new insight into the interaction of cisplatin with DNA: ROA spectroscopic studies on the therapeutic effect of the drug. AB - Raman optical activity (ROA) spectroscopy has been applied for the first time to study the interaction of cisplatin with DNA. The knowledge about the structure of DNA-metal ion cross-links and hence the mechanism of the drug action is fundamental for the development of new antitumor drugs. At the same time, there is an urgent need to search for new methods for monitoring of this effect at the therapeutic dose of a drug. We have demonstrated that ROA spectroscopy is a sensitive technique with the capability to follow the structural alteration of the whole DNA molecule upon drug binding via a direct observation of transformation undergoing within chiral sugar moieties. A ROA profile delivers clear evidence of a partial transition from the B-DNA to the A-form due to the formation of cisplatin-DNA cross-links. PMID- 26596763 TI - Down-regulation of tomato PHYTOL KINASE strongly impairs tocopherol biosynthesis and affects prenyllipid metabolism in an organ-specific manner. AB - Tocopherol, a compound with vitamin E (VTE) activity, is a conserved constituent of the plastidial antioxidant network in photosynthetic organisms. The synthesis of tocopherol involves the condensation of an aromatic head group with an isoprenoid prenyl side chain. The latter, phytyl diphosphate, can be derived from chlorophyll phytol tail recycling, which depends on phytol kinase (VTE5) activity. How plants co-ordinate isoprenoid precursor distribution for supplying biosynthesis of tocopherol and other prenyllipids in different organs is poorly understood. Here, Solanum lycopersicum plants impaired in the expression of two VTE5-like genes identified by phylogenetic analyses, named SlVTE5 and SlFOLK, were characterized. Our data show that while SlFOLK does not affect tocopherol content, the production of this metabolite is >80% dependent on SlVTE5 in tomato, in both leaves and fruits. VTE5 deficiency greatly impacted lipid metabolism, including prenylquinones, carotenoids, and fatty acid phytyl esters. However, the prenyllipid profile greatly differed between source and sink organs, revealing organ-specific metabolic adjustments in tomato. Additionally, VTE5-deficient plants displayed starch accumulation and lower CO2 assimilation in leaves associated with mild yield penalty. Taken together, our results provide valuable insights into the distinct regulation of isoprenoid metabolism in leaves and fruits and also expose the interaction between lipid and carbon metabolism, which results in carbohydrate export blockage in the VTE5-deficient plants, affecting tomato fruit quality. PMID- 26596764 TI - CHASE domain-containing receptors play an essential role in the cytokinin response of the moss Physcomitrella patens. AB - While the molecular basis for cytokinin action is quite well understood in flowering plants, little is known about the cytokinin signal transduction in early diverging land plants. The genome of the bryophyte Physcomitrella patens (Hedw.) B.S. encodes three classical cytokinin receptors, the CHASE domain containing histidine kinases, CHK1, CHK2, and CHK3. In a complementation assay with protoplasts of receptor-deficient Arabidopsis thaliana as well as in cytokinin binding assays, we found evidence that CHK1 and CHK2 receptors can function in cytokinin perception. Using gene targeting, we generated a collection of CHK knockout mutants comprising single (Deltachk1, Deltachk2, Deltachk3), double (Deltachk1,2, Deltachk1,3, Deltachk2,3), and triple (Deltachk1,2,3) mutants. Mutants were characterized for their cytokinin response and differentiation capacities. While the wild type did not grow on high doses of cytokinin (1 uM benzyladenine), the Deltachk1,2,3 mutant exhibited normal protonema growth. Bud induction assays showed that all three cytokinin receptors contribute to the triggering of budding, albeit to different extents. Furthermore, while the triple mutant showed no response in this bioassay, the remaining mutants displayed budding responses in a diverse manner to different types and concentrations of cytokinins. Determination of cytokinin levels in mutants showed no drastic changes for any of the cytokinins; thus, in contrast to Arabidopsis, revealing only small impacts of cytokinin signaling on homeostasis. In summary, our study provides a first insight into the molecular action of cytokinin in an early diverging land plant and demonstrates that CHK receptors play an essential role in bud induction and gametophore development. PMID- 26596765 TI - TCP2 positively regulates HY5/HYH and photomorphogenesis in Arabidopsis. AB - Light regulates plant growth and development via multiple photoreceptors including phytochromes and cryptochromes. Although the functions of photoreceptors have been studied extensively, questions remain regarding the involvement of cryptochromes in photomorphogenesis. In this study, we identified a protein, TEOSINTE-LIKE1, CYCLOIDEA, and PROLIFERATING CELL FACTOR 2 (TCP2), which interacts with the cryptochrome 1 (CRY1) protein in yeast and plant cells via the N-terminal domains of both proteins. Transgenic plants overexpressing TCP2 displayed a light-dependent short hypocotyl phenotype, especially in response to blue light. Moreover, light affected TCP2 expression in a wavelength dependent manner and TCP2 positively regulates mRNA expression of HYH and HY5. These results support the hypothesis that TCP2 is a transcription activator which acts downstream of multiple photoreceptors, including CRY1. PMID- 26596766 TI - Synergistic action of histone acetyltransferase GCN5 and receptor CLAVATA1 negatively affects ethylene responses in Arabidopsis thaliana. AB - GENERAL CONTROL NON-REPRESSIBLE 5 (GCN5) is a histone acetyltransferase (HAT) and the catalytic subunit of several multicomponent HAT complexes that acetylate lysine residues of histone H3. Mutants in AtGCN5 display pleiotropic developmental defects including aberrant meristem function. Shoot apical meristem (SAM) maintenance is regulated by CLAVATA1 (CLV1), a receptor kinase that controls the size of the shoot and floral meristems. Upon activation through CLV3 binding, CLV1 signals to the transcription factor WUSCHEL (WUS), restricting WUS expression and thus the meristem size. We hypothesized that GCN5 and CLV1 act together to affect SAM function. Using genetic and molecular approaches, we generated and characterized clv gcn5 mutants. Surprisingly, the clv1-1 gcn5-1 double mutant exhibited constitutive ethylene responses, suggesting that GCN5 and CLV signaling act synergistically to inhibit ethylene responses in Arabidopsis. This genetic and molecular interaction was mediated by ETHYLENE INSENSITIVE 3/ EIN3-LIKE1 (EIN3/EIL1) transcription factors. Our data suggest that signals from the CLV transduction pathway reach the GCN5-containing complexes in the nucleus and alter the histone acetylation status of ethylene-responsive genes, thus translating the CLV information to transcriptional activity and uncovering a link between histone acetylation and SAM maintenance in the complex mode of ethylene signaling. PMID- 26596767 TI - Resources Required for Semi-Automatic Volumetric Measurements in Metastatic Chordoma: Is Potentially Improved Tumor Burden Assessment Worth the Time Burden? AB - The Response Evaluation Criteria in Solid Tumors (RECIST) is the current standard for assessing therapy response in patients with malignant solid tumors; however, volumetric assessments are thought to be more representative of actual tumor size and hence superior in predicting patient outcomes. We segmented all primary and metastatic lesions in 21 chordoma patients for comparison to RECIST. Primary tumors were segmented on MR and validated by a neuroradiologist. Metastatic lesions were segmented on CT and validated by a general radiologist. We estimated times for a research assistant to segment all primary and metastatic chordoma lesions using semi-automated volumetric segmentation tools available within our PACS (v12.0, Carestream, Rochester, NY), as well as time required for radiologists to validate the segmentations. We also report success rates of semi automatic segmentation in metastatic lesions on CT and time required to export data. Furthermore, we discuss the feasibility of volumetric segmentation workflow in research and clinical settings. The research assistant spent approximately 65 h segmenting 435 lesions in 21 patients. This resulted in 1349 total segmentations (average 2.89 min per lesion) and over 13,000 data points. Combined time for the neuroradiologist and general radiologist to validate segmentations was 45.7 min per patient. Exportation time for all patients totaled only 6 h, providing time-saving opportunities for data managers and oncologists. Perhaps cost-neutral resource reallocation can help acquire volumes paralleling our example workflow. Our results will provide researchers with benchmark resources required for volumetric assessments within PACS and help prepare institutions for future volumetric assessment criteria. PMID- 26596769 TI - Tris(pyrazolyl)phosphines with copper(i): from monomers to polymers. AB - The parent tris(pyrazolyl)phosphine and its 3,5-Me2, 3-Ph, and 3-t-Bu derivatives have been prepared by a simple procedure and show modest Lewis basicity of the phosphorus apex as was established by the magnitude of the (1)JP,Se coupling constant of the phosphine selenides. Because of the chelating properties of both the N- and P-sites, neutral phosphorus-centered scorpion ligands allow coordination modes that are unavailable to the abundantly used anionic tris(pyrazolyl)borate scorpionates as we established for Cu(I)-complexation. The substituted P-scorpion ligands only allow for N-coordination, as the P-apex is presumably less accessible. Two X-ray crystal structures were obtained for the Cu complex of tris(3,5-dimethylpyrazolyl)-phosphine with acetonitrile and triphenylphosphine in the fourth coordination site. The parent P-scorpion ligand can chelate with both its pyrazolyl groups and its P-apex with the product depending on the ratio in which it is mixed with the Cu(I) complex. Reacting two equivalents of the ligand with [Cu(MeCN)4][PF6] resulted in a complex in which Cu is coordinated to the three pyrazolyl groups of one ligand and to the P-apex of the other ligand as confirmed by an X-ray crystal structure determination and a DFT computational analysis. Reacting the ligand and the Cu(I) complex in an equimolar ratio resulted in a remarkable one-dimensional P-scorpion coordination polymer for which a single crystal X-ray structure could be determined. A detailed analysis of the structural features is presented. PMID- 26596770 TI - International Code of Nomenclature of Prokaryotes. AB - This volume contains the edition of the International Code of Nomenclature of Prokaryotes that was presented in draft form and available for comment at the Plenary Session of the Fourteenth International Congress of Bacteriology and Applied Microbiology (BAM), Montreal, 2014, together with updated lists of conserved and rejected bacterial names and of Opinions issued by the Judicial Commission. As in the past it brings together those changes accepted, published and documented by the ICSP and the Judicial Commission since the last revision was published. Several new appendices have been added to this edition. Appendix 11 addresses the appropriate application of the Candidatus concept, Appendix 12 contains the history of the van Niel Prize, and Appendix 13 contains the summaries of Congresses. PMID- 26596768 TI - Nuclear factor, erythroid 2-like 2-associated molecular signature predicts lung cancer survival. AB - Nuclear factor, erythroid 2-like 2 (NFE2L2), a transcription factor also known as NF-E2-related factor 2 (Nrf2), is a key cytoprotective gene that regulates critical antioxidant and stress-responsive genes. Nrf2 has been demonstrated to be a promising therapeutic target and useful biomarker in malignant disease. We hypothesized that NFE2L2-mediated gene expression would reflect cancer severity and progression. We conducted a meta-analysis of microarray data for 240 NFE2L2 mediated genes that were enriched in tumor tissues. We then developed a risk scoring system based on NFE2L2 gene expression profiling and designated 50 tumor associated genes as the NFE2L2-associated molecular signature (NAMS). We tested the relationship between this gene expression signature and both recurrence-free survival and overall survival in lung cancer patients. We find that NAMS predicts clinical outcome in the training cohort and in 12 out of 20 validation cohorts. Cox proportional hazard regressions indicate that NAMS is a robust prognostic gene signature, independent of other clinical and pathological factors including patient age, gender, smoking, gene alteration, MYC level, and cancer stage. NAMS is an excellent predictor of recurrence-free survival and overall survival in human lung cancer. This gene signature represents a promising prognostic biomarker in human lung cancer. PMID- 26596771 TI - Emergent material properties of developing epithelial tissues. AB - BACKGROUND: Force generation and the material properties of cells and tissues are central to morphogenesis but remain difficult to measure in vivo. Insight is often limited to the ratios of mechanical properties obtained through disruptive manipulation, and the appropriate models relating stress and strain are unknown. The Drosophila amnioserosa epithelium progressively contracts over 3 hours of dorsal closure, during which cell apices exhibit area fluctuations driven by medial myosin pulses with periods of 1.5-6 min. Linking these two timescales and understanding how pulsatile contractions drive morphogenetic movements is an urgent challenge. RESULTS: We present a novel framework to measure in a continuous manner the mechanical properties of epithelial cells in the natural context of a tissue undergoing morphogenesis. We show that the relationship between apicomedial myosin fluorescence intensity and strain during fluctuations is consistent with a linear behaviour, although with a lag. We thus used myosin fluorescence intensity as a proxy for active force generation and treated cells as natural experiments of mechanical response under cyclic loading, revealing unambiguous mechanical properties from the hysteresis loop relating stress to strain. Amnioserosa cells can be described as a contractile viscoelastic fluid. We show that their emergent mechanical behaviour can be described by a linear viscoelastic rheology at timescales relevant for tissue morphogenesis. For the first time, we establish relative changes in separate effective mechanical properties in vivo. Over the course of dorsal closure, the tissue solidifies and effective stiffness doubles as net contraction of the tissue commences. Combining our findings with those from previous laser ablation experiments, we show that both apicomedial and junctional stress also increase over time, with the relative increase in apicomedial stress approximately twice that of other obtained measures. CONCLUSIONS: Our results show that in an epithelial tissue undergoing net contraction, stiffness and stress are coupled. Dorsal closure cell apical contraction is driven by the medial region where the relative increase in stress is greater than that of stiffness. At junctions, by contrast, the relative increase in the mechanical properties is the same, so the junctional contribution to tissue deformation is constant over time. An increase in myosin activity is likely to underlie, at least in part, the change in medioapical properties and we suggest that its greater effect on stress relative to stiffness is fundamental to actomyosin systems and confers on tissues the ability to regulate contraction rates in response to changes in external mechanics. PMID- 26596772 TI - Association between environmental exposures and granulomatosis with polyangiitis in Canterbury, New Zealand. AB - INTRODUCTION: Granulomatosis with polyangiitis (GPA) is a rare systemic vasculitis. While aetiology is unknown the prominent respiratory involvement suggests inhaled antigens may be involved. The aim of this study was to identify environmental risk factors associated with GPA in Canterbury, New Zealand. METHODS: A case-controlled study was undertaken. All GPA cases fulfilled American College of Rheumatology (ACR), Chapel Hill Consensus Criteria (CHCC) or the European Medicines Agency (EMA) criteria. Each case was gender matched with four controls - 2 musculoskeletal (osteoarthritis or fracture) and 2 respiratory (asthma or chronic obstructive pulmonary disease). One musculoskeletal control and one respiratory control were age matched with the case at the time of the interview (interview) and the remaining two controls were age matched at the time their case experienced the first symptom of vasculitis (index). A structured questionnaire to assess potential environmental agents was administered without blinding for case/control status. Data were analyzed using conditional logistic regression to allow for the individual matching of cases and controls to assess for association between environmental factors and GPA. RESULTS: 49 cases and 196 controls were recruited. 53 % were male and the mean +/- standard deviation (SD) age of the cases was 64.9 +/- 12.4 years, interview controls 65.1 +/- 12.4.years and index controls 53.9 +/- 14.5 years. Any reported exposure to dust (specifically silica and grain dust) was associated with GPA, odds ratio (OR) 3.6 (95 % confidence interval (CI); 1.5-8.3, p = 0.003). Occupation as a farm worker was associated with GPA OR 3.43 (1.5-7.5, p = 0.002). Specific gardening activities were associated with GPA including digging (OR 3.2; 1.4-7.0; p = 0.003), mowing (OR 2.7; 1.3-5.8; p = 0.008) and planting (OR 2.6; 1.2-5.5; p = 0.013). CONCLUSION: We have replicated findings from northern hemisphere studies identifying dust exposure as well as farm exposure as risk factors for the development of GPA. We have shown activities associated with exposure to inhaled antigens, in particular those related to farming or gardening activities may increase the risk of GPA. PMID- 26596773 TI - Energyless CO2 Absorption, Generation, and Fixation Using Atmospheric CO2. AB - From an economic and ecological perspective, the efficient utilization of atmospheric CO2 as a carbon resource should be a much more important goal than reducing CO2 emissions. However, no strategy to harvest CO2 using atmospheric CO2 at room temperature currently exists, which is presumably due to the extremely low concentration of CO2 in ambient air (approximately 400 ppm=0.04 vol%). We discovered that monoethanolamine (MEA) and its derivatives efficiently absorbed atmospheric CO2 without requiring an energy source. We also found that the absorbed CO2 could be easily liberated with acid. Furthermore, a novel CO2 generator enabled us to synthesize a high value-added material (i.e., 2 oxazolidinone derivatives based on the metal catalyzed CO2-fixation at room temperature) from atmospheric CO2. PMID- 26596774 TI - Local false discovery rate estimation using feature reliability in LC/MS metabolomics data. AB - False discovery rate (FDR) control is an important tool of statistical inference in feature selection. In mass spectrometry-based metabolomics data, features can be measured at different levels of reliability and false features are often detected in untargeted metabolite profiling as chemical and/or bioinformatics noise. The traditional false discovery rate methods treat all features equally, which can cause substantial loss of statistical power to detect differentially expressed features. We propose a reliability index for mass spectrometry-based metabolomics data with repeated measurements, which is quantified using a composite measure. We then present a new method to estimate the local false discovery rate (lfdr) that incorporates feature reliability. In simulations, our proposed method achieved better balance between sensitivity and controlling false discovery, as compared to traditional lfdr estimation. We applied our method to a real metabolomics dataset and were able to detect more differentially expressed metabolites that were biologically meaningful. PMID- 26596775 TI - Scale-Dependent Variability and Quantitative Regimes in Graph-Theoretic Representations of Human Cortical Networks. AB - Studying brain connectivity is important due to potential differences in brain circuitry between health and disease. One drawback of graph-theoretic approaches to this is that their results are dependent on the spatial scale at which brain circuitry is examined and explicitly on how vertices and edges are defined in network models. To investigate this, magnetic resonance and diffusion tensor images were acquired from 136 healthy adults, and each subject's cortex was parceled into as many as 50,000 regions. Regions were represented as nodes in a reconstructed network representation, and interregional connectivity was inferred via deterministic tractography. Network model behavior was explored as a function of nodal number and connectivity weighing. Three distinct regimes of quantitative behavior assumed by network models as a function of spatial scale are identified, and their existence may be modulated by the spatial folding scale of the cortex. The maximum number of network nodes used to model human brain circuitry in this study (~50,000) is larger than in previous macroscale neuroimaging studies. Results suggest that network model properties vary appreciably as a function of vertex assignment convention and edge weighing scheme and that graph-theoretic analysis results should not be compared across spatial scales without appropriate understanding of how spatial scale and model topology modulate network model properties. These findings have implications for comparing macro- to mesoscale studies of brain network models and understanding how choosing network-theoretic parameters affects the interpretation of brain connectivity studies. PMID- 26596776 TI - John Henryism Active Coping, Acculturation, and Psychological Health in Korean Immigrants. AB - This study aimed to explore the levels of John Henryism (JH) active coping and its association with acculturation status and psychological health (specifically perceived stress, acculturative stress, anxiety, and depression) in Korean immigrants to the United States. In 102 Korean immigrants, JH active coping was measured by the JH Scale; acculturation by the Bidimensional Acculturation Scale; perceived stress by the Perceived Stress Scale; acculturative stress by the Social, Attitudinal, Familial, and Environmental Scale; anxiety by the State Anxiety Subscale of the Spielberger State-Trait Anxiety Inventory; and depression by the Center for Epidemiological Studies Depression Scale. The levels of JH active coping in this sample of Korean immigrants appear to be lower than the levels reported in other racial groups. Independent of demographic factors, JH active coping was a significant predictor of higher acculturation status and better psychological health as indicated by lower levels of perceived stress, acculturative stress, anxiety, and depressive symptoms. PMID- 26596777 TI - Spatial working memory is enhanced in children by differential outcomes. AB - Working memory (WM) is essential to academic achievement. Any enhancement of WM abilities may improve children's school performance. We tested the usefulness of the differential outcomes procedure (DOP) to enhance typically developing children's performance on a spatial WM task. The DOP involves a conditional discriminative learning task in which a correct choice response to a specific stimulus-stimulus association is reinforced with a particular reinforcer (outcome). We adapted a spatial memory task to be used with the DOP. Participants had to learn and retain in their WM four target locations of eight possible locations where a shape could be presented. Two groups of 5- and 7-year-old children performed the low-attentional version of the spatial task, and an additional group of 7-year-old children performed the high-attentional version. The results showed that compared with the standard non-differential outcomes procedure (NOP), the DOP produced better memory-based performance in 5-year-old children with the low-attentional task and in 7-year-old children with the high attentional task. Additionally, delay intervals impaired performance in the NOP but not in the DOP. These findings suggest that the DOP may be a useful complement to other WM intervention programs targeted to improve children's academic performance at school. PMID- 26596778 TI - Competing Anisotropy-Tunneling Correlation of the CoFeB/MgO Perpendicular Magnetic Tunnel Junction: An Electronic Approach. AB - We intensively investigate the physical principles regulating the tunneling magneto-resistance (TMR) and perpendicular magnetic anisotropy (PMA) of the CoFeB/MgO magnetic tunnel junction (MTJ) by means of angle-resolved x-ray magnetic spectroscopy. The angle-resolved capability was easily achieved, and it provided greater sensitivity to symmetry-related d-band occupation compared to traditional x-ray spectroscopy. This added degree of freedom successfully solved the unclear mechanism of this MTJ system renowned for controllable PMA and excellent TMR. As a surprising discovery, these two physical characteristics interact in a competing manner because of opposite band-filling preference in space-correlated symmetry of the 3d-orbital. An overlooked but harmful superparamagnetic phase resulting from magnetic inhomogeneity was also observed. This important finding reveals that simultaneously achieving fast switching and a high tunneling efficiency at an ultimate level is improbable for this MTJ system owing to its fundamental limit in physics. We suggest that the development of independent TMR and PMA mechanisms is critical towards a complementary relationship between the two physical characteristics, as well as the realization of superior performance, of this perpendicular MTJ. Furthermore, this study provides an easy approach to evaluate the futurity of any emerging spintronic candidates by electronically examining the relationship between their magnetic anisotropy and transport. PMID- 26596779 TI - Defining habitat covariates in camera-trap based occupancy studies. AB - In species-habitat association studies, both the type and spatial scale of habitat covariates need to match the ecology of the focal species. We assessed the potential of high-resolution satellite imagery for generating habitat covariates using camera-trapping data from Sabah, Malaysian Borneo, within an occupancy framework. We tested the predictive power of covariates generated from satellite imagery at different resolutions and extents (focal patch sizes, 10-500 m around sample points) on estimates of occupancy patterns of six small to medium sized mammal species/species groups. High-resolution land cover information had considerably more model support for small, patchily distributed habitat features, whereas it had no advantage for large, homogeneous habitat features. A comparison of different focal patch sizes including remote sensing data and an in-situ measure showed that patches with a 50-m radius had most support for the target species. Thus, high-resolution satellite imagery proved to be particularly useful in heterogeneous landscapes, and can be used as a surrogate for certain in-situ measures, reducing field effort in logistically challenging environments. Additionally, remote sensed data provide more flexibility in defining appropriate spatial scales, which we show to impact estimates of wildlife-habitat associations. PMID- 26596780 TI - Correction to "Black Phosphorus: Narrow Gap, Wide Applications". PMID- 26596781 TI - Episodic entrainment of deep primordial mantle material into ocean island basalts. AB - Chemical differences between mid-ocean ridge basalts (MORBs) and ocean island basalts (OIBs) provide critical evidence that the Earth's mantle is compositionally heterogeneous. MORBs generally exhibit a relatively low and narrow range of (3)He/(4)He ratios on a global scale, whereas OIBs display larger variability in both time and space. The primordial origin of (3)He in OIBs has motivated hypotheses that high (3)He/(4)He ratios are the product of mantle plumes sampling chemically distinct material, but do not account for lower MORB like (3)He/(4)He ratios in OIBs, nor their observed spatial and temporal variability. Here we perform thermochemical convection calculations which show the variable (3)He/(4)He signature of OIBs can be reproduced by deep isolated mantle reservoirs of primordial material that are viscously entrained by thermal plumes. Entrainment is highly time-dependent, producing a wide range of (3)He/(4)He ratios similar to that observed in OIBs worldwide and indicate MORB like (3)He/(4)He ratios in OIBs cannot be used to preclude deep mantle-sourced hotspots. PMID- 26596782 TI - The Bromodomain: A New Target in Emerging Epigenetic Medicine. AB - The bromodomain (BrD) is a conserved protein modular domain found in many chromatin- and transcription-associated proteins that has the ability to recognize acetylated lysine residues. This activity allows bromodomains to play a vital role in many acetylation-mediated protein-protein interactions in the cell, ranging from substrate recruitment for histone acetyltransferases (HATs) to aiding in multiple-protein complex assembly for gene transcriptional activation or suppression in chromatin. In recent years, considerable efforts have been made to develop chemical inhibitors of these bromodomains in an effort to probe their cellular functions. Potent and selective inhibitors have been extensively developed for one group of the bromodomain family termed BET proteins that consist of tandem bromodomains followed by an extra terminal domain. Drug developers are actively designing inhibitors of other bromodomains and working to move the most successful inhibitors into the clinic. PMID- 26596783 TI - The impact of Cr adhesion layer on CNFET electrical characteristics. AB - The effect of a Cr adhesion layer on the transfer characteristics of Cr/Au contacted carbon nanotube field-effect transistors (CNFETs) based on individual single-walled carbon nanotubes (SWNTs) is presented in this paper. We show that a very thin Cr layer (~0.4 nm) already has an impact on the carrier transport in Schottky-barrier-modulated CNFETs. The ratio of the p- and n-branch current is reduced by eight times when the Cr adhesion layer thickness is increased from 0 to 8 nm. We suggest a change in Schottky barrier height at the contact as the determining mechanism for this result. Additionally, superior lifetime of devices is observed even for non-passivated CNFETs with preserved clean SWNT/Cr/Au contacts using Cr layer thinner than 2 nm. Our experiments show that the role of the adhesion layer in metal/nanotube contacts should be explicitly considered when designing CNTFET-based circuits, developing CNFET fabrication processes, and analyzing the corresponding properties of the electrical contacts. PMID- 26596784 TI - Detecting hepatocellular carcinoma in blood. AB - Liquid biopsy is ideal for early diagnosis of cancer and for prognosis upon treatment. Wen et al. describe a methylated CpG tandems amplification and sequencing method to profile hypermethylated CpG islands genome-widely in cell free DNA, and further identify high performance markers in blood for potential detection of early stage hepatocellular carcinoma. PMID- 26596785 TI - H1 provides the missing link. AB - Adding to the Histone Code at DNA double-strand breaks, Mailand and colleagues now uncover non-degradative ubiquitin marks on linker histone H1 as key signaling intermediates in the DNA damage signal transduction cascade. PMID- 26596787 TI - Inflammasome assembly: The wheels are turning. AB - Inflammasomes control host cell death and inflammation in response to sterile or infectious stimuli. Two recent reports published in Science reveal the structural basis for the assembly of NAIP-NLRC4 inflammasomes. PMID- 26596786 TI - RNA editing by ADAR1 marks dsRNA as "self". AB - A paper recently published in Science reports that adenosine deaminase acting on RNA 1-dependent adenosine-to-inosine editing marks endogenous double strand RNA as self and prevents their immune recognition by cytosolic RNA sensor MDA5. PMID- 26596788 TI - From wastewater to fertilisers--Technical overview and critical review of European legislation governing phosphorus recycling. AB - The present paper is based on an analysis of the EU legislation regulating phosphorus recovery and recycling from wastewater stream, in particular as fertiliser. To recover phosphorus, operators need to deal with market regulations, health and environment protection laws. Often, several permits and lengthy authorisation processes for both installation (e.g. environmental impact assessment) and the recovered phosphorus (e.g. End-of-Waste, REACH) are required. Exemptions to certain registration processes for recoverers are in place but rarely applied. National solutions are often needed. Emerging recovery and recycling sectors are affected by legislation in different ways: Wastewater treatment plants are obliged to remove phosphorus but may also recover it in low quantities for operational reasons. Permit processes allowing recovery and recycling operations next to water purification should thus be rationalised. In contrast, the fertiliser industry relies on legal quality requirements, ensuring their market reputation. For start-ups, raw-material sourcing and related legislation will be the key. Phosphorus recycling is governed by fragmented decision-making in regional administrations. Active regulatory support, such as recycling obligation or subsidies, is lacking. Legislation harmonisation, inclusion of recycled phosphorus in existing fertiliser regulations and support of new operators would speed up market penetration of novel technologies, reduce phosphorus losses and safeguard European quality standards. PMID- 26596789 TI - Investment subsidies and the adoption of electronic medical records in hospitals. AB - In February 2009 the U.S. Congress unexpectedly passed the Health Information Technology for Economic and Clinical Health Act (HITECH). HITECH provides up to $27 billion to promote adoption and appropriate use of Electronic Medical Records (EMR) by hospitals. We measure the extent to which HITECH incentive payments spurred EMR adoption by independent hospitals. Adoption rates for all independent hospitals grew from 48 percent in 2008 to 77 percent by 2011. Absent HITECH incentives, we estimate that the adoption rate would have instead been 67 percent in 2011. When we consider that HITECH funds were available for all hospitals and not just marginal adopters, we estimate that the cost of generating an additional adoption was $48 million. We also estimate that in the absence of HITECH incentives, the 77 percent adoption rate would have been realized by 2013, just 2 years after the date achieved due to HITECH. PMID- 26596790 TI - Comparison of mouse and human ankles and establishment of mouse ankle osteoarthritis models by surgically-induced instability. AB - OBJECTIVE: Prevalence of ankle osteoarthritis (OA) is lower than that of knee OA, however, the molecular mechanisms underlying the difference remain unrevealed. In the present study, we developed mouse ankle OA models for use as tools to investigate pathophysiology of ankle OA and molecular characteristics of ankle cartilage. DESIGN: We anatomically and histologically examined ankle and knee joints of C57BL/6 mice, and compared them with human samples. We examined joints of 8-week-old and 25-month-old mice. For experimental models, we developed three different ankle OA models: a medial model, a lateral model, and a bilateral model, by resection of respective structures. OA severity was evaluated 8 weeks after the surgery by safranin O staining, and cartilage degradation in the medial model was sequentially examined. RESULTS: Anatomical and histological features of human and mouse ankle joints were comparable. Additionally, the mouse ankle joint was more resistant to cartilage degeneration with aging than the mouse knee joint. In the medial model, the tibiotalar joint was markedly affected while the subtalar joint was less degenerated. In the lateral model, the subtalar joint was mainly affected while the tibiotalar joint was less altered. In the bilateral model, both joints were markedly degenerated. In the time course of the medial model, TdT-mediated dUTP nick end labeling (TUNEL) staining and Adamts5 expression were enhanced at early and middle stages, while Mmp13 expression was gradually increased during the OA development. CONCLUSION: Since human and mouse ankles are comparable, the present models will contribute to ankle OA pathophysiology and general cartilage research in future. PMID- 26596791 TI - Aortic valve prosthesis-patient mismatch and exercise capacity in adult patients with congenital heart disease. AB - OBJECTIVES: To report the prevalence of aortic valve prosthesis-patient mismatch (PPM) in an adult population with congenital heart disease (CHD) and its impact on exercise capacity. Adults with congenital heart disease (ACHD) with a history of aortic valve replacement may outgrow their prosthesis later in life. However, the prevalence and clinical consequences of aortic PPM in ACHD are presently unknown. METHODS: From the national Dutch Congenital Corvitia (CONCOR) registry, we identified 207 ACHD with an aortic valve prosthesis for this cross-sectional cohort study. Severe PPM was defined as an indexed effective orifice area <=0.65 cm2/m2 and moderate PPM as an indexed orifice area <=0.85 cm2/m2 measured using echocardiography. Exercise capacity was reported as percentage of predicted exercise capacity (PPEC). RESULTS: Of the 207 patients, 68% was male, 71% had a mechanical prosthesis and mean age at inclusion was 43.9 years +/-11.4. The prevalence of PPM was 42%, comprising 23% severe PPM and 19% moderate PPM. Prevalence of PPM was higher in patients with mechanical prostheses (p<0.001). PPM was associated with poorer exercise capacity (mean PPEC 84% vs. 92%; p=0.048, mean difference =-8.3%, p=0.047). Mean follow-up was 2.6+/-1.1 years during which New York Heart Association (NYHA) class remained stable in most patients. PPM showed no significant effect on death or hospitalisation during follow-up (p=0.218). CONCLUSIONS: In this study we report a high prevalence (42%) of PPM in ACHD with an aortic valve prosthesis and an independent association of PPM with diminished exercise capacity. PMID- 26596792 TI - Smoking status and life expectancy after acute myocardial infarction in the elderly. AB - OBJECTIVE: Smokers have lower short-term mortality after acute myocardial infarction (AMI) than non-smokers; however, little is known about the long-term effects of smoking on life expectancy after AMI. This study aimed to quantify the burden of smoking after AMI using life expectancy and years of life lost. METHODS: We analysed data from the Cooperative Cardiovascular Project, a medical record study of 158,349 elderly Medicare patients with AMI and over 17 years of follow-up, to evaluate the age-specific association of smoking with life expectancy and years of life lost after AMI. RESULTS: Our sample included 23,447 (14.8%) current smokers. Current smokers had lower crude mortality up to 5 years, which was largely explained by their younger age at AMI. After adjustment other patient characteristics, smoking was associated with lower 30-day (HR 0.91, 95% CI 0.87 to 0.94) but higher long-term mortality (17-year HR 1.19, 95% CI 1.17 to 1.20) after AMI. Overall, crude life expectancy estimates were lower for current smokers than non-smokers at all ages, which translated into sizeable numbers of life-years lost attributable to smoking. As age at AMI increased, the magnitude of life-years lost due to smoking decreased. After full risk adjustment, the differences in life expectancy between current smokers and non-smokers persisted at all ages. CONCLUSIONS: Current smoking is associated with lower life expectancy and large numbers of life-years lost after AMI. Our findings lend additional support to smoking cessation efforts after AMI. PMID- 26596793 TI - Health literacy and refugees' experiences of the health examination for asylum seekers - a Swedish cross-sectional study. AB - BACKGROUND: The purpose of the health examination for asylum seekers in most countries is to identify poor health in order to secure the well-being of seekers of asylum and to guarantee the safety of the population in the host country. Functional health literacy is an individual's ability to read information and instructions about health and to function effectively as a patient in the health system, and comprehensive health literacy is an individual's competence in accessing, understanding, appraising and applying health information. Little is known about refugees' health literacy and their experiences of the health examination for asylum seekers. The purposes of the study were to investigate refugees' experiences of communication during their health examination for asylum seekers and the usefulness of that examination, and whether health literacy is associated with those experiences. METHODS: A cross-sectional study was made among 360 adult refugees speaking Arabic, Dari, Somali or English. Health literacy was measured using the Swedish Functional Health Literacy Scale and the short European Health Literacy Questionnaire. Experiences of communication and the usefulness of the health examination were measured in several questions. Associations were sought using univariate and multivariate statistical models. RESULTS: In the health examination for asylum seekers, a poor quality of communication was experienced by 36 %, receiving little information about health care by 55 %, and receiving little new knowledge by 41 % and/or help by 26 %. Having inadequate as compared to sufficient comprehensive health literacy was associated with the experience of a poorer quality of communication (OR: 9.64, CI 95 %: 3.25-28.58) and the experience of receiving little valuable health care information (OR: 6.54, CI 95 %: 2.45-17.47). Furthermore, having inadequate as compared to sufficient comprehensive health literacy was associated with the experience of not receiving new knowledge (OR: 7.94, CI 95 %: 3.00-21.06) or receiving help with health problems (OR: 8.07, 95 % CI: 2.50-26.07. Functional healthy literacy was not associated with experiences of HEA. CONCLUSION: Refugees' experiences indicate that a low level of comprehensive health literacy can act as a barrier to fulfilling the purposes of the health examination for asylum seekers. Comprehensive health literacy seems to be of greater importance in that context than functional health literacy. PMID- 26596794 TI - Evaluating the Risk of a Fifth Metatarsal Stress Fracture by Measuring the Serum 25-Hydroxyvitamin D Levels. AB - BACKGROUND: The fifth metatarsal bone is a common site of stress fractures in soccer athletes. Although several endocrine risk factors for stress fractures have been proposed, the endocrine risks for fifth metatarsal (5-MT) stress fractures have not been evaluated. METHODS: To evaluate the endocrine risks of fifth metatarsal stress fractures, we conducted a cumulative case-control study. The present study included 37 athletes, of which 18 had a history of a zone 2 or zone 3 fifth metatarsal stress fracture and 19 controls. We analyzed serum 25 hydroxyvitamin D (25-OHD), serum parathyroid hormone (PTH), as well as biochemical markers of bone turnover by univariate or multivariate analyses. RESULTS: Logistic regression analyses adjusted for multiple confounders revealed that insufficient serum 25-OHD levels less than 30 ng/mL (odds ratio [OR], 23.3), higher serum PTH levels (OR, 1.01), or higher serum bone-specific isoform of alkaline phosphatase levels (OR, 1.10) rather than serum tartrate-resistant acid phosphatase 5b were associated with statistically significantly increased odds of 5-MT stress fractures. A postestimation calculation demonstrated that 25-OHD levels of 10 and 20 ng/mL were associated with 5.1 and 2.9 times greater odds for 5-MT stress fractures, respectively. CONCLUSION: 25-OHD insufficiency was associated with an increased incidence of 5-MT stress fractures. This insight may be useful for intervening to prevent 5-MT stress fractures. LEVEL OF EVIDENCE: Level III, case-control study. PMID- 26596795 TI - Return to Sports and Physical Activities After Primary Partial Arthrodesis for Lisfranc Injuries in Young Patients. AB - BACKGROUND: Research regarding outcomes in sports and physical activities after primary partial arthrodesis for Lisfranc injuries has been sparse. The purposes of this study were to assess various sports and physical activities in young patients following primary partial arthrodesis for Lisfranc injuries and to compare these with clinical outcomes. METHODS: Patients who underwent primary partial arthrodesis for a Lisfranc injury were identified by a retrospective registry review. Thirty-eight of 46 eligible patients (83%) responded for follow up at a mean of 5.2 (range, 1.0 to 9.3) years with a mean age at surgery of 31.8 (range, 16.8 to 50.3) years. Physical activity participation was assessed with a new sports-specific, patient-administered questionnaire. Clinical outcomes were assessed with the Foot and Ankle Outcome Score (FAOS). RESULTS: Patients participated in 29 different and 155 total physical activities preoperatively, and 27 different and 145 total physical activities postoperatively. Preoperatively, 47.1% were high impact, and postoperatively, 44.8% were high impact. The most common activities were walking, bicycling, running, and weightlifting. Compared to preoperatively, difficulty was the same in 66% and increased in 34% of physical activities. Participation levels were improved in 11%, the same in 64%, and impaired in 25% of physical activities. Patients spent on average 4.2 (range, 0.0 to 19.8) hours per week exercising postoperatively. In regard to return to physical activity, 97% of respondents were satisfied with their operative outcome. Mean postoperative FAOS subscores were significantly worse for patients who had increased physical activity difficulty. CONCLUSION: Most patients were able to return to their previous physical activities following primary partial arthrodesis for a Lisfranc injury, many of which were high impact. However, the decreased participation or increase in difficulty of some activities suggests that some patients experienced postoperative limitations in exercise. Future studies could compare sports outcomes between primary partial arthrodesis and open reduction internal fixation for Lisfranc injuries. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 26596796 TI - Transfibular Approach to Posterior Malleolus Fracture Fixation: Technique Tip. PMID- 26596797 TI - Prevention of postpartum haemorrhage: cost consequences analysis of misoprostol in low-resource settings. AB - BACKGROUND: While inferior to oxytocin injection in both efficacy and safety, orally administered misoprostol has been included in the World Health Organization Model List of Essential Medicines for use in the prevention of postpartum haemorrhage (PPH) in low-resource settings. This study evaluates the costs and health outcomes of use of oral misoprostol to prevent PPH in settings where injectable uterotonics are not available. METHODS: A cost-consequences analysis was conducted from the international health system perspective, using data from a recent Cochrane systematic review and WHO's Mother-Baby Package Costing Spreadsheet in a hypothetical cohort of 1000 births in a mixed hospital (40% births)/community setting (60% births). Costs were estimated based on 2012 US dollars. RESULTS: Using oxytocin in the hospital setting and misoprostol in the community setting in a cohort of 1000 births, instead of oxytocin (hospital setting) and no treatment (community setting), 22 cases of PPH could be prevented. Six fewer women would require additional uterotonics and four fewer women a blood transfusion. An additional 130 women would experience shivering and an extra 42 women fever. Oxytocin/misoprostol was found to be cost saving (US$320) compared to oxytocin/no treatment. If misoprostol is used in both the hospital and community setting compared with no treatment (i.e. oxytocin not available in the hospital setting), 37 cases of PPH could be prevented; ten fewer women would require additional uterotonics; and six fewer women a blood transfusion. An additional 217 women would experience shivering and 70 fever. The cost savings would be US$533. Sensitivity analyses indicate that the results are sensitive to the incidence of PPH-related outcomes, drug costs and the proportion of hospital births. CONCLUSIONS: Our findings confirm that, even though misoprostol is not the optimum choice in the prevention of PPH, misoprostol could be an effective and cost-saving choice where oxytocin is not or cannot be used due to a lack of skilled birth attendants, inadequate transport and storage facilities or where a quality assured oxytocin product is not available. These benefits need to be weighed against the large number of additional side effects such as shivering and fever, which have been described as tolerable and of short duration. PMID- 26596798 TI - CTLA-4 and Autoimmunity: New Twists in the Tale. AB - CTLA-4 has long been associated with control of autoimmunity. A recent study by Sharpe and colleagues explores this relationship in a model that enables conditional deletion of CTLA-4 in adult mice, with some surprising new conclusions. PMID- 26596800 TI - Genome-wide microarray screening for Bombyx mori genes related to transmitting the determination outcome of whether to produce diapause or nondiapause eggs. AB - The bivoltine silkworm Bombyx mori (Lepidoptera: Bombycidae) exhibits a maternally controlled embryonic diapause. Maternal silkworms decide whether to lay diapause or nondiapause eggs depending on environmental factors such as the temperature and photoperiod during the egg and larval stages, and then induce diapause eggs during the pupal stage. However, little is known about the molecular mechanism that conveys the outcome of whether to produce diapause or nondiapause eggs from the egg or larval stages to the pupal stage. This study used microarray analysis to investigate differentially expressed genes in the larval brains of diapause- and nondiapause-egg producers, to which bivoltine silkworms were destined by thermal or photic stimulation during the egg stage. The cytochrome P450 18a1 and Kruppel homolog 1 genes were upregulated in producers of diapause eggs compared with those of nondiapause eggs under both experimental conditions. Cytochrome P450 18a1 encodes a key enzyme for steroid hormone inactivation and Kruppel homolog 1 is an early juvenile hormone-inducible gene that mediates the repression of metamorphosis. The upregulation of these genes during the larval stage might be involved in the signaling pathway that transmits information about the diapause program from the egg stage to the pupal stage in the silkworm. PMID- 26596801 TI - Clinical research of intraperitoneal implantation of sustained-release 5 fluorouracil in advanced colorectal cancer. AB - BACKGROUND: The objective of this study was to investigate the safety and long term clinical effect of intraperitoneal implantation of sustained-release 5 fluorouracil in patients with advanced colorectal cancer during radical resection. METHODS: A total of 202 patients with advanced colorectal cancer undergoing radical operations were randomly divided into an experimental group (98 cases, intraoperative intraperitoneal implantation of sustained-release 5 fluorouracil 600 mg as local chemotherapy) and a control group (104 cases, without local chemotherapy). The clinical data of the two groups was compared including toxicity, complications, local recurrence rate, distant metastasis, disease-free survival, and 1-, 3-, and 5-year survival rates. RESULTS: Both groups of patients were followed up for more than 5 years, the longest follow-up time was 7.5 years. Bone marrow suppression, hepato-renal function, postoperative anastomotic leakage, pelvic effusion, incision infection, the incidence of intestinal obstruction, venting time, and hospital stay after operation (days) between two groups had no statistical significant difference. Locoregional recurrence and liver metastasis rate were decreased significantly in experimental group (P = 0.04 and 0.04). Extensive peritoneal metastasis and other organ metastasis rates had no significant difference between two groups. In the experimental group, 1-, 3-, and 5-year survival rates were higher than in the control group (95.92 vs 87.50 %, 77.55 vs 64.42 %, and 56.12 vs 40.38 %), which had significant difference. Disease-free survival (DFS) of the experimental group was higher than that of the control group (chi (2) = 5.00, P = 0.025). CONCLUSIONS: Intraperitoneal implantation of sustained-release 5-fluorouracil is safe for advanced colorectal cancer during radical resection, which can reduce locoregional recurrence rate and liver metastasis rate. The long-term efficacy was reliable, and long-term survival and disease-free survival rate can be improved. PMID- 26596799 TI - Exit Strategies: S1P Signaling and T Cell Migration. AB - Whereas the role of sphingosine 1-phosphate receptor 1 (S1PR1) in T cell egress and the regulation of S1P gradients between lymphoid organs and circulatory fluids in homeostasis are increasingly well understood, much remains to be learned about S1P signaling and distribution during an immune response. Recent data suggest that the role of S1PR1 in directing cells from tissues into circulatory fluids is reprised again and again, particularly in guiding activated T cells from non-lymphoid tissues into lymphatics. Conversely, S1P receptor 2 (S1PR2), which antagonizes migration towards chemokines, confines cells within tissues. Here we review the current understanding of the roles of S1P signaling in activated T cell migration. In this context, we outline open questions, particularly regarding the shape of S1P gradients in different tissues in homeostasis and inflammation, and discuss recent strategies to measure S1P. PMID- 26596802 TI - Understanding Heart Failure. AB - Heart failure (HF) is a growing global health concern that affects more than 20 million people worldwide. With an ever-growing segment of the population over the age of 65, the prevalence of HF and its associated costs are expected to increase exponentially over the next decade. Advances in the understanding of the pathophysiology and treatment of HF have resulted in the ability to enhance both the quantity and the quality of life of patients with HF. This article reviews the current understanding of the pathophysiology, cause, classification, and treatment of HF and describes areas of uncertainty that demand future study. PMID- 26596803 TI - Containing the Cost of Heart Failure Management: A Focus on Reducing Readmissions. AB - Heart failure (HF) consumes a large proportion of the total national health care budget. Incidence and prevalence of HF are increasing and may give rise to an unsustainable increase in health care spending. Hospitalizations account for the vast majority of HF-related expenses, and 20% to 25% of patients discharged with a diagnosis of HF are readmitted within 60 days. Thus, efforts to reduce HF readmissions are a reasonable target for reducing overall expenses. It is to be seen if targeting readmission rates will lead to significant cost savings, and more importantly, to improved patient outcomes. PMID- 26596805 TI - Exploring the Electrophysiologic and Hemodynamic Effects of Cardiac Resynchronization Therapy: From Bench to Bedside and Vice Versa. AB - Cardiac resynchronization therapy (CRT) is an important therapy for heart failure patients with prolonged QRS duration. In patients with left bundle branch block the altered left ventricular electrical activation results in dyssynchronous, inefficient contraction of the left ventricle. CRT aims to reverse these changes and to improve cardiac function. This article explores the electrophysiologic and hemodynamic changes that occur during CRT in patient and animal studies. It also addresses how novel techniques, such as multipoint and endocardial pacing, can further improve the electromechanical response. PMID- 26596806 TI - Newer Echocardiographic Techniques in Cardiac Resynchronization Therapy. AB - Echocardiographic imaging plays a major role in patient selection for cardiac resynchronization therapy (CRT). One-third of patients do not respond; there is interest in advanced echocardiographic imaging to improve response. Current guidelines favor CRT for patients with electrocardiographic (ECG) QRS width of 150 milliseconds or greater and left bundle branch block. ECG criteria are imperfect; there is interest in advanced echocardiographic imaging to improve patient selection. This discussion focuses on newer echocardiographic methods to improve patient selection, improve delivery, and identify patients at risk for poor outcomes and serious ventricular arrhythmias. PMID- 26596804 TI - Cellular and Molecular Aspects of Dyssynchrony and Resynchronization. AB - Dyssynchronous contraction of the ventricle significantly worsens morbidity and mortality in patients with heart failure (HF). Approximately one-third of patients with HF have cardiac dyssynchrony and are candidates for cardiac resynchronization therapy (CRT). The initial understanding of dyssynchrony and CRT was in terms of global mechanics and hemodynamics, but lack of clinical benefit in a sizable subgroup of recipients who appear otherwise appropriate has challenged this paradigm. This article reviews current understanding of these cellular and subcellular mechanisms, arguing that these aspects are key to improving CRT use, as well as translating its benefits to a wider HF population. PMID- 26596807 TI - The Role of Cardiovascular Magnetic Resonance in Cardiac Resynchronization Therapy. AB - Randomized, controlled trials have shown that cardiac resynchronization therapy (CRT) is beneficial in patients with heart failure, impaired left ventricular (LV) systolic function, and a wide QRS complex. Other studies have shown that targeting the LV pacing site can also improve patient outcomes. Cardiovascular magnetic resonance (CMR) is a radiation-free imaging modality that provides unparalleled spatial resolution. In addition, emerging data suggest that targeted LV lead deployment over viable myocardium improves the outcome of patients undergoing CRT. This review explores the role of CMR in the preoperative workup of patients undergoing CRT. PMID- 26596809 TI - Robotic-Assisted Left Ventricular Lead Placement. AB - Robot-assisted left ventricular lead implantation for cardiac resynchronization therapy is a feasible and safe technique with superior visualization, dexterity, and precision to target the optimal pacing site. The technique has been associated with clinical response and beneficial reverse remodeling comparable with the conventional approach via the coronary sinus. The lack of clinical superiority and a residual high nonresponder rate suggest that the appropriate clinical role for the technique remains as rescue therapy. PMID- 26596808 TI - Coronary Sinus Lead Positioning. AB - Although cardiac resynchronization therapy improves morbidity and mortality in patients with cardiomyopathy, heart failure, and electrical dyssynchrony, the rate of nonresponders using standard indications and implant techniques is still high. Optimal coronary sinus lead positioning is important to increase the chance of successful resynchronization. Patient factors such as cause of heart failure, type of dyssynchrony, scar burden, coronary sinus anatomy, and phrenic nerve capture may affect the efficacy of the therapy. Several modalities are under investigation. Alternative left ventricular lead implantation strategies are occasionally required when the transvenous route is not feasible or would result in a suboptimal lead position. PMID- 26596810 TI - Coronary Sinus Lead Extraction. AB - Expanded indications for cardiac resynchronization therapy and the increasing incidence of cardiac implantable electronic device infection have led to an increased need for coronary sinus (CS) lead extraction. The CS presents unique anatomical obstacles to successful lead extraction. Training and facility requirements for CS lead extraction should mirror those for other leads. Here we review the indications, technique, and results of CS lead extraction. Published success rates and complications are similar to those reported for other leads, although multiple techniques may be required. Re-implantation options may be limited, which should be incorporated into pre-procedural decision making. PMID- 26596811 TI - Cardiac Resynchronization Therapy: An Overview on Guidelines. AB - Cardiac resynchronization therapy (CRT) is included in international consensus guidelines as a treatment with proven efficacy in well-selected patients on top of optimal medical therapy. Although all the guidelines strongly recommend CRT for LBBB with QRS duration greater than 150 milliseconds, lower strength of recommendation is reported for QRS duration of 120 to 150 milliseconds, especially if not associated with LBBB. CRT is not recommended for a QRS of less than 120 milliseconds. No indication emerges for guiding the implant based on echocardiographic evaluation of dyssynchrony. Many data indicate that CRT is underused and there is heterogeneity in its implementation. PMID- 26596812 TI - Why the Authors Use Cardiac Resynchronization Therapy with Defibrillators. AB - Cardiac resynchronization therapy (CRT) improves left ventricular function, especially in patients with left bundle branch block or those receiving chronic right ventricular pacing. CRT is typically accomplished by placing a right ventricular endocardial pacing lead and a left ventricular pacing lead via the coronary sinus to a coronary vein overlying the lateral or posterolateral left ventricle. CRT can be combined with an implantable defibrillator or with a pacemaker. Limited data are available to compare these two versions of CRT head to head. This review summarizes the relevant trials and meta-analyses regarding these two forms of CRT. PMID- 26596813 TI - Why We Have to Use Cardiac Resynchronization Therapy-Pacemaker More. AB - Both cardiac resynchronization therapy with a pacemaker (CRT-P) and with a biventricular implantable cardioverter-defibrillator (CRT-D) are electrical treatment modalities validated for the management of chronic heart failure. There is no strong scientific evidence that a CRT-D must be offered to all candidates. Common sense should limit the prescription of these costly and complicated devices. The choice of CRT-P is currently acceptable. A direction to explore could be to downgrade from CRT-D to CRT-P at the time of battery depletion in patients with large reverse remodeling and no ventricular tachycardia and ventricular fibrillation detected. PMID- 26596814 TI - Cardiac Resynchronization Therapy in Women. AB - The benefits of cardiac resynchronization therapy (CRT) on the outcomes of patients with heart failure are unquestionable. Women are under-represented in all CRT studies. Most of the available data show that CRT produces a greater clinical benefit in women than men. In several studies, women have left bundle branch block more frequently than men. Women have a remarkably high (90%) CRT response over a wide range of QRS lengths (130-175 milliseconds). Use of a QRS duration of 150 milliseconds as the threshold for CRT prescription may deny a life-saving therapy to many women likely to benefit from CRT. PMID- 26596815 TI - Atrial Fibrillation During Cardiac Resynchronization Therapy. AB - The landmark trials on cardiac resynchronization therapy (CRT) have focused on patients with sinus rhythm at inclusion. Little data are available on the efficacy of CRT in patients with atrial fibrillation (AF), while AF has a high prevalence (20-40%) among patients receiving CRT. This review focuses on the detrimental effect of AF on CRT response and discusses management of patients with AF during CRT. Uncertainty remains as to which thresholds of AF burden can lead to a reduced response to CRT and every effort should be made in trying to assess and guarantee successful biventricular pacing in patients with AF. PMID- 26596816 TI - Atrioventricular Node Ablation. AB - Cardiac resynchronization therapy (CRT) is a device-based, nonpharmacologic approach that has shown to improve the outcome in patients with heart failure in terms of mortality and morbidity reduction. Large randomized trials have virtually enrolled patients in New York Heart Association class III-IV, with reduced left ventricular ejection fraction, with evidence of electrical dyssynchrony, and receiving optimal medical therapy and who were in sinus rhythm. Guidelines remain imprecise as to defining differentiated approaches according to the forms of atrial fibrillation other than permanent. These recommendations remain unsupported by evidence derived from randomized controlled trials, which are much needed. PMID- 26596817 TI - How to Improve Cardiac Resynchronization Therapy Benefit in Atrial Fibrillation Patients: Pulmonary Vein Isolation (and Beyond). AB - Although cardiac resynchronization therapy (CRT) is an important treatment of symptomatic heart failure patients in sinus rhythm with low left ventricular ejection fraction and ventricular dyssynchrony, its role is not well defined in patients with atrial fibrillation (AF). CRT is not as effective in patients with AF because of inadequate biventricular capture and loss of atrioventricular synchrony. Both can be addressed with catheter ablation of AF. It is still unclear if these therapies offer additive benefits in patients with ventricular dyssynchrony. This article discusses the role and techniques of catheter ablation of AF in patients with heart failure, and its application in CRT recipients. PMID- 26596818 TI - The Role of Atrioventricular and Interventricular Optimization for Cardiac Resynchronization Therapy. AB - Many patients with left ventricular systolic dysfunction may benefit from cardiac resynchronization therapy; however, approximately 30% of patients do not experience significant clinical improvement with this treatment. AV and VV delay optimization techniques have included echocardiography, device-based algorithms, and several other novel noninvasive techniques. Using these techniques to optimize device settings has been shown to improve hemodynamic function acutely; however, the long-term clinical benefit is limited. In most cases, an empiric AV delay with simultaneous biventricular or left ventricular pacing is adequate. The value of optimization of these intervals in "nonresponders" still requires further investigation. PMID- 26596819 TI - What We Can Learn from "Super-responders". AB - This review discusses the state of the art of knowledge to help decision making in patients who are candidates for cardiac resynchronization therapy (CRT) and to analyze the long-term total and cardiac mortality, sudden death, and CRT with a defibrillator intervention rate, as well as the evolution of echocardiographic parameters in patients with a left ventricular (LV) ejection fraction of greater than 50% after CRT implantation. Owing to normalization of LV function in super responders, the need for a persistent defibrillator backup is also considered. PMID- 26596820 TI - Cardiac Resynchronization Therapy: How to Decrease Nonresponders. AB - Nonresponse to cardiac resynchronization therapy (CRT) is still a major issue in therapy expansion. The description of fast, simple, cost-effective methods to optimize CRT could help in adapting pacing intervals to individual patients. A better understanding of the importance of appropriate patient selection, left ventricular lead placement, and device programming, together with a multidisciplinary approach and an optimal follow-up of the patients, may reduce the percentage of nonresponders. PMID- 26596821 TI - Cardiac Resynchronization Therapy Follow-up: Role of Remote Monitoring. AB - Cardiac resynchronization therapy (CRT) is increasingly used in heart failure treatment and management of these patients imposes significant challenges. Remote monitoring is becoming essential for CRT follow-up and allows close surveillance of device function and patient condition. It is helpful to reduce clinic visits, increase device longevity and provide early detection of device failure. Clinical effects include prevention of appropriate and inappropriate shocks and early detection of arrhythmias, such as atrial fibrillation. For modification of heart failure the addition of monitoring to CRT by means of device-based multiparameters may help to modify disease progression and improve survival. PMID- 26596822 TI - Arrhythmogenic Potential of Acute Idiopathic Pericarditis. PMID- 26596823 TI - Cardiac Resysnchronization Therapy: State of the Art. PMID- 26596824 TI - Cardiac Resynchronization Therapy: State of the Art. PMID- 26596825 TI - Behavioural alterations from exposure to Cu, phenanthrene, and Cu-phenanthrene mixtures: linking behaviour to acute toxic mechanisms in the aquatic amphipod, Hyalella azteca. AB - Phenanthrene (PHE) and Cu are two contaminants commonly co-occurring in marine and freshwater environments. Mixtures of PHE and Cu have been reported to induce more-than-additive lethality in the amphipod, Hyalella azteca, a keystone aquatic invertebrate, yet little is understood regarding the interactive toxic mechanisms that mediate more-than-additive toxicity. Understanding the interactions among toxic mechanisms among Cu and PHE will allow for better predictive power in assessing the ecological risks of Cu-PHE mixtures in aquatic environments. Here we use behavioural impairment to help understand the toxic mechanisms of Cu, PHE, and Cu-PHE mixture toxicity in the aquatic amphipod crustacean, Hyalella azteca. Our principal objective was to link alterations in activity and ventilation with respiratory rates, oxidative stress, and neurotoxicity in adult H. azteca. Adult amphipods were used for all toxicity tests. Amphipods were tested at sublethal exposures of 91.8- and 195-MUgL(-1) Cu and PHE, respectively, and a Cu-PHE mixture at the same concentrations for 24h. Neurotoxicity was measured as acetylcholinesterase (AChE) activity, where malathion was used as a positive control. Oxidative stress was measured as reactive oxygen species (ROS) production. Phenanthrene-exposed amphipods exhibited severe behavioural impairment, being hyperstimulated to the extent that they were incapable of coordinating muscle movements. In addition, respiration and AChE activity in PHE exposed amphipods were increased and reduced by 51% and 23% respectively. However, ROS did not increase following exposure to phenanthrene. In contrast, Cu had no effect on amphipod behaviour, respiration or AChE activity, but did lead to an increase in ROS. However, co-exposure to Cu antagonized the PHE-induced reduction in ventilation and negated any increase in respiration. The results suggest that PHE acts like an organophosphate pesticide (e.g., malathion) in H. azteca following 24h sublethal exposures, and that AChE inhibition is the likely mechanism by which PHE alters H. azteca behaviour. However, interactive aspects of neurotoxicity do not account for the previously observed more-than-additive mortality in H. azteca following exposure to Cu-PHE mixtures. PMID- 26596826 TI - Analysis of long-term performance and microbial community structure in bio cathode microbial desalination cells. AB - A microbial desalination cell (MDC) could desalinate salt water without energy consumption and simultaneously generate bioenergy. Compared with an abiotic cathode MDC, an aerobic bio-cathode MDC is more sustainable and is less expensive to operate. In this study, the long-term operation (5500 h) performance of a bio cathode MDC was investigated in which the power density, Coulombic efficiency, and salt removal rate were decreased by 71, 44, and 27 %, respectively. The primary reason for the system performance decrease was biofouling on the membranes, which increased internal resistance and reduced the ionic transfer and energy conversion efficiency. Changing membranes was an effective method to recover the MDC performance. The microbial community diversity in the MDC anode was low compared with that of the reported microbial fuel cell (MFC), while the abundance of Proteobacteria was 30 % higher. The content of Planctomycetes in the cathode biofilm sample was much higher than that in biofouling on the cation exchange membrane (CEM), indicating that Planctomycetes were relevant to cathode oxygen reduction. PMID- 26596827 TI - Effect of rice straw application on microbial community and activity in paddy soil under different water status. AB - Rice straw application and flooding are common practices in rice production, both of which can induce changes in the microbial community. This study used soil microcosms to investigate the impact of water status (saturated and nonsaturated) and straw application (10 g kg(-1) soil) on soil microbial composition (phospholipid fatty acid analysis) and activity (MicroResp(TM) method). Straw application significantly increased total PLFA amount and individual PLFA components independent of soil moisture level. The amount of soil fungal PLFA was less than Gram-negative, Gram-positive, and actinomycete PLFA, except the drained treatment with rice straw application, which had higher fungal PLFA than actinomycete PLFA at the initial incubation stage. Straw amendment and waterlogging had different effects on microbial community structure and substrate induced pattern. PLFA profiles were primarily influenced by straw application, whereas soil water status had the greater influence on microbial respiration. Of the variation in PLFA and respiration data, straw accounted for 30.1 and 16.7 %, while soil water status explained 7.5 and 29.1 %, respectively. Our results suggest that (1) the size of microbial communities in paddy soil is more limited by carbon substrate availability rather than by the anaerobic conditions due to waterlogging and (2) that soil water status is more important as a control of fungal growth and microbial community activity. PMID- 26596828 TI - Preterm labour: summary of NICE guidance. PMID- 26596829 TI - Differential effects of c-myc and ABCB1 silencing on reversing drug resistance in HepG2/Dox cells. AB - Multidrug resistance (MDR) in various kinds of cancers represents a true obstacle which hinders the successes of most of current available chemotherapies. ATP binding cassette (ABC) trasporter proteins have been shown to contribute to the majority of MDR in various types of malignancies. c-myc has recently been reported to participate, at least partly, in MDR to some types of cancers. This study aimed to test whether c-myc could play a role, solely or with coordination with other ABCs, in the resistance of HepG2 cells to doxorubicin (Dox). MDR has been induced in wild-type HepG2 and has been verified both on gene and protein levels. Various assays including efflux assays as well as siRNA targeting ABCB1 and c-myc have been employed to explore the role of both candidate molecules in MDR in HepG2. Results obtained, with regard to ABCB1 silencing on HepG2/Dox cells, have shown that ABCB1-deficient cells exhibited a significant reduction in ABCC1 expression as compared to ABCB1-sufficient cells. However, these cells did not show a significant reduction in other tested ABCs (ABCC5 and ABCC10) while c myc silencing had no significant effect on any of the studied ABCs. Moreover, silencing of ABCB1 on HepG2 significantly increased fluorescent calcein retention in HepG2 cells as compared to the control cells while downregulation of c-myc did not have any effect on fluorescent calcein retention. Altogether, this work clearly demonstrates that c-myc has no role in MDR of HepG2 to Dox which has been shown to be ABCB1-mediated in a mechanism which might involve ABCC1. PMID- 26596830 TI - The overexpression of miR-30a affects cell proliferation of chondrosarcoma via targeting Runx2. AB - MicroRNAs (miRNAs) are emerging as important epigenetic modulators of multiple target genes, leading to abnormal cellular signaling involving cellular proliferation in cancers. Aberrant miRNA expression has been observed in human chondrosarcoma (CS). The purpose of the present study was to evaluate the expression and molecular mechanisms of Runx2 and miR-30a in human CS tissues and CS cell lines JJ012, SW1353, and L3252. In the present study, we found that the expression of miR-30a was markedly downregulated in CS cell lines and human CS tissues, compared to matched non-tumor-associated tissues. Furthermore, miR-30a expression was inversely proportional to that of Runx2 messenger RNA (mRNA) and protein. Upregulation of miR-30a dramatically reduced the proliferation, colony formation, and cell cycle-related proteins of CS cells. Flow cytometry analysis showed that ectopic expression of miR-30a significantly decreased the percentage of S phase cells and increased the percentage of G1/G0 phase cells. Luciferase reporter assays confirmed that miR-30a binding to the 3'-untranslated region (3' UTR) region of Runx2 inhibited the expression of Runx2 in cancer cells. Taken together, our results suggest that miR-30a plays an important role to inhibit the proliferation of CS cells and presents a novel mechanism for direct miRNA mediated suppression of Runx2 in CS. Thus, miR-30a/Runx2 may have an important role in treatment of CS patients. PMID- 26596831 TI - MicroRNA-125b suppresses the epithelial-mesenchymal transition and cell invasion by targeting ITGA9 in melanoma. AB - Increasing evidence has shown that aberrant miRNAs contribute to the development and progression of human melanoma. Previous studies have shown that miR-125b functions as a suppressor in malignant melanoma. However, the molecular function and mechanism by which miR-125b influences melanoma growth and invasion are still unclear. In this study, we aimed to investigate the role of miR-125b in melanoma progression and metastasis. We found that miR-125b expression is significantly downregulated in primary melanoma, and an even greater downregulation was observed in metastatic invasion. Restored expression of miR-125b in melanoma suppressed cell proliferation and invasion both in vitro and in vivo. Furthermore, our findings demonstrate that upregulating miR-125b significantly inhibits malignant phenotypes by repressing the expression of integrin alpha9 (ITGA9). Finally, our data reveal that upregulated expression of ITGA9 in melanoma tissues is inversely associated with miR-125b levels. Together, our results demonstrate that upregulation of ITGA9 in response to the decrease in miR 125b in metastatic melanoma is responsible for melanoma tumor cell migration and invasion. PMID- 26596832 TI - Derivate isocorydine inhibits cell proliferation in hepatocellular carcinoma cell lines by inducing G2/M cell cycle arrest and apoptosis. AB - We have previously demonstrated that isocorydine (ICD) can be served as a potential antitumor agent in hepatocellular carcinoma (HCC). A novel derivate of isocorydine (d-ICD) could significantly improve its anticancer activity in tumors. However, the molecular mechanisms of d-ICD on HCC cells remain to be unclear. In this study, we observed that d-ICD inhibited cell proliferation and induced apoptosis of HCC cells in a concentration-dependent manner. We found d ICD induced G2/M cycle arrest of HCC cells via DNA damage 45 alpha (GADD45A) and p21 pathway in vitro and in vivo. In d-ICD-treated cells, cell cycle-related proteins cyclin B1 and p-CDC2 were upregulated and p-cyclin B1, CDC2, and E2F1 were inhibited. p21 expression can be reversed by knockdown of GADD45A in d-ICD treated HCC cells. Enforced expression of CCAAT/enhancer-binding protein beta (C/EBPbeta) in combination with d-ICD enhanced the p21 expression in HCC cells. Furthermore, the luciferase reporter assay showed that upregulation of GADD45A by C/EBPbeta was achieved through the increase of GADD45A promoter activity. These findings indicate that d-ICD inhibits cell proliferation and induces cell cycle arrest through activation of C/EBPbeta-GADD45A-p21 pathway in HCC cells. d-ICD might be a promising chemotherapeutic agent for the treatment of HCC. PMID- 26596833 TI - Upregulated miRNA-622 inhibited cell proliferation, motility, and invasion via repressing Kirsten rat sarcoma in glioblastoma. AB - Glioblastoma has been reported as one of the leading causes of cancer-related death, and some factors including oncogenic genes and environments are involved in tumorigenesis. MicroRNAs (miRNAs) act as a kind of small and noncoding RNA, which can target the downstream molecules. Emerging reports demonstrate that microRNAs regulate the initiation and progression of different cancers. In the present study, we conducted in vitro experiment as well as clinical studies in a cohort of 20 glioblastoma samples. We demonstrated that miR-622 expression was lower in tumor tissues and cells, when compared to normal brain tissues and normal human astrocyte (NHA) cells, while K-Ras messenger RNA (mRNA) and protein showed the opposite expression profile. Overexpression of miR-622 suppressed tumor cell proliferation, migration, and invasion of A172, U87, and U251 cells. Accordingly, the proliferating cell nuclear antigen (PCNA), matrix metallopeptidase 2 (MMP2), and MMP9 expressions were also decreased due to miR 622 overexpression. Importantly, we discovered that wild Kirsten rat sarcoma (K Ras) was a direct target of miR-622, which decreased the expression of K-Ras protein in A172, U87, and U251 cells. In conclusion, upregulated miRNA-622 inhibited cell proliferation, migration, and invasion via repressing K-Ras in the progression of glioblastoma, and miR-622-K-Ras pathway can be recommended as a potential target for treatment of glioblastoma. PMID- 26596834 TI - Prognostic significance of beta2-adrenergic receptor expression in malignant melanoma. AB - Recent studies cite beta2-adrenergic receptor (beta2AR) antagonists as novel therapeutic agents for melanoma, as they may reduce the disease progression. The beta2AR has shown to be expressed in malignant melanoma. However, it remains unclear whether the beta2AR expression has a clinical and pathological significance in patients with cutaneous malignant melanoma. We herein conducted a clinicopathological study to investigate the protein expression of beta2AR in malignant melanoma of the skin and its prognostic significance. One hundred thirty-three patients with surgically resected cutaneous malignant melanoma were evaluated. Tumor sections were stained by immunohistochemistry for beta2AR, Ki 67, the microvessel density (MVD) determined by CD34, and p53. beta2AR was highly expressed in 44.4 % (59 out of 133) of the patients. The expression of beta2AR was significantly associated with the tumor thickness, ulceration, T factor, N factor, disease stage, tumor size, cell proliferation (Ki-67), and MVD (CD34). Using Spearman's rank test, the beta2AR expression was correlated with Ki-67 (r = 0.278; 95 % CI, 0.108 to 0.432; P = 0.001), CD34 (r = 0.445; 95 %CI, 0.293 to 0.575; P < 0.001), and the tumor size (r = 0.226; 95 % CI, 0.053 to 0.386; P = 0.008). Using a univariate analysis, the tumor thickness, ulceration, disease stage, beta2AR, Ki-67, and CD34 had a significant relationship with the overall and progression-free survivals. A multivariable analysis confirmed that beta2AR was an independent prognostic factor for predicting a poor overall survival (HR 1.730; 95 % CI 1.221-2.515) and progression-free survival (HR 1.576; 95 % CI 1.176-2.143) of malignant melanoma of the skin. beta2AR can serve as a promising prognostic factor for predicting a worse outcome after surgical treatment and may play an important role in the development and aggressiveness of malignant melanoma. PMID- 26596835 TI - NIK- and IKKbeta-binding protein promotes colon cancer metastasis by activating the classical NF-kappaB pathway and MMPs. AB - The nuclear factor (NF)-kappaB pathway has been implicated in colorectal cancer (CRC) tumorigenesis. Here, we investigated the role of a novel NIK- and IKKbeta binding protein (NIBP) in CRC metastasis through activation of the canonical NF kappaB pathway. NIBP, p-p65, and matrix metalloproteases (MMPs) were assessed by immunohistochemistry in 114 CRC tissues, and the time to metastasis was recorded after surgery. Furthermore, the activity of the NF-kappaB pathway, MMP expression, and the metastatic potential of HT-29 cells overexpressing NIBP after treatment with the NF-kappaB inhibitor pyrrolidinecarbodithioic acid (PDTC) were examined in vitro and in vivo. NIBP-positive CRC exhibited a higher rate of metastasis, and the time to metastasis of NIBP-positive patients was shorter in the early tumor, lymph node, metastasis (TNM) stages (I and II), while NIBP and p p65 expression was higher in later TNM stages (III and IV). However, there was no difference in terms of the positive rate of NIBP, p-p65, MMP-2, and serum carcinoembryonic antigen (CEA) level was no difference in the pathological type, gender, tumor location, or size. The NF-kappaB pathway, MMP-2 and MMP-9 activity, and cell motility and invasion were increased in NIBP-overexpressing cells, even after PDTC treatment. Moreover, these cells exhibited high metastasis in mice, and p-p65, MMP-2, and MMP-9 expression levels were elevated in the primary tumor and liver metastases. In conclusion, NIBP overexpression increases the CRC metastatic potential through activation of the NF-kappaB pathway and increasing MMP-2 and MMP-9 expression. In addition, NIBP overexpression, at least in part, may reduce inhibition of the canonical NF-kappaB pathway and MMPs caused by PDTC treatment. PMID- 26596836 TI - High expression of FOXR2 in breast cancer correlates with poor prognosis. AB - Forkhead box protein R2 (FOXR2) is associated with human central nervous system neoplasms. However, the expression level of FOXR2 in breast cancer specimens remains largely unknown. To identify whether FOXR2 can serve as a biomarker for the diagnosis and prognosis of breast cancer, real-time PCR and immunohistochemistry (IHC) staining were utilized to detect the expression of FOXR2. The messenger RNA (mRNA) and protein levels of FOXR2 in breast cancer samples were novelty higher compared to non-tumorous breast tissues. IHC results revealed FOXR2 expression was significantly correlated to classifications tumor size (p = 0.007) and Ki-67 (p = 0.019). The patients with high expression of FOXR2 had a significantly poor prognosis compared to those of low expression (p = 0.003), especially in the patients with tumor size >=2 cm (p = 0.006) and lymph node metastasis status (p = 0.004). Furthermore, multivariate analysis indicated that FOXR2 expression was an independent prognostic factor for breast cancer patients (p = 0.035). This study first identifies that FOXR2 may be an important molecular marker for diagnosis and prognosis of breast cancer. PMID- 26596837 TI - Chronic unpredictable stress deteriorates the chemopreventive efficacy of pomegranate through oxidative stress pathway. AB - Chronic unpredictable stress (CUS) can influence the risk and progression of cancer through increased oxidative stress. Pomegranate is known to protect carcinogenesis through its anti-oxidative properties. This study is carried out to examine whether CUS affects the chemopreventive potential of pomegranate through oxidative stress pathway. Role of CUS on early stages of 7, 12 dimethyl benz(a) anthracene (DMBA) induced carcinogenesis, and its pre-exposure effect on chemopreventive efficacy of pomegranate juice (PJ) was examined in terms of in vivo antioxidant and biochemical parameters in Swiss albino rats. Rats were divided in various groups and were subjected to CUS paradigm, DMBA administration (65 mg/kg body weight, single dose), and PJ treatment. Exposure to stress (alone) and DMBA (alone) led to increased oxidative stress by significantly decreasing the antioxidant enzymes activities and altering the glutathione (GSH), malondialdehyde (MDA), glutamate oxaloacetate transaminase (GOT), and glutamate pyruvate transaminase (GPT) levels. A significant increase in DNA damage demonstrated by comet assay was seen in the liver cells. Stress exposure to DMBA treated rats further increased the oxidative stress and disturbed the biochemical parameters as compared to DMBA (alone)-treated rats. Chemoprevention with PJ in DMBA (alone)-treated rats restored the altered parameters. However, in the pre stress DMBA-treated rats, the overall antioxidant potential of PJ was significantly diminished. Our results indicate that chronic stress not only increases the severity of carcinogenesis but also diminishes the anti-oxidative efficacy of PJ. In a broader perspective, special emphasis should be given to stress management and healthy diet during cancer chemoprevention. PMID- 26596838 TI - Aspirin acetylates wild type and mutant p53 in colon cancer cells: identification of aspirin acetylated sites on recombinant p53. AB - Aspirin's ability to inhibit cell proliferation and induce apoptosis in cancer cell lines is considered to be an important mechanism for its anti-cancer effects. We previously demonstrated that aspirin acetylated the tumor suppressor protein p53 at lysine 382 in MDA-MB-231 human breast cancer cells. Here, we extended these observations to human colon cancer cells, HCT 116 harboring wild type p53, and HT-29 containing mutant p53. We demonstrate that aspirin induced acetylation of p53 in both cell lines in a concentration-dependent manner. Aspirin-acetylated p53 was localized to the nucleus. In both cell lines, aspirin induced p21(CIP1). Aspirin also acetylated recombinant p53 (rp53) in vitro suggesting that it occurs through a non-enzymatic chemical reaction. Mass spectrometry analysis and immunoblotting identified 10 acetylated lysines on rp53, and molecular modeling showed that all lysines targeted by aspirin are surface exposed. Five of these lysines are localized to the DNA-binding domain, four to the nuclear localization signal domain, and one to the C-terminal regulatory domain. Our results suggest that aspirin's anti-cancer effect may involve acetylation and activation of wild type and mutant p53 and induction of target gene expression. This is the first report attempting to characterize p53 acetylation sites targeted by aspirin. PMID- 26596839 TI - Increased expression of MyD88 and association with paclitaxel resistance in breast cancer. AB - MyD88 was reported to be associated with paclitaxel sensitivity in lung cancer; however, its roles in breast cancer remain unclear. The objective of this study is to investigate the expression and function of MyD88 in breast cancer. Immunohistochemistry (IHC) was used to analyze the expression of MyD88 in both breast cancer tissues and adjacent normal tissues. Real-time PCR and Western blots were further used to measure the messenger RNA (mRNA) and protein expression. The proliferation was assessed by WST-1. Flow cytometry was used to measure the cell cycle and apoptosis. The transwell assay was used to observe the change of migration and invasion of transfected cells. In breast cancer tissues, the expression of MyD88 was significantly higher than that in tumor-adjacent normal tissues (P < 0.001). MyD88 expression was found to be associated with the differentiation stages (P = 0.019). Kaplan-Meier survival curves showed statistically significant difference on survival in patients with high expression of MyD88 compared with those with normal expression of MyD88 (P = 0.018). Knockdown of MyD88 reduced the proliferation, migration, and invasion of MCF-7 cells and increased the sensitivity of MCF-7 cells to paclitaxel treatment through the inhibition of activation of NF-kappaB via PI3K/Akt. Our data indicate that MyD88 may be a potential target molecule to be used in diagnosis and treatment of breast cancer. PMID- 26596840 TI - Inhibition of pentose phosphate pathway suppresses acute myelogenous leukemia. AB - Pentose phosphate pathway (PPP) is a metabolic pathway that generates NADPH and pentose. PPP genes have been reported to be primarily or secondarily upregulated in many cancers. We aimed to study the general alteration of PPP in acute myelogenous leukemia (AML). We performed data mining and analysis of the Cancer Genome Atlas (TCGA) AML dataset for genetic alteration of the PPP gene set. In vitro studies including proliferation, migration, and invasion assays, together with metabolite consumption and oxidation assays, were performed. PPP genes were upregulated in 61 % of patients with AML. The majority of altered cases were expression changes measured by RNA sequencing. Expressions of critical PPP genes such as G6PD, PFKL, PFKP, and PGLS were consistently upregulated in all altered cases. Altered PPP is not associated with survival or disease relapse. PPP inhibition using 6-aminonicotinamide (6AN) increases glucose oxidative metabolism in AML. 6AN decreased the glucose oxidation and increased fatty acid oxidation. Here, we showed that PPP inhibition increased glucose oxidative metabolism in AML. PPP inhibition suppressed growth, migration, and invasion of AML, but not colony formation. PPP plays an important role in AML. Our results could contribute to the development of novel targeted treatment. PMID- 26596842 TI - Metabolomic study on the faecal extracts of atherosclerosis mice and its application in a Traditional Chinese Medicine. AB - The intestinal microbiota and their metabolites are closely related to the formation of atherosclerosis (AS). In this study, a metabolomic approach based on the reversed-phase liquid chromatography/quadrupole time-of-flight mass spectrometry (LC-Q-TOF-MS) platform was established to analyze the metabolic profiling of fecal extracts from AS mice model. The established metabolomic platform was also used for clearing the effective mechanism of a Traditional Chinese Medicine (TCM) named Sishen granule (SSKL). Totally, sixteen potential biomarkers in faeces of AS mice were identified and 5 of them could be reversed by SSKL. Through functional analysis of these biomarkers and the established network, lipid metabolism, cholesterol metabolism, energy cycle, and inflammation reaction were considered as the most relevant pathological changes in gastrointestinal tract of AS mice. The metabolomic study not only revealed the potential biomarkers in AS mice' faeces but also supplied a systematic view of the pathological changes in gastrointestinal metabolite in AS mice. This metabolomic study also demonstrated that SSKL had the therapeutic effectiveness on AS through partly reversing the lipid metabolism, inflammation and energy metabolism. PMID- 26596843 TI - Some Consensus has been Reached on the Labeling of Harmonics, Formants, and Resonances. PMID- 26596841 TI - A Prospective Study on Cardiovascular Dysfunction in Patients with Hyperthyroidism and Its Reversal After Surgical Cure. AB - BACKGROUND: Cardiovascular dysfunction (CVD) is a major cause of mortality and morbidity in hyperthyroidism. CVD and its reversibility after total thyroidectomy (TT) are not adequately addressed. This prospective case-control study evaluates the effect of hyperthyroidism on myocardium and its reversibility after TT. MATERIALS AND METHODS: Surgical candidates of new onset hyperthyroidism, Group A (n = 41, age < 60 years) was evaluated with 2D Echocardiography, serum n-terminal probrain natriuretic peptide (NT-proBNP) at the time of diagnosis (Point A), after achieving euthyroidism (Point B) with antithyroid drugs, and 3 months after TT (Point C). 20 patients with nontoxic benign thyroid nodules undergoing TT served as controls (Group B). RESULTS: Both groups were age and sex matched. Group A (n = 41) comprises Graves disease (n = 22) and Toxic Multinodular goiter (n = 19). At point A, CVD was evident in 26/41(63.4%), pulmonary hypertension (PHT) in 24/41(58.5%)--mild in 17/41(41.4%) and moderate in 7/41(17%)--dilated cardiomyopathy (DCM) in 8/41(19.5%), heart failure in 4/41(9.7%), and NT-proBNP elevated in 28/41(68.3%). At point B, recovery was observed in PHT 19/26(73.1%), DCM 4/8(50%), heart failure 4/4(100%), NT-proBNP in 3/28(10.7%). At Point C, further improvement occurred in PHT 23/24(95.8%), DCM 7/8(87.5%), heart failure 4/4(100%), and NT-proBNP in 24/28(85.7%). CONCLUSION: Pulmonary hypertension is completely reversible at 3 months after TT and is the most common cardiac event in Hyperthyroidism. Various parameters of CVD improved consistently after surgical cure. NT-proBNP levels correlated well with the severity and duration of CVD and hence can be an objective tool in monitoring of hyperthyroid cardiac dysfunction. PMID- 26596844 TI - The Prevalence of Teachers' Vocal Symptoms in Municipal Network of Education in Campo Grande, Mato Grosso do Sul, Brazil. AB - OBJECTIVE: This study aims to provide an epidemiological overview of the teacher's voice and to examine the prevalence of voice problems at Municipal Board Education in Campo Grande, Mato Grosso do Sul, Brazil. METHODS: This is a cross-sectional, descriptive, and quantitative study. Of the 4957 teachers registered with Municipal Board Education (Semed)/2013, 394 participated in this research. All seven urban areas of Campo Grande (Prosa, Bandeira, Anhanduizinho, Lagoa, Segredo, Centro, and Imbirussu) were sampled. The Ferreira et al. protocol was adapted and used for data collection. The Likert scale was used as the measurement method. RESULTS: There was a high prevalence of vocal symptoms. Teachers had multiple symptoms related to the use of voice at work and acknowledged that the symptoms had adverse effects on their professional performance. CONCLUSION: The severity of voice problems that the teachers experienced in daily speech therapy services and in the Municipal Network of Education was found in a significant number of participants in this research. PMID- 26596845 TI - Respiratory Laryngeal Coordination in Airflow Conservation and Reduction of Respiratory Effort of Phonation. AB - OBJECTIVE: This study evaluates the need of airflow conservation and the effect of glottal resistance on respiratory effort of phonation under different phonation conditions. METHODS: A computational model of the pressure-volume-flow relationship of the respiratory system is developed. RESULTS: Simulations show that increasing the glottal resistance reduces the glottal airflow and allows phonation to be sustained for a longer breath group duration. For a given breath group duration, the reduced airflow also allows phonation to be sustained within a narrow range of lung volumes, thus lowering the overall respiratory effort. CONCLUSIONS: This study shows that for breath group durations and subglottal pressures typical of normal conversational speech, airflow conservation or maintaining "effortless" respiratory support does not provide a stricter requirement on the glottal resistance than that required for initiating phonation. However, the need for airflow conservation and respiratory effort reduction becomes relevant when the target subglottal pressure and breath group duration increase as in prolonged speech or singing or in conditions of weakened pulmonary function. In those conditions, the glottal resistance is expected to increase proportionally with increasing subglottal pressure to conserve airflow consumption and reduce respiratory effort. PMID- 26596846 TI - Self-amplified BDNF transcription is a regulatory system for synaptic maturation in cultured cortical neurons. AB - Neuronal cell survival and synaptic plasticity are controlled through expression of various neurotrophic factors including brain-derived neurotrophic factor (BDNF). In the present study, we examined the mechanism behind BDNF-induced Bdnf mRNA production and the physiological role of its amplification system using cortical neurons. Exogenous BDNF was applied to the cultured cortical neurons at days in vitro (DIV) 3 and DIV 7 with or without inhibitors for intracellular signaling. Expression levels of total Bdnf and Bdnf variants (exon I, exon IV, and exon VI) were biphasically increased after the BDNF application in different developing stage of neurons. Inhibitor for extracellular signal-regulated kinase, calmodulin dependent protein kinase II, or protein kinase A repressed the BDNF induced Bdnf mRNA expression. Furthermore, we found that application of TrkB-Fc, which scavenges produced endogenous BDNF, resulted in weakened BDNF/TrkB signaling and decreased expression of postsynaptic proteins, suggesting that newly synthesized BDNF induced by the self-amplification system contributes to the synaptic maturation and function. PMID- 26596847 TI - Assessing Attachment in Psychotherapy: Validation of the Patient Attachment Coding System (PACS). AB - : The authors present and validate the Patient Attachment Coding System (PACS), a transcript-based instrument that assesses clients' in-session attachment based on any session of psychotherapy, in multiple treatment modalities. One-hundred and sixty clients in different types of psychotherapy (cognitive-behavioural, cognitive-behavioural-enhanced, psychodynamic, relational, supportive) and from three different countries were administered the Adult Attachment Interview (AAI) prior to treatment, and one session for each client was rated with the PACS by independent coders. Results indicate strong inter-rater reliability, and high convergent validity of the PACS scales and classifications with the AAI. These results present the PACS as a practical alternative to the AAI in psychotherapy research and suggest that clinicians using the PACS can assess clients' attachment status on an ongoing basis by monitoring clients' verbal activity. These results also provide information regarding the ways in which differences in attachment status play out in therapy sessions and further the study of attachment in psychotherapy from a pre-treatment client factor to a process variable. Copyright (c) 2015 John Wiley & Sons, Ltd. KEY PRACTITIONER MESSAGE: The Patient Attachment Coding System is a valid measure of attachment that can classify clients' attachment based on any single psychotherapy transcript, in many therapeutic modalities Client differences in attachment manifest in part independently of the therapist's contributions Client adult attachment patterns are likely to affect psychotherapeutic processes. PMID- 26596848 TI - Nucleus accumbens dimensions and surgical precision. PMID- 26596849 TI - Origins and outlook of interoceptive exposure. AB - BACKGROUND AND OBJECTIVES: Interoceptive exposure (IE) is a behavioral intervention that reduces anxiety sensitivity and distress associated with somatic sensations. In this discussion, we describe the history, current applications and additional clinical potential of IE. METHOD: We review the origins of IE and its historical application to panic disorder, as well as the accumulating evidence for transdiagnostic application to other disorders including post-traumatic stress disorder, social anxiety disorder, specific phobias and physical disorders. Then, we discuss ways in which IE could contribute to the treatment of additional disorders. RESULTS: IE is well established in the treatment of panic disorder and increasingly used to target anxiety-provoking physical sensations in other disorders. Research and clinical evidence suggests that anxiety sensitivity is present across a range of disorders, and may actually be one variation on a broader phenomenon of interoceptive sensitivity, or anxiety focused on physical sensations that have been conditioned to unpleasant emotional states. Moreover, somatic symptoms are central to the experience of most emotions and may contribute to avoidant coping, a maintenance factor for disorders of emotion. IE has potential as a transdiagnostic intervention targeting interoceptive sensitivity in disorders such as depression and eating disorders. Nevertheless, IE is underutilized by clinicians in practice. Recent research in inhibitory learning and extinction suggests strategies for maximizing the effectiveness of IE. LIMITATIONS: This review is not exhaustive in nature, and systematic research on transdiagnostic applications of IE remains scarce. CONCLUSIONS: IE is a potentially powerful yet understudied transdiagnostic intervention. PMID- 26596850 TI - How the context of ambulance care influences learning to become a specialist ambulance nurse a Swedish perspective. AB - OBJECTIVES: Ambulance emergency care is multifaceted with extraordinary challenges to implement accurate assessment and care. A clinical learning environment providing opportunities for mastering these essential skills is a key component in ensuring that prehospital emergency nurse (PEN) students acquire the necessary clinical competence. AIM: The aim is to understand how PEN students experience their clinically based training, focusing on their learning process. METHOD: We applied content analysis with its qualitative method to our material that consisted of three reflections each by 28 PEN students over their learning process during their 8 weeks of clinical ambulance practice. The research was carried out at the Center for Prehospital Care, University of Boras, Sweden. RESULTS: The broad spectrum of ambulance assignments seems to awaken great uncertainty and excessive respect in the students. Student vulnerability appears to decrease when the clinical supervisor behaves calmly, knowledgeably, confidently and reflectively. Early traumatic incidents on the other hand may increase the students' anxiety. Each student is offered a unique opportunity to learn how to approach patients and relatives in their own environments, and likewise an opportunity to gather information for assessment. Infrequency of missions seems to make PEN students less active in their student role, thereby preventing them from availing themselves of potential learning situations. Fatigue and hunger due to lack of breaks or long periods of transportation also inhibit learning mode. CONCLUSION: Our findings suggest the need for appraisal of the significance of the clinical supervisor, the ambulance environment, and student vulnerability. The broad spectrum of conditions in combination with infrequent assignments make simulation necessary. However, the unique possibilities provided for meeting patients and relatives in their own environments offer the PEN student excellent opportunities for learning how to make assessments. PMID- 26596851 TI - The top 100 most cited scientific reports focused on diabetes research. AB - AIMS: The number of citations that a paper has received reflects the impact of the article within a particular medical research area. However, which articles are cited most frequently in diabetes research is unknown. We aimed to identify the most frequently cited 100 articles that describe advances focused on diabetes research. METHODS: Science Citation Index Expanded database was used to determine the 100 most cited articles in diabetes research. The key characteristics of the top 100 cited articles, including citation ranking, year of publication, publishing journal, type of study, h-index, PMC citation, patent citation, country of origin, funding source, and authorship, were analyzed. RESULTS: The number of citations ranged from 10292 to 1121. The 100 most cited articles were published between 1962 and 2010. New England Journal of Medicine published the largest number of the most cited articles (n = 23), followed by Diabetes Care (n = 14) and Nature (n = 12). The greatest number of contributions came from the USA, followed by the UK and Canada. RCT was the most popular article type, followed by basic science studies and observational studies. There was a positive correlation between total citations and h-indexes and PMC citations, while there was no correlation with patent citations. CONCLUSIONS: The most influential report in diabetes research seems to be RCT, which is performed to confirm the effectiveness and outcome of anti-diabetes drugs in patients with diabetes. This study presents insight into the historical development of diabetes research, and provides foundations for further investigations. PMID- 26596852 TI - Rare Synchronous Alliance of Three Commonly Occurring Gastrointestinal Tumors-a Case Report and Brief Review of Literature. PMID- 26596853 TI - Extra-Gastrointestinal Stromal Tumor of the Greater Omentum: Unusual Case Report. AB - Gastrointestinal stromal tumors are the most common mesenchymal tumors of the gastrointestinal tract, originating from the interstitial cells of Cajal and most frequently expressing CD-117, a C-kit proto-oncogene, which can be detected immunohistochemically. Extra-gastrointestinal stromal tumors are neoplasms with similar immunohistological features arising outside the gastrointestinal tract with no connection to the gastric or intestinal wall.We report the case of a 61 year-old Moroccan man who presented with chronic abdominal pain along with progressive abdominal distension for the past last year. The clinical examination demonstrated a large abdominal mass and an abdominal computed tomography scan revealed a voluminous intraperitoneal mass measuring 30 cm in its greatest diameter. At laparotomy, this mass seemed to be arising from the greater omentum without continuity to the gastrointestinal tract. The mass was completely removed with clear margins and pathological examination was suggestive for high-risk gastrointestinal stromal tumor of the greater omentum. Due to the aggressive nature of this patient's tumor, he was assigned to receive imatinib as adjuvant chemotherapy for 3 years. He remains alive without any sign of recurrence after 4 years of follow-up.Extra-gastrointestinal stromal tumors of the greater omentum can grow slowly and remain clinically silent despite the large size of the tumor. Complete surgical resection is the only effective treatment approach. Nevertheless, adjuvant therapy following resection with imatinib has become a standard of care in cases of high risk disease. PMID- 26596854 TI - A Low Reabsorbing Luminescent Solar Concentrator Employing pi-Conjugated Polymers. AB - A highly efficient thin-film luminescent solar concentrator (LSC) utilizing two pi-conjugated polymers as antennae for small amounts of the valued perylene bisimide Lumogen F Red 305 is presented. The LSC exhibits high photoluminescence quantum yield, low reabsorption, and relatively low refractive indices for waveguide matching. A Monte Carlo simulation predicts the LSC to possess exceptionally high optical efficiencies on large scales. PMID- 26596855 TI - Family history of hematologic malignancies and risk of multiple myeloma: differences by race and clinical features. AB - PURPOSE: Multiple myeloma (MM) is the most common hematologic malignancy affecting Blacks in the USA, with standardized incidence rates that are twofold to threefold higher than Whites. The rationale for the disparity is unclear. METHODS: Using participants enrolled in the Molecular And Genetic Epidemiology study of myeloma (259 MM cases; 461 controls), we examined the risk of MM associated with family history of cancer, differences by race and among cases, defining clinical features. Risk estimates were calculated using odds ratios and corresponding 95% confidence intervals from logistic regression adjusted for confounders. RESULTS: Overall, MM risk in cases with relatives affected with any hematologic malignancy was significantly elevated compared to controls (OR 1.89, 95% CI 1.25-2.86). Myeloma risk associated with a family history of MM was higher than the risk associated with any hematologic malignancy (OR 3.75, 95% CI 1.75 8.05), and the effect was greater for Blacks (OR 20.9, 95% CI 2.59-168) than Whites (OR 2.04, 95% 0.83-5.04), among cases with early onset (<=60 years; OR 4.58, 95% CI 1.21-17.3) and with increasing numbers of affected relatives (p trend = 0.001). Overall, frequencies of end organ damage differed in cases with relatives affected with any hematologic malignancy and significantly more cases exhibited kappa light chain restriction (OR 3.23, 95% CI 1.13-9.26). CONCLUSIONS: The excess risk of MM observed in Blacks and the variation in clinical features observed in MM patients according to family history of hematologic malignancy may be attributed to a shared germline and environmental susceptibility. PMID- 26596856 TI - Disparities in colorectal cancer incidence among Latino subpopulations in California defined by country of origin. AB - PURPOSE: In California, colorectal cancer (CRC) is the second most common cancer in Latinos. Using data from the California Cancer Registry, we investigated demographic and clinical characteristics of 36,133 Latinos with CRC living in California during 1995-2011 taking into account subpopulations defined by country of origin. METHODS: Cases were defined as Latino according to the North American Association of Central Cancer Registries Hispanic Identification Algorithm, which was also used to group cases by country of origin: Mexico (9,678, 27 %), Central or South America (2,636, 7 %), Cuban (558, 2 %), Puerto Rico (295, 1 %), and other or unknown origin (22,966, 64 %; Other/NOS). 174,710 non-Hispanic white (NHW) CRC cases were included for comparison purposes. Annual age-adjusted incidence rates (AAIR) and proportional incidence ratios (PIRs) were calculated. RESULTS: Differences were observed for age at diagnosis, sex distribution, socioeconomic status (SES), nativity (US born vs. foreign born), stage, and tumor localization across Latino subpopulations and compared to NHW. Mexican Latinos had the lowest AAIR and Cuban Latinos had the highest. PIRs adjusted for age, SES, and nativity showed an excess of CRC males and female cases from Cuba, female cases from Puerto Rico and reduced number of female cases from Mexico. CONCLUSIONS: Differences in cancer incidence patterns and tumor characteristics were observed among Latino subpopulations in California. These disparities may reflect differences in cancer determinants among Latinos; therefore, given that country of origin information is unavailable for a large proportion of these patients, greater efforts to collect these data are warranted. PMID- 26596857 TI - Bacterial colonization status of cystic fibrosis children's toothbrushes: A pilot study. AB - BACKGROUND: Pseudomonas aeruginosa and Staphylococcus aureus toothbrush contamination in cystic fibrosis (CF) is unknown. This pilot study aimed to determine their prevalence and the potential involvement of toothbrushes in pulmonary infection. METHODS: Toothbrush bacteriological analysis for children aged 8-18 years was conducted on 27 CF patients, 15 healthy siblings, and 15 healthy children from the general population. RESULTS: S. aureus was detected on 22% of the patients' toothbrushes, and 13% of healthy children's toothbrushes and P. aeruginosa on 15% of patients' toothbrushes and 0-13% of healthy children's toothbrushes. There was no statistical correlation between pulmonary colonization and toothbrush contamination. P. aeruginosa genotyping showed two identical clones on the patients' toothbrushes and in their sputum, and between one patient's sputum and his sibling's toothbrush. CONCLUSION: S. aureus and P. aeruginosa can colonize CF patients' toothbrushes. The impact on pulmonary colonization remains unknown. Toothbrush decontamination methods need to consider these bacteria in CF patients. PMID- 26596858 TI - Mitochondrial division inhibitor 1 (Mdivi-1) offers neuroprotection through diminishing cell death and improving functional outcome in a mouse model of traumatic brain injury. AB - Mitochondria dysfunction, an enormous potential crisis, has attracted increasing attention. Disturbed regulation of mitochondrial dynamics, the balance of mitochondrial fusion and fission, has been implicated in neurodegenerative diseases, such as Parkinson's disease and cerebral ischemia/reperfusion. However the role of mitochondrial dynamics in traumatic brain injury (TBI) has not been illuminated. The aim of the present study was to investigate the role of Mdivi-1, a small molecule inhibitor of a key mitochondrial fission protein dynamin-related protein 1 (Drp1), in TBI-induced cell death and functional outcome deficits. Protein expression of Drp1 was first investigated. Outcome parameters consist of motor test, Morris water maze, brain edema and lesion volume. Cell death was detected by propidium iodide (PI) labeling, and mitochondrial morphology was assessed using transmission electron microscopy. In addition, the expression of apoptosis-related proteins cytochrome c (cyt-c) and caspase-3 was investigated. Our findings showed that up-regulation of Drp1 expression started at 1h post-TBI and peaked at 24 h, but inhibition of Drp1 by Mdivi-1 significantly alleviated TBI-induced behavioral deficits and brain edema, reduced morphological change of mitochondria, and decreased TBI-induced cell death together with lesion volume. Moreover, treatment with Mdivi-1 remarkably inhibited TBI-induced the release of cyt-c from mitochondria to cytoplasm, and activation of caspase-3 at 24 h after TBI. Taken together, these data imply that inhibition of Drp1 may help attenuate TBI-induced functional outcome and cell death through maintaining normal mitochondrial morphology and inhibiting activation of apoptosis. PMID- 26596860 TI - The causes of selection on flowering time through male fitness in a hermaphroditic annual plant. AB - Flowering is a key life-history event whose timing almost certainly affects both male and female fitness, but tests of selection on flowering time through male fitness are few. Such selection may arise from direct effects of flowering time, and indirect effects through covariance between flowering time and the environment experienced during reproduction. To isolate these intrinsically correlated associations, we staggered planting dates of Brassica rapa families with known flowering times, creating populations in which age at flowering (i.e., flowering time genotype) and Julian date of flowering (i.e., flowering time environment) were positively, negatively, or uncorrelated. Genetic paternity analysis revealed that male fitness was not strongly influenced by seasonal environmental changes. Instead, when age and date were uncorrelated, selection through male fitness strongly favored young age at flowering. Strategic sampling offspring for paternity analysis rejected covariance between sire age at flowering and dam quality as the cause of this selection. Results instead suggest a negative association between age at flowering and pollen competitive ability. The manipulation also revealed that, at least in B. rapa, the often-observed correlation between flowering time and flowering duration is environmental, not genetic, in origin. PMID- 26596861 TI - Palladium(II)-Catalyzed Synthesis of Sulfinates from Boronic Acids and DABSO: A Redox-Neutral, Phosphine-Free Transformation. AB - A redox-neutral palladium(II)-catalyzed conversion of aryl, heteroaryl, and alkenyl boronic acids into sulfinate intermediates, and onwards to sulfones and sulfonamides, has been realized. A simple Pd(OAc)2 catalyst, in combination with the sulfur dioxide surrogate 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) (DABSO), is sufficient to achieve rapid and high-yielding conversion of the boronic acids into the corresponding sulfinates. Addition of C- or N-based electrophiles then allows conversion into sulfones and sulfonamides, respectively, in a one-pot, two-step process. PMID- 26596859 TI - Targeting the nNOS/peroxynitrite/calpain system to confer neuroprotection and aid functional recovery in a mouse model of TBI. AB - Traumatic brain injury (TBI) derails nitric oxide (NO)-based anti-inflammatory and anti-excitotoxicity mechanisms. NO is consumed by superoxide to form peroxynitrite, leading to decreased NO bioavailability for S-nitrosoglutathione (GSNO) synthesis and regulation of neuroprotective pathways. Neuronal peroxynitrite is implicated in neuronal loss and functional deficits following TBI. Using a contusion mouse model of TBI, we investigated mechanisms for the opposed roles of GSNO versus peroxynitrite for neuroprotection and functional recovery. TBI was induced by controlled cortical impact (CCI) in adult male mice. GSNO treatment at 2h after CCI decreased the expression levels of phospho neuronal nitric oxide synthase (pnNOS), alpha II spectrin degraded products, and 3-NT, while also decreasing the activities of nNOS and calpains. Treatment of TBI with FeTPPS, a peroxynitrite scavenger, had effects similar to GSNO treatment. GSNO treatment of TBI also reduced neuronal degeneration and improved neurobehavioral function in a two-week TBI study. In a cell free system, SIN-1 (a peroxynitrite donor and 3-nitrotyrosinating agent) increased whereas GSNO (an S nitrosylating agent) decreased calpain activity, and these activities were reversed by, respectively, FeTPPS and mercuric chloride, a cysteine-NO bond cleaving agent. These data indicate that peroxynitrite-mediated activation and GSNO-mediated inhibition of the deleterious nNOS/calpain system play critical roles in the pathobiology of neuronal protection and functional recovery in TBI disease. Given GSNO's safety record in other diseases, its neuroprotective efficacy and promotion of functional recovery in this TBI study make low-dose GSNO a potential candidate for preclinical evaluation. PMID- 26596862 TI - Decrease in B-Type Natriuretic Peptide Levels and Successful Catheter Ablation for Atrial Fibrillation in Patients with Heart Failure. AB - BACKGROUND: Little is known about the association between B-type natriuretic peptide (BNP) levels and catheter ablation of atrial fibrillation (AF) in patients with heart failure. This study aimed to examine the impact of elimination of AF by catheter ablation on BNP levels in patients with left ventricular systolic dysfunction. METHODS: Fifty-four AF patients with left ventricular ejection fraction (LVEF) <= 50%, who underwent radiofrequency catheter ablation therapy of AF, were included. BNP sampling was performed at baseline, 3 days, and 1 month after ablation. RESULTS: After a follow-up period of 6 months, the BNP levels decreased significantly in the nonrecurrence group (n = 35; median 126.3 [interquartile 57.2-206.5] pg/mL, 63.5 [23.9-180.2] pg/mL, and 45.9 [21.9-160.3] pg/mL, P < 0.001, respectively), but not in the recurrence group (n = 19; 144.7 [87.1-217.3] pg/mL, 88.8 [12.9-213.2] pg/mL, and 118.5 [51.6 298.2] pg/mL, P = 0.368, respectively). The patients in the nonrecurrence group had a higher percentage relative reduction in BNP levels from baseline to 1 month after ablation than those in the recurrence group (56.5 [-9.0-77.4]% vs -2.4 [ 47.1-60.9]%, P = 0.027). Additionally, a relative reduction in BNP levels significantly correlated with an increase in LVEF after ablation (r = 0.486, P < 0.001). CONCLUSIONS: Plasma BNP levels decreased significantly with successful catheter ablation of AF in patients with impaired LVEF. The decrease in BNP levels might be associated with early recovery of cardiac function and subsequent maintenance of sinus rhythm at follow-up. PMID- 26596863 TI - Virulence factors of Clostridium difficile and their role during infection. AB - Clostridium difficile is the prominent etiological agent of healthcare-associated diarrhea. The disease symptoms range from mild diarrhea to life-threatening pseudomembranous colitis. The main risk factor for developing an infection after contamination by the resistant spores is the disruption of the gut microbiota, allowing the spores to germinate. The colonization of the gut is likely to be governed by the bacterial resistance to the host response and the bacterial adhesion to the mucosa. To date, several putative adhesins have been identified, most of them displaying MSCRAMM function, and studies of adhesin mutants have clearly underlined the multi-factorial feature of C. difficile adhesion to the host. Flagella have also been involved in the colonisation process, but their role depends on the tested strains. The clinical signs are mainly due to two large glucosylating toxins, TcdA and TcdB, which are essential for the disease manifestations. The importance of each toxin differs according to strains and experimental conditions, but TcdB seems to be the prominent one, as showed by mutant studies and the natural occurrence of pathogenic strains that do not produce TcdA. The role of the ADP ribosylating binary toxin expressed by some strains, including epidemic lineages, is not clearly established, although it has been related to higher morbidity and mortality. Production of low level of the glucosylating toxins and of the binary toxin seems to promote adhesion to host cells. Expression of the tcdA and tcdB genes is under the control of the second messenger c-di-GMP. This is also the case for other virulence factors, in particular for flagellar, pili type IV and some adhesin genes. Indeed, several studies using knock-out mutants suggest that C. difficile may undergo a switch between the adhesion phenotype and the motility phenotype during the course of infection, regulated by the c-di-GMP intracellular level. In vivo, this could result in biofilm formation that, associated with persistence of spores, could promote the occurrence of relapses observed in at least 20% of patients. PMID- 26596864 TI - Availability of Child Care in Rural Communities: Implications for Workforce Recruitment and Retention. AB - The objective of this study was to identify differences in child care availability by rural-urban location for all counties in Wisconsin, and describe implications for recruitment and retention of health care workforce. We used data on licensed child care slots for young children (age <5), socio-demographic characteristics, women's and men's labor force participation, and household structure for all counties in Wisconsin in 2013 (n = 72). Data came from KIDS COUNT, County Health Rankings, and the American Community Survey. We used t tests to analyze bivariate differences in child care availability and community characteristics by metropolitan, micropolitan, and non-core rural location. We then used ordinary least squares regression to analyze the relationship between geographic location and child care slots, adjusting for labor force participation and household structure. Rural counties had significantly fewer licensed child care slots per child than metropolitan and micropolitan counties. These counties also had, on average, higher rates of poverty and higher unemployment than micropolitan and metropolitan counties. The association between geographic location and child care availability remained, even after adjusting for household structure and labor force participation. The number of hours men worked and the percentage of men not working were both negatively associated with available child care slots, whereas there was not a significant relationship between women's labor force participation and child care availability. Rural areas face health care workforce shortages. Recruitment strategies to overcome shortages must move beyond individual-level incentives to focus on community context and family support, including availability of child care in rural counties. PMID- 26596865 TI - Localizing the lipid products of PI3Kgamma in neutrophils. AB - Class I phosphoinositide 3-kinases (PI3Ks) are important regulators of neutrophil migration in response to a range of chemoattractants. Their primary lipid products PtdIns(3,4,5)P3 and PtdIns(3,4)P2 preferentially accumulate near to the leading edge of migrating cells and are thought to act as an important cue organizing molecular and morphological polarization. We have investigated the distribution and accumulation of these lipids independently in mouse neutrophils using eGFP-PH reportersand electron microscopy (EM). We found that authentic mouse neutrophils rapidly polarized their Class I PI3K signalling, as read-out by eGFP-PH reporters, both at the up-gradient leading edge in response to local stimulation with fMLP as well as spontaneously and randomly in response to uniform stimulation. EM studies revealed these events occurred at the plasma membrane, were dominated by accumulation of PtdIns(3,4,5)P3, but not PtdIns(3,4)P2, and were dependent on PI3Kgamma and its upstream activation by both Ras and Gbetagammas. PMID- 26596866 TI - New insights into microRNAs in skin wound healing. AB - Chronic wounds are a major burden to overall healthcare cost and patient morbidity. Chronic wounds affect a large portion of the US, and billions of healthcare dollars are spent in their treatment and management. microRNAs (miRNAs) are small, noncoding double-stranded RNAs that post-transcriptionally downregulate the expression of protein-coding genes. Studies have identified miRNAs involved in all three phases of wound healing including inflammation, proliferation, and remodeling. Some miRNAs have been demonstrated in vitro with primary keratinocyte wound healing model and in vivo with mouse wound healing model through regulation of miRNA expression to affect the wound healing process. This review updates the current miRNAs involved in wound healing and discusses the future therapeutic implications and research directions. PMID- 26596867 TI - Lipid-Based Therapy for Ocular Surface Inflammation and Disease. AB - Ocular surface diseases such as dry eye, allergic keratoconjunctivitis, and infection are very prevalent conditions and involve ocular surface stress and inflammation. Recently, various lipid-based therapies have been advocated for the modulation of ocular surface inflammation. Here we review the latest developments and challenges of these strategies. These include administration of essential fatty acids, cyclooxygenase (COX) inhibitors and resolvin analogs. Lipids form part of the tear film and are crucial for tear film stability; loss of tear film stability can aggravate ocular surface inflammation. Strategies to replenish tear film lipids - namely, eyelid warming and eye drops containing natural or synthetic lipids - are evaluated. Recent advances in the use of lipids as ocular drug delivery vehicles, antioxidants, and diagnostic markers are discussed. PMID- 26596868 TI - Bioengineered FSTL1 Patches Restore Cardiac Function Following Myocardial Infarction. AB - Improving the limited ability of the heart to regenerate after infarction is crucial. Researchers now demonstrate that delivery of follistatin-like 1 (FSTL1) into injured hearts via collagen patches stimulates cardiomyocyte proliferation and cardiac functional recovery. These findings highlight the epicardium as a source of novel regenerative factors and biomimetic nanomaterials in cardiac translational medicine. PMID- 26596869 TI - Double-peak elution profile of a monoclonal antibody in cation exchange chromatography is caused by histidine-protonation-based charge variants. AB - We have systemically investigated unusual elution behaviors of an IgG4 (mAb A) in cation exchange chromatography (CEX). This mAb A exhibited two elution peaks under certain conditions when being purified by several strong CEX columns. When either of the two peaks was isolated and re-injected on the same column, the similar pattern was observed again during elution. The protein distribution between the two peaks could be altered by NaCl concentration in the feed, or NaCl concentration in wash buffer, or elution pH, suggesting two pH-associated strong and-weak binding configurations. The protein distributions under different pH values showed good correlation with protonated/un-protonated fractions of a histidine residue. These results suggest that the double-peak elution profile associates with histidine-protonation-based charge variants. By conducting pepsin digestion, amino-acid specific chemical modifications, peptide mapping, and measuring the effects of elution residence time, a histidine in the variable fragment (Fab) was identified to be the root cause. Besides double-peak pattern, mAb A can also exhibit peak-shouldering or single elution peak on different CEX resins, reflecting different resins' resolving capability on protonated/un protonated forms. This work characterizes a novel cause for unusual elution behaviors in CEX and also provides alternative avenues of purification development for mAbs with similar behaviors. PMID- 26596870 TI - Facile synthesis of copper(II)-decorated magnetic particles for selective removal of hemoglobin from blood samples. AB - In this report, the Cu(2+)-immobilized magnetic particles were prepared by a facile route and they were used as adsorbents for removal of high abundance of hemoglobin in blood based on immobilized metal affinity chromatography. Ethylenediaminetetraacetic acid modified magnetic particles (EDTA-Fe3O4) were first synthesized through a one-pot solvothermal method and then charged with copper ions. The as-prepared Cu(2+)-EDTA-Fe3O4 particles were characterized by Fourier transform infrared spectrometry, scanning electron microscopy, transmission electron microscopy, energy dispersive X-ray spectroscopy, vibrating sample magnetometry and zeta potential. Factors affecting the adsorption of bovine hemoglobin on Cu(2+)-EDTA-Fe3O4 particles (including contact time, solution pH, ionic strength and initial concentration of protein) were investigated. The adsorption process followed a pseudo-second-order kinetic model and the adsorption equilibrium could be achieved in 60min. The adsorption isotherm data could be well described by a Langmuir model and the maximum adsorption capacity was 1250mgg(-1). The as-prepared particles showed high efficiency and excellent selectivity for removal of hemoglobin from bovine and human blood. The removal process integrated the selectivity of immobilized metal affinity chromatography and the convenience of magnetic separation. The results demonstrated that Cu(2+)-EDTA-Fe3O4 particles had potential application in removal of abundant histidine-rich proteins in biomedical diagnosis analysis. PMID- 26596871 TI - Far-ultraviolet absorbance detection of sugars and peptides by high-performance liquid chromatography. AB - A far-ultraviolet (FUV)-absorbance detector with a transmission flow cell was developed and applied to detect absorbance of sugars and peptides by HPLC. The main inherent limitation of FUV-absorbance detection is the strong absorptions of solvents and atmospheric oxygen in the optical system as well as dissolved oxygen in the solvent. High absorptivity of the solvent and oxygen decreases transmission-light intensity in the flow cell and hinders the absorbance measurement. To solve the above drawbacks, the transmission-light intensity in the flow cell was increased by introducing a new optical system and a nitrogen purging unit to remove the atmospheric oxygen. The optical system has a photodiode for detecting the reference light at a position of the minus-first order diffracted light. In addition, acetonitrile and water were selected as usable solvents because of their low absorptivity in the FUV region. As a result of these implementations, the detectable wavelength of the FUV-absorbance detector (with a flow cell having an effective optical path length of 0.5mm) can be extended down to 175nm. Three sugars (glucose, fructose, and sucrose) were successfully detected with the FUV-absorbance detector. These detection results reveal that the absorption peak of sugar in liquid phase lies at around 178nm. The detection limit (S/N=3) in absorbance with a 0.5-mm flow cell at 180nm was 21MUAU, which corresponds to 33, 60 and 60MUM (198, 360, and 360pmol) for fructose, glucose, and sucrose, respectively. Also, the peptide Met-enkephalin could be detected with a high sensitivity at 190nm. The estimated detection limit (S/N=3) for Met-enkephalin is 29nM (0.29pmol), which is eight times lower than that at 220nm. PMID- 26596872 TI - Capillary ion-exchange chromatography with nanogram sensitivity for the analysis of monoclonal antibodies. AB - Ion-exchange chromatography (IEC) is widely used for profiling the charge heterogeneity of proteins, including monoclonal antibodies (mAbs). Despite good resolving power and robustness, ionic strength-based ion-exchange separations are generally product specific and can be time consuming to develop. In addition, conventional analytical scale ion-exchange separations require tens of micrograms of mAbs for each injection, amounts that are often unavailable in sample-limited applications. We report the development of a capillary IEC (c-IEC) methodology for the analysis of nanogram amounts of mAb charge variants. Several key modifications were made to a commercially available liquid chromatography system to perform c-IEC for charge variant analysis of mAbs with nanogram sensitivity. We demonstrate the method for multiple monoclonal antibodies, including antibody fragments, on different columns from different manufacturers. Relative standard deviations of <10% were achieved for relative peak areas of main peak, acidic and basic regions, which are common regions of interest for quantifying monoclonal antibody charge variants using IEC. The results herein demonstrate the excellent sensitivity of this c-IEC characterization method, which can be used for analyzing charge variants in sample-limited applications, such as early-stage candidate screening and in vivo studies. PMID- 26596873 TI - Automated two-step chromatography using an AKTA equipped with in-line dilution capability. AB - There has been a great emphasis on developing higher-throughput protein purification techniques to screen potential human therapeutics faster and more efficiently. Not only is it desirable to have high-throughput purification for initial screens but it is also desirable to efficiently purify selected protein therapeutics in the amounts and purity required for definitive assays. Current automated tandem technologies involve size exclusion as a second step that often fails to generate the required purity, is not robust and can only be operated at a limited scale. We have modified an AKTA to enable in-line dilution, assuring that the automated loading of a second column from a first column elution can be modified to a pH and ionic strength which is suitable for binding to the second column. For example, Protein A can be employed as a first step followed by direct loading on to a cation exchange column by conditioning the Protein A elution using the in-line diluter. Using this method as described, up to six samples of 1L each can be purified through two columns without human intervention per day per machine, and the system produces good yields of purified protein over a wide range of loading levels (12-300mg). In addition, the system employs guanidine HCl regeneration, followed by a sodium hydroxide wash between purification runs, minimizing the possibility of carryover contamination. The system is described at the 5mL and the 10mL column sizes; however, it could readily be programed for 100mL columns to enable larger-scale purifications. Using this system to automate two-column purifications minimizes human intervention, increases efficiency and minimizes the risk of human error. PMID- 26596874 TI - Spline modelling electron insert factors using routine measurements. AB - There are many methods available to predict electron output factors; however, many centres still measure the factors for each irregular electron field. Creating an electron output factor prediction model that approaches measurement accuracy--but uses already available data and is simple to implement--would be advantageous in the clinical setting. This work presents an empirical spline model for output factor prediction that requires only the measured factors for arbitrary insert shapes. Equivalent ellipses of the insert shapes are determined and then parameterised by width and ratio of perimeter to area. This takes into account changes in lateral scatter, bremsstrahlung produced in the insert material, and scatter from the edge of the insert. Agreement between prediction and measurement for the 12 MeV validation data had an uncertainty of 0.4% (1SD). The maximum recorded deviation between measurement and prediction over the range of energies was 1.0%. The validation methodology showed that one may expect an approximate uncertainty of 0.5% (1SD) when as little as eight data points are used. The level of accuracy combined with the ease with which this model can be generated demonstrates its suitability for clinical use. Implementation of this method is freely available for download at https://github.com/SimonBiggs/electronfactors. PMID- 26596875 TI - Mechanisms of sinus node cycle length changes during ventricular fibrillation. AB - OBJECTIVE: We have previously shown that up to one-third of patients develop no change or an increase in sinus node cycle length (SNCL) during ventricular fibrillation (VF). The purpose of the present study was to investigate the mechanism of SNCL changes during VF in a swine model. We hypothesized that changes in SNCL during VF are vagally-mediated. METHODS: In 33 anesthetized pigs DC current was used to induce VF for 10 s followed by defibrillation. SNCL changes were assessed during VF and compared to baseline. Animals that had ventriculo-atrial conduction during VF were excluded. Post-defibrillation, the pigs were randomized to receive atropine, propranolol, atropine + propranolol or placebo followed by repeat VF induction and measurement of SNCL changes. RESULTS: Ventriculo-atrial conduction was present in 14 pigs prohibiting SNCL measurements. In the remaining 19 animals, 10 demonstrated SNCL shortening (S Group) and 9 demonstrated non-shortening (NS-Group). Atropine decreased the absolute change in SNCL from 51.2 to 26.6 ms (n = 6; p = 0.03). It attenuated the SNCL shortening previously observed in the S-Group (-99.2 ms versus -47.9 ms, p = 0.04) and reversed the SNCL prolongation initially observed in the NS-Group (27.1 ms versus -6.5 ms, p = 0.13). Similarly, atropine + propranolol decreased the absolute change in SNCL from 33.3 to 12.2 ms (n = 4; p = 0.05). No significant changes were noted with propranolol or placebo. INTERPRETATION: The SNCL changes during VF appear to be vagally-mediated. The clinical implications vis-a-vis defibrillation threshold and future device programming await future studies. PMID- 26596877 TI - Methodological Research Priorities in Palliative Care and Hospice Quality Measurement. AB - Quality measurement is a critical tool for improving palliative care and hospice, but significant research is needed to improve the application of quality indicators. We defined methodological priorities for advancing the science of quality measurement in this field based on discussions of the Technical Advisory Panel of the Measuring What Matters consensus project of the American Academy of Hospice and Palliative Medicine and Hospice and Palliative Nurses Association and a subsequent strategy meeting to better clarify research challenges, priorities, and quality measurement implementation strategies. In this article, we describe three key priorities: 1) defining the denominator(s) (or the population of interest) for palliative care quality indicators, 2) developing methods to measure quality from different data sources, and 3) conducting research to advance the development of patient/family-reported indicators. We then apply these concepts to the key quality domain of advance care planning and address relevance to implementation of indicators in improving care. Developing the science of quality measurement in these key areas of palliative care and hospice will facilitate improved quality measurement across all populations with serious illness and care for patients and families. PMID- 26596876 TI - Sickle Cell Disease: A Review of Nonpharmacological Approaches for Pain. AB - CONTEXT: Sickle cell disease (SCD) is a life-threatening condition that affects more than seven million people worldwide. The most common complication experienced by persons living with SCD is pain. Evidence supports the use of nonpharmacologic therapies in managing psychological and social complications of pain in persons with SCD, but there is little consensus if these approaches can also be applied for the treatment of pain in SCD. OBJECTIVES: To describe and synthesize the use of nonpharmacological therapies for reducing pain of any type and origin in persons with SCD. METHODS: A literature search was conducted using PsycINFO, PsycARTICLES, PubMed, CINAHL, and Embase. Databases were searched using the following terms: sickle cell, pain, and nonpharmacological therapies. Interventions were graded for methodological quality and categorized as 1) peer support group therapies, 2) educational/psychological therapies, and 3) skill based therapies. RESULTS: Twenty-eight nonpharmacological interventions for persons with SCD were examined. Of these studies, a wide variety of nonpharmacological interventions were tested. Twelve studies yielded significant improvements in pain, three studies reported no positive effect or differences between experimental and control conditions on pain or a pain-related outcome, and one study reported a negative or detrimental intervention effect. CONCLUSION: Approximately half of the studies reviewed demonstrated success in alleviating pain, suggesting that patients are able to use nonpharmacological interventions to reduce pain with some degree of success. Questions still remain regarding the efficacy and generalizability of these interventions for persons with SCD. PMID- 26596878 TI - Improving Emergency Providers' Attitudes Toward Sickle Cell Patients in Pain. AB - BACKGROUND: Provider biases and negative attitudes are recognized barriers to optimal pain management in sickle cell disease, particularly in the emergency department (ED). MEASURES: This prospective cohort measures preintervention and postintervention providers' attitudes toward patients with sickle pain crises using a validated survey instrument. INTERVENTION: ED providers viewed an eight minute online video that illustrated challenges in sickle cell pain management, perspectives of patients and providers, as well as misconceptions and stereotypes of which to be wary. OUTCOMES: Ninety-six ED providers were enrolled. Negative attitude scoring decreased, with a mean difference -11.5 from baseline, and positive attitudes improved, with a mean difference +10. Endorsement of red-flag behaviors similarly decreased (mean difference -12.8). Results were statistically significant and sustained on repeat testing three months after intervention. CONCLUSIONS/LESSONS LEARNED: Brief video-based educational interventions can improve emergency providers' attitudes toward patients with sickle pain crises, potentially curtailing pain crises early, improving health outcomes and patient satisfaction scores. PMID- 26596879 TI - Feeling Heard and Understood: A Patient-Reported Quality Measure for the Inpatient Palliative Care Setting. AB - CONTEXT: As endorsed by the palliative care "Measuring What Matters" initiative, capturing patients' direct assessment of their care is essential for ongoing quality reporting and improvement. Fostering an environment where seriously ill patients feel heard and understood is of crucial importance to modern health care. OBJECTIVES: To describe the development and performance of a self-report field measure for seriously ill patients to report how well they feel heard and understood in the hospital environment. METHODS: As part of a larger ongoing cohort study of inpatient palliative care, we developed and administered the following point-of-care item: "Over the past two days, how much have you felt heard and understood by the doctors, nurses and hospital staff?" (completely, quite a bit, moderately, slightly, not at all). Participants completed the measure before and the day after palliative care consultation. For the postconsultation version, we changed the time frame from "past two days" to "today." RESULTS: One hundred sixty patients with advanced cancer completed the preconsultation assessment, and 87% of them completed the postconsultation version. Responses encompassed full use of the ordinal scale, did not exhibit ceiling or floor effects, and showed improvement from preassessment to postassessment. The item was quick to administer and easy for patients to complete. CONCLUSION: The "Heard & Understood" item is a promising self-report quality measure for the inpatient palliative care setting. PMID- 26596880 TI - Gender Differences in Hiccup Patients: Analysis of Published Case Reports and Case-Control Studies. AB - CONTEXT: Although sporadic male predominance in hiccup patients has been reported, the association between gender differences and triggering factors has rarely been evaluated in patients with hiccups. OBJECTIVES: The aim of this study was to investigate whether gender differences exist in hiccup patients by analyzing all previously published hiccup literature containing gender and etiology information. METHODS: Published literature on this topic was identified using a standardized search strategy in the PubMed, SCOPUS, and CINAHL electronic databases. The literature search included studies published from January 1990 to December 2013. Searches were limited to English-language publications. Of 476 identified studies, 318 studies were eligible including eight case-control studies that contained nonhiccup control groups. Triggering factors for hiccups were categorized into two types: central nervous system (CNS) and non-CNS causes. Odds ratios (ORs) were calculated for the eight case-control studies and event rates for the other studies by meta-analysis. In addition, gender differences and mean ages were analyzed for the case studies. RESULTS: Pooled OR was 2.42 (95% confidence interval [CI] 1.40-4.17) with inclination for male predominance. Subgroup analysis by cause showed clear male predominance in the non-CNS type with OR of 11.72 (95% CI 3.16-43.50), whereas indistinct in the CNS type with OR of 1.74 (95% CI 0.95-3.16). Of the remaining 310 studies with 864 patients, previous findings were consistent. Male predominance was consistent in non-CNS (85.1%, 95% CI 78.2-90.2) and unknown origin (82.2%, 95% CI 75.8-87.2) patients, whereas mitigating the sex discrepancy in those with CNS origin (65.8%, 95% CI 53.1-76.5). CONCLUSION: We demonstrated male predominance in hiccup patients. This gender difference for hiccups was more pronounced in patients with non-CNS causes, whereas indistinct in patients with CNS causes. PMID- 26596882 TI - ICU Bedside Nurses' Involvement in Palliative Care Communication: A Multicenter Survey. AB - CONTEXT: Successful and sustained integration of palliative care into the intensive care unit (ICU) requires the active engagement of bedside nurses. OBJECTIVES: To describe the perspectives of ICU bedside nurses on their involvement in palliative care communication. METHODS: A survey was designed, based on prior work, to assess nurses' perspectives on palliative care communication, including the importance and frequency of their involvement, confidence, and barriers. The 46-item survey was distributed via e-mail in 2013 to bedside nurses working in ICUs across the five academic medical centers of the University of California, U.S. RESULTS: The survey was sent to 1791 nurses; 598 (33%) responded. Most participants (88%) reported that their engagement in discussions of prognosis, goals of care, and palliative care was very important to the quality of patient care. A minority reported often discussing palliative care consultations with physicians (31%) or families (33%); 45% reported rarely or never participating in family meeting discussions. Participating nurses most frequently cited the following barriers to their involvement in palliative care communication: need for more training (66%), physicians not asking their perspective (60%), and the emotional toll of discussions (43%). CONCLUSION: ICU bedside nurses see their involvement in discussions of prognosis, goals of care, and palliative care as a key element of overall quality of patient care. Based on the barriers participants identified regarding their engagement, interventions are needed to ensure that nurses have the education, opportunities, and support to actively participate in these discussions. PMID- 26596883 TI - Subcutaneous Use of Lacosamide. PMID- 26596884 TI - Halosiccatus urmianus gen. nov., sp. nov., a haloarchaeon from a salt lake. AB - A novel, orange-pigmented, halophilic archaeon, strain DC8T, was isolated from Urmia salt lake in north-west Iran. The cells of strain DC8T were non-motile and pleomorphic, from small rods to triangular or disc shaped. The novel strain needed at least 2.5 M NaCl and 0.02 M MgCl2 for growth. Optimal growth was achieved at 4.0 M NaCl and 0.1 M MgCl2. The optimum pH and temperature for growth were pH 7.5 and 45 degrees C, respectively, and it was able to grow over a pH range of 7.0 to 8.5 and a temperature range of 25 to 55 degrees C. Analysis of the 16S rRNA gene sequence showed that strain DC8T was a member of the family Halobacteriaceae; however, its similarity was as low as 90.1 %, 89.3 % and 89.1 % to the most closely related haloarchaeal taxa, including type species of members of the genera Halosimplex, Halobaculum and Halomicrobium, respectively. The G+C content of its DNA was 68.1 mol%. Polar lipid analyses revealed that strain DC8T contained phosphatidylglycerol, phosphatidylglycerol phosphate methyl ester, phosphatidylglycerol sulfate and phosphatidic acid. One unknown phospholipid, two major glycolipids and one minor glycolipid were also detected. The only quinone present was MK-8 (II-H2). The physiological, biochemical and phylogenetic differences between strain DC8T and other extremely halophilic archaeal genera with validly published names supported that this strain represents a novel species of a new genus within the family Halobacteriaceae, for which the name Halosiccatus urmianus gen. nov., sp. nov. is proposed. The type strain is strain DC8T ( = IBRC-M 10911T = CECT 8793T). PMID- 26596881 TI - Spanish Validation of the Care Evaluation Scale for Measuring the Quality of Structure and Process of Palliative Care From the Family Perspective. AB - CONTEXT: A reliable and valid measure of the structure and process of end-of-life care is important for improving the outcomes of care. OBJECTIVES: This study evaluated the validity and reliability of the Spanish adaptation of a satisfaction tool of the Care Evaluation Scale (CES), which was developed in Japan to evaluate palliative care structure and process from the perspective of family members. METHODS: Standard forward-backward translation and a pilot test were conducted. A multicenter survey was conducted with the relatives of patients admitted to palliative care units for symptom control. The dimensional structure was assessed using confirmatory factor analyses. Concurrent and discriminant validity were tested by correlation with the SERQVHOS, a Spanish hospital care satisfaction scale and with an 11-point rating scale on satisfaction with care. The reliability of the CES was tested by Cronbach alpha and by test-retest correlation. RESULTS: A total of 284 primary caregivers completed the CES, with low missing response rates. The results of the factor analysis suggested a six factor solution explaining 69% of the total variance. The CES moderately correlated with the SERQVHOS and with the overall satisfaction scale (intraclass correlation coefficients of 0.66 and 0.44, respectively; P = 0.001). Cronbach alpha was 0.90 overall and ranged from 0.85 to 0.89 for subdomains. Intraclass correlation coefficient was 0.88 (P = 0.001) for test-retest analysis. CONCLUSION: The Spanish CES was found to be a reliable and valid measure of the satisfaction with end-of-life care structure and process from family members' perspectives. PMID- 26596885 TI - Low variability at the HLA-E promoter region in the Brazilian population. AB - Little information has been reported regarding the regulatory region of the HLA-E gene. Only a proximal segment (300 bp immediately before exon 1) has been described at IMGT/HLA database. We aimed to evaluate the genetic diversity of the promoter region by PCR amplification and DNA sequencing. We observed a pattern of sequencing interruption in the same position in all samples, suggesting the presence of a secondary structure hampering the DNA polymerase sliding during the sequencing process, which was confirmed after bioinformatics analysis. Considering the promoter region evaluated (nucleotide -440 to -1), only three variation sites were found, including one new variation site at position -104, and the concomitant deletions already described at positions -187 and -186. We concluded that the promoter region of the HLA-E gene presents few and rare variable sites in this population sample; however, the double-stranded branch formation hampered the evaluation of the distant promoter by conventional sequencing. PMID- 26596886 TI - Removal of 2-butoxyethanol gaseous emissions by biotrickling filtration packed with polyurethane foam. AB - The removal of 2-butoxyethanol from gaseous emissions was studied using two biotrickling filters (BTF1 and BTF2) packed with polyurethane foam. Two different inoculum sources were used: a pure culture of Pseudomonas sp. BOE200 (BTF1) and activated sludge from a municipal wastewater treatment plant (BTF2). The bioreactors were operated at inlet loads (ILs) of 130 and 195 g m(-3) hour(-1) and at an empty bed residence time (EBRT) of 12.5s. Under an IL of ~130 g m(-3) hour(-1), BTF1 presented higher elimination capacities (ECs) than BTF2, with average values of 106+/-7 and 68+/-8 g m(-3) hour(-1), respectively. However, differences in ECs between BTFs were decreased by reducing the irrigation intervals from 1 min every 12 min to 1 min every 2 hours in BTF2. Average values of EC were 111+/-25 and 90+/-7 g m(-3) hour(-1) for BTF1 and BTF2, respectively, when working at an IL of ~195 g m(-3) hour(-1). Microbial analysis revealed a significant shift in the microbial community of BTF1 inoculated with Pseudomonas sp. BOE200. At the end of the experiment, the species Microbacterium sp., Chryseobacterium sp., Acinetobacter sp., Pseudomonas sp. and Mycobacterium sp. were detected. In BTF2 inoculated with activated sludge, the denaturing gradient gel electrophoresis (DGGE) technique showed a diverse microbial community including species that was able to use 2-butoxyethanol as its carbon source, such as Pseudomonas aeruginosa and Pseudomonas putida as representative species. Although BTF1 inoculated with Pseudomonas sp. BOE200 and higher gas velocity (probably greater gas/liquid mass transfer rate) showed a slight improvement in performance, the use of activated sludge as inoculum seems to be a more feasible option for the industrial application of this technology. PMID- 26596887 TI - Newly isolated alkalophilic Advenella species bioaugmented in activated sludge for high p-cresol removal. AB - In this work, an alkalophilic bacterium (LVX-4) capable of using p-cresol as sole source of carbon and energy was screened and isolated from soil polluted by used oil. Phylogenetic (16S rRNA) and phenotypic characterization using Biolog GN microplates and API 20NE strips indicated that LVX-4 strain is a new Advenella species. It showed both the capability to degrade of p-cresol at high concentrations (750 mg/L) and to use p-cresol for growth in a pH from 7 to 10, although the optimum pH was 9. Moreover bioaugmentation of activated sludge with this strain lead to the complete removal of p-cresol in less than 100 h. This is the first study that shows the potential of Advenella sp. to be bioaugmented in activated sludge system for p-cresol biodegradation. PMID- 26596888 TI - Q&A: Mesenchymal stem cells - where do they come from and is it important? AB - Mesenchymal stem - or stromal - cells (MSCs) have been administered in hundreds of clinical trials for multiple indications, making them some of the most commonly used selected regenerative cells. Paradoxically, MSCs have also long remained the least characterized stem cells regarding native identity and natural function, being isolated retrospectively in long-term culture. Recent years have seen progress in our understanding of the natural history of these cells, and candidate native MSCs have been identified within fetal and adult organs. Beyond basic knowledge, deciphering the biology of innate MSCs may have important positive consequences for the therapeutic use of these cells. PMID- 26596889 TI - Agar agar-stabilized milled zerovalent iron particles for in situ groundwater remediation. AB - Submicron-scale milled zerovalent iron (milled ZVI) particles produced by grinding macroscopic raw materials could provide a cost-effective alternative to nanoscale zerovalent iron (nZVI) particles for in situ degradation of chlorinated aliphatic hydrocarbons in groundwater. However, the aggregation and settling of bare milled ZVI particles from suspension presents a significant obstacle to their in situ application for groundwater remediation. In our investigations we reduced the rapid aggregation and settling rate of bare milled ZVI particles from suspension by stabilization with a "green" agar agar polymer. The transport potential of stabilized milled ZVI particle suspensions in a diverse array of natural heterogeneous porous media was evaluated in a series of well-controlled laboratory column experiments. The impact of agar agar on trichloroethene (TCE) removal by milled ZVI particles was assessed in laboratory-scale batch reactors. The use of agar agar significantly enhanced the transport of milled ZVI particles in all of the investigated porous media. Reactivity tests showed that the agar agar-stabilized milled ZVI particles were reactive towards TCE, but that their reactivity was an order of magnitude less than that of bare, non-stabilized milled ZVI particles. Our results suggest that milled ZVI particles could be used as an alternative to nZVI particles as their potential for emplacement into contaminated zone, their reactivity, and expected longevity are beneficial for in situ groundwater remediation. PMID- 26596890 TI - Antibodies against High Mobility Group Box protein-1 (HMGB1) versus other anti nuclear antibody fine-specificities and disease activity in systemic lupus erythematosus. AB - INTRODUCTION: The non-histone nuclear protein high mobility group box protein-1 (HMGB1) is typically associated with nucleosomes, but may shuttle between the nucleus and the cytoplasm, and under some conditions also be released extracellularly and participate in systemic inflammation. Monoclonal HMGB1 targeting antibodies can ameliorate murine polyarthritis and lupus-like disease. Interestingly, autoantibodies against HMGB1 have also been described in patients with systemic lupus erythematosus (SLE), but their clinical implications remain elusive. The main aims of this study were to detect serum anti-HMGB1 antibodies in patients with SLE and relate them to other types of antinuclear antibodies (ANA), and to disease activity. METHODS: 188 Swedish SLE patients meeting the 1982 American College of Rheumatology classification criteria and/or the 2012 Systemic Lupus International Collaborating Clinics classification criteria participated in the study. Anti-HMGB1 antibody levels were analysed in patient and control (n = 112) sera by an in-house ELISA using recombinant histidine tagged HMGB1. SLE sera were also analysed for ANA by immunofluorescence (IF) microscopy (IF-ANA) using fixed HEp-2 cells, and by a line-blot assay for antigen fine-specificities. To quantify antibodies to double-stranded DNA, a fluoroenzyme immunoassay was employed. RESULTS: At inclusion, 23 % of the SLE patients were anti-HMGB1 antibody positive compared to 5 % of the controls. Anti-HMGB1 antibodies occurred in 49 % of the IF-ANA positive SLE patients, and in 34 % of IF-ANA negative cases (p = 0.004). Levels of anti-HMGB1 antibodies correlated with anti-dsDNA antibody levels (r = 0.49; p < 0.001). Significant, but less pronounced correlations were found regarding anti-HMGB1 and SLE disease activity index (SLEDAI-2K: r = 0.15; p = 0.04), classical complement function (r = -0.24; p = 0.002) and complement protein C4 (r = -0.23; p = 0.002). Average anti-HMGB1 antibody levels were significantly higher among patients with homogenous +/- other IF-ANA staining patterns (median 180 AU) compared to IF-ANA negative cases (median 83 AU) (p = 0.004). Rabbit anti-HMGB1 antibodies gave rise to cytoplasmic, but not nuclear, staining of HEp-2 cells. CONCLUSIONS: We confirm that anti-HMGB1 antibodies are common in SLE and correlate with disease activity variables. Although anti-HMGB1 antibodies measured by ELISA often coincide with nuclear IF-ANA staining, our results indicate that anti-HMGB1 antibodies do not give rise to nuclear staining of the predominantly used commercial HEp-2 cell slides. PMID- 26596891 TI - Extensive variation between tissues in allele specific expression in an outbred mammal. AB - BACKGROUND: Allele specific gene expression (ASE), with the paternal allele more expressed than the maternal allele or vice versa, appears to be a common phenomenon in humans and mice. In other species the extent of ASE is unknown, and even in humans and mice there are several outstanding questions. These include; to what extent is ASE tissue specific? how often does the direction of allele expression imbalance reverse between tissues? how often is only one of the two alleles expressed? is there a genome wide bias towards expression of the paternal or maternal allele; and finally do genes that are nearby on a chromosome share the same direction of ASE? Here we use gene expression data (RNASeq) from 18 tissues from a single cow to investigate each of these questions in turn, and then validate some of these findings in two tissues from 20 cows. RESULTS: Between 40 and 100 million sequence reads were generated per tissue across three replicate samples for each of the eighteen tissues from the single cow (the discovery dataset). A bovine gene expression atlas was created (the first from RNASeq data), and differentially expressed genes in each tissue were identified. To analyse ASE, we had access to unambiguously phased genotypes for all heterozygous variants in the cow's whole genome sequence, where these variants were homozygous in the whole genome sequence of her sire, and as a result we were able to map reads to parental genomes, to determine SNP and genes showing ASE in each tissue. In total 25,251 heterozygous SNP within 7985 genes were tested for ASE in at least one tissue. ASE was pervasive, 89 % of genes tested had significant ASE in at least one tissue. This large proportion of genes displaying ASE was confirmed in the two tissues in a validation dataset. For individual tissues the proportion of genes showing significant ASE varied from as low as 8 16 % of those tested in thymus to as high as 71-82 % of those tested in lung. There were a number of cases where the direction of allele expression imbalance reversed between tissues. For example the gene SPTY2D1 showed almost complete paternal allele expression in kidney and thymus, and almost complete maternal allele expression in the brain caudal lobe and brain cerebellum. Mono allelic expression (MAE) was common, with 1349 of 4856 genes (28 %) tested with more than one heterozygous SNP showing MAE. Across all tissues, 54.17 % of all genes with ASE favoured the paternal allele. Genes that are closely linked on the chromosome were more likely to show higher expression of the same allele (paternal or maternal) than expected by chance. We identified several long runs of neighbouring genes that showed either paternal or maternal ASE, one example was five adjacent genes (GIMAP8, GIMAP7 copy1, GIMAP4, GIMAP7 copy 2 and GIMAP5) that showed almost exclusive paternal expression in brain caudal lobe. CONCLUSIONS: Investigating the extent of ASE across 18 bovine tissues in one cow and two tissues in 20 cows demonstrated 1) ASE is pervasive in cattle, 2) the ASE is often MAE but ranges from MAE to slight overexpression of the major allele, 3) the ASE is most often tissue specific and that more than half the time displays divergent allele specific expression patterns across tissues, 4) across all genes there is a slight bias towards expression of the paternal allele and 5) genes expressing the same parental allele are clustered together more than expected by chance, and there are several runs of large numbers of genes expressing the same parental allele. PMID- 26596893 TI - Highly tunable fluorinated trispyrazolylborates [HB(3-CF3-5-{4-RPh}pz)3](-) (R = NO2, CF3, Cl, F, H, OMe and NMe2) and their copper(I) complexes. AB - The ethene and carbon monoxide adducts of copper(I) with seven trispyrazolylborate ligands ([HB(3-CF3-5-{4-RPh}pz)3](-); R = NO2 (4a), CF3 (4b), Cl (4c), F (4d), H (4e), OMe (4f) and NMe2 (4g)) were synthesized and characterized. The ligands were synthesized from their corresponding pyrazoles and sodium tetrahydridoborate and were obtained as solvent adducts of their sodium salts after workup. When the pyrazole with the most electron-withdrawing substituent (R = NO2) is used the asymmetric ligand [HB(3-CF3-5-{4-NO2Ph}pz)2(3 {4-NO2Ph}-5-CF3pz)](-) (4a') is formed as the major product. Copper(I) complexes with ethene or CO as a co-ligand were prepared in good yields and were structurally characterized using (1)H NMR, (13)C NMR and infrared spectroscopy. Single crystal X-ray crystallography analyses revealed the structures of Na4a', Na4b, four copper ethene complexes and four copper carbonyl complexes. The structures of the copper(I) complexes show Cu(I) ions in pseudo-tetrahedral coordination environments consisting of three nitrogen atoms of the trispyrazolylborate ligand and the carbonyl or eta(2)-coordinated ethene ligands, with nearly identical coordination environments around the Cu(I) ion. The compound [Na(4a')(H2O)]n crystallizes as one-dimensional chains with intermolecular NaO2N interactions. The sodium ions were found in severely distorted octahedral geometries with three nitrogen atoms from the trispyrazolylborate ligand, one aqua ligand and two oxygen atoms from the nitro group of an adjacent molecule. The compound [Na2(4b)2(MU-H2O)2] crystallizes as a centrosymmetric water-bridged dimer: two five-coordinate square-pyramidal sodium ions each are coordinated facially by three nitrogen atoms from a trispyrazolylborate ligand and two bridging water ligands. Below the base of the pyramidal structure one intermolecular and two intramolecular NaF short contacts are present. The (1)H and (13)C NMR spectra of the copper-ethene complexes show signals for the ethene ligands in the range of 4.84-4.96 ppm and 84.9-86.8 ppm respectively. The infrared spectra of the carbonyl complexes show CO stretching frequencies in the range of 2096-2120 cm(-1). Both the NMR signals for the ethene ligands and infrared signals for the carbonyl ligands were found to show good correlations with the Hammett sigmap parameters of the substituents on the phenyl rings of the ligands. PMID- 26596892 TI - Phosphonooxymethyl Prodrug of Triptolide: Synthesis, Physicochemical Characterization, and Efficacy in Human Colon Adenocarcinoma and Ovarian Cancer Xenografts. AB - A disodium phosphonooxymethyl prodrug of the antitumor agent triptolide was prepared from the natural product in three steps (39% yield) and displayed excellent aqueous solubility at pH 7.4 (61 mg/mL) compared to the natural product (17 MUg/mL). The estimated shelf life (t90) for hydrolysis of the prodrug at 4 degrees C and pH 7.4 was found to be two years. In a mouse model of human colon adenocarcinoma (HT-29), the prodrug administered intraperitoneally was effective in reducing or eliminating xenograft tumors at dose levels as low as 0.3 mg/kg when given daily and at 0.9 mg/kg when given less frequently. When given via intraperitoneal and oral routes at daily doses of 0.6 and 0.9 mg/kg, the prodrug was also effective and well tolerated in a mouse model of human ovarian cancer (A2780). PMID- 26596894 TI - Anaplasmataceae in wild ungulates and carnivores in northern Spain. AB - Wild vertebrates are essential hosts for tick-borne diseases but data on the prevalence and diversity of Anaplasma spp. in wildlife are scarce. In this study, we used real-time PCR to investigate the distribution of Anaplasma species in spleen samples collected from 625 wild animals (137 cervids, 227 wild boar, and 261 carnivores) in two regions in northern Spain. A first generic real-time PCR assay was used to screen for the presence of Anaplasma spp. followed by a second species-specific multiplex real-time PCR or partial sequencing of the 16S rRNA gene for species identification. Anaplasma phagocytophilum was highly prevalent in cervids (64.2%), but it was absent from wild boar and carnivores. Interestingly, Anaplasma marginale and Anaplasma ovis were not detected in cervids, but Anaplasma centrale was identified in 1 roe deer and 1 red deer, A. bovis in 4 roe deer, and a novel Ehrlichia sp. in one badger. These findings were highly associated with the tick burden identified in the different hosts. Thus, Ixodes ricinus, the recognized vector of A. phagocytophilum in Europe, was the main tick species parasitizing cervids (93.5%, 1674/1791), whereas Dermacentor reticulatus was the most abundant in wild boar (76.1%, 35/46) and Ixodes hexagonus in carnivores (58.4%, 265/454). More investigations are needed to assess the impact of the different Anaplasma species in wildlife and the risk of transmission to domestic animals. PMID- 26596895 TI - Management of atrial fibrillation in specific patient populations. PMID- 26596896 TI - COnteMporary Modalities In Treatment of Heart Failure: a report from the COMMIT HF registry. AB - BACKGROUND AND AIM: Heart failure (HF) has become a global health problem and is a significant burden for health-care systems worldwide. It is reported as the reason for 1-4% of all hospital admissions in developed countries. The prognosis in HF remains unfavourable. Having at our disposal a large group of patients with systolic HF at a high-volume reference cardiovascular centre with the possibility to implement complete diagnostics and therapy we decided to analyse the clinical data, administered therapies, and prognosis in HF patients. METHODS: The COMMIT HF is a single-centre observational study that is underway in the Third Chair and Department of Cardiology of the Silesian Centre for Heart Diseases in Zabrze. The study population is a cohort of adult HF patients with left ventricular ejection fraction (LVEF) <= 35%. Patients with acute coronary syndromes are excluded from the analysis. Complete patient demographics: medical history, hospitalisation data (diagnostic and therapeutic), and in-hospital results are collected. Twelve month follow-up is based on the information acquired from the national health care provider. RESULTS: As of 31 December 2013 a group of 1798 patients have been enrolled (mean age 60.9 +/- 12.8 years, 20.3% of subjects female, mean LVEF 26.06 +/- 6.09, ischaemic aetiology 64.5%, atrial fibrillation 33.2%, diabetes mellitus 41.2%, chronic kidney disease stage >= III 29%). A significant proportion of patients underwent invasive procedures (ICD/CRT-D implantation 61.1%, coronary angiography 56.2%, PCI 19.6%, CABG 5.1%, heart transplantation qualification 5.5%, IABP 2.5%). All-cause 12-month morality was 12.5%. HF-related rehospitalisation rate was 28.9%. CONCLUSIONS: The COMMIT-HF study will provide valuable information on the HF patient population. Initial analyses show that in this difficult patient population satisfactory long-term results can be achieved. PMID- 26596897 TI - The efficacy of an education-based secondary outpatient prevention programme after acute coronary syndrome hospitalisations and treatment in Poland. The Patient Club initiative. AB - BACKGROUND: Guidelines on cardiovascular prevention from the European Society of Cardiology advocate sustained educational measures to be undertaken by both doctors and nurses to ensure lifestyle changes for patients after acute coronary syndromes (ACS). A planned programme of a series of educational meetings for patients after ACS was initiated in form of the Patient Club. AIM: To assess the efficacy of the Patient Club initiative in terms of increased knowledge on cardiovascular risk factors as well as utilisation of healthy lifestyle in patents who attend the programme. METHODS: Patients in nine cardiology centres in Poland, who were treated for ACS between October and December 2014, were included. A dedicated questionnaire on healthy lifestyle and knowledge on cardiovascular risk factors was filled in by patients at hospital discharge. In January 2015 the same questionnaire was filled in by the same group of patients before their local Patient Club meeting. RESULTS: There were 1273 patients hospitalised for ACS who were invited to join the Patient Club initiative. Of them, 372 (29%) filled in the questionnaire both at discharge and at the Patient Club meeting. The percentage of patients who smoked cigarettes decreased from 14% to 5% (p < 0.001), and the number of those who had at least 30 min of physical activity daily increased from 50% to 58% (p = 0.015). CONCLUSIONS: Patients who attended Patient Club meetings usually four weeks after ACS showed significant benefit in terms of healthy lifestyle changes and more guideline-recommended management of cardiovascular risk factors. PMID- 26596898 TI - Sedentary Behavior and Sleep Duration Are Associated with Both Stress Symptoms and Suicidal Thoughts in Korean Adults. AB - Prolonged sedentary time and sleep deprivation are associated with mental health problems such as depression and stress symptoms. Moreover, mental illness is linked with suicidal thoughts and suicide attempts. However, it is not clear whether sedentary time and sleep duration are associated with stress symptoms and suicidal thoughts independent of physical activity. Thus, our study aimed to identify if sedentary time and sleep duration were associated with both stress symptoms and suicidal thoughts. The participants in present cross-sectional study were 4,674 general Korean adults (1,938 male; 2,736 female), aged >= 20 years. Prolonged sedentary time (>= 420 min/day) was significantly associated with the increased risk of stress symptoms (OR, 1.30; 95% CI, 1.04-1.62) compared with sedentary time of < 240 min/day. The OR for stress symptoms was significant for individuals who had <= 5 h/day of sleep time (OR, 1.88; 95% CI, 1.48-2.38) compared with sleep duration of >= 7 h/day. Moreover, prolonged sedentary time (OR, 1.55; 95% CI, 1.01-2.42 in >= 420 min/day vs. < 240 min/day) and short sleep duration (OR, 1.75; 95% CI, 1.17-2.62 in <= 5 h/day vs. >= 7 h/day) were significantly associated with an increased risk for suicidal thoughts after adjusting for confounding factors including physical activity. Thus, prolonged sedentary time and sleep deprivation are independently associated with both the risk of stress symptoms and suicidal thoughts. From a public health perspective, reducing sedentary time and improvement of sleep deprivation may serve as an effective strategy for preventing mental illness. PMID- 26596899 TI - Food intake response to exercise and active video gaming in adolescents: effect of weight status. AB - Although a few data are available regarding the impact of video games on energy intake (EI) in lean adolescents, there is no evidence on the effect of passive and active video gaming on food intake in both lean and obese youth. It is also unknown whether isoenergetic active video games and exercise differently affect food consumption in youth. In all, twelve lean and twelve obese adolescent boys (12-15 years old) had to complete four 1-h sessions in a cross-over design study: control (CON; sitting), passive video game (PVG; boxing game on Xbox 360), active video game (AVG; boxing game on Xbox Kinect 360) and exercise (EX; cycling). The exercise and active video game activities were designed to generate the same energy expenditure (EE). EE was measured using a K4b2 portable indirect calorimeter. Ad libitum food intake and appetite sensations were assessed following the sessions. AVG and EX-EE were significantly higher in obese participants and significantly higher compared with PVG and CON in both groups. Obese participants significantly ate more than lean ones in all four conditions (P<0.001). EI did not differ between conditions in obese participants (CON: 4935 (SD 1490) kJ; PVG: 4902 (SD 1307) kJ; AVG: 4728 (SD 1358) kJ; EX: 4643 (SD 1335) kJ), and was significantly lower in lean participants after EX (2847 (SD 577) kJ) compared with PVG (3580 (SD 863) kJ) and AVG (3485 (SD 643) kJ) (P<0.05). Macronutrient intake was not significantly different between the groups or conditions. Hunger was significantly higher and satiety was lower in obese participants but no condition effect was observed. Overall, moderate-intensity exercise provides better effect on energy balance than an isoenergetic hour of active video gaming in lean adolescent boys by dually affecting EE and EI. PMID- 26596900 TI - Hydrazide functionalized monodispersed silica microspheres: a novel probe with tunable selectivity for a versatile enrichment of phosphopeptides with different numbers of phosphorylation sites in MS analysis. AB - Hydrazide functionalized monodispersed silica microspheres (HFMSM) were developed for the enrichment of phosphopeptides for the first time. With the aid of the tunable selectivity of HFMSM, global enrichment or fractionation of phosphopeptides with different numbers of phosphorylation sites could be realized by a simple modulation of the concentrations of formic acid in buffers. PMID- 26596901 TI - Large-Scale Computational Screening Identifies First in Class Multitarget Inhibitor of EGFR Kinase and BRD4. AB - Inhibition of cancer-promoting kinases is an established therapeutic strategy for the treatment of many cancers, although resistance to kinase inhibitors is common. One way to overcome resistance is to target orthogonal cancer-promoting pathways. Bromo and Extra-Terminal (BET) domain proteins, which belong to the family of epigenetic readers, have recently emerged as promising therapeutic targets in multiple cancers. The development of multitarget drugs that inhibit kinase and BET proteins therefore may be a promising strategy to overcome tumor resistance and prolong therapeutic efficacy in the clinic. We developed a general computational screening approach to identify novel dual kinase/bromodomain inhibitors from millions of commercially available small molecules. Our method integrated machine learning using big datasets of kinase inhibitors and structure based drug design. Here we describe the computational methodology, including validation and characterization of our models and their application and integration into a scalable virtual screening pipeline. We screened over 6 million commercially available compounds and selected 24 for testing in BRD4 and EGFR biochemical assays. We identified several novel BRD4 inhibitors, among them a first in class dual EGFR-BRD4 inhibitor. Our studies suggest that this computational screening approach may be broadly applicable for identifying dual kinase/BET inhibitors with potential for treating various cancers. PMID- 26596902 TI - Psychometric attributes of the Cervantes short-form questionnaire for measuring health-related quality of life in menopausal women. AB - OBJECTIVE: To analyse the psychometric properties of the Cervantes scale short form (SF) in the peri- and post-menopausal periods. METHODS: Outpatients women 45 65 years with menstrual problems associated with the climacteric syndrome were analysed. Original and SF versions of the Cervantes scale were administered along with the EuroQol-5D (EQ-5D) and work productivity and activity impairment questionnaire (WPAI) scales. Conceptual model, burden of administration, feasibility, reliability, criteria validity and construct validity were assessed. RESULTS: 317 women [55.7+/-5.3 years (mean+/-standard deviation)] were recruited: 75.4% were post- and 22.3% were peri-menopausal. The Cervantes-SF was completed in 2.5+/-1.6min, and 86% answered all items. Cronbach's alpha was 0.820, and ranged from 0.510 (Aging) to 0.918 (Vasomotor Symptoms) for individual dimensions. The scale structure matched the structure of the original version, chi(2)/(degrees of freedom)=3.6, Comparative Fit Index=0.848, Tucker-Lewis Index=0.850, and root mean square error of approximation=0.099, although differences were found between sexual activity statuses. Criteria validity was good (r=0.890), concurrent validity was congruent with a priori hypothesis using either the EQ-5D or the WPAI scales. The scale discriminated significantly the severity of both vasomotor and genital climacteric associated symptoms. CONCLUSION: The Cervantes-SF has shown good psychometric properties for measuring Health related quality of life in peri- and post-menopausal women who regularly attended gynaecology clinics in Spain. PMID- 26596904 TI - Synthesis of Co(1.5)PW12O40 and its catalytic performance of completely converting methanol to ethylene. AB - A new catalyst Co(1.5)PW12O40 was synthesized with exceptional catalytic performance of converting methanol to ethylene. Under the optimal conditions, both the conversion of methanol and the selectivity of ethylene are almost 100%, which can thus avoid a product separation process. PMID- 26596903 TI - Age-related macular degeneration and risk of total and cause-specific mortality over 15 years. AB - OBJECTIVE: We aimed to investigate the independent association between AMD and risk of ischemic heart disease (IHD), stroke, and cardiovascular (CVD) mortality, and all-cause mortality over 15 years. METHODS: 3654 participants aged 49+ years at baseline were followed over 15 years. AMD was assessed from retinal photographs. Deaths and cause of death were confirmed by data linkage with the Australian National Death Index. Hazard ratios (HRs) and 95% confidence intervals (CIs) were assessed using Cox models. RESULTS: 71.4% (n=162) and 34.6% (n=1037) of participants with any AMD and no AMD, respectively, died over 15 years. After multivariable-adjustment, no significant associations were observed between AMD and total- and cause-specific mortality in the overall cohort. However, among men, late AMD at baseline was associated with an increased risk of all-cause mortality (n=22; 95.7%), 15 years later: multivariable-adjusted HR, 1.80 (95% CI 1.04-3.11). Women with late AMD had 2-fold increased risk of stroke mortality (n=15; 28.9%), HR 2.10 (95% CI 1.08-4.06). Early-stage AMD was not associated with mortality risk. CONCLUSION: Late AMD independently predicted all-cause mortality in men and stroke mortality in women, over 15 years. Although underlying mechanisms are unclear, these findings indicate that late AMD is a marker of biological aging. PMID- 26596905 TI - Buckling of Microtubules on a 2D Elastic Medium. AB - We have demonstrated compression stress induced mechanical deformation of microtubules (MTs) on a two-dimensional elastic medium and investigated the role of compression strain, strain rate, and a MT-associated protein in the deformation of MTs. We show that MTs, supported on a two-dimensional substrate by a MT-associated protein kinesin, undergo buckling when they are subjected to compression stress. Compression strain strongly affects the extent of buckling, although compression rate has no substantial effect on the buckling of MTs. Most importantly, the density of kinesin is found to play the key role in determining the buckling mode of MTs. We have made a comparison between our experimental results and the 'elastic foundation model' that theoretically predicts the buckling behavior of MTs and its connection to MT-associated proteins. Taking into consideration the role of kinesin in altering the mechanical property of MTs, we are able to explain the buckling behavior of MTs by the elastic foundation model. This work will help understand the buckling mechanism of MTs and its connection to MT-associated proteins or surrounding medium, and consequently will aid in obtaining a meticulous scenario of the compression stress induced deformation of MTs in cells. PMID- 26596906 TI - Simonsenia aveniformis sp. nov. (Bacillariophyceae), molecular phylogeny and systematics of the genus, and a new type of canal raphe system. AB - The genus Simonsenia is reviewed and S. aveniformis described as new for science by light and electron microscopy. The new species originated from estuarine environments in southern Iberia (Atlantic coast) and was isolated into culture. In LM, Simonsenia resembles Nitzschia, with bridges (fibulae) beneath the raphe, which is marginal. It is only electron microscope (EM) examination that reveals the true structure of the raphe system, which consists of a raphe canal raised on a keel (wing), supported by rib like braces (fenestral bars) and tube-like portulae; between the portulae the keel is perforated by open windows (fenestrae). Based on the presence of portulae and a fenestrated keel, Simonsenia has been proposed to be intermediate between Bacillariaceae and Surirellaceae. However, an rbcL phylogeny revealed that Simonsenia belongs firmly in the Bacillariaceae, with which it shares a similar chloroplast arrangement, rather than in the Surirellaceae. Lack of homology between the surirelloid and simonsenioid keels is reflected in subtle differences in the morphology and ontogeny of the portulae and fenestrae. The diversity of Simonsenia has probably been underestimated, particularly in the marine environment. PMID- 26596907 TI - Spin splitting in 2D monochalcogenide semiconductors. AB - We report ab initio calculations of the spin splitting of the uppermost valence band (UVB) and the lowermost conduction band (LCB) in bulk and atomically thin GaS, GaSe, GaTe, and InSe. These layered monochalcogenides appear in four major polytypes depending on the stacking order, except for the monoclinic GaTe. Bulk and few-layer epsilon-and gamma -type, and odd-number beta-type GaS, GaSe, and InSe crystals are noncentrosymmetric. The spin splittings of the UVB and the LCB near the Gamma-point in the Brillouin zone are finite, but still smaller than those in a zinc-blende semiconductor such as GaAs. On the other hand, the spin splitting is zero in centrosymmetric bulk and even-number few-layer beta-type GaS, GaSe, and InSe, owing to the constraint of spatial inversion symmetry. By contrast, GaTe exhibits zero spin splitting because it is centrosymmetric down to a single layer. In these monochalcogenide semiconductors, the separation of the non-degenerate conduction and valence bands from adjacent bands results in the suppression of Elliot-Yafet spin relaxation mechanism. Therefore, the electron- and hole-spin relaxation times in these systems with zero or minimal spin splittings are expected to exceed those in GaAs when the D'yakonov-Perel' spin relaxation mechanism is also suppressed. PMID- 26596908 TI - Mesoporous-silica nanofluidic channels for quick enrichment/extraction of trace pesticide molecules. AB - As nanofluidic channels, uniaxially oriented mesoporous-silica is, for the first time, in-situ self-assembled in a microfluidic chip for quick enrichment/extraction of ng L(-1)(ppt)-level organo-phosphorous (OP) pesticide residue from aqueous solution to ethanol. This micro/nano combined pre-treatment chip is essential for following gas chromatography-mass spectrometry (GC-MS) quantitative analysis. Featuring huge surface area and dense silanol groups at the inwall surface, the mesoporous-silica is uniaxially self-assembled in a micro reservoir to form a pile of nanofluidic channels (diameter = 2.1 nm). The captured/enriched pesticide molecules in the nanochannels can be efficiently extracted by much smaller volume of ethanol due to its much higher solubility to OP. In our affirming experiment, three mixed OP pesticides of dichlorvos, paraoxon and chlorpyrifos (in water) are captured/enriched by the nano-channels and eluted/extracted by only 0.6 mL ethanol. The whole process only takes 16 min. The GC-MS quantitative results for the extracted three pesticides indicate that the extraction recovery achieves 80%. The achieved limit of quantification (LOQ) and the limit of detection (LOD) are 100 ng L(-1) and 30 ng L(-1), respectively. The nanofluidic-channel pre-treatment technique is promising in various application fields like agriculture and food safety security. PMID- 26596910 TI - New memory devices based on the proton transfer process. AB - Memory devices operating due to the fast proton transfer (PT) process are proposed by the means of first-principles calculations. Writing information is performed using the electrostatic potential of scanning tunneling microscopy (STM). Reading information is based on the effect of the local magnetization induced at the zigzag graphene nanoribbon (Z-GNR) edge-saturated with oxygen or the hydroxy group-and can be realized with the use of giant magnetoresistance (GMR), a magnetic tunnel junction or spin-transfer torque devices. The energetic barriers for the hop forward and backward processes can be tuned by the distance and potential of the STM tip; this thus enables us to tailor the non-volatile logic states. The proposed system enables very dense packing of the logic cells and could be used in random access and flash memory devices. PMID- 26596909 TI - Reading between the Lines: "ADD"-ing Histone and DNA Methylation Marks toward a New Epigenetic "Sum". AB - Covalent modifications of both DNA and histones act in concert to define the landscape of our epigenome. In this review, we explore the interconnections between histone and DNA modifications by focusing on a conserved chromatin binding regulatory domain, the ATRX-DNMT3-DNMT3L (ADD) domain. New studies show that the ADD domain is capable of sensing, and therefore integrating, the status of multiple histone modifications. This in turn dictates the in vivo localization or allosteric regulation of the full-length ADD-containing protein and its ability to function in downstream chromatin remodeling events. Strategies to re engineer the ADD "reader pocket" in the de novo DNA methyltransferase DNMT3A such that it redirects this "writer" to new genomic loci proved useful in understanding important biological downstream consequences of mis-targeting of DNA methylation via altered reading of histone marks. Combined with genome editing tools, this approach stands as a poof-of-principle and will be broadly applicable to the elucidation of epigenetic networks that have been altered by "reader" mutations, either artificially or as naturally occurs in some human diseases. PMID- 26596911 TI - Attitudes and Experiences With Older Adults: A Case for Service Learning for Undergraduates. AB - The current study examined whether relationship quality with older adults currently and in childhood, as well as experience with older adults, was associated with biases toward older adults and interest in working with older adults as a possible career area. The authors sampled undergraduate students (N = 753, M = 18.97 years, SD = 2.11 years) from a Northern California university. In hierarchical regression analyses, higher perceived quality of relationships with older adult family members, higher perceived social support, and lower perceived conflict from relationships with older adults was significantly associated with positive attitudes toward older adults. Interest in working with older adults was significantly associated with taking courses in aging, providing care to an older adult, and volunteering with older adults. These results suggest that positive relationships with older adults are useful in reducing biases, though student interactions with older adults are key in helping to promote interest in working with older adults. PMID- 26596912 TI - Carbon-depleted outer core revealed by sound velocity measurements of liquid iron carbon alloy. AB - The relative abundance of light elements in the Earth's core has long been controversial. Recently, the presence of carbon in the core has been emphasized, because the density and sound velocities of the inner core may be consistent with solid Fe7C3. Here we report the longitudinal wave velocity of liquid Fe84C16 up to 70 GPa based on inelastic X-ray scattering measurements. We find the velocity to be substantially slower than that of solid iron and Fe3C and to be faster than that of liquid iron. The thermodynamic equation of state for liquid Fe84C16 is also obtained from the velocity data combined with previous density measurements at 1 bar. The longitudinal velocity of the outer core, about 4% faster than that of liquid iron, is consistent with the presence of 4-5 at.% carbon. However, that amount of carbon is too small to account for the outer core density deficit, suggesting that carbon cannot be a predominant light element in the core. PMID- 26596913 TI - Longitudinal associations between adiposity and change in knee pain: Tasmanian older adult cohort study. AB - OBJECTIVE: The aim of this study was to describe the longitudinal relationship between adiposity and change in knee pain. METHODS: A total of 1099 participants aged 50-79 were randomly selected from the local community in Southern Tasmania, of which 767 were followed up on average 5.1 years later. Knee pain was assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) at each time point. Consistent knee pain was defined as knee pain at all three time-points. The five pain subscales were grouped into weight-bearing pain and non-weight-bearing pain according to the nature of pain. Body fat and lean mass were assessed using dual energy x-ray absorptiometry (DXA). RESULTS: Baseline body mass index (BMI) and body fat mass were deleteriously associated with consistent knee pain over follow-up. BMI was consistently associated with increases in weight-bearing and non-weight-bearing pain. Fat mass was associated with an increase in non-weight-bearing pain. In mixed-model analyses, WOMAC total pain score was associated with BMI (beta = 1.27) and body fat mass (beta = 1.17). The association of lean mass was not significant after adjustment for fat mass. CONCLUSION: BMI is the most consistent correlate of knee pain in older adults. Fat mass is associated with non-weight-bearing knee pain suggesting systemic mechanisms are involved. PMID- 26596914 TI - Normal Brain Sparing With Increasing Number of Beams and Isocenters in Volumetric Modulated Arc Beam Radiosurgery of Multiple Brain Metastases. AB - Recent studies have reported about the application of volumetric-modulated arc radiotherapy in the treatment of multiple brain metastases. One of the key concerns for these radiosurgical treatments lies in the integral dose within the normal brain tissue, as it has been shown to increase with increasing number of brain tumors treated. In this study, we investigate the potential to improve normal brain tissue sparing specific to volumetric-modulated arc radiotherapy by increasing the number of isocenters and arc beams. Adopting a multi-institutional benchmark study protocol of planning multiple brain metastases via a radiosurgical apparatus, a flattening filter-free TrueBeam RapidArc delivery system (Varian Oncology, Palo Alto, California) was used for a volumetric modulated arc radiotherapy treatment planning study, where treatment plans for target combinations of N = 1, 3, 6, 9, and 12 targets were developed with increasing numbers of isocenters and arc beams. The treatment plans for each target combination were compared dosimetrically among each other and against the reference Gamma Knife treatment plan from the original benchmark study. We observed that as the number of isocenters or arc beams increased, the normal brain isodose volumes such as 12- to 4-Gy on average decreased by up to 15% for all the studied cases. However, when the best volumetric-modulated arc radiotherapy normal brain isodose volumes were compared against the corresponding reference Gamma Knife values, volumetric-modulated arc radiotherapy remained 100% to 200% higher than those of Gamma Knife for all target combinations. The study results, particularly for the solitary (N = 1) metastases case, directly challenged the general notion of dose equivalence among current radiosurgical modalities. In conclusion, multiple isocenter and multiple arc beam delivery solutions are capable of decreasing normal brain irradiation exposure for volumetric-modulated arc radiotherapy. However, there is further technological development in need for volumetric-modulated arc radiotherapy before similar dosimetric treatment plans could be achievable when compared to Gamma Knife radiosurgery. PMID- 26596915 TI - Automated Monte Carlo Simulation of Proton Therapy Treatment Plans. AB - Simulations of clinical proton radiotherapy treatment plans using general purpose Monte Carlo codes have been proven to be a valuable tool for basic research and clinical studies. They have been used to benchmark dose calculation methods, to study radiobiological effects, and to develop new technologies such as in vivo range verification methods. Advancements in the availability of computational power have made it feasible to perform such simulations on large sets of patient data, resulting in a need for automated and consistent simulations. A framework called MCAUTO was developed for this purpose. Both passive scattering and pencil beam scanning delivery are supported. The code handles the data exchange between the treatment planning system and the Monte Carlo system, which requires not only transfer of plan and imaging information but also translation of institutional procedures, such as output factor definitions. Simulations are performed on a high-performance computing infrastructure. The simulation methods were designed to use the full capabilities of Monte Carlo physics models, while also ensuring consistency in the approximations that are common to both pencil beam and Monte Carlo dose calculations. Although some methods need to be tailored to institutional planning systems and procedures, the described procedures show a general road map that can be easily translated to other systems. PMID- 26596917 TI - Inflammatory Bowel Disease: Historical Perspective, Epidemiology, and Risk Factors. AB - Inflammatory bowel disease (IBD) describes a group of closely related yet heterogeneous predominantly intestinal disease processes that are a result of an uncontrolled immune mediated inflammatory response. It is estimated that approximately one and a half million persons in North America have IBD. Pathogenesis of IBD involves an uncontrolled immune mediated inflammatory response in genetically predisposed individuals to a still unknown environmental trigger that interacts with the intestinal flora. There continues to be an enormous amount of information emanating from epidemiological studies providing expanded insight into the occurrence, distribution, determinants, and mechanisms of inflammatory bowel disease. PMID- 26596916 TI - Basolateral amygdala lesions abolish mutual reward preferences in rats. AB - In a recent study, we demonstrated that rats prefer mutual rewards in a Prosocial Choice Task. Here, employing the same task, we show that the integrity of basolateral amygdala was necessary for the expression of mutual reward preferences. Actor rats received bilateral excitotoxic (n=12) or sham lesions (n=10) targeting the basolateral amygdala and were subsequently tested in a Prosocial Choice Task where they could decide between rewarding ("Both Reward") or not rewarding a partner rat ("Own Reward"), either choice yielding identical reward to the actors themselves. To manipulate the social context and control for secondary reinforcement sources, actor rats were paired with either a partner rat (partner condition) or with an inanimate rat toy (toy condition). Sham-operated animals revealed a significant preference for the Both-Reward-option in the partner condition, but not in the toy condition. Amygdala-lesioned animals exhibited significantly lower Both-Reward preferences than the sham group in the partner but not in the toy condition, suggesting that basolateral amygdala was required for the expression of mutual reward preferences. Critically, in a reward magnitude discrimination task in the same experimental setup, both sham-operated and amygdala-lesioned animals preferred large over small rewards, suggesting that amygdala lesion effects were restricted to decision making in social contexts, leaving self-oriented behavior unaffected. PMID- 26596918 TI - Diagnostic Modalities for Inflammatory Bowel Disease: Serologic Markers and Endoscopy. AB - The evaluation, diagnosis, and monitoring of inflammatory bowel disease (IBD) has improved significantly over the past few decades. However, differentiation and management of the subtypes of IBD (Crohn's disease, ulcerative colitis, and indeterminate colitis) can still be challenging. The evolution of serologic markers has improved our understanding of the pathogenesis and natural history of IBD. In addition, advancements in endoscopy and endoscopic scoring systems have improved the accuracy of diagnosis and the efficacy of surveillance of IBD patients. This article reviews the recent literature on serologic markers, endoscopy, and endoscopy scoring systems. PMID- 26596919 TI - Imaging for Inflammatory Bowel Disease. AB - Multiple imaging modalities exist for inflammatory bowel disease. This article explores the use of plain radiographs, contrast radiologic imaging, computed tomography, MRI, ultrasound, and capsule endoscopy. History, technique, indications for use, limitations, and future directions are discussed for each modality. PMID- 26596920 TI - Medical Therapy for Inflammatory Bowel Disease. AB - Surgeons often care for patients with inflammatory bowel disease (IBD) who are receiving therapies that can include 5-ASA compounds, steroids, immunomodulators, and biologics. The goal of these agents is to suppress intestinal inflammation, ultimately improving the quality of life in patients afflicted with IBD. Traditionally, an acceptable therapeutic endpoint was the resolution of symptoms, defined as clinical remission. However, as a result of recent advances in therapy, clinicians can now strive to achieve more stringent endpoints, such as endoscopic or histologic remission. Many different classes of agents can be used, individually or in combination, to achieve mucosal healing. PMID- 26596921 TI - Crohn's Disease of the Foregut. AB - Crohn's disease of the foregut is more common than previously recognized, with up to 40% of patients with Crohn's disease in the distal intestine also having evidence of foregut disease. Esophageal disease is best managed medically with proton pump inhibition, steroids, thiopurines, methotrexate, and anti-tumor necrosis factor-alpha biologic medications. Esophageal strictures are dealt with using endoscopic dilation. Surgery is generally reserved of resistant strictures or esophageal fistulas. Patients with gastroduodenal disease more commonly come to surgery. The most commonly performed operations for gastroduodenal Crohn's disease are intestinal bypass or strictureplasty. The concomitant use of vagotomy remains controversial. PMID- 26596922 TI - Crohn's Disease of the Colon, Rectum, and Anus. AB - There is no cure for Crohn disease. Newer treatments, such as biological therapy, have led to an improved quality of life. This article focuses on the surgical management of Crohn disease of the colon, rectum, and anus. Restorative and nonrestorative surgical options for colonic Crohn disease are discussed. Treatment options for perianal Crohn disease are also reviewed. PMID- 26596923 TI - Indications and Options for Surgery in Ulcerative Colitis. AB - Ulcerative colitis affects differing lengths of the colon and rectum. Surgical treatment is considered curative when the entire colon and rectum is removed. However, surgical treatment of ulcerative colitis should only be pursued for additional complicating factors of the disease. In addition, the current physiologic status as well as the patient's desire to retain intestinal continuity should be considered. This article outlines the current indications for surgical treatment in patients with ulcerative colitis, the various surgical options, and the techniques used to accomplish these goals. PMID- 26596924 TI - Challenges in the Medical and Surgical Management of Chronic Inflammatory Bowel Disease. AB - Inflammatory bowel disease patients will likely come to the surgeon's attention at some point in their course of disease, and they present several unique anatomic, metabolic, and physiologic challenges. Specific and well-recognized complications of chronic Crohn disease and ulcerative colitis are presented as well as an organized and evidence-based approach to the medical and surgical management of such disease sequelae. Topics addressed in this article include intestinal fistula and short bowel syndrome, pouch complications, and deep venous thrombosis with emphasis placed on optimization of the patient's physiologic state for best outcomes. PMID- 26596925 TI - Extraintestinal Manifestations Associated with Inflammatory Bowel Disease. AB - Inflammatory bowel disease (IBD) affects multiple organ systems outside of the gastrointestinal tract. The clinician treating patients with IBD should be acutely aware of the diagnosis and treatment of extraintestinal manifestations in order to decrease morbidity. The management can be difficult and often times requires a multidisciplinary approach. Future research investigating the pathophysiology, diagnosis, and treatment is needed to further the care of these patients. PMID- 26596926 TI - Colorectal Neoplasia and Inflammatory Bowel Disease. AB - Inflammatory bowel disease is associated with an increased risk of gastrointestinal neoplasia. Ulcerative colitis increases the risk of colorectal cancer, and patients with this condition should undergo routine colonoscopic surveillance to detect neoplasia. Crohn's disease increases the risk of malignancy in inflamed segments of bowel, which may include small bowel, colon, rectum, and anus. PMID- 26596927 TI - Nutritional Support of Patient with Inflammatory Bowel Disease. AB - Ideally, surgical patients should be nutritionally optimized, as better nutritional status correlates with favorable outcomes during the perioperative period. As inflammatory bowel disease often leads to overall malnutrition, special consideration should be given to this patient population by surgeons. In this article, we review methods for nutritional assessment and provide nutritional recommendations for this special surgical population. PMID- 26596928 TI - Psychosocial Support of the Inflammatory Bowel Disease Patient. AB - Inflammatory bowel disease (IBD) is a chronic, debilitating disease whose effects spread far beyond the gut. IBD does not generally result in excess mortality; health care providers should thus focus their efforts on improving health-related quality of life and minimizing associated morbidity. A bidirectional relationship exists between IBD and psychiatric conditions; chronic inflammation can produce neuromodulatory effects with resultant mood disorders, and the course of IBD is worse in patients with anxiety and depression. Screening for the early signs of depression or anxiety and initiating appropriate treatment can lead to improved functioning and positively impact disease course. PMID- 26596929 TI - Inflammatory Bowel Disease. PMID- 26596930 TI - Inflammatory Bowel Disease. PMID- 26596931 TI - Urban-rural disparities in child nutrition-related health outcomes in China: The role of hukou policy. AB - BACKGROUND: Hukou is the household registration system in China that determines eligibility for various welfare benefits, such as health care, education, housing, and employment. The hukou system may lead to nutritional and health disparities in China. We aim at examining the role of the hukou system in affecting urban-rural disparities in child nutrition, and disentangling the institutional effect of hukou from the effect of urban/rural residence on child nutrition-related health outcomes. METHODS: This study uses data from the China Health and Nutrition Survey 1993-2009 with a sample of 9616 children under the age of 18. We compute height-for-age z-score and weight-for-age z-score for children. We use both descriptive statistics and multiple regression techniques to study the levels and significance of the association between child nutrition related health outcomes and hukou type. RESULTS: Children with urban hukou have 0.25 (P < 0.01) higher height z-scores and 0.15 (P < 0.01) higher weight z-scores than children with rural hukou, and this difference by urban vs. rural hukou status is larger than the difference in height and weight (0.23 and 0.09, respectively) by urban vs. rural residence. Controlling for place of residence, children with urban hukou had 0.18 higher height z-scores and 0.17 (P < 0.01) higher weight z-scores than children with rural hukou. CONCLUSIONS: The hukou system exacerbates urban-rural disparities in child nutrition-related health outcomes independent of the well-known disparity stemming from urban-rural residence. Fortunately, however, child health disparities due to hukou have been declining since 2000. PMID- 26596933 TI - Extended-Spectrum-Cephalosporin Resistance Genes in Escherichia coli from Beef Cattle. PMID- 26596932 TI - A synthetic growth switch based on controlled expression of RNA polymerase. AB - The ability to control growth is essential for fundamental studies of bacterial physiology and biotechnological applications. We have engineered an Escherichia coli strain in which the transcription of a key component of the gene expression machinery, RNA polymerase, is under the control of an inducible promoter. By changing the inducer concentration in the medium, we can adjust the RNA polymerase concentration and thereby switch bacterial growth between zero and the maximal growth rate supported by the medium. We show that our synthetic growth switch functions in a medium-independent and reversible way, and we provide evidence that the switching phenotype arises from the ultrasensitive response of the growth rate to the concentration of RNA polymerase. We present an application of the growth switch in which both the wild-type E. coli strain and our modified strain are endowed with the capacity to produce glycerol when growing on glucose. Cells in which growth has been switched off continue to be metabolically active and harness the energy gain to produce glycerol at a twofold higher yield than in cells with natural control of RNA polymerase expression. Remarkably, without any further optimization, the improved yield is close to the theoretical maximum computed from a flux balance model of E. coli metabolism. The proposed synthetic growth switch is a promising tool for gaining a better understanding of bacterial physiology and for applications in synthetic biology and biotechnology. PMID- 26596934 TI - Tree-Based Models for Predicting Mortality in Gram-Negative Bacteremia: Avoid Putting the CART before the Horse. AB - Increasingly, infectious disease studies employ tree-based approaches, e.g., classification and regression tree modeling, to identify clinical thresholds. We present tree-based-model-derived thresholds along with their measures of uncertainty. We explored individual and pooled clinical cohorts of bacteremic patients to identify modified acute physiology and chronic health evaluation (II) (m-APACHE-II) score mortality thresholds using a tree-based approach. Predictive performance measures for each candidate threshold were calculated. Candidate thresholds were examined according to binary logistic regression probabilities of the primary outcome, correct classification predictive matrices, and receiver operating characteristic curves. Three individual cohorts comprising a total of 235 patients were studied. Within the pooled cohort, the mean (+/- standard deviation) m-APACHE-II score was 13.6 +/- 5.3, with an in-hospital mortality of 16.6%. The probability of death was greater at higher m-APACHE II scores in only one of three cohorts (odds ratio for cohort 1 [OR1] = 1.15, 95% confidence interval [CI] = 0.99 to 1.34; OR2 = 1.04, 95% CI = 0.94 to 1.16; OR3 = 1.18, 95% CI = 1.02 to 1.38) and was greater at higher scores within the pooled cohort (OR4 = 1.11, 95% CI = 1.04 to 1.19). In contrast, tree-based models overcame power constraints and identified m-APACHE-II thresholds for mortality in two of three cohorts (P = 0.02, 0.1, and 0.008) and the pooled cohort (P = 0.001). Predictive performance at each threshold was highly variable among cohorts. The selection of any one predictive threshold value resulted in fixed sensitivity and specificity. Tree-based models increased power and identified threshold values from continuous predictor variables; however, sample size and data distributions influenced the identified thresholds. The provision of predictive matrices or graphical displays of predicted probabilities within infectious disease studies can improve the interpretation of tree-based model-derived thresholds. PMID- 26596935 TI - New Scheme of Intermittent Benznidazole Administration in Patients Chronically Infected with Trypanosoma cruzi: a Pilot Short-Term Follow-Up Study with Adult Patients. AB - There is a clinical need to test new schemes of benznidazole administration that are expected to be at least as effective as the current therapeutic scheme but safer. This study assessed a new scheme of benznidazole administration in chronic Chagas disease patients. A pilot study with intermittent doses of benznidazole at 5 mg/kg/day in two daily doses every 5 days for a total of 60 days was designed. The main criterion of response was the comparison of quantitative PCR (qPCR) findings prior to and 1 week after the end of treatment. The safety profile was assessed by the rate of suspensions and severity of adverse effects. Twenty patients were analyzed for safety, while qPCR was tested for 17 of them. The average age was 43 +/- 7.9 years; 55% were female. Sixty-five percent of treated subjects showed detectable qPCR results prior to treatment of 1.45 (0.63 to 2.81) and 2.1 (1.18 to 2.78) parasitic equivalents per milliliter of blood (par.eq/ml) for kinetoplastic DNA (kDNA) qPCR and nuclear repetitive sequence satellite DNA (SatDNA) qPCR, respectively. One patient showed detectable PCR at the end of treatment (1/17), corresponding to 6% treatment failure, compared with 11/17 (65%) patients pretreatment (P = 0.01). Adverse effects were present in 10/20 (50%) patients, but in only one case was treatment suspended. Eight patients showed mild adverse effects, whereas moderate reactions with increased liver enzymes were observed in two patients. The main accomplishment of this pilot study is the promising low rate of treatment suspension. Intermittent administration of benznidazole emerges a new potential therapeutic scheme, the efficacy of which should be confirmed by long-term assessment posttreatment. PMID- 26596936 TI - Potential of Tetracycline Resistance Proteins To Evolve Tigecycline Resistance. AB - Tigecycline is a glycylcycline antibiotic active against multidrug-resistant bacterial pathogens. The objectives of our study were to examine the potential of the Tet(A), Tet(K), Tet(M), and Tet(X) tetracycline resistance proteins to acquire mutations causing tigecycline resistance and to determine how this affects resistance to earlier classes of tetracyclines. Mutations in all four tet genes caused a significant increase in the tigecycline MIC in Escherichia coli, and strains expressing mutant Tet(A) and Tet(X) variants reached clinically relevant MICs (2 mg/liter and 3 mg/liter, respectively). Mutations predominantly accumulated in transmembrane domains of the efflux pumps, most likely increasing the accommodation of tigecycline as a substrate. All selected Tet(M) mutants contained at least one mutation in the functionally most important loop III of domain IV. Deletion of leucine 505 of this loop led to the highest increase of the tigecycline MIC (0.5 mg/liter) among Tet(M) mutants. It also caused collateral sensitivity to earlier classes of tetracyclines. A majority of the Tet(X) mutants showed increased activity against all three classes of tetracylines. All tested Tet proteins have the potential to acquire mutations leading to increased MICs of tigecycline. As tet genes are widely found in pathogenic bacteria and spread easily by horizontal gene transfer, resistance development by alteration of existing Tet proteins might compromise the future medical use of tigecycline. We predict that Tet(X) might become the most problematic future Tet determinant, since its weak intrinsic tigecycline activity can be mutationally improved to reach clinically relevant levels without collateral loss in activity to other tetracyclines. PMID- 26596937 TI - In Vitro Effects of Polyphosphate against Prevotella intermedia in Planktonic Phase and Biofilm. AB - Polyphosphate (polyP) has gained a wide interest in the food industry due to its potential as a decontaminating agent. In this study, we examined the effect of sodium tripolyphosphate (polyP3; Na5P3O10) against planktonic and biofilm cells of Prevotella intermedia, a major oral pathogen. The MIC of polyP3 against P. intermedia ATCC 49046 determined by agar dilution method was 0.075%, while 0.05% polyP3 was bactericidal against P. intermedia in time-kill analysis performed using liquid medium. A crystal violet binding assay for the assessment of biofilm formation by P. intermedia showed that sub-MICs of polyP3 significantly decreased biofilm formation. Under the scanning electron microscope, decreased numbers of P. intermedia cells forming the biofilms were observed when the bacterial cells were incubated with 0.025% or higher concentrations of polyP3. Assessment of biofilm viability with LIVE/DEAD staining and viable cell count methods showed that 0.05% or higher concentrations of polyP3 significantly decreased the viability of the preformed biofilms in a concentration-dependent manner. The zone sizes of alpha-hemolysis formed on horse blood agar produced by P. intermedia were decreased in the presence of polyP3. The expression of the genes encoding hemolysins and the genes of the hemin uptake (hmu) locus was downregulated by polyP3. Collectively, our results show that polyP is an effective antimicrobial agent against P. intermedia in biofilms as well as planktonic phase, interfering with the process of hemin acquisition by the bacterium. PMID- 26596938 TI - Characterization of a Novel lsa(E)- and lnu(B)-Carrying Structure Located in the Chromosome of a Staphylococcus aureus Sequence Type 398 Strain. PMID- 26596940 TI - Activity of Fosfomycin against Extended-Spectrum-beta-Lactamase-Producing Uropathogens in Patients in the Community and Hospitalized Patients. AB - Few oral antibiotics exist for the empirical treatment of extended-spectrum beta lactamase (ESBL) urinary tract infections (UTI). In this study, we sought to determine the activity of fosfomycin against ESBL-producing uropathogens from patients at 3 Veterans Affairs (VA) facilities between 2010 and 2013. Among the ESBL uropathogens, 19.9% were fosfomycin resistant. Klebsiella species were more likely than Escherichia coli to be resistant (46% versus 4%; P < 0.001). Fosfomycin remains active against a majority of the ESBL uropathogens, although resistance among Klebsiella spp. was higher than that in previous reports. PMID- 26596939 TI - Development of a New Antileishmanial Aziridine-2,3-Dicarboxylate-Based Inhibitor with High Selectivity for Parasite Cysteine Proteases. AB - Leishmaniasis is one of the major neglected tropical diseases of the world. Druggable targets are the parasite cysteine proteases (CPs) of clan CA, family C1 (CAC1). In previous studies, we identified two peptidomimetic compounds, the aziridine-2,3-dicarboxylate compounds 13b and 13e, in a series of inhibitors of the cathepsin L (CL) subfamily of the papain clan CAC1. Both displayed antileishmanial activity in vitro while not showing cytotoxicity against host cells. In further investigations, the mode of action was characterized in Leishmania major. It was demonstrated that aziridines 13b and 13e mainly inhibited the parasitic cathepsin B (CB)-like CPC enzyme and, additionally, mammalian CL. Although these compounds induced cell death of Leishmania promastigotes and amastigotes in vitro, the induction of a proleishmanial T helper type 2 (Th2) response caused by host CL inhibition was observed in vivo. Therefore, we describe here the synthesis of a new library of more selective peptidomimetic aziridine-2,3-dicarboxylates discriminating between host and parasite CPs. The new compounds are based on 13b and 13e as lead structures. One of the most promising compounds of this series is compound s9, showing selective inhibition of the parasite CPs LmaCatB (a CB-like enzyme of L. major; also named L. major CPC) and LmCPB2.8 (a CL-like enzyme of Leishmania mexicana) while not affecting mammalian CL and CB. It displayed excellent leishmanicidal activities against L. major promastigotes (50% inhibitory concentration [IC50] = 37.4 MUM) and amastigotes (IC50 = 2.3 MUM). In summary, we demonstrate a new selective aziridine-2,3-dicarboxylate, compound s9, which might be a good candidate for future in vivo studies. PMID- 26596941 TI - Mutant Alleles of lptD Increase the Permeability of Pseudomonas aeruginosa and Define Determinants of Intrinsic Resistance to Antibiotics. AB - Gram-negative bacteria provide a particular challenge to antibacterial drug discovery due to their cell envelope structure. Compound entry is impeded by the lipopolysaccharide (LPS) of the outer membrane (OM), and those molecules that overcome this barrier are often expelled by multidrug efflux pumps. Understanding how efflux and permeability affect the ability of a compound to reach its target is paramount to translating in vitro biochemical potency to cellular bioactivity. Herein, a suite of Pseudomonas aeruginosa strains were constructed in either a wild-type or efflux-null background in which mutations were engineered in LptD, the final protein involved in LPS transport to the OM. These mutants were demonstrated to be defective in LPS transport, resulting in compromised barrier function. Using isogenic strain sets harboring these newly created alleles, we were able to define the contributions of permeability and efflux to the intrinsic resistance of P. aeruginosa to a variety of antibiotics. These strains will be useful in the design and optimization of future antibiotics against Gram-negative pathogens. PMID- 26596942 TI - Role of Mitochondrial RNA Polymerase in the Toxicity of Nucleotide Inhibitors of Hepatitis C Virus. AB - Toxicity has emerged during the clinical development of many but not all nucleotide inhibitors (NI) of hepatitis C virus (HCV). To better understand the mechanism for adverse events, clinically relevant HCV NI were characterized in biochemical and cellular assays, including assays of decreased viability in multiple cell lines and primary cells, interaction with human DNA and RNA polymerases, and inhibition of mitochondrial protein synthesis and respiration. NI that were incorporated by the mitochondrial RNA polymerase (PolRMT) inhibited mitochondrial protein synthesis and showed a corresponding decrease in mitochondrial oxygen consumption in cells. The nucleoside released by the prodrug balapiravir (R1626), 4'-azido cytidine, was a highly selective inhibitor of mitochondrial RNA transcription. The nucleotide prodrug of 2'-C-methyl guanosine, BMS-986094, showed a primary effect on mitochondrial function at submicromolar concentrations, followed by general cytotoxicity. In contrast, NI containing multiple ribose modifications, including the active forms of mericitabine and sofosbuvir, were poor substrates for PolRMT and did not show mitochondrial toxicity in cells. In general, these studies identified the prostate cell line PC 3 as more than an order of magnitude more sensitive to mitochondrial toxicity than the commonly used HepG2 cells. In conclusion, analogous to the role of mitochondrial DNA polymerase gamma in toxicity caused by some 2'-deoxynucleotide analogs, there is an association between HCV NI that interact with PolRMT and the observation of adverse events. More broadly applied, the sensitive methods for detecting mitochondrial toxicity described here may help in the identification of mitochondrial toxicity prior to clinical testing. PMID- 26596943 TI - Multipurpose Prevention Approaches with Antiretroviral-Based Formulations. AB - We compared the preclinical safety and efficacy of tenofovir (TFV) 1% gel with that of MZC gel [containing 50 MUM MIV-150, 14 mM Zn(O2CCH3)2(H2O)2, and 3% carrageenan] through a series of in vitro, ex vivo, and in vivo assays. The two gels showed good antiviral therapeutic indexes (50% cytotoxic concentration/50% effective concentration ratios; range, >25 to 800). MZC showed greater anti simian-human immunodeficiency virus reverse transcriptase (SHIV-RT) activity than TFV 1% gel in rhesus macaque vaginal explants. MZC protected mice from vaginal herpes simplex virus 2 (HSV-2) challenge (P < 0.0001), but the TFV 1% gel did not. PMID- 26596944 TI - Mechanism of Action of ME1111, a Novel Antifungal Agent for Topical Treatment of Onychomycosis. AB - Despite the existing treatment options for onychomycosis, there remains a strong demand for potent topical medications. ME1111 is a novel antifungal agent that is active against dermatophytes, has an excellent ability to penetrate human nails, and is being developed as a topical agent for onychomycosis. In the present study, we investigated its mechanism of action. Trichophyton mentagrophytes mutants with reduced susceptibility to ME1111 were selected in our laboratory, and genome sequences were determined for 3 resistant mutants. The inhibitory effect on a candidate target was evaluated by a spectrophotometric enzyme assay using mitochondrial fractions. Point mutations were introduced into candidate genes by a reverse genetics approach. Whole-genome analysis of the 3 selected mutants revealed point mutations in the structural regions of genes encoding subunits of succinate dehydrogenase (complex II). All of the laboratory-generated resistant mutants tested harbored a mutation in one of the subunits of succinate dehydrogenase (SdhB, SdhC, or SdhD). Most of the mutants showed cross-resistance to carboxin and boscalid, which are succinate dehydrogenase inhibitors. ME1111 strongly inhibited the succinate-2,6-dichlorophenolindophenol reductase reaction in Trichophyton rubrum and T. mentagrophytes (50% inhibitory concentrations [IC50s] of 0.029 and 0.025 MUg/ml, respectively) but demonstrated only moderate inhibition of the same reaction in human cell lines. Furthermore, the target protein of ME1111 was confirmed by the introduction of point mutations causing the amino acid substitutions in SdhB, SdhC, and SdhD found in the laboratory generated resistant mutants, which resulted in reduced susceptibility to ME1111. Thus, ME1111 is a novel inhibitor of the succinate dehydrogenase of Trichophyton species, and its mechanism of action indicates its selective profile. PMID- 26596946 TI - Antagonism of Fluconazole and a Proton Pump Inhibitor against Candida albicans. AB - Hospitalized ill patients, at risk for invasive candidiasis, often receive multiple medications, including proton pump inhibitors (PPIs). The antifungal fluconazole perturbs the vacuolar proton ATPase. The PPI omeprazole antagonized Candida albicans growth inhibition by fluconazole. A C. albicans codon-adapted pHluorin, Ca.pHluorin, was generated to measure cytosolic pH. The fungal cytosol was acidified by omeprazole and realkalinized by coexposure to fluconazole. Vacuolar pH was alkalinized by fluconazole. Off-target effects of any medication on fungal pathogens may occur. PMID- 26596945 TI - Neomycin Sulfate Improves the Antimicrobial Activity of Mupirocin-Based Antibacterial Ointments. AB - In the midst of the current antimicrobial pipeline void, alternative approaches are needed to reduce the incidence of infection and decrease reliance on last resort antibiotics for the therapeutic intervention of bacterial pathogens. In that regard, mupirocin ointment-based decolonization and wound maintenance practices have proven effective in reducing Staphylococcus aureus transmission and mitigating invasive disease. However, the emergence of mupirocin-resistant strains has compromised the agent's efficacy, necessitating new strategies for the prevention of staphylococcal infections. Herein, we set out to improve the performance of mupirocin-based ointments. A screen of a Food and Drug Administration (FDA)-approved drug library revealed that the antibiotic neomycin sulfate potentiates the antimicrobial activity of mupirocin, whereas other library antibiotics did not. Preliminary mechanism of action studies indicate that neomycin's potentiating activity may be mediated by inhibition of the organism's RNase P function, an enzyme that is believed to participate in the tRNA processing pathway immediately upstream of the primary target of mupirocin. The improved antimicrobial activity of neomycin and mupirocin was maintained in ointment formulations and reduced S. aureus bacterial burden in murine models of nasal colonization and wound site infections. Combination therapy improved upon the effects of either agent alone and was effective in the treatment of contemporary methicillin-susceptible, methicillin-resistant, and high-level mupirocin-resistant S. aureus strains. From these perspectives, combination mupirocin-and-neomycin ointments appear to be superior to that of mupirocin alone and warrant further development. PMID- 26596947 TI - In Vivo Microdialysis To Determine Subcutaneous Interstitial Fluid Penetration and Pharmacokinetics of Fluconazole in Intensive Care Unit Patients with Sepsis. AB - The objective of the study was to describe the subcutaneous interstitial fluid (ISF) pharmacokinetics of fluconazole in critically ill patients with sepsis. This prospective observational study was conducted at two tertiary intensive care units in Australia. Serial fluconazole concentrations were measured over 24 h in plasma and subcutaneous ISF using microdialysis. The concentrations in plasma and microdialysate were measured using a validated high-performance liquid chromatography system with electrospray mass spectrometer detector method. Noncompartmental pharmacokinetic analysis was performed. Twelve critically ill patients with sepsis were enrolled. The mean in vivo fluconazole recovery rates +/- standard deviation (SD) for microdialysis were 51.4% +/- 16.1% with a mean (+/-SD) fluconazole ISF penetration ratio of 0.52 +/- 0.30 (coefficient of variation, 58%). The median free plasma area under the concentration-time curve from 0 to 24 h (AUC0-24) was significantly higher than the median ISF AUC0-24 (340.4 versus 141.1 mg . h/liter; P = 0.004). There was no statistical difference in median fluconazole ISF penetration between patients receiving and not receiving vasopressors (median, 0.28 versus 0.78; P = 0.106). Both minimum and the maximum concentrations of drug in serum (Cmax and Cmin) showed a significant correlation with the fluconazole plasma exposure (Cmax, R(2) = 0.86, P < 0.0001; Cmin, R(2) = 0.75, P < 0.001). Our data suggest that fluconazole was distributed variably, but incompletely, from plasma into subcutaneous interstitial fluid in this cohort of critically ill patients with sepsis. Given the variability of fluconazole interstitial fluid exposures and lack of clinically identifiable factors by which to recognize patients with reduced distribution/exposure, we suggest higher than standard doses to ensure that drug exposure is adequate at the site of infection. PMID- 26596948 TI - Drug-Drug Interactions between Sofosbuvir and Ombitasvir-Paritaprevir-Ritonavir with or without Dasabuvir. AB - The combination of ombitasvir (an NS5A inhibitor), paritaprevir (an NS3/4A inhibitor) coadministered with ritonavir (r), and dasabuvir (an NS5B nonnucleoside polymerase inhibitor), referred to as the 3D regimen, and the combination of ombitasvir-paritaprevir-r, referred to as the 2D regimen, have demonstrated high efficacy with and without ribavirin in hepatitis C virus (HCV) infected subjects. These regimens have potential for coadministration with sofosbuvir (nucleoside NS5B inhibitor) in the treatment of HCV. This phase 1, drug-drug interaction, open-label, multiple-dose study enrolled 32 healthy subjects to receive the 3D or 2D regimen in combination with sofosbuvir. Doses of study drugs were as follows: ombitasvir-paritaprevir-r, 25/150/100 mg daily (QD); dasabuvir, 250 mg twice daily (BID); and sofosbuvir, 400 mg QD. Blood samples were collected on study days 7, 14, and 21 for evaluating drug interaction at steady state. The effect of the 3D and 2D regimens on the pharmacokinetics of sofosbuvir and its circulating metabolite GS-331007 and vice versa was assessed by a repeated-measures analysis. Exposures of the 3D and 2D regimens were similar (<=20% change) during coadministration with sofosbuvir and during administration alone. Sofosbuvir exposures were 61% to 112% higher with the 3D regimen and 64% to 93% higher with the 2D regimen than with sofosbuvir alone. GS-331007 total exposures were 27% and 32% higher with the 3D and 2D regimens, respectively, than with sofosbuvir alone. Increases in sofosbuvir and GS-331007 exposures likely resulted from breast cancer resistance protein (BCRP) and/or P glycoprotein (P gp) transporter inhibition by paritaprevir and ritonavir. No subjects discontinued the study due to study drug-related adverse events. No dose adjustment is recommended for 3D, 2D, or sofosbuvir in clinical trials exploring the safety and efficacy of the combination. (This study has been registered at ClinicalTrials.gov under registration no. NCT02356562 and NCT02292719.). PMID- 26596950 TI - Evaluating 5-Nitrothiazoles as Trypanocidal Agents. AB - The growth-inhibitory properties of a 5-nitrothiazole series were evaluated against Trypanosoma brucei. A subset of related compounds displayed the greatest potency toward the parasite while exhibiting little cytotoxic effect on mammalian cells, with this antiparasitic activity dependent on expression of a type I nitroreductase by the trypanosome. We conclude that the 5-nitrothiazole class of nitroheterocyclic drugs may represent a new lead in the treatment of human African trypanosomiasis. PMID- 26596949 TI - Exposing a beta-Lactamase "Twist": the Mechanistic Basis for the High Level of Ceftazidime Resistance in the C69F Variant of the Burkholderia pseudomallei PenI beta-Lactamase. AB - Around the world, Burkholderia spp. are emerging as pathogens highly resistant to beta-lactam antibiotics, especially ceftazidime. Clinical variants of Burkholderia pseudomallei possessing the class A beta-lactamase PenI with substitutions at positions C69 and P167 are known to demonstrate ceftazidime resistance. However, the biochemical basis for ceftazidime resistance in class A beta-lactamases in B. pseudomallei is largely undefined. Here, we performed site saturation mutagenesis of the C69 position and investigated the kinetic properties of the C69F variant of PenI from B. pseudomallei that results in a high level of ceftazidime resistance (2 to 64 mg/liter) when expressed in Escherichia coli. Surprisingly, quantitative immunoblotting showed that the steady-state protein levels of the C69F variant beta-lactamase were ~4-fold lower than those of wild-type PenI (0.76 fg of protein/cell versus 4.1 fg of protein/cell, respectively). However, growth in the presence of ceftazidime increases the relative amount of the C69F variant to greater than wild-type PenI levels. The C69F variant exhibits a branched kinetic mechanism for ceftazidime hydrolysis, suggesting there are two different conformations of the enzyme. When incubated with an anti-PenI antibody, one conformation of the C69F variant rapidly hydrolyzes ceftazidime and most likely contributes to the higher levels of ceftazidime resistance observed in cell-based assays. Molecular dynamics simulations suggest that the electrostatic characteristics of the oxyanion hole are altered in the C69F variant. When ceftazidime was positioned in the active site, the C69F variant is predicted to form a greater number of hydrogen-bonding interactions than PenI with ceftazidime. In conclusion, we propose "a new twist" for enhanced ceftazidime resistance mediated by the C69F variant of the PenI beta lactamase based on conformational changes in the C69F variant. Our findings explain the biochemical basis of ceftazidime resistance in B. pseudomallei, a pathogen of considerable importance, and suggest that the full repertoire of conformational states of a beta-lactamase profoundly affects beta-lactam resistance. PMID- 26596951 TI - Development and In Vivo Evaluation of a Novel Histatin-5 Bioadhesive Hydrogel Formulation against Oral Candidiasis. AB - Oral candidiasis (OC), caused by the fungal pathogen Candida albicans, is the most common opportunistic infection in HIV(+) individuals and other immunocompromised populations. The dramatic increase in resistance to common antifungals has emphasized the importance of identifying unconventional therapeutic options. Antimicrobial peptides have emerged as promising candidates for therapeutic intervention due to their broad antimicrobial properties and lack of toxicity. Histatin-5 (Hst-5) specifically has exhibited potent anticandidal activity indicating its potential as an antifungal agent. To that end, the goal of this study was to design a biocompatible hydrogel delivery system for Hst-5 application. The bioadhesive hydroxypropyl methylcellulose (HPMC) hydrogel formulation was developed for topical oral application against OC. The new formulation was evaluated in vitro for gel viscosity, Hst-5 release rate from the gel, and killing potency and, more importantly, was tested in vivo in our mouse model of OC. The findings demonstrated a controlled sustained release of Hst-5 from the polymer and rapid killing ability. Based on viable C. albicans counts recovered from tongues of treated and untreated mice, three daily applications of the formulation beginning 1 day postinfection with C. albicans were effective in protection against development of OC. Interestingly, in some cases, Hst-5 was able to clear existing lesions as well as associated tissue inflammation. These findings were confirmed by histopathology analysis of tongue tissue. Coupled with the lack of toxicity as well as anti-inflammatory and wound-healing properties of Hst-5, the findings from this study support the progression and commercial feasibility of using this compound as a novel therapeutic agent. PMID- 26596952 TI - A Conserved Inhibitory Mechanism of a Lycorine Derivative against Enterovirus and Hepatitis C Virus. AB - Enterovirus 71 (EV71) (Picornaviridae family) and hepatitis C virus (HCV) (Flaviviridae family) are the causative agents of human hand, foot, and mouth disease (HFMD) and hepatitis C, resulting in a severe pandemic involving millions of infections in the Asia-Pacific region and worldwide. The great impact of EV71 and HCV on public health highlights the need to further our understanding of the biology of these two viruses and develop effective therapeutic antivirals. Here, we evaluated a total of 32 lycorine derivatives and demonstrated that 1 acetyllycorine suppressed the proliferation of multiple strains of EV71 in various cells. The results of the drug resistance analysis revealed that 1 acetyllycorine targeted a phenylalanine (F76) in EV71 2A protease (2A(pro)) to stabilize the conformation of a unique zinc finger. Most interestingly, the zinc binding site in EV71 2A(pro) is the exclusive homolog of HCV NS3 among all viruses. Further analysis revealed that 1-acetyllycorine also inhibits HCV with high efficacy, and the mutation on R118 in HCV NS3, which corresponds to F76 in EV71 2A(pro), confers the resistance of HCV to 1-acetyllycorine. These results revealed a conserved mechanism of 1-acetyllycorine against EV71 and HCV through targeting viral proteases. We also documented the significant synergistic anti EV71 and anti-HCV effects of 1-acetyllycorine with reported inhibitors, supporting potential combination therapy for the treatment of EV71 and HCV infections. PMID- 26596953 TI - Dibenzylideneacetones Are Potent Trypanocidal Compounds That Affect the Trypanosoma cruzi Redox System. AB - Despite ongoing efforts, the available treatments for Chagas' disease are still unsatisfactory, especially in the chronic phase of the disease. Our previous study reported the strong trypanocidal activity of the dibenzylideneacetones A3K2A1 and A3K2A3 against Trypanosoma cruzi (Z. Ud Din, T. P. Fill, F. F. de Assis, D. Lazarin-Bidoia, V. Kaplum, F. P. Garcia, C. V. Nakamura, K. T. de Oliveira, and E. Rodrigues-Filho, Bioorg Med Chem 22:1121-1127, 2014, http://dx.doi.org/10.1016/j.bmc.2013.12.020). In the present study, we investigated the mechanisms of action of these compounds that are involved in parasite death. We showed that A3K2A1 and A3K2A3 induced oxidative stress in the three parasitic forms, especially trypomastigotes, reflected by an increase in oxidant species production and depletion of the endogenous antioxidant system. This oxidative imbalance culminated in damage in essential cell structures of T. cruzi, reflected by lipid peroxidation and DNA fragmentation. Consequently, A3K2A1 and A3K2A3 induced vital alterations in T. cruzi, leading to parasite death through the three pathways, apoptosis, autophagy, and necrosis. PMID- 26596954 TI - Broadly Neutralizing Anti-HIV Antibodies Prevent HIV Infection of Mucosal Tissue Ex Vivo. AB - Broadly neutralizing monoclonal antibodies (nAbs) specific for HIV are being investigated for use in HIV prevention. Due to their ability to inhibit HIV attachment to and entry into target cells, nAbs may be suitable for use as topical HIV microbicides. As such, they would present an alternative intervention for individuals who may not benefit from using antiretroviral-based products for HIV prevention. We theorize that nAbs can inhibit viral transmission through mucosal tissue, thus reducing the incidence of HIV infection. The efficacy of the PG9, PG16, VRC01, and 4E10 antibodies was evaluated in an ex vivo human model of mucosal HIV transmission. nAbs reduced HIV transmission, causing 1.5- to 2-log10 reductions in HIV replication in ectocervical tissues and ~3-log10 reductions in HIV replication in colonic tissues over 21 days. These antibodies demonstrated greater potency in colonic tissues, with a 50-fold higher dose being required to reduce transmission in ectocervical tissues. Importantly, nAbs retained their potency and reduced viral transmission in the presence of whole semen. No changes in tissue viability or immune activation were observed in colonic or ectocervical tissue after nAb exposure. Our data suggest that topically applied nAbs are safe and effective against HIV infection of mucosal tissue and support further development of nAbs as a topical microbicide that could be used for anal as well as vaginal protection. PMID- 26596955 TI - Laparoscopy versus laparotomy for the management of early stage cervical cancer. AB - BACKGROUND: The possible advantages of laparoscopic radical hysterectomy (LRH) versus open radical hysterectomy (RH) have not been well reviewed systematically. The aim of this study was to systematically review the comparative effectiveness between LRH and RH in the treatment of cervical cancer based on the evaluation of the Perioperative outcomes, oncological clearance, complications and long-term outcomes. METHODS: The systematic review was conducted by searching PubMed, MEDLINE, EMBASE, the Cochrane Library and BIOSIS databases. All original studies that compared LRH with RH were included for critical appraisal. Data were pooled and analyzed. RESULTS: A total of twelve original studies that compared LRH (n = 754) with RH (n = 785) in patients with cervical cancer fulfilled quality criteria were selected for review and meta-analysis. LRH compared with RH was associated with a significant reduction of intraoperative blood loss (weighted mean difference = -268.4 mL (95 % CI -361.6, -175.1; p < 0.01), a reduced risk of postoperative complications (OR = 0.46; 95 % CI 0.34-0.63) and shorter hospital stay (weighted mean difference = -3.22 days; 95 % CI-4.21, -2.23 days; p < 0.01). These benefits were at the cost of longer operative time (weighted mean difference = 26.9 min (95 % CI 8.08-45.82). The rate of intraoperative complications was similar in the two groups. Lymph nodes yield and positive resection margins were similar between the two groups. There were no significant differences in 5-year overall survival (HR 0.91, 95 % CI 0.48-1.71; p = 0.76) and 5-year disease-free survival (hazard ratio [HR] 0.97, 95 % CI 0.56-1.68; p = 0.91). CONCLUSIONS: LRH shows better short term outcomes compared with RH in patients with cervical cancer. The oncologic outcome and 5-year survival were similar between the two groups. PMID- 26596956 TI - Antibiotic Prophylaxis Regimens in Trauma and Orthopaedic Surgery: Are We Providing Adequate Cover Against Colonizing Organisms? AB - Trauma, elective orthopaedics, and an aging population will result in an increasing health burden and work load. The move to surgical podiatrists in the National Health Service within the United Kingdom will shift the surgical workload away from orthopaedic surgeons. A devastating complication of foot and ankle surgery is postoperative infection. While postoperative infection is multifactorial in etiology, concomitant diabetes mellitus increases the general risk of trauma and orthopaedic surgical site infections up to 8-fold. We therefore undertook a prospective study of our unit antibiotic prophylaxis regimes. Fifty patients participated. Swabs were obtained using aseptic technique from the plantar aspect of the feet, between the toes, and subsequently cultured on agar plates. Specimens were then incubated for 48 hours before being exposed to antibiotic plates. Cultured organisms were classified as susceptible to an antibiotic regimen if susceptibility to cefuroxime, or susceptibility to either drug of the flucloxacillin/gentamicin combination, was demonstrated. Statistical analysis e was performed. A P value <.05 was considered significant. Fifty patients were recruited, 26 (52%) were male. Mean age of 53 +/- 19.4 years. The cohort included 15 diabetic, of which 11 (73.3%) insulin-dependent, and 35 nondiabetic patients. Comparing flucloxacillin/gentamicin against cefuroxime overall, susceptibility was noted in 84% and 70%, respectively (P = .096). Resistance to cefuroxime was significantly higher in diabetics than in nondiabetics (53% vs 25%, P = .046). The same pattern was observed for the flucloxacillin/gentamicin regimen (33% vs 9%, P = .049). While both regimens are active against colonizing organisms in this prospective observational study, flucloxacillin and gentamicin provide greater coverage overall. We have demonstrated that the use of flucloxacillin/gentamicin provides better coverage against commensal bacterial flora compared with cefuroxime alone. This is of even greater importance in the case of the specific high-risk subgroups, such as diabetic patients. LEVELS OF EVIDENCE: Level IV: Case Series. PMID- 26596957 TI - Externalities and article citations: experience of a national public health journal (Gaceta Sanitaria). AB - PURPOSE: The purpose of the study was to analyze the determinants of citations such as publication year, article type, article topic, article selected for a press release, number of articles previously published by the corresponding author, and publication language in a Spanish journal of public health. METHODS: Observational study including all articles published in Gaceta Sanitaria during 2007-2011. We retrieved the number of citations from the ISI Web of Knowledge database in June 2013 and also information on other variables such as number of articles published by the corresponding author in the previous 5 years (searched through PubMed), selection for a press release, publication language, article type and topic, and others. RESULTS: We included 542 articles. Of these, 62.5% were cited in the period considered. We observed an increased odds ratio of citations for articles selected for a press release and also with the number of articles published previously by the corresponding author. Articles published in English do not seem to increase their citations. CONCLUSIONS: Certain externalities such as number of articles published by the corresponding author and being selected for a press release seem to influence the number of citations in national journals. PMID- 26596958 TI - Race and ethnicity, neighborhood poverty and pediatric firearm hospitalizations in the United States. AB - PURPOSE: To better understand the effects of race and/or ethnicity and neighborhood poverty on pediatric firearm injuries in the United States, we compared overall and intent-specific firearm hospitalizations (FH) with those of pedestrian motor vehicle crash hospitalizations (PMVH). METHODS: We used Nationwide Inpatient Sample data (1998-2011) among 0-15 year-olds in a 1:1 case case study; 4725 FH and 4725 PMVH matched by age, year, and region. RESULTS: Risk of FH versus PMVH was 64% higher among black children, Odds ratio (OR) = 1.64, 95% confidence interval (95% CI) = 1.44-1.87, as compared to white children (P < .0001); this risk did not vary by neighborhood poverty (P interaction = .52). Risk of homicide FH versus PMVH was 842% higher among black (OR = 8.42, 95% CI = 6.27-11.3), 452% higher among Hispanics (OR = 4.52, 95% CI = 3.33-6.13) and 233% higher among other race (OR = 2.33, 95% CI = 1.52-3.59) compared to white children. There was a lower risk for unintentional FH among black OR = 0.73, 95% CI = 0.62-0.87, Hispanics (OR = 0.60, 95% CI = 0.49-0.74), and other (OR = 0.63, 95% CI = 0.47-0.83) compared to whites. These intent-specific risks attributed to race did not vary by neighborhood affluence. CONCLUSIONS: Black children were at greater likelihood of FH compared to white children regardless of neighborhood economic status. Minority children had an increased likelihood of intentional FH and a decreased likelihood of unintentional FH as compared to white children irrespective of neighborhood income. PMID- 26596959 TI - An overview of the role of microparticles/microvesicles in blood components: Are they clinically beneficial or harmful? AB - Blood cells and tissues generate heterogeneous populations of cell-derived vesicles, ranging from approximately 50 nm to 1 um in diameter. Under normal physiological conditions and as an essential part of an energy-dependent natural process, microparticles (MPs) are continuously shed into the circulation from membranes of all viable cells such as megakaryocytes, platelets, red blood cells, white blood cells and endothelial cells. MP shedding can also be triggered by pathological activation of inflammatory processes and activation of coagulation or complement systems, or even by shear stress in the circulation. Structurally, MPs have a bilayered phospholipid structure exposing coagulant-active phosphatidylserine and expressing various membrane receptors, and they serve as cell-to-cell shuttles for bioactive molecules such as lipids, growth factors, microRNAs, and mitochondria. It was established that ex vivo processing of blood into its components, involving centrifugation, processing by various apheresis procedures, leucoreduction, pathogen reduction, and finally storage in different media and different types of blood bags, can impact MP generation and content. This is mostly due to exposure of the collected blood to anticoagulant/storage media and due to shear stresses or activation, contact with artificial surfaces, or exposure to various leucocyte-removal filters and pathogen-reduction treatments. Such artificially generated MPs, which are added to the original pool of MPs collected from the donor, may exhibit specific functional characteristics, as MPs are not an inert element of blood components. Not surprisingly, MPs' roles and functionality are therefore increasingly seen to be fully relevant to the field of transfusion medicine, and as a parameter of blood safety that must be considered in haemovigilance programmes. Continual advancements in assessment methods of MPs and storage lesions are gradually leading to a better understanding of the impacts of blood collection on MP generation, while clinical research should clarify links of MPs with transfusion reactions and certain clinical disorders. Harmonization and consensus in sampling protocols, sample handling and processing, and assessment methods are needed to achieve consensual interpretations. This review focuses on the role of MPs as an essential laboratory tool and as a most effective player in transfusion science and medicine and in health and disease. PMID- 26596960 TI - Age-related trends in anti-Mullerian hormone serum level in women with unilateral and bilateral ovarian endometriomas prior to surgery. AB - BACKGROUND: Endometriosis is a well-known cause of infertility, and the anti Mullerian hormone (AMH) is an accepted biomarker of ovarian reserve and response to artificial reproductive technology procedures. The present study was a prospective analysis of age-dependent AMH serum concentration in women with bilateral and unilateral ovarian endometriomas before therapy onset compared with healthy controls. METHODS: This prospective cross-sectional study included 384 women aged 18-48 years. AMH serum concentration was assessed between days 3 and 6 of the menstrual cycle in 78 patients with bilateral and 157 patients with unilateral ovarian endometriomas and compared with 149 healthy controls. Ovarian endometriosis was confirmed histopathologically, and data were presented as medians with interquartile range (IQR). RESULTS: Stage III endometriosis was diagnosed in 53.2 %, stage IV in 18.3 %, stage V in 23.4 % and stage VI in 5.4 % of the patients. Patients with bilateral ovarian endometriomas showed the lowest median AMH levels compared with patients suffering from unilateral ovarian endometriosis (0.55; IQR: 0.59 vs. 2.00; IQR: 2.80; p < 0.001) and the control group (0.55; IQR: 0.59 vs. 2.84; IQR: 3.2; p < 0.001). Median AMH concentration values were not significantly different between patients with unilateral ovarian endometriosis and the healthy controls (2.00; IQR: 2.80 vs. 2.84; IQR: 3.2; p = 0.182). A strongly negative correlation between AMH levels and age was confirmed in healthy individuals (R = -0.834; p < 0.001) and women with unilateral ovarian endometriomas (R = -0.774; p < 0.001). Patients with bilateral ovarian endometriosis showed a significantly negative but only moderate correlation between AMH levels and age (R = -0.633; p < 0.001), which was significantly lower than in the healthy controls (R = -0.633 vs. R = -0.834; p = 0.006) but not in the patients with unilateral ovarian endometriosis (R = -0.663 vs. R-0.774; p = 0.093). Based on a multivariate regression analysis, only bilateral localization of ovarian endometrial cysts (p = 0.003) and patient age (p < 0.001), but not left/right localization of unilateral cyst or cyst volume, were negatively associated with AMH serum concentration. CONCLUSION: According to our data, unilateral ovarian endometriosis had a moderately negative and nonsignificant effect on AMH-based ovarian reserve evaluated prior to surgery, irrespective of age. In contrast, the ovarian reserve was significantly reduced in women with bilateral ovarian endometriomas. PMID- 26596961 TI - RFID monitoring indicates honeybees work harder before a rainy day. PMID- 26596962 TI - Effective treatments for paronychia caused by oncology pharmacotherapy. AB - Cutaneous adverse events are relatively common in patients being treated with molecular-targeted drugs. Paronychia is one of the cutaneous adverse events that influences the patient's quality of life because of pain, and it often affects anticancer treatments in severe cases. However, there are few effective treatments, especially for severe paronychia. Here, we present our experiences of treatment for paronychia due to oncology pharmacotherapy. Although we treated paronychia with various methods, only corticosteroid ointment and phenol chemical matricectomy significantly improved the paronychia. Dermatologists must perform appropriate and effective treatments for paronychia in order to enable patients to continue anticancer drug treatment without impairing their quality of life. PMID- 26596963 TI - Conceptual and institutional gaps: understanding how the WHO can become a more effective cross-sectoral collaborator. AB - BACKGROUND: Two themes consistently emerge from the broad range of academics, policymakers and opinion leaders who have proposed changes to the World Health Organization (WHO): that reform efforts are too slow, and that they do too little to strengthen WHO's capacity to facilitate cross-sectoral collaboration. This study seeks to identify possible explanations for the challenges WHO faces in addressing the broader determinants of health, and the potential opportunities for working across sectors. METHODS: This qualitative study used a mixed methods approach of semi-structured interviews and document review. Five interviewees were selected by stratified purposive sampling within a sampling frame of approximately 45 potential interviewees, and a targeted document review was conducted. All interviewees were senior WHO staff at the department director level or above. Thematic analysis was used to analyze data from interview transcripts, field notes, and the document review, and data coded during the analysis was analyzed against three central research questions. First, how does WHO conceptualize its mandate in global health? Second, what are the barriers and enablers to enhancing cross-sectoral collaboration between WHO and other intergovernmental organizations? Third, how do the dominant conceptual frames and the identified barriers and enablers to cross-sectoral collaboration interact? RESULTS: Analysis of the interviews and documents revealed three main themes: 1) WHO's role must evolve to meet the global challenges and societal changes of the 21st century; 2) WHO's cross-sectoral engagement is hampered internally by a dominant biomedical view of health, and the prevailing institutions and incentives that entrench this view; and 3) WHO's cross-sectoral engagement is hampered externally by siloed areas of focus for each intergovernmental organization, and the lack of adequate conceptual frameworks and institutional mechanisms to facilitate engagement across siloes. CONCLUSION: There are a number of external and internal pressures on WHO which have created an organizational culture and operational structure that focuses on a narrow, technical approach to global health, prioritizing disease-based, siloed interventions over more complex approaches that span sectors. The broader approach to promoting human health and wellbeing, which is conceptualized in WHO's constitution, requires cultural and institutional changes for it to be fully implemented. PMID- 26596964 TI - The Effect of Implementation of Standardized, Evidence-Based Order Sets on Efficiency and Quality Measures for Pediatric Respiratory Illnesses in a Community Hospital. AB - OBJECTIVE: Standardization of evidence-based care, resource utilization, and cost efficiency are commonly used metrics to measure inpatient clinical care delivery. The aim of our project was to evaluate the effect of pediatric respiratory order sets and an asthma pathway on the efficiency and quality measures of pediatric patients treated with respiratory illnesses in an adult community hospital setting. METHODS: We used a pre-post study to review pediatric patients admitted to the inpatient setting with the primary diagnoses of asthma, bronchiolitis, or pneumonia. Patients with concomitant chronic respiratory illnesses were excluded. After implementation of order sets and asthma pathway, we examined changes in respiratory medication use, hospital utilization cost, length of stay (LOS), and 30-day readmission rate. Statistical significance was measured via 2-tailed t test and Fisher test. RESULTS: After implementation of evidence-based order sets and asthma pathway, utilization of bronchodilators decreased and the hospital utilization cost of patients with asthma was reduced from $2010 per patient in 2009 to $1174 per patient in 2011 (P < .05). Asthma LOS decreased from 1.90 days to 1.45 days (P < .05), bronchiolitis LOS decreased from 2.37 days to 2.04 days (P < .05), and pneumonia LOS decreased from 2.3 days to 2.1 days (P = .083). Readmission rates were unchanged. CONCLUSION: The use of order sets and an asthma pathway was associated with a reduction in respiratory treatment use as well as hospitalization utilization costs. Statistically significant decrease in LOS was achieved within the asthma and bronchiolitis populations but not in the pneumonia population. No statistically significant effect was found on the 30-day readmission rates. PMID- 26596965 TI - Herpes Simplex Virus: New Testing, New Thinking. PMID- 26596966 TI - Cell biology and immunology lessons taught by Legionella pneumophila. AB - Legionella pneumophila is a facultative intracellular pathogen capable of replicating within a broad range of hosts. One unique feature of this pathogen is the cohort of ca. 300 virulence factors (effectors) delivered into host cells via its Dot/Icm type IV secretion system. Study of these proteins has produced novel insights into the mechanisms of host function modulation by pathogens, the regulation of essential processes of eukaryotic cells and of immunosurveillance. In this review, we will briefly discuss the roles of some of these effectors in the creation of a niche permissive for bacterial replication in phagocytes and recent advancements in the dissection of the innate immune detection mechanisms by challenging immune cells with L. pneumophila. PMID- 26596967 TI - Children are the guardians of our genome. PMID- 26596968 TI - Are changes in breast self-exam recommendations and early misperceptions of breast cancer risk increasing women's future risks? AB - OBJECTIVE: Young women, high school age, are exposed to breast cancer messages targeting adult women that can result in misperceptions, increasing future risks. Changes in breast self-exam screening recommendations may reduce nurse practitioner (NP) time addressing breast health. This study characterized misperceived knowledge of breast cancer risk in younger women. METHOD: A survey (338 high school students aged 14 to 19) was conducted to assess their perceptions of breast cancer etiologies and risk behaviors. RESULTS: Survey results indicated 20% to 50% of students had misperceptions about breast cancer risk, and the mean knowledge score for all items was 65.47%. There were no differences in students with familial breast cancer histories or those instructed in breast self-exam. Approximately 12% reported being fearful, avoiding public health messages, and approximately 20% thought breastfeeding increased breast cancer risk. IMPLICATIONS FOR PRACTICE: The findings suggest that school-based programs are not addressing misperceptions related to breast health effectively. A National Cancer Institute survey found that NPs and other providers are the most trusted sources of health information. Given the low rates of breast cancer in young women and recommendations against teaching breast self-exam, it is important for NPs to be knowledgeable about common misperceptions and address them with their patients. PMID- 26596969 TI - Effect of catchment land use and soil type on the concentration, quality, and bacterial degradation of riverine dissolved organic matter. AB - We studied the effects of catchment characteristics (soil type and land use) on the concentration and quality of dissolved organic matter (DOM) in river water and on the bacterial degradation of terrestrial DOM. The share of organic soil was the strongest predictor of high concentrations of dissolved organic carbon, nitrogen, and phosphorus (DOC, DON, and DOP, respectively), and was linked to DOM quality. Soil type was more important than land use in determining the concentration and quality of riverine DOM. On average, 5-9 % of the DOC and 45 % of the DON were degraded by the bacterial communities within 2-3 months. Simultaneously, the proportion of humic-like compounds in the DOM pool increased. Bioavailable DON accounted for approximately one-third of the total bioavailable dissolved nitrogen, and thus, terrestrial DON can markedly contribute to the coastal plankton dynamics and support the heterotrophic food web. PMID- 26596970 TI - Brain functional correlates of emotion regulation across adolescence and young adulthood. AB - Few studies have examined the neural correlates of emotion regulation across adolescence and young adulthood. Existing studies of cognitive reappraisal indicate that improvements in regulatory efficiency may develop linearly across this period, in accordance with maturation of prefrontal cortical systems. However, there is also evidence for adolescent differences in reappraisal specific to the activation of "social-information processing network" regions, including the amygdala and temporal-occipital cortices. Here, we use fMRI to examine the neural correlates of emotional reactivity and reappraisal in response to aversive social imagery in a group of 78 adolescents and young adults aged 15 25 years. Within the group, younger participants exhibited greater activation of temporal-occipital brain regions during reappraisal in combination with weaker suppression of amygdala reactivity-the latter being a general correlate of successful reappraisal. Further analyses demonstrated that these age-related influences on amygdala reactivity were specifically mediated by activation of the fusiform face area. Overall, these findings suggest that enhanced processing of salient social cues (i.e., faces) increases reactivity of the amygdala during reappraisal and that this relationship is stronger in younger adolescents. How these relationships contribute to well-known vulnerabilities of emotion regulation during this developmental period will be an important topic for ongoing research. PMID- 26596971 TI - Decitabine improves progression-free survival in older high-risk MDS patients with multiple autosomal monosomies: results of a subgroup analysis of the randomized phase III study 06011 of the EORTC Leukemia Cooperative Group and German MDS Study Group. AB - In a study of elderly AML patients treated with the hypomethylating agent decitabine (DAC), we noted a surprisingly favorable outcome in the (usually very unfavorable) subgroup with two or more autosomal monosomies (MK2+) within a complex karyotype (Lubbert et al., Haematologica 97:393-401, 2012). We now analyzed 206 myelodysplastic syndrome (MDS) patients (88 % of 233 patients randomized in the EORTC/GMDSSG phase III trial 06011, 61 of them with RAEBt, i.e. AML by WHO) with cytogenetics informative for MK status.. Endpoints are the following: complete/partial (CR/PR) and overall response rate (ORR) and progression-free (PFS) and overall survival (OS). Cytogenetic subgroups are the following: 63 cytogenetically normal (CN) patients, 143 with cytogenetic abnormalities, 73 of them MK-negative (MK-), and 70 MK-positive (MK+). These MK+ patients could be divided into 17 with a single autosomal monosomy (MK1) and 53 with at least two monosomies (MK2+). ORR with DAC in CN patients: 36.1 %, in MK- patients: 16.7 %, in MK+ patients: 43.6 % (MK1: 44.4 %, MK2+ 43.3 %). PFS was prolonged by DAC compared to best supportive care (BSC) in the CN (hazard ratio (HR) 0.55, 99 % confidence interval (CI), 0.26; 1.15, p = 0.03) and MK2+ (HR 0.50; 99 % CI, 0.23; 1.06, p = 0.016) but not in the MK-, MK+, and MK1 subgroups. OS was not improved by DAC in any subgroup. In conclusion, we demonstrate for the first time in a randomized phase III trial that high-risk MDS patients with complex karyotypes harboring two or more autosomal monosomies attain encouraging responses and have improved PFS with DAC treatment compared to BSC. PMID- 26596972 TI - Documentation of renal glomerular and tubular impairment and glomerular hyperfiltration in multitransfused patients with beta thalassemia. AB - Urinary albumin to creatinine (ACR) and beta2 microglobulin to creatinine ratios (BCR) are the surrogate and robust markers of renal glomerulopathy and tubulopathy, respectively. These markers predict short-term renal deterioration and mortality in various conditions. We aimed to assess the frequency and predictors of glomerular and tubular defects, renal impairment, and hyperfiltration in 96 adult patients with beta thalassemia intermedia and major. ACR > 300 mg/g creatinine and BCR > 300 MUg/g creatinine were used to define the renal glomerular and tubular damages, respectively. Glomerular filtration rate (eGFRcreat) was estimated according to 2009 the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Decreased eGFRcreat was defined as less than 60 mL/min per 1.73 m(2). Renal glomerular and/or tubular defects were observed in about 68.8 % of all patients. Forty percent of patients had glomerular hyperfiltration. None of the patients had a decreased eGFRcreat. T2* value <=20 msec on cardiac magnetic resonance (cMR) was the only independent predictor of glomerular damage (p = 0.013). Use of alendronate was associated with less renal tubular damage (p = 0.007). Female gender and previous history of splenectomy were the independent predictors of glomerular hyperfiltration in multivariate analysis (p < 0.001 and p = 0.040, respectively). Renal tubular and glomerular damage is frequent in adult patients with thalassemia intermedia and major. T2* value on cMR was the only independent predictor of glomerular damage. However, since we did not explore all the parameters of iron, it is not possible to draw a definite conclusion about the association of cMR and glomerular damage. There is no association with cardiac iron overload/accumulation and tubular damage or hyperfiltration. PMID- 26596973 TI - The use of thrombopoietin-receptor agonists (TPO-RAs) in immune thrombocytopenia (ITP): a "real life" retrospective multicenter experience of the Rete Ematologica Pugliese (REP). AB - Immune thrombocytopenia (ITP) is a disease which sees one-third of patients failing first and subsequent therapeutic approaches, including splenectomy. Thrombopoietin-receptor agonists (TPO-RAs) are recommended for adults who relapse after splenectomy or who have contraindications for splenectomy. In this multicenter study, a total of 124 patients were retrospectively evaluated: 55 (44.3 %) were treated by romiplostim and 69 (55.6 %) by eltrombopag. Mean age, number of young patients (<60 years), time from primary diagnosis of ITP to TPO RA treatment, and previous lines of therapy were similar in both groups. The overall response rate was 80 % (44/55) for romiplostim and 94.2 % (65/69) for eltrombopag; the duration of response and the time to response were similar (p = NS). The response rate to both drugs in non-splenectomized patients was higher than that of splenectomized patients (p < 0.05). The mean duration of response was 30 months for romiplostim and 15 months for eltrombopag, due to later commercialization of eltrombopag. Failure was the most frequent cause of discontinuation. Thrombotic events were the most consistent adverse events and were recorded in 2 and 3 % of patients treated by romiplostim and eltrombopag, respectively. In conclusion, romiplostim and eltrombopag are effective in the majority of patients with chronic ITP who failed several lines of therapy; whether TPO-RAs could substitute splenectomy is under discussion and studies are warranted. PMID- 26596975 TI - Evidence of interventions for the risk of dry eye in critically ill patients: An integrative review. AB - AIMS: Identify the best scientific evidence available to eye care in order to prevent dry eye. METHOD: Review study conducted according to the three steps of the evidence-based practice, guided by the following question, grounded in the Patient, Intervention, Comparison, and Outcome strategy: "What is the best scientific evidence available to eye care related to preventing dry eye?" Two databases were used, the web portal Medical Literature Analysis and Retrieval System Online and two digital libraries. Data were organized by using three structured forms. RESULTS: Ten studies made up the final sample, in English, with evidence levels between I and III. The results pointed out differences regarding the best or most appropriate occlusion and ocular lubrication methods to prevent dry eye. CONCLUSION: Several care methods showed strong scientific evidence to prevent dry eye, related to occlusion and ocular lubrication. There is a need for further studies to determine the strength of this evidence. PMID- 26596974 TI - Efficacy and safety of micafungin versus intravenous itraconazole as empirical antifungal therapy for febrile neutropenic patients with hematological malignancies: a randomized, controlled, prospective, multicenter study. AB - Micafungin, a clinically important echinocandin antifungal drug, needs to be investigated as empirical therapy in febrile neutropenia in comparison with azole compounds. A prospective randomized study was conducted to compare clinical outcomes between micafungin and intravenous itraconazole as an empirical therapy for febrile neutropenia in hematological malignancies. The antifungal drug (micafungin 100 mg or itraconazole 200 mg IV once daily) was given for high fever that was sustained despite the administration of appropriate antibiotics. Treatment success was determined by composite end points based on breakthrough invasive fungal infection (IFI), survival, premature discontinuation, defervescence, and treatment of baseline fungal infection. Duration of fever, hospital stay, and overall survival (OS) were studied. A total of 153 patients were randomized to receive micafungin or itraconazole. The overall success rate was 7.1 % point higher in the micafungin group (64.4 vs. 57.3 %, p = 0.404), satisfying the statistical criteria for the non-inferiority of micafungin. The duration of fever and hospital stay were significantly shorter in the micafungin group (6 vs. 7 days, p = 0.014; 22 vs. 27 days, p = 0.033, respectively). Grade 3 adverse events including hyperbilirubinemia (2 vs. 7), elevation of transaminase levels (2 vs. 4), electrolyte imbalance (1 vs. 2), atrial fibrillation (1 vs. 0), and anaphylaxis (1 vs. 0) occurred in 7 and 13 patients in the micafungin (10.4 %) and itraconazole (18.8 %) groups, respectively. Micafungin, when compared with itraconazole, had favorably comparable success rate and toxicity profiles on febrile neutropenia in patients with hematological malignancies. In addition, it showed superior effect on shortening the hospital stay. PMID- 26596976 TI - Psychometric evaluation of the Positions on Nursing Diagnosis scale. AB - AIM: To study the psychometric properties of the Positions on Nursing Diagnosis (PND) scale. BACKGROUND: The PND is a scale to measure nurses' attitudes toward nursing diagnosis. In previous studies, reliability of the scale was supported but its construct validity is still unclear with studies reporting both one factor and three-factor models. METHODS: A cross-sectional study was conducted with a convenience sample of 262 nurses enrolled from one general public hospital and three long-term care facilities in Italy. Construct validity was assessed with confirmatory factor analysis. Criterion and contrasting-group validities were tested, as well as internal consistency reliability. RESULTS: Confirmatory factor analysis showed the adequacy of a one-factor model of the PND scale. Criterion and contrasting-group validities were supportive, as was internal consistency reliability. CONCLUSIONS: The PND is a valid and reliable scale to measure nurses' attitudes toward nursing diagnosis. Its use in practice and research is recommended. PMID- 26596979 TI - From Atrial Fibrillation to Ventricular Fibrillation and Back. PMID- 26596977 TI - Mobile Health Devices as Tools for Worldwide Cardiovascular Risk Reduction and Disease Management. AB - We examined evidence on whether mobile health (mHealth) tools, including interactive voice response calls, short message service, or text messaging, and smartphones, can improve lifestyle behaviors and management related to cardiovascular diseases throughout the world. We conducted a state-of-the-art review and literature synthesis of peer-reviewed and gray literature published since 2004. The review prioritized randomized trials and studies focused on cardiovascular diseases and risk factors, but included other reports when they represented the best available evidence. The search emphasized reports on the potential benefits of mHealth interventions implemented in low- and middle-income countries. Interactive voice response and short message service interventions can improve cardiovascular preventive care in developed countries by addressing risk factors including weight, smoking, and physical activity. Interactive voice response and short message service-based interventions for cardiovascular disease management also have shown benefits with respect to hypertension management, hospital readmissions, and diabetic glycemic control. Multimodal interventions including Web-based communication with clinicians and mHealth-enabled clinical monitoring with feedback also have shown benefits. The evidence regarding the potential benefits of interventions using smartphones and social media is still developing. Studies of mHealth interventions have been conducted in >30 low- and middle-income countries, and evidence to date suggests that programs are feasible and may improve medication adherence and disease outcomes. Emerging evidence suggests that mHealth interventions may improve cardiovascular-related lifestyle behaviors and disease management. Next-generation mHealth programs developed worldwide should be based on evidence-based behavioral theories and incorporate advances in artificial intelligence for adapting systems automatically to patients' unique and changing needs. PMID- 26596980 TI - Free-Wall Rupture Post-Reperfused Acute Myocardial Infarction: Insights From Multimodality Cardiovascular Imaging. PMID- 26596981 TI - Letter by Abu Daya et al Regarding Article, "Myocardial Stiffness in Patients With Heart Failure and a Preserved Ejection Fraction, Contributions of Collagen and Titin". PMID- 26596982 TI - Letter by Karasawa and Takahashi Regarding Article, "Anti-inflammatory and Antiatherogenic Effects of the Inflammasome NLRP3 Inhibitor Arglabin in ApoE2.Ki Mice Fed a High-Fat Diet". PMID- 26596984 TI - Letter by Tuncez et al Regarding Article, "MacCallum Plaque Causes Acute Myocardial Infarction in a Young Man". PMID- 26596983 TI - Response to Letter Regarding Article, "Anti-inflammatory and Antiatherogenic Effects of the Inflammasome NLRP3 Inhibitor Arglabin in ApoE2.Ki Mice Fed a High Fat Diet". PMID- 26596985 TI - Response to Letter Regarding Article, "MacCallum Plaque Causes Acute Myocardial Infarction in a Young Man". PMID- 26596986 TI - Involvement of monoaminergic system in the antidepressant-like effect of (octylseleno)-xylofuranoside in the mouse tail suspension test. AB - Depression is one of the most commonly diagnosed neuropsychiatric disorders and several studies have demonstrated a role for selenium in mood disorders. For this reason, the present study investigated the role of the monoaminergic system in the antidepressant-like action of (octylseleno)-xylofuranoside (OSX), an organoselenium compound, in the tail suspension test (TST) in mice. For this purpose, OSX (0.001-10 mg/kg) was administered orally (p.o.) 30 min prior to testing, and all of the tested doses reduced the immobility time in the TST without changing the locomotor activity measured in the open field test (OFT). Furthermore, the antidepressant-like effect of OSX (0.01 mg/kg, p.o.) in the TSTwas prevented by pre-treatment in mice with ketanserin (1 mg/kg, intraperitoneal route (i.p.); a 5-HT2A/2C receptor antagonist),WAY100635 (0.1mg/kg, subcutaneous (s.c.); a selective 5-HT1A receptor antagonist), p chlorophenylalaninemethyl ester-PCPA (100mg/kg, i.p.; a selective inhibitor of tryptophan hydroxylase), prazosin (1 mg/kg, i.p.; an alpha1-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p.; an alpha2-adrenoceptor antagonist), SCH233390 (0.05 mg/kg, s.c., a dopaminergic D1 receptor antagonist) and sulpiride (50 mg/kg, i.p., a dopaminergic D2 receptor antagonist), but not with ondansetron (1 mg/kg, i.p.; a selective 5-HT3 receptor antagonist). Taken together, these data demonstrate that OSX has a potent antidepressant like effect in TST at lower doses (0.001-10 mg/kg), which is dependent on its interaction with the serotonergic, noradrenergic and dopaminergic systems. PMID- 26596988 TI - Recombination between the mouse Y chromosome short arm and an additional Y short arm-derived chromosomal segment attached distal to the X chromosome PAR. AB - In a male mouse, meiosis markers of processed DNA double strand breaks (DSBs) such as DMC1 and RAD51 are regularly seen in the non-PAR region of the X chromosome; these disappear late in prophase prior to entry into the first meiotic metaphase. Marker evidence for DSBs occurring in the non-PAR region of the Y chromosome is limited. Nevertheless, historically it has been documented that recombination can occur within the mouse Y short arm (Yp) when an additional Yp segment is attached distal to the X and/or the Y pseudoautosomal region (PAR). A number of recombinants identified among offsprings involved unequal exchanges involving repeated DNA segments; however, equal exchanges will have frequently been missed because of the paucity of markers to differentiate between the two Yp segments. Here, we discuss this historical data and present extensive additional data obtained for two mouse models with Yp additions to the X PAR. PCR genotyping enabled identification of a wider range of potential recombinants; the proportions of Yp exchanges identified among the recombinants were 9.7 and 22.4 %. The frequency of these exchanges suggests that the Yp segment attached to the X PAR is subject to the elevated level of recombinational DSBs that characterizes the PAR. PMID- 26596987 TI - Hox genes, evo-devo, and the case of the ftz gene. AB - The discovery of the broad conservation of embryonic regulatory genes across animal phyla, launched by the cloning of homeotic genes in the 1980s, was a founding event in the field of evolutionary developmental biology (evo-devo). While it had long been known that fundamental cellular processes, commonly referred to as housekeeping functions, are shared by animals and plants across the planet-processes such as the storage of information in genomic DNA, transcription, translation and the machinery for these processes, universal codon usage, and metabolic enzymes-Hox genes were different: mutations in these genes caused "bizarre" homeotic transformations of insect body parts that were certainly interesting but were expected to be idiosyncratic. The isolation of the genes responsible for these bizarre phenotypes turned out to be highly conserved Hox genes that play roles in embryonic patterning throughout Metazoa. How Hox genes have changed to promote the development of diverse body plans remains a central issue of the field of evo-devo today. For this Memorial article series, I review events around the discovery of the broad evolutionary conservation of Hox genes and the impact of this discovery on the field of developmental biology. I highlight studies carried out in Walter Gehring's lab and by former lab members that have continued to push the field forward, raising new questions and forging new approaches to understand the evolution of developmental mechanisms. PMID- 26596990 TI - Merkel Cell Carcinoma: Current Issues Regarding Diagnosis, Management, and Emerging Treatment Strategies. AB - Merkel cell carcinoma (MCC) is a rare but aggressive cutaneous tumor with a predilection for the head and neck of elderly Caucasian patients. Although much less common than melanoma, MCC has higher rates of sentinel lymph node involvement, local and regional recurrences, and mortality. The majority of MCC cases have been linked to the relatively newly discovered Merkel cell polyomavirus, which is a ubiquitous constituent of the skin flora. Recent discoveries regarding viral integration and carcinogenesis and the immunologic features of MCC have expanded the understanding of MCC. These discoveries have led to the development and application of emerging therapies such as somatostatin analogs, immune checkpoint inhibition, adoptive cell therapy, and other exciting possibilities for targeted therapy. PMID- 26596989 TI - Transitions between the Arabidopsis-type and the human-type telomere sequence in green algae (clade Caudivolvoxa, Chlamydomonadales). AB - Telomeres are nucleoprotein structures that distinguish native chromosomal ends from double-stranded breaks. They are maintained by telomerase that adds short G rich telomeric repeats at chromosomal ends in most eukaryotes and determines the TnAmGo sequence of canonical telomeres. We employed an experimental approach that was based on detection of repeats added by telomerase to identify the telomere sequence type forming the very ends of chromosomes. Our previous studies that focused on the algal order Chlamydomonadales revealed several changes in telomere motifs that were consistent with the phylogeny and supported the concept of the Arabidopsis-type sequence being the ancestral telomeric motif for green algae. In addition to previously described independent transitions to the Chlamydomonas type sequence, we report that the ancestral telomeric motif was replaced by the human-type sequence in the majority of algal species grouped within a higher order clade, Caudivolvoxa. The Arabidopsis-type sequence was apparently retained in the Polytominia clade. Regarding the telomere sequence, the Chlorogonia clade within Caudivolvoxa bifurcates into two groups, one with the human-type sequence and the other group with the Arabidopsis-type sequence that is solely formed by the Chlorogonium species. This suggests that reversion to the Arabidopsis-type telomeric motif occurred in the common ancestral Chlorogonium species. The human type sequence is also synthesized by telomerases of algal strains from Arenicolinia, Dunaliellinia and Stephanosphaerinia, except a distinct subclade within Stephanosphaerinia, where telomerase activity was not detected and a change to an unidentified telomeric motif might arise. We discuss plausible reasons why changes in telomeric motifs were tolerated during evolution of green algae. PMID- 26596991 TI - IL-17 Blockade in Psoriasis: Friend or Foe in Cardiovascular Risk? AB - Psoriasis is a chronic, immune-mediated inflammatory disorder associated with systemic inflammation and a significantly increased risk of cardiovascular disease. Common pathologic mechanisms are likely involved in the pathogenesis of psoriasis and atherosclerosis, including similar inflammatory cytokine profiles and proinflammatory cell types. The hypothesis that aggressive treatment of skin inflammation may decrease the risk of developing atherosclerosis and consequently cardiovascular disease is currently a focus of major attention. Interleukin (IL) 17 may be an important cytokine linking skin disease to vascular disease/inflammation. However, the role of IL-17 in atherosclerosis is still controversial, as IL-17 may exhibit pro-atherogenic or anti-atherogenic effects depending on the specific tissue, cellular, and immune context. Given the development of several IL-17 inhibitors, the investigation of IL-17 inhibition impact on cardiovascular outcome is extremely important. PMID- 26596992 TI - Causal influence in neural systems: Reconciling mechanistic-reductionist and statistical perspectives: Comment on "Foundational perspectives on causality in large-scale brain networks" by M. Mannino & S.L. Bressler. PMID- 26596993 TI - Reply to comments on "Foundational perspectives on causality in large-scale brain networks". PMID- 26596994 TI - Spatial coupled disease-behavior framework as a dynamic and adaptive system Reply to comments on "Coupled disease-behavior dynamics on complex networks: A review". PMID- 26596995 TI - The Impact of Peripheral Nerve Stimulation on Coronary Blood Flow and Endothelial Function. AB - PURPOSE: The gekoTM device is a small transcutaneous nerve stimulator that is applied non-invasively to the skin over the common peroneal nerve to stimulate peripheral blood flow. The purpose of this study was to investigate the effect of peripheral nerve stimulation on coronary flow dynamics and systemic endothelial function. METHODS: We enrolled 10 male patients, age 59 +/- 11 years, with symptomatic obstructive coronary disease undergoing percutaneous coronary intervention (PCI). Coronary flow dynamics were assessed invasively using Doppler flow wire at baseline and with nerve stimulation for 4 min. Measurements were taken in the stenotic coronary artery and in a control vessel without obstructive disease. At a separate visit, peripheral blood flow at the popliteal artery (using duplex ultrasound assessment) and endothelial function assessed by peripheral artery tonometry (PAT) were measured at baseline and after one hour of nerve stimulation. RESULTS: Compared to baseline, there was a significant increase in coronary blood flow as measured by average peak velocity (APV) in the control vessel with nerve stimulation (20.3 +/- 7.7 to 23.5 +/- 10 cm/s; p = 0.03) and non-significant increase in the stenotic vessel (21.9 +/- 12 to 23.9 +/ 12.9 cm/s; p = 0.23). Coronary flow reserve did not change significantly. Reactive hyperemia-peripheral arterial tonometry (Rh-PAT) increased from 2.28 +/- 0.39 to 2.67 +/- 0.6, p = 0.045. CONCLUSIONS: A few minutes of peripheral nerve stimulation may improve coronary blood flow. This effect is more prominent in non stenotic vessels. Longer stimulation improved endothelial function. PMID- 26596996 TI - Leeches of the genus Helobdella as model organisms for Evo-Devo studies. AB - Model organisms are important tools in modern biology and have been used elucidate mechanism underlying processes, such as development, heredity, neuronal signaling, and phototropism, to name but a few. In this context, the use of model organisms is predicated on uncovering evolutionarily conserved features of biological processes in the expectation that the findings will be applicable to organisms that are either inaccessible or intractable for direct experimentation. For the most part, particular species have been adapted as model organisms because they can be easily reared and manipulated in the laboratory. In contrast, a major goal in the field of evolutionary developmental biology (Evo-Devo) is to identify and elucidate the differences in developmental processes among species associated with the dramatic range of body plans among organisms, and how these differences have emerged over time in various branches of phylogeny. At first glance then, it would appear that the concept of model organisms for Evo-Devo is oxymoronic. In fact, however, laboratory-compatible, experimentally tractable species are of great use for Evo-Devo, subject to the condition that the ensemble of models investigated should reflect the range of taxonomic diversity, and for this purpose glossiphoniid leeches are useful. Four decades ago (1975), leeches of the species-rich genus Helobdella (Lophotrochozoa; Annelida; Clitellata; Hirudinida; Glossiphoniidae) were collected in Stow Lake, Golden Gate Park, San Francisco, CA (USA). These and other Helobdella species may be taken as Evo-Devo models of leeches, clitellate annelids, and the super-phylum Lophotrochozoa. Here we depict/discuss the biology/taxonomy of these Evo-Devo systems, and the challenges of identifying species within Helobdella. In addition, we document that H. austinensis has been established as a new model organism that can easily be cultivated in the laboratory. Finally, we provide an updated scheme illustrating the unique germ line/soma-differentiation during early development and speculate on the mechanisms of sympatric speciation in this group of aquatic annelids. PMID- 26596997 TI - An Exploratory Evaluation of the Family Meal Intervention for Adolescent Anorexia Nervosa. AB - Although weight restoration is a crucial factor in the recovery of anorexia nervosa (AN), there is scarce evidence regarding which components of treatment promote it. In this paper, the author reports on an effort to utilize research methods in her own practice, with the goal of evaluating if the family meal intervention (FMI) had a positive effect on increasing weight gain or on improving other general outcome measures. Twenty-three AN adolescents aged 12-20 years were randomly assigned to two forms of outpatient family therapy (with [FTFM] and without [FT]) using the FMI, and treated for a 6-month duration. Their outcome was compared at the end of treatment (EOT) and at a 6-month posttreatment follow-up (FU). The main outcome measure was weight recovery; secondary outcome measures were the Morgan Russell Global Assessment Schedule (MRHAS), amenorrhea, general psychological symptoms, and eating disorder symptoms. The majority of the patients in both groups improved significantly at EOT, and these changes were sustained through FU. Given its primarily clinical nature, findings of this investigation project preclude any conclusion. Although the FMI did not appear to convey specific benefits in causing weight gain, clinical observation suggests the value of a flexible stance in implementation of the FMI for the severely undernourished patient with greater psychopathology. PMID- 26596998 TI - Anterior temporal lobectomy. AB - BACKGROUND: Anterior temporal lobectomy is the most established neurosurgical procedure for temporal lobe epilepsy. Here we describe this technique. METHOD: A temporal craniotomy is performed flush with the middle fossa and exposing the Sylvian fissure. The posterior extent of resection is determined as 4.5 cm in the dominant temporal lobe and 5.5 cm in the nondominant one. The first stage consists of removing the lateral neocortex and part of the fusiform gyrus, parallel to the Sylvian fissure, while keeping the temporal horn as the medial limit in the coronal plane. Then, the amygdala, uncus, fimbriae, hippocampus and collateral eminence are identified, transected and resected with the parahippocampal gyrus to complete the procedure. CONCLUSION: Knowledge of the temporomesial anatomy, including neurovascular structures around the brainstem, is essential to keep this procedure safe and effective. PMID- 26596999 TI - Posterior-anterior gradient of zebrafish hes6 expression in the presomitic mesoderm is established by the combinatorial functions of the downstream enhancer and 3'UTR. AB - In vertebrates, the periodic formation of somites from the presomitic mesoderm (PSM) is driven by the molecular oscillator known as the segmentation clock. The hairy-related gene, hes6/her13.2, functions as a hub by dimerizing with other oscillators of the segmentation clock in zebrafish embryos. Although hes6 exhibits a posterior-anterior expression gradient in the posterior PSM with a peak at the tailbud, the detailed mechanisms underlying this unique expression pattern have not yet been clarified. By establishing several transgenic lines, we found that the transcriptional regulatory region downstream of hes6 in combination with the hes6 3'UTR recapitulates the endogenous gradient of hes6 mRNA expression. This downstream region, which we termed the PT enhancer, possessed several putative binding sites for the T-box and Ets transcription factors that were required for the regulatory activity. Indeed, the T-box transcription factor (Tbx16) and Ets transcription factor (Pea3) bound specifically to the putative binding sites and regulated the enhancer activity in zebrafish embryos. In addition, the 3'UTR of hes6 is required for recapitulation of the endogenous mRNA expression. Furthermore, the PT enhancer with the 3'UTR of hes6 responded to the inhibition of retinoic acid synthesis and fibroblast growth factor signaling in a manner similar to endogenous hes6. The results showed that transcriptional regulation by the T-box and Ets transcription factors, combined with the mRNA stability given by the 3'UTR, is responsible for the unique expression gradient of hes6 mRNA in the posterior PSM of zebrafish embryos. PMID- 26597000 TI - An age of enlightenment for cilia: The FASEB summer research conference on the "Biology of Cilia and Flagella". AB - From July 19-24, 2015, 169 clinicians and basic scientists gathered in the vertiginous heights of Snowmass, Colorado (2502 m) for the fourth FASEB summer research conference on the 'Biology of Cilia and Flagella'. Organizers Maureen Barr (Rutgers University), Iain Drummond (Massachusetts General Hospital/Harvard Medical School), and Jagesh Shah (Brigham and Women's Hospital/Harvard Medical School) assembled a program filled with new data and forward-thinking ideas documenting the ongoing growth of the field. Sixty oral presentations and 77 posters covered novel aspects of cilia structure, ciliogenesis, cilia motility, cilia-mediated signaling, and cilia-related disease. In this report, we summarize the meeting, highlight exciting developments and discuss open questions. PMID- 26597001 TI - Refurbishing the germline epigenome: Out with the old, in with the new. AB - Mammalian germline reprogramming involves the erasure and re-establishment of epigenetic information critical for germ cell function and inheritance in offspring. The bi-faceted nature of such reprogramming ensures germline repression of somatic programmes and the establishment of a carefully constructed epigenome essential for fertilisation and embryonic development in the next generation. While the majority of the germline epigenome is erased in preparation for embryonic development, certain genomic sequences remain resistant to this and may represent routes for transmission of epigenetic changes through the germline. Epigenetic reprogramming is regulated by highly conserved epigenetic modifiers, which function to establish, maintain and remove DNA methylation and chromatin modifications. In this review, we discuss recent findings from a considerable body of work illustrating the critical requirement of epigenetic modifiers that influence the epigenetic signature present in mature gametes, and have the potential to affect developmental outcomes in the offspring. We also briefly discuss the similarities of these mechanisms in the human germline and consider the potential for inheritance of epigenetically induced germline genetic errors that could impact on offspring phenotypes. PMID- 26597002 TI - A generalized procedure for analyzing sustained and dynamic vocal fold vibrations from laryngeal high-speed videos using phonovibrograms. AB - OBJECTIVE: This work presents a computer-based approach to analyze the two dimensional vocal fold dynamics of endoscopic high-speed videos, and constitutes an extension and generalization of a previously proposed wavelet-based procedure. While most approaches aim for analyzing sustained phonation conditions, the proposed method allows for a clinically adequate analysis of both dynamic as well as sustained phonation paradigms. MATERIALS AND METHODS: The analysis procedure is based on a spatio-temporal visualization technique, the phonovibrogram, that facilitates the documentation of the visible laryngeal dynamics. From the phonovibrogram, a low-dimensional set of features is computed using a principle component analysis strategy that quantifies the type of vibration patterns, irregularity, lateral symmetry and synchronicity, as a function of time. Two different test bench data sets are used to validate the approach: (I) 150 healthy and pathologic subjects examined during sustained phonation. (II) 20 healthy and pathologic subjects that were examined twice: during sustained phonation and a glissando from a low to a higher fundamental frequency. In order to assess the discriminative power of the extracted features, a Support Vector Machine is trained to distinguish between physiologic and pathologic vibrations. The results for sustained phonation sequences are compared to the previous approach. Finally, the classification performance of the stationary analyzing procedure is compared to the transient analysis of the glissando maneuver. RESULTS: For the first test bench the proposed procedure outperformed the previous approach (proposed feature set: accuracy: 91.3%, sensitivity: 80%, specificity: 97%, previous approach: accuracy: 89.3%, sensitivity: 76%, specificity: 96%). Comparing the classification performance of the second test bench further corroborates that analyzing transient paradigms provides clear additional diagnostic value (glissando maneuver: accuracy: 90%, sensitivity: 100%, specificity: 80%, sustained phonation: accuracy: 75%, sensitivity: 80%, specificity: 70%). CONCLUSIONS: The incorporation of parameters describing the temporal evolvement of vocal fold vibration clearly improves the automatic identification of pathologic vibration patterns. Furthermore, incorporating a dynamic phonation paradigm provides additional valuable information about the underlying laryngeal dynamics that cannot be derived from sustained conditions. The proposed generalized approach provides a better overall classification performance than the previous approach, and hence constitutes a new advantageous tool for an improved clinical diagnosis of voice disorders. PMID- 26597004 TI - Air Passivation of Chalcogen Vacancies in Two-Dimensional Semiconductors. AB - Defects play important roles in semiconductors (SCs). Unlike those in bulk SCs, defects in two-dimensional (2D) SCs are exposed to the surrounding environment, which can potentially modify their properties/functions. Air is a common environment, yet its impact on the defects in 2D SCs still remains elusive. Here we study the interaction between air and chalcogen vacancies (V(X)), the most typical defects in 2D SCs. Although the interaction is weak for most molecules in air, O2 can be chemisorbed at V(X) with a barrier that correlates with the SC cohesive energy and can be overcome even at room temperature for certain SCs. Importantly, the chemisorbed O2 changes the V(X) from commonly believed harmful carrier-traps to electronically benign sites. This unusual behavior originates from the isovalence between O2 and X when bonded with metal. Based on these findings, a facile approach is proposed to improve the performance of 2D SCs by using air/O2 to passivate the defects. PMID- 26597003 TI - Ventromedial prefrontal cortex damage alters relative risk tolerance for prospective gains and losses. AB - One paradigmatic example of "irrational" bias in human economic decision-making known as the "reflection effect"-is a tendency to prefer sure amounts over risky gambles in situations involving potential gain, but to prefer risky gambles over sure amounts in situations involving potential loss. To date, there is no causal evidence regarding the neural basis of the reflection effect. The ventromedial prefrontal cortex (vmPFC) is believed to play a critical role in mediating value based decision-making. In this study, we administered a behavioral test of the reflection effect to three groups of subjects: neurosurgical patients with focal bilateral vmPFC lesions, neurosurgical patients with lesions outside vmPFC, and neurologically healthy adults. Subjects made a series of choices between a sure amount (e.g., gain of $50) and a gamble (e.g., 50% chance of gaining $100, 50% chance of gaining $0). Half the trials featured potential gains while the other half featured potential losses. The sure amounts varied across trials. Relative to the two comparison groups, the vmPFC lesion patients exhibited a significantly greater reflection effect; more gambles selected in the loss condition and fewer gambles selected in the gain condition. This finding demonstrates a critical role for vmPFC in governing susceptibility to bias in decision-making. PMID- 26597008 TI - Semaphorin 7A Promotes Chemokine-Driven Dendritic Cell Migration. AB - Dendritic cell (DC) migration is essential for efficient host defense against pathogens and cancer, as well as for the efficacy of DC-based immunotherapies. However, the molecules that induce the migratory phenotype of DCs are poorly defined. Based on a large-scale proteome analysis of maturing DCs, we identified the GPI-anchored protein semaphorin 7A (Sema7A) as being highly expressed on activated primary myeloid and plasmacytoid DCs in human and mouse. We demonstrate that Sema7A deficiency results in impaired chemokine CCL21-driven DC migration in vivo. Impaired formation of actin-based protrusions, resulting in slower three dimensional migration, was identified as the mechanism underlying the DC migration defect. Furthermore, we show, by atomic force microscopy, that Sema7A decreases adhesion strength to extracellular matrix while increasing the connectivity of adhesion receptors to the actin cytoskeleton. This study demonstrates that Sema7A controls the assembly of actin-based protrusions that drive DC migration in response to CCL21. PMID- 26597007 TI - IL-21 Is Important for Induction of KLRG1+ Effector CD8 T Cells during Acute Intracellular Infection. AB - Microsporidia, a latent opportunistic infection associated with mild inflammation, is characterized by a strong CD8 T cell response, which has been shown to be CD4 T cell dependent. In this manuscript, we demonstrate that CD4 help is provided via IL-21 production, a common gamma-chain cytokine closely related to IL-2. The peak of IL-21 expression, observed during the acute infection, is associated with an elevated IL-21(+) CD4 T subset, and these cells bear a phenotypic resemblance to T follicular helper cells. We observed that, during per-oral microsporidial infection, IL-21 was critical for the generation of an optimal effector CD8 T cell immunity. Sharply decreased effector KLRG1(+) CD8 response was observed in IL-21R knockout mice, and although these cells exhibited reduced functional properties, they retained the ability to proliferate. The role of IL-21 in the generation of CD8 effectors was cell intrinsic, as stronger defects were observed in the IL-21-deficient compartment from the bone marrow chimeric mice (IL-21R knockout/wild-type). These findings are different from those reported for viral infections in which IL-21 has been primarily associated with the generation and maintenance of CD8 memory response. To the best of our knowledge, this report demonstrates a critical role for IL-21 in the generation of a primary effector CD8 T cell response to an infectious disease model. PMID- 26597009 TI - Selective CD28 Antagonist Blunts Memory Immune Responses and Promotes Long-Term Control of Skin Inflammation in Nonhuman Primates. AB - Novel therapies that specifically target activation and expansion of pathogenic immune cell subsets responsible for autoimmune attacks are needed to confer long term remission. Pathogenic cells in autoimmunity include memory T lymphocytes that are long-lived and present rapid recall effector functions with reduced activation requirements. Whereas the CD28 costimulation pathway predominantly controls priming of naive T cells and hence generation of adaptive memory cells, the roles of CD28 costimulation on established memory T lymphocytes and the recall of memory responses remain controversial. In contrast to CD80/86 antagonists (CTLA4-Ig), selective CD28 antagonists blunt T cell costimulation while sparing CTLA-4 and PD-L1-dependent coinhibitory signals. Using a new selective CD28 antagonist, we showed that Ag-specific reactivation of human memory T lymphocytes was prevented. Selective CD28 blockade controlled both cellular and humoral memory recall in nonhuman primates and induced long-term Ag specific unresponsiveness in a memory T cell-mediated inflammatory skin model. No modification of memory T lymphocytes subsets or numbers was observed in the periphery, and importantly no significant reactivation of quiescent viruses was noticed. These findings indicate that pathogenic memory T cell responses are controlled by both CD28 and CTLA-4/PD-L1 cosignals in vivo and that selectively targeting CD28 would help to promote remission of autoimmune diseases and control chronic inflammation. PMID- 26597010 TI - Acid Sphingomyelinase-Derived Ceramide Regulates ICAM-1 Function during T Cell Transmigration across Brain Endothelial Cells. AB - Multiple sclerosis (MS) is a chronic demyelinating disorder of the CNS characterized by immune cell infiltration across the brain vasculature into the brain, a process not yet fully understood. We previously demonstrated that the sphingolipid metabolism is altered in MS lesions. In particular, acid sphingomyelinase (ASM), a critical enzyme in the production of the bioactive lipid ceramide, is involved in the pathogenesis of MS; however, its role in the brain vasculature remains unknown. Transmigration of T lymphocytes is highly dependent on adhesion molecules in the vasculature such as intercellular adhesion molecule-1 (ICAM-1). In this article, we hypothesize that ASM controls T cell migration by regulating ICAM-1 function. To study the role of endothelial ASM in transmigration, we generated brain endothelial cells lacking ASM activity using a lentiviral shRNA approach. Interestingly, although ICAM-1 expression was increased in cells lacking ASM activity, we measured a significant decrease in T lymphocyte adhesion and consequently transmigration both in static and under flow conditions. As an underlying mechanism, we revealed that upon lack of endothelial ASM activity, the phosphorylation of ezrin was perturbed as well as the interaction between filamin and ICAM-1 upon ICAM-1 clustering. Functionally this resulted in reduced microvilli formation and impaired transendothelial migration of T cells. In conclusion, in this article, we show that ASM coordinates ICAM-1 function in brain endothelial cells by regulating its interaction with filamin and phosphorylation of ezrin. The understanding of these underlying mechanisms of T lymphocyte transmigration is of great value to develop new strategies against MS lesion formation. PMID- 26597011 TI - The IL-12 Response of Primary Human Dendritic Cells and Monocytes to Toxoplasma gondii Is Stimulated by Phagocytosis of Live Parasites Rather Than Host Cell Invasion. AB - As a major natural host for Toxoplasma gondii, the mouse is widely used for the study of the immune response to this medically important protozoan parasite. However, murine innate recognition of toxoplasma depends on the interaction of parasite profilin with TLR11 and TLR12, two receptors that are functionally absent in humans. This raises the question of how human cells detect and respond to T. gondii. In this study, we show that primary monocytes and dendritic cells from peripheral blood of healthy donors produce IL-12 and other proinflammatory cytokines when exposed to toxoplasma tachyzoites. Cell fractionation studies determined that IL-12 and TNF-alpha secretion is limited to CD16(+) monocytes and the CD1c(+) subset of dendritic cells. In direct contrast to their murine counterparts, human myeloid cells fail to respond to soluble tachyzoite extracts and instead require contact with live parasites. Importantly, we found that tachyzoite phagocytosis, but not host cell invasion, is required for cytokine induction. Together these findings identify CD16(+) monocytes and CD1c(+) dendritic cells as the major myeloid subsets in human blood-producing innate cytokines in response to T. gondii and demonstrate an unappreciated requirement for phagocytosis of live parasites in that process. This form of pathogen sensing is distinct from that used by mice, possibly reflecting a direct involvement of rodents and not humans in the parasite life cycle. PMID- 26597012 TI - TRPV4 Mechanosensitive Ion Channel Regulates Lipopolysaccharide-Stimulated Macrophage Phagocytosis. AB - Macrophage phagocytosis of particles and pathogens is an essential aspect of innate host defense. Phagocytic function requires cytoskeletal rearrangements that depend on the interaction between macrophage surface receptors, particulates/pathogens, and the extracellular matrix. In the present study we determine the role of a mechanosensitive ion channel, transient receptor potential vanilloid 4 (TRPV4), in integrating the LPS and matrix stiffness signals to control macrophage phenotypic change for host defense and resolution from lung injury. We demonstrate that active TRPV4 mediates LPS-stimulated murine macrophage phagocytosis of nonopsonized particles (Escherichia coli) in vitro and opsonized particles (IgG-coated latex beads) in vitro and in vivo in intact mice. Intriguingly, matrix stiffness in the range seen in inflamed or fibrotic lung is required to sensitize the TRPV4 channel to mediate the LPS-induced increment in macrophage phagocytosis. Furthermore, TRPV4 is required for the LPS induction of anti-inflammatory/proresolution cytokines. These findings suggest that signaling through TRPV4, triggered by changes in extracellular matrix stiffness, cooperates with LPS-induced signals to mediate macrophage phagocytic function and lung injury resolution. These mechanisms are likely to be important in regulating macrophage function in the context of pulmonary infection and fibrosis. PMID- 26597013 TI - Natural History of Food-Triggered Atopic Dermatitis and Development of Immediate Reactions in Children. AB - BACKGROUND: Case reports suggest that children with food-triggered atopic dermatitis (AD) on elimination diets may develop immediate reactions on accidental ingestion or reintroduction of an avoided food. OBJECTIVE: The objective of this study was to systematically study the incidence and risk factors associated with these immediate reactions. METHODS: A retrospective chart review of 298 patients presenting to a tertiary-care allergy-immunology clinic based on concern for food-triggered AD was performed. Data regarding triggering foods, laboratory testing, and clinical reactions were collected prospectively from the initial visit. Food-triggered AD was diagnosed by an allergist immunologist with clinical evaluation and laboratory testing. We identified immediate reactions as any reaction to a food for which there was evidence of sIgE and for which patients developed timely allergic signs and symptoms. Differences between children with and without new immediate reactions were determined by a Mann-Whitney, chi(2), or Fisher's exact test as appropriate. RESULTS: A total of 19% of patients with food-triggered AD and no previous history of immediate reactions developed new immediate food reactions after initiation of an elimination diet. Seventy percent of reactions were cutaneous but 30% were anaphylaxis. Cow's milk and egg were the most common foods causing immediate-type reactions. Avoidance of a food was associated with increased risk of developing immediate reactions to that food (P < .01). Risk was not related to specific IgE level nor a specific food. CONCLUSION: A significant number of patients with food-triggered AD may develop immediate-type reactions. Strict elimination diets need to be thoughtfully prescribed as they may lead to decreased oral tolerance. PMID- 26597014 TI - Recent advances in detection of AGEs: Immunochemical, bioanalytical and biochemical approaches. AB - Advanced glycation end products (AGEs) are a cohort of heterogeneous compounds that are formed after the nonenzymatic glycation of proteins, lipids and nucleic acids. Accumulation of AGEs in the body is implicated in various pathophysiological conditions like diabetes, cardiovascular diseases and atherosclerosis. Numerous studies have reported the connecting link between AGEs and the various complications associated with diseases. Hence, detection and measurement of AGEs becomes centrally important to understand and manage the menace created by AGEs inside the body. In recent years, an increasing number of immunotechniques as well as bioanalytical techniques have been developed to efficiently measure the levels of AGEs, but most of them are still far away from being clinically consistent, as relative disparity and ambiguity masks their standardization. This article is designed to critically review the recent advances and the emerging techniques for detection of AGEs. It is an attempt to summarize the major techniques that exist currently for the detection of AGEs both qualitatively and quantitatively. This review primarily focuses on the detection and quantification of AGEs which are formed in vivo. Immunochemical approach though costly but most effective and accurate method to measure the level of AGEs. Literature review suggests that detection of autoantibody targeting AGEs is a promising way that can be utilized for detection of AGEs. Future research efforts should be dedicated to develop this method in order to push forward the clinical applications of detection of AGEs. PMID- 26597015 TI - Merkel cell carcinoma: An algorithm for multidisciplinary management and decision making. AB - Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine tumor of the skin. Therapeutic approach is often unclear, and considerable controversy exists regarding MCC pathogenesis and optimal management. Due to its rising incidence and poor prognosis, it is imperative to establish the optimal therapy for both the tumor and the lymph node basin, and for treatment to include sentinel node biopsy. Sentinel node biopsy is currently the most consistent predictor of survival for MCC patients, although there are conflicting views and a lack of awareness regarding node management. Tumor and node management involve different specialists, and their respective decisions and interventions are interrelated. No effective systemic treatment has been made available to date, and therefore patients continue to experience distant failure, often without local failure. This review aims to improve multidisciplinary decision-making by presenting scientific evidence of the contributions of each team member implicated in MCC management. Following this review of previously published research, the authors conclude that multidisciplinary team management is beneficial for care, and propose a multidisciplinary decision algorithm for managing this tumor. PMID- 26597016 TI - Meta-analysis of regression of advanced solid tumors in patients receiving placebo or no anti-cancer therapy in prospective trials. AB - BACKGROUND: A meta-analysis of prospective trials systematically investigated regression of advanced solid tumors in patients receiving placebo or no anticancer therapy to inform on spontaneous regressions. PATIENT AND METHODS: Arms of randomized controlled trials (RCTs) of metastatic solid tumors receiving placebo or no anti-cancer therapy were used. Statistical analyses were conducted to calculate the overall response rate (ORR) and to detect differentials based on histology, progression at baseline and prior therapies. RESULTS: A total of 7676 patients were evaluable from 61 RCTs evaluating 18 solid tumors. The ORR was 1.95% (95% CI: 1.52-2.48%). There was no significant effect of histology (p=0.110), baseline progressive disease (p>0.20) or the line of therapy (p>0.20) on ORR. CONCLUSIONS: Spontaneous regressions are seen across all advanced solid tumors. Some malignancies demonstrated higher rates of spontaneous regressions and may be relatively immunotherapy responsive. PMID- 26597017 TI - Spinal metastases: Is stereotactic body radiation therapy supported by evidences? AB - Stereotactic body radiotherapy (SBRT) is becoming widely adopted in the treatment of primary and secondary tumors. Spinal bone metastases are frequently discovered in cancer patients, and in the past have been usually treated with a palliative goal. Nevertheless, in some particular clinical settings, such as oligometastatic patients and/or those with a long life expectancy, spinal SBRT could be considered a valid therapeutic option to obtain long-lasting palliation and, when possible, with a curative goal. This review aims to summarize available clinical and dosimetric data of published studies about spinal SBRT. PMID- 26597018 TI - Nanoparticle-siRNA: A potential cancer therapy? AB - PURPOSE: To explore current developments in short interfering RNA (siRNA) delivery systems in nanooncology, in particular nanoparticles that encapsulate siRNA for targeted treatment of cancer. siRNA has a high specificity towards the oncogenic mRNA in cancer cells, while application of nanoparticles can improve stable delivery and enhance efficacy. METHODS: A literature search was performed using the terms "siRNA", "nanoparticles", "targeted delivery", and "cancer". These databases included Medline, Embase, Cochrane Review, Pubmed, and Scopus. RESULTS: siRNA anti-cancer drugs utilize endogenous RNAi mechanisms to silence oncogene expression, which promotes cancer remission. However, current delivery methods have poor efficacy, requiring assistance by nanoparticles for successful delivery. Recently several preclinical studies have crossed into clinical trials utilizing siRNA nanoparticle therapeutics. CONCLUSION: Great potential exists for nano-siRNA drugs in cancer treatment, but issues exist with nanoparticle toxicity and off target siRNA effects. Further research is needed in this rapidly developing and promising field of nano-siRNA drugs. PMID- 26597019 TI - Polo-like kinase inhibitors in hematologic malignancies. AB - Polo-like kinases (Plk) are key regulators of the cell cycle and multiple aspects of mitosis. Two agents that inhibit the Plk signaling pathway have shown promising activity in patients with hematologic malignancies and are currently in phase III trials. Volasertib is a Plk inhibitor under evaluation combined with low-dose cytarabine in older patients with acute myeloid leukemia (AML) ineligible for intensive induction therapy. Rigosertib, a dual inhibitor of the Plk and phosphatidylinositol 3-kinase pathways, is under investigation in patients with myelodysplastic syndrome (MDS) who have failed azacitidine or decitabine treatment. The prognosis for patients with AML, who are ineligible for intensive induction therapy, and for those with MDS refractory/relapsed after a hypomethylating agent, remains poor. Novel approaches, such as Plk inhibitors, are urgently needed for these patients. Here, we provide a comprehensive overview of the current state of development of Plk inhibitors for the treatment of hematologic malignancies. PMID- 26597020 TI - Immunoglobulin M: Restrainer of Inflammation and Mediator of Immune Evasion by Plasmodium falciparum Malaria. AB - Immunoglobulin M (IgM) is an ancient antibody class that is found in all vertebrates, with the exception of coelacanths, and is indispensable in both innate and adaptive immunity. The equally ancient human malaria parasite, Plasmodium falciparum, formed an intimate relationship with IgM with which it co evolved. In this article, we discuss the association between IgM and human malaria parasites, building on several recent publications that implicate IgM as a crucial molecule that determines both host and parasite survival. Consequently, a better understanding of this association may lead to the development of improved intervention strategies. PMID- 26597021 TI - New Malaria Tests: Square Pegs for Round Holes? AB - To eradicate malaria new technologies are needed, not least in the detection of parasites. However, malaria program implementation is complex, and solutions that appear obvious fit less well on close inspection. Understanding the gaps in current programs is essential to selecting approaches likely to transition successfully to the field. PMID- 26597022 TI - Histopathological Characterization of the Lesions of Contagious Ovine Digital Dermatitis and Immunolabelling of Treponema-like Organisms. AB - Contagious ovine digital dermatitis (CODD) is a cause of severe lameness in sheep and the three Treponema phylogroups Treponema medium/Treponema vincentii-like, Treponema phagedenis-like and Treponema pedis have been associated with clinical disease. The aims of this study were: (1) to describe the histopathological changes associated with each previously established grade of clinical lesion, and (2) to investigate immunohistochemically the association of the Treponema-like organisms with the observed histopathological changes. Early lesions were characterized by lymphoplasmacytic infiltration of the distal digital skin, with suppurative coronitis and intracorneal pustules. In more advanced stages of the disease there was complete separation of the dorsal wall of the hoof with a necrotizing and fibrinosuppurative exudate and dermatitis. The later lesions were mostly resolved, but with milder suppurative changes remaining within the cornified layer and periosteal reaction of the dorsal aspect of the distal phalanx. Large numbers of Treponema-like organisms were identified within early grade lesions (as well as later, more advanced grade lesions) and were specifically associated with the observed histopathological changes. The results of this study provide some evidence in support of the hypothesis that the three CODD-associated Treponema phylogroups are involved in the aetiopathogenesis of this disease. PMID- 26597023 TI - Investigation of Knowledge and Perception of Tuberculosis Among Hispanics in Utah County, Utah. AB - This study aimed to assess extent of knowledge and perceptions of TB within the growing Hispanic community of Utah County, Utah, and the need for focused community educational intervention within that demographic. A mixed-method approach was used and included a survey of 166 adult males and females, and two focus groups with Hispanic women. TB was better known for its ability to kill (92.8 %) than for being contagious (64.5 %); while most knew that TB mainly affects the lungs (77.7 %) and is spread through coughing (75.3 %). Few believed that overcrowded living conditions were a risk factor for TB (30.1 %). Many believed that TB could be cured with medicine (75.3 %). And 65.7 % reported they had been tested for TB, and 7 % had been told by a doctor they had TB. Focus group data showed while most had knowledge of major TB symptoms, some had key misperceptions about disease transmission, testing, TB vaccine, and various protective factors. Enhanced education and dissemination of information on TB, to include an emphasis on symptoms, testing, and treatment within this demographic is recommended. A culturally-appropriate intervention should utilize a participatory approach, to include the local health department in partnership with various Hispanic community-based organizations. PMID- 26597024 TI - Human intestinal spirochetosis: right-side preference in the large intestine. AB - Human intestinal spirochetosis (HIS) is a colorectal bacterial infection, and its clinicopathologic features remain unclear. The aim of this study was to examine its characteristics. We histologically reviewed paraffin-embedded section slides made in 2001, 2006, and 2011 at a single institution in Japan. Cases histologically exhibiting a distinct fringe formation were considered to have HIS. Information was obtained from pathology request forms. We identified 85 HIS cases among 4930 patients (7 cases [0.5%) in 2001, 29 [1.7%] in 2006, and 49 [2.8%] in 2011]. Gastrointestinal symptoms were observed in 7.1% of HIS cases. Human intestinal spirochetosis was more frequent in the right-side large intestine than in the left side. Among 224 samples from HIS cases, conventional (tubular, tubulovillous, and villous) adenomas were found in 148 samples. These adenomas were more frequent in the right side than in the left side, although neither their size nor morphology differed between the sides. Histopathologic evaluation suggested a year-upon-year increasing prevalence of HIS in Japan. A small number exhibited gastrointestinal symptoms. Both histologic sign of HIS and conventional adenomas were more frequent in the right-side large intestine. Therefore, a right-side preference may be a characteristic of HIS. PMID- 26597025 TI - Heterologous recombinant protein with decapacitating activity prevents and reverts cryodamage in ram sperm: An emerging biotechnological tool for cryobiology. AB - During the last decades fundamental and applied aspects of mammalian ram sperm cryopreservation have been increasingly explored by scientists and biotechnologists. Many works report modifications in the composition of the freezing extenders and explore the beneficial and detrimental effects of seminal plasma or seminal plasma components in cryopreservation. Seminal plasma is known to contain stabilizing proteins, thereby this is a good start point to study the maintenance of membrane stability based on the basic knowledge of sperm physiology. However, seminal plasma composition is variable among rams and also the introduction of exogenous seminal plasma or its fractions to commercial semen can be associated with the transmission of viral diseases. Our work shows that a mouse protein, called SPINK3 (Serine Protease Inhibitor Kazal type 3) with decapacitating activity interacts with heterologous ram sperm when it is produced as a recombinant molecule. By immunocytochemistry assays we demonstrate that this protein (naturally expressed by mouse seminal vesicle under androgenic control) binds to the apical portion of both fresh and frozen ram sperm, the same localization described in mouse homologous sperm. Furthermore, it significantly improves sperm progressive motility compared to non-treated samples when it is added to freezing extenders and to dilution media after thawing. On the contrary, addition of SPINK3 does not modify sperm viability. The percentage of sperm with intact acrosome after ionophore induction was also significantly higher in sperm frozen in the presence of SPINK3 compared to control samples and the addition of SPINK3 after thawing significantly reduced both induced and non induced acrosomal loss, indicating that heterologous SPINK3 might act as a calcium inhibitor transport as described in mouse. Based on our results SPINK3 may find a place as a desirable biotechnological tool to achieve a higher proportion of competent sperm to fertilize. PMID- 26597026 TI - Acrosin-binding protein (ACRBP) in the testes of stallions. AB - Acrosin Binding Protein (ACRBP) is specifically localized in the acrosome of germ cells of several species, including mice, pigs, guinea pigs, and humans. The main objective of this study was to investigate ACRBP patterns in the germ cells of stallions at different reproductive stages and seminiferous tubule stages using Western blot, immunohistochemistry, and immunocytochemistry techniques. The stallion reproductive stages were classified as follows: pre-pubertal and post pubertal stages based on the presence/absence of lumen opening in the seminiferous tubules and full spermatogenesis. The protein band associated with the presence of ACRBP appeared at approximately 35-kDa position, indicating that the antibody used in this study recognizes the mature form of ACRBP. During the pre-pubertal stages, immunolabeling did not detect the presence of ACRBP in the germ cells. However, during the post-pubertal stage, immunolabeling of the ACRBP was observed in the pachytene spermatocyte as well as for round, elongating, and elongated spermatids, and in some spermatozoa. In conclusion, the ACRBP can be used as a molecular marker for pachytene spermatocytes, and for round, elongating, and elongated spermatids. The ACRBP can be used to monitor either normal spermatogenesis in the testicular tissues, or germ cell development in vitro. Because the ACRBP is present in the germ cells of stallions that have undergone puberty, it can be used as an indicator for the sexual maturation of stallions. PMID- 26597027 TI - [Risks of the use of big data in research in public health and epidemiology]. PMID- 26597028 TI - [An audit of breast cancer screening mammograms and the variability of radiological practice]. AB - OBJECTIVE: To audit the breast cancer screening mammograms performed in a general hospital and to assess the variation in medical practice in the diagnostic process. MATERIAL AND METHODS: A review was carried out on the screening mammograms performed between 1 May 2010 and 30 April 2011, with clinical follow up for two years, and a comparison with the published standards. RESULTS: Of the 3,878 women examined, 368 (9.48%) were called back to complete the study (97 [16.1%] in the initial screening and 271 [8.2%] in revisions). Forty three biopsies (1.1%) were indicated, of which 24 were diagnosed with cancer. The positive predictive value (PPV) in screening studies (PPV1) was 6.52%. For the recommended biopsy (PPV2) it was 55%, with a sensitivity of 100%, a specificity of 91% and a cancer detection rate of 6.1/1,000. There were no false negatives. Twenty tumours were invasive; with no axillary lymph node infiltration was observed 15 of them. In 6 cases, the size of the tumour was less than or equal to 10mm, and in 17 it was less than 15mm. There were a higher percentage of new appointments by two radiologists (12% and 17.2% versus 7.3%) (P<.001). In 217 cases (58.96%; P<.001) only one radiologist indicated new appointments. Of this group, 73% were discharged in the first visit, compared to 47.6% in the non discrepant group (P<.001). Four of the cancers were detected in these 217 patients. CONCLUSIONS: The observed results are adjusted to the reference values. The discordant data are the new appointments rate, both in the initial screening and in the review, with a significant variation depending on the radiology reader. PMID- 26597029 TI - [Prevalence of inappropriate prescription to polymedicated patients over 65 years old in a rural health area]. AB - OBJECTIVE: Describe the inappropriate prescription to polymedicated patients over 65 years old in rural areas. MATERIAL AND METHOD: An observational, descriptive, cross-sectional study conducted in health care units in the Guadalhorce Valley, a rural area of Malaga, Spain. The district has a catchment population of about 144,993 inhabitants. This study is focused on the population that is older than 65 years, and who use 10 or more medications (4.344 patients). The study has as a primary variable: the rates of inappropriate prescription. These are classified using the Screening Tool of Older Persons' potentially inappropriate Prescriptions (STOPP) criteria, as well as the criteria of the strategy of the approach to polymedicated of the Andalusian Health System. An application was used to create individualised forms that identified inappropriate prescribing criteria. For each patient, we used variables, such as the unit, drug group, medications, dose, and use of the STOPP and Andalusian Health System criteria were recorded for each patient. RESULTS: More than one-third (35.5%) of all patients have inappropriate prescription, according to STOPP criteria, related to some health problem (direct problems). The large majority (94%) have potentially inappropriate prescription according to the criteria of the Andalusian Health System. If the criteria directly related to prescribing medication for people over 65 (general) is taken into account, 100% of patients have some form of inappropriate or potentially inappropriate prescribing. CONCLUSIONS: The prevalence of polypharmacy and inappropriate prescription is a real problem in the population over 65 years old. An informatics tool provides us with the facilities to identify and approach inappropriate prescribing. PMID- 26597030 TI - Engineering of isoamylase: improvement of protein stability and catalytic efficiency through semi-rational design. AB - Isoamylase catalyzes the hydrolysis of alpha-1,6-glycosidic linkages in glycogen, amylopectin and alpha/beta-limit dextrins. A semi-rational design strategy was performed to improve catalytic properties of isoamylase from Bacillus lentus. Three residues in vicinity of the essential residues, Arg505, Asn513, and Gly608, were chosen as the mutation sites and were substituted by Ala, Pro, Glu, and Lys, respectively. Thermal stability of the mutant R505P and acidic stability of the mutant R505E were enhanced. The k cat /K m values of the mutant G608V have been promoted by 49%, and the specific activity increased by 33%. This work provides an effective strategy for improving the catalytic activity and stability of isoamylase, and the results obtained here may be useful for the improvement of catalytic properties of other alpha/beta barrel enzymes. PMID- 26597031 TI - Mono-(2-ethylhexyl) phthalate induces apoptosis through miR-16 in human first trimester placental cell line HTR-8/SVneo. AB - Phthalates have been linked to adverse pregnancy complications. Mono-(2 ethylhexyl) phthalate, an active metabolite of di-(2-ethylhexyl) phthalate and an endocrine disruptor, has been shown to induce apoptosis in various cell types including placental cells. However, the mechanism of action of MEHP induced apoptosis is still unknown. We hypothesized that apoptosis may be mediated in part through altered microRNA(s) in placenta under MEHP exposure. In the present study, we report that MEHP increases miR-16 expression in a time- and dose dependent manner (p<0.05), while inducing apoptosis in HTR-8/SVneo. Cells treated with MEHP showed a dose-dependent increase in cytotoxicity and reactive oxygen species along with decreased cell viability. Consistent with significant increase in apoptosis analyzed by flow cytometry, we detected decreased anti-apoptotic BCL 2 at transcriptional and translational levels with MEHP (p<0.05). Knockdown of miR-16 did not decrease the BCL-2/BAX protein expression ratio in the presence of MEHP when compared to negative control demonstrating that MEHP induces apoptosis directly through miR-16. In conclusion, our study demonstrates for the first time that MEHP induces miR-16, which in turn, alters BCL-2/BAX ratio leading to increased apoptosis. This study provides a novel insight into MEHP induced epigenetic regulation in placental apoptosis which may lead to pregnancy complications. PMID- 26597032 TI - A systematic review of the social and economic burden of influenza in low- and middle-income countries. AB - OBJECTIVES: The economic burden of seasonal influenza outbreaks as well as influenza pandemics in lower- and middle-income countries (LMIC) has yet to be specifically systematically reviewed. The aim of this systematic review is to assess the evidence of influenza economic burden assessment methods in LMIC and to quantify the economic consequences of influenza disease in these countries, including broader opportunity costs in terms of impaired social progress and economic development. METHODS: We conducted an all language literature search across 5 key databases using an extensive list of key words for the time period 1950-2013. We included studies which explored direct costs (medical and non medical), indirect costs (productivity losses), and broader economic impact in LMIC associated with different influenza outcomes such as confirmed seasonal influenza infection, influenza-like illnesses, and pandemic influenza. RESULTS: We included 62 full-text studies in English, Spanish, Russian, Chinese languages, mostly from the countries of Latin American and the Caribbean and East Asia and Pacific with pertinent cost data found in 39 papers. Estimates for direct and indirect costs were the highest in Latin American and the Caribbean. Compared to high-income economies, direct costs in LMIC were lower and productivity losses higher. Evidence on broader impact of influenza included impact on the wider national economy, security dimension, medical insurance policy, legal frameworks, distributional impact, and investment flows. CONCLUSION: The economic burden of influenza in LMIC encompasses multiple dimensions such as direct costs to the health service and households, indirect costs due to productivity losses as well as broader detriments to the wider economy. Evidence from sub-Saharan Africa and in pregnant women remains very limited. Heterogeneity of methods used to estimate cost components makes data synthesis challenging. There is a strong need for standardizing research, data collection and evaluation methods for both direct and indirect cost components. PMID- 26597033 TI - Introduction. PMID- 26597034 TI - The application of anti-Toso antibody enhances CD8(+) T cell responses in experimental malaria vaccination and disease. AB - Toso is a molecule highly expressed on B cells. It influences their survival and was identified as an IgM binding molecule. B cells and natural antibodies play a role in vaccination-induced CD8(+) T cell responses. We investigated the impact of an anti-Toso antibody on vaccination efficiency in a malaria vaccination model. In this model, CD8(+) T cells exert antiparasitic functions on infected hepatocytes in the liver stage of the disease. In vaccinated anti-Toso treated mice, more antigen-specific CD8(+) T cells were induced than in control mice and after infection with Plasmodium berghei ANKA (PbA) sporozoites, the liver parasite burden was lower. In B cell deficient mice, the anti-Toso antibody did not stimulate the CD8(+) T cell response, indicating that B cells were mediating this effect. Furthermore, we analyzed the influence of anti-Toso treatment on non vaccinated mice in the PbA infection model, in which CD8(+) T cells cause brain pathology. Anti-Toso treatment increased cerebral pathology and the accumulation of CD8(+) T cells in the brain. Thus, anti-Toso treatment enhanced the CD8(+) T cell response against PbA in a vaccination and in an infection model. Our findings indicate that Toso may be a novel target to boost vaccine-induced CD8(+) T cell responses. PMID- 26597035 TI - A cytomegalovirus DNA vaccine induces antibodies that block viral entry into fibroblasts and epithelial cells. AB - A vaccine to prevent congenital cytomegalovirus (CMV) infections is a national priority. Investigational vaccines have targeted the viral glycoprotein B (gB) as an inducer of neutralizing antibodies and phosphoprotein 65 (pp65) as an inducer of cytotoxic T cells. Antibodies to gB neutralize CMV entry into all cell types but their potency is low compared to antibodies that block epithelial cell entry through targeting the pentameric complex (gH/gL/UL128/UL130/UL131). Hence, more potent overall neutralizing responses may result from a vaccine that combines gB with pentameric complex-derived antigens. To assess the ability of pentameric complex subunits to generate epithelial entry neutralizing antibodies, DNA vaccines encoding UL128, UL130, and/or UL131 were formulated with Vaxfectin((r)), an adjuvant that enhances antibody responses to DNA vaccines. Mice were immunized with individual DNA vaccines or with pair-wise or trivalent combinations. Only the UL130 vaccine induced epithelial entry neutralizing antibodies and no synergy was observed from bi- or trivalent combinations. In rabbits the UL130 vaccine again induced epithelial entry neutralizing antibodies while UL128 or UL131 vaccines did not. To evaluate compatibility of the UL130 vaccine with DNA vaccines encoding gB or pp65, mono-, bi-, or trivalent combinations were evaluated. Fibroblast and epithelial entry neutralizing titers did not differ between rabbits immunized with gB alone vs. gB/UL130, gB/pp65, or gB/UL130/pp65 combinations, indicating a lack of antagonism from coadministration of DNA vaccines. Importantly, gB-induced epithelial entry neutralizing titers were substantially higher than activities induced by UL130, and both fibroblast and epithelial entry neutralizing titers induced by gB alone as well as gB/pp65 or gB/UL130/pp65 combinations were comparable to those observed in sera from humans with naturally-acquired CMV infections. These findings support further development of Vaxfectin((r))-formulated gB-expressing DNA vaccine for prevention of congenital CMV infections. PMID- 26597036 TI - The current situation of meningococcal disease in Latin America and updated Global Meningococcal Initiative (GMI) recommendations. AB - The Global Meningococcal Initiative (GMI) was established in 2009 and comprises an international team of scientists, clinicians, and public health officials with expertise in meningococcal disease (MD). Its primary goal is to promote global prevention of MD through education, research, international cooperation, and developing recommendations that include decreasing the burden of severe disease. The group held its first roundtable meeting with experts from Latin American countries in 2011, and subsequently proposed several recommendations to reduce the regional burden of MD. A second roundtable meeting was convened with Latin American representatives in June 2013 to reassess MD epidemiology, vaccination strategies, and unmet needs in the region, as well as to update the earlier recommendations. Special emphasis was placed on the emergence and spread of serogroup W disease in Argentina and Chile, and the control measures put in place in Chile were a particular focus of discussions. The impact of routine meningococcal vaccination programs, notably in Brazil, was also evaluated. There have been considerable improvements in MD surveillance systems and diagnostic techniques in some countries (e.g., Brazil and Chile), but the lack of adequate infrastructure, trained personnel, and equipment/reagents remains a major barrier to progress in resource-poor countries. The Pan American Health Organization's Revolving Fund is likely to play an important role in improving access to meningococcal vaccines in Latin America. Additional innovative approaches are needed to redress the imbalance in expertise and resources between countries, and thereby improve the control of MD. In Latin America, the GMI recommends establishment of a detailed and comprehensive national/regional surveillance system, standardization of laboratory procedures, adoption of a uniform MD case definition, maintaining laboratory-based surveillance, replacement of polysaccharide vaccines with conjugate formulations (wherever possible), monitoring and evaluating implemented vaccination strategies, conducting cost effectiveness studies, and developing specific recommendations for vaccination of high-risk groups. PMID- 26597037 TI - Primary adenocarcinoma of pigmented ciliary epithelium in a phthisical eye. AB - We report a case of adenocarcinoma of the pigmented ciliary epithelium arising in a phthisical eye. A 92-year-old man who initially presented with severe ocular pain had calcification extending from the posterior pole to ciliary body on B scan ultrasonography to a degree not previously reported. We highlight the importance of screening for intraocular neoplasms in adults with a long-standing phthisical eye. PMID- 26597038 TI - Streptomyces spongiicola sp. nov., an actinomycete derived from marine sponge. AB - A novel actinomycete (strain HNM0071T) was isolated from an unidentified marine sponge collected from the coast of Sanya City, PR China and its taxonomic position was investigated. The major menaquinones were MK-9 (H6) (65.6 %), MK-9 (H4) (23.8 %) and MK-9 (H8) (10.6 %). The predominant fatty acids were anteiso C15 : 0 (25.5 %), iso-C16 : 0 (19.5 %) and iso-C15 : 0 (15.4 %). The predominant phospholipids were diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine. In addition, four unidentified phospholipids were found. The G+C content of the genomic DNA was 69.8 mol%. Based on 16S rRNA gene sequence analysis, strain HNM0071T was most closely related to Streptomyces wuyuanensis FX61T (97.3 %). The 16S rRNA gene sequence similarity to all other species of the genus Streptomyces was less than 97.0 %. DNA-DNA hybridization between strain HNM0071T and its closest phylogenetic relative, Streptomyces wuyuanensis FX61T, showed 25.0 % relatedness. Based on phenotypic and genotypic characteristics, strain HNM0071T represents a novel species of the genus Streptomyces whose name is proposed as Streptomyes spongiicola sp. nov. The type strain is HNM0071T ( = CCTCCAA2015018T = KCTC 39604T). PMID- 26597039 TI - Chronological Evolution of Magnetic Resonance Imaging Findings in Children With Febrile Infection-Related Epilepsy Syndrome. AB - OBJECTIVE: To describe and analyze the chronological evolution of the radiological findings in seven children with febrile infection-related epilepsy syndrome. METHODS: This is a retrospective study describing the radiological findings and evolution in seven children with febrile infection-related epilepsy syndrome who presented from 2009 to 2013. The children all fit the defined clinical criteria for febrile infection-related epilepsy syndrome; all had a history of normal psychomotor development who presented with acute-onset catastrophic partial status epilepticus associated with a febrile illness or unspecific infectious process. The children were identified from the author's weekly review of the pediatric inpatient service, and then the data were collected and analyzed retrospectively. RESULTS: Six males and one female ranging from 3 months to 9 years of age presented with status epilepticus preceded by a febrile illness. Extensive investigations for infectious, autoimmune, and metabolic etiologies were unremarkable. Multiple antiepileptic medications were attempted, including drug-induced coma in all of them, with poor response. Immunotherapy with intravenous steroids or intravenous immunoglobulin (three patients had both) was tried in six of seven patients with a poor response. Ketogenic diet was initiated in four of seven patients with limited response. Serial magnetic resonance imaging studies, done from the initial presentation through 18 months of follow-up, showed evolution from normal imaging to severe cerebral atrophy. Progressive cytotoxic edema involving mostly bilateral hippocampi and temporal lobes was appreciated in one to three weeks. At one month from seizure onset, mild to moderate cerebral atrophy and hippocampal sclerosis was appreciated that continued to progress over the next year. After six to twelve months, most of the patients showed moderate to severe cerebral atrophy and by one year, cerebellar atrophy was also appreciated. CONCLUSION: Febrile infection-related epilepsy syndrome is a devastating epilepsy syndrome of childhood without a diagnostic biologic marker. The magnetic resonance imaging findings appear to be progressive and typical. Thus, combined with the clinical course, imaging findings can help to confirm the diagnosis (until a biologic marker is found). This hopefully will allow multicentered treatment protocols in the future. PMID- 26597040 TI - Bilateral posterior fracture-dislocation of the shoulders following epileptic seizures: a case report and review of the literature. AB - BACKGROUND: Bilateral posterior fracture-dislocation of the shoulders is an uncommon complication of grand mal seizures. We report a case of bilateral posterior dislocation of the shoulders with proximal humeral fractures following epileptic seizures. A posterior fracture-dislocation of the shoulder is very rare and can be caused by epileptic seizures, trauma, electrocution or electroconvulsive therapy. CASE PRESENTATION: A 62-year-old Sri Lankan male was admitted to our medical unit following four repeated generalized tonic-clonic convulsions, each lasting for several minutes. Following the second seizure he reported an inability to move both upper arms due to intense pain. There was no history of fall during the episodes of convulsions however but the bystanders have forcibly restrained his movements during the tonic-clonic convulsions. Clinical examination revealed severely restricted range of movement in both shoulders, with associated swelling and bruising of the shoulder joints and upper arms. Radiographs of the shoulders confirmed fractures at the level of surgical neck with posterior dislocation. CONCLUSION: Bilateral posterior fracture dislocation of shoulders complicating epileptic seizures are rare. Forcible restraining of the patient's upper limbs during seizures is the likely cause for the fracture dislocations in our patient and this had not been reported before. PMID- 26597041 TI - Occurrence and identification of hemotropic mycoplasmas (Hemoplasmas) in free ranging and laboratory rats (Rattus norvegicus) from two Brazilian zoos. AB - BACKGROUND: Hemotropic mycoplasmas (hemoplasmas), bacteria belonging to the class Mollicutes, are obligatory red blood cell pathogens of a variety of animal species. They may cause acute anemia that is life-threatening or chronic disease that is clinically silent, but may interfere with results of experimental studies when using infected animals. Since these bacteria cannot be cultivated, molecular techniques are the gold standard for diagnosing an infection, investigating its prevalence, and describing new species. Mycoplasma coccoides and M. haemomuris are the most commonly recognized hemoplasmas in the blood of wild and laboratory rodents. Neither the epidemiology nor clinical and molecular characterization of hemoplasma infection in free-ranging rodents in Brazil has been previously reported. The aims of this study were to investigate the occurrence of hemoplasmas in free-ranging rats (Rattus norvegicus) captured in the Passeio Publico and Curitiba Zoo and compare hematologic parameters of infected and non infected animals. RESULTS: Anti-coagulated blood samples collected from 43 free ranging and 20 nursery rats were included in the study. Overall 63.5% were positive using SYBR(r) Green quantitative PCR (qPCR) of the 16S rRNA gene to screen for hemoplasma infection (72% among free-ranging rats; 45% among laboratory-raised rats). Sequencing of the qPCR products showed that all but one sample had >98% identity to M. haemomuris. Phylogenetic analysis based on a fragment of approximately 1300 bp of the 16S rRNA gene showed 99% identity to a new hemoplasma from European rats and 98% identity to a hemotropic mycoplasma described infecting a European harvest mouse (Micromys minutus). No statistically significant changes in hematologic parameters between infected and non-infected rats were found, confirming the low pathogenicity and/or silent characteristics of the infection. CONCLUSIONS: Our findings suggest that hemoplasmas are likely endemic in rodent species in this region. The epidemiology, especially as it relates to the mode of transmission, needs to be further investigated as well as the possibility that other animal species, including humans, might become infected. PMID- 26597043 TI - Analysis of 3-MCPD- and 3-MCPD dipalmitate-induced proteomic changes in rat liver. AB - 3-Monochloropropane-1,2-diol (3-MCPD) and 3-MCPD fatty acid esters are process contaminants in foodstuff which are generated during thermal treatment. Long-term exposure to 3-MCPD or 3-MCPD esters causes toxicity especially in kidney and testis. 3-MCPD esters are efficiently hydrolyzed in the gastrointestinal tract, suggesting that their toxicity is mediated by free 3-MCPD. Combined exposure to free 3-MCPD and 3-MCPD released from 3-MCPD esters might lead to dietary consumption above the tolerable daily intake of 2 MUg/kg body weight/day. Suspected mechanisms of 3-MCPD toxicity include the inhibition of glycolysis and oxidative stress. Here, a comparative proteomic approach was followed to analyze the effects of 3-MCPD or 3-MCPD dipalmitate in livers from rats exposed to 10 mg/kg body weight 3-MCPD, an equimolar dose of 3-MCPD dipalmitate, or a 4-fold lower dose of the ester during a 28-day repeated-dose feeding study. Early cellular changes were monitored in the absence of overt toxicity. A comprehensive view of 3-MCPD- or 3-MCPD dipalmitate-triggered proteomic changes in rat liver links to previously proposed mechanisms of toxicity and substantially extends our knowledge on molecular hepatic effects of 3-MCPD. Organ-independent marker proteins altered upon 3-MCPD exposure, for example DJ-1/PARK7, were identified by comparison of the proteomic patterns of kidney, testis and liver. PMID- 26597044 TI - Endothelial colony-forming cells: Biological and functional abnormalities in patients with recurrent, unprovoked venous thromboembolic disease. AB - INTRODUCTION: Endothelial cells (ECs) are an important component of the blood coagulation system because it maintains blood fluid. Because in patients with venous thromboembolic disease (VTD) a thrombophilic condition is not found sometimes, we investigated if endothelial colony-forming cells (ECFCs) from these patients have biological and functional abnormalities. PATIENTS AND METHODS: Human mononuclear cells (MNCs) were obtained from peripheral blood from patients with VTD and controls to obtain ECFCs. These cells were assayed for their immunophenotype and electron microscopy characteristics and their ability to form capillary-like structures and to produce pro-inflammatory and pro-angiogenic cytokines and reactive oxygen species (ROS). RESULTS: ECFCs appeared at 7 and 21 days of culture in VTD patients and controls, respectively. ECFCs increased 8 fold in patients and emerged 1 week earlier. No differences in the size of the colonies of ECFCs were found. Numbers and time of appearance of ECFCs was different between groups. ECFC-derived ECs (ECFC-ECs) of both groups expressed CD31, CD34, CD146, and CD-309 but none expressed CD45, CD14, or CD90. Interest CD34 was highly expressed in ECFC-ECs from patients. In both groups, ECFC-ECs showed similar capacity to form capillary-like structures but ECFC-ECs from patients had significant abnormalities in the mitochondrial membrane. We found a significant increase in ROS production in ECFC-ECs from patients. There were significant differences in cytokine profiles between VTD patients and controls. CONCLUSIONS: We found a dysfunctional state in ECFC from VTD patients resembling some characteristics of dysfunctional ECs. These findings may help to understand some pathophysiological aspects of VTD. PMID- 26597042 TI - Comparative genomics and metabolic profiling of the genus Lysobacter. AB - BACKGROUND: Lysobacter species are Gram-negative bacteria widely distributed in soil, plant and freshwater habitats. Lysobacter owes its name to the lytic effects on other microorganisms. To better understand their ecology and interactions with other (micro)organisms, five Lysobacter strains representing the four species L. enzymogenes, L. capsici, L. gummosus and L. antibioticus were subjected to genomics and metabolomics analyses. RESULTS: Comparative genomics revealed a diverse genome content among the Lysobacter species with a core genome of 2,891 and a pangenome of 10,028 coding sequences. Genes encoding type I, II, III, IV, V secretion systems and type IV pili were highly conserved in all five genomes, whereas type VI secretion systems were only found in L. enzymogenes and L. gummosus. Genes encoding components of the flagellar apparatus were absent in the two sequenced L. antibioticus strains. The genomes contained a large number of genes encoding extracellular enzymes including chitinases, glucanases and peptidases. Various nonribosomal peptide synthase (NRPS) and polyketide synthase (PKS) gene clusters encoding putative bioactive metabolites were identified but only few of these clusters were shared between the different species. Metabolic profiling by imaging mass spectrometry complemented, in part, the in silico genome analyses and allowed visualisation of the spatial distribution patterns of several secondary metabolites produced by or induced in Lysobacter species during interactions with the soil-borne fungus Rhizoctonia solani. CONCLUSIONS: Our work shows that mining the genomes of Lysobacter species in combination with metabolic profiling provides novel insights into the genomic and metabolic potential of this widely distributed but understudied and versatile bacterial genus. PMID- 26597045 TI - A Protocol for the exo-Mono and exo,exo-Bis Functionalization of the Diazocine Ring of Troger's Base. AB - An efficient protocol has been developed for the exo-mono and exo,exo-bis functionalization of Troger's base in the benzylic 6 and 12 positions of the diazocine ring. The lithiation of Troger's base using s-BuLi/TMEDA followed by electrophilic quench affords exo-mono- and exo,exo-bis-substituted derivatives of Troger's base in good to excellent yields. The variation of the number of equivalents of s-BuLi/TMEDA and the order of addition of the electrophile strongly govern the outcome of the reaction for each electrophile. PMID- 26597047 TI - Regioselectivity in C-H activation: reagent control in cyclometallation of 2-(1 naphthyl)-pyridine. AB - 2-(1-Naphthyl)-pyridine () possesses sp(2) C-H bonds in both the gamma- and delta positions and is therefore a suitable substrate for studying the cyclometallation selectivity with different reagents and conditions. Such selectivity studies are reported. Based on deuterium-exchange experiments it is concluded that cycloruthenation with RuCl2(p-cymene) dimer is reversible with kinetic and thermodynamic preference for gamma-substitution. Electrophilic cycloborylation, on the other hand, shows unusual delta-substitution. The previously published cyclopalladation and cycloauration of the substrate was studied in detail and was shown to be irreversible; they proceed under kinetic control and give gamma- and delta-substitution for palladium and gold, respectively. PMID- 26597046 TI - Selective attention neutralizes the adverse effects of low socioeconomic status on memory in 9-month-old infants. AB - Socioeconomic status (SES) has a documented impact on brain and cognitive development. We demonstrate that engaging spatial selective attention mechanisms may counteract this negative influence of impoverished environments on early learning. We previously used a spatial cueing task to compare target object encoding in the context of basic orienting ("facilitation") versus a spatial selective attention orienting mechanism that engages distractor suppression ("IOR"). This work showed that object encoding in the context of IOR boosted 9 month-old infants' recognition memory relative to facilitation (Markant and Amso, 2013). Here we asked whether this attention-memory link further interacted with SES in infancy. Results indicated that SES was related to memory but not attention orienting efficacy. However, the correlation between SES and memory performance was moderated by the attention mechanism engaged during encoding. SES predicted memory performance when objects were encoded with basic orienting processes, with infants from low-SES environments showing poorer memory than those from high-SES environments. However, SES did not predict memory performance among infants who engaged selective attention during encoding. Spatial selective attention engagement mitigated the effects of SES on memory and may offer an effective mechanism for promoting learning among infants at risk for poor cognitive outcomes related to SES. PMID- 26597048 TI - High acetylene/ethylene separation in a microporous zinc(II) metal-organic framework with low binding energy. AB - A novel zinc(II) metal-organic framework UTSA-67a with narrow one-dimensional (1D) pore channels and inner cages of moderate size has been developed for highly selective separation of C2H2/C2H4 mixtures at room temperature. PMID- 26597049 TI - Anthropometric characteristics and body composition in Mexican older adults: age and sex differences. AB - Anthropometric reference data for older adults, particularly for the oldest old, are still limited, especially in developing countries. The aim of the present study was to describe sex- and age-specific distributions of anthropometric measurements and body composition in Mexican older adults. The methods included in the present study were assessment of height, weight, BMI, calf circumference (CC), waist circumference (WC) and hip circumference (HC) as well as knee height in a sample of 8883 Mexican adults aged 60 years and above and the estimation of sex- and age-specific differences in these measures. Results of the study (n 7865, 54% women) showed that men are taller, have higher BMI, and larger WC than women, whereas women presented higher prevalence of obesity and adiposity. Overall prevalence of underweight was 2.3% in men and 4.0% in women, with increasing prevalence with advancing age. Significant differences were found by age group for weight, height, WC, HC, CC, BMI and knee height (P<0.001), but no significant differences in waist-hip circumference were observed. Significant differences between men and women were found in height, weight, circumferences, BMI and knee height (P<0.001). These results, which are consistent with studies of older adults in other countries, can be used for comparison with other Mexican samples including populations living in the USA and other countries with similar developmental and socio-economic conditions. This information can also be used as reference in clinical settings as a tool for detection of individuals at risk of either underweight or overweight and obesity. PMID- 26597051 TI - Task-related increases in fatigue predict recovery time after academic stress. AB - OBJECTIVE: The aim of this study was to investigate the time course of recovery after an academic exam as a model of high workload and its association with stress-related fatigue. METHODS: Thirty-six medical students (17 females, 19 males) filled out diaries during an exam phase, starting 2 days prior to the exam, and a control phase 4 weeks after the exam for 14 days, respectively. Fatigue, distress, quality of sleep, and health complaints were assessed. Recovery time was determined for each individual and variable by comparing the 3 day average with the confidence interval of the control phase. Recovery time was predicted by Cox regression analyses. RESULTS: Recovery times of all variables except health complaints were predicted by stress-related fatigue. Half of the individuals had recovered after 6 days, and 80% of the individuals had recovered after 8 days. CONCLUSION: The time necessary for recovery from work demands is determined by fatigue as a measure of resource depletion. PMID- 26597050 TI - Prevalence of musculoskeletal symptoms among garment workers in Kandal province, Cambodia. AB - OBJECTIVES: The main objectives of this cross-sectional descriptive study were to identify the prevalence of musculoskeletal symptoms and workstation biomechanical risk levels for garment workers in Kandal Province, Cambodia. METHODS: This cross sectional descriptive study used multistage sampling techniques to select 714 workers from three garment factories among 22 medium-size factories (250-1,000 workers). Face-to-face interviews and direct observation using the rapid upper limb assessment scale (RULA) were used to collect data. RESULTS: The response rate was 98.3% (702/714), and the majority (89.3%) of the respondents were female. Ninety-two percent (95% CI=90.0-94.0) of the workers reported musculoskeletal symptoms in at least one body region in the previous 12 months and 89.0% (95% CI=86.7-91.3) of the workers reported such symptoms in the past seven-day period. The neck, shoulder, and lower back were the most affected body regions. In addition, the RULA data showed that 81.2% of the workers' postures were rated as action level 3, indicating that investigation and change were required soon, and that 7.5% their postures were rated as action level 4, indicating that investigation and change were required immediately. CONCLUSIONS: Cambodian garment workers reported a high prevalence of musculoskeletal symptoms in upper body regions, and their workplaces were rated as high risk ergonomically. PMID- 26597052 TI - Value of TIRADS, BSRTC and FNA-BRAF V600E mutation analysis in differentiating high-risk thyroid nodules. AB - The thyroid imaging reporting and data system (TIRADS) and Bethesda system for reporting thyroid cytopathology (BSRTC) have been used for interpretation of ultrasound and fine-needle aspiration cytology (FNAC) results of thyroid nodules. BRAF(V600E) mutation analysis is a molecular tool in diagnosing thyroid carcinoma. Our objective was to compare the diagnostic value of these methods in differentiating high-risk thyroid nodules. Total 220 patients with high-risk thyroid nodules were recruited in this prospective study. They all underwent ultrasound, FNAC and BRAF(V600E) mutation analysis. The sensitivity and specificity of TIRADS were 73.1% and 88.4%. BSRTC had higher specificity (97.7%) and similar sensitivity (77.6%) compared with TIRADS. The sensitivity and specificity of BRAF(V600E) mutation (85.1%, 100%) were the highest. The combination of BSRTC and BRAF(V600E) mutation analysis significantly increased the efficiency, with 97.8% sensitivity, 97.7% specificity. In patients with BSRTC I-III, the mutation rate of BRAF(V600E) was 64.5% in nodules with TIRADS 4B compared with 8.4% in nodules with TIRADS 3 or 4A (P < 0.001). Our study indicated that combination of BSRTC and BRAF(V600E) mutation analysis bears a great value in differentiating high-risk thyroid nodules. The TIRADS is useful in selecting high-risk patients for FNAB and patients with BSRTC I-III for BRAF(V600E) mutation analysis. PMID- 26597053 TI - Amelanism in the corn snake is associated with the insertion of an LTR retrotransposon in the OCA2 gene. AB - The corn snake (Pantherophis guttatus) is a new model species particularly appropriate for investigating the processes generating colours in reptiles because numerous colour and pattern mutants have been isolated in the last five decades. Using our captive-bred colony of corn snakes, transcriptomic and genomic next-generation sequencing, exome assembly, and genotyping of SNPs in multiple families, we delimit the genomic interval bearing the causal mutation of amelanism, the oldest colour variant observed in that species. Proceeding with sequencing the candidate gene OCA2 in the uncovered genomic interval, we identify that the insertion of an LTR-retrotransposon in its 11(th) intron results in a considerable truncation of the p protein and likely constitutes the causal mutation of amelanism in corn snakes. As amelanistic snakes exhibit white, instead of black, borders around an otherwise normal pattern of dorsal orange saddles and lateral blotches, our results indicate that melanocytes lacking melanin are able to participate to the normal patterning of other colours in the skin. In combination with research in the zebrafish, this work opens the perspective of using corn snake colour and pattern variants to investigate the generative processes of skin colour patterning shared among major vertebrate lineages. PMID- 26597054 TI - PRL-3 activates mTORC1 in Cancer Progression. AB - PRL-3, a metastasis-associated phosphatase, is known to exert its oncogenic functions through activation of PI3K/Akt, which is a key regulator of the rapamycin-sensitive mTOR complex 1 (mTORC1), but a coherent link between PRL-3 and activation of mTOR has not yet been formally demonstrated. We report a positive correlation between PRL-3 expression and mTOR phospho-activation in clinical tumour samples and mouse models of cancer and demonstrate that PRL-3 increased downstream signalling to the mTOR substrates, p70S6K and 4E-BP1, by increasing PI3K/Akt-mediated activation of Rheb-GTP via TSC2 suppression. We also show that PRL-3 increases mTOR translocation to lysosomes via increased mTOR binding affinity to Rag GTPases in an Akt-independent manner, demonstrating a previously undescribed mechanism of action for PRL-3. PRL-3 also enhanced matrix metalloproteinase-2 secretion and cellular invasiveness via activation of mTOR, attributes which were sensitive to rapamycin treatment. The downstream effects of PRL-3 were maintained even under conditions of environmental stress, suggesting that PRL-3 provides a strategic survival advantage to tumour cells via its effects on mTOR. PMID- 26597055 TI - Association Study of rs1333040 and rs1004638 Polymorphisms in the 9p21 Locus with Coronary Artery Disease in Southwest of Iran. AB - BACKGROUND: Coronary artery disease (CAD) is a multifactorial and heterogenic disease. Recently, genome-wide association studies have reported that rs1333040 (C/T) and rs1004638 (A/T) single nucleotide polymorphisms (SNPs) in the 9p21 locus have very strong association with CAD. This study aimed to examine these associations in Southwest of Iran. METHODS: Blood samples were collected from 200 CAD patients and 110 healthy individuals with no CAD. The association of two SNPs with CAD was evaluated by PCR and restriction fragment length polymorphism. RESULTS: Chi-square test showed no association between rs1333040 SNP and CAD (X2: 4.66, df: 2, P=0.09). Also, there was no association between rs1004638 SNP and CAD (X2: 0.27, df: 2, P=0.88). CONCLUSION: No association was observed between rs1333040 and rs1004638 SNPs in the 9P21 region and CAD in Southwest of Iran. PMID- 26597056 TI - Caenorhabditis elegans exhibit a coupling between the defecation motor program and directed locomotion. AB - Distinct motor programs can be coupled to refine the repertoire of behavior dynamics. However, mechanisms underlying such coupling are poorly understood. The defecation motor program (DMP) of C. elegans is composed of a succession of body contraction and expulsion steps, performed repeatedly with a period of 50-60 sec. We show that recurring patterns of directed locomotion are executed in tandem with, co-reset, and co-terminate with the DMP cycle. Calcium waves in the intestine and proton signaling were shown to regulate the DMP. We found that genetic manipulations affecting these calcium dynamics regulated the corresponding patterns of directed locomotion. Moreover, we observed the initiation of a recurring locomotion pattern 10 seconds prior to the posterior body contraction, suggesting that the synchronized motor program may initiate prior to the DMP. This study links two multi-step motor programs executed by C. elegans in synchrony, utilizing non-neuronal tissue to drive directed locomotion. PMID- 26597057 TI - Self-Assembled Monolayers of an Azobenzene Derivative on Silica and Their Interactions with Lysozyme. AB - The capability of the photoresponsive isomerization of azobenzene derivatives in self-assembled monolayer (SAM) surfaces to control protein adsorption behavior has very promising applications in antifouling materials and biotechnology. In this study, we performed an atomistic molecular dynamics (MD) simulation in combination with free-energy calculations to study the morphology of azobenzene terminated SAMs (Azo-SAMs) grafted on a silica substrate and their interactions with lysozyme. Results show that the Azo-SAM surface morphology and the terminal benzene rings' packing are highly correlated with the surface density and the isomer state. Higher surface coverage and the trans-isomer state lead to a more ordered polycrystalline backbone as well as more ordered local packing of benzene rings. On the Azo-SAM surface, water retains a high interfacial diffusivity, whereas the adsorbed lysozyme is found to have extremely low mobility but a relative stable secondary structure. The moderate desorption free energy (~60 kT) from the trans-Azo-SAM surface was estimated by using both the nonequilibrium theorem-based Jarzynski's equality and equilibrium umbrella sampling. PMID- 26597059 TI - Ultra-High-Density Arrays of Defect-Free AlN Nanorods: A "Space-Filling" Approach. AB - Nanostructured semiconductors have a clear potential for improved optoelectronic devices, such as high-efficiency light-emitting diodes (LEDs). However, most arrays of semiconductor nanorods suffer from having relatively low densities (or "fill factors") and a high degree of nonuniformity, especially when produced by self-organized growth. Ideally an array of nanorods for an optoelectronic emitter should have a fill factor close to 100%, with uniform rod diameter and height. In this article we present a "space-filling" approach for forming defect-free arrays of AlN nanorods, whereby the separation between each rod can be controlled to 5 nm due to a self-limiting process. These arrays of pyramidal-topped AlN nanorods formed over wafer-scale areas by metal organic chemical vapor deposition provide a defect-free semipolar top surface, for potential optoelectronic device applications with the highest reported fill factor at 98%. PMID- 26597058 TI - Combining Mean and Standard Deviation of Hounsfield Unit Measurements from Preoperative CT Allows More Accurate Prediction of Urinary Stone Composition Than Mean Hounsfield Units Alone. AB - INTRODUCTION AND OBJECTIVES: The mineral composition of a urinary stone may influence its surgical and medical treatment. Previous attempts at identifying stone composition based on mean Hounsfield Units (HUm) have had varied success. We aimed to evaluate the additional use of standard deviation of HU (HUsd) to more accurately predict stone composition. METHODS: We identified patients from two centers who had undergone urinary stone treatment between 2006 and 2013 and had mineral stone analysis and a computed tomography (CT) available. HUm and HUsd of the stones were compared with ANOVA. Receiver operative characteristic analysis with area under the curve (AUC), Youden index, and likelihood ratio calculations were performed. RESULTS: Data were available for 466 patients. The major components were calcium oxalate monohydrate (COM), uric acid, hydroxyapatite, struvite, brushite, cystine, and CO dihydrate (COD) in 41.4%, 19.3%, 12.4%, 7.5%, 5.8%, 5.4%, and 4.7% of patients, respectively. The HUm of UA and Br was significantly lower and higher than the HUm of any other stone type, respectively. HUm and HUsd were most accurate in predicting uric acid with an AUC of 0.969 and 0.851, respectively. The combined use of HUm and HUsd resulted in increased positive predictive value and higher likelihood ratios for identifying a stone's mineral composition for all stone types but COM. CONCLUSIONS: To the best of our knowledge, this is the first report of CT data aiding in the prediction of brushite stone composition. Both HUm and HUsd can help predict stone composition and their combined use results in higher likelihood ratios influencing probability. PMID- 26597060 TI - Nucleoside/tide Analogues in Modern Drug Design. PMID- 26597061 TI - Thiarabine, 1-(4-Thio-beta-D-arabinofuranosyl)cytosine. A Deoxycytidine Analog With Excellent Anticancer Activity. AB - Thiarabine has demonstrated exceptional antitumor activity against numerous human tumor xenografts in mice, being superior to gemcitabine, clofarabine, or cytarabine. Unlike cytarabine, thiarabine demonstrated excellent activity against solid tumor xenografts, suggesting that this agent has the kind of robust activity in animal models that leads to clinical utility. Thiarabine is effective orally (bioavailability of approximately 16%) and with once per day dosing: Two characteristics that distinguish it from cytarabine. Although both the structure and basic mechanism of action of thiarabine are similar to that of cytarabine, there are many quantitative differences in the biochemical pharmacology of these two agents that can explain the superior antitumor activity of thiarabine. Two important attributes are the long retention time of the 5'-triphosphate of thiarabine in tumor cells and its potent inhibition of DNA synthesis. The biochemical pharmacology of thiarabine is also different from that of gemcitabine. Thiarabine has been evaluated in three phase I clinical trials, where it has demonstrated some activity in heavily pretreated patients with hematologic malignancies and solid tumors. Because of its impressive activity against numerous human tumor xenografts in mice, its unique biochemical activity, and encouraging clinical results in phase I clinical trials, we believe thiarabine should continue to be evaluated in the clinic for treatment of hematologic and/or solid tumors. The preclinical results to date (superior in vivo antitumor activity, oral bioavailability, and once per day dosing), suggest that thiarabine could replace cytarabine in the treatment of acute myelogenous leukemia. PMID- 26597062 TI - Nucleoside Phosphate-Conjugates Come of Age: Catalytic Transformation, Polymerase Recognition and Antiviral Properties. AB - Over the past few decades, different types of nucleoside phosphate-conjugates have been under extensive investigation due to their favorable molecular lability with interesting catalytic hydrolysis mechanisms, recognition as polymerase substrates, and especially for their development as antiviral/ anticancer protide therapeutics. The antiviral conjugates such as nucleoside phosphoesters and phosphoramidates that were discovered and developed in the initial years have been well reviewed by the pioneers in the field. In the present review, we will discuss the basic chemical and biological principles behind consideration of some representative structural classes. We will also summarize the chemical and biological properties of some of the more recent analogues that were synthesized and evaluated in our laboratory and by others. This includes new principles for their application as direct substrates of polymerases, nucleobasedependent catalytic and antiviral activity, and a plausible 'prodrug of a prodrug' strategy for tissue/organ-specific targeted drug delivery. PMID- 26597063 TI - Predictors of hospital mortality and serious complications in patients admitted with excessive warfarin anticoagulation. AB - INTRODUCTION: Warfarin is the most commonly used oral anticoagulant and serious bleeding remains the most feared complication. Excessive warfarin anticoagulation (EWA) can be associated with adverse outcome. We aimed to identify the predictors of adverse clinical outcomes in patients admitted with EWA. METHODS AND MATERIALS: Medical records of patients admitted with EWA from March-2004 through Feb-2015 were reviewed. EWA was defined as international normalized ratio (INR)>3.5 in patients who have been receiving warfarin. Primary outcome was death within hospital and secondary outcome was major composite complications (MCC) defined as intracranial hemorrhage (ICH), a need for transfusing >= 4 units packed red blood cell (PRBC), a need for surgical intervention for hemostasis or death within hospital. RESULTS: 267 patients (153 females and 114 male) were enrolled. 25 patients (9.4%) died during hospitalization. ICH, upper gastrointestinal bleeding and hemoptysis were more common in patients who did not survive (P-value: <0.001, 0.033 and 0.028; respectively). There was no correlation between indication for anticoagulation and death within hospital or development of MCC. In multivariate analysis, O blood group, ICH and the number of transfused PRBC and fresh frozen plasma units were identified as independent predictors of death within hospital. Lower hemoglobin concentrations and higher pulmonary pressures on admission were independent predictors of MCC, which occurred in 47 patients (17.6%). CONCLUSION: Hospital mortality correlated with the severity of bleeding (requiring >= 4 units PRBC), intracranial hemorrhage and O blood group, while MCC associated with lower hemoglobin and pulmonary hypertension at the time of admission. PMID- 26597064 TI - The Importance of Fossils in Understanding the Evolution of Parasites and Their Vectors. AB - Knowledge concerning the diversity of parasitism and its reach across our current understanding of the tree of life has benefitted considerably from novel molecular phylogenetic methods. However, the timing of events and the resolution of the nature of the intimate relationships between parasites and their hosts in deep time remain problematic. Despite its vagaries, the fossil record provides the only direct evidence of parasites and parasitism in the fossil record of extant and extinct lineages. Here, we demonstrate the potential of the fossil record and other lines of geological evidence to calibrate the origin and evolution of parasitism by combining different kinds of dating evidence with novel molecular clock methodologies. Other novel methods promise to provide additional evidence for the presence or the life habit of pathogens and their vectors, including the discovery and analysis of ancient DNA and other biomolecules, as well as computed tomographic methods. PMID- 26597065 TI - The Geological Record of Parasitic Nematode Evolution. AB - This chapter discusses the evolutionary history of nematode parasites of invertebrates, vertebrates and plants based on fossil remains in amber, stone and coprolites dating from the Palaeozoic to the Holocene. The earliest parasitic nematode is a primitive plant parasite from the Devonian. Fossil invertebrate parasitic nematodes first appeared in the Early Cretaceous, while the earliest fossil vertebrate-parasitic nematodes are from Upper Triassic coprolites. Specific examples of fossil nematode parasites over time are presented, along with views on the origin and evolution of nematodes and their hosts. PMID- 26597066 TI - Constraining the Deep Origin of Parasitic Flatworms and Host-Interactions with Fossil Evidence. AB - Novel fossil discoveries have contributed to our understanding of the evolutionary appearance of parasitism in flatworms. Furthermore, genetic analyses with greater coverage have shifted our views on the coevolution of parasitic flatworms and their hosts. The putative record of parasitic flatworms is consistent with extant host associations and so can be used to put constraints on the evolutionary origin of the parasites themselves. The future lies in new molecular clock analyses combined with additional discoveries of exceptionally preserved flatworms associated with hosts and coprolites. Besides direct evidence, the host fossil record and biogeography have the potential to constrain their evolutionary history, albeit with caution needed to avoid circularity, and a need for calibrations to be implemented in the most conservative way. This might result in imprecise, but accurate divergence estimates for the evolution of parasitic flatworms. PMID- 26597067 TI - From Fossil Parasitoids to Vectors: Insects as Parasites and Hosts. AB - Within Metazoa, it has been proposed that as many as two-thirds of all species are parasitic. This propensity towards parasitism is also reflected within insects, where several lineages independently evolved a parasitic lifestyle. Parasitic behaviour ranges from parasitic habits in the strict sense, but also includes parasitoid, phoretic or kleptoparasitic behaviour. Numerous insects are also the host for other parasitic insects or metazoans. Insects can also serve as vectors for numerous metazoan, protistan, bacterial and viral diseases. The fossil record can report this behaviour with direct (parasite associated with its host) or indirect evidence (insect with parasitic larva, isolated parasitic insect, pathological changes of host). The high abundance of parasitism in the fossil record of insects can reveal important aspects of parasitic lifestyles in various evolutionary lineages. For a comprehensive view on fossil parasitic insects, we discuss here different aspects, including phylogenetic systematics, functional morphology and a direct comparison of fossil and extant species. PMID- 26597068 TI - Trace Fossil Evidence of Trematode-Bivalve Parasite-Host Interactions in Deep Time. AB - Parasitism is one of the most pervasive phenomena amongst modern eukaryotic life and yet, relative to other biotic interactions, almost nothing is known about its history in deep time. Digenean trematodes (Platyhelminthes) are complex life cycle parasites, which have practically no body fossil record, but induce the growth of characteristic malformations in the shells of their bivalve hosts. These malformations are readily preserved in the fossil record, but, until recently, have largely been overlooked by students of the fossil record. In this review, we present the various malformations induced by trematodes in bivalves, evaluate their distribution through deep time in the phylogenetic and ecological contexts of their bivalve hosts and explore how various taphonomic processes have likely biased our understanding of trematodes in deep time. Trematodes are known to negatively affect their bivalve hosts in a number of ways including castration, modifying growth rates, causing immobilization and, in some cases, altering host behaviour making the host more susceptible to their own predators. Digeneans are expected to be significant agents of natural selection. To that end, we discuss how bivalves may have adapted to their parasites via heterochrony and suggest a practical methodology for testing such hypotheses in deep time. PMID- 26597069 TI - Fossil Crustaceans as Parasites and Hosts. AB - Numerous crustacean lineages have independently moved into parasitism as a mode of life. In modern marine ecosystems, parasitic crustaceans use representatives from many metazoan phyla as hosts. Crustaceans also serve as hosts to a rich diversity of parasites, including other crustaceans. Here, we show that the fossil record of such parasitic interactions is sparse, with only 11 examples, one dating back to the Cambrian. This may be due to the limited preservation potential and small size of parasites, as well as to problems with ascribing traces to parasitism with certainty, and to a lack of targeted research. Although the confirmed stratigraphic ranges are limited for nearly every example, evidence of parasitism related to crustaceans has become increasingly more complete for isopod-induced swellings in decapods so that quantitative analyses can be carried out. Little attention has yet been paid to the origin of parasitism in deep time, but insight can be generated by integrating data on fossils with molecular studies on modern parasites. In addition, there are other traces left by parasites that could fossilize, but have not yet been recognized in the fossil record. PMID- 26597070 TI - A Prejudiced Review of Ancient Parasites and Their Host Echinoderms: CSI Fossil Record or Just an Excuse for Speculation? AB - Recognizing the presence of a parasite and identifying it is a relatively straightforward task for the twenty-first century parasitologist. Not so the pursuit of ancient parasites in fossil organisms, a much more difficult proposition. Herein, Boucot's seven-tiered scheme of reliability classes is applied as a measure of confidence of the recognition of putative parasitism in two echinoderm classes, Upper Palaeozoic crinoids and a Cretaceous echinoid (high confidence is 1, low confidence 7). Of the five examples, the parasitic(?) organism is preserved in only two of them. A zaphrentoid coral on the camerate crinoid Amphoracrinus may have robbed food from the arms (Category 1 or 2B). A pit in what appears to be a carefully selected site on the disparid crinoid Synbathocrinus is associated with a growth deformity of the cup (Category 4). Multiple pits in an Amphoracrinus theca are also associated with a deformed cup, but it is more difficult to interpret (Category 4 or 7). Some specimens of the camerate crinoid Neoplatycrinites have circular grooves or depressions posteriorly, presumably produced by coprophagic/parasitic platyceratid gastropods (Category 1). Site selectivity of pits in the echinoid Hemipneustes places them preferentially adjacent to respiratory tube feet (Category 4). From these examples it is deduced that sparse infestations of borings or epizoozoic organisms permit a more confident interpretation of organism/organism interactions; dense accumulations, possibly following multiple spatfalls, mask such patterns. PMID- 26597071 TI - Differentiating Parasitism and Other Interactions in Fossilized Colonial Organisms. AB - Colonial species occur in a wide range of aquatic invertebrates, some having excellent fossil records, notably corals, bryozoans and graptolite hemichordates. In contrast to unitary animals, colonial animals grow by adding repetitive modules known as zooids. The ability of colonies to endure partial mortality and the typically plastic growth of benthic colonial species facilitates the formation of macrosymbiotic associations, some of which may be parasitic. However, as with unitary fossils, it is notoriously difficult to identify whether the symbioses are parasitisms (+/-) or mutualisms (+/+). Intergrowths between host colonies of stromatoporoid sponges, corals or bryozoans, and skeletal or soft-bodied symbionts are particularly common in Ordovician-Devonian shallow water deposits. Soft-bodied symbionts in such intergrowths are represented by moulds in the host skeletons, a process of preservation termed bioclaustration. As yet, however, there is a lack of convincing data showing that any of these symbionts were parasites. By comparison with modern analogues, some fossil galls provide more convincing examples of parasitism, and the destructive effects of borings into the skeletons of benthic colonies also argue in favour of parasitism. Pelagic graptoloid hemichordates from the Early Palaeozoic occasionally contain cysts or tubes that have been attributed to parasites on the grounds that they would have adversely affected the hydrodynamics of the floating colonies. Future studies should test for parasitism by comparing the sizes of colonies hosting symbionts with those lacking symbionts. PMID- 26597072 TI - Palaeoparasitology - Human Parasites in Ancient Material. AB - Parasite finds in ancient material launched a new field of science: palaeoparasitology. Ever since the pioneering studies, parasites were identified in archaeological and palaeontological remains, some preserved for millions of years by fossilization. However, the palaeoparasitological record consists mainly of parasites found specifically in human archaeological material, preserved in ancient occupation sites, from prehistory until closer to 2015. The results include some helminth intestinal parasites still commonly found in 2015, such as Ascaris lumbricoides, Trichuris trichiura and hookworms, besides others such as Amoebidae and Giardia intestinalis, as well as viruses, bacteria, fungi and arthropods. These parasites as a whole provide important data on health, diet, climate and living conditions among ancient populations. This chapter describes the principal findings and their importance for knowledge on the origin and dispersal of infectious diseases. PMID- 26597073 TI - Human Parasites in Medieval Europe: Lifestyle, Sanitation and Medical Treatment. AB - Parasites have been infecting humans throughout our evolution. However, not all people suffered with the same species or to the same intensity throughout this time. Our changing way of life has altered the suitability of humans to infection by each type of parasite. This analysis focuses upon the evidence for parasites from archaeological excavations at medieval sites across Europe. Comparison between the patterns of infection in the medieval period allows us to see how changes in sanitation, herding animals, growing and fertilizing crops, the fishing industry, food preparation and migration all affected human susceptibility to different parasites. We go on to explore how ectoparasites may have spread infectious bacterial diseases, and also consider what medieval medical practitioners thought of parasites and how they tried to treat them. While modern research has shown the use of a toilet decreases the risk of contracting certain intestinal parasites, the evidence for past societies presented here suggests that the invention of latrines had no observable beneficial effects upon intestinal health. This may be because toilets were not sufficiently ubiquitous until the last century, or that the use of fresh human faeces for manuring crops still ensured those parasite species were easily able to reinfect the population. PMID- 26597074 TI - Immunology & Cell Biology Publication of the Year Awards 2014. PMID- 26597075 TI - Allergen-induced interleukin-18 promotes experimental eosinophilic oesophagitis in mice. PMID- 26597076 TI - Fabrication of ferroelectric polymer nanostructures on flexible substrates by soft-mold reverse nanoimprint lithography. AB - Conventional nanoimprint lithography with expensive rigid molds is used to pattern ferroelectric polymer nanostructures on hard substrate for use in, e.g., organic electronics. The main innovation here is the use of inexpensive soft polycarbonate molds derived from recordable DVDs and reverse nanoimprint lithography at low pressure, which is compatible with flexible substrates. This approach was implemented to produce regular stripe arrays with a spacing of 700 nm from vinylidene fluoride co trifluoroethylene ferroelectric copolymer on flexible polyethylene terephthalate substrates. The nanostructures have very stable and switchable piezoelectric response and good crystallinity, and are highly promising for use in organic electronics enhanced or complemented by the unique properties of the ferroelectric polymer, such as bistable polarization, piezoelectric response, pyroelectric response, or electrocaloric function. The soft-mold reverse nanoimprint lithography also leaves little or no residual layer, affording good isolation of the nanostructures. This approach reduces the cost and facilitates large-area, high-throughput production of isolated functional polymer nanostructures on flexible substrates for the increasing application of ferroelectric polymers in flexible electronics. PMID- 26597077 TI - Use of Single-Antigen Flow Beads Assays to Assess Anti-HLA Donor-Specific Antibody Strength. PMID- 26597078 TI - Reply to: Use of Single-Antigen Flow Beads Assays to Assess Anti-HLA Donor Specific Antibody Strength. PMID- 26597079 TI - European Group for Blood and Marrow Transplantation Centers with FACT-JACIE Accreditation Have Significantly Better Compliance with Related Donor Care Standards. AB - Previous studies have identified healthcare practices that may place undue pressure on related donors (RDs) of hematopoietic cell products and an increase in serious adverse events associated with morbidities in this population. As a result, specific requirements to safeguard RD health have been introduced to Foundation for the Accreditation of Cellular Therapy/The Joint Accreditation Committee ISCT and EBMT (FACT-JACIE) Standards, but the impact of accreditation on RD care has not previously been evaluated. A survey of transplant program directors of European Group for Blood and Marrow Transplantation member centers was conducted by the Donor Health and Safety Working Committee of the Center for International Blood and Marrow Transplant Research to test the hypothesis that RD care in FACT-JACIE accredited centers is more closely aligned with international consensus donor care recommendations than RD care delivered in centers without accreditation. Responses were received from 39% of 304 centers. Our results show that practice in accredited centers was much closer to recommended standards as compared with nonaccredited centers. Specifically, a higher percentage of accredited centers use eligibility criteria to assess RDs (93% versus 78%; P = .02), and a lower percentage have a single physician simultaneously responsible for an RD and their recipient (14% versus 35%; P = .008). In contrast, where regulatory standards do not exist, both accredited and nonaccredited centers fell short of accepted best practice. These results raise concerns that despite improvements in care, current practice can place undue pressure on donors and may increase the risk of donation-associated adverse events. We recommend measures to address these issues through enhancement of regulatory standards as well as national initiatives to standardize RD care. PMID- 26597080 TI - Significant Improvements in the Practice Patterns of Adult Related Donor Care in US Transplantation Centers. AB - Recent investigations have found a higher incidence of adverse events associated with hematopoietic cell donation in related donors (RDs) who have morbidities that if present in an unrelated donor (UD) would preclude donation. In the UD setting, regulatory standards ensure independent assessment of donors, one of several crucial measures to safeguard donor health and safety. A survey conducted by the Center for International Blood and Marrow Transplant Research (CIBMTR) Donor Health and Safety Working Committee in 2007 reported a potential conflict of interest in >70% of US centers, where physicians had simultaneous responsibility for RDs and their recipients. Consequently, several international organizations have endeavored to improve practice through regulations and consensus recommendations. We hypothesized that the changes in the 2012 Foundation for the Accreditation of Cellular Therapy and the Joint Accreditation Committee-International Society for Cellular Therapy and European Society for Blood and Marrow Transplantation standards resulting from the CIBMTR study would have significantly impacted practice. Accordingly, we conducted a follow-up survey of US transplantation centers to assess practice changes since 2007, and to investigate additional areas where RD care was predicted to differ from UD care. A total of 73 centers (53%), performing 79% of RD transplantations in the United States, responded. Significant improvements were observed since the earlier survey; 62% centers now ensure separation of RD and recipient care (P < .0001). This study identifies several areas where RD management does not meet international donor care standards, however. Particular concerns include counseling and assessment of donors before HLA typing, with 61% centers first disclosing donor HLA results to an individual other than the donor, the use of unlicensed mobilization agents, and the absence of long-term donor follow-up. Recommendations for improvement are made. PMID- 26597081 TI - Knowledge and perceptions about diet and physical activity among Sri Lankan adults with diabetes mellitus: a qualitative study. AB - BACKGROUND: Diabetes mellitus (DM) is a rapidly growing health concern in Sri Lanka. Diet and physical activity are important modifiable risk factors affecting the incidence, severity and management of DM. The present study aims to evaluate the knowledge and perceptions about dietary patterns and physical activity among a group of adults with DM in Sri Lanka using qualitative research methods. METHODS: Fifty adults from a cohort of diabetic patients attending the medical clinics at the National Hospital of Sri Lanka were invited for the study. Data were collected via 10 Focus Group Discussions. Verbatim recording and documenting emotional responses were conducted by two independent observers. Directed content analysis of qualitative data was done with the help of NVIVO v10.0. RESULTS: Mean age was 61.2 +/- 9.9 years and 46 % were males. Mean duration of diabetes was 10.4 +/- 7.5 years. All were aware of the importance of diet in the management of DM. But most had difficulty in incorporating this knowledge into their lives mostly due to social circumstances. The majority described a list of 'good foods' and 'bad foods' for DM. They believed that 'good' foods can be consumed at all times, irrespective of quantity and 'bad' foods should be completely avoided. Many believed that fruits were bad for diabetes, while vegetables were considered as a healthy food choice. The majority thought that there were 'special' foods that help to control blood glucose, the most common being curry leaves and bitter gourd. Most study participants were aware of the importance of being physical active. However, there was lack of consensus and clarity with regards to type, duration, timing and frequency of physical activity. CONCLUSIONS: Despite understanding the importance of dietary control and physical activity in the management of diabetes, adherence to practices were poor, mainly due to lack of clarity of information provided. There were many myths with regards to diet, some of which have originated from health care professionals. More evidence is needed to support or refute the claims about 'special' foods that the participants believe as being good for diabetes. PMID- 26597082 TI - Eukaryotic opportunists dominate the deep-subsurface biosphere in South Africa. AB - Following the discovery of the first Eukarya in the deep subsurface, intense interest has developed to understand the diversity of eukaryotes living in these extreme environments. We identified that Platyhelminthes, Rotifera, Annelida and Arthropoda are thriving at 1.4 km depths in palaeometeoric fissure water up to 12,300 yr old in South African mines. Protozoa and Fungi have also been identified; however, they are present in low numbers. Characterization of the different species reveals that many are opportunistic organisms with an origin due to recharge from surface waters rather than soil leaching. This is the first known study to demonstrate the in situ distribution of biofilms on fissure rock faces using video documentation. Calculations suggest that food, not dissolved oxygen is the limiting factor for eukaryal population growth. The discovery of a group of Eukarya underground has important implications for the search for life on other planets in our solar system. PMID- 26597083 TI - Co-expression of parathyroid hormone related protein and TGF-beta in breast cancer predicts poor survival outcome. AB - BACKGROUND: Better methods to predict prognosis can play a supplementary role in administering individualized treatment for breast cancer patients. Altered expressions of PTHrP and TGF-beta have been observed in various types of human cancers. The objective of the current study was to evaluate the association of PTHrP and TGF-beta level with the clinicopathological features of the breast cancer patients. METHODS: Immunohistochemistry was used to examine PTHrP and TGF beta protein expression in 497 cases of early breast cancer, and Kaplan-Meier method and COX's Proportional Hazard Model were applied to the prognostic value of PTHrP and TGF-beta expression. RESULTS: Both over-expressed TGF-beta and PTHrP were correlated with the tumor in larger size, higher proportion of axillary lymph node metastasis and later clinical stage. Additionally, the tumors with a high TGF-beta level developed poor differentiation, and only TGF-beta expression was associated with disease-free survival (DFS) of the breast cancer patients. Followed up for a median of 48 months, it was found that only the patients with negative TGF-beta expression had longer DFS (P < 0.05, log-rank test). Nevertheless, those with higher PTHrP expression tended to show a higher rate of bone metastasis (67.6 % vs. 45.8 %, P = 0.019). In ER negative subgroup, those who developed PTHrP positive expression presented poor prognosis (P < 0.05, log rank test). The patients with both positive TGF-beta and PTHrP expression were significantly associated with the high risk of metastases. As indicated by Cox's regression analysis, TGF-beta expression and the high proportion of axillary lymph node metastasis served as significant independent predictors for breast cancer recurrence. CONCLUSIONS: TGF-beta and PTHrP were confirmed to be involved in regulating the malignant progression in breast cancer, and PTHrP expression, to be associated with bone metastasis as a potential prognostic marker in ER negative breast cancer. PMID- 26597085 TI - The Nature of Co-Occurring Exposure to Violence and of Court Responses to Girls in the Juvenile Justice System. AB - This article examines the co-occurrence of different types of victimization and violence exposure, and the effects of court interventions for girls in juvenile court. A life history interview methodology was used to collect qualitative data from 27 girls who had penetrated deeply into a treatment-oriented county court system. The study revealed that early abuse and violence in the home made girls vulnerable to later intimate partner violence and sexual assault when they left to avoid continued victimization. Whereas some court interventions helped girls, others revictimized them. Implications for helpful court practices and future research are presented and discussed. PMID- 26597084 TI - Gene methylation of human ovarian carcinoma stromal progenitor cells promotes tumorigenesis. AB - BACKGROUND: This study aimed to investigate whether the DNA methylation of human ovarian carcinoma stromal progenitor cells (OCSPCs) could promote the tumorigenesis of ovarian carcinoma. METHODS: OCSPCs were first isolated from fresh tumor tissues and ascites of ovarian cancer patients. In vivo and in vitro experiments on the effect of the OCSPCs on tumorigenesis and the effects of DNA demethylation on the OCSPCs were then performed. RESULTS: The OCSPCs possessed self-renewal and multipotent differentiation capacity with elevated expressions of OCT4, NANOG, BMP2, BMP4, Rex-1, AC133 and TGF-beta. The OCSPCs, when combined with tumor cells in vivo could promote tumor growth. The methylation profiles of tumor suppressor genes (TSGs) were significantly higher in the OCSPCs than in ovarian cancer cells (p < 0.001). 5-aza-2-dC could alter the methylation levels of TSGs in OCSPCs and also inhibit the tumor promoting capabilities of the OCSPCs by decreasing the proliferation of tumors cells. The expression levels of TSGs were re-expressed by 5-aza-2-dC to inhibit the self-renewal and growth of OCSPCs. CONCLUSIONS: OCSPCs with decreased TSG expressions in the ovarian tumor microenvironment were able to promote tumorigenesis which could be reversed by DNA demethylation. DNA demethylation reversing the expression of TSGs in OCSPCs may represent a potential therapeutic target for ovarian cancer. PMID- 26597086 TI - Sorority Affiliation and Sexual Assault Victimization: Assessing Vulnerability Using Path Analysis. AB - The current research used survey data from 282 college women to investigate the relationship between female Greek membership and sexual assault victimization. Drawing from routine activity theory, low self-control, and social learning theory, this study tested a theoretical model that identified pertinent factors present among sorority environments to determine the relationships between Greek affiliation and sexual assault. Path analyses revealed that sorority women reported consuming more alcohol and with greater frequency, increased risk-taking behavior, delayed assessments of threat and responses to risk, and increased contact with fraternity men-all of which significantly predicted sexual assault. Future theory, research, and policy directions are proposed. PMID- 26597087 TI - Muscular forearm activation in hand-grip tasks with superimposition of mechanical vibrations. AB - The purpose of this paper is to evaluate the muscular activation of the forearm, with or without vibration stimuli at different frequencies while performing a grip tasks of 45s at various level of exerted force. In 16 individuals, 9 females and 7 males, the surface electromyogram (EMG) of extensor carpi radialis longus and the flexor carpi ulnari muscles were assessed. At a short latency from onset EMG, RMS and the level of MU synchronization were assessed to evaluate the muscular adaptations. Whilst a trend of decay of EMG Median frequency (MDFd) was employed as an index of muscular fatigue. Muscular tasks consists of the grip of an instrumented handle at a force level of 20%, 30%, 40%, 60% of the maximum voluntary force. Vibration was supplied by a shaker to the hand in mono frequential waves at 20, 30, 33 and 40Hz. In relation to EMG, RMS and MU synchronization, the muscular activation does not seem to change with the superimposition of the mechanical vibrations, on the contrary a lower MDFd was observed at 33Hz than in absence of vibration. This suggests an early muscular fatigue induced by vibration due to the fact that 33Hz is a resonance frequency for the hand-arm system. PMID- 26597088 TI - Measuring voluntary quadriceps activation: Effect of visual feedback and stimulus delivery. AB - INTRODUCTION: Quadriceps voluntary activation, assessed via the superimposed burst technique, has been extensively studied in a variety of populations as a measure of quadriceps function. However, a variety of stimulus delivery techniques have been employed, which may influence the level of voluntary activation as calculated via the central activation ratio (CAR). The purpose was to determine the effect of visual feedback, stimulus delivery, and perceived discomfort on maximal voluntary isometric contraction (MVIC) peak torque and the CAR. METHODS: Quadriceps CAR was assessed in 14 individuals on two days using three stimulus delivery methods; (1) manual without visual feedback, (2) manual with visual feedback, and (3) automated with visual feedback. RESULTS: MVIC peak torque and the CAR were not different between the automated with visual feedback (MVIC=3.25, SE=0.14Nm/kg; CAR=88.63, SE=1.75%) and manual with visual feedback (MVIC=3.26, SE=0.13Nm/kg, P=0.859; CAR=89.06, SE=1.70%, P=0.39) stimulus delivery methods. MVIC (2.99, SE=0.12Nm/kg) and CAR (85.32, SE=2.10%) were significantly lower using manual without visual feedback compared to manual with visual feedback and automated with visual feedback (CAR P<0.001; MVIC P<0.001). Perceived discomfort was lower in the second session (P<0.05). CONCLUSION: Utilizing visual feedback ensures participant MVIC, and may provide a more accurate assessment of quadriceps voluntary activation. PMID- 26597089 TI - The genetic landscape of the epileptic encephalopathies of infancy and childhood. AB - Epileptic encephalopathies of infancy and childhood comprise a large, heterogeneous group of severe epilepsies characterised by several seizure types, frequent epileptiform activity on EEG, and developmental slowing or regression. The encephalopathies include many age-related electroclinical syndromes with specific seizure types and EEG features. With the molecular revolution, the number of known monogenic determinants underlying the epileptic encephalopathies has grown rapidly. De-novo dominant mutations are frequently identified; somatic mosaicism and recessive disorders are also seen. Several genes can cause one electroclinical syndrome, and, conversely, one gene might be associated with phenotypic pleiotropy. Diverse genetic causes and molecular pathways have been implicated, involving ion channels, and proteins needed for synaptic, regulatory, and developmental functions. Gene discovery provides the basis for neurobiological insights, often showing convergence of mechanistic pathways. These findings underpin the development of targeted therapies, which are essential to improve the outcome of these devastating disorders. PMID- 26597090 TI - Development of epilepsy after ischaemic stroke. AB - For about 30% of patients with epilepsy the cause is unknown. Even in patients with a known risk factor for epilepsy, such as ischaemic stroke, only a subpopulation of patients develops epilepsy. Factors that contribute to the risk for epileptogenesis in a given individual generally remain unknown. Studies in the past decade on epilepsy in patients with ischaemic stroke suggest that, in addition to the primary ischaemic injury, existing difficult-to-detect microscale changes in blood vessels and white matter present as epileptogenic pathologies. Injury severity, location and type of pathological changes, genetic factors, and pre-injury and post-injury exposure to non-genetic factors (ie, the exposome) can divide patients with ischaemic stroke into different endophenotypes with a variable risk for epileptogenesis. These data provide guidance for animal modelling of post-stroke epilepsy, and for laboratory experiments to explore with increased specificity the molecular 'mechanisms, biomarkers, and treatment targets of post-stroke epilepsy in different circumstances, with the aim of modifying epileptogenesis after ischaemic stroke in individual patients without compromising recovery. PMID- 26597092 TI - Iso-population partition: An innovative epidemiological approach to mapping and analyzing spatially aggregated data. AB - In epidemiology, data are often aggregated using administrative boundaries or regular spatial lattices. Iso-population partitioning methods allow the aggregation of small units for which population data are available into larger units that are contiguous, as compact as possible, and have a similar population size. The objective of this paper was to study the influence of three spatial data aggregation approaches on data visualization and data analysis: iso populated units (IPUs), administrative units, and iso-geometric units. This study was conducted using results and simulations from the brucellosis clinical surveillance system for dairy cattle in France. Our findings indicate that using spatial partitioning methods for generating IPUs enhances the ability to interpret the spatial distribution of epidemiological indicators under study. In addition, it provides information on population density and improves the consistency of the power of statistical tests across units. By defining the target population size per spatial unit, IPUs can be used to control the statistical power of a study. Finally, by adding criteria based on environmental factors to generate spatial units, they can be used to control the variation of exposure to these factors within the units. PMID- 26597091 TI - Protocol for the "Implementation, adoption, and utility of family history in diverse care settings" study. AB - BACKGROUND: Risk assessment with a thorough family health history is recommended by numerous organizations and is now a required component of the annual physical for Medicare beneficiaries under the Affordable Care Act. However, there are several barriers to incorporating robust risk assessments into routine care. MeTree, a web-based patient-facing health risk assessment tool, was developed with the aim of overcoming these barriers. In order to better understand what factors will be instrumental for broader adoption of risk assessment programs like MeTree in clinical settings, we obtained funding to perform a type III hybrid implementation-effectiveness study in primary care clinics at five diverse healthcare systems. Here, we describe the study's protocol. METHODS/DESIGN: MeTree collects personal medical information and a three-generation family health history from patients on 98 conditions. Using algorithms built entirely from current clinical guidelines, it provides clinical decision support to providers and patients on 30 conditions. All adult patients with an upcoming well-visit appointment at one of the 20 intervention clinics are eligible to participate. Patient-oriented risk reports are provided in real time. Provider-oriented risk reports are uploaded to the electronic medical record for review at the time of the appointment. Implementation outcomes are enrollment rate of clinics, providers, and patients (enrolled vs approached) and their representativeness compared to the underlying population. Primary effectiveness outcomes are the percent of participants newly identified as being at increased risk for one of the clinical decision support conditions and the percent with appropriate risk based screening. Secondary outcomes include percent change in those meeting goals for a healthy lifestyle (diet, exercise, and smoking). Outcomes are measured through electronic medical record data abstraction, patient surveys, and surveys/qualitative interviews of clinical staff. DISCUSSION: This study evaluates factors that are critical to successful implementation of a web-based risk assessment tool into routine clinical care in a variety of healthcare settings. The result will identify resource needs and potential barriers and solutions to implementation in each setting as well as an understanding potential effectiveness. TRIAL REGISTRATION: NCT01956773. PMID- 26597093 TI - Comparison of mixed effects models of antimicrobial resistance metrics of livestock and poultry Salmonella isolates from a national monitoring system. AB - Antimicrobial use in agriculture is considered a pathway for the selection and dissemination of resistance determinants among animal and human populations. From 1997 through 2003 the U.S. National Antimicrobial Resistance Monitoring System (NARMS) tested clinical Salmonella isolates from multiple animal and environmental sources throughout the United States for resistance to panels of 16 19 antimicrobials. In this study we applied two mixed effects models, the generalized linear mixed model (GLMM) and accelerated failure time frailty (AFT frailty) model, to susceptible/resistant and interval-censored minimum inhibitory concentration (MIC) metrics, respectively, from Salmonella enterica subspecies enterica serovar Typhimurium isolates from livestock and poultry. Objectives were to compare characteristics of the two models and to examine the effects of time, species, and multidrug resistance (MDR) on the resistance of isolates to individual antimicrobials, as revealed by the models. Fixed effects were year of sample collection, isolate source species and MDR indicators; laboratory study site was included as a random effect. MDR indicators were significant for every antimicrobial and were dominant effects in multivariable models. Temporal trends and source species influences varied by antimicrobial. In GLMMs, the intra-class correlation coefficient ranged up to 0.8, indicating that the proportion of variance accounted for by laboratory study site could be high. AFT models tended to be more sensitive, detecting more curvilinear temporal trends and species differences; however, high levels of left- or right-censoring made some models unstable and results uninterpretable. Results from GLMMs may be biased by cutoff criteria used to collapse MIC data into binary categories, and may miss signaling important trends or shifts if the series of antibiotic dilutions tested does not span a resistance threshold. Our findings demonstrate the challenges of measuring the AMR ecosystem and the complexity of interacting factors, and have implications for future monitoring. We include suggestions for future data collection and analyses, including alternative modeling approaches. PMID- 26597094 TI - Simulated patients versus manikins in acute-care scenarios. AB - BACKGROUND: Manikins and simulated patients (SPs) are commonly used in health care education and assessment. SPs appear to offer a more realistic experience for learners than 'plastic' manikins, and might be expected to engender interactions that approximate real clinical practice more closely. The analyses of linguistic patterns and touch are methodologies that could be used to explore this hypothesis. Our research aims were: (1) to compare verbal interactions and the use of procedural touch by health care workers (HCWs) in scenarios with SPs and with manikins; and (2) to evaluate the methodologies used to inform a large scale study. METHODS: We conducted a pilot preliminary comparative study on conversations and touch in two scenarios in emergency care training, each performed using an SP and a high-fidelity manikin. The setting was a simulation centre. Two scripted acute-care scenarios (chest pain and acute breathlessness) were performed using both an SP and a high-fidelity manikin. Audiovisual recordings were subsequently analysed. Two teams comprising a clinician (medical student), a senior nurse and a clinical support worker took part in the study. The linguistics research methodology integrated a multimodal corpus-based approach and discourse analysis. Simulated patients appear to offer a more realistic experience for learners than 'plastic' manikins RESULTS: Overall, HCWs had far more interactions with the SPs than with the manikins, and the utterances and behaviours were more akin to what one would expect in real clinical practice. HCWs used procedural touch without the patient's permission much more frequently with the manikin. DISCUSSION: These methodologies offer opportunities for further research projects studying interactions with SPs, manikins and real clinical practice. PMID- 26597095 TI - Reply: Polycystic ovary syndrome and pregnancy. PMID- 26597096 TI - Connecting Local and Global Sensitivities in a Mathematical Model for Wound Healing. AB - The process of wound healing is governed by complex interactions between proteins and the extracellular matrix, involving a range of signaling pathways. This study aimed to formulate, quantify, and analyze a mathematical model describing interactions among matrix metalloproteinases (MMP-1), their inhibitors (TIMP-1), and extracellular matrix in the healing of a diabetic foot ulcer. De-identified patient data for modeling were taken from Muller et al. (Diabet Med 25(4):419 426, 2008), a research outcome that collected average physiological data for two patient subgroups: "good healers" and "poor healers," where classification was based on rate of ulcer healing. Model parameters for the two patient subgroups were estimated using least squares. The model and parameter values were analyzed by conducting a steady-state analysis and both global and local sensitivity analyses. The global sensitivity analysis was performed using Latin hypercube sampling and partial rank correlation analysis, while local analysis was conducted through a classical sensitivity analysis followed by an SVD-QR subset selection. We developed a "local-to-global" analysis to compare the results of the sensitivity analyses. Our results show that the sensitivities of certain parameters are highly dependent on the size of the parameter space, suggesting that identifying physiological bounds may be critical in defining the sensitivities. PMID- 26597097 TI - A Geometric Method for Model Reduction of Biochemical Networks with Polynomial Rate Functions. AB - Model reduction of biochemical networks relies on the knowledge of slow and fast variables. We provide a geometric method, based on the Newton polytope, to identify slow variables of a biochemical network with polynomial rate functions. The gist of the method is the notion of tropical equilibration that provides approximate descriptions of slow invariant manifolds. Compared to extant numerical algorithms such as the intrinsic low-dimensional manifold method, our approach is symbolic and utilizes orders of magnitude instead of precise values of the model parameters. Application of this method to a large collection of biochemical network models supports the idea that the number of dynamical variables in minimal models of cell physiology can be small, in spite of the large number of molecular regulatory actors. PMID- 26597099 TI - 21st Century Cures Act and similar policy efforts: at what cost? PMID- 26597098 TI - Present and Future Therapies in Neuromyelitis Optica Spectrum Disorders. AB - Neuromyelitis optica spectrum disorders (NMOSD) are important evolving entities, which have reached much attention in the recent years. NMOSD are characterized by inflammatory lesions in the optic nerves, spinal cord, and central parts of the brain, as well as an autoimmune process directed against aquaporin-4. As disability in NMOSD accumulates by inflammatory damage from attacks, both the treatment and prevention of attacks are decisive for the long-term outcome. NMOSD attacks are treated with high-dose intravenous corticosteroids and apheresis therapies, in particular therapeutic plasma exchange. In cases of incomplete remission, escalation of attack treatment is recommended. Preventive therapy is immunosuppressive and should by commenced as early as possible. Apart from classical immunosuppressants such as azathioprine and mycophenolate mofetil, repurposed biologicals are increasingly used. B-cell depletion with rituximab and other agents, inhibition of the interleukin-6 receptor with tocilizumab, and blockade of complement-mediated damage by eculizumab all are promising therapeutic strategies evaluated in randomized controlled trials. In this review, we will discuss present and future immunotherapies for NMOSD and also consider combination of treatments, plasma, cellular and other therapies. Current advances in immunopathological knowledge are translated into innovative concepts and begin a new era of NMOSD therapy. PMID- 26597101 TI - Patient Perceptions of the Environment of Care in Which Their Healthcare is Delivered. AB - OBJECTIVE: To measure patients' perceptions of the environment of care (EOC), with a focus on the physical environment, in which healthcare is delivered. BACKGROUND: The EOC may impact patient experiences, care perceptions, and health outcomes. EOC may be improved through redesign of existing physical structures or spaces or by adding nurturing amenities. METHODS: Demographics, health status, hospital use, and data on the environment (physical, comfort, orientation, and privacy) were collected via a mailed cross-sectional survey sent to patients seen at four hospital Centers of Innovation (COIs; that implemented many modifications to the healthcare environment to address physical, comfort, orientation, and privacy factors) and four matched controls, supplemented with checklist and VA administrative data. A modified Perceived Hospital Environment Quality Indicators instrument was used to measure patients' EOC perceptions. RESULTS: Respondents (3,321/5,117; 65% response) rated, [mean (SD)], exterior space highest, 3.09 (0.73), followed by interior space, 2.96 (0.74), and privacy, 2.44 (1.01). COIs had significantly higher ratings than controls on interior space (2.99 vs. 2.96, p = .02) and privacy (2.48 vs. 2.38, p = .005) but no differences for exterior space. Subscales with significantly higher ratings in COIs (vs. controls) in interior space were "spatial-physical comfort" and "orientation," for example, clean, good signage, spacious rooms, and for privacy included "not too crowded" and "able to talk without being overheard." Checklist findings confirmed the presence of EOC innovations rated highly by patients. CONCLUSIONS: Patients identified cleanliness, good signs/information points, adequate seating, nonovercrowding, and privacy for conversations as important. Hospital design modifications, with particular attention to the physical environment, can improve patient EOC perceptions. PMID- 26597102 TI - The Designed Environment and How it Affects Brain Morphology and Mental Health. AB - BACKGROUND: The environment is inextricably related to mental health. Recent research replicates findings of a significant, linear correlation between a childhood exposure to the urban environment and psychosis. Related studies also correlate the urban environment and aberrant brain morphologies. These findings challenge common beliefs that the mind and brain remain neutral in the face of worldly experience. AIM: There is a signature within these neurological findings that suggests that specific features of design cause and trigger mental illness. The objective in this article is to work backward from the molecular dynamics to identify features of the designed environment that may either trigger mental illness or protect against it. METHOD: This review analyzes the discrete functions putatively assigned to the affected brain areas and a neurotransmitter called dopamine, which is the primary target of most antipsychotic medications. The intention is to establish what the correlations mean in functional terms, and more specifically, how this relates to the phenomenology of urban experience. In doing so, environmental mental illness risk factors are identified. CONCLUSIONS: Having established these relationships, the review makes practical recommendations for those in public health who wish to use the environment itself as a tool to improve the mental health of a community through design. PMID- 26597103 TI - Mismatch of delayed perfusion volume between TTP and Tmax map of perfusion MRI. AB - OBJECTIVE: To look for another set of parameters to predict the change in infarct size in acute stroke patients with a perfusion-weighted imaging (PWI)-diffusion weighted imaging (DWI) mismatch. MATERIALS AND METHODS: We reviewed 54 patients who had PWI-DWI mismatch and vascular occlusion on initial MRI and no recanalization of occluded vessel. RESULTS: Time-to-peak and time-to-max (TTP Tmax) perfusion mismatch volume was independently significant as a correlate of infarct volume change (P=.004). CONCLUSIONS: The finding of a large TTP-Tmax perfusion delay mismatch volume in patients with acute stroke who have a PWI-DWI mismatch on an initial MRI may predict that the infarct volume will not increase despite persistent vascular occlusion. PMID- 26597104 TI - Reply to Letter: Long-term learning effect is essential. PMID- 26597100 TI - Immune response in pemphigus and beyond: progresses and emerging concepts. AB - Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are two severe autoimmune bullous diseases of the mucosae and/or skin associated with autoantibodies directed against desmoglein (Dsg) 3 and/or Dsg1. These two desmosomal cadherins, typifying stratified epithelia, are components of cell adhesion complexes called desmosomes and represent extra-desmosomal adhesion receptors. We herein review the advances in our understanding of the immune response underlying pemphigus, including human leucocyte antigen (HLA) class II-associated genetic susceptibility, characteristics of pathogenic anti-Dsg antibodies, antigenic mapping studies as well as findings about Dsg-specific B and T cells. The pathogenicity of anti-Dsg autoantibodies has been convincingly demonstrated. Disease activity and clinical phenotype correlate with anti-Dsg antibody titers and profile while passive transfer of anti-Dsg IgG from pemphigus patients' results in pemphigus-like lesions in neonatal and adult mice. Finally, adoptive transfer of splenocytes from Dsg3-knockout mice immunized with murine Dsg3 into immunodeficient mice phenotypically recapitulates PV. Although the exact pathogenic mechanisms leading to blister formation have not been fully elucidated, intracellular signaling following antibody binding has been found to be necessary for inducing cell-cell dissociation, at least for PV. These new insights not only highlight the key role of Dsgs in maintenance of tissue homeostasis but are expected to progressively change pemphigus management, paving the way for novel targeted immunologic and pharmacologic therapies. PMID- 26597105 TI - Should the heart rate including the heart rate variability be important prognostigators in cardiac arrest? PMID- 26597106 TI - Vital signs: Vital for surviving in-hospital cardiac arrest? PMID- 26597107 TI - What is Computer Simulation? PMID- 26597108 TI - Teaching Images in Headache: Convexity Subarachnoid Hemorrhage in an Octogenarian. PMID- 26597110 TI - Women's views on partnership working with midwives during pregnancy and childbirth. AB - OBJECTIVE: to explore whether the UK Government agenda for partnership working and choice was realised or desired for women during pregnancy and childbirth. DESIGN: a qualitative study was used to explore women's experience of partnership working with midwives. Data was generated using a diary interview method throughout pregnancy and birth. SETTING: 16 women were recruited from two district general hospitals in the South East of England. FINDINGS: three themes emerged from the data: organisation of care, relationships and choice. Women described their antenatal care as 'ticking the box', with midwives focusing on the bio-medical aspects of care but not meeting their psycho-social and emotional needs. Time poverty was a significant factor in this finding. Women rarely described developing a partnership relationship with midwives due to a lack of continuity of care and time in which to formulate such relationships. In contrast women attending birth centres for their antenatal care were able to form relationships with a group of midwives who shared a philosophy of care and had sufficient time in which to meet women's holistic needs. Most of the women in this study did not feel they were offered the choices as outlined in the national choice agenda (DoH, 2007). IMPLICATIONS FOR PRACTICE: NHS Trusts should review the models of care available to women to ensure that these are not only safe but support women's psycho-social and emotional needs as well. Partnership case loading models enable midwives and women to form trusting relationships that empowers women to feel involved in decision making and to exercise choice. Group antenatal and postnatal care models also effectively utilise midwifery time whilst increasing maternal satisfaction and social engagement. Technology should also be used more effectively to facilitate inter-professional communication and to provide a more flexible service to women. PMID- 26597109 TI - Intracellular antigens as targets for antibody based immunotherapy of malignant diseases. AB - This review discusses the potential use of intracellular tumor antigens as targets of antibody-based immunotherapy for the treatment of solid tumors. In addition, it describes the characteristics of the intracellular tumor antigens targeted with antibodies which have been described in the literature and have been identified in the authors' laboratory. Finally, the mechanism underlying the trafficking of the intracellular tumor antigens to the plasma membrane of tumor cells are reviewed. PMID- 26597111 TI - Cost-Effectiveness Analysis of Smoking Cessation Interventions in Japan Using a Discrete-Event Simulation. AB - BACKGROUND: Smoking cessation medications have been shown to yield higher success rates and sustained abstinence than unassisted quit attempts. In Japan, the treatments available include nicotine replacement therapy (NRT) and varenicline; however, unassisted attempts to quit smoking remain common. OBJECTIVE: The objective of this study was to compare the health and economic consequences in Japan of using pharmacotherapy to support smoking cessation with unassisted attempts and the current mix of strategies used. METHODS: A discrete-event simulation that models lifetime quitting behaviour and includes multiple quit attempts (MQAs) and relapses was adapted for these analyses. The risk of developing smoking-related diseases is estimated based on the duration of abstinence. Data collected from a survey conducted in Japan were used to determine the interventions selected by smokers initiating a quit attempt and the time between MQAs. Direct and indirect costs are assessed (expressed in 2014 Japanese Yen). RESULTS: Using pharmacotherapy (NRT or varenicline) to support quit attempts proved to be dominant when compared with unassisted attempts or the current mix of strategies (most are unassisted). The results of stratified analyses by age imply that smoking cessation improves health outcomes across all generations. Indirect costs due to premature death leading to lost wages are an important component of the total costs, exceeding the direct medical cost estimates. CONCLUSIONS: Increased utilisation of smoking cessation pharmacotherapy to support quit attempts is predicted to lead to an increase in the number of smokers achieving abstinence, and provide improvements in health outcomes over a lifetime with no additional costs. PMID- 26597112 TI - Scleral cross-linking by riboflavin and blue light application in young rabbits: damage threshold and eye growth inhibition. AB - BACKGROUND: Scleral cross-linking (SXL) by riboflavin and light application has been introduced as a possible treatment to increase scleral tissue stiffness and to inhibit excessive axial elongation of highly myopic eyes. We evaluated an ocular tissue damage threshold for blue light irradiation, and used SXL treatment to induce eye growth inhibition. METHODS: The sclera of 3-week-old rabbits (39 pigmented and 15 albino rabbits) were treated with different blue light intensities (450 +/- 50 nm) and riboflavin. Alterations and a damage threshold were detected in ocular tissues by means of light microscopy and immunohistochemistry. The influence of SXL on the eye growth was examined in 21 young rabbits and was measured by using A-scan ultrasonography, micrometer caliper, and for selected eyes additionally by MR imaging. RESULTS: Light microscopic examinations demonstrated degenerative changes in ocular tissue after irradiation with blue light intensities above 400 mW/cm(2) (with and without riboflavin application). Therefore, that light intensity was defined as the damage threshold. Tissue alteration in retina, choroid, and sclera and activation of retinal microglia cells and Muller cells could be earlier observed at blue light intensities of 150 and 200 mW/cm(2). Albino rabbits were less sensitive to this SXL treatment. A significant reduction of the eye growth could be detected by SXL treatment with the minimal efficient blue light intensity of 15 mW/cm(2) and maintained stable for 24 weeks. CONCLUSIONS: SXL with riboflavin and blue light intensities below a defined damage threshold can induce a long lasting growth inhibitory effect on young rabbit eyes. Therefore, SXL might be a realistic approach to inhibit eye elongation in highly myopic eyes. PMID- 26597113 TI - Stroke in Adults With Congenital Heart Disease: Incidence, Cumulative Risk, and Predictors. AB - BACKGROUND: Stroke is an important cause of morbidity and mortality, although there is a lack of comprehensive data on its incidence, cumulative risk, and predictors in patients with adult congenital heart disease. METHODS AND RESULTS: This retrospective study of 29 638 Quebec patients with adult congenital heart disease aged 18 to 64 years between 1998 and 2010 was based on province-wide administrative data. The cumulative risk of ischemic stroke estimated up to age 64 years was 6.1% (95% confidence interval [CI], 5.0-7.0%) in women and 7.7% (95% CI, 6.4-8.8%) in men; the risk of hemorrhagic stroke was 0.8% (95% CI, 0.4-1.2%) and 1.3% (95% CI, 0.8-1.8%), respectively. Compared with rates reported for the general Quebec population, age-sex standardized incidence rates of ischemic stroke were 9 to 12 times higher below age 55 years and 2 to 4 times higher in the age group 55 to 64 years; hemorrhagic stroke rates were 5 to 6 times (age <55 years) and 2 to 3 times higher. Using a combination of stepwise model selection and Bayesian model averaging, the strongest predictors of ischemic stroke were heart failure (odds ratio for age group 18-49 years, 5.94 [95% CI, 3.49-10.14], odds ratio for age group 50-64 years, 1.68 [95% CI, 1.06-2.66]), diabetes mellitus (odds ratio, 2.33 [95% CI, 1.66-3.28]), and recent myocardial infarction (odds ratio, 8.38 [95% CI, 1.77-39.58]). CONCLUSIONS: Among patients with adult congenital heart disease, 1 in 11 men and 1 in 15 women experienced a stroke between ages 18 and 64 years. Stroke incidence was considerably higher than in the general population, especially at a younger age. The most important predictors of ischemic stroke were heart failure, diabetes mellitus, and recent myocardial infarction. Additional research is required to see whether advances in the management of adult congenital heart disease may reduce this substantial stroke rate. PMID- 26597115 TI - Molecular mechanism mediating cytotoxic activity of axitinib in sunitinib resistant human renal cell carcinoma cells. AB - PURPOSE: This study aimed to clarify the molecular mechanism mediating the cytotoxicity of axitinib, a selective inhibitor of the vascular endothelial growth factor receptor (VEGFR), in sunitinib-resistant renal cell carcinoma (RCC). METHODS: In our previous study (Sakai et al. in BJU Int 112:E211-E220, 2013), a human RCC cell line, ACHN, resistant to sunitinib (ACHN/R), was developed from a parental cell line (ACHN/P). Differences in molecular phenotypes following treatment with sunitinib or axitinib between these two cell lines were compared. RESULTS: ACHN/R showed an approximately fivefold higher IC50 of sunitinib than ACHN/P; however, there was no significant difference in the sensitivity to axitinib between these two cell lines. In ACHN/R, despite the lack of a difference in the phosphorylated (p)-Akt or STAT-3 expression between treatment with sunitinib and axitinib, the expression of p-p44/42 mitogen activated protein kinase (MAPK) and p-VEGFR-2 after treatment with axitinib was markedly down-regulated compared with those after treatment with sunitinib. Furthermore, additional treatment of ACHN/R with an inhibitor of MAPK kinase significantly enhanced the cytotoxic activity of sunitinib, but not that of axitinib. In vivo growth of ACHN/R in nude mice after treatment with axitinib was significantly inhibited compared with that following treatment with sunitinib, accompanying the marked inhibition of angiogenesis. CONCLUSIONS: Antitumor activity of axitinib in RCC cells even after the acquisition of resistance to sunitinib could be explained, at least in part, by the inactivation of p44/42 MAPK and VEGFR-2, which were persistently phosphorylated in sunitinib-resistant RCC cells under treatment with sunitinib. PMID- 26597114 TI - Hoarding in Children and Adolescents: A Review. AB - The diagnostic conceptualization of hoarding has recently changed, and yet the application of these changes to hoarding in youth remains to be clarified. In this review we examine the literature on hoarding in youth. We discuss issues related to the assessment of pediatric hoarding, and the nature of hoarding in youth. We consider evidence for hoarding disorder as a distinct diagnosis in youth, and review the relationship between pediatric hoarding and other psychiatric disorders. Finally, we describe preliminary models of treatment for pediatric hoarding. We conclude that there is support for hoarding disorder as a distinct diagnosis in youth. However, more precise and developmentally appropriate assessment tools are needed to provide stronger evidence for this claim and to further our knowledge of prevalence and associated clinical characteristics. Although there is no evidence-based treatment for pediatric hoarding, preliminary evidence from case studies suggests that cognitive and behavioral methods may have promise. PMID- 26597116 TI - N-Nicotinoyl dopamine inhibits skin pigmentation by suppressing of melanosome transfer. AB - We investigated the inhibitory effects of a niacinamide derivative, N-Nicotinoyl dopamine (NND) on melanogenesis. NND inhibits melanosome transfer in a normal human melanocyte-keratinocyte co-culture system and through phagocytic ability without affecting viability of cells while it did not show inhibitory effects of tyrosinase and melanin synthesis in B16F10 mouse melanoma cells. In addition, safety of NND was verified through performing neural stem cell morphology assay. Our findings indicate that NND may potentially be used for cosmetic industry for improvement of skin whitening and therapies related with several skin disorders, and the effect of NND may be acquired via reduction of melanosome transfer. PMID- 26597117 TI - The activation of PI 3-kinase/Akt pathway is involved in the acute effects of simvastatin against ischaemia and reperfusion-induced arrhythmias in anaesthetised dogs. AB - The objective of this study was to examine whether the PI3-kinase/Akt pathway is involved in the activation of endothelial nitric oxide synthase (eNOS) and in the subsequent increase of nitric oxide (NO) production that has been proved to play a role in the antiarrhythmic effect of acute simvastatin treatment in anaesthetised dogs, subjected to a 25min occlusion and reperfusion of the left anterior descending coronary artery. Using the same model, 12 dogs out of the 26 controls (given the solvent of simvastatin) and 11 dogs out of the 23 animals treated with intracoronary administered simvastatin (0.1mg/kg), were now received wortmannin (1.5mg/kg, ic.), a selective inhibitor of PI3-kinase. In another 13 dogs the effects of DMSO (0.1%), the vehicle of wortmannin, were examined. Compared to the controls, simvastatin markedly reduced the severity of ischaemia (epicardial ST-segment, inhomogeneity) and ventricular arrhythmias that were reversed (except the occlusion-induced ventricular fibrillation [VF; 50%, 0%, 0%]) by the administration of wortmannin. Thus in these groups there were 310+/ 45, 62+/-14, 307+/-59 ectopic beats, 7.1+/-1.4, 0.3+/- 0.2, 4.3+/-1.3 tachycardiac episodes that occurred 93%, 17% and 73% of the dogs during occlusion, whereas survival following reperfusion was 0%, 67% and 0%, respectively. Simvastatin also increased the phosphorylation of eNOS and the plasma nitrate/nitrite levels, but reduced myocardial superoxide production on reperfusion. These effects of simvastatin were also abolished in the presence of wortmannin. We conclude that the NO-dependent antiarrhythmic effect of simvastatin involves the rapid activation of eNOS through the stimulation of the PI3-kinase/Akt pathway. PMID- 26597119 TI - Histopathological and immunohistochemical characterization of spontaneous pituitary tumors in dwarfs derived from Wistar Hannover GALAS rats. AB - Histopathological and immunohistochemical characteristics of spontaneous pituitary adenomas found in dwarfs derived from Wistar Hanover GALAS are being described for the first time. The adenomas were seen in 5 males aged 48 weeks or older and in 11 females aged 34 weeks or older. Immunohistochemically, 13 cases without post-mortem changes could be evaluated; 4 Thyroid stimulating hormone (TSH)-containing adenomas, 2 TSH- and prolactin (PRL)-containing adenomas, 1 PRL containing adenoma and 6 all-negative adenomas that did not react to any of the examined anti-hormone antibodies. The most common type were TSH-containing pituitary adenomas (a total of 6 cases; 46%) which occurred exclusively in females; the tumors consisted mainly of basophilic or amphophilic cells with bizarre nuclei and neoplastic cells and were positive for TSH in varying degrees. The TSH-containing pituitary adenomas, a characteristic of this mutant rat, could be induced by genetically-controlled hypothyroidism in dwarf rats, with higher sensitivity to possible disturbance of the pituitary-thyroid axis in females. PMID- 26597118 TI - High-risk human papillomavirus cervical infections among healthy women in Guadeloupe. AB - OBJECTIVE: To assess high-risk human papillomavirus (HR HPV) cervical infections and their type distribution among healthy women in Guadeloupe, French West Indies. METHODS: The details of consecutive non-pregnant women who attended cervical cancer screening and had HPV genotyping performed at the largest pathology laboratory on the island from January 1, 2013 to December 31, 2014 were recorded retrospectively. All women with available HPV genotyping results were included in the study. RESULTS: HR HPV genotyping results for 618 women (median age 42 years) were collected. The overall prevalence rate of HR HPV cervical infection was 36.1% (95% confidence interval (CI) 32.3-40.0%), with the following type distribution: HPV 16 or 18 irrespective of other HPV types, 7.3% (95% CI 5.4 9.6%); other HR HPV types excluding HPV 16 or 18, 28.8% (95% CI 25.3-32.5%). The prevalence rates of overall HR HPV and HR HPV other than 16 or 18 infection increased significantly (p<0.001) with the severity of cytology grade, from 19.7% for normal cytology to 53.8% in atypical squamous cells of undetermined significance (ASC-US) and 67.7% in low-grade squamous intraepithelial lesions (LSIL). CONCLUSION: The high prevalence rate of HR HPV cervical infection with genotypes other than 16 and 18 in Guadeloupe, irrespective of age and the cytology grade, suggests a potential benefit of the new nine-valent HPV vaccine to prevent HPV infection-related cancers in this Caribbean country. PMID- 26597120 TI - Impact of genetic strain on body fat loss, food consumption, metabolism, ventilation, and motor activity in free running female rats. AB - Chronic exercise is considered as one of the most effective means of countering symptoms of the metabolic syndrome (MS) such as obesity and hyperglycemia. Rodent models of forced or voluntary exercise are often used to study the mechanisms of MS and type 2 diabetes. However, there is little known on the impact of genetic strain on the metabolic response to exercise. We studied the effects of housing rats with running wheels (RW) for 65 days compared to sedentary (SED) housing in five female rat strains: Sprague-Dawley (SD), Long-Evans (LE), Wistar (WIS), spontaneously hypertensive (SHR), and Wistar-Kyoto (WKY). Key parameters measured were total distance run, body composition, food consumption, motor activity, ventilatory responses by plethysmography, and resting metabolic rate (MR). WKY and SHR ran significantly more than the WIS, LE, and SD strains. Running-induced reduction in body fat was affected by strain but not by distance run. LE's lost 6% fat after 21 d of running whereas WKY's lost 2% fat but ran 40% more than LE's. LE and WIS lost body weight while the SHR and WKY strains gained weight during running. Food intake with RW was markedly increased in SHR, WIS, and WKY while LE and SD showed modest increases. Exploratory motor activity was reduced sharply by RW in all but the SD strain. Ventilatory parameters were primarily altered by RW in the SHR, WKY, and WIS strains. MR was unaffected by RW. In an overall ranking of physiological and behavioral responses to RW, the SD strain was considered the least responsive whereas the WIS was scored as most responsive. In terms of RW-induced fat loss, the LE strain appears to be the most ideal. These results should be useful in the future selection of rat models to study benefits of volitional exercise. PMID- 26597121 TI - Effects of long and short simulated flights on the saccadic eye movement velocity of aviators. AB - Aircrew fatigue is a major contributor to operational errors in civil and military aviation. Objective detection of pilot fatigue is thus critical to prevent aviation catastrophes. Previous work has linked fatigue to changes in oculomotor dynamics, but few studies have studied this relationship in critical safety environments. Here we measured the eye movements of US Marine Corps combat helicopter pilots before and after simulated flight missions of different durations.We found a decrease in saccadic velocities after long simulated flights compared to short simulated flights. These results suggest that saccadic velocity could serve as a biomarker of aviator fatigue. PMID- 26597123 TI - Transfer Hydrosilylation. AB - Transfer hydrogenation is without question a common technology in industry and academia. Unlike its countless varieties, conceptually related transfer hydrosilylations had essentially been unreported until the recent development of a radical and an ionic variant. The new methods are both based on a silicon substituted cyclohexa-1,4-diene and hinge on the aromatization of the corresponding cyclohexadienyl radical and cation intermediates, respectively, concomitant with homo- or heterolytic fission of the Si-C bond. Both the radical and ionic transfer hydrosilylation are brought into context with one other in this Minireview, and early insight into the possibility of transfer hydrosilylation is included. Although the current state-of-the-art is certainly still limited, the recent advances have already revealed the promising potential of transfer hydrosilylation. PMID- 26597122 TI - Current concepts on microscopic colitis: evidence-based statements and recommendations of the Spanish Microscopic Colitis Group. AB - BACKGROUND: Microscopic colitis (MC) is an underdiagnosed inflammatory bowel disease. AIM: To develop an evidence-based clinical practice guide on MC current concepts. METHODS: Literature search was done on the Cochrane Library, EMBASE and MEDLINE electronic databases, which were consulted covering the period up until March 2015. Work groups were selected for each of the reviewed topics, with the purpose of drafting the initial statements and recommendations. They subsequently underwent a voting process based on the Delphi method. Each statement/recommendation was accompanied by the result of the vote the level of evidence, and discussion of the corresponding evidence. The grade of recommendation (GR) using the GRADE approach was established for diagnosis and treatment recommendations. RESULTS: Some key statements and recommendations are: advancing age increases the risk of developing MC, mainly in females. The symptoms of MC and IBS-D may be similar. If MC is suspected, colonoscopy taking biopsies is mandatory. Treatment with oral budesonide is recommended to induce clinical remission in patients with MC. Oral mesalazine is not recommended in patients with collagenous colitis for the induction of clinical remission. The use of anti-TNF-alpha drugs (infliximab, adalimumab) is recommended for the induction of remission in severe cases of MC that fail to respond to corticosteroids or immunomodulators, as an alternative to colectomy. CONCLUSIONS: This is the first consensus paper on MC based on GRADE methodology. This initiative may help physicians involved in care of these patients in taking decisions based on evidence. PMID- 26597126 TI - John Mudge. PMID- 26597124 TI - Implications of gamma band activity in the pedunculopontine nucleus. AB - The fact that the pedunculopontine nucleus (PPN) is part of the reticular activating system places it in a unique position to modulate sensory input and fight-or-flight responses. Arousing stimuli simultaneously activate ascending projections of the PPN to the intralaminar thalamus to trigger cortical high frequency activity and arousal, as well as descending projections to reticulospinal systems to alter posture and locomotion. As such, the PPN has become a target for deep brain stimulation for the treatment of Parkinson's disease, modulating gait, posture, and higher functions. This article describes the latest discoveries on PPN physiology and the role of the PPN in a number of disorders. It has now been determined that high-frequency activity during waking and REM sleep is controlled by two different intracellular pathways and two calcium channels in PPN cells. Moreover, there are three different PPN cell types that have one or both calcium channels and may be active during waking only, REM sleep only, or both. Based on the new discoveries, novel mechanisms are proposed for insomnia as a waking disorder. In addition, neuronal calcium sensor protein-1 (NCS-1), which is over expressed in schizophrenia and bipolar disorder, may be responsible for the dysregulation in gamma band activity in at least some patients with these diseases. Recent results suggest that NCS-1 modulates PPN gamma band activity and that lithium acts to reduce the effects of over expressed NCS-1, accounting for its effectiveness in bipolar disorder. PMID- 26597125 TI - Globus pallidus internus neuronal activity: a comparative study of linear and non linear features in patients with dystonia or Parkinson's disease. AB - Movement disorders such as Parkinson's disease (PD) and dystonia are associated with alterations of basal ganglia motor circuits and abnormal neuronal activity in the output nucleus, the globus pallidus internus (GPi). This study aims to compare the electrophysiological hallmarks for PD and dystonia in the linear and non-linear time stamp domains in patients who underwent microelectrode recordings during functional stereotactic surgery for deep brain stimulation (DBS) or pallidotomy. We analyzed single-unit neuronal activity in the posteroventral lateral region of the GPi in awake patients prior to pallidotomy or the implantation of DBS electrodes in 29 patients with PD (N = 83 neurons) and 13 patients with dystonia (N = 41 neurons) under comparable conditions. The discharge rate and the instantaneous frequency of the GPi in dystonia patients were significantly lower than in PD patients (P < 0.001), while the total number of bursts, the percentage of spikes in bursts and the mean duration of bursts were higher (P < 0.001). Further, non-linear analysis revealed higher irregularity or entropy in the data streams of GPi neurons of PD patients compared to the dystonia patients group (P < 0.001). This study indicates that both linear and non-linear features of neuronal activity in the human GPi differ between PD and dystonia. Our results may serve as the basis for future studies on linear and non-linear analysis of neuronal firing patterns in various movement disorders. PMID- 26597127 TI - Burden of transmitted multidrug resistance in epidemics of tuberculosis: a transmission modelling analysis. AB - BACKGROUND: Multidrug-resistant (MDR) tuberculosis can be acquired through de novo mutation during tuberculosis treatment or through transmission from other individuals with active MDR tuberculosis. Understanding the balance between these two mechanisms is essential when allocating resources for MDR tuberculosis. We aimed to create a dynamic transmission model of an MDR tuberculosis epidemic to estimate the contributions of treatment-related acquisition and person-to-person transmission of resistance to incident MDR tuberculosis cases. METHODS: In this modelling analysis, we constructed a dynamic transmission model of an MDR tuberculosis epidemic, allowing for both treatment-related acquisition and person to-person transmission of resistance. We used national tuberculosis notification data to inform Bayesian estimates of the proportion of each country's 2013 MDR tuberculosis incidence that resulted from MDR transmission rather than treatment related MDR acquisition. FINDINGS: Global estimates of 3.5% MDR tuberculosis prevalence among new tuberculosis notifications and 20.5% among re-treatment notifications translate into an estimate that resistance transmission rather than acquisition accounts for a median 95.9% (95% uncertainty range [UR] 68.0-99.6) of all incident MDR tuberculosis, and 61.3% (16.5-95.2) of incident MDR tuberculosis in previously treated individuals. The estimated proportion of MDR tuberculosis resulting from transmission varied substantially with different countries' notification data-ranging from 48% (95% UR 30-75) in Bangladesh to 99% (91-100) in Uzbekistan. Estimates were most sensitive to estimates of the transmissibility of MDR strains, the probability of acquiring MDR during tuberculosis treatment, and the responsiveness of MDR tuberculosis to first-line treatment. INTERPRETATION: Notifications of MDR prevalence from most high-burden settings are consistent with most incident MDR tuberculosis resulting from transmission rather than new treatment-related acquisition of resistance. Merely improving the treatment of drug-susceptible tuberculosis is unlikely to greatly reduce future MDR tuberculosis incidence. Improved diagnosis and treatment of MDR tuberculosis including new tests and drug regimens-should be highly prioritised. FUNDING: National Institutes of Health and the Bill & Melinda Gates Foundation. PMID- 26597128 TI - Restricted versus continued standard caloric intake during the management of refeeding syndrome in critically ill adults: a randomised, parallel-group, multicentre, single-blind controlled trial. AB - BACKGROUND: Equipoise exists regarding the benefits of restricting caloric intake during electrolyte replacement for refeeding syndrome, with half of intensive care specialists choosing to continue normal caloric intake. We aimed to assess whether energy restriction affects the duration of critical illness, and other measures of morbidity, compared with standard care. METHODS: We did a randomised, multicentre, single-blind clinical trial in 13 hospital intensive care units (ICUs) in Australia (11 sites) and New Zealand (two sites). Adult critically ill patients who developed refeeding syndrome within 72 h of commencing nutritional support in the ICU were enrolled and allocated to receive continued standard nutritional support or protocolised caloric restriction. 1:1 computer-based randomisation was done in blocks of variable size, stratified by enrolment serum phosphate concentration (>0.32 mmol/L vs <=0.32 mmol/L) and body-mass index (BMI; >18 kg/m(2)vs <=18 kg/m(2)). The primary outcome was the number of days alive after ICU discharge, with 60 day follow-up, in a modified intention-to-treat population of all randomly allocated patients except those mistakenly enrolled. Days alive after ICU discharge was a composite outcome based on ICU length of stay, overall survival time, and mortality. The Refeeding Syndrome Trial was registered with the Australian and New Zealand Clinical Trials Registry (ANZCTR number 12609001043224). FINDINGS: Between Dec 3, 2010, and Aug 13, 2014, we enrolled 339 adult critically ill patients: 170 were randomly allocated to continued standard nutritional support and 169 to protocolised caloric restriction. During the 60 day follow-up, the mean number of days alive after ICU discharge in 165 assessable patients in the standard care group was 39.9 (95% CI 36.4-43.7) compared with 44.8 (95% CI 40.9-49.1) in 166 assessable patients in the caloric restriction group (difference 4.9 days, 95% CI -2.3 to 13.6, p=0.19). Nevertheless, protocolised caloric restriction improved key individual components of the primary outcome: more patients were alive at day 60 (128 [78%] of 163 vs 149 [91%] of 164, p=0.002) and overall survival time was increased (48.9 [SD 1.46] days vs 53.65 [0.97] days, log-rank p=0.002). INTERPRETATION: Protocolised caloric restriction is a suitable therapeutic option for critically ill adults who develop refeeding syndrome. We did not identify any safety concerns associated with the use of protocolised caloric restriction. FUNDING: National Health and Medical Research Council of Australia. PMID- 26597129 TI - MDR tuberculosis control: time to change the dogma? PMID- 26597130 TI - Nutritional support and refeeding syndrome in critical illness. PMID- 26597131 TI - Childhood asthma prediction models: a systematic review. AB - Early identification of children at risk of developing asthma at school age is crucial, but the usefulness of childhood asthma prediction models in clinical practice is still unclear. We systematically reviewed all existing prediction models to identify preschool children with asthma-like symptoms at risk of developing asthma at school age. Studies were included if they developed a new prediction model or updated an existing model in children aged 4 years or younger with asthma-like symptoms, with assessment of asthma done between 6 and 12 years of age. 12 prediction models were identified in four types of cohorts of preschool children: those with health-care visits, those with parent-reported symptoms, those at high risk of asthma, or children in the general population. Four basic models included non-invasive, easy-to-obtain predictors only, notably family history, allergic disease comorbidities or precursors of asthma, and severity of early symptoms. Eight extended models included additional clinical tests, mostly specific IgE determination. Some models could better predict asthma development and other models could better rule out asthma development, but the predictive performance of no single model stood out in both aspects simultaneously. This finding suggests that there is a large proportion of preschool children with wheeze for which prediction of asthma development is difficult. PMID- 26597132 TI - Luffa acutangula agglutinin: Primary structure determination and identification of a tryptophan residue involved in its carbohydrate-binding activity using mass spectrometry. AB - A lectin from phloem exudates of Luffa acutangula (ridge gourd) was purified on chitin affinity chromatography and characterized for its amino acid sequence and to study the role of tryptophan in its activity. The purified lectin was subjected to various proteolytic digestions, and the resulting peptides were analyzed by liquid chromatography coupled electrospray ionization ion trap mass spectrometer. The peptide precursor ions were fragmented by collision-induced dissociation or electron transfer dissociation experiments, and a manual interpretation of MS/MS was performed to deduce amino acid sequence. This gave rise to almost complete sequence coverage of the lectin which showed high sequence similarity with deduced sequences of phloem lectins present in the database. Chemical modification of lysine, tyrosine, histidine, arginine, aspartic acid, and glutamic acid residues did not inhibit the hemagglutinating activity. However, the modification of tryptophan residues using N bromosuccinimide showed the loss of hemagglutinating activity. Additionally, the mapping of tryptophan residues was performed to determine the extent and number of residues modified, which revealed that six residues per molecule were oxidized suggesting their accessibility. The retention of the lectin activity was seen when the modifications were performed in the presence of chitooligosaccharides due to protection of a tryptophan residue (W102) in the protein. These studies taken together have led to the identification of a particular tryptophan residue (W102) in the activity of the lectin. PMID- 26597134 TI - [Medical examination: Preparation for ENT specialisation: Part 22]. PMID- 26597133 TI - Interferon-beta gene transfer inhibits melanoma cells adhesion and migration. AB - We evaluated the effects of expression of interferon-beta (IFNbeta) after lipofection on melanoma cells adhesion and migration. Three canine mucosal (Ak, Br and Ol) and one human dermal (SB2) melanomas were assayed. By means of the wound healing assay, we found a significant inhibitory effect of canine IFNbeta gene expression on cells migration in Br and Ol monolayers. This effect could be reproduced on unlipofected Ol cells with conditioned culture media obtained from canine IFNbeta gene-lipofected Ol cells, and with recombinant human IFNbeta on unlipofected SB2 cells. Furthermore, IFNbeta gene expression of the four tested tumor cells significantly inhibited their adhesion to extracellular matrix (ECM) proteins and their spreading from multicellular spheroids onto gelatin coating. The addition of catalase reverted the increase of reactive oxygen species (ROS) in Ol cells and the inhibition of cell migration in monolayers (Ol) and spheroids (Ol an SB2) produced by canine and human IFNbeta expression, suggesting the involvement of ROS as mediators of IFNbeta action on the cells interactions with ECM. Together with its known immune, antiangiogenic and cytotoxic effects, the present data strongly support more studies exploring the clinical potential of IFNbeta for cancer therapy. PMID- 26597135 TI - [Hygiene in otorhinolaryngology: Requirements and reality]. AB - Considering the physiological contamination of skin and mucous membranes in the ear, nose, and throat region by facultative pathogen microorganisms, as well as the increase in multidrug resistant organisms (MDRO), it is mandatory that hygienic procedures be observed in ENT institutions, in order to prevent transmission of bacteria and infections in patients. General guidelines for hygiene in otorhinolaryngology are presented based on the recommendations published by the German Commission on Hospital Hygiene and Infection Prevention (KRINKO). These encompass hand hygiene, surface disinfection, and reprocessing of medical devices. The correct reprocessing of the various components of ENT treatment units (including endoscopes, water bearing systems) is reported. Although law requires and KRINKO recommends that manufacturers of medical devices publish instructions for reprocessing their products, these reprocessing recommendations are often insufficient. Manufacturers should thus be called upon to improve their recommendations. In this paper, the requirements for handling of ENT treatment units are compared with the observations made by the Public Health Department in 7 ENT clinics and 32 ENT practices in Frankfurt/Main, Germany, in 2014. PMID- 26597136 TI - [Bradykinin-induced angioedema: Definition, pathogenesis, clinical presentation, diagnosis and therapy]. AB - The incidence of bradykinin-induced angioedema is considerably lower than that of histamine-induced forms; however, the same is true for the clinician's knowledge of this condition. Bradykinin-induced angioedemas include hereditary angioedema (HAE), as well as acquired forms induced by drugs or antibody formation, e.g., during the course of oncologic disease. Drug-induced forms affect almost exclusively the head and neck region, and are thus important for the otorhinolaryngologist. Clear differentiation between histamine-induced angioedema (e. g., connected to allergy/urticaria) and bradykinin-induced angioedema is essential for selection of the specific treatment and may be lifesaving. Antihistamines and cortisone derivatives have no relevant effect in bradykinin induced-angioedema, whereas blood-derived C1 esterase inhibitor and bradykinin receptor 2 antagonists represent effective therapeutic options--both for acute and prophylactic treatment. PMID- 26597137 TI - Genomic diversity of Mycobacterium tuberculosis Beijing strains isolated in Tuscany, Italy, based on large sequence deletions, SNPs in putative DNA repair genes and MIRU-VNTR polymorphisms. AB - The Beijing genotype of Mycobacterium tuberculosis is cause of global concern as it is rapidly spreading worldwide, is considered hypervirulent, and is most often associated to massive spread of MDR/XDR TB, although these epidemiological or pathological properties have not been confirmed for all strains and in all geographic settings. In this paper, to gain new insights into the biogeographical heterogeneity of the Beijing family, we investigated a global sample of Beijing strains (22% from Italian-born, 78% from foreign-born patients) by determining large sequence polymorphism of regions RD105, RD181, RD150 and RD142, single nucleotide polymorphism of putative DNA repair genes mutT4 and mutT2 and MIRU VNTR profiles based on 11 discriminative loci. We found that, although our sample of Beijing strains showed a considerable genomic heterogeneity, yielding both ancient and recent phylogenetic strains, the prevalent successful Beijing subsets were characterized by deletions of RD105 and RD181 and by one nucleotide substitution in one or both mutT genes. MIRU-VNTR analysis revealed 47 unique patterns and 9 clusters including a total of 33 isolates (41% of total isolates); the relatively high proportion of Italian-born Beijing TB patients, often occurring in mixed clusters, supports the possibility of an ongoing cross transmission of the Beijing genotype to autochthonous population. High rates of extra-pulmonary localization and drug-resistance, particularly MDR, frequently reported for Beijing strains in other settings, were not observed in our survey. PMID- 26597138 TI - Emotion regulation during the encoding of emotional stimuli: Effects on subsequent memory. AB - In the adult literature, emotional arousal is regarded as a source of the enhancing effect of emotion on subsequent memory. Here, we used behavioral and electrophysiological methods to examine the role of emotional arousal on subsequent memory in school-age children. Furthermore, we implemented a reappraisal instruction to manipulate (down-regulate) emotional arousal at encoding to examine the relation between emotional arousal and subsequent memory. Participants (8-year-old girls) viewed emotional scenes as electrophysiological (EEG) data were recorded and participated in a memory task 1 to 5days later where EEG and behavioral responses were recorded; participants provided subjective ratings of the scenes after the memory task. The reappraisal instruction successfully reduced emotional arousal responses to negative stimuli but not positive stimuli. Similarly, recognition performance in both event-related potentials (ERPs) and behavior was impaired for reappraised negative stimuli but not positive stimuli. The findings indicate that ERPs are sensitive to the reappraisal of negative stimuli in children as young as 8years. Furthermore, the findings suggest an interaction of emotion and memory during the school years, implicating the explanatory role of emotional arousal at encoding on subsequent memory performance in female children as young as 8years. PMID- 26597139 TI - Sympathetic recovery from anger is associated with emotion regulation. AB - Prior work has focused on how and whether autonomic reactivity in response to emotionally evocative events is associated with better emotion regulation skills in children, but little is known about autonomic recovery processes in children and how they might relate to regulation. In a sample of 67 3.5-year-olds, we examined sympathetic responding during an anger provocation and during a repair period immediately following. Piecewise latent growth curve models were used to estimate changes in pre-ejection period (PEP) that occurred during the provocation period and during the repair period. Mothers reported on global aspects of emotion regulation. On average, children showed a small but significant increase in sympathetic activity (PEP shortening) during the provocation period. Although a significant mean pattern of change was not detected during the repair period, there was significant variability in individual trajectories. These individual differences in physiological change during the repair period were associated with emotion regulation, such that children who were rated as having better emotion regulation showed greater sympathetic recovery (PEP lengthening) during the repair period. This suggests that effectively well-regulated preschoolers are more capable of terminating sympathetic responding after a provocation of anger has ended rather than continuing to be physiologically primed for fight-or-flight responding. PMID- 26597141 TI - Boomerang families and failure-to-launch: Commentary on adult children living at home. AB - With a shifting economic climate and changes in social norms, young adults are increasingly reported to be living with their parents, either through delayed launch or by launch and return. For young adults grappling with financial and domestic independence, the family home can represent a safe haven; however, living with parents can also pose a threat to autonomy and self-image as they strive for adult status. Parents, on the other hand, are often beleaguered by the economic and emotional demands of their dependent adult children and struggle to maintain their own independence. The roles and expectations of both parties need to be redefined in order to achieve optimal household functioning. PMID- 26597140 TI - Quantitative Western ligand blotting reveals common patterns and differential features of IGFBP-fingerprints in domestic ruminant breeds and species. AB - The insulin-like growth factor binding proteins (IGFBPs) are determinants of local IGF-effects and thus have an impact on growth and metabolism in vertebrate species. In farm animals, IGFBPs are associated with traits such as growth rate, body composition, milk production, or fertility. It may be assumed, that selective breeding and characteristic phenotypes of breeds are related to differential expression of IGFBPs. Therefore, the aim of the present study was to investigate the effects of selective breeding on blood IGFBP concentrations of farm animals. Breeds of the sheep, goat, and cattle species were investigated. IGFBP-3, -2, and -4 were analyzed with quantitative Western ligand blotting (qWLB), enabling comprehensive monitoring of intact IGFBPs with IGF-binding capacity. We show that in sera of all species and breeds investigated, IGFBP-3, 2, and -4 were simultaneously detectable by qWLB analysis. IGFBP-3 and the total amount of IGFBPs were significantly increased (P<0.05) in Cameroon sheep, if compared to 3 of 4 other sheep breeds, as well as in Dwarf goats versus Toggenburg and Boer goats (P<0.01). IGFBP-2 was elevated in Cameroon sheep and Boer goats, if compared to other breeds of these species (P<0.01), respectively. Holstein Friesian dairy cows had higher levels of IGFBP-4 (P<0.05), if compared to conventional crossbreeds of beef cattle. In Dwarf goats the ratio of IGFBP 3/IGFBP-2 was about 3-fold higher than in other goat breeds (P<0.001). The total IGFBP amount of Toggenburg goats was reduced (P<0.05), compared to the other goat breeds. In conclusion, our data indicate that common and specific features of IGFBP fingerprints are found in different ruminant species and breeds. Our findings may introduce quantitative Western ligand blotting as an attractive tool for biomarker development and molecular phenotyping in farm animal breeds. PMID- 26597142 TI - [Metastatic lymph node collision of a prostatic adenocarcinoma and an urothelial carcinoma and review of the literature]. AB - INTRODUCTION: Tumor collision is the encounter of two tumors from two different topographical sites. Cases of metastatic lymph node collision are exceptional. We report the case of a metastatic lymph node collision of an urothelial carcinoma and a prostatic adenocarcinoma. OBSERVATION: A 61-year-old man was hospitalized for a right nephroureterectomy with peri-ureteral lymph node dissection. He was followed since 2004 for prostatic adenocarcinoma and treated with radical prostatectomy then radiation therapy 4 years later due to a new increase of PSA. In the follow-up, an urothelial carcinoma of the lower right ureter was discovered in 2014. Histological analysis of a peri-ureteral lymph node showed a double metastasis of urothelial and prostatic origin. The prostatic adenocarcinoma was composed of acinar and ductal subtypes. Immunohistochemical study including CK7, CK20, PSA, GATA3, P63 antibodies confirmed the distinct phenotype of the 2 tumors. DISCUSSION: Metastatic collision of urothelial carcinoma and prostatic adenocarcinoma has been reported in 4 cases only. Our review of literature shows that prostatic adenocarcinoma always precedes the urothelial carcinoma. Immunohistochemical study, when carried out for distinguishing both tumors, should include CK7, CK20 and PSA. GATA3, androgen receptor and P63 could be added in a second time. PMID- 26597143 TI - Efficacy of medicinal essential oils against pathogenic Malassezia sp. isolates. AB - OBJECTIVES: The purposes of this study were to evaluate the distribution pattern and population size of Malassezia species in dogs with atopic dermatitis (AD) and the inhibitory efficacy of Zataria multiflora, Thymus kotschyanus, Mentha spicata, Artemisia sieberi, Rosmarinus officinalis and Heracleum persicum essential oils against pathogenic Malassezia isolates. METHODS: The samples were collected from 5 different anatomical sites of 33 atopic dogs and cultured onto modified Dixon agar (MDA) and Sabouraud dextrose agar (SDA) media. The essential oil extraction was performed by steam distillation using Clevenger system. Anti Malassezia efficacy of medicinal essential oils and standard drugs was evaluated using broth microdilution method. RESULTS: A total of 103 yeast colonies were isolated from dogs with AD. Eight different Malassezia species were identified as follows: Malassezia pachydermatis (81.4%), M. globosa (7.8%), M. restricta (3.9%), M. sloofiae (2.9%), M. furfur (1%), M. nana (1%), M. obtusa (1%) and M. sympodialis (1%). The most and least infected sites were: anal (21.2%) and ear (10.6%) respectively. M. pachydermatis was the most frequent Malassezia species isolated from both skin and mucosa of dogs with AD. Antifungal susceptibility test revealed the inhibitory efficacy of essential oils on pathogenic Malassezia isolates with minimum inhibitory concentration (MIC(90)) values ranging from 30 to 850 MUg/mL. Among the tested oils, Z. multiflora and T. kotschyanus exhibited the highest inhibitory effects (P<0.05). CONCLUSION: The essential oils of Z. multiflora and T. kotschyanus showed strong antifungal activity against pathogenic Malassezia species tested. PMID- 26597144 TI - Uptake of clinical yeast isolates by human epithelial cell line. AB - OBJECTIVE: The occurrence of yeast infections in humans has increased, with the species belonging to genus Candida still being the most common cause of infection. Nevertheless, infections caused by less common yeasts have been widely reported in recent years. The main objective of this study was to assess the potential of these less common saprophytic yeasts to invade the host cell, which is essential for causing systemic infections. MATERIAL AND METHODS: Various yeast isolates were identified by DNA sequence information of PCR amplified ITS region. The purported saprophytic yeasts were characterized for internalization by mammalian cells in vitro, by staining the F-actin. CONCLUSION: The identification of different yeast isolates from various patients revealed that 70% of the isolates belonged to the genus Candida, while remaining 30% of the isolates were yeasts not belonging to genus Candida. These non-Candida clinical isolates, either in yeast or hyphal forms, were efficiently internalized by human epithelial cells. The internalization was marked by a process of actin polymerization surrounding the invading yeast. Such uptake by epithelial cells signifies traversal of cell barrier by yeast cells during infection in vivo. PMID- 26597145 TI - Lactic acid bacteria as functional probiotic isolates for inhibiting the growth of Aspergillus flavus, A. parasiticus, A. niger and Penicillium chrysogenum. AB - OBJECTIVE: The aim of this study was to assess the potential of lactic acid bacteria (LAB) such as Lactobacillus acidophilus, L. rhamnosus, L. casei, L. paracasei and Bifidobacterium bifidum to inhibit the outgrowth of some common food-spoiling fungi including Aspergillus niger, A. flavus, A. parasiticus and Penicillium chrysogenum. METHODS: Bacterial isolates were cultured on Mann Rogosa Sharpe (MRS) broth and liquid cultures and supernatants were prepared. The antifungal activity was tested using the agar well diffusion method. RESULTS: Both liquid culture and supernatant of L. casei isolate exhibited high antifungal activity, followed by L. acidophilus and L. paracasei isolates. The least activity was recorded for the isolates B. bifidum, while the isolate L. rhamnosus was moderately active against tested fungi. The antifungal activity of the supernatants obtained from all probiotic isolates against fungi was significantly less than that of liquid cultures (P<0.05). Antifungal activity evaluation showed that A. flavus was the most inhibited fungus by probiotic bacteria, followed by P. chrysogenum, A. niger and A. parasiticus. CONCLUSION: These results suggest that probiotic bacteria strains have the ability to prevent the growth of pathogenic and mycotoxigenic fungi as antifungal agents for various biomedical applications. PMID- 26597146 TI - Pathogenicity of Candida viswanathii for normal and cortisone-treated mice. AB - The pathogenicity of Candida viswanathii, PCI 501/1 (CBS 4024), originally isolated from CSF of a fatal case of meningitis in India, is reported. Also, included is a global overview of the occurrence of C. viswanathii in clinical and environmental sources. The investigation was done in normal and cortisone-treated albino mice challenged intravenously with variable doses of 1*10(6), 4*10(6) and 16*10(6) actively growing yeast cells of the fungus. The animals were kept under observation up to 3 weeks when they were sacrificed for a mycological and histopathologic study. As apparent from the data on morbidity and mortality, the species exhibited low virulence for normal mice, whereas it caused significantly higher mortality (P<0.0008) and morbidity (macroscopic lesions) (P<0.0004) in cortisone group. Likewise, there was overall higher recovery of C. viswanathii in culture from the cortisone-treated than in the normal group of mice. These observations are indicative of C. viswanathii being an opportunistic pathogen. It is recognized that a definitive identification of C. viswanathii requires mycological expertise for comprehensive phenotypic characterization or the application of expensive techniques such as Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-TOF MS) and molecular techniques, facilities for which are generally lacking in a vast majority of laboratory diagnostic centers especially in developing countries. Consequently, the prevalence of C. viswanathii in clinical and environmental samples is currently likely to be underestimated. PMID- 26597147 TI - [Keratomycosis due to Fusarium oxysporum treated with the combination povidone iodine eye drops and oral fluconazole]. AB - In developing countries where systemic antifungal are often unavailable, treatment of filamentous fungi infection as Fusarium is sometimes very difficult to treat. We report the case of a keratomycosis due to Fusarium oxysporum treated by povidone iodine eye drops and oral fluconazole. The diagnosis of abscess in the cornea was retained after ophthalmological examination for a 28-year-old man with no previous ophthalmological disease, addressed to the Ophthalmological clinic at the University Hospital Le Dantec in Dakar for a left painful red eye with decreased visual acuity lasting for 15 days. The patient did not receive any foreign body into the eye. Samples by corneal scraping were made for microbiological analysis and the patient was hospitalized and treated with a reinforced eye drops based treatment (ceftriaxone+gentamicin). The mycological diagnosis revealed the presence of a mold: F. oxysporum, which motivated the replacement of the initial treatment by eye drops containing iodized povidone solution at 1% because of the amphotericin B unavailability. Due to the threat of visual loss, oral fluconazole was added to the local treatment with eye drops povidone iodine. The outcome was favorable with a healing abscess and visual acuity amounted to 1/200th. Furthermore, we noted sequels such as pannus and pillowcase. The vulgarization of efficient topical antifungal in developing countries would be necessary to optimize fungal infection treatment. PMID- 26597148 TI - Immunogenicity of a prototype enterotoxigenic Escherichia coli adhesin vaccine in mice and nonhuman primates. AB - Enterotoxigenic Escherichia coli (ETEC) are the most common cause of bacterial diarrhea in young children in developing countries and in travelers. Efforts to develop an ETEC vaccine have intensified in the past decade, and intestinal colonization factors (CFs) are somatic components of most investigational vaccines. CFA/I and related Class 5 fimbrial CFs feature a major stalk-forming subunit and a minor, antigenically conserved tip adhesin. We hypothesized that the tip adhesin is critical for stimulating antibodies that specifically inhibit ETEC attachment to the small intestine. To address this, we compared the capacity of donor strand complemented CfaE (dscCfaE), a stabilized form of the CFA/I fimbrial tip adhesin, and CFA/I fimbriae to elicit anti-adhesive antibodies in mice, using hemagglutination inhibition (HAI) as proxy for neutralization of intestinal adhesion. When given with genetically attenuated heat-labile enterotoxin LTR192G as adjuvant by intranasal (IN) or orogastric (OG) vaccination, dscCfaE exceeded CFA/I fimbriae in eliciting serum HAI titers and anti-CfaE antibody titers. Based on these findings, we vaccinated Aotus nancymaae nonhuman primates (NHP) with dscCfaE alone or admixed with one of two adjuvants, LTR192G and cholera toxin B-subunit, by IN and OG administration. Only IN vaccination with dscCfaE with either adjuvant elicited substantial serum HAI titers and IgA and IgG anti-adhesin responses, with the latter detectable a year after vaccination. In conclusion, we have shown that dscCfaE elicits robust HAI and anti-adhesin antibody responses in both mice and NHPs when given with adjuvant by IN vaccination, encouraging further evaluation of an ETEC adhesin based vaccine approach. PMID- 26597149 TI - Completion and compliance of childhood vaccinations in the United States. AB - BACKGROUND: The Advisory Committee on Immunization Practices recommends routine childhood vaccination by age 2 years, yet evidence suggests that only 2% to 26% of children receive vaccine doses at age-appropriate times (compliance). The objective of this study was to estimate vaccine completion and compliance rates between birth and age 2 years using recent, nationally representative data. METHODS: Using a sample of children aged 24 to 35 months from the 2012 National Immunization Survey (NIS), the present study examined completion and compliance of recommended childhood vaccines. A state-specific examination of vaccine completion and compliance was also conducted. RESULTS: An unweighted sample of 11,710 children (weighted to 4.1 million) was selected. Approximately 70% of children completed all doses of six recommended vaccines by 24 months of age. Completion rates varied by antigen, ranging from 68% completing two or three doses of rotavirus vaccine to 92% completing three doses of inactivated poliovirus vaccine. Vaccine completion rates also varied at different measurement periods, with the lowest rates observed at 18 months. Approximately 26% of children received all doses of six recommended vaccines on time. Among the 74% of children who received at least one late dose, 39% had >7 months of undervaccination. Patterns of completion and compliance also varied by geographic region. CONCLUSIONS: Completion of individual antigens approached Healthy People 2020 targets. However, overall completion of the recommended vaccine series and compliance with the recommended vaccination dosing schedule were low, indicating few children received vaccines at age-appropriate times. Additional clinical, policy, and educational interventions are needed to increase receipt of vaccines at optimal ages. PMID- 26597150 TI - Erratum to: Improvement in latent variable indirect response joint modeling of a continuous and a categorical clinical endpoint in rheumatoid arthritis. PMID- 26597151 TI - Alterations in functional connectivity of resting state networks during experimental endotoxemia - An exploratory study in healthy men. AB - Systemic inflammation impairs mood and cognitive functions, and seems to be involved in the pathophysiology of psychiatric disorders. Functional magnetic resonance imaging (fMRI) studies revealed altered task-related blood-oxygen-level dependent (BOLD) responses during experimental endotoxemia, but little is known about effects of systemic inflammation on resting-state activity of the brain. Thus, we conducted a randomized, placebo-controlled study in healthy men receiving an intravenous injection of either low-dose (0.4 ng/kg) lipopolysaccharide (LPS) (N=20) or placebo (N=25). Resting state activity was measured at baseline and 3.5h post-injection. Based on a two (condition) * two (group) design, we used multi-subject independent component analysis (ICA) to decompose and estimate functional connectivity within resting-state networks (RSNs). Seed-based analyses were applied to investigate the effect of LPS on the functional coupling for a priori-defined regions-of-interest (ROIs). ICA analyses identified 13 out of 35 components displaying common RSNs. Seed based analysis revealed greater functional connectivity between the left thalamus and the cerebellum after LPS compared to placebo administration, while the functional coupling between seeds within the amygdala, insula, and cingulate cortex and various brain regions including parieto-frontal networks was significantly reduced. Within the LPS group, endotoxin-induced increases in Interleukin (IL)-6 were significantly associated with resting-state connectivity between the left thalamus and left precuneus as well as the right posterior cingulate cortex. In summary, this exploratory study provides first evidence that systemic inflammation affects the coupling and regulation of multiple networks within the human brain at rest. PMID- 26597152 TI - Relation of Central Arterial Stiffness to Incident Heart Failure in the Community. AB - BACKGROUND: Arterial stiffness, pressure pulsatility, and wave reflection are associated with cardiovascular disease. Left ventricular function is coupled to proximal aortic properties, but the association of central aortic stiffness and hemodynamics with incident clinical heart failure (HF) is not well described. METHODS AND RESULTS: Framingham Study participants without clinical HF (n=2539, mean age 64 years, 56% women) underwent applanation tonometry to measure carotid femoral pulse wave velocity (CFPWV), central pulse pressure, forward wave amplitude, and augmentation index. CFPWV was inverse-transformed to reduce heteroscedasticity and multiplied by -1 to restore effect direction (iCFPWV). Over 10.1 (range 0.04-12.9) years, 170 HF events developed. In multivariable adjusted analyses, iCFPWV was associated with incident HF in a continuous, graded fashion (hazards ratio [HR] per SD unit [SDU] 1.29, 95% confidence interval [CI] 1.02-1.64, P=0.037). iCFPWV was associated with HF with reduced ejection fraction (HR=1.69/SDU, 95% CI 1.19-2.42, P=0.0037) in age- and sex-adjusted models, which was attenuated in multivariable-adjusted models (P=0.065). Central pulse pressure and forward wave amplitude were associated with HF in age- and sex-adjusted models (per SDU, HR=1.20, 95% CI 1.06-1.37, P=0.006, and HR=1.15, 95% CI 1.01 1.31, P=0.036, respectively), but not in multivariable-adjusted models (both P>=0.28). Augmentation index was not associated with HF risk (P>=0.19 in all models). CONCLUSIONS: In our prospective investigation of a large community-based sample of middle-aged to elderly individuals, greater aortic stiffness (reflected by higher iCFPWV) was associated with increased risk of HF. Future studies may investigate the impact of modifying aortic stiffness in reducing the community burden of HF. PMID- 26597153 TI - Maternal Cardiac Output and Fetal Doppler Predict Adverse Neonatal Outcomes in Pregnant Women With Heart Disease. AB - BACKGROUND: The mechanistic basis of the proposed relationship between maternal cardiac output and neonatal complications in pregnant women with heart disease has not been well elucidated. METHODS AND RESULTS: Pregnant women with cardiac disease and healthy pregnant women (controls) were prospectively followed with maternal echocardiography and obstetrical ultrasound scans at baseline, third trimester, and postpartum. Fetal/neonatal complications (death, small-for gestational-age or low birthweight, prematurity, respiratory distress syndrome, or intraventricular hemorrhage) comprised the primary study outcome. One hundred and twenty-seven women with cardiac disease and 45 healthy controls were enrolled. Neonatal events occurred in 28 pregnancies and were more frequent in the heart disease group as compared with controls (n=26/127 or 21% versus n=2/45 or 4%; P=0.01). Multiple complications in an infant were counted as a single outcome event. Neonatal complications in the heart disease group were small-for gestational-age/low birthweight (n=18), prematurity (n=14), and intraventricular hemorrhage/respiratory distress syndrome (n=5). Preexisting obstetric risk factors (P=0.003), maternal cardiac output decline from baseline to third trimester (P=0.017), and third trimester umbilical artery Doppler abnormalities (P<0.001) independently predicted neonatal complications and were incorporated into a novel risk index in which 0, 1, and >1 predictor corresponded to expected complication rates of 5%, 30%, and 76%, respectively. CONCLUSIONS: Decline in maternal cardiac output during pregnancy and abnormal umbilical artery Doppler flows independently predict neonatal complications. These findings will enhance the identification of higher risk pregnancies that would benefit from close antenatal surveillance. PMID- 26597154 TI - N-glycome Profile Levels Relate to Silent Brain Infarcts in a Cohort of Hypertensives. AB - BACKGROUND: Silent brain infarcts (SBIs) are highly prevalent in the aged population and relate to the occurrence of further stroke and dementia. Serum N glycome levels have been previously associated with aging and they might be related as well to the presence of SBIs and age-related white matter hyperintensities. METHODS AND RESULTS: We determined the serum N-glycome profile in a cohort study comprising 972 subjects and evaluated the relationship between N-glycome levels and the presence and number of SBIs and with age-related white matter hyperintensities grades, assessed by brain magnetic resonance imaging. Decreasing concentrations of bigalacto core-alpha-1,6-fucosylated biantennary glycan and increasing concentrations of branching alpha-1,3-fucosylated triantennary glycan remained as independent predictors of SBIs (odds ratio 0.4, 95% CI 0.3-0.7 and odds ratio 1.8, 95% CI 1-3.2, respectively), after controlling for the presence of age and classic vascular risk factors. A similar pattern was found to be related to an increasing number of SBIs and white matter hyperintensities grade. CONCLUSIONS: N-glycome levels might be potentially useful as biomarkers for the presence of silent cerebrovascular disease. PMID- 26597155 TI - Dysbiosis of Gut Microbiota With Reduced Trimethylamine-N-Oxide Level in Patients With Large-Artery Atherosclerotic Stroke or Transient Ischemic Attack. AB - BACKGROUND: Gut microbiota has been suggested to play a role in almost all major diseases including cardio- and cerebrovascular diseases. A possible mechanism is the transformation of dietary choline and l-carnitine into trimethylamine by gut bacteria. This metabolite is further oxidized into trimethylamine-N-oxide (TMAO) in liver and promotes atherogenesis. Nevertheless, little is known about gut microbial diversity and blood TMAO levels in stroke patients. METHODS AND RESULTS: We performed a case-control study of patients with large-artery atherosclerotic ischemic stroke and transient ischemic attack. TMAO was determined with liquid chromatography tandem mass spectrometry. Gut microbiome was profiled using Illumina sequencing of the 16S rRNA V4 tag. Within the asymptomatic control group, participants with and without carotid atherosclerotic plaques showed similar levels of TMAO without a significant difference in gut microbiota; however, the gut microbiome of stroke and transient ischemic attack patients was clearly different from that of the asymptomatic group. Stroke and transient ischemic attack patients had more opportunistic pathogens, such as Enterobacter, Megasphaera, Oscillibacter, and Desulfovibrio, and fewer commensal or beneficial genera including Bacteroides, Prevotella, and Faecalibacterium. This dysbiosis was correlated with the severity of the disease. The TMAO level in the stroke and transient ischemic attack patients was significantly lower, rather than higher, than that of the asymptomatic group. CONCLUSIONS: Participants with asymptomatic atherosclerosis did not exhibit an obvious change in gut microbiota and blood TMAO levels; however, stroke and transient ischemic attack patients showed significant dysbiosis of the gut microbiota, and their blood TMAO levels were decreased. PMID- 26597156 TI - From Arterial Stiffness to Heart Failure: Still a Long Way to Go. PMID- 26597157 TI - Glaciimonas frigoris sp. nov., a psychrophilic bacterium isolated from ancient Siberian permafrost sediment, and emended description of the genus Glaciimonas. AB - The bacterial strain N1-38T was isolated from ancient Siberian permafrost sediment. The strain was Gram-reaction-negative, motile by gliding, rod-shaped and psychrophilic, and showed good growth over a temperature range of - 5 to 25 degrees C. Phylogenetic analysis of 16S rRNA gene sequences revealed that strain N1-38T was most closely related to members of the genus Glaciimonas and shared the highest 16S rRNA gene sequence similarities with the type strains of Glaciimonas alpina (99.3 %), Glaciimonas immobilis (98.9 %) and Glaciimonas singularis (96.5 %). The predominant cellular fatty acids of strain N1-38T were summed feature 3 (C16 : 1omega7c and/or iso-C15 : 0 2-OH), C16 : 0 and C18 : 1omega7c. The major respiratory quinone was ubiquinone 8 and the major polar lipids were phosphatidylethanolamine and diphosphatidylglycerol. The genomic DNA G+C content was 53.0 mol%. Combined data of phenotypic, phylogenetic and DNA-DNA relatedness studies demonstrated that strain N1-38T represents a novel species of the genus Glaciimonas, for which the name Glaciimonas frigoris sp. nov. is proposed. The type strain is N1-38T ( = LMG 28868T = CCOS 838T). An emended description of the genus Glaciimonas is also provided. PMID- 26597158 TI - Purification and characterization of glutaminase free asparaginase from Pseudomonas otitidis: Induce apoptosis in human leukemia MOLT-4 cells. AB - Asparaginase is an important antineoplastic drug extensively used for the treatment of acute lymphoblastic leukemia, but the intrinsic glutaminase activity of this enzymatic drug is responsible for several life threatening side effects. This study describes the purification and characterization of glutaminase free asparaginase from Pseudomonas otitidis. The purified enzyme exhibited molecular mass of approximately 205+/-3 kDa on native-PAGE and 34+/-1 kDa on SDS-PAGE, revealing that the enzyme is homohexamer. The isoelectric point of enzyme was 5.5, calculated by 2D-PAGE. Optimum activity of asparaginase was achieved at 40 degrees C and pH 7.5, which is close to the internal environment of the human body. Monovalent cations (Na(+) and K(+)) and reducing agents (2-mercaptoethanol and glutathione) has enhanced asparaginase activity. Whereas, divalent (Ca(2+), Mg(2+), Zn(2+) and Mn(2+)), trivalent (Fe(3+)) cations and thiol group blocking agent (iodoacetamide) inhibited the enzyme activity significantly. In vitro serum and trypsin half life of asparaginase is almost 2 and 1.5 fold respectively, which is higher than commercial asparaginase. MTT assay results showed that the anticancer activity of purified asparaginase was comparable or higher than commercial E. coli asparaginase. Microscopic studies and cell cycle analysis suggested that purified enzyme induced apoptotic cell death in dose-dependent manner. Loss of mitochondrial membrane potential suggests that enzyme induces cell death via activation of intrinsic apoptotic pathway. Purified asparaginase was found to be nontoxic for human noncancerous FR-2 cells and human blood lymphocytes, which is a remarkable therapeutic feature. PMID- 26597159 TI - The relationship between stochastic and deterministic quasi-steady state approximations. AB - BACKGROUND: The quasi steady-state approximation (QSSA) is frequently used to reduce deterministic models of biochemical networks. The resulting equations provide a simplified description of the network in terms of non-elementary reaction functions (e.g. Hill functions). Such deterministic reductions are frequently a basis for heuristic stochastic models in which non-elementary reaction functions are used to define reaction propensities. Despite their popularity, it remains unclear when such stochastic reductions are valid. It is frequently assumed that the stochastic reduction can be trusted whenever its deterministic counterpart is accurate. However, a number of recent examples show that this is not necessarily the case. RESULTS: Here we explain the origin of these discrepancies, and demonstrate a clear relationship between the accuracy of the deterministic and the stochastic QSSA for examples widely used in biological systems. With an analysis of a two-state promoter model, and numerical simulations for a variety of other models, we find that the stochastic QSSA is accurate whenever its deterministic counterpart provides an accurate approximation over a range of initial conditions which cover the likely fluctuations from the quasi steady-state (QSS). We conjecture that this relationship provides a simple and computationally inexpensive way to test the accuracy of reduced stochastic models using deterministic simulations. CONCLUSIONS: The stochastic QSSA is one of the most popular multi-scale stochastic simulation methods. While the use of QSSA, and the resulting non elementary functions has been justified in the deterministic case, it is not clear when their stochastic counterparts are accurate. In this study, we show how the accuracy of the stochastic QSSA can be tested using their deterministic counterparts providing a concrete method to test when non-elementary rate functions can be used in stochastic simulations. PMID- 26597160 TI - Identification and characterization of a new G-quadruplex forming region within the kRAS promoter as a transcriptional regulator. AB - kRAS is one of the most prevalent oncogenic aberrations. It is either upregulated or mutationally activated in a multitude of cancers, including pancreatic, lung, and colon cancers. While a significant effort has been made to develop drugs that target kRAS, their clinical activity has been disappointing due to a variety of mechanistic hurdles. The presented works describe a novel mechanism and molecular target to downregulate kRAS expression--a previously undescribed G-quadruplex (G4) secondary structure within the proximal promoter acting as a transcriptional silencer. There are three distinct guanine-rich regions within the core kRAS promoter, including a previously examined region (G4near). Of these regions, the most distal region does not form an inducible and stable structure, whereas the two more proximal regions (termed near and mid) do form strong G4s. G4near is predominantly a tri-stacked structure with a discontinuous guanine run incorporated; G4mid consists of seven distinct runs of continuous guanines and forms numerous competing isoforms, including a stable three-tetrad stacked mixed parallel and antiparallel loop structures with longer loops of up to 10 nucleotides. Comprehensive analysis of the regulation of transcription by higher order structures has revealed that the guanine-rich region in the middle of the core promoter, termed G4mid, is a stronger repressor of promoter activity than G4near. Using the extensive guanine-rich region of the kRAS core promoter, and particularly the G4mid structure, as the primary target, future drug discovery programs will have potential to develop a potent, specifically targeted small molecule to be used in the treatment of pancreatic, ovarian, lung, and colon cancers. PMID- 26597161 TI - Identification and characterization of microsatellite loci in two socially complex old world tropical babblers (Family Timaliidae). AB - BACKGROUND: Although the highest diversity of birds occurs in tropical regions, little is known about the genetic mating systems of most tropical species. We describe microsatellite markers isolated in the chestnut-crested yuhina (Staphida everetti), endemic to the island of Borneo, and the grey-throated babbler (Stachyris nigriceps), widely distributed across Southeast Asia. Both species belong to the avian family Timaliidae and are highly social, putatively cooperatively breeding birds in which helpers attend the nests of members of their social group. We obtained DNA from individuals in social groups breeding in Kinabalu Park, Malaysian Borneo. RESULTS: We used a shotgun sequencing approach and 454-technology to identify 36 microsatellite loci in the yuhina and 40 in the babbler. We tested 13 primer pairs in yuhinas and 20 in babblers and characterized eight polymorphic loci in 20 unrelated female yuhinas and 21 unrelated female babblers. Polymorphism at the yuhina loci ranged from 3 to 9 alleles, observed heterozygosities from 0.58 to 1.00, and expected heterozygosities from 0.64 to 0.81. Polymorphism at the babbler loci ranged from 3 to 12 alleles, observed heterozygosities from 0.14 to 0.90 and expected heterozygosities from 0.14 to 0.87. One locus in the yuhina deviated significantly from Hardy-Weinberg equilibrium. We detected nonrandom allele associations between two pairs of microsatellite loci in each species. CONCLUSIONS: Microsatellite markers will be used to describe the genetic mating system of these socially complex species and to measure genetic parentage and relatedness within social groups. PMID- 26597162 TI - Airway epithelial dual oxidase 1 mediates allergen-induced IL-33 secretion and activation of type 2 immune responses. AB - BACKGROUND: The IL-1 family member IL-33 plays a critical role in type 2 innate immune responses to allergens and is an important mediator of allergic asthma. The mechanisms by which allergens provoke epithelial IL-33 secretion are still poorly understood. OBJECTIVE: Based on previous findings indicating involvement of the NADPH oxidase dual oxidase 1 (DUOX1) in epithelial wound responses, we explored the potential involvement of DUOX1 in allergen-induced IL-33 secretion and potential alterations in airways of asthmatic patients. METHODS: Cultured human or murine airway epithelial cells or mice were subjected to acute challenge with Alternaria alternata or house dust mite, and secretion of IL-33 and activation of subsequent type 2 responses were determined. The role of DUOX1 was explored by using small interfering RNA approaches and DUOX1-deficient mice. Cultured nasal epithelial cells from healthy subjects or asthmatic patients were evaluated for DUOX1 expression and allergen-induced responses. RESULTS: In vitro or in vivo allergen challenge resulted in rapid airway epithelial IL-33 secretion, which depended critically on DUOX1-mediated activation of epithelial epidermal growth factor receptor and the protease calpain-2 through a redox dependent mechanism involving cysteine oxidation within epidermal growth factor receptor and the tyrosine kinase Src. Primary nasal epithelial cells from patients with allergic asthma were found to express increased DUOX1 and IL-33 levels and demonstrated enhanced IL-33 secretion in response to allergen challenge compared with values seen in nasal epithelial cells from nonasthmatic subjects. CONCLUSION: Our findings implicate epithelial DUOX1 as a pivotal mediator of IL-33-dependent activation of innate airway type 2 immune responses to common airborne allergens and indicate that enhanced DUOX1 expression and IL 33 secretion might present important contributing features of allergic asthma. PMID- 26597163 TI - Atopic endotype in childhood. AB - BACKGROUND: The term atopic disorder is an early attempt to define specific endotypes of children with asthma, eczema, or both and increased IgE levels. OBJECTIVE: We performed a longitudinal analysis of the relevance of the atopic endotype from birth to age 13 years. METHODS: Allergic sensitization against 28 inhalant and food allergens was assessed at 1/2, 11/2, 4, 6, and 13 years of age in 399 children from the Copenhagen Prospective Study on Asthma in Childhood2000 birth cohort by using both skin prick test responses and specific IgE levels. Asthma and eczema were diagnosed longitudinally by strictly adhering to predefined algorithms. Associations between allergic sensitization, asthma, and eczema were estimated by means of logistic regression, and a machine learning approach was used to identify temporal phenotype clusters of these traits. RESULTS: Allergic sensitization showed no association with asthma through early childhood (0-6 years) when analyzed as any sensitization (odds ratio [OR] range, 0.78-1.29; P >= .48). However, at 13 years of age, any sensitization was associated with asthma (OR range, 4.02-5.94; all P < .001). In contrast, any sensitization was associated with eczema at 1/2, 11/2, and 6 years of age (OR range, 2.06-6.02; P <= .01) and borderline associated at 4 years of age (OR, 1.61 [95% CI, 0.96-2.69]; P = .07) but not at 13 years of age (OR, 1.57 [95% CI, 0.78 3.16]; P = .21). We identified 4 latent patterns of disease development that were either dominated by sensitization (37%), eczema (26%), asthma (14%), or healthy status (24%). CONCLUSION: We found very little interdependency between asthma, eczema, and allergic sensitization through childhood. The associations between those entities were strongly dependent on age, type of allergens, and method of testing for sensitization. Therefore, atopy in children is unlikely to represent a true endotype. PMID- 26597165 TI - Transvenous Lead Extraction of Cardiac Implantable Electronic Devices: Who, When, How and Where? PMID- 26597164 TI - RNA sequencing of transcriptomes in human brain regions: protein-coding and non coding RNAs, isoforms and alleles. AB - BACKGROUND: We used RNA sequencing to analyze transcript profiles of ten autopsy brain regions from ten subjects. RNA sequencing techniques were designed to detect both coding and non-coding RNA, splice isoform composition, and allelic expression. Brain regions were selected from five subjects with a documented history of smoking and five non-smokers. Paired-end RNA sequencing was performed on SOLiD instruments to a depth of >40 million reads, using linearly amplified, ribosomally depleted RNA. Sequencing libraries were prepared with both poly-dT and random hexamer primers to detect all RNA classes, including long non-coding (lncRNA), intronic and intergenic transcripts, and transcripts lacking poly-A tails, providing additional data not previously available. The study was designed to generate a database of the complete transcriptomes in brain region for gene network analyses and discovery of regulatory variants. RESULTS: Of 20,318 protein coding and 18,080 lncRNA genes annotated from GENCODE and lncipedia, 12 thousand protein coding and 2 thousand lncRNA transcripts were detectable at a conservative threshold. Of the aligned reads, 52 % were exonic, 34 % intronic and 14 % intergenic. A majority of protein coding genes (65 %) was expressed in all regions, whereas ncRNAs displayed a more restricted distribution. Profiles of RNA isoforms varied across brain regions and subjects at multiple gene loci, with neurexin 3 (NRXN3) a prominent example. Allelic RNA ratios deviating from unity were identified in > 400 genes, detectable in both protein-coding and non-coding genes, indicating the presence of cis-acting regulatory variants. Mathematical modeling was used to identify RNAs stably expressed in all brain regions (serving as potential markers for normalizing expression levels), linked to basic cellular functions. An initial analysis of differential expression analysis between smokers and nonsmokers implicated a number of genes, several previously associated with nicotine exposure. CONCLUSIONS: RNA sequencing identifies distinct and consistent differences in gene expression between brain regions, with non-coding RNA displaying greater diversity between brain regions than mRNAs. Numerous RNAs exhibit robust allele selective expression, proving a means for discovery of cis-acting regulatory factors with potential clinical relevance. PMID- 26597166 TI - Early developmental intervention programmes provided post hospital discharge to prevent motor and cognitive impairment in preterm infants. AB - BACKGROUND: Infants born preterm are at increased risk of developing cognitive and motor impairment compared with infants born at term. Early developmental interventions have been provided in the clinical setting with the aim of improving overall functional outcomes for these infants. Long-term benefits of these programmes remain unclear. OBJECTIVES: Primary objective To compare the effectiveness of early developmental intervention programmes provided post hospital discharge to prevent motor or cognitive impairment in preterm (< 37 weeks) infants versus standard medical follow-up of preterm infants at infancy (zero to < three years), preschool age (three to < five years), school age (five to < 18 years) and adulthood (>= 18 years). Secondary objectives To perform subgroup analyses to determine the following.* Effects of gestational age, birth weight and brain injury (periventricular leukomalacia (PVL)/intraventricular haemorrhage (IVH)) on cognitive and motor outcomes when early intervention is compared with standard follow-up. ? Gestational age: < 28 weeks, 28 to < 32 weeks, 32 to < 37 weeks. ? Birth weight: < 1000 grams, 1000 to < 1500 grams, 1500 to < 2500 grams. ? Brain injury: absence or presence of grade III or grade IV IVH or cystic PVL (or both) or an abnormal ultrasound/magnetic resonance image (MRI) before initiation of the intervention.* Effects of interventions started during inpatient stay with a post-discharge component versus standard follow-up care.* Effects of interventions focused on the parent-infant relationship, infant development or both compared with standard follow-up care.To perform sensitivity analysis to identify the following.* Effects on motor and cognitive impairment when early developmental interventions are provided within high-quality randomised trials with low risk of bias for sequence generation, allocation concealment, blinding of outcome measures and selective reporting bias. SEARCH METHODS: The search strategy of the Cochrane Neonatal Review Group was used to identify randomised and quasi-randomised controlled trials of early developmental interventions provided post hospital discharge. Two review authors independently searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE Advanced, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO and EMBASE (1966 to August 2015). SELECTION CRITERIA: Studies included had to be randomised or quasi-randomised controlled trials of early developmental intervention programmes that began within the first 12 months of life for infants born before 37 weeks' gestational age. Interventions could commence on an inpatient basis but had to include a post-discharge component for inclusion in this review. Outcome measures were not prespecified, other than that they had to assess cognitive outcomes, motor outcomes or both. Rates of cerebral palsy were documented. DATA COLLECTION AND ANALYSIS: Two independent review authors extracted and entered data. Cognitive and motor outcomes were pooled by four age groups: infancy (zero to < three years), preschool age (three to < five years), school age (five to < 18 years) and adulthood (>= 18 years). Meta-analysis using RevMan 5.1 was carried out to determine the effects of early developmental interventions at each age range. Subgroup analyses focused on gestational age, birth weight, brain injury, commencement of the intervention, focus of the intervention and study quality. MAIN RESULTS: Twenty-five studies met the inclusion criteria (3615 randomly assigned participants). Only 12 of these studies were randomised controlled trials with appropriate allocation concealment. Variability was evident with regard to focus and intensity of the intervention, participant characteristics and length of follow-up. Meta-analysis led to the conclusion that intervention improved cognitive outcomes at infancy (developmental quotient (DQ): standardised mean difference (SMD) 0.32 standard deviations (SDs), 95% confidence interval (CI) 0.16 to 0.47; P value < 0.001; 16 studies; 2372 participants) and at preschool age (intelligence quotient (IQ); SMD 0.43 SDs, 95% CI 0.32 to 0.54; P value < 0.001; eight studies; 1436 participants). However, this effect was not sustained at school age (IQ: SMD 0.18 SDs, 95% CI -0.08 to 0.43; P value = 0.17; five studies; 1372 participants). Heterogeneity between studies for cognitive outcomes at infancy and at school age was significant. With regards to motor outcomes, meta-analysis of 12 studies showed a significant effect in favour of early developmental interventions at infancy only; however, this effect was small (motor scale DQ: SMD 0.10 SDs, 95% CI 0.01 to 0.19; P value = 0.03; 12 studies; 1895 participants). No effect was noted on the rate of cerebral palsy among survivors (risk ratio (RR) 0.82, 95% CI 0.52 to 1.27; seven studies; 985 participants). Little evidence showed a positive effect on motor outcomes in the long term, but only five included studies reported outcomes at preschool age (n = 3) or at school age (n = 2). AUTHORS' CONCLUSIONS: Early intervention programmes for preterm infants have a positive influence on cognitive and motor outcomes during infancy, with cognitive benefits persisting into preschool age. A great deal of heterogeneity between studies was due to the variety of early developmental intervention programmes tested and to gestational ages of included preterm infants; thus, comparisons of intervention programmes were limited. Further research is needed to determine which early developmental interventions are most effective in improving cognitive and motor outcomes, and to discern the longer-term effects of these programmes. PMID- 26597167 TI - The human gut microbial ecology associated with overweight and obesity determines ellagic acid metabolism. AB - We recently identified three metabotypes (0, A and B) that depend on the metabolic profile of urolithins produced from polyphenol ellagic acid (EA). The gut microbiota and Gordonibacter spp. recently were identified as species able to produce urolithins. A higher percentage of metabotype B was found in patients with metabolic syndrome or colorectal cancer in comparison with healthy individuals. The aim of the present study was to analyse differences in EA metabolism between healthy overweight-obese and normoweight individuals and evaluate the role of gut microbial composition including Gordonibacter. Although the three metabotypes were confirmed in both groups, metabotype B prevailed in overweight-obese (31%) versus normoweight (20%) individuals while metabotype A was higher in normoweight (70%) than the overweight-obese group (57%). This suggests that weight gain favours the growth of bacteria capable of producing urolithin B and/or isourolithin A with respect to urolithin A-producing bacteria. Gordonibacter spp. levels were not significantly different between normoweight and overweight-obese groups but higher Gordonibacter levels were found in metabotype A individuals than in those with metabotype B. Other bacterial species have been reported to show a much closer relationship to obesity and dysbiosis than Gordonibacter. However, Gordonibacter levels are negatively correlated with metabotype B, which prevails in metabolic syndrome and colorectal cancer. This is the first report that links overweight and obesity with an alteration in the catabolism of EA, and where the correlation of Gordonibacter to this alteration is shown. Future investigation of Gordonibacter and urolithin metabotypes as potential biomarkers or therapeutic targets of obesity-related diseases is warranted. PMID- 26597168 TI - General and abdominal adiposity in a representative sample of Portuguese adults: dependency of measures and socio-demographic factors' influence - CORRIGENDUM. PMID- 26597169 TI - Early Postoperative Outcome of Off-Pump Coronary Artery Bypass Grafting: A Report from the Highest-Volume Center in Japan. AB - BACKGROUND: Off-pump coronary artery bypass grafting (OPCAB) has evolved into a standard technique in coronary artery bypass grafting. However, a detailed investigation in Japanese population undergoing OPCAB has not yet been fully elucidated. METHODS: A total of 1109 consecutive patients undergoing isolated OPCAB between 2006 and 2013 at Juntendo University were reviewed. The data was evaluated in the light of previously published OPCAB-associated reports. RESULTS: There were 904 male (81.5%) and a mean was 67.5 +/- 9.8 years. Eight patients (0.5%) died within 30 days postoperatively or before discharge, which was equivalent to or rather better than the previously reported mortality rates, including the European System for Cardiac Operation Risk Evaluation II (2.1 +/- 2.1) data. A morbidity analysis revealed that prolonged intubation (>24 h) occurred in 43 patients (3.6%), surgical site infections in 18 (1.9%), neurological complications in 13 (1.3%). A reduced preoperative left ventricular ejection fraction (less than 40%) was found to be a risk factor for early postoperative death (odds ratio 10.58, respectively, p <0.05) in our cohort. CONCLUSIONS: Early postoperative mortality and morbidity rates in Japanese population after OPCAB were rather satisfactory and similar to those reported by other countries. PMID- 26597170 TI - Determination of sex from various hand dimensions of Koreans. AB - In the case of disasters or crime scenes, forensic anthropometric methods have been utilized as a reliable way to quickly confirm the identification of victims using only a few parts of the body. A total of 321 measurement data (from 167 males and 154 females) were analyzed to investigate the suitability of detailed hand dimensions as discriminators of sex. A total of 29 variables including length, breadth, thickness, and circumference of fingers, palm, and wrist were measured. The obtained data were analyzed using descriptive statistics and t test. The accuracy of sex indication from the hand dimensions data was found using discriminant analysis. The age effect and interaction effect according to age and sex on hand dimensions were analyzed by ANOVA. The prediction accuracy on a wide age range was also compared. According to the results, the maximum hand circumference showed the highest accuracy of 88.6% for predicting sex for males and 89.6% for females. Although the breadth, circumference, and thickness of hand parts generally showed higher accuracy than the lengths of hand parts in predicting the sex of the participant, the breadth and circumference of some finger joints showed a significant difference according to age and gender. Thus, the dimensions of hand parts which are not affected by age or gender, such as hand length, palm length, hand breadth, and maximum hand thickness, are recommended to be used first in sex determination for a wide age range group. The results suggest that the detailed hand dimensions can also be used to identify sex for better accuracy; however, the aging effects need to be considered in estimating aged suspects. PMID- 26597172 TI - Single-Institution Experience with Robotic Partial Nephrectomy for Renal Masses Greater Than 4 cm. AB - PURPOSE: To review our institution's experience with robotic partial nephrectomy (RPN) for T1b and greater renal masses (>4 cm [T1b+]) in terms of perioperative and oncologic outcomes relative to a contemporary cohort of patients with T1a renal masses (<4 cm). PATIENTS AND METHODS: 232 patients underwent RPN at our institution between 2008 and 2014. Demographics, R.E.N.A.L. nephrometry score, and operative, pathologic, and renal function outcomes, as well as complications, were compared between the two groups (T1a vs T1b+). RESULTS: A total of 168 and 64 patients underwent RPN for T1a and T1b+ renal masses, respectively. T1b+ patients had a higher mean nephrometry score (8.2 vs 6.9), median pathologic tumor size (4.8 vs 2.6 cm), median blood loss (200 vs 100 mL), median warm ischemia time (23 vs 21 minutes), rate of conversion to radical nephrectomy (7.8% vs 1.2%), and rate of Clavien grade III or higher complications (14% vs 4.2%) compared with T1a patients. One patient was found to have disease recurrence in the T1a group, and no patients experienced recurrence in the T1b+ group. No patient died from the disease. CONCLUSIONS: The current series represents the largest single-institutional report of RPN for tumors >4 cm. The higher complexity of tumors resected in this series did not preclude a safe and oncologically efficacious operation; however, Clavien grade III complications were more common in patients with tumors >4 cm, likely from a higher rate of pseudoaneurysm. These data should be considered in preoperative counseling with patients before RPN for tumors >4 cm. PMID- 26597171 TI - Classification of Parkinson's Disease Genotypes in Drosophila Using Spatiotemporal Profiling of Vision. AB - Electrophysiological studies indicate altered contrast processing in some Parkinson's Disease (PD) patients. We recently demonstrated that vision is altered in Drosophila PD models and hypothesised that different types of genetic and idiopathic PD may affect dopaminergic visual signalling pathways differently. Here we asked whether visual responses in Drosophila could be used to identify PD mutations. To mimic a clinical setting a range of flies was used. Young flies from four control lines were compared to three early-onset PD mutations (PINK1, DJ-1alpha and DJ-1beta), and to two other neurodegenerative mutations, one in the fly LRRK2 orthologue (dLRRK) the other in eggroll, a model of general neurodegeneration in Drosophila. Stimuli were contrast reversing gratings spanning 64 spatiotemporal frequency combinations. We recorded the steady-state visually-evoked response amplitude across all combinations. We found that the pattern of neuronal responses differed between genotypes. Wild-type and early onset PD flies formed separate clusters; the late-onset mutation is an outlier. Neuronal responses in early-onset PD flies were stronger than in wild-types. Multivariate pattern analysis grouped flies by PD/non-PD genotype with an accuracy >85%. We propose that machine learning algorithms may be useful in increasing the diagnostic specificity of human electrophysiological measurements in both animal models and PD patients. PMID- 26597173 TI - Processing of frequency and location in human subcortical auditory structures. AB - To date it remains largely unknown how fundamental aspects of natural sounds, such as their spectral content and location in space, are processed in human subcortical structures. Here we exploited the high sensitivity and specificity of high field fMRI (7 Tesla) to examine the human inferior colliculus (IC) and medial geniculate body (MGB). Subcortical responses to natural sounds were well explained by an encoding model of sound processing that represented frequency and location jointly. Frequency tuning was organized in one tonotopic gradient in the IC, whereas two tonotopic maps characterized the MGB reflecting two MGB subdivisions. In contrast, no topographic pattern of preferred location was detected, beyond an overall preference for peripheral (as opposed to central) and contralateral locations. Our findings suggest the functional organization of frequency and location processing in human subcortical auditory structures, and pave the way for studying the subcortical to cortical interaction required to create coherent auditory percepts. PMID- 26597174 TI - Hypertonic saline (HS) for acute bronchiolitis: Systematic review and meta analysis. AB - BACKGROUND: Acute bronchiolitis is the commonest cause of hospitalisation in infancy. Currently management consists of supportive care and oxygen. A Cochrane review concluded that, "nebulised 3 % saline may significantly reduce the length of hospital stay". We conducted a systematic review of controlled trials of nebulised hypertonic saline (HS) for infants hospitalised with primary acute bronchiolitis. METHODS: Searches to January 2015 involved: Cochrane Central Register of Controlled Trials; Ovid MEDLINE; Embase; Google Scholar; Web of Science; and, a variety of trials registers. We hand searched Chest, Paediatrics and Journal of Paediatrics on 14 January 2015. Reference lists of eligible trial publications were checked. Randomised or quasi-randomised trials which compared HS versus either normal saline (+/- adjunct treatment) or no treatment were included. Eligible studies involved children less than 2 years old hospitalised due to the first episode of acute bronchiolitis. Two reviewers extracted data to calculate mean differences (MD) and 95 % Confidence Intervals (CIs) for length of hospital stay (LoS-primary outcome), Clinical Severity Score (CSS) and Serious Adverse Events (SAEs). Meta-analysis was undertaken using a fixed effect model, supplemented with additional sensitivity analyses. We investigated statistical heterogeneity using I(2). Risk of bias, within and between studies, was assessed using the Cochrane tool, an outcome reporting bias checklist and a funnel plot. RESULTS: Fifteen trials were included in the systematic review (n = 1922), HS reduced mean LoS by 0.36, (95 % CI 0.50 to 0.22) days, but with considerable heterogeneity (I(2) = 78 %) and sensitivity to alternative analysis methods. A reduction in CSS was observed where assessed [n = 516; MD -1.36, CI -1.52, 1.20]. One trial reported one possible intervention related SAE, no other studies described intervention related SAEs. CONCLUSIONS: There is disparity between the overall combined effect on LoS as compared with the negative results from the largest and most precise trials. Together with high levels of heterogeneity, this means that neither individual trials nor pooled estimates provide a firm evidence base for routine use of HS in inpatient acute bronchiolitis. PMID- 26597175 TI - Structures of the CDK12/CycK complex with AMP-PNP reveal a flexible C-terminal kinase extension important for ATP binding. AB - Cyclin-dependent kinase 12 (CDK12) promotes transcriptional elongation by phosphorylation of the RNA polymerase II C-terminal domain (CTD). Structure function studies show that this activity is dependent on a C-terminal kinase extension, as well as the binding of cyclin K (CycK). To better define these interactions we determined the crystal structure of the human CDK12/CycK complex with and without the kinase extension in the presence of AMP-PNP. The structures revealed novel features for a CDK, including a large beta4-beta5 loop insertion that contributes to the N-lobe interaction with the cyclin. We also observed two different conformations of the C-terminal kinase extension that effectively open and close the ATP pocket. Most notably, bound AMP-PNP was only observed when trapped in the closed state. Truncation of this C-terminal structure also diminished AMP-PNP binding, as well as the catalytic activity of the CDK12/CycK complex. Further kinetic measurements showed that the full length CDK12/CycK complex was significantly more active than the two crystallised constructs suggesting a critical role for additional domains. Overall, these results demonstrate the intrinsic flexibility of the C-terminal extension in CDK12 and highlight its importance for both ATP binding and kinase activity. PMID- 26597176 TI - Somatic and germline analyses of a long term melanoma survivor with a recurrent brain metastasis. AB - BACKGROUND: Median overall survival (OS) of patients with melanoma brain metastases (MBM) is usually 6 months or less. There are rare reports of patients with treated MBM who survived for years. These outlier cases represent valuable opportunities to study the somatic and germline factors that may have influenced patient outcome and led to extended survival. CASE PRESENTATION: Here we report the clinical scenario of a 67 year old man with a recurrent brain metastasis from melanoma who has survived over 12 years post-resection. We review the literature relating to clinical and molecular variables associated with long term survival post-brain metastasis. We present the somatic characteristics of this individual patient's tumor as well as an analysis of inherited genetic variants related to immune function. The patient's resected brain tumor is BRAF V600E mutated, NRAS wild type (WT), and TERT C250T mutated. The patient is a carrier of germline variants in immunomodulatory loci associated with prolonged survival. CONCLUSIONS: Our data suggest that genetic variants in immunomodulatory loci may partially contribute to this patient's unusually favorable outcome and should not be overlooked. With further and future investigation, knowledge of inherited single nucleotide polymorphisms (SNPs) may provide clinicians with more individualized prognostic information for melanoma patients, with potential implications for surveillance strategies and therapeutic interventions. PMID- 26597178 TI - Acute toxicity profile of craniospinal irradiation with intensity-modulated radiation therapy in children with medulloblastoma: A prospective analysis. AB - BACKGROUND: To report on the acute toxicity in children with medulloblastoma undergoing intensity-modulated radiation therapy (IMRT) with daily intrafractionally modulated junctions. METHODS: Newly diagnosed patients, aged 3 21, with standard-risk (SR) or high-risk (HR) medulloblastoma were eligible. A dose of 23.4 or 36.0 Gy in daily fractions of 1.8 Gy was prescribed to the craniospinal axis, followed by a boost to the primary tumor bed (54 or 55.8 Gy) and metastases (39.6-55.8 Gy), when indicated. Weekly, an intravenous bolus of vincristine was combined for patients with SR medulloblastoma and patients participating in the COG-ACNS-0332 study. Common toxicity criteria (CTC, version 2.0) focusing on skin, alopecia, voice changes, conjunctivitis, anorexia, dysphagia, gastro-intestinal symptoms, headache, fatigue and hematological changes were scored weekly during radiotherapy. RESULTS: From 2010 to 2014, data from 15 consecutive patients (SR, n = 7; HR, n = 8) were collected. Within 72 h from onset of treatment, vomiting (66 %) and headache (46 %) occurred. During week 3 of treatment, a peak incidence in constipation (33 %) and abdominal pain/cramping (40 %) was observed, but only in the subgroup of patients (n = 9) receiving vincristine (constipation: 56 vs 0 %, P = .04; pain/cramping: 67 vs 0 %, P = .03). At week 6, 73 % of the patients developed faint erythema of the cranial skin with dry desquamation (40 %) or moist desquamation confined to the skin folds of the auricle (33 %). No reaction of the skin overlying the spinal target volume was observed. CONCLUSIONS: Headache at onset and gastro-intestinal toxicity, especially in patients receiving weekly vincristine, were the major complaints of patients with medulloblastoma undergoing craniospinal irradiation with IMRT. PMID- 26597179 TI - Pharmacokinetics and Pharmacodynamics of the Nonvitamin K Antagonist Oral Anticoagulant Edoxaban When Administered Alone or After Switching from Rivaroxaban or Dabigatran Etexilate in Healthy Subjects. AB - BACKGROUND AND OBJECTIVES: Edoxaban is an oral, once-daily direct factor Xa inhibitor. To support the possibility that patients may choose to switch treatment from another nonvitamin K antagonist oral anticoagulant to edoxaban, this clinical study was conducted to evaluate the pharmacokinetic and pharmacodynamic effects of edoxaban after switching from rivaroxaban or dabigatran etexilate to edoxaban. METHODS: In this open-label, three-period, crossover study, healthy subjects received 3 days of edoxaban 60 mg daily, rivaroxaban 20 mg daily, or dabigatran etexilate 150 mg twice daily, followed by edoxaban 60 mg on day 4. RESULTS: Day 4 edoxaban pharmacokinetic parameters were similar for all treatments. The peak effect of edoxaban on prothrombin time (PT) after 4 days of edoxaban only was 21.8 +/- 2.46 s; after switching from rivaroxaban to edoxaban, peak effect on PT was similar at 21.8 +/- 2.88 s. After switching from dabigatran etexilate to edoxaban, least squares mean activated partial thromboplastin time (aPTT) at 2 h after administration was 47.6 vs 35.0 s for edoxaban alone. The treatment difference was 12.8 s (95% confidence interval 10.5-15.1; p < 0.0001). Post hoc analysis revealed that predose aPTT was elevated on day 3 of dabigatran etexilate administration, and on day 4, indicating a carryover effect from dabigatran. All treatments were well tolerated and there were no safety concerns upon switching, with no increased risk of bleeding. CONCLUSIONS: The study results suggest that switching to edoxaban from either rivaroxaban or dabigatran etexilate at the time of the next dose is well tolerated and maintains coagulation status. PMID- 26597177 TI - Anti-tumor enhancement of Fei-Liu-Ping ointment in combination with celecoxib via cyclooxygenase-2-mediated lung metastatic inflammatory microenvironment in Lewis lung carcinoma xenograft mouse model. AB - BACKGROUND: Fei-Liu-Ping (FLP) ointment is an oral prescription medication that has been widely applied to treat lung cancer patients in China. Regulation of the metastatic microenvironment is an important therapeutic approach for prevention and treatment of tumor recurrence and metastasis. The advantage of Traditional Chinese Medicine management of lung cancer lies in the prevention of recurrence and metastasis. Our previous study has demonstrated that FLP ointment could regulate lung inflammatory microenvironment in vitro. However, the effects of FLP on the tumor microenvironment in vivo are still poorly understood. The objective of this study is to investigate the effect of FLP alone or in combination with celecoxib in the prevention of lung cancer progression by Cyclooxygenase (Cox)-2 mediated tumor inflammatory microenvironment in vivo. METHODS: 120 Lewis lung carcinoma xenograft mice were divided equally into four groups: vehicle, FLP, celecoxib, and FLP plus celecoxib. The dynamic growth of the xenografted tumors was observed using an in vivo fluorescence imaging system. Mice were sacrificed on day 14, day 21, and day 28, and tumor specimens and lung tissues were harvested to detect the metastasis-associated protein expression. RESULTS: Tumor inhibition rate was 15.4, 44.2, 47.4 % at day 14, 37.3, 34.7, 61.5 % at day 21, and 15.5, 10.3, 32.5 % at day 28 after treatment of FLP, celecoxib, and FLP plus celecoxib, respectively. Upon treatment of FLP and celecoxib together, lung metastasis rate was 30 % (8 metastatic nodules) lower than other groups. FLP inhibited Cox-2 expression in a time-dependent manner. Moreover, FLP inhibited N cadherin, matrix metalloproteinases (MMP)-9, and Vimentin expression. Treatment of FLP in combination with celecoxib was more effective than FLP or celecoxib alone in inhibiting vascular endothelial growth factor, platelet-derived growth factor receptors beta, microsomal Prostaglandin E synthase-1, MMP-2, MMP-9, N cadherin, and Vimentin expression, but increased E-cadherin expression. CONCLUSIONS: FLP inhibited tumor growth and metastasis in a Lewis lung xenograft mice model through the Cox-2 pathway. FLP in combination with celecoxib enhanced the antitumor growth and anti-metastasis effects. Traditional Chinese herbs combined with anti-inflammatory drugs might offer a promising strategy to prevent tumor metastasis. PMID- 26597182 TI - Keeping tobacco products out of sight in shops reduces future risk of smoking in teenagers, US study shows. PMID- 26597180 TI - Pharmacokinetics and Exposure-Response Relationships of Dasotraline in the Treatment of Attention-Deficit/Hyperactivity Disorder in Adults. AB - BACKGROUND AND OBJECTIVES: Dasotraline is a novel inhibitor of dopamine and norepinephrine reuptake currently being investigated in clinical studies for the treatment of attention-deficit/hyperactivity disorder (ADHD). Uniquely, relative to current ADHD medications, dasotraline has a slow absorption and long elimination half-life. Here we relate the pharmacokinetics and pharmacodynamics of dasotraline to reduction in ADHD symptoms based on simulated clinical trial outcomes. METHODS: Dasotraline pharmacokinetics were analyzed by population pharmacokinetic methodologies using data collected from 395 subjects after single or multiple oral dose administrations ranging from 0.2 to 36 mg (three phase I studies and one phase II ADHD study). Population pharmacokinetic and pharmacodynamic models related individual dasotraline exposures to norepinephrine metabolite 3,4-dihydroxyphenylglycol (DHPG) concentrations, ADHD symptoms, and study discontinuation (probability of dropout). RESULTS: Dasotraline pharmacokinetics were described by a one-compartment model with dual (linear plus nonlinear) elimination. In an ADHD population treated with dasotraline 4 or 8 mg/day, dasotraline was characterized by a mean apparent half-life of 47 h and plasma concentrations reached steady-state by 10 days of dosing. A population pharmacokinetic and pharmacodynamic model of DHPG indicated clinically significant norepinephrine transporter inhibition was achieved as a function of time-matched dasotraline concentrations. Dasotraline exposure reduced ADHD symptoms in a sigmoid E max time-course model. Clinical trial simulations described the effects of dose, duration, and sample size on clinical outcomes. CONCLUSION: These results related dasotraline pharmacokinetics to pharmacological activity in ADHD, and support the novel concept that maintaining constant, steady state dopamine and norepinephrine reuptake inhibition throughout a 24-h dosing interval is a novel pharmacological approach to the management of ADHD symptoms. Clinicaltrials.gov identifier: NCT01692782. PMID- 26597181 TI - Comparative Clinical Pharmacokinetics of Midodrine and Its Active Metabolite Desglymidodrine in Cirrhotic Patients with Tense Ascites Versus Healthy Volunteers. AB - OBJECTIVE: Midodrine is an alpha-agonist prodrug of desglymidodrine used for the management of hypotension, and can also be used for hepatorenal syndrome and cirrhotic patients with tense ascites. The objective of the present work was to study the clinical pharmacokinetic parameters of midodrine and its active metabolite desglymidodrine in cirrhotic patients with tense ascites, which may help in dose selection and improve treatment outcome. METHOD: This was a prospective, open-label, single-dose, parallel-group study. At first, a pilot study was performed on one healthy volunteer by taking serial blood samples at scheduled time intervals to validate the method of analysis and sampling times. The full study was then conducted by selecting 12 cirrhotic patients with tense ascites in one group and taking nine blood samples. We also selected five healthy volunteers as the control group and took 11 blood samples. RESULTS: Statistically significant differences were observed between the healthy volunteer group and the patients group in the area under the concentration versus time curve (AUC0-t) and maximum plasma concentration (Cmax) values of midodrine and desglymidodrine. Based on the results of the pharmacokinetic analysis, the patient group was further subdivided into those receiving the interacting drug ranitidine (five patients) and those not receiving the interacting drug (seven patients). CONCLUSIONS: Pharmacokinetic parameters of midodrine can differ significantly in cirrhotic patients with tense ascites from those in healthy individuals. Drug monitoring, dose adjustments, and drug-drug interactions should all be considered during therapy in this vulnerable patient group. PMID- 26597183 TI - Mimicking the Human Brain and More: New Grand Challenge Initiatives. PMID- 26597185 TI - Circulation and in vivo distribution of duck hepatitis A virus types 1 and 3 in infected ducklings. AB - The circulation of duck hepatitis A virus types 1 (DHAV-1) and 3 (DHAV-3) in Southeast Asia has resulted in a continuously changing epidemiological scenario. In this study, a duplex real-time PCR assay for simultaneous quantitative detection of DHAV-1 and DHAV-3 was established, and 200 liver samples from dead ducklings collected from 31 different flocks in Shandong province, China, were tested. Fifty-eight (29.0 %) samples from 13 flocks were positive for DHAV-1 single infection, 113 (56.5 %) samples from 13 other flocks were positive for DHAV-3 single infection, and 24 samples (12.0 %) from four flocks were positive for both viruses. DHAV-1 and DHAV-3 were detected with high viral loads in all of the organs tested (liver, spleen, pancreas, kidney, heart, thymus, bursa of Fabricius and brain). No significant difference in DHAV-1 and DHAV-3 viral loads was found between singly infected and coinfected samples, and there was no correlation between the viral loads of the two viruses and the age of dead ducklings. To the best of our knowledge, this is the first report about the in vivo distribution of DHAV-1 and DHAV-3 in clinically infected ducklings. PMID- 26597186 TI - A new genotype of border disease virus with implications for molecular diagnostics. AB - Border disease virus (BDV) is a (+) single-stranded RNA pestivirus affecting mainly sheep and goats worldwide. Genetic typing of BDV has led to the identification of at least seven major genotypes. This study reports the detection of a BDV strain from a goat in northwestern Italy during routine investigations. Sequence analysis revealed mutations in the 5'-UTR of the virus with implications for BDV molecular diagnostics. Moreover, subsequent phylogenetic analysis based on the combined 5'-UTR and Npro/partial C genes, showed divergence from known BDV genotypes, revealing the detection of a novel pestivirus group, for which we propose the name BDV genotype 8. PMID- 26597187 TI - Molecular characterization of infectious bursal disease viruses detected in vaccinated commercial broiler flocks in Lusaka, Zambia. AB - Infectious bursal disease (IBD) is an acute, highly contagious, and immunosuppressive viral disease of young chickens and remains one of the economically most important diseases threatening the poultry industry worldwide. In this study, 16 and 11 nucleotide sequences of the VP2 hypervariable region (VP2-HVR) and part of VP1, respectively, of IBD virus (IBDV) detected in vaccinated broiler chickens in Lusaka in 2012 were determined. Phylogenetic analysis revealed that these Zambian IBDVs separated into three genotypes of very virulent (VV) IBDVs. Although the majority of these viruses belonged to the African VV type (VV1), which consisted of viruses from West Africa, South Africa and Zambia, one virus belonged to the East African VV type (VV2). Interestingly, a Zambian IBDV belonging to the VV3 genotype (composed of viruses from several continents) clustered with attenuated vaccine strains. Although sequence analysis of VP2-HVR showed that all detected Zambian IBDVs had conserved putative virulence marker amino acids (i.e., 222A, 242I, 256I, 294I and 299S), one virus had two unique amino acid substitutions, N280S and E300A. This study demonstrates the diversity of Zambian IBDVs and documents for the first time the possible involvement of attenuated vaccine strains in the epidemiology of IBD in Zambia. Strict biosecurity of poultry farms, monitoring of live vaccine use in the field, surveillance and characterization of IBDV in poultry and development of a vaccine from local or regional IBDV field strains are recommended for improved IBD control in Zambia. PMID- 26597188 TI - Activation of Toll-like receptor 3 inhibits Marek's disease virus infection in chicken embryo fibroblast cells. AB - Toll-like receptor 3 (TLR3) is a critical component of the innate immune system against viral infection and controls the activation of adaptive immunity. The role of TLR3 in Marek's disease virus (MDV) infection is not clear. In this study, we found that the abundance of TLR3 mRNA was significantly higher in chicken embryo fibroblast cells (CEF) infected with MDV than in a control group. Activated TLR3 signaling via TLR3 ligand stimulation inhibited replication of the RB1B strain of MDV in CEF cells. In contrast, CEF cells transfected with TLR3 siRNA promoted RB1B infection and replication. However, treatment with other TLR ligands, whether stimulatory (LPS, imiquimod and CpG) or inhibitory (TLR2/4 inhibitor and/or MyD88 inhibitor), had little effect on RB1B infection and replication. In addition, we found that the expression trend of TLR3 mRNA in RB1B infected CEF cells was similar to that of mdv1-mir-M4-5p (a functional ortholog of oncogenic miR-155 encoded by MDV). Inconsistent with this, the TLR3 protein level was sharply reduced in RB1B-infected CEF cells at 96 hpi, while there was an at least 200-fold increase in miR-M4-5p at the same time point. Additionally, CEF cells transfected with an mdv1-mir-M4-5p mimic promoted RB1B infection and replication, while an mdv1-mir-M4-5p inhibitor inhibited RB1B infection and replication. Similar results were observed in CEF cells transfected with a gga miR-155 mimic or inhibitor. These findings suggest that TLR3 and MDV-encoded miRNAs might be involved in MDV infection. PMID- 26597189 TI - Molecular diversity of bovine viral diarrhea virus in uruguay. AB - Bovine viral diarrhea (BVD) affects bovine production and reproduction causing significant economic losses all over the world. Two viral species has been recognized: BVDV-1 and BVDV-2, both distributed worldwide. Recently, novel specie of BVDV named HoBi-like pestivirus was discovered. The presence of BVDV was confirmed in 1996 in Uruguay, however, does not exist until today a schedule of compulsory vaccination along the country. Serological studies with samples from all Uruguayan herds were performed during 2000 and 2001 demonstrating that all of them were seropositive to BVDV with a mean prevalence of 69%. In addition, there have been no new studies done since those previously described and it is important to mention that the genetic diversity of BVD has never been described in Uruguay. Nowadays, there is strongly suspect that BVDV is one of the most important causes of reproductive failures in our herds. The aim of this study was to describe for the first time in Uruguay the genetic diversity of BVDV with samples collected from different regions along the country. Serological status of 390 non-vaccinated animals against BVDV with reproductive problems from farms of Rivera, Tacuarembo and Florida departments of Uruguay were studied. All herds were seropositive to BVDV and high proportion of animals were positive (298/390), while 4.1% (16/390) of the animals were positive to Antigen Capture ELISA test and Real Time PCR. Phylogenetic analysis performed with concatenated sequences from the 5'UTR and Npro genomic regions revealed that BVDV-1 and BVDV-2 are infecting our herds, being BVDV-1 the most frequently found. The major subtype was BVDV-1a, followed by BVDV-1i and BVDV-2b. This is the first study that describes the genetic diversity of BVDV in Uruguay and it will contribute to the elaboration of sanitization programs. PMID- 26597190 TI - Altered Expression of Transporters, its Potential Mechanisms and Influences in the Liver of Rodent Models Associated with Diabetes Mellitus and Obesity. AB - Diabetes mellitus is becoming an increasingly prevalent disease that concerns patients and healthcare professionals worldwide. Among many anti-diabetic agents in clinical uses, numerous reports are available on their altered pharmacokinetics because of changes in the expression of drug transporters and metabolic enzymes under diabetic states. These changes may affect the safety and efficacy of therapeutic agents and/or drug-drug interaction with co-administered agents. Therefore, the changes in transporter expression should be identified, and the underlying mechanisms should be clarified. This review summarizes the progress of recent studies on the alterations in important uptake and efflux transporters in liver of diabetic animals and their regulatory pathways. PMID- 26597191 TI - Subclinical Inflammation and Endothelial Dysfunction in Patients with Chronic Pancreatitis and Newly Diagnosed Pancreatic Cancer. AB - BACKGROUND: Recent studies have suggested that various cytokines may be important players in the development and progression of chronic pancreatitis (CP) and pancreatic adenocarcinoma (PC). AIMS: We studied endothelial dysfunction and subclinical inflammation in patients with newly diagnosed pancreatic adenocarcinoma and CP. METHODS: A total of 45 patients were included in the present investigation, 27 with CP and 18 with PC. In addition, the study included 13 age- and body weight-matched healthy subjects served as controls. In all subjects, plasma adiponectin, TNF-alfa, interleukin 6 (IL-6), interleukin 1beta (IL-1beta), E-selectin, thrombomodulin, adhesion molecules ICAM and VCAM, and endothelin-1 were assessed. RESULTS: PC and CP patients as compared with controls had significantly greater plasma adiponectin (13,292 and 12,227 vs 5408 ng/ml; p < 0.0003), TNF-alfa (22.1 and 23.1 vs 13 pg/ml; p < 0.0002), and IL-6 (6.6 and 7.3 vs 3.3 pg/ml; p < 0.0001). Moreover, there was significantly higher concentration of ICAM (931 and 492 vs 290 ng/ml; p < 0.005) and VCAM (1511 and 1080 vs 840 ng/ml; p < 0.01) in PC and CP patients. When PC and CP patients with and without diabetes were considered separately, there was no difference in adiponectin, cytokines, and parameters of endothelial dysfunction. CONCLUSION: In summary, our data indicate that patients with CP and PC express high levels of several cytokines compared with healthy individuals, especially adiponectin, TNF alpha and IL-6. Serum TNF-alpha and ICAM concentrations coordinately increase in advanced CP. Furthermore, especially in PC subjects, elevated markers of endothelial dysfunction are present. This study provides additional evidence that changes in inflammatory cytokine and adhesion molecules in PC and CP are not likely related to endocrine disorders. PMID- 26597193 TI - [Erratum to: Cardiac post-resuscitation care : An indication for trauma whole body CT?]. PMID- 26597192 TI - A Text Searching Tool to Identify Patients with Idiosyncratic Drug-Induced Liver Injury. AB - BACKGROUND: Idiosyncratic drug-induced liver injury (DILI) is an uncommon but important cause of liver disease that is challenging to diagnose and identify in the electronic medical record (EMR). AIM: To develop an accurate, reliable, and efficient method of identifying patients with bonafide DILI in an EMR system. METHODS: In total, 527,000 outpatient and ER encounters in an EPIC-based EMR were searched for potential DILI cases attributed to eight drugs. A searching algorithm that extracted 200 characters of text around 14 liver injury terms in the EMR were extracted and collated. Physician investigators reviewed the data outputs and used standardized causality assessment methods to adjudicate the potential DILI cases. RESULTS: A total of 101 DILI cases were identified from the 2564 potential DILI cases that included 62 probable DILI cases, 25 possible DILI cases, nine historical DILI cases, and five allergy-only cases. Elimination of the term "liver disease" from the search strategy improved the search recall from 4 to 19 %, while inclusion of the four highest yield liver injury terms further improved the positive predictive value to 64 % but reduced the overall case detection rate by 47 %. RUCAM scores of the 57 probable DILI cases were generally high and concordant with expert opinion causality assessment scores. CONCLUSIONS: A novel text searching tool was developed that identified a large number of DILI cases from a widely used EMR system. A computerized extraction of dictated text followed by the manual review of text snippets can rapidly identify bona fide cases of idiosyncratic DILI. PMID- 26597194 TI - [Acute posterior dislocation of the sternoclavicular joint: Reduction, fixation by endobutton system and alternative procedures]. AB - Acute posterior dislocation of the sternoclavicular (SC) joint is rare but can lead to life-threatening vascular injuries of the mediastinum; however, diagnosis is difficult and the injury can be initially overlooked so that surgical treatment is delayed. Although a variety of different treatment modalities have been published, the ideal fixation technique has not yet been identified. We report the case of a patient suffering from a locked posterior SC joint dislocation caused by a skiing accident. The injury was treated by transarticular endobutton fixation. This article describes the technique and highlights its advantages and disadvantages in comparison to previously published treatment options. PMID- 26597195 TI - [Bilateral hand salvage of subtotal left hand amputation and complex right wrist destruction]. AB - Complex injuries of the hand and wrist lead to severe loss of function. Complex trauma of the upper extremities may lead to severe disabilities and therefore meticulous reconstruction is of utmost importance to enable good functional outcome and to assure an adequate quality of life. We demonstrate the case of a patient who suffered from complex bilateral injuries at the wrist level including a subtotal amputation of the left hand and third degree open wrist destruction on the contralateral side. Due to the immediate bilateral operation including the unilateral use of an osteocutaneous free fibula flap, both hands could be salvaged in this case. Severe hand and wrist injuries also require intensive postoperative treatment including intensive physiotherapy, occupational therapy, pain therapy and psychological support to achieve a good functional result. PMID- 26597196 TI - The Complexity of Jokes Is Limited by Cognitive Constraints on Mentalizing. AB - Although laughter is probably of deep evolutionary origin, the telling of jokes, being language-based, is likely to be of more recent origin within the human lineage. In language-based communication, speaker and listener are engaged in a process of mutually understanding each other's intentions (mindstates), with a conversation minimally requiring three orders of intentionality. Mentalizing is cognitively more demanding than non-mentalizing cognition, and there is a well attested limit at five orders in the levels of intentionality at which normal adult humans can work. Verbal jokes commonly involve commentary on the mindstates of third parties, and each such mindstate adds an additional level of intentionality and its corresponding cognitive load. We determined the number of mentalizing levels in a sample of jokes told by well-known professional comedians and show that most jokes involve either three or five orders of intentionality on the part of the comedian, depending on whether or not the joke involves other individuals' mindstates. Within this limit there is a positive correlation between increasing levels of intentionality and subjective ratings of how funny the jokes are. The quality of jokes appears to peak when they include five or six levels of intentionality, which suggests that audiences appreciate higher mentalizing complexity whilst working within their natural cognitive constraints. PMID- 26597197 TI - Introducing this special issue. PMID- 26597198 TI - Moh Daha, a successful scientist with a strong personality, who loves to stimulate and support his colleagues. AB - Mohammed R. Daha is a successful and very productive scientist. He is internationally recognised for his expertise of Complement. In addition, he contributed to many other fields of Immunology, in particular Clinical Immunology within Internal Medicine. He did not only contribute to Nephrology and Transplantation, but also to Rheumatology, Infectious diseases and Pulmonology. He enjoyed teaching and he was also appreciated for his guidance of biomedical and clinical PhD's. PMID- 26597200 TI - The pivotal role of the mentor in triggering the research on Complement system. AB - Despite the fact that was one of the first systems to be discovered and investigated in the innate immunity, Complement is continuing to receive growing attention by the scientific community. Complement is involved in several diseases such as diabetes, atherosclerosis or Systemic Lupus Erythematous. Successful therapeutic intervention in treating Complement-mediated diseases such as Hemolytic Uremic Syndrome represent a promising advance to continue the research on Complement to develop specific inhibitors for treating human diseases. PMID- 26597199 TI - Reactivity in ELISA with DNA-loaded nucleosomes in patients with proliferative lupus nephritis. AB - Autoantibodies against nucleosomes are considered a hallmark of systemic lupus erythematosus (SLE). We compared in patients with proliferative lupus nephritis the diagnostic usefulness of a dsDNA-loaded nucleosome ELISA (anti-dsDNA-NcX) with ELISAs in which dsDNA or nucleosomes alone were coated. First, we analysed whether DNA loading on nucleosomes led to masking of epitopes by using defined monoclonal anti-DNA, anti-histone and nucleosome-specific autoantibodies to evaluate the accessibility of nucleosomal epitopes in the anti-dsDNA-NcX ELISA. Second, autoantibody levels were measured in these 3 ELISAs in 100 patients with proliferative lupus nephritis (LN) before immunosuppressive treatment and in 128 non-SLE disease controls. In patients with LN inter-assay comparisons and associations with clinical and serological parameters were analysed. The panel of monoclonal antibodies revealed that all epitopes were equally accessible in the anti-dsDNA-NcX ELISA as in the two other ELISAs. Patients with proliferative lupus nephritis were positive with dsDNA-loaded nucleosomes in 86%, with DNA in 66% and with nucleosomes in 85%. In the non-lupus disease control group these frequencies were 1.6% (2 out of 128) for both the anti-dsDNA-NcX and the anti dsDNA ELISA and 0% in the anti-nucleosome ELISA. The levels in the anti-dsDNA-NcX ELISA were high in a group of patients with LN that showed absent reactivity in the anti-DNA or low levels in the anti-nucleosome ELISA. Anti-dsDNA-NcX positivity was associated with higher SLEDAI scores within this group. Within nucleosome-based ELISAs, we propose the anti-dsDNA-NcX ELISA as the preferred test system. PMID- 26597201 TI - A tribute to Mohamed Daha. PMID- 26597202 TI - Parallel activities and interactions between antimicrobial peptides and complement in host defense at the airway epithelial surface. AB - Antimicrobial peptides and complement components contribute to host defense as well as inflammation and tissue injury in the respiratory tract. The airway epithelial surface is the main site of action of these immune effectors, and airway epithelial cells contribute markedly to their local production. Whereas both antimicrobial peptides and complement display overlapping functions, it is increasingly clear that both effector mechanisms also interact. Furthermore, excessive or uncontrolled release of antimicrobial peptides as well as complement activation may contribute to inflammatory lung diseases. Therefore, further knowledge of interactions between these systems may provide more insight into the pathogenesis of a range of lung diseases. In this review, recent findings on the functions, collaborations and other interactions between antimicrobial peptides and complement are discussed with a specific focus on the airway epithelium. PMID- 26597203 TI - Complement and phagocytes - A complicated interaction. AB - Mohamed Daha and I share a common interest in innate immunity. Working in institutes only 25 miles away from each other, that meant ample opportunity and relevance for collaboration. And so we did. Moreover, we have both been members of boards and councils of Dutch national organizations, and we have also become good friends. In this short recollection, I look back on 40 years of common activities in complement research and friendship. PMID- 26597204 TI - IgA as therapeutic antibody. AB - This review is focused on the promises of IgA as a new therapeutic antibody. For more than 30 years IgG molecules have been used in the clinic in the fields of oncology, hematology, auto immune diseases and infections. However, IgA might be a good alternative, since it recruits different effector cells, i.e. polymorphonuclear cells or neutrophils, but can also activate monocytes and macrophages. The present knowledge, but also future direction for IgA- based drugs are discussed. PMID- 26597205 TI - Trained immunity: A smart way to enhance innate immune defence. AB - The innate arm of the immune system is generally viewed as primitive and non specific and - in contrast to the adaptive immune arm - not to possess memory. However in plants and invertebrate animals that lack adaptive immunity, innate immunity will exhibit a prolonged enhanced functional state after adequate priming. A similar enhancement of function of the innate immunity has occasionally been described in vertebrates, including humans. Over the past few years we have studied this phenomenon in greater detail and we have coined the term 'Trained (innate) immunity' (TI). TI can be induced by a variety of stimuli, of which we have studied BCG and beta-glucan in greater detail. The non-specific protective effects of BCG that have been observed in vaccination studies in the literature are probably due to TI. Monocytes and macrophages are among the main cells of the innate immune arm that can be trained. We have discovered that both BCG (via NOD2 signalling) and beta-glucan (via dectin-1) induce epigenetic reprogramming, in particular stable changes in histone trimethylation at H3K4. These epigenetic changes lead to cellular activation, enhanced cytokine production and a change in the metabolic state of the cell with a shift from oxidative phosphorylation to aerobic glycolysis. TI is not only important for host defence and vaccine responses, but most probably also for diseases like atherosclerosis. Modulation of TI is a promising area for new treatments. PMID- 26597206 TI - Complement factor H in its alternative identity as adrenomedullin-binding protein 1. AB - Complement factor H has been extensively studied since its discovery 50 years ago, and its role in the complement system is quite well established. It has another role, however, as a binding protein for the regulatory peptide adrenomedullin. Part of this role appears to be protection of adrenomedullin from proteolytic degradation. The binding interaction is unusual and merits further investigation. Adrenomedullin has potential therapeutic uses in diseases affecting the vasculature, and factor H has been administered with adrenomedullin in some animal models of disease. PMID- 26597207 TI - Working Intricately with Moh Daha. AB - Moh Daha has been instrumental for initiating and coordinating many European consortia in the area of immunopathogenesis of glomerulonephritis including a number with the author. This review provides a personal history of these developments, ending with INTRICATE, an FP7 medium scale project investigating ANCA-associated vasculitis (AAV). The current status of this research and recent insight in the autoimmune reactions and autoantigens in AAV are briefly summarized. PMID- 26597208 TI - Complement system activation in ANCA vasculitis: A translational success story? AB - The ANCA-associated vasculitides (AAV) are characterized by pauci-immune necrotizing small to medium size vessel vasculitis frequently including necrotizing crescentric glomerulonephritis. Neutrophil activation by ANCA appears a primary pathogenic event. More recently, the complement system has been shown to be involved as well. Activation of the alternative pathway of complement, at least in part via activated neutrophils, results, amongst others, in the generation of C5a, a strong chemoattractant for neutrophils. C5a is also effective in neutrophil priming, a process leading to surface expression of the ANCA antigens so enabling neutrophils to be further activated by ANCA. Both in vitro and in vivo experimental data and histopathological studies from AAV patients underscore the role of complement, and particularly of C5a, in the pathophysiology of AAV. Preliminary data show that blocking of the C5a-receptor is a promising approach in the treatment of AAV. PMID- 26597209 TI - Membranous nephropathy: A fairy tale for immunopathologists, nephrologists and patients. AB - This article reviews the considerable progress which has been made in the recent years in the understanding of the pathophysiology of membranous nephropathy, a model of organ-specific auto-immune disease. It shows how experimental models developed more than 30 years ago have led to the identification of several human antigens including neutral endopeptidase in the neonate, phospholipase A2 receptor, and thrombospondin 1 domain 7A in the adult, and cationic bovine serum albumin in children. Thanks to a successful GWAS performed in European Caucasians, the genetics of the disease begins to be understood. These groundbreaking findings already have a major impact on patients' care owing to the development of reliable ELISA and immunofluorescence test for the detection of PLA2R antibodies and of PLA2R antigen screening in biopsies. This review will tell the story from the careful clinical observation of cases to the most recent therapeutic perspectives which have been made possible by these advances. Advances in medical science often proceed by steps which are highly interdependent. New, groundbreaking findings with important clinical implications often result from the combination of faithful experimental models and careful clinical observations. This is well illustrated by the story of membranous nephropathy which started more than 50 years ago. It is remarkable that in this disease, the experimental models predicted the pathophysiology of the human glomerulopathy. The stories that we will tell in this article are aimed at young clinical investigators who are sometimes reluctant to embark on research projects. We hope that they will convince them that bedside research performed with intellectual curiosity and a bit of chance can lead to significant progress in clinical medicine. PMID- 26597210 TI - Management of Necrotizing Fasciitis and Its Surgical Aspects. AB - Necrotizing fasciitis (NF) is a severe and rapidly progressive infectious disease that attacks superficial an as well as deep fascia, subcutaneous fat tissue, and muscle. Although the incidence is of relatively low frequency, the median mortality is high. NF is a great burden to patients and hospitals. The most common cause of NF is trauma injuries, followed by other conditions with comorbidity. A classification for NF was presented concerning microbial cause, depth of infection, and anatomy. But the value of classification is not convincing. Early diagnosis of NF is essential and still to be realized by far. Information from clinic or laboratory might contribute to the purpose. Surgery is used in exploration debridement and tissue reconstruction as the main method with NF. Negative pressure wound therapy has proved to be useful in improving wound bed preparation and healing. PMID- 26597211 TI - Statins are independently associated with increased HbA1c in type 1 diabetes--The Thousand & 1 Study. AB - AIMS: Statin use has been associated with increased risk of developing type 2 diabetes (T2DM), and with impaired glycemic control in T2DM patients. The association between statin use and glycemic control in type 1 diabetes (T1DM) is unknown. The association between use of statins and glycemic control in T1DM patients without known heart disease was examined. METHODS: Cross-sectional study of 1093 T1DM patients from the outpatient clinic at Steno Diabetes Center. Physical examination, questionnaires, and echocardiography were performed in all patients. Investigators were blinded to all laboratory measurements. Data were analyzed in uni-and multivariable models. RESULTS: Mean age 49.6 years, 53% men, mean diabetes duration 25.5 years, 475 (43.5%) received statins. In baseline analyses statin users tended to be older, have longer diabetes duration, and have more severe kidney disease. Left ventricular ejection fraction was not associated with statin use. In multivariable models including age, gender, diabetes duration, BMI, blood pressure, physical activity, family history of cardiovascular disease, physical activity, albuminuria, eGFR, retinopathy, smoking, cholesterol, ejection fraction, triglycerides, and use of ACE/ATII antagonists, aspirin, calcium-antagonists, betablockers or diuretics, statin use was independently and significantly associated with higher HbA1c (0.2% (95%CI: 0.1; 0.4) (2.0 mmol/mol (0.2; 3.8)), p=0.029). CONCLUSIONS: In T1DM, use of statins is independently associated with impaired glycemic control. A causal relationship cannot be determined from this study. Given the benefit on cardiovascular outcome, this should not cause patients to stop statin treatment, but may indicate a need to revisit dose of insulin when starting statin treatment. PMID- 26597213 TI - The effect of pH on the interlayer distances of elongated titanate nanotubes and their use as a Li-ion battery anode. AB - Titanate nanotubes are promising materials for Li-ion battery anodes because of their special morphology and high specific surface areas. These titanates provide high rate capability and low volume expansion upon lithiation. More importantly, their tubular structure helps the transport of ions through the crystal. In this study, we synthesized elongated titanate nanotubes and modified their interlayer distances by changing the pH (2-13). For the structural characterization XRD, BET, SEM and TEM techniques were used. In addition, the effect of interlayer distance on energy capacity and rate capability was investigated. The highest interlayer distance was obtained at pH 10 and with decreasing pH, the interlayer distance dropped until reaching a pH value of 4. Conversely, the specific surface area reached its maximum value of 204 m(2) g(-1) at a pH of 4. Different from anatase (TiO2), titanate nanotubes had broad peaks in cyclic voltammograms suggesting a pseudocapacitive behavior. The sloping profiles of potential capacity results also supported the pseudocapacitive property. For the titanate nanotubes obtained at pH 10, an initial discharge capacity of 980 mAh g(-1) was achieved. More importantly, titanate nanotubes showed exceptional rate capabilities and the capacities stayed almost constant at high current rates because of their elongated structure. It was found that the interlayer distance and the elongated structure play an important role in the electrochemical performance of the material. PMID- 26597212 TI - Long-term diabetes outcomes in multi-ethnic Asians living in Singapore. AB - AIMS: This study aims to assess ethnic and gender disparities on long-term complications among multi-ethnic Asians with Diabetes Mellitus (DM) living in Singapore. METHODS: We conducted a retrospective cohort study involving 3006 patients who attended a diabetes centre in a hospital from 2003 to 2011. Demographics and clinical data were obtained from standardised questionnaire and patient's case records. Age at onset of diabetes was calculated as current age minus duration of DM in years. Outcomes on Acute Myocardial Infarction (AMI), End Stage Renal Failure (ESRF) and all-cause death were ascertained by data linkage with national registries. RESULTS: The mean duration of diabetes exposure was 15.6 +/- 9.1 years for AMI, 15.4 +/- 9.0 years for ESRF and 17.0 +/- 9.0 years for death. After adjusting for traditional cardiovascular risk factors, Malay and Indian with diabetes remained significantly associated with AMI with HRs 2.81(95%CI, 1.81-4.37) and 2.03 (95%CI, 1.15-3.59), respectively. The effect of Malays on ESRF and death became attenuated post-adjustment. Besides mortality, there was preponderance for other adverse outcomes associated with male. CONCLUSIONS: Ethnic (Malay worse) and gender (male worse) disparities were observed in DM-related outcomes. The results may inform allocation of finite resources and to organize care targeted at high-risk groups. PMID- 26597214 TI - Secretome Analysis of Metarhizium anisopliae Under Submerged Conditions Using Bombyx mori Chrysalis to Induce Expression of Virulence-Related Proteins. AB - The entomopathogenic fungus Metarhizium anisopliae is used to control insect pests. This species is specialized for the secretion of an enzymatic complex consisting of proteases, lipases, and chitinases related to pathogenicity and virulence. In this context, the secretomes of strains IBCB 167 and IBCB 384 of M. anisopliae var. anisopliae, grown under submerged fermentation in the presence of chrysalis as an inducer, were analyzed. Analysis of two-dimensional gels showed qualitative and quantitative differences between secreted proteins in both isolates. Around 102 protein spots were analyzed, and 76 % of the corresponding proteins identified by mass spectrometry were grouped into different classes (hydrolases, oxidases, reductases, isomerases, kinases, WSC domains, and hypothetical proteins). Thirty-three per cent of all the proteins analyzed were found to be common in both strains. Several virulence-related proteins were identified as proteases and mannosidases. Endo-N-acetyl-beta-D-glucosaminidase expression was observed to be 10.14-fold higher for strain IBCB 384 than for strain IBCB 167, which may be an important contributor to the high virulence of IBCB 384 in Diatraea ssaccharalis. These results are important for elucidation of the host-pathogen relationship and the differences in virulence observed between the two strains. PMID- 26597215 TI - A lacZ Reporter-Based Strategy for Rapid Expression Analysis and Target Validation of Mycobacterium tuberculosis Latent Infection Genes. AB - We report a novel lacZ fusion vector and demonstrate its utility for expression analysis of genes associated with Mycobacterium tuberculosis latent infection. The vector contains E. coli (oriE) and mycobacterial (oriM) origins of replication, a kanamycin resistance gene (Km(r)) as selection marker, and a lacZ reporter gene in fusion with MCS for cloning of upstream regulatory sequence of the desired genes. beta-galactosidase activity of the vector was standardized for expression analysis under latent mycobacterial conditions using Phsp60, a constitutive mycobacterial promoter, utilizing Mycobacterium smegmatis as model organism. Validation of the vector was done by cloning and expression analysis of PhspX (alpha crystalline) and Picl (isocitrate lyase), promoters from two of the genes shown to be involved in M. tuberculosis persistence. Both genes showed appreciable levels of beta-galactosidase expression under hypoxia-induced persistent conditions in comparison to their actively replicating state. Expression analysis of a set of hypothetical genes was also done, of which Rv0628c showed increased expression under persistent conditions. The reported fusion vector and the strategy can be effectively used for short listing and validation of drug targets deduced from various non-conclusive approaches such as bioinformatics and microarray analysis against latent/persistent form of mycobacterial infection. PMID- 26597216 TI - [In Process Citation]. PMID- 26597217 TI - Sedation and analgosedation performed by pediatricians--experience made with the implementation of an in-house sedation standard: Sedation and analgosedation implemantation of an in-house standard. AB - BACKGROUND: (Analgo-) sedations for diagnostic and/or therapeutic procedures form part of the daily clinical routine for pediatric patients. National and international medical specialist associations have published guidelines indicating the general conditions of these procedures, yet the recommendations are not always consistent. Since anesthesiological activities are increasingly performed by nonanesthesiologists at our hospital, the Pediatric Clinic of the University Hospital of Saarland considered it necessary to develop an in-house standard. MATERIAL AND METHODS: On the basis of a standard dating back to 2005, which was developed and clinically applied by two of the authors of this article, we created our "Homburg standard", taking into account the guidelines of the specialist associations and the international literature. This standard covers patient information, the consumption of food and drink, monitoring before, during and after the sedation as well as documentation. We will present the process of how our standard was established by analyzing protocols of the "old" standard applied for a period of 18 months-and the application of our standard to two new studies performed at our hospital. RESULTS: In total, 159 sedations of the 18 month reference period could be evaluated; the two studies accounted for 72 sedations for diagnostic and/or interventional cardiac catheter examinations and 40 sedations for outpatient TEE examinations. None of the procedures was associated with complications endangering the safety of a patient. Whereas the documentation of the two studies was nearly complete, it varied considerably in the case of the 159 sedations, depending on how much time had passed since the most recent training. CONCLUSION: Our standard is a practicable and safe method of performing sedations and analgosedations in pediatric patients. In addition, this standard allows clinical studies to be carried out and evaluated, taking into account certain organizational measures. The development of a specific guideline by the DGKJ and/or the GNPI is considered desirable. PMID- 26597218 TI - Coherent interaction with two-level fluctuators using near field scanning microwave microscopy. AB - Near field Scanning Microwave Microscopy (NSMM) is a scanning probe technique that non-invasively can obtain material properties on the nano-scale at microwave frequencies. While focus has been on developing room-temperature systems it was recently shown that this technique can potentially reach the quantum regime, opening up for applications in materials science and device characterization in solid state quantum information processing. In this paper we theoretically investigate this new regime of NSMM. Specifically we show that interaction between a resonant NSMM probe and certain types of two-level systems become possible when the NSMM probe operates in the (sub-) single photon regime, and we expect a high signal-to-noise ratio if operated under the right conditions. This would allow to detect single atomic material defects with energy splittings in the GHz range with nano-scale resolution, provided that individual defects in the material under study are well enough separated. We estimate that this condition is fulfilled for materials with loss tangents below tan delta ~ 10(-3) which holds for materials used in today's quantum circuits and devices where typically tan delta < 10(-5). We also propose several extensions to a resonant NSMM that could improve sensitivity and functionality also for microscopes operating in a high power regime. PMID- 26597219 TI - Cross-Cultural Analysis of Prototypicality Norms Used by Male and Female Persian and American Speakers. AB - Human beings generally cut the realities of the world in various ways in order to express their thoughts and interact with other people. Naturally, words are linguistic categories which carry the intended concepts; however, humans tend to economize by bundling words into different conceptual classes. Accordingly, the present study sought to explore the prototypicality norms used by male and female Persian and American speakers adopting a cross cultural analysis. For this purpose, from the existing prototypes, four conceptual categories; namely, vehicles, vegetables, furniture, and clothes were randomly selected and used as the tertium comparationis for determining the way 120 male and female monolingual American and Persian speakers, sixty from each language, ranked the category membership of different conceptual members belonging to the targeted prototypes. The analysis of the obtained data based on participants' ranking of the prototypes along with the respective frequency values revealed that gender and culture played a significant role in identifying the category membership of various members of a given concept across different languages. The findings can have important implications for language teachers, material designers, and second language students since culture is an overriding factor in language learning. PMID- 26597220 TI - Ragnar Rommetveit's Approach to Everyday Spoken Dialogue from Within. AB - The following article presents basic concepts and methods of Ragnar Rommetveit's (born 1924) hermeneutic-dialogical approach to everyday spoken dialogue with a focus on both shared consciousness and linguistically mediated meaning. He developed this approach originally in his engagement of mainstream linguistic and psycholinguistic research of the 1960s and 1970s. He criticized this research tradition for its individualistic orientation and its adherence to experimental methodology which did not allow the engagement of interactively established meaning and understanding in everyday spoken dialogue. As a social psychologist influenced by phenomenological philosophy, Rommetveit opted for an alternative conceptualization of such dialogue as a contextualized, partially private world, temporarily co-established by interlocutors on the basis of shared consciousness. He argued that everyday spoken dialogue should be investigated from within, i.e., from the perspectives of the interlocutors and from a psychology of the second person. Hence, he developed his approach with an emphasis on intersubjectivity, perspectivity and perspectival relativity, meaning potential of utterances, and epistemic responsibility of interlocutors. In his methods, he limited himself for the most part to casuistic analyses, i.e., logical analyses of fictitious examples to argue for the plausibility of his approach. After many years of experimental research on language, he pursued his phenomenologically oriented research on dialogue in English-language publications from the late 1980s up to 2003. During that period, he engaged psycholinguistic research on spoken dialogue carried out by Anglo-American colleagues only occasionally. Although his work remained unfinished and open to development, it provides both a challenging alternative and supplement to current Anglo-American research on spoken dialogue and some overlap therewith. PMID- 26597221 TI - SPRINT Proves that Lower Is Better for Nondiabetic High-Risk Patients, but at a Price. PMID- 26597222 TI - Serology, virulence, antimicrobial susceptibility and molecular characteristics of clinical Vibrio parahaemolyticus strains circulating in southeastern China from 2009 to 2013. AB - Vibrio parahaemolyticus is a leading cause of food-borne diarrhoea in coastal countries. Although V. parahaemolyticus cases have been reported since 1950, they have been poorly documented. From July 2009 to June 2013, we collected 6951 faecal specimens for pathogen detection; V. parahaemolyticus strains were isolated from 563 specimens (8.1%). We then analysed the characteristics of the 501 V. parahaemolyticus strains that were isolated as the sole pathogen. Twenty one serotypes were identified among these strains; O3:K6 was the most common serotype (65.1%), followed by O4:K8, O4:K68 and O1:K36. One strain of the O4:K18 serotype was isolated from clinical patients for the first time. Pandemic O3:K6 clones were predominant and accounted for 69.1% of all of the pandemic strains. This is the first report of one strain expressing the O3:K8 serotype with a pandemic genotype. The presence of the haemolysin gene tdh (93.0%) was the key characteristic of the virulent strains; however, a few strains carried the trh gene. We also confirmed the presence of the type III secretion system 2 (T3SS2) genes in all of the pathogenic strains. Subsequent multilocus sequence typing split the isolates into 16 sequence types (STs), with ST3 and ST88 as the most prevalent in southeastern China. Most isolates were sensitive to common antimicrobial agents, apart from ampicillin. However, the resistance rate to ampicillin has apparently increased in this area. In conclusion, our results indicate that pandemic O3:K6 V. parahaemolyticus isolates are predominant in southeastern China, and additional surveillance should be conducted to facilitate control of the transmission of this pathogen. PMID- 26597224 TI - Halomonas garicola sp. nov., isolated from saeu-jeot, a Korean salted and fermented shrimp sauce. AB - A Gram-stain-negative, moderately halophilic and facultatively aerobic bacterium capable of respiration with nitrate, designated strain JJ-M1T, was isolated from saeu-jeot, a traditional Korean fermented shrimp sauce. Cells of the strain were non-motile short rods showing oxidase-negative and catalase-positive reactions and the production of pale-yellow pigments. Growth of strain JJ-M1T was observed at 20-37 degrees C (optimum, 30 degrees C), pH 5.5-9.5 (optimum, pH 7.0) and in the presence of 3-22.5 % (w/v) sea salts (optimum, 10 %). Strain JJ-M1T contained ubiquinone 9 (Q-9) as the predominant isoprenoid quinone and summed feature 8 (comprising C18 : 1omega7c and/or C18 : 1omega6c), C16 : 0, summed feature 3 (comprising C16 : 1omega7c and/or C16 : 1omega6c) and C12 : 0 3-OH as the major cellular fatty acids. The polar lipids consisted of phosphatidylglycerol, phosphatidylethanolamine, phosphoglycolipid, diphosphatidylglycerol and four unidentified phospholipids. The genomic DNA G+C content of strain JJ-M1T was 62.4 mol%. Phylogenetic and comparative analyses, based on 16S rRNA gene sequences, indicated that strain JJ-M1T formed a tight phyletic lineage with Halomonas jeotgali HwaT within the genus Halomonas and was most closely related to Halomonas jeotgali HwaT with 96.2 % 16S rRNA gene sequence similarity. Based on phylogenetic, phenotypic and chemotaxonomic features, strain JJ-M1T represents a novel species of the genus Halomonas, for which the name Halomonas garicola sp. nov. is proposed. The type strain is JJ-M1T ( = KACC 18117T = JCM 30151T). PMID- 26597223 TI - Two-photon interference at telecom wavelengths for time-bin-encoded single photons from quantum-dot spin qubits. AB - Practical quantum communication between remote quantum memories rely on single photons at telecom wavelengths. Although spin-photon entanglement has been demonstrated in atomic and solid-state qubit systems, the produced single photons at short wavelengths and with polarization encoding are not suitable for long distance communication, because they suffer from high propagation loss and depolarization in optical fibres. Establishing entanglement between remote quantum nodes would further require the photons generated from separate nodes to be indistinguishable. Here, we report the observation of correlations between a quantum-dot spin and a telecom single photon across a 2-km fibre channel based on time-bin encoding and background-free frequency downconversion. The downconverted photon at telecom wavelengths exhibits two-photon interference with another photon from an independent source, achieving a mean wavepacket overlap of greater than 0.89 despite their original wavelength mismatch (900 and 911 nm). The quantum-networking operations that we demonstrate will enable practical communication between solid-state spin qubits across long distances. PMID- 26597225 TI - Vesicular Nanostructure Formation by Self-Assembly of Anisotropic Penta-phenol Substituted Fullerene in Water. AB - A study on self-assembly of anisotropically substituted penta-aryl fullerenes in water has been reported. The penta-phenol-substituted amphiphilic fullerene derivative [C60Ph5(OH)5] exhibited self-assembled vesicular nanostructures in water under the experimental conditions. The size of the vesicles was observed to depend upon the kinetics of self-assembly and could be varied from ~300 to ~70 nm. Our mechanistic study indicated that the self-assembly of C60Ph5(OH)5 is driven by extensive intermolecular as well as water-mediated hydrogen bonding along with fullerene-fullerene hydrophobic interaction in water. The cumulative effect of these interactions is responsible for the stability of vesicular structures even on the removal of solvent. The substitution of phenol with anisole resulted in different packing and interaction of the fullerene derivative, as indicated in the molecular dynamics studies, thus resulting in different self-assembled nanostructures. The hollow vesicles were further encapsulated with a hydrophobic conjugated polymer and water-soluble dye as guest molecules. Such confinement of pi-conjugated polymers in fullerene has significance in bulk heterojunction devices for efficient exciton diffusion. PMID- 26597226 TI - Resource constrained flux balance analysis predicts selective pressure on the global structure of metabolic networks. AB - BACKGROUND: A universal feature of metabolic networks is their hourglass or bow tie structure on cellular level. This architecture reflects the conversion of multiple input nutrients into multiple biomass components via a small set of precursor metabolites. However, it is yet unclear to what extent this structural feature is the result of natural selection. RESULTS: We extend flux balance analysis to account for limited cellular resources. Using this model, optimal structure of metabolic networks can be calculated for different environmental conditions. We observe a significant structural reshaping of metabolic networks for a toy-network and E. coli core metabolism if we increase the share of invested resources for switching between different nutrient conditions. Here, hub nodes emerge and the optimal network structure becomes bow-tie-like as a consequence of limited cellular resource constraint. We confirm this theoretical finding by comparing the reconstructed metabolic networks of bacterial species with respect to their lifestyle. CONCLUSIONS: We show that bow-tie structure can give a system-level fitness advantage to organisms that live in highly competitive and fluctuating environments. Here, limitation of cellular resources can lead to an efficiency-flexibility tradeoff where it pays off for the organism to shorten catabolic pathways if they are frequently activated and deactivated. As a consequence, generalists that shuttle between diverse environmental conditions should have a more predominant bow-tie structure than specialists that visit just a few isomorphic habitats during their life cycle. PMID- 26597227 TI - Placental site trophoblastic tumor and choriocarcinoma: an unusual presentation. AB - BACKGROUND: Mixed trophoblastic tumor composed of choriocarcinoma and placental site trophoblastic tumor was diagnosed on histopathology slides review, is a very rare mixed tumor and cured after adjuvant chemotherapy. CASE PRESENTATION: Twenty nine years old, Para 2 female presented with 4 months history of irregular vaginal bleeding after an uncomplicated vaginal delivery. Abdominal examination showed 14 weeks uterus with beta-hCG level of 14,889 mIU/ml. Slides review confirmed the diagnosis of placental site trophoblastic tumor (PSTT). Patient underwent total abdominal hysterectomy and resection of anterior vaginal wall mass. Post operative (48 h) beta-hCG level was 6016 mIU/ml. Final pathology showed mixed trophoblastic tumor composed of choriocarcinoma (CC) and PSTT. Adjuvant chemotherapy started and continued for three cycles after achieving normal beta-hCG. CONCLUSION: PSTT is a rare disease and potentially curable. Differential diagnosis in women presented with vaginal bleeding and a uterine mass in the post partum period must include gestational trophoblastic disease. PMID- 26597228 TI - Transcriptomics of diapause in an isogenic self-fertilizing vertebrate. AB - BACKGROUND: Many vertebrate species have the ability to undergo weeks or even months of diapause (a temporary arrest of development during early ontogeny). Identification of diapause genes has been challenging due in part to the genetic heterogeneity of most vertebrate animals. RESULTS: Here we take the advantage of the mangrove rivulus fish (Kryptolebias marmoratus or Kmar)-the only vertebrate that is extremely inbred due to consistent self-fertilization-to generate isogenic lineages for transcriptomic dissection. Because the Kmar genome is not publicly available, we built de novo genomic (642 Mb) and transcriptomic assemblies to serve as references for global genetic profiling of diapause in Kmar, via RNA-Seq. Transcripts unique to diapause in Kmar proved to constitute only a miniscule fraction (0.1 %) of the total pool of transcribed products. Most genes displayed lower expression in diapause than in post-diapause. However, some genes (notably dusp27, klhl38 and sqstm1) were significantly up-regulated during diapause, whereas others (col9a1, dspp and fmnl1) were substantially down regulated, compared to both pre-diapause and post-diapause. CONCLUSION: Kmar offers a strong model for understanding patterns of gene expression during diapause. Our study highlights the importance of using a combination of genome and transcriptome assemblies as references for NGS-based RNA-Seq analyses. As for all identified diapause genes, in future studies it will be critical to link various levels of RNA expression with the functional roles of the coded products. PMID- 26597229 TI - Imaging and surgical utilization for pediatric cystinuria patients: A single institution cohort study. AB - OBJECTIVE: Although cystinuria is rare, its clinical manifestations are life long. Little is known about healthcare utilization in this population. STUDY DESIGN: Through billing records and chart review, we identified pediatric patients with cystinuria treated at our institution. Variables included demographics, gender, race, comorbidities, location of presentation, presenting symptoms, initial laboratory data, and stone characteristics. Outcomes included the number and type of imaging tests and procedures performed. Descriptive statistics were performed. Median annual frequencies of procedures and imaging were calculated. RESULTS: Twenty-three patients who presented between 1995 and 2011 were identified. The median age at presentation was 12 years, 48% of our patients were male, and 91% were Caucasian. Median follow-up was 4.6 years. Over half were diagnosed in clinic (13/23), while 30% (7/23) presented to the ED. Pain was the most common presenting symptom (13/23), followed by nausea/vomiting (6/23), gross hematuria (5/23), and fevers (5/23). Only one patient presented with acute renal failure. Five patients were discovered by sibling screening. The median number of stones at presentation was two and median size of the largest stone was 9 mm, with three staghorn calculi. During follow-up, a total of 110 stone procedures were performed in 15 patients. Five patients underwent 13 PCNLs, 11 patients underwent 44 ureteroscopy procedures, and nine underwent open or robotic surgery, including one nephrectomy. Among patients identified by sibling screening, most (4/5) were managed with medical therapy alone. A total of 390 imaging procedures were performed. Radiation-associated imaging comprised half of all imaging tests. DISCUSSION: The high rates of imaging and surgical utilization among pediatric cystinuria patients reflect the morbidity of this condition and the need for preventative management. By practicing the ALARA principle during urologic procedures, urologists can reduce radiation exposure. Multiple procedures are often required to render patients stone-free. URS/LL and PCNL are likely to be more effective than ESWL. In complex cases, robotic-assist lithotomy provides the advantage of a minimally invasive approach. Both sibling screening and transitional care represent long-term strategies with the potential to reduce life-long morbidity. The limitations of this study include its small sample size, retrospective nature, and single-center experience. CONCLUSIONS: Our study demonstrates that the clinical impact of disease among pediatric patients presenting with cystinuria at our institution is considerable, with most requiring surgery. Our population also generates heavy utilization of diagnostic imaging. Given the lifelong nature of this disease, research on improved preventive therapies is urgently needed. PMID- 26597232 TI - Superiority of charged particle therapy in treatment of hepatocellular carcinoma (Regarding Qi W.X. et al. charged particle therapy versus photon therapy for patients with hepatocellular carcinoma: A systematic review and meta-analysis). PMID- 26597230 TI - Predicted binding site information improves model ranking in protein docking using experimental and computer-generated target structures. AB - BACKGROUND: Protein-protein interactions (PPIs) mediate the vast majority of biological processes, therefore, significant efforts have been directed to investigate PPIs to fully comprehend cellular functions. Predicting complex structures is critical to reveal molecular mechanisms by which proteins operate. Despite recent advances in the development of new methods to model macromolecular assemblies, most current methodologies are designed to work with experimentally determined protein structures. However, because only computer-generated models are available for a large number of proteins in a given genome, computational tools should tolerate structural inaccuracies in order to perform the genome-wide modeling of PPIs. RESULTS: To address this problem, we developed eRank(PPI), an algorithm for the identification of near-native conformations generated by protein docking using experimental structures as well as protein models. The scoring function implemented in eRank(PPI) employs multiple features including interface probability estimates calculated by eFindSite(PPI) and a novel contact based symmetry score. In comparative benchmarks using representative datasets of homo- and hetero-complexes, we show that eRank(PPI) consistently outperforms state-of-the-art algorithms improving the success rate by ~10 %. CONCLUSIONS: eRank(PPI) was designed to bridge the gap between the volume of sequence data, the evidence of binary interactions, and the atomic details of pharmacologically relevant protein complexes. Tolerating structure imperfections in computer generated models opens up a possibility to conduct the exhaustive structure-based reconstruction of PPI networks across proteomes. The methods and datasets used in this study are available at www.brylinski.org/erankppi. PMID- 26597231 TI - Scanning proton beam therapy reduces normal tissue exposure in pelvic radiotherapy for anal cancer. AB - An inter-comparison planning study between photon beam therapy (IMRT) and scanning proton beam therapy (SPBT) for squamous cell carcinoma of the anus (SCCA) is presented. SPBT plans offer significant reduction (>50%, P=0.008) in doses to small bowel, and bone marrow thereby offering the potential to reduce bowel and hemotoxicities. PMID- 26597233 TI - A Novel Hemostatic Patch That Stops Bleeding in Cardiovascular and Peripheral Vascular Procedures. AB - BACKGROUND: Achieving hemostasis during surgery is a common challenge across surgical specialties and procedures, including cardiovascular and peripheral vascular procedures. Although several hemostatic agents are available, they all become less effective as bleeding becomes more vigorous. VerisetTM hemostatic patch is a topical hemostatic agent that has been approved for use on solid organs and in soft tissue. The primary aim of these studies was to assess the safety of Veriset hemostatic patch during cardiovascular and peripheral vascular procedures. METHODS: Adult domestic swine were given intraoperative anticoagulation and systemic antiplatelet therapy, and then underwent a variety of cardiovascular coronary artery bypass graft (CABG anastomosis and aortotomy closure) and peripheral vascular (carotid arteriotomy with patch angioplasty) procedures. Bleeding was identified or created from each anastomotic site and was brisk in many cases. Veriset hemostatic patch, Surgicel((r)) Nu-Knit((r)) absorbable hemostat, or standard of care treatment was applied topically to the site of bleeding, and time to hemostasis was monitored for each animal. Animals were assessed during and after the surgical procedure to determine the effects of treatment on vessel diameter, clinical laboratory parameters, and host tissue response and/or tissue integration. RESULTS: Application of Veriset hemostatic patch had no effect on vessel diameter, similar to Surgicel Nu-Knit absorbable hemostat and standard of care treatment. Approximately 28 days after application, Veriset hemostatic patch and Surgicel Nu-Knit absorbable hemostat were completely absorbed, with no impact on serum chemistry profiles. Furthermore, Veriset hemostatic patch was as effective or more effective than Surgicel Nu-Knit absorbable hemostat when applied during carotid arteriotomy (30.0 +/- 0.0 sec vs. 163.6 +/- 86.9 sec, P < 0.001) and CABG anastomosis (91.9 +/- 66.0 sec vs. 207.5 +/- 159.2 sec, P = 0.053). CONCLUSIONS: Veriset hemostatic patch exhibits similar safety as Surgicel Nu-Knit absorbable hemostat, with effectiveness against cardiovascular and peripheral vascular bleeding. If these preclinical results are confirmed in clinical trials, this highly effective patch with a topical application requiring less than 30 seconds is likely to prove useful in many clinical settings. PMID- 26597234 TI - Association of Perioperative Transfusion with 30-Day Morbidity and Mortality after Vascular Surgery: Re: Valentijn TM, et al. The impact of perioperative red blood cell transfusions on postoperative outcomes in vascular surgery patients. Ann Vasc Surg 2015; 29:511-9. PMID- 26597235 TI - Pseudoaneurysm of the Right Internal Mammary Artery Post Vacuum-Assisted Closure Therapy: A Rare Complication and Literature Review. AB - Vacuum-assisted closure (VAC) therapy in the management of sternal wound infection post cardiac surgery has gained popularity since last decade. It is very cost effective and has survival benefit compared with conventional management. Although there are few complications associated with VAC therapy including right ventricular free wall rupture and infectious erosion to aorta, there are now isolated reports of vein graft pseudoaneurysm associated with it. We describe an extremely rare complication of right internal mammary artery pseudoaneurysm post VAC therapy in a 56-year-old man which was successfully managed surgically. We also did a literature review on the possible complications of VAC therapy post cardiac surgery and its management. PMID- 26597236 TI - Use of Aortic Endograft for Repair of Intraoperative Iliocaval Injury during Anterior Spine Exposure. AB - Vascular injury during anterior lumbar interbody fusion (ALIF) is a well documented occurrence. Most vascular injuries continue to be managed with direct open repair. We report the outcome of a 61-year-old woman who experienced inferior vena cava and left common iliac vein injury during a difficult exposure for multilevel ALIF. The distal cava and common iliac vein were repaired with a Gore Excluder cuff and limb. The endovascular repair permitted control of the injury without more morbid maneuvers such as iliac artery transection. Thus endovascular repair of intraoperative caval injury is a valuable option in emergent situations with low morbidity and good durability. PMID- 26597237 TI - Current Status of Clot Removal for Acute Pulmonary Embolism. AB - Acute pulmonary embolism (PE) continues to carry a high mortality if not recognized early and treated aggressively. Rapid recognition and diagnosis remains the mainstay of all efforts. Risk stratification early is paramount to guide therapy and achieve successful outcomes. Pulmonary emboli can generally be classified as massive, submassive, or stable. Fibrinolysis and/or surgical embolectomy are recommended for the treatment of the patient with massive PE to rescue the patient and restore hemodynamic stability. Current trials support an aggressive approach. In submassive PE, determination of right ventricular (RV) strain by echocardiography and biomarker assessment (troponin and B-type natriuretic peptide) identify patients who can benefit from catheter-directed therapy with the therapeutic intent of achieving a rapid reduction of RV afterload, prevention of impending hemodynamic collapse and prolonged in-hospital and outpatient survival. Current trials have not shown long-term benefit for this approach to date, and thus, this therapy should only be offered to select patients. Stable PE can be treated using both an inpatient and an outpatient approach, based on the available infrastructure. Therapy for PE continues to evolve and stratification of risks and benefits remain the key to implementation of invasive strategies. PMID- 26597239 TI - Tracheoinnominate Fistula: Endovascular Treatment with a Stent Graft in a 4-Year Old Child. AB - A 4-year-old boy presented with acute and profuse bleeding at the tracheostomy site. An emergency angiography was performed and identified a pseudoaneurysm at the innominate artery. A selective catheterization of the artery was executed and 2 Advanta V12 balloon-expandable covered stents were implanted in an overlapping manner to occlude the pseudoaneurysm. Final angiography demonstrated patency of the innominate artery and no signs of bleeding. The patient had no postoperative complications and no further bleeding during follow-up. A contrasted computed tomography scan was performed after 20 days and demonstrated no signs of pseudoaneurysm or bleeding. After 4 months, the patient was readmitted to tracheal dilatation and change of T-tube and died of respiratory complications. PMID- 26597238 TI - Aortocaval Fistula: Is Endovascular Repair the Preferred Solution? AB - BACKGROUND: To compare outcomes of open and endovascular repair of aortocaval fistulas (ACFs) in the setting of abdominal aortic aneurysms (AAAs). METHODS: A literature review was undertaken on Pubmed from 1999 to 2014 to identify reported cases of both endovascular and open repair of ACF, including the index case, presented here. Primary outcomes for endovascular repair were: complications, presence of endoleak, and death. Primary outcomes for open repair were: complications and death. RESULTS: Forty articles were reviewed with a total of 67 patients, including the index case. Endovascular approach was used in 26 patients (39%). Endoleaks were present in 50%, whereas similarly 46% of patients had a reported complication. Five deaths (19%) occurred in the endovascular group. Open repair was performed in 41 cases (61%). The rate of complication and the death in open repair were 36% and 12%, respectively (P = 0.327 and P = 0.910, respectively) compared with endovascular. Mean follow-up was 7.7 months for the endovascular group and 8.5 months in the open group. CONCLUSIONS: Previous demonstrations of high morbidity and mortality with open repair of ACF in the setting of AAA have motivated endovascular approaches. However, endoleaks are a significant problem and were present in 50% of ACF cases. The continued presence of an endoleak in the setting of an ACF may result in persistence of the ACF, unlikely thrombosis of the endoleak, and continued sac enlargement. Endovascular repair presents theoretical benefit, yet is not associated with a reduced rate of complication or death versus open repair in this contemporary review. PMID- 26597240 TI - Extra-Anatomic Axillo-Mesenteric Reconstruction for Chronic Mesenteric Ischemia. AB - We present a case of extra-anatomic axillo-mesenteric reconstruction for chronic mesenteric ischemia. Endovascular access and retrograde bypass options were prohibited by severe aortoiliac occlusive disease. Standard antegrade bypass was impossible because of the presence of a thoracoabdominal aortic aneurysm. This unusual method of mesenteric reconstruction is a robust and viable option for patients with challenging anatomy and multiple comorbidities that preclude traditional endovascular and open surgical options. PMID- 26597241 TI - Temporary Axillorenal Bypass in Complex Aorto-Renal Surgery. AB - BACKGROUND: Prolonged renal ischemia during vascular surgery carries high morbidity and mortality. We report an alternative technique for maintaining renal circulation during suprarenal aortic or renal artery clamping. METHODS: Between October 2007 and May 2012, 16 patients undergoing aorto-renal surgery (13 men, 3 women) were operated using temporary axillorenal bypass. Operations were performed for supra- and juxtarenal aortic aneurysms (11), occlusive aortic disease (2), renal artery stenoses (2), and abdominal myofibroblastic tumor (1). In elective cases, axillorenal bypass was planned, when prolonged renal ischemia was expected based on preoperative information. Preoperative risk factors (renal dysfunction, hypertension, coronary disease, diabetes, smoking) and intraoperative variables (operating time, blood loss, renal ischemia time) were assessed and compared with postoperative kidney function (serum creatinine, urine output, dialysis) and in-hospital or 30-day-mortality. Even though renal blood flow was restored between clampings, the total cumulative ischemia time was used in analysis. Acute renal failure postoperatively was based on RIFLE criteria. RESULTS: Preoperatively, 44% (7) of the patients had normal renal function (S crea <= 100 mmol/L). Renal function was moderately present in 50% (8) (S-crea 100 200 mmol/L) and severely in 6% (1) (S-crea >= 200 mmol/L). Median operation time was 393 min (251-535 min) and median renal ischemia time was 24.5 min (range 8-50 min). Transient acute renal dysfunction occurred in 6 (38%) patients, and 4 of them had renal insufficiency preoperatively. Transient renal replacement therapy was needed in 1 (6%) patient only. In 1-month control, postoperative renal function had returned to its baseline level or improved and in-hospital or 30-day mortality was zero. CONCLUSIONS: Temporary axillorenal bypass is a considerable option to minimize renal ischemia time during high-risk vascular surgery. PMID- 26597242 TI - A True Distal Brachial Artery Aneurysm Treated with a Bifurcated Saphenous Vein Graft. AB - Brachial artery aneurysms are rare, mostly consisting of false ones secondary to infectious, traumatic, or iatrogenic arterial lesions. True aneurysms of the brachial artery are even more uncommon. Here, we report a case of a 40-year-old fisherman, without any pathological antecedent, who presented with a painful pulsatile mass of the left anterior arm. There was a slight edema with no ischemic signs. The computed tomographic angiography revealed a true 3.7 * 4.2 * 6 cm aneurysm of the distal brachial artery, partially thrombosed, which extended to the bifurcation. A surgical repair was indicated. Intervention consisted of an aneurysmectomy with interposition of an autologous reversed bifurcated saphenous vein graft. Early outcome was good and a 1-year follow-up showed a patent graft with no aneurysmal recurrence. A review of the literature on this rare location of true artery aneurysm and treatment options is outlined in this work. PMID- 26597243 TI - Tissue Factor Activity in Dialysis Access Grafts. AB - BACKGROUND: Intimal hyperplasia at the venous anastomosis of dialysis grafts causes early failure. We developed a sheep model of arteriovenous prosthetic grafts that fail rapidly due to intimal hyperplasia with histologic features nearly identical to human access grafts. A prominent feature of lesion development in this model is formation of luminal thrombus that becomes organized into stenosing lesions by macrophage and myofibroblast infiltration. To better understand this process, we examined the presence and activity of tissue factor (TF) in this system. This protein is the physiological initiator of coagulation in vivo and is known to contribute to development of intimal hyperplasia after vascular injury. METHODS: Expanded polytetrafluorethylene (ePTFE) grafts were placed between the carotid artery and external jugular vein in sheep. Grafts were examined for luminal TF activity using a novel ex vivo assay. In a separate series of grafts, immunohistochemistry was used to localize smooth muscle cells, monocytes, and TF protein. RESULTS: At 2 days, luminal TF activity already was higher in the venous and arterial end of the graft than in the adventitia. This high level of activity persisted at 8 weeks. TF activity was higher in the venous end of the grafts than in the arterial end at 2 and 8 weeks (40% and 47% increase, n = 5, n = 3, respectively, P < 0.05). Immunohistochemistry revealed TF protein localized in regions with or adjacent to fibrin accumulation and often in regions close to the lumen. CONCLUSIONS: This study further examines the development of intimal hyperplasia in ePTFE dialysis access grafts. In this model, TF levels on the luminal surface were increased throughout the arteriovenous grafts and the adjacent vessels as early as 2 days after engraftment and for as long as 8 weeks thereafter. The highest levels of activity were found in the venous end of the graft, where hyperplasia is most robust. Increased activity of TF is associated with luminal thrombus, which provides a scaffolding for development of intimal hyperplasia. These findings present an opportunity to develop strategies to limit TF activity within the graft. Further studies using agents delivered locally or incorporated into the graft matrix to block the luminal activity of TF are warranted. PMID- 26597244 TI - Surgical Site Infections (SSI) after Lower Limb Varicose Vein Surgery: Redo Surgery Doubles the Risk of SSI. PMID- 26597245 TI - Apparatus for Comparison of Pullout Forces for Various Thoracic Stent Grafts at Varying Neck Angulations and Oversizes. AB - BACKGROUND: The purpose of this study is to provide an apparatus for comparison of pullout forces for various thoracic stent grafts at varying neck angulations and oversizes. METHODS: An in vitro platform capable of performing pullout tests was used on stent grafts in angulated silicone tubes designed for this study (0 degrees , 45 degrees , 90 degrees , and 135 degrees with a 32-mm inner diameter) in a temperature-controlled chamber (37 +/- 2 degrees C). Three commercial stent grafts with sizes commonly used in Taiwan (Valiant: 34, 36, 38, and 40 mm; Zenith TX2: 34, 36, 38, and 40 mm; and TAG: 34, 37, and 40 mm) were used, and each size was tested 8 times for each angulation condition. RESULTS: The mean dislodgement forces (DFs) at 0 degrees angulation within 10-20% oversize were approximately 22.7, 9.6, and 9.0 N for the Valiant, Zenith TX2, and TAG devices, respectively, whereas the mean DFs decreased by 46%, 38%, and 50% to 12.3, 5.9, and 4.5 N when the angulation reached 135 degrees . Regression analysis shows that neck angulation was a significant factor for the Valiant and Zenith TX2 devices (P < 0.0001 and P < 0.0001, respectively) but not for the TAG device (P = 0.483). In addition, oversize and interactions between variables (angulation * oversize) exhibited significant effects on the DFs for all devices (P < 0.0001). CONCLUSIONS: We successfully built up an apparatus for comparison of pullout forces for various thoracic stent grafts at varying neck angulations and oversizes. With the empirical comparative data of different brand stent grafts under various conditions shown and compared, our findings suggest that aortic neck angulation has a negative correlation with stent-graft fixation. To have better stent-graft fixation and seal in the aortic arch for thoracic endovascular aortic repair, a longer landing zone with cautiously selected oversize is a more suitable selection. PMID- 26597246 TI - Evaluation of Nitinol Stents Using a 3-Dimensional Printed Superficial Femoral Artery Model: A Preliminary Study. AB - BACKGROUND: Mechanical tests assessing Nitinol stents used for the superficial femoral artery (SFA) are designed without taking into account their deployment environments. The objectives of this study were (1) to create normal and pathologic femoral artery models, (2) to run mechanical tests reproducing the stresses of the SFA, and (3) to study and compare Nitinol stents in those conditions. METHODS: Femoral artery models with identical mechanical properties to the SFA were created using the 3-dimensional printing technology. Those models were designed with and without an asymmetric focal 50% stenosis. Three mechanical tests (bending-compression, bending-compression-torsion, and multiple bending tests) were created and 1 flexible stent was tested, of 6 and 7-mm diameter. Three samples of the stent, LifeStent (Bard((r))), were deployed and tested in the models. Stents alone were evaluated in the same conditions. The analysis focused on the comparison of rheologic curves, level of kink, and the energy deployed for each stent to kink. RESULTS: In the 3 tests, all stents deployed in the models presented a kink during their evaluation. When tested alone, during the compression-bending and bending-compression-torsion tests, no plicature was observed. During the multiple bending test, the energy deployed to plicature for the stent tested alone was of 1.4 +/- 0.10 and 2.84 +/- 0.1 J compared with 9.7 +/- 0.6 and 8.25 +/- 0.6 J when deployed in the model for the Lifestent 6 * 80 and 7 * 80 mm, respectively. For all of these 3 tests, 6-mm diameter stents exhibited a level of kink and energy of kink higher than 7 mm stents. The behavior of the stents changed in the stenosed model whatever diameter is taken into account. Analysis of the rheologic curves showed a decrease in the inflection of the curve related to the plication. In the bending-compression test, the presence of a stenosis lead to an early plication of the model, with less deployed kinking energy whereas in the bending, compression, and torsion test, this earliness was absent. CONCLUSIONS: This study permitted the creation of a mechanical test platform evaluating Nitinol stents in bending situations. It tends to confirm the mechanical deleterious effect of excessive oversizing. This study confirms the necessity to evaluate Nitinol stents in their deployment environments. PMID- 26597247 TI - Endovascular Treatment of Aortoduodenal Syndrome. AB - PURPOSE: Duodenal obstruction caused by aneurysmal dilatation of the abdominal aorta is a rare clinical entity that is traditionally treated by open aneurysm repair, aneurysmorrhaphy, and duodenal release. We present here the case of aortoduodenal syndrome treated by endovascular therapy. CASE REPORT: A 73-year old man diagnosed simultaneously with sigmoidovesical fistula and an abdominal aortic aneurysm (AAA) underwent resection of the sigmoid colon followed by colostomy. On postoperative day 34, the patient experienced nausea and vomiting. Computed tomography revealed the AAA causing duodenal obstruction by direct compression. We chose endovascular therapy for treating the AAA rather than graft replacement because of the risk of infection by the colostomy orifice. Postoperatively, the patient reacquired the ability to eat. However, postoperative computed tomography revealed that the diameter of the AAA had not changed. CONCLUSIONS: We considered that the decreased intra-aneurysmal pressure caused a release of duodenal obstruction. PMID- 26597248 TI - Iliac Artery Stenting Combined with Open Iliofemoral Endarterectomy Facilitated by a Novel Ultrasonic Ablation Instrument for Diffuse Iliofemoral Occlusive Disease. AB - An 81-year-old male complained of intermittent claudication of the right leg. Computed tomography (CT) revealed a right external iliac artery (EIA) stenosis with severe calcification extending to the common femoral artery. A hybrid procedure of endarterectomy and stenting was performed. EIA endarterectomy was performed using a novel Cavitron Ultrasonic Surgical Aspirator which ablated the inside of the distal EIA without arterial injury. A stent graft was placed in the proximal EIA covering the margin of endarterectomized distal EIA. Postoperative CT showed no stenosis, and symptoms in the leg disappeared. This could be an alternative procedure for iliofemoral occlusive disease. PMID- 26597249 TI - Phosphatidylinositol- 3-kinase inhibitor induces chemosensitivity to a novel derivative of doxorubicin, AD198 chemotherapy in human bladder cancer cells in vitro. AB - BACKGROUND: Doxorubicin (Dox) is widely used to treat progressed bladder cancer after transurethral resection. The use of Dox-chemotherapy has been limited due to induced drug resistance and cumulative cardiotoxic effects. N-benzyladriamycin 14-valerate (AD198), a novel derivative of Dox, has a potential to become a more effective treatment than Dox by overcoming drug resistance and cardio-toxicity as shown in the rodent model of lymphoma in vivo. The purpose of this study was to compare the efficacy of Dox and AD198 and explore their mechanisms in inhibition on human bladder cancer cells in vitro. METHODS: We evaluated the effects of Dox and AD198 on cell viability of human transitional cell carcinoma (TCC) cell lines T24 and UMUC3 by MTS assay in vitro. The effects of Dox and AD198 on cell apoptosis were determined by caspase 3/7 assay, generation of reactive oxygen species (ROS), and Western Blotting (WB) analysis. RESULTS: AD198 was more effective than Dox in inhibition of cell viability of T24 and UMUC3 cells in vitro. Both Dox and AD198 significantly increased the generation of ROS and induced apoptosis in caspase-dependent and -independent manner in T24 and UMUC3 cells. AD 198 induced significantly higher production of ROS as compared to Dox in human TCC cells. Dox and AD198 activated the pro-apoptotic p38 MAPK pathway; however, on the other hand also increased phosphorylation of AKT, an anti apoptotic signaling pathway, in T24 and UMUC3 cells. Combined treatment of PI3K inhibitor (LY294002) with Dox or AD198 inhibited cell viability of T24 and UMUC3 cells more effectively than any of drug treatments alone. CONCLUSIONS: These data suggest that AD198 as novel derivative of Dox, could be a used as effective treatment for bladder cancer. Dox and AD198 induced PI3K/AKT signaling pathway that is a one of the indicators of pro-survival and possible drug-resistance mechanisms of chemotherapies in bladder cancer. Combined therapies of Dox or AD198 with inhibitors of PI3K/AKT signaling pathway might lead to more effective treatment outcome for patients diagnosed with bladder cancer based on our in vitro experiments. PMID- 26597250 TI - Evidence-based support for the use of proton pump inhibitors in cancer therapy. AB - 'We can only cure what we can understand first', said Otto H. Warburg, the 1931 Nobel laureate for his discovery on tumor metabolism. Unfortunately, we still don't know too much the mechanisms underlying of cancer development and progression. One of the unsolved mystery includes the strategies that cancer cells adopt to cope with an adverse microenvironment. However, we knew, from the Warburg's discovery, that through their metabolism based on sugar fermentation, cancer cells acidify their microenvironment and this progressive acidification induces a selective pressure, leading to development of very malignant cells entirely armed to survive in the hostile microenvironment generated by their own metabolism. One of the most mechanism to survive to the acidic tumor microenvironment are proton exchangers not allowing intracellular acidification through a continuous elimination of H(+) either outside the cells or within the internal vacuoles. This article wants to comment a translational process through which from the preclinical demonstration that a class of proton pump inhibitors (PPI) exploited worldwide for peptic ulcer treatment and gastroprotection are indeed chemosensitizers as well, we have got to the clinical proof of concept that PPI may well be included in new anti-cancer strategies, and with a solid background and rationale. PMID- 26597251 TI - Dosimetric evaluation of synthetic CT relative to bulk density assignment-based magnetic resonance-only approaches for prostate radiotherapy. AB - BACKGROUND: Magnetic resonance imaging (MRI) has been incorporated as an adjunct to CT to take advantage of its excellent soft tissue contrast for contouring. MR only treatment planning approaches have been developed to avoid errors introduced during the MR-CT registration process. The purpose of this study is to evaluate calculated dose distributions after incorporating a novel synthetic CT (synCT) derived from magnetic resonance simulation images into prostate cancer treatment planning and to compare dose distributions calculated using three previously published MR-only treatment planning methodologies. METHODS: An IRB-approved retrospective study evaluated 15 prostate cancer patients that underwent IMRT (n = 11) or arc therapy (n = 4) to a total dose of 70.2-79.2 Gy. Original treatment plans were derived from CT simulation images (CT-SIM). T1-weighted, T2-weighted, and balanced turbo field echo images were acquired on a 1.0 T high field open MR simulator with patients immobilized in treatment position. Four MR-derived images were studied: bulk density assignment (10 HU) to water (MRW), bulk density assignments to water and bone with pelvic bone values derived either from literature (491 HU, MRW+B491) or from CT-SIM population average bone values (300 HU, MRW+B300), and synCTs. Plans were recalculated using fixed monitor units, plan dosimetry was evaluated, and local dose differences were characterized using gamma analysis (1 %/1 mm dose difference/distance to agreement). RESULTS: While synCT provided closest agreement to CT-SIM for D95, D99, and mean dose (<0.7 Gy (1 %)) compared to MRW, MRW+B491, and MRW+B300, pairwise comparisons showed differences were not significant (p < 0.05). Significant improvements were observed for synCT in the bladder, but not for rectum or penile bulb. SynCT gamma analysis pass rates (97.2 %) evaluated at 1 %/1 mm exceeded those from MRW (94.7 %), MRW+B300 (94.0 %), or MRW+B491 (90.4 %). One subject's synCT gamma (1 %/1 mm) results (89.9 %) were lower than MRW (98.7 %) and MRW+B300 (96.7 %) due to increased rectal gas during MR-simulation that did not affect bulk density assignment-based calculations but was reflected in higher rectal doses for synCT. CONCLUSIONS: SynCT values provided closest dosimetric and gamma analysis agreement to CT-SIM compared to bulk density assignment-based CT surrogates. SynCTs may provide additional clinical value in treatment sites with greater air to-soft tissue ratio. PMID- 26597252 TI - Liraglutide in Type 2 Diabetes Mellitus: Clinical Pharmacokinetics and Pharmacodynamics. AB - Liraglutide is an acylated glucagon-like peptide-1 analogue with 97 % amino acid homology with native glucagon-like peptide-1 and greatly protracted action. It is widely used for the treatment of type 2 diabetes mellitus, and administered by subcutaneous injection once daily. The pharmacokinetic properties of liraglutide enable 24-h exposure coverage, a requirement for 24-h glycaemic control with once daily dosing. The mechanism of protraction relates to slowed release from the injection site, and a reduced elimination rate owing to metabolic stabilisation and reduced renal filtration. Drug exposure is largely independent of injection site, as well as age, race and ethnicity. Increasing body weight and male sex are associated with reduced concentrations, but there is substantial overlap between subgroups; therefore, dose escalation should be based on individual treatment outcome. Exposure is reduced with mild, moderate or severe renal or hepatic impairment. There are no clinically relevant changes in overall concentrations of various drugs (e.g. paracetamol, atorvastatin, griseofulvin, digoxin, lisinopril and oral combination contraceptives) when co-administered with liraglutide. Pharmacodynamic studies show multiple beneficial actions with liraglutide, including improved fasting and postprandial glycaemic control (mediated by increased insulin and reduced glucagon levels and minor delays in gastric emptying), reduced appetite and energy intake, and effects on postprandial lipid profiles. The counter-regulatory hormone response to hypoglycaemia is largely unaltered. The effects of liraglutide on insulin and glucagon secretion are glucose dependent, and hence the risk of hypoglycaemia is low. The pharmacokinetic and pharmacodynamic properties of liraglutide make it an important treatment option for many patients with type 2 diabetes. PMID- 26597253 TI - The Effect of Famotidine, a MATE1-Selective Inhibitor, on the Pharmacokinetics and Pharmacodynamics of Metformin. AB - INTRODUCTION: Pharmacokinetic outcomes of transporter-mediated drug-drug interactions (TMDDIs) are increasingly being evaluated clinically. The goal of our study was to determine the effects of selective inhibition of multidrug and toxin extrusion protein 1 (MATE1), using famotidine, on the pharmacokinetics and pharmacodynamics of metformin in healthy volunteers. METHODS: Volunteers received metformin alone or with famotidine in a crossover design. As a positive control, the longitudinal effects of famotidine on the plasma levels of creatinine (an endogenous substrate of MATE1) were quantified in parallel. Famotidine unbound concentrations in plasma reached 1 uM, thus exceeding the in vitro concentrations that inhibit MATE1 [concentration of drug producing 50 % inhibition (IC50) 0.25 uM]. Based on current regulatory guidance, these concentrations are expected to inhibit MATE1 clinically [i.e. maximum unbound plasma drug concentration (C max,u)/IC50 >0.1]. RESULTS: Consistent with MATE1 inhibition, famotidine administration significantly altered creatinine plasma and urine levels in opposing directions (p < 0.005). Interestingly, famotidine increased the estimated bioavailability of metformin [cumulative amount of unchanged drug excreted in urine from time zero to infinity (A einfinity)/dose; p < 0.005] without affecting its systemic exposure [area under the plasma concentration-time curve (AUC) or maximum concentration in plasma (C max)] as a result of a counteracting increase in metformin renal clearance. Moreover, metformin famotidine co-therapy caused a transient effect on oral glucose tolerance tests [area under the glucose plasma concentration-time curve between time zero and 0.5 h (AUCglu,0.5); p < 0.005]. CONCLUSIONS: These results suggest that famotidine may improve the bioavailability and enhance the renal clearance of metformin. PMID- 26597254 TI - Artesunate/Amodiaquine Versus Artemether/Lumefantrine for the Treatment of Uncomplicated Malaria in Uganda: A Randomized Trial. AB - BACKGROUND: In treating malaria in Uganda, artemether-lumefantrine (AL) has been associated with a lower risk of recurrent parasitemia, compared with artesunate amodiaquine (AS/AQ), but changing treatment practices may have altered parasite susceptibility. METHODS: We enrolled 602 children aged 6-59 months with uncomplicated falciparum malaria from 3 health centers in 2013-2014 and randomly assigned them to receive treatment with AS/AQ or AL. Primary outcomes were risks of recurrent parasitemia within 28 days, with or without adjustment to distinguish recrudescence from new infection. Drug safety and tolerability and Plasmodium falciparum resistance-mediating polymorphisms were assessed. RESULTS: Of enrolled patients, 594 (98.7%) completed the 28-day study. Risks of recurrent parasitemia were lower with AS/AQ at all 3 sites (overall, 28.6% vs 44.6%; P < .001). Recrudescences were uncommon, and all occurred after AL treatment (0% vs 2.5%; P = .006). Recovery of the hemoglobin level was greater with AS/AQ (1.73 vs 1.39 g/dL; P = .04). Both regimens were well tolerated; serious adverse events were uncommon (1.7% in the AS/AQ group and 1.0% in the AL group). AS/AQ selected for mutant pfcrt/pfmdr1 polymorphisms and AL for wild-type pfcrt/pfmdr1 polymorphisms associated with altered drug susceptibility. CONCLUSIONS: AS/AQ treatment was followed by fewer recurrences than AL treatment, contrasting with older data. Each regimen selected for polymorphisms associated with decreased treatment response. Research should consider multiple or rotating regimens to maintain treatment efficacies. PMID- 26597255 TI - Substantial Influenza Vaccine Effectiveness in Households With Children During the 2013-2014 Influenza Season, When 2009 Pandemic Influenza A(H1N1) Virus Predominated. AB - BACKGROUND: We examined the influenza vaccine effectiveness (VE) during the 2013 2014 influenza season, in which 2009 pandemic influenza A(H1N1) virus (influenza A[H1N1]pdm09) predominated. In 2 previous years when influenza A(H3N2) virus predominated, the VE was low and negatively affected by prior year vaccination. METHODS: We enrolled and followed 232 households with 1049 members, including 618 children; specimens were collected from subjects with acute respiratory illnesses. The VE in preventing laboratory-confirmed influenza A(H1N1)pdm09 infection was estimated in adjusted models. Preseason hemagglutination-inhibition and neuraminidase-inhibition antibody titers were determined to assess susceptibility. RESULTS: Influenza A(H1N1)pdm09 was identified in 25 households (10.8%) and 47 individuals (4.5%). Adjusted VE against infection with influenza A(H1N1)pdm09 was 66% (95% confidence interval [CI], 23%-85%), with similar point estimates in children and adults, and against both community-acquired and household-acquired infections. VE did not appear to be different for live attenuated and inactivated vaccines among children aged 2-8 years, although numbers were small. VE was similar for subjects vaccinated in both current and prior seasons and for those vaccinated in the current season only; susceptibility titers were consistent with this observation. CONCLUSIONS: Findings, including substantial significant VE and a lack of a negative effect of repeated vaccination on VE, were in contrast to those seen in prior seasons in which influenza A(H3N2) virus predominated. PMID- 26597257 TI - Deployment of the French Military Field Laboratory Dedicated to Ebola Virus Infected Patients in Guinea, January-July 2015. PMID- 26597256 TI - Whole-Exome Sequencing Reveals Mutations in Genes Linked to Hemophagocytic Lymphohistiocytosis and Macrophage Activation Syndrome in Fatal Cases of H1N1 Influenza. AB - BACKGROUND: Severe H1N1 influenza can be lethal in otherwise healthy individuals and can have features of reactive hemophagocytic lymphohistiocytosis (HLH). HLH is associated with mutations in lymphocyte cytolytic pathway genes, which have not been previously explored in H1N1 influenza. METHODS: Sixteen cases of fatal influenza A(H1N1) infection, 81% with histopathologic hemophagocytosis, were identified and analyzed for clinical and laboratory features of HLH, using modified HLH-2004 and macrophage activation syndrome (MAS) criteria. Fourteen specimens were subject to whole-exome sequencing. Sequence alignment and variant filtering detected HLH gene mutations and potential disease-causing variants. Cytolytic function of the PRF1 p.A91V mutation was tested in lentiviral transduced NK-92 natural killer (NK) cells. RESULTS: Despite several lacking variables, cases of influenza A(H1N1) infection met 44% and 81% of modified HLH 2004 and MAS criteria, respectively. Five subjects (36%) carried one of 3 heterozygous LYST mutations, 2 of whom also possessed the p.A91V PRF1 mutation, which was shown to decrease NK cell cytolytic function. Several patients also carried rare variants in other genes previously observed in MAS. CONCLUSIONS: This cohort of fatal influenza A(H1N1) infections confirms the presence of hemophagocytosis and HLH pathology. Moreover, the high percentage of HLH gene mutations suggests they are risk factors for mortality among individuals with influenza A(H1N1) infection. PMID- 26597258 TI - Cytomegalovirus Infection in Human Immunodeficiency Virus (HIV)-Exposed and HIV Infected Infants: A Systematic Review. AB - Cytomegalovirus is highly prevalent worldwide and an important opportunistic pathogen in human immunodeficiency virus (HIV)-infected individuals. The effects of cytomegalovirus infection on HIV-exposed infants are poorly understood. We conducted a systematic review to assess the relationship between cytomegalovirus and HIV infections among HIV-exposed infants. Limited evidence suggests that HIV induced immunosuppression in the mother increases the rate of congenital cytomegalovirus infection, while maternal antiretroviral therapy may reduce it. Limited information exists on the direction of the relationship between cytomegalovirus and HIV transmission among HIV-exposed infants. Only 2 studies have addressed this temporal sequence of events, and they suggest that cytomegalovirus can lead to subsequent HIV infection in HIV-exposed infants. Most evidence suggests that early cytomegalovirus infection accelerates HIV disease progression in infants. Gaps remain in understanding the role that cytomegalovirus infection plays in HIV-exposed infants. Decreasing cytomegalovirus transmission prenatally and in infancy might further decrease HIV transmission and lead to better health among HIV-exposed infants. PMID- 26597259 TI - Human Polymorphisms in Placentally Expressed Genes and Their Association With Susceptibility to Congenital Trypanosoma cruzi Infection. AB - BACKGROUND: It is currently unclear why only a proportion of children born to Trypanosoma cruzi-infected mothers acquire the infection. We have examined the association of 11 single-nucleotide polymorphisms (SNPs) located in genes coding for placental expression enzymes as genetic markers of susceptibility to congenital T. cruzi infection (hereafter, "congenital infection"): rs2014683 and rs1048988 in ALPP; rs11244787 and rs1871054 in ADAM12; rs243866, rs243865, rs17859821, rs243864, and rs2285053 in MMP2; and rs3918242 and rs2234681 in MMP9. METHODS: Two groups of children born to mothers seropositive for T. cruzi were compared: 101 had congenital infection, and 116 were uninfected. Novel high resolution melting and capillary electrophoresis genotyping techniques were designed and used. RESULTS: Logistic regression analysis showed that mutations in rs11244787 and rs1871054 (in ADAM12) and rs243866, rs17859821, and rs2285053 (in MMP2) were associated with susceptibility to congenital infection. Multifactor dimensionality reduction revealed that genotyping results for rs11244787, rs1871054, rs243866, rs17859821 and rs243864 sites would be a good predictor of congenital infection. CONCLUSIONS: Our results suggest an important role of human polymorphisms in proteins involved in extracellular matrix remodeling and the immune response during congenital infection. To our knowledge, this is the first study demonstrating the association between mutations in placentally expressed genes and susceptibility to congenital infection. PMID- 26597260 TI - Mosquito Surveillance for 15 Years Reveals High Genetic Diversity Among West Nile Viruses in Israel. AB - West Nile Virus (WNV) is endemic in Israel and has been the cause of several outbreaks in recent years. In 2000, a countrywide mosquito survey was established to monitor WNV activity and characterize viral genotypes in Israel. We analyzed data from 7135 pools containing 277 186 mosquitoes collected over the past 15 years and, here, report partial sequences of WNV genomes obtained from 102 of the 336 positive mosquito pools. Phylogenetic analysis demonstrated that cluster 4 and the Mediterranean and Eastern European subtypes of cluster 2 within WNV lineage 1 circulated in Israel, as did WNV lineage 2, highlighting a high genetic diversity of WNV genotypes in our region. As a major crossroads for bird migration between Africa and Eurasia and with a long history of human infection, Israel serves as a resource hub for WNV in Africa and Eurasia and provides valuable information on WNV circulation in these regions. PMID- 26597261 TI - Partner Human Papillomavirus Viral Load and Incident Human Papillomavirus Detection in Heterosexual Couples. AB - BACKGROUND: The association between partner human papillomavirus (HPV) viral load and incident HPV detection in heterosexual couples is unknown. METHODS: HPV genotypes were detected in 632 human immunodeficiency virus (HIV)-negative couples followed for 2 years in a male circumcision trial in Rakai, Uganda, using the Roche HPV Linear Array. This assay detects 37 genotypes and provides a semiquantitative measure of viral load based on the intensity (graded 1-4) of the genotype-specific band; a band intensity of 1 indicates a low genotype-specific HPV load, whereas an intensity of 4 indicates a high load. Using Poisson regression with generalized estimating equations, we measured the association between partner's genotype-specific viral load and detection of that genotype in the HPV-discordant partner 1 year later. RESULTS: Incident detection of HPV genotypes was 10.6% among men (54 of 508 genotype-specific visit intervals) and 9.0% among women (55 of 611 genotype-specific visit intervals). Use of male partners with a baseline genotype-specific band intensity of 1 as a reference yielded adjusted relative risks (aRRs) of 1.14 (95% confidence interval [CI], .58 2.27]) for incident detection of that genotype among women whose male partner had a baseline band intensity of 2, 1.75 (95% CI, .97-3.17) among those whose partner had an intensity of 3, and 2.52 (95% CI, 1.40-4.54) among those whose partner had an intensity of 4. Use of female partners with a baseline genotype-specific band intensity of 1 as a reference yielded an aRR of 2.83 (95% CI, 1.50-5.33) for incident detection of that genotype among men whose female partner had a baseline band intensity of 4. These associations were similar for high-risk and low-risk genotypes. Male circumcision also was associated with significant reductions in incident HPV detection in men (aRR, 0.53 [95% CI, .30-.95]) and women (aRR, 0.42 [95% CI, .23-.76]). CONCLUSIONS: In heterosexual couples, the genotype-specific HPV load in one partner is associated with the risk of new detection of that genotype in the other partner. Interventions that reduce the HPV load may reduce the incidence of HPV transmission. PMID- 26597262 TI - Measles Virus Neutralizing Antibody Response, Cell-Mediated Immunity, and Immunoglobulin G Antibody Avidity Before and After Receipt of a Third Dose of Measles, Mumps, and Rubella Vaccine in Young Adults. AB - BACKGROUND: Two doses of measles, mumps, and rubella (MMR) vaccine are 97% effective against measles, but waning antibody immunity to measles and failure of the 2-dose vaccine occur. We administered a third MMR dose (MMR3) to young adults and assessed immunogenicity over 1 year. METHODS: Measles virus (MeV) neutralizing antibody concentrations, cell-mediated immunity (CMI), and immunoglobulin G (IgG) antibody avidity were assessed at baseline and 1 month and 1 year after MMR3 receipt. RESULTS: Of 662 subjects at baseline, 1 (0.2%) was seronegative for MeV-neutralizing antibodies (level, <8 mIU/mL), and 23 (3.5%) had low antibody levels (8-120 mIU/mL). One month after MMR3 receipt, 1 subject (0.2%) was seronegative, and 6 (0.9%) had low neutralizing antibodies, with only 21 of 662 (3.2%) showing a >= 4-fold rise in neutralizing antibodies. One year after MMR3 receipt, no subject was seronegative, and 10 of 617 (1.6%) had low neutralizing antibody levels. CMI analyses showed low levels of spot-forming cells after stimulation, suggesting the presence of T-cell memory, but the response was minimal after MMR3 receipt. MeV IgG avidity did not correlate with findings of neutralization analyses. CONCLUSIONS: Most subjects were seropositive before MMR3 receipt, and very few had a secondary immune response after MMR3 receipt. Similarly, CMI and avidity analyses showed minimal qualitative improvements in immune response after MMR3 receipt. We did not find compelling data to support a routine third dose of MMR vaccine. PMID- 26597265 TI - Thrombus Features in Hyperacute Ischemic Stroke: A Perspective on Using Length and Density Evaluation. AB - BACKGROUND: More insights in the etiopathogenesis of thrombi could be helpful in the treatment of patients with acute ischemic stroke (AIS). One of the most confident and early imaging findings of stroke includes arterial hyperdensity. The purpose of this study was to determine whether thrombi's density and length would be useful for predicting their origin. METHODS: We evaluated 68 consecutive patients with AIS to correlate the presence of thrombi and their imaging features with the stroke subtype. RESULTS: After excluding patients with small-artery occlusion mechanism and undetermined and other causes, the stroke etiologic subtypes were large-artery atherosclerosis (LAA) in 59.0% of the patients, cardioembolism in 31.0%, and cervical artery dissection (CAD) in 10.0%. CAD more often caused thrombi with the longest length and highest attenuation, while thrombi that originated from the LAA had the smallest length and lowest attenuation. The mean Hounsfield unit (HU) values of all thrombi (with and without hyperdensity) on noncontrast computed tomography were 62.4 (50.0-70.0) in CAD, 53.8 (42.0-65.0) in cardioembolism, and 48.6 (27.0-65.0) in LAA. The length measurements were 28.5 mm (12.0-52.0) in CAD, 13.7 mm (5.0-31.0) in cardioembolism, and 10.8 mm (3.0-25.0) in the LAA subtype. The minimum cutoff value of 60 HU and a length greater than 20 mm were able to discriminate the CAD thrombi with an accuracy of 86.8% and 92.6%, respectively. CONCLUSION: Our study findings show how important thrombus analysis is in patients with AIS. Thrombus analysis can allow early suspicion of CAD before dedicated imaging of the cervical arteries is performed. PMID- 26597263 TI - Stepped care for depression and anxiety in visually impaired older adults: multicentre randomised controlled trial. AB - STUDY QUESTION: Is stepped care compared with usual care effective in preventing the onset of major depressive, dysthymic, and anxiety disorders in older people with visual impairment (caused mainly by age related eye disease) and subthreshold depression and/or anxiety? METHODS: 265 people aged >=50 were randomly assigned to a stepped care programme plus usual care (n=131) or usual care only (n=134). Supervised occupational therapists, social workers, and psychologists from low vision rehabilitation organisations delivered the stepped care programme, which comprised watchful waiting, guided self help based on cognitive behavioural therapy, problem solving treatment, and referral to a general practitioner. The primary outcome was the 24 month cumulative incidence (seven measurements) of major depressive dysthymic and/or anxiety disorders (panic disorder, agoraphobia, social phobia, and generalised anxiety disorder). Secondary outcomes were change in symptoms of depression and anxiety, vision related quality of life, health related quality of life, and adaptation to vision loss over time up to 24 months' follow-up. STUDY ANSWER AND LIMITATIONS: 62 participants (46%) in the usual care group and 38 participants (29%) from the stepped care group developed a disorder. The intervention was associated with a significantly reduced incidence (relative risk 0.63, 95% confidence interval 0.45 to 0.87; P=0.01), even if time to the event was taken into account (adjusted hazard ratio 0.57, 0.35 to 0.93; P=0.02). The number needed to treat was 5.8 (3.5 to 17.3). The dropout rate was fairly high (34.3%), but rates were not significantly different for the two groups, indicating that the intervention was as acceptable as usual care. Participants who volunteered and were selected for this study might not be representative of visually impaired older adults in general (responders were significantly younger than non-responders), thereby reducing the generalisability of the outcomes. WHAT THIS STUDY ADDS: Stepped care seems to be a promising way to deal with depression and anxiety in visually impaired older adults. This approach could lead to standardised strategies for the screening, monitoring, treatment, and referral of visually impaired older adults with depression and anxiety. FUNDING, COMPETING INTERESTS, DATA SHARING: Funded by ZonMw InZicht, the Dutch Organisation for Health Research and Development-InSight Society. There are no competing interests. Full dataset and statistical code are available from the corresponding author.Study registration www.trialregister.nl NTR3296. PMID- 26597264 TI - The Etiologies of Early Neurological Deterioration after Thrombolysis and Risk Factors of Ischemia Progression. AB - BACKGROUND: We investigated the incidence and risk factors of early neurological worsening according to ischemia progression among acute cerebral infarction patients after intravenous thrombolysis. METHODS: The medical records of consecutive cerebral infarction patients treated with intravenous thrombolysis from 2 university hospitals were reviewed. Early neurological deterioration (END) was defined as 2 or more National Institutes of Health Stroke Scale aggravations within 24 hours after thrombolysis, and its etiologies were categorized by follow up imaging into 3 groups: ischemia progression, symptomatic hemorrhage, and brain edema. We compared clinical variables between the group of patients with ischemia progression and the patients without neurological deterioration to derive etiology-specific risk factors. RESULTS: A total of 210 patients were included in this study, with 57 (26.2%) patients experiencing neurological deterioration. The prevalence of patients with END due to ischemia progression (27 patients, 12.9%) outnumbered the prevalence of patients with neurological deterioration due to symptomatic hemorrhage (n = 13) or brain edema (n = 15). Compared to the group of patients without END, the patients with ischemia progression were more likely to have a stroke subtype of large-artery atherosclerosis, to be current smokers, and to have less severe initial neurological deficits. Multivariate logistic regression analysis revealed that large-artery atherosclerosis was an independent predictor of END due to ischemia progression (odds ratio = 3.8, confidence interval = 1.6-9.3). CONCLUSIONS: A major contributor to END within 24 hours after intravenous thrombolysis was ischemia progression, and the stroke subtype of large-artery atherosclerosis predicted ischemia progression. PMID- 26597266 TI - Multi-institutional Experience in Laparoendoscopic Single-site Surgery (LESS): For Major Extirpative and Reconstructive Procedures in Pediatric Urology. AB - OBJECTIVE: To review peri-procedural outcomes from a large, multi-institutional series of pediatric urology patients treated with laparaendoscopic single-site surgery (LESS) for major extirpative and reconstructive procedures. MATERIALS AND METHODS: Consecutive LESS cases between January 2011 and May 2014 from three free standing pediatric referral centers were reviewed. Data include age, sex, operative time, blood loss, length of stay, and complications according to the modified Clavien-Dindo classification. Hasson technique was used for peritoneal entry, GelPOINT advanced access platform was inserted, and standard 5mm laparoscopic instruments were used. RESULTS: Fifty-nine patients (median age 5 years, 4 months-17 years) met inclusion criteria: 29 nephrectomies, 9 nephroureterectomies, 3 bilateral nephrectomies, 5 heminephrectomies, 5 renal cyst decortications, 3 bilateral gonadectomies, 2 Malone antegrade continence enema, 2 calyceal diverticulectomy, and 1 ovarian detorsion with cystectomy. Median operative times for each case type were comparable to published experiences with traditional laparoscopy. Overall mean and median length of stay was 36.2 hours and 1 day, respectively. There were two complications: port site hernia requiring surgical repair (Clavien IIIb) and a superficial port site infection that resolved with antibiotics (Clavien II). Cosmetic outcomes were subjectively well received by patients and their parents. Operative time was significantly shorter between the first half of the experience and the second half (102 vs 70 minutes, P < .05). CONCLUSION: LESS approach can be broadly applied across many major extirpative and reconstructive procedures within pediatric urology. Our series advances our field's utilization of this technique and its safety. PMID- 26597268 TI - Spontaneous Rupture of Anaplastic Pancreatic Cancer. PMID- 26597267 TI - Review: mapping epidermal beta-protein distribution in the lizard Anolis carolinensis shows a specific localization for the formation of scales, pads, and claws. AB - The epidermis of lizards is made of multiple alpha- and beta-layers with different characteristics comprising alpha-keratins and corneous beta-proteins (formerly beta-keratins). Three main modifications of body scales are present in the lizard Anolis carolinensis: gular scales, adhesive pad lamellae, and claws. The 40 corneous beta-proteins present in this specie comprise glycine-rich and glycine-cysteine-rich subfamilies, while the 41 alpha-keratins comprise cysteine poor and cysteine-rich subfamilies, the latter showing homology to hair keratins. Other genes for corneous proteins are present in the epidermal differentiation complex, the locus where corneous protein genes are located. The review summarizes the main sites of immunolocalization of beta-proteins in different scales and their derivatives producing a unique map of body distribution for these structural proteins. Small glycine-rich beta-proteins participate in the formation of the mechanically resistant beta-layer of most scales. Small glycine cysteine beta-proteins have a more varied localization in different scales and are also present in the pliable alpha-layer. In claws, cysteine-rich alpha keratins prevail over cysteine-poor alpha-keratins and mix to glycine-cysteine rich beta-proteins. The larger beta-proteins with a molecular mass similar to that of alpha-keratins participate in the formation of the fibrous meshwork present in differentiating beta-cells and likely interact with alpha-keratins. The diverse localization of alpha-keratins, beta-proteins, and other proteins of the epidermal differentiation complex gives rise to variably pliable, elastic, or hard corneous layers in different body scales. The corneous layers formed in the softer or harder scales, in the elastic pad lamellae, or in the resistant claws possess peculiar properties depending on the ratio of specific corneous proteins. PMID- 26597269 TI - A Cohort Study for Derivation and Validation of Early Detection of Pancreatic Fistula After Pancreaticoduodenectomy. AB - BACKGROUND: Pancreatic fistula (PF) remains the most important morbidity after pancreaticoduodenectomy (PD). Early drain removal was recently recommended. However, this is not applicable to all cases because the development of severe PF may not be obvious until a later postoperative day (POD). This study aimed to discover ways to detect clinically relevant PF early during the postoperative stage after PD. METHODS: We studied 120 patients who underwent PD. Grades B/C PF classified according to the International Study Group of Pancreatic Surgery guidelines were defined as clinically relevant PF. Logistic regression was used to identify detection factors for clinically relevant PF. Receiver operating characteristic curves were used to identify the optimal cutoff value for clinically relevant PF, and the k-fold cross-validation model to validate the cutoff value. RESULTS: Drain amylase on POD 1 and C-reactive protein (CPR) on POD 2 were independent factors for clinically relevant PF. Drain amylase >1300 IU/l on POD 1 and CRP >12.8 g/dl on POD 2 were the best cutoff values for clinically relevant PF detection and were confirmed by k-fold cross-validation. The sensitivity and specificity values were 79 and 81 %, respectively. CONCLUSIONS: Values of drain amylase and CRP combined were useful to distinguish clinically relevant PF. PMID- 26597270 TI - Endoscopic Vacuum Therapy in Colorectal Surgery. AB - INTRODUCTION: Endoscopic vacuum therapy (EVT) has been established in Germany for the treatment of anastomotic leakage after rectal resection. Continuous or intermittent suction and drainage decrease bacterial contamination, secretion, and local edema promoting perfusion and granulation at the same time. However, data for use and long-term results of EVT in colorectal surgery are still scarce and are often limited by short-term follow-up. OBJECTIVES: Here, we aimed at analyzing the treatment spectrum and long-term outcome of EVT for defects of the lower gastrointestinal tract. METHODS: This is a retrospective single-center analysis of EVT for defects of the lower gastrointestinal tract of different etiology in 41 patients over a time period of 8 years (2007-2015) with a mean follow-up of 36 (2-89) months. RESULTS: In total, 426 polyurethane sponges were placed in lower GI defects of 41 patients (31 male, 10 female) with a median age of 70 years (range, 29-91). Most frequent indications for EVT were anastomotic leakage after rectal resection (n = 20), Hartmann's stump insufficiency (n = 12), and rectal perforation (n = 3). The median number of sponge insertions was six (range, 1-37) with a mean changing interval of 3 days (range, 1-5). Median time of therapy was 20 days. A successful vacuum therapy with local control of the septic focus was achieved in 18 of 20 patients (90 %) with anastomotic leakage after rectal resection and in nine of 12 patients with a Hartmann's stump insufficiency. In 15 of 19 (79 %) patients with a diverting stoma, take-down after successful treatment was possible. Median time to closure was 244 days (range, 152-488 days). CONCLUSION: To our knowledge, this retrospective observation of EVT application for rectal lesions represents the largest patient series in literature. EVT has earned its indication in complication management after colorectal surgery and can achieve a successful control of a local septic focus in the majority of patients. PMID- 26597271 TI - Society for Surgery of the Alimentary Tract Presidential Address: Advanced GI Surgery Training: Past and Future Role of the SSAT. PMID- 26597272 TI - [Inhaled loxapine for emergency treatment of agitated patients with borderline personality disorder : A series of five cases]. PMID- 26597273 TI - [Psychiatric comorbidities with tobacco-related disorders]. AB - The coincidence of tobacco smoking and psychiatric disorders is of great epidemiological and therapeutic importance. Tobacco smoking by people with mental disorders leads to disproportionately high somatic health risks, an adverse clinical course, poorer clinical outcomes and reduced quality of life (QoL). The etiological causes of the high comorbidity between smoking and mental disorders are still unclear: currently, tobacco smoking is discussed as being either the consequence or contributory cause of psychological disorders or both disorders share common antecedents and interactions. Psychiatric patients are motivated to quit and smoking cessation is not generally less effective with smokers with mental disorders than with mentally healthy individuals. Specific smoking cessation programs in the inpatient and outpatient settings are time-consuming and complex but effective. Within the framework of the current S3 guidelines the international evidence has been updated and transformed into treatment guidelines following an elaborate consensus process. Basically the same interventional measures should be used as with mentally healthy individuals; however, smokers with a psychological comorbidity often need more intensive adjuvant psychotherapeutic interventions and often need pharmaceutical support, (bupropion, varenicline and nicotine replacement therapy). Due to the overall unsatisfactory findings the treatment guidelines are partially based on clinical consensus decisions. In this field, a considerable need for research has been determined. PMID- 26597275 TI - [Advantages and controversies of depot antipsychotics in the treatment of patients with schizophrenia]. AB - BACKGROUND: The objective of this article is to give an overview of the advantages and disadvantages of the use of depot antipsychotics in the treatment of schizophrenia. The focus is on efficacy, tolerability, relapse prevention, patient compliance and satisfaction compared to oral administration forms. MATERIAL AND METHODS: A literature search was conducted in medical databases. The results of meta-analyses, randomized controlled trials and systematic reviews from the years 1999-2014 were included. RESULTS AND DISCUSSION: Depot antipsychotics ensure maintenance of constant blood levels and a continuous medication delivery. The efficacy and tolerability of depot antipsychotics are comparable to oral administration forms. Due to an improved medication compliance a reduction of relapse and hospitalization rates can be achieved. This is a key focus for improving outcomes and reducing costs in the treatment of schizophrenia. PMID- 26597274 TI - [Depression and epilepsy : Two clinical pictures with common causes?]. AB - BACKGROUND: Epilepsy and depressive disorders show a high rate of comorbidity. Thus, neurobiological similarities and a bidirectional relationship in terms of pathogenesis have been suggested. OBJECTIVES: The aim of this article is to present the common neurobiological features of both disorders, to characterize the bidirectional relationship and to provide an overview of therapeutic consequences. MATERIAL AND METHODS: A review of the current literature and evaluation of studies on the topics of depression and epilepsy are presented. RESULTS: Epilepsy and depression share common neurobiological features. In epileptic patients depression should be diagnosed early and reliably as the successful treatment has a great influence on the prognosis, quality of life and suicide risk in these individuals. In therapeutic doses, antidepressive medication with noradrenergic and specific serotonergic antidepressants (NaSSA) or selective serotonin reuptake inhibitors (SSRI) imparts no clinically relevant epileptogenic potential; however, it increases the quality of life and could have anticonvulsant effects in patients with epilepsy. Clomipramine, bupropion and maprotiline, however, should not be administered to patients with epilepsy as they are known to lower the seizure threshold. PMID- 26597276 TI - Susceptibility to ceftriaxone and occurrence of penicillinase plasmids in Neisseria gonorrhoeae strains isolated in Poland in 2012-2013. AB - Recent years have seen rising concerns over increasing antibiotic resistance of the gonorrhea-causing bacterium, Neisseria gonorrhoeae. This is especially true for third-generation cephalosporins, which are currently recommended for the treatment of such infections. Therefore, susceptibility to these antibiotics should be monitored internationally to the greatest extent possible. The susceptibility of N. gonorrhoeae strains to ceftriaxone and penicillin, as well as production of beta-lactamase by the Cefinase test was determined. Moreover, the presence and type of penicillinase plasmids were determined by PCR. All strains were susceptible to ceftriaxone, the minimal inhibitory concentration (MIC) values ranged from 0.002 to 0.125 mg/L; MIC50 was =0.016 mg/L and MIC90 was =0.064 mg/L. As much as 7.7 % of the strains demonstrated ceftriaxone MIC of 0.125 mg/L. For penicillin, the MICs ranged from 0.064 to 32 mg/L; MIC50 was =0.5 mg/L and MIC90 was =4 mg/L. It was shown that only 1.5 % of the strains were sensitive to penicillin according to The European Committee on Antimicrobial Susceptibility Testing (EUCAST). Among the penicillin-resistant strains, six (30.0 %) produced penicillinase. The MICs of penicillin were substantially higher for penicillinase-producing than for penicillin-resistant, penicillinase-negative strains. MICs of ceftriaxone for penicillinase-producing strains were low (0.002 0.016 mg/L). Three of the penicillinase-producing strains possessed plasmids of African type (50 %) and three Toronto/Rio type (50 %). An increase of the proportion of beta-lactamase-positive strains in the last years as well as emergence of strains with elevated MIC of ceftriaxone indicate a need to constantly monitor N. gonorrhoeae strains for their susceptibility to beta-lactam antibiotics, as well as for their ability to produce beta-lactamases. PMID- 26597278 TI - Identification, characterization and expression analysis of lineage-specific genes within sweet orange (Citrus sinensis). AB - BACKGROUND: With the availability of rapidly increasing number of genome and transcriptome sequences, lineage-specific genes (LSGs) can be identified and characterized. Like other conserved functional genes, LSGs play important roles in biological evolution and functions. RESULTS: Two set of citrus LSGs, 296 citrus-specific genes (CSGs) and 1039 orphan genes specific to sweet orange, were identified by comparative analysis between the sweet orange genome sequences and 41 genomes and 273 transcriptomes. With the two sets of genes, gene structure and gene expression pattern were investigated. On average, both the CSGs and orphan genes have fewer exons, shorter gene length and higher GC content when compared with those evolutionarily conserved genes (ECs). Expression profiling indicated that most of the LSGs expressed in various tissues of sweet orange and some of them exhibited distinct temporal and spatial expression patterns. Particularly, the orphan genes were preferentially expressed in callus, which is an important pluripotent tissue of citrus. Besides, part of the CSGs and orphan genes expressed responsive to abiotic stress, indicating their potential functions during interaction with environment. CONCLUSION: This study identified and characterized two sets of LSGs in citrus, dissected their sequence features and expression patterns, and provided valuable clues for future functional analysis of the LSGs in sweet orange. PMID- 26597279 TI - A qualitative study of the views of adolescents on their caries risk and prevention behaviours. AB - BACKGROUND: The purpose of this study was to explore the attitudes and beliefs of adolescents towards dental caries and their use or non-use of caries prevention regimens. METHODS: Adolescents aged 16 years from four state-funded secondary schools in North West of England (n = 19). Purposive sampling strategically selected participants with characteristics to inform the study aims (gender, ethnicity, and caries status). Semi-structured interviews were transcribed verbatim and analysed using a framework approach. RESULTS: 14 codes within five overarching themes were identified: "Personal definition and understanding of oral health"; "Knowledge of oral health determinants"; "Influences on oral health care"; Reason for oral health behaviours"; and "Oral health in the future". Adolescents conceptualise oral health as the absence of oral pathology and the ability to function, which included an aesthetic component. Appearing to have healthy teeth was socially desirable and equated with positive self-image. The dominant influence over oral health behaviours was habitual practice encouraged by parents from a young age, with limited reinforcement at school or by dental practices. At this transitional age, participants recognised the increasing influence of peers over health behaviours. Self-efficacy pertained to diet modification (reduction in sugar-ingestion) and oral hygiene behaviour (tooth brushing). A lack of understanding of caries aetiology was evident. Behaviours were mitigated by a lack of environmental support; and a desire for immediate gratification often overcame attempts at risk-reducing behaviour. CONCLUSIONS: Parents primarily influence the habitual behaviours of adolescents. With age, the external environment (availability of sugar and peers) has an increasing influence on behaviour. This suggests that to improve adolescent health, oral health promoters should engage with parents from early childhood and create supportive environments including public policy on sugar availability to encourage uptake of risk-minimising behaviours. PMID- 26597277 TI - Gene-expression signature functional annotation of breast cancer tumours in function of age. AB - BACKGROUND: Breast cancer biological characteristics change as age advances. Today, there is a lack of knowledge regarding age-specific molecular alterations that characterize breast tumours, notably in elderly patients. The vast majority of studies that aimed at exploring breast cancer in function of age are based on clinico-pathological data. Gene-expression signatures (GES), which in some ways capture biological information in a non-reductionist manner, represent powerful tools able to explore tumour heterogeneity. METHODS: Twenty-five GES were used for functional annotation of breast tumours in function of age: five for molecular subtyping, seven for immune response, three for metabolism, seven for critical pathways in cancer and three for prognosis. Affymetrix(r) genomics datasets were exclusively used to avoid cross-platform normalization issues. Available corresponding clinico-pathological data were also retrieved and analysed. RESULTS: Fifteen publicly available datasets were pooled for a total of 2378 breast cancer patients (whole cohort), out of whom 1413 were of Caucasian origin. Three age groups were defined: <= 40 years (AG1), > 40 to < 70 years (AG2) and >= 70 years (AG3). We confirmed that age influenced the incidence of molecular subtypes. We found a significant growing incidence of luminal B and a decreasing kinetics for basal-like in function of age. We showed that AG3 luminal B tumours were less aggressive than AG1 luminal B tumours based on different GES (iron metabolism, mitochondrial oxidative phosphorylation and reactive stroma), recurrence score prognostic GES and histological grade (SBR). Contrary to tumours of young patients, tumours of elderly patients concentrated favourable GES scores: high oestrogen receptor and mitochondrial oxidative phosphorylation, low proliferation, basal-like, glycolysis, chromosomal instability and iron metabolism, and low GES prognostic scores (van't Veer 70-GES, genomic grade index and recurrence score). CONCLUSIONS: Functional annotation of breast tumours by means of 25 GES demonstrated a decreasing aggressiveness of breast tumours in function of age. This strategy, which can be strengthened by increasing the number of representative GES to gain more insight into biological systems involved in this disease, provides a framework to develop rational therapeutic strategies in function of age. PMID- 26597280 TI - Is nutritional support needed in late preterm infants? AB - BACKGROUND: Late preterm birth accounts for 70 % of all preterm births. While the impact of feeding problems in very preterm infants has been widely investigated, data on late preterm infants' feeding issues are scarce. The aim of the present study was to investigate the need of nutritional support during hospital stay in a cohort of late preterm infants and to identify the factors that most contribute to its occurrence. METHODS: We analyzed the medical records of late preterm infants, born 2011-2013, admitted to a single institution. Neonatal data, the need for nutritional support, defined as the need for parenteral nutrition or intravenous fluids or tube feeding, and the feeding status at discharge were retrieved. The occurrence of respiratory distress syndrome, congenital malformations/chromosomal diseases, cardiac diseases, sepsis, hypoglycemia, poor feeding and the need for surgical intervention were also collected. RESULTS: A total of 1768 late preterm infants were included. Among the 592 infants requiring a nutritional support, 228 developed a respiratory distress syndrome, two developed a sepsis, one presented with a cardiac disease, 24 underwent a surgical intervention, eight had a chromosomal disease/congenital malformation, 80 had hypoglycemia. In addition, 100 infants required nutritional support due to poor feeding and 149 were born small for gestational age. Birth weight <=2000 g (adjusted OR = 12.2, 95 % CI 7.5-19.9, p < 0.0001), gestational age of 34 weeks (adjusted OR = 4.08, 95 % CI 2.8-5.9, p < 0.0001), being small for gestational age (adjusted OR = 2.17, 95 % CI 2.8-5.9, p=0.001), having a respiratory distress syndrome (adjusted OR = 79.6, 95 % CI 47.2-134.3, p < 0.0001) and the need of surgical intervention (adjusted OR = 49.4, 95 % CI 13.9-174.5, p < 0.0001) were associated with a higher risk of need of nutritional support during hospital stay. CONCLUSIONS: Late preterm infants are at relatively high risk of requiring nutritional support during hospital stay, especially if they have a birth weight <=2000 g, a gestational age of 34 weeks, are born small for gestational age, develop a respiratory distress syndrome and require a surgical intervention. The present findings add to the knowledge of late preterm infants' feeding issues and may contribute to tailoring nutritional approaches for these infants. PMID- 26597281 TI - Breath-hold imaging of the coronary arteries using Quiescent-Interval Slice Selective (QISS) magnetic resonance angiography: pilot study at 1.5 Tesla and 3 Tesla. AB - BACKGROUND: Coronary magnetic resonance angiography (MRA) is usually obtained with a free-breathing navigator-gated 3D acquisition. Our aim was to develop an alternative breath-hold approach that would allow the coronary arteries to be evaluated in a much shorter time and without risk of degradation by respiratory motion artifacts. For this purpose, we implemented a breath-hold, non-contrast enhanced, quiescent-interval slice-selective (QISS) 2D technique. Sequence performance was compared at 1.5 and 3 Tesla using both radial and Cartesian k space trajectories. METHODS: The left coronary circulation was imaged in six healthy subjects and two patients with coronary artery disease. Breath-hold QISS was compared with T2-prepared 2D balanced steady-state free-precession (bSSFP) and free-breathing, navigator-gated 3D bSSFP. RESULTS: Approximately 10 2.1-mm thick slices were acquired in a single ~20-s breath-hold using two-shot QISS. QISS contrast-to-noise ratio (CNR) was 1.5-fold higher at 3 Tesla than at 1.5 Tesla. Cartesian QISS provided the best coronary-to-myocardium CNR, whereas radial QISS provided the sharpest coronary images. QISS image quality exceeded that of free-breathing 3D coronary MRA with few artifacts at either field strength. Compared with T2-prepared 2D bSSFP, multi-slice capability was not restricted by the specific absorption rate at 3 Tesla and pericardial fluid signal was better suppressed. In addition to depicting the coronary arteries, QISS could image intra-cardiac structures, pericardium, and the aortic root in arbitrary slice orientations. CONCLUSIONS: Breath-hold QISS is a simple, versatile, and time-efficient method for coronary MRA that provides excellent image quality at both 1.5 and 3 Tesla. Image quality exceeded that of free breathing, navigator-gated 3D MRA in a much shorter scan time. QISS also allowed rapid multi-slice bright-blood, diastolic phase imaging of the heart, which may have complementary value to multi-phase cine imaging. We conclude that, with further clinical validation, QISS might provide an efficient alternative to commonly used free-breathing coronary MRA techniques. PMID- 26597283 TI - What Is the Plural of a 'Yellow' Anecdote? PMID- 26597282 TI - Dose escalated intensity modulated radiotherapy in the treatment of cervical cancer. AB - PURPOSE: Standard dose of external beam radiotherapy seems to be insufficient for satisfactory control of loco-regionally advanced cervical cancer. Aim of our study is to evaluate the outcome as well as early and chronic toxicities in patients with loco-regionally advanced cervical cancer, treated with dose escalated intensity modulated radiotherapy (IMRT) combined with cisplatin chemotherapy. MATERIAL AND METHODS: Thirty-nine patients with cervical carcinoma FIGO stage IB2 - IVA were treated with curative intent between 2006 and 2010. The dose of 50.4 Gy was prescribed to the elective pelvic nodal volume. Primary tumors < 4 cm in diameter (n = 6; 15.4 %) received an external beam radiotherapy (EBRT) boost of 5.4 Gy, primary tumors > 4 cm in diameter (n = 33; 84.6 %) received an EBRT boost of 9 Gy. Patients with positive lymph nodes detected with (18)FDG-PET/CT (n = 22; 56.4 %) received a boost to a total dose of 59.4 - 64.8 Gy. The para-aortic region was included in the radiation volume in 8 (20.5 %) patients and in 5 (12.8 %) patients the para-aortic macroscopic lymph nodes received an EBRT boost. IMRT was followed with a 3D planned high dose rate intrauterine brachytherapy given to 36 (92.3 %) patients with a total dose ranging between 15-18 Gy in three fractions (single fraction: 4-6.5 Gy). Patients without contraindications (n = 31/79.5 %) received concomitantly a cisplatin based chemotherapy (40 mg/kg) weekly. Toxicities were graded according to the common terminology criteria for adverse events (CTCAE v 4.0). RESULTS: Mean overall survival for the entire cohort was 61.1 months (+/-3.5 months). Mean disease free survival was 47.2 months (+/-4.9 months) and loco-regional disease free survival was 55.2 months (+/-4.4 months). 65 % of patients developed radiotherapy associated acute toxicities grade 1, ca. 30 % developed toxicities grade 2 and just two (5.2 %) patients developed grade 3 toxicities, one acute diarrhea and one acute cystitis. 16 % of patients had chronic toxicities grade 1, 9 % grade 2 and one patient (2.6 %) toxicities grade 3 in the form of vaginal dryness. CONCLUSION: Dose escalated IMRT appears to have a satisfactory outcome with regards to mean overall survival, disease free and loco-regional disease free survival, whereas the treatment-related toxicities remain reasonably low. PMID- 26597284 TI - Clinical practice guidelines for using acupuncture to treat depression. AB - A clinical practice guideline of acupuncture for depression was compiled according to the grading of recommendations assessment, development and evaluation (GRADE) method, including the clinical characteristics, diagnosis, treatment and other information about depression, while several acupuncture treatments of depression, severe depression, depression after stroke were recommended. PMID- 26597285 TI - Holistic approach to functional constipation: Perspective of traditional Persian medicine. AB - Traditional Persian medicine (TPM) proposes a different viewpoint to the chronic diseases. Diagnosis and implemented treatment are based on individual differences among patients. Constipation or Ea'teghal-e-batn is a condition in which the patient develops difficult or painful defecation. Based on TPM concepts, the fifirst digestion step starts from halq (oral cavity), and ends via defecation from the maq'ad (anus). Avicenna believed that four faculties, ha'zemeh (digestive), ja'zebeh (absorptive), ma'sekeh (retentive) and da'fe'eh (propulsive), are involved in the process of digestion and absorption of the ingested food and expelling the waste materials. The bowel movement and appearance of the stool is a measure for evaluating the gastrointestinal healthy function. Defecation should be with no pain and fecal material should have no burning and acuity. Low food intake or foods with dry temperament, dryness of gastrointestinal tract, diaphoresis and heavy exercise as well as intestine sensory loss were discussed as main causes of constipation. Management of constipation in TPM includes dietary schemes, oil massages and subsequently simple herbal medicines. According to TPM theories, the fifirst step in treating a disease is the elimination of disease causes (asbabe- maraz) and also providing the causes of health (asbab-e-sehhat). Health care providers should know the proper condition which the herbal medicines should be administered in and be able to guide the patients about the benefifits and hazards of herbal remedies, commonly used in their living origin. PMID- 26597286 TI - An elderly patient with advanced lung cancer achieved long-term survival using Chinese medicine: An alternative treatment strategy for cancer patients aged 80 or older without a tissue confirmed diagnosis. PMID- 26597287 TI - Sini powder () decoction alleviates mood disorder of insomnia by regulating cation-chloride cotransporters in hippocampus. AB - OBJECTIVE: To investigate the mechanism of Sini Powder () decoction (SND) in the treatment of insomnia. METHODS: The rats were randomly divided into four groups: control, model, SND-treated, and Estazolamtreated groups (n=15 in each group). Sleep deprivation (SD) rat model was established using the modifified multiple platform method for 14 h per day for 14 days, and the behavior of the rats were observed. Na-K-Cl-cotransporter (NKCC1) and K+/Cl- cotransporter (KCC2) in the hippocampus were tested by immunohistochemistry, real-time polymerase chain reaction, and western blot. RESULTS: SD rats displayed anxiety-like behavior, which was alleviated by SND. The protein expressions of NKCC1 and KCC2 in the hippocampus were signifificantly decreased in SD rats compared with those in control rats (P<0.05); these proteins were signifificantly increased by SND (P<0.05). The mRNA expression of KCC2 was signifificantly decreased in SD rats (0.62+/-0.35 vs. 2.29+/-0.56; P=0.044), while SND showed a tendency to increase the mRNA of KCC2 in SD rats (P>0.05). By contrast, the mRNA expression of NKCC1 was signifificantly increased in the hippocampus of SD rats (6.58+/-1.54 vs. 2.82+/-0.32; P=0.011), while SND decreased the mRNA expression of NKCC1 (6.58+/ 1.54 vs. 2.79+/-0.81; P=0.016). CONCLUSIONS: Chinese medicine SND could alleviate mood disorder of SD rats by regulating cation-chloride cotransporters, such as NKCC1 and KCC2. These fifindings would have major implications in the mechanism of SND to relieve insomnia. PMID- 26597288 TI - Uptake and Elimination of 4-Nonylphenol in the Enchytraeid Enchytraeus albidus. AB - We determined the uptake and elimination kinetics of 4-nonylphenol (4-NP) in Enchytraeus albidus. A relatively fast degradation of 4-NP in test soil occurred at 20 degrees C (lambda = 0.11 day(-1)). The concentration of 4-NP in worm tissue followed a three-phase kinetics model, with a short phase of fast 4-NP accumulation shortly after exposure start (k u = 0.97 mg kg(-1) day(-1)), followed by partial elimination (K e1 = 1.47 day(-1)) until reaching the equilibrium phase (A = 44.7 mg kg(-1) fresh tissue), and finally the elimination upon transfer to uncontaminated soil (K e2 = 0.67 day(-1)). During uptake, the internal concentration was similar to the concentration found in the soil, with a BAF ~ 1. In un-spiked soil, elimination took place within the first 24 h (elimination t1/2 ~ 1 day). PMID- 26597289 TI - Exceedance Frequency Analysis of Contaminants in Streams Under Dry-Weather Conditions in Denton, Texas. AB - Percentages of dry-weather stream samples exceeding water quality criteria for ten parameters were compiled for mixed land use watersheds in north-central Texas. Most problematic were total suspended solids (TSS), total dissolved solids (TDS), ammonia, nitrate, phosphorus and copper. Nutrients had much higher exceedance frequency at a sampling station impacted by wastewater discharge. Whereas, TSS and TDS exceedance frequency was highest in predominantly agricultural and rangeland watersheds, and urbanized watersheds respectively. Total dissolved solids was most often exceeded in urbanized watersheds. For several parameters, especially TDS, TSS, ammonia and copper, median concentrations were below water quality thresholds in most watersheds, but exceedance frequency was high. For example, median TSS was less than its threshold in every watershed, but exceedance frequency was higher than 10 % in four of five watersheds - and nearly 43 % in one watershed. This pattern reflects the skewed nature of water quality data; often times, many observations cluster around the lowest values, causing the median to be relatively low, but several (high) outliers form the right-hand tail of the distribution. Results of this study indicate a need to examine exceedance frequency in addition to traditional descriptive measures to better understand dry-weather stream quality in watersheds. PMID- 26597291 TI - Population Pharmacokinetics of Paritaprevir, Ombitasvir, Dasabuvir, Ritonavir, and Ribavirin in Patients with Hepatitis C Virus Genotype 1 Infection: Combined Analysis from 9 Phase 1b/2 Studies. AB - Direct-acting antiviral agents (DAAs) are established as the standard of care for chronic hepatitis C virus (HCV) infection. One of the newest additions to the HCV arsenal is an oral three-DAA combination therapy (i.e., the 3D regimen) that does not require concomitant use of pegylated interferon. The clinical development program for the 3D regimen has yielded a robust dataset that is inclusive of various dosing schemes and a diverse patient population. Using data from nine phase 1b/2a/2b studies that enrolled patients with HCV genotype 1 infection, population pharmacokinetic models were developed for each component of the 3D regimen (ombitasvir, paritaprevir, ritonavir, and dasabuvir) and for ribavirin, an adjunctive therapy used to enhance therapeutic efficacy in some populations. Formulation effects, accumulation, relative bioavailability, and interactions between DAAs were assessed during model development, and demographic and clinical covariates were identified and evaluated for their effects on drug exposures. Proposed models were assessed via goodness-of-fit plots, visual predictive checks, and bootstrap evaluations. Population pharmacokinetic models adequately described their respective plasma concentration-time data with precise and reliable model parameter estimates and with good predictive performance. Covariates, including age, sex, body weight, cytochrome P450 2C8 inhibitor use, non-Hispanic ethnicity, and creatinine clearance, were associated with apparent clearance and/or apparent volume parameters; however, the magnitude of effect on drug exposure was modest and not considered to be clinically significant. No patient-related or clinical parameters were identified that would necessitate dose adjustment of the 3D regimen in patients with HCV genotype 1 infection. PMID- 26597290 TI - R4 Regulator of G Protein Signaling (RGS) Proteins in Inflammation and Immunity. AB - G protein-coupled receptors (GPCRs) have important functions in both innate and adaptive immunity, with the capacity to bridge interactions between the two arms of the host responses to pathogens through direct recognition of secreted microbial products or the by-products of host cells damaged by pathogen exposure. In the mid-1990s, a large group of intracellular proteins was discovered, the regulator of G protein signaling (RGS) family, whose main, but not exclusive, function appears to be to constrain the intensity and duration of GPCR signaling. The R4/B subfamily--the focus of this review--includes RGS1-5, 8, 13, 16, 18, and 21, which are the smallest RGS proteins in size, with the exception of RGS3. Prominent roles in the trafficking of B and T lymphocytes and macrophages have been described for RGS1, RGS13, and RGS16, while RGS18 appears to control platelet and osteoclast functions. Additional G protein independent functions of RGS13 have been uncovered in gene expression in B lymphocytes and mast cell mediated allergic reactions. In this review, we discuss potential physiological roles of this RGS protein subfamily, primarily in leukocytes having central roles in immune and inflammatory responses. We also discuss approaches to target RGS proteins therapeutically, which represents a virtually untapped strategy to combat exaggerated immune responses leading to inflammation. PMID- 26597292 TI - MicroRNA involvement in mechanism of endogenous protection induced by fastigial nucleus stimulation based on deep sequencing and bioinformatics. AB - BACKGROUND: Neurogenic neuroprotection is a promising approach for treating patients with ischemic brain lesions. Fastigial nucleus stimulation (FNS) has been shown to reduce the tissue damage resulting from focal cerebral ischemia in the earlier studies. However, the mechanisms of neuroprotection induced by FNS remain unclear. MicroRNAs (miRNAs) are a newly discovered group of non-coding small RNA molecules that negatively regulate target gene expression and involved in the regulation of pathological process. To date, there is a lack of knowledge on the expression of miRNA in response to FNS. Thus, we study the regulation of miRNAs in the rat ischemic brain by the neuroprotection effect of FNS. METHODS: In this study, we used an established focal cerebral ischemia/reperfusion (IR) model in rats. MiRNA expression profile of rat ischemic cortex after 1 h of FNS were investigated using deep sequencing. Microarray was performed to study the expression pattern of miRNAs. Functional annotation on the miRNA was carried out by bioinformatics analysis. RESULTS: Two thousand four hundred ninety three miRNAs were detected and found to be miRNAs or miRNA candidates using deep sequencing technology. We found that the FNS-related miRNAs were differentially expressed according microarray data. Bioinformatics analysis indicated that several differentially expressed miRNAs might be a central node of neuroprotection-associated genetic networks and contribute to neuroprotection induced by FNS. CONCLUSIONS: MiRNA acts as a novel regulator and contributes to FNS-induced neuroprotection. Our study provides a better understanding of neuroprotection induced by FNS. PMID- 26597293 TI - Pre-announcement of symbiotic guests: transcriptional reprogramming by mycorrhizal lipochitooligosaccharides shows a strict co-dependency on the GRAS transcription factors NSP1 and RAM1. AB - BACKGROUND: More than 80 % of all terrestrial plant species establish an arbuscular mycorrhiza (AM) symbiosis with Glomeromycota fungi. This plant-microbe interaction primarily improves phosphate uptake, but also supports nitrogen, mineral, and water aquisition. During the pre-contact stage, the AM symbiosis is controled by an exchange of diffusible factors from either partner. Amongst others, fungal signals were identified as a mix of sulfated and non-sulfated lipochitooligosaccharides (LCOs), being structurally related to rhizobial nodulation (Nod)-factor LCOs that in legumes induce the formation of nitrogen fixing root nodules. LCO signals are transduced via a common symbiotic signaling pathway (CSSP) that activates a group of GRAS transcription factors (TFs). Using complex gene expression fingerprints as molecular phenotypes, this study primarily intended to shed light on the importance of the GRAS TFs NSP1 and RAM1 for LCO-activated gene expression during pre-symbiotic signaling. RESULTS: We investigated the genome-wide transcriptional responses in 5 days old primary roots of the Medicago truncatula wild type and four symbiotic mutants to a 6 h challenge with LCO signals supplied at 10(-7/-8) M. We were able to show that during the pre-symbiotic stage, sulfated Myc-, non-sulfated Myc-, and Nod-LCO activated gene expression almost exclusively depends on the LysM receptor kinase NFP and is largely controled by the CSSP, although responses independent of this pathway exist. Our results show that downstream of the CSSP, gene expression activation by Myc-LCOs supplied at 10(-7/-8) M strictly required both the GRAS transcription factors RAM1 and NSP1, whereas those genes either co- or specifically activated by Nod-LCOs displayed a preferential NSP1-dependency. RAM1, a central regulator of root colonization by AM fungi, controled genes activated by non-sulfated Myc-LCOs during the pre-symbiotic stage that are also up-regulated in areas with early physical contact, e.g. hyphopodia and infecting hyphae; linking responses to externally applied LCOs with early root colonization. CONCLUSIONS: Since both RAM1 and NSP1 were essential for the pre symbiotic transcriptional reprogramming by Myc-LCOs, we propose that downstream of the CSSP, these GRAS transcription factors act synergistically in the transduction of those diffusible signals that pre-announce the presence of symbiotic fungi. PMID- 26597294 TI - Candida concentrations determined following concentrated oral rinse culture reflect clinical oral signs. AB - BACKGROUND: Oral candidiasis is an infection caused by a yeast-like fungus called Candida. Various methods can be used to isolate Candida from the oral cavity. However, it is difficult to correctly and satisfactorily diagnose oral candidiasis because currently no microbiological or laboratory standards based on samples from the oral cavity are available. The aim of this study is to establish a reliable laboratory test for diagnosing oral candidiasis. METHODS: Oral swab, rinse and concentrated rinse samples were obtained from 200 consecutive outpatients (103 male patients and 97 female patients; mean age, 47.2 years; age range, 9-89 years). Candida colonies from cultured samples were enumerated to compare the sensitivities and specificities of the above sampling methods, and the associations between Candida detection or concentration and the clinical oral signs were examined. RESULTS: The mean colony numbers were 263 +/- 590 CFU/swab for the swab method, 2894 +/- 6705 CFU/100 MUL for the rinse method, and 9245 +/- 19,030 CFU/100 MUL for the concentrated rinse method. The median numbers were 23 CFU/swab for the swab method, 56 CFU/100 MUL for the rinse method, and 485 CFU/100 MUL for the concentrated rinse method. Candida was detected in the oral cavity of 33.5 % and 52.0 % of the outpatients by the swab method and concentrated rinse, respectively. Candida concentrations determined by the concentrated rinse were closely related to the severity of the clinical oral signs. The positive predictive values of residual root, redness of the oral mucosa, denture, glossalgia, dry mouth, and taste disorder were useful predictors of oral candidiasis. CONCLUSIONS: Concentrated rinse sampling is suitable for evaluating oral candidiasis, and Candida concentrations examined using this method strongly associated with the oral signs associated with Candida infection. PMID- 26597295 TI - Protocol for a randomized controlled dismantling study of a brief telephonic psychological intervention applied to non-professional caregivers with symptoms of depression. AB - BACKGROUND: Although depression is a common problem in caregivers and there are effective cognitive-behavioral interventions for its prevention, the ability of caregivers to attend these treatments is often limited by logistics. Furthermore, the efficacy of the components of these interventions is unknown. The objectives of this study are to (a) evaluate the efficacy of a telephone-administered cognitive-behavioral intervention to prevent depression with all its components (cognitive and behavioral) and only with behavioral activation, and to (b) analyze the mediators of the change in depressive symptoms. METHODS/DESIGN: A randomized controlled clinical trial was designed to dismantle the components of a cognitive-behavioral intervention. Caregivers with elevated depressive symptoms will be randomly assigned to a cognitive-behavioral intervention, an intervention with only the behavioral activation component, or a usual care control group. Each condition will consist of approximately 60 participants. The two interventions will consist of five sessions lasting 90 min each, applied to groups of about 5 participants at a time via conference call. Trained interviewers, blind to the experimental conditions, will conduct the assessments at the pre-treatment, post-treatment and 1-, 3-, 6- and 12-month follow-ups. DISCUSSION: This study will provide evidence of the efficacy of a cognitive behavioral intervention to prevent depression in caregivers with elevated depressive symptoms administered via conference call, and on the impact of the behavioral activation component on the overall efficacy of the program. If we find favorable results, it would mean that we have developed a program of prevention of depression of higher clinical utility and efficacy than those currently available, which would make it possible for a large number of caregivers to have access to such resources. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02292394. Registered 6 November 2014. PMID- 26597296 TI - Three-dimensional verification of 125I seed stability after permanent implantation in the parotid gland and periparotid region. AB - OBJECTIVE: To evaluate seed stability after permanent implantation in the parotid gland and periparotid region via a three-dimensional reconstruction of CT data. MATERIAL AND METHODS: Fifteen patients treated from June 2008 to June 2012 at Peking University School and Hospital of Stomatology for parotid gland tumors with postoperative adjunctive (125)I interstitial brachytherapy were retrospectively reviewed in this study. Serial CT data were obtained during follow-up. Mimics and Geomagic Studio software were used for seed reconstruction and stability analysis, respectively. RESULTS: Seed loss and/or migration outside of the treated area were absent in all patients during follow-up (23-71 months). Total seed cluster volume was maximized on day 1 post-implantation due to edema and decreased significantly by an average of 13.5 % (SD = 9.80 %; 95 % CI, 6.82 17.68 %) during the first two months and an average of 4.5 % (SD = 3.60 %; 95 % CI, 2.29-6.29 %) during the next four months. Volume stabilized over the subsequent six months. CONCLUSIONS: (125)I seed number and location were stable with a general volumetric shrinkage tendency in the parotid gland and periparotid region. Three-dimensional seed reconstruction of CT images is feasible for visualization and verification of implanted seeds in parotid brachytherapy. PMID- 26597298 TI - Influence of Content of Al2O3 on Structure and Properties of Nanocomposite Nb-B Al-O films. AB - Nb-B-Al-O nanocomposite films with different power of Al2O3 were successfully deposited on the Si substrate via multi-target magnetron co-sputtering method. The influences of Al2O3's content on structure and properties of obtained nanocomposite films through controlling Al2O3's power were investigated. Increasing the power of Al2O3 can influence the bombarding energy and cause the momentum transfer of NbB2. This can lead to the decreasing content of Al2O3. Furthermore, the whole films showed monocrystalline NbB2's (100) phase, and Al2O3 shaded from amorphous to weak cubic-crystalline when decreasing content of Al2O3. This structure and content changes were proof by X-ray diffraction (XRD) and high resolution transmission electron microscopy (TEM) and X-ray photoelectron spectroscopy (XPS). When NbB2 grains were far from each other in lower power of Al2O3, the whole films showed a typical nanocomposite microstructure with crystalline NbB2 grains embedded in a matrix of an amorphous Al2O3 phase. Continuing increasing the power of Al2O3, the less content of Al2O3 tended to cause crystalline of cubic-Al2O3 between the close distances of different crystalline NbB2 grains. The appearance of cubic-crystallization Al2O3 can help to raise the nanocomposite films' mechanical properties to some extent. The maximum hardness and elastic modulus were up to 21.60 and 332.78 GPa, which were higher than the NbB2 and amorphous Al2O3 monolithic films. Furthermore, this structure change made the chemistry bond of O atom change from the existence of O Nb, O-B, and O-Al bonds to single O-Al bond and increased the specific value of Al and O. It also influenced the hardness in higher temperature, which made the hardness variation of different Al2O3 content reduced. These results revealed that it can enhance the films' oxidation resistance properties and keep the mechanical properties at high temperature. The study highlighted the importance of controlling the Al2O3's content to prepare well-defined films with high mechanical properties and thermal stability. PMID- 26597297 TI - BluB/CobT2 fusion enzyme activity reveals mechanisms responsible for production of active form of vitamin B12 by Propionibacterium freudenreichii. AB - BACKGROUND: Propionibacterium freudenreichii is a food grade bacterium that has gained attention as a producer of appreciable amounts of cobalamin, a cobamide with activity of vitamin B12. Production of active form of vitamin is a prerequisite for attempts to naturally fortify foods with B12 by microbial fermentation. Active vitamin B12 is distinguished from the pseudovitamin by the presence of 5,6-dimethylbenzimidazole (DMBI) as the lower ligand. Genomic data indicate that P. freudenreichii possesses a fusion gene, bluB/cobT2, coding for a predicted phosphoribosyltransferase/nitroreductase, which is presumably involved in production of vitamin B12. Understanding the mechanisms affecting the synthesis of different vitamin forms is useful for rational strain selection and essential for engineering of strains with improved B12 production properties. RESULTS: Here, we investigated the activity of heterologously expressed and purified fusion enzyme BluB/CobT2. Our results show that BluB/CoBT2 is responsible for the biosynthesis of the DMBI base and its activation into alpha ribazole phosphate, preparing it for attachment as the lower ligand of cobalamin. The fusion enzyme was found to be efficient in metabolite channeling and the enzymes' inability to react with adenine, a lower ligand present in the pseudovitamin, revealed a mechanism favoring the production of the active form of the vitamin. P. freudenreichii did not produce cobalamin under strictly anaerobic conditions, confirming the requirement of oxygen for DMBI synthesis. In vivo experiments also revealed a clear preference for incorporating DMBI over adenine into cobamide under both microaerobic and anaerobic conditions. CONCLUSIONS: The herein described BluB/CobT2 is responsible for the production and activation of DMBI. Fusing those two activities results in high pressure towards production of the true vitamin B12 by efficiently activating DMBI formed within the same enzymatic complex. This indicates that BluB/CobT2 is the crucial enzyme in the B12 biosynthetic pathway of P. freudenreichii. The GRAS organism status and the preference for synthesizing active vitamin form make P. freudenreichii a unique candidate for the in situ production of vitamin B12 within food products. PMID- 26597299 TI - Psychiatric and neurological disorders in late adolescence and risk of convictions for violent crime in men. AB - BACKGROUND: The relationship between mental illness and violent crime is complex because of the involvement of many other confounding risk factors. In the present study, we analysed psychiatric and neurological disorders in relation to the risk of convictions for violent crime, taking into account early behavioural and socio economic risk factors. METHODS: The study population consisted of 49,398 Swedish men, who were thoroughly assessed at conscription for compulsory military service during the years 1969-1970 and followed in national crime registers up to 2006. Five diagnostic groups were analysed: anxiety-depression/neuroses, personality disorders, substance-related disorders, mental retardation and neurological conditions. In addition, eight confounders measured at conscription and based on the literature on violence risk assessment, were added to the analyses. The relative risks of convictions for violent crime during 35 years after conscription were examined in relation to psychiatric diagnoses and other risk factors at conscription, as measured by odds ratios (ORs) and confidence intervals (CIs) from bivariate and multivariate logistic regression analyses. RESULTS: In the bivariate analyses there was a significant association between receiving a psychiatric diagnosis at conscription and a future conviction for violent crime (OR = 3.83, 95 % CI = 3.47-4.22), whereas no significant association between neurological conditions and future violent crime (OR = 1.03, 95 % CI = 0.48-2.21) was found. In the fully adjusted multivariate logistic regression model, mental retardation had the strongest association with future violent crime (OR = 3.60, 95 % CI = 2.73-4.75), followed by substance-related disorders (OR = 2.81, 95 % CI = 2.18-3.62), personality disorders (OR = 2.66, 95 % CI = 2.21-3.19) and anxiety-depression (OR = 1.29, 95 % CI = 1.07-1.55). Among the other risk factors, early behavioural problem had the strongest association with convictions for violent crime. CONCLUSIONS: Mental retardation, substance related disorders, personality disorders and early behavioural problems are important predictors of convictions for violent crime in men. PMID- 26597300 TI - Compositional regulation of poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) by replacement of granule-associated protein in Ralstonia eutropha. AB - BACKGROUND: Phasin (PhaP), a kind of polyhydroxyalkanoate (PHA) granule associated proteins, has a role in controlling the properties of PHA granules surface, and is thought to have influence on PHA biosynthesis in PHA-producing bacteria. This study focused on the phaP1(Re) locus in Ralstonia eutropha as a site of chromosomal modification for production of flexible poly(3 hydroxybutyrate-co-3-hydroxyhexanoate) [P(3HB-co-3HHx)] from soybean oil. RESULTS: Considering the high expression level of phaP1(Re), phaJ(Ac) [encoding (R)-specific enoyl-CoA hydratase from Aeromonas caviae] was inserted into the downstream of phaP1(Re) on chromosome 1 of R. eutropha strain NSDG harboring phaC(NSDG) (encoding PHA synthase with broad substrate specificity). The constructed strain efficiently accumulated P(3HB-co-3HHx) on soybean oil with higher 3HHx composition when compared to the previous strain having phaJ(Ac) within pha operon. Insertion of the second phaC(NSDG) along with phaJ(Ac) at the phaP1(Re) locus led to incorporation of much larger 3HHx fraction into PHA chains, although the molecular weight was markedly reduced. The R. eutropha strains were further engineered by replacing phaP1(Re) with phaP(Ac) (encoding phasin from A. caviae) on the chromosome. Interestingly, the phasin replacement increased 3HHx composition in the soybean oil-based PHA with keeping high cellular contents, nevertheless no modification was conducted in the metabolic pathways. Kinetic and Western blot analyses of PHA synthase using cellular insoluble fractions strongly suggested that the phasin replacement not only enhanced activity of PHA synthase from A. caviae but also increased affinity especially to longer (R)-3HHx-CoA. It was supposed that the increased affinity of PHA synthase to (R)-3HHx-CoA was responsible for the higher 3HHx composition in the copolyester. CONCLUSIONS: The downstream of phaP1(Re) was a useful site for integration of genes to be overexpressed during PHA accumulation in R. eutropha. The results also clarified that polymerization properties of PHA synthase was affected by the kind of phasin co-existed on the surface of PHA granules, leading to altered composition of the resulting P(3HB-co-3HHx). The phasin replacement is a novel engineering strategy for regulation of composition of PHA copolyesters. PMID- 26597301 TI - Therapeutic application of hydrogen sulfide donors: the potential and challenges. AB - Hydrogen sulfide (H2S), a colorless gas smelling of rotten egg, has long been considered a toxic gas and environment hazard. However, evidences show that H2S plays a great role in many physiological and pathological activities, and it exhibits different effects when applied at various doses. In this review, we summarize the chemistry and biomedical applications of H2S-releasing compounds, including inorganic salts, phosphorodithioate derivatives, derivatives of Allium sativum extracts, derivatives of thioaminoacids, and derivatives of antiinflammatory drugs. PMID- 26597302 TI - Optimal Dosing for Targeted Therapies in Oncology: Drug Development Cases Leading by Example. AB - One of the key objectives of oncology first-in-human trials has often been to establish the maximum tolerated dose (MTD). However, targeted therapies might not exhibit dose-limiting toxicities (DLT) at doses significantly higher than sufficiently active doses, and there is frequently a limited ability to objectively quantify adverse events. Thus, while MTD-based determination of recommended phase II dose may have yielded appropriate dosing for some cytotoxics, targeted therapeutics (including monoclonal antibodies and/or immunotherapies) sometimes need alternative or complementary strategies to help identify dose ranges for a randomized dose-ranging study. One complementary strategy is to define a biologically efficacious dose (BED) using an "effect marker." An effect marker could be a target engagement, pharmacodynamic, or disease progression marker (change in tumor size for solid tumors or bone marrow blast count for some hematologic tumors). Although the concept of BED has been discussed extensively, we review specific examples in which the approach influenced oncology clinical development. Data extracted from the literature and the examples support improving dose selection strategies to benefit patients, providers, and the biopharmaceutical industry. Although the examples illustrate key contributions of effect markers in dose selection, no one-size-fits-all approach to dosing can be justified. Higher-than-optimal dosing can increase toxicity in later trials (and in clinical use), which can have a negative impact on efficacy (via lower adherence or direct sequelae of toxicities). Proper dose selection in oncology should follow a multifactorial decision process leading to a randomized, dose-ranging study instead of a single phase II dose. PMID- 26597305 TI - Plasticity of the human vestibulo-ocular reflex during off-vertical axis rotation. AB - OBJECTIVE: We investigated whether adaptive plasticity of the vestibulo-ocular reflex in humans occurs in response to visual-vestibular conflict stimulation during rotation about a 30 degrees incline (off-vertical earth axis rotation, OVAR). METHODS: Subjects were 26 healthy adults (17 males and 9 females), ranging in age from 22 to 33 years (mean: 24.4) with no history of neurotological symptoms. Each testing session consisted of a pre-test, an adaptation period, and a post-test. The pre-test and the post-test were performed in complete darkness with the subjects' eyes opened. Subjects were rotated sinusoidally at 0.16Hz under OVAR, with a maximum angular velocity of 60 degrees /s for 30s. Subjects were divided into two groups depending on the kind of visual stimulation. One group of subjects was rotated sinusoidally at 0.16Hz and 60 degrees /s peak velocity under OVAR for 20min while viewing optokinetic stripes, which moved at the same frequency and peak velocity as the rotational chair but in the opposite direction (X2 adaptation paradigm). The other group of subjects was rotated sinusoidally at 0.16Hz and 60 degrees /s peak velocity under OVAR for 20min while viewing optokinetic stripes, which moved at the same frequency and peak velocity as the rotatory chair but in the same direction (X0 adaptation paradigm). RESULTS: There was no significant difference in gain before or after adaptation using the X2 adaptation paradigm. VOR gain decreased significantly after adaptation using the X0 adaptation paradigm. CONCLUSION: We hypothesize that attenuation of VOR gain increase after the X2 adaptation paradigm is caused by tilt suppression. In the X0 adaptation paradigm, the decrease in VOR gain was facilitated by tilt suppression in addition to the plastic change of the VOR gain caused by visual-vestibular conflict stimulation. Consequently, the VOR gain change ratio in the X0 adaptation paradigm increased significantly compared to that in the X2 adaptation paradigm. PMID- 26597304 TI - Acid-Base Homeostasis. AB - Acid-base homeostasis and pH regulation are critical for both normal physiology and cell metabolism and function. The importance of this regulation is evidenced by a variety of physiologic derangements that occur when plasma pH is either high or low. The kidneys have the predominant role in regulating the systemic bicarbonate concentration and hence, the metabolic component of acid-base balance. This function of the kidneys has two components: reabsorption of virtually all of the filtered HCO3(-) and production of new bicarbonate to replace that consumed by normal or pathologic acids. This production or generation of new HCO3(-) is done by net acid excretion. Under normal conditions, approximately one-third to one-half of net acid excretion by the kidneys is in the form of titratable acid. The other one-half to two-thirds is the excretion of ammonium. The capacity to excrete ammonium under conditions of acid loads is quantitatively much greater than the capacity to increase titratable acid. Multiple, often redundant pathways and processes exist to regulate these renal functions. Derangements in acid-base homeostasis, however, are common in clinical medicine and can often be related to the systems involved in acid-base transport in the kidneys. PMID- 26597306 TI - The Proceedings of the 141st Tokai-Hokuriku Regional Meeting of the Japanese Society of Neurology. PMID- 26597307 TI - The Proceedings of the 102nd Kinki Regional Meeting of the Japanese Society of Neurology. PMID- 26597303 TI - Epithelial-Mesenchymal Transition Predicts Polo-Like Kinase 1 Inhibitor-Mediated Apoptosis in Non-Small Cell Lung Cancer. AB - PURPOSE: To identify new therapeutic targets for non-small cell lung cancer (NSCLC), we systematically searched two cancer cell line databases for sensitivity data on a broad range of drugs. We identified polo-like kinase 1 (PLK1) as the most promising target for further investigation based on a subset of sensitive NSCLC cell lines and inhibitors that were in advanced clinical development. EXPERIMENTAL DESIGN: To identify potential biomarkers of response of NSCLC to PLK1 inhibition and mechanisms of PLK1 inhibitor-induced apoptosis, integrated analysis of gene and protein expression, gene mutations, and drug sensitivity was performed using three PLK1 inhibitors (volasertib, BI2536, and GSK461364) with a large panel of NSCLC cell lines. RESULTS: The NSCLC cell lines had different sensitivities to PLK1 inhibition, with a minority demonstrating sensitivity to all three inhibitors. PLK1 inhibition led to G2-M arrest, but only treatment-sensitive cell lines underwent substantial apoptosis following PLK1 inhibition. NSCLC lines with high epithelial-mesenchymal transition (EMT) gene signature scores (mesenchymal cell lines) were more sensitive to PLK1 inhibition than epithelial lines (P< 0.02). Likewise, proteomic profiling demonstrated that E-cadherin expression was higher in the resistant cell lines than in the sensitive ones (P< 0.01). Induction of an epithelial phenotype by expression of the miRNA miR-200 increased cellular resistance to PLK1 inhibition. Also, KRAS mutation and alterations in the tight-junction, ErbB, and Rho signaling pathways correlated with drug response of NSCLC. CONCLUSIONS: In this first reported large scale integrated analysis of PLK1 inhibitor sensitivity, we demonstrated that EMT leads to PLK1 inhibition sensitivity of NSCLC cells. Our findings have important clinical implications for mesenchymal NSCLC, a significant subtype of the disease that is associated with resistance to currently approved targeted therapies. PMID- 26597312 TI - One-Step Pyrolysis Preparation of 1.1.1 Oriented Gold Nanoplatelets Supported on Graphene and Six Orders of Magnitude Enhancement of the Resulting Catalytic Activity. AB - Pyrolysis of chitosan films containing Au(3+) renders 1.1.1 oriented Au nanoplatelets (20 nm lateral size, 3-4 nm height) on a few layers of N-doped graphene (Au/fl-G), while the lateral sides were 0.0.1 oriented. Comparison of the catalytic activity of Au/fl-G films with powders of unoriented Au NPs supported on graphene showed that Au/fl-G films exhibit six orders of magnitude enhancement for three gold-catalyzed reactions, namely, Ullmann-like homocoupling, C-N cross coupling, and the oxidative coupling of benzene to benzoic acid. This enhancement is the result of the defined morphology, facet orientation of Au nanocrystals, and strong gold-graphene interaction. PMID- 26597311 TI - Effect of Intravaginal Prasterone on Sexual Dysfunction in Postmenopausal Women with Vulvovaginal Atrophy. AB - INTRODUCTION: Previous data have shown that intravaginal dehydroepiandrosterone (DHEA, prasterone) improved all the domains of sexual function, an effect most likely related to the local formation of androgens from DHEA. AIMS: To confirm in a placebo-controlled, prospective, double-blind and randomized study the benefits of daily intravaginal DHEA for 12 weeks on sexual function using the Female Sexual Function Index (FSFI) questionnaire. METHODS: Placebo was administered daily to 157 women while 325 women received 0.50% (6.5 mg) DHEA daily for 12 weeks. All women were postmenopausal meeting the criteria of vulvovaginal atrophy (VVA), namely moderate to severe dyspareunia as their most bothersome symptom of VVA in addition to having <=5% of vaginal superficial cells and vaginal pH > 5.0. The FSFI questionnaire was filled at baseline (screening and day 1), 6 weeks and 12 weeks. Comparison between DHEA and placebo of the changes from baseline to 12 weeks was made using the analysis of covariance test, with treatment group as the main factor and baseline value as the covariate. MAIN OUTCOME MEASURES: The six domains and total score of the FSFI questionnaire were evaluated. RESULTS: The FSFI domain desire increased over placebo by 0.24 unit (+49.0%, P = 0.0105), arousal by 0.42 unit (+56.8%, P = 0.0022), lubrication by 0.57 unit (+36.1%, P = 0.0005), orgasm by 0.32 unit (+33.0%, P = 0.047), satisfaction by 0.44 unit (+48.3%, P = 0.0012), and pain at sexual activity by 0.62 unit (+39.2%, P = 0.001). The total FSFI score, on the other hand, has shown a superiority of 2.59 units in the DHEA group over placebo or a 41.3% greater change than placebo (P = 0.0006 over placebo). CONCLUSION: The present data show that all the six domains of the FSFI are improved over placebo (from P = 0.047 to 0.0005), thus confirming the previously observed benefits of intravaginal DHEA on female sexual dysfunction by an action exerted exclusively at the level of the vagina, in the absence of biologically significant changes of serum steroids levels. PMID- 26597313 TI - Platelet-derived microparticles trigger THP-1 monocytic cell aggregation and release of pro-coagulant tissue factor-expressing microparticles in vitro. AB - Microparticles (MPs) released by blood or endothelial cells are present in plasma for transfusion. They originate from the collected donor blood or are triggered by the variable steps taking place during collection and production/storage processes of blood components. While MPs may contribute to hemostasis, their presence in transfused plasma may lead to uncontrolled thrombin generation when transfused to susceptible cancer or hypercoagulable patients. Understanding the biochemical and cellular triggers of MP-mediated thrombogenesis is therefore crucial. We isolated platelet MPs (PMPs) present in platelet concentrate supernatant plasma (N-PMPs) or prepared by activation of isolated platelets using 0.1 IU/mL thrombin (T-PMPs). N-PMPs and T-PMPs were characterized by dynamic light scattering and counted by tunable resistive pulse sensing to determine population size and number. T-MPMs, but not N-PMPs, induced immediate, long lasting, strong aggregation of THP-1 monocytic cells in vitro. In addition, co cultures of THP-1 cells with both N-PMPs and T-PMPs triggered the generation of pro-coagulant tissue factor (TF)-bearing MPs from THP-1 cells. Therefore, some PMPs may induce THP-1 monocytic cell aggregation in vitro and trigger immune cell mediated thrombogenicity linked to the release of pro-coagulant tissue factor bearing MPs. Controlling the impact of the presence of PMPs in transfused blood components in certain patient population or critically ill patients deserves in depth consideration. PMID- 26597315 TI - Stereoselective Synthesis of 1,3-Diaminotruxillic Acid Derivatives: An Advantageous Combination of C-H-ortho-Palladation and On-Flow [2+2] Photocycloaddition in Microreactors. AB - The stereoselective synthesis of epsilon-isomers of dimethyl esters of 1,3 diaminotruxillic acid in three steps is reported. The first step is the ortho palladation of (Z)-2-aryl-4-aryliden-5(4H)-oxazolones 1 to give dinuclear complexes 2 with bridging carboxylates. The reaction occurs through regioselective activation of the ortho-C?H bond of the 4-arylidene ring in carboxylic acids. The second step is the [2+2]-photocycloaddition of the C?C exocyclic bonds of the oxazolone skeleton in 2 to afford the corresponding dinuclear ortho-palladated cyclobutanes 3. This key step was performed very efficiently by using LED light sources with different wavelengths (465, 525 or 625 nm) in flow microreactors. The final step involved the depalladation of 3 by hydrogenation in methanol to afford the epsilon-1,3-diaminotruxillic acid derivatives as single isomers. PMID- 26597314 TI - Red blood cell alloimmunization in transfused patients in sub-Saharan Africa: A systematic review and meta-analysis. AB - BACKGROUND AND OBJECTIVES: Previous studies of Sub-Saharan Africans show significant alloimmunization to red blood cell (RBC) antigens, but country specific data are limited. Thus, the aim of this study was to estimate, by meta analysis, the overall proportion of red blood cell alloantibodies among transfused patients. METHODS: We systematically searched Medline, Embase, and the Africa-Wide Information database to identify relevant studies in any language. Case reports, comments, letters, conference abstracts, editorials, and review articles were excluded. Of the 269 potentially relevant articles, 11 studies fulfilled our selection criteria. RESULTS: Overall proportions of alloimmunization were 6.7 (95% CI: 5.7, 7.8) per 100 transfused patients. With regard to antibody specificity, among clinically significant antibodies, anti-E ranked as the most common, followed by anti-K, anti-C and anti-D. CONCLUSION: Meta-analysis of available literature quantifies and qualifies the clinical challenge of RBC alloimmunization among transfused patients in Sub-Saharan Africa. These results should drive policy decisions in favour of routine testing of RBC antigens and irregular antibodies for transfused patients as a standard of care throughout Sub-Saharan Africa. PMID- 26597316 TI - The radiolytic studies of cefpirome sulfate in the solid state. AB - The possibility of applying radiation sterilization to cefpirome sulfate was investigated. The lack of changes in the chemical structure of cefpirome sulfate irradiated with a dose of 25 kGy, required to attain sterility, was confirmed by UV, FT-IR, Raman, DSC and chromatographic methods. Some radical defects with concentration no more than over a several dozen ppm were created by radiation. The antibacterial activity of cefpirome sulfate for two Gram-positive and three Gram-negative strains was changed. The radiation sterilised cefpirome sulfate was not in vitro cytotoxic against fibroblast cells. PMID- 26597317 TI - Detection and analysis of tupaia hepatocytes via mAbs against tupaia serum albumin. AB - On the basis of its close phylogenetic relationship with primates, the development of Tupaia belangeri as an infection animal model and drug metabolism model could provide a new option for preclinical studies, especially in hepatitis virus research. As a replacement for primary human hepatocytes (PHHs), primary tupaia hepatocytes (PTHs) have been widely used. Similar to human serum albumin, tupaia serum albumin (TSA) is the most common liver synthesis protein and is an important biomarker for PTHs and liver function. However, no detection or quantitative method for TSA has been reported. In this study, mouse monoclonal antibodies (mAbs) 4G5 and 9H3 against TSA were developed to recognize PTHs, and they did not show cross-reactivity with serum albumin from common experimental animals, such as the mouse, rat, cow, rabbit, goat, monkey, and chicken. The two mAbs also exhibited good performance in fluorescence activated cell sorting (FACS) analysis and immunofluorescence (IF) detection of PTHs. A chemiluminescent enzyme immune assay method using the two mAbs, with a linear range from 96.89 pg/ml to 49,609.38 pg/ml, was developed for the quantitative detection of TSA. The mAbs and the CLEIA method provide useful tools for research on TSA and PTHs. PMID- 26597318 TI - Building Giant Carbocycles by Reversible C-C Bond Formation. AB - We describe a simple way to build giant macrocyclic hydrocarbons by the reversible formation of carbon-carbon bonds. Specifically, extended spirobifluorene-substituted derivatives of Wittig's hydrocarbon were synthesized and found to undergo oligomerization, giving the largest hydrocarbon that has been crystallized and characterized by X-ray diffraction to date. PMID- 26597319 TI - Unique expression of cytoskeletal proteins in human soft palate muscles. AB - The human oropharyngeal muscles have a unique anatomy with diverse and intricate functions. To investigate if this specialization is also reflected in the cytoarchitecture of muscle fibers, intermediate filament proteins and the dystrophin-associated protein complex have been analyzed in two human palate muscles, musculus uvula (UV) and musculus palatopharyngeus (PP), with immunohistochenmical and morphological techniques. Human limb muscles were used as reference. The findings show that the soft palate muscle fibers have a cytoskeletal architecture that differs from the limb muscles. While all limb muscles showed immunoreaction for a panel of antibodies directed against different domains of cytoskeletal proteins desmin and dystrophin, a subpopulation of palate muscle fibers lacked or had a faint immunoreaction for desmin (UV 11.7% and PP 9.8%) and the C-terminal of the dystrophin molecule (UV 4.2% and PP 6.4%). The vast majority of these fibers expressed slow contractile protein myosin heavy chain I. Furthermore, an unusual staining pattern was also observed in these fibers for beta-dystroglycan, caveolin-3 and neuronal nitric oxide synthase nNOS, which are all membrane-linking proteins associated with the dystrophin C terminus. While the immunoreaction for nNOS was generally weak or absent, beta dystroglycan and caveolin-3 showed a stronger immunostaining. The absence or a low expression of cytoskeletal proteins otherwise considered ubiquitous and important for integration and contraction of muscle cells indicate a unique cytoarchitecture designed to meet the intricate demands of the upper airway muscles. It can be concluded that a subgroup of muscle fibers in the human soft palate appears to have special biomechanical properties, and their unique cytoarchitecture must be taken into account while assessing function and pathology in oropharyngeal muscles. PMID- 26597320 TI - Histochemical localization of palmitoyl protein thioesterase-1 activity. AB - Infantile neuronal ceroid lipofuscinosis (INCL, Infantile Batten disease) is an invariably fatal neurodegenerative pediatric disorder caused by an inherited mutation in the PPT1 gene. Patients with INCL lack the lysosomal enzyme palmitoyl protein thioesterase-1 (PPT1, EC 3.1.2.22), resulting in intracellular accumulation of autofluorescent storage material and subsequent neuropathology. The Ppt1(-/-) mouse is deficient in PPT1 activity and represents a useful animal model of INCL that recapitulates most of the clinical and pathological aspects of the disease. Preclinical therapeutic experiments performed in the INCL mouse include CNS-directed gene therapy and recombinant enzyme replacement therapy; both seek to re-establish therapeutic levels of the deficient enzyme. We present a novel method for the histochemical localization of PPT1 activity in the Ppt1(-/ ) mouse. By utilizing the substrate CUS-9235, tissues known to be positive for PPT1 activity turn varying intensities of blue. Presented here are histochemistry data showing the staining pattern in Ppt1(-/-), wild type, and Ppt1(-/-) mice treated with enzyme replacement therapy or AAV2/9-PPT1-mediated gene therapy. Results are paired with quantitative biochemistry data that confirm the ability of CUS-9235 to detect and localize PPT1 activity. This new method complements the current tools for the study of INCL and evaluation of effective therapies. PMID- 26597321 TI - Immune response to enzyme replacement therapies in lysosomal storage diseases and the role of immune tolerance induction. AB - The US Food and Drug Administration (FDA) and National Organization for Rare Disease (NORD) convened a public workshop titled "Immune Responses to Enzyme Replacement Therapies: Role of Immune Tolerance Induction" to discuss the impact of anti-drug antibodies (ADAs) on efficacy and safety of enzyme replacement therapies (ERTs) intended to treat patients with lysosomal storage diseases (LSDs). Participants in the workshop included FDA staff, clinicians, scientists, patients, industry, and advocacy group representatives. The risks and benefits of implementing prophylactic immune tolerance induction (ITI) to reduce the potential clinical impact of antibody development were considered. Complications due to immune responses to ERT are being recognized with increasing experience and lengths of exposure to ERTs to treat several LSDs. Strategies to mitigate immune responses and to optimize therapies are needed. Discussions during the workshop resulted in the identification of knowledge gaps and future areas of research, as well as the following proposals from the participants: (1) systematic collection of longitudinal data on immunogenicity to better understand the impact of ADAs on long-term clinical outcomes; (2) development of disease specific biomarkers and outcome measures to assess the effect of ADAs and ITI on efficacy and safety; (3) development of consistent approaches to ADA assays to allow comparisons of immunogenicity data across different products and disease groups, and to expedite reporting of results; (4) establishment of a system to widely share data on antibody titers following treatment with ERTs; (5) identification of components of the protein that are immunogenic so that triggers and components of the immune responses can be targeted in ITI; and (6) consideration of early ITI in patients who are at risk of developing clinically relevant ADA that have been demonstrated to worsen treatment outcomes. PMID- 26597323 TI - Made up by makeup--A case report about an exceptional kind of self-inflicted "injuries". AB - BACKGROUND: Self-inflicted injuries are a known, but challenging topic in the healthcare sector and the judicial system. Therefore, differentiation of these injuries from a third-party-interference is crucial in the field of forensic medicine. However, self-painted injuries with makeup, which entail misleading of medical staff and the administration of justice, have apparently not been described in the literature so far. CASE: A case of a rare kind of victim role staging in a 26-year-old Caucasian woman in the field of forensic medicine is presented. She supposedly had been robbed and harmed by two unknown men. The forensic examination revealed subjective symptoms and objective findings, such as skin discolorations appearing as fresh bruises. However, a closer look revealed makeup. After removal, no injuries were seen. CONCLUSIONS: Awareness of the existence of exceptional cases of victim role staging is essential in the daily routine of healthcare, judicial and forensic professionals. Therefore, a questioning attitude within the physical examination as well as proper assessment of objective findings is crucial. Furthermore, the importance of an interdisciplinary approach of possible factitious disorders is demonstrated. The sensitization may exclude a third-party-interference, prevent damages to the health care system, avoid misleading of the administration of justice, and, therefore, reduce socioeconomic costs. Moreover, the recognition may enable adequate interventions and provide patients with professional help. PMID- 26597322 TI - In vivo monitoring of urea cycle activity with (13)C-acetate as a tracer of ureagenesis. AB - BACKGROUND: The hepatic urea cycle is the main metabolic pathway for detoxification of ammonia. Inborn errors of urea cycle function present with severe hyperammonemia and a high case fatality rate. Long-term prognosis depends on the residual activity of the defective enzyme. A reliable method to estimate urea cycle activity in-vivo does not exist yet. The aim of this study was to evaluate a practical method to quantify (13)C-urea production as a marker for urea cycle function in healthy subjects, patients with confirmed urea cycle defect (UCD) and asymptomatic carriers of UCD mutations. METHODS: (13)C-labeled sodium acetate was applied orally in a single dose to 47 subjects (10 healthy subjects, 28 symptomatic patients, 9 asymptomatic carriers). RESULTS: The oral (13)C-ureagenesis assay is a safe method. While healthy subjects and asymptomatic carriers did not differ with regards to kinetic variables for urea cycle flux, symptomatic patients had lower (13)C-plasma urea levels. Although the (13)C ureagenesis assay revealed no significant differences between individual urea cycle enzyme defects, it reflected the heterogeneity between different clinical subgroups, including male neonatal onset ornithine carbamoyltransferase deficiency. Applying the (13)C-urea area under the curve can differentiate between severe from more mildly affected neonates. Late onset patients differ significantly from neonates, carriers and healthy subjects. CONCLUSION: This study evaluated the oral (13)C-ureagenesis assay as a sensitive in-vivo measure for ureagenesis capacity. The assay has the potential to become a reliable tool to differentiate UCD patient subgroups, follow changes in ureagenesis capacity and could be helpful in monitoring novel therapies of UCD. PMID- 26597324 TI - Effect of repeated mass drug administration with praziquantel and track and treat of taeniosis cases on the prevalence of taeniosis in Taenia solium endemic rural communities of Tanzania. AB - This study evaluated the effect of mass drug administration (MDA) with praziquantel administered to school-aged children (SAC) combined with 'track and treat' of taeniosis cases in the general population on the copro-antigen (Ag) prevalence of taeniosis. The study was conducted in 14 villages in Mbozi and Mbeya district, Tanzania. SAC made up 34% of the population and received MDA with praziquantel (40mg/kg) in 2012 (both districts) and in 2013 (Mbozi only). Three cross-sectional population-based surveys were performed in 2012 (R0), 2013 (R1), and 2014 (R2). In each survey approximately 3000 study subjects of all ages were tested for taeniosis using copro-Ag-ELISA. In total 9064 people were tested and copro-Ag-ELISA positive cases were offered treatment 6-8 months after sampling. The copro-Ag prevalence of taeniosis was significantly higher (Chi2-test, p=0.007) in Mbozi (3.0%) at R0 compared to Mbeya (1.5%). Twelve months after MDA in both districts (R1), the copro-Ag prevalence had dropped significantly in both Mbozi (2.0%, p=0.024) and in Mbeya (0.3%, p=0.004), but the significant difference between the districts persisted (Chi2-test, p<0.001). Ten months after the second round of MDA in Mbozi and 22 month after the first MDA (R2), the copro Ag prevalence had dropped significantly again in Mbozi (0.8%, p<0.001), but had slightly increased in Mbeya (0.5%, p=0.051), with no difference between the two districts (Chi2-test, p=0.51). The taeniosis cases tracked and treated between round R0 and R2 represented 9% of the projected total number of taeniosis cases within the study area, based on the copro-Ag prevalence and village population data. Among SAC in Mbozi, infection significantly decreased at R1 (p=0.004, OR 0.12, CI: 0.02-0.41) and R2 (p=0.001, OR 0.24, CI: 0.09-0.53) when comparing to R0. In Mbeya infection significant decreased at R1 (p=0.013, OR 0.14, CI: 0.02 0.55), but no difference was found for R2 (p=0. 089), when comparing to R0 among SAC. This study showed that school-based MDA with praziquantel in combination with 'track and treat' of taeniosis cases significantly reduced the copro-Ag prevalence of taeniosis, and that annual MDA was significantly better than single MDA. The persistence of taeniosis cases illustrates that a One Health approach must be emphasized for effective control. PMID- 26597326 TI - Alzheimer's disease biomarker states. PMID- 26597325 TI - Transition rates between amyloid and neurodegeneration biomarker states and to dementia: a population-based, longitudinal cohort study. AB - BACKGROUND: In a 2014 cross-sectional analysis, we showed that amyloid and neurodegeneration biomarker states in participants with no clinical impairment varied greatly with age, suggesting dynamic within-person processes. In this longitudinal study, we aimed to estimate rates of transition from a less to a more abnormal biomarker state by age in individuals without dementia, as well as to assess rates of transition to dementia from an abnormal state. METHODS: Participants from the Mayo Clinic Study of Aging (Olmsted County, MN, USA) without dementia at baseline were included in this study, a subset of whom agreed to multimodality imaging. Amyloid PET (with (11)C-Pittsburgh compound B) was used to classify individuals as amyloid positive (A(+)) or negative (A(-)). (18)F fluorodeoxyglucose ((18)F-FDG)-PET and MRI were used to classify individuals as neurodegeneration positive (N(+)) or negative (N(-)). We used all observations, including those from participants who did not have imaging results, to construct a multistate Markov model to estimate four different age-specific biomarker state transition rates: A(-)N(-) to A(+)N(-); A(-)N(-) to A(-)N(+) (suspected non Alzheimer's pathology); A(+)N(-) to A(+)N(+); and A(-)N(+) to A(+)N(+). We also estimated two age-specific rates to dementia: A(+)N(+) to dementia and A(-)N(+) to dementia. Using these state-to-state transition rates, we estimated biomarker state frequencies by age. FINDINGS: At baseline (between Nov 29, 2004, to March 7, 2015), 4049 participants did not have dementia (3512 [87%] were clinically normal and 537 [13%] had mild cognitive impairment). 1541 individuals underwent imaging between March 28, 2006, to April 30, 2015. Transition rates were low at age 50 years and, with one exception, exponentially increased with age. At age 85 years compared with age 65 years, the rate was nearly 11-times higher (17.2 vs 1.6 per 100 person-years) for the transition from A(-)N(-) to A(-)N(+), three times higher (20.8 vs 6.1) for A(+)N(-) to A(+)N(+), and five-times higher (13.2 vs 2.6) for A(-)N(+) to A(+)N(+). The rate of transition was also increased at age 85 years compared with age 65 years for A(+)N(+) to dementia (7.0 vs 0.8) and for A(-)N(+) to dementia (1.7 vs 0.6). The one exception to an exponential increase with age was the transition rate from A(-)N(-) to A(+)N(-), which increased from 4.0 transitions per 100 person-years at age 65 years to 6.9 transitions per 100 person-years at age 75 and then plateaued beyond that age. Estimated biomarker frequencies by age from the multistate model were similar to cross-sectional biomarker frequencies. INTERPRETATION: Our transition rates suggest that brain ageing is a nearly inevitable acceleration toward worse biomarker and clinical states. The one exception is the transition to amyloidosis without neurodegeneration, which is most dynamic from age 60 years to 70 years and then plateaus beyond that age. We found that simple transition rates can explain complex, highly interdependent biomarker state frequencies in our population. FUNDING: National Institute on Aging, Alexander Family Professorship of Alzheimer's Disease Research, the GHR Foundation. PMID- 26597328 TI - HPV primary screening: unanswered questions. PMID- 26597327 TI - TLR 9 involvement in early protection induced by immunization with rPb27 against Paracoccidioidomycosis. AB - Paracoccidioidomycosis is caused by fungi of the Paracoccidioides genus and constitutes the most prevalent deep mycosis in Latin America. Toll-like receptors promote immune response against infectious agents. Recently, it was reported that TLR9 is crucial for mice survival during the first 48 h of P. brasiliensis infection. In this study, we used CPG oligodeoxynucleotide motif as an adjuvant with and without rPb27 to immunize mice against Paracoccidioidomycosis. CPG adjuvant induced differential recruitment of lymphocytes in the inflammatory process and a lower recruitment of neutrophils. In addition, CPG induced the production of pro-inflammatory cytokines such as IL-1beta, TNF-alpha, IL-6 and IL 12; increased phagocytic ability and microbicidal activity by macrophages; and induced differential production of lgG2a and lgG2b, subtypes of Ig. Knockout mice for TLR9 and IL-12 showed higher fungal loads and rates of mortality compared to control mice after 30 days of infection. The association between CPG and rPb27 induced a high level of protection against Paracoccidioidomycosis after the first 30 days of infection but not at 60 days. Our findings demonstrate that TLR 9 plays a role in the protection induced by immunization with rPb27 and confirms the importance of TLR9 in the initial protection against Paracoccidioidomycosis. PMID- 26597329 TI - Tracheal intubation with a VivaSight-SL endotracheal tube by paramedics in a cervical-immobilized manikin. PMID- 26597330 TI - Sodium bicarbonate administration during ongoing resuscitation is associated with increased return of spontaneous circulation. AB - PURPOSE: Sodium bicarbonate is frequently used for patients unresponsive to cardiopulmonary resuscitation (CPR). Its use may be associated with longer resuscitation duration as well as more severe metabolic acidosis. We applied a new analytical method based on a matched case-control study design to control for the potential confounders. BASIC PROCEDURES: Out-of-hospital cardiac arrest patients resuscitated in an emergency department for at least 20 minutes, unless there was any return of spontaneous circulation (ROSC) within the time frame, were analyzed. Patients without ROSC for 20 minutes of CPR were matched to those with ROSC based on initial bicarbonate level categorized using cutoff points of 10, 15, 20, 25, and 30 mEq/L, and their observation durations were trimmed to match their pairs. The association between sodium bicarbonate and ROSC was examined using conditional logistic regression analysis. MAIN FINDINGS: Two matched groups, one with ROSC and the other without (both n = 258), were generated. Sodium bicarbonate administration and its total cumulative dose were significantly associated with an increased ROSC, with odds ratios for ROSC of 1.86 (95% confidence interval [CI], 1.09-3.16; P = .022) and 1.18 (per 20 mEq; 95% CI, 1.04-1.33; P = .008), respectively. The positive associations remained unchanged after multivariable adjustment, with odds ratios for ROSC of 2.49 (95% CI, 1.33-4.65; P = .004) and 1.27 (95% CI, 1.11-1.47; P = .001), respectively. PRINCIPAL CONCLUSION: Sodium bicarbonate administration during CPR in emergency department was associated with increased ROSC. PMID- 26597331 TI - Evaluation of myocardial injury through serum troponin I and echocardiography in anaphylaxis. AB - BACKGROUND: Anaphylaxis is an acute, lethal, multisystem syndrome that results from the sudden release of mast cell- and basophil-derived mediators. Although anaphylaxis can cause cardiac complications, the incidence of myocardial injury using troponin I (TnI) has not been characterized. In addition, patterns of cardiomyopathy have not been evaluated in patients with elevated TnI. Therefore, we studied the occurrence and patterns of myocardial injury with TnI and echocardiography in anaphylaxis. METHODS: We conducted a retrospective review of 300 consecutive anaphylaxis cases that were diagnosed in the emergency department (ED) over 53 months (2011-2015). Myocardial injury was defined as elevation of TnI within 24hrs after arrival at the ED. We investigated systolic function and regional wall motion abnormality (RWMA) through echocardiography within 5 hours after arrival at the ED in patients with myocardial injury. RESULTS: Among 300 patients (median age, 55 years), 22 patients demonstrated myocardial injury (7.3%). The median TnI was 0.222 ng/mL with a range from 0.057 ng/mL to 19.4 ng/mL. Three patients presented reduced systolic function and 4 patients showed RWMA. One patient showed reverse Takotsubo cardiomyopathy and other 2 patients had RWMA discordant to the distribution of coronary arteries. Another patient showed RWMA (inferior wall) with ST elevation of II, III, and aVF. All 4 patients were discharge after recovery of cardiomyopathy without any specific intervention for cardiomyopathy. CONCLUSIONS: Myocardial injury developed in 7.3% of patients with anaphylaxis. Various cardiomyopathy, including Kounis syndrome and Takotsubo cardiomyopathy, has been observed in patients with myocardial injury. PMID- 26597332 TI - Breslow thickness and (18)F-FDG PET-CT result in initial staging of cutaneous melanoma: Can a cut-off point be established? AB - AIM: To establish a Breslow Thickness (BT) cut-off point for indication of PET-CT of cutaneous melanoma in early stages and evaluate its prognostic value. MATERIAL AND METHODS: Retrospective analysis of 347 PET-CT studies with diagnosis of melanoma, of which 108 were performed for initial staging. Thirty-one patients were excluded, and a final sample of 77 patients remained. A ROC curve analysis was performed to establish an optimal cut-off point. A survival analysis was performed, considering death assignable to melanoma as the main event, for the evaluation of its prognostic value. RESULTS: Forty-seven (61.04%) of all 77 patients selected were men, and 11 (14.29%) had a positive PET-CT result. Mean age was 65.17+/-15.00 years. The median BT in patients with a negative PET-CT result was 2.75 mm (IQR 1.83-4.50) and in the positive group 6.25 mm (IQR 5.40 7.50) (P=.0013). In the ROC curve analysis (AUC 0.804, SE 0.054), an optimal value of 5 mm BT with the following values was obtained: sensitivity 90.91%, specificity 78.79%, negative predictive value (NPV) 98.1%, positive predictive value (PPV) 41.7%, diagnostic OR 37.1, and accuracy 80.52%. Mean follow-up was 18.66+/-14,35 months, detecting 2/53 (3.77%) deaths in the BT<5 mm group, and 7/24 (29.17%) in the BT>=5 mm group. Survival curves between both groups were significantly different (P=.0013). CONCLUSIONS: A 5 mm cut-off point correctly distinguishes those patients with positive PET-CT from those with negative results in the early stages of cutaneous melanoma; therefore it could be included in initial staging of this subgroup of patients. PMID- 26597333 TI - Evolution of public cooperation in a monitored society with implicated punishment and within-group enforcement. AB - Monitoring with implicated punishment is common in human societies to avert freeriding on common goods. But is it effective in promoting public cooperation? We show that the introduction of monitoring and implicated punishment is indeed effective, as it transforms the public goods game to a coordination game, thus rendering cooperation viable in infinite and finite well-mixed populations. We also show that the addition of within-group enforcement further promotes the evolution of public cooperation. However, although the group size in this context has nonlinear effects on collective action, an intermediate group size is least conductive to cooperative behaviour. This contradicts recent field observations, where an intermediate group size was declared optimal with the conjecture that group-size effects and within-group enforcement are responsible. Our theoretical research thus clarifies key aspects of monitoring with implicated punishment in human societies, and additionally, it reveals fundamental group-size effects that facilitate prosocial collective action. PMID- 26597334 TI - Detrusor Muscle in TUR-Derived Bladder Tumor Specimens: Can We Actually Improve the Surgical Quality? AB - INTRODUCTION: Published series of transurethral resection of bladder tumor (TURBT) show high rates (18%-52%) of procedures resulting in no detrusor muscle (DM) layer being present in the pathologic specimen. This is of clinical importance since DM inclusion in surgical specimens is invariably associated with better oncologic results and is considered a surrogate marker of surgical quality. We sought to assess rates and predictors of DM absence (DM-) at a final pathology report in a series of consecutive TURBTs performed at a single tertiary referral academic center. MATERIALS AND METHODS: We retrospectively collected data from 437 TURBTs performed over 1 year. Complete endoscopic perioperative data were available for all patients; surgeons were categorized as either staff physicians or residents. Likewise, pathologic data, including tumor grade and stage, and DM status (present vs absent) were recorded. Only procedures with bladder cancer (BCa) at final pathology were included in the analyses. Logistic regression analyses tested potential predictors of DM-. Kaplan-Meier analyses were applied to assess the impact of DM- on postoperative tumor recurrence. RESULTS: Overall, BCa was found in 302 (69.1%) specimens at final pathology; DM- occurred in 29 (9.6%) cases. A comparable rate of DM- was observed for procedures conducted by staff physicians and residents (9% [23/232] vs 12.8% [6/41], respectively; p = 0.6). Flat morphology emerged as the most informative predictor of DM- after adjusting for tumor size, number of lesions, tumor stage and grade, surgeon experience, and resection modality. At Kaplan-Meier analysis, DM- was not associated with worse outcomes in terms of postoperative recurrence-free survival. CONCLUSIONS: Current findings showed a rate of roughly 10% of DM- at TURBT. Flat morphology emerged as the most significant predictor of DM-, whereas surgeon experience was not associated with DM-. PMID- 26597335 TI - Development of and Clinical Experience with a Simple Device for Performing Intraoperative Fluorescein Fluorescence Cerebral Angiography: Technical Notes. AB - To perform intraoperative fluorescence angiography (FAG) under a microscope without an integrated FAG function with reasonable cost and sufficient quality for evaluation, we made a small and easy to use device for fluorescein FAG (FAG filter). We investigated the practical use of this FAG filter during aneurysm surgery, revascularization surgery, and brain tumor surgery. The FAG filter consists of two types of filters: an excitatory filter and a barrier filter. The excitatory filter excludes all wavelengths except for blue light and the barrier filter passes long waves except for blue light. By adding this FAG filter to a microscope without an integrated FAG function, light from the microscope illuminating the surgical field becomes blue, which is blocked by the barrier filter. We put the FAG filter on the objective lens of the operating microscope correctly and fluorescein sodium was injected intravenously or intra-arterially. Fluorescence (green light) from vessels in the surgical field and the dyed tumor were clearly observed through the microscope and recorded by a memory device. This method was easy and could be performed in a short time (about 10 seconds). Blood flow of small vessels deep in the surgical field could be observed. Blood flow stagnation could be evaluated. However, images from this method were inferior to those obtained by currently commercially available microscopes with an integrated FAG function. In brain tumor surgery, a stained tumor on the brain surface could be observed using this method. FAG could be performed with a microscope without an integrated FAG function easily with only this FAG filter. PMID- 26597336 TI - The use of nerve monitoring in the placement of vagal nerve stimulators. PMID- 26597338 TI - Biogeographic patterns of nutrient resorption from Quercus variabilis Blume leaves across China. AB - The variation in nutrient resorption has been studied at different taxonomic levels and geographic ranges. However, the variable traits of nutrient resorption at the individual species level across its distribution are poorly understood. We examined the variability and environmental controls of leaf nutrient resorption of Quercus variabilis, a widely distributed species of important ecological and economic value in China. The mean resorption efficiency was highest for phosphorus (P), followed by potassium (K), nitrogen (N), sulphur (S), magnesium (Mg) and carbon (C). Resorption efficiencies and proficiencies were strongly affected by climate and respective nutrients concentrations in soils and green leaves, but had little association with leaf mass per area. Climate factors, especially growing season length, were dominant drivers of nutrient resorption efficiencies, except for C, which was strongly related to green leaf C status. In contrast, green leaf nutritional status was the primary controlling factor of leaf nutrient proficiencies, except for C. Resorption efficiencies of N, P, K and S increased significantly with latitude, and were negatively related to growing season length and mean annual temperature. In turn, N, P, K and S in senesced leaves decreased with latitude, likely due to their efficient resorption response to variation in climate, but increased for Mg and did not change for C. Our results indicate that the nutrient resorption efficiency and proficiency of Q. variabilis differed strongly among nutrients, as well as growing environments. Our findings provide important insights into understanding the nutrient conservation strategy at the individual species level and its possible influence on nutrient cycling. PMID- 26597339 TI - Toxoplasma gondii Infection in Hunted Wild Boars (Sus scrofa): Heart Meat Juice as an Alternative Sample to Serum for the Detection of Antibodies. AB - Toxoplasmosis is a global zoonosis caused by the protozoan parasite Toxoplasma gondii. Detection of antibodies to T. gondii in serum samples from hunted animals may represent a key step for public health protection. It is also important to assess the circulation of this parasite in wild boar population. However, in hunted animals, collection of blood is not feasible and meat juice may represent an alternative sample. The purpose of the present study was to evaluate heart meat juice of hunted wild boars as an alternative sample for post-mortem detection of antibodies to T. gondii by modified agglutination test (MAT). The agreement beyond chance between results from meat juice assessed with Cohen's kappa coefficient revealed that the 1:20 meat juice dilution provided the highest agreement. McNemars's test further revealed 1:10 as the most suitable meat juice dilution, as the proportion of positive paired samples (serum and meat juice from the same animal) did not differ at this dilution. All together, these results suggest a reasonable accuracy of heart meat juice to detect antibodies to T. gondii by MAT and support it as an alternative sample in post-mortem analysis in hunted wild boars. PMID- 26597340 TI - Crosslinking of peanut allergen Ara h 2 by polyphenol oxidase: digestibility and potential allergenicity assessment. AB - BACKGROUND: Peanut is one of the eight major food allergens. Its allergen, Ara h 2, can be recognized by over 90% of serum IgE samples from peanut-allergic patients. Therefore, reducing the allergenicity of Ara h 2 is especially important. RESULTS: In the present study, polyphenol oxidase (PPO), a protein cross-linking reaction catalyst that acts on tyrosine residue, was used to modify Ara h 2. After crosslinking, the microstructure, digestibility, IgG binding capability and IgE binding capability of Ara h 2 were analyzed. Cross-linking decreased the potential allergenicity of Ara h 2 by masking the allergen epitope, while the antigenicity of Ara h 2 changed slightly. After crosslinking, the apparent diameter of Ara h 2 was altered from 300 to 1700 nm or 220 nm, indicating that polymerization could either be inter- or intramolecular. Regarding digestibility, crosslinked Ara h 2 was relatively more easily digested by gastric fluid compared with the untreated Ara h 2, but much more difficult in the intestinal fluid. CONCLUSION: The crosslinking reaction catalyzed by PPO, as a non-thermal process, may be beneficial for avoiding food allergy. The reaction could mask allergen epitopes, decreasing the allergenicity of Ara h 2. (c) 2015 Society of Chemical Industry. PMID- 26597341 TI - Effectiveness of a Geriatric Care Model for frail older adults in primary care: Results from a stepped wedge cluster randomized trial. AB - BACKGROUND: Primary care-based comprehensive care programs have the potential to improve outcomes in frail older adults. We evaluated the impact of the Geriatric Care Model (GCM) on the quality of life of community-dwelling frail older adults. METHODS: A 24-month stepped wedge cluster randomized controlled trial was conducted between May 2010 and March 2013 in 35 primary care practices in the Netherlands, and included 1147 frail older adults. The intervention consisted of a geriatric in-home assessment by a practice nurse, followed by a tailored care plan. Reassessment occurred every six months. Nurses worked together with primary care physicians and were supervised and trained by geriatric expert teams. Complex patients were reviewed in multidisciplinary consultations. The primary outcome was quality of life (SF-12). Secondary outcomes were health-related quality of life, functional limitations, self-rated health, psychological wellbeing, social functioning and hospitalizations. RESULTS: Intention-to-treat analyses based on multilevel modeling showed no significant differences between the intervention group and usual care regarding SF-12 and most secondary outcomes. Only for IADL limitations we found a small intervention effect in patients who received the intervention for 18months (B=-0.25, 95%CI=-0.43 to 0.06, p=0.007), but this effect was not statistically significant after correction for multiple comparisons. CONCLUSION: The GCM did not show beneficial effects on quality of life in frail older adults in primary care, compared to usual care. This study strengthens the idea that comprehensive care programs add very little to usual primary care for this population. TRIAL REGISTRATION: The Netherlands National Trial Register NTR2160. PMID- 26597342 TI - Cruising between Scylla and Charybdis ... Just a hope? PMID- 26597343 TI - A woman with recurrent chest pain and ST-segment elevation. AB - A 32-year-old female presents with recurrent episodes of unprovoked chest pain associated with inferior ST-segment elevation and reciprocal ST-segment depression. Coronary angiography during one of these episodes revealed coronary artery spasm that spontaneously resolved followed by resolution of these electrocardiographic changes. There was no atherosclerotic occlusive disease. Her cardiac markers were normal and echocardiogram showed no regional wall motion abnormalities. Electrocariogram and angiography findings are shown in Fig. 1. PMID- 26597344 TI - [Delphi study to identify the management skills of nursing executives]. AB - OBJECTIVE: To determine and update the skills map for the position of Nurse Administrator in hospitals and Primary Care. METHOD: An observational, descriptive, cross-sectional study based on a Delphi technique was conducted in hospital and Primary Care settings. Two nominal groups with 15 nurses each were used to define the contents of the questionnaire 0 in the Delphi technique. All nurses registered in the professional associations of Alicante, Castellon and Valencia were invited to participate. The results of the Delphi study was submitted to factor analysis to identify the set of skills and, subsequently, compare them with the offer of post-graduate course in colleges and universities during the 2014-15 academic year. RESULTS: Forty-five competences were extracted during the Nominal groups. In total, 705 nurses replied to the first wave in the Delphi Technique, and 394 in the second (response rate of 56%). Factorial analysis grouped the skills chosen into 10 factors: managing people, conflict management, independent learning, ethics, emotional balance, commitment, self discipline, continuous improvement, critical-thinking, and innovation. Four skills groups identified in this study (emotional balancing, commitment, self discipline and courage) were not usually included in the post-graduate courses CONCLUSIONS: The nurse administrator skills should be related to relational and ethical behaviour. The training offer of the post-graduate courses must be reoriented. PMID- 26597345 TI - Tetranectin gene deletion induces Parkinson's disease by enhancing neuronal apoptosis. AB - Parkinson's disease (PD) is a chronic neurodegenerative disorder characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). We previously identified tetranectin (TET) as a potential biomarker for PD whose expression is downregulated in the cerebrospinal fluid of PD patients. In the present study, we investigate the role of TET in neurodegeneration in vitro and in vivo. Our results showed that siRNA knockdown of TET decreased cell viability and the number of tyrosine hydroxylase (TH) positive cells, whereas it increased caspase-3 activity and the Bax/Bcl-2 ratio in cultured primary dopaminergic neurons. Overexpression of TET protected dopaminergic neurons against neuronal apoptosis in 1-methyl-4-phenylpyridinium cell culture model in vitro. In TET knockdown mouse model of PD, TET gene deletion decreased the number of TH positive cells in the SNpc, induced apoptosis via the p53/Bax pathway, and significantly impaired the motor behavior of transgenic mice. The findings suggest that TET plays a neuroprotective role via reducing neuron apoptosis and could be a valuable biomarker or potential therapeutic target for the treatment of patients with PD. PMID- 26597346 TI - The treatment of pharyngoesophageal perforation following anterior cervical spine intervention. AB - OBJECTIVE: We aimed to investigate the diagnostic and therapeutic approaches in pharyngoesophageal perforation (PEP) following anterior cervical spine intervention (ACSI). METHODS: We reviewed the records of four patients with PEP after ACSI. Symptoms, physical examination findings, imaging results, treatment, and follow-up characteristics were evaluated. RESULTS: All four patients had undergone ACSI for either cervical trauma or cervical disc herniation with cervical cage reconstruction. Symptoms developed within the first 10 days of the postoperative period in three patients, and in the eighth month in one patient. Mucosal defects were detected during neck exploration in three patients. Reconstruction with primary suture and a local muscle flap was utilized in two patients. Three patients were discharged 3-8 weeks after surgical treatment. CONCLUSION: In cases of PEP after ACSI, a good prognosis can be achieved when symptoms are detected in the early period and reconstruction with local muscle flap is applied. PMID- 26597347 TI - Premalignant disease in the genital tract in pregnancy. AB - Cervical intraepithelial neoplasia (CIN) is the most common premalignant disease of the lower genital tract encountered during pregnancy. As in the non-pregnant state, abnormal cytology should be referred for colposcopy. However, the role of colposcopy in pregnant women is to exclude invasive cancer by visual inspection and defer biopsy and definitive treatment until the post-partum period. Colposcopic exclusion of invasive disease is the only absolute indication for conisation in pregnancy. It is now evident that treatment for CIN outside of pregnancy, that involves >15 mm deep excision is associated with an increased risk of preterm delivery. Vulval intraepithelial neoplasia (VIN) and vaginal intraepithelial neoplasia (VaIN) rarely present in women of childbearing age; nevertheless, medical management should be postponed until after delivery, unless symptoms are particularly severe. PMID- 26597349 TI - Clindamycin for first-time or recurrent canine staphylococcal pyoderma. PMID- 26597350 TI - Drug Reaction with Eosinophilia and Systemic Symptoms Syndrome Induced by Levetiracetam in a Pediatric Patient. AB - BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare, life-threatening hypersensitivity drug reaction. Patients present with cutaneous rash, fever, lymphadenopathy, hematologic abnormalities with eosinophilia and atypical lymphocytes, and visceral organ involvement. The prognosis of DRESS syndrome is related to the degree of end-organ damage, and the mortality rate is approximately 10%. CASE REPORT: We report a 9-year-old girl treated with only levetiracetam because of intracranial space occupying mass related seizures. The patient developed pharyngitis accompanied by exudative membrane, bilateral cervical lymphadenopathy, tender hepatomegaly, skin rash, and fever after 19 days of levetiracetam therapy. Laboratory findings revealed leukocytosis, lymphocytosis with an atypical lymphocytosis, eosinophilia, thrombocytopenia, and elevated serum transaminases. Serologic studies of viruses were negative. The patient was diagnosed with DRESS syndrome and antiepileptic therapy was ceased immediately. The systemic signs and symptoms of the patient were improved after systemic steroid and antihistamine therapy. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: It is important that emergency physicians be aware of the possibility of DRESS syndrome when attending children that present with clinical viral infections. We would like to emphasize that obtaining a careful and detailed medication history is an essential part of clinical assessment for the diagnosis of DRESS syndrome. PMID- 26597348 TI - Total Western Diet Alters Mechanical and Thermal Sensitivity and Prolongs Hypersensitivity Following Complete Freund's Adjuvant in Mice. AB - Obesity and chronic pain are often comorbid and their rates are increasing. It is unknown whether increased pain is caused by greater weight or poor diet quality or both. Therefore, we utilized a Total Western Diet (TWD) to investigate the functional and physiologic consequences of nutritionally poor diet in mice. For 13 weeks on the commercially available TWD, based on the National Health and Nutrition Examination Survey, thresholds of TWD-fed mice significantly increased in both thermal and mechanical tests. Quantitative magnetic resonance imaging revealed a significant increase in fat mass with a concomitant decrease in lean mass in the TWD-fed mice. In addition, there were significant increases in levels of serum leptin and inflammatory cytokines. After chronic pain induction using complete Freund's adjuvant, hypersensitivity was more pronounced and significantly prolonged in the TWD-fed mice. Therefore, prolonged exposure to poor diet quality resulted in altered acute nociceptive sensitivity, systemic inflammation, and persistent pain after inflammatory pain induction. PERSPECTIVE: These results highlight the negative effects of poor diet quality with respect to recovery from hypersensitivity and susceptibility to chronic pain. A complete understanding of the impact of diet can aid in treatment and recovery dynamics in human clinical patients. PMID- 26597351 TI - True navigation in migrating gulls requires intact olfactory nerves. AB - During migratory journeys, birds may become displaced from their normal migratory route. Experimental evidence has shown that adult birds can correct for such displacements and return to their goal. However, the nature of the cues used by migratory birds to perform long distance navigation is still debated. In this experiment we subjected adult lesser black-backed gulls migrating from their Finnish/Russian breeding grounds (from >60 degrees N) to Africa (to < 5 degrees N) to sensory manipulation, to determine the sensory systems required for navigation. We translocated birds westward (1080 km) or eastward (885 km) to simulate natural navigational challenges. When translocated westwards and outside their migratory corridor birds with olfactory nerve section kept a clear directional preference (southerly) but were unable to compensate for the displacement, while intact birds and gulls with the ophthalmic branch of the trigeminal nerve sectioned oriented towards their population-specific migratory corridor. Thus, air-borne olfactory information seems to be important for migrating gulls to navigate successfully in some circumstances. PMID- 26597352 TI - Crowdsourcing Assessment of Surgeon Dissection of Renal Artery and Vein During Robotic Partial Nephrectomy: A Novel Approach for Quantitative Assessment of Surgical Performance. AB - INTRODUCTION: We sought to describe a methodology of crowdsourcing for obtaining quantitative performance ratings of surgeons performing renal artery and vein dissection of robotic partial nephrectomy (RPN). We sought to compare assessment of technical performance obtained from the crowdsourcers with that of surgical content experts (CE). Our hypothesis is that the crowd can score performances of renal hilar dissection comparably to surgical CE using the Global Evaluative Assessment of Robotic Skills (GEARS). METHODS: A group of resident and attending robotic surgeons submitted a total of 14 video clips of RPN during hilar dissection. These videos were rated by both crowd and CE for technical skills performance using GEARS. A minimum of 3 CE and 30 Amazon Mechanical Turk crowdworkers evaluated each video with the GEARS scale. RESULTS: Within 13 days, we received ratings of all videos from all CE, and within 11.5 hours, we received 548 GEARS ratings from crowdworkers. Even though CE were exposed to a training module, internal consistency across videos of CE GEARS ratings remained low (ICC = 0.38). Despite this, we found that crowdworker GEARS ratings of videos were highly correlated with CE ratings at both the video level (R = 0.82, p < 0.001) and surgeon level (R = 0.84, p < 0.001). Similarly, crowdworker ratings of the renal artery dissection were highly correlated with expert assessments (R = 0.83, p < 0.001) for the unique surgery-specific assessment question. CONCLUSIONS: We conclude that crowdsourced assessment of qualitative performance ratings may be an alternative and/or adjunct to surgical experts' ratings and would provide a rapid scalable solution to triage technical skills. PMID- 26597353 TI - Culprit Vessel-Only vs. Staged Multivessel Percutaneous Coronary Intervention Strategies in Patients With Multivessel Coronary Artery Disease Undergoing Primary Percutaneous Coronary Intervention for ST-Segment Elevation Myocardial Infarction. AB - BACKGROUND: We assessed the current status of treatment strategy in ST-segment elevation myocardial infarction (STEMI) with multivessel disease (MVD) in real world practice, focusing on the benefit of staged percutaneous coronary intervention (PCI). METHODS AND RESULTS: From the CREDO-Kyoto AMI Registry, 2,010 STEMI patients with MVD undergoing primary PCI were analyzed. Only 96 patients (4.8%) received acute multivessel PCI, and the majority of patients (n=1,914, 95.2%) had culprit-only PCI acutely. After excluding 699 patients (acute multivessel PCI, Killip class >=3, age >=90 years, coronary artery bypass grafting within 90 days, or clinical events within 90 days), 681 MVD patients underwent staged PCI for angiographically significant non-culprit lesions within 90 days (staged PCI group), while 630 MVD patients received primary PCI only (culprit-only PCI group). The cumulative 5-year incidence of and adjusted risk for all-cause death were significantly lower in the staged PCI group compared with the culprit-only PCI group (9.5% vs. 16.0%, P<0.001; HR, 0.69; 95% CI: 0.50 0.96, P=0.03). The risks for MI and any coronary revascularization favored the staged PCI strategy. CONCLUSIONS: The staged PCI strategy for angiographically significant non-culprit lesions was associated with lower 5-year mortality compared with the culprit-only PCI strategy in STEMI patients with MVD who underwent primary PCI. PMID- 26597354 TI - The What, When, Who, Why, How and Where of Myocardial Infarction With Non Obstructive Coronary Arteries (MINOCA). AB - Myocardial infarction with non-obstructive coronary arteries (MINOCA) is an intriguing clinical entity that is being increasingly recognized with the more common use of coronary angiography during acute myocardial infarction. This review systematically addresses the contemporary understanding of MINOCA, including, (1) what are the diagnostic criteria, (2) when the diagnosis should be considered, (3) who is at risk, (4) why this new syndrome should be diagnosed, (5) how these patients should be managed, and (6) where to next? PMID- 26597355 TI - Determinants and Prognostic Impact of Hyperuricemia in Hospitalization for Acute Heart Failure. AB - BACKGROUND: Hyperuricemia is a prognostic factor in patients with chronic heart failure, but whether uric acid level can predict clinical outcome of acute heart failure (AHF) remains to be elucidated. We therefore investigated the association of uric acid with mortality in patients hospitalized for AHF. METHODS AND RESULTS: Data for patients hospitalized for AHF were drawn from an intramural registry. Biochemistry data, echocardiographic characteristics, and uric acid level were collected. National Death Registry was linked for the identification of mortality data. Among a total of 1,835 participants (age, 75 +/- 13 years, 68% men), 794 patients died during follow-up. Patients who died were older, had lower hemoglobin and estimated glomerular filtration rate, and higher pulmonary artery systolic pressure, NT-proBNP, and uric acid. Uric acid was a significant predictor of mortality on univariate analysis (HR per 1 SD, 1.18; 95% CI: 1.11 1.26) and in multivariate Cox models (HR, 1.15; 95% CI: 1.02-1.29). Survival analysis showed an increasing risk of death along the quartile distribution of uric acid level. Given renal function, cardiac performance, and kidney perfusion as major determinants of hyperuricemia, the prognostic impact of uric acid level was diminished as renal function deteriorated. CONCLUSIONS: Uric acid level was an independent predictor of mortality in patients hospitalized for AHF, but the prognostic impact of hyperuricemia was attenuated by worsening renal function. PMID- 26597356 TI - Improving key enzyme activities and quality of rice under various methods of zinc application. AB - Zinc (Zn) is an important micronutrient for the physiology of plants. It is poorly available to the plants in soil solution. A pot experiment was conducted to evaluate effectiveness of various Zn application methods on key enzyme activities and protein content of two contrasting rice genotypes viz., PD16 (Zn efficient) and NDR359 (Zn inefficient). The treatments were, control (0 mg Zn kg( 1) soil), soil application (5 mg Zn kg(-1) soil), foliar application (0.5 % ZnSO4 + 0.25 % lime at 30, 60 and 90 days after transplanting), soil (5 mg Zn kg(-1) soil) + foliar application of 0.5 % ZnSO4 + 0.25 % lime at 30, 60 and 90 days after transplanting. Among all the methods tested soil+foliar application of Zn fertilizers was found most effective in increasing superoxide dismutase (SOD) and carbonic anhydrase (CA) activities as well as chlorophyll and protein content in both the rice varieties. NDR359, showed higher enzyme activities and more chlorophyll content in leaves than PD16, when Zn was applied either through foliar spray alone or in soil along with foliar application. Regarding the protein content in grains, PD16 showed higher protein content than NDR359, thus showed better translocation of Zn from leaves to grains. PMID- 26597357 TI - Mediastinal schwannoma with atypical localization diagnosed by endobronchial ultrasound. AB - INTRODUCTION: Schwannoma is a peripheral nerve sheath tumor usually originating from the posterior mediastinum. Because schwannomas can exhibit high fluorodeoxyglucose uptake on positron emission tomography, they cannot be distinguished from malignant tumors. OBJECTIVES: We present this case to stress the importance of endobronchial ultrasonography in the diagnosis of intrapulmonary masses with rare occurrence and different localization. METHODS: A patient was referred to our clinic for further workup of a soft tissue mass in the anterior mediastinum and diagnosed with a benign schwannoma by endobronchial ultrasonography. RESULTS: The diagnosis is thus largely based on pathological examination. Until today schwannomas have been diagnosed by pathology examination of lesions excised surgically for suspected malignancy. CONCLUSION: This article was reported since intrapulmonary schwannoma is a very rare tumor and this was the first case of an anterior mediastinal schwannoma diagnosed by endobronchial ultrasonography. PMID- 26597360 TI - Subjective and objective voice outcomes after transoral laser microsurgery for early glottic cancer. AB - OBJECTIVES/HYPOTHESIS: Transoral laser microsurgery (TLM) continues to gain popularity as a treatment modality for early glottic cancer. Oncologic outcomes have been well-defined, but there are little data to date describing functional outcomes accounting for stage of resection. STUDY DESIGN: Retrospective review. METHODS: We retrospectively reviewed patient-rated voice handicap and observer rated vocal quality of patients who underwent TLM for early glottic carcinoma. Patients were grouped by European Laryngological Society (ELS) resection type, and the data were combined for ELS type I-III and compared with advanced resections (ELS IV-VI). The Voice Handicap Index (VHI) was used for patient-rated voice outcomes, and voice recordings were graded by two senior speech-language pathologists. Voice recordings and VHI scores were taken preoperatively and at least 1 month postoperatively. RESULTS: No major complications were encountered. Six of 49 patients underwent repeat resection for suspicious findings with pathology, demonstrating moderate dysplasia in two cases, carcinoma in situ in two cases, and inflamed mucosa only in two cases. There was no significant difference in preoperative VHI scores or objective voice grades among patients who underwent limited (ELS I-III) and those who required more advanced (ELS IV VI) resection. There was a significant improvement in VHI scores in patients after ELS type I to III resection, from 38.77 to 22.86 (P = .006). There was no significant difference between mean preoperative and postoperative perceptual evaluation scores in patients who underwent ELS type I, II, or III resections (62.25 and 64.32 respectively, P = .621). CONCLUSIONS: Patients who undergo limited ELS resections can be assured of having a similar to improved voice after healing. Patients who undergo extended resections have poorer vocal outcomes. LEVEL OF EVIDENCE: 4. PMID- 26597361 TI - Fornix deep brain stimulation enhances acetylcholine levels in the hippocampus. AB - Deep brain stimulation (DBS) of the fornix has gained interest as a potential therapy for advanced treatment-resistant dementia, yet the mechanism of action remains widely unknown. Previously, we have reported beneficial memory effects of fornix DBS in a scopolamine-induced rat model of dementia, which is dependent on various brain structures including hippocampus. To elucidate mechanisms of action of fornix DBS with regard to memory restoration, we performed c-Fos immunohistochemistry in the hippocampus. We found that fornix DBS induced a selective activation of cells in the CA1 and CA3 subfields of the dorsal hippocampus. In addition, hippocampal neurotransmitter levels were measured using microdialysis before, during and after 60 min of fornix DBS in a next experiment. We observed a substantial increase in the levels of extracellular hippocampal acetylcholine, which peaked 20 min after stimulus onset. Interestingly, hippocampal glutamate levels did not change compared to baseline. Therefore, our findings provide first experimental evidence that fornix DBS activates the hippocampus and induces the release of acetylcholine in this region. PMID- 26597362 TI - Prognostic Role of Multiple Lymphatic Basin Drainage in Sentinel Lymph Node Negative Trunk Melanoma Patients: A Multicenter Study from the Italian Melanoma Intergroup. AB - BACKGROUND: Multiple lymphatic basin drainage (MLBD) is frequently observed in patients with trunk melanoma undergoing sentinel lymph node (SLN) biopsy. Conflicting data regarding the prognostic association of MLBD in SLN-negative patients have been reported. This study aimed to investigate the prognostic role of MLBD in patients with negative SLN biopsy. METHODS: Retrospective data from 656 melanoma patients who underwent a SLN biopsy (1991-2012) at six Italian centers were gathered in a multicenter database. MLBD was defined as lymphoscintigraphic and intraoperative identification of an SLN in more than one nodal basin. Clinical and pathologic variables were recorded and analyzed for their impact on survival. RESULTS: SLN-negative patients with MLBD were at lower risk of melanoma recurrence [hazard ratio (HR) 0.73, P = 0.05) and melanoma related death (HR 0.68, P = 0.001) independent of common staging features. Multivariable Cox analyses of disease-free interval (DFI) and disease-specific survival (DSS) showed that MLBD maintained a favorable role and ulceration an unfavorable role. Histologic regression was independently associated only with DFI. When survival was stratified according to presence of MLBD, histologic regression and Breslow thickness <2 mm were associated with improved DFI (5-year DFI: 96.9 vs. 66,1 %, respectively; HR 0.48, P < 0.001) and DSS (5-year DSS: 96.7 vs. 71.8 %, respectively; HR 0.52, P = 0.005) compared to patients without these three favorable parameters. CONCLUSIONS: Patients with negative SLN biopsy results have better prognosis when two or more lymphatic basins are identified and analyzed. Further research is required to investigate the mechanisms behind this evidence. PMID- 26597363 TI - Totally Laparoscopic Colectomy with Intracorporeal Side-to-End Colorectal Anastomosis and Transrectal Specimen Extraction for Sigmoid and Rectal Cancers. AB - BACKGROUND: The techniques of intracorporeal anastomosis and specimen extraction after laparoscopic colectomy via a natural orifice have gained interest increasingly. We evaluated the feasibility of our unique techniques for colorectal reconstruction and report immediate postoperative outcomes in patients with rectosigmoid cancer. METHODS: Patients with sigmoid or rectal cancer were selected depending on the size of the tumor and its distance from the anal verge. Demographic data, operative parameters, and postoperative outcomes were assessed. After complete resection of the tumor, all patients underwent an intracorporeal side-to-end colorectal anastomosis following transrectal specimen extraction. RESULTS: Laparoscopic resection with our technique of intracorporeal anastomosis was successful in 32 patients. The average operative time was 192 +/- 29 min, and mean blood loss was 51 +/- 18 ml. All patients experienced mild postoperative pain, and bowel function returned before postoperative day 3 in most patients. They had an uneventful postoperative course with a median hospital stay of 6 days. Major perioperative complications or anastomotic leak were not encountered in this study. The mean size of the lesion was 3.3 +/- 1.8 cm, and the mean number of harvested nodes was 14 +/- 6. During the follow-up period, there were no functional disorders associated with the intracorporeal anastomosis or transrectal specimen extraction. CONCLUSIONS: Intracorporeal side-to-end colorectal anastomosis with transrectal specimen extraction in laparoscopic colorectal surgery is a safe and effective procedure for patients with rectosigmoid malignancy. PMID- 26597364 TI - Type B versus Type C Radical Hysterectomy After Neoadjuvant Chemotherapy in Locally Advanced Cervical Carcinoma: A Propensity-Matched Analysis. AB - OBJECTIVE: The aim of this study was to evaluate the feasibility and safety of type B radical hysterectomy (RH) in the management of patients affected by locally advanced cervical cancer with favorable prognostic factors (tumor diameter <40 mm, negative nodes, or lymphovascular space involvement) and clinical response to neoadjuvant chemotherapy (NACT). METHODS: The data of women undergoing platinum-based NACT followed by RH plus bilateral systematic pelvic lymphadenectomy were collected. Patients undergoing type B RH (Group A) were compared with those undergoing type C RH (Group B); a propensity-matched comparison (1:1) was carried out to minimize selection biases. Postoperative complications were reported and 5-year survival outcomes were assessed using the Kaplan-Meier model. RESULTS: Thirty-six node-negative patients undergoing type B RH (Group A) were compared with 36 propensity-matched patients undergoing type C RH (Group B). The bladder dysfunction rate was significantly lower in Group A compared with Group B (13.9 vs. 69.4 %; p < 0.0001), and no statistically significant difference in 5-year overall survival (OS) and disease-free survival (DFS) between groups was reported (OS 93.0 vs. 96.7 %, p = 0.42; DFS 88.6 and 85.5 %, p = 0.77). CONCLUSIONS: Type B RH after NACT in well-selected patients is a safe procedure that upholds the results of type C, reducing operative time and late postoperative morbidity, without detrimental effect on survival. Further prospective trials are warranted to confirm our results on a large scale. PMID- 26597365 TI - Observation versus Resection for Small Asymptomatic Pancreatic Neuroendocrine Tumors: A Matched Case-Control Study. AB - OBJECTIVE: To analyze the natural history of small asymptomatic pancreatic neuroendocrine tumors (PanNET) and to present a matched comparison between groups who underwent either initial observation or resection. Management approach for small PanNET is uncertain. METHODS: Incidentally discovered, sporadic, small (<3 cm), stage I-II PanNET were analyzed retrospectively between 1993 and 2013. Diagnosis was determined either by pathology or imaging characteristics. Intention-to-treat analysis was applied. RESULTS: A total of 464 patients were reviewed. Observation was recommended for 104 patients (observation group), and these patients were matched to 77 patients in the resection group based on tumor size at initial imaging. The observation group was significantly older (median 63 vs. 59 years, p = 0.04) and tended towards shorter follow-up (44 vs. 57 months, p = 0.06). Within the observation group, 26 of the 104 patients (25 %) underwent subsequent tumor resection after a median observation interval of 30 months (range 7-135). At the time of last follow-up of the observation group, the median tumor size had not changed (1.2 cm, p = 0.7), and no patient had developed evidence of metastases. Within the resection group, low-grade (G1) pathology was recorded in 72 (95 %) tumors and 5 (6 %) developed a recurrence, which occurred after a median of 5.1 (range 2.9-8.1) years. No patient in either group died from disease. Death from other causes occurred in 11 of 181 (6 %) patients. CONCLUSIONS: In this study, no patient who was initially observed developed metastases or died from disease after a median follow-up of 44 months. Observation for stable, small, incidentally discovered PanNET is reasonable in selected patients. PMID- 26597366 TI - Is There Any Role of Adjuvant Chemotherapy for T3N0M0 or T1N2M0 Gastric Cancer Patients in Stage II in the 7th TNM but Stage I in the 6th TNM System? AB - BACKGROUND: Controversy surrounds adjuvant chemotherapy (CTx) for T3N0M0 and T1N2M0 in the American Joint Committee on Cancer (AJCC) 7th edition stage IIA gastric cancer patients. The purpose of this study was to evaluate the benefit of adjuvant CTx for stage IIA cancer, including T3N0M0 and T1N2M0. METHODS: A total of 630 patients with stage IIA cancer who underwent a radical gastrectomy between January 1999 and December 2009 at Seoul National University Hospital were retrospectively analyzed. We compared the outcomes of 434 patients who did not receive CTx (the non-CTx group) with those of 196 patients who received CTx comprising of 5-fluorouracil-based regimens (the CTx group). RESULTS: The 5-year overall survival (OS) rates of the non-CTx and CTx groups were 86.4 and 89.3 %, respectively (p = 0.047). In the subgroup analysis of T2N1M0 (6th II/7th IIA), there was a significant difference in OS between the non-CTx and CTx groups (p = 0.003), but no differences were observed in T3N0M0 and T1N2M0 (6th IB/7th IIA) (p = 0.574 and p = 0.934). The multivariate analysis showed that a tumor size greater than 5 cm in T3N0M0 [odds ratio (OR) 1.929; p = 0.030], no adjuvant CTx in T2N1M0 (OR 4.853; p = 0.025), and no factors in T1N2M0 were found to be risk factors for recurrence-free survival. CONCLUSIONS: Adjuvant CTx may be associated with an improved outcome of patients with T2N1M0 (6th II/7th IIA), but not T3N0M0 or T1N2M0 (6th IB/7th IIA), gastric cancer. To confirm these results, further studies are needed. PMID- 26597367 TI - Clinicopathologic and Prognostic Features in Patients with Peritoneal Metastasis from Mucinous Adenocarcinoma, Adenocarcinoma with Signet Ring Cells, and Adenocarcinoid of the Appendix Treated with Cytoreductive Surgery and Perioperative Intraperitoneal Chemotherapy. AB - BACKGROUND: Tumors that show a signet ring or adenocarcinoid histomorphology have been associated with a poor prognosis. This study aimed to analyze the clinicopathologic and prognostic features in patients with peritoneal metastasis from mucinous adenocarcinoma (PMCA), adenocarcinoma with signet ring cell (PMCA S), or adenocarcinoid (PMCA-A) of the appendix treated with cytoreductive surgery and perioperative intraperitoneal chemotherapy. METHODS: Retrospective analysis of a prospectively maintained database for all patients treated for appendiceal adenocarcinoma from 1989 to 2012 was performed. RESULTS: The study cohort consisted of 494 patients including 361 patients with PMCA (73.1 %), 80 patients with PMCA-S (16.2 %), and 53 patients with PMCA-A (10.7 %). The patients comprised 273 men (55.3 %) and 221 women (44.7 %) with a mean age at presentation of 50.7 years for the PMCA-S patients, 47.3 years for the PMCA patients, and 47.5 years for the PMCA-A patients (p < 0.03). The 3- and 5-year survival rates were respectively 51 and 38 % for PMCA compared with 30 and 22 % for PMCA-S and 26 and 15 % for PMCA-A. The median survival time was 45.4 months for PMCA compared with 18.9 months for PMCA-S and 26.8 months for PMCA-A (p < 0.000). The groups did not differ significantly in the completeness of cytoreduction achieved, with 53.5 % of the PMCA patients having a CC0/1 compared with 46.2 % of the PMCA-S patients and 41.6 % of the PMCA-A patients (p < 0.20). In the multivariate analysis, the independent predictors of a reduced survival were incompleteness of cytoreduction, histomorphology of PMCA-S or PMCA-A, and distant metastasis. CONCLUSION: The findings showed that PMCA-S or PMCA-A histomorphology contributes to the poor prognosis associated with peritoneal metastasis from appendiceal adenocarcinoma. The independent predictors for a poor overall survival included incompleteness of cytoreduction, PMCA-S and PMCA-A histomorphology, and distant metastasis. PMID- 26597368 TI - Results of a Randomized Controlled Multicenter Phase III Trial of Percutaneous Hepatic Perfusion Compared with Best Available Care for Patients with Melanoma Liver Metastases. AB - PURPOSE: There is no consensus for the treatment of melanoma metastatic to the liver. Percutaneous hepatic perfusion with melphalan (PHP-Mel) is a method of delivering regional chemotherapy selectively to the liver. In this study, we report the results of a multicenter, randomized controlled trial comparing PHP Mel with best alternative care (BAC) for patients with ocular or cutaneous melanoma metastatic to the liver. PATIENTS AND METHODS: A total of 93 patients were randomized to PHP-Mel (n = 44) or BAC (n = 49). On the PHP-Mel arm, melphalan was delivered via the hepatic artery, and the hepatic effluent captured and filtered extracorporeally prior to return to the systemic circulation via a venovenous bypass circuit. PHP-Mel was repeatable every 4-8 weeks. The primary endpoint was hepatic progression-free survival (hPFS), and secondary endpoints included overall PFS (oPFS), overall survival (OS), hepatic objective response (hOR), and safety. RESULTS: hPFS was 7.0 months for PHP-Mel and 1.6 months for BAC (p < 0.0001), while oPFS was 5.4 months for PHP-Mel and 1.6 months for BAC (p < 0.0001). Median OS was not significantly different (PHP-Mel 10.6 months vs. BAC 10.0 months), likely due to crossover to PHP-Mel treatment (57.1 %) from the BAC arm, and the hOR was 36.4 % for PHP-Mel and 2.0 % for BAC (p < 0.001). The majority of adverse events were related to bone marrow suppression. Four deaths were attributed to PHP-Mel, three in the primary PHP-Mel group, and one post crossover to PHP-Mel from BAC. CONCLUSION: This randomized, phase III study demonstrated the efficacy of the PHP-Mel procedure. hPFS, oPFS, and hOR were significantly improved with PHP-Mel. PHP with melphalan should provide a new treatment option for unresectable metastatic melanoma in the liver. PMID- 26597369 TI - Transanal Total Mesorectal Excision Versus Laparoscopic Surgery for Rectal Cancer Receiving Neoadjuvant Chemoradiation: A Matched Case-Control Study. AB - BACKGROUND: Neoadjuvant chemoradiation therapy (nCRT) has been indicated for locally advanced rectal cancer. While utilization of laparoscopy in rectal cancer surgery has been popular in recent years, tumors receiving nCRT is still a surgical challenge. Transanal total mesorectal excision (TaTME) has emerged as a focused area of laparoscopic surgery that is becoming an increasingly acceptable approach in the field of rectal surgery. METHODS: Between December 2013 and April 2015, a total of 50 patients (38 males) with post-nCRT middle or lower rectal cancer who then underwent TaTME at two separate institutions were prospectively documented. Overall, 100 matched control cohorts who received conventional laparoscopic rectal surgery (LapTME) were simultaneously retrieved from a prospectively registered database. Four parameters of sex, age, clinical stage, and American Society of Anesthesiologists (ASA) score were matched for surgical outcomes, and short-term oncological results, including complications and pathological outcomes, were analyzed. RESULTS: Both the TaTME and LapTME groups received 5-fluorouracil-based chemotherapy and 5 weeks of long-course radiation therapy. Mean operative time for the TaTME group was 182.1 +/- 55.4 min (156.6 +/ 37.8 min in two-team-approach cases) and 178.7 +/- 34.8 min for the LapTME group. The TaTME group yielded longer distal margin lengths. No significant differences were observed in blood loss, intraoperative complication rate, conversion rate, anastomosis type, and free circumferential margin rate. CONCLUSION: This matched case-control study demonstrated that TaTME is safe and feasible. Compared with LapTME, TaTME not only achieves identical circumferential margin status without compromising other operative and quality parameters but also benefits patients by achieving a longer distal margin. Thus, TaTME has the potential to become an option in managing irradiated rectal cancer. PMID- 26597370 TI - High temperature transformations of waste printed circuit boards from computer monitor and CPU: Characterisation of residues and kinetic studies. AB - This paper investigates the high temperature transformation, specifically the kinetic behaviour of the waste printed circuit board (WPCB) derived from computer monitor (single-sided/SSWPCB) and computer processing boards - CPU (multi layered/MLWPCB) using Thermo-Gravimetric Analyser (TGA) and Vertical Thermo Gravimetric Analyser (VTGA) techniques under nitrogen atmosphere. Furthermore, the resulting WPCB residues were subjected to characterisation using X-ray Fluorescence spectrometry (XRF), Carbon Analyser, X-ray Photoelectron Spectrometer (XPS) and Scanning Electron Microscopy (SEM). In order to analyse the material degradation of WPCB, TGA from 40 degrees C to 700 degrees C at the rates of 10 degrees C, 20 degrees C and 30 degrees C and VTGA at 700 degrees C, 900 degrees C and 1100 degrees C were performed respectively. The data obtained was analysed on the basis of first order reaction kinetics. Through experiments it is observed that there exists a substantial difference between SSWPCB and MLWPCB in their decomposition levels, kinetic behaviour and structural properties. The calculated activation energy (EA) of SSWPCB is found to be lower than that of MLWPCB. Elemental analysis of SSWPCB determines to have high carbon content in contrast to MLWPCB and differences in materials properties have significant influence on kinetics, which is ceramic rich, proving to have differences in the physicochemical properties. These high temperature transformation studies and associated analytical investigations provide fundamental understanding of different WPCB and its major variations. PMID- 26597371 TI - Phytoextraction of chloride from a cement kiln dust (CKD) contaminated landfill with Phragmites australis. AB - Cement kiln dust (CKD) is a globally produced by-product from cement manufacturing that is stockpiled or landfilled. Elevated concentrations of chloride pose toxic threats to plants and aquatic communities, as the anion is highly mobile in water and can leach into surrounding water sources. Re vegetation and in situ phytoextraction of chloride from a CKD landfill in Bath, ON, Canada, was investigated with the resident invasive species Phragmites australis (haplotype M). Existing stands of P. australis were transplanted from the perimeter of the site into the highest areas of contamination (5.9*10(3)MUg/g). Accumulation in the shoots of P. australis was quantified over one growing season by collecting samples from the site on a bi-weekly basis and analyzing for chloride. Concentrations decreased significantly from early May (24+/-2.2*10(3)MUg/g) until mid-June (15+/-2.5*10(3)MUg/g), and then remained stable from June to August. Shoot chloride accumulation was not significantly affected by water level fluctuations at the site, however elevated potassium concentrations in the soil may have contributed to uptake. Based on shoot chloride accumulation and total biomass, it was determined that phytoextraction from the CKD landfill can remove 65+/-4kg/km(2) of chloride per season. Based on this extraction rate, removal of chloride present in the highly contaminated top 10cm of soil can be achieved in 3-9years. This is the first study to apply phytotechnologies at a CKD landfill, and to successfully demonstrate in situ phytoextraction of chloride. PMID- 26597372 TI - Greener approach for the extraction of copper metal from electronic waste. AB - Technology innovations resulted into a major move from agricultural to industrial economy in last few decades. Consequently, generation of waste electronic and electrical equipments (WEEE) has been increased at a significant rate. WEEE contain large amount of precious and heavy metals and therefore, can be considered a potential secondary resource to overcome the scarcity of metals. Also, presence of these metals may affect the ecosystem due to lack of adequate management of WEEE. Building upon our previous experimental investigations for metal extraction from spent catalyst, present study explores the concept of green technology for WEEE management. Efforts have been made to recover base metal from a printed circuit board using eco-friendly chelation technology and results were compared with the conventional acid leaching method. 83.8% recovery of copper metal was achieved using chelation technology whereas only 27% could be recovered using acid leaching method in absence of any oxidant at optimum reaction conditions. Various characterization studies (energy dispersive X-ray analysis, scanning electron microscopy, X-ray diffraction, inductive coupled plasma spectrophotometry) of Printed Circuit Board (PCB) and residues were performed for qualitative and quantitative analysis of samples. Significant metal extraction, more than 96% recovery of chelating agent, recycling of reactant in next chelation cycle and nearly zero discharge to the environment are the major advantages of the proposed green process which articulate the transcendency of chelation technology over other conventional approaches. Kinetic investigation suggests diffusion controlled process as the rate determining step for the chelate assisted recovery of copper from WEEE with activation energy of 22kJ/mol. PMID- 26597373 TI - Consumer preferences for reduced packaging under economic instruments and recycling policy. AB - This study was conducted using a web-based survey and bidding game in contingent valuation method to evaluate consumer preferences for packaging with less material. Results revealed that people who live in a municipality implementing unit-based pricing of waste have a higher willingness-to-pay (WTP) for a product. Economic instruments can affect the purchase of products with reduced packaging because a higher disposal cost increases the attractiveness of source reduction. However, unit-based pricing combined with plastic separation for recycling reduces WTP. This result suggests that recycling policy weakens the effect of economic instruments on source reduction of waste. PMID- 26597374 TI - Characterisation of recycled mixed plastic solid wastes: Coupon and full-scale investigation. AB - In Australia, the plastic solid waste (PSW) comprises 16% by weight of municipal solid waste but only about one-fourth are recycled. One of the best options to increase the recycling rate of mixed PSW is to convert them into products suitable for construction. However, a comprehensive understanding on the mechanical behaviour of mixed PSW under different loading conditions is important for their widespread use as a construction material. This study focuses on investigating the mechanical behaviour of recycled mixed PSW containing HDPE, LDPE and PP using coupon and full-scale specimens. From coupon test, the strength values were found to be 14.8, 19.8, 20, 5.6MPa in tension, compression, flexure and shear respectively, while the modulus of elasticity are 0.91, 1.03, 0.72GPa in tension, compression and flexure respectively. The coefficient of variance of the measured properties for coupon and fullscale specimens was less than 10% indicating that consistent material properties can be obtained for mixed PSW. More importantly, the strength properties of mixed PSW are comparable to softwood structural timber. The flexural behaviour of full-scale specimens was also predicted using fibre model analysis and finite element modelling. Comparison showed that using coupon specimen's properties, the flexural behaviour of the full-scale specimens can be predicted reliably which can eliminate the costly and time consuming arrangements for full-scale experimental tests. PMID- 26597375 TI - Essential oil of Algerian Eucalyptus citriodora: Chemical composition, antifungal activity. AB - OBJECTIVE: Essential oil of Eucalyptus citriodora is a natural product which has been attributed for various medicinal uses. In the present investigation, E. citriodora essential oil was used to evaluate its antifungal effect against medically important dermatophytes. MATERIAL AND METHODS: Essential oil from the Algerian E. citriodora leaves was analyzed by GC and GC/MS. The antifungal effect of E. citriodora essential oil was evaluated against four dermatophytes: Microsporum canis, Microsporum gypseum, Trichophyton mentagrophytes, Trichophyton rubrum using disc diffusion method, disc volatilization method, and agar dilution method. RESULTS: The chemical composition of the oil revealed the presence of 22 compounds accounting for 95.27% of the oil. The dominant compounds were citronellal (69.77%), citronellol (10.63%) and isopulegol (4.66%). The disc diffusion method, MIC and MFC determination, indicated that E. citriodora essential oil had a higher antifungal potential against the tested strains with inhibition zone diameter which varied from (12 to 90mm) and MIC and MFC values ranged from (0.6 to 5MUL/mL and 1.25 to 5MUL/mL) respectively. The M. gypseum was the most resistant to the oil. CONCLUSION: The results of the present study indicated that E. citriodora essential oil may be used as a new antifungal agent recommended by the pharmaceutical industries. PMID- 26597376 TI - Atorvastatin attenuates cognitive deficits through Akt1/caspase-3 signaling pathway in ischemic stroke. AB - Neuronal damage in the hippocampal formation is more sensitive to ischemic stimulation and easily injured, causing severe learning and memory impairment. Therefore, protection of hippocampal neuronal damage is the main contributor for learning and memory impairment during cerebral ischemia. Atorvastatin has been reported to ameliorate ischemic brain damage after ischemia reperfusion (I/R). However, its molecular mechanism has not been elucidated clearly. In this study, we established four-vessel occlusion model in rats with cerebral ischemia. Here, we demonstrated that atorvastatin significantly improves the behavior of I/R-rat in open field tasks. We also found that atorvastatin significantly shortens the distance and time of loading onto the hidden platform in the positioning navigation process, decreases the latency in the space exploration process when cognitive testing with Morris water maze was performed during ischemic stroke in rats. Furthermore, the survival rate of neurons in the CA1 area of the hippocampus and the phosphorylation of Akt (Ser473) in the neurons are increased, whereas the expression of caspase-3 are inhibited by atorvastatin. However, after an intracerebroventricular injection of LY294002 (an inhibitor of Akt1), the above neuroprotective effects of atorvastatin are attenuated. In summary, our results imply atorvastatin may improve the survival rate of hippocampal neurons and reduce the impairment of learning and memory by downregulating the activation of the caspase-3 via increasing the phosphorylation of Akt1 during ischemia/reperfusion. PMID- 26597377 TI - Case-control study of vitamin D receptor gene polymorphism in Pakistani rheumatoid arthritis patients. PMID- 26597378 TI - A Prognostic Instrument to Estimate the Survival of Elderly Patients Irradiated for Metastatic Epidural Spinal Cord Compression From Lung Cancer. AB - BACKGROUND: Elderly patients with lung cancer need personalized treatment in palliative situations such as metastatic epidural spinal cord compression (MESCC). It is crucial to know a patient's survival prognosis to be able to provide optimal and individualized care. Therefore, a prognostic instrument enabling physicians to estimate a patient's survival time is required. We created such an instrument in the present study. PATIENTS AND METHODS: The data from 201 elderly patients with lung cancer irradiated for MESCC were retrospectively evaluated. The radiation regimen used plus 10 factors were analyzed for associations with survival, including age, gender, histologic features, performance status, interval from lung cancer diagnosis until irradiation of MESCC, interval to developing motor weakness before irradiation, number of affected vertebrae, visceral metastases, other bone metastases, and the ability to walk before irradiation. The factors significant on multivariate analysis were included in the predictive instrument. The factor scores were obtained by dividing the 6-month survival rate by 10, and the patient scores were determined from the sum of the factor scores. RESULTS: Performance status (P = .003), interval to developing motor weakness (P = .006), visceral metastases (P < .001), and the ability to walk (P = .002) were associated with survival. Taking into account the 6-month survival rates of these factors, the patient scores ranged from 5 to 19 points. Thus, 4 groups were designated: those with 5 to 10 points (n = 95), 11 to 13 points (n = 46), 14 to 16 points (n = 33), and 18 to 19 points (n = 27). The corresponding 6-month survival rates were 4%, 26%, 58%, and 81% (P < .001). The corresponding median survival times were 2, 4, 7, and 10 months. CONCLUSION: This new instrument will enable physicians to predict the survival prognosis of elderly patients with lung cancer-related MESCC, facilitating individualized treatment care. PMID- 26597379 TI - Cervical cancer stem cells. AB - The concept of cancer stem cells (CSC) has been established over the past decade or so, and their role in carcinogenic processes has been confirmed. In this review, we focus on cervical CSCs, including (1) their purported origin, (2) markers used for cervical CSC identification, (3) alterations to signalling pathways in cervical cancer and (4) the cancer stem cell niche. Although cervical CSCs have not yet been definitively identified and characterized, future studies pursuing them as therapeutic targets may provide novel insights for treatment of cervical cancer. PMID- 26597380 TI - microRNA-762 promotes breast cancer cell proliferation and invasion by targeting IRF7 expression. AB - OBJECTIVES: miRNAs play crucial roles in human tumourigenesis. This study was performed to measure expression and function of miR-762 in breast cancer. MATERIALS AND METHODS: Expression of miR-762 in breast tissues and cell lines (SK BR-3, DA-MB-435s, MCF-7 and MDA-MB-231, HBL-100) was measured by using real-time RT-PCR. We restored expression of miR-762 in MCF-7 cells to measure its functional roles. Luciferase assays were performed to reveal the target gene of miR-762. RESULTS: Expression of miR-762 was high in both breast cancer cell lines and specimens, and its overexpression increased breast cancer cell proliferation and invasion. Interferon regulatory factor 7 (IRF7) is a direct target of miR-762 and overexpression of miR-762 reduced expression of IRF7. Moreover, IRF7 was repressed, its levels inversely correlated to miR-762 expression. IRF7 rescued miR-762-induced cell invasion and proliferation. CONCLUSIONS: These results demonstrate that miR-762 tumour effect was achieved by targeting IRF7 in human breast cancer specimens. PMID- 26597381 TI - Tumour cell population growth inhibition and cell death induction of functionalized 6-aminoquinolone derivatives. AB - OBJECTIVES: A number of previous studies has provided evidence that the well known anti-bacterial quinolones may have potential as anti-cancer drugs. The aim of this study was to evaluate potential anti-tumour activity and selectivity of a set of 6-aminoquinolones showing some chemical similarity to naphthyridone derivative CX-5461, recently described as innovative anti-cancer agent. MATERIALS AND METHODS: In-house quinolones 1-8 and ad hoc synthesized derivatives 9-13 were tested on Michigan Cancer Foundation-7 (MCF-7) breast cancer cells and mesenchymal progenitor (MePR2B) cell lines, analysing their effects on the cell cycle and cell death using FACS methodology. Activation of p53 was evaluated by western blotting. RESULTS: Benzyl esters 4, 5 and their amide counterparts 12, 13 drastically modulated MCF-7 cell cycles inducing DNA fragmentation and cell death, thus proving to be potential anti-tumour compounds. When assayed in non tumour MePR2B cells, compounds 4 and 5 were cytotoxic while 12 and 13 had a certain degree of selectivity, with compound 12 emerging as the most promising. Western blot analysis revealed that severe p53-K382ac activation was promoted by benzylester 5. In contrast, amide 12 exerted only a moderate effect which was, however, comparable to that of suberoylanilide hydoxamic acid (SAHA). CONCLUSIONS: Taken together, these results further reinforce evidence that quinolones have potential as anti-cancer agents. Future work will be focused on understanding compound 12 mechanisms of action, and to obtain more potent and selective compounds. PMID- 26597382 TI - "Like a dialogue": Teach-back in the emergency department. AB - OBJECTIVE: Teach-back may improve communication, but has not been well studied in the emergency setting. The goal of this study was to characterize perceptions of teach-back in the emergency department (ED) by health literacy. METHODS: We conducted an in-depth interview study on the ED discharge process examining teach back techniques in two tertiary care centers (adult and pediatric), using asthma as a model system for health communication. Participants were screened for health literacy, and purposive sampling was used to balance the sample between literacy groups. Interviews were conducted until thematic saturation was reached for each literacy group at each site; audiotaped, transcribed, coded, and analyzed using a modified grounded theory approach. RESULTS: Fifty-one interviews were completed (31 parents; 20 patients). Across all groups, participants felt that teach-back would help them confirm learning, avoid forgetting key information, and improve doctor-patient communication. Participants with limited health literacy raised concerns about teach-back being condescending, but suggested techniques for introducing the technique to avoid this perception. CONCLUSION: Most participants were supportive of teach-back techniques, but many were concerned about perceived judgment from providers. PRACTICE IMPLICATIONS: Future investigations should focus on feasibility and efficacy of teach-back in the ED and using participant generated wording to introduce teach-back. PMID- 26597383 TI - "It is just another test they want to do": Patient and caregiver understanding of the colonoscopy procedure. AB - OBJECTIVE: Colonoscopy is a complex procedure that requires bowel preparation, sedation, and has the potential for substantial risk. Given this, we investigated colonoscopy patients' perceived and actual understanding of the procedure. METHODS: Consecutive colonoscopy patients were enrolled and surveyed, with their caregivers, immediately prior to their procedure. Demographics, health literacy, socioeconomic status and perceived risks/benefits were assessed. Thematic analysis was conducted on open-ended responses and a 3-level outcome variable was created to categorize correctness of patients' and caregivers' understanding. Multinomial logistic regression was used to determine predictors of response level. RESULTS: Patients (N=1821) were 77% White, 60% female, and averaged 54 years old; caregivers were demographically similar. Among patients, bivariate analysis revealed that younger age, minority race, and low income, education, and health literacy were associated with incomplete understanding. Multinomial regression revealed that age, education, health literacy, first-time colonoscopy, and perceived risk-benefit difference discriminated among groups. Bivariate and multinomial results for caregivers were similar. CONCLUSION: Patients and caregivers varied on information, understanding and misconceptions about colonoscopy. Implications are discussed for inadequate: 1. informed consent, 2. bowel preparation, and 3. emotional preparation for cancer detection or adverse events. PRACTICE IMPLICATIONS: Attention should be paid to patients' understanding of the purpose, anatomy, and logistics of colonoscopy, preferably prior to bowel preparation. PMID- 26597384 TI - E-consulting in a medical specialist setting: Medicine of the future? AB - OBJECTIVE: Today's technology provides new ways of consulting between patients and medical specialists in health care, such as videoconferencing and web messaging. In this systematic review we assessed the effects of e-consulting between medical specialists and patients. METHODS: We searched MEDLINE, EMBASE, Psychlit and Cochrane Library for randomized clinical trials assessing the use of e-consulting methods (videoconferencing (VC) or web-messaging (WM)), as compared to conventional care (face-to-face (FF) or telephone consultations (TC)) in a medical specialist setting. We extracted patient-related, physician-related, cost, time and follow-up outcomes. RESULTS: We included 21 trials, of which 17 addressed VC compared to FF, two compared WM with FF, one VC with TC, and one WM with TC. Physicians appeared to prefer face-to-face consultations over videoconferencing. Patients appeared to be as satisfied with videoconferencing as with face-to-face contacts, but preferred videoconferencing and web-messaging over telephone consultations. Videoconferencing was more expensive regarding equipment, but saved patient-related costs in terms of time, transportation, and missed work. Variable results were found for consult time and follow-up visits. CONCLUSIONS AND PRACTICE IMPLICATIONS: We cautiously conclude that e-consulting seems a feasible alternative to medical specialists' face-to-face follow-up or telephone appointments, but may be less suitable for initial consultations requiring physical examination. PMID- 26597385 TI - Born small, die young: Intrinsic, size-selective mortality in marine larval fish. AB - Mortality during the early stages is a major cause of the natural variations in the size and recruitment strength of marine fish populations. In this study, the relation between the size-at-hatch and early survival was assessed using laboratory experiments and on field-caught larvae of the European sardine (Sardina pilchardus). Larval size-at-hatch was not related to the egg size but was significantly, positively related to the diameter of the otolith-at-hatch. Otolith diameter-at-hatch was also significantly correlated with survival-at-age in fed and unfed larvae in the laboratory. For sardine larvae collected in the Bay of Biscay during the spring of 2008, otolith radius-at-hatch was also significantly related to viability. Larval mortality has frequently been related to adverse environmental conditions and intrinsic factors affecting feeding ability and vulnerability to predators. Our study offers evidence indicating that a significant portion of fish mortality occurs during the endogenous (yolk) and mixed (yolk /prey) feeding period in the absence of predators, revealing that marine fish with high fecundity, such as small pelagics, can spawn a relatively large amount of eggs resulting in small larvae with no chances to survive. Our findings help to better understand the mass mortalities occurring at early stages of marine fish. PMID- 26597386 TI - HeartWare left ventricular assist device for the treatment of advanced heart failure. AB - The importance of mechanical circulatory support in the therapy of advanced heart failure is steadily growing. The rapid developments in the field of mechanical support are characterized by continuous miniaturization and enhanced performance of the assist devices, providing increased pump durability and prolonged patient survival. The HeartWare left ventricular assist device system (HeartWare Inc., Framingham, MA, USA) is a mechanical ventricular assist device with over 8000 implantations worldwide. Compared with other available assist devices it is smaller in size and used in a broad range of patients. The possibility of minimally invasive procedures is one of the major benefits of the device - allowing implants and explants, as well as exchanges of the device with reduced surgical impact. We present here a review of the existing literature on the treatment of advanced heart failure using the HeartWare left ventricular assist device system. PMID- 26597387 TI - Does Age Have an Effect on Systemic Inflammatory Response? PMID- 26597388 TI - Factors Affecting Platelet Reactivity 2 Hours After P2Y12 Receptor Antagonist Loading in Primary Percutaneous Coronary Intervention for ST-Elevation Myocardial Infarction - Impact of Pain-to-Loading Time. AB - BACKGROUND: Delay in the onset of antiplatelet action occurs in patients with ST elevation myocardial infarction (STEMI) and is likely due to disturbed absorption. We hypothesized that patients presenting relatively late after the onset of symptoms would have faster antiplatelet action. METHODS AND RESULTS: We analyzed patient-level data from 5 studies of 207 P2Y12 receptor antagonist-naive patients with STEMI undergoing primary percutaneous coronary intervention (PCI). All patients had available platelet reactivity (PR) assessment with the VerifyNow assay (in P2Y12 reaction units; PRU) prior to and 2 h after loading. High PR (HPR) was defined as >= 208 PRU. Pain-to-antiplatelet loading time independently predicted PR at 2 h after loading: every 1-h increase in pain-to-antiplatelet loading time produced a 7% decrease in PR (P=0.001). Pretreatment PR, body mass index, morphine and novel P2Y12 receptor antagonist also affected PR 2 h after loading. Novel P2Y12 receptor antagonist use and per hour increase in pain-to antiplatelet loading time were independently associated with lower probability for HPR with an OR (95% CI) of 0.145 (0.095-0.220) and 0.776 (0.689-0.873), P<0.001 for both (C-statistic, 0.752; 95% CI: 0.685-0.819). CONCLUSIONS: In STEMI patients undergoing primary PCI, pain-to-antiplatelet loading interval is a newly described factor affecting PR shortly after P2Y12 receptor antagonist loading, according to patient-level data pooled analysis. PMID- 26597389 TI - Does Age Have an Effect on Systemic Inflammatory Response? - Reply. PMID- 26597390 TI - Do the Components of CHA2DS2-VAsc Score Affect Stroke Severity and Outcome? PMID- 26597391 TI - Transplantation of amniotic fluid-derived neural stem cells as a potential novel therapy for Hirschsprung's disease. AB - BACKGROUND/PURPOSE: We have previously shown that embryonic enteric neural stem cells (NSCs) isolated from the intestine colonize aganglionic intestine upon transplantation, but posttransplantation cell survival limits efficacy. The aims of this study were to investigate whether transplantation of amniotic fluid (AF) derived NSCs could improve survival of the engrafted cells and promote functional recovery of the diseased colon. METHODS: AF cells were induced into NSCs with neurogenic medium, and further differentiated into neurons and glial cells. Ednrb knockout mice received an intestinal intramuscular injection of 20,000 AF-derived NSCs into the aganglionic colon. Engrafted cells were visualized and characterized by immunohistochemistry for GFP, neuronal, and glial cell markers. Colonic motility was quantified by colonic bead expulsion time. RESULTS: AF derived NSCs had increased expression levels of the NSC marker Nestin and the glial cell marker GFAP compared to enteric NSCs. Transplanted AF-derived NSCs had decreased apoptosis and increased survival compared to enteric NSCs. Colonic motility was significantly improved in Ednrb knockout mice transplanted with AF derived NSCs, as demonstrated by significantly decreased colonic bead expulsion time. CONCLUSION: AF-derived NSCs have enhanced survival upon transplantation into a defective enteric nervous system. Transplantation of AF-derived NSCs may represent a potential novel future therapy for the treatment of Hirschsprung's disease. PMID- 26597392 TI - Pediatric emergency department thoracotomy: A 40-year review. AB - BACKGROUND/PURPOSE: Emergency department thoracotomy (EDT) has been proposed to be futile in the pediatric patient population. This extreme procedure has survival rates of 0 to 26% in the nonadult population. When taking into consideration that the mechanism of injury is one of the strongest predictors of survival, we hypothesize that the low survival rate in pediatric patients is attributable to a higher rate of blunt trauma compared to their adolescent counterparts. METHODS: Prospective data collected from our level 1 trauma center from 1974 to 2014 on all patients undergoing EDT at our institution were evaluated for age 18years or younger. Patient predictor variables included injury mechanism, injury pattern, and detected cardiac activity in the field. Outcomes included successful resuscitation (reestablish of blood pressure and taken to operating room) and overall survival. Patients were dichotomized by age into pediatric (age<=15years) and adolescent (16-18years) categories. RESULTS: 1691 patients who underwent EDT were evaluated for age of 18years or less, which included 179 patents (11%). Overall survival in the adult population was 6.1%, compared to 3.4% in the nonadult population (p=0.157). Pediatric patients were more likely to sustain blunt injury than adolescents (72% vs 32%, p<0.001). This also corresponded to differences in anatomic injury patterns and more multisystem trauma (52% vs 44%, p=0.001). Adolescents had significantly higher survival rates than pediatric patients (5% vs 0%, p=0.036). CONCLUSION: In nonadult patients undergoing EDT, adolescents have a higher survival rate than pediatric patients. The pediatric population had a significantly lower incidence of penetrating trauma and higher incidence of head injury. The discrepancy in survival between adolescent and pediatric patients appears to be attributable to differences in mechanism. Therefore, those pediatric patients with penetrating thoracic injuries may still benefit from EDT. PMID- 26597393 TI - Factors associated with neonatal ostomy complications. AB - BACKGROUND: Neonatal ostomies, either temporary or permanent, are created for numerous reasons. Limited attention has been given to understanding what factors might place infants at risk for surgical wound complications. PURPOSE: The purpose of the study is to identify factors associated with risk of significant abdominal wound complications (wound dehiscence and wound infection) following neonatal ostomy creation. METHODS: This is a retrospective chart review of infants undergoing ostomy between January 2009 and December 2013 at the University of Alberta Hospital. MAIN FINDINGS: 66 infants were identified of which 18.2% (12/66) had wound complications. Variables associated with wound dehiscence included: findings of bowel necrosis during laparotomy (7/9 wound dehiscence, 18/57 none, p=0.008), perioperative sepsis (3/9 wound dehiscence, 3/57 none, p=0.006), and perioperative blood transfusion (9/9 wound dehiscence, 30/57 none, p=0.007). Wound infection was not predicted by any variables collected. CONCLUSIONS: Neonates undergoing creation of an ostomy appear to be at substantial risk for wound complications. As wound complications are significant issues for infants undergoing surgery, emerging strategies should be explored to either avoid ostomy creation or promote wound healing. PMID- 26597394 TI - Efficacy of neuromuscular electrical stimulation in patients with COPD followed in intensive care unit. AB - INTRODUCTION: Serious problems on muscle strength and functional status can be seen in bedridden-patients with chronic obstructive pulmonary diseases (COPD) receiving mechanical ventilation. We aimed to investigate the impact of active extremity mobilization and neuromuscular electrical stimulation (NMES) on weaning processes, discharge from hospital and inflammatory mediators in COPD patients receiving mechanical ventilation. METHODS: Thirty conscious COPD patients (F/M:15/15) hospitalized in the intensive care unit (ICU) with diagnosis of respiratory failure were enrolled to this study. Patients were randomized into three groups, including 10 patients for each. Active extremity-exercise training and NMES were applied to Group-1, only NMES was applied to Group-2 and active extremity exercise training was applied to Group-3. Muscle strengths, mobilization duration and weaning situation were evaluated. Serum cytokine levels were evaluated. RESULTS: Lower extremity muscle-strength was significantly improved in Group-1 (from 3.00 to 5.00, P = 0.014) and 2 (from 4.00 to 5.00, P = 0.046). Upper extremity muscle strength was also significantly improved in all three groups (from 4.00 to 5.00 for all groups, P = 0.038, P = 0.046 and P = 0.034, respectively). Duration of mobilization and discharge from the ICU were similar among groups. There was a significant decrease in serum interleukin (IL) 6 level in Group-1 and in serum IL-8 level in Group-1 and Group-2 after rehabilitation. CONCLUSION: This study indicates that pulmonary rehabilitation can prevent loss of muscle strength in ICU. Nevertheless, we consider that further studies with larger populations are needed to examine the impact of NMES and/or active and passive muscle training in bedridden ICU patients who are mechanically ventilated. PMID- 26597395 TI - Injection-Site Nodules Associated With the Use of Exenatide Extended-Release Reported to the U.S. Food and Drug Administration Adverse Event Reporting System. PMID- 26597396 TI - Israeli survey of anesthesia practice related to placenta previa and accreta. AB - BACKGROUND: Anesthesia practices for placenta previa (PP) and accreta (PA) impact hemorrhage management and other supportive strategies. We conducted a survey to assess reported management of PP and PA in all Israeli labor and delivery units. METHODS: After Institutional Review Board waiver, we surveyed all 26 Israeli hospitals with a labor and delivery unit by directly contacting the representatives of obstetric anesthesiology services in every department (unit director or department chair). Each director surveyed provided information about the anesthetic and transfusion management in their labor and delivery units for three types of abnormal placentation based on antenatal placental imaging: PP, low suspicion for PA, and high suspicion for PA. The primary outcome was use of neuraxial or general anesthesia for PP and PA Cesarean delivery. Univariate statistics were used for survey responses using counts and percentages. RESULTS: The response rate was 100%. Spinal anesthesia is the preferred anesthetic mode for PP cases, used in 17/26 (65.4%) of labor and delivery units. By comparison, most representatives reported that they perform general anesthesia for patients with PA: 18/26 (69.2%) for all low suspicion cases of PA and 25/26 (96.2%) for all high suspicion cases of PA. Although a massive transfusion protocol was available in the majority of hospitals (84.6%), the availability of thromboelastography and cell salvage was much lower (53.8% and 19.2% hospitals respectively). CONCLUSIONS: In our survey, representatives of anesthesia labor and delivery services in Israel are almost exclusively using general anesthesia for women with high suspicion for PA; however, almost two-thirds use spinal anesthesia for PP without suspicion of PA. Among representatives, we found wide variations in anesthesia practice patterns with regard to anesthesia mode, multidisciplinary management, and hemorrhage anticipation strategies. PMID- 26597397 TI - KAHA Ligation at Serine. AB - Oxazetidine assisted KAHA ligation was developed by the Bode group as an efficient peptide segment ligation strategy at native serine residues. This milestone achievement should enable the chemical synthesis of difficult-to prepare proteins for biological studies. PMID- 26597398 TI - Hypopharyngeal squamous cell carcinoma: Three-dimensional or Intensity-modulated radiotherapy? A single institution's experience. AB - OBJECTIVES/HYPOTHESIS: Compare outcomes of hypopharyngeal carcinoma that received conventional radiotherapy versus intensity-modulated radiotherapy (IMRT). STUDY DESIGN: Retrospective single-institution trial. METHODS: Between April 1990 and May 2011, 100 patients with hypopharyngeal cancer underwent curative radiotherapy (RT) at our institution: 50 with IMRT and 50 with conventional RT. The median age was 63 years. There were 12 T1, 22 T2, 37 T3, and 28 T4 patients. The majority of patients (82%) had nodal disease: 54% N2 and 8% N3. The majority of patients (83%) received chemotherapy. Of the patients who received chemotherapy, 84% received a platinum-based regimen. The median RT dose was 7,000 cGy. The majority of patients (62%) had prophylactic percutaneous endoscopic gastrostomy tube placement. Toxicities were reviewed. Local control (LC), locoregional control (LRC), freedom from distant metastasis (FFM) rates, functional larynx preservation (LP), laryngectomy-free survival (LFS), and overall-survival (OS) curves were generated using the Kaplan-Meier method. The log-rank test was used to test prognostic variables. RESULTS: With a median follow up of 48.4 months, the 3/5-year LC, LRC, FFM, LP, LFS and OS rates were 74%/69%, 77%/74%, 70%/66%, 51%/29%, 49.6%/31.8%, and 49%/34%, respectively. The median OS was 2.9 years. The 3-year LC rate for IMRT was 77% versus 81% for conventional RT (P = .91); 3-year LRC for IMRT was 85% versus 76% for conventional RT (P = .32). There was no increased local failure with IMRT. There was no difference in the rate of stricture with IMRT (32%) versus conventional RT (25.3%) (P = .86). CONCLUSIONS: IMRT achieved comparable LC and LRC rates to conventional RT. LEVEL OF EVIDENCE: 4 Laryngoscope, 126:620-626, 2016. PMID- 26597400 TI - CYP2D6 Metabolism in Frail Elderly Compared to Non-Frail Elderly: A Pilot Feasibility Study. AB - BACKGROUND: Frailty is a clinical phenotype that is associated with adverse health outcomes. Since frail patients may be more prone for adverse drug events and about 15-20 % of commonly prescribed drugs are metabolized by CYP2D6, we hypothesized that CYP2D6 metabolism is decreased in frail patients compared with healthy subjects. METHODS: The (13)C-dextromethorphan breath test (DM-BT) was used to determine CYP2D6 phenotype using (13)C-dextromethorphan ((13)C-DM) as a probe. Eleven frail and 22 non-frail (according to the Fried criteria) subjects aged 70-85 years were phenotyped for CYP2D6. RESULTS: Despite inequalities in CYP2D6 genotype between frail and non-frail subjects, the CYP2D6 gene activity score was equally distributed between the two groups (1.33 +/- 0.50 vs. 1.28 +/- 0.752). In male patients, no difference in total and free serum testosterone levels was observed between frail and non-frail men. Serum dehydroepiandrostenedione sulfate (DHEAS) levels were lower in frail subjects (1.56 MUmol/L) compared with non-frail subjects (2.36 MUmol/L), but the difference was not significant (p = 0.15). Body mass index was significantly correlated to CYP2D6 phenotype, whereas frailty score and individual parameters of frailty, Karnofsky score, and activities of daily living score were not significantly correlated to CYP2D6 phenotype. Although there was no difference in CYP2D6 phenotype observed between frail mean +/- standard deviation (mean +/- SD) area under the curve for delta over baseline values (0-2 h) (AUCDOB2h) 319 +/- 169 0/00 min] and non-frail subjects (mean +/- SD AUCDOB2h 298 +/- 159 0/00 min), the present sample size is considered too small to draw any firm conclusions regarding a potential phenoconversion of CYP2D6 in frail elderly as compared with healthy subjects. CONCLUSION: Frail and non-frail subjects did not differ in CYP2D6 phenotype, taking into account that the precalculated sample size was not achieved. Further studies with more patients are needed in order to adequately understand a possible correlation. PMID- 26597401 TI - Prevention of Adverse Drug Reactions in Hospitalised Older Patients Using a Software-Supported Structured Pharmacist Intervention: A Cluster Randomised Controlled Trial. AB - BACKGROUND: Proven interventions to reduce adverse drug reactions (ADRs) in older hospitalised patients are lacking. Previous randomised controlled trial (RCT) data indicate that a structured pharmacist review of medication (SPRM) can reduce inappropriate prescribing in older hospitalised patients. However, no RCT data show that an SPRM reduces ADRs in this population. METHODS: We performed a cluster RCT comparing a clinical decision support software (CDSS)-supported SPRM intervention with standard pharmaceutical care in older patients hospitalised with an acute unselected illness. Over 13 months, we screened 1833 patients aged >=65 years admitted to specialist services other than geriatric medicine for study inclusion. We randomised 361 patients to the trial intervention arm and 376 patients to the control arm, applying the intervention at a single timepoint within 48 h of admission. The primary endpoint (ADR incidence) was assessed at 7 10 days post-admission or at discharge (whichever came first). The secondary endpoints were the median hospital length of stay (LOS) and hospital mortality rate. RESULTS: Attending clinicians in the intervention group implemented 54.8% of SPRM/CDSS prescribing recommendations. Ninety-one ADRs occurred in 78 control patients (20.7%) compared with 61 ADRs in 50 intervention patients (13.9%), i.e., an absolute risk reduction of 6.8%. The number needed to treat (NNT) to prevent one patient having one ADR was 15; the total NNT to prevent one ADR was 14. The median LOS and hospital mortality were not significantly different. CONCLUSION: An SPRM delivered on a CDSS platform significantly reduces ADR incidence in acutely hospitalised older people. PMID- 26597402 TI - Influence of reverse Trendelenburg position on aortocaval compression in obese pregnant women. AB - INTRODUCTION: Obese pregnant women are at risk of aortocaval compression and associated hypotension with neuraxial anaesthesia. We hypothesised that addition of reverse Trendelenburg tilt to the standard practice of pelvic tilt may attenuate aortocaval compression. METHODS: After ethical approval and consent, six women with a singleton pregnancy and booking body mass index of 30-35kg/m(2) underwent magnetic resonance imaging scanning in six different positions: right lateral decubitus; left lateral decubitus; supine with pelvic tilt; and reverse Trendelenburg positions of 5 degrees , 10 degrees and 15 degrees . Dimensions of the inferior vena cava and abdominal aorta at the L2-3 intervertebral disc level were obtained from axial images using medical imaging software OsiriXTM. RESULTS: Inferior vena cava dimensions were higher in left lateral decubitus position compared to supine with pelvic tilt (P=0.002). Inferior vena cava compression was noted in all participants (59+/-33%, 95% CI 32 to 86). Addition of 15 degrees reverse Trendelenburg tilt to standard pelvic tilt produced a non-statistically significant increase in inferior vena cava area (10.54+/-9.91cm(2), 95% CI 2.61 to 18.47, P=0.06). CONCLUSION: A non-statistically significant improvement of aortocaval compression was noted with the addition of 15 degrees reverse Trendelenburg tilt to the supine with pelvic tilt position in obese pregnant women. PMID- 26597403 TI - Preferences of Jehovah's Witnesses regarding haematological supports in an obstetric setting: experience of a single university teaching hospital. AB - BACKGROUND: Jehovah's Witnesses have been shown to be at increased risk of mortality and morbidity as a consequence of obstetric haemorrhage and refusal of blood products. Since 2004, however, Jehovah's Witnesses have been allowed to accept minor fractions of blood at their own discretion. We sought to determine the preferences of pregnant Jehovah's Witnesses regarding haematological supports since this policy change. METHODS: This is a retrospective observational study of consecutive Jehovah's Witnesses attending a university-affiliated tertiary referral centre between 1 January 2007 and 31 December 2013. The main outcome measure was the proportion of women who would be willing to accept blood products and other haematological supports in the event of life-threatening bleeding, should it occur. RESULTS: Seventy-six Jehovah's Witnesses attended for obstetric care during the study period. Major fractions of blood (red cells, plasma or platelets) were acceptable to 7.9% and 50% would accept some minor fractions. Some blood components were acceptable to 70.3% of nulliparous women compared to 48.9% of multiparous women. In women with advance directives some blood components were acceptable to 70.5% compared with 37.5% of those without. Recombinant factor VIIa was acceptable to 53.9%. Black African women had the lowest acceptance of any ethnic group of any blood products. CONCLUSION: The spectrum of acceptance of blood products is wide ranging within our obstetric Jehovah's Witnesses population. Recombinant factors are not universally acceptable despite their identification as non-blood products. A multidisciplinary approach with individualized consent is recommended. PMID- 26597404 TI - Transversus abdominis plane and ilioinguinal/iliohypogastric blocks for cesarean delivery in a patient with type II spinal muscular atrophy. AB - While neuraxial and general anesthetic techniques are most commonly utilized for cesarean delivery, there are rare instances in which alternative techniques may be considered. We report a patient with type II spinal muscular atrophy who had relative contraindications to both neuraxial and general anesthesia, and had experienced significant discomfort during two previous cesarean deliveries performed with local anesthetic infiltration. We describe the successful use of bilateral ultrasound-guided transversus abdominis plane and ilioinguinal/iliohypogastric blocks, in addition to intravenous sedation, for cesarean delivery anesthesia. PMID- 26597405 TI - Global Surgery 2030: evidence and solutions for achieving health, welfare, and economic development. PMID- 26597406 TI - Differences in lumbar dural sac dimension in supine and lateral positions in late pregnancy: a magnetic resonance imaging study. AB - BACKGROUND: This study was designed to quantitatively investigate differences in lumbar dural sac dimensions between the lateral and supine positions in late pregnancy. METHODS: Ten healthy volunteers with singleton pregnancies at 28 39weeks of gestation were included. Magnetic resonance imaging was performed in random order while subjects were in the left lateral and supine positions. Lumbosacral axial scans were obtained at the L1-2, L2-3, L3-4, L4-5 and L5-S1 intervertebral disc levels. The axial section area, anteroposterior maximum diameter and transversal maximum diameter of the dural sac were measured and differences between these parameters in the lateral and supine positions were compared. RESULTS: The axial section areas of the dural sac at L1-2 (P<0.001), L2 3 (P=0.001), L3-4 (P<0.001) and L4-5 (P=0.005) and the transversal maximum diameter of the dural sac at L1-2 (P<0.001), L2-3 (P<0.001), L3-4 (P<0.001) and L4-5 (P=0.001) were greater in the lateral position compared with the supine position. The anteroposterior maximum diameter of the dural sac at L4-5 was greater in the lateral position compared with the supine position (P=0.019) but there were no significant differences at other levels. The magnitude of the differences in axial section area and transverse maximal diameter were similar among the levels studied. CONCLUSIONS: The axial section area and the transversal maximum diameter of the dural sac in the lumbar area are reduced in the supine compared with the lateral position in late pregnancy. PMID- 26597407 TI - Effect of neuraxial technique after inadvertent dural puncture on obstetric outcomes and anesthetic complications. AB - BACKGROUND: The aim of this study was to evaluate labor and delivery outcomes in parturients with inadvertent dural puncture managed by either insertion of an intrathecal catheter or a resited epidural catheter. METHODS: This was a retrospective cohort review of 235 parturients who had an inadvertent dural puncture during epidural placement over a six-year period. The primary outcome was the proportion of women with a delayed second stage of labor. Secondary outcomes were the proportion of cesarean deliveries, the proportion of cases resulting in post-dural puncture headache, and the incidence of failed labor analgesia. RESULTS: Baseline characteristics such as age, body mass index and parity were similar between the two groups. Among the 236 cases of inadvertent dural puncture, 173 women (73%) had an intrathecal catheter placed while 63 women (27%) had the epidural catheter resited. Comparing intrathecal with epidural catheters, there was no observed difference in the proportion of cases of prolonged second stage of labor (13% vs. 16%, P=0.57) and the overall rate of cesarean deliveries (17% vs. 16%, P=0.78). However, we observed a lower rate of post-dural puncture headache in women who had cesarean delivery compared to vaginal delivery (53% vs. 74%, P=0.007). A greater proportion of failed labor analgesia was observed in the intrathecal catheter group (14% vs. 2%, P=0.005). CONCLUSION: The choice of neuraxial technique following inadvertent dural puncture does not appear to alter the course of labor and delivery. Cesarean delivery decreased the incidence of post-dural puncture headache by 35%. Intrathecal catheters were associated with a higher rate of failed analgesia. PMID- 26597408 TI - Anterior cutaneous nerve entrapment syndrome: an unusual cause of abdominal pain during pregnancy. PMID- 26597409 TI - Intracranial subdural haematoma following neuraxial anaesthesia in the obstetric population: a literature review with analysis of 56 reported cases. AB - BACKGROUND: Intracranial subdural haematoma is a rare but serious complication of neuraxial anaesthesia. With early diagnosis and treatment, severe neurological sequelae can be avoided. A literature search of intracranial subdural haematoma following neuraxial anaesthesia in obstetric patients was performed. Based on the findings, a flow chart on how to assess postpartum headache following a neuraxial procedure is proposed. METHODS: Medline, Embase and Cochrane databases were searched for cases of intracranial subdural haematoma following neuraxial anaesthesia in obstetric patients. Epidemiological factors, clinical symptoms and signs, treatment, outcome and the effect of performing an epidural blood patch were assessed. RESULTS: Review of the literature identified 56 cases following neuraxial procedures (epidural n=34, spinal n=20, combined spinal-epidural n=2). Predisposing risk factors were present in only a minority of patients. Persistent headache that stopped responding to postural change was the most important symptom with occurrence in 83% of patients. Focal neurological signs were present in 69% of women. Eleven percent of women were left with residual neurological deficits; the mortality rate was 7%. CONCLUSION: Intracranial subdural haematoma following neuraxial anaesthesia in obstetric patients is rare but serious complications may result. Vigilance is required whenever a headache becomes non postural, prolonged and/or whenever focal neurological signs occur. PMID- 26597411 TI - Valvular heart disease in pregnancy. PMID- 26597410 TI - Use of continuous fetal heart rate monitoring during discectomy at 24weeks of gestation. PMID- 26597412 TI - [Salvage concomitant chemoradiation therapy for non-metastatic inflammatory breast cancer after chemotherapy failure]. AB - PURPOSE: To evaluate the surgical possibility following concomitant chemoradiotherapy for inflammatory breast cancer, after unsucessful neoadjuvant chemotherapy. PATIENTS AND METHODS: The data from ten patients with inflammatory breast cancer treated between 1996 and 2010 by concomitant chemoradiotherapy after unsucessful neoadjuvant chemotherapy were analysed. All patients had an invasive carcinoma. All patients received a neoadjuvant chemotherapy, including anthracyclin, six patients received taxan and one received trastuzumab. Radiotherapy was delivered to the breast and regional lymph nodes in all patients at a dose of 50Gy; a boost of 20Gy was delivered to one patient. Concomitant chemotherapy was based on weekly cisplatin for six patients, on cisplatin and 5 fluorouracil the first and last weeks of radiotherapy for four patients. RESULTS: The median follow-up for all patients was 44 months. Mastectomy was performed in nine patients. Two- and 5-year overall survival rates were respectively 70 % and 60 %. Median local recurrence delay was 5 months; six patients died (all from cancer), seven developped metastasis. Grade 1 and 2 epithelite was respectively observed in six and two patients, grade 2 renal toxicity in three patients, grade 2 neutropenia in one patient. CONCLUSION: Concomitant chemoradiotherapy for inflammatory breast cancer after unsucessful neoadjuvant chemotherapy may control the disease in some patients and lead to mastectomy. These results have to be confirmed through a multicentric study with more patients. PMID- 26597413 TI - The role of stress and beta-adrenergic system in melanoma: current knowledge and possible therapeutic options. AB - PURPOSE: The aim of the present review was to discuss recent findings on the role of beta-adrenergic system in melanoma, in order to provide information on the biological responses elicited by its activation and its potential application for melanoma treatment. METHODS: A literature search was performed, and evidences regarding the involvement of stress and beta-adrenergic system in cancer and melanoma were found and discussed. RESULTS: Our search pointed out that beta adrenergic system is a key regulator of important biological processes involved in the onset and progression of some solid tumors. In the last decade, functional beta-adrenoceptors have been also identified on melanoma cells, as well as on their microenvironment cells. Similarly to other common cancers too, the activation of such adrenoceptors by catecholamines, usually released under stress conditions, has been found to trigger pro-tumorigenic pathways contributing to cell proliferation and motility, immune system regulation, apoptosis, epithelial mesenchymal transition, invasion and neoangiogenesis. CONCLUSIONS: The biological evidences we found clarify and sustain the clinical evidences reporting the involvement of chronic stress in melanoma onset and progression. In such scenario, it is conceivable that a therapeutic approach targeting beta-adrenergic system could constitute a novel and promising strategy for melanoma treatment. PMID- 26597414 TI - Patient-centered physical activity coaching in COPD (Walk On!): A study protocol for a pragmatic randomized controlled trial. AB - BACKGROUND: Physical inactivity is significantly associated with more frequent hospitalizations and increased mortality in COPD even after adjusting for disease severity. While practice guidelines recommend regular physical activity for all patients with COPD, health systems are challenged in operationalizing an effective and sustainable approach to assist patients in being physically active. METHODS: A pragmatic randomized controlled trial design was used to determine the effectiveness of a 12-month home and community-based physical activity coaching intervention (Walk On!) compared to standard care for 1650 patients at high risk for COPD exacerbations from a large integrated health care system. Eligible patients with a COPD-related hospitalization, emergency department visit, or observational stay in the previous 12months were automatically identified from the electronic medical records (EMR) system and randomized to treatment arms. The Walk On! intervention included collaborative monitoring of step counts, semi automated step goal recommendations, individualized reinforcement from a physical activity coach, and peer/family support. RESULTS: The primary composite outcome included all-cause hospitalizations, emergency department visits, observational stays, and death in the 12months following randomization. Secondary outcomes included COPD-related utilization, cardio-metabolic markers, physical activity, symptoms, and health-related quality of life. With the exception of patient reported outcomes, all utilization and clinical variables were automatically captured from the EMR. CONCLUSIONS: If successful, findings from this multi stakeholder driven trial of a generalizable and scalable physical activity intervention, carefully designed with sufficient flexibility, intensity, and support for a large ethnically diverse sample could re-define the standard of care to effectively address physical inactivity in COPD. PMID- 26597416 TI - Increased risk of epilepsy in children with Tourette syndrome: A population-based case-control study. AB - The association between epilepsy and Tourette syndrome has rarely been investigated. In this retrospective cohort study, we analyzed a dataset of 1,000,000 randomly sampled individuals from the Taiwan National Health Insurance Research Database to determine the risk of epilepsy in children with Tourette syndrome. The study cohort consisted of 1062 patients with Tourette syndrome aged <= 18 years, and the control group consisted of three times the number of age- and sex-matched patients without Tourette syndrome, who were insurants, from the same database during the same period. The Tourette syndrome group had an 18.38 fold increased risk of epilepsy than the control group [hazard ratio=18.38, 95% confidence interval (CI)=8.26-40.92; P<0.001]. Even after adjusting for the comorbidities, the risk of epilepsy in the Tourette syndrome group with comorbidities remained high (hazard ratio=16.27, 95% CI=6.26-18.46; P<0.001), indicating that the increased risk was not associated with comorbidities. This population-based retrospective cohort study provides the first and strong evidence that Tourette syndrome is associated with a higher risk of epilepsy. A close follow-up of children with Tourette syndrome for the development of epilepsy is warranted. PMID- 26597415 TI - The rationale, design, and baseline characteristics of PREVENT-DM: A community based comparative effectiveness trial of lifestyle intervention and metformin among Latinas with prediabetes. AB - Promotora Effectiveness Versus Metformin Trial (PREVENT-DM) is a randomized comparative effectiveness trial of a lifestyle intervention based on the Diabetes Prevention Program delivered by community health workers (or promotoras), metformin, and standard care. Eligibility criteria are Hispanic ethnicity, female sex, age >= 20 years, fluent Spanish-speaking status, BMI >= 23 kg/m(2), and prediabetes. We enrolled 92 participants and randomized them to one of the following three groups: standard care, DPP-based lifestyle intervention, or metformin. The primary outcome of the trial is the 12-month difference in weight between groups. Secondary outcomes include the following cardiometabolic markers: BMI, waist circumference, blood pressure, and fasting plasma glucose, hemoglobin A1C (HbA1c), total cholesterol, triglycerides, LDL cholesterol, HDL cholesterol, and insulin. PREVENT-DM participants are socioeconomically disadvantaged Latinas with a mean annual household income of $15,527 +/- 9922 and educational attainment of 9.7 +/- 3.6 years. Eighty-six percent of participants are foreign born, 20% have a prior history of gestational diabetes, and 71% have a first degree relative with diagnosed diabetes. At baseline, PREVENT-DM participants had a mean age of 45.1 +/- 12.5 years, weight of 178.8 +/- 39.3 lbs, BMI of 33.3 +/- 6.5 kg/m(2), HbA1c of 5.9 +/- 0.2%, and waist circumference of 97.4 +/- 11.1cm. Mean baseline levels of other cardiometabolic markers were normal. The PREVENT-DM study successfully recruited and randomized an understudied population of Latinas with prediabetes. This trial will be the first U.S. study to test the comparative effectiveness of metformin and lifestyle intervention versus standard care among prediabetic adults in a "real-world" setting. PMID- 26597418 TI - Two-dimensional (2D), three-dimensional static (3D) and real-time (4D) contrast enhanced voiding urosonography (ceVUS) versus voiding cystourethrography (VCUG) in children with vesicoureteral reflux. AB - BACKGROUND: Two-dimensional (2DUS) contrast enhanced voiding urosonography has been used in the diagnosis and treatment monitoring of the vesicoureteral reflux in children for over 15 years. The opportunity of performing this examination with the use of three-dimensional static (3DUS) and real-time (4DUS) techniques opens up new diagnostic horizons. OBJECTIVE: To analyze if 3DUS/4DUS bring additional information leading to an increased detection rate or change in the grading of reflux compared to 2DUS and voiding cystouretrography. MATERIAL AND METHODS: We evaluated 69 patients (mean 4.1 years) who underwent 2DUS/3DUS/4DUS contrast enhanced voiding urosonography (ceVUS) and voiding cystourethrography (VCUG) for the diagnosis and grading of vesicoureteral reflux. RESULTS: 2DUS and 3DUS/4DUS urosonography diagnosed 10 more refluxes (7.25%) than cystourethrography and in 3 refluxes (2.17%) detected a higher grade. In 9 refluxes (6.52%) 3DUS/4DUS urosonography and cystourethrography diagnosed a higher grade than 2DUS. There was a statistically significant difference between cystourethrography and 3DUS/4DUS urosonography when the number of detected refluxes and differences in grading were compared. 4DUS enabled a better visualization of reflux than 3DUS. CONCLUSIONS: 3DUS/4DUS techniques bring additional information leading to a change in reflux grading compared to 2DUS and a detect higher number of refluxes compared to cystourethrography. PMID- 26597417 TI - Siloxane Nanoprobes for Labeling and Dual Modality Functional Imaging of Neural Stem Cells. AB - Cell therapy represents a promising therapeutic for a myriad of medical conditions, including cancer, traumatic brain injury, and cardiovascular disease among others. A thorough understanding of the efficacy and cellular dynamics of these therapies necessitates the ability to non-invasively track cells in vivo. Magnetic resonance imaging (MRI) provides a platform to track cells as a non invasive modality with superior resolution and soft tissue contrast. We recently reported a new nanoprobe platform for cell labeling and imaging using fluorophore doped siloxane core nanoemulsions as dual modality ((1)H MRI/Fluorescence), dual functional (oximetry/detection) nanoprobes. Here, we successfully demonstrate the labeling, dual-modality imaging, and oximetry of neural progenitor/stem cells (NPSCs) in vitro using this platform. Labeling at a concentration of 10 MUL/10(4) cells with a 40%v/v polydimethylsiloxane core nanoemulsion, doped with rhodamine, had minimal effect on viability, no effect on migration, proliferation and differentiation of NPSCs and allowed for unambiguous visualization of labeled NPSCs by (1)H MR and fluorescence and local pO2 reporting by labeled NPSCs. This new approach for cell labeling with a positive contrast (1)H MR probe has the potential to improve mechanistic knowledge of current therapies, and guide the design of future cell therapies due to its clinical translatability. PMID- 26597420 TI - Role of Case Conferences in Dementia-Specific vs Traditional Care Units in German Nursing Homes. PMID- 26597419 TI - Antihypertensive and Statin Medication Use and Motor Function in Community Dwelling Older Adults. AB - OBJECTIVES: To investigate whether the use of antihypertensive and statin medication in very old adults is associated with the level of motor performance. DESIGN: Cross-sectional study. SETTINGS: A community-based study recruited from over 40 residential facilities across the metropolitan Chicago area. PARTICIPANTS: Community-dwelling very old adults (n = 1520; mean age 80.2; standard deviation 7.7). MEASUREMENTS: Eleven motor performances were summarized using a composite motor score. All prescription and over the counter medications taken by participants were inspected and coded using the Medi-Span Data Base System. Demographic characteristics and medical history were obtained by means of detailed interview and medical examinations. RESULTS: In multiple linear regression models, antihypertensive medications were associated with global motor score [beta = -0.075, standard error (SE) 0.011, P < .001]. Thus, motor function in an individual with antihypertensive medication, was on average, about 7.5% lower than an age-, sex-, and education-matched individual without antihypertensive medication. The number of antihypertensive medications, which were being used had an additive effect, such that a reduction in the level of motor function was observed with each additional medication, and receiving 3 or more antihypertensive medications was associated with about a 15% reduction in the level of motor function. The association between antihypertensive medications and motor function was robust, and remained unchanged after adjusting for confounding by indication using several potentially confounding variables: smoking, hypertension, diabetes, stroke, congestive heart failure, myocardial infarction, and intermittent claudication (beta = -0.05, SE 0.015, P = .001). In contrast, the use of statin medications was not related to motor function (unadjusted: beta = 0.003, SE 0.015, P = .826; fully adjusted: beta = 0.018, SE 0.014, P = .216). CONCLUSIONS: The use of antihypertensive medications is associated with a lower level of motor function in very old adults. The nature of this association warrants further investigation. PMID- 26597421 TI - Integrating smoking cessation into routine care in hospitals--a randomized controlled trial. AB - AIMS: To evaluate the effectiveness of a pharmacist-led multi-component smoking cessation programme (GIVE UP FOR GOOD) compared with usual care in hospitalized smokers. DESIGN: Randomized, assessor-blinded, parallel-group trial. SETTING: Three tertiary public hospitals in Australia. PARTICIPANTS: A total of 600 adult in-patient smokers [mean +/- standard deviation (SD), age 51 +/- 14 years; 64% male] available for 12 months follow-up. INTERVENTIONS: Multi-component hospital pharmacist-led behavioural counselling and/or pharmacotherapy provided during hospital stay, on discharge and 1 month post-discharge, with further support involving community health professionals (n = 300). Usual care comprised routine care provided by hospitals (n = 300). MEASUREMENTS: Two primary end-points were tested using intention-to-treat analysis: carbon monoxide (CO)-validated 1-month sustained abstinence at 6-month follow-up and verified 6-month sustained abstinence at 12-month follow-up. Smoking status and pharmacotherapy usage were assessed at baseline, discharge, 1, 6 and 12 months. FINDINGS: Sustained abstinence rates for intervention and control groups were not significantly different at both 6 months [11.6% (34 of 294) versus 12.6% (37 of 294); odds ratio (OR) = 0.91, 95% confidence interval (CI) = 0.55-1.50] and 12 months [11.6% (34 of 292) versus 11.2% (33 of 294); OR = 1.04, 95% CI = 0.63-1.73]. Secondary end-points, self-reported continuous abstinence at 6 and 12 months, also agreed with the primary end-points. Use of pharmacotherapy was higher in the intervention group, both during hospital stay [52.3% (157 of 300) versus 42.7% (128 of 300); P = 0.016] and after discharge [59.6% (174 of 292) versus 43.5% (128 of 294); P < 0.001]. CONCLUSIONS: A pharmacist-led multi-component smoking cessation intervention provided during hospital stay did not improve sustained abstinence rates at either 6 or 12 months compared with routine hospital care. PMID- 26597422 TI - Introduction. PMID- 26597424 TI - The challenge of resistance in antimicrobial drug development. PMID- 26597423 TI - Wearable Fall Detector using Integrated Sensors and Energy Devices. AB - Wearable devices have attracted great attentions as next-generation electronic devices. For the comfortable, portable, and easy-to-use system platform in wearable electronics, a key requirement is to replace conventional bulky and rigid energy devices into thin and deformable ones accompanying the capability of long-term energy supply. Here, we demonstrate a wearable fall detection system composed of a wristband-type deformable triboelectric generator and lithium ion battery in conjunction with integrated sensors, controllers, and wireless units. A stretchable conductive nylon is used as electrodes of the triboelectric generator and the interconnection between battery cells. Ethoxylated polyethylenimine, coated on the surface of the conductive nylon electrode, tunes the work function of a triboelectric generator and maximizes its performance. The electrical energy harvested from the triboelectric generator through human body motions continuously recharges the stretchable battery and prolongs hours of its use. The integrated energy supply system runs the 3-axis accelerometer and related electronics that record human body motions and send the data wirelessly. Upon the unexpected fall occurring, a custom-made software discriminates the fall signal and an emergency alert is immediately sent to an external mobile device. This wearable fall detection system would provide new opportunities in the mobile electronics and wearable healthcare. PMID- 26597425 TI - Using combination therapy to thwart drug resistance. AB - Drug combination therapy is a promising strategy to extend the lifespan of our antimicrobials. Drug combinations used in treatment must be carefully selected to minimize the evolution of resistance, either by carefully determining drug pairs that hinder the acquisition of resistance mechanisms, or by screening for combinations that inhibit growth and show reduced vulnerability to resistance. Modeling of interactions between drugs has provided intriguing insights into strategies for combination therapy deployment. Ultimately, more rigorous clinical trials need to be performed to evaluate the laboratory and modeling results and advance treatment options. PMID- 26597426 TI - Bisphosphocins: novel antimicrobials for enhanced killing of drug-resistant and biofilm-forming bacteria. AB - The global prevalence of antibiotic resistance and the threat posed by drug resistant superbugs are a leading challenge confronting modern medicine in the 21st century. However, the progress on the development of novel antibiotics to combat this problem is severely lagging. A more concerted effort to develop novel therapeutic agents with robust activity and unique mechanisms of action will be needed to overcome the problem of drug resistance. Furthermore, biofilm forming bacteria are known to be increasingly resistant to the actions of antibiotics and are a leading cause of mortality or morbidity in nosocomial infections. Bisphosphocins (also scientifically known as nubiotics) are novel small protonated deoxynucleotide molecules, and exert their antibacterial activity by depolarization of the bacterial cell membrane, causing bacterial cell death. Bisphosphocins may represent an effective weapon against antibiotic-resistant and biofilm-forming pathogenic bacteria. Preclinical efficacy studies in animals have shown that the compounds are safe and, efficacious against various bacterial infections, including drug-resistant pathogens. In vitro biochemical analysis confirmed that the bactericidal activity of bisphosphocins is mediated by depolarization of the bacterial cell membrane, and these compounds are better able to penetrate through bacterial biofilm and kill the biofilm encased bacteria. This article will cover the structure, mode of action, safety, efficacy and the current state of development of bisphosphocins. Together, the information presented here will present a strong case for bisphosphocins to be considered for use as new weapons to complement the existing arsenal of antimicrobial drugs and as a first line defence against drug-resistant and biofilm-forming bacteria. PMID- 26597427 TI - Is a wound swab for microbiological analysis supportive in the clinical assessment of infection of a chronic wound? AB - AIM: To determine whether bacteriological analysis of a wound swab is supportive in the clinical assessment of infection of a chronic wound. METHODS: Patients attending an outpatient wound clinic who had endured a chronic wound for more than 3 weeks were clinically assessed for infection. In addition, standardized wound swabs were taken according to the Levine technique and the microbiological findings of the swabs compared with the clinical assessment of the wounds. RESULTS: There was no significant relationship between the clinical assessments of the chronic wounds and the qualitative or quantitative bacteriological results of the swabs. CONCLUSION: Microbiological analysis of wound swabs taken from chronic wounds to support clinical assessment of the wounds is waste of time and money. It may be preferable to assess chronic wounds clinically, however, validation studies of these signs and symptoms are needed. PMID- 26597429 TI - Effectiveness of Disaster-prevention Technologies against Quake-induced Damage of MR Scanners during the Great East Japan Earthquake. AB - In the present study, we have performed a statistical analysis to investigate damages in magnetic resonance (MR) scanners caused by the Great East Japan Earthquake (GEJE, magnitude 9.0) and evaluated whether these disaster-prevention technologies contributed to the reduction of damages in the GEJE or not. It was confirmed that the extent of damage was significantly different between seismic scale (SS) 5 and SS over 6. Our survey study demonstrated that anchoring of MR facilities reduced damages due to quakes and demonstrated that anchoring is an efficient method for quake-induced damage prevention. The odds ratio revealed that base isolation was very useful to prevent damages in MR scanners. PMID- 26597430 TI - Heavily T2-Weighted 3D-FLAIR Improves the Detection of Cochlear Lymph Fluid Signal Abnormalities in Patients with Sudden Sensorineural Hearing Loss. AB - PURPOSE: To compare the signal increase in cochlear lymph fluid on three dimensional fluid-attenuated inversion recovery (3D-FLAIR) in patients with sudden sensorineural hearing loss (SNHL) between regular contrast 3D-FLAIR (FL) and heavily T2-weighted 3D-FLAIR (HF). METHODS: Twenty-five patients with unilateral sudden SNHL and eight healthy volunteers were included. Patients were divided into two groups: the mild group consisted of 9 patients, with an average hearing level of 60 dB or less; the severe group consisted of 16 patients, with an average hearing level of more than 60 dB. All patients and healthy volunteers underwent magnetic resonance (MR) cisternography for anatomical reference of the fluid space with FL and HF at 3 T. The region of interest (ROI) was manually drawn on the mid-modiolar section of the MR cisternography around the cochlea. The ROI for noise was drawn within the air space. ROIs were copied onto the FL and HF images. The contrast-to-noise ratio (CNR) between the affected and non affected ear was measured in the patient group and the CNR between the right and left ear was also measured in the control group. Differences in the CNR on FL and HF images among the three groups were tested by one-way analysis of variance (ANOVA). RESULTS: There was a statistically significant difference in mean CNR on HF among the three groups (P < 0.001). Furthermore, based on pairwise comparisons, there was a statistically significant difference between them in mean CNR on HF (P < 0.05). There was no statistically significant difference in mean CNR on FL among the three groups (P = 0.074). CONCLUSIONS: HF is more sensitive to signal alterations in cochleae with sudden SNHL than FL. PMID- 26597431 TI - Outcomes of mucosal melanoma of the head and neck. AB - INTRODUCTION: Mucosal melanoma of the head and neck is a rare disease with limited data available on outcomes; therefore, we reviewed our institutional experience. METHODS: An institutional database was queried and 38 patients with head and neck mucosal melanoma were identified. Charts were abstracted and local control (LC), progression-free survival (PFS) and overall survival (OS) were calculated. RESULTS: Most patients had T4 disease (86%), although nodes were positive in 11%. En bloc or endoscopic resection was performed on 93%. Adjuvant or definitive radiotherapy to a median dose of 60 Gy was utilized in 90%. Chemotherapy was given in 21%, and 16% received interferon. Three-year LC, PFS and OS were 90%, 48% and 59%, respectively. Median OS was 4.6 years. Site of first failure was distant in 52% of cases. CONCLUSION: With aggressive therapy median OS was 4.6 years in this cohort. Distant recurrence remains the primary mode of failure. It may be reasonable to include mucosal melanoma patients in trials of systemic agents along with high-risk cutaneous melanomas. PMID- 26597432 TI - Foot Position of an Infant with Sacroiliac Joint Arthritis. PMID- 26597433 TI - Old and new tests for early-onset sepsis in neonates. PMID- 26597434 TI - Sertraline-Associated Cholestasis and Ductopenia Consistent with Vanishing Bile Duct Syndrome. AB - An adolescent with depression treated with sertraline developed cholestasis and bile duct paucity, which resolved with medication discontinuation. Vanishing bile duct syndrome is an acquired destruction of interlobular bile ducts. This type of drug-induced liver injury has been associated with other medications and requires practitioners' awareness of potential hepatotoxicity. PMID- 26597428 TI - Role of dendritic cell-pathogen interactions in the immune response to pulmonary cryptococcal infection. AB - This review discusses the unique contributions of dendritic cells (DCs) to T-cell priming and the generation of effective host defenses against Cryptococcus neoformans (C.neo) infection. We highlight DC subsets involved in the early and later stages of anticryptococcal immune responses, interactions between C.neo pathogen-associated molecular patterns and pattern recognition receptors expressed by DC, and the influence of DC on adaptive immunity. We emphasize recent studies in mouse models of cryptococcosis that illustrate the importance of DC-derived cytokines and costimulatory molecules and the potential role of DC epigenetic modifications that support maintenance of these signals throughout the immune response to C.neo. Lastly, we stipulate where these advances can be developed into new, immune-based therapeutics for treatment of this global pathogen. PMID- 26597435 TI - Symptomatic Congenital Cytomegalovirus Infection Is Underdiagnosed in British Columbia. AB - Records were reviewed from all infants tested for congenital cytomegalovirus infection in British Columbia, Canada from 2006 to June 2014. Fourteen of 701 infants, or approximately 4.2 per 100,000 live births, had a positive test, indicating that >90% of expected symptomatic congenital cytomegalovirus infection cases were not diagnosed using clinician-initiated testing. PMID- 26597436 TI - Tooth wear and feeding ecology in mountain gorillas from Volcanoes National Park, Rwanda. AB - OBJECTIVES: Ecological factors have a dramatic effect on tooth wear in primates, although it remains unclear how individual age contributes to functional crown morphology. The aim of this study is to determine how age and individual diet are related to tooth wear in wild mountain gorillas (Gorilla beringei beringei) from Volcanoes National Park, Rwanda. MATERIAL AND METHODS: We calculated the percent of dentine exposure (PDE) for all permanent molars (M1-M3) of known-age mountain gorillas (N = 23), to test whether PDE varied with age using regression analysis. For each molar position, we also performed stepwise multiple linear regression to test the effects of age and percentage of time spent feeding on different food categories on PDE, for individuals subject to long-term observational studies by the Dian Fossey Gorilla Fund International's Karisoke Research Center. RESULTS: PDE increased significantly with age for both sexes in all molars. Moreover, a significant effect of gritty plant root consumption on PDE was found among individuals. Our results support prior reports indicating reduced tooth wear in mountain gorillas compared to western gorillas, and compared to other known-aged samples of primate taxa from forest and savanna habitats. DISCUSSION: Our findings corroborate that mountain gorillas present very low molar wear, and support the hypothesis that age and the consumption of particular food types, namely roots, are significant determinants of tooth wear variation in mountain gorillas. Future research should characterize the mineral composition of the soil in the Virunga habitat, to test the hypothesis that the physical and abrasive properties of gritty foods such as roots influence intra- and interspecific patterns of tooth wear. PMID- 26597437 TI - Effect of Channel Sidewalls on Joule Heating Induced Sample Dispersion in Rectangular Ducts. AB - In this article, we analyze the effect of channel sidewalls on the broadening of analyte bands resulting from Joule heating during their electrokinetic migration through a rectangular conduit. A method-of-moments formulation has been used to numerically evaluate the Taylor-Aris dispersivity of sample zones under these conditions for thin electrical double layers applicable to a majority of microfluidic assays. Our analysis shows that the larger surface area to volume ratio around the side regions of a rectangular channel causes these corners to stay cooler than the rest of the conduit. While such a thermal profile does not modify the electroosmotic flow in the system for a fixed temperature at the channel walls, it reduces the electrophoretic transport rate by about 10% for small temperature differentials across the channel cross-section (<10 degrees C). The effect of these thermal gradients on the hydrodynamic dispersion of analyte bands is more significant however, increasing such band broadening by nearly an order of magnitude in large aspect ratio designs. Our analyses further show that the trends noted above are magnified when a fixed heat transfer coefficient is assumed at the channel walls, in which case, the temperature along this boundary is no longer constant. The non-isothermal channel walls combined with the temperature dependence of zeta potential and other material properties in this situation leads to a non-uniform electroosmotic slip velocity in the system modifying both fluid and analyte transport rates. Again, while the resulting solute flow profile reduces the migration velocity of sample zones only to a moderate extent, it is found to increase the hydrodynamic dispersion of analyte bands by several orders of magnitude in large aspect ratio rectangular channels. PMID- 26597438 TI - DFT Methods to Study the Reaction Mechanism of Iridium-Catalyzed Hydrogenation of Olefins: Which Functional Should be Chosen? AB - To enable the selection of more accurate computational methods for the future theoretical exploration of the reaction mechanism of Ir-catalyzed olefin hydrogenation, we compared high-level ab initio coupled cluster and DFT calculations with a simplified model of Pfaltz's Ir/P,N-type catalyst for all four previously proposed Ir(I) /Ir(III) and Ir(III) /Ir(V) mechanisms. Through the systematic assessment of the DFT performances, the DFT empirical dispersion correction (DFT-D3) is found to be indispensable for improving the accuracy of relative energies between the Ir(I) /Ir(III) and Ir(III) /Ir(V) mechanisms. After including the DFT-D3 correction, the three best performing density functionals (DFs) are B2-PLYP, BP86, and TPSSh. In these recommended DFs, the computationally more expensive double-hybrid functional B2-PLYP-D3 has a balanced and outstanding performance for calculations of the reaction barriers, reaction energies, and energy gaps between different mechanisms, whereas the less costly BP86-D3 and TPSSh-D3 methods have outstanding, but relatively less uniform performances. PMID- 26597439 TI - Optical focusing inside scattering media with time-reversed ultrasound microbubble encoded light. AB - Focusing light inside scattering media in a freely addressable fashion is challenging, as the wavefront of the scattered light is highly disordered. Recently developed ultrasound-guided wavefront shaping methods are addressing this challenge, albeit with relatively low modulation efficiency and resolution limitations. In this paper, we present a new technique, time-reversed ultrasound microbubble encoded (TRUME) optical focusing, which can focus light with improved efficiency and sub-ultrasound wavelength resolution. This method ultrasonically destroys microbubbles, and measures the wavefront change to compute and render a suitable time-reversed wavefront solution for focusing. We demonstrate that the TRUME technique can create an optical focus at the site of bubble destruction with a size of ~2 MUm. We further demonstrate a twofold enhancement in addressable focus resolution in a microbubble aggregate target by exploiting the nonlinear pressure-to-destruction response of the microbubbles. The reported technique provides a deep tissue-focusing solution with high efficiency, resolution, and specificity. PMID- 26597441 TI - Intraneural hemangioma: A rare cause of intermittent carpal tunnel syndrome. PMID- 26597440 TI - Combination of mTOR and EGFR targeting in an orthotopic xenograft model of head and neck cancer. AB - OBJECTIVES/HYPOTHESIS: Recent preclinical and clinical studies on head and neck squamous cell carcinoma (HNSCC) revealed synergistic effects when combining anti EGFR agents with conventional chemotherapeutic drugs. Activation of the PI3 kinase/AKT/mTOR signaling pathway has been identified as an important mechanism implicated in tumor progression and resistance to EGFR inhibitors. The aim of this study was to investigate the effects of combining the mTOR inhibitor temsirolimus (Tem) with the anti-EGFR agent cetuximab (Cet) and conventional chemotherapeutic drugs (cisplatin and fluorouracil (C/F)) on an orthotopic model of HNSCC. STUDY DESIGN: Preclinical in vivo study. METHODS: We evaluated the anti tumor efficacy (measured tumor volume) of Tem, Cet, and C/F, administered alone or in combination. Investigations were performed using a human HNSCC cell line, CAL33, injected into the mouth floor of nude mice. RESULTS: As compared with the control, the combination of Tem and Cet led to the highest tumor inhibition and induced almost complete tumor growth arrest (P = 0.001). Tem significantly enhanced the impact of the Cet-C/F combination on tumor growth (P < 0.001). The highest inhibitory effects of treatments on cell proliferation (Ki67 labeling), MAPK (pP42/44 labeling), and PI3K/AKT/mTOR (pS6R labeling) signaling pathways were found with the Tem-Cet association. CONCLUSION: In this orthotopic HNSCC model, the combination of Tem with Cet produced synergistic effects on tumor growth. These results were corroborated by a strong inhibition of both MAPK and PI3K-mTOR signaling pathways. LEVEL OF EVIDENCE: N/A. PMID- 26597443 TI - Phase I study of cetuximab in combination with 5-fluorouracil, mitomycin C and radiotherapy in patients with locally advanced anal cancer. AB - BACKGROUND: 5-fluorouracil (5FU) and mitomycin C (MMC)-based chemoradiotherapy (CRT) is standard treatment for anal squamous cell carcinoma. In this phase I study cetuximab was added and the primary aim was to determine the maximum tolerated dose (MTD) of 5FU and MMC in this combination. METHODS AND MATERIALS: Patients with locally advanced anal cancer, T2 (>=4 cm)-4N0-3M0, received weekly standard doses of cetuximab starting 1 week before CRT. Intensity modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) with simultaneous integrated boost (SIB) was given to 57.5/54.0/48.6 Gy in 27 fractions to primary tumour/lymph node metastases/adjuvant lymph node regions. 5FU/MMC was given concomitantly on RT weeks 1 and 5 according to a predefined dose escalation schedule. RESULTS: Thirteen patients were enrolled. Two patients discontinued cetuximab due to hypersensitivity reaction. The median age was 65 years (range 46 70), nine were females, and 85% had stage IIIB disease. Dose-limiting toxicity events (diarrheoa, febrile neutropenia and thrombocytopenia) occurred in 3 of 11 patients. The most common grade 3-4 side-effects were radiation dermatitis (63%), haematologic toxicity (54%), and diarrheoa (36%). No treatment-related deaths occurred. Three months following completion of treatment, ten patients (91%) had a local complete remission (CR), but two patients had developed liver metastases, yielding a total CR rate of 73%. CONCLUSION: The MTDs were determined as 5FU 800 mg/m(2) on RT days 1-4 and 29-32 and MMC 8 mg/m(2) on days 1 and 29 when combined with IMRT/VMAT with SIB and cetuximab in locally advanced anal cancer. PMID- 26597442 TI - Sentinel European Node Trial (SENT): 3-year results of sentinel node biopsy in oral cancer. AB - PURPOSE: Optimum management of the N0 neck is unresolved in oral cancer. Sentinel node biopsy (SNB) can reliably detect microscopic lymph node metastasis. The object of this study was to establish whether the technique was both reliable in staging the N0 neck and a safe oncological procedure in patients with early-stage oral squamous cell carcinoma. METHODS: An European Organisation for Research and Treatment of Cancer-approved prospective, observational study commenced in 2005. Fourteen European centres recruited 415 patients with radiologically staged T1 T2N0 squamous cell carcinoma. SNB was undertaken with an average of 3.2 nodes removed per patient. Patients were excluded if the sentinel node (SN) could not be identified. A positive SN led to a neck dissection within 3 weeks. Analysis was performed at 3-year follow-up. RESULTS: An SN was found in 99.5% of cases. Positive SNs were found in 23% (94 in 415). A false-negative result occurred in 14% (15 in 109) of patients, of whom eight were subsequently rescued by salvage therapy. Recurrence after a positive SNB and subsequent neck dissection occurred in 22 patients, of which 16 (73%) were in the neck and just six patients were rescued. Only minor complications (3%) were reported following SNB. Disease specific survival was 94%. The sensitivity of SNB was 86% and the negative predictive value 95%. CONCLUSION: These data show that SNB is a reliable and safe oncological technique for staging the clinically N0 neck in patients with T1 and T2 oral cancer. EORTC Protocol 24021: Sentinel Node Biopsy in the Management of Oral and Oropharyngeal Squamous Cell Carcinoma. PMID- 26597444 TI - Prognostic score for patients with advanced melanoma treated with ipilimumab. AB - BACKGROUND: Immunotherapies like the cytotoxic T-lymphocyte antigen 4 inhibitor ipilimumab show durable clinical benefit in patients with advanced melanoma. Reliable prognostic markers and risk scores in the era of immunotherapy are still lacking. PATIENTS AND METHODS: We collected characteristics and outcomes on 134 patients with metastatic melanoma treated with ipilimumab between 2011 and 2014 at a single centre. Cox regression including multivariable fractional polynomials was used to identify independent markers for overall survival (OS). Internal model validation was done using bootstrap procedures. RESULTS: After a median follow-up of 16.1 months the median OS was 7.1 months (95% confidence interval [CI], 6.5-9.8). Nineteen of 134 patients (14.2%) had tumour remissions, 16 partial and 3 complete; 75% had progressive disease. We identified three independent adverse factors for OS: elevated lactate dehydrogenase (LDH) (hazard ratio [HR] 1.03, 95% CI 1.02-1.04), Eastern Cooperative Oncology Group performance status >0 (HR 1.91, 95% CI 1.10-3.30), and number of organs involved (NOI) (HR 1.51, 95% CI 1.22-1.86). To build an easy-to-apply risk score, we dichotomized LDH (>upper limit of normal) and NOI (>2) to built 3 prognostic groups: favourable (no adverse factors, N = 17), intermediate (1 adverse factor, N = 38), and poor prognosis (>=2 adverse factors, N = 73). Respective 12 and 18 month OS for the risk groups were: 85% and 73% (favourable), 41% and 29% (intermediate), and 12% and 6% (poor) (p < 0.001). CONCLUSION: We propose a simple prognostic score for survival in patients with advanced melanoma treated with ipilimumab using readily available clinical parameters. PMID- 26597445 TI - Insulin resistance and endometrial cancer risk: A systematic review and meta analysis. AB - AIM: It has been suggested that chronic hyperinsulinemia from insulin resistance is involved in the etiology of endometrial cancer (EC). We performed a systematic review and meta-analysis to assess whether insulin resistance is associated with the risk of EC. METHODS: We searched PubMed-Medline, Embase, Scopus, and Web of Science for articles published from database inception through 30th September 2014. We included all observational studies evaluating components defining insulin resistance in women with and without EC. Quality of the included studies was assessed by Newcastle-Ottawa scale. Random-effects models and inverse variance method were used to meta-analyze the association between insulin resistance components and EC. RESULTS: Twenty-five studies satisfied our inclusion criteria. Fasting insulin levels (13 studies, n = 4088) were higher in women with EC (mean difference [MD] 33.94 pmol/L, 95% confidence interval [CI] 15.04-52.85, p = 0.0004). No differences were seen in postmenopausal versus pre- and postmenopausal subgroup analysis. Similarly, non-fasting/fasting C-peptide levels (five studies, n = 1938) were also higher in women with EC (MD 0.14 nmol/L, 95% CI 0.08-0.21, p < 0.00001). Homeostatic model assessment - insulin resistance (HOMA-IR) values (six studies, n = 1859) in EC patients were significantly higher than in women without EC (MD 1.13, 95% CI 0.20-2.06, p = 0.02). There was moderate-to-high heterogeneity among the included studies. CONCLUSION: Currently available epidemiologic evidence is suggestive of significantly higher risk of EC in women with high fasting insulin, non fasting/fasting C-peptide and HOMA-IR values. PMID- 26597446 TI - A phase II trial of low-dose estradiol in postmenopausal women with advanced breast cancer and acquired resistance to aromatase inhibition. AB - BACKGROUND: High-dose oestrogen (HDE) is effective but toxic in postmenopausal women with advanced breast cancer (ABC). Prolonged oestrogen deprivation sensitises BC cell lines to estrogen and we hypothesised that third-generation aromatase inhibitors (AIs) would sensitise BCs to low-dose estradiol (LDE). METHODS: A single-arm phase II study of LDE (2 mg estradiol valerate daily) in postmenopausal women with estrogen receptor-positive (ER+) ABC. The primary end point was clinical benefit (CB) rate. If LDE was ineffective, HDE was offered. If LDE was effective, retreatment with the pre-LDE AI was offered on progression. RESULTS: Twenty-one patients were recruited before the trial was closed early due to slow accrual; 19 were assessable for efficacy and toxicity. CB was seen in 5 in 19 patients (26%; 95% confidence interval 9.1-51.2%), all with prolonged SD (median duration 16.8 months; range 11.0-29.6). Treatment was discontinued for toxicity in 4 in 19 patients (21%) and 8 in 11 women without hysterectomy experienced vaginal bleeding (VB). After primary LDE failure, three patients received HDE and one achieved a partial response (PR). Following CB on LDE, four patients restarted pre-LDE AI and three achieved CB including one PR. Those with CB to LDE had a significantly longer duration of first-line endocrine therapy for ABC than those without (54.9 versus 16.8 months; p < 0.01) CONCLUSION: LDE is an effective endocrine option in women with evidence of prolonged sensitivity to AI therapy. LDE is reasonably well tolerated although VB is an issue. Re-challenge with the pre-LDE AI following progression confirms re-sensitisation as a true phenomenon. PMID- 26597447 TI - Type II toxin: antitoxin systems. More than small selfish entities? AB - Toxin-antitoxin (TA) modules regulate metabolism and viability of bacteria and archaea. In type II TA systems these functions are generally thought to be performed by two small proteins. However, evidence is increasing that the toxins are much more diverse and can form multi-domain proteins. Recently, we published a novel type II TA system in which toxin and antitoxin are covalently linked into a single polypeptide chain. In this review we summarize the current knowledge on these elongated toxin homologs and provide perspectives for future study. PMID- 26597448 TI - Meeting the Challenges of Intervention Research in Health Science: An Argument for a Multimethod Research Approach. AB - Research within health science is often based on developing, implementing and evaluating interventions in a randomized controlled trial (RCT) design, with patients or other health care users as the target group. The results of RCTs can have limited generalizability. Since a trial often takes place in a controlled setting, it may be difficult to implement the results in other settings. Successful implementation in practice requires knowledge of the context and the social mechanisms and processes through which an intervention works. It is therefore important to secure such knowledge of high quality. The aim of this paper was to present and discuss how intervention research in RCT designs can be developed and strengthened by using a multimethod research approach. First, we focus on four considerations relating to the use of RCTs, namely objectivity and linearity, contextual dimensions, generalizability, and complex interventions. Second, a multimethod research approach including the terms 'research style' and 'forms of integration' is presented to address the four considerations. Third, a Danish intervention study is presented in order to discuss the potential of this multimethod research approach. We conclude by suggesting that future intervention studies should consider the potential for combining different research styles and forms of integration to the benefits of the patients and other health care users as the target group. PMID- 26597449 TI - The Whole Family Serves: Supporting Sexual Minority Youth in Military Families. AB - Sexual minority youth in military families have a unique set of stressors that affect their mental, emotional, and physical health. There is a pronounced gap in data addressing the specific stressors of this population and how they interact to impact the health of the adolescent. The culture of the United States military has historically been heterosexist and homophobic, propelled primarily by policies that restricted the recruitment and service of lesbian, gay, bisexual, or transgender individuals, leading to a continued secrecy around sexual orientation that may affect how sexual minority youth within the community view themselves. Homophobia, social stigma, and victimization lead to significant health disparities among sexual minority youth, and youth connected to the military have additional stressors as a result of frequent moves, parental deployment, and general military culture. Primary care providers must be aware of these stressors to provide a safe environment, thorough screening, and competent care for these adolescents. PMID- 26597451 TI - S1PR1 expression correlates with inflammatory responses to Newcastle disease virus infection. AB - Newcastle disease virus (NDV) is the causative agent of Newcastle disease, which is characterized by inflammatory pathological changes in the organs of chickens. The inflammatory response to this disease has not been well characterized. Previous reports showed that the sphingosine-1-phosphate-1 receptor (S1PR1), a G protein-coupled receptor, is important to the activation of inflammatory responses. To understand better the viral pathogenesis and host inflammatory response, we analyzed S1PR1 expression during NDV infection. We observed a direct correlation between chicken embryo fibroblast (CEF) cellular inflammatory responses and S1PR1 expression. Virulent NDV-infected CEF cells also had elevated levels of pro-inflammatory cytokines (IL-1beta, IL-6 and IL-18). When S1PR1 was inhibited by using the specific antagonist W146, pro-inflammatory cytokine production declined. Overexpression of S1PR1 resulted in increased virus-induced IL-1beta production. S1PR1 expression levels did not impact significantly NDV replication. These findings highlight the important role of S1PR1 in inflammatory responses in NDV infection. PMID- 26597450 TI - The distinct distribution and phylogenetic characteristics of dengue virus serotypes/genotypes during the 2013 outbreak in Yunnan, China: Phylogenetic characteristics of 2013 dengue outbreak in Yunnan, China. AB - Since 2000, sporadic imported cases of dengue fever were documented almost every year in Yunnan Province, China. Unexpectedly, a large-scale outbreak of dengue virus (DENV) infection occurred from August to December 2013, with 1538 documented cases. In the current study, 81 dengue-positive patient samples were collected from Xishuangbanna, the southernmost prefecture of the Yunnan province, and 23 from Dehong, the westernmost prefecture of the Yunnan province. The full length envelope genes were amplified and sequenced. Phylogenetic analysis revealed that nine strains (39.1%) and 14 strains (60.9%) from the Dehong prefecture were classified as genotype I of DENV-1 and Asian I genotype of DENV 2, respectively. All strains from Xishuangbanna were identified as genotype II of DENV-3. Bayesian coalescent analysis indicates that the outbreak originated from bordering southeastern Asian countries. These three epidemic genotypes were predicted to originate in Thailand and then migrate into Yunnan through different routes. PMID- 26597452 TI - An investigation into the optimal number of distractors in single-best answer exams. AB - In UK medical schools, five-option single-best answer (SBA) questions are the most widely accepted format of summative knowledge assessment. However, writing SBA questions with four effective incorrect options is difficult and time consuming, and consequently, many SBAs contain a high frequency of implausible distractors. Previous research has suggested that fewer than five-options could hence be used for assessment, without deterioration in quality. Despite an existing body of empirical research in this area however, evidence from undergraduate medical education is sparse. The study investigated the frequency of non-functioning distractors in a sample of 480 summative SBA questions at Cardiff University. Distractor functionality was analysed, and then various question models were tested to investigate the impact of reducing the number of distractors per question on examination difficulty, reliability, discrimination and pass rates. A survey questionnaire was additionally administered to 108 students (33 % response rate) to gain insight into their perceptions of these models. The simulation of various exam models revealed that, for four and three option SBA models, pass rates, reliability, and mean item discrimination remained relatively constant. The average percentage mark however consistently increased by 1-3 % with the four and three-option models, respectively. The questionnaire survey revealed that the student body had mixed views towards the proposed format change. This study is one of the first to comprehensively investigate distractor performance in SBA examinations in undergraduate medical education. It provides evidence to suggest that using three-option SBA questions would maximise efficiency whilst maintaining, or possibly improving, psychometric quality, through allowing a greater number of questions per exam paper. PMID- 26597453 TI - Characteristics of users and usage of different types of electronic cigarettes: findings from an online survey. AB - AIMS: Studying users of e-cigarettes is important to help determine whether these devices aid smoking cessation. Obtaining data in representative samples is difficult, but online surveys of users may begin to build a picture. Therefore, this study aimed, through a large online survey, to describe usage and characteristics of users of e-cigarettes. DESIGN: Cross-sectional internet survey between 2012 and 2014. SETTING AND PARTICIPANTS: A total of 2807 current e cigarette users enrolled via e-cigarette and smoking cessation websites, who lived in France (n = 988), the United States (n = 579), Switzerland (n = 310), the United Kingdom (n = 143) and other countries (n = 787). MEASUREMENTS: Type of e-cigarette used: pre-filled cartridges (n = 71), unmodified refillable tanks (n = 758), modified refillable tanks (n = 392), patterns of use, perceived effects. FINDINGS: Pre-filled models were perceived to be less effective than unmodified refillable tanks for smoking cessation by former smokers ('definitely helped': 74% vs. 94%, P < 0.001) and by current smokers for smoking reduction ('definitely helped': 37% vs. 78%, P < 0.001). Users modified their e-cigarettes mainly to obtain a better taste ('very true' 60%, 55.5-64.5%). Modified tanks were perceived to make it easier to abstain from smoking than unmodified tanks 95% vs. 89%, P < 0.001); 34% of users of pre-filled cartridges, 60% of users of unmodified tanks and 83% of users of modified tanks were men (P < 0.001). CONCLUSIONS: Newer-generation e-cigarettes were perceived to be more satisfactory and more effective for refraining from smoking than older models. Women tended to use pre-filled, unmodified models, which were perceived by participants to be the least effective in terms of abstaining from smoking. PMID- 26597454 TI - Description of Vogesella oryzae sp. nov., isolated from the rhizosphere of saline tolerant pokkali rice. AB - Three strains, namely L3B39(T), L3D16, and L1E9, were obtained while studying the cultivable rhizosphere bacteria of saline tolerant pokkali rice, at Kerala, India. The novel strains were negative for many plant growth promoting plate assays such as phytohormone and siderophore production, 1-aminocyclopropane-1 carboxylate (ACC) deaminase and growth in nitrogen free agar medium but found to utilize malic acid, citrate, D-glucose, L-arabinose, and D-maltose, important components of the plant root exudates, indicating that they are normal plant rhizosphere residents without yet known benefits to the plant. The 16S rRNA gene analysis placed these strains in the genus Vogesella, forming a separate branch independent of the previously described type strains of this genus in all tree making algorithms applied. Vogesella perlucida DS-28(T) was the type strain with highest 16S rRNA sequence similarity (97.59%). DNA-DNA hybridization values among these novel strains were above 85% andthat with Vogesella perlucida LMG 24214(T) was below 50%. Phenotypically, the novel strains can be differentiated from Vogesella perlucida LMG 24214(T) by many characters such as NaCl tolerance, growth temperature, and utilization of L-arabinose, D-maltose, and citrate. These novel strains contain C16:1omega6c/C16:1omega7c and C16:0 as major fatty acids, ubiquinone Q-8 as the major respiratory quinone, and phosphatidylethanolamine and phosphatidylglycerol as major polar lipids. Based on the results obtained from the polyphasic taxonomic approach we conclude that the strains belong to a novel Vogesella species for which the name Vogesella oryzae sp.nov. is proposed. The type strain is L3B39(T) (= LMG 28272(T)=DSM 28780(T)). PMID- 26597455 TI - Kosakonia pseudosacchari sp. nov., an endophyte of Zea mays. AB - A beige pigmented bacterial strain (JM-387(T)), isolated from field-grown corn root tissue, Tallassee, Alabama, was studied for its taxonomic allocation. A comparison of the 16S rRNA gene sequence with those of the type strains of most closely related species of the family Enterobacteriaceae showed highest sequence similarities to the type strain of Kosakonia sacchari (99.5%), "Enterobacter oryzendophyticus" (98.8%), and Kosakonia radicincitans (98.6%). Construction of phylogenetic trees based on the 16S rRNA gene and partial sequences of four protein-coding genes, rpoB, gyrB, infB, and atpD (multilocus sequence analysis, MLSA) showed a distinct clustering of strain JM-387(T) with Kosakonia sacchari. DNA-DNA hybridizations between JM-387(T) and the type strains of most similar Kosakonia/"Enterobacter" species including K. sacchari LMG 26783(T), "E. oryzendophyticus" LMG 26432(T), K. radicincitans D5/23(T), K. oryzae LMG 24251(T), E. cancerogenus LMG 2693(T), and E. cloacae subsp. dissolvens CCUG 25230(T) were in the range of 14.4-60.2%. The average nucleotide identity (ANI) of the genome sequence of the new strain to K. sacchari SP1(T) was 94.47%. Strain JM-387(T) had a typical enterobacterial fatty acid pattern consisting of the major fatty acids C16:0, C16:1 omega7c/C16:1 omega6c/C15:0 2OH, C18:1 omega7c/C18:1 omega6c with C14:0 3-OH as hydroxylated fatty acid. Genotypic data and the differentiating biochemical and chemotaxonomic properties showed that strain JM-387(T) represents a novel species of the genus Kosakonia, for which the name Kosakonia pseudosacchari sp. nov. (type strain JM-387(T)=CIP 110597(T)=DSM 27151(T)) is proposed. PMID- 26597456 TI - EASL Clinical Practice Guidelines: Liver transplantation. PMID- 26597458 TI - Intrinsic magnetic properties of single-phase Mn(1+x)Ga (0=5 years old with an acute (<24 hours) nonpenetrating elbow injury. METHODS: This prospective study included a convenience sample of patients undergoing plain radiographs of an injured elbow in 3 emergency departments. Before imaging, treating clinicians completed a standardized data collection sheet including mechanism of injury and 4-way ROM findings (full extension, flexion to 90 degrees , full pronation and supination). Radiographic interpretation by a staff radiologist was used to ascertain the presence of fracture or joint effusion. RESULTS: The median age of the 251 patients was 24 years. Ninety-two patients (36.7%) had active 4-way ROM, and 159 patients (63.3%) demonstrated limited ROM. Negative radiographs were present in 152 patients (60.6%), whereas 99 patients (39.4%) had abnormal radiographs: 75 with explicit fractures and 24 with only joint effusions. The 4-way ROM elbow test had a sensitivity of 0.99 (95% confidence interval [CI], 0.94-1.00), specificity of 0.60 (95% CI, 0.52-0.68), positive predictive value of 0.62 (95% CI, 0.54-0.69), and negative predictive value of 0.99 (95% CI, 0.94-1.00). CONCLUSIONS: Active 4 way ROM test is 99% sensitive for all radiographic injures following blunt elbow trauma and 100% sensitive for injuries requiring surgical intervention. Caution should be used in relying on this test in the pediatric population until it is validated in a larger cohort. PMID- 26597496 TI - Prehospital endotracheal intubation and survival after out-of-hospital cardiac arrest: results from the Korean nationwide registry. AB - PURPOSE: Optimal out-of-hospital cardiac arrest (OHCA) airway management strategies are still controversial. Recent studies reported survival was higher among patients who received bag-valve-mask (BVM) than those receiving endotracheal intubation (ETI) or supraglottic airway (SGA). The aim of this study was to compare neurologically favorable survival outcomes among adult nontraumatic OHCA patients by prehospital airway. METHODS: We used the Korean nationwide OHCA cohort database from 2010 to 2013. The inclusion criteria were all OHCA adults with presumed cardiac etiology, resuscitated by level-1 emergency medical technician. Patients were excluded if their information about the method of prehospital airway or clinical outcomes at hospital discharge could not be captured. The primary outcome was neurologically favorable survival to discharge. We compared the outcomes among 3 groups (ETI, SGA, or BVM) by prehospital airway using multivariable logistic regression with interaction model. RESULTS: Of 98896 patients with OHCA, 32513 were included in analysis. Patients receiving BVM were 29684 and 2829 underwent advanced airway management including 1634 with SGA and 1195 with ETI. The odds of neurologically favorable survival to discharge was significantly higher in the ETI group compared to the BVM group (adjusted OR, 1.405; 95% CI, 1.1001-1.971). In the interaction model by witnessed status, the effect of ETI on good clinical outcomes was shown only in the patients whose arrest was unwitnessed. CONCLUSION: In this Korean nationwide, population-based OHCA cohort, neurologically favorable survival to hospital discharge rates was significantly higher among patients who received ETI than those receiving BVM or SGA. PMID- 26597497 TI - Effect of phenylephrine and terbutaline on ischemic priapism: a retrospective review. AB - BACKGROUND: Ischemic priapism is the most common cause of priapism due to low blood flow. Current guidelines recommend penile aspiration and the use of intracavernous injection of vasoactive agents. The data to support these recommendations are limited and rely on expert consensus. OBJECTIVE: The objective was to determine the effectiveness of terbutaline and phenylephrine on detumescence of ischemic priapism. METHODS: This was a retrospective review of patients presenting to the emergency department with a chief concern of priapism who received oral or subcutaneous terbutaline or intracavernous phenylephrine. The primary outcome is successful detumescence. The secondary outcome is drug related adverse drug events. RESULTS: A total of 31 cases of ischemic priapism were included, with 8 patients receiving terbutaline and 23 receiving phenylephrine. Of the cases treated with terbutaline, 25% had successful detumescence compared with phenylephrine with a 74% success rate. No drug-related adverse events were reported or identified. CONCLUSIONS: Patients receiving intracavernous irrigation with phenylephrine were more likely to achieve successful detumescence than those treated with oral or subcutaneous terbutaline. PMID- 26597494 TI - Utilizing the chicken as an animal model for human craniofacial ciliopathies. AB - The chicken has been a particularly useful model for the study of craniofacial development and disease for over a century due to their relatively large size, accessibility, and amenability for classical bead implantation and transplant experiments. Several naturally occurring mutant lines with craniofacial anomalies also exist and have been heavily utilized by developmental biologist for several decades. Two of the most well known lines, talpid(2) (ta(2)) and talpid(3) (ta(3)), represent the first spontaneous mutants to have the causative genes identified. Despite having distinct genetic causes, both mutants have recently been identified as ciliopathic. Excitingly, both of these mutants have been classified as models for human craniofacial ciliopathies: Oral-facial-digital syndrome (ta(2)) and Joubert syndrome (ta(3)). Herein, we review and compare these two models of craniofacial disease and highlight what they have revealed about the molecular and cellular etiology of ciliopathies. Furthermore, we outline how applying classical avian experiments and new technological advances (transgenics and genome editing) with naturally occurring avian mutants can add a tremendous amount to what we currently know about craniofacial ciliopathies. PMID- 26597498 TI - Partial segmental thrombosis of the corpus cavernosum presenting to the ED. PMID- 26597499 TI - Ethical activity profile of nurse managers. AB - AIM: To describe the ethical activity profile of nurse managers (NM). BACKGROUND: Ethical responsibilities require nurse managers to perform certain ethical activities. In this study, these activities are referred to as an ethical activity profile and are divided into five dimensions: (1) developing one's own ethics knowledge, (2) influencing ethical issues, (3) conducting or implementing ethics research, (4) identifying and (5) solving ethical problems. This paper focuses on the first four dimensions. METHODS: Survey data were collected in 2011 using a questionnaire (mainly open questions) amongst managers at the ward, middle and strategic levels (n = 122). The data were analysed using inductive content analysis and quantification. RESULTS: The ethical activity profile of nurse managers was high, referring to the identification of various work-related ethical problems [related to staff (31%), the nurse managers themselves (29%), resources (17%), patients (12%), superiors (7%) and organisations (4%)]. However, developing one's own ethics knowledge, influencing ethical issues and conducting or implementing research dimensions of the ethical activity profile were low. CONCLUSIONS: There is room to improve the ethical activity profile of nurse managers. IMPLICATIONS FOR NURSING MANAGEMENT: Organisations have to demand that nurse managers meet all their ethical responsibilities and support this via organisational structures. PMID- 26597500 TI - A Rare SNP Identified a TCP Transcription Factor Essential for Tendril Development in Cucumber. AB - Rare genetic variants are abundant in genomes but less tractable in genome-wide association study. Here we exploit a strategy of rare variation mapping to discover a gene essential for tendril development in cucumber (Cucumis sativus L.). In a collection of >3000 lines, we discovered a unique tendril-less line that forms branches instead of tendrils and, therefore, loses its climbing ability. We hypothesized that this unusual phenotype was caused by a rare variation and subsequently identified the causative single nucleotide polymorphism. The affected gene TEN encodes a TCP transcription factor conserved within the cucurbits and is expressed specifically in tendrils, representing a new organ identity gene. The variation occurs within a protein motif unique to the cucurbits and impairs its function as a transcriptional activator. Analyses of transcriptomes from near-isogenic lines identified downstream genes required for the tendril's capability to sense and climb a support. This study provides an example to explore rare functional variants in plant genomes. PMID- 26597501 TI - Transport Across Chloroplast Membranes: Optimizing Photosynthesis for Adverse Environmental Conditions. AB - Chloroplasts are central to solar light harvesting and photosynthesis. Optimal chloroplast functioning is vitally dependent on a very intensive traffic of metabolites and ions between the cytosol and stroma, and should be attuned for adverse environmental conditions. This is achieved by an orchestrated regulation of a variety of transport systems located at chloroplast membranes such as porines, solute channels, ion-specific cation and anion channels, and various primary and secondary active transport systems. In this review we describe the molecular nature and functional properties of the inner and outer envelope and thylakoid membrane channels and transporters. We then discuss how their orchestrated regulation affects thylakoid structure, electron transport and excitation energy transfer, proton-motive force partition, ion homeostasis, stromal pH regulation, and volume regulation. We link the activity of key cation and anion transport systems with stress-specific signaling processes in chloroplasts, and discuss how these signals interact with the signals generated in other organelles to optimize the cell performance, with a special emphasis on Ca(2+) and reactive oxygen species signaling. PMID- 26597502 TI - Anal Douche Practices and Willingness to Use a Rectal Microbicide Enema for HIV Prevention and Associated Factors Among an Internet Sample of HIV-Negative and HIV-Discordant Male Couples in the US. AB - A significant proportion of MSM acquire HIV from their primary relationship partners. Rectal microbicides are currently being studied to determine their efficacy for HIV prevention, yet willingness to use rectal microbicides among male couples is largely unknown. Dyadic data from 333 HIV-negative and HIV discordant male couples, representing 631 HIV-negative men, were used to assess anal douching practices and willingness to use a rectal microbicide for HIV prevention. 17 % of men douched 100 % of the time before having anal sex within their primary partner. Among those who had sex outside of their relationship, 36 % had douched 100 % of the time before having anal sex with a casual MSM partner. Most men (63 %) indicated a willingness to use a theoretically effective rectal microbicide prior to anal sex for HIV prevention. If found effective, rectal microbicides delivered as an anal douche may be an acceptable format for HIV prevention to some MSM who already engage in anal douching. Understanding current douching practices will be important in successfully promoting the uptake of rectal microbicides. PMID- 26597503 TI - Polarization of macrophages towards M1 phenotype by a combination of 2-deoxy-d glucose and radiation: Implications for tumor therapy. AB - 2-Deoxy-d-glucose (2-DG) has been found to enhance the cytotoxicity of ionizing radiation and chemotherapeutic drugs in several tumor cell lines in vitro. Systemic administration of 2-DG together with localized irradiation of the tumor leads to tumor regression and cure (disease free survival), which correlate with the differential levels of anti-tumor immunity observed in Ehrlich ascites tumor (EAT) bearing mice. Macrophages being a major player of the innate immune system, we investigated the activation status of splenic macrophages during radio sensitization of EAT in mice as well as in peritoneal macrophages ex vivo and macrophagic cell line (Raw 264.7) in vitro. Results suggest that under in vivo conditions, the combined treatment (2-DG+radiation) restores the M1 phenotype in spleen that correlated with the tumor response. However, 2-DG neither induced significant cytotoxicity nor enhanced radiation-induced cell death in peritoneal macrophages and the macrophage cell line (Raw 264.7). Further, increased arborization and enhanced functional status (expression of MHC class II, CD80, CD86 and phagocytosis) were observed after the combined treatment. Besides this activation, the combined treatment also skewed the macrophages towards M1 phenotype as evidenced by the enhanced secretion of IL-12, IL-2, TNF-alpha and IFN-gamma. These observations suggest that 2-DG not only preserves the survival of normal macrophages during irradiation, but also activates macrophages by polarizing towards M1 phenotype, which is known to be tumoricidal in nature. This study for the first time sheds light on a potential antitumor immune activation by 2-DG involving macrophagic stimulation during in vivo radio-sensitization of tumors, besides the other known antitumor effects of this glucose analogue. PMID- 26597504 TI - Behavior Change Techniques in Apps for Medication Adherence: A Content Analysis. AB - INTRODUCTION: There are a vast number of smartphone applications (apps) aimed at promoting medication adherence on the market; however, the theory and evidence base in terms of applying established health behavior change techniques underpinning these apps remains unclear. This study aimed to code these apps using the Behavior Change Technique Taxonomy (v1) for the presence or absence of established behavior change techniques. METHODS: The sample of apps was identified through systematic searches in both the Google Play Store and Apple App Store in February 2015. All apps that fell into the search categories were downloaded for analysis. The downloaded apps were screened with exclusion criteria, and suitable apps were reviewed and coded for behavior change techniques in March 2015. Two researchers performed coding independently. RESULTS: In total, 166 medication adherence apps were identified and coded. The number of behavior change techniques contained in an app ranged from zero to seven (mean=2.77). A total of 12 of a possible 96 behavior change techniques were found to be present across apps. The most commonly included behavior change techniques were "action planning" and "prompt/cues," which were included in 96% of apps, followed by "self-monitoring" (37%) and "feedback on behavior" (36%). CONCLUSIONS: The current extent to which established behavior change techniques are used in medication adherence apps is limited. The development of medication adherence apps may not have benefited from advances in the theory and practice of health behavior change. PMID- 26597505 TI - Physical Activity Levels in U.S. Latino/Hispanic Adults: Results From the Hispanic Community Health Study/Study of Latinos. AB - INTRODUCTION: Physical activity (PA) prevalence among U.S. Latino/Hispanic adults of diverse backgrounds is not well known. This study describes PA among a representative sample of U.S. Latino/Hispanic adults. METHODS: A population-based cohort of Hispanic/Latino adults (aged 18-74 years) participating in the Hispanic Community Health Study/Study of Latinos from March 2008 to June 2011 (N=16,415) was recruited in four urban areas from Miami, the Bronx, Chicago, and San Diego. Participants wore an Actical hip accelerometer for 1 week (n=12,253) and completed the Global Physical Activity Questionnaire (n=15,741). Data were analyzed in 2015. RESULTS: Based on accelerometry, Hispanics/Latinos engaged in 23.8 minutes/day (10.3 minutes/day when only considering minutes from sustained 10-minute bouts) of moderate to vigorous PA (MVPA). Individuals of Puerto Rican and Dominican background had the most minutes/day of MVPA (32.1 and 29.1, respectively), whereas those of Cuban background had the fewest (15.3). Based on the Global Physical Activity Questionnaire, 65% of Hispanic/Latinos met the aerobic component of 2008 Physical Activity Guidelines for Americans. Men and individuals of Puerto Rican background had the most minutes/day of leisure-time MVPA (30.3 and 30.2, respectively). Individuals of Puerto Rican and Dominican background had the most minutes/day of transportation-related PA (48.7 and 39.7, respectively). Individuals of Mexican and Central American background had the most minutes/day of work-related MVPA (90.7 and 93.2, respectively). CONCLUSIONS: Among Hispanics/Latinos, self-reported data provided information on the type of PA and helped explain variability identified from accelerometer-assessed PA. These findings highlight variability in PA among Hispanics from diverse ethnic backgrounds. PMID- 26597506 TI - Urban Vegetative Cover Fragmentation in the U.S.: Associations With Physical Activity and BMI. AB - INTRODUCTION: Urban vegetative cover provides a range of ecosystem services including contributions to human health and well-being. Urbanization exerts tremendous pressure on this natural resource, causing fragmentation and loss of urban greenspace. This study aimed to examine associations between vegetative cover fragmentation and physical activity and BMI at the county scale in the U.S. metropolitan statistical areas greater than 1 million in population. METHODS: National Land Cover Database 2006 and Behavioral Risk Factor Surveillance System 2008 provided land cover and human health data, respectively. Analyses were performed in 2013 at the county scale where the health data were reported. Spearman rank correlation and stepwise and hierarchical regression models were applied to estimate relationships between land cover and health variables. RESULTS: After controlling for median household income and race, greater forest edge density (beta=0.272, p<0.05) and larger size of herbaceous patches (beta=0.261, p<0.01) were associated with a higher percentage of participation in physical activity within counties. More connections between forest and developed area (beta=0.37, p<0.01) and greater edge density of shrubland (beta=0.646, p<0.001) were positively associated with a higher percentage of normal BMI (<25) within counties. CONCLUSIONS: Forest land cover and some degree of fragmentation are associated with population physical activity. Future studies should examine how built environments and varying land cover configurations influence physical activity and weight status. PMID- 26597509 TI - Message from the New President. PMID- 26597507 TI - Meta-analysis of colistin for the treatment of Acinetobacter baumannii infection. AB - Multidrug resistant among Acinetobacter baumannii infection is associated with a high mortality rate and limits the therapeutic options. The aim of this study was to assess the safety and efficacy of colistin monotherapy vs. other single antibiotic therapy AND colistin-based combination therapy (with other antibiotics) vs. colistin alone for the treatment of Acinetobacter baumannii infection. Online electronic database were searched for studies evaluating colistin with or without other antibiotics in treatment of patients with drug resistant Acinetobacter baumannii infection. Totally, twelve studies met the inclusion criteria. For colistin-based combination therapy, six articles including 668 patients were included. Our results showed that the overall clinical response did not differ significantly between colistin-based combination therapy and monotherapy (OR = 1.37, 95% CI = 0.86-2.19, P = 0.18). This insignificance was also detected in ICU mortality, length of stay and nephrotoxicity (P > 0.05). However, the colistin-based combination therapy was shown increasing the microbiological response (OR = 2.14, 95% CI = 1.48-3.07, P < 0.0001). For colistin monotherapy, six studies involving 491 patients were analyzed. The results were in concordance with the findings of the colistin-based combination therapy group. Our results suggest that colistin may be a promising therapy as safe and efficacious as standard antibiotics for the treatment of drug resistant Acinetobacter baumannii infection. PMID- 26597510 TI - Reducing emergency CT radiation doses with simple techniques: A quality initiative project. AB - INTRODUCTION: Use of indication-specific CT protocols and adjustment of scan parameters to decrease radiation exposure may result in significant dose reduction. We implemented these strategies and compare pre- and post implementation radiation dose in emergency department (ED) patients. METHOD: This was a descriptive, retrospective study. Patients older than 15 years who had undergone emergency CT examinations of the head, chest, abdomen, pelvis and abdominopelvic region in periods before and after dose-reduction implementation were included. The primary outcome was volume CT dose index (CTDIvol ) and dose length products (DLP). RESULTS: There were 786 studies in the pre-implementation (group 1) and 955 studies in the post-implementation (group 2) periods. Radiation dose from all CT types significantly reduced in the post-implementation period. Average CTDIvol for head, chest, abdomen, pelvis and abdominopelvic region (doses during pre-implementation period in parentheses) were 51.5 (109), 8.1 (30.4), 13.1 (41.8), 11 (38), 11.2 (41.8) mGy, respectively. Average DLP was also significantly lower (pre-implementation dose in parentheses) in all CT types, which were 943 (2232), 324 (2517), 944 (5605), 280 (4024), 809 (7118) mGy?cm, respectively. Patients' age, gender, body mass index and size were not significantly different between the two groups. Image quality decreased but almost all examinations received an acceptable diagnostic subjective image quality. CONCLUSION: Simple methods could help significantly reduce CT radiation exposure in ED patients while maintaining an acceptable level of diagnostic image quality. PMID- 26597511 TI - Speed modulation alone is not enough. PMID- 26597512 TI - A hybrid configuration of a left ventricular assist device and venovenous extracorporeal membrane oxygenation. PMID- 26597513 TI - Fixed versus dynamic subaortic stenosis: Hemodynamics and resulting differences in Doppler echocardiography and aortic pressure contour. PMID- 26597514 TI - Spontaneous and evoked pain-associated behaviors in a rat model of neuropathic pain respond differently to drugs with different mechanisms of action. AB - Given that patients with neuropathic pain suffer a mixture of spontaneous and evoked pain symptoms, we assessed the effects of drugs with different mechanism of action on spontaneous and evoked pain-associated behaviors in a rat model of neuropathic pain induced by chronic constriction injury (CCI) of the sciatic nerve. Frequent aberrant limb movement on the operated side was measured to assess spontaneous pain-associated behavior, and mechanical allodynia and thermal hyperalgesia were evaluated to assess evoked pain-associated behaviors. These three types of behavior were assessed after administration of the following drugs: pregabalin (alpha2delta-subunit ligand), morphine (MU-opioid receptor agonist), perampanel (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid [AMPA] receptor antagonist), clonidine, dexmedetomidine (alpha2-adrenoceptor agonists), and diclofenac (non-steroidal anti-inflammatory drug [NSAID]). Pregabalin at an oral dose of 10 or 30mg/kg significantly alleviated frequent aberrant limb movement and mechanical allodynia, but not thermal hyperalgesia. Morphine at a subcutaneous dose of 1 or 3mg/kg significantly improved all three types of behavior. Perampanel at an oral dose of 1mg/kg attenuated only frequent aberrant limb movement. Intraperitoneal administration of clonidine (0.01 or 0.03mg/kg) and dexmedetomidine (0.03mg/kg) significantly improved all three types of behavior, while diclofenac did not relieve any of the behaviors. Pregabalin, clonidine, and dexmedetomidine significantly decreased motor performance at doses close to analgesic doses in the rotarod test. The present study demonstrates that responses to spontaneous and evoked pain symptoms in neuropathic pain condition differ depending on a drug's mechanism of action. The selection and application of drugs according to the specific symptoms would be considered for the medication of patients with neuropathic pain. PMID- 26597515 TI - An heuristic filtering tool to identify phenotype-associated genetic variants applied to human intellectual disability and canine coat colors. AB - BACKGROUND: Identification of one or several disease causing variant(s) from the large collection of variants present in an individual is often achieved by the sequential use of heuristic filters. The recent development of whole exome sequencing enrichment designs for several non-model species created the need for a species-independent, fast and versatile analysis tool, capable of tackling a wide variety of standard and more complex inheritance models. With this aim, we developed "Mendelian", an R-package that can be used for heuristic variant filtering. RESULTS: The R-package Mendelian offers fast and convenient filters to analyze putative variants for both recessive and dominant models of inheritance, with variable degrees of penetrance and detectance. Analysis of trios is supported. Filtering against variant databases and annotation of variants is also included. This package is not species specific and supports parallel computation. We validated this package by reanalyzing data from a whole exome sequencing experiment on intellectual disability in humans. In a second example, we identified the mutations responsible for coat color in the dog. This is the first example of whole exome sequencing without prior mapping in the dog. CONCLUSION: We developed an R-package that enables the identification of disease-causing variants from the long list of variants called in sequencing experiments. The software and a detailed manual are available at https://github.com/BartBroeckx/Mendelian. PMID- 26597516 TI - Surgical caseload and the risk of surgical Never Events in England. AB - Never Events are medical errors that are believed to be preventable with appropriate measures. We surveyed all English acute NHS trusts to determine the number of surgical Never Events and surgical caseload for 2011-2014. There were 742 surgically related Never Events in three years, with no change in the number annually. The risk of a surgical Never Event was 1 in 16 423 operations (95% CI 1 in 15 283 to 1 in 17 648) or 1 Never Event per 12.9 operating theatres per year (95% CI 1 in 12.1 to 1 in 13.9). The risk of severe harm due to a Never Event was approximately 1 in 238 939 operations. There was no meaningful association between number of Never Events and other safety indicators. Surgical Never Events are undoubtedly important to individual patients, but they are not a useful metric to judge quality of care. PMID- 26597517 TI - Exploring the diary as a recovery-oriented therapeutic tool. AB - Diary writing is a centuries-old method of recording events, experiences, thoughts, and feelings that might offer potential as a tool that consumers and nurses could utilize in recovery-oriented practice. While the diary has been used within health disciplines to detail and communicate personal experiences to enable collaborative examination of progress, a diary can also provide a more complete picture of what life is like; not only within the confines of a health service environment, but also outside. In recent times, the diary appears to be experiencing a renewed interest in terms of health care. People experiencing a mental health challenge might use diary-based forms of communication to promote understanding between themselves and mental health workers, and ultimately the use of this form of narrative therapy might facilitate person-centred, recovery based actions. The present study paper, therefore, explores multiple perspectives on the use of diaries in the therapeutic context. Suggesting that diaries have not yet been utilized to their fullest potential by and with consumers and clinicians, this discussion raises issues and offers clarity about diary forms and their uses in the health context. It also discusses the barriers to their use and how to engage consumers and clinicians in recovery-oriented work. PMID- 26597519 TI - Impact of patient-related factors on the outcomes of office-based injection laryngoplasty. AB - OBJECTIVES/HYPOTHESIS: In-office percutaneous injection laryngoplasty (IL) is a common treatment for glottal insufficiency. The objective of this prospective study was to determine if voice outcomes from IL are affected by age, gender, or initial disease severity. STUDY DESIGN: Prospective case series. METHODS: Consecutive adult patients undergoing awake injection laryngoplasty were recruited from a subspecialty laryngology clinic. Voice Handicap Index (VHI-30); Consensus Auditory-Perceptual Evaluation of Voice (CAPE-V); and Grade, Roughness, Breathiness, Asthenia and Strain (GRBAS) Dysphonia Scale were evaluated prior to and 2 months after injection. Patients who had more severe disease were defined as those patients with greater initial perception of handicap, with a VHI score greater than 60. RESULTS: Thirty-five subjects were enrolled, and 27 (16 male; mean age 61.6 +/- 13.2 years) had complete data. No impact from age or gender was seen on outcomes from IL as measured by VHI-30 (P = 0.397 for age; P = 0.764 for gender), CAPE-V (P = 0.675 for age, P = 0.975 for gender), or GRBAS (P = 0.213 for age, P = 0.983 for gender). Patients with poorer initial VHI tended to have more significant improvement (P = 0.002), which may represent a ceiling effect. CONCLUSIONS: In this prospective clinical study, age and gender did not affect outcome in IL. Patients with more severe disease appeared to have greater improvement. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:1806-1809, 2016. PMID- 26597529 TI - Heterologous Expression and Characterization of a Thermostable Exo-beta-D Glucosaminidase from Aspergillus oryzae. AB - An exo-beta-D-glucosaminidase (AorCsxA) from Aspergillus oryzae FL402 was heterologously expressed and purified. The deduced amino acid sequence indicated that AorCsxA belonged to glycoside hydrolase family 2. AorCsxA digested colloid chitosan into glucosamine but not into chitosan oligosaccharides, demonstrating exo-beta-D-glucosaminidase (CsxA) activity. AorCsxA exhibited optimal activity at pH 5.5 and 50 degrees C; however, the enzyme expressed in Pichia pastoris (PpAorCsxA) showed much stronger thermostability at 50 degrees C than that expressed in Escherichia coli (EcAorCsxA), which may be related to glycosylation. AorCsxA activity was inhibited by EDTA and most of the tested metal ions. A single amino acid mutation (F769W) in AorCsxA significantly enhanced the specific activity and hydrolysis velocity as revealed by comparison of Vmax and kcat values with those of the wild-type enzyme. The three-dimensional structure suggested the tightened pocket at the active site of F769W enabled efficient substrate binding. The AorCsxA gene was heterologously expressed in P. pastoris, and one transformant was found to produce 222 U/ml activity during the high-cell density fermentation. This AorCsxA-overexpressing P. pastoris strain is feasible for large-scale production of AorCsxA. PMID- 26597530 TI - Alteration of the Metabolome Profile in Endothelial Cells by Overexpression of miR-143/145. AB - Communication between endothelial cells (ECs) and smooth muscle cells (SMCs) via miR-143/145 clusters is vital to vascular stability. Previous research demonstrates that miR-143/145 released from ECs can regulate SMC proliferation and migration. In addition, a recent study has found that SMCs also have the capability of manipulating EC function via miR-143/145. In the present study, we artificially increased the expression of miR-143/145 in ECs, to mimic a similar change caused by miR-143/145 released by SMCs, and applied untargeted metabolomics analysis, aimed at investigating the consequential effect of miR 143/145 overexpression. Our results showed that miR-143/145 overexpression alters the levels of metabolites involved in energy production, DNA methylation, and oxidative stress. These changed metabolites indicate that metabolic pathways, such as the SAM cycle and TCA cycle, exhibit significant differences from the norm with miR-143/145 overexpression. PMID- 26597531 TI - Hydrogel Dressing with a Nano-Formula against Methicillin-Resistant Staphylococcus aureus and Pseudomonas aeruginosa Diabetic Foot Bacteria. AB - This study proposes an alternative approach for the use of chitosan silver-based dressing for the control of foot infection with multidrug-resistant bacteria. Sixty-five bacterial isolates were isolated from 40 diabetic patients. Staphylococcus aureus (37%) and Pseudomonas aeruginosa (18.5%) were the predominant isolates in the ulcer samples. Ten antibiotics were in vitro tested against diabetic foot clinical bacterial isolates. The most resistant S. aureus and P. aeruginosa isolates were then selected for further study. Three chitosan sources were tested individually for chelating silver nanoparticles. Squilla chitosan silver nanoparticles (Sq. Cs-Ag(0)) showed the maximum activity against the resistant bacteria when mixed with amikacin that showed the maximum synergetic index. This, in turn, resulted in the reduction of the amikacin MIC value by 95%. For evaluation of the effectiveness of the prepared dressing using Artemia salina as the toxicity biomarker, the LC50 was found to be 549.5, 18,000, and 10,000 MUg/ml for amikacin, Sq. Cs-Ag(0), and dressing matrix, respectively. Loading the formula onto chitosan hydrogel dressing showed promising antibacterial activities, with responsive healing properties for the wounds in normal rats of those diabetic rats (polymicrobial infection). It is quite interesting to note that no emergence of any side effect on either kidney or liver biomedical functions was noticed. PMID- 26597528 TI - The mathematics of cancer: integrating quantitative models. AB - Mathematical modelling approaches have become increasingly abundant in cancer research. The complexity of cancer is well suited to quantitative approaches as it provides challenges and opportunities for new developments. In turn, mathematical modelling contributes to cancer research by helping to elucidate mechanisms and by providing quantitative predictions that can be validated. The recent expansion of quantitative models addresses many questions regarding tumour initiation, progression and metastases as well as intra-tumour heterogeneity, treatment responses and resistance. Mathematical models can complement experimental and clinical studies, but also challenge current paradigms, redefine our understanding of mechanisms driving tumorigenesis and shape future research in cancer biology. PMID- 26597532 TI - Apoptotic Effects of Cordycepin Through the Extrinsic Pathway and p38 MAPK Activation in Human Glioblastoma U87MG Cells. AB - We first demonstrated that cordycepin inhibited cell growth and triggered apoptosis in U87MG cells with wild-type p53, but not in T98G cells with mutant type p53. Western blot data revealed that the levels of procaspase-8, -3, and Bcl 2 were downregulated in cordycepintreated U87MG cells, whereas the levels of Fas, FasL, Bak, cleaved caspase-3, -8, and cleaved PARP were upregulated, indicating that cordycepin induces apoptosis by activating the death receptor-mediated pathway in U87MG cells. Cordycepin-induced apoptosis could be suppressed by only SB203580, a p38 MAPK-specific inhibitor. These results suggest that cordycepin triggered apoptosis in U87MG cells through p38 MAPK activation and inhibition of the Akt survival pathway. PMID- 26597533 TI - Cytoprotective Effect of Makgeolli Lees on Paraquat Induced Oxidative Stress in A549 Cells via Activation of NRF2 and Antioxidant Genes. AB - Makgeolli lees (ML) has several physiological effects such as antioxidant, antidiabetic, and anticancer properties, but its biological functions have not been determined definitively. Here, we tested whether ML has a cytoprotective effect on paraquat (PQ)-induced oxidative stress in the human lung carcinoma cell line A549. At 0.1 mg/ml ML, viability of PQ-exposed A549 cells was restored by 12.4%, 18.5%, and 48.6% after 24, 48, and 72 h, respectively. ML also reduced production of the intracellular reactive oxygen species (ROS) that were generated by PQ treatment. Further experiments revealed that ML treatment enhanced the expression and nuclear translocation of nuclear factor erythroid 2-related factor 2 (NRF2) as well as ARE-GFP reporter activity. ML treatment also effectively increased the expression of NRF2's target genes NAD(P)H dehydrogenase quinone 1 (NQO1) and heme oxygenase 1 (HO-1). Moreover, we found that expression of cytoprotective genes, including glutathione peroxidases (GPXs), superoxide dismutase (SOD1), catalase (CAT), peroxiredoxin 3 (PRDX3), and peroxiredoxin 4 (PRDX4), was greatly enhanced by treatment with ML during PQ exposure. Taken together, the data suggest that treatment of PQ-exposed A549 cells with ML ameliorates cytotoxicity through induction of NRF2 expression and its target genes HO-1, NQO1, and other antioxidant genes. Thus, ML may serve as a functional food applicable to ROS-mediated human diseases. PMID- 26597527 TI - Cysteine cathepsin proteases: regulators of cancer progression and therapeutic response. AB - Cysteine cathepsin protease activity is frequently dysregulated in the context of neoplastic transformation. Increased activity and aberrant localization of proteases within the tumour microenvironment have a potent role in driving cancer progression, proliferation, invasion and metastasis. Recent studies have also uncovered functions for cathepsins in the suppression of the response to therapeutic intervention in various malignancies. However, cathepsins can be either tumour promoting or tumour suppressive depending on the context, which emphasizes the importance of rigorous in vivo analyses to ascertain function. Here, we review the basic research and clinical findings that underlie the roles of cathepsins in cancer, and provide a roadmap for the rational integration of cathepsin-targeting agents into clinical treatment. PMID- 26597534 TI - Fragment-assisted hit investigation involving integrated HTS and fragment screening: Application to the identification of phosphodiesterase 10A (PDE10A) inhibitors. AB - Fragment-based drug design (FBDD) relies on direct elaboration of fragment hits and typically requires high resolution structural information to guide optimization. In fragment-assisted drug discovery (FADD), fragments provide information to guide selection and design but do not serve as starting points for elaboration. We describe FADD and high-throughput screening (HTS) campaign strategies conducted in parallel against PDE10A where fragment hit co crystallography was not available. The fragment screen led to prioritized fragment hits (IC50's ~500MUM), which were used to generate a hypothetical core scaffold. Application of this scaffold as a filter to HTS output afforded a 4MUM hit, which, after preparation of a small number of analogs, was elaborated into a 16nM lead. This approach highlights the strength of FADD, as fragment methods were applied despite the absence of co-crystallographical information to efficiently identify a lead compound for further optimization. PMID- 26597535 TI - Kinetic and molecular orbital analyses of dicarboxylic acylcarnitine methylesterification show that derivatization may affect the screening of newborns by tandem mass spectrometry. AB - Newborns are routinely screened for organic acidemias by acylcarnitine analysis. We previously reported the partial catalytic methylesterification of dicarboxylic acylcarnitines by benzenesulfonic acid moiety in the solid extraction cartridge during extraction from serum. Since the diagnosis of organic acidemias by tandem mass spectrometry is affected by the higher molecular weight of these derivatized acylcarnitines, we investigated the methylesterification conditions. The kinetic constants for the methylesterification of carboxyl groups on the acyl and carnitine sides of carnitine were 2.5 and 0.24h(-1), respectively. The physical basis underlying this difference in methylesterification rates was clarified theoretically, illustrating that methylesterification during extraction proceeds easily and must be prevented. PMID- 26597536 TI - Identification of a potent inhibitor targeting human lactate dehydrogenase A and its metabolic modulation for cancer cell line. AB - Targeting LDHA represents a promising strategy for the development of new anti cancer agents. We report herein the identification of a potent compound as a direct LDHA inhibitor. The in vitro enzymatic assay revealed that the VS-2 had good inhibitory potency (IC50=0.25MUM) to LDHA. Cytotoxic assay suggested that the VS-2 could inhibit MCF-7 cancer cell growth, with the IC50 value low to 1.54MUM. The seahorse XF24 experiment validated that the VS-2 served as a modulator to reprogram MCF-7 cancer cell metabolism from glycolysis to mitochondrial respiration. PMID- 26597537 TI - Synthesis and evaluation of the anticoccidial activity of trifluoropyrido[1,2 a]pyrimidin-2-one derivatives. AB - Screening of our chemical library to discover new molecules exhibiting in vitro activity against the invasion of host cells by Eimeria tenella revealed a lead compound with an IC50 of 15MUM. Structure-activity relationship studies were conducted with 34 newly synthesized compounds to identify more active molecules and enhance in vitro activity against the parasite. Four compounds were more effective in inhibiting MDBK cell invasion in vitro than the lead compound. PMID- 26597539 TI - Ultrasound response of aqueous poly(ionic liquid) solution. AB - Ultrasound (US) effects on aqueous poly(ionic liquid) (PIL) solution were investigated using viscosity and FT-IR spectroscopy after exposure to US of 23, 43, and 96 kHz frequencies at 50 W. The viscosity of the poly(1-vinyl-3-butyl imidazolium chloride) (PIL) aqueous solution decreased during exposure to US. It then increased gradually within about 10 min as US stopped. The aqueous PIL behavior was then observed using FT-IR spectroscopy. The US exposure enhanced the FT-IR band intensity of the OH stretching. The band intensity returned to its original value after the US stopped. These results responded cyclically to the US on/off. Analysis of the FT-IR spectra revealed that US influenced the breakage and reformation of hydrogen bonds in the PIL and water. Two-dimensional correlation and deconvolution were used to analyze the change of components in the region of 3000-3700 cm(-1) for US exposure. Results of these analyses suggest that US exposure might break hydrogen bonds between PIL segments and water. In the absence of US, hydrogen bonds reformation was also observed between the PIL and water. PMID- 26597538 TI - Inflammation and neuronal death in the motor cortex of the wobbler mouse, an ALS animal model. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder of the upper and lower motor neurons, characterized by rapid progressive weakness, muscle atrophy, dysarthria, dysphagia, and dyspnea. Whereas the exact cause of ALS remains uncertain, the wobbler mouse (phenotype WR; genotype wr/wr) equally develops a progressive degeneration of motor neurons in the spinal cord and motor cortex with striking similarities to sporadic human ALS, suggesting the possibility of a common pathway to cell death. METHODS: With the aid of immunohistochemistry, confocal laser scanning microscopy, and transmission electron microscopy techniques, we analyze the proliferation behavior of microglial cells and astrocytes. We also investigate possible motor neuron death in the mouse motor cortex at different stages of the wobbler disease, which so far has not received much attention. RESULTS: An abnormal density of Iba-1 positive microglial cells expressing pro-inflammatory tumor necrosis factor (TNF) alpha- and glial fibrillary acidic protein (GFAP)-positive activated astroglial cells was detected in the motor cortex region of the WR mouse 40 days postnatal (d.p.n.). Motor neurons in the same area show caspase 3 activation indicating neurodegenerative processes, which may cause progressive paralysis of the WR mice. It could also cause cell degeneration, such as vacuolization, dilation of the ER, and swollen mitochondria at the same time, and support the assumption that inflammation might be an important contributing factor of motor neuron degeneration. This would appear to be confirmed by the fact that there was no conspicuous increase of microglial cells and astrocytes in the motor cortex of control mice at any time. CONCLUSIONS: Activated microglial cells secrete a variety of pro-inflammatory and neurotoxic factors, such as TNF alpha, which could initiate apoptotic processes in the affected wobbler motor neurons, as reflected by caspase 3 activation, and thus, the neuroinflammatory processes might influence or exacerbate the neurodegeneration. Although it remains to be clarified whether the immune response is primary or secondary and how harmful or beneficial it is in the WR motor neuron disease, anti-inflammatory treatment might be considered. PMID- 26597540 TI - Degradation of 4-chloro 2-aminophenol using a novel combined process based on hydrodynamic cavitation, UV photolysis and ozone. AB - The degradation of 4-chloro 2-aminophenol (4C2AP), an acute toxic organic compound, has been studied using different approaches based on the hydrodynamic cavitation (HC) with orifice plate as cavitating device, photolysis (UV) and ozonation (O3). The dependency of extent of degradation on operating parameters like operating pressure (2-5 bar), initial pH (3-8) and temperature (30-38 degrees C) have been established initially to maximize the efficacy of hydrodynamic cavitation. Subsequently the degradation has been studied using combined treatment strategies as HC+UV, HC+O3, UV+O3 and HC+UV+O3 at the established optimum parameters of operating temperature as 30 degrees C, initial pH of 6 and inlet pressure of 4 bar. The maximum extent of degradation as 96.85% and 73.6% reduction in TOC has been obtained using hydrodynamic cavitation in combination with UV photolysis and ozonation under the optimized operating conditions. The degradation products of 4C2AP have been identified using GC-MS. The present work has clearly established the efficacy of combined treatment approach (HC+UV+O3) for the removal of organic pollutant for the first time. PMID- 26597541 TI - Preparation of cube micrometer potassium niobate (KNbO3) by hydrothermal method and sonocatalytic degradation of organic dye. AB - Cube micrometer potassium niobate (KNbO3) powder, as a high effective sonocatalyst, was prepared using hydrothermal method, and then, was characterized by X-ray diffractometer (XRD), scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDX). In order to evaluate the sonocatalytic activity of prepared KNbO3 powder, the sonocatalytic degradation of some organic dyes was studied. In addition, some influencing factors such as heat-treatment temperature and heat-treatment time on the sonocatalytic activity of prepared KNbO3 powder and catalyst added amount and ultrasonic irradiation time on the sonocatalytic degradation efficiency were examined by using UV-visible spectrophotometer and Total Organic Carbon (TOC) determination. The experimental results showed that the best sonocatalytic degradation ratio (69.23%) of organic dyes could be obtained when the conditions of 5.00 mg/L initial concentration, 1.00 g/L prepared KNbO3 powder (heat-treated at 400 degrees C for 60 min) added amount, 5.00 h ultrasonic irradiation (40 kHz frequency and 300 W output power), 100mL total volume and 25-28 degrees C temperature were adopted. Therefore, the micrometer KNbO3 powder could be considered as an effective sonocatalyst for treating non- or low-transparent organic wastewaters. PMID- 26597543 TI - A multicenter prospective quasi-experimental study on the impact of a transition oriented generic patient education program on health service participation and quality of life in adolescents and young adults. AB - OBJECTIVE: The aim of the study was to test the effects of a generic transition oriented patient education program on adolescents' health service participation and quality of life (QoL). METHODS: We conducted a controlled trial comparing participants of 29 transition workshops with treatment as usual in 274 adolescents (16.8 mean age, SD=1.76) diagnosed with type I diabetes (DM), cystic fibrosis (CF) or inflammatory bowel disease (IBD). A two-day transition workshop was carried out at 12 sites in Germany, focusing in standardized modules on adjustment to adult care settings, organization of future disease management, career choices and partnership. Study outcomes were health-related transition competence, self-efficacy, satisfaction with care, patient activation and QoL. Measures were assessed at baseline and six-month follow-up. RESULTS: Repeated measurement covariance analysis using age as a covariate showed that the transition workshop significantly affected transition competence, self-efficacy and satisfaction with school care six months post intervention. The intervention did not significantly affect patient activation and QoL. However, post-hoc analysis suggested different effects across conditions. CONCLUSION: The program has a positive effect on the competence of adolescents in the transition phase. PRACTICE IMPLICATIONS: The study demonstrates that an intervention can be effective in preparing adolescents with chronic conditions for transitions. PMID- 26597542 TI - Fetal stress-mediated hypomethylation increases the brain susceptibility to hypoxic-ischemic injury in neonatal rats. AB - BACKGROUND AND PURPOSE: Fetal hypoxia increases brain susceptibility to hypoxic ischemic (HI) injury in neonatal rats. Yet mechanisms remain elusive. The present study tested the hypothesis that DNA hypomethylation plays a role in fetal stress induced increase in neonatal HI brain injury. METHODS: Pregnant rats were exposed to hypoxia (10.5% O2) from days 15 to 21 of gestation and DNA methylation was determined in the developing brain. In addition, 5-aza-2'-deoxycytidine (5-Aza) was administered in day 7 pups brains and the HI treatment was conducted in day 10 pups. Brain injury was determined by in vivo MRI 48 h after the HI treatment and neurobehavioral function was evaluated 6 weeks after the HI treatment. RESULTS: Fetal hypoxia resulted in DNA hypomethylation in the developing brain, which persisted into 30-day old animals after birth. The treatment of neonatal brains with 5-Aza induced similar hypomethylation patterns. Of importance, the 5 Aza treatment significantly increased HI-induced brain injury and worsened neurobehavioral function recovery six weeks after the HI-treatment. In addition, 5-Aza significantly increased HIF-1alpha mRNA and protein abundance as well as matrix metalloproteinase (MMP)-2 and MMP-9, but decreased MMP-13 protein abundance in neonatal brains. Consistent with the 5-Aza treatment, hypoxia resulted in significantly increased expression of HIF-1alpha in both fetal and neonatal brains. Inhibition of HIF-1alpha blocked 5-Aza-mediated changes in MMPs and abrogated 5-Aza-induced increase in HI-mediated brain injury. CONCLUSION: The results suggest that fetal stress-mediated DNA hypomethylation in the developing brain causes programming of hypoxic-ischemic sensitive phenotype in the brain and increases the susceptibility of neonatal brain to hypoxic-ischemic injury in a HIF-1alpha-dependent manner. PMID- 26597544 TI - Short linear shadows connecting pulmonary segmental arteries to oblique fissures in volumetric thin-section CT images: comparing CT, micro-CT and histopathology. AB - OBJECTIVES: To retrospectively evaluate short linear shadows connecting pulmonary segmental arteries to oblique fissures in thin-section CT images and determine their anatomical basis. METHODS: CT scanning was performed on 108 patients and 11 lung specimens with no lung diseases around the oblique fissures or hila. Two radiologists evaluated the imaging. The parameters included length, thickness of short linear shadows, pulmonary segmental artery variations, and traction interlobar fissures, etc. RESULTS: The short linear shadows were not related to sex, age, or smoking history. The lengths of the short linear shadows were generally within 10 mm. The thicknesses of the short linear shadows ranged from 1 to 2 mm. Of the patients, 26.9 % showed pulmonary segmental artery variations; 66.7 % of short linear shadows pulled oblique fissures. In three-dimensional images, the short linear shadows appeared as arc planes, with one side edge connected to the oblique fissure, one side edge connected to a pulmonary segmental artery. On the tissue slices, the short linear shadow exhibited a band structure composed of connective tissues, small blood vessels, and small lymphatic vessels. CONCLUSIONS: Short linear shadows are a type of normal intrapulmonary membranes and can maintain the integrity of the oblique fissures and hilar structure. KEY POINTS: * Volumetric thin-section CT scanning is commonly used to study lung anatomy. * Short linear shadows are a common intrapulmonary structure in thin-section CT. * Short linear shadows correlate with band structures on the correlative tissue slices. PMID- 26597545 TI - Magnetic resonance enterography/enteroclysis in acquired small bowel diverticulitis and small bowel diverticulosis. AB - PURPOSE: Small bowel (SB) diverticulosis is a rare disorder that may entail serious complications, including SB diverticulitis. Both are often missed in imaging. Magnetic resonance enterography/enteroclysis (MRE) is increasingly used to assess SB disease; awareness of the appearance of SB diverticulitis is essential to ensure appropriate management. Our aim was to systematically describe imaging characteristics of SB diverticulosis and diverticulitis in MRE. METHODS: This retrospective, HIPAA-compliant study identified 186 patients with suspected SB diverticulosis/diverticulitis in medical databases of two tertiary medical centres between 2005 and 2011. Patients with surgically confirmed diagnoses of SB diverticulosis/diverticulitis were included. Two observers analyzed MR images for the presence, location, number, and size of diverticula, wall thickness, and mural and extramural patterns of inflammation. RESULTS: Seven patients were recruited. MRI analysis showed multiple diverticula in all (100 %). Diverticular size ranged from 0.5 to 6 cm. Prevalence of diverticula was higher in the proximal than the distal SB (jejunum 86 %, ileum 57 %, distal ileum43%). Diverticulitis occurred in 3/7 patients (43 %) showing asymmetric bowel wall thickening and focal mesenteric inflammation. CONCLUSION: SB diverticulitis demonstrates characteristic MRE imaging features to distinguish this rare disorder from more common diseases. Asymmetric, focal mesenteric and mural inflammation and presence of multiple diverticula are keys to diagnosis. KEY POINTS: * Small bowel diverticulosis and diverticulitis is rare and often missed in imaging * Acquired small bowel diverticula are variable in size and number * Small bowel diverticulitis demonstrates characteristic features on MR enterography/enteroclysis * A focal or segmental asymmetric small bowel inflammation should prompt the search for diverticula. PMID- 26597546 TI - Mineral particles modulate osteo-chondrogenic differentiation of embryonic stem cell aggregates. AB - Pluripotent stem cell aggregates offer an attractive approach to emulate embryonic morphogenesis and skeletal development. Calcium phosphate (CaP) based biomaterials have been shown to promote bone healing due to their osteoconductive and potential osteoinductive properties. In this study, we hypothesized that incorporation of CaP-coated hydroxyapatite mineral particles (MPs) within murine embryonic stem cell (ESC) aggregates could promote osteo-chondrogenic differentiation. Our results demonstrated that MP alone dose-dependently promoted the gene expression of chondrogenic and early osteogenic markers. In combination with soluble osteoinductive cues, MPs enhanced the hypertrophic and osteogenic phenotype, and mineralization of ESC aggregates. Additionally, MPs dose dependently reduced ESC pluripotency and thereby decreased the size of teratomas derived from MP-incorporated ESC aggregates in vivo. Our data suggested a novel yet simple means of using mineral particles to control stem cell fate and create an osteochondral niche for skeletal tissue engineering applications. STATEMENT OF SIGNIFICANCE: Directing stem cell differentiation and morphogenesis via biomaterials represents a novel strategy to promote cell fates and tissue formation. Our study demonstrates the ability of calcium phosphate-based mineral particles to promote osteochondrogenic differentiation of embryonic stem cell aggregates as well as modulate teratoma formation in vivo. This hybrid biomaterial-ESC aggregate approach serves as an enabling platform to evaluate the ability of biomaterials to regulate stem cell fate and regenerate functional skeletal tissues for clinical applications. PMID- 26597547 TI - Silica particles with immobilized protein molecules and polymer brushes. AB - In this research thermo-responsive polymer brushes and protein molecules are immobilized on the surfaces of silica particles by covalent bonds. Pyridyl disulfide functionalized silica particles are prepared by surface chemical reactions, and thiol-terminated poly(oligo(ethylene glycol) monomethyl ether methacrylate) (POEGMA) and bovine serum albumin (BSA) molecules are grafted to the silica particles by thiol-disulfide exchange reactions. X-ray photoelectron spectroscopy, thermogravimetric analysis, dynamic light scattering, confocal laser scanning microscopy, far-UV circular dichroism and transmission electron microscopy are employed to characterize the polymer/protein mixed layers on silica particles. The POEGMA brushes not only protect the protein molecules but also improve the dispersibility of the hybrid particles in aqueous solution. The activity of the immobilized BSA protein can be controlled by the thermo responsive POEGMA brushes. At a temperature below the lower critical solution temperature (LCST) of POEGMA, BSA activity is not affected by polymer brushes; however, BSA activity decreases significantly at a temperature above the LCST of POEGMA. STATEMENT OF SIGNIFICANCE: In this research, both protein molecules and polymer brushes were anchored to the silica particles by highly efficient thiol disulfide exchange reaction, and their grafting density can easily be determined by UV-vis. Owing to the temperature-sensitive nature of the grafted polymer brushes, the protein molecules can be protected by the collapsed polymer brushes above the LCST, and their catalytic activity can be controlled. Moreover, the protein molecules on silica particles can be easily separated from the solution and can be reused. PMID- 26597548 TI - Quantifying consistent individual differences in habitat selection. AB - Habitat selection is a fundamental behaviour that links individuals to the resources required for survival and reproduction. Although natural selection acts on an individual's phenotype, research on habitat selection often pools inter individual patterns to provide inferences on the population scale. Here, we expanded a traditional approach of quantifying habitat selection at the individual level to explore the potential for consistent individual differences of habitat selection. We used random coefficients in resource selection functions (RSFs) and repeatability estimates to test for variability in habitat selection. We applied our method to a detailed dataset of GPS relocations of brown bears (Ursus arctos) taken over a period of 6 years, and assessed whether they displayed repeatable individual differences in habitat selection toward two habitat types: bogs and recent timber-harvest cut blocks. In our analyses, we controlled for the availability of habitat, i.e. the functional response in habitat selection. Repeatability estimates of habitat selection toward bogs and cut blocks were 0.304 and 0.420, respectively. Therefore, 30.4 and 42.0 % of the population-scale habitat selection variability for bogs and cut blocks, respectively, was due to differences among individuals, suggesting that consistent individual variation in habitat selection exists in brown bears. Using simulations, we posit that repeatability values of habitat selection are not related to the value and significance of beta estimates in RSFs. Although individual differences in habitat selection could be the results of non-exclusive factors, our results illustrate the evolutionary potential of habitat selection. PMID- 26597550 TI - Comparison of Tibial Tunnel Techniques in Posterior Cruciate Ligament Reconstruction: C-Arm Versus Anatomic Fovea Landmark. AB - PURPOSE: To evaluate the accuracy of the posterior cruciate ligament (PCL) fovea landmark against conventional fluoroscopic pin placement retrospectively using 3 dimensional computed tomography (3D CT). METHODS: This retrospective comparison focused on the tibial tunnel locations determined in consecutive 26 patients using the fluoroscopic imaging technique (group I) and in consecutive 23 patients using the PCL fovea landmark technique without the help of the fluoroscopy (group II) for tibial tunnel formation. The 3D surface-modeled CT images that appropriately located the position of the PCL fovea on the tibial plateau were used. Ratios between total length of the fovea and length of the tunnel center from the medial border (coronal) and posterior edge (sagittal) were evaluated. RESULTS: The ratios between sagittal tunnel length and total sagittal length for groups I and II were 35.4% +/- 12.2% and 44.1% +/- 23.1%, respectively (P = .07). The ratios between the coronal tunnel lengths and total coronal lengths for groups I and II were 47.3% +/- 9.2% and 57.3% +/- 18.1%, respectively: group II showed a more laterally positioned tibial tunnel than did group I (P = .03). CONCLUSIONS: A more laterally located tibial tunnel was produced using the PCL fovea landmark technique. However, the differences in centers were small and probably not clinically relevant. Therefore, the PCL fovea landmark technique might be an alternative method to the fluoroscopic imaging technique for locating the anatomic tibial tunnel during transtibial PCL reconstruction. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 26597551 TI - [Type 3 congenital arteriovenous malformation: Complex multiple direct arteriovenous anastomoses affecting the large retinal vessels]. PMID- 26597549 TI - Phylogenetic and ecological factors impact the gut microbiota of two Neotropical primate species. AB - Recent studies suggest that variation in diet across time and space results in changes in the mammalian gut microbiota. This variation may ultimately impact host ecology by altering nutritional status and health. Wild animal populations provide an excellent opportunity for understanding these interactions. However, compared to clinical studies, microbial research targeting wild animals is currently limited, and many published studies focus only on a single population of a single host species. In this study we utilize fecal samples from two species of howler monkey (Alouatta pigra and A. palliata) collected at four sites to investigate factors influencing the gut microbiota at three scales: taxonomic (host species), ecosystemic (forest type), and local (habitat disturbance/season). The results demonstrate that the effect of host species on the gut microbiota is stronger than the effect of host forest type, which is stronger than the effect of habitat disturbance or seasonality. Nevertheless, within host species, gut microbiota composition differs in response to forest type, habitat disturbance, and season. Variations in the effect size of these factors are associated both with host species and environment. This information may be beneficial for understanding ecological and evolutionary questions associated with Mesoamerican howler monkeys, as well as determining conservation challenges facing each species. These mechanisms may also provide insight into the ecology of other species of howler monkeys, non-human primates, and mammals. PMID- 26597552 TI - Indications and clinical outcomes of capsular tension ring implantation in phacoemulsification surgery at a tertiary teaching hospital: A review of 4316 cataract surgeries. AB - PURPOSE: To reveal the indications, clinical outcomes and complications of capsular tension ring (CTR) implantation in a series of consecutive phacoemulsification surgeries during a three-year interval. METHODS: A review of all patients undergoing cataract surgery with insertion of a CTR between 2010 and 2013 was conducted at our tertiary teaching ophthalmology department. The demographic details of patients, indications and clinical outcomes of CTR implantation were evaluated. RESULTS: Between 2010 and 2013, 4316 phacoemulsification surgeries were performed and of these surgeries CTR implantation was done in 41 eyes of 36 patients. The indications of CTR implantation were zonular dehiscence or weakness associated with mature cataract (29.2%), trauma (24.3%), pseudoexfoliation syndrome (19.5%), retinitis pigmentosa (14.6%), degenerative myopia (9.7%), and lens coloboma (2.4%). Posterior chamber intraocular lens (PCIOL) was implanted into the capsular bag in all eyes. Dislocation of PCIOL was not observed in any case. Transient IOP increased in 5 eyes (12%) and corneal edema in 14 eyes were noted. Posterior capsular opasification in 1 eye (2.4%), anterior capsule phimosis in 1 eye (2.4%) and cystoid macular edema in 1 eye (2.4%) were detected as late complications. CONCLUSION: The frequency of CTR implantation was 0.97% due to our study. In complicated cataract surgeries, CTR implantation seems to improve clinical outcomes. PMID- 26597553 TI - [Diabetes and reticular macular dystrophy]. PMID- 26597554 TI - [Vascular factors in glaucoma]. AB - The exact pathophysiology of glaucoma is not fully understood. Understanding of the vascular pathophysiology of glaucoma requires: knowing the techniques for measuring ocular blood flow and characterizing the topography of vascular disease and the mechanisms involved in this neuropathy. A decreased mean ocular perfusion pressure and a loss of vascular autoregulation are implicated in glaucomatous disease. Early decrease in ocular blood flow has been identified in primary open angle glaucoma and normal pressure glaucoma, contributing to the progression of optic neuropathy. The vascular damage associated with glaucoma is present in various vascular territories within the eye (from the ophthalmic artery to the retina) and is characterized by a decrease in basal blood flow associated with a dysfunction of vasoregulation. PMID- 26597555 TI - [Double cilioretinal artery]. PMID- 26597556 TI - [Uveitis in children: Report of 10 cases]. PMID- 26597557 TI - Treatment Options for Pediatric Obstructive Sleep Apnea. AB - There are a variety of therapies available for the treatment of pediatric obstructive sleep apnea syndrome (OSAS). In children with enlarged adenoids or tonsils, adenotonsillectomy (AT) is the preferred treatment, but other surgical options include partial tonsillectomy and lingual tonsillectomy. In specific populations, craniofacial or bariatric surgery may be indicated, and tracheostomy should be reserved for cases where there is no other therapeutic option. Positive airway pressure (PAP) is the most effective non-surgical therapy for OSAS as it can be successfully used in even cases of severe OSAS. Nasal steroids and leukotriene receptor antagonists may be used in the treatment of mild or moderate OSAS. Rapid maxillary expansion and dental appliances may be effective in select populations with dental problems. Other non-surgical therapies, such as positional therapy, supplemental oxygen, and weight loss have not been shown to be effective in most pediatric populations. PMID- 26597558 TI - Organizational Behavior: A Brief Overview and Safety Orientation. AB - Organizational Behavior (OB) is a discipline of social science that seeks explanations for human behavior in organizations. OB draws on core disciplines such as psychology, sociology, anthropology, economics, communication, and law to create and investigate multilevel explanations of why people engage in particular behaviors, and which behaviors under which circumstances lead to better outcomes in organizations. Created using an applied or pragmatic lens and tested with a wide range of both quantitative and qualitative methodologies, most OB theories and research have direct implications for managers and for other organizational participants. Not surprisingly, one focal area of OB research concerns safety in organizations, and a growing body of safety-oriented literature in OB is based on data collected during simulation training across a variety of organizations such as hospitals, airlines, nuclear power plants, and other high reliability organizations. PMID- 26597559 TI - Ediacaran Marine Redox Heterogeneity and Early Animal Ecosystems. AB - Oxygenation has widely been viewed as a major factor driving the emergence and diversification of animals. However, links between early animal evolution and shifts in surface oxygen levels have largely been limited to extrapolation of paleoredox conditions reconstructed from unfossiliferous strata to settings in which contemporaneous fossils were preserved. Herein, we present a multi-proxy paleoredox study of late Ediacaran (ca. 560-551 Ma) shales hosting the Miaohe Konservat-Lagerstatte of South China and, for comparison, equivalent non-fossil bearing shales at adjacent sections. For the fossiliferous strata at Miaohe there is geochemical evidence for anoxic conditions, but paleontological evidence for at least episodically oxic conditions. An oxygen-stressed environment is consistent with the low diversity and simple morphology of Miaohe Biota macrofossils. However, there is no evidence for euxinic (anoxic and sulphidic) conditions for the fossiliferous strata at Miaohe, in contrast to adjacent unfossiliferous sections. Our results indicate that Ediacaran marine redox chemistry was highly heterogeneous, even at the kilometre-scale. Therefore, our study provides direct-rather than inferred-evidence that anoxia played a role in shaping a landmark Ediacaran ecosystem. If the anoxic conditions characteristic of the studied sections were widespread in the late Neoproterozoic, environmental stress would have hindered the development of complex ecosystems. PMID- 26597560 TI - Streptomyces lonarensis sp. nov., isolated from Lonar Lake, a meteorite salt water lake in India. AB - A novel alkaliphilic actinomycete, strain NCL716(T), was isolated from a soil sample collected from the vicinity of Lonar Lake, an alkaline salt water meteorite lake in Buldhana district of Maharashtra State in India. The strain was characterised using a polyphasic taxonomic approach which confirmed that it belongs to the genus Streptomyces. Growth was observed over a pH range of 7-11 at 28 degrees C. The cell wall was found to contain LL-diaminopimelic acid and traces of meso-diaminopimelic acid. The major fatty acid components were identified as iso-C16:0 (46.8 %), C17:1 (12.4 %), anteiso-C15:0 (5.1 %) and anteiso-C17:1 (4.8 %). The major polar lipids were identified as diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol and phosphatidylinositol. The major menaquinones were determined to be MK-9 (H6) (70.3 %), MK-9 (H4) (15.5 %) and MK-9 (H8) (7.2 %). The G+C content of the DNA of the type strain was determined to be 71.4 mol %. The 16S rRNA gene sequence has been deposited in GenBank with accession number FJ919811. Although the 16S rRNA gene sequence analysis revealed that strain NCL716(T) shares >99 % similarity with that of Streptomyces bohaiensis strain 11A07(T), DNA-DNA hybridization revealed only 33.2 +/- 3.0 % relatedness between them. Moreover, these two strains can be readily distinguished by some distinct phenotypic characteristics. Hence, on the basis of phenotypic and genetic analyses, it is proposed that strain NCL716(T) represents a novel species of the genus Streptomyces, for which the name Streptomyces lonarensis sp. nov., is proposed. The type strain is NCL 716(T) (=DSM 42084(T) = MTCC 11708(T) = KCTC 39684(T)). PMID- 26597561 TI - Erratum to: Roseovarius algicolus sp. nov., isolated from culture fluid of Cochlodinium polykrikoides. PMID- 26597562 TI - Reply to T.J. Cole & M. Cortina Borja. PMID- 26597563 TI - Efficacy of diffusion-weighted MRI in the differentiation of all liver hydatid cyst types. AB - INTRODUCTION: The aim of this study was to evaluate the efficacy of diffusion weighted images (DWIs) in the differentiation of hydatid cysts (HCs) of the liver. METHODS: In this prospective study, 54 patients with 92 HC lesions were evaluated. The mean apparent diffusion coefficient (ADC) values of each lesion were calculated using the ADC maps derived from the DWIs at b-values of 50, 500 and 1000 s/mm(2). We compared the mean ADC values of the different HC types, which had already been classified using the sonographic criteria. A receiver operator curve (ROC) analysis was used for determining the diagnostic performance of the ADC values of the HC types. RESULTS: When the mean ADC values of each type of HC were compared using each of the b-values, no statistically significant differences were obtained between (cystic echinococcosis) CE1 and CE2 or CE3, CE2 and CE3, CE3 and CE4, or CE4 and CE5. In addition, the mean ADC values of CE1 and CE2 were significantly higher than those of CE4 and CE5. For discrimination between types CE1, CE2 and CE3, and types CE4 and CE5, the sensitivity and specificity values were, respectively, 75.9 and 89.5 for the b50 DWI, 87.0 and 86.8 for the b500 DWI, and 75.9 and 89.5 for the b1000 DWI in the ROC analysis. CONCLUSION: Diffusion-weighted imaging may be useful for providing additional data to determine the type of HC, and for differentiating types CE1, CE2 and CE3 from types CE4 and CE5. PMID- 26597564 TI - Merits of partial shielding in dumping sediment spoils. AB - The commonly adopted method of dumping dredge spoil at sea using split-hull barges leads to considerable sediment loss to the water column and a subsequent dispersion of fine material that can pose a risk to sensitive "downstream" habitats such as coral reefs. Containing sediment loads using stitched closed geotextile bags is practiced for minimizing loss of contaminated sediment, but is expensive in terms of operational efficiency. Following promising observations from initial laboratory trials, the plunging of partially shielded sediment loads, released on open sea, was studied. The partial shielding was achieved with rigid, open containers as well as flexible, open bags. The loss of sediment from these modes of shielding was measured, and it was observed that even limited and unstitched shielding can be effective in debilitating the entrainment of water into the descending load. In particular, long-sleeved flexible bags practically self-eliminated the exposure of the load and thus losses. PMID- 26597566 TI - Inhibitory effect and cell damage on bacterial flora of fish caused by chitosan, nisin and sodium lactate. AB - The effect of the combined use of chitosan, nisin and sodium lactate on the growth of Listeria innocua, Shewanella putrefaciens and psychrophilic bacteria isolated from fish was investigated in broth by means of minimum inhibitory concentrations (MIC). Furthermore, the sites of cell-injury caused by mentioned antimicrobials and their combinations on L. innocua and S. putrefaciens were studied. MIC of antimicrobial mixtures were evaluated by Berembaum design and check board method. Antimicrobials' sites of injury were investigated by the evaluation of cell constituents' release, cell surface hydrophobicity and differential scanning calorimetry. Results depended on antimicrobial used; several combinations inhibited the growth of L. innocua and S. putrefaciens and all combinations inhibited psychrophilic bacteria. Besides, some mixtures showed synergistic effects. All the mixtures affected ribosomes and DNA of the studied bacteria. Regarding cellular envelope, antimicrobials acted according to the structural characteristics of target microorganisms. Cell damage was higher when antimicrobials were combined, which could explain the observed synergistic effects. This study demonstrates and justifies the synergistic action of chitosan, nisin and sodium lactate on the inhibition of microorganisms related to fish spoilage and remarks the promissory use of the synergic combination of antimicrobials for fish preservation. PMID- 26597565 TI - Assessing Drug Consumption Behavior With the Heidelberger Drogenbogen (Heidelberg Drug Scales): Reliabilities, Validities, and Cut-Off Criteria. AB - BACKGROUND: The Heidelberger Drogenbogen (HDB) is a German language assessment of substance-specific knowledge and consumption patterns of the illicit psychoactive substances cannabis, MDMA (ecstasy), amphetamines, cocaine, and hallucinogens. The behavior modules for each of these five drugs/drug groups allow for a diagnostic evaluation of the extent of harmful consumption behavior. Each of the five modules represents a single standardized test. OBJECTIVES: This paper outlines several statistical parameters, Cronbach's alpha, retest reliabilities, as well as numerous validity and cut-off-criteria of the behavioral modules. METHODS: Participants (N = 4,794) were recruited at schools, universities, in subcultural contexts, and in institutions of substance abuse treatment. RESULTS: Internal consistencies range from = .68 to .79 while test-retest reliabilities between .87 and .94 were found. The behavior modules of the HDB can discriminate between populations with and without clinical levels of substance use. Furthermore, this measure has incremental validity and higher diagnostic accuracy over competing measures. CONCLUSIONS: The behavior modules of the HDB are reliable and valid measures of substance use and misuse. PMID- 26597567 TI - Optimization of Regeneration Conditions and In Vitro Propagation of Sideritis Stricta Boiss & Heldr. AB - In this study the micropropagation of endemic species Sideritis stricta was investigated. Leaf segments and shoot explants (hypocotyl, single node and shoot tips) taken from in vitro growing plantlets and cultured on MS and B5 media containing different growth regulators combinations BAP (0.0, 1.0, 2.0 and 3.0mg/l) and NAA (0.0, 0.1 and 0.5mg/l). MS and B5 media supplemented with BAP (1.0, 2.0 and 3.0mg/l) and NAA (0.1mg/l) combinations or only BAP and kinetin (2.0 and 3.0mg/l) were used at the subculture experiments of shoots and MS and B5 media supplemented with different concentrations of IBA (0.0, 1.5, 3.0, 4.5 and 10.mg/l) were used at the rooting experiments. S. stricta seeds germinated at the rate of 100% when the seed coat was removed and endoperm with embryo part cultured on B5 medium. The single node explants taken from in vitro germinated and grown 30-40 days plantlets on B5 medium have been determined as the most successful explant at all used hormone combinations. B5 medium supplemented with 1.0mg/l BAP+0.1mg/l NAA and 2.0mg/l BAP+0.5mg/l NAA was determined as the most effective medium on shoot formation. At the first and second subculture, the highest shoot formation was maintained on medium supplemented with 1.0mg/l BAP+0.1mg/l NAA and the number of shoots per explant were 4 and 2.11, respectively. The highest multiplication rate has been determined as 33.76 at the end of second subculture. The best rooting was achieved on B5 medium supplemented with 4.5mg/l IBA. The rooted shoots were successfully acclimatized to outdoor conditions and survival rate was determined as 90%. PMID- 26597568 TI - Functional properties of chitosan built nanohydrogel with enhanced glucose sensitivity. AB - A new approach to design multifunctional chitosan based nanohydrogel with enhanced glucose sensitivity, stability, drug loading and release profile are reported. Two approaches were followed for functionalization of chitosan based nanohydrogel with 3-APBA via EDC and 3-APTES. The effective functionalization, structure and morphology of Chitosan based IPN respectively were confirmed by FTIR, SEM and AFM. At physiological conditions, the glucose-induced volume phase transition and release profile of the model drug Alizarin Red with 1,2-diol structure (comparative to insulin as a drug as well as a dye for bio separation) were studied at various glucose concentrations, pH and ionic strengths. The results suggested a new concept for diabetes treatment and diols sensitivity in view of their potential hi-tech applications in self-regulated on-off response to the treatment (drug delivery and bio separation concurrently). PMID- 26597570 TI - An efficacy and safety comparison between different stentriever designs in acute ischaemic stroke: a systematic review and meta-analysis. AB - AIM: To assess the recanalisation rates and long-term functional outcomes of the Solitaire and Trevo devices; to compare these results to those from the Solitaire With the Intention For Thrombectomy (SWIFT) trial and TREVO 2 studies; and to assess for statistical differences in the outcomes between the two devices. MATERIALS AND METHODS: A systematic review and meta-analysis of studies that utilised stentrievers in the treatment of acute ischaemic stroke was conducted. The results were compared to those of the SWIFT and TREVO 2 trials and outcome differences between Trevo (Stryker, Kalamazoo, Michigan, USA) and Solitaire (ev3/Covidien, Irvine, California, USA) were analysed statistically. RESULTS: Solitaire had a lower mortality rate compared to Trevo (16.2% [95% confidence interval {CI}: 13.1%, 19.8%] versus 22.2% [95% CI: 10.8%, 40.2%]) and achieved a higher rate of functional independence (52.1% [95% CI: 46.3%, 57.8%] versus 47.6% [95% CI: 36.7%, 58.8%]). Statistical tests, however, failed to demonstrate significant differences in either functional outcomes or 3-month mortality rates. No significant differences were noted in weighted mean recanalisation rates between the Solitaire and Trevo groups. CONCLUSION: Stentrievers achieve a high rate of recanalisation and functional independence in acute ischaemic stroke and have a relatively good safety profile. No significant differences in functional outcomes, mortality, and symptomatic intra-cranial haemorrhage could be demonstrated between two popular stentrievers designs, namely Trevo and Solitaire. PMID- 26597569 TI - Consensus statement on prevention and detection of ovarian hyperstimulation syndrome. AB - BACKGROUND: Ovarian hyperstimulation syndrome is an important condition with considerable morbidity and a small risk of mortality, which most commonly results as an iatrogenic condition following follicular stimulation of the ovaries. AIM: To produce evidence-based and consensus statements on the prevention and detection of ovarian hyperstimulation syndrome (OHSS). METHOD: The CREI Consensus Group met in 2008 and identified issues for inclusion and review. Review of the available evidence was conducted and consensus statements prepared. Areas of dissent of expert opinion and for further research were noted. RESULTS: The group considered that there is a need for standardisation of the definition and classification of the clinical syndrome of OHSS to allow further conclusive research. Interventions with evidence of effect in reducing OHSS include the use of metformin in women with PCOS, use of GnRH antagonist rather than GnRH agonist and use of GnRH agonist triggers in GnRH antagonist stimulation cycles. The consensus view was that reducing the dose of FSH, freezing all embryos and transferring a single embryo were appropriate interventions to reduce OHSS. Agreement could not be reached on coasting, the lowest number of oocytes to consider freezing all embryos and management after cancellation of oocyte collection. CONCLUSION: OHSS is a serious condition for which there are a number of proven preventative strategies. OHSS is an area requiring ongoing research and development of a universally agreed definition will allow development of optimal prevention strategies and facilitate improved early detection of women at risk. PMID- 26597571 TI - MSAIndelFR: a scheme for multiple protein sequence alignment using information on indel flanking regions. AB - BACKGROUND: The alignment of multiple protein sequences is one of the most commonly performed tasks in bioinformatics. In spite of considerable research and efforts that have been recently deployed for improving the performance of multiple sequence alignment (MSA) algorithms, finding a highly accurate alignment between multiple protein sequences is still a challenging problem. RESULTS: We propose a novel and efficient algorithm called, MSAIndelFR, for multiple sequence alignment using the information on the predicted locations of IndelFRs and the computed average log-loss values obtained from IndelFR predictors, each of which is designed for a different protein fold. We demonstrate that the introduction of a new variable gap penalty function based on the predicted locations of the IndelFRs and the computed average log-loss values into the proposed algorithm substantially improves the protein alignment accuracy. This is illustrated by evaluating the performance of the algorithm in aligning sequences belonging to the protein folds for which the IndelFR predictors already exist and by using the reference alignments of the four popular benchmarks, BAliBASE 3.0, OXBENCH, PREFAB 4.0, and SABRE (SABmark 1.65). CONCLUSIONS: We have proposed a novel and efficient algorithm, the MSAIndelFR algorithm, for multiple protein sequence alignment incorporating a new variable gap penalty function. It is shown that the performance of the proposed algorithm is superior to that of the most-widely used alignment algorithms, Clustal W2, Clustal Omega, Kalign2, MSAProbs, MAFFT, MUSCLE, ProbCons and Probalign, in terms of both the sum-of-pairs and total column metrics. PMID- 26597572 TI - The Chlamydia trachomatis Ctad1 invasin exploits the human integrin beta1 receptor for host cell entry. AB - Infection of human cells by the obligate intracellular bacterium Chlamydia trachomatis requires adhesion and internalization of the infectious elementary body (EB). This highly complex process is poorly understood. Here, we characterize Ctad1 (CT017) as a new adhesin and invasin from C. trachomatis serovar E. Recombinant Ctad1 (rCtad1) binds to human cells via two bacterial SH3 domains located in its N-terminal half. Pre-incubation of host cells with rCtad1 reduces subsequent adhesion and infectivity of bacteria. Interestingly, protein coated latex beads revealed Ctad1 being an invasin. rCtad1 interacts with the integrin beta1 subunit on human epithelial cells, and induces clustering of integrins at EB attachment sites. Receptor activation induces ERK1/2 phosphorylation. Accordingly, rCtad1 binding to integrin beta1-negative cells is significantly impaired, as is the chlamydial infection. Thus interaction of C. trachomatis Ctad1 with integrin beta1 mediates EB adhesion and induces signaling processes that promote host-cell invasion. PMID- 26597574 TI - Variation in costs among surgeons and hospitals in Pediatric tympanostomy tube placement. AB - OBJECTIVES/HYPOTHESIS: 1) Identify the major expenses for outpatient pediatric tympanostomy tube placement in a multihospital network. 2) Compare differences for variations in costs among hospitals and surgeons. METHODS: An observational cohort study in a multihospital network using a standardized activity-based accounting system to determine hospital costs for tympanostomy tube placement from February 2011 to January 2015. Children aged 6 months to less than 3 years old who underwent same-day surgery (SDS) for tympanostomy tubes at 15 hospital facilities were included. Subjects with additional procedures were excluded. Hospital costs were subdivided into categories including operating room (OR), SDS preoperative, SDS postoperative, postanesthesia care unit, anesthesia, pharmacy, and OR supplies. RESULTS: The study cohort included 5,623 patients undergoing tympanostomy tube placement by 67 surgeons. Mean cost per surgery was $769 +/- $3. Significant variations (P < 0.001) in mean cost per procedure were identified by hospital (range $1212 +/- $38 to $509 +/- $11) and by surgeon (range $1330 +/- $75 to $660 +/- $11). Operating room and SDS preoperative were the greatest expenditures; each category accounted for over 30% of overall costs. Pharmacy costs and OR costs were some of the major drivers of cost variation among surgeons. CONCLUSION: This study demonstrates that OR and SDS preoperative costs accounted for the greatest expenditure in tympanostomy tube placement, and significant variation exists among surgeons and hospitals within a multihospital network. Further research is needed to elucidate factors accounting for such variation in cost and the overall impact on patient outcomes. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:1935-1939, 2016. PMID- 26597575 TI - Evolution and Biological Roles of Alternative 3'UTRs. AB - More than half of human genes use alternative cleavage and polyadenylation to generate alternative 3' untranslated region (3'UTR) isoforms. Most efforts have focused on transcriptome-wide mapping of alternative 3'UTRs and on the question of how 3'UTR isoform ratios may be regulated. However, it remains less clear why alternative 3'UTRs have evolved and what biological roles they play. This review summarizes our current knowledge of the functional roles of alternative 3'UTRs, including mRNA localization, mRNA stability, and translational efficiency. Recent work suggests that alternative 3'UTRs may also enable the formation of protein protein interactions to regulate protein localization or to diversify protein functions. These recent findings open an exciting research direction for the investigation of new biological roles of alternative 3'UTRs. PMID- 26597577 TI - Effectiveness of cold therapy in reducing pain, trismus, and oedema after impacted mandibular third molar surgery: a randomized, self-controlled, observer blind, split-mouth clinical trial. AB - Cold therapy is a conventional and widely used modality for reducing pain, trismus, and oedema after dentoalveolar surgeries. However, information reported in the literature on its effectiveness is insufficient and controversial. This study was performed to evaluate the effect of local cold application in reducing pain, trismus, and swelling after impacted mandibular third molar surgery. Thirty patients (seven males and 23 females) with bilateral symmetrical mandibular impacted third molars were enrolled in this randomized, self-controlled, observer blind clinical trial. The patients were aged between 18 and 30 years. After surgical removal of the tooth on one side (intervention), ice pack therapy was given for 24h after surgery; for the other side (control), no cold therapy was given. The time interval between the two surgeries was at least 4 weeks. The amount of pain, trismus, and facial swelling was measured on days 2 and 7 postoperative, and patient satisfaction with the cold therapy vs. no cold therapy was assessed. The amount of pain, trismus, and facial swelling, and the extent of patient satisfaction were not significantly different between the intervention and control sides. Cold therapy had no beneficial effects on postoperative sequelae after impacted mandibular third molar surgery. PMID- 26597576 TI - HSF1: Guardian of Proteostasis in Cancer. AB - Proteomic instability is causally related to human diseases. In guarding proteome stability, the heat shock factor 1 (HSF1)-mediated proteotoxic stress response plays a pivotal role. Contrasting with its beneficial role of enhancing cell survival, recent findings have revealed a compelling pro-oncogenic role for HSF1. However, the mechanisms underlying the persistent activation and function of HSF1 within malignancy remain poorly understood. Emerging evidence reveals that oncogenic signaling mobilizes HSF1 and that cancer cells rely on HSF1 to avert proteomic instability and repress tumor-suppressive amyloidogenesis. In aggregate, these new developments suggest that cancer cells endure chronic proteotoxic stress and that proteomic instability is intrinsically associated with the malignant state, a characteristic that could be exploited to combat cancer. PMID- 26597578 TI - Inhibition of Tumor Growth and Metastasis in Pancreatic Cancer Models by Interference With CD44v6 Signaling. AB - BACKGROUND & AIMS: Cancer cells with high metastatic potential and stem cell-like characteristics express the cell surface marker CD44. CD44 isoforms that include the v6 exon are co-receptors for the receptor tyrosine kinases MET and Vascular Endothelial Growth factor Receptor-2 (VEGFR-2). We studied CD44v6 signaling in several pancreatic cancer cell lines, and its role in tumor growth and metastasis in several models of pancreatic cancer. METHODS: We analyzed the effects of v6 peptides that interfere with the co-receptor functions of CD44v6 for MET and VEGFR-2 in tumors and metastases grown from cells that express different CD44 isoforms, including CD44v6. The peptides were injected into rats with syngeneic tumors and mice with orthotopic or xenograft tumors. We also tested the effects of the peptides in mice with xenograft tumors grown from patient tumor samples and mice that express an oncogenic form of RAS and develop spontaneous pancreatic cancer (KPC mice). We measured levels of CD44v6 messenger RNA (mRNA) in pancreatic cancer tissues from 136 patients. RESULTS: Xenograft tumors grown from human cancer cells injected with v6 peptides were smaller and formed fewer metastases in mice. The v6 peptide was more efficient than the MET inhibitor crizotinib and/or the VEGFR-2 inhibitor pazopanib in reducing xenograft tumor growth and metastasis. Injection of KPC mice with the v6 peptide increased their survival time. Injection of mice and rats bearing metastases with the v6 peptide induced regression of metastases. Higher levels of CD44v6 mRNA in human pancreatic tumor tissues were associated with increased expression of MET, tumor metastasis, and shorter patient survival times. CONCLUSIONS: Peptide inhibitors of CD44v6 isoforms block tumor growth and metastasis in several independent models of pancreatic cancer. The v6 peptides induced regression of metastases. Levels of CD44v6 mRNA are increased, along with those of MET mRNA, in patients with metastatic pancreatic tumors, compared with nonmetastatic tumors; the increased levels correlated with shorter patient survival time. PMID- 26597579 TI - Introduction--Neuroendocrine neoplasms of the lung. PMID- 26597580 TI - Diagnostic difficulties with the diagnosis of small cell carcinoma of the lung. AB - Small cell carcinoma of the lung (SCLC) is a well characterized form of lung cancer that is frequently already metastatic at diagnosis. Thus, patients with SCLC are usually treated with chemotherapy, and therefore emphasis has been placed on distinguishing that tumor from squamous cell carcinomas, large cell carcinomas and other pulmonary neoplasms that can more often be managed surgically. SCLC can be readily and accurately diagnosed in biopsy specimens or cytological preparations, but in selected cases, it can pose difficult diagnostic dilemmas. This review discusses selected problems encountered during the pathologic diagnosis of SCLC, including its distinction from other neuroendocrine lesions such as large cell neuroendocrine carcinoma and "carcinoid" tumors." The role of immunohistology is also considered in this context. PMID- 26597581 TI - Reduced Field of View Diffusion-Weighted Imaging in the Evaluation of Congenital Spine Malformations. AB - BACKGROUND: Reduced field of view diffusion-weighted imaging (rFOV DWI) is a more recently described technique in the evaluation of spine pathology. In adults, this technique has been shown to increase clinician confidence in identification of diffusion restricting lesions. PURPOSE: In this study, we evaluate the image quality and diagnostic confidence of the rFOV DWI technique in pediatric spine MRI. METHODS: We included patients with MRI of the lumbar spine for suspected congenital abnormalities who had conventional SS-EPI (single shot echo planar imaging) with full field of view (fFOV) and rFOV DWI performed. Images were graded for image quality and observer confidence for detection of lesions with reduced diffusion. Position of the conus and L3 vertebral body measurements were recorded. Comparisons were made between the fFOV and rFOV scores. RESULTS: Fifty children (30 girls, 20 boys) were included (median 3.6 years). Compared to the fFOV images, the rFOV images scored higher in image quality (P < 0.0001) and for confidence in detecting lesions with reduced diffusion (P < 0.0001). The average spread of identified conus position was smaller for in rFOV compared to fFOV (P = 0.0042). There was no significant difference in the L3 vertebral body measurements between the two methods. In rFOV, the anterior aspects of the vertebral bodies were excluded in a few studies due to narrow FOV. CONCLUSION: rFOV DWI of the lumbar spine in the pediatric population has qualitatively improved image quality and observer confidence for lesion detection when compared to conventional fFOV SS-EPI DWI. PMID- 26597583 TI - [Dynamic concept of oral lichen planus. The diagnosis easy at early stages may become difficult in ancient lichen planus]. AB - Dynamic concept of oral lichen planus. The diagnosis easy at early stages may become difficult in ancient lichen planus. Lichen planus is a chronic inflammatory dermatosis of the skin, skin appendages and mucous membranes, which frequently affects the oral mucosa. Its aetiology still remains unknown, and currently accepted pathogenesis is that of an autoimmune cell-mediated disease. To the contrary of skin lichen planus, oral lichen planus is a long-term chronic disease with dynamic evolution, in which progressive and profound changes of the clinical and histopathological aspects occur over time and under the influence of various exogenous factors. By convention, in the history of the oral lichen planus four successive stages can be distinguished without well-defined boundaries between them. These stages can be defined as an initial phase; a long intermediate phase with alternating periods of activity and quiescence, which has a gradually increasing risk of malignant transformation; a late stage which activity is traditionally diminished; and a post-lichen cicatricial stage with an absent or negligible and undetectable activity, often undiagnosed because clinically unrecognized; in this stage, the lesion does not respond to usual treatments, but retains the same risk of malignant transformation. PMID- 26597584 TI - [Hepatic encephalopathy]. AB - Hepatic encephalopathy is a severe complication of liver cirrhosis and is an important therapeutic challenge, with a social and economic issue. If, now, the pathophysiology is not totally understood (main role of ammonia, but a better understanding of cerebral mechanisms), the clinical presentation is well-known. Some treatments are useful (disaccharides, treatment of the trigger) but their efficiency is limited. Nevertheless, the emergence of new treatments, such as non absorbable antibiotics (rifaximin essentially), is an interesting therapeutic tool. PMID- 26597582 TI - Amelioration of Japanese encephalitis by blockage of 4-1BB signaling is coupled to divergent enhancement of type I/II IFN responses and Ly-6C(hi) monocyte differentiation. AB - BACKGROUND: Japanese encephalitis (JE), a neuroinflammation caused by zoonotic JE virus, is the major cause of viral encephalitis worldwide and poses an increasing threat to global health and welfare. To date, however, there has been no report describing the regulation of JE progression using immunomodulatory tools for developing therapeutic strategies. We tested whether blocking the 4-1BB signaling pathway would regulate JE progression using murine JE model. METHODS: Infected wild-type and 4-1BB-knockout (KO) mice were examined daily for mortality and clinical signs, and neuroinflammation in the CNS was evaluated by infiltration of inflammatory leukocytes and cytokine expression. In addition, viral burden, JEV specific T cell, and type I/II IFN (IFN-I/II) innate responses were analyzed. RESULTS: Blocking the 4-1BB signaling pathway significantly increased resistance to JE and reduced viral burden in extraneural tissues and the CNS, rather than causing a detrimental effect. In addition, treatment with 4-1BB agonistic antibody exacerbated JE. Furthermore, JE amelioration and reduction of viral burden by blocking the 4-1BB signaling pathway were associated with an increased frequency of IFN-II-producing NK and CD4(+) Th1 cells as well as increased infiltration of mature Ly-6C(hi) monocytes in the inflamed CNS. More interestingly, DCs and macrophages derived from 4-1BB KO mice showed potent and rapid IFN-I innate immune responses upon JEV infection, which was coupled to strong induction of PRRs (RIG-I, MDA5), transcription factors (IRF7), and antiviral ISG genes (ISG49, ISG54, ISG56). Further, the ablation of 4-1BB signaling enhanced IFN-I innate responses in neuron cells, which likely regulated viral spread in the CNS. Finally, we confirmed that blocking the 4-1BB signaling pathway in myeloid cells derived from hematopoietic stem cells (HSCs) played a dominant role in ameliorating JE. In support of this finding, HSC-derived leukocytes played a dominant role in generating the IFN-I innate responses in the host. CONCLUSIONS: Blocking the 4-1BB signaling pathway ameliorates JE via divergent enhancement of IFN-II-producing NK and CD4(+) Th1 cells and mature Ly 6C(hi) monocyte infiltration, as well as an IFN-I innate response of myeloid derived cells. Therefore, regulation of the 4-1BB signaling pathway with antibodies or inhibitors could be a valuable therapeutic strategy for the treatment of JE. PMID- 26597585 TI - [Characteristics and predictive factors of success in critical reading exam among medical students. School of Medicine, Rouen (France), 2012-2013]. PMID- 26597587 TI - The impact of klotho gene polymorphisms on urinary tract stone disease. AB - OBJECTIVES: To investigate the effect of klotho gene and beta-glucuronidase activity on stone formation in patients with urinary tract stone disease (UTSD). METHODS: A total of 103 patients with UTSD and 102 controls with no specific urolithiasis history were enrolled into the study. G395A and C1818T polymorphisms of klotho gene were analyzed with PCR method. Serum levels of calcium and phosphorus and 24-h urine levels of beta-glucuronidase activity, calcium and phosphorus levels were measured biochemically. RESULTS: A total of 103 of patients were male (50.2 %) and 102 were female (49.8 %) (p 0.945). Twenty-four hour urine levels of calcium were significantly higher in UTSD group, whereas no difference was observed in phosphorus levels (p < 0.001, p 0.074, respectively). As for the G395A polymorphism, type of GG was significantly higher in the patient group compared to the controls (p = 0.02), while GA genotype was significantly higher in the controls (p = 0.001). There was no significant difference in F352V and C1818T polymorphism between the patient and control groups. beta glucuronidase activity was slightly lower in the patient group without significance (p 0.932).When patients with GG genotype and the rest were compared, there were no significant difference in all parameters. CONCLUSIONS: Any polymorphism altering the function of klotho gene may result with stone formation. We found that there are more GG sequences of G395A gene in patients with UTSD. That may be a polymorphism of klotho gene which results with stone formation. Further studies with more patients should be accomplished which are combining the genetic and epigenetic factors associated with urolithiasis and klotho gene to enlighten the etiology of this disease. PMID- 26597588 TI - A special case of recurrent gross hematuria: Questions. PMID- 26597586 TI - PI3K/AKT Pathway and Its Mediators in Thyroid Carcinomas. AB - Thyroid malignancies are the most common endocrine system carcinomas, with four histopathological forms. The phosphoinositide 3-kinase-protein kinase B/AKT (PI3K PKB/AKT) pathway is one of the most critical molecular signaling pathways implicated in key cellular processes. Its continuous activation by several aberrant receptor tyrosine kinases (RTKs) and genetic mutations in its downstream effectors result in high cell proliferation in a broad number of cancers, including thyroid carcinomas. In this review article, the role of different signaling pathways of PI3K/AKT in thyroid cancers, with the emphasis on the PI3K/AKT/mammalian target of rapamycin (mTOR), PI3K/AKT/forkhead box O (FOXO) and PI3K/AKT/phosphatase and tensin homolog deleted on chromosome ten (PTEN) pathways, and various therapeutic strategies targeting these pathways have been summarized. In most of the in vitro studies, agents inhibiting mTOR in monotherapy or in combination with chemotherapy for thyroid malignancies have been introduced as promising anticancer therapies. FOXOs and PTEN are two outstanding downstream targets of the PI3K/AKT pathway. At the present time, no study has been undertaken to consider thyroid cancer treatment via FOXOs and PTEN targeting. According to the critical role of these proteins in cell cycle arrest, it seems that a treatment strategy based on the combination of FOXOs or PTEN activity induction with PI3K/AKT downstream mediators (e.g., mTOR) inhibition will be beneficial and promising in thyroid cancer treatment. PMID- 26597589 TI - Identification and characterization of a cathepsin L-like cysteine protease from Rhipicephalus (Boophilus) annulatus. AB - The tick Rhipicephalus (Boophilus) annulatus is one of the most important ectoparasites of bovines and is responsible for the transmission of different pathogens such as Babesia and Anaplasma. Cysteine proteases are involved in several host-tick interactions including invasion of host tissues, immune evasion, pathogen transmission, embryogenesis and blood digestion. In this study, the gene encoding R. annulatus cathepsin L-like enzyme (RaCL1) was cloned into pTZ57R/T vector, sequenced and analyzed using bioinformatics approaches. The nucleotide length of RaCL1 was 999 bp. Bioinformatics analysis showed 332 amino acids with an approximate molecular weight of 36.3 kDa which contained a signal peptide sequence (18 amino acids), pro-region (97 amino acids) and mature enzyme (217 amino acids). Multiple sequence alignment of the RaCL1 revealed high similarity to cathepsin L-like cysteine proteases from other tick species such as Rhipicephalus (Boophilus) microplus and Amblyomma variegatum. Based on bioinformatics analyses, results of this work suggest that RaCL1 can be a suitable candidate for the development of vaccine against R. annulatus. PMID- 26597590 TI - Erratum to: Genetic diversity of Ixodes pavlovskyi and I. persulcatus (Acari: Ixodidae) from the sympatric zone in the south of Western Siberia and Kazakhstan. PMID- 26597591 TI - Incidence and prognostic significance of non-enhancing cortical signal abnormality in glioblastoma. AB - INTRODUCTION: The presence of non-enhancing cortical signal abnormality is useful for differentiating between glioblastoma and metastatic disease, but its significance has not been studied. We aimed to determine the incidence and prognostic implications of non-enhancing cortical signal abnormality in glioblastomas. METHODS: Patients with a new diagnosis of glioblastoma between September 2007 and December 2010 were identified. Only patients with at least fluid-attenuated inversion recovery (FLAIR) and post-contrast T1-weighted sequences were included. Pre-operative MRIs were reviewed together by two readers to determine whether there was evidence of non-enhancing cortical signal abnormality, based primarily on the FLAIR sequence. The results were compared with patient survival using both univariate and multivariate analysis. RESULTS: One hundred fifty-one patients met the inclusion criteria. Seventy-seven patients (51%) had evidence of non-enhancing cortical signal abnormality. On both univariate and multivariate analysis, there was overall no significant difference in survival between patients with non-enhancing cortical signal abnormality and those without. Peripheral enhancing lesions (51 patients) were generally associated with the longest survival, but subgroup analysis suggested that non enhancing signal abnormality was associated with worse survival in these patients (P = 0.004), conveying an intermediate prognosis. CONCLUSIONS: Non-enhancing cortical signal abnormality is a common feature of glioblastomas, occurring in about half of cases. It does not affect survival overall, but appears to be associated with worse survival in the setting of a peripherally located enhancing lesion. This has the potential to alter surgical management. PMID- 26597592 TI - Selective distillation phenomenon in two-species Bose-Einstein condensates in open boundary optical lattices. AB - We investigate the formation of discrete breathers (DBs) and the dynamics of the mixture of two-species Bose-Einstein condensates (BECs) in open boundary optical lattices using the discrete nonlinear Schrodinger equations. The results show that the coupling of intra- and interspecies interaction can lead to the existence of pure single-species DBs and symbiotic DBs (i.e., two-species DBs). Furthermore, we find that there is a selective distillation phenomenon in the dynamics of the mixture of two-species BECs. One can selectively distil one species from the mixture of two-species BECs and can even control dominant species fraction by adjusting the intra- and interspecies interaction in optical lattices. Our selective distillation mechanism may find potential application in quantum information storage and quantum information processing based on multi species atoms. PMID- 26597594 TI - Characterization and antimicrobial application of biosynthesized gold and silver nanoparticles by using Microbacterium resistens. AB - Various microorganisms were found to be cable of synthesizing gold and silver nanoparticles when gold and silver salts were supplied in the reaction system. The main objective of this study was to evaluate the extracellular synthesis of gold and silver nanoparticles by the type strain Microbacterium resistens(T) [KACC14505]. The biosynthesized gold and silver nanoparticles were characterized by ultraviolet-visible spectroscopy (UV-Vis), field emission transmission electron micrograph (FE-TEM), energy dispersive X-ray spectroscopy (EDX), elemental mapping, and dynamic light scattering (DLS). Moreover, the nanoparticles were evaluated for antimicrobial potential against various pathogenic microorganisms such as Vibrio parahaemolyticus [ATCC 33844], Salmonella enterica [ATCC 13076], Staphylococcus aureus [ATCC 6538], Bacillus anthracis [NCTC 10340], Bacillus cereus [ATCC 14579], Escherichia coli [ATCC 10798], and Candida albicans [KACC 30062]. The silver nanoparticles were found as a potent antimicrobial agent whereas gold nanoparticles not showed any ability. Therefore, the current study describes the simple, green, and extracellular synthesis of gold and silver nanoparticles by the type strain Microbacterium resistens(T) [KACC14505]. PMID- 26597593 TI - Positional plasticity in regenerating Amybstoma mexicanum limbs is associated with cell proliferation and pathways of cellular differentiation. AB - BACKGROUND: The endogenous ability to dedifferentiate, re-pattern, and re differentiate adult cells to repair or replace damaged or missing structures is exclusive to only a few tetrapod species. The Mexican axolotl is one example of these species, having the capacity to regenerate multiple adult structures including their limbs by generating a group of progenitor cells, known as the blastema, which acquire pattern and differentiate into the missing tissues. The formation of a limb regenerate is dependent on cells in the connective tissues that retain memory of their original position in the limb, and use this information to generate the pattern of the missing structure. Observations from recent and historic studies suggest that blastema cells vary in their potential to pattern distal structures during the regeneration process; some cells are plastic and can be reprogrammed to obtain new positional information while others are stable. Our previous studies showed that positional information has temporal and spatial components of variation; early bud (EB) and apical late bud (LB) blastema cells are plastic while basal-LB cells are stable. To identify the potential cellular and molecular basis of this variation, we compared these three cell populations using histological and transcriptional approaches. RESULTS: Histologically, the basal-LB sample showed greater tissue organization than the EB and apical-LB samples. We also observed that cell proliferation was more abundant in EB and apical-LB tissue when compared to basal-LB and mature stump tissue. Lastly, we found that genes associated with cellular differentiation were expressed more highly in the basal-LB samples. CONCLUSIONS: Our results characterize histological and transcriptional differences between EB and apical LB tissue compared to basal-LB tissue. Combined with our results from a previous study, we hypothesize that the stability of positional information is associated with tissue organization, cell proliferation, and pathways of cellular differentiation. PMID- 26597595 TI - A 4-gene expression score associated with high levels of Wilms Tumor-1 (WT1) expression is an adverse prognostic factor in acute myeloid leukaemia. AB - Wilms Tumor-1 (WT1) expression level is implicated in the prognosis of acute myeloid leukaemia (AML). We hypothesized that a gene expression profile associated with WT1 expression levels might be a good surrogate marker. We identified high WT1 gene sets by comparing the gene expression profiles in the highest and lowest quartiles of WT1 expression in two large AML studies. Two high WT1 gene sets were found to be highly correlated in terms of the altered genes and expression profiles. We identified a 17-probe set signature of the high WT1 set as the optimal prognostic predictor in the first AML set, and showed that it was able to predict prognosis in the second AML series after adjustment for European LeukaemiaNet genetic groups. The gene signature also proved to be of prognostic value in a third AML series of 163 samples assessed by RNA sequencing, demonstrating its cross-platform consistency. This led us to derive a 4-gene expression score, which faithfully predicted adverse outcome. In conclusion, a short gene signature associated with high WT1 expression levels and the resultant 4-gene expression score were found to be predictive of adverse prognosis in AML. This study provides new clues to the molecular pathways underlying high WT1 states in leukaemia. PMID- 26597596 TI - Comparative review of dipeptidyl peptidase-4 inhibitors and sulphonylureas. AB - Type 2 diabetes (T2DM) is a progressive disease, and pharmacotherapy with a single agent does not generally provide durable glycaemic control over the long term. Sulphonylurea (SU) drugs have a history stretching back over 60 years, and have traditionally been the mainstay choice as second-line agents to be added to metformin once glycaemic control with metformin monotherapy deteriorates; however, they are associated with undesirable side effects, including increased hypoglycaemia risk and weight gain. Dipeptidyl peptidase (DPP)-4 inhibitors are, by comparison, more recent, with the first compound being launched in 2006, but the class now globally encompasses at least 11 different compounds. DPP-4 inhibitors improve glycaemic control with similar efficacy to SUs, but do not usually provoke hypoglycaemia or weight gain, are relatively free from adverse side effects, and have recently been shown not to increase cardiovascular risk in large prospective safety trials. Because of these factors, DPP-4 inhibitors have become an established therapy for T2DM and are increasingly being positioned earlier in treatment algorithms. The present article reviews these two classes of oral antidiabetic drugs (DPP-4 inhibitors and SUs), highlighting differences and similarities between members of the same class, as well as discussing the potential advantages and disadvantages of the two drug classes. While both classes have their merits, the choice of which to use depends on the characteristics of each individual patient; however, for the majority of patients, DPP-4 inhibitors are now the preferred choice. PMID- 26597597 TI - Increased monocyte/neutrophil and pro-coagulant microparticle levels and overexpression of aortic endothelial caveolin-1beta in dyslipidemic sand rat, Psammomys obesus. AB - AIMS: To compare the effects of a high-energy diet (HED) with those of a low energy diet (LED) on biochemical parameters, microparticle (MP) subpopulations and endothelial caveolin-1 (cav-1) protein expression in Psammomys obesus (P. obesus). METHODS: After 12weeks of feeding with either the HED or LED, fasting plasma glucose and lipid parameters were measured using an enzymatic colorimetric kit while serum insulin concentration was determined with radioimmunoassay kits. MP subpopulations and cav-1 protein expression were quantified using flow cytometry and western blot analysis, respectively. RESULTS: We observed that the HED caused a marked increase in lipid parameters, even in normoglycemic P. obesus. The total number of circulating MPs and the numbers of platelet-, leukocyte-, and erythrocyte-derived MPs were unaltered in the HED group. However, the HED induced increases in the numbers of monocytes/neutrophils and procoagulant MPs and a decrease in the endothelial MP levels. Cav-1beta protein expression and reactive oxygen species production were increased in the vascular endothelium of HED-treated P. obesus. CONCLUSION: From these findings, it is indicated that the HED exerts deleterious effects on the vascular system by increasing the monocyte/neutrophil and procoagulant MP levels, which may lead to cav-1beta protein overexpression in dyslipidemic P. obesus. PMID- 26597598 TI - Placental antioxidant enzyme status and lipid peroxidation in pregnant women with type 1 diabetes: The effect of vitamin C and E supplementation. AB - AIM: In view of the increased rates of pre-eclampsia observed in diabetic pregnancy and the lack of ex vivo data on placental biomarkers of oxidative stress in T1 diabetic pregnancy, the aim of the current investigation was to examine placental antioxidant enzyme status and lipid peroxidation in pregnant women with type 1 diabetes. A further objective of the study was to investigate the putative impact of vitamin C and E supplementation on antioxidant enzyme activity and lipid peroxidation in type 1 diabetic placentae. METHODS: The current study measured levels of antioxidant enzyme [glutathione peroxidase (Gpx), glutathione reductase (Gred), superoxide dismutase (SOD) and catalase] activity and degree of lipid peroxidation (aqueous phase hydroperoxides and 8-iso prostaglandin F2alpha) in matched central and peripheral samples from placentae of DAPIT (n=57) participants. Levels of vitamin C and E were assessed in placentae and cord blood. RESULTS: Peripheral placentae demonstrated significant increases in Gpx and Gred activities in pre-eclamptic in comparison to non-pre eclamptic women. Vitamin C and E supplementation had no significant effect on cord blood or placental levels of these vitamins, nor on placental antioxidant enzyme activity or degree of lipid peroxidation in comparison to placebo supplementation. CONCLUSION: The finding that maternal supplementation with vitamin C/E does not augment cord or placental levels of these vitamins is likely to explain the lack of effect of such supplementation on placental indices including antioxidant enzymes or markers of lipid peroxidation. PMID- 26597600 TI - EMPA-REG - the "diuretic hypothesis". PMID- 26597599 TI - Pulmonary function tests in type 1 diabetes adolescents with diabetic cardiovascular autonomic neuropathy. AB - Chronic diabetic complications may afflict all organ tissues including cardiovascular and respiratory system. The aim of the study was to establish if the presence of cardiovascular autonomic neuropathy (CAN) was associated with impaired pulmonary function tests in adolescents with type 1 diabetes (T1D). 46 adolescents with T1D and 25 healthy subjects at the age 15-19years were enrolled to the study. Basic anthropometric data, diabetes onset and duration, plasma glucose and A1c were established. Pulmonary function tests were measured by spirometry and the presence of CAN was examined by heart rate variability. Adolescents with T1D had significantly lower pulmonary function test parameters - FVC (p<0.01), FEV1 (p<0.01), MMEF (p<0.05) and PEFR (p<0.05) compared to the control subjects. In diabetic group, patients with CAN (CAN+, n=19) had significantly lower FVC (p<0.05), FEV1 (p<0.05) and PEFR (p<0.05) compared to patients without CAN (CAN-, n=27). All spirometric parameters were significantly lower in CAN+ subjects compared to healthy controls; however, no significant difference was found in these parameters between CAN- subjects and healthy controls. Spirometric parameters (FVC, FEV1) significantly positively correlated with diabetes onset and body mass index; and negatively correlated with diabetes duration and resting heart rate. Our results indicate that CAN may be associated with reduced pulmonary functions in adolescents with T1D. PMID- 26597601 TI - Estimating glomerular filtration rate: Performance of the CKD-EPI equation over time in patients with type 2 diabetes. AB - AIMS: To assess the performance of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation at baseline and longitudinally in people with type 2 diabetes. METHODS: Adults with type 2 diabetes attending Austin Health, Melbourne, with>=3 prospective GFR measurements were included in this retrospective study. Plasma disappearance rate of DTPA (diethylene-triamine-penta acetic acid) was used to calculate measured GFR (mGFR) and compared to estimated GFR (eGFR). The agreement between mGFR and eGFR was estimated using Intraclass Correlation Coefficient (ICC). RESULTS: 152 patients had a median of 4 (IQR: 3, 5) mGFR measurements over a period of 11years (IQR: 9, 12). The difference between mGFR and eGFR increased proportionally to the magnitude of the GFR, increasing by 0.2ml/min/1.73m(2) for every 1ml/min/1.73m(2) increase in mGFR, indicative of proportional bias. At lower mGFR levels, eGFR overestimated mGFR, and at higher mGFR levels, eGFR underestimated mGFR. There was a significant association between LDL cholesterol, triglycerides, HbA1c, diastolic blood pressure and the difference between mGFR and eGFR. CONCLUSIONS: The CKD-EPI formula underestimates mGFR and the rate of decline of mGFR in patients with type 2 diabetes with an mGFR greater than 60ml/min/1.73m(2). The association between LDL cholesterol, triglycerides, HbA1c, diastolic blood pressure and the difference between mGFR and eGFR warrants further study. PMID- 26597602 TI - Chronic fructose intake accelerates non-alcoholic fatty liver disease in the presence of essential hypertension. AB - BACKGROUND: The growing epidemic of metabolic syndrome has been related to the increased use of fructose by the food industry. In fact, the use of fructose as an ingredient has increased in sweetened beverages, such as sodas and juices. We thus hypothesized that fructose intake by hypertensive rats would have a worse prognosis in developing metabolic disorder and non-alcoholic fatty liver disease. METHODS: Male Wistar and SHR rats aged 6weeks were given water or fructose (10%) for 6weeks. Blood glucose was measured every two weeks, and insulin and glucose sensitivity tests were assessed at the end of the follow-up. Systolic blood pressure was measure by plethysmography. Lean mass and abdominal fat mass were collected and weighed. Liver tissue was analyzed to determine interstitial fat deposition and fibrosis. RESULTS: Fasting glucose increased in animals that underwent a high fructose intake, independent of blood pressure levels. Also, insulin resistance was observed in normotensive and mostly in hypertensive rats after fructose intake. Fructose intake caused a 2.5-fold increase in triglycerides levels in both groups. Fructose intake did not change lean mass. However, we found that fructose intake significantly increased abdominal fat mass deposition in normotensive but not in hypertensive rats. Nevertheless, chronic fructose intake only increased fat deposition and fibrosis in the liver in hypertensive rats. CONCLUSIONS: We demonstrated that, in normotensive and hypertensive rats, fructose intake increased triglycerides and abdominal fat deposition, and caused insulin resistance. However, hypertensive rats that underwent fructose intake also developed interstitial fat deposition and fibrosis in liver. PMID- 26597603 TI - Editorial overview: Cell biology: From signals to cell shape and function. PMID- 26597604 TI - Familial intracranial aneurysm, the relationship of the aortic diameter. AB - OBJECTIVES: Familial predisposition appears as an identified risk factor for cerebrovascular disease. The primary objective of our study was to assess intracranial aneurysm (IA) recurrence rate in a population of familial IA. Secondary objectives were first to analyse the inheritance categorisation/pattern of these families and second to assess the correlation between the aortic diameter on MRI and the aneurysmal characteristics. PATIENTS AND METHODS: Over a period of 20 years (1990-2010), 26 patients from 23 families, identified from a regional register, accepted to participate in this prospective trial in order to determine, the inheritance pattern, the screening of de novo aneurysms by CT angioscan, and the aortic mensuration by MRI. The transmission pattern was categorised into autosomal dominant inheritance, autosomal recessive and autosomal dominance with incomplete penetrance. The aortic diameter was measured: anatomic coverage in the caudo-cranial direction from the iliac arteries to the ventriculo-aortic junction. RESULTS: All 26 patients [from 55.4 +/- 11.2 years, sex ratio female/male: 1.36] were reviewed after a mean follow-up of 7.9 +/- 6.6 years after the diagnosis of a cerebral aneurysm. The characteristics of this population were the diagnostic circumstances such as a subarachnoid hemorrhage (SAH) in 14 (53.8%), the multiple locations in 10 (38.5%) and a giant aneurysm in 4 (15.4%). Four de novo aneurysms were diagnosed in 3 patients (11.5%) after a mean follow-up of 22.3 +/- 4 years, which corresponds to an annual incidence of 1.9 (95% CI 1.4-2.6%). The transmission pattern was autosomal dominant in 16 (61.5%), recessive in 3 (11.5%) and not defined in 7 (26.9%). As regards the aortic diameter, a significant decrease in the aortic diameter was observed in patients with an aneurysmal diameter superior to 10mm. CONCLUSION: The rate of de novo aneurysm justifies prolonged monitoring by imaging of these patients with familial intracranial aneurysm. The narrowing of the terminal part of the aorta could be a hemodynamic factor involved into the IA development. PMID- 26597605 TI - Adult recurrent pilocytic astrocytoma: Clinical, histopathological and molecular study. AB - BACKGROUND: PA is a grade I glial tumor that mostly occurs in children. However, although apparently similar to paediatric PA, adult PA presents a different clinical follow-up that could arise from specific molecular alterations. A variety of genetic alterations have been identified as diagnostic or prognostic glioma molecular markers. MATERIAL AND METHODS: We describe a right infratentorial tumor that occurred in a 58-year-old man. Neuroimaging and neuropathological examination suggested PA as an initial diagnosis. The tumor was completely resected. Unexpectedly, two years later, a rapidly growing tumor on the operative site was observed with a second location in the pineal region. Immunohistochemical reactions (IHC), Multiplex ligation probe amplification (MLPA) and fluorescence in situ hybridization (FISH) was performed in both primary and relapse tumor. RESULTS: Neuroimaging and neuropathological examinations suggested an unusual diagnosis for adult patients: a recurrent PA. Both MLPA and FISH analysis contribute to diagnostic confirmation by KIAA1549: BRAF fusion detection. Additional genetic results revealed interesting findings that justified the tumor aggressivity. CONCLUSION: Molecular analysis of adult PA cases should be routinely combined with histopathological and neuroimaging examination to further refine prognostic diagnoses. PMID- 26597606 TI - Spontaneous epidural hematoma due to cervico-thoracic angiolipoma. AB - Epidural angiolipomas are uncommon benign tumors of the spine. Their clinical presentation is usually a progressive spinal cord compression. We report the case of a 22-year-old patient who presented with an acute paraparesis and a spontaneous epidural hematoma, which revealed a epidural angiolipoma which extended from C7 to T3. The patient underwent a C7-T3 laminectomy, in emergency, with evacuation of the hematoma and extradural complete resection of a fibrous epidural tumor bleeding. The postoperative course was favorable with regression of neurological symptoms. Epidural angiolipomas can be revealed by spontaneous intratumoral hemorrhage without traumatism. The standard treatment is total removal by surgery. PMID- 26597607 TI - Application of a stand-alone anchored spacer in noncontiguous anterior cervical arthrodesis with radiologic analysis of the intermediate segment. AB - The purpose of this study was to describe the clinical features of noncontiguous cervical degenerative disc disease (cDDD), investigate the efficacy and complications of a stand-alone anchored spacer (SAAS) for patients with noncontiguous cDDD, and present radiologic analysis of the intermediate segment (IS) after skip-level fusion. Nineteen consecutive patients with noncontiguous cDDD who underwent skip-level anterior cervical discectomy and fusion (ACDF) with SAAS from January 2010 to December 2012 were enrolled in this study. Clinical outcomes were assessed preoperatively and at 24 months postoperatively using the Japanese Orthopaedic Association score, Neck Disability Index, and Visual Analog Scale. Overall cervical alignment (OCA) of the cervical spine, and the range of motion (ROM), intervertebral disc height (IDH), disc signal intensity and disc protrusion of IS were measured and compared before and after surgery. Clinical outcomes significantly improved compared to preoperative scores. The OCA was corrected and maintained at 24 months postoperatively compared with preoperative values (p<0.05). There were no significant differences in the ROM and IDH of the IS at each follow-up (p>0.05). However, decreased signal intensity on T2-weighted MRI was evidenced in three mobile IS at final follow-up (20.0%). Skip-level ACDF with SAAS may be an efficacious option for the treatment of noncontiguous cDDD. PMID- 26597608 TI - Venous thromboembolism in brain tumor patients. AB - Venous thromboembolism (VTE) is a relatively common and well-described condition, affecting approximately 1-2% of the general population. VTE can lead to significant morbidity and death via pulmonary embolism (PE). During the post operative period, VTE occurs at higher rates due to natural thrombotic responses to injury and limited post-operative mobility. In general, rates of post operative VTE are higher in patients undergoing operations for cranial and spinal lesions than for lesions of other types, a phenomenon that is not fully explained. Proposed mechanisms include increased local synthesis of tissue factor in brain tumor patients and a higher rate of paresis in patients undergoing operations on the central nervous system. Several studies have demonstrated that other risk factors for VTE include age, sex, ethnicity, hospital stay length, and coagulation state. Tumor type and size have also been explored as potential risk factors. Despite higher rates of VTE development, neurosurgeons are often hesitant to prescribe post-operative anticoagulants for fear of hemorrhage. Here we review the literature on VTE in brain tumor patients, with a focus on their etiology, diagnosis, treatment, and prophylaxis. In most brain tumor patients, aggressive chemical and mechanical VTE prophylaxis is indicated in the post operative period to prevent the formation of VTE. PMID- 26597609 TI - Pure agraphia after infarction in the superior and middle portions of the left precentral gyrus: Dissociation between Kanji and Kana. AB - The present study describes a Japanese patient with pure agraphia displaying differential disturbances in processing Kanji (morphogram) and Kana (syllabogram) letters after an infarction in the middle and superior portions of the left precentral gyrus. Kana errors reflected the patient's difficulty with retrieving both motor and visual letter images, whereas Kanji errors included partial letter stroke omissions or additions. This present case suggests that differences in writing disturbances between Kana and Kanji letters are caused by a differential dependency on letter motor images. PMID- 26597611 TI - Th17 skewing in the GALT of a Crohn disease patient upon Lactobacillus rhamnosus GG consumption. PMID- 26597612 TI - Prostate cancer: STHLM3 model for prostate cancer screening. PMID- 26597610 TI - Common gamma chain cytokines in combinatorial immune strategies against cancer. AB - Common gamma chain (gammaC) cytokines, namely IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 are important for the proliferation, differentiation, and survival of lymphocytes that display antitumor activity, thus stimulating considerable interest for the use of cytokines in cancer immunotherapy. In this review, we will focus on the gammaC cytokines that demonstrate the greatest potential for immunotherapy, IL-2, IL-7, IL-15, and IL-21. We will briefly cover their biological function, potential applications in cancer therapy, and update on their use in combinatorial immune strategies for eradicating tumors and hematopoietic malignancies. PMID- 26597613 TI - Use of ureteral access sheaths in ureteroscopy. AB - The ureteral access sheath (UAS) facilitates the use of flexible ureteroscopy, enabling improved minimally invasive management of complex upper urinary tract diseases. The UAS, which comes in a variety of diameters and lengths, is passed in a retrograde fashion, aided by a hydrophilic coating and other features designed to confer smooth passage into the ureter with sufficient resistance to kinking and buckling. Use of a UAS has the advantage of enabling repeated passage of the ureteroscope while minimizing damage to the ureter, thus improving the flow of irrigation fluid and visualization within the urethra with reductions in operative times, which improves both the effectiveness of the surgery and reduces the costs. Placement of the UAS carries an increased risk of ureteral wall ischaemia and injury to the mucosal or muscular layers of the ureter, and a theoretically increased risk of ureteral strictures. A ureteral stent is typically placed after ureteroscopy with a UAS. Endourologists have found several additional practical uses of a UAS, such as the percutaneous treatment of patients with ureteral stones, and solutions to other endourological challenges. PMID- 26597614 TI - Bladder cancer in 2015: Improving indication, technique and outcome of radical cystectomy. AB - Radical cystectomy is the standard treatment for patients with bladder cancer, but the prognosis of patients undergoing this procedure has not changed for decades. Small steps towards improvement include better selection of high-risk T1 patients, the use of perioperative chemotherapy and, maybe, robotic cystectomy. PMID- 26597615 TI - Prostate cancer: Elective pelvic nodal radiotherapy: is the jury still out? PMID- 26597616 TI - Prostate cancer: Castration impairs DNA repair. PMID- 26597617 TI - Prostate cancer: Molecular stratification and repair defects: revealing hidden treasures. PMID- 26597618 TI - Bladder cancer: A step closer to individualized treatment for bladder cancer. PMID- 26597620 TI - Divergence in the results of plasma catecholamine levels in different studies on patients with takotsubo syndrome: Why? PMID- 26597621 TI - Cord blood banking and quality issues. AB - BACKGROUND: Food and Drug Administration guidelines are designed to assure the quality and safety of the cord blood product used for transplantation. It is valuable to determine whether the actions called for in these guidelines are effective. STUDY DESIGN AND METHODS: We applied our cell therapy quality system to all cord blood units shipped into our cellular therapy laboratory for transplant at the University of Minnesota between 2011 and 2013. The quality issues were categorized as likely, potentially, or unlikely to have a clinical impact. RESULTS: A total of 249 units of umbilical cord blood (UCB) were received from 16 cord blood banks. A total of 159 units (64%) had a total of 245 issues. Of these, 117 (48%) pertained to medical history, 120 (49%) to quality control, and eight (3%) to labeling and documentation. Units with quality issues were no more likely to fail to engraft, and no specific kind of quality issue was associated with failure to engraft. Compared to a similar study 10 years ago, there was a decrease in the number of issues per unit. DISCUSSION: The cost of collecting, testing, processing, and storing UCB is very high. However, there may be activities that do not contribute to the quality or safety of the cord blood. The guidelines could be reviewed to determine their value based on years of experience. PMID- 26597622 TI - Retinoid level dynamics during gonad recycling in the limpet Patella vulgata. AB - Germ cell commitment and meiosis initiation are among the multitude of physiological roles of retinoic acid (RA) in vertebrates. Acting via receptor mediated transcription, RA induces the expression of meiotic factors, triggering meiosis. Contrasting with vertebrates, invertebrate RA metabolism is scarcely understood. Still, some physiological processes appear to be conserved. Here we set to evaluate the role of retinoids in the gonad maturation process of the marine gastropod Patella vulgata. We found that retinoid concentration in gonadal tissue, namely RA, varies between breeding and resting specimens, with maxima attained in the latter. Additionally, we isolated and quantified the expression of both the retinoic acid receptor (RAR) and the retinoid X receptor (RXR) in gonads. In view of the stability of retinoid receptor expression, we suggest that the balance of RA levels operates through the enzymatic control of synthetic and catabolic processes. Overall, the reported data are supportive for a developmental role of RA during gonadal maturation in P. vulgata, which should be addressed in other protostome lineages. PMID- 26597623 TI - Alcohol Consumption, Craving, and Craving Control Efforts Assessed Daily in the Context of Readiness to Change Among Individuals with Alcohol Dependence and PTSD. AB - Research has demonstrated the positive association between alcohol craving and alcohol use and has identified craving as a central component of alcohol use disorders (AUD). Despite potential clinical implications, few studies have examined the relationship between craving and alcohol use in individuals with AUD and common psychiatric comorbidities or explored possible moderators of the craving-alcohol use relationship. The current study used daily monitoring data to: 1) replicate previous findings detecting a positive relationship between craving and alcohol use in individuals with AUD and co-occurring posttraumatic stress disorder (PTSD) and 2) extend these findings by examining the influence of initial change motivation on the craving-use relationship and within-day associations among craving, efforts to control craving, and alcohol consumption. Participants were 84 individuals with alcohol dependence and PTSD enrolled in an intervention study. Generalized estimating equations using pre-treatment baseline daily data revealed significant main effects for craving, craving control, and motivation to change alcohol use. Daily craving was positively related to alcohol use. Greater change motivation and craving control (i.e., efforts to resist craving, avoidance of thoughts and feelings related to craving) were negatively related to alcohol use. A significant interaction was detected between baseline change motivation and daily craving indicating that the association between craving and alcohol use was significantly stronger for those with low baseline change motivation. A significant interaction was also detected between craving control and daily craving, suggesting that participants were more likely to consume alcohol when experiencing high levels of craving if they reported low levels of craving control. Findings bolster the idea that efforts to prevent or ameliorate craving are critical to treatment success for individuals with AUD and PTSD who are seeking to reduce or quit drinking. PMID- 26597624 TI - Stimulant use following the publicity of cardiovascular safety and the introduction of patient medication guides. AB - PURPOSE: To explore changes in stimulant utilization and pre-treatment electrocardiography (ECG) screening in response to cardiovascular (CV) safety concerns. METHODS: Two source populations were established from Florida Medicaid Fee-for-service beneficiaries between 2001 and 2008: approximately 44 571 newly diagnosed attention deficit/hyperactivity disorder patients and 33 000 new stimulant users. Time-series design and Joinpoint analysis were used to describe monthly trend changes in stimulant initiation, persistence, dosing, and pre treatment ECG screening. RESULTS: Initial and maintenance daily dose declined 6 mg (95% confidence interval [CI] -14 to -1.9) methylphenidate (MPH) equivalent dose from a steady 27 mg after Canada withdrew Adderall XR in February 2005; the trend rebounded to a daily dose of 23 mg, after the remarketing of Adderall XR and a debate in the US over issuing a boxed warning on stimulant CV safety in early 2006. Monthly initiation increased 3.9% (CI -1.0 to 9.1) after the boxed warning debate to 54 per 100 patients per month (CI 44 to 68), but declined 2.4% (CI -3.6 to -1.2) after requirement of medication guides in February 2007. Monthly ECG screening increased 3.2% (CI 2.3 to 4.2) after Adderall XR withdrawal and further increased 13% (CI 4 to 23) after the American Heart Association recommended pre-treatment ECG screening to 40 per 100 patients per month (CI 17 to 48). CONCLUSIONS: The first signal of stimulant CV safety concerns was followed by varying responses depending on the outcome measure used, suggesting that patients and physicians responded at different times after the publicity of safety concerns. Clinical consequences of the changes are uncertain. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26597625 TI - Identification of pathways related to FAF1/H. pylori-associated gastric carcinogenesis through an integrated approach based on iTRAQ quantification and literature review. AB - Previously we showed that down-regulation of tumor suppressor FAF1 mRNA, potentially caused by H. pylori, correlated with increasing tumor differentiation and distant metastasis in gastric cancer. To identify molecular details about how FAF1 and H. pylori contribute to gastric carcinogenesis, we used the iTRAQ labeling approach involving LC-MS/MS to perform proteomic analysis of HGC-27 gastric cancer cells stably transfected with an FAF1 transgene and/or infected with H. pylori. Of the 2926 proteins examined, proteomics identified 157 for which the expression was altered as a result of FAF1 expression, 500 with altered expression as a result of H. pylori infection, and 246 with altered expression as a combined result of FAF1 expression and H. pylori infection. A literature review identified 21 proteins as being differentially expressed in H. pylori-associated gastric cancer in at least two studies. These two complementary analyses were combined in Ingenuity Pathway software, which predicted that FAF1/H. pylori associated gastric carcinogenesis alters primarily biochemical pathways related to mitochondrial dysfunction, oxidative phosphorylation, integrin signaling, cholesterol/leucine metabolism and G2/M checkpoint regulation. Differential expression of key proteins in several of these pathways was validated by immunoblotting in HGC-27 cells. This integrated approach combining proteomics and literature searching may prove fruitful for elucidating how FAF1 expression and H. pylori infection affect gastric carcinogenesis. BIOLOGICAL SIGNIFICANCE: We established, for the first time, the proteomics databases of gastric cancer cell HGC-27 overexpressing FAF1 and infected with H. pylori through an integrated approach based on iTRAQ quantification and literature review, this strategy responded to the call for greater focus on data integration in primary/previous proteomic studies; and provided an integrated picture of the reference pathways and networks behind FAF1/H. pylori-associated gastric carcinogenesis, particularly pathways of mitochondrial dysfunction, oxidative phosphorylation, integrin signaling, cholesterol/leucine metabolism and G2/M checkpoint regulation. PMID- 26597626 TI - Comparative proteome analysis of Actinoplanes sp. SE50/110 grown with maltose or glucose shows minor differences for acarbose biosynthesis proteins but major differences for saccharide transporters. AB - Actinoplanes sp. SE50/110 is known for the production of the alpha-glucosidase inhibitor and anti-diabetic drug acarbose. Acarbose (acarviosyl-maltose) is produced as the major product when the bacterium is grown in medium with maltose, while acarviosyl-glucose is the major product when glucose is the sole carbon source in the medium. In this study, a state-of-the-art proteomics approach was applied combining subcellular fractionation, in vivo metabolic labeling and shotgun mass spectrometry to analyze differences in the proteome of Actinoplanes sp. SE50/110 cultures grown in minimal medium containing either maltose or glucose as the sole carbon source. To study proteins in distinct subcellular locations, a cytosolic, an enriched membrane, a membrane shaving and an extracellular fraction were included in the analysis. Altogether, quantitative proteome data was obtained for 2497 proteins representing about 30% of the ca. 8270 predicted proteins of Actinoplanes sp. SE50/110. When comparing protein quantities of maltose- to glucose-grown cultures, differences were observed for saccharide transport and metabolism proteins, whereas differences for acarbose biosynthesis gene cluster proteins were almost absent. The maltose-inducible alpha-glucosidase/maltase MalL as well as the ABC-type saccharide transporters AglEFG, MalEFG and MstEAF had significantly higher quantities in the maltose growth condition. The only highly abundant saccharide transporter in the glucose condition was the monosaccharide transporter MstEAF, which may indicate that MstEAF is the major glucose importer. Taken all findings together, the previously observed formation of acarviosyl-maltose and acarviosyl-glucose is more closely connected to the transport of saccharides than to a differential expression of the acarbose gene cluster. BIOLOGICAL SIGNIFICANCE: Diabetes is a global pandemic accounting for about 11% of the worldwide healthcare expenditures (>600 billion US dollars) and is projected to affect 592 million people by 2035 (www.idf.org). Whether Actinoplanes sp. SE50/110 produces type 2 diabetes drug acarbose (acarviosyl-maltose) or another acarviose metabolite such as acarviosyl-glucose as the major product depends on the offered carbon source. The differences observed in this proteome in this study suggest that the differences in the formation of acarviosyl-maltose and acarviosyl-glucose are more closely connected to the transport of saccharides than to a differential expression of the acarbose gene cluster. In addition, the present study provides a comprehensive overview of the proteome of Actinoplanes sp. SE50/110. PMID- 26597627 TI - Gynecologic health and disease in relation to the microbiome of the female reproductive tract. AB - It is well established that the vagina is colonized by bacteria that serve important roles in homeostasis. Imbalances in the proportion of bacteria may lead to a predisposition to infection or reproductive complications. Molecular-based approaches demonstrated a greater degree of microbial diversity both within and between women than previously recognized. The vaginal microbiome may fluctuate during various states of health, such as during the menstrual cycle or after menopause, and there may be differences in the vaginal microbiome between women of different ethnicities. Furthermore, the specific composition of the vaginal microbiome may influence the predisposition to dysbiosis and the transmission of sexually transmitted infections. An understanding of the diversity of the vaginal microbial environment during states of health is essential for the identification of risk factors for disease and the development of appropriate treatment. PMID- 26597628 TI - Reproductive tract microbiome in assisted reproductive technologies. AB - The human microbiome has gained much attention recently for its role in health and disease. This interest has come as we have begun to scratch the surface of the complexity of what has been deemed to be our "second genome" through initiatives such as the Human Microbiome Project. Microbes have been hypothesized to be involved in the physiology and pathophysiology of assisted reproduction since before the first success in IVF. Although the data supporting or refuting this hypothesis remain somewhat sparse, thanks to sequencing data from the 16S rRNA subunit, we have begun to characterize the microbiome in the male and female reproductive tracts and understand how this may play a role in reproductive competence. In this review, we discuss what is known about the microbiome of the reproductive tract as it pertains to assisted reproductive technologies. PMID- 26597629 TI - Supply of and demand for assisted reproductive technologies in the United States: clinic- and population-based data, 1995-2010. AB - OBJECTIVE: To study national-level trends in assisted reproduction technology (ART) treatments and outcomes as well as the characteristics of women who have sought this form of infertility treatment. DESIGN: Population-based study. SETTING: Not applicable. PATIENT(S): For CDC: All reporting clinics from 1996 2010. For NSFG: for the logistic analysis, sample comprising 2,325 women aged 22 44 years who have ever used medical help to get pregnant, excluding women who used only miscarriage prevention services. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): CDC data (number of cycles, live birth deliveries, live births, patient diagnoses); and NSFG data (individual use of ART procedures). RESULT(S): Between 1995 and 2010, use of ART increased. Parity and age are strong predictors of using ART procedures. The other correlates are higher education, having had tubal surgery, and having a current fertility problem. CONCLUSION(S): The two complementary data sets highlight the trends of ART use. An increase in the use of ART services over this time period is seen in both data sources. Nulliparous women aged 35-39 years are the most likely to have ever used ART services. PMID- 26597630 TI - Factors affecting length of stay in forensic hospital setting: need for therapeutic security and course of admission. AB - BACKGROUND: Patients admitted to a secure forensic hospital are at risk of a long hospital stay. Forensic hospital beds are a scarce and expensive resource and ability to identify the factors predicting length of stay at time of admission would be beneficial. The DUNDRUM-1 triage security scale and DUNDRUM-2 triage urgency scale are designed to assess need for therapeutic security and urgency of that need while the HCR-20 predicts risk of violence. We hypothesized that items on the DUNDRUM-1 and DUNDRUM-2 scales, rated at the time of pre-admission assessment, would predict length of stay in a medium secure forensic hospital setting. METHODS: This is a prospective study. All admissions to a medium secure forensic hospital setting were collated over a 54 month period (n = 279) and followed up for a total of 66 months. Each patient was rated using the DUNDRUM-1 triage security scale and DUNDRUM-2 triage urgency scale as part of a pre admission assessment (n = 279) and HCR-20 within 2 weeks of admission (n = 187). Episodes of harm to self, harm to others and episodes of seclusion whilst an in patient were collated. Date of discharge was noted for each individual. RESULTS: Diagnosis at the time of pre-admission assessment (adjustment disorder v other diagnosis), predicted legal status (sentenced v mental health order) and items on the DUNDRUM-1 triage security scale and the DUNDRUM-2 triage urgency scale, also rated at the time of pre-admission assessment, predicted length of stay in the forensic hospital setting. Need for seclusion following admission also predicted length of stay. CONCLUSIONS: These findings may form the basis for a structured professional judgment instrument, rated prior to or at time of admission, to assist in estimating length of stay for forensic patients. Such a tool would be useful to clinicians, service planners and commissioners given the high cost of secure psychiatric care. PMID- 26597631 TI - Transmission of SARS and MERS coronaviruses and influenza virus in healthcare settings: the possible role of dry surface contamination. AB - Viruses with pandemic potential including H1N1, H5N1, and H5N7 influenza viruses, and severe acute respiratory syndrome (SARS)/Middle East respiratory syndrome (MERS) coronaviruses (CoV) have emerged in recent years. SARS-CoV, MERS-CoV, and influenza virus can survive on surfaces for extended periods, sometimes up to months. Factors influencing the survival of these viruses on surfaces include: strain variation, titre, surface type, suspending medium, mode of deposition, temperature and relative humidity, and the method used to determine the viability of the virus. Environmental sampling has identified contamination in field settings with SARS-CoV and influenza virus, although the frequent use of molecular detection methods may not necessarily represent the presence of viable virus. The importance of indirect contact transmission (involving contamination of inanimate surfaces) is uncertain compared with other transmission routes, principally direct contact transmission (independent of surface contamination), droplet, and airborne routes. However, influenza virus and SARS-CoV may be shed into the environment and be transferred from environmental surfaces to hands of patients and healthcare providers. Emerging data suggest that MERS-CoV also shares these properties. Once contaminated from the environment, hands can then initiate self-inoculation of mucous membranes of the nose, eyes or mouth. Mathematical and animal models, and intervention studies suggest that contact transmission is the most important route in some scenarios. Infection prevention and control implications include the need for hand hygiene and personal protective equipment to minimize self-contamination and to protect against inoculation of mucosal surfaces and the respiratory tract, and enhanced surface cleaning and disinfection in healthcare settings. PMID- 26597632 TI - Establishment of a multi-species biofilm model to evaluate chlorhexidine efficacy. AB - BACKGROUND: Chronic infections, for example, diabetic foot ulcers, have a large impact in terms of patient morbidity and mortality. These wounds are characterized by complex polymicrobial communities of bacteria, which may include a number of difficult-to-eradicate multidrug-resistant pathogens. AIM: To establish a multi-species biofilm model to test the efficacy of chlorhexidine and chlorhexidine-containing formulas in eradication of polymicrobial biofilms. METHODS: A Centers for Disease Control and Prevention bioreactor was used to establish a multi-species biofilm incorporating Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus and Enterococcus faecalis with equal numbers of each pathogen. This model was used to test the effectiveness of chlorhexidine at controlling the pre-formed biofilm. FINDINGS: Chlorhexidine digluconate (CHD) was added to the bioreactor at a range of concentrations. K. pneumoniae and P. aeruginosa survived within multi-species biofilms, up to and including 4% CHD, whereas S. aureus was reduced to below the level of detection at 1%. Wiping the biofilm-containing coupons from the bioreactor with chlorhexidine-containing medical wipes resulted in >3 to <4log10 reduction after 24h, for all species. When the coupons were embedded in a simulated wound bed, formed in an agar plate, CHD-containing medical dressings completely eliminated S. aureus (>8log10 reduction), but had minimal effect (<3log10) against the other species tested. CONCLUSION: The study demonstrates that the effectiveness of chlorhexidine may be limited in settings where it is required to act on multi species biofilms. This may compromise the ability of chlorhexidine to control the infection and spread of these pathogens. PMID- 26597633 TI - Use of terminal filters to prevent Legionnaires' disease. PMID- 26597634 TI - New technology markedly improves hand-hygiene performance among healthcare workers after restroom visits. AB - The risks to patients from pathogens present on healthcare workers' (HCWs') hands are high; however, compliance with hand hygiene among HCWs is low. We devised a prospective intervention trial of a new hand-hygiene dispensing technology to improve HCWs' compliance with hand hygiene. Baseline hand-hygiene compliance was observed for three months before and after an intervention consisting of implementation of an electronic device that reminds people to comply with hand hygiene after restroom visits. Compliance in hand-hygiene performance after restroom visits increased among HCWs from 66% to 91% after the intervention. PMID- 26597635 TI - Transmission of metallo-beta-lactamase-producing Pseudomonas aeruginosa in a nephrology-transplant intensive care unit with potential link to the environment. AB - Pseudomonas aeruginosa has been recovered in hospitals from many different sources including sinks and taps. Because P. aeruginosa is one of the main agents of nosocomial infections and increasingly resistant to antibiotics, environmental reservoirs in hospital settings are of great concern. We report here on a cluster of five cases of infection by P. aeruginosa expressing VIM carbapenemases (VIM PA) in a nephrology intensive care unit. Our investigation pointed to transmission of VIM-PA via hands related to a contaminated tap. VIM-PA may be cross-transmitted to other patients if an environmental reservoir exists. Sinks and taps should be well designed and thoroughly cleaned and disinfected, and use of alcohol hand rub should be promoted. PMID- 26597636 TI - How and why to monitor Pseudomonas aeruginosa infections in the long term at a cystic fibrosis centre. AB - BACKGROUND: Pseudomonas aeruginosa is a major cystic fibrosis (CF) pathogen causing chronic respiratory infections and posing a risk for cross-infection between patients with CF. AIM: To propose an algorithm for long-term surveillance of P. aeruginosa and assess its suitability for monitoring the epidemiological situation at a CF centre with approximately 300 patients. METHODS: Over a nine year period, over 300 P. aeruginosa isolates from 131 infected patients were tested by multi-locus sequence typing (MLST) and/or random amplified polymorphic DNA (RAPD) assay. FINDINGS: MLST analysis led to the identification of 97 different sequence types which were distributed among 17 RAPD-generated (pseudo)clusters. This indicates that the easy-to-perform RAPD assay is only suitable for intra-individual, not interindividual, strain analyses. No epidemic strains were observed. Longitudinal analysis revealed that 110 of the 131 patients were infected with the same strain over the observation period, whereas 21 patients had a strain replacement or a new infection. Chronic infection was found in 99 of the 131 patients, and the remaining 32 patients met the criteria for intermittent infection (as defined by the Leeds criteria). Eighteen of the 32 patients (56%) with intermittent infection were infected with the same strain for up to nine years. CONCLUSION: The strain type only changed in 16% of 131 patients with chronic or intermittent infection. As many as 56% of patients considered to have intermittent infection were actually chronically infected with the same strain for many years. PMID- 26597637 TI - Impact of infection with extended-spectrum beta-lactamase-producing Escherichia coli or Klebsiella species on outcome and hospitalization costs. AB - BACKGROUND: Extended-spectrum beta-lactamase (ESBL)-producing bacteria are important sources of infection; however, Canadian data evaluating the impact of ESBL-associated infection are lacking. AIM: To determine whether patients infected with ESBL-producing Escherichia coli or Klebsiella species (ESBL-EcKs) exhibit differences in clinical outcome, microbiological outcome, mortality, and/or hospital resource use compared to patients infected with non-ESBL producing strains. METHODS: A retrospective case-control study of 75 case patients with ESBL-EcKs matched to controls infected with non-ESBL-EcKs who were hospitalized from June 2010 to April 2013 was conducted. Patient-level cost data were provided by the institution's business office. Clinical data were collected using the electronic databases and paper charts. FINDINGS: Median infection related hospitalization costs per patient were greater for cases than controls (C$10,507 vs C$7,882; median difference: C$3,416; P = 0.04). The primary driver of increased costs was prolonged infection-related hospital length of stay (8 vs 6 days; P = 0.02) with patient location (ward, ICU) and indirect care costs (including costs associated with infection prevention and control) as the leading cost categories. Cases were more likely to experience clinical failure (25% vs 11%; P = 0.03), with a higher all-cause mortality (17% vs 5%; P = 0.04). Less than half of case patients were prescribed appropriate empiric antimicrobial therapy, whereas controls received adequate initial treatment in nearly all circumstances (48% vs 96%; P < 0.01). CONCLUSION: Patients with infection caused by ESBL-EcKs are at increased risk for clinical failure and mortality, with additional cost to the Canadian healthcare system of C$3,416 per patient. PMID- 26597638 TI - PET imaging studies show enhanced expression of mGluR5 and inflammatory response during progressive degeneration in ALS mouse model expressing SOD1-G93A gene. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative motor neuron disorder. Genetic studies have linked mutation of the gene SOD1 to ALS pathology as well as several other pathological processes including modulation of glutamatergic function and inflammatory processes. Since therapeutic approaches for ALS are focused on glutamatergic function, we investigated modulation of glutamate transport based on its receptor function as well as excitotoxicity-induced inflammatory response. METHODS: In vivo positron emission tomography (PET) imaging studies of metabotropic glutamate receptor subtype 5 (mGluR5) using [(18)F]FPEB ([(18)F]3-fluoro-5-(2 pyridylethynyl)benzonitrile) and inflammatory response using [(11)C]PBR28 (peripheral benzodiazepine receptor ligand 28) were done in an early and a late phase of neurodegeneration in four ALS mice expressing SOD1-G93A gene and four control base mice (C57/BL6). Accumulation of [(18)F]FPEB and [(11)C]PBR28 were quantitated in several brain areas and spinal cord to determine degeneration induced modulation. The studies were completed with immunohistochemical analyses of mGluR5 and inflammatory response. RESULTS: These studies showed enhanced binding potential of [(18)F]FPEB in several brain areas including striatum, hippocampus, and frontal cortex. In the whole brain, the binding potential increased 49 +/- 9 % from base mice to ALS-type mice and further enhanced 23 +/- 4 % during disease progression. Also, in the spinal cord 6-22 %, enhanced accumulation of [(18)F]FPEB was observed during progression of the disease. The accumulation of [(11)C]PBR28 increased by 110 +/- 33 % in the whole brain during progression of the disease indicating significant inflammatory process. [(11)C]PBR28 accumulation enhanced 89-264 % in the spinal cord and 204 % in the lungs. The end point immunohistochemical analyses verified the enhanced mGluR5 expression and inflammation. CONCLUSIONS: These results confirm the role of glutamate and inflammation in ALS-type pathology. These data also support the hypothesis that excessive glutamate may contribute to inflammation in the chronic neurodegenerative processes in ALS. PMID- 26597639 TI - Spatial Bayesian belief networks as a planning decision tool for mapping ecosystem services trade-offs on forested landscapes. AB - An integrated methodology, based on linking Bayesian belief networks (BBN) with GIS, is proposed for combining available evidence to help forest managers evaluate implications and trade-offs between forest production and conservation measures to preserve biodiversity in forested habitats. A Bayesian belief network is a probabilistic graphical model that represents variables and their dependencies through specifying probabilistic relationships. In spatially explicit decision problems where it is difficult to choose appropriate combinations of interventions, the proposed integration of a BBN with GIS helped to facilitate shared understanding of the human-landscape relationships, while fostering collective management that can be incorporated into landscape planning processes. Trades-offs become more and more relevant in these landscape contexts where the participation of many and varied stakeholder groups is indispensable. With these challenges in mind, our integrated approach incorporates GIS-based data with expert knowledge to consider two different land use interests - biodiversity value for conservation and timber production potential - with the focus on a complex mountain landscape in the French Alps. The spatial models produced provided different alternatives of suitable sites that can be used by policy makers in order to support conservation priorities while addressing management options. The approach provided provide a common reasoning language among different experts from different backgrounds while helped to identify spatially explicit conflictive areas. PMID- 26597640 TI - Cyclohexane-1,2-dicarboxylic acid diisononyl ester and metabolite effects on rat epididymal stromal vascular fraction differentiation of adipose tissue (2015) Environmental Research 140: 145-156 Reply to the letter by Otter R. PMID- 26597641 TI - [Topical ambroxol for the treatment of neuropathic pain: A first clinical observation. German version]. AB - BACKGROUND: Neuropathic pain is difficult to treat and available options are frequently not sufficient. The expectorant ambroxol also works as a strong local anesthetic and blocks sodium channels about 40 times more potently than lidocaine. Ambroxol preferentially inhibits the channel subtype Nav 1.8, which is expressed particularly in nociceptive C fibers. Due to the low toxicity, topical ambroxol seemed to represent a reasonable therapeutic attempt for treatment of neuropathic pain resistant to other standard options. MATERIALS AND METHODS: Medical records of 7 patients with severe neuropathic pain, in whom many attempts at treatment with approved substances were not sufficient or possible, are reported retrospectively. Patients were then treated with topical ambroxol 20% cream applied in the area of neuropathic pain. RESULTS: Causes of neuropathic pain were postherpetic neuralgia (2-*), mononeuropathy multiplex, phantom pain, deafferentation pain, postoperative neuralgia and an unclear allodynia of the foot. Mean pain intensity was reported as 4-6/10 on a numeric rating scale (NRS) and maximum pain intensity as 6-10/10. Pain reduction following ambroxol cream was 2-8 points (NRS) within 15-30 min and lasted 3-8 h. Pain attacks were reduced in all 5 patients presenting this problem. Topical ambroxol achieved pain reduction in 4 patients with no improvement after lidocaine 5% and 1 patient with no response to capsaicin 8%. No adverse events or skin changes have been observed, and the longest treatment duration is currently 4 years. CONCLUSION: Ambroxol acts as a strong local anesthetic and preferentially inhibits the nociceptive-relevant sodium channel subtype Nav 1.8. For the first time, we report relevant pain reduction following topical Ambroxol 20% cream in patients with neuropathic pain. Regarding the advantageous profile with rare side effects, the clinical benefit for pain patients should be further investigated. PMID- 26597642 TI - A retrospective analysis of factors influencing the success of autotransplanted posterior teeth. AB - BACKGROUND: Survival and success rates of tooth transplantations even after long follow-up periods have been shown to be very high. Nevertheless, it is important to analyse factors potentially influencing these rates. The aim of this study was to assess the influence on success of potential factors. METHODS: The research was based on a retrospective analysis of clinical and radiological data from a sample of 59 subjects (75 transplanted teeth). The follow-up period varied from 0.44 to 12.28 years (mean 3.95 years). Success rates were calculated and depicted with Kaplan-Meier plots. Log-rank tests were used to analyse the effect of root development stage, apex width, the use of enamel matrix proteins or the surgeon on success of transplantations. RESULTS: Results for success of premolar transplantations were comparable with already published data, while molars performed worse than shown in other studies. The surgeon performing the transplantation (p = 0.001) and tooth type (p <= 0.001) were significantly associated with transplantation success. Use of enamel matrix proteins (p = 0.10), root development stage (p = 0.13), the recipient area (p = 0.48) and apex width (p = 0.59) were not significantly associated with success. CONCLUSIONS: Molar transplantations were not as successful as premolar transplantations; however, success rates varied greatly depending on the surgeon's experience. The use of enamel matrix proteins as well as root development stage, the recipient area and apex width did not show significant associations with success of tooth transplantations. PMID- 26597643 TI - [Complications of Descemet's membrane endothelial keratoplasty]. AB - Descemet's membrane endothelial keratoplasty (DMEK) is a relatively new, but now established surgical procedure to cure corneal endothelial disorders. However, there are donor- and recipient-associated sources of potential complications, some of which can be identified and addressed prior to the procedure and others that may lead to intra- or postoperative problems. Preoperatively, risk factors for a limited visual outcome (ocular comorbidities, previous ocular surgery, subepithelial/stromal scars) and the specific indication for DMEK should be discussed with the patient. Intraoperatively, young donor age can be associated with a particularly elastic graft, which may be difficult to unfold. Such transplants are not appropriate for particularly difficult recipient situations (very opaque cornea, history of vitreoretinal surgery). Postoperatively, transplant dehiscence is the most common complication, which in many cases can be managed by reinjection of air (or a 20 % SF6 gas/air mix) into the anterior chamber. An elevation of the intraocular pressure after DMEK is often caused by a reaction to topical steroid therapy. Although immune rejections after DMEK are less likely than after Descemet's stripping automated endothelial keratoplasty (DSAEK) and perforating keratoplasty, adequate treatment with topical steroidal drugs is recommended. These common and several rare complications are discussed in this review. PMID- 26597644 TI - From Fantasy to Reality: A Grounded Theory of Experiences in the Swinging Lifestyle. AB - Swinger couples-committed couples who consensually engage in extra-relational sex for recreational purposes-are difficult for researchers to access due to the social stigma associated with swinging. This study builds upon the limited research on swinger couples by examining personal experiences with swinging. Specifically, 32 semi-structured interviews with swingers (16 husband-wife dyads, interviewed separately) were analyzed using grounded theory methods to understand the process of transitioning into and maintaining marital satisfaction in the swinging lifestyle. The model formed included (a) antecedent steps taken to enter into the lifestyle, (b) types of desires fulfilled, (c) stated benefits of being in the lifestyle, and (d) rules that guided couples throughout the process. Although variations were found across couples, the effective use of verbal and non-verbal communication to increase sexual and marital satisfaction within these non-monogamous couples was paramount to their experiences. PMID- 26597645 TI - Factors Associated With Sexual Coercion in a Representative Sample of Men in Australian Prisons. AB - Very little research has focused on men or prisoners as victims of sexual violence. This study provides the first population-based analysis of factors associated with sexual coercion of men in Australian prisons, and the first to use a computer-assisted telephone interview to collect this information in a prison setting. A random sample of men in New South Wales and Queensland prisons were surveyed using computer-assisted telephone interviewing. We asked participants about sexual coercion, defined as being forced or frightened into doing something sexually that was unwanted while in prison. Associations between sexual coercion in prison and sociodemographics, sexual coercion history outside of prison, and prison-related factors were examined. Logistic regression was used to estimate adjusted odds ratios in examining factors associated with sexual coercion in prisons. Of 2626 eligible men, 2000 participated. Participants identifying as non-heterosexual and those with a history of sexual coercion outside prison were found to be most at risk. Those in prison for the first time and those who had spent more than 5 years in prison ever were also more likely to report sexual coercion. Although prison policies and improving prison officer training may help address immediate safety and health concerns of those at risk, given the sensitivity of the issue and likely under-reporting to correctional staff, community-based organizations and prisoner peer-based groups arguably have a role too in providing both preventive and trauma-focused support. PMID- 26597647 TI - Femininity and Kin-Directed Altruism in Androphilic Men: A Test of an Evolutionary Developmental Model. AB - Androphilia refers to sexual attraction and arousal toward males whereas gynephilia refers to sexual attraction and arousal toward females. This study tested the adaptive feminine phenotype model of the evolution of male androphilia via kin selection, which posits that the development of an evolved disposition toward elevated kin-directed altruism among androphilic males is contingent on the behavioral expression of femininity. Gynephilic men, androphilic women, and androphilic men (N = 387) completed measures of childhood and adulthood gender expression and concern for kin's well-being. Adulthood femininity correlated positively with uncle/aunt-like tendencies among androphilic men and women. Although androphilic women reported greater willingness to invest in nieces and nephews than gynephilic and androphilic men, mediation analyses indicated that adult femininity completely mediated these group differences. In addition, changes in the expression of femininity between childhood and adulthood were associated with parallel changes in concern for the well-being of kin among androphilic men. Thus, these findings suggest that femininity is key to the expression of kin-directed altruism among androphilic males and may have been important in the evolution of male androphilia. PMID- 26597646 TI - Oral vs. Vaginal Sex Experiences and Consequences Among First-Year College Students. AB - To fully understand late adolescents' experiences of oral sex, we must consider both risk and normative developmental perspectives. Sexual experiences include a range of behaviors, but research on sexual behaviors and consequences focuses primarily on vaginal sex. Oral sex occurs at rates similar to vaginal sex, and carries some, though less, risk than vaginal sex. The current study examined the event-level prevalence and consequences of oral sex compared to vaginal sex with other-sex partners in first-year college students. Daily data were from recently sexually active first-year college students (N = 253 people, 834 days; M age, 18.4 years; SD = 0.4; 56% female; 31% Hispanic/Latino; 17% African American, 14% Asian American/Pacific Islander, 25% European American, 12% multiracial) who reported on sexual behaviors and consequences. Both positive (intimacy, physical satisfaction) and negative (worrying about health, guilt) consequences were less common for oral than vaginal sex. Gender differences suggested that female adolescents may find vaginal sex more rewarding than oral sex, whereas male adolescents may find them equally rewarding. PMID- 26597648 TI - Neural Correlates of Psychosis and Gender Dysphoria in an Adult Male. AB - Gender dysphoria (GD) (DSM-5) or transsexualism (ICD-10) refers to the marked incongruity between the experience of one's gender and the sex at birth. In this case report, we describe the use of LSD as a triggering factor of confusion in the gender identity of a 39-year-old male patient, with symptoms of psychosis and 25 years of substance abuse, who sought psychiatric care with the desire to undergo sex reassignment surgery. The symptoms of GD/psychosis were resolved by two therapeutic measures: withdrawal of psychoactive substances and use of a low dose antipsychotic. We discuss the hypothesis that the superior parietal cortical area may be an important locus for body image and that symptoms of GD may be related to variations underlying this brain region. Finally, this case report shows that some presentations of GD can be created by life experience in individuals who have underlying mental or, synonymously, neurophysiological abnormalities. PMID- 26597649 TI - Lay Conceptions of Sexual Minority Groups. AB - Bisexual people are often implored to "pick a side," implying that bisexuality is both more controllable and less desirable than heterosexuality or homosexuality. Bisexual people's status as a social group perceived to fall between a traditionally advantaged group and a traditionally disadvantaged group may have the potential to clarify lay conceptions of sexual orientation. We examined participants' views of groups varying in sexual orientation by randomly assigning participants (including heterosexual men and women as well as gay men and lesbian women) from four samples to evaluate heterosexual, bisexual, or homosexual targets (N = 1379). Results provided strong evidence for the previously untested theoretical argument that bisexuality is perceived as less stable than heterosexuality or homosexuality. In addition, participants low in Personal Need for Structure rated female (but not male) bisexuality as relatively stable, suggesting that a preference for simple, binary thinking can partially explain a negative conception of an ostensibly "intermediate" identity. Bisexual targets were perceived as falling between heterosexual and homosexual targets in terms of gender nonconformity, and less decisive, less monogamous, and lacking in positive traits that were associated with homosexual targets. In sum, views of bisexual people were both more negative than and qualitatively different from views of gay men and lesbian women. We discuss the results as an illustration of the complex ways that perceivers' attitudes can differ depending on which target groups they are considering, suggesting that intergroup bias cannot be fully understood without attending to social categories viewed as intermediate. PMID- 26597650 TI - Early phonetic development in typically developing children: A longitudinal investigation from Cypriot-Greek child data. AB - The current longitudinal study examined the acquisition of consonantal singleton segments in Cypriot-Greek. The study's aims were: (a) to determine the acquisition of segments for manner and place of articulation as a function of age and word position, (b) to provide preliminary normative data, and (c) to further support the cross-linguistic data pool regarding developmental phonology patterns. Participants were 14 Cypriot-Greek speaking typically developing toddlers, examined at ages 24, 28, 32 and 36 months. Spontaneously produced and elicited glossable utterances were used in constructing each child's inventory. Findings revealed an increase of segmental acquisition across all age levels. Group trend analysis for manner and place of articulation indicated bilabial and alveolar stops and nasals to be among the earlier segments to develop. A word medial position advantage was also evident. The findings are discussed in terms of phonological universals and language-specific factors. Implications for early evidence-based phonetic assessment are discussed. PMID- 26597651 TI - Subclonal heterogeneity in chronic lymphocytic leukaemia: revealing the importance of the lymphoid tumour microenvironment. PMID- 26597652 TI - Editorial: Recent Advances in Molecular Detection of Human Papillomavirus and Cervical Cancer Screening. PMID- 26597654 TI - Comparison of (90)Y activity measurements in nuclear medicine in Germany. AB - In 2014, PTB and the company Eckert & Ziegler organized a national comparison exercise to determine the activity of a (90)Y solution. One aim of the comparison was to assess the measurement capability of hospitals and medical practices in Germany. P6-type vials were filled with aliquots of a radioactive (90)Y solution and then sent to 19 participants who were asked to measure the activity in the ampoules as well as in their own standard geometry using syringes. Most of the submitted results have a deviation of less than +/-10% from the PTB reference activity when measured in the P6-type vials. The spread is somewhat larger when measured in a syringe geometry. The comparison revealed that some participants have difficulties in applying decay corrections and only a few participants were capable of estimating realistic measurement uncertainties. PMID- 26597653 TI - Assuring access to topical mosquito repellents within an intensive distribution scheme: a case study in a remote province of Cambodia. AB - BACKGROUND: The public health value of a vector control tool depends on its epidemiological efficacy, but also on its ease of implementation. This study describes an intensive distribution scheme of a topical repellent implemented in 2012 and 2013 for the purpose of a cluster-randomized trial using the existing public health system. The trial aimed to assess the effectiveness of repellents in addition to long-lasting insecticidal nets (LLIN) and occurred in a province of Cambodia. Determinants for accessibility and consumption of this tool were explored. METHODS: 135 individuals were appointed to be repellent distributors in 57 villages. A 2-weekly bottle exchange programme was organized. Distributors recorded information regarding the amount of bottles exchanged, repellent leftover, and reasons for not complying in household data sheets. Distributor household contact rates and average 2-weekly consumption of repellent were calculated. Household and distributors characteristics were obtained using questionnaires, surveying 50 households per cluster and all distributors. Regression models were used to explore associations between contact and consumption rates and determinants such as socio-economic status. Operational costs for repellent and net distribution were obtained from the MalaResT project and the provincial health department. RESULTS: A fourfold increase in distributor household contact rates was observed in 2013 compared to 2012 (median2012 = 20 %, median2013 = 88.9 %). Consumption rate tripled over the 2-year study period (median2012 = 20 %, median2013 = 57.89 %). Contact rates were found to associate with district, commune and knowing the distributor, while consumption was associated with district and household head occupation. The annual operational cost per capita for repellent distribution was 31 times more expensive than LLIN distribution (USD 4.33 versus USD 0.14). DISCUSSION: After the existing public health system was reinforced with programmatic and logistic support, an intense 2 weekly distribution scheme of a vector control tool over a 2-year period was operated successfully in the field. Lack of associations with socio-economic status suggested that the free distribution strategy resulted in equitable access to repellents. The operational costs for the repellent distribution and exchange programme were much higher than LLIN distribution. Such effort could only be justified in the context of malaria elimination where these interventions are expected to be limited in time. PMID- 26597655 TI - Distribution of radionuclides in an iron calibration standard for a free release measurement facility. AB - A Europallet-sized calibration standard composed of 12 grey cast iron tubes contaminated with (60)Co and (110m)Ag with a mass of 246kg was developed. As the tubes were produced through centrifugal casting it was of particular concern to study the distribution of radionuclides in the radial direction of the tubes. This was done by removing 72 small samples (swarf) of ~0.3g each on both the inside and outside of the tubes. All of the samples were measured in the underground laboratory HADES. PMID- 26597656 TI - An SNP in Exon 11 of Chicken 5'-AMP-Activated Protein Kinase Gamma 3 Subunit Gene was Associated with Meat Water Holding Capacity. AB - The 5'-Adenosine-monophosphate -activated protein kinase plays a key role in regulating cellular energy homeostasis, and it was reported that nucleotide variants in the genes coding the protein were associated with meat quality. In the present study, genetic variations in the exons of gamma non-catalytic subunit genes of the protein kinase were screened among 284 White Plymouth Rock chickens from 7 families with denaturing gradient gel electrophoresis, and their meat quality traits including drip loss and cooked meat rate which reflect water holding capacity and serum biochemical indices were also measured, and the association between the genotypes and the traits was analyzed with a SAS GLM procedure. Our results showed that there were three G/A nucleotide variants including one in exon 6 of the gamma subunit 2 gene and two in exon 11 of the gamma subunit 3 gene, which resulted in amino acid substitutions V150I, V315 M, and A337 T, respectively. And locus V315 M was associated with water holding capacity significantly (P < 0.05). The studied polymorphic locus has the potential to be used as a genetic marker for poultry breeding work. PMID- 26597657 TI - Association of recently described adipokines with liver histology in biopsy proven non-alcoholic fatty liver disease: a systematic review. AB - The prevalence of non-alcoholic fatty liver disease (NAFLD) is rising, as is the prevalence of obesity and type 2 diabetes. It is increasingly recognized that an impaired pattern in adipokine secretion could play a pivotal role in the development of NAFLD. We performed a systematic review to evaluate the potential link between newly described adipokines and liver histology in biopsy-proven NAFLD patients. A computerized literature search was performed in PubMed, EMBASE and Web of Science electronic databases. Thirty-one cross-sectional studies were included, resulting in a total of seven different investigated adipokines. Studies included in this review mainly had a good methodological quality. Most adipokines were suggested to be involved in the inflammatory response that develops within the context of NAFLD, either at hepatic or systemic level, and/or hepatic insulin resistance. Based on literature, clinical studies suggest that chemerin, resistin and adipocyte-fatty-acid-binding protein potentially are involved in NAFLD pathogenesis and/or progression. However, major inconsistency still exists, and there is a high need for larger studies, together with the need of standardized assays to determine adipokine levels. PMID- 26597658 TI - A comparison of normal and osteoarthritic humeral head size and morphology. AB - BACKGROUND: The purpose of this study was to evaluate and to compare the size and morphologic patterns among normal and osteoarthritic (OA) humeral heads. METHODS: This comparative anatomic imaging study evaluated 150 humeral heads that were separated into 3 cohorts: normal, OA with symmetric glenoid erosion, and OA with asymmetric (type B2) glenoid erosion. Three-dimensional models were created of the humeral head from computed tomography data, and point coordinates were extracted for evaluation. Parameters measured were diameter (sphere fit and circle fit), chord distance (superoinferior and anteroposterior), and humeral head height. RESULTS: The sphere-fit diameter of the humeral head for the entire OA cohort (100 patients; mean diameter, 59 +/- 9 mm) was significantly greater (P < .001) than that of the normal cohort (50 patients; mean diameter, 49 +/- 5 mm). Similarly, the humeral head circle-fit diameters in the superoinferior and anteroposterior planes were significantly greater (P < .001) in the combined OA cohorts (59 +/- 9 mm and 56 +/- 10 mm, respectively) compared with the normal cohort (51 +/- 5 mm and 47 +/- 5 mm, respectively). However, there were no significant differences (P >= .099) between the symmetric and asymmetric OA cohorts in sphere-fit or circle-fit diameters. The mean values of humeral head heights were not significantly different (P = .382) between cohorts, 19 +/- 2 mm, 18 +/- 2 mm, and 18 +/- 2 mm for the normal, symmetric, and asymmetric cohorts, respectively. DISCUSSION: Although OA humeral head morphology varies significantly from normal, it does not vary as a function of the Walch classification between symmetric and asymmetric glenoids. Understanding of the morphologic variability of the pathologic humeral head may provide insight into the pathoanatomy of osteoarthritis and the development of various erosion patterns. PMID- 26597659 TI - Development and evaluation of a real-time RT-PCR assay for the detection of Ebola virus (Zaire) during an Ebola outbreak in Guinea in 2014-2015. AB - In early February 2014, an outbreak of the Ebola virus disease caused by Zaire ebolavirus (EBOV) occurred in Guinea; cases were also recorded in other West African countries with a combined population of approximately 25 million. A rapid, sensitive and inexpensive method for detecting EBOV is needed to effectively control such outbreak. Here, we report a real-time reverse transcription PCR assay for Z. ebolavirus detection used by the Specialized Anti epidemic Team of the Russian Federation during the Ebola virus disease prevention mission in the Republic of Guinea. The analytical sensitivity of the assay is 5 * 10(2) viral particles per ml, and high specificity is demonstrated using representative sampling of viral, bacterial and human nucleic acids. This assay can be applied successfully for detecting the West African strains of Z. ebolavirus as well as on strains isolated in the Democratic Republic of the Congo in 2014. PMID- 26597660 TI - A prospective clinical trial of HIFU hemiablation for clinically localized prostate cancer. AB - BACKGROUND: Focal therapy is an emerging mini-invasive treatment modality for localized prostate cancer aimed to reduce the morbidity associated with radical therapy while maintaining optimal cancer control. We report the mid-term oncological and functional results of primary hemiablation high-intensity focused ultrasound (HIFU) in a prospective cohort of patients. METHODS: Over 8 years, hemiablation HIFU was primarily performed in 50 selected patients with biopsy proven clinically localized unilateral, low-intermediate risk prostate cancer in complete concordance with the prostate cancer lesions identified by magnetic resonance imaging with precise loci matching on multimodal approach. Post treatment follow-up included regular serial PSA measurements. Biochemical recurrence was reported using Stuttgart and Phoenix criteria. The latter was used as a threshold to offer whole-gland biopsies. RESULTS: Complete follow-up was available for all patients and the median follow-up was 39.5 months (range: 6 94). Mean nadir PSA value was 1.6 ng ml(-1), which represents 72% reduction compared with initial PSA pre-treatment value (P<0.001). Median time to achieve PSA nadir was 3 months. Biochemical recurrence, according to Phoenix and Stuttgart definition, occurred in 28 and 36% of patients, respectively. The 5 year actuarial metastases-free survival, cancer-specific survival and overall survival rates were 93, 100 and 87%, respectively. Out of the eight patients undergoing biopsy, six patients had a positive biopsy for cancer occurring in the untreated contralateral (n=3) or treated ipsilateral lobe (n=1) or bilaterally (n=2). A Clavien-Dindo grade 3b complication occurred in two patients. Complete continence (no pads) and erection sufficient for intercourse were documented in 94 or 80% of patients, respectively. CONCLUSION: Hemiablation HIFU therapy, delivered with intention to treat, for carefully selected patients affords mid term promising functional and oncological outcomes. The effectiveness of this technique should be now compared with whole-gland radical therapy. PMID- 26597663 TI - Genetic factors influencing ferritin levels in 14,126 blood donors: results from the Danish Blood Donor Study. AB - BACKGROUND: Many biologic functions depend on sufficient iron levels, and iron deficiency is especially common among blood donors. Genetic variants associated with iron levels have been identified, but the impact of genetic variation on iron levels among blood donors remains unclear. STUDY DESIGN AND METHODS: The effect of six single-nucleotide polymorphisms (SNPs) on ferritin levels in 14,126 blood donors were investigated in four genes: in Human Hemochromatosis Protein gene (HFE; rs1800562 and rs179945); in Transmembrane Protease gene, Serine 6 (TMPRSS6-regulating hepcidin; rs855791); in BTB domain containing protein gene (BTBD9-associated with restless legs syndrome; rs9357271); and in the Transferrin gene (TF; rs2280673 and rs1830084). Multiple linear and logistic regression analyses were used to evaluate the effect of each SNP on ferritin levels and the risk of iron deficiency (ferritin < 15 ng/mL). RESULTS: In HFE, the G-allele of rs1800562 was associated with lower iron stores in both sexes. This was also true for the C-allele of rs179945, but in men only. Also, the T-allele of TMPRSS6 rs855791 was negatively associated with iron stores in men. Homozygocity for C in rs1799945 was associated with iron deficiency in women. Results for all other genetic variants were insignificant. CONCLUSION: Genetic variants associated with hemochromatosis may protect donors against depleted iron stores. In addition, we showed that presence of the T-allele at rs855791 in TMPRSS6 was associated with lower iron stores in men. PMID- 26597662 TI - Genetic assessment of additional endophenotypes from the Consortium on the Genetics of Schizophrenia Family Study. AB - The Consortium on the Genetics of Schizophrenia Family Study (COGS-1) has previously reported our efforts to characterize the genetic architecture of 12 primary endophenotypes for schizophrenia. We now report the characterization of 13 additional measures derived from the same endophenotype test paradigms in the COGS-1 families. Nine of the measures were found to discriminate between schizophrenia patients and controls, were significantly heritable (31 to 62%), and were sufficiently independent of previously assessed endophenotypes, demonstrating utility as additional endophenotypes. Genotyping via a custom array of 1536 SNPs from 94 candidate genes identified associations for CTNNA2, ERBB4, GRID1, GRID2, GRIK3, GRIK4, GRIN2B, NOS1AP, NRG1, and RELN across multiple endophenotypes. An experiment-wide p value of 0.003 suggested that the associations across all SNPs and endophenotypes collectively exceeded chance. Linkage analyses performed using a genome-wide SNP array further identified significant or suggestive linkage for six of the candidate endophenotypes, with several genes of interest located beneath the linkage peaks (e.g., CSMD1, DISC1, DLGAP2, GRIK2, GRIN3A, and SLC6A3). While the partial convergence of the association and linkage likely reflects differences in density of gene coverage provided by the distinct genotyping platforms, it is also likely an indication of the differential contribution of rare and common variants for some genes and methodological differences in detection ability. Still, many of the genes implicated by COGS through endophenotypes have been identified by independent studies of common, rare, and de novo variation in schizophrenia, all converging on a functional genetic network related to glutamatergic neurotransmission that warrants further investigation. PMID- 26597664 TI - Risk of venous thromboembolic events following inferior vena cava resection and reconstruction. AB - OBJECTIVE: The perioperative risk of an acute venous thromboembolism (VTE) event after inferior vena cava (IVC) reconstruction is unknown. We sought to describe VTE outcomes of our 15-year IVC reconstruction experience. METHODS: We performed a retrospective institutional review of all patients who underwent IVC reconstruction (September 1999-October 2014) and describe perioperative VTE outcomes. RESULTS: Sixty-five patients (mean age 58 +/- 2 years) underwent IVC reconstruction (primary repair, 25%; patch, 43%; graft, 32%), most commonly for renal cell carcinoma (51%) and retroperitoneal sarcoma (22%). The overall incidence of perioperative VTE was 22% (n = 14), including isolated deep vein thrombosis (DVT) in 9% (n = 6) and pulmonary embolism in 12% (n = 8; 4 with concomitant DVT). Median time to diagnosis was 6 days (range, 1-37 days). Most VTE patients were symptomatic (57%; 8 of 14), including lower extremity edema in 50%, acute desaturation in 43%, and hemodynamic compromise in 36%. No patient died as a result of his or her VTE. There was a trend for more overall VTE events in patients who underwent graft reconstruction (primary, 13%; patch, 18%; graft, 33%; P = .06). VTE was also significantly associated with larger tumor size, renal vein reimplantation, and blood transfusions (P <= .05). Late complications of VTE included lower extremity edema in two patients and graft thrombosis in one patient. CONCLUSIONS: IVC reconstruction can be performed safely with low VTE associated morbidity. Routine anticoagulation might not be warranted in these patients, but early postoperative screening for DVT should be considered, especially in cases with large tumor burden or when graft reconstruction is performed. PMID- 26597665 TI - Isolated superior mesenteric artery dissection in China. AB - OBJECTIVE: This study investigated the status of isolated superior mesenteric artery (SMA) dissection in the most populous country, China. METHODS: The Chinese language literature published before December 2014 was reviewed. All case reports and series were included. If multiple reports originated from the same hospital and included overlapping time frames, only the most recent report was included. The clinical characteristics, imaging features, and treatment were analyzed. "Symptom relief" was used as the outcome measure. RESULTS: A total of 622 patients (88.5% male) with isolated SMA dissection were found in the Chinese language literature. Patients were a mean age of 55.4 years. Analysis of the demographic data showed that isolated SMA dissection was most reported from the developed areas of China. The most common symptom (91.1%) was abdominal pain, and 42.7% patients had hypertension as a complication. Contrast-enhanced computed tomography was used to diagnose 95.2% of patients. The mean distance from the SMA ostium to the beginning of the dissection was 20.1 mm (range, 0-65.0 mm). The mean length of dissection was 63.1 mm (range, 10.7-205.9 mm). The percentages of patients who underwent primary conservative, surgical, and endovascular treatments were 63.2%, 3.2% and 33.6%, respectively. As primary management, the symptom relief rate of conservative management, with or without anticoagulation, was 62.6% and 86.5%, respectively. The best result of conservative treatment was achieved in cases of Yun type I and Luan classification type B. The symptom relief rate of surgical and endovascular treatment was 100% and 95.2%, respectively. CONCLUSIONS: The incidence of isolated SMA dissection may not be as rare as previously reported. Endovascular treatment of isolated SMA dissection is commonly used in China as a first-line treatment. PMID- 26597666 TI - Results of repeated percutaneous interventions on failing arteriovenous fistulas and grafts and factors affecting outcomes. AB - OBJECTIVE: Repeated percutaneous interventions on failing arteriovenous fistulas (AVFs) and arteriovenous grafts (AVGs) for hemodialysis are common, but the outcomes are largely unknown. We sought to determine the results of the second percutaneous intervention on failing AVGs and AVFs and to identify factors associated with loss of patency. METHODS: For the purpose of this study, the second percutaneous intervention was identified as the index procedure. We reviewed the second percutaneous interventions on failing AVFs and AVGs at a single institution between 2007 and 2013. Patient comorbidities, graft or fistula configuration, lesion characteristics, and procedural characteristics of the intervention performed were analyzed with respect to technical success, primary patency, primary assisted patency, and secondary patency. Patency was defined per Society for Vascular Surgery recommended reporting standards and was determined from the time of the index procedure. Cox proportional hazards multivariable modeling was performed to identify independent determinants of loss of patency. RESULTS: Among 91 patients, 96 second-time percutaneous interventions were performed on 52 AVFs and 44 AVGs. Patients included 56% men and 44% women with a mean age of 64 +/- 17 years. The lesions intervened on were primarily located along the accessed portion of the outflow in AVFs and within the length of the graft and at the venous anastomosis in AVGs. Transluminal angioplasty alone was performed in 82 procedures (85%), and uncovered or covered stents were placed in 15 procedures (16%). Pharmacomechanical thrombectomy was performed in 32 patients (34%) and was more commonly performed in AVGs compared with AVFs (53% vs 17%; P = .0002). Technical success was achieved in 90 procedures (97%; n = 92). One-year primary patency, assisted primary patency, and secondary patency rates were 35%, 86%, and 86%, respectively. One-year primary patency did not differ between AVFs and AVGs, but secondary patency was lower for AVG in comparison to AVF (P = .04). On multivariable analysis, only the need for pharmacomechanical thrombectomy significantly predicted failure of primary patency (hazard ratio, 2.6; 95% confidence interval, 1.6-4.3). The presence of an AVG rather than an AVF independently predicted failure of secondary patency (hazard ratio, 2.9; 95% confidence interval, 1.0-8.2). CONCLUSIONS: The second percutaneous interventions on AVFs and AVGs are associated with excellent technical success but poor primary patency. The need for pharmacomechanical thrombectomy predicts the need for additional percutaneous intervention to maintain patency. With additional interventions, acceptable secondary patency out to 5 years can be achieved, although AVGs have inferior secondary patency to AVFs. To develop optimal practice management algorithms, the effectiveness of repeated percutaneous interventions for failing AVGs and AVFs vs creation of a new access should be further investigated. PMID- 26597667 TI - Resolution of plasma sample mix-ups through comparison of patient antibody patterns to E. coli. AB - BACKGROUND: Accidental sample mix-ups and the need for their swift resolution is a challenge faced by every analytical laboratory. To this end, we developed a simple immunoblot-based method, making use of a patient's characteristic plasma antibody profile to Escherichia coli (E. coli) proteins. METHODS: Nitrocellulose strips of size-separated proteins from E. coli whole-cell lysates were incubated with patient plasma and visualised with an enzyme-coupled secondary antibody and substrate. Plasma samples of 20 random patients as well as five longitudinal samples of three patients were analysed for antibody band patterns, to evaluate uniqueness and consistency over time, respectively. For sample mix-ups, antibody band patterns of questionable samples were compared with samples of known identity. RESULTS: Comparison of anti-E. coli antibody patterns of 20 random patients showed a unique antibody profile for each patient. Antibody profiles remained consistent over time, as shown for three patients over several years. Three example cases demonstrate the use of this methodology in mis-labelling or pipetting incidences. CONCLUSION: Our simple method for resolving plasma sample mix-ups between non-related individuals can be performed with basic laboratory equipment and thus can easily be adopted by analytical laboratories. PMID- 26597669 TI - A New Diagnostic Clue to Osteomyelitis in Chronic Leg Ulcers. AB - BACKGROUND: Chronic leg ulcers are not infrequently complicated by chronic osteomyelitis, which mandates special treatment but may not be evident on radiography. Inflammatory cytokines may cause reactive thrombocytosis in chronic osteomyelitis. METHODS: Platelet counts were compared in a group of 24 inpatients with chronic leg ulcers and proven chronic osteomyelitis and 24 inpatients with chronic leg ulcers in whom osteomyelitis was not found. RESULTS: Mean and median platelet counts were significantly higher in the leg ulcer and osteomyelitis group vs the leg ulcer group (P <.001). At a cutoff of >350 * 10(9)/L, sensitivity was 62.5%, but specificity was 91.7%, with a positive predictive value of 88%. CONCLUSION: Thrombocytosis in chronic leg ulcers is a new, simple, readily available and inexpensive clue to osteomyelitis in chronic leg ulcers when identified, but its absence cannot rule it out. PMID- 26597668 TI - Lifetime Risk of Venous Thromboembolism in Two Cohort Studies. AB - BACKGROUND: Greater public awareness of venous thromboembolism may be an important next step for optimizing venous thromboembolism prevention and treatment. "Lifetime risk" is an easily interpretable way of presenting risk information. Therefore, we sought to calculate the lifetime risk of venous thromboembolism (deep vein thrombosis or pulmonary embolism) using data from 2 large, prospective cohort studies: the Cardiovascular Health Study (CHS) and the Atherosclerosis Risk in Communities (ARIC) study. METHODS: We followed participants aged 45-64 years in ARIC (n = 14,185) and >=65 in CHS (n = 5414) at baseline visits (1987-1989 in ARIC, 1989-1990 and 1992-1993 in CHS) for incident venous thromboembolism (n = 728 in ARIC through 2011 and n = 172 in CHS through 2001). We estimated lifetime risks and 95% confidence intervals of incident venous thromboembolism using a modified Kaplan-Meier method, accounting for the competing risk of death from other causes. RESULTS: At age 45 years, the remaining lifetime risk of venous thromboembolism in ARIC was 8.1% (95% confidence interval, 7.1-8.7). High-risk groups were African Americans (11.5% lifetime risk), those with obesity (10.9%), heterozygous for the factor V Leiden (17.1%), or with sickle cell trait or disease (18.2%). Lifetime risk estimates differed by cohort; these differences were explained by differences in time period of venous thromboembolism ascertainment. CONCLUSIONS: At least 1 in 12 middle-aged adults will develop venous thromboembolism in their remaining lifetime. This estimate of lifetime risk may be useful to promote awareness of venous thromboembolism and guide decisions at both clinical and policy levels. PMID- 26597670 TI - Suboptimal Addiction Interventions for Patients Hospitalized with Injection Drug Use-Associated Infective Endocarditis. AB - BACKGROUND: Infective endocarditis is a serious infection, often resulting from injection drug use. Inpatient treatment regularly focuses on management of infection without attention to the underlying addiction. We aimed to determine the addiction interventions done in patients hospitalized with injection drug use associated infective endocarditis. METHODS: This is a retrospective review of patients hospitalized with injection drug use-associated infective endocarditis from January, 2004 through August, 2014 at a large academic tertiary care center in Boston, Massachusetts. For the initial and subsequent admissions, data were collected regarding addiction interventions, including consultation by social work, addiction clinical nurse and psychiatry, documentation of addiction in the discharge summary plan, plan for medication-assisted treatment and naloxone provision. RESULTS: There were 102 patients admitted with injection drug use associated infective endocarditis, 50 patients (49.0%) were readmitted and 28 (27.5%) patients had ongoing injection drug use at readmission. At initial admission, 86.4% of patients had social work consultation, 23.7% had addiction consultation, and 24.0% had psychiatry consultation. Addiction was mentioned in 55.9% of discharge summary plans, 7.8% of patients had a plan for medication assisted treatment, and naloxone was never prescribed. Of 102 patients, 26 (25.5%) are deceased. The median age at death was 40.9 years (interquartile range 28.7-48.7). CONCLUSIONS: We found that patients hospitalized with injection drug use-associated infective endocarditis had high rates of readmission, recurrent infective endocarditis and death. Despite this, addiction interventions were suboptimal. Improved addiction interventions are imperative in the treatment of injection drug use-associated infective endocarditis. PMID- 26597671 TI - ECG as an Entrustable Professional Activity: CDIM Survey Results, ECG Teaching and Assessment in the Third Year. PMID- 26597672 TI - Inferolateral ST-segment Elevation in Boerhaave Syndrome. PMID- 26597674 TI - Factors related to the mobility of hospitalized older adults: A prospective cohort study. AB - A low ambulation rate is common even among acutely ill hospitalized older adults. This prospective observational study conducted among 769 older adults (>=70) hospitalized in acute-care units tested the relationship of satisfaction with hospital environment, sleep-medication consumption, and in-hospital caloric intake to mobility levels during hospitalization on 3 consecutive hospitalization days. Approximately 20% of the patients did not walk, 30% walked only in their room, and 50% mobilized outside their room. A multinomial-logistic regression, controlling for potential intervening factors, showed that sleep-medication avoidance (AOR = 1.99; p < 0.01) and higher caloric intake (AOR = 9.69; p < 0.001) differentiated patients walking outside the room from non-walking patients. Satisfaction with the physical environment was lower in the non-mobile group than in the other two. Results suggest that hospital environment, sleep medication consumption, and caloric intake during hospitalization need to be addressed in attempts to improve in-hospital mobility in older adults. PMID- 26597673 TI - Oral Azole Antifungal Medications and Risk of Acute Liver Injury, Overall and by Chronic Liver Disease Status. AB - BACKGROUND: Reports on associations between azole antifungal medications and acute liver injury are inconsistent and have not been based on liver-related laboratory tests. We evaluated incidence rates of acute liver injury associated with oral azole antifungals. METHODS: We conducted a cohort study among Kaiser Permanente Northern California members who initiated an oral azole antifungal in an outpatient setting during 2004-2010. We determined development of: (1) liver aminotransferases >200 U/L, (2) severe acute liver injury (coagulopathy with hyperbilirubinemia), and (3) acute liver failure. We calculated incidence rates of endpoints. Cox regression was used to determine whether chronic liver disease was a risk factor for outcomes. RESULTS: Among 195,334 azole initiators (178,879 fluconazole; 14,296 ketoconazole; 1653 itraconazole; 478 voriconazole; 28 posaconazole), incidence rates (events/1000 person-years [95% confidence intervals (CIs)]) of liver aminotransferases >200 U/L were similarly low with fluconazole (13.0 [11.4-14.6]), ketoconazole (19.3 [13.8-26.3]), and itraconazole (24.5 [10.6-48.2]). Rates were higher with voriconazole (181.9 [112.6-278.0]) and posaconazole (191.1 [23.1-690.4]), but comparable. Severe acute liver injury was uncommon with fluconazole (2.0 [1.4-2.7]), ketoconazole (2.9 [1.1-6.3]), and itraconazole (0.0 [0.0-11.2]), but more frequent with voriconazole (16.7 [2.0 60.2]) and posaconazole (93.4 [2.4-520.6]). One patient developed acute liver failure due to ketoconazole. Pre-existing chronic liver disease increased risks of aminotransferases >200 U/L (hazard ratio 4.68 [95% CI, 3.68-5.94]) and severe acute liver injury (hazard ratio 5.62 [95% CI, 2.56-12.35]). CONCLUSIONS: Rates of acute liver injury were similarly low for fluconazole, ketoconazole, and itraconazole. Events were more common among voriconazole and posaconazole users but were comparable. Pre-existing chronic liver disease increased risk of azole induced liver injury. PMID- 26597675 TI - Evaluation of the role of Care Sport Connectors in connecting primary care, sport, and physical activity, and residents' participation in the Netherlands: study protocol for a longitudinal multiple case study design. AB - BACKGROUND: The number of people with one or more chronic diseases is increasing, but this trend could be reduced by promoting physical activity. Therefore, in 2012, the Dutch Ministry of Health, Welfare, and Sport introduced Care Sport Connectors (CSCs), to whom a broker role has been ascribed. The defined outcome of CSCs role is an increased number of residents participating in local sports facilities and being physically active in their own neighbourhood. To realize this, primary care and sports professionals need to collaborate, and local sports facilities and neighbourhoods need to offer accessible physical activities for people in the locality, including people with one or more chronic diseases or at increased risk of chronic disease(s). Adequate scientific research is needed to assess CSCs' impact on: 1) connecting primary care, sport, and physical activity and 2) increasing the number of residents who engage in physical activity to promote their health. METHODS AND DESIGN: To study the role and the impact of CSCs, a longitudinal multiple case study will be conducted, in nine municipalities spread over the Netherlands, from 2014 until 2017. A mixed methodology will be used to perform action research and process evaluation. Study I focuses on the expected alliances of CSCs and the preconditions that facilitate or hinder CSCs in the formation of these alliances. The study population will consist of intermediary target groups. A literature review, interviews, focus groups, and document analysis will be undertaken. Study II will concentrate on lifestyle program participants to identify health and physical activity behavior changes. For this purpose, interviews, literature studies, a Delphi study, fitness tests, and questionnaires will be used. DISCUSSION: Linking and integrating results gained by multiple methods, at different levels, will provide a validated assessment of CSCs' impact on connecting the primary care and sports sectors. This will reveal changes in residents' physical activity behavior, and also the circumstances under which this will happen. The assessment in combination with general lessons learned from the different case studies will make it possible to determine whether CSCs are able to fulfill the policy aspiration and whether it would be beneficial to extend this function. TRIAL REGISTRATION: Nederlands Trialregister NTR4986 . Registered 14 December 2014. PMID- 26597676 TI - Azithromycin drives alternative macrophage activation and improves recovery and tissue sparing in contusion spinal cord injury. AB - BACKGROUND: Macrophages persist indefinitely at sites of spinal cord injury (SCI) and contribute to both pathological and reparative processes. While the alternative, anti-inflammatory (M2) phenotype is believed to promote cell protection, regeneration, and plasticity, pro-inflammatory (M1) macrophages persist after SCI and contribute to protracted cell and tissue loss. Thus, identifying non-invasive, clinically viable, pharmacological therapies for altering macrophage phenotype is a challenging, yet promising, approach for treating SCI. Azithromycin (AZM), a commonly used macrolide antibiotic, drives anti-inflammatory macrophage activation in rodent models of inflammation and in humans with cystic fibrosis. METHODS: We hypothesized that AZM treatment can alter the macrophage response to SCI and reduce progressive tissue pathology. To test this hypothesis, mice (C57BL/6J, 3-month-old) received daily doses of AZM (160 mg/kg) or vehicle treatment via oral gavage for 3 days prior and up to 7 days after a moderate-severe thoracic contusion SCI (75-kdyn force injury). Fluorescent-activated cell sorting was used in combination with real-time PCR (rtPCR) to evaluate the disposition and activation status of microglia, monocytes, and neutrophils, as well as macrophage phenotype in response to AZM treatment. An open-field locomotor rating scale (Basso Mouse Scale) and gridwalk task were used to determine the effects of AZM treatment on SCI recovery. Bone marrow-derived macrophages (BMDMs) were used to determine the effect of AZM treatment on macrophage phenotype in vitro. RESULTS: In accordance with our hypothesis, SCI mice exhibited significantly increased anti-inflammatory and decreased pro-inflammatory macrophage activation in response to AZM treatment. In addition, AZM treatment led to improved tissue sparing and recovery of gross and coordinated locomotor function. Furthermore, AZM treatment altered macrophage phenotype in vitro and lowered the neurotoxic potential of pro-inflammatory, M1 macrophages. CONCLUSIONS: Taken together, these data suggest that pharmacologically intervening with AZM can alter SCI macrophage polarization toward a beneficial phenotype that, in turn, may potentially limit secondary injury processes. Given that pro-inflammatory macrophage activation is a hallmark of many neurological pathologies and that AZM is non-invasive and clinically viable, these data highlight a novel approach for treating SCI and other maladaptive neuroinflammatory conditions. PMID- 26597677 TI - On the proper study design applicable to experimental balneology. AB - The simple message of this paper is that it is the high time to reevaluate the strategies and optimize the efforts for investigation of thermal (spa) waters. Several articles trying to clear mode of action of medicinal waters have been published up to now. Almost all studies apply the unproven hypothesis, namely the inorganic ingredients are in close connection with healing effects of bathing. Change of paradigm would be highly necessary in this field taking into consideration the presence of several biologically active organic substances in these waters. A successful design for experimental mechanistic studies is approved. PMID- 26597678 TI - An Autogenously Regulated Expression System for Gene Therapeutic Ocular Applications. AB - The future of treating inherited and acquired genetic diseases will be defined by our ability to introduce transgenes into cells and restore normal physiology. Here we describe an autogenous transgene regulatory system (ARES), based on the bacterial lac repressor, and demonstrate its utility for controlling the expression of a transgene in bacteria, eukaryotic cells, and in the retina of mice. This ARES system is inducible by the small non-pharmacologic molecule, Isopropyl beta-D-1-thiogalactopyranoside (IPTG) that has no off-target effects in mammals. Following subretinal injection of an adeno-associated virus (AAV) vector encoding ARES, luciferase expression can be reversibly controlled in the murine retina by oral delivery of IPTG over three induction-repression cycles. The ability to induce transgene expression repeatedly via administration of an oral inducer in vivo, suggests that this type of regulatory system holds great promise for applications in human gene therapy. PMID- 26597679 TI - Medical stabilization of adolescents with nutritional insufficiency: a clinical care path. AB - PURPOSE: Nutritional insufficiency (NI) is a potential consequence of restrictive eating disorders. NI patients often require hospitalization for refeeding to restore medical stability and prevent complications such as refeeding syndrome. Limited information is available on the optimal approach to refeeding. In this study, we describe an inpatient NI care path and compare treatment outcomes at an academic medical center and a community hospital. METHODS: A retrospective chart review was conducted on inpatients treated using a standardized NI care path at either the academic site, from August 2012 to July 2013 (n = 51), or the community site, from August 2013 to July 2014 (n = 39). Demographic information, eating disorder history, and treatment variables were recorded for each patient. Data were compared using the Kruskal-Wallis test and Fisher's exact test. RESULTS: Patients admitted to the community site had shorter hospital stays than patients admitted to the academic site (IQR 2-4 vs. 2-7 days, p = 0.03). All patients were discharged in <14 days with a median stay of 3 days. The median initial calorie prescription was 2200 calories for both groups. No clinical cases of refeeding syndrome occurred, with only one patient developing hypophosphatemia during refeeding. CONCLUSIONS: A standardized care path with a higher-calorie intervention allows for short-term hospitalization of NI patients without increasing the risk of refeeding syndrome, regardless of treatment site. This study demonstrates the efficiency and safety of treating NI patients on a regular medical floor at a community hospital. PMID- 26597680 TI - Inter- and intra-patient clonal and subclonal heterogeneity of chronic lymphocytic leukaemia: evidences from circulating and lymph nodal compartments. AB - Whole exome sequencing and copy number aberration (CNA) analysis were performed on cells taken from peripheral blood (PB) and lymph nodes (LN) of patients with chronic lymphocytic leukaemia (CLL). Of 64 non-silent somatic mutations, 54 (84.4%) were clonal in both compartments, 3 (4.7%) were PB-specific and 7 (10.9%) were LN-specific. Most of the LN- or PB-specific mutations were subclonal in the other corresponding compartment (variant frequency 0.5-5.3%). Of 41 CNAs, 27 (65.8%) were shared by both compartments and 7 (17.1%) were LN- or PB-specific. Overall, 6 of 9 cases (66.7%) showed genomic differences between the compartments. At subsequent relapse, Case 10, with 6 LN-specific lesions, and Case 100, with 6 LN-specific and 8 PB-specific lesions, showed, in the PB, the clonal expansion of LN-derived lesions with an adverse impact: SF3B1 mutation, BIRC3 deletion, del8(p23.3-p11.1), del9(p24.3-p13.1) and gain 2(p25.3-p14). CLL shows an intra-patient clonal heterogeneity according to the disease compartment, with both LN and PB-specific mutations/CNAs. The LN microenvironment might contribute to the clonal selection of unfavourable lesions, as LN-derived mutations/CNAs can appear in the PB at relapse. PMID- 26597681 TI - Clinical and neuroradiological features of the 9p deletion syndrome. AB - BACKGROUND: The 9p deletion syndrome is a rare condition, which associates trigonocephaly, facial dysmorphism and developmental delay. The neuroradiological aspects of this syndrome have not yet been described. The purpose of this article is to identify the clinical and neuroradiological features, that should be recognized by all specialists treating these children, for a proper and early diagnosis. METHODS: Among patients with trigonocephaly treated at our institution, we retrospectively analyzed the clinical and neuroradiological aspects of children with genetically confirmed 9p deletion syndrome. RESULTS: 6 patients were identified. Beside trigonocephaly, the most frequent clinical findings were small ears, long philtrum, upslanting palpebral fissures, flat nasal bridge and variable psycho-motor delay. Hypertelorism was present in 4 of 6 patient, which is opposite to the hypotelorism typical of non-syndromic trigonocephaly. Among neuroradiological findings, large, anteriorly rotated sylvian cisterns and altered shape of the septum pellucidum were found in all patients, as well as the compression of the frontal cortex due to the metopic synostosis (MS). A thin or dysmorphic corpus callosum and a diffuse white matter hypoplasia were present in more than half of the cases. Futhermore we compared these MRI findings with those of a control group of 30 non-syndromic trigonocephalies. CONCLUSIONS: Some recurrent neuroradiological alterations can be found in 9p deletion syndrome. The presence of these signs on MRI of a trigonocephalic patient should raise the suspicion of an underlying chromosomal alteration, such as the 9p deletion syndrome and prompt genetic investigations. PMID- 26597683 TI - Ventricular access device placement in the fourth ventricle to treat malignant fourth ventricle brain tumors: technical note. AB - PURPOSE: Ventricular access devices (VADs) are commonly placed in the lateral ventricle but rarely placed in other ventricular compartments. This manuscript describes technical aspects of VAD placement into the fourth ventricle for the purpose of treating malignant posterior fossa brain tumors. METHODS: As part of a pilot clinical trial to treat recurrent malignant brain tumors in children, seven patients underwent posterior fossa craniotomy and placement of a ventricular catheter under direct vision into the fourth ventricle. The catheter was placed without passing through any brain parenchyma. It was then connected to a VAD placed subcutaneously at the inferior aspect of the incision. Three of the seven patients underwent simultaneous subtotal resection of recurrent tumor located in the fourth ventricle or cerebellum, and one patient underwent simultaneous tumor biopsy. The VAD was used to administer chemotherapy (methotrexate) in five of the seven patients. RESULTS: Six patients had no new neurological deficits after surgery, and one patient had partial left-sided facial weakness that was attributed to resection of tumor close to the floor of the fourth ventricle. No new neurological deficits were caused by VAD placement or by methotrexate infusions into the fourth ventricle. CONCLUSIONS: A VAD for chemotherapy infusion can be placed safely into the fourth ventricle without damaging the brainstem or cerebellum. Attention to anatomical details specific to the fourth ventricle are important when placing a fourth ventricle VAD and when using it to administer chemotherapy. PMID- 26597682 TI - Pediatric thalamic tumors in the MRI era: a Canadian perspective. AB - BACKGROUND: Thalamic gliomas are rare. The natural history is unpredictable, and the optimal management of these tumors in children is poorly defined. The aim was to identify outcomes, prognostic factors, and response to various modalities of treatment in a relatively large population of pediatric thalamic tumors from many centers within a fairly homogeneous health care system. METHODS: We performed a Canadian multicenter retrospective review of pediatric thalamic tumors presenting during the MRI era (1989-2012). Radiology and pathology were reviewed by central independent reviewers. Paraffin shavings for RNA extraction were taken and tested for fusion events involving KIAA1549:BRAF. Tumors were classified as unilateral or bithalamic based on their origin on imaging. Univariate and multivariate analyses on factors influencing survival were performed. RESULTS: Seventy-two thalamic tumors were identified from 11 institutions. Females represented 53% of the study population, and the mean age at presentation was 8.9 years. Sixty-two tumors were unilateral and 10 bithalamic. Unilateral tumors had a greater propensity to grow inferiorly towards the brainstem. These tumors were predominantly low grade in comparison to bithalamic tumors which were high-grade astrocytomas. The 5-year overall survival was 61 +/- 13% for unithalamic tumors compared to 37 +/- 32% for bithalamic tumors (p = 0.097). Multivariate analysis indicated tumor grade as the only significant prognostic factor for unithalamic tumors. Six unilateral tumors, all low grade, were BRAF fusion positive. CONCLUSION: Unilateral and bilateral thalamic tumors behave differently. Surgical resection is an appropriate treatment option in unilateral tumors, most of which are low grade, but outcome is not related to extent of resection (EOR). Bilateral thalamic tumors have a poorer prognosis, but the occasional patient does remarkably well. The efficacy of chemotherapy and radiotherapy has not been clearly demonstrated. Novel therapeutic approaches are required to improve the prognosis for malignant unilateral thalamic tumors and bilateral thalamic tumors. PMID- 26597684 TI - Norepinephrine Protects Cerebral Autoregulation and Reduces Hippocampal Necrosis after Traumatic Brain Injury via Blockade of ERK MAPK and IL-6 in Juvenile Pigs. AB - Traumatic brain injury (TBI) contributes to morbidity in children, and boys are disproportionately represented. Cerebral autoregulation is impaired after TBI, contributing to poor outcome. Cerebral perfusion pressure (CPP) is often normalized by use of vasoactive agents to increase mean arterial pressure (MAP). In prior studies of 1- to 5-day-old newborn piglets, we observed that norepinephrine (NE) preferentially protected cerebral autoregulation and prevented hippocampal necrosis in females but not males after fluid percussion injury (FPI). The ERK isoform of mitogen activated protein kinase (MAPK) produces hemodynamic impairment after FPI, but less is known about the role of the cytokine interleukin-6 (IL-6). We investigated whether NE protects autoregulation and limits histopathology after FPI in older juvenile (4-week-old) pigs and the role of ERK and IL-6 in that outcome by sex. Results show that NE significantly protects autoregulation and prevents reduction in cerebral blood flow (CBF) in both male and female juvenile pigs after FPI; co-administration of the ERK antagonist U 0126 with NE fully protects both indices of outcome. Papaverine induced dilation was unchanged by FPI and NE. NE blunted ERK MAPK and IL-6 upregulation in both males and females after FPI. NE attenuated loss of neurons in CA1 and CA3 hippocampus of males and females after FPI. These data indicate that NE protects autoregulation and limits hippocampal neuronal cell necrosis via blockade of ERK and IL-6 after FPI in both male and female juvenile pigs. These data suggest that use of NE to improve outcome after TBI is both sex and age dependent. PMID- 26597685 TI - Transsynaptic Coordination of the Formation of Morphofunctional Contacts between the Brain and the Neurotransplant: an Ulrastructural Study. AB - We studied the role of neurotransmitter signaling mediated by synaptic vesicles in the formation of aberrant functional connections between fascia dentata grafts and the somatosensory neocortex in adult rats. Quantitative analysis of the different populations of synaptic vesicles in the ectopic giant axonal endings of granular neurons was performed and the results were compared with the normal. Two pools of small clear vesicles (rapidly releasable pool and pool of reserve vesicles circulating in the active zone) and one pool of large dense-core vesicles were analyzed. Significant differences from the control suggest that synaptic integration of the transplants into the recipient brain is coordinated by transsynaptic signaling and mediated by different populations of synaptic vesicles. PMID- 26597686 TI - Effect of Paclitaxel on Antitumor Activity of Cyclophosphamide: Study on Two Transplanted Tumors in Mice. AB - Antitumor effect of paclitaxel used as the monotherapy or in combination with cyclophosphamide was studied on CBA/LacSto mice with transplanted LS and RLS tumors characterized by high (LS) and low (RLS) sensitivity to cyclophosphamide. The therapeutic effects of cyclophosphamide and paclitaxel were summed in animals with drug-resistant RLS tumor, while combined use of these drugs in LS tumor highly sensitive to the apoptogenic effect of cyclophosphamide was no more effective than cyclophosphamide alone. PMID- 26597687 TI - Optimized Protocol for Isolation of Multipotent Mesenchymal Stromal Cells from Human Umbilical Cord. AB - Extraembryonic tissues, in particular, umbilical cord stroma are promising sources of multipotent mesenchymal stromal cells for regenerative medicine. In recent years, methods for isolation of mesenchymal stromal cells from different compartments of the umbilical cords based on enzymatic disaggregation of the tissue or on tissue explants have been proposed. Here we propose a protocol of isolation of multipotent mesenchymal stromal cells from the whole umbilical cord that combines the advantages of each approach and ensures sufficient cell yield for further experimental and clinical applications. A combination of short-term incubation of tissue fragments on cold collagenase solution followed by their culturing in the form of explants significantly increased the yield of cells with high proliferative activity, typical pluripotent mesenchymal stromal cell phenotype, and preserved differentiation capacity. PMID- 26597688 TI - Therapy of Chronic Cardiosclerosis in WAG Rats Using Cultures of Cardiovascular Cells Enriched with Cardiac Stem Cell. AB - We developed a protocol for preparing cardiac cell culture from rat heart enriched with regional stem cells based on clonogenic properties and proliferation in culture in a medium with low serum content. Experiments on WAG rats with experimental ischemic myocardial damage showed that implantation of autologous regional stem cells into the left ventricle reduced the volume of cicatricial tissue, promoted angiogenesis in the damaged zone, and prevented the risk of heart failure development. PMID- 26597689 TI - Oligopeptides of Chorionic Gonadotropin beta-Subunit in Induction of T Cell Differentiation into Treg and Th17. AB - The role of oligopeptides of chorionic gonadotropin beta-subunit (LQGV, AQGV, and VLPALP) in induction of differentiation into T-regulatory lymphocytes (Treg) and IL-17-producing lymphocytes (Th17) was studied in an in vitro system. Chorionic gonadotropin and oligopeptides promoted CD4(+) cell differentiation into functionally active Treg (FOXP3(+)GITR(+) and FOXP3(+)CTLA-4(+)), while chorionic gonadotropin and AQGV additionally stimulated IL-10 production by these cells. In parallel, chorionic gonadotropin and oligopeptides prevented CD4(+) cell differentiation into Th17 lymphocytes (ROR-gt(+)IL-17A(+)) and suppressed IL-17A secretion. Hence, oligopeptides of chorionic gonadotropin beta-subunit promoted differentiation of CD4(+) cells into Treg and, in parallel, suppress Th17 induction, thus virtually completely reproducing the effects of the hormone, which opens new vista for their use in clinical practice. PMID- 26597690 TI - Antiangiogenic Activity of Alofanib, an Allosteric Inhibitor of Fibroblast Growth Factor Receptor 2. AB - Alofanib is a potential allosteric inhibitor of FGFR2 used in oncology. The inhibitor blocks the extracellular part of the receptor and prevents its binding with the ligand. Alofanib suppressed proliferation of endothelial cells, their migration activity, and ability to form vessellike structures in vitro and significantly decreased the number of microvessels in Matrigel implant and in ovarian cancer (SKOV-3) xenograft in vivo. The results indicate that Alofanib can inhibit angiogenesis. PMID- 26597691 TI - In Vitro Effect of Laser-Induced Hydrodynamics on Cancer Cells. AB - We studied the effect of laser-induced hydrodynamic on viability of Colo-26 murine colon carcinoma cells in vitro. Laser-induced hydrodynamics was generated by a laser (lambda=1.56 MU, power 3 W, 5 min exposure); to this end, the fiber end was submersed into a buffer above the cell monolayer. It was found that laser induced hydrodynamics destructed the monolayer at standoff distances of between the working end of the laser fiber to cell monolayer of 1 and 5 mm and triggers apoptotic and necrotic death in remaining cells at a distance of 4 mm from the emitter. PMID- 26597692 TI - Agonistic 4-1BB antibody fails to reduce disease burden during acute respiratory syncytial virus (RSV) infection. AB - Respiratory Syncytial Virus (RSV) remains a leading cause of infant morbidity and mortality worldwide. Despite this, there are limited therapeutic options. CD8 T cells have an integral role in controlling viral infections; strategies to enhance these responses may be clinically relevant. The T cell costimulatory receptor, 4-1BB, is known to play a role in expansion of antiviral CD8 T cells. In this study, we examined the effect of agonistic 4-1BB antibody at the time of RSV infection in mice. We show that this antibody did not improve outcomes in the setting of RSV infection but rather, led to increased weight loss and a reduction in RSV specific CD8 T cells in the lung. This work suggests caution in the use of agonistic 4-1BB antibody in the setting of viral infections. PMID- 26597694 TI - Deterioration in physical activity and function differs according to treatment type in non-small cell lung cancer - future directions for physiotherapy management. AB - OBJECTIVES: To investigate in non-surgically and surgically treated non-small cell lung cancer (NSCLC): (1) changes in physical activity, function, health related quality of life (HRQoL) and symptoms after diagnosis; and (2) the association between physical activity and outcomes. DESIGN: Prospective observational study. SETTING: Three acute tertiary hospitals. PARTICIPANTS: Sixty nine individuals (43 male, median [IQR] age 68 [61 to 74] years) with stage I-IV NSCLC. MAIN OUTCOME MEASURES: The primary outcome (Physical Activity Scale for the Elderly) and secondary outcome (six-minute walk test and questionnaires assessing HRQoL, function, symptoms, mood) were measured at diagnosis (pre treatment), and eight to ten weeks post-diagnosis (post-operative and/or during chemotherapy/radiotherapy). RESULTS: Individuals treated surgically (n=27) experienced a deterioration in physical activity levels (baseline median [IQR]=74 [51 to 135]; follow-up median [IQR]=29 [24 to 73]; median difference=45, effect size=0.3). At follow-up physical activity was inversely related to depression, pain and appetite loss (rho>0.5, p<0.05). In contrast non-surgical individuals (n=42) did not experience a change in physical activity, however did experience deterioration in function, functional capacity, global HRQoL, fatigue and dyspnoea. Physical activity levels were low in this group and at follow-up the strongest relationships with physical activity levels were global HRQoL, function, fatigue and mood (inverse, rho>0.5, p<0.05). CONCLUSIONS: Surgically treated individuals experienced a reduction in physical activity levels after diagnosis, which was not seen in the non-surgical group. Lower physical activity levels were associated with poorer outcomes, particularly in non-surgically treated individuals. Further research is required to establish the optimal intervention to improve physical activity levels in these cohorts. PMID- 26597695 TI - Defect chemistry and lithium transport in Li3OCl anti-perovskite superionic conductors. AB - Lithium-rich anti-perovskites (LiRAPs) are a promising family of solid electrolytes, which exhibit ionic conductivities above 10(-3) S cm(-1) at room temperature, among the highest reported values to date. In this work, we investigate the defect chemistry and the associated lithium transport in Li3OCl, a prototypical LiRAP, using ab initio density functional theory (DFT) calculations and classical molecular dynamics (MD) simulations. We studied three types of charge neutral defect pairs, namely the LiCl Schottky pair, the Li2O Schottky pair, and the Li interstitial with a substitutional defect of O on the Cl site. Among them the LiCl Schottky pair has the lowest binding energy and is the most energetically favorable for diffusion as computed by DFT. This is confirmed by classical MD simulations, where the computed Li ion diffusion coefficients for LiCl Schottky systems are significantly higher than those for the other two defects considered and the activation energy in LiCl deficient Li3OCl is comparable to experimental values. The high conductivities and low activation energies of LiCl Schottky systems are explained by the low energy pathways of Li between the Cl vacancies. We propose that Li vacancy hopping is the main diffusion mechanism in highly conductive Li3OCl. PMID- 26597693 TI - Non-invasive electrocardiographic assessments of cardiac autonomic modulation in individuals with spinal cord injury. AB - STUDY DESIGN: Review. OBJECTIVES: The purpose of this review is to discuss the utility of linear and non-linear heart rate variability (HRV) as well as the QT variability index (QTVI) as indices of cardiac autonomic control in individuals with spinal cord injury (SCI). SETTING: Brock University, Department of Kinesiology, St Catharines, Ontario, Canada. Brock-Niagara Centre for Health and Well-being, St Catharines, Ontario, Canada. METHODS: Literature review. CONCLUSION: Non-invasive markers determined from the electrocardiogram, such as linear and non-linear HRV, and, more recently, the QTVI have all shown some promise as indices of cardiac autonomic regulation in the SCI population. However, there are inconsistencies in the literature that call to question their true validity in this regard. Studies using pharmacological blockade, sympathetic manoeuvres and exercise suggest that both linear and non-linear HRV reflect cardiac parasympathetic activity, whereas their ability to quantify cardiac sympathetic outflow remains uncertain. The QTVI, although a novel method, correlates with both limbs of the autonomic nervous system and therefore may hold value as a measure of both cardiac sympathetic and parasympathetic activity in individuals with SCI; however, more research is required to confirm its utility. PMID- 26597696 TI - Fourier-based integration of quasi-periodic gait accelerations for drift-free displacement estimation using inertial sensors. AB - BACKGROUND: In biomechanical studies Optical Motion Capture Systems (OMCS) are considered the gold standard for determining the orientation and the position (pose) of an object in a global reference frame. However, the use of OMCS can be difficult, which has prompted research on alternative sensing technologies, such as body-worn inertial sensors. METHODS: We developed a drift-free method to estimate the three-dimensional (3D) displacement of a body part during cyclical motions using body-worn inertial sensors. We performed the Fourier analysis of the stride-by-stride estimates of the linear acceleration, which were obtained by transposing the specific forces measured by the tri-axial accelerometer into the global frame using a quaternion-based orientation estimation algorithm and detecting when each stride began using a gait-segmentation algorithm. The time integration was performed analytically using the Fourier series coefficients; the inverse Fourier series was then taken for reconstructing the displacement over each single stride. The displacement traces were concatenated and spline interpolated to obtain the entire trace. RESULTS: The method was applied to estimate the motion of the lower trunk of healthy subjects that walked on a treadmill and it was validated using OMCS reference 3D displacement data; different approaches were tested for transposing the measured specific force into the global frame, segmenting the gait and performing time integration (numerically and analytically). The width of the limits of agreements were computed between each tested method and the OMCS reference method for each anatomical direction: Medio-Lateral (ML), VerTical (VT) and Antero-Posterior (AP); using the proposed method, it was observed that the vertical component of displacement (VT) was within +/-4 mm (+/-1.96 standard deviation) of OMCS data and each component of horizontal displacement (ML and AP) was within +/-9 mm of OMCS data. CONCLUSIONS: Fourier harmonic analysis was applied to model stride-by stride linear accelerations during walking and to perform their analytical integration. Our results showed that analytical integration based on Fourier series coefficients was a useful approach to accurately estimate 3D displacement from noisy acceleration data. PMID- 26597698 TI - From the bench to clinical practice: understanding the challenges and uncertainties in immunogenicity testing for biopharmaceuticals. AB - Unlike conventional chemical drugs where immunogenicity typically does not occur, the development of anti-drug antibodies following treatment with biologics has led to concerns about their impact on clinical safety and efficacy. Hence the elucidation of the immunogenicity of biologics is required for drug approval by health regulatory authorities worldwide. Published ADA 'incidence' rates can vary greatly between same-class products and different patient populations. Such differences are due to disparate bioanalytical methods and interpretation approaches, as well as a plethora of product-specific and patient-specific factors that are not fully understood. Therefore, the incidence of ADA and their association with clinical consequences cannot be generalized across products. In this context, the intent of this review article is to discuss the complex nature of ADA and key nuances of the methodologies used for immunogenicity assessments, and to dispel some fallacies and myths. PMID- 26597697 TI - Brain pathologies in extreme old age. AB - With an emphasis on evolving concepts in the field, we evaluated neuropathologic data from very old research volunteers whose brain autopsies were performed at the University of Kentucky Alzheimer's Disease Center, incorporating data from the Georgia Centenarian Study (n = 49 cases included), Nun Study (n = 17), and University of Kentucky Alzheimer's Disease Center (n = 11) cohorts. Average age of death was 102.0 (range: 98-107) years overall. Alzheimer's disease pathology was not universal (62% with "moderate" or "frequent" neuritic amyloid plaque densities), whereas frontotemporal lobar degeneration was absent. By contrast, some hippocampal neurofibrillary tangles (including primary age-related tauopathy) were observed in every case. Lewy body pathology was seen in 16.9% of subjects and hippocampal sclerosis of aging in 20.8%. We describe anatomic distributions of pigment-laden macrophages, expanded Virchow-Robin spaces, and arteriolosclerosis among Georgia Centenarians. Moderate or severe arteriolosclerosis pathology, throughout the brain, was associated with both hippocampal sclerosis of aging pathology and an ABCC9 gene variant. These results provide fresh insights into the complex cerebral multimorbidity, and a novel genetic risk factor, at the far end of the human aging spectrum. PMID- 26597699 TI - Heterosexual transmission of HIV in the Dominican Republic: gendered indicators are associated with disparities in condom use. AB - BACKGROUND: Gendered dynamics in heterosexual relationships compromise women's self-efficacy and increase their vulnerability to acquiring HIV. This study examines the impact of socioeconomic determinants, media exposure, and sexual expectations on sexual behaviors of men and women in the Dominican Republic (DR). METHODS: We analyzed cross-sectional data from 51,018 adults in the Dominican Republic age 15 to 45 years collected by the Demographics and Health Survey (DHS) in 2007. Measures included demographic and socioeconomic indicators, social exposures, sexual expectations and sexual behaviors. Logistic regression models explored gender differences in condom use. RESULTS: Study findings indicated that women were less likely to use a condom at last intercourse than men (odds ratio [OR] = 0.29; 95 % CI = 0.27, 0.31). Among men, secondary (OR = 1.43; 95 % CI = 1.16, 1.76) and higher education (OR = 1.58; 95 % CI = 1.25, 2.00), being in the richest quintile (OR = 1.25; 95 % CI = 1.07, 1.47), and living in a female-headed household (OR = 1.13; 95 % CI 1.03, 1.23) increased the likelihood of condom use. Compared to never married men, currently and formerly married men were less likely to use condoms (OR = 0.03; 95 % CI = 0.03, 0.04 and OR = 0.67; 95 % CI = 0.60, 0.75, respectively). The odds of condom use increased for young women 15-19 years old in comparison with women age 30-34 years, but decreased as they grew older. For women, being in the richer quintile (OR = 1.28; 95 % CI = 1.06, 1.54), living in a female-headed household (OR = 1.26; 1.12, 1.41), and having good access to media (OR = 1.24; 95 % CI = 1.12, 1.42) increased the likelihood of condom use. Being currently married or formerly married and living in rural areas decreased such likelihood among women. CONCLUSIONS: Study findings provide evidence that, in the DHS, socioeconomic and cultural differences between men and women affects condom use. Efforts to reduce HIV transmission within heterosexual relationships in the DR call for tailored, gender-specific interventions that take into account gender differences of power and sexual behaviors. PMID- 26597700 TI - SDF1-CXCR4 signaling contributes to persistent pain and hypersensitivity via regulating excitability of primary nociceptive neurons: involvement of ERK dependent Nav1.8 up-regulation. AB - BACKGROUND: Pain is one critical hallmark of inflammatory responses. A large number of studies have demonstrated that stromal cell-derived factor 1 (SDF1, also named as CXCL12) and its cognate receptor C-X-C chemokine receptor type 4 (CXCR4) play an important role in immune reaction and inflammatory processes. However, whether and how SDF1-CXCR4 signaling is involved in inflammatory pain remains unclear. METHODS: Under the intraplantar (i.pl.) bee venom (BV) injection induced persistent inflammatory pain state, the changes of SDF1 and CXCR4 expression and cellular localization in the rat dorsal root ganglion (DRG) were detected by immunofluorescent staining. The role of SDF1 and CXCR4 in the hyperexcitability of primary nociceptor neurons was assessed by electrophysiological recording. Western blot analysis was used to quantify the DRG Nav1.8 and phosphorylation of ERK (pERK) expression. Behavioral tests were conducted to evaluate the roles of CXCR4 as well as extracellular signal regulated kinase (ERK) and Nav1.8 in the BV-induced persistent pain and hypersensitivity. RESULTS: We showed that both SDF1 and CXCR4 were dramatically up-regulated in the DRG in i.pl. BV-induced inflammatory pain model. Double immunofluorescent staining showed that CXCR4 was localized in all sizes (large, medium, and small) of DRG neuronal soma, while SDF1 was exclusively expressed in satellite glial cells (SGCs). Electrophysiological recording showed that bath application with AMD3100, a potent and selective CXCR4 inhibitor, could reverse the hyperexcitability of medium- and small-sized DRG neurons harvested from rats following i.pl. BV injection. Furthermore, we demonstrated that the BV-induced ERK activation and Nav1.8 up-regulation in the DRG could be blocked by pre antagonism against CXCR4 in the periphery with AMD3100 as well as by blockade of ERK activation by intrathecal (i.t.) or intraplantar (i.pl.) U0126. At behavioral level, the BV-induced persistent spontaneous pain as well as primary mechanical and thermal hypersensitivity could also be significantly suppressed by blocking CXCR4 and Nav1.8 in the periphery as well as by inhibition of ERK activation at the DRG level. CONCLUSIONS: The present results suggest that peripheral inflammatory pain state can trigger over release of SDF1 from the activated SGCs in the DRG by which SGC-neuronal cross-talk is mediated by SDF1-CXCR4 coupling that result in subsequent ERK-dependent Nav1.8 up-regulation, leading to hyperexcitability of tonic type of the primary nociceptor cells and development and maintenance of persistent spontaneous pain and hypersensitivity. PMID- 26597701 TI - Cross-talk between lysophosphatidic acid receptor 1 and tropomyosin receptor kinase A promotes lung epithelial cell migration. AB - Lysophosphatidic acid (LPA) is a bioactive lysophospholipid, which plays a crucial role in the regulation of cell proliferation, migration, and differentiation. LPA exerts its biological effects mainly through binding to cell surface LPA receptors (LPA1-6), which belong to the G protein-coupled receptor (GPCR) family. Recent studies suggest that cross-talk between receptor tyrosine kinases (RTKs) and GPCRs modulates GPCRs-mediated signaling. Tropomyosin receptor kinase A (TrkA) is a RTK, which mediates nerve growth factor (NGF)-induced biological functions including cell migration in neuronal and non-neuronal cells. Here, we show LPA1 transactivation of TrkA in murine lung epithelial cells (MLE12). LPA induced tyrosine phosphorylation of TrkA in both time- and dose dependent manners. Down-regulation of LPA1 by siRNA transfection attenuated LPA induced phosphorylation of TrkA, suggesting a cross-talk between LPA1 and TrkA. To investigate the molecular regulation of the cross-talk, we focused on the interaction between LPA1 and TrkA. We found that LPA induced interaction between LPA1 and TrkA. The LPA1/TrkA complex was localized on the plasma membrane and in the cytoplasm. The C-terminus of LPA1 was identified as the binding site for TrkA. Inhibition of TrkA attenuated LPA-induced phosphorylation of TrkA and LPA1 internalization, as well as lung epithelial cell migration. These studies provide a molecular mechanism for the transactivation of TrkA by LPA, and suggest that the cross-talk between LPA1 and TrkA regulates LPA-induced receptor internalization and lung epithelial cell migration. PMID- 26597702 TI - Peroxisomal Pex11 is a pore-forming protein homologous to TRPM channels. AB - More than 30 proteins (Pex proteins) are known to participate in the biogenesis of peroxisomes-ubiquitous oxidative organelles involved in lipid and ROS metabolism. The Pex11 family of homologous proteins is responsible for division and proliferation of peroxisomes. We show that yeast Pex11 is a pore-forming protein sharing sequence similarity with TRPM cation-selective channels. The Pex11 channel with a conductance of Lambda=4.1 nS in 1.0M KCl is moderately cation-selective (PK(+)/PCl(-)=1.85) and resistant to voltage-dependent closing. The estimated size of the channel's pore (r~0.6 nm) supports the notion that Pex11 conducts solutes with molecular mass below 300-400 Da. We localized the channel's selectivity determining sequence. Overexpression of Pex11 resulted in acceleration of fatty acids beta-oxidation in intact cells but not in the corresponding lysates. The beta-oxidation was affected in cells by expression of the Pex11 protein carrying point mutations in the selectivity determining sequence. These data suggest that the Pex11-dependent transmembrane traffic of metabolites may be a rate-limiting step in the beta-oxidation of fatty acids. This conclusion was corroborated by analysis of the rate of beta-oxidation in yeast strains expressing Pex11 with mutations mimicking constitutively phosphorylated (S165D, S167D) or unphosphorylated (S165A, S167A) protein. The results suggest that phosphorylation of Pex11 is a mechanism that can control the peroxisomal beta-oxidation rate. Our results disclose an unexpected function of Pex11 as a non-selective channel responsible for transfer of metabolites across peroxisomal membrane. The data indicate that peroxins may be involved in peroxisomal metabolic processes in addition to their role in peroxisome biogenesis. PMID- 26597703 TI - Heart regeneration. AB - Regenerating an injured heart holds great promise for millions of patients suffering from heart diseases. Since the human heart has very limited regenerative capacity, this is a challenging task. Numerous strategies aiming to improve heart function have been developed. In this review we focus on approaches intending to replace damaged heart muscle by new cardiomyocytes. Different strategies for the production of cardiomyocytes from human embryonic stem cells or human induced pluripotent stem cells, by direct reprogramming and induction of cardiomyocyte proliferation are discussed regarding their therapeutic potential and respective advantages and disadvantages. Furthermore, different methods for the transplantation of pluripotent stem cell-derived cardiomyocytes are described and their clinical perspectives are discussed. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel. PMID- 26597704 TI - Leukotriene B4 receptor-2 contributes to chemoresistance of SK-OV-3 ovarian cancer cells through activation of signal transducer and activator of transcription-3-linked cascade. AB - Inflammation and inflammatory mediators are intimately linked with chemoresistance through complex pathways in the tumor microenvironment. However, the mechanism by which inflammatory mediators (e.g., eicosanoids) contribute to chemoresistance remains elusive. In this study, we found that the low-affinity leukotriene B4 receptor-2 (BLT2) and its ligand leukotriene B4 were highly up regulated in cisplatin-resistant SK-OV-3 ovarian cancer cells and play critical roles in mediating the chemoresistance through the activation of signal transducer and activator of transcription-3 (STAT-3) and the subsequent up regulation of interleukin-6 (IL-6). BLT2 depletion with siRNA clearly abolished the chemoresistance to cisplatin in SK-OV-3 ovarian cancer cells and further increased cell sensitivity to cisplatin chemotherapy by down-regulating the 'STAT 3-IL-6' cascade. Enlarged tumor formation due to the cisplatin resistance of SK OV-3 cells in cisplatin-treated athymic mice was also substantially reduced by co treatment with the BLT2 inhibitor in vivo. Our study demonstrates that BLT2 is a novel contributor to cisplatin resistance in SK-OV-3 ovarian cancer cells and thus may be a potential therapeutic target for the treatment of cisplatin resistant ovarian cancer. PMID- 26597705 TI - Fibrin Sealant with Polyglycolic Acid Felt vs Fibrinogen-Based Collagen Fleece at the Liver Cut Surface for Prevention of Postoperative Bile Leakage and Hemorrhage: A Prospective, Randomized, Controlled Study. AB - BACKGROUND: The incidence of postoperative biliary leakage and hemorrhage is low, but these factors remain important in liver surgery, and this study's objective was to explore the efficacy of fibrin sealant (FS) with polyglycolic acid (PGA) vs fibrinogen-based collagen fleece (CF) at the liver cut surface. Fibrinogen based collagen fleece is generally used for hemostasis; PGA-FS has reduced biliary leakage in several retrospective studies. STUDY DESIGN: We designed a multicenter, randomized, controlled trial. The primary outcome was the rate of biliary leakage and hemorrhage. Secondary outcomes included morbidities and effusion at the liver cut surface at 3 months post-surgery. Biliary leakage was diagnosed when the drain/serum bilirubin ratio was >5. Hemorrhage was diagnosed when relaparotomy or transfusion was needed. RESULTS: Of 786 patients from 11 institutions enrolled from 2009 to 2014, a total of 391 were randomly assigned to PGA-FS and 395 to CF. Regarding primary outcomes, rates of biliary leakage were 4.1% with PGA-FS and 5.1% with CF, and rates of hemorrhage were 1.0% in each group; groups did not differ significantly. For secondary outcomes, morbidity rates were 18.7% in the PGA-FS group and 24.6% in the CF group (p = 0.0450). Effusion at the cut liver surface was less with PGA-FS (22.2%) than with CF (32.9%) (p = 0.0142). Regarding morbidity, infection around the liver, jaundice, and abdominal paracentesis were less in the PGA-FS group. CONCLUSIONS: Compared with CF, PGA-FS did not reduce biliary leakage and hemorrhage. Surgical site infection around the liver, effusion at the liver cut surface, and abdominal paracentesis were less in the PGA-FS group. PMID- 26597706 TI - Validation of the Denver Emergency Department Trauma Organ Failure Score to Predict Post-Injury Multiple Organ Failure. AB - BACKGROUND: Early recognition of trauma patients at risk for multiple organ failure (MOF) is important to reduce the morbidity and mortality associated with MOF. The objective of the study was to externally validate the Denver Emergency Department (ED) Trauma Organ Failure (TOF) Score, a 6-item instrument that includes age, intubation, hematocrit, systolic blood pressure, blood urea nitrogen, and white blood cell count, which was designed to predict the development of MOF within 7 days of hospitalization. STUDY DESIGN: We performed a prospective multicenter study of adult trauma patients between November, 2011 and March, 2013. The primary outcome was development of MOF within 7 days of hospitalization, assessed using the Sequential Organ Failure Assessment Score. Hierarchical logistic regression analysis was performed to determine associations between the Denver ED TOF Score and MOF. Discrimination was assessed and quantified using a receiver operating characteristics (ROC) curve. The predictive accuracy of the Denver ED TOF score was compared with attending emergency physician estimation of the likelihood of MOF. RESULTS: We included 2,072 patients with a median age of 46 years (interquartile range [IQR] 30 to 61 years); 68% were male. The median Injury Severity Score was 9 (IQR 5 to 17), and 88% of patients had blunt mechanism injury. Among participants, 1,024 patients (49%) were admitted to the ICU, and 77 (4%) died. Multiple organ failure occurred in 120 (6%; 95% CI 5% to 7%) patients and of these, 37 (31%; 95% CI 23% to 40%) died. The area under the ROC curve for the Denver ED TOF Score prediction of MOF was 0.89 (95% CI 0.86 to 0.91) and for physician estimation of the likelihood of MOF was 0.78 (95% CI 0.73 to 0.83). CONCLUSIONS: The Denver ED TOF Score predicts development of MOF within 7 days of hospitalization. Its predictive accuracy outperformed attending emergency physician estimation of the risk of MOF. PMID- 26597708 TI - A simple scoring system to train surgeons in basic laparoscopic skills. AB - AIM: To develop and validate a scoring system for a training assessment tool using a box trainer which can objectively demonstrate progression in laparoscopic skills. METHOD: 170 assessments were performed over a 5-year period by doctors working in a busy paediatric surgical department. Each participant was scored based on experience and then undertook six laparoscopic tasks in a box trainer in a dry skills lab. The quicker and more accurate the performance, the lower the score. Validity and reliability tests were applied. RESULTS: Pearson correlation coefficient demonstrated that more experienced surgeons performed better than novices with an r of -0.63 (p < 0.001). The mean assessment scores improved (reduced) with increasing experience score [4140 (0-20), 2696 (21-40), 1969 (>40) p < 0.001]. Improvement in score was seen at all experience levels with greatest improvement seen in the less experienced (2315, 1820, 1571 p < 0.001). Cronbach's alpha was 0.70 and the intraclass correlation coefficient for test-retest reliability was 0.81. CONCLUSION: Construct validity with adequate reliability has been demonstrated for this simple training tool and scoring system. All experience levels demonstrated improvement in their laparoscopic skills by simulation training in a laparoscopic box trainer. PMID- 26597707 TI - Conversion of a light-driven proton pump into a light-gated ion channel. AB - Interest in microbial rhodopsins with ion pumping activity has been revitalized in the context of optogenetics, where light-driven ion pumps are used for cell hyperpolarization and voltage sensing. We identified an opsin-encoding gene (CsR) in the genome of the arctic alga Coccomyxa subellipsoidea C-169 that can produce large photocurrents in Xenopus oocytes. We used this property to analyze the function of individual residues in proton pumping. Modification of the highly conserved proton shuttling residue R83 or its interaction partner Y57 strongly reduced pumping power. Moreover, this mutation converted CsR at moderate electrochemical load into an operational proton channel with inward or outward rectification depending on the amino acid substitution. Together with molecular dynamics simulations, these data demonstrate that CsR-R83 and its interacting partner Y57 in conjunction with water molecules forms a proton shuttle that blocks passive proton flux during the dark-state but promotes proton movement uphill upon illumination. PMID- 26597710 TI - Correction: Size and shape dependent photoluminescence and excited state decay rates of diamondoids. AB - Correction for 'Size and shape dependent photoluminescence and excited state decay rates of diamondoids' by Robert Richter et al., Phys. Chem. Chem. Phys., 2014, 16, 3070-3076. PMID- 26597709 TI - Substrate affinity and catalytic efficiency are improved by decreasing glycosylation sites in Trichoderma reesei cellobiohydrolase I expressed in Pichia pastoris. AB - OBJECTIVES: To modify two main N-glycosylation residues of cellobiohydrolase I from Trichoderma reesei by site-directed mutagenesis for decreasing the extent of glycosylation and exploring possible effects on its properties. RESULTS: Asparagine 45 and 64 residues were mutated to alanine to make single/double mutants and expressed in P. pastoris. Decreasing N-glycosylation of the recombinant CBH I resulted in an increased affinity of the enzyme for carboxymethylcellulose and also improved the Kcat/Km while the specific activity was decreased. Also, the enzymes were stable up to 80 degrees C. There was no significant change of the optimum pH and temperature by decrease of glycosylation in the mutated enzymes in comparison to the wild-type at constant incubation time of assay. CONCLUSION: Post-translational glycan-modification of CBH I in P. pastoris has different impacts on the properties of the secreted enzymes. Substrate affinity and catalytic efficiency were improved significantly while the activity and high temperature stability were negatively affected. PMID- 26597711 TI - Importance of physical health and health-behaviors in adolescence for risk of dropout from secondary education in young adulthood: an 8-year prospective study. AB - BACKGROUND: Education and health constitute two interlinked assets that are highly important to individuals. In Iceland, prevalence of dropout from secondary education poses a considerable problem. This 8-year prospective study assesses to what extent poor physical health and negative health-behaviors of Icelandic adolescents predict increased odds of dropout from secondary education. METHODS: The sample included n = 201 Icelandic children who participated at age 15 (baseline) and again at age 23 (follow-up). Data included objective measurements of physical health and questionnaires assessing health-behaviors, education status, parental education, neighborhood characteristics, self-esteem, and depression. Independent t-tests and chi-square were used to assess differences in physical health and health-behaviors at follow-up stratified by education status. Ordinal regression models were conducted to assess whether physical health and health-behaviors at age 15 predicted increased odds of dropout from secondary education at age 23, independent of gender, parental education and psychological factors. RESULTS: At age 23, 78 % of girls and 71 % of boys had completed a secondary education. Completion of a secondary education was associated with significant health benefits, especially among women. Women without a secondary education had lower fitness, more somatic complaints, higher diastolic blood pressure, less sports participation, and poorer sleep, whilst men without a secondary education watched more television. In logistic regression models somatic complaints during adolescence were associated with 1.09 (95 % CI: 1.02 1.18) higher odds of dropout from secondary education in young adulthood, independent of covariates. Health-behaviors associated with higher dropout odds included smoking (3.67, 95 % CI: 1.50-9.00), alcohol drinking (2.57, 95 % CI: 1.15-5.75), and time spent watching television (1.27, 95 % CI:1.03-1.56), which were independent of most covariates. Finally, mother's higher education was strongly associated with significantly lower dropout odds (OR 0.54, 95 % CI: 0.34 0.88) independent of father's education and psychological factors, whilst high self-esteem was independently associated with lower dropout odds (OR 0.91, 95 % CI: 0.85-0.98). CONCLUSIONS: Completion of a secondary education yields substantial physical health benefits for young women, but not for men. Importantly, somatic complaints and negative health-behaviors among adolescent boys and girls adversely impact their educational outcomes later in life, and may have widespread consequences for their future prospects. PMID- 26597713 TI - On the definition and identifiability of the alleged "hiatus" in global warming. AB - Recent public debate and the scientific literature have frequently cited a "pause" or "hiatus" in global warming. Yet, multiple sources of evidence show that climate change continues unabated, raising questions about the status of the "hiatus". To examine whether the notion of a "hiatus" is justified by the available data, we first document that there are multiple definitions of the "hiatus" in the literature, with its presumed onset spanning a decade. For each of these definitions we compare the associated temperature trend against trends of equivalent length in the entire record of modern global warming. The analysis shows that the "hiatus" trends are encompassed within the overall distribution of observed trends. We next assess the magnitude and significance of all possible trends up to 25 years duration looking backwards from each year over the past 30 years. At every year during the past 30 years, the immediately preceding warming trend was always significant when 17 years (or more) were included in the calculation, alleged "hiatus" periods notwithstanding. If current definitions of the "pause" used in the literature are applied to the historical record, then the climate system "paused" for more than 1/3 of the period during which temperatures rose 0.6 K. PMID- 26597712 TI - Enhanced maltose production through mutagenesis of acceptor binding subsite +2 in Bacillus stearothermophilus maltogenic amylase. AB - Maltogenic amylases are used to decrease the maltotriose content of high maltose syrups. However, due to the interplay between the hydrolysis and transglycosylation activities of maltogenic amylases, the maltotriose contents of these syrups are still greater than that necessary for pure maltose preparation. In this study, the maltogenic amylase from Bacillus stearothermophilus was engineered to decrease its transglycosylation activity with the expectation that this would enhance maltose production. Site-directed mutagenesis was used to generate Trp 177 variants W177F, W177Y, W177L, W177N, and W177S. The transglycosylation activities of the mutant enzymes decreased as the hydrophilicity of the residue at position 177 increased. The mutant enzymes exhibited notable enhancements in maltose production, with a minimum of maltotriose contents of 0.2%, compared with 3.2% for the wild-type enzyme. Detailed characterization of the mutant enzymes suggests that the best of them, W177S, will deliver performance superior to that of the wild-type under industrial conditions. PMID- 26597714 TI - Synthesis and conductive performance of indium-substituted ternary heteropoly acids with Keggin structures. AB - Two new high-proton conductors, indium-substituted ternary heteropoly acids with Keggin structures, H4[In(H2O)PW11O39].11H2O and H5[In(H2O)SiW11O39].8H2O, have been synthesized and characterized using elemental analysis, IR, UV, XRD and TG DTA. Their proton conductivities were measured using electrochemical impedance spectroscopy (EIS), and the results indicate that H4[In(H2O)PW11O39].11H2O and H5[In(H2O)SiW11O39].8H2O are solid high-proton conductors with a conductivity of 2.60 * 10(-4) S cm(-1) and 5.25 * 10(-4) S cm(-1), respectively, at 18 degrees C and 80% relative humidity (RH). Their activation energies are 33.40 kJ mol(-1) and 28.52 kJ mol(-1), which suggests that the mechanism of proton conduction is the vehicle mechanism. In the range of the measured temperatures, the conductivity of both heteropoly acids increases with higher temperatures. PMID- 26597715 TI - Systematic review of structural interventions for intimate partner violence in low- and middle-income countries: organizing evidence for prevention. AB - BACKGROUND: Despite growing attention to intimate partner violence (IPV) globally, systematic evaluation of evidence for IPV prevention remains limited. This particularly is true in relation to low- and middle-income countries (LMIC), where researchers often organize evidence by current interventions strategies rather than comprehensive models of IPV. Applying the concept of structural interventions to IPV, we systematically reviewed the quantitative impact of such interventions for prevention of male-to-female IPV in LMIC in order to (a) highlight current opportunities for IPV research and programming and (b) demonstrate how structural interventions may provide an organizing framework through which to build an evidence base for IPV prevention. METHODS: We identified articles by systematically searching PubMed and Web of Science, reviewing references of selected studies, and contacting 23 experts. Inclusion criteria included original research, written in English, published between January 2000 and May 2015 in the peer-reviewed literature. Studies evaluated the quantitative impact of structural interventions for the prevention of male-to female IPV in LMIC through (a) IPV incidence or prevalence or (b) secondary outcomes theoretically linked to IPV by study authors. After initial screening, we evaluated full text articles for inclusion and extracted data on study characteristics, outcomes, and risk of bias, using forms developed for the review. RESULTS: Twenty articles (16 studies) from nine countries met inclusion criteria, representing 13 randomized control trials and seven additional studies, all of which reported results from economic, social, or combined economic and social interventions. Standardized at p < 0.05 or 95 % confidence intervals not including unity, 13 studies demonstrated statistically significant effects for at least one primary or secondary outcome, including decreased IPV and controlling behaviors; improved economic wellbeing; enhanced relationship quality, empowerment, or social capital; reduced acceptability of IPV; new help seeking behaviors; and more equitable gender norms. Risk of bias, however, varied in meaningful ways. CONCLUSIONS: Our findings support the potential effectiveness of structural interventions for IPV prevention. Structural interventions, as an organizing framework, may advance IPV prevention by consolidating available evidence; highlighting opportunities to assess a broader range of interventions, including politico-legal and physical approaches; and emphasizing opportunities to improve evaluation of such interventions. PMID- 26597717 TI - Re: 'Management of Chronic Venous Disease: Clinical Practice Guidelines of the European Society for Vascular Surgery (ESVS)'. PMID- 26597716 TI - Osteopontin-integrin interaction as a novel molecular target for antibody mediated immunotherapy in adult T-cell leukemia. AB - BACKGROUND: Adult T-cell leukemia (ATL) is a CD4(+) T-cell neoplasm with a poor prognosis. A previous study has shown that there is a strong correlation between the secreted matricellular protein osteopontin (OPN) level and disease severity in ATL patients. Here, we investigated the role of OPN in ATL pathogenesis and the possible application of anti-OPN monoclonal antibody (mAb) for ATL immunotherapy in NOD/Shi-scid,IL-2Rg (null) (NOG) mice. RESULTS: Subcutaneous inoculation of ATL cell lines into NOG mice increased the plasma level of OPN, which significantly correlated with metastasis of the inoculated cells and survival time. Administration of an SVVYGLR motif-recognizing anti-OPN mAb resulted in inhibition not only of tumor growth but also of tumor invasion and metastasis. The number of fibroblast activating protein-positive fibroblasts was also reduced by this mAb. We then co-inoculated mouse embryonic fibroblasts (MEFs) isolated from wild-type (WT) or OPN knockout mice together with ATL derived TL-OmI cells into the NOG mice. The mice co-inoculated with WT MEFs displayed a significant decrease in survival relative to those injected with TL OmI cells alone and the absence of OPN in MEFs markedly improved the survival rate of TL-OmI-inoculated mice. In addition, tumor volume and metastasis were also reduced in the absence of OPN. CONCLUSION: We showed that the xenograft NOG mice model can be a useful system for assessment of the physiological role of OPN in ATL pathogenesis. Using this xenograft model, we found that fibroblast-derived OPN was involved in tumor growth and metastasis, and that this tumor growth and metastasis was significantly suppressed by administration of the anti-OPN mAbs. Our findings will lead to a novel mAb-mediated immunotherapeutic strategy targeting against the interaction of OPN with integrins on the tumor of ATL patients. PMID- 26597718 TI - Intravenous iron administration in restless legs syndrome : An observational study in geriatric patients. AB - BACKGROUND: This observational study was carried out to investigate the effect of intravenous (i.v.) iron administration on the clinical symptoms of restless legs syndrome (RLS) in geriatric outpatients over 65 years old. METHODS: In this study geriatric outpatients (mean 4.5 +/- 3.4 comorbidities and 5.7 +/- 4.4 drugs taken) were recruited according to the following inclusion criteria: >= 65 years, diagnosis of RLS due to iron deficiency, i.e. ferritin < 50 ug/l or transferrin saturation (TFS) < 16 %) as well as no other iron therapy within 2 weeks prior to the study. Of the patients 7 (41 %) received 500 mg ferric carboxymaltose (FCM) and 10 patients (59 %) received iron gluconate (62.5 mg) based on the degree of iron deficiency. As assessed by the international RLS severity scale (IRLS) symptoms were recorded 3 times: at the beginning of iron therapy (t0), after 2 weeks (t1) and after 12 weeks (t2). RESULTS: A total of 17 patients (13 female, 4 male, mean age 73.2 +/- 5.9 years) were included. The IRLS score significantly improved in all patients as shown by an average decrease from 30.2 (+/- 4.3) to 20.2 (+/- 4.7) (p < 0.001) after 2 weeks of i.v. iron treatment and to 23.2 +/- 6.6 (p < 0.001) after 12 weeks. There was a high correlation between ferritin values and the IRLS score (C 0.729, p < 0.001). The part of the IRLS referring to activities of daily living (ADL) improved from a median of 3 (scores 3-4) to 2 (scores 2-3, p = 0.001) after 2 weeks (effect size - 0.6). CONCLUSION: In this study group of geriatric outpatients i.v. administration of iron was associated with a significant improvement of symptoms in RLS as assessed by the IRLS score 2 weeks after treatment. In geriatric patients with RLS associated with iron deficiency, i.v. iron administration should be considered regarding improvement of RLS symptoms and ADL. PMID- 26597719 TI - Influence of glutathione availability on cell damage induced by human immunodeficiency virus type 1 viral protein R. AB - The human immunodeficiency virus type 1 (HIV-1) encodes for accessory viral protein R (Vpr), which arrests the cell cycle of host cells at G2 and causes mitochondrial dysfunction and alterations in glycolysis. High-level expression of Vpr protein correlates with increased viral production and disease progression. Vpr causes structural and functional injury in many types of eukaryotic cells, whether or not they are permissive for viral replication; among them is the budding yeast Saccharomyces cerevisiae. We hypothesized that the dramatic Vpr induced injuries in yeast could be prevented by strengthening their redox response capacity. We show that exogenous addition of glutathione (GSH) or its prodrug, N-acetylcysteine (NAC), protected budding yeasts from Vpr-induced cytopathic effects. Moreover, addition of adenosine triphosphate (ATP) to growing cultures of Vpr-producing yeast returned cellular growth to control levels, whereas the addition dehydroascorbic acid (DHA) had only a minor protective effect. The diminished protein levels of Cox2p and Cox4p in wild typeVpr producing yeasts together with the acute sensitivity of petite yeasts to Vpr activity may have been caused by low intracellular ATP levels. As a consequence of this energy deficit, eukaryotic cells would be unable to synthetize adequate supplies of GSH or to signal the mitochondrial retrograde response. Our findings strongly suggest that the cytopathogenic effect of Vpr protein in eukaryotic cells can be prevented by increasing intracellular antioxidant stores or, alternatively, supplying external ATP. Furthermore, these results support a potentially promising future for S. cerevisiae expression as a modality to search for Vpr-targeted inhibitors. PMID- 26597720 TI - Phylogenetic analysis of a novel reassortant orthoreovirus strain detected in partridge (Perdix perdix). AB - Avian orthoreoviruses cause various diseases in wild birds and domesticated poultry. In this study we report the detection and genomic characterization of a partridge (Perdix perdix) origin reovirus strain, D1007/2008. The virus was isolated on cell culture from acute pneumonia and infra-orbital sinusitis. The 23,497 nucleotide long genome sequence was obtained by combined use of semiconductor and capillary sequencing. Sequence and phylogenetic analyses showed that the partridge reovirus strain was related to orthoreoviruses of gallinaceous birds. In fact, five (lambdaB, lambdaC, MUB, sigmaC, sigmaNS) and one (sigmaB) out of 10 genes clustered definitely with turkey or chicken origin orthoreoviruses, respectively, whereas in the lambdaA, MUA, MUNS and sigmaA phylogenies a more distant genetic relationship was observed. Our data indicate that the identified reovirus strain is composed of a mixture of chicken and turkey orthoreovirus related alleles. This finding implies that partridges may serve as natural reservoirs for orthoreoviruses of domesticated poultry. PMID- 26597722 TI - Ti(IV) oxalate complex-derived hierarchical hollow TiO2 materials with dye degradation properties in water. AB - Ti(IV)-based complexes have been demonstrated as candidates for preparing hybrid and functional materials, and have received considerable attention. In this paper, hierarchical hollow titania materials with different surface nanostructures were synthesized successfully using a hydrothermal process via the transformation of a Ti(IV) oxalate complex as a precursor. Different concentrations of ammonia were used to adjust the morphologies and crystalline forms of the hydrothermal products. The hierarchical hollow anatase titania materials, HHTM-1 (cal) and HHTM-2 (cal), have high surface areas of up to 132 m(2) g(-1) and 84 m(2) g(-1), respectively, and show superior performance for dye degradation in water. PMID- 26597721 TI - Loss of Polo ameliorates APP-induced Alzheimer's disease-like symptoms in Drosophila. AB - The amyloid precursor protein (APP) has been implicated in the pathogenesis of Alzheimer's disease (AD). Despite extensive studies, little is known about the regulation of APP's functions in vivo. Here we report that expression of human APP in Drosophila, in the same temporal-spatial pattern as its homolog APPL, induced morphological defects in wings and larval NMJ, larva and adult locomotion dysfunctions, male choice disorder and lifespan shortening. To identify additional genes that modulate APP functions, we performed a genetic screen and found that loss of Polo, a key regulator of cell cycle, partially suppressed APP induced morphological and behavioral defects in larval and adult stages. Finally, we showed that eye-specific expression of APP induced retina degeneration and cell cycle re-entry, both phenotypes were mildly ameliorated by loss of Polo. These results suggest Polo is an important in vivo regulator of the pathological functions of APP, and provide insight into the role of cell cycle re-entry in AD pathogenesis. PMID- 26597723 TI - Extracellular nucleotides as novel, underappreciated pro-metastatic factors that stimulate purinergic signaling in human lung cancer cells. AB - BACKGROUND: One of the challenging problems of current radio-chemotherapy is recurrence and metastasis of cancer cells that survive initial treatment. We propose that one of the unwanted effects of radiochemotherapy is the release from damaged ("leaky") cells of nucleotides such as ATP and UTP that exert pro metastatic functions and can directly stimulate chemotaxis of cancer cells. METHODS: To address this problem in a model of human lung cancer (LC), we employed several complementary in vitro and in vivo approaches to demonstrate the role of extracellular nucleotides (EXNs) in LC cell line metastasis and tumor progression. We measured concentrations of EXNs in several organs before and after radiochemotherapy. The purinergic receptor agonists and antagonists, inhibiting all or selected subtypes of receptors, were employed in in vitro and in vivo pro-metastatic assays. RESULTS: We found that EXNs accumulate in several organs in response to radiochemotherapy, and RT-PCR analysis revealed that most of the P1 and P2 receptor subtypes are expressed in human LC cells. EXNs were found to induce chemotaxis and adhesion of LC cells, and an autocrine loop was identified that promotes the proliferation of LC cells. Most importantly, metastasis of these cells could be inhibited in immunodeficient mice in the presence of specific small molecule inhibitors of purinergic receptors. CONCLUSIONS: Based on this result, EXNs are novel pro-metastatic factors released particularly during radiochemotherapy, and inhibition of their pro-metastatic effects via purinergic signaling could become an important part of anti metastatic treatment. PMID- 26597724 TI - Socioeconomic variations in nicotine dependence in rural southwest China. AB - BACKGROUND: This study examines how nicotine dependence is distributed across socioeconomic gradients in rural Yunnan province, which has the most ethnic minorities in one province in southwest China. METHODS: A cross-sectional survey was conducted in four rural areas of Yunnan province among 17,158 consenting individuals aged >=18 years in 2011. Information on demographic characteristics and smoking habits was obtained using a standard questionnaire. The Fagerstrom Test for Nicotine Dependence (FTND) was applied to assess nicotine dependence. Multilevel logistic regression was used to model the variation in prevalence of nicotine dependence. RESULTS: In the study population, the overall prevalence of current smokers and nicotine dependence was 32.4 % and 31.6 %, respectively. Females were much less likely to have nicotine addiction than males: odds ratio (OR) of 0.01 (95 % CI: 0.008 - 0.012). Higher annual household income was associated with a greater risk of nicotine dependence (OR 1.09, 95 % CI: 1.01 - 1.17). Adults who grew tobacco were more likely to have nicotine addiction (OR 1.22, 95 % CI 1.07 - 1.41). Individual educational level was inversely associated with the probability of nicotine dependence (OR 0.63, 95 % CI 0.55 - 0.72), lower community educational level was also associated with an increased risk of nicotine dependence (OR 0.94, 95 % CI 0.92 - 0.98). CONCLUSIONS: Nicotine dependence showed significant variations across different indicators of both contextual and individual socioeconomic status in rural southwest China. Future interventions on tobacco cessation should give increased attention to men, tobacco farmers, less educated or poorer persons, and lower educational level communities. PMID- 26597725 TI - [Childhood vasculitis]. AB - BACKGROUND: The primary vasculitides are rare conditions in childhood. The most common disease subtypes are Schonlein-Henoch purpura and Kawasaki's syndrome, which frequently have a self-limiting course. In the majority of vasculitides, the etiology remains unknown. Environmental exposure, including infections, is suspected to trigger an autoinflammatory response in predisposed individuals. GOAL: The aim of this review is to present the various aspects of childhood vasculitis. MATERIALS AND METHODS: Reviews and special original papers on childhood vasculitis, published classification criteria and current therapy guidelines were reviewed and summarized. RESULTS: The classification of vasculitides in childhood has been modified from the previous adult Chapel Hill classification for vasculitides in 2008. Most therapy recommendations for children are adapted from results of studies in adults. This review covers the current classifications, pathogenesis, clinical manifestations and therapy recommendations for children. DISCUSSION: Although etiology and pathogenesis of many vasculitides in childhood are still unknown, clarifying diagnostic methods and effective therapeutic options are available. The knowledge about various forms of disease manifestation may contribute to an early diagnosis and timely initiation of treatment, which may prevent devastating irreversible impairment. PMID- 26597726 TI - [Vasculitides]. PMID- 26597727 TI - Minnelide effectively eliminates CD133(+) side population in pancreatic cancer. AB - BACKGROUND: Pancreatic Ductal Adenocarcinoma (PDAC) is a devastating disease hallmarked by limited patient survival. Resistance to chemotherapy, a major cause of treatment failure in PDAC patients, is often attributed to Cancer Stem Cells (CSCs). Pancreatic CSCs are a small subset of quiescent cells within a tumor represented by surface markers like CD133. These cells are responsible not only for tumor recurrence, but also poor prognosis based on their "stem-like" characteristics. At present, conventional therapy is directed towards rapidly dividing PDAC cells and thus fails to target the CSC population. METHODS: MIA PaCa-2, S2-013 and AsPC-1 were treated with 12.5 nM triptolide (12 T cells) for 7 days. The surviving cells were recovered briefly in drug-free growth media and then transferred to Cancer Stem cell Media (CSM). As a control, untreated cells were also transferred to CSM media (CSM). The 12 T and CSM cells were tested for stemness properties using RNA and protein markers. Low numbers of CSM and 12 T cells were implanted subcutaneously in athymic nude mice to study their tumorigenic potential. 12 T and CSM cells were sorted for CD133 expression and assayed for their colony forming ability and sphere forming ability. Invasiveness of 12 T cells, CSM and MIA PaCa-2 were compared using Boyden chamber assays. RESULTS: Treated 12 T cells displayed increased expression of the surface marker CD133 and the drug transporter ABCG2 compared to untreated cells (CSM cells). Both 12 T and CSM cells formed subcutaneous tumors in mice confirming their tumor initiating properties. When tested for invasion, 12 T cells had increased invasiveness compared to CSM cells. CD133(+) cells in both CSM and 12 T showed greater colony and sphere forming ability compared to CD133(-) cells from each group. Consistent with these data, when injected subcutaneously in mice, CD133(-) cells from CSM or 12 T did not form any tumors whereas CD133(+) cells from both groups showed tumor formation at a very low cell number. Despite pre-exposure to triptolide in 12 T CD133(+) cells, treatment of tumors formed by these cells with Minnelide, a triptolide pro-drug, showed significant tumor regression. CONCLUSION: Our results indicated that triptolide enhanced and enriched the "stemness" in the PDAC cell lines at a low dose of 12.5 nM, but also resulted in the regression of tumors derived from these cells. PMID- 26597729 TI - Developing an Objective Structured Assessment of Technical Skills for Laparoscopic Suturing and Intracorporeal Knot Tying. AB - OBJECTIVE: To develop a teaching and assessment tool for laparoscopic suturing and intracorporeal knot tying. DESIGN AND SETTING: We designed an Objective Structured Assessment of Technical Skills (OSATS) tool that includes a procedure specific checklist (PSC) and global rating scale (GRS) to assess laparoscopic suturing and intracorporeal knot-tying performance. Obstetrics and Gynecology residents at our institution were videotaped while performing a laparoscopic suturing and intracorporeal knot-tying task at a surgical simulation workshop. A total of 2 expert reviewers assessed resident performance using the OSATS tool during live performance and 1 month later using the videotaped recordings. OSATS scores were analyzed using the Wilcoxon rank-sum test. Data are presented as median scores (interquartile range [IQR]). Intrarater and interrater reliabilities were assessed using a Spearman correlation and are presented as an r correlation coefficient and p value. An r >= 0.8 was considered as a high correlation. After testing, we received feedback from residents and faculty to improve the OSATS tool as part of an iterative design process. PARTICIPANTS: In all, 14 of 21 residents (66.7%) completed the study, with 9 junior residents and 5 senior residents. RESULTS: Junior residents had a lower score on the PSC than senior residents did; however, this was not statistically significant (median = 6.0 [IQR: 4.0-10.0] and median = 13.0 [IQR: 10.0-13.0]; p = 0.09). There was excellent intrarater reliability with our OSATS tool (for PSC component, r = 0.88 for Rater 1 and 0.93 for Rater 2, both p < 0.0001; for GRS component, r = 0.85 for Rater 1 and 0.88 for Rater 2, both p <= 0.0002). The PSC also has high interrater reliability during live evaluation (r = 0.92; p < 0.0001), and during the videotape scoring with r = 0.77 (p = 0.001). CONCLUSIONS: Our OSATS tool may be a useful assessment and teaching tool for laparoscopic suturing and intracorporeal knot-tying skills. Overall, good intrarater reliability was demonstrated, suggesting that this tool may be useful for longitudinal assessment of surgical skills. PMID- 26597728 TI - Exendin-4 attenuates adverse cardiac remodelling in streptozocin-induced diabetes via specific actions on infiltrating macrophages. AB - In addition to its' established metabolic and cardioprotective effects, glucagon like peptide-1 (GLP-1) reduces post-infarction heart failure via preferential actions on the extracellular matrix (ECM). Here, we investigated whether the GLP 1 mimetic, exendin-4, modulates cardiac remodelling in experimental diabetes by specifically targeting inflammatory/ECM pathways, which are characteristically dysregulated in this setting. Adult mice were subjected to streptozotocin (STZ) diabetes and infused with exendin-4/insulin/saline from 0 to 4 or 4-12 weeks. Exendin-4 and insulin improved metabolic parameters in diabetic mice after 12 weeks, but only exendin-4 reduced cardiac diastolic dysfunction and interstitial fibrosis in parallel with altered ECM gene expression. Whilst myocardial inflammation was not evident at 12 weeks, CD11b-F4/80(++) macrophage infiltration at 4 weeks was increased and reduced by exendin-4, together with an improved cytokine profile. Notably, media collected from high glucose-treated macrophages induced cardiac fibroblast differentiation, which was prevented by exendin-4, whilst several cytokines/chemokines were differentially expressed/secreted by exendin-4-treated macrophages, some of which were modulated in STZ exendin-4 treated hearts. Our findings suggest that exendin-4 preferentially protects against ECM remodelling and diastolic dysfunction in experimental diabetes via glucose-dependent modulation of paracrine communication between infiltrating macrophages and resident fibroblasts, thereby indicating that cell-specific targeting of GLP-1 signalling may be a viable therapeutic strategy in this setting. PMID- 26597730 TI - An International Surgical Rotation as a Systems-Based Elective: The Botswana University of Pennsylvania Surgical Experience. AB - OBJECTIVE: There is a growing need to address the global burden of surgical disease along with increasing interest in international surgical practice, necessitating an understanding of the challenges and issues that arise on a systems level when practicing abroad. DESIGN: This elective is a month-long rotation in which senior surgical residents participate in patient care as part of a surgical team in the main tertiary and teaching hospital in Gaborone, the capital city of Botswana. Clinical experience is combined with formal readings and educational sessions, with the attending surgeon supervising the program to develop a systems-based curriculum that contextualizes the clinical experience. A formal debriefing and written reflections by the residents at the conclusion of the rotation are used to qualitatively assess resident development and insight into systems-based international surgical practice. SETTING: Princess Marina Hospital, Gaborone, Botswana. PARTICIPANTS: General surgery residents in their fourth clinical year of training. RESULTS: Our elective met important requirements outlined in the literature for foreign practice, including adequate supervision of the American trainees and care to not detract from local trainees' educational experience. Residents' debriefing and written reflections demonstrated an increased understanding of systems-based practice and awareness of issues important to successful international surgical practice and collaboration. CONCLUSIONS: Our global surgery elective with a focus on systems based practice sensitizes residents to the challenges and issues they must be aware of when practicing internationally. PMID- 26597731 TI - Are There Detrimental Effects From Proficiency-Based Training in Fundamentals of Laparoscopic Surgery Among Novices? An Exploration of Goal Theory. AB - INTRODUCTION: Goal theory states that novices may experience unintended, detrimental learning effects, with decreased performance, when given performance goals on complex tasks. In these situations, it may be more appropriate to give novices learning goals to help avoid these negative consequences. The purpose of this study was to see whether this tenant of goal theory applied to novices learning 2 tasks of fundamentals of laparoscopic surgery (FLS). MATERIALS AND METHODS: Medical and physician assistant students were randomized to a performance goals group and a learning goals group. The performance goals consisted of the published proficiency standards of FLS. Both groups were pretested on perception of surgery, self-efficacy, and general affect. Each group underwent a practice session for the peg transfer task. They were tested and scored per the published standards of FLS. The participants completed NASA Task Load Index, task complexity, and postaffect questionnaires related to the peg transfer task. This was repeated with the suture with intracorporeal knot task. Posttest perception of surgery and self-efficacy questionnaires were completed. RESULTS: In total, 48 students participated in the study: 23 in the performance goals group and 25 in the learning goals group. Most of the participants (n = 40) were first-year medical and physician assistant students. There were no significant differences between the groups in perception of surgery, affect, goal commitment, subjective task complexity, subjective workload, and self-efficacy. There were no differences between the groups concerning overall FLS score for both the peg transfer and suturing tasks. Both groups exhibited significant increases in self-efficacy and perception of surgery (p < 0.05). CONCLUSION: FLS skills can be given to novice learners without concern for detrimental effects as might be expected by other work on goal theory. Given that performance was the same for both groups, surgical educators may have multiple pathways to educational success when incorporating goals into training programs for basic surgical skills. PMID- 26597733 TI - Can rechallenge be done safely after mild or moderate drug-induced liver injury? PMID- 26597732 TI - Reversal of neuromuscular blockade by sugammadex in laparoscopic bariatric surgery: In support of dose reduction. AB - INTRODUCTION: Sugammadex is the first molecule able to antagonize steroidal muscle relaxants with few adverse effects. Doses are adjusted to body weight and the level of neuromuscular blockade. Sleeve gastrectomy is becoming a very popular form of bariatric surgery. It requires deep muscle relaxation followed by complete and rapid reversal to decrease postoperative and especially post anaesthetic morbidity. Sugammadex is therefore particularly indicated in this setting. The objective of this study was to evaluate the deep neuromuscular blockade reversal time after administration of various doses of sugammadex (based on real weight or at lower doses). Secondary endpoints were the interval between the sugammadex injection and extubation and transfer from the operating room to the recovery room. We then investigated any complications observed in the recovery room. MATERIALS AND METHODS: This pilot, prospective, observational, clinical practice evaluation study was conducted in the Amiens University Hospital. Neuromuscular blockade was induced by rocuronium. At the end of the operation, deep neuromuscular blockade was reversed by sugammadex at the dose of 4mg/kg. RESULTS: Sixty-four patients were included: 31 patients received sugammadex at a dosage based on their real weight (RW) and 33 patients received a lower dose (based on ideal weight [IW]). For identical rocuronium doses calculated based on IBW, sugammadex doses were significantly lower in the IW group: 349 (+/- 65) mg versus 508 (+/- 75) mg (P<0.0001). Despite this dose reduction, neuromuscular blockade reversal took 115 (+/- 69) s in the IW group versus 87 (+/- 40) s in the RW group, but with no significant difference between the two groups (P=0.08). The intervals between injection of sugammadex and extubation (P=0.07) and transfer from the operating room to the recovery room (P=0.68) were also non-significantly longer in the IW group. The mean dose of sugammadex used by anaesthetists in the IW group was 4mg/kg of ideal weight increased by 35% to 50% (n=20; 351+/-34mg). No sugammadex adverse effects and no residual neuromuscular blockades were observed. Postoperative nausea and vomiting (PONV) was observed in 19.4% of patients in the real weight group versus 27.3% in the ideal weight group (P=NS). CONCLUSION: Reversal of deep neuromuscular blockades by sugammadex in obese subjects can be performed at doses of 4mg/kg of ideal weight plus 35-50% with no clinical consequences and no accentuation of adverse effects. PMID- 26597734 TI - Sources of variability in language development of children with cochlear implants: age at implantation, parental language, and early features of children's language construction. AB - The aim of the present study was to analyze the relative influence of age at implantation, parental expansions, and child language internal factors on grammatical progress in children with cochlear implants (CI). Data analyses used two longitudinal corpora of spontaneous speech samples, one with twenty-two and one with twenty-six children, implanted between 0;6 and 3;10. Analyses were performed on the combined and separate samples. Regression analyses indicate that early child MLU is the strongest predictor of child MLU two and two-and-a-half years later, followed by parental expansions and age at implantation. Associations between earliest MLU gains and MLU two years later point to stability of individual differences. Early type and token frequencies of determiners predict MLU two years later more strongly than early frequency of lexical words. We conclude that features of CI children's very early language have considerable predictive value for later language outcomes. PMID- 26597735 TI - Sex- and age-related variation in metal content of penguin feathers. AB - The presence of xenobiotics, such as metals, in ecosystems is concerning due to their durability and they pose a threat to the health and life of organisms. Moreover, mercury can biomagnify in many marine food chains and, therefore, organisms at higher trophic levels can be adversely impacted. Although feathers have been used extensively as a bio-monitoring tool, only a few studies have addressed the effect of both age and sex on metal accumulation. In this study, the concentrations of trace elements were determined in the feathers of all members of a captive colony of African Penguins (Spheniscus demersus) housed in a zoological facility in Italy. Tests were performed by inductively coupled plasma mass spectrometry to detect aluminum, arsenic, cadmium, cobalt, chromium, copper, iron, manganese, nickel, lead, selenium, tin, vanadium, and zinc. Mercury was detected by a direct mercury analyzer. Sexing was performed by a molecular approach based on analyzing the chromo-helicase-DNA-binding1 gene, located on the sex chromosomes. Sex- and age-related differences were studied in order to investigate the different patterns of metal bioaccumulation between male and female individuals and between adults and juveniles. Juvenile females had significantly higher arsenic levels than males, while selenium levels increased significantly with age in both sexes. Penguins kept in controlled environments given that diet and habitat are under strict control-represent a unique opportunity to determine if and how metal bioaccumulation is related to sex and age. PMID- 26597737 TI - Primary aldosteronism and pregnancy. AB - Primary aldosteronism is the most common cause of secondary hypertension. Less than 50 cases of pregnancy in women with primary aldosteronism have been reported, suggesting the disorder is significantly underdiagnosed in confinement. Accurate diagnosis is complicated by physiological changes in the renin angiotensin-aldosterone axis in pregnancy, leading to a risk of false negative results on screening tests. The course of primary aldosteronism during pregnancy is highly variable, although overall it is associated with a very high risk of fetal and maternal morbidity and mortality. The optimal management of primary aldosteronism during pregnancy is unclear, with uncertainty regarding the safety of mineralocorticoid antagonists and amiloride, their relative efficacy compared with the antihypertensive medications commonly used during pregnancy, and as to whether prognosis is improved by laparoscopic adrenalectomy where an adrenal adenoma can be demonstrated. PMID- 26597736 TI - Subcellular distribution, modulation of antioxidant and stress-related genes response to arsenic in Brassica napus L. AB - Arsenic (As) is an environmental toxin pollutant that affects the numerous physiological processes of plants. In present study, two Brassica napus L. cultivars were subjected to various concentrations (0, 50, 100, and 200 uM) of As for 14 days, plants were examined for As subcellular distribution, photosynthesis parameters, oxidative stress, and ultrastructural changes under As-stress. Differential fraction analysis showed that significant amount of As was accumulated in the cell wall as compared to other organelles. Decline in photosynthetic efficiency under As stress was observed in term of reduced pigment contents and gas exchange parameters. Differential responses of antioxidants at both enzymatic and gene levels to higher As stress were more pronounced in cultivar ZS 758 as compared to Zheda 622. The qRT-PCR analysis showed that heat shock protein 90 (Hsp90) and metallothionein were over-expressed in As stressed B. napus plants. Disorganization of cell structure and the damages in different organelles were some of the obvious variations in cultivar Zheda 622 as compared to ZS 758. PMID- 26597738 TI - Maternal serum ratio of ghrelin to obestatin decreased in preeclampsia. AB - OBJECTIVE: Ghrelin, an endogenous for the growth hormone secretagogue receptor, has been shown to participate in blood pressure regulation. Obestatin, encoded by the same gene as ghrelin, is described as a physiological opponent of ghrelin. We hypothesized that ghrelin/obestatin imbalance played a role in the pathogenesis. This study was designed to determine the alterations of ghrelin and obestatin concentrations and ghrelin/obestatin ratio in maternal serum in preeclampsia. METHOD: This retrospective case-control study included 31 preeclampsia and 31 gestational week-matched normal pregnancies. Ghrelin and obestatin concentrations in maternal serum were determined by radioimmunoassay, and the ghrelin/obestatin ratio was calculated. RESULTS: The ghrelin concentration and ghrelin/obestatin ratio in maternal serum were significantly lower in preeclampsia than in normal pregnancies (214.34+/-14.27pg/mL vs 251.49+/-16.15pg/mL, P=0.041, 1.07+/-0.09 vs 0.82+/-0.08, P=0.023). The obestatin concentration in maternal serum was significantly higher in preeclampsia than in normal pregnancies (276.35+/ 15.38pg/mL vs 223.53+/-18.61pg/mL, P=0.019). The systolic blood pressure in preeclampsia was negatively correlated with ghrelin concentration and ghrelin/obestatin ratio (r=-0.549, P=0.003; r=-0.491, P=0.004) and was positively correlated with obestatin concentrations in preeclampsia (r=0.388, P=0.013). CONCLUSIONS: The findings of this study suggested disturbance of ghrelin and obestatin in maternal serum in preeclampsia, and ghrelin/obestatin imbalance might play a role in the pathogenesis of preeclampsia. PMID- 26597739 TI - Transforming growth factor beta-1 (TGF-beta1) gene single nucleotide polymorphisms (SNPs) and susceptibility to pre-eclampsia in Iranian women: A case control study. AB - OBJECTIVES: Pre-eclampsia (PE) is a disorder of pregnancy characterized by high blood pressure and proteinuria. Transforming growth factor beta-1 (TGF-beta1) is an important replicated PE candidate gene, and few studies have evaluated the direct association of TGF-beta polymorphisms and risk to PE. The aim of this study was to investigate the association between three SNPs of TGF-beta1 and serum level of this cytokine in PE patients and controls. DESIGN AND METHODS: In this study the polymorphisms of the TGF-beta1 gene at the coding region, and positions 29T->C (Leu 10 Pro), 74G->C (Arg 25 Pro) and 788C->T (Thr 263 Ile) were studied in 123 PE and 120 normal subjects using PCR-restriction fragment length polymorphism PCR-(RFLP) and amplification refractory mutation system (ARMS)-PCR methods. Moreover, serum TGF-beta1 was determined by enzyme-linked immunosorbent assay (ELISA) technique. RESULTS: At positions 74G->C and 29T->C the genotypes and allele frequencies showed no significant differences between PE patients and normal controls (P=0.3 and P=0.5 respectively). While in the case of position 788C->T both genotypes and allele frequencies were significantly different between PE patients and controls (P=0.02). Haplotype analysis on three polymorphic sites showed no significant differences between PE and control individuals (P=0.8). TGC and CGC haplotypes were the most frequent in both studied groups. The mean serum TGF-beta1 level was significantly higher (62.73ng/ml) in PE patients compared with pregnant (47.01ng/ml) and non-pregnant (40.68ng/ml) control groups (P=0.0001). CONCLUSIONS: The results of this study suggest that TGF-beta1 gene 788C->T polymorphism is an important factor mediating the casual pathway of preeclampsia. PMID- 26597740 TI - The effect of calcium supplementation on blood pressure in non-pregnant women with previous pre-eclampsia: An exploratory, randomized placebo controlled study. AB - BACKGROUND: Epidemiological findings suggest that the link between poverty and pre-eclampsia might be dietary calcium deficiency. Calcium supplementation has been associated with a modest reduction in pre-eclampsia, and also in blood pressure (BP). METHODS: This exploratory sub-study of the WHO Calcium and Pre eclampsia (CAP) trial aims to determine the effect of 500mg/day elemental calcium on the blood pressure of non-pregnant women with previous pre-eclampsia. Non pregnant women with at least one subsequent follow-up trial visit at approximately 12 or 24weeks after randomization were included. RESULTS: Of 836 women randomized by 9 September 2014, 1st visit data were available in 367 women of whom 217 had previously had severe pre-eclampsia, 2nd visit data were available in 201 women. There was an overall trend to reduced BP in the calcium supplementation group (1-2.5mmHg) although differences were small and not statistically significant. In the subgroup with previous severe pre-eclampsia, the mean diastolic BP change in the calcium group (-2.6mmHg) was statistically larger than in the placebo group (+0.8mmHg), (mean difference -3.4, 95% CI -0.4 to -6.4; p=0.025). The effect of calcium on diastolic BP at 12weeks was greater than in those with non-severe pre-eclampsia (p=0.020, ANOVA analysis). CONCLUSIONS: There is an overall trend to reduced BP but only statistically significant in the diastolic BP of women with previous severe pre-eclampsia. This is consistent with our hypothesis that this group is more sensitive to calcium supplementation, however results need to be interpreted with caution. PMID- 26597743 TI - A wash step at collection of placental biopsies from preeclamptic pregnancies does not adversely affect levels of sFlt-1 or endoglin. AB - There is recent interest for uniform placental collection protocols so laboratories can share samples. However, concerns have been raised a wash step at collection causes significant loss of sFlt-1 and soluble endoglin, among the most studied proteins in placentology. We measured Flt-1 and endoglin mRNA and protein in 10 preeclamptic placentas that were washed, or left unwashed. Reassuringly, there was no significant change in the Flt-1, sFlt-1-e15a or sFlt-1-i13 mRNA or Flt-1 or sFlt-1 protein expression or localization. There was also no change in endoglin mRNA expression or protein localization. Washing preeclamptic placental samples does not alter anti-angiogenic factor expression. PMID- 26597742 TI - Cerebrovascular, cardiovascular and renal hypertensive disease after hypertensive disorders of pregnancy. AB - BACKGROUND: Strong associations have been established in nationwide registry studies between hypertensive disorders of pregnancy (HDP) and later vascular morbidities and mortality. The aim of this case-control study is to examine the interdependent relationships of different predictive factors for vascular disease and HDP, because they are not clearly elucidated due to lack of detail in registries. METHODS AND RESULTS: We assembled three different case groups of women who had cerebrovascular, cardiovascular, or hypertensive kidney disease before the age of 55. The control group consisted of age-matched women who underwent hysterectomy for benign reasons. We assessed the occurrence of HDP in previous pregnancies. The strength of the association with vascular morbidities was tested with multivariable logistic regression in comparison with classic vascular risk factors. In all case groups, previous HDP occurred more frequent than in the control group. In logistic regression analysis, previous HDP were the strongest predictor in the cerebrovascular group (OR 4.2; 95% confidence interval [CI] 1.6-11.0). In the cardiovascular group and the kidney failure group a similar association was found, however, this was not statistically significant (OR 4.4 (95% CI 0.82-4) and 2.9 (95% CI 0.61-14), respectively). CONCLUSIONS: Previous hypertensive disorders of pregnancy are a strong predictor for later vascular morbidity. This is partially mediated through the presence of classic vascular risk factors, but our data suggest it is also an independent predictor. PMID- 26597741 TI - Baseline placental growth factor levels for the prediction of benefit from early aspirin prophylaxis for preeclampsia prevention. AB - OBJECTIVE: Placental growth factor (PlGF) levels early in pregnancy are lower in women who ultimately develop preeclampsia. Early initiation of low-dose aspirin reduces preeclampsia risk in some high risk women. We hypothesized that low PlGF levels may identify women at increased risk for preeclampsia who would benefit from aspirin. STUDY DESIGN: Secondary analysis of the MFMU High-Risk Aspirin study including singleton pregnancies randomized to aspirin 60mg/d (n=102) or placebo (n=72), with PlGF collected at 13w 0d-16w 6d. Within the placebo group, we estimated the probability of preeclampsia by PlGF level using logistic regression analysis, then determined a potential PlGF threshold for preeclampsia prediction using ROC analysis. We performed logistic regression modeling for potential confounders. RESULTS: ROC analysis indicated 87.71pg/ml as the threshold between high and low PlGF for preeclampsia-prediction. Within the placebo group high PlGF weakly predicted preeclampsia (AUC 0.653, sensitivity/specificity 63%/66%). We noted a 2.6-fold reduction in preeclampsia with aspirin in the high-PlGF group (12.15% aspirin vs 32.14% placebo, p=0.057), but no significant differences in preeclampsia in the low PlGF group (21.74% vs 15.91%, p=0.445). CONCLUSIONS: Unlike other studies, we found that high rather than low PlGF levels were associated with an increased preeclampsia risk. Low PlGF neither identified women at increased risk of preeclampsia nor women who benefitted from aspirin. Further research is needed to determine whether aspirin is beneficial in women with high PlGF, and whether the paradigm linking low PlGF and preeclampsia needs to be reevaluated. CONDENSATION: High-risk women with low baseline PlGF, a risk factor for preeclampsia, did not benefit from early initiation of low-dose aspirin. PMID- 26597744 TI - Should the spot albumin-to-creatinine ratio replace the spot protein-to creatinine ratio as the primary screening tool for proteinuria in pregnancy? AB - OBJECTIVES: To determine the correlation between the spot albumin-to-creatinine (ACR) ratio and protein-to-creatinine ratio (PCR) in pregnancy and if either test is predictive of adverse pregnancy outcome. STUDY DESIGN: Prospective consecutive cohort study in a single tertiary centre examining 181 patients undergoing proteinuria screening after 20weeks of pregnancy. A spot PCR and ACR was performed on the first void of the day. Comparison was with linear and logistic regression and ROC curve. Optimal values for the ACR were obtained and compared to a PCR value of 30mg/mmol with respect to adverse pregnancy outcomes. MAIN OUTCOME MEASURES: Birth weight <10th centile, preterm birth <32 and <37weeks, placental abruption, caesarean section, induction of labour, fetal death in utero or neonatal death, Apgar score <5 at 1min and/or 5min, pulmonary oedema, sustained blood pressure >170/110mmHg, magnesium infusion or labetalol infusion during labour. RESULTS: 254 tests were performed. The ACR and PCR were highly correlated (r=0.95, p<0.001) and the area under ROC curve was 0.98. An ACR of 13.4mg/mmol corresponded to a PCR of 30mg/mmol. Neither was more predictive of adverse pregnancy outcome nor was the level of proteinuria. CONCLUSIONS: The ACR is not inferior to nor does it perform better than the PCR in screening for proteinuria in pregnancy. Clinicians should use the test with which they are more familiar and may wish to assess local laboratory costs and methods in their selection. PMID- 26597745 TI - Microalbuminuria is a predictor of adverse pregnancy outcomes including preeclampsia. AB - OBJECTIVES: Abnormal urinary protein loss is a marker associated with a diverse range of renal diseases including preeclampsia. Current measures of urine protein used in the diagnostic criteria for the diagnosis of preeclampsia includes urine protein:creatinine ratio and 24-h urine protein. However very little is known about the value of urine albumin:creatinine ratio (uACR) in pregnancy. In this study we examined the prognostic value of microalbuminuria detected antepartum to predict adverse pregnancy outcomes. DESIGN: This is a single-centre retrospective analysis of 84 pregnant women over the age of 16 attending a tertiary 'high-risk' pregnancy outpatient clinic between July 2010 and June 2013. Utilising medical records, antepartum peak uACR level and pregnancy maternal and fetal outcomes were recorded. FINDINGS: The primary outcome was a composite of poor maternal and fetal outcomes including preeclampsia, maternal death, eclampsia, stillbirth, neonatal death, IUGR, premature delivery and placental abruption. As the antepartum peak uACR level (in mg/mmol) increased from normoalbuminuria (uACR<3.5) to microalbuminuria (uACR 3.5-35) to macroalbuminuria (>35), the percentage of women with the primary composite outcome increased in a stepwise fashion (13.8% to 24.1% to 62.1% respectively, p<0.001). After adjusting for covariates including history of hypertension, chronic kidney disease and aspirin therapy during pregnancy, micro- and macroalbuminuria remained significant predictors of the primary outcome. CONCLUSIONS: We have shown that antepartum peak uACR is a useful simple marker to help predict adverse maternal and fetal outcomes. Further studies are required to utilise uACR as a prognostic tool in pregnancy before it can be applied in clinical practice. PMID- 26597746 TI - Dietary fructose in pregnancy induces hyperglycemia, hypertension, and pathologic kidney and liver changes in a rodent model. AB - PURPOSE: The incidence of pregnancies complicated by hyperglycemia and hypertension is increasing along with associated morbidities to mother and offspring. The high fructose diet is a well-studied model that induces hyperglycemia and hypertension in male rodents, but may not affect females. We hypothesized that the physiologic stress of pregnancy may alter metabolic responses to dietary fructose. MATERIALS AND METHODS: In this study female Sprague-Dawley rats were divided into two gestational dietary groups: (1) 60% carbohydrate standard rat chow (Pregnant-S-controls) and (2) 60% fructose enriched chow (Pregnant-F). Body weight, blood pressure, blood glucose, triglycerides, and insulin were measured in pregnancy and during the post-partum period. Maternal organ weight and histological changes were also assessed after delivery. RESULTS: By midpregnancy Pregnant-F rats had increased weight, elevated blood pressure, higher fasting glucose, and elevated triglycerides compared with Pregnant-S rats. Both groups demonstrated elevated gestational insulin levels with signs of insulin resistance (increased HOMA-IR). Pregnant-F rats showed significant histopathologic hepatic steatosis and renal tubular changes characterized by tubular dilation and glomerulosclerosis. CONCLUSION: Our study provides a model in which dietary change during pregnancy can be examined. We demonstrate, moreover, that high dietary fructose ingestion in pregnant rats may result in profound systemic and pathologic changes not appreciated during routine pregnancy. PMID- 26597747 TI - Development and internal validation of a multivariable model to predict perinatal death in pregnancy hypertension. AB - OBJECTIVE: To develop and internally validate a prognostic model for perinatal death that could guide community-based antenatal care of women with a hypertensive disorder of pregnancy (HDP) in low-resourced settings as part of a mobile health application. STUDY DESIGN: Using data from 1688 women (110 (6.5%) perinatal deaths) admitted to hospital after 32weeks gestation with a HDP from five low-resourced countries in the miniPIERS prospective cohort, a logistic regression model to predict perinatal death was developed and internally validated. Model discrimination, calibration, and classification accuracy were assessed and compared with use of gestational age alone to determine prognosis. MAIN OUTCOME MEASURES: Stillbirth or neonatal death before hospital discharge. RESULTS: The final model included maternal age; a count of symptoms (0, 1 or ?2); and dipstick proteinuria. The area under the receiver operating characteristic curve was 0.75 [95% CI 0.71-0.80]. The model correctly identified 42/110 (38.2%) additional cases as high-risk (probability >15%) of perinatal death compared with use of only gestational age <34weeks at assessment with increased sensitivity (48.6% vs. 23.8%) and similar specificity (86.6% vs. 90.0%). CONCLUSION: Using simple, routinely collected measures during antenatal care, we can identify women with a HDP who are at increased risk of perinatal death and who would benefit from transfer to facility-based care. This model requires external validation and assessment in an implementation study to confirm performance. PMID- 26597748 TI - Transfer function analysis of dynamic cerebral autoregulation in preeclampsia. AB - OBJECTIVE: The cerebral circulatory effects of preeclampsia on the latency (phase) and the efficiency (gain) of the cerebral autoregulatory response is unknown. Preeclampsia causes a progressive impairment of the cerebral autoregulatory response. We sought to identify these dynamic cerebral autoregulation changes in preeclampsia. STUDY DESIGN: We simultaneously measured continuously beat to beat outputs of mean arterial pressure (MAP) (Pilot 9200) and beat to beat, systolic, diastolic, and mean cerebral blood flow (MCBFV) (Nicolet Vascular TCD) for 2min with the patient during supine rest. Five preeclamptic and 5 matched normotensive controls were studied. R-R intervals, MAP, and MCBFV were analyzed in the frequency domain. Data sets were fast Fourier transformed and power spectral densities were calculated. We calculated the phase angle (which represents the temporal relationship between the MAP and mean MCBFV) and the transfer function (amplitude or gain between changes in the MCBFV signal and the MAP signal). All continuous data was compared between the two groups using T tests. RESULTS: We identified a significant difference between (1) the gain between the normotensive and preeclamptic groups (.29+/-.07 vs .10+/-.04) (p<.01, and (2) the phase angle (59+/-12 vs 129+/-31), p<.01. The preeclamptic group showed significant decrease in gain but an increase in phase angle). CONCLUSION: Preeclampsia paradoxically results in a significant improvement in dynamic cerebral autoregulation as demonstrated by an increase in phase and a decrease in gain. Clinical studies that can systematically assess the progression of these dynamic autoregulation changes are needed. PMID- 26597749 TI - Elevated inflammatory markers in preeclamptic pregnancies, but no relation to systemic arterial stiffness. AB - OBJECTIVES: To investigate if circulating markers of systemic and vascular inflammation are associated with systemic arterial properties at term and 6months post-partum in women with preeclampsia (PE) and normal pregnancy (NP). STUDY DESIGN: Longitudinal, sampling at term and 6months post-partum in 34 women (32+/ 6years) with PE and 61 women (32+/-5years) with NP. MAIN OUTCOME MEASURES: Circulating markers related to systemic and vascular inflammation were measured by enzyme immune-assay. Systemic arterial properties were estimated by Doppler (transthoracic echocardiography) and calibrated right subclavian artery pulse traces. RESULTS: CXCL16, soluble tumor necrosis factor receptor type 1 (sTNF-R1), monocyte chemoattractant peptide 1, pentraxin 3 and soluble vascular adhesion molecule 1 (sVCAM-1) were elevated at term in PE, and sTNF-R1 remained elevated 6months post partum compared to NP. However, apart from a negative correlation between mean arterial pressure and sTNF-R1 and sVCAM-1 at term, no associations between systemic and vascular inflammatory markers and systemic arterial properties as reflected by characteristic impedance and arterial elastance, representing proximal aortic stiffness and effective arterial elastance, were found at any time point. CONCLUSIONS: Preeclamptic pregnancies are characterized by increased circulating levels of systemic and vascular inflammatory markers. However, these are not associated with systemic arterial properties at term or 6months post partum. PMID- 26597750 TI - Accuracy of angiogenic biomarkers at ?20weeks' gestation in predicting the risk of pre-eclampsia: A WHO multicentre study. AB - OBJECTIVE: To assess the accuracy of angiogenic biomarkers to predict pre eclampsia. DESIGN: Prospective multicentre study. From 2006 to 2009, 5121 pregnant women with risk factors for pre-eclampsia (nulliparity, diabetes, previous pre-eclampsia, chronic hypertension) from Argentina, Colombia, Peru, India, Italy, Kenya, Switzerland and Thailand had their serum tested for sFlt-1, PlGF and sEng levels and their urine for PlGF levels at ?20, 23-27 and 32 35weeks' gestation (index tests, results blinded from carers). Women were monitored for signs of pre-eclampsia, diagnosed by systolic blood pressure ?140mmHg and/or diastolic blood pressure ?90mmHg, and proteinuria (protein/creatinine ratio ?0.3, protein ?1g/l, or one dipstick measurement ?2+) appearing after 20weeks' gestation. Early pre-eclampsia was defined when these signs appeared ?34weeks' gestation. MAIN OUTCOME MEASURE: Pre-eclampsia. RESULTS: Pre-eclampsia was diagnosed in 198 of 5121 women tested (3.9%) of whom 47 (0.9%) developed it early. The median maternal serum concentrations of index tests were significantly altered in women who subsequently developed pre-eclampsia than in those who did not. However, the area under receiver operating characteristics curve at ?20weeks' gestation were closer to 0.5 than to 1.0 for all biomarkers both for predicting any pre-eclampsia or at ?34weeks' gestation. The corresponding sensitivity, specificity and likelihood ratios were poor. Multivariable models combining sEng with clinical features slightly improved the prediction capability. CONCLUSIONS: Angiogenic biomarkers in first half of pregnancy do not perform well enough in predicting the later development of pre eclampsia. PMID- 26597751 TI - Association between maternal haemoglobin at 27-29weeks gestation and intrauterine growth restriction. AB - OBJECTIVE: To examine the relationship between maternal haemoglobin concentration (Hb) at 27-29weeks' gestation and fetal growth restriction (FGR). DESIGN: This was a retrospective, case control study. SETTING: A University hospital in London, UK. POPULATION: Pregnant women attending for routine antenatal care at 27 29weeks of pregnancy. METHODS: Maternal Hb, measured routinely at 27-29weeks in pregnancies complicated by FGR (n=491) was compared to normal controls (n=491). Multiple regression analysis was used to examine the association between Hb and maternal characteristics. MAIN OUTCOME MEASURES: Birthweight z-score, admission to the Neonatal Unit (NNU) and adverse perinatal outcome. RESULTS: Increased Hb at 27-29weeks gestation is associated with reduced birthweight, with an inverse relationship between maternal Hb and fetal birthweight z-score (R(2)=0.10, p<0.0001). In addition, for the prediction of admission to the NNU (R(2)=0.24, p<0.0001) and serious adverse neonatal outcome (R(2)=0.10, p<0.0001), maternal Hb is an independent predictor with a linear and quadratic relationship, respectively. Therefore, both increased and decreased maternal Hb levels increase the risk of serious neonatal complications. CONCLUSIONS: Raised Hb at 27-29weeks gestation is associated with FGR and with an increased risk of admission to the NNU and adverse fetal outcome. PMID- 26597752 TI - Effects of normal and high circulating concentrations of activin A on vascular endothelial cell functions and vasoactive factor production. AB - OBJECTIVES: Activin A, a TGFbeta family member, circulates in the maternal blood at increasing concentrations throughout gestation during a healthy pregnancy. The circulating concentration of activin A is further increased in pre-eclampsia (PE), a hypertensive disorder of pregnancy that is marked by systemic maternal vascular endothelial cell dysfunction. The effect of increasing activin A concentrations on the maternal vascular endothelium is unknown. The study aim was to investigate the effect of physiological and pathological activin A concentrations observed in normotensive and PE pregnancies respectively, on vascular endothelial cell function. METHODS AND RESULTS: Immunostaining demonstrated the presence of the activin A receptor, ACVR2A, in SGHEC-7 cells used to model the vascular endothelium. SGHEC-7 cells were treated with activin A concentrations representative of concentrations throughout gestation in normotensive (0-10ng/ml) and PE (50ng/ml) pregnancies. xCELLigence functional assays revealed that normotensive activin A concentrations increased SGHEC-7 proliferation and migration, which was inhibited by PE concentrations. Additionally, fluorescence based assays showed that PE concentrations increased endothelial permeability. None of the tested activin A concentrations affected cell apoptosis. PE concentrations also resulted in an imbalance of the vasoactive factors eNOS, PTGIS and EDN1, as determined by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assays. CONCLUSION: Compared with normotensive activin A concentrations, the higher PE activin A concentrations resulted in abnormal endothelial functions, which may contribute to the systemic maternal vascular endothelial cell dysfunction observed in the disorder. PMID- 26597753 TI - Evidence of inflammation and predisposition toward metabolic syndrome after pre eclampsia. AB - BACKGROUND: Pre-eclampsia (PE) is a hypertensive disorder of pregnancy characterized by exaggerated inflammatory and metabolic responses. Women with a history of PE are at increased risk of the metabolic syndrome (MetS) and cardiovascular disease although the pathophysiological underpinnings of this association remain unclear. This study aimed to compare levels of plasma immunoregulatory factors with the presence of cardiovascular and MetS risk factors in women with and without a history of PE. STUDY DESIGN: Maternal plasma and general health survey data were collected from women 5 to 7months postpartum of uncomplicated pregnancies (n=28) and pregnancies complicated by PE (n=35). Maternal plasma samples were analyzed for 14 immunoregulatory factors using a high-sensitivity cytokine profiling array. Cardiovascular risk profiles were compiled on each participant for comparison against cytokine data. RESULTS: Women with a history of PE exhibited increased blood pressure and plasma triglyceride levels compared to controls, although similar for parameters of obesity, fasting cholesterols, and glucose. While plasma levels of immunoregulatory cytokines were similar between control and PE subjects, PE subjects exhibited unique patterns of correlation between biophysical parameters and plasma cytokines. In particular, plasma IL-23, MIP-1alpha, IL-1beta and IFN-gamma levels were significantly correlated with parameters considered for MetS diagnosis in women without clinical evidence of the syndrome. CONCLUSIONS: We report unique associations between pro-inflammatory markers and MetS criteria within a year following PE. Subclinical inflammation in women with a history of PE who are otherwise healthy may indicate a sensitization of these women toward metabolic disturbances, in particular MetS. PMID- 26597754 TI - Is preeclampsia an independent predictor of diastolic dysfunction? A retrospective cohort study. AB - OBJECTIVE: To determine if preeclampsia is an independent predictor of diastolic dysfunction and what factors among patients with preeclampsia are associated with diastolic dysfunction. METHODS: This is a retrospective cohort study of patients who delivered between 2008 and 2013 at a single institution who had a maternal echocardiogram during their pregnancy or within 5months of delivery. Patients with structural heart disease, ejection fraction less than 45%, pulmonary embolus, or age over 45years were excluded. Medical records were reviewed for medical and obstetric complications and echocardiogram findings. Demographic characteristics and rate of diastolic dysfunction were compared between patients with preeclampsia and without preeclampsia. Multivariate logistic regression was performed controlling for age, ethnicity, gestational age at delivery, diabetes, preeclampsia, intrauterine growth restriction (IUGR), antihypertensive use and magnesium sulfate administration. RESULTS: Sixty-six patients were identified, of which 39 (59%) had preeclampsia. Past history of preeclampsia, IUGR in the current pregnancy, antihypertensive use and magnesium sulfate use were higher in the preeclampsia group. Fifteen patients (39%) in the preeclampsia group were African-American compared to 2 (3%) in the control group (p<0.01). Seventeen (44%) of the patients with preeclampsia were found to have diastolic dysfunction compared to 3 (11%) controls (OR=6.18, 95% CI 1.59,24.02; p=0.006). Logistic regression analysis did not reveal other independent predictors of diastolic dysfunction. In the patients with preeclampsia, history of preeclampsia with severe features and IUGR were not associated with diastolic dysfunction. CONCLUSIONS: Our study supports previous findings that preeclampsia is associated with diastolic dysfunction. PMID- 26597755 TI - The effect of maternal hypertension on mortality in infants 22, 29weeks gestation. AB - OBJECTIVE: To evaluate the effect of maternal hypertension on mortality risk prior to discharge, in infants 22+0 to 29+6weeks gestational age. STUDY DESIGN: We evaluated 88,275 North American infants whose births were recorded in Vermont Oxford Network centers between 2008 and 2011 Infants born between 22+0 and 29+6weeks gestational age were evaluated in 2-week gestational age cohorts and followed until death or discharge. Logistic regression was used to adjust for birth weight, antenatal steroid exposure, infant sex, maternal race, inborn/outborn, prenatal care and birth year. RESULTS: 21,896 infants were born to hypertensive mothers; 13% died prior to Neonatal Intensive Care Unit discharge compared to 20% of the 66,379 infants born to mothers without hypertension. After adjustment, infants had significantly lower mortality compared to preterm infants not born to hypertensive mothers, at all gestational ages examined (22/23: odds ratio (OR)=0.65 (95% Confidence Interval (CI): 0.55, 0.77; 24/25); OR=0.77 (95% CI: 0.71, 0.84); 26/27: OR=0.66 (95% CI: 0.59, 0.74); 28/29: OR=0.58 (95% CI: 0.51, 0.67). Additionally, births associated with maternal hypertension increase dramatically by gestational age, resulting in a larger proportion of births associated with maternal hypertension at later gestational ages. CONCLUSIONS: Preterm birth due to any cause carries significant risk of mortality, especially at the earliest of viable gestational ages. Maternal hypertension independently influences mortality, with lower odds of mortality seen in infants born to hypertensive mothers, after adjustment, and should be taken into consideration as an element in counseling parents. PMID- 26597756 TI - Back to Basics to Eliminate Postpartum Hemorrhage at Vaginal Birth. PMID- 26597757 TI - Breathing pattern and breathlessness in idiopathic pulmonary fibrosis: An observational study. AB - BACKGROUND AND OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is characterized by progressive decline in lung function and increasing dyspnoea. The aim of this study was to investigate the relationship among IPF, pulmonary function, resting tidal breathing patterns and level of breathlessness. METHODS: Thirty-one participants with IPF and 17 matched healthy controls underwent lung function testing, followed by a 2-min period of resting tidal breathing. The IPF cohort was stratified according to disease severity, based on their forced vital capacity and diffusion capacity for carbon monoxide. RESULTS: In comparison to the healthy controls, the IPF cohort showed a higher tidal volume, VT , of 0.22 L (P = 0.026) and a raised minute ventilation in the severest IPF group, while no differences in the timing of inspiration or expiration were observed. In the IPF cohort, the ratio of VT to forced vital capacity was around 15% higher. These changes corresponded with an increase in the self-reported sensation of breathlessness. CONCLUSION: Those with IPF increased their depth of breathing with worsening disease severity, with IPF-induced changes in pulmonary function and breathlessness associated with an altered tidal breathing pattern. PMID- 26597758 TI - TNFalpha driven HIF-1alpha-hexokinase II axis regulates MHC-I cluster stability through actin cytoskeleton. AB - Hypoxia-inducible Factor-1alpha (HIF-1alpha)-regulated expression of Hexokinase II (HKII) remains a cornerstone in the maintenance of high metabolic demands subserving various pro-tumor functions including immune evasion in gliomas. Since inflammation-induced HIF-1alpha regulates Major Histocompatibility Complex class I (MHC-I) gene expression, and as cytoskeletal dynamics affect MHC-I membrane clusters, we investigated the involvement of HIF-1alpha-HKII axis in Tumor Necrosis Factor-alpha (TNFalpha)-mediated MHC-I membrane cluster stability in glioma cells and the involvement of actin cytoskeleton in the process. TNFalpha increased the clustering and colocalization of MHC-I with cortical actin in a HIF 1alpha dependent manner. siRNA mediated knockdown of HIF-1alpha as well as enzymatic inhibition of HK II by Lonidamine, delocalized mitochondrially bound HKII. This altered subcellular HKII localization affected TNFalpha-induced cofilin activation and actin turnover, as pharmacological inhibition of HKII by Lonidamine decreased Actin-related protein 2 (ARP2)/cofilin interaction. Photobleaching studies revealed destabilization of TNFalpha- induced stable MHC-I membrane clusters in the presence of Lonidamine and ARP2 inhibitor CK666. This work highlights how TNFalpha triggers a previously unknown function of metabolic protein HKII to influence an immune related outcome. Our study establishes the importance of inflammation induced HIF-1alpha in integrating two crucial components- the metabolic and immune, through reorganization of cytoskeleton. PMID- 26597759 TI - Isolation and characterization of circulating lymphatic endothelial colony forming cells. AB - RATIONALE: The identification of circulating endothelial progenitor cells has led to speculation regarding their origin as well as their contribution to neovascular development. Two distinct types of endothelium make up the blood and lymphatic vessel system. However, it has yet to be determined whether there are distinct lymphatic-specific circulating endothelial progenitor cells. OBJECTIVE: This study aims to isolate and characterize the cellular properties and global gene expression of lymphatic-specific endothelial progenitor cells. METHODS AND RESULTS: We isolated circulating endothelial colony forming cells (ECFCs) from whole peripheral blood. These cells are endothelial in nature, as defined by their expression of endothelial markers and their ability to undergo capillary morphogenesis in three-dimensional culture. A subset of isolated colonies express markers of lymphatic endothelium, including VEGFR-3 and Prox-1, with low levels of VEGFR-1, a blood endothelial marker, while the bulk of the isolated cells express high VEGFR-1 levels with low VEGFR-3 and Prox-1 expression. The different isolates have differential responses to VEGF-C, a lymphatic endothelial specific cytokine, strongly suggesting that there are lymphatic specific and blood specific ECFCs. Global analysis of gene expression revealed key differences in the regulation of pathways involved in cellular differentiation between blood and lymphatic-specific ECFCs. CONCLUSION: These data indicate that there are two distinguishable circulating ECFC types, blood and lymphatic, which are likely to have discrete functions during neovascularization. PMID- 26597760 TI - The extracellular matrix in breast cancer predicts prognosis through composition, splicing, and crosslinking. AB - The extracellular matrix in the healthy breast has an important tumor suppressive role, whereas the abnormal ECM in tumors can promote aggressiveness, and has been linked to breast cancer relapse, survival and resistance to chemotherapy. This review article gives an overview of the elements of the ECM which have been linked to prognosis of breast cancers, including changes in ECM protein composition, splicing, and microstructure. PMID- 26597761 TI - Hole Transfer from Photoexcited Quantum Dots: The Relationship between Driving Force and Rate. AB - We have investigated the relationship between driving force and rate for interfacial hole transfer from quantum dots (QDs). This relationship is experimentally explored by using six distinct molecular hole acceptors with an 800 meV range in driving force. Specifically, we have investigated ferrocene derivatives with alkyl thiol moieties that strongly bind to the surface of cadmium chalcogenide QDs. The redox potentials of these ligands are controlled by functionalization of the cyclopentadiene rings on ferrocene with electron withdrawing and donating substituents, thus providing an avenue for tuning the driving force for hole transfer while holding all other system parameters constant. The relative hole transfer rate constant from photoexcited CdSe/CdS core/shell QDs to tethered ferrocene derivatives is determined by measuring the photoluminescence quantum yield of these QD-molecular conjugates at varying ferrocene coverage, as determined via quantitative NMR. The resulting relationship between rate and energetic driving force for hole transfer is not well modeled by the standard two-state Marcus model, since no inverted region is observed. Alternative mechanisms for charge transfer are posited, including an Auger-assisted mechanism that provides a successful fit to the results. The observed relationship can be used to design QD-molecular systems that maximize interfacial charge transfer rates while minimizing energetic losses associated with the driving force. PMID- 26597762 TI - The hippocampus participates in the control of locomotion speed. AB - The hippocampus role in sensory-motor integration remains unclear. In these experiments we study its function in the locomotor control. To establish the connection between the hippocampus and the locomotor system, electrical stimulation in the CA1 region was applied and EMG recordings were obtained. We also evaluated the hindlimbs and forelimbs kinematic patterns in rats with a penetrating injury (PI) in the hippocampus as well as in a cortex-injured group (CI), which served as control. After the PI, tamoxifen a selective estrogen receptor modulator (SERM) that has been described as a neuroprotector and antiinflammatory drug, or vehicle was administered. Electrical stimulation in the hippocampus produces muscle contractions in the contralateral triceps, when 6 Hz or 8 Hz pulse trains were applied. The penetrating injury in the hippocampus reduced the EMG amplitude after the electrical stimulation. At 7 DPI (days post injury) we observed an increase in the strides speed in all four limbs of the non treated group, decreasing the correlation percentage of the studied joints. After 15 DPI the strides speed in the non-treated returned to normal. These changes did not occur in the tamoxifen group nor in cortex-injured group. After 30 days, the nontreated group presented a reduction in the number of pyramidal cell layer neurons at the injury site, in comparison to the tam-treated group. The loss of neurons, may cause the interruption of the trisynaptic circuit and changes in the locomotion speed. Tamoxifen preserves the pyramidal neurons after the injury, probably resulting in the strides speed recovery. PMID- 26597763 TI - Presynaptic NMDA receptors: Roles and rules. AB - NMDA receptors (NMDARs) are glutamate-gated ion channels widely expressed in the central nervous system (CNS) and endowed with unique biophysical, pharmacological and signaling properties. These receptors are best known for their critical roles in synaptic plasticity and their implications in a variety of neurological and psychiatric disorders. Since their discovery three decades ago, NMDARs have been thoroughly studied as components of postsynaptic excitatory potentials. Early on, however, both anatomical and physiological evidence pointed out to the existence of NMDARs away from the postsynaptic density. Some were found to be extrasynaptic, while others seemed to be specifically present at presynaptic (i.e. axonal) elements. Although presynaptic NMDARs (preNMDARs) were at first thought to be exceptional, there is now strong evidence that these receptors are relatively widespread in the CNS and regulate synaptic strength in specific sets of synapses. In this review, we compile our current knowledge on preNMDARs, presenting their anatomical distribution, developmental regulation, subunit composition, activation mechanisms as well as their downstream effects on synapse function. Contentious issues that animate the field are also discussed. Finally, particular emphasis is put on the molecular and cellular diversity of preNMDARs which translates into a variety of effects, both short- and long-term, on synaptic efficacy. Overshadowed by their postsynaptic counterparts, preNMDARs are progressively emerging as important regulators of neuronal signaling. PMID- 26597764 TI - Antisense precision polymer micelles require less poly(ethylenimine) for efficient gene knockdown. AB - Therapeutic nucleic acids are powerful molecules for shutting down protein expression. However, their cellular uptake is poor and requires transport vectors, such as cationic polymers. Of these, poly(ethylenimine) (PEI) has been shown to be an efficient vehicle for nucleic acid transport into cells. However, cytotoxicity has been a major hurdle in the development of PEI-DNA complexes as clinically viable therapeutics. We have synthesized antisense-polymer conjugates, where the polymeric block is completely monodisperse and sequence-controlled. Depending on the polymer sequence, these can self-assemble to produce micelles of very low polydispersity. The introduction of linear poly(ethylenimine) to these micelles leads to aggregation into size-defined PEI-mediated superstructures. Subsequently, both cellular uptake and gene silencing are greatly enhanced over extended periods compared to antisense alone, while at the same time cellular cytotoxicity remains very low. In contrast, gene silencing is not enhanced with antisense polymer conjugates that are not able to self-assemble into micelles. Thus, using antisense precision micelles, we are able to achieve significant transfection and knockdown with minimal cytotoxicity at much lower concentrations of linear PEI then previously reported. Consequently, a conceptual solution to the problem of antisense or siRNA delivery is to self-assemble these molecules into 'gene-like' micelles with high local charge and increased stability, thus reducing the amount of transfection agent needed for effective gene silencing. PMID- 26597765 TI - Trends and New Evidence in the Management of Acute and Chronic Post-Thoracotomy Pain-An Overview of the Literature from 2005 to 2015. PMID- 26597766 TI - Analysis of 43 Intraoperative Cardiac Surgery Case Cancellations. AB - OBJECTIVE: Late cancellation of surgery cases imposes significant emotional distress on the patient and their family and results in wasted resources, including loss of operating room and personnel time. This study was designed to determine the causes of cancellation, preventability, total operating room time, and postoperative destination. DESIGN: This study was a retrospective review of the 43 cardiac surgical cases that were cancelled while the patient was in the operating room (OR) but prior to surgical incision. SETTING: The cases were performed at the Massachusetts General Hospital, a teaching hospital of Harvard Medical School. PARTICIPANTS: Forty-three out of 5,110 scheduled cardiac cases were identified that were cancelled after the patient had entered the operating room between January 1, 2010 and December 31, 2013. INTERVENTIONS: No interventions were made. This was a retrospective study. MEASUREMENTS AND MAIN RESULTS: The most common causes of cancellation included a change in the patient's health status (44%), problems associated with central catheter placement (18.6%), and unsatisfactory donor organs for planned transplantation (12%). The majority were inpatients (65%) prior to the procedure. The cumulative OR time for all cancelled cases was 5,374 minutes (89 hours and 34 minutes). CONCLUSIONS: The reason for cancellation, preventability, total operating room time, and postoperative destination were determined. The information can be utilized to decrease the number of future cancellations. PMID- 26597767 TI - Genetically Encoded Fluorescent Probe for Imaging Apoptosis in Vivo with Spontaneous GFP Complementation. AB - Apoptosis plays a pivotal role in development and tissue homeostasis in multicellular organisms. Dysfunction of apoptosis is involved in many fatal diseases such as cancer. Visualization of apoptosis in living animals is necessary to understand the mechanism of apoptosis-related diseases. Here, we describe a genetically encoded fluorescent probe for imaging apoptosis in living multicellular organisms, based on spontaneous complementation of two fragments of a green fluorescent protein (GFP) variant (GFP OPT). The probe is designed for detection of mitochondria-mediated apoptosis during which a mitochondrial protein of Smac is released into cytosol. The Smac is connected with a carboxy-terminal fragment of GFP OPT (GFP11), whereas the remainder of GFP OPT (GFP(1-10)) is located in the cytosol. Under an apoptotic condition, the Smac is released from mitochondria into cytosol, allowing complementation of the GFP-OPT fragments and the emission of fluorescence. Live-cell imaging demonstrates that the probe enables detection of apoptosis in living cells with a high signal-to-background ratio. We applied the probe to living zebrafish, in which apoptotic cells were visualized with fluorescence. The technique provides a useful tool for the study of apoptosis in living animals, facilitating elucidation of the mechanisms of apoptosis-related diseases. PMID- 26597768 TI - Chikungunya nsP2 protease is not a papain-like cysteine protease and the catalytic dyad cysteine is interchangeable with a proximal serine. AB - Chikungunya virus is the pathogenic alphavirus that causes chikungunya fever in humans. In the last decade millions of cases have been reported around the world from Africa to Asia to the Americas. The alphavirus nsP2 protein is multifunctional and is considered to be pivotal to viral replication, as the nsP2 protease activity is critical for proteolytic processing of the viral polyprotein during replication. Classically the alphavirus nsP2 protease is thought to be papain-like with the enzyme reaction proceeding through a cysteine/histidine catalytic dyad. We performed structure-function studies on the chikungunya nsP2 protease and show that the enzyme is not papain-like. Characterization of the catalytic dyad cysteine residue enabled us to identify a nearby serine that is catalytically interchangeable with the dyad cysteine residue. The enzyme retains activity upon alanine replacement of either residue but a replacement of both cysteine and serine residues results in no detectable activity. Protein dynamics appears to allow the use of either the cysteine or the serine residue in catalysis. This switchable dyad residue has not been previously reported for alphavirus nsP2 proteases and would have a major impact on the nsP2 protease as an anti-viral target. PMID- 26597769 TI - Comparison of the microstructure and phase stability of as-cast, CAD/CAM and powder metallurgy manufactured Co-Cr dental alloys. AB - OBJECTIVE: The objective of this study was to identify the different microstructures produced by CC, PM and as-cast techniques for Co-Cr alloys and their phase stability following porcelain firings. METHODS: Three bi-layer porcelain veneered Co-Cr specimens and one monolithic Co-Cr specimen of each alloy group [cast, powder metallurgy (PM), CAD/CAM (CC)] were manufactured and analyzed using electron backscatter diffraction (EBSD), energy dispersive spectrometry (EDS) and X-ray diffraction (XRD). Specimens were treated to incremental numbers of porcelain firings (control 0, 5, 15) with crystallographic data, grain size and chemical composition subsequently obtained and analyzed. RESULTS: EBSD datasets of the cast alloy indicated large grains >200 MUm whereas PM and CC alloy consisted of mean arithmetic grain sizes of 29.6 MUm and 19.2 MUm respectively. XRD and EBSD results both indicated the highest increase in hcp content (>13vol%) for cast Co-Cr alloy after treatment with porcelain firing while PM and CC indicated <2vol% hcp content. A fine grain interfacial layer developed on all surfaces of the alloy after porcelain firing. The depth of this layer increased with porcelain firings for as-cast and PM but no significant increase (p>.05) was observed in CC. EDS line scans indicated an increase in Cr content at the alloy surface after porcelain firing treatment for all three alloys. SIGNIFICANCE: PM and CC produced alloy had superior fcc phase stability after porcelain firings compared to a traditional cast alloy. It is recommended that PM and CC alloys be used for porcelain-fused-to-metal restorations. PMID- 26597770 TI - Metabolic vitamin B12 deficiency: a missed opportunity to prevent dementia and stroke. AB - The purpose of this narrative review is to highlight insights into the importance and frequency of metabolic vitamin B12 (B12) deficiency, reasons why it is commonly missed, and reasons for the widespread but mistaken belief that treatment of B12 deficiency does not prevent stroke or improve cognitive function. Metabolic B12 deficiency is common, being present in 10%-40% of the population; is frequently missed; is easily treated; and contributes importantly to cognitive decline and stroke in older people. Measuring serum B12 alone is not sufficient for diagnosis; it is necessary to measure holotranscobalamin or functional markers of B12 adequacy such as methylmalonic acid or plasma total homocysteine. B-vitamin therapy with cyanocobalamin reduces the risk of stroke in patients with normal renal function but is harmful (perhaps because of thiocyanate accumulation from cyanide in cyanocobalamin) in patients with renal impairment. Methylcobalamin may be preferable in renal impairment. B12 therapy slowed gray matter atrophy and cognitive decline in the Homocysteine and B Vitamins in Cognitive Impairment Trial. Undiagnosed metabolic B12 deficiency may be an important missed opportunity for prevention of dementia and stroke; in patients with metabolic B12 deficiency, it would be prudent to offer inexpensive and nontoxic supplements of oral B12, preferably methylcobalamin or hydroxycobalamin. Future research is needed to distinguish the effects of thiocyanate from cyanocobalamin on hydrogen sulfide, and effects of treatment with methylcobalamin on cognitive function and stroke, particularly in patients with renal failure. PMID- 26597771 TI - Everolimus-eluting bioresorbable vascular scaffolds versus everolimus-eluting metallic stents: a meta-analysis of randomised controlled trials. AB - BACKGROUND: Bioresorbable coronary stents might improve outcomes of patients treated with percutaneous coronary interventions. The everolimus-eluting bioresorbable vascular scaffold is the most studied of these stent platforms; however, its performance versus everolimus-eluting metallic stents remains poorly defined. We aimed to assess the efficacy and safety of everolimus-eluting bioresorbable vascular scaffolds versus everolimus-eluting metallic stents in patients with ischaemic heart disease treated with percutaneous revascularisation. METHODS: We searched Medline, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), scientific sessions abstracts, and relevant websites for randomised trials investigating everolimus-eluting bioresorbable vascular scaffolds versus everolimus-eluting metallic stents published or posted between Nov 30, 2006, and Oct 12, 2015. The primary efficacy outcome was target lesion revascularisation and the primary safety outcome was definite or probable stent (scaffold) thrombosis. Secondary outcomes were target lesion failure (the composite of cardiac death, target-vessel myocardial infarction, or ischaemia-driven target lesion revascularisation), myocardial infarction, death, and in-device late lumen loss. We derived odds ratios (ORs) and weighted mean differences with 95% CIs, and calculated the risk estimates for the main outcomes according to a random-effects model. This study is registered with PROSPERO, number CRD42015026374. FINDINGS: We included six trials, comprising data for 3738 patients randomised to receive percutaneous coronary intervention with either an everolimus-eluting bioresorbable vascular scaffold (n=2337) or an everolimus-eluting metallic stent (n=1401). Median follow-up was 12 months (IQR 9-12). Patients treated with bioresorbable vascular scaffolds had a similar risk of target lesion revascularisation (OR 0.97 [95% CI 0.66-1.43]; p=0.87), target lesion failure (1.20 [0.90-1.60]; p=0.21), myocardial infarction (1.36 [0.98-1.89]; p=0.06), and death (0.95 [0.45-2.00]; p=0.89) as those treated with metallic stents. Patients treated with a bioresorbable vascular scaffold had a higher risk of definite or probable stent thrombosis than those treated with a metallic stent (OR 1.99 [95% CI 1.00-3.98]; p=0.05), with the highest risk between 1 and 30 days after implantation (3.11 [1.24-7.82]; p=0.02). Lesions treated with a bioresorbable vascular scaffold had greater in-device late lumen loss than those treated with a metallic stent (weighted mean difference 0.08 [95% CI 0.05-0.12]; p<0.0001). INTERPRETATION: Compared with everolimus-eluting metallic stents, everolimus-eluting bioresorbable vascular scaffolds had similar rates of repeat revascularisation at 1 year of follow-up, despite inferior mid term angiographic performance. However, patients treated with a bioresorbable vascular scaffold had an increased risk of subacute stent thrombosis. Studies with extended follow-up in a larger number of patients are needed to fully assess the long-term advantages of everolimus-eluting bioresorbable vascular scaffolds. FUNDING: None. PMID- 26597772 TI - The clinical challenge of disappearing stents. PMID- 26597773 TI - Sulphur Atoms from Methionines Interacting with Aromatic Residues Are Less Prone to Oxidation. AB - Methionine residues exhibit different degrees of susceptibility to oxidation. Although solvent accessibility is a relevant factor, oxidation at particular sites cannot be unequivocally explained by accessibility alone. To explore other possible structural determinants, we assembled different sets of oxidation sensitive and oxidation-resistant methionines contained in human proteins. Comparisons of the proteins containing oxidized methionines with all proteins in the human proteome led to the conclusion that the former exhibit a significantly higher mean value of methionine content than the latter. Within a given protein, an examination of the sequence surrounding the non-oxidized methionine revealed a preference for neighbouring tyrosine and tryptophan residues, but not for phenylalanine residues. However, because the interaction between sulphur atoms and aromatic residues has been reported to be important for the stabilization of protein structure, we carried out an analysis of the spatial interatomic distances between methionines and aromatic residues, including phenylalanine. The results of these analyses uncovered a new determinant for methionine oxidation: the S-aromatic motif, which decreases the reactivity of the involved sulphur towards oxidants. PMID- 26597774 TI - Inference of directional selection and mutation parameters assuming equilibrium. AB - In a classical study, Wright (1931) proposed a model for the evolution of a biallelic locus under the influence of mutation, directional selection and drift. He derived the equilibrium distribution of the allelic proportion conditional on the scaled mutation rate, the mutation bias and the scaled strength of directional selection. The equilibrium distribution can be used for inference of these parameters with genome-wide datasets of "site frequency spectra" (SFS). Assuming that the scaled mutation rate is low, Wright's model can be approximated by a boundary-mutation model, where mutations are introduced into the population exclusively from sites fixed for the preferred or unpreferred allelic states. With the boundary-mutation model, inference can be partitioned: (i) the shape of the SFS distribution within the polymorphic region is determined by random drift and directional selection, but not by the mutation parameters, such that inference of the selection parameter relies exclusively on the polymorphic sites in the SFS; (ii) the mutation parameters can be inferred from the amount of polymorphic and monomorphic preferred and unpreferred alleles, conditional on the selection parameter. Herein, we derive maximum likelihood estimators for the mutation and selection parameters in equilibrium and apply the method to simulated SFS data as well as empirical data from a Madagascar population of Drosophila simulans. PMID- 26597775 TI - Meis1 promotes poly (rC)-binding protein 2 expression and inhibits angiotensin II induced cardiomyocyte hypertrophy. AB - The poly(rC)-binding protein 2 (PCBP2) is currently reported to inhibit cardiac hypertrophy. However, how PCBP2 is regulated at transcriptional level remains unknown. Here, we show that Meis1, a PBX1-related homeobox gene, binds to PCBP2 promoter and promotes its transcription. In human failing heart tissues and murine hypertrophic heart tissues, the mRNA and protein levels of Meis1 are markedly downregulated, and the level of Meis1 significantly correlates with levels of Nppa, Myh7, and PCBP2. In neonatal rat cardiomyocytes, angiotensin II (Ang II) treatment induces hypertrophic growth of the cells (increase in cell size, enhanced protein synthesis, and hyperexpression of hypertrophic fetal genes), which are significantly inhibited by Meis1 overexpression or promoted by Meis1 knockdown. Meis1 also reduces Ang II-induced activation of Akt-mTOR pathway. Finally, we show that PCBP2 overexpression rescues the Meis1 effects of Akt-mTOR pathway and hypertrophy of cardiomyocytes. (c) 2015 IUBMB Life, 68(1):13 22, 2016. PMID- 26597776 TI - A personalized paced-breathing intervention to increase heart rate variability among individuals with first-episode psychosis following stress exposure. PMID- 26597778 TI - Induction and subcellular redistribution of progesterone receptor A and B by tamoxifen in the hypothalamic ventromedial neurons of young adult female Wistar rats. AB - The ventrolateral division of the hypothalamic ventromedial nucleus (VMNvl) is a brain center for estrogen-dependent triggering of female sexual behavior upon progesterone receptor (PR) activation. We examined the agonistic and antagonistic actions of tamoxifen in this nucleus by analyzing its effects on the total number of PR-immunoreactive neurons, PR mRNA and protein levels, and subcellular location of PRs in ovariectomized Wistar rats. The results show that tamoxifen has no agonistic action in the number of PR-immunoreactive neurons, but increases PR expression and labeling in the nucleus and cytoplasm of VMNvl neurons that constitutively express PRs. As an antagonist, tamoxifen partially inhibited the estradiol-dependent increase in the number of PR-immunoreactive neurons and in PR mRNA and protein levels, without interfering with the subcellular location of the protein. We suggest that tamoxifen influence on PR expression in the VMNvl critically depends on the presence or absence of estradiol. PMID- 26597779 TI - Unzipping of carbon nanotubes is geometry-dependent. AB - Carbon nanotube (CNT) unzipping is a facile and efficient technique to produce narrow graphene nanoribbons. The diameter and chirality of CNTs control the geometry of the unzipped nanoribbons. In this work, we analyze the energetics of oxidation- and hydrogenation-induced unzipping processes. Empirical reactive potential-based energy calculations show that there is a geometry-dependent energy barrier for oxidation-induced unzipping, which is absent in the exothermal hydrogenation process. These results are discussed by considering the unzipping process as crack nucleation and propagation processes in a pre-stressed cylindrical shell. Fitting our simulation data through the theoretical model provides a quantitative way to estimate the key parameters in CNT unzipping that can be used to optimize the experimental procedure. PMID- 26597777 TI - Intratumoral heterogeneity of steroidogenesis in aldosterone-producing adenoma revealed by intensive double- and triple-immunostaining for CYP11B2/B1 and CYP17. AB - INTRODUCTION: Cytochrome P450 11B2 (CYP11B2) plays a pivotal role in aldosterone synthesis, while cytochrome P450 11B1 (CYP11B1) and cytochrome P450 17A1 (CYP17) are involved in cortisol synthesis in normal human adrenal glands. However, their detailed distribution in aldosterone-producing adenoma (APA) remains incompletely settled. MATERIALS AND METHODS: We examined the status of CYP11B1/CYP11B2 and CYP11B2/CYP17A1 expressions in 27 APA (double staining) cases and 21 APA (triple staining) cases by using immunofluorescence staining and semi-quantitative evaluation. RESULTS: Tumor cells co-expressing CYP11B1/B2 (hybrid cell type A), CYP11B2/17 (hybrid cell type B), CYP11B1/17 (hybrid cell type C), and CYP11B1/B2/17 (triple-positive cell) were identified. The area and cell number of these cells were relatively small, but the size of individual hybrid cells were different between three hybrid cell types (A/B/C) and triple-positive cells. CONCLUSION: The presence of hybrid cells indicated the marked intratumoral heterogeneity of steroidogenesis in APAs, particularly in those producing glucocorticoids and mineralocorticoids. PMID- 26597780 TI - [The HLA system in the Moroccan population: General review]. AB - The Moroccan population is an interesting study model of Human Leukocyte Antigen (HLA) polymorphism given its ethnic and genetic diversity. Through an analysis of the literature, this work proposes to establish a balance of knowledge for this population in the field of histocompatibility: HLA diversity, anthropology, transplantation and HLA associations and diseases. This analysis shows that the HLA system has not been fully explored within the Moroccan population. However, the results obtained allowed us to initiate a database reflecting the specific healthy Moroccan population HLA polymorphism to identify immigration flows and relationships with different people of the world and to reveal the association of certain HLA alleles with frequent pathologies. We also propose to analyze the reasons hindering the development of this activity in Morocco and we will try to identify some perspectives. PMID- 26597781 TI - Src siRNA prevents corticosteroid-associated osteoporosis in a rabbit model. AB - In an established steroid-associated osteonecrosis (SAON) rabbit model we found recently that blockage Src by siRNA could improve reconstructive repair of osteonecrosis via enhancing osteogenesis and inhibiting bone resorption. The current study investigated if blocking Src was able to prevent steroid-associated osteoporosis (SAOP) in the same SAON animal model. Rabbits were treated with pulsed lipopolysaccharide (LPS) and corticosteroid methylprednisolone (MPS). At 2, 4, and 6weeks after induction, Src siRNA, control siRNA and saline were intramedullary injected into proximal femur, respectively. Two fluorescent dyes xylenol orange and calcein green were injected before sacrificing the animals for in vivo labeling of the newly formed bone. At week 6 after induction, proximal femora of rabbits were dissected for micro-CT and histological analysis. Results showed significant bone loss in the metaphysis of femoral head in the control rabbits after SAON induction. Src siRNA treatment was able to prevent steroid associate bone loss in trabecular bone and increase cortical bone thickness at femoral neck. Histomorphometry showed that Src siRNA increased the osteoblastic bone formation and decreased the eroded bone surfaces suggesting decreased osteoclastic bone resorption. This was the first study to report bone loss after SAON induction in rabbit model that could be prevented by knocking down Src by siRNA. PMID- 26597782 TI - Sports Participation and Juvenile Delinquency: A Meta-Analytic Review. AB - Participation in sports activities is very popular among adolescents, and is frequently encouraged among youth. Many psychosocial health benefits in youth are attributed to sports participation, but to what extent this positive influence holds for juvenile delinquency is still not clear on both the theoretical and empirical level. There is much controversy on whether sports participation should be perceived as a protective or a risk factor for the development of juvenile delinquency. A multilevel meta-analysis of 51 published and unpublished studies, with 48 independent samples containing 431 effect sizes and N = 132,366 adolescents, was conducted to examine the relationship between sports participation and juvenile delinquency and possible moderating factors of this association. The results showed that there is no overall significant association between sports participation and juvenile delinquency, indicating that adolescent athletes are neither more nor less delinquent than non-athletes. Some study, sample and sports characteristics significantly moderated the relationship between sports participation and juvenile delinquency. However, this moderating influence was modest. Implications for theory and practice concerning the use of sports to prevent juvenile delinquency are discussed. PMID- 26597783 TI - The Longitudinal Associations Between Discrimination, Depressive Symptoms, and Prosocial Behaviors in U.S. Latino/a Recent Immigrant Adolescents. AB - The links between discrimination and adjustment in U.S. Latino/a immigrant adolescents is an important but understudied phenomenon. We aimed to investigate the longitudinal associations (across 1 year) among discrimination, prosocial behaviors, and depressive symptoms in U.S. Latino immigrant adolescents using two competing models: associations between discrimination and prosocial behaviors via depressive symptoms (mental health strain model), and associations between discrimination and depressive symptoms via prosocial behaviors (prosociality strain model). Participants were 302 Latino/a recent immigrant adolescents (53.3 % boys, M age = 14.51 years at Time 1, SD = .88 years) who completed measures of discrimination, depressive symptoms, and prosocial behaviors at 6-month intervals. The results provided support for both proposed models. The discussion examines the importance of prosocial behaviors in understanding adjustment and effects of discrimination among recently immigrated U.S. Latino adolescents. PMID- 26597784 TI - Vitamin A deficiency suppresses high fructose-induced triglyceride synthesis and elevates resolvin D1 levels. AB - BACKGROUND/AIMS: Vitamin A and its metabolites are known to regulate lipid metabolism. However so far, no study has assessed, whether vitamin A deficiency per se aggravates or attenuates the development of non-alcoholic fatty liver disease (NAFLD). Therefore, here, we tested the impact of vitamin A deficiency on the development of NAFLD. METHODS: Male weanling Wistar rats were fed one of the following diets; control, vitamin A-deficient (VAD), high fructose (HFr) and VAD with HFr (VADHFr) of AIN93G composition, for 16weeks, except half of the VAD diet fed rats were shifted to HFr diet (VAD(s)HFr), at the end of 8(th) week. RESULTS: Animals fed on VAD diet with HFr displayed hypotriglyceridemia (33.5mg/dL) with attenuated hepatic triglyceride accumulation (8.2mg/g), compared with HFr diet (89.5mg/dL and 20.6mg/g respectively). These changes could be partly explained by the decreased activity of glycerol 3-phosphate dehydrogenase (GPDH) and the down regulation of stearoyl CoA desaturase 1 (SCD1), both at gene and protein levels, the key determinants of triglyceride biosynthesis. On the other hand, n-3 long chain polyunsaturated fatty acid, docosahexaenoic acid and its active metabolite; resolvin D1 (RvD1) levels were elevated in the liver and plasma of VAD diet-fed groups, which was negatively associated with triglyceride levels. All these factors confer vitamin A deficiency-mediated protection against the development of hepatic steatosis, which was also evident from the group shifted from VAD to HFr diet. CONCLUSIONS: Vitamin A deficiency attenuates high fructose-induced hepatic steatosis, by regulating triglyceride synthesis, possibly through GPDH, SCD1 and RvD1. PMID- 26597785 TI - Palmitic acid (16:0) competes with omega-6 linoleic and omega-3 alpha-linolenic acids for FADS2 mediated Delta6-desaturation. AB - Sapienic acid, 16:1n-10 is the most abundant unsaturated fatty acid on human skin where its synthesis is mediated by FADS2 in the sebaceous glands. The FADS2 product introduces a double bond at the Delta6, Delta4 and Delta8 positions by acting on at least ten substrates, including 16:0, 18:2n-6, and 18:3n-3. Our aim was to characterize the competition for accessing FADS2 mediated Delta6 desaturation between 16:0 and the most abundant polyunsaturated fatty acids (PUFA) in the human diet, 18:2n-6 and 18:3n-3, to evaluate whether competition may be relevant in other tissues and thus linked to metabolic abnormalities associated with FADS2 or fatty acid levels. MCF7 cells stably transformed with FADS2 biosynthesize 16:1n-10 from exogenous 16:0 in preference to 16:1n-7, the immediate product of SCD highly expressed in cancer cell lines, and 16:1n-9 via partial beta-oxidation of 18:1n-9. Increasing availability of 18:2n-6 or 18:3n-3 resulted in decreased bioconversion of 16:0 to 16:1n-10, simultaneously increasing the levels of highly unsaturated products. FADS2 cells accumulate the desaturation-elongation products 20:3n-6 and 20:4n-3 in preference to the immediate desaturation products 18:3n-6 and 18:4n-3 implying prompt/coupled elongation of the nascent desaturation products. MCF7 cells incorporate newly synthesized 16:1n-10 into phospholipids. These data suggest that excess 16:0 due to, for instance, de novo lipogenesis from high carbohydrate or alcohol consumption, inhibits synthesis of highly unsaturated fatty acids, and may in part explain why supplemental preformed EPA and DHA in some studies improves insulin resistance and other factors related to diabetes and metabolic syndrome aggravated by excess calorie consumption. PMID- 26597786 TI - Ustekinumab for patients with primary biliary cholangitis who have an inadequate response to ursodeoxycholic acid: A proof-of-concept study. AB - The interleukin (IL)-12 signaling cascade has been associated with primary biliary cholangitis (PBC). This multicenter, open-label, proof-of-concept study evaluated the anti-IL12/23 monoclonal antibody, ustekinumab (90 mg subcutaneous at weeks 0 and 4, then every 8 weeks through week 20), in adults with PBC and an inadequate response to ursodeoxycholic acid therapy (i.e., alkaline phosphatase [ALP] >1.67* upper limit of normal [ULN] after >=6 months). ALP response was defined as a >40% decrease from baseline and ALP remission as ALP normalization (if baseline ALP 1.67*-2.8* ULN) or <1.67* ULN (if baseline ALP >2.8* ULN). Changes in Enhanced Liver Fibrosis (ELF) scores and serum bile acids were also assessed. At baseline, patients had median disease duration of 3.2 years, median ELF score of 9.8, and highly elevated total bile acid concentration (median, 43.3 MUmol/L); 13 of 20 (65%) patients had baseline ALP >3* ULN. Although steady-state serum ustekinumab concentrations were reached by week 12, no patient achieved ALP response or remission. Median percent ALP reduction from baseline to week 28 was 12.1%. ELF score decreased slightly from baseline to week 28 (median reduction: 0.173), and total serum bile acid concentrations decreased from baseline to week 28 (median reduction: 8.8 MUmol/L). No serious infections or discontinuations resulting from adverse events were reported through week 28. One patient had a serious upper gastrointestinal hemorrhage considered unrelated to test agent by the investigator. CONCLUSION: Open-label ustekinumab therapy, though associated with a modest decrease in ALP after 28 weeks of therapy, did not otherwise appreciably change ALP and overt proof-of-concept was not established as per prespecified primary endpoint of proposed efficacy. No new ustekinumab safety signals were observed. (Hepatology 2016;64:189-199). PMID- 26597787 TI - Tianweitania sediminis gen. nov., sp. nov., a member of the family Phyllobacteriaceae, isolated from subsurface sediment core. AB - A bacterial strain, designated Z8T, was isolated from the terrestrial sediment of the Mohe Basin in north-east China. Phylogenetic analyses of 16S rRNA genes showed that this strain belonged to the family Phyllobacteriaceae, and was most closely related to Phyllobacterium bourgognense, with a sequence similarity of 96.9 %. The major cellular fatty acids were summed feature 4 (iso-C17 : 1 I and/or anteiso-C17 : 1 B) and summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c). The major respiratory quinone was ubiquinone-10. The three major polar lipids of strain Z8T consisted of glycolipids, phosphatidylethanolamine and phosphatidylmethylethanolamine. The DNA G+C content was 59.6 mol%. The chemotaxonomic characteristics of strain Z8T differed in some respects from those of members of the family Phyllobacteriaceae. Based on phylogenetic, phenotypic and chemotaxonomic data, strain Z8T is considered to represent a novel species of a novel genus within the family Phyllobacteriaceae, for which the name Tianweitania sediminis gen. nov., sp. nov. is proposed. The type strain is Z8T ( = CGMCC 1.12944T = JCM 30358T). PMID- 26597788 TI - Characterization of stem/progenitor cell cycle using murine circumvallate papilla taste bud organoid. AB - Leucine-rich repeat-containing G-protein coupled receptor 5-expressing (Lgr5(+)) cells have been identified as stem/progenitor cells in the circumvallate papillae, and single cultured Lgr5(+) cells give rise to taste cells. Here we use circumvallate papilla tissue to establish a three-dimensional culture system (taste bud organoids) that develops phenotypic characteristics similar to native tissue, including a multilayered epithelium containing stem/progenitor in the outer layers and taste cells in the inner layers. Furthermore, characterization of the cell cycle of the taste bud progenitor niche reveals striking dynamics of taste bud development and regeneration. Using this taste bud organoid culture system and FUCCI2 transgenic mice, we identify the stem/progenitor cells have at least 5 distinct cell cycle populations by tracking within 24-hour synchronized oscillations of proliferation. Additionally, we demonstrate that stem/progenitor cells have motility to form taste bud organoids. Taste bud organoids provides a system for elucidating mechanisms of taste signaling, disease modeling, and taste tissue regeneration. PMID- 26597789 TI - Preclinical evaluation of collagen type I scaffolds, including gelatin-collagen microparticles and loaded with a hydroglycolic Calendula officinalis extract in a lagomorph model of full-thickness skin wound. AB - Previously, we have developed collagen type I scaffolds including microparticles of gelatin-collagen type I (SGC) that are able to control the release of a hydroglycolic extract of the Calendula officinalis flower. The main goal of the present work was to carry out the preclinical evaluation of SGC alone or loaded with the C. officinalis extract (SGC-E) in a lagomorph model of full-thickness skin wound. A total of 39 rabbits were distributed in three groups, of 13 animals each. The first group was used to compare wound healing by secondary intention (control) with wound healing observed when wounds were grafted with SGC alone. Comparison of control wounds with wounds grafted with SGC-E was performed in the second group, and comparison of wounds grafted with SGC with wounds grafted with SGC-E was performed in the third group. Clinical follow-ups were carried in all animals after surgery, and histological and histomorphometric analyses were performed on tissues taken from the healed area and healthy surrounding tissue. Histological and histomorphometric results indicate that grafting of SGC alone favors wound healing and brings a better clinical outcome than grafting SGC-E. In vitro collagenase digestion data suggested that the association of the C. officinalis extract to SGC increased the SGC-E cross-linking, making it difficult to degrade and affecting its biocompatibility. PMID- 26597790 TI - "Primary" nocardial brain abscess in a renal transplant patient. AB - BACKGROUND: Intracranial abscesses are rare among transplant recipients, and Nocardia is responsible for less than 2 % of them. Nocardiosis, a chronic infection and is difficult to treat. Primary infection involves lungs and eventually disseminates. Primary nocardial abscesses are rare and we report a case from Sri Lanka. CASE PRESENTATION: A 38 year old Sri Lankan, who has received his 2nd ABO matched live donor transplantation, which was complicated with perinephric hematoma and massive transfusion syndrome. He presented with fever, worsening headache and papilledema. An urgent magnetic resonance image (MRI) showed an occipital abscess with midline shift. Craniotomy and drainage followed by 3 week course of imipenem and levofloxacin, which rendered him symptom free. After 12 months he has stayed recurrence free. Imaging and bacteriology of the respiratory tract failed to demonstrate Nocardia infection. CONCLUSION: Isolated (Primary) nocardial brain abscess are rare, and have an excellent response to medical therapy. We achieved a good response from a relatively short course of antibiotics (not using sulfonamides, due to allergy), where long courses of antibiotic had been the norm. PMID- 26597791 TI - Characteristics of Older Adults on Waiting Lists for Meals on Wheels: Identifying Areas for Intervention. AB - The purpose of this study was to characterize the population of seniors on Meals on Wheels' (MOW) waiting lists and identify their rate of depression, anxiety, falls, and fear of falling. Data come from surveys of 626 seniors on waiting lists across the country and the 2013 National Health and Aging Trends Study (NHATS). Results suggest that seniors on waiting lists for MOW were more likely to be widowed, less educated, older, Black, Hispanic, and receive Medicaid than the population of community-dwelling older adults. In addition, 31% of seniors on MOW waiting lists were depressed, compared with 12% of seniors in the national population ( p < .001), and 28% exhibited signs and symptoms of anxiety, compared with 10% of the national population of seniors ( p < .001). Seniors on waiting lists were significantly more likely to have fallen in the last month and be fearful of falling than the national population of seniors ( p < .001). Individuals on MOW waiting lists are a vulnerable and high-risk group. By seeking to better understand clients' needs, appropriate services can be tailored to promote independent living and improve older adults' well-being. PMID- 26597792 TI - Socio-Spatial Integration of Older Adults in Four Types of Residential Environments in Israel. AB - The socio-spatial integration of older people in different types of residential environments is a key factor affecting the well-being of older people. This study, which included a convenience sample of 565 participants, examined the socio-spatial integration of older people living in two different regional areas (central and peripheral) and four different residential environments (metropolitan hub, city, and town and rural settlements) in Israel. Willing participants were asked to complete a self-administered questionnaire. Socio spatial integration was assessed by recognition of their neighbors and sense of belonging to the residential environment. The findings show that older adults who resided in the town and in rural settlements were more socio-spatially integrated in their living environments compared with their counterparts who resided in cities. The best predictors of socio-spatial integration were a combination of personal characteristics and characteristics of the environment (perceived accessibility) except for rural settlements, where none of the variables predicted socio-spatial integration. PMID- 26597794 TI - Alcohol Marketing on Twitter and Instagram: Evidence of Directly Advertising to Youth/Adolescents. AB - AIMS: Assess whether alcohol companies restrict youth/adolescent access, interaction, and exposure to their marketing on Twitter and Instagram. METHODS: Employed five fictitious male and female Twitter (n = 10) and Instagram (n = 10) user profiles aged 13, 15, 17, 19 and/or 21. Using cellular smartphones, we determined whether profiles could (a) interact with advertising content-e.g. retweet, view video or picture content, comment, share URL; and/or (b) follow and directly receive advertising material updates from the official Instagram and Twitter pages of 22 alcohol brands for 30 days. RESULTS: All user profiles could fully access, view, and interact with alcohol industry content posted on Instagram and Twitter. Twitter's age-gate, which restricts access for those under 21, successfully prevented underage profiles from following and subsequently receiving promotional material/updates. The two 21+ profiles collectively received 1836 alcohol-related tweets within 30 days. All Instagram profiles, however, were able to follow all alcohol brand pages and received an average of 362 advertisements within 30 days. The quantity of promotional updates increased throughout the week, reaching their peak on Thursday and Friday. Representatives/controllers of alcohol brand Instagram pages would respond directly to our underage user's comments. CONCLUSION: The alcohol industry is in violation of their proposed self-regulation guidelines for digital marketing communications on Instagram. While Twitter's age-gate effectively blocked direct to phone updates, unhindered access to post was possible. Everyday our fictitious profiles, even those as young as 13, were bombarded with alcohol industry messages and promotional material directly to their smartphones. PMID- 26597793 TI - Impact of whole-body MRI in a general population study. AB - This study examined the long-term impact of whole-body MRI and the disclosure of incidental findings on quality of life (QoL) and depressive symptoms in a general population cohort. Analyses were conducted among 4420 participants of the Study of Health in Pomerania SHIP-Trend cohort, of which 2188 received a whole-body MRI examination. A 2.5-year postal follow-up of SHIP-Trend (response: 86%) included the Short Form Health Survey (SF-12), based on which the Mental Health Component Summary Score (MCS), and Physical Health Component Summary Score (PCS) were computed. The Patient Health Questionnaire (PHQ-9) was applied to assess depressive symptoms. Generalized estimation equation models were used to assess intervention effects, and statistical weights were applied to account for selective attrition. MRI participants had higher levels of education and employment than nonparticipants. Mean QoL indicators differed little at baseline between MRI participants and nonparticipants. Intervention effects per year on depression and QoL were negligible in (1) MRI participants versus nonparticipants [PCS: unstandardized beta = -0.06 (95% CI -0.30 to 0.18); MCS: beta = -0.01 (95% CI -0.29 to 0.29); PHQ-9: 0.08 (-0.03 to 0.18)], and (2) MRI participants with a disclosed incidental finding versus those without [PCS: beta = -0.03 (-0.39 to 0.33); MCS: beta = -0.26 (95% CI -0.65 to 0.13); PHQ-9: 0.03 (-0.10 to 0.15)]. The body site of the finding had only minor effects on the course of our studied outcomes. Whole-body MRI can be implemented in a population-based study without long-term effects on QoL indicators and depressive symptoms. This does not exclude the possibility of effects on more subtle psychosocial outcomes, such as health concerns or health behaviour, all of which require further attention. PMID- 26597795 TI - Orexin in Patients with Alcohol Dependence Treated for Relapse Prevention: A Pilot Study. AB - AIM: The aim of the study was to assess the blood concentration of orexin and its association with other clinical factors in patients with alcohol dependence. METHODS: Thirty-two males hospitalized on an addiction treatment ward due to alcohol dependence and 23 healthy men as a control group were enrolled in the study. The measurement of orexin in the blood was made at the beginning of the treatment (after withdrawal symptoms had stopped) and again after 4 weeks of observation. RESULTS: At the beginning of the observation, the alcohol-dependent patients had significantly greater orexin blood concentration than the control group. After 4 weeks of treatment for relapse prevention, the blood orexin level decreased significantly to a value similar to that in the control group. At the beginning of the study, more severely alcohol-dependent patients (Short Alcohol Dependence Data [SADD] score range: 20-45) had significantly greater orexin blood concentration than individuals with moderate addiction severity (SADD score range: 10-19). However, after 4 weeks of abstinence, the peptide blood concentration was similar in both groups of alcoholic patients. CONCLUSIONS: Orexin or its receptor is a potential target for relapse prevention treatment, but further study with long-term observation is needed to verify the usefulness of blood orexin determination as a marker of alcohol relapse risk. PMID- 26597796 TI - A simple and rapid method for calixarene-based selective extraction of bioactive molecules from natural products. AB - Natural products derived from medicinal plants have gained an important role in drug discovery due to their complex and abundant composition of secondary metabolites, with their structurally unique molecular components bearing a significant number of stereo-centers exhibiting high specificity linked to biological activity. Usually, the extraction process of natural products involves various techniques targeting separation of a specific class of compounds from a highly complex matrix. Aiding the process entails the use of well-defined and selective molecular extractants with distinctly configured structural attributes. Calixarenes conceivably belong to that class of molecules. They have been studied intensely over the years in an effort to develop new and highly selective receptors for biomolecules. These macrocycles, which display remarkable structural architectures and properties, could help usher a new approach in the efficient separation of specific classes of compounds from complex matrices in natural products. A simple and rapid such extraction method is presented herein, based on host-guest interaction(s) between a calixarene synthetic receptor, 4 tert-butyl-calix[6]arene, and natural biomolecular targets (amino acids and peptides) from Helleborus purpurascens and Viscum album. Advanced physicochemical methods (including GC-MS and chip-based nanoESI-MS analysis) suggest that the molecular structure and specifically the calixarene cavity size are closely linked to the nature of compounds separated. Incorporation of biomolecules and modification of the macrocyclic architecture during separation were probed and confirmed by scanning electronic microscopy and atomic force microscopy. The collective results project calixarene as a promising molecular extractant candidate, facilitating the selective separation of amino acids and peptides from natural products. PMID- 26597797 TI - BMA rebuts concern that junior doctors on strike wouldn't attend major incident. PMID- 26597798 TI - [Management of extensor mechanism injuries following total knee arthroplasty]. AB - Extensor mechanism injuries in total knee arthroplasty include disruption of the quadriceps tendon, disruption of the patellar tendon, and/or patellar fractures. While these injuries are rare, they are a devastating complication to manage. This review summarizes the anatomy of the extensor mechanism, risk factors for extensor mechanism injuries, and the prevalence and diagnosis of extensor mechanism injuries. In addition, this review outlines non-operative and operative management options. A new surgical approach for the reconstruction and augmentation of the extensor mechanism with the use of a synthetic mesh is described in detail. In multiple publications and in our own experience this newly developed technique shows promising results. PMID- 26597799 TI - Psychosocial program standards for NICU parents. AB - This article provides a rationale for and brief description of the process of developing recommendations for program standards for psychosocial support of parents with babies in the neonatal intensive care unit (NICU). A multidisciplinary workgroup of professional organizations and NICU parents was convened by the National Perinatal Association. Six interdisciplinary committees (family-centered developmental care, peer-to-peer support, mental health professionals in the NICU, palliative and bereavement care, follow-up support and staff education and support) worked to produce the recommendations found in this supplemental issue. NICU parents contributed to the work of each committee. PMID- 26597800 TI - Recommendations for mental health professionals in the NICU. AB - This article describes recommended activities of social workers, psychologists and psychiatric staff within the neonatal intensive care unit (NICU). NICU mental health professionals (NMHPs) should interact with all NICU parents in providing emotional support, screening, education, psychotherapy and teleservices for families. NMHPs should also offer educational and emotional support for the NICU health-care staff. NMHPs should function at all levels of layered care delivered to NICU parents. Methods of screening for emotional distress are described, as well as evidence for the benefits of peer-to-peer support and psychotherapy delivered in the NICU. In the ideal NICU, care for the emotional and educational needs of NICU parents are outcomes equal in importance to the health and development of their babies. Whenever possible, NMHPs should be involved with parents from the antepartum period through after discharge. PMID- 26597801 TI - Recommendations for palliative and bereavement care in the NICU: a family centered integrative approach. AB - Technological advances have increased our ability to detect a life-threatening, life-limiting or lethal problem early in pregnancy, leaving parents months to anticipate a death or a prematurely born infant. Babies can also be born with unanticipated problems that could lead to death. In either scenario, perinatal palliative care should be offered as a strategy for family support. Since the preponderance of professional training focuses on saving lives, many health professionals are uncomfortable with palliative care. This article's purpose is to define best practices for the provision of family-centered perinatal and neonatal palliative care and provision of support to bereaved families experiencing anticipated and unanticipated life-limiting conditions or death of their infant. An overview of core concepts and values is presented, followed by intervention strategies to promote an integrated family-centered approach to palliative and bereavement care. The concluding section presents evidence-based recommendations. PMID- 26597802 TI - NICU discharge planning and beyond: recommendations for parent psychosocial support. AB - Parents will interact with a multitude of teams from various disciplines during their child's admission to the neonatal intensive care unit. Recognition of the emotional stressors experienced by these parents is a first step in working to provide the crucial support and parenting skills needed for bonding and caring for their infant from admission through discharge and beyond. Family-centered care involves time-sensitive two-way communication between parents and the multidisciplinary team members who coordinate care transition by providing emotional, educational, medical and home visitor support for these families. To do this well, a thoughtful exchange of information between team members and parents is essential to identify psychosocial stress and ameliorate family concerns. Parents will need emotional and educational support and follow-up resources. Establishing individualized, flexible but realistic, pre- and post discharge plans with parents is needed to start their healthy transition to home and community. PMID- 26597804 TI - Recommendations for involving the family in developmental care of the NICU baby. AB - Family involvement is a key to realize the potential for long-lasting positive effects on physical, cognitive and psychosocial development of all babies, including those in the neonatal intensive care unit (NICU). Family-centered developmental care (FCDC) recognizes the family as vital members of the NICU health-care team. As such, families are integrated into decision-making processes and are collaborators in their baby's care. Through standardized use of FCDC principles in the NICU, a foundation is constructed to enhance the family's lifelong relationship with their child and optimize development of the baby. Recommendations are made for supporting parental roles as caregivers of their babies in the NICU, supporting NICU staff participation in FCDC and creating NICU policies that support this type of care. These recommendations are designed to meet the basic human needs of all babies, the special needs of hospitalized babies and the needs of families who are coping with the crisis of having a baby in the NICU. PMID- 26597805 TI - Recommendations for peer-to-peer support for NICU parents. AB - Peer-to-peer support provided by 'veteran' neonatal intensive care unit (NICU) parents to those with current NICU babies is a legitimate and unique form of support that can complement or supplement, but not replace, services provided by professional NICU staff. Peer support can be delivered through hospital- or community-based programs that offer one-to-one in-person or telephone matches, or support groups that meet in-person or via the Internet. Issues in program development, volunteer training and program operation are discussed. Recommendations for offering peer support to all NICU parents as an integral component of family-centered care and comprehensive family support are presented. PMID- 26597803 TI - Recommendations for enhancing psychosocial support of NICU parents through staff education and support. AB - Providing psychosocial support to parents whose infants are hospitalized in the neonatal intensive care unit (NICU) can improve parents' functioning as well as their relationships with their babies. Yet, few NICUs offer staff education that teaches optimal methods of communication with parents in distress. Limited staff education in how to best provide psychosocial support to families is one factor that may render those who work in the NICU at risk for burnout, compassion fatigue and secondary traumatic stress syndrome. Staff who develop burnout may have further reduced ability to provide effective support to parents and babies. Recommendations for providing NICU staff with education and support are discussed. The goal is to deliver care that exemplifies the belief that providing psychosocial care and support to the family is equal in importance to providing medical care and developmental support to the baby. PMID- 26597806 TI - Runx2 Expression as a Potential Prognostic Marker in Invasive Ductal Breast Carcinoma. AB - The Runx family of transcription factors has been implicated in cancer progression, both positively and negatively. Recent studies assigned a role for Runx2 in promoting breast cancer metastasis. However, the role of Runx2 during the early stage of breast carcinoma and its association with clinical outcomes remain unknown. Assessing the clinicopathological significance of Runx2 expression in a cohort of breast invasive ductal carcinomas (IDC). The correlation of nuclear Runx2 LI with clinicopathological parameters was assessed in 84 IDCs. To study the association of Runx2 with patient outcomes, in addition to treating it as a continuous variable, Runx2 was categorized by its median value (65) and by an additional two cut-off points determined by ROC curve analyses, at 45 for disease free survival (DFS) and 40 for overall survival (OS). Multivariate Cox regression models were also constructed. We used the best subset regression to identify models that predict DFS and OS with as few predictors as possible, and validation was performed. Based on the "Predicted R(2)", the three best models were identified. Using Cox-regression, the interaction between Runx2 and other clinicopathological terms was tested. Runx2 LI was significantly associated only with positive Her-2 status, and did not correlate significantly with other clinicopathological parameters. Although Runx2 LI, in the continuous form and when categorized by the median, did not correlate significantly with DFS and OS; after it was categorized using the optimal cut-off points determined using ROC curve analysis, the patients with Runx2 LI >45 % showed a significantly higher event rate and shorter DFS (P = 0.047), whereas patients with Runx2 LI >40 % showed a significantly shorter OS (P = 0.050). Moreover, Runx2 LI contributed significantly in the models built to predict DFS and OS. For DFS, no interaction terms contributed significantly to the models. However, among stage IV cases, the interaction term between centred Runx2 and ER significantly contributed to the prediction of OS. Runx2 was a significant predictor of OS in this model. Runx2 has a role in biological behaviour and affects the outcome of IDC; therefore, its inhibition may be a new therapeutic strategy. The predictability of Runx2 for OS in stage IV tumours differs with different ER states. The pattern of this difference was not determined because the sample size was not sufficient to allow pattern testing. PMID- 26597808 TI - The development of a complex intervention in China: the 'Caring for Couples Coping with Cancer "4Cs" Programme' to support couples coping with cancer. AB - BACKGROUND: As the primary informal caregiver for cancer patients, spousal caregivers are a population at a high risk of hidden morbidity. The factors impacting couples coping with cancer are complex, and within spousal caregiver patient dyads the impact is mutual. The aim of this study is to explain the process that led to the development of an acceptable, feasible, and potentially effective 'Caring for Couples Coping with Cancer "4Cs" Programme' to support couples coping with cancer as the unit of intervention in China. METHODS: The Medical Research Council's (MRC) framework for developing and evaluating complex interventions was adopted to develop an intervention for couples coping with cancer. Three steps were taken in the process of developing the 4Cs programme, namely: (1) identifying the evidence base by conducting a series of extensive reviews of the relevant literature and conducting a focus group study; (2) identifying/developing a theory by proposing a preliminary Live with Love Conceptual Framework 'P-LLCF' for cancer couple dyads; and (3) modelling the process and outcomes of the 4Cs programme. RESULTS: The programme that was developed is comprised of six individual sessions to be delivered by the researcher/therapists over 6 weeks. The main contents of the sessions of the 4Cs programme are: primary stressors (section 1); secondary stressors (section 2); dyadic mediator (section 3); dyadic appraisal (section 4); dyadic coping (section 5); and a programme overview (section 6). The emphasis of the programme is on supporting couples coping with cancer. A booklet was developed to provide the participants with easy access to written information about their common concerns in caring for loved ones with cancer. CONCLUSIONS: Guided by the MRC guidelines, a potentially effective, feasible, and acceptable 4Cs programme aimed at supporting couples coping with cancer as a dyad was developed. Future research is needed to pilot and evaluate the feasibility, modelling, and outcomes of this 4Cs programme. PMID- 26597809 TI - Catalytic processes and new materials and technologies in water/wastewater treatment. PMID- 26597807 TI - Characterization of Burkholderia pseudomallei protein BPSL1375 validates the Putative hemolytic activity of the COG3176 N-Acyltransferase family. AB - BACKGROUND: There are still numerous protein subfamilies within families and superfamilies that do not yet have conclusive empirical experimental evidence providing a specific function. These proteins persist in databases with the annotation of a specific 'putative' function made by association with discernible features in the protein sequence. RESULTS: Here, we report the characterization of one such protein produced by the pathogenic soil bacterium Burkholderia pseudomallei, BPSL1375, which provided evidence for putative hemolysins in the COG3176 family to have experimentally validated hemolytic activity. BPSL1375 can be classified into the N-acyltransferase superfamily, specifically to members of the COG3176 family. Sequence alignments identified seven highly conserved residues (Arg54, Phe58, Asp75, Asp78, Arg99, Glu132 and Arg135), of which several have been implicated with N-acyltransferase activity in previously characterized examples. Using the 3D model of an N-acyltransferase example as a reference, an acyl homoserine lactone synthase, we generated 3D structure models for mutants of six of the seven N-acyltransferase conserved residues (R54, D75, D78, R99, E132 and R135). Both the R99 and R135 mutants resulted in a loss of hemolytic activity while mutations at the other five positions resulted in either reduction or increment in hemolytic activity. CONCLUSIONS: The implication of residues previously characterized to be important for N-acyltransferase activity to hemolytic activity for the COG3176 family members of the N-acyltransferase provides validation of the correct placement of the hemolytic capability annotation within the N-acyltransferase superfamily. PMID- 26597810 TI - Resource recovery: Efficient approaches to sustainable water and wastewater treatment. PMID- 26597812 TI - Phylogenetic comparison of Desulfotomaculum species of subgroup 1a and description of Desulfotomaculum reducens sp. nov. AB - A genome and physiological comparison was made of the type strains of Desulfotomaculum species belonging to subgroup 1a and of 'Desulfotomaculum reducens' strain MI-1. Phenotypically, 'Desulfotomaculum reducens' strain MI-1 can be distinguished from the other described Desulfotomaculum species of subgroup 1a by its ability to grow with propionate and butyrate. In addition, the strain is able to use a variety of metals as electron acceptors. Metal reduction has not been tested in the other species, but seems likely based on our genome analysis. Phylogenetic 16S rRNA gene sequence analysis and the average nucleotide identity between the genomes of the species of subgroup 1a show that strain MI-1 represents a novel species within the Desulfotomaculum 1a subgroup, Desulfotomaculum reducens sp. nov. The type strain is MI-1T. PMID- 26597811 TI - Estimate of heritability and genetic trend of intervertebral disc calcification in Dachshunds in Finland. AB - BACKGROUND: Intervertebral disc disease (IDD) is a hereditary condition particularly common in Dachshunds. The breed is predisposed to early intervertebral disc degeneration and intervertebral disc calcification (IDC). When calcified, these severely degenerated discs are visible in spinal radiographs. Since the number of calcified discs (NCD) is associated with IDD, spinal radiography can be utilized in screening programmes in attempts to diminish the incidence of IDD in Dachshunds. Our aims were to estimate the heritability and genetic trend of NCD in Dachshunds in Finland and to explore the effect of age at the time of radiographic screening. Since the NCD has a highly skewed distribution, a log-transformed NCD (lnNCD) was also used as an analysed trait. The variance components for both traits were estimated, using the restricted maximum likelihood method. The fixed effects of breed variant, sex, as well as year of screening and the random effects of litter and animal were included in the model. The genetic trends in the NCD and lnNCD were assessed from the estimated breeding values (EBVs) of individual dogs by comparing the mean EBV of dogs born in different years. The breeding values were estimated, using the best linear unbiased prediction animal model. The pedigree in the genetic analyses included a total of 9027 dogs, of which 1567 showed results for NCDs. RESULTS: The heritability estimates of the NCD and lnNCD in Dachshunds were high (0.53 and 0.45, respectively). Small genetic improvements were seen as the mean EBVs increased from 100 to 104 and 105 over a 15-year period. The gain in the entire Dachshund population in Finland may differ from that observed, since less than 10 % of the Dachshunds registered have a screening result for NCD. Age at the time of the screening did not significantly affect the NCD or lnNCD. CONCLUSIONS: We recommend systematic radiographic screening for IDC in Dachshunds and adopting EBVs as a tool for selecting breeding dogs. Age at the time of the radiographic screening may not be as important as previously suggested. PMID- 26597813 TI - Adverse Clinical Effects of Botulinum Toxin Intramuscular Injections for Spasticity. AB - OBJECTIVE: The adverse events (AEs) with botulinum toxin type-A (BoNTA), used for indications other than spasticity, are widely reported in the literature. However, the site, dose, and frequency of injections are different for spasticity when compared to the treatment for other conditions and hence the AEs may be different as well. The objective of this study was to summarize the AEs reported in Canada and systematically review the AEs with intramuscular botulinum toxin injections to treat focal spasticity. METHODS: Data were gathered from Health Canada (2009-2013) and major electronic databases. RESULTS: In a 4 year period, 285 AEs were reported. OnabotulinumtoxinA (n=272 events): 68% females, 53% serious, 18% hospitalization, and 8% fatalities. The type of AEs reported were - muscle weakness (19%), oropharyngeal (14%), respiratory (14%), eye related (8%), bowel/bladder related (8%), and infection (5%). IncobotulinumtoxinA (n=13): 38% females, 62% serious, and 54% hospitalization. The type of AEs reported were - muscle weakness (15%), oropharyngeal (15%), respiratory (38%), eye related (23%), bowel/bladder related (15%), and infection (15%). Commonly reported AEs in the literature were muscle weakness, pain, oropharyngeal, bowel/bladder, blood circulation, neurological, gait, and respiratory problems. CONCLUSION: While BoNTA is useful in managing spasticity, future studies need to investigate the factors that can minimize AEs. A better understanding of the underlying mechanisms of the AEs can also improve guidelines for BoNTA administration and enhance outcomes. PMID- 26597815 TI - Chronic inhalation of cigarette smoke reduces phagocytosis in peripheral blood leukocytes. AB - BACKGROUND: Phagocytosis activity of peripheral blood leukocytes in smokers or chronic obstructive pulmonary disease patients was found to be controversial and dependent on the phagocytic stimulus. RESULTS: We demonstrated that long-term exposure to cigarette smoke in mice clearly suppressed the phagocytosis of granulocytes and monocytes from peripheral blood. CONCLUSIONS: Impaired phagocytosis activity of peripheral blood leukocytes may have a systemic effect and potentially contribute to smoking-associated diseases such as pneumonia and lung cancer. PMID- 26597814 TI - Efficacy of sorafenib correlates with Memorial Sloan-Kettering Cancer Center (MSKCC) risk classification and bone metastasis in Chinese patients with metastatic renal cell carcinoma. AB - PURPOSE: Several prognostic models have been developed to assess the efficacy and safety of sorafenib for metastatic renal cell carcinoma (mRCC), but few studies have validated its use in Chinese patients. The objective of this single center, single arm retrospective study was to examine the efficacy and safety of sorafenib and its related prognostic clinico-pathologic factors in Chinese mRCC patients. METHODS: One hundred thirty four mRCC patients were enrolled. All patients received 400 mg of sorafenib orally twice daily. The dose was subsequently adjusted in the event of treatment-induced toxicity. Tumor response, progression-free survival (PFS), overall survival (OS) and adverse events (AEs) were determined. RESULTS: The median PFS and OS were 10 months (1-36 months) and 22 months (2-37 months), respectively. Complete, partial, and stable disease were observed in two (1.49%), 24 (17.91%), and 99 (73.88%) patients, respectively. Hand/foot skin reactions, diarrhea and fatigue were the most commonly observed AEs following sorafenib treatment. Among the AEs, only 13 grades 3 and 4 were observed. Multivariate analysis revealed that independent predictive factors for PFS included Eastern Cooperative Oncology Group (ECOG) status, Memorial Sloan Kettering Cancer Center (MSKCC) risk status, and bone metastasis (all p < 0.05). Factors associated with OS included MSKCC risk values, bone metastasis and sorafenib-induced hypertension (all p < 0.05). CONCLUSION: The introduction of sorafenib therapy for mRCC in Chinese patients may lead to a favorable disease control with acceptable tolerability. In addition, the parameters predicting favorable outcomes, including ECOG status, MSKCC risk status and bone metastasis, may have prognostic value in clinical practice. PMID- 26597816 TI - Bioaccumulation of heavy metals in Mbaa River and the impact on aquatic ecosystem. AB - The bioaccumulation and toxic effects of heavy metals have caused ecological damage to aquatic ecosystem. In this study, concentration of heavy metals including zinc, lead, cadmium, iron, and copper were determined in the sediment and water as well as in the muscle, gill, and intestine of two fish species (Pelmatochromis guentheri and Pelmatochromis pulcher) of Mbaa River in Southeastern Nigeria. Samples were collected at three different spots from the river, and the level of heavy metals specified above were determined by atomic absorption spectroscopy (AAS) after a modified wet digestion process. The results indicated that sediment had the highest concentration of the heavy metals investigated while water had the lowest concentration. Fish tissues showed appreciable bioaccumulation of these metals as evidenced by a higher concentration profile when compared with that of water. Furthermore, the concentration of these heavy metals in water and their bioconcentration factor in the fish were above the recommended limit by WHO and FEPA, indicating that Mbaa River along Inyishi may not be suitable for drinking nor the fish safe for human consumption. The study also reveals the use of fish as bioindicator of aquatic environment. PMID- 26597817 TI - New Associate Editor: Olufemi R. Ayeni. PMID- 26597818 TI - The effect of leg length discrepancy on clinical outcome after TKA and identification of possible risk factors. AB - PURPOSE: This study was investigated on the leg length discrepancy (LLD) after computer-assisted total knee arthroplasty (TKA), and its effects on the post operative function and patient satisfaction. It is hypothesized that LLD after computer-assisted TKA would affect the clinical outcomes for knee scores. METHODS: A total of 148 cases were analysed retrospectively with a minimum of 2 years of follow-up. Eighty-one knees involved a <15-mm LLD, and 67 knees involved more than a 15-mm LLD. The radiographic outcomes, clinical outcomes, patients' satisfaction, and perception of LLD were also evaluated. RESULTS: There was a significant difference in the Knee Society function score and the score for the difficulty with ascending the stairs in the Western Ontario and McMaster Universities score between the groups. There was a statistically significant difference between the two groups in the results of their perception questionnaires, but no difference in the results of their satisfaction questionnaires. The odds ratio for the risk of post-operative LLD increased with the increased pre-operative LLD and the unilateral TKA. CONCLUSIONS: In conclusion, the functional outcomes of more than 15-mm post-operative LLD after computer-assisted TKA were lower than those of the <15-mm LLD. Thus, the reduced post-operative LLD should be considered to improve the functional outcomes of primary TKA. A careful treatment plan for degenerative arthritis should be considered and discussed with patients, especially in unilateral TKAs. LEVEL OF EVIDENCE: IV. PMID- 26597819 TI - Vascular Matrix Metalloproteinase Inhibition, a New Mechanism for How Peroxisome Proliferator-Activated Receptor-gamma Protects Target Organ Damage. PMID- 26597820 TI - Orphan Nuclear Receptor Nur77 Inhibits Angiotensin II-Induced Vascular Remodeling via Downregulation of beta-Catenin. AB - Angiotensin II (Ang II) is the predominant effector peptide of the renin angiotensin system. Ang II contributes to vascular remodeling in many cardiovascular diseases (eg, hypertension, atherosclerosis, restenosis, and aneurysm). Orphan nuclear receptor Nur77 has a crucial role in the functional regulation of vascular cells. The objective of this study was to define the specific role of Nur77 in Ang II-induced vascular remodeling. Nur77 expression was initially found to be elevated in medial vascular smooth muscle cells (VSMCs) of thoracic aortas from mice continuously infused with Ang II for 2 weeks using a subcutaneous osmotic minipump. Cellular studies revealed that Nur77 expression was upregulated by Ang II via the MAPK/PKA-CREB signaling pathway. Ang II-induced proliferation, migration, and phenotypic switching were significantly enhanced in VSMCs isolated from Nur77(-/-) mice compared with wild-type VSMCs. Consistent with the role in VSMCs, we found that compared with wild-type mice, Nur77(-/-) mice had elevated aortic medial areas and luminal diameters, more severe elastin disruption and collagen deposition, increased VSMC proliferation and matrix metalloproteinase production, and decreased VSMC-specific genes SM-22alpha and alpha-actin expression, after 2 weeks of exogenous Ang II administration. The results of additional experiments suggested that Nur77 suppressed Ang II-induced beta-catenin signaling pathway activation by promoting beta-catenin degradation and inhibiting its transcriptional activity. Our findings indicated that Nur77 is a critical negative regulator of Ang II-induced VSMC proliferation, migration, and phenotypic switching via the downregulation of beta-catenin activity. Nur77 may reduce Ang II-induced vascular remodeling involved in many cardiovascular diseases. PMID- 26597821 TI - Association of Central Versus Brachial Blood Pressure With Target-Organ Damage: Systematic Review and Meta-Analysis. AB - Accumulating evidence suggests that central blood pressure (BP) may reflect the hemodynamic stress on target organs more accurately than brachial BP. A systematic review assessing the relationship of central versus brachial BP with preclinical target-organ damage was performed. Meta-analysis of cross-sectional data showed that central compared with brachial systolic BP was more closely associated with (1) left ventricular mass index (12 studies, n=6431; weighted age [SD], 49.9 [13.1] years; 51% hypertensives): pooled correlation coefficients r=0.30; 95% confidence interval (CI), 0.23-0.37 versus r=0.26; 95% CI, 0.19-0.33, respectively; P<0.01 for difference; (2) carotid intima-media thickness (7 studies, n=6136; weighted age, 55.6 [13.2] years; 48% hypertensives): r=0.27; 95% CI, 0.19-0.34 versus r=0.23; 95% CI, 0.16-0.30, respectively; P<0.01 for difference; (3) pulse-wave velocity (14 studies, n=3699; weighted age, 53.9 [13.3] years; 53% hypertensives): r=0.42; 95% CI, 0.37-0.47 versus r=0.39; 95% CI, 0.33-0.45, respectively; P<0.01 for difference. Four studies assessing urine albumin excretion (n=3718; weighted age, 56.4 [5] years; 69% hypertensives) reported similar correlations (P=not significant) with central (r=0.22; 95% CI, 0.14-0.29) and brachial systolic BP (r=0.22; 95% CI, 0.12-0.32). Similar findings were observed for central compared with brachial pulse pressure in terms of relationship with target-organ damage. Metaregression analyses did not reveal any significant effect of age. In conclusion, central compared with brachial BP seems to be more strongly associated with most of the investigated indices of preclinical organ damage. PMID- 26597822 TI - Nrf2 as an Endothelial Mechanosensitive Transcription Factor: Going With the Flow. PMID- 26597824 TI - Evidence for a Prognostic Role of Orthostatic Hypertension on Survival in a Very Old Institutionalized Population. AB - In old individuals, regulation of blood pressure during postural changes is impaired. Several studies have assessed the clinical impact of orthostatic hypotension (OHypoT) during the aging process. By contrast, the prevalence and prognostic role of the increase in blood pressure in upright position (orthostatic hypertension, OHyperT) in old adults remain unknown. We investigated the association of OHyperT with cardiovascular morbidity and mortality in a population of old institutionalized subjects. A 2-year follow-up longitudinal study was conducted on 972 subjects (mean age [SD] 88 [5]) from the PARTAGE (Predictive Values of Blood Pressure and Arterial Stiffness in Institutionalized Very Aged Population) study, able to maintain a standing position. OHyperT was defined as an increase in systolic blood pressure >=20 mm Hg during the first and third minute of standing. Three groups of subjects were compared: orthostatic normotension (n=540), OHypoT (n=157), and OHyperT (n=275). OHyperT prevalence (28%) was higher than OHypoT (16%). Sitting systolic blood pressure was higher in OHypoT compared with orthostatic normotension and OHyperT groups (146 [23] versus 136 [21] and 136 [20] mm Hg, respectively, P<0.001). The OHyperT group was associated with a greater risk of cardiovascular morbidity and mortality than orthostatic normotension (hazard ratio 1.51 [1.09-2.08], P<0.01) and remained unchanged after adjustment for age, sex, sitting systolic blood pressure, and comorbidities. No difference in cardiovascular morbidity and mortality was observed between OHyperT and OHypoT groups. In conclusion, in a old frail population, the increase in systolic blood pressure during upright position occurs frequently and is associated with higher cardiovascular morbidity and mortality independently of sitting blood pressure levels and major comorbidities. Health professional should take into account not only the decrease but also the increase in blood pressure when standing up. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00901355. PMID- 26597823 TI - Protective Role for Tissue Inhibitor of Metalloproteinase-4, a Novel Peroxisome Proliferator-Activated Receptor-gamma Target Gene, in Smooth Muscle in Deoxycorticosterone Acetate-Salt Hypertension. AB - Loss of peroxisome proliferator-activated receptor-gamma (PPARgamma) function causes hypertension, whereas its activation lowers blood pressure. Evidence suggests that these effects may be attributable to PPARgamma activity in the vasculature. However, the specific transcriptional targets of PPARgamma in vessels remain largely unidentified. In this study, we examined the role of smooth muscle PPARgamma during salt-sensitive hypertension and investigated its transcriptional targets and functional effect. Transgenic mice expressing dominant-negative PPARgamma (S-P467L) in smooth muscle cells were more prone to deoxycorticosterone acetate-salt-induced hypertension and mesenteric arterial dysfunction compared with nontransgenic controls. Despite similar morphometry at baseline, vascular remodeling in conduit and small arteries was enhanced in S P467L after deoxycorticosterone acetate-salt treatment. Gene expression profiling in aorta and mesenteric arteries revealed significantly decreased expression of tissue inhibitor of metalloproteinase-4 (TIMP-4) in S-P467L. Expression of TIMP-4 was increased by deoxycorticosterone acetate-salt treatment, but this increase was ablated in S-P467L. Interference with PPARgamma activity either by treatment with a PPARgamma inhibitor, GW9662, or by expressing P467L PPARgamma markedly suppressed TIMP-4 in primary smooth muscle cells. PPARgamma binds to a PPAR response element (PPRE) in chromatin close to the TIMP-4 gene in smooth muscle cells, suggesting that TIMP-4 is a novel target of PPARgamma. The interference with PPARgamma and decrease in TIMP-4 were accompanied by an increase in total matrix metalloproteinase activity. PPARgamma-mediated loss of TIMP-4 increased, whereas overexpression of TIMP-4 decreased smooth muscle cell migration in a scratch assay. Our findings highlight a protective mechanism induced by PPARgamma in deoxycorticosterone acetate-salt treatment, establishing a novel mechanistic link between PPARgamma and TIMP-4. PMID- 26597825 TI - Hypertensive Encephalopathy and Renal Failure in a Young Man. PMID- 26597826 TI - Genes targeted by the Hedgehog-signaling pathway can be regulated by Estrogen related receptor beta. AB - BACKGROUND: Nuclear receptor family member, Estrogen related receptor beta, and the Hedgehog signal transduction pathway are both reported to relate to tumorigenesis and induced pluripotent stem cell reprogramming. We hypothesize that Estrogen related receptor beta can modulate the Hedgehog signaling pathway and affect Hedgehog driven downstream gene expression. RESULTS: We established an estrogen related receptor beta-expressing Hedgehog-responsive NIH3T3 cell line by Esrrb transfection, and performed mRNA profiling using RNA-Seq after Hedgehog ligand conditioned medium treatment. Esrrb expression altered 171 genes, while Hedgehog signaling activation alone altered 339 genes. Additionally, estrogen related receptor beta expression in combination with Hedgehog signaling activation affects a group of 109 Hedgehog responsive mRNAs, including Hsd11b1, Ogn, Smoc2, Igf1, Pdcd4, Igfbp4, Stmn1, Hp, Hoxd8, Top2a, Tubb4b, Sfrp2, Saa3, Prl2c3 and Dpt. CONCLUSIONS: We conclude that Estrogen related receptor beta is capable of interacting with Hh-signaling downstream targets. Our results suggest a new level of regulation of Hedgehog signaling by Estrogen related receptor beta, and indicate modulation of Estrogen related receptor beta can be a new strategy to regulate various functions driven by the Hedgehog signaling pathway. PMID- 26597827 TI - Vitamin D-mediated hypercalcemia in multicentric Castleman's disease. AB - Multicentric Castleman's disease (MCD) is a rare lymphoproliferative disorder, which represents various symptoms caused by the hyperproduction of interleukin-6 (IL-6). However, case studies of MCD accompanied by hypercalcemia have rarely been reported thus far. A 78-year-old male had generalized fatigue, and his laboratory data revealed elevated serum calcium (Ca) and 1,25-dihydroxyvitamin D [1,25(OH)2D] levels (11.5 mg/dl and 80 pg/ml, respectively), while the serum intact parathyroid hormone level was low (4 pg/ml). Computed tomography showed multicentric lymphadenopathy. The serum IL-6 level was elevated (20.7 pg/ml), and pathological examination of a supraclavicular lymph node specimen led us to diagnose MCD. Moreover, immunostaining analysis showed that vitamin D-activating enzyme 25-hydroxyvitamin D 1-alpha-hydroxylase was expressed in lymph node macrophages. Prednisolone treatment improved the hypercalcemia and decreased the levels of 1,25(OH)2D and IL-6. We first reported a case of vitamin D-mediated hypercalcemia in MCD. PMID- 26597828 TI - Low-Density Lipoprotein Cholesterol Concentrations and Association of High Sensitivity C-Reactive Protein Concentrations With Incident Coronary Heart Disease in the Multi-Ethnic Study of Atherosclerosis. AB - High-sensitivity C-reactive protein (hs-CRP) has been associated with coronary heart disease (CHD) in numerous but not all observational studies, and whether low levels of low-density lipoprotein cholesterol (LDL-C) alter this association is unknown. In the Multi-Ethnic Study of Atherosclerosis (2000-2012), we prospectively assessed the association of hs-CRP concentrations with incident CHD in participants who did not receive lipid-lowering therapy, as well as in those with LDL-C concentrations less than 130 mg/dL (n = 3,106) and those with LDL-C concentrations of 130 mg/dL or greater (n = 1,716) at baseline (2000-2002). Cox proportional hazard analyses were used to assess the associations after adjustment for socioeconomic status, traditional risk factors, body mass index, diabetes, aspirin use, kidney function, and coronary artery calcium score. Loge hs-CRP was associated with incident CHD in participants with LDL-C concentrations of 130 mg/dL or higher (hazard ratio (HR) = 1.29, 95% confidence interval (CI): 1.05, 1.60) but not in those with LDL-C concentrations less than 130 mg/dL (HR = 0.88, 95% CI: 0.74, 1.05; P for interaction = 0.003). As a whole, loge hs-CRP was not associated with incident CHD in participants who had not received lipid lowering therapy at baseline (HR = 1.05, 95% CI: 0.92, 1.20) and who had mean LDL C concentrations less than 130 mg/dL. These findings suggest that LDL-C concentrations might be a moderator of the contribution of hs-CRP to CHD. PMID- 26597829 TI - Overrepresentation of Th1- and Th17-like Follicular Helper T Cells in Coronary Artery Disease. AB - T cells and B cells play substantial roles in the process of coronary artery disease (CAD). Here, we examined the role of circulating follicular helper T (Tfh) cells in CAD. Compared to non-CAD controls, CAD patients had increased levels of circulating Tfh. Also, circulating Tfh in CAD patients exhibited increased frequencies of Th1- and Th17-like phenotypes and aberrant cytokine expressions. Coculture experiments with B cells showed that Tfh from CAD patients were more potent at inducing antibody production from B cells, enhancing plasmablast differentiation and suppressing B10 cell differentiation. Importantly, we found that the skewing of circulating Tfh toward the Th1/Th17 like cells was directly correlated with B cell inflammation and low density lipoprotein level in CAD patients. Together, our data demonstrated a skewing of blood Tfh composition in CAD patients, which resulted in significant changes in B cell inflammation. PMID- 26597830 TI - Clostridium liquoris sp. nov., isolated from a fermentation pit used for the production of Chinese strong-flavoured liquor. AB - Strain BEY10T was isolated from an old fermentation pit, which had been used for the production of Chinese strong-flavoured liquor for over 20 years. The strain was strictly anaerobic, Gram-stain positive, rod-shaped, non-motile and spore forming. Strain BEY10T grew at temperatures of 22-47 degrees C (optimum 37 degrees C), at pH 5.5-9.0 (optimum pH 7.5-8.5) and with NaCl concentrations of 0 4 % (w/v) (optimum 0 %). The isolate was able to utilize glucose, mannitol, lactose, xylose, maltose, glycerol, cellobiose and trehalose as carbon sources for growth. The major end-products from glucose fermentation were ethanol and butyric acid. The polar lipids consisted of phosphatidylglycerol, phosphatidylethanolamine, phospholipids, a glycolipid and an aminolipid. The predominant fatty acids (>10 %) were C20 : 0, C18 : 0, C16 : 0, C12 : 0 and C14 : 0. The DNA G+C content was 34.4 mol%. Sequence analysis of the 16S rRNA gene indicated that strain BEY10T belongs to the genus Clostridium in the family Clostridiaceae. The closest phylogenetic neighbour is Clostridium lundense DSM 17049T, showing 97.6 % 16S rRNA gene sequence similarity with strain BEY10T. DNA DNA relatedness values of strain BEY10T with Clostridium lundense DSM 17049T, Clostridium tetanomorphum DSM 4474T and Clostridium pascui DSM 10365T were 58.8 %, 57.9 % and 42.2 %, respectively. This characterization based on phylogenetic, phenotypic and chemotaxonomic evidence demonstrated that strain BEY10T represents a novel species of the genus Clostridium, for which the name Clostridium liquoris sp. nov. is proposed. The type strain is BEY10T ( = ACCC 00785T = DSM 100320T). PMID- 26597831 TI - A dual K-space UNFOLD method for 3D functional brain imaging: A preliminary study. AB - PURPOSE: To investigate a method of dual k-space unaliasing by Fourier-encoding the overlaps using the temporal dimension (DUNFOLD), a novel technique for high temporal resolution 3D functional brain imaging. METHODS: Two different methods of unaliasing by Fourier-encoding the overlaps using the temporal dimension (UNFOLD), excitation UNFOLD (XUNFOLD) and acquisition UNFOLD, were merged to obtain a DUNFOLD. The feasibility of the DUNFOLD technique was examined by using a phantom and comparing its result to that of the previous XUNFOLD method. A high temporal resolution 3D functional brain imaging study was also performed, focusing on the microvascular response. Three different temporal resolutions, 20s, 10s and 5s, were tested with a spatial resolution of 0.6(3) mm3 to evaluate the method. The vascular regions of interest were selected for data analysis. RESULTS: The DUNFOLD method achieved a temporal resolution approximately four times greater than those of the UNFOLD and XUNFOLD methods, without apparent signal degradation. The vascular responses in the visual cortex were obtained with high spatiotemporal resolution by using the DUNFOLD method during visual stimulation. For small vessels, the percentage change in the signal reached 18%. CONCLUSION: The proposed DUNFOLD method yields a temporal resolution higher than those of the previous UNFOLD and XUNFOLD methods. The conclusions are likely to be important for functional imaging studies, especially those targeting cerebral vascular responsiveness. PMID- 26597832 TI - A model-based reconstruction technique for fast dynamic T1 mapping. AB - PURPOSE: To present a technique for dynamic T1 mapping. MATERIALS AND METHODS: A recently proposed model-based reconstruction entitled IR-MAP allows T1 mapping of a single slice from a single radial inversion recovery Look-Locker FLASH acquisition. To enable dynamic T1 mapping, multiple of these acquisitions are consecutively performed, each followed by a waiting period of 3s for relaxation. Next, IR-MAP is used to reconstruct an individual T1 map for each of these acquisitions. Finally, T1 errors caused by insufficient relaxation between subsequent IR pulses are iteratively corrected. RESULTS: The functionality of the proposed setup was validated in a phantom and in seven healthy volunteers. Systematic deviations between subsequent T1 maps originating from insufficient relaxation periods were effectively corrected. Additionally, the approach was successfully applied to monitor the T1 dynamic in a patient with primary lymphoma after the intravenous injection of contrast agent. CONCLUSION: The proposed setup enables dynamic T1 mapping of a single slice with a spatial resolution of 1.6 mm * 1.6 mm * 3 mm and a temporal resolution of one parameter map every 9 s. It therefore represents a new opportunity to track changes in T1 over time, as it is desirable in many applications such as dynamic contrast-enhanced MRI. PMID- 26597834 TI - Breast MRI background parenchymal enhancement (BPE) correlates with the risk of breast cancer. AB - OBJECTIVES: To investigate whether background parenchymal enhancement (BPE) and breast cancer would correlate searching for any significant difference of BPE pattern distribution in case of benign or malignant lesions. METHODS: 386 patients, including 180 pre-menopausal (group 1) and 206 post-menopausal (group 2), underwent MR examination. Two radiologists evaluated MR images classifying normal BPE as minimal, mild, moderate or marked. The two groups of patients were subdivided into 3 categories based on MRI findings (negative, benign and malignant lesions). The distribution of BPE patterns within the two groups and within the three MR categories was calculated. The chi2 test was used to evaluate BPE type distribution in the three patient categories and any statistically significant correlation of BPE with lesion type was calculated. The Student t test was applied to search for any statistically significant difference between BPE type rates in group 1 and 2. RESULTS: The chi2 test demonstrated a statistically significant difference in the distribution of BPE types in negative patients and benign lesions as compared with malignant ones (p<0.05). A significantly higher prevalence of moderate and marked BPE was found among malignant lesions (group 1: 32% and 42%, respectively; group 2: 31% and 46%, respectively) while a predominance of minimal and mild BPE among negative patients (group 1: 60% and 36%, respectively; group 2: 68% and 32%, respectively) and benign lesions (group 1: 54% and 38%, respectively; group 2: 75% and 17%, respectively) was found. The Student t test did not show a statistically significant difference between BPE type rates in group 1 and 2 (p>0.05). CONCLUSION: Normal BPE could correlate with the risk of breast cancer being such BPE patterns as moderate and marked associated with patients with malignant lesions in both pre and post-menopausal women. PMID- 26597833 TI - 2D AMESING multi-echo (31)P-MRSI of the liver at 7T allows transverse relaxation assessment and T2-weighted averaging for improved SNR. AB - PURPOSE: Liver diseases are a major global health concern often requiring invasive assessment by needle biopsy. (31)P magnetic resonance spectroscopic imaging (MRSI) allows non-invasive probing of important liver metabolites. Recently, the adiabatic multi-echo spectroscopic imaging sequence with spherical k-space sampling (AMESING) was introduced at 7T, enabling acquisition of T2 information. T2-weighed averaging of the multiple echoes improves signal-to-noise ratio (SNR). The purpose of our study was to implement AMESING MRSI of the liver at 3T and 7T, derive localized T2 information and compare T2-weighted average spectra in terms of SNR. METHODS: Ten male volunteers underwent 2D AMESING MRSI at 3T and 7T after a minimum four-hour fast. SNR was calculated for PC, PE, Pi, GPE, GPC and alpha-ATP using maximum peak amplitudes and the SD of the noise. Metabolite peak ratios were calculated after fitting in jMRUI. SNR values and peak ratios were compared with the Wilcoxon signed-rank test. RESULTS: For the first time liver metabolites' T2 values at 7T were measured: PE (55.6+/-3.5 ms), PC (51.2+/-2.3 ms), Pi (46.4+/-1.1 ms), GPE (44.0+/-0.8 ms), GPC (50.4+/-0.8 ms) and alpha-ATP (18.2+/-0.4 ms). SNR gain using T2-weighted averaging at 7T resulted in a 1.2* SNR gain. In conjunction with higher field strength and improved coil set-up T2-weighted averaging at 7T allowed a total 3.2* SNR gain compared to 3T FID-only. CONCLUSION: AMESING 2D MRSI of the liver at 7T provides T2 values that allow T2-weighted averaging of data from multiple echoes resulting in improved SNR. PMID- 26597835 TI - Gastric carcinoma: Evaluation with diffusion-tensor MR imaging and tractography ex vivo. AB - PURPOSE: To determine the feasibility of diffusion-tensor imaging (DTI) and tractography as means of evaluating the depth of mural invasion by gastric carcinomas. MATERIALS AND METHODS: This study was approved by our institutional review board, and written informed consent was obtained from each patient. Twenty gastric specimens containing a carcinoma were studied with a 7.0-T MR imaging system equipped with a four-channel phased-array surface coil. DTI was performed by using a field of view of 50-60 mm * 25-30 mm, matrix of 256 * 128, section thickness of 1mm, b value of 1000 s/mm2, and motion-probing gradients in seven noncollinear directions. The MR images were compared with the histopathologic findings as the reference standard. RESULTS: In all 20 carcinomas (100%) the diffusion-weighted images, apparent diffusion coefficient (ADC) maps, fractional anisotropy (FA) maps, lambda1 maps, and direction-encoded color FA maps made it possible to identify the same depth of tumor invasion of the gastric wall as observed during histopathologic examination. The lambda1 maps provided the best contrast between the carcinomas and the layers of the gastric wall. The carcinomas also had lower ADC values and lower FA values than the normal gastric wall; thus, the carcinomas were clearly demarcated from the normal gastric wall. Tractography images were also useful for determining the depth of tumor invasion of the gastric wall. CONCLUSIONS: DTI and tractography are feasible means of evaluating gastric specimens and provide excellent diagnostic accuracy for evaluating mural invasion by gastric carcinomas. PMID- 26597837 TI - On the suppression of background signals originating from NMR hardware components. Application to zero echo time imaging and relaxation time analysis. AB - Modern NMR imaging systems used for biomedical research are equipped with B0 gradient systems with strong maximum gradient strength and short switching time enabling (1)H NMR measurements of samples with very short transverse relaxation times. However, background signal originating from non-optimized RF coils may hamper experiments with ultrashort delays between RF excitation and signal reception. We demonstrate that two simple means, outer volume suppression and the use of shaped B0 fields produced by higher-order shim coils, allow a considerable suppression of disturbing background signals. Thus, the quality of NMR images acquired at ultrashort or zero echo time is improved and systematic errors in quantitative data evaluation are avoided. Fields of application comprise MRI with ultrashort echo time or relaxation time analysis, for both biomedical research and characterizing porous media filled with liquids or gases. PMID- 26597836 TI - Quantification of regional aortic stiffness using MR elastography: A phantom and ex-vivo porcine aorta study. AB - MR Elastography (MRE) is a noninvasive technique for measuring tissue stiffness that has been used to assess the average stiffness of the abdominal aorta. The utility of aortic MRE would be improved if it could provide information about local variations in aortic stiffness. We hypothesize that regional variations in aortic stiffness can also be measured with MRE and the purpose of this work was to demonstrate that MRE can measure regional stiffness variations in a vascular phantom and in ex vivo porcine aortas. A vascular phantom was fabricated, containing two silicone tubes embedded in gel. A segment of one of the tubes was modified to increase its stiffness. MRE was performed on the phantom with a continuous flow of water through the tubes. The stiffness distribution along the modified tube was measured and compared to the reference tube. MRE was also performed in porcine aortas embedded in gel with segments treated with saline or formalin for 4 days. The stiffness difference between saline- and formalin treated aortic segments was measured by MRE and mechanical tests. A positive correlation was found between the regional stiffnesses measured by MRE and mechanical tests. The results indicate that MRE can be used to evaluate the local stiffness distribution in silicone tubes and ex vivo porcine aortas. It may therefore be possible to apply MRE to measure regional stiffness variations of the aorta in vivo. PMID- 26597838 TI - An experimental study on the assessment of rabbit hepatic fibrosis by using magnetic resonance T1rho imaging. AB - OBJECTIVE: To explore the correlation between the T1rho values of liver and liver fibrosis by using magnetic resonance (MR) T1rho imaging. MATERIALS AND METHODS: The study consisted of the control group and the hepatic fibrosis (HF) group. Carbon tetrachloride (CCl4) injection was performed once a week for 10 weeks (week 1-10) in the HF group which was divided into 5 subgroups and underwent MR examinations at weeks 4, 5, 6, 10, and 15 respectively post the first CCl4 injection (week 1). According to Scheuer Classification, the stage of HF of all rabbits was classified as S0-S4. Mann-Whitney U test was performed to compare the T1rho values, and p<0.05 was considered statistically significant. RESULTS: The control group included 11 rabbits and the HF group included 46 rabbits. The T1rho values in the HF group tended to increase with the increase of CCl4 injection duration or in higher HF stages. The T1rho values were significantly lower (p=0.036) in the control group (or the stage S0 group) (23.5+/-4.0 ms) compared to the whole HF group (or S1-S4 group) (26.1+/-3.7 ms), and dropped at week 15 (p=0.043) after the CCl4 injection was stopped at week 10. CONCLUSION: T1rho imaging is closely associated with the severity of HF and may play an important role in the early diagnosis of HF. PMID- 26597839 TI - Stimulation of autophagy promotes functional recovery in diabetic rats with spinal cord injury. AB - In this study we examined the relationship between autophagy and apoptosis in diabetic rats after spinal cord injury (SCI), also we determined the role of autophagy in diabetes-aggravated neurological injury in vivo and in vitro. Our results showed that diabetes decreased the survival of neurons, promoted astrocytes proliferation, increased inflammatory cells infiltration and inhibited functional recovery after SCI. Diabetes was shown to confer increased activation of apoptotic pathways, along with an increase in autophagy; similar effects were also observed in vitro in neuronal PC12 cells. Treatment with rapamycin, an autophagy activator, partially abolished the adverse effect of diabetes, suggesting that diabetes may enhance neurological damage and suppress locomotor recovery after SCI, in addition to its effects on apoptosis and autophagy. In contrast, further stimulation of autophagy improved neurological function via inhibition of apoptosis. These results explained how diabetes exacerbates SCI in cellular level and suggested autophagy stimulation to be a new therapeutic strategy for diabetic SCI. PMID- 26597840 TI - Screening for cryptococcal antigenemia using the lateral flow assay in antiretroviral therapy-naive HIV-positive adults at an Ethiopian hospital clinic. AB - BACKGROUND: Since treatment for latent cryptococcal infection (CI) before starting antiretroviral therapy (ART) reduces mortality in HIV-infected subjects, screening for cryptococcal antigen (CrAg) in blood is recommended for individuals with CD4 cell counts < 100 cells/uL in regions with high CI prevalence. We assessed CrAg screening using the lateral flow assay in HIV-infected adults eligible for ART in central Ethiopia. RESULTS: HIV-positive patients (age >= 18 years, CD4 cell count < 350 cells/MUL and/or WHO stage IV, no current or previous ART) were recruited at Adama Regional Hospital, Ethiopia (February 2013 until March 2014). CrAg was determined in plasma by lateral flow assay. Among 129 included participants (median age 35 years, 64 % female) the median CD4 cell count was 210 cells/MUL (interquartile range 110-309); 29 (23 %) had CD4 cell count < 100 cells/MUL. Two (1.6 %) participants were CrAg-positive (CD4 cell counts 171 vs. 250 cells/uL), one of whom had clinically manifest cryptococcal meningitis at the time of testing. CONCLUSIONS: In contrast to two recent reports from Ethiopia, we found few cases of CI among ART-naive adults. Our study, which is the first using lateral flow assay for CrAg screening in this country, illustrates the need of larger surveys of CI prevalence among ART-naive patients before defining recommendations on CI screening. PMID- 26597841 TI - Association of Hearing Loss and Loneliness in Older Adults. AB - OBJECTIVE: The objective of this study is to determine factors associated with loneliness in older adults presenting for hearing loss treatment. METHOD: A cross sectional analysis was conducted of 145 participants (aged 50-94) who presented for hearing aids or cochlear implants and were enrolled in the Studying Multiple Outcomes After Aural Rehabilitative Treatment (SMART) study from 2011 to 2013. Social, communicative, physical, and mental health functioning were assessed using self-administered questionnaires, and loneliness using the University of California, Los Angeles (UCLA) Loneliness Scale. RESULTS: Younger age and greater hearing loss were significantly associated with greater loneliness. Metrics of depressive symptoms and hearing-related quality of life, communication difficulties, and emotional well-being, mental health, and 36-Item Medical Outcomes Study Short-Form (SF-36) scores were moderately or highly correlated with loneliness. DISCUSSION: Younger age and greater hearing loss are independently associated with higher levels of loneliness in older adults presenting to clinic for hearing loss treatment. Further studies needed to determine whether hearing treatment can reduce loneliness in older adults. PMID- 26597842 TI - Comparing the Overall Health, Stress, and Characteristics of Canadians with Early Onset and Late-Onset Dementia. AB - OBJECTIVE: Dementia is increasingly recognized as a public health priority, but little is known about persons with early-onset dementia (EOD). The objectives of this article are (a) to compare the socio-demographic and health characteristics of people with EOD and late-onset dementia (LOD) and (b) to examine the relationships between EOD and overall health and life stress. METHOD: Data were from the Survey on Living With Neurological Conditions in Canada (SLNCC). Logistic regression models were used to identify the characteristics associated with EOD and LOD, and to assess the impact of EOD on overall health and life stress. RESULTS: Compared with LOD, individuals with EOD were more likely to be male, to have a mood disorder, and to have a longer illness duration. EOD was associated with high life stress, but not with negative overall health. DISCUSSION: This study identified attributes associated with EOD that have important implications for service planning. PMID- 26597843 TI - Blunted cardiac reactivity to psychological stress associated with higher trait anxiety: a study in peacekeepers. AB - BACKGROUND: Both exaggerated and diminished reactivity to stress can be maladaptive. Previous studies have shown that performing increasingly difficult tasks leads first to increased reactivity and then to a blunted response when success is impossible. Our aim was to investigate the influence of trait anxiety on cardiac and cortisol response to and recovery from a standardized psychosocial stress task (Trier Social Stress Task) in a homogeneous sample of healthy peacekeepers. We hypothesized that participants with higher trait anxiety would show blunted reactivity during the performance of an overwhelmingly difficult and stressful task. Participants (N = 50) delivered a speech and performed an arithmetic task in the presence of critical evaluators. Cortisol samples and electrocardiogram data were collected. Participants completed the State-Trait Anxiety Inventory-Trait version, the Posttraumatic Stress Disorder Checklist Civilian Version (PCL-C) and the Military Peace Force Stressor Inventory. RESULTS: For heart rate, the findings showed that peacekeepers with higher trait anxiety reacted less to the speech task (p = 0.03) and to the arithmetic task (p = 0.008) than those with lower trait anxiety. Trait anxiety did not modulate cortisol responses to the task. Despite the high trait anxiety group having higher PCL-C scores than the low trait anxiety group (p < 0.0001), this did not influence the cardiac results. CONCLUSIONS: We concluded that individuals with higher trait anxiety had less tachycardia in response to acute psychological stress than those with lower trait anxiety. The present results point to a higher risk for more anxious individuals of a maladaptive reaction to stressful events. PMID- 26597844 TI - Perception and satisfaction of cervical cancer screening by Visual Inspection with Acetic acid (VIA) at Meknes-Tafilalet Region, Morocco: a population-based cross-sectional study. AB - BACKGROUND: This study aims to explore the perception and satisfaction of cervical cancer screening by Visual Inspection with Acetic acid (VIA) in Meknes Tafilalet Region among target women. METHODS: A cross-sectional study was conducted using face-to-face interviews with women, routinely attending health centers, who met the inclusion criteria. Descriptive analysis was undertaken to report data. RESULTS: A total of 324 women were included in the study. Results revealed low awareness about cervical cancer (19.6 %) and a very high acceptability of VIA screening (94.5 %). Of the 306 women screened, 99 % stated that they would recommend the VIA testing to their friends and female relatives. All those women who were screened negative expressed their intent to repeat the test every three years. Those found VIA positive affirmed they would perform confirmatory explorations. The majority (96.3 %) of the women believed that screening by VIA could save their lives; cervical cancer was a concern for 98.6 %; and only 11.6 % felt anxious about repeating the VIA test. The majority of women (98.6 %) were satisfied with the service received at the health center. CONCLUSIONS: This study showed that the participants had a strong perception about cervical cancer screening and were willing to have further confirmation or future retests. PMID- 26597845 TI - 1 H-13 C independently tuned radiofrequency surface coil applied for in vivo hyperpolarized MRI. AB - PURPOSE: To develop a lump-element double-tuned common-mode-differential-mode (CMDM) radiofrequency (RF) surface coil with independent frequency tuning capacity for MRS and MRI applications. METHODS: The presented design has two modes that can operate with different current paths, allowing independent frequency adjustment. The coil prototype was tested on the bench and then examined in phantom and in vivo experiments. RESULTS: Standard deviations of frequency and impedance fluctuations measured in one resonator, while changing the tuning capacitor of another resonator, were less than 13 kHz and 0.55 Omega. The unloaded S21 was -36 dB and -41 dB, while the unloaded Q factor was 260 and 287, for 13 C and 1 H, respectively. In vivo hyperpolarized 13 C MR spectroscopy data demonstrated the feasibility of using the CMDM coil to measure the dynamics of lactate, alanine, pyruvate and bicarbonate signal in a normal rat head along with acquiring 1 H anatomical reference images. CONCLUSION: Independent frequency tuning capacity was demonstrated in the presented lump-element double-tuned CMDM coil. This CMDM coil maintained intrinsically decoupled magnetic fields, which provided sufficient isolation between the two resonators. The results from in vivo experiments demonstrated high sensitivity of both the 1 H and 13 C resonators. Magn Reson Med 76:1612-1620, 2016. (c) 2015 International Society for Magnetic Resonance in Medicine. PMID- 26597846 TI - Systemic Adiponectin Values in Humans Require Standardized Units. PMID- 26597848 TI - Mechanism for the Direct Synthesis of H2O2 on Pd Clusters: Heterolytic Reaction Pathways at the Liquid-Solid Interface. AB - Direct synthesis (H2 + O2 -> H2O2) is a promising reaction for producing H2O2, which can replace chlorinated oxidants in industrial processes. The mechanism of this reaction and the reasons for the importance of seemingly unrelated factors (e.g., Pd cluster size and solvent pH) remain unclear despite significant research. We propose a mechanism for H2O2 formation on Pd clusters consistent with steady-state H2O2 and H2O formation rates measured as functions of reactant pressures and temperature and the interpretations of proton concentration effects. H2O2 forms by sequential proton-electron transfer to O2 and OOH surface intermediates, whereas H2O forms by O-O bond rupture within OOH surface species. Direct synthesis, therefore, does not proceed by the Langmuir-Hinshelwood mechanism often invoked. Rather, H2O2 forms by heterolytic reaction pathways resembling the two-electron oxygen reduction reaction (ORR); however, the chemical potential of H2 replaces an external electrical potential as the thermodynamic driving force. Activation enthalpies (DeltaH(?)) for H2O formation increase by 14 kJ mol(-1) when Pd cluster diameters increase from 0.7 to 7 nm because changes in the electronic structure of Pd surface atoms decrease their propensity to cleave O-O bonds. DeltaH(?) values for H2O2 remain nearly constant because barriers for proton-electron transfer depend weakly on the coordinative saturation of Pd surface atoms. Collectively, these results provide a self consistent mechanism, which clarifies many studies in which H2O2 rates and selectivities were shown to depend on the concentration of acid/halide additives and Pd cluster size. These findings will guide the rational design of selective catalysts for direct synthesis. PMID- 26597847 TI - End-tidal carbon dioxide monitoring may be associated with a higher possibility of return of spontaneous circulation during out-of-hospital cardiac arrest: a population-based study. AB - BACKGROUND: During cardiac arrest, end-tidal carbon dioxide (ETCO2) monitoring is recommended as a chest compression performance indicator. However, its frequency of use during out-of-hospital cardiac arrest (OHCA) and its benefits have never been evaluated in real clinical situations. OBJECTIVE: We investigated OHCA patients in Taiwan to evaluate the frequency of ETCO2 monitoring and its effects on sustained return of spontaneous circulation (ROSC). METHODS: We sampled the Taiwan National Health Insurance claims database, which contains 1 million beneficiaries. All adult beneficiaries older than 18 years who presented with OHCA and received chest compression between 1 January 2005 and 31 December 2012 were enrolled. We further identified patients with ETCO2 monitoring and matched each 1 with 20 patients who did not receive ETCO2 monitoring based on their propensity scores. A simple conditional logistic regression model was applied to compare the odds ratio (OR) for sustained ROSC in the matched cohorts. RESULTS: A total of 5041 OHCA patients were enrolled. The frequency of ETCO2 monitoring has increased since 2010 but still is low. After matching, 53 patients with ETCO2 monitoring and 1060 without ETCO2 monitoring were selected. The OR of sustained ROSC in the ETCO2 group was significantly increased (2.38, 95 % CI 1.28-4.42). CONCLUSION: Patients who received ETCO2 monitoring during OHCA had a higher possibility of sustained ROSC, but the overall use of ETCO2 monitoring is still low despite strong recommendations for its use. PMID- 26597849 TI - Good sleep quality is associated with better academic performance among Sudanese medical students. AB - BACKGROUND: There is increasing awareness about the association of sleep quality and academic achievement among university students. However, the relationship between sleep quality and academic performance has not been examined in Sudan; this study assessed the relationship between sleep quality and academic performance among Sudanese medical students. METHODS: A case-control study was conducted among 165 male and female medical students at two Sudanese universities. Excellent (A) and pass (C) academic groups were invited to respond to a self-administered questionnaire, using the Pittsburgh Sleep Quality Index (PSQI). Students also completed a diary detailing their sleep habits for 2 weeks prior to filling out the questionnaire. Various parameters of sleep quality were then compared between the two groups. RESULTS: A significant difference (p < 0.001) between the excellent and average groups was found for overall sleep quality, subjective sleep rating, bedtime later than midnight, sleep latency, and daytime dysfunction (during driving, preparing a meal, etc.). No differences were found between groups for the use of sleep medications. The mean sleeping hours was (7 +/- 1.9) and (6.3 +/- 1.9) for the excellent and pass groups respectively (p < 0.05). A significant difference (p < 0.001) between the excellent and average groups was found for weekday and weekend bedtime, weekend wake-up time, and weekend wake-up delay. No differences were found between groups for the weekday's wake- up time, and bedtime delay during weekends. Besides, snoring was present in 9.2 % of the excellent group versus 28 % in pass group (p < 0.005). PMID- 26597850 TI - Is memory organized by temporal contiguity? AB - The hypotheses that memories are ordered according to time and that contiguity is central to learning have recently reemerged in the human memory literature. This article reviews some of the key empirical findings behind this revival and some of the evidence against it, and finds the evidence for temporal organization unconvincing. A central problem is that, as many memory experiments are done, they have a prospective, as well as a retrospective, component. That is, if subjects can anticipate how they will be tested, they encode the to-be-remembered material in a way that they believe will facilitate performance on the anticipated test. Experiments that avoid this confounding factor have shown little or no evidence of organization by contiguity. PMID- 26597851 TI - Promoting the experimental dialogue between working memory and chunking: Behavioral data and simulation. AB - Working memory (WM) is a cognitive system allowing short-term maintenance and processing of information. Maintaining information in WM consists, classically, in rehearsing or refreshing it. Chunking could also be considered as a maintenance mechanism. However, in the literature, it is more often used to explain performance than explicitly investigated within WM paradigms. Hence, the aim of the present paper was (1) to strengthen the experimental dialogue between WM and chunking, by studying the effect of acronyms in a computer-paced complex span task paradigm and (2) to formalize explicitly this dialogue within a computational model. Young adults performed a WM complex span task in which they had to maintain series of 7 letters for further recall while performing a concurrent location judgment task. The series to be remembered were either random strings of letters or strings containing a 3-letter acronym that appeared in position 1, 3, or 5 in the series. Together, the data and simulations provide a better understanding of the maintenance mechanisms taking place in WM and its interplay with long-term memory. Indeed, the behavioral WM performance lends evidence to the functional characteristics of chunking that seems to be, especially in a WM complex span task, an attentional time-based mechanism that certainly enhances WM performance but also competes with other processes at hand in WM. Computational simulations support and delineate such a conception by showing that searching for a chunk in long-term memory involves attentionally demanding subprocesses that essentially take place during the encoding phases of the task. PMID- 26597852 TI - Feeding rates affect growth, intestinal digestive and absorptive capabilities and endocrine functions of juvenile blunt snout bream Megalobrama amblycephala. AB - This study aimed to investigate the optimal feeding rate for juvenile blunt snout bream (average initial weight 23.74 +/- 0.09 g) based on the results on growth performance, intestinal digestive and absorptive capabilities and endocrine functions. A total of 840 fish were randomly distributed into 24 cages and fed a commercial feed at six feeding rates ranging from 2.0 to 7.0% body weight (BW)/day. The results indicated that weight gain rate increased significantly (P < 0.05) as feeding rates increased from 2.0 to 5.0% BW/day, but decreased with the further increasing feeding rates (P > 0.05). Protein efficiency ratio and nitrogen and energy retention all showed a similar trend. However, feed conversion ratio increased significantly (P < 0.05) with increasing feeding rates. Feeding rates have little effects (P > 0.05) on whole-body moisture, ash and protein contents, but significantly (P < 0.05) affect both lipid and energy contents with the highest values both observed in fish fed 4.0% BW/day. In addition, moderate ration sizes (2.0-4.0% BW/day) resulted in the enhanced activities of intestinal enzymes, including lipase, protease, Na(+), K(+)-ATPase, alkaline phosphatase and creatine kinase. Furthermore, the mRNA levels of growth hormone, insulin-like growth factors-I, growth hormone receptor and neuropeptide all increased significantly (P < 0.05) as feeding rates increased from 2.0 to 5.0% and 6.0% BW/day, but decreased significantly (P < 0.05) with the further increase in feeding rates, whereas both leptin and cholecystokinin expressions showed an opposite trend. Based on the broken-line regression analysis of SGR against feeding rates, the optimal feeding rate for juvenile blunt snout bream was estimated to be 4.57% BW/day. PMID- 26597854 TI - Influence of heat-labile serum components in the presence of OmpA on the outer membrane of Salmonella gallinarum. AB - Salmonella gallinarum is the causative agent of fowl typhoid. Being a Gram negative bacteria, its outer membrane proteins (OMP) can be regulated by different microenvironments. S. gallinarum was cultured under the following conditions: nutrient broth (NB), NB supplemented with serum from specific pathogen-free birds (NBS) and NB with serum incubated at 56 degrees C prior to incubation with the bacteria (NBSD); OMP were subsequently extracted. Several changes were observed in the apparent expression of OMP, mainly a decrease in an OMP with a size of 30 kDa, approximately, under the NBS condition. In contrast, the same event was not observed in NB and NBSD when using one- and two dimensional polyacrylamide gels (SDS-PAGE). Using the OMP with a size of 30 kDa, approximately, as antigen in indirect ELISA, we were able to differentiate serum from healthy and vaccinated birds, as well as birds infected with S. gallinarum and S. enteritidis. The amino-terminal of this protein was sequenced, showing 100 % identity with OmpA of S. typhimurium. Subsequently, we designed primers to amplify the gene by PCR. The partial sequence of the amplified gene showed 100 % identity with OmpA of S. gallinarum. (1) Heat-labile serum components influence the presence of OmpA in the OM of S. gallinarum; (2) by the way of ELISA, OmpA allows to specifically differentiate healthy from diseased birds. PMID- 26597853 TI - Expression of nuclear factor of activated T cells (NFAT) and downstream muscle specific proteins in ground squirrel skeletal and heart muscle during hibernation. AB - The thirteen-lined ground squirrel (Ictidomys tridecemlineatus) undergoes remarkable adaptive changes during hibernation. Interestingly, skeletal muscle remodelling occurs during the torpor-arousal cycle of hibernation to prevent net muscle loss despite inactivity. Reversible cardiomyocyte hypertrophy occurs in cardiac muscle, allowing the heart to preserve cardiac output during hibernation, while avoiding chronic maladaptive hypertrophy post-hibernation. We propose that calcium signalling proteins [calcineurin (Cn), calmodulin (CaM), and calpain], the nuclear factor of activated T cell (NFAT) family of transcription factors, and the NFAT targets myoferlin and myomaker contribute significantly to adaptations taking place in skeletal and cardiac muscle during hibernation. Protein-level analyses were performed over several conditions: euthermic room temperature (ER), euthermic cold room (EC), entrance into (EN), early (ET), and late torpor (LT) time points, in addition to early (EA), interbout (IA), and late arousal (LA) time points using immunoblotting and DNA-protein interaction (DPI) enzyme-linked immunosorbent assay (ELISAs). In skeletal and cardiac muscle, NFATc2 protein levels were elevated during torpor. NFATc4 increased throughout the torpor-arousal cycle in both tissues, and NFATc1 showed this trend in cardiac muscle only. NFATc3 showed an elevation in DNA-binding activity but not expression during torpor. Myoferlin protein levels dramatically increased during torpor in both skeletal and cardiac muscle. Myomaker levels also increased significantly in cardiac muscle during torpor. Cardiac Cn levels remained stable, whereas CaM and calpain decreased throughout the torpor-arousal cycle. Activation and/or upregulation of NFATc2, c3, myoferlin, and myomaker at torpor could be part of a stress-response mechanism to preserve skeletal muscle mass, whereas CaM and calpain appear to initiate the rapid reversal of cardiac hypertrophy during arousal through downregulation of the NFAT-Cn pathway. PMID- 26597855 TI - Valence-band offset and forward-backward charge transfer in manganite/NiO and manganite/LaNiO3 heterostructures. AB - The valence-band offset (VBO) of the La(0.67)Sr(0.33)MnO(3)/NiO (LSMO/NiO), LaMnO(3)/NiO (LMO/NiO), LSMO/LaNiO(3) (LSMO/LNO) and LMO/LaNiO(3) (LSMO/LNO) heterostructures has been investigated using X-ray photoemission spectroscopy. The VBO values are calculated to be -0.72, -0.05, +1.43 and +1.51 eV for the LSMO/NiO, LSMO/LNO, LMO/LNO and LMO/NiO heterostructures, respectively. Hence, when compared with NiO and LNO, the valence band of LSMO is shifted to a lower binding energy, whereas that of LMO is shifted to a higher binding energy. In addition, the charge transfer at the interfaces has been depicted as Mn(3.3+) + 0.7e-> Mn(2.6+), Mn(3.3+) + 0.1e-> Mn(3.2+), Mn(3.0+)- 0.4e-> Mn(3.4+) and Mn(3.0+)- 0.5e-> Mn(3.5+) for the LSMO/NiO, LSMO/LNO, LMO/LNO and LMO/NiO heterostructures, respectively. Thus, the charge transfer procedure can be described as electron hopping from NiO and LNO to LSMO in the LSMO/NiO and LSMO/LNO heterostructures, and electron hopping from LMO to NiO and LNO in the LMO/NiO and LSMO/LNO heterostructures. Therefore, the charge transfer is dependent on the VBO, and the charge transfer direction can be determined from the negative or positive values of the VBO. PMID- 26597856 TI - Quasispecies on Fitness Landscapes. AB - Selection-mutation dynamics is studied as adaptation and neutral drift on abstract fitness landscapes. Various models of fitness landscapes are introduced and analyzed with respect to the stationary mutant distributions adopted by populations upon them. The concept of quasispecies is introduced, and the error threshold phenomenon is analyzed. Complex fitness landscapes with large scatter of fitness values are shown to sustain error thresholds. The phenomenological theory of the quasispecies introduced in 1971 by Eigen is compared to approximation-free numerical computations. The concept of strong quasispecies understood as mutant distributions, which are especially stable against changes in mutations rates, is presented. The role of fitness neutral genotypes in quasispecies is discussed. PMID- 26597857 TI - Antisickling and toxicological evaluation of the leaves of Scoparia dulcis Linn (Scrophulariaceae). AB - BACKGROUND: Scoparia dulcis Linn (Scrophulariaceae) together with other medicinal plants serve as antisickling remedies in Africa. This study was aimed at investigating the antisickling activity of the leaves of the plant as well as establishing the toxicological profile. METHOD: Chemical tests were employed in phytochemical investigations. Evaluation of the antisickling activity involved the inhibition of sodium metabisulphite-induced sickling of the HbSS red blood cells obtained from confirmed sickle cell patients who were not in crises. Concentrations of the crude extract and its fractions were tested with normal saline and p-hydroxybenzoic acid serving as controls. Acute toxicological evaluation was carried out in mice while 30-day assessment was done in rats. RESULTS: Phytochemical screening revealed the presence of alkaloids, tannins, flavonoids and saponins. Percentage sickling inhibitions of the aqueous methanol extracts of S. dulcis were significant all through the period of assay p < 0. 05 compared to normal saline, but not significant with PHBA. The fractions had less activity compared to the crude extracts. The LD 50 of the extract in mice was above 8000 mg/kg body weight when administered orally. Toxicological evaluations at 250 and 500 mg/kg showed mild congestion in virtually all the target organs. CONCLUSION: The antisickling results confirmed traditional usage of Scoparia dulcis in the management of Sickle cell disorders and a candidate for further investigations. PMID- 26597858 TI - Novel aryl carbamate derivatives of metronidazole as potential antiamoebic agents. AB - A series of novel aryl carbamate derivatives of metronidazole (MNZ) were designed, synthesized, and screened for antiamoebic activity. As compared to MNZ, most of the derivatives exhibited moderate to excellent activity against the HM1:IMSS strain of Entamoeba histolytica. Compounds 7, 14, 16, 19, and 21 exhibited the most promising antiamoebic activity with IC50 values of 0.24, 0.08, 0.26, 0.26, and 0.15 MUM, respectively, compared to that of MNZ (1.78 MUM). Moreover, from the toxicological studies of these compounds on human melanocytes, the melan-a cell line revealed that the potent compounds are nontoxic at concentrations ranging from 2.5 to 50 MUM. PMID- 26597859 TI - Inhibition of VCAM-1 expression on mouse vascular smooth muscle cells by lobastin via downregulation of p38, ERK 1/2 and NF-kappaB signaling pathways. AB - Atherosclerosis is a chronic inflammatory disease, the progression of which is associated with the increased expression of cell adhesion molecules on vascular smooth muscle cells (VSMCs). Lobastin is a new pseudodepsidone isolated from Stereocaulon alpinum, Antarctic lichen, which is known to have antioxidant and antibacterial activities. However, the nature of the biological effects of lobastin still remains unclear. In the present study, we examine the effect of lobastin on the expression of vascular cell adhesion molecules (VCAM-1) induced by TNF-alpha in the cultured mouse VSMC cell line, MOVAS-1. Pretreatment of VSMCs for 2 h with lobastin (0.1-10 MUg/ml) concentration-dependently inhibited TNF alpha-induced protein expression of VCAM-1. Lobastin also inhibited TNF-alpha induced production of intracellular reactive oxygen species (ROS). Lobastin abrogated TNF-alpha-induced phosphorylation of p38 and ERK 1/2, but not JNK, and also inhibited TNF-alpha-induced NK-kappaB activation. In addition, lobastin suppressed TNF-alpha-induced IkappaB kinase activation, subsequent degradation of IkappaBalpha and nuclear translocation of p65 NF-kappaB. Our results indicate that lobastin downregulates the TNF-alpha-mediated induction of VCAM-1 in VSMC by inhibiting the p38, ERK 1/2 and NF-kappaB signaling pathways and intracellular ROS generation. Thus, lobastin may be an important regulator of inflammation in the atherosclerotic lesion and a novel therapeutic drug for the treatment of atherosclerosis. PMID- 26597860 TI - Paenibacillus marchantiophytorum sp. nov., isolated from the liverwort Herbertus sendtneri. AB - A Gram-stain-positive, aerobic, motile, rod-shaped, endospore-forming bacterium, designated strain R55T, was isolated from the liverwort Herbertus sendtneri growing at Gawalong glacier, Tibet, and characterized by using a polyphasic taxonomic approach. The major fatty acids of strain R55T were anteiso-C15 : 0, C16 : 0 and iso-C16 : 0. Diphosphatidylglycerol, phosphatidylethanolamine and phosphatidylglycerol were the predominant polar lipids and occurred along with two unidentified aminophospholipids, one unidentified phospholipid and one unidentified aminolipid. Strain R55T contained MK-7 as the dominant menaquinone and meso-diaminopimelic acid as the major diagnostic diamino acid in the cell wall peptidoglycan. The G+C content of the genomic DNA was 36.9 mol%. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain R55T was affiliated to species of the genus Paenibacillus, and was related most closely to Paenibacillus ferrarius CY1T (97.1 % similarity). However, the DNA-DNA relatedness between this strain and strain R55T was only 44.1 %. Based on phenotypic, chemotaxonomic and phylogenetic properties, strain R55T is considered to represent a novel species of the genus Paenibacillus, for which the name Paenibacillus marchantiophytorum sp. nov. is proposed. The type strain is R55T ( = CGMCC 1.15043T = DSM 29850T). PMID- 26597861 TI - Mushtaq A. Khan, DVM, PhD: Unwavering Supporter for Digestive Diseases Research. PMID- 26597862 TI - Enteral glutamine supplementation in critically ill patients. PMID- 26597863 TI - Effects of diphenylhydantoin on locomotion and thigmotaxis of larval zebrafish. AB - Antiepileptic effects of diphenylhydantoin (DPH) have been documented in animal studies and clinical research, while little is known about the effects of the drug on basic behaviors and anxiety-related behaviors. In order to understand neuroactivities of DPH deeply and administrate DPH in clinic rationally, it is necessary to study neurobehavioral effects of the drug. In the present study, the effects of DPH on the locomotor activity and thigmotaxis of zebrafish larvae at 5 days post fertilization (dpf) were explored under different illumination conditions. The influence of DPH on zebrafish larval responses to visual stimuli (sudden illumination transition from light to dark) was also investigated. Under light or dark condition, exposure to high concentrations of DPH resulted in decreased locomotor activity and thigmotaxis, whereas DPH treatment at low doses enhanced the locomotor activity. Additionally, sudden illumination transition induced robust increase in the locomotor activity and this phenomenon was not modified by DPH treatment. Our results suggest that DPH has potential stimulatory and inhibitory effects on the locomotor activity and possesses anxiolytic properties. In addition, responses of 5-dpf zebrafish larvae to visual stimuli were not modified by DPH treatment. PMID- 26597865 TI - Palliative care coding practices in Canada since the introduction of guidelines and the HSMR indicator. AB - OBJECTIVES: This study examines palliative care (PC) coding practices since the introduction of a national coding standard and assesses a potential association with hospital standardised mortality ratio (HSMR) results. SETTING: Acute-care hospitals in Canada. PARTICIPANTS: ~16 million hospital discharges recorded in Canadian Institute for Health Information (CIHI)'s Discharge Abstract Database from April 2006 to March 2013. PRIMARY AND SECONDARY OUTCOME MEASURES: In hospital mortality, patient characteristics and service utilisation among all hospitalisations, HSMR cases and palliative patients. METHODS: We assessed all separations in the Discharge Abstract Database between fiscal years 2006-2007 and 2012-2013 for PC cases at national, provincial and facility levels. In-hospital mortality was measured among all hospitalisations (including HSMR cases) and palliative patients. We calculated a variant HSMR-PC that included PC cases. RESULTS: There was an increase in the frequency of PC coding over the study period (from 0.78% to 1.12% of all separations), and year-over-year improvement in adherence to PC coding guidelines. Characteristics and resource utilisation of PC patients remained stable within provinces. Crude mortality among HSMR cases declined from 8.7% to 7.3%. National HSMR declined by 22% during the study period, compared with a 17% decline in HSMR-PC. Provincial results for HSMR-PC are not significantly different from regular HSMR calculation. CONCLUSIONS: The introduction of a national coding standard resulted in increased identification of palliative patients and services. Aside from PC coding practices, we note numerous independent drivers of improving HSMR results, notably, a significant reduction of in-hospital mortality, and increase in admissions accompanied by a greater number of coded comorbidities. While PC impacts the HSMR indicator, its influence remains modest. PMID- 26597864 TI - Prevalence of foot disease and risk factors in general inpatient populations: a systematic review and meta-analysis. AB - OBJECTIVE: To systematically review studies reporting the prevalence in general adult inpatient populations of foot disease disorders (foot wounds, foot infections, collective 'foot disease') and risk factors (peripheral arterial disease (PAD), peripheral neuropathy (PN), foot deformity). METHODS: A systematic review of studies published between 1980 and 2013 was undertaken using electronic databases (MEDLINE, EMBASE and CINAHL). Keywords and synonyms relating to prevalence, inpatients, foot disease disorders and risk factors were used. Studies reporting foot disease or risk factor prevalence data in general inpatient populations were included. Included study's reference lists and citations were searched and experts consulted to identify additional relevant studies. 2 authors, blinded to each other, assessed the methodological quality of included studies. Applicable data were extracted by 1 author and checked by a second author. Prevalence proportions and SEs were calculated for all included studies. Pooled prevalence estimates were calculated using random-effects models where 3 eligible studies were available. RESULTS: Of the 4972 studies initially identified, 78 studies reporting 84 different cohorts (total 60 231 517 participants) were included. Foot disease prevalence included: foot wounds 0.01 13.5% (70 cohorts), foot infections 0.05-6.4% (7 cohorts), collective foot disease 0.2-11.9% (12 cohorts). Risk factor prevalence included: PAD 0.01-36.0% (10 cohorts), PN 0.003-2.8% (6 cohorts), foot deformity was not reported. Pooled prevalence estimates were only able to be calculated for pressure ulcer-related foot wounds 4.6% (95% CI 3.7% to 5.4%)), diabetes-related foot wounds 2.4% (1.5% to 3.4%), diabetes-related foot infections 3.4% (0.2% to 6.5%), diabetes-related foot disease 4.7% (0.3% to 9.2%). Heterogeneity was high in all pooled estimates (I(2)=94.2-97.8%, p<0.001). CONCLUSIONS: This review found high heterogeneity, yet suggests foot disease was present in 1 in every 20 inpatients and a major risk factor in 1 in 3 inpatients. These findings are likely an underestimate and more robust studies are required to provide more precise estimates. PMID- 26597866 TI - Diffusion of anti-VEGF injections in the Portuguese National Health System. AB - OBJECTIVES: To analyse the temporal and geographical diffusion of antivascular endothelial growth factor (anti-VEGF) interventions, and its determinants in a National Health System (NHS). SETTING: NHS Portuguese hospitals. PARTICIPANTS: All inpatient and day cases related to eye diseases at all Portuguese public hospitals for the period 2002-2012 were selected on the basis of four International Classification of Diseases 9th revision, Clinical Modification (ICD 9-CM) codes for procedures: 1474, 1475, 1479 and 149. PRIMARY AND SECONDARY OUTCOME MEASURES: We measured anti-VEGF treatment rates by year and county. The determinants of the geographical diffusion were investigated using generalised linear modelling. RESULTS: We analysed all hospital discharges from all NHS hospitals in Portugal (98,408 hospital discharges corresponding to 57,984 patients). National rates of hospitals episodes for the codes for procedures used were low before anti-VEGF approval in 2007 (less than 12% of hospital discharges). Between 2007 and 2012, the rates of hospital episodes related to the introduction of anti-VEGF injections increased by 27% per year. Patients from areas without ophthalmology departments received fewer treatments than those from areas with ophthalmology departments. The availability of an ophthalmology department in the county increased the rates of hospital episodes by 243%, and a 100-persons greater density per km(2) raised the rates by 11%. CONCLUSIONS: Our study shows a large but unequal diffusion of anti-VEGF treatments despite the universal coverage and very low copayments. The technological innovation in ophthalmology may thus produce unexpected inequalities related to financial constraints unless the implementation of innovative techniques is planned and regulated. PMID- 26597867 TI - Diagnosing Potentially Preventable Hospitalisations (DaPPHne): protocol for a mixed-methods data-linkage study. AB - INTRODUCTION: Rates of potentially preventable hospitalisations (PPH) are used as a proxy measure of effectiveness of, or access to community-based health services. The validity of PPH as an indicator in Australia has not been confirmed. Available evidence suggests that patient-related, clinician-related and systems-related factors are associated with PPH, with differences between rural and metropolitan settings. Furthermore, the proportion of PPHs which are actually preventable is unknown. The Diagnosing Potentially Preventable Hospitalisations study will determine the proportion of PPHs for chronic conditions that are deemed preventable and identify potentially modifiable factors driving these, in order to develop effective interventions to reduce admissions and improve measures of health system performance. METHODS AND ANALYSIS: This mixed methods data linkage study of approximately 1000 eligible patients with chronic PPH admissions to one metropolitan and two regional hospitals over 12 months will combine data from multiple sources to assess the: extent of preventability of chronic PPH admissions; validity of the Preventability Assessment Tool (PAT) in identifying preventable admissions; factors contributing to chronic PPH admissions. Data collected from patients (quantitative and qualitative methods), their general practitioners, hospital clinicians and hospital records, will be linked with routinely collected New South Wales (NSW) Admitted Patient Data Collection, the NSW Registry of Births, Death and Marriages death registration and Australian Bureau of Statistics mortality data. The validity of the PAT will be assessed by determining concordance between clinician assessment and that of a 'gold standard' panel. Multivariable logistic regression will identify the main predictor variables of admissions deemed preventable, using study-specific and linked data. ETHICS AND DISSEMINATION: The NSW Population and Health Services Research Ethics Committee granted ethical approval. Dissemination mechanisms include engagement of policy stakeholders through a project Steering Committee, and the production of summary reports for policy and clinical audiences in addition to peer-review papers. PMID- 26597868 TI - Understanding medical symptoms: a conceptual review and analysis. AB - The aim of this article is to present a conceptual review and analysis of symptom understanding. Subjective bodily sensations occur abundantly in the normal population and dialogues about symptoms take place in a broad range of contexts, not only in the doctor's office. Our review of symptom understanding proceeds from an initial subliminal awareness by way of attribution of meaning and subsequent management, with and without professional involvement. We introduce theoretical perspectives from phenomenology, semiotics, social interactionism, and discourse analysis. Drew Leder's phenomenological perspectives deal with how symptom perception occurs when any kind of altered balance brings forward a bodily attention. Corporeality is brought to explicit awareness and perceived as sensations. Jesper Hoffmeyer's biosemiotic perspectives provide access to how signs are interpreted to attribute meaning to the bodily messages. Symptom management is then determined by the meaning of a symptom. Dorte E. Gannik's concept "situational disease" explains how situations can be reviewed not just in terms of their potential to produce signs or symptoms, but also in terms of their capacity to contain symptoms. Disease is a social and relational phenomenon of containment, and regulating the situation where the symptoms originate implies adjusting containment. Discourse analysis, as presented by Jonathan Potter and Margaret Wetherell, provides a tool to notice the subtle ways in which language orders perceptions and how language constructs social interaction. Symptoms are situated in culture and context, and trends in modern everyday life modify symptom understanding continuously. Our analysis suggests that a symptom can only be understood by attention to the social context in which the symptom emerges and the dialogue through which it is negotiated. PMID- 26597869 TI - Negative mechanistic reasoning in medical intervention assessment. AB - Traditionally, mechanistic reasoning has been assigned a negligible role in standard EBM (evidence-based medicine) literature, although some recent authors have argued for an upgrade. Even so, the mechanistic reasoning that has received attention has almost exclusively been positive--both in an epistemic sense of claiming that there is a mechanistic chain and in a health-related sense of there being claimed benefits for the patient. Negative mechanistic reasoning has been neglected, both in the epistemic and in the health-related sense. I distinguish three main types of negative mechanistic reasoning and subsume them under a new definition of mechanistic reasoning in the context of assessing medical interventions. This definition is wider than a previous suggestion in the literature. Each negative type corresponds to a range of evidential strengths, and it is argued that there are differences with respect to typical evidential strengths. The variety of negative mechanistic reasoning should be acknowledged in EBM, and it presents a serious challenge to proponents of so-called medical hierarchies of evidence. PMID- 26597870 TI - Fingerprint resampling: A generic method for efficient resampling. AB - In resampling methods, such as bootstrapping or cross validation, a very similar computational problem (usually an optimization procedure) is solved over and over again for a set of very similar data sets. If it is computationally burdensome to solve this computational problem once, the whole resampling method can become unfeasible. However, because the computational problems and data sets are so similar, the speed of the resampling method may be increased by taking advantage of these similarities in method and data. As a generic solution, we propose to learn the relation between the resampled data sets and their corresponding optima. Using this learned knowledge, we are then able to predict the optima associated with new resampled data sets. First, these predicted optima are used as starting values for the optimization process. Once the predictions become accurate enough, the optimization process may even be omitted completely, thereby greatly decreasing the computational burden. The suggested method is validated using two simple problems (where the results can be verified analytically) and two real-life problems (i.e., the bootstrap of a mixed model and a generalized extreme value distribution). The proposed method led on average to a tenfold increase in speed of the resampling method. PMID- 26597871 TI - Temporal trends in the systemic inflammatory response syndrome, sepsis, and medical coding of sepsis. AB - BACKGROUND: Recent reports using administrative claims data suggest the incidence of community- and hospital-onset sepsis is increasing. Whether this reflects changing epidemiology, more effective diagnostic methods, or changes in physician documentation and medical coding practices is unclear. METHODS: We performed a temporal-trend study from 2008 to 2012 using administrative claims data and patient-level clinical data of adult patients admitted to Barnes-Jewish Hospital in St. Louis, Missouri. Temporal-trend and annual percent change were estimated using regression models with autoregressive integrated moving average errors. RESULTS: We analyzed 62,261 inpatient admissions during the 5-year study period. 'Any SIRS' (i.e., SIRS on a single calendar day during the hospitalization) and 'multi-day SIRS' (i.e., SIRS on 3 or more calendar days), which both use patient level data, and medical coding for sepsis (i.e., ICD-9-CM discharge diagnosis codes 995.91, 995.92, or 785.52) were present in 35.3 %, 17.3 %, and 3.3 % of admissions, respectively. The incidence of admissions coded for sepsis increased 9.7 % (95 % CI: 6.1, 13.4) per year, while the patient data-defined events of 'any SIRS' decreased by 1.8 % (95 % CI: -3.2, -0.5) and 'multi-day SIRS' did not change significantly over the study period. Clinically-defined sepsis (defined as SIRS plus bacteremia) and severe sepsis (defined as SIRS plus hypotension and bacteremia) decreased at statistically significant rates of 5.7 % (95 % CI: -9.0, -2.4) and 8.6 % (95 % CI: -4.4, -12.6) annually. All-cause mortality, SIRS mortality, and SIRS and clinically-defined sepsis case fatality did not change significantly during the study period. Sepsis mortality, based on ICD-9-CM codes, however, increased by 8.8 % (95 % CI: 1.9, 16.2) annually. CONCLUSIONS: The incidence of sepsis, defined by ICD-9-CM codes, and sepsis mortality increased steadily without a concomitant increase in SIRS or clinically-defined sepsis. Our results highlight the need to develop strategies to integrate clinical patient level data with administrative data to draw more accurate conclusions about the epidemiology of sepsis. PMID- 26597872 TI - A mechanism of mesh-related post-herniorrhaphy neuralgia. AB - PURPOSE: The objective is to compare nerve densities in explanted polypropylene meshes in patients with or without chronic pain. Pain has supplanted recurrences as a complication of hernia surgery. The increased incidence of pain mirrors a parallel increase in the use of polypropylene meshes. Neither triple neurectomy nor careful nerve preservation has brought relief. Perhaps because we have forgotten that nerves, in response to some evolutionary mechanism, tend to regenerate, undergo changes imposed by prosthetic elements and architecture, mimicking entrapment and compartment syndromes. METHODS: A total of 33 hernia meshes have been analyzed: 17 excised due to severe pain, two for combined pain and recurrence, 14 sampled during revision for recurrence without pain. Each mesh had standardized sampling for histology and the nerves were highlighted by S100 stain. Nerve densities were assessed within the mesh spaces and in tissue outside the mesh. RESULTS: The density of nerves present in the standardized mesh samples of patients complaining of pain was much more elevated than in the mesh of those patients who had a recurrence but no pain. The difference was statistically significant (p < 0.001). Excluding two patients who had both pain and recurrence, the difference was even more marked (p < 0.0001). CONCLUSIONS: Re-innervation and neo-innervation are known to take place following hernia repairs in indigenous tissue as well as through polypropylene meshes. However, when pain is an overriding issue dictating mesh explant, the degree of mesh innervation is significantly higher when compared to mesh excised for recurrence. That increase has been confirmed statistically. PMID- 26597873 TI - The impact of healthcare rationing on elective and emergency hernia repair. AB - PURPOSE: In 2011 the local clinical commissioning group introduced a policy restricting funding for elective hernia repairs. Anecdotally, it was felt that this resulted in an increased number of emergency hernia repairs in our trust. Our primary objective was to assess whether this was actually the case. Our secondary objective was to quantify the risks of non-elective hernia repair. METHODS: We performed a retrospective cohort study, analysing all hernia surgeries performed between 2010 and 2013. The data were obtained from the trust Patient Information System. A total of 2556 patients underwent repair of inguinal, umbilical, incisional, femoral or ventral hernias over this time. RESULTS: As the policy intended, the number of elective hernia repairs reduced from 857 over 12 months before the funding restrictions to 606 in the same period afterwards (p < 0.001). Over the same time period, however, a significant rise in total emergency hernia repairs was demonstrated, increasing from 98 to 150 (p < 0.001). 30-day readmission rates also increased from 5.1 % before the policy introduction to 8.5 % afterwards (p = 0.006). In our data, the rate of bowel resection rises from 0.97 to 12.9 % for emergency operation compared to elective hernia repair (p < 0.001), while the median length of stay rises from less than 24 h to 3 days. CONCLUSIONS: Our data suggest that the funding restrictions introduced in 2011 were followed by a statistically significant and unintended increase in emergency hernia repairs in our trust, with associated increased risks to patient safety. PMID- 26597874 TI - Use of double-layer autologous dermal flap in the treatment of recurrent and/or infected incisional hernias: presentation of the surgical technique and the results of 1-year follow-up-a prospective, consecutive cohort study. AB - INTRODUCTION: The difficulties of treating recurrent and/or infected incisional hernias are well known in surgical practice. Several surgical techniques and various types of grafts are available for surgeons. This study presents a new surgical technique option together with the results of the 1-year follow-up. PURPOSE: The primary aim of the study is to present the surgical technique of the procedure suitable for the treatment of recurrent and/or infected incisional hernias. The secondary aim is to determine the recurrence rate and analyse the surgical complications. The tertiary aim is to present the quality of life test results performed 3, 6 and 12 months after the surgery. PATIENTS AND METHOD: The authors evaluated the results of 36 recurrent and/or infected incisional hernia surgeries (11 men, average age 60.6 years; 25 women, average age 58.9 years) performed with their own surgical method in the framework of a tightly controlled, prospective, interventional and observational consecutive cohort study conducted between 1 January 2011 and 31 December 2013 at a university surgical department. The study evaluates the results of the 1-year follow-up period. All 36 patients had at least one recurrence of abdominal wall hernia; 12 of them also had concurrent infection of the synthetic graft and a complicating fistula. The mean BMI was 31.82 kg/m(2) (25.2-43.5 kg/m(2)). The average size of the abdominal wall defect was 145.9 cm(2) (59-275 cm(2)). The abdominal wall reconstruction was performed using an autologous, double-layer dermal flap. The grafts, which had been inserted during previous surgeries, were removed completely. The autologous dermal tissue was prepared using the flap harvested during dermolipectomy. The reconstruction was achieved using a tension-free technique. The essence of the abdominal wall reconstruction is the completion of the abdominal wall defect by a double-layer autologous dermal flap. The original abdominal wall defect was not closed by direct sutures. The quality of the prepared dermal flap was histologically evaluated. IAPMS (intra-abdominal pressure monitoring set) was applied to verify intra-abdominal pressure in the post-operative period. The result of the surgeries was assessed using a quality of life questionnaire. RESULTS: No recurrence of the abdominal wall hernia was registered during the 1-year follow-up period. Abdominal bulking was observed in case of three patients (8.3 %). Wound infection occurred in one patient (2.77 %) and skin dehiscence in two patients (5.55 %). Haematoma was registered in case of one patient (2.77 %) on the fifth post-operative day. Seroma formation occurred in case of eight patients (22.22 %), which required percutaneous tapping. A fistula formation was observed in one patient (2.77 %) 45 days after the surgery. The intra-abdominal pressure remained moderately elevated during the early post operative period (9.65-5.76 mmHg on post-operative days 1 and 5). Reoperation was performed in one case due to haematoma. No fatality occurred. CONCLUSIONS: The 1 year recurrence rate in case of the abdominal wall reconstruction using double layer autologous dermal flap is favourable. Being compliant with the surgical technique developed, the procedure is safe to perform. The number of surgical site infections and fistula formations is low. Based on the questionnaires evaluated, all patients would choose this method instead of the previous reconstruction(s). The method is cost-effective. Based on the results, this procedure is feasible for the treatment of recurrent and/or infected abdominal wall, incisional ventral hernias in obese "high risk" patients. PMID- 26597875 TI - Building a resident research program in emergency medicine. AB - Residency training programs requirements state, "Residents should participate in scholarly activity." However, there is little consensus regarding how best to achieve these requirements. The objective of this study is to implement a resident research program that emphasizes resident participation in quantitative or qualitative empirical work. A three-step program "Think, Do, Write" roughly follows the 3 years of the residency. During the first phase, the resident chooses a topic, formulates a hypothesis, and completes standard research certifications. Phase 2 involves obtaining Institutional Review Board approval, and conducting the study. The final phase entails analyzing and interpreting the data, and writing an abstract to present during an annual research day. Residents are encouraged to submit their projects for presentation at scientific conferences and for publication. Multiple departmental resources are available, including a Resident Research Fund, and full support of the faculty. Prior to the new program, most scholarly activity consisted of case reports, book chapters, review articles, or other miscellaneous projects; only 27 % represented empirical studies. Starting in 2012, the new program was fully implemented, resulting in notable growth in original empirical works among residents. Currently there is almost 100 % participation in studies, and numerous residents have presented at national conferences, and have peer-reviewed publications. With a comprehensive and supported program in place, emergency medicine residents proved capable of conducting high-quality empirical research within their relatively limited time. Overall, residents developed valuable skills in research design and statistical analysis, and greatly increased their productivity as academic and clinical researchers. PMID- 26597876 TI - Renal function is impaired in normotensive chronic HCV patients: role of insulin resistance. AB - Renal dysfunction is an independent predictor for cardiovascular morbidity and mortality. We investigated whether chronic hepatitis C virus (HCV) infection and the related insulin resistance/hyperinsulinemia influence renal function in comparison with a group of healthy subjects and with another group with metabolic syndrome. We enrolled 130 newly diagnosed HCV outpatients matched for age and gender with 130 patients with metabolic syndrome and 130 healthy subjects. Renal function was evaluated by calculation of glomerular filtration rate (e-GFR, mL/min/1.73 m(2)) using the CKD-EPI equation. The following laboratory parameters were measured: fasting plasma glucose and insulin, total, LDL- and HDL cholesterol, triglyceride, creatinine, and HOMA to evaluate insulin sensitivity. HCV patients with respect to both healthy subjects and metabolic syndrome patients have a decreased e-GFR: 86.6 +/- 16.1 vs 120.2 +/- 23.1 mL/min/1.73 m(2) (P < 0.0001) and 94.9 +/- 22.6 mL/min/1.73 m(2) (P = 0.003), respectively. Regarding biochemical variables, HCV patients, in comparison with healthy subjects, have a higher triglyceride level, creatinine, fasting insulin and HOMA (3.4 +/- 1.4 vs 2.6 +/- 1.3; P < 0.0001). At linear regression analysis, the correlation between e-GFR and HOMA is similar in the metabolic syndrome (r = 0.555, P < 0.0001) and HCV (r = -0.527, P < 0.0001) groups. At multiple regression analysis, HOMA is the major determinant of e-GFR in both groups, accounting for, respectively, 30.8 and 27.8 % of its variation in the metabolic syndrome and HCV. In conclusion, we demonstrate that HCV patients have a significant reduction of e-GFR and that insulin resistance is the major predictor of renal dysfunction. PMID- 26597877 TI - Early computed tomography in victims of non-traumatic out-of-hospital cardiac arrest. AB - Although early cranial and thoracic computed tomography (CT) is recommended in the early in-hospital treatment of victims of out-of-hospital cardiac arrest (OHCA), hardly anything is known regarding the proportions of therapy-relevant findings with this method. Victims of OHCA who were admitted to our hospital between January 1, 2008 and December 31, 2014 were studied. CT was classified as early if performed within the first 4 h following hospital admission. There were 32 (12.7 %) cranial, 31 (12.3 %) thoracic and 15 (6.0 %) abdominal CT. The major findings and associated number of patients were: intracranial bleeding in two patients (0.8 %), acute cerebral ischemia in two (0.8 %), cerebral oedema in four (1.6 %), pulmonary emboli in three (1.2 %), hemothorax in two (0.8 %), tracheal rupture in one (0.4 %), pneumonia in 11 (4.4 %), paralytic ileus in one (0.4 %), ascites in three (1.2 %), pneumoperitoneum in one (0.4 %), acute cholecystitis in two (0.8 %), mesenteric vascular occlusion in one (0.4 %) and ruptured abdominal aortic aneurysm in one (0.4 %). In victims of OHCA, early diagnostic CT provides therapy-relevant findings in a high proportion (42.3 %) of patients examined. PMID- 26597878 TI - Pharmacological basis of the use of the root bark of Zizyphus nummularia Aubrev. (Rhamnaceae) as anti-inflammatory agent. AB - BACKGROUND: The root bark of Zizyphus nummularia (Rhamnaceae) is traditionally used as an anti-inflammatory agent. The current study aimed to explore the anti inflammatory activity (in vivo) of a crude ethanolic extract (EE) and the pure identified octadecahydro-picene-2,3,14,15-tetranone (IC) in the root bark of Z. nummularia. IC was further subjected to suitable in vitro and in silico studies to find out the mechanistic pharmacology. METHODS: EE (100 and 200 mg/kg, p.o.) and (IC) (400 and 600 MUg/kg, p.o.) were subjected to in vivo anti-inflammatory assays to evaluate the anti-inflammatory activity and predict the probable mechanism(s) of action. Suitable acute (carrageenan-induced paw edema, arachidonic acid-induced ear edema, xylene-induced ear edema) and chronic (cotton pellet granuloma) models were employed to investigate in vivo the anti inflammatory activity. Based on in vivo observation, IC was further subjected to in vitro assays to estimate the inhibition of nitric oxide (NO), prostaglandin-E2 (PGE-2) and tumor necrosis factor-alpha (TNF-alpha) production in PBS stimulated RAW 264.7 cells. Based on the observation of in vitro studies, finally, ADME prediction and molecular docking studies of IC were performed for better understanding of interaction of IC with TNF-alpha. RESULTS: Oral administration of EE (100 and 200 mg/kg) exhibited significant inhibition of carrageenan (p < 0.05) and arachidonic acid (p < 0.05) induced oedema, and the reduced the granuloma tissue formation (p < 0.05) in experimental mice. IC (400 and 600 MUg/kg, p.o.) exhibited significant (p < 0.01) inhibition of carrageenan, xylene and arachidonic acid-induced edema, and reduced the granuloma tissue formation. In in vitro assays, IC caused a concentration-dependent inhibition of LPS stimulated NO (up to ~ 67.4% at 50 MUM) and TNF-alpha (~84.5% at 50 MUM) production. However, the PGE-2 inhibition did not follow dose dependent pattern. Based on in vitro observations, the molecular docking has been performed on the basis of interaction with TNF-alpha. In in silico studies, it was observed that IC showed hydrogen bonding with GLN 47 amino acid residue of TNF-alpha protein. CONCLUSIONS: IC possibly produces anti-inflammatory activity through inhibition of TNF-alpha and NO production. PMID- 26597879 TI - The effects of spiritual intervention and changes in dopamine receptor gene expression in breast cancer patients. AB - Breast cancer is the most common cancer in females in Iran and in most of the developed countries. Studies have shown that having chronic stress in individuals predisposes several types of cancer including breast cancer. Research results showed that spiritual factors correlate with indices of physical consequences such as heart disease, cancer, and death, so do psychiatric conditions and changes in receptor gene expression in depression, anxiety, and social dysfunction. Different studies demonstrated the role of neurotransmitters in occurrence and progression of cancers. They affected cells by their various types of receptors. An effective gene in mental and physical conditions is Dopamine receptor. Accordingly, the study was conducted to evaluate effects of psychotherapy (spiritual intervention) on changes in Dopamine receptor gene expressions in breast cancer patients. 90 female volunteers, including 30 healthy individuals and 60 diagnosed with breast cancer, considering exclusion criteria, were selected for the purpose of the study. The breast cancer patients were further categorized into experimental and control groups of 30 each. Blood samples were collected both prior to and following the spiritual intervention to analyze changes in their dopamine gene receptor expressions. We observed that DRD2-DRD4 in the control group (breast cancer patients) PBMC increased compared to healthy individuals. Also, DRD2-DRD4 in intervention group PBMC decreased compared to the control group and to even lower than those of healthy individuals. The findings were of great significance in management and treatment of cancer because they revealed the possibility of using alternative treatments (e.g., spiritual interventions) apart from conventional medical treatments. PMID- 26597880 TI - Dipeptidyl Peptidase 4 Distribution in the Human Respiratory Tract: Implications for the Middle East Respiratory Syndrome. AB - Dipeptidyl peptidase 4 (DPP4, CD26), a type II transmembrane ectopeptidase, is the receptor for the Middle Eastern respiratory syndrome coronavirus (MERS-CoV). MERS emerged in 2012 and has a high mortality associated with severe lung disease. A lack of autopsy studies from MERS fatalities has hindered understanding of MERS-CoV pathogenesis. We investigated the spatial and cellular localization of DPP4 to evaluate an association MERS clinical disease. DPP4 was rarely detected in the surface epithelium from nasal cavity to conducting airways with a slightly increased incidence in distal airways. DPP4 was also found in a subset of mononuclear leukocytes and in serous cells of submucosal glands. In the parenchyma, DPP4 was found principally in type I and II cells and alveolar macrophages and was also detected in vascular endothelium (eg, lymphatics) and pleural mesothelia. Patients with chronic lung disease, such as chronic obstructive pulmonary disease and cystic fibrosis, exhibited increased DPP4 immunostaining in alveolar epithelia (type I and II cells) and alveolar macrophages with similar trends in reactive mesothelia. This finding suggests that preexisting pulmonary disease could increase MERS-CoV receptor abundance and predispose individuals to MERS morbidity and mortality, which is consistent with current clinical observations. We speculate that the preferential spatial localization of DPP4 in alveolar regions may explain why MERS is characterized by lower respiratory tract disease. PMID- 26597882 TI - Platelets Regulate the Migration of Keratinocytes via Podoplanin/CLEC-2 Signaling during Cutaneous Wound Healing in Mice. AB - Podoplanin is an endogenous ligand for C-type lectin-like receptor 2 (CLEC-2), which is expressed on platelets. Recent evidence indicates that this specific marker of lymphatic endothelial cells is also expressed by keratinocytes at the edge of wounds. However, whether podoplanin or platelets play a role in keratinocyte activity during wound healing remains unknown. We evaluated the effect of podoplanin expression levels on keratinocyte motility using cultured primary normal human epidermal keratinocytes (NHEKs). Down-regulation of podoplanin in NHEKs via transfection with podoplanin siRNA inhibited their migration, indicating that podoplanin plays a mandatory role in this process. In addition, down-regulation of podoplanin was correlated with up-regulation of E cadherin, suggesting that podoplanin-mediated stimulation of keratinocyte migration is associated with a loss of E-cadherin. Both the addition of platelets and treatment with CLEC-2 inhibited the migration of NHEKs. The down-regulation of RhoA activity and the up-regulation of E-cadherin in keratinocytes were also induced by CLEC-2. In conclusion, these results suggest that podoplanin/CLEC-2 signaling regulates keratinocyte migration via modulating E-cadherin expression through RhoA signaling. Altering the regulation of keratinocyte migration by podoplanin might be a novel therapeutic approach to improve wound healing. PMID- 26597883 TI - Sex-Specific Differences in an ApoE(-/-):Ins2(+/Akita) Mouse Model of Accelerated Atherosclerosis. AB - Diabetic patients have a twofold to fourfold increased risk of cardiovascular disease. Despite a vast amount of research, the underlying mechanisms that predispose individuals with diabetes to the development of cardiovascular disease are unclear. To further our understanding of how diabetes promotes atherosclerosis, we have established, characterized, and manipulated a new model of hyperglycemia-induced atherosclerosis: the apolipoprotein E-deficient (ApoE(-/ )):Ins2(+/Akita) mouse. All mice were fed a standard chow diet. Male ApoE(-/ ):Ins2(+/Akita) mice developed chronic hyperglycemia, which significantly accelerated atherosclerosis. Female ApoE(-/-):Ins2(+/Akita) mice presented hyperglycemia that normalized by 15 weeks of age. Despite the transient hyperglycemia, advanced atherosclerosis was observed at 15 weeks of age compared with ApoE(-/-) females. To better understand these differences, subsets of mice were castrated or ovariectomized at 5 weeks of age. Castrated ApoE(-/ ):Ins2(+/Akita) mice showed a reduction in blood glucose levels that correlated with the amelioration of atherosclerosis. Interestingly, castrated normoglycemic ApoE(-/-) mice developed larger atherosclerotic lesions than sham-operated on controls. Ovariectomized ApoE(-/-):Ins2(+/Akita) mice presented chronic hyperglycemia, and atherosclerosis appeared to be advanced. We have characterized the distinctive sex-specific phenotypes exhibited by the ApoE(-/-):Ins2(+/Akita) mouse model and present evidence for the action of sex hormones on pancreatic beta-cell function and the vasculature that affect the regulation of blood glucose levels and the development of atherosclerosis. This model will provide a test bed to further delineate these effects. PMID- 26597881 TI - Inhibition of Mast Cell-Derived Histamine Decreases Human Cholangiocarcinoma Growth and Differentiation via c-Kit/Stem Cell Factor-Dependent Signaling. AB - The tumor microenvironment of cholangiocarcinoma (CCA) is composed of numerous cells, including mast cells (MCs). MCs release histamine, which increases CCA progression and angiogenesis. Cholangiocytes secrete stem cell factor, which functions via the MC growth factor receptor c-Kit. Here, we show that cholangiocytes express histidine decarboxylase and its inhibition reduces CCA growth. MC recruitment in the tumor microenvironment increased CCA growth. MC infiltration and MC markers were detected by toluidine blue staining and real time PCR in human biopsies and in tumors from athymic mice treated with saline, histamine, histidine decarboxylase inhibitor, or cromolyn sodium. Tumor growth, angiogenesis, and epithelial-mesenchymal transition (EMT)/extracellular matrix (ECM) markers were measured in mice treated with cromolyn sodium. In vitro, human CCA cells were treated with MC supernatant fluids before evaluating angiogenesis and EMT/ECM expression. Migration assays were performed with CCA cells treated with the stem cell factor inhibitor. MC supernatant fluids increased CCA histidine decarboxylase, vascular endothelial growth factor, and MC/EMT/ECM expression that decreased with pretreatment of cromolyn sodium. MCs were found in human biopsies. In mice treated with cromolyn sodium, MC infiltration and tumor growth decreased. Inhibition of CCA stem cell factor blocked MC migration and MC/EMT/ECM in CCA. MCs migrate into CCA tumor microenvironment via c-Kit/stem cell factor and increase tumor progression, angiogenesis, EMT switch, and ECM degradation. PMID- 26597884 TI - S100A8 and S100A9 Are Induced by Decreased Hydration in the Epidermis and Promote Fibroblast Activation and Fibrosis in the Dermis. AB - The most critical function of the epidermis is to prevent water loss and maintain skin homeostasis. Disruption of the functional skin barrier causes delayed wound healing, hypertrophic scarring, and many skin diseases. Herein, we show that reduced hydration increases the expression of S100 protein family members, S100A8/S100A9, in stratified keratinocyte culture and human ex vivo skin culture. Immunohistological analyses show that S100A8/A9 are highly expressed in the epidermis of human hypertrophic scar and keloid tissues. Reduced hydration demonstrates activation of fibroblasts in the keratinocyte-fibroblast co-culture. In contrast, knockdown of S100A8 or S100A9 by RNA interference in keratinocytes failed to activate fibroblasts. Pretreatment with pharmacological blockers of S100A8/A9 receptors, Toll-like receptor 4 and receptor for advanced glycation end products, inhibits fibroblast activation induced by recombinant S100A8/A9 proteins. Moreover, we observe that local delivery of S100A8 protein results in a marked increase in hypertrophic scarring in the in vivo rabbit ear scar model. Our results indicate that hydration status promotes fibroblast activation and fibrosis by directly affecting the expression of inflammatory signaling in keratinocytes, thereby strongly suggesting S100A8/A9 to be novel targets in preventing scarring. PMID- 26597885 TI - Macrophage Polarization in IL-10 Treatment of Particle-Induced Inflammation and Osteolysis. AB - This study investigated the therapeutic influence and potential mechanism of IL 10 in ameliorating orthopedic debris particle-induced inflammation and osteolysis. A murine air pouch with bone implantation and polyethylene particles was also used to evaluate the therapeutic effects of IL-10. The data suggested that the particle challenges significantly promoted macrophage activation and osteoclastogenesis, with dramatically increased macrophage infiltration into the pouch membranes and elevated tartrate-resistant acid phosphatase-positive cell deposition. Immunohistochemical stains revealed a significantly higher ratio of induced nitric oxide synthase-expressing cells in the particle-challenged group; treatment with IL-10 resulted in marked switching to CD163(+) cells. Also, IL-10 effectively reduced tartrate-resistant acid phosphatase-positive stained cells in the pouch membranes, and minimized the bone mineral density loss compared with untreated samples. Real-time PCR and Western blot examination indicated that IL 10 treatment significantly diminished the particle-induced IL-1beta expression but promoted expression of CD163, transforming growth factor-beta1, and CCR2. Furthermore, IL-10 significantly inhibited the ultra-high-molecular-weight polyethylene particle-elevated phospho-STAT1 and phospho-NF-kappaB p65 productions, and promoted phospho-STAT3 expression. Overall, the data indicate the pivotal effects of IL-10 on macrophage polarization. The effects of IL-10 in ameliorating local inflammation and osteolysis may be associated with macrophage polarization through the up-regulation of the Janus activating kinase/STAT3 signaling pathway, and the down-regulation of NF-kappaB and Janus activating kinase/STAT1 expression. PMID- 26597886 TI - Corticotropin-Releasing Hormone Receptor 2 Signaling Promotes Mucosal Repair Responses after Colitis. AB - The corticotropin-releasing hormone family mediates functional responses in many organs, including the intestine. Activation of corticotropin-releasing hormone receptor 2 (CRHR2) in the colonic mucosa promotes inflammation during acute colitis but inhibits inflammation during chronic colitis. We hypothesized that specific modulation of CRHR2 signaling in the colonic mucosa can promote restoration of the epithelium through stimulation of cell proliferative, migratory, and wound healing responses. Mucosal repair was assessed after dextran sodium sulfate (DSS)-induced colitis in mice receiving intracolonic injections of a CRHR2 antagonist or vehicle and in Crhr2(-/-) mice. Histologic damage, cytokine expression, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling, and Ki-67 immunoreactivity were evaluated. Cell viability, proliferation, and migration were compared between parental and CRHR2 overexpressing colonic epithelial cells. Protein lysates were processed for phosphoprotein assays and a wound healing assay performed in vitro. Administration of a CRHR2 antagonist after DSS-induced colitis increased disease activity, delayed healing, and decreased epithelial cell proliferation in vivo. Colons from these mice also showed increased apoptosis and proinflammatory cytokine expression. Compared with controls, Crhr2(-/-) mice showed increased mortality in the DSS healing protocol. CRHR2-overexpressing cells had increased proliferation and migration compared with parental cells. Wound healing and signal transducer and activator of transcription 3 activity were elevated in CRHR2-overexpressing cells after urocortin 2 and IL-6 treatment, suggesting advanced healing progression. Our results suggest that selective CRHR2 activation may provide a targeted approach to enhance mucosal repair pathways after colitis. PMID- 26597887 TI - Association of familial macular degeneration with specific genetic markers: a case report. AB - INTRODUCTION: Age-related macular degeneration is a serious visual disorder of the central retina and was recently reported to be associated with genetic background. Here we describe a genetic link to early onset age-related macular degeneration in members of an Asian family. CASE PRESENTATION: A 73-year-old Asian woman developed age-related macular degeneration in the fifth decade of her life and her 49-year-old daughter developed age-related macular degeneration. Because of the family history and the early onset, family members were tested for two single nucleotide polymorphism variants (rs10490924 and rs11200638) at a recently identified susceptibility locus for age-related macular degeneration. Both alleles in the 73-year-old woman were of the high-risk variants (T/T for rs10490924 and A/A for rs11200638), and her two daughters and a grandson each carried the risk variants (T and A) one on each allele. CONCLUSIONS: In a case where multiple family members had early onset age-related macular degeneration, we found two high-risk single nucleotide polymorphism variants in the age-related macular degeneration susceptibility locus, suggesting the combination of the known single nucleotide polymorphism variants as a potent age-related macular degeneration diagnostic indicator. PMID- 26597888 TI - Visual working memory organization is subject to top-down control. AB - The limited capacity of visual working memory (VWM) can be maximized by combining multiple features into a single representation through grouping principles such as connection, proximity, and similarity. In this study, we sought to understand how VWM organizes information by investigating how connection and similarity cues are used either alone or in the presence of another grouping cue. Furthermore, we examined whether the use of one cue over another is within volitional control. Participants remembered displays of objects that contained no grouping cues, connection cues only, similarity cues only, or both connection and similarity cues. We found that it is possible to use either connection or similarity cues, although connection cues tend to dominate if the cues are in conflict with one another. However, it is possible to flexibly use either similarity or connection cues if both are present, depending on the task goals. PMID- 26597889 TI - The automaticity of perceiving animacy: Goal-directed motion in simple shapes influences visuomotor behavior even when task-irrelevant. AB - Visual processing recovers not only simple features, such as color and shape, but also seemingly higher-level properties, such as animacy. Indeed, even abstract geometric shapes are readily perceived as intentional agents when they move in certain ways, and such percepts can dramatically influence behavior. In the wolfpack effect, for example, subjects maneuver a disc around a display in order to avoid several randomly moving darts. When the darts point toward the disc, subjects (falsely) perceive that the darts are chasing them, and this impairs several types of visuomotor performance. Are such effects reflexive, automatic features of visual processing? Or might they instead arise only as contingent strategies in tasks in which subjects must interact with (and thus focus on the features of) such objects? We explored these questions in an especially direct way-by embedding such displays into the background of a completely independent "foraging" task. Subjects now moved their disc to collect small "food" dots (which appeared sequentially in random locations) as quickly as possible. The darts were task-irrelevant, and subjects were encouraged to ignore them. Nevertheless, foraging was impaired when the randomly moving darts pointed at the subjects' disc, as compared to control conditions in which they were either oriented orthogonally to the subjects' disc or pointed at another moving shape thereby controlling for nonsocial factors. The perception of animacy thus influences downstream visuomotor behavior in an automatic manner, such that subjects cannot completely override the influences of seemingly animate shapes even while attempting to ignore them. PMID- 26597890 TI - Understanding the contribution of target repetition and target expectation to the emergence of the prevalence effect in visual search. AB - Behavior in visual search tasks is influenced by the proportion of trials on which a target is presented (the target prevalence). Previous research has shown that when target prevalence is low (2 % prevalence), participants tend to miss targets, as compared with higher prevalence levels (e.g., 50 % prevalence). There is an ongoing debate regarding the relative contributions of target repetition and the expectation that a target will occur in the emergence of prevalence effects. In order to disentangle these two factors, we went beyond previous studies by directly manipulating participants' expectations regarding how likely a target was to appear on a given trial. This we achieved without using cues or feedback. Our results indicated that both target repetition and target expectation contribute to the emergence of the prevalence effect. PMID- 26597891 TI - The influence of contextual diversity on word learning. AB - In a series of analyses over mega datasets, Jones, Johns, and Recchia (Canadian Journal of Experimental Psychology, 66(2), 115-124, 2012) and Johns et al. (Journal of the Acoustical Society of America, 132:2, EL74-EL80, 2012) found that a measure of contextual diversity that takes into account the semantic variability of a word's contexts provided a better fit to both visual and spoken word recognition data than traditional measures, such as word frequency or raw context counts. This measure was empirically validated with an artificial language experiment (Jones et al.). The present study extends the empirical results with a unique natural language learning paradigm, which allows for an examination of the semantic representations that are acquired as semantic diversity is varied. Subjects were incidentally exposed to novel words as they rated short selections from articles, books, and newspapers. When novel words were encountered across distinct discourse contexts, subjects were both faster and more accurate at recognizing them than when they were seen in redundant contexts. However, learning across redundant contexts promoted the development of more stable semantic representations. These findings are predicted by a distributional learning model trained on the same materials as our subjects. PMID- 26597892 TI - Childhood contact predicts hemispheric asymmetry in cross-race face processing. AB - Participants typically process same-race faces more quickly and more accurately than cross-race faces. This deficit is amplified in the right hemisphere of the brain, presumably due to its involvement in configural processing. The present research tested the idea that cross-race contact tunes cognitive and perceptual systems, influencing this asymmetric race-based deficit in face processing. Participants with high and low levels of contact performed a lateralized recognition task with same- and cross-race faces. Replicating prior work, participants with minimal contact showed cross-race deficits in processing that were larger in the right hemisphere. For participants with more contact, this lateralized deficit disappeared. This effect of contact seems to be independent of race-based attitudes (e.g., prejudice). PMID- 26597894 TI - Nanoimaging: photophysical and pharmaceutical characterization of poly-lactide-co glycolide nanoparticles engineered with quantum dots. AB - Quantum dots (QDs) and polymeric nanoparticles (NPs) are considered good binomials for the development of multifunctional nanomedicines for multimodal imaging. Fluorescent imaging of QDs can monitor the behavior of QD-labeled NPs in both cells and animals with high temporal and spatial resolutions. The comprehension of polymer interaction with the metallic QD surface must be considered to achieve a complete chemicophysical characterization of these systems and to describe the QD optical properties to be used for their unequivocal identification in the tissue. In this study, by comparing two different synthetic procedures to obtain polymeric nanoparticles labeled with QDs, we investigated whether their optical properties may change according to the formulation methods, as a consequence of the different polymeric environments. Atomic force microscopy, transmission electron microscopy, confocal and fluorescence lifetime imaging microscopy characterization demonstrated that NPs modified with QDs after the formulation process (post-NPs-QDs) conserved the photophysical features of the QD probe. In contrast, by using a polymer modified with QDs to formulate NPs (pre-NPs-QDs), a significant quenching of QD fluorescence and a blueshift in its emission spectra were observed. Our results suggest that the packaging of QDs into the polymeric matrix causes a modification of the QD optical properties: these effects must be characterized in depth and carefully considered when developing nanosystems for imaging and biological applications. PMID- 26597893 TI - BML-111 Attenuates Renal Ischemia/Reperfusion Injury Via Peroxisome Proliferator Activated Receptor-alpha-Regulated Heme Oxygenase-1. AB - We examine whether BML-111, a lipoxin receptor agonist, inhibits renal ischemia/reperfusion (I/R) injury, and whether peroxisome proliferator-activated receptor-alpha (PPARalpha) or heme oxygenase-1 (HO-1) is involved in protective effects of BML-111 on kidney against I/R injury. Rats subjected to renal I/R injury were treated with or without BML-111. Renal histological and immunohistochemical studies were performed. Expressions of phosphorylated p38 mitogen-activated protein kinase (pp38 MAPK), phosphorylated PPARalpha (pPPARalpha), and HO-1 were assessed in NRK-52E cells exposed to BML-111. The binding activity of PPARalpha to peroxisome proliferator-responsive element (PPRE) on HO-1 promoter in the cells was determined. BML-111 treatment resulted in a marked reduction in the severity of histological features of renal I/R injury, and attenuated the rise in renal myeloperoxidase and malondialdehyde, blood urea nitrogen and creatinine, urinary N-acetyl-beta-glucosaminidase, and leucine aminopeptidase levels caused by I/R injury. BML-111 stimulated the renal expressions of pPPARalpha and HO-1, and cellular messenger RNA (mRNA) and protein expressions of pPPARalpha and HO-1 which were both blocked by GW6471, a selective PPARalpha antagonist, and ZnPP-IX, a specific inhibitor of HO-1 pretreatment. The pp38 MAPK inhibitor SB203580 blocked the BML-111-induced expressions of pp38 MAPK, pPPARalpha, and HO-1 in NRK-52E cells. The binding activity of PPARalpha to PPRE in nuclear extracts of NRK-52E cells was enhanced by treatment of the cells with BML-111, and was suppressed by GW6471 and SB203580. BML-111 protects the kidney against I/R injury via activation of p38 MAPK/PPARalpha/HO-1 pathway. PMID- 26597895 TI - The estrogen-dependent baroreflex dysfunction caused by nicotine in female rats is mediated via NOS/HO inhibition: Role of sGC/PI3K/MAPKERK. AB - We have previously reported that estrogen (E2) exacerbates the depressant effect of chronic nicotine on arterial baroreceptor activity in female rats. Here, we tested the hypothesis that this nicotine effect is modulated by nitric oxide synthase (NOS) and/or heme oxygenase (HO) and their downstream soluble guanylate cyclase (sGC)/phosphatidylinositol 3-kinase (PI3K)/mitogen-activated protein kinases (MAPKs) signaling. We investigated the effects of (i) inhibition or facilitation of NOS or HO on the interaction of nicotine (2mg/kg/day i.p., 2 weeks) with reflex bradycardic responses to phenylephrine in ovariectomized (OVX) rats treated with E2 or vehicle, and (ii) central pharmacologic inhibition of sGC, PI3K, or MAPKs on the interaction. The data showed that the attenuation by nicotine of reflex bradycardia in OVXE2 rats was abolished after treatment with hemin (HO inducer) or l-arginine (NOS substrate). The hemin or l-arginine effect disappeared after inhibition of NOS (Nomega-Nitro-l-arginine methyl ester hydrochloride, L-NAME) and HO (zinc protoporphyrin IX, ZnPP), respectively, denoting the interaction between the two enzymatic pathways. E2-receptor blockade (ICI 182,780) reduced baroreflexes in OVXE2 rats but had no effect on baroreflex improvement induced by hemin or l-arginine. Moreover, baroreflex enhancement by hemin was eliminated following intracisternal (i.c.) administration of wortmannin, ODQ, or PD98059 (inhibitors of PI3K, sGC, and extracellular signal regulated kinases, MAPKERK, respectively). In contrast, the hemin effect was preserved after inhibition of MAPKp38 (SB203580) or MAPKJNK (SP600125). Overall, NOS/HO interruption underlies baroreflex dysfunction caused by nicotine in female rats and the facilitation of NOS/HO-coupled sGC/PI3K/MAPKERK signaling might rectify the nicotine effect. PMID- 26597896 TI - Highlight report: Translocation of nanoparticles through barriers. PMID- 26597897 TI - Highlight report: reporter cell lines for prediction of skin sensitization. PMID- 26597898 TI - Highlight report: metabolism and toxicity by fumonisins. PMID- 26597899 TI - Highlight report: epoxide hydrolases-protection from reactive compounds and risk of cardiovascular disease. PMID- 26597901 TI - Effects of passive leg raising and volume expansion on mean systemic pressure and venous return in shock in humans. AB - INTRODUCTION: The aim of this study was to assess how mean systemic pressure (Psm) and resistance to venous return (Rvr) behave during passive leg raising (PLR) in cases of fluid responsiveness and fluid unresponsiveness. METHOD: In 30 patients with an acute circulatory failure, in order to estimate the venous return curve, we constructed the regression line between pairs of cardiac index (CI) and central venous pressure (CVP). Values were measured during end inspiratory and end-expiratory ventilatory occlusions performed at two levels of positive end-expiratory pressure. The x-axis intercept was used to estimate Psm and the inverse of the slope to quantify Rvr. These measurements were obtained at baseline, during PLR and after fluid infusion. Patients in whom fluid infusion increased CI by more than 15 % were defined as "fluid-responders". RESULTS: In fluid-responders (n = 15), CVP and Psm significantly increased (from 7 +/- 3 to 9 +/- 4 mmHg and from 25 +/- 13 to 31 +/- 13 mmHg, respectively) during PLR. The Psm-CVP gradient significantly increased by 20 +/- 30 % while Rvr did not change significantly during PLR. In fluid-nonresponders, CVP and Psm increased significantly but the Psm-CVP gradient did not change significantly during PLR. PLR did not change the intra-abdominal pressure in the whole population (14 +/- 6 mmHg before vs. 13 +/- 5 mmHg during PLR, p = 0.26) and in patients with intra abdominal hypertension at baseline (17 +/- 4 mmHg before vs. 16 +/- 4 mmHg during PLR, p = 0.14). In the latter group, PLR increased Psm from 22 +/- 11 to 27 +/- 10 mmHg (p <0.01) and did not change Rvr (5.1 +/- 2.6 to 5.2 +/- 3 mmHg/min/m(2)/mL, p = 0.71). In fluid-responders, Psm, CVP and the Psm-CVP gradient significantly increased during fluid infusion while the Rvr did not change. In fluid-nonresponders, CVP and Psm increased significantly during fluid infusion while the Psm-CVP gradient and Rvr did not change. CONCLUSION: PLR significantly increased Psm without modifying Rvr. This was also the case in patients with intra-abdominal hypertension. In case of fluid responsiveness, PLR increased venous return by increasing Psm to a larger extent than CVP. In patients with fluid unresponsiveness, PLR increased Psm but did not change the Psm-CVP gradient. Fluid infusion induced similar effects on Psm and Rvr. PMID- 26597903 TI - Study of the Edge-on Self-Assembly of Axially Substituted Silicon(IV) Phthalocyanine Derivatives in a Template on the HOPG Surface. AB - Molecular conformation is an important issue related to the self-assembly architecture and property. The self-assembly of silicon(IV) phthalocyanines covalently linked to the 5-N-cytidine or 4-carboxyphenoxy moiety at the axial positions, namely, SiPc(NC)2 and SiPc(CP)2, respectively, has been studied by means of scanning tunneling microscopy (STM) at the solid-liquid interface. The intermolecular axial hydrogen bonding in combination with the stabilizing role of the TCDB template brings about supramolecular self-assembled structures of silicon(IV) phthalocyanines in an edge-on orientation. Two pyridine compounds, 4,4'-bipyridine (BPY) and 1,2-di(4-pyridyl)ethylene (DPE), can tune the supramolecular structure, leading to interestingly axial self-assemblies of SiPc(CP)2 with BPY and DPE in an edge-on manner by hydrogen bonding. The results indicate that the axial substituents and the axial ligands can regulate and precisely control the conformation and arrangement of the phthalocyanine moiety on the graphite surface. PMID- 26597902 TI - Improving confidence and competence of healthcare professionals in end-of-life care: an evaluation of the 'Transforming End of Life Care' course at an acute hospital trust. AB - BACKGROUND: UK policymakers, clinicians and public wish to see improvements in end-of-life care (EoLC). However, healthcare professionals' skills and knowledge to deliver high-quality care are often lacking. Since May 2012, palliative care staff in an inner-city tertiary hospital have run a 2-day Transforming End of Life Care (TEoLC) course to improve EoLC confidence, and competence among hospital and community staff. AIM: To evaluate course participants' self-rated confidence, competence and knowledge of EoLC topics. EVALUATION DESIGN: A before and-after design using self-completion questionnaires, precourse and postcourse. 14 self-assessment questions examined confidence, understanding and knowledge of EoLC topics. Mean change scores and paired t tests were calculated and free-text responses analysed thematically. PARTICIPANTS: 236 staff members completed the course between May 2012 and April 2014. 42% worked in hospitals and 55% in the community; the most frequent staff roles were qualified nurses (49%), senior nurses (16%) and general practitioners (15%). RESULTS: All 14 self-assessment topics improved significantly (p<0.001); most improved was 'understanding and implementing Fast Track discharge'. Qualitative data showed increased knowledge and confidence in EoLC, particularly in communication, commitment to team work and holistic care. Overall, 217 (92%) participants would recommend the course and 215 (98%) indicated it would influence their practice. CONCLUSIONS: The TEoLC course improved participants' self-rated confidence, competence and knowledge in EoLC. Findings have utility beyond the UK in light of the international policy recommendations to improve the palliative care skills of generalist healthcare providers. PMID- 26597904 TI - Fates of identified pioneer cells in the developing antennal nervous system of the grasshopper Schistocerca gregaria. AB - In the early embryonic grasshopper, two pairs of sibling cells near the apex of the antenna pioneer its dorsal and ventral nerve tracts to the brain. En route, the growth cones of these pioneers contact a so-called base pioneer associated with each tract and which acts as a guidepost cell. Both apical and basal pioneers express stereotypic molecular labels allowing them to be uniquely identified. Although their developmental origins are largely understood, the fates of the respective pioneers remain unclear. We therefore employed the established cell death markers acridine orange and TUNEL to determine whether the apical and basal pioneers undergo apoptosis during embryogenesis. Our data reveal that the apical pioneers maintain a consistent molecular profile from their birth up to mid-embryogenesis, at which point the initial antennal nerve tracts to the brain have been established. Shortly after this the apical pioneers undergo apoptosis. Death occurs at a developmental stage similar to that reported elsewhere for pioneers in a leg - an homologous appendage. Base pioneers, by contrast, progressively change their molecular profile and can no longer be unequivocally identified after mid-embryogenesis. At no stage up to then do they exhibit death labels. If they persist, the base pioneers must be assumed to adopt a new role in the developing antennal nervous system. PMID- 26597905 TI - The Current State of U.S. Geropsychiatric Graduate Nursing Education: Results of the National Geropsychiatric Graduate Nursing Education Survey. AB - Advanced Practice Registered Nurses (APRNs) must be prepared to care for the rapidly increasing numbers of older adults with mental health needs. All 363 graduate nursing programs in the United States were surveyed regarding the nature and extent of geropsychiatric nursing (GPN) content across program curricula and their perceptions of the influence that the APRN Consensus Model has exerted on preparing the next generation of APRNs to meet the growing needs of the older adult population. Of the 202 schools responding, 138 reported GPN content in one or more clinical programs, with the majority of content in non-PMHNP programs. Only 17 schools reported offering a GPN program, track, or minor. The majority of schools (n = 169) perceived that they were adequately well-prepared to meet the APRN Consensus Model's guidelines regarding inclusion of aging-related didactic and clinical educational experiences in all APRN education programs; nearly two thirds (n = 132) perceived a moderate to significant influence of the Consensus Model on institutional infusion of GPN into curricula. Compared with a similar survey 10 years ago, there was little change in the proportion of schools reporting GPN in clinical programs and few schools provide GPN programs, tracks, or minors. Implications for nursing education and practice are discussed. PMID- 26597906 TI - A Telehealth Case Study: The Use of Telepresence Robot for Delivering Integrated Clinical Care. PMID- 26597907 TI - How Patients and Nurses Experience an Open Versus an Enclosed Nursing Station on an Inpatient Psychiatric Unit. AB - The inpatient environment is a critical space for nurses and patients in psychiatric settings. In this article, we describe nurses' and patients' perceptions of the inpatient environment both before the removal of a Plexiglas enclosure around a nurses' station and after its removal. Nurses had mixed feelings about the enclosure, reporting that it provided for confidentiality and a concentrated work space but also acknowledged the challenge of the barrier for communication with their patients. Patients unanimously preferred the nurses' station without the barrier, reporting increased feelings of freedom, safety, and connection with the nurses after its removal. It is important to consider the implications of environmental decisions in inpatient settings in order to promote a healthy workplace and healing environment for all community members. PMID- 26597908 TI - Salvia miltiorrhiza extract protects white matter and the hippocampus from damage induced by chronic cerebral hypoperfusion in rats. AB - BACKGROUND: Salvia miltiorrhiza (SM), an herbal plant, is traditionally used in the treatment of cardiovascular and cerebrovascular diseases in Asian countries. SM has multiple biological effects including anti-inflammatory activity. The present study is aimed at investigating the effects of SM extract in rats with chronic cerebral hypoperfusion. METHODS: Chronic cerebral hypoperfusion was induced in male Wistar rats by permanent bilateral common carotid artery occlusion (BCCAo). The rats were divided into 3 groups: sham-control, BCCAo treated with vehicle, and BCCAo treated with SM extract. Vehicle or SM extract (200 mg/kg) were administered daily by oral gavage beginning on day 21 after BCCAo and continuing to day 42. Immunohistochemical analyses were used to measure Iba-1-positive microglia and myelin basic protein (MBP) in white matter and hippocampal tissue. In addition, the expression levels of proinflammatory cytokines, including TNF-alpha, IL-1beta, and IL-6, and the toll-like receptor (TLR) pathway in the hippocampus, were analyzed by western blot. RESULTS: Administration of SM extract attenuated the activation of microglial cells in the white matter and hippocampus after BCCAo. SM extract also prevented neuroinflammation after BCCAo by reducing hippocampal levels of TNF-alpha, IL 1beta, and IL-6, and increasing the reduced levels of MBP in the white matter and hippocampus. Further, the administration of SM extract alleviated the up regulation of hippocampal TLR4 and myeloid differentiation primary response gene 88 (MyD88) in rats with chronic BCCAo. CONCLUSIONS: Our findings suggest that SM may be a promising therapeutic candidate in vascular dementia because of its protective effects against damage to the white matter and hippocampus after BCCAo. PMID- 26597909 TI - Nanochelating based nanocomplex, GFc7, improves quality and quantity of human mesenchymal stem cells during in vitro expansion. AB - INTRODUCTION: Human mesenchymal stem cells (hMSCs) have been approved for therapeutic applications. Despite the advances in this field, in vitro approaches are still required to improve the essential indices that would pave the way to a bright horizon for an efficient transplantation in the future. Nanotechnology could help to improve these approaches. Studies signified the important role of iron in stem cell metabolism and efficiency of copper chelation application for stem cell expansion METHODS: For the first time, based on novel Nanochelating technology, we design an iron containing copper chelator nano complex, GFc7 and examined on hMSCs during in vitro expansion. In this study, the hMSCs were isolated, characterized and expanded in vitro in two media (with or without GFc7). Then proliferation, cell viability, cell cycle analysis, surface markers, HLADR, pluripotency genes expression, homing and antioxidative defense at genes and protein expression were investigated. Also we analyzed the spontaneous differentiation and examined osteogenic and lipogenic differentiation. RESULTS: GFc7 affected the expression of key genes, improving both the stemness and fitness of the cells in a precise and balanced manner. We observed significant increases in cell proliferation, enhanced expression of pluripotency genes and homing markers, improved antioxidative defense, repression of genes involved in spontaneous differentiation and exposing the hMSCs to differentiation medium indicated that pretreatment with GFc7 increased the quality and rate of differentiation. CONCLUSIONS: Thus, GFc7 appears to be a potential new supplement for cell culture medium for increasing the efficiency of transplantation. PMID- 26597910 TI - Synthesis and antitumor evaluation of novel sulfonylcycloureas derived from nitrogen mustard. AB - A new series of sulfonylcycloureas derivatives have been synthesized and evaluated in vitro for their antitumor activity against four cancer cell lines (A431, Jurkat, U266, and K562). These compounds were prepared by the condensation of several sulfonamides (2a-m) with ethyl bis(2-chloroethyl)carbamate (1a). The relative cytotoxicity of these new derivatives in comparison to chlorambucil is reported. PMID- 26597912 TI - Occupational exposure to noise in maxillofacial operating theatres: an initial prospective study. AB - Exposure to excessive noise could impair surgical performance and communication, and lead to long-term hearing loss, but it is only recently that studies on occupational exposure to noise in operating theatres have been published. The aim of this prospective study was to assess mean and peak levels of noise during maxillofacial operations. We found that both were comparable to those in other surgical specialties such as orthopaedics in which power tools are used. PMID- 26597914 TI - Quantification of phosphatidylethanol 16:0/18:1, 18:1/18:1, and 16:0/16:0 in venous blood and venous and capillary dried blood spots from patients in alcohol withdrawal and control volunteers. AB - Phosphatidylethanol species (PEths) are promising biomarkers of alcohol consumption. Here, we report on the set-up, validation, and application of a novel UHPLC-ESI-MS/MS method for the quantification of PEth 16:0/18:1, PEth 18:1/18:1, and PEth 16:0/16:0 in whole blood (30 MUL) and in venous (V, 30 MUL) or capillary (C, 3 punches (3 mm)) dried blood spots (DBS). The methods were linear from 10 (LLOQ) to 2000 ng/mL for PEth 16:0/18:1, from 10 (LLOQ) to 1940 ng/mL for PEth 18:1/18:1, and from 19 (LLOQ) to 3872 ng/mL for PEth 16:0/16:0. Extraction efficiencies were higher than 55% (RSD < 18%) and matrix effects compensated for by IS were between 77 and 125% (RSD < 10%). Accuracy, repeatability, and intermediate precision fulfilled acceptance criteria (bias and RSD below 13%). Validity of the procedure for determination of PEth 16:0/18:1 in blood was demonstrated by the successful participation in a proficiency test. The quantification of PEths in C-DBS was not significantly influenced by the hematocrit, punch localization, or spot volume. The stability of PEths in V-DBS stored at room temperature was demonstrated up to 6 months. The method was applied to authentic samples (whole blood, V-DBS, and C-DBS) from 50 inpatients in alcohol withdrawal and 50 control volunteers. Applying a cut-off value to detect inpatients at 221 ng/mL for PEth 16:0/18:1 provided no false positive results and a good sensitivity (86%). Comparison of quantitative results (Bland Altman plot, Passing-Bablok regression, and Wilcoxon signed rank test) revealed that V-DBS and C-DBS were valid alternatives to venous blood for the detection of alcohol consumption. PMID- 26597915 TI - Novel dual ligand co-functionalized fluorescent gold nanoclusters as a versatile probe for sensitive analysis of Hg(2+) and oxytetracycline. AB - In this work, we present a direct one-step strategy for rapidly preparing dual ligand co-functionalized fluorescent Au nanoclusters (NCs) by using threonine (Thr) and 11-mercaptoundecanoic acid (MUA) as assorted reductants and capping agents in aqueous solution at room temperature. Fluorescence spectra, high resolution transmission electron microscopy (HRTEM), X-ray photoelectron spectroscopy (XPS), dynamic light scattering (DLS), and infrared (IR) spectroscopy were performed to demonstrate the optical properties and chemical composition of the as-prepared AuNCs. They possess many attractive features such as near-infrared emission (lambdaem = 606 nm), a large Stoke's shift (>300 nm), high colloidal stability (pH, temperature, salt, and time stability), and water dispersibility. Subsequently, the as-prepared AuNCs were used as a versatile probe for "turn off" sensing of Hg(2+) based on aggregation-induced fluorescence quenching and for "turn-on" sensing of oxytetracycline (OTC). This assay provided good linearity ranging from 37.5 to 3750 nM for Hg(2+) and from 0.375 to 12.5 MUM for OTC, with detection limits of 8.6 nM and 0.15 MUM, respectively. Moreover, the practical application of this assay was further validated by detecting OTC in human serum samples. PMID- 26597916 TI - Comparison of copper and zinc in vitro bioaccessibility from cyanobacteria rich in proteins and a synthetic supplement containing gluconate complexes: LC-MS mapping of bioaccessible copper complexes. AB - An analytical procedure was proposed to estimate bioaccessibility of copper and zinc in Spirulina Pacifica tablets with respect to that of copper and zinc in gluconate complexes. Spirulina is the common name for diet supplements produced primarily from two species of cyanobacteria, namely Arthrospira platensis and Arthrospira maxima. Spirulina tablets are an excellent source of proteins, vitamins and minerals. To obtain information about the bioavailability of these elements, an in vitro bioaccessibility test was performed by application of a two step protocol which simulated the gastric (pepsin) and intestinal (pancreatin) digestion. The species obtained were investigated by size exclusion chromatography on a chromatograph coupled to a mass spectrometer with inductively coupled plasma (SEC-ICP-MS) and an on-capillary liquid chromatograph coupled to an electrospray mass spectrometer (MU-HPLC-ESI-MS). Both copper and zinc were found to be highly bioaccessible in Spirulina tablets (90-111%) and those containing gluconate complexes (103% for Cu and 62% for Zn). In Spirulina tablets, copper was found to form two types of complex: (1) polar ones with glycine and aspartic acid and (2) more hydrophobic ones containing amino acids with cyclic hydrocarbons (phenylalanine, histidine, proline and tyrosine). Zinc and copper were also proved to form complexes during the digestion process with products of pepsin digestion, but the stability of these complexes is lower than that of the complexes formed in Spirulina. The results proving the involvement of proteins in the enhancement of copper and zinc bioaccessibility will be useful for the design of new copper and zinc supplements. PMID- 26597917 TI - Intensive care at the end of life in patients dying due to non-cancer chronic diseases versus cancer: a nationwide study in Denmark. AB - INTRODUCTION: It is unknown to what extent use of palliative care and focus on proactive planning of end-of-life (EOL) care among cancer patients is also reflected by less use of intensive care. We aimed to examine the use of intensive care in the EOL in patients dying as a result of non-cancer diseases compared with patients dying due to cancer. METHODS: We conducted a nationwide follow-up study among 240,757 adults dying as a result of either non-cancer chronic disease or cancer in Denmark between 2005 and 2011. Using the Danish Intensive Care Database, we identified all admissions and treatments in intensive care units (ICU) during the patients' last 6 months before death. We used prevalence ratios (aPRs) adjusted for age, sex, comorbidity, marital status and residential region to compare the 6-month prevalence of ICU admissions as well as treatment with invasive mechanical ventilation (MV), non-invasive ventilation (NIV), renal replacement therapy (RRT) and inotropes and/or vasopressors. In addition, length of ICU stay and death during ICU admission were compared among non-cancer and cancer patients dying between 2009 and 2011. RESULTS: Overall 12.3 % of non cancer patients were admitted to an ICU within their last 6 months of life, compared with 8.7 % of cancer patients. The overall aPR for ICU admission was 2.11 [95 % confidence interval (CI) 1.98-2.24] for non-cancer patients compared with cancer patients and varied widely within the non-cancer patients (patients with dementia, aPR 0.19, 95 % CI 0.17-0.21; patients with chronic obstructive lung disease, aPR 3.19, 95 % CI 2.97-3.41). The overall aPRs for treatment among non-cancer patients compared with cancer patients were 1.40 (95 % CI 1.35-1.46) for MV, 1.62 (95 % CI 1.50-1.76) for NIV, 1.19 (95 % CI 1.07-1.31) for RRT and 1.05 (95 % CI 0.87-1.28) for inotropes and/or vasopressors. No difference in admission length was observed. Non-cancer patients had an increased risk of dying in an ICU (aPR 1.23, 95 % CI 0.99-1.54) compared with cancer patients. CONCLUSIONS: Overall, patients dying as a result of non-cancer diseases were twice as likely to be admitted to ICUs at the EOL as patients dying due to cancer. Further studies are warranted to explore whether this difference in use of intensive care reflects an unmet need of palliative care, poor communication about the EOL or lack of prognostic tools for terminally ill non-cancer patients. PMID- 26597918 TI - Distribution of ischemic infarction and stenosis of intra- and extracranial arteries in young Chinese patients with ischemic stroke. AB - BACKGROUND: The distribution of cerebral ischemic infarction and stenosis in ischemic stroke may vary with age-group, race and gender. This study was conducted to understand the risk factors and characteristics of cerebral infarction and stenosis of vessels in young Chinese patients with ischemic stroke. METHODS: This was a retrospective study, from January 2007 to July 2012, of 123 patients <=50 years diagnosed with acute ischemic stroke. Patient characteristics were compared according to sex (98 males and 25 females) and age group (51 patients were <=45 years and 72 patients were 46-50 years). Characteristics of acute ischemic infarction were studied by diffusion weighted imaging. Stenosis of intra- and extracranial arteries was diagnosed by duplex sonography, head magnetic resonance angiography (MRA) or cervical MRA. RESULTS: Common risk factors were hypertension (72.4 %), dyslipidemia (55.3 %), smoking (54.4 %) and diabetes (33.3 %). Lacunar Infarction was most common in our patients (41.5 %). Partial anterior circulation infarction was predominant in females (52.0 vs 32.7 %; P = 0.073) and posterior circulation infarction in males (19.8 vs 4 %; P = 0.073). Multiple brain infarctions were found in 38 patients (30.9 %). Small artery atherosclerosis was found in 54 patients (43.9 %), with higher prevalence in patients of the 46-50 years age-group. Intracranial stenosis was more common than extracranial stenosis, and middle cerebral artery stenosis was most prevalent (27.3 %). Stenosis in the anterior circulation was more frequent than in the posterior circulation (P < 0.001). CONCLUSIONS: In these young patients, hypertension, smoking, dyslipidemia and diabetes were common risk factors. Intracranial stenosis was most common. The middle cerebral artery was highly vulnerable. PMID- 26597919 TI - Maternal Plane of Nutrition During Late-Gestation and Weaning Age Alter Steer Calf Longissimus Muscle Adipogenic MicroRNA and Target Gene Expression. AB - The main objective was to evaluate if different planes of maternal nutrition during late gestation and weaning age alter microRNA (miRNA) and target gene expression in offspring longissimus muscle (LM). Early (EW) and normal weaned (NW) Angus * Simmental calves (n = 30) born to cows that were grazing endophyte infected tall fescue and red clover pastures with no supplement [low plane of nutrition (LPN)], or supplemented with 2.3 and 9.1 kg of dried distiller's grains with solubles and soy hulls [medium and high plane of nutrition (MPN, HPN), respectively] during the last 105 +/- 11 days of gestation were used. Biopsies of LM were harvested at 78 (early weaning), 187 (normal weaning) and 354 days of age. Results indicate a role of pro-adipogenic miRNA in the control of adipogenesis in LM of NW-MPN steers between 78 and 187 days of age through upregulation of (1) miR-103 which inhibits CAV1, a protein that destabilizes INSR and leads to insulin resistance; (2) miR-143 which inhibits DLK1, a protein that inhibits adipocyte differentiation; and (3) miR-21 which impairs TGFBR2-induced inhibition of adipocyte differentiation. Among the studied anti-adipogenic miRNA, cow plane of nutrition resulted in downregulation of miR-34a expression in MPN steers compared with HPN and LPN at 78 days of age. Data for miR-34a provided a potential sign of epigenetic regulation of LM in beef offspring due to the cow plane of nutrition during late gestation. PMID- 26597920 TI - The fate of triaged and rejected manuscripts. AB - In 2011, Nephrology Dialysis and Transplantation (NDT) established a more restrictive selection process for manuscripts submitted to the journal, reducing the acceptance rate from 25% (2008-2009) to currently about 12-15%. To achieve this goal, we decided to score the priority of manuscripts submitted to NDT and to reject more papers at triage than in the past. This new scoring system allows a rapid decision for the authors without external review. However, the risk of such a restrictive policy may be that the journal might fail to capture important studies that are eventually published in higher-ranked journals. To look into this problem, we analysed random samples of papers (~10%) rejected by NDT in 2012. Of the papers rejected at triage and those rejected after regular peer review, 59 and 61%, respectively, were accepted in other journals. A detailed analysis of these papers showed that only 4 out of 104 and 7 out of 93 of the triaged and rejected papers, respectively, were published in journals with an impact factor higher than that of NDT. Furthermore, for all these papers, independent assessors confirmed the evaluation made by the original reviewers. The number of citations of these papers was similar to that typically obtained by publications in the corresponding journals. Even though the analyses seem reassuring, previous observations made by leading journals warn that the risk of 'big misses', resulting from selective editorial policies, remains a real possibility. We will therefore continue to maintain a high degree of alertness and will periodically track the history of manuscripts rejected by NDT, particularly papers that are rejected at triage by our journal. PMID- 26597923 TI - Mantled howler monkey spatial foraging decisions reflect spatial and temporal knowledge of resource distributions. AB - An animal's ability to find and relocate food items is directly related to its survival and reproductive success. This study evaluates how mantled howler monkeys make spatial foraging decisions in the wild. Specifically, discrete choice models and agent-based simulations are used to test whether mantled howler monkeys on Barro Colorado Island, Panama, integrate spatial information in order to maximize new leaf flush and fruit gain while minimizing distance traveled. Several heuristic models of decision making are also tested as possible alternative strategies (movement to core home range areas instead of individual trees, travel along a sensory gradient, movement along arboreal pathway networks without a predetermined destination, straight-line travel in a randomly chosen direction, and random walks). Results indicate that although leaves are the single most abundant item in the mantled howler monkey diet, long-distance travel bouts target the areas with the highest concentrations of mature fruits. Observed travel patterns yielded larger estimated quantities of fruit in shorter distances traveled than all alternative foraging strategies. Thus, this study both provides novel information regarding how primates select travel paths and suggests that a highly folivorous primate integrates knowledge of spatiotemporal resource distributions in highly efficient foraging strategies. PMID- 26597921 TI - Acute kidney injury in critically ill patients with haematological malignancies: results of a multicentre cohort study from the Groupe de Recherche en Reanimation Respiratoire en Onco-Hematologie. AB - BACKGROUND: Cancer patients are at high risk for acute kidney injury (AKI), which is associated with high morbidity and mortality. We sought to appraise the incidence, risk factors, and outcome of AKI in a large multicentre cohort study of critically ill patients with haematological malignancies. METHODS: We used a retrospective analysis of a prospectively collected database. The study was carried out in 17 university or university-affiliated centres in France and Belgium between 2010 and 2012. AKI was defined according to the Acute Kidney Injury Network (AKIN) definition. RESULTS: Of the 1011 patients admitted into the intensive care unit (ICU) during the study period, 1009 were included in this study. According to the AKIN definition, 671 patients (66.5%) developed an AKI during their ICU stay, of which 258 patients (38.4%) were AKI stage 1, 75 patients (11.2%) AKI stage 2 and 338 patients (50.4%) AKI stage 3. After adjustment for confounders, main adverse risk factors of AKI were older age, severity [non-renal Sequential Organ Failure Assessment (SOFA)], history of hypertension, tumour lysis syndrome, exposure to nephrotoxic agents and myeloma. Hospital mortality was 44.3% in patients with AKI and 25.4% in patients without AKI (P < 0.0001). After adjustment for confounders, AKI was independently associated with hospital mortality [OR 1.65 (95% CI 1.19-2.29)]. Overall, 271 patients required renal replacement therapy (RRT), of whom 57.2% died during their hospital stay as compared with 31.2% (P < 0.0001) in those not requiring RRT. CONCLUSION: Two-thirds of critically ill patients with haematological malignancies developed AKI. Hospital mortality in this population of patients developing AKI or requiring RRT is close to that in general ICU population. PMID- 26597924 TI - Work-Family Conflict and Self-Rated Health: the Role of Gender and Educational Level. Baseline Data from the Brazilian Longitudinal Study of Adult Health (ELSA Brasil). AB - PURPOSE: This study examined gender differences in the association between work family conflict and self-rated health and evaluated the effect of educational attainment. METHOD: We used baseline data from ELSA-Brasil, a cohort study of civil servants from six Brazilian state capitals. Our samples included 12,017 active workers aged 34-72 years. Work-family conflict was measured by four indicators measuring effects of work on family, effects of family in work and lack of time for leisure and personal care. RESULTS: Women experienced more frequent work-family conflict, but in both genders, increased work-family conflict directly correlated with poorer self-rated health. Women's educational level interacted with three work-family conflict indicators. For time-based effects of work on family, highly educated women had higher odds of suboptimal self-rated health (OR = 1.54; 95 % CI = 1.19-1.99) than less educated women (OR = 1.14; 95 % CI = 0.92-1.42). For strain-based effects of work on family, women with higher and lower education levels had OR = 1.91 (95 % CI 1.48-2.47) and OR = 1.40 (95 % CI 1.12-1.75), respectively. For lack of time for leisure and personal care, women with higher and lower education levels had OR = 2.60 (95 % CI = 1.95 3.47) and OR = 1.11 (95 % CI = 0.90-1.38), respectively. CONCLUSION: Women's education level affects the relationship between work-family conflict and self rated health. The results may contribute to prevention activities. PMID- 26597926 TI - Renin-Angiotensin System Inhibitors and Kidney and Cardiovascular Outcomes in Patients With CKD: A Bayesian Network Meta-analysis of Randomized Clinical Trials. AB - BACKGROUND: There is much uncertainty regarding the relative effects of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) in populations with chronic kidney disease (CKD). STUDY DESIGN: Systematic review and Bayesian network meta-analysis. SETTING & POPULATION: Patients with CKD treated with renin-angiotensin system (RAS) inhibitors. SELECTION CRITERIA FOR STUDIES: Randomized trials in patients with CKD treated with RAS inhibitors. PREDICTOR: ACE inhibitors and ARBs compared to each other and to placebo and active controls. OUTCOME: Primary outcome was kidney failure; secondary outcomes were major cardiovascular events, all-cause death. RESULTS: 119 randomized controlled trials (n = 64,768) were included. ACE inhibitors and ARBs reduced the odds of kidney failure by 39% and 30% (ORs of 0.61 [95% credible interval, 0.47-0.79] and 0.70 [95% credible interval, 0.52-0.89]), respectively, compared to placebo, and by 35% and 25% (ORs of 0.65 [95% credible interval, 0.51 0.80] and 0.75 [95% credible interval, 0.54-0.97]), respectively, compared with other active controls, whereas other active controls did not show evidence of a significant effect on kidney failure. Both ACE inhibitors and ARBs produced odds reductions for major cardiovascular events (ORs of 0.82 [95% credible interval, 0.71-0.92] and 0.76 [95% credible interval, 0.62-0.89], respectively) versus placebo. Comparisons did not show significant effects on risk for cardiovascular death. ACE inhibitors but not ARBs significantly reduced the odds of all-cause death versus active controls (OR, 0.72; 95% credible interval, 0.53-0.92). Compared with ARBs, ACE inhibitors were consistently associated with higher probabilities of reducing kidney failure, cardiovascular death, or all-cause death. LIMITATIONS: Trials with RAS inhibitor therapy were included; trials with direct comparisons of other active controls with placebo were not included. CONCLUSIONS: Use of ACE inhibitors or ARBs in people with CKD reduces the risk for kidney failure and cardiovascular events. ACE inhibitors also reduced the risk for all-cause mortality and were possibly superior to ARBs for kidney failure, cardiovascular death, and all-cause mortality in patients with CKD, suggesting that they could be the first choice for treatment in this population. PMID- 26597927 TI - Blue emitting ZnO nanostructures grown through cellulose bio-templates. AB - This paper presents a green and cost-effective recipe for the synthesis of blue emitting ZnO nanoparticles (NPs) using cellulose bio-templates. Azadirachta indica (neem) leaf extract prepared in different solvents were used as biological templates to produce nanostructures of wurtzite ZnO with a particle size ~12-36 nm. A cellulose-driven capping mechanism is used to describe the morphology of ZnO NPs. The scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), Fourier transform infra-red (FTIR) and photoluminescence (PL) studies showed that solvents affect the growth process and the capping mechanism of bio-template severely. Structural changes in ZnO NPs were evident with variation in pH, dielectric constants (DC) and boiling points (BP) of solvents. Furthermore, an energy band model is proposed to explain the origin of the blue emission in the as-obtained ZnO NPs. PL excitation studies and the theoretical enthalpy values of individual defects were used to establish the association between the interstitial-zinc-related defect levels and the blue emission. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26597925 TI - Cost-effectiveness of Simvastatin plus Ezetimibe for Cardiovascular Prevention in CKD: Results of the Study of Heart and Renal Protection (SHARP). AB - BACKGROUND: Simvastatin, 20mg, plus ezetimibe, 10mg, daily (simvastatin plus ezetimibe) reduced major atherosclerotic events in patients with moderate to severe chronic kidney disease (CKD) in the Study of Heart and Renal Protection (SHARP), but its cost-effectiveness is unknown. STUDY DESIGN: Cost-effectiveness of simvastatin plus ezetimibe in SHARP, a randomized controlled trial. SETTING & POPULATION: 9,270 patients with CKD randomly assigned to simvastatin plus ezetimibe versus placebo; participants in categories by 5-year cardiovascular risk (low, <10%; medium, 10%-<20%; or high, >=20%) and CKD stage (3, 4, 5 not on dialysis, or on dialysis therapy). MODEL, PERSPECTIVE, & TIMELINE: Assessment during SHARP follow-up from the UK perspective; long-term projections. INTERVENTION: Simvastatin plus ezetimibe (2015 UK L1.19 per day) during 4.9 years' median follow-up in SHARP; scenario analyses with high-intensity statin regimens (2015 UK L0.05-L1.06 per day). OUTCOMES: Additional health care costs per major atherosclerotic event avoided and per quality-adjusted life-year (QALY) gained. RESULTS: In SHARP, the proportional reductions per 1mmol/L of low-density lipoprotein (LDL) cholesterol reduction with simvastatin plus ezetimibe in all major atherosclerotic events of 20% (95% CI, 6%-32%) and in the costs of vascular hospital episodes of 17% (95% CI, 4%-28%) were similar across participant categories by cardiovascular risk and CKD stage. The 5-year reduction in major atherosclerotic events per 1,000 participants ranged from 10 in low-risk to 58 in high-risk patients and from 28 in CKD stage 3 to 36 in patients on dialysis therapy. The net cost per major atherosclerotic event avoided with simvastatin plus ezetimibe compared to no LDL-lowering regimen ranged from L157,060 in patients at low risk to L15,230 in those at high risk (L30,500-L39,600 per QALY); and from L47,280 in CKD stage 3 to L28,180 in patients on dialysis therapy (L13,000-L43,300 per QALY). In scenario analyses, generic high-intensity statin regimens were estimated to yield similar benefits at substantially lower cost. LIMITATIONS: High-intensity statin-alone regimens were not studied in SHARP. CONCLUSIONS: Simvastatin plus ezetimibe prevented atherosclerotic events in SHARP, but other less costly statin regimens are likely to be more cost-effective for reducing cardiovascular risk in CKD. PMID- 26597928 TI - Bioprocessing strategies for the large-scale production of human mesenchymal stem cells: a review. AB - Human mesenchymal stem cells (hMSCs), also called mesenchymal stromal cells, have been of great interest in regenerative medicine applications because of not only their differentiation potential but also their ability to secrete bioactive factors that can modulate the immune system and promote tissue repair. This potential has initiated many early-phase clinical studies for the treatment of various diseases, disorders, and injuries by using either hMSCs themselves or their secreted products. Currently, hMSCs for clinical use are generated through conventional static adherent cultures in the presence of fetal bovine serum or human-sourced supplements. However, these methods suffer from variable culture conditions (i.e., ill-defined medium components and heterogeneous culture environment) and thus are not ideal procedures to meet the expected future demand of quality-assured hMSCs for human therapeutic use. Optimizing a bioprocess to generate hMSCs or their secreted products (or both) promises to improve the efficacy as well as safety of this stem cell therapy. In this review, current media and methods for hMSC culture are outlined and bioprocess development strategies discussed. PMID- 26597929 TI - Effects of Anodal Transcranial Direct Current Stimulation on Working Memory: A Systematic Review and Meta-Analysis of Findings From Healthy and Neuropsychiatric Populations. AB - BACKGROUND: Several studies have trialled anodal transcranial direct current stimulation (a-tDCS) for the enhancement of working memory (WM) in both healthy and neuropsychiatric populations. However, the efficacy of this technique remains to be clearly established. OBJECTIVE: This review provides a quantitative synthesis of the published literature investigating the effects of a-tDCS, compared to sham, on WM, as assessed using the n-back, Sternberg and digit-span tasks. We also separated results from tasks performed 'online' (during stimulation) and 'offline' (following stimulation). The secondary aim was to assess for any additional effects of current density and stimulation duration. METHODS: Comprehensive literature searches were performed using MEDLINE, Embase, PsychINFO, CENTRAL and Scopus from July 1998 to June 2014. RESULTS: In healthy cohorts, a-tDCS produced a trend towards improvement for offline WM accuracy (p = 0.05) and a small, but significant improvement in reaction time (p = 0.04); however, no significant effects were observed for online tasks (accuracy [p = 0.29], reaction time [p = 0.42]). In the neuropsychiatric cohort, a-tDCS significantly improved accuracy for online (p = 0.003), but not offline (p = 0.87) tasks, and no effect was seen for either online (p = 0.20) or offline (p = 0.49) reaction times. Secondary analyses controlling for current density and stimulation duration provided limited support for the role of these factors in influencing a-tDCS efficacy. CONCLUSIONS: This review provides some evidence of a beneficial effect of a-tDCS on WM performance. However, the small effect sizes obtained, coupled with non-significant effects on several analyses require cautious interpretation and highlight the need for future research aimed at investigating more optimised stimulation approaches. PMID- 26597930 TI - The Efficacy of Daily Prefrontal Repetitive Transcranial Magnetic Stimulation (rTMS) for Burning Mouth Syndrome (BMS): A Randomized Controlled Single-blind Study. AB - BACKGROUND: Burning mouth syndrome (BMS) is a burning oral sensation without any corresponding abnormal findings. In some cases, BMS is refractory to pharmacologic treatments. Repetitive transcranial magnetic stimulation (rTMS) over left prefrontal cortex induces analgesic effect in both acute and chronic pain. However, its effect for BMS has not been evaluated. OBJECTIVE: The aim of this randomized, controlled, single-blind study was to assess the efficacy of prefrontal rTMS for BMS. METHOD: Twenty patients with BMS were recruited and randomized to receive 30,000 pulses in total at 10 Hz TMS (n = 12) or sham TMS (n = 8). We assessed the change of BMS pain condition, functional status and mood until 2 months after the beginning of treatment. RESULTS: In the real group, the BMS pain intensity decreased 67%, and 75% of the patients reported >50% pain decrease on final assessment compared to baseline, without heavy side effects. There was significant pain reduction in subjects in the real group immediately after 1 week of treatment, whereas there was none in those in the sham group. Similar tendency was confirmed in change of functional status. Mood and the affective aspect of pain were not changed in this study. CONCLUSION: BMS pain was significantly improved with 2 weeks of treatment of high frequency rTMS over left DLPFC compared to sham stimulation. Further study is needed to refine and improve TMS as a potential treatment of BMS. PMID- 26597931 TI - Antibiotic combination therapy can select for broad-spectrum multidrug resistance in Pseudomonas aeruginosa. AB - Combination therapy with several antibiotics is one strategy that has been applied in order to limit the spread of antimicrobial resistance. We compared the de novo evolution of resistance during combination therapy with the beta-lactam ceftazidime and the fluoroquinolone ciprofloxacin with the resistance evolved after single-drug exposure. Combination therapy selected for mutants that displayed broad-spectrum resistance, and a major resistance mechanism was mutational inactivation of the repressor gene mexR that regulates the multidrug efflux operon mexAB-oprM. Deregulation of this operon led to a broad-spectrum resistance phenotype that decreased susceptibility to the combination of drugs applied during selection as well as to unrelated antibiotic classes. Mutants isolated after single-drug exposure displayed narrow-spectrum resistance and carried mutations in the MexCD-OprJ efflux pump regulator gene nfxB conferring ciprofloxacin resistance, or in the gene encoding the non-essential penicillin binding protein DacB conferring ceftazidime resistance. Reconstruction of resistance mutations by allelic replacement and in vitro fitness assays revealed that in contrast to single antibiotic use, combination therapy consistently selected for mutants with enhanced fitness expressing broad-spectrum resistance mechanisms. PMID- 26597932 TI - Endogenous immunoglobulins and sepsis: New perspectives for guiding replacement therapies. AB - The recently emerging concept of immunosuppression developing in the field of severe sepsis generated the need to measure circulating immunoglobulins as part of the necessary tests to evaluate immunocompetence status in patients suffering from this condition. Serum concentrations can be used as a surrogate marker of the final outcome and as a biomarker to explore the need for supplementation of the host with intravenous immunoglobulin preparations. Available evidence from recent clinical studies pinpoints the main observations. The first is that circulating IgM is a phenomenon associated with progression from severe sepsis to septic shock. Deficient kinetics of circulating IgM during the first 7 days following the start of vasopressors is linked with unfavourable outcome. The second is the development of immunoscores using low levels of IgM, IgG1 and IgA. These immunoscores can predict 28-day mortality with an odds ratio ranging between 3 and 5. Novel techniques for evaluating patient's immune status are shedding new light on the development of modern therapeutics where immunoglobulin replacement may be part of a personalised therapeutic approach. PMID- 26597933 TI - Analysis of garenoxacin distribution in the mediastinum using endobronchial ultrasound-guided transbronchial needle aspiration. PMID- 26597934 TI - Living with complexity; marshalling resources: a systematic review and qualitative meta-synthesis of lived experience of mental and physical multimorbidity. AB - BACKGROUND: Multimorbidity poses a major health burden worldwide yet most healthcare is still orientated towards the management of single diseases. Literature on the experience of living with multimorbidity is accumulating but has not yet been synthesised in a manner conducive to informing the design of self-management interventions for this population. This study aimed to systematically review and synthesise findings from published, in-depth qualitative studies about the experience of multimorbidity, with a view to identifying the components and motivation for successful self-management in this population. METHODS: Systematic review of and meta-synthesis of qualitative studies that evaluated patient experience of living with and/or self-managing mental and/or physical multimorbidity. MEDLINE, Embase, PsycINFO, CINAHL, and ASSIA along with reference lists of existing reviews and content pages of non indexed specialists comorbidity journals were searched. RESULTS: Nineteen studies from 23 papers were included. A line of argument synthesis was articulated around three third-order constructs: 1) Encounters with complexity; 2) Marshalling medicines, emotions, and resources; and 3) Self-preservation and prevention. Our interpretation revealed how mental and physical multimorbidity is experienced as moments of complexity rather than mere counts of illnesses. Successful self management of physical symptoms was contingent upon the tactical use of medicines, whilst emotional health was more commonly managed by engaging in behavioural strategies, commonly with a social or spiritual component. Motivations for self-management were underpinned by a sense of moral purpose to take responsibility for their health, but also by a desire to live a purposeful life beyond an immediate context of multimorbidity. CONCLUSIONS: Understanding how people experience the complexities of mental and physical multimorbidity may be crucial to designing and delivering interventions to support successful self management in this population. Future self-management interventions should aim to support patients to exert responsibility and autonomy for medical self-management and promote agency and self-determination to lead purposeful lives via improved access to appropriate social and psychological support. PMID- 26597935 TI - Femoral derotation osteotomy with multi-level soft tissue procedures in children with cerebral palsy: Does it improve gait quality? AB - PURPOSE: Poor motor control and delayed thumb function and a delay in walking are the main factors which retard the natural decrease of the femoral anteversion (FA) with age. In addition, cerebral palsy (CP) patients usually have muscular imbalance around the hip as well as muscle contractures, both of which are main factors accounting for the increased FA which is commonly present in CP patients. The purpose of this retrospective study was to analyze the mid-term results of femoral derotational osteotomy (FDO) on the clinical findings, temporospatial and kinematic parameters of gait in children with CP. METHODS: We performed a retrospective review of all patients diagnosed with CP and increased FA who were treated with FDO with multi-level soft tissue surgeries at a single institution between 1992 and 2011. FA assessment was done in the prone position, and internal (IR) and external rotation (ER) of the hip was measured in the absence of pelvis rotation. Surgical procedures were performed on the basis of both clinical findings and video analysis. Clinical findings, Edinburgh Visual Gait Scores (EVGS) and results from three-dimensional gait analysis were analyzed preoperatively and last follow-up. RESULTS: A total of 93 patients with 175 affected extremities were included in this review. Mean age was 6.2 +/- 3.1 (standard deviation) at initial surgery. The average length of the follow-up period was 6.3 +/- 3.7 years. At the last follow-up, the postoperative hip IR had significantly decreased (73.9 degrees vs. 46.2 degrees ; p < 0.0001), the hip ER had significantly improved (23.8 degrees vs. 37 degrees ; p < 0.0001) and the popliteal angle had significantly decreased (64.2 degrees vs. 55.8 degrees ; p < 0.0001). The total EVGS showed significant improvement after FDO (35.2 +/- 6.4 vs. 22.5 +/- 6.1; p < 0.001). Computed gait analysis showed significant improvement in the foot progression angle (FPA; 8.1 degrees vs. -16.9 degrees ; p = 0.005) and hip rotation (-13.9 degrees vs. 5.7 degrees ; p = 0.01) at the last follow-up. Stance time was improved (60.2 vs. 65.1 %; p = 0.02) and swing time was decreased (39.9 vs. 35.2 %; p = 0.03). Double support time and cadence were both decreased (p = 0.032 and p = 0.01). CONCLUSIONS: Our data suggest that the FDO is an appropriate treatment strategy for the correction of FA and associated in-toeing gait in children with CP. Improvements in clinical and kinematic parameters were observed in both groups after FDO with multi-level soft tissue release. The most prominent effects of FDO were on transverse plane hip rotation and FPA. PMID- 26597936 TI - [Ovarian failure: New treatments in perspective?]. AB - The premature loss of ovarian function may have physical and psychological consequences. A better understanding of its mechanism is therefore needed. Because they are affecting the oocyte quality, the decline of the ovarian reserve and high maternal age are implicated in many defects leading to chromosomal defects, modifications of gene expression or alterations of the mitochondrial pattern of the oocyte. However, cellular therapies such as ovarian follicle activation or isolation of ovarian stem cells are promising treatments of ovarian failure. PMID- 26597937 TI - The influence of a biopsychosocial educational internet-based intervention on pain, dysfunction, quality of life, and pain cognition in chronic low back pain patients in primary care: a mixed methods approach. AB - BACKGROUND: Low back pain is the highest reported musculoskeletal problem worldwide. Up to 90 % of patients with low back pain have no clear explanation for the source and origin of their pain. These individuals commonly receive a diagnosis of non-specific low back pain. Patient education is a way to provide information and advice aimed at changing patients' cognition and knowledge about their chronic state through the reduction of fear of anticipatory outcomes and the resumption of normal activities. Information technology and the expedited communication processes associated with this technology can be used to deliver health care information to patients. Hence, this technology and its ability to deliver life-changing information has grown as a powerful and alternative health promotion tool. Several studies have demonstrated that websites can change and improve chronic patients' knowledge and have a positive impact on patients' attitudes and behaviors. The aim of this project is to identify chronic low back pain patients' beliefs about the origin and meaning of pain to develop a web based educational tool using different educational formats and gamification techniques. METHODS/DESIGN: This study has a mixed-method sequential exploratory design. The participants are chronic low back pain patients between 18-65 years of age who are attending a primary care setting. For the qualitative phase, subjects will be contacted by their family physician and invited to participate in a personal semi-structured interview. The quantitative phase will be a randomized controlled trial. Subjects will be randomly allocated using a simple random sample technique. The intervention group will be provided access to the web site where they will find information related to their chronic low back pain. This information will be provided in different formats. All of this material will be based on the information obtained in the qualitative phase. The control group will follow conventional treatment provided by their family physician. DISCUSSION: The main outcome of this project is to identify chronic low back pain patients' beliefs about the origin and meaning of pain to develop a web-based educational tool using different educational formats and gamification techniques. TRIAL REGISTRATION: ClinicalTrials.gov NCT02369120 Date: 02/20/2015. PMID- 26597938 TI - Quantitative In Vitro Assessment of Liposome Stability and Drug Transfer Employing Asymmetrical Flow Field-Flow Fractionation (AF4). AB - PURPOSE: In the present study we introduce an efficient approach for a size-based separation of liposomes from plasma proteins employing AF4. We investigated vesicle stability and release behavior of the strongly lipophilic drug temoporfin from liposomes in human plasma for various incubation times at 37 degrees C. METHODS: We used the radioactive tracer cholesteryl oleyl ether (COE) or dipalmitoyl-phosphocholine (DPPC) as lipid markers and (14)C-labeled temoporfin. First, both lipid labels were examined for their suitability as liposome markers. Furthermore, the influence of plasma origin on liposome stability and drug transfer was investigated. The effect of membrane fluidity and PEGylation on vesicle stability and drug release characteristics was also analyzed. RESULTS: Surprisingly, we observed an enzymatic transfer of (3)H-COE to lipoproteins due to the cholesterol ester transfer protein (CETP) in human plasma in dependence on membrane rigidity and were able to inhibit this transfer by plasma preincubation with the CETP inhibitor torcetrapib. This effect was not seen when liposomes were incubated in rat plasma. DPPC labels suffered from hydrolysis effects during preparation and/or storage. Fluid liposomes were less stable in human plasma than their PEGylated analogues or a rigid formulation. In contrast, the transfer of the incorporated drug to lipoproteins was higher for the rigid formulations. CONCLUSIONS: The observed effects render COE-labels questionable for in vivo studies using CEPT-rich species. Here, choline labelled (14)C-DPPC was found to be the most promising alternative. Bilayer composition has a high influence on stability and drug release of a liposomal formulation in human plasma. PMID- 26597939 TI - The Precipitation Behavior of Poorly Water-Soluble Drugs with an Emphasis on the Digestion of Lipid Based Formulations. AB - An increasing number of newly discovered drugs are poorly water-soluble and the use of natural and synthetic lipids to improve the oral bioavailability of these drugs by utilizing the digestion pathway in-vivo has proved an effective formulation strategy. The mechanisms responsible for lipid digestion and drug solubilisation during gastrointestinal transit have been explored in detail, but the implications of drug precipitation beyond the potential adverse effect on bioavailability have received attention only in recent years. Specifically, these implications are that different solid forms of drug on precipitation may affect the total amount of drug absorbed in-vivo through their different physico chemical properties, and the possibility that the dynamic environment of the small intestine may afford re-dissolution of precipitated drug if present in a high-energy form. This review describes the events that lead to drug precipitation during the dispersion and digestion of lipid based formulations, common methods used to inhibit precipitation, as well as conventional and newly emerging characterization techniques for studying the solid state form of the precipitated drug. Moreover, selected case studies are discussed where drug precipitation has ensued from the digestion of lipid based formulations, as well as the apparent link between drug ionisability and altered solid forms on precipitation, culminating in a discussion about the importance of the solid form on precipitation with relevance to the total drug absorbed. PMID- 26597941 TI - Microbial identification and automated antibiotic susceptibility testing directly from positive blood cultures using MALDI-TOF MS and VITEK 2. AB - The study addresses the utility of Matrix Assisted Laser Desorption/Ionisation Time-Of-Flight mass spectrometry (MALDI-TOF MS) using VITEK MS and the VITEK 2 antimicrobial susceptibility testing (AST) system for direct identification (ID) and timely AST from positive blood culture bottles using a lysis-filtration method (LFM). Between July and December 2014, a total of 140 non-duplicate mono microbial blood cultures were processed. An aliquot of positive blood culture broth was incubated with lysis buffer before the bacteria were filtered and washed. Micro-organisms recovered from the filter were first identified using VITEK MS and its suspension was used for direct AST by VITEK 2 once the ID was known. Direct ID and AST results were compared with classical methods using solid growth. Out of the 140 bottles tested, VITEK MS resulted in 70.7 % correct identification to the genus and/ or species level. For the 103 bottles where identification was possible, there was agreement in 97 samples (94.17 %) with classical culture. Compared to the routine method, the direct AST resulted in category agreement in 860 (96.5 %) of 891 bacteria-antimicrobial agent combinations tested. The results of direct ID and AST were available 16.1 hours before those of the standard approach on average. The combined use of VITEK MS and VITEK 2 directly on samples from positive blood culture bottles using a LFM technique can result in rapid and reliable ID and AST results in blood stream infections to result in early institution of targeted treatment. The combination of LFM and AST using VITEK 2 was found to expedite AST more reliably. PMID- 26597940 TI - Curcumin Delivery by Poly(Lactide)-Based Co-Polymeric Micelles: An In Vitro Anticancer Study. AB - PURPOSE: This work describes the synthesis of block co-polymeric micelles, methoxy-poly(ethylene glycol)-poly(D,L-lactide) (mPEG-PLA) to encapsulate Curcumin (CUR), thereby improving the dispersibility and chemical stability of curcumin, prolonging its cellular uptake and enhancing its bioavailability. METHODS: CUR-mPEG-PLA micelles, was prepared using the thin-film hydration method and evaluated in vitro. The preparation process was optimized with a central composite design (CCD). Micelles were characterized by size, transmission electron microscopy, loading capacity, and critical micelle concentration (CMC). The cytotoxicity of CUR-mPEG-PLA micelles was investigated against murine melanoma cells, B16F10 and human breast cancer cells, MDA-MB-231. RESULTS: The average size of the CUR-mPEG-PLA micelles was 110 +/- 5 nm with polydispersity index in the range of 0.15-0.31, and the encapsulating efficiency for CUR was 91.89 +/- 1.2, and 11.06 +/- 0.8% for drug-loading. Sustained release of CUR from micelles was observed with 9.73% CUR release from micelles compared to 64.24% release of free curcumin in first 6 h under sink condition. The CUR-mPEG-PLA was efficiently taken up by the cancer cells, B16F10 and MDA-MB-231. Following 24 h incubation, CUR-mPEG-PLA induced higher cytotoxicity compared to free CUR in MDA MB-231 cell lines indicating exposure of higher dose of free CUR to cells lead to up-regulation of drug efflux mechanisms leading to decreased cell death in case of free CUR administration. CONCLUSION: Our results indicate that the proposed micellar system has the potential to serve as an efficient carrier for CUR by effectively solubilizing, stabilizing and delivering the drug in a controlled manner to the cancer cells. PMID- 26597942 TI - Anterior segment spectral domain optical coherence tomography imaging of patients with anterior scleritis. AB - The purpose of the study was to describe the findings seen on anterior segment spectral domain optical coherence tomography (SD-OCT) in patients with anterior scleritis and determine the feasibility of using SD-OCT to image and grade the degree of scleral inflammation and monitor response to treatment. All patients underwent slit lamp examination by a uveitis specialist, and the degree of scleral inflammation was recorded. Spectral domain OCT imaging was then performed of the conjunctiva and scleral tissue using a standardized acquisition protocol. The scans were graded and compared to clinical findings. Twenty-eight patients with anterior scleritis and ten patients without ocular disease were included in the study. Seventeen of the scleritis patients were followed longitudinally. Common findings on SD-OCT in patients with active scleritis included changes in hyporeflectivity within the sclera, nodules, and visible vessels within the sclera. There was significant variation in findings on SD-OCT within each clinical grade of active scleritis. These changes on SD-OCT improved with treatment and clinical improvement. SD-OCT imaging provided various objective measures that could be used in the future to grade inflammatory activity in patients with anterior scleritis. Longitudinal imaging of patients with active scleritis demonstrated that SD-OCT may have great utility in monitoring response to treatment. PMID- 26597943 TI - Reflections of a Darwinian Engineer. PMID- 26597944 TI - A Quarter Century of In Vitro Selection. PMID- 26597945 TI - Erratum to: Comprehensive evaluation of differential gene expression analysis methods for RNA-seq data. PMID- 26597946 TI - Report of the Canadian Neurological Society Manpower Survey 2012. AB - BACKGROUND: The Canadian Neurological Society commissioned a manpower survey in 2012 to assess Canadian neurological manpower and resources. METHODS: Surveys were sent electronically to all Canadian neurologists with available email addresses. Responses were analysed for effects of physician gender, age, geographic location (eastern or western Canada) or type of practice (academic, community). Questions focused on work patterns, neurologic conditions treated, access to or performance of procedures, and service and manpower issues. RESULTS: A total of 694 of 854 neurologists in Canada were surveyed and 219 (32%) responded. Respondents were 70% male with mean age of 50 years. Neurologists worked an average of 57 hours/week and saw a mean of 40 patients per week. There were significant differences in number of patients seen, types of practice, and areas of neurological specialization between community and academic neurologists. Fifty percent of neurologists report shortages of neurologists in their community, particularly of general adult neurologists. Wait times for neurological services exceeded international standards for consultations and also were longer than Canadian averages for other specialists. More community (18%) than academic (5%) neurologists planned to retire within the next 5 years. CONCLUSIONS: The demand for neurological services continues to outstrip resources despite the increased number of neurologists. Impending retirement of community neurologists will exacerbate manpower issues unless adequate numbers of trainees choose general neurologic practice in the community as a career. PMID- 26597949 TI - Imaging and extent of surgical resection predict risk of meningioma recurrence better than WHO histopathological grade. AB - BACKGROUND: Risk stratification of meningiomas by histopathological grade alone does not reliably predict which patients will progress/recur after treatment. We sought to determine whether preoperative imaging and clinical characteristics could predict histopathological grade and/or improve prognostication of progression/recurrence (P/R). METHODS: We retrospectively reviewed preoperative MR and CT imaging features of 144 patients divided into low-grade (2007 WHO grade I; n = 118) and high-grade (2007 WHO grades II/III; n = 26) groups that underwent surgery between 2002 and 2013 (median follow-up of 49 months). RESULTS: Multivariate analysis demonstrated that the risk factors most strongly associated with high-grade histopathology were male sex, low apparent diffusion coefficient (ADC), absent calcification, and high peritumoral edema. Remarkably, multivariate Cox proportional hazards analysis demonstrated that, in combination with extent of resection, ADC outperformed WHO histopathological grade for predicting which patients will suffer P/R after initial treatment. Stratification of patients into 3 risk groups based on non-Simpson grade I resection and low ADC as risk factors correlated with the likelihood of P/R (P < .001). The high-risk group (2 risk factors; n = 39) had a 45% cumulative incidence of P/R, whereas the low-risk group (0 risk factors; n = 31) had no P/R events at 5 years after treatment. Independent of histopathological grade, high-risk patients who received adjuvant radiotherapy had a lower 5-year crude rate of P/R than those without (17% vs 59%; P = .04). CONCLUSIONS: Patients with non-Simpson grade I resection and low ADC meningiomas are at significantly increased risk of P/R and may benefit from adjuvant radiotherapy and/or additional surgery. PMID- 26597950 TI - How safe is internal iliac artery embolisation prior to EVAR? A 10-year retrospective review. AB - PURPOSE: Internal iliac artery (IIA) embolisation is commonly performed prior to endovascular aneurysm repair (EVAR) of aortoiliac aneurysms to prevent type 2 endoleaks via the internal iliac arteries. The safety of this procedure is controversial due to the high incidence of pelvic ischaemic complications. METHODS: We undertook a retrospective review of all patients undergoing IIA embolisation before EVAR from 2002 to 2012, to determine incidence of, and factors associated with pelvic ischaemia. RESULTS: Eight of 25 patients (32 %) experienced new-onset ischaemia, including erectile dysfunction (4 %), and buttock claudication (28 %) that persisted >6 months in only four patients (16 %). Both bilateral IIA embolisation and a shorter time interval to EVAR correlate with increased risk (p = 0.006 and p = 0.044). No co-morbidities or demographic factors were predictive. CONCLUSIONS: We conclude that IIA embolisation remains a beneficial procedure, however, to minimise the risk of buttock claudication we advise against both bilateral IIA embolisation and short time intervals between embolisation and subsequent EVAR. PMID- 26597947 TI - More than the genes, the tumor microenvironment in neuroblastoma. AB - Neuroblastoma is the second most common solid tumor in children. Since the seminal discovery of the role of amplification of the MYCN oncogene in the pathogenesis of neuroblastoma in the 1980s, much focus has been on the contribution of genetic alterations in the progression of this cancer. However it is now clear that not only genetic events play a role but that the tumor microenvironment (TME) substantially contributes to the biology of neuroblastoma. In this article, we present a comprehensive review of the literature on the contribution of the TME to the ten hallmarks of cancer in neuroblastoma and discuss the mechanisms of communication between neuroblastoma cells and the TME that underlie the influence of the TME on neuroblastoma progression. We end our review by discussing how the knowledge acquired over the last two decades in this field is now leading to new clinical trials targeting the TME. PMID- 26597951 TI - Clinical and economic benefit of general practitioner integration to a symptomatic breast service. AB - BACKGROUND: Integration of general practitioners (GPs) into a tertiary care team is a model used internationally to assist with provision of patient care. Symptomatic breast clinics have seen significant increases in attendances and consequential staffing issues. We wished to analyze the integration of GPs into a tertiary breast care team and establish whether their inclusion is a cost effective approach. METHODS: A prospectively maintained database was used to identify 1614 new and 1453 review patients seen in the clinic between September and December 2013. The triple assessment clinical, radiological, and biopsy scores of patients assessed by GPs were compared to those assessed by registrars and to the overall number of patients seen. A cost analysis was performed based on the hourly rates of GPs and registrars. RESULTS: 1614 new patients seen over the 4-month period. GPs reviewed a mean of 153.6 new patients and registrars reviewed a mean of 97.8. Registrars reviewed patients who were allocated higher 'S' scores, with 46 % of patients allocated an S4 and 21 % of patients allocated an S5 score. GPs reviewed a mean of 115.6 return patients and registrars reviewed a mean of 110.1 return patients. The weekly cost of employing 3 GPs for 15 h was ?835. This compares favorably to the cost of employing a full-time registrar. CONCLUSION: This study demonstrates that GPs can play a substantial role in the provision of a symptomatic breast service. In addition, the incorporation of GPs in this setting can prove cost-effective. PMID- 26597952 TI - Edaravone offers neuroprotection for acute diabetic stroke patients. AB - INTRODUCTION: Edaravone, a novel free-radical scavenger, has been shown to alleviate cerebral ischemic injury and protect against vascular endothelial dysfunction. However, the effects of edaravone in acute diabetic stroke patients remain undetermined. METHODS: A randomized, double-blind, placebo-controlled study was performed to prospectively evaluate the effects of edaravone on acute diabetic stroke patients admitted to our hospital within 24 h of stroke onset. The edaravone group received edaravone (30 mg twice per day) diluted with 100 ml of saline combined with antiplatelet drug aspirin and atorvastatin for 14 days. The non-edaravone group was treated only with 100 ml of saline twice per day combined with aspirin and atorvastatin. Upon admission, and on days 7, 14 post stroke onset, neurological deficits and activities of daily living were assessed using the National Institutes of Health Stroke Scale (NIHSS) and the Barthel Index (BI), respectively. The occurrence of hemorrhage transformation, pulmonary infection, progressive stroke and epilepsy was also evaluated on day 14 post treatment. RESULTS: A total of 65 consecutive acute diabetic stroke patients were enrolled, of whom 35 were allocated to the edaravone group and 30 to the non edaravone group. There was no significant group difference in baseline clinical characteristics, but mean NIHSS scores were lower (60 %), and BI scores were 1.7 fold higher, in edaravone-treated patients vs. controls on day 14. Furthermore, the incidence of hemorrhage transformation, pulmonary infection, progressive stroke and epilepsy was markedly reduced in the edaravone vs. non-edaravone group. CONCLUSION: Edaravone represents a promising neuroprotectant against cerebral ischemic injury in diabetic patients. PMID- 26597953 TI - A model for chromosome organization during the cell cycle in live E. coli. AB - Bacterial chromosomal DNA is a highly compact nucleoid. The organization of this nucleoid is poorly understood due to limitations in the methods used to monitor the complexities of DNA organization in live bacteria. Here, we report that circular plasmid DNA is auto-packaged into a uniform dual-toroidal-spool conformation in response to mechanical stress stemming from sharp bending and un winding by atomic force microscopic analysis. The mechanism underlying this phenomenon was deduced with basic physical principles to explain the auto packaging behaviour of circular DNA. Based on our observations and previous studies, we propose a dynamic model of how chromosomal DNA in E. coli may be organized during a cell division cycle. Next, we test the model by monitoring the development of HNS clusters in live E. coli during a cell cycle. The results were in close agreement with the model. Furthermore, the model accommodates a majority of the thus-far-discovered remarkable features of nucleoids in vivo. PMID- 26597954 TI - The complement of family M1 aminopeptidases of Haemonchus contortus- Biotechnological implications. AB - Although substantial research has been focused on the 'hidden antigen' H11 of Haemonchus contortus as a vaccine against haemonchosis in small ruminants, little is know about this and related aminopeptidases. In the present article, we reviewed genomic and transcriptomic data sets to define, for the first time, the complement of aminopeptidases (designated Hc-AP-1 to Hc-AP-13) of the family M1 with homologues in Caenorhabditis elegans, characterised by zinc-binding (HEXXH) and exo-peptidase (GAMEN) motifs. The three previously published H11 isoforms (accession nos. X94187, FJ481146 and AJ249941) had most sequence similarity to Hc AP-2 and Hc-AP-8, whereas unpublished isoforms (accession nos. AJ249942 and AJ311316) were both most similar to Hc-AP-3. The aminopeptidases characterised here had homologues in C. elegans. Hc-AP-1 to Hc-AP-8 were most similar in amino acid sequence (28-41%) to C. elegans T07F10.1; Hc-AP-9 and Hc-AP-10 to C. elegans PAM-1 (isoform b) (53-54% similar); Hc-AP-11 and Hc-AP-12 to C. elegans AC3.5 and Y67D8C.9 (26% and 50% similar, respectively); and Hc-AP-13 to C. elegans C42C1.11 and ZC416.6 (50-58% similar). Comparative analysis suggested that Hc-AP-1 to Hc AP-8 play roles in digestion, metabolite excretion, neuropeptide processing and/or osmotic regulation, with Hc-AP-4 and Hc-AP-7 having male-specific functional roles. The analysis also indicated that Hc-AP-9 and Hc-AP-10 might be involved in the degradation of cyclin (B3) and required to complete meiosis. Hc AP-11 represents a leucyl/cystinyl aminopeptidase, predicted to have metallopeptidase and zinc ion binding activity, whereas Hc-AP-12 likely encodes an aminopeptidase Q homologue also with these activities and a possible role in gonad function. Finally, Hc-AP-13 is predicted to encode an aminopeptidase AP-1 homologue of C. elegans with hydrolase activity, suggested to operate, possibly synergistically with a PEPT-1 ortholog, as an oligopeptide transporter in the gut for protein uptake and normal development and/or reproduction of the worm. An appraisal of structure-based amino acid sequence alignments revealed that all conceptually translated Hc-AP proteins, with the exception of Hc-AP-12, adopt a topology similar to those observed for the two subgroups of mammalian M1 aminopeptidases, which possess either three (I, II and IV) or four (I-IV) domains. In contrast, Hc-AP-12 lacks the N-terminal domain (I), but possesses a substantially expanded domain III. Although further work needs to be done to assess amino acid sequence conservation of the different aminopeptidases among individual worms within and among H. contortus populations, we hope that these insights will support future localisation, structural and functional studies of these molecules in H. contortus as well as facilitate future assessments of a recombinant subunit or cocktail vaccine against haemonchosis. PMID- 26597955 TI - Clinical medication reviews in elderly patients with polypharmacy: a cross sectional study on drug-related problems in the Netherlands. AB - BACKGROUND: Knowledge of drug-related problems (DRPs) identified in the medication of home-dwelling elderly patients with polypharmacy has been based predominantly on medication reviews conducted in research settings rather than in daily practice. OBJECTIVE: To evaluate the prevalence of DRPs identified by means of a clinical medication review (CMR) and the implementation rate of proposed interventions in a large group of older patients with polypharmacy in the daily practice of community pharmacies. SETTING: 318 Dutch community pharmacies. METHOD: A cross-sectional study based on CMR-data of 3807 older patients (>=65 years) with polypharmacy (>=5 drugs) completed between January and August 2012. Data were extracted from community pharmacists' databases and entailed: year of birth, gender, dispensing data, number and nature of identified DRPs, consultations performed, proposed and implemented interventions. Main outcome measure Prevalence of DRPs, drug classes involved in overtreatment and undertreatment, and proposed and implemented interventions. RESULTS: A median of two DRPs (interquartile range 1-4; mean 3.0) was identified per patient. The DRP categories overtreatment (25.5 %) and undertreatment (15.9 %) were found most frequently. 46.2 % of the proposed interventions to solve DRPs were implemented as proposed, in 22.4 % of cases, the intervention differed from the proposal. In 31.3 % of cases no intervention was implemented. CONCLUSION: By conducting a CMR community pharmacists identified a median of two DRPs in older patients with polypharmacy. Overtreatment and undertreatment accounted for 41.4 % of the DRPs identified. In dealing with DRPs, pharmacists proposed a variety of interventions of which the majority (69.9 %) was either implemented or led to alternative interventions. A set of explicit criteria should be applied during a CMR to solve and prevent DRPs. PMID- 26597956 TI - The effects of GLP-1 analogues in obese, insulin-using type 2 diabetes in relation to eating behaviour. AB - BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1 RA) added to insulin in type 2 diabetes patients have shown to lower body weight, improve glycaemic control and reduce total daily insulin dose in short term studies, although the individual response greatly varies. OBJECTIVE: To evaluate GLP-1 RA treatment on body weight, glycaemic control and total daily insulin dose in obese, insulin using type 2 diabetes patients after 2 years follow-up in a real life setting and to explore a possible relation with eating behaviour. SETTING: The Martini Hospital and the University Medical Center in Groningen in the Netherlands. METHODS: Eligible patients were at least 18 years of age, were on insulin therapy and obese (BMI > 30 kg/m(2)), started GLP-1 RA treatment. At baseline eating behaviour was classified according to the validated Dutch Eating Behaviour Questionnaire. A 2 years follow-up was performed. Main outcome measures Body weight, HbA1c and total daily insulin dose. RESULTS: 151 Patients started with exenatide or liraglutide. 120 patients completed the 2 years follow-up. From baseline to 2 years, body weight (mean +/- SD) changed from 117.9 +/- 22.1 to 107.9 +/- 22.9 kg (P < 0.0001), HbA1c (median, IQR) changed from 7.9 (7.2-8.9) to 7.6 (6.9-8.3) % [63 (55-74) to 60 (52-67) mmol/mol] (P < 0.0001), total daily insulin dose changed from 90 (56-150) to 60 (0-100) Units/day (P < 0.0001). Weight change differed between eating behaviour groups (P < 0.001) in which external eating behaviour (n = 17) resulted in the smallest decline (-3.1 %) and restrained (n = 41) in the greatest (-10.3 %) in comparison with emotional (n = 37, -8.5 %) and indifferent (n = 25, -9.6 %) eating behaviours. CONCLUSION: Two year of GLP-1 RA treatment resulted in a sustained reduction of weight, HbA1c and total daily insulin dose in obese, insulin-using type 2 diabetes patients in a real life setting. Largest weight loss was achieved in patients with a predominant restraint eating pattern while a predominant external eating pattern resulted in the smallest weight reduction. PMID- 26597957 TI - Fluorescence-Based Automated Screening Assay for the Study of the pH-Sensitive Channel ASIC1a. AB - Acid-sensing ion channel 1a (ASIC1a) is involved in several pathologies, including neurodegenerative and neuroinflammatory disorders, stroke, epilepsy, and inflammatory pain. ASIC1a has been the subject of intense drug discovery programs devoted to the development of new pharmacological tools for its modulation. However, these efforts to generate new compounds have faced the lack of an efficient screening procedure. In the past decades, improvements in screening technologies and fluorescent sensors for the study of ion channels have provided new opportunities in this field. Unfortunately, ASIC1a is mainly a Na(+) permeable channel and undergoes desensitization after its activation, two features that make the use of the available screening procedures problematic. We propose here a novel screening approach for the study of ASIC1a activity in full automation. Our method is based on the stimulation of ASIC1a-expressing cells by protons and the use of electrochromic fluorescent voltage sensors as a readout of ion channel activation. This method will prove to be useful for drug screening programs aimed at ASIC1a modulation. PMID- 26597958 TI - Modulation of NF-kappaB Signaling as a Therapeutic Target in Autoimmunity. AB - Autoimmune diseases arise from the loss of tolerance to endogenous self-antigens, resulting in a heterogeneous range of chronic conditions that cause considerable morbidity and mortality worldwide. In Western countries, over 5% of the population is affected by some form of autoimmune disease, with enhanced or inappropriate activation of nuclear factor (NF)-kappaB implicated in a number of these conditions. Although treatment strategies for autoimmunity have improved significantly in recent years, current therapeutics are still not capable of achieving satisfactory disease management in all patients, and as such, the therapeutic modulation of NF-kappaB is an attractive target in autoimmunity. To date, no NF-kappaB inhibitors have progressed to the clinic for the treatment of autoimmunity, but a variety of promising approaches targeting multiple stages of the NF-kappaB pathway are currently being explored. This review focuses on the current strategies being investigated for the inhibition of the NF-kappaB pathway in autoimmune diseases and considers potential future strategies for the therapeutic targeting of this crucial transcription factor. PMID- 26597959 TI - Improved production of melanin from Aspergillus fumigatus AFGRD105 by optimization of media factors. AB - Melanins are indolic polymers produced by many genera included among plants, animals and microorganisms and targeted mainly for their wide range of applications in cosmetics, agriculture and medicine. An approach to analyse the cumulative effect of parameters for enhanced melanin production was carried out using response surface methodology. In this present study, optimization of media and process parameters for melanin production from Aspergillus fumigatus AFGRD105 (GenBank: JX041523; NFCCI accession number: 3826) was carried out by an initial univariate approach followed by statistical response surface methodology. The univariate approach was used to standardise the parameters that can be used for the 12-run Plackett-Burman design that is used for screening for critical parameters. Further optimization of parameters was analysed using Box-Behnken design. The optimum conditions observed were temperature, moisture and sodium dihydrogen phosphate concentration. The yield of every run of both designs were confirmed to be melanin by laboratory tests of analysis in the presence of acids, base and water. This is the first report confirming an increase in melanin production A. fumigatus AFGRD105 without the addition of costly additives. PMID- 26597961 TI - Phenotypic and Physiological Characterization of the Epibiotic Interaction Between TM7x and Its Basibiont Actinomyces. AB - Despite many examples of obligate epibiotic symbiosis (one organism living on the surface of another) in nature, such an interaction has rarely been observed between two bacteria. Here, we further characterize a newly reported interaction between a human oral obligate parasitic bacterium TM7x (cultivated member of Candidatus Saccharimonas formerly Candidate Phylum TM7), and its basibiont Actinomyces odontolyticus species (XH001), providing a model system to study epiparasitic symbiosis in the domain Bacteria. Detailed microscopic studies indicate that both partners display extensive morphological changes during symbiotic growth. XH001 cells manifested as short rods in monoculture, but displayed elongated and hyphal morphology when physically associated with TM7x. Interestingly, these dramatic morphological changes in XH001 were also induced in oxygen-depleted conditions, even in the absence of TM7x. Targeted quantitative real-time PCR (qRT-PCR) analyses revealed that both the physical association with TM7x as well as oxygen depletion triggered up-regulation of key stress response genes in XH001, and in combination, these conditions act in an additive manner. TM7x and XH001 co-exist with relatively uniform cell morphologies under nutrient replete conditions. However, upon nutrient depletion, TM7x-associated XH001 displayed a variety of cell morphologies, including swollen cell body, clubbed ends, and even cell lysis, and a large portion of TM7x cells transformed from ultrasmall cocci into elongated cells. Our study demonstrates a highly dynamic interaction between epibiont TM7x and its basibiont XH001 in response to physical association or environmental cues such as oxygen level and nutritional status, as reflected by their morphological and physiological changes during symbiotic growth. PMID- 26597962 TI - Site Specific Genetic Incorporation of Azidophenylalanine in Schizosaccharomyces pombe. AB - The diversity of protein functions is impacted in significant part by the chemical properties of the twenty amino acids, which are used as building blocks for nearly all proteins. The ability to incorporate unnatural amino acids (UAA) into proteins in a site specific manner can vastly expand the repertoire of protein functions and also allows detailed analysis of protein function. In recent years UAAs have been incorporated in a site-specific manner into proteins in a number of organisms. In nearly all cases, the amber codon is used as a sense codon, and an orthogonal tRNA/aminoacyl-tRNA synthetase (RS) pair is used to generate amber suppressing tRNAs charged with the UAA. In this work, we have developed tools to incorporate the cross-linking amino acid azido-phenylalanine (AzF) through the use of bacterial tRNA(Tyr) and a modified version of TyrRS, AzFRS, in Schizosaccharomyces pombe, which is an attractive model organism for the study of cell behavior and function. We have incorporated AzF into three different proteins. We show that the majority of AzF is modified to amino-phenyl alanine, but protein cross-linking was still observed. These studies set the stage for exploitation of this new technology for the analysis of S. pombe proteins. PMID- 26597963 TI - Cognitive Risk and Protective Factors for Suicidal Ideation: A Two Year Longitudinal Study in Adolescence. AB - Adolescence is a developmental period associated with heightened risk for both the onset and escalation of suicidal ideation (SI). Given that SI is a potent predictor of suicidal behavior, it is important to develop models of vulnerability for and protection against SI, particularly among young adolescents. This study examined the relative impact of several cognitive vulnerabilities, as well as protective factors, for SI among young adolescents over a 2-year interval encompassing their transition to mid-adolescence. At baseline, 324 adolescents (M = 12.39 years; SD = 0.63; 52.5 % female) completed measures of depressive symptoms, self-referent information processing biases, negative inferential style, and responses to negative affect. Further, the adolescents and their mothers were administered a diagnostic interview to assess current and past depressive disorders and SI. Over follow-up, adolescents and their mothers were administered the diagnostic interview every 12 months and adolescents completed a self-report measure inquiring about SI every 6 months to assess interviewer-rated and self-reported SI. Logistic regressions indicated that preferential endorsement of negative adjectives as self-referent (only among girls), rumination in response to negative affect, and a negative inferential style prospectively predicted SI. Additionally, young adolescents' tendency to respond to negative affect with distraction and problem-solving buffered against their risk for exhibiting SI. When these factors were entered simultaneously, preferential endorsement of negative adjectives as self-referent and the use of distraction and problem-solving skills remained the only significant prospective predictors of SI. No previous studies have examined these variables as predictors of SI, thereby highlighting their potential utility in improving the predictive validity of extant models of suicide risk and resilience. PMID- 26597964 TI - Pathogenesis and Therapeutic Strategies in Alzheimer's Disease: From Brain to Periphery. AB - Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative disorder. At present, there are no effective disease-modifying therapies, and the cause of the disease remains unclear. Previously, almost all researchers focus on the brain for exploring the pathogenesis and therapeutic strategies in AD. A recent study by Xiang et al. (Acta Neuropathol 130:487-499, 2015) reported the significance of the physiological capacity of peripheral tissues and organs in clearing brain-derived amyloid-beta (Abeta), which opens a novel avenue to understand the AD pathogenesis and develop therapies for AD. PMID- 26597965 TI - A Nanoscale Multichannel Closed Bipolar Electrode Array for Electrochemiluminescence Sensing Platform. AB - In this work, we report a nanoscale multichannel closed bipolar electrode (BPE) array based on the poly(ethylene terephthalate) (PET) membrane for the first time. With our design, oxidants, coreactants, quenchers, and even biomarkers can be detected in a Ru(bpy)3(2+)/TPA (tripropylamine) electrochemiluminescence (ECL) system. The multichannel PET membrane was etched according to our desire by NaOH, and then Au nanofibers were decorated in the inner region of the channel as a BPE array. Using ECL as a signal readout, a series of targets including TPA, Ru(bpy)3(2+), dopamine, H2O2, alpha-fetoprotein (AFP), and carcino-embryonic antigen (CEA) can be detected with this device. The practical application of the proposed multichannel closed BPE array was verified in the detection of AFP and CEA in human serum with satisfying results. This kind of nanoscale device holds promising potential for multianalysis. More importantly, as the PET membrane used in this device can be etched with a desirable diameter (nano- to microscale) and different BPE array densities (ion tracks of 10(8)/cm(2), 10(6)/cm(2), 10(4)/cm(2)), our design can be served as a useful platform for future advances in nanoscale bipolar electrochemistry. PMID- 26597967 TI - Spatial Distribution of Adults of Triozoida limbata (Enderlein) (Hemiptera: Triozidae) in Guava Plants. AB - The psyllid Triozoida limbata (Enderlein) (Hemiptera: Triozidae) is a major pest in guava, feeding primarily on new shoots. Despite its importance, there are no studies on the spatial distribution of T. limbata on guava. Such studies are needed to establish sequential sampling plans for decision making in pest control. Thus, an experiment was carried out in a 9-year-old commercial guava orchard divided into 100 sampling units or plots. Double-sided yellow sticky traps were placed on one plant per plot (sample unit) to capture and monitor T. limbata adults from April 2011 to May 2012. To determine the insect distribution in the area, we calculated the variance-to-mean ratio index (I), the Morisita index (I delta ), Green's coefficient (Cx), and the k exponent of the negative binomial distribution. Most of the samples showed that the adults had a moderate to highly aggregated distribution. Statistical models were also used to study the pest spatial distribution by fitting the number of adults captured to the Poisson and negative binomial distributions. The negative binomial distribution model best fitted the data of the number of adult psyllids captured by the traps, which is consistent with an aggregated distribution. PMID- 26597968 TI - Variation in the Abundance of Neotropical Bees in an Unpredictable Seasonal Environment. AB - This study provides information on the number of orchid bees based on a long-term monitoring study in an antropized savanna region in Southeastern Brazil. Sampling was carried out using chemical lures, and 77 samples were monthly collected to assess the number of individuals as well as the annual and seasonal species fluctuation. The number of species varied significantly among years but not among months, and there was a positive correlation between the number of species and the number of individuals in each sample. Monthly number counts revealed a seasonal pattern for Eulaema nigrita Lepeletier and Exaerete smaragdina Perty, which were more numerous during humid months but peaked in December, January, and February. Different species of Euglossa presented a significant variation in number among years, but not among months, with no pattern along the years. The community and the populations studied were less stable when compared to those of well-preserved habitats of equatorial forests. The El Nino phenomenon of 1997/98 did not result in negative effects in the populations studied; on the contrary, there was a peak in the number of E. nigrita. The amplitude in the yearly variation of the male orchid bee population reflects the evolutionary history of species living in unpredictable seasonal weather that led to the development of particular adaptive traits designed to deal with environmental uncertainties. This study suggests that the plasticity of the life cycle may explain population stability and provide greater resilience to severe climate change events in the future. PMID- 26597966 TI - Telomere binding protein TRB1 is associated with promoters of translation machinery genes in vivo. AB - Recently we characterised TRB1, a protein from a single-myb-histone family, as a structural and functional component of telomeres in Arabidopsis thaliana. TRB proteins, besides their ability to bind specifically to telomeric DNA using their N-terminally positioned myb-like domain of the same type as in human shelterin proteins TRF1 or TRF2, also possess a histone-like domain which is involved in protein-protein interactions e.g., with POT1b. Here we set out to investigate the genome-wide localization pattern of TRB1 to reveal its preferential sites of binding to chromatin in vivo and its potential functional roles in the genome wide context. Our results demonstrate that TRB1 is preferentially associated with promoter regions of genes involved in ribosome biogenesis, in addition to its roles at telomeres. This preference coincides with the frequent occurrence of telobox motifs in the upstream regions of genes in this category, but it is not restricted to the presence of a telobox. We conclude that TRB1 shows a specific genome-wide distribution pattern which suggests its role in regulation of genes involved in biogenesis of the translational machinery, in addition to its preferential telomeric localization. PMID- 26597969 TI - Roles of Proton-Sensing Receptors in the Transition from Acute to Chronic Pain. AB - Chronic pain, when not effectively treated, is a leading health and socioeconomic problem and has a harmful effect on all aspects of health-related quality of life. Therefore, understanding the molecular mechanism of how pain transitions from the acute to chronic phase is essential for developing effective novel analgesics. Accumulated evidence has shown that the transition from acute to chronic pain is determined by a cellular signaling switch called hyperalgesic priming, which occurs in primary nociceptive afferents. The hyperalgesic priming is triggered by inflammatory mediators and is involved in a signal switch from protein kinase A (PKA) to protein kinase Cepsilon (PKCepsilon) located in both isolectin B4 (IB4)-positive (nonpeptidergic) and IB4-negative (peptidergic) nociceptors. Acidosis may be the decisive factor regulating the PKA-to-PKCepsilon signal switch in a proton-sensing G-protein-coupled receptor-dependent manner. Protons can also induce the hyperalgesic priming in IB4-negative muscle nociceptors in a PKCepsilon-independent manner. Acid-sensing ion channel 3 (ASIC3) and transient receptor potential/vanilloid receptor subtype 1 (TRPV1) are 2 major acid sensors involved in the proton-induced hyperalgesic priming. The proton-induced hyperalgesic priming in muscle afferents can be prevented by a substance P-mediated signaling pathway. In this review, we summarize the factors that modulate hyperalgesic priming in both IB4-positive and IB4-negative nociceptors and discuss the role of acid signaling in inflammatory and noninflammatory pain as well as orofacial muscle pain. PMID- 26597970 TI - Zinc oxide nanoring embedded lacey graphene nanoribbons in symmetric/asymmetric electrochemical capacitive energy storage. AB - This article describes the synthesis and characterization of ZnO nanoring embedded graphene nanoribbons. Patterned holes (mesopore dia.) in graphene nanoribbons are chemically generated, leading to a high density of the edge planes. These planes carry negatively charged surface groups (like -COOH and -OH) and therefore anchor the metal ions in a cordial fashion forming a string of metal ions along the edge planes. These strings of imbibed metal ions precipitate as tiny ZnO nanorings over lacey graphene nanoribbons. The thus obtained graphene nanoribbon (GNR) based hierarchical ZnO mesoporous structures are three dimensionally accessible to the electrolyte and demonstrate high performance in capacitive energy storage. The ZnO/GNR nanocomposite electrode in an asymmetric supercapacitor device with lacey reduced graphene oxide nanoribbons (LRGONRs) as a negative electrode exhibits a 2.0 V potential window in the aqueous electrolyte and an ultra-short time constant (0.08 s). The wide potential window consequently increased the energy density from 6.8 Wh kg(-1) (ZnO/GNR symmetric) to 9.4 Wh kg( 1) (ZnO/GNR||LRGONR asymmetric). The relaxation time constant obtained for the asymmetric supercapacitor device was three orders of magnitude less compared to the ZnO (symmetric, 33 s) supercapacitor device. The high cycling stability of ZnO/GNR||LRGONR up to 96.7% capacitance retention, after 5000 GCD cycles at 2 mA cm(-2), paves the way to a high performance aqueous electrochemical supercapacitive energy storage. PMID- 26597971 TI - Preparing to respond: Irish nurses' perceptions of preparedness for an influenza pandemic. AB - INTRODUCTION: The aim of this research was to garner opinion on: the concerns of nurses in respect of the key issues that they may face in the event of an influenza pandemic; the perceived impact of an influenza pandemic on these nurses; and the current level of perceived preparedness in their hospital. Of particular significance is the fact that data for this study were gathered from nursing staff during a period when there was a heightened risk of an outbreak. METHODS: The data for this study were gathered using a structured, self administered questionnaire, which was distributed to 127 nurses. A response rate of 72% was achieved. The questionnaire was based on the instrument used by Wong et al. in their 2008 study of preparedness for an avian influenza pandemic in Singapore. RESULTS: Although the results reveal a number of concerns raised by nurses, it is clear that the majority (90%) view treating and caring for influenza patients as core to their role. While recognising their professional responsibilities, they reveal apprehension about certain aspects of their work, such as an increased likelihood of infection, added workload and pressures, an increased concern for those close to them who could become infected as well as the overall increase in stress levels at work. The extent of professional and personal preparedness, together with the concerns and perceptions of nurses, could affect the hospital's overall capacity to respond and these concerns should be addressed by those responsible for the development of pandemic response plan. PMID- 26597973 TI - Rasch analysis reveals comparative analyses of activities of daily living/instrumental activities of daily living summary scores from different residential settings is inappropriate. AB - OBJECTIVES: To internally validate a 15-item dichotomous activities of daily living (ADL) and instrumental activities of daily living (IADL) index. STUDY DESIGN AND SETTING: Data were extracted from The Older Persons and Informal Caregivers Survey Minimum DataSet (TOPICS-MDS). Using Rasch modeling, six aspects of the ADL/IADL scale were assessed: (1) overall fit, (2) internal consistency, (3) individual item and person fit, (4) local dependency, (5) targeting, and (6) differential item functioning (DIF) (RUMM 2030). All analyses were stratified by living situation [community-dwelling (n = 21,926) or residential care facility (n = 2,458)]. RESULTS: In both settings, "eating" was the easiest activity on the scale and "performing household tasks" was the most difficult activity. However, based on the location on the logit scale, the level of difficulty for certain items varied between residential settings, suggesting summary scores are not equivalent between these settings. DIF by gender and age group was observed for several items, indicating potential measurement bias in the scale. CONCLUSION: Unless adjustments are undertaken, ADL/IADL summary scores retrieved from older persons residing in the community or residential care facilities should not be directly compared. This 15-item scale is poorly targeted for a community-dwelling older population, underscoring the need for items with improved discriminative ability. PMID- 26597972 TI - Sensitivity subgroup analysis based on single-center vs. multi-center trial status when interpreting meta-analyses pooled estimates: the logical way forward. AB - OBJECTIVES: Prior studies regarding whether single-center trial estimates are larger than multi-center are equivocal. We examined the extent to which single center trials yield systematically larger effects than multi-center trials. STUDY DESIGN AND SETTING: We searched the 119 core clinical journals and the Cochrane Database of Systematic Reviews for meta-analyses (MAs) of randomized controlled trials (RCTs) published during 2012. In this meta-epidemiologic study, for binary variables, we computed the pooled ratio of ORs (RORs), and for continuous outcomes mean difference in standardized mean differences (SMDs), we conducted weighted random-effects meta-regression and random-effects MA modeling. Our primary analyses were restricted to MAs that included at least five RCTs and in which at least 25% of the studies used each of single trial center (SC) and more trial center (MC) designs. RESULTS: We identified 81 MAs for the odds ratio (OR) and 43 for the SMD outcome measures. Based on our analytic plan, our primary analysis (core) is based on 25 MAs/241 RCTs (binary outcome) and 18 MAs/173 RCTs (continuous outcome). Based on the core analysis, we found no difference in magnitude of effect between SC and MC for binary outcomes [RORs: 1.02; 95% confidence interval (CI): 0.83, 1.24; I(2) 20.2%]. Effect sizes were systematically larger for SC than MC for the continuous outcome measure (mean difference in SMDs: -0.13; 95% CI: -0.21, -0.05; I(2) 0%). CONCLUSIONS: Our results do not support prior findings of larger effects in SC than MC trials addressing binary outcomes but show a very similar small increase in effect in SC than MC trials addressing continuous outcomes. Authors of systematic reviews would be wise to include all trials irrespective of SC vs. MC design and address SC vs. MC status as a possible explanation of heterogeneity (and consider sensitivity analyses). PMID- 26597974 TI - How to communicate effect sizes for continuous outcomes: a review of existing options and introducing a new metric. AB - BACKGROUND AND OBJECTIVE: Communicating the results of studies is an important problem. For binary outcomes, communication is relatively straightforward and supported by several statistical tools (e.g., the risk ratio and the number needed to treat [NNT]). For continuous outcomes, the situation is much worse. We discuss several alternatives and propose a new metric, NNTthreshold, that is analogous to the NNT statistic for binary outcomes and that is useful when a clinically meaningful threshold can be identified. METHOD: We use both statistical theory and a statistical simulation to demonstrate how to compute NNTthreshold and to investigate how it behaves. RESULTS: NNTthreshold appears to function well, though is slightly conservative in our simulation. CONCLUSION: Study authors need to think carefully about how to discuss study results when outcomes are continuously scaled. NNTthreshold should be helpful in situations in which a clinically meaningful threshold can be identified. PMID- 26597975 TI - SensPrecOptimizer: a software tool that combined search queries to design efficient search strategies. PMID- 26597976 TI - Effects of general health checks differ under two different analyses perspectives the Inter99 randomized study. PMID- 26597977 TI - Deficiencies in reporting of statistical methodology in recent randomized trials of nonpharmacologic pain treatments: ACTTION systematic review. AB - OBJECTIVE: The goal of this study was to assess the quality of reporting of statistical methods in randomized clinical trials (RCTs), including identification of primary analyses, missing data accommodation, and multiplicity adjustment, in studies of nonpharmacologic, noninterventional pain treatments (e.g., physical therapy, cognitive behavioral therapy, acupuncture, and massage). STUDY DESIGN: Systematic review of 101 articles reporting RCTs of pain treatments that were published between January 2006 and June 2013 in the European Journal of Pain, the Journal of Pain, and Pain. SETTING: Systematic review. RESULTS: Sixty two percent of studies identified a primary outcome variable, 46% identified a primary analysis, and of those with multiple primary analyses, only 21% adjusted for multiplicity. Slightly over half (55%) of studies reported using at least one method to accommodate missing data. Only four studies reported prespecifying at least one of these four study methods. CONCLUSION: This review identified deficiencies in the reporting of primary analyses and methods to adjust for multiplicity and accommodate missing data in articles disseminating results of nonpharmacologic, noninterventional trials. Investigators should be encouraged to indicate whether their analyses were prespecified and to clearly and completely report statistical methods in clinical trial publications to maximize the interpretability of trial results. PMID- 26597978 TI - Coronary endothelial function assessment using self-gated cardiac cine MRI and k t sparse SENSE. AB - PURPOSE: Electrocardiogram (ECG)-gated cine MRI, paired with isometric handgrip exercise, can be used to accurately, reproducibly, and noninvasively measure coronary endothelial function (CEF). Obtaining a reliable ECG signal at higher field strengths, however, can be challenging due to rapid gradient switching and an increased heart rate under stress. To address these limitations, we present a self-gated cardiac cine MRI framework for CEF measurements that operates without ECG signal. METHODS: Cross-sectional slices of the right coronary artery (RCA) were acquired using a two-dimensional golden angle radial trajectory. This sampling approach, combined with the k-t sparse SENSE algorithm, allows for the reconstruction of both real-time images for self-gating signal calculations and retrospectively reordered self-gated cine images. CEF measurements were quantitatively compared using both the self-gated and the standard ECG-gated approach. RESULTS: Self-gated cine images with high-quality, temporal, and spatial resolution were reconstructed for 18 healthy volunteers. CEF as measured in self-gated images was in good agreement (R2 = 0.60) with that measured by its standard ECG-gated counterpart. CONCLUSION: High spatial and temporal resolution cross-sectional cine images of the RCA can be obtained without ECG signal. The coronary vasomotor response to handgrip exercise compares favorably with that obtained with the standard ECG-gated method. Magn Reson Med 76:1443-1454, 2015. (c) 2015 International Society for Magnetic Resonance in Medicine. PMID- 26597979 TI - Protocolised Management In Sepsis (ProMISe): a multicentre randomised controlled trial of the clinical effectiveness and cost-effectiveness of early, goal directed, protocolised resuscitation for emerging septic shock. AB - BACKGROUND: Early goal-directed therapy (EGDT) is recommended in international guidance for the resuscitation of patients presenting with early septic shock. However, adoption has been limited and uncertainty remains over its clinical effectiveness and cost-effectiveness. OBJECTIVES: The primary objective was to estimate the effect of EGDT compared with usual resuscitation on mortality at 90 days following randomisation and on incremental cost-effectiveness at 1 year. The secondary objectives were to compare EGDT with usual resuscitation for requirement for, and duration of, critical care unit organ support; length of stay in the emergency department (ED), critical care unit and acute hospital; health-related quality of life, resource use and costs at 90 days and at 1 year; all-cause mortality at 28 days, at acute hospital discharge and at 1 year; and estimated lifetime incremental cost-effectiveness. DESIGN: A pragmatic, open, multicentre, parallel-group randomised controlled trial with an integrated economic evaluation. SETTING: Fifty-six NHS hospitals in England. PARTICIPANTS: A total of 1260 patients who presented at EDs with septic shock. INTERVENTIONS: EGDT (n = 630) or usual resuscitation (n = 630). Patients were randomly allocated 1 : 1. MAIN OUTCOME MEASURES: All-cause mortality at 90 days after randomisation and incremental net benefit (at L20,000 per quality-adjusted life-year) at 1 year. RESULTS: Following withdrawals, data on 1243 (EGDT, n = 623; usual resuscitation, n = 620) patients were included in the analysis. By 90 days, 184 (29.5%) in the EGDT and 181 (29.2%) patients in the usual-resuscitation group had died [p = 0.90; absolute risk reduction -0.3%, 95% confidence interval (CI) -5.4 to 4.7; relative risk 1.01, 95% CI 0.85 to 1.20]. Treatment intensity was greater for the EGDT group, indicated by the increased use of intravenous fluids, vasoactive drugs and red blood cell transfusions. Increased treatment intensity was reflected by significantly higher Sequential Organ Failure Assessment scores and more advanced cardiovascular support days in critical care for the EGDT group. At 1 year, the incremental net benefit for EGDT versus usual resuscitation was negative at -L725 (95% CI -L3000 to L1550). The probability that EGDT was more cost-effective than usual resuscitation was below 30%. There were no significant differences in any other secondary outcomes, including health-related quality of life, or adverse events. LIMITATIONS: Recruitment was lower at weekends and out of hours. The intervention could not be blinded. CONCLUSIONS: There was no significant difference in all-cause mortality at 90 days for EGDT compared with usual resuscitation among adults identified with early septic shock presenting to EDs in England. On average, costs were higher in the EGDT group than in the usual-resuscitation group while quality-adjusted life-years were similar in both groups; the probability that it is cost-effective is < 30%. FUTURE WORK: The ProMISe (Protocolised Management In Sepsis) trial completes the planned trio of evaluations of EGDT across the USA, Australasia and England; all have indicated that EGDT is not superior to usual resuscitation. Recognising that each of the three individual, large trials has limited power for evaluating potentially important subgroups, the harmonised approach adopted provides the opportunity to conduct an individual patient data meta-analysis, enhancing both knowledge and generalisability. TRIAL REGISTRATION: Current Controlled Trials ISRCTN36307479. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 97. See the NIHR Journals Library website for further project information. PMID- 26597980 TI - Addiction Medicine: Current Status of Certification, Maintenance of Certification, Training, and Practice. AB - Addiction medicine (ADM) is an emerging medical field. It will soon be recognized by the American Board of Medical Specialties as a multispecialty subspecialty, sponsored by the American Board of Preventive Medicine. Certification and maintenance of certification in ADM are available currently through the American Board of Addiction Medicine (ABAM). There is an urgent need for trained and certified ADM physicians to serve the needs of patients and society. Thirty-seven addiction medicine fellowships of 12 months duration are now available, and their number is increasing. Physicians specializing in medical toxicology have educational, training, and practice overlap with addiction medicine. Medical toxicology physicians usually meet ADM examination eligibility requirements, based on clinical practice experience and continuing medical education activities. Those with fellowship training or in a fellowship bring training experience which has commonalities to ADM fellowship training, and therefore are particularly prepared for examination and practice in ADM. There are opportunities for partnerships in training, practice, and leadership between addiction medicine and medical toxicology. PMID- 26597981 TI - "Thermal Stabilization Effect" of Al2O3 nano-dopants improves the high temperature dielectric performance of polyimide. AB - Insulation performance of the dielectrics under extreme conditions always attracts widespread attention in electrical and electronic field. How to improve the high-temperature dielectric properties of insulation materials is one of the key issues in insulation system design of electrical devices. This paper studies the temperature-dependent corona resistance of polyimide (PI)/Al2O3 nanocomposite films under high-frequency square-wave pulse conditions. Extended corona resistant lifetime under high-temperature conditions is experimentally observed in the 2 wt% nanocomposite samples. The "thermal stabilization effect" is proposed to explain this phenomenon which attributes to a new kind of trap band caused by nanoparticles. This effect brings about superior space charge characteristics and corona resistance under high temperature with certain nano doping concentration. The proposed theory is experimentally demonstrated by space charge analysis and thermally stimulated current (TSC) tests. This discovered effect is of profound significance on improving high-temperature dielectric properties of nanocomposites towards various applications. PMID- 26597982 TI - Systemic Cytokine Profiles in Strongyloides stercoralis Infection and Alterations following Treatment. AB - Strongyloides stercoralis is a soil-transmitted helminth organism that infects ~50 to 100 million people worldwide. Despite its widespread prevalence, very little is known about the immune response that characterizes human S. stercoralis infection. To study the systemic cytokine profile characteristic of Strongyloides infection, we measured the circulating levels of a large panel of pro- and anti inflammatory cytokines in asymptomatic, infected individuals (n = 32) and compared them to those in uninfected, controls (n = 24). Infected individuals exhibited significantly lower circulating levels of proinflammatory cytokines (gamma interferon [IFN-gamma], tumor necrosis factor alpha [TNF-alpha], and interleukin-1beta [IL-1beta]) and significantly higher levels of anti inflammatory cytokines (IL-4, IL-5, IL-9, IL-10, IL-13, IL-27, IL-37, and transforming growth factor beta [TGF-beta]). Moreover, treatment of Strongyloides infection resulted in a significant reversal of the cytokine profile, with increased levels of proinflammatory (IFN-gamma, TNF-alpha, IL-2, IL-17A, IL-17F, IL-22, IL-23, and IL-1beta) and decreased levels of anti-inflammatory (IL-4, IL 5, IL-9, IL-10, IL-13, IL-27, IL-37, and TGF-beta) cytokines following treatment. Thus, S. stercoralis infection is characterized by alterations in the levels of systemic cytokines, reflecting major alterations in the underlying immune response to this chronic helminth infection. PMID- 26597983 TI - ALL2, a Homologue of ALL1, Has a Distinct Role in Regulating pH Homeostasis in the Pathogen Cryptococcus neoformans. AB - Cryptococcus neoformans is a facultative intracellular fungal pathogen that has a polysaccharide capsule and causes life-threatening meningoencephalitis. Its capsule, as well as its ability to survive in the acidic environment of the phagolysosome, contributes to the pathogen's resilience in the host environment. Previously, we reported that downregulation of allergen 1 (ALL1) results in the secretion of a shorter, more viscous exopolysaccharide with less branching and structural complexity, as well as altered iron homeostasis. Now, we report on a homologous coregulated gene, allergen 2 (ALL2). ALL2's function was characterized by generating null mutants in C. neoformans. In contrast to ALL1, loss of ALL2 attenuated virulence in the pulmonary infection model. The all2Delta mutant shed a less viscous exopolysaccharide and exhibited higher sensitivity to hydrogen peroxide than the wild type, and as a result, the all2Delta mutant was more resistant to macrophage-mediated killing. Transcriptome analysis further supported the distinct function of these two genes. Unlike ALL1's involvement in iron homeostasis, we now present data on ALL2's unique function in maintaining intracellular pH in low-pH conditions. Thus, our data highlight that C. neoformans, a human-pathogenic basidiomycete, has evolved a unique set of virulence-associated genes that contributes to its resilience in the human niche. PMID- 26597984 TI - Impaired Immunogenicity of Meningococcal Neisserial Surface Protein A in Human Complement Factor H Transgenic Mice. AB - Neisserial surface protein A (NspA) is a highly conserved outer membrane protein previously investigated as a meningococcal vaccine candidate. Despite eliciting serum bactericidal activity in mice, a recombinant NspA vaccine failed to elicit serum bactericidal antibodies in a phase 1 clinical trial in humans. The discordant results may be explained by the recent discovery that NspA is a human specific ligand of the complement inhibitor factor H (FH). Therefore, in humans but not mice, NspA would be expected to form a complex with FH, which could impair human anti-NspA protective antibody responses. To investigate this question, we immunized human FH transgenic BALB/c mice with three doses of recombinant NspA expressed in Escherichia coli microvesicles, with each dose being separated by 3 weeks. Three of 12 (25%) transgenic mice and 13 of 14 wild type mice responded with bactericidal titers of >=1:10 in postimmunization sera (P = 0.0008, Fisher's exact test). In contrast, human FH transgenic and wild-type mice immunized with a control meningococcal native outer membrane vesicle vaccine had similar serum bactericidal antibody responses directed at PorA, which is not known to bind human FH, and a mutant factor H binding protein (FHbp) antigen with a >50-fold lower level of FH binding than wild-type FHbp antigen binding.Thus, human FH can impair anti-NspA serum bactericidal antibody responses, which may explain the poor immunogenicity of the NspA vaccine previously tested in humans. A mutant NspA vaccine engineered to have decreased binding to human FH may increase protective antibody responses in humans. PMID- 26597985 TI - The Vaccine Candidate Substrate Binding Protein SBP2 Plays a Key Role in Arginine Uptake, Which Is Required for Growth of Moraxella catarrhalis. AB - Moraxella catarrhalis is an exclusively human pathogen that is an important cause of otitis media in children and lower respiratory tract infections in adults with chronic obstructive pulmonary disease. A vaccine to prevent M. catarrhalis infections would have an enormous global impact in reducing morbidity resulting from these infections. Substrate binding protein 2 (SBP2) of an ABC transporter system has recently been identified as a promising vaccine candidate antigen on the bacterial surface of M. catarrhalis. In this study, we showed that SBP1, -2, and -3 individually bind different basic amino acids with exquisite specificity. We engineered mutants that each expressed a single SBP from this gene cluster and showed in growth experiments that SBP1, -2, and -3 serve a nutritional function through acquisition of amino acids for the bacterium. SBP2 mediates uptake of arginine, a strict growth requirement of M. catarrhalis. Adherence and invasion assays demonstrated that SBP1 and SBP3 play a role in invasion of human respiratory epithelial cells, consistent with a nutritional role in intracellular survival in the human respiratory tract. This work demonstrates that the SBPs of an ABC transporter system function in the uptake of basic amino acids to support growth of M. catarrhalis. The critical role of SBP2 in arginine uptake may contribute to its potential as a vaccine antigen. PMID- 26597986 TI - Enhanced Direct Major Histocompatibility Complex Class I Self-Antigen Presentation Induced by Chlamydia Infection. AB - The direct major histocompatibility complex (MHC) class I antigen presentation pathway ensures intracellular peptides are displayed at the cellular surface for recognition of infected or transformed cells by CD8(+) cytotoxic T lymphocytes. Chlamydia spp. are obligate intracellular bacteria and, as such, should be targeted by CD8(+) T cells. It is likely that Chlamydia spp. have evolved mechanisms to avoid the CD8(+) killer T cell responses by interfering with MHC class I antigen presentation. Using a model system of self-peptide presentation which allows for posttranslational control of the model protein's stability, we tested the ability of various Chlamydia species to alter direct MHC class I antigen presentation. Infection of the JY lymphoblastoid cell line limited the accumulation of a model host protein and increased presentation of the model protein-derived peptides. Enhanced self-peptide presentation was detected only when presentation was restricted to defective ribosomal products, or DRiPs, and total MHC class I levels remained unaltered. Skewed antigen presentation was dependent on a bacterial synthesized component, as evidenced by reversal of the observed phenotype upon preventing bacterial transcription, translation, and the inhibition of bacterial lipooligosaccharide synthesis. These data suggest that Chlamydia spp. have evolved to alter the host antigen presentation machinery to favor presentation of defective and rapidly degraded forms of self-antigen, possibly as a mechanism to diminish the presentation of peptides derived from bacterial proteins. PMID- 26597987 TI - The Chromosome-Encoded Hypothetical Protein TC0668 Is an Upper Genital Tract Pathogenicity Factor of Chlamydia muridarum. AB - We previously associated a missense mutation of the tc0668 gene of serial in vitro-passaged Chlamydia muridarum, a murine model of human urogenital C. trachomatis, with severely attenuated disease development in the upper genital tract of female mice. Since these mutants also contained a TC0237 Q117E missense mutation that enhances their in vitro infectivity, an effort was made here to isolate and characterize a tc0668 single mutant to determine its individual contribution to urogenital pathogenicity. Detailed genetic analysis of C. muridarum passages revealed a truncated variant with a G216* nonsense mutation of the 408-amino-acid TC0668 protein that does not produce a detectable product. Intracellular growth and infectivity of C. muridarum in vitro remain unaffected in the absence of TC0668. Intravaginal inoculation of the TC0668 null mutant into C3H/HeJ mice results in a typical course of lower genital tract infection but, unlike a pathogenic isogenic control, is unable to elicit significant chronic inflammation of the oviduct and fails to induce hydrosalpinx. Thus, TC0668 is demonstrated as an important chromosome-encoded urogenital pathogenicity factor of C. muridarum and the first with these characteristics to be discovered for a Chlamydia pathogen. PMID- 26597988 TI - The GraS Sensor in Staphylococcus aureus Mediates Resistance to Host Defense Peptides Differing in Mechanisms of Action. AB - Staphylococcus aureus uses the two-component regulatory system GraRS to sense and respond to host defense peptides (HDPs). However, the mechanistic impact of GraS or its extracellular sensing loop (EL) on HDP resistance is essentially unexplored. Strains with null mutations in the GraS holoprotein (DeltagraS) or its EL (DeltaEL) were compared for mechanisms of resistance to HDPs of relevant immune sources: neutrophil alpha-defensin (human neutrophil peptide 1 [hNP-1]), cutaneous beta-defensin (human beta-defensin 2 [hBD-2]), or the platelet kinocidin congener RP-1. Actions studied by flow cytometry included energetics (ENR); membrane permeabilization (PRM); annexin V binding (ANX), and cell death protease activation (CDP). Assay conditions simulated bloodstream (pH 7.5) or phagolysosomal (pH 5.5) pH contexts. S. aureus strains were more susceptible to HDPs at pH 7.5 than at pH 5.5, and each HDP exerted a distinct effect signature. The impacts of DeltagraS and DeltaEpsilonL on HDP resistance were peptide and pH dependent. Both mutants exhibited defects in ANX response to hNP-1 or hBD-2 at pH 7.5, but only hNP-1 did so at pH 5.5. Both mutants exhibited hyper-PRM, -ANX, and -CDP responses to RP-1 at both pHs and hypo-ENR at pH 5.5. The actions correlated with DeltagraS or DeltaEpsilonL hypersusceptibility to hNP-1 or RP-1 (but not hBD 2) at pH 7.5 and to all study HDPs at pH 5.5. An exogenous EL mimic protected mutant strains from hNP-1 and hBD-2 but not RP-1, indicating that GraS and its EL play nonredundant roles in S. aureus survival responses to specific HDPs. These findings suggest that GraS mediates specific resistance countermeasures to HDPs in immune contexts that are highly relevant to S. aureus pathogenesis in humans. PMID- 26597989 TI - PACSAB: Coarse-Grained Force Field for the Study of Protein-Protein Interactions and Conformational Sampling in Multiprotein Systems. AB - Molecular dynamics simulations of proteins are usually performed on a single molecule, and coarse-grained protein models are calibrated using single-molecule simulations, therefore ignoring intermolecular interactions. We present here a new coarse-grained force field for the study of many protein systems. The force field, which is implemented in the context of the discrete molecular dynamics algorithm, is able to reproduce the properties of folded and unfolded proteins, in both isolation, complexed forming well-defined quaternary structures, or aggregated, thanks to its proper evaluation of protein-protein interactions. The accuracy and computational efficiency of the method makes it a universal tool for the study of the structure, dynamics, and association/dissociation of proteins. PMID- 26597990 TI - Pulse EPR-enabled interpretation of scarce pseudocontact shifts induced by lanthanide binding tags. AB - Pseudocontact shifts (PCS) induced by tags loaded with paramagnetic lanthanide ions provide powerful long-range structure information, provided the location of the metal ion relative to the target protein is known. Usually, the metal position is determined by fitting the magnetic susceptibility anisotropy (Deltachi) tensor to the 3D structure of the protein in an 8-parameter fit, which requires a large set of PCSs to be reliable. In an alternative approach, we used multiple Gd(3+)-Gd(3+) distances measured by double electron-electron resonance (DEER) experiments to define the metal position, allowing Deltachi-tensor determinations from more robust 5-parameter fits that can be performed with a relatively sparse set of PCSs. Using this approach with the 32 kDa E. coli aspartate/glutamate binding protein (DEBP), we demonstrate a structural transition between substrate-bound and substrate-free DEBP, supported by PCSs generated by C3-Tm(3+) and C3-Tb(3+) tags attached to a genetically encoded p azidophenylalanine residue. The significance of small PCSs was magnified by considering the difference between the chemical shifts measured with Tb(3+) and Tm(3+) rather than involving a diamagnetic reference. The integrative sparse data approach developed in this work makes poorly soluble proteins of limited stability amenable to structural studies in solution, without having to rely on cysteine mutations for tag attachment. PMID- 26597992 TI - Telemedicine for general practice: a systematic review protocol. AB - BACKGROUND: The use of information technology in healthcare is fast becoming an alternative and supporting method of providing many forms of services in a healthcare and health management setting. Telephone technology is used readily to deliver services such as disease management, consultations and behaviour coaching. Telemedicine provides a promising alternative and supporting service for face-to-face general practice care. The aim of this review is to utilise a systematic review to collate evidence on the use of telemedicine as a lead in and an alternative to general practice visits. METHODS/DESIGN: A systematic search of MEDLINE, CINAHL, the Cochrane Library and the International Clinical Trials Registry Platform will be performed using the search terms for the intervention (telemedicine) and the comparator (general practice) to search the databases. The systematic review aims to identify randomised control trials; however, if none are identified, an updated search will be conducted to identify lower levels of evidence. Papers will be reviewed and assessed for quality and data extracted using two reviewers; if consensus is required, a third reviewer will be consulted. If applicable, a meta-analysis of relevant outcomes will be conducted. The protocol has been reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocols (PRISMA-P) guidelines. DISCUSSION: The intervention and comparator have the potential to provide a vast range of healthcare services to a range of diseases and health conditions. There is likely to be difficulty in identifying relevant clinical outcome measures for the patient population. A range of outcome measures will therefore be collected in the data extraction phase. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015025225. PMID- 26597993 TI - Varying hemin concentrations affect Porphyromonas gingivalis strains differently. AB - Porphyromonas gingivalis requires heme to grow, however, heme availability and concentration in the periodontal pockets vary. Fluctuations in heme concentration may affect each P. gingivalis strain differently, however, this was never fully demonstrated. Here, we elucidated the effects of varying hemin concentrations in representative P. gingivalis strains. Throughout this study, representative P. gingivalis strains [FDC381 (type I), MPWIb-01 (type Ib), TDC60 (type II), ATCC49417 (type III), W83 (type IV), and HNA99 (type V)] were used and grown for 24 h in growth media under varying hemin concentrations (5 * , 1 * , 0.5 * , 0.1 * ). Samples were lysed and protein standardized. Arg-gingipain (Rgp), H2O2, and superoxide dismutase (SOD) levels were subsequently measured. We focused our study on 24 h-grown strains which excluded MPWIb-01 and HNA99. Rgp activity among the 4 remaining strains varied with Rgp peaking at: 1 * for FDC381, 5 * for TDC60, 0.5 * for ATCC49417, 5 * and 0.5 * for W83. With regards to H2O2 and SOD amounts: FDC381 had similar H2O2 amounts in all hemin concentrations while SOD levels varied; TDC60 had the lowest H2O2 amount at 1 * while SOD levels became higher in relation to hemin concentration; ATCC49417 also had similar H2O2 amounts in all hemin concentrations while SOD levels were higher at 1 * and 0.5 * ; and W83 had statistically similar H2O2 and SOD amounts regardless of hemin concentration. Our results show that variations in hemin concentration affect each P. gingivalis strain differently. PMID- 26597991 TI - How Professionals View Multifamily Psychoeducation: A Qualitative Study. AB - Severe mental illness causes suffering for the patient as well as the patient's immediate family. The Swedish National Board of Health and Welfare has recommended the implementation of multifamily psychoeducation in order to assist patient and family in the recovery process. The aim of this study was to determine how introducing multifamily psychoeducation in Sweden has been viewed by professionals. Semi-structured interviews were conducted with 11 service providers, who were involved in evaluating multifamily psychoeducation. Our main findings fell under the headings of defensive culture and unsuitable model. Resistance to introducing the new intervention was found on multiple levels. The model proposed was considered too rigid for both the target group and the organizations because it could not be adjusted to the needs of patients, families, or facilitators. Despite good evidence for the effectiveness of the intervention, there were difficulties introducing the multifamily psychoeducation model in clinical practice. The feasibility of an intervention needs to be evaluated before adopting it as a national guideline. PMID- 26597994 TI - Behavioral and physiological response to onset and termination of social instability in female mice. AB - Chronic stress has been associated with several negative health outcomes and psychopathological conditions. One source of chronic stress might be from ones social environment (e.g., being excluded from a group, losing a loved one, etc.). Specifically, social instability, or frequent changes in the social environment, can result in both physiological and behavioral stress responses. Corticosterone is the primary stress-responsive biomarker in rodents, and it reflects the activity of the hypothalamic-pituitary-adrenal (HPA) axis. Historically, research on the effects of stress has relied on collection of blood, saliva, or other bodily fluids that yield information about moment-to-moment changes in stress physiology. Recently, new sampling techniques involving quantification of glucocorticoids in hair has allowed researchers to view patterns of stress physiology over extended periods of time. This study assessed the effects of chronic social instability on corticosterone levels in female mice. Mice that were subjected to social instability showed elevated hair corticosterone compared to baseline levels and as compared to controls. Additionally, when mice were returned to stable social environments, corticosterone levels returned to levels comparable to baseline and to control animals. This suggests that the corticosterone in hair from female mice can serve as a useful biomarker of chronic stress, and that social instability is a sufficient stressor to elicit an extended HPA response. PMID- 26597995 TI - Effects of dietary leucine supplementation in low crude protein diets on performance, nitrogen balance, whole-body protein turnover, carcass characteristics and meat quality of finishing pigs. AB - Eighteen Duroc * Landrace * Yorkshire barrows, with an average initial body weight (BW) of 75.4 +/- 2.0 kg, were randomly allotted to one of three diets with six replicates per treatment for 25 days. The diets comprised a normal protein diet (NP, 14.5% crude protein), a low crude protein diet supplemented with 0.27% alanine (LP + Ala, 10.0% crude protein), or a low crude protein diet supplemented with 0.40% leucine (LP + Leu, 10.0% crude protein). The whole-body protein synthesis rate, whole-body protein breakdown rate and protein deposition rate in pigs fed the LP + Leu diet were similar to the NP diet (P > 0.05), and both were significantly higher than pigs fed the LP + Ala diet (P < 0.05). The Longissimus muscle area (LMA) of pigs fed the LP + Leu diet was larger than those fed the LP + Ala diet (P = 0.05). In addition, drip loss and intramuscular fat of pigs fed the LP + Ala diet were higher than that of the others (P < 0.05). In conclusion, supplementation of leucine in low protein diet could stimulate protein deposition and improve the meat quality of finishing pigs more than an alanine-supplemented one. PMID- 26597996 TI - Diagnosis of HIV infection on the basis of histoplasmosis-related oral ulceration. AB - Histoplasmosis is an endemic systemic mycosis caused by the dimorphic fungus Histoplasma capsulatum. In immunocompromised patients, histoplasmosis generally occurs as an opportunistic disease, with dissemination to various organs. Cutaneous involvement is observed in 38% to 85% of cases, with oral mucosal involvement in 30% to 60% of cases. This article describes the case study of a 32 year-old woman who presented an extensive tongue ulcer due to histoplasmosis and had the HIV infection diagnosis based on laboratory tests requested by the dentist. PMID- 26597997 TI - Characterization of the binding of paylean and DNA by fluorescence, UV spectroscopy and molecular docking techniques. AB - The interaction of paylean (PL) with calf thymus DNA (ctDNA) was investigated using fluorescence spectroscopy, UV absorption, melting studies, ionic strength, viscosity experiments and molecular docking under simulated physiological conditions. Values for the binding constant Ka between PL and DNA were 5.11 * 10(3) , 2.74 * 10(3) and 1.74 * 10(3) L mol(-1) at 19, 29 and 39 degrees C respectively. DNA quenched the intrinsic fluorescence of PL via a static quenching procedure as shown from Stern-Volmer plots. The relative viscosity and the melting temperature of DNA were basically unchanged in the presence of PL. The fluorescence intensity of PL-DNA decreased with increasing ionic strength. The value of Ka for PL with double-stranded DNA (dsDNA) was larger than that for PL with single-stranded DNA (ssDNA). All the results revealed that the binding mode was groove binding, and molecular docking further indicated that PL was preferentially bonded to A-T-rich regions of DNA. The values for DeltaH, DeltaS and DeltaG suggested that van der Waals forces or hydrogen bonding might be the main acting forces between PL and DNA. The binding distance was determined to be 3.37 nm based on the theory of Forster energy transference, which indicated that a non-radiation energy transfer process occurred. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26597998 TI - Absence of both CD56 and CD117 expression on malignant plasma cells is related with a poor prognosis in patients with newly diagnosed multiple myeloma. AB - We retrospectively evaluated the association between the expression of CD56 and CD117 on neoplastic plasma cells and patients prognosis in 50 newly diagnosed multiple myeloma (MM) patients. The overall survival (OS) was measured and Cox proportional hazards model was used to evaluate CD56 and CD117 as possible prognostic factors for OS. CD56+ and CD117+ were detected in 74% and 32% multiple myeloma cases, respectively. In Kaplan-Meier analysis, CD56 and CD117 expression demonstrated potential prognostic impacts and were associated with longer OS (CD56: p=0.004, CD117: p=0.022), absence of both of them showed significantly shorter OS (p=0.046 compared to CD56+/CD117+ group, p=0.014 compared to CD56 /CD117+ or CD56+/CD117- group). Multivariate analysis showed that CD56 was independently prognostic of longer OS (p=0.012). After induction chemotherapy, overall response rates (ORR) was higher in CD56-positive group compared to CD56 negative group (70.6% versus 30.0%, p=0.024), however, there was no difference between CD117-positive and CD117-negative group (69.2% versus 58.1%, p=0.448). This study demonstrated the prognostic value of CD56 and CD117 in patients with newly diagnosed MM patients. Absence of both of them was associated with the poorest prognosis. PMID- 26597999 TI - Try-It-On: Experiential Learning of Holistic Stress Management in a Graduate Nursing Curriculum. AB - The aim of this article is to relate how nursing students in a graduate curriculum can learn, personally practice, and prepare to disseminate stress management strategies to patients. Advanced practice nurses often provide care for patients experiencing stress-related disorders while concurrently trying to manage their own high levels of stress. Through the innovative Try-It-On teaching learning strategy, graduate students experimented with holistic stress management approaches, with the intention of sharing with patients what worked effectively. Student comments on course evaluations were positive regarding Try-It-On. In the pilot trial of a quantitative survey to expand the evaluation of the strategy, students who trialed holistic stress management techniques reported satisfaction, engagement, perceived relevance, and intention to trial techniques with patients in future clinical courses. Modeling role modeling theory and the Kirkpatrick evaluation model guided the project, which filled gaps in current knowledge about experiential learning in graduate nursing programs. PMID- 26598000 TI - Evaluation of a Meditation Intervention to Reduce the Effects of Stressors Associated With Compassion Fatigue Among Nurses. AB - PURPOSE OF STUDY: This pilot study evaluated whether short (less than 10 minutes) structured meditations decrease compassion fatigue and improve compassion satisfaction in oncology nurses. DESIGN OF STUDY: A nonrandomized, pre-post intervention study. METHODS USED: Participants used specific meditations designed to establish a sense of calm, relaxation, and self-compassion 5 days a week for 4 weeks. Meditations were provided on an audio-CD after brief individual instruction. The Professional Quality of Life Survey, Version 5, was administered pre and post intervention along with supplementary questions. FINDINGS: Fifteen nurses participated in the study over a 6-month period in 2014. Paired t test revealed that the intervention demonstrated a statistically significant increase in Compassion Satisfaction scores (mean difference = -2.66, 95% confidence interval [CI] = [-4.98, -0.36], t[14] = -2.48, p = .027, d = 0.63) and decreases in Burnout (mean difference = 4.13, 95% CI = [1.66, 6.60], t[14] = 3.581, p = .003, d = 0.92) and Secondary Trauma (mean difference = 3.00, 95% CI = [0.40, 5.96], t[14] = 2.174, p = .047, d = 0.56) scores. All participants reported increased feelings of relaxation and well-being on supplemental questions. CONCLUSIONS: Even in this small sample, the practice of short breathing and meditation exercises was effective in improving nurse outcomes. A larger study is warranted including tracking sustained effects relative to maintaining a meditation practice. PMID- 26598001 TI - Utilization of Cavity Vortex To Delay the Wetting Transition in One-Dimensional Structured Microchannels. AB - Frictional resistance across rough surfaces depends on the existence of slip on the liquid-gas interface; therefore, prolonging the existence of liquid-gas interface becomes relevant. In this work, we explore manipulation of the cavity shape in order to delay the wetting transition. We propose that liquid-driven vortices generated in the air cavity dissipate sufficient energy to delay the Cassie-Wenzel transition. Toward this, we fabricated cavities on the side walls of a polydimethylsiloxane-based microchannel for easy visualization and analysis of the dynamics of the liquid-gas interface. Two distinct flow regimes are identified in the experimental envelope. In the first regime, the liquid-gas interface is found to be protruding into the flow field, thus increasing the pressure drop at low Reynolds number. In the second regime, flow rate and geometry-based wetting transitions are established at moderate to high Reynolds numbers. We then investigate the effect of different cavity shapes (square, trapezoidal, and U-shape) in delaying the wetting transition by manipulating liquid-driven vortices. Out of the shapes considered in this study, trapezoidal cavities perform better than cavities with vertical walls in delaying the wetting transition due to geometrical squeezing of vortices toward the liquid-gas interface. Numerical simulations corroborate the experimental findings in that cavities with inclined walls exert more force on the liquid-gas interface, thus delaying their wetting transition. The proposed method being passive in nature appears more attractive than previous active methods. PMID- 26598002 TI - Chlorogenic acid protects against cholestatic liver injury in rats. AB - The aim of this study was to investigate the protective effect of chlorogenic acid (CA) on liver injury caused by bile duct ligation (BDL), as well as the potential mechanism. Permanent bile duct ligation induced liver injury was evaluated by liver index, liver function and pathological observation. Oral administration of CA for 3 weeks markedly attenuated liver swelling and fibrosis. Blood biochemistry results revealed that CA decreased alanine transaminase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, direct bilirubin and total bile acid. PCR analysis indicated that collagen I, collagen III, transforming growth factor and vascular endothelial growth factor mRNA were increased markedly by BDL treatment but these increases were suppressed by CA. Additionally, CA effectively alleviated the expression of alpha-smooth muscle actin induced by BDL. Taken together, our data indicate that CA can efficiently inhibit BDL-induced liver injury in rats, which is a candidate drug for preventing liver injury against cholestasis. PMID- 26598003 TI - Goshajinkigan reduces bortezomib-induced mechanical allodynia in rats: Possible involvement of kappa opioid receptor. AB - In the present study, we investigated the effect of a Kampo medicine Goshajinkigan (GJG) on the bortezomib-induced mechanical allodynia in von Frey test in rats. The single administration of tramadol (10 mg/kg), GJG (1.0 g/kg) and its component processed Aconiti tuber (0.1 g/kg) significantly reversed the reduction in withdrawal threshold by bortezomib. These effects were abolished by the intrathecal injection of nor-binaltorphimine (10 MUg/body), kappa opioid receptor antagonist. These findings suggest that kappa opioid receptor is involved in the effect of GJG on the bortezomib-induced mechanical allodynia. PMID- 26598004 TI - Compensatory role of the Nrf2-ARE pathway against paraquat toxicity: Relevance of 26S proteasome activity. AB - Oxidative stress and the ubiquitin-proteasome system play a key role in the pathogenesis of Parkinson disease. Although the herbicide paraquat is an environmental factor that is involved in the etiology of Parkinson disease, the role of 26S proteasome in paraquat toxicity remains to be determined. Using PC12 cells overexpressing a fluorescent protein fused to the proteasome degradation signal, we report here that paraquat yielded an inhibitory effect on 26S proteasome activity without an obvious decline in 20S proteasome activity. Relative low concentrations of proteasome inhibitors caused the accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2), which is targeted to the ubiquitin-proteasome system, and activated the antioxidant response element (ARE) dependent transcription. Paraquat also upregulated the protein level of Nrf2 without increased expression of Nrf2 mRNA, and activated the Nrf2-ARE pathway. Consequently, paraquat induced expression of Nrf2-dependent ARE-driven genes, such as gamma-glutamylcysteine synthetase, catalase, and hemeoxygenase-1. Knockdown of Nrf2 or inhibition of gamma-glutamylcysteine synthetase and catalase exacerbated paraquat-induced toxicity, whereas suppression of hemeoxygenase-1 did not. These data indicate that the compensatory activation of the Nrf2-ARE pathway via inhibition of 26S proteasome serves as part of a cellular defense mechanism to protect against paraquat toxicity. PMID- 26598005 TI - JTT-130, a novel intestine-specific inhibitor of microsomal triglyceride transfer protein, ameliorates lipid metabolism and attenuates atherosclerosis in hyperlipidemic animal models. AB - JTT-130 was developed as an intestine-specific MTP inhibitor designed to rapidly catabolize after absorption to avoid causing hepatotoxicity due to hepatic MTP inhibition. In previous reports, we have demonstrated that JTT-130 suppresses dietary lipid absorption in the small intestine without inducing hepatic steatosis. Thus, in this report, JTT-130 was administered to hyperlipidemic animals fed a Western diet to investigate the effect of intestinal MTP inhibition on lipid metabolism and progression of atherosclerosis. JTT-130 potently lowered plasma non-high density lipoprotein-cholesterol, and elevated plasma high density lipoprotein-cholesterol (HDL-C), indicating improvement in atherogenic index in hamsters. HDL fractions obtained after two weeks treatment with JTT-130 significantly increased the efflux of cholesterol from macrophages, as an index parameter of HDL function. Furthermore, long-term treatment with JTT-130 also improved the plasma lipid profile without inducing hepatic steatosis in rabbits, resulting in the suppression of atherosclerosis formation in aortas. From these results, JTT-130 ameliorates lipid metabolism accompanied with the enhancement of the anti-atherosclerotic function of HDL, and attenuates the progression of atherosclerosis in hyperlipidemic animals. These findings indicate that intestinal MTP inhibition may be atherogenic in vivo and that JTT-130 may be a useful compound for the treatment of dyslipidemia and a potential anti atherogenic drug. PMID- 26598006 TI - Effects of antihistamine on up-regulation of histamine H1 receptor mRNA in the nasal mucosa of patients with pollinosis induced by controlled cedar pollen challenge in an environmental exposure unit. AB - In the present study, we examined the effects of antihistamine on the up regulation of H1R mRNA in the nasal mucosa of patients with pollinosis induced by controlled exposure to pollen using an environmental exposure unit. Out of 20 patients, we designated 14 responders, whose levels of H1R mRNA in the nasal mucosa were increased after the first pollen exposure and excluded 6 non responders. Accordingly, the first exposure to pollen without treatment significantly induced both nasal symptoms and the up-regulation of H1R mRNA in the nasal mucosa of the responders. Subsequently, prophylactic administration of antihistamine prior to the second pollen exposure significantly inhibited both of the above effects in the responders. Moreover, the nasal expression of H1R mRNA before the second pollen exposure in the responders pretreated with antihistamine was significantly decreased, as compared with that before the first pollen exposure without treatment. These findings suggest that antihistamines suppressed histamine-induced transcriptional activation of H1R gene in the nasal mucosa, in addition to their blocking effect against histamine on H1R, resulting in a decrease of nasal symptoms. These findings further suggest that by their inverse agonistic activity, antihistamines suppress the basal transcription of nasal H1R in the absence of histamine in responders. PMID- 26598007 TI - High incidence of atrial fibrillation after coronary surgery. AB - OBJECTIVES: Postoperative atrial fibrillation (POAF) affects a third of all patients after coronary artery bypass surgery (CABG), but short-term follow-up of heart rhythm after discharge has been sporadic and shown varied results. The aim of this study was to examine the incidence of post-discharge atrial fibrillation (AF) for 30 days following hospital discharge after CABG. METHODS: A total of 67 patients, 19 (28%) with POAF during the initial hospitalization and 48 (72%) without POAF were included. Patients recorded intermittent electrocardiogram registrations three times daily, and additionally in case of arrhythmia symptoms. Presence of post-discharge AF was compared between the groups. All patients were in sinus rhythm at discharge. RESULTS: Twenty of 67 patients (30%) were diagnosed with post-discharge AF. Overall, 35% of them were entirely asymptomatic. POAF patients had a higher incidence of post-discharge AF (11 of 19, 58%) than non POAF patients (9 of 48, 19%), with six times the odds of developing post discharge AF compared with non-POAF patients [odds ratio (OR) 6.0; 95% CI 1.9-19, P = 0.002]. Patients with POAF registered episodes of post-discharge AF earlier during the follow-up period (mean Day 3 after discharge, range 1-9 days) than non POAF patients (Day 10, range 7-14 days, P < 0.001). CONCLUSIONS: A high incidence of both symptomatic and asymptomatic AF was recorded during 30 days following hospital discharge after CABG. The incidence was highest among patients with POAF, of whom more than half experienced post-discharge AF. PMID- 26598008 TI - Celsior preserves cardiac mechano-energetics better than University of Wisconsin solution by preventing oxidative stress. AB - OBJECTIVES: Identity of the optimal heart preservation solution remains unknown. Because oxidative stress contributes to contractile failure in the ischaemic/reperfused myocardium and the main characteristic of Celsior is its antioxidant effect, it is important to elucidate the relationship between the inhibitory effect on oxidative stress and cardiac mechano-energetics. We therefore evaluated the efficacy of Celsior from both aspects by comparison with the University of Wisconsin solution (UWS). METHODS: We used 18 excised cross circulated canine hearts. Excised hearts were preserved with UWS (n = 6) or Celsior (n = 6) for 3 h at 4 degrees C; the remaining six served as controls. Hearts were then cross-circulated and rewarmed. The end-systolic pressure-volume ratio (LV Emax) and the ventricular pressure-volume area, which is a measure of total mechanical energy, were assessed after reperfusion. Biopsies were taken from the endocardium after excising the heart, before reperfusion, after reperfusion and 4 h after reperfusion to assess the inhibitory effect of each agent on oxidative stress. Endo-myocardial biopsy samples were studied immunohistochemically for expression of 4-hydroxy-2-nonenal (HNE)-modified protein, which is a major lipid peroxidation product. RESULTS: Emax in the UWS group was significantly smaller than in the control group, whereas the Emax in the Celsior group was preserved. Oxygen cost of Emax in the UWS group was significantly higher than in the Celsior group. Myocardial HNE-modified protein levels increased gradually, both under preservation and after reperfusion in the UWS group. Myocardial HNE-modified protein levels in the Celsior group were lower, mainly before and 4 h after reperfusion compared with the UWS group. CONCLUSIONS: Celsior may maintain cardiac contractility and conserve oxygen cost by inhibiting oxidative stress. PMID- 26598011 TI - Oral. PMID- 26598009 TI - Identification of novel autophagic Radix Polygalae fraction by cell membrane chromatography and UHPLC-(Q)TOF-MS for degradation of neurodegenerative disease proteins. AB - With its traditional use in relieving insomnia and anxiety, our previous study has identified onjisaponin B from Radix Polygalae (RP), as a novel autophagic enhancer with potential neuroprotective effects. In current study, we have further identified a novel active fraction from RP, contains 17 major triterpenoid saponins including the onjisaponin B, by the combinational use of cell membrane chromatography (CMC) and ultra-performance liquid chromatography coupled to (quadrupole) time-of-flight mass spectrometry {UHPLC-(Q)TOF-MS}. By exhibiting more potent autophagic effect in cells, the active fraction enhances the clearance of mutant huntingtin, and reduces protein level and aggregation of alpha-synuclein in a higher extent when compared with onjisaponin B. Here, we have reported for the first time the new application of cell-based CMC and UHPLC (Q)TOF-MS analysis in identifying new autophagy inducers with neuroprotective effects from Chinese medicinal herb. This result has provided novel insights into the possible pharmacological actions of the active components present in the newly identified active fraction of RP, which may help to improve the efficacy of the traditional way of prescribing RP, and also provide new standard for the quality control of decoction of RP or its medicinal products in the future. PMID- 26598012 TI - Poster - Gastroenterology. PMID- 26598010 TI - NK cell compartment in the peripheral blood and spleen in adult patients with primary immune thrombocytopenia. AB - Immune thrombocytopenic purpura (ITP) is a disease characterized by antibody mediated platelet destruction. The T- and B-cell subsets have been extensively studied in primary ITP, but the NK cell compartment has been less thoroughly explored. We investigated the NK cell receptor repertoire and the functionality of NK cells in the peripheral blood and spleen in patients with primary ITP. An immunophenotypic analysis of peripheral blood lymphocytes from patients revealed that the numbers of CD19+ B lymphocytes, CD4+ and CD8+ T lymphocytes and CD3 CD56+ NK cells were within the normal range. No major alteration to the expression of distinct inhibitory or activating NK cell receptors was observed. The functionality of NK cells, as evaluated by their ability to degranulate in conditions of natural cytotoxicity or antibody-dependent cell cytotoxicity (ADCC), was preserved in these patients. By contrast, these stimuli induced lower levels of IFNgamma production by the NK cells of ITP patients than by those of healthy controls. We then compared the splenic NK cell functions of ITP patients with those of cadaveric heart-beating donors (CHBD) as controls. The splenic NK cells of ITP patients tended to be less efficient in natural cytotoxicity conditions and more efficient in ADCC conditions than control splenic NK cells. Finally, we found that infusions of intravenous immunoglobulin led to the inhibition of NK cell activation through the modulation of the interface between target cells and NK cells. PMID- 26598013 TI - Poster - Endoscopy. PMID- 26598014 TI - Poster Liver. PMID- 26598015 TI - Poster- Surgery. PMID- 26598017 TI - Total body irradiation after high-dose cytarabine in mantle cell lymphoma: a comparison of Nordic MCL2, HOVON-45, and European MCL Younger trials. PMID- 26598019 TI - [Provision of information from workplace to re-work institution]. PMID- 26598018 TI - Axl activates fibroblast growth factor receptor pathway to potentiate survival signals in B-cell chronic lymphocytic leukemia cells. PMID- 26598020 TI - Aging of the cingulum in the human brain: Preliminary study of a diffusion tensor imaging study. AB - The cingulum, a major structure of the limbic system, is closely associated with memory function. In the current study, we investigated aging of the cingulum according to the location of the cingulum in each part of the cingulum after dividing the cingulum into five parts in normal subjects, using DTT parameters (fractional anisotropy (FA) and fiber number (FN)). Ninety healthy subjects (males: 44, females: 46, mean age: 49.0 years; range: 20-78 years) were enrolled in this study. Subjects were categorized according to six groups by age intervals of 10 years; each age group consisted of 15 subjects. The cingulum was divided into five parts (anterior, anterior superior, posterior superior cingulum, posterior, and inferior cingulum). The FA and FN of each part were measured. The FA value indicates the degree of directionality and integrity of white matter microstructures such as axons, myelin, and microtubules, and the FN reflects the total number of fibers in a neural tract. Age-related decline in the FA value may indicate demyelination, and a decline in the number of myelinated fibers of a neural tract can also lead to a decline of the FN. Significant differences in the FA value of the anterior cingulum and anterior superior cingulum, and the FN of the inferior cingulum were observed between age groups (AVOVA, p<0.05). A significant decrease was observed in the FA values of the anterior and anterior superior cingulum of the 60s and 70s age groups compared with those of the 20s and 30s age groups, and in the FN of the inferior cingulum of the 60s and 70s age groups compared with that of the 20s age group (LSD post hoc test, p<0.05). Aging of the cingulum began at both ends of the cingulum in the 20s or 30s, and progressed steadily at a near continuous rate over the lifespan and a significant degenerative aging effect at both ends of the cingulum occurred into the 60s, compared with the 20s or 30s. PMID- 26598021 TI - Longitudinal study of children with perinatal brain damage in whom early neurohabilitation was applied: Preliminary report. AB - OBJECTIVE: The neurohabilitation treatment has been shown to be a successful method for decreasing the sequelae of perinatal brain damage (PBD) in Hungarian population. The goal of this pilot trial was to introduce this procedure by describing the results of its application in infants with PBD as demonstrated by clinical, developmental and MRI studies. As this procedure has proved to be useful, according the declaration of Helsinki, no control clinical trial was permitted. PARTICIPANTS: Infants younger than 2 months of corrected age (CA) with prenatal and/or perinatal risk factors for brain damage. Two groups were considered. One group was treated using the "neurohabilitation" method (n=20), and the other was not treated (n=13) because treatment was voluntarily discontinued after the initial evaluation. Evaluations were carried out prior to 2 months of CA and at 6-8 years of age. All children showed abnormal clinical and MRI characteristics in the first study. RESULTS: The treated group had a higher percentage (90%) of children with normal outcome than did the non-treated group (38%; OR=2.37, CI 95%=1.2-4.7; p<0.005). In this latter group, only one out of five (20%) children born at or before 34 weeks of gestational age had a normal outcome. In contrast, eight out of nine treated preterm infants had normal outcomes (8/9=89%, OR=4.45, CI 95%=0.7-26; p=0.017). CONCLUSIONS: This pilot trial confirms previous studies suggesting that Neurohabilitation decreases the neurological and cognitive sequelae of preterm and at-term infants with PBD. PMID- 26598023 TI - Intraventricular infusion of a low fraction of serum enhances neurogenesis and improves recovery in a rodent stroke model. AB - Enhancing endogenous neurogenesis is a potential therapeutic strategy in stroke treatment. We have previously demonstrated that treatment with a fraction of serum with molecular weight of less than 100 kDa (100K) combined with bFGF promoted neurogenesis of cultured stem and progenitor cells (NSPCs). In this study, we further evaluated the efficacy of intraventricular administration of 100K with bFGF (100K/bFGF) in a rat model of transient middle cerebral artery occlusion (MCAO). Rats administered 100K/bFGF on post-stroke day 1 exhibited a higher number of Ki67 and Nestin immunoreactive cells at the subventricular zone (SVZ) area and in the infarcted brain, indicating promotion of NSPCs proliferation. The 100K/bFGF treatment also predominantly increased the number of MAP-2 immunoreactive cells rather than GFAP immunoreactive cells at the SVZ area and in the infarcted regions, implying that 100K/bFGF dominated NSPCs differentiating into neurons rather than astrocytes. Importantly, treatment with 100K/bFGF significantly improved the animals' motor coordination. These findings demonstrated that treatment with a low serum fraction and bFGF benefited ischemic stroke likely through promotion of the proliferation and neuronal differentiation of endogenous NSPCs. PMID- 26598022 TI - Reduction of spinal glycine receptor-mediated miniature inhibitory postsynaptic currents in streptozotocin-induced diabetic neuropathic pain. AB - Diabetic neuropathic pain (DNP) is a common clinical problem, and the mechanisms underlying the onset and progression of this complication are poorly understood. The present study examined the glycine receptors (GlyR) in the control of synaptic input to dorsal horn neurons in diabetes. Male Sprague-Dawley rats with or without streptozotocin (STZ) intraperitoneal injections were used. Tactile sensitivities were assessed by measuring paw withdrawal thresholds to von Frey filaments for four weeks. The extent of GlyR-mediated inhibition controlling primary afferent-evoked excitation in dorsal horn neurons was examined by using the whole cell patch clamp recording technique in isolated adult rat spinal cord slices. The content of the spinal dorsal horn glycine levels was measured by microdialysis. An intrathecal glycine agonist injection was used to test whether mimicking endogenous glycine-receptor-mediated inhibition reduces DNP. We found that persistent hyperglycemia induced by the administration of STZ caused a decrease in the paw withdrawal latency to mechanical stimuli. The miniature inhibitory post-synaptic current (mIPSC) rise, decay kinetics and mean GlyR mediated mIPSC amplitude were not affected in DNP. The mean frequency of GlyR mediated mIPSC of lamina I neurons from DNP rats was, however, significantly reduced when compared with neurons from control rats. Principal passive and active membrane properties and the firing patterns of spinal lamina I neurons were not changed in DNP rats. Spinal microdialysis rats had a significantly decreased glycine level following its initial elevation. The intrathecal administration of glycine diminished tactile pain hypersensitivity in DNP rats. In conclusion, these results indicate that long-lasting hyperglycemia induced by STZ injections leads to a reduced glycinergic inhibitory control of spinal lamina I neurons through a presynaptic mechanism. PMID- 26598024 TI - Does retigabine affect the development of alcohol dependence?--A pharmaco-EEG study. AB - New antiepileptic drugs have been investigated for their potential role in the treatment of alcohol dependence. One of these drugs is retigabine and this study examines the effect of retigabine co-administered with ethanol on the development of alcohol dependence and the course of acute withdrawal syndrome. A pharmaco-EEG method was used to examine this impact in selected brain structures of rabbits (midbrain reticular formation, hippocampus and frontal cortex). Retigabine was administered p.o. at a dose of 5mg/kg/day with ethanol ad libitum for 6 weeks and then alone for 2 weeks during an abstinence period. Changes in bioelectric activity, which demonstrated the inhibitory effect of alcohol on the brain structures, were already visible after 2 weeks of ethanol administration. In the abstinence period, changes were of a different nature and significant neuronal hyperactivity was observed, particularly in the midbrain reticular formation and the hippocampus. This findings reveal that retigabine decreased ethanol-induced changes during both alcohol administration and abstinence periods. In particular, the modulatory effect of retigabine on the hippocampus may be a significant element of its mechanism of action in alcohol dependence therapy. PMID- 26598025 TI - Taxonomic revision of the Nippostrongylinae (Nematoda, Heligmonellidae) parasites of Muridae from the Australasian region. The genus Odilia Durette-Desset, 1973. AB - The species of the genus Odilia Durette-Desset, 1973 (Heligmonellidae, Nippostrongylinae) are re-distributed among eight genera of which five are new. This classification is mainly based on certain characters of the synlophe not previously taken into account at the supraspecific level. These characters mainly include the presence or absence of a careen, the relative size of the ridges forming the careen, the development and position of ridge 1', the development of the left ridge and right ridge, and the distribution of the largest ridges. Eighteen of the 20 known species are rearranged in the following genera: Odilia sensu stricto Durette-Desset, 1973 with Odilia mackerrasae (Mawson, 1961) as type species, Chisholmia n. gen. with Chisholmia bainae (Beveridge & Durette-Desset, 1992) n. comb. as type species, Equilophos n. gen. with Equilophos polyrhabdote (Mawson, 1961) n. comb. as type species, Hasegawanema n. gen. with Hasegawanema mamasaense (Hasegawa, Miyata & Syafruddin, 1999) n. comb. as type species, Hughjonestrongylus Digiani & Durette-Desset, 2014 with Hughjonestrongylus ennisae (Smales & Heinrich, 2010) as type species, Lesleyella n. gen. with Lesleyella wauensis (Smales, 2010) n. comb. as type and sole species, Parasabanema szalayi Smales & Heinrich, 2010, and Sanduanensis n. gen. with Sanduanensis dividua (Smales, 2010) as type and sole species. Odilia uromyos Mawson, 1961 and Odilia carinatae Smales, 2008 are not included in the new classification. A key to the proposed genera is provided. The new generic arrangement follows a distribution more related to the biogeographical areas than to the host groups. PMID- 26598026 TI - Source analysis of P3a and P3b components to investigate interaction of depression and anxiety in attentional systems. AB - This study examined the impact of depressive disorders, anxiety disorders and the comorbidity of these disorders on the regional electrophysiological features of brain activity. Sixty-four-channel event-related potentials (ERP) were acquired during a visual oddball task in patients with depressive disorder, patients with anxiety disorders, patients with comorbid depressive and anxiety disorders and healthy subjects. An fMRI-constrained source model was applied to ERP to identify different cortical activities in the patient and control groups. Comorbid patients showed an abnormal frontal-greater-than-parietal P3b topography in the right hemisphere and the highest P3a amplitude at frontal and central sites at the scalp midline. For P3b, depressed patients showed decreased right-lateralized activity in the precentral sulcus (PrCS) and posterior parietal cortex (PPC). Anxious patients demonstrated hyperactive prefrontal cortices (PFC). Comorbid patients presented decreased activity in the cingulate gyrus, right PrCS and right PPC and increased activity in the left PFC and left insular (INS). For P3a, hyperactive left PrCS was found in comorbid patients. Comorbid patients showed both anxiety-related and depression-related activity. A superimposition effect of depression and anxiety was identified with (1) aggravated hypo-function of the right-lateralized dorsal attention and salience networks and (2) complicated anxiety-related hyper-function of the left-lateralized ventral attention and salience networks. PMID- 26598027 TI - Transcriptome analysis of stress tolerance in entomopathogenic nematodes of the genus Steinernema. AB - Entomopathogenic nematodes of the genus Steinernema are effective biological control agents. The infective stage of these parasites can withstand environmental stresses such as desiccation and heat, but the molecular and physiological mechanisms involved in this tolerance are poorly understood. We used 454 pyrosequencing to analyse transcriptome expression in Steinernema spp. that differ in their tolerance to stress. We compared these species, following heat and desiccation treatments, with their non-stressed counterparts. More than 98% of the transcripts found matched homologous sequences in the UniRef90 database, mostly nematode genes (85%). Among those, 60.8% aligned to the vertebrate parasites including Ascaris suum, Loa loa, and Brugia malayi, 23.3% aligned to bacteriovores, mostly from the genus Caenorhabditis, and 1% aligned to EPNs. Analysing gene expression patterns of the stress response showed a large fraction of down-regulated genes in the desiccation-tolerant nematode Steinernema riobrave, whereas a larger fraction of the genes in the susceptible Steinernema feltiae Carmiel and Gvulot strains were up-regulated. We further compared metabolic pathways and the expression of specific stress-related genes. In the more tolerant nematode, more genes were down-regulated whereas in the less tolerant strains, more genes were up-regulated. This phenomenon warrants further exploration of the mechanism governing induction of the down-regulation process. The present study revealed many genes and metabolic cycles that are differentially expressed in the stressed nematodes. Some of those are well known in other nematodes or anhydrobiotic organisms, but several are new and should be further investigated for their involvement in desiccation and heat tolerance. Our data establish a foundation for further exploration of stress tolerance in entomopathogenic nematodes and, in the long term, for improving their ability to withstand suboptimal environmental conditions. PMID- 26598028 TI - Comprehensive analysis of hospital-based prospective cohort reveals the unique effectiveness and safety for nucleos(t)ide analogues in HBV patients. AB - BACKGROUND: Nucleos(t)ide analogues (NAs) including lamivudine (LAM), telbivudine (LDT), adefovir dipivoxil(ADV), and entecavir (ETV) have been widely used as anti HBV drugs. We aimed to study the effectiveness and safety of various NAs. METHODS: Two thousand three hundred and eighty patients with chronic hepatitis B (CHB) were enrolled. The rate of virologic response, optimization therapy, and serologic responses were analyzed. RESULTS: HBV DNA inhibitory capacity was shown to be LAM+ADV~ETV>LDT>LAM>ADV. Virologic breakthrough rate and proportion of optimized treatment were LAM>ADV>LDT>LAM+ADV>ETV. However, virological response rate showed the opposite trend. The selection of anti-virals, HBeAg-negative, and lower HBV DNA levels after one year of anti-viral treatment, are favorable factors for the maintenance of virologic response. CONCLUSIONS: This study's results were consistent with the major clinical guidelines to recommend ETV and TDF as the preferred treatment for CHB patients. LAM could be used for patients with lower HBV DNA load; ADV may be more applicable to non-cirrhotic patients with HBeAg-negative and lower HBV DNA load. LDT can be used to treat patients with HBeAg-positive, low HBV DNA load, and higher ALT levels due to higher HBeAg conversion rate in a baseline optimized population. The effectiveness of LAM+ADV is similar to and sometimes better than ETV treatment in a CHB population. PMID- 26598029 TI - Impact of Host Heterogeneity on the Efficacy of Interventions to Reduce Staphylococcus aureus Carriage. AB - BACKGROUND: Staphylococcus aureus is a common cause of bacterial infections worldwide. It is most commonly carried in and transmitted from the anterior nares. Hosts are known to vary in their proclivity for S. aureus nasal carriage and may be divided into persistent carriers, intermittent carriers, and noncarriers, depending on duration of carriage. Mathematical models of S. aureus to predict outcomes of interventions have, however, typically assumed that all individuals are equally susceptible to colonization. OBJECTIVE: To characterize biases created by assuming a homogeneous host population in estimating efficacy of control interventions. DESIGN: Mathematical model. METHODS: We developed a model of S. aureus carriage in the healthcare setting under the homogeneous assumption as well as a heterogeneous model to account for the 3 types of S. aureus carriers. In both models, we calculated the equilibrium carriage prevalence to predict the impact of control measures (reducing contact and decolonization). RESULTS: The homogeneous model almost always underestimates S. aureus transmissibility and overestimates the impact of intervention strategies in lowering carriage prevalence compared to the heterogeneous model. This finding is generally consistent regardless of changes in model setting that vary the proportions of various carriers in the population and the duration of carriage for these carrier types. CONCLUSIONS: Not accounting for host heterogeneity leads to systematic and substantial biases in predictions of the effects of intervention strategies. Further understanding of the clinical impacts of heterogeneity through modeling can help to target control measures and allocate resources more efficiently. PMID- 26598030 TI - The Mossbauer Parameters of the Proximal Cluster of Membrane-Bound Hydrogenase Revisited: A Density Functional Theory Study. AB - An unprecedented [4Fe-3S] cluster proximal to the regular [NiFe] active site has recently been found to be responsible for the ability of membrane-bound hydrogenases (MBHs) to oxidize dihydrogen in the presence of ambient levels of oxygen. Starting from proximal cluster models of a recent DFT study on the redox dependent structural transformation of the [4Fe-3S] cluster, (57)Fe Mossbauer parameters (electric field gradients, isomer shifts, and nuclear hyperfine couplings) were calculated using DFT. Our results revise the previously reported correspondence of Mossbauer signals and iron centers in the [4Fe-3S](3+) reduced state proximal cluster. Similar conflicting assignments are also resolved for the [4Fe-3S](5+) superoxidized state with particular regard to spin-coupling in the broken-symmetry DFT calculations. Calculated (57)Fe hyperfine coupling (HFC) tensors expose discrepancies in the experimental set of HFC tensors and substantiate the need for additional experimental work on the magnetic properties of the MBH proximal cluster in its reduced and superoxidized redox states. PMID- 26598031 TI - Systematic analysis of hematopoietic gene expression profiles for prognostic prediction in acute myeloid leukemia. AB - Acute myeloid leukemia (AML) is a hematopoietic disorder initiated by the leukemogenic transformation of myeloid cells into leukemia stem cells (LSCs). Preexisting gene expression programs in LSCs can be used to assess their transcriptional similarity to hematopoietic cell types. While this relationship has previously been examined on a small scale, an analysis that systematically investigates this relationship throughout the hematopoietic hierarchy has yet to be implemented. We developed an integrative approach to assess the similarity between AML patient tumor profiles and a collection of 232 murine hematopoietic gene expression profiles compiled by the Immunological Genome Project. The resulting lineage similarity scores (LSS) were correlated with patient survival to assess the relationship between hematopoietic similarity and patient prognosis. This analysis demonstrated that patient tumor similarity to immature hematopoietic cell types correlated with poor survival. As a proof of concept, we highlighted one cell type identified by our analysis, the short-term reconstituting stem cell, whose LSSs were significantly correlated with patient prognosis across multiple datasets, and showed distinct patterns in patients stratified by traditional clinical variables. Finally, we validated our use of murine profiles by demonstrating similar results when applying our method to human profiles. PMID- 26598032 TI - Minimal residual disease evaluation by flow cytometry is a complementary tool to cytogenetics for treatment decisions in acute myeloid leukaemia. AB - The clinical utility of minimal residual disease (MRD) analysis in acute myeloid leukaemia (AML) is not yet defined. We analysed the prognostic impact of MRD level at complete remision after induction therapy using multiparameter flow cytometry in 306 non-APL AML patients. First, we validated the prognostic value of MRD-thresholds we have previously proposed (>= 0.1%; >= 0.01-0.1%; and <0.01), with a 5-year RFS of 38%, 50% and 71%, respectively (p=0.002). Cytogenetics is the most relevant prognosis factor in AML, however intermediate risk cytogenetics represent a grey zone that require other biomarkers for risk stratification, and we show that MRD evaluation discriminate three prognostic subgroups (p=0.03). Also, MRD assessments yielded relevant information on favourable and adverse cytogenetics, since patients with favourable cytogenetics and high MRD levels have poor prognosis and patients with adverse cytogenetics but undetectable MRD overcomes the adverse prognosis. Interestingly, in patients with intermediate or high MRD levels, intensification with transplant improved the outcome as compared with chemotherapy, while the type of intensification therapy did not influenced the outcome of patients with low MRD levels. Multivariate analysis revealed age, MRD and cytogenetics as independent variables. Moreover, a scoring system, easy in clinical practice, was generated based on MRD level and cytogenetics. PMID- 26598033 TI - [Sarcopenia or uremic myopathy in CKD patients]. AB - Often underestimated or misunderstood in chronic renal failure (CRF), muscle wasting is nevertheless common and concerns about 50% of dialysis patients. The consequences of this myopathy on quality of life and outcomes of patients are unfavorable, identical to those observed in sarcopenia in elderly subjects with sarcopenia. The similarities between the two situations also concern the symptoms, the underlying muscle damages and the pathogenic mechanisms and may be partly explained by the frequently high age of ESRD patients. Skeletal muscle involvement should be systematically investigated in the IRC patient as in the elderly with sarcopenia to propose as early as possible a treatment of which physical activity and nutritional interventions are the mainstay. PMID- 26598034 TI - Environmental Legionella spp. collected in urban test sites of South East Queensland, Australia, are virulent to human macrophages in vitro. AB - Legionellae are frequent contaminants of potable water supplies, resulting in sporadic infections and occasional outbreaks. Isolates of Legionella were collected from urban test sites within South East Queensland and evaluated for their virulence potential in vitro. Two strains (from the species Legionella londiniensis and Legionella quinlivanii) were demonstrated to have the ability to infect human macrophages, while a strain from the species Legionella anisa did not maintain an infection over the same time course. This suggests that the spectrum of urban environmentally associated Legionella with potential to cause human disease might be greater than currently considered. PMID- 26598035 TI - Attitudes of dentists toward persons with intellectual disabilities in Jordanian hospitals. AB - This study examined attitudes of dentists in Jordanian hospitals toward persons with intellectual disabilities. The study also assessed the effect of gender and years of experience of the dentists on their attitudes. Fifty-four dentists were asked to rank their attitudes toward persons with intellectual disabilities on an attitude survey. The results revealed highly positive attitudes of dentists toward persons with intellectual disabilities at Jordanian hospitals. There was no significant effect of years of experiences or gender of the dentists on these attitudes. The positive attitudes of dentists in this study can be used to encourage the medical sector to focus on improvement of services. PMID- 26598036 TI - Quality of Care and Satisfaction With Care on Palliative Care Units. AB - CONTEXT: There is little research on quality of care specific to palliative care units (PCUs). OBJECTIVES: To delineate important aspects of satisfaction with care and quality of care on a PCU, as described by inpatients, family caregivers, and health care professionals. METHODS: Qualitative interviews and focus groups were conducted across four Toronto PCUs, with a total of 46 patient/caregiver interviews and eight staff focus groups. Interviews and focus groups were semistructured to elicit comments about satisfaction with care and quality of care for inpatients and families on a PCU. Data were analyzed using a grounded theory method, with an inductive, constant comparison approach to identify themes, and were coded to saturation. RESULTS: Key elements of quality care and patient satisfaction on a PCU were grouped into six domains: 1) interprofessional team: a team of experts comprising multiple disciplines functioning as a unit; 2) communication: developing rapport, addressing expectations, providing information, listening actively, and facilitating end-of-life discussions; 3) attentive, personalized care: anticipatory and responsive compassionate care with tailored management of physical and nonphysical symptoms; 4) family-centered: support of patients and caregivers within a family; 5) accessible and consistent: appropriate resources and adequate staff to provide consistent care; and 6) supportive setting: a bright noninstitutionalized setting allowing both privacy and socialization. CONCLUSION: The elements identified support the delivery of quality care. They may act as a guide for those planning to develop PCUs and form the basis for measures of satisfaction with care. PMID- 26598038 TI - Shock Index and Decreased Level of Consciousness as Terminal Cancer Patients' Survival Time Predictors: A Retrospective Cohort Study. AB - CONTEXT: Predicting prognosis using noninvasive and objective tools may facilitate end-of-life decisions for terminal cancer patients, their families, and other health care professionals. OBJECTIVES: To investigate if the shock index (SI), along with decreased level of consciousness (DLOC), is a reliable tool for predicting short-term survival time in terminal cancer patients. METHODS: A two-part retrospective cohort study was performed on 670 consecutive adult hospice patients. Part 1 of the study was performed to investigate the reliability of SI and DLOC on admission and to make a simple tool for predicting survival time. Part 2 of the study was to validate the tool's reproducibility and analyze the correlation between SI, DLOC, and survival time. RESULTS: In Part 1, multivariate Cox proportional hazards analyses for all study patients revealed that SI >= 1.0 in patients with DLOC was a significant risk factor of death (hazard ratio 3.08; 95% CI 1.72-5.53; P = 0.000). Generalized additive models confirmed that DLOC patients with SI = 1.0 had 9.58 days of mean survival time (MST). Receiver operating characteristic curve analyses of SI in patients with DLOC revealed that a survival time of less than three days was most reliably predicted. In Part 2, an increase in SI statistically decreased survival time. The upper 95% CIs of the calculated mean survival time for DLOC patients with SI >= 1.0 were less than one week. Bootstrap analyses revealed that the 95% CIs of the predicted survival time were 4.54-6.18 days in DLOC patients with SI = 1.0. CONCLUSION: An SI >= 1.0 along with DLOC is a highly reliable tool for predicting short-term survival time in terminal cancer patients. PMID- 26598037 TI - Blinded Patient Preference for Morphine Compared to Placebo in the Setting of Chronic Refractory Breathlessness--An Exploratory Study. AB - CONTEXT: Patients' preference for morphine therapy has received little attention in the setting of chronic refractory breathlessness. However, this is one important factor in considering longer term therapy. OBJECTIVES: The aim of this secondary analysis was to explore blinded patient preference of morphine compared to placebo for this indication and to define any predictors of preference. METHODS: Data were pooled from three randomized, double-blind, crossover, placebo controlled studies of morphine (four days each) in chronic refractory breathlessness. Blinded patient preferences were chosen at the end of each study. A multivariable regression model was used to establish patient predictors of preference. RESULTS: Sixty-five participants provided sufficient data (60 men; median age 74 years; heart failure 55%, chronic obstructive pulmonary disease 45%; median Eastern Cooperative Oncology Group performance status 2). Forty-three percent of participants preferred morphine (32% placebo and 25% no preference). Morphine preference and younger age were strongly associated: odds ratio = 0.85, 95% confidence interval 0.78-0.93; P < 0.001). There was also an inverse association between morphine preference and sedation (odds ratio = 0.77, 95% confidence interval 0.60-0.99; P < 0.05). An inverse association was also seen between nausea and morphine preference in the univariate model only (P < 0.05). No association was seen between morphine preference and breathlessness intensity, either at baseline or change from baseline. CONCLUSION: Participants preferred morphine over placebo for the relief of chronic refractory breathlessness. Morphine offers clinically important improvement, but net benefit can be easily outweighed by side effects, reducing net benefits. Side effects require aggressive management to allow more patients to realize benefits. PMID- 26598039 TI - Establishing Cutoff Points for Defining Symptom Severity Using the Edmonton Symptom Assessment System-Revised Japanese Version. AB - CONTEXT: Symptom screening is important for appropriate symptom management. It remains uncertain as to which scores on the Edmonton Symptom Assessment System Revised (ESAS-r) comprise the optimal cutoff points to determine symptom severity for Japanese cancer patients. OBJECTIVES: To investigate optimal cutoff points for individual ESAS-r items for detecting symptom severity and to evaluate the screening performance of the ESAS-r depression item in Japanese cancer patients. METHODS: We recruited cancer patients receiving palliative care from five tertiary acute hospitals in Japan. We asked participants to complete the ESAS-r Japanese version, Verbal Rating Symptom Severity Scale, and Quick Inventory of Depressive Symptomatology-Self-Report Japanese version. We calculated sensitivity and specificity for detecting severe and moderate/severe symptoms evaluated by the Verbal Rating Symptom Severity Scale at different cutoff points of the ESAS r. We also calculated sensitivity and specificity for detecting both the presence of depression and moderate/severe depression evaluated by the Quick Inventory of Depressive Symptomatology-Self-Report at various cutoff points for the depression item of the ESAS-r Japanese version. RESULTS: A total of 292 participants completed the questionnaire. For most of the ESAS-r symptoms, cutoff points to achieve the best balance between sensitivity and specificity were 5-7 for determining severe intensity and 3-4 for determining moderate/severe intensity. For the ESAS-r depression item, a cutoff point of 2 achieved the best balance between sensitivity and specificity for detecting both the presence of depression and moderate/severe depression. CONCLUSION: The ESAS-r Japanese version can accurately represent the severity of many symptoms. The cutoff points established for determining the level of symptom severity using ESAS-r provides a guide for symptom management in Japanese cancer patients. PMID- 26598040 TI - Validation of the Modified Glasgow Prognostic Score in Advanced Cancer Patients Receiving Palliative Care. AB - CONTEXT: The modified Glasgow Prognostic Score (mGPS) is a well-known marker of systemic inflammatory response previously associated with poor prognoses in cancer. OBJECTIVES: We investigated the relationships between mGPS and clinical variables and the prognostic impact of mGPS in patients with advanced cancer starting palliative care (PC). METHODS: Data from two prospective studies conducted at a tertiary cancer center were analyzed (N = 459). Data regarding patient characteristics, Karnofsky Performance Status, and blood samples were collected at the initial evaluation. The mGPS was calculated as follows: C reactive protein (CRP) < 10 mg/L = 0; CRP > 10 mg/L = 1, CRP > 10 mg/L and albumin < 35 g/L = 2. Chi-square or Fisher exact tests were used for comparisons of categorical variables; continuous variables were compared using the Mann Whitney U test. For the survival analysis, Cox regression analyses were performed. RESULTS: mGPS of 0, 1, and 2 were assigned to 79.7%, 6.8%, and 13.5% of the patients, respectively. A positive association between hepatic metastasis (P = 0.004), primary lung cancer (P = 0.021), PC only (P < 0.001), lower Karnofsky Performance Status (P < 0.001), and higher systemic inflammation (mGPS 1/2) was found. Median overall survival was 1, 3, and 5.7 months for mGPS of 2, 1, and 0, respectively. After multivariate analyses, mGPS remained an independent prognostic marker (mGPS 1, hazard ratio 2.066, P = 0.001; mGPS 2, hazard ratio 2.664, P < 0.001). CONCLUSION: Systemic inflammatory response is associated with a low functional status, primary lung cancers, and tumors with hepatic metastasis. When starting PC, an mGPS definition may have clinical utility implications, by identifying three groups of patients with advanced cancer patients with distinct survival outcomes. PMID- 26598041 TI - Numb Chin Syndrome: A Case Report. PMID- 26598042 TI - Susceptibility to insecticides and activities of glutathione S-transferase and esterase in populations of Lygus lineolaris (Hemiptera: Miridae) in Mississippi. AB - BACKGROUND: Lygus lineolaris (Palisot de Beauvois) is a serious pest of cotton (Gossypium hirsutum L.) in Mississippi, particularly in the Delta region. This may be due to decreased insecticide susceptibility in that region. Research has revealed populations of L. lineolaris in the Delta region with high levels of insecticide resistance; however, comparisons with populations in the remainder of the state are limited. RESULTS: Experiments were undertaken to compare the LC50 values and activities of detoxification enzymes of L. lineolaris populations. The results of these studies indicated that the LC50 values were not different between the Delta and Hills regions, but differences were significant between populations within and across regions. Results of the detoxifying enzyme activity assays revealed significantly higher esterase activity in the Delta region when compared with the Hills. Glutathione S-transferase activity was not different between regions, but differences within and across regions were significant. CONCLUSION: The results indicated that glass-vial assays to determine and compare LC50 values may be less accurate than enzymatic assays for detecting insecticide susceptibility differences. Higher esterase activity is likely a contributing factor to the difficulties with managing L. lineolaris in the Mississippi Delta region. (c) 2015 Society of Chemical Industry. PMID- 26598043 TI - [Hodgkin disease revealed by a nephrotic syndrome: A case report]. AB - Pediatric nephrotic syndrome (NS) is most often idiopathic or primary but in rare cases, it can be secondary to neoplasia. We report on a case of steroid-resistant NS revealing as a paraneoplastic syndrome of Hodgkin disease (HD) in a 12-year old boy. The onset of the NS can be earlier, later, or simultaneous to the HD. Treatment of the lymphoma allows the disappearance of the NS. In the case we observed, the diagnosis of HD was delayed because HD presented with an isolated, hilar adenopathy in the absence of retroperitoneal or peripheral locations. In children aged 10 years or more presenting with NS, steroid-resistant or otherwise, a possible paraneoplastic origin such as Hodgkin lymphoma should always be taken into consideration and eventually eliminated. PMID- 26598044 TI - [Juvenile dermatomyositis and new autoantibodies: Cases and review]. AB - Juvenile dermatomyositis (JDM) is the most common inflammatory myopathy in children. Its diagnosis is usually made on a clinical basis following the criteria of Bohan and Peter (1975). Recently, the presence of myositis-specific autoantibodies (MSAs) have started to be associated with specific outcome in adult patients; the diagnosis and prognosis value of these autoantibodies remains to be identified in children. We report four cases of JDM with MSAs focusing on clinical, biological, and radiological manifestations, and then we describe associated treatment. The cohort comprises four girls with an average age of 8.5 years. The time to diagnosis was 1 week to 4 months. For these patients, the immunologic study found one patient positive for the MDA5 antibody (or CADM 140), one positive for the TIF1gamma antibody (or p155/140), and two patients positive for the NXP2 antibody (or p140/MJ). Each patient showed specific and characteristic cutaneous manifestations. For example, the girl positive for the TIF1gamma antibody presented the most severe skin disease with urticaria, face edema, and vascularity of the neck and shoulders. However, regarding muscular features, proximal weakness was present in most of the cohort, except for the child positive for the MDA5 antibody, who presented no sign of muscular disease at the beginning with low CK levels. Importantly, acute pancreatitis also affected this patient. Concerning radiological indications, muscular MRI evidenced hyperinflammation, a sign of diffuse myositis, in all these patients. Treatments consisted in corticosteroids together with methotrexate or mycofenolate mofetil associated or not with intravenous immunoglobulin therapy. This report highlights the importance of systematic detection and analysis of MSA in diagnosis and characterization of JDM, and describes a new approach that would allow more focused treatments and be a useful predictor of clinical complications and prognosis in JDM-affected subjects. PMID- 26598045 TI - Nutritional composition, antioxidant properties, and toxicology evaluation of the sclerotium of Tiger Milk Mushroom Lignosus tigris cultivar E. AB - The Tiger Milk Mushroom (Lignosus spp.) is an important medicinal mushroom in Southeast Asia and has been consumed frequently by the natives as a cure for a variety of illnesses. In this study, we hypothesized that Lignosus tigris (cultivar E) sclerotium may contain high nutritional value and antioxidant properties, is nontoxic and a potential candidate as a dietary supplement. The chemical and amino acid compositions of the sclerotium were evaluated and antioxidant activities of the sclerotial extracts were assessed using ferric reducing antioxidant power; 1,1-diphenyl-2-picrylhydrazyl; and superoxide anion radical scavenging assays. Acute toxicity of the L. tigris E sclerotium was assessed using a rat model study. The sclerotium was found to be rich in carbohydrate, protein, and dietary fibers with small amounts of fat, calories, and sugar. The amino acid composition of the protein contains all essential amino acids, with a protein score of 47. The sclerotial extracts contain phenolics, terpenoids, and glucan. The ferric reducing antioxidant power values of the various sclerotial extracts (hot water, cold water, and methanol) ranged from 0.008 to 0.015 mmol min(-1) g(-1) extract, while the 1,1-diphenyl-2 picrylhydrazyl and superoxide anion radical scavenging activities ranged from 0.11 to 0.13, and -2.81 to 9.613 mmol Trolox equivalents g(-1) extract, respectively. Acute toxicity assessment indicated that L. tigris E sclerotial powder was not toxic at the dose of 2000 mg kg(-1). In conclusion, L. tigris E sclerotium has the potential to be developed into a functional food and nutraceutical. PMID- 26598046 TI - The serpulid Ficopomatus enigmaticus () as candidate organisms for ecotoxicological assays in brackish and marine waters. AB - Ficopomatus enigmaticus is an ubiquitous fouling reef-forming species, easy to sample and recognize, diecious with gamete spawning along different seasons in different salinity conditions. Due to its characteristics it could become a good candidate for the monitoring of both marine and brackish waters. The suitability of F. enigmaticus as a promising model organism in ecotoxicological bioassays was evaluated by a sperm toxicity and a larval development assay. The fertilization rate in different salinity conditions (range 5-350/00) was first assessed in order to detect the salinity threshold within which profitably perform the assays. Afterward copper (Cu2+), cadmium (Cd2+), sodium dodecyl sulfate (SDS) and 4-n-nonylphenol (NP) were used as reference toxicants in exposure experiments with spermatozoids (sperm toxicity assay) and zygotes (larval development assay). A dose-response effect was obtained for all tested toxicants along all salinity conditions except for 50/00 salinity condition where a too low (<30%) fertilization rate was observed. NP showed the highest degree of toxicity both in sperm toxicity and larval development assay. In some cases the results, expressed as EC50 values at 350/00 salinity condition, were similar to those observed in the literature for marine organisms such as the sea urchin (Paracentrotus lividus) and the marine serpulid Hydroides elegans, while the exposure of F. enigmaticus spermatozoids' to Cd2+ and NP resulted in toxicity effects several orders of magnitude higher than observed in P. lividus. Spermatozoids resulted to be slightly more sensitive then zygotes to all different toxicants. PMID- 26598047 TI - Generation-dependent effect of PAMAM dendrimers on human insulin fibrillation and thermal stability. AB - We have studied the effect of polyamidoamine (PAMAM) dendrimers of various generations on the thermal stability and fibrillation of human insulin. Thermostability of human insulin used differential scanning calorimetry (DSC), which showed two phase-transitions for insulin at 60 and 82 degrees C. After adding dendrimers at 0.6 MUmol/l, the first peaks disappeared and the second peaks were higher. We posited that, in the presence of dendrimers, the dimers in the solution were transformed into hexamers. The effect of dendrimers on insulin fibrillation was monitored by measuring ThT fluorescence, and visualization of insulin fibrils by transmission electron microscopy (TEM) and atomic force microscopy (AFM). The effect of PAMAM dendrimers on insulin fibrillation was strongly dependent on the dendrimers generation and dendrimer:protein ratio. PMID- 26598048 TI - Partial knockdown of TRF2 increase radiosensitivity of human mesenchymal stem cells. AB - Telomere repeat binding factor TRF2 is a member of shelterin complex with an important role in protecting and stabilizing chromosomal ends. In the present study, we investigated the effect of partial knockdown of TRF2 on radiosensitivity of telomerase immortalized human mesenchymal stem cells (hMSC telo1), which have a higher radioresistance compared to non telomerized counterpart. Partial knockdown of the protein achieved 15-20% reduction in TRF2 protein levels. The study compared the effect of 2.5Gy radiation in two-four days after irradiation for hMSC-telo1 cells and the cells transfected with siTRF2 and null control vector. Radio-response of the cells were examined using senescence associated beta-Gal assay (beta-Gal), colony forming assay (CFU) and gamma-H2AX phosphorylation. TRF2 deficiency substantially increased radiosensitivity of cells compared to controls in both proliferation and senescence assay (2.4 fold increase in beta-Gal, 1.6 fold decrease in CFU). In addition, it increased the gamma-H2AX foci as revealed by both immunfluorescence and Western blot analysis. Our data suggests that partial knockdown of TRF2 in hMSC-telo1 cells cause increased gamma-H2AX foci which led to fail TRF2 to protect telomeres from radiation thus TRF2 deficiency led to a 1,5-2 fold increase in the radiosensitivity of hMSC-telo1 cells through telomere destabilization. PMID- 26598049 TI - Magnetic resonance imaging to evaluate gastrointestinal function. AB - Magnetic resonance imaging of gastrointestinal (GI) function has advanced substantially in the last few years. The ability to obtain high resolution images of the undisturbed bowel with tunable tissue contrast and using no ionizing radiation are clear advantages, particularly for children and women of reproductive age. Barriers to diffusion in clinical practice so far include the need to demonstrate clinical value and the burden of data processing. Both difficulties are being addressed and the technique is providing novel insights into both upper and lower GI disorders of function at an ever increasing rate. PMID- 26598050 TI - Quantification and variability in colonic volume with a novel magnetic resonance imaging method. AB - BACKGROUND: Segmental distribution of colorectal volume is relevant in a number of diseases, but clinical and experimental use demands robust reliability and validity. Using a novel semi-automatic magnetic resonance imaging-based technique, the aims of this study were to describe: (i) inter-individual and intra-individual variability of segmental colorectal volumes between two observations in healthy subjects and (ii) the change in segmental colorectal volume distribution before and after defecation. METHODS: The inter-individual and intra-individual variability of four colorectal volumes (cecum/ascending colon, transverse, descending, and rectosigmoid colon) between two observations (separated by 52 +/- 10) days was assessed in 25 healthy males and the effect of defecation on segmental colorectal volumes was studied in another seven healthy males. KEY RESULTS: No significant differences between the two observations were detected for any segments (All p > 0.05). Inter-individual variability varied across segments from low correlation in cecum/ascending colon (intra-class correlation coefficient [ICC] = 0.44) to moderate correlation in the descending colon (ICC = 0.61) and high correlation in the transverse (ICC = 0.78), rectosigmoid (ICC = 0.82), and total volume (ICC = 0.85). Overall intra individual variability was low (coefficient of variance = 9%). After defecation the volume of the rectosigmoid decreased by 44% (p = 0.003). The change in rectosigmoid volume was associated with the true fecal volume (p = 0.02). CONCLUSIONS & INFERENCES: Imaging of segmental colorectal volume, morphology, and fecal accumulation is advantageous to conventional methods in its low variability, high spatial resolution, and its absence of contrast-enhancing agents and irradiation. Hence, the method is suitable for future clinical and interventional studies and for characterization of defecation physiology. PMID- 26598051 TI - Role of Bulk Water Environment in Regulation of Functional Hydrogen-Bond Network in Photoactive Yellow Protein. AB - Photoactive yellow protein is a soluble photoreceptor protein involved in signal transduction for phototaxis. A hydrogen-bond between the chromophore, p-coumaric acid (pCA), and a nearby carboxyl group of Glu46 at the active site is known to play a crucial role in the formation of the signaling state in the photoactivation. Since the hydrogen-bond at the active site as well as the extensive conformational changes of the protein in the formation of the signaling state are considered to be controlled by water molecules, we theoretically examined influence of bulk water environment on the functionally important hydrogen-bond by means of molecular simulations. Theoretical analysis of potential energy profiles of the proton transfer between pCA and Glu46 with quantum mechanical/molecular mechanical (QM/MM) calculations revealed critical effect of electrostatic screening of bulk water on the electronic character of the hydrogen-bond. Moreover, QM/MM free energy geometry optimizations identified the water-penetrating state where Glu46 forming a putative low-barrier hydrogen bond with pCA is hydrated by water molecules penetrating from bulk environment in addition to the water-excluded state which corresponds to X-ray crystallographic structures. The present results suggest that the water-penetrating state is a precursory conformational substate that leads to efficient formation of the signaling state. PMID- 26598052 TI - Making (common) sense of outcome measures. PMID- 26598053 TI - Industrial biotechnology: Tools and applications. PMID- 26598054 TI - The Expanding Role of Immunotherapy in Melanoma--Introduction. PMID- 26598055 TI - Immunotherapy Combinations With Checkpoint Inhibitors in Metastatic Melanoma: Current Approaches and Future Directions. AB - Based on the complexity of the immune response to cancer and the mechanisms of tumor evasion, it is likely that therapeutic modulation of multiple immune mediated pathways will be needed to maximally induce tumor regression in patients with advanced melanoma. The rationale of using combination checkpoint inhibitor based regimens may include the concomitant effects on re-activation of T cells, increased trafficking of tumor reactive lymphocytes into the tumor tissue, and enhanced killing of cancer cells. The administration of nivolumab in combination with ipilimumab demonstrated increased response rates, tumor shrinkage, and median progression-free survival using combined therapy compared with either treatment alone. Although toxicity was also increased, this trial established proof of principle that combination immunotherapy could enhance the efficacy seen with single-agent programmed cell death protein-1 (PD-1) pathway blockade for the unselected patient. Current and future trials are evaluating alternative schedules and other combinations of immunotherapies to determine if they could provide similar efficacy with less toxicity. In addition, efforts are underway to determine how best to integrate combination immunotherapy with other treatment approaches for patients with advanced melanoma. PMID- 26598056 TI - Practical Approaches to Immunotherapy in the Clinic. AB - The development of immunotherapy using checkpoint blockade has altered the treatment landscape for patients who had but few options only several years ago. Currently, approved anti-checkpoint agents include ipilimumab, the first approved treatment aimed against the cytotoxic T-lymphocyte antigen-4 (CTLA-4) pathway, and pembrolizumab and nivolumab, which inhibit the programmed death-1 (PD-1) pathway. Careful monitoring and early intervention for immune-mediated side effects is important to mitigate toxicity. Immune-mediated response patterns may differ from response associated with conventional therapies, and so it is important to use caution against early abandonment of treatment. Biomarkers as predictive and prognostic markers of efficacy are still under investigation in an attempt to guide treatment selection in patients with advanced melanoma, and additional studies are needed to provide guidance for selection of checkpoint inhibitors to be used in sequence or combination. PMID- 26598057 TI - Current and Emerging Perspectives on Immunotherapy for Melanoma. AB - Novel immunotherapeutic treatments are aimed at reversing the action of inhibitory pathways that restrain the T-cell-dominated immune-mediated defense against cancer. The first immune-inhibitory protein to be discovered was cytotoxic T-lymphocyte antigen-4 (CTLA-4). The effectiveness of a CTLA-targeted antibody in treating melanoma was an impetus for the use of programmed cell death 1 (PD-1) inhibitors in cancer treatment. Important differences between the use of CTLA-4 inhibitors and PD-1 inhibitors in treatment include the patterns of expression of each receptor and its ligands and sites of action, as CTLA-4 blockade has been noted to provide more global effects, whereas those of PD-1 inhibition are observed at the tumor site. Although each treatment has been associated with impressive benefits in advanced melanoma, recent comparative studies suggest that PD-1 inhibitors may be more effective than CTLA-4 inhibition and that the most optimal results may be observed using both agents in those who can tolerate the increased toxicity that accompanies combination treatment. The most common adverse reactions include skin effects using either CTLA-4-blocking antibody or PD-1 inhibitors, colitis using CTLA-4 blockade, or thyroid disease using PD-1 inhibitors. PMID- 26598058 TI - Cultural Evolutionary Perspectives on Creativity and Human Innovation. AB - Cultural traits originate through creative or innovative processes, which might be crucial to understanding how culture evolves and accumulates. However, because of its complexity and apparent subjectivity, creativity has remained largely unexplored as the dynamic underpinning of cultural evolution. Here, we explore the approach to innovation commonly taken in theoretical studies of cultural evolution and discuss its limitations. Drawing insights from cognitive science, psychology, archeology, and even animal behavior, it is possible to generate a formal description of creativity and to incorporate a dynamic theory of creativity into models of cultural evolution. We discuss the implications of such models for our understanding of the archaeological record and the history of hominid culture. PMID- 26598059 TI - Patterns of Alternative Tobacco Product Use: Emergence of Hookah and E-cigarettes as Preferred Products Amongst Youth. AB - PURPOSE: There is a growing public health concern related to the rapid increase in the use of multiple tobacco products among adolescents. This study examined patterns of adolescent use of cigarettes, e-cigarettes, cigars/cigarillo, hookah/waterpipe, and smokeless/dip/chewing tobacco in a population of southern California adolescents. METHODS: Data from 2,097 11th- and 12th-grade participants in the Southern California Children's Health Study were collected via self-report in 2014. Study participants were asked about lifetime and current (past 30 days) use of cigarettes, cigars/cigarillos/little cigars, e-cigarettes, hookah/waterpipe, and smokeless/dip/chewing tobacco. Latent class analysis (LCA) was used to identify patterns of tobacco use. RESULTS: Hookah/waterpipe tobacco use had the highest current prevalence (10.7%) followed by e-cigarettes (9.6%). The prevalence of use of smokeless/dip/chewing tobacco was lowest, with 2.2% of adolescents reporting current use. The LCA suggested four distinct classes, comprising nonusers (72.3% of the sample), polytobacco experimenters (13.9%), e cigarette/hookah users (8.2%), and polytobacco users (5.6%). Multinomial logistic regression based on these four classes found that males had double the odds to be polytobacco users relative to nonusers compared to females (odds ratio, 2.3; 95% confidence interval, 1.26-4.25). CONCLUSIONS: By identifying naturally occurring configurations of tobacco product use in teens, these findings may be useful to practitioners and policymakers to identify the need for tobacco control interventions that address specific tobacco products and particular combinations of polytobacco use. LCA can be used to identify segments of the population overrepresented among certain tobacco use classes (e.g., boys) that may benefit most from targeted polyproduct intervention approaches. PMID- 26598060 TI - Polyvictimization and Youth Violence Exposure Across Contexts. AB - PURPOSE: The current research used latent class analysis to uncover groups of youth with specific victimization profiles and identify factors that are associated with membership in each victimization group. METHODS: This study used data from National Survey of Children Exposure to Violence II. Random digit dialing and address-based sampling were used to obtain a nationally representative sample of 2,312 youth ages 10-17 years. Phone interviews, averaging 55 minutes in length, were conducted with caregivers to obtain both consent and background information and then with youths themselves. RESULTS: Six groups of youth emerged: (1) nonvictims (26.4%), (2) home victims (8.4%), (3) school victims (20.8%), (4) home and school victims (21.3%), (5) community victims (5.4%), and (6) polyvictims (17.8%). Polyvictims were likely to have been victimized in multiple settings by multiple perpetrators and experienced the most serious aggravating characteristics, including incidents involving a weapon, injury, or a sexual component. Youth in the polyvictim class experienced the highest number of different victimizations types in the past year and had the most problematic profile in other ways, including greater likelihood of living in disordered communities, high probabilities of engaging in delinquency of all types, elevated lifetime adversity, low levels of family support, and the highest trauma symptom scores. CONCLUSIONS: The study supports the contention that a core basis of the particularly damaging effects of polyvictimization is the experience of victimization across multiple domains of the child's life. PMID- 26598061 TI - Self-Perceived Weight and Anabolic Steroid Misuse Among US Adolescent Boys. AB - PURPOSE: Anabolic steroid misuse is a growing concern among adolescent boys, and chronic misuse is associated with multisystemic health consequences. However, little is known about weight related predictors of anabolic steroid misuse. We examined the prediction of lifetime anabolic steroid misuse as a function of self perceived weight status among US adolescent boys. METHODS: Analysis was undertaken using the 2013 Youth Risk Behavior Survey, a nationally representative data set sampling public and private high school students throughout the United States. Data from a total of 6,000 US adolescent boys were used in the present study. RESULTS: The prevalence of ever misusing anabolic androgenic steroids was 12.6% among boys who viewed themselves as very underweight, 11.9% for boys who viewed themselves as very overweight, compared with 3.8% for boys who viewed themselves as about the right weight. Compared to boys who viewed themselves as about the right weight, boys who self-perceived themselves as very underweight (adjusted odds ratio = 6.9, 95% confidence interval: 2.7-17.7, p < .001) and very overweight (adjusted odds ratio = 3.8, 95% confidence interval: 1.8-7.7, p < .001) were significantly associated with increased risk of anabolic androgenic steroid misuse. CONCLUSIONS: Large effect size estimates were revealed, suggesting that anabolic androgenic steroid misuse is not solely a function of boys desiring increased mass; boys who desire leanness are also likely to misuse anabolic androgenic steroids. Future prevention efforts should target not only boys who view themselves as underweight but also those who perceive themselves as overweight. PMID- 26598062 TI - The Impact of Intergenerational Cultural Dissonance on Alcohol Use Among Vietnamese and Cambodian Adolescents in the United States. AB - PURPOSE: Rates of alcohol use may be increasing among Asian-American adolescents. Among youth from Asian-immigrant families, intergenerational cultural dissonance (ICD), a difference in acculturation between children and caregivers, is associated with adverse childhood outcomes. This study investigates the longitudinal association of ICD and alcohol use among youth from immigrant Vietnamese and Cambodian families in the United States. METHODS: Two waves of annual data, wave 4 (baseline for this study) and wave 5 (follow-up), were obtained from the Cross-Cultural Families Project, a longitudinal study of 327 Vietnamese and Cambodian immigrant families in Washington State. The Asian American Family Conflicts Scale was used to measure ICD. Adolescent alcohol use was measured as any drinking in the past 30 days. A multiple logistic regression model was estimated with the outcome, alcohol use, measured at the follow-up visit and all predictors, including ICD, measured at baseline. Sex, nationality, nativity, and acculturation were tested as modifiers of the ICD-alcohol use relationship. RESULTS: Nine percent of adolescents (age range 13-18 years) reported alcohol use at baseline and this increased significantly (p < .0001) to 16% one year later. ICD was associated with increased odds of alcohol use at follow-up (odds ratio: 1.57; 95% confidence interval: 1.03-2.41; p = .04). None of the interactions were statistically significant. CONCLUSIONS: ICD is a significant predictor of alcohol use among Vietnamese and Cambodian adolescents. Interventions that should be targeted toward reducing ICD through enhancing parent-child communication and teaching bicultural competence skills may help prevent alcohol use problems among youth from immigrant families. PMID- 26598063 TI - Global Prioritization of Disease Candidate Metabolites Based on a Multi-omics Composite Network. AB - The identification of disease-related metabolites is important for a better understanding of metabolite pathological processes in order to improve human medicine. Metabolites, which are the terminal products of cellular regulatory process, can be affected by multi-omic processes. In this work, we propose a powerful method, MetPriCNet, to predict and prioritize disease candidate metabolites based on integrated multi-omics information. MetPriCNet prioritized candidate metabolites based on their global distance similarity with seed nodes in a composite network, which integrated multi-omics information from the genome, phenome, metabolome and interactome. After performing cross-validation on 87 phenotypes with a total of 602 metabolites, MetPriCNet achieved a high AUC value of up to 0.918. We also assessed the performance of MetPriCNet on 18 disease classes and found that 4 disease classes achieved an AUC value over 0.95. Notably, MetPriCNet can also predict disease metabolites without known disease metabolite knowledge. Some new high-risk metabolites of breast cancer were predicted, although there is a lack of known disease metabolite information. A predicted disease metabolic landscape was constructed and analyzed based on the results of MetPriCNet for 87 phenotypes to help us understand the genetic and metabolic mechanism of disease from a global view. PMID- 26598064 TI - Validation of a Modified German Version of the Brief Pain Inventory for Use in Nursing Home Residents with Chronic Pain. AB - The Brief Pain Inventory (BPI) has been psychometrically evaluated worldwide in adult patients with cancer-related and chronic pain in several languages, but never in nursing home residents with chronic pain. To address this gap, we evaluated the validity of a modified version of the BPI, the BPI for nursing home residents (BPI-NHR) in individuals who resided in German nursing homes. One analytic sample included 137 nursing home residents (mean age, 83.3 years; SD, 8.0 years) without any missing values. An extended sample also included individuals with previous missing values that were substituted with the personal mean (n = 163; mean age, 83.3 years; SD, 8.3 years). Principal axis factoring with oblimin rotation was used to compute the final 2-factor solution for the substituted sample. These factors explained 71.7% of the variance. Internal consistency was calculated using Cronbach alpha, and showed excellent results. Concurrent validity was tested using nonparametric correlation analyses of the BPI-NHR with the pain medication scale. The present findings support the reliability and validity of the BPI-NHR for very old nursing home residents. Further evaluation of this measure is needed to examine face validity and the effect of multimorbidity on pain interference with function. PERSPECTIVE: In this article we present psychometric properties of the BPI originally developed to assess cancer pain, extended to measure chronic nonmalignant pain in younger and middle-aged patients, and now further developed to measure pain intensity and interference with function among very old nursing home residents. Thus, the BPI NHR might assist clinicians and researchers interested in assessment of pain intensity and interference in elderly individuals who reside in nursing homes. PMID- 26598065 TI - Prevalence and prognostic significance of hyperkalemia in hospitalized patients with cirrhosis. AB - BACKGROUND: The prevalence and clinical significance of hyponatremia in cirrhotics have been well studied; however, there are limited data on hyperkalemia in cirrhotics. AIM: We evaluated the prevalence and prognostic significance of hyperkalemia in hospitalized patients with cirrhosis and developed a prognostic model incorporating potassium for prediction of liver related death in these patients. METHODS: The training derivative cohort of patients was used for development of prognostic scores (Group A, n = 1160), which were validated in a large prospective cohort of cirrhotic patients. (Group B, n = 2681) of cirrhosis. RESULTS: Hyperkalemia was seen in 189 (14.1%) and 336 (12%) in Group A and Group B, respectively. Potassium showed a significant association that was direct with creatinine (P < 0.001) and urea (P < 0.001) and inverse with sodium (P < 0.001). Mortality was also significantly higher in patients with hyperkalemia (P = 0.0015, Hazard Ratio (HR) 1.3, 95% confidence interval 1.11 1.57). Combination of all these parameters into a single value predictor, that is, renal dysfunction index predicted mortality better than the individual components. Combining renal dysfunction index with other known prognostic markers (i.e. serum bilirubin, INR, albumin, hepatic encephalopathy, and ascites) in the "K" model predicted both short-term and long-term mortality with an excellent accuracy (Concordance-index 0.78 and 0.80 in training and validation cohorts, respectively). This was also superior to Model for End-stage Liver Disease, Model for End-stage liver disease sodium (MELDNa), and Child-Turcott-Pugh scores. CONCLUSIONS: Cirrhotics frequently have impaired potassium homeostasis, which has a prognostic significance. Serum potassium correlates directly with serum creatinine and urea and inversely with serum sodium. The model incorporating serum potassium developed from this study ("K"model) can predict death in advanced cirrhotics with an excellent accuracy. PMID- 26598067 TI - Fluoxetine effects on molecular, cellular and behavioral endophenotypes of depression are driven by the living environment. PMID- 26598066 TI - Micro-electrode array recordings reveal reductions in both excitation and inhibition in cultured cortical neuron networks lacking Shank3. AB - Numerous risk genes have recently been implicated in susceptibility to autism and schizophrenia. Translating such genetic findings into disease-relevant neurobiological mechanisms is challenging due to the lack of throughput assays that can be used to assess their functions on an appropriate scale. To address this issue, we explored the feasibility of using a micro-electrode array (MEA) as a potentially scalable assay to identify the electrical network phenotypes associated with risk genes. We first characterized local and global network firing in cortical neurons with MEAs, and then developed methods to analyze the alternation between the network active period (NAP) and the network inactive period (NIP), each of which lasts tens of seconds. We then evaluated the electric phenotypes of neurons derived from Shank3 knockout (KO) mice. Cortical neurons cultured on MEAs displayed a rich repertoire of spontaneous firing, and Shank3 deletion led to reduced firing activity. Enhancing excitation with CX546 rescued the deficit in the spike rate in the Shank3 KO network. In addition, the Shank3 KO network produced a shorter NIP, and this altered network firing pattern was normalized by clonazepam, a positive modulator of the GABAA receptor. MEA recordings revealed electric phenotypes that displayed altered excitation and inhibition in the network lacking Shank3. Thus, our study highlights MEAs as an experimental framework for measuring multiple robust neurobiological end points in dynamic networks and as an assay system that could be used to identify electric phenotypes in cultured neuronal networks and to analyze additional risk genes identified in psychiatric genetics. PMID- 26598068 TI - Linkage and association analysis of ADHD endophenotypes in extended and multigenerational pedigrees from a genetic isolate. AB - Attention-deficit/hyperactivity disorder (ADHD) is a heritable, chronic, neurodevelopmental disorder with serious long-term repercussions. Despite being one of the most common cognitive disorders, the clinical diagnosis of ADHD is based on subjective assessments of perceived behaviors. Endophenotypes (neurobiological markers that cosegregate and are associated with an illness) are thought to provide a more powerful and objective framework for revealing the underlying neurobiology than syndromic psychiatric classification. Here, we present the results of applying genetic linkage and association analyses to neuropsychological endophenotypes using microsatellite and single nucleotide polymorphisms. We found several new genetic regions linked and/or associated with these endophenotypes, and others previously associated to ADHD, for example, loci harbored in the LPHN3, FGF1, POLR2A, CHRNA4 and ANKFY1 genes. These findings, when compared with those linked and/or associated to ADHD, suggest that these endophenotypes lie on shared pathways. The genetic information provided by this study offers a novel and complementary method of assessing the genetic causes underpinning the susceptibility to behavioral conditions and may offer new insights on the neurobiology of the disorder. PMID- 26598069 TI - Dnmt3a2: a hub for enhancing cognitive functions. AB - The mechanisms responsible for fear memory formation and extinction are far from being understood. Uncovering the molecules and mechanisms regulating these processes is vital for identifying molecular targets for the development of novel therapeutic strategies for anxiety and fear disorders. Cognitive abilities require the activation of gene expression necessary to the consolidation of lasting changes in neuronal function. In this study we established a key role for an epigenetic factor, the de novo DNA methyltransferase, Dnmt3a2, in memory formation and extinction. We found that Dnmt3a2 overexpression in the hippocampus of young adult mice induced memory enhancements in a variety of situations; it converted a weak learning experience into long-term memory, enhanced fear memory formation and facilitated fear memory extinction. Dnmt3a2 overexpression was also associated with the increased expression of plasticity-related genes. Furthermore, the knockdown of Dnmt3a2 expression impaired the animals' ability to extinguish memories, identifying Dnmt3a2 as a key player in extinction. Thus, Dnmt3a2 is at the core of memory processes and represents a novel target for cognition-enhancing therapies to ameliorate anxiety and fear disorders and boost memory consolidation. PMID- 26598070 TI - Modulation of synchronous sympathetic firing behaviors by endogenous GABA(A) and glycine receptor-mediated activities in the neonatal rat spinal cord in vitro. AB - Delivering effective commands in the nervous systems require a temporal integration of neural activities such as synchronous firing. Although sympathetic nerve discharges are characterized by synchronous firing, its temporal structures and how it is modulated are largely unknown. This study used a collagenase dissociated splanchnic sympathetic nerve-thoracic spinal cord preparation of neonatal rats in vitro as an experimental model. Several single-fiber activities were recorded simultaneously and verified by rigorous computational algorithms. Among 3763 fiber pairs that had spontaneous fiber activities, 382 fiber pairs had firing positively correlated. Their temporal relationship was quantitatively evaluated by cross-correlogram. On average, correlated firing in a fiber pair occurred in scales of ~40ms lasting for ~11ms. The relative frequency distribution curves of correlogram parametrical values pertinent to the temporal features were best described by trimodal Gaussians, suggesting a correlated firing originated from three or less sources. Applications of bicuculline or gabazine (noncompetitive or competitive GABA(A) receptor antagonist) and/or strychnine (noncompetitive glycine receptor antagonist) increased, decreased, or did not change individual fiber activities. Antagonist-induced enhancement and attenuation of correlated firing were demonstrated by a respective increase and decrease of the peak probability of the cross-correlograms. Heterogeneity in antagonistic responses suggests that the inhibitory neurotransmission mediated by GABA(A) and glycine receptors is not essential for but can serve as a neural substrate to modulate synchronous firing behaviors. Plausible neural mechanisms were proposed to explain the temporal structures of correlated firing between sympathetic fibers. PMID- 26598071 TI - Preterm gut microbiota and metabolome following discharge from intensive care. AB - The development of the preterm gut microbiome is important for immediate and longer-term health following birth. We aimed to determine if modifications to the preterm gut on the neonatal intensive care unit (NICU) impacted the gut microbiota and metabolome long-term. Stool samples were collected from 29 infants ages 1-3 years post discharge (PD) from a single NICU. Additional NICU samples were included from 14/29 infants. Being diagnosed with disease or receiving increased antibiotics while on the NICU did not significantly impact the microbiome PD. Significant decreases in common NICU organisms including K. oxytoca and E. faecalis and increases in common adult organisms including Akkermansia sp., Blautia sp., and Bacteroides sp. and significantly different Shannon diversity was shown between NICU and PD samples. The metabolome increased in complexity, but while PD samples had unique bacterial profiles we observed comparable metabolomic profiles. The preterm gut microbiome is able to develop complexity comparable to healthy term infants despite limited environmental exposures, high levels of antibiotic administration, and of the presence of serious disease. Further work is needed to establish the direct effect of weaning as a key event in promoting future gut health. PMID- 26598072 TI - Evaluation of the germline single nucleotide polymorphism rs583522 in the TNFAIP3 gene as a prognostic marker in esophageal cancer. AB - Most esophageal cancer patients die because of disease relapse, hence an accurate prognosis of disease relapse and survival is essential. Genetic variations in cancer patients may serve as important indicators. Three genotypes (GG, AG, and AA) are displayed by the single nucleotide polymorphism (SNP) rs583522, which maps to the TNFAIP3 gene on chromosome 6. Evaluation of the potential prognostic value of the TNFAIP3-SNP in esophageal cancer (EC) was the aim of this study. A total of 158 patients underwent complete surgical resection of the esophagus for EC. None of them received any neoadjuvant or adjuvant treatment. Peripheral blood was sampled, and genomic DNA was extracted from leukocytes before each operation. Clinicopathologic parameters, tumor cell dissemination in bone marrow, and clinical outcome were correlated with the TNFAIP3-SNP. A-allele carriers showed advanced tumor stages compared with those of homozygous G-allele carriers (P<0.001). Patients with an A-allele genotype (AA or AG) were significantly more likely to experience a relapse (P=0.003). Survival analysis (log-rank test) revealed a significant difference in overall survival between the three groups (P=0.039); however, none of the genotypes was identified as a disease stage independent prognostic marker. In conclusion, TNFAIP3-SNP stratifies patients into different risk groups; however, it could not be identified as an independent prognostic marker. PMID- 26598073 TI - Should Alcohol-Based Handrub Use Be Customized to Healthcare Workers' Hand Size? AB - We evaluated whether the volume of alcohol-based handrub used by healthcare workers affects the residual bacterial concentration on their hands according to hand size. Bacterial reduction was significantly lower for large hands compared with small hands, which suggests a need for customizing the volume of alcohol based handrub for hand hygiene. PMID- 26598074 TI - Computational Characterization of Redox Non-Innocence in Cobalt Bis(Diaryldithiolene)-Catalyzed Proton Reduction. AB - Localized orbital bonding analysis (LOBA) was employed to probe the oxidation state in cobalt-bis(diaryldithiolene)-catalyzed proton reduction in nonaqueous media. LOBA calculations provide both the oxidation state and chemically intuitive views of bonding in cobalt-bis(diaryldithiolene) species and therefore allow characterization of the role of the redox non-innocent dithiolene ligand. LOBA results show that the reduction of the monoanion species [1Br](-) is metal centered and gives a cobalt(II) ion species, [1Br](2-), coordinated to two dianionic ene-1,2-dithiolates. This electronic configuration is in agreement with the solution magnetic moment observed for the analogous salt [1F](2-) (MUeff = 2.39 MUB). Protonation of [1Br](2-) yields the cobalt(III)-hydride [1Br(CoH)](-) species in which the Co-H bond is computed to be highly covalent (Lowdin populations close to 0.50 on cobalt and hydrogen atoms). Further reduction of [1Br(CoH)](-) forms a more basic cobalt(II)-H intermediate [1Br(CoH)](2-) (S = 0) from which protonation at sulfur gives a S-H bond syn to the Co-H bond. Formation of a cobalt-dihydrogen [1Br(CoH2)](-) intermediate is calculated to occur via a homocoupling (H(*) + H(*) -> H2) step with a free energy of activation of 5.9 kcal/mol in solution (via C-PCM approach). PMID- 26598075 TI - Exciton-dominated Dielectric Function of Atomically Thin MoS2 Films. AB - We systematically measure the dielectric function of atomically thin MoS2 films with different layer numbers and demonstrate that excitonic effects play a dominant role in the dielectric function when the films are less than 5-7 layers thick. The dielectric function shows an anomalous dependence on the layer number. It decreases with the layer number increasing when the films are less than 5-7 layers thick but turns to increase with the layer number for thicker films. We show that this is because the excitonic effect is very strong in the thin MoS2 films and its contribution to the dielectric function may dominate over the contribution of the band structure. We also extract the value of layer-dependent exciton binding energy and Bohr radius in the films by fitting the experimental results with an intuitive model. The dominance of excitonic effects is in stark contrast with what reported at conventional materials whose dielectric functions are usually dictated by band structures. The knowledge of the dielectric function may enable capabilities to engineer the light-matter interactions of atomically thin MoS2 films for the development of novel photonic devices, such as metamaterials, waveguides, light absorbers, and light emitters. PMID- 26598076 TI - Parenting styles and bullying. The mediating role of parental psychological aggression and physical punishment. AB - Studies concerning parenting styles and disciplinary practices have shown a relationship between both factors and bullying involvement in adolescence. The scarce available evidence suggests that abusive disciplinary practices increase teenagers' vulnerability to abuse in school or the likelihood of them becoming abusers of their peers in the same context. However, there is a lack of knowledge about the indirect effect of parenting styles in adolescents' bullying involvement through disciplinary practices, although a relationship between parenting styles and disciplinary practices has been shown. The aim of this research was to determine the mediating role of punitive parental discipline (physical punishment and psychological aggression) between the dimensions of parents' parenting styles and their children's involvement in bullying victimization and aggression. We used a sample comprising 2060 Spanish high school students (47.9% girls; mean age=14.34). Structural equation modeling was performed to analyze the data. The results confirmed the mediating role of parental discipline between the parenting practices analyzed and students' aggression and victimization. Significant gender-related differences were found for aggression involvement, where boys were for the most part linked to psychological aggression disciplinary practices and girls to physical punishment. Victimization directly correlated with parental psychological aggression discipline behavior across both sexes. In conclusion, the results seem to suggest that non-democratic parenting styles favor the use of punitive discipline, which increases the risk of adolescents' bullying involvement. Therefore, intervention programs must involve parents to make them aware about the important role they play in this process and to improve their parenting styles. PMID- 26598077 TI - A randomized, controlled, crossover study in patients with mild and moderate asthma undergoing treatment with traditional Chinese acupuncture. AB - OBJECTIVES: This study sought to verify the effects of acupuncture as an adjuvant treatment for the control of asthma. METHODS: This was a randomized, controlled, crossover trial conducted at the Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo. A total of 74 patients with mild/moderate, persistent asthma were randomized into two therapeutic groups: Group A - 31 patients underwent 10 real weekly acupuncture sessions, followed by a 3-week washout period and 10 sham weekly acupuncture sessions; and Group B - 43 patients underwent 10 sham weekly acupuncture sessions, followed by a 3-week washout period and 10 real weekly acupuncture sessions. Patients used short- and long acting beta-2 agonists and inhaled corticosteroids when necessary. Prior to treatment and after each period of 10 treatment sessions, the patients were evaluated for spirometry, induced sputum cell count, exhaled nitric oxide (NO) and with the Short Form 36 (SF-36) and Questionnaire on Quality of Life-Asthma (QQLA) questionnaires. Daily peak flow and symptom diaries were registered. The level of significance adopted was 5% (alpha=0.05). RESULTS: In Group B, after real acupuncture, there was a decrease in eosinophils (p=0.035) and neutrophils (p=0.047), an increase in macrophages (p=0.001) and an improvement in peak flow (p=0.01). After sham acupuncture treatment, patients experienced less coughing (p=0.037), wheezing (p=0.013) and dyspnea (p=0.014); similarly, after real acupuncture, patients reported less coughing (p=0.040), wheezing (p=0.012), dyspnea (p<0.001) and nocturnal awakening episodes (p=0.009). In Group A, there was less use of rescue medication (p=0.043). After the sham procedure, patients in Group A experienced less coughing (p=0.007), wheezing (p=0.037), dyspnea (p<0.001) and use of rescue medication (p<0.001) and after real acupuncture, these patients showed improvements in functional capacity (p=0.004), physical aspects (p=0.002), general health status (p<0.001) and vitality (p=0.019). Sham acupuncture also led to significant differences in symptoms, but these were not different from those seen with real acupuncture. Spirometry and exhaled NO levels did not show a difference between sham and real acupuncture treatment. In addition, no significant difference was demonstrated between treatments regarding the quality of life evaluation. CONCLUSION: Real and sham acupuncture have different effects and outcomes on asthma control. The crossover approach was not effective in this study because both interventions led to improvement of asthma symptoms, quality of life and inflammatory cell counts. Thus, sham acupuncture cannot serve as a placebo in trials with acupuncture as the main intervention for asthma. PMID- 26598078 TI - Evaluation of multidrug resistance-1 gene C>T polymorphism frequency in patients with asthma. AB - OBJECTIVES: Asthma is a chronic inflammatory lung disease characterized by bronchial hyperresponsiveness and airflow obstruction. Genetic and oxidative stress factors, in addition to pulmonary and systemic inflammatory processes, play a pivotal role in the pathogenesis of asthma. The products of the multidrug resistance-1 gene protect lung tissue from oxidative stress. Here, we aimed to evaluate the association between the multidrug resistance-1 gene C>T polymorphism and asthma with regard to oxidative stress-related parameters of asthmatic patients. METHODS: Forty-five patients with asthma and 27 healthy age-matched controls were included in this study. Blood samples were collected in tubes with ethylenediaminetetraacetic acid. DNA was extracted from the blood samples. The multidrug resistance-1 gene polymorphism was detected by polymerase chain reaction and a subsequent enzyme digestion technique. The serum levels of total oxidant status and total antioxidant status were determined by the colorimetric measurement method. RESULTS: The heterozygous polymorphic genotype was the most frequent in both groups. A significant difference in the multidrug resistance-1 genotype frequencies between groups indicated an association of asthma with the TT genotype. A significant difference between groups was found for wild type homozygous participants and carriers of polymorphic allele participants. The frequency of the T allele was significantly higher in asthmatic patients. The increase in the oxidative stress index parameter was significant in the asthma group compared with the control group. CONCLUSIONS: The multidrug resistance-1 gene C/T polymorphism may be an underlying genetic risk factor for the development of asthma via oxidant-antioxidant imbalance, leading to increased oxidative stress. PMID- 26598079 TI - Carbon dioxide contrast medium for endovascular treatment of ilio-femoral occlusive disease. AB - OBJECTIVES: Compare the use of carbon dioxide contrast medium with iodine contrast medium for the endovascular treatment of ilio-femoral occlusive disease in patients without contraindications to iodine. MATERIALS AND METHODS: From August 2012 to August 2014, 21 consecutive patients with ilio-femoral occlusive disease who were eligible for endovascular treatment and lacked contraindications to either iodine contrast or carbon dioxide were randomized into the carbon dioxide or iodine groups and subjected to ilio-femoral angioplasty.We analyzed the feasibility of the procedures, the surgical and clinical outcomes, the procedure lengths, the endovascular material costs, the contrast costs and the quality of the angiographic images in each group. RESULTS: No conversions to open surgery and no contrast media related complications were noted in either group. A post-operative femoral pulse was present in 88.9% of the iodine group and 80% of the carbon dioxide group. No differences in procedure length, endovascular material cost or renal function variation were noted between the groups. Four patients in the carbon dioxide group required iodine supplementation to complete the procedure. Contrast media expenses were reduced in the carbon dioxide group. Regarding angiographic image quality, 82% of the carbon dioxide images were graded as either good or fair by observers. CONCLUSIONS: The use of carbon dioxide contrast medium is a good option for ilio-femoral angioplasty in patients without contraindications to iodine and is not characterized by differences in endovascular material costs, procedure duration and surgical outcomes. In addition, carbon dioxide has lower contrast expenses compared with iodine. PMID- 26598080 TI - Association of CYP1A1 A4889G and T6235C polymorphisms with the risk of sporadic breast cancer in Brazilian women. AB - OBJECTIVES: We examined the influence of CYP1A1 A4889G and T6235C polymorphisms on the risk of sporadic breast cancer. METHODS: DNA from 742 sporadic breast cancer patients and 742 controls was analyzed using the polymerase chain reaction, followed by the restriction fragment length polymorphism technique. RESULTS: More patients had the CYP1A1 4889AG+GG genotype compared to controls (29.0% versus 23.2%, p=0.004). The G allele carriers had a 1.50-fold increased risk (95% CI: 1.14-1.97) of sporadic breast cancer compared to the other study participants. The frequency of the 4889AG+GG genotype among the Caucasian patients was higher than in the non-Caucasian patients (30.4% versus 20.2%, p=0.03) and controls (30.4% versus 23.2%, p=0.002). Caucasians and G allele carriers had a 1.61-fold increased risk (95% CI: 1.20-2.15) of sporadic breast cancer compared to other subjects. The CYP1A1 4889AG+GG genotype was more common among patients with a younger median age at first full-term pregnancy than among controls (33.8% versus 23.2%, p=0.001) and subjects whose first full-term pregnancies occurred at an older age (33.8% versus 26.1%, p=0.03). Women with the CYP1A1 4889AG+GG genotype and earlier first full-term pregnancies had a 1.87-fold (95% CI: 1.32-2.67) increased risk of sporadic breast cancer compared to the other study participants. Excess CYP1A1 4889AG+GG (39.8% versus27.1%, p=0.01) and 6235TC+CC (48.4% versus 35.9%, p=0.02) genotypes were also observed in patients with grade I and II tumors compared to patients with grade III tumors and controls (39.8% versus 23.2%, p=0.04; 48.4% versus 38.6%, p=0.04). The G and C allele carriers had a 2.44-fold (95% CI: 1.48-4.02) and 1.67-fold (95% CI: 1.03 2.69) increased risk, respectively, of developing grade I and II tumors compared to other subjects. CONCLUSIONS: The CYP1A1 A4889G and T6235C polymorphisms may alter the risk of sporadic breast cancer in Brazilian women. PMID- 26598081 TI - Association between interleukin-22 genetic polymorphisms and bladder cancer risk. AB - OBJECTIVE: The cytokine interleukin-22 (IL-22), which is produced by T cells and natural killer cells, is associated with tumorigenesis and tumor progression in cancers. However, the role of IL-22 in bladder cancer has not been investigated. MATERIALS AND METHODS: A prospective hospital-based case-control study comprising 210 patients with pathologically proven bladder cancer and 210 age- and gender matched healthy controls was conducted. The genotypes of 3 common polymorphisms ( 429 C/T, +1046 T/A and +1995 A/C) of the IL-22 gene were determined with fluorogenic 5' exonuclease assays. RESULTS: Patients with bladder cancer had a significantly higher frequency of the IL-22 -429 TT genotype [odds ratio (OR)=2.04, 95% confidence interval (CI)=1.19, 3.49; p=0.009] and -429 T allele (OR=1.42, 95% CI=1.08, 1.87; p=0.01) than the healthy controls. These findings were still significant after a Bonferroni correction. When stratifying according to the stage of bladder cancer, we found that patients with superficial bladder cancer had a significantly lower frequency of the IL-22 -429 TT genotype (OR=0.48, 95% CI=0.23, 0.98; p=0.04). When stratifying according to the grade and histological type of bladder cancer, we found no statistical association. The IL 22 +1046 T/A and IL-22 +1995 A/C gene polymorphisms were not associated with the risk of bladder cancer. CONCLUSION: To the authors' knowledge, this is the first report documenting that the IL-22 -429 C/T gene polymorphism is associated with bladder cancer risk. Additional studies are required to confirm this finding. PMID- 26598082 TI - Proteinuria is common among HIV patients: what are we missing? AB - OBJECTIVES: HIV-related renal diseases are the leading causes of chronic kidney diseases worldwide. The present study aimed to investigate the prevalence of pathological proteinuria and its risk factors among HIV patients. METHODS: A review of the medical records of 666 HIV-infected individuals aged 18 years or older in an urban HIV/AIDS clinic based in Porto Alegre in southern Brazil. Overt proteinuria was defined as a protein-to-creatinine ratio greater than 150 mg/g according to Kidney Disease: Improving Global Outcomes. RESULTS: The prevalence of pathological proteinuria in the present study cohort was 20%. Characteristics associated with pathological proteinuria after univariate analysis included alcohol abuse, hepatitis C virus coinfection, the occurrence of diabetes and therapy including tenofovir. Adjusted residuals analysis indicated an association between pathological proteinuria and both a CD4 lymphocyte count below 200 cells/mm3 and a viral load higher than 1000 copies/mL. Additionally, an absence of pathological proteinuria was associated with a CD4 lymphocyte count higher than 500 cells/mm3. After adjustment for variables with p<0.2 in the univariate analysis using a Poisson regression model, tenofovir-containing regimens and a CD4 lymphocyte count below 200 cells/mm3 were significantly associated with pathological proteinuria. CONCLUSION: The risk of chronic kidney diseases in this large contemporary cohort of HIV-infected individuals appeared to be attributable to a combination of HIV-related risk factors. In addition to the traditional risk factors cited in the literature, both regimens containing tenofovir and HIV disease severity seem to be associated with chronic kidney diseases in patients with HIV. Assessment of proteinuria constitutes a novel method for chronic kidney disease staging in HIV-infected individuals and may be effectively used to stratify the risk of progression to end-stage renal disease. PMID- 26598083 TI - Adherence to colonoscopy recommendations for first-degree relatives of young patients diagnosed with colorectal cancer. AB - OBJECTIVES: Colorectal cancer is the third leading cause of cancer death in the United States. The American College of Gastroenterology recommends screening for first-degree relatives of patients diagnosed with colorectal cancer before the age of 50. A colonoscopy is one of the most commonly recommended exams due to its specificity and the possibility to resect pre-malignant lesions. Nevertheless, the rate of physician adherence to this recommendation is unknown. METHODS: This transversal study was performed at a major cancer center in Brazil with 62 patients, aged 18 to 50, who completed a questionnaire on information received from their physicians regarding screening their first-degree relatives. We used the answers from patients who provided explicit consent. RESULTS: Two hundred and three patients were eligible to participate and 93 (45.8%) agreed to complete the questionnaire. Twenty-three questionnaires (24.73%) were returned and 39 were completed by telephone. Of the patients who answered the questionnaire, 39 (62.9%) had received a colonoscopy recommendation for their first-degree relatives and 23 (37.1%) were not informed of the recommendation. Among the patients who received the recommendations, 20.51% affirmed that all relatives completed the exam and 51.28% stated that no relatives completed the exam. DISCUSSION: The adherence rate of our physicians to the ACG guideline recommendations was 62.9%. Considering that our study was performed at a leading center for cancer treatment in Latin America, we had expected better adherence. The results show that adherence to the colorectal cancer screening recommendations for high-risk patients must be improved. PMID- 26598084 TI - Effects of estrogen on functional and neurological recovery after spinal cord injury: An experimental study with rats. AB - OBJECTIVES: To evaluate the functional and histological effects of estrogen as a neuroprotective agent after a standard experimentally induced spinal cord lesion. METHODS: In this experimental study, 20 male Wistar rats were divided into two groups: one group with rats undergoing spinal cord injury (SCI) at T10 and receiving estrogen therapy with 17-beta estradiol (4mg/kg) immediately following the injury and after the placement of skin sutures and a control group with rats only subjected to SCI. A moderate standard experimentally induced SCI was produced using a computerized device that dropped a weight on the rat's spine from a height of 12.5 mm. Functional recovery was verified with the Basso, Beattie and Bresnahan scale on the 2nd, 7th, 14th, 21st, 28th, 35th and 42nd days after injury and by quantifying the motor-evoked potential on the 42nd day after injury. Histopathological evaluation of the SCI area was performed after euthanasia on the 42nd day. RESULTS: The experimental group showed a significantly greater functional improvement from the 28th to the 42nd day of observation compared to the control group. The experimental group showed statistically significant improvements in the motor-evoked potential compared with the control group. The results of pathological histomorphometry evaluations showed a better neurological recovery in the experimental group, with respect to the proportion and diameter of the quantified nerve fibers. CONCLUSIONS: Estrogen administration provided benefits in neurological and functional motor recovery in rats with SCI beginning at the 28th day after injury. PMID- 26598085 TI - Chemical composition modulates the adverse effects of particles on the mucociliary epithelium. AB - OBJECTIVE: We compared the adverse effects of two types of real ambient particles; i.e., total suspended particles from an electrostatic precipitator of a steel mill and fine air particles from an urban ambient particulate matter of 2.5 um, on mucociliary clearance. METHOD: Mucociliary function was quantified by mucociliary transport, ciliary beating frequency and the amount of acid and neutral mucous in epithelial cells through morphometry of frog palate preparations. The palates were immersed in one of the following solutions: total suspended particles (0.1 mg/mL), particulate matter 2.5 um 0.1 mg/mL (PM0.1) or 3.0 mg/mL (PM3.0) and amphibian Ringer's solution (control). Particle chemical compositions were determined by X-ray fluorescence and gas chromatography/mass spectrometry. RESULTS: Exposure to total suspended particles and PM3.0 decreased mucociliary transport. Ciliary beating frequency was diminished by total suspended particles at all times during exposure, while particulate matter of 2.5 um did not elicit changes. Particulate matter of 2.5 um reduced epithelial mucous and epithelium thickness, while total suspended particles behaved similarly to the control group. Total suspended particles exhibited a predominance of Fe and no organic compounds, while the particulate matter 2.5 um contained predominant amounts of S, Fe, Si and, to a lesser extent, Cu, Ni, V, Zn and organic compounds. CONCLUSION: Our results showed that different compositions of particles induced different airway epithelial responses, emphasizing that knowledge of their individual characteristics may help to establish policies aimed at controlling air pollution. PMID- 26598086 TI - Extramedullary versus intramedullary tibial alignment technique in total knee arthroplasty: A meta-analysis of randomized controlled trials. AB - The aim of this study was to establish whether the use of an extramedullary or intramedullary tibial cutting guide leads to superior mechanical leg axis and implant positioning. A meta-analysis of six randomized controlled trials including 350 knees was performed. For the mechanical axis, frontal tibial component angle and tibial slope, there were no significant differences in the mean values or the number of outliers (+/-3 degrees ) between the extramedullary and intramedullary groups. A reduced tourniquet time was associated with the intramedullary guide. No significant difference in the complication rate was noted between the two groups. Neither extramedullary nor intramedullary tibial alignment was more accurate in facilitating the tibial cut. Use of an intramedullary guide results in a shorter tourniquet time and exhibits a similar complication rate as the extramedullary guide. PMID- 26598087 TI - The compatibility of Tacrine molecule with poly(n-butylcyanoacrylate) and Chitosan as efficient carriers for drug delivery: A molecular dynamics study. AB - According to the critical role of drug delivery in the treatment of diseases of the central nervous system (CNS), the selection of a suitable carrier plays an important role in the greater effectiveness of drugs. Due to good biocompatibility, biodegradability and low toxicity of polymeric nanoparticles, especially poly(n-butylcyanoacrylate) (PBCA) and Chitosan, these nanoparticles are considered as efficient carriers in drug delivery to the brain. In order to investigate the compatibility of these two polymers with different degrees of polymerization versus a Tacrine unit as the most well known drug for the treatment of Alzheimer's disease, molecular dynamics simulation (MD) is used as a principal tool for studying molecular systems. Interaction energy of the polymer/Tacrine systems, the radius of gyration of the Chitosan and PBCA during the simulation time, solubility and Flory-Huggins interaction parameters has been calculated. According to the results, the Tacrine molecule exhibited higher compatibility with PBCA than Chitosan. Moreover, the interaction between the Tacrine molecules and PBCA nanoparticles became stronger by increasing the length of polymer chain while it was not observed as a regular trend for Chitosan/Tacrine systems. By using these MD simulations, it is possible to find the most appropriate polymer as an efficient drug carrier. We note that the methodology applied here for modeling the polymer/Tacrine system is not restricted to the specific formulations of Tacrine and Chitosan (or PBCA) in the current work and can be extended to various other traditional or new drugs and different polymer drug carriers. PMID- 26598089 TI - The Art and Science of Reviewing the Pharmacotherapy Literature. PMID- 26598088 TI - Anti-obesity and anti-diabetic effects of flavonoid derivative (Fla-CN) via microRNA in high fat diet induced obesity mice. AB - 3-O-[(E)-4-(4-cyanophenyl)-2-oxobut-3-en-1-yl]kaempferol (Fla-CN), a semi synthesized flavonoid derivative of tiliroside, reduces whole-body adiposity, ameliorates metabolic lipid disorder, improves insulin sensitivity and benefits other disorders characterized by insulin resistance in high fat diet induced obesity mice. The improvement of insulin sensitivity and the reduction of weight gain are correlated with the changes of leptin and adiponectin levels. As a result, Fla-CN treatment could increase the expressions of pAMPK and miR-27 in the liver and adipose tissues. Meanwhile, we discovered that the expressions of various adipogenesis genes were downregulated, which were target genes of miR-27. This is the first report for the action of miR-27 by flavonoid derivative in rodents. The action of Fla-CN might be through multiple approaches including AMPK activation and enhancement in miR-27 expression. PMID- 26598090 TI - Effect of Acarbose on Glycemic Variability in Patients with Poorly Controlled Type 2 Diabetes Mellitus Receiving Stable Background Therapy: A Placebo Controlled Trial. AB - STUDY OBJECTIVE: To evaluate the effect of acarbose on glycemic control and glycemic variability, using a continuous glucose-monitoring system, in patients with type 2 diabetes mellitus who were not well controlled on metformin and vildagliptin therapy. DESIGN: Multicenter, randomized, double-blind, placebo controlled study. SETTING: Clinical research units at three hospitals in Italy. PATIENTS: Fifty-three patients with type 2 diabetes who were taking stable dosages of metformin 850 mg 3 times/day and vildagliptin 50 mg twice/day for at least 3 months and who were not adequately controlled with these therapies. INTERVENTION: Patients were randomized to either placebo or acarbose 100 mg 3 times/day to be added to their metformin-vildagliptin regimen. MEASUREMENTS AND MAIN RESULTS: Glycemic excursions were assessed by using a continuous glucose monitoring system for 1 week. Glycemic control was estimated as the mean blood glucose (MBG) level, the area under the glucose concentration-time curve for a glucose level above 70 mg/dl (AUC above 70) or 180 mg/dl (AUC above 180), and the percentage of time that the glucose level was above 70 mg/dl (T above 70) or 180 mg/dl (T above 180). Intraday glycemic variability was assessed by the standard deviation of the blood glucose level, the mean amplitude of glycemic excursions (MAGE), the M value, and continuous overlapping net glycemic action. Day-to-day glycemic variability was assessed as the mean of daily difference (MODD). The MBG level was ~20 mg/dl lower in the acarbose group than in the placebo group (p<0.05), particularly during the postprandial period. The AUC above 70 did not significantly differ between the two groups, whereas the AUC above 180 was ~40% lower in the acarbose group than in the placebo group during the daytime (p<0.01). The T above 180 was significantly higher in the placebo group than in the acarbose group (31% vs 8%, p<0.01. Moreover, the standard deviation and MAGE values were significantly lower in the acarbose group. The MODD value was not significantly changed in either group, and no significant differences were recorded between groups. All adverse events were mild in both groups, with only a significantly greater frequency of flatulence noted in the acarbose group (5% with acarbose vs 0.5% with placebo, p<0.05). CONCLUSION: The addition of acarbose to metformin and vildagliptin background therapy in patients with inadequately controlled type 2 diabetes decreased intraday glycemic variability, especially postprandial variability, but it was not associated with a significant change in interday glycemic variability. PMID- 26598091 TI - Influenza Antiviral Expenditures and Outpatient Prescriptions in the United States, 2003-2012. AB - STUDY OBJECTIVES: The clinical efficacy and cost-effectiveness of influenza antiviral use are controversial, with recent analyses suggesting potentially limited value. Thus, the objectives of this study were to describe influenza antiviral expenditures overall and by health care setting over a 10-year period (2003-2012) and to assess the correlation between outpatient influenza antiviral prescription use and influenza-like illness (ILI) outpatient visits. DESIGN: Retrospective, cross-sectional study. DATA SOURCES: IMS Health National Sales Perspectives and Xponent databases and Centers for Disease Control and Prevention ILINet national influenza surveillance system database. PATIENTS: All prescriptions for oseltamivir, rimantadine, or zanamivir from community pharmacies, mail order pharmacies, clinics, nonfederal hospitals, and other health care settings (federal hospitals, military facilities, jails and prisons, universities, staff-model health maintenance organizations, veterinary hospitals and clinics, and long-term care facilities) between January 1, 2003, and December 31, 2012. MEASUREMENTS AND MAIN RESULTS: Prescribing rates were calculated (prescriptions/1000 persons) for each year from 2003 to 2012 by using U.S. Census Bureau data. Influenza season was defined as July 1-June 30 of each calendar year. Linear regression assessed the correlation between influenza antiviral expenditures, prescription use, and ILI diagnoses. From 2003 to 2012, influenza antiviral drug expenditures accounted for $3.74 billion, with the majority from community pharmacies. After adjusting for inflation, no growth was observed for expenditures. A total of 32.8 million influenza antiviral prescriptions were dispensed from community pharmacies during the study period, and these prescriptions experienced 133.2% growth from 2003 to 2012. One third of expenditures and one quarter of dispensed prescriptions were in 2009. Influenza seasons were correlated with ILI and antiviral prescriptions. Annual community pharmacy expenditures were also associated with influenza antiviral prescriptions dispensed over the 10-year period. CONCLUSION: Influenza antivirals totaled $3.74 billion in the United States from 2003 to 2012, with the majority in 2009 and from community pharmacies. Influenza antivirals constituted a small proportion of total medication expenditures, but unforeseen pandemics resulted in unusually high use and expenditures. Influenza antiviral prescriptions dispensed from community pharmacies were associated with ILI and drug expenditures. PMID- 26598092 TI - Effect of Statins on the Incidence of Postoperative Atrial Fibrillation after Cardiac Valve Surgery. AB - STUDY OBJECTIVE: To evaluate the effect of preoperative statin use on the incidence of postoperative atrial fibrillation (POAF) in patients undergoing isolated cardiac valve surgery. DESIGN: Single-center retrospective cohort study. SETTING: Mixed medical-surgical intensive care unit in a community hospital. PATIENTS: A total of 244 adults who underwent isolated cardiac valve surgery between April 2007 and July 2012; of these patients, 102 received preoperative statins (defined as receiving at least one dose of a statin within 24 hours prior to surgery), and 142 did not receive preoperative statins (control group). MEASUREMENTS AND MAIN RESULTS: The primary outcome was the occurrence of POAF. Logistic regression was used to determine the association between preoperative statin use and occurrence of POAF. A propensity score-matched (PSM) analysis was also performed. Patients in the statin group were older, had a higher body mass index, frequency of diabetes mellitus, hypertension, cerebrovascular disease, peripheral artery disease, myocardial infarction, and preoperative beta-blocker use. POAF occurred in 35 patients (34.3%) in the statin group and 39 patients (27.5%) in the control group. Univariate analysis demonstrated no association between statin use and the occurrence of POAF (odds ratio [OR] 1.38, 95% confidence interval [CI] 0.796-2.39). Multivariable analysis also showed no association between POAF and preoperative statin use (OR 1.09, 95% CI 0.566 2.09). Repeating the analysis in 128 PSM patients demonstrated no association (OR 1.08, 95% CI 0.507-2.29). CONCLUSION: Preoperative statin use was not associated with a decreased incidence of POAF in patients undergoing isolated cardiac valve surgery. Additional studies are needed to further elucidate the pharmacodynamics of statins in patients undergoing cardiac surgery because statins have demonstrated a decrease in the risk of POAF in other cardiac surgery populations. PMID- 26598093 TI - Monitoring Enoxaparin with Antifactor Xa Levels in Obese Patients. AB - STUDY OBJECTIVES: To characterize antifactor Xa peak levels (as therapeutic, subtherapeutic, and supratherapeutic) in morbidly obese patients receiving treatment doses of enoxaparin, using a therapeutic range of 0.5-1.1 units/ml, and to assess the occurrence of bleeding complications in these patients. DESIGN: Retrospective cohort study. SETTING: Community hospital. PATIENTS: Ninety-nine morbidly obese patients (body mass index [BMI] higher than 40 kg/m(2) or total body weight more than 150 kg) who received at least three doses of the standard treatment dosage of enoxaparin and had steady-state antifactor Xa peak levels between April 2009 and January 2014. MEASUREMENTS AND MAIN RESULTS: Data were collected from patients' medical records on age, sex, height, weight, BMI, serum creatinine concentration, creatinine clearance (using lean body weight as well as adjusted body weight), antifactor Xa level, and time of blood collection for measurement of antifactor Xa level. Enoxaparin therapy was monitored by using antifactor Xa levels; steady-state enoxaparin antifactor Xa levels were measured 4 hours after administration of the third dose for peak level monitoring. The primary outcome was the proportion of patients whose steady-state antifactor Xa peak values were in the therapeutic (0.5-1.1 units/ml), subtherapeutic, and supratherapeutic ranges. The secondary outcome was occurrence of major bleeding. Univariate regression analysis was performed to identify the correlation between baseline patient characteristics and antifactor Xa levels. Most of the patients (50 [50.5%]) had supratherapeutic levels, 35 (35.4%) had levels within the therapeutic peak range (0.5-1.1 units/ml), and 14 (14.1%) had subtherapeutic levels. No bleeding was observed in any of the 99 patients. Univariate analysis revealed a negative association between antifactor Xa levels and serum creatinine concentration (r = -0.262, p=0.009). CONCLUSION: Based on the results of this study, monitoring antifactor Xa levels is warranted to ensure the safety and efficacy of enoxaparin in the obese patient population (defined as a total body weight more than 150 kg or BMI higher than 40 kg/m(2)). Enoxaparin dose individualization and antifactor Xa level monitoring need further validation with clinical outcomes. PMID- 26598094 TI - Probiotics and Fecal Microbiota Transplant for Primary and Secondary Prevention of Clostridium difficile Infection. AB - Clostridium difficile infection (CDI) is the most common cause of nosocomial diarrhea and is associated with an increased risk of mortality. The use of probiotics and fecal microbiota transplantation (FMT) has been studied to reduce the incidence and severity of this infection, but variable efficacy and safety data have been reported. Probiotics are hypothesized to be effective in the management of CDI through a number of mechanisms that include maintenance of normal gastrointestinal flora, antimicrobial and antitoxin properties, and immunomodulatory effects. Despite promising results in small trials and meta analyses, prospective, randomized, controlled trials have not demonstrated probiotics to be effective in the primary prevention of C. difficile-associated diarrhea (CDAD). Probiotics may be effective for secondary prevention in patients with recurrent CDI, but guidelines acknowledge the lack of compelling evidence. Trials are limited by the use of varying types of strains, numbers of strains, and doses of probiotics, as well the definitions of CDI and CDAD. FMT has been proposed as a method for restoring gut microbiota and has been shown to significantly increase the rate of cure in patients with recurrent CDI. Current studies have demonstrated minimal adverse effects, with no reports of transmission of infectious diseases; however, the optimal delivery method, sample preparation, and donor selection remain unclear. In this review, findings from recent literature are highlighted, and guideline recommendations for the use of these agents in the primary and secondary prevention of CDI are summarized. PMID- 26598095 TI - Making a Case for Pediatric Antimicrobial Stewardship Programs. AB - Although antimicrobials are commonly used in children, it is important to remember that they can have a profound impact on this unique patient population. Inadvertent consequences of antiinfective use in children include antimicrobial resistance, infection caused by Clostridium difficile, increased risk of obesity, and adverse drug events. In addition, compared with adults, children have different dosing requirements, antimicrobial formulation needs, pharmacokinetics, and antimicrobial susceptibility profiles. Therefore, pediatric-specific antimicrobial stewardship efforts are needed to promote appropriate use of antimicrobials in children. The primary purposes of this review article are to provide a rationale behind pediatric-focused antimicrobial stewardship and to describe currently available evidence regarding the initiatives of pediatric antimicrobial stewardship programs (ASPs). A literature search of the Medline database was performed (from inception through March 2015). The studies included in this review focus on antimicrobial stewardship interventions in inpatient pediatric settings. Ten inpatient studies involving pediatric-focused antimicrobial stewardship interventions were identified from the published literature. Four studies used the core strategy of prospective audit with feedback; two used prior approval. The remaining four used supplemental antimicrobial stewardship strategies (guidelines, clinical pathways, and computerized decision support tools). In general, the interventions resulted in decreased antimicrobial use, reduced antimicrobial costs, and fewer prescribing errors. Children have unique medical needs related to antimicrobials and deserve focused ASP efforts. The literature regarding pediatric antimicrobial stewardship interventions is limited, but published interventions may serve as paradigms for developing pediatric ASPs as demonstrated by the general success of these interventions. PMID- 26598096 TI - Isavuconazole: Pharmacology, Pharmacodynamics, and Current Clinical Experience with a New Triazole Antifungal Agent. AB - Coinciding with the continually increasing population of immunocompromised patients worldwide, the incidence of invasive fungal infections has grown over the past 4 decades. Unfortunately, infections caused by both yeasts such as Candida and molds such as Aspergillus or Mucorales remain associated with unacceptably high morbidity and mortality. In addition, the available antifungals with proven efficacy in the treatment of these infections remain severely limited. Although previously available second-generation triazole antifungals have significantly expanded the spectrum of the triazole antifungal class, these agents are laden with shortcomings in their safety profiles as well as formulation and pharmacokinetic challenges. Isavuconazole, administered as the prodrug isavuconazonium, is the latest second-generation triazole antifungal to receive U.S. Food and Drug Administration approval. Approved for the treatment of both invasive aspergillosis and invasive mucormycosis, and currently under investigation for the treatment of candidemia and invasive candidiasis, isavuconazole may have therapeutic advantages over its predecessors. With clinically relevant antifungal potency against a broad range of yeasts, dimorphic fungi, and molds, isavuconazole has a spectrum of activity reminiscent of the polyene amphotericin B. Moreover, clinical experience thus far has revealed isavuconazole to be associated with fewer toxicities than voriconazole, even when administered without therapeutic drug monitoring. These characteristics, in an agent available in both a highly bioavailable oral and a beta-cyclodextrin-free intravenous formulation, will likely make isavuconazole a welcome addition to the triazole class of antifungals. PMID- 26598097 TI - A Review of Antibiotic Use in Pregnancy. AB - During pregnancy, untreated sexually transmitted or urinary tract infections are associated with significant morbidity, including low birth weight, preterm birth, and spontaneous abortion. Approximately one in four women will be prescribed an antibiotic during pregnancy, accounting for nearly 80% of prescription medications in pregnant women. Antibiotic exposures during pregnancy have been associated with both short-term (e.g., congenital abnormalities) and long-term effects (e.g., changes in gut microbiome, asthma, atopic dermatitis) in the newborn. However, it is estimated that only 10% of medications have sufficient data related to safe and effective use in pregnancy. Antibiotics such as beta lactams, vancomycin, nitrofurantoin, metronidazole, clindamycin, and fosfomycin are generally considered safe and effective in pregnancy. Fluoroquinolones and tetracyclines are generally avoided in pregnancy. Physiologic changes in pregnancy lead to an increase in glomerular filtration rate, increase in total body volume, and enhanced cardiac output. These changes may lead to pharmacokinetic alterations in antibiotics that require dose adjustment or careful monitoring and assessment. PMID- 26598098 TI - Implications of Augmented Renal Clearance on Drug Dosing in Critically Ill Patients: A Focus on Antibiotics. AB - Augmented renal clearance (ARC) has been reported in approximately 30-65% of patients in the intensive care unit (ICU) despite the presence of a normal serum creatinine concentration. In certain ICU patient populations (e.g., patients with sepsis or trauma), the incidence increases to roughly 50-85%. Risk factors for ARC include the following: age younger than 50-55 years, male sex, higher diastolic blood pressure, fewer comorbidities, and a lower Acute Physiology and Chronic Health Evaluation II (APACHE II) or modified Sequential Organ Failure Assessment (SOFA) score at ICU admission. In addition, patient populations with the highest reported incidence of ARC include those with major trauma, sepsis, traumatic brain injury, subarachnoid hemorrhage, and central nervous system infection. Due to the high incidence of ARC in patients with a normal serum creatinine concentration, clinicians should consider screening ICU patients deemed high risk by using the ARC scoring system or the identification and assessment algorithm provided in this review. In addition, an 8-hour continuous urine collection should be considered to assess a measured creatinine clearance for evaluating the necessity of medication dosage adjustments. There is a clear association between ARC and subtherapeutic antibiotic concentrations as well as literature suggesting worse clinical outcomes; thus, the risk of underdosing antibiotics in a patient with ARC could increase the risk of treatment failure. This review examines strategies to overcome ARC and summarizes current pharmacokinetic and pharmacodynamic literature in patients with ARC in an effort to provide dosing guidance for this patient population. PMID- 26598099 TI - Principles in the Evaluation of Systematic Reviews. AB - Literature reviews summarize information from individual studies and are an important tool in the practice of evidence-based medicine. Various types of reviews, including narrative and systematic reviews, may be found within the biomedical literature. Systematic reviews are the strongest type and are often rated as the highest level of evidence. Thus it is important that clinicians understand how to evaluate them critically. This article is intended to enhance clinicians' understanding of the unique methods commonly used in systematic reviews by using the reporting standards to formulate evaluation principles. Explanations of the statistical tests and types of biases that are frequently encountered in systematic reviews are discussed. Lastly, an evaluation of a meta analysis using these principles is provided. PMID- 26598100 TI - Implementation and Clinical Outcomes of an Employer-Sponsored, Pharmacist Provided Medication Therapy Management Program. AB - Our objective was to describe the implementation and clinical outcomes of an employer-sponsored, pharmacist-provided medication therapy management (MTM) program for health plan beneficiaries with diabetes mellitus and/or hypertension. We conducted a single-center retrospective medical record review. The setting was a Pharmacy MTM Clinic at a self-insured health system consisting of six hospitals and several ancillary facilities. A total of 161 health plan beneficiaries with diabetes identified during annual wellness screenings for the health plan in 2012 and 225 health plan beneficiaries with diabetes and/or hypertension identified during annual wellness screenings for the health plan in 2013 were referred to the MTM clinic based on specific criteria. In 2012 the health system expanded its existing wellness program by implementing a voluntary diabetes care program for health plan beneficiaries with uncontrolled diabetes (hemoglobin A(1c) [A1C] 7% or higher); a similar program was added for hypertension for the 2013 plan year. All participants' A1C and blood pressure results were tracked from the date of their wellness screening through the end of the plan year. The pharmacists involved had the capability to directly implement drug regimen changes according to hospital protocol or provide recommendations to the physician, as specified by the referring physician. For the 2012-2013 plan year, the mean difference in A1C from baseline to program completion was -0.38% (95% confidence interval [CI] 0.58 to -0.18%, p<0.05). For beneficiaries with a baseline A1C of 7% or higher, the mean difference was -0.69% (95% CI -0.99 to -0.39%, p<0.05). For the 2013 2014 plan year, the mean difference in A1C from baseline to program completion was -0.62% (95% CI -0.81 to -0.44%, p<0.05). In that year, the mean difference in A1C for beneficiaries with A1C 7% or higher was -0.97% (95% CI -1.23 to -0.72%, p<0.05). For those referred for hypertension, a mean difference of -13 mm Hg (95% CI -18.59 to -7.73, p<0.05) from baseline to program completion was seen in systolic blood pressure, and the mean difference in diastolic blood pressure was 7 mm Hg (95% CI -9.92 to -4.04, p<0.05). This study demonstrated that health plan beneficiaries who participated in the employer-sponsored, pharmacist-provided MTM program had significant decreases in A1C and blood pressure. PMID- 26598101 TI - Possible Rivaroxaban Failure during the Postpartum Period. AB - Rivaroxaban, a factor Xa inhibitor, is a direct-acting oral anticoagulant (DOAC) indicated for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and for reducing the risk of DVT and PE recurrence. To our knowledge, no data are presently available to guide DOAC dosing in the postpartum period when pharmacokinetic and pharmacodynamic changes induced by pregnancy have an impact on drug clearance and increase hypercoagulability for a period of 6-8 weeks after delivery. We describe the case of a 35-year-old postpartum woman who presented to the emergency department with a diagnosis of a new multiple segmental PE 5 days after starting rivaroxaban therapy for a diagnosis of DVT. No precipitating cause, including noncompliance, was identified as a source of thrombosis embolization or extension. The patient was admitted, a heparin infusion was started for the management of PE, and rivaroxaban was discontinued. She was transitioned to enoxaparin 1 mg/kg (90 mg) subcutaneously every 12 hours the next day, bridged to warfarin, and discharged home on the overlapping regimen with close follow-up by the pharmacist-managed outpatient Anticoagulation Management Service. To our knowledge, this is the first case report of potential failure associated with rivaroxaban therapy in the postpartum period, possibly due to pharmacokinetic alterations seen in the postpartum period contributing to decreased drug exposure, yielding reduced anticoagulant efficacy. Clinicians should carefully weigh the risks and benefits of DOAC therapy in postpartum patients or other special populations requiring anticoagulation therapy. This report also highlights the need for further research identifying the impact of pharmacokinetic changes induced by special populations and the need to develop monitoring assays for such clinical situations. PMID- 26598102 TI - Azithromycin-Induced, Biopsy-Proven Acute Interstitial Nephritis in an Adult Successfully Treated with Low-Dose Corticosteroids. AB - Acute interstitial nephritis (AIN) is a form of acute kidney injury (AKI) characterized by a rapid deterioration of renal function, inflammatory infiltration of interstitial tissues, and renal edema. Drug-induced AIN is the most common etiology of AIN, but AIN can also have infectious, autoimmune, or idiopathic causes. beta-Lactam antibacterials, nonsteroidal antiinflammatory drugs, and proton pump inhibitors are recognized as leading causes of AIN; however, many other drugs have been identified as causes. We describe the case of a 59-year-old white male who developed AIN that required hemodialysis following azithromycin treatment. He presented to the hospital with complaints of nausea, vomiting, malaise, and fever over the past 3 days, along with no urine output in the preceding 24 hours. Two weeks earlier, he had completed a 5-day course of azithromycin 500 mg on day 1 followed by 250 mg/day on days 2-5 (total dose 1.5 g) for an upper respiratory tract infection. On admission, the patient's serum creatinine (S(cr)) concentration was 7.4 mg/dl (baseline = 1.3 mg/dl). He reported a similar episode of kidney failure 2 years earlier after taking azithromycin; however, at that time it was believed the AKI was likely due to benazepril use in the setting of acute infection, and a kidney biopsy was not performed. His S(cr) concentration peaked at 11.4 mg/dl, and three sessions of hemodialysis were required. A kidney biopsy was performed that revealed AIN. Low dose prednisone 0.3 mg/kg (30 mg)/day, tapered over the next 3 months, was administered, and his renal function improved to near baseline prior to discharge; 6 months later, his Scr concentration was 1.4 mg/dl. Despite lower than recommended dosing, this patient responded well to prednisone and did not experience long-term sequelae from renal injury. Use of the Naranjo Adverse Drug Reaction Probability Scale indicated a definite relationship (score of 10) between azithromycin exposure and the manifestation of AIN. To our knowledge, this is the first report of azithromycin-induced acute interstitial nephritis with near-complete resolution of renal injury in an adult. This case report illustrates the importance of rapid recognition of drug-induced renal injuries and discontinuation of the offending agent. Select use of corticosteroids may improve both time to and extent of renal function recovery. PMID- 26598104 TI - Infectious disease burden and cognitive function in young to middle-aged adults. AB - Prior research has suggested an association between exposure to infectious disease and neurocognitive function in humans. While most of these studies have explored individual viral, bacterial, and even parasitic sources of infection, few have considered the potential neurocognitive burden associated with multiple infections. In this study, we utilized publically available data from a large dataset produced by the Centers for Disease Control and Prevention that included measures of neurocognitive function, sociodemographic variables, and serum antibody data for several infectious diseases. Specifically, immunoglobulin G antibodies for toxocariasis, toxoplasmosis, hepatitis A, hepatitis B, and hepatitis C, cytomegalovirus, and herpes 1 and 2 were available in 5662 subjects. We calculated an overall index of infectious-disease burden to determine if an aggregate measure of exposure to infectious disease would be associated with neurocognitive function in adults aged 20-59 years. The index predicted processing speed and learning and memory but not reaction time after controlling for age, sex, race-ethnicity, immigration status, education, and the poverty-to income ratio. Interactions between the infectious-disease index and some sociodemographic variables were also associated with neurocognitive function. In summary, an index aggregating exposure to several infectious diseases was associated with neurocognitive function in young- to middle-aged adults. PMID- 26598105 TI - Biochemical basis of alphamethrin resistance in different life stages of Anopheles stephensi strains of Bangalore, India. AB - BACKGROUND: Anopheles stephensi is an important urban malaria vector in the Indian subcontinent. Extensive application of insecticides evokes microevolution, which results in resistance that can be traced back to their genotypes. In this study, resistant and susceptible strains of An. stephensi for alphamethrin were selected by selective inbreeding for 27 and ten generations respectively. The biochemical basis of resistance in all the life stages was investigated. Quantitative assays were performed for proteins (total and soluble), esterases (alpha, beta and acetylcholine) and phosphatases (acid and alkaline) by spectrophotometry, and qualitative assays for the enzymes by native polyacrylamide gel electrophoresis. RESULTS: The enzyme quantities significantly varied in all life stages of the resistant strain as compared with the susceptible ones. Qualitative studies showed seven isoforms for alpha- and beta esterases, three each for acetylcholinesterase and alkaline phosphatase and two for acid phosphatase. Exclusive bands were found in the resistant strain, such as alpha-Est 1 and beta-Est 1 in eggs and larvae, beta-Est 3 in adult males, beta Est 2 in adult females and AlkP 1, AlkP 2 and AlkP 3 in adult females, larvae and adult males respectively. CONCLUSION: Variations in the quantity and specific enzyme isoforms play a key role in the development of alphamethrin resistance in An. stephensi. (c) 2015 Society of Chemical Industry. PMID- 26598107 TI - Distal radioulnar synostosis after primary combined replacements for treatment of highly comminuted distal radius fracture in an elderly patient. PMID- 26598108 TI - Reverse hemi-hamate arthroplasty for volar fracture dislocation of the proximal interphalangeal joint of the finger. PMID- 26598106 TI - Polyunsaturated fatty acids moderate the effect of poor sleep on depression risk. AB - Although potentially modifiable risk factors for interferon-alpha (IFN-alpha) associated depression (IFN-MDD) have been identified, it is not currently known how they interact to confer risk. In the present study we prospectively investigated interactions among poor sleep quality, high-stress, pre-existing depressive symptoms, and polyunsaturated fatty acid status. Non-depressed hepatitis C patients (n=104) were followed prospectively during IFN-alpha therapy. IFN-MDD occurs in 20-40% of patients and was diagnosed using the Structured Clinical Interview of DSM-IV (SCID-IV), with incidence examined using Cox regression. Baseline Pittsburgh Sleep Quality Inventory (PSQI), Perceived Stress Scale (PSS), Beck Depression Inventory (BDI), and a range of plasma long chain fatty acid levels were measured (gas chromatography) - focusing on the ratio of arachidonic acid (AA) to docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) (AA/EPA+DHA). The AA/EPA+DHA ratio (Beta=0.40 +/- 0.16; p=0.006), PSQI (Beta=0.12 +/- 0.04; p=0.001), PSS (Beta=0.07 +/- 0.02; p<0.001), and baseline BDI (Beta=0.05 +/- 0.02; p<0.001) each individually predicted IFN-MDD incidence. In step-wise Cox regression eliminating non-significant variables, two interactions remained significantly predictive: PSQI*AA/EPA+DHA (p=0.008) and PSS*AA/EPA+DHA (p=0.01). Receiver Operator Curves (ROC) were used to examine the specificity and sensitivity of IFN-MDD prediction. When sleep was normal (PSQI<5), AA/EPA+DHA was strongly predictive of IFN-MDD (AUC=91 +/- 6; p=0.002). For example, among those with AA/EPA+DHA less than the median (4.15), none with PSQI<5 developed depression. Conversely, neither PSS nor PSQI was statistically associated with depression risk in those with an elevated AA/EPA+DHA ratio. These data demonstrate that the AA/EPA+DHA ratio moderates the effect of poor sleep on risk for developing IFN-MDD and may have broader implications for predicting and preventing MDD associated with inflammation. PMID- 26598109 TI - Midcarpal instability. AB - Midcarpal instability is a collective term for a number of conditions where the instability of the wrist is predominantly between the proximal and distal carpal rows. It has been regarded as relatively rare and infrequently requires surgical treatment. Palmar midcarpal instability is the most commonly found type of midcarpal instability and can be responsible for causing a clunking and painful wrist. The diagnosis is made on clinical grounds using the midcarpal instability provocative tests. Standard imaging and arthroscopic inspection do not usually confirm a definite diagnosis, but are important in excluding other pathologies. The classification and staging has been described using the extent of palmar translocation of the distal carpal row, which is elicited on passive stress tests. As this is a functional instability, it may be that a functional staging description might be better, and a proposed scheme is described. Treatment options including partial wrist fusions, tenodesis stabilizations and arthroscopic capsular shrinkage have been described in small case series with limited follow-up. There are no comparative series or randomized studies because of the relative rarity of this condition. PMID- 26598110 TI - Type III interferon gene expression in response to influenza virus infection in chicken and duck embryonic fibroblasts. AB - Type III interferons (IFN-lambdas) comprise a group of newly identified antiviral cytokines that are functionally similar to type I IFNs and elicit first-line antiviral responses. Recently, type III IFNs were identified in several species; however, little information is available about type III IFNs in ducks. We compared the expression of type III IFNs and their receptor in chicken embryonic fibroblasts (CEFs) and duck embryonic fibroblasts (DEFs) in response to influenza virus infection. The results showed that the expression of type III IFNs was upregulated in both DEFs and CEFs following infection with H1N1 influenza virus or treatment with poly (I:C), and expression levels were significantly higher in CEFs than in DEFs at each time point. The expression of the receptor for type III IFNs (IL-28Ralpha) was also upregulated following infection with H1N1 virus or treatment with poly (I:C) and was significantly higher in CEFs than in DEFs at each time point. The expression of the receptor for type III IFNs occurred from 8 hpi and remained at similar levels until 36 hpi in CEFs, but the expression level was elevated from 36 hpi in DEFs. These findings revealed the existence of distinct expression patterns for type III IFNs in chickens and ducks in response to influenza virus infection. The provided data are fundamentally useful in furthering our understanding of type III IFNs and innate antiviral responses in different species. PMID- 26598111 TI - Characterization of 40 full-length MHC class IIA functional alleles in miiuy croaker: Polymorphism and positive selection. AB - The major histocompatibility complex is a highly polymorphic gene superfamily in vertebrates that plays an important role in adaptive immune response. In the present study, we identified 40 full-length miiuy croaker MHC class IIA (Mimi DAA) functional alleles from 26 miiuy croaker individuals and found that the alleles encode 30 amino acid sequences. A high level of polymorphism in Mimi-DAA was detected in miiuy croaker. The rate of non-synonymous substitutions (d(N)) occurred at a significantly higher frequency than that of synonymous substitutions (d(S)) in the peptide-binding region (PBR) and non-PBR. This result suggests that balancing selection maintains polymorphisms at the Mimi-DAA locus. Phylogenetic analysis based on the full-length sequences showed that the Mimi-DAA alleles clustered into three groups. However, the phylogenetic tree constructed using the exon 2 sequences indicated that the Mimi-DAA alleles clustered into two groups. A total of 22 positively selected sites were identified on the Mimi-DAA alleles after testing for positive selection, and five sites were predicted to be associated with the binding of peptide antigen, suggesting that a few selected residues may play a significant role in immune function. PMID- 26598112 TI - Clearance of HBV DNA in immunized children born to HBsAg-positive mothers, years after being diagnosed with occult HBV infection. AB - In a previous study, we observed immunoprophylaxis failure due to occult hepatitis B virus (HBV) infection (OBI) despite the presence of adequate levels of anti-HBs in 21 (28%) of 75 children born to HBsAg-positive mothers. The aim of the study was to explore the maintenance of this cryptic condition in this population. Of 21 OBI-positive children, 17 were enrolled. HBV serological profiles were determined by enzyme-linked immunosorbent assay. Highly sensitive real-time and standard PCR followed by direct sequencing were applied in positive cases. The mean age (+/-SD) of studied patients was 6.57 +/- 2.75 years. All children still were negative for HBsAg. All but one (94%) were negative for HBV DNA. Only two children were positive for anti-HBc. The results of the most recent anti-HBs titration showed that 4 (23.5%) and 13 (76.5%) had low (<10 IU/mL) and adequate (>10 IU/mL) levels of anti-HBs, respectively. The only still OBI positive patient had an HBV DNA level of 50 copy/mL, carried the G145R mutation when tested in 2009 and again in 2013 in the 'a' determinant region of the surface protein. Further follow-up showed that after 18 months, he was negative for HBV DNA. In high-risk children, the initial HBV DNA positivity early in the life (vertical infection) does not necessarily indicate a prolonged persistence of HBV DNA (occult infection). Adequate levels of anti-HBs after vaccine and hepatitis B immune globulin immunoprophylaxis following birth could eventually clear the virus as time goes by. Periodic monitoring of these children at certain time intervals is highly recommended. PMID- 26598113 TI - Conformational Diversity of the Helix 12 of the Ligand Binding Domain of PPARgamma and Functional Implications. AB - Nuclear hormone receptors (NR) are transcription factors that activate gene expression in response to ligands. Structural and functional studies of the ligand binding domains (LBD) of NRs revealed that the dynamics of their C terminal helix (H12) is fundamental for NR activity. H12 is rigid and facilitates binding of coactivator proteins in the agonist-bound LBD. In the absence of ligand, H12 exhibits increased flexibility. To provide a comprehensive picture of the H12 conformational equilibrium, extensive molecular dynamics simulations of the LBD of the PPARgamma receptor in the presence or absence of ligand, and of coactivators and corepressor peptides, were performed. Free-energy profiles of the conformational variability of the H12 were obtained from more than four microseconds of simulations using adaptive biasing-force calculations. Our results demonstrate that, without ligand, multiple conformations of the H12 are accessible, including agonist-like conformations. We also confirm that extended H12 conformations are not accessible at ordinary temperatures. Ligand binding stabilizes the agonist H12 conformation relative to other structures, promoting a conformational selection. Similar effects are observed with coactivator association. The presence of corepressor peptides stabilizes conformations not allowed in the ligand-free, Rosiglitazone-bound or coactivator-bound LBDs. Corepressor binding, therefore, induces a conformational transition in the protein. Nevertheless, initial stages of corepressor dissociation could be induced by the ligand as it stabilizes the H12 in agonist form. Therefore, the present results provide a comprehensive picture of the H12 motions and their functional implications, with molecular resolution. PMID- 26598114 TI - Editors' message. PMID- 26598115 TI - Predictors and outcomes of endoleaks in the Veterans Affairs Open Versus Endovascular Repair (OVER) Trial of Abdominal Aortic Aneurysms. AB - OBJECTIVE: The Veterans Affairs Open Versus Endovascular Repair (OVER) Trial of Abdominal Aortic Aneurysms study was a randomized controlled trial comparing open vs endovascular repair (EVAR) in standard-risk patients with infrarenal aortic aneurysms. The analysis reported here identifies characteristics, risk factors, and long-term outcome of endoleaks in patients treated with EVAR in the OVER cohort. METHODS: The OVER trial enrolled 881 patients, of whom 439 received successful EVAR. Logistic regression analysis was used to identify predictors for endoleaks and secondary interventions. Kaplan-Meier survival analysis, longitudinal plots, and generalized linear mixed models methods were used to describe time to endoleak detection, resolution, or death. RESULTS: During a mean follow-up of 6.2 +/- 2.4 years, 135 patients (30.5%) developed 187 endoleaks. Four patients with EVAR went on to rupture; these four patients did not all have an endoleak. Mortality between patients who did and did not develop endoleaks was not significantly different. The 187 endoleaks included 12% type I, 76% type II, 3% type III, 3% type IV, and 6% indeterminate. Patient demographics and vascular risk factors were not associated with endoleak development. The presence of endoleaks resulted in an increase in aneurysm diameter over time (P < .0001). Fifty-three percent of endoleaks resolved spontaneously, and 31.9% received secondary interventions. The initial aneurysm size independently predicted a need for secondary interventions (P < .0003). Delayed type II endoleaks (detected >1 year after EVAR) were associated with aneurysm enlargement compared with the early counterpart. There was no difference in aneurysm size or length of survival between type II and other types of endoleak. CONCLUSIONS: We present one of the most comprehensive and longest follow-up analyses of patients treated with aortic endografts. Endoleaks were common and negatively affected aneurysm diameter reduction. Delayed type II endoleaks were associated with late aneurysm diameter enlargement. Endoleaks and aneurysm diameter enlargement were not associated with excess mortality compared with those without these features. PMID- 26598116 TI - Discussion. PMID- 26598118 TI - Invited commentary. PMID- 26598117 TI - Postoperative renal dysfunction independently predicts late mortality in patients undergoing aortic reconstruction. AB - OBJECTIVE: Preoperative chronic kidney disease (CKD) has been shown to predict postoperative renal complications and mortality after open aortic surgery; the impact of postoperative renal complications less severe than permanent dialysis are unknown. We evaluated the impact of postoperative renal dysfunction severity on survival using a regional quality improvement registry. METHODS: Patients undergoing intact open aortic reconstruction in the Vascular Study Group of New England registry (2003-2012) were stratified by severity of postoperative renal complications; none, creatinine increase of greater than 0.5 mg/dL (incCr), or any hemodialysis (HD). Predictors of renal dysfunction and impact of renal complications on survival were analyzed using multivariable methods. RESULTS: We included 2695 patients, of which 65% (n = 1733) underwent open abdominal aortic aneurysm repair, and 35% (n = 962) open aortoiliac reconstruction. At baseline, 15% of patients had preoperative moderate CKD and 1.2% had severe CKD. Postoperative renal complications of incCr occurred in 8.5% of patients, and 1.5% required HD. Multivariable cumlogit regression identified severe baseline CKD (odds ratio [OR], 15; 95% confidence interval [CI], 6.4-34; P < .001, moderate CKD (OR, 2.8; 95% CI, 1.9-3.3; P < .001), suprarenal clamp use (OR, 2.2; 95% CI, 1.6-2.9; P < .001), perioperative vasopressor requirements (OR, 2.2; 95% CI, 1.6 2.9; P < .001), operating time (OR, 1.004 per minute; 95% CI, 1.003-1.006; P < .001), and chronic obstructive pulmonary disease (OR, 1.5; 95% CI, 1.2-1.8; P < .001) as independent predictors of worsening strata of postoperative renal dysfunction. Multivariable logistic regression analysis showed that patient age (OR, 1.06 per year; 95% CI, 1.01-1.1; P = .01), baseline chronic obstructive pulmonary disease (OR, 1.6; 95% CI, 1.2-2.2; P < .01), incCr (OR, 3.7; 95% CI, 1.8-7.4; P = .009), and HD (OR, 4.8; 95% CI, 1.8-12.7); P = .009) independently increased 30-day mortality. Risk-adjusted multivariable Cox regression showed that incCr (hazard ratio, 1.8; 95% CI, 1.3-2.6; P < .001) and HD (hazard ratio, 4.4; 95% CI, 2.8-6.9; P < .001) increased risk of late death independent of a variety of other clinical variables, including baseline CKD. The 5-year survival was lower (log-rank P < .001) in patients with incCr (66% +/- 4%), and HD (38% +/ 10%) compared with those with no renal complications (77% +/- 1%). CONCLUSIONS: Increasing severity of postoperative renal dysfunction independently predicts increased risk of late mortality after open aortic surgery. Perioperative measures to decrease renal complications may potentially prolong the survival of patients after open aortic surgery. PMID- 26598119 TI - Invited commentary. PMID- 26598120 TI - Recanalization of chronic obstruction of common iliac artery in the presence of an ectopic renal artery. PMID- 26598121 TI - Absence of the infrarenal inferior vena cava. PMID- 26598122 TI - To treat or not to treat: On what should surgical therapy be based? AB - Dr C. Autious has just returned from the most prestigious vascular surgery meeting in America. At the meeting, one of the most prominent complex aneurysm surgeons arose to discuss a paper concerning a procedure he had developed and popularized over the last decade. Dr L. Uminous stunned the audience with his declaration that he no longer recommends that his namesake procedure be performed. Instead, he proclaimed that a new, radically different procedure be adopted immediately. He showed slides detailing the novel proposal but did not give data concerning results obtained. The recommended procedure is technically possible but seems to require a different skill set. Dr Autious has a patient scheduled for elective surgery that he had planned to use the Uminous procedure to treat. What should he do? A. Do the recommended procedure as best you can. B. Refer the patient to Dr Uminous. C. Offer the recommended procedure with full disclosure. D. Give full disclosure and let the patient decide which procedure to use. E. Put the procedure on hold until more information becomes available. PMID- 26598123 TI - The model for Fundamentals of Endovascular Surgery (FEVS) successfully defines the competent endovascular surgeon. AB - OBJECTIVE: Fundamental skills testing is now required for certification in general surgery. No model for assessing fundamental endovascular skills exists. Our objective was to develop a model that tests the fundamental endovascular skills and differentiates competent from noncompetent performance. METHODS: The Fundamentals of Endovascular Surgery model was developed in silicon and virtual reality versions. Twenty individuals (with a range of experience) performed four tasks on each model in three separate sessions. Tasks on the silicon model were performed under fluoroscopic guidance, and electromagnetic tracking captured motion metrics for catheter tip position. Image processing captured tool tip position and motion on the virtual model. Performance was evaluated using a global rating scale, blinded video assessment of error metrics, and catheter tip movement and position. Motion analysis was based on derivations of speed and position that define proficiency of movement (spectral arc length, duration of submovement, and number of submovements). RESULTS: Performance was significantly different between competent and noncompetent interventionalists for the three performance measures of motion metrics, error metrics, and global rating scale. The mean error metric score was 6.83 for noncompetent individuals and 2.51 for the competent group (P < .0001). Median global rating scores were 2.25 for the noncompetent group and 4.75 for the competent users (P < .0001). CONCLUSIONS: The Fundamentals of Endovascular Surgery model successfully differentiates competent and noncompetent performance of fundamental endovascular skills based on a series of objective performance measures. This model could serve as a platform for skills testing for all trainees. PMID- 26598124 TI - Evaluation and management of congenital peripheral arteriovenous malformations. AB - The International Society for Study of Vascular Anomalies (ISSVA) broadly categorizes vascular anomalies into vascular tumors and vascular malformations. Vascular malformations are further divided based on their flow properties into slow-flow venous and lymphatic malformations, high-flow arteriovenous malformations (AVMs), and congenital mixed syndromes, which can include combinations thereof. Whether occurring in isolation or as part of a broader syndrome, congenital high-flow AVMs are arguably the most complicated, challenging, and gratifying of all vascular malformations to diagnose and manage. Various configurations exist depending on location and coexisting clinical features. Transcatheter embolization has evolved into the mainstay of treatment for most congenital peripheral AVMs with surgical excision playing a growingly limited role as an adjunctive modality. Successful treatment requires technical precision, creativity, patience, and persistence given the ever-evolving angioarchitecture and hemodynamic profile of these lesions. Despite these challenges, certain fundamental principles have been established as our understanding of the pathogenesis, natural history, hemodynamics, and treatment outcomes has expanded and evolved over the last few decades. These principles are crucial to adhere to in the overall management of these lesions and are highlighted and expanded upon herein. PMID- 26598125 TI - Regarding "Increased use of brachiocephalic arteriovenous fistulas improves functional primary patency". PMID- 26598126 TI - Reply: To PMID 25935277. PMID- 26598127 TI - Regarding "The Abdominal Aortic Aneurysm Statistically Corrected Operative Risk Evaluation (AAA SCORE) for predicting mortality after open and endovascular interventions". PMID- 26598128 TI - Reply: To PMID 24985535. PMID- 26598129 TI - Regarding "Poststent ballooning is associated with increased periprocedural stroke and death rate in carotid artery stenting". PMID- 26598130 TI - Reply: To PMID 26033011. PMID- 26598131 TI - The role of the multidisciplinary team in decision making for vascular graft infection. PMID- 26598132 TI - Gelsolin interacts with LamR, hnRNP U, nestin, Arp3 and beta-tubulin in human melanoma cells as revealed by immunoprecipitation and mass spectrometry. AB - Gelsolin, a multifunctional actin binding protein, plays a not yet fully understood role in tumorigenesis. Therefore the goal of this study was to identify additional molecular partners of gelsolin in human melanoma cells, separately in the cytoplasmic compartment and cell nuclei. For this purpose we performed immunoprecipitation experiments based on a modified protocol followed by mass spectrometry. The obtained results were confirmed by Western blot analysis, proximity ligation assays and confocal microscopy. As expected gelsolin interacted with actin, in particular we demonstrate its interaction with cytoplasmic beta and gamma actins, and a newly discovered actin isoform, actbl2. As new gelsolin-interacting partners we identified the ribosomal protein Rpsa, also known as a non-integrin laminin receptor (LamR), and the heterogeneous nuclear ribonucleoprotein hnRNP U. Our data furthermore indicate that gelsolin interacts with particular components of the three cytoskeleton systems: nestin (intermediate filaments), Arp3 (actin cytoskeleton) and beta-tubulin (microtubules). We also report for the first time that gelsolin is a constituent of midbodies, a tubulin containing structure formed at the end of cytokinesis. PMID- 26598133 TI - Transgenic mouse model for imaging of interleukin-1beta-related inflammation in vivo. AB - Inflammation is a biological response associated with symptoms of various diseases, and its study is important in gaining an understanding of the pathological conditions of such diseases and in making strategic plans for promoting healing. It is therefore essential to develop technologies for the detection of inflammatory conditions. Interleukin-1beta (IL-1beta) is a proinflammatory cytokine produced and secreted mainly by monocytes and macrophages in response to inflammatory stimulation. The activation of IL-1beta is regulated through transcriptional induction by the promoter and post translational processing by the inflammasome. Here we have developed a reporter gene to monitor the activation status of IL-1beta by using a dual regulation system and, by using the reporter gene, we have established a mouse model that permits low-invasive visualization of the inflammatory status. Previous reporter systems dependent on the transcription or processing of IL-1beta show problems in terms of background noise or signal specificity. Our reporter system overcomes these weaknesses by combining advantages from regulation by a promoter and processing of IL-1beta. Our mouse model detected specific physiological inflammation in the liver and pancreas caused by hepatitis or pancreatitis models, respectively. Our reporter gene and mouse model are therefore expected to become useful bioresources for future medical science. PMID- 26598134 TI - Sacral erosion and insufficiency fracture secondary to dural ectasia in patient with Marfan syndrome. PMID- 26598135 TI - Integrative genomic mining for enzyme function to enable engineering of a non natural biosynthetic pathway. AB - The ability to biosynthetically produce chemicals beyond what is commonly found in Nature requires the discovery of novel enzyme function. Here we utilize two approaches to discover enzymes that enable specific production of longer-chain (C5-C8) alcohols from sugar. The first approach combines bioinformatics and molecular modelling to mine sequence databases, resulting in a diverse panel of enzymes capable of catalysing the targeted reaction. The median catalytic efficiency of the computationally selected enzymes is 75-fold greater than a panel of naively selected homologues. This integrative genomic mining approach establishes a unique avenue for enzyme function discovery in the rapidly expanding sequence databases. The second approach uses computational enzyme design to reprogramme specificity. Both approaches result in enzymes with >100 fold increase in specificity for the targeted reaction. When enzymes from either approach are integrated in vivo, longer-chain alcohol production increases over 10-fold and represents >95% of the total alcohol products. PMID- 26598136 TI - Safety and tolerability of diazoxide in Japanese patients with hyperinsulinemic hypoglycemia. AB - Diazoxide is a non-diuretic benzothiadiazine derivative, one of a group of substances introduced into clinical practice in the 1950s for the treatment of hypertension. Fajans reported the use of diazoxide for the treatment of insulinoma in 1979. Although patients with hyperinsulinemic hypoglycemia worldwide have been treated with diazoxide for more than 30 years, there are no recent reports about the adverse effects of this drug in Asian patients, including Japanese patients. Herein, we report the results of our retrospective clinical record review of 6 Japanese patients (3 females and 3 males, ranging in age from 58 to 91 years) with hyperinsulinemic hypoglycemia and inoperable insulinoma treated with diazoxide. Diazoxide improved control of hypoglycemic symptoms and maintained normoglycemia in 5 of the 6 patients, and was ineffective in one patient. Surprisingly, although all 6 patients received diazoxide according to the treatment strategy recommended in Western patients, 5 of the 6 patients developed edema and two developed congestive heart failure. Thus, when starting treatment with diazoxide in Japanese patients, the symptoms and signs of fluid retention should be evaluated carefully. Also, appropriate protocols for treatment with diazoxide should be evaluated by means of clinical trials in Japanese patients with hyperinsulinemic hypoglycemia. PMID- 26598137 TI - Triterpenoids and an alkamide from Ganoderma tsugae. AB - Ganoderma tsugae is a medicinal mushroom. In a continual study on the bioactive constituents of this fungus, a new lanostanoid, 3beta-acetoxy-16alpha-hydroxy 24xi-methyl-5alpha-lanosta-8,25-dien-21-oic acid, named tsugaric acid F (1) and a novel palmitamide, N-(3'alpha,4'beta-dihydroxy-2'beta-(hydroxymethyl)-1'beta (cyclobutyl)palmitamide (2) were isolated and characterized from the fruit bodies of G. tsugae, and three novel seco-lanostanoids, 3,4-seco-8alpha,9alpha-epoxy 5alpha-lanosta-21-oic acid 3,4 lactone (5), 3,4-seco-5beta-lanosta-7,9(11),4(29) trien-3,21-dioic acid-3-methyl ester (6), 3,4-seco-5beta-lanosta-7,9(11),4(29) trien-3,21-dioic acid (7), and a known compound, 3-oxo-5alpha-lanosta-8-en-21-oic acid (4) were prepared from 3. The structures of new compounds, 1, 2, 5-7 were determined by spectroscopic methods. Compounds 1 and 4 showed inhibitory effects on xanthine oxidase (XO) with an IC50 values of 313.3 +/- 80.0 and 43.9 +/- 29.9 MUM, respectively when 7 exhibited potent inhibitory effect on superoxide anion generation in rat neutrophils stimulated with formyl-Met-Leu-Phe (fMLP)/cytochalasin B (CB) with an IC50 values of 1.3 +/- 0.2 MUM. Compounds 4-7 showed weak cytotoxic activities against PC3 cells. These results indicated that 4 and 7 may be used as cancer chemopreventive agents. PMID- 26598138 TI - Monoterpene derivatives with anti-allergic activity from red peony root, the root of Paeonia lactiflora. AB - The methanolic extract and its subfractions from red peony root, the dried roots of Paeonia lactiflora Pallas showed potent antiallergic effects, as inhibition of immunoglobulin E (IgE)-mediated degranulation in rat basophil leukemia (RBL)-2H3 cells. Bioassay-guided fractionation led to the isolation of 16 monoterpene derivatives, including 3 new compounds, paeoniflorol (1), 4' hydroxypaeoniflorigenone (2) and 4-epi-albiflorin (3), together with 13 known ones (4-16). The chemical structures of the new compounds were elucidated on the basis of spectroscopic and chemical evidences. Among the isolated monoterpene derivatives, nine compounds showed potent anti-allergic effects and compound 1 was the most effective. A primary structure-activity relationship of monoterpene derivatives was discussed. PMID- 26598139 TI - Shape recognition: convexities, concavities and things in between. AB - Visual objects are effortlessly recognized from their outlines, largely irrespective of viewpoint. Previous studies have drawn different conclusions regarding the importance to shape recognition of specific shape features such as convexities and concavities. However, most studies employed familiar objects, or shapes without curves, and did not measure shape recognition across changes in scale and position. We present a novel set of random shapes with well-defined convexities, concavities and inflections (intermediate points), segmented to isolate each feature type. Observers matched the segmented reference shapes to one of two subsequently presented whole-contour shapes (target or distractor) that were re-scaled and re-positioned. For very short segment lengths, performance was significantly higher for convexities than for concavities or intermediate points and for convexities remained constant with increasing segment length. For concavities and intermediate points, performance improved with increasing segment length, reaching convexity performance only for long segments. No significant differences between concavities and intermediates were found. These results show for the first time that closed curvilinear shapes are encoded using the positions of convexities, rather than concavities or intermediate regions. A shape-template model with no free parameters gave an excellent account of the data. PMID- 26598140 TI - Aerococcus viridans var. homari: The presence of capsule and the relationship to virulence in American lobster (Homarus americanus). AB - The relationship between virulence and encapsulation of Aerococcus viridans var. homari was evaluated by growing virulent (Rabin's) and avirulent (ATCC 10400) strains under varying culture conditions, and during challenge trials. Changes in capsule thickness were monitored using a modified lysine-ruthenium red (LRR) fixation method and transmission electron microscopy. The virulent Rabin's strain possessed a prominent capsule of 0.252 MUm+/-0.061 MUm that was diminished by in vitro growth conditions to 0.206 MUm+/-0.076 MUm. The ATCC 10400 strain capsule thickness decreased from 0.157 MUm+/-0.043 MUm to 0.117 MUm+/-0.043 MUm after 10 in vitro passages. The virulent Rabin's strain capsule was significantly thicker than the avirulent ATCC 10400 strain under all growth conditions. Rabin's strain, regardless of pre-challenge growth conditions or dose (high dose 10(7) or low dose 10(2)), was able to kill lobsters in 7 days at 15 degrees C. ATCC 10400 strain, regardless of pre-challenge growth conditions, killed lobster only at high doses (10(7)) with varying median time to death of ~15 days, while at low doses (10(2)) all lobsters survived and no bacteria were present after 42 days. This work demonstrates the importance of the thickness of the A. viridans capsule to virulence in the American lobster. PMID- 26598142 TI - First-in-human trial of a live-attenuated Mycobacterium tuberculosis vaccine. PMID- 26598141 TI - Safety of human immunisation with a live-attenuated Mycobacterium tuberculosis vaccine: a randomised, double-blind, controlled phase I trial. AB - BACKGROUND: Tuberculosis remains one of the world's deadliest transmissible diseases despite widespread use of the BCG vaccine. MTBVAC is a new live tuberculosis vaccine based on genetically attenuated Mycobacterium tuberculosis that expresses most antigens present in human isolates of M tuberculosis. We aimed to compare the safety of MTBVAC with BCG in healthy adult volunteers. METHODS: We did this single-centre, randomised, double-blind, controlled phase 1 study at the Centre Hospitalier Universitaire Vaudois (CHUV; Lausanne, Switzerland). Volunteers were eligible for inclusion if they were aged 18-45 years, clinically healthy, HIV-negative and tuberculosis-negative, and had no history of active tuberculosis, chemoprophylaxis for tuberculosis, or BCG vaccination. Volunteers fulfilling the inclusion criteria were randomly assigned to three cohorts in a dose-escalation manner. Randomisation was done centrally by the CHUV Pharmacy and treatments were masked from the study team and volunteers. As participants were recruited within each cohort, they were randomly assigned 3:1 to receive MTBVAC or BCG. Of the participants allocated MTBVAC, those in the first cohort received 5 * 10(3) colony forming units (CFU) MTBVAC, those in the second cohort received 5 * 10(4) CFU MTBVAC, and those in the third cohort received 5 * 10(5) CFU MTBVAC. In all cohorts, participants assigned to receive BCG were given 5 * 10(5) CFU BCG. Each participant received a single intradermal injection of their assigned vaccine in 0.1 mL sterile water in their non-dominant arm. The primary outcome was safety in all vaccinated participants. Secondary outcomes included whole blood cell-mediated immune response to live MTBVAC and BCG, and interferon gamma release assays (IGRA) of peripheral blood mononuclear cells. This trial is registered with ClinicalTrials.gov, number NCT02013245. FINDINGS: Between Jan 23, 2013, and Nov 6, 2013, we enrolled 36 volunteers into three cohorts, each of which consisted of nine participants who received MTBVAC and three who received BCG. 34 volunteers completed the trial. The safety of vaccination with MTBVAC at all doses was similar to that of BCG, and vaccination did not induce any serious adverse events. All individuals were IGRA negative at the end of follow-up (day 210). After whole blood stimulation with live MTBVAC or BCG, MTBVAC was at least as immunogenic as BCG. At the same dose as BCG (5*10(5) CFU), although no statistical significance could be achieved, there were more responders in the MTBVAC group than in the BCG group, with a greater frequency of polyfunctional CD4+ central memory T cells. INTERPRETATION: To our knowledge, MTBVAC is the first live-attenuated M tuberculosis vaccine to reach clinical assessment, showing similar safety to BCG. MTBVAC seemed to be at least as immunogenic as BCG, but the study was not powered to investigate this outcome. Further plans to use more immunogenicity endpoints in a larger number of volunteers (adults and adolescents) are underway, with the aim to thoroughly characterise and potentially distinguish immunogenicity between MTBVAC and BCG in tuberculosis-endemic countries. Combined with an excellent safety profile, these data support advanced clinical development in high-burden tuberculosis endemic countries. FUNDING: Biofabri and Bill & Melinda Gates Foundation through the TuBerculosis Vaccine Initiative (TBVI). PMID- 26598143 TI - Healthcare use and costs associated with post-traumatic stress syndrome in a community sample of older adults: results from the ESA-Services study. AB - BACKGROUND: Studies have shown higher healthcare utilization and costs associated with post-traumatic stress syndrome (PTSS) in veterans and community adult populations. Given the aging population and the impact on health system resources, it is important to understand the economic consequences of PTSS. METHODS: The data retained came from 1,456 older adults aged 65 years and over recruited in primary medical clinics in the province of Quebec. PTSS was measured with the PTSS scale. Healthcare services (outpatient, emergency department (ED) visits, and inpatient stay) and medication use were captured separately from provincial administrative databases. Healthcare costs incurred in the past year included costs related to outpatient and ED visits, physician fees, inpatient stay, and medication use. Costs were calculated using a healthcare system perspective. chi 2 and Mann-Whitney analyses were used to assess healthcare use. Generalized linear models (GLM) with a gamma distribution (Log Link) were used to evaluate the healthcare costs associated with PTSS. RESULTS: Results showed a significant difference in the number mental health outpatient visits, the number of total prescriptions and the use (presence of at least one prescription) of antidepressants (ADs) and benzodiazepines (BZDs). The multivariate analyses showed that costs associated with outpatient visits, ED visits, mental health inpatient stays, physician fees, and medication use were significantly associated with the presence of PTSS. The total adjusted healthcare cost difference between groups was significant and reached $838 CAN. CONCLUSIONS: Respondents with PTSS were more likely to be prescribed psychotropic medications and to have higher ambulatory costs but not inpatient services related costs, more research is required to better understand whether the mental health needs of individuals with a probable PTSS are being met. PMID- 26598144 TI - Perspectives on Basis Sets Beautiful: Seasonal Plantings of Diffuse Basis Functions. AB - We present a perspective on the use of diffuse basis functions for electronic structure calculations by density functional theory and wave function theory. We especially emphasize minimally augmented basis sets and calendar basis sets. We base our conclusions on our previous experience with commonly computed quantities, such as bond energies, barrier heights, electron affinities, noncovalent (van der Waals and hydrogen bond) interaction energies, and ionization potentials, on Stephens et al.'s results for optical rotation and on our own new calculations (presented here) of polarizabilities and of potential energy curves of van der Waals complexes. We emphasize the benefits of partial augmentation of the higher-zeta basis sets in preference to full augmentation at a lower zeta level. Benefits and limitations of the use of fully, partially, and minimally augmented basis sets are reviewed for different electronic structure methods and molecular properties. We have found that minimal augmentation is almost always enough for density functional theory (DFT) when applied to ionization potentials, electron affinities, atomization energies, barrier heights, and hydrogen-bond energies. For electric dipole polarizabilities, we find that augmentation beyond minimal has an average effect of 8% at the polarized triple-zeta level and 5% at the polarized quadruple-zeta level. The effects are larger for potential energy curves of van der Waals complexes. The effects are also larger for wave function theory (WFT). Even for WFT though, full augmentation is not needed for most purposes, and a level of augmentation between minimal and full is optimal for most problems. The calendar basis sets named after the months provide a convergent sequence of partially augmented basis sets that can be used for such calculations. The jun-cc-pV(T+d)Z basis set is very useful for MP2-F12 calculations of barrier heights and hydrogen bond strengths. PMID- 26598145 TI - Singular Value Decomposition for Analyzing Temperature- and Pressure-Dependent Radial Distribution Functions: Decomposition into Grund RDFs (GRDFs). AB - Singular value decomposition paves the way for systematic investigations of temperature- and pressure-dependent radial distribution functions. The decomposition into (weighted) Grund radial distribution functions (GRDF) shows that the temperature-dependent water structure can easily be understood by only three contributions: a major temperature-independent contribution from the first GRDF, a major temperature-dependent contribution from the second GRDF, and a minor temperature-dependent fine structure contribution from the third GRDF. PMID- 26598146 TI - Locality and Fluctuations: Trends in Imidazolium-Based Ionic Liquids and Beyond. AB - Three different imidazolium-based ionic liquids, 1,3-dimethylimidazolium chloride, 1-ethyl-3-methylimidazolium thiocyanate, and 1-ethyl-3 methylimidazolium dicyanamide, are investigated by Car-Parrinello simulations. A common behavior, such as a broad electric dipole moment distribution of the ions and a related high degree of locality, is found to characterize all these systems. Going beyond imidazolium-based systems, we found that even for the protic ionic liquid monomethyl ammonium nitrate, the same features hold. These results represent a strong support to the hypothesis of rattling ions in long living ion cages proposed in the last years. PMID- 26598147 TI - LISTb: a Better Direct Approach to LIST. AB - Following our recent paper on linear-expansion shooting techniques (LIST) [Wang, Y. A.; Yam, C. Y.; Chen, Y. K.; Chen, G. H. J. Chem. Phys.2011, 134, 241103], in which the direct approach (LISTd) and the indirect approach (LISTi) were proposed to accelerate the self-consistent field convergence, we discovered a highly simple solution to cure the linear-dependence problem of LISTd. The resultant method, LISTb, is a better direct approach to LIST and muscles similar performances to existing LIST methods. More promisingly, LISTb even outshines the best LIST method, LISTi, for systems involving transition-metal atoms. PMID- 26598148 TI - Perferryl Fe(V)-Oxo Nonheme Complexes: Do They Have High-Spin or Low-Spin Ground States? AB - Nonheme perferryl Fe(V)?O species are studied herein by means of coupled cluster (CCSD(T)) calculations with a complete basis set limit estimate and density functional B3LYP computations. It is shown that the high-spin/low-spin (HS/LS) energy order in these Fe(V)?O species is highly dependent on the electronic nature of the ligand sphere and the geometric position of ligands relative to the Fe(V)?O moiety. When only sigma-donor amines ligate Fe(V)?O, the LS state is slightly lower than the HS states. However, when a strong pi-donor ligand such as hydroxyl is cis to Fe(V)?O, the HS state becomes highly favored. And on the contrary, if the pi-donor ligand is trans to Fe(V)?O, the LS state is predicted here to be highly favored. This last type of perferryl complex has not yet been made by experimental means. Generally, our findings are consistent with the available experimental data. (4a, 6, 7) Some implications of these findings on the behavior of experimental systems are discussed. PMID- 26598149 TI - Structural and Vibrational Properties of Liquid Water from van der Waals Density Functionals. AB - We present results for the structural and vibrational properties of the water molecule, water dimer, and liquid water at the experimental equilibrium density, as obtained with several van der Waals density functionals. The functional form originally proposed by Dion et al. [ Phys. Rev. Lett. 2004 , 92 , 246401 ], with an appropriately chosen local exchange functional, yields a description of the liquid superior to that of the semilocal functional PBE. In particular, a specific choice of the local exchange functional (optB88) fitted to quantum chemistry calculations yields the best agreement with experimental results for pair correlation functions although it is slightly inferior to other van der Waals functionals in describing infrared spectra. When using optB88, liquid water displays a hydrogen-bonded network less tightly bound than when using the PBE approximation. The performance of optB88 is definitely inferior to that of the PBE0 hybrid functional for the isolated molecule but only moderately so for the liquid. However, the computational cost of optB88 is much less than that of hybrid functionals; therefore the use of optB88 appears to be a sensible alternative to calculations implying the evaluation of the Fock operator, in cases when simulations of large systems are required. PMID- 26598150 TI - Recursive Taylor Series Expansion Method for Rigid-Body Molecular Dynamics. AB - Molecular dynamics computer simulation methods are very important for understanding mechanisms of chemical, physical, and biological processes. The reliability of molecular dynamics simulations strongly depends on the integration schemes used in the simulations. In this work, we developed new rigid body integration schemes for molecular dynamics simulations. Our approach is based on a numerically exact solution to the free rigid body problem, which is used in the classical propagator splitting scheme. We use the Taylor series expansion of rotational dynamical variables in conjunction with the recursive solution for higher order derivatives of these variables. Such an approach is computationally very efficient, robust, and easy to implement, and it does not employ Jacobi elliptic functions, while still providing the numerically exact solution of the free rigid body problem. Our studies showed that the new integration methods have long-time stability and accuracy properties which are comparable to those of existing symplectic integrators. The extension to the case of a canonical ensemble is also developed, allowing one to perform simulations at constant temperatures. PMID- 26598151 TI - Size-Dependent Phase Changes in Water Clusters. AB - We investigate melting behavior of water clusters (H2O)N (N = 7, 8, 11, and 12) by using multicanonical-ensemble molecular dynamics simulations. Our simulations show that the melting behavior of water clusters is highly size dependent. Based on the computed canonical average of the potential energy and heat capacity CV, we conclude that (H2O)8 and (H2O)12 exhibit first-order-like phase change, while (H2O)7 and (H2O)11 exhibit continuous-like phase change. The melting temperature range for (H2O)8 and (H2O)12 can be defined based on the peak position of CV(T) and dCV(T)/dT (where T is the temperature). Moreover, for (H2O)8 and (H2O)12, the solid- and liquid-like phases separate temporally in the course of simulation. In contrast, no temporal separation of solid- and liquid-like phases is observed for (H2O)7 and (H2O)11. In light of the notable temporal separation of solid- and liquid-like phases for(H2O)8 and (H2O)12, an alternative computer approach for estimating the melting temperature range is proposed based on the time-dependent Lindemann parameters. We find that the melting temperature range estimated from both definitions is consistent with each other for (H2O)8 and (H2O)12 but not for (H2O)7 and (H2O)11. We also find that the melting behavior of small water clusters can be conveniently assessed if the energy differences of neighbor-sized clusters at zero temperature are known. PMID- 26598152 TI - Multireference Double Electron Attached Coupled Cluster Method with Full Inclusion of the Connected Triple Excitations: MR-DA-CCSDT. AB - The multireference (MR) double electron attached (DA) coupled cluster (CC) method with full inclusion of the connected triple excitations has been applied to study various kinds of MR situations. The MR-DA-CCSDT (S, Singles; D, Doubles; T, Triples) equations have been derived and implemented in an efficient way with n(6) scaling for the target multireference states. They can be used for producing potential energy curves (PECs) for some classes of molecules, e.g., when double molecular cations separate into two closed shell fragments, illustrated with the example of the Na2 molecule. Correct PECs have also been obtained on dissociation of the N-N and C-C bonds in N2H4 and C2H6 molecules, respectively. Another application is the behavior of the molecular energy when we change dihedral angle in the ethylene molecule: with the MR-DA-CC, we see immediate improvement of the results with smooth, cusp free, behavior around the 90 degrees region. PMID- 26598153 TI - Linear Scaling Hierarchical Integration Scheme for the Exchange-Correlation Term in Molecular and Periodic Systems. AB - An adaptive numerical integration scheme for efficient evaluation of the exchange correlation term using localized basis functions and atom-centered grids is presented. The method treats molecules and systems with periodic boundary conditions on an equal footing. Its computational efficiency and O(N) scaling with the system size is achieved by a hierarchical spatial grouping of basis functions and grid points using an octree. This allows for an efficient screening of negligible contributions and an optimal use of hardware-optimized matrix matrix multiplication subroutines, such as BLAS. The implementation of the method within the TURBOMOLE program package demonstrates consistent accuracy and efficiency across molecular and periodic systems. PMID- 26598154 TI - Quantum Electrodynamics Effects in Rovibrational Spectra of Molecular Hydrogen. AB - The dissociation energies from all rovibrational levels of H2 and D2 in the ground electronic state are calculated with high accuracy by including relativistic and quantum electrodynamics (QED) effects in the nonadiabatic treatment of the nuclear motion. For D2, the obtained energies have theoretical uncertainties of 0.001 cm(-1). For H2, similar uncertainties are for the lowest levels, while for the higher ones the uncertainty increases to 0.005 cm(-1). Very good agreement with recent high-resolution measurements of the rotational v = 0 levels of H2, including states with large angular momentum J, is achieved. This agreement would not have been possible without accurate evaluation of the relativistic and QED contributions and may be viewed as the first observation of the QED effects, mainly the electron self-energy, in a molecular spectrum. For several electric quadrupole transitions, we still observe certain disagreement with experimental results, which remains to be explained. PMID- 26598155 TI - Correlation Energy Expressions from the Adiabatic-Connection Fluctuation Dissipation Theorem Approach. AB - We explore several random phase approximation (RPA) correlation energy variants within the adiabatic-connection fluctuation-dissipation theorem approach. These variants differ in the way the exchange interactions are treated. One of these variants, named dRPA-II, is original to this work and closely resembles the second-order screened exchange (SOSEX) method. We discuss and clarify the connections among different RPA formulations. We derive the spin-adapted forms of all the variants for closed-shell systems and test them on a few atomic and molecular systems with and without range separation of the electron-electron interaction. PMID- 26598156 TI - Segmented Contracted Douglas-Kroll-Hess Adapted Basis Sets for Lanthanides. AB - Segmented contracted scalar-relativistic (23s16p12d6f)/[18s12p9d3f] all-electron basis sets for lanthanides La-Lu primarily for use in second-order Douglas-Kroll Hess density functional calculations are presented. Atomic test calculations at the scalar-relativistic Hartree-Fock level reveal an accurate description of the first to fourth ionization potentials as well as low-energy d-f and d-p excitation energies; i.e., reference data obtained with optimized (34s28p22d16f) even-tempered basis sets are reproduced with mean absolute errors of 0.003 (IP1), 0.013 (IP2), 0.030 (IP3), 0.098 (IP4), 0.070 (d-f), and 0.018 (d-p) eV. Results of molecular test calculations are presented for the lanthanide trihalides LnX3 (Ln = La-Lu, X = F, Cl, Br, I) at the PBE0 hybrid density functional theory level. Compared to recently published basis sets of identical size, the sets proposed here show substantially smaller errors in the atomic test calculations as well as lower total energies and produce results of similar accuracy in the molecular calibration study. PMID- 26598157 TI - Molecular Monte Carlo Simulations Using Graphics Processing Units: To Waste Recycle or Not? AB - In the waste recycling Monte Carlo (WRMC) algorithm, (1) multiple trial states may be simultaneously generated and utilized during Monte Carlo moves to improve the statistical accuracy of the simulations, suggesting that such an algorithm may be well posed for implementation in parallel on graphics processing units (GPUs). In this paper, we implement two waste recycling Monte Carlo algorithms in CUDA (Compute Unified Device Architecture) using uniformly distributed random trial states and trial states based on displacement random-walk steps, and we test the methods on a methane-zeolite MFI framework system to evaluate their utility. We discuss the specific implementation details of the waste recycling GPU algorithm and compare the methods to other parallel algorithms optimized for the framework system. We analyze the relationship between the statistical accuracy of our simulations and the CUDA block size to determine the efficient allocation of the GPU hardware resources. We make comparisons between the GPU and the serial CPU Monte Carlo implementations to assess speedup over conventional microprocessors. Finally, we apply our optimized GPU algorithms to the important problem of determining free energy landscapes, in this case for molecular motion through the zeolite LTA. PMID- 26598158 TI - Excited States and Absorption Spectra of UF6: A RASPT2 Theoretical Study with Spin-Orbit Coupling. AB - Uranium hexafluoride (UF6) is an important compound in nuclear chemistry. The theoretical investigation of its excited states is difficult due to the large number of uranium valence orbitals and ligand lone pairs. We report here a detailed relativistic quantum chemical investigation of its excited states up to about 10 eV using restricted active space second-order perturbation theory (RASPT2). Scalar and spin-orbit (SO) relativistic effects are treated by a relativistic small-core pseudopotential. The RASPT2/SO results remain moderately accurate when the electrons in the active space are restricted to single and double excitations. All eight major spectral peaks corresponding to ligand-to metal charge transfer have been reproduced within an accuracy of about 0.2 eV and are tentatively assigned. We find that BLYP-based hybrid density functional with 35% Hartree-Fock exchange well reproduce the excitation energies of UF6. PMID- 26598159 TI - Magnetic Properties of Ni(2+)(aq) from First Principles. AB - The aqueous solution of the Ni(2+) ion was investigated using a first principles molecular dynamics (FPMD) simulation based on periodic density-functional theory (DFT) calculations. Statistical averages of the magnetic properties corresponding to the triplet spin state of the ion, the hyperfine coupling, g and zero-field splitting tensors, as well as the resulting paramagnetic nuclear magnetic resonance (pNMR) shielding terms were calculated using DFT from instantaneous simulation snapshots extracted from the FPMD trajectory. We report comprehensive tests of the reliability of systematically selected DFT functionals for the properties. The isotropic nuclear shielding of the (17)O nuclei can be obtained with good predictive power. The accuracy of the calculated (1)H shieldings is limited by the fact that the spin-density on the proton sites is not reproduced reliably with the tested functionals, rendering the dominant Fermi contact isotropic shielding term less well-defined. On the other hand, the dominant spin dipole term of the shielding anisotropy, which gives a practically vanishing isotropic contribution, can be obtained with good reliability for both the (1)H and (17)O nuclei. The anisotropic shielding tensor can be thus utilized reliably in the calculation of Curie-type paramagnetic relaxation. We discuss the evolution of the pNMR properties through the first and second solvation shells of the ion, toward the bulk solvent. The magnetic properties of the dominant, six coordinated solution are compared to those of the metastable, 5-fold coordinated intermediate occurring in the dissociative exchange process. PMID- 26598160 TI - Density Functional Restricted-Unrestricted/Molecular Mechanics Theory for Hyperfine Coupling Constants of Molecules in Solution. AB - A density functional restricted-unrestricted approach, capable of evaluating hyperfine coupling constants with the inclusion of spin polarization effects in a spin-restricted Kohn-Sham method, has been extended to incorporate environmental effects. This is accomplished by means of a hybrid quantum mechanics/molecular mechanics formalism which allows for a granular representation of the polarization and electrostatic interactions with the classically described medium. By this technique, it is possible to trace the physical origin of hyperfine coupling constants in terms of spin polarization and spin density contributions and disentangle the dependence of these contributions on molecular geometry and solvent environment, something that increases the prospects for optimal design of spin labels for particular applications. A demonstration is given for the nitrogen isotropic hyperfine coupling constant in di-tert-butyl nitroxide solvated in water. The results indicate that the direct spin density contribution is about 5 times smaller than the spin polarization contribution to the nitrogen isotropic hyperfine coupling constant and that the latter contribution is solely responsible for the solvent shift of the constant. The developed approach is found capable of achieving satisfactory accuracy in prediction of the hyperfine coupling constants of solvated di-tert-butyl nitroxide and other similar nitroxides without the inclusion of solvent molecules in the quantum region provided polarizable force fields are used for the description of these molecules. PMID- 26598161 TI - Double-Hybrid Density Functionals Provide a Balanced Description of Excited (1)La and (1)Lb States in Polycyclic Aromatic Hydrocarbons. AB - The time-dependent density functional theory (TD-DFT) double-hybrid methods TD-B2 PLYP and TD-B2GP-PLYP are applied to five linear and 12 nonlinear polycyclic aromatic hydrocarbons. The absolute errors compared to experiment for the two lowest-lying (1)La and (1)Lb excited states are evaluated and it is also tested whether the energetic order of those states and their energy difference is reproduced correctly. The results are compared to published CC2, global hybrid, and long-range corrected hybrid TD-DFT results. The two double-hybrids outmatch the other methods in terms of absolute and relative accuracy without an empirical adjustment of parameters. Although of different electronic character, both types of states are described on an equal footing by the double-hybrids. Particularly, the B2GP-PLYP functional yields very good results, which is in accordance with previous benchmarks. PMID- 26598162 TI - Scalar Relativistic Computations of Nuclear Magnetic Shielding and g-Shifts with the Zeroth-Order Regular Approximation and Range-Separated Hybrid Density Functionals. AB - Density functional theory (DFT) calculations of NMR chemical shifts and molecular g tensors with Gaussian-type orbitals are implemented via second-order energy derivatives within the scalar relativistic zeroth order regular approximation (ZORA) framework. Nonhybrid functionals, standard (global) hybrids, and range separated (Coulomb-attenuated, long-range corrected) hybrid functionals are tested. Origin invariance of the results is ensured by use of gauge-including atomic orbital (GIAO) basis functions. The new implementation in the NWChem quantum chemistry package is verified by calculations of nuclear shielding constants for the heavy atoms in HX (X = F, Cl, Br, I, At) and H2X (X = O, S, Se, Te, Po) and (125)Te chemical shifts in a number of tellurium compounds. The basis set and functional dependence of g-shifts is investigated for 14 radicals with light and heavy atoms. The problem of accurately predicting (19)F NMR shielding in UF6-nCln, n = 1-6, is revisited. The results are sensitive to approximations in the density functionals, indicating a delicate balance of DFT self-interaction vs correlation. For the uranium halides, the range-separated functionals are not clearly superior to global hybrids. PMID- 26598163 TI - Theoretical Study of the Luminescent States and Electronic Spectra of UO2Cl2 in an Argon Matrix. AB - The electronic absorption and emission spectra of free UO2Cl2 and its Ar coordinated complexes below 27 000 cm(-1) are investigated at the levels of ab initio complete active space second-order perturbation theory (CASPT2) and coupled-cluster singles and doubles and perturbative triples [CCSD(T)] using valence 3zeta-polarized basis sets. The influence of the argon matrix in the 12K experiment on the electronic spectra is explored by investigating the excited states of argon complexes ArnUO2Cl2. The calculated two most stable complexes with n = 2, 3 can explain the observed two matrix sites corresponding to the experimental two-component luminescence decay. In these uranyl complexes, Ar coordination is found to have little influence on the (3)Phi (Omega = 2g) character of the luminescent state and on the electronic spectral shape. The calculations yield a coherent assignment of the experimental excitation spectra that improves on previous assignments. The simulated luminescence spectral curves based on the calculated spectral parameters of UO2Cl2 from both CASPT2 and CCSD(T) agree well with experiment. PMID- 26598164 TI - Time-Dependent Density Functional Tight Binding: New Formulation and Benchmark of Excited States. AB - A new formulation of time-dependent density functional tight binding (TD-DFTB) is reported in this paper. It is derived from the application of the linear response theory to the ground state DFTB Hamiltonian, without the introduction of additional parameters for the description of the excited states. The method is validated for several sets of organic compounds, against the best theoretical estimates from the literature, density functional theory, semiempirical methods, and experimental data. The comparison shows that TD-DFTB gives reliable results both for singlet and triplet excitation energies. In addition, the application of TD-DFTB to open-shell systems shows promising results. PMID- 26598165 TI - On the Origin of the Chiro-Optical Activity in Supramolecular Assemblies: A Quantum Chemical Study of C3 Octopolar Systems. AB - First-principles quantum chemical approach has been used to understand the origin of the chiro-optical signal induced by the chiral aggregation of an achiral chromophore. The study was focused in predicting the circular dichroism (CD) spectra of different pi-stacked columnar oligomers built with C3 star-shape molecular bricks. We studied the influence of the relevant structural self assembly parameters on the CD spectra (i.e., the number of units, the rotation angle and the intermonomer distance). A detailed analysis was based on the MO topologies and the magnetic and electric transition dipole moments, the vectors which determine the CD intensities, has been conducted. We have rationalized the influence of the various structural factors of supramolecular self-assemblies in connection with the nature of their CD spectroscopic signal, which provides new avenues for structure-spectroscopic relationships. PMID- 26598166 TI - Basis Set Dependence of Vibrational Raman and Raman Optical Activity Intensities. AB - We present a systematic study of the basis set dependence of the backscattering vibrational Raman intensities and Raman Optical Activity (ROA) intensity differences. The accuracies of computed Raman intensities and ROA intensity differences for a series of commonly used basis sets are reported, relative to large reference basis sets, using the B3LYP density functional. This study attempts to separately quantify the relative accuracies obtained from particular basis set combinations: one for the geometry optimization and force field computation and the other for the computation of Raman and ROA tensors. We demonstrate here that the basis set requirements for the geometry and force fields are not similar to those of the Raman and ROA tensors. The Raman and ROA tensors require basis sets with diffuse functions, while geometry optimizations and force field computations typically do not. Eleven molecules were examined: (S)-methyloxirane, (S)-methylthirane, (R)-epichlorhydrin, (S)-CHFClBr, (1S,5S) alpha-pinene, (1S,5S)-beta-pinene, (1S,4S)-norborneneone, (M)-sigma-[4]-helicene, an enone precursor to a cytotoxic sesquiterpene, the gauche-gauche conformer of the monosaccharide methyl-beta-d-glucopyranose, and the dipeptide Ac-(alanine)2 NH2. For the molecules examined here, intensities and intensity differences obtained from Raman and ROA tensors computed using the aug-cc-pVDZ basis set are nearly equivalent to those computed with the larger aug-cc-pVTZ basis set. We find that modifying the aug-cc-pVDZ basis set by removing the set of diffuse d functions on all atoms (while keeping the diffuse s and p sets), denoted as aug(sp)-cc-pVDZ, results in a basis set which is significantly faster without much reduction in the overall accuracy. In addition, the popular rDPS basis set introduced by Zuber and Hug offers a good compromise between accuracy and efficiency. The combination of either the aug(sp)-pVDZ or rDPS basis for the computation of the Raman and ROA tensors with the 6-31G* basis set for the geometry optimization and force field calculation is a reliable and cost effective method for obtaining Raman intensities and ROA intensity differences. PMID- 26598167 TI - Comparison of Tetrahedral Order, Liquid State Anomalies, and Hydration Behavior of mTIP3P and TIP4P Water Models. AB - The relationship between local tetrahedral order, tagged particle potential energy, and coordination number is studied for mTIP3P and TIP4P models of water in the bulk as well as in the neighborhood of a small peptide. The tendency of water molecules with different binding or tagged particle potential energies to occupy environments with different degrees of disorder can be effectively illustrated by constructing tetrahedral order distributions and corresponding entropy metrics conditional on restricted ranges of local binding energy. At the state point corresponding to the onset of the density anomaly, the correlation between tetrahedral entropy versus tagged potential energy is strong and virtually identical for mTIP3P and TIP4P. In TIP4P, this correlation is retained up to temperatures as high as 300 K, while it is lost by 250 K in mTIP3P. In the 250-300 K regime that is important for biomolecular simulations, mTIP3P behaves essentially as a simple liquid while TIP4P shows the density and related anomalies characteristic of water. We also study the number of water molecules, the tetrahedral order, and the tagged molecule potential energies for water molecules as a function of the distance from the peptide for the 16-residue beta hairpin fragment of 2GB1 in mTIP3P and TIP4P solvents. The hydration shell coordination profiles (n(r)) of the number of water molecules are almost identical in the two solvents, but the radial variation in the local energies and local order show significant differences. The residue-wise variation in the tagged potential energy of water molecules within the first hydration shell is qualitatively similar in the two models. A comparison of the tetrahedral order distributions of water molecules lying at different distances from the biomolecular solute shows that the perturbation in the local tetrahedral order distributions of the bulk solvent due to the presence of the solute is marginal. Thus, in the 250-300 K regime, the mTIP3P and TIP4P water models show qualitatively different behavior in terms of the relationship between tetrahedral order and local energy, but as solvents in the neighborhood of a biomolecular solute, the differences between the two models are only quantitative and not qualitative. PMID- 26598168 TI - GROMOS++ Software for the Analysis of Biomolecular Simulation Trajectories. AB - GROMOS++ is a set of C++ programs for pre- and postprocessing of molecular dynamics simulation trajectories and as such is part of the GROningen MOlecular Simulation software for (bio)molecular simulation. It contains more than 70 programs that can be used to prepare data for the production of molecular simulation trajectories and to analyze these. These programs are reviewed and the various structural, dynamic, and thermodynamic quantities that can be analyzed using time series, correlation functions, and distributions are described together with technical aspects of their implementation in GROMOS. A few examples of the use of GROMOS++ for the analysis of MD trajectories are given. A full list of all GROMOS++ programs, together with an indication of their capabilities, is given in the Appendix . PMID- 26598169 TI - On the Role of Water Models in Quantifying the Binding Free Energy of Highly Conserved Water Molecules in Proteins: The Case of Concanavalin A. AB - The ability of ligands to displace conserved water molecules in protein binding sites is of significant interest in drug design and is particularly pertinent in the case of glycomimetic drugs. This concept was explored in previous work [ Clarke et al. J. Am. Chem. Soc. 2001 , 123 , 12238 - 12247 and Kadirvelraj et al. J. Am. Chem. Soc. 2008 , 130 , 16933 - 16942 ] for a highly conserved water molecule located in the binding site of the prototypic carbohydrate-binding protein Concanavalin A (Con A). A synthetic ligand was designed with the aim of displacing such water. While the synthetic ligand bound to Con A in an analogous manner to that of the natural ligand, crystallographic analysis demonstrated that it did not displace the conserved water. In order to quantify the affinity of this particular water for the Con A surface, we report here the calculated standard binding free energy for this water in both ligand-bound and free Con A, employing three popular water models: TIP3P, TIP4P, and TIP5P. Although each model was developed to perform well in simulations of bulk-phase water, the computed binding energies for the isolated water molecule displayed a high sensitivity to the model. Both molecular dynamics simulation and free energy results indicate that the choice of water model may greatly influence the characterization of surface water molecules as conserved (TIP5P) or not (TIP3P) in protein binding sites, an observation of considerable significance to rational drug design. Structural and theoretical aspects at the basis of the different behaviors are identified and discussed. PMID- 26598170 TI - Do Two Different Reaction Mechanisms Contribute to the Hydroxylation of Primary Amines by Cytochrome P450? AB - Three possible mechanisms have been suggested for the hydroxylation of primary and secondary amines by the cytochrome P450 enzyme family. We show that for the hydroxylation of primary alkyl amines, both the hydrogen abstraction and rebound mechanism and the direct oxygen transfer mechanism can contribute to the formation of the hydroxylated product. We also show that in the hydrogen abstraction and rebound mechanism the rebound step has higher activation energy than the hydrogen abstraction step, which is the opposite of the hydroxylation of aliphatic carbon atoms. PMID- 26598171 TI - Hybrid Quantum and Classical Simulations of the Dihydrofolate Reductase Catalyzed Hydride Transfer Reaction on an Accurate Semi-Empirical Potential Energy Surface. AB - Dihydrofolate reductase (DHFR) catalyzes the reduction of 7,8-dihydrofolate by nicotinamide adenine dinucleotide phosphate hydride (NADPH) to form 5,6,7,8 tetrahydrofolate and oxidized nicotinamide. DHFR is a small, flexible, monomeric protein with no metals or SS bonds and serves as one of the enzymes commonly used to examine basic aspects in enzymology. In the current work, we present extensive benchmark calculations for several model reactions in the gas phase that are relevant to the DHFR catalyzed hydride transfer. To this end, we employ G4MP2 and CBS-QB3 ab initio calculations as well as numerous density functional theory methods. Using these results, we develop two specific reaction parameter (SRP) Hamiltonians based on the semiempirical AM1 method. The first generation SRP Hamiltonian does not account for dispersion, while the second generation SRP accounts for dispersion implicitly via the AM1 core-repulsion functions. These SRP semiempirical Hamiltonians are subsequently used in hybrid quantum mechanics/molecular mechanics simulations of the DHFR catalyzed reaction. Finally, kinetic isotope effects are computed using a mass-perturbation-based path-integral approach. PMID- 26598172 TI - Gating and Intermolecular Interactions in Ligand-Protein Association: Coarse Grained Modeling of HIV-1 Protease. AB - Most biological processes are initiated or mediated by the association of ligands and proteins. This work studies multistep, ligand-protein association processes by Brownian dynamics simulations with coarse-grained models for HIV-1 protease (HIVp) and its neutral ligands. We report the average association times when the ligand concentration is 100 MUM. The influence of crowding on the simulated binding time was also studied. HIVp has flexible loops that serve as a gate during the ligand binding processes. It is believed that the flaps are partially closed most of the time in its free state. To accelerate our simulations, we fixed a part of the HIVp and reparameterized our coarse-grained model, using atomistic molecular dynamics simulations, to reproduce the "gating" motions of HIVp. HIVp-ligand interactions changed the gating behavior of HIVp and helped ligands diffuse on HIVp surface to accelerate binding. The structural adjustment of the ligand toward its final stable state was the limiting step in the binding processes, which is highly system dependent. The intermolecular attraction between the ligands and crowder proteins contributes the most to the crowding effects. The results highlight broader implications in recognition pathways under more complex environment that considers molecular dynamics and conformational changes. This work brings insights into ligand-protein associations and is helpful in the design of targeted ligands. PMID- 26598173 TI - Structures, Energetics, and IR Spectra of Monohydrated Inorganic Acids: Ab initio and DFT Study. AB - We carried out extensive calculations of diverse inorganic acids interacting with a single water molecule, through a detailed analysis of many possible conformations. The optimized structures were obtained by using density functional theory (DFT) and the second order Moller-Plesset perturbation theory (MP2). For the most stable conformers, we calculated the interaction energies at the complete basis set (CBS) limit using coupled cluster theory with single, double, and perturbative triple excitations [CCSD(T)]. The -OH stretching harmonic and anharmonic frequencies are provided as fingerprints of characteristic conformers. The zero-point energy (ZPE) uncorrected/corrected (DeltaEe/DeltaE0) interaction energies and the enthalpies/free energies (DeltaHr/DeltaGr at room temperature and 1 bar) are reported. Various comparisons are made between many diverse inorganic acids (HmXOn where X = B/N/P/Cl/Br/I, m = 1-3, and n = 0-4) as well as other simple inorganic acids. In many cases, we find that the dispersion-driven van der Waals interactions between X in inorganic acid molecules and O in water molecules as well as the X(+)...O(-) electrostatic interactions are important. PMID- 26598174 TI - Renal and Gastrointestinal Considerations in Patients Undergoing Elective Orthopaedic Surgery. AB - To minimize perioperative complications after orthopaedic procedures, patients may undergo medical optimization, which includes an assessment of their renal function and gastrointestinal (GI) system. The GI and renal systems are complex, and their proper optimization in the preoperative period can influence the success of any procedure. Several factors can prevent complications and reduce morbidity, mortality, and the cost of care, including a thorough evaluation and screening, with particular emphasis on anemia and its renal and GI causes; management of medications that are metabolized by the liver and excreted by the kidneys; and careful attention to the patient's nutritional status. PMID- 26598175 TI - Experimental Study of the Triplet Synchronization of Coupled Nonidentical Mechanical Metronomes. AB - Triplet synchrony is an interesting state when the phases and the frequencies of three coupled oscillators fulfill the conditions of a triplet locking, whereas every pair of systems remains asynchronous. Experimental observation of triplet synchrony is firstly realized in three coupled nonidentical mechanical metronomes. A more direct method based on the phase diagram is proposed to observe and determine triplet synchronization. Our results show that the stable triplet synchrony is observed in several intervals of the parameter space. Moreover, the experimental results are verified according to the theoretical model of the coupled metronomes. The outcomes are useful to understand the inner regimes of collective dynamics in coupled oscillators. PMID- 26598176 TI - Postanesthesia Care for the Elderly Patient. AB - PURPOSE: As the general population lives longer, the perioperative physician is more likely to encounter disease states that increase in incidence in an aging population. This review focuses on anesthetic considerations for rational drug choices during the perioperative care of elderly patients. The primary aim of the review was to identify intraoperative and postanesthetic considerations for diseases associated with advancing age; it includes highlights of the commonly impaired major organs (eg, cardiovascular, pulmonary, neurologic, renal, hepatic systems). We also outline an approach to frequent issues that arise in the immediate postsurgical period while caring for these patients. METHODS: A systematic review was performed on aspects of the perioperative and postoperative periods that relate to the elderly. A list of pertinent key words was derived from the authors, and a PubMed database search was performed. FINDINGS: The anesthesiologist must account for changes in various organ systems that affect perioperative care, including the cardiovascular, pulmonary, renal, hepatic, and central nervous systems. The pharmacokinetic principles frequently differ and are often unpredictable because of anatomic changes and decreased renal and hepatic function. The most important pharmacodynamic consideration is that elderly patients tend to exhibit an exaggerated hypoactivity after anesthesia. IMPLICATIONS: Before surgery, it is essential to identify those patients at risk for delirium and other commonly encountered postanesthesia scenarios. Failure to manage these conditions appropriately can lead to an escalation of care and prolonged hospitalization. PMID- 26598177 TI - Perioperative Cognitive Protection-Cognitive Exercise and Cognitive Reserve (The Neurobics Trial): A Single-blind Randomized Trial. AB - PURPOSE: The Neurobics Trial is a single-blind, parallel-group, randomized, controlled trial. The main study objective is to compare effectiveness of preoperative cognitive exercise versus no intervention for lowering the incidence of postoperative delirium. Enrollment began March 2015 and is ongoing. METHODS: Eligible participants include patients older than 60 years of age scheduled for nonemergent, noncardiac, nonneurological surgery at our institution. Patients provide consent and are screened at our Outpatient Preoperative Assessment Clinic to rule out preexisting cognitive dysfunction, significant mental health disorders, and history of surgery requiring general anesthesia in the preceding 6 months. Participants meeting criteria are randomized to complete 1 hour daily of electronic tablet-based cognitive exercise for 10 days before surgery or no preoperative intervention. Compliance with the effective dose of 10 total hours of preoperative exercise is verified on return of the patient for surgery with time logs created by the software application and by patient self-reporting. After surgery, patients are evaluated for delirium in the postanesthesia recovery area, and then twice daily for the remainder of their hospitalization. Additionally, postoperative quality of recovery is assessed daily, along with pain scores and opiate use. More comprehensive cognitive assessments are completed just before discharge for baseline comparison, and quality of recovery is assessed via telephone interview 7, 30, and 90 days post-surgery. The primary outcome is the incidence of delirium during the postoperative hospitalization period. Randomization is computer generated, with allocation concealment in opaque envelopes. All postoperative assessments are completed by blinded study personnel. FINDINGS: The study is actively recruiting with 19 patients having provided consent to date, and a total of 264 patients is required for study completion; therefore, no data analysis is currently under way (www.clinicaltrials.gov; NCT02230605). IMPLICATIONS: To our knowledge, the Neurobics Trial is the first randomized, controlled study to investigate the effectiveness of a significant preoperative cognitive exercise regimen for the prevention of delirium after noncardiac, nonneurological surgery in elderly patients. PMID- 26598178 TI - The future of left atrial appendage occlusions: When extraordinary claims require evidence.... PMID- 26598180 TI - [SGTB orthopedic regime to correct protrusive skeletal anomalies: a developmental path through evolution, renovation and innovation]. AB - Sagittal-guidance Twin-block appliance (SGTB), an orthopedic therapy that has been widely implemented in orthodontic practice since it was introduced by the author a decade ago. This overview was aimed to clarify the fundamental mechanism of SGTB in correction of skeletal malocclusions, i.e., retraction of the maxilla triggered by the muscular force generated from mandibular forward positioning. This overview was also designed to summarize the evolutionary pathway through which SGTB regime originated and developed from removable, bonded and to the latest form of clear aligner SGTB. It was concluded that SGTB promised to be an efficient orthopedic approach to manage complicated and severe dentofacial anomalies with skeletal element. PMID- 26598181 TI - [The effect of estrogen on adipogenic differentiation of rat bone mesenchymal stem cells]. AB - PURPOSE: In this study, 10-9 mol/L 17 beta-estradiol (E2) was applied in the adipogenic differentiation of rat bone mesenchymal stem cells (rBMSCs) and the effect of E2 was explored. METHODS: Rat BMSCs were obtained from the femurs and tibias of SD rats. 10-9 mol/L E2 was involved in the adipogenic differentiation of rBMSCs. Oil red staining, real time PCR and Western blot were carried out to detect the effect of 10-9 mol/L E2 on adipogenic differentiation of rBMSCs. The data was statistically analyzed using SPSS 19.0 software package. RESULTS: The use of 10-9 mol/L E2 decreased the amount of lipid droplets in rBMSCs and weakened the expression of adipogenic related genes and proteins like C/EBP alpha, C/EBP beta, PPAR gamma, aP2, and ARDP, which were significantly lower than the adipogenic induced group. CONCLUSIONS: The use of 10-9 mol/L E2 inhibited adipogenic differentiation of rBMSCs significantly in vitro. PMID- 26598179 TI - Structural Studies of Geosmin Synthase, a Bifunctional Sesquiterpene Synthase with alphaalpha Domain Architecture That Catalyzes a Unique Cyclization Fragmentation Reaction Sequence. AB - Geosmin synthase from Streptomyces coelicolor (ScGS) catalyzes an unusual, metal dependent terpenoid cyclization and fragmentation reaction sequence. Two distinct active sites are required for catalysis: the N-terminal domain catalyzes the ionization and cyclization of farnesyl diphosphate to form germacradienol and inorganic pyrophosphate (PPi), and the C-terminal domain catalyzes the protonation, cyclization, and fragmentation of germacradienol to form geosmin and acetone through a retro-Prins reaction. A unique alphaalpha domain architecture is predicted for ScGS based on amino acid sequence: each domain contains the metal-binding motifs typical of a class I terpenoid cyclase, and each domain requires Mg(2+) for catalysis. Here, we report the X-ray crystal structure of the unliganded N-terminal domain of ScGS and the structure of its complex with three Mg(2+) ions and alendronate. These structures highlight conformational changes required for active site closure and catalysis. Although neither full-length ScGS nor constructs of the C-terminal domain could be crystallized, homology models of the C-terminal domain were constructed on the basis of ~36% sequence identity with the N-terminal domain. Small-angle X-ray scattering experiments yield low resolution molecular envelopes into which the N-terminal domain crystal structure and the C-terminal domain homology model were fit, suggesting possible alphaalpha domain architectures as frameworks for bifunctional catalysis. PMID- 26598182 TI - [Preparation of lyophilized lentiviral vector of bone morphogenetic protein 2]. AB - PURPOSE: To construct recombinant lentiviral vectors of bone morphogenetic protein 2(BMP-2) gene and prepare a stable lyophilized state. METHODS: The BMP-2 gene lentiviral vector was constructed by recombinant DNA technology and mixed with different stabilizers in an appropriate proportion and then lyophilized. The optimum stabilizer was selected according to the appearance and virus titer after being lyophilized. The quality of lyophilized product was measured by thermal stability of the virus, PCR and gene sequencing. SPSS13.0 software package was used for statistical analysis. RESULTS: Recombinant BMP-2 lentiviral vector was successfully constructed. 10% trehalose, 1% bovine serum albumin, 3%mannitol and 0.5% gelatin in group B showed good protection on BMP-2 gene lentiviral vector. The virus titer decreased 0.42 LgPFU/mL after being lyophilized, which was better than group A, C and the control group and the difference was statistically significant (P<0.05); Lyophilized protective agent made from group B still maintained a good appearance at 37 degrees centigrade after 28 days and the virus titer decreased 0.63 LgPFU/mL. The virus titer in liquid lentiviral infection control group decreased rapidly to 2.37 LgPFU/mL 1 week later and the difference between the two groups was statistically significant (P<0.05); PCR and gene sequencing showed that the target gene information after redissolve had no loss or mutation. CONCLUSIONS: Appropriate selection of lyoprotectants can effectively protect the biological stability of recombinant BMP-2 gene lentiviral vector. PMID- 26598183 TI - [Study of antimicrobial activity of carboxymethyl chitosan zinc complex material against cariogenic bacteria]. AB - PUPPOSE: To evaluate the antimicrobial activity of carboxymethyl chitosan zinc (CMCSZ) and carboxymethyl chitosan zinc-active peptide complex material (CMCSZP) on oral cariogenic bacteria. METHODS: Agar dilution method and K-B disk diffusion susceptibility agents were used to measure the antimicrobial activity of two agents against S.mutans, Lactobacillus, S.sanguinis and Actinomyces viscosus. The former method was used to measure the minimal inhibitory concentration (MIC) and latter was used to measure the inhibitory zone. The effects of pH value, temperature, light, ultraviolet and storage temperature on the active substances were investigated to determine the stability of CMCSZ and CMCSZP. SPSS17.0 software package was used for statistical analysis. RESULTS: All the bacteria were susceptible to active peptide, CMCSZ and CMCSZP with the MIC of CMCSZ/CMCSZP being 625, 1250, 1250 and 2500 mg/L, respectively. At the same concentration, the inhibitory zone of CMCSZP was significantly bigger than that of CMCSZ. Acidic conditions were conducive to increase the antimicrobial activity of CMCSZ, while the effect on CMCSZP was not significant. CMCSZ and CMCSZP exhibited good stability against light, but their antimicrobial activity gradually weakened as the bath temperature rising. In the temperature of 85 degrees centigrade, their antibacterial activity disappeared. CONCLUSIONS: CMCSZ have CMCSZP had strong antimicrobial activity against 4 kinds of cariogenic bacteria. They have good stability against light, but poor thermal stability. This study provides theoretical foundation for the application of CMCSZ/CMCSZP in prevention of cariogenic diseases. PMID- 26598184 TI - [Occluding effects of desensitizer containing NovaMin combined with fluor protector on dentinal tubules:an in vitro study]. AB - PUPPOSE: To observe the occlusion effect, acid resistance and abrasion resistance of desensitizer containing NovaMin combined with fluor protector on dentin tubules, in order to provide theoretical basis for clinical treatment of dentin hypersensitivity. METHODS: Thirty extracted intact and non-carious human premolars for orthodontic treatment were selected and made into 2 mm thick dentin slices. Each slice was cut into 4 parts to form 120 sensitive dentin models and randomly divided into 4 groups (n=30). Distilled water (group A), fluor protector (group B), Ominq desensitizer (group C) and fluor protector combined with Ominq desensitizer (group D)were applied respectively on the exposed dentin surfaces. After immersed in the artificial saliva for 24 h, each group was divided into 3 subgroups randomly to undergo direct observation, acid corrosion and tooth brushing test, then the plugging rate of dentin tubules was statistically analyzed with SPSS 13.0 software package. RESULTS: Dentin tubules in group A were completely open, while good occluding effects were found in group B, C and D. Among them, group D displayed the best occlusion effect, and ability of acid and abrasion resistance compared with other 3 groups (P0.05). The ARI did not show any significant difference before and after CPP-ACP treatment. CONCLUSIONS: After tooth bleaching, CPP-ACP treatment have little influence on the shear bond strength of orthodontic brackets. PMID- 26598186 TI - [Influence of different restorations on the fracture resistance of endodontically treated premolars with minor loss of dental defect]. AB - PURPOSE: To evaluate the influence of 3 different restorations on the fracture resistance of endodontically treated premolars with minor loss of dental defect in order to direct clinical design. METHODS: Seventy-two recently extracted intact and single-rooted human mandibular premolars for orthodontic reason were collected and randomly divided into 3 groups (group A, B, C, n=24). Each group was respectively prepared into 1/3 defect of occlusal surface (group A), 1/2 defect of occlusal surface (group B) and 1/3 defect of proximal-occlusal surface model (group C). Then each group was divided into 3 subgroups with one restored with a light-curing composite resin(group A1, B1, C1), one restored with cast metal full crowns following a light-curing composite resin (group A2, B2, C2), and one restored with fiber posts and resin cores and cast full crowns after teeth preparations (group A3, B3, C3, n=8). Static loading tests were performed on each specimen until cracked.Fracture strength was tested and fracture patterns were examined. The data was analyzed using SPSS17.0 software package. RESULTS: The fracture resistance of subgroup A2 was different when compared with subgroup A1 and subgroup A3. In group B and C, the fracture resistance of teeth in subgroup B2, B3, C2 and C3 were significantly higher than that in subgroup B1 and C1. There was no significant difference in the fracture mode of 3 restorations in group A, B and C. CONCLUSIONS: A composite resin combined with cast metal full crowns can be used as the first choice to restore endodontically treated premolars with proximal-occlusal 1/3 defects and occlusal defects that do not surpass 1/2 dimension of occlusion. PMID- 26598187 TI - [Effects of micro-arc oxidation on the biological behaviors of MC3T3-E1 cells on titanium]. AB - PURPOSE: This study was intended to modify the surface of pure titanium by micro arc oxidation (MAO), and to investigate the effects of MAO process on the biological behavior of MC3T3-E1 osteoblastic cells. METHODS: MAO treatment of specimens were carried out using a staggered voltage boost procedure. The surface topography of the prepared specimens were observed by field emission scanning electron microscopy. Contact angle measurements were tested on a contact angle measuring system. MC3T3-E1 cells were cultured on specimens and the number of adhesion cells at 60 and 120 min were investigated by MTT. After 4 h of culture, cytoskeleton of the attached cells were examined using laser confocal scanning microscope. After 24, 72, 120 and 168 h of post seeding, cell proliferation were assessed using MTT assay. On day 16 of culture, the expressions of osteogenesis related genes were analyzed through real time fluorescence quantitative polymerase chain reaction (qPCR). The data was analyzed using SPSS 16.0 software package. RESULTS: A porous oxide layer was grown on pure titanium substrates via MAO process. The contact angles for water and glycerol on the MAO surface were smaller than polished surface. At 2 culture times, the MAO surface showed significantly higher cell adhesion than polished surface. Actin staining indicated that the cells spread well on the MAO surface. At 72, 120 and 168 h, better cell proliferation were seen for MAO surfaces compared with that on the polished surface, but there was no significant difference. The qPCR showed that no obvious variations in gene expression of RUNX2 and ALP by MC3T3-E1 cells were observed on 2 different surfaces. CONCLUSIONS: Compared with polished surface, better adhesion of MC3T3-E1 cells are observed on MAO surface. However, no obvious change in gene expression of RUNX2 and ALP were observed between the MAO surface and polished surface. PMID- 26598188 TI - [Effect of cyclosporine A on TGF-beta/Smad3 signaling in rat gingival fibroblasts]. AB - PURPOSE: The aim of the study was to investigate the effect of cyclosporine A (CsA) on TGF-beta/Smad3 signaling in rat gingival fibroblasts and to explore the mechanism of CsA induced gingival overgrowth. METHODS: Healthy Sprague-Dawley rat gingival fibroblasts were cultured with different concentrations of CsA and the cell proliferations were assessed with CCK-8 assay. The mRNA levels of TGF-beta1, Smad3 and collagen I were measured by real-time PCR. The protein level of TGF beta1, Smad3, p-Smad3 and collagen I were determined using western blot and immumofluorescence. Cell migration ability was detected by cell wound scratch assay. The data was analyzed with SPSS 20.0 software package. RESULTS: The use of 200 ng/mL CsA stimulated proliferation and migration of gingival fibroblasts. The mRNA levels of TGF-beta1 and collagen I were significantly promoted after CsA exposure. The protein syntheses of TGF-beta1, p-Smad3 and Collagen I were also increased by CsA stimulation. CONCLUSIONS: CsA may activate TGF-beta/Smad3 signaling pathway, thus promoting the proliferation and migration of rat gingival fibroblasts as well as collagen accumulation, which eventually lead to gingival overgrowth. PMID- 26598189 TI - [Effect of 3 saliva collection methods on salivary secretion]. AB - PURPOSE: This study compared the effect of 3 saliva collection methods on salivary secretion, in order to select optimum collection method for follow-up studies. METHODS: Fifty-five young healthy volunteers' saliva samples were collected by EP tube collecting emulated with natural flow (ETC), rotating mouth swab slightly (RMS) and chewing mouth swab (CMS) before and after stimulating with acid. The salivary flow rate, salivary alpha-amylase (sAA) activity of each saliva sample and its ratio before and after stimulating with acid were detected to provide the basis for the preferred method of collecting saliva. SPSS 17 software package was used to compare the results before and after acid stimulation. RESULTS: The salivary flow rate ratio (1.73 +/- 1.35 and 1.37 +/- 0.82, respectively), sAA activity ratio (1.22 +/- 0.38 and 1.10 +/- 0.30, respectively) and unit time total sAA activity ratio (2.12 +/- 1.57 and 1.56 +/- 1.18, respectively) of ETC and RMS increased after acid stimulation with the same tendency, and the detection rate of the indexes were closer between ETC and RMS (salivary flow rates: 80%, 78.2%; sAA activity:67.3%, 60.0%; unit time total sAA activity: 83.6%, 76.4%, respectively). Among them, RMS had the advantage of objective and paralleled to collect sufficient amount of saliva. However, the results of CMS were quite different with the first two methods. The detection rate of each index ratio increased in the CMS (salivary flow rate, sAA activity and unit time total sAA activity were 67.3%, 40%, 61.8%, respectively) was significantly lower than the first two, and did not accurately reflect the status of sAA activity in healthy people after acid stimulation. CONCLUSIONS: RMS is recommended when studying on the variation of salivary secretion before and after salivary gland stimulated by acid. PMID- 26598190 TI - [Expression and clinical significance of T lymphoma invasion and metastasis inducing factor 1 in oral squamous cell carcinoma]. AB - PURPOSE: T lymphoma invasion and metastasis inducing factor 1 (TIAM1) overexpression has been reported in a variety of human cancers. However, the investigation of TIAM1 in oral squamous cell carcinoma (OSCC) was extremely rare. The aim of the study was to assess TIAM1 expression and explore its role in OSCC. METHODS: Immunohistochemistry staining was performed in 80 primary OSCC patients and 20 normal oral mucosa samples. The expression of TIAM1 and its association with clinicopathological parameters were analyzed using SPSS19.0 software package. RESULTS: TIAM1 expression was significantly stronger in OSCC tissues (91.25%) compared with normal oral mucosa (10.00%); TIAM1 overexpression was significantly correlated with histological grade (P=0.019), clinical stage (P<0.001) and lymph node metastasis (P=0.004), but not significantly correlated with sex or age. CONCLUSIONS: TIAM1 may play an important role in the occurrence, development and metastasis of OSCC, which may be a potentially therapeutic target in the future. PMID- 26598191 TI - [Comparative analysis of 6 kinds of bacteria in the subgingival plaque in different types of patients with periodontal diseases]. AB - PURPOSE: To detect the existence of Aa,Pg,Tf,Cr,Ec and Pn in the subgingival plaque, and determine their relationships among different types of periodontal diseases. METHODS: Dental plaques from 120 subjects were sampled, including 40 volunteers with health periodontal status(Group A) , forty patients with dental plaque-induced gingival diseases(Group B) and 40 patients with moderate or severe chronic periodontitis (Group C) . These samples were detected based on bacterial composition using the terminal restriction fragment length polymorphism of 16S rRNA genes by multiple-polymerase chain reaction. The data was analysed with SPSS 13.0 software package for Chi-square test. RESULTS: The detection rate of Pn, Cr and Pg had significant differences between group A and B. The detection rate of Ec, Cr, Pg, Aa and Tf had significant differences between group C and B. The detection rate of Ec, Pn, Cr, Pg, Aa and Tf had significant differences between group A and C. CONCLUSIONS: The rate of Ec, Pn, Cr, Pg and Tf detected in moderate or patients with moderate or severe chronic periodontitis are significantly higher than that in healthy subjects, indicating that these bacteria have certain correlation with chronic periodontitis. The rate of Ec, Cr, Pg and Tf detected in severe chronic periodontitis are significantly higher than that in dental-induced gingivitis, suggesting their close relationship with the progress of periodontal disease. PMID- 26598192 TI - [The effect of modified Nance arch on treating maxillary impacted canine transposed with first premolar]. AB - PURPOSE: To explore the effect of modified Nance arch on treating maxillary canine-first premolar transposition cases, in which the anchorage and force direction were discussed. METHODS: Modified Nance arch was applied to 5 cases with maxillary impacted canine-first premolar transposition. First, a lingual knot button was bonded on the surface of the canine crown. Modified Nance arch was decorated with a hook that moved horizontally and buccally. Then the location of the hook was gradually adjusted in order to move the canine cross the root of the first premolar and move the canine to the right position. At last the canine was moved downward by straight wire appliance. RESULTS: Five maxillary transposed canines were fully erupted in their right position, with normal pulp activity and gingival morphology. No obvious root resorption was detected. The mean treatment time was 30 months. CONCLUSIONS: Modified Nance arch has advantages in treating canine-first premolar transposition. PMID- 26598193 TI - [Postoperative infection bacteria and drug resistance in patients with oral and maxillofacial tumors]. AB - PURPOSE: To evaluate postoperative infection patterns of patients suffering from oral and maxillofacial neoplasms. The risk factors giving rise to postoperative infections were analyzed. Infection bacteria and antibiotic resistance were investigated. METHODS: Fifty-three cases suffering from postoperative infection were selected during 2007.12-2012.12 at the Department of Oral & Maxillofacial Surgery, West China College of Stomatology. The relationship between infections and factors including patients' sex, age, type of tumor, operation time and methods were evaluated with Excel and SPSS 21.0 software package, putting emphasis on infection bacteria and drug-resistance. RESULTS: Postoperative infection mainly occurred in patients with oral malignant tumors. Operation types and time had important influence on postoperative infection. The infection bacteria included gram-positive (59.5%) and gram-negative ones (40.5%). Streptococcus pyogenes accounted for the majority of G- bacteria, which was very sensitive to beta-lactam antibiotics. Pseudomonas aeruginosa were multi-drug resistant G- bacteria, which brought difficulties to the treatment of the infection. CONCLUSIONS: Integrant bacterial culture and drug sensitivity test should be performed to choose appropriate antibiotics, and monitor multi-drug resistant bacteria, so as to improve the control rates of postoperative infection. PMID- 26598194 TI - [The relationship between chronic periodontitis and the instability of carotid atherosclerotic plaque by serum level of MMP-9, MCP-1 and MMP-7]. AB - PURPOSE: To study the serum level of matrix metalloproteinase-9 (MMP-9), matrix metalloproteinase-7(MMP-7) and monocyte chemo attractant protein-1(MCP-1) in patients with chronic periodontitis in whom the stability of carotid atherosclerotic plaque is affected. METHODS: One hundred and twenty-nine patients were collected from People's Hospital of Liaoning Province, and divided into 3 groups. Group A (healthy group): 32 cases; Group B (periodontitis group): 31 cases; Group C (periodontitis with carotid atherosclerosis plaque group): 66 cases. According to carotid atherosclerotic plaque stability, Group C was further divided into carotid atherosclerotic plaque stable subgroup (C1, 30 cases) and unstable subgroup (C2, 36 cases). Each patient received periodontal examination, and serum levels of MMP-9, MMP-7, MCP-1 were assayed by ELISA. The data was statistically analyzed with SPSS19.0 software package. RESULTS: The age, gender, drinking and smoking history in each group had no significant difference (P>0.05). The periodontal baseline status in group B was worse than group A, in group C was worse than group B and in group C2 was worse than group C1, and the differences were significant (P<0.05). Serum level of MMP-9, MCP-1 and MMP-7 in group C was significantly higher than in group B and group A (P<0.05), and in group B were significantly higher than group A (P<0.05), in group C2 was significantly higher than in group C1 (P<0.05). Serum level of MMP-9, MCP-1 and MMP-7 were correlated with carotid atherosclerotic plaque stability (r=0.989, P<0.05; r=0.605, P<0.05; r=0.389, P<0.05, respectively). CONCLUSIONS: Serum inflammatory cytokines MMP-9, MMP-7 and MCP-1 are associated with the development of periodontitis. The serum inflammatory cytokines MMP-9, MCP-1, MMP-7 as mediating factors may indicate the severity of periodontal disease and affect the stability of carotid atherosclerotic plaques. PMID- 26598195 TI - [Clinical research of EDTA pretreatment on the bonding strength of resin]. AB - PURPOSE: This study was to evaluate clinical results of adhesives to sclerotic dentin in non-carious cervical lesions pretreated with ethylene diamine tetraacetic acid (EDTA). METHODS: Twelve patients who had at least one pair of teeth with typical cervical wedge-shaped defects and class III sclerotic dentin were selected. The teeth were randomly divided into experimental and control groups. In the experimental group, EDTA was used to pretreat dentin surface first and then self-etching resin adhesive; In the control group, only self-etching resin adhesive was used. Modified USPHS rating system was applied in baseline, 6 months and 12 months after treatment. SAS 8.02 software package was used for two sample rank sum test. RESULTS: At the time point of 6-month and 12-month, the scores in the experimental group were significantly better than the control group (P<0.05). CONCLUSIONS: EDTA pretreatment of the sclerotic dentin of cervical wedge-shaped defects could improve the resin bonding strength, marginal discoloration, marginal form and surface quality. PMID- 26598196 TI - [Levels of IL-8,IL-10 in patients with chronic periodontitis and coronary heart disease]. AB - PURPOSE: To detect the level of interleukin-8 (IL-8) and interleukin-10 (IL-10) in serum and gingival crevicular fluid in patients with chronic severe periodontitis (CP) and coronary heart disease (CHD) and investigate the relationship between CP and CHD. METHODS: Thirty patients with CHD and CP(group A), twenty-five patients with only CP(group B) and thirty healthy controls (group C) were included in this study. Gingival crevicular fluid and serum IL-8, IL-10 levels were detected by ELISA. SPSS 11.5 software package was used for statistical analysis. RESULTS: The periodontal indexes including bleeding on probing and probing depth were significantly different among the 3 groups. In group A and B, the level of IL-8 in gingival crevicular fluid and serum were significantly lower, whereas the IL-10 level was significantly higher, in comparison to those in group C (P<0.05). CONCLUSIONS: IL-8 and IL-10 may be associated with the pathogenesis of periodontitis and CHD. There may be a relationship between CHD and CP. PMID- 26598197 TI - [Comparison of subgingival debridement efficacy of air polishing and manual scaling]. AB - PURPOSE: To assess the efficacy of subgingival air polishing and traditional manual scaling in 3-6 mm pockets. METHODS: Patients with chronic periodontitis who were in the maintenance phase were randomly assigned to receive subgingival air polishing (experimental group) and manual scaling (control group) in 4 teeth with probing depths of 3 to 6 mm. Clinical variables including plaque index (PI), probing depth (PD), probing on bleeding (BOP) and gingival recession (GR) were recorded at baseline, 7 and 30 days post-treatment. "Pocket closure" [PD <= 4 mm and BOP-] was also calculated as supplementary data. The data of the 2 groups were compared using paired t test with SAS 8.2 software package. RESULTS: Thirty one patients were enrolled and PI was 0.8 during the study. Both treatment procedures resulted in significant reductions of PD at day 7 (P<0.0001). BOP% had significant reduction in the experimental group at day 7 (P=0.0390), but there was no significant difference compared to baseline at day 30. Meanwhile, BOP% in the control group demonstrated downward trends during the study, and significant improvement at day 30. The percentages of sites of "pocket closure" significantly increased in both groups (P=0.0329 and P=0.0035, respectively). CONCLUSIONS: The study indicates that subgingival air polishing and traditional manual scaling are both effective for improving clinical variables during supportive periodontal therapy (SPT) in teeth with probing depths of 3 to 6 mm. But the results reveal no significant difference between the 2 modalities. PMID- 26598198 TI - [Esthetic analysis on immediate single-tooth implant restoration in anterior maxilla]. AB - PURPOSE: To evaluate the esthetic outcomes of immediate single-tooth implant restoration in anterior maxilla with the pink esthetic score (PES). METHODS: Nine patients were treated with 9 Straumann implants by immediate single-tooth implant restoration in anterior maxilla. Assessment of PES after crown placement at 1 week (baseline) and 6 months after implantation was conducted. Statistical analysis was performed using SPSS 16.0 software package. RESULTS: Nine implants achieved a retention rate of 100%. PES for single-tooth implant was 10.33 +/- 1.50 at 1 week and 11.44 +/- 0.88 at 6 months after crown placement. The difference was significant(P=0.021). CONCLUSIONS: This study indicates that immediate single-tooth implant restoration in anterior maxilla is predictable. Immediate single-tooth implantation can result in good clinical esthetic results in most patients with single-tooth missing in anterior maxilla. PMID- 26598199 TI - [A study of dental caries and risk factors in children of Guangxi area]. AB - PURPOSE: To observe the trends of dental caries and identify risk factors which may be associated with caries among children in Guangxi province between 2011 and 2013. METHODS: Three age groups of children (3-year-old, 6-year-old, 12-year-old) were selected from 3 urban and rural areas in Guilin, Baise and Beihai of Guangxi province and examined annually from 2011 to 2013.The caries prevalence, mean DMFT/dmft, caries incidence rate and filling rate were recorded. The data was analyzed with SPSS19.0 software package. RESULTS: The caries prevalence, mean DMFT/dmft and caries incidence rate in the 3 groups were increased year by year. The caries prevalence of deciduous teeth in 3-year-old group was 53.2%, 68.7% and 79.1% respectively, and the growth rate was 48.6%; The mean dmft was 2.34, 4.06 and 5.68, and the caries incidence rate increased from 55.9% to 61.2%. In the 6 year-old group, the caries prevalence of permanent teeth was 8.6%, 21.6% and 48.0% respectively, and the growth rate was 458.1%; The mean DMFT was 0.13, 0.34 and 0.99, and the caries incidence rate increased from 15.6% to 36.6%. The caries prevalence of permanent teeth in 12-year-old group was 52.8%, 60.2% and 71.3%, and the growth rate was 35.0%; The mean DMFT was 1.49, 1.92 and 2.96, and the caries incidence rate increased from 26.1% to 46.9%. The frequency of drinking soft drink or sweet, taking sweets at bedtime or after brushing teeth, brushing teeth with help, frequency of brushing, fluoride toothpaste may be the risk factors related to dental caries among children in this study. CONCLUSIONS: Dental caries increase fast among children in Guangxi area. It is necessary to take appropriate measures to improve children's oral health. PMID- 26598200 TI - [The appearance of parotid neoplasms on real-time elastosonography]. AB - PURPOSE: To evaluate the features of parotid neoplasms on real-time elastosonography. METHODS: The elastograms of parotid lesions in 43 patients with 48 neoplasms were analyzed and classified into 5 grades, with pathologic diagnosis as the gold standard for comparision. The data was statistically analyzed with SPSS13.0 software package. RESULTS: The elastographic grades of most benign neoplasms were I-II, while those of malignancies were III-IV. The elastographic grades of benign and malignant lesions were of significant difference (P<0.05). CONCLUSIONS: Some typical features of different parotid lesions on elastosonography are found, which are useful for differential diagnosis of parotid lesions. PMID- 26598201 TI - [Analysis of effect of military outpatients' psychological feelings on doctor patient relationship in orthodontic treatment]. AB - PURPOSE: To explore the effect of military outpatients' psychological feelings on doctor-patient relationship in orthodontic treatment. METHODS: A total of 95 clinic patients who were undergoing orthodontic treatment were asked to complete the questionnaire of dental visit satisfaction scale (DVSS) and orthodontist patient relationship scale (OPRS). The results of different groups according to identity, gender, age and treatment time were compared. The data was analyzed with SPSS 20.0 software package for correlation analysis and stepwise regression. RESULTS: Except 6-18 months group, psychological feelings of patients had significant impact on doctor-patient relationship (P<0.01). The correlation coefficient was 0.610 between patients' satisfaction of outpatient treatment and doctor-patient relationship (P<0.001). Among 9 psychological feelings of orthodontic treatment, five kinds had significant effect on doctor-patient relationship, including three kinds of positive correlation and two kinds of negative correlation. CONCLUSIONS: The patients' psychological feelings are closely related to doctor-patient relationship. Doctors should try to improve medical quality, strengthen service level and pay much attention to the patients' psychological and social needs. PMID- 26598202 TI - [Comparing the anchorage effects of micro-implant and J hook on treating patients with maxillary protrusion]. AB - PURPOSE: To investigate the differences in anchorage effects between micro implants and J hook in treating patients with Class II division 1 maxillary protrusion. METHODS: Thirty-one cases of adult patients with Class II division 1 maxillary protrusion were treated. They were divided into 2 groups depending on their selection. The first group included 17 patients for micro-implant anchorage, who adopted micro-implant and sliding mechanism to close maxillary extraction space and depress the mandibular molar. The second group encompassed 14 cases for J hook, who adopted sliding mechanism, J hooks in high traction and Class II intermaxillary traction to close extraction space. X-ray lateral cephalometric radiographs were measured before and after treatment, and SPSS16.0 software package was employed to compare the differences in soft and hard tissue changes before and after treatment between 2 groups. RESULTS: There were statistically significant differences in SNB, ANB, MP-FH, U1-Y, U6-Y, L6-MP, NLA, and UL-Y between the 2 groups before and after treatment, while there was no significant difference in SNA, U1-SN, U1-X, and U6-X between the 2 groups. CONCLUSIONS: In treating patients with Class II division 1 maxillary protrusion, micro-implant has stronger anchorage effects than J hook, while at the same time depressing the mandibular molars, and making it more favorable to improve Class II faces. PMID- 26598203 TI - [Clinical analysis of 817 cases of neck mass]. AB - PURPUSE: To investigate the distribution of non-thyroid and non-salivary gland neck lesions, in order to improve the diagnosis of cervical masses. METHODS: Eight hundred and seventeen patients with neck mass treated in our department between 2000 and 2013 were collected for retrospective analysis. RESULTS: There were 236 inflammatory masses, 276 congenital masses, 99 benign tumors, 80 primary malignant tumors and 126 metastatic malignant tumors, which accounted for 28.89%, 33.78%, 12.11%, 9.79% and 15.42%, respectively. The clinical characteristics were different among different lesions. CONCLUSIONS: Neck masses are in various forms. To understand the characteristics and patterns of onset, appropriate preoperative examination and multi-parameter comprehensive diagnosis is the key to improve diagnostic rate. PMID- 26598204 TI - [Application of peer-assisted learning in evidence-based dentistry teaching]. AB - PURPOSE: To explore the effects of peer-assisted learning (PAL) for evidence based dentistry (EBD) teaching. METHODS: Four hundred and eleven students who attended EBD class were randomly classified into PAL group (n=75) and traditional teaching group (n=326) via a ratio of 1:5. Students in traditional teaching group received traditional theoretical teaching; while PAL group received traditional theoretical teaching and group study with tutors introduced and finished study protocols given by the teachers. Teaching effects were evaluated by final examinations, questionnaires and published articles via bibliographic searching. Statistical analysis was carried out with STATA 11.0 software package. RESULTS: In the final examination, students in PAL group had 6.9 higher scores than traditional teaching group (P<0.05). The results of questionnaires showed that students in PAL group had higher interests and contentments in EBD class (P<0.05), and PAL had positive effects on their usage of EBD methodology and involvement in EBD research (P<0.05). In publication of articles, the number and ratios of article publication in PAL group were significantly higher than the traditional group (P<0.05). CONCLUSIONS: PAL has positive effects on EBD teaching. PMID- 26598205 TI - [Root canal treatment of mandibular first premolar with 4 root canals: a case report]. AB - The mandibular first premolar can be considered one of the most challenging teeth to treat, due to the complexity of its root canal morphology and increased incidence of multiple canals. A case of endodontic treatment of a mandibular first premolar exhibiting a total of 4 distinct root canals and 4 apical foramina was described. Anatomic variation of root canal morphology should be considered in endodontic treatment to ensure a favorable healing outcome, and its identification could be enhanced by careful examination using a dental operating microscope. Obturation of root canals using a warm vertical compaction technique with a highly-radiopaque root canal sealer, such as AH Plus, after careful ultrasonic activated irrigation might allow the flow of sealer into the narrowed but unprepared part of the canal, thereby facilitating optimum chemo-mechanical debridement of the root canal system. PMID- 26598206 TI - Prolonged anti-bacterial activity of ion-complexed doxycycline for the treatment of osteomyelitis. AB - The main purposes of the present study are the fabrication of an ion-complexed antibiotic which allows for the continuous release of the drug for sufficient periods of time without any additional matrix leading to unfavorable tissue responses, and the feasibility study of the ion-complexed antibiotic as a therapeutic system for osteomyelitis using an animal model. An ion-complexed doxycycline (icDX) as an antibiotic was prepared by simple mixing of positively charged doxycycline hyclate (DX) and negatively charged multivalent Na2HPO4 (2Na(+) HPO4(2-)) aqueous solutions. The icDX showed a controlled release of the DX up to 6 weeks. From the in vivo feasibility study using an osteomyelitis rat model, the icDX group showed a more effective therapeutic effect for the osteomyelitis, at 3 and 6 weeks, compared to the non-treated control and free DX groups. This was due to the sustained release of DX from the icDX in the osteomyelitis bone (medullary cavity) without migration. These findings suggest that the icDX may be a promising local delivery system in the clinical field for the treatment of the osteomyelitis. PMID- 26598207 TI - Mucoadhesive vs. mucopenetrating particulate drug delivery. AB - Mucus layer is a hydrophilic absorption barrier found in various regions of the body. The use of particulate delivery systems showed potential in drug delivery to mucosal membranes by either prolonging drug residence time at the absorption or target membrane or promoting permeation of particles across mucus gel layer to directly reach underlying epithelium. Mucoadhesive particles (MAP) are advantageous for delivering drug molecules to various mucosal membranes including eyes, oral cavity, bladder and vagina by prolonging drug residence time on those membranes. In contrast, a broader particle distribution and deeper penetration of the mucus gel layer are accomplished by mucopenetrating particles (MPP) especially in the gastrointestinal tract. Based on the available literature in particular dealing with in vivo results none of both systems (MAP and MPP) seems to be advantageous over the other. The choice of system primarily depends on the therapeutic target and peculiar properties of the target mucosa including thickness of the mucus gel layer, mucus turnover rate and water movement within the mucus. Future trends are heading in the direction of combining both systems to one i.e. mucoadhesive and mucopenetrating properties on the same particles. PMID- 26598208 TI - Characterization of cornified oral mucosa for iontophoretically enhanced delivery of chlorhexidine. AB - Topical administration of chlorhexidine for periodontal disease can provide advantages over systemic delivery, but is limited by the permeability of the cornified oral mucosal tissue. In the present study, passive and iontophoretic transport of tetraethylammonium, salicylate, mannitol, dexamethasone, fluoride, and chlorhexidine across bovine palate was investigated to (a) determine the intrinsic barrier properties of bovine palate for its eventual use as a model of human cornified oral mucosa, (b) examine the feasibility of iontophoretically enhanced transport of chlorhexidine into and across bovine palate, and (c) identify the transport mechanisms involved in iontophoretic transport across the palate. The histology study suggests that bovine and human palates have similar cornified epithelium structures; bovine palate could be a model tissue of human hard palate for drug delivery studies. Transport study of tetraethylammonium, salicylate, and mannitol suggests that bovine palate was net negatively charged and the cornified epithelial layer was the rate-determining barrier. The direct field effect (electrophoresis) was shown to be the dominant flux-enhancing mechanism in iontophoretic transport of ionic compounds. Electroosmosis also contributed to the iontophoretic transport of both neutral and ionic permeants. Anodal iontophoresis enhanced the delivery of chlorhexidine into and across the palate, reduced the transport lag time, and provided tissue concentration above the drug minimum inhibitory concentration, and therefore could be a promising method to assist in the treatment of periodontal disease. PMID- 26598209 TI - Mucus permeating thiolated self-emulsifying drug delivery systems. AB - CONTEXT: Mucus represents a critical obstacle for self-emulsifying drug delivery systems (SEDDS) targeting the epithelial membrane site. OBJECTIVE: The aim of the study was the development of a novel SEDDS to overcome the mucus barrier. MATERIALS AND METHODS: Two novel conjugates N-dodecyl-4-mercaptobutanimidamide (thiobutylamidine-dodecylamine, TBA-D) and 2-mercapto-N-octylacetamide (thioglycolicacid-octylamine, TGA-O) were synthesized, incorporated into SEDDS and analyzed for stability, cytotoxicity and physico-chemical characteristics using dynamic light scattering. Mucus interaction studies were performed using in vitro assays based on multiple particle tracking, rotational silicone tubes and rheology. RESULTS AND DISCUSSION: TBA-D was synthesized using dodecylamine and iminothiolane as thiol precursor (yield=55 +/- 5%). TGA-O was obtained via crosslinking of octylamine with SATA ((2,5-dioxopyrrolidin-1-yl) 2 acetylsulfanylacetate) (yield=70 +/- 6%). The chemical structure of target compounds was confirmed via NMR analysis. The thiol-conjugates were incorporated in an amount of 3% (m/m) into SEDDS (Cremophor EL 30%, Capmul MCM 30%, Captex 355 30% and propylene glycol 10%), namely thiolated SEDDS leading to a droplet size around 50 nm and zeta potential close to 0 mV. Thiolated SEDDS with an effective diffusion coefficient of up to 0.871 +/- 0.122 cm(2) s(-1) * 10(-9) were obtained. Rotational silicone studies show increased permeation of the thiolated SEDDS A in comparison with unthiolated control. Rheological studies confirmed the mucolytic activity of the thiol-conjugates which differed only by 3% from DTT (dithiothreitol) serving as positive control. CONCLUSION: Low molecular weight thiol-conjugates were identified to improve the mucus permeation, leading to highly efficient mucus permeating SEDDS, which were superior to conventional SEDDS and might thus be a new carrier for lipophilic drug delivery. PMID- 26598210 TI - Evaluation of ribonucleic acid amplification protocols for human oocyte transcriptome analysis. AB - OBJECTIVE: To develop a reliable, reproducible, and sensitive method for investigating gene-expression profiles from individual human oocytes. DESIGN: Five commercially available protocols were investigated for their efficiency to amplify messenger RNA (mRNA) from 54 single human oocytes. Protocols resulting in sufficient yields were further validated using microarray technology. For the validation, mRNA was isolated from 25 human oocytes. To eliminate biological variation, RNA from 13 human oocytes was pooled together and split into 12 identical samples for further mRNA amplification. From 12 oocytes, mRNA was individually isolated. SETTING: University medical center and university microarray laboratory. PATIENT(S): Couples undergoing intracytoplasmic sperm injection treatment were asked to donate their immature oocytes for research, and written informed consent was obtained in all cases. Seventy-nine human oocytes were used in total. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Amplification efficiency and microarray profiles. RESULT(S): Two of the five protocols (WT Ovation One-Direct and Arcturus RiboAMp HS Plus) resulted in sufficient yields and high success rates and were further validated for their performance in obtaining reliable, reproducible, and sensitive expression profiles from individual human oocytes. Evaluation of these two protocols demonstrated that they both displayed low technical variation and produced highly reproducible profiles (r >= 0.95). One of them identified significantly more transcripts but also had a higher number of false discoveries. CONCLUSION(S): Two protocols generated ample amounts of mRNA for (quantitative) polymerase chain reaction, microarray, and sequencing techniques. Further validation using a design that discriminates between biological and technical variation showed that both protocols can be used for gene-expression profiling of individual human oocytes. PMID- 26598211 TI - Morphokinetic analysis and embryonic prediction for blastocyst formation through an integrated time-lapse system. AB - OBJECTIVE: To describe the events associated with the blastocyst formation and implantation that occur in embryos during preimplantation development based on the largest sample size ever described with time-lapse monitoring. DESIGN: Observational, retrospective, single-center clinical study. SETTING: University affiliated private IVF center. PATIENT(S): A total of 7,483 zygotes from 990 first treatments of intracytoplasmic sperm injection (ICSI; 627 of oocyte donor vs. 363 autologous oocyte cycles), of which 832 blastocysts were transferred. INTERVENTION(S): No patient intervention. Embryos were cultured in a time-lapse monitoring system, and the embryos were transferred on day 5 after ICSI. Embryo selection was based on the multivariable model previously developed and on blastocyst morphology. MAIN OUTCOME MEASURE(S): Using a time-lapse system, embryo images were acquired every 15 minutes for 120 hours. Embryos cleavage time points up to the 9-cell stage (t2-t9) as well as to the morula stage (tM) and blastocyst formation (tB) were registered in hours after ICSI. Additionally, duration of the cell cycle and synchrony of the second and third cell cycles were defined. As a result, we have monitored the embryonic development of a total of 3,215 blastocysts, of which 832 were transferred. Finally, we analyzed the characteristics of embryonic development of blastocyst (phase 1) and of implanted and not implanted (phase 2) embryos as finally validated in an independent data set (phase 3). RESULT(S): A detailed retrospective analysis of cleavage times was made for 7,483 zygotes. We analyzed 17 parameters and found several significantly correlated with subsequent blastocyst formation and implantation. The most predictive parameters for blastocyst formation were time of morula formation, tM (81.28-96.0 hours after ICSI), and t8-t5 (<=8.78 hours) or time of transition of 5-blastomere embryos to 8-blastomere embryos with a receiver operating characteristic curve (ROC) value = 0.849 (95% confidence interval [CI], 0.835 0.854; phase 1). These parameters were less predictive of implantation, with a ROC value = 0.546 (95% CI, 0.507-0.585). We also observed that time for expansion blastocyst, tEB (107.9-112.9 hours after ICSI), and t8-t5 (<=5.67 hours after ICSI) predict blastocyst implantation, with a ROC value = 0.591 (95% CI, 0.552 0.630; phase 2). The model was validated on an independent data set and gave a ROC of 0.596 (0.526-0.666; phase 3). CONCLUSION(S): The inclusion of kinetic parameters into score evaluation may improve blastocyst selection criteria and can predict blastocyst formation with high accuracy. We propose two multivariable models based on our findings to classify embryos according to their probabilities of blastocyst stage and implantation in the largest data set ever reported of human blastocysts. PMID- 26598212 TI - An evaluation of constrained randomization for the design and analysis of group randomized trials. AB - In group-randomized trials, a frequent practical limitation to adopting rigorous research designs is that only a small number of groups may be available, and therefore, simple randomization cannot be relied upon to balance key group-level prognostic factors across the comparison arms. Constrained randomization is an allocation technique proposed for ensuring balance and can be used together with a permutation test for randomization-based inference. However, several statistical issues have not been thoroughly studied when constrained randomization is considered. Therefore, we used simulations to evaluate key issues including the following: the impact of the choice of the candidate set size and the balance metric used to guide randomization; the choice of adjusted versus unadjusted analysis; and the use of model-based versus randomization-based tests. We conducted a simulation study to compare the type I error and power of the F-test and the permutation test in the presence of group-level potential confounders. Our results indicate that the adjusted F-test and the permutation test perform similarly and slightly better for constrained randomization relative to simple randomization in terms of power, and the candidate set size does not substantially affect their power. Under constrained randomization, however, the unadjusted F-test is conservative, while the unadjusted permutation test carries the desired type I error rate as long as the candidate set size is not too small; the unadjusted permutation test is consistently more powerful than the unadjusted F-test and gains power as candidate set size changes. Finally, we caution against the inappropriate specification of permutation distribution under constrained randomization. An ongoing group-randomized trial is used as an illustrative example for the constrained randomization design. PMID- 26598213 TI - Rarity in aquatic microbes: placing protists on the map. AB - Most microbial richness at any given time tends to be represented by low abundance (rare) taxa, which are collectively referred to as the "rare biosphere". Here we review works on the rare biosphere using high-throughput sequencing (HTS), with a particular focus on unicellular eukaryotes or protists. Evidence thus far indicates that the rare biosphere encompasses dormant as well as metabolically active microbes that could potentially play key roles in ecosystem functioning. Rare microbes appear to have biogeography, and sometimes the observed patterns can be similar to what is observed among abundant taxa, suggesting similar community-structuring mechanisms. There is limited evidence indicating that the rare biosphere contains taxa that are phylogenetically distantly related to abundant counterparts; therefore, the rare biosphere may act as a reservoir of deep-branching phylogenetic diversity. The potential role of the rare biosphere as a bank of redundant functions that can help to maintain continuous ecosystem function following oscillations in taxonomic abundances is hypothesized as its main ecological role. Future studies focusing on rare microbes are crucial for advancing our knowledge of microbial ecology and evolution and unveiling their links with ecosystem function. PMID- 26598214 TI - Influence of headspace pressure on methane production in Biochemical Methane Potential (BMP) tests. AB - The biochemical methane potential test is the most commonly applied method to determine methane production from organic wastes. One of the parameters measured is the volume of biogas produced which can be determined manometrically by keeping the volume constant and measuring increases in pressure. In the present study, the effect of pressure accumulation in the headspace of the reactors has been studied. Triplicate batch trials employing cocoa shell, waste coffee grounds and dairy manure as substrates have been performed under two headspace pressure conditions. The results obtained in the study showed that headspace overpressures higher than 600mbar affected methane production for waste coffee grounds. On the contrary, headspace overpressures within a range of 600-1000mbar did not affect methane production for cocoa shell and dairy manure. With the analyses performed in the present work it has not been possible to determine the reasons for the lower methane yield value obtained for the waste coffee grounds under high headspace pressures. PMID- 26598215 TI - An alternative reaction for heme degradation catalyzed by the Escherichia coli O157:H7 ChuS protein: Release of hematinic acid, tripyrrole and Fe(III). AB - As part of the machinery to acquire, internalize and utilize heme as a source of iron from the host, some bacteria possess a canonical heme oxygenase, where heme plays the dual role of substrate and cofactor, the later catalyzing the cleavage of the heme moiety using O2 and electrons, and resulting in biliverdin, carbon monoxide and ferrous non-heme iron. We have previously reported that the Escherichia coli O157:H7 ChuS protein, which is not homologous to heme oxygenases, can bind and degrade heme in a reaction that releases carbon monoxide. Here, we have pursued a detailed characterization of such heme degradation reaction using stopped-flow UV-visible absorption spectrometry, the characterization of the intermediate species formed in such reaction by EPR spectroscopy and the identification of reaction products by NMR spectroscopy and Mass spectrometry. We show that hydrogen peroxide (in molar equivalent) is the key player in the degradation reaction, at variance to canonical heme oxygenases. While the initial intermediates of the reaction of ChuS with hydrogen peroxide (a ferrous keto pi neutral radical and ferric verdoheme, both identified by EPR spectroscopy) are in common with heme oxygenases, a further and unprecedented reaction step, involving the cleavage of the porphyrin ring at adjacent meso carbons, results in the release of hematinic acid (a monopyrrole moiety identified by NMR spectroscopy), a tripyrrole product (identified by Mass spectrometry) and non-heme iron in the ferric oxidation state (identified by EPR spectroscopy). Overall, the unprecedented reaction of E. coli O157:H7 ChuS provides evidence for a novel heme degradation activity in a Gram-negative bacterium. PMID- 26598216 TI - Laterality and mental disorders in the postgenomic age--A closer look at schizophrenia and language lateralization. AB - Most people are right-handed and show left-hemispheric language lateralization, but a minority exhibits left-handedness and right-hemispheric language lateralization. This atypical laterality pattern is observed significantly more often in schizophrenia patients than in the general population, which led several authors to conclude that there is a genetic link between laterality and schizophrenia. It has even been suggested that a failure in the lateralization process, orchestrated by genes, could be the primary cause of schizophrenia. However, the molecular genetic evidence for a link between laterality and schizophrenia is weak. Recent genetic evidence indicates that schizophrenia is not a single disorder but a group of heritable disorders caused by different genotypic networks leading to distinct clinical symptoms. To uncover the link between schizophrenia and laterality we therefore suggest a paradigm shift where genetics are not mapped on schizophrenia as a whole but on discrete schizophrenia symptoms. In addition, we provide a critical evaluation of current theories on the genetic link between schizophrenia and brain asymmetry. PMID- 26598217 TI - Global impacts of the 1980s regime shift. AB - Despite evidence from a number of Earth systems that abrupt temporal changes known as regime shifts are important, their nature, scale and mechanisms remain poorly documented and understood. Applying principal component analysis, change point analysis and a sequential t-test analysis of regime shifts to 72 time series, we confirm that the 1980s regime shift represented a major change in the Earth's biophysical systems from the upper atmosphere to the depths of the ocean and from the Arctic to the Antarctic, and occurred at slightly different times around the world. Using historical climate model simulations from the Coupled Model Intercomparison Project Phase 5 (CMIP5) and statistical modelling of historical temperatures, we then demonstrate that this event was triggered by rapid global warming from anthropogenic plus natural forcing, the latter associated with the recovery from the El Chichon volcanic eruption. The shift in temperature that occurred at this time is hypothesized as the main forcing for a cascade of abrupt environmental changes. Within the context of the last century or more, the 1980s event was unique in terms of its global scope and scale; our observed consequences imply that if unavoidable natural events such as major volcanic eruptions interact with anthropogenic warming unforeseen multiplier effects may occur. PMID- 26598218 TI - Ballistic Transport in Graphene Antidot Lattices. AB - The bulk carrier mobility in graphene was shown to be enhanced in graphene-boron nitride heterostructures. However, nanopatterning graphene can add extra damage and drastically degrade the intrinsic properties by edge disorder. Here we show that graphene embedded into a heterostructure with hexagonal boron nitride (hBN) on both sides is protected during a nanopatterning step. In this way, we can prepare graphene-based antidot lattices where the high mobility is preserved. We report magnetotransport experiments in those antidot lattices with lattice periods down to 50 nm. We observe pronounced commensurability features stemming from ballistic orbits around one or several antidots. Due to the short lattice period in our samples, we can also explore the boundary between the classical and the quantum transport regime, as the Fermi wavelength of the electrons approaches the smallest length scale of the artificial potential. PMID- 26598219 TI - Validity of Forster Theory for Vibrational Energy Transfer in Low-Dimensional Water. AB - Kinetics of vibrational Forster resonance energy transfer between the OH bonds of one-, two-, and three-dimensional liquid water is modeled by a Forster type of theory reflecting the excluded volume of intermolecular pairs of the bonds. When the size of excluded volume is comparable to so-called Forster radius of the bonds, the energy transfer kinetics is delayed from the prediction of Forster theory. The delay persists longer in the lower dimensions and results in the quantum yield of energy transfer to deviate more largely from the prediction of Forster theory. The excluded volume which is not taken into account by Forster theory is a critical factor for the correct description of vibrational Forster resonance energy transfer particularly in low-dimensional water. PMID- 26598220 TI - Transcatheter Aortic Valve Implantation: Finding Its Path. PMID- 26598221 TI - Drug delivery to bony tissue. PMID- 26598222 TI - The role of Notch signaling in diabetic endothelial progenitor cells dysfunction. AB - AIMS: To investigate the role of Notch signaling pathway in vasculogenic dysfunction of diabetic EPCs (DM-EPCs). METHODS: The study was performed in mice and diabetes was induced with Streptozotocin. The functional consequences of Notch pathway modulation were studied by assessment of colony forming capacity (EPC colony forming assay), EPC differentiation capacity (% of definitive EPC-CFU (dEPC-CFU)), circulating EPCs (EPC culture assay) and migrated cells (migration assay); in the presence of Notch inhibitor (gamma-secretase inhibitors (GSI)) compared to control. Notch pathway and VEGF involvement in DM- EPCs were assessed by gene expression (RT-qPCR). RESULTS: DM demonstrated to increase Notch pathway expression in bone marrow (BM) EPCs followed by lower EPC-CFU number, EPCs differentiation capacity, number of circulating EPCs, migrated cells and VEGF expression compared to control (p<0.05). Inhibition of Notch pathway by GSI rescued vasculogenic dysfunction in DM-EPCs as represented by increase in EPC-CFU number, differentiation capacity and number of circulating EPCs (p<0.05). CONCLUSION: Our findings indicate the involvement of Notch pathway in mediating DM-EPCs dysfunction including less number of EPC-CFU, circulating EPCs and migrated cell number compared to control. Further in vitro inhibition of Notch pathway by GSI rescued DM-EPC dysfunction. Therefore targeting Notch pathway in DM may provide a target to restore DM-EPC dysfunction. PMID- 26598223 TI - Ketoacidosis at diagnosis in childhood-onset diabetes and the risk of retinopathy 20years later. AB - AIMS: To investigate on the relationship between severity of ketoacidosis, an important risk factor for C-peptide preservation, and long-term microvascular complications in childhood-onset type 1 diabetes mellitus (T1DM). METHODS: 230 childhood-onset diabetic patients (177 pre-pubertal), aged 7.0+/-3.8years followed for at least 15years after their diagnosis, were enrolled. Clinical and laboratory data at diagnosis, and C-peptide levels in a subset of patients, were compared with the severity of retinopathy and nephropathy, after a mean of 19.6+/ 3.8years of disease. Digital retinal photographs were taken in all patients, and centrally graded. Repeated measurements of HbA1c and microalbuminuria for the whole duration of diabetes were collected in over half of the cases. RESULTS: Out of 230 patients, those with the lowest age at diagnosis had the most severe DKA and clinical conditions (p<0.05), and lower C-peptide levels (p<0.0001) at diagnosis. There was a significant relationship between pH and clinical severity (r=-0.783, p<0.0001), and between pH and C-peptide levels (r=0.278, p<0.05). The severity of ketoacidosis had no relationship with subsequent lifetime HbA1c values and long-term microvascular complications. In logistic regression analysis, the only variables that independently influenced severity of retinopathy were lifetime HbA1c (B=0.838, p<0.001), duration of disease (B=0.208, p<0.005) and age at diagnosis (B=0.116, p<0.05). CONCLUSIONS: The degree of metabolic derangement at diagnosis is not associated with retinopathy and nephropathy in childhood-onset T1DM. Age at diagnosis seems to be an important variable to be considered when evaluating the long-term effects of residual beta cell function. PMID- 26598224 TI - Proline biosynthesis augments tumor cell growth and aerobic glycolysis: involvement of pyridine nucleotides. AB - The metabolism of the nonessential amino acid proline contributes to tumor metabolic reprogramming. Previously we showed that MYC increases proline biosynthesis (PB) from glutamine. Here we show MYC increases the expression of the enzymes in PB at both protein and mRNA levels. Blockade of PB decreases tumor cell growth and energy production. Addition of Delta(1)-pyrroline-5-carboxylate (P5C) or proline reverses the effects of P5C synthase knockdown but not P5C reductases knockdown. Importantly, the reversal effect of proline was blocked by concomitant proline dehydrogenase/oxidase (PRODH/POX) knockdown. These findings suggest that the important regulatory contribution of PB to tumor growth derives from metabolic cycling between proline and P5C rather than product proline or intermediate P5C. We further document the critical role of PB in maintaining pyridine nucleotide levels by connecting the proline cycle to glycolysis and to the oxidative arm of the pentose phosphate pathway. These findings establish a novel function of PB in tumorigenesis, linking the reprogramming of glucose, glutamine and pyridine nucleotides, and may provide a novel target for antitumor therapy. PMID- 26598225 TI - Variants in the LGALS9 Gene Are Associated With Development of Liver Disease in Heavy Consumers of Alcohol. AB - BACKGROUND & AIMS: Alcohol consumption is a major cause of chronic liver disease and contributes to a large proportion of cirrhosis-related deaths worldwide. However, only a fraction of heavy consumers of alcohol develop advanced alcoholic liver disease (ALD), so there are likely to be other risk factors. We investigated whether polymorphisms in the gene encoding galectin-9 (LGALS9), previously shown to mediate liver injury, were associated with the development of ALD. METHODS: We isolated DNA from peripheral blood mononuclear cells (PBMCs) of 575 individuals with at-risk alcohol consumption but no other risk factors for chronic liver disease; all subjects were white Europeans who had consumed more than 80 grams ethanol per day. Of the subjects, 388 had ALD (including, 268 with cirrhosis and 74 with alcoholic hepatitis; mean age, 49 y; 72% male) and 187 had normal liver function with no biochemical or clinical evidence of liver disease (controls; mean age, 42 y; 73% male). Select LGALS9 polymorphisms were genotyped using allelic discrimination. We also genotyped and measured expression of LGALS9 messenger RNA in PBMCs from individuals who were not heavy consumers of alcohol. RESULTS: We used data from the HapMap project to identify 5 single-nucleotide polymorphisms (SNPs) that tag all the common haplotypes. When we looked for these SNPs in individuals with vs without liver disease, 4 (rs3751093, rs4239242, rs732222, and rs4794976) were associated with an increased risk of developing ALD. We found that levels of LGALS9 messenger RNA and protein expressed were associated with an allele carried by PBMCs. Multivariate analysis confirmed that rs4239242 and rs4794976 were associated with an increased risk of ALD. CONCLUSIONS: In a genetic analysis of heavy consumers of alcohol, we associated 2 SNPS in LGALS9 with the development of ALD. Although larger studies are required, this information could be used to determine the risk of individuals developing ALD or to develop therapeutic agents. PMID- 26598226 TI - Long-term Outcomes of Thalidomide Therapy for Adults With Refractory Crohn's Disease. AB - BACKGROUND & AIMS: Little is known about the efficacy and safety of thalidomide therapy for patients with refractory Crohn's disease (CD), particularly in respect to long-term outcomes of patients. METHODS: We conducted a retrospective multicenter observational study to evaluate thalidomide efficacy and the probability of its withdrawal because of either toxicity or lack/loss of efficacy. We analyzed data from 77 patients with active intestinal and/or perineal CD, refractory to conventional immunosuppressive therapies, treated with thalidomide at 5 tertiary referral inflammatory bowel disease centers in France. We also analyzed the long-term efficacy of thalidomide. RESULTS: Fifty-four percent of the patients were in clinical remission after thalidomide treatment within the first year. The proportions of patients from whom thalidomide was withdrawn because of lack/loss of efficacy and/or toxicity were 35% at 3 months of treatment, 69% at 12 months, and 88% at 24 months. The proportions of patients from whom thalidomide was withdrawn because of toxicity alone were 22% at 3 months, 34% at 12 months, and 46% at 24 months. Overall, neuropathy occurred in 30 patients and was the main reason for thalidomide withdrawal. CONCLUSIONS: On the basis of a retrospective multicenter observational study, thalidomide therapy is effective in most patients with refractory active intestinal and/or perineal CD. However, its toxicity limits its use as a maintenance therapy. PMID- 26598227 TI - Esophageal Stricture of an Unusual Etiology. PMID- 26598228 TI - Development and Validation of an Inflammatory Bowel Diseases Monitoring Index for Use With Mobile Health Technologies. AB - BACKGROUND & AIMS: Mobile health technologies are advancing rapidly as smartphone use increases. Patients with inflammatory bowel disease (IBD) might be managed remotely through smartphone applications, but no tools are yet available. We tested the ability of an IBD monitoring tool, which can be used with mobile technologies, to assess disease activity in patients with Crohn's disease (CD) or ulcerative colitis (UC). METHODS: We performed a prospective observational study to develop and validate a mobile health index for CD and UC, which monitors IBD disease activity using patient-reported outcomes. We collected data from disease specific questionnaires completed by 110 patients with CD and 109 with UC who visited the University of California, Los Angeles, Center for IBD from May 2013 through January 2014. Patient-reported outcomes were compared with clinical disease activity index scores to identify factors associated with disease activity. Index scores were validated in 301 patients with CD and 265 with UC who visited 3 tertiary IBD referral centers (in California or Europe) from April 2014 through March 2015. RESULTS: We assessed activity of CD based on liquid stool frequency, abdominal pain, patient well-being, and patient-assessed disease control, and activity of UC based on stool frequency, abdominal pain, rectal bleeding, and patient-assessed disease control. The indices identified clinical disease activity with area under the receiver operating characteristic curve values of 0.90 in patients with CD and 0.91 in patients with UC. They identified endoscopic activity with area under the receiver operating characteristic values of 0.63 in patients with CD and 0.82 in patients with UC. Both scoring systems responded to changes in disease activity (P < .003). The intraclass correlation coefficient for test-retest reliability was 0.94 for CD and for UC. CONCLUSIONS: We developed and validated a scoring system to monitor disease activity in patients with CD and UC that can be used with mobile technologies. The indices identified clinical disease activity with area under the receiver operating characteristic curve values of 0.9 or higher in patients with CD or UC, and endoscopic activity in patients with UC but not CD. PMID- 26598229 TI - Incorporating Serum Level of Hepatitis B Surface Antigen or Omitting Level of Hepatitis B Virus DNA Does not Affect Calculation of Risk for Hepatocellular Carcinoma in Patients Without Cirrhosis. AB - BACKGROUND & AIMS: Tests for hepatitis B virus (HBV) DNA are expensive, and levels of hepatitis B surface antigen (HBsAg) can help determine the risk for hepatocellular carcinoma (HCC) in patients with chronic HBV infection. We investigated how adding data to knowing the level of HBsAg or excluding measurement of HBV DNA affected the accuracy of the Risk Estimation for Hepatocellular Carcinoma in Chronic Hepatitis B (REACH-B) scoring system in determining the risk for HCC. METHODS: We collected data from 3584 patients with chronic HBV infection who were positive for HBsAg, free of cirrhosis, and participated in the community-based Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer (REVEAL)-HBV cohort (208 cases of HCC) from 1991 through 1992; they were followed up until December 31, 2008. Data from this cohort were used to derive our scoring system. We validated our system using data from 2688 HBsAg-seropositive patients (191 cases of HCC) who participated in the hospital-based Elucidation of Risk Factors for Disease Control or Advancement in Taiwanese Hepatitis B Carriers (ERADICATE-B) study at the National Taiwan University Hospital from 1985 through 2000; they were followed up until December 31, 2010. We also validated the system using data from 426 patients with chronic HBV infection who participated in the Chinese University of Hong Kong (CUHK) study (46 cases of HCC) from 1997 through 2000; patients were followed up for a median of 225 weeks. Discrimination and calibration were evaluated using area under the receiver operating characteristic (AUROC) curves and calibration charts. RESULTS: When data on HBsAg were added to the REACH-B scoring system, it identified patients in the ERADICATE-B study who developed HCC within 3, 5, and 10 years, with AUROC curve values of 0.92 (95% confidence interval [CI], 0.82 1.02), 0.78 (95% CI, 0.70-0.86), and 0.80 (95% CI, 0.76-0.84), respectively. It identified patients in the CUHK study who developed HCC in 3, 5, and 10 years, with AUROC curve values of 0.85 (95% CI, 0.75-0.95), 0.82 (95% CI, 0.70-0.93), and 0.78 (95% CI, 0.70-0.870), respectively. When data on HBV DNA were removed from the REACH-B scoring system, it identified patients in the ERADICATE-B cohort who developed HCC in 3, 5, and 10 years, with AUROC curve values of 0.90 (95% CI, 0.81-1.0), 0.76 (95% CI, 0.68-0.85), and 0.78 (95% CI, 0.73-0.82), respectively. It identified patents in the CUHK cohort who developed HCC in 3, 5, and 10 years, with AUROC curve values of 0.84 (95% CI, 0.79-0.92), 0.81 (95% CI, 0.71-0.91), and 0.79 (95% CI, 0.72-0.87). These modified systems identified patients who developed HCC with similar levels of accuracy as the original REACH-B score (P > .05 in tests of noninferiority). CONCLUSIONS: Including data on serum level of HBsAg or removing data on level of HBV DNA do not alter the accuracy of the REACH B scoring system in determining HCC risk in patients with chronic HBV infection without cirrhosis. It might be cost effective to replace the test for HBV DNA with assays to measure HBsAg in determining HCC risk. These modified scoring systems might replace the REACH-B system in specific situations. PMID- 26598230 TI - Intractable Electrical Storm After Coronary Artery Bypass Grafting Originating in Abnormal Purkinje Fibers. AB - Electrical storm is a rare but critical complication following revascularization in patients with ischemic heart disease. We report the case of a 67-year-old man who developed drug refractory intractable electrical storm after emergent coronary artery bypass grafting for ischemic cardiomyopathy. The electrical storm was successfully eliminated by percutaneous endocardial radiofrequency catheter ablation targeting the abnormal Purkinje-related triggering ventricular premature contractions in a low-voltage zone. PMID- 26598232 TI - Effect of auditory stimuli on conditioned vocal behavior of budgerigars. AB - The budgerigar (Melopsittacus undulatus) is a highly social species and serves as an excellent model of vocal learning and production. This species can be trained to vocalize as a conditioned response using an operant conditioning paradigm. In addition, the birds can be trained to produce different vocalizations in response to different visual signals. Budgerigars may be fairly unique in the capability for vocal production under operant control. Whether acoustic features of the bird's natural social milieu can influence this conditioned vocal output is uncertain. The present study asked whether conditioned vocal behavior in budgerigars can be influenced by hearing vocalizations of other birds. The results show that birds vocalizing under operant control produced louder calls in the presence of vocalizations from other birds, than in pure tones or in quiet. The acoustic variation of the conditioned vocalization also increased when it is in the context of hearing other . These results reveal a functional connection between the vocal production under operant control and the perceptual mechanisms subserving vocal production in the budgerigars' natural social milieu. PMID- 26598233 TI - Small Sample Sizes Yield Biased Allometric Equations in Temperate Forests. AB - Accurate quantification of forest carbon stocks is required for constraining the global carbon cycle and its impacts on climate. The accuracies of forest biomass maps are inherently dependent on the accuracy of the field biomass estimates used to calibrate models, which are generated with allometric equations. Here, we provide a quantitative assessment of the sensitivity of allometric parameters to sample size in temperate forests, focusing on the allometric relationship between tree height and crown radius. We use LiDAR remote sensing to isolate between 10,000 to more than 1,000,000 tree height and crown radius measurements per site in six U.S. forests. We find that fitted allometric parameters are highly sensitive to sample size, producing systematic overestimates of height. We extend our analysis to biomass through the application of empirical relationships from the literature, and show that given the small sample sizes used in common allometric equations for biomass, the average site-level biomass bias is ~+70% with a standard deviation of 71%, ranging from -4% to +193%. These findings underscore the importance of increasing the sample sizes used for allometric equation generation. PMID- 26598231 TI - Gekko japonicus genome reveals evolution of adhesive toe pads and tail regeneration. AB - Reptiles are the most morphologically and physiologically diverse tetrapods, and have undergone 300 million years of adaptive evolution. Within the reptilian tetrapods, geckos possess several interesting features, including the ability to regenerate autotomized tails and to climb on smooth surfaces. Here we sequence the genome of Gekko japonicus (Schlegel's Japanese Gecko) and investigate genetic elements related to its physiology. We obtain a draft G. japonicus genome sequence of 2.55 Gb and annotated 22,487 genes. Comparative genomic analysis reveals specific gene family expansions or reductions that are associated with the formation of adhesive setae, nocturnal vision and tail regeneration, as well as the diversification of olfactory sensation. The obtained genomic data provide robust genetic evidence of adaptive evolution in reptiles. PMID- 26598234 TI - miR-223 Deficiency Protects against Fas-Induced Hepatocyte Apoptosis and Liver Injury through Targeting Insulin-Like Growth Factor 1 Receptor. AB - The biological functions and molecular mechanisms of miR-223 action in liver cells and liver diseases remain unclear. We therefore determined the effect and mechanism of action of miR-233 in Fas-induced hepatocyte apoptosis and liver injury. Wild-type (WT) and miR-223 knockout (KO) mice were treated i.p. with 0.5 MUg/g body weight anti-Fas antibody Jo2, and the animals were monitored for survival and the extent of liver injury. Although WT mice died 4 to 6 hours after Jo2 injection (n = 6), all of the miR-223 KO mice (n = 6) survived. In comparison to WT mice, the miR-223 KO mice showed resistance to Fas-induced liver injury, as indicated by less tissue damage under histopathological examination, fewer apoptotic hepatocytes under caspase-3 immunostaining, and less elevation of serum transaminases. miR-223 KO livers showed less caspase-3, caspase-8, and caspase-9 activation and less poly (ADP-ribose) polymerase cleavage compared with WT livers (P < 0.05). Furthermore, tail vein injection of miR-223 lentiviral vector to miR 223 KO mice restored Jo2-induced liver injury. Transfection of miR-223 KO hepatocytes with miR-223 mimic enhanced Jo2-induced activation of caspase-3, caspase-8, and caspase-9, whereas transfection of WT hepatocytes with the miR-223 inhibitor attenuated Jo2-induced apoptosis. These findings demonstrate that miR 223 deficiency protects against Fas-induced hepatocyte apoptosis and liver injury. Further in vitro and in vivo data indicate that miR-223 regulates Fas induced hepatocyte apoptosis and liver injury by targeting the insulin-like growth factor 1 receptor. PMID- 26598235 TI - Myofibroblastic Conversion and Regeneration of Mesothelial Cells in Peritoneal and Liver Fibrosis. AB - Mesothelial cells (MCs) form a single epithelial layer and line the surface of body cavities and internal organs. Patients who undergo peritoneal dialysis often develop peritoneal fibrosis that is characterized by the accumulation of myofibroblasts in connective tissue. Although MCs are believed to be the source of myofibroblasts, their contribution has remained obscure. We determined the contribution of peritoneal MCs to myofibroblasts in chlorhexidine gluconate (CG) induced fibrosis compared with that of phenotypic changes of liver MCs. CG injections resulted in disappearance of MCs from the body wall and the accumulation of myofibroblasts in the connective tissue. Conditional linage tracing with Wilms tumor 1 (Wt1)-CreERT2 and Rosa26 reporter mice found that 17% of myofibroblasts were derived from MCs in peritoneal fibrosis. Conditional deletion of transforming growth factor-beta type II receptor in Wt1(+) MCs substantially reduced peritoneal fibrosis. The CG treatment also induced myofibroblastic conversion of MCs in the liver. Lineage tracing with Mesp1-Cre mice revealed that Mesp1(+) mesoderm gave rise to liver MCs but not peritoneal MCs. During recovery from peritoneal fibrosis, peritoneal MCs, but not liver MCs, contribute to the regeneration of the peritoneal mesothelium, indicating an inherent difference between parietal and visceral MCs. In conclusion, MCs partially contribute to myofibroblasts in peritoneal and liver fibrosis, and protection of the MC layer leads to reduced development of fibrous tissue. PMID- 26598236 TI - Osteoprotective Effects of IL-33/ST2 Link to Osteoclast Apoptosis. AB - The relevance of IL-33 and its receptor ST2 for bone remodeling is not well defined. Our aim was to assess the role and underlying mechanisms of IL-33/ST2 in mechanically induced bone remodeling. BALB/c (wild type) and ST2 deficient (St2( /-)) mice were subjected to mechanical loading in alveolar bone. Microtomography, histology, and real-time quantitative PCR were performed to analyze bone parameters, apoptosis and bone cell counts, and expression of bone remodeling markers, respectively. MC3T3-E1 osteoblastic cells and bone marrow cells were used to verify if mechanical force triggered IL-33 and ST2 expression as well as the effects of IL-33 on osteoclast differentiation and activity. Mechanical loading increased the expression of IL-33 and ST2 in alveolar bone in vivo and in osteoblastic cells in vitro. St2(-/-) mice had increased mechanical loading induced bone resorption, number of osteoclasts, and expression of proresorptive markers. In contrast, St2(-/-) mice exhibited reduced numbers of osteoblasts and apoptotic cells in periodontium and diminished expression of osteoblast signaling molecules. In vitro, IL-33 treatment inhibited osteoclast differentiation and activity even in the presence of receptor activator of NF-kappaB ligand. IL-33 also increased the expression of pro-apoptotic molecules, including Bcl-2 associated X protein (BAX), cell-surface Fas receptor (FAS), FASL, FAS-associated death domain, tumor necrosis factor-related apoptosis-inducing ligand, and BH3 interacting-domain death (BID). Overall, these findings suggest that IL-33/ST2 have anti-osteoclastogenic effects and reduce osteoclast formation and activity by inducing their apoptosis. PMID- 26598237 TI - Does a Microphthalmia-Associated Transcription Factor-Pigment Epithelium-Derived Factor Axis Exist in All Types of Pigment Cells? AB - This Correspondence relates to the article by Dadras et al (A Novel Role for Microphthalmia-Associated Transcription Factor-Regulated Pigment Epithelium Derived Factor during Melanoma Progression. Am J Pathol 2015, 185:252-265). PMID- 26598238 TI - Protein Structure Is Related to RNA Structural Reactivity In Vivo. AB - We assessed whether in vivo mRNA structural reactivity and the structure of the encoded protein are related. This is the first investigation of such a relationship that utilizes information on RNA structure obtained in living cells. Based on our recent genome-wide Structure-seq analysis in Arabidopsis thaliana, we report that, as a meta property, regions of individual mRNAs that code for protein domains generally have higher reactivity to DMS (dimethyl sulfate), a chemical that covalently modifies accessible As and Cs, than regions that encode protein domain junctions. This relationship is prominent for proteins annotated for catalytic activity and reversed in proteins annotated for binding and transcription regulatory activity. Upon analyzing intrinsically disordered proteins, we found a similar pattern for disordered regions as compared to ordered regions: regions of individual mRNAs that code for ordered regions have significantly higher DMS reactivity than regions that code for intrinsically disordered regions. Based on these effects, we hypothesize that the decreased DMS reactivity of RNA regions that encode protein domain junctions or intrinsically disordered regions may reflect increased RNA structure that may slow translation, allowing time for the nascent protein domain or ordered region of the protein to fold, thereby reducing protein misfolding. In addition, a drop in DMS reactivity was observed on portions of mRNA sequences that correspond to the C-termini of protein domains, suggesting ribosome protection at these mRNA regions. Structural relationships between mRNAs and their encoded proteins may have evolved to allow efficient and accurate protein folding. PMID- 26598239 TI - [Comments about: "Anterior mandibular bone augmentation techniques. Literature review"]. PMID- 26598240 TI - [Pseudo-tumoral aspergillus rhinosinusitis: About two cases]. AB - INTRODUCTION: Pseudo-tumoral fongal rhinosinusitis is a rare and benign illness due to saprophyte germ, Aspergillus flavus. OBSERVATION: We reported two cases of invasive pseudo-tumoral fongal rhinosinusitis. CT scan helped with diagnosis and allowed for extension assessment. Complete surgical excision was done through external approach. Bacteriological examination evidenced the germ. DISCUSSION: Pseudo-tumoral invasive fongal rhinosinusitis remains a potentially serious pathology because of its local aggressiveness and its multiple extensions. PMID- 26598241 TI - [Transoral coronoidectomy: Technical note]. AB - INTRODUCTION: Among the skeletal causes of limited mouth opening, uni- or bilateral coronoid process hypertrophy, or Langenbeck disease, is the most frequent. It can be associated with an osteochondroma or a coronoid-malar bone conflict and is then called Jacob disease, an unilateral pathology. Treatment rests on coronoidectomy in both cases. This technique is illustrated via two cases, one Langenbeck and one Jacob disease. TECHNICAL NOTE: A transoral approach was performed. After subperiosteal dissection, the coronoid process was cleared. The process was than severed at its base by means of a burr, freed from its temporal muscular fibers and removed. Mouth opening improved peroperatively. The surgical procedure was completed by active long-term physiotherapy beginning immediately after surgery. DISCUSSION: Transoral coronoidectomy is a simple, quick and safe procedure. Extra-oral approaches present a high risk of facial nerve injury. In our first case, mouth opening improved from 24 to 36 mm after bilateral coronoidectomy and to 40 mm after physiotherapy. In our second case, mouth opening improved from 22 to 38 mm after unilateral coronoidectomy and to 43 mm after one year physiotherapy. Long-term post-operative physiotherapy is mandatory to get and maintain good results. PMID- 26598242 TI - [The use of deoxycholic acid (ATX-101) in aesthetic medicine: A promising treatment]. AB - ATX-101 is a synthetic derivative from deoxycholic acid, which leads to destruction of adipocytes and to a skin retraction. The US Food and Drug Administration (FDA) has authorized ATX-101 injections for reduction of moderate to severe submental fat. The purpose of this note is to review the data of literature regarding the deoxycholic acid (ATX-101) where a significant difference for the submental fat between the treated group and the placebo group according to clinical and morphological criteria was observed (Refine Study 1 and 2). Side effects of this molecule seems to be limited. PMID- 26598243 TI - Computer-aided design and computer-aided modeling (CAD/CAM) generated surgical splints, cutting guides and custom-made implants: Which indications in orthognathic surgery? AB - INTRODUCTION: The purpose of the present report was to describe our indications, results and complications of computer-aided design and computer-aided modeling CAD/CAM surgical splints, cutting guides and custom-made implants in orthognathic surgery. PATIENTS AND METHODS: We analyzed the clinical and radiological data of ten consecutive patients with dentofacial deformities treated using a CAD/CAM technique. Four patients had surgical splints and cutting guides for correction of maxillomandibular asymmetries, three had surgical cutting guides and customized internal distractors for correction of severe maxillary deficiencies and three had custom-made implants for additional chin contouring and/or mandibular defects following bimaxillary osteotomies and sliding genioplasty. We recorded age, gender, dentofacial deformity, surgical procedure and intra- and postoperative complications. RESULTS: All of the patients had stable cosmetic results with a high rate of patient satisfaction at the 1-year follow-up examination. No intra- and/or postoperative complications were encountered during any of the different steps of the procedure. DISCUSSION: This study demonstrated that the application of CAD/CAM patient-specific surgical splints, cutting guides and custom-made implants in orthognathic surgery allows for a successful outcome in the ten patients presented in this series. PMID- 26598245 TI - NH4(+) Resides Inside the Water 20-mer Cage As Opposed to H3O(+), Which Resides on the Surface: A First Principles Molecular Dynamics Simulation Study. AB - Experimental vibrational predissociation spectra of the magic NH4(+)(H2O)20 clusters are close to those of the magic H3O(+)(H2O)20 clusters. It has been assumed that the geometric features of NH4(+)(H2O)20 clusters might be close to those of H3O(+)(H2O)20 clusters, in which H3O(+) resides on the surface. Car Parrinello molecular dynamics simulations in conjunction with density functional theory calculations are performed to generate the infrared spectra of the magic NH4(+)(H2O)20 clusters. In comparison with the experimental vibrational predissociation spectra of NH4(+)(H2O)20, we find that NH4(+) is inside the cage structure of NH4(+)(H2O)20 as opposed to on the surface structure. This shows a clear distinction between the structures of NH4(+)(H2O)20 and H3O(+)(H2O)20 as well as between the hydration phenomena of NH4(+) and H3O(+). PMID- 26598244 TI - In vitro digestion and fermentation characteristics of canola co-products simulate their digestion in the pig intestine. AB - Canola co-products are sources of amino acid and energy in pig feeds, but their fermentation characteristics in the pig intestine are unknown. Thus, we determined the in vitro fermentation characteristics of the canola co-products Brassica juncea solvent-extracted canola meal (JSECM), Brassica napus solvent extracted canola meal (NSECM), B. napus expeller-pressed canola meal (NEPCM) and B. napus cold-pressed canola cake (NCPCC) in comparison with soybean meal (SBM). Samples were hydrolysed in two steps using pepsin and pancreatin. Subsequently, residues were incubated in a buffer solution with fresh pig faeces as inocula for 72 h to measure gas production. Concentration of volatile fatty acids (VFA) per gram of dry matter (DM) of feedstuff was measured in fermented solutions. Apparent ileal digestibility (AID) and apparent hindgut fermentation (AHF) of gross energy (GE) for feedstuffs were obtained from pigs fed the same feedstuffs. On DM basis, SBM, JSECM, NSECM, NEPCM and NCPCC contained 15, 19, 22, 117 and 231 g/kg ether extract; and 85, 223, 306, 208 and 176 g/kg NDF, respectively. In vitro digestibility of DM (IVDDM) of SBM (82.3%) was greater (P<0.05) than that of JSECM (68.5%), NSECM (63.4%), NEPCM (67.5%) or NCPCC (69.8%). The JSECM had greater (P<0.05) IVDDM than NSECM. The IVDDM for NSECM was lower (P<0.05) than that for NEPCM, which was lower (P<0.05) than that for NCPCC. Similarly, AID of GE was greatest for SBM followed by NCPCC, JSECM, NEPCM and then NSECM. Total VFA production for SBM (0.73 mmol/g) was lower (P<0.05) than that of JSECM (1.38 mmol/g) or NSECM (1.05 mmol/g), but not different from that of NEPCM (0.80 mmol/g) and NCPCC (0.62 mmol/g). Total VFA production of JSECM was greater (P<0.05) than that of NSECM. Total VFA production of NSECM was greater (P<0.05) than that of NEPCM or NCPCC, which differed (P<0.05). The ranking of feedstuffs for total VFA production was similar to AHF of GE. In conclusion, in vitro fermentation characteristics of canola co-products and SBM simulated their fermentation in the small and large intestine of pigs, respectively. The 30% greater VFA production for JSECM than NSECM due to lower lignified fibre of JSECM indicates that fermentation characteristics differ between canola species. The NSECM had the highest fermentability followed by NEPCM and then NCPCC, indicating that fat in canola co-products can limit their fermentability in the hindgut. PMID- 26598246 TI - How Different Are Aromatic pi Interactions from Aliphatic pi Interactions and Non pi Stacking Interactions? AB - We compare aromatic pi interactions with aliphatic pi interactions of double- and triple-bonded pi systems and non-pi stacking interactions of single-bonded sigma systems. The model dimer systems of acetylene (C2H2)2, ethylene (C2H4)2, ethane (C2H6)2, benzene (C6H6)2, and cyclohexane (C6H12)2 are investigated. The ethylene dimer has large dispersion energy, while the acetylene dimer has strong electrostatic energy. The aromatic pi interactions are strong with particularly large dispersion and electrostatic energies, which would explain why aromatic compounds are frequently found in crystal packing and molecular self-engineering. It should be noted that the difference in binding energy between the benzene dimer (aromatic-aromatic interactions) and the cyclohexane dimer (aliphatic aliphatic interactions) is not properly described in most density functionals. PMID- 26598247 TI - Use of Direct Dynamics Simulations to Determine Unimolecular Reaction Paths and Arrhenius Parameters for Large Molecules. AB - In a previous study (J. Chem. Phys.2008, 129, 094701) it was shown that for a large molecule, with a total energy much greater than its barrier for decomposition and whose vibrational modes are harmonic oscillators, the expressions for the classical Rice-Ramsperger-Kassel-Marcus (RRKM) (i.e., RRK) and classical transition-state theory (TST) rate constants become equivalent. Using this relationship, a molecule's unimolecular rate constants versus temperature may be determined from chemical dynamics simulations of microcanonical ensembles for the molecule at different total energies. The simulation identifies the molecule's unimolecular pathways and their Arrhenius parameters. In the work presented here, this approach is used to study the thermal decomposition of CH3-NH-CH?CH-CH3, an important constituent in the polymer of cross-linked epoxy resins. Direct dynamics simulations, at the MP2/6 31+G* level of theory, were used to investigate the decomposition of microcanonical ensembles for this molecule. The Arrhenius A and Ea parameters determined from the direct dynamics simulation are in very good agreement with the TST Arrhenius parameters for the MP2/6-31+G* potential energy surface. The simulation method applied here may be particularly useful for large molecules with a multitude of decomposition pathways and whose transition states may be difficult to determine and have structures that are not readily obvious. PMID- 26598248 TI - Bipolar Reaction Path Hamiltonian Approach for Reactive Scattering Problems. AB - In this work we present a method for calculating the stationary state wave functions and reaction probabilities of a multidimensional reactive scattering system. Our approach builds upon the counter-propagating wave methodology (CPWM) developed by Poirier and co-workers for calculating one-dimensional stationary state wave functions. The method involves the formulation of a bipolar decomposition for multidimensional stationary scattering wave functions within the context of a reaction path Hamiltonian, so we refer to this work as the bipolar reaction path Hamiltonian (BRPH) approach. Benchmark calculations are presented for several 2D model scattering systems with linear reaction coordinates. We show that the BRPH approach is competitive with conventional calculations based on discrete variable representation (DVR) methods. PMID- 26598249 TI - On the Intramolecular Hydrogen Bond in Solution: Car-Parrinello and Path Integral Molecular Dynamics Perspective. AB - The issue of the symmetry of short, low-barrier hydrogen bonds in solution is addressed here with advanced ab initio simulations of a hydrogen maleate anion in different environments, starting with the isolated anion, going through two crystal structures (sodium and potassium salts), then to an aqueous solution, and finally in the presence of counterions. By Car-Parrinello and path integral molecular dynamics simulations, it is demonstrated that the position of the proton in the intramolecular hydrogen bond of an aqueous hydrogen maleate anion is entirely related to the solvation pattern around the oxygen atoms of the intramolecular hydrogen bond. In particular, this anion has an asymmetric hydrogen bond, with the proton always located on the oxygen atom that is less solvated, owing to the instantaneous solvation environment. Simulations of water solutions of hydrogen maleate ion with two different counterions, K(+) and Na(+), surprisingly show that the intramolecular hydrogen-bond potential in the case of the Na(+) salt is always asymmetric, regardless of the hydrogen bonds to water, whereas for the K(+) salt, the potential for H motion depends on the location of the K(+). It is proposed that repulsion by the larger and more hydrated K(+) is weaker than that by Na(+) and competitive with solvation by water. PMID- 26598250 TI - Magnetic Coupling in Transition-Metal Binuclear Complexes by Spin-Flip Time Dependent Density Functional Theory. AB - Spin-flip time-dependent density functional theory (SF-TDDFT) has been applied to predict magnetic coupling constants for a database of 12 spin-1/2 homobinuclear transition-metal complexes previously studied by Phillips and Peralta employing spin-projected broken-symmetry density functional theory (Phillips, J. J.; Peralta, J. E. J. Chem. Phys.2011, 134, 034108). Several global hybrid density functionals with a range of percentages of Hartree-Fock exchange from 20% to 100% have been employed within the collinear-spin formalism, and we find that both the high-spin reference state and low-spin state produced by SF-TDDFT are generally well adapted to spin symmetry. The magnetic coupling constants are calculated from singlet-triplet energy differences and compared to values arising from the popular broken-symmetry approach. On average, for the density functionals that provide the best comparison with experiment, the SF-TDDFT approach performs as well as or better than the spin-projected broken-symmetry strategy. The constrained density functional approach also performs quite well. The SF-TDDFT magnetic coupling constants show a much larger dependence on the percentage of Hartree-Fock exchange than on the other details of the exchange functionals or the nature of the correlation functionals. In general, SF-TDDFT calculations not only avoid the ambiguities associated with the broken-symmetry approach, but also show a considerably reduced systematic deviation with respect to experiment and a larger antiferromagnetic character. We recommend MPW1K as a well-validated hybrid density functional to calculate magnetic couplings with SF-TDDFT. PMID- 26598251 TI - Toward Reliable DFT Investigations of Mn-Porphyrins through CASPT2/DFT Comparison. AB - The low-energy spectroscopies of Mn(II) and Mn(III) porphyrin (P) complexes were investigated using complete active space and subsequent perturbative treatment (CASPT2) as well as DFT-based calculations. Starting from DFT optimizations of Mn(II)P and Mn(III)PCl using crystallographic data, the CASPT2 results show that whatever the relative position of the Mn(II) ion with respect to the porphyrin cavity, the high-spin state S = 5/2 of the [MnP] unit lies much lower in energy than the intermediate S = 3/2 state. Not only are these results in agreement with experimental observations but they also differ from previous theoretical conclusions. In the Mn(III) complexes, sigma and pi charge redistributions compete to result in a S = 2 ground state. The performances of different functionals have been tested in the reproduction of the CASPT2 spin gaps. Our results confirm that the Mn(II) system is very challenging, as GGA functionals fail in the spin states ordering and in the reproduction of the gaps, unless a high percentage of exact HF exchange (55%), as in KMLYP, is incorporated. This inspection demonstrates the need for specific active space functional to investigate the low-energy spectroscopy of [MnP] units. PMID- 26598252 TI - Energy-Specific Linear Response TDHF/TDDFT for Calculating High-Energy Excited States. AB - An energy-specific TDHF/TDDFT method is introduced in this article for excited state calculations. This approach extends the conventional TDHF/TDDFT implementation to obtain excited states above a predefined energy threshold. The method introduced and developed in this work enables computationally efficient yet rigorous calculations of energy-specific spectra, e.g., X-ray absorption involving extremely high-energy transitions. All transitions are solved in the full molecular orbital space, and orthogonality to the ground state and lower lying excited states is preserved for each high-energy excited state. Encouraging computational savings are observed in calculating the targeted energy spectrum, while the transition energies, as well as oscillator strengths, remain identical to the results from the standard implementation. PMID- 26598253 TI - Two-Dimensional Scan of the Performance of Generalized Gradient Approximations with Perdew-Burke-Ernzerhof-Like Enhancement Factor. AB - We assess the performance of the whole class of functionals defined by the Perdew Burke-Ernzerhof (PBE) exchange-correlation enhancement factor, by performing a two-dimensional scan of the MU and kappa parameters (keeping beta fixed by the recovery of the local density approximation linear response). We consider molecular (atomization energies, bond lengths, and vibrational frequencies), intermolecular (hydrogen-bond and dipole interactions), and solid-state (lattice constant and cohesive energies) properties. We find, for the energetical properties, a whole family of functionals (with MU and kappa interrelated) giving very similar results and the best accuracy. Overall, we find that the original PBE and the recently proposed APBE functional [Phys. Rev. Lett.2011, 106, 186406], based on the asymptotic expansion of the semiclassical neutral atom, give the highest global accuracy, with a definite superior performance of the latter for all of the molecular properties. PMID- 26598254 TI - Determination of Local Spins by Means of a Spin-Free Treatment. AB - This work describes a Mulliken-type partitioning of the expectation value of the spin-squared operator corresponding to an N-electron system. Our algorithms, which are based on a spin-free formulation, predict appropriate spins for the molecular fragments (at equilibrium geometries and at dissociation limits) and can be applied to any spin symmetry. Numerical determinations performed in selected closed- and open-shell systems at correlated level are reported. A comparison between these results and their counterpart ones arising from other alternative approaches is analyzed in detail. PMID- 26598255 TI - Comprehensive Benchmarking of a Density-Dependent Dispersion Correction. AB - Standard density functional approximations cannot accurately describe interactions between nonoverlapping densities. A simple remedy consists in correcting for the missing interactions a posteriori, adding an attractive energy term summed over all atom pairs. The density-dependent energy correction, dDsC, presented herein, is constructed from dispersion coefficients computed on the basis of a generalized gradient approximation to Becke and Johnson's exchange hole dipole moment formalism. dDsC also relies on an extended Tang and Toennies damping function accounting for charge-overlap effects. The comprehensive benchmarking on 341 diverse reaction energies divided into 18 illustrative test sets validates the robust performance and general accuracy of dDsC for describing various intra- and intermolecular interactions. With a total MAD of 1.3 kcal mol( 1), B97-dDsC slightly improves the results of M06-2X and B2PLYP-D3 (MAD = 1.4 kcal mol(-1) for both) at a lower computational cost. The density dependence of both the dispersion coefficients and the damping function makes the approach especially valuable for modeling redox reactions and charged species in general. PMID- 26598256 TI - Influence of Triplet Instabilities in TDDFT. AB - Singlet and triplet vertical excitation energies from time-dependent density functional theory (TDDFT) can be affected in different ways by the inclusion of exact exchange in hybrid or Coulomb-attenuated/range-separated exchange correlation functionals; in particular, triplet excitation energies can become significantly too low. To investigate these issues, the explicit dependence of excitation energies on exact exchange is quantified for four representative molecules, paying attention to the effect of constant, short-range, and long range contributions. A stability analysis is used to verify that the problematic TDDFT triplet excitations can be understood in terms of the ground state triplet instability problem, and it is proposed that a Hartree-Fock stability analysis should be used to identify triplet excitations for which the presence of exact exchange in the TDDFT functional is undesirable. The use of the Tamm-Dancoff approximation (TDA) significantly improves the problematic triplet excitation energies, recovering the correct state ordering in benzoquinone; it also affects the corresponding singlet states, recovering the correct state ordering in naphthalene. The impressive performance of the TDA is maintained for a wide range of molecules across representative functionals. PMID- 26598257 TI - Assessment of Popular DFT and Semiempirical Molecular Orbital Techniques for Calculating Relative Transition State Energies and Kinetic Product Distributions in Enantioselective Organocatalytic Reactions. AB - The performance of computationally accessible levels of calculation for the transition states of organocatalytic reaction has been assessed. Reference post Hartree-Fock single point energy calculations were used as standards for the gas phase Born-Oppenheimer relative energies of pairs of alternative transition states that lead to the two product enantiomers. We show that semiempirical methods cannot even be relied on to yield qualitatively correct results. The geometries (optimized, for instance, with DFT) have a large impact on the results of high-level post-HF calculations, so that it is essential to use an adequate DFT technique and basis set. DFT can yield quantitatively correct results that are consistent with post-HF calculations if functionals that consider dispersion are used. Geometries for large systems show larger errors than those for smaller ones but are treated better by functionals such as M06-2X and w97Bxd that include dispersion implicitly or explicitly. Local correlation techniques introduce errors of comparable magnitude to those given by different levels of geometry optimization. We recommend RICC2/TZVP//M06-2X/TZVP, RI-MP2/TZVP// M06-2X/TZVP, and M06-2X/TZVP// M06-2X/TZVP calculations in that order, depending on the size of the system. PMID- 26598258 TI - Time-Reversible Velocity Predictors for Verlet Integration with Velocity Dependent Right-Hand Side. AB - Time-reversible velocity predictors (TRVPs) with increasing orders of the time reversibility error are developed to be used with the Verlet integrator for equations of motion with the right-hand side depending on velocities. The method performs outside a possible SHAKE algorithm to constrain bond lengths and does not require repeated SHAKE iterations nor RATTLE. We have tested the TRVPs with the Nose-Hoover thermostat on four model systems (coupled harmonic and anharmonic oscillators, liquid argon, SPC/E water, and a small peptide), comparing them to the Gear integrator with the Lagrangian formulation of constraint dynamics, the Martyna, Tuckerman, Tobias, and Klein (MTTK) method, and the velocity iteration method. The TRVP method performs similarly to the iteration method. In addition, we discuss three methodology improvements: (i) We tested several formulas for the kinetic energy compatible with the Verlet/SHAKE algorithm and found that the leapfrog velocities are usually the best; (ii) we proposed two modifications of the MTTK method; and (iii) we suggest that thermostats directly controlling the translational kinetic temperature may give more accurate values of some thermodynamic quantities. PMID- 26598259 TI - Adaptive-Partitioning Redistributed Charge and Dipole Schemes for QM/MM Dynamics Simulations: On-the-fly Relocation of Boundaries that Pass through Covalent Bonds. AB - Recently, Heyden, Lin, and Truhlar (J. Phys. Chem. B2007, 111, 2231-2241) formularized the adaptive-partitioning schemes for quantum mechanical and molecular mechanical (QM/MM) molecular dynamics simulations. The adaptive partitioning schemes permit on-the-fly reclassification of atoms/groups as part of the QM or MM subsystems during dynamics simulations. Test simulations of argon atoms in a periodic box with dual-level MM potentials in the microcanonical ensemble demonstrated that the adaptive-partitioning schemes conserved energy and momentum, which is critical to ensure correct sampling of configuration spaces of desired ensembles. In this work, we reported the extension of the adaptive partitioning schemes to deal with groups that are molecular fragments. The newly developed adaptive-partitioning redistributed charge scheme and adaptive partitioning redistributed charge and dipole schemes allow on-the-fly relocation of the QM/MM boundaries that cut through covalent bonds during dynamics simulations. Test QM/MM simulations with a variety of QM levels of theory in the microcanonical ensembles demonstrated that the new schemes conserve energy and momentum. PMID- 26598260 TI - Linear-Scaling Time-Dependent Density Functional Theory Based on the Idea of "From Fragments to Molecule". AB - To circumvent the cubic scaling and convergence difficulties encountered in the standard top-down localization of the global canonical molecular orbitals (CMOs), a bottom-up localization scheme is proposed based on the idea of "from fragments to molecule". That is, the global localized MOs (LMOs), both occupied and unoccupied, are to be synthesized from the primitive fragment LMOs (pFLMOs) obtained from subsystem calculations. They are orthonormal but are still well localized on the parent fragments of the pFLMOs and can hence be termed as "fragment LMOs" (FLMOs). This has been achieved by making use of two important factors. Physically, it is the transferability of the locality of the fragments that serves as the basis. Mathematically, it is the special block-diagonalization of the Kohn-Sham matrix that allows retention of the locality: The occupied occupied and virtual-virtual diagonal blocks are only minimally modified when the occupied-virtual off-diagonal blocks are annihilated. Such a bottom-up localization scheme is applicable to systems composed of all kinds of chemical bonds. It is then shown that, by a simple prescreening of the particle-hole pairs, the FLMO-based time-dependent density functional theory (TDDFT) can achieve linear scaling with respect to the system size, with a very small prefactor. As a proof of principle, representative model systems are taken as examples to demonstrate the accuracy and efficiency of the algorithms. As both the orbital picture and integral number of electrons are retained, the FLMO-TDDFT offers a clear characterization of the nature of the excited states in line with chemical/physical intuition. PMID- 26598261 TI - Some Comments on Topological Approaches to the pi-Electron Currents in Conjugated Systems. AB - Within the past two years, three sets of independent authors (Mandado, Ciesielski et al., and Randic) have proposed methods in which pi-electron currents in conjugated systems are estimated by invoking the concept of circuits of conjugation. These methods are here compared with ostensibly similar approaches published more than 30 years ago by two of the present authors (Gomes and Mallion) and (likewise independently) by Gayoso. Patterns of bond currents and ring currents computed by these methods for the nonalternant isomer of coronene that was studied by Randic are also systematically compared with those calculated by the Huckel-London-Pople-McWeeny (HLPM) "topological" approach and with the ab initio, "ipso-centric" current-density maps of Balaban et al. These all agree that a substantial diamagnetic pi-electron current flows around the periphery of the selected structure (which could be thought of as a "perturbed" [18] annulene), and consideration is given to the differing trends predicted by these several methods for the pi-electron currents around its central six-membered ring and in its internal bonds. It is observed that, for any method in which calculated pi-electron currents respect Kirchhoff's Laws of current conservation at a junction, consideration of bond currents-as an alternative to the more traditional ring currents-can give a different insight into the magnetic properties of conjugated systems. However, provided that charge/current conservation is guaranteed-or Kirchhoff's First Law holds for bond currents instead of the more-general current-densities-then ring currents represent a more efficient way of describing the molecular reaction to the external magnetic field: ring currents are independent quantities, while bond currents are not. PMID- 26598262 TI - MSINDO-sCIS: A New Method for the Calculation of Excited States of Large Molecules. AB - Theoretical background, parametrization, and performance of the semiempirical configuration interaction singles (CIS) method MSINDO-sCIS designed for the calculation of optical spectra of large organic molecules are presented. The CIS Hamiltonian is modified by scaling of the Coulomb and exchange integrals and a semiempirical correction. For a recently proposed benchmark set of 28 medium sized organic molecules, vertical excitation energies for singlet and triplet states are calculated and statistically evaluated. A full reparameterization of the MSINDO method for both ground and excited state properties was necessary. The results of the reparameterized MSINDO-sCIS method are compared to the currently best semiempirical method for excited states, OM3-CISDTQ, and to other standard methods, such as MNDO and INDO/S. The mean absolute deviation with respect to the theoretical best estimates (TBEs) for MSINDO-sCIS is 0.44 eV, comparable to the OM3 method but significantly smaller than for INDO/S. The computational effort is strongly reduced compared to OM3-CISDTQ and OM3-MRCISD, since only single excitations are taken into account. Higher excitations are implicitly included by parametrization and an empirical correction term. By application of the Davidson Liu block diagonalization method, high computational efficiency is achieved. Furthermore, it is demonstrated that the MSINDO-sCIS method correctly describes charge-transfer (CT) states that represent a problem for time-dependent density functional theory (TD-DFT) methods. PMID- 26598263 TI - Excited-State Studies of Polyacenes: A Comparative Picture Using EOMCCSD, CR EOMCCSD(T), Range-Separated (LR/RT)-TDDFT, TD-PM3, and TD-ZINDO. AB - The low-lying excited states (La and Lb) of polyacenes from naphthalene to heptacene (N = 2-7) are studied using various time-dependent computational approaches. We perform high-level excited-state calculations using equation of motion coupled cluster with singles and doubles (EOMCCSD) and completely renormalized equation of motion coupled cluster with singles, doubles, and perturbative triples (CR-EOMCCSD(T)) and use these results to evaluate the performance of various range-separated exchange-correlation functionals within linear-response (LR) and real-time (RT) time-dependent density functional theories (TDDFT). As has been reported recently, we find that the range-separated family of functionals addresses the well-documented TDDFT failures in describing these low-lying singlet excited states to a large extent and are as about as accurate as results from EOMCCSD on average. Real-time TDDFT visualization shows that the excited state charged densities are consistent with the predictions of the perimeter free electron orbital (PFEO) model. This corresponds to particle-on a-ring confinement, which leads to the well-known red-shift of the excitations with acene length. We also use time-dependent semiempirical methods like TD-PM3 and TD-ZINDO, which are capable of handling very large systems. Once reparametrized to match the CR-EOMCCSD(T) results, TD-ZINDO becomes roughly as accurate as range-separated TDDFT, which opens the door to modeling systems such as large molecular assemblies. PMID- 26598264 TI - Dual Fluorescence of Fluorazene in Solution: A Computational Study. AB - The fluorazene molecule presents dual fluorescence in polar solvents. Its absorption and emission properties in gas phase and in acetonitrile solution have been studied theoretically using the complete active space second-order perturbation//complete active space self-consistent field quantum methodology and average solvent electrostatic potential from molecular dynamics for the solvent effects. In gas phase, two optimized excited-state geometries were obtained, one of them corresponds to a local excitation (LE), and the other is an intramolecular charge transfer (ICT) and lies higher in energy. In acetonitrile solution, a second ICT structure where the molecule remains planar is found, and the energy differences are reduced. Fluorescence energies from LE and the planar ICT have a good agreement with the experimental bands, but emission from the bent ICT has too low an energy. PMID- 26598265 TI - Accurate Anharmonic Vibrational Frequencies for Uracil: The Performance of Composite Schemes and Hybrid CC/DFT Model. AB - The vibrational spectrum (frequencies as well as intensities) of uracil has been investigated at a high level of theory. The harmonic force field has been evaluated at the coupled-cluster (CC) level in conjunction with a triple-zeta basis set. Extrapolation to the basis set limit as well as inclusion of core correlation and diffuse-function corrections have been considered by means of the second-order Moller-Plesset perturbation theory. To go beyond the harmonic approximation, a hybrid CC/DFT approach has been employed, which will be proved to provide state-of-the-art results. As the spectroscopic investigation of uracil is hampered by numerous Fermi resonances, models for explicitly taking them into account have been implemented and applied. On general grounds, the computational procedure presented is able to provide the proper accuracy to support experimental investigations of large molecules of biological interest. PMID- 26598266 TI - Polarizable Force Fields and Polarizable Continuum Model: A Fluctuating Charges/PCM Approach. 1. Theory and Implementation. AB - We present a combined fluctuating charges-polarizable continuum model approach to describe molecules in solution. Both static and dynamic approaches are discussed: analytical first and second derivatives are shown as well as an extended lagrangian for molecular dynamics simluations. In particular, we use the polarizable continuum model to provide nonperiodic boundary conditions for molecular dynamics simulations of aqueous solutions. The extended lagrangian method is extensively discussed, with specific reference to the fluctuating charge model, from a numerical point of view by means of several examples, and a rationalization of the behavior found is presented. Several prototypical applications are shown, especially regarding solvation of ions and polar molecules in water. PMID- 26598267 TI - Insights into the Solvation and Mobility of the Hydroxyl Radical in Aqueous Solution. AB - A detailed description of the local solvation structure and mobility of hydroxyl radicals (OH*) in aqueous solution near ambient conditions is provided by Car Parrinello molecular dynamics simulations. Here, we demonstrate that for HCTH/120 and BLYP functionals, smaller systems (i.e., 31.H2O-OH*) are contaminated by system size effects, being biased for the presence of a three-electron two centered hemibond structure between the oxygen atoms of a water molecule and the radical. Radial and spatial distribution functions of relatively large 63.H2O-OH* systems reveal the existence of a 4-fold coordinated "inactive" OH* structure with three H-bond donating neighbors and a strongly coordinated H-bond accepting neighbor. The local hydration structure around the radical exhibits more H-bond ordering than has been predicted by recent simulations employing classical force fields. Local structural fluctuations can end with spontaneous H-transfer reactions from the nearest H-bond donor water molecule, facilitated by the formation of an "active" OH* state, resembling the proton transfer mechanism of hydrated OH(-) (i.e., slight polarization of the (H3O2)* complex). A comparison of the free energy barriers for the H-transfer reaction obtained by both DFT functionals and for both system sizes is also provided, demonstrating that this can be a very rapid process in water. PMID- 26598268 TI - Accurate Molecular Crystal Lattice Energies from a Fragment QM/MM Approach with On-the-Fly Ab Initio Force Field Parametrization. AB - We combine quantum and classical mechanics in a fragment-based many-body interaction model to predict organic molecular crystal lattice energies. Individual molecules in the central unit cell and their short-range pairwise interactions are modeled quantum mechanically, while long-range pairwise and many body interactions are approximated classically. The classical contributions are evaluated using an accurate ab initio force field that is constructed on-the-fly from quantum mechanical calculations on the individual molecules in the unit cell. The force field parameters include ab initio distributed multipole moments, distributed polarizabilities, and isotropic two- and three-body atomic dispersion coefficients. This QM/MM fragment model reproduces full periodic MP2 lattice energies to within a couple kJ/mol at substantially reduced cost. When high-level electronic structure methods are coupled with the ab initio force field, molecular crystal lattice energies are predicted to within 2 kJ/mol of their experimental values for six of the seven crystals examined here. Finally, Axilrod Teller-Muto three-body dispersion energy plays a nontrivial role in several of the molecular crystals studied here. PMID- 26598269 TI - Comparison of the Efficiency of the LIE and MM/GBSA Methods to Calculate Ligand Binding Energies. AB - We have evaluated the efficiency of two popular end-point methods to calculate ligand-binding free energies, LIE (linear interaction energy) and MM/GBSA (molecular mechanics with generalized Born surface-area solvation), i.e. the computational effort needed to obtain estimates of a similar precision. As a test case, we use the binding of seven biotin analogues to avidin. The energy terms used by MM/GBSA and LIE exhibit a similar correlation time (~5 ps), and the equilibration time seems also to be similar, although it varies much between the various ligands. The results show that the LIE method is more effective than MM/GBSA, by a factor of 2-7 for a truncated spherical system with a radius of 26 A and by a factor of 1.0-2.4 for the full avidin tetramer (radius 47 A). The reason for this is the cost for the MM/GBSA entropy calculations, which more than compensates for the extra simulation of the free ligand in LIE. On the other hand, LIE requires that the protein is neutralized, whereas MM/GBSA has no such requirements. Our results indicate that both the truncation and neutralization of the proteins may slow the convergence and emphasize small differences in the calculations, e.g., differences between the four subunits in avidin. Moreover, LIE cannot take advantage of the fact that avidin is a tetramer. For this test case, LIE gives poor results with the standard parametrization, but after optimizing the scaling factor of the van der Waals terms, reasonable binding affinities can be obtained, although MM/GBSA still gives a significantly better predictive index and correlation to the experimental affinities. PMID- 26598270 TI - A New Coarse-Grained Force Field for Membrane-Peptide Simulations. AB - We present a new coarse-grained (CG) model for simulations of lipids and peptides. The model follows the same topology and parametrization strategy as the MARTINI force field but is based on our recently developed big multipole water (BMW) model for water (J. Phys. Chem. B2010, 114, 10524-10529). The new BMW MARTINI force field reproduces many fundamental membrane properties and also yields improved energetics (when compared to the original MARTINI force-field) for the interactions between charged amino acids with lipid membranes, especially at the membrane-water interface. A stable attachment of cationic peptides (e.g., Arg8) to the membrane surface is predicted, consistent with experiment and in contrast to the MARTINI model. The model predicts electroporation when there is a charge imbalance across the lipid bilayer, an improvement over the original MARTINI. Moreover, the pore formed during electroporation is toroidal in nature, similar to the prediction of atomistic simulations but distinct from results of polarizable MARTINI for small charge imbalances. The simulations emphasize the importance of a reasonable description of the electrostatic properties of water in CG simulations. The BMW-MARTINI model is particularly suitable for describing interactions between highly charged peptides with lipid membranes, which is crucial to the study of antimicrobial peptides, cell penetrating peptides, and other proteins/peptides involved in the remodeling of biomembranes. PMID- 26598271 TI - A New Approach for Investigating the Molecular Recognition of Protein: Toward Structure-Based Drug Design Based on the 3D-RISM Theory. AB - A new approach to investigate a molecular recognition process of protein is presented based on the three-dimensional reference interaction site model (3D RISM) theory, a statistical mechanics theory of molecular liquids. Numerical procedure for solving the conventional 3D-RISM equation consists of two steps. In step 1, we solve ordinary RISM (or 1D-RISM) equations for a solvent mixture including target ligands in order to obtain the density pair correlation functions (PCF) among molecules in the solution. Then, we solve the 3D-RISM equation for a solute-solvent system to find three-dimensional density distribution functions (3D-DDF) of solvent species around a protein, using PCF obtained in the first step. A key to the success of the method was to regard a target ligand as one of "solvent" species. However, the success is limited due to a difficulty of solving the 1D-RISM equation for a solvent mixture, including large ligand molecules. In the present paper, we propose a method which eases the limitation concerning solute size in the conventional method. In this approach, we solve a solute-solute 3D-RISM equations for a protein-ligand system in which both proteins and ligands are regarded as "solutes" at infinite dilution. The 3D- and 1D-RISM equations are solved for protein-solvent and ligand-solvent systems, respectively, in order to obtain the 3D- and 1D-DDF of solvent around the solutes, which are required for solving the solute-solute 3D-RISM equation. The method is applied to two practical and noteworthy examples concerning pharmaceutical design. One is an odorant binding protein in the Drosophila melanogaster , which binds an ethanol molecule. The other is phospholipase A2, which is known as a receptor of acetylsalicylic acid or aspirin. The result indicates that the method successfully reproduces the binding mode of the ligand molecules in the binding sites measured by the experiments. PMID- 26598272 TI - Unraveling the Molecular Mechanism of Enthalpy Driven Peptide Folding by Polyol Osmolytes. AB - Many polyols and carbohydrates serve in different organisms as protective osmolytes that help to stabilize proteins in their native, functional state, even under a variety of environmental stresses. However, despite their important role, much of the molecular mechanism by which these osmolytes exert their action remains elusive. We have recently shown experimentally that, although polyols and carbohydrates are excluded from protein and peptide interfaces, as also expected for the known entropic "crowding" mechanism, the osmolyte folding action can in fact primarily be enthalpic in nature. To follow this newly resolved enthalpically driven stabilization mechanism, we report here on molecular dynamics simulations of a model peptide that can fold in solution into a beta hairpin. In agreement with experiments, our simulations indicate that sorbitol, a representative polyol, promotes peptide folding by preferential exclusion. At the molecular level, simulations further show that peptide stabilization can be explained by sorbitol's perturbation of the solution hydrogen bonding network in the peptide first hydration shells. Consequently, fewer hydrogen bonds between peptide and solvating water are lost upon folding, and additional internal peptide hydrogen bonds are formed in the presence of sorbitol, while internal peptide and water-associated hydrogen bonds are strengthened, resulting in stabilization of the peptide folded state. We further find that changes in water orientational entropy are reduced upon folding in sorbitol solution, reflecting the struggle of water molecules to maintain optimal hydrogen bonding in the presence of competing polyols. By providing first molecular underpinnings for enthalpically driven osmolyte stabilization of peptides and proteins, this mechanism should allow a better understanding of the variety of physical forces by which protective osmolytes act in biologically realistic solutions. PMID- 26598273 TI - A Simple Mechanism Underlying the Effect of Protecting Osmolytes on Protein Folding. AB - Osmolytes are small organic compounds that confer to the cell an enhanced adaptability to external conditions. Many osmolytes not only protect the cell from osmotic stress but also stabilize the native structure of proteins. While simplified models able to predict changes to protein stability are available, a general physicochemical explanation of the underlying microscopic mechanism is still missing. Here, we address this issue by performing very long all-atom MD simulations, free energy calculations, and experiments on a well-characterized mini-protein, the villin headpiece. Comparisons between the folding free energy landscapes in pure water and osmolyte solutions, together with experimental validation by means of circular dichroism, unfolding experiments, and NMR, led us to formulate a simple hypothesis for the protecting mechanism. Taken together, our results support a novel mechanistic explanation according to which the main driving force behind native state protection is a change in the solvent rotational diffusion. PMID- 26598274 TI - On the possible cause of distinct El Nino types in the recent decades. AB - Distinct El Nino types have been observed in the recent decades with warm anomalies in the eastern Pacific (Canonical El Nino, EL) and central Pacific (El Nino Modoki, EM). Among these, a basinwide tropical Pacific (TP) warming is seen during 2009 and recently during 2014. We carried out data analysis and numerical simulation experiments to understand the possible cause for different El Nino flavours. The results reveal that the co-evolution of ocean-atmospheric conditions are critically important. Stronger boreal spring (Mar-May) through summer (June-September) westerly wind anomalies (WWA), with relatively stronger ocean pre-conditioning can lead to EL, weaker ocean pre-conditioning and weaker WWA can generate EM, while stronger ocean preconditioning and weaker WWA can lead to basinwide warming pattern. The strength of the WWA is crucial in determining the strength of the ocean dynamic response and the thermocline displacements in the Pacific. The study has important implications for understanding the nature of El Nino in advance. PMID- 26598275 TI - Chaperone BAG6 is dispensable for MHC class I antigen processing and presentation. AB - Antigen processing for direct presentation on MHC class I molecules is a multistep process requiring the concerted activity of several cellular complexes. The essential steps at the beginning of this pathway, namely protein synthesis at the ribosome and degradation via the proteasome, have been known for years. Nevertheless, there is a considerable lack of factors identified to function between protein synthesis and degradation during antigen processing. Here, we analyzed the impact of the chaperone BAG6 on MHC class I cell surface expression and presentation of virus-derived peptides. Although an essential role of BAG6 in antigen processing has been proposed previously, we found BAG6 to be dispensable in this pathway. Still, interaction of BAG6 and the model antigen tyrosinase was enhanced during proteasome inhibition pointing towards a role of BAG6 in antigen degradation. Redundant chaperone pathways potentially mask the contribution of BAG6 to antigen processing and presentation. PMID- 26598276 TI - "Bind and Crawl" Association Mechanism of Leishmania major Peroxidase and Cytochrome c Revealed by Brownian and Molecular Dynamics Simulations. AB - Leishmania major, the parasitic causative agent of leishmaniasis, produces a heme peroxidase (LmP), which catalyzes the peroxidation of mitochondrial cytochrome c (LmCytc) for protection from reactive oxygen species produced by the host. The association of LmP and LmCytc, which is known from kinetics measurements to be very fast (~10(8) M(-1) s(-1)), does not involve major conformational changes and has been suggested to be dominated by electrostatic interactions. We used Brownian dynamics simulations to investigate the mechanism of formation of the LmP-LmCytc complex. Our simulations confirm the importance of electrostatic interactions involving the negatively charged D211 residue at the LmP active site, and reveal a previously unrecognized role in complex formation for negatively charged residues in helix A of LmP. The crystal structure of the D211N mutant of LmP reported herein is essentially identical to that of wild-type LmP, reinforcing the notion that it is the loss of charge at the active site, and not a change in structure, that reduces the association rate of the D211N variant of LmP. The Brownian dynamics simulations further show that complex formation occurs via a "bind and crawl" mechanism, in which LmCytc first docks to a location on helix A that is far from the active site, forming an initial encounter complex, and then moves along helix A to the active site. An atomistic molecular dynamics simulation confirms the helix A binding site, and steady state activity assays and stopped-flow kinetics measurements confirm the role of helix A charges in the association mechanism. PMID- 26598277 TI - A low vitamin D status at diagnosis is associated with an early conversion to secondary progressive multiple sclerosis. AB - Low circulating 25-hydroxyvitamin D (25(OH)D) levels have been associated with an increased risk of relapses in relapsing remitting multiple sclerosis (RRMS), but an association with disability progression is uncertain. Lower 25(OH)D levels are found in secondary progressive MS (SPMS) when compared to RRMS. We hypothesized that a poor vitamin D status in RRMS is associated with an increased risk of conversion to SPMS. In a retrospective longitudinal study we measured 25(OH)D levels at the start of a 3-year follow-up, and analyzed whether these levels predict the risk of RRMS to SPMS conversion. In 338 RRMS patients, vitamin D status did not predict the 3-year risk of conversion to SPMS (n=51; OR 0.970; p=0.65). However, in diagnostic blood samples of SPMS patients with a relatively short RRMS duration (n=19) 25(OH)D levels were significantly lower (38nmol/L; Q1 Q3: 24-50) than in diagnostic samples of matched RRMS patients with no progression to SPMS ((n=38; 55nmol/L; Q1-Q3: 40-70) (p<0.01). These data indicate an association between a low vitamin D status at the start of RRMS and the early conversion to SPMS. Therefore, time to SPMS conversion is of interest as clinical measure in (follow-up of) clinical vitamin D supplementation studies. PMID- 26598278 TI - Progesterone neuroprotection: The background of clinical trial failure. AB - Since the first pioneering studies in the 1990s, a large number of experimental animal studies have demonstrated the neuroprotective efficacy of progesterone for brain disorders, including traumatic brain injury (TBI). In addition, this steroid has major assets: it easily crosses the blood-brain-barrier, rapidly diffuses throughout the brain and exerts multiple beneficial effects by acting on many molecular and cellular targets. Moreover, progesterone therapies are well tolerated. Notably, increased brain levels of progesterone are part of endogenous neuroprotective responses to injury. The hormone thus emerged as a particularly promising protective candidate for TBI and stroke patients. The positive outcomes of small Phase 2 trials aimed at testing the safety and potential protective efficacy of progesterone in TBI patients then provided support and guidance for two large, multicenter, randomized and placebo-controlled Phase 3 trials, with more than 2000 TBI patients enrolled. The negative outcomes of both trials, named ProTECT III and SyNAPSE, came as a big disappointment. If these trials were successful, progesterone would have become the first efficient neuroprotective drug for brain-injured patients. Thus, progesterone has joined the numerous neuroprotective candidates that have failed in clinical trials. The aim of this review is a reappraisal of the preclinical animal studies, which provided the proof of concept for the clinical trials, and we critically examine the design of the clinical studies. We made efforts to present a balanced view of the strengths and limitations of the translational studies and of some serious issues with the clinical trials. We place particular emphasis on the translational value of animal studies and the relevance of TBI biomarkers. The probability of failure of ProTECT III and SyNAPSE was very high, and we present them within the broader context of other unsuccessful trials. PMID- 26598279 TI - The efficacy, bioavailability and safety of a novel hydroalcoholic testosterone gel 2% in hypogonadal men: results from phase II open-label studies. AB - Pharmacokinetics, pharmacodynamics and safety of a novel hydroalcoholic testosterone gel 2% (TG) were evaluated in phase II sequential dose escalation studies using 3 application sites (thigh, abdomen and shoulder/upper arm) and 2 application methods. Hypogonadal men (n = 40), 18-75 years, with serum testosterone <300 ng dl(-1) were included in both studies. Study 1 evaluated hand applied multiple doses of TG 1.25, 2.50 and 3.75 ml (23, 46 and 70 mg of testosterone, respectively), once daily for 10 days to shoulder/upper arm. Study 2 evaluated applicator-applied (TG 1.25, 2.50 and 3.75 ml) versus hand-applied (TG 2.5 ml) doses, once daily for 7 days to shoulder/upper arm. Primary endpoint for both studies was responder rate (Cave testosterone levels between 298 and 1050 ng dl(-1) ). In Study 1 following multiple applications, >70% participants in each group were responders. Dose-dependent increase was observed in PK values for total testosterone, free testosterone and DHT. In Study 2, responder rate was dose proportional: 16.7%, 50.0% and 77.8% responders in TG 1.25, 2.50 and 3.75 ml groups respectively. The bioavailability was highest for the shoulder application. There was a significant improvement in almost all the domains of sexual functioning. Applicator-application was preferred over hand-application by majority of the participants. TG was found to be safe and well tolerated in hypogonadal men. PMID- 26598280 TI - Dosage compensation of X-chromosome inactivation center-linked genes in porcine preimplantation embryos: Non-chromosome-wide initiation of X-chromosome inactivation in blastocysts. AB - X-chromosome inactivation (XCI) is an epigenetic mechanism that occurs in the eutherian embryo development to equalize the dosage of X-linked genes between males and females. This event is regulated by various factors, and the genes located in the X-chromosome inactivation center (XIC), which is known to be an evolutionary conserved region, are associated with XCI; however, a number of studies regarding this epigenetic event and genomic region are primarily performed in mouse models despite its species-specific features. Thus, in this study, the porcine XIC was identified, and we analyzed the expression of XIC linked genes in porcine preimplantation embryos. Comparative sequence analysis revealed that the porcine XIC is synteny with that of human and the non-coding RNAs were less conserved compared with the protein coding genes in the XIC. Among the XIC-linked genes, the expression levels of CHIC1 and RLIM were decreased from morula to blastocyst development and their dosage was compensated between the male and female blastocysts. Additionally, the CpG sites of CHIC1 were approximately 50% methylated in parthenote blastocysts. Contrary to these genes, XIST and LOC102165544, an uncharacterized non-coding gene, showed dramatically increased expression levels after the morula stage and preferential female expression in blastocysts. Imprinted XIST expression was not observed, and their CpG sites were hypo-methylated in parthenogenic blastocysts. These results demonstrate that the porcine XIC consists of an evolutionary conserved structure with fewer sequences conserved non-coding RNAs. In addition, a few XIC-linked genes would likely achieve dosage compensation, but XCI would not be completed in porcine blastocysts. PMID- 26598282 TI - Removal of Cr(III) from chrome tanning wastewater by adsorption using two natural carbonaceous materials: Eggshell and powdered marble. AB - In the present paper, eggshell and powdered marble, two carbonaceous materials, were used to remove Cr(III) ions from a real chrome tanning wastewater. The effects of initial effluent pH, adsorbent dose, contact time and temperature were studied. The maximum uptake of chromium ions was obtained at pH 5.0 with the dose 20 g L(-1) and 12 g L(-1) for eggshell and powdered marble respectively. Adsorption equilibrium was reached after 14 h contact time for eggshell and only after 30 min for powdered marble. Under these conditions, almost 99% Cr(III) was removed from chrome tanning wastewater having an initial concentration of chromium of 3.21 g L(-1). Kinetic data were satisfactorily described by a pseudo second order chemical sorption model. The equilibrium rate constant was notably greater for powdered marble than for eggshell with 1.142.10(-3) (g mg(-1) min( 1)) and 0.041.10(-3) (g mg(-1) min(-1)) respectively. The adsorption isotherm were well described by a Langmuir model and showed that the interaction of chromium with the two adsorbents surface is a localized monolayer adsorption with a smaller energy constant for the powdered marble than for eggshell (0.020 (L mg( 1)) and 0.083 (L mg(-1)) respectively). The powdered marble was able to adsorb faster a large amount of Cr (III) in comparison to eggshell. The use of a standardized lettuce seed bioassay allowed evaluating a better effectiveness of the Cr adsorption on the powdered marble, removing up to 40% of the treated effluent toxicity than by eggshell 25%. The powdered marble could be considered as an effective, low cost carbonaceous material to be used for chromium removal from tanning wastewater. PMID- 26598283 TI - Simultaneous removal of Ni(II), As(III), and Sb(III) from spiked mine effluent with metakaolin and blast-furnace-slag geopolymers. AB - The mining industry is a major contributor of various toxic metals and metalloids to the aquatic environment. Efficient and economical water treatment methods are therefore of paramount importance. The application of natural or low-cost sorbents has attracted a great deal of interest due to the simplicity of its process and its potential effectiveness. Geopolymers represent an emerging group of sorbents. In this study, blast-furnace-slag and metakaolin geopolymers and their raw materials were tested for simultaneous removal of Ni(II), As(III) and Sb(III) from spiked mine effluent. Blast-furnace-slag geopolymer proved to be the most efficient of the studied materials: the experimental maximum sorption capacities for Ni, As and, Sb were 3.74 mg/g, 0.52 mg/g, and 0.34 mg/g, respectively. Although the capacities were relatively low due to the difficult water matrix, 90-100% removal of Ni, As, and Sb was achieved when the dose of sorbent was increased appropriately. Removal kinetics fitted well with the pseudo second-order model. Our results indicate that geopolymer technology could offer a simple and effective way to turn blast-furnace slag to an effective sorbent with a specific utilization prospect in the mining industry. PMID- 26598281 TI - Hormonal control of cold stress responses in plants. AB - Cold stress responses in plants are highly sophisticated events that alter the biochemical composition of cells for protection from damage caused by low temperatures. In addition, cold stress has a profound impact on plant morphologies, causing growth repression and reduced yields. Complex signalling cascades are utilised to induce changes in cold-responsive gene expression that enable plants to withstand chilling or even freezing temperatures. These cascades are governed by the activity of plant hormones, and recent research has provided a better understanding of how cold stress responses are integrated with developmental pathways that modulate growth and initiate other events that increase cold tolerance. Information on the hormonal control of cold stress signalling is summarised to highlight the significant progress that has been made and indicate gaps that still exist in our understanding. PMID- 26598284 TI - Use of a temporary supramalleolar orthosis to manage foot pain in a patient with rheumatoid arthritis: A case report. AB - BACKGROUND: Rheumatoid arthritis is a chronic inflammatory condition characterized by joint pain, stiffness, and functional disability. Approximately 90% of patients will report symptoms in the foot or ankle during the course of their disease. CASE DESCRIPTION: A case of a 40-year-old woman with a 12-year history of rheumatoid arthritis referred to outpatient physical therapy with a chief complaint of pain in the lateral rearfoot and forefoot is presented. At the time of the initial examination, the patient reported persistent pain ranging from 3 to 9/10, aggravated when standing and walking during activities of daily living. Treatment consisted of the fabrication of a supramalleolar orthosis that incorporated an in-shoe foot orthosis to address functional limitations and abnormal foot and ankle posture. A home exercise program was prescribed to address potential balance deficits and strength loss following the application of the orthosis. OUTCOMES: Clinically significant improvements were seen in pain, gait speed, and on the Foot Function Index following the implementation of the orthotic device. The patient returned to standing and walking with minimal symptom limitations. DISCUSSION: This case report highlights the short-term clinical outcomes when using a supramalleolar orthosis in conjunction with an in shoe foot orthosis to manage lateral rearfoot and forefoot pain in a patient with rheumatoid arthritis. PMID- 26598285 TI - Gestational surrogacy and the role of routine embryo screening: Current challenges and future directions for preimplantation genetic testing. AB - Preimplantation genetic screening (PGS) is a component of IVF entailing selection of an embryo for transfer on the basis of chromosomal normalcy. If PGS were integrated with single embryo transfer (SET) in a surrogacy setting, this approach could improve pregnancy rates, minimize miscarriage risk, and limit multiple gestations. Even without PGS, pregnancy rates for IVF surrogacy cases are generally satisfactory, especially when treatment utilizes embryos derived from young oocytes and transferred to a healthy surrogate. However, there could be a more general role for PGS in surrogacy, since background aneuploidy in embryos remains a major factor driving implantation failure and miscarriage for all infertility patients. At present, the proportion of IVF cases involving GS is limited, while the number of IVF patients requesting PGS appears to be increasing. In this report, the relevance of PGS for surrogacy in the rapidly changing field of assisted fertility medicine is discussed. PMID- 26598286 TI - Can pet keeping be considered the only criterion of exposure to cat/dog allergens in the first year of life? PMID- 26598287 TI - Training community-based primary care physicians in the screening and management of mental health disorders among Latino primary care patients. AB - OBJECTIVE: To evaluate a quality improvement intervention to improve the screening and management (e.g., referral to psychiatric care) of common mental disorders in small independent Latino primary care practices serving patient populations of predominantly low-income Latino immigrants. METHODS: In seven practices, academic detailing and consultation/liaison psychiatry were first implemented (Stage 1) and then supplemented with appointment scheduling and reminders to primary care physicians (PCPs) by clinic staff (Stage 2). Acceptability and feasibility were assessed with independent patient samples during each stage. RESULTS: Participating PCP found the interventions acceptable and noted that referrals to language-matched specialty care and case-by-case consultation on medication management were particularly beneficial. The academic detailing and consultation/liaison intervention (Stage 1) did not significantly affect PCP screening, management or patient satisfaction with care. When support for appointment scheduling and reminders (Stage 2) was added, however, PCP referral to psychiatric services increased (P=.04), and referred patients were significantly more likely to follow through and have more visits to mental health professionals (P=.04). CONCLUSION: Improving the quality of mental health care in low-resourced primary care settings may require academic detailing and consultation/liaison psychiatric intervention supplemented with staff outreach to achieve meaningful improvement in the processes of care. PMID- 26598288 TI - Prevalence of probable mental disorders and help-seeking behaviors among veteran and non-veteran community college students. AB - OBJECTIVE: Millions of disadvantaged youth and returning veterans are enrolled in community colleges. Our objective was to determine the prevalence of mental disorders and help-seeking behaviors among community college students. METHODS: Veterans (n=211) and non-veterans (n=554) were recruited from 11 community colleges and administered screeners for depression (PHQ-9), generalized anxiety (GAD-7), posttraumatic stress disorder (PC-PTSD), non-lethal self-injury, suicide ideation and suicide intent. The survey also asked about the perceived need for, barriers to and utilization of services. Regression analysis was used to compare prevalence between non-veterans and veterans adjusting for non-modifiable factors (age, gender and race/ethnicity). RESULTS: A large proportion of student veterans and non-veterans screened positive and unadjusted bivariate comparisons indicated that student veterans had a significantly higher prevalence of positive depression screens (33.1% versus 19.5%, P<.01), positive PTSD screens (25.7% versus 12.6%, P<.01) and suicide ideation (19.2% versus 10.6%, P=.01). Adjusting for age, gender and race/ethnicity, veterans were significantly more likely than non-veterans to screen positive for depression (OR=2.10, P=.01) and suicide ideation (OR=2.31, P=.03). Student veterans had significantly higher odds of perceiving a need for treatment than non-veterans (OR=1.93, P=.02) but were more likely to perceive stigma (beta=0.28, P=.02). Despite greater need among veterans, there were no significant differences between veterans and non-veterans in use of psychotropic medications, although veterans were more likely to receive psychotherapy (OR=2.35, P=.046). CONCLUSIONS: Findings highlight the substantial gap between the prevalence of probable mental health disorders and treatment seeking among community college students. Interventions are needed to link community college students to services, especially for student veterans. PMID- 26598290 TI - "You Blame Me, Therefore I Blame Me": The Importance of First Disclosure Partner Responses on Trauma-Related Cognitions and Distress. AB - Trauma recovery processes may be understood within a socioecological model. Individual factors (such as sex of the survivor) and microsystem factors (including trauma characteristics) have been studied extensively. However, there is a paucity of research examining the effects of macrosystem factors on the impact of trauma-especially examining how the response of the first person to whom the survivor disclosed affects trauma-related cognitions and distress. Sixty three college student participants reported a history of disclosing at least one traumatic event in an online, anonymous survey. Participants also provided information on the first person they told about the trauma, the social reactions of that person, general social reactions to trauma disclosure, the participants' trauma-related cognitions and psychological distress (PTSD, other mental health issues), details about the traumatic event, and basic demographic information. Paired sample t tests showed that participants experienced the responses of the first person they told about their trauma as more favorable than the responses of the all of the people to whom they told about the event. Women and survivors of non-interpersonal trauma reported more supportive responses than men and survivors of interpersonal trauma. Hierarchical linear regressions showed that interpersonal trauma and victim blame on the part of the first person the survivor told were associated with more negative trauma-related cognitions. Interpersonal trauma, emotional support, and victim blame were associated with a greater degree of trauma-related distress. The results suggest that participants perceived the response of the first person they told as more beneficial than the response of the rest of their exosystem. However, the reactions of the first person the survivor told differed based on the sex of the survivor and the type of trauma they experienced. Consistent with previous research, interpersonal trauma and victim blame by the first person the survivor told about the trauma were associated with more trauma-related distress and negative cognitions. Trauma related distress was also associated with greater emotional support by the disclosure partner. The results support the use of the socioeological model to better understand the complex nature of trauma recovery and have implications for prevention. PMID- 26598289 TI - Donepezil-associated manic episode with psychotic features: a case report and review of the literature. AB - OBJECTIVE: Reports of manic episodes associated with the use of cholinesterase inhibitors (including donepezil) are limited. Despite the previous notion of procholinergic drugs potentially inducing depression, the contemporary evidence for cholinesterase inhibitors appears to also indicate a trend for elevated mood (in patients with or without a history of depressive disorder). METHOD: Case report. RESULTS: The authors report a case of a manic episode with psychotic features associated with the up-titration of donepezil in a patient with Alzheimer's disease and a distant history of major depression but without a preexisting bipolar disorder. CONCLUSION: Pathophysiology of donepezil-induced mania appears to contradict the traditional cholinergic-adrenergic hypothesis. Donepezil-associated mania should be suspected after donepezil initiation/dose up titration when correlated to new onset of mania. Donepezil should be used more cautiously in patients with current or previous mood episodes or in those who are otherwise at high risk for manic episodes (e.g., cerebrovascular disease). Although this requires further investigation in different patient populations, there may be subtypes of older patients with neurocognitive disorders who are particularly vulnerable to activation effects of cholinesterase inhibitors. PMID- 26598291 TI - Intimate Partner Violence in the First 2 Years of Life: Implications for Toddlers' Behavior Regulation. AB - Intimate partner violence (IPV) is prevalent in families with young children and challenges their healthy development. This study examined characteristics of IPV (e.g., mother- vs. partner-perpetrated, types and severity) and investigated potential effects of IPV on toddlers' behavioral regulation in a sample of families at risk for IPV. We also examined whether maternal depression and child rearing attitudes and behavior would moderate IPV-child behavior links. These questions were addressed in a sample ( N = 400) of first-time adolescent mothers and their toddlers (1-2 years of age). Families were visited in their homes; data were collected via maternal report and observations. Partner- and self perpetrated IPV was assessed using the Conflict Tactics Scale questionnaire; child behavior regulation was measured using the Brief Infant-Toddler Social and Emotional Assessment questionnaire. Approximately 80% of families experienced psychological aggression; almost one third reported physical assault in the past year. Both physical and psychological IPV were associated with greater toddler behavior problems. Neither maternal depression, mothers' attitudes about corporal punishment, nor nonhostile interaction moderated IPV-behavior problem links, though mothers' reports of maltreating behavior did. Among children whose mothers did not use corporal punishment/physical violence, IPV did not differentially affect behavior problems. Children whose mothers used corporal punishment/physical violence with them showed behavior problems in the context of IPV (severe psychological aggression). Results underscore the importance of exposure to IPV during the first year of life, and the prevalence of IPV perpetrated by both mothers and their partners in families with adolescent mothers. PMID- 26598292 TI - Strain and Opportunity: A Theory of Repeat Victimization. AB - General strain theory is often applied to explain the origin of deviant behavior, while the risky lifestyles and opportunities perspective is often used to examine the ongoing risk for victimization. However, given evidence that the delinquent coping mechanisms operationalized by the general strain tests and the risky behaviors measured in the risky lifestyles models are often the same behaviors, the current study argues that these two models can be constructed as a uniform framework to explain the onset and continuity of victimization, including involvement in delinquency, from childhood through adolescence. Experiences of child maltreatment are posited to trigger feelings of negative emotions more likely managed with forms of coping that can foster opportunities for suffering further victimization. Using data from the first three waves of the National Longitudinal Study of Adolescent Health (Add Health), the results show that youth who adopt maladaptive forms of coping with childhood abuse and neglect, including engaging in substance abuse, running away from home, and drug selling, are at further risk for subsequent experiences of victimization in adolescence. However, the model provides only one pathway linking child maltreatment to adolescent victimization, and the strength of support varies based on the measures of negative emotions and coping strategies. PMID- 26598293 TI - Managing the Threat of Violence: Coping Strategies Among Juvenile Inmates. AB - This article reports findings on violence, safety, and coping strategies from interviews conducted with 281 male youth incarcerated in California's Division of Juvenile Justice (DJJ). Descriptive analyses revealed that youth report that violence is a common occurrence and that some locations, such as school or housing units, were particularly dangerous. Analysis of how youth avoid violence revealed three distinct precautionary or coping strategies. These three categories highlight a range of conflict management techniques from avoidance to aggression. Those youth who were younger, sex offenders, or newer to the facility used more passive avoidance techniques while gang members and those more active in violent misconduct used more aggressive techniques. A third group, those youth proactively navigating their interactions, had spent more time in their current institution and were marginally more likely to be adult court commitments. Intervention and policy implications of this study are also discussed. PMID- 26598294 TI - Dynamin-related protein 1 mediates mitochondria-dependent apoptosis in chlorpyrifos-treated SH-SY5Y cells. AB - Recent studies have demonstrated that dynamin-related protein 1 (Drp1), a mitochondrial fission protein, mediates mitochondria-dependent apoptosis through mitochondrial division. However, little is known about the mechanism by which Drp1 modulates apoptosis in response to chlorpyrifos (CPF)-induced toxicity. In this study, we determined that CPF-induced mitochondrial apoptosis is mediated by Drp1 translocation in SH-SY5Y human neuroblastoma cells. Our results showed that CPF treatment induced intrinsic apoptosis by activating caspase-9, caspase-3, and cytochrome c release in SH-SY5Y cells. Cytosolic Drp1 translocated to the mitochondria in CPF-treated cells and was phosphorylated at Ser616. Treating cells with CPF induced the generation of reactive oxygen species (ROS) and activation of mitogen-activated protein kinases (MAPKs). Inhibiting this ROS generation and MAPK activation abolished CPF-induced expression of phospho-Drp1. Furthermore, Drp1 was required for p53 to translocate to the mitochondria under CPF-induced oxidative stress. Treating cells with mitochondrial-division inhibitor-1 (mdivi-1), which blocks Drp1 translocation, increased the viability of CPF-treated cells by abrogating Drp1 translocation and caspase-3 activation. Specifically, pretreating cells with mdivi-1 inhibited Bax translocation to the mitochondria by blocking p53 signaling. Taken together, these data reveal a novel mechanism by which Drp1 activates mitochondrial-dependent apoptosis and indicate that inhibiting Dpr1 function can protect against CPF-induced cytotoxicity. We propose that inhibiting Drp1 is a possible therapeutic approach for pesticide induced toxicity when hyperactivated Drp1 contributes to pathology. PMID- 26598296 TI - Organocatalytic Synthesis of Fused Bicyclic 2,3-Dihydro-1,3,4-oxadiazoles through an Intramolecular Cascade Cyclization. AB - Hydrazone-carboxylic acids undergo intramolecular cyclization in the presence of pivaloyl chloride, iPr(2)NEt, and catalytic DABCO to form a range of substituted fused tricyclic 2,3-dihydro-1,3,4-oxadiazoles in high yields. PMID- 26598297 TI - Integrating Studies on Plant-Pollinator and Plant-Herbivore Interactions. AB - Research on herbivore-induced plant defence and research on pollination ecology have had a long history of separation. Plant reproduction of most angiosperm species is mediated by pollinators, and the effects of herbivore-induced plant defences on pollinator behaviour have been largely neglected. Moreover, there is expected to be a trade-off between plant reproductive strategies and defence mechanisms. To investigate this trade-off, it is essential to study herbivore induced plant resistance and allocation of resources by plants, within the same system, and to test if indirect plant resistance can conflict with pollinator attraction. Here, I review the key literature highlighting connection between plant defence and reproduction, and propose to exploit natural variation among plant species to assess the ecological costs of plant responses to herbivores and pollinators. PMID- 26598295 TI - Individual differences in orexin-I receptor modulation of motivation for the opioid remifentanil. AB - Orexin-1 receptors (Ox1Rs) have been implicated in the motivation for drugs of abuse. Here, we utilized a within-session behavioral-economics threshold procedure to screen for individual differences in economic demand for the ultra short-acting opioid remifentanil and to test whether antagonism of Ox1Rs reduces remifentanil demand. The behavioral-economics procedure revealed robust individual differences in free consumption of remifentanil (Q0 parameter; hedonic set point). Rats with low baseline Q0 (low takers) displayed high demand elasticity (alpha parameter; reduced responding as drug price increased indicating low motivation for drug), whereas subjects with a higher Q0 (high takers) exhibit low demand elasticity (low alpha) by continuing to self administer remifentanil despite increased cost (reflecting higher motivation for drug). In a punished responding paradigm utilizing footshock, subjects that were classified as high takers at baseline withstood twice as much shock as low takers to continue self-administering remifentanil. Interestingly, Ox1R antagonism with SB-334867 reduced Q0 and increased alpha in low takers but not in high takers. Similarly, the Ox1R antagonist attenuated cue-induced, but not drug-induced, reinstatement of remifentanil seeking in low takers but had no significant effect on reinstatement of drug seeking in high takers. Together, these data reveal a novel role of orexins in demand for remifentanil: Ox1Rs modulate demand in low takers but not in individuals that exhibit addictive-like behaviors (high takers). Finally, the behavioral assays in this study can serve as a novel laboratory model for studying individual differences in opioid use disorders. PMID- 26598298 TI - Autophagy in Plants--What's New on the Menu? AB - Autophagy is a major cellular degradation pathway in eukaryotes. Recent studies have revealed the importance of autophagy in many aspects of plant life, including seedling establishment, plant development, stress resistance, metabolism, and reproduction. This is manifested by the dual ability of autophagy to execute bulk degradation under severe environmental conditions, while simultaneously to be highly selective in targeting specific compartments and protein complexes to regulate key cellular processes, even during favorable growth conditions. Delivery of cellular components to the vacuole enables their recycling, affecting the plant metabolome, especially under stress. Recent research in Arabidopsis has further unveiled fundamental mechanistic aspects in autophagy which may have relevance in non-plant systems. We review the most recent discoveries concerning autophagy in plants, touching upon all these aspects. PMID- 26598299 TI - Increasing Use of Long-Acting Reversible Contraception to Decrease Unplanned Pregnancy. AB - Unintended pregnancy remains high in the United States, accounting for one-half of pregnancies. Both contraceptive nonuse and imperfect use contribute to unplanned pregnancies. Long-acting reversible contraception (LARC) have greater efficacy than shorter acting methods. Data from large studies show that unplanned pregnancy rates are lower among women using LARC. However, overall use of LARC is low; of the reproductive age women using contraception, less than 10% are LARC users. Barriers include lack of knowledge and high up-front cost, and prevent more widespread use. Overcoming these barriers and increasing the number of women using LARC will decrease unplanned pregnancies and abortions. PMID- 26598300 TI - Immediate Postpartum Intrauterine Contraception Insertion. AB - The immediate postpartum period is a favorable time for initiating contraception because women who have recently given birth are often highly motivated to use contraception, pregnancy is excluded, and the hospital setting offers convenience for patients and providers. This article addresses immediate postpartum intrauterine contraception (IUC) insertion for copper and levonorgestrel IUC. Immediate postpartum IUC is safe and effective, with a majority of IUC devices retained at 6 and 12 months. There are increased rates of expulsion, compared with delayed postpartum insertion and interval insertion, which need to be weighed against the risk of patients not returning for postpartum follow-up. PMID- 26598301 TI - Immediate Intrauterine Device Insertion Following Surgical Abortion. AB - Placement of an intrauterine device (IUD) immediately after a first or second trimester surgical abortion is safe and convenient and decreases the risk of repeat unintended pregnancy. Immediate postabortion IUD placement is not recommended in the setting of postprocedure hemorrhage, uterine perforation, infection, or hematometra. Otherwise, there are few contraindications to IUD placement following surgical abortion. Sexually transmitted infection screening should follow US Centers for Disease Control and Prevention guidelines. No additional antibiotics are needed beyond those used for the abortion. Placing immediate postabortion IUDs makes highly-effective long-acting reversible contraception more accessible to women. PMID- 26598302 TI - Therapeutic Options for Unscheduled Bleeding Associated with Long-Acting Reversible Contraception. AB - Long-acting reversible contraception (LARC) is the most effective form of reversible contraception. Although most women are satisfied with LARC methods, unscheduled bleeding and spotting are common reasons for method dissatisfaction and discontinuation. This systematic analysis of the current literature delineates treatment options for unscheduled bleeding related to LARC use. Although consistent results are lacking, all devices seem to have the best response to nonsteroidal antiinflammatory drugs for 5 to 7 days or the antifibrinolytic agent tranexamic acid. Additional studies are necessary to identify improved treatment interventions for unscheduled bleeding with LARC use. PMID- 26598303 TI - Contraceptive Coverage and the Affordable Care Act. AB - A major goal of the Patient Protection and Affordable Care Act is reducing healthcare spending by shifting the focus of healthcare toward preventive care. Preventive services, including all FDA-approved contraception, must be provided to patients without cost-sharing under the ACA. No-cost contraception has been shown to increase uptake of highly effective birth control methods and reduce unintended pregnancy and abortion; however, some institutions and corporations argue that providing contraceptive coverage infringes on their religious beliefs. The contraceptive coverage mandate is evolving due to legal challenges, but it has already demonstrated success in reducing costs and improving access to contraception. PMID- 26598304 TI - Over-the-Counter Access to Oral Contraceptives. AB - Making oral contraceptives (OCs) available over the counter (OTC) could help to reduce the high rate of unintended pregnancy in the United States. Surveys show widespread support for OTC access to OCs among US women. Studies indicate that women can accurately use checklists to identify contraindications to OCs. Continuation is as good or better among OTC users compared with women using OCs obtained by prescription. Women and clinicians have expressed concerns related to making OCs available OTC. These concerns can be addressed by existing data or through research required by the Food and Drug Administration as part of the application to make OCs available OTC. PMID- 26598305 TI - Providing Contraception to Adolescents. AB - Adolescents have high rates of unintended pregnancy and face unique reproductive health challenges. Providing confidential contraceptive services to adolescents is important in reducing the rate of unintended pregnancy. Long-acting contraception such as the intrauterine device and contraceptive implant are recommended as first-line contraceptives for adolescents because they are highly effective with few side effects. The use of barrier methods to prevent sexually transmitted infections should be encouraged. Adolescents have limited knowledge of reproductive health and contraceptive options, and their sources of information are often unreliable. Access to contraception is available through a variety of resources that continue to expand. PMID- 26598306 TI - Safety and Efficacy of Contraceptive Methods for Obese and Overweight Women. AB - Increasing rates of obesity have become a major public health challenge. Given the added health risks that obese women have during pregnancy, preventing unwanted pregnancy is imperative. Clinicians who provide contraception must understand the efficacy, risks, and the weight changes associated with various contraceptive methods. Despite differences in the pharmacokinetics and pharmacodynamics of hormonal contraceptives in overweight and obese women, efficacy does not appear to be severely impacted. Both estrogen-containing contraceptives and obesity increase the risk of venous thromboembolism, but the absolute risk remains acceptably low in reproductive age women. PMID- 26598307 TI - Contraceptive Method Initiation: Using the Centers for Disease Control and Prevention Selected Practice Guidelines. AB - The US Selected Practice Recommendations is a companion document to the Medical Eligibility Criteria for Contraceptive Use that focuses on how providers can use contraceptive methods most effectively as well as problem-solve common issues that may arise. These guidelines serve to help clinicians provide contraception safely as well as to decrease barriers that prevent or delay a woman from obtaining a desired method. This article summarizes the Selected Practice Recommendations on timing of contraceptive initiation, examinations, and tests needed prior to starting a method and any necessary follow-up. PMID- 26598308 TI - Why Stop Now? Extended and Continuous Regimens of Combined Hormonal Contraceptive Methods. AB - Combined hormonal contraceptives (CHCs) have traditionally been prescribed in 28 day cycles, with 21 days of active hormones followed by a 7-day hormone-free interval. Extended and continuous CHC regimens, defined as regimens with greater than 28 days of active hormones, offer many benefits, including a decrease in estrogen-withdrawal symptoms and likely greater efficacy because of more reliable ovulation suppression. Bleeding profiles are favorable, and unscheduled bleeding decreases over time with these regimens. Extended and continuous regimens of combined oral contraceptives and the contraceptive vaginal ring are safe and have high user acceptability and satisfaction. However, despite numerous benefits, extended and continuous CHC regimens are underused. PMID- 26598309 TI - Does the Progestogen Used in Combined Hormonal Contraception Affect Venous Thrombosis Risk? AB - Combined hormonal contraceptives (CHCs) use a combination of estrogen and progestogen to provide contraception. The most important risk of using CHCs is venous thromboembolism (VTE). It is unclear whether the type of progestogen used in a method augments that risk. Although the evidence supporting an increase in thrombosis risk is not conclusive, neither is the evidence supporting the benefit of newer progestogens in terms of tolerability or continuation. The benefits of CHCs outweigh the risks and the absolute risk of VTE remains small. A balanced discussion of potential risks and benefits of particular CHC formulations is warranted during contraception counseling. PMID- 26598310 TI - Emergency Contraception: Do Your Patients Have a Plan B? AB - Emergency contraception is used after unprotected sex, inadequately protected sex, or sexual assault to reduce the risk of pregnancy. Of emergency contraceptive methods available in the United States, the copper intrauterine device has the highest efficacy, followed by ulipristal acetate, levonorgestrel containing emergency contraceptive pills, and the Yuzpe method. However, access to the most effective methods is limited. Although advanced prescription of emergency contraceptive pills and counseling on emergency contraception to all reproductive-aged women is recommended, women should be advised to contact their health care providers after taking emergency contraceptive pills to discuss possible copper intrauterine device placement and other follow-up. PMID- 26598311 TI - Sterilization: A Review and Update. AB - Sterilization is a frequently used method of contraception. Female sterilization is performed 3 times more frequently than male sterilization, and it can be performed immediately postpartum or as an interval procedure. Methods include mechanical occlusion, coagulation, or tubal excision. Female sterilization can be performed using an abdominal approach, or via laparoscopy or hysteroscopy. When an abdominal approach or laparoscopy is used, sterilization occurs immediately. When hysteroscopy is used, tubal occlusion occurs over time, and additional testing is needed to confirm tubal occlusion. Comprehensive counseling about sterilization should include discussion about male sterilization (vasectomy) and long-acting reversible contraceptive methods. PMID- 26598312 TI - Contraceptive Needs--A Gateway to the Obstetrician-Gynecologist's Office. PMID- 26598313 TI - Contraception. PMID- 26598315 TI - Suarez et al (J Infect Dis 2015; 212:213-22). PMID- 26598314 TI - Prevention and control of multi-drug-resistant Gram-negative bacteria: recommendations from a Joint Working Party. PMID- 26598318 TI - Reply to the Editor--Regarding the Role of Advanced Interatrial Block Pattern as a Predictor of Atrial Fibrillation. PMID- 26598317 TI - The role, mechanism and potentially novel biomarker of microRNA-17-92 cluster in macrosomia. AB - Macrosomia is one of the most common perinatal complications of pregnancy and has life-long health implications for the infant. microRNAs (miRNAs) have been identified to regulate placental development, yet the role of miRNAs in macrosomia remains poorly understood. Here we investigated the role of miR-17-92 cluster in macrosomia. The expression levels of five miRNAs in miR-17-92 cluster were significantly elevated in placentas of macrosomia, which may due to the up regulation of miRNA-processing enzyme Drosha and Dicer. Cell cycle pathway was identified to be the most relevant pathways regulated by miR-17-92 cluster miRNAs. Importantly, miR-17-92 cluster increased proliferation, attenuated cell apoptosis and accelerated cells entering S phase by targeting SMAD4 and RB1 in HTR8/SVneo cells. Furthermore, we found that expression of miR-17-92 cluster in serum had a high diagnostic sensitivity and specificity for macrosomia (AUC: 80.53%; sensitivity: 82.61%; specificity: 69.57%). Our results suggested that miR 17-92 cluster contribute to macrosomia development by targeting regulators of cell cycle pathway. Our findings not only provide a novel insight into the molecular mechanisms of macrosomia, but also the clinical value of miR-17-92 cluster as a predictive biomarker for macrosomia. PMID- 26598319 TI - Junctophilin-2 at the intersection of arrhythmia and pathologic cardiac remodeling. PMID- 26598320 TI - Distinctive property and pharmacology of voltage-gated sodium current in rat atrial vs ventricular myocytes. AB - BACKGROUND: Several mammalian species display distinct biophysical properties between atrial and ventricular voltage-gated sodium current (INa); however, the potential mechanism behind this phenomenon is unknown. OBJECTIVE: The purpose of this study was to investigate the potential molecular identities of the different INa in atrial and ventricular myocytes of rat hearts. METHODS: Whole-cell patch voltage-clamp and molecular biology techniques were used in the study. RESULTS: Ventricular INa exhibited a slower inactivation, more positive potential of inactivation, and quicker recovery from inactivation compared to atrial INa. Real time polymerase chain reaction and western blot analysis revealed that mRNA and protein levels of NaVbeta2 and NaVbeta4 subunits, but not NaV1.5, were greater in ventricular myocytes than in atrial myocytes. INa in heterologous HEK 293 cell expression system with coexpressing hNaV1.5 and hNaVbeta2/hNaVbeta4 showed similar biophysical properties to ventricular INa. Greater protein expression of NaVbeta2 and NaVbeta4 subunits was also observed in human ventricles. Interestingly, pharmacologic study revealed that the antiarrhythmic drug dronedarone (10 MUM) inhibited atrial INa more (by 73%) than ventricular INa (by 42%), and shifted its inactivation to more negative voltages (-4.6 mV) compared to ventricular INa. CONCLUSION: The results of this study demonstrate the novel information that the distinctive biophysical properties of INa in atrial and ventricular myocytes can be attributed to inhomogeneous expression of NaVbeta2 and NaVbeta4 subunits, and that atrial INa is more sensitive to inhibition by dronedarone. PMID- 26598321 TI - Fast and spurious: Correcting the QT interval. PMID- 26598323 TI - To the Editor--The role of advanced interatrial block pattern as a predictor of atrial fibrillation. PMID- 26598322 TI - Cardiac output and vasodilation in the vasovagal response: An analysis of the classic papers. AB - The simple faint is secondary to hypotension and bradycardia resulting in transient loss of consciousness. According to Ohm's law applied to the circulation, BP = SVR * CO, hypotension can result from a decrease in systemic vascular resistance (SVR), cardiac output (CO), or both. It is important to understand that when blood pressure (BP) is falling, SVR and CO do not change reciprocally as they do in the steady state. In 1932, Lewis, assuming that decreased SVR alone accounted for hypotension, defined "the vasovagal response" along pathophysiologic lines to denote the association of vasodilation with vagal induced bradycardia in simple faint. Studies performed by Barcroft and Sharpey Schafer between 1940 and 1950 used volume-based plethysmography to demonstrate major forearm vasodilation during extreme hypotension and concluded that the main mechanism for hypotension was vasodilation. Plethysmographic measurements were intermittent and not frequent enough to capture rapid changes in blood flow during progressive hypotension. However, later investigations by Weissler, Murray, and Stevens performed between 1950 and 1970 used invasive beat-to-beat BP measurements and more frequent measurements of CO using the Fick principle. They demonstrated that CO significantly fell before syncope, and little vasodilation occurred until very late in the vasovagal reaction Thus, since the 1970s, decreasing cardiac output rather than vasodilation has been regarded as the principal mechanism for the hypotension of vasovagal syncope. PMID- 26598324 TI - Cellulose-Rich Nanofiber-Based Functional Nanoarchitectures. AB - Surface self-assembly of functional molecules or nanoscale building blocks is an effective strategy for the syntheses of advanced materials. Natural cellulose rich substances have unique macro-to-nano hierarchical structural features. The fabrication of nanoarchitectures, employing specific guest species on the surfaces of the fine structures of such substances, results in corresponding artificial nanomaterials that possess the chemical functionalities and physical properties of both sides. Metal oxide thin film coatings with nanometer precision on the nanofibers of bulk cellulose-rich substances not only yield replicas of nanostructured materials, but also make it possible for further assemblies of functional units on the surfaces. Hence, nanostructured metal oxides and further composites, as well as surface-functionalized cellulose-based composites are fabricated by employing cellulose-rich substances as templates or scaffolds. The three-dimensional cross-linked porous structures, with the high surface area of the resultant nanomaterials or composites, lead to superior performance when employed as photocatalysts, electrode materials, and sensing matrices, on which this report is focused. PMID- 26598326 TI - Knockout mouse production assisted by Blm knockdown. AB - Production of knockout mice using targeted embryonic stem cells (ESCs) is a powerful approach for investigating the function of specific genes in vivo. Although the protocol for gene targeting via homologous recombination (HR) in ESCs is already well established, the targeting efficiency varies at different target loci and is sometimes too low. It is known that knockdown of the Bloom syndrome gene, BLM, enhances HR-mediated gene targeting efficiencies in various cell lines. However, it has not yet been investigated whether this approach in ESCs is applicable for successful knockout mouse production. Therefore, we attempted to answer this question. Consistent with previous reports, Blm knockdown enhanced gene targeting efficiencies for three gene loci that we examined by 2.3-4.1-fold. Furthermore, the targeted ESC clones generated good chimeras and were successful in germline transmission. These data suggest that Blm knockdown provides a general benefit for efficient ESC-based and HR-mediated knockout mouse production. PMID- 26598325 TI - Restoration of skilled locomotion by sprouting corticospinal axons induced by co deletion of PTEN and SOCS3. AB - The limited rewiring of the corticospinal tract (CST) only partially compensates the lost functions after stroke, brain trauma and spinal cord injury. Therefore it is important to develop new therapies to enhance the compensatory circuitry mediated by spared CST axons. Here by using a unilateral pyramidotomy model, we find that deletion of cortical suppressor of cytokine signaling 3 (SOCS3), a negative regulator of cytokine-activated pathway, promotes sprouting of uninjured CST axons to the denervated spinal cord. A likely trigger of such sprouting is ciliary neurotrophic factor (CNTF) expressed in local spinal neurons. Such sprouting can be further enhanced by deletion of phosphatase and tensin homolog (PTEN), a mechanistic target of rapamycin (mTOR) negative regulator, resulting in significant recovery of skilled locomotion. Ablation of the corticospinal neurons with sprouting axons abolishes the improved behavioural performance. Furthermore, by optogenetics-based specific CST stimulation, we show a direct limb motor control by sprouting CST axons, providing direct evidence for the reformation of a functional circuit. PMID- 26598327 TI - Profile of muscle tissue gene expression specific to water buffalo: Comparison with domestic cattle by genome array. AB - In contrast with the past, the water buffalo is now not only a draft animal, but also an important food source of milk and meat. It is increasingly apparent that the water buffalo have huge potential for meat production, but its breeding needs to be investigated. Regarding the molecular mechanisms involved in the meat quality difference between the buffalo (Bubalus bulabis) and yellow cattle (Bos taurus), 12 chemical-physical characteristics related to the meat quality of longissimus thoracis muscles (LTM) have been compared at the age of 36 months. Intramuscular lipid and b* (yellowness) were greater in cattle than the buffalo, whereas a* (redness) was greater in the buffalo. Gene expression profiles were constructed by bovine genome array. A total of 8884 and 10,960 probes were detected in buffalo and cattle, respectively, with 1580 genes being differentially expressed. Over 400 probes were upregulated and nearly 1200 were downregulated in LTM of the buffalo, most being involved in ribosomal RNA (rRNA) processing, cholesterol homeostasis, regulation of transcription, response to hypoxia, and glycolysis. Quantitative real-time PCR was used to validate the microarray data. Enriched GO analyses of highly expressed genes in LTM showed that protein biosynthesis, striated muscle contraction, iron homeostasis, iron transport, glycolysis and glucose metabolism were similar between the buffalo and cattle. High protein content, low fat content and deep meat color of buffalo LTM may be closely associated with the increased expression of genes involved in cholesterol and iron homeostasis, while also reducing the expression of genes involved in ubiquitin-mediated proteolysis and protein oxidative phosphorylation. These results establish the groundwork for further studies on buffalo meat quality and will be beneficial in improving water buffalo breeding by molecular biotechnology. PMID- 26598329 TI - Individual-based models for adaptive diversification in high-dimensional phenotype spaces. AB - Most theories of evolutionary diversification are based on equilibrium assumptions: they are either based on optimality arguments involving static fitness landscapes, or they assume that populations first evolve to an equilibrium state before diversification occurs, as exemplified by the concept of evolutionary branching points in adaptive dynamics theory. Recent results indicate that adaptive dynamics may often not converge to equilibrium points and instead generate complicated trajectories if evolution takes place in high dimensional phenotype spaces. Even though some analytical results on diversification in complex phenotype spaces are available, to study this problem in general we need to reconstruct individual-based models from the adaptive dynamics generating the non-equilibrium dynamics. Here we first provide a method to construct individual-based models such that they faithfully reproduce the given adaptive dynamics attractor without diversification. We then show that a propensity to diversify can be introduced by adding Gaussian competition terms that generate frequency dependence while still preserving the same adaptive dynamics. For sufficiently strong competition, the disruptive selection generated by frequency-dependence overcomes the directional evolution along the selection gradient and leads to diversification in phenotypic directions that are orthogonal to the selection gradient. PMID- 26598328 TI - Mutations in the heat-shock protein A9 (HSPA9) gene cause the EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia. AB - We and others have reported mutations in LONP1, a gene coding for a mitochondrial chaperone and protease, as the cause of the human CODAS (cerebral, ocular, dental, auricular and skeletal) syndrome (MIM 600373). Here, we delineate a similar but distinct condition that shares the epiphyseal, vertebral and ocular changes of CODAS but also included severe microtia, nasal hypoplasia, and other malformations, and for which we propose the name of EVEN-PLUS syndrome for epiphyseal, vertebral, ear, nose, plus associated findings. In three individuals from two families, no mutation in LONP1 was found; instead, we found biallelic mutations in HSPA9, the gene that codes for mHSP70/mortalin, another highly conserved mitochondrial chaperone protein essential in mitochondrial protein import, folding, and degradation. The functional relationship between LONP1 and HSPA9 in mitochondrial protein chaperoning and the overlapping phenotypes of CODAS and EVEN-PLUS delineate a family of "mitochondrial chaperonopathies" and point to an unexplored role of mitochondrial chaperones in human embryonic morphogenesis. PMID- 26598330 TI - Translating global commitments on NCDs into national action: the role of civil society. PMID- 26598332 TI - Accelerated Purification Using Generalized Nonpurifying Intermediate Functions for Large-Scale Self-Consistent Field Calculations. AB - Purification is a widely used technique to calculate idempotent density matrices from a Hamiltonian in large-scale electronic structure calculations. However, the initial guess of a density matrix usually contains large errors, which require many iterations to remove them, using standard recursive schemes such as those derived by McWeeny or Holas. In this Letter, we propose a way to obtain a converged density matrix much more rapidly by removing the stability conditions that the functions have fixed points and vanishing derivatives at 0 and 1, assumptions usually made in most traditional purification methods. That is, by extending the recursive function space, which gives the approximated step function via the generalized nonpurifying intermediate functions, and optimizing them, we reduce the purification cost approximately by a factor of 1.5 compared to grand canonical purification algorithms for the linear alkanes, diamondoid, and a protein endothelin that has a very small band gap. PMID- 26598331 TI - Return to Sport Among French Alpine Skiers After an Anterior Cruciate Ligament Rupture: Results From 1980 to 2013. AB - BACKGROUND: There is little known about return to sport and performance after anterior cruciate ligament (ACL) tear in high-level alpine skiers. PURPOSE: To analyze the parameters that influence the return to sport and performance after an ACL tear in French alpine skiers from 1980 to 2013. STUDY DESIGN: Descriptive epidemiology study. METHODS: The study population included 239 male and 238 female skiers who competed on the national French alpine ski team for at least 1 season between 1980 and 2013 in the speed (downhill and super-G) and technical disciplines (giant slalom and slalom). Two groups were formed: group 1 (G1) included athletes who had sustained an ACL rupture, and group 2 (G2) included athletes who had never sustained an ACL rupture. Three performance indicators were selected: International Ski Federation (FIS) points calculation, FIS ranking, and podium finishes in the World Cup, World Championships, and Olympic Games. RESULTS: The first-decile FIS points and international FIS ranking showed that G1 skiers obtained better performance than did G2 skiers. The mean +/- SD career length of G1 skiers (men, 7.9 +/- 4.7 years; women, 7.1 +/- 4.1 years) was longer than that of G2 skiers (men, 4.5 +/- 3.3 years; women, 4.2 +/- 3.5 years). In addition, 12.8% (61 of 477) of the skiers achieved at least a podium finish during their careers: 23.0% (34 of 148) in G1 and 8.3% (27 of 329) in G2. The mean age at ACL rupture was 22.6 +/- 4.1 years for men and 19.9 +/- 3.5 years for women. In G1, 55 podiums were achieved before ACL rupture and 176 after in all competitions. Skiers who improved their performances after ACL rupture were significantly younger (men, 22.2 +/- 3.0 years; women, 18.7 +/- 2.2 years; P < .0001) at the time of injury than those showing a performance deterioration after ACL rupture (men, 25.3 +/- 4.2 years; women, 22.4 +/- 4.0 years). All skiers who had ACL tears continued their competitive careers after the injury. CONCLUSION: The overall results showed that it is possible to return to preinjury or even higher levels of performance after an ACL rupture and that age is the main element that guides postsurgical recovery. PMID- 26598333 TI - Performance of the van der Waals Density Functional VV10 and (hybrid)GGA Variants for Thermochemistry and Noncovalent Interactions. AB - The nonlocal van der Waals density functional VV10 (Vydrov, O. A.; Van Voorhis, T. J. Chem. Phys.2010, 133, 244103) is tested for the thermochemical properties of 1200+ atoms and molecules in the GMTKN30 database in order to assess its global accuracy. Five GGA and hybrid functionals in unmodified form are augmented by the nonlocal (NL) part of the VV10 functional (one parameter adjusted). The addition of the NL dispersion energy definitely improves the results of all tested functionals. On the basis of little empiricism and basic physical insight, DFT-NL can be recommended as a fully electronic, robust electronic structure method. PMID- 26598334 TI - A Multibox Splitting Scheme: Robust Approximation For ab Initio Molecular Dynamics. AB - In this work, the multibox (M-box) simulation scheme is introduced, which can be considered as a generalization of the QM/MM scheme for multifragment (molecular) systems. This scheme exploits the natural locality of multifragment molecular based systems by mapping the system into force-coupled block subspaces. Where defined in this way, the entire system can be fully modeled under a quantum mechanical force field. This allows the description of each subspace explicitly by means of a robust electronic structure theory without the requirement for large computational resources. An adequate block-to-block coupling by means of shared subsystem fragments is applied to preserve the long-distance structural correlation in the system during a molecular dynamic (MD) simulation. Since electronic structure descriptions play a central role in the formulation of several parametric models for charge or energy transport, we expect that this space-time correlated scheme can become a reliable computational tool for charge/energy transport/transfer applications. The efficiency of the method is demonstrated by performing statistical and time-resolved analysis using both the multifragment box and full ab initio approaches. We illustrate the method using as examples the melting process of a one-dimensional benzene chain (weak interaction situation) and NVE dynamics for the CnHn polymeric chain (strong interaction situation). We also have extended the threshold of applicability of our model, demonstrating how it can cope with MD simulation with more complex systems and processes. PMID- 26598335 TI - On the Use of Enveloping Distribution Sampling (EDS) to Compute Free Enthalpy Differences between Different Conformational States of Molecules: Application to 310-, alpha-, and pi-Helices. AB - Enveloping distribution sampling (EDS) is a powerful method to compute relative free energies from simulation. So far, the EDS method has only been applied to alchemical free energy differences, i.e., between different Hamiltonians defining different systems, and not yet to obtain free energy differences between different conformations or conformational states of a system. In this article, we extend the EDS formalism such that it can be applied to compute free energy differences of different conformations and apply it to compute the relative free enthalpy DeltaG of 310-, alpha-, and pi-helices of an alanine deca-peptide in explicit water solvent. The resulting DeltaG values are compared to those obtained by standard thermodynamic integration (TI) and from so-called end-state simulations. A TI simulation requires the definition of a lambda-dependent pathway which in the present case is based on hydrogen bonds of the different helical conformations. The values of ?(?VTI)/(?lambda)?lambda show a sharp change for a particular range of lambda values, which is indicative of an energy barrier along the pathway, which lowers the accuracy of the resulting DeltaG value. In contrast, in a two-state EDS simulation, an unphysical reference-state Hamiltonian which connects the parts of conformational space that are relevant to the different end states is constructed automatically; that is, no pathway needs to be defined. In the simulation using this reference state, both helices were sampled, and many transitions between them occurred, thus ensuring the accuracy of the resulting free enthalpy difference. According to the EDS simulations, the free enthalpy differences of the pi-helix and the 310-helix versus the alpha helix are 5 kJ mol(-1) and 47 kJ mol(-1), respectively, for an alanine deca peptide in explicit SPC water solvent using the GROMOS 53A6 force field. The EDS method, which is a particular form of umbrella sampling, is thus applicable to compute free energy differences between conformational states as well as between systems and has definite advantages over the traditional TI and umbrella sampling methods to compute relative free energies. PMID- 26598336 TI - Accuracy of Density Functionals in the Prediction of Electronic Proton Affinities of Amino Acid Side Chains. PMID- 26598337 TI - Validation of Relativistic DFT Approaches to the Calculation of NMR Chemical Shifts in Square-Planar Pt(2+) and Au(3+) Complexes. AB - Recently implemented hybrid density functional methods of calculating nuclear magnetic shielding using the two-component zeroth-order regular approximation approach (J. Phys. Chem. A2009, 113, 11495) have been employed for a series of compounds containing heavy transition-metal atoms. These include Pt(2+), Pd(2+), and Au(3+) organometallics and metal complexes with azines, some of which exhibit interesting biological and catalytic activities. In this study we investigate the effects of geometry, exchange-correlation functional, solvent, and scalar relativistic and spin-orbit corrections on the nuclear magnetic shielding-mainly for (13)C and (15)N atoms connected to a heavy-atom center. Our calculations demonstrate that the B3LYP method using effective core potentials and a cc-pwCVTZ PP/6-31G** basis set augmented with the polarizable continuum model of the dimethylsulfoxide solvent provides geometries for the complexes in question which are compatible with the experimental NMR results in terms of both the trends and the absolute values of the (13)C shifts. The important role of the exact exchange admixture parameter for hybrid functionals based on B3LYP and PBE0 is investigated systematically for selected Pt(2+) and Au(3+) complexes. The (13)C and (15)N NMR chemical shifts are found to be best reproduced by using a B3LYP or PBE0 approach with 30% and 40-50% exact exchange admixtures for the Pt(2+) and Au(3+) complexes, respectively. The spin-orbit contributions to the (15)N NMR chemical shifts reflect metal-ligand bonding that is much more ionic for the Au(3+) than for the Pt(2+) complex. Finally, an optimized density functional method is applied to a series of transition-metal complexes to estimate the scope and the limitations of the current approach. PMID- 26598338 TI - Complete Basis Set Extrapolation and Hybrid Schemes for Geometry Gradients of Noncovalent Complexes. AB - In this paper, we focus on the performance of popular WFT (MP2, MP2.5, MP3, SCS(MI)-MP2, CCSD(T)) and DFT (M06-2X, TPSS-D) methods in optimizations of geometries of noncovalent complexes. Apart from the straightforward comparison of the accuracy of the resulting geometries with respect to the most accurate, computationally affordable, reference method, we have also attempted to determine the most efficient utilization of the information contained in the gradient of a particular method and basis set. Essentially, we have transferred the ideas successfully used for noncovalent interaction energy calculations to geometry optimizations. We have assessed the performance of the hybrid gradients (for instance, MP2 and CCSD(T) calculated in different basis sets), investigated the possibility of extrapolating gradients calculated with a particular method in a series of systematically built basis sets, and finally compared the extrapolated gradients with the counterpoise(CP)-corrected optimizations, in order to determine which of these approaches is more efficient, in terms of their convergence toward the CBS geometry for the respective calculation cost. Further, we compared the efficiency of the CP-corrected, extrapolated, and hybrid gradients in terms of the rate of convergence with respect to basis set size. We have found that CCSD(T) geometries are most faithfully reproduced by the MP2.5 and MP3 methods, followed by the comparably well performing SCS(MI)-MP2 and MP2 methods, and finally by the worst performing DFT-D and M06 methods. Basis set extrapolation of gradients was shown to improve the results and can be considered as a low-cost alternative to the use of CP-corrected gradients. A hybrid gradient scheme was shown to deliver geometries close to the regular gradient reference. Analogously to a similar hybrid scheme, which nowadays is routinely used for the calculation of interaction energies, such a hybrid gradient scheme can save a huge amount of computer time, when high accuracy is desired. PMID- 26598339 TI - Evaluation of the Nonlinear Optical Properties for Annulenes with Huckel and Mobius Topologies. AB - Recently, much attention has been focused on the design and synthesis of molecules with aromatic Mobius topology. One of the most promising applications is the manufacture of Huckel-to-Mobius topological optical switches with high nonlinear optical properties. In this work, we evaluate the electronic and vibrational contributions to static and dynamic nonlinear optical properties of the CS Huckel and C2 Mobius topologies synthesized by Herges and co-workers (Ajami, D. et al. Nature2003, 426, 819). Calculations are performed at the HF, B3LYP, BHandHLYP, BMK, M052X, CAM-B3LYP, and MP2 levels with the 6-31+G(d) basis set. Our results conclude that the BHandHLYP, M052X, and CAM-B3LYP methods correctly reproduce the X-ray crystal structure and provide similar nonlinear optical properties. PMID- 26598340 TI - Dispersion Interactions with Density-Functional Theory: Benchmarking Semiempirical and Interatomic Pairwise Corrected Density Functionals. AB - We present a comparative assessment of the accuracy of two different approaches for evaluating dispersion interactions: interatomic pairwise corrections and semiempirical meta-generalized-gradient-approximation (meta-GGA)-based functionals. This is achieved by employing conventional (semi)local and (screened )hybrid functionals, as well as semiempirical hybrid and nonhybrid meta-GGA functionals of the M06 family, with and without interatomic pairwise Tkatchenko Scheffler corrections. All of those are tested against the benchmark S22 set of weakly bound systems, a representative larger molecular complex (dimer of NiPc molecules), and a representative dispersively bound solid (hexagonal boron nitride). For the S22 database, we also compare our results with those obtained from the pairwise correction of Grimme (DFT-D3) and nonlocal Langreth-Lundqvist functionals (vdW-DF1 and vdW-DF2). We find that the semiempirical kinetic-energy density dependence introduced in the M06 functionals mimics some of the nonlocal correlation needed to describe dispersion. However, long-range contributions are still missing. Pair-wise interatomic corrections, applied to conventional semilocal or hybrid functionals, or to M06 functionals, provide for a satisfactory level of accuracy irrespectively of the underlying functional. Specifically, screened-hybrid functionals such as the Heyd-Scuseria-Ernzerhof (HSE) approach reduce self-interaction errors in systems possessing both localized and delocalized orbitals and can be applied to both finite and extended systems. Therefore, they serve as a useful underlying functional for dispersion corrections. PMID- 26598341 TI - Field-Extremum Model for Short-Range Contributions to Hydration Free Energy. AB - The performance in describing hydration free energies of a broad class of neutral, cationic, and anionic solutes is tested for the recently proposed FESR (Field-Extremum Short-Range) implicit solvation model for interactions between the solute and nearby water molecules, as taken in conjunction with the previously developed SS(V)PE (Surface and Simulation of Volume Polarization for Electrostatics) dielectric continuum model for long-range interactions with bulk water. The empirical FESR model mainly describes solute-water hydrogen bonding interactions by correlating them with the maximum and minimum values of the electric field produced by the solute at the surface of the cavity that excludes solvent. A preliminary report showed that, with only four adjustable parameters, the FESR model, in conjunction with SS(V)PE, can produce hydration energies comparable to the best analogous efforts in the literature that utilized many more parameters. Here, the performance of the FESR model is more fully documented in several respects. The dependence on the underlying quantum mechanical method used to treat the internal electronic structure of the solute is tested by comparing uncorrelated Hartree-Fock to correlated density functional calculations and by comparing a modest sized to a large basis set. The influence of cavity size is studied in connection with an isodensity contour construction of the cavity. The sensitivity of the results to the parameters in the FESR model is considered, and it is found that the dependence on the electric field strength is quite nonlinear, with an optimum exponent consistently in the range of 3 to 4. Overall, it is concluded that the FESR model shows considerable utility for improving the accuracy of implicit models of aqueous solvation. PMID- 26598342 TI - Multiconfigurational Second-Order Perturbation Theory Restricted Active Space (RASPT2) Studies on Mononuclear First-Row Transition-Metal Systems. AB - A series of model transition-metal complexes, CrF6, ferrocene, Cr(CO)6, ferrous porphin, cobalt corrole, and FeO/FeO(-), have been studied using second-order perturbation theory based on a restricted active space self-consistent field reference wave function (RASPT2). Several important properties (structures, relative energies of different structural minima, binding energies, spin state energetics, and electronic excitation energies) were investigated. A systematic investigation was performed on the effect of: (a) the size and composition of the global RAS space, (b) different (RAS1/RAS2/RAS3) subpartitions of the global RAS space, and (c) different excitation levels (out of RAS1/into RAS3) within the RAS space. Calculations with active spaces, including up to 35 orbitals, are presented. The results obtained with smaller active spaces (up to 16 orbitals) were compared to previous and current results obtained with a complete active space self-consistent field reference wave function (CASPT2). Higly accurate RASPT2 results were obtained for the heterolytic binding energy of ferrocene and for the electronic spectrum of Cr(CO)6, with errors within chemical accuracy. For ferrous porphyrin the intermediate spin (3)A2g ground state is (for the first time with a wave function-based method) correctly predicted, while its high magnetic moment (4.4 MUB) is attributed to spin-orbit coupling with very close lying (5)A1g and (3)Eg states. The toughest case met in this work is cobalt corrole, for which we studied the relative energy of several low-lying Co(II) corrole pi radical states with respect to the Co(III) ground state. Very large RAS spaces (25-33 orbitals) are required for this system, making compromises on the size of RAS2 and/or the excitation level unavoidable, thus increasing the uncertainty of the RASPT2 results by 0.1-0.2 eV. Still, also for this system, the RASPT2 method is shown to provide distinct improvements over CASPT2, by overcoming the strict limitations in the size of the active space inherent to the latter method. PMID- 26598343 TI - Dispersion-Weighted Explicitly Correlated Coupled-Cluster Theory [DW-CCSD(T**) F12]. AB - We propose a procedure denoted dispersion-weighted explicitly correlated coupled cluster [DW-CCSD(T**)-F12] which mixes CCSD(T**)-F12a and CCSD(T**)-F12b so as to correct the small errors exhibited by each of the approximations in a small basis set, allowing for a black-box method that can provide high-quality interaction energies for a variety of nonbonded interactions. Relative to CCSD(T**)-F12a and CCSD(T**)-F12b, DW-CCSD(T**)-F12 reduces the mean absolute deviation by a factor of 2 and the maximum error by a factor of 3 (formic acid dimer) and 4 (stacked adenine-thymine) for the aug-cc-pVDZ basis set. PMID- 26598344 TI - Spline Implementation of Generalized Gradient Approximations to the Exchange Correlation Functional and Study of the Sensitivity of Density Functional Accuracy to Localized Domains of the Reduced Density Gradient. AB - We present a natural cubic spline implementation of the exchange enhancement factor as a function of the reduced density gradient, and we demonstrate its performance by replicating the results of common GGA functionals. We also investigate the effect on the accuracy of various calculated properties of changing the shape of the exchange enhancement factor and an analogous factor for correlation. The properties considered are main group atomization energies, ionization potentials, electron affinities, proton affinities, alkyl bond dissociation energies, difficult hydrocarbon cases, barrier heights for chemical reactions, noncovalent interactions, atomic energies, metal bond energies, and main group bond lengths. PMID- 26598345 TI - Assembling Small Silicon Clusters Using Criteria of Maximum Matching of the Fukui Functions. AB - In this work, we present a methodology inspired by criteria of "maximum matching" between the Fukui functions to predict the best interaction between small silicon clusters to form larger ones. The model is based on the topological analysis of the Fukui functions. We tested the methodology in the formation of Si4-Si8 using a set of small Si2-Si6 clusters as building blocks in ground state structures in singlet and triplet multiplicities. In all of the cases, the Fukui function predicts the formation of the large cluster in its ground state structure, but the number of reaction channels increases with the cluster size. PMID- 26598346 TI - Assessment of Theoretical Methods for Complexes of Gold(I) and Gold(III) with Unsaturated Aliphatic Hydrocarbon: Which Density Functional Should We Choose? AB - Gold-substrate interaction is essential in gold-catalyzed organic transformations. This study uses high-level coupled cluster calculations with core-valence correlation and complete basis set (CBS) limit extrapolation as a reference, for assessing the performance of popular density functional theory (DFT) approximations for a variety of Au(I)/Au(III) complexes with unsaturated aliphatic hydrocarbon CnHm substrates (ethene, ethyne, and allene). The tested functionals cover from LDA to GGA and meta-GGA, and to hybrids and double hybrids (LSDA, PBE, M06-L, TPSS, B3LYP, PBE0, M06, M06-2X, TPSSh, B2-PLYP, B2GP-PLYP). Both the geometry and bond dissociation energy (De) of the Au-CnHm complexes are studied. Our findings show that B2GP-PLYP, PBE0, and B2-PLYP are the best performing functionals for this set of Au-CnHm complexes. DFT dispersion correction (DFT-D3), though very helpful for some functionals (e.g., B3LYP and B2 PLYP), does not uniformly improve the results of all functionals. Ab initio methods like MP2 and SCSMP2 are also tested. MP2 is found to be the worst performing method, and while SCSMP2 greatly improves the results, still its accuracy is lower than that of the best functionals, B2GP-PLYP, PBE0, and B2 PLYP. PMID- 26598347 TI - On the Importance of the Orbital Relaxation in Ground-State Coupled Cluster Calculations in Solution with the Polarizable Continuum Model of Solvation. AB - In the description of the electrostatic interaction between a solute treated at coupled cluster (CC) level of theory and a solvent modeled as a continuum dielectric, the solvent response depends on various contributions: the choice of the reference wave function, the correlation density, and the orbital relaxation. In previous work, we examined the first two factors with the coupled cluster singles and doubles (CCSD) method and its variant Brueckner doubles (BD) method. The CC wave function was combined with the polarizable continuum model (PCM) of solvation in an integrated and efficient method able to describe energy and molecular properties through analytic energy gradients. Additionally, we investigated some approximations, and proposed new ones, that reduce the computational cost to nearly that of gas phase CC while keeping most of the complete model description. In this work, we study the contribution of the orbital relaxation and compare it to the other effects. Such contribution is introduced with a self-consistent macroiteration procedure, where the reaction field is updated with a refined density. The results presented here show that the effect of the orbital relaxation is small for CCSD, while for BD the integrated and self-consistent approaches are equivalent. Thus, these results further confirm that the integrated CCSD-PCM and BD-PCM methods, especially with their respective approximations, are an efficient approach to perform high-level electronic structure calculations in solution. PMID- 26598348 TI - Incorporating Linear Synchronous Transit Interpolation into the Growing String Method: Algorithm and Applications. AB - The growing string method is a powerful tool in the systematic study of chemical reactions with theoretical methods which allows for the rapid identification of transition states connecting known reactant and product structures. However, the efficiency of this method is heavily influenced by the choice of interpolation scheme when adding new nodes to the string during optimization. In particular, the use of Cartesian coordinates with cubic spline interpolation often produces guess structures which are far from the final reaction path and require many optimization steps (and thus many energy and gradient calculations) to yield a reasonable final structure. In this paper, we present a new method for interpolating and reparameterizing nodes within the growing string method using the linear synchronous transit method of Halgren and Lipscomb. When applied to the alanine dipeptide rearrangement and a simplified cationic alkyl ring condensation reaction, a significant speedup in terms of computational cost is achieved (30-50%). PMID- 26598349 TI - An Automated Force Field Topology Builder (ATB) and Repository: Version 1.0. AB - The Automated force field Topology Builder (ATB, http://compbio.biosci.uq.edu.au/atb ) is a Web-accessible server that can provide topologies and parameters for a wide range of molecules appropriate for use in molecular simulations, computational drug design, and X-ray refinement. The ATB has three primary functions: (1) to act as a repository for molecules that have been parametrized as part of the GROMOS family of force fields, (2) to act as a repository for pre-equilibrated systems for use as starting configurations in molecular dynamics simulations (solvent mixtures, lipid systems pre-equilibrated to adopt a specific phase, etc.), and (3) to generate force field descriptions of novel molecules compatible with the GROMOS family of force fields in a variety of formats (GROMOS, GROMACS, and CNS). Force field descriptions of novel molecules are derived using a multistep process in which results from quantum mechanical (QM) calculations are combined with a knowledge-based approach to ensure compatibility (as far as possible) with a specific parameter set of the GROMOS force field. The ATB has several unique features: (1) It requires that the user stipulate the protonation and tautomeric states of the molecule. (2) The symmetry of the molecule is analyzed to ensure that equivalent atoms are assigned identical parameters. (3) Charge groups are assigned automatically. (4) Where the assignment of a given parameter is ambiguous, a range of possible alternatives is provided. The ATB also provides several validation tools to assist the user to assess the degree to which the topology generated may be appropriate for a given task. In addition to detailing the steps involved in generating a force field topology compatible with a specific GROMOS parameter set (GROMOS 53A6), the challenges involved in the automatic generation of force field parameters for atomic simulations in general are discussed. PMID- 26598350 TI - Solvent Effects on the Radiative and Nonradiative Decay of a Model of the Rhodopsin Chromophore. AB - The radiative and nonradiative decay of a model with five double bonds of the 11 cis-retinal protonated Schiff base was studied both in vacuum and in methanol solution using an extended version of the averaged solvent electrostatic potential from molecular dynamics data (ASEP/MD) method that allows the location of crossing points between free energy surfaces both in equilibrium and in frozen solvent conditions. The multireference quantum method CASSCF was used for the description of the states of interest, while the solvent structure was obtained from molecular dynamics simulations. Electron dynamic correlation corrections to the energy were included at CASPT2 level. Unlike in gas phase, where only two states seem to be implicated, in methanol solution, three states are necessary to describe the photoisomerization process. At the Franck-Condon point the S1 and S2 states are almost degenerate; consequently, the S1 surface has a region with an ionic character ((1)Bu-like) and another one with a covalent character ((2)Ag like). Emission from the ionic minima is responsible for the low-frequency part of the fluorescence band, while emission from the covalent minima originates the high-frequency part. The ionic minimum is separated from the conical intersection yielding the all-trans isomer by an energy barrier that was estimated in 0.7 kcal/mol. The geometry of the optimized conical intersection was found at a torsion angle of the central double bond close to 90 degrees both in vacuum and in methanol solution. This large torsion in addition to the accompanying charge displacements forces a strong solvent reorganization during the de-excitation process which slows down the photoisomerization kinetics in methanol with respect to the gas phase. Solvent fluctuations modulate the minima depth and the barrier height and could explain the multiexponential relaxation time observed in the experiments. PMID- 26598351 TI - Chemiluminescence and Fluorescence States of a Small Model for Coelenteramide and Cypridina Oxyluciferin: A CASSCF/CASPT2 Study. AB - Fluorescence and chemiluminescence phenomena are often confused in experimental and theoretical studies on the luminescent properties of chemical systems. To establish the patterns that distinguish both processes, the fluorescent and chemiluminescent states of 2-acetamido-3-methylpyrazine, which is a small model of the coelenterazine/coelenteramide and Cypridina luciferin/oxyluciferin bioluminescent systems, were characterized by using the complete active space second-order perturbation (CASPT2) method. Differences in geometries and electronic structures among the states responsible for light emission were found. On the basis of the findings, some recommendations for experimental studies on chemiluminescence are suggested, and more appropriate theoretical approaches are proposed. PMID- 26598352 TI - Pople Style Basis Sets for the Calculation of NMR Spin-Spin Coupling Constants: the 6-31G-J and 6-311G-J Basis Sets. AB - We present a modification of the small and popular Pople basis sets, 6-31G and 6 311G, for density functional theory calculations of Fermi contact dominated NMR indirect nuclear spin-spin coupling constants. These new basis sets, 6-31G-J and 6-311G-J, contain twice the number of contracted s-type functions but the same number of contracted p-type functions as the original Pople basis set. For our test set of 12 one-, two- and three-bond coupling constants, the new basis sets augmented with the standard diffuse and polarization functions, i.e., the 6-31+G* J and 6-311++G**-J basis sets, lead to a maximum deviation of 5 and 2 Hz, respectively, compared to results obtained with the 6 or more times larger aug pcJ-4 basis set. In correlated wave function calculations using the second-order polarization propagator approximation, the deviations with respect to the aug-ccJ pVQZ basis set are 8 and 3 Hz and thus slightly larger. PMID- 26598353 TI - Optimized Basis Sets for Calculation of Electron Paramagnetic Resonance Hyperfine Coupling Constants: aug-cc-pVTZ-J for the 3d Atoms Sc-Zn. AB - The hyperfine coupling tensor of electron paramagnetic resonance (EPR), describing the interaction between an electron and a given nuclei, depends strongly on the electron density at the nucleus. With standard Gaussian-type orbital basis sets (GTOs), employed in most calculations, it is difficult to obtain converged results of the hyperfine coupling tensor, and basis sets with more flexible core regions have therefore been devised. To this class of core property basis sets belong the aug-cc-pVTZ-J basis sets developed for the s- and p-block atoms. Here, we extend the aug-cc-pVTZ-J basis sets to include the 3d elements Sc-Zn. The converged optimal basis sets are throughout the series described by a (25s17p10d3f2g)/[17s10p7d3f2g] contraction scheme, where four tight s-, one tight p-, and one tight d-type function have been added to the original aug-cc-pVTZ basis sets. The basis sets are generally contracted, and molecular orbital coefficients are used as contraction coefficients. By validation studies with different functionals and compounds, it is shown that the values of the contraction coefficient are effectively independent of the compound used in their generation and the exchange-correlation functional employed in the calculation. PMID- 26598354 TI - Essential on the Photophysics and Photochemistry of the Indole Chromophore by Using a Totally Unconstrained Theoretical Approach. AB - Indole is a chromophore present in many different molecules of biological interest, such as the essential amino acid tryptophan and the neurotransmitter serotonin. On the basis of CASPT2//CASSCF quantum chemical calculations, the photophysical properties of the system after UV irradiation have been studied through the exploration of the potential energy hypersurfaces of the singlet and triplet low-lying valence excited states. In contrast to previous studies, the present work has been carried out without imposing any restriction to the geometry of the molecule (C1 symmetry) and by performing minimum energy path calculations, which is the only instrument able to provide the lowest-energy evolution of the system. Relevant findings to the photophysics of bare indole have been obtained, which compete with the currently accepted mechanism for the energy decay in the molecule. The results show the presence of a conical intersection (CI) between the initially populated (1)(La pipi*) and the (1)(Lb pipi*) state, easily accessible through a barrierless pathway from the Franck Condon region. At this CI region, part of the population is switched from the bright (1)(La pipi*) state to the (1)(Lb pipi*) state, and the system evolves toward a minimum structure from which the expected fluorescence takes place. The reported low values of the fluorescence quantum yield are explained by means of a new nonradiative mechanism specific for the (1)(Lb pipi*) state, in which the presence of an ethene-like CI between the (Lb pipi*) and ground states is the main feature. PMID- 26598355 TI - Direct Calculations of Mid- and Near-IR Absorption and Circular Dichroism Spectra of Chiral Molecules Using QM/MM Molecular Dynamics Simulation Method. AB - The infrared (IR) and vibrational circular dichroism (VCD) spectra of (1S)-(-) beta-pinene in the mid- and near- IR frequency regions are numerically simulated by using a time-correlation function theory and mixed quantum/classical simulation method. Anharmonic vibrational dynamics and fluctuating atomic partial charges of the chiral pinene were obtained by carrying out quantum mechanical/molecular mechanical (QM/MM) molecular dynamics (MD) simulations. Thus obtained time-correlation functions of electric and magnetic dipole moments are used to calculate the IR absorption and VCD spectra, and they are directly compared with experimental results. Not only the fundamental transition bands but also first overtone and combination bands in the near-IR frequency region are successfully simulated. It is shown that the polarizable nature of the solute is particularly important in quantitatively reproducing the near-IR spectra, whereas such polarization effects on dipole and rotational strengths of lower-frequency and large-amplitude vibrations are less critical. We anticipate that the present QM/MM MD method in combination with mixed quantum/classical time-correlation function theory to calculate both mid- and near-IR absorption and VCD spectra will be of critical use in interpreting vibrational optical activity properties of even conformationally flexible chiral molecules, such as proteins. PMID- 26598356 TI - Accuracy of Calculated Chemical Shifts in Carbon 1s Ionization Energies from Single-Reference ab Initio Methods and Density Functional Theory. AB - A database of 77 adiabatic carbon 1s ionization energies has been prepared, covering linear and cyclic alkanes and alkenes, linear alkynes, and methyl- or fluoro-substituted benzenes. Individual entries are believed to carry uncertainties of less than 30 meV in ionization energies and less than 20 meV for shifts in ionization energies. The database provides an unprecedented opportunity for assessing the accuracy of theoretical schemes for computing inner-shell ionization energies and their corresponding chemical shifts. Chemical shifts in carbon 1s ionization energies have been computed for all molecules in the database using Hartree-Fock, Moller-Plesset (MP) many-body perturbation theory of order 2 and 3 as well as various approximations to full MP4, and the coupled cluster approximation with single- and double-excitation operators (CCSD) and also including a perturbational estimate of the energy effect of triple excitation operators (CCSD(T)). Moreover, a wide range of contemporary density functional theory (DFT) methods are also evaluated with respect to computing experimental shifts in C1s ionization energies. Whereas the top ab initio methods reproduce the observed shifts almost to within the experimental uncertainty, even the best-performing DFT approaches meet with twice the root-mean-squared error and thrice the maximum error compared to CCSD(T). However, a number of different density energy functionals still afford sufficient accuracy to become tools in the analysis of complex C1s photoelectron spectra. PMID- 26598357 TI - A Benchmark Test Set for Alchemical Free Energy Transformations and Its Use to Quantify Error in Common Free Energy Methods. AB - There is a significant need for improved tools to validate thermophysical quantities computed via molecular simulation. In this paper we present the initial version of a benchmark set of testing methods for calculating free energies of molecular transformation in solution. This set is based on molecular changes common to many molecular design problems, such as insertion and deletion of atomic sites and changing atomic partial charges. We use this benchmark set to compare the statistical efficiency, reliability, and quality of uncertainty estimates for a number of published free energy methods, including thermodynamic integration, free energy perturbation, the Bennett acceptance ratio (BAR) and its multistate equivalent MBAR. We identify MBAR as the consistently best performing method, though other methods are frequently comparable in reliability and accuracy in many cases. We demonstrate that assumptions of Gaussian distributed errors in free energies are usually valid for most methods studied. We demonstrate that bootstrap error estimation is a robust and useful technique for estimating statistical variance for all free energy methods studied. This benchmark set is provided in a number of different file formats with the hope of becoming a useful and general tool for method comparisons. PMID- 26598358 TI - Micellization Studied by GPU-Accelerated Coarse-Grained Molecular Dynamics. AB - The computational design of advanced materials based on surfactant self-assembly without ever stepping foot in the laboratory is an important goal, but there are significant barriers to this approach, because of the limited spatial and temporal scales accessible by computer simulations. In this paper, we report our work to bridge the gap between laboratory and computational time scales by implementing the coarse-grained (CG) force field previously reported by Shinoda et al. [Shinoda, W.; DeVane, R.; Klein, M. L. Mol. Simul. 2007, 33, 27-36] into the HOOMD-Blue graphical processing unit (GPU)-accelerated molecular dynamics (MD) software package previously reported by Anderson et al. [Anderson, J. A.; Lorenz, C. D.; Travesset, A. J. Comput. Phys. 2008, 227, 5342-5359]. For a system of 25 750 particles, this implementation provides performance on a single GPU, which is superior to that of a widely used parallel MD simulation code running on an optimally sized CPU-based cluster. Using our GPU setup, we have collected 0.6 ms of MD trajectory data for aqueous solutions of 7 different nonionic polyethylene glycol (PEG) surfactants, with most of the systems studied representing ~1 000 000 atoms. From this data, we calculated various properties as a function of the length of the hydrophobic tails and PEG head groups. Specifically, we determined critical micelle concentrations (CMCs), which are in good agreement with experimental data, and characterized the size and shape of micelles. However, even with the microsecond trajectories employed in this study, we observed that the micelles composed of relatively hydrophobic surfactants are continuing to grow at the end of our simulations. This suggests that the final micelle size distributions of these systems are strongly dependent on initial conditions and that either longer simulations or advanced sampling techniques are needed to properly sample their equilibrium distributions. Nonetheless, the combination of coarse-grained modeling and GPU acceleration marks a significant step toward the computational prediction of the thermodynamic properties of slowly evolving surfactant systems. PMID- 26598359 TI - Methods for Computing Accurate Atomic Spin Moments for Collinear and Noncollinear Magnetism in Periodic and Nonperiodic Materials. AB - The partitioning of electron spin density among atoms in a material gives atomic spin moments (ASMs), which are important for understanding magnetic properties. We compare ASMs computed using different population analysis methods and introduce a method for computing density derived electrostatic and chemical (DDEC) ASMs. Bader and DDEC ASMs can be computed for periodic and nonperiodic materials with either collinear or noncollinear magnetism, while natural population analysis (NPA) ASMs can be computed for nonperiodic materials with collinear magnetism. Our results show Bader, DDEC, and (where applicable) NPA methods give similar ASMs, but different net atomic charges. Because they are optimized to reproduce both the magnetic field and the chemical states of atoms in a material, DDEC ASMs are especially suitable for constructing interaction potentials for atomistic simulations. We describe the computation of accurate ASMs for (a) a variety of systems using collinear and noncollinear spin DFT, (b) highly correlated materials (e.g., magnetite) using DFT+U, and (c) various spin states of ozone using coupled cluster expansions. The computed ASMs are in good agreement with available experimental results for a variety of periodic and nonperiodic materials. Examples considered include the antiferromagnetic metal organic framework Cu3(BTC)2, several ozone spin states, mono- and binuclear transition metal complexes, ferri- and ferro-magnetic solids (e.g., Fe3O4, Fe3Si), and simple molecular systems. We briefly discuss the theory of exchange correlation functionals for studying noncollinear magnetism. A method for finding the ground state of systems with highly noncollinear magnetism is introduced. We use these methods to study the spin-orbit coupling potential energy surface of the single molecule magnet Fe4C40H52N4O12, which has highly noncollinear magnetism, and find that it contains unusual features that give a new interpretation to experimental data. PMID- 26598360 TI - Statistical Convergence of Equilibrium Properties in Simulations of Molecular Solutes Embedded in Lipid Bilayers. AB - In recent years, atomistic molecular simulations have become a method of choice for studying the interaction of small molecules, peptides, and proteins with biological membranes. Here, we critically examine the statistical convergence of equilibrium properties in molecular simulations of two amino acid side-chain analogs, leucine and arginine, in the presence of a hydrated phospholipid bilayer. To this end, the convergence of the standard binding free energy for the reversible insertion of the solutes in the bilayer is systematically assessed by evaluating dozens of separate sets of umbrella sampling calculations for a total simulation time exceeding 400 MUs. We identify rare and abrupt transitions in bilayer structure as a function of solute insertion depth. These transitions correspond to the slow reorganization of ionic interactions involving zwitterionic phospholipid headgroups when the solutes penetrate the lipid-water interface and when arginine is forced through the bilayer center. These rare events are shown to constitute hidden sampling barriers that limit the rate of convergence of equilibrium properties and result in systematic sampling errors. Our analysis demonstrates that the difficulty of attaining convergence for lipid bilayer-embedded solutes has, in general, been drastically underestimated. This information will assist future studies in improving accuracy by selecting a more appropriate reaction coordinate or by focusing computational resources on those regions of the reaction coordinate that exhibit slow convergence of equilibrium properties. PMID- 26598361 TI - A Hybrid All-Atom Structure-Based Model for Protein Folding and Large Scale Conformational Transitions. AB - Structure-based models are successful at conjugating the essence of the energy landscape theory of protein folding with an easy and efficient implementation. Recently, their realm expanded beyond a single protein structure, and structure based potentials have been used profitably to widely study complex conformational transitions. Still, when dealing with structural rearrangements between two, or more, well-defined structures, an unbiased and transferable description of the local backbone and side chain interactions could be advantageous. Here, we propose an all-atom model that merges a classical force field description of these local interactions with a structure-based long-range potential that takes into account the different conformations. We first validate the model simulating and characterizing the folding reaction and the transition state of two well known proteins: the villin headpiece and the SH3 domain. Then, we characterize the activation mechanism of the catalytic domain of c-Src kinase. Such a process involves the conformational rearrangement of a large loop and the swing of an alpha helix. The appearance of a stable intermediate state in the free energy landscape between the two conformational end points suggests the mechanism of the loop opening. The low computational cost of the model together with the satisfactory accuracy of the results make it a promising approach to studying conformational transitions in large protein systems. PMID- 26598362 TI - Detailed Investigation of the OH Radical Quenching by Natural Antioxidant Caffeic Acid Studied by Quantum Mechanical Models. AB - The effectiveness of naturally occurring antioxidant caffeic acid in the inactivation of the very damaging hydroxyl radical has been theoretically investigated by means of hybrid density functional theory. Three possible pathways by which caffeic acid may inactivate free radicals were analyzed: hydrogen abstraction from all available hydrogen atoms, hydroxyl radical addition to all carbon atoms in the molecule, and single electron transfer. The reaction paths were traced independently, and the respective thermal rate constants were calculated using variational transition-state theory including the contribution of tunneling. The more reactive sites in caffeic acid are the C4OH phenolic group and the C4 carbon atom, for the hydrogen abstraction and radical addition, respectively. The single electron transfer process seems to be thermodynamically unfavored, in both polar and nonpolar media. Both hydrogen abstraction and radical addition are very feasible, with a slight preference for the latter, with a rate constant of 7.29 * 10(10) M(-1) s(-1) at 300 K. Tunnel effects are found to be quite unimportant in both cases. Results indicate caffeic acid as a potent natural antioxidant in trapping and scavenging hydroxyl radicals. PMID- 26598363 TI - Operational derivation of Boltzmann distribution with Maxwell's demon model. AB - The resolution of the Maxwell's demon paradox linked thermodynamics with information theory through information erasure principle. By considering a demon endowed with a Turing-machine consisting of a memory tape and a processor, we attempt to explore the link towards the foundations of statistical mechanics and to derive results therein in an operational manner. Here, we present a derivation of the Boltzmann distribution in equilibrium as an example, without hypothesizing the principle of maximum entropy. Further, since the model can be applied to non equilibrium processes, in principle, we demonstrate the dissipation-fluctuation relation to show the possibility in this direction. PMID- 26598365 TI - Biased Gene Conversion in Rhizobium etli Is Caused by Preferential Double-Strand Breaks on One of the Recombining Homologs. AB - Gene conversion, the nonreciprocal transfer of information during homologous recombination, is the main process that maintains identity between members of multigene families. Gene conversion in the nitrogenase (nifH) multigene family of Rhizobium etli was analyzed by using a two-plasmid system, where each plasmid carried a copy of nifH. One of the nifH copies was modified, creating restriction fragment length polymorphisms (RFLPs) spaced along the gene. Once the modified plasmid was introduced into R. etli, selection was done for cointegration with a resident plasmid lacking the RFLPs. Most of the cointegrate molecules harbor gene conversion events, biased toward a gain of RFLPs. This bias may be explained under the double-strand break repair model by proposing that the nifH gene lacking the RFLPs suffers a DNA double-strand break, so the incoming plasmid functions as a template for repairing the homolog on the resident plasmid. To support this proposal, we cloned an SceI site into the nifH homolog that had the RFLPs used for scoring gene conversion. In vivo expression of the meganuclease I SceI allowed the generation of a double-strand break on this homolog. Upon introduction of this modified plasmid into an R. etli strain lacking I-SceI, biased gene conversion still favored the retention of markers on the incoming plasmid. In contrast, when the recipient strain ectopically expressed I-SceI, a dramatic reversal in gene conversion bias was seen, favoring the preservation of resident sequences. These results show that biased gene conversion is caused by preferential double-strand breaks on one of the recombining homologs. IMPORTANCE: In this work, we analyzed gene conversion by using a system that entails horizontal gene transfer followed by homologous recombination in the recipient cell. Most gene conversion events are biased toward the acquisition of the incoming sequences, ranging in size from 120 bp to 800 bp. This bias is due to preferential cutting of resident DNA and can be reversed upon introduction of a double-strand break on the incoming sequence. Since conditions used in this work are similar to those in horizontal gene transfer, it provides evidence that, upon transfer, the resident DNA preferentially acquires gene variants. PMID- 26598364 TI - Regulation of Type IV Pili Contributes to Surface Behaviors of Historical and Epidemic Strains of Clostridium difficile. AB - The intestinal pathogen Clostridium difficile is an urgent public health threat that causes antibiotic-associated diarrhea and is a leading cause of fatal nosocomial infections in the United States. C. difficile rates of recurrence and mortality have increased in recent years due to the emergence of so-called "hypervirulent" epidemic strains. A great deal of the basic biology of C. difficile has not been characterized. Recent findings that flagellar motility, toxin synthesis, and type IV pilus (TFP) formation are regulated by cyclic diguanylate (c-di-GMP) reveal the importance of this second messenger for C. difficile gene regulation. However, the function(s) of TFP in C. difficile remains largely unknown. Here, we examine TFP-dependent phenotypes and the role of c-di-GMP in controlling TFP production in the historical 630 and epidemic R20291 strains of C. difficile. We demonstrate that TFP contribute to C. difficile biofilm formation in both strains, but with a more prominent role in R20291. Moreover, we report that R20291 is capable of TFP-dependent surface motility, which has not previously been described in C. difficile. The expression and regulation of the pilA1 pilin gene differs between R20291 and 630, which may underlie the observed differences in TFP-mediated phenotypes. The differences in pilA1 expression are attributable to greater promoter-driven transcription in R20291. In addition, R20291, but not 630, upregulates c-di-GMP levels during surface-associated growth, suggesting that the bacterium senses its substratum. The differential regulation of surface behaviors in historical and epidemic C. difficile strains may contribute to the different infection outcomes presented by these strains. IMPORTANCE: How Clostridium difficile establishes and maintains colonization of the host bowel is poorly understood. Surface behaviors of C. difficile are likely relevant during infection, representing possible interactions between the bacterium and the intestinal environment. Pili mediate bacterial interactions with various surfaces and contribute to the virulence of many pathogens. We report that type IV pili (TFP) contribute to biofilm formation by C. difficile. TFP are also required for surface motility, which has not previously been demonstrated for C. difficile. Furthermore, an epidemic associated C. difficile strain showed higher pilin gene expression and greater dependence on TFP for biofilm production and surface motility. Differences in TFP regulation and their effects on surface behaviors may contribute to increased virulence in recent epidemic strains. PMID- 26598366 TI - csrT Represents a New Class of csrA-Like Regulatory Genes Associated with Integrative Conjugative Elements of Legionella pneumophila. AB - Bacterial evolution is accelerated by mobile genetic elements. To spread horizontally and to benefit the recipient bacteria, genes encoded on these elements must be properly regulated. Among the legionellae are multiple integrative conjugative elements (ICEs) that each encode a paralog of the broadly conserved regulator csrA. Using bioinformatic analyses, we deduced that specific csrA paralogs are coinherited with particular lineages of the type IV secretion system that mediates horizontal spread of its ICE, suggesting a conserved regulatory interaction. As a first step to investigate the contribution of csrA regulators to this class of mobile genetic elements, we analyzed here the activity of the csrA paralog encoded on Legionella pneumophila ICE-betaox. Deletion of this gene, which we name csrT, had no observed effect under laboratory conditions. However, ectopic expression of csrT abrogated the protection to hydrogen peroxide and macrophage degradation that ICE-betaox confers to L. pneumophila. When ectopically expressed, csrT also repressed L. pneumophila flagellin production and motility, a function similar to the core genome's canonical csrA. Moreover, csrT restored the repression of motility to csrA mutants of Bacillus subtilis, a finding consistent with the predicted function of CsrT as an mRNA binding protein. Since all known ICEs of legionellae encode coinherited csrA-type IV secretion system pairs, we postulate that CsrA superfamily proteins regulate ICE activity to increase their horizontal spread, thereby expanding L. pneumophila versatility. IMPORTANCE: ICEs are mobile DNA elements whose type IV secretion machineries mediate spread among bacterial populations. All surveyed ICEs within the Legionella genus also carry paralogs of the essential life cycle regulator csrA. It is striking that the csrA loci could be classified into distinct families based on either their sequence or the subtype of the adjacent type IV secretion system locus. To investigate whether ICE-encoded csrA paralogs are bona fide regulators, we analyzed ICE-betaox as a model system. When expressed ectopically, its csrA paralog inhibited multiple ICE betaox phenotypes, as well as the motility of not only Legionella but also Bacillus subtilis. Accordingly, we predict that CsrA regulators equip legionellae ICEs to promote their spread via dedicated type IV secretion systems. PMID- 26598369 TI - Pharmaphobes, pharmascolds and conflict denialists. PMID- 26598367 TI - Regulation of a Protein Acetyltransferase in Myxococcus xanthus by the Coenzyme NADP. AB - NADP(+) is a vital cofactor involved in a wide variety of activities, such as redox potential and cell death. Here, we show that NADP(+) negatively regulates an acetyltransferase from Myxococcus xanthus, Mxan_3215 (MxKat), at physiologic concentrations. MxKat possesses an NAD(P)-binding domain fused to the Gcn5-type N acetyltransferase (GNAT) domain. We used isothermal titration calorimetry (ITC) and a coupled enzyme assay to show that NADP(+) bound to MxKat and that the binding had strong effects on enzyme activity. The Gly11 residue of MxKat was confirmed to play an important role in NADP(+) binding using site-directed mutagenesis and circular dichroism spectrometry. In addition, using mass spectrometry, site-directed mutagenesis, and a coupling enzymatic assay, we demonstrated that MxKat acetylates acetyl coenzyme A (acetyl-CoA) synthetase (Mxan_2570) at Lys622 in response to changes in NADP(+) concentration. Collectively, our results uncovered a mechanism of protein acetyltransferase regulation by the coenzyme NADP(+) at physiological concentrations, suggesting a novel signaling pathway for the regulation of cellular protein acetylation. IMPORTANCE: Microorganisms have developed various protein posttranslational modifications (PTMs), which enable cells to respond quickly to changes in the intracellular and extracellular milieus. This work provides the first biochemical characterization of a protein acetyltransferase (MxKat) that contains a fusion between a GNAT domain and NADP(+)-binding domain with Rossmann folds, and it demonstrates a novel signaling pathway for regulating cellular protein acetylation in M. xanthus. We found that NADP(+) specifically binds to the Rossmann fold of MxKat and negatively regulates its acetyltransferase activity. This finding provides novel insight for connecting cellular metabolic status (NADP(+) metabolism) with levels of protein acetylation, and it extends our understanding of the regulatory mechanisms underlying PTMs. PMID- 26598368 TI - Functional Analysis of Bacteriophage Immunity through a Type I-E CRISPR-Cas System in Vibrio cholerae and Its Application in Bacteriophage Genome Engineering. AB - The classical and El Tor biotypes of Vibrio cholerae serogroup O1, the etiological agent of cholera, are responsible for the sixth and seventh (current) pandemics, respectively. A genomic island (GI), GI-24, previously identified in a classical biotype strain of V. cholerae, is predicted to encode clustered regularly interspaced short palindromic repeat (CRISPR)-associated proteins (Cas proteins); however, experimental evidence in support of CRISPR activity in V. cholerae has not been documented. Here, we show that CRISPR-Cas is ubiquitous in strains of the classical biotype but excluded from strains of the El Tor biotype. We also provide in silico evidence to suggest that CRISPR-Cas actively contributes to phage resistance in classical strains. We demonstrate that transfer of GI-24 to V. cholerae El Tor via natural transformation enables CRISPR Cas-mediated resistance to bacteriophage CP-T1 under laboratory conditions. To elucidate the sequence requirements of this type I-E CRISPR-Cas system, we engineered a plasmid-based system allowing the directed targeting of a region of interest. Through screening for phage mutants that escape CRISPR-Cas-mediated resistance, we show that CRISPR targets must be accompanied by a 3' TT protospacer-adjacent motif (PAM) for efficient interference. Finally, we demonstrate that efficient editing of V. cholerae lytic phage genomes can be performed by simultaneously introducing an editing template that allows homologous recombination and escape from CRISPR-Cas targeting. IMPORTANCE: Cholera, caused by the facultative pathogen Vibrio cholerae, remains a serious public health threat. Clustered regularly interspaced short palindromic repeats and CRISPR-associated proteins (CRISPR-Cas) provide prokaryotes with sequence specific protection from invading nucleic acids, including bacteriophages. In this work, we show that one genomic feature differentiating sixth pandemic (classical biotype) strains from seventh pandemic (El Tor biotype) strains is the presence of a CRISPR-Cas system in the classical biotype. We demonstrate that the CRISPR-Cas system from a classical biotype strain can be transferred to a V. cholerae El Tor biotype strain and that it is functional in providing resistance to phage infection. Finally, we show that this CRISPR-Cas system can be used as an efficient tool for the editing of V. cholerae lytic phage genomes. PMID- 26598370 TI - Right to die in Canada: respecting the wishes of physician conscientious objectors. PMID- 26598372 TI - Canadian experts seek pediatric formulary. PMID- 26598371 TI - Potential harms of proton pump inhibitor therapy: rare adverse effects of commonly used drugs. PMID- 26598373 TI - Medicine at sea: the front line of the migrant crisis. PMID- 26598374 TI - Periorbital erythema following alcohol ingestion during treatment with topical tacrolimus. PMID- 26598375 TI - Acute optic neuritis in multiple sclerosis. PMID- 26598377 TI - Urinary urgency and frequency in a 53-year-old woman. PMID- 26598376 TI - Resting heart rate and all-cause and cardiovascular mortality in the general population: a meta-analysis. AB - BACKGROUND: Data on resting heart rate and risk of all-cause and cardiovascular mortality are inconsistent; the magnitude of associations between resting heart rate and risk of all-cause and cardiovascular mortality varies across studies. We performed a meta-analysis of prospective cohort studies to quantitatively evaluate the associations in the general population. METHODS: We searched PubMed, Embase and MEDLINE from inception to Jan. 1, 2015. We used a random-effects model to combine study-specific relative risks and 95% confidence intervals (CIs). We used restricted cubic spline functions to assess the dose-response relation. RESULTS: A total of 46 studies were included in the meta-analysis, involving 1 246 203 patients and 78 349 deaths for all-cause mortality, and 848 320 patients and 25 800 deaths for cardiovascular mortality. The relative risk with 10 beats/min increment of resting heart rate was 1.09 (95% CI 1.07-1.12) for all cause mortality and 1.08 (95% CI 1.06-1.10) for cardiovascular mortality. Compared with the lowest category, patients with a resting heart rate of 60-80 beats/min had a relative risk of 1.12 (95% CI 1.07-1.17) for all-cause mortality and 1.08 (95% CI 0.99-1.17) for cardiovascular mortality, and those with a resting heart rate of greater than 80 beats/min had a relative risk of 1.45 (95% CI 1.34-1.57) for all-cause mortality and 1.33 (95% CI 1.19-1.47) for cardiovascular mortality. Overall, the results did not differ after adjustment for traditional risk factors for cardiovascular disease. Compared with 45 beats/min, the risk of all-cause mortality increased significantly with increasing resting heart rate in a linear relation, but a significantly increased risk of cardiovascular mortality was observed at 90 beats/min. Substantial heterogeneity and publication bias were detected. INTERPRETATION: Higher resting heart rate was independently associated with increased risks of all-cause and cardiovascular mortality. This indicates that resting heart rate is a predictor of all-cause and cardiovascular mortality in the general population. PMID- 26598378 TI - Inequalities in access to bariatric surgery in Canada. PMID- 26598379 TI - Reimbursement discussions exclude surrogates, donors. PMID- 26598382 TI - Correction. PMID- 26598380 TI - Differential impact of high and low penetrance TNFRSF1A gene mutations on conventional and regulatory CD4+ T cell functions in TNFR1-associated periodic syndrome. AB - TNFR-associated periodic syndrome is an autoinflammatory disorder caused by autosomal-dominant mutations in TNFRSF1A, the gene encoding for TNFR superfamily 1A. The lack of knowledge in the field of TNFR-associated periodic syndrome biology is clear, particularly in the context of control of immune self tolerance. We investigated how TNF-alpha/TNFR superfamily 1A signaling can affect T cell biology, focusing on conventional CD4(+)CD25(-) and regulatory CD4(+)CD25(+) T cell functions in patients with TNFR-associated periodic syndrome carrying either high or low penetrance TNFRSF1A mutations. Specifically, we observed that in high penetrance TNFR-associated periodic syndrome, at the molecular level, these alterations were secondary to a hyperactivation of the ERK1/2, STAT1/3/5, mammalian target of rapamycin, and NF-kappaB pathways in conventional T cells. In addition, these patients had a lower frequency of peripheral regulatory T cells, which also displayed a defective suppressive phenotype. These alterations were partially found in low penetrance TNFR associated periodic syndrome, suggesting a specific link between the penetrance of the TNFRSF1A mutation and the observed T cell phenotype. Taken together, our data envision a novel role for adaptive immunity in the pathogenesis of TNFR associated periodic syndrome involving both CD4(+) conventional T cells and Tregs, suggesting a novel mechanism of inflammation in the context of autoinflammatory disorders. PMID- 26598383 TI - Correction. PMID- 26598387 TI - Upfront combination therapy: does the AMBITION study herald a new era in the treatment of pulmonary arterial hypertension? PMID- 26598385 TI - Effectiveness of Practices To Increase Timeliness of Providing Targeted Therapy for Inpatients with Bloodstream Infections: a Laboratory Medicine Best Practices Systematic Review and Meta-analysis. AB - BACKGROUND: Bloodstream infection (BSI) is a major cause of morbidity and mortality throughout the world. Rapid identification of bloodstream pathogens is a laboratory practice that supports strategies for rapid transition to direct targeted therapy by providing for timely and effective patient care. In fact, the more rapidly that appropriate antimicrobials are prescribed, the lower the mortality for patients with sepsis. Rapid identification methods may have multiple positive impacts on patient outcomes, including reductions in mortality, morbidity, hospital lengths of stay, and antibiotic use. In addition, the strategy can reduce the cost of care for patients with BSIs. OBJECTIVES: The purpose of this review is to evaluate the evidence for the effectiveness of three rapid diagnostic practices in decreasing the time to targeted therapy for hospitalized patients with BSIs. The review was performed by applying the Centers for Disease Control and Prevention's (CDC's) Laboratory Medicine Best Practices Initiative (LMBP) systematic review methods for quality improvement (QI) practices and translating the results into evidence-based guidance (R. H. Christenson et al., Clin Chem 57:816-825, 2011, http://dx.doi.org/10.1373/clinchem.2010.157131). SEARCH STRATEGY: A comprehensive literature search was conducted to identify studies with measurable outcomes. A search of three electronic bibliographic databases (PubMed, Embase, and CINAHL), databases containing "gray" literature (unpublished academic, government, or industry evidence not governed by commercial publishing) (CIHI, NIHR, SIGN, and other databases), and the Cochrane database for English-language articles published between 1990 and 2011 was conducted in July 2011. DATES OF SEARCH: The dates of our search were from 1990 to July 2011. SELECTION CRITERIA: Animal studies and non-English publications were excluded. The search contained the following medical subject headings: bacteremia; bloodstream infection; time factors; health care costs; length of stay; morbidity; mortality; antimicrobial therapy; rapid molecular techniques, polymerase chain reaction (PCR); in situ hybridization, fluorescence; treatment outcome; drug therapy; patient care team; pharmacy service, hospital; hospital information systems; Gram stain; pharmacy service; and spectrometry, mass, matrix-assisted laser desorption-ionization. Phenotypic as well as the following key words were searched: targeted therapy; rapid identification; rapid; Gram positive; Gram negative; reduce(ed); cost(s); pneumoslide; PBP2; tube coagulase; matrix-assisted laser desorption/ionization time of flight; MALDI TOF; blood culture; EMR; electronic reporting; call to provider; collaboration; pharmacy; laboratory; bacteria; yeast; ICU; and others. In addition to the electronic search being performed, a request for unpublished quality improvement data was made to the clinical laboratory community. MAIN RESULTS: Rapid molecular testing with direct communication significantly improves timeliness compared to standard testing. Rapid phenotypic techniques with direct communication likely improve the timeliness of targeted therapy. Studies show a significant and homogeneous reduction in mortality associated with rapid molecular testing combined with direct communication. AUTHORS' CONCLUSIONS: No recommendation is made for or against the use of the three assessed practices of this review due to insufficient evidence. The overall strength of evidence is suggestive; the data suggest that each of these three practices has the potential to improve the time required to initiate targeted therapy and possibly improve other patient outcomes, such as mortality. The meta-analysis results suggest that the implementation of any of the three practices may be more effective at increasing timeliness to targeted therapy than routine microbiology techniques for identification of the microorganisms causing BSIs. Based on the included studies, results for all three practices appear applicable across multiple microorganisms, including methicillin-resistant Staphylococcus aureus (MRSA), methicillin-sensitive S. aureus (MSSA), Candida species, and Enterococcus species. PMID- 26598386 TI - Effectiveness of Preanalytic Practices on Contamination and Diagnostic Accuracy of Urine Cultures: a Laboratory Medicine Best Practices Systematic Review and Meta-analysis. AB - BACKGROUND: Urinary tract infection (UTI) in the United States is the most common bacterial infection, and urine cultures often make up the largest portion of workload for a hospital-based microbiology laboratory. Appropriately managing the factors affecting the preanalytic phase of urine culture contributes significantly to the generation of meaningful culture results that ultimately affect patient diagnosis and management. Urine culture contamination can be reduced with proper techniques for urine collection, preservation, storage, and transport, the major factors affecting the preanalytic phase of urine culture. OBJECTIVES: The purposes of this review were to identify and evaluate preanalytic practices associated with urine specimens and to assess their impact on the accuracy of urine culture microbiology. Specific practices included collection methods for men, women, and children; preservation of urine samples in boric acid solutions; and the effect of refrigeration on stored urine. Practice efficacy and effectiveness were measured by two parameters: reduction of urine culture contamination and increased accuracy of patient diagnosis. The CDC Laboratory Medicine Best Practices (LMBP) initiative's systematic review method for assessment of quality improvement (QI) practices was employed. Results were then translated into evidence-based practice guidelines. SEARCH STRATEGY: A search of three electronic bibliographic databases (PubMed, SCOPUS, and CINAHL), as well as hand searching of bibliographies from relevant information sources, for English language articles published between 1965 and 2014 was conducted. SELECTION CRITERIA: The search contained the following medical subject headings and key text words: urinary tract infections, UTI, urine/analysis, urine/microbiology, urinalysis, specimen handling, preservation, biological, preservation, boric acid, boric acid/borate, refrigeration, storage, time factors, transportation, transport time, time delay, time factor, timing, urine specimen collection, catheters, indwelling, urinary reservoirs, continent, urinary catheterization, intermittent urethral catheterization, clean voided, midstream, Foley, suprapubic, bacteriological techniques, and microbiological techniques. MAIN RESULTS: Both boric acid and refrigeration adequately preserved urine specimens prior to their processing for up to 24 h. Urine held at room temperature for more than 4 h showed overgrowth of both clinically significant and contaminating microorganisms. The overall strength of this body of evidence, however, was rated as low. For urine specimens collected from women, there was no difference in rates of contamination for midstream urine specimens collected with or without cleansing. The overall strength of this evidence was rated as high. The levels of diagnostic accuracy of midstream urine collection with or without cleansing were similar, although the overall strength of this evidence was rated as low. For urine specimens collected from men, there was a reduction in contamination in favor of midstream clean-catch over first-void specimen collection. The strength of this evidence was rated as high. Only one study compared midstream collection with cleansing to midstream collection without cleansing. Results showed no difference in contamination between the two methods of collection. However, imprecision was due largely to the small event size. The diagnostic accuracy of midstream urine collection from men compared to straight catheterization or suprapubic aspiration was high. However, the overall strength of this body of evidence was rated as low. For urine specimens collected from children and infants, the evidence comparing contamination rates for midstream urine collection with cleansing, midstream collection without cleansing, sterile urine bag collection, and diaper collection pointed to larger reductions in the odds of contamination in favor of midstream collection with cleansing over the other methods of collection. This body of evidence was rated as high. The accuracy of diagnosis of urinary tract infection from midstream clean-catch urine specimens, sterile urine bag specimens, or diaper specimens compared to straight catheterization or suprapubic aspiration was varied. AUTHORS' CONCLUSIONS: No recommendation for or against is made for delayed processing of urine stored at room temperature, refrigerated, or preserved in boric acid. This does not preclude the use of refrigeration or chemical preservatives in clinical practice. It does indicate, however, that more systematic studies evaluating the utility of these measures are needed. If noninvasive collection is being considered for women, midstream collection with cleansing is recommended, but no recommendation for or against is made for midstream collection without cleansing. If noninvasive collection is being considered for men, midstream collection with cleansing is recommended and collection of first-void urine is not recommended. No recommendation for or against is made for collection of midstream urine without cleansing. If noninvasive collection is being considered for children, midstream collection with cleansing is recommended and collection in sterile urine bags, from diapers, or midstream without cleansing is not recommended. Whether midstream collection with cleansing can be routinely used in place of catheterization or suprapubic aspiration is unclear. The data suggest that midstream collection with cleansing is accurate for the diagnosis of urinary tract infections in infants and children and has higher average accuracy than sterile urine bag collection (data for diaper collection were lacking); however, the overall strength of evidence was low, as multivariate modeling could not be performed, and thus no recommendation for or against can be made. PMID- 26598388 TI - Quantitative evaluation of the transplanted lin(-) hematopoietic cell migration kinetics. AB - Stem cells take part in organogenesis, cell maturation and injury repair. The migration is necessary for each of these functions to occur. The aim of this study was to investigate the kinetics of transplanted hematopoietic lin(-) cell population (which consists mainly of the stem and progenitor cells) in BALB/c mouse contact hypersensitivity model and quantify the migration to the site of inflammation in the affected foot and other healthy organs. Quantitative analysis was carried out with the real-time polymerase chain reaction method. Spleen, kidney, bone marrow, lung, liver, damaged and healthy foot tissue samples at different time points were collected for analysis. The quantitative data normalization was performed according to the comparative quantification method. The analysis of foot samples shows the significant migration of transplanted cells to the recipient mice affected foot. The quantity was more than 1000 times higher, as compared with that of the untreated foot. Due to the inflammation, the number of donor origin cells migrating to the lungs, liver, spleen and bone marrow was found to be decreased. Our data shows that transplanted cells selectively migrated into the inflammation areas of the foot edema. Also, the inflammation caused a secondary migration in ectopic spleen of hematopoietic stem cell niches and re-homing from the spleen to the bone marrow took place. PMID- 26598389 TI - Reply: Does morphological assessment have a role in classifying oligoastrocytoma as 'oligodendroglial' versus 'astrocytic'? Or - who's afraid of the ... liger? PMID- 26598391 TI - Epidemiology, genetic, natural history and clinical presentation of giant cerebral aneurysms. AB - Giant cerebral aneurysms represent 5% of intracranial aneurysms, and become symptomatic between 40 and 70 years with a female predominance. In the paediatric population, the giant aneurysm rate is higher than in the adult population. Classified as saccular, fusiform and serpentine, the natural history of giant cerebral aneurysms is characterized by thrombosis, growth and rupture. The pathogenesis of these giant aneurysms is influenced by a number of risk factors, including genetic variables. Genome-wide association studies have identified some chromosomes highlighting candidate genes. Although these giant aneurysms can occur at the same locations as their smaller counterparts, a predilection for the cavernous location has been observed. Giant aneurysms present with symptoms caused by a mass effect depending on their location or by rupture; ischemic manifestations rarely reveal the aneurysm. If the initial clinical descriptions have been back up by imagery, the clinical context with a pertinent analysis of the risk factors remain the cornerstone for the management decisions of these lesions. Five year cumulative rupture rates for patients with giant aneurysm were 40% for those located on the anterior part of circle of Willis and 50% for those on the posterior part. The poor outcome of untreated patients justifies the therapeutic risks. PMID- 26598392 TI - Foreign body of the brainstem by penetrating injury: Conservative treatment. AB - Traumatic brainstem injuries usually lead to severe lesions and unfavourable outcome. In the literature, the few cases with favourable outcome all benefited from surgical removal of the foreign body. We report a very unusual case of a penetrating brainstem injury with a crossbow arrow with conservative treatment and favourable clinical course despite an infectious complication (brainstem abscess). This case illustrates an important gap between a good clinical status and the severity of the lesion highlighted by CT scan. In addition, a collegial decision was made not to treat the lesion surgically, but only the complication, the abscess, by stereotactic puncture. The treatment must thus be tailored in this type of lesion. PMID- 26598390 TI - Genome-wide alterations in hippocampal 5-hydroxymethylcytosine links plasticity genes to acute stress. AB - Environmental stress is among the most important contributors to increased susceptibility to develop psychiatric disorders, including anxiety and post traumatic stress disorder. While even acute stress alters gene expression, the molecular mechanisms underlying these changes remain largely unknown. 5 hydroxymethylcytosine (5hmC) is a novel environmentally sensitive DNA modification that is highly enriched in post-mitotic neurons and is associated with active transcription of neuronal genes. Recently, we found a hippocampal increase of 5hmC in the glucocorticoid receptor gene (Nr3c1) following acute stress, warranting a deeper investigation of stress-related 5hmC levels. Here we used an established chemical labeling and affinity purification method coupled with high-throughput sequencing technology to generate the first genome-wide profile of hippocampal 5hmC following exposure to acute restraint stress and a one-hour recovery. This approach found a genome-wide disruption in 5hmC associated with acute stress response, primarily in genic regions, and identified known and potentially novel stress-related targets that have a significant enrichment for neuronal ontological functions. Integration of these data with hippocampal gene expression data from these same mice found stress-related hydroxymethylation correlated to altered transcript levels and sequence motif predictions indicated that 5hmC may function by mediating transcription factor binding to these transcripts. Together, these data reveal an environmental impact on this newly discovered epigenetic mark in the brain and represent a critical step toward understanding stress-related epigenetic mechanisms that alter gene expression and can lead to the development of psychiatric disorders. PMID- 26598393 TI - Acute myeloid leukemia--major progress over four decades and glimpses into the future. AB - In this Review, the progress in research and therapy of acute myeloid leukemia is detailed. PMID- 26598394 TI - Rilmenidine suppresses proliferation and promotes apoptosis via the mitochondrial pathway in human leukemic K562 cells. AB - Imidazoline I1 receptor signaling is associated with pathways that regulate cell viability leading to varied cell-type specific phenotypes. We demonstrated that the antihypertensive drug rilmenidine, a selective imidazoline I1 receptor agonist, modulates proliferation and stimulates the proapoptotic protein Bax thus inducing the perturbation of the mitochondrial pathway and apoptosis in human leukemic K562 cells. Rilmenidine acts through a mechanism which involves deactivation of Ras/MAP kinases ERK, p38 and JNK. Moreover, rilmenidine renders K562 cells, which are particularly resistant to chemotherapeutic agents, susceptible to the DNA damaging drug doxorubicin. The rilmenidine co-treatment with doxorubicin reverses G2/M arrest and triggers apoptotic response to DNA damage. Our data offer new insights into the pathways associated with imidazoline I1 receptor activation in K562 cells suggesting rilmenidine as a valuable tool to deepen our understanding of imidazoline I1 receptor signaling in hematologic malignancies and to search for medicinally active agents. PMID- 26598395 TI - Characterization of magnetic nanoparticles from Magnetospirillum Gryphiswaldense as potential theranostics tools. AB - We investigated the theranostic properties of magnetosomes (MNs) extracted from magnetotactic bacteria, promising for nanomedicine applications. Besides a physico-chemical characterization, their potentiality as mediators for magnetic fluid hyperthermia and contrast agents for magnetic resonance imaging, both in vitro and in vivo, are here singled out. The MNs, constituted by magnetite nanocrystals arranged in chains, show a superparamagnetic behaviour and a clear evidence of Verwey transition, as signature of magnetite presence. The phospholipid membrane provides a good protection against oxidation and the MNs oxidation state is stable over months. Using an alternate magnetic field, the specific absorption rate was measured, resulting among the highest reported in literature. The MRI contrast efficiency was evaluated by means of the acquisition of complete NMRD profiles. The transverse relaxivity resulted as high as the one of a former commercial contrast agent. The MNs were inoculated into an animal model of tumour and their presence was detected by magnetic resonance images two weeks after the injection in the tumour mass. PMID- 26598396 TI - Inflation and Bi-Axial Tensile Testing of Healthy Porcine Carotid Arteries. AB - Knowledge of the intrinsic material properties of healthy and diseased arterial tissue components is of great importance in diagnostics. This study describes an in vitro comparison of 13 porcine carotid arteries using inflation testing combined with functional ultrasound and bi-axial tensile testing. The measured tissue behavior was described using both a linear, but geometrically non-linear, one-parameter (neo-Hookean) model and a two-parameter non-linear (Demiray) model. The shear modulus estimated using the linear model resulted in good agreement between the ultrasound and tensile testing methods, GUS = 25 +/- 5.7 kPa and GTT = 23 +/- 5.4 kPa. No significant correspondence was observed for the non-linear model aUS = 1.0 +/- 2.7 kPa vs. aTT = 17 +/- 8.8 kPa, p ~ 0); however, the exponential parameters were in correspondence (bUS = 12 +/- 4.2 vs. bTT = 10 +/- 1.7, p > 0.05). Estimation of more complex models in vivo is cumbersome considering the sensitivity of the model parameters to small changes in measurement data and the absence of intraluminal pressure data, endorsing the use of a simple, linear model in vivo. PMID- 26598398 TI - Degradation Mechanisms of Solution-Processed Planar Perovskite Solar Cells: Thermally Stimulated Current Measurement for Analysis of Carrier Traps. AB - Degradation mechanisms of CH3 NH3 PbI3 -based planar perovskite solar cells (PSCs) are investigated using a thermally stimulated current technique. Hole traps lying above the valence-band edge of the CH3 NH3 PbI3 are detected in PSCs degraded by continuous simulated solar illumination. One source of the hole traps is the photodegradation of CH3 NH3 PbI3 in the presence of water. PMID- 26598397 TI - Does a host country capture knowledge of migrant doctors and how might it? A study of UK doctors in New Zealand. AB - OBJECTIVES: To investigate International Medical Graduate (IMG) perspectives on opportunities to share technical knowledge and professional experience with host country professionals and mechanisms for this. METHODS: All IMGs from the UK registered with the New Zealand Medical Council who had arrived within the decade to 2014 were surveyed (n = 1357). The main outcome measures were respondent perceptions of host country receptivity to their potential knowledge contribution, and mechanisms through which knowledge might be shared. RESULTS: The survey response rate was 47 % (n = 632). 82 % of respondents agreed colleagues had been receptive to their knowledge contribution; 67 % felt they had been encouraged to share professional knowledge gained abroad; 60 % agreed they had been encouraged to share knowledge of the UK or other health systems. Only 45 % believed there were clear mechanisms in place for knowledge sharing. Statistically significant differences by age and professional practice designation were found. CONCLUSIONS: Knowledge transfer in the New Zealand context appeared to be relatively ad hoc. Options for improving knowledge transfer include formal organisational arrangements, use of knowledge brokers and building communities of practice in different areas. PMID- 26598399 TI - SCCER BIOSWEET - The Swiss Competence Center for Energy Research on Bioenergy. PMID- 26598400 TI - Biochemical Conversion Processes of Lignocellulosic Biomass to Fuels and Chemicals - A Review. AB - Lignocellulosic biomass - such as wood, agricultural residues or dedicated energy crops - is a promising renewable feedstock for production of fuels and chemicals that is available at large scale at low cost without direct competition for food usage. Its biochemical conversion in a sugar platform biorefinery includes three main unit operations that are illustrated in this review: the physico-chemical pretreatment of the biomass, the enzymatic hydrolysis of the carbohydrates to a fermentable sugar stream by cellulases and finally the fermentation of the sugars by suitable microorganisms to the target molecules. Special emphasis in this review is put on the technology, commercial status and future prospects of the production of second-generation fuel ethanol, as this process has received most research and development efforts so far. Despite significant advances, high enzyme costs are still a hurdle for large scale competitive lignocellulosic ethanol production. This could be overcome by a strategy termed 'consolidated bioprocessing' (CBP), where enzyme production, enzymatic hydrolysis and fermentation is integrated in one step - either by utilizing one genetically engineered superior microorganism or by creating an artificial co-culture. Insight is provided on both CBP strategies for the production of ethanol as well as of advanced fuels and commodity chemicals. PMID- 26598401 TI - Improving Heterogeneous Catalyst Stability for Liquid-phase Biomass Conversion and Reforming. AB - Biomass is a possible renewable alternative to fossil carbon sources. Today, many bio-resources can be converted to direct substitutes or suitable alternatives to fossil-based fuels and chemicals. However, catalyst deactivation under the harsh, often liquid-phase reaction conditions required for biomass treatment is a major obstacle to developing processes that can compete with the petrochemical industry. This review presents recently developed strategies to limit reversible and irreversible catalyst deactivation such as metal sintering and leaching, metal poisoning and support collapse. Methods aiming to increase catalyst lifetime include passivation of low-stability atoms by overcoating, creation of microenvironments hostile to poisons, improvement of metal stability, or reduction of deactivation by process engineering. PMID- 26598402 TI - Application of Ionic Liquids in the Downstream Processing of Lignocellulosic Biomass. AB - Chemical transformations of lignocellulosic substrates to valuable platform chemicals are challenging as lignin and cellulose have high thermal and chemical stabilities. However, certain ionic liquids are able to dissolve and deconstruct biomass and, in the presence of catalysts, convert the dissolved/deconstructed species into useful platform chemicals. Herein, we provide a concise overview of the role of ionic liquids in biomass processing. Using 5-hydroxymethylfurfural as an example of a renewable building block, available from cellulose, we show how ionic liquids can facilitate its production. PMID- 26598403 TI - Chemicals from Lignin by Catalytic Fast Pyrolysis, from Product Control to Reaction Mechanism. AB - Conversion of lignin into renewable and value-added chemicals by thermal processes, especially pyrolysis, receives great attention. The products may serve as feedstock for chemicals and fuels and contribute to the development of a sustainable society. However, the application of lignin conversion is limited by the low selectivity from lignin to the desired products. The opportunities for catalysis to selectively convert lignin into useful chemicals by catalytic fast pyrolysis and our efforts to elucidate the mechanism of lignin pyrolysis are discussed. Possible research directions will be identified. PMID- 26598404 TI - Reactors for Catalytic Methanation in the Conversion of Biomass to Synthetic Natural Gas (SNG). AB - Production of Synthetic Natural Gas (SNG) from biomass is an important step to decouple the use of bioenergy from the biomass production with respect to both time and place. While anaerobic digestion of wet biomass is a state-of-the art process, wood gasification to producer gas followed by gas cleaning and methanation has only just entered the demonstration scale. Power-to-Gas applications using biogas from biomass fermentation or producer gas from wood gasification as carbon oxide source are under development. Due to the importance of the (catalytic) methanation step in the production of SNG from dry biomass or within Power-to-Gas applications, the specific challenges of this step and the developed reactor types are discussed in this review. PMID- 26598405 TI - CO Methanation for Synthetic Natural Gas Production. AB - Energy from woody biomass could supplement renewable energy production towards the replacement of fossil fuels. A multi-stage process involving gasification of wood and then catalytic transformation of the producer gas to synthetic natural gas (SNG) represents progress in this direction. SNG can be transported and distributed through the existing pipeline grid, which is advantageous from an economical point of view. Therefore, CO methanation is attracting a great deal of attention and much research effort is focusing on the understanding of the process steps and its further development. This short review summarizes recent efforts at Paul Scherrer Institute on the understanding of the reaction mechanism, the catalyst deactivation, and the development of catalytic materials with benign properties for CO methanation. PMID- 26598407 TI - A Short History of the Use of Plants as Medicines from Ancient Times. AB - A concise historical overview on the use of plants for medical treatments from ancient times is discussed. PMID- 26598406 TI - Opportunities for Switzerland to Contribute to the Production of Algal Biofuels: the Hydrothermal Pathway to Bio-Methane. AB - Microalgae have a significant potential to be a sustainable source of fuel and thus are of interest in the transition to a sustainable energy system, in particular for resource-dependent countries such as Switzerland. Independence of fossil fuels, considerable reduction of CO(2) emissions, and abandoning nuclear energy may be possible with an integrated system approach including the sourcing of biofuels from different types of biomass. Today, a full carbon-to-fuel conversion is possible, and has been recently demonstrated with an advanced hydrothermal technology. The potential to develop algal biofuels is viewed as high thanks to the possibility they offer to uncouple bioenergy from food production. Nevertheless, technological breakthroughs must take place before commercial production becomes a reality, especially to meet the necessary cost savings and efficiency gains in the algae cultivation structure. In addition, an integrated management of waste resources to promote the nutrient recovery appears today as imperative to further improve the economic viability and the environmental sustainability of algal production. We provide here a review that includes the global technological status of both algae production and their conversion into biofuels in order to understand first the added value of algal energy in general before we focus on the potential of algae to contribute specifically to the Swiss energy system to the horizon 2050. In this respect, the hydrothermal conversion pathway of microalgal biomass into synthetic natural gas (SNG) is emphasized, as research into this technology has received considerable attention in Switzerland during the last decade. In addition, SNG is a particularly relevant fuel in the Swiss context due to the existing gas grid and to the opportunity it offers to cover a wide spectrum of energy applications, in particular cogeneration of heat and electricity or use as a transport fuel in the growing gas car fleet. PMID- 26598408 TI - Molecular and Chemical Mechanism in Epigenetics - Swiss Summer School 2015 July 12-17, 2015, Hotel Kurhaus, Arolla, Switzerland. PMID- 26598409 TI - Chemical Modification of Polyhydroxyalkanoates (PHAs) for the Preparation of Hybrid Biomaterials. AB - Polyhydroxyalkanoates (PHAs) are biopolyesters produced by bacteria as intracellular granules under metabolic stress conditions. Many carbon sources such as alkanes, alkenes, alcohols, sugars, fatty acids can be used as feedstock and thus a wide variety of polyesters and monomer units can be potentially synthetized. The work presented here describes the process to chemically modify such biopolymers in order to render them readily available for the preparation of bio-molecular conjugates as promising new classes of biocompatible biomaterials. Such hybrid biomaterials belong to the rapidly growing class of biocompatible polymers, which are of great interest for medical and therapeutic applications. In this work, the biosynthesis of a new PHA homopolymer and the chemical modification, an epoxidation reaction, are described. PMID- 26598410 TI - One Step ahead in Cell Cultivation - International Advanced Training Course at ZHAW Waedenswil. AB - At ZHAW Waedenswil, students from all over the world meet to gain an insight into the laboratories and learn the latest processes in cell cultivation to produce drugs, vaccines and cosmetics. Under the guidance of Professor Regine Eibl, head of cell culture technology, they follow lectures, get to know how to handle insect, hamster and tobacco cells as part of a traineeship and visit industrial research labs - a unique opportunity to build up a network for the future. PMID- 26598411 TI - Where Experts Meet to Exchange Knowledge: Biotechnet's Summer School on Advanced Biotechnology. AB - Science and progress thrive on an open mind and a transnational exchange of ideas and experience. That's why, in 2005, two scientists with a vision launched the biotechnet Summer School on Advanced Biotechnology. This year, too, the Summer School - now held at ZHAW in Waedenswil - is attracting researchers from all over the globe, and is also celebrating its 10(th) anniversary. PMID- 26598414 TI - An efficient screening method for the isolation of heterotrophic bacteria influencing growth of diatoms under photoautotrophic conditions. AB - Interactions between photoautotrophic diatoms and heterotrophic bacteria are important for the biogeochemical C-cycle in the oceans. Additionally, biofilms formed by diatoms and bacteria are the initiating step of biofouling processes, which causes high costs in shipping. Despite this ecological and economical importance, the knowledge about biochemical and molecular mechanisms underlying these interkingdom interactions is relatively small. For analyzing these mechanisms, laboratory model systems are required. In this study, an efficient screening method for isolating bacteria influencing photoautotrophic diatom growth was established. First, diatom cultures of Phaeodactylum tricornutum and Thalassiosira pseudonana were made axenic by applying beta-lactam antibiotics. Second, a non-invasive method for measuring growth of multiple parallel diatom cultures by chlorophyll fluorescence was established. This method allowed semi quantitative chlorophyll determination of cultures with up to 3 MUg (chlorophyll) ml(-1). Axenic diatom cultures were then used for enriching bacteria and led to the isolation of 24 strains influencing growth of both diatom strains in various ways. For example, Rheinheimera sp. strain Tn16 inhibited growth of T. pseudonana, while it stimulated growth and cell aggregation of P. tricornutum. Thus, this screening method is appropriate for isolating heterotrophic bacteria showing different interactions with different diatom species ranging from synergistic to antagonistic. In consecutive applications, this method will be useful to screen for bacterial mutants with altered phenotypes regarding the influence on diatom growth. PMID- 26598415 TI - A Sustainable Route from Biomass Byproduct Okara to High Content Nitrogen-Doped Carbon Sheets for Efficient Sodium Ion Batteries. AB - A sustainable route from the biomass byproduct okara as a natural nitrogen fertilizer to high-content N-doped carbon sheets is demonstrated. The as-prepared unique structure exhibits high specific capacity (292 mAh g(-1) ) and extremely long cycle life (exceeding 2000 cycles). A full battery is devised for the practical use of materials with a flexible/wearable LED screen. PMID- 26598416 TI - [Guidelines 2015 - old wine in new skins?]. PMID- 26598417 TI - Efficacy and safety of catheter ablation vs. rate control of atrial fibrillation in systolic left ventricular dysfunction : A meta-analysis and systematic review. AB - PURPOSE: It is unclear what constitutes the optimal strategy for management of atrial fibrillation (AF) in patients with systolic left ventricular (LV) dysfunction. We hypothesized that catheter ablation of AF had benefits compared with rate control in patients with systolic LV dysfunction. METHODS: PubMed, Embase, and the Cochrane Library were searched for randomized controlled trials and nonrandomized, observational studies. Weighted mean differences (WMD) and 95 % confidence intervals (CIs) were calculated to compare the improvement of left ventricular ejection fraction (LVEF), functional capacity, and quality of life between a catheter ablation group and a rate control group. RESULTS: Six trials with 324 patients were included in the analysis. Patients in the catheter ablation group had greater improvement of LVEF (WMD: 8.89; 95 % CI: 6.93-10.86; p < 0.001), 6-min walk distance (WMD: 46.9; 95 % CI: 28.5-65.4; p < 0.001), and lower Minnesota Living With Heart Failure Questionnaire (MLHFQ) scores (WMD: - 19.6; 95 % CI: - 23.6-- 15.7; p < 0.001) compared with patients in the rate control group. Overall, there were only ten procedure-related events and the procedure-related events rate was 4.9 % per procedure and 5.6 % per patient. CONCLUSION: The present analysis suggests that catheter ablation of AF has benefits in terms of an improvement in LVEF, in functional capacity, and in quality of life compared with rate control in patients with systolic LV dysfunction, and the risk of complications related to procedures is acceptable. PMID- 26598418 TI - Procedural sedation during transradial coronary angiography to prevent spasm. AB - AIM: Radial artery spasm is common during transradial procedures and is the most common cause of procedural failure. The objectives of this study were to assess whether the routine administration of sedation at the beginning of transradial coronary angiography with the use of hydrophilic-coated and smaller sheaths/catheters would reduce the incidence of radial artery spasm. PATIENTS AND METHODS: Patients undergoing transradial coronary angiography were prospectively randomized to receive midazolam during the procedure or no sedative treatment. The primary endpoint was angiographically confirmed radial artery spasm. Stenosis of the radial artery was measured with a computer-assisted quantification method. RESULTS: In all, 150 patients were randomized into a treatment group and a control group. Spasm occurred in 15 patients of the treatment group (20 %) versus 16 in the control group (21.3 %). There were no differences between the two groups regarding the incidence of spasm and the distribution of spasm severity (p > 0.05). No significant differences were observed between the two groups in terms of 30-day mortality or repeat hospitalization for any cause (p > 0.05). CONCLUSION: Routine use of midazolam could not reduce the occurrence of radial artery spasm during transradial coronary angiography. PMID- 26598419 TI - Glucocorticoid receptor but not mineralocorticoid receptor mediates the activation of ERK pathway and CREB during morphine withdrawal. AB - Recent research suggests that glucocorticoids are involved in the development of addiction to drugs of abuse. They share this role with dopamine (DA), and with different signalling pathways and/or transcription factors such as extracellular signal regulated kinases (ERK) and cAMP response element binding protein (CREB). However, the relation between them is not completely elucidated. In this report, we further characterize the role of glucocorticoid and mineralocorticoid receptor (GR and MR) signalling in DA turnover at the Nacc, and in opiate withdrawal induced tyrosine hydroxylase (TH) expression, ERK and CREB phosphorylation (activation) in the nucleus of tractus solitarius (NTS-A2 ). The role of GR and MR signalling was assessed with the selective GR antagonist, mifepristone or the MR antagonist, spironolactone (i.p.). Rats were implanted two morphine (or placebo) pellets. Six days later rats were pretreated with mifepristone, spironolactone or vehicle 30 min before naloxone, and DA turnover, TH expression, ERK and CREB phosphorylation, were measured using HPLC and immunoblotting. Glucocorticoid receptor blockade attenuated ERK and CREB phosphorylation and the TH expression induced by morphine withdrawal. In contrast, no changes were seen after MR blockade. Finally, GR and MR blockade did not alter the morphine withdrawal-induced increase seen both in DA turnover and DA metabolite production, in the NAcc. These results show that not only ERK and CREB phosphorylation but also TH expression in the NTS is modulated by GR signalling. The present results suggest that GR is a therapeutic target to improve aversive events associated with opiate withdrawal. PMID- 26598420 TI - Complete genome sequence of Rufibacter tibetensis strain 1351, a radiation resistant bacterium from Tibet plateau. AB - Rufibacter tibetensis strain 1351, isolated from the soil of the Tibet plateau of China, belongs to the family of Cytophagaceae. It is a red-pigmented, gram negative, strictly aerobic and rod-shaped bacterium and shows resistance to UV radiation. Here, we report its complete genome sequence, which can help us find the key genes of the carotenoid biosynthesis and resistance to UV radiation. PMID- 26598421 TI - Use of near infrared fluorescence during robot-assisted laparoscopic partial nephrectomy. AB - BACKGROUND: Partial nephrectomy is the treatment of choice for T1a tumours. The open approach is still the standard method. Robot-assisted laparoscopic surgery offers advantages that are applicable to partial nephrectomy, such as the use of the Firefly(r) system with near-infrared fluorescence. OBJECTIVE: To demonstrate the implementation of fluorescence in nephron-sparing surgery. CASE REPORT: This case concerned a 37-year-old female smoker, with obesity. The patient had a right kidney tumour measuring 31 mm, which was found using tomography. She therefore underwent robot-assisted laparoscopic partial nephrectomy, with a warm ischaemia time of 22 minutes and the use of fluorescence with the Firefly(r) system to guide the resection. There were no complications. The tumour was a pT1aN0M0 renal cell carcinoma, with negative margins. Robot-assisted renal laparoscopic surgery is employed for nephron-sparing surgery, with good oncological and functional results. The combination of the Firefly(r) technology and intraoperative ultrasound can more accurately delimit the extent of the lesion, increase the negative margins and decrease the ischaemia time. CONCLUSION: Near-infrared fluorescence in robot-assisted partial nephrectomy is useful for guiding the tumour resection and can potentially improve the oncological and functional results. PMID- 26598422 TI - Stable immediate early gene expression patterns in medial prefrontal cortex and striatum after long-term cocaine self-administration. AB - The transition from casual to compulsive drug use is thought to occur as a consequence of repeated drug taking leading to neuroadaptive changes in brain circuitry involved in emotion and cognition. At the basis of such neuroadaptations lie changes in the expression of immediate early genes (IEGs) implicated in transcriptional regulation, synaptic plasticity and intracellular signalling. However, little is known about how IEG expression patterns change during long-term drug self-administration. The present study, therefore, compares the effects of 10 and 60-day self-administration of cocaine and sucrose on the expression of 17 IEGs in brain regions implicated in addictive behaviour, i.e. dorsal striatum, ventral striatum and medial prefrontal cortex (mPFC). Increased expression after cocaine self-administration was found for 6 IEGs in dorsal and ventral striatum (c-fos, Mkp1, Fosb/DeltaFosb, Egr2, Egr4, and Arc) and 10 IEGs in mPFC (same 6 IEGs as in striatum, plus Bdnf, Homer1, Sgk1 and Rgs2). Five of these 10 IEGs (Egr2, Fosb/DeltaFosb, Bdnf, Homer1 and Jun) and Trkb in mPFC were responsive to long-term sucrose self-administration. Importantly, no major differences were found between IEG expression patterns after 10 or 60 days of cocaine self-administration, except Fosb/DeltaFosb in dorsal striatum and Egr2 in mPFC, whereas the amount of cocaine obtained per session was comparable for short term and long-term self-administration. These steady changes in IEG expression are, therefore, associated with stable self-administration behaviour rather than the total amount of cocaine consumed. Thus, sustained impulses to IEG regulation during prolonged cocaine self-administration may evoke neuroplastic changes underlying compulsive drug use. PMID- 26598423 TI - Short-Term Tolvaptan Increases Water Intake and Effectively Decreases Urinary Calcium Oxalate, Calcium Phosphate and Uric Acid Supersaturations. AB - PURPOSE: Some patients cannot effectively increase water intake and urine volume to prevent urinary stones. Tolvaptan, a V2 receptor antagonist, blocks water reabsorption in the collecting duct and should decrease urinary supersaturation of stone forming solutes, although this action has never been proved. MATERIALS AND METHODS: We conducted a double-blind, randomized, placebo controlled, crossover study of 21 calcium urinary stone formers stratified into majority calcium oxalate (10 patients) and calcium phosphate (11) groups. Patients received 45 mg tolvaptan per day or placebo for 1 week, followed by a washout week and crossover to tolvaptan or placebo for week 3. A 24-hour urine sample was collected at the end of weeks 1 and 3. RESULTS: Tolvaptan vs placebo decreased urinary osmolality (mean +/- SD 204 +/- 96 vs 529 +/- 213 mOsm/kg, p <0.001) and increased urinary volume (4.8 +/- 2.9 vs 1.8 +/- 0.9 L, p <0.001). The majority of urinary solute excretion rates, including sodium and calcium, did not change significantly, although oxalate secretion increased slightly (from mean +/- SD 15 +/- 8 to 23 +/- 8 mg per 24 hours, p = 0.009). Mean +/- SD urinary calcium oxalate supersaturation (-0.01 +/- 1.14 vs 0.95 +/- 0.87 dG, p <0.001), calcium phosphate supersaturation (-1.66 +/- 1.17 vs -0.13 +/- 1.02 dG, p <0.001) and uric acid supersaturation (-2.05 +/- 4.05 vs -5.24 +/- 3.12 dG, p = 0.04) all dramatically decreased. Effects did not differ between the calcium oxalate and calcium phosphate groups (p >0.05 for all interactions). CONCLUSIONS: Tolvaptan increases urine volume and decreases urinary supersaturation in calcium stone formers. Further study is needed to determine if long-term use of V2 receptor antagonists results in fewer stone events. PMID- 26598424 TI - Clinical Relevance of Incidental Prostatic Lesions on FDG-Positron Emission Tomography/Computerized Tomography-Should Patients Receive Further Evaluation? AB - PURPOSE: FDG ((18)F-fluoro-2-deoxy-D-glucose)-PET/CT (positron emission tomography)/(computerized tomography) is a widely used diagnostic tool for whole body imaging. Incidental prostatic uptake is often found on FDG-PET/CT. The objective of this study was to determine the clinical relevance of incidental prostatic uptake on FDG-PET/CT. MATERIALS AND METHODS: We analyzed 108 consecutive male patients with bladder cancer who underwent FDG-PET/CT and subsequently radical cystoprostatectomy between May 2009 and November 2014. PET/CT scans were blindly reviewed by a dedicated nuclear medicine physician for incidental prostatic FDG uptake. If present, the maximum standardized uptake value was determined. Subsequently incidental prostatic uptake was categorized as suspect, indeterminate or nonsuspect for prostate cancer. RESULTS: Incidental prostatic uptake was present in 43 of 108 patients (40%). Of these 43 patients 13 (30%) had occult prostate cancer in cystoprostatectomy specimens. Overall prostate cancer was found in 25 of 108 specimens (23%). If all incidental prostatic uptake was regarded as prostate cancer, the sensitivity and specificity of FDG-PET/CT for prostate cancer detection were 52% and 64%, respectively. Positive and negative predictive values were 30% and 82%, respectively. If only lesions labeled suspect or indeterminate were regarded as prostate cancer, sensitivity, specificity, and positive and negative predictive values were 32%, 76%, 29% and 79%, respectively. Categorizing indeterminate lesions as nonprostate cancer did not improve diagnostic accuracy. Gleason score did not correlate with maximum standardized uptake value or serum prostate specific antigen. CONCLUSIONS: Incidental prostatic uptake on FDG-PET/CT has a low positive predictive value for prostate cancer. An attempt to classify lesions as suspect or nonsuspect did not increase diagnostic accuracy. Based on these results physicians should be cautious about applying invasive diagnostic methods to detect prostate cancer in case of incidental prostatic uptake on FDG-PET/CT. PMID- 26598425 TI - Medical Expulsive Therapy is Underused for the Management of Renal Colic in the Emergency Setting. AB - PURPOSE: Although the 2007 AUA (American Urological Association) guidelines established it as first line therapy for ureteral stones less than 10 mm, widespread adoption of medical expulsive therapy has been low. We determined the current penetrance of medical expulsive therapy guideline recommendations and the efficacy of medical expulsive therapy in reducing the requirement for urological procedures after emergency department visits for ureteral stones. MATERIALS AND METHODS: In a retrospective analysis of patients seen in the emergency department we included 2,105 emergency department visits associated with an ICD-9 diagnosis of urolithiasis in which computerized tomography abdomen/pelvis scan was performed. Outcomes were reviewed for spontaneous passage or required urological procedure. RESULTS: Ureteral stones were found in 48.8% of patients, including 50.0% in whom medical expulsive therapy was prescribed. There was no significant difference between patients who did and did not receive medical expulsive therapy. Within 12 weeks of the initial emergency department visit there was no difference in the rate of urological procedures performed in those who received medical expulsive therapy or in the rate of return to the emergency department. Patients treated with medical expulsive therapy experienced a shorter time to spontaneous expulsion (7.1 vs 12.8 days, p = 0.048). CONCLUSIONS: Medical expulsive therapy for renal colic in the emergency setting remains underused. Half of the patients who met criteria for medical expulsive therapy in this study did not receive the standard of care. Patients treated with medical expulsive therapy achieved spontaneous passage more quickly but there was no difference in the requirement for a urological procedure. These results highlight the need for personnel at emergency departments to better standardize care for patients with ureteral stones. PMID- 26598426 TI - A Retrospective Analysis of the Effect on Survival of Time from Diagnosis to Neoadjuvant Chemotherapy to Cystectomy for Muscle Invasive Bladder Cancer. AB - PURPOSE: We determine the impact of the timing of radical cystectomy from the diagnosis of muscle invasive bladder cancer on survival in patients also treated with neoadjuvant chemotherapy. MATERIALS AND METHODS: We performed a retrospective chart review of consecutive patients with muscle invasive bladder cancer who received neoadjuvant chemotherapy followed by cystectomy between 1996 and 2014 at a single institution. Cox proportional hazards regression models were used to investigate the effect of treatment time intervals on overall survival. Three treatment intervals were analyzed for survival impact, from diagnosis of muscle invasive bladder cancer to initiation of neoadjuvant chemotherapy, from initiation of neoadjuvant chemotherapy to cystectomy and from diagnosis to cystectomy. Other pretreatment and posttreatment clinicopathological parameters were also analyzed. RESULTS: Median time from the diagnosis of muscle invasive bladder cancer to radical cystectomy was 28 weeks. Cystectomy performed less than 28 weeks from the diagnosis did not result in significant improvement in overall survival outcomes (HR 0.68, 95% CI 0.28-1.63, p=0.388). Neither the timing of neoadjuvant chemotherapy initiation from diagnosis (median 6 weeks) nor the timing of cystectomy from neoadjuvant chemotherapy initiation (median 22 weeks) was associated with survival. Patient age, variant histology, extravesical and/or lymph node involvement (T3-4 and/or N1 or greater) were significantly associated with survival. CONCLUSIONS: The timing of radical cystectomy in relation to muscle invasive bladder cancer diagnosis date does not significantly impact overall survival in patients with muscle invasive bladder cancer receiving neoadjuvant chemotherapy. PMID- 26598427 TI - Determinants of Prostate Specific Antigen Screening among Black Men in the United States in the Contemporary Era. AB - PURPOSE: Although black men represent a high risk population for prostate specific antigen screening for prostate cancer, recommendations in black men are unclear. To our knowledge the resultant effect of conflicting recommendations and disparities in access to care on prostate specific antigen screening in black men is unknown. MATERIALS AND METHODS: We compared the rate of self-reported prostate specific antigen screening in black men relative to that in nonHispanic white men. The BRFSS (Behavioral Risk Factor Surveillance System) 2012 data set was used to identify asymptomatic men 40 to 99 years old who reported undergoing prostate specific antigen screening in the last 12 months. Age, education, income, residence location, marital status, health insurance, regular access to a health care provider and a health care provider recommendation to undergo screening were extracted. Subgroup analyses by race and age were performed using complex samples logistic regression models to assess the odds of undergoing prostate specific antigen screening. RESULTS: In 2012 there were 122,309 survey respondents (weighted estimate 54.5 million) in the study population, of whom 29% of black and 32% of nonHispanic white men reported undergoing prostate specific antigen screening. Younger black males had higher rates and odds of screening than nonHispanic white men of a similar age (ages 45 to 49, 50 to 54 and 55 to 59 years OR 1.66, 1.58 and 1.36, respectively). Among black men only a higher education level (graduates vs nongraduates OR 2.12), regular access to a health care provider (OR 2.05) and a health care provider recommendation for screening (OR 8.43) were independently associated with prostate specific antigen screening. CONCLUSIONS: Despite long-standing disparities in health care access black males 45 to 60 years old have a higher rate and probability of prostate specific antigen screening than nonHispanic white men. Among black men educational attainment had a more pronounced association. In contrast the association with health care provider recommendations was less pronounced relative to that in nonHispanic white men. Future research may shed more light on the gamut of factors that influence the decision making process for prostate specific antigen testing. PMID- 26598428 TI - Diagnostic contribution of quantitative analysis of salivary scintigraphy in patients with suspected Sjogren's syndrome. AB - AIM: The evaluation of the salivary scintigraphy is part of the classification criteria of Sjogren's syndrome (SS). The aim of the study was to determine a method of quantitative evaluation of this technique with easy application and high diagnostic accuracy. MATERIAL AND METHODS: A review was carried out on a total of 111 patients with clinical suspicion of SS, referred to our department over the last 4 years (94 women, range 14-82 years). Thirty-minute dynamic studies were performed after injection of (99m)Tc-pertechnetate, with secretory stimulus at 15 minutes. After drawing regions of interest in both parotids, submandibular glands, and in the background, quantitative parameters were determined. These included the ejection fraction, uptake ratio at 15 min, and the percentage uptake (PC). Based on the definitive diagnosis, the subjects were classified into patients with SS, with sicca syndrome, and healthy subjects. RESULTS: Significant differences were found between the SS group and healthy subjects in the 3 quantitative parameters for the 4 glands. Significant differences in the PC parameter were observed between the group with sicca syndrome and healthy subjects. ROC analysis showed that the best differentiation parameter for the 3 groups was the PC in both parotid and submandibular glands. CONCLUSIONS: The quantitative analysis of salivary scintigraphy has proved to be a useful method and easy to apply in daily practice to differentiate patients with SS from healthy subjects, with the PC, both in parotid and submandibular glands, being the parameter with highest diagnostic accuracy. PMID- 26598430 TI - Genotypic characterisation of human papillomavirus infections among persons living with HIV infection; a case-control study in Kumasi, Ghana. AB - OBJECTIVES: The objective of this study is to describe the burden of human papillomavirus (HPV) infection among women living with HIV and non-infected women in Ghana. METHODS: A case-control study was conducted involving 107 women living with HIV aged between 18 and 59 years (cases) and 100 non-HIV-infected apparently healthy women (controls) who were recruited from the Kumasi South Hospital, from July to December, 2014. Cervicovaginal swabs were taken from study participants to characterise 28 high- and low-risk HPV genotypes using a multiplex real-time PCR. RESULTS: The overall mean age for the participants was 40.10 +/- 9.76 years. The prevalence of high-risk (hr)-HPV genotypes was significantly higher among the cases than the controls (77.4% vs. 41.6%, P < 0.0001). Overall, HPV 58 and 54 were the most predominant high-risk (18.8%) and low-risk (15.0%) genotypes detected. The two most common hr-HPV genotype isolates were 58 (18.8%) and 35 (15.9%) with 58 being the most prevalent among age group 35-44 years compared with hr-HPV 16, 18, 35 and 45, found predominantly among 18-34 age group. CONCLUSIONS: Significant variations exist in HPV genotypes among HIV-infected and uninfected women. PMID- 26598429 TI - Individualised dosimetry in patients with differentiated thyroid cancer based on external dose-rate. Optimisation of the number of measurements. AB - OBJECTIVES: To compare the results of individual dosimetry in differentiated thyroid cancer patients treated with (131)I at our centre with the established limits and dosimetry results of published studies. Analysis of the optimal number of measurements necessary to reduce the impact of dosimetry for the comfort of the patient and, secondly, on the workload of health workers. MATERIAL AND METHODS: Dosimetry was performed in the Nuclear Medicine Department of the University and Polytechnic Hospital La Fe, on 29 patients suffering from differentiated thyroid cancer and treated with activities between 1.02 and 5.51 GBq (mean 2.68 GBq) of (131)I. The Spanish Society of Medical Physics (SEFM) protocol was used, based on measurements of external dose rate adjusted to a bi exponential curve according to a two compartment model. Different dosimetries were performed on each patient, taking different selections of the available measurements in order to find the optimal number. RESULTS: Results are well below the dosimetry limits, and are consistent with those obtained in other centres. The number of measurements can be reduced from 5, as proposed in the SEFM protocol, to 4 without significant loss of accuracy. Further reducing measures may be justified in individual cases. CONCLUSIONS: The values obtained for the dosimetry quantities are significantly below the established limits. A reduction in measurements can be assumed at the cost of a moderate increase in uncertainty, benefiting the patient. PMID- 26598431 TI - Development of a track in global and humanitarian health for neurology residents. PMID- 26598433 TI - Multifocal cerebellar liponeurocytoma. PMID- 26598432 TI - Summary of comprehensive systematic review: Rehabilitation in multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. AB - OBJECTIVE: To systematically review the evidence regarding rehabilitation treatments in multiple sclerosis (MS). METHODS: We systematically searched the literature (1970-2013) and classified articles using 2004 American Academy of Neurology criteria. RESULTS: This systematic review highlights the paucity of well-designed studies, which are needed to evaluate the available MS rehabilitative therapies. Weekly home/outpatient physical therapy (8 weeks) probably is effective for improving balance, disability, and gait (MS type unspecified, participants able to walk >=5 meters) but probably is ineffective for improving upper extremity dexterity (1 Class I). Inpatient exercises (3 weeks) followed by home exercises (15 weeks) possibly are effective for improving disability (relapsing-remitting MS [RRMS], primary progressive MS [PPMS], secondary progressive MS [SPMS], Expanded Disability Status Scale [EDSS] 3.0-6.5) (1 Class II). Six weeks' worth of comprehensive multidisciplinary outpatient rehabilitation possibly is effective for improving disability/function (PPMS, SPMS, EDSS 4.0-8.0) (1 Class II). Motor and sensory balance training or motor balance training (3 weeks) possibly is effective for improving static and dynamic balance, and motor balance training (3 weeks) possibly is effective for improving static balance (RRMS, SPMS, PPMS) (1 Class II). Breathing-enhanced upper extremity exercises (6 weeks) possibly are effective for improving timed gait and forced expiratory volume in 1 second (RRMS, SPMS, PPMS, mean EDSS 4.5); this change is of unclear clinical significance. This technique possibly is ineffective for improving disability (1 Class II). Inspiratory muscle training (10 weeks) possibly improves maximal inspiratory pressure (RRMS, SPMS, PPMS, EDSS 2-6.5) (1 Class II). PMID- 26598434 TI - Positive straight leg raising test secondary to conjoined lumbosacral nerve roots. PMID- 26598435 TI - Comprehensive Opportunities for Research and Teaching Experience (CORTEX): A mentorship program. PMID- 26598436 TI - Prevalence and distribution of VZV in temporal arteries of patients with giant cell arteritis. PMID- 26598437 TI - Mystery Case: Scalpel sign: Dorsal thoracic arachnoid web. PMID- 26598439 TI - Teaching NeuroImages: A case of Hirayama disease presenting with polymyoclonus. PMID- 26598438 TI - Clinical Reasoning: A 50-year-old man with "elephantiasis" and headache. PMID- 26598440 TI - Dizziness as a sign of stroke. PMID- 26598441 TI - Kinds, mechanisms, contents and origins of musical empathizing: Reply to comments on "Music, empathy, and cultural understanding". PMID- 26598442 TI - What is the nature of causality in the brain? - Inherently probabilistic: Comment on "Foundational perspectives on causality in large-scale brain networks" by M. Mannino and S.L. Bressler. PMID- 26598444 TI - Uromastyx acanthinura as a natural treatment in a mouse model of type 2 diabetes. AB - AIMS: Oral testimonies from North Africa attribute anti-diabetic effects to medicinal preparations of the lizard Uromastyx acanthinura (UA). No scientific evidence of such effects is currently available. The acute effects of oral administration of UA to C57Bl/6J mice with diet-induced diabetes were tested and, if effectiveness was shown, the effect of subchronic UA administration was assessed in the same model. METHODS: Mice were fed a diet containing 60% fat for at least 12 weeks. To assess acute effects, different doses of UA or saline were orally administered with 2g of glucose/kg during an oral glucose tolerance test (OGTT) on different days in a randomised crossover design. The most effective dose was then fed together with the high-fat diet for 90 days and compared to high-fat diet alone in a parallel design. Body weight (BW), food consumption, welfare, and external appearance were assessed weekly. HbA1c, OGTT, and intraperitoneal insulin tolerance tests (IPITT) were performed at baseline and after treatment. Severity of neuropathy was evaluated by cold allodynia response in the acetone test. RESULTS: UA significantly decreased glucose levels as compared to saline 15min after administration. After 90 days of treatment, no differences were seen in OGTT or HbA1c between the groups, while IPITT showed higher glucose levels in UA-treated animals. Although weight increase was similar in both groups, weight tended to be higher in the treated group, which had a significantly higher daily food consumption. Cold allodynia response improved in frequency and intensity in the UA group. CONCLUSIONS: Orally administered UA acutely decreased blood glucose in diabetic mice. Paradoxically, long-term administration of UA increased food consumption, weight, and insulin resistance. Improved nociceptive response suggested an effect on pain and/or neuropathy. Although additional studies are needed to elucidate the properties and potential applications of UA, our results highlight the value of ethnomedical approaches to African traditional medicine as starting point to evaluate new bioactive components. PMID- 26598445 TI - A rare reason for acute abdomen: Intraperitoneal liver hydatid cyst rupture. PMID- 26598443 TI - Transcription factor activating protein 2 beta (TFAP2B) mediates noradrenergic neuronal differentiation in neuroblastoma. AB - Neuroblastoma is an embryonal pediatric tumor that originates from the developing sympathetic nervous system and shows a broad range of clinical behavior, ranging from fatal progression to differentiation into benign ganglioneuroma. In experimental neuroblastoma systems, retinoic acid (RA) effectively induces neuronal differentiation, and RA treatment has been therefore integrated in current therapies. However, the molecular mechanisms underlying differentiation are still poorly understood. We here investigated the role of transcription factor activating protein 2 beta (TFAP2B), a key factor in sympathetic nervous system development, in neuroblastoma pathogenesis and differentiation. Microarray analyses of primary neuroblastomas (n = 649) demonstrated that low TFAP2B expression was significantly associated with unfavorable prognostic markers as well as adverse patient outcome. We also found that low TFAP2B expression was strongly associated with CpG methylation of the TFAP2B locus in primary neuroblastomas (n = 105) and demethylation with 5-aza-2'-deoxycytidine resulted in induction of TFAP2B expression in vitro, suggesting that TFAP2B is silenced by genomic methylation. Tetracycline inducible re-expression of TFAP2B in IMR-32 and SH-EP neuroblastoma cells significantly impaired proliferation and cell cycle progression. In IMR-32 cells, TFAP2B induced neuronal differentiation, which was accompanied by up-regulation of the catecholamine biosynthesizing enzyme genes DBH and TH, and down-regulation of MYCN and REST, a master repressor of neuronal genes. By contrast, knockdown of TFAP2B by lentiviral transduction of shRNAs abrogated RA-induced neuronal differentiation of SH-SY5Y and SK-N-BE(2)c neuroblastoma cells almost completely. Taken together, our results suggest that TFAP2B is playing a vital role in retaining RA responsiveness and mediating noradrenergic neuronal differentiation in neuroblastoma. PMID- 26598446 TI - [Congenital lobar emphysema and pulmonary valve agenesis]. PMID- 26598447 TI - [Thrombin injection in an arterial pseudoaneurysm in a neonate]. PMID- 26598448 TI - Metabolic pathways link childhood adversity to elevated blood pressure in midlife adults. AB - Childhood adversity is a risk factor for adult health outcomes, including obesity and hypertension. This study examines whether childhood adversity predicted mean arterial pressure through mechanisms of central obesity and leptin, adiponectin, and/or insulin resistance, and including dietary quality. 210 Black/African Americans and White/European Americans, mean age=45.8; +/-3.3 years, were studied cross-sectionally. Path analyses were used to specify a chain of predictive variables in which childhood adversity predicted waist-hip ratio and dietary quality, circulating levels of hormones, and in turn, mean arterial pressure, adjusting for race, gender, and antihypertensive medications. Direct paths were found between childhood adversity, waist-hip ratio, and leptin levels and between leptin and dietary quality to mean arterial pressure. Systolic and diastolic blood pressures were similarly predicted. Early adversity appears to developmentally overload and dysregulate endocrine systems through increased risk for obesity, and through a direct impact on leptin that in turn, impacts blood pressure. PMID- 26598449 TI - Does motivational interviewing improve retention or outcome in cognitive behaviour therapy for overweight and obese adolescents? AB - This study aimed to determine whether motivational interviewing improved retention and/or outcome in cognitive behaviour therapy for overweight and obese adolescents (M=14.4, SD=2.0; 52% female). The first 23 participants were allocated to a standard semi-structure assessment interview, the remaining 19 to a motivational interview, prior to commencing the intervention. The groups did not differ at baseline or on anthropometric (weight, BMI, BMI-z-score, waist circumference, waist-hip or waist-height ratio), body composition (percent body fat, fat mass, lean mass) or attrition measures post-treatment or post maintenance (p>.01). MI did not improve retention or outcome of cognitive behaviour therapy for adolescent overweight and obesity. PMID- 26598450 TI - The Diagnosis of Polycystic Ovary Syndrome in Adolescents. AB - Consensus has recently been reached by international pediatric subspecialty societies that otherwise unexplained persistent hyperandrogenic anovulation using age- and stage-appropriate standards are appropriate diagnostic criteria for polycystic ovary syndrome (PCOS) in adolescents. The purpose of this review is to summarize these recommendations and discuss their basis and implications. Anovulation is indicated by abnormal uterine bleeding, which exists when menstrual cycle length is outside the normal range or bleeding is excessive: cycles outside 19 to 90 days are always abnormal, and most are 21 to 45 days even during the first postmenarcheal year. Continued menstrual abnormality in a hyperandrogenic adolescent for 1 year prognosticates at least 50% risk of persistence. Hyperandrogenism is best indicated by persistent elevation of serum testosterone above adult norms as determined in a reliable reference laboratory. Because hyperandrogenemia documentation can be problematic, moderate-severe hirsutism constitutes clinical evidence of hyperandrogenism. Moderate-severe inflammatory acne vulgaris unresponsive to topical treatment is an indication to test for hyperandrogenemia. Treatment of PCOS is symptom-directed. Cyclic estrogen-progestin oral contraceptives are ordinarily the preferred first-line medical treatment because they reliably improve both the menstrual abnormality and hyperandrogenism. First-line treatment of the comorbidities of obesity and insulin resistance is lifestyle modification with calorie restriction and increased exercise. Metformin in conjunction with behavior modification is indicated for glucose intolerance. Although persistence of hyperandrogenic anovulation for >=2 years ensures the distinction of PCOS from physiologic anovulation, early workup is advisable to make a provisional diagnosis so that combined oral contraceptive treatment, which will mask diagnosis by suppressing hyperandrogenemia, is not unnecessarily delayed. PMID- 26598451 TI - Stochastic Resonance Effects on Apnea, Bradycardia, and Oxygenation: A Randomized Controlled Trial. AB - OBJECTIVE: To evaluate the effect of stochastic resonance (SR) stimulation on preterm infant oxygen desaturation, bradycardia, and apnea events. We hypothesized that SR stimulation will reduce these events. METHODS: This was a randomized crossover study conducted from April 2012 to July 2014. Eligible preterm infants were not receiving ventilation support and had at least 1 clinically documented apnea, bradycardia, and/or oxygen desaturation event. The 3 outcome variables were as follows: oxygen desaturation, bradycardia, and apnea events. Infants received up to two 3- or 4-hour intervention periods of 30-minute alternating intervals of SR stimulation and no SR stimulation. The first intervention period was randomly assigned to begin with SR stimulation either on or off, whereas the next intervention period automatically began with the opposite on/off state. We compared the SR stimulation "on" periods with the SR stimulation "off" periods with each infant serving as his or her own control. RESULTS: The sample consisted of 36 infants with a mean (+/-SD) gestational age of 30.5 +/- 3 weeks and a birth weight of 1409 +/- 450 g. SR stimulation decreased the number of apneic events by 50%. SR stimulation ameliorated every aspect of clinically significant oxygen desaturation events, with a 20% to 35% decrease in the number, duration, and intensity of oxygen desaturation events when SR stimulation was on. Also, SR stimulation produced a nearly 20% reduction in the intensity of bradycardia events. CONCLUSIONS: SR stimulation may be a noninvasive and nonpharmacologic treatment option for apnea, oxygen desaturation, and some aspects of bradycardia in premature infants. PMID- 26598452 TI - Model for Service Delivery for Developmental Disorders in Low-Income Countries. AB - As in many low-income countries, the treatment gap for developmental disorders in rural Pakistan is near 100%. We integrated social, technological, and business innovations to develop and pilot a potentially sustainable service for children with developmental disorders in 1 rural area. Families with developmental disorders were identified through a mobile phone-based interactive voice response system, and organized into "Family Networks." "Champion" family volunteers were trained in evidence-based interventions. An Avatar-assisted Cascade Training and information system was developed to assist with training, implementation, monitoring, and supervision. In a population of ~30,000, we successfully established 1 self-sustaining Family Network consisting of 10 trained champion family volunteers working under supervision of specialists, providing intervention to 70 families of children with developmental disorders. Each champion was responsible for training and providing ongoing support to 5 to 7 families from his or her village, and the families supported each other in management of their children. A pre-post evaluation of the program indicated that there was significant improvement in disability and socioemotional difficulties in the child, reduction in stigmatizing experiences, and greater family empowerment to seek services and community resources for the child. There was no change in caregivers' well-being. To replicate this service more widely, a social franchise model has been developed whereby the integrated intervention will be "boxed" up and passed on to others to replicate with appropriate support. Such integrated social, technological, and business innovations have the potential to be applied to other areas of health in low-income countries. PMID- 26598453 TI - FDA Safety Reviews on Drugs, Biologics, and Vaccines: 2007-2013. AB - BACKGROUND AND OBJECTIVES: In 2002, Congress mandated that the US Food and Drug Administration (FDA) monitor postmarketing pediatric adverse events and present safety reports to the FDA's Pediatric Advisory Committee (PAC). These safety reviews play a critical role in the postmarketing surveillance and identification of pediatric safety issues. This article follows a previous review ending in 2007 and summarizes 6 years of recent pediatric safety reporting, recommendations by the PAC, and actions by the FDA, including labeling changes. METHODS: An analysis of the FDA's PAC safety reviews performed from November 2007 through September 2013 was conducted. PAC recommendations for subsequent labeling changes, future studies, or other safety issues were reviewed. RESULTS: There were 6930 serious adverse event reports in 181 reviews. These findings resulted in 33 (18%) recommended labeling changes, and 21 (64%) of these changes were adopted. For 10 products, information was added to the Warning and Precautions section of the label. The PAC also discussed or recommended additional studies for certain products. CONCLUSIONS: This article highlights the importance of the FDA's ongoing pediatric postmarketing safety reviews of regulated products, advice from the PAC, and FDA actions in the best interest of pediatric patients. This mandated process facilitates detection of safety concerns that may not be identified in prelicensure clinical trials. It continues to identify critical safety concerns, including unlabeled adverse events, frequent off-label use, product misuse, and secondary exposures in children. PMID- 26598454 TI - Stimulant Medications and Sleep for Youth With ADHD: A Meta-analysis. AB - CONTEXT: Mixed findings exist on whether stimulant medications alter youth sleep. OBJECTIVE: To determine the effect of stimulant medications on sleep. DATA STUDIES: Studies published through March 2015 were collected via CINAHL, PsycINFO, and PubMed. References of retrieved articles were reviewed. STUDY SELECTION: Eligibility criteria included studies with children/adolescents who had attention-deficit/hyperactivity disorder (ADHD), random assignment to stimulants, and objective sleep measurement. Studies that did not include information about key variables were excluded. DATA EXTRACTION: Study-level, child-level, and sleep data were extracted by 2 independent coders. Effect sizes were calculated by using random effects models. Potential moderators were examined by using mixed effect models. RESULTS: A total of 9 articles (N = 246) were included. For sleep latency, the adjusted effect size (0.54) was significant, indicating that stimulants produce longer sleep latencies. Frequency of dose per day was a significant moderator. For sleep efficiency, the adjusted effect size (-0.32) was significant. Significant moderators included length of time on medication, number of nights of sleep assessed, polysomnography/actigraphy, and gender. Specifically, the effect of medication was less evident when youth were taking medication longer. For total sleep time, the effect size (-0.59) was significant, such that stimulants led to shorter sleep duration. LIMITATIONS: Limitations include few studies, limited methodologic variability, and lack of unpublished studies. CONCLUSIONS: Stimulant medication led to longer sleep latency, worse sleep efficiency, and shorter sleep duration. Overall, youth had worse sleep on stimulant medications. It is recommended that pediatricians carefully monitor sleep problems and adjust treatment to promote optimal sleep. PMID- 26598455 TI - Periventricular/Intraventricular Hemorrhage and Neurodevelopmental Outcomes: A Meta-analysis. AB - CONTEXT: Periventricular/intraventricular hemorrhage (PIVH) is a common short term morbidity in preterm infants, but its long-term neurodevelopmental impact, particularly with mild PIVH, remains unclear. OBJECTIVE: To systematically review and meta-analyze the neurodevelopmental outcomes of preterm infants <=34 weeks' gestation with mild and severe PIVH, compared with no PIVH. DATA SOURCES: Medline, Embase, CINAHL, and PsychINFO databases from January 2000 through June 2014. STUDY SELECTION: Studies reporting long-term neurodevelopmental outcomes based on severity of PIVH were included. DATA EXTRACTION: Study characteristics, inclusion/exclusion criteria, exposures, and outcome assessment data extracted independently by 2 coauthors. RESULTS: The pooled unadjusted odds ratios of the primary outcome of death or moderate-severe neurodevelopmental impairment (NDI) were higher with both mild (1.48, 95% CI 1.26-1.73; 2 studies) and severe PIVH (4.72, 4.21-5.31; 3 studies); no studies reported adjusted odds ratios. Among survivors, odds of moderate-severe NDI were higher with mild and severe PIVH in both unadjusted (1.75, 1.40-2.20; 3 studies; 3.36, 3.06-3.68; 5 studies) and adjusted (1.39, 1.09-1.77; 3 studies; 2.44, 1.73-3.42; 2 studies) pooled analyses. Adjusted odds of cerebral palsy and cognitive delay were higher with severe but not mild PIVH. LIMITATIONS: Only observational studies were included. Fifteen of 21 included studies had a moderate-high risk of bias. CONCLUSIONS: Mild and severe PIVH are associated with progressively higher odds of death or moderate-severe NDI compared with no PIVH, but no studies adjusted for confounders. Among survivors, mild PIVH was associated with higher odds of moderate-severe NDI compared with no PIVH. PMID- 26598456 TI - Impaired Neurodevelopmental Outcome After Mild Germinal Matrix-Intraventricular Hemorrhage. PMID- 26598457 TI - Creating a Shared Values Agenda to Advance Child Health. PMID- 26598458 TI - Food Allergy in Infants With Atopic Dermatitis: Limitations of Food-Specific IgE Measurements. AB - BACKGROUND AND OBJECTIVES: Children with atopic dermatitis (AD) have a higher risk for development of food allergies. The objective of this study was to examine incidence of food allergy development in infants with AD and the predictive value of food-antigen-specific immunoglobulin E measurements. METHODS: This trial examined the long-term safety and efficacy of pimecrolimus cream 1% in >1000 infants (3-18 months) with mild-to-severe AD without a history of food allergy. Food allergy development was followed throughout a 36-month randomized double-blind phase followed by an open-label (OL) phase up to 33 months. Additionally, sIgE for cow's milk, egg white, peanut, wheat, seafood mix, and soybean was measured by ImmunoCAP at baseline, end of the double-blind phase, and end of OL phase. RESULTS: By the end of the OL phase, 15.9% of infants with AD developed at least 1 food allergy; allergy to peanut was most common (6.6%), followed by cow's milk (4.3%) and egg white (3.9%). Seafood, soybean, and wheat allergies were rare. Levels of sIgE for milk, egg, and peanut increased with severity of AD, as determined by Investigator's Global Assessment score. We assigned sIgE decision points for the 6 foods and tested their ability to predict definite food allergy in this population. Positive predictive values for published and newly developed sIgE decision points were low (<0.6 for all values tested). CONCLUSIONS: In a large cohort of infants at risk for development of food allergy, sIgE levels were not clinically useful for predicting food allergy development. PMID- 26598459 TI - Child Care Services, Socioeconomic Inequalities, and Academic Performance. AB - OBJECTIVE: To determine if child-care services (CCS) at a population level can reduce social inequalities in academic performance until early adolescence. METHODS: A 12-year population-based prospective cohort study of families with a newborn (n = 1269). Two CCS variables were estimated: "intensity" (low, moderate, and high number of hours) and "center-based CCS type" (early onset, late onset, and never exposed to center-based CCS). RESULTS: Children from low socioeconomic status (SES) families who received high-intensity CCS (any type), compared with those who received low-intensity CCS, had significantly better reading (standardized effect size [ES] = 0.37), writing (ES = 0.37), and mathematics (ES = 0.46) scores. Children from low-SES families who received center-based CCS, compared with those who never attended center care, had significantly better reading (ESearly onset = 0.68; ESlate onset = 0.37), writing (ESearly onset = 0.79), and mathematics (ESearly onset = 0.66; ESlate onset = 0.39) scores. Furthermore, early participation in center-based CCS eliminated the differences between children of low and adequate SES on all 3 examinations (ES = -0.01, 0.13, and -0.02 for reading, writing, and mathematics, respectively). These results were obtained while controlling for a wide range of child and family variables from birth to school entry. CONCLUSIONS: Child care services (any type) can reduce the social inequalities in academic performance up to early adolescence, while early participation in center-based CCS can eliminate this inequality. CCS use, especially early participation in center-based CCS, should be strongly encouraged for children growing up in a low-SES family. PMID- 26598460 TI - Diversification of edaravone via palladium-catalyzed hydrazine cross-coupling: Applications against protein misfolding and oligomerization of beta-amyloid. AB - N-Aryl derivatives of edaravone were identified as potentially effective small molecule inhibitors of tau and beta-amyloid aggregation in the context of developing disease-modifying therapeutics for Alzheimer's disease (AD). Palladium catalyzed hydrazine monoarylation protocols were then employed as an expedient means of preparing a focused library of 21 edaravone derivatives featuring varied N-aryl substitution, thereby enabling structure-activity relationship (SAR) studies. On the basis of data obtained from two functional biochemical assays examining the effect of edaravone derivatives on both fibril and oligomer formation, it was determined that derivatives featuring an N-biaryl motif were four-fold more potent than edaravone. PMID- 26598461 TI - Fluorinated betulinic acid derivatives and evaluation of their anti-HIV activity. AB - Several fluorinated derivatives of the anti-HIV maturation agent bevirimat (1) were synthesized and evaluated for anti-HIV replication activity. The modified positions were the C-2, C-3, C-28, and C-30 positions, either directly on the betulinic acid (2) skeleton or in the attached side chains. Compound 18, which has a trifluoromethyl group added to C-30 of its isopropenyl group, exhibited similar potency to 1 against HIV-1NL4-3. In total, our current studies support our prior conclusion that C-30 allylic modification is unlikely to be a pharmacophore for anti-HIV activity, but could be a meaningful route to manipulate other properties of 2-related compounds. PMID- 26598462 TI - Synthesis and biological evaluation of picolinamides and thiazole-2-carboxamides as mGluR5 (metabotropic glutamate receptor 5) antagonists. AB - We described here the synthesis and biological evaluation of picolinamides and thiazole-2-carboxamides as potential mGluR5 antagonists. We found that a series of thiazole derivatives 6 showed better inhibitory activity against mGluR5. Compounds 6bc and 6bj have been identified as potent antagonists (IC50=274 and 159nM) showing excellent in vitro stability profile. Molecular docking study using the crystal structure of mGluR5 revealed that our compounds 6bc and 6bj fit the allosteric binding site of mavoglurant well. PMID- 26598463 TI - Synthesis, antiviral activity, 3D-QSAR, and interaction mechanisms study of novel malonate derivatives containing quinazolin-4(3H)-one moiety. AB - A series of novel malonate derivatives containing quinazolin-4(3H)-one moiety were synthesized and evaluated for their antiviral activities against cucumber mosaic virus (CMV). Results indicated that the title compounds exhibited good antiviral activities. Notably, compounds g15, g16, g17, and g18 exhibited excellent curative activities in vivo against CMV, with 50% effective concentration (EC50) values of 208.36, 153.78, 181.47, and 164.72MUg/mL, respectively, which were better than that of Ningnanmycin (256.35MUg/mL) and Ribavirin (523.34MUg/mL). Moreover, statistically valid three-dimensional quantitative structure-activity relationship (3D-QSAR) models with good correlation and predictive power were obtained with comparative molecular field analysis (CoMFA) steric and electrostatic fields (r(2)=0.990, q(2)=0.577) and comparative molecular similarity indices analysis (CoMSIA) with combined steric, electrostatic, hydrophobic and hydrogen bond acceptor fields (r(2)=0.977, q(2)=0.516), respectively. Based on those models, compound g25 was designed, synthesized, and showed better curative activity (146.30MUg/mL) than that of compound g16. The interaction of between cucumber mosaic virus coat protein (CMV CP) and g25 with 1:1.83 ratio is typically spontaneous and exothermic with micromole binding affinity by isothermal titration calorimetry (ITC) and fluorescence spectroscopy investigation. PMID- 26598464 TI - Ovary Apical Abortion under Water Deficit Is Caused by Changes in Sequential Development of Ovaries and in Silk Growth Rate in Maize. AB - Grain abortion allows the production of at least a few viable seeds under water deficit but causes major yield loss. It is maximum for water deficits occurring during flowering in maize (Zea mays). We have tested the hypothesis that abortion is linked to the differential development of ovary cohorts along the ear and to the timing of silk emergence. Ovary volume and silk growth were followed over 25 to 30 d under four levels of water deficit and in four hybrids in two experiments. A position-time model allowed characterizing the development of ovary cohorts and their silk emergence. Silk growth rate decreased in water deficit and stopped 2 to 3 d after first silk emergence, simultaneously for all ovary cohorts, versus 7 to 8 d in well-watered plants. Abortion rate in different treatments and positions on the ear was not associated with ovary growth rate. It was accounted for by the superposition of (1) the sequential emergence of silks originating from ovaries of different cohorts along the ear with (2) one event occurring on a single day, the simultaneous silk growth arrest. Abortion occurred in the youngest ovaries whose silks did not emerge 2 d before silk arrest. This mechanism accounted for more than 90% of drought-related abortion in our experiments. It resembles the control of abortion in a large range of species and inflorescence architectures. This finding has large consequences for breeding drought-tolerant maize and for modeling grain yields in water deficit. PMID- 26598465 TI - The evolution of utility functions and psychological altruism. AB - Numerous studies show that humans tend to be more cooperative than expected given the assumption that they are rational maximizers of personal gain. As a result, theoreticians have proposed elaborated formal representations of human decision making, in which utility functions including "altruistic" or "moral" preferences replace the purely self-oriented "Homo economicus" function. Here we review mathematical approaches that provide insights into the mathematical stability of alternative utility functions. Candidate utility functions may be evaluated with help of game theory, classical modeling of social evolution that focuses on behavioral strategies, and modeling of social evolution that focuses directly on utility functions. We present the advantages of the latter form of investigation and discuss one surprisingly precise result: "Homo economicus" as well as "altruistic" utility functions are less stable than a function containing a preference for the common welfare that is only expressed in social contexts composed of individuals with similar preferences. We discuss the contribution of mathematical models to our understanding of human other-oriented behavior, with a focus on the classical debate over psychological altruism. We conclude that human can be psychologically altruistic, but that psychological altruism evolved because it was generally expressed towards individuals that contributed to the actor's fitness, such as own children, romantic partners and long term reciprocators. PMID- 26598466 TI - Practical integration: The art of balancing values, institutions and knowledge - lessons from the History of British Public Health and Town Planning. AB - The paper uses two historical examples, public health (1840-1880) and town planning (1945-1975) in Britain, to analyse the challenges faced by goal-driven research, an increasingly important trend in science policy, as exemplified by the prominence of calls for addressing Grand Challenges. Two key points are argued. (1) Given that the aim of research addressing social or global problems is to contribute to improving things, this research should include all the steps necessary to bring science and technology to fruition. This need is captured by the idea of practical integration, which brings this type of research under the umbrella of collective practical reason rather than under the aegis of science. Achieving practical integration is difficult for many reasons: the complexity of social needs, the plurality of values at stake, the limitation of our knowledge, the elusive nature of the skills needed to deal with uncertainty, incomplete information and asymmetries of power. Nevertheless, drawing from the lessons of the case studies, it is argued that (2) practical integration needs a proper balance between values, institutions and knowledge: i.e. a combination of mutual support and mutual limitation. Pursuing such a balance provides a flexible strategy for approximating practical integration. PMID- 26598468 TI - In This Issue. Randomized Controlled Trials in the Era of Big Data. PMID- 26598467 TI - Structure of the Human Factor VIII C2 Domain in Complex with the 3E6 Inhibitory Antibody. AB - Blood coagulation factor VIII is a glycoprotein cofactor that is essential for the intrinsic pathway of the blood coagulation cascade. Inhibitory antibodies arise either spontaneously or in response to therapeutic infusion of functional factor VIII into hemophilia A patients, many of which are specific to the factor VIII C2 domain. The immune response is largely parsed into "classical" and "non classical" inhibitory antibodies, which bind to opposing faces cooperatively. In this study, the 2.61 A resolution structure of the C2 domain in complex with the antigen-binding fragment of the 3E6 classical inhibitory antibody is reported. The binding interface is largely conserved when aligned with the previously determined structure of the C2 domain in complex with two antibodies simultaneously. Further inspection of the B factors for the C2 domain in various X-ray crystal structures indicates that 3E6 antibody binding decreases the thermal motion behavior of surface loops in the C2 domain on the opposing face, thereby suggesting that cooperative antibody binding is a dynamic effect. Understanding the structural nature of the immune response to factor VIII following hemophilia A treatment will help lead to the development of better therapeutic reagents. PMID- 26598469 TI - Psychiatric Hospitalization of Children With Autism or Intellectual Disability: Consensus Statements on Best Practices. PMID- 26598470 TI - The Importance of Early Nurturance for Social Development. PMID- 26598471 TI - Double TEAM: Enhancing Response and Treating Depression in Patients With Bipolar Disorder During a Mixed or Manic Episode. PMID- 26598473 TI - Psychoeducational Group Intervention for Adolescents With Psychosis and Their Families: A Two-Year Follow-Up. AB - OBJECTIVE: To investigate whether the beneficial effects of a structured, psychoeducational, parallel-group program for adolescents with early-onset psychosis and their families observed immediately after the intervention were maintained 2 years later. METHOD: The present study examines the longitudinal efficacy of a randomized controlled trial based on a psychoeducational, problem solving, structured group intervention for adolescents with early-onset psychosis and their families (PE) and compares it with that of a nonstructured group intervention (NS) after a 2-year follow-up. We analyzed whether the differences between PE and NS found after the intervention persisted 2 years later. Intergroup differences in number and duration of hospitalizations, symptoms, and functioning were also assessed. RESULTS: After 2 years of follow-up, we were able to reassess 89% of patients. In the PE group, 13% of patients had visited the emergency department, compared with 50% in the NS group (p = .019). However, no statistically significant differences were found between the groups for negative symptoms or number and duration of hospitalizations. A significant improvement in Positive and Negative Syndrome Scale (PANSS) general symptoms was observed in the PE group. CONCLUSION: Our psychoeducational group intervention showed sustained effects by diminishing the number of visits to emergency departments 2 years after the intervention. Our findings indicate that this psychoeducational intervention could provide patients with long-lasting resources to manage crises more effectively. Clinical trial registration information-Intervention Module AGES (AGES-CM); http://clinicaltrials.gov/; NCT02101372. PMID- 26598474 TI - Continued Effectiveness of Relapse Prevention Cognitive-Behavioral Therapy Following Fluoxetine Treatment in Youth With Major Depressive Disorder. AB - OBJECTIVE: To evaluate the continued effect of a sequential treatment strategy (fluoxetine followed by continued medication plus relapse prevention cognitive behavioral therapy [RP-CBT]) on relapse prevention beyond the treatment phase. METHOD: Youth (aged 8-17 years) with major depressive disorder (MDD) were treated with fluoxetine for 6 weeks. Responders (>=50% reduction on the Children's Depression Rating Scale-Revised [CDRS-R]) were randomized to continued medication management alone (MM) or continued medication management plus RP-CBT (MM+CBT) for an additional 6 months. Long-term follow-up assessments were conducted at weeks 52 and 78. RESULTS: Of 144 youth randomized to MM (n = 69) or MM+CBT (n = 75), 67% had at least 1 follow-up assessment, with equal rates in the 2 groups. Remission rates were high, although most had remitted during the 30-week treatment period. Only 6 additional participants remitted during long-term follow up, and there were no differences on time to remission between MM+CBT and MM. The MM+CBT group had a significantly lower risk of relapse than the MM group throughout the 78-week follow-up period (hazard ratio = 0.467, 95% CI = 0.264 to 0.823; chi(2) = 6.852, p = .009). The estimated probability of relapse during the 78-week period was lower with MM+CBT than MM only (36% versus 62%). Mean time to relapse was also significantly longer with MM+CBT compared to MM alone by approximately 3 months (p = .007). CONCLUSION: The addition of RP-CBT after acute response to medication management had a continued effect on reducing risk of relapse even after the end of treatment. Clinical trial registration information Sequential Treatment of Pediatric MDD to Increase Remission and Prevent Relapse; http://clinicaltrials.gov/; NCT00612313. PMID- 26598472 TI - High-Quality Foster Care Mitigates Callous-Unemotional Traits Following Early Deprivation in Boys: A Randomized Controlled Trial. AB - OBJECTIVE: Callous-unemotional (CU) traits in childhood are a developmental precursor to psychopathy, yet the origins and etiology of CU traits are not known. We examined CU traits among 12-year-old children exposed to severe early deprivation and evaluated whether a high-quality foster care intervention mitigated the development of high levels of CU traits. METHOD: Participants were from the Bucharest Early Intervention Project, a randomized controlled trial of foster care for children in institutions. Children were recruited from institutions in Bucharest, Romania, along with age- and sex-matched children who were never institutionalized. Children raised in institutional settings were randomized (mean age = 22 months) to either a foster care group (n = 68) or a care-as-usual group (n = 68). CU traits were assessed at age 12.75 years in available participants from the randomized trial (n = 95) and children who were never institutionalized (n = 50). RESULTS: Children who experienced institutional rearing as young children had significantly higher levels of CU traits in early adolescence compared to children who were never institutionalized. Intent-to treat analysis indicated that, among boys, CU traits were significantly lower among those who received the foster care intervention compared to those randomized to care as usual. Caregiver responsiveness to distress, but not caregiver warmth, mediated the intervention effect on CU traits in boys. CONCLUSION: These findings provide the first evidence to date that psychosocial intervention can prevent the onset of CU traits. Although severe early deprivation predicted higher levels of CU traits, high-quality foster care that emphasized responsive caregiving reduced the impact of deprivation on CU trait development for boys. CLINICAL TRIAL REGISTRATION INFORMATION: The Bucharest Early Intervention Project; http://clinicaltrials.gov; NCT00747396. PMID- 26598475 TI - Depression and Suicidality Outcomes in the Treatment of Early Age Mania Study. AB - OBJECTIVE: To assess the efficacy of mood-stabilizing medications for depression and suicidality in pediatric bipolar disorder. METHOD: The Treatment of Early Age Mania (TEAM) study is a multicenter, prospective, randomized, masked comparison of divalproex sodium (VAL), lithium carbonate (LI), and risperidone (RISP) in an 8-week parallel clinical trial. A total of 279 children and adolescents with DSM IV diagnoses of bipolar I disorder, mixed or manic, aged 6 to 15 years were enrolled. The primary outcome measure was improvement on the Clinical Global Impression scale for depression (CGI-BP-I-D). Secondary outcome measures included the Children's Depression Rating Scale (CDRS-R) and suicidality status. Statistics included longitudinal analysis of outcomes using generalized linear mixed models with random intercept both for the complete data set and by using last observation carried forward. RESULTS: CGI-BP-I-D ratings were better in the RISP group (60.7%) as compared to the LI (42.2%; p = .03) or VAL (35.0%; p = .003) groups from baseline to the end of the study. CDRS scores in all treatment groups improved equally by study end. In week 1, scores were lower with RISP compared to VAL (mean = 4.72, 95% CI = 2.67, 6.78), and compared to LI (mean = 3.63, 95% CI = 1.51, 5.74), although group differences were not present by the end of the study. Suicidality was infrequent, and there was no overall effect of treatment on suicidality ratings. CONCLUSION: Depressive symptoms, present in the acutely manic or mixed phase of pediatric bipolar disorder, improved with all 3 medications, though RISP appeared to yield more rapid improvement than LI or VAL and was superior using a global categorical outcome. Clinical trial registration information-Study of Outcome and Safety of Lithium, Divalproex and Risperidone for Mania in Children and Adolescents (TEAM); http://clinicaltrials.gov; NCT00057681. PMID- 26598476 TI - Treatment of Early-Age Mania: Outcomes for Partial and Nonresponders to Initial Treatment. AB - OBJECTIVE: The Treatment of Early Age Mania (TEAM) study evaluated lithium, risperidone, and divalproex sodium (divalproex) in children with bipolar I disorder who were naive to antimanic medication, or were partial or nonresponders to 1 of 3 study medications. This report evaluates the benefit of either an add on or a switch of antimanic medications for an 8-week trial period in partial responders and nonresponders, respectively. METHOD: TEAM is a randomized, controlled trial of individuals (N = 379) aged 6 to 15 years (mean +/- SD = 10.2 +/- 2.7 years) with DSM-IV bipolar I disorder (mixed or manic phase). Participants (n = 154) in this report were either nonresponders or partial responders to 1 of the 3 study medications. Nonresponders (n = 89) were randomly assigned to 1 of the other 2 antimanic medications and cross-tapered. Partial responders (n = 65) were randomly assigned to 1 of 2 other antimanic medications as an add-on to their initial medication. Adverse event (AE) rates are reported only for the add-on group. RESULTS: Response rate for children switched to risperidone (47.6%) was higher than for those switched to either lithium (12.8%; p = .005; number needed to treat [NNT] = 3; 95% CI = 1.71-9.09) or divalproex (17.2%; p = .03; NNT = 3; 95% CI = 1.79-20.10); response rate for partial responders who added risperidone (53.3%) was higher than for those who added divalproex (0%; p = .0002; NNT = 2; 95% CI = 1.27-3.56) and trended higher for lithium (26.7%; p = .07; NNT = 4). Reported AEs in the add-on group were largely consistent with the known AE profile for the second medication. Weight gain (kg) was observed for all add-on medications: lithium add-on (n = 29 of 30) = 1.66 +/- 1.97; risperidone add-on (n = 15 of 15) = 2.8 +/- 1.34; divalproex add-on (n = 19 of 20) = 1.42 +/- 1.96. There was no evidence at the 5% significance level that the average weight gain was different by study medication for partial responders (p = .07, 1-way analysis of variance). CONCLUSION: Risperidone appears to be more useful than lithium or divalproex for children with bipolar I disorder and other comorbid conditions who are nonresponders or partial responders to an initial antimanic medication trial. Clinical trial registration information-Study of Outcome and Safety of Lithium, Divalproex and Risperidone for Mania in Children and Adolescents (TEAM); http://clinicaltrials.gov/; NCT00057681. PMID- 26598477 TI - Adjunctive Maintenance Lamotrigine for Pediatric Bipolar I Disorder: A Placebo Controlled, Randomized Withdrawal Study. AB - OBJECTIVE: This study aimed to compare the efficacy of lamotrigine versus placebo in 10- to 17-year-olds with bipolar I disorder (BP-I) who were receiving conventional bipolar disorder treatment. METHOD: In this randomized withdrawal trial, patients with BP-I of at least moderate severity received lamotrigine during an <=18-week open-label phase. Patients who maintained a stable lamotrigine dose for >=2 weeks and Clinical Global Impression-Bipolar Severity of Illness (CGI-BP[S]) score of <=3 for >=6 consecutive weeks were randomized to double-blind lamotrigine or placebo for <=36 weeks. RESULTS: Of 301 patients enrolled, 298 comprised the open-label intention-to-treat population, with 173 (58%) randomized. Of these patients, 41 (24%) completed the study. In the open label phase, the mean (SD) baseline CGI-BP(S) rating was 4.4 (0.57), and the mean (standard error [SE]) time to stabilization was 101 (1.6) days. During the randomized phase, mean (SE) time to occurrence of a bipolar event (TOBE) for lamotrigine versus placebo (primary endpoint) was 155 (14.7) versus 50 (3.8), 163 (12.2) versus 120 (12.2), and 136 (15.4) versus 107 (13.8) days for the 3 index mood states (depressed, manic/hypomanic, mixed). The primary stratified log-rank analysis of TOBE was not statistically significant (hazard ratio [HR] = 0.63; p = .072); however, the prespecified Cox regression analysis favored lamotrigine (p = .047). In 13- to 17-year-olds, log-rank analysis of TOBE significantly favored lamotrigine (HR = 0.46; p = .015), but not in 10- to 12-year-olds (HR = 0.93; p = .877). Dermatologic events were reported in 4% (open-label phase) and 2% (randomized phase) of patients receiving lamotrigine. Suicidality-related adverse events were reported in 7% (open-label phase) and 7% (randomized phase) of patients receiving lamotrigine. CONCLUSION: Although the primary analysis failed to detect a benefit of add-on lamotrigine for BP-I in 10- to 17-year-olds, lamotrigine may be effective in a subset of older adolescents. Clinical trial registration information-Lamictal as Add-on Treatment for Bipolar I Disorder in Pediatric Patients; http://clinicaltrials.gov/; NCT00723450. PMID- 26598478 TI - Asenapine for the Acute Treatment of Pediatric Manic or Mixed Episode of Bipolar I Disorder. AB - OBJECTIVE: To evaluate asenapine versus placebo in 403 patients aged 10 to 17 years with bipolar I disorder currently in manic or mixed episodes. METHOD: In this double-blind, placebo-controlled, international trial, patients were randomized 1:1:1:1 to placebo, asenapine 2.5, 5, or 10 mg b.i.d. (twice daily). Primary efficacy measure was change from baseline in Young-Mania Rating Scale (YMRS) total score at day 21. Analyses of patients with/without attention deficit/hyperactivity disorder (ADHD) and with/without stimulant use were performed. RESULTS: The mean difference in asenapine versus placebo in YMRS was 3.2 (p = .0008), -5.3 (p < .001), and -6.2 (p < .001) for asenapine 2.5, 5, and 10 mg b.i.d., respectively. Treatment-emergent adverse events with an incidence >=5% and at least twice placebo were somnolence, sedation, hypoesthesia oral, paresthesia oral, and increased appetite. The asenapine groups had a higher incidence of >=7% weight gain (range, 8.0%-12.0%) versus placebo (1.1%; p < .05). The mean change from baseline in fasting insulin was larger for patients treated with asenapine than those with placebo (asenapine 2.5 mg b.i.d.: 73.375 pmol/L; asenapine 5 mg b.i.d.: 114.042 pmol/L; asenapine 10 mg b.i.d.: 59.846 pmol/L; placebo: 3.690 pmol/L). The mean changes from baseline for lipid parameters and glucose were also larger in asenapine groups than in the placebo group. No safety differences were observed with respect to ADHD and stimulant use. CONCLUSION: All asenapine doses versus placebo were superior based on change in YMRS at day 21. Asenapine was generally well tolerated in patients aged 10 to 17 years with bipolar I disorder in manic or mixed states. Increases in weight and fasting insulin were associated with asenapine. Clinical trial registration information Efficacy and Safety of Asenapine Treatment for Pediatric Bipolar Disorder; http://clinicaltrials.gov; NCT01244815. PMID- 26598481 TI - Connecting: Editor's Annual Report-Volume 54, 2015. PMID- 26598482 TI - Invisible Allies: Thanking Our Reviewers. PMID- 26598479 TI - Trajectories of Sensation Seeking Among Puerto Rican Children and Youth. AB - OBJECTIVE: To document the natural course of sensation seeking from childhood to adolescence, characterize distinct sensation seeking trajectories, and examine how these trajectories vary according to selected predictors. METHOD: Data were obtained from the Boricua Youth Study, a longitudinal study of 2,491 children and adolescents of Puerto Rican background (3 assessments from 2000 to 2004). First, age-specific sensation seeking levels were characterized, and then age-adjusted residuals were analyzed using growth mixture models. RESULTS: On average, sensation seeking was stable in childhood (ages 5-10 years) and increased during adolescence (ages 11-17 years). Mean scores of sensation seeking were higher in the South Bronx versus Puerto Rico and among males versus females. Four classes of sensation seeking trajectories were observed: most study participants had age expected sensation seeking trajectories following the average for their age ("normative," 43.8%); others (37.2%) remained consistently lower than the expected average for their age ("low" sensation seeking); some (12.0%) had an "accelerated" sensation seeking trajectory, increasing at a faster rate than expected; and a minority (7.0%) had a decreasing sensation seeking trajectory that started high but decreased, reaching scores slightly higher than the age average sensation seeking scores ("stabilizers"). Site (South Bronx versus Puerto Rico) and gender were predictors of membership in a specific class of sensation seeking trajectory. CONCLUSION: It is important to take a developmental approach when examining sensation seeking and to consider gender and the social environment when trying to understand how sensation seeking evolves during childhood and adolescence. PMID- 26598484 TI - The Faulty Analysis of Breast Cancer Screening Data. PMID- 26598485 TI - Research Challenges and Opportunities for Clinically Oriented Academic Radiology Departments. AB - Between 2004 and 2012, US funding for the biomedical sciences decreased to historic lows. Health-related research was crippled by receiving only 1/20th of overall federal scientific funding. Despite the current funding climate, there is increased pressure on academic radiology programs to establish productive research programs. Whereas larger programs have resources that can be utilized at their institutions, small to medium-sized programs often struggle with lack of infrastructure and support. To address these concerns, the Association of University Radiologists' Radiology Research Alliance developed a task force to explore any untapped research productivity potential in these smaller radiology departments. We conducted an online survey of faculty at smaller clinically funded programs and found that while they were interested in doing research and felt it was important to the success of the field, barriers such as lack of resources and time were proving difficult to overcome. One potential solution proposed by this task force is a collaborative structured research model in which multiple participants from multiple institutions come together in well-defined roles that allow for an equitable distribution of research tasks and pooling of resources and expertise. Under this model, smaller programs will have an opportunity to share their unique perspective on how to address research topics and make a measureable impact on the field of radiology as a whole. Through a health services focus, projects are more likely to succeed in the context of limited funding and infrastructure while simultaneously providing value to the field. PMID- 26598486 TI - Nomenclature: The Nidus for Change. PMID- 26598487 TI - Integrin-mediated active tumor targeting and tumor microenvironment response dendrimer-gelatin nanoparticles for drug delivery and tumor treatment. AB - Due to the high morbidity and mortality of cancer, it has become an urgent matter to develop an effective and a safe treatment strategy. Nanoparticles (NP) based drug delivery systems have gained much attention nowadays but they faced a paradoxical issue in delivering drugs into tumors: NP with large size were characterized with weak tumor penetration, meanwhile NP with small size resulted in poor tumor retention. To solve this problem, we proposed a multistage drug delivery system which could intelligently shrink its size from large size to small size in the presence of matrix metalloproteinase-2 (MMP-2) which were highly expressed in tumor tissues, therefore the multistage system could benefit from its large size for better retention effect in tumor and then shrunk to small size to contribute to better penetration efficiency. The multistage drug delivery system, RGD-DOX-DGL-GNP, was constructed by 155.4nm gelatin NP core (the substrate of MMP-2) and surface decorated with doxorubicin (DOX) and RGD peptide conjugated dendritic poly-l-lysine (DGL, 34.3nm in diameter). In vitro, the size of multistage NP could effectively shrink in the presence of MMP-2. Thus, the RGD DOX-DGL-GNP could penetrate deep into tumor spheroids. In vivo, this multistage drug delivery system showed higher tumor retention and deeper penetration than both DOX-DGL and DOX-GNP. Consequently, RGD-DOX-DGL-GNP successfully combined the advantages of dendrimers and GNP in vivo, resulting in an outstanding anti-tumor effect. In conclusion, the multistage drug delivery system could intelligently shrink from large size to small size in the tumor microenvironment and displayed better retention and penetration efficiency, making it an impressing system for cancer treatment. PMID- 26598488 TI - The UK Biobank. PMID- 26598489 TI - Autonomic failure and reduced survival in multiple system atrophy. PMID- 26598490 TI - New insights into acquired temozolomide resistance in glioblastoma? PMID- 26598491 TI - Lipidated APOE has effects on cognitive function that are independent of amyloid beta pathology. PMID- 26598492 TI - The complex link between amyloid and neuronal dysfunction in Alzheimer's disease. PMID- 26598493 TI - The evolving spectrum of PRRT2-associated paroxysmal diseases. AB - Next-generation sequencing has identified mutations in the PRRT2 (proline-rich transmembrane protein 2) gene as the leading cause for a wide and yet evolving spectrum of paroxysmal diseases. PRRT2 mutations are found in the majority of patients with benign familial infantile epilepsy, infantile convulsions and choreoathetosis and paroxysmal kinesigenic dyskinesia, confirming a common disease spectrum that had previously been suggested based on gene linkage analyses and shared clinical features. Beyond these clinical entities, PRRT2 mutations have been described in other childhood-onset movement disorders, different forms of seizures, headache disorders, and intellectual disability. PRRT2 encodes a protein that is expressed in the central nervous system and is thought to be involved in the modulation of synaptic neurotransmitter release. The vast majority of mutations lead to a truncated protein or no protein at all and thus to a haploinsufficient state. The subsequent reduction of PRRT2 protein may lead to altered synaptic neurotransmitter release and dysregulated neuronal excitability in various regions of the brain, resulting in paroxysmal movement disorders and seizure phenotypes. In this review, we examine the genetics and neurobiology of PRRT2 and summarize the evolving clinical and molecular spectrum of PRRT2-associated diseases. Through a comprehensive review of 1444 published cases, we provide a detailed assessment of the demographics, disease characteristics and genetic findings of patients with PRRT2 mutations. Benign familial infantile epilepsy (41.7%; n = 602), paroxysmal kinesigenic dyskinesia (38.7%; n = 560) and infantile convulsions and choreoathetosis (14.3%; n = 206) constitute the vast majority of PRRT2-associated diseases, leaving 76 patients (5.3%) with a different primary diagnosis. A positive family history is present in 89.1% of patients; and PRRT2 mutations are familial in 87.1% of reported cases. Seventy-three different disease-associated PRRT2 mutations (35 truncating, 22 missense, three extension mutations, six putative splice site changes, and seven changes that lead to a complete PRRT2 deletion) have been described to date, with the c.649dupC frameshift mutation accounting for the majority of cases (78.5%). Expanding the genetic landscape, 15 patients with biallelic PRRT2 mutations and six patients with 16p11.2 microdeletions and a paroxysmal kinesigenic dyskinesia phenotype have been reported. Probing the phenotypic boundaries of PRRT2-associated disorders, several movement, seizure and headache disorders have been linked to PRRT2 mutations in a subset of patients. Of these, hemiplegic migraine emerges as a novel PRRT2-associated phenotype. With this comprehensive review of PRRT2-associated diseases, we hope to provide a scientific resource for informing future research, both in laboratory models and in clinical studies. PMID- 26598496 TI - Corrigendum. PMID- 26598494 TI - The clinical and genetic heterogeneity of paroxysmal dyskinesias. AB - Paroxysmal dyskinesia can be subdivided into three clinical syndromes: paroxysmal kinesigenic dyskinesia or choreoathetosis, paroxysmal exercise-induced dyskinesia, and paroxysmal non-kinesigenic dyskinesia. Each subtype is associated with the known causative genes PRRT2, SLC2A1 and PNKD, respectively. Although separate screening studies have been carried out on each of the paroxysmal dyskinesia genes, to date there has been no large study across all genes in these disorders and little is known about the pathogenic mechanisms. We analysed all three genes (the whole coding regions of SLC2A1 and PRRT2 and exons one and two of PNKD) in a series of 145 families with paroxysmal dyskinesias as well as in a series of 53 patients with familial episodic ataxia and hemiplegic migraine to investigate the mutation frequency and type and the genetic and phenotypic spectrum. We examined the mRNA expression in brain regions to investigate how selective vulnerability could help explain the phenotypes and analysed the effect of mutations on patient-derived mRNA. Mutations in the PRRT2, SLC2A1 and PNKD genes were identified in 72 families in the entire study. In patients with paroxysmal movement disorders 68 families had mutations (47%) out of 145 patients. PRRT2 mutations were identified in 35% of patients, SLC2A1 mutations in 10%, PNKD in 2%. Two PRRT2 mutations were in familial hemiplegic migraine or episodic ataxia, one SLC2A1 family had episodic ataxia and one PNKD family had familial hemiplegic migraine alone. Several previously unreported mutations were identified. The phenotypes associated with PRRT2 mutations included a high frequency of migraine and hemiplegic migraine. SLC2A1 mutations were associated with variable phenotypes including paroxysmal kinesigenic dyskinesia, paroxysmal non-kinesigenic dyskinesia, episodic ataxia and myotonia and we identified a novel PNKD gene deletion in familial hemiplegic migraine. We found that some PRRT2 loss-of-function mutations cause nonsense mediated decay, except when in the last exon, whereas missense mutations do not affect mRNA. In the PNKD family with a novel deletion, mRNA was truncated losing the C-terminus of PNKD-L and still likely loss-of-function, leading to a reduction of the inhibition of exocytosis, and similar to PRRT2, an increase in vesicle release. This study highlights the frequency, novel mutations and clinical and molecular spectrum of PRRT2, SLC2A1 and PNKD mutations as well as the phenotype-genotype overlap among these paroxysmal movement disorders. The investigation of paroxysmal movement disorders should always include the analysis of all three genes, but around half of our paroxysmal series remain genetically undefined implying that additional genes are yet to be identified. PMID- 26598497 TI - Eustachian Tube as a Landmark to the Internal Carotid Artery in Endoscopic Skull Base Surgery. AB - OBJECTIVE: The purpose of this study was to probe the relationship between the eustachian tube and the internal carotid artery in skull base surgery by an intranasal endoscopic approach. STUDY DESIGN: Cadaver study and illustrative cases. SETTING: Minimally invasive surgery laboratory and operating room. SUBJECTS AND METHODS: A series of 5 cadaveric heads were dissected to elaborate on the relevant surgical anatomy about the eustachian tube and the internal carotid artery. Three cases were presented to illustrate the application of our laboratory findings. RESULTS: The bony-cartilaginous junction of the eustachian tube was just anterior to the first genu of the internal carotid artery by an intranasal endoscopic approach. The 3 patients in our study tolerated the procedure well and experienced no serious complications after surgery. CONCLUSIONS: The anatomic data and clinical cases in this study confirmed that the eustachian tube is a consistent and reliable landmark to the internal carotid artery to avoid its injury in skull base surgery through the endoscopic endonasal route. PMID- 26598495 TI - Vascular amyloidosis impairs the gliovascular unit in a mouse model of Alzheimer's disease. AB - Reduced cerebral blood flow impairs cognitive function and ultimately causes irreparable damage to brain tissue. The gliovascular unit, composed of neural and vascular cells, assures sufficient blood supply to active brain regions. Astrocytes, vascular smooth muscle cells, and pericytes are important players within the gliovascular unit modulating vessel diameters. While the importance of the gliovascular unit and the signals involved in regulating local blood flow to match neuronal activity is now well recognized, surprisingly little is known about this interface in disease. Alzheimer's disease is associated with reduced cerebral blood flow. Here, we studied how the gliovascular unit is affected in a mouse model of Alzheimer's disease, using a combination of ex vivo and in vivo imaging approaches. We specifically labelled vascular amyloid in living mice using the dye methoxy-XO4. We elicited vessel responses ex vivo using either pharmacological stimuli or cell-specific calcium uncaging in vascular smooth muscle cells or astrocytes. Multi-photon in vivo imaging through a cranial window allowed us to complement our ex vivo data in the presence of blood flow after label-free optical activation of vascular smooth muscle cells in the intact brain. We found that vascular amyloid deposits separated astrocyte end-feet from the endothelial vessel wall. High-resolution 3D images demonstrated that vascular amyloid developed in ring-like structures around the vessel circumference, essentially forming a rigid cast. Where vascular amyloid was present, stimulation of astrocytes or vascular smooth muscle cells via ex vivo Ca(2+) uncaging or in vivo optical activation produced only poor vascular responses. Strikingly, vessel segments that were unaffected by vascular amyloid responded to the same extent as vessels from age-matched control animals. We conclude that while astrocytes can still release vasoactive substances, vascular amyloid deposits render blood vessels rigid and reduce the dynamic range of affected vessel segments. These results demonstrate a mechanism that could account in part for the reduction in cerebral blood flow in patients with Alzheimer's disease.media 1vid110.1093/brain/awv327_video_abstractawv327_video_abstract. PMID- 26598498 TI - Postoperative Complications in Elderly Patients Undergoing Head and Neck Surgery: Opportunities for Quality Improvement. AB - OBJECTIVE: To assess the frequency and nature of postoperative complications that occur in elderly patients, as compared with younger patients, following head and neck surgery. STUDY DESIGN: Cohort study of national database. SETTING: American College of Surgeons National Surgical Quality Improvement Program from 2005 to 2013. SUBJECTS AND METHODS: We identified 29,891 patients who had head and neck surgery during the study period and classified them as having upper aerodigestive tract surgery (n = 8383) or endocrine/salivary gland (n = 21,508) surgery. We analyzed patients stratified by age categories: young (<65 years), intermediate age (65-75 years), and elderly (>=75 years). Risk-adjusted 30-day morbidity and mortality outcomes were compared across age categories with multivariable logistic regression models to adjust for patient characteristics, comorbidities, and surgical procedure. RESULTS: Elderly patients had increased odds for morbidity (adjusted odds ratio [OR] = 1.47, 95% CI: 1.22-1.78; OR = 1.89, 95% CI: 1.46-2.44) for upper aerodigestive tract and endocrine/salivary gland groups, respectively, versus young patients and for mortality (OR = 2.52, 95% CI: 1.26 5.06; OR = 3.73, 95% CI: 1.32-10.52). Elderly patients were more likely to develop pulmonary, urologic, and blood clotting-related complications. Elderly patients undergoing endocrine/salivary gland surgery were significantly more likely to have cardiac complications; however, this was not the case for aerodigestive tract operations. CONCLUSIONS: Head and neck surgery in the elderly carries an increased risk of certain types of postoperative complications as compared with younger patients treated similarly. Quality improvement efforts should focus on minimizing the risk of cardiac, pulmonary, and urologic complications in elderly patients. PMID- 26598499 TI - 4D MRI for the Localization of Parathyroid Adenoma: A Novel Method in Evolution. AB - The sestamibi scan (MIBI) and ultrasound (US) are used for preoperative localization of parathyroid adenoma (PTA), with sensitivity as high as 90%. We developed 4-dimensional magnetic resonance imaging (4D MRI) as a novel tool for identifying PTAs. Eleven patients with PTA were enrolled. 4D MRI from the mandible to the aortic arch was used. Optimization of the timing of image acquisition was obtained by changing dynamic and static sequences. PTAs were identified in all except 1 patient. In 9 patients, there was a complete match between the 4D MRI and the US and MIBI, as well as with the operative finding. In 1 patient, the adenoma was correctly localized by 4D MRI, in contrast to the US and MIBI scan. The sensitivity of the 4D MRI was 90% and after optimization, 100%. Specificity was 100%. We concluded that 4D MRI is a reliable technique for identification of PTAs, although more studies are needed. PMID- 26598500 TI - The Usefulness of Preoperative Thyroid-Stimulating Hormone for Predicting Differentiated Thyroid Microcarcinoma. AB - OBJECTIVE: Thyroid-stimulating hormone (TSH) is a known thyroid growth factor, but the pathogenic role of TSH in thyroid tumorigenesis is controversial. The aim of this study is to examine the relationship between preoperative TSH and differentiated thyroid microcarcinoma (DTMC). DATA SOURCES: We searched PubMed, EMBASE, Ovid, Web of Science, and the Cochrane Library from their inception to March 2015 and performed a systematic literature review of original studies. REVIEW METHODS: Published studies that explored the relationship between preoperative TSH and DTMC were included for the review. We calculated odds ratio referring to different TSH concentrations between DTMC and control groups and used random effects model for the meta-analysis. RESULTS: Nine eligible studies that included 6523 patients were identified. Meta-analysis revealed that DTMC was associated with high TSH concentration (odds ratio = 1.23, 95% confidence interval = 1.03-1.46, P = .001). Metaregression analysis indicated that the disparity of control groups was the possible factor resulting in heterogeneity among the studies. CONCLUSIONS: The risk of DTMC increases significantly in parallel with TSH concentration. These results support the hypothesis that TSH is involved in tumorgenesis of differentiated thyroid cancer. PMID- 26598501 TI - Reflections: Using a Second Language to Build a Practice. AB - The US Census Bureau reports that 20.7% of Americans speak a language other than English. This is an opportunity of otolaryngologists to build their practice on a second language. This Reflections piece reviews my personal experiences of using my language fluency in Chinese to build a practice in Philadelphia. Through translating office documents, networking with Chinese-speaking physicians, and volunteering at the free clinic in Chinatown, I was able to serve this non English-speaking community. Although there are translator services in the hospital, there are terms that get lost in translation and cultural norms that outsiders may not understand. I encourage the otolaryngology community to celebrate its diversity and increase access to our specialty for non-English speaking patients. PMID- 26598502 TI - Hiding the tobacco power wall reduces cigarette smoking risk in adolescents: using an experimental convenience store to assess tobacco regulatory options at retail point-of-sale. AB - OBJECTIVES: This experiment tested whether changing the location or visibility of the tobacco power wall in a life sized replica of a convenience store had any effect on adolescents' susceptibility to future cigarette smoking. METHODS: The study was conducted in the RAND StoreLab (RSL), a life sized replica of a convenience store that was developed to experimentally evaluate how changing aspects of tobacco advertising displays in retail point-of-sale environments influences tobacco use risk and behaviour. A randomised, between-subjects experimental design with three conditions that varied the location or visibility of the tobacco power wall within the RSL was used. The conditions were: cashier (the tobacco power wall was located in its typical position behind the cash register counter); sidewall (the tobacco power wall was located on a sidewall away from the cash register); or hidden (the tobacco power wall was located behind the cashier but was hidden behind an opaque wall). The sample included 241 adolescents. RESULTS: Hiding the tobacco power wall significantly reduced adolescents' susceptibility to future cigarette smoking compared to leaving it exposed (ie, the cashier condition; p=0.02). Locating the tobacco power wall on a sidewall away from the cashier had no effect on future cigarette smoking susceptibility compared to the cashier condition (p=0.80). CONCLUSIONS: Hiding the tobacco power wall at retail point-of-sale locations is a strong regulatory option for reducing the impact of the retail environment on cigarette smoking risk in adolescents. PMID- 26598503 TI - Restoring Anticancer Immune Response by Targeting Tumor-Derived Exosomes With a HSP70 Peptide Aptamer. AB - BACKGROUND: Exosomes, via heat shock protein 70 (HSP70) expressed in their membrane, are able to interact with the toll-like receptor 2 (TLR2) on myeloid derived suppressive cells (MDSCs), thereby activating them. METHODS: We analyzed exosomes from mouse (C57Bl/6) and breast, lung, and ovarian cancer patient samples and cultured cancer cells with different approaches, including nanoparticle tracking analysis, biolayer interferometry, FACS, and electron microscopy. Data were analyzed with the Student's t and Mann-Whitney tests. All statistical tests were two-sided. RESULTS: We showed that the A8 peptide aptamer binds to the extracellular domain of membrane HSP70 and used the aptamer to capture HSP70 exosomes from cancer patient samples. The number of HSP70 exosomes was higher in cancer patients than in healthy donors (mean, ng/mL +/- SD = 3.5 +/ 1.7 vs 0.17 +/- 0.11, respectively, P = .004). Accordingly, all cancer cell lines examined abundantly released HSP70 exosomes, whereas "normal" cells did not. HSP70 had higher affinity for A8 than for TLR2; thus, A8 blocked HSP70/TLR2 association and the ability of tumor-derived exosomes to activate MDSCs. Treatment of tumor-bearing C57Bl/6 mice with A8 induced a decrease in the number of MDSCs in the spleen and inhibited tumor progression (n = 6 mice per group). Chemotherapeutic agents such as cisplatin or 5FU increase the amount of HSP70 exosomes, favoring the activation of MDSCs and hampering the development of an antitumor immune response. In contrast, this MDSC activation was not observed if cisplatin or 5FU was combined with A8. As a result, the antitumor effect of the drugs was strongly potentiated. CONCLUSIONS: A8 might be useful for quantifying tumor-derived exosomes and for cancer therapy through MDSC inhibition. PMID- 26598505 TI - Notice of Redundant Publication. PMID- 26598504 TI - Proceedings of the 2015 ASPEN Research Workshop-Taste Signaling. AB - This article summarizes research findings from 6 experts in the field of taste and feeding that were presented at the 2015 American Society for Parenteral and Enteral Nutrition Research Workshop. The theme was focused on the interaction of taste signals with those of a postingestive origin and how this contributes to regulation of food intake through both physiological and learning processes. Gastric bypass results in exceptional loss of fat mass and increases in circulating levels of key gut peptides, some of which are also expressed along with their cognate receptors in taste buds. Changes in taste preference and food selection in both bariatric surgery patients and rodent models have been reported. Accordingly, the effects of this surgery on taste-related behavior were examined. The conservation of receptor and peptide signaling mechanisms in gustatory and extraoral tissues was discussed in the context of taste responsiveness and the regulation of metabolism. New findings detailing the features of neural circuits between the caudal nucleus of the solitary tract (NST), receiving visceral input from the vagus nerve, and the rostral NST, receiving taste input, were discussed, as was how early life experience with taste stimuli and learned associations between flavor and postoral consequences of nutrients can exert potent and long-lasting effects on feeding. PMID- 26598506 TI - TRPC3 channel confers cerebrovascular remodelling during hypertension via transactivation of EGF receptor signalling. AB - AIMS: Ionic perturbation in vascular smooth muscle cells contributes to cerebrovascular remodelling in the setting of hypertension, but the role of transient receptor potential (TRP) channel superfamily remains unknown. The present study was conducted to define the contribution of TRP channels to cerebrovascular remodelling. METHODS AND RESULTS: By integrating quantitative PCR, western blotting, patch clamping, and Ca(2+) imaging, we identified TRP channel, subfamily canonical, member 3 (TRPC3) as the channel subtype most considerably elevated in basilar arteries of two-kidney, two-clip stroke-prone hypertensive rats. Importantly, administration of pyrazole 3 (Pyr3), a TRPC3 channel blocker, attenuated cerebrovascular remodelling. During hypertension, epidermal growth factor receptor (EGFR) was transactivated, as evidenced by marked EGFR phosphorylation, increased pro-HB-EGF shedding, and elevated activity of ADAM17 (HB-EGF sheddase). ADAM17 activity was increased owing to enhanced activation rather than elevated expression. Remarkably, Pyr3 treatment suppressed EGFR transactivation in hypertension. In proliferating basilar artery smooth muscle cells or basilar arteries of hypertensive rats, co-immunoprecipitation assay revealed an interaction between TRPC3 and ADAM17 upon Ang II stimulation. CONCLUSION: Collectively, we demonstrated that enhanced EGFR transactivation, due to increased TRPC3 expression and functional coupling of TRPC3/ADAM17, resulted in cerebrovascular remodelling. Therefore, TRPC3-induced EGFR transactivation may be therapeutically exploited to prevent hypertension-induced cerebrovascular remodelling. PMID- 26598507 TI - Pim1 kinase promotes angiogenesis through phosphorylation of endothelial nitric oxide synthase at Ser-633. AB - AIMS: Posttranslational modification, such as phosphorylation, plays an essential role in regulating activation of endothelial NO synthase (eNOS). In the present study, we aim to determine whether eNOS could be phosphorylated and regulated by a novel serine/threonine-protein kinase Pim1 in vascular endothelial cells (ECs). METHODS AND RESULTS: Using immunoprecipitation and protein kinase assays, we demonstrated that Pim1 specifically interacts with eNOS, which leads to a marked phosphorylation of eNOS at Ser-633 and increased production of nitric oxide (NO). Intriguingly, in response to VEGF stimulation, eNOS phosphorylation at Ser-633 exhibits two distinct phases: transient phosphorylation occurring between 0 and 60 min and sustained phosphorylation occurring between 2 and 24 h, which are mediated by the protein kinase A (PKA) and Pim1, respectively. Inhibiting Pim1 by either pharmacological inhibitor SMI-4a or the dominant-negative form of Pim1 markedly attenuates VEGF-induced tube formation, while Pim1 overexpression significantly increases EC tube formation and migration in an NO-dependent manner. Importantly, Pim1 expression and eNOS phosphorylation at Ser-633 were substantially decreased in high glucose-treated ECs and in the aorta of db/db diabetic mice. Increased Pim1 expression ameliorates impaired vascular angiogenesis in diabetic mice, as determined by an ex vivo aortic ring assay. CONCLUSION: Our findings demonstrate Pim1 as a novel kinase that is responsible for the phosphorylation of eNOS at Ser-633 and enhances EC sprouting of aortic rings from diabetic mice, suggesting that Pim1 could potentially serve as a novel therapeutic target for revascularization strategies. PMID- 26598508 TI - A novel role of endothelium in activation of latent pro-membrane type 1 MMP and pro-MMP-2 in rat aorta. AB - AIMS: Aortic stiffness is an independent risk factor for progression of cardiovascular diseases. Degradation of elastic fibres in aorta due to angiotensin II (ANGII)-stimulated overactivation of latent membrane type 1 matrix metalloproteinase (MT1MMP) and matrix metalloproteinase-2 (MMP2) is regarded to represent an important cause of aortic stiffness. Therefore, clarification of the causal mechanisms triggering the overactivation of these MMPs is of utmost importance. This study addresses the endothelium as a novel key activator of latent pro-MT1MMP and pro-MMP2 in rat aorta. METHODS AND RESULTS: Using a co culture model of rat aortic endothelial cells (ECs) and smooth muscle cells (SMCs), we found that ANGII stimulation resulted in activation of latent pro MT1MMP and pro-MMP2 in SMCs exclusively when co-cultured with ECs (assessed with western blot and gelatin zymography, respectively). EC-specific AT1 receptor stimulation triggered endothelin-1 release and paracrine action on SMCs. Endothelin-1 increased expression and activity of pro-protein convertase furin in SMCs via endothelin receptor type A (assessed with qPCR and furin activity assay, respectively). Consequently, furin acted in two ways. First, it increased the activation of latent pro-MT1MMP and, second, it activated pro-alphavbeta3 integrin. Both pathways led to overactivation of latent pro-MMP2. In vitro findings in the co-culture model were fully consistent with the ex vivo findings obtained in isolated rat aorta. CONCLUSIONS: We propose that the endothelium under ANGII stimulation acts as a novel and key activator of latent pro-MT1MMP and pro-MMP2 in SMCs of rat aorta. Therefore, endothelium may critically contribute to pathophysiology of aortic stiffness. PMID- 26598509 TI - Statins up-regulate SmgGDS through beta1-integrin/Akt1 pathway in endothelial cells. AB - AIMS: The pleiotropic effects of HMG-CoA reductase inhibitors (statins) independent of cholesterol-lowering effects have attracted much attention. We have recently demonstrated that the pleiotropic effects of statins are partly mediated through up-regulation of small GTP-binding protein dissociation stimulator (SmgGDS) with a resultant Rac1 degradation and reduced oxidative stress. However, it remains to be elucidated what molecular mechanisms are involved. METHODS AND RESULTS: To first determine in what tissue statins up regulate SmgGDS expression, we examined the effects of two statins (atorvastatin 10 mg/kg per day and pravastatin 50 mg/kg per day for 1 week) on SmgGDS expression in mice in vivo. The two statins increased SmgGDS expression especially in the aorta. Atorvastatin also increased SmgGDS expression in cultured human umbilical venous endothelial cells (HUVEC) and human aortic endothelial cells, but not in human aortic vascular smooth muscle cells. Furthermore, Akt phosphorylation was transiently enhanced only in HUVEC in response to atorvastatin. Then, to examine whether Akt is involved for up regulation of SmgGDS by statins, we knocked out Akt1 by its siRNA in HUVEC, which abolished the effects by atorvastatin to up-regulate SmgGDS. Furthermore, when we knocked down beta1-integrin to elucidate the upstream molecule of Akt1, the effect of atorvastatin to up-regulate SmgGDS was abolished. Finally, we confirmed that Akt activator, SC79, significantly up-regulate SmgGDS in HUVEC. CONCLUSION: These results indicate that statins selectively up-regulate SmgGDS in endothelial cells, for which the beta1-integrin/Akt1 pathway may be involved, demonstrating the novel aspects of the pleiotropic effects of statins. PMID- 26598510 TI - Nitrated fatty acids suppress angiotensin II-mediated fibrotic remodelling and atrial fibrillation. AB - AIM: Atrial fibrosis, one of the most striking features in the pathology of atrial fibrillation (AF), is promoted by local and systemic inflammation. Electrophilic fatty acid nitroalkenes, endogenously generated by both metabolic and inflammatory reactions, are anti-inflammatory mediators that in synthetic form may be useful as drug candidates. Herein we investigate whether an exemplary nitro-fatty acid can limit atrial fibrosis and AF. METHODS AND RESULTS: Wild-type C57BL6/J mice were treated for 2 weeks with angiotensin II (AngII) and vehicle or nitro-oleic acid (10-nitro-octadec-9-enoic acid, OA-NO2, 6 mg/kg body weight) via subcutaneous osmotic minipumps. OA-NO2 significantly inhibited atrial fibrosis and depressed vulnerability for AF during right atrial electrophysiological stimulation to levels observed for AngII-naive animals. Left atrial epicardial mapping studies demonstrated preservation of conduction homogeneity by OA-NO2. The protection from fibrotic remodelling was mediated by suppression of Smad2 dependent myofibroblast transdifferentiation and inhibition of Nox2-dependent atrial superoxide formation. CONCLUSION: OA-NO2 potently inhibits atrial fibrosis and subsequent AF. Nitro-fatty acids and possibly other lipid electrophiles thus emerge as potential therapeutic agents for AF, either by increasing endogenous levels through dietary modulation or by administration as synthetic drugs. PMID- 26598511 TI - Cardiac mTOR complex 2 preserves ventricular function in pressure-overload hypertrophy. AB - AIMS: Mammalian target of rapamycin (mTOR), a central regulator of growth and metabolism, has tissue-specific functions depending on whether it is part of mTOR complex 1 (mTORC1) or mTORC2. We have previously shown that mTORC1 is required for adaptive cardiac hypertrophy and maintenance of function under basal and pressure-overload conditions. In the present study, we aimed to identify functions of mTORC2 in the heart. METHODS AND RESULTS: Using tamoxifen-inducible cardiomyocyte-specific gene deletion, we generated mice deficient for cardiac rapamycin-insensitive companion of mTOR (rictor), an essential and specific component of mTORC2. Under basal conditions, rictor deficiency did not affect cardiac growth and function in young mice and also had no effects in adult mice. However, transverse aortic constriction caused dysfunction in the rictor deficient hearts, whereas function was maintained in controls after 1 week of pressure overload. Adaptive increases in cardiac weight and cardiomyocyte cross sectional area, fibrosis, and hypertrophic and metabolic gene expression were not different between the rictor-deficient and control mice. In control mice, maintained function was associated with increased protein levels of rictor, protein kinase C (PKC)betaII, and PKCdelta, whereas rictor ablation abolished these increases. Rictor deletion also significantly decreased PKCepsilon at baseline and after pressure overload. Our data suggest that reduced PKCepsilon and the inability to increase PKCbetaII and PKCdelta abundance are, in accordance with their known function, responsible for decreased contractile performance of the rictor-deficient hearts. CONCLUSION: Our study demonstrates that mTORC2 is implicated in maintaining contractile function of the pressure-overloaded male mouse heart. PMID- 26598512 TI - Principal component analysis in ground reaction forces and center of pressure gait waveforms of people with transfemoral amputation. AB - BACKGROUND: The alterations in gait pattern of people with transfemoral amputation leave them more susceptible to musculoskeletal injury. Principal component analysis is a method that reduces the amount of gait data and allows analyzing the entire waveform. OBJECTIVES: To use the principal component analysis to compare the ground reaction force and center of pressure displacement waveforms obtained during gait between able-bodied subjects and both limbs of individuals with transfemoral amputation. STUDY DESIGN: This is a transversal study with a convenience sample. METHODS: We used a force plate and pressure plate to record the anterior-posterior, medial-lateral and vertical ground reaction force, and anterior-posterior and medial-lateral center of pressure positions of 12 participants with transfemoral amputation and 20 able-bodied subjects during gait. The principal component analysis was performed to compare the gait waveforms between the participants with transfemoral amputation and the able-bodied individuals. RESULTS: The principal component analysis model explained between 74% and 93% of the data variance. In all ground reaction force and center of pressure waveforms relevant portions were identified; and always at least one principal component presented scores statistically different (p < 0.05) between the groups of participants in these relevant portions. CONCLUSION: Principal component analysis was able to discriminate many portions of the stance phase between both lower limbs of people with transfemoral amputation compared to the able-bodied participants. CLINICAL RELEVANCE: Principal component analysis reduced the amount of data, allowed analyzing the whole waveform, and identified specific sub-phases of gait that were different between the groups. Therefore, this approach seems to be a powerful tool to be used in gait evaluation and following the rehabilitation status of people with transfemoral amputation. PMID- 26598513 TI - Cardioprotection and Second Malignant Neoplasms Associated With Dexrazoxane in Children Receiving Anthracycline Chemotherapy: A Systematic Review and Meta Analysis. AB - BACKGROUND: Several randomized controlled trials (RCTs) have demonstrated that dexrazoxane reduces anthracycline cardiotoxicity in adults, but use in children has been hindered by lack of direct evidence of cardioprotection and concerns regarding second malignant neoplasms (SMNs). This study aimed to systematically review the evidence regarding dexrazoxane in children. METHODS: We searched Medline, Embase, the Cochrane Library, and abstracts for RCTs and nonrandomized studies (NRSs) that compared dexrazoxane to no cardioprotection among children. We combined findings using random-effects models. All statistical tests were two sided. RESULTS: Eleven eligible publications reported results from five RCTs (1254 patients), and 15 publications reported results from 12 NRSs (3385 patients). Dexrazoxane did not impact clinical cardiotoxicity in RCTs because of a low cardiotoxic event rate (three events among all patients) but was associated with a reduction in subclinical cardiotoxicity. Among NRSs, dexrazoxane was associated with a reduction in clinical cardiotoxicity (relative risk (RR) = 0.29, P = .001) and clinical+subclinical cardiotoxicity (RR = 0.43, P < .001). Among RCTs, 17 of 635 (2.7%) patients treated with dexrazoxane developed an SMN compared with seven of 619 (1.1%) who did not receive dexrazoxane (RR = 2.37, P = .06). Two RCTs that used concurrent etoposide reported an increased risk of acute myeloid leukemia, while one that used cranial radiation reported an increased risk of brain tumors. Event-free survival did not differ (P = .91). CONCLUSION: Dexrazoxane is associated with a statistically significant risk reduction for most cardiotoxic outcomes. Dexrazoxane is associated with a statistically borderline increase in SMNs, possibly because of an interaction with concurrent cancer therapies. The decision to use dexrazoxane in children should balance the risks of cardiotoxicity and SMNs specific to each treatment protocol. PMID- 26598514 TI - Treatment Algorithms Based on Tumor Molecular Profiling: The Essence of Precision Medicine Trials. AB - With the advent of high-throughput molecular technologies, several precision medicine (PM) studies are currently ongoing that include molecular screening programs and PM clinical trials. Molecular profiling programs establish the molecular profile of patients' tumors with the aim to guide therapy based on identified molecular alterations. The aim of prospective PM clinical trials is to assess the clinical utility of tumor molecular profiling and to determine whether treatment selection based on molecular alterations produces superior outcomes compared with unselected treatment. These trials use treatment algorithms to assign patients to specific targeted therapies based on tumor molecular alterations. These algorithms should be governed by fixed rules to ensure standardization and reproducibility. Here, we summarize key molecular, biological, and technical criteria that, in our view, should be addressed when establishing treatment algorithms based on tumor molecular profiling for PM trials. PMID- 26598516 TI - The Obesity Paradox and the Role of Inflammation. PMID- 26598515 TI - Prediagnosis Plasma Adiponectin in Relation to Colorectal Cancer Risk According to KRAS Mutation Status. AB - BACKGROUND: Low levels of adiponectin (ADIPOQ; HGNC ID; HGNC:13633), an adipokine, are associated with obesity, adiposity, excess energy balance, and increased risk of colorectal neoplasia. Given the reported association of increased body mass index (BMI) and low-level physical activity with KRAS-mutated colorectal tumor, we hypothesized that low-level plasma adiponectin might be associated with increased risk of KRAS-mutant colorectal carcinoma but not with risk of KRAS wild-type carcinoma. METHODS: We conducted molecular pathological epidemiology research using a nested case-control study design (307 incident rectal and colon cancer case patients and 593 matched control individuals) within prospective cohort studies, the Nurses' Health Study (152 case patients and 297 control individuals, with blood collection in 1989-1990) and the Health Professionals Follow-up Study (155 case patients and 296 control individuals, with blood collection in 1993-1995). Multivariable conditional logistic regression models and two-sided likelihood ratio tests were used to assess etiologic heterogeneity of the associations. RESULTS: The association of low level plasma adiponectin with colorectal cancer risk statistically significantly differed by KRAS mutation status (P heterogeneity = .004). Low levels of plasma adiponectin were associated with KRAS-mutant colorectal cancer (for the lowest vs highest tertile: multivariable odds ratio [OR] = 2.83, 95% confidence interval [CI] = 1.50 to 5.34, P trend = .002) but not with KRAS wild-type cancer (for the lowest vs highest tertile: multivariable OR = 0.83, 95% CI = 0.49 to 1.43, P trend = .48). In secondary analyses, the association between plasma adiponectin and colorectal cancer did not appreciably differ by BRAF or PIK3CA oncogene mutation status. CONCLUSIONS: Low-level plasma adiponectin is associated with KRAS-mutant colorectal cancer risk but not with KRAS wild-type cancer risk. PMID- 26598517 TI - O-Linked beta-N-acetylglucosamine (O-GlcNAc) Acts as a Glucose Sensor to Epigenetically Regulate the Insulin Gene in Pancreatic Beta Cells. AB - The post-translational protein modification O-linked beta-N-acetylglucosamine (O GlcNAc) is a proposed nutrient sensor that has been shown to regulate multiple biological pathways. This dynamic and inducible enzymatic modification to intracellular proteins utilizes the end product of the nutrient sensing hexosamine biosynthetic pathway, UDP-GlcNAc, as its substrate donor. Type II diabetic patients have elevated O-GlcNAc-modified proteins within pancreatic beta cells due to chronic hyperglycemia-induced glucose overload, but a molecular role for O-GlcNAc within beta cells remains unclear. Using directed pharmacological approaches in the mouse insulinoma-6 (Min6) cell line, we demonstrate that elevating nuclear O-GlcNAc increases intracellular insulin levels and preserves glucose-stimulated insulin secretion during chronic hyperglycemia. The molecular mechanism for these observed changes appears to be, at least in part, due to elevated O-GlcNAc-dependent increases in Ins1 and Ins2 mRNA levels via elevations in histone H3 transcriptional activation marks. Furthermore, RNA deep sequencing reveals that this mechanism of altered gene transcription is restricted and that the majority of genes regulated by elevated O-GlcNAc levels are similarly regulated by a shift from euglycemic to hyperglycemic conditions. These findings implicate the O-GlcNAc modification as a potential mechanism for hyperglycemic regulated gene expression in the beta cell. PMID- 26598518 TI - Regulation of c-Myc Expression by Ahnak Promotes Induced Pluripotent Stem Cell Generation. AB - We have previously reported that Ahnak-mediated TGFbeta signaling leads to down regulation of c-Myc expression. Here, we show that inhibition of Ahnak can promote generation of induced pluripotent stem cells (iPSC) via up-regulation of endogenous c-Myc. Consistent with the c-Myc inhibitory role of Ahnak, mouse embryonic fibroblasts from Ahnak-deficient mouse (Ahnak(-/-) MEF) show an increased level of c-Myc expression compared with wild type MEF. Generation of iPSC with just three of the four Yamanaka factors, Oct4, Sox2, and Klf4 (hereafter 3F), was significantly enhanced in Ahnak(-/-) MEF. Similar results were obtained when Ahnak-specific shRNA was applied to wild type MEF. Of note, expressionof Ahnak was significantly induced during the formation of embryoid bodies from embryonic stem cells, suggesting that Ahnak-mediated c-Myc inhibition is involved in embryoid body formation and the initial differentiation of pluripotent stem cells. The iPSC from 3F-infected Ahnak(-/-) MEF cells (Ahnak(-/ )-iPSC-3F) showed expression of all stem cell markers examined and the capability to form three primary germ layers. Moreover, injection of Ahnak(-/-)-iPSC-3F into athymic nude mice led to development of teratoma containing tissues from all three primary germ layers, indicating that iPSC from Ahnak(-/-) MEF are bona fide pluripotent stem cells. Taken together, these data provide evidence for a new role for Ahnak in cell fate determination during development and suggest that manipulation of Ahnak and the associated signaling pathway may provide a means to regulate iPSC generation. PMID- 26598519 TI - Collapsin Response Mediator Protein-1 Regulates Arp2/3-dependent Actin Assembly. AB - Listeria monocytogenes is a bacterial parasite that uses host proteins to assemble an Arp2/3-dependent actin comet tail to power its movement through the host cell. Initiation of comet tail assembly is more efficient in cytosol than it is under defined conditions, indicating that unknown factors contribute to the reaction. We therefore fractionated cytosol and identified CRMP-1 as a factor that facilitates Arp2/3-dependent Listeria actin cloud formation in the presence of Arp2/3 and actin alone. It also scored as an important factor for Listeria actin comet tail formation in brain cytosol. CRMP-1 does not nucleate actin assembly on its own, nor does it directly activate the Arp2/3 complex. Rather, CRMP-1 scored as an auxiliary factor that promoted the ability of Listeria ActA protein to activate the Arp2/3 complex to trigger actin assembly. CRMP-1 is one member of a family of five related proteins that modulate cell motility in response to extracellular signals. Our results demonstrate an important role for CRMP-1 in Listeria actin comet tail formation and open the possibility that CRMP 1 controls cell motility by modulating Arp2/3 activation. PMID- 26598520 TI - The Physiological Characterization of Connexin41.8 and Connexin39.4, Which Are Involved in the Striped Pattern Formation of Zebrafish. AB - The zebrafish has a striped skin pattern on its body, and Connexin41.8 (Cx41.8) and Cx39.4 are involved in striped pattern formation. Mutations in these connexins change the striped pattern to a spot or labyrinth pattern. In this study, we characterized Cx41.8 and Cx39.4 after expression in Xenopus oocytes. In addition, we analyzed Cx41.8 mutants Cx41.8I203F and Cx41.8M7, which caused spot or labyrinth skin patterns, respectively, in transgenic zebrafish. In the electrophysiological analysis, the gap junctions formed by Cx41.8 and Cx39.4 showed distinct sensitivity to transjunctional voltage. Analysis of non junctional (hemichannel) currents revealed a large voltage-dependent current in Cx39.4-expressing oocytes that was absent in cells expressing Cx41.8. Junctional currents induced by both Cx41.8 and Cx39.4 were reduced by co-expression of Cx41.8I203F and abolished by co-expression of Cx41.8M7. In the transgenic experiment, Cx41.8I203F partially rescued the Cx41.8 null mutant phenotype, whereas Cx41.8M7 failed to rescue the null mutant, and it elicited a more severe phenotype than the Cx41.8 null mutant, as evidenced by a smaller spot pattern. Our results provide evidence that gap junctions formed by Cx41.8 play an important role in stripe/spot patterning and suggest that mutations in Cx41.8 can effect patterning by way of reduced function (I203F) and dominant negative effects (M7). Our results suggest that functional differences in Cx41.8 and Cx39.4 relate to spot or labyrinth mutant phenotypes and also provide evidence that these two connexins interact in vivo and in vitro. PMID- 26598521 TI - Runx1 Phosphorylation by Src Increases Trans-activation via Augmented Stability, Reduced Histone Deacetylase (HDAC) Binding, and Increased DNA Affinity, and Activated Runx1 Favors Granulopoiesis. AB - Src phosphorylates Runx1 on one central and four C-terminal tyrosines. We find that activated Src synergizes with Runx1 to activate a Runx1 luciferase reporter. Mutation of the four Runx1 C-terminal tyrosines to aspartate or glutamate to mimic phosphorylation increases trans-activation of the reporter in 293T cells and allows induction of Cebpa or Pu.1 mRNAs in 32Dcl3 myeloid cells, whereas mutation of these residues to phenylalanine to prevent phosphorylation obviates these effects. Three mechanisms contribute to increased Runx1 activity upon tyrosine modification as follows: increased stability, reduced histone deacetylase (HDAC) interaction, and increased DNA binding. Mutation of the five modified Runx1 tyrosines to aspartate markedly reduced co-immunoprecipitation with HDAC1 and HDAC3, markedly increased stability in cycloheximide or in the presence of co-expressed Cdh1, an E3 ubiquitin ligase coactivator, with reduced ubiquitination, and allowed DNA-binding in gel shift assay similar to wild-type Runx1. In contrast, mutation of these residues to phenylalanine modestly increased HDAC interaction, modestly reduced stability, and markedly reduced DNA binding in gel shift assays and as assessed by chromatin immunoprecipitation with the -14-kb Pu.1 or +37-kb Cebpa enhancers after stable expression in 32Dcl3 cells. Affinity for CBFbeta, the Runx1 DNA-binding partner, was not affected by these tyrosine modifications, and in vitro translated CBFbeta markedly increased DNA affinity of both the translated phenylalanine and aspartate Runx1 variants. Finally, further supporting a positive role for Runx1 tyrosine phosphorylation during granulopoiesis, mutation of the five Src-modified residues to aspartate but not phenylalanine allows Runx1 to increase Cebpa and granulocyte colony formation by Runx1-deleted murine marrow. PMID- 26598522 TI - Loss of Gsalpha in the Postnatal Skeleton Leads to Low Bone Mass and a Blunted Response to Anabolic Parathyroid Hormone Therapy. AB - Parathyroid hormone (PTH) is an important regulator of osteoblast function and is the only anabolic therapy currently approved for treatment of osteoporosis. The PTH receptor (PTH1R) is a G protein-coupled receptor that signals via multiple G proteins including Gsalpha. Mice expressing a constitutively active mutant PTH1R exhibited a dramatic increase in trabecular bone that was dependent upon expression of Gsalpha in the osteoblast lineage. Postnatal removal of Gsalpha in the osteoblast lineage (P-Gsalpha(OsxKO) mice) yielded markedly reduced trabecular and cortical bone mass. Treatment with anabolic PTH(1-34) (80 MUg/kg/day) for 4 weeks failed to increase trabecular bone volume or cortical thickness in male and female P-Gsalpha(OsxKO) mice. Surprisingly, in both male and female mice, PTH administration significantly increased osteoblast numbers and bone formation rate in both control and P-Gsalpha(OsxKO) mice. In mice that express a mutated PTH1R that activates adenylyl cyclase and protein kinase A (PKA) via Gsalpha but not phospholipase C via Gq/11 (D/D mice), PTH significantly enhanced bone formation, indicating that phospholipase C activation is not required for increased bone turnover in response to PTH. Therefore, although the anabolic effect of intermittent PTH treatment on trabecular bone volume is blunted by deletion of Gsalpha in osteoblasts, PTH can stimulate osteoblast differentiation and bone formation. Together these findings suggest that alternative signaling pathways beyond Gsalpha and Gq/11 act downstream of PTH on osteoblast differentiation. PMID- 26598523 TI - Autoinhibitory Interdomain Interactions and Subfamily-specific Extensions Redefine the Catalytic Core of the Human DEAD-box Protein DDX3. AB - DEAD-box proteins utilize ATP to bind and remodel RNA and RNA-protein complexes. All DEAD-box proteins share a conserved core that consists of two RecA-like domains. The core is flanked by subfamily-specific extensions of idiosyncratic function. The Ded1/DDX3 subfamily of DEAD-box proteins is of particular interest as members function during protein translation, are essential for viability, and are frequently altered in human malignancies. Here, we define the function of the subfamily-specific extensions of the human DEAD-box protein DDX3. We describe the crystal structure of the subfamily-specific core of wild-type DDX3 at 2.2 A resolution, alone and in the presence of AMP or nonhydrolyzable ATP. These structures illustrate a unique interdomain interaction between the two ATPase domains in which the C-terminal domain clashes with the RNA-binding surface. Destabilizing this interaction accelerates RNA duplex unwinding, suggesting that it is present in solution and inhibitory for catalysis. We use this core fragment of DDX3 to test the function of two recurrent medulloblastoma variants of DDX3 and find that both inactivate the protein in vitro and in vivo. Taken together, these results redefine the structural and functional core of the DDX3 subfamily of DEAD-box proteins. PMID- 26598524 TI - The Retinoblastoma Tumor Suppressor Protein (pRb)/E2 Promoter Binding Factor 1 (E2F1) Pathway as a Novel Mediator of TGFbeta-induced Autophagy. AB - TGFbeta is a multifunctional cytokine that regulates cell proliferation, cell immortalization, and cell death, acting as a key homeostatic mediator in various cell types and tissues. Autophagy is a programmed mechanism that plays a pivotal role in controlling cell fate and, consequently, many physiological and pathological processes, including carcinogenesis. Although autophagy is often considered a pro-survival mechanism that renders cells viable in stressful conditions and thus might promote tumor growth, emerging evidence suggests that autophagy is also a tumor suppressor pathway. The relationship between TGFbeta signaling and autophagy is context-dependent and remains unclear. TGFbeta mediated activation of autophagy has recently been suggested to contribute to the growth inhibitory effect of TGFbeta in hepatocarcinoma cells. In the present study, we define a novel process of TGFbeta-mediated autophagy in cancer cell lines of various origins. We found that autophagosome initiation and maturation by TGFbeta is dependent on the retinoblastoma tumor suppressor protein/E2 promoter binding factor (pRb/E2F1) pathway, which we have previously established as a critical signaling axis leading to various TGFbeta tumor suppressive effects. We further determined that TGFbeta induces pRb/E2F1-dependent transcriptional activation of several autophagy-related genes. Together, our findings reveal that TGFbeta induces autophagy through the pRb/E2F1 pathway and transcriptional activation of autophagy-related genes and further highlight the central relevance of the pRb/E2F1 pathway downstream of TGFbeta signaling in tumor suppression. PMID- 26598526 TI - Self-reported Symptom Burden in Individuals with Inflammatory Bowel Disease. AB - BACKGROUND AND AIMS: Individuals with inflammatory bowel disease experience debilitating symptoms on a daily basis, but little is known about symptom burden in IBD. The objectives were to (i) identify the most prevalent symptoms and the average number of symptoms experienced; (ii) assess symptom frequency, severity and distress; and (iii) determine the most burdensome symptoms experienced by individuals with inflammatory bowel disease. METHODS: A cross-sectional descriptive design was used to collect data in a single regional treatment centre in Ireland. A consecutive and unique sample of 247 individuals diagnosed with Crohn's disease and ulcerative colitis completed a modified disease-specific version of the Memorial Symptom Assessment Scale. RESULTS: Participants reported experiencing a median of 10 symptoms during the last week, but as many as 16 symptoms were experienced by those with active disease. Of the symptoms experienced, lack of energy was identified as the most burdensome symptom. Bowel symptoms of urgency and diarrhoea and irritable bowel syndrome-type symptoms such as feeling bloated and flatulence were also problematic. Worry was ranked the most burdensome psychological symptom experienced. Symptom burden scores varied according to disease type and disease status, with significant differences found between those with active and inactive disease. CONCLUSIONS: Individuals with inflammatory bowel disease experience a considerable number of symptoms and are burdened by both physical and psychological symptoms, particularly during active disease. Healthcare professionals' focus of assessment needs to be broadened to encompass multiple symptoms. Greater attention needs to be given to fatigue and psychological symptoms. PMID- 26598527 TI - Bimatoprost (0.03%)-induced accommodative spasm and pseudomyopia. AB - Bimatoprost is a prostaglandin analogue used topically in the treatment of glaucoma. Commonly known side effects include eyelash growth, iris pigmentation and conjunctival hyperemia. While pseudomyopia is reported to be caused by parasympathomimetics, such an effect precipitated by bimatoprost has not yet been reported. We report a case demonstrating pseudomyopia and accommodative spasm caused after starting bimatoprost 0.03% in a young patient with glaucoma. PMID- 26598525 TI - Low-density Lipoprotein Receptor-related Proteins in a Novel Mechanism of Axon Guidance and Peripheral Nerve Regeneration. AB - The low-density lipoprotein receptor-related protein receptors 1 and 2 (LRP1 and LRP2) are emerging as important cell signaling mediators in modulating neuronal growth and repair. We examined whether LRP1 and LRP2 are able to mediate a specific aspect of neuronal growth: axon guidance. We sought to identify LRP1 and LRP2 ligands that could induce axonal chemoattraction, which might have therapeutic potential. Using embryonic sensory neurons (rat dorsal root ganglia) in a growth cone turning assay, we tested a range of LRP1 and LRP2 ligands for the ability to guide growth cone navigation. Three ligands were chemorepulsive: alpha-2-macroglobulin, tissue plasminogen activator, and metallothionein III. Conversely, only one LRP ligand, metallothionein II, was found to be chemoattractive. Chemoattraction toward a gradient of metallothionein II was calcium-dependent, required the expression of both LRP1 and LRP2, and likely involves further co-receptors such as the tropomyosin-related kinase A (TrkA) receptor. The potential for LRP-mediated chemoattraction to mediate axonal regeneration was examined in vivo in a model of chemical denervation in adult rats. In these in vivo studies, metallothionein II was shown to enhance epidermal nerve fiber regeneration so that it was complete within 7 days compared with 14 days in saline-treated animals. Our data demonstrate that both LRP1 and LRP2 are necessary for metallothionein II-mediated chemotactic signal transduction and that they may form part of a signaling complex. Furthermore, the data suggest that LRP-mediated chemoattraction represents a novel, non-classical signaling system that has therapeutic potential as a disease-modifying agent for the injured peripheral nervous system. PMID- 26598528 TI - Muddy clinical waters: a missed betel nut in the bronchus. AB - A toddler presented with a 5-month history of recurrent episodes of cough, wheezing and fever. Before referral, the toddler had been initially diagnosed as having bronchial asthma and later as having pulmonary tuberculosis. On examination, the patient was febrile and had severe respiratory distress. Chest radiograph and high-resolution CT of the chest revealed collapse of the entire left lung with diffuse bronchiectasis along with a grossly hyperinflated right lung. CT virtual bronchoscopy did not reveal any foreign body. The parents denied any history suggestive of foreign body aspiration and refused consent for rigid bronchoscopy. Nine days after admission, chest physiotherapy was inadvertently prescribed to the patient. Within an hour, the patient experienced acute respiratory deterioration and died. Autopsy revealed a piece of betel nut in the right main bronchus; it had got dislodged from its initial site in the left main bronchus following the chest physiotherapy session. PMID- 26598529 TI - A dual injury of the shoulder: acromioclavicular joint dislocation (type IV) coupled with ipsilateral mid-shaft clavicle fracture. AB - A direct blow to the shoulder, as may be sustained in a road traffic accident (RTA), can result in various combinations of fracture dislocations in the shoulder joint complex. Among these, a rare variety is an acromioclavicular joint (ACJ) dislocation coupled with ipsilateral mid-shaft clavicle fracture. Diverse treatment options have been described in the literature, ranging from non operative and operative, to hybrid management. Treatment for this complex injury is predominantly dictated by the type of dislocation and displacement of the clavicle fracture, as well as age and demand of the patient. Acute high grades of ACJ dislocation require restoration of the coracoclavicular relationship (in place of torn coracoclavicular (CC) ligament) by some form of internal fixation, thereby maintaining the ACJ reduction. An arthroscopic reinstatement of the coracoclavicular relationship using a dog bone button and fibre tape implant for this composite injury pattern has not been previously described. Furthermore, a comprehensive review of the literature associated with this injury pattern is briefly described. PMID- 26598530 TI - Longitudinal behavior of autoimmune GH deficiency: from childhood to transition age. AB - BACKGROUND: Some cases of apparently idiopathic GH deficiency (GHD) may be caused by pituitary autoimmunity. OBJECTIVE: To study the variations in pituitary function and antipituitary antibodies (APA) from childhood to transition age in patients with apparently idiopathic GHD. DESIGN: We conducted a longitudinal study. PATIENTS AND METHODS: Pituitary function and APA detection by immunofluorescence were investigated in 24 childhood patients with isolated GHD before starting recombinant GH therapy and after the stopping of this therapy in transition age. Sera of patients positive for APA were processed by double immunofluorescence to identify their pituitary target. RESULTS: At diagnosis, 16 out of 24 patients were APA positive targeting only somatotrophs (group 1), while the remaining eight were APA negative (group 2). When retested off therapy, 12 out of 16 patients in group 1 persisted being APA positive, while the remaining four became negative with recovery of pituitary function. All patients in group 2 persisted being APA negative but still showing GHD. Of the 12 patients persistently APA positive, eight with confirmed GHD showed APA still targeting somatotrophs, whereas four showed APA targeting only gonadotrophs associated with isolated hypogonadotropic hypogonadism (HH). CONCLUSION: Patients with APA at middle but not at high titer in childhood may show a remission of autoimmune GHD in childhood after GH replacement therapy. As APA may shift their target in transition period, an early characterization of APA by double immunofluorescence is advisable in APA positive GHD patients showing delayed puberty, to allow an early diagnosis and an appropriate therapy, thus preventing the progression toward HH. PMID- 26598531 TI - Fundamental physical cellular constraints drive self-organization of tissues. AB - Morphogenesis is driven by small cell shape changes that modulate tissue organization. Apical surfaces of proliferating epithelial sheets have been particularly well studied. Currently, it is accepted that a stereotyped distribution of cellular polygons is conserved in proliferating tissues among metazoans. In this work, we challenge these previous findings showing that diverse natural packed tissues have very different polygon distributions. We use Voronoi tessellations as a mathematical framework that predicts this diversity. We demonstrate that Voronoi tessellations and the very different tissues analysed share an overriding restriction: the frequency of polygon types correlates with the distribution of cell areas. By altering the balance of tensions and pressures within the packed tissues using disease, genetic or computer model perturbations, we show that as long as packed cells present a balance of forces within tissue, they will be under a physical constraint that limits its organization. Our discoveries establish a new framework to understand tissue architecture in development and disease. PMID- 26598532 TI - A novel family of fluorescent hypoxia sensors reveal strong heterogeneity in tumor hypoxia at the cellular level. AB - Hypoxia is an intensively investigated condition with profound effects on cell metabolism, migration, and angiogenesis during development and disease. Physiologically, hypoxia is linked to tissue homeostasis and maintenance of pluripotency. Hypoxia also contributes to pathologies including cardiovascular diseases and cancer. Despite its importance, microscopic visualization of hypoxia is largely restricted to the detection of reductively activated probes by immunostaining. Here, we describe a novel family of genetically encoded fluorescent sensors that detect the activation of HIF transcription factors reported by the oxygen-independent fluorescent protein UnaG. It comprises sensors with different switching and memory behavior and combination sensors that allow the distinction of hypoxic and reoxygenated cells. We tested these sensors on orthotopically transplanted glioma cell lines. Using a cranial window, we could visualize hypoxia intravitally at cellular resolution. In tissue samples, sensor activity was detected in regions, which were largely devoid of blood vessels, correlated with HIF-1alpha stabilization, and were highly heterogeneous at a cellular level. Frequently, we detected recently reoxygenated cells outside hypoxic areas in the proximity of blood vessels, suggestive of hypoxia-promoted cell migration. PMID- 26598533 TI - Confounding of the Association between Radiation Exposure from CT Scans and Risk of Leukemia and Brain Tumors by Cancer Susceptibility Syndromes. AB - BACKGROUND: Recent studies linking radiation exposure from pediatric computed tomography (CT) to increased risks of leukemia and brain tumors lacked data to control for cancer susceptibility syndromes (CSS). These syndromes might be confounders because they are associated with an increased cancer risk and may increase the likelihood of CT scans performed in children. METHODS: We identify CSS predisposing to leukemia and brain tumors through a systematic literature search and summarize prevalence and risk estimates. Because there is virtually no empirical evidence in published literature on patterns of CT use for most types of CSS, we estimate confounding bias of relative risks (RR) for categories of radiation exposure based on expert opinion about the current and previous patterns of CT scans among CSS patients. RESULTS: We estimate that radiation related RRs for leukemia are not meaningfully confounded by Down syndrome, Noonan syndrome, or other CSS. In contrast, RRs for brain tumors may be overestimated due to confounding by tuberous sclerosis complex (TSC) while von Hippel-Lindau disease, neurofibromatosis type 1, or other CSS do not meaningfully confound. Empirical data on the use of CT scans among CSS patients are urgently needed. CONCLUSIONS: Our assessment indicates that associations with leukemia reported in previous studies are unlikely to be substantially confounded by unmeasured CSS, whereas brain tumor risks might have been overestimated due to confounding by TSC. IMPACT: Future studies should identify TSC patients in order to avoid overestimation of brain tumor risks due to radiation exposure from CT scans. PMID- 26598534 TI - Diagnostic Metabolomic Blood Tests for Endoluminal Gastrointestinal Cancer--A Systematic Review and Assessment of Quality. AB - Advances in analytics have resulted in metabolomic blood tests being developed for the detection of cancer. This systematic review aims to assess the diagnostic accuracy of blood-based metabolomic biomarkers for endoluminal gastrointestinal (GI) cancer. Using endoscopic diagnosis as a reference standard, methodologic and reporting quality was assessed using validated tools, in addition to pathway based informatics to biologically contextualize discriminant features. Twenty nine studies (15 colorectal, 9 esophageal, 3 gastric, and 2 mixed) with data from 10,835 participants were included. All reported significant differences in hematologic metabolites. In pooled analysis, 246 metabolites were found to be significantly different after multiplicity correction. Incremental metabolic flux with disease progression was frequently reported. Two promising candidates have been validated in independent populations (both colorectal biomarkers), and one has been approved for clinical use. Networks analysis suggested modulation of elements of up to half of Edinburgh Human Metabolic Network subdivisions, and that the poor clinical applicability of commonly modulated metabolites could be due to extensive molecular interconnectivity. Methodologic and reporting quality was assessed as moderate-to-poor. Serum metabolomics holds promise for GI cancer diagnostics; however, future efforts must adhere to consensus standardization initiatives, utilize high-resolution discovery analytics, and compare candidate biomarkers with peer nonendoscopic alternatives. PMID- 26598535 TI - Long-Term Impact of the Dutch Colorectal Cancer Screening Program on Cancer Incidence and Mortality-Model-Based Exploration of the Serrated Pathway. AB - BACKGROUND: We aimed to predict the long-term colorectal cancer incidence, mortality, and colonoscopy demand of the recently implemented Dutch colorectal cancer screening program. METHODS: The Adenoma and Serrated pathway to Colorectal Cancer model was set up to simulate the Dutch screening program consisting of biennial fecal immunochemical testing combined with the new Dutch surveillance guidelines, between 2014 and 2044. The impact of screening and surveillance was evaluated under three sets of natural history assumptions differing in the contribution of the serrated pathway to colorectal cancer incidence. In sensitivity analyses, other assumptions concerning the serrated pathway were varied. Model-predicted outcomes were yearly colorectal cancer incidence, mortality, and colonoscopy demand per year. RESULTS: Assuming an aging population, colorectal cancer incidence under 30 years of screening is predicted to decrease by 35% and 31% for a contribution of 0% and 30% of the serrated pathway to colorectal cancer, respectively. For colorectal cancer mortality, reductions are 47% and 45%. In 2044, 110,000 colonoscopies will be required annually assuming no contribution of the serrated pathway (27 per 1,000 individuals in the screening age range). Including the serrated pathway influences predicted screening effectiveness if serrated lesions are neither detected nor treated at colonoscopy, and/or if colorectal cancers arising from serrated lesions have substantially lower survival rates than those arising from adenomas. CONCLUSIONS: The Dutch screening program will markedly decrease colorectal cancer incidence and mortality but considerable colonoscopy resources will be required. IMPACT: Predictions of long-term screening effectiveness are preferably based on both pathways to colorectal cancer to transparently describe the impact of uncertainties regarding the serrated pathway on long-term predictions. PMID- 26598536 TI - Acrylamide and Glycidamide Hemoglobin Adducts and Epithelial Ovarian Cancer: A Nested Case-Control Study in Nonsmoking Postmenopausal Women from the EPIC Cohort. AB - BACKGROUND: Acrylamide was classified as "probably carcinogenic to humans (group 2A)" by the International Agency for Research on Cancer. Epithelial ovarian cancer (EOC) is the fourth cause of cancer mortality in women. Five epidemiological studies have evaluated the association between EOC risk and dietary acrylamide intake assessed using food frequency questionnaires, and one nested case-control study evaluated hemoglobin adducts of acrylamide (HbAA) and its metabolite glycidamide (HbGA) and EOC risk; the results of these studies were inconsistent. METHODS: A nested case-control study in nonsmoking postmenopausal women (334 cases, 417 controls) was conducted within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Unconditional logistic regression models were used to estimate ORs and 95% confidence intervals (CI) for the association between HbAA, HbGA, HbAA+HbGA, and HbGA/HbAA and EOC and invasive serous EOC risk. RESULTS: No overall associations were observed between biomarkers of acrylamide exposure analyzed in quintiles and EOC risk; however, positive associations were observed between some middle quintiles of HbGA and HbAA+HbGA. Elevated but nonstatistically significant ORs for serous EOC were observed for HbGA and HbAA+HbGA (ORQ5vsQ1, 1.91; 95% CI, 0.96-3.81 and ORQ5vsQ1, 1.90; 95% CI, 0.94-3.83, respectively); however, no linear dose-response trends were observed. CONCLUSION: This EPIC nested case-control study failed to observe a clear association between biomarkers of acrylamide exposure and the risk of EOC or invasive serous EOC. IMPACT: It is unlikely that dietary acrylamide exposure increases ovarian cancer risk; however, additional studies with larger sample size should be performed to exclude any possible association with EOC risk. PMID- 26598537 TI - Prognostic value of programmed-death-1 receptor (PD-1) and its ligand 1 (PD-L1) in testicular germ cell tumors. AB - BACKGROUND: Testicular germ cell tumors (TGCTs) belong to the most chemosensitive solid tumors; however, a small proportion of patients fail to be cured with cisplatin-based chemotherapy. Inhibitors of PD-1/PD-L1 pathways represent a new class of promising drugs in anticancer therapy. The aim of this study was to evaluate expression and prognostic value of PD-1 and PD-L1 in TGCTs. PATIENTS AND METHODS: Surgical specimens from 140 patients with TGCTs (131 with primary testicular tumor and 9 with extragonadal GCTs) were included into the translational study. PD-1 and PD-L1 expression was detected in the tumor tissue by immunohistochemistry using monoclonal antibodies, scored by the multiplicative quickscore (QS) method, compared with their expression in normal testicular tissue and correlated with clinicopathological characteristics and clinical outcome. RESULTS: None of the GCTs exhibited PD-1 protein, although expression of PD-L1 was significantly higher in GCTs in comparison with normal testicular tissue (mean QS = 5.29 versus 0.32, P < 0.0001). Choriocarcinomas exhibit the highest level of PD-L1 with decreasing positivity in embryonal carcinoma, teratoma, yolk sac tumor and seminoma. PD-L1 expression was associated with poor prognostic features, including >=3 metastatic sites, increased serum tumor markers and/or non-pulmonary visceral metastases. Patients with low PD-L1 expression had significantly better progression-free survival [hazard ratio (HR) = 0.40, 95% confidence interval (CI) 0.16-1.01, P = 0.008] and overall survival (HR = 0.43, 95% CI 0.15-1.23, P = 0.040) compared with patients with high PD-L1 expression. CONCLUSIONS: In this translational study, we showed, for the first time, the prognostic value of PD-L1 expression in TGCTs and our data imply that the PD-1/PD-L1 pathway could be a novel therapeutic target in TGCTs. PMID- 26598538 TI - Seeking the driver in tumours with apparent normal molecular profile on comparative genomic hybridization and targeted gene panel sequencing: what is the added value of whole exome sequencing? AB - BACKGROUND: Molecular tumour profiling technologies have become increasingly important in the era of precision medicine, but their routine use is limited by their accessibility, cost, and tumour material availability. It is therefore crucial to assess their relative added value to optimize the sequence and combination of such technologies. PATIENTS AND METHODS: Within the MOSCATO-01 trial, we investigated the added value of whole exome sequencing (WES) in patients that did not present any molecular abnormality on array comparative genomic hybridization (aCGH) and targeted gene panel sequencing (TGPS) using cancer specific panels. The pathogenicity potential and actionability of mutations detected on WES was assessed. RESULTS: Among 420 patients enrolled between December 2011 and December 2013, 283 (67%) patients were analysed for both TGPS and aCGH. The tumour sample of 25 (8.8%) of them presented a flat (or low-dynamic) aCGH profile and no pathogenic mutation on TGPS. We selected the first eligible 10 samples-corresponding to a heterogeneous cohort of different tumour types-to perform WES. This allowed identifying eight mutations of interest in two patients: FGFR3, PDGFRB, and CREBBP missense single-nucleotide variants (SNVs) in an urothelial carcinoma; FGFR2, FBXW7, TP53, and MLH1 missense SNVs as well as an ATM frameshift mutation in a squamous cell carcinoma of the tongue. The FGFR3 alteration had been previously described as an actionable activating mutation and might have resulted in treatment by an FGFR inhibitor. CREBBP and ATM alterations might also have suggested a therapeutic orientation towards epigenetic modifiers and ataxia-telangectasia and Rad3-related inhibitors, respectively. CONCLUSION: The therapeutic added value of performing WES on tumour samples that do not harbour any genetic abnormality on TGPS and aCGH might be limited and variable according to the histotype. Alternative techniques, including RNASeq and methylome analysis, might be more informative in selected cases. PMID- 26598539 TI - Annals of oncology in 2015: the year in review. PMID- 26598540 TI - Clinical validity of tumor-infiltrating lymphocytes analysis in patients with triple-negative breast cancer. AB - BACKGROUND: Although tumor-infiltrating lymphocytes (TILs) have been associated with a favorable prognosis in triple-negative breast cancer (TNBC) patients, this marker is not currently considered robust enough for entering the clinical practice. In the present study, we assessed the clinical validity of the guidelines recently issued by the International TIL Working Group in a large retrospective series of well-annotated TNBC patients. PATIENTS AND METHODS: TILs were evaluated in all the full-face H&E sections from 897 consecutive TNBC (i.e. tumors with <1% of ER and PgR immunoreactivity and absence of HER2 overexpression or amplification) patients diagnosed and treated at the European Institute of Oncology between 1995 and 2010 (median follow-up 8.2 years, range 6 months to 18 years). All mononuclear cells were evaluated in the stromal area within the borders of the invasive tumor, reported as a percentage value and treated as a continuous variable in survival analysis. RESULTS: The median percentage of TILs was 20%, and 21.9% of the cases had >=50% (lymphocyte predominant breast cancer, LPBC) TILs. At univariable survival analysis, TILs were a significant predictor of better disease-free survival (DFS), distant disease-free survival (DDFS) and overall survival (OS) (P < 0.0001). Multivariable analysis confirmed that each 10% increase in TILs strongly predicted better survival, independent of patients' age, lymph node status, tumor size, histological grade, peritumoral vascular invasion and Ki-67 labeling index. Patients with LPBC had a 10-year survival rate of 71%, 84% and 96% for DFS, DDFS and OS, respectively. Stratified analysis revealed a positive correlation between TILs and OS across all the subgroups analyzed. CONCLUSION: Our data support the analytical validity of the recently issued TILs evaluation guidelines in the clinical practice. PMID- 26598541 TI - The influential and inspirational Gianni Bonadonna's life commitment to evidence based cancer medicine. PMID- 26598542 TI - Beyond the exome: the role of non-coding somatic mutations in cancer. AB - The comprehensive identification of mutations contributing to the development of cancer is a priority of large cancer sequencing projects. To date, most studies have scrutinized mutations in coding regions of the genome, but several recent discoveries, including the identification of recurrent somatic mutations in the TERT promoter in multiple cancer types, support the idea that mutations in non coding regions are also important in tumour development. Furthermore, analysis of whole-genome sequencing data from tumours has elucidated novel mutational patterns and processes etched into cancer genomes. Here, we present an overview of insights gleaned from the analysis of mutations from sequenced cancer genomes. We then review the mechanisms by which non-coding mutations can play a role in cancer. Finally, we discuss recent efforts aimed at identifying non-coding driver mutations, as well as the unique challenges that the analysis of non-coding mutations present in contrast to the identification of driver mutations in coding regions. PMID- 26598543 TI - Environmental emissions, public health and lung cancer risk. PMID- 26598544 TI - Waldenstrom's macroglobulinemia: a clinical perspective in the era of novel therapeutics. AB - Waldenstrom's macroglobulinemia (WM) is a rare, low-grade malignancy with no established standard of care. Rituximab regimens are most commonly used, supported by their efficacy in hematologic malignancies, including WM. A growing number of investigational regimens for WM have been evaluated in phase II clinical trials, including single-agent and combination strategies that include newer-generation monoclonal antibodies (ofatumumab and alemtuzumab), proteasome inhibitors (bortezomib and carfilzomib), immunomodulatory agents (thalidomide and lenalidomide), phosphoinositide 3-kinase/protein kinase B (Akt)/mammalian target of rapamycin pathway inhibitors (everolimus and perifosene), a Bruton's tyrosine kinase inhibitor (ibrutinib), and a histone deacetylase inhibitor (panobinostat). Other novel agents are in early-stage development for WM. International treatment guidelines for WM suggest suitable regimens in the newly diagnosed and relapsed/refractory settings, in accordance with patient age, disease presentation, and efficacy and safety profiles of particular drugs. These factors must be considered when choosing appropriate therapy for individual patients with WM, to maximize response and prolong survival, while minimizing the risk of adverse events. This review article provides a clinical perspective of the modern management of patients with WM, in the context of available trial data for novel regimens and recently updated treatment guidelines. PMID- 26598545 TI - Molecular imaging as a tool to investigate heterogeneity of advanced HER2 positive breast cancer and to predict patient outcome under trastuzumab emtansine (T-DM1): the ZEPHIR trial. AB - BACKGROUND: Only human epidermal growth factor receptor (HER)2 status determined by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) has been validated to predict efficacy of HER2-targeting antibody-drug-conjugate trastuzumab emtansine (T-DM1). We propose molecular imaging to explore intra /interpatient heterogeneity in HER2 mapping of metastatic disease and to identify patients unlikely to benefit from T-DM1. PATIENTS AND METHODS: HER2-positive mBC patients with IHC3+ or FISH >= 2.2 scheduled for T-DM1 underwent a pretreatment HER2-positron emission tomography (PET)/computed tomography (CT) with (89)Zr trastuzumab. [(18)F]2-fluoro-2-deoxy-D-glucose (FDG)-PET/CT was performed at baseline and before T-DM1 cycle 2. Patients were grouped into four HER2-PET/CT patterns according to the proportion of FDG-avid tumor load showing relevant (89)Zr-trastuzumab uptake (>blood pool activity): patterns A and B were considered positive (>50% or all of the tumor load 'positive'); patterns C and D were considered negative (>50% or all of the tumor load 'negative'). Early FDG PET/CT was defined as nonresponding when >50% of the tumor load showed no significant reduction of FDG uptake (<15%). Negative (NPV) and positive predictive values (PPV) of HER2-PET/CT, early FDG response and their combination were assessed to predict morphological response (RECIST 1.1) after three T-DM1 cycles and time-to-treatment failure (TTF). RESULTS: In the 56 patients analyzed, 29% had negative HER2-PET/CT while intrapatient heterogeneity (patterns B and C) was found in 46% of patients. Compared with RECIST1.1, respective NPV/PPV for HER2-PET/CT were 88%/72% and 83%/96% for early FDG-PET/CT. Combining HER2-PET/CT and FDG-PET/CT accurately predicted morphological response (PPV and NPV: 100%) and discriminated patients with a median TTF of only 2.8 months [n = 12, 95% confidence interval (CI) 1.4-7.6] from those with a TTF of 15 months (n = 25, 95% CI 9.7-not calculable). CONCLUSIONS: Pretreatment imaging of HER2 targeting, combined with early metabolic response assessment holds great promise for improving the understanding of tumor heterogeneity in mBC and for selecting patients who will/will not benefit from T-DM1. CLINICALTRIALSGOV IDENTIFIER: NCT01565200. PMID- 26598546 TI - Breast implant-associated anaplastic large cell lymphoma: two distinct clinicopathological variants with different outcomes. AB - BACKGROUND: ALK-negative anaplastic large cell lymphoma associated with breast implant (i-ALCL) has been recently recognized as a distinct entity. Among 43 830 lymphomas registered in the French Lymphopath network since 2010, 300 breast lymphomas comprising 25 peripheral T-cell lymphomas (PTCL) were reviewed. Among PTCL, ALK-negative ALCL was the most frequent and all of them were associated with breast implants. PATIENTS AND METHODS: Since 2010, all i-ALCL cases were collected from different institutions through Lymphopath. Immuno-morphologic features, molecular data and clinical outcome of 19 i-ALCLs have been retrospectively analyzed. RESULTS: The median age of the patients was 61 years and the median length between breast implant and i-ALCL was 9 years. Most implants were silicone-filled and textured. Implant removal was performed in 17 out of 19 patients with additional treatment based on mostly CHOP or CHOP-like chemotherapy regimens (n = 10/19) or irradiation (n = 1/19). CHOP alone or ABVD following radiation without implant removal have been given in two patients. The two clinical presentations, i.e. effusion and less frequently tumor mass correlated with distinct histopathologic features: in situ i-ALCL (anaplastic cell proliferation confined to the fibrous capsule) and infiltrative i-ALCL (pleomorphic cells massively infiltrating adjacent tissue with eosinophils and sometimes Reed-Sternberg-like cells mimicking Hodgkin lymphoma). Malignant cells were CD30-positive, showed a variable staining for EMA and were ALK negative. Most cases had a cytotoxic T-cell immunophenotype with variable T-cell antigen loss and pSTAT3 nuclear expression. T-cell receptor genes were clonally rearranged in 13 out of 13 tested cases. After 18 months of median follow-up, the 2-year overall survival for in situ and infiltrative i-ALCL was 100% and 52.5%, respectively. CONCLUSIONS: In situ i-ALCLs have an indolent clinical course and generally remain free of disease after implant removal. However, infiltrative i ALCLs could have a more aggressive clinical course that might require additional therapy to implant removal. PMID- 26598547 TI - Lung cancer patients with HER2 mutations treated with chemotherapy and HER2 targeted drugs: results from the European EUHER2 cohort. AB - BACKGROUND: HER2 mutations have been identified as oncogenic drivers in lung cancers and are found in 1-2% of lung adenocarcinomas. There is, to date, no standard of care for these patients. We thus aim to study the therapeutic outcomes of patients harboring HER2 mutations and establish the efficacy of various drug regimens. PATIENTS AND METHODS: This retrospective cohort study in European centers assessed patients with advanced non-small-cell lung cancer (NSCLC), a known HER2 exon-20 insertion, treated with chemotherapy and/or HER2 targeted drugs. RESULTS: We identified 101 eligible patients from 38 centers: median age 61 years (range: 30-87), 62.4% women, 60.4% never-smokers. All tumors were adenocarcinomas. Concomitant EGFR mutations, ALK translocations, and ROS translocations were observed in 5, 1, and 1 patients, respectively. The median number of treatment lines was 3 (range: 1-11). The median overall survival was 24 months. Overall response rate (ORR) and the median progression-free survival (PFS) with conventional chemotherapy (excluding targeted therapies) were 43.5% and 6 months in first-line (n = 93), and 10% and 4.3 months in second-line (n = 52) therapies. Sixty-five patients received HER2-targeted therapies: trastuzumab = 57, neratinib = 14, afatinib = 9, lapatinib = 5, T-DM1 = 1. ORR was 50.9% and PFS was 4.8 months with trastuzumab or T-DM1. CONCLUSION: This series shows the chemosensitivity of HER2-driven NSCLC, and the potential interest of HER2 targeted agents. Our results should help to define the best therapeutic strategy for these patients and to orient future clinical trials. PMID- 26598548 TI - Phase II trial of dasatinib for recurrent or metastatic c-KIT expressing adenoid cystic carcinoma and for nonadenoid cystic malignant salivary tumors. AB - BACKGROUND: Adenoid cystic carcinoma (ACC) is a subtype of malignant salivary gland tumors (MSGT), in which 90% of cases express cKIT. Dasatinib is a potent and selective inhibitor of five oncogenic protein tyrosine kinases (PTKs)/kinase families including cKIT. We conducted a phase II study to determine the antitumor activity of dasatinib in ACC and non-ACC MSGT. PATIENTS AND METHODS: In a two stage design, patients with progressive, recurrent/metastatic ACC (+cKIT) and non ACC MSGT (separate cohort) were treated with dasatinib 70 mg p.o. b.i.d. Response was assessed every 8 weeks using RECIST. RESULTS: Of 54 patients: 40 ACC, 14 non ACC (1, ineligible excluded); M:F = 28 : 26, median age 56 years (range 20-82 years), ECOG performance status 0 : 1 : 2 = 24 : 28 : 2, prior radiation: 44, prior chemotherapy: 21. The most frequent adverse events (AEs) (as % of patients, worst grade 2 or higher) were: fatigue (28%), nausea (19%), headache (15%), lymphopenia (7%), dyspnea (11%), alanine aminotransferase increased (7%), anorexia (7%), vomiting (7%), alkaline phosphatase increased (6%), diarrhea (6%), neutropenia (6%), and noncardiac chest pain (6%). No grade 4 AE occurred, 15 patients experienced a grade 3 AE, primarily dyspnea (5) and fatigue (4), and cardiac toxicity (1 prolonged QTc). Among ACC patients, best response to dasatinib: 1 patient (2.5%) had partial response, 20 patients (50%) had stable disease (SD) (3-14 months), 12 patients (30%) had PD, 2 withdrew, 3 discontinued therapy due to AE, and 2 died before cycle 2. Median progression-free survival was 4.8 months. Median overall survival was 14.5 months. For 14 assessable non ACC patients, none had objective response, triggering early stopping rule. Seven had SD (range 1-7 months), 4 PD, 2 discontinued therapy due to AE, and 1 died before cycle 2. CONCLUSION: Although there was only one objective response, dasatinib is well tolerated, with tumor stabilization achieved by 50% of ACC patients. Dasatinib demonstrated no activity in non-ACC MSGT. PMID- 26598549 TI - Efficient Protocol for Isolation of Rhaponticin and Rhapontigenin with Consecutive Sample Injection from Fenugreek (Trigonella foenum-graecum L.) by HSCCC. AB - High efficiency and less solvent consumption are the essential requirements of high-speed countercurrent chromatography (HSCCC), especially for the large-scale preparation. In this study, an efficient HSCCC strategy with consecutive sample injection was successfully developed to rapidly separate and purify rhaponticin and rhapontigenin from the seeds of the Chinese medicinal herb fenugreek (Trigonella foenum-graecum L.). The effective separation was achieved using n hexane-ethyl acetate-methanol-water (1:4:2:6, v/v/v/v) as the two-phase solvent system, in which the mobile phase was eluted at an optimized flow rate of 2.2 mL/min and a revolution speed of 850 rpm. After consecutively loading four identical fenugreek samples, each containing 120 mg, HSCCC separation yielded 146.4 mg of rhaponticin and 174.8 mg of rhapontigenin with purities of 98.6 and 99.1%, respectively, as determined by high-performance liquid chromatography at 320 nm. Their chemical structures were identified using UV spectroscopy, (1)H-NMR and (13)C-NMR. The HSCCC method with consecutive sample injection allowed faster separation and produced less solvent waste, suggesting that it is an efficient way to rapidly separate and purify natural products on a large scale. PMID- 26598550 TI - Epinephrine after cardiac arrest. PMID- 26598551 TI - Role of Angiomotin-like 2 mono-ubiquitination on YAP inhibition. AB - LATS1/2 (large tumor suppressor) kinases and the Angiomotin family proteins are potent inhibitors of the YAP (yes-associated protein) oncoprotein, but the underlying molecular mechanism is not fully understood. Here, we report for the first time that USP9X is a deubiquitinase of Angiomotin-like 2 (AMOTL2) and that AMOTL2 mono-ubiquitination is required for YAP inhibition. USP9X knockdown increased the LATS-mediated phosphorylation of YAP and decreased the transcriptional output of YAP. Conversely, over-expression of USP9X reactivated YAP in densely cultured cells. Both genetic and biochemical approaches identified AMOTL2 as a target of USP9X. AMOTL2 was found to be ubiquitinated at K347 and K408, which both reside in the protein's coiled-coil domain. The AMOTL2 K347/408R mutant, which cannot be ubiquitinated, was impaired in its ability to inhibit YAP. Furthermore, ubiquitinated AMOTL2 can bind to the UBA domain of LATS kinase, and this domain is required for the function of LATS. Our results provide novel insights into the activation mechanisms of core Hippo pathway components. PMID- 26598552 TI - Ral GTPase and the exocyst regulate autophagy in a tissue-specific manner. AB - Autophagy traffics cellular components to the lysosome for degradation. Ral GTPase and the exocyst have been implicated in the regulation of stress-induced autophagy, but it is unclear whether they are global regulators of this process. Here, we investigate Ral function in different cellular contexts in Drosophila and find that it is required for autophagy during developmentally regulated cell death in salivary glands, but does not affect starvation-induced autophagy in the fat body. Furthermore, knockdown of exocyst subunits has a similar effect, preventing autophagy in dying cells but not in cells of starved animals. Notch activity is elevated in dying salivary glands, this change in Notch signaling is influenced by Ral, and decreased Notch function influences autophagy. These data indicate that Ral and the exocyst regulate autophagy in a context-dependent manner, and that in dying salivary glands, Ral mediates autophagy, at least in part, by regulation of Notch. PMID- 26598553 TI - Loss of PGL-1 and PGL-3, members of a family of constitutive germ-granule components, promotes germline apoptosis in C. elegans. AB - In Caenorhabditis elegans, the mechanisms regulating germline apoptosis remain largely unknown, except for the core machinery. Here, we found that mutants of pgl-1 and pgl-3, encoding members of a family of constitutive protein components of germline-specific P granules, showed increased germline apoptosis under both physiological and DNA-damaged conditions. We also found that the number of germ cells that lost PGL proteins increased significantly following UV irradiation, and that only those PGL-absent germ cells were selectively engulfed by gonadal sheath cells in adult hermaphrodite gonads. We further revealed that CEP-1, the p53 homolog, and the caspase CED-3 promoted elimination of PGL-1 from germ cells following UV irradiation. Furthermore, protein levels of CED-4, the Apaf-1 homolog, and cytoplasmic translocation of SIR-2.1, a Sirtuin homolog, significantly increased in pgl mutants and increased even more following UV irradiation. CED-4 and SIR-2.1 were essential for high levels of germline apoptosis in pgl mutants. We conclude that PGL proteins suppress excessive germline apoptosis by repressing both the protein levels of CED-4 and the cytoplasmic translocation of SIR-2.1. Our study has revealed new roles for PGL-1 and PGL-3 in the control of germline apoptosis. PMID- 26598554 TI - PAK6 targets to cell-cell adhesions through its N-terminus in a Cdc42-dependent manner to drive epithelial colony escape. AB - The six serine/threonine kinases in the p21-activated kinase (PAK) family are important regulators of cell adhesion, motility and survival. PAK6, which is overexpressed in prostate cancer, was recently reported to localize to cell-cell adhesions and to drive epithelial cell colony escape. Here we report that PAK6 targeting to cell-cell adhesions occurs through its N-terminus, requiring both its Cdc42/Rac interactive binding (CRIB) domain and an adjacent polybasic region for maximal targeting efficiency. We find PAK6 localization to cell-cell adhesions is Cdc42-dependent, as Cdc42 knockdown inhibits PAK6 targeting to cell cell adhesions. We further find the ability of PAK6 to drive epithelial cell colony escape requires kinase activity and is disrupted by mutations that perturb PAK6 cell-cell adhesion targeting. Finally, we demonstrate that all type II PAKs (PAK4, PAK5 and PAK6) target to cell-cell adhesions, albeit to differing extents, but PAK1 (a type I PAK) does not. Notably, the ability of a PAK isoform to drive epithelial colony escape correlates with its targeting to cell-cell adhesions. We conclude that PAKs have a broader role in the regulation of cell-cell adhesions than previously appreciated. PMID- 26598555 TI - VE-cadherin facilitates BMP-induced endothelial cell permeability and signaling. AB - Several vascular disorders, such as aberrant angiogenesis, atherosclerosis and pulmonary hypertension, have been linked to dysfunctional BMP signaling. Vascular hyperpermeability via distortion of endothelial cell adherens junctions is a common feature of these diseases, but the role of BMPs in this process has not been investigated. BMP signaling is initiated by binding of ligand to, and activation of, BMP type I (BMPRI) and type II (BMPRII) receptors. Internalization of VE-cadherin as well as c-Src kinase-dependent phosphorylation have been implicated in the loosening of cell-cell contacts, thereby modulating vascular permeability. Here we demonstrate that BMP6 induces hyperpermeabilization of human endothelial cells by inducing internalization and c-Src-dependent phosphorylation of VE-cadherin. Furthermore, we show BMP-dependent physical interaction of VE-cadherin with the BMP receptor ALK2 (BMPRI) and BMPRII, resulting in stabilization of the BMP receptor complex and, thereby, the support of BMP6-Smad signaling. Our results provide first insights into the molecular mechanism of BMP-induced vascular permeability, a hallmark of various vascular diseases, and provide the basis for further investigations of BMPs as regulators of vascular integrity, both under physiological and pathophysiological conditions. PMID- 26598556 TI - CULD is required for rhodopsin and TRPL channel endocytic trafficking and survival of photoreceptor cells. AB - Endocytosis of G-protein-coupled receptors (GPCRs) and associated channels contributes to desensitization and adaptation of a variety of signaling cascades. In Drosophila melanogaster, the main light-sensing rhodopsin (Rh1; encoded by ninaE) and the downstream ion channel, transient receptor potential like (TRPL), are endocytosed in response to light, but the mechanism is unclear. By using an RNA-Sequencing (RNA-Seq) approach, we discovered a protein we named CULD, a photoreceptor-cell enriched CUB- and LDLa-domain transmembrane protein, that is required for endocytic trafficking of Rh1 and TRPL. CULD localized to endocytic Rh1-positive or TRPL-positive vesicles. Mutations in culd resulted in the accumulation of Rh1 and TRPL within endocytic vesicles, and disrupted the regular turnover of endocytic Rh1 and TRPL. In addition, loss of CULD induced light- and age-dependent retinal degeneration, and reduced levels of Rh1, but not of TRPL, suppressed retinal degeneration in culd-null mutant flies. Our data demonstrate that CULD plays an important role in the endocytic turnover of Rh1 and TRPL, and suggest that CULD-dependent rhodopsin endocytic trafficking is required for maintaining photoreceptor integrity. PMID- 26598557 TI - Wnt/beta-catenin and LIF-Stat3 signaling pathways converge on Sp5 to promote mouse embryonic stem cell self-renewal. AB - Activation of leukemia inhibitor factor (LIF)-Stat3 or Wnt/beta-catenin signaling promotes mouse embryonic stem cell (mESC) self-renewal. A myriad of downstream targets have been identified in the individual signal pathways, but their common targets remain largely elusive. In this study, we found that the LIF-Stat3 and Wnt/beta-catenin signaling pathways converge on Sp5 to promote mESC self-renewal. Forced Sp5 expression can reproduce partial effects of Wnt/beta-catenin signaling but mimics most features of LIF-Stat3 signaling to maintain undifferentiated mESCs. Moreover, Sp5 is able to convert mouse epiblast stem cells into a naive pluripotent state. Thus, Sp5 is an important component of the regulatory network governing mESC naive pluripotency. PMID- 26598559 TI - Sieve estimation in a Markov illness-death process under dual censoring. AB - Semiparametric methods are well established for the analysis of a progressive Markov illness-death process observed up to a noninformative right censoring time. However, often the intermediate and terminal events are censored in different ways, leading to a dual censoring scheme. In such settings, unbiased estimation of the cumulative transition intensity functions cannot be achieved without some degree of smoothing. To overcome this problem, we develop a sieve maximum likelihood approach for inference on the hazard ratio. A simulation study shows that the sieve estimator offers improved finite-sample performance over common imputation-based alternatives and is robust to some forms of dependent censoring. The proposed method is illustrated using data from cancer trials. PMID- 26598558 TI - Reducing Lissencephaly-1 levels augments mitochondrial transport and has a protective effect in adult Drosophila neurons. AB - Defective transport of mitochondria in axons is implicated in the pathogenesis of several age-associated neurodegenerative diseases. However, the regulation and function of axonal mitochondrial motility during normal ageing is poorly understood. Here, we use novel imaging procedures to characterise axonal transport of these organelles in the adult Drosophila wing nerve. During early adult life there is a boost and progressive decline in the proportion of mitochondria that are motile, which is not due to general changes in cargo transport. Experimental inhibition of the mitochondrial transport machinery specifically in adulthood accelerates the appearance of focal protein accumulations in ageing axons, which is suggestive of defects in protein homeostasis. Unexpectedly, lowering levels of Lissencephaly-1 (Lis1), a dynein motor co-factor, augments axonal mitochondrial transport in ageing wing neurons. Lis1 mutations suppress focal protein accumulations in ageing neurons, including those caused by interfering with the mitochondrial transport machinery. Our data provide new insights into the dynamics of mitochondrial motility in adult neurons in vivo, identify Lis1 as a negative regulator of transport of these organelles, and provide evidence of a link between mitochondrial movement and neuronal protein homeostasis. PMID- 26598561 TI - Postmortem Diagnosis of Dengue as an Epidemiological Surveillance Tool. AB - Dengue remains a problem in Brazil, and a substantial number of cases that progress to death are not diagnosed by health services. We evaluated the impact of a protocol adopted by the Coroner's Office Rocha Furtado (CO-RF) for the detection of unreported deaths from dengue in Brazil. We evaluated prospectively cases of deaths referred to the CO-RF with suspicion of dengue and those referred with other diagnosis in which the pathologists suspected dengue as the cause of death. Biological material was collected from all bodies autopsied, for which the suspected cause of death was dengue, between January 2011 and December 2012. Of the 214 bodies autopsied, 134 (62.6%) tested positive for dengue; of these cases, 121 were classified as dengue according to the World Health Organization's case definition (1997 or 2009, as appropriate). Thus, CO-RF detected 90 deaths from dengue, which were not suspected during disease progression. This CO-RF protocol, through a combined effort of the surveillance and laboratory teams, increased the detection of fatal dengue cases by 5-fold. This is the largest series of autopsies performed in cases of death related to dengue in the world to date. PMID- 26598562 TI - Ectopic Schistosoma mansoni Eggs Inside a Lipoma. AB - Ectopic schistosomiasis is uncommon and tends to occur when the parasite's eggs or adult forms are located far from their normal site. This report presents the first described case of ectopic Schistosoma mansoni eggs inside a subcutaneous lipoma far from the tissues of this worm's life cycle and with no connection to either portal veins or any other vascular system. These eggs were found inside giant cells surrounded by inflammatory cells. In conclusion, in humans, ectopic S. mansoni eggs can be found far from the tissues of the described life cycle of this worm, with no connection to portal veins or other blood vessels used for their migration. PMID- 26598563 TI - Serologic Evidence for Fecal-Oral Transmission of Helicobacter pylori. AB - Helicobacter pylori infection is among the most prevalent infections in the world and a key cause of gastric diseases; however, its route of transmission remains unclear. This study aimed to assess the potential for fecal-oral transmission of H. pylori by leveraging its association with a disease with known etiology. Utilizing serology data from the National Health and Nutrition Examination Survey (NHANES 1999; N = 6,347), the association between H. pylori and hepatitis A virus (HAV), a sensitive indicator for fecal-oral exposure, was assessed. Survey weighted kappa and multiple logistic regression were used to quantify the association between H. pylori and HAV after controlling for age, sex, race, poverty, birthplace, crowding, smoking, and alcohol use. Concordant serological results were found among 69.8% of participants (survey-weighted kappa = 0.30, 95% confidence interval [CI] = 0.26, 0.35). The adjusted odds of H. pylori seropositivity were over two times higher after adjusting for confounders (odds ratio = 2.27, 95% CI = 1.79, 2.87). Results from this study suggest H. pylori and HAV infections are strongly associated. Since HAV is primarily transmitted through the fecal-oral route, fecal-oral transmission may be an important pathway for H. pylori spread. PMID- 26598564 TI - Detection of Persistent Chikungunya Virus RNA but not Infectious Virus in Experimental Vertical Transmission in Aedes aegypti from Malaysia. AB - Vertical transmission may contribute to the maintenance of arthropod-borne viruses, but its existence in chikungunya virus (CHIKV) is unclear. Experimental vertical transmission of infectious clones of CHIKV in Aedes aegypti mosquitoes from Malaysia was investigated. Eggs and adult progeny from the second gonotrophic cycles of infected parental mosquitoes were tested. Using polymerase chain reaction (PCR), 56.3% of pooled eggs and 10% of adult progeny had detectable CHIKV RNA, but no samples had detectable infectious virus by plaque assay. Transfected CHIKV RNA from PCR-positive eggs did not yield infectious virus in BHK-21 cells. Thus, vertical transmission of viable CHIKV was not demonstrated. Noninfectious CHIKV RNA persists in eggs and progeny of infected Ae. aegypti, but the mechanism and significance are unknown. There is insufficient evidence to conclude that vertical transmission exists in CHIKV, as positive results reported in previous studies were almost exclusively based only on viral RNA detection. PMID- 26598565 TI - Identification and Characterization of the Trypanosoma cruzi B-cell Superantigen Tc24. AB - Trypanosoma cruzi causes life-long disease after infection and leads to cardiac disease in 30% of infected individuals. After infection, the parasites are readily detectable in the blood during the first few days before disseminating to infect numerous cell types. Preliminary data suggested that the Tc24 protein that localizes to the T. cruzi membrane during all life stages possesses B-cell superantigenic properties. These antigens facilitate immune escape by interfering with antibody-mediated responses, particularly the avoidance of catalytic antibodies. These antibodies are an innate host defense mechanism present in the naive repertoire, and catalytic antibody-antigen binding results in hydrolysis of the target. We tested the B-cell superantigenic properties of Tc24 by comparing the degree of Tc24 hydrolysis by IgM purified from either Tc24 unexposed or exposed mice and humans. Respective samples were subjected to sodium dodecyl sulfate polyacrylamide gel electrophoresis, silver stained, and the degree of hydrolysis was measured. Data presented in this report suggest that the T. cruzi Tc24 is a B-cell superantigen based on the observations that 1) Tc24 was hydrolyzed by IgM present in serum of unexposed mice and humans and 2) exposure to Tc24 eliminated catalytic activity as early as 4 days after T. cruzi infection. PMID- 26598566 TI - Monoclonal Antibodies for the Diagnosis of Borrelia crocidurae. AB - Relapsing fever borreliae, produced by ectoparasite-borne Borrelia species, cause mild to deadly bacteremia and miscarriage. In the perspective of developing inexpensive assays for the rapid detection of relapsing fever borreliae, we produced 12 monoclonal antibodies (MAbs) against Borrelia crocidurae and characterized the two exhibiting the highest titers. P3A10 MAb reacts with the 35.6-kDa flagellin B (flaB) of B. crocidurae while P6D9 MAb recognizes a 35.1-kDa variable-like protein (Vlp) in B. crocidurae and a 35.2-kDa Vlp in Borrelia duttonii. Indirect immunofluorescence assay incorporating relapsing fever and Lyme group borreliae and 11 blood-borne organisms responsible for fever in West Africa confirmed the reactivity of these two MAbs. Combining these two MAbs in indirect immunofluorescence assays detected relapsing fever borreliae including B. crocidurae in ticks and the blood of febrile Senegalese patients. Both antibodies could be incorporated into inexpensive and stable formats suited for the rapid point-of-care diagnosis of relapsing fever. These first-ever MAbs directed against African relapsing fever borreliae are available for the scientific community to promote research in this neglected field. PMID- 26598567 TI - Malaria Parasitemia Among Febrile Patients Seeking Clinical Care at an Outpatient Health Facility in an Urban Informal Settlement Area in Nairobi, Kenya. AB - Nairobi is considered a low-risk area for malaria transmission, but travel can influence transmission of malaria. We investigated the demographic characteristics and travel history of patients with documented fever and malaria in a study clinic in a population-based surveillance system over a 5-year period, January 1, 2007 to December 31, 2011. During the study period, 11,480 (68%) febrile patients had a microscopy test performed for malaria, of which 2,553 (22%) were positive. Malaria was detected year-round with peaks in January, May, and September. Children aged 5-14 years had the highest proportion (28%) of positive results followed by children aged 1-4 years (23%). Almost two-thirds of patients with malaria reported traveling outside Nairobi; 79% of these traveled to three counties in western Kenya. History of recent travel (i.e., in past month) was associated with malaria parasitemia (odds ratio: 10.0, 95% confidence interval: 9.0-11.0). Malaria parasitemia was frequently observed among febrile patients at a health facility in the urban slum of Kibera, Nairobi. The majority of patients had traveled to western Kenya. However, 34% reported no travel history, which raises the possibility of local malaria transmission in this densely populated, urban setting. These findings have important implications for malaria control in large Nairobi settlements. PMID- 26598568 TI - Infant and Young Child Feces Management and Enabling Products for Their Hygienic Collection, Transport, and Disposal in Cambodia. AB - In Cambodia, children's feces are rarely disposed of in an improved sanitation facility. This study examines current practices and the role that enabling products may play in increasing hygienic management of infant and young child (IYC) feces in households with access to improved sanitation. A survey was conducted with the primary caregiver of a child under 5 years of age in 130 homes with an improved latrine in 21 villages across two provinces in Cambodia. Two focus group discussions per province were conducted after the survey to obtain caregiver feedback on new enabling products for hygienic management. Among caregivers, 63% reported child feces disposal in an improved latrine but only 36% reported doing so consistently. Besides child age, years of latrine ownership, caregiver age, consistency of adult latrine use, and presence of child feces management tools in the latrine were associated with hygienic disposal. The youngest caretakers with the newest latrines and youngest children were least likely to dispose of IYC feces hygienically, representing a key target group for interventions to improve hygienic disposal in Cambodia. Reusable diapers, child friendly potties, and possibly latrine seats, that offer child safety, time and cost savings, and easy disposal and cleaning could potentially facilitate hygienic disposal for these ages. PMID- 26598569 TI - Burden of Norovirus and Rotavirus in Children After Rotavirus Vaccine Introduction, Cochabamba, Bolivia. AB - The effectiveness of rotavirus vaccine in the field may set the stage for a changing landscape of diarrheal illness affecting children worldwide. Norovirus and rotavirus are the two major viral enteropathogens of childhood. This study describes the prevalence of norovirus and rotavirus 2 years after widespread rotavirus vaccination in Cochabamba, Bolivia. Stool samples from hospitalized children with acute gastroenteritis (AGE) and outpatients aged 5-24 months without AGE were recruited from an urban hospital serving Bolivia's third largest city. Both viruses were genotyped, and norovirus GII.4 was further sequenced. Norovirus was found much more frequently than rotavirus. Norovirus was detected in 69/201 (34.3%) of specimens from children with AGE and 13/71 (18.3%) of those without diarrhea. Rotavirus was detected in 38/201 (18.9%) of diarrheal specimens and 3/71 (4.2%) of non-diarrheal specimens. Norovirus GII was identified in 97.8% of norovirus-positive samples; GII.4 was the most common genotype (71.4% of typed specimens). Rotavirus G3P[8] was the most prevalent rotavirus genotype (44.0% of typed specimens) and G2P[4] was second most prevalent (16.0% of typed specimens). This community is likely part of a trend toward norovirus predominance over rotavirus in children after widespread vaccination against rotavirus. PMID- 26598570 TI - Clinical Research and the Training of Host Country Investigators: Essential Health Priorities for Disease-Endemic Regions. AB - The health-care needs and resources of disease-endemic regions such as west Africa have been a major focus during the recent Ebola outbreak. On the basis of that experience, we call attention to two priorities that have unfortunately been ignored thus far: 1) the development of clinical research facilities and 2) the training of host country investigators to ensure that the facilities and expertise necessary to evaluate candidate interventions are available on-site in endemic regions when and where they are needed. In their absence, as illustrated by the recent uncertainty about the use of antivirals and other interventions for Ebola virus disease, the only treatment available may be supportive care, case fatality rates may be unacceptably high and there may be long delays between the time potential interventions become available and it becomes clear whether those interventions are safe or effective. On the basis of our experience in Mali, we urge that the development of clinical research facilities and the training of host country investigators be prioritized in disease-endemic regions such as west Africa. PMID- 26598571 TI - Sustaining the Control of Schistosoma mansoni in Western Cote d'Ivoire: Baseline Findings Before the Implementation of a Randomized Trial. AB - We report baseline findings before the implementation of a 4-year intervention trial designed to assess the impact of three different school-based treatment schedules with praziquantel to sustain the control of intestinal schistosomiasis. The baseline survey was conducted in 75 schools of western Cote d'Ivoire previously identified with moderate Schistosoma mansoni endemicity (prevalence: 10-24% in children aged 13-14 years). Three stool samples collected over consecutive days were subjected to duplicate Kato-Katz thick smears each. A questionnaire was administered to collect village-specific information that is relevant for schistosomiasis transmission. Overall, 4,953 first graders (aged 5-8 years) and 7,011 school children (aged 9-12 years) had complete parasitologic data. The overall prevalence of S. mansoni was 5.4% among first graders and 22.1% in 9- to 12-year-old children. Open defecation was practiced in all villages. The current baseline findings will be important to better understand the dynamics of S. mansoni prevalence and intensity over the course of this trial that might be governed by village characteristics and specific treatment interventions. PMID- 26598572 TI - Prevalence and Distribution of Leishmania RNA Virus 1 in Leishmania Parasites from French Guiana. AB - In South America, the presence of the Leishmania RNA virus type 1 (LRV1) was described in Leishmania guyanensis and Leishmania braziliensis strains. The aim of this study was to determine the prevalence distribution of LRV1 in Leishmania isolates in French Guiana given that, in this French overseas department, most Leishmania infections are due to these parasite species. The presence of the virus was observed in 74% of Leishmania spp. isolates, with a highest presence in the internal areas of the country. PMID- 26598573 TI - Loop-Mediated Isothermal Amplification Assay for Identification of Five Human Plasmodium Species in Malaysia. AB - The lack of rapid, affordable, and accurate diagnostic tests represents the primary hurdle affecting malaria surveillance in resource- and expertise-limited areas. Loop-mediated isothermal amplification (LAMP) is a sensitive, rapid, and cheap diagnostic method. Five species-specific LAMP assays were developed based on 18S rRNA gene. Sensitivity and specificity of LAMP results were calculated as compared with microscopic examination and nested polymerase chain reaction. LAMP reactions were highly sensitive with the detection limit of one copy for Plasmodium vivax, Plasmodium falciparum, and Plasmodium malariae and 10 copies for Plasmodium knowlesi and Plasmodium ovale. LAMP positively detected all human malaria species in all positive samples (N = 134; sensitivity = 100%) within 35 minutes. All negative samples were not amplified by LAMP (N = 67; specificity = 100%). LAMP successfully detected two samples with very low parasitemia. LAMP may offer a rapid, simple, and reliable test for the diagnosis of malaria in areas where malaria is prevalent. PMID- 26598574 TI - Serologic Evidence of the Geographic Distribution of Bacterial Zoonotic Agents in Kenya, 2007. AB - Diseases of zoonotic origin contribute to the burden of febrile illnesses in developing countries. We evaluated serologic evidence of exposure to Bacillus anthracis, Brucella spp., spotted fever group rickettsioses (SFGR), and typhus group rickettsioses (TGR) from samples of persons aged 15-64 years collected during a nationwide human immunodeficiency virus (HIV) serosurvey conducted in 2007 in Kenya. The seropositivity observed for pathogens was B. anthracis 11.3%, Brucella spp. 3.0%, SFGR 23.3%, and TGR 0.6%. On univariate analysis, seropositivity for each pathogen was significantly associated with the following risk factors: B. anthracis with province of residence; Brucella spp. with sex, education level, and wealth; SFGR with age, education level, wealth, and province of residence; and TGR with province of residence. On multivariate analysis, seropositivity remained significantly associated with wealth and province for B. anthracis; with sex and age for Brucella spp; and with sex, education level, and province of residence for SFGR whereas TGR had no significance. High IgG seropositivity to these zoonotic pathogens (especially, B. anthracis and SFGR) suggests substantial exposure. These pathogens should be considered in the differential diagnosis of febrile illness in Kenya. PMID- 26598575 TI - Neuroretinal rim area and ocular haemodynamic parameters in patients with normal tension glaucoma with differing intracranial pressures. AB - PURPOSE: To assess the differences in the neuroretinal rim area (NRA) and ocular haemodynamic parameters in patients with normal-tension glaucoma (NTG) with differing intracranial pressure (ICP) values. METHODS: 40 patients (11 males) with NTG (age 61.1 (11.5)) were included in the prospective study. Intraocular pressure (IOP), non-invasive ICP, retrobulbar blood flow (RBF) and confocal laser scanning tomography for optic nerve disc (OND) structural parameters were assessed. Non-invasive ICP was measured using a novel two-depth Transcranial Doppler device. RBF was measured using colour Doppler imaging in the ophthalmic artery (OA). The patients were divided into two groups, ICP >= and <8.3 mm Hg, based on the statistical median of ICP. p Values <0.05 were considered statistically significant. RESULTS: Patients with NTG had mean ICP 8.8 (2.5) mm Hg, IOP 13.6 (2.1) mm Hg, OND size 2.3 (0.6) mm(2), NRA 1.2 (0.4) mm(2). Lower ICP was correlated with decreased NRA (r=0.51, p=0.001). Patients with NTG having lower ICP (N=20) had significantly lower NRA 1.0 (0.3) mm(2), than patients with NTG having higher ICP (N=20) 1.3 (0.3) mm(2), p=0.002, although there were no significant differences in OND size (accordingly, 2.2 (0.5) and 2.3 (0.6) mm(2), p=0.55) and IOP (accordingly, 13.5 (2.4) and 13.7 (1.8) mm Hg, p=0.58). Patients with NTG having lower ICP had significantly lower OA blood flow velocities (peak systolic volume (PSV) 28.7 (8.0), end-diastolic volume (EDV) 6.9 (3.0) cm/s), compared with patients with NTG having higher ICP (PSV 35.5 (10.2), EDV 9.4 (4.1) cm/s), p<0.04. CONCLUSIONS: Patients with NTG having lower ICP have decreased neuroretinal rim area and OA blood flow parameters compared with patients having higher ICP. Further longitudinal studies are needed to analyse the involvement of ICP in NTG management. PMID- 26598576 TI - Vision screening in children: a retrospective study of social and demographic factors with regards to visual outcomes. AB - BACKGROUND: Amblyopia and its risk factors have been demonstrated to be more common among children from low socioeconomic backgrounds. We sought to investigate this association in a region with orthoptic-delivered screening and whole population coverage, and to also examine the association of the Health Plan Indicator (HPI) with screening outcome. METHODS: Screening examination outcomes, postcodes and HPIs were extracted from the community child health database for every child who underwent preschool vision screening between March 2010 and February 2011 Tayside. We obtained the Scottish Index of Multiple Deprivation score for every child as a measure of area-based deprivation. We assessed the vulnerability/needs of the individual family through the HPI-'Core' (children and families receiving universal health visiting service), 'Additional' (receiving additional health/social support) and 'Intensive' (receiving high levels of support). The outcomes from follow-up examinations for those who failed screening were extracted from the orthoptic department database. RESULTS: 4365 children were screened during the year 2010-2011 of whom 523 (11.9%) failed. The odds of children from the least deprived socioeconomic group passing the visual screening test was 1.4 times higher than those from the most deprived socioeconomic group (OR 1.4, 95% CI 1.07 to 1.89, p=0.01). The odds of a child from a family assigned as 'Intensive' failing the preschool visual screening test was three times greater than the odds of a child from a family assigned as 'Core' (OR 3.59, 95% CI 1.6 to 7.8, p=0.001). CONCLUSIONS: We found that children from the most deprived backgrounds and those from unstable homes were more likely to fail preschool vision screening. PMID- 26598577 TI - Efficacy and safety of immunosuppressive agents in the treatment of necrotising scleritis: a retrospective, multicentre study in Korea. AB - AIM: To investigate the efficacy and safety of cyclophosphamide and other immunosuppressive agents (ISAs) in the treatment of necrotising scleritis. METHODS: We reviewed the medical records of patients with necrotising scleritis at 11 tertiary care centres in South Korea from 2002 to 2012, treated with ISAs within 3 months of follow-up period. We divided patients into two groups: a group treated with cyclophosphamide (CYC group) and a group treated with other ISAs; azathioprine, ciclosporin, methotrexate and mycophenolate mofetil (OISA group). Main outcome measures evaluated were remission rate, relapse rate, rate of visual loss, steroid-sparing rate, adverse effects and discontinuation of medication due to adverse effects. RESULTS: CYC group had a remission in 95.2% of the patients and OISA group had in 96.3%. Remission rate, relapse rate, visual loss rate and steroid-sparing rate were not significantly different between the two groups (all p>0.05). The median duration of steroid use was longer in CYC group than in other OISA group (55 vs 16 days, p=0.09). The incidence of adverse effects in the CYC group was comparable with that of the OISA group (61.9% vs 41.4%, p=0.15). However, the incidence of leucopenia, haemorrhagic cystitis and discontinuation of medication due to adverse effects were much higher in the CYC group (p<0.001, p<0.001, p=0.05, respectively). CONCLUSION: The efficacy of cyclophosphamide in the treatment of necrotising scleritis was comparable with that of other ISAs. However, the rate of discontinuation due to side effects was much higher in the CYC group. PMID- 26598578 TI - Asymptomatic giant appendicolith managed conservatively. AB - A 67-year-old lady was found to have a giant appendicolith during a colorectal cancer screening colonoscopy, following a positive faecal occult blood test. Computed tomography confirmed the presence of a calcified giant appendicolith within the base of the appendix, which otherwise appeared normal. Appendicoliths are widely believed to be a major cause of acute appendicitis via obstruction of the appendix lumen, although this is disputed due to a lack of strong evidence. They may also cause chronic abdominal pain. All of the few cases of giant appendicoliths reported so far have been managed by extracting the lesions. Our patient was asymptomatic and had bilateral lung transplants, so a conservative watchful waiting approach was adopted. The authors propose expectant management of giant appendicoliths as a reasonable option in patients with significant operative risks. PMID- 26598580 TI - The Gut-Brain Axis: The Missing Link in Depression. AB - The gut microbiota is essential to human health and the immune system and plays a major role in the bidirectional communication between the gut and the brain. Based on evidence, the gut microbiota is associated with metabolic disorders such as obesity, diabetes mellitus and neuropsychiatric disorders such as schizophrenia, autistic disorders, anxiety disorders and major depressive disorders. In the past few years, neuroscientific research has shown the importance of the microbiota in the development of brain systems. Recent studies showed that the microbiota could activate the immune and central nervous systems, including commensal and pathogenic microorganisms in the gastrointestinal tract. Gut microorganisms are capable of producing and delivering neuroactive substances such as serotonin and gamma-aminobutyric acid, which act on the gut-brain axis. Preclinical research in rodents suggested that certain probiotics have antidepressant and anxiolytic activities. Effects may be mediated via the immune system or neuroendocrine systems. Herein, we present the latest literature examining the effects of the gut microbiota on depression. PMID- 26598581 TI - Efficacy of Adjunctive High Frequency Repetitive Transcranial Magnetic Stimulation of Right Prefrontal Cortex in Adolescent Mania: A Randomized Sham Controlled Study. AB - OBJECTIVE: To examine the efficacy of adjunctive right prefrontal high-frequency repetitive transcranial magnetic stimulation (rTMS) treatment in adolescent mania patients as compared to sham stimulation. METHODS: Twenty six right handed patients aged 12-17 years diagnosed with bipolar mania were randomized to receive daily sessions of active or sham rTMS (20 Hz, 110% of motor threshold, 20 trains, 10 s intertrain interval) over the right dorsolateral prefrontal cortex for 10 days. Mania was rated using Young Mania Rating Scale (YMRS) and Clinical Global Impression (CGI) at baseline, and after 5th and 10th rTMS. RESULTS: For YMRS scores, repeated measures analysis of variance (ANOVA) showed a significant main effect (F=44.49, degree of freedom [df]=1.2/29.29, p<0.001, Greenhouse-Geisser corrected, effect size eta(2)=0.65), but the interaction effect was not significant (F=0.03, df=1.2/29.29, p=0.912, Greenhouse-Geisser corrected). For CGI-Severity, repeated measures ANOVA showed a significant main effect (F=24.49, df=1.42/34.21, p<0.001, Greenhouse-Geisser corrected, effect size eta(2)=0.51), but the interaction effect was not significant (F=0.06, df=1.2/29.29, p=0.881, Greenhouse-Geisser corrected). CONCLUSION: High-frequency right prefrontal rTMS was found to be ineffective as add-on to standard pharmacotherapy in adolescent mania. PMID- 26598579 TI - Classic Studies on the Interaction of Cocaine and the Dopamine Transporter. AB - The dopamine transporter is responsible for recycling dopamine after release. Inhibitors of the dopamine transporter, such as cocaine, will stop the reuptake of dopamine and allow it to stay extracellularly, causing prominent changes at the molecular, cellular, and behavioral levels. There is much left to be known about the mechanism and site(s) of binding, as well as the effect that cocaine administration does to dopamine transporter-cocaine binding sites and gene expression which also plays a strong role in cocaine abusers and their behavioral characteristics. Thus, if more light is shed on the dopamine transporter-cocaine interaction, treatments for addiction and even other diseases of the dopaminergic system may not be too far ahead. As today's ongoing research expands on the shoulders of classic research done in the 1990s and 2000s, the foundation of core research done in that time period will be reviewed, which forms the basis of today's work and tomorrow's therapies. PMID- 26598582 TI - Association between ABCB1 Polymorphisms and Antidepressant Treatment Response in Taiwanese Major Depressive Patients. AB - OBJECTIVE: The multidrug resistance 1 (ABCB1, MDR1) gene, encoding P glycoprotein, is extensively distributed and expressed in various tissues, such as a blood-brain barrier transporter. P-glycoprotein plays an important role in controlling the passage of substances between the blood and brain. The current study aimed to investigate possible associations of functional ABCB1polymorphisms (C3435T, G2677T and C1236T) with response to antidepressant treatment and serum cortisol levels in Taiwanese patients with major depressive disorder (MDD). METHODS: We recruited 112 MDD patients who were randomized to fluoxetine (n=58, mean dose: 21.4+/-4.5 mg/day) or venlafaxine (n=54, 80.2+/-34.7 mg/day) treatment for 6 weeks. The 21-item Hamilton Depression Rating Scale (HDRS) was administered initially and biweekly after treatment, and cortisol levels were assessed initially and after 6-week antidepressant treatment. RESULTS: The initial HDRS scores and the HDRS scores after six weeks of antidepressant treatment were not significantly different among the different genotypes in each polymorphism of ABCB1. The percentage changes of HDRS scores over time were significantly different in the polymorphisms of ABCB1G2677T (p=0.002). MDD patients with the G/G genotype of ABCB1G2677T had a worse antidepressant treatment response. However, the polymorphisms of ABCB1genotypes were not significantly associated with cortisol levels before and after antidepressant treatment in MDD patients. CONCLUSION: The results suggested that the variants of ABCB1may influence the short-term antidepressant response in MDD patients. Further details of the underlying mechanisms of ABCB1in antidepressant treatment remain to be clarified. PMID- 26598583 TI - Gender Differences in the Clinical Characteristics of Psychotic Depression: Results from the CRESCEND Study. AB - OBJECTIVE: To test whether there are gender differences in the clinical characteristics of patients with psychotic depression (PD). METHODS: Using data from the Clinical Research Center for Depression (CRESCEND) study in South Korea, we tested for potential gender differences in clinical characteristics among 53 patients with PD. The Psychotic Depression Assessment Scale (PDAS) and other psychometric scales were used to evaluate various clinical features of the study subjects. Independent t-tests were performed for normally distributed variables, Mann-Whitney U-tests for non-normally distributed variables, and chi(2)tests for discrete variables. In addition, to exclude the effects of confounding variables, we carried out an analysis of covariance (ANCOVA) for the normally distributed variables and binary logistic regression analyses for discrete variables, after adjusting the effects of marital status. RESULTS: We identified more prevalent suicidal ideation (adjusted odds ratio [aOR]=10.316, p=0.036) and hallucinatory behavior (aOR=8.332, p=0.016), as well as more severe anxiety symptoms (degrees of freedom [df]=1, F=6.123, p=0.017), and poorer social and occupational functioning (df=1, F=6.265, p=0.016) in the male patients compared to the female patients. CONCLUSION: Our findings suggest that in South Korean patients with PD, suicidal ideation, hallucinatory behavior, and anxiety is more pronounced among males than females. This should be taken into consideration in clinical practice. PMID- 26598584 TI - Risk Factors for Anxiety in Major Depressive Disorder Patients. AB - OBJECTIVE: To analyze the sociodemographic and clinical factors related to anxiety in patients with major depressive disorder (MDD). METHODS: This study involved a secondary analysis of data obtained from the Diagnostic Assessment Service for People with Bipolar Disorders in China (DASP), which was initiated by the Chinese Society of Psychiatry (CSP) and conducted from September 1, 2010 to February 28, 2011. Based on the presence or absence of anxiety-related characteristics, 1,178 MDD patients were classified as suffering from anxious depression (n=915) or non-anxious depression (n=263), respectively. RESULTS: Compared with the non-anxious group, the anxious-depression group had an older age at onset (t=-4.39, p<0.001), were older (t=-4.69, p<0.001), reported more lifetime depressive episodes (z=-3.24, p=0.001), were more likely to experience seasonal depressive episodes (chi(2)=6.896, p=0.009) and depressive episodes following stressful life events (chi2=59.350, p <0.001), and were more likely to have a family history of psychiatric disorders (chi(2)=6.091, p=0.014). Their positive and total scores on the Mood Disorder Questionnaire (MDQ) and the 32 item Hypomania Checklist (HCL-32) (p<0.05) were also lower. The logistic regression analysis indicated that age (odds ratio [OR]=1.03, p<0.001), a lower total MDQ score (OR=0.94, p=0.011), depressive episodes following stressful life events (OR=3.04, p<0.001), and seasonal depressive episodes (OR=1.75, p=0.039) were significantly associated with anxious depression. CONCLUSION: These findings indicate that older age, fewer subclinical bipolar features, an increased number of depressive episodes following stressful life events, and seasonal depressive episodes may be risk factors for anxiety-related characteristics in patients with MDD. PMID- 26598585 TI - The Changes of Psychometric Profiles after Medical Treatment of Lower Urinary Tract Symptoms Suggestive of Benign Prostatic Hyperplasia. AB - OBJECTIVE: To investigate the relationship of somatization and depression with the degree of lower urinary tract symptoms suggestive of benign prostate hyperplasia (LUTS/BPH) and changes in psychometric profiles including somatization and depression after treatment of LUTS/BPH. METHODS: Subjects were evaluated at baseline and at week 12 following routine treatment for LUTS/BPH using the International Prostate Symptom Score (IPSS) to measure the severity of LUTS/BPH, the Overactive Bladder Symptom Score (OABSS) to measure the severity of OAB, the Patient Health Questionnaire-9 (PHQ-9) to assess depression, and the Patient Health Questionnaire-15 (PHQ-15) to evaluate somatization. The correlation of somatization and depression with the degree of LUTS/BPH symptoms at baseline and changes in somatization and depression after LUTS/BPH treatment were assessed using relevant statistical analyses. RESULTS: One hundred and twenty patients agreed to participate in this study, and 101 (84.2%) completed the 12-week trial and responded to the study questionnaires. At baseline, total IPSS score was correlated with PHQ-9 (r=0.475, p=0.005) and PHQ-15 (r=0.596, p<0.001) scores. The results after the 12-week treatment clearly show significant improvement in both PHQ-9 (p <0.001) and PHQ-15 (p=0.019) scores, and the PHQ-9 (r=0.509, p=0.048) and PHQ-15 (r=0.541, p=0.016) scores were positively correlated with total IPSS. CONCLUSION: Our preliminary results indicated that severity of LUTS is correlated with severity of somatization and depression. Further, the improvement of LUTS after treatment may have positive impacts on somatization and depression. PMID- 26598586 TI - Antipsychotic Prescribing Patterns in First-episode Schizophrenia: A Five-year Comparison. AB - OBJECTIVE: Early treatment choice is critical in first-episode schizophrenia spectrum disorders. The purpose of this study was to describe prescribing trends of antipsychotics use in patients with first-episode schizophrenia in 2005 and 2010, respectively. METHODS: We reviewed the medical records of newly treated patients with schizophrenia from a university psychiatric hospital in 2005 (n=47) and 2010 (n=52). We defined patients as receiving a high antipsychotic dose if their ratio of prescribed daily dose (PDD) to defined daily dose (DDD) was greater than 1.5. RESULTS: The rates of high-dose antipsychotic prescription were 61.7% and 53.8% in 2005 and 2010, respectively. The rates of antipsychotic polypharmacy were 34.6% in 2005 and 34.0% in 2010. The most common first prescribed antipsychotics were (in descending order of prescription frequency) olanzapine, risperidone, aripiprazole, and haloperidol in 2005 and risperidone, quetiapine, paliperidone, and olanzapine in 2010. High-dose antipsychotics were significantly associated with antipsychotic polypharmacy (odds ratio=23.97; p<0.01). More individuals were treated with mood stabilizers in 2010 than in 2005 (p=0.003). CONCLUSION: The practice of prescribing high-dose antipsychotics and associated antipsychotic polypharmacy were common even for initial treatment of first-episode schizophrenia in 2005 and 2010. In 2010, the list of the most common first-prescribed antipsychotics changed, and the use of mood stabilizers increased in non-affective schizophrenia. PMID- 26598587 TI - Brain-derived Neurotrophic Factor Is Associated with Cognitive Impairment in Elderly Korean Individuals. AB - OBJECTIVE: Brain-derived neurotrophic factor (BDNF) is a neurotrophin that is widely expressed in the mammalian brain and acts to regulate neuronal survival and influence cognitive processes. The present study measured serum BDNF levels to investigate the associations of the BDNF Val66Met and 5-hydroxytryptamine transporter linked promoter region (5-HTTLPR) polymorphisms with cognitive function in elderly Korean individuals. METHODS: Over 60 years, a total of 834 subjects were recruited for the present study. The subjects were classified into groups based on the degree of cognitive impairment (age-associated cognitive decline, mild cognitive impairment, and Alzheimer's disease) and compared with normal controls in terms of a neuropsychological assessment and a clinical evaluation. RESULTS: Of the initial 834 study participants, 165 (59 controls and 106 subjects with cognitive impairments) completed the study. There was a significant increase in serum BDNF levels in subjects with cognitive impairments relative to the control group and the BDNF Val66Met polymorphism was significantly associated with cognitive function but not serum BDNF levels. The 5 HTTLPR polymorphism did not have any associations with cognitive impairment or serum BDNF levels. CONCLUSION: The present findings suggest that BDNF may play a role in the pathophysiology of cognitive impairment and the BDNF Val66Met polymorphism may be an important factor in the susceptibility to these age related deficits. PMID- 26598588 TI - The Relationship between Language Ability and Cognitive Function in Patients with Schizophrenia. AB - OBJECTIVE: Cognitive dysfunction is common in people with schizophrenia, and language disability is one of the most notable cognitive deficits. This study assessed the use and comprehension ability of the Korean language in patients with schizophrenia and the correlations between language ability and cognitive function. METHODS: Eighty-six patients with schizophrenia and a group of 29 healthy controls were recruited. We assessed both clinical symptoms and cognitive functions including Korean language ability. For clinical symptoms, the Positive and Negative Syndrome Scale, Clinical Global Impression-Schizophrenia Scale, and Social and Occupational Functioning Assessment Scale were used. For the Korean language ability assessment, a portion of the Korean Broadcasting System (KBS) Korean Language Test was used. The Short-form of Korean-Wechsler Adult Intelligence Scale, the Korean version of the University of California San Diego (UCSD) Performance-based Skills Assessment (K-UPSA), and the Wisconsin Card Sorting Test (WCST) were used to assess cognitive functions. RESULTS: Schizophrenic patients had significantly lower scores in the language and cognitive function tests both in the total and subscale scores. Various clinical scores had negative correlations with reading comprehension ability of the KBS Korean Language Test. The WCST and a part of the K-UPSA had positive correlations with multiple domains of the language test. CONCLUSION: A significant difference was found between schizophrenic patients and controls in language ability. Correlations between Korean language ability and several clinical symptoms and cognitive functions were demonstrated in patients with schizophrenia. Tests of cognitive function had positive correlations with different aspects of language ability. PMID- 26598589 TI - Relationship between Suicidality and Low Self-esteem in Patients with Schizophrenia. AB - OBJECTIVE: Low self-esteem is associated with suicide risk in the general psychiatric population. The aim of this study was to examine associations between suicidality and self-esteem in patients with schizophrenia. METHODS: Subjects meeting the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) diagnostic criteria for schizophrenia were enrolled. Sociodemographic and clinical variables, including previous suicide attempt history, were assessed. Psychopathology, self-esteem, and self-perceived stigma were also measured using the Positive and Negative Syndrome Scale, the Rosenberg Self Esteem Scale (SES), the Beck Depression Inventory (BDI), the Beck Hopelessness Scale, and the Korean version of the Internalized Stigma of Mental Illness scale (K-ISMI). RESULTS: Of the total of 87 participants, 20 (23.0%) had attempted suicide. Patients with a history of suicide attempts had significantly higher scores on the BDI (p=0.036) and K-ISMI (p=0.009), and significantly lower scores on the SES (p=0.001). Analysis of covariance revealed that the SES scores were significantly lower in patients with a history of previous suicide attempts than in those with no history, after controlling for K-ISMI and BDI scores (p=0.039). CONCLUSION: Low self-esteem appears to represent a psychological dimension that is closely related to suicide risk. Therefore, clinical attention should be paid to the evaluation and enhancement of low self-esteem in schizophrenia patients with suicidality. A longitudinal prospective study is required to ascertain whether low self-esteem leads suicide attempts. PMID- 26598590 TI - High Prevalence of Psychotropics Overdose among Suicide Attempters in Korea. AB - OBJECTIVE: The availability of suicide methods affects the risk of suicide attempts. This study examined the patterns of substances ingested by suicide attempters (SAs) and the characteristics of SAs using psychotropic overdoses. METHODS: Data for 384 of the 462 eligible SAs who used self-poisoning were analyzed. Demographic variables, clinical characteristics, and factors related to the suicide attempts were examined. RESULTS: There were 256 (66.7%) females and 128 (33.3%) males. Roughly half the SAs ingested psychotropics (n=179, 46.6%). Agricultural chemicals (n=84, 21.9%) were the second most frequently ingested substances, followed by analgesics (n=62, 16.1%), household products (n=27, 7.0%), and other prescribed medications (n=23, 6.0%). Among psychotropics, the most frequently overdosed drugs were sedative-hypnotics, including hypnotics (n=104) and benzodiazepines (n=78). SAs favored Z-drugs and alprazolam. When compared with SAs with non-psychotropic overdoses, significantly more SAs with psychotropic overdoses were female (76% vs. 58.5%, p<0.001) and had a psychiatric history (59.8% vs. 29.8%, p<0.001). They had significantly more previous suicide attempts (0.52+/-1.02 vs. 0.32+/-0.80, p<0.05) and lower risk (7.96+/-1.49 vs. 8.44+/-1.99, p<0.01) and medical severity (3.06+/-0.81 vs. 3.37+/-0.93, p<0.005) scores. CONCLUSION: Psychotropic overdose, especially with sedative-hypnotics, was a major method in suicide attempts. It is important that psychiatric patients are carefully evaluated and monitored for suicidality when prescribing psychotropics. PMID- 26598591 TI - Characteristic Risk Factors Associated with Planned versus Impulsive Suicide Attempters. AB - OBJECTIVE: The present study aimed to investigate predictors for planned suicide attempters. METHODS: This study included 1,003 patients who attempted suicide and visited emergency department. They were divided into two groups, planned suicide attempters (SAs; n=133 [13.3%]) and impulsive SAs (n=870, [86.7%]), and the demographic variables, clinical characteristics, factors related to suicide, and psychiatric resources of the groups were compared. RESULTS: Major depressive disorder and substance use disorders were more common among planned SAs than among impulsive SAs. Additionally, the planned SAs were older, more likely to be divorced, separated or widowed, and more likely to have comorbid medical illnesses, severe depression, higher suicidality, and self-blaming tendencies than the impulsive SAs. Financial problems and physical illnesses were more common in planned SAs but interpersonal conflicts were more frequent in impulsive SAs. Planned SAs had fewer previous suicide attempts but these were more serious suicide attempts. The presence of the hope to die, a written will, and suicidal ideation of a repetitive, intense, and continuous nature were predictive of planned SAs. CONCLUSION: The present findings demonstrated that planned SAs had more severe psychopathology and medical illnesses than impulsive SAs. Therefore, screening for depression, substance use disorders, and suicidal plans among old and medically ill patients may be important for preventing suicide attempts. PMID- 26598592 TI - Emerging Hyperprolactinemic Galactorrhea in Obsessive Compulsive Disorder with a Stable Dose of Fluoxetine. AB - While fluoxetine (FXT) is a frequently prescribed selective serotonin reuptake inhibitor (SSRI), with few major side-effects; altered serotonergic transmissions in hypothalamic pathways might lead to a distressing, and often embarrassing, manifestation of galactorrhea by altering prolactin release in those on FXT. We report here a case of FXT-induced hyperprolactinemic galactorrhea developing late into treatment on a stable regimen, who responded well to subsequent replacement with sertraline. Based on present finding, we suggest that while SSRIs may share similar mechanisms of action, there exist individual differences in their effects on prolactin secretion pathways. PMID- 26598593 TI - The Accompanying Changes in Brain Structure of a Remitted Depression Patient with the Bupropion Treatment. AB - The impacts from the bupropion on the brain structures have seldom been mentioned in the literature. The bupropion is a kind of antidepressant with dual action in the norepinephrine and dopamine receptors. Here we have a case to share about the bupropion-related effects in the brain structure. PMID- 26598594 TI - Atomoxetine Augmentation in a Case of Treatment Resistant Panic Disorder with Multiple Augments Failure: A Case Report. AB - Atomoxetine, a selective norepinephrine inhibitor, is effective in comorbid anxiety and attention deficit hyperactivity disorder, however its role in panic disorder is unknown. We are presenting a case of panic disorder, who initially partially responded to clonazepam. When clonazepam was added with sertraline, escitalopram, desvenlafaxin, she did not improve significantly until paroxetine was added. When clonazepam-paroxetine combination was added with propranolol, etizolam, olanzepine, risperidone and amisulpride the symptom remission did not occur until a trial of Atomoxetine was done. PMID- 26598595 TI - A Case of Nasu-Hakola Disease without Fractures or Consanguinity Diagnosed Using Exome Sequencing and Treated with Sodium Valproate. AB - Nasu-Hakola disease (NHD) is a rare autosomal recessive neuropsychiatric disorder characterized by bone cysts, fractures, and cognitive impairment. Two genes are responsible for the development of NHD; TYROBPand TREM2. Although it presents with typical signs and symptoms, diagnosing this disease remains difficult. This case report describes a male with NHD with no family or past history of bone fractures who was diagnosed using exome sequencing. His frontal lobe psychiatric symptoms recovered partially following treatment with sodium valproate, but not with an antipsychotic. PMID- 26598596 TI - Primary Prevention of Alzheimer's Disease in Developing Countries. PMID- 26598597 TI - Early Intervention for Psychosis with N-Methyl-D-Aspartate Receptor Modulators. PMID- 26598598 TI - The Effects of Bolus Volume and Texture on Pharyngeal Pressure Events Using High resolution Manometry and Its Comparison with Videofluoroscopic Swallowing Study. AB - BACKGROUND/AIMS: The purpose of this study was to develop new parameters of high resolution manometry (HRM) and to applicate these to quantify the effect of bolus volume and texture on pharyngeal swallowing. METHODS: Ten healthy subjects prospectively swallowed dry, thin fluid 2 mL, thin fluid 5 mL, thin fluid 10 mL, and drinking twice to compare effects of bolus volume. To compare effect of texture, subjects swallowed thin fluid 5 mL, yogurt 5 mL, and bread twice. A 32 sensor HRM catheter and BioVIEW ANALYSIS software were used for data collection and analysis. HRM data were synchronized with kinematic analysis of videofluoroscopic swallowing study (VFSS) using epiglottis tilting. RESULTS: Linear correlation analysis for volume showed significant correlation for area of velopharynx, duration of velopharynx, pre-upper esophageal sphincter (UES) maximal pressure, minimal UES pressure, UES activity time, and nadir UES duration. In the correlation with texture, all parameters were not significantly different. The contraction of the velopharynx was faster than laryngeal elevation. Thedurations of UES relaxation was shorter in the kinematic analysis than HRM. CONCLUSIONS: The bolus volume was shown to have significant effect on pharyngeal pressure and timing, but the texture did not show any effect on pharyngeal swallowing. The parameters of HRM were more sensitive than those of kinematic analysis. As the parameters of HRM are based on precise anatomic structure and the kinematic analysis reflects the actions of multiple anatomic structures, HRM and VFSS should be used according to their purposes. PMID- 26598599 TI - ImPortance of IP-10 in hepatitis B. PMID- 26598600 TI - Going clean: structure and dynamics of peptides in the gas phase and paths to solvation. AB - The gas phase is an artificial environment for biomolecules that has gained much attention both experimentally and theoretically due to its unique characteristic of providing a clean room environment for the comparison between theory and experiment. In this review we give an overview mainly on first-principles simulations of isolated peptides and the initial steps of their interactions with ions and solvent molecules: a bottom up approach to the complexity of biological environments. We focus on the accuracy of different methods to explore the conformational space, the connections between theory and experiment regarding collision cross section evaluations and (anharmonic) vibrational spectra, and the challenges faced in this field. PMID- 26598601 TI - p53 Restoration in Induction and Maintenance of Senescence: Differential Effects in Premalignant and Malignant Tumor Cells. AB - The restoration of p53 has been suggested as a therapeutic approach in tumors. However, the timing of p53 restoration in relation to its efficacy during tumor progression still is unclear. We now show that the restoration of p53 in murine premalignant proliferating pineal lesions resulted in cellular senescence, while p53 restoration in invasive pineal tumors did not. The effectiveness of p53 restoration was not dependent on p19(Arf) expression but showed an inverse correlation with Mdm2 expression. In tumor cells, p53 restoration became effective when paired with either DNA-damaging therapy or with nutlin, an inhibitor of p53-Mdm2 interaction. Interestingly, the inactivation of p53 after senescence resulted in reentry into the cell cycle and rapid tumor progression. The evaluation of a panel of human supratentorial primitive neuroectodermal tumors (sPNET) showed low activity of the p53 pathway. Together, these data suggest that the restoration of the p53 pathway has different effects in premalignant versus invasive pineal tumors, and that p53 activation needs to be continually sustained, as reversion from senescence occurs rapidly with aggressive tumor growth when p53 is lost again. Finally, p53 restoration approaches may be worth exploring in sPNET, where the p53 gene is intact but the pathway is inactive in the majority of examined tumors. PMID- 26598602 TI - Tet1 and Tet2 Protect DNA Methylation Canyons against Hypermethylation. AB - DNA methylation is a dynamic epigenetic modification with an important role in cell fate specification and reprogramming. The Ten eleven translocation (Tet) family of enzymes converts 5-methylcytosine to 5-hydroxymethylcytosine, which promotes passive DNA demethylation and functions as an intermediate in an active DNA demethylation process. Tet1/Tet2 double-knockout mice are characterized by developmental defects and epigenetic instability, suggesting a requirement for Tet-mediated DNA demethylation for the proper regulation of gene expression during differentiation. Here, we used whole-genome bisulfite and transcriptome sequencing to characterize the underlying mechanisms. Our results uncover the hypermethylation of DNA methylation canyons as the genomic key feature of Tet1/Tet2 double-knockout mouse embryonic fibroblasts. Canyon hypermethylation coincided with disturbed regulation of associated genes, suggesting a mechanistic explanation for the observed Tet-dependent differentiation defects. Based on these results, we propose an important regulatory role of Tet-dependent DNA demethylation for the maintenance of DNA methylation canyons, which prevents invasive DNA methylation and allows functional regulation of canyon-associated genes. PMID- 26598603 TI - Natural Functions of PLIN2 Mediating Wnt/LiCl Signaling and Glycogen Synthase Kinase 3 (GSK3)/GSK3 Substrate-Related Effects Are Modulated by Lipid. AB - Belonging to the PLIN family, PLIN2 associates with lipid storage droplets (LSDs), but other functions of PLIN2 remain unclear. Here, we suggest that PLIN2 mediates Wnt signaling because PLIN2 small interfering RNA (siRNA) suppresses activation of Wnt/coreceptor pathways. The mediation in the Wnt/Frizzled pathway seems to occur from Dishevelleds to axin/glycogen synthase kinase 3(GSK3)/beta catenin complexes (AGbetaC) as Wnt decreases Dishevelled/PLIN2 but increases AGbetaC/PLIN2 associations. Augmenting cellular LSDs that affect PLIN2 associations with these proteins, oleic acid (OA) treatment inhibits Wnt increased AGbetaC/PLIN2 associations and beta-catenin T-cell factor signaling (beta-CTS). Revealing that PLIN2 is a GSK3-associated protein, the study explored PLIN2-mediated effects on GSK3/GSK3 substrates. PLIN2 siRNA reduces inhibitory GSK3 levels and lithium chloride (LiCl)-upregulated beta-catenin or CCAAT/enhancer binding protein alpha (c/EBPalpha) expression. OA treatment decreases LiCl-increased c/EBPalpha via PLIN2-c/EBPalpha dissociation. In addition to PLIN2 overexpression increasing beta-CTS, PLIN2 depletion or overexpression drops or adds expression of GSK3 substrates, such as beta-catenin, c/EBPalpha,c-Myc, cyclin D1, and insulin receptor substrate 1, and cell growth/survival. PLIN2 N or C terminus overexpression that is associated with higher levels of the substrates suggests that those substrates bind to specific regions of PLIN2. Mimicking the possible high lipid concentrations in cells in the human body under conditions of hyperlipidemia/obesity, OA-treated cells gain or reduce GSK3 substrate expression in parallel with a decrease (a Wnt-like effect) or increase in GSK3 activity, likely regulated by GSK3/PLIN2/GSK3 substrate associations. PMID- 26598604 TI - LMO2 Oncoprotein Stability in T-Cell Leukemia Requires Direct LDB1 Binding. AB - LMO2 is a component of multisubunit DNA-binding transcription factor complexes that regulate gene expression in hematopoietic stem and progenitor cell development. Enforced expression of LMO2 causes leukemia by inducing hematopoietic stem cell-like features in T-cell progenitor cells, but the biochemical mechanisms of LMO2 function have not been fully elucidated. In this study, we systematically dissected the LMO2/LDB1-binding interface to investigate the role of this interaction in T-cell leukemia. Alanine scanning mutagenesis of the LIM interaction domain of LDB1 revealed a discrete motif, R(320)LITR, required for LMO2 binding. Most strikingly, coexpression of full-length, wild type LDB1 increased LMO2 steady-state abundance, whereas coexpression of mutant proteins deficient in LMO2 binding compromised LMO2 stability. These mutant LDB1 proteins also exerted dominant negative effects on growth and transcription in diverse leukemic cell lines. Mass spectrometric analysis of LDB1 binding partners in leukemic lines supports the notion that LMO2/LDB1 function in leukemia occurs in the context of multisubunit complexes, which also protect the LMO2 oncoprotein from degradation. Collectively, these data suggest that the assembly of LMO2 into complexes, via direct LDB1 interaction, is a potential molecular target that could be exploited in LMO2-driven leukemias resistant to existing chemotherapy regimens. PMID- 26598605 TI - Essential Nonredundant Function of the Catalytic Activity of Histone Deacetylase 2 in Mouse Development. AB - The class I histone deacetylases (HDACs) HDAC1 and HDAC2 play partially redundant roles in the regulation of gene expression and mouse development. As part of multisubunit corepressor complexes, these two deacetylases exhibit both enzymatic and nonenzymatic functions. To examine the impact of the catalytic activities of HDAC1 and HDAC2, we generated knock-in mice expressing catalytically inactive isoforms, which are still incorporated into the HDAC1/HDAC2 corepressor complexes. Surprisingly, heterozygous mice expressing catalytically inactive HDAC2 die within a few hours after birth, while heterozygous HDAC1 mutant mice are indistinguishable from wild-type littermates. Heterozygous HDAC2 mutant mice show an unaltered composition but reduced associated deacetylase activity of corepressor complexes and exhibit a more severe phenotype than HDAC2-null mice. They display changes in brain architecture accompanied by premature expression of the key regulator protein kinase C delta. Our study reveals a dominant negative effect of catalytically inactive HDAC2 on specific corepressor complexes resulting in histone hyperacetylation, transcriptional derepression, and, ultimately, perinatal lethality. PMID- 26598606 TI - Binding of the Extracellular Eight-Cysteine Motif of Opy2 to the Putative Osmosensor Msb2 Is Essential for Activation of the Yeast High-Osmolarity Glycerol Pathway. AB - To adapt to environmental high osmolarity, the budding yeast Saccharomyces cerevisiae activates the Hog1 mitogen-activated protein kinase, which regulates diverse osmoadaptive responses. Hog1 is activated through the high-osmolarity glycerol (HOG) pathway, which consists of independent upstream signaling routes termed the SLN1 branch and the SHO1 branch. Here, we report that the extracellular cysteine-rich (CR) domain of the transmembrane-anchor protein Opy2 binds to the Hkr1-Msb2 homology (HMH) domain of the putative osmosensor Msb2 and that formation of the Opy2-Msb2 complex is essential for osmotic activation of Hog1 through the MSB2 subbranch of the SHO1 branch. By analyzing the phenotypes of mutants with Opy2 cysteine-to-alanine mutations, we deduced that the CR domain forms four intramolecular disulfide bonds. To probe for the potential induction of conformational changes in the Opy2-Msb2 complex by osmostress, we constructed mutants with a site-specific Cys-to-Ala mutation of the Opy2 CR domain and mutants with a Cys substitution of the Msb2 HMH domain. Each of these mutants had a reduced cysteine. These mutants were then combinatorially cross-linked using chemical cross-linkers of different lengths. Cross-linking between Opy2 Cys48 and Msb2 Cys1023 was sensitive to osmotic changes, suggesting that osmostress induced a conformational change. We therefore propose that the Opy2-Msb2 complex might serve as an osmosensor. PMID- 26598608 TI - Thomas Pucadyil: Piecing together membrane fission. PMID- 26598607 TI - Role of Ostm1 Cytosolic Complex with Kinesin 5B in Intracellular Dispersion and Trafficking. AB - In humans and in mice, mutations in the Ostm1 gene cause the most severe form of osteopetrosis, a major bone disease, and neuronal degeneration, both of which are associated with early death. To gain insight into Ostm1 function, we first investigated by sequence and biochemical analysis an immature 34-kDa type I transmembrane Ostm1 protein with a unique cytosolic tail. Mature Ostm1 is posttranslationally processed and highly N-glycosylated and has an apparent mass of ~60 kDa. Analysis the subcellular localization of Ostm1 showed that it is within the endoplasmic reticulum, trans-Golgi network, and endosomes/lysosomes. By a wide protein screen under physiologic conditions, several novel cytosolic Ostm1 partners were identified and validated, for which a direct interaction with the kinesin 5B heavy chains was demonstrated. These results determined that Ostm1 is part of a cytosolic scaffolding multiprotein complex, imparting an adaptor function to Ostm1. Moreover, we uncovered a role for the Ostm1/KIF5B complex in intracellular trafficking and dispersion of cargos from the endoplasmic reticulum to late endosomal/lysosomal subcellular compartments. These Ostm1 molecular and cellular functions could elucidate all of the pathophysiologic mechanisms underlying the wide phenotypic spectrum of Ostm1-deficient mice. PMID- 26598610 TI - Mitosis is swell. AB - Cell volume and dry mass are typically correlated. However, in this issue, Zlotek Zlotkiewicz et al. (2015. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201505056) and Son et al. (2015. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201505058) use new live-cell techniques to show that entry to mitosis coincides with rapid cell swelling, which is reversed before division. PMID- 26598611 TI - Regulating the regulator: Numb acts upstream of p53 to control mammary stem and progenitor cell. AB - In this issue, Tosoni et al. (2015. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201505037) report that cell fate determinant and tumor suppressor Numb imposes asymmetric cell divisions in mammary stem cells by regulating p53. Numb thereby restricts mammary stem cell expansion and controls the proliferation and lineage-specific characteristics of their progeny. PMID- 26598613 TI - Resonant microchannel volume and mass measurements show that suspended cells swell during mitosis. AB - Osmotic regulation of intracellular water during mitosis is poorly understood because methods for monitoring relevant cellular physical properties with sufficient precision have been limited. Here we use a suspended microchannel resonator to monitor the volume and density of single cells in suspension with a precision of 1% and 0.03%, respectively. We find that for transformed murine lymphocytic leukemia and mouse pro-B cell lymphoid cell lines, mitotic cells reversibly increase their volume by more than 10% and decrease their density by 0.4% over a 20-min period. This response is correlated with the mitotic cell cycle but is not coupled to nuclear osmolytes released by nuclear envelope breakdown, chromatin condensation, or cytokinesis and does not result from endocytosis of the surrounding fluid. Inhibiting Na-H exchange eliminates the response. Although mitotic rounding of adherent cells is necessary for proper cell division, our observations that suspended cells undergo reversible swelling during mitosis suggest that regulation of intracellular water may be a more general component of mitosis than previously appreciated. PMID- 26598612 TI - The multifaceted roles of the HORMA domain in cellular signaling. AB - The HORMA domain is a multifunctional protein-protein interaction module found in diverse eukaryotic signaling pathways including the spindle assembly checkpoint, numerous DNA recombination/repair pathways, and the initiation of autophagy. In all of these pathways, HORMA domain proteins occupy key signaling junctures and function through the controlled assembly and disassembly of signaling complexes using a stereotypical "safety belt" peptide interaction mechanism. A recent explosion of structural and functional work has shed new light on these proteins, illustrating how strikingly similar structural mechanisms give rise to radically different functional outcomes in each family of HORMA domain proteins. PMID- 26598614 TI - Optical volume and mass measurements show that mammalian cells swell during mitosis. AB - The extent, mechanism, and function of cell volume changes during specific cellular events, such as cell migration and cell division, have been poorly studied, mostly because of a lack of adequate techniques. Here we unambiguously report that a large range of mammalian cell types display a significant increase in volume during mitosis (up to 30%). We further show that this increase in volume is tightly linked to the mitotic state of the cell and not to its spread or rounded shape and is independent of the presence of an intact actomyosin cortex. Importantly, this volume increase is not accompanied by an increase in dry mass and thus corresponds to a decrease in cell density. This mitotic swelling might have important consequences for mitotic progression: it might contribute to produce strong pushing forces, allowing mitotic cells to round up; it might also, by lowering cytoplasmic density, contribute to the large change of physicochemical properties observed in mitotic cells. PMID- 26598615 TI - The synaptonemal complex is assembled by a polySUMOylation-driven feedback mechanism in yeast. AB - During meiotic prophase I, proteinaceous structures called synaptonemal complexes (SCs) connect homologous chromosomes along their lengths via polymeric arrays of transverse filaments (TFs). Thus, control of TF polymerization is central to SC formation. Using budding yeast, we show that efficiency of TF polymerization closely correlates with the extent of SUMO conjugation to Ecm11, a component of SCs. HyperSUMOylation of Ecm11 leads to highly aggregative TFs, causing frequent assembly of extrachromosomal structures. In contrast, hypoSUMOylation leads to discontinuous, fragmented SCs, indicative of defective TF polymerization. We further show that the N terminus of the yeast TF, Zip1, serves as an activator for Ecm11 SUMOylation. Coexpression of the Zip1 N terminus and Gmc2, a binding partner of Ecm11, is sufficient to induce robust polySUMOylation of Ecm11 in nonmeiotic cells. Because TF assembly is mediated through N-terminal head-to-head associations, our results suggest that mutual activation between TF assembly and Ecm11 polySUMOylation acts as a positive feedback loop that underpins SC assembly. PMID- 26598616 TI - Titration of mitochondrial fusion rescues Mff-deficient cardiomyopathy. AB - Defects in mitochondrial fusion or fission are associated with many pathologies, raising the hope that pharmacological manipulation of mitochondrial dynamics may have therapeutic benefit. This approach assumes that organ physiology can be restored by rebalancing mitochondrial dynamics, but this concept remains to be validated. We addressed this issue by analyzing mice deficient in Mff, a protein important for mitochondrial fission. Mff mutant mice die at 13 wk as a result of severe dilated cardiomyopathy leading to heart failure. Mutant tissue showed reduced mitochondrial density and respiratory chain activity along with increased mitophagy. Remarkably, concomitant deletion of the mitochondrial fusion gene Mfn1 completely rescued heart dysfunction, life span, and respiratory chain function. Our results show for the first time that retuning the balance of mitochondrial fusion and fission can restore tissue integrity and mitochondrial physiology at the whole-organ level. Examination of liver, testis, and cerebellum suggest, however, that the precise balance point of fusion and fission is cell type specific. PMID- 26598617 TI - Protocadherins control the modular assembly of neuronal columns in the zebrafish optic tectum. AB - Cell-cell recognition guides the assembly of the vertebrate brain during development. delta-Protocadherins comprise a family of neural adhesion molecules that are differentially expressed and have been implicated in a range of neurodevelopmental disorders. Here we show that the expression of delta protocadherins partitions the zebrafish optic tectum into radial columns of neurons. Using in vivo two-photon imaging of bacterial artificial chromosome transgenic zebrafish, we show that pcdh19 is expressed in discrete columns of neurons, and that these columnar modules are derived from proliferative pcdh19(+) neuroepithelial precursors. Elimination of pcdh19 results in both a disruption of columnar organization and defects in visually guided behaviors. These results reveal a fundamental mechanism for organizing the developing nervous system: subdivision of the early neuroepithelium into precursors with distinct molecular identities guides the autonomous development of parallel neuronal units, organizing neural circuit formation and behavior. PMID- 26598618 TI - Histone demethylase KDM4B regulates otic vesicle invagination via epigenetic control of Dlx3 expression. AB - In vertebrates, the inner ear arises from the otic placode, a thickened swathe of ectoderm that invaginates to form the otic vesicle. We report that histone demethylase KDM4B is dynamically expressed during early stages of chick inner ear formation. A loss of KDM4B results in defective invagination and striking morphological changes in the otic epithelium, characterized by abnormal localization of adhesion and cytoskeletal molecules and reduced expression of several inner ear markers, including Dlx3. In vivo chromatin immunoprecipitation reveals direct and dynamic occupancy of KDM4B and its target, H3K9me3, at regulatory regions of the Dlx3 locus. Accordingly, coelectroporations of DLX3 or KDM4B encoding constructs, but not a catalytically dead mutant of KDM4B, rescue the ear invagination phenotype caused by KDM4B knockdown. Moreover, a loss of DLX3 phenocopies a loss of KDM4B. Collectively, our findings suggest that KDM4B play a critical role during inner ear invagination via modulating histone methylation of the direct target Dlx3. PMID- 26598619 TI - The Numb/p53 circuitry couples replicative self-renewal and tumor suppression in mammary epithelial cells. AB - The cell fate determinant Numb orchestrates tissue morphogenesis and patterning in developmental systems. In the human mammary gland, Numb is a tumor suppressor and regulates p53 levels. However, whether this function is linked to its role in fate determination remains unclear. Here, by exploiting an ex vivo system, we show that at mitosis of purified mammary stem cells (SCs), Numb ensures the asymmetric outcome of self-renewing divisions by partitioning into the progeny that retains the SC identity, where it sustains high p53 activity. Numb also controls progenitor maturation. At this level, Numb loss associates with the epithelial-to-mesenchymal transition and results in differentiation defects and reacquisition of stemness features. The mammary gland of Numb-knockout mice displays an expansion of the SC compartment, associated with morphological alterations and tumorigenicity in orthotopic transplants. This is because of low p53 levels and can be inhibited by restoration of Numb levels or p53 activity, which results in successful SC-targeted treatment. PMID- 26598620 TI - PAK4 promotes kinase-independent stabilization of RhoU to modulate cell adhesion. AB - P21-activated kinase 4 (PAK4) is a Cdc42 effector protein thought to regulate cell adhesion disassembly in a kinase-dependent manner. We found that PAK4 expression is significantly higher in high-grade human breast cancer patient samples, whereas depletion of PAK4 modifies cell adhesion dynamics of breast cancer cells. Surprisingly, systematic analysis of PAK4 functionality revealed that PAK4-driven adhesion turnover is neither dependent on Cdc42 binding nor kinase activity. Rather, reduced expression of PAK4 leads to a concomitant loss of RhoU expression. We report that RhoU is targeted for ubiquitination by the Rab40A-Cullin 5 complex and demonstrate that PAK4 protects RhoU from ubiquitination in a kinase-independent manner. Overexpression of RhoU rescues the PAK4 depletion phenotype, whereas loss of RhoU expression reduces cell adhesion turnover and migration. These data support a new kinase-independent mechanism for PAK4 function, where an important role of PAK4 in cellular adhesions is to stabilize RhoU protein levels. Thus, PAK4 and RhoU cooperate to drive adhesion turnover and promote cell migration. PMID- 26598621 TI - TDP-43 is intercellularly transmitted across axon terminals. AB - Transactive response DNA-binding protein 43 kD (TDP-43) is an aggregation-prone prion-like domain-containing protein and component of pathological intracellular aggregates found in most amyotrophic lateral sclerosis (ALS) patients. TDP-43 oligomers have been postulated to be released and subsequently nucleate TDP-43 oligomerization in recipient cells, which might be the molecular correlate of the systematic symptom spreading observed during ALS progression. We developed a novel protein complementation assay allowing quantification of TDP-43 oligomers in living cells. We demonstrate the exchange of TDP-43 between cell somata and the presence of TDP-43 oligomers in microvesicles/exosomes and show that microvesicular TDP-43 is preferentially taken up by recipient cells where it exerts higher toxicity than free TDP-43. Moreover, studies using microfluidic neuronal cultures suggest both anterograde and retrograde trans-synaptic spreading of TDP-43. Finally, we demonstrate TDP-43 oligomer seeding by TDP-43 containing material derived from both cultured cells and ALS patient brain lysate. Thus, using an innovative detection technique, we provide evidence for preferentially microvesicular uptake as well as both soma-to-soma "horizontal" and bidirectional "vertical" synaptic intercellular transmission and prion-like seeding of TDP-43. PMID- 26598623 TI - Correction: Synaptopodin couples epithelial contractility to alpha-actinin-4 dependent junction maturation. PMID- 26598622 TI - A bacterial type III secretion-based protein delivery tool for broad applications in cell biology. AB - Methods enabling the delivery of proteins into eukaryotic cells are essential to address protein functions. Here we propose broad applications to cell biology for a protein delivery tool based on bacterial type III secretion (T3S). We show that bacterial, viral, and human proteins, fused to the N-terminal fragment of the Yersinia enterocolitica T3S substrate YopE, are effectively delivered into target cells in a fast and controllable manner via the injectisome of extracellular bacteria. This method enables functional interaction studies by the simultaneous injection of multiple proteins and allows the targeting of proteins to different subcellular locations by use of nanobody-fusion proteins. After delivery, proteins can be freed from the YopE fragment by a T3S-translocated viral protease or fusion to ubiquitin and cleavage by endogenous ubiquitin proteases. Finally, we show that this delivery tool is suitable to inject proteins in living animals and combine it with phosphoproteomics to characterize the systems-level impact of proapoptotic human truncated BID on the cellular network. PMID- 26598625 TI - Method for identification of Cryptococcus neoformans and Cryptococcus gattii useful in resource-limited settings. AB - AIMS: The high HIV/AIDS burden in Sub-Saharan Africa has led to cryptococcosis becoming a public health concern. In this resource-limited setting, conventional identification methods are mainly used to diagnose cryptococcal infections. However, these methods are often inconsistent, and importantly, cannot discriminate between the aetiological agents, Cryptococcus neoformans and C. gattii. Therefore, there is a need for an alternative reliable method to identify these species. METHODS: We examined the usefulness of a PCR method, including a restriction digest, in identifying clinical C. neoformans and C. gattii isolates. In addition, matrix-assisted laser desorption ionisation time-of-flight mass spectrometry (MALDI-ToF MS) was performed for validation purposes. RESULTS: The intraspecific variation between tested strains allowed for their delineation into three traditional varieties of C. neoformans, that is, varietal forms: neoformans, grubii and gattii. Furthermore, we uncovered a restriction site (signature sequence: 5'-AATATT-3') that is present only in the distinct species C. neoformans (varietal forms neoformans and grubii), and is, importantly, absent in the distinct species C. gattii (C. neoformans var. gattii). Thus, we were able to discriminate the distinct species by directly digesting the PCR amplicons using the endonuclease SspI. It was also possible to delineate some tested isolates as either C. neoformans or C. gattii using our MALDI-ToF MS data. CONCLUSIONS: The possibility of performing only a restriction digest makes the outlined method, similar to conventional techniques, economical and easy to optimise for routine use in resource-limited settings. PMID- 26598624 TI - Molecular mechanisms in multiple myeloma drug resistance. AB - Multiple myeloma (MM) is predominantly an incurable malignancy despite high-dose chemotherapy, autologous stem cell transplant and novel agents. MM is a genetically heterogeneous disease and the complexity increases as the disease progresses to a more aggressive stage. MM arises from a plasma cell, which produces and secretes non-functioning immunoglobulins. Most MM cells are sensitive to proteasome inhibitors (PIs), which have become the main drug in the treatment of newly diagnosed and relapsed MM. However, not all MM is sensitive to PIs. This review summarises the literature regarding molecular biology of MM with a focus on the unfolded protein response and explores how this could affect drug sensitivity and progression of disease. PMID- 26598626 TI - Quality assessment and preservation of RNA from biobank tissue specimens: a systematic review. AB - It is well recognised that genomic, proteomic and biomarker studies require properly annotated and well-characterised biospecimens. Consequently, this necessitates biobanks to collect, store and distribute biospecimens under stringent quality control and assurance measures. However, despite this realisation, there remains a lack of standardisation in quality management among biobanks and consensus as to which quality indicators provide the optimal molecular diagnostic performance tools and information for biospecimens. In an attempt to identify key factors that predict tissue specimen integrity and quality, this systematic review investigated the measures reported in the literature, which characterised the collection, processing and storage of high quality tissue specimens. Our findings demonstrated RNA integrity, alone, may not be an effective measure of tissue quality. Furthermore, the frequently reported parameters related to biospecimen integrity, such as storage time, temperature, time to cryopreservation and tissue morphology were also not effective indicators of quality control and assurance. These findings suggest that it is unlikely that a single marker will provide the optimal diagnostic and performance information for biospecimens, but rather, a panel of markers assessing the molecular integrity of the lifespan of the biospecimen is required. Further work is needed to identify which factors predict specimen integrity and quality in biobanked tissue specimens. PMID- 26598627 TI - Twenty-five years of the trauma audit and research network: a continuing evolution to drive improvement. PMID- 26598628 TI - The trials of being a national trauma registry. PMID- 26598629 TI - The changing face of major trauma in the UK. AB - AIM: Major trauma (MT) has traditionally been viewed as a disease of young men caused by high-energy transfer mechanisms of injury, which has been reflected in the configuration of MT services. With ageing populations in Western societies, it is anticipated that the elderly will comprise an increasing proportion of the MT workload. The aim of this study was to describe changes in the demographics of MT in a developed Western health system over the last 20 years. METHODS: The Trauma Audit Research Network (TARN) database was interrogated to identify all cases of MT (injury severity score >15) between 1990 and the end of 2013. Age at presentation, gender, mechanism of injury and use of CT were recorded. For convenience, cases were categorised by age groups of 25 years and by common mechanisms of injury. Longitudinal changes each year were recorded. RESULTS: Profound changes in the demographics of recorded MT were observed. In 1990, the mean age of MT patients within the TARN database was 36.1, the largest age group suffering MT was 0-24 years (39.3%), the most common causative mechanism was road traffic collision (59.1%), 72.7% were male and 33.6% underwent CT. By 2013, mean age had increased to 53.8 years, the single largest age group was 25-50 years (27.1%), closely followed by those >75 years (26.9%), the most common mechanism was low falls (39.1%), 68.3% were male and 86.8% underwent CT. CONCLUSIONS: This study suggests that the MT population identified in the UK is becoming more elderly, and the predominant mechanism that precipitates MT is a fall from <2 m. Significant improvements in outcomes from MT may be expected if services targeting the specific needs of the elderly are developed within MT centres. PMID- 26598630 TI - A profile of suspected child abuse as a subgroup of major trauma patients. AB - INTRODUCTION: Non-accidental injury (NAI) in children is an important cause of major injury. The Trauma Audit Research Network (TARN) recently analysed data on the demographics of paediatric trauma and highlighted NAI as a major cause of death and severe injury in children. This paper examined TARN data to characterise accidental versus abusive cases of major injury. METHODS: The national trauma registry of England and Wales (TARN) database was interrogated for the classification of mechanism of injury in children by intent, from January 2004 to December 2013. Contributing hospitals' submissions were classified into accidental injury (AI), suspected child abuse (SCA) or alleged assault (AA) to enable demographic and injury comparisons. RESULTS: In the study population of 14 845 children, 13 708 (92.3%, CI 91.9% to 92.8%) were classified as accidental injury, 368 as alleged assault (2.5%, CI 2.2% to 2.7%) and 769 as SCA (5.2%, CI 4.8% to 5.5%). Nearly all cases of severely injured children suffering trauma because of SCA occurred in the age group of 0-5 years (751 of 769, 97.7%), with 76.3% occurring in infants under the age of 1 year. Compared with accidental injury, suspected victims of abuse have higher overall injury severity scores, have a higher proportion of head injury and a threefold higher mortality rate of 7.6% (CI 5.51% to 9.68%) vs 2.6% (CI 2.3% to 2.9%). CONCLUSIONS: This study highlights that major injury occurring as a result of SCA has a typical demographic pattern. These children tend to be under 12 months of age, with more severe injury. Understanding these demographics could help receiving hospitals identify children with major injuries resulting from abuse and ensure swift transfer to specialist care. PMID- 26598631 TI - Resuscitative endovascular balloon occlusion of the aorta (REBOA): a population based gap analysis of trauma patients in England and Wales. AB - INTRODUCTION: Non-compressible torso haemorrhage (NCTH) carries a high mortality in trauma as many patients exsanguinate prior to definitive haemorrhage control. Resuscitative endovascular balloon occlusion of the aorta (REBOA) is an adjunct that has the potential to bridge patients to definitive haemostasis. However, the proportion of trauma patients in whom REBOA may be utilised is unknown. METHODS: We conducted a population based analysis of 2012-2013 Trauma Audit and Research Network (TARN) data. We identified the number of patients in whom REBOA may have been utilised, defined by an Abbreviated Injury Scale score >=3 to abdominal solid organs, abdominal or pelvic vasculature, pelvic fracture with ring disruption or proximal traumatic lower limb amputation, together with a systolic blood pressure <90 mm Hg. Patients with non-compressible haemorrhage in the mediastinum, axilla, face or neck were excluded. RESULTS: During 2012-2013, 72 677 adult trauma patients admitted to hospitals in England and Wales were identified. 397 patients had an indication(s) and no contraindications for REBOA with evidence of haemorrhagic shock: 69% men, median age 43 years and median Injury Severity Score 32. Overall mortality was 32%. Major trauma centres (MTCs) received the highest concentration of potential REBOA patients, and would be anticipated to receive a patient in whom REBOA may be utilised every 95 days, increasing to every 46 days in the 10 MTCs with the highest attendance of this injury type. CONCLUSIONS: This TARN database analysis has identified a small group of severely injured, resource intensive patients with a highly lethal injury that is theoretically amenable to REBOA. The highest density of these patients is seen at MTCs, and as such a planned evaluation of REBOA should be further considered in these hospitals. PMID- 26598632 TI - Top 10 TARN research publications. AB - The last 25 years have seen Trauma Audit and Research Network's (TARN) research agenda develop into a significant portfolio of over 100 publications, including a number of international collaborations. Holding the largest trauma registry in Europe, TARN continues to provide researchers with the ability to pursue their interests in both epidemiological and clinical topics relating to traumatic injury. This edition of the Emergency Medicine Journal provides an opportunity to celebrate some of these papers with a 'Top 10', which have been voted by members of the TARN Research Committee on the basis of their impact. PMID- 26598633 TI - A woman with recurrent vomiting and body cramps. PMID- 26598634 TI - BET 1: Intravenous tranexamic acid in the treatment of acute epistaxis. AB - A short-cut review was carried out to establish whether intravenous tranexamic acid is beneficial in managing acute epistaxis. Seven papers were found in Medline, Embase and the Cochrane Library using the reported searches, but none presented any evidence to answer the clinical question. It is concluded that there is no evidence to support or refute the use of intravenous tranexamic acid in acute epistaxis and that local advice should be followed. PMID- 26598636 TI - BET 2: role of vinegar in Irukandji syndrome. AB - A shortcut review was carried out to establish whether dousing areas of contact with vinegar could relieve the symptoms of Irukandji syndrome. Four studies were directly relevant to the question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these papers are tabulated. The clinical bottom line is there is a lack of evidence for effectiveness and the latest local guidelines should be followed. PMID- 26598637 TI - BET 3: Bedside ultrasound for the diagnosis of sternal fracture. AB - A shortcut review was carried out to establish whether ultrasound is an effective diagnostic tool for the diagnosis of sternal fractures. 27 papers were found of which 4 presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these best papers are tabulated. The clinical bottom line is that in patients with blunt thoracic injury and suspected isolated sternal fracture, ultrasound seems superior to conventional radiology to diagnose sternal fracture. PMID- 26598639 TI - QuantFusion: Novel Unified Methodology for Enhanced Coverage and Precision in Quantifying Global Proteomic Changes in Whole Tissues. AB - Single quantitative platforms such as label-based or label-free quantitation (LFQ) present compromises in accuracy, precision, protein sequence coverage, and speed of quantifiable proteomic measurements. To maximize the quantitative precision and the number of quantifiable proteins or the quantifiable coverage of tissue proteomes, we have developed a unified approach, termed QuantFusion, that combines the quantitative ratios of all peptides measured by both LFQ and label based methodologies. Here, we demonstrate the use of QuantFusion in determining the proteins differentially expressed in a pair of patient-derived tumor xenografts (PDXs) representing two major breast cancer (BC) subtypes, basal and luminal. Label-based in-spectra quantitative peptides derived from amino acid coded tagging (AACT, also known as SILAC) of a non-malignant mammary cell line were uniformly added to each xenograft with a constant predefined ratio, from which Ratio-of-Ratio estimates were obtained for the label-free peptides paired with AACT peptides in each PDX tumor. A mixed model statistical analysis was used to determine global differential protein expression by combining complementary quantifiable peptide ratios measured by LFQ and Ratio-of-Ratios, respectively. With minimum number of replicates required for obtaining the statistically significant ratios, QuantFusion uses the distinct mechanisms to "rescue" the missing data inherent to both LFQ and label-based quantitation. Combined quantifiable peptide data from both quantitative schemes increased the overall number of peptide level measurements and protein level estimates. In our analysis of the PDX tumor proteomes, QuantFusion increased the number of distinct peptide ratios by 65%, representing differentially expressed proteins between the BC subtypes. This quantifiable coverage improvement, in turn, not only increased the number of measurable protein fold-changes by 8% but also increased the average precision of quantitative estimates by 181% so that some BC subtypically expressed proteins were rescued by QuantFusion. Thus, incorporating data from multiple quantitative approaches while accounting for measurement variability at both the peptide and global protein levels make QuantFusion unique for obtaining increased coverage and quantitative precision for tissue proteomes. PMID- 26598640 TI - Identification of Serum Biomarkers for Gastric Cancer Diagnosis Using a Human Proteome Microarray. AB - We aimed to globally discover serum biomarkers for diagnosis of gastric cancer (GC). GC serum autoantibodies were discovered and validated using serum samples from independent patient cohorts encompassing 1,401 participants divided into three groups, i.e. healthy, GC patients, and GC-related disease group. To discover biomarkers for GC, the human proteome microarray was first applied to screen specific autoantibodies in a total of 87 serum samples from GC patients and healthy controls. Potential biomarkers were identified via a statistical analysis protocol. Targeted protein microarrays with only the potential biomarkers were constructed and used to validate the candidate biomarkers using 914 samples. To provide further validation, the abundance of autoantibodies specific to the biomarker candidates was analyzed using enzyme-linked immunosorbent assays. Receiver operating characteristic curves were generated to evaluate the diagnostic accuracy of the serum biomarkers. Finally, the efficacy of prognosis efficacy of the final four biomarkers was evaluated by analyzing the clinical records. The final panel of biomarkers consisting of COPS2, CTSF, NT5E, and TERF1 provides high diagnostic power, with 95% sensitivity and 92% specificity to differentiate GC patients from healthy individuals. Prognosis analysis showed that the panel could also serve as independent predictors of the overall GC patient survival. The panel of four serum biomarkers (COPS2, CTSF, NT5E, and TERF1) could serve as a noninvasive diagnostic index for GC, and the combination of them could potentially be used as a predictor of the overall GC survival rate. PMID- 26598642 TI - Multistep Fractionation and Mass Spectrometry Reveal Zwitterionic and Anionic Modifications of the N- and O-glycans of a Marine Snail. AB - Various studies in the past have revealed that molluscs can produce a wide range of rather complex N-glycan structures, which vary from those occurring in other invertebrate animals; particularly methylated glycans have been found in gastropods, and there are some reports of anionic glycans in bivalves. Due to the high variability in terms of previously described structures and methodologies, it is a major challenge to establish glycomic workflows that yield the maximum amount of detailed structural information from relatively low quantities of sample. In this study, we apply differential release with peptide:N-glycosidases F and A followed by solid-phase extraction on graphitized carbon and reversed phase materials to examine the glycome of Volvarina rubella (C. B. Adams, 1845), a margin snail of the clade Neogastropoda. The resulting four pools of N-glycans were fractionated on a fused core RP-HPLC column and subject to MALDI-TOF MS and MS/MS in conjunction with chemical and enzymatic treatments. In addition, selected N-glycan fractions, as well as O-glycans released by beta-elimination, were analyzed by porous graphitized carbon-LC-MS and MS(n). This comprehensive approach enabled us to determine a number of novel modifications of protein linked glycans, including N-methyl-2-aminoethylphosphonate on mannose and N acetylhexosamine residues, core beta1,3-linked mannose, zwitterionic moieties on core Galbeta1,4Fuc motifs, additional mannose residues on oligomannosidic glycans, and bisubstituted antennal fucose; furthermore, typical invertebrate N glycans with sulfate and core fucose residues are present in this gastropod. PMID- 26598641 TI - Dynamics of Hippocampal Protein Expression During Long-term Spatial Memory Formation. AB - Spatial memory depends on the hippocampus, which is particularly vulnerable to aging. This vulnerability has implications for the impairment of navigation capacities in older people, who may show a marked drop in performance of spatial tasks with advancing age. Contemporary understanding of long-term memory formation relies on molecular mechanisms underlying long-term synaptic plasticity. With memory acquisition, activity-dependent changes occurring in synapses initiate multiple signal transduction pathways enhancing protein turnover. This enhancement facilitates de novo synthesis of plasticity related proteins, crucial factors for establishing persistent long-term synaptic plasticity and forming memory engrams. Extensive studies have been performed to elucidate molecular mechanisms of memory traces formation; however, the identity of plasticity related proteins is still evasive. In this study, we investigated protein turnover in mouse hippocampus during long-term spatial memory formation using the reference memory version of radial arm maze (RAM) paradigm. We identified 1592 proteins, which exhibited a complex picture of expression changes during spatial memory formation. Variable linear decomposition reduced significantly data dimensionality and enriched three principal factors responsible for variance of memory-related protein levels at (1) the initial phase of memory acquisition (165 proteins), (2) during the steep learning improvement (148 proteins), and (3) the final phase of the learning curve (123 proteins). Gene ontology and signaling pathways analysis revealed a clear correlation between memory improvement and learning phase-curbed expression profiles of proteins belonging to specific functional categories. We found differential enrichment of (1) neurotrophic factors signaling pathways, proteins regulating synaptic transmission, and actin microfilament during the first day of the learning curve; (2) transcription and translation machinery, protein trafficking, enhancement of metabolic activity, and Wnt signaling pathway during the steep phase of memory formation; and (3) cytoskeleton organization proteins. Taken together, this study clearly demonstrates dynamic assembly and disassembly of protein-protein interaction networks depending on the stage of memory formation engrams. PMID- 26598643 TI - Site-specific O-Glycosylation Analysis of Human Blood Plasma Proteins. AB - Site-specific glycosylation analysis is key to investigate structure-function relationships of glycoproteins, e.g. in the context of antigenicity and disease progression. The analysis, though, is quite challenging and time consuming, in particular for O-glycosylated proteins. In consequence, despite their clinical and biopharmaceutical importance, many human blood plasma glycoproteins have not been characterized comprehensively with respect to their O-glycosylation. Here, we report on the site-specific O-glycosylation analysis of human blood plasma glycoproteins. To this end pooled human blood plasma of healthy donors was proteolytically digested using a broad-specific enzyme (Proteinase K), followed by a precipitation step, as well as a glycopeptide enrichment and fractionation step via hydrophilic interaction liquid chromatography, the latter being optimized for intact O-glycopeptides carrying short mucin-type core-1 and -2 O glycans, which represent the vast majority of O-glycans on human blood plasma proteins. Enriched O-glycopeptide fractions were subjected to mass spectrometric analysis using reversed-phase liquid chromatography coupled online to an ion trap mass spectrometer operated in positive-ion mode. Peptide identity and glycan composition were derived from low-energy collision-induced dissociation fragment spectra acquired in multistage mode. To pinpoint the O-glycosylation sites glycopeptides were fragmented using electron transfer dissociation. Spectra were annotated by database searches as well as manually. Overall, 31 O-glycosylation sites and regions belonging to 22 proteins were identified, the majority being acute-phase proteins. Strikingly, also 11 novel O-glycosylation sites and regions were identified. In total 23 O-glycosylation sites could be pinpointed. Interestingly, the use of Proteinase K proved to be particularly beneficial in this context. The identified O-glycan compositions most probably correspond to mono- and disialylated core-1 mucin-type O-glycans (T-antigen). The developed workflow allows the identification and characterization of the major population of the human blood plasma O-glycoproteome and our results provide new insights, which can help to unravel structure-function relationships. The data were deposited to ProteomeXchange PXD003270. PMID- 26598644 TI - MASH Suite Pro: A Comprehensive Software Tool for Top-Down Proteomics. AB - Top-down mass spectrometry (MS)-based proteomics is arguably a disruptive technology for the comprehensive analysis of all proteoforms arising from genetic variation, alternative splicing, and posttranslational modifications (PTMs). However, the complexity of top-down high-resolution mass spectra presents a significant challenge for data analysis. In contrast to the well-developed software packages available for data analysis in bottom-up proteomics, the data analysis tools in top-down proteomics remain underdeveloped. Moreover, despite recent efforts to develop algorithms and tools for the deconvolution of top-down high-resolution mass spectra and the identification of proteins from complex mixtures, a multifunctional software platform, which allows for the identification, quantitation, and characterization of proteoforms with visual validation, is still lacking. Herein, we have developed MASH Suite Pro, a comprehensive software tool for top-down proteomics with multifaceted functionality. MASH Suite Pro is capable of processing high-resolution MS and tandem MS (MS/MS) data using two deconvolution algorithms to optimize protein identification results. In addition, MASH Suite Pro allows for the characterization of PTMs and sequence variations, as well as the relative quantitation of multiple proteoforms in different experimental conditions. The program also provides visualization components for validation and correction of the computational outputs. Furthermore, MASH Suite Pro facilitates data reporting and presentation via direct output of the graphics. Thus, MASH Suite Pro significantly simplifies and speeds up the interpretation of high-resolution top down proteomics data by integrating tools for protein identification, quantitation, characterization, and visual validation into a customizable and user-friendly interface. We envision that MASH Suite Pro will play an integral role in advancing the burgeoning field of top-down proteomics. PMID- 26598645 TI - Cryo-slicing Blue Native-Mass Spectrometry (csBN-MS), a Novel Technology for High Resolution Complexome Profiling. AB - Blue native (BN) gel electrophoresis is a powerful method for protein separation. Combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS), it enables large scale identification of protein complexes and their subunits. Current BN-MS approaches, however, are limited in size resolution, comprehensiveness, and quantification. Here, we present a new methodology combining defined sub-millimeter slicing of BN gels by a cryo-microtome with high performance LC-MS/MS and label-free quantification of protein amounts. Application of this cryo-slicing BN-MS approach to mitochondria from rat brain demonstrated a high degree of comprehensiveness, accuracy, and size resolution. The technique provided abundance-mass profiles for 774 mitochondrial proteins, including all canonical subunits of the oxidative respiratory chain assembled into 13 distinct (super-)complexes. Moreover, the data revealed COX7R as a constitutive subunit of distinct super-complexes and identified novel assemblies of voltage-dependent anion channels/porins and TOM proteins. Together, cryo slicing BN-MS enables quantitative profiling of complexomes with resolution close to the limits of native gel electrophoresis. PMID- 26598646 TI - Histone H4 Lysine 20 (H4K20) Methylation, Expanding the Signaling Potential of the Proteome One Methyl Moiety at a Time. AB - Covalent post-translational modifications (PTMs) of proteins can regulate the structural and functional state of a protein in the absence of primary changes in the underlying sequence. Common PTMs include phosphorylation, acetylation, and methylation. Histone proteins are critical regulators of the genome and are subject to a highly abundant and diverse array of PTMs. To highlight the functional complexity added to the proteome by lysine methylation signaling, here we will focus on lysine methylation of histone proteins, an important modification in the regulation of chromatin and epigenetic processes. We review the signaling pathways and functions associated with a single residue, H4K20, as a model chromatin and clinically important mark that regulates biological processes ranging from the DNA damage response and DNA replication to gene expression and silencing. PMID- 26598647 TI - Osteoblast-released Matrix Vesicles, Regulation of Activity and Composition by Sulfated and Non-sulfated Glycosaminoglycans. AB - Our aging population has to deal with the increasing threat of age-related diseases that impair bone healing. One promising therapeutic approach involves the coating of implants with modified glycosaminoglycans (GAGs) that mimic the native bone environment and actively facilitate skeletogenesis. In previous studies, we reported that coatings containing GAGs, such as hyaluronic acid (HA) and its synthetically sulfated derivative (sHA1) as well as the naturally low sulfated GAG chondroitin sulfate (CS1), reduce the activity of bone-resorbing osteoclasts, but they also induce functions of the bone-forming cells, the osteoblasts. However, it remained open whether GAGs influence the osteoblasts alone or whether they also directly affect the formation, composition, activity, and distribution of osteoblast-released matrix vesicles (MV), which are supposed to be the active machinery for bone formation. Here, we studied the molecular effects of sHA1, HA, and CS1 on MV activity and on the distribution of marker proteins. Furthermore, we used comparative proteomic methods to study the relative protein compositions of isolated MVs and MV-releasing osteoblasts. The MV proteome is much more strongly regulated by GAGs than the cellular proteome. GAGs, especially sHA1, were found to severely impact vesicle-extracellular matrix interaction and matrix vesicle activity, leading to stronger extracellular matrix formation and mineralization. This study shows that the regulation of MV activity is one important mode of action of GAGs and provides information on underlying molecular mechanisms. PMID- 26598649 TI - Reply to Betsch et al.: Highlighting risks of diseases shifts vaccine attitudes. PMID- 26598648 TI - Proteomic Analysis of Dynein-Interacting Proteins in Amyotrophic Lateral Sclerosis Synaptosomes Reveals Alterations in the RNA-Binding Protein Staufen1. AB - Synapse disruption takes place in many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). However, the mechanistic understanding of this process is still limited. We set out to study a possible role for dynein in synapse integrity. Cytoplasmic dynein is a multisubunit intracellular molecule responsible for diverse cellular functions, including long-distance transport of vesicles, organelles, and signaling factors toward the cell center. A less well characterized role dynein may play is the spatial clustering and anchoring of various factors including mRNAs in distinct cellular domains such as the neuronal synapse. Here, in order to gain insight into dynein functions in synapse integrity and disruption, we performed a screen for novel dynein interactors at the synapse. Dynein immunoprecipitation from synaptic fractions of the ALS model mSOD1(G93A) and wild-type controls, followed by mass spectrometry analysis on synaptic fractions of the ALS model mSOD1(G93A) and wild-type controls, was performed. Using advanced network analysis, we identified Staufen1, an RNA binding protein required for the transport and localization of neuronal RNAs, as a major mediator of dynein interactions via its interaction with protein phosphatase 1-beta (PP1B). Both in vitro and in vivo validation assays demonstrate the interactions of Staufen1 and PP1B with dynein, and their colocalization with synaptic markers was altered as a result of two separate ALS linked mutations: mSOD1(G93A) and TDP43(A315T). Taken together, we suggest a model in which dynein's interaction with Staufen1 regulates mRNA localization along the axon and the synapses, and alterations in this process may correlate with synapse disruption and ALS toxicity. PMID- 26598650 TI - Don't try to convert the antivaccinators, instead target the fence-sitters. PMID- 26598651 TI - Reply to Slesak et al.: So much about Rickettsia felis infection to be discovered. PMID- 26598652 TI - Leeches as further potential vectors for rickettsial infections. PMID- 26598653 TI - Corporate funding and ideological polarization about climate change. AB - Drawing on large-scale computational data and methods, this research demonstrates how polarization efforts are influenced by a patterned network of political and financial actors. These dynamics, which have been notoriously difficult to quantify, are illustrated here with a computational analysis of climate change politics in the United States. The comprehensive data include all individual and organizational actors in the climate change countermovement (164 organizations), as well as all written and verbal texts produced by this network between 1993 2013 (40,785 texts, more than 39 million words). Two main findings emerge. First, that organizations with corporate funding were more likely to have written and disseminated texts meant to polarize the climate change issue. Second, and more importantly, that corporate funding influences the actual thematic content of these polarization efforts, and the discursive prevalence of that thematic content over time. These findings provide new, and comprehensive, confirmation of dynamics long thought to be at the root of climate change politics and discourse. Beyond the specifics of climate change, this paper has important implications for understanding ideological polarization more generally, and the increasing role of private funding in determining why certain polarizing themes are created and amplified. Lastly, the paper suggests that future studies build on the novel approach taken here that integrates large-scale textual analysis with social networks. PMID- 26598655 TI - Low-cost solution to the grid reliability problem with 100% penetration of intermittent wind, water, and solar for all purposes. AB - This study addresses the greatest concern facing the large-scale integration of wind, water, and solar (WWS) into a power grid: the high cost of avoiding load loss caused by WWS variability and uncertainty. It uses a new grid integration model and finds low-cost, no-load-loss, nonunique solutions to this problem on electrification of all US energy sectors (electricity, transportation, heating/cooling, and industry) while accounting for wind and solar time series data from a 3D global weather model that simulates extreme events and competition among wind turbines for available kinetic energy. Solutions are obtained by prioritizing storage for heat (in soil and water); cold (in ice and water); and electricity (in phase-change materials, pumped hydro, hydropower, and hydrogen), and using demand response. No natural gas, biofuels, nuclear power, or stationary batteries are needed. The resulting 2050-2055 US electricity social cost for a full system is much less than for fossil fuels. These results hold for many conditions, suggesting that low-cost, reliable 100% WWS systems should work many places worldwide. PMID- 26598654 TI - Ion-binding properties of a K+ channel selectivity filter in different conformations. AB - K(+) channels are membrane proteins that selectively conduct K(+) ions across lipid bilayers. Many voltage-gated K(+) (KV) channels contain two gates, one at the bundle crossing on the intracellular side of the membrane and another in the selectivity filter. The gate at the bundle crossing is responsible for channel opening in response to a voltage stimulus, whereas the gate at the selectivity filter is responsible for C-type inactivation. Together, these regions determine when the channel conducts ions. The K(+) channel from Streptomyces lividians (KcsA) undergoes an inactivation process that is functionally similar to KV channels, which has led to its use as a practical system to study inactivation. Crystal structures of KcsA channels with an open intracellular gate revealed a selectivity filter in a constricted conformation similar to the structure observed in closed KcsA containing only Na(+) or low [K(+)]. However, recent work using a semisynthetic channel that is unable to adopt a constricted filter but inactivates like WT channels challenges this idea. In this study, we measured the equilibrium ion-binding properties of channels with conductive, inactivated, and constricted filters using isothermal titration calorimetry (ITC). EPR spectroscopy was used to determine the state of the intracellular gate of the channel, which we found can depend on the presence or absence of a lipid bilayer. Overall, we discovered that K(+) ion binding to channels with an inactivated or conductive selectivity filter is different from K(+) ion binding to channels with a constricted filter, suggesting that the structures of these channels are different. PMID- 26598656 TI - Tracking the origins of Yakutian horses and the genetic basis for their fast adaptation to subarctic environments. AB - Yakutia, Sakha Republic, in the Siberian Far East, represents one of the coldest places on Earth, with winter record temperatures dropping below -70 degrees C. Nevertheless, Yakutian horses survive all year round in the open air due to striking phenotypic adaptations, including compact body conformations, extremely hairy winter coats, and acute seasonal differences in metabolic activities. The evolutionary origins of Yakutian horses and the genetic basis of their adaptations remain, however, contentious. Here, we present the complete genomes of nine present-day Yakutian horses and two ancient specimens dating from the early 19th century and ~5,200 y ago. By comparing these genomes with the genomes of two Late Pleistocene, 27 domesticated, and three wild Przewalski's horses, we find that contemporary Yakutian horses do not descend from the native horses that populated the region until the mid-Holocene, but were most likely introduced following the migration of the Yakut people a few centuries ago. Thus, they represent one of the fastest cases of adaptation to the extreme temperatures of the Arctic. We find cis-regulatory mutations to have contributed more than nonsynonymous changes to their adaptation, likely due to the comparatively limited standing variation within gene bodies at the time the population was founded. Genes involved in hair development, body size, and metabolic and hormone signaling pathways represent an essential part of the Yakutian horse adaptive genetic toolkit. Finally, we find evidence for convergent evolution with native human populations and woolly mammoths, suggesting that only a few evolutionary strategies are compatible with survival in extremely cold environments. PMID- 26598657 TI - Advancing biomedical imaging. AB - Imaging reveals complex structures and dynamic interactive processes, located deep inside the body, that are otherwise difficult to decipher. Numerous imaging modalities harness every last inch of the energy spectrum. Clinical modalities include magnetic resonance imaging (MRI), X-ray computed tomography (CT), ultrasound, and light-based methods [endoscopy and optical coherence tomography (OCT)]. Research modalities include various light microscopy techniques (confocal, multiphoton, total internal reflection, superresolution fluorescence microscopy), electron microscopy, mass spectrometry imaging, fluorescence tomography, bioluminescence, variations of OCT, and optoacoustic imaging, among a few others. Although clinical imaging and research microscopy are often isolated from one another, we argue that their combination and integration is not only informative but also essential to discovering new biology and interpreting clinical datasets in which signals invariably originate from hundreds to thousands of cells per voxel. PMID- 26598660 TI - Correction for Sit et al., Variable genetic architectures produce virtually identical molecules in bacterial symbionts of fungus-growing ants. PMID- 26598659 TI - Evidence for extensive horizontal gene transfer from the draft genome of a tardigrade. AB - Horizontal gene transfer (HGT), or the transfer of genes between species, has been recognized recently as more pervasive than previously suspected. Here, we report evidence for an unprecedented degree of HGT into an animal genome, based on a draft genome of a tardigrade, Hypsibius dujardini. Tardigrades are microscopic eight-legged animals that are famous for their ability to survive extreme conditions. Genome sequencing, direct confirmation of physical linkage, and phylogenetic analysis revealed that a large fraction of the H. dujardini genome is derived from diverse bacteria as well as plants, fungi, and Archaea. We estimate that approximately one-sixth of tardigrade genes entered by HGT, nearly double the fraction found in the most extreme cases of HGT into animals known to date. Foreign genes have supplemented, expanded, and even replaced some metazoan gene families within the tardigrade genome. Our results demonstrate that an unexpectedly large fraction of an animal genome can be derived from foreign sources. We speculate that animals that can survive extremes may be particularly prone to acquiring foreign genes. PMID- 26598661 TI - Regenerative medicine: Current therapies and future directions. AB - Organ and tissue loss through disease and injury motivate the development of therapies that can regenerate tissues and decrease reliance on transplantations. Regenerative medicine, an interdisciplinary field that applies engineering and life science principles to promote regeneration, can potentially restore diseased and injured tissues and whole organs. Since the inception of the field several decades ago, a number of regenerative medicine therapies, including those designed for wound healing and orthopedics applications, have received Food and Drug Administration (FDA) approval and are now commercially available. These therapies and other regenerative medicine approaches currently being studied in preclinical and clinical settings will be covered in this review. Specifically, developments in fabricating sophisticated grafts and tissue mimics and technologies for integrating grafts with host vasculature will be discussed. Enhancing the intrinsic regenerative capacity of the host by altering its environment, whether with cell injections or immune modulation, will be addressed, as well as methods for exploiting recently developed cell sources. Finally, we propose directions for current and future regenerative medicine therapies. PMID- 26598662 TI - Synthetic biology devices for in vitro and in vivo diagnostics. AB - There is a growing need to enhance our capabilities in medical and environmental diagnostics. Synthetic biologists have begun to focus their biomolecular engineering approaches toward this goal, offering promising results that could lead to the development of new classes of inexpensive, rapidly deployable diagnostics. Many conventional diagnostics rely on antibody-based platforms that, although exquisitely sensitive, are slow and costly to generate and cannot readily confront rapidly emerging pathogens or be applied to orphan diseases. Synthetic biology, with its rational and short design-to-production cycles, has the potential to overcome many of these limitations. Synthetic biology devices, such as engineered gene circuits, bring new capabilities to molecular diagnostics, expanding the molecular detection palette, creating dynamic sensors, and untethering reactions from laboratory equipment. The field is also beginning to move toward in vivo diagnostics, which could provide near real-time surveillance of multiple pathological conditions. Here, we describe current efforts in synthetic biology, focusing on the translation of promising technologies into pragmatic diagnostic tools and platforms. PMID- 26598664 TI - Weaker axially dipolar time-averaged paleomagnetic field based on multidomain corrected paleointensities from Galapagos lavas. AB - The geomagnetic field is predominantly dipolar today, and high-fidelity paleomagnetic mean directions from all over the globe strongly support the geocentric axial dipole (GAD) hypothesis for the past few million years. However, the bulk of paleointensity data fails to coincide with the axial dipole prediction of a factor-of-2 equator-to-pole increase in mean field strength, leaving the core dynamo process an enigma. Here, we obtain a multidomain corrected Pliocene-Pleistocene average paleointensity of 21.6 +/- 11.0 uT recorded by 27 lava flows from the Galapagos Archipelago near the Equator. Our new result in conjunction with a published comprehensive study of single-domain behaved paleointensities from Antarctica (33.4 +/- 13.9 uT) that also correspond to GAD directions suggests that the overall average paleomagnetic field over the past few million years has indeed been dominantly dipolar in intensity yet only ~ 60% of the present-day field strength, with a long-term average virtual axial dipole magnetic moment of the Earth of only 4.9 +/- 2.4 * 10(22) A ? m(2). PMID- 26598658 TI - HLA-DRB1*11 and variants of the MHC class II locus are strong risk factors for systemic juvenile idiopathic arthritis. AB - Systemic juvenile idiopathic arthritis (sJIA) is an often severe, potentially life-threatening childhood inflammatory disease, the pathophysiology of which is poorly understood. To determine whether genetic variation within the MHC locus on chromosome 6 influences sJIA susceptibility, we performed an association study of 982 children with sJIA and 8,010 healthy control subjects from nine countries. Using meta-analysis of directly observed and imputed SNP genotypes and imputed classic HLA types, we identified the MHC locus as a bona fide susceptibility locus with effects on sJIA risk that transcended geographically defined strata. The strongest sJIA-associated SNP, rs151043342 [P = 2.8 * 10(-17), odds ratio (OR) 2.6 (2.1, 3.3)], was part of a cluster of 482 sJIA-associated SNPs that spanned a 400-kb region and included the class II HLA region. Conditional analysis controlling for the effect of rs151043342 found that rs12722051 independently influenced sJIA risk [P = 1.0 * 10(-5), OR 0.7 (0.6, 0.8)]. Meta analysis of imputed classic HLA-type associations in six study populations of Western European ancestry revealed that HLA-DRB1*11 and its defining amino acid residue, glutamate 58, were strongly associated with sJIA [P = 2.7 * 10(-16), OR 2.3 (1.9, 2.8)], as was the HLA-DRB1*11-HLA-DQA1*05-HLA-DQB1*03 haplotype [6.4 * 10(-17), OR 2.3 (1.9, 2.9)]. By examining the MHC locus in the largest collection of sJIA patients assembled to date, this study solidifies the relationship between the class II HLA region and sJIA, implicating adaptive immune molecules in the pathogenesis of sJIA. PMID- 26598663 TI - Nanotechnologies for biomedical science and translational medicine. AB - In 2000 the United States launched the National Nanotechnology Initiative and, along with it, a well-defined set of goals for nanomedicine. This Perspective looks back at the progress made toward those goals, within the context of the changing landscape in biomedicine that has occurred over the past 15 years, and considers advances that are likely to occur during the next decade. In particular, nanotechnologies for health-related genomics and single-cell biology, inorganic and organic nanoparticles for biomedicine, and wearable nanotechnologies for wellness monitoring are briefly covered. PMID- 26598665 TI - Plasmodium evasion of mosquito immunity and global malaria transmission: The lock and-key theory. AB - Plasmodium falciparum malaria originated in Africa and became global as humans migrated to other continents. During this journey, parasites encountered new mosquito species, some of them evolutionarily distant from African vectors. We have previously shown that the Pfs47 protein allows the parasite to evade the mosquito immune system of Anopheles gambiae mosquitoes. Here, we investigated the role of Pfs47-mediated immune evasion in the adaptation of P. falciparum to evolutionarily distant mosquito species. We found that P. falciparum isolates from Africa, Asia, or the Americas have low compatibility to malaria vectors from a different continent, an effect that is mediated by the mosquito immune system. We identified 42 different haplotypes of Pfs47 that have a strong geographic population structure and much lower haplotype diversity outside Africa. Replacement of the Pfs47 haplotypes in a P. falciparum isolate is sufficient to make it compatible to a different mosquito species. Those parasites that express a Pfs47 haplotype compatible with a given vector evade antiplasmodial immunity and survive. We propose that Pfs47-mediated immune evasion has been critical for the globalization of P. falciparum malaria as parasites adapted to new vector species. Our findings predict that this ongoing selective force by the mosquito immune system could influence the dispersal of Plasmodium genetic traits and point to Pfs47 as a potential target to block malaria transmission. A new model, the "lock-and-key theory" of P. falciparum globalization, is proposed, and its implications are discussed. PMID- 26598666 TI - Uterine glucocorticoid receptors are critical for fertility in mice through control of embryo implantation and decidualization. AB - In addition to the well-characterized role of the sex steroid receptors in fertility and reproduction, organs of the female reproductive tract are also regulated by the hypothalamic-pituitary-adrenal axis. These endocrine organs are sensitive to stress-mediated actions of glucocorticoids, and the mouse uterus contains high levels of the glucocorticoid receptor (GR). Although the presence of GR in the uterus is well established, uterine glucocorticoid signaling has been largely ignored in terms of its reproductive and/or immunomodulatory functions on fertility. To define the direct in vivo function of glucocorticoid signaling in adult uterine physiology, we generated a uterine-specific GR knockout (uterine GR KO) mouse using the PR(cre) mouse model. The uterine GR KO mice display a profound subfertile phenotype, including a significant delay to first litter and decreased pups per litter. Early defects in pregnancy are evident as reduced blastocyst implantation and subsequent defects in stromal cell decidualization, including decreased proliferation, aberrant apoptosis, and altered gene expression. The deficiency in uterine GR signaling resulted in an exaggerated inflammatory response to induced decidualization, including altered immune cell recruitment. These results demonstrate that GR is required to establish the necessary cellular context for maintaining normal uterine biology and fertility through the regulation of uterine-specific actions. PMID- 26598668 TI - High economic inequality leads higher-income individuals to be less generous. AB - Research on social class and generosity suggests that higher-income individuals are less generous than poorer individuals. We propose that this pattern emerges only under conditions of high economic inequality, contexts that can foster a sense of entitlement among higher-income individuals that, in turn, reduces their generosity. Analyzing results of a unique nationally representative survey that included a real-stakes giving opportunity (n = 1,498), we found that in the most unequal US states, higher-income respondents were less generous than lower-income respondents. In the least unequal states, however, higher-income individuals were more generous. To better establish causality, we next conducted an experiment (n = 704) in which apparent levels of economic inequality in participants' home states were portrayed as either relatively high or low. Participants were then presented with a giving opportunity. Higher-income participants were less generous than lower-income participants when inequality was portrayed as relatively high, but there was no association between income and generosity when inequality was portrayed as relatively low. This research finds that the tendency for higher-income individuals to be less generous pertains only when inequality is high, challenging the view that higher-income individuals are necessarily more selfish, and suggesting a previously undocumented way in which inequitable resource distributions undermine collective welfare. PMID- 26598667 TI - Animal origin of 13th-century uterine vellum revealed using noninvasive peptide fingerprinting. AB - Tissue-thin parchment made it possible to produce the first pocket Bibles: Thousands were made in the 13th century. The source of this parchment, often called "uterine vellum," has been a long-standing controversy in codicology. Use of the Latin term abortivum in many sources has led some scholars to suggest that the skin of fetal calves or sheep was used. Others have argued that it would not be possible to sustain herds if so many pocket Bibles were produced from fetal skins, arguing instead for unexpected alternatives, such as rabbit. Here, we report a simple and objective technique using standard conservation treatments to identify the animal origin of parchment. The noninvasive method is a variant on zooarchaeology by mass spectrometry (ZooMS) peptide mass fingerprinting but extracts protein from the parchment surface by using an electrostatic charge generated by gentle rubbing of a PVC eraser on the membrane surface. Using this method, we analyzed 72 pocket Bibles originating in France, England, and Italy and 293 additional parchment samples that bracket this period. We found no evidence for the use of unexpected animals; however, we did identify the use of more than one mammal species in a single manuscript, consistent with the local availability of hides. These results suggest that ultrafine vellum does not necessarily derive from the use of abortive or newborn animals with ultrathin hides, but could equally well reflect a production process that allowed the skins of maturing animals of several species to be rendered into vellum of equal quality and fineness. PMID- 26598669 TI - Associative learning rapidly establishes neuronal representations of upcoming behavioral choices in crows. AB - The ability to form associations between behaviorally relevant sensory stimuli is fundamental for goal-directed behaviors. We investigated neuronal activity in the telencephalic area nidopallium caudolaterale (NCL) while two crows (Corvus corone) performed a delayed association task. Whereas some paired associates were familiar to the crows, novel associations had to be learned and mapped to the same target stimuli within a single session. We found neurons that prospectively encoded the chosen test item during the delay for both familiar and newly learned associations. These neurons increased their selectivity during learning in parallel with the crows' increased behavioral performance. Thus, sustained activity in the NCL actively processes information for the upcoming behavioral choice. These data provide new insights into memory representations of behaviorally meaningful stimuli in birds, and how such representations are formed during learning. The findings suggest that the NCL plays a role in learning arbitrary associations, a cornerstone of corvids' remarkable behavioral flexibility and adaptability. PMID- 26598670 TI - The Engineering of Biology and Medicine. PMID- 26598671 TI - Attention searches nonuniformly in space and in time. AB - Difficult search tasks are known to involve attentional resources, but the spatiotemporal behavior of attention remains unknown. Are multiple search targets processed in sequence or in parallel? We developed an innovative methodology to solve this notoriously difficult problem. Observers performed a difficult search task during which two probes were flashed at varying delays. Performance in reporting probes at each location was considered a measure of attentional deployment. By solving a second-degree equation, we determined the probability of probe report at the most and least attended probe locations on each trial. Because these values differed significantly, we conclude that attention was focused on one stimulus or subgroup of stimuli at a time, and not divided uniformly among all search stimuli. Furthermore, this deployment was modulated periodically over time at ~ 7 Hz. These results provide evidence for a nonuniform spatiotemporal deployment of attention during difficult search. PMID- 26598672 TI - Myeloid differentiation architecture of leukocyte transcriptome dynamics in perceived social isolation. AB - To define the cellular mechanisms of up-regulated inflammatory gene expression and down-regulated antiviral response in people experiencing perceived social isolation (loneliness), we conducted integrative analyses of leukocyte gene regulation in humans and rhesus macaques. Five longitudinal leukocyte transcriptome surveys in 141 older adults showed up-regulation of the sympathetic nervous system (SNS), monocyte population expansion, and up-regulation of the leukocyte conserved transcriptional response to adversity (CTRA). Mechanistic analyses in a macaque model of perceived social isolation confirmed CTRA activation and identified selective up-regulation of the CD14(++)/CD16(-) classical monocyte transcriptome, functional glucocorticoid desensitization, down regulation of Type I and II interferons, and impaired response to infection by simian immunodeficiency virus (SIV). These analyses identify neuroendocrine related alterations in myeloid cell population dynamics as a key mediator of CTRA transcriptome skewing, which may both propagate perceived social isolation and contribute to its associated health risks. PMID- 26598673 TI - Army ants dynamically adjust living bridges in response to a cost-benefit trade off. AB - The ability of individual animals to create functional structures by joining together is rare and confined to the social insects. Army ants (Eciton) form collective assemblages out of their own bodies to perform a variety of functions that benefit the entire colony. Here we examine "bridges" of linked individuals that are constructed to span gaps in the colony's foraging trail. How these living structures adjust themselves to varied and changing conditions remains poorly understood. Our field experiments show that the ants continuously modify their bridges, such that these structures lengthen, widen, and change position in response to traffic levels and environmental geometry. Ants initiate bridges where their path deviates from their incoming direction and move the bridges over time to create shortcuts over large gaps. The final position of the structure depended on the intensity of the traffic and the extent of path deviation and was influenced by a cost-benefit trade-off at the colony level, where the benefit of increased foraging trail efficiency was balanced by the cost of removing workers from the foraging pool to form the structure. To examine this trade-off, we quantified the geometric relationship between costs and benefits revealed by our experiments. We then constructed a model to determine the bridge location that maximized foraging rate, which qualitatively matched the observed movement of bridges. Our results highlight how animal self-assemblages can be dynamically modified in response to a group-level cost-benefit trade-off, without any individual unit's having information on global benefits or costs. PMID- 26598675 TI - Evolution in leaps: The punctuated accumulation and loss of cultural innovations. AB - Archaeological accounts of cultural change reveal a fundamental conflict: Some suggest that change is gradual, accelerating over time, whereas others indicate that it is punctuated, with long periods of stasis interspersed by sudden gains or losses of multiple traits. Existing models of cultural evolution, inspired by models of genetic evolution, lend support to the former and do not generate trajectories that include large-scale punctuated change. We propose a simple model that can give rise to both exponential and punctuated patterns of gain and loss of cultural traits. In it, cultural innovation comprises several realistic interdependent processes that occur at different rates. The model also takes into account two properties intrinsic to cultural evolution: the differential distribution of traits among social groups and the impact of environmental change. In our model, a population may be subdivided into groups with different cultural repertoires leading to increased susceptibility to cultural loss, whereas environmental change may lead to rapid loss of traits that are not useful in a new environment. Taken together, our results suggest the usefulness of a concept of an effective cultural population size. PMID- 26598676 TI - Correction for Sharma et al., In silico selection of therapeutic antibodies for development: Viscosity, clearance, and chemical stability. PMID- 26598674 TI - Multifaceted contribution of the TLR4-activated IRF5 transcription factor in systemic sclerosis. AB - Systemic sclerosis (SSc) is a multisystem autoimmune disorder with clinical manifestations resulting from tissue fibrosis and extensive vasculopathy. A potential disease susceptibility gene for SSc is IFN regulatory factor 5 (IRF5), whose SNP is associated with milder clinical manifestations; however, the underlying mechanisms of this association remain elusive. In this study we examined IRF5-deficient (Irf5(-/-)) mice in the bleomycin-treated SSc murine model. We show that dermal and pulmonary fibrosis induced by bleomycin is attenuated in Irf5(-/-) mice. Interestingly, we find that multiple SSc-associated events, such as fibroblast activation, inflammatory cell infiltration, endothelial-to-mesenchymal transition, vascular destabilization, Th2/Th17 skewed immune polarization, and B-cell activation, are suppressed in these mice. We further provide evidence that IRF5, activated by Toll-like receptor 4 (TLR4), binds to the promoters of various key genes involved in SSc disease pathology. These observations are congruent with the high level of expression of IRF5, TLR4, and potential endogenous TLR4 ligands in SSc skin lesions. Our study sheds light on the TLR4-IRF5 pathway in the pathology of SSc with clinical implications of targeting the IRF5 pathways in the suppression of disease development. PMID- 26598678 TI - The structure of tropical forests and sphere packings. AB - The search for simple principles underlying the complex architecture of ecological communities such as forests still challenges ecological theorists. We use tree diameter distributions--fundamental for deriving other forest attributes -to describe the structure of tropical forests. Here we argue that tree diameter distributions of natural tropical forests can be explained by stochastic packing of tree crowns representing a forest crown packing system: a method usually used in physics or chemistry. We demonstrate that tree diameter distributions emerge accurately from a surprisingly simple set of principles that include site specific tree allometries, random placement of trees, competition for space, and mortality. The simple static model also successfully predicted the canopy structure, revealing that most trees in our two studied forests grow up to 30-50 m in height and that the highest packing density of about 60% is reached between the 25- and 40-m height layer. Our approach is an important step toward identifying a minimal set of processes responsible for generating the spatial structure of tropical forests. PMID- 26598677 TI - Subsecond dopamine fluctuations in human striatum encode superposed error signals about actual and counterfactual reward. AB - In the mammalian brain, dopamine is a critical neuromodulator whose actions underlie learning, decision-making, and behavioral control. Degeneration of dopamine neurons causes Parkinson's disease, whereas dysregulation of dopamine signaling is believed to contribute to psychiatric conditions such as schizophrenia, addiction, and depression. Experiments in animal models suggest the hypothesis that dopamine release in human striatum encodes reward prediction errors (RPEs) (the difference between actual and expected outcomes) during ongoing decision-making. Blood oxygen level-dependent (BOLD) imaging experiments in humans support the idea that RPEs are tracked in the striatum; however, BOLD measurements cannot be used to infer the action of any one specific neurotransmitter. We monitored dopamine levels with subsecond temporal resolution in humans (n = 17) with Parkinson's disease while they executed a sequential decision-making task. Participants placed bets and experienced monetary gains or losses. Dopamine fluctuations in the striatum fail to encode RPEs, as anticipated by a large body of work in model organisms. Instead, subsecond dopamine fluctuations encode an integration of RPEs with counterfactual prediction errors, the latter defined by how much better or worse the experienced outcome could have been. How dopamine fluctuations combine the actual and counterfactual is unknown. One possibility is that this process is the normal behavior of reward processing dopamine neurons, which previously had not been tested by experiments in animal models. Alternatively, this superposition of error terms may result from an additional yet-to-be-identified subclass of dopamine neurons. PMID- 26598679 TI - Formamide reaction network in gas phase and solution via a unified theoretical approach: Toward a reconciliation of different prebiotic scenarios. AB - Increasing experimental and theoretical evidence points to formamide as a possible hub in the complex network of prebiotic chemical reactions leading from simple precursors like H2, H2O, N2, NH3, CO, and CO2 to key biological molecules like proteins, nucleic acids, and sugars. We present an in-depth computational study of the formation and decomposition reaction channels of formamide by means of ab initio molecular dynamics. To this aim we introduce a new theoretical method combining the metadynamics sampling scheme with a general purpose topological formulation of collective variables able to track a wide range of different reaction mechanisms. Our approach is flexible enough to discover multiple pathways and intermediates starting from minimal insight on the systems, and it allows passing in a seamless way from reactions in gas phase to reactions in liquid phase, with the solvent active role fully taken into account. We obtain crucial new insight into the interplay of the different formamide reaction channels and into environment effects on pathways and barriers. In particular, our results indicate a similar stability of formamide and hydrogen cyanide in solution as well as their relatively facile interconversion, thus reconciling experiments and theory and, possibly, two different and competing prebiotic scenarios. Moreover, although not explicitly sought, formic acid/ammonium formate is produced as an important formamide decomposition byproduct in solution. PMID- 26598682 TI - Correction for Suvilehto et al., Topography of social touching depends on emotional bonds between humans. PMID- 26598680 TI - Glucocorticoids enhance muscle endurance and ameliorate Duchenne muscular dystrophy through a defined metabolic program. AB - Classic physiology studies dating to the 1930s demonstrate that moderate or transient glucocorticoid (GC) exposure improves muscle performance. The ergogenic properties of GCs are further evidenced by their surreptitious use as doping agents by endurance athletes and poorly understood efficacy in Duchenne muscular dystrophy (DMD), a genetic muscle-wasting disease. A defined molecular basis underlying these performance-enhancing properties of GCs in skeletal muscle remains obscure. Here, we demonstrate that ergogenic effects of GCs are mediated by direct induction of the metabolic transcription factor KLF15, defining a downstream pathway distinct from that resulting in GC-related muscle atrophy. Furthermore, we establish that KLF15 deficiency exacerbates dystrophic severity and muscle GC-KLF15 signaling mediates salutary therapeutic effects in the mdx mouse model of DMD. Thus, although glucocorticoid receptor (GR)-mediated transactivation is often associated with muscle atrophy and other adverse effects of pharmacologic GC administration, our data define a distinct GR-induced gene regulatory pathway that contributes to therapeutic effects of GCs in DMD through proergogenic metabolic programming. PMID- 26598681 TI - Engineering opportunities in cancer immunotherapy. AB - Immunotherapy has great potential to treat cancer and prevent future relapse by activating the immune system to recognize and kill cancer cells. A variety of strategies are continuing to evolve in the laboratory and in the clinic, including therapeutic noncellular (vector-based or subunit) cancer vaccines, dendritic cell vaccines, engineered T cells, and immune checkpoint blockade. Despite their promise, much more research is needed to understand how and why certain cancers fail to respond to immunotherapy and to predict which therapeutic strategies, or combinations thereof, are most appropriate for each patient. Underlying these challenges are technological needs, including methods to rapidly and thoroughly characterize the immune microenvironment of tumors, predictive tools to screen potential therapies in patient-specific ways, and sensitive, information-rich assays that allow patient monitoring of immune responses, tumor regression, and tumor dissemination during and after therapy. The newly emerging field of immunoengineering is addressing some of these challenges, and there is ample opportunity for engineers to contribute their approaches and tools to further facilitate the clinical translation of immunotherapy. Here we highlight recent technological advances in the diagnosis, therapy, and monitoring of cancer in the context of immunotherapy, as well as ongoing challenges. PMID- 26598685 TI - Correction for Marques et al., Holocentromeres in Rhynchospora are associated with genome-wide centromere-specific repeat arrays interspersed among euchromatin. PMID- 26598683 TI - Topographical mapping of alpha- and beta-keratins on developing chicken skin integuments: Functional interaction and evolutionary perspectives. AB - Avian integumentary organs include feathers, scales, claws, and beaks. They cover the body surface and play various functions to help adapt birds to diverse environments. These keratinized structures are mainly composed of corneous materials made of alpha-keratins, which exist in all vertebrates, and beta keratins, which only exist in birds and reptiles. Here, members of the keratin gene families were used to study how gene family evolution contributes to novelty and adaptation, focusing on tissue morphogenesis. Using chicken as a model, we applied RNA-seq and in situ hybridization to map alpha- and beta-keratin genes in various skin appendages at embryonic developmental stages. The data demonstrate that temporal and spatial alpha- and beta-keratin expression is involved in establishing the diversity of skin appendage phenotypes. Embryonic feathers express a higher proportion of beta-keratin genes than other skin regions. In feather filament morphogenesis, beta-keratins show intricate complexity in diverse substructures of feather branches. To explore functional interactions, we used a retrovirus transgenic system to ectopically express mutant alpha- or antisense beta-keratin forms. alpha- and beta-keratins show mutual dependence and mutations in either keratin type results in disrupted keratin networks and failure to form proper feather branches. Our data suggest that combinations of alpha- and beta-keratin genes contribute to the morphological and structural diversity of different avian skin appendages, with feather-beta-keratins conferring more possible composites in building intrafeather architecture complexity, setting up a platform of morphological evolution of functional forms in feathers. PMID- 26598684 TI - Neural mechanisms tracking popularity in real-world social networks. AB - Differences in popularity are a key aspect of status in virtually all human groups and shape social interactions within them. Little is known, however, about how we track and neurally represent others' popularity. We addressed this question in two real-world social networks using sociometric methods to quantify popularity. Each group member (perceiver) viewed faces of every other group member (target) while whole-brain functional MRI data were collected. Independent functional localizer tasks were used to identify brain systems supporting affective valuation (ventromedial prefrontal cortex, ventral striatum, amygdala) and social cognition (dorsomedial prefrontal cortex, precuneus, temporoparietal junction), respectively. During the face-viewing task, activity in both types of neural systems tracked targets' sociometric popularity, even when controlling for potential confounds. The target popularity-social cognition system relationship was mediated by valuation system activity, suggesting that observing popular individuals elicits value signals that facilitate understanding their mental states. The target popularity-valuation system relationship was strongest for popular perceivers, suggesting enhanced sensitivity to differences among other group members' popularity. Popular group members also demonstrated greater interpersonal sensitivity by more accurately predicting how their own personalities were perceived by other individuals in the social network. These data offer insights into the mechanisms by which status guides social behavior. PMID- 26598686 TI - The modular and integrative functional architecture of the human brain. AB - Network-based analyses of brain imaging data consistently reveal distinct modules and connector nodes with diverse global connectivity across the modules. How discrete the functions of modules are, how dependent the computational load of each module is to the other modules' processing, and what the precise role of connector nodes is for between-module communication remains underspecified. Here, we use a network model of the brain derived from resting-state functional MRI (rs fMRI) data and investigate the modular functional architecture of the human brain by analyzing activity at different types of nodes in the network across 9,208 experiments of 77 cognitive tasks in the BrainMap database. Using an author-topic model of cognitive functions, we find a strong spatial correspondence between the cognitive functions and the network's modules, suggesting that each module performs a discrete cognitive function. Crucially, activity at local nodes within the modules does not increase in tasks that require more cognitive functions, demonstrating the autonomy of modules' functions. However, connector nodes do exhibit increased activity when more cognitive functions are engaged in a task. Moreover, connector nodes are located where brain activity is associated with many different cognitive functions. Connector nodes potentially play a role in between-module communication that maintains the modular function of the brain. Together, these findings provide a network account of the brain's modular yet integrated implementation of cognitive functions. PMID- 26598687 TI - Acceleration of diabetic wound healing using a novel protease-anti-protease combination therapy. AB - Nonhealing chronic wounds are major complications of diabetes resulting in >70,000 annual lower-limb amputations in the United States alone. The reasons the diabetic wound is recalcitrant to healing are not fully understood, and there are limited therapeutic agents that could accelerate or facilitate its repair. We previously identified two active forms of matrix metalloproteinases (MMPs), MMP-8 and MMP-9, in the wounds of db/db mice. We argued that the former might play a role in the body's response to wound healing and that the latter is the pathological consequence of the disease with detrimental effects. Here we demonstrate that the use of compound ND-336, a novel highly selective inhibitor of gelatinases (MMP-2 and MMP-9) and MMP-14, accelerates diabetic wound healing by lowering inflammation and by enhancing angiogenesis and re-epithelialization of the wound, thereby reversing the pathological condition. The detrimental role of MMP-9 in the pathology of diabetic wounds was confirmed further by the study of diabetic MMP-9-knockout mice, which exhibited wounds more prone to healing. Furthermore, topical administration of active recombinant MMP-8 also accelerated diabetic wound healing as a consequence of complete re-epithelialization, diminished inflammation, and enhanced angiogenesis. The combined topical application of ND-336 (a small molecule) and the active recombinant MMP-8 (an enzyme) enhanced healing even more, in a strategy that holds considerable promise in healing of diabetic wounds. PMID- 26598688 TI - CK2 acts as a potent negative regulator of receptor-mediated insulin release in vitro and in vivo. AB - G protein-coupled receptors (GPCRs) regulate virtually all physiological functions including the release of insulin from pancreatic beta-cells. beta-Cell M3 muscarinic receptors (M3Rs) are known to play an essential role in facilitating insulin release and maintaining proper whole-body glucose homeostasis. As is the case with other GPCRs, M3R activity is regulated by phosphorylation by various kinases, including GPCR kinases and casein kinase 2 (CK2). At present, it remains unknown which of these various kinases are physiologically relevant for the regulation of beta-cell activity. In the present study, we demonstrate that inhibition of CK2 in pancreatic beta-cells, knockdown of CK2alpha expression, or genetic deletion of CK2alpha in beta-cells of mutant mice selectively augmented M3R-stimulated insulin release in vitro and in vivo. In vitro studies showed that this effect was associated with an M3R-mediated increase in intracellular calcium levels. Treatment of mouse pancreatic islets with CX4945, a highly selective CK2 inhibitor, greatly reduced agonist-induced phosphorylation of beta-cell M3Rs, indicative of CK2-mediated M3R phosphorylation. We also showed that inhibition of CK2 greatly enhanced M3R stimulated insulin secretion in human islets. Finally, CX4945 treatment protected mice against diet-induced hyperglycemia and glucose intolerance in an M3R dependent fashion. Our data demonstrate, for the first time to our knowledge, the physiological relevance of CK2 phosphorylation of a GPCR and suggest the novel concept that kinases acting on beta-cell GPCRs may represent novel therapeutic targets. PMID- 26598689 TI - Mid-Pleistocene climate transition drives net mass loss from rapidly uplifting St. Elias Mountains, Alaska. AB - Erosion, sediment production, and routing on a tectonically active continental margin reflect both tectonic and climatic processes; partitioning the relative importance of these processes remains controversial. Gulf of Alaska contains a preserved sedimentary record of the Yakutat Terrane collision with North America. Because tectonic convergence in the coastal St. Elias orogen has been roughly constant for 6 My, variations in its eroded sediments preserved in the offshore Surveyor Fan constrain a budget of tectonic material influx, erosion, and sediment output. Seismically imaged sediment volumes calibrated with chronologies derived from Integrated Ocean Drilling Program boreholes show that erosion accelerated in response to Northern Hemisphere glacial intensification (~ 2.7 Ma) and that the 900-km-long Surveyor Channel inception appears to correlate with this event. However, tectonic influx exceeded integrated sediment efflux over the interval 2.8-1.2 Ma. Volumetric erosion accelerated following the onset of quasi periodic (~ 100-ky) glacial cycles in the mid-Pleistocene climate transition (1.2 0.7 Ma). Since then, erosion and transport of material out of the orogen has outpaced tectonic influx by 50-80%. Such a rapid net mass loss explains apparent increases in exhumation rates inferred onshore from exposure dates and mapped out of-sequence fault patterns. The 1.2-My mass budget imbalance must relax back toward equilibrium in balance with tectonic influx over the timescale of orogenic wedge response (millions of years). The St. Elias Range provides a key example of how active orogenic systems respond to transient mass fluxes, and of the possible influence of climate-driven erosive processes that diverge from equilibrium on the million-year scale. PMID- 26598690 TI - An antimicrobial peptide essential for bacterial survival in the nitrogen-fixing symbiosis. AB - In the nitrogen-fixing symbiosis between legume hosts and rhizobia, the bacteria are engulfed by a plant cell membrane to become intracellular organelles. In the model legume Medicago truncatula, internalization and differentiation of Sinorhizobium (also known as Ensifer) meliloti is a prerequisite for nitrogen fixation. The host mechanisms that ensure the long-term survival of differentiating intracellular bacteria (bacteroids) in this unusual association are unclear. The M. truncatula defective nitrogen fixation4 (dnf4) mutant is unable to form a productive symbiosis, even though late symbiotic marker genes are expressed in mutant nodules. We discovered that in the dnf4 mutant, bacteroids can apparently differentiate, but they fail to persist within host cells in the process. We found that the DNF4 gene encodes NCR211, a member of the family of nodule-specific cysteine-rich (NCR) peptides. The phenotype of dnf4 suggests that NCR211 acts to promote the intracellular survival of differentiating bacteroids. The greatest expression of DNF4 was observed in the nodule interzone II-III, where bacteroids undergo differentiation. A translational fusion of DNF4 with GFP localizes to the peribacteroid space, and synthetic NCR211 prevents free-living S. meliloti from forming colonies, in contrast to mock controls, suggesting that DNF4 may interact with bacteroids directly or indirectly for its function. Our findings indicate that a successful symbiosis requires host effectors that not only induce bacterial differentiation, but also that maintain intracellular bacteroids during the host-symbiont interaction. The discovery of NCR211 peptides that maintain bacterial survival inside host cells has important implications for improving legume crops. PMID- 26598691 TI - Microbes are trophic analogs of animals. AB - In most ecosystems, microbes are the dominant consumers, commandeering much of the heterotrophic biomass circulating through food webs. Characterizing functional diversity within the microbiome, therefore, is critical to understanding ecosystem functioning, particularly in an era of global biodiversity loss. Using isotopic fingerprinting, we investigated the trophic positions of a broad diversity of heterotrophic organisms. Specifically, we examined the naturally occurring stable isotopes of nitrogen ((15)N:(14)N) within amino acids extracted from proteobacteria, actinomycetes, ascomycetes, and basidiomycetes, as well as from vertebrate and invertebrate macrofauna (crustaceans, fish, insects, and mammals). Here, we report that patterns of intertrophic (15)N-discrimination were remarkably similar among bacteria, fungi, and animals, which permitted unambiguous measurement of consumer trophic position, independent of phylogeny or ecosystem type. The observed similarities among bacterial, fungal, and animal consumers suggest that within a trophic hierarchy, microbiota are equivalent to, and can be interdigitated with, macrobiota. To further test the universality of this finding, we examined Neotropical fungus gardens, communities in which bacteria, fungi, and animals are entwined in an ancient, quadripartite symbiosis. We reveal that this symbiosis is a discrete four-level food chain, wherein bacteria function as the apex carnivores, animals and fungi are meso-consumers, and the sole herbivores are fungi. Together, our findings demonstrate that bacteria, fungi, and animals can be integrated within a food chain, effectively uniting the macro- and microbiome in food web ecology and facilitating greater inclusion of the microbiome in studies of functional diversity. PMID- 26598692 TI - A haploid genetic screen identifies the G1/S regulatory machinery as a determinant of Wee1 inhibitor sensitivity. AB - The Wee1 cell cycle checkpoint kinase prevents premature mitotic entry by inhibiting cyclin-dependent kinases. Chemical inhibitors of Wee1 are currently being tested clinically as targeted anticancer drugs. Wee1 inhibition is thought to be preferentially cytotoxic in p53-defective cancer cells. However, TP53 mutant cancers do not respond consistently to Wee1 inhibitor treatment, indicating the existence of genetic determinants of Wee1 inhibitor sensitivity other than TP53 status. To optimally facilitate patient selection for Wee1 inhibition and uncover potential resistance mechanisms, identification of these currently unknown genes is necessary. The aim of this study was therefore to identify gene mutations that determine Wee1 inhibitor sensitivity. We performed a genome-wide unbiased functional genetic screen in TP53 mutant near-haploid KBM-7 cells using gene-trap insertional mutagenesis. Insertion site mapping of cells that survived long-term Wee1 inhibition revealed enrichment of G1/S regulatory genes, including SKP2, CUL1, and CDK2. Stable depletion of SKP2, CUL1, or CDK2 or chemical Cdk2 inhibition rescued the gamma-H2AX induction and abrogation of G2 phase as induced by Wee1 inhibition in breast and ovarian cancer cell lines. Remarkably, live cell imaging showed that depletion of SKP2, CUL1, or CDK2 did not rescue the Wee1 inhibition-induced karyokinesis and cytokinesis defects. These data indicate that the activity of the DNA replication machinery, beyond TP53 mutation status, determines Wee1 inhibitor sensitivity, and could serve as a selection criterion for Wee1-inhibitor eligible patients. Conversely, loss of the identified S-phase genes could serve as a mechanism of acquired resistance, which goes along with development of severe genomic instability. PMID- 26598693 TI - High-resolution crystal structure of a hepatitis B virus replication inhibitor bound to the viral core protein. AB - The hepatitis B virus (HBV) core protein is essential for HBV replication and an important target for antiviral drug discovery. We report the first, to our knowledge, high-resolution crystal structure of an antiviral compound bound to the HBV core protein. The compound NVR-010-001-E2 can induce assembly of the HBV core wild-type and Y132A mutant proteins and thermostabilize the proteins with a Tm increase of more than 10 degrees C. NVR-010-001-E2 binds at the dimer-dimer interface of the core proteins, forms a new interaction surface promoting protein protein interaction, induces protein assembly, and increases stability. The impact of naturally occurring core protein mutations on antiviral activity correlates with NVR-010-001-E2 binding interactions determined by crystallography. The crystal structure provides understanding of a drug efficacy mechanism related to the induction and stabilization of protein-protein interactions and enables structure-guided design to improve antiviral potency and drug-like properties. PMID- 26598694 TI - Smart nanosystems: Bio-inspired technologies that interact with the host environment. AB - Nanoparticle technologies intended for human administration must be designed to interact with, and ideally leverage, a living host environment. Here, we describe smart nanosystems classified in two categories: (i) those that sense the host environment and respond and (ii) those that first prime the host environment to interact with engineered nanoparticles. Smart nanosystems have the potential to produce personalized diagnostic and therapeutic schema by using the local environment to drive material behavior and ultimately improve human health. PMID- 26598695 TI - Timing of androgen receptor disruption and estrogen exposure underlies a spectrum of congenital penile anomalies. AB - Congenital penile anomalies (CPAs) are among the most common human birth defects. Reports of CPAs, which include hypospadias, chordee, micropenis, and ambiguous genitalia, have risen sharply in recent decades, but the causes of these malformations are rarely identified. Both genetic anomalies and environmental factors, such as antiandrogenic and estrogenic endocrine disrupting chemicals (EDCs), are suspected to cause CPAs; however, little is known about the temporal window(s) of sensitivity to EDCs, or the tissue-specific roles and downstream targets of the androgen receptor (AR) in external genitalia. Here, we show that the full spectrum of CPAs can be produced by disrupting AR at different developmental stages and in specific cell types in the mouse genital tubercle. Inactivation of AR during a narrow window of prenatal development results in hypospadias and chordee, whereas earlier disruptions cause ambiguous genitalia and later disruptions cause micropenis. The neonatal phase of penile development is controlled by the balance of AR to estrogen receptor alpha (ERalpha) activity; either inhibition of androgen or augmentation of estrogen signaling can induce micropenis. AR and ERalpha have opposite effects on cell division, apoptosis, and regulation of Hedgehog, fibroblast growth factor, bone morphogenetic protein, and Wnt signaling in the genital tubercle. We identify Indian hedgehog (Ihh) as a novel downstream target of AR in external genitalia and show that conditional deletion of Ihh inhibits penile masculinization. These studies reveal previously unidentified cellular and molecular mechanisms by which antiandrogenic and estrogenic signals induce penile malformations and demonstrate that the timing of endocrine disruption can determine the type of CPA. PMID- 26598696 TI - Progress in material design for biomedical applications. AB - Biomaterials that interface with biological systems are used to deliver drugs safely and efficiently; to prevent, detect, and treat disease; to assist the body as it heals; and to engineer functional tissues outside of the body for organ replacement. The field has evolved beyond selecting materials that were originally designed for other applications with a primary focus on properties that enabled restoration of function and mitigation of acute pathology. Biomaterials are now designed rationally with controlled structure and dynamic functionality to integrate with biological complexity and perform tailored, high level functions in the body. The transition has been from permissive to promoting biomaterials that are no longer bioinert but bioactive. This perspective surveys recent developments in the field of polymeric and soft biomaterials with a specific emphasis on advances in nano- to macroscale control, static to dynamic functionality, and biocomplex materials. PMID- 26598697 TI - CD11b+Ly6G- myeloid cells mediate mechanical inflammatory pain hypersensitivity. AB - Pain hypersensitivity at the site of inflammation as a result of chronic immune diseases, pathogenic infection, and tissue injury is a common medical condition. However, the specific contributions of the innate and adaptive immune system to the generation of pain during inflammation have not been systematically elucidated. We therefore set out to characterize the cellular and molecular immune response in two widely used preclinical models of inflammatory pain: (i) intraplantar injection of complete Freund's adjuvant (CFA) as a model of adjuvant and pathogen-based inflammation and (ii) a plantar incisional wound as a model of tissue injury-based inflammation. Our findings reveal differences in temporal patterns of immune cell recruitment and activation states, cytokine production, and pain in these two models, with CFA causing a nonresolving granulomatous inflammatory response whereas tissue incision induced resolving immune and pain responses. These findings highlight the significant differences and potential clinical relevance of the incisional wound model compared with the CFA model. By using various cell-depletion strategies, we find that, whereas lymphocyte antigen 6 complex locus G (Ly)6G(+)CD11b(+) neutrophils and T-cell receptor (TCR) beta(+) T cells do not contribute to the development of thermal or mechanical pain hypersensitivity in either model, proliferating CD11b(+)Ly6G(-) myeloid cells were necessary for mechanical hypersensitivity during incisional pain, and, to a lesser extent, CFA-induced inflammation. However, inflammatory (CCR2(+)Ly6C(hi)) monocytes were not responsible for these effects. The finding that a population of proliferating CD11b(+)Ly6G(-) myeloid cells contribute to mechanical inflammatory pain provides a potential cellular target for its treatment in wound inflammation. PMID- 26598698 TI - Highly efficient Cas9-mediated gene drive for population modification of the malaria vector mosquito Anopheles stephensi. AB - Genetic engineering technologies can be used both to create transgenic mosquitoes carrying antipathogen effector genes targeting human malaria parasites and to generate gene-drive systems capable of introgressing the genes throughout wild vector populations. We developed a highly effective autonomous Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-associated protein 9 (Cas9)-mediated gene-drive system in the Asian malaria vector Anopheles stephensi, adapted from the mutagenic chain reaction (MCR). This specific system results in progeny of males and females derived from transgenic males exhibiting a high frequency of germ-line gene conversion consistent with homology-directed repair (HDR). This system copies an ~ 17-kb construct from its site of insertion to its homologous chromosome in a faithful, site-specific manner. Dual anti Plasmodium falciparum effector genes, a marker gene, and the autonomous gene drive components are introgressed into ~ 99.5% of the progeny following outcrosses of transgenic lines to wild-type mosquitoes. The effector genes remain transcriptionally inducible upon blood feeding. In contrast to the efficient conversion in individuals expressing Cas9 only in the germ line, males and females derived from transgenic females, which are expected to have drive component molecules in the egg, produce progeny with a high frequency of mutations in the targeted genome sequence, resulting in near-Mendelian inheritance ratios of the transgene. Such mutant alleles result presumably from nonhomologous end-joining (NHEJ) events before the segregation of somatic and germ-line lineages early in development. These data support the design of this system to be active strictly within the germ line. Strains based on this technology could sustain control and elimination as part of the malaria eradication agenda. PMID- 26598699 TI - Battle of sex hormones in genitalia anomalies. PMID- 26598701 TI - Altered Escherichia coli membrane protein assembly machinery allows proper membrane assembly of eukaryotic protein vitamin K epoxide reductase. AB - Functional overexpression of polytopic membrane proteins, particularly when in a foreign host, is often a challenging task. Factors that negatively affect such processes are poorly understood. Using the mammalian membrane protein vitamin K epoxide reductase (VKORc1) as a reporter, we describe a genetic selection approach allowing the isolation of Escherichia coli mutants capable of functionally expressing this blood-coagulation enzyme. The isolated mutants map to components of membrane protein assembly and quality control proteins YidC and HslV. We show that changes in the VKORc1 sequence and in the YidC hydrophilic groove along with the inactivation of HslV promote VKORc1 activity and dramatically increase its expression level. We hypothesize that such changes correct for mismatches in the membrane topogenic signals between E. coli and eukaryotic cells guiding proper membrane integration. Furthermore, the obtained mutants allow the study of VKORc1 reaction mechanisms, inhibition by warfarin, and the high-throughput screening for potential anticoagulants. PMID- 26598700 TI - ER trapping reveals Golgi enzymes continually revisit the ER through a recycling pathway that controls Golgi organization. AB - Whether Golgi enzymes remain localized within the Golgi or constitutively cycle through the endoplasmic reticulum (ER) is unclear, yet is important for understanding Golgi dependence on the ER. Here, we demonstrate that the previously reported inefficient ER trapping of Golgi enzymes in a rapamycin-based assay results from an artifact involving an endogenous ER-localized 13-kD FK506 binding protein (FKBP13) competing with the FKBP12-tagged Golgi enzyme for binding to an FKBP-rapamycin binding domain (FRB)-tagged ER trap. When we express an FKBP12-tagged ER trap and FRB-tagged Golgi enzymes, conditions precluding such competition, the Golgi enzymes completely redistribute to the ER upon rapamycin treatment. A photoactivatable FRB-Golgi enzyme, highlighted only in the Golgi, likewise redistributes to the ER. These data establish Golgi enzymes constitutively cycle through the ER. Using our trapping scheme, we identify roles of rab6a and calcium-independent phospholipase A2 (iPLA2) in Golgi enzyme recycling, and show that retrograde transport of Golgi membrane underlies Golgi dispersal during microtubule depolymerization and mitosis. PMID- 26598702 TI - Systematic identification of arsenic-binding proteins reveals that hexokinase-2 is inhibited by arsenic. AB - Arsenic is highly effective for treating acute promyelocytic leukemia (APL) and has shown significant promise against many other tumors. However, although its mechanistic effects in APL are established, its broader anticancer mode of action is not understood. In this study, using a human proteome microarray, we identified 360 proteins that specifically bind arsenic. Among the most highly enriched proteins in this set are those in the glycolysis pathway, including the rate-limiting enzyme in glycolysis, hexokinase-1. Detailed biochemical and metabolomics analyses of the highly homologous hexokinase-2 (HK2), which is overexpressed in many cancers, revealed significant inhibition by arsenic. Furthermore, overexpression of HK2 rescued cells from arsenic-induced apoptosis. Our results thus strongly implicate glycolysis, and HK2 in particular, as a key target of arsenic. Moreover, the arsenic-binding proteins identified in this work are expected to serve as a valuable resource for the development of synergistic antitumor therapeutic strategies. PMID- 26598703 TI - Structural basis of substrate recognition by a bacterial deubiquitinase important for dynamics of phagosome ubiquitination. AB - Manipulation of the host's ubiquitin network is emerging as an important strategy for counteracting and repurposing the posttranslational modification machineries of the host by pathogens. Ubiquitin E3 ligases encoded by infectious agents are well known, as are a variety of viral deubiquitinases (DUBs). Bacterial DUBs have been discovered, but little is known about the structure and mechanism underlying their ubiquitin recognition. In this report, we found that members of the Legionella pneumophila SidE effector family harbor a DUB module important for ubiquitin dynamics on the bacterial phagosome. Structural analysis of this domain alone and in complex with ubiquitin vinyl methyl ester (Ub-VME) reveals unique molecular contacts used in ubiquitin recognition. Instead of relying on the Ile44 patch of ubiquitin, as commonly used in eukaryotic counterparts, the SdeADub module engages Gln40 of ubiquitin. The architecture of the active-site cleft presents an open arrangement with conformational plasticity, permitting deubiquitination of three of the most abundant polyubiquitin chains, with a distinct preference for Lys63 linkages. We have shown that this preference enables efficient removal of Lys63 linkages from the phagosomal surface. Remarkably, the structure reveals by far the most parsimonious use of molecular contacts to achieve deubiquitination, with less than 1,000 A(2) of accessible surface area buried upon complex formation with ubiquitin. This type of molecular recognition appears to enable dual specificity toward ubiquitin and the ubiquitin like modifier NEDD8. PMID- 26598704 TI - Poly(ADP-ribose) polymerase 1 is a novel target to promote axonal regeneration. AB - Therapeutic options for the restoration of neurological functions after acute axonal injury are severely limited. In addition to limiting neuronal loss, effective treatments face the challenge of restoring axonal growth within an injury environment where inhibitory molecules from damaged myelin and activated astrocytes act as molecular and physical barriers. Overcoming these barriers to permit axon growth is critical for the development of any repair strategy in the central nervous system. Here, we identify poly(ADP-ribose) polymerase 1 (PARP1) as a previously unidentified and critical mediator of multiple growth-inhibitory signals. We show that exposure of neurons to growth-limiting molecules--such as myelin-derived Nogo and myelin-associated glycoprotein--or reactive astrocyte produced chondroitin sulfate proteoglycans activates PARP1, resulting in the accumulation of poly(ADP-ribose) in the cell body and axon and limited axonal growth. Accordingly, we find that pharmacological inhibition or genetic loss of PARP1 markedly facilitates axon regeneration over nonpermissive substrates. Together, our findings provide critical insights into the molecular mechanisms of axon growth inhibition and identify PARP1 as an effective target to promote axon regeneration. PMID- 26598705 TI - Head to toe, in the head. PMID- 26598706 TI - Estrogen receptor-alpha directly regulates the hypoxia-inducible factor 1 pathway associated with antiestrogen response in breast cancer. AB - A majority of breast cancers are driven by estrogen via estrogen receptor-alpha (ERalpha). Our previous studies indicate that hypoxia-inducible factor 1alpha (HIF-1alpha) cooperates with ERalpha in breast cancer cells. However, whether ERalpha is implicated in the direct regulation of HIF-1alpha and the role of HIF 1alpha in endocrine therapy response are unknown. In this study we found that a subpopulation of HIF-1alpha targets, many of them bearing both hypoxia response elements and estrogen response elements, are regulated by ERalpha in normoxia and hypoxia. Interestingly, the HIF-1alpha gene itself also bears an estrogen response element, and its expression is directly regulated by ERalpha. Clinical data revealed that expression of the HIF-1alpha gene or a hypoxia metagene signature is associated with a poor outcome to endocrine treatment in ERalpha(+) breast cancer. HIF-1alpha was able to confer endocrine therapy resistance to ERalpha(+) breast cancer cells. Our findings define, for the first time to our knowledge, a direct regulatory pathway between ERalpha and HIF-1alpha, which might modulate hormone response in treatment. PMID- 26598707 TI - Structure and control of charge density waves in two-dimensional 1T-TaS2. AB - The layered transition metal dichalcogenides host a rich collection of charge density wave phases in which both the conduction electrons and the atomic structure display translational symmetry breaking. Manipulating these complex states by purely electronic methods has been a long-sought scientific and technological goal. Here, we show how this can be achieved in 1T-TaS2 in the 2D limit. We first demonstrate that the intrinsic properties of atomically thin flakes are preserved by encapsulation with hexagonal boron nitride in inert atmosphere. We use this facile assembly method together with transmission electron microscopy and transport measurements to probe the nature of the 2D state and show that its conductance is dominated by discommensurations. The discommensuration structure can be precisely tuned in few-layer samples by an in plane electric current, allowing continuous electrical control over the discommensuration-melting transition in 2D. PMID- 26598708 TI - New class of turbulence in active fluids. AB - Turbulence is a fundamental and ubiquitous phenomenon in nature, occurring from astrophysical to biophysical scales. At the same time, it is widely recognized as one of the key unsolved problems in modern physics, representing a paradigmatic example of nonlinear dynamics far from thermodynamic equilibrium. Whereas in the past, most theoretical work in this area has been devoted to Navier-Stokes flows, there is now a growing awareness of the need to extend the research focus to systems with more general patterns of energy injection and dissipation. These include various types of complex fluids and plasmas, as well as active systems consisting of self-propelled particles, like dense bacterial suspensions. Recently, a continuum model has been proposed for such "living fluids" that is based on the Navier-Stokes equations, but extends them to include some of the most general terms admitted by the symmetry of the problem [Wensink HH, et al. (2012) Proc Natl Acad Sci USA 109:14308-14313]. This introduces a cubic nonlinearity, related to the Toner-Tu theory of flocking, which can interact with the quadratic Navier-Stokes nonlinearity. We show that as a result of the subtle interaction between these two terms, the energy spectra at large spatial scales exhibit power laws that are not universal, but depend on both finite-size effects and physical parameters. Our combined numerical and analytical analysis reveals the origin of this effect and even provides a way to understand it quantitatively. Turbulence in active fluids, characterized by this kind of nonlinear self-organization, defines a new class of turbulent flows. PMID- 26598709 TI - Inhibition of host cell translation elongation by Legionella pneumophila blocks the host cell unfolded protein response. AB - Cells of the innate immune system recognize bacterial pathogens by detecting common microbial patterns as well as pathogen-specific activities. One system that responds to these stimuli is the IRE1 branch of the unfolded protein response (UPR), a sensor of endoplasmic reticulum (ER) stress. Activation of IRE1, in the context of Toll-like receptor (TLR) signaling, induces strong proinflammatory cytokine induction. We show here that Legionella pneumophila, an intravacuolar pathogen that replicates in an ER-associated compartment, blocks activation of the IRE1 pathway despite presenting pathogen products that stimulate this response. L. pneumophila TLR ligands induced the splicing of mRNA encoding XBP1s, the main target of IRE1 activity. L. pneumophila was able to inhibit both chemical and bacterial induction of XBP1 splicing via bacterial translocated proteins that interfere with host protein translation. A strain lacking five translocated translation elongation inhibitors was unable to block XBP1 splicing, but this could be rescued by expression of a single such inhibitor, consistent with limitation of the response by translation elongation inhibitors. Chemical inhibition of translation elongation blocked pattern recognition receptor-mediated XBP1 splicing, mimicking the effects of the bacterial translation inhibitors. In contrast, host cell-promoted inhibition of translation initiation in response to the pathogen was ineffective in blocking XBP1 splicing, demonstrating the need for the elongation inhibitors for protection from the UPR. The inhibition of host translation elongation may be a common strategy used by pathogens to limit the innate immune response by interfering with signaling via the UPR. PMID- 26598710 TI - Direct observation of processive exoribonuclease motion using optical tweezers. AB - Bacterial RNases catalyze the turnover of RNA and are essential for gene expression and quality surveillance of transcripts. In Escherichia coli, the exoribonucleases RNase R and polynucleotide phosphorylase (PNPase) play critical roles in degrading RNA. Here, we developed an optical-trapping assay to monitor the translocation of individual enzymes along RNA-based substrates. Single molecule records of motion reveal RNase R to be highly processive: one molecule can unwind over 500 bp of a structured substrate. However, enzyme progress is interrupted by pausing and stalling events that can slow degradation in a sequence-dependent fashion. We found that the distance traveled by PNPase through structured RNA is dependent on the A+U content of the substrate and that removal of its KH and S1 RNA-binding domains can reduce enzyme processivity without affecting the velocity. By a periodogram analysis of single-molecule records, we establish that PNPase takes discrete steps of six or seven nucleotides. These findings, in combination with previous structural and biochemical data, support an asymmetric inchworm mechanism for PNPase motion. The assay developed here for RNase R and PNPase is well suited to studies of other exonucleases and helicases. PMID- 26598711 TI - The peptide agonist-binding site of the glucagon-like peptide-1 (GLP-1) receptor based on site-directed mutagenesis and knowledge-based modelling. AB - Glucagon-like peptide-1 (7-36)amide (GLP-1) plays a central role in regulating blood sugar levels and its receptor, GLP-1R, is a target for anti-diabetic agents such as the peptide agonist drugs exenatide and liraglutide. In order to understand the molecular nature of the peptide-receptor interaction, we used site directed mutagenesis and pharmacological profiling to highlight nine sites as being important for peptide agonist binding and/or activation. Using a knowledge based approach, we constructed a 3D model of agonist-bound GLP-1R, basing the conformation of the N-terminal region on that of the receptor-bound NMR structure of the related peptide pituitary adenylate cyclase-activating protein (PACAP21). The relative position of the extracellular to the transmembrane (TM) domain, as well as the molecular details of the agonist-binding site itself, were found to be different from the model that was published alongside the crystal structure of the TM domain of the glucagon receptor, but were nevertheless more compatible with published mutagenesis data. Furthermore, the NMR-determined structure of a high-potency cyclic conformationally-constrained 11-residue analogue of GLP-1 was also docked into the receptor-binding site. Despite having a different main chain conformation to that seen in the PACAP21 structure, four conserved residues (equivalent to His-7, Glu-9, Ser-14 and Asp-15 in GLP-1) could be structurally aligned and made similar interactions with the receptor as their equivalents in the GLP-1-docked model, suggesting the basis of a pharmacophore for GLP-1R peptide agonists. In this way, the model not only explains current mutagenesis and molecular pharmacological data but also provides a basis for further experimental design. PMID- 26598712 TI - Structure and function of echinoderm telomerase RNA. AB - Telomerase is a ribonucleoprotein (RNP) enzyme that requires an integral telomerase RNA (TR) subunit, in addition to the catalytic telomerase reverse transcriptase (TERT), for enzymatic function. The secondary structures of TRs from the three major groups of species, ciliates, fungi, and vertebrates, have been studied extensively and demonstrate dramatic diversity. Herein, we report the first comprehensive secondary structure of TR from echinoderms-marine invertebrates closely related to vertebrates-determined by phylogenetic comparative analysis of 16 TR sequences from three separate echinoderm classes. Similar to vertebrate TR, echinoderm TR contains the highly conserved template/pseudoknot and H/ACA domains. However, echinoderm TR lacks the ancestral CR4/5 structural domain found throughout vertebrate and fungal TRs. Instead, echinoderm TR contains a distinct simple helical region, termed eCR4/5, that is functionally equivalent to the CR4/5 domain. The urchin and brittle star eCR4/5 domains bind specifically to their respective TERT proteins and stimulate telomerase activity. Distinct from vertebrate telomerase, the echinoderm TR template/pseudoknot domain with the TERT protein is sufficient to reconstitute significant telomerase activity. This gain-of-function of the echinoderm template/pseudoknot domain for conferring telomerase activity presumably facilitated the rapid structural evolution of the eCR4/5 domain throughout the echinoderm lineage. Additionally, echinoderm TR utilizes the template-adjacent P1.1 helix as a physical template boundary element to prevent nontelomeric DNA synthesis, a mechanism used by ciliate and fungal TRs. Thus, the chimeric and eccentric structural features of echinoderm TR provide unparalleled insights into the rapid evolution of telomerase RNP structure and function. PMID- 26598713 TI - Chronic lymphocytic thyroiditis and BRAF V600E in papillary thyroid carcinoma. AB - It has been reported that papillary thyroid carcinoma (PTC) with chronic lymphocytic thyroiditis (CLT) is less associated with extrathyroidal extension (ETE), advanced tumor stage and lymph node (LN) metastasis. Other studies have suggested that concurrent CLT could antagonize PTC progression, even in BRAF positive patients. Since the clinical significance of the BRAF mutation has been particularly associated with conventional PTC, the purpose of this study was to determine the clinical significance of CLT according to BRAF mutation status in conventional PTC patients. We retrospectively reviewed the medical records of 3332 conventional PTC patients who underwent total thyroidectomy with bilateral central neck dissection at the Thyroid Cancer Center of Samsung Medical Center between January 2008 and June 2015. In this study, the prevalence of BRAF mutation was significantly less frequent in conventional PTC patients with CLT (76.9% vs 86.6%). CLT was an independent predictor for low prevalence of ETE in both BRAF-negative (OR=0.662, P=0.023) and BRAF-positive (OR=0.817, P=0.027) conventional PTC patients. In addition, CLT was an independent predictor for low prevalence of CLNM in both BRAF-negative (OR=0.675, P=0.044) and BRAF-positive (OR=0.817, P=0.030) conventional PTC patients. In conclusion, BRAF mutation was significantly less frequent in conventional PTC patients with CLT. However, CLT was an independent predictor for less aggressiveness in conventional PTC patients regardless of BRAF mutation status. PMID- 26598715 TI - Antibacterial properties of biosurfactants against selected Gram-positive and negative bacteria. AB - The antibacterial properties and ability to disrupt biofilms of biosurfactants (rhamnolipids, sophorolipids) and sodium dodecyl sulphate (SDS) in the presence and absence of selected organic acids were investigated. Pseudomonas aeruginosa PAO1 was inhibited by sophorolipids and SDS at concentrations >5% v/v, and the growth of Escherichia coli NCTC 10418 was also inhibited by sophorolipids and SDS at concentrations >5% and 0.1% v/v, respectively. Bacillus subtilis NCTC 10400 was inhibited by rhamnolipids, sophorolipids and SDS at concentrations >0.5% v/v of all three; the same effect was observed with Staphylococcus aureus ATCC 9144. The ability to attach to surfaces and biofilm formation of P. aeruginosa PAO1, E. coli NCTC 10418 and B. subtilis NCTC 10400 was inhibited by sophorolipids (1% v/v) in the presence of caprylic acid (0.8% v/v). In the case of S. aureus ATCC 9144, the best results were obtained using caprylic acid on its own. It was concluded that sophorolipids are promising compounds for the inhibition/disruption of biofilms formed by Gram-positive and Gram-negative microorganisms and this activity can be enhanced by the presence of booster compounds such as caprylic acid. PMID- 26598716 TI - Is there an association between tendinopathy and diabetes mellitus? A systematic review with meta-analysis. AB - BACKGROUND: Musculoskeletal symptoms limit adherence to exercise interventions for individuals with type 2 diabetes. People with diabetes may be susceptible to tendinopathy due to chronically elevated blood glucose levels. Therefore, we aimed to investigate this potential association by systematically reviewing and meta-analysing case-control, cross-sectional, and studies that considered both of these conditions. METHODS: Nine medical databases and hand searching methods were used without year limits to identify all relevant English language articles that considered diabetes and tendinopathy. Two authors applied exclusion criteria and one author extracted data with verification by a second author. Meta-analysis was conducted using a random effects model. Results were expressed as odds ratio (OR), mean difference or standardised mean difference with a confidence intervals (95% CI). Heterogeneity was assessed by I(2). FINDINGS: 31 studies were included in the final analysis of which 26 recruited people with diabetes and five recruited people with tendinopathy. Tendinopathy was more prevalent in people with diabetes (17 studies, OR 3.67, 95% CI 2.71 to 4.97), diabetes was more prevalent in people with tendinopathy (5 studies, OR 1.28, 95% CI 1.10 to 1.49), people with diabetes and tendinopathy had a longer duration of diabetes than people with diabetes only (6 studies, mean difference 5.26 years, 95% CI 4.15 to 6.36) and people with diabetes had thicker tendons than controls (9 studies, standardised mean difference 0.79 95% CI 0.47 to 1.12). INTERPRETATION: These findings provide strong evidence that diabetes is associated with higher risk of tendinopathy. This is clinically relevant as tendinopathy may affect adherence to exercise interventions for diabetes. PMID- 26598717 TI - Misshapen/NIK-related kinase (MINK1) is involved in platelet function, hemostasis, and thrombus formation. AB - The sterile-20 kinase misshapen/Nck-interacting kinase (NIK)-related kinase 1 (MINK1) is involved in many important cellular processes such as growth, cytoskeletal rearrangement, and motility. Here, with MINK1-deficient (MINK1(-/-)) mice, we showed that MINK1 plays an important role in hemostasis and thrombosis via the regulation of platelet functions. In the tail-bleeding assay, MINK1(-/-) mice exhibited a longer bleeding time than wild-type (WT) mice (575.2 +/- 59.7 seconds vs 419.6 +/- 66.9 seconds). In a model of ferric chloride-induced mesenteric arteriolar thrombosis, vessel occlusion times were twice as long in MINK1(-/-) mice as in WT mice. In an in vitro microfluidic whole-blood perfusion assay, thrombus formation on a collagen matrix under arterial shear conditions was significantly reduced in MINK1(-/-) platelets. Moreover, MINK1(-/-) platelets demonstrated impaired aggregation and secretion in response to low doses of thrombin and collagen. Furthermore, platelet spreading on fibrinogen was largely hampered in MINK1(-/-) platelets. The functional differences of MINK1(-/-) platelets could be attributed to impaired adenosine 5'-diphosphate secretion. Signaling events associated with MINK1 appeared to involve extracellular signal regulated kinase, p38, and Akt. Hence, MINK1 may be an important signaling molecule that mediates mitogen-activated protein kinase signaling and participates in platelet activation and thrombus formation. PMID- 26598718 TI - Detection of septic transfusion reactions to platelet transfusions by active and passive surveillance. AB - Septic transfusion reactions (STRs) resulting from transfusion of bacterially contaminated platelets are a major hazard of platelet transfusion despite recent interventions. Active and passive surveillance for bacterially contaminated platelets was performed over 7 years (2007-2013) by culture of platelet aliquots at time of transfusion and review of reported transfusion reactions. All platelet units had been cultured 24 hours after collection and released as negative. Five sets of STR criteria were evaluated, including recent AABB criteria; sensitivity and specificity of these criteria, as well as detection by active and passive surveillance, were determined. Twenty of 51,440 platelet units transfused (0.004%; 389 per million) were bacterially contaminated by active surveillance and resulted in 5 STRs occurring 9 to 24 hours posttransfusion; none of these STRs had been reported by passive surveillance. STR occurred only in neutropenic patients transfused with high bacterial loads. A total of 284 transfusion reactions (0.55%) were reported by passive surveillance. None of these patients had received contaminated platelets. However, 6 to 93 (2.1%-32.7%) of these 284 reactions met 1 or more STR criteria, and sensitivity of STR criteria varied from 5.1% to 45.5%. These results document the continued occurrence of bacterial contamination of platelets resulting in STR in neutropenic patients, failure of passive surveillance to detect STR, and lack of specificity of STR criteria. These findings highlight the limitations of reported national STR data based on passive surveillance and the need to implement further measures to address this problem such as secondary testing or use of pathogen reduction technologies. PMID- 26598719 TI - Eradication of tetanus. AB - INTRODUCTION: The causative agent of tetanus, Clostridium tetani is widespread in the environment throughout the world and cannot be eradicated. To reduce the number of cases of tetanus efforts are focussed on prevention using vaccination and post-exposure wound care. SOURCES OF DATA: Medline, Pubmed and Cochrane databases; World Health Organization and United Nations Children's Fund publications. AREAS OF AGREEMENT: The maternal and neonatal tetanus elimination initiative has resulted in significant reductions in mortality from neonatal tetanus throughout the world. AREAS OF CONTROVERSY: Although there are few data available it is likely that large numbers of children and adults, particularly men, remain unprotected due to lack of booster immunization. AREAS TIMELY FOR DEVELOPING RESEARCH: It remains unclear how HIV and malaria affect both responses to vaccination and transplacental transfer of antibodies or how this might affect timing of vaccination doses. PMID- 26598720 TI - Introduction to 'Homology and convergence in nervous system evolution'. AB - The origin of brains and central nervous systems (CNSs) is thought to have occurred before the Palaeozoic era 540 Ma. Yet in the absence of tangible evidence, there has been continued debate whether today's brains and nervous systems derive from one ancestral origin or whether similarities among them are due to convergent evolution. With the advent of molecular developmental genetics and genomics, it has become clear that homology is a concept that applies not only to morphologies, but also to genes, developmental processes, as well as to behaviours. Comparative studies in phyla ranging from annelids and arthropods to mammals are providing evidence that corresponding developmental genetic mechanisms act not only in dorso-ventral and anterior-posterior axis specification but also in segmentation, neurogenesis, axogenesis and eye/photoreceptor cell formation that appear to be conserved throughout the animal kingdom. These data are supported by recent studies which identified Mid Cambrian fossils with preserved soft body parts that present segmental arrangements in brains typical of modern arthropods, and similarly organized brain centres and circuits across phyla that may reflect genealogical correspondence and control similar behavioural manifestations. Moreover, congruence between genetic and geological fossil records support the notion that by the 'Cambrian explosion' arthropods and chordates shared similarities in brain and nervous system organization. However, these similarities are strikingly absent in several sister- and outgroups of arthropods and chordates which raises several questions, foremost among them: what kind of natural laws and mechanisms underlie the convergent evolution of such similarities? And, vice versa: what are the selection pressures and genetic mechanisms underlying the possible loss or reduction of brains and CNSs in multiple lineages during the course of evolution? These questions were addressed at a Royal Society meeting to discuss homology and convergence in nervous system evolution. By integrating knowledge ranging from evolutionary theory and palaeontology to comparative developmental genetics and phylogenomics, the meeting covered disparities in nervous system origins as well as correspondences of neural circuit organization and behaviours, all of which allow evidence-based debates for and against the proposition that the nervous systems and brains of animals might derive from a common ancestor. PMID- 26598721 TI - Homology, convergence and parallelism. AB - Homology is a relation of correspondence between parts of parts of larger wholes. It is used when tracking objects of interest through space and time and in the context of explanatory historical narratives. Homologues can be traced through a genealogical nexus back to a common ancestral precursor. Homology being a transitive relation, homologues remain homologous however much they may come to differ. Analogy is a relationship of correspondence between parts of members of classes having no relationship of common ancestry. Although homology is often treated as an alternative to convergence, the latter is not a kind of correspondence: rather, it is one of a class of processes that also includes divergence and parallelism. These often give rise to misleading appearances (homoplasies). Parallelism can be particularly hard to detect, especially when not accompanied by divergences in some parts of the body. PMID- 26598722 TI - Xenacoelomorpha: a case of independent nervous system centralization? AB - Centralized nervous systems (NSs) and complex brains are among the most important innovations in the history of life on our planet. In this context, two related questions have been formulated: How did complex NSs arise in evolution, and how many times did this occur? As a step towards finding an answer, we describe the NS of several representatives of the Xenacoelomorpha, a clade whose members show different degrees of NS complexity. This enigmatic clade is composed of three major taxa: acoels, nemertodermatids and xenoturbellids. Interestingly, while the xenoturbellids seem to have a rather 'simple' NS (a nerve net), members of the most derived group of acoel worms clearly have ganglionic brains. This interesting diversity of NS architectures (with different degrees of compaction) provides a unique system with which to address outstanding questions regarding the evolution of brains and centralized NSs. The recent sequencing of xenacoelomorph genomes gives us a privileged vantage point from which to analyse neural evolution, especially through the study of key gene families involved in neurogenesis and NS function, such as G protein-coupled receptors, helix-loop helix transcription factors and Wnts. We finish our manuscript proposing an adaptive scenario for the origin of centralized NSs (brains). PMID- 26598723 TI - Loss of neurogenesis in Hydra leads to compensatory regulation of neurogenic and neurotransmission genes in epithelial cells. AB - Hydra continuously differentiates a sophisticated nervous system made of mechanosensory cells (nematocytes) and sensory-motor and ganglionic neurons from interstitial stem cells. However, this dynamic adult neurogenesis is dispensable for morphogenesis. Indeed animals depleted of their interstitial stem cells and interstitial progenitors lose their active behaviours but maintain their developmental fitness, and regenerate and bud when force-fed. To characterize the impact of the loss of neurogenesis in Hydra, we first performed transcriptomic profiling at five positions along the body axis. We found neurogenic genes predominantly expressed along the central body column, which contains stem cells and progenitors, and neurotransmission genes predominantly expressed at the extremities, where the nervous system is dense. Next, we performed transcriptomics on animals depleted of their interstitial cells by hydroxyurea, colchicine or heat-shock treatment. By crossing these results with cell-type specific transcriptomics, we identified epithelial genes up-regulated upon loss of neurogenesis: transcription factors (Dlx, Dlx1, DMBX1/Manacle, Ets1, Gli3, KLF11, LMX1A, ZNF436, Shox1), epitheliopeptides (Arminins, PW peptide), neurosignalling components (CAMK1D, DDCl2, Inx1), ligand-ion channel receptors (CHRNA1, NaC7), G-Protein Coupled Receptors and FMRFRL. Hence epitheliomuscular cells seemingly enhance their sensing ability when neurogenesis is compromised. This unsuspected plasticity might reflect the extended multifunctionality of epithelial-like cells in early eumetazoan evolution. PMID- 26598724 TI - Independent origins of neurons and synapses: insights from ctenophores. AB - There is more than one way to develop neuronal complexity, and animals frequently use different molecular toolkits to achieve similar functional outcomes. Genomics and metabolomics data from basal metazoans suggest that neural signalling evolved independently in ctenophores and cnidarians/bilaterians. This polygenesis hypothesis explains the lack of pan-neuronal and pan-synaptic genes across metazoans, including remarkable examples of lineage-specific evolution of neurogenic and signalling molecules as well as synaptic components. Sponges and placozoans are two lineages without neural and muscular systems. The possibility of secondary loss of neurons and synapses in the Porifera/Placozoa clades is a highly unlikely and less parsimonious scenario. We conclude that acetylcholine, serotonin, histamine, dopamine, octopamine and gamma-aminobutyric acid (GABA) were recruited as transmitters in the neural systems in cnidarian and bilaterian lineages. By contrast, ctenophores independently evolved numerous secretory peptides, indicating extensive adaptations within the clade and suggesting that early neural systems might be peptidergic. Comparative analysis of glutamate signalling also shows numerous lineage-specific innovations, implying the extensive use of this ubiquitous metabolite and intercellular messenger over the course of convergent and parallel evolution of mechanisms of intercellular communication. Therefore: (i) we view a neuron as a functional character but not a genetic character, and (ii) any given neural system cannot be considered as a single character because it is composed of different cell lineages with distinct genealogies, origins and evolutionary histories. Thus, when reconstructing the evolution of nervous systems, we ought to start with the identification of particular cell lineages by establishing distant neural homologies or examples of convergent evolution. In a corollary of the hypothesis of the independent origins of neurons, our analyses suggest that both electrical and chemical synapses evolved more than once. PMID- 26598725 TI - Phototaxis and the origin of visual eyes. AB - Vision allows animals to detect spatial differences in environmental light levels. High-resolution image-forming eyes evolved from low-resolution eyes via increases in photoreceptor cell number, improvements in optics and changes in the neural circuits that process spatially resolved photoreceptor input. However, the evolutionary origins of the first low-resolution visual systems have been unclear. We propose that the lowest resolving (two-pixel) visual systems could initially have functioned in visual phototaxis. During visual phototaxis, such elementary visual systems compare light on either side of the body to regulate phototactic turns. Another, even simpler and non-visual strategy is characteristic of helical phototaxis, mediated by sensory-motor eyespots. The recent mapping of the complete neural circuitry (connectome) of an elementary visual system in the larva of the annelid Platynereis dumerilii sheds new light on the possible paths from non-visual to visual phototaxis and to image-forming vision. We outline an evolutionary scenario focusing on the neuronal circuitry to account for these transitions. We also present a comprehensive review of the structure of phototactic eyes in invertebrate larvae and assign them to the non visual and visual categories. We propose that non-visual systems may have preceded visual phototactic systems in evolution that in turn may have repeatedly served as intermediates during the evolution of image-forming eyes. PMID- 26598726 TI - From damage response to action potentials: early evolution of neural and contractile modules in stem eukaryotes. AB - Eukaryotic cells convert external stimuli into membrane depolarization, which in turn triggers effector responses such as secretion and contraction. Here, we put forward an evolutionary hypothesis for the origin of the depolarization contraction-secretion (DCS) coupling, the functional core of animal neuromuscular circuits. We propose that DCS coupling evolved in unicellular stem eukaryotes as part of an 'emergency response' to calcium influx upon membrane rupture. We detail how this initial response was subsequently modified into an ancient mechanosensory-effector arc, present in the last eukaryotic common ancestor, which enabled contractile amoeboid movement that is widespread in extant eukaryotes. Elaborating on calcium-triggered membrane depolarization, we reason that the first action potentials evolved alongside the membrane of sensory-motile cilia, with the first voltage-sensitive sodium/calcium channels (Nav/Cav) enabling a fast and coordinated response of the entire cilium to mechanosensory stimuli. From the cilium, action potentials then spread across the entire cell, enabling global cellular responses such as concerted contraction in several independent eukaryote lineages. In animals, this process led to the invention of mechanosensory contractile cells. These gave rise to mechanosensory receptor cells, neurons and muscle cells by division of labour and can be regarded as the founder cell type of the nervous system. PMID- 26598727 TI - A flexible genetic toolkit for arthropod neurogenesis. AB - Arthropods show considerable variations in early neurogenesis. This includes the pattern of specification, division and movement of neural precursors and progenitors. In all metazoans with nervous systems, including arthropods, conserved genes regulate neurogenesis, which raises the question of how the various morphological mechanisms have emerged and how the same genetic toolkit might generate different morphological outcomes. Here I address this question by comparing neurogenesis across arthropods and show how variations in the regulation and function of the neural genes might explain this phenomenon and how they might have facilitated the evolution of the diverse morphological mechanisms of neurogenesis. PMID- 26598728 TI - Nervous systems and scenarios for the invertebrate-to-vertebrate transition. AB - Older evolutionary scenarios for the origin of vertebrates often gave nervous systems top billing in accordance with the notion that a big-brained Homo sapiens crowned a tree of life shaped mainly by progressive evolution. Now, however, tree thinking positions all extant organisms equidistant from the tree's root, and molecular phylogenies indicate that regressive evolution is more common than previously suspected. Even so, contemporary theories of vertebrate origin still focus on the nervous system because of its functional importance, its richness in characters for comparative biology, and its central position in the two currently prominent scenarios for the invertebrate-to-vertebrate transition, which grew out of the markedly neurocentric annelid and enteropneust theories of the nineteenth century. Both these scenarios compare phyla with diverse overall body plans. This diversity, exacerbated by the scarcity of relevant fossil data, makes it challenging to establish plausible homologies between component parts (e.g. nervous system regions). In addition, our current understanding of the relation between genotype and phenotype is too preliminary to permit us to convert gene network data into structural features in any simple way. These issues are discussed here with special reference to the evolution of nervous systems during proposed transitions from invertebrates to vertebrates. PMID- 26598729 TI - The larval nervous system of the penis worm Priapulus caudatus (Ecdysozoa). AB - The origin and extreme diversification of the animal nervous system is a central question in biology. While most of the attention has traditionally been paid to those lineages with highly elaborated nervous systems (e.g. arthropods, vertebrates, annelids), only the study of the vast animal diversity can deliver a comprehensive view of the evolutionary history of this organ system. In this regard, the phylogenetic position and apparently conservative molecular, morphological and embryological features of priapulid worms (Priapulida) place this animal lineage as a key to understanding the evolution of the Ecdysozoa (i.e. arthropods and nematodes). In this study, we characterize the nervous system of the hatching larva and first lorica larva of the priapulid worm Priapulus caudatus by immunolabelling against acetylated and tyrosinated tubulin, pCaMKII, serotonin and FMRFamide. Our results show that a circumoral brain and an unpaired ventral nerve with a caudal ganglion characterize the central nervous system of hatching embryos. After the first moult, the larva attains some adult features: a neck ganglion, an introvert plexus, and conspicuous secondary longitudinal neurites. Our study delivers a neuroanatomical framework for future embryological studies in priapulid worms, and helps illuminate the course of nervous system evolution in the Ecdysozoa. PMID- 26598730 TI - The molecular evolution of the vertebrate behavioural repertoire. AB - How the sophisticated vertebrate behavioural repertoire evolved remains a major question in biology. The behavioural repertoire encompasses the set of individual behavioural components that an organism uses when adapting and responding to changes in its external world. Although unicellular organisms, invertebrates and vertebrates share simple reflex responses, the fundamental mechanisms that resulted in the complexity and sophistication that is characteristic of vertebrate behaviours have only recently been examined. A series of behavioural genetic experiments in mice and humans support a theory that posited the importance of synapse proteome expansion in generating complexity in the behavioural repertoire. Genome duplication events, approximately 550 Ma, produced expansion in the synapse proteome that resulted in increased complexity in synapse signalling mechanisms that regulate components of the behavioural repertoire. The experiments demonstrate the importance to behaviour of the gene duplication events, the diversification of paralogues and sequence constraint. They also confirm the significance of comparative proteomic and genomic studies that identified the molecular origins of synapses in unicellular eukaryotes and the vertebrate expansion in proteome complexity. These molecular mechanisms have general importance for understanding the repertoire of behaviours in different species and for human behavioural disorders arising from synapse gene mutations. PMID- 26598731 TI - Animal-microbe interactions and the evolution of nervous systems. AB - Animals ubiquitously interact with environmental and symbiotic microbes, and the effects of these interactions on animal physiology are currently the subject of intense interest. Nevertheless, the influence of microbes on nervous system evolution has been largely ignored. We illustrate here how taking microbes into account might enrich our ideas about the evolution of nervous systems. For example, microbes are involved in animals' communicative, defensive, predatory and dispersal behaviours, and have likely influenced the evolution of chemo- and photosensory systems. In addition, we speculate that the need to regulate interactions with microbes at the epithelial surface may have contributed to the evolutionary internalization of the nervous system. PMID- 26598733 TI - Evolution of central pattern generators and rhythmic behaviours. AB - Comparisons of rhythmic movements and the central pattern generators (CPGs) that control them uncover principles about the evolution of behaviour and neural circuits. Over the course of evolutionary history, gradual evolution of behaviours and their neural circuitry within any lineage of animals has been a predominant occurrence. Small changes in gene regulation can lead to divergence of circuit organization and corresponding changes in behaviour. However, some behavioural divergence has resulted from large-scale rewiring of the neural network. Divergence of CPG circuits has also occurred without a corresponding change in behaviour. When analogous rhythmic behaviours have evolved independently, it has generally been with different neural mechanisms. Repeated evolution of particular rhythmic behaviours has occurred within some lineages due to parallel evolution or latent CPGs. Particular motor pattern generating mechanisms have also evolved independently in separate lineages. The evolution of CPGs and rhythmic behaviours shows that although most behaviours and neural circuits are highly conserved, the nature of the behaviour does not dictate the neural mechanism and that the presence of homologous neural components does not determine the behaviour. This suggests that although behaviour is generated by neural circuits, natural selection can act separately on these two levels of biological organization. PMID- 26598732 TI - Genealogical correspondence of a forebrain centre implies an executive brain in the protostome-deuterostome bilaterian ancestor. AB - Orthologous genes involved in the formation of proteins associated with memory acquisition are similarly expressed in forebrain centres that exhibit similar cognitive properties. These proteins include cAMP-dependent protein kinase A catalytic subunit (PKA-Calpha) and phosphorylated Ca(2+)/calmodulin-dependent protein kinase II (pCaMKII), both required for long-term memory formation which is enriched in rodent hippocampus and insect mushroom bodies, both implicated in allocentric memory and both possessing corresponding neuronal architectures. Antibodies against these proteins resolve forebrain centres, or their equivalents, having the same ground pattern of neuronal organization in species across five phyla. The ground pattern is defined by olfactory or chemosensory afferents supplying systems of parallel fibres of intrinsic neurons intersected by orthogonal domains of afferent and efferent arborizations with local interneurons providing feedback loops. The totality of shared characters implies a deep origin in the protostome-deuterostome bilaterian ancestor of elements of a learning and memory circuit. Proxies for such an ancestral taxon are simple extant bilaterians, particularly acoels that express PKA-Calpha and pCaMKII in discrete anterior domains that can be properly referred to as brains. PMID- 26598734 TI - Neuronal factors determining high intelligence. AB - Many attempts have been made to correlate degrees of both animal and human intelligence with brain properties. With respect to mammals, a much-discussed trait concerns absolute and relative brain size, either uncorrected or corrected for body size. However, the correlation of both with degrees of intelligence yields large inconsistencies, because although they are regarded as the most intelligent mammals, monkeys and apes, including humans, have neither the absolutely nor the relatively largest brains. The best fit between brain traits and degrees of intelligence among mammals is reached by a combination of the number of cortical neurons, neuron packing density, interneuronal distance and axonal conduction velocity--factors that determine general information processing capacity (IPC), as reflected by general intelligence. The highest IPC is found in humans, followed by the great apes, Old World and New World monkeys. The IPC of cetaceans and elephants is much lower because of a thin cortex, low neuron packing density and low axonal conduction velocity. By contrast, corvid and psittacid birds have very small and densely packed pallial neurons and relatively many neurons, which, despite very small brain volumes, might explain their high intelligence. The evolution of a syntactical and grammatical language in humans most probably has served as an additional intelligence amplifier, which may have happened in songbirds and psittacids in a convergent manner. PMID- 26598736 TI - Correction to 'Experimental studies illuminate the cultural transmission of percussive technologies in Homo and Pan'. PMID- 26598735 TI - Ecological innovations in the Cambrian and the origins of the crown group phyla. AB - Simulation studies of the early origins of the modern phyla in the fossil record, and the rapid diversification that led to them, show that these are inevitable outcomes of rapid and long-lasting radiations. Recent advances in Cambrian stratigraphy have revealed a more precise picture of the early bilaterian radiation taking place during the earliest Terreneuvian Series, although several ambiguities remain. The early period is dominated by various tubes and a moderately diverse trace fossil record, with the classical 'Tommotian' small shelly biota beginning to appear some millions of years after the base of the Cambrian at ca 541 Ma. The body fossil record of the earliest period contains a few representatives of known groups, but most of the record is of uncertain affinity. Early trace fossils can be assigned to ecdysozoans, but deuterostome and even spiralian trace and body fossils are less clearly represented. One way of explaining the relative lack of clear spiralian fossils until about 536 Ma is to assign the various lowest Cambrian tubes to various stem-group lophotrochozoans, with the implication that the groundplan of the lophotrochozoans included a U-shaped gut and a sessile habit. The implication of this view would be that the vagrant lifestyle of annelids, nemerteans and molluscs would be independently derived from such a sessile ancestor, with potentially important implications for the homology of their sensory and nervous systems. PMID- 26598737 TI - ENVIRONMENTAL MONITORING WITH PASSIVE DETECTORS AT CTN IN PORTUGAL. AB - The aim of this work is to present the methods in use for environmental dose assessment with passive detectors at Campus Tecnologico e Nuclear (CTN) of Instituto Superior Tecnico, in Portugal. The methods are based on LiF:Mg,Ti (TLD 100) detectors inserted in Harshaw holders placed at four locations and exchanged on a quarterly basis. An initial group of measurements allowed the estimation of the time interval necessary to attain a stable value, the determination of a fading factor, as well as the calculation method for the assessment of the ambient dose equivalent rate. PMID- 26598738 TI - DOSE AND GAMMA-RAY SPECTRA FROM NEUTRON-INDUCED RADIOACTIVITY IN MEDICAL LINEAR ACCELERATORS FOLLOWING HIGH-ENERGY TOTAL BODY IRRADIATION. AB - Production of radioisotopes in medical linear accelerators (linacs) is of concern when the beam energy exceeds the threshold for the photonuclear interaction. Staff and patients may receive a radiation dose as a result of the induced radioactivity in the linac. Gamma-ray spectroscopy was used to identify the isotopes produced following the delivery of 18 MV photon beams from a Varian 21EX and an Elekta Synergy. The prominent radioisotopes produced include 187W, 63Zn, 56Mn, 24Na and 28Al in both linac models. The dose rate was measured at the beam exit window (12.6 uSv in the first 10 min) following 18 MV total body irradiation (TBI) beams. For a throughput of 24 TBI patients per year, staff members are estimated to receive an annual dose of up to 750 MUSv at the patient location. This can be further reduced to 65 MUSv by closing the jaws before re-entering the treatment bunker. PMID- 26598739 TI - DRD2 Schizophrenia-Risk Allele Is Associated With Impaired Striatal Functioning in Unaffected Siblings of Schizophrenia Patients. AB - A recent Genome-Wide Association Study showed that the rs2514218 single nucleotide polymorphism (SNP) in close proximity to dopamine receptor D2 is strongly associated with schizophrenia. Further, an in silico experiment showed that rs2514218 has a cis expression quantitative trait locus effect in the basal ganglia. To date, however, the functional consequence of this SNP is unknown. Here, we used functional Magnetic resonance imaging to investigate the impact of this risk allele on striatal activation during proactive and reactive response inhibition in 45 unaffected siblings of schizophrenia patients. We included siblings to circumvent the illness specific confounds affecting striatal functioning independent from gene effects. Behavioral analyses revealed no differences between the carriers (n= 21) and noncarriers (n= 24). Risk allele carriers showed a diminished striatal response to increasing proactive inhibitory control demands, whereas overall level of striatal activation in carriers was elevated compared to noncarriers. Finally, risk allele carriers showed a blunted striatal response during successful reactive inhibition compared to the noncarriers. These data are consistent with earlier reports showing similar deficits in schizophrenia patients, and point to a failure to flexibly engage the striatum in response to contextual cues. This is the first study to demonstrate an association between impaired striatal functioning and the rs2514218 polymorphism. We take our findings to indicate that striatal functioning is impaired in carriers of the DRD2 risk allele, likely due to dopamine dysregulation at the DRD2 location. PMID- 26598740 TI - Altered Thalamo-Cortical White Matter Connectivity: Probabilistic Tractography Study in Clinical-High Risk for Psychosis and First-Episode Psychosis. AB - Disrupted thalamo-cortical connectivity is regarded as a core psychopathology in patients diagnosed with schizophrenia. However, whether the thalamo-cortical white matter connectivity is disrupted before the onset of psychosis is still unknown. To determine this gap in knowledge, the strength of thalamo-cortical white matter anatomical connectivity in subjects at clinical-high risk for psychosis (CHR) was compared to that of first-episode psychosis (FEP) and healthy controls. A total of 37 CHR, 21 FEP, and 37 matched healthy controls underwent diffusion-weighted magnetic resonance imaging to examine the number of probabilistic tractography "counts" representing thalamo-cortical white matter connectivity. We also investigated the relationship with psychopathology. For FEP, the connectivity between the thalamus and parietal cortex was significantly increased (F= 5.65,P< .05) compared to that of healthy controls. However, the connectivity between thalamus and orbitofrontal cortex was significantly reduced compared to both healthy controls (F= 11.86,P< .005) and CHR (F= 6.63,P< .05). Interestingly, CHR exhibited a similar pattern as FEP, albeit with slightly reduced magnitude. Compared to healthy controls, there was a significant decrease (F= 4.16,P< .05) in CHR thalamo-orbitofrontal connectivity. Also, the strength of the thalamo-orbitofrontal connectivity was correlated with the Global Assessment of Functioning score in CHR (r= .35,P< .05). This observed pattern of white matter connectivity disruptions in FEP and in CHR suggests that this pattern of disconnectivity not only highlights the involvement of thalamus but also might be useful as an early biomarker for psychosis. PMID- 26598741 TI - Reply to L. Dal Maso et al. PMID- 26598742 TI - Precise Diagnosis of Intraoperative Frozen Section Is an Effective Method to Guide Resection Strategy for Peripheral Small-Sized Lung Adenocarcinoma. AB - PURPOSE: This study investigated the accuracy of intraoperative frozen section (FS) diagnosis for predicting the final pathology (FP) of peripheral small-sized lung adenocarcinoma and evaluated its usefulness in sublobar resection. PATIENTS AND METHODS: The records of 803 patients with clinical stage I peripheral lung adenocarcinoma who underwent sublobar resection for FS diagnosis to guide surgical strategy were reviewed. The surgical extension was mainly based on FS. The FS were stratified into atypical adenomatous hyperplasia, adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma. The diagnostic accuracy of FS, the reasons for the discrepancy between FS and FP, and the clinical influence of the FS errors were evaluated. To assess the survival of patients with different subtypes after surgery, 301 patients were identified for prognosis evaluation. RESULTS: The total concordance rate between FS and FP was 84.4%. When atypical adenomatous hyperplasia, AIS, and MIA were classified together as a low-risk group, the concordance rate was 95.9%. Most discrepant cases were the underestimation of AIS and MIA. The diagnostic accuracy of FS for tumors <= 1 cm and larger than 1 cm in diameter was 79.6% and 90.8%, respectively (P < .01). The FS errors had significant clinical impact on 0.9% of the 803 patients due to insufficient resection. The 5-year recurrence-free survival rate (100%) was significantly better for the patients with AIS/MIA than for patients with invasive adenocarcinoma (74.1%, P < .01). CONCLUSION: Frozen pathology has a high concordance rate with FP. Precise diagnosis by intraoperative FS is an effective method to guide resection strategy for peripheral small-sized lung adenocarcinoma. PMID- 26598743 TI - Pediatric Palliative Oncology: A New Training Model for an Emerging Field. PMID- 26598744 TI - Adjuvant Lapatinib and Trastuzumab for Early Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: Results From the Randomized Phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization Trial. AB - BACKGROUND: Lapatinib (L) plus trastuzumab (T) improves outcomes for metastatic human epidermal growth factor 2-positive breast cancer and increases the pathologic complete response in the neoadjuvant setting, but their role as adjuvant therapy remains uncertain. METHODS: In the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial, patients with centrally confirmed human epidermal growth factor 2-positive early breast cancer were randomly assigned to 1 year of adjuvant therapy with T, L, their sequence (T->L), or their combination (L+T). The primary end point was disease-free survival (DFS), with 850 events required for 80% power to detect a hazard ratio (HR) of 0.8 for L+T versus T. RESULTS: Between June 2007 and July 2011, 8,381 patients were enrolled. In 2011, due to futility to demonstrate noninferiority of L versus T, the L arm was closed, and patients free of disease were offered adjuvant T. A protocol modification required P <= .025 for the two remaining pairwise comparisons. At a protocol-specified analysis with a median follow-up of 4.5 years, a 16% reduction in the DFS hazard rate was observed with L+T compared with T (555 DFS events; HR, 0.84; 97.5% CI, 0.70 to 1.02; P = .048), and a 4% reduction was observed with T >L compared with T (HR, 0.96; 97.5% CI, 0.80 to 1.15; P = .61). L-treated patients experienced more diarrhea, cutaneous rash, and hepatic toxicity compared with T-treated patients. The incidence of cardiac toxicity was low in all treatment arms. CONCLUSION: Adjuvant treatment that includes L did not significantly improve DFS compared with T alone and added toxicity. One year of adjuvant T remains standard of care. PMID- 26598746 TI - Prospective Evaluation of the 21-Gene Recurrence Score Assay for Breast Cancer Decision-Making in Ontario. AB - PURPOSE: To evaluate the 21-gene recurrence score (RS) on decision-making in a population-based cohort. PATIENTS AND METHODS: Patients with axillary node negative or nodal micrometastases, estrogen receptor-positive, and human epidermal growth factor receptor 2-negative breast cancer being considered for chemotherapy were eligible. All cancer treatment centers in Ontario, Canada, participated. Oncologists made a preliminary recommendation for endocrine therapy with or without chemotherapy on the basis of Adjuvant! Online (AOL) risk estimation. Patients were asked for their preference regarding chemotherapy. After RSs were available, patients returned for final decision-making. Patient satisfaction was measured by using the decisional conflict scale. RESULTS: Between January 2012 and July 2013, 1,000 patients were recruited. RSs were available for 979 patients. In 58% of patients, risk was categorized as low (RS, 0 to 18); in 33%, intermediate (RS, 19 to 30); and in 9%, high (RS, >= 31). Oncologists' recommendations pretest and post-test remained the same in 464 patients (48%), changed from unsure or chemotherapy to no chemotherapy in 365 (38%), and changed from unsure or no chemotherapy to chemotherapy in 143 (15%). After the test, oncologists recommended chemotherapy for 236 patients, 81% of whom received chemotherapy. Of 151 patients in whom risk was classified as intermediate by means of AOL, 41% were a low risk and 44% intermediate risk with RS. Of 298 patients at high risk with AOL, 16% had a high risk RS. None of 236 patients with grade I tumors had a high-risk RS. Mean total decisional conflict scale score significantly improved from pretest to post-test from 34 to 19 (P < .001). CONCLUSION: The RS substantially influenced both oncologists' recommendations and patients' preferences for chemotherapy. The major effect was avoidance of chemotherapy when AOL indicated high or intermediate risk. PMID- 26598745 TI - Symptomatic Profiles of Patients With Polycythemia Vera: Implications of Inadequately Controlled Disease. AB - PURPOSE: Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) associated with disabling symptoms and a heightened risk of life-threatening complications. Recent studies have demonstrated the effectiveness of JAK inhibitor therapy in patients with PV patients who have a history of prior hydroxyurea (HU) use (including resistance or intolerance), phlebotomy requirements, and palpable splenomegaly. We aimed to determine how these features contribute alone and in aggregate to the PV symptom burden. PATIENTS AND METHODS: Through prospective evaluation of 1,334 patients with PV who had characterized symptom burden, we assessed patient demographics, laboratory data, and the presence of splenomegaly by disease feature (ie, known HU use, known phlebotomy requirements, splenomegaly). RESULTS: The presence of each feature in itself is associated with a moderately high symptom burden (MPN symptom assessment form [SAF] total symptom score [TSS] range, 27.7 to 29.2) that persists independent of PV risk category. In addition, symptoms incrementally increase in severity with the addition of other features. Patients with PV who had all three features (PV-HUPS) faced the highest total score (MPN-SAF TSS, 32.5) but had similar individual symptom scores to patients with known HU use (PV-HU), known phlebotomy (PV-P), and splenomegaly (PV-S). CONCLUSION: The results of this study suggest that patients with PV who have any one of the features in question (known HU use, known phlebotomy, or splenomegaly) have significant PV-associated symptoms. Furthermore, it demonstrates that many PV symptoms remain severe independent of the number of features present. PMID- 26598747 TI - Alectinib in Crizotinib-Refractory ALK-Rearranged Non-Small-Cell Lung Cancer: A Phase II Global Study. AB - PURPOSE: Crizotinib confers improved progression-free survival compared with chemotherapy in anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC), but progression invariably occurs. We investigated the efficacy and safety of alectinib, a potent and selective ALK inhibitor with excellent CNS penetration, in patients with crizotinib-refractory ALK-positive NSCLC. PATIENTS AND METHODS: Alectinib 600 mg was administered orally twice daily. The primary end point was objective response rate (ORR) by central independent review committee (IRC). RESULTS: Of the 138 patients treated, 84 patients (61%) had CNS metastases at baseline, and 122 were response evaluable (RE) by IRC. ORR by IRC was 50% (95% CI, 41% to 59%), and the median duration of response (DOR) was 11.2 months (95% CI, 9.6 months to not reached). In 96 patients (79%) previously treated with chemotherapy, the ORR was 45% (95% CI, 35% to 55%). Median IRC assessed progression-free survival for all 138 patients was 8.9 months (95% CI, 5.6 to 11.3 months). CNS disease control rate was 83% (95% CI, 74% to 91%), and the median CNS DOR was 10.3 months (95% CI, 7.6 to 11.2 months). CNS ORR in 35 patients with baseline measurable CNS lesions was 57% (95% CI, 39% to 74%). Of the 23 patients with baseline CNS metastases (measurable or nonmeasurable) and no prior radiation, 10 (43%) had a complete CNS response. At 12 months, the cumulative CNS progression rate (24.8%) was lower than the cumulative non-CNS progression rate (33.2%) for all patients. Common adverse events were constipation (33%), fatigue (26%), and peripheral edema (25%); most were grade 1 to 2. CONCLUSION: Alectinib is highly active and well tolerated in patients with advanced, crizotinib-refractory ALK-positive NSCLC, including those with CNS metastases. PMID- 26598748 TI - Anastrozole-Induced Carpal Tunnel Syndrome: Results From the International Breast Cancer Intervention Study II Prevention Trial. AB - PURPOSE: Carpal tunnel syndrome (CTS) occurs when the median nerve is compressed at the wrist in the carpal tunnel. It has been suggested that hormonal risk factors may be involved in the pathogenesis of CTS, and a higher incidence of CTS has been reported in randomized clinical trials with aromatase inhibitors (AIs) compared with tamoxifen. PATIENTS AND METHODS: This was an exploratory analysis of the International Breast Cancer Intervention Study II, a double-blind randomized clinical trial in which women at increased risk of breast cancer were randomly assigned to receive anastrozole or placebo. This is the first report of risk factors for and characteristics of CTS in women taking an AI in a placebo controlled trial. RESULTS: Overall, 96 participants with CTS were observed: 65 (3.4%) in the anastrozole arm and 31 (1.6%) in the placebo arm (odds ratio, 2.16 [1.40 to 3.33]; P < .001). Ten participants were reported as having severe CTS, of which eight were taking anastrozole (P = .08). Eighteen women (0.9%) in the anastrozole arm and six women (0.3%) in the placebo arm reported surgical intervention, which was significantly different (odds ratio, 3.06 [1.21 to 7.72], P = .018). Six women discontinued with the allocated treatment because of the onset of CTS. Apart from treatment allocation, a high body mass index and an a prior report of musculoskeletal symptoms after trial entry were the only other risk factors for CTS identified in these postmenopausal women. CONCLUSIONS: The use of anastrozole was associated with a higher incidence of CTS but few participants required surgery. Further investigations are warranted into the risk factors and treatment of AI-induced CTS. PMID- 26598749 TI - Adjuvant Chemotherapy Use and Health Care Costs After Introduction of Genomic Testing in Breast Cancer. AB - PURPOSE: We assessed the associations between the 21-gene recurrence score assay (RS) receipt, subsequent chemotherapy use, and medical expenditures among patients with early-stage breast cancer. PATIENTS AND METHODS: Data from the Pennsylvania Cancer Registry were used to assemble a retrospective cohort of women with early-stage breast cancer from 2007 to 2010 who underwent initial surgical treatment. These data were merged with administrative claims from the 12 month periods before and after diagnosis to identify comorbidities, treatments, and expenditures (n = 7,287). Propensity score-weighted regression models were estimated to identify the effects of RS receipt on chemotherapy use and medical spending in the year after diagnosis. RESULTS: The associations between RS receipt and outcomes varied markedly by patient age. RS use was associated with lower chemotherapy use among women younger than 55 (19.2% lower; 95% CI, 10.6 to 27.9). RS use was associated with higher chemotherapy use among women 75 to 84 years old (5.7% higher; 95% CI, 0.4 to 11.0). RS receipt was associated with lower adjusted 1-year medical spending among women younger than 55 ($15,333 lower; 95% CI, $2,841 to $27,824) and with higher spending among women who were 75 to 84 years old ($3,489 higher; 95% CI, $857 to $6,122). CONCLUSION: RS receipt was associated with reduced use of adjuvant chemotherapy and lower health care spending among women with breast cancer who were younger than 55. Conversely, among women 75 and older, RS testing was associated with a modest increase in chemotherapy use and slightly higher spending. From a population perspective, the impact of RS testing on breast cancer treatment and health care costs is much greater in younger women. PMID- 26598750 TI - Randomized Trial Comparing Telephone Versus In-Person Weight Loss Counseling on Body Composition and Circulating Biomarkers in Women Treated for Breast Cancer: The Lifestyle, Exercise, and Nutrition (LEAN) Study. AB - PURPOSE: Obesity is associated with a higher risk of breast cancer mortality. The gold standard approach to weight loss is in-person counseling, but telephone counseling may be more feasible. We examined the effect of in-person versus telephone weight loss counseling versus usual care on 6-month changes in body composition, physical activity, diet, and serum biomarkers. METHODS: One hundred breast cancer survivors with a body mass index >= 25 kg/m(2) were randomly assigned to in-person counseling (n = 33), telephone counseling (n = 34), or usual care (UC) (n = 33). In-person and telephone counseling included 11 30 minute counseling sessions over 6 months. These focused on reducing caloric intake, increasing physical activity, and behavioral therapy. Body composition, physical activity, diet, and serum biomarkers were measured at baseline and 6 months. RESULTS: The mean age of participants was 59 +/- 7.5 years old, with a mean BMI of 33.1 +/- 6.6 kg/m(2), and the mean time from diagnosis was 2.9 +/- 2.1 years. Fifty-one percent of the participants had stage I breast cancer. Average 6-month weight loss was 6.4%, 5.4%, and 2.0% for in-person, telephone, and UC groups, respectively (P = .004, P = .009, and P = .46 comparing in-person with UC, telephone with UC, and in-person with telephone, respectively). A significant 30% decrease in C-reactive protein levels was observed among women randomly assigned to the combined weight loss intervention groups compared with a 1% decrease among women randomly assigned to UC (P = .05). CONCLUSION: Both in person and telephone counseling were effective weight loss strategies, with favorable effects on C-reactive protein levels. Our findings may help guide the incorporation of weight loss counseling into breast cancer treatment and care. PMID- 26598751 TI - Survival and Clinical Outcomes in Surgically Treated Patients With Metastatic Epidural Spinal Cord Compression: Results of the Prospective Multicenter AOSpine Study. AB - PURPOSE: Although surgery is used increasingly as a strategy to complement treatment with radiation and chemotherapy in patients with metastatic epidural spinal cord compression (MESCC), the impact of surgery on health-related quality of life (HRQoL) is not well established. We aimed to prospectively evaluate survival, neurologic, functional, and HRQoL outcomes in patients with MESCC who underwent surgical management. PATIENTS AND METHODS: One hundred forty-two patients with a single symptomatic MESCC lesion who were treated surgically were enrolled onto a prospective North American multicenter study and were observed at least up to 12 months. Clinical data, including Brief Pain Inventory, ASIA (American Spinal Injury Association) impairment scale, SF-36 Short Form Health Survey, Oswestry Disability Index, and EuroQol 5 dimensions (EQ-5D) scores, were obtained preoperatively, and at 6 weeks and 3, 6, 9, and 12 months postoperatively. RESULTS: Median survival time was 7.7 months. The 30-day and 12 month mortality rates were 9% and 62%, respectively. There was improvement at 6 months postoperatively for ambulatory status (McNemar test, P < .001), lower extremity and total motor scores (Wilcoxon signed rank test, P < .001), and at 6 weeks and 3, 6, and 12 months for Oswestry Disability Index, EQ-5D, and pain interference (paired t test, P < .013). Moreover, at 3 months after surgery, the ASIA impairment scale grade was improved (Stuart-Maxwell test P = .004). SF-36 scores improved postoperatively in six of eight scales. The incidence of wound complications was 10% and 2 patients required a second surgery (screw malposition and epidural hematoma). CONCLUSION: Surgical intervention, as an adjunct to radiation and chemotherapy, provides immediate and sustained improvement in pain, neurologic, functional, and HRQoL outcomes, with acceptable risks in patients with a focal symptomatic MESCC lesion who have at least a 3 month survival prognosis. PMID- 26598752 TI - DBCG-IMN: A Population-Based Cohort Study on the Effect of Internal Mammary Node Irradiation in Early Node-Positive Breast Cancer. AB - PURPOSE: It is unknown whether irradiation of the internal mammary lymph nodes improves survival in patients with early-stage breast cancer. A possible survival benefit might be offset by radiation-induced heart disease. We assessed the effect of internal mammary node irradiation (IMNI) in patients with early-stage node-positive breast cancer. PATIENTS AND METHODS: In this nationwide, prospective population-based cohort study, we included patients who underwent operation for unilateral early-stage node-positive breast cancer. Patients with right-sided disease were allocated to IMNI, whereas patients with left-sided disease were allocated to no IMNI because of the risk of radiation-induced heart disease. The primary end point was overall survival. Secondary end points were breast cancer mortality and distant recurrence. Analyses were by intention to treat. RESULTS: A total of 3,089 patients were included. Of these, 1,492 patients were allocated to IMNI, whereas 1,597 patients were allocated to no IMNI. With a median of 8.9 years of follow-up time, the 8-year overall survival rates were 75.9% with IMNI versus 72.2% without IMNI. The adjusted hazard ratio (HR) for death was 0.82 (95% CI, 0.72 to 0.94; P = .005). Breast cancer mortality was 20.9% with IMNI versus 23.4% without IMNI (adjusted HR, 0.85; 95% CI, 0.73 to 0.98; P = .03). The risk of distant recurrence at 8 years was 27.4% with IMNI versus 29.7% without IMNI (adjusted HR, 0.89; 95% CI, 0.78 to 1.01; P = .07). The effect of IMNI was more pronounced in patients at high risk of internal mammary node metastasis. Equal numbers in each group died of ischemic heart disease. CONCLUSION: In this naturally allocated, population-based cohort study, IMNI increased overall survival in patients with early-stage node-positive breast cancer. PMID- 26598753 TI - Racial Differences in the Use and Outcome of Neoadjuvant Chemotherapy for Breast Cancer: Results From the National Cancer Data Base. AB - PURPOSE: To explore racial differences in the use and outcome of neoadjuvant chemotherapy for breast cancer. METHODS: The National Cancer Data Base was queried to identify women with stage 1 to 3 breast cancer diagnosed in 2010 and 2011. Chemotherapy use and rate of pathologic complete response (pCR) was determined for various racial/ethnic groups. RESULTS: Of 278,815 patients with known race and ethnicity, 127,417 (46%) received chemotherapy, and of 121,446 where the timing of chemotherapy was known, 27,300 (23%) received neoadjuvant chemotherapy. Chemotherapy, and neoadjuvant chemotherapy in particular, was given more frequently to black, Hispanic, and Asian women than to white women (P < 0.001). This difference was largely explained by more advanced stage, higher grade tumors, and a greater proportion of triple-negative and human epidermal growth factor receptor 2 (HER2)-positive tumors in these women. Of 17,970 patients with known outcome, 5,944 (33%) had a pCR. No differences in response rate for estrogen receptor (ER)/progesterone receptor (PR)-positive tumors were found, but compared with white women, black but not Hispanic or Asian women had a lower rate of pCR for ER/PR-negative, HER2-positive (43% v 54%, P = 0.001) and triple-negative tumors (37% v 43%, P < 0.001). This difference persisted when adjusted for age, clinical T stage, clinical N stage, histology, grade, comorbidity index, facility type, geographic region, insurance status, and census derived median income and education for the patient's zip code (odds ratio, 0.84; 95% CI, 0.77 to 0.93). CONCLUSION: Neoadjuvant chemotherapy is given more frequently to black, Hispanic, and Asian women than to white women. Black women have a lower likelihood of pCR for triple-negative and HER2-positive breast cancer. Whether this is due to biologic differences in chemosensitivity or to treatment or socioeconomic differences that could not be adjusted for is unknown. PMID- 26598754 TI - Reply to J.M. Snaman et al. PMID- 26598756 TI - Reply to A. Addeo and A. Bahl. PMID- 26598757 TI - All-Cause and Cancer-Specific Mortality Among Patients With Cancer Infected or Not Infected With HIV. PMID- 26598755 TI - Racial Variation in the Uptake of Oncotype DX Testing for Early-Stage Breast Cancer. AB - PURPOSE: Oncotype DX (ODX) is a tumor gene-profiling test that aids in adjuvant chemotherapy decision-making. ODX has the potential to improve quality of care; however, if not equally accessible across racial groups, disparities in cancer care quality may persist or worsen. We examined racial disparities in ODX testing uptake. METHODS: We used data from the Carolina Breast Cancer Study, phase III, a longitudinal, population-based study of 2,998 North Carolina women who received a diagnosis of breast cancer between 2008 and 2014. Our primary analysis used modified Poisson regression to determine the association between race and whether ODX testing was ordered among two strata: node-negative and node-positive breast cancer. RESULTS: A total of 1,468 women with estrogen receptor-positive, human epidermal growth factor receptor-2-negative, stage I or II breast cancer met inclusion criteria. Black patients had higher-grade and larger tumors, more comorbidities, younger age at diagnosis, and lower socioeconomic status than non black women. Overall, 42% of women had ODX test results in their pathology reports. Compared with those who did not receive ODX testing, women who received ODX testing tended to be younger and have medium tumor size and grade. Our regression analyses indicated no racial disparities in ODX uptake among node negative patients. However, racial differences were detected among node-positive patients, with black patients being 46% less likely to receive ODX testing than non-black women (adjusted relative risk, 0.54; 95% CI, 0.35 to 0.84; P = .006). CONCLUSION: We did not find racial disparities in ODX testing for node-negative patients for whom ODX testing is guideline recommended and widely covered by insurers. However, our findings suggest that a newer, non-guideline-concordant application of ODX testing for node-positive breast cancer was accessed less by black women than by non-black women, reflecting more guideline concordant care among black women. PMID- 26598758 TI - Do All High- and Intermediate-Risk Patients With Metastatic Castration-Resistant Prostate Cancer Really Benefit From Abiraterone? PMID- 26598759 TI - Comparison of hypertension healthcare outcomes among older people in the USA and England. AB - BACKGROUND: The USA and England have very different health systems. Comparing hypertension care outcomes in each country enables an evaluation of the effectiveness of each system. METHOD: The English Longitudinal Study of Ageing and the Health and Retirement Survey are used to compare the prevalence of controlled, uncontrolled and undiagnosed hypertension within the hypertensive population (diagnosed or measured within the survey data used) aged 50 years and above in the USA and in England. RESULTS: Controlled hypertension is more prevalent within the hypertensive population in the USA (age 50-64: 0.53 (0.50 to 0.57) and age 65+: 0.51 (0.49 to 0.53)) than in England (age 50-64: 0.45 (0.42 to 0.48) and age 65+: 0.42 (0.40 to 0.45)). This difference is driven by lower undiagnosed hypertension in the USA (age 50-64: 0.18 (0.15-0.21) and age 65+: 0.13 (0.12 to 0.14)) relative to England (age 50-64: 0.26 (0.24 to 0.29) and age 65+: 0.22 (0.20 to 0.24)). The prevalence of uncontrolled hypertension within the hypertensive population is very similar in the USA (age 50-64: 0.29 (0.26 to 0.32) and age 65+: 0.36 (0.34 to 0.38)) and England (age 50-64: 0.29 (0.26 to 0.32) and age 65+: 0.36 (0.34 to 0.39)). Hypertension care outcomes are comparable across US insurance categories. In both countries, undiagnosed hypertension is positively correlated with wealth (ages 50-64). Uncontrolled hypertension declines with rising wealth in the USA. CONCLUSIONS: Different diagnostic practices are likely to drive the cross-country differences in undiagnosed hypertension. US government health systems perform at least as well as private healthcare and are more equitable in the distribution of care outcomes. Higher undiagnosed hypertension among the affluent may reflect less frequent medical contact. PMID- 26598761 TI - Index of microvascular resistance: a potential enhancement to coronary arteriography for patients with Takotsubo syndrome. PMID- 26598762 TI - Stability Studies of Extemporaneously Compounded Clobazam Oral Suspension. PMID- 26598763 TI - What a waste! PMID- 26598764 TI - Hypothyroidism in adults: treat symptomatic patients. PMID- 26598760 TI - Tim-3 enhances FcepsilonRI-proximal signaling to modulate mast cell activation. AB - T cell (or transmembrane) immunoglobulin and mucin domain protein 3 (Tim-3) has attracted significant attention as a novel immune checkpoint receptor (ICR) on chronically stimulated, often dysfunctional, T cells. Antibodies to Tim-3 can enhance antiviral and antitumor immune responses. Tim-3 is also constitutively expressed by mast cells, NK cells and specific subsets of macrophages and dendritic cells. There is ample evidence for a positive role for Tim-3 in these latter cell types, which is at odds with the model of Tim-3 as an inhibitory molecule on T cells. At this point, little is known about the molecular mechanisms by which Tim-3 regulates the function of T cells or other cell types. We have focused on defining the effects of Tim-3 ligation on mast cell activation, as these cells constitutively express Tim-3 and are activated through an ITAM-containing receptor for IgE (FcepsilonRI), using signaling pathways analogous to those in T cells. Using a variety of gain- and loss-of-function approaches, we find that Tim-3 acts at a receptor-proximal point to enhance Lyn kinase-dependent signaling pathways that modulate both immediate-phase degranulation and late-phase cytokine production downstream of FcepsilonRI ligation. PMID- 26598765 TI - Guest Editors' Introduction to the Special Issue on Bayesian Nonparametrics. PMID- 26598766 TI - Guest Editors' Introduction: Special Section on Higher Order Graphical Models in Computer Vision. PMID- 26598767 TI - Report presses for fund focusing on prevention. PMID- 26598769 TI - Introduction to the Special Section on Real-World Face Recognition. PMID- 26598768 TI - Chest X-ray Quiz. PMID- 26598770 TI - Elder justice: Preventing and intervening in elder mistreatment. PMID- 26598771 TI - Putting "health" in the electronic health record: A call for collective action. PMID- 26598772 TI - Consensus Paper: Probing Homeostatic Plasticity of Human Cortex With Non-invasive Transcranial Brain Stimulation. AB - Homeostatic plasticity is thought to stabilize neural activity around a set point within a physiologically reasonable dynamic range. Over the last ten years, a wide range of non-invasive transcranial brain stimulation (NTBS) techniques have been used to probe homeostatic control of cortical plasticity in the intact human brain. Here, we review different NTBS approaches to study homeostatic plasticity on a systems level and relate the findings to both, physiological evidence from in vitro studies and to a theoretical framework of homeostatic function. We highlight differences between homeostatic and other non-homeostatic forms of plasticity and we examine the contribution of sleep in restoring synaptic homeostasis. Finally, we discuss the growing number of studies showing that abnormal homeostatic plasticity may be associated to a range of neuropsychiatric diseases. PMID- 26598774 TI - In Memory of Professor Chu-Wan Kim. PMID- 26598783 TI - Algorithm to select optimal systemic anti-psoriatic drugs in relation with patients' Psoriasis Area and Severity Index score for plaque psoriasis. AB - This study sought to develop a therapeutic algorithm for selecting the optimal systemic drugs to treat moderate to severe psoriasis, based on the patient's Psoriasis Area Severity Index (PASI) score. Data from 191 patients undergoing treatment for plaque psoriasis were retrospectively analyzed. Pre- and post treatment PASI scores were compared across patients treated with acitretin of retinoic acid (RA; n = 95), methotrexate (MTX; n = 41) or cyclosporin A (CsA; n = 55). The PASI score improvement was examined at weeks 4 (primary end-point) and 12 (secondary end-point). MTX and CsA had a higher global therapeutic efficacy, with more patients exhibiting a marked improvement (>=75% improvement in PASI [PASI 75]) at week 12 with MTX (56.1%, P = 0.028) and CsA (54.5%, P = 0.025) than RA (35.8%). Multivariate analysis adjusting for confounders produced consistent results (P = 0.026). For patients with severe psoriasis (PASI >12), the PASI 75 response was higher with CsA (55.6%) than RA (31.5%) (P = 0.023) at week 4 and higher with MTX (57.1%, P = 0.029) and CsA (61.5%, P = 0.017) than RA (21.7%) at week 12. Because RA is a standard systemic drug, the RA group was divided into two subgroups based on the PASI 50 response at week 12. Marked or moderate improvement (PASI >=50) with RA was observed in patients with a pretreatment PASI score less than 14. Thus, oral RA is recommended as a first-line drug for patients with PASI of less than 14, and MTX or CsA are recommended for patients with PASI of 14 or more. PMID- 26598784 TI - Whose life is it anyway? PMID- 26598785 TI - Human behavior preceding dog bites to the face. AB - Facial injuries caused by dog bites pose a serious problem. The aims of this study were to determine human behavior immediately preceding a dog bite to the face and to assess the effects of victim age and gender and dog sex and size on the location of the bite to the face and the need for medical treatment. Complete data on 132 incidents of bites to the face were analysed. A human bending over a dog, putting the face close to the dog's face, and gazing between victim and dog closely preceded a dog bite to the face in 76%, 19% and 5% of cases, respectively. More than half of the bites were directed towards the central area of the victim's face (nose, lips). More than two thirds of the victims were children, none of the victims was an adult dog owner and only adult dogs bit the face. Victim's age and gender and dog's sex and size did not affect the location of the bite on the face. People who were bitten by large dogs sought medical treatment more often than people who were bitten by small dogs (P <0.01). Risk factors such as bending over the dog, putting the face close to the dog's face and gazing between human and dog should be avoided, and children should be carefully and constantly supervised when in the presence of dogs. PMID- 26598786 TI - Saddles and girths: What is new? AB - Several studies have shown that there is a high prevalence of ill-fitting saddles. Many riders do not have saddle fit professionally assessed on at least an annual basis. Back dimensions can change considerably over the period of a year and therefore saddle fit should be assessed several times yearly, especially if work intensity has been altered. Saddle fit should be evaluated before and after exercise because back dimensions can change during work. Ideally, horses should be ridden in individual purpose-fitted saddles, rather than the same saddle being used on several horses. There remains little scientific rationale for the use of pads and numnahs under a saddle, except to temporarily improve saddle fit, and the use of numnahs that exert pressure on the spinous processes can be detrimental to performance. Although saddle slip consistently to one side can be associated with poor saddle fit or asymmetry of the horse's back, the most common cause is hindlimb lameness. PMID- 26598787 TI - A systematic review of animal based indicators of sheep welfare on farm, at market and during transport, and qualitative appraisal of their validity and feasibility for use in UK abattoirs. AB - In the UK, it has been suggested that abattoirs are ideal locations to assess the welfare of sheep as most are slaughtered at abattoirs either as finished lambs or cull ewes. Data from abattoirs could provide benchmarks for welfare indicators at a national level, as well as demonstrating how these change over time. Additionally, feedback could be provided to farmers and regulatory authorities to help improve welfare and identify high or low standards for quality assurance or risk-based inspections. A systematic review of the scientific literature was conducted, which identified 48 animal-based indicators of sheep welfare that were categorised by the Five Freedoms. Their validity as measures of welfare and feasibility for use in abattoirs were evaluated as potential measures of prior sheep welfare on the farm of origin, at market, or during transportation to the abattoir. A total of 19 indicators were considered valid, of which nine were considered theoretically feasible for assessing sheep welfare at abattoirs; these were body cleanliness, carcass bruising, diarrhoea, skin lesions, skin irritation, castration, ear notching, tail docking and animals recorded as 'obviously sick'. Further investigation of these indicators is required to test their reliability and repeatability in abattoirs. Novel welfare indicators are needed to assess short-term hunger and thirst, prior normal behaviour and long term fear and distress. PMID- 26598789 TI - Halogen-Bonding-Assisted Iodosylbenzene Activation by a Homogenous Iron Catalyst. AB - The iron(III) complex of hexadentate N,N,N'-tris(2-pyridylmethyl)ethylendiamine N'-acetate (tpena(-) ) is a more effective homogenous catalyst for selective sulfoxidation and epoxidation with insoluble iodosylbenzene, [PhIO]n , compared with soluble methyl-morpholine-N-oxide (NMO). We propose that two molecules of [Fe(tpena)](2+) cooperate to solubilize PhIO, extracting two equivalents to form the halogen-bonded dimeric {[Fe(tpena)OIPh]2}(4+). The closest intradimeric I???O distance, 2.56 A, is nearly 1 A less than the sum of the van de Waals radii of these atoms. A correlation of the rates of the reaction of {[Fe(tpena)OIPh]2}(4+) with para-substituted thioanisoles indicate that this species is a direct metal based oxidant rather than a derived ferryl or perferryl complex. A study of gas phase reactions indicate that an ion at m/z=231.06100 originates from solution state {[Fe(tpena)OIPh]2}(4+) and is ascribed to [Fe(III) (tpenaO)](2+), derived from an intramolecular O atom insertion into an Fe-tpena donor bond. Proposed ion pairs, {[Fe(tpena)OIPh]Cl}(+) and {[Fe(tpena)OIPh]ClO4}(+), are more stable than native [Fe(tpena)OIPh](2+) ions, suggesting that halogen-bonding, as for the solution and solid states, operates also in the gas phase. PMID- 26598788 TI - Linking Functional Connectivity and Structural Connectivity Quantitatively: A Comparison of Methods. AB - Structural connectivity in the brain is the basis of functional connectivity. Quantitatively linking the two, however, remains a challenge. For a pair of regions of interest (ROIs), anatomical connections derived from diffusion weighted imaging are often quantified by fractional anisotropy (FA) or edge weight, whereas functional connections, derived from resting-state functional magnetic resonance imaging, can be characterized by non-time-series measures such as zero-lag cross correlation and partial correlation, as well as by time-series measures such as coherence and Granger causality. In this study, we addressed the question of linking structural connectivity and functional connectivity quantitatively by considering two pairs of ROIs, one from the default mode network (DMN) and the other from the central executive network (CEN), using two different data sets. Selecting (1) posterior cingulate cortex and medial prefrontal cortex of the DMN as the first pair of ROIs and (2) left dorsal lateral prefrontal cortex and left inferior parietal lobule of the CEN as the second pair of ROIs, we show that (1) zero-lag cross correlation, partial correlation, and pairwise Granger causality were not significantly correlated with either mean FA or edge weight and (2) conditional Granger causality (CGC) was significantly correlated with edge weight but not with mean FA. These results suggest that (1) edge weight may be a more appropriate measure to quantify the strength of the anatomical connection between ROIs and (2) CGC, which statistically removes common input and the indirect influences between a given ROI pair, may be a more appropriate measure to quantify the strength of the functional interaction enabled by the fibers linking the two ROIs. PMID- 26598790 TI - Unveiling the elusive and exotic: Venomics of the Malayan blue coral snake (Calliophis bivirgata flaviceps). AB - The venom proteome of the Malayan blue coral snake, Calliophis bivirgata flaviceps from west Malaysia was investigated by 1D-SDS-PAGE and shotgun-LCMS/MS. A total of 23 proteins belonging to 11 protein families were detected from the venom proteome. For the toxin proteins, the venom consists mainly of phospholipase A2 (41.1%), cytotoxin (22.6%), SVMPs (18.7%) and vespryns (14.6%). However, in contrast to the venoms of New World coral snakes and most elapids, there was no post-synaptic alpha-neurotoxin detected. The proteome also revealed a relatively high level of phosphodiesterase (1.3%), which may be associated with the reported high level of adenosine in the venom. Also detected were 5' nucleotidase (0.3%), hyaluronidase (0.1%) and cysteine-type endopeptide inhibitor (0.6%). Enzymatic studies confirmed the presence of phospholipase A2, phosphodiesterase, 5'-nucleotidase and acetylcholinesterase activities but not l amino acid oxidase activity. The venom exhibited moderate cytotoxic activity against CRL-2648 fibroblast cell lines (IC50=62.14+/-0.87 MUg/mL) and myotoxicity in mice, presumably due to the action of its cytotoxin or its synergistic action with phospholipase A2. Interestingly, the venom lethality could be cross neutralized by a neurotoxic bivalent antivenom from Taiwan. Together, the findings provide insights into the composition and functions of the venom of this exotic oriental elapid snake. BIOLOGICAL SIGNIFICANCE: While venoms of the New World coral snake have been extensively studied, literature pertaining to the Old World or Asiatic coral snake venoms remains lacking. This could be partly due to the inaccessibility to the venom of this rare species and infrequent cases of envenomation reported. This study identified and profiled the venom proteome of the Malayan blue coral snake (C. b. flaviceps) through SDS-PAGE and a high resolution nano-LCMS/MS method, detailing the types and abundance of proteins found in the venom. The biological and toxic activities of the venom were also investigated, offering functional correlation to the venom proteome studied. Of note, the venom contains a unique toxin profile predominated with phospholipase A2 and cytotoxin with no detectable post-synaptic neurotoxin. The venom is moderately lethal to mice and the fatal effect could be cross-neutralized by a heterologous elapid bivalent antivenom from Taiwan. The findings enrich snake toxin databases and provide insights into the composition and pathogenesis of the venom of this exotic species. PMID- 26598792 TI - Catalytic Activity of Cationic and Neutral Silver(I)-XPhos Complexes with Nitrogen Ligands or Tolylsulfonate for Mannich and Aza-Diels-Alder Coupling Reactions. AB - Cationic and neutral silver(I)-L complexes (L=Buchwald-type biaryl phosphanes) with nitrogen co-ligands or organosulfonate counter ions have been synthesised and characterised through their structural and spectroscopic properties. At room temperature, both cationic and neutral silver(I)-L complexes are extremely active catalysts in the promotion of the single and double A(3) coupling of terminal (di)alkynes, pyrrolidine and formaldehyde. In addition, the aza-Diels-Alder two- and three-component coupling reactions of Danishefsky's diene with an imine or amine and aldehyde are efficiently catalysed by these cationic or neutral silver(I)-L complexes. The solvent influences the catalytic performance due to limited complex solubility or solvent decomposition and reactivity. The isolation of new silver(I)-L complexes with reagents as ligands lends support to mechanistic proposals for such catalytic processes. The activity, stability and metal-distal arene interaction of these silver(I)-L catalysts have been compared with those of analogous cationic gold(I) and copper(I) complexes. PMID- 26598793 TI - The natural scorpion peptide, BmK NT1 activates voltage-gated sodium channels and produces neurotoxicity in primary cultured cerebellar granule cells. AB - The scorpion Buthus martensii Karsch has been used in Traditional Chinese Medicine to treat neuronal diseases such as neuropathic pain, paralysis and epilepsy for thousands of years. Studies have demonstrated that scorpion venom is the primary active component. Although scorpion venom can effectively attenuate pain in the clinic, it also produces neurotoxic response. In this study, toxicity guided purification led to identify a mammalian toxin termed BmK NT1 comprising of 65 amino acid residues and an amidated C-terminus, a mature peptide encoded by the nucleotide sequence (GenBank No. AF464898). In contract to the recombinant product of the same nucleotide sequence, BmK AGAP, which displayed analgesic and anti-tumor effect, intravenous injection (i.v.) of BmK NT1 produced acute toxicity in mice with an LD50 value of 1.36 mg/kg. In primary cultured cerebellar granule cells, BmK NT1 produced a concentration-dependent cell death with an IC50 value of 0.65 MUM (0.41-1.03 MUM, 95% Confidence Intervals, 95% CI) which was abolished by TTX, a voltage-gated sodium channel (VGSC) blocker. We also demonstrated that BmK NT1 produced modest sodium influx in cerebellar granule cell cultures with an EC50 value of 2.19 MUM (0.76-6.40 MUM, 95% CI), an effect similar to VGSC agonist, veratridine. The sodium influx response was abolished by TTX suggesting that BmK NT1-induced sodium influx is solely through activation of VGSC. Considered these data together, we demonstrated that BmK NT1 activated VGSC and produced neurotoxicity in cerebellar granule cell cultures. PMID- 26598791 TI - Hemodynamic response function abnormalities in schizophrenia during a multisensory detection task. AB - Functional magnetic resonance imaging (fMRI) of the blood oxygen level dependent (BOLD) response has commonly been used to investigate the neuropathology underlying cognitive and sensory deficits in patients with schizophrenia (SP) by examining the positive phase of the BOLD response, assuming a fixed shape for the hemodynamic response function (HRF). However, the individual phases (positive and post-stimulus undershoot (PSU)) of the HRF may be differentially affected by a variety of underlying pathologies. The current experiment used a multisensory detection task with a rapid event-related fMRI paradigm to investigate both the positive and PSU phases of the HRF in SP and healthy controls (HC). Behavioral results indicated no significant group differences during task performance. Analyses that examined the shape of the HRF indicated two distinct group differences. First, SP exhibited a reduced and/or prolonged PSU following normal task-related positive BOLD activation in secondary auditory and visual sensory areas relative to HC. Second, SP did not show task-induced deactivation in the anterior node of the default-mode network (aDMN) relative to HC. In contrast, when performing traditional analyses that focus on the positive phase, there were no group differences. Interestingly, the magnitude of the PSU in secondary auditory and visual areas was positively associated with the magnitude of task induced deactivation within the aDMN, suggesting a possible common neural mechanism underlying both of these abnormalities (failure in neural inhibition). Results are consistent with recent views that separate neural processes underlie the two phases of the HRF and that they are differentially affected in SP. Hum Brain Mapp 37:745-755, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26598794 TI - Collective Synthesis and Biological Evaluation of Tryptophan-Based Dimeric Diketopiperazine Alkaloids. AB - A concise two one-pot synthesis of WIN 64821, eurocristatine, 15,15'-bis-epi eurocristatine, ditryptophenaline, ditryptoleucine A, WIN 64745, cristatumin C, asperdimin, naseseazine A, and naseseazine B is detailed, based on a unique bioinspired dimerization reaction of tryptophan derivatives in aqueous acidic solution and a one-pot procedure for the construction of diketopiperazine rings. Total yields of these alkaloid syntheses were from 10 up to 27 %. In addition, 1' (2-phenylethylene)-ditryptophenaline was synthesized by using three one-pot operations. The studies detailed herein provided synthesized natural products for inhibitory activities of ubiquitin-specific protease 7 (USP7) and foam cell formation in macrophages. The newly listed biological evaluation for tryptophan based dimeric diketopiperazine alkaloids discovered 15,15'-bis-epi eurocristatine, 1'-(2-phenylethylene)-ditryptophenaline, and WIN 64745 as new drug candidates. PMID- 26598795 TI - Multidetector CT diagnosis of non-traumatic gastroduodenal perforation. AB - INTRODUCTION: To identify reliable CT features and assess the diagnostic performance of 64-multidetector CT (MDCT) in diagnosing non-traumatic gastroduodenal perforation (GDP). METHODS: We retrospectively reviewed 136 CT scans of patients with surgically proven non-traumatic gastrointestinal perforation during 7 years. 92 patients had GDP and 44 patients had other sites of perforation. CT features of perforation were evaluated and the sensitivity, specificity and likelihood ratios of each CT feature were estimated. RESULTS: The cause of GDP was peptic ulcer in 90 patients, gastric cancer in one patient, and foreign body of duodenal diverticulum in one patient. Extraluminal gas (97%) was most common CT feature of GDP, following by fluid or fat strand along gastroduodenum (89%), ascites (89%), wall defect and/or ulcer (84%), and wall thickening (72%). Of CT features, wall defect and/or ulcer showed the best positive likelihood ratios for GDP (36.83). Wall thickening also showed high positive likelihood ratios (10.52). Combined, these CT features showed 95% sensitivity and 93% specificity for localization of perforation site of GDP. CONCLUSION: MDCT is useful in diagnosis of presence and site of GDP. Wall defect and/or ulcer and wall thickening have a high positive predictive value for localization of perforation site. PMID- 26598796 TI - Hemodynamic Impact of Systolic Blood Pressure and Hematocrit Calculated by Computational Fluid Dynamics in Patients with Intracranial Atherosclerosis. AB - OBJECTIVE: Success in clinical trials of intracranial atherosclerosis (ICAS) is related to accurate identification of high-risk patients. Noninvasive computational fluid dynamics (CFD) of stenotic lesions may enhance therapeutic decision-making. We determined whether physiologic parameters change downstream cerebral hemodynamics in patients with ICAS. METHODS: Consecutive ICAS patients who underwent both CT angiography (CTA) and digital subtraction angiography were enrolled. CFD models were made using CTA source images. Inlet boundary conditions were defined using three ranges of systolic blood pressure (BP) (109.2, 158, and 225 mmHg) and hematocrit (27.3, 40.2, and 48.8). Ratios of pressure, shear strain rates (SSR), and flow velocity across the lesion were calculated using CFD simulations. A linear mixed model was used for the statistical analysis of repeated simulations. RESULTS: Among the 56 patients, 32 had moderate stenosis (50-69%) and 24 had severe stenosis (70-99%). A linear mixed model revealed that the ratio of pressure was predicted by systolic BP and stenosis group interaction (P = .036). These pressure decreases were associated with systolic BP (P < .001) and stenosis group (P < .001), but not with hematocrit (P = .337). Post-hoc analysis revealed that pressure decreases were more profound in the severe stenosis than the moderate stenosis group when comparing high and low systolic BP (P = .0108). Ratios of SSR and velocity were only associated in the stenosis group. CONCLUSIONS: Our study showed that systolic BP along with the degree of stenosis was associated with pressure decreases across stenotic lesions. Physiologic conditions may superimpose further changes in post-stenotic or downstream blood flow. PMID- 26598797 TI - TGF-beta signalopathies as a paradigm for translational medicine. AB - This review focusses on impact of a better knowledge of pathogenic mechanisms of Marfan and related disorders on their treatment strategies. It was long believed that a structural impairment formed the basis of Marfan syndrome as deficiency in the structural extracellular matrix component, fibrillin-1 is the cause of Marfan syndrome. However, the study of Marfan mouse models has revealed the strong involvement of the transforming growth factor-beta signalling pathway in the pathogenesis of Marfan. Similarly, this pathway was demonstrated to be key in the pathogenesis of Loeys-Dietz and Shprintzen-Goldberg syndrome. The elucidation of the underlying pathogenic mechanisms has led to new treatment strategies, targeting the overactive TGF-beta pathway. Various clinical trials are currently investigating the potential new treatment options. A meta-analysis will contribute to a better understanding of the various trial results. PMID- 26598799 TI - The costs of producing a unit of blood in Zimbabwe. AB - BACKGROUND: There is lack of published data on the costs of blood and blood transfusion in sub-Saharan Africa. This study aimed to assess the unit costs of producing blood in Zimbabwe using an activity-based costing (ABC) method. STUDY DESIGN AND METHODS: A management accounting approach, based on the ABC method, was used to develop a cost model for blood. The production of blood was broken down into recruitment, collection, testing, processing, and storage plus distribution. Data for the year 2013 were collected retrospectively from budgets, financial and expenditure reports, databases, and interviews with transfusion personnel and managers. All direct and indirect costs, in 2013 US$, were allocated, accordingly, to the activities of blood acquisition. RESULTS: The total cost of producing safe blood in Zimbabwe for the year 2013 was US$8.6 million. Variable costs accounted for 51.2% of the total cost of production. The unit production costs for red blood cells (RBCs) were US$15.94 for recruitment, US$34.62 for collection, US$17.88 for testing, US$11.49 for processing, and US$3.06 for storage plus distribution. The overall cost of production of one unit of whole blood was US$118.42 and RBCs was US$130.94 constituting 12.4 and 13.7% of the country's annual GDP per capita. CONCLUSIONS: The high unit cost of producing blood relative to the annual GDP per capita demonstrates that acquiring safe blood is a burden on the health care sector in Zimbabwe. Introducing additional safety measures, such as nucleic acid amplification testing and pathogen reduction technology, although desirable, will further increase this burden. PMID- 26598798 TI - Effect of Diabetes Mellitus on Survival in Patients with Pancreatic Cancer: A Systematic Review and Meta-analysis. AB - Concurrent diabetes has been linked with an increased risk of death in many cancers, but findings in pancreatic cancer have been inconsistent. We performed a systematic review and meta-analysis to assess the effect of diabetes on survival in patients with pancreatic cancer. Of 4, 463 original articles, 41 were included in the review; 29 studies with 33 risk estimates were included in the meta analysis. In the overall comparison of patients with pancreatic cancer and diabetes with their nondiabetic counterparts, the former had significantly higher all-cause mortality (pooled HR: 1.13; 95% CI: 1.04-1.22). Subgroup analyses showed that diabetes was associated with poor survival in patients with resectable disease (HR: 1.37; 95% CI: 1.15-1.63) but not in those with unresectable disease (HR: 1.07; 95% CI: 0.89-1.29). The HR (95% CI) was 1.52 (1.20-1.93) for patients with new-onset diabetes (<= 2 years of diabetes duration) and 1.22 (0.83-1.80) for those with longstanding diabetes (> 2 years). Diabetes was associated with higher mortality overall in patients with pancreatic cancer. The effect of diabetes on overall survival was associated with the stages of tumor and the duration of diabetes. PMID- 26598801 TI - Nanoring Arrays on Fe Coated Substrate: Formation and Guidance for the Growth of Hierarchical CNTs. AB - In this article, we report the formation of nanoring structures on Fe coated substrate and their application in guiding the growth of carbon nanotube (CNT) patterns with hierarchical structures. The formation of nanorings involves the etching of polystyrene (PS) monolayer colloidal crystals (MCCs) under reactive ion etching (RIE), and the redeposition and cross-linkage of the active degradation products at the contact line between the MCCs and the substrate. After washing out the MCCs, insoluble nanorings with hexagonal order on the substrate are developed. The RIE process can control the morphology of the nanorings, as well as the distribution of the Fe element on the substrate; thus, a continuous Fe layer and separated Fe discs on the substrate are created on substrate after washing, depending on the etching time and the shield of MCCs. The surviving Fe element can work as the catalyst to initiate the in situ growth of aligned CNTs in the following chemical vapor deposition (CVD) process, while the Fe element underneath the nanorings keep its inactivity. Eventually, CNT patterns with hierarchical structures are formed. One level originates from the surviving Fe layer; the other level is templated from the nanoring structures, which cause the blank area in the CNT bundles. PMID- 26598800 TI - A Preliminary Study of the Ability of the 4Kscore test, the Prostate Cancer Prevention Trial-Risk Calculator and the European Research Screening Prostate Risk Calculator for Predicting High-Grade Prostate Cancer. AB - INTRODUCTION: To prevent the overdiagnosis and overtreatment of prostate cancer (PC), therapeutic strategies have been established such as active surveillance and focal therapy, as well as methods for clarifying the diagnosis of high-grade prostate cancer (HGPC) (defined as a Gleason score >=7), such as multiparametric magnetic resonance imaging and new markers such as the 4Kscore test (4KsT). By means of a pilot study, we aim to test the ability of the 4KsT to identify HGPC in prostate biopsies (Bx) and compare the test with other multivariate prognostic models such as the Prostate Cancer Prevention Trial Risk Calculator 2.0 (PCPTRC 2.0) and the European Research Screening Prostate Cancer Risk Calculator 4 (ERSPC RC 4). MATERIAL AND METHODS: Fifty-one patients underwent a prostate Bx according to standard clinical practice, with a minimum of 10 cores. The diagnosis of HGPC was agreed upon by 4 uropathologists. We compared the predictions from the various models by using the Mann-Whitney U test, area under the ROC curve (AUC) (DeLong test), probability density function (PDF), box plots and clinical utility curves. RESULTS: Forty-three percent of the patients had PC, and 23.5% had HGPC. The medians of probability for the 4KsT, PCPTRC 2.0 and ERSPC-RC 4 were significantly different between the patients with HGPC and those without HGPC (p<=.022) and were more differentiated in the case of 4KsT (51.5% for HGPC [25-75 percentile: 25-80.5%] vs. 16% [P 25-75: 8-26.5%] for non-HGPC; p=.002). All models presented AUCs above 0.7, with no significant differences between any of them and 4KsT (p>=.20). The PDF and box plots showed good discriminative ability, especially in the ERSPC-RC 4 and 4KsT models. The utility curves showed how a cutoff of 9% for 4KsT identified all cases of HGPC and provided a 22% savings in biopsies, which is similar to what occurs with the ERSPC-RC 4 models and a cutoff of 3%. CONCLUSIONS: The assessed predictive models offer good discriminative ability for HGPCs in Bx. The 4KsT is a good classification model as a whole, followed by ERSPC-RC 4 and PCPTRC 2.0. The clinical utility curves help suggest cutoff points for clinical decisions: 9% for 4KsT and 3% for ERSPC-RC 4. This preliminary study should be interpreted with caution due to its limited sample size. PMID- 26598802 TI - Screening of HER2 Overexpressed Breast Cancer Subtype In Vivo by the Validation of High-Performance, Long-Term, and Noninvasive Fluorescence Tracer. AB - The high-performance and noninvasive screening of heterogeneous tumor subtypes in vivo is particularly desirable for the diagnosis and symptomatic treatment of cancer. Therefore, we report a near-infrared (NIR) fluorescence tracer "smartly identified HER2" (SI-HER2) for rapid, accurate, and highly specific screening of HER2 overexpressed breast cancer. An antibody against HER2 protein receptor, EP1045Y, was conjugated with NIR emitting CdSeTe/CdS/ZnS QDs via polyhistidine driven self-assembly approach. The further adsorption of black hole quencher 3 on antibody enabled a "turn on" fluorescence response of the fluorescence tracer to HER2 protein receptor. Aside from the capability of differentiating the HER2 overexpressed MCF-7 cells from its counterparts, the fluorescence tracer can also accurately and rapidly identify the HER2 overexpressed breast tumor subtype in two tumors-bearing mouse model, providing a platform for the investigation of advanced pathways to distinguish the different breast cancer subtypes. PMID- 26598803 TI - Concomitant drug-induced liver and skin reactions: An Indian experience. PMID- 26598804 TI - Sexual orientation disparities in smoking vary by sex and household smoking among US adults: Findings from the 2003-2012 National Health and Nutrition Examination Surveys. AB - OBJECTIVE: This study examined whether sexual orientation-related smoking disparities in males and females varied by household smoking behaviors in a nationally representative sample of American adults. METHODS: Data were drawn from the 2003-2012 National Health and Nutrition Examination Surveys, which assessed 14,972 individuals ages 20 to 59years for sexual orientation, current smoking status, and household smoking. Weighted multivariable logistic models were fit to examine whether differences in current smoking status among sexual minority adults compared to heterosexuals was moderated by household smoking and sex, adjusting for covariates. RESULTS: The main effects of identifying as a sexual minority, being male, and living with a household smoker were all associated with a significantly higher odds of being a current smoker. However, there also was a significant three-way interaction among these variables (adjusted odds ratio=3.75, 95% confidence interval: 1.33, 10.54). Follow-up analyses by sex indicated that the interaction between sexual identity and household smoking was significant for both males (AOR=6.40, 95% confidence interval: 1.27, 32.28) and females (AOR=0.43, 95% confidence interval: 0.23, 0.81) but was in the opposite direction. Among males, living with a smoker was associated more strongly with greater odds of smoking among gay and bisexual males, compared to heterosexual males. In contrast, among females, living with a smoker was more strongly associated with greater odds of smoking for heterosexuals compared to lesbians and bisexuals. CONCLUSIONS: Future research is warranted to examine characteristics of households, including smoking behaviors and composition, to guide more effective and tailored smoking cessation interventions for males and females by sexual orientation. PMID- 26598805 TI - Providers' beliefs about the effectiveness of the HPV vaccine in preventing cancer and their recommended age groups for vaccination: Findings from a provider survey, 2012. AB - BACKGROUND: The human papillomavirus (HPV) vaccine was recommended in 2007 by the Advisory Committee on Immunization Practices (ACIP) to preadolescent and adolescent girls. Vaccination initiation was recommended at age 11-12 years with the option to start at age 9. Catchup vaccination was recommended to females aged 13-26 previously not vaccinated. However, vaccination coverage remains low. Studies show that the HPV vaccine can prevent cervical, vulvar, vaginal, anal and some oropharyngeal cancers and that provider recommendation of vaccines can improve low vaccination rates. METHODS: Using data from 2012 DocStyles, an annual, web-based survey of U.S. healthcare professionals including physicians and nurse practitioners (n=1753), we examined providers' knowledge about the effectiveness of the HPV vaccine in preventing cancer and their vaccine recommendation to all age-eligible females (9-26 years). Descriptive statistics and Chi-square tests were used to assess differences across specialties. RESULTS: Knowledge about HPV vaccine effectiveness in preventing cervical cancer was highly prevalent (96.9%), but less so for anal, vaginal, vulvar and oropharyngeal cancers. Only 14.5% of providers recommended the vaccine to all age-eligible females and 20.2% recommended it to females aged 11-26 years. Knowledge assessment of cancers associated with HPV and vaccination recommendations varied significantly among providers (p<0.01). Providers more frequently recommended the vaccine to girls older than 11-12 years. CONCLUSIONS: Improving providers' knowledge about HPV-associated cancers and the age for vaccination initiation, communicating messages focusing on the vaccine safety and benefits in cancer prevention and on the importance of its delivery prior to sexual onset, may improve HPV vaccine coverage. PMID- 26598806 TI - Combined effect of change in humeral neck-shaft angle and retroversion on shoulder range of motion in reverse total shoulder arthroplasty - A simulation study. AB - BACKGROUND: We studied combined effect of change in humeral neck shaft angle and retroversion on shoulder ROM in reverse total shoulder arthroplasty using 3 dimensional simulations. METHODS: Using a 3D model construct based on the CT scans of 3 males and a 3-dimensional analysis program, a humeral component of reverse total shoulder arthroplasty was implanted in 0 degrees , 10 degrees , 20 degrees , 30 degrees ,40 degrees retroversion and 135 degrees , 145 degrees , and 155 degrees neck shaft angle. Total horizontal range of motion (sum of horizontal adduction and abduction) at 30 degrees and 60 degrees scaption, adduction in the scapular plane and IR behind the back were measured for various combinations of neck shaft angle and retroversion. FINDINGS: Change in retroversion didn't show any effect on total horizontal range of motion. Total horizontal range of motion at both 30 degrees and 60 degrees scaption, showed maximum values at 135 degrees neck shaft angle and minimum values at 155 degrees neck shaft angle. With any combination of retroversion angles, adduction deficit was maximum at 155 degrees neck shaft angle and no adduction deficit at 135 degrees neck shaft angle. Every 10 degrees decrease in neck shaft angle resulted in an average 10.4 degrees increase in adduction. For every 10 degrees increase in retroversion, there was loss of internal rotation behind the back up to at least one vertebral level. INTERPRETATION: 135 degrees neck shaft angle resulted in maximum total horizontal range of motion both at 30 degrees and 60 degrees scaption regardless of retroversion angles. 135 degrees neck shaft angle also reduced the chances of scapular impingement. Decrease in retroversion angle resulted in more amount of internal rotation behind the back. PMID- 26598807 TI - Kinematic compensation for wing loss in flying damselflies. AB - Flying insects can tolerate substantial wing wear before their ability to fly is entirely compromised. In order to keep flying with damaged wings, the entire flight apparatus needs to adjust its action to compensate for the reduced aerodynamic force and to balance the asymmetries in area and shape of the damaged wings. While several studies have shown that damaged wings change their flapping kinematics in response to partial loss of wing area, it is unclear how, in insects with four separate wings, the remaining three wings compensate for the loss of a fourth wing. We used high-speed video of flying blue-tailed damselflies (Ischnura elegans) to identify the wingbeat kinematics of the two wing pairs and compared it to the flapping kinematics after one of the hindwings was artificially removed. The insects remained capable of flying and precise maneuvering using only three wings. To compensate for the reduction in lift, they increased flapping frequency by 18+/-15.4% on average. To achieve steady straight flight, the remaining intact hindwing reduced its flapping amplitude while the forewings changed their stroke plane angle so that the forewing of the manipulated side flapped at a shallower stroke plane angle. In addition, the angular position of the stroke reversal points became asymmetrical. When the wingbeat amplitude and frequency of the three wings were used as input in a simple aerodynamic model, the estimation of total aerodynamic force was not significantly different (paired t-test, p=0.73) from the force produced by the four wings during normal flight. Thus, the removal of one wing resulted in adjustments of the motions of the remaining three wings, exemplifying the precision and plasticity of coordination between the operational wings. Such coordination is vital for precise maneuvering during normal flight but it also provides the means to maintain flight when some of the wings are severely damaged. PMID- 26598808 TI - Antimicrobial potentials and structural disorder of human and animal defensins. AB - Defensins are moonlighting peptides which are broadly distributed throughout all the living kingdoms. They play a multitude of important roles in human health and disease, possessing several immunoregulatory functions and manifesting broad antimicrobial activities against viruses, bacteria, and fungi. Based on their patterns of intramolecular disulfide bridges, these small cysteine-rich cationic proteins are divided into three major types, alpha-, beta-, and theta-defensins, with the alpha- and beta-defensins being further subdivided into a number of subtypes. The various roles played by the defensins in the innate (especially mucosal) and adoptive immunities place these polypeptides at the frontiers of the defense against the microbial invasions. Current work analyzes the antimicrobial activities of human and animal defensins in light of their intrinsic disorder propensities. PMID- 26598809 TI - [TINU syndrome: A case report]. PMID- 26598810 TI - Swollen eyelid reveals multiple intracranial hydatid cysts associated with a palpebral cyst. AB - We report a case of a hydatid cyst of the eyelid in a 12-year-old boy associated with cerebral involvement. The patient was initially treated by neurosurgeons for brain cysts. The course after an interval of two months was marked by regression of the palpebral cyst on albendazole. PMID- 26598813 TI - How to Define Family Meals in "Shokuiku" (Food and Nutrition Education). AB - The Japanese government has set 11 targets to promote "Shokuiku." However, among the 11 targets, only two targets (frequency of shared family meals and the proportion of breakfast skipping in children and young men) are quantitative goals. The increase in children eating alone is often lamented in the popular media, but the methodology for identifying the status of family meals ("Kyoshoku"), or how the responses should be validated, is rarely discussed. In the current review, we attempt to clarify how a family meal and survey responses are defined, by searching literature published after 2009, using the following keywords: "family meals" or "shared meals," in the PubMed database for English. For literature published in Japanese, we searched the Igakuchuo-Zassi Database and Google Scholar for relevant studies. In the English literature, questions were likely to focus on whether a dinner or any meal was eaten together with family members living together, while Japanese literature was more focused on "breakfast or dinner" eaten together with family members. The response options varied across different studies, such as the number of family meals a week, or the number of days (per week) these family meals were eaten. We found it quite difficult to compare across the studies, as there is no standardized definition or response options for "family meals." Further studies are needed in order to develop a standardized method to assess the current status of "family meals." PMID- 26598811 TI - [Posterior pole arterial vascular variant]. PMID- 26598814 TI - Beneficial Effects of Camellia Oil (Camellia oleifera Abel.) on Hepatoprotective and Gastroprotective Activities. AB - Epidemiological studies have shown that increased dietary intake of natural antioxidants is beneficial for health because of their bioactivities, including antioxidant and anti-inflammation actions. Camellia oil made from tea seed (Camellia oleifera Abel.) is commonly used as an edible oil and a traditional medicine in Taiwan and China. Until now, the camellia oil has been widely considered as a dietary oil for heath. In this review, we summarize the protective effects of camellia oil with antioxidant activity against oxidative stress leading to hepatic damage and gastrointestinal ulcers. The information in this review leads to the conclusion that camellia oil is not only an edible oil but also a vegetable oil with a potential function for human health. PMID- 26598815 TI - Probiotics as an Immune Modulator. AB - Probiotics are nonpathogenic live microorganism that can provide a diverse health benefits on the host when consumed in adequate amounts. Probiotics are consumed in diverse ways including dairy product, food supplements and functional foods with specific health claims. Recently, many reports suggest that certain probiotic strains or multi strain mixture have potent immunomodulatory activity in diverse disorders including allergic asthma, atopic dermatitis and rheumatoid arthritis. However, underlying mechanism of action is still unclear and efficacy of probiotic administration is quite different depending on the type of strains and the amounts of doses. We and others have suggested that live probiotics or their metabolites could interact with diverse immune cells (antigen presenting cells and T cells) and confer them to have immunoregulatory functions. Through this interaction, probiotics could contribute to maintaining immune homeostasis by balancing pro-inflammatory and anti-inflammatory immune responses. However, the effect of probiotics in prevention or modulation of ongoing disease is quite diverse even within a same species. Therefore, identification of functional probiotics with specific immune regulatory property is a certainly important issue. Herein, we briefly review selection methods for immunomodulatory probiotic strains and the mechanism of action of probiotics in immune modulation. PMID- 26598816 TI - Diversity of Food Allergy. AB - Food allergy is defined as an immune system-mediated adverse reaction to food components. Food allergic reactions are mostly IgE mediated and also known as immediate type hypersensitivity (type I reaction). There are several characteristic clinical types of food allergy, such as Anaphylaxis, Food dependent exercise-induced anaphylaxis (FDEIA), and Oral allergy syndrome (OAS). In addition, food allergy is also classified into two types (class 1 and class 2) based on the pathophysiological mechanism. In the class 2 food allergy, pollen allergy causes plant food allergy; therefore this type of allergy is sometimes called Pollen-food allergy syndrome (PFAS). The risk of food allergy (allergenicity) may vary with the treatment of the food allergens. The formation or status of the causative food affects its allergenicity. Class 1 food allergens are generally heat-, enzyme-, and low pH-resistant glycoproteins ranging in size from 10 to 70 kD. Class 1 food allergens induce allergic sensitization via the gastrointestinal tract and are responsible for systemic reactions. Class 2 food allergens are generally heat-labile, susceptible to digestion, and highly homologous with pollen allergens. Taken together, it may be important to consider the diversity of food allergy in order to fight against food allergy. PMID- 26598817 TI - Food and Natural Materials Target Mechanisms to Effectively Regulate Allergic Responses. AB - An immune hypersensitivity disorder called allergy is caused by diverse allergens entering the body via skin contact, injection, ingestion, and/or inhalation. These allergic responses may develop into allergic disorders, including inflammations such as atopic dermatitis, asthma, anaphylaxis, food allergies, and allergic rhinitis. Several drugs have been developed to treat these allergic disorders; however, long-term intake of these drugs could have adverse effects. As an alternative to these medicines, food and natural materials that ameliorate allergic disorder symptoms without producing any side effects can be consumed. Food and natural materials can effectively regulate successive allergic responses in an allergic chain-reaction mechanism in the following ways: [1] Inhibition of allergen permeation via paracellular diffusion into epithelial cells, [2] suppression of type 2 T-helper (Th) cell-related cytokine production by regulating Th1/Th2 balance, [3] inhibition of pathogenic effector CD4(+) T cell differentiation by inducing regulatory T cells (Treg), and [4] inhibition of degranulation in mast cells. The immunomodulatory effects of food and natural materials on each target mechanism were scientifically verified and shown to alleviate allergic disorder symptoms. Furthermore, consumption of certain food and natural materials such as fenugreek, skullcap, chitin/chitosan, and cheonggukjang as anti-allergics have merits such as safety (no adverse side effects), multiple suppressive effects (as a mixture would contain various components that are active against allergic responses), and ease of consumption when required. These merits and anti-allergic properties of food and natural materials help control various allergic disorders. PMID- 26598818 TI - Novel Physiological Functions of Branched-Chain Amino Acids. AB - Branched-chain amino acids (BCAAs) are essential amino acids for humans and are major building blocks of proteins. Recent studies indicate that BCAAs act not only as components of proteins, but also as nutrasignals. In this review, we summarize the findings of recent studies investigating the physiological functions of BCAAs in the regulation of protein and glucose metabolism and brain function. PMID- 26598819 TI - Peri-Operative Care for Gastrectomy to Enhance Recovery. AB - Gastric cancer is one of the most common gastrointestinal cancer, which gastrectomy offers best curative intent. Multidisciplinary team cares enhance gastrectomy cases fast recovery. PMID- 26598820 TI - Mg, Zn and Cu Transport Proteins: A Brief Overview from Physiological and Molecular Perspectives. AB - Essential major and trace elements, including magnesium (Mg), zinc (Zn) and copper (Cu), are involved in numerous physiological processes. These elements are important components for maintaining proper protein structure and function. They are also used as catalytic cofactors for enzymes and as mediators in signaling cascades. Thus, systemic homeostasis of these metals is sophisticatedly regulated at a molecular level. A balance between absorption and excretion of these metals is critical, and transport proteins play a key role in this balance. In particular, transport proteins in intestinal epithelial cells are indispensable and ensure adequate metal absorption. Regulation of the expression and activity of these proteins is complicated. Thus, dysfunction of these proteins causes an imbalance in the systemic homeostasis of corresponding metals, and thus likely links to disease pathogenesis. In this review, we briefly describe the importance of mammalian metal transport proteins, including Mg channels, and Zn and Cu transporters, focusing on their roles in the absorption process in intestinal epithelial cells. Specifically, TRPM6 channels in Mg absorption, ZIP4 and ZnT1 transporters for Zn absorption, and CTR1 and ATP7A for Cu absorption are overviewed. PMID- 26598821 TI - The Role of Sodium-Dependent Phosphate Transporter in Phosphate Homeostasis. AB - Inorganic phosphate (Pi) is an essential compound for several biologic functions. Pi levels outside the normal range, however, contribute to several pathological processes. Hypophosphatemia leads to bone abnormalities, such as rickets/osteomalacia. Hyperphosphatemia contributes to vascular calcification in patients with chronic kidney disease and hemodialysis patients and is independently associated with cardiac mortality.Pi homeostasis is regulated by the coordinated function of renal and intestinal sodium-dependent phosphate (NaPi) transporters with dietary Pi, parathyroid hormone, 1,25-dihydroxyvitamin D3, and fibroblast growth factor 23. The type II NaPi transporter/SLC34 family, with three members identified to date, is mainly responsible for Pi homeostasis in the body. SLC34A1 and SCL34A3 are predominantly expressed in the kidney, whereas SLC34A2 is expressed in the small intestine. The role of each SLC34 in the body was recently established by studies of gene-targeted mice. Mutation of SLC34A1 causes Fanconi syndrome and mutation of SLC34A3 causes autosomal recessive hereditary hypophosphatemic rickets with hypercalciuria. SLC34A2 is thought to be a major intestinal NaPi transporter and mutation of SLC34A2 causes pulmonary alveolar microlithiasis. A detailed understanding of Pi regulation in the body is important toward maintaining health. PMID- 26598822 TI - Effect of Exericse and Nutrition upon Lifestyle-Related Disease and Cognitive Function. AB - Bray has proposed the "MONA LISA" hypothesis, an acronym for Most Obesities kNown Are Low In Sympathetic Activity indicating that obesity is associated with a relative or absolute reduction in the activity of the thermogenic component of the sympathetic nervous system. Our series of studies have suggested a potential reversibility in ANS activity regulating fat metabolism and appetite control by regular exercise training in middle aged individuals and obese children with depressed ANS activity. In other words habitual exercise plays a vital role in enhancing not only fat and glucose metabolism, but also ANS activities in the prevention of obesity and appetite control. There are growing expectations that too much sitting is a real and substantial risk to health. One of the intriguing findings from these accelerometer measurement studies is that breaks in sedentary time were shown to have beneficial associations with metabolic biomarkers, due possibly to challenging and enhancing autonomic nervous system that regulates body weight and appetite. Recent findings of brain-derived neurotrophic factors (BDNF) seem to have shed some light upon age-related neurodegenerative diseases and appear to influence energy metabolism, appetite and aspects of neuro cognitive function. These data strongly suggest that a lack of exercise as characterized by a sedentary lifestyle and an unhealthy diet may lead to accelerated ageing, diseases of the body and brain, and an overall decline in the quality of life. PMID- 26598823 TI - Role of Exercise and Nutrition in the Prevention of Sarcopenia. AB - The age-associated loss of skeletal muscle mass and strength (sarcopenia) has been shown to increase the risk of injury due to falls and incidence of metabolic complications including insulin resistance and diabetes, which subsequently becomes a significant factor to disability among the elderly population. Nutrient intake is the most important anabolic stimulus for skeletal muscle. Specifically, the amino acid leucine and meal-induced insulin both independently stimulate muscle protein synthesis. However, age-specific changes in muscle anabolic responses to leucine become apparent when sub-maximal amounts of amino acids are administered in older subjects. Furthermore, insulin resistance of muscle protein metabolism with aging has been demonstrated in healthy non-diabetic older subjects. Resistance exercise is another anabolic stimulus which increases myofibrillar muscle protein synthesis in both young and older individuals. The increased muscle anabolism is apparent within 2-3 h after a single bout of heavy resistance exercise and remains elevated up to 2 d following the exercise. The mTOR signaling pathway in skeletal muscle is associated with an increased rate of muscle protein synthesis during the early recovery phase following a bout of resistance exercise. Finally, recent evidence on the cumulative effect of resistance exercise in combination with nutritional supplement on muscle protein metabolism will be discussed to propose a possible preventative measure against sarcopenia. PMID- 26598824 TI - Food Components Modulate Obesity and Energy Metabolism via the Transcriptional Regulation of Lipid-Sensing Nuclear Receptors. AB - Obesity is a major risk factor for chronic diseases such as diabetes, cardiovascular diseases, and hypertension. Many modern people have a tendency to overeat owing to stress and loosening of self-control. Moreover, energy expenditure varies greatly among individuals. Scientific reduction of obesity is important under these circumstances. Furthermore, recent research on molecular levels has clarified the differentiation of adipocytes, the level of subsequent fat accumulation, and the secretion of the biologically active adipokines by adipocytes. Adipose tissues and obesity have become the most important target for the prevention and treatment of many chronic diseases. We have identified various food-derived compounds modulating nuclear receptors, especially peroxisome proliferators-activated receptor(PPAR), in the regulation of energy metabolism and obesity. In this review, we discuss the PPARs that are most important in obesity and energy metabolism. PMID- 26598825 TI - Roles of National and Local Governments and the Dietetic Association in Nutrition Assistance Response to Natural Disasters: Systems and Experiences in Japan and the USA. AB - In the first half of this symposium, the disaster response system in Japan will be introduced. The ultimate aim of nutrition assistance is to keep people in disaster areas healthy. This is a task for the Ministry of Health, Labour and Welfare and the health departments of prefectural governments. Our first speaker, Dr. Yasuhiro Kanatani, National Institute of Public Health, will briefly overview the disaster response system in Japan and its related laws. He will also mention how the Ministry responded to the Great East Japan Earthquake. In the second presentation, I will play one chapter of DVD that we released in last September. In that chapter, Ms. Makiko Sawaguchi, a registered dietitian working for a public health center in the area affected by the Great East Japan Earthquake, talks about her experience in supporting disaster victims. As an employee of Iwate Prefectural Government, she helped affected municipal governments and coordinated outside support. One type of outside support was registered dietitians dispatched by the Japan Dietetic Association (JDA). Dr. Nobuyo Tsuboyama-Kasaoka will report what those dietitians did in the affected areas. She will also explain the aim and training of the JDA-Disaster Assistance Team. Provision of food is essential in nutrition assistance. This is a task for the Ministry of Agriculture, Forestry and Fisheries. Our fourth speaker, Mr. Kunihiro Doi, analyzed the government procurement data and will discuss the limitations of government emergency food supplies and lessons learned from the Great East Japan Earthquake. As for the systems and experiences in the US, we invited Ms. Toni Abernathy from the Office of Emergency Management, Food and Nutrition Service (FNS), United States Department of Agriculture. PMID- 26598826 TI - Immune-Signaling Molecules and Obesity-Induced Inflammation. AB - Obesity-induced inflammation is closely associated with the development of metabolic complications such as insulin resistance and type 2 diabetes. Several immune-signaling receptors and their counterpart ligands are known to be crucial for crosstalk between the adaptive and innate immune system, and they are implicated in various inflammatory pathologies. In this mini-review, I will discuss the involvement of the immune costimulatory molecule 4-1BB and its ligand in obesity-induced inflammation and metabolic complications. PMID- 26598827 TI - Positive and Negative Aspects of Food with Health Claims in Japan. AB - Developments in food science and technology have accelerated the production and availability of health foods. Although consumers may acquire health benefits from some products, they may also suffer adverse health effects and economic losses. Unlike medicine, which is administered by health professionals, foods are chosen directly by the consumer and can be used at their own discretion. Food labeling plays a major role in providing consumers with proper information when choosing the desired products; however, the food labeling system is complex and inadequately understood by consumers. Moreover, there are some products that do not follow food labeling laws and contain ingredients that have not undergone proper effectiveness and safety evaluations. With the increasing popularity of health foods, it is becoming more important to ensure that they are effective and safely used. The biggest concern is that some consumers may mistake health foods for medicines that can cure or prevent diseases. The main reason that consumers are confused and misled is due to the vast amount of information that is available. This paper provides an overview of the following four approaches that we have taken in order to develop countermeasures against health foods being used improperly by consumers: (1) conducting a survey of actual health food use; (2) collecting data on adverse events suspected to be caused by health foods, and evaluating the causal relationship with methods suited to investigating health foods; (3) examining the safety of natural ingredients used in health foods; and (4) constructing an online database that compiles information on the safety and effectiveness of health foods and/or ingredients, and sharing such information with consumers and health professionals. PMID- 26598828 TI - US Dietary Supplement Labeling Rules and the Possibility of Medical Cost Reduction. AB - US dietary supplements classified as foods are regulated under the Dietary Supplement Health and Education Act (DSHEA) and other rules. After the DSHEA established in 1994, the supplement market grew by about 4 times and reached $32 billion as of 2012. One of the major reasons for this market expansion is that consumers can recognize functions of the supplements by the structure/function (S/F) claims. S/F claims must not be false or misleading, and must be based upon reliable scientific evidence, especially clinical studies. At the same time, disclaimers must be shown on the package, which are "These statements have not been evaluated by the Food and Drug Administration (FDA). These products are not intended to diagnose, treat, cure or prevent any disease." Both the FDA and Federal Trade Commission (FTC) are responsible for label claims and advertisement of dietary supplements. S/F claims are not medical claims, but these may have impact on people's mindset to be healthier. Recent research shows utilizing dietary supplements in 4 major areas with 10 popular ingredients could hypothetically reduce medical costs by over $50 billion in the US in the period of 2013-2020. Predicted fewer health problems and reduced medical cost information will further increase awareness of supplement usage and thus may raise quality of life. These may reduce the medical cost significantly, if the products are used appropriately with sufficient consumer education. PMID- 26598829 TI - Osteoporosis and Lifestyle. AB - Skeletal tissue is formed during the first two decades of life; then a constant bone mass is maintained until 40 y of age. In the case of women, the bone mass is rapidly reduced at menopause at around 50 y of age. After that, bone mass slowly decreases in both men and women who have passed the 70-y-old mark. The National Institute of Health Consensus Conference adopted the definition of osteoporosis as a skeletal disorder that is characterized by compromised bone strength leading to a predisposition for and an increased risk of fracture. Since osteoporotic fractures are the third-highest cause for becoming bedridden, the maintenance of healthy bones is an important factor in extending a person's healthy lifespan. Bone mass is influenced by many factors, such as nutrition, physical activity, smoking and alcohol intake, as well as by genetic factors. Thus, a healthy diet providing balanced nutrients including calcium, vitamin D, vitamin K and protein, regular physical activity, and not smoking help maintain bone health and delay or prevent osteoporosis. Some functional foods containing soy isoflavones, milk basic protein and n-3 fatty acid may help promote bone health. PMID- 26598830 TI - Responsibilities of the USDA-Food and Nutrition Service in Nutrition Assistance Response to Natural Disasters. AB - USDA makes sure that nutritious USDA Foods are made available to States, Indian Tribal Organizations and Emergency Feeding Organizations to help feed survivors of natural disasters and other emergencies when needed. PMID- 26598831 TI - Effects of Soy Phytoestrogens and New Zealand Functional Foods on Bone Health. AB - New Zealand is a rich source of food components that may have bioactivity on bone. Docosahexaenoic acid (DHA) from fish oil has been shown to maintain bone in ovariectomised (OVX) rats. Kiwifruit, a source of fibre and carotenoids, may also affect bone via a prebiotic as well as direct cell-based mechanisms. We aimed to 1) ascertain the effects of DHA on two cell models, including interactions with soy isoflavones; 2) and investigate the specific effects of carotenoids from kiwifruit as well as whole kiwifruit in cell-based and rodent models as well as in a human study. RAW 264.7 mouse monocytes or mouse bone marrow was used to generate osteoclasts (OC). Cells were exposed to the agents between 5 and 21 d and formation and activity of OC measured, including molecular markers. DHA inhibited OC formation in both cell models, including expression of cathepsin K, NFATc1 as well as actin ring formation. Combination with isoflavones enhanced these effects. In OVX rats and mice fed with kiwifruit for 8 wk, green kiwifruit reduced the rate of bone loss after OVX, and in mice it reduced C-telopeptide of Type 1 collagen (CTX) levels and RANKL expression while in menopausal women, green kiwifruit affected blood lipids and bone markers positively. PMID- 26598832 TI - True Niacin Deficiency in Quinolinic Acid Phosphoribosyltransferase (QPRT) Knockout Mice. AB - Pyridine nucleotide coenzymes (PNCs) are involved in over 500 enzyme reactions. PNCs are biosynthesized from the amino acid L-tryptophan (L-Trp), as well as the vitamin niacin. Hence, "true" niacin-deficient animals cannot be "created" using nutritional techniques. We wanted to establish a truly niacin-deficient model animal using a protocol that did not involve manipulating dietary L-Trp. We generated mice that are missing the quinolinic acid phosphoribosyltransferase (QPRT) gene. QPRT activity was not detected in qprt(-/-)mice. The qprt(+/+), qprt(+/-) or qprt(-/-) mice (8 wk old) were fed a complete diet containing 30 mg nicotinic acid (NiA) and 2.3 g L-Trp/kg diet or an NiA-free diet containing 2.3 g L-Trp/kg diet for 23 d. When qprt(-/-)mice were fed a complete diet, food intake and body weight gain did not differ from those of the qprt(+/+) and the qprt(+/-) mice. On the other hand, in the qprt(-/-) mice fed the NiA-free diet, food intake and body weight were reduced to 60% (p<0.01) and 70% (p<0.05) of the corresponding values for the qprt(-/-) mice fed the complete diet at day 23, respectively. The nutritional levels of niacin such as blood and liver NAD concentrations were also lower in the qprt(-/-) mice than in the qprt(+/+) and the qprt(+/-) mice. Urinary excretion of quinolinic acid was greater in the qprt( /-) mice than in the qprt(+/+) and the qprt(+/-) mice (p<0.01). These data suggest that we generated truly niacin-deficient mice. PMID- 26598833 TI - Regulation of Folate-Mediated One-Carbon Metabolism by Glycine N Methyltransferase (GNMT) and Methylenetetrahydrofolate Reductase (MTHFR). AB - Folate-mediated one-carbon metabolism is an important therapeutic target of human diseases. We extensively investigated how gene-nutrient interactions may modulate human cancer risk in 2 major folate metabolic genes, MTHFR and GNMT. The biochemical impacts of MTHFR and GNMT on methyl group supply, global DNA methylation, nucleotide biosynthesis, DNA damage, and partitioning of the folate dependent 1-carbon group were carefully studied. The distinct model systems used included: EB virus-transformed lymphoblasts expressing human MTHFR polymorphic genotypes; liver-derived GNMT-null cell-lines with and without GNMT overexpression; and HepG2 cells with stabilized inhibition of MTHFR using shRNA, GNMT wildtype, heterozygotous (GNMT(het)) and knockout (GNMT(nul)) mice. We discovered that the MTHFR TT genotype significantly reduces folate-dependent remethylation under folate restriction, but it assists purine synthesis when folate is adequate. The advantage of de novo purine synthesis found in the MTHFR TT genotype may account for the protective effect of MTHFR in human hematological malignancies. GNMT affects transmethylation kinetics and S-adenosylmethionine (adoMet) synthesis, and facilitates the conservation of methyl groups by limiting homocysteine remethylation fluxes. Restoring GNMT assists methylfolate-dependent reactions and ameliorates the consequences of folate depletion. GNMT expression in vivo improves folate retention and bioavailability in the liver. Loss of GNMT impairs nucleotide biosynthesis. Over-expression of GNMT enhances nucleotide biosynthesis and improves DNA integrity by reducing uracil misincorporation in DNA both in vitro and in vivo. The systematic series of studies gives new insights into the underlying mechanisms by which MTHFR and GNMT may participate in human tumor prevention. PMID- 26598834 TI - Environmental Interventions for Obesity and Chronic Disease Prevention. AB - Innovative approaches are needed to impact obesity and other diet-related chronic diseases, including tested interventions at the environmental and policy levels. We have conducted multi-level community trials in low-income minority settings in the United States and other countries that test interventions to improve the food environment, support policy, and reduce the risk for developing obesity and other diet-related chronic diseases. All studies have examined change from pre- to post study, comparing an intervention with a comparison group. Our results have shown consistent positive effects of these trials on consumer psychosocial factors, food purchasing, food preparation and diet, and, in some instances, obesity. We have recently implemented a systems science model to support programs and policies to improve urban food environments. Environmental interventions are a promising approach for addressing the global obesity epidemic due to their wide reach. Further work is needed to disseminate, expand and sustain these initiatives through policy at the city, state and federal levels. PMID- 26598835 TI - Functions of Cholesterol Metabolites. AB - Cholesterol is a major component of membrane lipids. Thus, adjusting the membrane cholesterol composition is essential for maintaining cellular homeostasis. Cholesterol biosynthesis and uptake by LDL receptors are tightly regulated at the transcriptional level through negative feedback control, which is mediated by sterol regulatory element-binding proteins (SREBPs). In particular, SREBP-2 is activated in a cholesterol-dependent manner and, thus, is significantly involved in regulating the expression of those genes associated with cholesterol metabolism. Cholesterol metabolites such as oxysterols are involved in regulating sterol metabolism by binding to the nuclear receptor, liver X receptor (LXR). Cholesterol catabolites, i.e., bile acids, are agonists for another nuclear receptor, farnesoid X receptor (FXR), and a bile acid receptor, TGR5. Activated FXR regulates bile acid metabolism and TGR5 improves glucose metabolism through the actions of glucagon-like peptide-1 (GLP-1). PMID- 26598836 TI - Navigating the Shallows and Rapids of Cholesterol Synthesis Downstream of HMGCR. AB - Cholesterol is vital for human life, but its levels must be tightly regulated. Too little cholesterol leads to developmental disorders, but too much is widely appreciated as contributing to heart disease. Levels are regulated through the coordinated control of cholesterol synthesis, uptake and efflux. Here, we focus on cholesterol synthesis. The cholesterol synthesis pathway involves more than twenty enzymes, but most research so far has focused on a very early enzyme, 3 hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), a well characterised control point. This is largely because HMGCR is the target of the successful cholesterol-lowering drugs, the statins. Our recent work has examined several other enzymes in the pathway and revealed complex regulatory mechanisms that also contribute to the control of cholesterol synthesis. In this review, we discuss the transcriptional regulation of the two terminal enzymes, 7- and 24 dehydrocholesterol reductase (DHCR7 and DHCR24), where we have found that a cooperative transcriptional program exists. We also discuss the post translational regulation of another critical enzyme, squalene monooxygenase (SM), which has its protein levels controlled by cholesterol, and DHCR24, which has its activity affected by sterols and related compounds, as well as via phosphorylation/signalling. There is an unforeseen complexity in the regulation of cholesterol synthesis which requires further investigation. PMID- 26598837 TI - Lipid Nutrition and Healthy Aging. AB - Bioactive food factors are considered to be critical for health promotion and play an important role in the prevention of lifestyle-related diseases. Metabolic syndrome, a typical common disease, is a cluster of metabolic disorders, such as abdominal obesity, the combination of hypertriglyceridemia and lower level of HDL, hypertension and diabetes mellitus, that contribute to increased cardiovascular morbidity and mortality. In addition, the incidence of metabolic syndrome and non-alcoholic fatty liver disease (NAFLD) is closely linked with the increase in inflammation and the disorders of lipid metabolism. The pathogenesis of metabolic syndrome and related diseases is complicated. However, food factors have been recognized as contributing factors in the development and prevention of these diseases. Provocative evidence profoundly supports the preventive role of dietary bioactive lipids, polyphenols and other food ingredients. Recent studies suggest the central role of nuclear transcription factors in the pathogenesis of obesity and NAFLD. The goal of the present symposium is to enhance our understanding of cellular and molecular effects of bioactive food factors against obesity related pathogenesis. PMID- 26598838 TI - Functional Lipids in Metabolic Syndrome. AB - Metabolic syndrome is a cluster of metabolic disorders that contribute to increased cardiovascular morbidity and mortality. Although the pathogenesis of metabolic syndrome is complicated, dietary lipids have been recognized as contributory factors in the development and the prevention of cardiovascular risk clustering. We investigated the physiological functions and molecular actions of functional lipids, especially omega3-polyunsaturated fatty acid (PUFA)-containing lipids, in the development of metabolic syndrome using obese model animals. Feeding of omega3-PUFA-containing lipids, such as eicosapentaenoic acid, docosapentaenoic acid, docosahexaenoic acid, tetracosahexaenoic acid, and omega3 phosphatidylcholine, alleviated hepatic lipid accumulation through the suppression of lipogenic gene expression in the liver. Additionally, dietary omega3-PUFA-containing lipids increased serum adiponectin levels in obese animal models. Their molecular actions in the prevention and alleviation of metabolic syndrome could be attributed to the regulation of the activity or abundance of several transcriptional factors in the liver and adipose tissue. Dietary functional lipids would be useful to prevent or alleviate metabolic syndrome in obese animals. In particular, the function of omega3-containing lipids as dietary adiponectin inducers deserves attention with respect to alleviation of metabolic syndrome by dietary manipulation. PMID- 26598839 TI - The Japan Society for Innovative Cuisine: Exploring New Visions of Japanese Cuisine. AB - Kyoto cuisine has a long history and its traditions have been practiced for hundreds of years. In Kyoto, a group of scientists and renowned chefs strives to better understand traditional Kyoto cuisine in order to foster culinary innovation within traditional Kyoto cuisine. We launched a research project in April 2009 using a specially equipped "laboratory-kitchen" located in Kyoto University. Chefs chose a variety of topics related to basic concepts and techniques for cooking. We conducted culinary experimentation, thorough analysis, and diligent discussion on each topic for approximately 6 mo. In the symposium, chefs will present the results of their experiments, discussing their techniques and bringing samples of final products. PMID- 26598840 TI - Continuity and Change: Kyoto Chefs Engage with Science. AB - Kyoto's chefs have reacted proactively to changes brought about by the most recent phase of globalization, hoping to ensure the continued existence and resonance of Kyoto cuisine by using science to adapt it to contemporary circumstances. These chefs are breaking new ground in their pursuit of a scientific understanding of how Kyoto cuisine works. They meet once a month in a kitchen laboratory at Kyoto University to present and analyze culinary experiments in keeping with a predetermined theme. They use their acquired knowledge to more precisely hone their culinary skills and to explain Kyoto cuisine to a global audience. Chefs visit local elementary schools, appear on national television, and welcome chefs from abroad into their kitchens so that people across the world will better understand what authentic Kyoto cuisine consists of. Although these chefs' efforts are groundbreaking, there is also remarkable continuity to their approach. Not only has Kyoto cuisine always been in a steady state of transformation, but the chefs in the Laboratory are engaging with science and a global audience specifically so that they can ascertain Kyoto cuisine's continued existence and importance. Though their means of understanding and articulating what Kyoto cuisine is differs from that of their predecessors, concepts like shun (seasonality) and hin (refinement) still guide chefs today. Ultimately, then, based on interviews and participant observation conducted in and outside of the Japanese Cuisine Laboratory in 2012 and 2013, I argue that by engaging with contemporary food science, Kyoto's chefs achieve a strategic balance of protecting their culinary heritage while adapting it to contemporary circumstances. PMID- 26598841 TI - Product Structuring for Sodium Reduction. AB - Salt is an essential ingredient to enhance the flavour of food products. However, high salt intake has been linked to cardiovascular diseases. Methods to reduce salt in food products based on product structuring have gained increasing attention in the past few years. These methods attempt to deliver as much salt as possible from the food products to the taste buds without increasing the salt content in the products. This paper gives a brief review of the different product structuring methods that influence how the salt is released from the food matrix and/or how the salt is transported to the taste receptors. PMID- 26598842 TI - Protein/Polysaccharide Electrostatic Complexes and Their Applications in Stabilizing Oil-in-Water Emulsions. AB - Consumers are becoming increasingly fastidious in demanding food products with improved quality and functionality. This largely relies on rational design of food structures. As the two key food ingredients, protein and polysaccharides play important roles in food structuring. The combination of protein and polysaccharide provides rich opportunities for food structure and function designs through molecular interaction and assembly. This paper provides a brief review on the formation and characterization of protein/polysaccharide electrostatic complexes and their applications in stabilizing oil-in-water emulsions, particularly those containing polyunsaturated fatty acids. PMID- 26598843 TI - Monitoring Obesity Trends in Health Japan 21. AB - Prevention of non-communicable diseases is more important than ever especially for the elderly to live a healthy life in the super-aged society of Japan. In 2000, the Ministry of Health, Labor and Welfare of Japan started Health Japan 21 as goal-oriented health promotion plan like Healthy People in the US and the Health of the Nation in the UK. Its second term started in 2013 with the aim of prolonging healthy life expectancy and reducing health inequalities. Improvement in both individuals' lifestyle and their social environment will help achieve the goal of the 2nd Health Japan 21. The National Health and Nutrition Survey (NHNS) is conducted every year to monitor the health and nutritional situation of the Japanese using a representative population. The NHNS data are useful for target setting and evaluation of the 2nd Health Japan 21, and the NHNS has shown an increasing trend of overweight (BMI>=25) only for male adults in the most recent 10 y. In contrast, the dietary intake survey of the NHNS shows a decreasing trend of total energy intake both in male and female adults aged 69 y old or younger, and the trend for physical activity is not well known. Thus, we need further investigations on the causes of the obesity trend in Japan. PMID- 26598844 TI - Cardiovascular Diseases and Fat Soluble Vitamins: Vitamin D and Vitamin K. AB - Recently, the associations between insufficiency of fat soluble vitamins and cardiovascular diseases (CVDs) have been reported. Vitamin D affects the cardiovascular system via several pathways, such as suppression of parathyroid hormone, the renin- angiotensin-aldosterone system and vascular endothelial growth and the immune system. Cross-sectional and longitudinal studies have shown the association between the concentration of serum 25-hydroxyvitamin D (25OHD), which is a vitamin D metabolite indicating nutritional vitamin D status, and hypertension, myocardial infarction, heart failure and CVD mortality. On the other hand, the association between vitamin K status and CVDs, especially vascular calcification, has been also reported. Cross-sectional and cohort studies show that high vitamin K status is associated with reduced coronary artery calcification, CVDs and mortality risk. Epidemiological and basic studies indicate that vitamin K possesses a benefit in the prevention of the progression of coronary artery calcification via activation of matrix-gla protein (MGP). While these data in epidemiological and basic studies suggest the protective role of vitamin D and K in CVDs, the benefits of supplementation of both vitamins have not been validated in randomized controlled trials. Further basic and interventional studies are needed to confirm the benefit of both vitamins in protection against CVDs. PMID- 26598845 TI - Niacin and Chronic Kidney Disease. AB - Chronic kidney disease (CKD) is an increasing problem worldwide. The number of end-stage renal disease patients requiring treatment by dialysis is estimated to be increasing by 10,000 patients per year in Japan. Furthermore, an estimated 13 million people are living with CKD in Japan. Various complications are associated with CKD, including cardiovascular disease (CVD). More than one-third of CKD patients die from CVD. Thus, prevention of CVD is a primary concern for the treatment of CKD patients. CKD-mineral and bone disorder (CKD-MBD) is a serious complication that typically leads to CVD. Hyperphosphatemia is thought to be a central-risk factor for CKD-MBD. Therefore, managing hyperphosphatemia is crucial to prevent CKD-MBD and CVD. It is difficult to achieve the target serum phosphate level through dietary modifications alone in patients with hyperphosphatemia, because most foods contain phosphate. Thus, phosphate binders such as calcium carbonate are commonly prescribed to CKD patients with hyperphosphatemia, but these have undesirable side effects. Inhibition of intestinal phosphate transport activity has also been investigated as an alternative approach for controlling serum phosphate levels in CKD patients. Nicotinamide, which is the amide of niacin, can inhibit intestinal phosphate transport. Niacin and related compounds have also been developed as drugs for hyperlipidemia conditions, especially hypertriglyceridemia with low high-density lipoprotein. This type of dyslipidemia is frequently observed in CKD patients and is a modifiable risk factor for CVD. Thus, niacin and related compounds may have utility for the treatment of both hyperphosphatemia and dyslipidemia in CKD patients to prevent CVD. PMID- 26598846 TI - The Issue of Nutrition in an Aging Society. AB - Viewed from a global perspective, Japan is often considered a country where the progression towards a low birthrate and longevity has been prominent. In 2007, the ratio of the aged population reached 21.5%, propelling Japan into the classification of a super aging society. The long-term care insurance system in Japan was initiated in the year 2000, as a general long-term care service system for the whole society, covering the nutrition, medical care, and welfare fields. The goal of nutrition in an aged society is the extension of healthy life expectancy. The ratio of elderly citizens with malnutrition is high. Due to the loss of teeth, and a decrease in digestive and physical functions, there is often a decrease in appetite, and the inability to obtain enough nutrition for physical homeostasis is related to such conditions as frailty and the partial loss of physical functions due to sarcopenia, as well as a decrease in the quality of life (QOL). The elderly can easily fall into a state of protein and energy malnutrition (PEM), due to a variety of causes. Accordingly, it is important to adopt an appropriate approach that ensures a correct understanding of the causes of malnutrition and the special characteristics of malnutrition in the elderly. PMID- 26598847 TI - Improving Clinical Outcome in the Nutritional Management of Sarcopenia at the National Center for Geriatric Health and Research Institute (NCGH-RI), Philippines. AB - Background: One of the National Center for Geriatric Health-Research Institute (NCGH-RI) mission is to be the leader in innovative health care approaches to improve the quality of life of the Senior Citizens in the country, and one of its strategies to attain its mission is to look into at how it can promote clinical outcomes in conditions that are prevalent in this population. One such condition that has been identified is "Sarcopenia" which up to this point has been the subject of intensive research both in basic and clinical levels. However, it is still not part of the daily routine clinical experience of medical providers both in the ambulatory or out-patient and acute or in-patient encounter. To achieve this, the NCHG-RI has included it in the screening for geriatric syndromes using the Comprehensive Geriatric Assessment (CGA). PMID- 26598848 TI - Nano-Science-Engineering-Technology Applications to Food and Nutrition. AB - Nanoscale Science, Engineering and Technology are applied to Food and Nutrition. Various delivery systems include nanoemulsions, microemulsions, solid lipid nanoparticles, micelles, and liposomes. The nanoscale systems have advantages, such as higher bioavailabitity, and other physicochemical properties. The symposium will provide an overview of the formulation, characterization, and utilization of nanotechnology-based food and nutrition. PMID- 26598849 TI - Micronutrient Fortification of Food: Issues for Asia. AB - More than 2 billion individuals globally suffer some degree of deficiency of one or more micronutrients, with the largest numbers in Africa and Asia. Fortification of foods with vitamins and minerals is a proven public health intervention. In Asia, salt iodization, fortified flour and condiments such as fish sauce and soy sauce are reaching hundreds of millions. However, many individuals still do not have adequate intakes of numerous micronutrients, and better fortification strategies and practices will help to alleviate these deficiencies. The International Life Sciences Institute (ILSI) has supported research and scientific dialog about technical and health issues related to micronutrients. Recent studies have indicated widespread vitamin D deficiency among children in SE Asia, and in India. A new trial shows the efficacy of vitamin D-fortified milk in addressing deficiencies, which may have applicability in school feeding programs in India and other parts of Asia. Infant nutrition is also critical, and complementary foods can play an important role after exclusive breastfeeding in providing critical nutrients. A formulation developed in China, Ying Yang Bao, has shown significant reduction of anemia and improved growth in infants. Fortification in Asia has the potential to greatly reduce micronutrient deficiencies and improve health, but more structured efforts are needed to achieve these goals. PMID- 26598851 TI - Industry Approach to Nutrition-Based Product Development and Reformulation in Asia. AB - In the recent years there has been a proliferation of initiatives to classify food products according to their nutritional composition (e.g., high in fat/sugar) to better guide consumer choices and regulate the food environment. This global trend, lately introduced in Asia as well, utilizes nutrient profiling (NP) to set compositional criteria for food products. Even though the use of NP to set targets for product reformulation has been proposed for years, to date only two NP systems have been specifically developed for that purpose. The majority of the NP applications, especially in Asia, focus on marketing and/or health claim regulation, as well as front-of-pack labeling. Product reformulation has been identified, by the World Health Organization and other official bodies, as a key tool for the food industry to help address public health nutrition priorities and provide support towards the reduction of excessive dietary sugar, salt and fats. In the United Kingdom, the Responsibility Deal is an excellent example of a public-private collaborative initiative that successfully reduced the salt content of products available in the supermarkets by 20-30%, resulting in an estimated 10% reduction in salt intake at the population level. Validation of NP systems targeted towards reformulation supports the hypothesis that, by adopting them, the industry can actively support existing policies in the direction of lowering consumptions in public health-sensitive nutrients. The symposium presented a discussion on the current NP landscape in Asia, the importance of reformulation for public health and the Nestle approach to improve the food environment in Asia through NP. PMID- 26598852 TI - Dietary Intake Research in Asian Children: Significance and Challenges. AB - Food intake studies have a long history. However, until a few decades ago, there was limited quantitative data on feeding patterns and food intake in infants and children living in South Asia. The recent SEANUT study and MING study have provided several new insights into the dietary patterns of children living in China, Indonesia, Malaysia, Thailand and Vietnam. The complexity and variety of Asian diets makes the collation of dietary information a challenge. The double burden of under-nutrition and over-nutrition is prevalent in many Asian countries. Compared to obesity, stunting is widespread in South East Asia. Our future challenge is to develop food intake assessment techniques which can be refined and made available as a common dietary assessment tool across this region. Successful nutritional intervention can only be achieved if we know what Asian children eat. Dietary intake research will be a key factor in realizing our goal to eradicate malnutrition in this region. PMID- 26598853 TI - Role of Protein and Amino Acids in Infant and Young Child Nutrition: Protein and Amino Acid Needs and Relationship with Child Growth. AB - Over a third of all deaths of children under the age of five are linked to undernutrition. At a 90% coverage level, a core group of ten interventions inclusive of infant and young child nutrition could save one million lives of children under 5 y of age (15% of all deaths) (Lancet 2013). The infant and young child nutrition package alone could save over 220,000 lives in children under 5 y of age. High quality proteins (e.g. milk) in complementary, supplementary and rehabilitation food products have been found to be effective for good growth. Individual amino acids such as lysine and arginine have been found to be factors linked to growth hormone release in young children via the somatotropic axis and high intakes are inversely associated with fat mass index in pre-pubertal lean girls. Protein intake in early life is positively associated with height and weight at 10 y of age. This paper will focus on examining the role of protein and amino acids in infant and young child nutrition by examining protein and amino acid needs in early life and the subsequent relationship with stunting. PMID- 26598854 TI - Role of Protein and Amino Acids in Infant and Young Child Nutrition: Considerations for the Development and Delivery of High Quality Complementary Food Supplements. AB - Prevention of malnutrition in infants and children is multifaceted and requires the following: access to and intake of nutritious food starting at birth with exclusive breastfeeding for the first 6 mo of life, continued breastfeeding in combination with complementary foods from 6-24 mo of age, access to clean drinking water and sanitation, and access to preventive and curative health care (including prenatal). Nutrient-dense complementary foods can improve nutritional status and have long-term benefits; however, in a review of plant-based complementary foods in developing countries, most of them failed to meet many micronutrient requirements. There is need to provide other cost-effective alternatives to increase the quality of the diet during the complementary feeding stage of the lifecycle. This paper provides an overview of the development, testing, efficacy and effectiveness of the delivery of KOKO Plus on the growth and nutritional status of infants 6-24 mo of age. PMID- 26598856 TI - Micronutrient Deficiency Control in Vietnam from Policy and Research to Implementation: Keys for Success, Challenges and Lessons Learned. AB - Micronutrient deficiencies are still a public health problem in Vietnam. The Government of Vietnam has taken several steps to improve the situation through issuing supportive policy documents over the last several decades. Food fortification is an important complementary strategy to help bridge the nutrient gap in the population. Currently technical regulations are in place and food fortification is taking place on a voluntary basis, along with other complementary targeted programs including home fortification of complementary foods with micronutrient powders and a communications campaign to reach adolescent girls. These have been built on innotative partnerships with industries on a voluntary, market basis. Other innovative targeted nutrition programs are also being piloted, including a micronutrient supplement project in four provinces and a campain to reach adolescent girls through sports. High level political commitment and resources is a crucial element to scale up in Vietnam. A micronutrient survey planned in 2015 will help provide the evidence to support a possible mandatory decree on food fortification. Vietnam has built a solid foundation in order to scale up its national food fortification program in the future to reach the majority of the population with improved intakes of iron, vitamin A, zinc, and iodine. PMID- 26598857 TI - DOHaD (Developmental Origins of Health and Disease) and Birth Cohort Research. AB - Epidemiological and animal experimental studies are disclosing that the malnutrition or overnutrition in utero would induce epigenetic changes of fetus, what is the origin of lifestyle-related disease in adult. Representative birth cohorts studies in DOHaD are explained. PMID- 26598858 TI - Role of School Meal Service in Nutrition. AB - School meal service programs are essential for children's long-term nutrition and health promotion. The programs vary in content, depending on the economic condition, health condition and the food supply situation in each country. Children are encouraged to improve their nutrition, and choose healthy foods and learn good dietary habits through school meals and nutrition education. In Japan, the school lunch program started in 1889. The percentage of elementary schools serving school lunches had reached 99.2% in 2014, and the Nutrition Teacher system started in 2004. Nutrition teachers are to play the roles of teachers on food and nutrition education in addition to managers of foodservice operations in schools. Nutrition teachers are expected to have effects on school nutrition programs by providing meal service together with nutrition education. And so, significant effort is needed from both academia and the field to raise the related nutritional issues. PMID- 26598859 TI - Functional Food Science in Japan: Present State and Perspectives. PMID- 26598860 TI - Leptin and the Regulation of Food Intake and Body Weight. PMID- 26598862 TI - Multi-Stakeholders and Multi-Strategic Approaches for Food and Nutrition Security. PMID- 26598863 TI - Chemistry and Safegurding Marine Resources from Natural Contaminants. PMID- 26598864 TI - The Early Life Origins of Non-Communicable Diseases: An Overview of Recent Advances. PMID- 26598865 TI - Nutrition and Health Promotion--From Molecular to Physiological Modulation. PMID- 26598866 TI - There Is an Obesity Metabolic Program in Muscle. PMID- 26598867 TI - Nutrigenomics and Nutrigenetics: the New Paradigm for Optimising Health and Preventing Disease. PMID- 26598868 TI - Why Do Behavior Interventions Fail? Insights from Behavioral Economics. PMID- 26598870 TI - Obesity Epidemic in Asia: Issues and Challenges. PMID- 26598869 TI - The Impact of Overweight and Obesity on Adolescence: Consequences on Metabolic Biomarkers. PMID- 26598871 TI - Nutrient Standards. PMID- 26598872 TI - Food-Based Dietary Guidelines of Southeast Asia: An Analysis of Key Messages. PMID- 26598873 TI - Food and Nutrition Security for Healthy Aging. PMID- 26598874 TI - The School Meal System and School-Based Nutrition Education in Korea. AB - Since the school meal was first served in Korea in 1953, there have been many changes, particularly during the last decade. Recently, the representative features of the school meal system became free school meals for all pupils in elementary school and a nutrition teacher system in schools. These policies were suggested to implement more and more the educational role of the school meal. The rate of schools serving school meals reached 100% as of 2013, and 99.6% students eat a school meal each school day. Nutrition teachers were assigned to schools from 2007, and 4,704 (47.9%) nutrition teachers of all nutrition employees were employed in schools as of 2013. At present, various nutrition education materials are being development by local education offices and government agencies, and various education activities are being implemented spiritedly. The ultimate goal of school meals and school-based nutrition education are as follows: 1) improvement of the health of students; 2) promotion of the traditional Korean diet; and 3) extension of opportunities for a healthier dietary life. PMID- 26598875 TI - Food Composition Tables of Japan and the Nutrient Table/Database. AB - A global food composition database has been constructed by the United Nations Food and Agriculture Organization (FAO) based on food composition tables from every country in the world. To improve this database, the FAO has organized the International Network of Food Data Systems (INFOODS). The most recent version of the food composition table for Japan was published by the Ministry of Education, Culture, Sports, Science and Technology and is presented in three books: "Standard Tables of Food Composition Japan-2010-," "Fatty Acid Composition of Foods-2005-," and "Amino Acid Composition of Foods-2010-." The Standard Tables of Food Composition in Japan-2015- (Energy, General Components, Minerals, Vitamins, etc. Section; Fatty Acids Section; Amino Acids Section; Carbohydrates Section) will be published in 2015 and is expected to play an important role as one of the main tables of the East Asia food composition tables. PMID- 26598876 TI - Advances in Food Composition Tables of Japan--Amino Acid, Fatty Acid and Available Carbohydrate Tables. AB - The new revised version of the Standard Tables of Food Composition in Japan (STFCJ 2015) will be published in 2015. The aim of the present paper is to share information on issues we have encountered during the revision. New analytical data on amino acid composition will be provided for approximately 230 foods, fatty acid composition for approximately 140 foods, and available carbohydrate (starch, glucose, fructose, sucrose, maltose, and lactose) composition for approximately 340 foods. These data will be published separately as three supplements to the STFCJ 2015: amino acid tables, fatty acid tables, and available carbohydrate tables. Available carbohydrate tables will also provide polyol (sorbitol and mannitol) and organic acid (acetic acid, lactic acid, citric acid, etc.) data. In the supplements, amino acid content will be adjusted for protein content calculated as reference nitrogen multiplied by a nitrogen to protein conversion factor, and fatty acid content adjusted for extractable lipid content, as in previous revisions. Available carbohydrate content, however, will be adjusted for water content. Values of protein content calculated as the sum of amino acid residues , lipid content expressed as triacylglycerol equivalents of fatty acids , and available carbohydrate content will appear in the main tables of the STFCJ 2015. Protein, fat and available carbohydrate contents were significantly decreased when the preferred analytical methods of FAO were applied instead of the acceptable methods. Online publication of Japanese and English versions of these tables, reference materials, and a retrievable food composition database is planned. PMID- 26598877 TI - Selection of a Dietary Assessment Method in Accordance with an Objective and Evaluation of the Results. AB - In recent years, many studies have used epidemiological techniques to investigate the relationships of daily energy and nutrition intake to food intake, and to disease onset and treatment or prevention. Therefore, dietary assessments are now being used in various situations. A range of dietary assessment methods exists, and each has advantages and disadvantages. However, there is no absolute and universally applicable dietary assessment method. The most appropriate method or a combination of methods must be selected in accordance with factors such as the objective of a study and the number of subjects. Moreover, it is necessary to interpret dietary assessment results multilaterally and to grasp dietary habits, elements of a daily lifestyle environment, and physical conditions that could influence the diet. PMID- 26598878 TI - Challenges in Dietary Exposure Assessment in Epidemiology: Research Trends. AB - Although exposure assessment of the usual diet is an essential component of nutrition epidemiology, it remains one of the most challenging issues in the field. Dietary exposure is widely measured using Food Frequency Questionnaires (FFQs), which impose a low burden on respondents and are inexpensive in large scale studies. FFQs have long satisfied the needs of epidemiological research, and have helped deliver the tremendous recent growth in knowledge of the diet disease association. However, issues surrounding measurement errors with FFQs have attracted substantial research interest around the world. Attenuation of the diet-disease association due to measurement errors identified in Western populations has led to extended methodological investigations comparing the performance of FFQs with biomarkers. The need for better dietary assessment methods has increased. Dietary records or recall provide relatively accurate estimates of intake for specific days, and of the usual diet if collected on multiple days. Until recently, however, their use in large-scale studies was not feasible, mainly due to cost. One innovative tool which may overcome the limitations of dietary records or recall is computerized 24-h dietary recall systems. These systems have been demonstrated to provide high-quality dietary intake data among Western populations. Incorporation of such new technology into large-scale epidemiological studies would make multiple-day administration of 24 h recall feasible in terms of cost. Research efforts to improve dietary assessment among Japanese and Asian populations are still under development. The development of innovative methods for Japanese remains an urgent research challenge. PMID- 26598879 TI - Why Is Creating a Healthy Food Environment So Crucial to Making Improvements in Diet-Related NCDs? AB - Non-communicable diseases (NCDs) such as cardiovascular diseases, cancers, chronic respiratory diseases, and diabetes are the leading cause of death worldwide. To decrease the global burden of NCDs and strengthen national efforts to combat NCDs, the World Health Organization (WHO) released the Global Action Plan for the Prevention and Control of NCDs 2013-2020. This plan provides established procedures and several policy options for member countries and other partners. Although many countries recognize that prevention of NCDs is an important health priority, their governments currently face a challenge: How do they adopt a multi-sectoral approach to promoting a healthy lifestyle among their populations? For this, all sectors of the food system (primary production, food processing, distribution, marketing, retail, catering, and food service) need to coordinate with each other for future governance. Since regulatory policy intervention areas for diet-related NCDs are widespread throughout the global food system, for future perspectives, comprehensive and coordinated approaches are needed for policy development and implementation across all levels of governments and food sectors in order to ensure sustainable policy action. PMID- 26598880 TI - Unilever Nutrition Strategy and Examples in Asia. AB - Millions of people in Asia are facing challenges from undernutrition, obesity, and diet-related non-communicable diseases. Unilever, as a global food business, has a simple approach to nutrition strategy: 'better products' help people to enjoy 'better diets' and live 'better lives.' For 'Better Products,' Unilever strives to improve the taste and nutritional qualities of all our products. By 2020, we commit to double the proportion of our entire global portfolio meeting the highest nutrition standards, based on globally recognised dietary guidelines. Unilever sets a clear plan to achieve reduction of sodium, saturated fat, trans fat, sugar, and calories in our products. Unilever developed fortified seasoning and spread products in 2013 for Vietnam, Indonesia, and the Philippines in collaboration with government bodies to address nutrient deficiencies. For 'Better Diets and Better Lives,' Unilever uses targeted communication to raise awareness and promote behavior change for healthy lifestyles. We committed to full nutrition labeling on our food products by 2015. We contribute experience to science-based regional initiatives on product labeling as well as nutrient profiling. Unilever collaborated with international, regional and country bodies to promote consumer understanding and food accessibility on public health priorities such as proper salt consumption, healthier meals, and employee well being programs. Looking ahead, we are continuing to improve the nutritional profile of our products as well as our communication to improve diets and lives. Collaboration between industry, government and public health organizations is needed to address complex diet and life style issues. PMID- 26598881 TI - Review of the Effectiveness of the Nutrition Care Process. AB - This author (A.I.) has witnessed the introduction of the Nutrition Care Process (NCP) and its subsequent adjustment over 10 y of her career in an acute and critical setting. A.I. observed that the NCP went through several revisions to better suit the actual clinical practices and the NCP was gradually incorporated into everyday work and accepted in a clinical setting. The NCP helped ensure that all practicing registered dietitians (RDs, RDNs) have up-to-date skill sets. The NCP is a systematic problem-solving tool with four distinct and interrelated steps that help RDs to improve critical thinking and address practice-related problems so that RDs can more effectively intervene and evaluate. In summary, RDs using the NCP are producing consistent and easy-to-read documentation of clinical practices that benefit other healthcare members. The intention to provide diagnosis-oriented assessment and to treat nutrition problems with intervention plans opens up opportunities for communication within healthcare teams and clients. The best practice requires interactive and ongoing communication with healthcare teams and clients. The NCP has resulted in improved productivity as the RDs are writing diagnosis- focused documentation with specific plans for intervention. In addition, analysis of common problems and nutrition diagnoses resolution rates appear to be in process in some facilities and may further promote RD roles in practice settings. In conclusion, the NCP is an effective tool to provide improved nutrition care. PMID- 26598882 TI - Overview of Inherited Zinc Deficiency in Infants and Children. AB - Zinc nutrition is of special practical importance in infants and children. Poor zinc absorption causes zinc deficiency, which leads to a broad range of consequences such as alopecia, diarrhea, skin lesions, taste disorders, loss of appetite, impaired immune function and neuropsychiatric changes and growth retardation, thus potentially threatening life in infants and children. In addition to dietary zinc deficiency, inherited zinc deficiency, which rarely occurs, is found during the infant stage and early childhood. Recent molecular genetic studies have identified responsible genes for two inherited zinc deficiency disorders, acrodermatitis enteropathica (AE) and transient neonatal zinc deficiency (TNZD), clarifying the pathological mechanisms. Both of these zinc deficiencies are caused by mutations of zinc transporters, although the mechanisms are completely different. AE is an autosomal recessive disorder caused by mutations of the ZIP4 gene, consequently resulting in defective absorption of zinc in the small intestine. In contrast, TNZD is a disorder caused by mutations of the ZnT2 gene, which results in low zinc breast milk in the mother, consequently causing zinc deficiency in the breast-fed infant. In both cases, zinc deficiency symptoms are ameliorated by a daily oral zinc supplementation for the patients. Zinc is definitely one of the key factors for the healthy growth of infants and children, and thus zinc nutrition should receive much attention. PMID- 26598883 TI - Health Economics of Nutrition Intervention in Asia: Cost of Malnutrition. AB - Asia has recorded the fastest economic growth in the world. However, some countries are still struggling with economic stagnation and poverty. Even in the emerging countries, there are economic disparities between urban and rural areas within a country. Reflecting the situations, nutritional issues in Asia came to be the antithetical situation of excess and insufficiency. The rate of overweight and obesity keeps increasing, especially in emerging countries. Meanwhile, underweight is still a critical problem in the region. Although the importance of nutrition is well recognized for social and economic development, it is difficult to identify the immediate outcome of nutrition interventions. Evidence-based decision-making is an important element of quality health care and efficiency and effectiveness are always key words. Along with enhanced attention to accountability and transparency of budget use in health services, attention to the economic evaluation of nutrition interventions has increased in recent years. In this symposium, we will review the current situation of nutritional issues and economic evaluation of nutrition interventions in Asia through experience of an international organization, the basis and trends for health care economics, and also efforts have been made in an Asian country. Discussion will be made about efficient and effective ways to evaluate projects/programmes for nutrition improvement. PMID- 26598884 TI - The Impact of Nutritional Insults during Fetal Life on Blood Pressure. AB - Numerous epidemiological and experimental studies provide compelling evidence that nutritional insults that impact fetal growth program a marked increase in blood pressure in later life. Sex and age also influence the developmental programming of hypertension; yet the exact mechanisms that permanently change the structure, physiology, and endocrine health of an individual across their lifespan following exposure to a nutritional insult are not entirely clear. Fetal exposure to maternal glucocorticoids is postulated as an initiating event. In addition, inappropriate suppression or activation of the renin angiotensin system (RAS) and/or activation of the sympathetic nervous system (SNS) leading to marked increases in oxidative stress and endothelin production are implicated in the etiology of hypertension that has its origins in fetal life. The risk of hypertension and chronic disease in one generation is transmitted to the next in the absence of an additional prenatal insult implicating epigenetic processes. Yet, further studies are needed to fully elucidate the mechanisms that contribute to hypertension programmed in response to nutritional insults during early life in order to improve the cardiovascular health of an individual across their lifespan. PMID- 26598885 TI - Assessment and Management of Health Claims in Europe 9 Years after the Adoption of the Regulation. AB - The European regulation 1924/2006 foresees that any nutrition or health claim should be assessed by EFSA and authorised by the European Commission and the Member States (with scrutiny by the European Parliament and the Council), the outcomes of which are published in the EU Register of Nutrition and Health Claims. Since 2007, EFSA has evaluated 230 dossiers submitted under Article 13.5 or Article 14. In addition, out of the 44,000 'general function claims', defined under Article 13.1, proposed by Member States, a list of 4,637 claims was compiled, EFSA completed evaluation of 2,849 of them, and published the results in 365 opinions, providing the basis for a list of 229 permitted health claims. For maintaining consistency over time and scientific areas, EFSA developed a systematic approach (for food characterisation, effect characterisation and scientific substantiation). Pertinent human studies of sufficient quality are central for the substantiation; any other study type can be used as supportive. This approach is summarized in 6 guidance documents. These guidance documents are revised progressively, which includes systematic submission to public consultation. PMID- 26598886 TI - Food Safety Program in Asian Countries. AB - By using the ILSI network in Asia, we are holding a session focused on food safety programs in several Asian areas. In view of the external environment, it is expected to impact the global food system in the near future, including the rapid increase in food demand and in public health services due to population growth, as well as the threats to biosecurity and food safety due to the rapid globalization of the food trade. Facilitating effective information sharing holds promise for the activation of the food industry. At this session, Prof. Hwang shares the current situation of Food Safety and Sanitation Regulations in Taiwan. Dr. Liu provides a talk on the role of risk assessment in food regulatory control focused on aluminum-containing food additives in China. After the JECFA evaluation of aluminum-containing food additives in 2011, each country has carried out risk assessment based on dietary intake surveys. Ms. Chan reports on the activities of a working group on Food Standards Harmonization in ASEAN. She also explains that the ILSI Southeast Asia Region has actively supported the various ASEAN Working Groups in utilizing science to harmonize food standards. Prof. Park provides current research activities in Korea focused on the effect of climate change on food safety. Climate change is generally seen as having a negative impact on food security, particularly in developing countries. We use these four presentations as a springboard to vigorous discussion on issues related to Food Safety in Asia. PMID- 26598887 TI - Food and Nutritional Improvement Action of Communities in Japan: Lessons for the World. AB - In Japan, the national health policy "Healthy Japan 21 (second term)" was introduced in 2013 to support prevention of lifestyle-related disease. Policy has also been recently revised on the promotion of nutrition education (shokuiku). Community-based food and nutrition actions were developed based on those policies and aimed to reinforce the linkages across the food chain, looking along its length "from field to food", including production, processing, preparation, eating and disposal. Local government is responsible for identifying the important food and nutritional problems, to devise and group effective actions on the basis of local health issues. The National Institute of Public Health (NIPH) is responsible for carrying out public health staff training on policy-based health issues. Training carried out by the NIPH, the Japan Dietetic Association and the Japan Public Health Association was designed to create an enabling environment for nutrition action. The community-based actions, including nutrition education and information, are carried out by several bodies, including local government, schools, facilities, volunteer groups, residents' associations, and commercial companies, to establish sustainable food systems promoting healthy diets. The community-empowering actions and effective cooperation are reported as good practice models in an annual white paper by the Cabinet Office. Japanese dieticians are expected to share their experiences of local nutrition improvement activities in Japan with international colleagues. Experience from elsewhere, including from Japanese dieticians working in developing countries, should also be applied on their return. PMID- 26598888 TI - Cooperation between Japanese and Cambodian Dietitians in Setting up a Hospital Diet Management System. AB - Cambodia faces a considerably high percentage of the stunted under 5 (Unicef, 2014). Despite the National Nutrition Strategy Launched by the Ministry of Health in cooperation with development partners, nutrition improvement projects have not always been effective. It is generally said these issues are addressed in many other developing nations, and the literature largely documented that successful nutrition programmes are community-based programmes because of their sustainability and the intensive communications between health workers and beneficiaries. Learning from the past experiences, the Foundation for International Development/Relief organized a project team with a Cambodian dietitian and an experienced Japanese dietitian to implement a hospital diet programme for children from April 2006 to March 2014 in the National Pediatric Hospital (NPH) in Cambodia. The project has two objectives: establishing a hospital diet management system, and developing the capacity of NPH staff. Hospital food menus were created paying particular attention to Cambodian culture, eating habits and accessibility to the ingredients for the purpose of continuous supply. We have also put emphasis on the communication between dietitians and family members of the children to let them understand the importance of a nutritious diet. After 8 y of project implementation, the hospital diet management system was established providing 7 types of menu with nutritious diets. The final evaluation of the project showed that NPH staff have the intention to continue hospital food supply with their acquired knowledge and capacity. In practice, a Cambodian dietitian currently takes the initiative for a continuous nutritional diet in NPH. The key to this success is the collaboration between Japanese dietitians with experience and Cambodian dietitians with knowledge of Cambodian eating habits. Taking our experience into account, it is highly recommended to educate Cambodian dietitians, as they are extremely scarce, and to increase the awareness of health care staff towards the importance of nutrition management. PMID- 26598889 TI - Role of Integrated Outreach Activities in Improving Nutritional Status among Under-Five Children in Yemen. AB - This paper intends to review the feasibility of scaling-up nutrition activities through integrated outreach activities to respond to development challenges. Evaluating the efficiency and effectiveness of current packages of outreach services during the period of 2006-2014 is the aim of this review for better access to basic and social services and economic opportunities in Yemen. The two components of health system performance are related to: (i) the levels of coverage for health interventions; and (ii) financial risk protection, with a focus on equity. In this sense, Yemen's intervention coverage indicators of the health-related MDGs, such as immunization, integrated management of childhood illnesses (IMCI), reproductive health (RH) and disease control including non communicable diseases (NCDs) have shown good progress. Yet, malnutrition is still highly prevalent among under-five children in the country. Coverage indicators of the outreach approach in Yemen, which started in 2006, indicate a strong role of the integrated services in reaching under-five children of the most vulnerable communities with basic health services including preventive and curative ones. As well, these activities respond to the financial risk protection challenges with enhancing efficiency in the provision of health services. Considering that nutrition is part of the package of integrated outreach services, inter-related measures of universal coverage in Yemen are to be addressed together with setting the impact indicators for essential health services coverage targeting the neediest populations. Coverage of health services encompasses the full targeted population in the most malnutrition-affected areas, especially the west coast of the country, for intervention and for the age group these services are directed to. PMID- 26598890 TI - What Are the Current Situations and the Challenges of Maternal and Child Malnutrition in Asia? AB - Changes in lifestyle have led to better nutrition or increasing the risk of NCDs in Asia, while there are still many children and reproductive-aged women (RAW) suffering undernutrition whose lives are at risk in the same region. The MDG of reducing the prevalence of underweight <5 children to half has been achieved already or nearly achieved in many Asian countries, whereas South Asian (SA) countries and several other countries (Cambodia, Laos, East Timor and Yemen) have difficulties in achieving the goal by 2015. In particular, East Timor and Yemen are in a critical situation with undernutrition. There is a strong concern about a rapid increase in overweight and obesity rates in West Asian (WA) and some Central Asian (CA) countries. Iron deficiency is one of the most important risk factors that threaten healthy life among RAW especially in SA, followed by Southeast Asia (SEA) and CA. The same issue is observed among children (1-4 y) in the same regions. Dietary risks (based on DALYS) increase with advancing age in most Asian regions whereas high Body Mass Index is the most important risk factor in WA and some CA countries. High priority should be placed on measures to tackle undernutrition and micronutrient deficiencies including iron deficiency in SA and some countries in SEA and WA; overweight and obesity in WA and CA; and dietary risks among RAW, in most Asian regions. PMID- 26598891 TI - Effects of Socioeconomic Status on Nutrition in Asia and Future Nutrition Policy Studies. AB - Evidence of health disparities has been reported around the world. One of the intermediate factors between socioeconomic status (SES) and health is nutrition. Many studies reported socioeconomically disadvantaged people had more risk of obesity and lifestyle-related diseases than others in western society. Micronutrient intake affected by SES, but little evidence indicates that SES affects either energy intake or the macronutrient composition of the diet in western countries. In contrast, there is not enough evidence of a consistent relationship between SES and nutrition in Asian countries at present. The present status of nutrition disparities in Asia is considered to vary by economic level of the country. For developing countries in Asia, India and Vietnam, SES associates with BMI positively in women. For relatively developed countries in Asia, Korea and Japan, SES associates with BMI negatively in women. Low SES groups consume more carbohydrate, and less protein and fat, so not only micronutrient but also macronutrient intake is affected by SES both in developing and in developed Asian countries. There are some studies on the pathway from SES to diet/nutrition. The association between low SES and obesity may be mediated, in part, by the low cost of energy-dense foods, concern about food price and dietary knowledge. Nutrition policy research is required to reduce nutrition disparities in Asia. We need a collaborative study of the impact of potential political options on diet and on health with other academic fields. PMID- 26598892 TI - Nutrition Economics: How to Eat Better for Less. AB - Food prices and diet costs contribute to socioeconomic disparities in diet quality and health. Lower-cost diets provide ample calories but lack essential nutrients. Nutrition economics can remedy health disparities by helping to identify food patterns that are nutrient-rich, affordable, and appealing. First, nutrient profiling models--such as the Nutrient Rich Food (NRF) family of indices -are able to separate foods that are energy-dense from those that are nutrient rich. Whereas energy-dense foods contain more calories than nutrients, nutrient rich foods contain more nutrients than calories. Second, new value metrics have identified affordable healthy foods, based on nutrients per unit cost. Third, these methods have now been applied to the analyses of individual foods and beverages, meals, menus, and the total diet. The Healthy Eating Index (HEI), based on compliance with dietary guidelines, was the principal measure of total diet quality. Although healthier diets did generally cost more, some population subgroups managed to obtain nutrient-dense diets at a lower cost. Being able to create affordable, healthy food patterns on limited budgets is an example of nutrition resilience. PMID- 26598893 TI - "+10 min of Physical Activity per Day": Japan Is Looking for Efficient but Feasible Recommendations for Its Population. AB - Prospective cohort studies have shown that people with a larger amount of physical activity (PA) and exercise have lower risks of non-communicable diseases (NCDs). In Japan, the Ministry of Health, Labour and Welfare published in March 2013 the "Active-Guide," i.e. the Japanese official PA guidelines for health promotion. In this document, the most important message is "+10," standing for "add 10 min of MVPA per day." The establishment of the "+10" recommendation is supported by strong scientific evidence. Firstly, a meta-analysis including 26 cohort studies indicated that an increment of 10 min of moderate-to-vigorous PA per day can result in a 3.2% reduction of the average relative risk of NCDs, dementia, joint-musculoskeletal impairment, and mortality. Secondly, the National Health and Nutrition Survey (Japan, 2010) reported that 60.8% of the Japanese population is inclined to add the equivalent of 10 min of PA in their daily life. In line with these results, the "+10" recommendation is viewed as feasible and efficient for the Japanese population. To our knowledge, this implementation of an additional low-dose PA recommendation in a governmental health promotion policy is a world first. We hope that the Japanese PA policy will inspire other national and international public health agencies. PMID- 26598894 TI - Dysphagia Rehabilitation in Japan. AB - In Japan, one of the most common causes of death in elderly people is aspiration pneumonia. Maintenance of oral hygiene and feeding functions are important elements, especially in patients with dysphagia caused by stroke, neurological diseases, and after operations on the head and neck cancer, as well as in the elderly to prevent aspiration pneumonia. It should also be noted that not only oral health care and physical therapy related to feeding functions but also dental treatment is included in the clinical management during interventions whenever needed. On the other hand, for the patients and/or elderly in need of assistance in maintaining a safe diet, it is recommended that a specialized team comprising physicians, dentists, and speech therapists in functional rehabilitation observes meal conditions of the subjects and evaluates such factors as meal contents, posture during meals, usage of dishes and cutlery, meal times, status of consciousness, perception, and motivation. First, I will present the clinical interventions to those patients, which include oral health care, dental treatment, physical therapy and meal assistance, as well as team approaches in those circumstances. In addition, clinical and basic research results will be introduced, which are expected to foster the understanding of physiology in chewing and swallowing. These results are also expected to develop the clinical technology to maintain or recover the feeding functions. PMID- 26598895 TI - Significance of Oral Function for Dietary Intakes in Old People. AB - There is growing interest in the connection between oral health and systemic health. In recent years, oral health in particular is considered a predictor of circulatory mortality. Two major pathways may mediate this relationship, namely (1) the inflammatory effects of chronic periodontal infection on the circulatory system and (2) the effects of masticatory dysfunction on dietary behavior, nutrition and systemic diseases. Previous studies have shown that adults who are edentulous, or have fewer natural teeth are less likely to eat fruits, vegetables and meats. Because it can be easily assessed, the number of teeth has frequently been used as an indicator of oral health in investigations of food intake. However, the number of teeth alone presents a misleading picture. The role of prosthetic rehabilitation (i.e., dentures) on oral function must be taken into account as well. We investigated the association of occlusal force with food and nutrient intakes after adjusting for the number of teeth in independently living 70-y-old Japanese. After adjusting for socioeconomic status and the number of remaining teeth, decline of occlusal force was significantly associated with lower intakes of vegetables, vitamins A, C, and B6, folate, and dietary fiber (p for trend<0.05). It is concluded that occlusal force as a representative of oral function was significantly associated with intakes of vitamins and dietary fiber rather than number of remaining teeth. PMID- 26598896 TI - Modulation of Signal Transduction and Gene Expression by Vitamin E via PI3Kgamma/PKB and hTAP1/SEC14L2-Mediated Lipid Exchange. AB - The ability of vitamin E to modulate signal transduction and gene expression has been observed in numerous cell culture and animal studies. These cellular signalling effects of vitamin E have been mainly explained as result of protection of lipids and signal transduction enzymes from random modification by free radicals or by specifically influencing their redox state. Alternatively, the observed signalling may reflect specific interactions of vitamin E with enzymes, structural proteins, and transcription factors and/or result from vitamin E-induced alterations of physical and structural properties of membrane lipid domains in which it is embedded. A novel signal transduction mechanism of vitamin E is proposed in which lipid transfer proteins (LTP) facilitate phosphorylation of phosphatidyl-inositol by exchanging it with vitamin E and presenting it to phosphatidylinositol-3-kinase (PI3K). PMID- 26598897 TI - Determination of Phosphatidylcholine Hydroperoxide (PCOOH) as a Marker of Membrane Lipid Peroxidation. AB - Increasing evidence for phosphatidylcholine hydroperoxide (PCOOH) as a marker of oxidative food deterioration and oxidative diseases has revealed the need for a pure PCOOH standard and a reliable quantification method. Recently, we synthesized the PCOOH isomers 1-palmitoyl-2-(9-hydroperoxyoctadecadienoyl)-sn glycero-3-phosphocholine, (16:0/9-HpODE PC) and 1-palmitoyl-2-(13 hydroperoxyoctadecadienoyl)-sn-glycero-3-phosphocholine (16:0/13-HpODE PC). Using these standards along with liquid chromatography-tandem mass spectrometry, a reliable quantification method was developed. This mini-review describes these analytical techniques, with a particular emphasis on clinical sample analysis. PMID- 26598900 TI - Prevention of Cardiovascular Diseases by Garlic-Derived Sulfur Compounds. AB - Lifestyle-related diseases have complex pathogenesis which consists of several different steps. Basic causes of the diseases are attributed to unhealthy lifestyles in dietary habits, physical activity and suffering stress. The unhealthy lifestyles induce risk factors such as hypertension, dyslipidemia, obesity, and hyperglycemia. These risk factors all promote arteriosclerosis leading to serious vascular complications (i.e., thrombotic diseases), myocardial infarction and cerebral infarction. The total number of deaths from these thrombotic diseases almost equals that from cancer in our country. Cancer is also a typical lifestyle-related disease. Food has three different functions: the primary function is to provide enough nutrients to meet the metabolic requirements. The secondary function is the one relating to food preference. The third function is to control our body functions, which help reduction of the risk of diseases. Some of the compounds derived from food, especially phytochemicals in edible plants, vegetables and herbs, have potent functions to control our body functions and contribute to promoting our health. In this review article, we overview the lifestyle-related diseases and food functions involving prevention and amelioration of the diseases by food components especially from edible plants and vegetables. As an example, we will describe the food function of garlic and the prevention of lifestyle-related diseases by its components. Allyl sulfides are characteristic flavor compounds derived from garlic, and these organosulfur compounds are responsible for the food function of garlic. PMID- 26598901 TI - Food Compounds Activating Thermosensitive TRP Channels in Asian Herbal and Medicinal Foods. AB - There are several thermosensitive transient receptor potential (TRP) ion channels including capsaicin receptor, TRPV1. Food components activating TRPV1 inhibit body fat deposition through sympathetic nerve stimulation. TRPA1 is another pungency sensor for pungent compounds and is mainly coexpressed with TRPV1 in sensory nerve endings. Therefore, TRPA1 activation is expected to have an anti obesity effect similar to TRPV1 activation. We have searched for agonists for TRPV1 and TRPA1 in vitro from Asian spices by the use of TRPV1- and TRPA1 expressing cells. Further, we performed food component addition tests to high-fat and high-sucrose diets in mice. We found capsiate, capsiconiate, capsainol from hot and sweet peppers, several piperine analogs from black pepper, gingeriols and shogaols from ginger, and sanshools and hydroxysanshools from sansho (Japanese pepper) to be TRPV1 agonists. We also identified several sulfides from garlic and durian, hydroxy fatty acids from royal jelly, miogadial and miogatrial from mioga (Zingiber mioga), piperine analogs from black pepper, and acetoxychavicol acetate (ACA) from galangal (Alpinia galanga) as TRPA1 agonists. Piperine addition to diets diminished visceral fats and increased the uncoupling protein 1 (UCP1) in interscapular brown adipose tissue (IBAT), and black pepper extract showed stronger effects than piperine. Cinnamaldehyde and ACA as TRPA1 agonists inhibited fat deposition and increased UCP1. We found that several agonists of TRPV1 and TRPA1 and some agonists of TRPV1 and TRPA1 inhibit visceral fat deposition in mice. The effects of such compounds on humans remain to be clarified, but we expect that they will be helpful in the prevention of obesity. PMID- 26598902 TI - Nutrients and Circadian Rhythms in Mammals. AB - The circadian rhythm is generally existed in mammalian behavior and metabolic processes, which results from the self-sustained circadian clocks. The mammalian circadian clocks are composed of a master clock located in the hypothalamic suprachiasmatic nucleus (SCN), and of many peripheral clocks in tissues and extra SCN brain regions. It is indicated that feeding could take over part of the SCN signaling, and affect internal synchrony between the master clock and the peripheral clocks. Thus, recent studies focus more on the relationship between the nutrients and circadian rhythms. Various nutrient components (glucose, amino acid, alcohol) are found to be able to directly affect the circadian rhythm of clock genes. Moreover, the feeding schedule of nutrients is as important as the nutrient components in maintaining a healthy circadian rhythm. Therefore, the circadian homeostasis needs not only balanced nutrient components but also regular timed nutrients. PMID- 26598903 TI - Chrononutrition. AB - Well-regulated eating habits are said to be important for health. A major breakthrough was the discovery of the negative regulatory feedback for transcription via the binding of Clock/Bmal1 to E-box, which forms the basis of biological clocks. Well-regulated eating habits normalize the liver clock gene, the rhythm of CYP7A1 gene, and blood cholesterol levels through insulin secretion. Moreover, well-regulated eating habits actively contribute to better lipid metabolism such as obesity, even if animals ingest a high-fat diet. From reported results so far, chrononutition has two important functions: 1) meal timing is important for our health, and 2) meal timing entrains our body clock. PMID- 26598904 TI - Food Safety and Infectious Diseases. AB - Food hygiene and a sufficient food supply are essential requirements to stay healthy. However, this can be hindered by foodborne infections, which are known to be prevalent throughout the world. The World Health Organization reports that, annually, diarrheal disease is responsible for the deaths of over 2 million people worldwide. The majority of these deaths occur in developing countries, following the ingestion of pathogen-contaminated food and water. In the developed world, outbreaks of foodborne diseases are also frequently documented, reflecting the global importance of following good food hygiene practices. PMID- 26598905 TI - Food Safety-Related Aspects of Parasites in Foods. AB - As natural foods derive from soil or water environments, they may contain the infective stages of parasites endemic to these environments. Infective stages may enter the human food supply via infected animal hosts so there is a need for increased awareness of the impact of parasites on the food supply. Safe handling of food and good kitchen hygiene can prevent or reduce the risk posed by contaminated foodstuffs. In addition, parasites cannot cause a health problem in any thoroughly cooked foods. PMID- 26598906 TI - A Perspective of the Research on Food Factors in Human Health: A Return to the Mechanistic Approach. AB - Food is a mixture of several nutrients and non-nutrients. The functions of food in human health can be categorized as its primary function in nutrition, its secondary function in palatability and its tertiary function in bioregulation. Nutrients contribute mainly to the primary function, while many non-nutrients in foods and foodstuffs are strongly associated with the secondary and/or tertiary functions. Individual food ingredients and ingredients as a whole are the so called food factors. Much interest has arisen in the tertiary function of food factors related to the prevention of lifestyle-related diseases and promoting health in an aging society. This is why many studies evaluating the tertiary functions of food factors are now in progress all over the world. This symposium aims to present cutting-edge knowledge from celebrated Asian professors on the molecular mechanisms for the tertiary functions of food factors, in particular, polyphenols in soybeans and green tea, and n-6 polyunsaturated fatty acids in fish. In this context, this article will briefly review recent trends in research on the tertiary function of food factors. PMID- 26598907 TI - Impact of intravenous contrast enhancement phase on target definition for hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (IHC): Observations from patients enrolled on a prospective phase 2 trial. AB - BACKGROUND: The safety and efficacy of radiation therapy for hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (IHC) depend on accurate definition of gross tumor volume (GTV), but GTV often varies between phases of multiphasic computed tomography (CT) imaging. METHODS: We contoured GTVs on arterial, portal venous, and delayed phases of multiphasic CT scans for 32 patients treated on an institutional review board-approved prospective trial of proton therapy for primary liver tumors and determined which phase provided optimal GTV visualization. We assessed agreement between individual phase GTVs to determine if GTV for each phase was encompassed in a 5-mm expansion of either the smallest or the best-visualized GTV. RESULTS: There were 19 HCC lesions and 14 IHC lesions. HCC lesions were best identified on the arterial phase in 42% (n = 8), portal venous phase in 32% (n = 6), and delayed phase in 26% (n = 5). IHC lesions were best identified on portal venous phase in 64% (n = 9) and the arterial phase in 29% (n = 4), with 1 case equally visualized on arterial and portal venous phases. In all 33 lesions, a 5-mm expansion around the smallest GTV failed to cover GTVs defined on other available phases. A 5-mm expansion around the best-visualized GTV provided satisfactory coverage of all available phases' GTVs in 6/18 HCC cases and 2/9 IHC cases. CONCLUSIONS: Variability between GTVs on multiphasic CT scans could not be overcome with a 5-mm expansion of either the smallest GTV or the best-visualized GTV. Assessment of all available intravenous contrast phases is essential to accurately define the GTV. PMID- 26598908 TI - Benefits of improving processes in cancer care with a care pathway-based electronic medical record. AB - PURPOSE: We analyzed the intermediate and longer term changes in patients' waiting times following the implementation of an electronic medical record (EMR) dedicated to ambulatory treatment in both medical and radiation oncology. METHODS AND MATERIALS: A pre-post study design was developed to assess improvements in patients' waiting times, defined as the number of days between key steps in patient management preceding the first treatment. The postperiod began 1 year after the EMR go-live to allow for a preliminary period of adjustment to the new EMR. The EMR under study was closely integrated into the clinicians' workflow, being designed as a care pathway information system to provide real-time support to the coordination of the entirety of care processes involving all the care personnel. RESULTS: The large majority of the waiting-time indicators decreased over time, with decreases ranging from 2 to 28 days. However, an important time lag was necessary to see an improvement, to the extent that better access was only observed in the final months of the postperiod. CONCLUSION: The study highlights the potential to design EMR applications that capitalize on tight workflow integration, both in medical and radiation oncology, to deal with the fundamentally collaborative nature of cancer care delivery. PMID- 26598909 TI - It's never too late: Smoking cessation after stereotactic body radiation therapy for non-small cell lung carcinoma improves overall survival. AB - PURPOSE: As stereotactic body radiation therapy (SBRT) has emerged as a quick, effective, and well-tolerated treatment for early stage non-small cell lung carcinoma (NSCLC), it can be difficult to convince patients to quit smoking in follow-up. We evaluated whether there was a survival benefit to smoking cessation after SBRT. METHODS AND MATERIALS: Patients with early-stage NSCLC treated from 2004 to 2013 who were still smoking tobacco at the time of SBRT were identified from a prospective institutional review board-approved registry. Peripheral tumors were treated to 54 Gy in 3 fractions and central tumors to 50 Gy in 5 fractions. Patients were reviewed for overall survival (OS) and disease progression. The log-rank and Cox regression tests were used to identify factors predictive of OS. RESULTS: Thirty-two patients (27%) quit smoking after SBRT, and 87 (73%) continued smoking. Median follow-up was 22 months (range, 2-87). On multivariate analysis, smoking status (hazard ratio, 2.1; 95% confidence interval, 1.02-4.2; P = .045), increasing age-adjusted Charlson comorbidity score and larger tumor size were predictive of worse OS. The prior number of cigarette pack-years was not significant (P = .62). In a Kaplan-Meier comparison, smoking cessation after SBRT was associated with improved 2-year OS, 78% versus 69% (P = .014). There was no significant difference in 2-year progression-free survival (75% vs 55%, P = .23) or local control (97% vs 88%, P = .63). CONCLUSION: OS is significantly improved in patients who stop smoking after SBRT for early-stage NSCLC, no matter their previous smoking history. Encouraging smoking cessation should be an important part of every posttreatment visit. PMID- 26598910 TI - Safer radiation therapy treatment resulting from an equipment transition: A mixed methods study. AB - PURPOSE: To realize individualized safe radiation therapy, reliable treatment equipment is essential in combination with a system-level improvement approach. We hypothesized that implementation of a system that integrated all required treatment equipment would result in improved safety and stability of the irradiation treatment process. METHODS AND MATERIALS: Seven accelerators, portal imaging, and the treatment planning software were replaced by an integrated system that included 6 accelerators. The number of reported safety incidents and root causes were recorded between 2010 and 2014. Time series analysis was performed, and quantitative results were explored by structured interviews. Additionally, downtime was recorded. RESULTS: From January 2010 to July 2014, 5085 incidents were reported. Reports related to the accelerators decreased from 33% (2010) to 20% (2013-2014) of total reports, whereas the number of delivered fractions per accelerator increased by 20% (2010: 643 per month; 2013: 795 per month). Reports related to portal imaging decreased from 16.5 reports per month (2010) to 3.1 (2013-2014). Of these portal imaging reports, 316 had at least 1 technical cause in 2010, which decreased to 13 in 2013-2014. Interviewees attributed the decreased reporting to the equipment transition, not to decreased safety awareness. Downtime decreased by 46%, from 5.4% in 2010 to 2.9% in 2013. CONCLUSIONS: The number of reported accelerator- and portal imaging-related incidents decreased significantly, whereas safety awareness remained stable. In addition, accelerator downtime decreased, possibly resulting in less rescheduling of patients and fewer disruptions of work processes. Therefore, we conclude that the risk for serious safety incidents and patient harm decreased after implementation of the new integrated system. PMID- 26598911 TI - Reducing Food Insecurity and Improving Fruit and Vegetable Intake Among Farmers' Market Incentive Program Participants. AB - OBJECTIVE: To determine whether participation in a farmers' market incentive pilot program had an impact on food security and fruit and vegetable (F&V) intake of participants. METHODS: Participants in the Supplemental Nutrition Assistance Program were eligible to receive a dollar-per-dollar match up to $10/wk in farmers' market incentives. The researchers used a pretest-posttest design to measure F&V intake and food security status of 54 adult participants before and after receiving farmers' market incentives. The 6-item Behavior Risk Factor Surveillance System questionnaire and US Household Food Security Survey Module were used to measure F&V intake and food security, respectively. Wilcoxon signed rank test was used to compare scores of F&V intake. RESULTS: After receiving incentives, fewer individuals reported experiencing food insecurity-related behaviors. A significantly increased intake (P < .05) was found among selected vegetables. CONCLUSION AND IMPLICATIONS: Participation in a farmers' market incentive program was positively related to greater food security and intake of select vegetables among participants in the Supplemental Nutrition Assistance Program. PMID- 26598912 TI - Polyphyllin I induced-apoptosis is enhanced by inhibition of autophagy in human hepatocellular carcinoma cells. AB - BACKGROUND: Polyphyllin I (PPI), a bioactive phytochemical isolated from the rhizoma of Paris polyphyllin, exerts preclinical anticancer efficacy in various cancer models. However, the effects of PPI on regulatory human hepatocellular carcinoma (HCC) cell proliferation and its underlying mechanisms remain unknown. PURPOSE: This study investigated the antiproliferation effect of PPI on HCC cells and its underlying mechanisms. METHODS: Cell viability was measured by MTT assay. Cell death, apoptosis and acidic vesicular organelles (AVOs) formation were determined by flow cytometry. Protein levels were analyzed by Western blot analysis. RESULTS: PPI induced apoptosis through the caspase-dependent pathway and activated autophagy through the PI3K/AKT/mTOR pathway. Blockade of autophagy by pharmacological inhibitors or RNA interference enhanced the cytotoxicity and antiproliferation effects of PPI. Moreover, chloroquine (CQ) enhanced the antiproliferation effect of PPI on HCC cells via the caspase-dependent apoptosis pathway by inhibiting protective autophagy. Therefore, the combination therapy of CQ and PPI exhibited synergistic effects on HCC cells compared with CQ or PPI alone. CONCLUSION: The current findings strongly indicate that PPI can induce protective autophagy in HCC cells, thereby providing a novel target in potentiating the anticancer effects of PPI and other chemotherapeutic drugs in liver cancer treatment. Moreover, the combination therapy of CQ and PPI is an effective and promising candidate to be further developed as therapeutic agents in the treatment of liver cancer. PMID- 26598913 TI - Radix Saposhnikovia extract suppresses mouse allergic contact dermatitis by regulating dendritic-cell-activated Th1 cells. AB - BACKGROUND: Radix Saposhnikovia (RS), called "Fangfeng" in China, is commonly used in Chinese medicinal formulae to treat allergic and inflammatory diseases. However, the underlying mechanisms of RS in ameliorating allergy remain unknown. PURPOSE: To study the effects of RS extract on allergic contact dermatitis (ACD) in a mouse model and to investigate the underlying mechanisms in vivo and ex vivo. METHODS: ACD was induced by sensitizing the mice and treating an ear auricle with 1-chloro-2,4-dinitrobenzene (DNCB). RS extract was administered during the sensitization and/or elicitation phase. Ear swelling was noted and lymphocytic infiltration was investigated with hematoxylin and eosin staining. The cytokines in the sera and the supernatants of lymphocyte cultures were determined with enzyme-linked immunosorbent assays. Lymphocyte proliferation was assessed with a 3-(4,5)-dimethylthiazol-2-y1)-2,5-diphenyltetrazolium bromide (MTT) assay. The maturation of dendritic cells (DCs) and the differentiation of T cells were examined with flow cytometry. The mRNA expression of T-bet, GATA-3, and forkhead box p3 (Foxp3) was evaluated with real-time PCR. RESULTS: RS extract (1.3 or 2.6 g/kg) markedly reduced the ear swelling and the intense cellular infiltration of inflammatory cells in the ear tissue. The ratio of interferon gamma (IFN-gamma)/interleukin 4 (IL-4) was reduced in the sera of the DNCB sensitized mice and the lymphocyte culture supernatants after treatment with the extract. Further study of the initial stage of ACD revealed that RS extract prevented the differentiation of naive T cells into Th1 cells, reduced the proportion of CD3(+)CD4(+) (Th) cells, and suppressed the secretion of IFN-gamma and the expression of T-bet mRNA in lymphocytes. The RS extract also reduced the proportion of DCs in the sensitized mouse lymphocytes and the expression of CD40(+)CD86(+) cells in the DCs. CONCLUSION: RS extract is effective in treating ACD because it regulates the development of DCs and DC-activated Th1 differentiation. PMID- 26598914 TI - Kaempferitrin prevents bone lost in ovariectomized rats. AB - BACKGROUND: Podocarpium podocarpum (DC.), an edible and medicinal plant popularly used for the treatment of bruises and fracture in Chinese folk medicine, has been proved to possess significant antiosteoporotic effect in our latest research. PURPOSE: Our study aimed to investigate the in vitro and in vivo antiosteoporotic effect of kaempfertrin (KN), a principal flavonoid in P. podocarpum obtained through bio-guided isolation. METHODS: An ovariectomized (OVX) rat model of osteoporosis as well as in vitro osteoblast and osteoclast cell lines were employed to evaluate the antiosteoporotic potency of KN. RESULTS: KN significantly improved the bone mass and microarchitecture in OVX rats, with little estrogen-like side effect compared with estradiol valerate. KN also exhibited stimulatory effect on osteoblastic cells and inhibitory action on osteoclastic cells, which down-regulated the phosphorylation level of I-kappaB. CONCLUSION: KN possessed significant antiosteoporotic activity. Combined with its limited estrogen-like side effect, KN can be regarded as an idealistic antiosteoporotic candidate for human osteoporosis diseases. PMID- 26598915 TI - Potential of butein, a tetrahydroxychalcone to obliterate cancer. AB - BACKGROUND: Despite the major advances made in the field of cancer biology, it still remains one of the most fatal diseases in the world. It is now well established that natural products are safe and efficacious and have high potential in the prevention and treatment of different diseases including cancer. Butein is one such compound which is now found to have anti-cancer properties against various malignancies. PURPOSE: To thoroughly review the literature available on the anti-cancer properties of butein against different cancers and its molecular targets. METHODS: A thorough literature search has been done in PubMed for butein, its biological activities especially cancer and its molecular targets. RESULTS: Our search retrieved several reports on the various biological activities of butein in which around 43 articles reported that butein shows potential anti-proliferative effect against a wide range of neoplasms and the molecular target varies with cancer types. Most often it targets NF-kappaB and its downstream pathways. In addition, butein induces the expression of genes which mediate the cell death and apoptosis in cancer cells. It also inhibits tumor angiogenesis, invasion and metastasis in prostate, liver and bladder cancers through the inhibition of MMPs, VEGF etc. Moreover, it inhibits the overexpression of several proteins and enzymes such as STAT3, ERK, CXCR4, COX-2, Akt, EGFR, Ras etc. involved in tumorigenesis. CONCLUSION: Collectively, all these findings suggest the enormous potential and efficacy of butein as a multitargeted chemotherapeutic, chemopreventive and chemosensitizing agent against a wide range of cancers with minimal or no adverse side effects. PMID- 26598916 TI - Bronchipret(r) syrup containing thyme and ivy extracts suppresses bronchoalveolar inflammation and goblet cell hyperplasia in experimental bronchoalveolitis. AB - BACKGROUND/PURPOSE: Acute bronchitis (AB) is a common lung condition characterized by inflammation of the large bronchi in response to infection. Bronchipret((r)) syrup (BRO), a fixed combination of thyme and ivy extracts has been effectively used for the treatment of AB. Combining in vivo and mechanistic in vitro studies we aimed to provide a better understanding of the therapeutic potential of BRO on key aspects of AB and to identify potential mechanisms of action. METHODS: Bronchoalveolitis in rats was induced by intratracheal LPS instillation. BRO was administered p.o. once daily at 1- to 10-fold equivalents of the human daily dose. Animals were sacrificed 24-72 h post LPS challenge to analyze leukocyte numbers in lung tissue, bronchoalveolar lavage fluid (BALF) and blood as well as goblet cells in bronchial epithelium. Inhibitory effects of BRO analogue on leukotriene (LT) production were determined in human neutrophils and monocytes as well as on isolated 5-lipoxygenase (5-LO). RESULTS: BRO significantly reversed the LPS-induced increase in leukocyte numbers in lung tissue, BALF and blood as well as goblet cell numbers in bronchial epithelium. In vitro, BRO analogue suppressed cellular release of LTB4 (IC50 = 36 ug?ml(-1)) and cysLT (IC50 = 10 ug?ml(-1)) and inhibited the activity of isolated 5-LO (IC50 = 19 ug?ml(-1)). CONCLUSION: BRO exerts significant anti-inflammatory effects and attenuates goblet cell metaplasia in LPS-induced bronchoalveolitis in vivo potentially via interference with 5-LO/LT signaling. These effects may contribute to its observed clinical efficacy in AB. PMID- 26598917 TI - Antidepressant-like effect of the water extract of the fixed combination of Gardenia jasminoides, Citrus aurantium and Magnolia officinalis in a rat model of chronic unpredictable mild stress. AB - BACKGROUND: Water extract of the fixed combination of Gardenia jasminoides Ellis fruit, Citrus aurantium L. fruit and Magnolia officinalis Rehd. et Wils. bark, traditional name - Zhi-Zi-Hou-Po (ZZHPD) is used for treatment of depressive-like symptoms in traditional Chinese medicine for centuries. HYPOTHESIS/PURPOSE: The present study aimed to explore antidepressant-like effects and potential mechanisms of ZZHPD in a rat model of chronic unpredictable mild stress (CUMS). STUDY DESIGN: Antidepressant-like effects of ZZHPD were investigated through behavioral tests, and potential mechanism was assessed by neuroendocrine system, neurotrophin and hippocampal neurogenesis. METHODS: Antidepressant-like effects of ZZHPD (3.66, 7.32 and 14.64 g/kg/day) were estimated through coat state test, sucrose preference test, forced swimming test and open-field test. Effects of ZZHPD on hypothalamic-pituitary-adrenal (HPA) axis were evaluated by hormones measurement and dexamethasone suppression test. In addition, the expression of brain-derived neurotrophic factor (BDNF) in hippocampus was measured, as well as hippocampal neurogenesis was investigated by doublecortin (DCX) and 5-bromo-2 deoxyuridine/neuronal nuclei (BrdU/NeuN). RESULTS: The results demonstrated that ZZHPD significantly reversed the depressive-like behaviors, normalized the levels of adrenocorticotropic hormone (ACTH) and corticosterone (CORT), restored the negative feedback loop of HPA axis and improved the levels of BDNF, DCX and BrdU/NeuN compared with those in CUMS-induced rats. CONCLUSION: The above results revealed that ZZHPD exerted antidepressant-like effects possibly by normalizing HPA axis function, increasing expression of BDNF in hippocampus and promoting hippocampal neurogenesis. PMID- 26598918 TI - Medicarpin and millepurpan, two flavonoids isolated from Medicago sativa, induce apoptosis and overcome multidrug resistance in leukemia P388 cells. AB - BACKGROUND: High consumption of flavonoids has been associated with a decrease risk of cancer. Alfalfa (Medicago sativa) leaves have been widely used in traditional medicine and is currently used as a dietary supplement because of their high nutrient content. We previously reported the cytotoxic activity of alfalfa leaf extracts against several sensitive and multidrug resistant tumor cell lines. HYPOTHESIS/PURPOSE: We aimed to determine whether medicarpin and millepurpan, two isoflavonoids isolated from alfalfa leaves, may have pro apoptotic effects against drug-sensitive (P388) and multidrug resistant P388 leukemia cells (P388/DOX). STUDY DESIGN/METHODS: Cells were incubated with medicarpin or millepurpan for the appropriate time. Cell viability was assessed by the MTT assay. DNA fragmentation was analyzed by agarose gel electrophoresis. Cell cycle analysis was realized by flow cytometry technics. Caspases 3 and 9 activities were measured using Promega caspACE assay kits. Proteins and genes expression were visualized respectively by western-blot using specific antibodies and RT-PCR assay. RESULTS: P-glycoprotein-expressing P388/DOX cells did not show resistance to medicarpin (IC50 ~ 90 uM for P388 and P388/DOX cells) and millepurpan (IC50 = 54 uM and 69 uM for P388 and P388/DOX cells, respectively). Treatment with medicarpin or millepurpan triggered apoptosis in sensitive as well as multidrug resistant P388 cells. These effects were mediated through the mitochondrial pathway by modifying the balance pro/anti-apoptotic proteins. While 3 uM doxorubicin alone could not induce cell death in P388/DOX cells, concomitant treatment with doxorubicin and subtoxic concentration of medicarpin or millepurpan restored the pro-apoptotic cascade. Each compound increased sensitivity of P388/DOX cells to doxorubicin whereas they had no effect in sensitive P388 cells. Vinblastine cytotoxicity was also enhanced in P388/DOX cells (IC50 = 210 nM to 23 and 25 nM with medicarpin and millepurpan, respectively). This improved sensitivity was mediated by an increased uptake of doxorubicin in P388/DOX cells expressing P-gp. P-gp expression was not altered by exposure to medicarpin and millepurpan. CONCLUSION: These data indicate that medicarpin and millepurpan possess pro-apoptotic properties and potentiate the cytotoxicity of chemotherapy drugs in multidrug resistant P388 leukemia cells by modulating P-gp-mediated efflux of drugs. These flavonoids may be used as chemopreventive agents or as sensitizer to enhance cytotoxicity of chemotherapy drugs in multidrug resistant cancer cells. PMID- 26598919 TI - Antitussive effect of a fixed combination of Justicia adhatoda, Echinacea purpurea and Eleutherococcus senticosus extracts in patients with acute upper respiratory tract infection: A comparative, randomized, double-blind, placebo controlled study. AB - BACKGROUND: Kan Jang(r) oral solution (KJ) is a fixed combination of aqueous ethanolic extracts of Justicia adhatoda L. leaf, Echinacea purpurea (L.) Moench root, and Eleutherococcus senticosus (Rupr. & Maxim.) Harms root. It is approved in Scandinavia as an herbal medicinal product for respiratory tract infection treatment. PURPOSE: The present clinical trial aimed to compare the antitussive effect of KJ with placebo (PL) and bromhexine (BH) among patients of 18-65 years old with non-complicated upper respiratory infections (URI; i.e., common cold). STUDY DESIGN: We performed a parallel-group, randomized, double-blinded, placebo controlled trial in in 177 patients with acute URI over a 5 day period. METHODS: We investigated the antitussive effects of a KJ (30 ml/day; 762 mg genuine extracts with standardized contents of 0.2 mg/ml vasicine, 0.8 mg/ml chicoric acid, and 0.03 mg/ml eleutherosides B and E), bromhexine hydrochloride (24 mg/30 ml/day) and PL on cough and blood markers. The primary outcome was cough relief, which was assessed as the change of cough frequency from baseline (cough index). Secondary outcomes were safety with regards to reported adverse events (AEs) and hematological data. RESULTS: Both KJ and BH relieved cough more effectively than placebo. On the third and fourth days of treatment, we observed faster improvement in the group receiving KJ compared to in the groups receiving BH (100%) or PL (100%), indicating a slightly shorter recovery time in the KJ group. KJ showed a good tolerability and safety profile. CONCLUSION: KJ exerted significant antitussive effects in URI. The present data further support the therapeutic use of KJ in upper respiratory tract infections. PMID- 26598920 TI - Drug-induced liver injury: A 2-year retrospective study of 1169 hospitalized patients in a single medical center. AB - BACKGROUND: Although herbal medicines (HMs) are widely used in Asian and Western countries, medicinal information concerning their hepatic toxicity or interaction with conventional medicines (CMs) is sparse. PURPOSE: The aim of our study was to estimate the prevalence of drug-induced liver injury (DILI) among total inpatients prescribed HMs or CMs. Furthermore, we noted all medications suspected to be associated with hepatotoxicity in the liver injury group during the period of hospitalization. STUDY DESIGN: We retrospectively observed medical records of 1169 inpatients in a single medical center from January 2012 to July 2014. METHODS: Based on a database of the 1169 inpatients at a single medical center, we researched the occurrence rate and type of liver injury according to the criteria of the Council for International Organization of Medical Science (CIOMS). We also utilized a simplified Roussel Uclaf Causality Assessment Method (RUCAM) score for probable causality assessment between drugs and liver injury. RESULTS: Among a total of 1169 inpatients, 13 cases whose baseline LFTs had been in the normal range at admission had abnormal liver parameters at the time of follow-up, and 11 of them (0.94%) were attributed to drugs: 0.43% (5 of 1169) to HMs, 0.43% (5 of 1169) to CMs, and 0.09% (1 of 1169) to combined drug classes. Two of them were found to have liver injury because of pneumonia and sepsis. As for liver injury type, 8 cases were hepatocellular, 2 were cholestatic, and 1 was of mixed pattern. The common causative HMs for hepatotoxicity were Ephedrae Herba and Scutellariae Radix, while CMs included antidepressants, antihistamines, and antibacterials. CONCLUSIONS: We investigated approximate incidence rates and analyzed suspicious drugs associated with liver damage, which revealed a low frequency of liver injury induced by HMs. However, further study, based on a well designed, long-term, multicenter prospective study, will be required to determine the safety of HMs. PMID- 26598921 TI - Multicentric Castleman Disease With Tubulointerstitial Nephritis Mimicking IgG4 related Disease: Two Case Reports. AB - Multicentric Castleman disease is a benign lymphoproliferative disorder with heterogenous clinical symptoms and involves systemic organs in addition to lymph nodes. Elevated serum IgG4 levels and IgG4-positive plasma cell (IgG4+PC) infiltrates have been reported in lymph nodes, lung and skin in some multicentric Castleman disease cases, resembling IgG4-related disease (IgG4-RD) histologically. However, no report has been available regarding IgG4+PC infiltration in the kidneys of multicentric Castleman disease. Here, we report 2 cases of multicentric Castleman disease complicated by IgG4-related disease (IgG4 RD) histologically. However, there has been no report published on PC-rich tubulointerstitial nephritis, lymphadenopathy, with numerous IgG4+PC infiltration, and elevated serum IgG4 levels, mimicking IgG4-RD. The blood examinations revealed systemic inflammation and elevated C-reactive protein and interleukin-6 levels. Corticosteroid therapy was partially effective in both cases, and combination therapy of corticosteroid and tocilizumab was needed in both cases. Moreover, after triple therapy with corticosteroid, rituximab and cyclophosphamide were used in 1 case to tame the severe inflammation. The present cases suggest that if continuously elevated serum C-reactive protein levels and partial corticosteroid responsiveness are encountered, multicentric Castleman disease should be considered rather than IgG4-RD as a differential diagnosis even if serum IgG4 is elevated and IgG4+PCs infiltrate systemic organs. PMID- 26598922 TI - Refined Dummy Atom Model of Mg(2+) by Simple Parameter Screening Strategy with Revised Experimental Solvation Free Energy. AB - Metal ions play an important role in the catalysis of metalloenzymes. To investigate metalloenzymes via molecular modeling, a set of accurate force field parameters for metal ions is highly imperative. To extend its application range and improve the performance, the dummy atom model of metal ions was refined through a simple parameter screening strategy using the Mg(2+) ion as an example. Using the AMBER ff03 force field with the TIP3P model, the refined model accurately reproduced the experimental geometric and thermodynamic properties of Mg(2+). Compared with point charge models and previous dummy atom models, the refined dummy atom model yields an enhanced performance for producing reliable ATP/GTP-Mg(2+)-protein conformations in three metalloenzyme systems with single or double metal centers. Similar to other unbounded models, the refined model failed to reproduce the Mg-Mg distance and favored a monodentate binding of carboxylate groups, and these drawbacks needed to be considered with care. The outperformance of the refined model is mainly attributed to the use of a revised (more accurate) experimental solvation free energy and a suitable free energy correction protocol. This work provides a parameter screening strategy that can be readily applied to refine the dummy atom models for metal ions. PMID- 26598924 TI - Dendrite-Free Polygonal Sodium Deposition with Excellent Interfacial Stability in a NaAlCl4-2SO2 Inorganic Electrolyte. AB - Room-temperature Na-metal-based rechargeable batteries, including Na-O2 and Na-S systems, have attracted attention due to their high energy density and the abundance of sodium resources. Although these systems show considerable promise, concerns regarding the use of Na metal should be addressed for their success. Here, we report dendrite-free Na-metal electrode for a Na rechargeable battery, engineered by employing nonflammable and highly Na(+)-conductive NaAlCl4.2SO2 inorganic electrolyte, as a result, showing superior electrochemical performances to those in conventional organic electrolytes. We have achieved a hard-to-acquire combination of nondendritic Na electrodeposition and highly stable solid electrolyte interphase at the Na-metal electrode, enabled by inducing polygonal growth of Na deposit using a highly concentrated Na(+)-conducting inorganic electrolyte and also creating highly dense passivation film mainly composed of NaCl on the surface of Na-metal electrode. These results are highly encouraging in the development of room-temperature Na rechargeable battery and provide another strategy for highly reliable Na-metal-based rechargeable batteries. PMID- 26598923 TI - Effect of hypoxia on tissue factor pathway inhibitor expression in breast cancer. AB - ESSENTIALS: A hypoxic microenvironment is a common feature of tumors that may influence activation of coagulation. MCF-7 and SK-BR-3 breast cancer cells and breast cancer tissue samples were used. The results showed transcriptional repression of tissue factor pathway inhibitor expression in hypoxia. Hypoxia inducible factor 1alpha may be a target for the therapy of cancer-related coagulation and thrombosis. BACKGROUND: Activation of coagulation is a common finding in patients with cancer, and is associated with an increased risk of venous thrombosis. As a hypoxic microenvironment is a common feature of solid tumors, we investigated the role of hypoxia in the regulation of tissue factor (TF) pathway inhibitor (TFPI) expression in breast cancer. OBJECTIVES: To explore the transcriptional regulation of TFPI by hypoxia-inducible factor (HIF)-1alpha in breast cancer cells and their correlation in breast cancer tissues. METHODS AND RESULTS: MCF-7 and SK-BR-3 breast cancer cells were cultured in 1% oxygen or treated with cobalt chloride (CoCl2 ) to mimic hypoxia. Time-dependent and dose dependent downregulation of TFPI mRNA (quantitative RT-PCR) and of free TFPI protein (ELISA) were observed in hypoxia. Western blotting showed parallel increases in the levels of HIF-1alpha protein and TF. HIF-1alpha inhibitor abolished or attenuated the hypoxia-induced downregulation of TFPI. Luciferase reporter assay showed that both hypoxia and HIF-1alpha overexpression caused strong repression of TFPI promoter activity. Subsequent chromatin immunoprecipitation and mutagenesis analysis demonstrated a functional hypoxia response element within the TFPI promoter, located at -1065 to -1060 relative to the transcriptional start point. In breast cancer tissue samples, gene expression analyses showed a positive correlation between the mRNA expression of TFPI and that of HIF-1alpha. CONCLUSIONS: This study demonstrates that HIF-1alpha is involved in the transcriptional regulation of the TFPI gene, and suggests that a hypoxic microenvironment inside a breast tumor may induce a procoagulant state in breast cancer patients. PMID- 26598925 TI - Exploring the role of the sampler housing in limiting uptake of semivolatile organic compounds in passive air samplers. AB - Passive air samplers (PASs) are simple, versatile devices that are increasingly used to determine the concentrations of semivolatile organic compounds (SVOCs) in the atmosphere. Using PAS and interpreting PAS-derived data with confidence requires a detailed understanding of the factors that control the uptake kinetics. A number of experiments were aimed at clarifying the role that the housing has in limiting the uptake of SVOCs in a PAS. Specifically, we quantified the gradient in the amount of polychlorinated biphenyls (PCBs) accumulated in XAD filled mesh cylinders with increasing distance from the PAS housing's opening. That gradient was non-existent in an artificially ventilated housing (i.e. different segments of a cylinder contained the same amount of PCBs), minor during outdoor deployments (i.e. the bottom third of the cylinder sampled approximately 20% more PCBs than the top third), and strong during indoor deployments (i.e. the bottom third of the cylinder sampled twice the amount sampled by the top third). This is consistent with the thickness of the air boundary layer surrounding the XAD-resin increasing with increasing distance from the housing's opening and decreasing with increasing air turbulence. An experiment with housings absorbing different amounts of sunlight revealed that heat-induced convection has a minor effect on the gradient within the mesh cylinder and on the total amount of accumulated PCB. Similarly, this gradient and the total amount sorbed was also not influenced by the number of XAD-filled mesh cylinders placed within a housing as long as they were deployed outdoors. However, if four mesh cylinders were placed in one housing in a calm indoor setting, the top third of the mesh cylinders was notably starved of PCBs, suggestive of an air concentration gradient within the sampler housing. PMID- 26598926 TI - Time Course of Visual Attention to High-Calorie Virtual Food in Individuals with Bulimic Tendencies. AB - The aim of the present study was to use an eye-tracking device to investigate attention bias and its mechanism toward high-calorie virtual food in individuals with bulimic tendencies (BT). A total of 76 participants were divided into two groups: a BT group (n = 38) and a control group (n = 38). The eye movements of all participants were continuously measured while the participants were confronted with pairs of high-calorie, low-calorie, and nonfood virtual stimuli (pictures). It was found that the BT group detected high-calorie food more quickly than they did the low-calorie food and nonfood stimuli, but they also avoided the high-calorie food. These results indicate that individuals with BT automatically allocate their attention toward high-calorie food and, subsequently, try to avoid it. Based on these results, we suggest that this approach-avoidance pattern for high-calorie virtual food could be a factor in the development and maintenance of bulimia symptoms by encouraging individuals with BT to be in conflict with the urge to overeat. PMID- 26598927 TI - Synthesis, characterization and carbonic anhydrase inhibitory activity of novel benzothiazole derivatives. AB - N-protected amino acids were reacted with substituted benzothiazoles to give the corresponding N-protected amino acid-benzothiazole conjugates (60-89%). Their structures were confirmed by proton nuclear magnetic resonance ((1)H NMR), carbon 13 nuclear magnetic resonance ((13)C NMR), IR and elemental analysis. Their carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activities were determined against two cytosolic human isoforms (hCA I and hCA II), one membrane-associated (hCA IV) and one transmembrane (hCA XII) enzyme by a stopped-flow CO2 hydrase assay method. The new compounds showed rather weak, micromolar inhibitory activity against most of these enzymes. PMID- 26598928 TI - Weight Management in Phenylketonuria: What Should Be Monitored. AB - BACKGROUND: Severe intellectual disability and growth impairment have been overcome by the success of early and continuous treatment of patients with phenylketonuria (PKU). However, there are some reports of obesity, particularly in women, suggesting that this may be an important comorbidity in PKU. It is becoming evident that in addition to acceptable blood phenylalanine control, metabolic dieticians should regard weight management as part of routine clinical practice. SUMMARY: It is important for practitioners to differentiate the 3 levels for overweight interpretation: anthropometry, body composition and frequency and severity of associated metabolic comorbidities. The main objectives of this review are to suggest proposals for the minimal standard and gold standard for the assessment of weight management in PKU. While the former aims to underline the importance of nutritional status evaluation in every specialized clinic, the second objective is important in establishing an understanding of the breadth of overweight and obesity in PKU in Europe. KEY MESSAGES: In PKU, the importance of adopting a European nutritional management strategy on weight management is highlighted in order to optimize long-term health outcomes in patients with PKU. PMID- 26598929 TI - Editorial overview: Mechanistic biology: Dynamic interactions in biology - sensing change. PMID- 26598930 TI - Effects and Mechanism of Action of Inducible Nitric Oxide Synthase on Apoptosis in a Rat Model of Cerebral Ischemia-Reperfusion Injury. AB - Inducible nitric oxide synthase (iNOS) is a key enzyme in regulating nitric oxide (NO) synthesis under stress, and NO has varying ability to regulate apoptosis. The aim of this study was to investigate the effects and possible mechanism of action of iNOS on neuronal apoptosis in a rat model of cerebral focal ischemia and reperfusion injury in rats treated with S-methylisothiourea sulfate (SMT), a high-selective inhibitor of iNOS. Seventy-two male Sprague-Dawley (SD) rats were randomly divided into three groups: the sham, middle cerebral artery occlusion (MCAO) + vehicle, and MCAO + SMT groups. Neurobehavioral deficits, infarct zone size, and cortical neuron morphology were evaluated through the modified Garcia scores, 2,3,5-triphenyltetrazolium chloride (TTC), and Nissl staining, respectively. Brain tissues and serum samples were collected at 72 hr post reperfusion for immunohistochemical analysis, Western blotting, Terminal deoxynucleotidyl transferase-mediated dUTP-biotin Nick End Labeling assay (TUNEL) staining, and enzyme assays. The study found that inhibition of iNOS significantly attenuated the severity of the pathological changes observed as a result of ischemia-reperfusion injury: SMT reduced NO content as well as total nitric oxide synthase (tNOS) and iNOS activities in both ischemic cerebral hemisphere and serum, improved neurobehavioral scores, reduced mortality, reduced the infarct volume ratio, attenuated morphological changes in cortical neurons, decreased the rate of apoptosis (TUNEL and caspase-3-positive), and increased phospho (p)-AKT expression in ischemic penumbra. These results suggested that inhibition of iNOS might reduce the severity of ischemia-reperfusion injury by inhibiting neuronal apoptosis via maintaining p-AKT activity. PMID- 26598931 TI - Modification of both d33 and TC in a potassium-sodium niobate ternary system. AB - In this work, we simultaneously achieved a giant d33 and a high TC in a lead-free piezoelectric ternary system of (1-x-y)K0.48Na0.52NbO3-xBiFeO3-yBi0.5Na0.5ZrO3 {(1-x-y)KNN-xBF-yBNZ}. Owing to the rhombohedral-orthorhombic-tetragonal (R-O-T) phase coexistence and the enhanced dielectric and ferroelectric properties, the ceramics with a composition of (x = 0.006, y = 0.04) show a giant d33 of ~428 pC N(-1) together with a TC of ~318 degrees C, thereby proving that the design of ternary systems is an effective way to achieve both high d33 and high TC in KNN based materials. In addition, a good thermal stability for piezoelectricity was also observed in these ceramics (e.g., d33 > 390 pC N(-1), T <= 300 degrees C). This is the first time such a good comprehensive performance in potassium-sodium niobate materials has been obtained. As a result, we believe that this type of material system with both giant d33 and high TC is a promising candidate for high temperature piezoelectric devices. PMID- 26598932 TI - Importance of Phox2B Immunohistochemical Stain for Detecting Metastatic Neuroblastoma Cells in Bone Marrow Specimens. PMID- 26598933 TI - Hepatobiliary and Pancreatic: Acute hepatitis in the setting of chronic Schistosoma mansoni infection and post-praziquantel therapy. PMID- 26598934 TI - Pd-indenyl-diphosphine: an effective catalyst for the preparation of triarylamines. AB - A new Buchwald-type diphosphine ligand has been developed for applications in Pd catalyzed amination reactions towards the preparation of triarylamines. The catalyst can be used to perform the amination of a diverse array of aryl and heteroaryl chlorides. PMID- 26598935 TI - Gaps in evidence: Management of pediatric obstructive sleep apnea without tonsillar hypertrophy. AB - OBJECTIVES/HYPOTHESIS: Persistent obstructive sleep apnea (OSA) is demonstrated in 40% of children after adenotonsillectomy. We previously evaluated the basis of management decisions in children with OSA without tonsillar hypertrophy and found that 61% of decisions were non-evidence based. The aim of this study was to identify gaps in evidence for the management of children with OSA without tonsillar hypertrophy. STUDY DESIGN: Case series. METHODS: We recorded all real time decisions made by pediatric subspecialists from eight disciplines that participated in an upper airway clinic and management conferences. Practitioners were immediately queried regarding the basis of their decisions, and non-evidence based decisions were categorized. RESULTS: During 10 case conferences and five clinics, 507 decisions were made for 63 children (43% with Down syndrome, 20% with Pierre Robin sequence). The 309 non-evidence-based decisions most commonly pertained to follow-up timing and appropriate subspecialty clinic location (116/309, 38%) as well as timing for repeat polysomnography (35/309, 11%), especially in children at high risk for persistent OSA after treatment. Additional gaps identified included the likelihood of OSA improvement from weight loss, and effectiveness of sleep surgical procedures (i.e., lingual tonsillectomy, posterior midline glossectomy, and craniofacial surgery) alone or in combination. CONCLUSIONS: Identified gaps in evidence included timing and location of follow-up, appropriate use of polysomnography for surveillance, effectiveness of specific surgical procedures performed alone and in combination, and the use of oral appliances and continuous positive airway pressure therapy in children with Down syndrome. We also found a need for studies to compare the effectiveness of these treatment options in diverse patient populations. LEVEL OF EVIDENCE: 4 Laryngoscope, 126:758-762, 2016. PMID- 26598936 TI - Acetazolamide-responsive paroxysmal dyskinesia in a 12-week-old female golden retriever dog. PMID- 26598937 TI - The Impact of Trachomatous Trichiasis on Quality of Life: A Case Control Study. AB - BACKGROUND: Trachomatous trichiasis is thought to have a profound effect on quality of life (QoL), however, there is little research in this area. We measured vision and health-related QoL in a case-control study in Amhara Region, Ethiopia. METHODOLOGY/PRINCIPAL FINDINGS: We recruited 1000 adult trichiasis cases and 200 trichiasis-free controls, matched to every fifth trichiasis case on age (+/- two years), sex and location. Vision-related quality of life (VRQoL) and health-related quality of life (HRQoL) were measured using the WHO/PBD-VF20 and WHOQOL-BREF questionnaires. Comparisons were made using linear regression adjusted for age, sex and socioeconomic status. Trichiasis cases had substantially lower VRQoL than controls on all subscales (overall eyesight, visual symptom, general functioning and psychosocial, p<0.0001), even in the sub group with normal vision (p<0.0001). Lower VRQoL scores in cases were associated with longer trichiasis duration, central corneal opacity, visual impairment and poor contrast sensitivity. Trichiasis cases had lower HRQoL in all domains (Physical-health, Psychological, Social, Environment, p<0.0001), lower overall QoL (mean, 34.5 v 64.6; p<0.0001) and overall health satisfaction (mean, 38.2 v 71.7; p<0.0001). This association persisted in a sub-group analysis of cases and controls with normal vision. Not having a marriage partner (p<0.0001), visual impairment (p = 0.0068), daily labouring (p<0.0001), presence of other health problems (p = 0.0018) and low self-rated wealth (p<0.0001) were independently associated with lower overall QoL scores in cases. Among cases, trichiasis caused 596 (59%) to feel embarrassed, 913 (91.3%) to worry they may lose their remaining eyesight and 681 (68.1%) to have sleep disturbance. CONCLUSIONS/SIGNIFICANCE: Trachomatous trichiasis substantially reduces vision and health related QoL and is disabling, even without visual impairment. Prompt trichiasis intervention is needed both to prevent vision loss and to alleviate physical and psychological suffering, social exclusion and improve overall well-being. Implementation of the full SAFE strategy is needed to prevent the development of trachomatous trichiasis. PMID- 26598938 TI - Synergistic health effects between chemical pollutants and electromagnetic fields. AB - Humans and ecosystems are exposed to highly variable and unknown cocktail of chemicals and radiations. Although individual chemicals are typically present at low concentrations, they can interact with each other resulting in additive or potentially synergistic mixture effects. This was also observed with products obtained by radiation actions such as sunlight or electromagnetic fields that can change the effects of chemicals, such as pesticides, and metal trace elements on health. Concomitant presence of various pesticides and their transformation products adds further complexity to chemical risk assessment since chronic inflammation is a key step for cancer promotion. Degradation of a parent molecule can produce several by-products which can trigger various toxic effects with different impacts on health and environment. For instance, the cocktail of sunlight irradiated sulcotrione pesticide has a greater cytotoxicity and genotoxicity than parent molecule, sulcotrione, and questions about the impact of photochemical process on environment. Adjuvants were shown to modify the biological features of pesticides. Addition of other elements, metals or biological products, can differently enhance cell toxicity of pesticides or electromagnetic radiations suggesting a synergy in living organisms. Electromagnetic fields spreading, pesticide by-products and mixtures monitoring become greater for environmental contamination evaluations. PMID- 26598939 TI - Gulf War illness: an overview of events, most prevalent health outcomes, exposures, and clues as to pathogenesis. AB - INTRODUCTION: During or very soon after the 1990-1991 Persian Gulf War, veterans of the conflict began to report symptoms of illness. Common complaints included combinations of cognitive difficulties, fatigue, myalgia, rashes, dyspnea, insomnia, gastrointestinal symptoms and sensitivity to odors. Gradually in the USA, and later in the UK, France, Canada, Denmark and Australia, governments implemented medical assessment programs and epidemiologic studies to determine the scope of what was popularly referred to as "the Gulf War syndrome". Attention was drawn to numerous potentially toxic deployment-related exposures that appeared to vary by country of deployment, by location within the theater, by unit, and by personal job types. Identifying a single toxicant cause was considered unlikely and it was recognized that outcomes were influenced by genetic variability in xenobiotic metabolism. METHODS: Derived from primary papers and key reports by the Research Advisory Committee on Gulf War Veterans' Illnesses and the Institute of Medicine, a brief overview is presented of war related events, symptoms and diagnostic criteria for Gulf War illness (GWV), some international differences, the various war-related exposures and key epidemiologic studies. Possible exposure interactions and pathophysiologic mechanisms are discussed. RESULTS: Exposures to pyridostigmine bromide, pesticides, sarin and mustard gas or combinations thereof were most associated with GWI, especially in some genotype subgroups. The resultant oxidant stress and background exposome must be assumed to have played a role. CONCLUSION: Gulf War (GW) exposures and their potential toxic effects should be considered in the context of the human genome, the human exposome and resultant oxidant stress to better characterize this unique environmentally-linked illness and, ultimately, provide a rationale for more effective interventions and future prevention efforts. PMID- 26598940 TI - Low light intensity and nitrogen starvation modulate the chlorophyll content of Scenedesmus dimorphus. AB - AIMS: Chlorophyll is a photosynthetic pigment found in plants and algal organisms and is a bioproduct with human health benefits and a great potential for use in the food industry. The chlorophyll content in microalgae strains varies in response to environmental factors. In this work, we assessed the effect of nitrogen depletion and low light intensity on the chlorophyll content of the Scenedesmus dimorphus microalga. METHODS AND RESULTS: The growth of S. dimorphus under low light intensity led to a reduction in cell growth and volume as well as increased cellular chlorophyll content. Nitrogen starvation led to a reduction in cell growth and the chlorophyll content, changes in the yield and productivity of chlorophylls a and b. Transmission electron microscopy was used to investigate the ultrastructural changes in the S. dimorphus exposed to nitrogen and light deficiency. CONCLUSIONS: In contrast to nitrogen depletion, low light availability was an effective mean for increasing the total chlorophyll content of green microalga S. dimorphus. SIGNIFICANCE AND IMPACT OF THE STUDY: The findings acquired in this work are of great biotechnological importance to extend knowledge of choosing the right culture condition to stimulate the effectiveness of microalgae strains for chlorophyll production purposes. PMID- 26598941 TI - Microbial diversity--exploration of natural ecosystems and microbiomes. AB - Microorganisms are the pillars of life on Earth. Over billions of years, they have evolved into every conceivable niche on the planet. Microbes reshaped the oceans and atmosphere and gave rise to conditions conducive to multicellular organisms. Only in the past decade have we started to peer deeply into the microbial cosmos, and what we have found is amazing. Microbial ecosystems behave, in many ways, like large-scale ecosystems, although there are important exceptions. We review recent advances in our understanding of how microbial diversity is distributed across environments, how microbes influence the ecosystems in which they live, and how these nano-machines might be harnessed to advance our understanding of the natural world. PMID- 26598943 TI - Breast cancer therapy-associated cardiovascular disease. AB - Breast cancer treatments have evolved over the past decades, although several widely used treatments have adverse cardiac effects. Radiotherapy generally improves the survival of women with breast cancer, although its deleterious cardiovascular effects pose competing risks of morbidity and/or mortality. In the past, radiation-associated cardiovascular disease was a phenomenon considered to take more than a decade to manifest, but newer research suggests that this latency is much shorter. Knowledge of coronary anatomy relative to the distribution of the delivered radiation dose has improved over time, and as a result, techniques have enabled this risk to be decreased. Studies continue to be performed to better understand, prevent and mitigate against radiation-associated cardiovascular disease. Treatments such as anthracyclines, which are a mainstay of chemotherapy for breast cancer, and newer targeted agents such as trastuzumab both have established risks of cardiotoxicity, which can limit their effectiveness and result in increased morbidity and/or mortality. Interest in whether beta-blockers, statins and/or angiotensin-converting enzyme (ACE) inhibitors might have therapeutic and/or preventative effects in these patients is currently increasing. This Review summarizes the incidence, risks and effects of treatment-induced cardiovascular disease in patients with breast cancer and describes strategies that might be used to minimize this risk. PMID- 26598942 TI - Combination cancer immunotherapies tailored to the tumour microenvironment. AB - Evidence suggests that cancer immunotherapy will be a major part of the combination treatment plan for many patients with many cancer types in the near future. There are many types of immune processes involving different antitumour and tumour-promoting leucocytes, and tumour cells use many strategies to evade the immune response. The tumour microenvironment can help determine which immune suppressive pathways become activated to restrain antitumour immunity. This includes immune checkpoint receptors on effector T-cells and myeloid cells, and release of inhibitory cytokines and metabolites. Therapeutic approaches that target these pathways, particularly immune-checkpoint receptors, can induce durable antitumour responses in patients with advanced-stage cancers, including melanoma. Nevertheless, many patients do not have a good response to monotherapy approaches and alternative strategies are required to achieve optimal therapeutic benefit. These strategies include eliminating the bulk of tumour cells to provoke tumour-antigen release and antigen-presenting cell (APC) function, using adjuvants to enhance APC function, and using agents that enhance effector-cell activity. In this Review, we discuss the stratification of the tumour microenvironment according to tumour-infiltrating lymphocytes and PD-L1 expression in the tumour, and how this stratification enables the design of optimal combination cancer therapies tailored to target different tumour microenvironments. PMID- 26598945 TI - Surgery: Limitations of prospective surgical oncology trials - a US view. PMID- 26598944 TI - Revisiting tumour aneuploidy - the place of ploidy assessment in the molecular era. AB - Chromosome instability (CIN) is gaining increasing interest as a central process in cancer. CIN, either past or present, is indicated whenever tumour cells harbour an abnormal quantity of DNA, termed 'aneuploidy'. At present, the most widely used approach to detecting aneuploidy is DNA cytometry - a well-known research assay that involves staining of DNA in the nuclei of cells from a tissue sample, followed by analysis using quantitative flow cytometry or microscopic imaging. Aneuploidy in cancer tissue has been implicated as a predictor of a poor prognosis. In this Review, we have explored this hypothesis by surveying the current landscape of peer-reviewed research in which DNA cytometry has been applied in studies with disease-appropriate clinical follow up. This area of research is broad, however, and we restricted our survey to results published since 2000 relating to seven common epithelial cancers (those of the breast; endometrium, ovary, and uterine cervix; oesophagus; colon and rectum; lung; prostate; and bladder). We placed particular emphasis on results from multivariate analyses to pinpoint situations in which the prognostic value of aneuploidy as a biomarker is strong compared with that of existing indicators, such as clinical stage, histological grade, and specific molecular markers. We summarize the implications of our findings for the prognostic use of ploidy analysis in the clinic and for the theoretical understanding of the role of CIN in carcinogenesis. PMID- 26598948 TI - CNS cancer: Astrocytoma cells interconnect to resist radiotherapy. PMID- 26598946 TI - Computational oncology--mathematical modelling of drug regimens for precision medicine. AB - Computational oncology is a generic term that encompasses any form of computer based modelling relating to tumour biology and cancer therapy. Mathematical modelling can be used to probe the pharmacokinetics and pharmacodynamics relationships of the available anticancer agents in order to improve treatment. As a result of the ever-growing numbers of druggable molecular targets and possible drug combinations, obtaining an optimal toxicity-efficacy balance is an increasingly complex task. Consequently, standard empirical approaches to optimizing drug dosing and scheduling in patients are now of limited utility; mathematical modelling can substantially advance this practice through improved rationalization of therapeutic strategies. The implementation of mathematical modelling tools is an emerging trend, but remains largely insufficient to meet clinical needs; at the bedside, anticancer drugs continue to be prescribed and administered according to standard schedules. To shift the therapeutic paradigm towards personalized care, precision medicine in oncology requires powerful new resources for both researchers and clinicians. Mathematical modelling is an attractive approach that could help to refine treatment modalities at all phases of research and development, and in routine patient care. Reviewing preclinical and clinical examples, we highlight the current achievements and limitations with regard to computational modelling of drug regimens, and discuss the potential future implementation of this strategy to achieve precision medicine in oncology. PMID- 26598947 TI - Integrating palliative care into the trajectory of cancer care. AB - Over the past five decades, palliative care has evolved from serving patients at the end of life into a highly specialized discipline focused on delivering supportive care to patients with life-limiting illnesses throughout the disease trajectory. A growing body of evidence is now available to inform the key domains in the practice of palliative care, including symptom management, psychosocial care, communication, decision-making, and end-of-life care. Findings from multiple studies indicate that integrating palliative care early in the disease trajectory can result in improvements in quality of life, symptom control, patient and caregiver satisfaction, illness understanding, quality of end-of-life care, survival, and costs of care. In this narrative Review, we discuss various strategies to integrate oncology and palliative care by optimizing clinical infrastructures, processes, education, and research. The goal of integration is to maximize patient access to palliative care and, ultimately, to improve patient outcomes. We provide a conceptual model for the integration of supportive and/or palliative care with primary and oncological care. We also discuss how health care systems and institutions need to tailor integration based on their resources, size, and the level of primary palliative care available. PMID- 26598949 TI - Improved charge transfer and photoelectrochemical performance of CuI/Sb2S3/TiO2 heterostructure nanotube arrays. AB - Charge transfer is important for the performance of a photoelectrochemical cell. Understanding photogenerated charge accumulation and separation is mandatory for the design and optimisation of photoelectrochemical cells. Unique stacked and embedded heterostructure of Sb2S3/TiO2 nanotube arrays (NTAs) was fabricated through anodic oxidation with the hydrothermal method. Surface photovoltage spectroscopy, phase spectra and photoluminescence measurements were performed to explore the mechanism by which the inorganic hole transport material CuI affects the charge transfer and photoelectrochemical properties of Sb2S3/TiO2 heterostructure NTAs. The interfacial separation and transport of photoinduced charge carriers were also examined by applying current-voltage characteristics (J V), incident-photon-to-current conversion efficiency (IPCE) and Mott-Schottky techniques. Results show that CuI acts not only as a hole-conducting and electron blocking material but also as a light-absorbing material in the ultraviolet range. Efficient charge transfer processes exist in CuI/Sb2S3/TiO2 heterostructure NTAs. The photoelectrochemical performance of CuI/Sb2S3/TiO2 heterostructure NTAs is dramatically improved. Under AM 1.5G illumination at 100mW/cm(2), the short-circuit current density and open-circuit voltage are 3.51mA/cm(2) and 0.87V, respectively. The photoelectric conversion efficiency of CuI/Sb2S3/TiO2 heterostructure NTAs (0.95%) is 36% higher than that of Sb2S3/TiO2 heterostructure NTAs (0.66%). PMID- 26598950 TI - The association of ESBL-producing Enterobacteriaceae (ESBL-E) carriage in humans with pigs - a reply. PMID- 26598951 TI - Topical diphencyprone for the treatment of locoregional intralymphatic melanoma metastases of the skin; the 5-year Norwich experience. PMID- 26598952 TI - Is Every Smoker Interested in Price Promotions? An Evaluation of Price-Related Discounts by Cigarette Brands. AB - CONTEXT: Raising unit price is one of the most effective ways of reducing cigarette consumption. A large proportion of US adult smokers use generic brands or price discounts in response to higher prices, which may mitigate the public health impacts of raising unit price. OBJECTIVE: The main purpose of this study was to evaluate the retail price impact and the determinants of price-related discount use among US adult smokers by their most commonly used cigarette brand types. METHODS: Data from the 2009-2010 National Adult Tobacco Survey, a telephone survey of US adults 18 years or older, was used to assess price-related discount use by cigarette brands. Price-related discounts included coupons, rebates, buy 1 get 1 free, 2 for 1, or any other special promotions. Multivariate logistic regression was used to assess sociodemographic and tobacco use determinants of discount use by cigarette brands. RESULTS: Discount use was most common among premium brand users (22.1%), followed by generic (13.3%) and other brand (10.8%) users. Among premium brand users, those who smoked 10 to 20 cigarettes per day were more likely to use discounts, whereas elderly smokers, non-Hispanic blacks, those with greater annual household income, dual users of cigarettes and other combustible tobacco products, and those who had no quit intentions were less likely to do so. Among generic brand users, those who had no quit intentions and those who smoked first cigarette within 60 minutes after waking were more likely to use discounts. CONCLUSIONS: Frequent use of discounts varies between smokers of premium and generic cigarette brands. Setting a high minimum price, together with limiting the use of coupons and promotions, may uphold the effect of cigarette excise taxes to reduce smoking prevalence. PMID- 26598953 TI - Community Palliative Care in Turkey: A Collaborative Promoter to a New Concept in the Middle East. AB - The Middle East has been struggling with basic issues of cancer care, and in specific, palliative care, at the primary health care level in the communities. The Middle East Cancer Consortium designated this issue as the highest priority of its activities in the region. Following basic and advanced courses and national and international workshops, local governments recognized the essentiality of developing palliative care services in their respective countries. As the result of these training activities, in 2010, the Ministry of Health in Turkey initiated a novel program whereby population-based and home based palliative care teams were developed throughout the country, including peripheral regions in the countries where appropriate care was not available. This initiative led to a dramatic increase in the number of cancer patients receiving palliative care at their homes. The Turkish initiative can serve as a model to other countries in the Middle East and beyond it. PMID- 26598954 TI - Acute respiratory distress syndrome following cardiovascular surgery: current concepts and novel therapeutic approaches. AB - PURPOSE OF REVIEW: This review gives an update on current treatment options and novel concepts on the prevention and treatment of the acute respiratory distress syndrome (ARDS) in cardiovascular surgery patients. RECENT FINDINGS: The only proven beneficial therapeutic options in ARDS are those that help to prevent further ventilator-induced lung injury, such as prone position, use of lung protective ventilation strategies, and extracorporeal membrane oxygenation. In the future also new approaches like mesenchymal cell therapy, activation of hypoxia-elicited transcription factors or targeting of purinergic signaling may be successful outside the experimental setting. Owing to the so far limited treatment options, it is of great importance to determine patients at risk for developing ARDS already perioperatively. In this context, serum biomarkers and lung injury prediction scores could be useful. SUMMARY: Preventing ARDS as a severe complication in the cardiovascular surgery setting may help to reduce morbidity and mortality. As cardiovascular surgery patients are of greater risk to develop ARDS, preventive interventions should be implemented early on. Especially, use of low tidal volumes, avoiding of fluid overload and restrictive blood transfusion regimes may help to prevent ARDS. PMID- 26598955 TI - Randomized Intervention of Self-Collected Sampling for Human Papillomavirus Testing in Under-Screened Rural Women: Uptake of Screening and Acceptability. AB - BACKGROUND: Our aim was to determine if cervical cancer screening uptake would increase among under-screened women living in rural Ontario, Canada, if at-home self-collected sampling for human papillomavirus (HPV) testing was offered as a primary cervical cancer screening modality, compared to invited papanicolaou (Pap) testing or routine opportunistic screening. METHODS: Women 30-70 years of age who were overdue for cervical cancer screening were randomized to receive (1) an at-home self-collected HPV kit, (2) a reminder invitation for Pap testing, or (3) standard of care opportunistic screening. The first two arms were also asked demographic and screening history questions. Women randomized to arm 1 were asked about acceptability. RESULTS: In total, 818 eligible women were identified in a small rural community in Southwestern Ontario: 335 received a self-collected HPV testing kit, 331 received a reminder letter, and 152 received standard of care. In the HPV self-collection arm, 21% (70/335) returned the sample and questionnaire and 11% (37/335) opted to undergo Pap testing. In total, 32% from the HPV self-collection arm, 15% (51/331) from the Pap invitation arm, and 8.5% (13/152) with standard of care were screened. Women receiving the self-collected HPV kit were 3.7 (95% confidence interval 2.2-6.4) times more likely to undergo screening compared to the standard of care arm. In the HPV self-sampling arm, 80% (56/70) said they would be very likely to choose self-collected sampling in the future. CONCLUSIONS: Providing self-collected sampling for HPV testing was more effective than sending reminder letters to increase screening coverage in under screened women. PMID- 26598956 TI - Drug evaluation review: dupilumab in atopic dermatitis. AB - Atopic dermatitis (AD) is characterized by type 2 helper T (Th2) cell-driven inflammation. Dupilumab is a fully human monoclonal antibody directed against the IL-4 receptor alpha subunit that blocks the signaling of IL-4 and IL-13, both key cytokines in Th2-mediated pathways. In Phase I and II studies of adults with moderate-to-severe AD, dupilumab administered as monotherapy or with topical corticosteroids resulted in rapid, significant improvements in clinical efficacy, patient-reported outcomes, and Th2-related serum and tissue biomarkers, and shifted the RNA expression profile of lesional skin to a more nonlesional signature. In all clinical studies to date, dupilumab has shown a favorable safety profile with no dose-limiting toxicity. The robust effects of dupilumab on skin inflammation and pruritus confirm the pathogenic role of IL-4 and IL-13 signaling in adult AD, and further support the application of Th2 cytokine antagonists in the treatment of this disease. PMID- 26598958 TI - Health implications of social networks for children living in public housing. AB - This study sought to examine whether: (1) the health composition of the social networks of children living in subsidized housing within market rate developments (among higher-income neighbors) differs from the social network composition of children living in public housing developments (among lower-income neighbors); and (2) children's social network composition is associated with children's own health. We found no significant differences in the health characteristics of the social networks of children living in these different types of public housing. However, social network composition was significantly associated with several aspects of children's own health, suggesting the potential importance of social networks for the health of vulnerable populations. PMID- 26598959 TI - Cycling for transport and recreation: Associations with the socio-economic, natural and built environment. AB - This study examined associations between objective environmental attributes and, separately, transport (TC) and recreational cycling (RC). Environmental attributes were more strongly associated with TC than RC. Distances to areas with the best bicycle infrastructure and urban amenities may be key environmental attributes influencing TC but not RC. Government investments in bicycle infrastructure within inner Brisbane appear to have resulted in more TC than in outer areas and to appeal to residents of both the most and least disadvantaged neighbourhoods. Extending this infrastructure to residents living in disadvantaged and advantaged neighbourhoods outside the CBD could expand TC participation. PMID- 26598960 TI - Captive-breeding of captive and wild-reared Gunnison sage-grouse. AB - Gunnison sage-grouse (Centrocercus minimus) distribution in North America has decreased over historical accounts and has received federal protection under the Endangered Species Act. We investigated captive-breeding of a captive-flock of Gunnison sage-grouse created from individuals reared in captivity from wild collected eggs we artificially incubated. We also introduced wild-reared individuals into captivity. Our captive-flock successfully bred and produced fertile eggs. We controlled the timing and duration of male-female breeding interactions and facilitated a semi-natural mating regime. Males established a strutting ground in captivity that females attended for mate selection. In 2010, we allowed females to establish eight nests, incubate, and hatch eggs. Females in captivity were more successful incubating nests than raising broods. Although there are many technical, financial, and logistic issues associated with captive breeding, we recommend that federal biologists and managers work collaboratively with state wildlife agencies and consider developing a captive-flock as part of a comprehensive conservation strategy for a conservation-reliant species like the Gunnison sage-grouse. The progeny produced from a captive-rearing program could assist in the recovery if innovative approaches to translocation are part of a comprehensive proactive conservation program. PMID- 26598961 TI - Subset of Kappa and Lambda Germline Sequences Result in Light Chains with a Higher Molecular Mass Phenotype. AB - In our previous work, we showed that electrospray ionization of intact polyclonal kappa and lambda light chains isolated from normal serum generates two distinct, Gaussian-shaped, molecular mass distributions representing the light-chain repertoire. During the analysis of a large (>100) patient sample set, we noticed a low-intensity molecular mass distribution with a mean of approximately 24 250 Da, roughly 800 Da higher than the mean of the typical kappa molecular-mass distribution mean of 23 450 Da. We also observed distinct clones in this region that did not appear to contain any typical post-translational modifications that would account for such a large mass shift. To determine the origin of the high molecular mass clones, we performed de novo bottom-up mass spectrometry on a purified IgM monoclonal light chain that had a calculated molecular mass of 24 275.03 Da. The entire sequence of the monoclonal light chain was determined using multienzyme digestion and de novo sequence-alignment software and was found to belong to the germline allele IGKV2-30. The alignment of kappa germline sequences revealed ten IGKV2 and one IGKV4 sequences that contained additional amino acids in their CDR1 region, creating the high-molecular-mass phenotype. We also performed an alignment of lambda germline sequences, which showed additional amino acids in the CDR2 region, and the FR3 region of functional germline sequences that result in a high-molecular-mass phenotype. The work presented here illustrates the ability of mass spectrometry to provide information on the diversity of light-chain molecular mass phenotypes in circulation, which reflects the germline sequences selected by the immunoglobulin-secreting B-cell population. PMID- 26598957 TI - Overview of current immunotherapeutic strategies for glioma. AB - In the last decade, numerous studies of immunotherapy for malignant glioma (glioblastoma multiforme) have brought new knowledge and new hope for improving the prognosis of this incurable disease. Some clinical trials have reached Phase III, following positive outcomes in Phase I and II, with respect to safety and immunological end points. Results are encouraging especially when considering the promise of sustained efficacy by inducing antitumor immunological memory. Progress in understanding the mechanisms of tumor-induced immune suppression led to the development of drugs targeting immunosuppressive checkpoints, which are used in active clinical trials for glioblastoma multiforme. Insights related to the heterogeneity of the disease bring new challenges for the management of glioma and underscore a likely cause of therapeutic failure. An emerging therapeutic strategy is represented by a combinatorial, personalized approach, including the standard of care: surgery, radiation, chemotherapy with added active immunotherapy and multiagent targeting of immunosuppressive checkpoints. PMID- 26598962 TI - Relationship of aggression, negative affect, substance use problems, and childhood delinquency to DWI recidivism. AB - BACKGROUND: Driving under the influence remains a pervasive problem. Approximately 30% of those arrested for impaired driving offenses each year are repeat offenders, suggesting that current rehabilitative efforts are not sufficiently effective for reducing driving while intoxicated (DWI) recidivism. Aggression, negative affect, substance use problems, and childhood delinquency have been noted in the population of impaired drivers, but study of these variables on recidivism has been limited. OBJECTIVES: The aim of the current study was to examine the effects of aggression, negative affect, substance use problems, and childhood delinquency on DWI recidivism among first time offenders. METHODS: In 1992, 6436 individuals in impaired driver programs in New York State were surveyed. A total of 3511 individuals provided names so that state driver abstracts could be reviewed in the future. A total of 2043 matches were found and 1770 remained after excluding those with previous DWI convictions. Driver records were reviewed in 2010 and 2012, providing between 18 and 20 years of follow-up. RESULTS: During the follow-up period, 16.5% of individuals were arrested for an impaired driving offense. Multivariate analysis suggested that recidivism was a function of several problems, including: alcohol problem severity, aggression, negative affect, drug problem severity, criminal history, and childhood delinquency. CONCLUSION: Impaired driving programs should assess for childhood delinquency, aggressive tendencies, and negative affect as these constructs, along with substance use, are evident among impaired drivers who recidivate. Interventions addressing aggression and negative affect may ultimately prove useful in reducing recidivism. PMID- 26598963 TI - Single muscle fiber contractile properties in diabetic RAT muscle. AB - INTRODUCTION: Diabetes is associated with accelerated loss of muscle mass and function. We compared the contractile properties of single muscle fibers in young rat soleus muscle of uncontrolled streptozotocin-induced diabetic animals (n = 10) and nondiabetic controls (n = 10). METHODS: Single fiber maximal force, shortening velocity, and power were assessed during maximal activation with calcium using the slack test 4 weeks after induction. Myosin heavy chain expression was determined using sodium dodecyl sulfate polyacrylamide gel electrophoresis. Oxidized myosin levels were detected by analyzing protein carbonyls in muscle homogenates. All fibers expressed the type I myosin heavy chain isoform. RESULTS: Diabetic rats had higher blood glucose (537 vs. 175 mg/dl; P < 0.001) and lower body weight (171 vs. 356 g; P < 0.001) than controls. Muscle fibers from diabetic rats showed smaller cross-sectional area (1128 vs. 1812 MUm(2) ), lower maximal force (258 vs. 492 MUN), and reduced absolute power (182 vs. 388 MUN FL/s) (all P < 0.0001). No differences were seen in shortening velocity, specific force or specific power. Myosin carbonylation was higher (P < 0.01) in diabetic rats. CONCLUSIONS: After 4 weeks of untreated diabetes, there are significant alterations in muscle at the level of isolated single fibers and myosin protein, although some contractile properties seem to be protected. Muscle Nerve, 2015 Muscle Nerve 53: 958-964, 2016. PMID- 26598964 TI - Porous palladium coated conducting polymer nanoparticles for ultrasensitive hydrogen sensors. AB - Hydrogen, a clean-burning fuel, is of key importance to various industrial applications, including fuel cells and in the aerospace and automotive industries. However, hydrogen gas is odorless, colorless, and highly flammable; thus appropriate safety protocol implementation and monitoring are essential. Highly sensitive hydrogen leak detection and surveillance sensor systems are needed; additionally, the ability to maintain uniformity through repetitive hydrogen sensing is becoming increasingly important. In this report, we detail the fabrication of porous palladium coated conducting polymer (3-carboxylate polypyrrole) nanoparticles (Pd@CPPys) to detect hydrogen gas. The Pd@CPPys are produced by means of facile alkyl functionalization and chemical reduction of a pristine 3-carboxylate polypyrrole nanoparticle-contained palladium precursor (PdCl(2)) solution. The resulting Pd@CPPy-based sensor electrode exhibits ultrahigh sensitivity (0.1 ppm) and stability toward hydrogen gas at room temperature due to the palladium sensing layer. PMID- 26598965 TI - General Method for the Preparation of Electron-Deficient Imidazo[1,2-a]pyridines and Related Heterocycles. AB - A new annulation method for the preparation of the imidazo[1,2-a]pyridine ring system under mild conditions is presented. Treatment of a 2-aminopyridine with a dimethylketal tosylate in acetonitrile at elevated temperature (80-140 degrees C) in the presence of catalytic Sc(OTf)3 provides the imidazo[1,2-a]pyridine product in good yield. The annulation method is broadly applicable to electron poor 2-aminopyridines and displays a complementary profile to the classic preparation of the imidazo[1,2-a]pyridine ring system by reaction of a bromoketone with electron-rich and -neutral substrates. The scope of the process and mechanistic considerations are discussed. PMID- 26598966 TI - Pandora's box opens for cholestatic liver disease. PMID- 26598967 TI - Tunneled Pleural Catheter Placement with and without Talc Poudrage for Treatment of Pleural Effusions Due to Congestive Heart Failure. AB - RATIONALE: There is a paucity of evidence regarding the role of tunneled pleural catheters in pleural effusions caused by congestive heart failure that is refractory to medical management. OBJECTIVES: The aim of this study was to assess the feasibility of tunneled pleural catheter drainage for treatment of refractory pleural effusions associated with congestive heart failure, either when used alone or with concomitant talc pleurodesis performed during thoracoscopy. METHODS: This was a retrospective cohort study. We identified patients with congestive heart failure and recurrent symptomatic pleural effusions who were treated between 2005 and 2015 by placement of a tunneled pleural catheter. Patients underwent either thoracoscopy followed by talc poudrage and pleural catheter placement (group 1) or catheter insertion alone (group 2). MEASUREMENTS AND MAIN RESULTS: Forthy-three catheters were inserted in 36 patients, with 15 placed in group 1 and 28 in group 2. Successful pleurodesis was seen in 80% in group 1 and 25% in group 2. The median time of catheter placement was 11.5 days in group 1 and 66 days in group 2. There was a significant decrease in hospital admissions and pleural interventions after catheter placement compared with before insertion (P < 0.05). CONCLUSIONS: This single-center, retrospective study demonstrated the feasibility of catheter placement used alone or with talc poudrage for the treatment of refractory pleural effusions associated with congestive heart failure. The addition of talc poudrage might increase the pleurodesis rate and reduce the days to catheter removal in highly selected patients. Prospective studies on a larger number of patients are warranted to verify the safety and efficacy of this intervention. PMID- 26598968 TI - Evaluation of Partial Cut-out of Sacroiliac Screws From the Sacral Ala Slope via Pelvic Inlet and Outlet View. AB - STUDY DESIGN: An anatomic and radiographic study of placement of sacroiliac screws. OBJECTIVE: The aim of this study was to quantitatively assess the risk of partial cut-out of sacroiliac screws from the sacral ala slope via inlet and outlet view. SUMMARY OF BACKGROUND DATA: The partial cut-out of sacroiliac screws from the superior surface of sacral ala can jeopardize the L5 nerve root, which is difficult to identify on the pelvic inlet and outlet views. METHODS: Computed tomography images of 60 patients without pelvic ring deformity or injury were used to measure the width (on inlet view) and height (on outlet view) of the sacral ala. The angle of the sacral ala slope was measured on lateral view. According to the measured parameters, the theoretical safe trajectories of screw placement were calculated using inverse trigonometric functions. Under fluoroscopic guidance, a sacroiliac screw was placed close to the midline on both inlet and outlet views, including posterosuperior, posteroinferior, anterosuperior, and anteroinferior regions to the midline. The incidence of screw partial cut-out from the superior surface of sacral ala was identified. RESULTS: The measured widths and heights of the sacral alas were 28.1 +/- 2.8 and 29.8 +/- 3.1 mm, respectively. The average angle between the superior aspect of the S1 vertebral body and the superior aspect of the sacral ala was 37.2 +/- 2.5 degrees. The rate of partial cut-out of the screws from the superior surface of sacral ala slope was 12.5% (5/40) in posterosuperior, 0% (0/40) in posteroinferior, 70% (28/40) in anterosuperior, and 20% (8/40) in anteroinferior. CONCLUSION: To avoid the risk of partial cut-out from sacroiliac screw placement, more precise description should be added to the conventional description: the sacroiliac screws should be placed at the inferior half portion on outlet view and at the posterior half portion on inlet view. LEVEL OF EVIDENCE: 4. PMID- 26598969 TI - Anti-TNF agents for paediatric psoriasis. AB - BACKGROUND: Psoriasis is a chronic skin disease that may develop at any age. Estimates for the United States and Europe suggest that psoriasis accounts for 4% of skin diseases in children. In most cases, the condition is mild and can be treated with creams. However, a small percentage of children have moderate to severe disease that requires drugs, such as ciclosporin or methotrexate, and some will require injections with newer biological agents, such as anti-TNF (tumour necrosis factor) drugs. Anti-TNF drugs (among them etanercept, infliximab, and adalimumab) are designed to reduce inflammation in the body caused by tumour necrosis factor. Evidence for the safety and efficacy of these biological agents in paediatric psoriasis is lacking. OBJECTIVES: To assess the efficacy and safety of anti-TNF agents for the treatment of paediatric psoriasis. SEARCH METHODS: We searched the following databases up to July 2015: the Cochrane Skin Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 6), MEDLINE (from 1946), Embase (from 1974), and LILACS (from 1982). We also searched 13 trials registers and checked the reference lists of included studies and key review articles for further references to relevant randomised controlled trials (RCTs). We handsearched conference proceedings and attempted to contact trial authors and relevant pharmaceutical manufacturers. We searched the US Food and Drug Administration's and European Medicines Agency's adverse effects databases. SELECTION CRITERIA: All relevant RCTs that evaluated the efficacy and safety of anti-TNF agents for the treatment of chronic plaque psoriasis in individuals less than 18 years of age. DATA COLLECTION AND ANALYSIS: Two review authors independently checked titles and abstracts and performed data extraction and 'Risk of bias' assessment of the included studies. One review author entered data into Review Manager (RevMan), and a second review author checked the data. We also attempted to obtain unclear data from the trial authors where possible.Our primary outcomes were investigator-assessed number of participants achieving a 75% improvement in Psoriasis Area and Severity Index-75 (PASI 75) compared to baseline, improvement in quality of life using an instrument such as Children's Dermatology Life Quality Index (CDLQI), and adverse effects. Our secondary outcomes included the proportion of participants achieving PASI 50 and the Physician's Global Assessment (PGA). MAIN RESULTS: We included one study with 211 participants (median age 13 years), in which etanercept (dosage ranged from 0.8 to 50 mg per kilogram of body weight) was compared to placebo. Follow-up was over a 48-week period.At week 12, 57% versus 11% who received etanercept or placebo, respectively, achieved the PASI 75 (risk ratio 4.95, 95% confidence interval (CI) 2.83 to 8.65; high-quality evidence). Absolute risk reduction and the number needed to treat to obtain a benefit with etanercept was 45% (95% CI 33.95 to 56.40) and 2 (95% CI 1.77 to 2.95), respectively.The percentage improvement from baseline of the CDLQI scores at week 12 was better in the etanercept group than the placebo group (52.3% versus 17.5%, respectively (P = 0.0001)). Analysis between the groups showed an effect size that was clinically important (mean difference 2.30, 95% CI 0.85 to 3.75; high-quality evidence). However, means, medians, and minimal important difference results and results of the Pediatric Quality of Life Inventory, Stein Impact on Family Scale, and Harter Self-Perception Profile for Children scores must be interpreted with caution, as they were not prespecified outcomes.Three serious adverse events were reported, but they were resolved without sequelae. Deaths or other events such as malignant tumours, opportunistic infections, tuberculosis, or demyelination were not reported in the included study.Also, 13% of participants in the placebo group and 53% in the etanercept group had a PGA of clear or almost clear (risk ratio 3.96, 95% CI 2.36 to 6.66; high-quality evidence) at week 12. AUTHORS' CONCLUSIONS: This review found only one RCT evaluating the use of this type of biological therapy. Although the risk of publication bias was high, as we included only one industry-sponsored RCT, the risk of allocation, selection, performance, attrition, and selective reporting biases for all outcomes (except for CDLQI) was low, and no short-term serious adverse events were found.We can conclude, based on this single included study, that etanercept seems to be efficacious and safe (at least in the short term) for the treatment of paediatric psoriasis. However, as the GRADE approach refers not to individual studies but to a body of evidence, we shall wait for the results of the ongoing studies in a future update of this review. In addition, future studies should evaluate quality-of-life endpoints established a priori and standardise primary outcome measures such as PASI 75, and should include the PGA as a secondary endpoint. Also, collating and reporting adverse events uniformly is required to better evaluate safety. PMID- 26598970 TI - Influence of Serotonin Transporter Gene Polymorphisms and Adverse Life Events on Depressive Symptoms in the Elderly: A Population-Based Study. AB - BACKGROUND: Depression is common in the elderly. The role of genetic and environmental factors in modulating depressive symptoms is not clear. METHODS: We evaluated the influence of serotonin transporter gene polymorphisms and recent adverse life events on depressive symptoms in an elderly Italian population. We used data from "InveCe.Ab", a population-based study of 1321 subjects aged 70-74 years. We used the 15-item Geriatric Depression Scale (GDS) to assess depressive symptoms-a GDS score >=5 points (GDS>=5) indicated the presence of clinically relevant symptoms-and performed 5-HTTLPR and rs25531 genotyping to obtain the triallelic polymorphism of the serotonin transporter. We used the Geriatric Adverse Life Events Scale to measure adverse life events, and logistic regression models to evaluate the role of genotype and recent adverse life events in depressive symptoms, controlling for potential confounders and independent predictors. RESULTS: Two hundred subjects (15.76%) had a GDS>=5. The 5-HTTLPR triallelic polymorphism was significantly associated with GDS>=5. Only S'S' carriers showed an increased risk of depressive symptoms (ORadj = 1.81, p = .022); one extra adverse life event increased this risk by 14% (p = .061) independently of genotype. Other factors significantly related to GDS>=5 were: female gender (ORadj = 2.49, p < .001), age (ORadj = 1.19, p = .007), a history of depression (ORadj = 4.73, p < .001), and comorbidity (ORadj = 1.23, p = .001). One extra adverse life event increased the risk of depressive symptoms by 57% (p = .005) only in the L'L' carriers, while antidepressant intake was directly related to GDS>=5 in the L'S' carriers (ORadj = 2.46, p = .036) and borderline significant in the S'S' carriers (ORadj = 2.41, p = .081). DISCUSSION: The S'S' genotype and recent exposure to adverse life events were independently associated with depressive symptoms. The S'S' genotype, compared with the environment, exerted a predominant effect on depressive symptoms, suggesting that it reduces the efficacy of antidepressant therapy. We conclude that genetics may be an important risk factor for depressive symptoms in late adulthood. PMID- 26598971 TI - Functional Inactivation of Putative Photosynthetic Electron Acceptor Ferredoxin C2 (FdC2) Induces Delayed Heading Date and Decreased Photosynthetic Rate in Rice. AB - Ferredoxin (Fd) protein as unique electron acceptor, involved in a variety of fundamental metabolic and signaling processes, which is indispensable for plant growth. The molecular mechanisms of Fd such as regulation of electron partitioning, impact of photosynthetic rate and involvement in the carbon fixing remain elusive in rice. Here we reported a heading date delay and yellowish leaf 1 (hdy1) mutant derived from Japonica rice cultivar "Nipponbare" subjected to EMS treatment. In the paddy field, the hdy1 mutant appeared at a significantly late heading date and had yellow-green leaves during the whole growth stage. Further investigation indicated that the abnormal phenotype of hdy1 was connected with depressed pigment content and photosynthetic rate. Genetic analysis results showed that the hdy1 mutant phenotype was caused by a single recessive nuclear gene mutation. Map-based cloning revealed that OsHDY1 is located on chromosome 3 and encodes an ortholog of the AtFdC2 gene. Complementation and overexpression, transgenic plants exhibited the mutant phenotype including head date, leaf color and the transcription levels of the FdC2 were completely rescued by transformation with OsHDY1. Real-time PCR revealed that the expression product of OsHDY1 was detected in almost all of the organs except root, whereas highest expression levels were observed in seeding new leaves. The lower expression levels of HDY1 and content of iron were detected in hdy1 than WT's. The FdC2::GFP was detected in the chloroplasts of rice. Real-time PCR results showed that the expression of many photosynthetic electron transfer related genes in hdy1 were higher than WT. Our results suggest that OsFdC2 plays an important role in photosynthetic rate and development of heading date by regulating electron transfer and chlorophyll content in rice. PMID- 26598972 TI - Titin-Based Nanoparticle Tension Sensors Map High-Magnitude Integrin Forces within Focal Adhesions. AB - Mechanical forces transmitted through integrin transmembrane receptors play important roles in a variety of cellular processes ranging from cell development to tumorigenesis. Despite the importance of mechanics in integrin function, the magnitude of integrin forces within adhesions remains unclear. Literature suggests a range from 1 to 50 pN, but the upper limit of integrin forces remains unknown. Herein we challenge integrins with the most mechanically stable molecular tension probe, which is comprised of the immunoglobulin 27th (I27) domain of cardiac titin flanked with a fluorophore and gold nanoparticle. Cell experiments show that integrin forces unfold the I27 domain, suggesting that integrin forces exceed ~30-40 pN. The addition of a disulfide bridge within I27 "clamps" the probe and resists mechanical unfolding. Importantly, incubation with a reducing agent initiates SH exchange, thus unclamping I27 at a rate that is dependent on the applied force. By recording the rate of S-S reduction in clamped I27, we infer that integrins apply 110 +/- 9 pN within focal adhesions of rat embryonic fibroblasts. The rates of S-S exchange are heterogeneous and integrin subtype-dependent. Nanoparticle titin tension sensors along with kinetic analysis of unfolding demonstrate that a subset of integrins apply tension many fold greater than previously reported. PMID- 26598973 TI - The burden of disease attributable to cannabis use in Canada in 2012. AB - BACKGROUND AND AIMS: Cannabis use is associated with several adverse health effects. However, little is known about the cannabis-attributable burden of disease. This study quantified the age-, sex- and adverse health effect-specific cannabis-attributable (1) mortality, (2) years of life lost due to premature mortality (YLLs), (3) years of life lost due to disability (YLDs) and (4) disability-adjusted life years (DALYs) in Canada in 2012. DESIGN: Epidemiological modeling. SETTING: Canada. PARTICIPANTS: Canadians aged >= 15 years in 2012. MEASUREMENTS: Using comparative risk assessment methodology, cannabis attributable fractions were computed using Canadian exposure data and risk relations from large studies or meta-analyses. Outcome data were obtained from Canadian databases and the World Health Organization. The 95% confidence intervals (CIs) were computed using Monte Carlo methodology. FINDINGS: Cannabis use was estimated to have caused 287 deaths (95% CI = 108, 609), 10,533 YLLs (95% CI = 4760, 20,833), 55,813 YLDs (95% CI = 38,175, 74,094) and 66,346 DALYs (95% CI = 47,785, 87,207), based on causal impacts on cannabis use disorders, schizophrenia, lung cancer and road traffic injuries. Cannabis-attributable burden of disease was highest among young people, and males accounted for twice the burden than females. Cannabis use disorders were the most important single cause of the cannabis-attributable burden of disease. CONCLUSIONS: The cannabis attributable burden of disease in Canada in 2012 included 55,813 years of life lost due to disability, caused mainly by cannabis use disorders. Although the cannabis-attributable burden of disease was substantial, it was much lower compared with other commonly used legal and illegal substances. Moreover, the evidence base for cannabis-attributable harms was smaller. PMID- 26598974 TI - Automatic segmentation of the optic nerve head for deformation measurements in video rate optical coherence tomography. AB - Optical coherence tomography (OCT) imaging has become a standard diagnostic tool in ophthalmology, providing essential information associated with various eye diseases. In order to investigate the dynamics of the ocular fundus, we present a simple and accurate automated algorithm to segment the inner limiting membrane in video-rate optic nerve head spectral domain (SD) OCT images. The method is based on morphological operations including a two-step contrast enhancement technique, proving to be very robust when dealing with low signal-to-noise ratio images and pathological eyes. An analysis algorithm was also developed to measure neuroretinal tissue deformation from the segmented retinal profiles. The performance of the algorithm is demonstrated, and deformation results are presented for healthy and glaucomatous eyes. PMID- 26598976 TI - Undifferentiated Carcinoma of the Endometrium: An Expanded Immunohistochemical Analysis Including PAX-8 and Basal-Like Carcinoma Surrogate Markers. AB - Undifferentiated carcinoma of the endometrium (UCAe) is an aggressive, underrecognized high-grade carcinoma that can occur either in pure form or in conjunction with low-grade endometrioid adenocarcinoma (i.e. dedifferentiated carcinoma). The typical solid growth pattern of UCAe can create a diagnostic dilemma as it is frequently misinterpreted as the solid component of an endometrial carcinoma or as a sarcoma. In addition, the high nuclear:cytoplasmic ratio, high mitotic index, and geographic necrosis are reminiscent of basal-like carcinoma of breast (BLCB). This study was undertaken to determine the role of a selected group of immunomarkers in the distinction of UCAe from other endometrial carcinomas, and assess the expression of DNA mismatch repair proteins, and surrogate BLCB immunomarkers in this type of tumor. Cases of UCAe were stained with antibodies against keratin cocktail, CK8/18, PAX-8, and estrogen receptor: 35 cases; progesterone receptor and Her-2/neu: 33 cases; CD44, e-cadherin, p16, and p53: 32 cases; and CK5/6, EGFR, and c-Kit: 18 cases. In addition, mismatch repair protein markers MLH1, MSH2, MSH6, and PMS2 were performed in 34 cases. We found that PAX-8 expression was lost in most cases (83%). In addition, estrogen and progesterone receptors were negative in 83% and 82% of cases, respectively. Seventy-seven percent of cases were positive for keratin cocktail and keratin 8/18, whereas only 11% of cases were positive for keratin 5/6. p16 was diffusely positive in 34% of cases, whereas p53 was expressed in >75% of the tumor cells in 31% of cases. MLH1 and PMS2 were concurrently lost in 50% of cases, whereas MSH2 and MSH6 were lost in 1 case (3%). E-cadherin and CD44 were completely lost in 50% of cases, whereas Her-2/neu was negative in all cases. EGFR was negative in 67% of cases, whereas 22% of cases showed diffuse membranous staining for this marker. UCAe is a high-grade carcinoma of Mullerian origin which tends to be negative for PAX-8. The loss of this marker appears to be a more reliable discriminator than the loss of keratin expression in the differential diagnosis with endometrioid carcinoma or serous carcinoma. UCAe tends to be diffusely positive for p53, but patchy positive for p16. Although UCAe appears to share not only some histologic features with BLCB, but also some of its immunohistochemical features (loss of estrogen receptor, progesterone receptor, and Her-2/neu, a tendency to loose e-cadherin and to express CD44), UCAe appears not to be related to BLCB because it usually lacks the expression EGFR, CK5/6, and c-Kit. PMID- 26598975 TI - A Potent, Selective, and Cell-Active Inhibitor of Human Type I Protein Arginine Methyltransferases. AB - Protein arginine methyltransferases (PRMTs) play a crucial role in a variety of biological processes. Overexpression of PRMTs has been implicated in various human diseases including cancer. Consequently, selective small-molecule inhibitors of PRMTs have been pursued by both academia and the pharmaceutical industry as chemical tools for testing biological and therapeutic hypotheses. PRMTs are divided into three categories: type I PRMTs which catalyze mono- and asymmetric dimethylation of arginine residues, type II PRMTs which catalyze mono- and symmetric dimethylation of arginine residues, and type III PRMT which catalyzes only monomethylation of arginine residues. Here, we report the discovery of a potent, selective, and cell-active inhibitor of human type I PRMTs, MS023, and characterization of this inhibitor in a battery of biochemical, biophysical, and cellular assays. MS023 displayed high potency for type I PRMTs including PRMT1, -3, -4, -6, and -8 but was completely inactive against type II and type III PRMTs, protein lysine methyltransferases and DNA methyltransferases. A crystal structure of PRMT6 in complex with MS023 revealed that MS023 binds the substrate binding site. MS023 potently decreased cellular levels of histone arginine asymmetric dimethylation. It also reduced global levels of arginine asymmetric dimethylation and concurrently increased levels of arginine monomethylation and symmetric dimethylation in cells. We also developed MS094, a close analog of MS023, which was inactive in biochemical and cellular assays, as a negative control for chemical biology studies. MS023 and MS094 are useful chemical tools for investigating the role of type I PRMTs in health and disease. PMID- 26598977 TI - Nomogram to Predict Risk of Lymph Node Metastases in Patients With Endometrioid Endometrial Cancer. AB - Pelvic lymphadenectomy in early-stage endometrial cancer is controversial, but the findings influence prognosis and treatment decisions. Noninvasive tools to identify women at high risk of lymph node metastasis can assist in determining the need for lymph node dissection and adjuvant treatment for patients who do not have a lymph node dissection performed initially. A retrospective review of surgical pathology was conducted for endometrioid endometrial adenocarcinoma at our institution. Univariate and multivariate logistic regression analysis of selected pathologic features were performed. A nomogram to predict for lymph node metastasis was constructed. From August 1996 to October 2013, 296 patients underwent total abdominal or laparoscopic hysterectomy, bilateral salpingo oophorectomy, and selective lymphadenectomy for endometrioid endometrial adenocarcinoma. Median age at surgery was 62.7 yr (range, 24.9-93.6 yr). Median number of lymph nodes removed was 13 (range, 1-72). Of all patients, 38 (12.8%) had lymph node metastases. On univariate analysis, tumor size >=4 cm, grade, lymphovascular space involvement, cervical stromal involvement, adnexal or serosal or parametrial involvement, positive pelvic washings, and deep (more than one half) myometrial invasion were all significantly associated with lymph node involvement. In a multivariate model, lymphovascular space involvement, deep myometrial invasion, and cervical stromal involvement remained significant predictors of nodal involvement, whereas tumor size of >=4 cm was borderline significant. A lymph node predictive nomogram was constructed using these factors. Our nomogram can help estimate risk of nodal disease and aid in directing the need for additional surgery or adjuvant therapy in patients without lymph node surgery. Lymphovascular space involvement is the most important predictor for lymph node metastases, regardless of grade, and should be consistently assessed. PMID- 26598978 TI - Primary Extranodal Marginal Cell Lymphoma, MALT Type, of the Endometrium Arising in a Patient With Rheumatoid Arthritis: Report of a Case. AB - Primary marginal zone B-cell MALT-type lymphomas of the uterine corpus are exceedingly rare entities, with only 6 cases reported in the literature to date. We present the additional case of a 70-yr-old white woman who underwent a laparoscopic total hysterectomy with bilateral salpingo-oophorectomy for an asymptomatic ovarian cyst. At microscopic examination, endometrial samples showed a dense, nodular lymphocytic infiltrate, suggestive of a lymphoproliferative disorder. Morphology, immunohistochemistry, and molecular analysis supported the diagnosis of MALT-type lymphoma of the endometrium. Benign reactive conditions, such as endometritis and other small B-cell lymphomas were ruled out. Moreover, we investigated the pathogenesis of our case, focusing on Chlamydia trachomatis infection, chromosomal translocations affecting the NF-kB pathway, and discussing the role of autoimmunity in the development of MALT-type lymphomas. PMID- 26598979 TI - Uterine Tumor Resembling Ovarian Sex Cord Tumor (UTROSCT) Commonly Exhibits Positivity With Sex Cord Markers FOXL2 and SF-1 but Lacks FOXL2 and DICER1 Mutations. AB - Uterine tumor resembling ovarian sex cord tumor (UTROSCT) is a rare neoplasm which morphologically and immunohistochemically exhibits overlap with an ovarian sex cord tumor. Although many of these neoplasms are positive with markers of ovarian sex cord-stromal tumors, staining is often limited and the pathogenesis of UTROSCT is unknown. To further explore the sex cord lineage of UTROSCT, we studied 19 of these neoplasms and examined the expression of 2 recently described markers of ovarian sex cord-stromal tumors, FOXL2, and steroidogenic factor-1. We also undertook FOXL2 and DICER1 mutation analysis in these cases; a somatic missense mutation in codon C134W (402C->G) of FOXL2 gene has been demonstrated in the vast majority (>95%) of ovarian adult granulosa cell tumors and somatic DICER1 mutations are found in approximately 60% of ovarian Sertoli-Leydig cell tumors. Ten of 19 cases (53%) exhibited nuclear immunoreactivity with FOXL2 and 11 of 19 (58%) exhibited nuclear staining with steroidogenic factor-1. Neither FOXL2 nor DICER1 mutations were identified in any case where there was sufficient tumor tissue for analysis (18 and 9 cases, respectively). Despite exhibiting an immunophenotype characteristic of a sex cord-stromal tumor, mutations in FOXL2 and DICER1, the 2 most common mutations hitherto reported in ovarian sex cord stromal tumors, are not a feature of UTROSCT. PMID- 26598980 TI - Primary Endometrial Yolk Sac Tumor With Endodermal-Intestinal Differentiation Masquerading as Metastatic Colorectal Adenocarcinoma. AB - Yolk sac tumors (YSTs) with a somatic glandular pattern can be difficult to recognize histologically because they reproduce developing intestinal, hepatic, or lung tissue and can express markers such as CDX2 and TTF1. We report an unusual case of a primary endometrial YST showing florid endodermal-intestinal differentiation in a 63-yr-old woman with a history of colorectal adenocarcinoma. Histologically, the tumor exhibited a glandular and papillary architecture and showed widespread immunoreactivity for CDX2 and focal staining for CK20 and CEA, mimicking metastatic colorectal carcinoma on biopsy. The presence of subnuclear cytoplasmic clearing and positive staining for germ cell markers, however, pointed toward a diagnosis of primary endometrial YST, and this was supported by the radiologic and the subsequent pathologic finding of a primary endometrial based lesion. YSTs in this age group usually arise in association with somatic tumors and in this case a small focus of coexistent endometrioid adenocarcinoma was identified within the uterus. Despite surgery and adjuvant chemotherapy, the patient showed disease progression with liver and lung metastases 6 mo postoperatively. PMID- 26598981 TI - Pleomorphic Liposarcoma Arising in a Lipoleiomyosarcoma of the Uterus: Report of a Case With Genetic Profiling by a Next Generation Sequencing Panel. AB - Uterine tumors with adipocytic differentiation are very uncommon. Mature adipocytes are sometimes seen as an element of smooth muscle neoplasms, more often as lipoleiomyoma, but also in the rare lipoleiomyosarcoma. Exceptional cases have been reported of various subtypes of liposarcoma associated with uterine smooth muscle tumors with or without adipocytic differentiation. We present a case of pleomorphic liposarcoma arising in a lipoleiomyosarcoma of the uterus. Genomic profiling was performed using a validated next generation sequencing panel covering 410 common cancer genes. Alterations were identified in TP53, PTEN, RB1, FAT1 and TERT. The patient's presentation and clinical course as well as the tumor's morphologic, immunohistochemical and molecular genetic findings are reviewed. PMID- 26598982 TI - Calibration and Optimization of p53, WT1, and Napsin A Immunohistochemistry Ancillary Tests for Histotyping of Ovarian Carcinoma: Canadian Immunohistochemistry Quality Control (CIQC) Experience. AB - The Canadian Immunohistochemistry Quality Control provides proficiency testing for immunohistochemistry in Canadian laboratories. Canadian Immunohistochemistry Quality Control Run 42 assessed WT1, Napsin A, and p53; commonly used markers for histotyping ovarian carcinomas. A 42-core tissue microarray, which included the 5 major histotypes of ovarian carcinomas with a subset having known TP53 mutational status, was used for this Canadian Immunohistochemistry Quality Control challenge. Participants included 43 laboratories for p53, 29 for WT1, and 26 for Napsin A. p53 was scored as aberrant if the staining was strong and diffuse or absent. Napsin A and WT1 were scored positive if any tumor cells stained. The reference p53 expression pattern was inferred by TP53 mutation type when available. For WT1, Napsin A, and cases lacking mutational data, the reference staining pattern was based on the majority staining result. The error rate for p53 was 8.8%. Most errors (84%) were due to weak staining. The sensitivity and specificity of aberrant p53 expression for an underlying TP53 mutation was 91.6% and 87.9%, respectively. The error rate for WT1 was 0.76% with all errors occurring in laboratories using the 6F-h2 clone. The average errors for laboratories using 6F-h2 were 2.4 compared with 0 for WT-49. The error rate for Napsin A was 4%. The average errors for laboratories using polyclonal Napsin A were 3 compared with 1.1 for monoclonal Napsin A. Weak p53 staining increases interpretative errors, primarily due to absence of staining in tumors with wild type TP53. p53 immunohistochemistry correlates strongly with TP53 mutational status. Polyclonal Napsin A and 6F-h2 may lack specificity in comparison to monoclonal Napsin A and WT-49. PMID- 26598983 TI - Microfocus of Anaplastic Carcinoma Arising in Mural Nodule of Ovarian Mucinous Borderline Tumor With Very Rapid and Fatal Outcome. AB - A 36-yr-old woman presented with abdominal discomfort. A computed tomography scan revealed a large left cystic and solid pelvic mass without evidence of metastatic disease. Total hysterectomy with bilateral salpingo-oophorectomy and tumor staging was performed. Grossly, the ovarian mass measured 20*18 cm and the cut surface was multiloculated with 1 single mural nodule measuring 2*1.5 cm. The histologic diagnosis of ovarian mucinous borderline tumor with a microfocus of anaplastic carcinoma arising in sarcoma-like mural nodule, FIGO Stage IA was rendered. After 3 mo, the patient returned with symptomatic anemia. A computed tomography scan showed enlarged retroperitoneal and pelvic lymph nodes. Image guided biopsy of the pelvic lymph node showed a metastatic anaplastic carcinoma from her primary ovarian carcinoma. Chemotherapy was initiated, but the patient developed fulminant disseminated intravascular coagulation within <1 wk of her presentation which was fatal. PMID- 26598984 TI - Assessing Residents' Frozen Section Skills for Endometrial Cancer. AB - Intraoperative frozen section (IFS) on endometrial cancer is an invaluable skill for pathologists-in-training to master. Within limited time constraints, pathologists are expected to determine tumor type, grade, and depth of myometrial invasion. During their training, pathology residents gradually gain experience in handling the majority of cases. However, significant errors can still be seen among senior level trainees. We aimed to improve training effectiveness by evaluating our trainees' performance, identifying common errors, and recommending focused curriculum. Twenty-two residents [postgraduate year (PGY)-1-PGY-4] performed 260 IFS during a 4-yr period. We compared their independent IFS diagnoses with final diagnoses. Overall resident IFS accuracy was 73%. Accuracy for tumor type and depth of myometrial invasion was 80% and 93%, respectively. Two thirds of errors were due to sampling with the rest because of interpretation. Major deficiencies lay in recognizing high-risk histologic types (serous, clear cell, sarcoma) and unconventional myometrial invasion patterns (MELF, adenoma malignum, and adenomyosis-like). Resident IFS errors would theoretically result in suboptimal staging for 32 (12%) patients and unnecessary staging for 1 (0.4%). Overall IFS performance improved as training level increased (76% accuracy for PGY-1 accompanied by PGY-5; 59% for PGY-2; 74% for PGY-3; and 86% for PGY-4). We recommend a dedicated curriculum targeting these difficult yet clinically important entities through review literature and a collection of classic cases demonstrating the diverse morphology variations. Implementing such focused training would greatly improve our trainees' competence on IFS, preparing them to handle a wide variety of cases and situations in future practice. PMID- 26598985 TI - Study of Correlation of Cervical Epithelial Thickness With the Grade of Colposcopic Abnormality. AB - Low epithelial thickness has been identified as the cause for nonvisualization of high-grade cervical intraepithelial neoplasia (CIN) on colposcopy in an earlier study. Multiple random biopsies are recommended by some authors to detect these "thin" CIN lesions in absence of colposcopic abnormalities. The present study was conducted to evaluate the correlation between the severity of colposcopic impression and the thickness of the epithelium so that the results of previous study could be validated. The cross-sectional study examined 209 histopathology slides with normal, human papillomavirus, or CIN diagnosis from a population based study. Average epithelial thickness was measured by obtaining mean of the thicknesses at thinnest and thickest areas. Average thickness of dysplastic layer was also measured. These values were correlated with age, human papillomavirus status, colposcopic appearance and histopathology. Mean epithelial thicknesses were 212.8 MUm for normal (N=28), 297.3 MUm for human papillomavirus changes (N=48), 245.3 MUm for CIN1 (N=46), 191.4 MUm for CIN2 (N=50), and 218.5 MUm for CIN3 (N=37). Within each histologic category, no correlation was observed between epithelial thickness and severity of colposcopic appearance. Mean epithelial thickness of CIN1/CIN2 lesions with normal colposcopy was more than that of CIN1/CIN2 lesions with high-grade appearance on colposcopy. Thickness of CIN3 lesions with high-grade abnormalities was higher than those without visible colposcopic abnormality but the difference was not statistically significant. Thickness of dysplasia increased with higher grades of CIN but did not have any relation to colposcopic appearance. Colposcopic appearance does not depend on the thickness of the epithelium affected by CIN. False-negative colposcopy in presence of high-grade CIN is likely due to failure of detecting small or predominantly endocervical lesions rather than "thin" CIN. PMID- 26598986 TI - Seromucinous Tumors of the Ovary. What's in a Name? AB - The recent 2014 World Health Organization (WHO) Classification of Tumours of the Female Reproductive Organs introduced a new category of ovarian neoplasm designated "seromucinous tumours". The recognition of this distinctive group of tumors is an important addition to the classification but the term "seromucinous" has serious flaws that obscures the nature of these neoplasms. Morphologically, seromucinous tumors in addition to serous and endocervical-type mucinous epithelium, contain endometrioid, indifferent and squamous type epithelium. Their immunoprofile is characterized by frequent expression of ER, PR, infrequent expression of WT1 and lack of expression of CK20 and CDX2, an immunostaining pattern consistent with a "mullerian" immunophenotype. Unlike serous and intestinal type mucinous tumors, seromucinous tumors are frequently associated with endometriosis making them more analogous to endometrioid and clear cell neoplasms. Indeed, recent studies have shown that a high proportion of seromucinous tumors lost expression of ARID1A, a tumor suppressor gene, that is mutated in approximately 50% of endometrioid and clear cell tumors, in sharp contrast to serous and intestinal-type mucinous tumors which do not contain ARID1A mutations or lose its expression. Therefore, based on their clinicopathologic, immunohistochemical and molecular genetic features we believe a more appropriate designation for this group of tumors is "mixed mullerian tumors" which can be subcategorized as "mixed mullerian cystadenomas", "mixed mullerian atypical proliferative (borderline) tumors" and "mixed mullerian carcinomas". PMID- 26598988 TI - Influence of the phenols on the biogeochemical behavior of cadmium in the mangrove sediment. AB - Phenols exert a great influence on the dynamic process of Cd in the soil-plant interface. We investigated the influence of phenols on the biogeochemical behavior of cadmium in the rhizosphere of Avicennia marina (Forsk) Vierh. All combinations of four levels of cadmium (0, 1, 2 and 4 mg/kg DW) and two levels of phenol (0 and 15 mg/kg DW) were included in the experimental design. We found that phenols facilitated increasing concentrations of exchangeable cadmium (Ex Cd), acid volatile sulfide (AVS) and reactive solid-phase Fe (II) in sediments, and iron in plants, but inhibited Cd accumulation in iron plaque and roots. The concentrations of AVS and reactive solid-phase Fe (II) were significantly positively correlated with Cd treatment. As for the biogeochemical behavior of Cd in mangrove sediments, this research revealed that phenols facilitated activation and mobility of Cd. They disturbed the "source-sink" balance of Cd and turned it into a "source", whilst decreasing Cd absorption in A. marina. Additionally, phenols facilitated iron absorption in the plant and alleviated the Fe limit for mangrove plant growth. PMID- 26598987 TI - Characterizing non-hydrolyzing Neisseria meningitidis serogroup A UDP-N acetylglucosamine (UDP-GlcNAc) 2-epimerase using UDP-N-acetylmannosamine (UDP ManNAc) and derivatives. AB - Neisseria meningitidis serogroup A non-hydrolyzing uridine 5'-diphosphate-N acetylglucosamine (UDP-GlcNAc) 2-epimerase (NmSacA) catalyzes the interconversion between UDP-GlcNAc and uridine 5'-diphosphate-N-acetylmannosamine (UDP-ManNAc). It is a key enzyme involved in the biosynthesis of the capsular polysaccharide [ 6ManNAcalpha1-phosphate-]n of N. meningitidis serogroup A, one of the six serogroups (A, B, C, W-135, X, and Y) that account for most cases of N. meningitidis-caused bacterial septicemia and meningitis. N. meningitidis serogroup A is responsible for large epidemics in the developing world, especially in Africa. Here we report that UDP-ManNAc could be used as a substrate for C-terminal His6-tagged recombinant NmSacA (NmSacA-His6) in the absence of UDP GlcNAc. NmSacA-His6 was activated by UDP-GlcNAc and inhibited by 2 acetamidoglucal and UDP. Substrate specificity study showed that NmSacA-His6 could tolerate several chemoenzymatically synthesized UDP-ManNAc derivatives as substrates although its activity was much lower than non-modified UDP-ManNAc. Homology modeling and molecular docking revealed likely structural determinants of NmSacA substrate specificity. This is the first detailed study of N. meningitidis serogroup A UDP-GlcNAc 2-epimerase. PMID- 26598989 TI - Effects of Pisha sandstone content on solute transport in a sandy soil. AB - In sandy soil, water, nutrients and even pollutants are easily leaching to deeper layers. The objective of this study was to assess the effects of Pisha sandstone on soil solute transport in a sandy soil. The miscible displacement technique was used to obtain breakthrough curves (BTCs) of Br(-) as an inert non-adsorbed tracer and Na(+) as an adsorbed tracer. The incorporation of Pisha sandstone into sandy soil was able to prevent the early breakthrough of both tracers by decreasing the saturated hydraulic conductivity compared to the controlled sandy soil column, and the impeding effects increased with Pisha sandstone content. The BTCs of Br(-) were accurately described by both the convection-dispersion equation (CDE) and the two-region model (T-R), and the T-R model fitted the experimental data slightly better than the CDE. The two-site nonequilibrium model (T-S) accurately fit the Na(+) transport data. Pisha sandstone impeded the breakthrough of Na(+) not only by decreasing the saturated hydraulic conductivity but also by increasing the adsorption capacity of the soil. The measured CEC values of Pisha sandstone were up to 11 times larger than those of the sandy soil. The retardation factors (R) determined by the T-S model increased with increasing Pisha sandstone content, and the partition coefficient (K(d)) showed a similar trend to R. According to the results of this study, Pisha sandstone can successfully impede solute transport in a sandy soil column. PMID- 26598990 TI - DDT degradation efficiency and ecotoxicological effects of two types of nano sized zero-valent iron (nZVI) in water and soil. AB - Nano-scale zero-valent iron (nZVI) has been conceived for cost-efficient degradation of chlorinated pollutants in soil as an alternative to e.g permeable reactive barriers or excavation. Little is however known about its efficiency in degradation of the ubiquitous environmental pollutant DDT and its secondary effects on organisms. Here, two types of nZVI (type B made using precipitation with borohydride, and type T produced by gas phase reduction of iron oxides under H2) were compared for efficiency in degradation of DDT in water and in a historically (>45 years) contaminated soil (24 mg kg(-1) DDT). Further, the ecotoxicity of soil and water was tested on plants (barley and flax), earthworms (Eisenia fetida), ostracods (Heterocypris incongruens), and bacteria (Escherichia coli). Both types of nZVI effectively degraded DDT in water, but showed lower degradation of aged DDT in soil. Both types of nZVI had negative impact on the tested organisms, with nZVI-T giving least adverse effects. Negative effects were mostly due to oxidation of nZVI, resulting in O2 consumption and excess Fe(II) in water and soil. PMID- 26598991 TI - Enrichment, geo-accumulation and risk surveillance of toxic metals for different environmental compartments from Mehmood Booti dumping site, Lahore city, Pakistan. AB - The present study was designed to probe the levels of heavy metals (Cd, Pb, Cr, Mn, Cu, Ni, Zn and Fe) for different environmental matrices (ground water, wastewater, sediment, soil, dust and leachates). Impact of solid waste dumping site on nearby human population has also been assessed. The results revealed that concentration of Pb, Fe, Cd, Mn and Cu surpassed the permissible limits of World Health Organization (WHO) and US Environmental Protection Agency (USEPA) in water, soil, sediments, while aforesaid metals in wastewater were above the National Environmental Quality Standards (NEQS). Our results for enrichment factor (EF) and geo-accumulation (I(geo)) values revealed that soils and sediments were contaminated with Cd, Pb, Ni and Mn. The Cd content caused a considerably high potential ecological risk (E(r)(i) >= 320) in soil and sediments. Pb and Cd caused high health risk (HR > 1) to local residents via dust and drinking water intake. Potential cancer risk for Pb was higher than USEPA standard values (1.0E-06-1.0E-04) through water intake. The Mehmood Booti dumping site is a potential source of toxic pollutants contamination to the surrounding population. It is recommended to take proper actions for its management to resolve this issue. PMID- 26598992 TI - 3D QSAR studies of hydroxylated polychlorinated biphenyls as potential xenoestrogens. AB - Mono-hydroxylated polychlorinated biphenyls (OH-PCBs) are found in human biological samples and lack of data on their potential estrogenic activity has been a source of concern. We have extended our previous in silico 2D QSAR study through the application of advance techniques such as docking and 3D QSAR to gain insights into their estrogen receptor (ERalpha) binding. The results support our earlier findings that the hydroxyl group is the most important feature on the compounds; its position, orientation and surroundings in the structure are influential for the binding of OH-PCBs to ERalpha. This study has also revealed the following additional interactions that influence estrogenicity of these chemicals (a) the aromatic interactions of the biphenyl moieties with the receptor, (b) hydrogen bonding interactions of the p-hydroxyl group with key amino acids ARG394 and GLU353, (c) low or no electronegative substitution at para positions of the p-hydroxyl group, (d) enhanced electrostatic interactions at the meta position on the B ring, and (e) co-planarity of the hydroxyl group on the A ring. In combination the 2D and 3D QSAR approaches have led us to the support conclusion that the hydroxyl group is the most important feature on the OH-PCB influencing the binding to estrogen receptors, and have enhanced our understanding of the mechanistic details of estrogenicity of this class of chemicals. Such in silico computational methods could serve as useful tools in risk assessment of chemicals. PMID- 26598993 TI - Measurement of Setschenow constants for six hydrophobic compounds in simulated brines and use in predictive modeling for oil and gas systems. AB - Treatment and reuse of brines, produced from energy extraction activities, requires aqueous solubility data for organic compounds in saline solutions. The presence of salts decreases the aqueous solubility of organic compounds (i.e. salting-out effect) and can be modeled using the Setschenow Equation, the validity of which has not been assessed in high salt concentrations. In this study, we used solid-phase microextraction to determine Setschenow constants for selected organic compounds in aqueous solutions up to 2-5 M NaCl, 1.5-2 M CaCl2, and in Na-Ca binary electrolyte solutions to assess additivity of the constants. These compounds exhibited log-linear behavior up to these high NaCl concentrations. Log-linear decreases in solubility with increasing salt concentration were observed up to 1.5-2 M CaCl2 for all compounds, and added to a sparse database of CaCl2 Setschenow constants. Setschenow constants were additive in binary electrolyte mixtures. New models to predict CaCl2 and KCl Setschenow constants from NaCl Setschenow constants were developed, which successfully predicted the solubility of the compounds measured in this study. Overall, data show that the Setschenow Equation is valid for a wide range of salinity conditions typically found in energy-related technologies. PMID- 26598994 TI - The changes in biochar properties and sorption capacities after being cultured with wheat for 3 months. AB - Biochars that were produced from pig manure at three different temperatures were amended to sand and cropped with wheat to examine the effect of wheat roots on biochar properties and its sorption capacity. After being aged with wheat roots for three months, the biochar samples showed significant changes in their physicochemical properties, which depended on biochar types and their distances from the roots. In general, the ash content and micropores decreased and the polarity increased after root aging. The changes in the biochar properties in turn affected biochar sorption capacities. The sorption of atrazine and phenanthrene by the biochar that was produced at 300 degrees C (BC300) both increased by different extents after aging, significantly decreased for BC700, and there were little changes for BC500. The complex changes were due to the different dominant sorption mechanisms for different biochars and different chemicals. For BC700, hydrophobic partition and pore-filling were the main processes, especially for phenanthrene, whereas for BC300, polar interactions dominated. PMID- 26598995 TI - Chemical behavior of different species of phosphorus in coagulation. AB - Phosphorus is one of the elements that have a significant impact on such environmental problems as eutrophication or algal bloom. Phosphorus compounds in water can be hydrolyzed to orthophosphate that is the only form of phosphorus that algae can assimilate. In this study, phosphorus removal in terms of orthophosphate and total phosphorus from wastewater was studied using alum or ferric ions as coagulants. It was observed that alum shows higher phosphorus removal efficiency than ferric ions in the same mole ratio concentrations. The proportion of orthophosphate among total phosphorus did not change significantly during coagulation process when the coagulant concentration is low. However, the proportion becomes gradually decreased as the coagulant concentration increases. Not only the electrolyte concentration difference in solution, but the characteristics of orthophosphate and polyphosphate such as reactivity and ionic size might also cause the differences in the removal rate. Orthophosphate that has greater reactivity than other phosphorus species would be involved in chemical reactions dominantly when large amounts of coagulants are applied. However, the effect of reactivity was diminished due to the large ionic size of polyphosphate and low concentration of electrolyte in low coagulant concentration during the coagulation process. PMID- 26598996 TI - The fate of two isothiazolinone biocides, 5-chloro-2-methylisothiazol-3(2H)-one (CMI) and 2-methylisothiazol-3(2H)-one (MI), in liquid air fresheners and assessment of inhalation exposure. AB - There exist public concerns regarding the two most widely used isothiazolinones (5-chloro-2-methylisothiazol-3(2H)-one (CMI) and 2-methylisothiazol-3(2H)-one (MI)) in various consumer products because they cause allergic responses in dermatitis and are potentially harmful when inhaled. Hydrolysis and photolysis tests for CMI and MI at pH 4, 7, and 9 were performed to evaluate their stability. While MI did not degrade under the test conditions, CMI slightly degraded at pH 9 via hydrolysis and at pH 4 via photolysis. To better understand human exposure to MI and CMI during the use of consumer products, the vaporization rates of MI and CMI from two commercial air fresheners were quantified in a custom-made chamber. The evaporation of MI was almost negligible over 7 d, whereas a significant amount of CMI evaporated over the same period. Because the volume of air freshener decreases over time due to evaporation of water, the MI concentration in the product increased by a factor of 1.8-2.2. The air concentration of CMI was predicted using a ConsExpo model using a fixed weight fraction (model 1) and a new model that reflects changes in the concentrations of active ingredients and the product volume over time (model 2). The concentration determined using model 1 reached a steady-state value of 0.032 ug L(-1), whereas that predicted using model 2 increased consistently. Inhalation exposure was also assessed using two exposure scenarios: a room and a car. Both calculated values of margin of exposure were much higher than 300, indicating a negligible inhalation risk. PMID- 26598997 TI - Natural origin arsenic in aquatic organisms from a deep oligotrophic lake under the influence of volcanic eruptions. AB - Volcanic eruptions are recognized sources of toxic elements to freshwater, including arsenic (As). In order to study the short term changes in the bioaccumulation of naturally occurring As by aquatic organisms in Lake Nahuel Huapi (Argentina), located close to the Puyehue-Cordon Caulle volcanic complex (PCCVC), we described As concentrations at different trophic levels and food web transfer patterns in three sites of the lake prior to the last PCCVC eruption (June 2011), and compared As concentrations in biota before and after the eruption. The highest As concentrations and greater variations both between sites and position in the water column, were observed in phytoplankton (3.9-64.8 ug g( 1) dry weight, DW) and small zooplankton (4.3-22.3 ug g(-1) DW). The pattern of As accumulation in aquatic organisms (whole body or muscle) was: primary producers (phytoplankton) > scrapper mollusks (9.3-15.3 ug g(-1) DW) > filter feeding mollusks (5.4-15.6 ug g(-1) DW) > omnivorous invertebrates (0.4-9.2 ug g( 1) DW) > zooplankton (1.2-3.5 ug g(-1) DW) > fish (0.2-1.9 ug g(-1) DW). We observed As biodilution in the whole food web, and in salmonids food chains, feeding on fish prey; but biomagnification in the food chain of creole perch, feeding on benthic crayfish. The impact of the 2011 PCCVC eruption on the As levels of biota was more evident in pelagic-associated organisms (zooplankton and planktivorous fish), but only in the short term, suggesting a brief high bioavailability of As in water after ash deposition. In benthic organisms As variations likely responded to shift in diet due to coverage of the littoral zone with ashes. PMID- 26598998 TI - Uric acid increases erythrocyte aggregation: Implications for cardiovascular disease. AB - Uric acid may be a risk factor for atherosclerotic cardiovascular disease, although the data conflict and the mechanism by which it may cause cardiovascular disease is uncertain. This study was performed to test the hypothesis that uric acid, an anion at physiologic pH, can cause erythrocyte aggregation, which itself is associated with cardiovascular disease. Normal erythrocytes and erythrocytes with a positive direct antiglobulin test for surface IgG were incubated for 15 minutes in 14.8 mg/dL uric acid. Erythrocytes without added uric acid were used as controls. Erythrocytes were then examined microscopically for aggregation. Aggregates of up to 30 erythrocytes were noted when normal erythrocytes were incubated in uric acid. Larger aggregates were noted when erythrocytes with surface IgG were incubated in uric acid. Aggregation was negligible in controls. These data show that uric acid causes erythrocyte aggregation. The most likely mechanism is decreased erythrocyte zeta potential. Erythrocyte aggregates will increase blood viscosity at low shear rates and increase the risk of atherothrombosis. In this manner, hyperuricemia and decreased zeta potential may be risk factors for atherosclerotic cardiovascular disease. PMID- 26598999 TI - Differentiation of subtypes of renal cell carcinoma with contrast-enhanced ultrasonography. AB - We aimed to assess the difference of enhancement patterns among the three RCC subtypes with contrast-enhanced ultrasound (CEUS). Two hundreds cases of pathologically proved clear cell renal cell carcinomas (ccRCC), 58 papillary renal cell carcinomas (pRCC) and 51 chromophobe renal cell carcinomas (chRCC) underwent preoperative conventional ultrasound and CEUS. The wash-in and wash-out pattern, peak enhancement degree and homogeneity, and the presence of pseudocapsule were evaluated by two blinded observers respectively. The interreader agreement in the characterization of CEUS features between two observers was good (kappa = 0.649-0.775). Compared with pRCCs and chRCCs, ccRCCs demonstrated higher frequency of simultaneous wash-in pattern, hyperenhancement and heterogeneity with necrotic areas. Most pRCCs and chRCCs manifested hypoenhancement, homogeneity, fast wash-out and presence of pseudocapsule. The only difference we obtained between pRCC and chRCC was the wash-in pattern, with slow wash-in in pRCC and simultaneous wash-in in chRCC. In small lesions with long diameter<=3 cm, the majority of the three subtypes of RCC showed homogeneous enhancement and there was no difference among them. CEUS was a useful method to preoperatively differentiate the ccRCC from non-ccRCC subtypes. There were no distinguishing features identifid on CEUS that allowed reliable differentiation of pRCC from chRCC. PMID- 26599001 TI - Machine Learning Based Classification of Microsatellite Variation: An Effective Approach for Phylogeographic Characterization of Olive Populations. AB - Finding efficient analytical techniques is overwhelmingly turning into a bottleneck for the effectiveness of large biological data. Machine learning offers a novel and powerful tool to advance classification and modeling solutions in molecular biology. However, these methods have been less frequently used with empirical population genetics data. In this study, we developed a new combined approach of data analysis using microsatellite marker data from our previous studies of olive populations using machine learning algorithms. Herein, 267 olive accessions of various origins including 21 reference cultivars, 132 local ecotypes, and 37 wild olive specimens from the Iranian plateau, together with 77 of the most represented Mediterranean varieties were investigated using a finely selected panel of 11 microsatellite markers. We organized data in two '4 targeted' and '16-targeted' experiments. A strategy of assaying different machine based analyses (i.e. data cleaning, feature selection, and machine learning classification) was devised to identify the most informative loci and the most diagnostic alleles to represent the population and the geography of each olive accession. These analyses revealed microsatellite markers with the highest differentiating capacity and proved efficiency for our method of clustering olive accessions to reflect upon their regions of origin. A distinguished highlight of this study was the discovery of the best combination of markers for better differentiating of populations via machine learning models, which can be exploited to distinguish among other biological populations. PMID- 26599002 TI - Correction: Differences in CD44 Surface Expression Levels and Function Discriminates IL-17 and IFN-gamma Producing Helper T Cells. PMID- 26599000 TI - Microbial Response to Experimentally Controlled Redox Transitions at the Sediment Water Interface. AB - The sediment-water interface of freshwater lakes is characterized by sharp chemical gradients, shaped by the interplay between physical, chemical and microbial processes. As dissolved oxygen is depleted in the uppermost sediment, the availability of alternative electron acceptors, e.g. nitrate and sulfate, becomes the limiting factor. We performed a time series experiment in a mesocosm to simulate the transition from aerobic to anaerobic conditions at the sediment water interface. Our goal was to identify changes in the microbial activity due to redox transitions induced by successive depletion of available electron acceptors. Monitoring critical hydrochemical parameters in the overlying water in conjunction with a new sampling strategy for sediment bacteria enabled us to correlate redox changes in the water to shifts in the active microbial community and the expression of functional genes representing specific redox-dependent microbial processes. Our results show that during several transitions from oxic heterotrophic condition to sulfate-reducing condition, nitrate-availability and the on-set of sulfate reduction strongly affected the corresponding functional gene expression. There was evidence of anaerobic methane oxidation with NOx. DGGE analysis revealed redox-related changes in microbial activity and expression of functional genes involved in sulfate and nitrite reduction, whereas methanogenesis and methanotrophy showed only minor changes during redox transitions. The combination of high-frequency chemical measurements and molecular methods provide new insights into the temporal dynamics of the interplay between microbial activity and specific redox transitions at the sediment-water interface. PMID- 26599003 TI - Evaluating Functional Outcomes of Botulinum Toxin Type A Injection Combined with Occupational Therapy in the Upper Limbs of Children with Cerebral Palsy: A 9 Month Follow-Up from the Perspectives of Both Child and Caregiver. AB - OBJECTIVE: To assess the effectiveness of combining botulinum toxin type A (BoNT A) with functional occupational therapy (OT) at 9-month follow-up in children with cerebral palsy (CP) with bilateral upper limb impairments from the perspectives of both child and caregiver. METHODS: Twelve children with CP and their caregivers were assessed across 5 time points over 9 months based on the ICF after BoNT-A injection and functional OT in this open-label study. RESULTS: Significant differences were found across the 5 time points (p < .05) for both grasp and visual-motor integration with small effects (effect sizes = 0.12-0.24) and the self-care capability and performance of social function (p < .05). However, based on the effect sizes (0.02-0.14), no significant effects were found at the 4 post-test time points. Small effects were found on the psychological domain (effect sizes = 0.25-0.37) and environmental domains (effect size = 0.27) at follow-ups. CONCLUSION: Combining a BoNT-A injection with OT not only reduced the muscle tone and increased ROM but also improved the upper limb function and self-care capability in children with CP. More importantly, these effects persisted for up to 9 months. Functional OT extends the effectiveness of a BoNT-A injection. PMID- 26599004 TI - Urban Planning and Health Inequities: Looking in a Small-Scale in a City of Cape Verde. AB - BACKGROUND: The lack of high-quality data to support evidence-based policies continues to be a concern in African cities, which present marked social, economic and cultural disparities that may differently impact the health of the groups living in different urban contexts. This study explores three urban units- formal, transition and informal--of the capital of Cape Verde, in terms of overweight/obesity, cardiometabolic risk, physical activity and other aspects related to the urban environment. METHODS: Quantitative and qualitative research methods were used in this intra-urban study. A proportional stratified random sample (n = 1912 adults), based on geographical coordinates of private households, was selected to apply the UPHI-STAT questionnaire. In a second stage (n = 599), local nutritionists collected anthropometric measurements (e.g., height, waist circumference) and body composition by bioelectric impedance (e.g., body weight, body fat, muscle mass). In a third stage, pedometers were used to count study participants' steps on working and non-working days for one week (n = 118). After a preliminary statistical analysis, a qualitative study was developed to complement the quantitative approach. Generalized linear models, among others, were used in the multivariate analysis. RESULTS: Insecurity was the main concern among survey respondents in the three units, notwithstanding with significant differences (p < 0.001) among units. About three-quarters (76.6%) of the participants of the informal unit emphasised the need for more security. The formal unit presents an older age structure (61.3% above 40 years old) and the transition unit a younger age structure (only 30.5% above 40 years old). Some health-related variables were analysed in each unit, revealing an excess of chronic conditions reported by inhabitants of informal unit, compared with the formal unit despite the informal unit's younger age profile. The self-reported hypertension varied significantly among urban units (p < 0.001), with 19.3% in the formal unit, 11.4% in the transition unit and 22.5% in the informal unit. Women of the urban units present significant differences (5% level) for body mass index calculated from self-reported measures (p < 0.001), fat mass (p = 0.005), waist circumference (p = 0.046) and waist-to-height ratio (p = 0.017). For women, overall physical activity was 67.4% (95%CI [64.8,70.0]), with differences among urban units (p = 0.025). For men it was of 85.2% (95%CI [82.3,87.6]), without significant differences among urban units (p = 0.266). The percentage of women and men who reported physical activity in leisure time was discrepant, with 95%CI [22.6, 27.4] and [53.2, 60.2], respectively. The results of pedometers also indicated that men walk significantly more than women (p < 0.001), with a difference of approximately 2000 steps/day. CONCLUSIONS: The data collection process itself also gave us some clues on the involvement of local communities, exploring the potential of social capital of these settings and the role of the woman in family and society in Cape Verde. The higher participation of women and residents of informal unit (the most disadvantaged groups) suggests these as the priority target groups for health promotion campaigns. The link between health planning, urban planning and security of the city needs to be reinforced to minimize health, social and gender inequalities. PMID- 26599005 TI - Rising United States Hospital Admissions for Acute Bacterial Skin and Skin Structure Infections: Recent Trends and Economic Impact. AB - BACKGROUND: The number of ambulatory patients seeking treatment for skin and skin structure infections (SSSI) are increasing. The objective of this study is to determine recent trends in hospital admissions and healthcare resource utilization and identify covariates associated with hospital costs and mortality for hospitalized adult patients with a primary SSSI diagnosis in the United States. METHODS: We performed a retrospective cross-sectional analysis (years 2005-2011) of data from the US Healthcare Cost and Utilization Project National Inpatient Sample. Recent trends, patient characteristics, and healthcare resource utilization for patients hospitalized with a primary SSSI diagnosis were evaluated. Descriptive and bivariate analyses were conducted to assess patient and hospital characteristics. RESULTS: A total of 1.8% of hospital admissions for the years 2005 through 2011 were for adult patients with a SSSI primary diagnosis. SSSI-related hospital admissions significantly changed during the study period (P < .001 for trend) ranging from 1.6% (in 2005) to 2.0% (in 2011). Mean hospital length of stay (LOS) decreased from 5.4 days in the year 2005 to 5.0 days in the year 2011 (overall change, P < .001) with no change in hospital costs. Patients with postoperative wound infections had the longest hospital stays (adjusted mean, 5.81 days; 95% confidence interval (CI), 5.80-5.83) and highest total costs (adjusted mean, $9388; 95% CI, $9366-$9410). Year of hospital admission was strongly associated with mortality; infection type, all patient refined diagnosis related group severity of illness level, and LOS were strongly associated with hospital costs. CONCLUSIONS: Hospital admissions for adult patients in the United States with a SSSI primary diagnosis continue to increase. Decreasing hospital inpatient LOS and mortality rate may be due to improved early treatment. Future research should focus on identifying alternative treatment processes for patients with SSSI that could shift management from inpatient to outpatient treatment settings. PMID- 26599006 TI - Methacholine-Induced Variations in Airway Volume and the Slope of the Alveolar Capnogram Are Distinctly Associated with Airflow Limitation and Airway Closure. AB - Mechanisms driving alteration of lung function in response to inhalation of a methacholine aerosol are incompletely understood. To explore to what extent large and small airways contribute to airflow limitation and airway closure in this context, volumetric capnography was performed before (n = 93) and after (n = 78) methacholine provocation in subjects with an intermediate clinical probability of asthma. Anatomical dead space (VDaw), reflecting large airway volume, and the slope of the alveolar capnogram (slope3), an index of ventilation heterogeneity linked to small airway dysfunction, were determined. At baseline, VDaw was positively correlated with lung volumes, FEV1 and peak expiratory flow, while slope3 was not correlated with any lung function index. Variations in VDaw and slope3 following methacholine stimulation were correlated to a small degree (R2 = -0.20). Multivariate regression analysis identified independent associations between variation in FEV1 and variations in both VDaw (Standardized Coefficient SC = 0.66) and Slope3 (SC = 0.35). By contrast, variation in FVC was strongly associated with variations in VDaw (SC = 0.8) but not Slope3. Thus, alterations in the geometry and/or function of large and small airways were weakly correlated and contributed distinctly to airflow limitation. While both large and small airways contributed to airflow limitation as assessed by FEV1, airway closure as assessed by FVC reduction mostly involved the large airways. PMID- 26599008 TI - Depression and Health-Related Quality of Life among Patients with Type 2 Diabetes Mellitus: A Cross-Sectional Study in Nepal. AB - BACKGROUND: Diabetes is accompanied by a marked reduction in patient's quality of life (QOL) and leads to higher disability-adjusted life years than most diseases. Depression further deteriorates QOL and is associated with poor treatment outcomes and lowered glycemic control in diabetes. We analysed the QOL and depression among the people living with diabetes in Nepal. METHODS: We conducted a cross-sectional survey among a random sample of 157 diabetic patients visiting diabetes clinic at a major teaching hospital in Kathmandu, Nepal. We administered the Nepali version of WHO-BREF for face to face interviews to obtain data on QOL scores. The Nepali version of Patient Health Questionnaire-9was also used to record responses on depression items. RESULTS: More than half of the respondents (54.1%) experienced depression with mean PHQ-9 score of 6.15 +/- 5.01 on a scale of 0-27. On a scale of 0 to 100, highest QOL mean score was reported in social relationship domain (57.32 +/- 11.83), followed by environment domain (54.71 +/- 7.74), psychological health (53.25 +/- 10.32) and physical health (50.74 +/- 11.83). After adjusting for other covariates, urban residence decreased the physical health score by 4.74 (beta = -4.74, 95% CI: -8.664,-0.821), social relationship domain score by 3.420 (beta = -3.420, 95% CI: -6.433,-0.406) and the overall QOL by 2.773 (beta = -2.773, 95% CI: -5.295,-0.252). Having diagnosed with diabetes since more than 10 years increased physical health by 5.184 score points (beta = 5.184; 95% CI: 0.753, 9.615).Similarly, having severe depression decreased social relation domain score by 6.053 (beta = -6.053, 95% CI:-11.169, .936). CONCLUSION: Having urban residence significantly decreased the physical health and social relation domain scores as well as the overall QOL scores. Similarly, having diagnosed since more than 10 years increased physical health domain score. Severe depression decreased social relationship domain score. Since depression affects QOL, we suggest early diagnosis and prompt treatment of depression in T2DM people as part of their routine primary care in Nepal. PMID- 26599007 TI - A Jump-from-Cavity Pyrophosphate Ion Release Assisted by a Key Lysine Residue in T7 RNA Polymerase Transcription Elongation. AB - Pyrophosphate ion (PPi) release during transcription elongation is a signature step in each nucleotide addition cycle. The kinetics and energetics of the process as well as how it proceeds with substantial conformational changes of the polymerase complex determine the mechano-chemical coupling mechanism of the transcription elongation. Here we investigated detailed dynamics of the PPi release process in a single-subunit RNA polymerase (RNAP) from bacteriophage T7, implementing all-atom molecular dynamics (MD) simulations. We obtained a jump from-cavity kinetic model of the PPi release utilizing extensive nanosecond MD simulations. We found that the PPi release in T7 RNAP is initiated by the PPi dissociation from two catalytic aspartic acids, followed by a comparatively slow jump-from-cavity activation process. Combining with a number of microsecond long MD simulations, we also found that the activation process is hindered by charged residue associations as well as by local steric and hydrogen bond interactions. On the other hand, the activation is greatly assisted by a highly flexible lysine residue Lys472 that swings its side chain to pull PPi out. The mechanism can apply in general to single subunit RNA and DNA polymerases with similar molecular structures and conserved key residues. Remarkably, the flexible lysine or arginine residue appears to be a universal module that assists the PPi release even in multi-subunit RNAPs with charge facilitated hopping mechanisms. We also noticed that the PPi release is not tightly coupled to opening motions of an O helix on the fingers domain of T7 RNAP according to the microsecond MD simulations. Our study thus supports the Brownian ratchet scenario of the mechano chemical coupling in the transcription elongation of the single-subunit polymerase. PMID- 26599009 TI - Functional Status Predicts Acute Care Readmissions from Inpatient Rehabilitation in the Stroke Population. AB - OBJECTIVE: Acute care readmission risk is an increasingly recognized problem that has garnered significant attention, yet the reasons for acute care readmission in the inpatient rehabilitation population are complex and likely multifactorial. Information on both medical comorbidities and functional status is routinely collected for stroke patients participating in inpatient rehabilitation. We sought to determine whether functional status is a more robust predictor of acute care readmissions in the inpatient rehabilitation stroke population compared with medical comorbidities using a large, administrative data set. METHODS: A retrospective analysis of data from the Uniform Data System for Medical Rehabilitation from the years 2002 to 2011 was performed examining stroke patients admitted to inpatient rehabilitation facilities. A Basic Model for predicting acute care readmission risk based on age and functional status was compared with models incorporating functional status and medical comorbidities (Basic-Plus) or models including age and medical comorbidities alone (Age Comorbidity). C-statistics were compared to evaluate model performance. FINDINGS: There were a total of 803,124 patients: 88,187 (11%) patients were transferred back to an acute hospital: 22,247 (2.8%) within 3 days, 43,481 (5.4%) within 7 days, and 85,431 (10.6%) within 30 days. The C-statistics for the Basic Model were 0.701, 0.672, and 0.682 at days 3, 7, and 30 respectively. As compared to the Basic Model, the best-performing Basic-Plus model was the Basic+Elixhauser model with C-statistics differences of +0.011, +0.011, and + 0.012, and the best performing Age-Comorbidity model was the Age+Elixhauser model with C-statistic differences of -0.124, -0.098, and -0.098 at days 3, 7, and 30 respectively. CONCLUSIONS: Readmission models for the inpatient rehabilitation stroke population based on functional status and age showed better predictive ability than models based on medical comorbidities. PMID- 26599010 TI - Identification of General and Heart-Specific miRNAs in Sheep (Ovis aries). AB - MicroRNAs (miRNAs or miRs) are small regulatory RNAs crucial for modulation of signaling pathways in multiple organs. While the link between miRNAs and heart disease has grown more readily apparent over the past three years, these data are primarily limited to small animal models or cell-based systems. Here, we performed a high-throughput RNA sequencing (RNAseq) analysis of left ventricle and other tissue from a pre-clinical ovine model. We identified 172 novel miRNA precursors encoding a total of 264 mature miRNAs. Notably, 84 precursors were detected in both the left ventricle and other tissues. However, 10 precursors, encoding 11 mature sequences, were specific to the left ventricle. Moreover, the total 168 novel miRNA precursors included 22 non-conserved ovine-specific sequences. Our data identify and characterize novel miRNAs in the left ventricle of sheep, providing fundamental new information for our understanding of protein regulation in heart and other tissues. PMID- 26599011 TI - Tie2-Expressing Monocytes Are Associated with Identification and Prognoses of Hepatitis B Virus Related Hepatocellular Carcinoma after Resection. AB - BACKGROUND: Tie2-expressing monocytes (TEMs) are found in various tumors, involved in forming tumor blood vessels and expressing several important proangiogenic factors. The goals of this study were to evaluate the value of TEMs in diagnosing and predicting the prognosis of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). METHODS: Flow cytometry was performed to identify and count TEMs in peripheral blood monocytes from HCC patients (n = 84) receiving hepatectomy, HBV cirrhotic patients (n = 21), benign tumors patients (n = 15) and healthy volunteers (n = 23). Angiopoietin-2 (Ang-2) levels in the plasma were determined by enzyme linked immunosorbent assay. The distribution of TEMs in tumor tissue was observed by immunofluorescence staining. Then we determined the vascular area as a percentage of tumor area (vascular area/tumor area) by immunohistochemical staining. Finally the prognostic significance of TEMs and other clinicopathologic factors was evaluated. RESULTS: Percentage of TEMs in peripheral blood monocytes significantly increased in HCC patients compared with HBV cirrhotic patients and healthy donors (both P< 0.001). However there was no significance in benign liver tumor (P = 0.482). In addition, the percentage of circulating TEMs was positively correlated with plasma Ang-2 concentration (P<0.001, r2 = 0.294) and vascular area/tumor area (P<0.001, r2 = 0.126). Furthermore the percentage of intratumoral TEMs was significantly higher than that of paratumoral TEMs (P<0.001). Increased circulating TEMs was associated with poor overall survival (P = 0.043) and a shorter time to recurrence (P = 0.041). Multivariate Cox analysis also revealed that the percentage of TEMs in peripheral blood was an independent factor for HCC patients' prognosis. CONCLUSIONS: TEMs may promote angiogenesis in HCC regarding the angiopoietin/Tie2 signal pathway. Percentage of TEMs in peripheral blood monocytes may be applied as a biomarker for identifying HBV-related HCC and predicting the prognosis of these patients after resection. PMID- 26599012 TI - Chromodomain Helicase/ATPase DNA-Binding Protein 1-Like Gene (CHD1L) Expression and Implications for Invasion and Metastasis of Breast Cancer. AB - BACKGROUND: Chromodomain helicase/ATPase DNA-binding protein 1-like gene (CHD1L), also known as ALC1 (amplified in liver cancer 1 gene), is a new oncogene amplified in many solid tumors. Whether this gene plays a role in invasion and metastasis of breast cancer is unknown. METHODS: Immunohistochemistry was performed to detect the expression of CHD1L in patients with invasive ductal carcinoma and normal mammary glands. Chemotaxis, wound healing, and Transwell invasion assays were also performed to examine cell migration and invasion. Western blot analysis was conducted to detect the expression of CHD1L, MMP-2, MMP 9, pAkt/Akt, pARK5/ARK5, and pmTOR/mTOR. Moreover, ELISA was carried out to detect the expression levels of MMP-2 and MMP-9. Nude mice xenograft model was used to detect the invasion and metastasis of breast cancer cell lines. RESULTS: CHD1L overexpression was observed in 112 of 268 patients (41.8%). This overexpression was associated with lymph node metastasis (P = 0.008), tumor differentiation (P = 0.020), distant metastasis (P = 0.026), MMP-2 (P = 0.035), and MMP-9 expression (P = 0.022). In the cell experiment, reduction of CHD1L inhibited the invasion and metastasis of breast cancer cells by mediating MMP-2 and MMP-9 expression. CHD1L knockdown via siRNA suppressed EGF-induced pAkt, pARK5, and pmTOR. This knockdown inhibited the metastasis of breast cancer cells into the lungs of SCID mice. CONCLUSIONS: CHD1L promoted the invasion and metastasis of breast cancer cells via the PI3K/Akt/ARK5/mTOR/MMP signaling pathway. This study identified CHD1L as a potential anti-metastasis target for therapeutic intervention in breast cancer. PMID- 26599013 TI - RNA-Seq Analysis Reveals MAPKKK Family Members Related to Drought Tolerance in Maize. AB - The mitogen-activated protein kinase (MAPK) cascade is an evolutionarily conserved signal transduction pathway that is involved in plant development and stress responses. As the first component of this phosphorelay cascade, mitogen activated protein kinase kinase kinases (MAPKKKs) act as adaptors linking upstream signaling steps to the core MAPK cascade to promote the appropriate cellular responses; however, the functions of MAPKKKs in maize are unclear. Here, we identified 71 MAPKKK genes, of which 14 were novel, based on a computational analysis of the maize (Zea mays L.) genome. Using an RNA-seq analysis in the leaf, stem and root of maize under well-watered and drought-stress conditions, we identified 5,866 differentially expressed genes (DEGs), including 8 MAPKKK genes responsive to drought stress. Many of the DEGs were enriched in processes such as drought stress, abiotic stimulus, oxidation-reduction, and metabolic processes. The other way round, DEGs involved in processes such as oxidation, photosynthesis, and starch, proline, ethylene, and salicylic acid metabolism were clearly co-expressed with the MAPKKK genes. Furthermore, a quantitative real-time PCR (qRT-PCR) analysis was performed to assess the relative expression levels of MAPKKKs. Correlation analysis revealed that there was a significant correlation between expression levels of two MAPKKKs and relative biomass responsive to drought in 8 inbred lines. Our results indicate that MAPKKKs may have important regulatory functions in drought tolerance in maize. PMID- 26599014 TI - The Role of Regulatory CD4 T Cells in Maintaining Tolerance in a Mouse Model of Autoimmune Hepatitis. AB - BACKGROUND: The role of regulatory CD4 T cells (Treg) in immune-mediated liver disease is still under debate. It remains disputed whether Treg suppress T cell mediated hepatitis in vivo and whether hepatic regulatory T cells are functional in patients with autoimmune hepatitis. METHODS: We used TF-OVA mice, which express ovalbumin in hepatocytes, to investigate the impact of Treg in a model of autoimmune hepatitis. Treg isolated from inflamed livers of TF-OVA mice were tested for their functionality in vitro. By employing double transgenic TF OVAxDEREG (DEpletion of REGulatory T cells) mice we analyzed whether Treg depletion aggravates autoimmune inflammation in the liver in vivo. RESULTS: CD25+Foxp3+ CD4 T cells accumulated in the liver in the course of CD8 T cell mediated hepatitis. Treg isolated from inflamed livers were functional to suppress CD8 T-cell proliferation in vitro. Depletion of Treg in TF-OVAxDEREG mice dramatically amplified T cell-mediated hepatitis. Repeated administration of antigen-specific CD8 T cells led to a second wave of inflammation only after depletion of Treg. CONCLUSION: Our data add to the evidence for an important role of Treg in autoimmune hepatitis and show that Treg reduce the severity of T-cell mediated hepatitis in vivo. They constitute a key immune cell population that actively maintains a tolerogenic milieu in the liver and protects the liver against repeated inflammatory challenges. PMID- 26599015 TI - Effects of Partial Replacement of Corn with Glycerin on Ruminal Fermentation in a Dual-Flow Continuous Culture System. AB - The objective of this study was to evaluate the effects of partially replacing dry ground corn with glycerin on ruminal fermentation using a dual-flow continuous culture system. Six fermenters (1,223 +/- 21 ml) were used in a replicated 3x3 Latin square arrangement with three periods of 10 d each, with 7 d for diet adaptation and 3 d for sample collections. All diets contained 75% concentrate and three dietary glycerin levels (0, 15, and 30% on dry matter basis), totaling six replicates per treatment. Fermenters were fed 72 g of dry matter/d equally divided in two meals/d, at 0800 and 2000 h. Solid and liquid dilution rates were adjusted daily to 5.5 and 11%/h, respectively. On d 8, 9, and 10, samples of 500 ml of solid and liquid digesta effluent were mixed, homogenized, and stored at -20 degrees C. Subsamples of 10 ml were collected and preserved with 0.2 mL of a 50% H2SO4 solution for later determination of NH3-N and volatile fatty acids. Microbial biomass was isolated from fermenters for chemical analysis at the end of each experimental period. Data were analyzed using the MIXED procedure in SAS with alpha = 0.05. Glycerin levels did not affect apparent digestibility of DM (PLin. = 0.13; PQuad. = 0.40), OM (PLin. = 0.72; PQuad. = 0.15), NDF (PLin. = 0.38; PQuad. = 0.50) and ADF (PLin. = 0.91; PQuad. = 0.18). Also, glycerin inclusion did not affect true digestibility of DM (PLin. = 0.35; PQuad. = 0.48), and OM (PLin. = 0.08; PQuad. = 0.19). Concentrations of propionate (P < 0.01) and total volatile fatty acids (P < 0.01) increased linearly and concentrations of acetate (P < 0.01), butyrate (P = 0.01), iso-valerate (P < 0.01), and total branched-chain volatile fatty acids, as well as the acetate: propionate ratio (P < 0.01) decreased with glycerin inclusion. Linear increases on NH3-N concentration in digesta effluent (P < 0.01) and on NH3 N flow (P < 0.01) were observed due to glycerin inclusion in the diets. Crude protein digestibility (P = 0.04) and microbial N flow (P = 0.04) were greater in the control treatment compared with the other treatments and responded quadratically with glycerin inclusion. Furthermore, the inclusion of glycerin linearly decreased (P = 0.02) non-ammonia N flow. Glycerin levels did not affect the flows of total N (PLin. = 0.79; PQuad. = 0.35), and dietary N (PLin. = 0.99; PQuad. = 0.07), as well as microbial efficiency (PLin. = 0.09; PQuad. = 0.07). These results suggest that partially replacing dry ground corn with glycerin may change ruminal fermentation, by increasing total volatile fatty acids, and propionate concentration without affecting microbial efficiency, which may improve glucogenic potential of beef cattle diets. PMID- 26599016 TI - Rap1A Regulates Osteoblastic Differentiation via the ERK and p38 Mediated Signaling. AB - Rap1A is a member of small G proteins belonging to the Ras family. Recently, an integration of human genome-wide association studies (GWAS) and gene expression profiling study revealed that single-nucleotide polymorphisms (SNPs) within human Rap1A were strongly associated with narrow neck width in women. However, the regulatory role of Rap1A in osteoblasts remains to be elucidated. Here we report that Rap1A is a key regulator in osteoblast differentiation. Rap1A expression and activity were gradually enhanced during the induced differentiation of multipotent mesenchymal progenitor cells (C2C12) and preosteoblastic cells (MC3T3 E1). Knockdown of endogenous Rap1A significantly inhibited the osteogenic marker gene expression and matrix mineralization in cells with osteogenesis. In addition, knockdown of endogenous Rap1A suppressed the activation of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK), while overexpression of Rap1A accelerated osteoblast differentiation and enhanced the phosphorylation of ERK and p38. Taken together, our study suggests that Rap1A regulates osteoblast differentiation through modulating the ERK/p38 signaling. PMID- 26599017 TI - Increased Notch Signaling Enhances Radioresistance of Malignant Stromal Cells Induced by Glioma Stem/ Progenitor Cells. AB - BACKGROUND: Host malignant stromal cells induced by glioma stem/progenitor cells were revealed to be more radiation-resistant than the glioma stem/progenitor cells themselves after malignant transformation in nude mice. However, the mechanism underlying this phenomenon remains unclear. METHODS: Malignant stromal cells induced by glioma stem/progenitor cell 2 (GSC-induced host brain tumor cells, ihBTC2) were isolated and identified from the double color-coded orthotopic glioma nude mouse model. The survival fraction at 2 Gy (SF2) was used to evaluate the radiation resistance of ihBTC2, the human glioma stem/progenitor cell line SU3 and its radiation-resistant sub-strain SU3-5R and the rat C6 glioma cell line. The mRNA of Notch 1 and Hes1 from ihBTC2 cells were detected using qPCR before and after 4 Gy radiation. The expression of the Notch 1, pAkt and Bcl 2 proteins were investigated by Western blot. To confirm the role of the Notch pathway in the radiation resistance of ihBTC2, Notch signaling blocker gamma secretase inhibitors (GSIs) were used. RESULTS: The ihBTC2 cells had malignant phenotypes, such as infinite proliferation, hyperpentaploid karyotype, tumorigenesis in nude mice and expression of protein markers of oligodendroglia cells. The SF2 of ihBTC2 cells was significantly higher than that of any other cell line (P<0.05, n = 3). The expression of Notch 1 and Hes1 mRNAs from ihBTC2 cells was significantly increased after radiation. Moreover, the Notch 1, pAkt and Bcl-2 proteins were significantly increased after radiation (P<0.05, n = 3). Inhibition of Notch signaling markedly enhanced the radiosensitivity of ihBTC2 cells. CONCLUSIONS: In an orthotopic glioma model, the malignant transformation of host stromal cells was induced by glioma stem/progenitor cells. IhBTC2 cells are more radiation-resistant than the glioma stem/progenitor cells, which may be mediated by activation of the Notch signaling pathway. PMID- 26599018 TI - Use of Fish Scale-Derived BioCornea to Seal Full-Thickness Corneal Perforations in Pig Models. AB - The aim of this study was to test the use of BioCornea, a fish scale-derived collagen matrix for sealing full-thickness corneal perforations in mini-pigs. Two series of experiments were carried out in 8 Lan-Yu and 3 Gottingen mini-pigs, respectively. A 2mm central full thickness corneal perforation was made with surgical scissors and 2mm trephines. The perforations were sealed immediately by suturing BioCornea to the wounded cornea. The conditions of each patched cornea were followed-up daily for 3 or 4 days. Status of operated eyes was assessed with slit lamp examination or optical coherence tomography (OCT). Animals were sacrificed after the study period and the corneas operated were fixated for histological examination. Both OCT imaging and handheld slit lamp observations indicated that a stable ocular integrity of the perforated corneas was maintained, showing no leakage of aqueous humor, normal depth of anterior chamber and only mild swelling of the wounded cornea. Hematoxylin and eosin staining of the patched cornea showed no epithelial ingrowths to the perforated wounds and no severe leucocyte infiltration of the stroma. The fish scale-derived BioCornea is capable to seal full-thickness corneal perforation and stabilize the integrity of ocular anterior chamber in pre-clinic mini-pig models. BioCornea seems to be a safe and effective alternative for emergency treatment of corneal perforations. PMID- 26599020 TI - Adsorption mechanism of graphene-like ZnO monolayer towards CO2 molecules: enhanced CO2 capture. AB - This work aims to efficiently capture CO2 on two-dimensional (2D) nanostructures for effective cleaning of our atmosphere and purification of exhausts coming from fuel engines. Here, we have performed extensive first principles calculations based on density functional theory (DFT) to investigate the interaction of CO2 on a recently synthesized ZnO monolayer (ZnO-ML) in its pure, defected and functionalized form. A series of rigorous calculations yielded the most preferential binding configurations of the CO2 gas molecule on a ZnO-ML. It is observed that the substitution of one oxygen atom with boron, carbon and nitrogen on the ZnO monolayer resulted into enhanced CO2 adsorption. Our calculations show an enriched adsorption of CO2 on the ZnO-ML when substituting with foreign atoms like B, C and N. The improved adsorption energy of CO2 on ZnO suggests the ZnO-ML could be a promising candidate for future CO2 capture. PMID- 26599019 TI - Metformin Radiosensitizes p53-Deficient Colorectal Cancer Cells through Induction of G2/M Arrest and Inhibition of DNA Repair Proteins. AB - The present study addressed whether the combination of metformin and ionizing radiation (IR) would show enhanced antitumor effects in radioresistant p53 deficient colorectal cancer cells, focusing on repair pathways for IR-induced DNA damage. Metformin caused a higher reduction in clonogenic survival as well as greater radiosensitization and inhibition of tumor growth of p53-/- than of p53+/+ colorectal cancer cells and xenografts. Metformin combined with IR induced accumulation of tumor cells in the G2/M phase and delayed the repair of IR induced DNA damage. In addition, this combination significantly decreased levels of p53-related homologous recombination (HR) repair compared with IR alone, especially in p53-/- colorectal cancer cells and tumors. In conclusion, metformin enhanced radiosensitivity by inducing G2/M arrest and reducing the expression of DNA repair proteins even in radioresistant HCT116 p53-/- colorectal cancer cells and tumors. Our study provides a scientific rationale for the clinical use of metformin as a radiosensitizer in patients with p53-deficient colorectal tumors, which are often resistant to radiotherapy. PMID- 26599021 TI - Strengthening the Science and Practice of Health Equity in Public Health. PMID- 26599022 TI - Promoting Health and Behavioral Health Equity in California. AB - Behavioral health disparities are not usually considered part of the same system of health disparities. However, the California Department of Public Health focused its health equity strategies on reducing behavioral health disparities through its California Statewide Plan to Promote Health and Mental Health Equity. This statewide plan was developed through a community-wide stakeholder engagement and outreach process. In addition, the California Reducing Disparities Project is a prevention and early intervention effort to reduce mental health disparities in underserved populations. This strategic plan represents the voice of several racial/ethnic communities, such as African American, Asian and Pacific Islander, Latino, Native American, as well as lesbian, gay, bisexual, transgender, and queer and questioning communities in California, through 5 strategic planning workgroups. The workgroups were composed of a broad range of stakeholders, including community leaders, mental health care providers, consumer and family members, individuals with lived experience, and academia. This case example highlights the various efforts of California's Office of Health Equity in eliminating behavioral health disparities and promoting mental health equity, as well as discusses the unique statutory and regulatory role of the Office of Health Equity's deputy director. PMID- 26599023 TI - Integrating Health Equity Into Practice and Policy. AB - Achieving health equity across all population groups is a goal that will require vision and commitment from all sectors. The Centers for Disease Control and Prevention (CDC) has a central role to play in this undertaking. In 2014, the Health Disparities Subcommittee of the Advisory Committee to the Director of the CDC made a series of recommendations to achieve health equity: (1) develop a CDC framework for action to achieve health equity; (2) identify and monitor indicators of health equity; (3) align universal interventions that promote better public health with more targeted, culturally tailored interventions in communities at highest risk; (4) support rigorous evaluation of all programs and interventions; (5) build community capacity to implement and sustain programs; and (6) support training and professional development of the workforce. These recommendations may serve as a useful blueprint for achieving health equity by state and local health agencies or other organizations. PMID- 26599024 TI - On the Very Idea of Health Equity. PMID- 26599025 TI - Building Health Equity: A Community-Driven Approach to Confront Racism, Promote Racial Healing, and Sustain Equitable Opportunities for Optimal Health. PMID- 26599026 TI - Differences in Chronic Disease Behavioral Indicators by Sexual Orientation and Sex. AB - CONTEXT: Lesbian, gay, and bisexual (LGB) populations experience significant health inequities in preventive behaviors and chronic disease compared with non LGB populations. OBJECTIVES: To examine differences in physical activity and diet by sexual orientation and sex subgroups and to assess the influences of home and neighborhood environments on these relationships. DESIGN: A population-based survey conducted in 2013-2014. SETTING: A stratified, simple, random sample of households in 20 sites in the United States. PARTICIPANTS: A total of 21 322 adult LGB and straight-identified men and women. OUTCOME MEASURES: Any leisure time physical activity in the past month; physical activity 150 min/wk or more; daily frequency of consumption of vegetables, fruit, water, and sugar-sweetened beverages; and the number of meals prepared away from home in the past 7 days. RESULTS: Physical activity and diet varied by sexual orientation and sex; differences persisted after adjusting for sociodemographic factors and household and community environments. Bisexual men reported a higher odds of engaging in frequent physical activity than straight men (odds ratio [OR] = 3.10; 95% confidence interval [CI], 1.57-6.14), as did bisexual women compared with straight women (OR = 1.84; 95% CI, 1.20-2.80). LGB subgroups reported residing in more favorable walking and cycling environments. In contrast, gay men and lesbian and bisexual women reported a less favorable community eating environment (availability, affordability, and quality of fruit and vegetables) and a lower frequency of having fruit or vegetables in the home. Lesbian women reported lower daily vegetable consumption (1.79 vs 2.00 mean times per day; difference = -0.21; 95% CI, -0.03 to -0.38), and gay men reported consumption of more meals prepared away from home (3.17 vs 2.63; difference = 0.53; 95% CI, 0.11-0.95) than straight women and men, respectively. Gay men and lesbian and bisexual women reported a higher odds of sugar-sweetened beverage consumption than straight men and women. CONCLUSIONS: Findings highlight opportunities for targeted approaches to promote physical activity and mitigate differences in diet to reduce health inequities. PMID- 26599028 TI - Toward Achieving Health Equity: Emerging Evidence and Program Practice. AB - Health equity, in the context of public health in the United States, can be characterized as action to ensure all population groups living within a targeted jurisdiction have access to the resources that promote and protect health. There appear to be several elements in program design that enhance health equity. These design elements include consideration of sociodemographic characteristics, understanding the evidence base for reducing health disparities, leveraging multisectoral collaboration, using clustered interventions, engaging communities, and conducting rigorous planning and evaluation. This article describes selected examples of public health programs the Centers for Disease Control and Prevention (CDC) has supported related to these design elements. In addition, it describes an initiative to ensure that CDC extramural grant programs incorporate program strategies to advance health equity, and examples of national reports published by the CDC related to health disparities, health equity, and social determinants of health. PMID- 26599027 TI - Measurement of Health Disparities, Health Inequities, and Social Determinants of Health to Support the Advancement of Health Equity. AB - Reduction of health disparities and advancement of health equity in the United States require high-quality data indicative of where the nation stands vis-a-vis health equity, as well as proper analytic tools to facilitate accurate interpretation of these data. This article opens with an overview of health equity and social determinants of health. It then proposes a set of recommended practices in measurement of health disparities, health inequities, and social determinants of health at the national level to support the advancement of health equity, highlighting that (1) differences in health and its determinants that are associated with social position are important to assess; (2) social and structural determinants of health should be assessed and multiple levels of measurement should be considered; (3) the rationale for methodological choices made and measures chosen should be made explicit; (4) groups to be compared should be simultaneously classified by multiple social statuses; and (5) stakeholders and their communication needs can often be considered in the selection of analytic methods. Although much is understood about the role of social determinants of health in shaping the health of populations, researchers should continue to advance understanding of the pathways through which they operate on particular health outcomes. There is still much to learn and implement about how to measure health disparities, health inequities, and social determinants of health at the national level, and the challenges of health equity persist. We anticipate that the present discussion will contribute to the laying of a foundation for standard practice in the monitoring of national progress toward achievement of health equity. PMID- 26599029 TI - Promoting Health Equity and Optimal Health for All. PMID- 26599030 TI - Policy Approaches to Advancing Health Equity. AB - Public health policy approaches have demonstrated measurable improvements in population health. Yet, "one-size-fits-all" approaches do not necessarily impact all populations equally and, in some cases, can widen existing disparities. It has been argued that interventions, including policy interventions, can have the greatest impact when they target the social determinants of health. The intent of this article was to describe how selected current policies and policy areas that have a health equity orientation are being used with the aim of reducing health disparities and to illustrate contemporary approaches that can be applied broadly to a variety of program areas to advance health equity. Applying a health equity lens to a Health in All Policies approach is described as a means to develop policies across sectors with the explicit goal of improving health for all while reducing health inequities. Health equity impact assessment is described as a tool that can be effective in prospectively building health equity into policy planning. The discussion suggests that eliminating health inequities will benefit from a deliberate focus on health equity by public health agencies working with other sectors that impact health outcomes. PMID- 26599031 TI - Sustaining a Focus on Health Equity at the Centers for Disease Control and Prevention Through Organizational Structures and Functions. AB - The public health infrastructure required for achieving health equity is multidimensional and complex. The infrastructure should be responsive to current and emerging priorities and capable of providing the foundation for developing, planning, implementing, and evaluating health initiatives. This article discusses these infrastructure requirements by examining how they are operationalized in the organizational infrastructure for promoting health equity at the Centers for Disease Control and Prevention, utilizing the nation's premier public health agency as a lens. Examples from the history of the Centers for Disease Control and Prevention's work in health equity from its centers, institute, and offices are provided to identify those structures and functions that are critical to achieving health equity. Challenges and facilitators to sustaining a health equity organizational infrastructure, as gleaned from the Centers for Disease Control and Prevention's experience, are noted. Finally, we provide additional considerations for expanding and sustaining a health equity infrastructure, which the authors hope will serve as "food for thought" for practitioners in state, tribal, or local health departments, community-based organizations, or nongovernmental organizations striving to create or maintain an impactful infrastructure to achieve health equity. PMID- 26599032 TI - Integrating Equity in a Public Health Funding Strategy. AB - OBJECTIVE: Equity can be valuable to guide decision makers about where to target funds; however, there are few studies for modeling vertical equity in public health program funding strategies. This case study modeled vertical equity in the funding strategy of the Centers for Disease Control and Prevention's Colorectal Cancer Control Program. DESIGN: To integrate vertical equity by using historical funding and health data, we (a) examined the need for colorectal cancer screening, (b) conducted multiple regressions to examine the relationship between factors of need and funding of states, (c) stratified states into similar need groups, (d) estimated vertical equity within groups, and (e) assessed equity in the funding distribution. RESULTS: Certain states with similar needs had high relative funding, whereas other states with similar needs had low relative funding. CONCLUSION: The methods used to integrate vertical equity in this case study could be applied in publicly funded programs to potentially minimize inequities and improve outcomes. PMID- 26599033 TI - State and Territorial Infrastructure for Health Equity and Minority Health. AB - OBJECTIVE: With support from the National Partnership for Action to End Health Disparities, the Association of State and Territorial Health Officials conducted a survey of state and territorial health agencies (STHAs) to identify agencies' infrastructure and capacity for addressing health equity and improving minority health outcomes. DESIGN: The Minority Health Infrastructure Survey was a census design survey distributed to STHAs in 2007, 2010, and 2014. Both cross-sectional and select longitudinal data are presented. METHODS: Descriptive data from the Association of State and Territorial Health Officials' Minority Health Infrastructure Survey were recorded, and chi tests were performed on selected variables. RESULTS: In 2007, 95.7% of jurisdictions had a primary contact person for health equity initiatives. That number rose to 98.0% in 2010 and to 100% in 2014. In STHAs with a primary contact person, that individual worked full-time on health equity initiatives in 63.6% of STHAs in 2007, 82.0% of STHAs in 2010, and 81.1% of STHAs in 2014. The proportion of STHAs with an organizational unit devoted to minority health was 78.3% in 2007, 90.2% in 2010, and 84.9% in 2014. In 2014, 92.6% of STHAs had included minority health in an agencywide or dedicated strategic plan. The most common strategies for addressing health equity included in strategic plans were collecting and tracking disparities data (91.8%), leveraging and engaging public/private partners in solutions for health disparities (87.8%), and increasing cultural competency or health literacy (87.8%). All respondents collaborated with external partners on health equity initiatives in some way. CONCLUSIONS: STHAs increased their organizational resources to address minority health between 2007 and 2010, but resources leveled off or decreased in some areas between 2010 and 2014. Closing the disparities gap will require substantial nationwide investment and implementing strategies with the potential to make a lasting impact. PMID- 26599034 TI - Health Equity Is the Issue We Have Been Waiting for. PMID- 26599035 TI - Cross-Sectoral Collaboration: The State Health Official's Role in Elevating and Promoting Health Equity in All Policies in Minnesota. AB - CONTEXT: For many years, the Minnesota Department of Health (MDH) has been intentionally engaged in decreasing race- and ethnicity-based health disparities in the state. It has seen modest success in some areas, but overall, the disparities remain. Research over the last several decades has shown that race- and ethnicity-based health disparities are the result of persistent social and economic inequities, which have a greater influence on health outcomes than either individual choices or interventions by the health care system. SETTING: The MDH leaders recognized that to focus health improvement efforts solely on access to health care and individual behavior change (the traditional public health approaches of the last 30 years) would fail to make adequate advances in eliminating health disparities. Working with a statewide group known as the Healthy Minnesota Partnership, MDH decided to shift the public conversations about health in Minnesota to focus on the factors that actually create health. CONCLUSIONS: This effort to develop and implement a new narrative about health, focused on upstream issues such as education, employment, and home ownership, led to an emphasis on health in all policies approach for MDH and its partners. This case example will highlight Minnesota's efforts and discuss the new Council on Institutional Collaboration initiative in partnering large research universities with state health departments in addressing the social determinants of health. PMID- 26599036 TI - Balancing Tribal Sovereignty and the Role of Interjurisdictional Partnerships in Oklahoma. AB - CONTEXT: Oklahoma has a history of strong partnerships with their tribal health leaders and tribal communities. In 2012, the Oklahoma State Department of Health (OSDH) established the Office of the Tribal Liaison, as Oklahoma has 39 tribal nations in the state, of which 38 are federally recognized. The Office of the Tribal Liaison is responsible for promoting relationships with Oklahoma Tribal Nations and implementing the OSDH Tribal Consultation policy. SETTING: The strength of the partnership between the OSDH and the Tribal Nations enabled a new collaboration during an event hosted by a tribal casino event center that brought tattoo artists to provide tattoos to patrons over 3 days. Licensure issues that crossed the jurisdiction boundaries of the OSDH emerged before the event, which required the OSDH, Indian Health Service, and the Tribal Nation to work together to protect the public's health. The 3 jurisdictions drew upon their previously established partnership, OSDH's tribal consultation policy, and their open and trusting relationship to come together quickly to protect the public's health. CONCLUSIONS: This event and interjurisdictional partnership highlighted the importance of adopting the "Spectrum of Processes for Collaboration and Consensus Building" model as outlined by Orenstein et al to help guide and support state, tribal, and federal collaborations. This case example highlights the opportunities for collaboration between different regulatory public health and tribal bodies to improve the communities' health. PMID- 26599037 TI - Are Eye Clinics Safe For The Road? An Observational Report. AB - We report an observational study, based on the examination of 319 medical records, identifying the proportion of patients whose driving status was documented on the first and subsequent glaucoma clinic visits. We also established the proportion of patients with documented Driving and Vehicle Licencing Agency (DVLA)-related advice when they did not meet driving standards based on their visual acuity and/or visual fields (VF). On presentation, driving status was assessed in 61% (n=195) patients. Of the remaining 124, 44% (n=55) had their driving status documented at a subsequent visit, on an average 8 years later. Of all patients (78%, n=250) whose driving status was assessed at some stage, 42% (n=134) were drivers. Of the 203 patients who were either drivers or whose driving status was unknown, 37% (n=75) were assessed as having a visual acuity or bilateral VF defect that was below the legal limit for driving, 39 of whom were known drivers. Only 13 were advised to inform the DVLA, and only 5 patients were advised to update their spectacles or listed for surgery to improve their vision. We therefore potentially failed to perform our DVLA duty in 76% (n=57) of patients. We have made suggestions for improving the current performance in this respect based on the findings of this study. PMID- 26599038 TI - The Effectiveness of Lactobacillus Beverages in Controlling Infections among the Residents of an Aged Care Facility: A Randomized Placebo-Controlled Double-Blind Trial. AB - BACKGROUNDS/AIMS: To clarify the usefulness of Lactobacillus casei strain Shirota (LcS)-fermented milk in the normalization of bowel movements and improvement of infection control for the elderly residents and staff of facilities for the elderly. METHODS: A randomized placebo-controlled double-blind test was performed among the elderly residents (average age, 85) and staff members (average age, 37) of facilities for the elderly. The participants randomly received either LcS fermented milk or a placebo beverage once daily for 6 months. Clinical data and enteric conditions were compared between the 2 groups. RESULTS: A significantly lower incidence of fever and improved bowel movements were seen in the LcS fermented milk group (n = 36) in comparison to the placebo group (n = 36). The numbers of Bifidobacterium and Lactobacillus were significantly higher (p < 0.01), the numbers of destructive bacteria such as Clostridium difficile were significantly lower (p < 0.05), and the fecal acetic acid concentration and total acidity were significantly higher in the LcS group. A significant difference in the intestinal microbiota, fecal acetic acid, and pH was also observed between the LcS and placebo groups among the facility's staff members. CONCLUSIONS: The long-term consumption of LcS-fermented milk may be useful for decreasing the daily risk of infection and improving the quality of life among the residents and staff of facilities for the elderly. PMID- 26599039 TI - Red wine polyphenols modulate fecal microbiota and reduce markers of the metabolic syndrome in obese patients. AB - This study evaluated the possible prebiotic effect of a moderate intake of red wine polyphenols on the modulation of the gut microbiota composition and the improvement in the risk factors for the metabolic syndrome in obese patients. Ten metabolic syndrome patients and ten healthy subjects were included in a randomized, crossover, controlled intervention study. After a washout period, the subjects consumed red wine and de-alcoholized red wine over a 30 day period for each. The dominant bacterial composition did not differ significantly between the study groups after the two red wine intake periods. In the metabolic syndrome patients, red wine polyphenols significantly increased the number of fecal bifidobacteria and Lactobacillus (intestinal barrier protectors) and butyrate producing bacteria (Faecalibacterium prausnitzii and Roseburia) at the expense of less desirable groups of bacteria such as LPS producers (Escherichia coli and Enterobacter cloacae). The changes in gut microbiota in these patients could be responsible for the improvement in the metabolic syndrome markers. Modulation of the gut microbiota by using red wine could be an effective strategy for managing metabolic diseases associated with obesity. PMID- 26599040 TI - Morphologic, Pathologic, and Genetic Investigations of Bolbophorus Species Affecting Cultured Channel Catfish in the Mississippi Delta. AB - Trematodes belonging to the genus Bolbophorus have recently been reported as the cause of substantial morbidity and mortality in cultured channel catfish Ictalurus punctatus in Mississippi and Louisiana. Previous investigators identified only a single species, B. confusus. In this investigation, genetic techniques were used to identify all stages of the parasite in all of its hosts. The 18s rRNA genes from specimens collected in Mississippi were sequenced and compared; this analysis revealed that there are two distinct species, B. damnificus (previously identified as B. confusus) and another, undescribed species. (Phylogenetic analysis indicated that a third species, B. levantinus, is also closely related to the Mississippi species.) Species-specific polymerase chain reaction assays capable of identifying and differentiating between these two parasites were developed. Both species were found to infect the first intermediate host (the ram's horn snail Planorbella trivolvis) in commercial channel catfish ponds, but only B. damnificus was recovered from the fish themselves. The new, unidentified Bolbophorus species was determined to be highly pathogenic to a number of fish species. The contribution of B. damnificus to disease in cultured channel catfish remains undetermined. Future investigations of these parasites must now take into account the presence of two distinct species. PMID- 26599041 TI - Dose Titration of Walleye Dermal Sarcoma (WDS) Tumor Filtrate. AB - Walleyes Stizostedion vitreum were challenged with a topical application of a dilution series of cell-free dermal sarcoma tumor filtrates to determine the minimum dose of virus needed to induce these walleye tumors. A series of six 10 fold dilutions of the filtrate were applied to the side of the fish, which were allowed to develop grossly visible tumors at 15 degrees C for 20 weeks. Quantification of the virus in the filtrates was accomplished by quantitative (real-time) reverse transcriptase-polymerase chain reaction. We determined that there are approximately 10(10) viral RNA copies in 100 MUL of walleye dermal sarcoma inoculum. The minimum dose of walleye dermal sarcoma virus that could induce tumors by the topical challenge method was the 1,000-fold dilution of this 10(10) inoculum, or approximately 10(7) viral RNA copies. PMID- 26599042 TI - The Epidemiology of Bacterial Diseases in Food-Size Channel Catfish. AB - Enteric septicemia of catfish (ESC) and columnaris are the most economically important bacterial diseases affecting the channel catfish Ictalurus punctatus industry in the United States. Although these two diseases have been extensively researched, little is known about their prevalence and epidemiology in production systems. In 1997, a two-part survey of catfish producers in Alabama, Arkansas, Louisiana, and Mississippi was conducted to estimate the proportion of ponds and catfish operations that have these diseases and to develop information on the risk factors associated with reporting an occurrence. The response rates to the two phases of the survey were 65.6% and 75.3%, respectively. Overall, 78.1% of all operations and 42.1% of all ponds experienced problems with ESC/columnaris. Higher percentages of large operations and ponds on large operations experienced these problems. The most frequently reported average loss per outbreak of the two diseases was 200-2,000 lb (1 lb = 0.454 kg) per outbreak. Univariate analysis and multivariable regression modeling of the survey data identified three possible risk factors associated with ESC/columnaris, namely, operation size, stocking density, and feeding rate. Conversely, operations that produced their own fingerlings and those that drained ponds at intervals of 3 years or less were less likely to report losses. The associations identified in this study do not establish firm causal relationships, but they do generate hypotheses about managerial and environmental interactions that represent substantial risks to production. PMID- 26599043 TI - Histopathological Evidence of Regeneration following Hepatotoxic Effects of the Cyanotoxin Microcystin-LR in the Hardhead Catfish and Gulf Killifish. AB - The cyanobacterial toxin microcystin-LR (MC-LR) causes liver damage in several freshwater fish species. In the present study, two estuarine species, hardhead catfish Arius felis and gulf killifish Fundulus grandis, were injected intraperitoneally with MC-LR at 45-300 MUg/kg and their livers examined histopathologically for up to 23 d postinjection (PI) in the catfish and 5 d PI in the killifish. The livers from both species exhibited extensive, diffuse hepatocellular necrosis by 6 h PI. The necrosis persisted, and by day 2 large numbers of basophilic cells had emerged throughout the liver parenchyma. These cells occurred individually or in small clusters. By 72 h, the basophilic cells appeared to be highly proliferative with numerous mitotic figures and were arranged in cords and tubules similar to mature hepatic parenchyma. Regeneration of the liver parenchyma was noted in gulf killifish at 5 d PI, as tracts of basophilic cells were still evident. In hardhead catfish, there were no signs of necrosis or proliferating basophilic cells by 9 d PI, and the hepatic parenchyma appeared normal except for the vacuolation of many hepatocytes and some areas of hepatic megalocytosis. The degenerative changes in the two species studied were similar to but more pronounced than those observed in freshwater fish species exposed to MC-LR. Evidence of regeneration from the hepatotoxic effects of MC-LR suggests that the toxin can be used to study regenerative processes in fish livers. PMID- 26599044 TI - The Effects of Two Rearing Salinities on Survival and Stress of Winter Flounder Broodstock. AB - The goal of this study was to determine rearing conditions that would improve the survival of broodstock of winter flounder Pleuronectes americanus. We hypothesized that keeping wild winter flounder in iso-osmotic water would reduce the energy costs related to osmoregulation; the resulting energy gain could then be used for growth or immune responses. Eighty fish were randomly separated into four tanks, two containing seawater (SW; 28.7 +/- 0.90/00 (mean +/- SD)) and two containing brackish water (BW; 14.7 +/- 1.70/00). Fish were sampled after 2 and 5 months of captivity for evaluation of their condition and stress status. Between the second and fifth months, the condition index increased significantly in both salinity groups, whereas body water content decreased. No salinity effect in terms of growth, condition, or energy reserves was found. However, the fish in BW showed much lower mortality. We found that the fish in SW had higher levels of the physiological indicators of stress than those in BW, which could have increased the risk of opportunistic infections in the former. Also, thrombocytes were absent in the SW fish after 2 months of captivity, which may have contributed to some mortalities. The lower resistance of certain opportunistic pathogens to BW is another possible explanation as to why fish in BW had lower occurrences of infectious diseases. PMID- 26599045 TI - Vaccination against Furunculosis in Arctic Char: Efficacy of a Commercial Vaccine. AB - Arctic char Salvelinus alpinus are susceptible to furunculosis, a serious bacterial disease that affects the productivity of salmonid farms around the world. The objective of this laboratory study was to evaluate the efficacy of a commercially available vaccine against furunculosis in two strains of Arctic char. Labrador and Nauyuk char were injected with Aqua Health Furogen 2 or 0.9% NaCl. At 87 and 108 d postvaccination, fish were challenged with Aeromonas salmonicida by immersion. In both challenges, the Aqua Health vaccine provided significant protection against furunculosis; percent cumulative mortality was significantly (P = 0.005) greater for the fish vaccinated with 0.9% NaCl than for those vaccinated with Furogen 2. Strain (P = 0.30), days since vaccination (P = 0.38), and the interaction between vaccine and strain (P = 0.40) were not significant. The point estimate for the preventive fraction (PF) was greater than 0.90 for the Labrador fish vaccinated with Furogen 2; for the Nauyuk fish, the PF was 0.89 and 0.38 at 87 and 108 d, respectively. Relative proportion survival values were also estimated and were usually similar to, but always lower than, the PF estimates. PMID- 26599046 TI - Pathology of Oropharyngeal Fibropapillomatosis in Green Turtles Chelonia mydas. AB - Complete gross and histopathologic examinations of the oral cavity, tongue, pharynx, larynx, and glottis were performed in five Hawaiian green turtles Chelonia mydas with fibropapillomatosis. These examinations demonstrated that the oropharyngeal fibropapillomas were similar to characteristic external fibropapillomas previously described for green turtles. The size, appearance, and anatomic site of the tumors confirmed that these turtles presented total or partial occlusion of the nasopharynx, glottis, larynx, and adjacent tissues. The fibropapillomas of the oropharynx were considered locally invasive and severely modified the morphophysiology of respiration and feeding in these turtles. To the best of our knowledge, this is the first report of oropharyngeal fibropapillomatosis in sea turtles. PMID- 26599047 TI - Case Report: Viral Infectious Pancreatic Necrosis in Farmed Rainbow Trout from Mexico. AB - This case report provides pathologic and confirmatory diagnostic documentation of the first reported clinical epizootic of infectious pancreatic necrosis (IPN) in farmed rainbow trout Oncorhynchus mykiss from central Mexico. Both the gross and microscopic pathology were consistent with IPN. A virus was isolated in cell culture with the cytopathic effect typical of the IPN virus (IPNV). Positive identification as IPNV was achieved by means of an IPNV-specific indirect fluorescent antibody test and reverse transcription-polymerase chain reaction. Further genotyping identified this isolate as the Buhl strain of IPNV, which is a member of the West Buxton (A1) serotype of aquatic birnavirus serogroup A. PMID- 26599048 TI - Errata. PMID- 26599049 TI - Longitudinal Protein Changes in Blood Plasma Associated with the Rate of Cognitive Decline in Alzheimer's Disease. AB - Biomarkers of Alzheimer's disease (AD) progression are needed to support the development of urgently needed disease modifying drugs. We employed a SOMAscan assay for quantifying 1,001 proteins in blood samples from 90 AD subjects, 37 stable mild cognitive impaired (MCI) subjects, 39 MCI subjects converting to AD within a year and 69 controls at baseline and one year follow up. We used linear mixed effects models to identify proteins changing significantly over one year with the rate of cognitive decline, which was quantified as the reduction in Mini Mental State Examination (MMSE) scores. Additionally, we investigated proteins changing differently across disease groups and during the conversion from MCI to AD. We found that levels of proteins belonging to the complement cascade increase significantly in fast declining AD patients. Longitudinal changes in the complement cascade might be a surrogate biomarker for disease progression. We also found that members of the cytokine-cytokine receptor interaction pathway change during AD when compared to healthy aging subjects. PMID- 26599050 TI - Progression of Extrapyramidal Signs in Alzheimer's Disease: Clinical and Neuropathological Correlates. AB - BACKGROUND: Extrapyramidal signs (EPS) are frequent in Alzheimer's disease (AD) and core manifestation of related diseases, i.e., dementia with Lewy bodies and Parkinson's disease; furthermore, Lewy bodies and AD-type pathology occur in all three conditions. OBJECTIVE: To identify clusters of EPS progression over time and their clinical and neuropathological correlates. METHODS: 3,502 AD patients with longitudinal assessment from the National Alzheimer's Coordinating Center database were included; 394 provided neuropathological data. k-means algorithm was employed to identify clusters of EPS progression and those were compared in terms of cognitive profile, neuropsychiatric features and neuropathological findings. RESULTS: Three clusters of EPS progression were identified: no/low (n = 1,583), medium (n = 1,259), and high (n = 660) EPS burden. Compared to those with no/low and medium EPS, those with high EPS had greater cognitive and neuropsychiatric impairment, specifically hallucinations. Despite similar AD pathology across the three clusters, the high EPS cluster had a significantly number of subjects diagnosed with dementia with Lewy bodies. CONCLUSIONS: Cluster analysis of EPS progression over time identified different subgroups of AD patients with distinct clinical and neuropathological features. PMID- 26599051 TI - Upregulation of Connexin 43 Expression Via C-Jun N-Terminal Kinase Signaling in Prion Disease. AB - Prion infection leads to neuronal cell death, glial cell activation, and the accumulation of misfolded prion proteins. However, the altered cellular environments in animals with prion diseases are poorly understood. In the central nervous system, cells connect the cytoplasm of adjacent cells via connexin (Cx) assembled gap junction channels to allow the direct exchange of small molecules, including ions, neurotransmitters, and signaling molecules, which regulate the activities of the connected cells. Here, we investigate the role of Cx43 in the pathogenesis of prion diseases. Upregulated Cx43 expression, which was dependent on c-Jun N-Terminal Kinase (JNK)/c-Jun signaling cascades, was found in prion affected brain tissues and hippocampal neuronal cells. Scrapie infection-induced Cx43 formed aggregated plaques within the cytoplasmic compartments at the cell cell interfaces. The ethidium bromide (EtBr) uptake assay and scrape-loading dye transfer assay demonstrated that increased Cx43 has functional consequences for the activity of Cx43 hemichannels. Interestingly, blockade of PrPSc accumulation reduced Cx43 expression through the inhibition of JNK signaling, indicating that PrPSc accumulation may be directly involved in JNK activation-mediated Cx43 upregulation. Overall, our findings describe a scrapie infection-mediated novel regulatory signaling pathway of Cx43 expression and may suggest a role for Cx43 in the pathogenesis of prion diseases. PMID- 26599052 TI - Cycloheximide Treatment Causes a ZVAD-Sensitive Protease-Dependent Cleavage of Human Tau in Drosophila Cells. AB - Neurofibrillary tangles are the main pathological feature of Alzheimer's disease. Insoluble tau protein is the major component of neurofibrillary tangles. Defects in the tau protein degradation pathway in neurons can lead to the accumulation of tau and its subsequent aggregation. Currently, contradictory results on the tau degradation pathway have been reported by different groups. This discrepancy is most likely due to different cell lines and methods used in those studies. In this study, we found that cycloheximide treatment induced mild activation of a ZVAD-sensitive protease in Drosophila Kc cells, resulting in cleavage of tau at its C-terminus; this cleavage could generate misleading tau protein degradation pattern results depending on the antibodies used in the assay. Because cycloheximide is a broadly used chemical reagent for the study of protein degradation, the unexpected artificial effect we observed here indicates that cycloheximide is not suitable for the study of tau degradation. Other methods, such as inducible expression systems and pulse-chase assays, may be more appropriate for studying tau degradation under physiological conditions. PMID- 26599053 TI - Anemia and Mild Cognitive Impairment in the German General Population. AB - There is increasing evidence that anemia is associated with cognitive impairment. Therefore, the aim of the study was to examine the cross-sectional association of anemia as well as the persistence of anemia over the last five years with mild cognitive impairment (MCI) and MCI subtypes (amnestic/non-amnestic MCI (aMCI/naMCI)). Out of 4,157 participants (50% men, 50-80 years) of the second examination (t1) of a cohort study (baseline (t0) 2000-2003), we included 4,033 participants with available hemoglobin information and complete cognitive assessment. Anemia was defined as hemoglobin <13 g/dl in men (n = 84) and <12 g/dl in women (n = 79). Group comparisons were used to compare the cognitive subtests. To determine the association of MCI with anemia at t1, with anemia five years prior to the cognitive assessment (t0) and anemia at both time points, we used logistic regression models and included 579 participants with MCI and 1,438 cognitively normal participants out of the total cohort. Anemic participants showed lower performances in verbal memory and executive functions. The fully adjusted odds ratios (OR) for MCI, aMCI, and naMCI in anemic versus non-anemic participants were 1.92 (95% -CI, 1.09-3.39), 1.96 (1.00-3.87), and 1.88 (0.91 3.87). Anemia at both times points showed a non-significant association with naMCI (OR 3.74, 0.94-14.81, fully adjusted). Our results suggest that anemia is associated with an increased risk of MCI independent of traditional cardiovascular risk factors. The association of anemia and MCI has important clinical relevance, because many causes of anemia can be treated effectively. PMID- 26599054 TI - Accurate Prediction of Conversion to Alzheimer's Disease using Imaging, Genetic, and Neuropsychological Biomarkers. AB - A variety of imaging, neuropsychological, and genetic biomarkers have been suggested as potential biomarkers for the identification of mild cognitive impairment (MCI) in patients who later develop Alzheimer's disease (AD). Here, we systematically evaluated the most promising combinations of these biomarkers regarding discrimination between stable and converter MCI and reflection of disease staging. Alzheimer's Disease Neuroimaging Initiative data of AD (n = 144), controls (n = 112), stable (n = 265) and converter (n = 177) MCI, for which apolipoprotein E status, neuropsychological evaluation, and structural, glucose, and amyloid imaging were available, were included in this study. Naive Bayes classifiers were built on AD and controls data for all possible combinations of these biomarkers, with and without stratification by amyloid status. All classifiers were then applied to the MCI cohorts. We obtained an accuracy of 76% for discrimination between converter and stable MCI with glucose positron emission tomography as a single biomarker. This accuracy increased to about 87% when including further imaging modalities and genetic information. We also identified several biomarker combinations as strong predictors of time to conversion. Use of amyloid validated training data resulted in increased sensitivities and decreased specificities for differentiation between stable and converter MCI when amyloid was included as a biomarker but not for other classifier combinations. Our results indicate that fully independent classifiers built only on AD and controls data and combining imaging, genetic, and/or neuropsychological biomarkers can more reliably discriminate between stable and converter MCI than single modality classifiers. Several biomarker combinations are identified as strongly predictive for the time to conversion to AD. PMID- 26599055 TI - Impaired Parahippocampus Connectivity in Mild Cognitive Impairment and Alzheimer's Disease. AB - BACKGROUND: The parahippocampal gyrus (PHG) is an important region of the limbic system that plays an important role in episodic memory. Elucidation of the PHG connectivity pattern will aid in the understanding of memory deficits in neurodegenerative diseases. OBJECTIVE: To investigate if disease severity associated altered PHG connectivity in Alzheimer's disease (AD) exists. METHODS: We evaluated resting-state functional magnetic resonance imaging data from 18 patients with amnestic mild cognitive impairment (MCI), 35 patients with AD, and 21 controls. The PHG connectivity pattern was examined by calculating Pearson's correlation coefficients between the bilateral PHG and whole brain. Group comparisons were performed after controlling for the effects of age and gender. The functional connectivity strength in each identified region was correlated with the MMSE score to evaluate the relationship between connectivity and cognitive ability. RESULTS: Several brain regions of the default mode network showed reduced PHG connectivity in the AD patients, and PHG connectivity was associated with disease severity in the MCI and AD subjects. More importantly, correlation analyses showed that there were positive correlations between the connectivity strengths of the left PHG-PCC/Pcu and left PHG-left MTG and the Mini Mental State Examination, indicating that with disease progression from MCI to severe AD, damage to the functional connectivity of the PHG becomes increasingly severe. CONCLUSIONS: These results indicate that disease severity is associated with altered PHG connectivity, contributing to knowledge about the reduction in cognitive ability and impaired brain activity that occur in AD/MCI. These early changes in the functional connectivity of the PHG might provide some potential clues for identification of imaging markers for the early detection of MCI and AD. PMID- 26599056 TI - Cognitive Impairment after Mild Stroke: Development and Validation of the SIGNAL2 Risk Score. AB - BACKGROUND: Post stroke cognitive impairment (PSCI), an important complication of strokes, has numerous risk factors. A scale adequately classifying risk of cognitive impairment 3-6 months after mild stroke will be useful for clinicians. OBJECTIVE: To develop a risk score based on clinical and neuroimaging variables that will be useful in identifying mild ischemic stroke patients at high risk for PSCI. METHODS: The risk score development cohort comprised of a retrospective dataset of 209 mild stroke patients with MRI confirmed infarcts, without pre stroke cognitive impairment, and evaluated within 6 months post-stroke for PSCI. Logistic regression identified factors predictive of PSCI and a risk score was developed based on regression coefficients. The risk score was checked for stability using 10-fold cross-validation and validated in an independent prospective cohort of 185 ischemic mild stroke patients. RESULTS: Within 6 months post-stroke, 37.32% developed PSCI in the retrospective dataset. A 15-point risk score based on age, education, acute cortical infarcts, white matter hyperintensity, chronic lacunes, global cortical atrophy, and intracranial large vessel stenosis was highly predictive of PSCI with an AUC of 0.829. 10.11% with low scores, 52.69% with moderate scores, and 74.07% with high scores developed PSCI. In the prospective validation cohort, the model had an AUC of 0.776, and exhibited similar accuracy and stability statistics at both 6 and 12 months. CONCLUSION: The seven item risk score adequately identified mild stroke patients who are at an increased risk of developing PSCI. PMID- 26599057 TI - Matrix Metalloproteinase in Blood-Brain Barrier Breakdown in Dementia. AB - The neurovascular unit, which consists of astrocytic end-feet, neurons, pericytes, and endothelial cells, plays a key role in maintaining brain homeostasis by forming the blood-brain barrier and carefully controlling local cerebral blood flow. When the blood-brain barrier is disrupted, blood components can leak into the brain, damage the surrounding tissue and lead to cognitive impairment. This disruption in the blood-brain barrier and subsequent impairment in cognition are common after stroke and during cerebral amyloid angiopathy and Alzheimer's disease. Matrix metalloproteinases are proteases that degrade the extracellular matrix as well as tight junctions between endothelial cells and have been implicated in blood-brain barrier breakdown in neurodegenerative diseases. This review will focus on the roles of MMP2 and MMP9 in dementia, primarily post-stroke events that lead to dementia, cerebral amyloid angiopathy, and Alzheimer's disease. PMID- 26599058 TI - Self-Consciousness in Patients with Behavioral Variant Frontotemporal Dementia. AB - Self-consciousness (SC) is multifaceted and considered to be the consciousness of one's own mental states. The medial prefrontal cortex may play a critical role in SC. The main aim of this paper was to examine SC in patients with behavioral variant frontotemporal dementia, who are characterized more by changes in personal, social, and emotional conduct and loss of insight than by cognitive disturbances. Control and patient groups of 21 subjects each, matched by age, educational level, gender, and nationality were assessed using a SC questionnaire. It measures several aspects: Personal identity, Anosognosia, Affective state, Body representation, Prospective memory, Introspection, and Moral judgments. The most disturbed ones in patients were Anosognosia, Affective state, and Moral judgments, and the least disturbed aspects were awareness of identity and of body representation. No significant correlations were found between the SC score and any clinical or demographical characteristics. The core deficiency of SC in patients was related to behavioral SC aspects, which are more dependent on orbito-frontal functioning. PMID- 26599059 TI - Atrial flutter after surgical maze: incidence, diagnosis, and management. AB - PURPOSE OF REVIEW: The prevalence of atrial fibrillation is increasing and surgical ablation is becoming more common, both as a stand-alone procedure and when performed concomitantly with other cardiac surgery. Although surgical ablation is effective, with it unique challenges arise, including iatrogenic macroreentrant tachycardias that are often highly symptomatic and difficult to manage conservatively. RECENT FINDINGS: Postsurgical ablation, localization of the arrhythmic circuit is difficult to determine using surface ECG alone because of alterations in the atrial myocardium, and multiple different pathways are often present. Most, however, localize to the left atrium, and percutaneous catheter ablation is emerging as an effective treatment modality. SUMMARY: Patients with complex postoperative arrhythmias should be referred to a dedicated atrial fibrillation center when possible and symptomatic arrhythmias mapped and ablated. Knowledge of the previously performed surgical lesion set is of vital importance in understanding the mechanism of the arrhythmia and increasing procedural success rates. VIDEO ABSTRACT: http://links.lww.com/HCO/A31. PMID- 26599060 TI - Dyslipidemia and cardiovascular changes in children. AB - PURPOSE OF REVIEW: In this review, we firstly highlight the role of dyslipidemia as a trigger in the initiation and progression of endothelial dysfunction, considered the earliest atherosclerotic lesion and patent in children with risk factors.In this context, we also revise methods that reflect the impact of endothelial dysfunction not only on arterial stiffness but also on cardiovascular morphology, namely, the common carotid intima-media thickness and the ventricular geometry. RECENT FINDINGS: In view of its atherogenic burden, the most widely studied lipoprotein has been low density lipoprotein cholesterol. However, the smaller, denser, low density lipoprotein cholesterol particles, the nonhigh density lipoprotein cholesterol fraction, appear to be more atherogenic and a more sensitive cardiovascular risk marker. Studies have shown that in children, atherogenic lipids have also been linked to cardiovascular morphological changes, such as the common carotid intima-media thickness and the ventricular geometry, both independent cardiovascular risk markers. SUMMARY: In infancy, atherosclerosis is a preclinical disorder in which dyslipidemia plays a crucial role. Due to its impact on cardiovascular structures, potentially reversible during childhood, dyslipidemia ought to be managed aggressively to prevent further disease progression that will ultimately culminate in cardiac disease, a leading cause of mortality in adults. PMID- 26599061 TI - Premature ventricular contraction-induced cardiomyopathy. AB - PURPOSE OF REVIEW: There has been a resurgent interest in frequent premature ventricular contractions (PVCs) led by the novel concept that they may be a potential cause of, or at least contribute to, cardiomyopathy. This review evaluates recent advances in our understanding of PVC-induced cardiomyopathy. RECENT FINDINGS: Recent studies have focused on identifying the predictors of PVC induced cardiomyopathy, with the most consistent predictors being PVC burden and PVC QRS duration. Multiple studies have investigated the effect of catheter ablation on PVC burden and resultant left ventricular function, with the efficacy of catheter ablation and the overall PVC response rates varying between 60 and 88%. After successful ablation, the rates of improvement in left ventricular ejection fraction have varied between 47 and 100%. A recent study raises the question that perhaps even a lower PVC burden could result in PVC cardiomyopathy and adverse outcomes. SUMMARY: There is an increasing body of literature supporting a causal role of frequent PVCs in the development of left ventricular dysfunction. Effective therapy for PVCs exists; however, the optimal indications for therapy have yet to be determined. PMID- 26599062 TI - Recent advances in transcatheter pulmonary valve delivery. AB - PURPOSE OF REVIEW: Transcatheter pulmonary valve replacement has only been both approved and widely available for most congenital heart disease centers for a few years; its use and familiarity for interventionalists have greatly expanded our knowledge of its applicability to a multitude of clinical situations. Expanded worldwide use and longer time from implant have both served to better understand procedural limits and uncommon late adverse events. RECENT FINDINGS: Although currently approved for implantation in the USA only in dysfunctional and circumferential right ventricle to pulmonary artery conduits, with expanded experience operators have been able to adapt the delivery of this valve in a large number of additional clinical scenarios. Rare technical limitations of the procedure, most importantly coronary compression, are now being better defined. Although not frequent, a significant number of infective endocarditis episodes have been reported, but more recently several studies have deepened our understanding of this late adverse event for the most commonly implanted transcatheter pulmonary valve prosthesis. SUMMARY: Expanded and widened use has extended our understanding of who may benefit from transcatheter pulmonary valve implantation (TPVI), the current limits of TPVI, and uncommon but important late issues following TPVI. PMID- 26599063 TI - Dynamic Control of Optical Response in Layered Metal Chalcogenide Nanoplates. AB - Tunable optical transitions in ultrathin layered 2-dimensional (2D) materials unveil the electronic structures of materials and provide exciting prospects for potential applications in optics and photonics. Here, we present our realization of dynamic optical modulation of layered metal chalcogenide nanoplates using ionic liquid (IL) gating over a wide spectral range. The IL gating significantly increased the tuning range of the Fermi level and, as a result, substantially altered the optical transitions in the nanoplates. Using heavily n-doped Bi2Se3 nanoplates, we substantially modulated the light transmission through the ultrathin layer. A tunable, high-transmission spectral window in the visible to near-infrared region has been observed due to simultaneous shifts of both the plasma edge and absorption edge of the material. On the other hand, optical response of multilayer MoSe2 flakes gated by IL has shown enhanced transmission in both positive and negative biases, which is consistent with their ambipolar electrical behavior. The electrically controlled optical property tuning in metal chalcogenide material systems provides new opportunities for potential applications, such as wide spectral range optical modulators, optical filters, and electrically controlled smart windows with extremely low material consumption. PMID- 26599064 TI - Nonoperative management of rectal cancer. AB - Surgery has long been the primary curative modality for localized rectal cancer. Neoadjuvant chemoradiation has significantly improved local control rates and, in a significant minority, eradicated all disease. Patients who achieve a pathologic complete response to neoadjuvant therapy have an excellent prognosis, although the combination treatment is associated with long-term morbidity. Because of this, a nonoperative management (NOM) strategy has been pursued to preserve sphincter function in select patients. Clinical and radiographic findings are used to identify patients achieving a clinical complete response to chemoradiation, and they are then followed with intensive surveillance. Incomplete, nonresponding and those demonstrating local progression are referred for salvage with standard surgery. Habr-Gama and colleagues have published extensively on this treatment strategy and have laid the groundwork for this approach. This watch-and-wait strategy has evolved over time, and several groups have now reported their results, including recent prospective experiences. Although initial results appear promising, several significant challenges remain for NOM of rectal cancer. Further study is warranted before routine implementation in the clinic. PMID- 26599065 TI - Role of fluorine-18 fluoride PET-CT scan in the assessment of unilateral condylar hyperplasia in faciomandibular asymmetry patients: a preliminary study. AB - OBJECTIVES: This prospective study was aimed to determine and quantify the change in mandibular condylar hyperactivity over a period of time by using a fluorine-18 (18F) fluoride PET-computed tomography (CT) scan. MATERIALS AND METHODS: Sixteen patients (age 19.50 +/- 2.58 years) with noticeable faciomandibular asymmetry caused by unilateral condylar hyperplasia (UCH) were included in the test group and underwent an 18F-fluoride PET-CT scan at the beginning of the study (T0); these patients were then followed up for a minimum of 12 months, after which the 18F-fluoride PET-CT scan was repeated at first follow-up (T1). An age-matched control group consisted of 10 patients with apparently symmetrical faces whose PET-CT scans were acquired for some other medical conditions. Statistical analysis of maximum standardized uptake values (SUV max) obtained through 18F fluoride PET-CT was performed using the paired t-test. RESULTS: Mean SUV max of the affected condyle at T0 and T1 was 9.18 +/- 4.07 and 9.18 +/- 3.88, respectively. The mean SUV max of the contralateral condyle at T0 and T1 was 6.21 +/- 2.30 and 6.66 +/- 2.64, respectively. The mean right-left difference in tracer uptake between the test and control groups both at T0 and T1 was statistically significant. Right-left percentage difference of isotope uptake of the test group was 16.87 +/- 15.75% at T0 and 14.97 +/- 12.72% at T1. Right-left percentage difference of isotope uptake of the control group was 5.51 +/- 5.72%. Although these differences were statistically significant, their clinical relevance was insignificant. SUV max of the higher uptake side and the lower uptake side of the control group was 5.63 +/- 1.85 and 5.09 +/- 1.83, respectively. CONCLUSION: Great diversity exists in the clinical presentation of UCH. The growth trend of UCH is highly variable because of the age and sex of patients. The results of the present study show that the 18F-fluoride PET-CT scan may guide us in determining the right time and in making the right choice of surgico-orthodontic intervention in UCH patients. The clinical presentation and SUV max of PET-CT of UCH patients were in agreement with each other. The baseline values of the control group indicated that these could also be used to differentiate normal from abnormal condylar growth in potential class III skeletal pattern cases - that is, patients having sagittal skeletal dysplasia resulting from either maxillary deficiency or mandibular protrusion, or both in combination, thus resulting in a concave facial profile. PMID- 26599066 TI - Interobserver and intraobserver variability for the assessment of brown adipose tissue activity on 18F-FDG PET-CT. AB - OBJECTIVE: Measurement of brown adipose tissue (BAT) activity is the focus of intensive research, among others as a potential target for weight-lowering strategies. In this, BAT activity is visualized and quantified using F fluorodeoxyglucose (F-FDG) PET-CT. The aim of this study was to determine the interobserver and intraobserver variability for detecting and quantifying BAT on F-FDG PET-CTs. METHODS: Three observers retrospectively independently assessed 55 F-FDG PET-CTs (performed between April 2013 and January 2014) for BAT activity parameters: BAT volume, the maximal and mean standardized uptake value (SUVmax and SUVmean) obtained in healthy male controls. One observer reassessed the scans after 2 months for the intraobserver variability. Interobserver and intraobserver variability were expressed using Lin's concordance coefficient (LCC) and Bland Altman plots. Correlations between the three parameters were assessed using Spearman's correlation. RESULTS: The LCCs for the interobserver and intraobserver concordance for SUVmax were the highest (LCC SUVmax varied between 0.998 and 0.999, for SUVmean between 0.989 and 0.991 and for volume between 0.947 and 0.972). The Bland-Altman analysis showed a small absolute mean difference between all observers for both SUVmax and SUVmean, but the differences for volume were markedly higher. All parameters correlated statistically strongly and positively. CONCLUSION: The SUVmax showed the lowest interobserver and intraobserver variation. Although SUVmean and BAT volume had a higher interobserver and intraobserver variation, the variation is still within acceptable limits. Therefore, all parameters can be used to describe BAT activity. However, for an adequate comparison between studies, we recommend the use of SUVmax. PMID- 26599067 TI - Erratum. PMID- 26599068 TI - "Delayed Villous Maturation" in Placental Reporting: Concordance among Consultant Pediatric Pathologists at a Single Specialist Center. AB - Delayed villous maturation (DVM) has been associated with an increased risk of adverse pregnancy outcome, including stillbirth, in the late third trimester, but there are limited published data. Moreover, it is recognized that the assessment of villous maturation is subjective and hampered by both intraobserver and interobserver variability. This audit aims to assess concordance in the reporting of DVM among pediatric pathologists at a single specialist center to improve reproducibility of this potentially important diagnosis. This is a retrospective review of singleton placentas from pregnancies at 35 weeks gestation or greater submitted for histopathologic examination between June 2013 and December 2013. Placental slides were reviewed independently by 4 pediatric pathologists, blinded to the original report, apart from gestational age; villous maturation was assessed as appropriate, accelerated, or delayed for the stated gestational age. A total of 464 placental histopathology reports were reviewed, of which 164 were greater than 35 weeks gestation; of those, 42 (26%) were originally reported as DVM. Following the audit slide review, 38 cases (23%) were assessed to show DVM by at least 1 pathologist. Consensus, with at least 3 pathologists agreeing to a diagnosis of DVM, was achieved in only 14 cases (9% of all cases reviewed; 37% of all cases called DVM). However, the proportion of overall agreement between 2 of the pathologists was 0.92. Concordance for DVM is poor among pathologists and subject to much interobserver variability. Consistency may be improved by consensus histologic review of all the placentas in which the diagnosis of DVM is being considered and stringent application of the published diagnostic criteria. PMID- 26599069 TI - Dr Marian Malone. PMID- 26599070 TI - Lack of Evidence for Molecular Mimicry in HIV-Infected Subjects. AB - Previous studies in HIV patients have reported autoantibodies to several human proteins, including erythropoietin (EPO), interferon-alpha (IFN-alpha), interleukin-2 (IL-2), and HLA-DR, as potential mediators of anemia or immunosuppression. The etiology of these autoantibodies has been attributed to molecular mimicry between HIV epitopes and self-proteins. Here, the Luciferase Immunoprecipitation System (LIPS) was used to investigate the presence of such autoantibodies in HIV-infected adults. High levels of antibodies to HIV proteins such as capsid (p24), matrix (p17), envelope (gp41), and reverse transcriptase (RT) were detected using LIPS in both untreated and anti-retroviral-treated HIV infected individuals but not in uninfected controls. LIPS readily detected anti EPO autoantibodies in serum samples from subjects with presumptive pure red cell aplasia but not in any of the samples from HIV-infected or uninfected individuals. Similarly, subjects with HIV lacked autoantibodies to IFN-alpha, IL 2, HLA-DR and the immunoglobulin lambda light chain; all purported targets of molecular mimicry. While molecular mimicry between pathogen proteins and self proteins is a commonly proposed mechanism for autoantibody production, the findings presented here indicate such a process is not common in HIV disease. PMID- 26599071 TI - Same/Different Abstract Concept Learning by Archerfish (Toxotes chatareus). AB - While several phylogenetically diverse species have proved capable of learning abstract concepts, previous attempts to teach fish have been unsuccessful. In this report, the ability of archerfish (Toxotes chatareus) to learn the concepts of sameness and difference using a simultaneous two-item discrimination task was tested. Six archerfish were trained to either select a pair of same or different stimuli which were presented simultaneously. Training consisted of a 2-phase approach. Training phase 1: the symbols in the same and different pair did not change, thereby allowing the fish to solve the test through direct association. The fish were trained consecutively with four different sets of stimuli to familiarize them with the general procedure before moving on to the next training phase. Training phase 2: six different symbols were used to form the same or different pairs. After acquisition, same/different concept learning was tested by presenting fish with six novel stimuli (transfer test). Five fish successfully completed the first training phase. Only one individual passed the second training phase, however, transfer performance was consistent with chance. This individual was given further training using 60 training exemplars but the individual was unable to reach the training criterion. We hypothesize that archerfish are able to solve a limited version of the same/different test by learning the response to each possible stimulus configuration or by developing a series of relatively simple choice contingencies. We conclude that the simultaneous two-item discrimination task we describe cannot be successfully used to test the concepts of same and different in archerfish. In addition, despite considerable effort training archerfish using several tests and training methods, there is still no evidence that fish can learn an abstract concept-based test. PMID- 26599072 TI - Life-Cycle Perspectives on Aquatic Ecotoxicity of Common Ionic Liquids. AB - This study compares the aquatic ecotoxicity impacts of production- and use-phase release of five common ionic liquids (ILs). Integrating toxicity data, physical properties, and fate and transport parameters with the USEtox model, we report, for the first time, the freshwater ecotoxicity characterization factors for [Bmim](+)[Br](-), [Bmim](+)[Cl], [Bmim](+)[BF4](-), [Bmim](+)[PF6](-), and [BPy](+)[Cl](-) as 624, 748, 823, 927, and 1768 CTUe/kg, respectively. IL Production life cycle inventories were modeled and utilized to estimate their production-side ecotoxicity impacts. Literature on environmental aspects of ILs propagates either their green characteristics (no air emissions and high recyclability) or their nongreen aspects due to toxicity concerns of their release to water. This study adds a third dimension by showing that the upstream ecotoxicity impacts of producing ILs could outweigh the potential ecotoxicity impacts of direct release during use. Furthermore, for the studied ILs, an average of 83% of ecotoxicity impacts associated with their production can be linked to chemicals and materials released during the upstream synthesis steps, while only 17% of ecotoxicity impacts relate to life-cycle energy consumption. The findings underscore the need to develop sustainable synthesis routes, tight control over chemical releases during production, and careful selection of precursor materials and production processes. PMID- 26599073 TI - Bone Mass and Strength in School-Age Children Exhibit Sexual Dimorphism Related to Differences in Lean Mass: The Generation R Study. AB - Bone strength, a key determinant of fracture risk, has been shown to display clear sexual dimorphism after puberty. We sought to determine whether sex differences in bone mass and hip bone geometry as an index of strength exist in school-age prepubertal children and the degree to which the differences are independent of body size and lean mass. We studied 3514 children whose whole-body and hip scans were measured using the same densitometer (GE-Lunar iDXA) at a mean age of 6.2 years. Hip dual-energy X-ray absorptiometry (DXA) scans underwent hip structural analyses (HSA) with derivation of bone strength indices. Sex differences in these parameters were assessed by regression models adjusted for age, height, ethnicity, weight, and lean mass fraction (LMF). Whole-body bone mineral density (BMD) and bone mineral content (BMC) levels were 1.3% and 4.3% higher in girls after adjustment by LMF. Independent of LMF, boys had 1.5% shorter femurs, 1.9% and 2.2% narrower shaft and femoral neck with 1.6% to 3.4% thicker cortices than girls. Consequent with this geometry configuration, girls observed 6.6% higher stresses in the medial femoral neck than boys. When considering LMF, the sexual differences on the derived bone strength indices were attenuated, suggesting that differences in muscle loads may reflect an innate disadvantage in bone strength in girls, as consequence of their lower muscular acquisition. In summary, we show that bone sexual dimorphism is already present at 6 years of age, with boys having stronger bones than girls, the relation of which is influenced by body composition and likely attributable to differential adaptation to mechanical loading. Our results support the view that early life interventions (ie, increased physical activity) targeted during the pre- and peripubertal stages may be of high importance, particularly in girls, because before puberty onset, muscle mass is strongly associated with bone density and geometry in children. (c) 2015 American Society for Bone and Mineral Research. PMID- 26599074 TI - Intestinal Rotation and Physiological Umbilical Herniation During the Embryonic Period. AB - Drastic changes occur during the formation of the intestinal loop (IL), including elongation, physiological umbilical herniation (PUH), and midgut rotation. Fifty four sets of magnetic resonance images of embryos between Carnegie stage (CS) 14 and CS 23 were used to reconstruct embryonic digestive tract in three dimensions in the Amira program. Elongation, PUH, and rotation were quantified in relation to the proximal part of the superior mesenteric artery (SMA), designated as the origin. Up to CS 16, IL rotation was initially observed as a slight deviation of the duodenum and colorectum from the median plane. The PUH was noticeable after CS 17. At CS 18, the IL showed a hairpin-like structure, with the SMA running parallel to the straight part and the cecum located to the left. After CS 19, the IL began to form a complex structure as a result of the rapid growth of the small intestinal portion. By CS 20, the IL starting point had moved from the right cranial region to an area caudal to the origin, though elongation of the duodenum was not conspicuous-this was a change of almost 180 degrees in position. The end of the IL remained in roughly the same place, to the left of and caudal to the origin. Notably, the IL rotated around the origin only during earlier stages and gradually moved away, running transversely after CS 19. The movements of the IL may be explained as the result of differential growth, suggesting that IL rotation is passive. PMID- 26599075 TI - Between-Trial Forgetting Due to Interference and Time in Motor Adaptation. AB - Learning a motor task with temporally spaced presentations or with other tasks intermixed between presentations reduces performance during training, but can enhance retention post training. These two effects are known as the spacing and contextual interference effect, respectively. Here, we aimed at testing a unifying hypothesis of the spacing and contextual interference effects in visuomotor adaptation, according to which forgetting between trials due to either spaced presentations or interference by another task will promote between-trial forgetting, which will depress performance during acquisition, but will promote retention. We first performed an experiment with three visuomotor adaptation conditions: a short inter-trial-interval (ITI) condition (SHORT-ITI); a long ITI condition (LONG-ITI); and an alternating condition with two alternated opposite tasks (ALT), with the same single-task ITI as in LONG-ITI. In the SHORT-ITI condition, there was fastest increase in performance during training and largest immediate forgetting in the retention tests. In contrast, in the ALT condition, there was slowest increase in performance during training and little immediate forgetting in the retention tests. Compared to these two conditions, in the LONG ITI, we found intermediate increase in performance during training and intermediate immediate forgetting. To account for these results, we fitted to the data six possible adaptation models with one or two time scales, and with interference in the fast, or in the slow, or in both time scales. Model comparison confirmed that two time scales and some degree of interferences in either time scale are needed to account for our experimental results. In summary, our results suggest that retention following adaptation is modulated by the degree of between-trial forgetting, which is due to time-based decay in single adaptation task and interferences in multiple adaptation tasks. PMID- 26599076 TI - Nanoparticle self-assembly in mixtures of phospholipids with styrene/maleic acid copolymers or fluorinated surfactants. AB - Self-assembling nanostructures in aqueous mixtures of bilayer-forming lipids and micelle-forming surfactants are relevant to in vitro studies on biological and synthetic membranes and membrane proteins. Considerable efforts are currently underway to replace conventional detergents by milder alternatives such as styrene/maleic acid (SMA) copolymers and fluorinated surfactants. However, these compounds and their nanosized assemblies remain poorly understood as regards their interactions with lipid membranes, particularly, the thermodynamics of membrane partitioning and solubilisation. Using (19)F and (31)P nuclear magnetic resonance spectroscopy, static and dynamic light scattering, and isothermal titration calorimetry, we have systematically investigated the aggregational state of a zwitterionic bilayer-forming phospholipid upon exposure to an SMA polymer with a styrene/maleic acid ratio of 3 : 1 or to a fluorinated octyl phosphocholine derivative called F(6)OPC. The lipid interactions of SMA(3 : 1) and F(6)OPC can be thermodynamically conceptualised within the framework of a three-stage model that treats bilayer vesicles, discoidal or micellar nanostructures, and the aqueous solution as distinct pseudophases. The exceptional solubilising power of SMA(3 : 1) is reflected in very low membrane saturating and solubilising polymer/lipid molar ratios of 0.10 and 0.15, respectively. Although F(6)OPC saturates bilayers at an even lower molar ratio of 0.031, this nondetergent does not solubilise lipids even at >1000-fold molar excess, thus highlighting fundamental differences between these two types of mild membrane-mimetic systems. We rationalise these findings in terms of a new classification of surfactants based on bilayer-to-micelle transfer free energies and discuss practical implications for membrane-protein research. PMID- 26599077 TI - A Novel MVA-Based Multiphasic Vaccine for Prevention or Treatment of Tuberculosis Induces Broad and Multifunctional Cell-Mediated Immunity in Mice and Primates. AB - Bacille Calmette-Guerin (BCG) vaccination of new born babies can protect children against tuberculosis (TB), but fails to protect adults consistently against pulmonary TB underlying the urgent need to develop novel TB vaccines. Majority of first generation TB vaccine candidates have relied on a very limited number of antigens typically belonging to the active phase of infection. We have designed a multi-antigenic and multiphasic vaccine, based on the Modified Vaccinia Ankara virus (MVA). Up to fourteen antigens representative of the three phases of TB infection (active, latent and resuscitation) were inserted into MVA. Using three different strains of mouse (BALB/c, C57BL/6 and C3H/HeN), we show that a single vaccination results in induction of both CD4 and CD8 T cells, displaying capacity to produce multiple cytokines together with cytolytic activity targeting a large array of epitopes. As expected, dominance of responses was linked to the mouse haplotype although for a given haplotype, responses specific of at least one antigen per phase could always be detected. Vaccination of non-human primates with the 14 antigens MVA-TB candidate resulted in broad and potent cellular-based immunogenicity. The remarkable plasticity of MVA opens the road to development of a novel class of highly complex recombinant TB vaccines to be evaluated in both prophylactic and therapeutic settings. PMID- 26599078 TI - Computational Modelling of Metastasis Development in Renal Cell Carcinoma. AB - The biology of the metastatic colonization process remains a poorly understood phenomenon. To improve our knowledge of its dynamics, we conducted a modelling study based on multi-modal data from an orthotopic murine experimental system of metastatic renal cell carcinoma. The standard theory of metastatic colonization usually assumes that secondary tumours, once established at a distant site, grow independently from each other and from the primary tumour. Using a mathematical model that translates this assumption into equations, we challenged this theory against our data that included: 1) dynamics of primary tumour cells in the kidney and metastatic cells in the lungs, retrieved by green fluorescent protein tracking, and 2) magnetic resonance images (MRI) informing on the number and size of macroscopic lesions. Critically, when calibrated on the growth of the primary tumour and total metastatic burden, the predicted theoretical size distributions were not in agreement with the MRI observations. Moreover, tumour expansion only based on proliferation was not able to explain the volume increase of the metastatic lesions. These findings strongly suggested rejection of the standard theory, demonstrating that the time development of the size distribution of metastases could not be explained by independent growth of metastatic foci. This led us to investigate the effect of spatial interactions between merging metastatic tumours on the dynamics of the global metastatic burden. We derived a mathematical model of spatial tumour growth, confronted it with experimental data of single metastatic tumour growth, and used it to provide insights on the dynamics of multiple tumours growing in close vicinity. Together, our results have implications for theories of the metastatic process and suggest that global dynamics of metastasis development is dependent on spatial interactions between metastatic lesions. PMID- 26599079 TI - Surgery for complete (full-thickness) rectal prolapse in adults. AB - BACKGROUND: Complete (full-thickness) rectal prolapse is a lifestyle-altering disability that commonly affects older people. The range of surgical methods available to correct the underlying pelvic floor defects in full-thickness rectal prolapse reflects the lack of consensus regarding the best operation. OBJECTIVES: To assess the effects of different surgical repairs for complete (full-thickness) rectal prolapse. SEARCH METHODS: We searched the Cochrane Incontinence Group Specialised Register up to 3 February 2015; it contains trials from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE in process, ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) as well as trials identified through handsearches of journals and conference proceedings. We also searched EMBASE and EMBASE Classic (1947 to February 2015) and PubMed (January 1950 to December 2014), and we specifically handsearched theBritish Journal of Surgery (January 1995 to June 2014), Diseases of the Colon and Rectum (January 1995 to June 2014) and Colorectal Diseases (January 2000 to June 2014), as well as the proceedings of the Association of Coloproctology meetings (January 2000 to December 2014). Finally, we handsearched reference lists of all relevant articles to identify additional trials. SELECTION CRITERIA: All randomised controlled trials (RCTs) of surgery for managing full-thickness rectal prolapse in adults. DATA COLLECTION AND ANALYSIS: Two reviewers independently selected studies from the literature searches, assessed the methodological quality of eligible trials and extracted data. The four primary outcome measures were the number of patients with recurrent rectal prolapse, number of patients with residual mucosal prolapse, number of patients with faecal incontinence and number of patients with constipation. MAIN RESULTS: We included 15 RCTs involving 1007 participants in this third review update. One trial compared abdominal with perineal approaches to surgery, three trials compared fixation methods, three trials looked at the effects of lateral ligament division, one trial compared techniques of rectosigmoidectomy, two trials compared laparoscopic with open surgery, and two trials compared resection with no resection rectopexy. One new trial compared rectopexy versus rectal mobilisation only (no rectopexy), performed with either open or laparoscopic surgery. One new trial compared different techniques used in perineal surgery, and another included three comparisons: abdominal versus perineal surgery, resection versus no resection rectopexy in abdominal surgery and different techniques used in perineal surgery.The heterogeneity of the trial objectives, interventions and outcomes made analysis difficult. Many review objectives were covered by only one or two studies with small numbers of participants. Given these caveats, there is insufficient data to say which of the abdominal and perineal approaches are most effective. There were no detectable differences between the methods used for fixation during rectopexy. Division, rather than preservation, of the lateral ligaments was associated with less recurrent prolapse but more postoperative constipation. Laparoscopic rectopexy was associated with fewer postoperative complications and shorter hospital stay than open rectopexy. Bowel resection during rectopexy was associated with lower rates of constipation. Recurrence of full-thickness prolapse was greater for mobilisation of the rectum only compared with rectopexy. There were no differences in quality of life for patients who underwent the different kinds of prolapse surgery. AUTHORS' CONCLUSIONS: The lack of high quality evidence on different techniques, together with the small sample size of included trials and their methodological weaknesses, severely limit the usefulness of this review for guiding practice. It is impossible to identify or refute clinically important differences between the alternative surgical operations. Longer follow-up with current studies and larger rigorous trials are needed to improve the evidence base and to define the optimum surgical treatment for full-thickness rectal prolapse. PMID- 26599080 TI - The Impact of PNPLA3 rs738409 SNP on Liver Fibrosis Progression, Portal Hypertension and Hepatic Steatosis in HIV/HCV Coinfection. AB - BACKGROUND: Faster fibrosis progression and hepatic steatosis are hallmarks of HIV/HCV coinfection. A single nucleotide polymorphism (SNP) of the PNPLA3-gene is associated with development of non-alcoholic steatohepatitis and a worse outcome in alcoholic liver disease. However, the role of PNPLA3 rs738409 SNP on liver fibrosis and steatosis, portal hypertension, and virological response in HIV/HCV coinfection remains unclear. METHODS: In this cross-sectional study PNPLA3 (rs738409) and IL28B (rs12979860) SNPs were determined in 177 HIV/HCV coinfected patients. Liver fibrosis and steatosis-staged by liver biopsy and transient elastography using the Controlled Attenuation Parameter (CAP)-and portal hypertension (hepatic venous pressure gradient, HVPG) were compared across PNPLA3 genotypes. RESULTS: 75 (42.4%) patients tested positive for a PNPLA3 minor/major risk allele (G/C:66; G/G:9) showed comparable fibrosis stages (median F2 vs. F2; p = 0.292) and similar amounts of hepatic steatosis (CAP: 203.5 +/- 41.9 vs. 215.5 +/- 59.7 dB/m; p = 0.563) as compared to patients without a PNPLA3 risk allele. Advanced liver fibrosis was neither associated with PNPLA3 (p = 0.253) nor IL28B-genotype (p = 0.628), but with HCV-GT3 (p = 0.003), higher BMI (p = 0.008) and higher age (p = 0.007). Fibrosis progression rate (0.27 +/- 0.41 vs. 0.20 +/- 0.26 units/year; p = 0.984) and HVPG (3.9 +/- 2.6 vs. 4.4 +/- 3.0 mmHg; p = 0.472) were similar in patients with and without PNPLA3 risk alleles. SVR rates to PEGIFN/RBV therapy were similar across PNPLA3 genotypes. CONCLUSIONS: The presence of a PNPLA3 risk allele had no independent impact on liver disease or virological response rates to PEGIFN/RBV therapy in our cohort of HIV/HCV coinfected patients. PMID- 26599081 TI - General N-and O-Linked Glycosylation of Lipoproteins in Mycoplasmas and Role of Exogenous Oligosaccharide. AB - The lack of a cell wall, flagella, fimbria, and other extracellular appendages and the possession of only a single membrane render the mycoplasmas structurally simplistic and ideal model organisms for the study of glycoconjugates. Most species have genomes of about 800 kb and code for few proteins predicted to have a role in glycobiology. The murine pathogens Mycoplasma arthritidis and Mycoplasma pulmonis have only a single gene annotated as coding for a glycosyltransferase but synthesize glycolipid, polysaccharide and glycoproteins. Previously, it was shown that M. arthritidis glycosylated surface lipoproteins through O-linkage. In the current study, O-linked glycoproteins were similarly found in M. pulmonis and both species of mycoplasma were found to also possess N linked glycans at residues of asparagine and glutamine. Protein glycosylation occurred at numerous sites on surface-exposed lipoproteins with no apparent amino acid sequence specificity. The lipoproteins of Mycoplasma pneumoniae also are glycosylated. Glycosylation was dependent on the glycosidic linkages from host oligosaccharides. As far as we are aware, N-linked glycoproteins have not been previously described in Gram-positive bacteria, the organisms to which the mycoplasmas are phylogenetically related. The findings indicate that the mycoplasma cell surface is heavily glycosylated with implications for the modulation of mycoplasma-host interactions. PMID- 26599082 TI - TRIM59 Promotes the Proliferation and Migration of Non-Small Cell Lung Cancer Cells by Upregulating Cell Cycle Related Proteins. AB - TRIM protein family is an evolutionarily conserved gene family implicated in a number of critical processes including inflammation, immunity, antiviral and cancer. In an effort to profile the expression patterns of TRIM superfamily in several non-small cell lung cancer (NSCLC) cell lines, we found that the expression of 10 TRIM genes including TRIM3, TRIM7, TRIM14, TRIM16, TRIM21, TRIM22, TRIM29, TRIM59, TRIM66 and TRIM70 was significantly upregulated in NSCLC cell lines compared with the normal human bronchial epithelial (HBE) cell line, whereas the expression of 7 other TRIM genes including TRIM4, TRIM9, TRIM36, TRIM46, TRIM54, TRIM67 and TRIM76 was significantly down-regulated in NSCLC cell lines compared with that in HBE cells. As TRIM59 has been reported to act as a proto-oncogene that affects both Ras and RB signal pathways in prostate cancer models, we here focused on the role of TRIM59 in the regulation of NSCLC cell proliferation and migration. We reported that TRIM59 protein was significantly increased in various NSCLC cell lines. SiRNA-induced knocking down of TRIM59 significantly inhibited the proliferation and migration of NSCLC cell lines by arresting cell cycle in G2 phase. Moreover, TRIM59 knocking down affected the expression of a number of cell cycle proteins including CDC25C and CDK1. Finally, we knocked down TRIM59 and found that p53 protein expression levels did not upregulate, so we proposed that TRIM59 may promote NSCLC cell growth through other pathways but not the p53 signaling pathway. PMID- 26599084 TI - Double-Layer Magnetic Nanoparticle-Embedded Silica Particles for Efficient Bio Separation. AB - Superparamagnetic Fe3O4 nanoparticles (NPs) based nanomaterials have been exploited in various biotechnology fields including biomolecule separation. However, slow accumulation of Fe3O4 NPs by magnets may limit broad applications of Fe3O4 NP-based nanomaterials. In this study, we report fabrication of Fe3O4 NPs double-layered silica nanoparticles (DL MNPs) with a silica core and highly packed Fe3O4 NPs layers. The DL MNPs had a superparamagnetic property and efficient accumulation kinetics under an external magnetic field. Moreover, the magnetic field-exposed DL MNPs show quantitative accumulation, whereas Fe3O4 NPs single-layered silica nanoparticles (SL MNPs) and silica-coated Fe3O4 NPs produced a saturated plateau under full recovery of the NPs. DL MNPs are promising nanomaterials with great potential to separate and analyze biomolecules. PMID- 26599083 TI - Prevalence and Correlates of Client-Perpetrated Violence against Female Sex Workers in 13 Mexican Cities. AB - BACKGROUND: Globally, client-perpetrated violence against female sex workers (FSWs) has been associated with multiple health-related harms, including high risk sexual behavior and increased exposure to HIV/STIs. This study examined correlates of client-perpetrated sexual, physical, and economic violence (e.g., robbery) against FSWs in 13 cities throughout Mexico. METHODS: FSWs (N = 1,089) who were enrolled in a brief, evidence-based, sexual risk reduction intervention for FSWs (Mujer Segura) were interviewed about their work context, including experiences of violence perpetrated by clients, sexual risk and substance use practices, financial need, and social supports. Three broad categories of factors (sociodemographic, work context, behavioral and social characteristics of FSWs) were examined as correlates of sexual, physical, and economic violence. RESULTS: The prevalence of different types of client-perpetrated violence against FSWs in the past 6 months was: sexual (11.7%), physical (11.8%), economic (16.9%), and any violence (22.6%). Greater financial need, self-identification as a street worker, and lower perceived emotional support were independently associated with all three types of violence. Alcohol use before or during sex with clients in the past month was associated with physical and sexual violence. Using drugs before or during sex with clients, injection drug use in the past month, and population size of city were associated with sexual violence only, and FSWs' alcohol use score (AUDIT-C) was associated with economic violence only. CONCLUSIONS: Correlates of client-perpetrated violence encompassed sociodemographic, work context, and behavioral and social factors, suggesting that approaches to violence prevention for FSWs must be multi-dimensional. Prevention could involve teaching FSWs strategies for risk avoidance in the workplace (e.g., avoiding use of alcohol with clients), enhancement of FSWs' community-based supports, development of interventions that deliver an anti-violence curriculum to clients, and programs to address FSWs' financial need by increasing their economic opportunities outside of the sex trade. PMID- 26599085 TI - Effects of low level laser therapy on inflammatory and angiogenic gene expression during the process of bone healing: A microarray analysis. AB - The process of bone healing as well as the expression of inflammatory and angiogenic genes after low level laser therapy (LLLT) were investigated in an experimental model of bone defects. Sixty Wistar rats were distributed into control group and laser group (830nm, 30mW, 2,8J, 94seg). Histopathological analysis showed that LLLT was able to modulate the inflammatory process in the area of the bone defect and also to produce an earlier deposition of granulation tissue and newly formed bone tissue. Microarray analysis demonstrated that LLLT produced an up-regulation of the genes related to the inflammatory process (MMD, PTGIR, PTGS2, Ptger2, IL1, 1IL6, IL8, IL18) and the angiogenic genes (FGF14, FGF2, ANGPT2, ANGPT4 and PDGFD) at 36h and 3days, followed by the decrease of the gene expression on day 7. Immunohistochemical analysis revealed that the subjects that were treated presented a higher expression of COX-2 at 36h after surgery and an increased VEGF expression on days 3 and 7 after surgery. Our findings indicate that LLLT was efficient on accelerating the development of newly formed bone probably by modulating the inflammatory and angiogenic gene expression as well as COX2 and VEGF immunoexpression during the initial phase of bone healing. PMID- 26599086 TI - A Risk Assessment of the Jaffe vs Enzymatic Method for Creatinine Measurement in an Outpatient Population. AB - BACKGROUND: The Jaffe and enzymatic methods are the two most common methods for measuring serum creatinine. The Jaffe method is less expensive than the enzymatic method but is also more susceptible to interferences. Interferences can lead to misdiagnosis but interferences may vary by patient population. The overall risk associated with the Jaffe method depends on the probability of misclassification and the consequences of misclassification. This study assessed the risk associated with the Jaffe method in an outpatient population. We analyzed the discordance rate in the estimated glomerular filtration rate based on serum creatinine measurements obtained by the Jaffe and enzymatic method. METHODS: Method comparison and risk analysis. Five hundred twenty-nine eGFRs obtained by the Jaffe and enzymatic method were compared at four clinical decision limits. We determined the probability of discordance and the consequence of misclassification at each decision limit to evaluate the overall risk. RESULTS: We obtained 529 paired observations. Of these, 29 (5.5%) were discordant with respect to one of the decision limits (i.e. 15, 30, 45 or 60 ml/min/1.73m2). The magnitude of the differences (Jaffe result minus enzymatic result) were significant relative to analytical variation in 21 of the 29 (72%) of the discordant results. The magnitude of the differences were not significant relative to biological variation. The risk associated with misclassification was greatest at the 60 ml/min/1.73m2 decision limit because the probability of misclassification and the potential for adverse outcomes were greatest at that decision limit. CONCLUSION: The Jaffe method is subject to bias due to interfering substances (loss of analytical specificity). The risk of misclassification is greatest at the 60 ml/min/1.73m2 decision limit; however, the risk of misclassification due to bias is much less than the risk of misclassification due to biological variation. The Jaffe method may pose low risk in selected populations if eGFR results near the 60 ml/min/1.73m2 decision limit are interpreted with caution. PMID- 26599088 TI - Evaluation of Salmonella Gallinarum ghost formulated with MontanideTM ISA 70 VG adjuvant as a vaccine against fowl typhoid. AB - Escherichia coli heat-labile enterotoxin B subunit (LTB) protein is a potent adjuvant. Salmonella Gallinarum ghosts carrying LTB (S. Gallinarum-LTB ghosts) were genetically constructed using a plasmid, pJHL187-LTB, designed for the co expression of the LTB and E lysis proteins. This study evaluates the immunopotentiating effects of MontanideTM ISA 70 VG on S. Gallinarum-LTB ghost vaccination against fowl typhoid. Five-week-old layer chickens were injected intramuscularly with sterile PBS (non-immunised control, Group A), S. Gallinarum LTB ghost (Group B) or S. Gallinarum-LTB ghost emulsified with MontanideTM ISA 70 VG adjuvant (Group C). Chickens from both Groups B and C showed significant induction of antigen-specific systemic IgG response compared to controls; in addition, Group C showed enhanced induction of systemic IgG response compared to Group B. We observed significant induction of antigen-specific lymphocyte proliferative response and increased mRNA levels of Th1 cytokines (IFN-gamma and IL2) in both Groups B and C. Furthermore, in the challenge experiment with a virulent strain of S. Gallinarum, Group C showed higher survival rates compared with other groups. These results indicate that vaccination with the S. Gallinarum LTB ghost in combination with MontanideTM ISA 70 VG may enhance the protective immunity against fowl typhoid. PMID- 26599087 TI - Antimicrobial Activity of a Novel Vascular Access Film Dressing Containing Chlorhexidine Gluconate. AB - BACKGROUND: Covering insertion sites with chlorhexidine impregnated dressings has been proven to be clinically effective in reducing catheter related blood stream infections (CR-BSI). Two chlorhexidine gluconate (CHG)-impregnated dressings are commercially available, a polyurethane foam disk and a film dressing containing a chlorhexidine gluconate-impregnated gel pad. While both have demonstrated efficacy in clinical settings, the major drawback of high cost and impaired IV insertion site visibility limits their usage. A new, simple film dressing containing CHG within its adhesive layer is now available. The objective of this study was to test the in vitro antimicrobial efficacy of the new dressing in comparison to the CHG-impregnated gel dressing. METHODS: Quantitative aliquots of suspensions (concentration of 1.0x106 to 5.0x106 cfu/sample) of clinically relevant challenge organisms (Staphylococcus species, gram-negative bacilli, Candida albicans) were incubated in contact with the new CHG-containing film dressing, a placebo version of the same (negative control) and the commercially available CHG-impregnated gel dressing (positive control). Serial dilutions of the surviving organisms were quantified using the pour plate after 1, 3, 5, and 7 days of incubation in order to calculate an antimicrobial log10 reduction for each organism/dressing combination at each point in time. RESULTS: The new CHG containing film dressing delivered greater than 5.0 log10 reduction throughout the 7 days on all aerobic gram-negative bacilli and Staphylococcus species tested. As of day 1 the CHG-containing film dressing provided greater than 5.0 log10 reduction on Candida albicans. There were no statistically significant differences in the log10 reduction between the two dressings tested. CONCLUSION: The new CHG-containing film dressing was found to be as effective as the chlorhexidine gluconate-impregnated gel dressing on clinically relevant microbes. PMID- 26599089 TI - Antimicrobial susceptibility of Bordetella Avium and Ornithobacterium Rhinotracheale strains from wild and domesticated birds in Hungary. AB - The antimicrobial susceptibility of 19 Bordetella avium and 36 Ornithobacterium rhinotracheale strains was tested by the Kirby-Bauer disk diffusion method, and the minimal inhibitory concentrations (MIC) of amoxicillin, doxycycline and erythromycin were also determined. Most O. rhinotracheale strains were resistant to nalidixic acid, sulphamethoxazole-trimethoprim and gentamicin, and were susceptible to ampicillin, chloramphenicol, spectinomycin and tilmicosin. All B. avium strains were resistant to ceftiofur and lincomycin and susceptible to doxycycline, gentamicin, polymyxin B, spectinomycin and sulphonamides. The MICs ranged widely for all three antibiotics tested against O. rhinotracheale strains, from 0.12 MUg/ml to 32 MUg/ml for amoxicillin and erythromycin, and from 0.6 MUg/ml to 32 MUg/ml for doxycycline. For B. avium isolates, the MIC values ranged from <= 0.03 MUg/ml to 1 MUg/ml for amoxicillin, from <= 0.03 MUg/ml to 0.12 MUg/ml for doxycycline and from 8 MUg/ml to 16 MUg/ml for erythromycin. These findings support the idea that the use of antibiotics in a region or a farm may affect antimicrobial resistance and underline the need for prudent application of antibiotic therapy based on proper antimicrobial susceptibility testing. PMID- 26599090 TI - Conjugative IncF and IncI1 plasmids with tet(A) and class 1 integron conferring multidrug resistance in F18(+) porcine enterotoxigenic E. coli. AB - Enterotoxigenic E. coli (ETEC) bacteria frequently cause watery diarrhoea in newborn and weaned pigs. Plasmids carrying genes of different enterotoxins and fimbrial adhesins, as well as plasmids conferring antimicrobial resistance are of prime importance in the epidemiology and pathogenesis of ETEC. Recent studies have revealed the significance of the porcine ETEC plasmid pTC, carrying tetracycline resistance gene tet(B) with enterotoxin genes. In contrast, the role of tet(A) plasmids in transferring resistance of porcine ETEC is less understood. The objective of the present study was to provide a comparative analysis of antimicrobial resistance and virulence gene profiles of porcine post-weaning ETEC strains representing pork-producing areas in Central Europe and in the USA, with special attention to plasmids carrying the tet(A) gene. Antimicrobial resistance phenotypes and genotypes of 87 porcine ETEC strains isolated from cases of post weaning diarrhoea in Austria, the Czech Republic, Hungary and the Midwest USA was determined by disk diffusion and by PCR. Central European strains carrying tet(A) or tet(B) were further subjected to molecular characterisation of their tet plasmids. Results indicated that > 90% of the ETEC strains shared a common multidrug resistant (MDR) pattern of sulphamethoxazole (91%), tetracycline (84%) and streptomycin (80%) resistance. Tetracycline resistance was most frequently determined by the tet(B) gene (38%), while tet(A) was identified in 26% of all isolates with wide ranges for both tet gene types between some countries and with class 1 integrons and resistance genes co-transferred by conjugation. The virulence gene profiles included enterotoxin genes (lt, sta and/or stb), as well as adhesin genes (k88/f4, f18). Characterisation of two representative tet(A) plasmids of porcine F18(+) ETEC from Central Europe revealed that the IncF plasmid (pES11732) of the Czech strain (~120 kb) carried tet(A) in association with catA1 for chloramphenicol resistance. The IncI1 plasmid (pES2172) of the Hungarian strain (~138 kb) carried tet(A) gene and a class 1 integron with an unusual variable region of 2,735 bp composed by two gene cassettes: estX-aadA1 encoding for streptothricin-spectinomycin/streptomycin resistance exemplifying simultaneous recruitment, assembly and transfer of multidrug resistance genes by the tet(A) plasmid of porcine ETEC. By this we provide the first description of IncF and IncI1 type plasmids of F18(+) porcine enterotoxigenic E. coli responsible for cotransfer of the tet(A) gene with multidrug resistance. Additionally, the unusual determinant estX, encoding for streptothricin resistance, is first reported here in porcine enterotoxigenic E. coli. PMID- 26599091 TI - Identification of a proposed new serovar of Actinobacillus Pleuropneumoniae: Serovar 16. AB - Five Actinobacillus pleuropneumoniae strains isolated from pathological lesions of porcine pleuropneumonia in Hungary could not be assigned to any of the accepted 15 serovars. Using hyperimmune serum raised against these unty-pable serovar A. pleuropneumoniae strains in rabbits, indirect haemagglutination tests proved that they form a distinct group and there is no cross-reaction between them and the type strains of A. pleuropneumoniae. All five strains harboured the toxin-associated genes for the production (apxIA) and secretion (apxIB) of ApxI, the gene for the expression of ApxII and the largest-size (2800 bp) apxIV gene. The carbon source utilisation pattern and the sequence analysis of the 16S rRNA gene confirmed the species identification of the suggested type strain, A. pleuropneumoniae A-85/14. A new serovar of A. pleuropneumoniae - serovar 16 - is proposed with A. pleuropneumoniae A-85/14 as reference strain. PMID- 26599092 TI - Quality of life and pain in dogs with early-stage mammary tumours. AB - Quality of life (QOL) was evaluated in bitches with mammary tumours (MTs) by applying a scale to assess QOL in dogs with pain secondary to cancer. Two groups were constituted: Group 1 with 80 bitches with MT, oncologically classified as stage I (mean age +/- SD = 9.9 +/- 3.8 years), and Group 2 consisting of 80 healthy bitches without MT (mean age: 7.7 +/- 1.8 years). The results were based on responses from owners using a standardised, internationally accepted pain scale questionnaire. This prospective and descriptive study showed that 63% of the dogs in Group 1 had a change in QOL due to the presence of MT. The risk of QOL impairment was 2.1 times higher in Group 1 animals than in bitches without MT. Mammary tumour increased the presence of pain 8.3 times and defecation difficulties 10 times. It can be concluded that even small MTs can elicit pain in dogs, which interferes with their quality of life. PMID- 26599093 TI - Occurrence of mitral valve insufficiency in clinically healthy Beagle dogs. AB - Chronic degenerative valve disease (CDVD) is the most common cardiac disease in dogs, usually resulting in mitral valve insufficiency (MVI). The goal of this study was to investigate the occurrence of MVI in clinically healthy Beagle populations. A total of 79 adult healthy Beagles (41 females and 38 males; age: 5.6 +/- 2.7 years, range 1.4 to 11.7 years) were examined. The diagnosis of MVI was based on the detection of a systolic murmur heard above the mitral valve, and was confirmed by colour flow Doppler (CFD) echocardiography. Systolic mitral valve murmurs were detected in 20/79 dogs (25.3%), of them 11 males and 9 females with no statistically significant gender difference (P = 0.6059). The strength of the murmur on the semi-quantitative 0/6 scale yielded intensity grade 1/6 in 10 dogs, grade 2/6 in 4 dogs, and grade 3/6 in 6 dogs. Mild to moderate MVI was detected by CFD in all these 20 dogs with systolic murmurs. Of them, 17 dogs had mild and 3 demonstrated moderate MVI, showing 10-30% and 30-50% regurgitant jets compared to the size of the left atrium, respectively. The age of dogs with MVI was 7.1 +/- 2.3 years, which was significantly different from that of dogs without MVI (5.1 +/- 2.7 years, P = 0.0029). No significant differences in body weight (P = 0.1724) were found between dogs with MVI (13.8 +/- 2.8 kg) and those without MVI (12.8 +/- 3.0 kg). Mitral valve disease causing MVI is relatively common in Beagle dogs, just like in other small breed dogs reported in the literature. PMID- 26599094 TI - Parasitic infections of two invasive fish species, the Caucasian dwarf goby and the Amur sleeper, in Hungary. AB - In recent years and decades, two new fish species, the Caucasian dwarf goby (Knipowitschia caucasica) and the Amur sleeper (Perccottus glenii) have become members of the Hungarian fish fauna. In a 14-month study on the parasite fauna of these species, the authors detected 11 parasite species in the Caucasian dwarf goby and 17 species in the Amur sleeper. All parasites found in dwarf goby belong to species commonly occurring also in native Hungarian fishes, but three species (Goussia obstinata, Gyrodactylus perccotti and Nippotaenia mogurndae) collected from the Amur sleeper are introduced species new for the Hungarian fauna. PMID- 26599095 TI - Effects of dibutyryl cyclic adenosine monophosphate and human chorionic gonadotropin on the formation of antral follicle-like structures by bovine cumulus-oocyte complexes. AB - This study evaluated the effect of dibutyryl cyclic adenosine monophos-phate (dbcAMP) and human chorionic gonadotropin (hCG) on the formation of antral follicle-like structures (AFLSs) and on the meiotic status of bovine cumulus- oocyte complexes (COCs) embedded in collagen gel. Supplementation with dbcAMP increased the mean diameter of AFLSs during days 4-8 of culture compared with that of control COCs, irrespective of the concentration of dbcAMP used (0.5-2.0 mM). When the embedded COCs were cultured for 8 days with hCG, the diameters of AFLSs after 4 days of culture tended to be lower in the supplemented COCs than in the control COCs without hCG, irrespective of the concentration used (1-100 IU/mL). Supplementation with 10 IU/mL hCG increased the concentrations of anti Mullerian hormone but not progesterone and oestradiol in the culture medium after 4 days of culture. Almost all oocytes collected from AFLSs had resumed meiosis by the end of culture, irrespective of supplementation of dbcAMP and hCG. These results indicate that although dbcAMP had a positive effect on AFLS formation and development, supplementation with hCG was detrimental. Moreover, hCG supplementation did not influence the luteinisation of granulosa cells in the AFLS for 4 days after the start of culture. PMID- 26599096 TI - Detection and partial genetic characterisation of a novel variant of Avian nephritis virus in Indian poultry flocks showing diverse clinical signs. AB - Avian nephritis virus (ANV) infects poultry flocks worldwide, but no confirmed cases have been reported from India so far. In the current study, disease investigation was carried out in 21 broiler flocks at different parts of India with clinical signs of nephritis, uneven and stunted growth, diarrhoea, reduced body weight, and mortality up to 9.72%. Out of the 21 flocks screened, two were found positive for ANV in RT-PCR assay. BLAST analysis revealed that the ANV of Indian origin was closely related to ANV-1 strains reported from Japan, Hungary and China. However, comparison of a small portion (~12% of nucleotides, i.e. ~60 nts, common site for ANV-1 and ANV-3, position 2200-2260 of ORF 1a gene) of the Indian ANV sequence with ANV-3 sequences revealed 89-93% identities with different ANV-3 isolates. Phylogenetically, ANV-1 forms three clades, and the Indian ANV clustered under clade II. This study confirms the existence of ANV in Indian poultry flocks and is the first report on the molecular detection and genetic characterisation of ANV from India. PMID- 26599097 TI - Random sampling of the Central European bat fauna reveals the existence of numerous hitherto unknown adenoviruses. AB - From over 1250 extant species of the order Chiroptera, 25 and 28 are known to occur in Germany and Hungary, respectively. Close to 350 samples originating from 28 bat species (17 from Germany, 27 from Hungary) were screened for the presence of adenoviruses (AdVs) using a nested PCR that targets the DNA polymerase gene of AdVs. An additional PCR was designed and applied to amplify a fragment from the gene encoding the IVa2 protein of mastadenoviruses. All German samples originated from organs of bats found moribund or dead. The Hungarian samples were excrements collected from colonies of known bat species, throat or rectal swab samples, taken from live individuals that had been captured for faunistic surveys and migration studies, as well as internal organs of dead specimens. Overall, 51 samples (14.73%) were found positive. We detected 28 seemingly novel and six previously described bat AdVs by sequencing the PCR products. The positivity rate was the highest among the guano samples of bat colonies. In phylogeny reconstructions, the AdVs detected in bats clustered roughly, but not perfectly, according to the hosts' families (Vespertilionidae, Rhinolophidae, Hipposideridae, Phyllostomidae and Pteropodidae). In a few cases, identical sequences were derived from animals of closely related species. On the other hand, some bat species proved to harbour more than one type of AdV. The high prevalence of infection and the large number of chiropteran species worldwide make us hypothesise that hundreds of different yet unknown AdV types might circulate in bats. PMID- 26599099 TI - Effect of vitamin D3 on thyroid function and de-iodinase 2 expression in diabetic rats. AB - OBJECTIVE: This study aimed to assess the effect of vitamin D3 administration to diabetic rats on thyroid profile and deiodinase 2 (D2). METHODS: Thirty male Wistar rats were included into three groups; control, streptozotocin-induced diabetic and diabetic supplemented with vitamin D3 groups. Ten weeks later, serum levels of free T4, free T3 and TSH were measured. Tissue homogenates from liver, kidney, muscle, femur bone, heart and brain were obtained and assessed for D2 mRNA. RESULTS: Diabetic rats demonstrated significant increase in free T4 and significant decrease in free T3. These changes were ameliorated by vitamin D3 administration. D2 mRNA was significantly reduced in all tissue homogenates obtained from diabetic rats, while vitamin D3 treatment significantly enhanced D2 in liver and brain homogenates. CONCLUSION: Diabetes mellitus inhibited peripheral conversion of T4 into T3 secondary to reduction in D2 expression. Vitamin D3 greatly corrected the alterations in thyroid profile and D2 expression. PMID- 26599098 TI - Rhinovirus Load Is High despite Preserved Interferon-beta Response in Cystic Fibrosis Bronchial Epithelial Cells. AB - Lung disease in cystic fibrosis (CF) is often exacerbated following acute upper respiratory tract infections caused by the human rhinovirus (HRV). Pathophysiology of these exacerbations is presently unclear and may involve deficient innate antiviral or exaggerated inflammatory responses in CF airway epithelial cells. Furthermore, responses of CF cells to HRV may be adversely affected by pre-exposure to virulence factors of Pseudomonas (P.) aeruginosa, the microorganism that frequently colonizes CF airways. Here we examined production of antiviral cytokine interferon-beta and inflammatory chemokine interleukin-8, expression of the interferon-responsive antiviral gene 2'-5'-oligoadenylate synthetase 1 (OAS1), and intracellular virus RNA load in primary CF (delF508 CFTR) and healthy airway epithelial cells following inoculation with HRV16. Parallel cells were exposed to virulence factors of P. aeruginosa prior to and during HRV16 inoculation. CF cells exhibited production of interferon-beta and interleukin-8, and expression of OAS1 at levels comparable to those in healthy cells, yet significantly higher HRV16 RNA load during early hours post inoculation with HRV16. In line with this, HRV16 RNA load was higher in the CFBE41o- dF cell line overexpessing delF508 CFTR, compared with the isogenic control CFBE41o- WT (wild-type CFTR). Pre-exposure to virulence factors of P. aeruginosa did not affect OAS1 expression or HRV16 RNA load, but potentiated interleukin-8 production. In conclusion, CF cells demonstrate elevated HRV RNA load despite preserved interferon-beta and OAS1 responses. High HRV load in CF airway epithelial cells appears to be due to deficiencies manifesting early during HRV infection, and may not be related to interferon-beta. PMID- 26599100 TI - Lgr5 Methylation in Cancer Stem Cell Differentiation and Prognosis-Prediction in Colorectal Cancer. AB - OBJECTIVE: Leucine-rich-repeat-containing G-protein-coupled receptor 5 (lgr5) is a candidate marker for colorectal cancer stem cells (CSC). In the current study, we investigated the methylation status within thelgr5 promoter and evaluated its relationship with CSC differentiation, prognosis for colorectal cancer, and its clinicopathological features. METHODS: The methylation status within Lgr5 promoter was detected with a methylation-specific PCR in six colorectal cancer cell lines as well as 169 primary colorectal tumor tissues. Differentiation of CSC was examined with immunofluorescence and immunocytochemistry. Down-regulation of lgr5 was achieved with gene-specific siRNA. The associations between lgr5 methylation and the clinicopathological features as well as survival of patients were analyzed with statistical methods. RESULTS: The lgr5 promoter was methylated to different degrees for the six colorectal cell lines examined, with complete methylation observed in HCT116 cells in which the lgr5 expression was partially recovered following DAC treatment. The stem-cell sphere formation from HCT116 cells was accompanied by increasing methylation within the lgr5 promoter and decreasing expression of lgr5. Knocking down lgr5 by siRNA also led to stem-cell spheres formation. Among primary colorectal tumors, 40% (67/169) were positive for lgr5 methylation, while none of the normal colon tissues were positive for lgr5 methylation. Furthermore, lgr5 methylation significantly associated with higher tumor grade, and negative distant metastasis (p < 0.05), as well as better prognosis (p = 0.001) in patients with colorectal cancer. CONCLUSIONS: Our data suggests that lgr5 methylation, through the regulation of lgr5 expression and colorectal CSC differentiation, may constitute a novel prognostic marker for colorectal cancer patients. PMID- 26599101 TI - Cell-Free Expression and In Situ Immobilization of Parasite Proteins from Clonorchis sinensis for Rapid Identification of Antigenic Candidates. AB - Progress towards genetic sequencing of human parasites has provided the groundwork for a post-genomic approach to develop novel antigens for the diagnosis and treatment of parasite infections. To fully utilize the genomic data, however, high-throughput methodologies are required for functional analysis of the proteins encoded in the genomic sequences. In this study, we investigated cell-free expression and in situ immobilization of parasite proteins as a novel platform for the discovery of antigenic proteins. PCR-amplified parasite DNA was immobilized on microbeads that were also functionalized to capture synthesized proteins. When the microbeads were incubated in a reaction mixture for cell-free synthesis, proteins expressed from the microbead-immobilized DNA were instantly immobilized on the same microbeads, providing a physical linkage between the genetic information and encoded proteins. This approach of in situ expression and isolation enables streamlined recovery and analysis of cell-free synthesized proteins and also allows facile identification of the genes coding antigenic proteins through direct PCR of the microbead-bound DNA. PMID- 26599102 TI - Anti- C N1A antibodies in South Australian patients with inclusion body myositis. PMID- 26599103 TI - Three-dimensional ultrastructural analysis of development at the supraspinatus insertion by using focused ion beam/scanning electron microscope tomography in rats. AB - To obtain a successful outcome after rotator cuff repair, the repaired tendon must be biologically anchored to the bone. However, the histological structure at the repaired tendon-bone interface differs from that of the site of normal tendon insertion. Therefore, analyzing postnatal development in detail will contribute to understanding the repaired tendon-bone interface after rotator cuff repair. In this study, we analyzed postnatal development at the tendon-bone insertion in terms of temporal changes in SOX9/SCX expression and three-dimensional (3D) ultrastructure with FIB/SEM tomography, a new scanning electron microscopic method. Sixteen postnatal Sprague-Dawley rats were used for the study. One-, two , three-, and four-week-old rats were sacrificed and both right and left shoulders were removed; eight normal supraspinatus tendon insertions were isolated for each time point. At each time point, four specimens were evaluated with fluorescent immunostaining for SOX9/SCX expression, and the remaining four specimens were evaluated with FIB/SEM tomography. Even in postnatal development, SOX9(+) /SCX(+) expression was observed at the tendon insertion; expression gradually decreased with postnatal development at the normal tendon insertion. In 3D ultrastructure, the morphology of the cells and the number/orientation of the cell processes drastically changed by postnatal week 4. The pattern of SOX9/SCX expression and 3D ultrastructural changes obtained in this study contribute to an understanding of the complicated development of normal tendon-bone insertion. Therefore, this study helps elucidate the pathophysiology of tendon-bone insertion, especially in cases of rotator cuff tear and repair. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:969-976, 2016. PMID- 26599104 TI - Phenotypic and Genotypic Comparison of Epidemic and Non-Epidemic Strains of Pseudomonas aeruginosa from Individuals with Cystic Fibrosis. AB - Epidemic strains of Pseudomonas aeruginosa have been found worldwide among the cystic fibrosis (CF) patient population. Using pulse-field gel electrophoresis, the Prairie Epidemic Strain (PES) has recently been found in one-third of patients attending the Calgary Adult CF Clinic in Canada. Using multi-locus sequence typing, PES isolates from unrelated patients were found to consistently have ST192. Though most patients acquired PES prior to enrolling in the clinic, some patients were observed to experience strain replacement upon transitioning to the clinic whereby local non-epidemic P. aeruginosa isolates were displaced by PES. Here we genotypically and phenotypically compared PES to other P. aeruginosa epidemic strains (OES) found around the world as well as local non-epidemic CF P. aeruginosa isolates in order to characterize PES. Since some epidemic strains are associated with worse clinical outcomes, we assessed the pathogenic potential of PES to determine if these isolates are virulent, shared properties with OES, and if its phenotypic properties may offer a competitive advantage in displacing local non-epidemic isolates during strain replacement. As such, we conducted a comparative analysis using fourteen phenotypic traits, including virulence factor production, biofilm formation, planktonic growth, mucoidy, and antibiotic susceptibility to characterize PES, OES, and local non-epidemic isolates. We observed that PES and OES could be differentiated from local non-epidemic isolates based on biofilm growth with PES isolates being more mucoid. Pairwise comparisons indicated that PES produced significantly higher levels of proteases and formed better biofilms than OES but were more susceptible to antibiotic treatment. Amongst five patients experiencing strain replacement, we found that super-infecting PES produced lower levels of proteases and elastases but were more resistant to antibiotics compared to the displaced non-epidemic isolates. This comparative analysis is the first to be completed on a large scale between groups of epidemic and non-epidemic CF P. aeruginosa isolates. PMID- 26599105 TI - Desmopressin acetate as a haemostatic elevator in individuals with combined deficiency of factors V and VIII: a clinical trial. AB - ESSENTIALS: Combined factor V (FV) and factor VIII (FVIII) deficiency (CF5F8D) is an autosomal recessive coagulation disorder. Desmopressin acetate (DDAVP) was intravenously infused in 20 adult patients with CF5F8D. DDAVP can enhance FVIII levels but has no effect on FV levels in patients with CF5F8D. DDAVP can be substituted for FVIII concentrates in patients with CF5F8D. OBJECTIVES: Combined factor V (FV) and FVIII deficiency (CF5F8D) is a rare inherited autosomal recessive double-gene disorder most frequently seen in the Middle East. Although affected individuals have deficiency of two coagulation factors (range 5-30%), their bleeding tendencies are similar to patients who have deficiency of a single coagulation factor at the same level. The mainstay of their treatment is infusion of FVIII concentrate and fresh frozen plasma. Here, the effect of intravenous infusion of desmopressin acetate (DDAVP) on elevation of coagulation FV and FVIII was investigated through a clinical trial in May 2015. PATIENTS AND METHODS: In a registered controlled trial, DDAVP (dosage 0.3 MUg kg(-1) ) was intravenously infused into 20 adult patients with CF5F8D over 20 min. After an hour, blood samples were collected and plasma levels of FV and FVIII were measured. RESULTS AND CONCLUSION: This study revealed that DDAVP can enhance FVIII levels but has no effect on FV plasma concentration in patients with CF5F8D. Based on these findings, FVIII concentrates may be substituted for DDAVP in patients with CF5F8D. PMID- 26599106 TI - Multi-Parametric MRI and Texture Analysis to Visualize Spatial Histologic Heterogeneity and Tumor Extent in Glioblastoma. AB - BACKGROUND: Genetic profiling represents the future of neuro-oncology but suffers from inadequate biopsies in heterogeneous tumors like Glioblastoma (GBM). Contrast-enhanced MRI (CE-MRI) targets enhancing core (ENH) but yields adequate tumor in only ~60% of cases. Further, CE-MRI poorly localizes infiltrative tumor within surrounding non-enhancing parenchyma, or brain-around-tumor (BAT), despite the importance of characterizing this tumor segment, which universally recurs. In this study, we use multiple texture analysis and machine learning (ML) algorithms to analyze multi-parametric MRI, and produce new images indicating tumor-rich targets in GBM. METHODS: We recruited primary GBM patients undergoing image guided biopsies and acquired pre-operative MRI: CE-MRI, Dynamic-Susceptibility weighted-Contrast-enhanced-MRI, and Diffusion Tensor Imaging. Following image coregistration and region of interest placement at biopsy locations, we compared MRI metrics and regional texture with histologic diagnoses of high- vs low-tumor content (>=80% vs <80% tumor nuclei) for corresponding samples. In a training set, we used three texture analysis algorithms and three ML methods to identify MRI-texture features that optimized model accuracy to distinguish tumor content. We confirmed model accuracy in a separate validation set. RESULTS: We collected 82 biopsies from 18 GBMs throughout ENH and BAT. The MRI-based model achieved 85% cross-validated accuracy to diagnose high- vs low-tumor in the training set (60 biopsies, 11 patients). The model achieved 81.8% accuracy in the validation set (22 biopsies, 7 patients). CONCLUSION: Multi-parametric MRI and texture analysis can help characterize and visualize GBM's spatial histologic heterogeneity to identify regional tumor-rich biopsy targets. PMID- 26599108 TI - Correction: Family-Based Cluster Randomized Controlled Trial Enhancing Physical Activity and Motor Competence in 4-7-Year-Old Children. PMID- 26599107 TI - Study of the Differential Activity of Thrombin Inhibitors Using Docking, QSAR, Molecular Dynamics, and MM-GBSA. AB - Non-peptidic thrombin inhibitors (TIs; 177 compounds) with diverse groups at motifs P1 (such as oxyguanidine, amidinohydrazone, amidine, amidinopiperidine), P2 (such as cyanofluorophenylacetamide, 2-(2-chloro-6-fluorophenyl)acetamide), and P3 (such as phenylethyl, arylsulfonate groups) were studied using molecular modeling to analyze their interactions with S1, S2, and S3 subsites of the thrombin binding site. Firstly, a protocol combining docking and three dimensional quantitative structure-activity relationship was performed. We described the orientations and preferred active conformations of the studied inhibitors, and derived a predictive CoMSIA model including steric, donor hydrogen bond, and acceptor hydrogen bond fields. Secondly, the dynamic behaviors of some selected TIs (compounds 26, 133, 147, 149, 162, and 177 in this manuscript) that contain different molecular features and different activities were analyzed by creating the solvated models and using molecular dynamics (MD) simulations. We used the conformational structures derived from MD to accomplish binding free energetic calculations using MM-GBSA. With this analysis, we theorized about the effect of van der Waals contacts, electrostatic interactions and solvation in the potency of TIs. In general, the contents reported in this article help to understand the physical and chemical characteristics of thrombin inhibitor complexes. PMID- 26599109 TI - Factors Associated with Postpartum Maternal Functioning in Women with Positive Screens for Depression. AB - BACKGROUND: Functional assessment may represent a valuable addition to postpartum depression screening, providing a more thorough characterization of the mother's health and quality of life. To the authors' knowledge, this analysis represents the first examination of postpartum maternal functioning, as measured by a patient-centered validated tool aimed at ascertainment of functional status explicitly, and its clinical and sociodemographic correlates. MATERIALS AND METHODS: A total of 189 women recruited from a large, urban women's hospital in the northeastern United States who both (1) screened positive for depression between 4 and 6 weeks postpartum and (2) completed a subsequent home (baseline) visit between October 1, 2008, and September 4, 2009, were included in this analysis. Multiple linear regression was conducted to ascertain which clinical and sociodemographic variables were independently associated with maternal functioning. RESULTS: The multivariate analysis revealed independent associations between bipolar status, atypical depression, depression score (17-item Hamilton Rating Scale for Depression), and insurance type with postpartum maternal functioning. The beta coefficient for bipolar status indicates that on average we would expect those with bipolar disorder to have maternal functioning scores that are 5.6 points less than those without bipolar disorder. CONCLUSIONS: Healthcare providers treating postpartum women with complicating mental health conditions should be cognizant of the potential ramifications on maternal functioning. Impaired functioning in the maternal role is likely to impact child development, although the precise nature of this relationship is yet to be elucidated. PMID- 26599110 TI - Identification of 14-3-3 Family in Common Bean and Their Response to Abiotic Stress. AB - 14-3-3s are a class of conserved regulatory proteins ubiquitously found in eukaryotes, which play important roles in a variety of cellular processes including response to diverse stresses. Although much has been learned about 14-3 3s in several plant species, it remains unknown in common bean. In this study, 9 common bean 14-3-3s (PvGF14s) were identified by exhaustive data mining against the publicly available common bean genomic database. A phylogenetic analysis revealed that each predicted PvGF14 was clustered with two GmSGF14 paralogs from soybean. Both epsilon-like and non-epsilon classes of PvGF14s were found in common bean, and the PvGF14s belonging to each class exhibited similar gene structure. Among 9 PvGF14s, only 8 are transcribed in common bean. Expression patterns of PvGF14s varied depending on tissue type, developmental stage and exposure of plants to stress. A protein-protein interaction study revealed that PvGF14a forms dimer with itself and with other PvGF14 isoforms. This study provides a first comprehensive look at common bean 14-3-3 proteins, a family of proteins with diverse functions in many cellular processes, especially in response to stresses. PMID- 26599111 TI - Image Quality and Radiation Dose of CT Coronary Angiography with Automatic Tube Current Modulation and Strong Adaptive Iterative Dose Reduction Three-Dimensional (AIDR3D). AB - PURPOSE: To investigate image quality and radiation dose of CT coronary angiography (CTCA) scanned using automatic tube current modulation (ATCM) and reconstructed by strong adaptive iterative dose reduction three-dimensional (AIDR3D). METHODS: Eighty-four consecutive CTCA patients were collected for the study. All patients were scanned using ATCM and reconstructed with strong AIDR3D, standard AIDR3D and filtered back-projection (FBP) respectively. Two radiologists who were blinded to the patients' clinical data and reconstruction methods evaluated image quality. Quantitative image quality evaluation included image noise, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR). To evaluate image quality qualitatively, coronary artery is classified into 15 segments based on the modified guidelines of the American Heart Association. Qualitative image quality was evaluated using a 4-point scale. Radiation dose was calculated based on dose-length product. RESULTS: Compared with standard AIDR3D, strong AIDR3D had lower image noise, higher SNR and CNR, their differences were all statistically significant (P<0.05); compared with FBP, strong AIDR3D decreased image noise by 46.1%, increased SNR by 84.7%, and improved CNR by 82.2%, their differences were all statistically significant (P<0.05 or 0.001). Segments with diagnostic image quality for strong AIDR3D were 336 (100.0%), 486 (96.4%), and 394 (93.8%) in proximal, middle, and distal part respectively; whereas those for standard AIDR3D were 332 (98.8%), 472 (93.7%), 378 (90.0%), respectively; those for FBP were 217 (64.6%), 173 (34.3%), 114 (27.1%), respectively; total segments with diagnostic image quality in strong AIDR3D (1216, 96.5%) were higher than those of standard AIDR3D (1182, 93.8%) and FBP (504, 40.0%); the differences between strong AIDR3D and standard AIDR3D, strong AIDR3D and FBP were all statistically significant (P<0.05 or 0.001). The mean effective radiation dose was (2.55+/-1.21) mSv. CONCLUSION: Compared with standard AIDR3D and FBP, CTCA with ATCM and strong AIDR3D could significantly improve both quantitative and qualitative image quality. PMID- 26599113 TI - Cellular and Molecular Aspects of Bone Remodeling. AB - Bone remodeling is a highly coordinated process responsible for bone resorption and formation. It is initiated and modulated by a number of factors including inflammation, changes in hormonal levels and lack of mechanical stimulation. Bone remodeling involves the removal of mineralized bone by osteoclasts followed by the formation of bone matrix through osteoblasts that subsequently becomes mineralized. In addition to the traditional bone cells (osteoclasts, osteoblasts and osteocytes) that are necessary for bone remodeling, several immune cells such as polymorphonuclear neutrophils, B cells and T cells have also been implicated in bone remodelling. Through the receptor activator of nuclear factor x03BA;B/receptor activator of the NF-x03BA;B ligand/osteoprotegerin system the process of bone resorption is initiated and subsequent formation is tightly coupled. Mediators such as prostaglandins, interleukins, chemokines, leukotrienes, growth factors, wnt signalling and bone morphogenetic proteins are involved in the regulation of bone remodeling. We discuss here cells and mediators involved in the cellular and molecular machanisms of bone resorption and bone formation. PMID- 26599112 TI - Periodontal Ligament and Alveolar Bone in Health and Adaptation: Tooth Movement. AB - The periodontal ligament (PDL) and alveolar bone are two critical tissues for understanding orthodontic tooth movement. The current literature is replete with descriptive studies of multiple cell types and their matrices in the PDL and alveolar bone, but is deficient with how stem/progenitor cells differentiate into PDL and alveolar bone cells. Can one type of orthodontic force with a specific magnitude and frequency activate osteoblasts, whereas another force type activates osteoclasts? This chapter will discuss the biology of not only mature cells and their matrices in the periodontal ligament and alveolar bone, but also stem/progenitor cells that differentiate into fibroblasts, osteoblasts and osteoclasts. Key advances in tooth movement rely on further understanding of osteoblast and fibroblast differentiation from mesenchymal stem/progenitor cells, and osteoclastogenesis from the hematopoietic/monocyte lineage. PMID- 26599114 TI - Bone Remodeling Under Pathological Conditions. AB - Bone is masterfully programmed to repair itself through the coupling of bone formation following bone resorption, a process referred to as coupling. In inflammatory or other conditions, the balance between bone resorption and bone formation shifts so that a net bone loss results. This review focuses on four pathologic conditions in which remodeling leads to net loss of bone, postmenopausal osteoporosis, arthritis, periodontal disease, and disuse bone loss, which is similar to bone loss associated with microgravity. In most of these there is an acceleration of the resorptive process due to increased formation of bone metabolic units. This initially leads to a net bone loss since the time period of resorption is much faster than the time needed for bone formation that follows. In addition, each of these processes is characterized by an uncoupling that leads to net bone loss. Mechanisms responsible for increased rates of bone resorption, i.e. the formation of more bone metabolic units, involve enhanced expression of inflammatory cytokines and increased expression of RANKL. Moreover, the reasons for uncoupling are discussed which range from a decrease in expression of growth factors and bone morphogenetic proteins to increased expression of factors that inhibit Wnt signaling. PMID- 26599115 TI - Regional Acceleratory Phenomenon. AB - The regional acceleratory phenomenon (RAP) is a tissue reaction to a noxious stimulus that increases the healing capacities of the affected tissues. It is typical not only of hard tissues such as bone and cartilage, but also of soft tissues. The RAP is characterized by acceleration of the normal cellular activities, as an 'SOS' phenomenon of the body that has to respond to the new perturbation. In the alveolar bone, the RAP is characterized, at a cellular level, by increased activation of the basic multicellular units (BMUs), thereby increasing the remodeling space. At the tissue level, the RAP is characterized by the production of woven bone, with the typical unorganized pattern, that will be reorganized into lamellar bone at a later stage. In the alveolar bone, the RAP occurs typically in the healing process of the alveolar sockets after tooth extraction, in periodontal disease, after surgery and trauma and during orthodontic tooth movement. In relation to orthodontic tooth movement, the RAP can be seen as a tissue response to the mechanical cyclical perturbation that induces the formation of microdamage that has to be removed to avoid their accumulation and the following bone failure. The adaptation to the new orthodontically induced mechanical environment is ensured by an increased activation of the BMU that returns to normal levels after few months. PMID- 26599116 TI - Tissue Reaction and Biomechanics. AB - Tissue reaction to orthodontic force has been a subject of research with the purpose of providing the orthodontists with information necessary for the application of a force system that can generate a maximum of tooth movement and modeling of the alveolar process with a minimum of damage. Traditionally, the studies of bone biological reactions have been distinguishable from those performed by bone biologists. This has led to a controversy regarding both the terminology and perception of the reaction to mechanical perturbation. The present chapter, with its basis in bone biology, surveys the attempts by orthodontists to optimize the tissue reaction and shorten treatment time. PMID- 26599117 TI - Orthodontic Tooth Movement: A Historic Prospective. AB - The earliest report on orthodontic tooth movement in the English literature was published in 1911. Oppenheim carried out studies on baboons to determine what histologic changes occurred during tooth movement. Reitan and many others carried out research into the nature of tooth movement. The pressure-tension model of tooth movement developed from these studies, whereby the two sides of the tooth responded to forces as if in isolation. A second theory, proposed by Stuteville in 1938, was the hydraulic theory of tooth movement. In this theory, fluid from the vasculature, lymphatic system and intercellular spaces responds to the forces of tooth movement, damping the force and limiting movement. Bien and Baumrind expanded on this theory with their own studies in the 1960s. It is clear that both the pressure-tension and fluid flow concepts have merit, but considerable work needs to be done to ascertain the details so that tooth movement can be managed and controlled. PMID- 26599118 TI - Stability and Retention. AB - Stability of tooth position in the broader sense considers all the forces that may act on the tooth. Reitan reported that significant forces remained in the periodontium after tooth movement, and he carried out research that demonstrated residual stretching of the crestal periodontal fibers more than 7 months after tooth movement. Brain demonstrated that severing the fibers reduced the relapse in tooth position in dogs. Edwards published a series of papers exploring the effects of surgical transection of the gingival fibers on tooth stability, recommending that circumferential fiberotomy be performed in order to increase posttreatment tooth stability. Other researchers have suggested ways to increase the stability of the incisors, which are typically most prone to relapse. Peck and Peck recommended that interproximal reduction be done to broaden the contact point. Boese also recommended interproximal reduction as part of a four-pronged approach to retention. PMID- 26599119 TI - Neurologic Regulation and Orthodontic Tooth Movement. AB - Pain and discomfort are prevalent symptoms among the vast majority of patients with fixed orthodontic appliances and is the most disliked aspect of treatment. The periodontium is a highly innervated structure that also provides the necessary trophic factors, such as nerve growth factor, which promote neuronal survival, maintenance and axonal growth, via interaction with specific nerve surface receptors, such as TrkA. Various types of nerves are found in the periodontium, including thinly myelinated and unmyelinated sensory fibers that express the neuropeptides substance P and calcitonin gene-related peptide among others. Tooth movement activates peripheral sensory nerve endings, which transmit painful signals to the brain after being processed at the trigeminal spinal nucleus, resulting in local expression of pain related genes, such as c-Fos. Concurrently, an attendant inflammatory process is detected in the trigeminal spinal nucleus, including activation of astrocytes, microglia and neurons. This complex neurologic reaction to tooth movement mediates orthodontic pain and also serves a source of neurogenic inflammation exhibited in the trigeminal spinal nucleus and the periodontium. Activated periodontal sensory fibers release neuropeptides in the periodontal environment, which in turn induce a local inflammatory cascade aiding in alveolar bone turnover and tooth movement per se. Control of pain with nonsteroidal anti-inflammatory drugs and other prescription or over-the-counter pain killers effectively reduce this neurologic reaction and alleviate the attendant pain, but also reduce the neurogenic inflammatory component of orthodontic tooth movement causing a slowdown in bone turnover and consequently delaying orthodontic treatment. PMID- 26599120 TI - Osteoclastogenesis and Osteogenesis during Tooth Movement. AB - It is a well-known concept that bone remodeling occurs during orthodontic tooth movement. The orthodontic literature is vastly full of information about the changes occurring on the periodontal ligament level. However, changes occurring in the alveolar bone are being elucidated. The purpose of this chapter is to present some of the studies describing the bone changes associated with orthodontic tooth movement. Initiation of osteoclastogenesis requires inflammation in the adjacent area. Tissue biomarker RANKL responds to the compressive forces. Conversely, an increase in osteoprotegrin biomarker causes a decrease in RANKL and inhibits tooth movement. Osteocyte activity during tooth movement is not well understood. Emerging studies are showing the effect of osteocytes on orthodontic tooth movement. Nitric oxide (NO), produced by osteocytes, is an important regulator of bone response to loading and has been shown to mediate osteoclast activity. iNOS (which produces NO) has been shown to mediate inflammation-induced bone resorption on the compression side. Several molecules have been linked to osteogenesis in tooth movement: TGF-beta, BSP, BMPs and epidermal growth factor. Osteogenesis on the tension side is not well understood. Studies have shown increase in the expression of Runx2 on the tension side. Additionally, eNOS (produces NO) mediates bone formation on the tension side. The concept of osteoclastogenesis and osteogenesis is being unraveled. PMID- 26599121 TI - Nonsurgical Methods for the Acceleration of the Orthodontic Tooth Movement. AB - While acceleration of the orthodontic tooth movement by surgical techniques has been shown to be effective for decades, noninvasive and nonsurgical methods have always been preferred by both the clinicians and the patients. These techniques have ranged from application of biological molecules to innovative technologies such as resonance vibration, cyclic forces, light electrical currents, magnetic field forces, low-intensity laser irradiation and low-level light therapy. Endogenously produced biologicals have been tested based on their roles in the turnover of alveolar bone in response to orthodontic tooth movement as well as during wound healing. The premise behind this approach is that these exogenously applied compounds will mimic their counterparts produced in vivo. Meanwhile, technologies tested so far target these pathways for the acceleration of the orthodontic tooth movement. All these approaches have shown favorable outcomes with varying success. This chapter presents the current knowledge and a discussion over their limitations with an emphasis on the mechanism of action for each technique. PMID- 26599122 TI - Surgical Methods for the Acceleration of the Orthodontic Tooth Movement. AB - Surgical techniques for the acceleration of the orthodontic tooth movement have been tested for more than 100 years in clinical practice. Since original methods have been extremely invasive and have been associated with increased tooth morbidity and various other gaps, the research in this field has always followed an episodic trend. Modern approaches represent a well-refined strategy where the concept of the bony block has been abandoned and only a cortical plate around the orthodontic tooth movement has been desired. Selective alveolar decortication has been a reproducible gold standard to this end. Its proposed mechanism has been the induction of rapid orthodontic tooth movement through the involvement of the periodontal ligament. More recent techniques included further refinement of this procedure through less invasive techniques such as the use of piezoelectricity and corticision. This chapter focuses on the evolution of the surgical approaches and the mechanistic concepts underlying the biological process during the surgically accelerated orthodontic tooth movement. PMID- 26599123 TI - PiezocisionTM: Accelerating Orthodontic Tooth Movement While Correcting Hard and Soft Tissue Deficiencies. AB - PiezocisionTM-assisted orthodontics is an innovative, minimally invasive surgical procedure designed to help achieve rapid orthodontic tooth movement while correcting/preventing mucogingival defects by adding bone and/or soft tissues. Microsurgical interproximal openings are done in the buccal gingiva to let the piezoelectric knife create the bone injury that will lead to transient demineralization and subsequent accelerated tooth movement. This technique can be used for the whole mouth, the cuts being simultaneously performed at the maxilla and the mandible (generalized Piezocision) or for segments of the dentition (localized Piezocision) to achieve specific localized results (intrusion, extrusion, distalization of teeth, etc.). PMID- 26599124 TI - Corticision: A Flapless Procedure to Accelerate Tooth Movement. AB - Orthodontic tooth movement results from applied forces to the teeth evoking cellular responses in the teeth and their surrounding tissues, including the periodontal ligament, alveolar bone and gingiva. It is advantageous for the orthodontist to be well informed of the detailed process of the biological events that unfold during tooth movement, since some of these details may differ from one person to another due to biological differences such as periodontal metabolism or alveolar bone density. This led us to emphasize that orthodontics is a field of endeavor where the integration of mechanics and biology is materialized, and to affirm the fact that tooth movement is conducted in individual human beings, each composed of a unique and intricate physiological system. Biological variations may be the foundation of the differences that are frequently observed in the outcomes of orthodontic treatment in particular with reference to treatment duration between patients with similar malocclusions and who were treated identically. A wide diversity of clinical trials has been carried out to control the tissue resistance to facilitate orthodontic tooth movement, which involves biomechanical, pharmaceutical, surgical, electrical regimens or tissue engineering technology. The term 'Corticision' is a neologism which indicates 'cortical bone incision'. It is a minimally invasive periodontal procedure without flap elevation, thus accelerating tooth movement with an enhanced turnover rate of the surrounding structures. This chapter introduces the technical procedure, and the biological background of how such a minor surgical procedure can receive the accelerated tooth movement with impunity and thereby shorten the duration of treatment. PMID- 26599125 TI - Photobiomodulation and Lasers. AB - Photobiomodulation is discussed to be a noninvasive method to accelerate orthodontic tooth movement. The stimulatory effect of low-level laser therapy is well known and includes enhancement in tissue growth and tissue regeneration, resolvement of inflammation and pain. In recent research projects, the effect of laser therapy was tested regarding the stimulatory effect on bone remodeling with the potential to influence the tooth movement rate. The results are divers. The effect of laser regarding the reduction of the postadjustment pain could be proved, but not all authors describe the acceleration of tooth movement. Depending on the protocol, low-level laser therapy with low dosage increases the amount of tooth movement while high dosage seems to result in inhibitory effects. In conclusion, future studies are necessary to find the right protocol delivering beneficial results regarding the influence on bone remodeling and tooth movement to implement this therapy in daily orthodontic routine. PMID- 26599126 TI - A Comparison between Osteotomy and Corticotomy-Assisted Tooth Movement. AB - Osteotomies and corticotomies used in combination with orthodontic tooth movement can activate different bone responses that may be exploited to accelerate tooth movement. Segmental osteotomies around dental roots can create a tooth-bearing transport disk that may be distracted and positioned with orthodontic appliances and archwires. In difficult craniofacial repairs, alveolar segments can be guided into position with archwires and orthodontic mechanics. The corticotomy extending into the marrow space can activate bone injury repair mechanisms that accelerate bone turnover as the alveolar bone surrounding the dental roots transitions from a demineralization phase to a fibrous replacement phase and, finally, a mineralization phase. The controlled demineralization and replacement of alveolar bone provides a window of opportunity for roots to move though less dense bone prior to remineralization. Although the corticotomies and osteotomies are minor surgeries compared to orthognathic surgery, the goal of future research is to produce similar bone responses by using smaller surgeries or by eliminating the surgeries altogether. PMID- 26599127 TI - Conclusion and Future Directions. PMID- 26599128 TI - Feasibility and Clinical Outcomes of Peripheral Drug-Coated Balloon in High-Risk Patients with Femoropopliteal Disease. AB - BACKGROUND: Clinical outcomes of the drug-coated balloon (DCB) procedure in high risk patients with femoropopliteal (FP) disease have not been investigated sufficiently. METHODS: This retrospective, single-center study analyzed 87 patients (39% dialysis) and 97 affected legs (64% critical limb ischemia [CLI]) that underwent DCB for symptomatic FP disease from March 2013 to September 2014. Risk stratification was based on FeDCLIP (female, diabetes, dialysis, CLI, lesion length >150 mm and poor runoff) score. The DCB outcomes among the different risk groups were compared and factors predicting restenosis were analyzed during follow-up. RESULTS: Most of study participants (84%) were moderate to high-risk patients. The procedural success rate was 100% and the 30-day major adverse vascular event rate was 2.1%. The mean lesion length was 178 +/- 106 mm and the mean follow-up time was 428 +/- 145 (range 50-782) days. The binary restenosis free and clinically driven target lesion revascularization (CD-TLR)-free rates at 12 months were 77.5% and 84.3%, respectively, for all participants. No significant differences were observed in 1-year binary restenosis and CD-TLR rates in the low-, moderate-, and high-risk groups (60%, 84%, and 73%: p = 0.396; 78%, 89%, and 80%: p = 0.635, respectively). In multivariate analysis, lesion length >150 mm (Hazard ratio [HR]: 8.00, 95% confidence interval (CI) 1.12 to 55.6, p = 0.038) and Rutherford class 6 (HR: 7.09, 95% CI, 1.15 to 43.5, p = 0.034) were identified as independent predictors of binary restenosis. CONCLUSIONS: Despite general comorbidities and advanced limb ischemia, 1-year outcomes of DCB in high-risk patients with FP disease were effective. The DCB procedure holds promise to improve vessel patency; however, lesion length >150 mm and major tissue loss were independent predictors for binary restenosis after the treatment. PMID- 26599129 TI - Exploratory Cohort Study of Associations between Serum C - Reactive Protein and Fatigue after Stroke. AB - BACKGROUND AND AIM: Post-stroke fatigue is a common and distressing problem but little is known about its biological mechanisms. This cohort study was to investigate associations between C-reactive protein (CRP) and fatigue after stroke. METHODS: Patients were assessed at one, six and 12 months after their stroke onset, with the Fatigue Assessment Scale, a case definition of post-stroke fatigue, Hospital Anxiety and Depression Scale, and daily step counts. Blood samples were collected at each assessment and the CRP level was determined by a standard CRP immunoassay. Cross-sectional associations between CRP and fatigue at each time point were determined by Pearson correlation coefficient and independent-samples t-test. Whether CRP levels at one month predict fatigue scores at six and 12 months was explored by multiple linear regression, with anxiety, depression, and daily step counts as covariates. RESULTS: Sixty-five patients (mean age 67 years, 65% men) were included: 61 at one month, 49 at six months, and 41 at 12 months. CRP levels and fatigue scores were not associated at one month (p = 0.88) or 12 months (p = 0.56), but weakly associated at six months (r = 0.27, p = 0.04); however, this association was no longer significant (p = 0.14) after controlling for the effects of covariates. The CRP level was not associated with the fulfilment of case definition of post-stroke fatigue at any time points (all p > 0.05). The CRP level at one month was not a significant predictor for fatigue levels at either six months (p = 0.93) or 12 months (p = 0.78). CONCLUSIONS: There is insufficient evidence for the association between CRP and PSF in stroke patients. Future studies with larger sample sizes and controlling for potential confounders are needed to investigate whether this association exists. PMID- 26599130 TI - Discovery of Black Dye Crystal Structure Polymorphs: Implications for Dye Conformational Variation in Dye-Sensitized Solar Cells. AB - We present the discovery of a new crystal structure polymorph (1) and pseudopolymorph (2) of the Black Dye, one of the world's leading dyes for dye sensitized solar cells, DSSCs (10.4% device performance efficiency). This reveals that Black Dye molecules can adopt multiple low-energy conformers. This is significant since it challenges existing models of the Black Dye...TiO2 adsorption process that renders a DSSC working electrode; these have assumed a single molecular conformation that refers to the previously reported Black Dye crystal structure (3). The marked structural differences observed between 1, 2, and 3 make the need for modeling multiple conformations more acute. Additionally, the ordered form of the Black Dye (1) provides a more appropriate depiction of its anionic structure, especially regarding its anchoring group and NCS bonding descriptions. The tendency toward NCS ligand isomerism, evidenced via the disordered form 2, has consequences for electron injection and electron recombination in Black Dye embedded DSSC devices. Dyes 2 and 3 differ primarily by the absence or presence of a solvent of crystallization, respectively; solvent environment effects on the dye are thereby elucidated. This discovery of multiple Black Dye conformers from diffraction, with atomic-level definition, complements recently reported nanoscopic evidence for multiple dye conformations existing at a dye...TiO2 interface, for a chemically similar DSSC dye; those results emanated from imaging and spectroscopy, but were unresolved at the submolecular level. Taken together, these findings lead to the general notion that multiple dye conformations should be explicitly considered when modeling dye...TiO2 interfaces in DSSCs, at least for ruthenium-based dye complexes. PMID- 26599131 TI - Long-term outcomes after randomization to buprenorphine/naloxone versus methadone in a multi-site trial. AB - AIMS: To compare long-term outcomes among participants randomized to buprenorphine or methadone. DESIGN, SETTING AND PARTICIPANTS: Follow-up was conducted in 2011-14 of 1080 opioid-dependent participants entering seven opioid treatment programs in the United States between 2006 and 2009 and randomized (within each program) to receive open-label buprenorphine/naloxone or methadone for up to 24 weeks; 795 participants completed in-person interviews (~74% follow up interview rate) covering on average 4.5 years. MEASUREMENTS: Outcomes were indicated by mortality and opioid use. Covariates included demographics, site, cocaine use and treatment experiences. FINDINGS: Mortality was not different between the two randomized conditions, with 23 (3.6%) of 630 participants randomized to buprenorphine having died versus 26 (5.8%) of 450 participants randomized to methadone. Opioid use at follow-up was higher among participants randomized to buprenorphine relative to methadone [42.8 versus 31.7% positive opioid urine specimens, P < 0.01, effect size (h) = 0.23 (0.09, 0.38); 5.8 days versus 4.4 days of past 30-day heroin use, P < 0.05, effect size (d) = 0.14 (0.00, 0.28)]. Opioid use during the follow-up period by randomization condition was also significant (F(7,39,600) = 3.16; P < 0.001) due mainly to less treatment participation among participants randomized to buprenorphine than methadone. Less opioid use was associated with both buprenorphine and methadone treatment (relative to no treatment); no difference was found between the two treatments. Individuals who are white or used cocaine at baseline responded better to methadone than to buprenorphine. CONCLUSIONS: There are few differences in long term outcomes between buprenorphine and methadone treatment for opioid dependence, and treatment with each medication is associated with a strong reduction in opioid use. PMID- 26599132 TI - Structural, conformational and thermodynamic aspects of groove-directed intercalation of flavopiridol into DNA. AB - Certain plant-derived alkaloids and flavonoids have shown propitious cytotoxic acitvity against different types of cancer, having deoxyribose nucleic acid (DNA) as their main cellular target. Flavopiridol, a semi-synthetic derivative of rohitukine (a natural compound isolated from Dysoxylum binectariferum plant), has attained much attention owing to its anticancer potential against various haematological malignancies and solid tumours. This work focuses on investigating interaction between flavopiridol and DNA at molecular level in order to decipher its underlying mechanism of action, which is not well understood. To define direct influence of flavopiridol on the structural, conformational and thermodynamic aspects of DNA, various spectroscopic and calorimetric techniques have been used. ATR-FTIR and SERS spectral outcomes indicate a novel insight into groove-directed-intercalation of flavopiridol into DNA via direct binding with nitrogenous bases guanine (C6=O6) and thymine (C2=O2) in DNA groove together with slight external binding to its sugar-phosphate backbone. Circular dichroism spectral analysis of flavopiridol-DNA complexes suggests perturbation in native B conformation of DNA and its transition into C-form, which may be localized up to a few base pairs of DNA. UV-visible spectroscopic results illustrate dual binding mode of flavopiridol when interacts with DNA having association constant, Ka = 1.18 * 10(4) M(-1). This suggests moderate type of interaction between flavopiridol and DNA. Further, UV melting analysis also supports spectroscopic outcomes. Thermodynamically, flavopiridol-DNA complexation is an enthalpy-driven exothermic process. These conclusions drawn from this study could be helpful in unveiling mechanism of cytoxicity induced by flavopiridol that can be further applied in the development of flavonoid-based new chemotherapeutics with more specificity and better efficacy. PMID- 26599133 TI - Sulfated progesterone metabolites in the pathogenesis of intrahepatic cholestasis of pregnancy: Another loop in the ascending spiral of medical knowledge. PMID- 26599134 TI - The hippocampi of children with chromosome 22q11.2 deletion syndrome have localized anterior alterations that predict severity of anxiety. AB - BACKGROUND: Individuals with 22q11.2 deletion syndrome (22q11.2DS) have an elevated risk for schizophrenia, which increases with history of childhood anxiety. Altered hippocampal morphology is a common neuroanatomical feature of 22q11.2DS and idiopathic schizophrenia. Relating hippocampal structure in children with 22q11.2DS to anxiety and impaired cognitive ability could lead to hippocampus-based characterization of psychosis-proneness in this at-risk population. METHODS: We measured hippocampal volume using a semiautomated approach on MRIs collected from typically developing children and children with 22q11.2DS. We then analyzed hippocampal morphology with Localized Components Analysis. We tested the modulating roles of diagnostic group, hippocampal volume, sex and age on local hippocampal shape components. Lastly, volume and shape components were tested as covariates of IQ and anxiety. RESULTS: We included 48 typically developing children and 69 children with 22q11.2DS in our study. Hippocampal volume was reduced bilaterally in children with 22q11.2DS, and these children showed greater variation in the shape of the anterior hippocampus than typically developing children. Children with 22q11.2DS had greater inward deformation of the anterior hippocampus than typically developing children. Greater inward deformation of the anterior hippocampus was associated with greater severity of anxiety, specifically fear of physical injury, within the 22q11.2DS group. LIMITATIONS: Shape alterations are not specific to hippocampal subfields. CONCLUSION: Alterations in the structure of the anterior hippocampus likely affect function and may impact limbic circuitry. We suggest these alterations potentially contribute to anxiety symptoms in individuals with 22q11.2DS through modulatory pathways. Altered hippocampal morphology may be uniquely linked to anxiety risk factors for schizophrenia, which could be a powerful neuroanatomical marker of schizophrenia risk and hence protection. PMID- 26599135 TI - Frontal fasciculi and psychotic symptoms in antipsychotic-naive patients with schizophrenia before and after 6 weeks of selective dopamine D2/3 receptor blockade. AB - BACKGROUND: Psychotic symptoms are core clinical features of schizophrenia. We tested recent hypotheses proposing that psychotic, or positive, symptoms stem from irregularities in long-range white matter tracts projecting into the frontal cortex, and we predicted that selective dopamine D2/3 receptor blockade would restore white matter. METHODS: Between December 2008 and July 2011, antipsychotic naive patients with first-episode schizophrenia and matched healthy controls underwent baseline examination with 3 T MRI diffusion tensor imaging and clinical assessments. We assessed group differences of fractional anisotropy (FA) using voxelwise tract-based spatial statistics (TBSS) and anatomic region of interest (ROI)-based analyses. Subsequently, patients underwent 6 weeks of antipsychotic monotherapy with amisulpride. We repeated the examinations after 6 weeks. RESULTS: We included 38 patients with first-episode schizophrenia and 38 controls in our analysis, and 28 individuals in each group completed the study. At baseline, whole brain TBSS analyses revealed lower FA in patients in the right anterior thalamic radiation (ATR), right cingulum, right inferior longitudinal fasciculus and right corticospinal tract (CT). Fractional anisotropy in the right ATR correlated with positive symptoms (z = 2.64, p= 0.008). The ROI analyses showed significant associations between positive symptoms and FA of the frontal fasciculi, specifically the right arcuate fasciculus (z = 2.83, p= 0.005) and right superior longitudinal fasciculus (z = -3.31, p= 0.001). At re-examination, all correlations between positive symptoms and frontal fasciculi had resolved. Fractional anisotropy in the ATR increased more in patients than in controls (z = -4.92, p< 0.001). The amisulpride dose correlated positively with FA changes in the right CT (t= 2.52, p= 0.019). LIMITATIONS: Smoking and a previous diagnosis of substance abuse were potential confounders. Long-term effects of amisulpride on white matter were not evaluated. CONCLUSION: Antipsychotic-naive patients with schizophrenia displayed subtle deficits in white matter, and psychotic symptoms appeared specifically associated with frontal fasciculi integrity. Six weeks of amisulpride treatment normalized white matter. Potential remyelinating effects of dopamine D2/3 receptor antagonism warrant further clarification. PMID- 26599136 TI - An immunomagnetic separation/loop-mediated isothermal amplification method for rapid direct detection of thermotolerant Campylobacter spp. during poultry production. AB - AIMS: To develop a rapid test for thermotolerant Campylobacter in poultry faeces. METHODS AND RESULTS: The reported method is based on immunomagnetic separation and loop-mediated isothermal DNA amplification (IMS/LAMP). This LAMP assay is specific (demonstrated using 10 Campylobacter strains and 13 non-Campylobacter bacterial species) and sensitive (95% probability of detecting 22 genome copies). A competitive internal amplification control (IAC) has been incorporated to give unambiguous determination of negative results. Immunoseparation of Campylobacter allows direct LAMP detection from poultry boot swab samples in 90 min without enrichment or DNA purification (74% probability of detecting 10(4) CFU ml(-1) of a boot swab suspension). The analysis of 17 samples from commercial turkey farms showed 100% correlation with parallel results obtained by standard microbiological methods. CONCLUSIONS: A rapid test has been developed for direct detection of thermotolerant Campylobacter spp. in boot swab samples, thus bypassing culture enrichment or DNA extraction. The test has potential to be carried out by farm personnel on site. SIGNIFICANCE AND IMPACT OF THE STUDY: The method offers an inexpensive approach to monitor poultry infection in near real time, assisting flock management and controls to prevent introduction of Campylobacter into the food chain. PMID- 26599138 TI - Syntheses, crystal structures and physical properties of three new chalcogenides: NaGaGe3Se8, K3Ga3Ge7S20, and K3Ga3Ge7Se20. AB - Three new chalcogenides, namely NaGaGe3Se8, K3Ga3Ge7S20, and K3Ga3Ge7Se20, of an A-Ga-Ge-Q (A = Na, K; Q = S, Se) system were obtained for the first time. They crystallize into two different new structures, albeit both in the monoclinic space group P21/c. NaGaGe3Se8 has a layered structure consisting of two dimensional [M4Se8](-) layers separated by Na(+) cations, while the structures of K3Ga3Ge7Q20 (Q = S, Se) are constructed by incompletely isolated quasi-2D [M10Q21](5-) layers, leading to large channels loosely occupied by K(+) cations. Interestingly, thermal analysis indicates that the three title compounds are all congruent-melting compounds, which is uncommon for quaternary compounds, and makes bulk crystal growth using the Bridgman technique possible. UV-vis-NIR spectroscopy measurements reveal that the optical band gaps of the three compounds are 2.35, 3.25, and 2.23 eV. In addition, the electronic structure calculations on NaGaGe3Se8 show that the band gap is mainly determined by the GaSe4 and GeSe4 groups. PMID- 26599137 TI - Imaging of the internal nasal valve using long-range Fourier domain optical coherence tomography. AB - OBJECTIVES/HYPOTHESIS: To evaluate for the first time the feasibility and methodology of long-range Fourier domain optical coherence tomography (LR-OCT) imaging of the internal nasal valve (INV) area in healthy individuals. STUDY DESIGN: Prospective individual cohort study. METHODS: For 16 individuals, OCT was performed in each nare. The angle and the cross-sectional area of the INV were measured. OCT images were compared to corresponding digital pictures recorded with a flexible endoscope. RESULTS: INV angle measured by OCT was found to be 18.3 degrees +/- 3.1 degrees (mean +/- standard deviation). The cross-sectional area was 0.65 +/- 0.23 cm(2) . The INV angle measured by endoscopy was 18.8 degrees +/- 6.9 degrees . There was no statistically significant difference between endoscopy and OCT concerning the mean INV angle (P = .778), but there was a significant difference in test precision (coefficient of variance 50% vs. 15%; P < .001). CONCLUSIONS: LR-OCT proved to be a fast and easily performed method. OCT could accurately quantify the INV area. The values of the angle and the cross sectional area of the INV were reproducible and correlated well with the data seen with other methods. Changes in size could be reliably delineated. Endoscopy showed similar values but was significantly less precise. LEVEL OF EVIDENCE: 2b. Laryngoscope, 126:E97-E102, 2016. PMID- 26599139 TI - Using hysteresis analysis of high-resolution water quality monitoring data, including uncertainty, to infer controls on nutrient and sediment transfer in catchments. AB - A large proportion of nutrients and sediment is mobilised in catchments during storm events. Therefore understanding a catchment's hydrological behaviour during storms and how this acts to mobilise and transport nutrients and sediment to nearby watercourses is extremely important for effective catchment management. The expansion of available in-situ sensors is allowing a wider range of water quality parameters to be monitored and at higher temporal resolution, meaning that the investigation of hydrochemical behaviours during storms is increasingly feasible. Studying the relationship between discharge and water quality parameters in storm events can provide a valuable research tool to infer the likely source areas and flow pathways contributing to nutrient and sediment transport. Therefore, this paper uses 2 years of high temporal resolution (15/30 min) discharge and water quality (nitrate-N, total phosphorus (TP) and turbidity) data to examine hysteretic behaviour during storm events in two contrasting catchments, in the Hampshire Avon catchment, UK. This paper provides one of the first examples of a study which comprehensively examines storm behaviours for up to 76 storm events and three water quality parameters. It also examines the observational uncertainties using a non-parametric approach. A range of metrics was used, such as loop direction, loop area and a hysteresis index (HI) to characterise and quantify the storm behaviour. With two years of high resolution information it was possible to see how transport mechanisms varied between parameters and through time. This study has also clearly shown the different transport regimes operating between a groundwater dominated chalk catchment versus a surface-water dominated clay catchment. This information, set within an uncertainty framework, means that confidence can be derived that the patterns and relationships thus identified are statistically robust. These insights can thus be used to provide information regarding transport processes and biogeochemical processing within river catchments. PMID- 26599140 TI - Will enhanced turbulence in inland waters result in elevated production of autochthonous dissolved organic matter? AB - Biological activity in lakes is strongly influenced by hydrodynamic conditions, not least turbulence intensity; which increases the encounter rate between plankter and nutrient patches. To investigate whether enhanced turbulence in shallow and eutrophic lakes may result in elevated biological production of autochthonous chromophoric dissolved organic matter (CDOM), a combination of field campaigns and mesocosm experiments was used. Parallel factor analysis identified seven components: four protein-like, one microbial humic-like and two terrestrial humic-like components. During our field campaigns, elevated production of autochthonous CDOM was recorded in open water with higher wind speed and wave height than in inner bays, implying that elevated turbulence resulted in increased production of autochthonous CDOM. Confirming the field campaign results, in the mesocosm experiment enhanced turbulence resulted in a remarkably higher microbial humic-like C1 and tryptophan-like C3 (p<0.01), indicating that higher turbulence may have elevated the production of autochthonous CDOM. This is consistent with the significantly higher mean concentrations of chlorophyll-a (Chl-a) and dissolved organic carbon (DOC) and the enhanced phytoplanktonic alkaline phosphatase activity (PAPA) recorded in the experimental turbulence groups than in the control group (p<0.05). The C:N ratio (from 3.34 to 25.72 with a mean of 13.13+/-4.08) for the mesocosm CDOM samples further suggested their probable autochthonous origin. Our results have implications for the understanding of CDOM cycling in shallow aquatic ecosystems influenced by wind-induced waves, in which the enhanced turbulence associated with extreme weather conditions may be further stimulated by the predicted global climate change. PMID- 26599141 TI - Challenges in evaluating PM concentration levels, commuting exposure, and mask efficacy in reducing PM exposure in growing, urban communities in a developing country. AB - Particulate matter (PM) contributes to an increased risk of respiratory and cardiovascular illnesses, cancer, and preterm birth complications. This project assessed PM exposure in Eastern Indonesia's largest city, where air quality has not been comprehensively monitored. We examined the efficacy of wearing masks as an individual intervention effort to reduce in-transit PM exposures. Handheld particulate counters were used to investigate ambient air quality for spatial analysis, as well as the differences in exposure to PM2.5 and PM10 (MUg/m(3)) by different transportation methods [e.g. motorcycle (n=97), pete-pete (n=53), and car (n=55); note: n=1 means 1m(3) of air sample]. Mask efficacy to reduce PM exposure was evaluated [e.g. surgical masks (n=39), bandanas (n=52), and motorcycle masks (n=39)]. A Monte Carlo simulation was used to provide a range of uncertainty in exposure assessment. Overall PM10 levels (91+/-124 MUg/m(3)) were elevated compared to the World Health Organization (WHO)'s 24-hour air quality guideline (50 MUg/m(3)). While average PM2.5 levels (9+/-14 MUg/m(3)) were below the WHO's guideline (25 MUg/m(3)), measurements up to 139 MUg/m(3) were observed. Compared to cars, average motorcycle and pete-pete PM exposures were four and three times higher for PM2.5, and 13 and 10 times higher for PM10, respectively. Only surgical masks were consistent in lowering PM2.5 and PM10 (p<0.01). Young children (<=5) were the most vulnerable age group, and could not reach the safe dosage even when wearing surgical masks. Individual interventions can effectively reduce individual PM exposures; however, policy interventions will be needed to improve the overall air quality and create safer transportation. PMID- 26599142 TI - Occurrence and health risk assessment of halogenated disinfection byproducts in indoor swimming pool water. AB - Swimming pool disinfection byproducts (DBPs) have become a concern in many countries all over the world. In this study, the concentrations of several categories of DBPs, including trihalomethanes (THMs), haloacetic acids (HAAs), haloacetonitriles (HANs), haloketones (HKs) and trichloronitromethane (TCNM), in 13 public indoor swimming pools in Nanjing, China were determined, the correlations between DBPs and water quality parameters as well as between different DBP categories were evaluated, and the health risks of the DBPs to human were examined. The results indicate that the DBP levels in the swimming pools in Nanjing were relatively high, with HAAs as the most dominant category, followed by THMs, HANs, HKs and TCNM sequentially. Bromochloroacetic acid (BCAA), trichloromethane (TCM), dichloroacetonitrile (DCAN), and 1,1,1-trichloropropanone (1,1,1-TCP) were the most dominant species among HAAs, THMs, HANs, and HKs, respectively. For all the different categories of DBPs, the concentrations in the pool disinfected with ozonation/chlorination were lower than those in the pool disinfected with chlorination. The DBP levels were generally not affected by the number of swimmers and the DBP levels on different dates were relatively stable. Besides, the chlorine residual seemed to be a critical concern in most of the swimming pools in this study. Moreover, there were some correlations between DBPs and water quality parameters as well as between different DBP categories. It is to be noted that the predicted cancer and health risks of the DBPs in these swimming pools were generally higher than the regulatory limits by USEPA, and thus DBPs in these swimming pools should be concerned. PMID- 26599143 TI - Nocebo responses to high-voltage power lines: Evidence from a prospective field study. AB - BACKGROUND: Experimental studies suggest that nocebo responses might occur after exposure to equipment emitting electromagnetic fields such as high voltage power lines (HVPLs) or mobile phone base stations. OBJECTIVES: The present study investigates to what extent health responses to a new HVPL can be explained by beliefs of residents regarding the health effects of HVPLs. METHODS: We used a quasi-experimental prospective field study design with two pretests during the construction of a new HVPL, and two posttests after it has been put into operation. Residents living near (0-300 m, n=229; 300-500 m, n=489) and farther away (500-2000 m, n=536) filled out questionnaires about their health and their beliefs about the negative health effects of power lines. Longitudinal mediation models were applied to investigate to what extent these beliefs could explain a change in reported symptoms after the new line was put into operation. RESULTS: Significant (p<.01) indirect effects were found for proximity on the increase in reported cognitive (R(2)=0.41) and somatic (R(2)=0.79) symptoms after the power line was put into operation through an increase in the belief that power lines causes health effects. The direct effects of proximity on an increase in reported symptoms were not significant. CONCLUSIONS: Our findings suggest that increases in reported health complaints after a new HVPL has been put into operation can be explained by nocebo mechanisms. Future field studies are needed to know whether our findings extend to other environmental health issues in a community. PMID- 26599144 TI - Long-term monitoring and seasonal analysis of polycyclic aromatic hydrocarbons (PAHs) measured over a decade in the ambient air of Porto, Portugal. AB - The present paper reports the analytical results of PAHs concentrations in ambient air obtained in the PM10 and gas-phase, from 2004 to 2014, in Porto, Portugal. As part of a monitoring programme conducted by IDAD - Institute of Environment and Development and supported by the regional municipal solid waste (MSW) management authorities, an extensive database of PAH concentrations in ambient air was collected in Porto's metropolitan area. During this period a total of 201 samples were collected in two sites classified as suburban. Analytical results showed a clear decreasing trend of total PAHs (?PAH) and benzo[a]pyrene (BaP) levels during the period of study, especially in the first years of monitoring. The average annual concentrations of BaP were, throughout the monitoring period, lower than the target value for the annual average (1 ng m(-3)) defined in the European legislation. PAHs levels showed a strong seasonality, with higher concentrations values during the colder months. The winter/summer ratio of ?PAH for the eleven years of study was 5, revealing the seasonal variation of PAHs in the studied area. The estimated toxic equivalency factors (TEFs) used to assess the contribution of the carcinogenic potential, confirmed a significant presence of the moderately active carcinogenic BaP and dibenz[ah]anthracene (DahA) in the samples collected in Porto. The ratio values of individual PAHs concentrations were used as diagnostic tool to identify the possible origin of PAH in the ambient air of Porto. Based on diagnostic ratios, it may be concluded that automobile traffic emissions, mainly related to diesel vehicles, were the major contribution of PAH levels in the ambient air, although some others contributions, such as coal and wood combustion, were identified. PMID- 26599145 TI - Differences in tolerance to anthropogenic stress between invasive and native bivalves. AB - Tolerance towards environmental stress has been frequently considered as one of the key determinants of invasion success. However, empirical evidence supporting the assumption that invasive species can better endure unfavorable conditions compared with native species is limited and has yielded opposing results. In this study, we examined the tolerance to different stress conditions (thermal stress and trace metal zinc pollution stress) in two phylogenetically related and functionally similar freshwater bivalve species, the native Anodonta anatina and the invasive Sinanodonta woodiana. We assessed potential differences in response to stress conditions using several cellular response assays: efficiency of the multixenobiotic resistance mechanism, respiration estimate (INT reduction capacity), and enzymatic biomarkers. Our results demonstrated that the invasive species overall coped much better with unfavorable conditions. The higher tolerance of S. woodiana was evident from (i) significantly decreased Rhodamine B accumulation indicating more efficient multixenobiotic resistance mechanism; (ii) significantly higher INT reduction capacity and (iii) less pronounced alterations in the activity of stress-related enzymes (glutathione-S-transferase, catalase) and of a neurotoxicity biomarker (cholinesterase) in the majority of treatment conditions in both stress trials. Higher tolerance to thermal extremes may provide physiological benefit for further invasion success of S. woodiana in European freshwaters, especially in the context of climate change. PMID- 26599146 TI - Description of the behavior of an aquifer by using continuous radon monitoring in a thermal spa. AB - Radon ((222)Rn) levels in air and water have been analyzed continuously for almost a year in Las Caldas de Besaya thermal spa, north Spain. Radon is a naturally occurring noble gas from the decay of radium ((226)Ra) both constituents of radioactive uranium 238 series. It has been recognized as a lung carcinogen by the World Health Organization (WHO) and International Agency for Research on Cancer (IARC). Furthermore the Royal Decree R.D 1439/2010 of November, 2010 establishes the obligation to study occupational activities where workers and, where appropriate, members of the public are exposed to inhalation of radon in workplaces such as spas. Together with radon measures several physico chemical parameters were obtained such as pH, redox potential, electrical conductivity and air and water temperature. The devices used for the study of the temporal evolution of radon concentration have been the RTM 2100, the Radon Scout and gamma spectrometry was complementarily used to determine the transfer factor of the silicone tubes in the experimental device. Radon concentrations obtained in water and air of the spa are high, with an average of 660 Bq/l and 2900 Bq/m(3) respectively, where water is the main source of radon in the air. Radiation dose for workers and public was estimated from these levels of radon. The data showed that the thermal processes can control the behavior of radon which can be also influenced by various physical and chemical parameters such as pH and redox potential. PMID- 26599147 TI - Towards an Agro-Industrial Ecology: A review of nutrient flow modelling and assessment tools in agro-food systems at the local scale. AB - Improvement in nutrient recycling in agriculture is essential to maintain food production while minimising nutrient pollution of the environment. For this purpose, understanding and modelling nutrient cycles in food and related agro industrial systems is a crucial task. Although nutrient management has been addressed at the plot and farm scales for many years now in the agricultural sciences, there is a need to upscale these approaches to capture the additional drivers of nutrient cycles that may occur at the local, i.e. district, scale. Industrial ecology principles provide sound bases to analyse nutrient cycling in complex systems. However, since agro-food social-ecological systems have specific ecological and social dimensions, we argue that a new field, referred to as "Agro Industrial Ecology", is needed to study these systems. In this paper, we review the literature on nutrient cycling in complex social-ecological systems that can provide a basis for Agro-Industrial Ecology. We identify and describe three major approaches: Environmental Assessment tools, Stock and Flow Analysis methods and Agent-based models. We then discuss their advantages and drawbacks for assessing and modelling nutrient cycles in agro-food systems in terms of their purpose and scope, object representation and time-spatial dynamics. We finally argue that combining stock-flow methods with both agent-based models and environmental impact assessment tools is a promising way to analyse the role of economic agents on nutrient flows and losses and to explore scenarios that better close the nutrient cycles at the local scale. PMID- 26599148 TI - Characteristics of pristine volcanic materials: Beneficial and harmful effects and their management for restoration of agroecosystem. AB - Eruption of Sinabung volcano in Indonesia began again in 2010 after resting for 1200 years. The volcano is daily emitting ash and pyroclastic materials since September 2013 to the present, damaging agroecosystems and costing for management restoration. The objective of the study was to assess properties and impacts of pristine volcanic material depositions on soil properties and to provide management options for restoring the affected agroecosytem. Land satellite imagery was used for field studies to observe the distribution, thickness and properties of ashfall deposition. The pristine ashfall deposits and the underlying soils were sampled for mineralogical, soluble salt, chemical, physical and toxic compound analyses. Results showed that uneven distribution of rainfall at the time of violent eruption caused the areas receiving mud ashfall developed surface encrustation, which was not occur in areas receiving dry ashfall. Ashfall damaged the agroecosytem by burning vegetation, forming surface crusts, and creating soil acidity and toxicity. X-ray diffraction (XRD) and scanning electron microscope (SEM) analyses of encrustated layer indicated the presence of gypsum and jarosite minerals. Gypsum likely acted as a cementing agent in the formation of the encrustation layer with extremely low pH (2.9) and extremely high concentrations of Al, Ca and S. Encrustation is responsible for limited water infiltration and root penetration, while the extremely high concentration of Al is responsible for crop toxicity. Mud ashfall and dry ashfall deposits also greatly changed the underlying soil properties by decreasing soil pH and cation exchange capacity and by increasing exchangeable Ca, Al, and S availability. Despite damaging vegetation in the short-term, the volcanic ashfall enriched the soil in the longer term by adding nutrients like Ca, Mg, K, Na, P, Si and S. Suggested management practices to help restore the agroecosystem after volcanic eruptions include: (i) the application of lime to increase soil pH, increase cation exchange capacity and decrease Al and S toxicities, (ii) the selection of crops which are tolerant to low pH and high concentrations of soluble Al and S, (iii) physically disrupting the hard surface crusts that form on some soils (if <2 cm thick) to allow water infiltration and root penetration, (iv) application of N and K fertilizers, and (v) incorporation of dry ashfall into the soil (if <5 cm thick) to exploit the newly deposited nutrients. PMID- 26599149 TI - The impacts of Segura River (Spain) channelization on the coastal seabed. AB - Human actions over rivers and coasts have generated great changes along seaboard. In order to know future development of those changes, it is necessary to understand the development of the coast during the past. When there is a complex morphologic system as a result of the combination of natural elements with human construction elements, the study of the abovementioned changes requires a wider perspective than the one provided by traditional two-dimensional methods. Thus, the Geographic Information Systems (GIS) become a suitable tool for that kind of studies. In this work, GIS are used to understand changes in bathymetry, sediments properties and transport, as well as surface variations of plant species occurred in the Segura River mouth (Spain) within a period of 17 years due to the channelization of the river low course. The methodology followed here implies the integration of data coming from different sources and with different formats in a GIS, what allows for a spatial analysis. Results obtained show the grain-size spatial distribution for every period of time studied, as well as bathymetry changes and seabed morphology. It can be concluded that the construction works carried out in the riverbed have affected sediment grain-size in the area. Clays have nearly disappeared and consequently there is a descent of seabed level that affects plant species, such as Posidonia oceanica. PMID- 26599150 TI - Occurrence and variability of iodinated trihalomethanes concentrations within two drinking-water distribution networks. AB - Non-iodo-containing trihalomethanes (TTHM) are frequently detected in chlorinated tap water and currently regulated against their carcinogenic potential. Iodinated THM (ITHM) may also form in disinfected with chlorine waters that are high in iodine content, but little is known about their magnitude and variability within the drinking-water pipe distribution network of urban areas. The main objective of this study was to determine the magnitude and variability of ITHM and TTHM levels and their corresponding daily intake estimates within the drinking water distribution systems of Limassol and Nicosia cities of Cyprus, using tap samples collected from individual households (n=37). In Limassol, mean household tap water ITHM and TTHM levels was 0.58 and 38 MUg L(-1), respectively. Dichloroiodomethane (DCIM) was the dominant species of the two measured ITHM compounds accounting for 77% of total ITHM and in the range of 0.032 and 1.65 MUg L(-1). The range of DCIM concentrations in Nicosia tap water samples was narrower (0.032 - 0.848 MUg L(-1)). Mean total iodine concentration in tap water samples from the seaside city of Limassol was 15 MUg L(-1) and approximately twice to those observed in samples from the mainland Nicosia city. However, iodine concentrations did not correlate with the ITHM levels. The calculated chronic daily intake rates of ITHM were low when compared with those of TTHM, but because of their widespread occurrence in tap water and their enhanced mammalian cell toxicity, additional research is warranted to assess the magnitude and variability of human ITHM exposures. PMID- 26599151 TI - Maternal prenatal iron status and tissue organization in the neonatal brain. AB - BACKGROUND: Children prenatally exposed to inadequate iron have poorer motor and neurocognitive development. No prior study to our knowledge has assessed the influence of maternal prenatal iron intake on newborn brain tissue organization in full-term infants. METHODS: Third trimester daily iron intake was obtained using the Automated Self-Administered 24-h Dietary Recall with n = 40 healthy pregnant adolescents (aged 14-19 y). Cord blood ferritin was collected in a subsample (n = 16). Newborn (mean = 39 gestational weeks at birth; range 37-41) magnetic resonance imaging scans were acquired on a 3.0 Tesla MR Scanner. Diffusion Tensor Imaging (DTI) slices were acquired to measure the directional diffusion of water indexed by fractional anisotropy (FA). RESULTS: Reported iron intake was inversely associated with newborn FA values (P <= 0.0001) predominantly in cortical gray matter. FA findings were similar using cord blood ferritin values. CONCLUSION: Higher maternal prenatal iron intake accentuates, and lower intake attenuates, the normal age-related decline in FA values in gray matter, perhaps representing increasing dendritic arborization and synapse formation with higher iron intake. These DTI results suggest that typical variation in maternal iron outside the scope of standard clinical surveillance exerts subtle effects on infant brain development. PMID- 26599152 TI - Housing conditions and sacrifice protocol affect neural activity and vocal behavior in a songbird species, the zebra finch (Taeniopygia guttata). AB - Individual cages represent a widely used housing condition in laboratories. This isolation represents an impoverished physical and social environment in gregarious animals. It prevents animals from socializing, even when auditory and visual contact is maintained. Zebra finches are colonial songbirds that are widely used as laboratory animals for the study of vocal communication from brain to behavior. In this study, we investigated the effect of single housing on the vocal behavior and the brain activity of male zebra finches (Taeniopygia guttata): male birds housed in individual cages were compared to freely interacting male birds housed as a social group in a communal cage. We focused on the activity of septo-hypothalamic regions of the "social behavior network" (SBN), a set of limbic regions involved in several social behaviors in vertebrates. The activity of four structures of the SBN (BSTm, medial bed nucleus of the stria terminalis; POM, medial preoptic area; lateral septum; ventromedial hypothalamus) and one associated region (paraventricular nucleus of the hypothalamus) was assessed using immunoreactive nuclei density of the immediate early gene Zenk (egr-1). We further assessed the identity of active cell populations by labeling vasotocin (VT). Brain activity was related to behavioral activities of birds like physical and vocal interactions. We showed that individual housing modifies vocal exchanges between birds compared to communal housing. This is of particular importance in the zebra finch, a model species for the study of vocal communication. In addition, a protocol that daily removes one or two birds from the group affects differently male zebra finches depending of their housing conditions: while communally-housed males changed their vocal output, brains of individually housed males show increased Zenk labeling in non VT cells of the BSTm and enhanced correlation of Zenk-revealed activity between the studied structures. These results show that housing conditions must gain some attention in behavioral neuroscience protocols. PMID- 26599153 TI - Empirical fitness models for hepatitis C virus immunogen design. AB - Hepatitis C virus (HCV) afflicts 170 million people worldwide, 2%-3% of the global population, and kills 350 000 each year. Prophylactic vaccination offers the most realistic and cost effective hope of controlling this epidemic in the developing world where expensive drug therapies are not available. Despite 20 years of research, the high mutability of the virus and lack of knowledge of what constitutes effective immune responses have impeded development of an effective vaccine. Coupling data mining of sequence databases with spin glass models from statistical physics, we have developed a computational approach to translate clinical sequence databases into empirical fitness landscapes quantifying the replicative capacity of the virus as a function of its amino acid sequence. These landscapes explicitly connect viral genotype to phenotypic fitness, and reveal vulnerable immunological targets within the viral proteome that can be exploited to rationally design vaccine immunogens. We have recovered the empirical fitness landscape for the HCV RNA-dependent RNA polymerase (protein NS5B) responsible for viral genome replication, and validated the predictions of our model by demonstrating excellent accord with experimental measurements and clinical observations. We have used our landscapes to perform exhaustive in silico screening of 16.8 million T-cell immunogen candidates to identify 86 optimal formulations. By reducing the search space of immunogen candidates by over five orders of magnitude, our approach can offer valuable savings in time, expense, and labor for experimental vaccine development and accelerate the search for a HCV vaccine. ABBREVIATIONS: HCV-hepatitis C virus, HLA-human leukocyte antigen, CTL-cytotoxic T lymphocyte, NS5B-nonstructural protein 5B, MSA-multiple sequence alignment, PEG-IFN-pegylated interferon. PMID- 26599154 TI - History of Asthma in Patients with Chronic Obstructive Pulmonary Disease. A Comparative Study of Economic Burden. AB - RATIONALE: A diagnosis of asthma is considered an independent risk factor for chronic obstructive pulmonary disease (COPD). However, little is known about health service use patterns in patients with COPD who have a history of asthma in comparison with those without such a history, especially regarding comorbid conditions. OBJECTIVES: To estimate the excess costs of COPD in patients with a history of asthma (COPD+asthma) versus those with COPD without such a history (COPD-only); to estimate excess costs attributable to inpatient care, outpatient care, medications, and community care; and to estimate excess costs attributable to comorbid conditions. METHODS: We used vital statistics, inpatient and outpatient encounters, filled prescription records, and community care data of patients in British Columbia, Canada, from 1997 to 2012 to create propensity score-matched COPD+asthma and COPD-only cohorts. We calculated and compared the excess medical costs (in 2012 Canadian dollars [$]) between the two groups on the basis of billing information. Comorbidities were ascertained from the inpatient and outpatient records and were classified on the basis of major categories of the International Classification of Diseases, 10th Revision. MEASUREMENTS AND MAIN RESULTS: The final sample consisted of 22,565 individuals within each group (mean age at baseline, 67.9 yr; 57.0% female; average follow-up, 4.07 yr). Excess costs of COPD+asthma were $540.7 per patient-year (PY) (95% confidence interval [CI], $301.7-$779.8; P < 0.001). Costs of medications ($657.9/PY; P < 0.001) and outpatient services ($127.6/PY; P < 0.001) were higher in COPD+asthma, but costs of hospitalizations were lower (-$271.0/PY; P = 0.002). Community care costs in the two groups were similar (P = 0.257). The excess cost of respiratory-related conditions was $856.2/PY (P < 0.001), with $552.6/PY being due to respiratory related medications (P < 0.001); costs of all other conditions combined were lower in COPD+asthma, mainly due to lower costs of cardiovascular diseases ( $201.8/PY; P < 0.001). CONCLUSIONS: Patients with COPD with a previous history of asthma consume more health care resources than those with COPD alone, but there are important differences in cost components and costs attributable to comorbid conditions. Further research is required to examine whether the lower costs of cardiovascular disease in these patients is due to lower levels of related risk factors or to intrinsic differences in COPD phenotypes. PMID- 26599155 TI - Strengths and weaknesses of state of the art fiber tractography pipelines--A comprehensive in-vivo and phantom evaluation study using Tractometer. AB - Many different tractography approaches and corresponding isolated evaluation attempts have been presented over the last years, but a comparative and quantitative evaluation of tractography algorithms still remains a challenge, particularly in-vivo. The recently presented evaluation framework Tractometer is the first attempt to approach this challenge in a quantitative, comparative, persistent and open-access way. Tractometer is currently based on the evaluation of several global connectivity and tract-overlap metrics on hardware phantom data. The work presented in this paper focuses on extending Tractometer with a metric that enables the assessment of the local consistency of tractograms with the underlying image data that is not only applicable to phantom dataset but allows the quantitative and purely data-driven evaluation of in-vivo tractography. We furthermore present an extensive reference-based evaluation study of 25,000 tractograms obtained on phantom and in-vivo datasets using the presented local metric as well as all the methods already established in Tractometer. The experiments showed that the presented local metric successfully reflects the behavior of in-vivo tractography under different conditions and that it is consistent with the results of previous studies. Additionally our experiments enabled a multitude of conclusions with implications for fiber tractography in general, including recommendations regarding optimal choice of a local modeling technique, tractography algorithm, and parameterization, confirming and complementing the results of earlier studies. PMID- 26599157 TI - Laboratory and Hatchery-Scale Evaluation of Sand Filters and Their Efficacy at Controlling Whirling Disease Infection. AB - In two separate tests rapid sand filtration was evaluated as a means of removing the waterborne triactinomyxon actinospores (TAMs) of Myxobolus cerebralis, the causative agent of salmonid whirling disease, from contaminated water. In the first test we independently evaluated two sizes of sandblast sands: #4010 (effective size, (ES) = 250 MUm) and #4060 (ES = 300 MUm). The product number relates to the sand's size composition, and each had a different effective size. Effective size is defined by that size fraction at which only 10% of smaller particles remain. Rainbow trout Oncorhynchus mykiss were stocked into two separate systems with filters containing either one or the other size of sand, and TAMs were added to each system three times per week for all but the final 2 weeks of the 16-week test. A positive control (in which fish were exposed to the same number of TAMs without filtration) and a negative control (in which fish were not exposed to TAMs) were also included. Infection quantified by the pepsin trypsin digest method showed no infection in fish from the two filter treatments. The average myxospore load among the positive controls was over 90,000 spores per fish head. In a final test, a nonreplicated comparison of filtration systems was conducted. The three systems used were as follows: (1) a drum filter in line with a UV filter, (2) a media filter followed by an ultraviolet (UV) unit, and (3) a sand filter containing three layers of sand. Water contaminated with TAMS was run through each filtration system, as well as through a positive control system, to raceways containing rainbow trout. Both of the dual-component commercial systems were 100% effective at preventing infection; the sand filter was 92% effective. PMID- 26599156 TI - High-throughput histopathological image analysis via robust cell segmentation and hashing. AB - Computer-aided diagnosis of histopathological images usually requires to examine all cells for accurate diagnosis. Traditional computational methods may have efficiency issues when performing cell-level analysis. In this paper, we propose a robust and scalable solution to enable such analysis in a real-time fashion. Specifically, a robust segmentation method is developed to delineate cells accurately using Gaussian-based hierarchical voting and repulsive balloon model. A large-scale image retrieval approach is also designed to examine and classify each cell of a testing image by comparing it with a massive database, e.g., half million cells extracted from the training dataset. We evaluate this proposed framework on a challenging and important clinical use case, i.e., differentiation of two types of lung cancers (the adenocarcinoma and squamous carcinoma), using thousands of lung microscopic tissue images extracted from hundreds of patients. Our method has achieved promising accuracy and running time by searching among half-million cells . PMID- 26599158 TI - Disease Susceptibility of Hatchery Snake River Spring-Summer Chinook Salmon with Different Juvenile Migration Histories in the Columbia River. AB - Various methods have been developed to mitigate the effects of dams on juvenile Pacific salmon Oncorhynchus spp. migrating to the Pacific Ocean through the Columbia River basin. In this study, we examined the health of hatchery Snake River spring and summer Chinook salmon relative to two mitigating strategies: dam bypass and transportation (e.g., barging). The health of out-migrants was assessed in terms of the difference in the incidence of mortality among fish, categorically grouped into no-bypass, bypass, and transportation life histories, in response to challenge with the marine pathogen Listonella anguillarum during seawater holding. These three life histories were defined as follows: (1) fish that were not detected at any of the juvenile bypass systems above Bonneville Dam were classified as having a no-bypass life history; (2) fish that were detected at one or more juvenile bypass systems above Bonneville Dam were classified as having a bypass life history; and (3) fish that were barged were classified as having the transportation life history. Barged fish were found to be less susceptible to L. anguillarum than in-river fish-whether bypassed or not-which suggests that transportation may help mitigate the adverse health effects of the hydropower system of the Columbia River basin on Snake River spring-summer Chinook salmon. The findings of this study are not necessarily transferable to other out-migrant stocks in the Columbia River basin, given that only one evolutionarily significant unit, that is, Snake River spring-summer Chinook salmon, was used in this study. PMID- 26599159 TI - Virulence Comparisons of Infectious Hematopoietic Necrosis Virus U and M Genogroups in Sockeye Salmon and Rainbow Trout. AB - Infectious hematopoietic necrosis virus (IHNV) is an aquatic rhabdovirus that infects salmonids in the Pacific Northwest of the United States, Europe, and Asia. Isolates of IHNV have been phylogenetically classified into three major viral genogroups, designated U, M, and L. To characterize virulence of IHNV in the context of these three viral genogroups, seven strains of IHNV (three U genogroup strains, three M strains, and one L strain) were compared for their pathogenicity in juvenile sockeye salmon Oncorhynchus nerka, kokanee (lacustrine sockeye salmon), and rainbow trout O. mykiss. Fish were waterborne-exposed to the different viral strains, and virulence was assessed by comparing mortality curves and final cumulative percent mortality (CPM) in both species of fish at 10 degrees C and 15 degrees C. In sockeye salmon and kokanee, the U genogroup virus types were extremely virulent, causing average CPMs of 69-100%, while the M genogroup virus types caused very little or no mortality (CPM = 0-4%). The endangered Redfish Lake sockeye salmon stock exhibited extreme differences in susceptibility to the U and M genogroups. Conversely, in two stocks of rainbow trout, the M genogroup virus types were more virulent, inducing average CPMs of 25-85%, while the U genogroup viruses caused lower mortality (CPM = 5-41%). In both fish species, the single L genogroup strain caused low to intermediate mortality (CPM = 13-53%). Viral glycoprotein sequence comparisons of the seven challenge strains revealed three amino acid sites (247, 256, and 270) that consistently differed between the U and M genogroups, possibly contributing to pathogenicity differences. PMID- 26599160 TI - Tumor Prevalence in Mummichogs from the Delaware Estuary Watershed. AB - Mummichogs Fundulus heteroclitus were collected in 2002-2004 from six locations within the Delaware Estuary watershed and examined histopathologically. The objective was to compare the prevalence of skin and liver tumors in fish from locations with a range of sediment polynuclear aromatic hydrocarbons (PAHs) based on available data. Fish were collected from (1) three locations within the industrialized Christina River subwatershed (Hershey Run, Newport Marsh (upriver and downriver)); (2) one location in the Motiva Enterprises refinery discharge canal to the Delaware River; (3) one location in the St. Jones River; and (4) one location in Blackbird Creek. Adult mummichogs (>=70 mm; n = 21-30 fish per location) were seined and held for necropsy. No neoplastic skin lesions were diagnosed in any fish. No liver tumors were diagnosed in the St. Jones, Motiva, Newport Marsh upriver, or Newport Marsh downriver collections. One of 30 Blackbird Creek mummichogs had foci of hepatocellular alteration (a putative preneoplastic lesion) and one had hepatocellular carcinoma. There was a significant difference in hepatocellular carcinoma prevalence in Hershey Run mummichogs in 2002 (9 of 21 fish, or 43%) and in 2003 (3 of 29 fish, or 10%) compared with all other locations pooled (1 of 145 fish, or 0.7%). Hershey Run is contaminated with creosote from an adjacent Superfund site, where sediments were frequently reported to have total PAH concentrations greater than 100 mg of total PAH/kg and a maximum of 13,300 mg/kg. No other locations had reports of total PAHs higher than 11 mg/kg. In conclusion, liver neoplasia was associated with exposure to sediment containing high concentrations of PAHs derived from creosote. Studies that include tumor prevalence, biomarkers (e.g., DNA adducts and PAH metabolites in bile), and sediment and/or tissue chemistry are recommended to develop a weight of evidence for specific chemical classes. PMID- 26599161 TI - An Isolate of Piscirickettsia salmonis from White Seabass is Fully Virulent for Coho Salmon. AB - The virulence of the WSB-98 isolate of Piscirickettsia salmonis from white seabass Atractoscion nobilis was compared with that of the American Type Culture Collection type strain LF-89, which was originally isolated from coho salmon Oncorhynchus kisutch in Chile. In controlled laboratory challenges of juvenile coho salmon, the isolate from white seabass exhibited virulence that was equal to or greater than that of LF-89. The cumulative percent mortality (CPM) was similar between groups of coho salmon receiving an intraperitoneal injection of WSB-98 at 10(4.5) tissue culture infectious dose with 50% endpoint (TCID50)/fish (CPM = 98%) or an injection of LF-89 at 10(4.8) TCID50/fish (CPM = 95%). The mean day to death of 9.3 d for WSB-98 and 18.6 d for LF-89, however, differed significantly (P < 0.0001) between the two isolates. The virulence of an isolate of P. salmonis from white seabass for a salmonid species is consistent with the hypothesis that nonsalmonids can serve as natural marine hosts for the bacterium and potential sources for infection of salmonids. PMID- 26599162 TI - Histopathological Examination of Wild American Eels Infected with Anguillicola crassus. AB - We describe for the first time the histopathology caused in wild American eels Anguilla rostrata by the introduced nematode Anguillicola crassus. All of the American eels examined showed signs of previous or ongoing infections with A. crassus. Gross observations included opacity of the normally translucent swim bladder and dilation of blood vessels. The swim bladders of infected American eels showed focal, multifocal, and diffuse histological changes. Consistently observed pathologies included abnormal papillose appearance of the mucosa; hyperplasia of the lamina propria, muscularis mucosa, and submucosa; edema of the mucosa and muscularis mucosa; dilation of the blood vessels; and damage in the submucosa caused by migrating A. crassus L3 and L4 larvae. Less-common pathologies included fibrosis and lymphocytic aggregates around L3 and L4 larvae in the submucosa; destruction of the mucosa, which in some cases completely exposed the mucosal blood vessels; L2 larval penetration of the tissues of the swim bladder; bacterial infections in the submucosa and muscularis mucosa; and migration of an L4 larva through the rete mirabile. PMID- 26599163 TI - PDL-1/PDL-2 blockade in mice dendritic cells by RNAi techniques to induce antitumor immunity. AB - AIM: We provided potent dendritic cells (DCs) for induction of stronger antitumor immune responses. MATERIALS & METHODS: Using siRNA and shRNA systems, PDL-1 and PDL-2 were knocked down and then DC in vitro and in vivo properties were evaluated. RESULTS: Mild suppression of PDL-1/PDL-2 molecules was accompanied by appropriate expression of DCs co-stimulatory molecules and release of proinflammatory cytokines. In vitro T-cell engagement induced the proliferation and secretion of Th1 cytokines. Injection of DCs to a 4T1 mice model induced intratumor CD8(+) infiltrating lymphocytes, splenocytes expansion, Th1 cytokine profile shift, and a mild drift to tumor growth inhibition and mice survival. CONCLUSION: Manipulated DCs induced significant antitumor immunity, but this subject needs further evaluation in different animals. PMID- 26599164 TI - The European preexposure prophylaxis revolution. AB - PURPOSE OF REVIEW: The review describes the European epidemic and the challenges in moving from clinical trials of preexposure prophylaxis (PrEP) to routine practice. RECENT FINDINGS: Two European trials conducted in gay and other MSM and transgender women reported a high and consistent reduction in HIV incidence using oral PrEP with tenofovir/emtricitabine (TDF/FTC). The incidence of HIV infection in the control group was much higher than anticipated, based on routine surveillance data in MSM, in spite of the highest standard of HIV prevention available. SUMMARY: Recent results have highlighted the urgent need to make PrEP available to key populations in Europe as an additional prevention tool. Gilead has not yet submitted an application to use TDF/FTC as PrEP in Europe. Although regulatory approval would accelerate implementation, countries are already dispensing TDF/FTC as postexposure prophylaxis without this. Services for prevention are diverse across countries ranging from free, walk-in services for the diagnosis and treatment of HIV and other sexually transmitted infections, to insurance-dependent reimbursement of private clinical services. Momentum is gathering in Europe with PrEP demonstration projects in MSM and a growing demand from community organizations. Each Member State urgently needs to identify their key populations and determine the service best placed to provide this new prevention strategy within a comprehensive prevention package. PMID- 26599165 TI - The preexposure prophylaxis revolution: from clinical trials to routine practice: implementation view from the USA. AB - PURPOSE OF REVIEW: This article describes the use of tenofovir/emtricitabine (Truvada) as prevention for exposure to HIV [preexposure prophylaxis (PrEP)] infection in the USA. The use of PrEP and the challenges of implementation are very instructive as other countries adopt this intervention and it becomes a fundamental part of worldwide efforts for HIV prevention and much can be learned from the first 3 years in the USA. RECENT FINDINGS: Randomized trials and demonstration projects have shown the benefits of PrEP for men and women who are at risk for HIV. Numerous studies have showed that the level of prevention is excellent when the drug is taken at least four times weekly, once adequate levels are obtained. However, adherence remains a critical issue as well as tailoring delivery models for specific populations. Six recent studies are discussed, that support excellent efficacy and significantly support PrEP as a means of prevention. These projects have shown high acceptance of PrEP with excellent adherence by individuals demonstrated by those at risk remaining free of HIV over extended periods of time. SUMMARY: The USA faces three significant challenges in scaling up PrEP. The first challenge in implementation in the USA is to get individuals to recognize the actual risks that their behaviors represent and to engage with providers to address these issues. The second challenge is getting a population of providers to recognize the exact same issues and offer PrEP in a compassionate, nonjudgmental fashion. The third challenge is identifying the set of providers and locations to scale-up the response in a timely, cost-effective fashion. PMID- 26599167 TI - Immune activation during acute HIV infection and the impact of early antiretroviral therapy. AB - PURPOSE OF REVIEW: The purpose of this review is to outline recent data pertaining to mechanisms of immune activation in acute infection and describe new developments that seek to determine if early antiretroviral treatment can mitigate chronic immune activation. RECENT FINDINGS: Following the detection of HIV RNA, highly activated CD8 T cells expand and peak approximately 2 weeks following peak viral load whereas levels of proinflammatory soluble markers coincide with a rise in viral load. Immune activation during acute infection is driven by many factors including pyroptosis, replicative capacity of the infecting virus, and loss of Th17 cells within the gut. Early antiretroviral therapy (ART), particularly if initiated in Fiebig I (HIV IgM-), preserved mucosal CD4 T cells, possibly preventing the release of microbial products associated with immune activation. Viral reservoirs were restricted by the early initiation of ART, and heightened systemic immune activation was partially prevented compared with chronic HIV infection. A strong correlation was found between the size of the viral reservoir and cellular immune activation. SUMMARY: The timing of immune activation during acute infection occurs shortly after exposure. Recent studies demonstrated that ART mitigates inflammatory responses, preserves CD4 T cells, and limits reservoir seeding if provided early in acute HIV infection. PMID- 26599166 TI - Immune activation and cardiovascular disease in chronic HIV infection. AB - PURPOSE OF REVIEW: This article describes the potential contribution of immune activation in the pathogenesis of HIV-associated cardiovascular disease (CVD) - a leading cause of morbidity and mortality among HIV-positive persons with access to antiretroviral therapy (ART). RECENT FINDINGS: We review recent literature that suggests abnormalities in both adaptive and innate immunity contributes to CVD risk among persons with HIV infection. In particular, potentially atherogenic T-cell mechanisms include persistent high-level T-cell activation (and associated proinflammatory mechanisms), as well as the presence of copathogens (e.g., cytomegalovirus) providing an ongoing stimulus for cytotoxic T-cell responses. More recent data have then emphasized the potential impact of monocyte /macrophage-mediated inflammation and injury within atherosclerotic lesions. The abnormality driving innate immune activation many not fully reverse with antiretroviral therapy, highlighting the need for interventions that target inflammation as a CVD prevention strategy. SUMMARY: Premature CVD among persons with HIV infection is due, in part, to persistent abnormalities in immune activation and systemic inflammation despite viral suppression. Prevention strategies for persons with HIV infection include those that target traditional CVD risk factors, as well as newer candidate treatments with potential immunomodulatory benefits. PMID- 26599168 TI - Solid-State Thin-Film Supercapacitors with Ultrafast Charge/Discharge Based on N Doped-Carbon-Tubes/Au-Nanoparticles-Doped-MnO2 Nanocomposites. AB - Although carbonaceous materials possess long cycle stability and high power density, their low-energy density greatly limits their applications. On the contrary, metal oxides are promising pseudocapacitive electrode materials for supercapacitors due to their high-energy density. Nevertheless, poor electrical conductivity of metal oxides constitutes a primary challenge that significantly limits their energy storage capacity. Here, an advanced integrated electrode for high-performance pseudocapacitors has been designed by growing N-doped-carbon tubes/Au-nanoparticles-doped-MnO2 (NCTs/ANPDM) nanocomposite on carbon fabric. The excellent electrical conductivity and well-ordered tunnels of NCTs together with Au nanoparticles of the electrode cause low internal resistance, good ionic contact, and thus enhance redox reactions for high specific capacitance of pure MnO2 in aqueous electrolyte, even at high scan rates. A prototype solid-state thin-film symmetric supercapacitor (SSC) device based on NCTs/ANPDM exhibits large energy density (51 Wh/kg) and superior cycling performance (93% after 5000 cycles). In addition, the asymmetric supercapacitor (ASC) device assembled from NCTs/ANPDM and Fe2O3 nanorods demonstrates ultrafast charge/discharge (10 V/s), which is among the best reported for solid-state thin-film supercapacitors with both electrodes made of metal oxide electroactive materials. Moreover, its superior charge/discharge behavior is comparable to electrical double layer type supercapacitors. The ASC device also shows superior cycling performance (97% after 5000 cycles). The NCTs/ANPDM nanomaterial demonstrates great potential as a power source for energy storage devices. PMID- 26599171 TI - The Harvest Moon: Samuel Palmer. PMID- 26599172 TI - Cancer Immunotherapy Researchers Focus on Refining Checkpoint Blockade Therapies. PMID- 26599182 TI - Learning Systems at Scale: Where Policy Meets Practice. PMID- 26599183 TI - A PIECE OF MY MIND. A Hobson's Choice. PMID- 26599184 TI - Prevalence of Body Mass Index Lower Than 16 Among Women in Low- and Middle-Income Countries. AB - IMPORTANCE: Body mass index (BMI) lower than 16 is the most severe category of adult undernutrition and is associated with substantial morbidity, increased mortality, and poor maternal-fetal outcomes such as low-birth-weight newborns. Little is known about the prevalence and distribution of BMI lower than 16 in low and middle-income countries (LMIC). OBJECTIVE: To determine the prevalence and distribution of BMI lower than 16 and its change in prevalence over time in women in LMIC. DESIGN, SETTINGS, AND PARTICIPANTS: Cross-sectional data analysis composed of nationally representative surveys from 1993 through 2012 from the Demographic and Health Surveys Program. Women aged 20 through 49 years from 60 LMIC (N = 500,761) and a subset of 40 countries with repeated surveys (N = 604,144) were examined. EXPOSURES: Wealth was measured using a validated asset index, age was categorized in deciles, education by highest completed level (none, primary, secondary, or greater), and place of residence as urban vs rural. MAIN OUTCOMES AND MEASURES: The primary outcome was BMI lower than 16. Analyses assessed the prevalence of BMI lower than 16, its association with sociodemographic factors, and change in prevalence. Logistic regression models were used to calculate odds ratios (ORs), adjusting for survey design and age structure. RESULTS: Among countries examined, the pooled, weighted, and age standardized prevalence of BMI lower than 16 was 1.8% (95% CI, 1.7% to 1.8%) with the highest prevalence in India (6.2% [95% CI, 5.9% to 6.5%]), followed by Bangladesh (3.9% [95% CI, 3.4% to 4.3%]), Madagascar (3.4% [95% CI, 2.8% to 4.0%], Timor-Leste (2.9% [95% CI, 2.4% to 3.2%]), Senegal (2.5% [95% CI, 1.9% to 3.2%]), and Sierra Leone (2.2% [95% CI, 1.3% to 3.0%]); and 6 countries had prevalences lower than 0.1% (Albania, Bolivia, Egypt, Peru, Swaziland, and Turkey). The prevalence of BMI lower than 16 in women with a secondary or higher education level was 0.51% (95% CI, 0.47% to 0.55%), and in mutually adjusted models, a less than primary education level was associated with an OR of 1.4 (95% CI, 1.2 to 1.6). The prevalence of BMI lower than 16 was 0.43% (95% CI, 0.37% to 0.48%) in the highest wealth quintile with an OR of 3.0 (95% CI, 2.4 to 3.7) in the lowest wealth quintile. Among the 24 of 39 countries with repeated surveys, there was no decrease in prevalence. In Bangladesh and India, rates were declining with an average absolute change annually of -0.52% (95% CI, -0.58% to 0.46%) in Bangladesh and -0.11% (95% CI, -0.12% to -0.10%) in India. CONCLUSIONS AND RELEVANCE: Among women in 60 LMIC, the prevalence of BMI lower than 16 was 1.8%, and was associated with poverty and low education levels. Prevalence of BMI lower than 16 did not decrease over time in most countries studied. PMID- 26599186 TI - Red-Brown Plaques and Papules in a Patient With Breast Cancer. PMID- 26599187 TI - VEGF Inhibitors for AMD and Diabetic Macular Edema. PMID- 26599185 TI - Distal Symmetric Polyneuropathy: A Review. AB - IMPORTANCE: Peripheral neuropathy is a highly prevalent and morbid condition affecting 2% to 7% of the population. Patients frequently experience pain and are at risk of falls, ulcerations, and amputations. We aimed to review recent diagnostic and therapeutic advances in distal symmetric polyneuropathy, the most common subtype of peripheral neuropathy. OBSERVATIONS: Current evidence supports limited routine laboratory testing in patients with distal symmetric polyneuropathy. Patients without a known cause should undergo a complete blood cell count, comprehensive metabolic panel, vitamin B12 measurement, serum protein electrophoresis with immunofixation, fasting glucose measurement, and glucose tolerance test. The presence of atypical features such as asymmetry, non-length dependence, motor predominance, acute or subacute onset, and prominent autonomic involvement should prompt a consultation with a neurologist or neuromuscular specialist. Electrodiagnostic tests and magnetic resonance imaging of the neuroaxis contribute substantial cost to the diagnostic evaluation, but evidence supporting their use is lacking. Strong evidence supports the use of tricyclic antidepressants, serotonin norepinephrine reuptake inhibitors, and voltage-gated calcium channel ligands in the treatment of neuropathic pain. More intensive glucose control substantially reduces the incidence of distal symmetric polyneuropathy in patients with type 1 diabetes but not in those with type 2 diabetes. CONCLUSIONS AND RELEVANCE: The opportunity exists to improve guideline concordant testing in patients with distal symmetric polyneuropathy. Moreover, the role of electrodiagnostic tests needs to be further defined, and interventions to reduce magnetic resonance imaging use in this population are needed. Even though several efficacious medications exist for neuropathic pain treatment, pain is still underrecognized and undertreated. New disease-modifying medications are needed to prevent and treat peripheral neuropathy, particularly in type 2 diabetes. PMID- 26599188 TI - Association Between the Affordable Care Act Dependent Coverage Expansion and Cervical Cancer Stage and Treatment in Young Women. PMID- 26599189 TI - Cost-effectiveness of Statin Therapy for ASCVD. PMID- 26599190 TI - Cost-effectiveness of Statin Therapy for ASCVD--Reply. PMID- 26599191 TI - Maternal Malignancies Detected With Noninvasive Prenatal Testing. PMID- 26599192 TI - Maternal Malignancies Detected With Noninvasive Prenatal Testing--Reply. PMID- 26599194 TI - Dedication of the National Institute of Health. PMID- 26599195 TI - JAMA PATIENT PAGE. Diabetic Neuropathy. PMID- 26599196 TI - Loss of the Sexually Dimorphic Neuro-Inflammatory Response in a Transgenic Mouse Model of Huntington's Disease. AB - BACKGROUND: We previously reported sex differences in depression-like behaviours in a mouse model of Huntington's disease (HD). OBJECTIVE: We hypothesized that immune response could also be altered in HD mice in a sex-dependent manner. METHODS: Here, we assessed the molecular effects of an acute challenge with lipopolysaccharides (LPS) in female versus male R6/1 transgenic HD mice. RESULTS: We found an enhancement of LPS-induced TNF-alpha gene expression in the hypothalamus of female HD mice. TNF-alpha serum levels following LPS administration were also higher in female HD mice compared to WT animals. In contrast, male HD mice exhibited reduced LPS-induced TNF-alpha gene expression compared to WT animals. DISCUSSION: Our findings suggest that immune response to LPS is altered in HD mice in a sex-dependent manner. These pro-inflammatory abnormalities may contribute to the sexually dimorphic depression-like behaviours displayed by this mouse model of HD. PMID- 26599198 TI - Editorial Consultants. PMID- 26599197 TI - Impact of gastric pH profiles on the proteolytic digestion of mixed betalg Xanthan biopolymer gels. AB - The understanding of how foods are digested and metabolised is essential to enable the design/selection of foods as part of a balanced diet. Essential to this endeavour is the development of appropriate biorelevant in vitro digestion tools. In this work, the influence of gastric pH profile on the in vitro digestion of mixtures of beta-lactoglobulin (betalg) and xanthan gum prior to and after heat induced gelation was investigated. A conventional highly acidic (pH 1.9) gastric pH profile was compared to two dynamic gastric pH profiles (initial pH of 6.0 vs. 5.2 and H(+) secretion rates of 60 vs. 36 mmol h(-1)) designed to mimic the changes in gastric pH observed during clinical trials with high protein meals. In moving away from the pH 1.9 model, to a pH profile reflecting in vivo conditions, the initial rate and degree of protein digestion halved during the first 45 minutes. After 90 minutes of gastric digestion, all three pH profiles caused similar extents of protein digestion. Given that 50% gastric emptying times of (test) meals are in range of 30-90 min, it would seem highly relevant to use a dynamic pH gastric model rather than a pH 1.9 (USP) or pH 3 model (INFOGEST) in assessing the impact of food structuring approaches on protein digestion. The impact that heat induced gelation had on the degree of gel digestion by pepsin was also investigated. Surprisingly, it was found that heat induced gelation of betalg-xanthan mixtures at 70-90 degrees C for 20 minutes lead to a considerable decrease in the rate of proteolysis, which contrasts many studies of dispersed aggregates and gels of betalg alone whose heating accelerates pepsin activity due to unfolding. In the present case, the formation of a dense protein network created a fine pore structure which restricted pepsin access into the gel thereby slowing proteolysis. This work not only has implications for the in vitro assessment of protein digestion, but also highlights how protein digestion might be slowed, learnings that might have an influence on the design of foods as part of a satisfying balanced diet. PMID- 26599200 TI - Pd-Catalyzed Isocyanide Assisted Reductive Cyclization of 1-(2-Hydroxyphenyl) propargyl Alcohols for 2-Alkyl/Benzyl Benzofurans and Their Useful Oxidative Derivatization. AB - An unusual Pd-catalyzed isocyanide assisted 5-exo-dig reductive cyclization of 1 (2-hydroxyphenyl)-propargyl alcohols is achieved for 2-alkyl/benzyl benzofurans. The reaction features a high substrate scope, insensitivity to air, and excellent product yielding. Further, a direct metal-free C-H functionalization (azidation, alkoxylation, and hydroxylation) and selective oxidative cleavage of thus synthesized 2-benzylfurans are described for azido-, alkoxy-, hydroxyl-, amide-, and tetrazolyl adducts. PMID- 26599199 TI - Potential risks associated with traditional herbal medicine use in cancer care: A study of Middle Eastern oncology health care professionals. AB - BACKGROUND: The authors assessed the use of herbal medicine by Middle Eastern patients with cancer, as reported by their oncology health care professionals (HCPs). Herbal products identified by the study HCPs were evaluated for potential negative effects. METHODS: Oncology HCPs from 16 Middle Eastern countries received a 17-item questionnaire asking them to list 5 herbal products in use by their patients with cancer. A literature search (PubMed, Micromedex, AltMedDex, and the Natural Medicine Comprehensive Database) was conducted to identify safety related concerns associated with the products listed. RESULTS: A total of 339 HCPs completed the study questionnaire (response rate of 80.3%), identifying 44 herbal and 3 nonherbal nutritional supplements. Safety-related concerns were associated with 29 products, including herb-drug interactions with altered pharmacodynamics (15 herbs), direct toxic effects (18 herbs), and increased in vitro response of cancer cells to chemotherapy (7 herbs). CONCLUSIONS: Herbal medicine use, which is prevalent in Middle Eastern countries, has several potentially negative effects that include direct toxic effects, negative interactions with anticancer drugs, and increased chemosensitivity of cancer cells, requiring a reduction in dose-density. Oncology HCPs working in countries in which herbal medicine use is prevalent need to better understand the implications of this practice. The presence of integrative physicians with training in complementary and traditional medicine can help patients and their HCPs reach an informed decision regarding the safety and effective use of these products. PMID- 26599201 TI - Long-term effects of executive process training in young and old adults. AB - Prior studies have examined the magnitude of training and transfer effects after process-based training in early and late adulthood. However, little is known about how long-lasting these effects are. Here we investigate the degree of stability of training gains and transfer effects in younger and older adults 18 months after completion of executive process training, tapping updating, inhibition, and shifting. From the original sample, 24 out of 30 older participants, and 19 out of 29 young adults, returned for follow-up assessment at which the criterion and transfer tests from pre- and post-test were re administered. The results demonstrated stability of training gains in the updating criterion task (Letter Memory Running Span), and in a near transfer updating task (Number Memory Running Span) for both age groups. The young adults improved performance in two complex working memory tasks immediately after training. These transfer effects did not survive across time. Our results provide evidence that executive process training has its greatest effect on transfer tasks with a substantial process overlap with the trained tasks: only those effects are maintained over an 18 month period in both early and late adulthood. PMID- 26599202 TI - Anatomic Interosseus Membrane Reconstruction Utilizing the Biceps Button and Screw Tenodesis for Essex-Lopresti Injuries. AB - Longitudinal radioulnar dissociation, also known as the Essex-Lopresti lesion, is a potentially debilitating condition causing painful instability of the forearm that often results from high-injury trauma with compromise of the proximal radius, triangular fibrocartilage complex, and the interosseous membrane. Indications for reconstruction of the interosseous membrane primarily include chronic instability of the forearm. Our reconstructive technique utilizes an anatomic allograft reconstruction with intraosseous fixation, in an effort to biologically reconstruct and anatomically tension the central band of the interosseus membrane. PMID- 26599203 TI - Enzymatic Hydrolysis of Polyester Thin Films: Real-Time Analysis of Film Mass Changes and Dissipation Dynamics. AB - Cleavage of ester bonds by extracellular microbial hydrolases is considered a key step during the breakdown of biodegradable polyester materials in natural and engineered systems. Here we present a novel analytical approach for simultaneous detection of changes in the masses and rigidities of polyester thin films during enzymatic hydrolysis using a Quartz Crystal Microbalance with Dissipation monitoring (QCM-D). In experiments with poly(butylene succinate) (PBS) and the lipase of Rhizopus oryzae (RoL), we detected complete hydrolysis of PBS thin films at pH 5 and 40 degrees C that proceeded through soft and water-rich film intermediates. Increasing the temperature from 20 to 40 degrees C resulted in a larger increase of the enzymatic hydrolysis rate of PBS than of nonpolymeric dibutyl adipate. This finding was ascribed to elevated accessibility of ester bonds to the catalytic site of RoL due to increasing polyester chain mobility. When the pH of the solution was changed from 5 to 7, initial hydrolysis rates were little affected, while a softer film intermediate that lead to incomplete film hydrolysis was formed. Hydrolysis dynamics of PBS, poly(butylene adipate), poly(lactic acid), and poly(ethylene terephthalate) in assays with RoL showed distinct differences that we attribute to differences in the polyester structure. PMID- 26599204 TI - Subparaneurial ganglion cysts of the fibular and tibial nerves: A new variant of intraneural ganglion cysts. AB - Over the last decade, the mechanism of formation of intraneural ganglion cysts has been established through a meticulous review of clinical findings and correlation with patterns produced on magnetic resonance imaging (MRI). Pathognomonic imaging patterns distinguish these rare lesions from the more common extraneural variants in almost all cases. In this report, we present a new pattern of cyst occurrence in the subparaneurial compartment of the nerve and provide potential anatomic explanations for its pathogenesis. Using an anatomic framework of connective tissue compartments of the nerve, we reviewed 63 (56 fibular and seven tibial) intraneural ganglion cysts in the knee region evaluated at our institution and all reports with MRI in the world's literature for evidence of cyst occurrence in the subparaneurial compartment. We identified six cases (five in the common fibular nerve and one in the tibial nerve) at our institution that had MR evidence of cyst in the subparaneurial compartment with a new complex lobulated pattern. All cases had articular branch connections to the superior tibiofibular joint, which at operation were resected along with the joints. Follow-up revealed complete recovery in all instances and no clinical or radiological signs of recurrence. Three cases out of 80 in the literature exhibited the new complex lobulated MRI pattern. We present a new pattern of intraneural ganglion cyst occurrence in a potential space that surrounds peripheral nerves--the subparaneurial compartment. We believe that the unifying articular theory applies to the pathogenesis and management of these rare variants. PMID- 26599205 TI - Histological Development of the Immune Tissues of a Marsupial, the Red-Tailed Phascogale (Phascogale calura). AB - Red-tailed phascogale (Phascogale calura) pouch young at birth were relatively underdeveloped in comparison with their eutherian counterparts, and the lymphoid tissues of the immune system were found to be histologically immature. The phascogale thymus rapidly developed in the first few days of pouch life and was quickly populated with lymphocytes. By the end of pouch life, involution of the thymus was underway. The bone marrow started to develop in the early stage of pouch life, although adipocytes and megakaryocytes were not observed until slightly later. The liver was hematopoietic from birth and reached histological maturity toward the end of pouch life. The lymph nodes were difficult to detect macroscopically because of their small size, but were easily identified microscopically later in pouch life, particularly in the mesentery, and these lymph nodes exhibited germinal centers by the end of pouch life. The early spleen was predominately mesenchymal, but exhibited some erythropoiesis. Follicles with well-developed germinal centers were not observed until the latest stage of pouch life. Although intraepithelial lymphocytes were detected in the intestines early in pouch life, the discrete lymphoid aggregates and Peyer's patches characteristic of the gut-associated lymphoid tissue (GALT) were not detected until later in pouch life. This is the first report of histological development in phascogale pouch young, as well as the first report of the thymus, bone marrow, and lymph nodes in this dasyurid species at any age. PMID- 26599206 TI - Ionizing radiation improves glioma-specific targeting of superparamagnetic iron oxide nanoparticles conjugated with cmHsp70.1 monoclonal antibodies (SPION cmHsp70.1). AB - The stress-inducible 72 kDa heat shock protein Hsp70 is known to be expressed on the membrane of highly aggressive tumor cells including high-grade gliomas, but not on the corresponding normal cells. Membrane Hsp70 (mHsp70) is rapidly internalized into tumor cells and thus targeting of mHsp70 might provide a promising strategy for theranostics. Superparamagnetic iron oxide nanoparticles (SPIONs) are contrast negative agents that are used for the detection of tumors with MRI. Herein, we conjugated the Hsp70-specific antibody (cmHsp70.1) which is known to recognize mHsp70 to superparamagnetic iron nanoparticles to assess tumor specific targeting before and after ionizing irradiation. In vitro experiments demonstrated the selectivity of SPION-cmHsp70.1 conjugates to free and mHsp70 in different tumor cell types (C6 glioblastoma, K562 leukemia, HeLa cervix carcinoma) in a dose-dependent manner. High-resolution MRI (11 T) on T(2) weighted images showed the retention of the conjugates in the C6 glioma model. Accumulation of SPION-cmHsp70.1 nanoparticles in the glioma resulted in a nearly 2-fold drop of T*(2) values in comparison to non-conjugated SPIONs. Biodistribution analysis using NLR-M(2) measurements showed a 7-fold increase in the tumor-to-background (normal brain) uptake ratio of SPION-cmHsp70.1 conjugates in glioma-bearing rats in comparison to SPIONs. This accumulation within Hsp70 positive glioma was further enhanced after a single dose (10 Gy) of ionizing radiation. Elevated accumulation of the magnetic conjugates in the tumor due to radiosensitization proves the combination of radiotherapy and application of Hsp70-targeted agents in brain tumors. PMID- 26599208 TI - Inselect: Automating the Digitization of Natural History Collections. AB - The world's natural history collections constitute an enormous evidence base for scientific research on the natural world. To facilitate these studies and improve access to collections, many organisations are embarking on major programmes of digitization. This requires automated approaches to mass-digitization that support rapid imaging of specimens and associated data capture, in order to process the tens of millions of specimens common to most natural history collections. In this paper we present Inselect-a modular, easy-to-use, cross platform suite of open-source software tools that supports the semi-automated processing of specimen images generated by natural history digitization programmes. The software is made up of a Windows, Mac OS X, and Linux desktop application, together with command-line tools that are designed for unattended operation on batches of images. Blending image visualisation algorithms that automatically recognise specimens together with workflows to support post processing tasks such as barcode reading, label transcription and metadata capture, Inselect fills a critical gap to increase the rate of specimen digitization. PMID- 26599207 TI - A Comprehensive Analysis of Common and Rare Variants to Identify Adiposity Loci in Hispanic Americans: The IRAS Family Study (IRASFS). AB - Obesity is growing epidemic affecting 35% of adults in the United States. Previous genome-wide association studies (GWAS) have identified numerous loci associated with obesity. However, the majority of studies have been completed in Caucasians focusing on total body measures of adiposity. Here we report the results from genome-wide and exome chip association studies focusing on total body measures of adiposity including body mass index (BMI), percent body fat (PBF) and measures of fat deposition including waist circumference (WAIST), waist hip ratio (WHR), subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) in Hispanic Americans (nmax = 1263) from the Insulin Resistance Atherosclerosis Family Study (IRASFS). Five SNPs from two novel loci attained genome-wide significance (P<5.00x10-8) in IRASFS. A missense SNP in the isocitrate dehydrogenase 1 gene (IDH1) was associated with WAIST (rs34218846, MAF = 6.8%, PDOM = 1.62x10-8). This protein is postulated to play an important role in fat and cholesterol biosynthesis as demonstrated in cell and knock-out animal models. Four correlated intronic SNPs in the Zinc finger, GRF-type containing 1 gene (ZGRF1; SNP rs1471880, MAF = 48.1%, PDOM = 1.00x10-8) were strongly associated with WHR. The exact biological function of ZGRF1 and the connection with adiposity remains unclear. SNPs with p-values less than 5.00x10-6 from IRASFS were selected for replication. Meta-analysis was computed across seven independent Hispanic-American cohorts (nmax = 4156) and the strongest signal was rs1471880 (PDOM = 8.38x10-6) in ZGRF1 with WAIST. In conclusion, a genome-wide and exome chip association study was conducted that identified two novel loci (IDH1 and ZGRF1) associated with adiposity. While replication efforts were inconclusive, when taken together with the known biology, IDH1 and ZGRF1 warrant further evaluation. PMID- 26599209 TI - IL4I1 Is a Novel Regulator of M2 Macrophage Polarization That Can Inhibit T Cell Activation via L-Tryptophan and Arginine Depletion and IL-10 Production. AB - Interleukin 4-induced gene-1 (IL4I1) was initially described as an early IL-4 inducible gene in B cells. IL4I1 protein can inhibit T cell proliferation by releasing its enzymatic catabolite, H2O2, and this effect is associated with transient down-regulation of T cell CD3 receptor-zeta (TCRzeta) expression. Herein, we show that IL4I1 contributes to the regulation of macrophage programming. We found that expression of IL4I1 increased during bone marrow derived macrophage (BMDM) differentiation, expression of IL4I1 is much higher in primary macrophages than monocytes, and IL4I1 expression in BMDMs could be induced by Th1 and Th2 cytokines in two different patterns. Gene expression analysis revealed that overexpression of IL4I1 drove the expression of M2 markers (Fizz1, Arg1, YM-1, MR) and inhibited the expression of M1-associated cytokines. Conversely, knockdown of IL4I1 by siRNA resulted in opposite effects, and also attenuated STAT-3 and STAT-6 phosphorylation. Furthermore, IL4I1 produced by macrophages catalyzed L-tryptophan degradation, while levo-1-methyl-tryptophan (L 1-MT), but not dextro-1-methyl-tryptophan, partially rescued IL4I1-dependent inhibition of T cell activation. Other inhibitors, such as diphenylene iodonium (DPI), an anti-IL-10Ralpha blocking antibody, and a nitric oxide synthase inhibitor, NG-monomethyl-L-arginine, also had this effect. Overall, our findings indicate that IL4I1 promotes an enhanced M2 functional phenotype, which is most likely associated with the phosphorylation of STAT-6 and STAT-3. Moreover, DPI, L 1-MT, NG-monomethyl-L-arginine, and anti-IL-10Ralpha blocking antibody were all found to be effective IL4I1 inhibitors in vitro. PMID- 26599210 TI - Wiring microbial biofilms to the electrode by osmium redox polymer for the performance enhancement of microbial fuel cells. AB - An osmium redox polymer, PAA-PVI-[Os(4,4'-dimethyl-2,2'-bipyridine)2Cl]+/2+ that has been used in enzymatic fuel cells and microbial sensors, was applied for the first time to the anode of single-chamber microbial fuel cells with the mixed culture inoculum aiming at enhancing performance. Functioning as a molecular wire connecting the biofilm to the anode, power density increased from 1479 mW m(-2) without modification to 2355 mW m(-2) after modification of the anode. Evidence from cyclic voltammetry showed that the catalytic activity of an anodic biofilm was greatly enhanced in the presence of an osmium redox polymer, indicating that electrons were more efficiently transferred to the anode via co-immobilized osmium complex tethered to wiring polymer chains at the potential range of -0.3 V +0.1 V (vs. SCE). The optimum amount of the redox polymer was determined to be 0.163 mg cm(-2). PMID- 26599211 TI - Characterization and Comparison of Clavibacter michiganensis subsp. nebraskensis Strains Recovered from Epiphytic and Symptomatic Infections of Maize in Iowa. AB - Clavibacter michiganensis subsp. nebraskensis (Cmn), the causal organism of Goss's wilt and leaf blight of maize, can be detected in the phyllosphere of its host prior to disease development. We compared the morphology and pathogenicity of 37 putative isolates of Cmn recovered from asymptomatic and symptomatic maize leaves. Thirty-three of the isolates produced mucoid orange colonies, irrespective of the source of isolation and all but four of these isolates were pathogenic on maize. The remaining 4 isolates recovered from asymptomatic leaves had large fluidal yellow colonies, and were non-pathogenic on maize. Isolates varied in their aggressiveness on a susceptible hybrid of maize but no significant differences in aggressiveness were detected between epiphytic isolates and those recovered from diseased maize tissues. The genomics of Cmn is poorly understood; therefore as a first step to determining what genes may play a role in virulence, we compared 33 putative virulence gene sequences from 6 pathogenic and a non-pathogenic isolate recovered from the phyllosphere. Sequence polymorphisms were detected in 5 genes, cellulase A, two endoglucanases, xylanase B and a pectate lyase but there was no relationship with pathogenicity. Further research is needed to determine what genes play a role in virulence of Cmn. Our data show however, that the virulence factors in Cmn likely differ from those reported for the closely related subspecies michiganensis and sepedonicus. PMID- 26599212 TI - Interventions for the management of external root resorption. AB - BACKGROUND: External root resorption is a pathological process, which tends to occur following a wide range of mechanical or chemical stimuli such as infection, pressure, trauma or orthodontic tooth movement. Although it is predominantly detected by radiography, in some cases root resorption may be identified by clinical symptoms such as pain, swelling and mobility of the tooth. Treatment alternatives are case-dependent and aim to address the cause of the resorption and aid the regeneration of the resorptive lesion. OBJECTIVES: To evaluate the effectiveness of any interventions that can be used in the management of external root resorption in permanent teeth. SEARCH METHODS: The following electronic databases were searched: the Cochrane Oral Health Group Trials Register (to 14 October 2015), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2015, Issue 9), MEDLINE via OVID (1946 to 14 October 2015) and EMBASE via OVID (1980 to 14 October 2015). We searched the US National Institutes of Health Trials Register (http://clinicaltrials.gov) and the WHO Clinical Trials Registry Platform for ongoing trials. No restrictions were placed on the language or date of publication when searching the electronic databases. SELECTION CRITERIA: We included randomised controlled trials of permanent teeth with any type of external root resorption, which has been confirmed by clinical and radiological examination, comparing one type of intervention (root canal medications and canal filling, splinting or extraction of teeth or the surgical removal of any relevant pathology) with another, or with placebo or no treatment. DATA COLLECTION AND ANALYSIS: Two review authors screened search records independently. Full papers were obtained for potentially relevant trials. If data had been extracted, the statistical guidelines set out in the Cochrane Handbook would have been followed. MAIN RESULTS: No randomised controlled trials that met the inclusion criteria were identified. However, we identified one ongoing study that is potentially relevant to this review and will be assessed when it is published. AUTHORS' CONCLUSIONS: We were unable to identify any reports of randomised controlled trials regarding the efficacy of different interventions for the management of external root resorption. In view of the lack of reliable evidence on this topic, clinicians must decide on the most appropriate means of managing this condition according to their clinical experience with regard to patient-related factors. There is a need for well designed and conducted clinical trials on this topic, which conform to the CONSORT statement (www.consort statement.org/). PMID- 26599213 TI - Red Queen Processes Drive Positive Selection on Major Histocompatibility Complex (MHC) Genes. AB - Major Histocompatibility Complex (MHC) genes code for proteins involved in the incitation of the adaptive immune response in vertebrates, which is achieved through binding oligopeptides (antigens) of pathogenic origin. Across vertebrate species, substitutions of amino acids at sites responsible for the specificity of antigen binding (ABS) are positively selected. This is attributed to pathogen driven balancing selection, which is also thought to maintain the high polymorphism of MHC genes, and to cause the sharing of allelic lineages between species. However, the nature of this selection remains controversial. We used individual-based computer simulations to investigate the roles of two phenomena capable of maintaining MHC polymorphism: heterozygote advantage and host-pathogen arms race (Red Queen process). Our simulations revealed that levels of MHC polymorphism were high and driven mostly by the Red Queen process at a high pathogen mutation rate, but were low and driven mostly by heterozygote advantage when the pathogen mutation rate was low. We found that novel mutations at ABSs are strongly favored by the Red Queen process, but not by heterozygote advantage, regardless of the pathogen mutation rate. However, while the strong advantage of novel alleles increased the allele turnover rate, under a high pathogen mutation rate, allelic lineages persisted for a comparable length of time under Red Queen and under heterozygote advantage. Thus, when pathogens evolve quickly, the Red Queen is capable of explaining both positive selection and long coalescence times, but the tension between the novel allele advantage and persistence of alleles deserves further investigation. PMID- 26599214 TI - Oroxin A inhibits breast cancer cell growth by inducing robust endoplasmic reticulum stress and senescence. AB - Breast cancer is a major cause of cancer death among women. Although various anticancer drugs have been used in clinics, drugs that are effective against advanced and metastatic breast cancer are still lacking and in great demand. In this study, we found that oroxin A, an active component isolated from the herb Oroxylum indicum (L.) Kurz, effectively inhibited the growth of human breast cancer cells MDA-MB-231 and MCF7 by inducing endoplasmic reticulum (ER) stress mediated senescence. Oroxin A caused breast cancer cell cycle arrest at the G2/M stage, and reorganization of microtubules and actin cytoskeleton accompanied by a decrease in cellular mitosis. ER-specific probe ER-Tracker Red and confocal microscope imaging showed that ER-Tracker Red-positive cells increased in an oroxin A dosage-dependent manner. In addition, oroxin A increased cell population with high beta-Gal activity and SAHF-positive staining; these data suggest that oroxin A induces breast cancer cell ER stress and senescence. Mechanistic studies showed that oroxin A led to a significant increase in intracellular reactive oxygen species levels, promoted expression of ER stress markers ATF4 and GRP78, and increased the phosphorylation of a key stress-response signaling protein p38, resulting in an ER stress-mediated senescence. Taken together, our data indicate that oroxin A exerts its antibreast cancer effects by inducing ER stress-mediated senescence, activating the key stress p38 signaling pathway, and increasing key ER stress genes ATF4 and GRP78 expression levels. PMID- 26599215 TI - Colloidal Lock-and-Key Dimerization Reactions of Hard Annular Sector Particles Controlled by Osmotic Pressure. AB - Colloidal annular sectors are a broad class of shapes that offer the interesting possibility of dimerization when osmotically compressed to high densities while undergoing Brownian motion in two dimensions (2D). Here, we lithographically create and form a stable aqueous dispersion of many microscale prismatic 270 degrees annular sectors, and we explore their near-equilibrium behavior in a tilted 2D gravitational column. Near the top of the column where the 2D gravitational osmotic pressure Pi(2D) is low, we observe a gas-like phase composed almost entirely of monomers. However, below the surface and deeper into the column where Pi(2D) is higher, we observe a reaction zone where monomers and dimers coexist, followed by an arrested region containing a very high percentage of interpenetrating, lock-and-key dimers that are a racemic mixture of positive and negative chiralities. We determine particle area fractions of monomers and dimers as a function of depth and use these to obtain the system's 2D osmotic equation of state. In the reaction zone, where dimers transiently form and break up, we also use these to calculate the equilibrium constant K associated with the monomer-dimer reaction, which increases exponentially with Pi(2D). This dependence can be attributed the reduction in number of accessible microstates for dimers as they become more tightly compressed. PMID- 26599216 TI - The Different Association between Serum Ferritin and Mortality in Hemodialysis and Peritoneal Dialysis Patients Using Japanese Nationwide Dialysis Registry. AB - BACKGROUND/AIMS: Monitoring of serum ferritin levels is widely recommended in the management of anemia among patients on dialysis. However, associations between serum ferritin and mortality are unclear and there have been no investigations among patients undergoing peritoneal dialysis (PD). METHODS: Baseline data of 191,902 patients on dialysis (age, 65 +/- 13 years; male, 61.1%; median dialysis duration, 62 months) were extracted from a nationwide dialysis registry in Japan at the end of 2007. Outcomes, such as one-year mortality, were then evaluated using the registry at the end of 2008. RESULTS: Within one year, a total of 15,284 (8.0%) patients had died, including 6,210 (3.2%) cardiovascular and 2,707 (1.4%) infection-related causes. Higher baseline serum ferritin levels were associated with higher mortality rates among patients undergoing hemodialysis (HD). In contrast, there were no clear associations between serum ferritin levels and mortality among PD patients. Multivariate Cox regression analysis of HD patients showed that those in the highest serum ferritin decile group had higher rates of all-cause and cardiovascular mortality than those in the lowest decile group (hazard ratio [HR], 1.54; 95% confidence interval [CI], 1.31-1.81 and HR, 1.44; 95% CI, 1.13-1.84, respectively), whereas associations with infection related mortality became non-significant (HR, 1.14; 95% CI, 0.79-1.65). CONCLUSIONS: Using Japanese nationwide dialysis registry, higher serum ferritin values were associated with mortality not in PD patients but in HD patients. PMID- 26599218 TI - Advantage of multiple spot urine collections for estimating daily sodium excretion: comparison with two 24-h urine collections as reference. AB - OBJECTIVE: Several estimation methods for 24-h sodium excretion using spot urine sample have been reported, but accurate estimation at the individual level remains difficult. We aimed to clarify the most accurate method of estimating 24 h sodium excretion with different numbers of available spot urine samples. METHODS: A total of 370 participants from throughout Japan collected multiple 24 h urine and spot urine samples independently. Participants were allocated randomly into a development and a validation dataset. Two estimation methods were established in the development dataset using the two 24-h sodium excretion samples as reference: the 'simple mean method' estimated by multiplying the sodium-creatinine ratio by predicted 24-h creatinine excretion, whereas the 'regression method' employed linear regression analysis. The accuracy of the two methods was examined by comparing the estimated means and concordance correlation coefficients (CCC) in the validation dataset. RESULTS: Mean sodium excretion by the simple mean method with three spot urine samples was closest to that by 24-h collection (difference: -1.62 mmol/day). CCC with the simple mean method increased with an increased number of spot urine samples at 0.20, 0.31, and 0.42 using one, two, and three samples, respectively. This method with three spot urine samples yielded higher CCC than the regression method (0.40). When only one spot urine sample was available for each study participant, CCC was higher with the regression method (0.36). CONCLUSION: The simple mean method with three spot urine samples yielded the most accurate estimates of sodium excretion. When only one spot urine sample was available, the regression method was preferable. PMID- 26599217 TI - Positive Allosteric Modulation of Kv Channels by Sevoflurane: Insights into the Structural Basis of Inhaled Anesthetic Action. AB - Inhalational general anesthesia results from the poorly understood interactions of haloethers with multiple protein targets, which prominently includes ion channels in the nervous system. Previously, we reported that the commonly used inhaled anesthetic sevoflurane potentiates the activity of voltage-gated K+ (Kv) channels, specifically, several mammalian Kv1 channels and the Drosophila K-Shaw2 channel. Also, previous work suggested that the S4-S5 linker of K-Shaw2 plays a role in the inhibition of this Kv channel by n-alcohols and inhaled anesthetics. Here, we hypothesized that the S4-S5 linker is also a determinant of the potentiation of Kv1.2 and K-Shaw2 by sevoflurane. Following functional expression of these Kv channels in Xenopus oocytes, we found that converse mutations in Kv1.2 (G329T) and K-Shaw2 (T330G) dramatically enhance and inhibit the potentiation of the corresponding conductances by sevoflurane, respectively. Additionally, Kv1.2-G329T impairs voltage-dependent gating, which suggests that Kv1.2 modulation by sevoflurane is tied to gating in a state-dependent manner. Toward creating a minimal Kv1.2 structural model displaying the putative sevoflurane binding sites, we also found that the positive modulations of Kv1.2 and Kv1.2-G329T by sevoflurane and other general anesthetics are T1-independent. In contrast, the positive sevoflurane modulation of K-Shaw2 is T1-dependent. In silico docking and molecular dynamics-based free-energy calculations suggest that sevoflurane occupies distinct sites near the S4-S5 linker, the pore domain and around the external selectivity filter. We conclude that the positive allosteric modulation of the Kv channels by sevoflurane involves separable processes and multiple sites within regions intimately involved in channel gating. PMID- 26599219 TI - Microvascular effects of the inhibition of dipeptidylpeptidase IV by linagliptin in nondiabetic hypertensive patients. AB - BACKGROUND: Recent studies suggest vascular benefits of dipeptidylpeptidase IV (DPP-IV) inhibition in patients with diabetes mellitus. Only little is known about potential vascular effects of DPP-IV inhibitors in nondiabetic individuals. The aim of this study was to investigate the effect of DPP-IV inhibition in a nondiabetic hypertensive population. METHOD: This was a double-blinded, randomized, placebo-controlled, mechanistic study, comparing microvascular effects of the DPP-IV inhibitor linagliptin with placebo in nondiabetic individuals with a history of arterial hypertension. Twenty-one patients received 5 mg linagliptin (5 women; age 67.6 +/- 6.0 years; mean +/- SD), whereas 22 patients were randomized to placebo (5 women; age 64.8 +/- 7.1 years). RESULTS: At baseline, after 6 and 12 weeks, retinal microcirculation and arterial blood pressure profiles were assessed. Moreover, blood samples were taken for the measurement of HbA1c, asymmetric dimethylarginine, C-reactive peptide, cyclic guanosinmonophosphate, transforming growth factor beta (TGF-beta1) and cystatin C. Retinal capillary perfusion increased by 23.7 +/- 10.3% (mean +/- SEM; P < 0.05), retinal arterial flow by 7.6 +/- 0.6 (P < 0.05) and the retinal hyperemic response by 290 +/- 263% (P < 0.05) during treatment with linagliptin. No change in retinal blood flow was found in the placebo group. Although blood pressure declined in both groups, a significant decline in TGF-beta1 by 9.3 +/- 4.5% (P < 0.05) could only be observed in the linagliptin group. No significant change in other laboratory parameters could be observed in both groups. CONCLUSION: Our study suggests microvascular and antifibrotic effects of linagliptin in a nondiabetic, hypertensive population. PMID- 26599221 TI - Orthostatic hypotension and drug therapy in patients at an outpatient comprehensive geriatric assessment unit. AB - OBJECTIVE: To assess the rate of orthostatic hypotension and factors associated with it among elderly patients who underwent a comprehensive, ambulatory geriatric assessment. METHODS: The study included patients 65 years and older who were assessed in the outpatient comprehensive geriatric assessment unit. Data were collected from the computerized medical record including sociodemographic data, lifestyle, falls, blood pressure, BMI, functional and cognitive status, medications, and comorbidity. RESULTS: The study population consisted of 571 patients who underwent assessment over a nine-year period. The mean age was 83.7 +/- 6.1, 35.9% were men, and 183 (32.1%) were diagnosed with orthostatic hypotension. Multiple drugs, in general, and multiple drugs with the potential to cause orthostatic hypotension in particular increased the risk for orthostatic hypotension after adjustment for age, sex, chronic comorbidity, and supine systolic blood pressure >=150 mmHg [odds ratio (OR) = 1.09, 95% confidence interval (CI): 1.03-1.14 and OR = 1.22, 95% CI: 1.08-1.37, respectively]. In addition, alpha-blockers and calcium channel blockers increased the risk for orthostatic hypotension after similar adjustments (OR = 1.82, 95% CI: 1.01-3.16 and OR = 1.66, 95% CI: 1.11-2.48, respectively). Similarly, two additional drug types increased the risk for orthostatic hypotension: selective serotonin reuptake inhibitors (OR = 2.09, 95% CI: 1.33-3.19) and tricyclic antidepressants (OR = 4.36, 95% CI: 1.85-10.06). There were no specific associations between age, cognitive and functional state, morbidity (as measured by the Charlson Comorbidity Index), and specific diseases, and orthostatic hypotension. CONCLUSION: The results of the present study reinforce evidence of an association between drug therapy and orthostatic hypotension. PMID- 26599220 TI - Visit-to-visit variability of blood pressure and death, end-stage renal disease, and cardiovascular events in patients with chronic kidney disease. AB - OBJECTIVES: Visit-to-visit variability of blood pressure (VVV of BP) is an important independent risk factor for premature death and cardiovascular events, but relatively little is known about this phenomenon in patients with chronic kidney disease (CKD) not yet on dialysis. METHODS: We conducted a retrospective study in a community-based cohort of 114 900 adults with CKD stages 3-4 (estimated glomerular filtration rate 15-59 ml/min per 1.73 m). We hypothesized that VVV of BP would be independently associated with higher risks of death, incident treated end-stage renal disease, and cardiovascular events. We defined systolic VVV of BP using three metrics: coefficient of variation, standard deviation of the mean SBP, and average real variability. RESULTS: The highest versus the lowest quintile of the coefficient of variation was associated with higher adjusted rates of death (hazard ratio 1.22; 95% confidence interval 1.11 1.34) and hemorrhagic stroke (hazard ratio 1.91; confidence interval 1.36-2.68). VVV of BP was inconsistently associated with heart failure, and was not significantly associated with acute coronary syndrome and ischemic stroke. Results were similar when using the other two metrics of VVV of BP. VVV of BP had inconsistent associations with end-stage renal disease, perhaps because of the relatively low incidences of this outcome. CONCLUSION: Higher VVV of BP is independently associated with higher rates of death and hemorrhagic stroke in patients with moderate to advanced CKD not yet on dialysis. PMID- 26599222 TI - Effects of potassium supplementation on markers of osmoregulation and volume regulation: results of a fully controlled dietary intervention study. AB - OBJECTIVE: Lifestyle measures including dietary sodium restriction and increased potassium intake are recognized to lower blood pressure (BP). Potassium was found to be effective in reducing BP at higher levels of sodium intake, but to have little effect when sodium intake is restricted. The humoral mechanisms underlying these sodium intake dependent effects of potassium are unknown. We investigated the effects of potassium supplementation on top of a fully controlled sodium restricted diet on markers of osmoregulation and volume regulation. METHODS: In this post-hoc analysis, we included 35 (pre)hypertensive individuals participating in a randomized, double-blind, placebo-controlled crossover trial. Individuals received capsules containing sodium [3.0 g (130 mmol)/day], potassium [2.8 g (72 mmol)/day], or placebo for three four-week periods. Linear mixed effect models were used to estimate the effects of potassium supplementation compared with placebo. Skewed data were ln-transformed before analysis. RESULTS: Increased potassium intake was associated with a significant decrease in 24-h BP (-3.6/-1.6 mmHg). Furthermore, we found a significant decrease in ln MR-proANP [ 0.08 (95% confidence interval -0.15, -0.01) pmol/l, P = 0.03] and significant increases in 24-h heart rate [2.5 (0.9, 4.0) bpm, P = 0.002], ln plasma copeptin [0.11 (0.01, 0.20) pmol/l, P = 0.02], ln renin [0.34 (0.08, 0.60) MUIU/ml, P = 0.01], and ln aldosterone [0.14 (0.07, 0.22) nmol/l, P < 0.001] compared with placebo. CONCLUSIONS: We found that potassium has BP-lowering effects during sodium restriction. These BP-lowering effects, however, seem mitigated by several counter regulatory mechanisms (i.e. increased secretion of vasopressin, stimulation of RAAS, and increased heart rate) that were activated to maintain volume homeostasis and counterbalance the decrease in BP. PMID- 26599224 TI - Blood pressure in children and adolescents: current insights. AB - The available data concerning childhood blood pressure (BP) have increased substantially over the last four decades. Clinicians can use the available pediatric reference BP data to determine whether BP is in the normal range or is at a level that warrants evaluation or preventive intervention. It has also become possible to refine BP-derived parameters and to identify subclinical end organ damage through measures and markers now far more sensitive than those available years ago. The progress to date should provide an impetus for research advances that may translate into clinical practice. Findings that are becoming ready to incorporate into clinical use include data showing the importance of detecting prehypertension or high-normal BP, the meaning of BP obtained out of the clinic setting and the importance of central BP determinations. Furthermore, new information about large and small vessels during the early stages of BP elevation, the clustering of metabolic abnormalities with BP and the relevance of perinatal programming may lead to better strategies for reducing the impact of BP elevation on cardiovascular health. PMID- 26599223 TI - Endogenous endothelin-1 and femoral artery shear rate: impact of age and implications for atherosclerosis. AB - BACKGROUND: Both altered shear rate and endothelin-1 (ET-1) are associated with the age-related development of atherosclerosis. However, the role of ET-1, a potent endogenous vasoconstrictor, in altering shear rate in humans, especially in the atherosclerotic-prone vasculature of the leg, is unknown. Therefore, this study examined the contribution of ET-1 to the age-related alterations in common femoral artery (CFA) shear rate. METHOD: BQ-123, a specific endothelin type A (ET(A)) receptor antagonist, was infused into the CFA, and diameter and blood velocity were measured by Doppler ultrasound in young (n = 8, 24 +/- 2 years) and old (n = 9, 70 +/- 2 years) study participants. RESULTS AND CONCLUSION: The old had greater intima-media thickening in the CFA, indicative of a preatherogenic phenotype. Prior to infusion, the old study participants exhibited reduced mean shear rate (27 +/- 3/s) compared with the young study participants (62 +/- 9/s). This difference was likely driven by attenuated antegrade shear rate in the old as retrograde shear rate was similar in the young and old. Inhibition of ETA receptors, by BQ-123, increased leg blood flow in the old, but not in the young, abolishing age-related differences. Older study participants had a larger CFA (young: 0.82 +/- 0.03 cm, old: 0.99 +/- 0.03 cm) in which BQ-123 induced significant vasodilation (5.1 +/- 1.0%), but had no such effect in the young ( 0.8 +/- 0.8%). Interestingly, despite the age-specific, BQ-123-induced increase in leg blood flow and CFA diameter, shear rate patterns remained largely unchanged. Therefore, ET-1, acting through the ETA receptors, exerts a powerful age-specific vasoconstriction. However, removal of this vasoconstrictor stimulus does not augment mean shear rate in the old. PMID- 26599225 TI - Silent brain infarcts in high blood pressure patients with cardiac implantable electronic devices: unmasking silent atrial fibrillation. AB - BACKGROUND: Hypertensive patients present a higher risk for developing atrial fibrillation and its complications. Cardiac implantable electronic devices (CIEDs) have shown reliable atrial fibrillation detection as atrial high-rate episodes (AHREs). The presence of AHRE more than 5 min has been related to increased risk of stroke, but a high proportion of ischemic brain lesions (IBLs) could be subclinical and thromboembolic risk underestimated. METHODS: We included hypertensive patients with CIED and we analyzed the incidence of AHRE and the presence of IBL on computed tomography (CT) scan. RESULTS: One hundred and twenty three patients (57% men) aged 77 +/- 8 years were evaluated during a mean follow up of 15 +/- 9 months. AHREs were documented in 46 patients (37%). Cranial CT scan showed silent IBL in 34 patients (27%). Univariate analysis showed that age, CHADS2 and CHADS2VA2Sc scores, history of prior stroke/ transient ischemic attack and the presence of AHRE were significantly related to higher risk for IBL on CT scan (P < 0.05). Multivariate analysis showed that the presence of AHRE more than 5 min [odds ratio 3.05 (1.19-7.81; P < 0.05)] was an independent predictor of IBL. CONCLUSION: Silent atrial fibrillation detected by CIED as AHRE is really prevalent in hypertensive patients. AHREs were independently associated with a higher incidence of silent IBL on CT scan. PMID- 26599226 TI - From risk factors to treatment of hypertension. PMID- 26599227 TI - Spleen Volume Variation in Patients with Locally Advanced Non-Small Cell Lung Cancer Receiving Platinum-Based Chemo-Radiotherapy. AB - There is renewed interest in the immune regulatory role of the spleen in oncology. To date, very few studies have examined macroscopic variations of splenic volume in the setting of cancer, prior to or during therapy, especially in humans. Changes in splenic volume may be associated with changes in splenic function. The purpose of this study was to investigate variations in spleen volume in NSCLC patients during chemo-radiotherapy. Sixty patients with stage I IIIB NSCLC underwent radiotherapy (60 Gy/30 fractions) for six weeks with concomitant carboplatin/paclitaxel (Ca/P; n = 32) or cisplatin/etoposide (Ci/E; n = 28). A baseline PET/CT scan was performed within 2 weeks prior to treatment and during Weeks 2 and 4 of chemo-radiotherapy. Spleen volume was measured by contouring all CT slices. Significant macroscopic changes in splenic volume occurred early after the commencement of treatment. A significant decrease in spleen volume was observed for 66% of Ca/P and 79% of Ci/E patients between baseline and Week 2. Spleen volume was decreased by 14.2% for Ca/P (p<0.001) and 19.3% for Ci/E (p<0.001) patients. By Week 4, spleen volume was still significantly decreased for Ca/P patients compared to baseline, while for Ci/E patients, spleen volume returned to above baseline levels. This is the first report demonstrating macroscopic changes in the spleen in NSCLC patients undergoing radical chemo-radiotherapy that can be visualized by non-invasive imaging. PMID- 26599228 TI - Towards Clinical Applications of Blood-Borne miRNA Signatures: The Influence of the Anticoagulant EDTA on miRNA Abundance. AB - BACKGROUND: Circulating microRNAs (miRNAs) from blood are increasingly recognized as biomarker candidates for human diseases. Clinical routine settings frequently include blood sampling in tubes with EDTA as anticoagulant without considering the influence of phlebotomy on the overall miRNA expression pattern. We collected blood samples from six healthy individuals each in an EDTA blood collection tube. Subsequently, the blood was transferred into PAXgeneTM tubes at three different time points, i.e. directly (0 min), 10 min, and 2 h after phlebotomy. As control blood was also directly collected in PAXgeneTM blood RNA tubes that contain a reagent to directly lyse blood cells and stabilize their content. For all six blood donors at the four conditions (24 samples) we analyzed the abundance of 1,205 miRNAs by human Agilent miRNA V16 microarrays. RESULTS: While we found generally a homogenous pattern of the miRNA abundance in all 24 samples, the duration of the EDTA treatment appears to influence the miRNA abundance of specific miRNAs. The most significant changes are observed after longer EDTA exposition. Overall, the impact of the different blood sample conditions on the miRNA pattern was substantially lower than intra-individual variations. While samples belonging to one of the six individuals mostly cluster together, there was no comparable clustering for any of the four tested blood sampling conditions. The most affected miRNA was miR-769-3p that was not detected in any of the six PAXgene blood samples, but in all EDTA 2h samples. Accordingly, hsa miR-769-3p was also the only miRNA that showed a significantly different abundance between the 4 blood sample conditions by an ANOVA analysis (Benjamini Hochberg adjusted p-value of 0.003). Validation by qRT-PCR confirmed this finding. CONCLUSION: The pattern of blood-borne miRNA abundance is rather homogenous between the four tested blood sample conditions of six blood donors. There was a clustering between the miRNA profiles that belong to a specific blood donor, but not between any of the four tested blood sampling conditions. The results show a limited overall impact of the blood sampling conditions on the miRNA pattern. Notwithstanding, the abundance of single miRNAs can be significantly altered by different blood sampling conditions. PMID- 26599229 TI - Identification of novel putative adipomyokines by a cross-species annotation of secretomes and expression profiles. AB - Adipose tissue and skeletal muscle are organs that respond strongly to obesity and physical activity exhibiting high secretory activity. To identify novel putative adipomyokines, comparative expression studies of skeletal muscle and adipose tissue of lean (C57BL/6J) and obese (C57BL/6J on a high-fat diet and NZO) mice, of sedentary and endurance trained C57BL/6J mice and of cattle characterized by different amounts of intramuscular fat were combined with human secretome data and scored. In highly regulated transcripts, we identified 119 myokines, 79 adipokines and 22 adipomyokines. Network analysis of these candidates revealed remodelling of extracellular matrix and tissue fibrosis as relevant functions of several of these candidates. Given the pathophysiogical relevance of fibrosis for adipose-muscle-cross-talk in obesity and type 2 diabetes and its physiological role in exercise adaptation and meat quality of farm animals, they represent interesting candidates for further investigations in different research areas and species. PMID- 26599231 TI - Aboveground vs. Belowground Carbon Stocks in African Tropical Lowland Rainforest: Drivers and Implications. AB - BACKGROUND: African tropical rainforests are one of the most important hotspots to look for changes in the upcoming decades when it comes to C storage and release. The focus of studying C dynamics in these systems lies traditionally on living aboveground biomass. Belowground soil organic carbon stocks have received little attention and estimates of the size, controls and distribution of soil organic carbon stocks are highly uncertain. In our study on lowland rainforest in the central Congo basin, we combine both an assessment of the aboveground C stock with an assessment of the belowground C stock and analyze the latter in terms of functional pools and controlling factors. PRINCIPAL FINDINGS: Our study shows that despite similar vegetation, soil and climatic conditions, soil organic carbon stocks in an area with greater tree height (= larger aboveground carbon stock) were only half compared to an area with lower tree height (= smaller aboveground carbon stock). This suggests that substantial variability in the aboveground vs. belowground C allocation strategy and/or C turnover in two similar tropical forest systems can lead to significant differences in total soil organic C content and C fractions with important consequences for the assessment of the total C stock of the system. CONCLUSIONS/SIGNIFICANCE: We suggest nutrient limitation, especially potassium, as the driver for aboveground versus belowground C allocation. However, other drivers such as C turnover, tree functional traits or demographic considerations cannot be excluded. We argue that large and unaccounted variability in C stocks is to be expected in African tropical rain-forests. Currently, these differences in aboveground and belowground C stocks are not adequately verified and implemented mechanistically into Earth System Models. This will, hence, introduce additional uncertainty to models and predictions of the response of C storage of the Congo basin forest to climate change and its contribution to the terrestrial C budget. PMID- 26599230 TI - The Functional SNPs in the 5' Regulatory Region of the Porcine PPARD Gene Have Significant Association with Fat Deposition Traits. AB - Peroxisome proliferator-activated receptor delta (PPARD) is a key regulator of lipid metabolism, insulin sensitivity, cell proliferation and differentiation. In this study, we identified two Single Nucleotide Polymorphisms (SNPs, g.1015 A>G and g.1018 T>C) constituting four haplotypes (GT, GC, AC and AT) in the 5' regulatory region of porcine PPARD gene. Functional analysis of the four haplotypes showed that the transcriptional activity of the PPARD promoter fragment carrying haplotype AC was significantly lower than that of the other haplotypes in 3T3-L1, C2C12 and PK-15 cells, and haplotype AC had the lowest binding capacities to the nuclear extracts. Transcription factor 7-like 2 (TCF7L2) enhanced the transcription activities of promoter fragments of PPARD gene carrying haplotypes GT, GC and AT in C2C12 and 3T3-L1 cells, and increased the protein expression of PPARD gene in C2C12 myoblasts. TCF7L2 differentially bound to the four haplotypes, and the binding capacity of TCF7L2 to haplotype AC was the lowest. There were significant associations between -655A/G and fat deposition traits in three pig populations including the Large White * Meishan F2 pigs, France and American Large White pigs. Pigs with genotype GG had significantly higher expression of PPARD at both mRNA and protein level than those with genotype AG. These results strongly suggested that the SNPs in 5' regulatory region of PPARD genes had significant impact on pig fat deposition traits. PMID- 26599232 TI - Effectiveness of a Multimodal Therapy for Patients with Chronic Low Back Pain Regarding Pre-Admission Healthcare Utilization. AB - OBJECTIVE: The aim of the study was to examine the effectiveness of an intensive inpatient three-week multimodal therapy. We focused especially on the impact on the multimodal therapy outcome of the pre-admission number of treatment types patients had received and of medical specialist groups patients had consulted. METHODS: 155 patients with chronic low back pain and indication for multimodal therapy were evaluated with respect to pain intensity, depression, anxiety, well being, and pre-admission health care utilization. In our controlled clinical trial we compared N = 66 patients on the waiting list with N = 89 patients who received immediate treatment. The waiting list patients likewise attended multimodal therapy after the waiting period. Longitudinal post-treatment data for both were collected at three- and twelve-month follow-ups. The impact of pre admission health care utilization on multimodal therapy outcome (post) was analysed by structural equation model. RESULTS: Compared to the control group, multimodal therapy patients' pain intensity and psychological variables were significantly reduced. Longitudinal effects with respect to pre-measures were significant at three-month follow-up for pain intensity (ES = -0.48), well-being (ES = 0.78), anxiety (ES = -0.33), and depression (ES = -0.30). Effect sizes at twelve-month follow-up were small for anxiety (ES = -0.22), and moderate for general well-being (ES = 0.61). Structural equation model revealed that a higher number of pre-admission treatment types was associated with poorer post-treatment outcomes in pain intensity, well-being, and depression. CONCLUSION: Multimodal therapy proved to be effective with regard to improvements in pain intensity, depression, anxiety, and well-being. The association between treatment effect and number of pre-admission pain treatment types suggests that patients would benefit more from attending multimodal therapy in an earlier stage of health care. PMID- 26599233 TI - Expression and Localization of Lung Surfactant Proteins in Human Testis. AB - BACKGROUND: Surfactant proteins (SPs) have been described in various tissues and fluids including tissues of the nasolacrimal apparatus, airways and digestive tract. Human testis have a glandular function as a part of the reproductive and the endocrine system, but no data are available on SPs in human testis and prostate under healthy and pathologic conditions. OBJECTIVE: The aim of the study was the detection and characterization of the surfactant proteins A, B, C and D (SP-A, SP-B, SP-C, SP-D) in human testis. Additionally tissue samples affected by testicular cancer were investigated. RESULTS: Surfactant proteins A, B, C and D were detected using RT-PCR in healthy testis. By means of Western blot analysis, these SPs were detected at the protein level in normal testis, seminoma and seminal fluid, but not in spermatozoa. Expression of SPs was weaker in seminoma compared to normal testicular tissue. SPs were localized in combination with vimentin immunohistochemically in cells of Sertoli and Leydig. CONCLUSION: Surfactant proteins seem to be inherent part of the human testis. By means of physicochemical properties the proteins appear to play a role during immunological and rheological process of the testicular tissue. The presence of SP-B and SP-C in cells of Sertoli correlates with their function of fluid secretion and may support transportation of spermatozoa. In seminoma the expression of all SP's was generally weaker compared to normal germ cells. This could lead to a reduction of immunomodulatory and rheology processes in the germ cell tumor. PMID- 26599234 TI - Bicyclic-Capped Histone Deacetylase 6 Inhibitors with Improved Activity in a Model of Axonal Charcot-Marie-Tooth Disease. AB - Charcot-Marie-Tooth (CMT) disease is a disorder of the peripheral nervous system where progressive degeneration of motor and sensory nerves leads to motor problems and sensory loss and for which no pharmacological treatment is available. Recently, it has been shown in a model for the axonal form of CMT that histone deacetylase 6 (HDAC6) can serve as a target for the development of a pharmacological therapy. Therefore, we aimed at developing new selective and activity-specific HDAC6 inhibitors with improved biochemical properties. By utilizing a bicyclic cap as the structural scaffold from which to build upon, we developed several analogues that showed improved potency compared to tubastatin A while maintaining excellent selectivity compared to HDAC1. Further screening in N2a cells examining both the acetylation of alpha-tubulin and histones narrowed down the library of compounds to three potent and selective HDAC6 inhibitors. In mutant HSPB1-expressing DRG neurons, serving as an in vitro model for CMT2, these inhibitors were able to restore the mitochondrial axonal transport deficits. Combining structure-based development of HDAC6 inhibitors, screening in N2a cells and in a neuronal model for CMT2F, and preliminary ADMET and pharmacokinetic profiles, resulted in the selection of compound 23d that possesses improved biochemical, functional, and druglike properties compared to tubastatin A. PMID- 26599235 TI - Alteration of Connective Tissue Growth Factor (CTGF) Expression in Orbital Fibroblasts from Patients with Graves' Ophthalmopathy. AB - Graves' ophthalmopathy (GO) is a disfiguring and sometimes blinding disease, which is characterized by inflammation and swelling of orbital tissues, with fibrosis and adipogenesis being predominant features. The aim of this study is to investigate whether the expression levels of fibrosis-related genes, especially that of connective tissue growth factor (CTGF), are altered in orbital fibroblasts of patients with GO. The role of oxidative stress in the regulation of CTGF expression in GO orbital fibroblasts is also examined. By a SYBR Green based real time quantitative PCR (RT-QPCR), we demonstrated that the mRNA expression levels of fibronectin, apolipoprotein J, and CTGF in cultured orbital fibroblasts from patients with GO were significantly higher than those of age matched normal controls (p = 0.007, 0.037, and 0.002, respectively). In addition, the protein expression levels of fibronectin, apolipoprotein J, and CTGF analyzed by Western blot were also significantly higher in GO orbital fibroblasts (p = 0.046, 0.032, and 0.008, respectively) as compared with the control. Furthermore, after treatment of orbital fibroblasts with a sub-lethal dose of hydrogen peroxide (200 MUM H2O2), we found that the H2O2-induced increase of CTGF expression was more pronounced in the GO orbital fibroblasts as compared with those in normal controls (20% vs. 7%, p = 0.007). Importantly, pre-incubation with antioxidants including N-acetylcysteine (NAC) and vitamin C, respectively, resulted in significant attenuation of the induction of CTGF in GO orbital fibroblasts in response to H2O2 (p = 0.004 and 0.015, respectively). Taken together, we suggest that oxidative stress plays a role in the alteration of the expression of CTGF in GO orbital fibroblasts that may contribute to the pathogenesis and progression of GO. Antioxidants may be used in combination with the therapeutic agents for effective treatment of GO. PMID- 26599236 TI - Impact of expiratory strength training in amyotrophic lateral sclerosis. AB - INTRODUCTION: We evaluated the feasibility and impact of expiratory muscle strength training (EMST) on respiratory and bulbar function in persons with amyotrophic lateral sclerosis (ALS). METHODS: Twenty-five ALS patients participated in this delayed intervention open-label clinical trial. Following a lead-in period, patients completed a 5-week EMST protocol. Outcome measures included: maximum expiratory pressure (MEP); physiologic measures of swallow and cough; and penetration-aspiration scale (PAS) scores. RESULTS: Of participants who entered the active phase of the study (n = 15), EMST was well tolerated and led to significant increases in MEPs and maximum hyoid displacement during swallowing post-EMST (P < 0.05). No significant differences were observed for PAS scores or cough spirometry measures. CONCLUSIONS: EMST was feasible and well tolerated in this small cohort of ALS patients and led to improvements in expiratory force-generating pressures and swallow kinematics. Further investigation is warranted to confirm these preliminary findings. Muscle Nerve 54: 48-53, 2016. PMID- 26599237 TI - Ensuring safety and functionality of electroglottography measurements during dynamic pulmonary MRI. AB - PURPOSE: To combine vocal tract measurements with dynamic MRI of the lungs to provide fundamental insights into the lung physiology during singing. METHODS: To analyze vocal fold oscillatory patterns during dynamic lung MRI, an electroglottography (EGG) system was modified to allow for simultaneous EGG measurements during MR image acquisitions. A low-pass filter was introduced to suppress residual radiofrequency (RF) coupling into the EGG signal. RF heating was tested in a gel phantom to ensure MR safety, and functionality of the EGG device was assessed in a volunteer experiment at singing frequencies from A5 to A3. In the recorded EGG signals, remaining RF interferences were removed by independent component analysis post processing, and standard EGG parameters such as fundamental frequency, contact quotient and jitter were calculated. In a second volunteer experiment, EGG recordings were compared with lung diameter measurements from 2D time-resolved trueFISP acquisitions. RESULTS: RF heating measurements resulted in less than 1.2 degrees C temperature increase in the gel phantom. EGG parameters measured during MR imaging are within the range of ideal values. In the lung measurement, both the lung diameter and the EGG recordings could be successfully performed with only minimal interference. CONCLUSION: EGG recording is pos sible during dynamic lung MRI, and glottal activity can be studied safely at 1.5T. Magn Reson Med 76:1629-1635, 2016. (c) 2015 International Society for Magnetic Resonance in Medicine. PMID- 26599239 TI - Letter to the Editor: Treat-and-Extend Intravitreal Bevacizumab for Branch Retinal Vein Occlusion. PMID- 26599238 TI - Radioprotective Effect of Aminothiol PrC-210 on Irradiated Inner Ear of Guinea Pig. AB - Radiotherapy of individuals suffering with head & neck or brain tumors subserve the risk of sensorineural hearing loss. Here, we evaluated the protective effect of Aminothiol PrC-210 (3-(methyl-amino)-2-((methylamino)methyl)propane-1-thiol) on the irradiated inner ear of guinea pigs. An intra-peritoneal or intra-tympanic dose of PrC-210 was administered prior to receiving a dose of gamma radiation (3000 cGy) to each ear. Auditory Brainstem Responses (ABRs) were recorded one week and two weeks after the radiation and compared with the sham animal group. ABR thresholds of guinea pigs that received an intra-peritoneal dose of PrC-210 were significantly better compared to the non-treated, control animals at one week post-radiation. Morphologic analysis of the inner ear revealed significant inflammation and degeneration of the spiral ganglion in the irradiated animals not treated with PrC-210. In contrast, when treated with PrC-210 the radiation effect and injury to the spiral ganglion was significantly alleviated. PrC-210 had no apparent cytotoxic effect in vivo and did not affect the morphology or count of cochlear hair cells. These findings suggest that aminothiol PrC-210 attenuated radiation-induced cochlea damage for at least one week and protected hearing. PMID- 26599240 TI - Current Methods to Reduce Endophthalmitis After Intravitreal Injection. PMID- 26599241 TI - Clinical Experience With the First Commercially Available Intraoperative Optical Coherence Tomography System. AB - BACKGROUND AND OBJECTIVE: A retrospective, single-center case-series was initiated to evaluate initial clinical experience with the first commercially available intraoperative optical coherence tomography system (iOCT). PATIENTS AND METHODS: The Rescan 700 iOCT (Zeiss, Oberkochen, Germany), a spectral-domain OCT system integrated into a surgical microscope, was used in 40 consecutive cases. A standardized review was used to assess whether iOCT imaging resulted in additional information and/or altered decision-making. RESULTS: The iOCT system was usable in conjunction with common chromovitrectomy dyes and tamponades. The surgeons reported that iOCT imaging provided additional information in 74.1% of the posterior and combined surgical cases, which resulted in altered decision making in 41.9% of the cases. The iOCT imaging time, on average, amounted to 167 seconds. In anterior procedures, the surgeons reported gaining additional information in 22.2% of all cases, but no cases of altered decision-making were reported. Hereby, the iOCT imaging time amounted to 117 seconds, on average. CONCLUSION: The demonstrated results suggest iOCT has the potential to improve the quality of posterior and anterior segment surgery. PMID- 26599242 TI - Quantitative Assessment of Retinal Degeneration in Birdshot Chorioretinopathy Using Optical Coherence Tomography. AB - BACKGROUND AND OBJECTIVE: Retinal degeneration in birdshot chorioretinopathy (BSCR) has been assessed qualitatively using spectral-domain optical coherence tomography (SD-OCT). The purpose of this study was to determine whether these changes could be quantified. PATIENTS AND METHODS: The charts of 22 eyes of 11 patients with BSCR and 22 eyes of 22 controls were reviewed. SD-OCT was used to determine the photoreceptor outer segment (PROS) volume and choroidal thickness. RESULTS: PROS volume in patients with BSCR was lower than in controls (P < .003). Furthermore, the PROS volume in BSCR patients with abnormalities on electroretinography (ERG) was lower than the PROS volume in BSCR patients with normal ERGs (P < .02). There was no correlation between PROS volume and choroidal thickness (r = 0.27; P = .22). CONCLUSION: SD-OCT can be used to quantitate retinal degeneration in BSCR. The retinal and choroidal degeneration in BSCR are not correlated, suggesting that the inflammatory pathophysiology affecting these two structures may be different. PMID- 26599243 TI - Acute Macular Neuroretinopathy Following Non-Ocular Trauma: A Hypothesis Regarding Pathophysiologic Mechanism. AB - BACKGROUND AND OBJECTIVE: To describe the imaging characteristics and clinical course of acute macular neuroretinopathy (AMN) following non-ocular trauma, and to hypothesize a pathophysiologic mechanism for this syndrome. PATIENTS AND METHODS: The records of five patients who developed symptoms and findings suggestive of AMN following trauma to the face or chest were retrospectively reviewed. Optical coherence tomography (OCT), infrared reflectance, fundus autofluorescence, fluorescein and indocyanine green angiography, and multifocal electroretinography were evaluated. RESULTS: Visual symptoms started immediately or very soon after non-ocular trauma, and scotomas persisted at last follow-up (2 weeks to 10 years after trauma). OCT imaging performed within days of the trauma demonstrated focal areas of hyper-reflectivity in the outer plexiform and outer nuclear layers with eventual thinning of the outer nuclear layer, as well as variable loss of the ellipsoid and interdigitation zones. CONCLUSION: Acute ischemic injury caused by trauma-induced hypotension and/or catecholamine release and involving the deep retinal capillary plexus is the pathogenic mechanism that most plausibly explains trauma-associated AMN. PMID- 26599244 TI - Intravitreal Aflibercept for Neovascular AMD: Short-Term Clinical Effects of Intravitreal Aflibercept Injection as a Predictor of Long-Term Results. AB - BACKGROUND AND OBJECTIVE: To study the relationship between early response to intravitreal aflibercept injection (IAI) for neovascular age-related macular degeneration (nAMD) and long-term visual outcomes PATIENTS AND METHODS: Seventeen patients with nAMD participated in this prospective clinical trial. All patients received three initial monthly IAIs, followed by IAIs at 8-week intervals. Study visits were scheduled at 1 week, followed by every 2 weeks for the first 3 months and then every 4 weeks until the conclusion of the study at 48 weeks. RESULTS: Eight eyes (47%) were dry on spectral-domain optical coherence tomography by week 2 (early responders), and the remaining nine eyes took an average of 7.5 weeks for fluid resolution (late responders). The mean change in best-corrected visual acuity (BCVA) at the final visit was +11.9 letters from baseline (P = .002). Average BCVA gain in early responders was +11.6 letters compared to +12.2 letters in late responders (P = .7). CONCLUSIONS: Although there was not a statistically significant correlation between early response to IAI and better long-term outcomes, both early and late responders maintained excellent visual outcomes at 48 weeks. PMID- 26599245 TI - Effect of a Strict 'No-Talking' Policy During Intravitreal Injection on Post Injection Endophthalmitis. AB - BACKGROUND AND OBJECTIVE: To report the effect of a "no-talking" policy during intravitreal injection (IVI) on post-injection endophthalmitis. PATIENTS AND METHODS: Retrospective, comparative, consecutive case series of patients receiving IVI between Jan. 1, 2009, and Dec. 31, 2012. A 24-month "usual care" period was compared to a 24-month no-talking period, during which a strategy to further minimize speech during IVI was implemented. RESULTS: During the usual care period, 47,155 IVIs were performed, with nine culture-positive cases (0.019%), including seven due to oral pathogens (0.015%). During the no-talking period, 82,658 IVIs were performed, with eight culture-positive cases (0.010%), including two due to oral pathogens (0.002%). The no-talking policy was associated with a decreased endophthalmitis risk (P = .004), including oral pathogen-associated endophthalmitis (P = .02). CONCLUSION: This study demonstrates that a more stringent no-talking policy during IVI may reduce the risk of post-injection endophthalmitis. PMID- 26599246 TI - Ultrasonography Findings in Eyes With Stage 5 Retinopathy of Prematurity. AB - BACKGROUND AND OBJECTIVE: To evaluate ultrasonography outcomes in eyes with stage 5 retinopathy of prematurity (ROP). PATIENTS AND METHODS: Patients with bilateral stage 5 ROP were evaluated retrospectively. Ultrasonography examination was performed in all cases. Patients' demographic features and ultrasonography findings such as axial eye length, funnel configuration, subretinal hemorrhage, anterior loop traction, retinal cyst, and calcification were assessed, and correlations between variables were analyzed. RESULTS: Three hundred eyes of 150 patients were included. Sixty-one patients (40.7%) were female. The mean gestational age was 28.8 weeks +/- 2.6 weeks, and the mean birth weight was 1,277 g +/- 360 g. The mean axial eye length was 14.7 mm +/- 1.8 mm. Two hundred forty five eyes (81.7%) had closed-closed retinal detachment configuration, 32 (10.7%) had open-closed retinal detachment configuration, 17 (5.7%) had open-open retinal detachment configuration, and six (2%) had closed-open retinal detachment configuration. Subretinal hemorrhage (25.7%), anterior loop traction (24%), retinal cyst (2.3%), and calcification (1.3%) were also observed. CONCLUSION: Closed-closed funnel configuration, reduced axial diameter, and subretinal hemorrhage are associated with poor prognosis, and ocular ultrasonography examination for ascertaining these parameters is very important in cases with stage 5 ROP. In the present study, closed-closed retinal detachment configuration was noted in almost 80% of the cases with stage 5 ROP, which is probably the reason for the surgical failure in these end-stage cases. PMID- 26599247 TI - ReSure Sealant for Pars Plana Vitrectomy Wound Closure. AB - BACKGROUND AND OBJECTIVE: ReSure Sealant (Ocular Therapeutix, Bedford, MA) is an ocular sealant that demonstrated both safety and effectiveness in a prospective, randomized clinical trial for sealing clear corneal incisions following cataract surgery and intraocular lens placement in adults.1 PATIENTS AND METHODS: This is the first literature report of ReSure Sealant used for the closure of 23-gauge (G) pars plana vitrectomy (PPV) sclerotomies. A 70-year-old pseudophakic female with a history of epiretinal membrane and branch retinal vein occlusion of the right eye underwent 23-G PPV, membrane peel, and air-fluid exchange and was found to have leaking subconjunctival air at the end of the case. A linear conjunctival incision was performed to access the sclerotomy site. The incisions were then carefully dried before the sealant was applied to seal both the sclera and conjunctiva. RESULTS: After polymerization, the sealant formed a polyethylene glycol (PEG) hydrogel that was 89% water and 9.44% PEG. PEG is a synthetic material that is non-toxic and inert and, thus, suitable for use in medical products. CONCLUSION: ReSure Sealant may be a safe, quick method to close sclerotomy wounds in select cases. [ PMID- 26599248 TI - Pedicle Internal Limiting Membrane Transposition Flap Technique for Refractory Macular Hole. AB - BACKGROUND AND OBJECTIVE: To determine the efficacy of the pedicle internal limiting membrane (ILM) transposition flap technique for refractory macular holes (MHs) in which the inverted ILM flap technique cannot be performed. PATIENTS AND METHODS: The pedicle ILM flap transposition technique was conducted by transconjunctival microincision vitrectomy. The authors attempted to peel the remaining ILM inferior from the MH to create an ILM flap. This ILM was still attached to the retina at the upper part of the MH and covered the MH. Finally, fluid-gas exchange was performed. After surgery, patients remained face-down for 1 week. This procedure was performed in two eyes. RESULTS: There were no adverse events, and MHs were closed successfully in both study eyes. CONCLUSION: The pedicle ILM flap transposition technique has the potential to improve functional and anatomical outcomes in patients with refractory MHs. PMID- 26599249 TI - Secondary Vitreoretinal Lymphoma Masquerading as Acute Retinal Necrosis. AB - Intraocular lymphoma is considered a uveitis masquerade syndrome and may rarely present with features resembling a necrotizing viral retinitis. The authors report a secondary vitreoretinal lymphoma presenting in this fashion, which was treated with a unique combination of intravitreal methotrexate and rituximab. PMID- 26599250 TI - Optical Coherence Tomography Angiography Compared to Fluorescein Angiography in Branch Retinal Artery Occlusion. AB - A case of embolic branch retinal artery occlusion (BRAO) was evaluated utilizing both fluorescein angiography (FA) and novel optical coherence topography angiography (OCTA). OCTA demonstrated a well-demarcated area of flow interruption secondary to the retinal artery embolus, as well as capillary nonperfusion in the involved region corresponding to FA findings. Therefore, OCTA can demonstrate vascular features of embolic BRAO correlating to FA findings. In this case, OCTA also revealed an increased perfusion defect in the superficial vascular capillary plexus that was not seen on FA. PMID- 26599251 TI - Optical Coherence Tomography Angiography Imaging of Quiescent Choroidal Neovascularization in Age-Related Macular Degeneration. AB - A 67-year-old asymptomatic man presented with bilateral drusen. Spectral-domain optical coherence tomography (OCT) showed no signs of choroidal neovascularization (CNV) and no intraretinal or subretinal fluid. OCT angiography (OCTA) revealed the presence of a type 1 CNV in the right eye. Management options were discussed with the patient, who opted for a clinical follow-up. This is the first description demonstrating the OCTA characteristics of a quiescent CNV secondary to age-related macular degeneration. PMID- 26599252 TI - Optical Coherence Tomography Follow-up of an Unusual Case of Old Rhegmatogenous Retinal Detachment With a Hemorrhagic Macrocyst at the Macula. AB - A 32-year-old female presented with visual acuity of hand movement close to face, an old inferior rhegmatogenous retinal detachment (RRD), and a large hemorrhagic macular macrocyst (HMM) in the right eye. After 2 weeks of successful vitreoretinal surgery, the HMM started decreasing in height and resolved by 3 months. On optical coherence tomography, a zone of hyperreflectivity in the outer retinal layers was evident on resolution of the cyst. At final follow-up, the visual acuity improved to 1/60 only. Though HMM resolved completely after retinal reattachment, alteration and thickening of microarchitecture of the outer retinal layers ensued. PMID- 26599253 TI - Spectral-Domain Optical Coherence Tomography of Polypoidal Choroidal Vasculopathy Associated With Benign Choroidal Nevus. AB - Two cases of polypoidal choroidal vasculopathy (PCV) complicating benign choroidal nevus and their tomographic features at spectral-domain optical coherence tomography (SD-OCT) are reported. Two eyes with choroidal nevus and associated subretinal fluid underwent complete ophthalmological examination, SD OCT, fundus fluorescein angiography, and indocyanine green angiography (ICGA). SD OCT and ICGA confirmed the diagnosis of PCV in both cases. Ophthalmologists should be aware of this rare combination between choroidal nevus and PCV. If a choroidal nevus presents with subretinal fluid, this does not always herald malignant transformation, and PCV should be ruled out so that the correct treatment can be planned. PMID- 26599254 TI - Intraocular Nematode Affixed to Posterior Lens Capsule. AB - The clinical presentation of an intraocular nematode unusually affixed to the posterior lens capsule is described. A 64-year-old female patient presented with a 7-year history of gradually declining vision and enlarging central scotoma, but no inflammation. On follow-up 2 years later, vision had further declined and a non-motile, 8-mm nematode was seen affixed to the posterior lens capsule that remained unchanged through final follow-up. The patient disclosed having resided in Africa as a child. Systemic review revealed no evidence of extraocular involvement. Nematode carcasses may remain preserved in the human eye for extended periods without ongoing inflammation. PMID- 26599255 TI - Positive Auto-Antibody Activity With Retina and Optic Nerve in Smokers and Non Smokers: The Controversy Continues. AB - Auto-antibodies assist with the diagnosis of ocular paraneoplastic syndromes and autoimmune ocular conditions; however, the frequency of positive test results as a possible precursor to future disease is unknown. The frequency of positive antibodies in heavy smokers who may be at risk for autoimmune-related retinopathy and optic neuropathy was evaluated. Serum antibody activity was evaluated through the use of Western blot reactions from pig retina and optic nerve extract. Fifty one patients were included: 35 patients were smokers (average: 40.9 pack-year history) and 26 patients had no past smoking history. None of the patients had any visual complaints or known eye disease. Of the patients studied, 76.5% (39 patients: 18 smokers, 21 non-smokers) had positive antiretinal antibodies, and 19.6% (10 patients: 3 smokers, 7 non-smokers) had positive antioptic nerve antibodies. Anti-retinal antibodies were seen in a majority of randomly selected patients with and without a past smoking history. Anti-optic nerve bodies were less common, but more prevalent in those who never smoked. The specificity of these antibodies remains greatly uncertain and clinical correlation is warranted. PMID- 26599256 TI - Infantile Primary Orbital Angiosarcoma. PMID- 26599257 TI - Screening for Cervical Cancer Among Low-Risk Populations: Orthodox Jewish Women as a Model. AB - OBJECTIVE: To explore the prevalence of abnormal Papanicolaou (PAP) smears among asymptomatic Orthodox Jewish women, characterized by conservative sexual habits, in comparison to secular Jewish women. METHODS: A retrospective analytical cohort study of 600 consecutive PAP smears, performed as a screening test on asymptomatic Orthodox Jewish women (mean age 43.4 +/- 12.6 years), compared to 600 consecutive smears performed on secular Jewish women (mean age 38.2 +/- 11.5 years). Primary outcome measures comprised incidence and clinical significance of abnormal cytological findings among the two subgroups. Secondary outcome measures included possible risk factors for abnormal cytological findings within the study population. RESULTS: In the Orthodox group, only seven (1.2%) PAP smears were interpreted as abnormal, compared with 33 (5.5%) abnormal smears among the secular group (p < 0.001). All seven abnormal PAP smears from the Orthodox Jewish group were classified as atypical squamous cells of undetermined significance (ASCUS), compared with 16 ASCUS smears and 17 low-grade squamous intraepithelial lesion smears in the secular group (2.67% and 2.83% of the secular women, respectively). The vast majority of ASCUS cases in the Orthodox Jewish group were followed up with repeated normal PAP smears. CONCLUSIONS: The incidence rate of abnormal PAP smears taken as a routine screening test among Orthodox Jewish women is very low (1.2%). Furthermore, the vast majority of abnormal smears in these women were later found to be false positive, with no clinical significance. These findings raise doubt as to the need for systematic screening and/or comprehensive vaccination against the papilloma virus among low-risk populations. PMID- 26599258 TI - Enhanced Metastatic Potential in a 3D Tissue Scaffold toward a Comprehensive in Vitro Model for Breast Cancer Metastasis. AB - Metastasis is clinically the most challenging and lethal aspect of breast cancer. While animal-based xenograft models are expensive and time-consuming, conventional two-dimensional (2D) cell culture systems fail to mimic in vivo signaling. In this study we have developed a three-dimensional (3D) scaffold system that better mimics the topography and mechanical properties of the breast tumor, thus recreating the tumor microenvironment in vitro to study breast cancer metastasis. Porous poly(epsilon-caprolactone) (PCL) scaffolds of modulus 7.0 +/- 0.5 kPa, comparable to that of breast tumor tissue were fabricated, on which MDA MB-231 cells proliferated forming tumoroids. A comparative gene expression analysis revealed that cells growing in the scaffolds expressed increased levels of genes implicated in the three major events of metastasis, viz., initiation, progression, and the site-specific colonization compared to cells grown in conventional 2D tissue culture polystyrene (TCPS) dishes. The cells cultured in scaffolds showed increased invasiveness and sphere formation efficiency in vitro and increased lung metastasis in vivo. A global gene expression analysis revealed a significant increase in the expression of genes involved in cell-cell and cell matrix interactions and tissue remodeling, cancer inflammation, and the PI3K/Akt, Wnt, NF-kappaB, and HIF1 signaling pathways-all of which are implicated in metastasis. Thus, culturing breast cancer cells in 3D scaffolds that mimic the in vivo tumor-like microenvironment enhances their metastatic potential. This system could serve as a comprehensive in vitro model to investigate the manifold mechanisms of breast cancer metastasis. PMID- 26599260 TI - Docking and DFT studies on ligand binding to Quercetin 2,3-dioxygenase. AB - Simple molecular docking calculations on quercetin, kojic acid and diethylcarbamatodithoic acid using the software package MOE are shown to be close to the geometries reported in the X-ray crystal structures of the protein co crystallized with the respective ligands. Furthermore, DFT optimization of the docked conformations is shown to reproduce the essential features of previous studies on quercetin, showing that docking can be used to provide good starting structures for mechanistic study. The flavone ligand, lacking the hydroxyl group of the quercetin is shown by docking to be unable to approach closely the copper atom, indicating the necessity of the presence of the hydroxyl group and providing a prediction of the likely binding environment of this ligand. PMID- 26599259 TI - Differentiation therapy for hepatocellular carcinoma: Multifaceted effects of miR 148a on tumor growth and phenotype and liver fibrosis. AB - The death rate from hepatocellular carcinoma (HCC) is increasing, and liver cancer is the second leading cause of cancer-related mortality worldwide. Most patients with HCC have underlying liver cirrhosis and compromised liver function, limiting treatment options. Cirrhosis is associated with cell dedifferentiation and expansion of hepatocholangiolar progenitor cells. We identified a microRNA signature associated with HCC and hepatocytic differentiation of progenitor cells. We further identified miR-148a as an inducer of hepatocytic differentiation that is down-regulated in HCC. MiR-148a-mimetic treatment in vivo suppressed tumor growth, reduced tumor malignancy and liver fibrosis, and prevented tumor development. These effects were associated with an increased differentiated phenotype and mediated by IkappaB kinase alpha/NUMB/NOTCH signaling. CONCLUSION: miR-148a is an inhibitor of the IkappaB kinase alpha/NUMB/NOTCH pathway and an inducer of hepatocytic differentiation that when deregulated promotes HCC initiation and progression. Differentiation-targeted therapy may be a promising strategy to treat and prevent HCC. PMID- 26599261 TI - Analytical performances of food microbiology laboratories - critical analysis of 7 years of proficiency testing results. AB - AIM: Based on the results of 19 food microbiology proficiency testing (PT) schemes, this study aimed to assess the laboratory performances, to highlight the main sources of unsatisfactory analytical results and to suggest areas of improvement. METHODS AND RESULTS: The 2009-2015 results of REQUASUD and IPH PT, involving a total of 48 laboratories, were analysed. On average, the laboratories failed to detect or enumerate foodborne pathogens in 3.0% of the tests. Thanks to a close collaboration with the PT participants, the causes of outliers could be identified in 74% of the cases. The main causes of erroneous PT results were either pre-analytical (handling of the samples, timing of analysis), analytical (unsuitable methods, confusion of samples, errors in colony counting or confirmation) or postanalytical mistakes (calculation and encoding of results). CONCLUSIONS: PT schemes are a privileged observation post to highlight analytical problems, which would otherwise remain unnoticed. In this perspective, this comprehensive study of PT results provides insight into the sources of systematic errors encountered during the analyses. SIGNIFICANCE AND IMPACT OF THE STUDY: This study draws the attention of the laboratories to the main causes of analytical errors and suggests practical solutions to avoid them, in an educational purpose. The observations support the hypothesis that regular participation to PT, when followed by feed-back and appropriate corrective actions, can play a key role in quality improvement and provide more confidence in the laboratory testing results. PMID- 26599262 TI - Why sinonasal disease spares the inferior turbinate: An immunohistochemical analysis. AB - OBJECTIVES/HYPOTHESIS: Clinically, inflammatory polyps are found in the middle turbinate (MT) in patients with chronic rhinosinusitis (CRS) but not in the inferior turbinate (IT). The purpose of this study was to investigate differences in protein expression between IT and MT tissue in patients with CRS. STUDY DESIGN: Prospective cohort. METHODS: Pathologic specimens obtained from patients with CRS undergoing functional endoscopic sinus surgery with IT reduction were evaluated by immunohistochemical analysis of inflammatory markers cysteinyl leukotriene 1 receptor (CysLT1R), toll-like receptor 2 (TLR2), and vascular cell adhesion molecule 1 (VCAM1). Protein expression was quantified with nuance multispectral analysis and results compared between MT and IT tissue. RESULTS: The total expression of VCAM1 and CysLT1R was decreased in the IT compared to the MT. There was no difference in total TLR2 expression between the IT and MT. When comparing patients with eosinophilic CRS to noneosinophilic CRS (neCRS), there was decreased expression of VCAM1 in the IT of patients with neCRS. When comparing patients with nasal polyposis to those without polyps, there was decreased expression of VCAM1 in the IT of patients without polyps. CONCLUSIONS: There is a difference in protein receptor expression of VCAM1 and CysLT1R in MT compared to IT tissue. Although the leukotrienes are a well-known target for treatment of chronic sinusitis, this is the first study demonstrating an upregulation of VCAM1 expression in the MT and could be a potential future target for the treatment of CRS. LEVEL OF EVIDENCE: NA Laryngoscope, 126:E179-E183, 2016. PMID- 26599263 TI - Health service utilisation by people living with chronic non-cancer pain: findings from the Pain and Opioids IN Treatment (POINT) study. AB - Objective The aims of the present study were to describe the use, and barriers to the use, of non-medication pain therapies and to identify the demographic and clinical correlates of different non-opioid pain treatments. Methods The study was performed on a cohort (n=1514) of people prescribed pharmaceutical opioids for chronic non-cancer pain (CNCP). Participants reported lifetime and past month use of healthcare services, mental and physical health, pain characteristics, current oral morphine equivalent daily doses and financial and access barriers to healthcare services. Results Participants reported the use of non-opioid pain treatments, both before and after commencing opioid therapy. Services accessed most in the past month were complementary and alternative medicines (CAMs; 41%), physiotherapy (16%) and medical and/or pain specialists (15%). Higher opioid dose was associated with increased financial and access barriers to non-opioid treatment. Multivariate analyses indicated being younger, female and having private health insurance were the factors most commonly associated with accessing non-opioid treatments. Conclusions Patients on long-term opioid therapy report using multiple types of pain treatments. High rates of CAM use are concerning given limited evidence of efficacy for some therapies and the low-income status of most people with CNCP. Financial and insurance barriers highlight the importance of considering how different types of treatments are paid for and subsidised. What is known about the topic? Given concerns regarding long-term efficacy, adverse side-effects and risk of misuse and dependence, prescribing guidelines recommend caution in prescribing pharmaceutical opioids in cases of CNCP, typically advising a multidisciplinary approach to treatment. There is a range of evidence supporting different (non-drug) treatment approaches for CNCP to reduce pain severity and increase functioning. However, little is known about the non-opioid treatments used among those with CNCP and the demographic and clinical characteristics that may be associated with the use of different types of treatments. Understanding the use of non-drug therapy among people with CNCP is crucial given the potential to improve pain control for these patients. What does this paper add? The present study found that a wide range of non-opioid treatments was accessed by the study sample, both before and after commencing opioids, indicating that in this sample opioids were not the sole strategy used for pain management. The most common treatment (other than opioids) was CAM, reported by two-fifths of the sample. Having private health insurance was associated with increased use of non-opioid treatments for pain, highlighting the importance of considering how treatments are paid for and potential financial barriers to effective treatments. What are the implications for practitioners? Patients' beliefs and financial barriers may affect the uptake of different treatments. Many patients may be using complementary and alternative approaches with limited evidence to support their use, highlighting the need for clinicians to discuss with patients the range of prescribed and non-prescribed treatments they are accessing and to help them understand the benefits and risks of treatments that have not been tested sufficiently, or have inconsistent evidence, as to their efficacy in improving pain outcomes. PMID- 26599264 TI - NHC carbene supported half-sandwich hydridosilyl complexes of ruthenium: the impact of supporting ligands on Si???H interligand interactions. AB - Reaction of complex [CpRu(pyr)3][PF6] (3) with the NHC carbene IPr (IPr = 1,3 bis(2,6-diisopropylphenyl)imidazol-2-ylidene) results in the NHC complex [Cp(IPr)Ru(pyr)2][PF6] (4), which was studied by NMR specroscopy and X-ray diffraction analysis. Reaction of [Cp(IPr)Ru(pyr)2][PF6] (4) with LiAlH4 leads to the trihydride Cp(IPr)RuH3 (5) characterised by spectroscopic methods. Heating compound 5 with hydrosilanes gives the dihydrido silyl derivatives Cp(IPr)RuH2(SiR3) (6). Systematic X-ray diffraction studies suggest that complexes 6 have stronger interligand Si???H interactions than the isolobal phosphine complexes Cp(Pr3P)RuH2(SiR3). PMID- 26599265 TI - Viral Genome-Linked Protein (VPg) Is Essential for Translation Initiation of Rabbit Hemorrhagic Disease Virus (RHDV). AB - Rabbit hemorrhagic disease virus (RHDV), the causative agent of rabbit hemorrhagic disease, is an important member of the caliciviridae family. Currently, no suitable tissue culture system is available for proliferating RHDV, limiting the study of the pathogenesis of RHDV. In addition, the mechanisms underlying RHDV translation and replication are largely unknown compared with other caliciviridae viruses. The RHDV replicon recently constructed in our laboratory provides an appropriate model to study the pathogenesis of RHDV without in vitro RHDV propagation and culture. Using this RHDV replicon, we demonstrated that the viral genome-linked protein (VPg) is essential for RHDV translation in RK-13 cells for the first time. In addition, we showed that VPg interacts with eukaryotic initiation factor 4E (eIF4E) in vivo and in vitro and that eIF4E silencing inhibits RHDV translation, suggesting the interaction between VPg and eIF4E is involved in RHDV translation. Our results support the hypothesis that VPg serves as a novel cap substitute during the initiation of RHDV translation. PMID- 26599266 TI - Early Recruitment of Cerebral Microcirculation by Neuronal Nitric Oxide Synthase Inhibition in a Juvenile Ischemic Rat Model. AB - BACKGROUND: The development of collateral circulation is proposed as an inherent compensatory mechanism to restore impaired blood perfusion after ischemia, at least in the penumbra. We have studied the dynamic macro- and microcirculation after ischemia-reperfusion in the juvenile rat brain and evaluated the impact of neuronal nitric oxide synthase (nNOS) inhibition on the collateral flow. METHODS: Fourteen-day-old (P14) rats were subjected to ischemia-reperfusion and treated with either PBS or 7-nitroindazole (7-NI, an nNOS inhibitor, 25 mg/kg). Arterial blood flow (BF) was measured using 2D-color-coded pulsed ultrasound imaging. Laser speckle contrast (LSC) imaging and sidestream dark-field videomicroscopy were used to measure cortical and microvascular BF, respectively. RESULTS: In basal conditions, 7-NI reduced BF in the internal carotids (by ~ 25%) and cortical (by ~ 30%) BF, as compared to PBS. During ischemia, the increased mean BF velocity in the basilar trunk after both PBS and 7-NI demonstrated the establishment of collateral support and patency. Upon re-flow, BF immediately recovered to basal values in the internal carotid arteries under both conditions. The 7-NI group showed increased collateral flow in the penumbral tissue during early re-flow compared to PBS, as shown with both LSC imaging and side-stream dark-field videomicroscopy. The proportion of perfused capillaries was significantly increased under 7-NI as compared to PBS when given before ischemia (67.0 +/- 3.9 vs. 46.8 +/- 8.8, p < 0.01). Perfused capillaries (63.1 +/- 17.7 vs. 81.1 +/- 20.7, p < 0.001) and the BF index (2.4 +/- 0.6 vs. 1.3 +/- 0.1, p < 0.001) significantly increased under 7-NI given at the re-flow onset. CONCLUSIONS: Collateral support in the penumbra is initiated during ischemia, and may be increased during early re-flow by neuronal NOS inhibition (given in pre- and post-treatment), which may preserve brain tissue in juvenile rats. PMID- 26599267 TI - Monocyte Caspase-1 Is Released in a Stable, Active High Molecular Weight Complex Distinct from the Unstable Cell Lysate-Activated Caspase-1. AB - Mononuclear phagocytes utilize caspase-1 activation as a means to respond to danger signals. Although caspase-1 was discovered using highly concentrated cell extracts that spontaneously activate caspase-1, it is now clear that in live cell models caspase-1 activation occurs in the process of its cellular release and is not an intracellular event. Therefore, we compared the characteristics of caspase 1 activation in the cell lysate model to that of caspase-1 that is released in response to exogenous inflammasome activation. Whereas both models generated active caspase-1, the cell-lysate induced caspase-1 required highly concentrated cell lysates and had a short half-life (~15 min) whereas, the activation induced released caspase-1 required 2-3 log fold fewer cells and was stable for greater than 12 h. Both forms were able to cleave proIL-1beta but unexpectedly, the released activity was unable to be immunodepleted by caspase-1 antibodies. Size exclusion chromatography identified two antigenic forms of p20 caspase-1 in the activation induced released caspase-1: one at the predicted size of tetrameric, p20/p10 caspase-1 and the other at >200 kDa. However, only the high molecular weight form had stable functional activity. These results suggest that released caspase-1 exists in a unique complex that is functionally stable and protected from immunodepletion whereas cell-extract generated active caspase-1 is rapidly inhibited in the cytosolic milieu. PMID- 26599268 TI - Attentional Control Theory in Childhood: Enhanced Attentional Capture by Non Emotional and Emotional Distractors in Anxiety and Depression. AB - Attentional control theory (ACT) proposes that anxiety is associated with executive functioning deficits. The theory has been widely investigated in adults. The current study tested whether symptoms of childhood anxiety and depression were associated with experimentally measured attentional control in the context of non-emotional and emotional stimuli. Sixty-one children (mean age = 9.23 years, range = 8.39-10.41) reported their trait anxiety and depression symptoms and completed three visual search tasks. The tasks used a variant of an irrelevant singleton paradigm and measured attentional capture by task-irrelevant non-emotional (color) and emotional (facial expressions) distractors. Significant attentional capture by both non-emotional and emotional distractors was observed, and was significantly correlated with trait anxiety and symptoms of depression. The strength of relationship between attentional capture and the symptoms did not differ significantly for non-emotional and emotional distractors. The results suggest that symptoms of childhood anxiety and depression are associated with poorer attentional control both in the presence of emotional and non-emotional stimuli, supporting ACT in younger populations. This attentional deficit in the context of non-emotional information might be as central to childhood internalizing symptoms as attentional biases often observed on tasks investigating processing of emotional stimuli. PMID- 26599269 TI - Mutation Profiling of Lung Cancers with Long-Term Response to Gefitinib Therapy. AB - BACKGROUND: The role of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) in the treatment of patients with advanced non-small cell lung cancer (NSCLC) and unknown EGFR mutation status has recently been questioned. PATIENTS AND METHODS: We conducted a retrospective study of patients with unknown EGFR mutation status and long-term response (LTR) to gefitinib in the Swiss Iressa expanded access program (EAP). We assessed patient characteristics, and performed Sanger sequencing and next generation sequencing on archived tumor tissue. We hypothesized that EGFR mutations are prevalent in patients with LTR. RESULTS: Of 430 patients in the EAP, 18 (4%) fulfilled our definition of LTR, and 16 of them had archived tumor tissue. Patient characteristics were as expected for age, sex, and smoking history. Median duration of therapy was 38 months (range 24-142 months). Sanger sequencing revealed EGFR exon 18-21 mutations in 6 (38%) of the tumors. Next generation sequencing revealed no further EGFR-mutated cases, but reported in 15 (94%) of the tumors mutations in other genes (ALK, BRAF, DDR2, KEAP1, MET, PTEN, STK11) previously associated with NSCLC. CONCLUSION: Larger studies are needed to define the prognostic values of different driver mutations in patients with NSCLC. PMID- 26599270 TI - Impact of p16 Alterations and Pretreatment Anemia on Toxicity in Head and Neck Cancer Patients Undergoing Definitive Radiochemotherapy. AB - BACKGROUND: Human papilloma virus (HPV) infection, p16 expression and hypoxia may play important roles in the carcinogenesis, treatment response and toxicities of head and neck squamous cell carcinoma (HNSCC). The aim of this analysis was to assess whether there is any correlation between pre-radiotherapy (RT) anemia, p16 expression and toxicities and local control for patients undergoing definitive therapy. METHODS: 79 HNSCC patients who had undergone radiochemotherapy (RCT) or RT-antibody therapy were retrospectively analyzed. p16 (INK4A) expression was detected by immunohistochemical analysis. Factors predisposing for acute side effects were examined by uni- and multivariate analysis. RESULTS: p16 overexpression was detected in 32 cases. Pretreatment anemia was present in one third of patients. Only 5% of patients were characterized by both pre-RT anemia and p16 overexpression. p16 expression was significantly associated with acute grade 3 toxicity. 47% of p16-positive patients developed grade >= 3 radiodermatitis compared to 26% of p16-negative patients (p = 0.04). A reduced risk of severe skin toxicities was noted for patients with hypoxic blood values before RT. p16 expression was significantly correlated with local control (p = 0.002). CONCLUSIONS: p16 expression is associated with better response to definitive combined treatment (RCT, RT + cetuximab), but also significantly related to acute high-grade toxicity. PMID- 26599271 TI - Limited Prognostic Value of SUV max Measured by F-18 FDG PET/CT in Newly Diagnosed Small Cell Lung Cancer Patients. AB - BACKGROUND: The purpose of this study was to evaluate the prognostic value of the maximum standard uptake value (SUV max) measured by 18-F fluoro-2-deoxy-d-glucose (F-18 FDG) positron emission tomography/computed tomography (PET/CT) in newly diagnosed small cell lung cancer (SCLC) patients. METHODS: We reviewed the medical records of newly diagnosed SCLC patients who were given a histological diagnosis from June 2008 to June 2014. 82 patients who satisfied the inclusion criteria were enrolled for final analysis (male n = 75, female n = 7). The relationship between SUV max and overall survival (OS) and progression-free survival (PFS) was evaluated. RESULTS: Median follow-up was 25.0 months (range 11.6-55.5 months). The median OS was 11.2 months (range 1.6-55.5 months), and the median PFS was 6.1 months (range 0.9-55.5 months). Survival analysis showed no statistical differences in OS and PFS between high and low SUV max groups. CONCLUSION: This study does not support the use of SUV max of pretreatment F-18 FDG PET/CT scans as a prognostic tool for patients with SCLC. PMID- 26599272 TI - Glycine Decarboxylase Expression Increased in p53-Mutated B Cell Lymphoma Mice. AB - BACKGROUND: p53 gene mutations are associated with human tumors, and are among the most common genetic abnormalities. To understand the relationship between p53 mutations and glycine decarboxylase (GLDC) expression in B cell lymphoma, we established B cell lymphoma animal models to study GLDC expression in B cell lymphoma mice. MATERIALS AND METHODS: Based on immunohistochemical staining results, BALB/c nude mice were divided into a p53 protein-positive group and a p53 protein-negative group. GLDC mRNA expression was determined by real-time polymerase chain reaction, and GLDC protein expression was determined by Western blot. We designed a GLDC-specific interference fragment siRNA-transfected human B cell lymphoma cell line (Raji) to establish a B cell lymphoma animal model. RESULTS: The results showed both GLDC mRNA and protein expression increased in the B cell lymphoma tissue of the p53 protein-positive group compared with the p53 protein-negative group. The proliferation ability of GLDC siRNA-transfected cells decreased significantly compared with the negative-control siRNA group and the blank control group (p < 0.05), which showed that the GLDC gene can promote cell proliferation in p53-mutated B cell lymphoma. CONCLUSION: These studies support a direct relationship between p53 mutations and GLDC expression in B cell lymphoma. GLDC can induce dramatic changes in glycolysis and glycine/serine metabolism, leading to changes in pyrimidine metabolism and tumor development. PMID- 26599273 TI - Communication Preferences in Young, Middle-Aged, and Elderly Cancer Patients. AB - BACKGROUND: While psychosocial distress and supportive care needs of young adult cancer patients have been increasingly studied, little knowledge exists about preferences for communicating bad news. We aimed to analyze patients' communication preferences against their actual experiences with regard to doctor patient interactions. PATIENTS AND METHODS: We surveyed a total of 270 cancer patients with different tumor entities. 3 age groups (young, middle-aged, and elderly) were compared concerning their communication preferences (MPP; Measure of Patients' Preferences questionnaire) and the impact on distress (National Comprehensive Cancer Network Distress Thermometer). RESULTS: We found no age differences of communication preferences and the content of bad news. A significant difference was found in the dimension 'professional expertise/patient orientation (p < 0.01) which was rated as more important by younger patients. Binary logistic regression showed an impact of 'children' (odds ratio (OR) 0.296; 95% confidence interval (CI) 0.155, 0.563), tumor staging (OR 1.737, 95% CI 1.028, 2.936), and insufficient 'privacy' (OR 0.987; 95% CI 0.978, 0.997) and 'clarity' (OR 1.013; 95% CI 1.002, 1.025) on distress. CONCLUSION: Communication preferences related to breaking bad news depend less on age differences than on other variables. Future studies should investigate the long-term impact of ineffective patient-physician communication, taking into account unmet patient preferences in different age groups. PMID- 26599274 TI - Patients with Advanced Pancreatic Cancer and Hyperbilirubinaemia: Review and German Expert Opinion on Treatment with nab-Paclitaxel plus Gemcitabine. AB - In patients with advanced unresectable pancreatic cancer, the prognosis is generally poor. Within recent years, new treatment options such as the FOLFIRINOX regimen (5-fluorouracil, leucovorin, irinotecan and oxaliplatin) or the combination of nanoparticle albumin-bound (nab)-paclitaxel plus gemcitabine have shown a clinically relevant survival benefit over the standard gemcitabine in patients with good performance status. Unfortunately, patients with hyperbilirubinaemia, who constitute a substantial proportion of the pancreatic cancer patients, have been excluded from most clinical studies. Consequently, our knowledge on the appropriate medical treatment of this patient group is limited. In a meeting of German medical oncology experts, the available clinical evidence and own clinical experience regarding the management of patients with advanced pancreatic cancer and hyperbilirubinaemia was discussed. The present publication summarises the discussion outcomes with regard to appropriate management of these patients, including consensus-based recommendations for nab paclitaxel/gemcitabine treatment, according to the best available evidence. In summary, knowledge of the underlying aetiology of hyperbilirubinaemia and the metabolisation routes of the cytotoxic drugs is crucial before initiating chemotherapy. As effective treatment options should also be made available to patients with comorbid conditions, including hyperbilirubinaemia, the experts provide advice for an initial dose reduction of chemotherapy with nab paclitaxel/gemcitabine based on the total bilirubin level in patients with biliary obstruction or extensive liver metastasis. PMID- 26599276 TI - Correction: Use of Modern Family Planning Methods in Fishing Communities of Lake Victoria, Uganda. PMID- 26599277 TI - The Impact of Human Mobility on HIV Transmission in Kenya. AB - Disease spreads as a result of people moving and coming in contact with each other. Thus the mobility patterns of individuals are crucial in understanding disease dynamics. Here we study the impact of human mobility on HIV transmission in different parts of Kenya. We build an SIR metapopulation model that incorporates the different regions within the country. We parameterise the model using census data, HIV data and mobile phone data adopted to track human mobility. We found that movement between different regions appears to have a relatively small overall effect on the total increase in HIV cases in Kenya. However, the most important consequence of movement patterns was transmission of the disease from high infection to low prevalence areas. Mobility slightly increases HIV incidence rates in regions with initially low HIV prevalences and slightly decreases incidences in regions with initially high HIV prevalence. We discuss how regional HIV models could be used in public-health planning. This paper is a first attempt to model spread of HIV using mobile phone data, and we also discuss limitations to the approach. PMID- 26599278 TI - Maternal Smoking and Metabolic Health Biomarkers in Newborns. AB - BACKGROUND: Maternal smoking has been associated with elevated risk of type 2 diabetes among the offspring in adulthood. The mechanisms underlying this fetal "programming" effect remain unclear. The present study sought to explore whether maternal smoking affects metabolic health biomarkers in fetuses/newborns. METHODS: In a prospective singleton pregnancy cohort (n = 248), we compared metabolic health biomarkers in the newborns of smoking and non-smoking mothers. Outcomes included cord plasma insulin, proinsulin, insulin-like growth factor I (IGF-I), IGF-II, leptin and adiponectin concentrations, glucose-to-insulin ratio (an indicator of insulin sensitivity) and proinsulin-to-insulin ratio (an indicator of beta-cell function). RESULTS: Independent of maternal (glucose tolerance, age, ethnicity, parity, education, body mass index, alcohol use) and infant (sex, gestational age, birth weight z score, mode of delivery, cord blood glucose concentration) characteristics, the newborns of smoking mothers had lower IGF-I concentrations (mean: 6.7 vs. 8.4 nmol/L, adjusted p = 0.006), and marginally higher proinsulin-to-insulin ratios (0.94 vs. 0.72, adjusted p = 0.06) than the newborns of non-smoking mothers. Cord plasma insulin, proinsulin, IGF II, leptin and adiponectin concentrations and glucose-to-insulin ratios were similar in the newborns of smoking and non-smoking mothers. CONCLUSIONS: Maternal smoking was associated with decreased fetal IGF-I levels, and borderline lower fetal beta-cell function. Larger cohort studies are required to confirm the latter finding. The preliminary findings prompt the hypothesis that these early life metabolic changes may be involved in the impact of maternal smoking on future risk of metabolic syndrome related disorders in the offspring. PMID- 26599279 TI - Correction: A Multi-Methodological MR Resting State Network Analysis to Assess the Changes in Brain Physiology of Children with ADHD. AB - [This corrects the article DOI: 10.1371/journal.pone.0099119.]. PMID- 26599281 TI - Adsorption and co-adsorption of diclofenac and Cu(II) on calcareous soils. AB - Pharmaceuticals are emerging contaminants and their presence in different compartments of the environment has been detected in many countries. In this study, laboratory batch experiments were conducted to characterize the adsorption of diclofenac, a widely used non-steroidal anti-inflammatory drug, on six calcareous soils. The adsorption of diclofenac was relatively low, which may lead to a risk of groundwater contamination and plant uptake. A correlation between the soil-water distribution coefficient Kd and soil characteristics has been highlighted. Indeed, diclofenac adsorption as a function of soil organic matter content (% OM) and Rt=% CaCO3/% OM was successfully described through a simple empirical model, indicating the importance of considering the inhibiting effect of CaCO3 on OM retention properties for a better assessment of diclofenac fate in the specific case of calcareous soils. The simultaneous co-adsorption of diclofenac and copper - a ubiquitous pollutant in the environment - at the water/soil interface, was also investigated. It appeared quite unexpectedly that copper did not have a significant influence on diclofenac retention. PMID- 26599280 TI - Urinary Volatile Organic Compounds for the Detection of Prostate Cancer. AB - The aim of this work was to investigate volatile organic compounds (VOCs) emanating from urine samples to determine whether they can be used to classify samples into those from prostate cancer and non-cancer groups. Participants were men referred for a trans-rectal ultrasound-guided prostate biopsy because of an elevated prostate specific antigen (PSA) level or abnormal findings on digital rectal examination. Urine samples were collected from patients with prostate cancer (n = 59) and cancer-free controls (n = 43), on the day of their biopsy, prior to their procedure. VOCs from the headspace of basified urine samples were extracted using solid-phase micro-extraction and analysed by gas chromatography/mass spectrometry. Classifiers were developed using Random Forest (RF) and Linear Discriminant Analysis (LDA) classification techniques. PSA alone had an accuracy of 62-64% in these samples. A model based on 4 VOCs, 2,6-dimethyl 7-octen-2-ol, pentanal, 3-octanone, and 2-octanone, was marginally more accurate 63-65%. When combined, PSA level and these four VOCs had mean accuracies of 74% and 65%, using RF and LDA, respectively. With repeated double cross-validation, the mean accuracies fell to 71% and 65%, using RF and LDA, respectively. Results from VOC profiling of urine headspace are encouraging and suggest that there are other metabolomic avenues worth exploring which could help improve the stratification of men at risk of prostate cancer. This study also adds to our knowledge on the profile of compounds found in basified urine, from controls and cancer patients, which is useful information for future studies comparing the urine from patients with other disease states. PMID- 26599282 TI - High expression of Solute Carrier Family 1, member 5 (SLC1A5) is associated with poor prognosis in clear-cell renal cell carcinoma. AB - Solute Carrier Family 1, member 5 (SLC1A5), also named as ASCT2, a major glutamine transporter, is highly expressed in various malignancies and plays a critical role in the transformation, growth and survival of cancer cells. The aim of this study was to assess the clinical significance of SLC1A5 in patients with clear-cell renal cell carcinoma (ccRCC). SLC1A5 expression was evaluated by immunohistochemistry on tissue microarrays. Kaplan-Meier method was conducted to compare survival curves. Univariate and multivariate Cox regression models were applied to assess the impact of prognostic factors on overall survival (OS). A nomogram was then constructed on the basis of the independent prognosticators identified on multivariate analysis. The predictive ability of the models was compared using Receiver operating characteristic (ROC) analysis. Our data indicated that high expression of SLC1A5 was significantly associated with advanced TNM stage, higher Fuhrman grade and shorter OS in ccRCC patients. Multivariate analysis confirmed that SLC1A5 was an independent prognosticator for OS. A nomogram integrating SLC1A5 and other independent prognosticators was constructed, which showed a better prognostic value for OS than TNM staging system. In conclusion, high SLC1A5 expression is an independent predictor of adverse clinical outcome in ccRCC patients after surgery. PMID- 26599283 TI - Role of endocytosis in sonoporation-mediated membrane permeabilization and uptake of small molecules: a electron microscopy study. AB - Sonoporation is a physical method that has been successfully used to deliver drugs into living cells both in vitro and in vivo for experimental and therapeutic purposes. Despite numerous studies on this topic, often reporting successful outcomes, very little is known about the mechanisms involved in the hypothesized membrane permeabilization processes. In this study, electron microscopy was used to investigate the ultra-structural modifications of cell membranes, induced by sonoporation. Here, we demonstrate that sonoporation in the presence of microbubbles induces the formation of a significant number of transient and permeant structures at the membrane level. These structures were transient with a half-life of 10 min and had a heterogeneous size distribution ranging from a few nanometers to 150 nm. We demonstrated that the number and the size of these structures were positively correlated with the enhanced intracellular uptake of small molecules. In addition, we showed that these structures were associated with caveolae-dependent endocytosis for two thirds of the recorded events, with the remaining one third related to non-specific routes such as membrane disruptions as well as caveolae-independent endocytosis. In conclusion, our observations provide direct evidences of the involvement of caveolae-endocytosis in cell membrane permeabilization to small molecules after sonoporation. PMID- 26599284 TI - Prevalence of Lebanese stroke survivors: A comparative pilot study. AB - Stroke is a leading cause of morbidity and mortality worldwide and its late burden has mainly been attributable to developing countries. Lebanon is one of these countries where epidemiological studies on stroke burden are scarce but necessary. Thus, the present study was conducted to assess the prevalence of stroke survivors among Lebanese inhabitants. A cross-sectional survey was carried out using randomly selected landline phone numbers on all governorates to retrieve data on stroke survivors and their sociodemographic characteristics. Results were then standardized over the Lebanese and the World Health Organization (WHO) world populations. A total of 6963 Lebanese inhabitants were included in the study; among these were 56 stroke survivors. This led to an adjusted stroke prevalence of 0.50% [95% confidence interval (CI)=0.33-0.66%] and a world-standardized prevalence of 0.60% (95% CI=0.42-0.78%). A significantly higher stroke prevalence was found among older age groups and more socioeconomically privileged areas. Overall, the study showed a relatively higher prevalence of stroke in this sample of Lebanese inhabitants when compared to other developing countries. However, larger community-based studies with a clinical assessment of stroke cases are needed to confirm our findings. PMID- 26599285 TI - New insights into myeloid-derived suppressor cells and their roles in feto maternal immune cross-talk. AB - Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of myeloid cells that suppress both innate and adaptive immune responses through multiple mechanisms. In recent years, much of our knowledge of the function of MDSCs has come from cancer studies. However, a few recent advances have begun to characterize MDSCs in feto-maternal immune cross-talk. The microenvironment at the fetal-maternal interface is a complex milieu of trophoblasts and maternally derived cells, which are biased to tolerogenic and Th2-type responses. Current data reveal that MDSCs accumulate at the fetal-maternal interface in healthy pregnancies. Yet, little is known about how MDSCs develop and why the response of MDSCs is heavily granulocytic. In this review, we discuss recent findings on the molecular mechanisms that regulate the expansion and function of MDSCs, in addition to various roles of MDSCs implicated in the modulation of feto-maternal immune cross-talk. Understanding the roles of MDSCs in inducing maternal-fetal tolerance, which is compromised in patients suffering from pregnancy complications, including preeclampsia, intrauterine growth restriction, spontaneous abortion, and preterm birth, we thus propose that the immunomodulatory activity of MDSCs should be carefully considered for the therapeutic approaches targeting pregnancy complications. PMID- 26599286 TI - Depression Is Associated with Readmission for Acute Exacerbation of Chronic Obstructive Pulmonary Disease. AB - RATIONALE: Hospitalization for acute exacerbation of chronic obstructive pulmonary disease (COPD) is associated with significant morbidity and health care costs, and hospitals in the United States are now penalized by the Centers for Medicare and Medicaid Services for excessive readmissions. Identifying patients at risk of readmission is important, but modifiable risk factors have not been clearly established, and the potential contributing role of psychological disease has not been examined adequately. We hypothesized that depression and anxiety would increase the risk of both short- and long-term readmissions for acute exacerbation of COPD. OBJECTIVES: To characterize the associations between depression and anxiety and COPD readmission risk. METHODS: We examined the medical records for all patients with a primary diagnosis of acute exacerbation of COPD by International Classification of Diseases, Ninth Revision codes admitted to the University of Alabama at Birmingham Hospital between November 2010 and October 2012. Those who did not meet the standardized study criteria for acute exacerbation of COPD and those with other respiratory illnesses as the primary diagnosis were excluded. Comorbidities were recorded on the basis of physician documentation of the diagnosis and/or the use of medications in the electronic medical record. Multivariable regression analyses identified factors associated with readmission for acute exacerbation of COPD at 1 year and within 30 and 90 days. MEASUREMENTS AND MAIN RESULTS: Four hundred twenty-two patients were included, with 132 readmitted in 1 year. Mean age was 64.8 +/- 11.7 years, and mean percent predicted FEV1 was 48.1 +/- 18.7%. On univariate analysis, readmitted patients had lower percent predicted FEV1 (44.9 +/- 17.3% vs. 50.2 +/- 19.4%; P = 0.05) and a higher frequency of depression (47.7% vs. 23.4%; P < 0.001). On multivariable analysis, 1-year readmission was independently associated with depression (adjusted odds ratio [OR], 2.67; 95% confidence interval [CI], 1.59-4.47) and in-hospital tobacco cessation counseling (adjusted OR, 0.34; 95% CI, 0.18-0.66). Depression also predicted readmission at 30 days (adjusted OR, 3.83; 95% CI, 1.84-7.96) and 90 days (adjusted OR, 2.47; 95% CI, 1.34-4.55). CONCLUSIONS: Depression is an independent risk factor for both short- and long-term readmissions for acute exacerbation of COPD and may represent a modifiable risk factor. In-hospital tobacco cessation counseling was also associated with reduced 1-year readmission. PMID- 26599288 TI - Resolutions. PMID- 26599287 TI - Applications in high-content functional protein microarrays. AB - Protein microarray technology provides a versatile platform for characterization of hundreds to thousands of proteins in a parallel and high-throughput manner. Over the last decade, applications of functional protein microarrays in particular have flourished in studying protein function at a systems level and have led to the construction of networks and pathways describing these functions. Relevant areas of research include the detection of various binding properties of proteins, the study of enzyme-substrate relationships, the analysis of host microbe interactions, and profiling antibody specificity. In addition, discovery of novel biomarkers in autoimmune diseases and cancers is emerging as a major clinical application of functional protein microarrays. In this review, we will summarize the recent advances of functional protein microarrays in both basic and clinical applications. PMID- 26599289 TI - Awards. PMID- 26599290 TI - Immunization Update, 1985. PMID- 26599291 TI - Health investment behaviours and oral/gingival health condition, a cross sectional study among Swedish 19-year olds. AB - OBJECTIVES: To test the hypothesis that certain individual, environmental and lifestyle factors are positively associated with beneficial health investment behaviours and oral/periodontal health among adolescents. METHODS: Five hundred and six randomly selected 19-year old subjects living in two different areas (Fyrbodal and Skaraborg) in the county council of Vastra Gotaland, Sweden participated in a clinical examination and answered questionnaires covering psycho-social and health behavioural issues. Two oral-health models were estimated with gingivitis score as an objective and self-perceived oral health as a subjective indicator. Three health- investment behaviour models were designed with indicators directly related to oral health and two with indicators related to general health as well. The explanatory variables included gender, upper secondary education programme, native country, living area, general self-efficacy and parents' education level. RESULTS: In the objective oral-health model, theoretical studies and living in the Skaraborg area were both positively associated with a lower gingivitis score. For the subjective oral-health indicator, none of the explanatory variables showed statistical significance. In the investment-behaviour model with 'tooth-brushing >= 2 times daily' as a health indicator, female gender and theoretical studies showed statistically significant associations. With the indicators 'no/few missed dental appointments', 'no tobacco use' and 'weekly exercise', theoretical studies were statistically significant and positively associated. In the investment model with 'perceived oral health care attention' as an indicator, a high score of general self efficacy was significantly associated with the feeling of taking good care of the teeth. CONCLUSIONS: Individual, environmental and lifestyle factors are associated with young individuals' oral health investment behaviours and gingival health conditions. PMID- 26599293 TI - Pheochromocytoma and paraganglioma: molecular testing and personalized medicine. AB - PURPOSE OF REVIEW: Pheochromocytomas and paragangliomas (PPGLs) are rare tumours, strongly associated with inherited susceptibility gene mutations, and presenting limited therapeutic options for patients with metastatic disease. This review discusses the recent developments in the characterization of PPGL genetic heterogeneity and associated tumorigenesis pathways, together with their potential clinical relevance. RECENT FINDINGS: The mutational landscape of PPGL is now well defined, especially with the contribution of next-generation sequencing. Up to 70% of these tumours harbour a germline or a somatic mutation in one of the numerous predisposing genes. In parallel, 'omics' analyses have identified mutation-linked subsets of tumours substantially associated with molecular signatures suggesting new therapeutic targets for patients with a malignant transformation of the disease. SUMMARY: In the near future, extended molecular testing of PPGL could be used to determine therapeutic approaches and assess diagnosis and prognosis biomarkers. Considering the current development of next-generation sequencing-based genetic screening, this technology appears as a good option to improve both PPGL molecular diagnosis and patient management. PMID- 26599294 TI - Editorial: from cancer genotypes to phenotypes: a never-ending complexity. PMID- 26599292 TI - Posttranscriptional methylation of transfer and ribosomal RNA in stress response pathways, cell differentiation, and cancer. AB - PURPOSE OF REVIEW: Significant advances have been made in understanding the functional roles of evolutionarily conserved chemical modifications in RNA. By focusing on cytosine-5 methylation, we will highlight the latest insight into the mechanisms how posttranscriptional methylation contributes to cell fate decisions, with implications for cancer development. RECENT FINDINGS: Several mutations in RNA-modifying enzymes have been identified to cause complex human diseases, and linked posttranscriptional modifications to fundamental cellular processes. Distinct posttranscriptional modifications are implicated in the regulation of stem cell maintenance and cellular differentiation. The dynamic deposition of a methyl mark into noncoding RNAs modulates the adaptive cellular responses to stress and alterations of methylation levels may lead to cancer. SUMMARY: Posttranscriptional modifications such as cytosine-5 methylation are dynamically regulated and may influence tumour development, maintenance, and progression. PMID- 26599295 TI - Test-retest reliability and minimal detectable change scores of twelve functional fitness tests in adults with Down syndrome. AB - AIM: The purpose of the study was to explore the test-retest reliability and minimal detectable change of selected functional fitness test items in adults with Down syndrome. METHODS: Forty-three adults with Down syndrome (24 men and 19 women) aged 18-50 years completed a battery of tests twice in a two-week period. The battery of tests consisted of two balance items, two flexibility items, five muscular strength and endurance items, two aerobic items, and one functional task. All items were considered valid and reliable tests in a general elderly or intellectually disabled population. The test-retest relative reliability for all repeated tests was assessed with intraclass correlation coefficient performing one-way analysis of variance. The test-retest absolute variability was measured by using the standard error of measurement (SEM) to calculate the minimal detectable change at the 90% confidence interval (MDC90). Reliability data was visualised with a Bland-Altman plot. RESULTS: All tests showed excellent intraclass correlation coefficients (ICC's>0.9). All SEM values demonstrated acceptable measurement precision (SEM=30 kg/m2), and as metabolically healthy (0-1 metabolic abnormality) or metabolically unhealthy (>=2 abnormalities). Abnormalities included individual components of the metabolic syndrome, high-sensitivity C-reactive protein, and insulin resistance. RESULTS: A total of 3088 (age 55.6+/-12.6 years, 51.3% females) had all measurements. Of these, 890 (28.8%), 1361 (44.1%) and 837 (27.1%) were normal weight, overweight and obese, respectively. Overall, 19.0% of normal weight in contrast to 54.9% of overweight and 77.7% of obese individuals had >=3 risk factors (p<0.001). Among normal weight individuals, 43.1% were metabolically unhealthy, and age >=65 years, female, and highest socioeconomic groups were more likely to have this pattern. In contrast, only 16.4% of overweight and 3.9% of obese individuals were metabolically healthy and, compared to Lima, the rural and urban sites in Puno were more likely to have a metabolically healthier profile. CONCLUSIONS: Most Peruvians with overweight and obesity have additional risk factors for cardiovascular disease, as well as a majority of those with a healthy weight. Prevention programs aimed at individuals with a normal BMI, and those who are overweight and obese, are urgently needed, such as screening for elevated fasting cholesterol and glucose. PMID- 26599323 TI - Tacrolimus Induces Insulin Resistance and Increases the Glucose Absorption in the Jejunum: A Potential Mechanism of the Diabetogenic Effects. AB - BACKGROUND: The use of the immunosuppressive drug tacrolimus (TAC) is related to new onset diabetes after transplantation. Herein, we examined the effect of intraperitoneal administered TAC on intestinal glucose absorption in mice. METHODS: Animals received low, medium, or high dose TAC (0.5, 1, or 5 mg/kg/d, respectively), or 0.9% saline solution (control) for 14 days. Oral glucose tolerance test (OGTT), insulin concentration test, and serum TAC concentration measurements was performed after 14 days of TAC exposure. Plasma insulin was assessed and electrogenic glucose absorption were measured by the sodium dependent increase of the short-circuit current. Expression levels of the glucose transporters sodium glucose co-transporter (SGLT) 1, glucose transporter (GLUT) 2, and GLUT5 were also determined. RESULTS: Oral glucose absorption assessed by OGTT was significantly enhanced in the low, medium, and high groups. Serum insulin was elevated in the medium and high group compared with the control. Moreover, glucose-induced Isc was significantly higher in TAC administrated groups, which indicates that SGLT1 activity increased. Transcription levels and protein abundance of SGLT1 in the experimental groups also increased compared with the control. CONCLUSIONS: TAC induced insulin resistance and strengthened intestinal glucose absorption by increasing the activity and expression of the glucose transporter, SGLT1. PMID- 26599324 TI - High Blood Pressure among Students in Public and Private Schools in Maceio, Brazil. AB - The prevalence of hypertension in childhood is increasing, and investigation of its distribution is important for planning timely interventions. This study assessed the prevalence of high blood pressure (HBP) and associated factors in students between 9 and 11 years of age enrolled in public and private schools in Maceio, Brazil. A cross-sectional study was performed in a probabilistic sample of students (10.3 +/- 0.5 years). The students were selected from a systematic sampling of 80 schools (40 public and 40 private). To maintain similar proportions of students existing in public and private schools in Maceio, 21 and 14 students were randomly selected from each public and private school, respectively. The prevalence ratio (PR) was estimated using Poisson regression. A total of 1,338 students were evaluated (800 from public schools and 538 from private schools). No differences were observed between school types in terms of student age and gender (p > 0.05). The prevalence of obesity (19.9% vs. 9.0%; PR = 2.2; 95% CI = 1.67-2.92) and hypertension (21.2% vs. 11.4%; PR = 1.86; 95% CI = 1.45-2.40) were higher in private schools. The association between high blood pressure and type of school (public or private) remained statistically significant even after adjustment for obesity (PR = 1.53; 95% CI = 1.19-1.97). IN CONCLUSION: (a) students from private schools have higher socioeconomic status, BMI, and HBP prevalence compared to those of public school; (b) among the evaluated students, the prevalence of obesity only partially explained the higher prevalence of high blood pressure among students from private schools. Other factors related to lifestyle of children from private schools may explain the higher prevalence of HBP. This results show the need to implement measures to promote healthy lifestyles in the school environment, since children with HBP are more likely to become hypertensive adults. Therefore, early detection and intervention in children with HBP is an important action for the prevention of hypertension in adulthood. PMID- 26599325 TI - Sixty-Seven Years of Land-Use Change in Southern Costa Rica. AB - Habitat loss and fragmentation of forests are among the biggest threats to biodiversity and associated ecosystem services in tropical landscapes. We use the vicinity of the Las Cruces Biological Station in southern Costa Rica as a regional case study to document seven decades of land-use change in one of the most intensively studied sites in the Neotropics. Though the premontane wet forest was largely intact in 1947, a wave of immigration in 1952 initiated rapid changes over a short period. Overall forest cover was reduced during each time interval analyzed (1947-1960, 1960-1980, 1980-1997, 1997-2014), although the vast majority of forest loss (>90%) occurred during the first two time intervals (1947 1960, 1960-1980) with an annual deforestation rate of 2.14% and 3.86%, respectively. The rate dropped to <2% thereafter and has been offset by forest recovery in fallow areas more recently, but overall forest cover has continued to decline. Approximately 27.9% of the study area is forested currently. Concomitantly, the region shifted from a single contiguous forest to a series of progressively smaller forest fragments with each successive survey. A strong reduction in the amount of core habitat was paralleled by an increased proportion of edge habitat, due to the irregular shape of many forest fragments. Structural connectivity, however, remains high, with an expansive network of >100 km of linear strips of vegetation within a 3 km radius of the station, which may facilitate landscape-level movement for some species. Despite the extent of forest loss, a substantial number of regional landscape-level studies over the past two decades have demonstrated the persistence of many groups of organisms such as birds and mammals. Nonetheless, the continued decline in the quantity and quality of remaining habitat (~30% of remaining forest is secondary), as well as the threat of an extinction debt (or time lag in species loss), may result in the extirpation of additional species if more proactive conservation measures are not taken to reverse current trends-a pattern that reflects many other tropical regions the world over. PMID- 26599326 TI - Highly proliferative primitive fetal liver hematopoietic stem cells are fueled by oxidative metabolic pathways. AB - Hematopoietic stem cells (HSCs) in the fetal liver (FL) unlike adult bone marrow (BM) proliferate extensively, posing different metabolic demands. However, metabolic pathways responsible for the production of energy and cellular building blocks in FL HSCs have not been described. Here, we report that FL HSCs use oxygen dependent energy generating pathways significantly more than their BM counterparts. RNA-Seq analysis of E14.5 FL versus BM derived HSCs identified increased expression levels of genes involved in oxidative phosphorylation (OxPhos) and the citric acid cycle (TCA). We demonstrated that FL HSCs contain more mitochondria than BM HSCs, which resulted in increased levels of oxygen consumption and reactive oxygen species (ROS) production. Higher levels of DNA repair and antioxidant pathway gene expression may prevent ROS-mediated (geno)toxicity in FL HSCs. Thus, we here for the first time highlight the underestimated importance of oxygen dependent pathways for generating energy and building blocks in FL HSCs. PMID- 26599327 TI - Characterization of neurons from immortalized dental pulp stem cells for the study of neurogenetic disorders. AB - A major challenge to the study and treatment of neurogenetic syndromes is accessing live neurons for study from affected individuals. Although several sources of stem cells are currently available, acquiring these involve invasive procedures, may be difficult or expensive to generate and are limited in number. Dental pulp stem cells (DPSCs) are multipotent stem cells that reside deep the pulp of shed teeth. To investigate the characteristics of DPSCs that make them a valuable resource for translational research, we performed a set of viability, senescence, immortalization and gene expression studies on control DPSC and derived neurons. We investigated the basic transport conditions and maximum passage number for primary DPSCs. We immortalized control DPSCs using human telomerase reverse transcriptase (hTERT) and evaluated neuronal differentiation potential and global gene expression changes by RNA-seq. We show that neurons from immortalized DPSCs share morphological and electrophysiological properties with non-immortalized DPSCs. We also show that differentiation of DPSCs into neurons significantly alters gene expression for 1305 transcripts. Here we show that these changes in gene expression are concurrent with changes in protein levels of the transcriptional repressor REST/NRSF, which is known to be involved in neuronal differentiation. Immortalization significantly altered the expression of 183 genes after neuronal differentiation, 94 of which also changed during differentiation. Our studies indicate that viable DPSCs can be obtained from teeth stored for >=72 h, these can then be immortalized and still produce functional neurons for in vitro studies, but that constitutive hTERT immortalization is not be the best approach for long term use of patient derived DPSCs for the study of disease. PMID- 26599328 TI - Nutritional advice for improving outcomes in multiple pregnancies. AB - BACKGROUND: Multiple pregnancies are associated with higher rates of perinatal mortality and morbidity than singleton pregnancies, mainly due to an increased risk of preterm birth. Because fetal outcome is best at a particular range of maternal weight gain, it has been suggested that women with multiple pregnancies should take special diets (particularly high-calorie diets) designed to boost weight gain. However, 'optimal weight gain' in the mother in retrospective studies may merely reflect good growth of her babies and delivery at or near term (both associated with a good outcome) and artificially boosting weight gain by nutritional input may confer no advantage. Indeed, a high-calorie diet may be unpleasant to consume, and could lead to long-term problems of being overweight. It is therefore important to establish if specialised diets are actually of benefit to women with multiple pregnancies and their babies. OBJECTIVES: To assess the effects of specialised diets or nutritional advice for women with multiple pregnancies (two or more fetuses). SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (15 June 2015). SELECTION CRITERIA: Randomised controlled trials, 'quasi-random' studies, and cluster-randomised trials of women with multiple pregnancies (two or more fetuses) either nulliparous or multiparous and their babies. Cross-over trials and studies reported only as abstracts were not eligible for inclusion. DATA COLLECTION AND ANALYSIS: We identified no trials for inclusion in this review. MAIN RESULTS: A comprehensive search of the Cochrane Pregnancy and Childbirth Group's Trials Register found no potentially eligible trial reports. AUTHORS' CONCLUSIONS: There is no robust evidence from randomised trials to indicate whether specialised diets or nutritional advice for women with multiple pregnancies do more good than harm. There is a clear need to undertake a randomised controlled trial. PMID- 26599330 TI - Remodeling and Tenacity of Inhibitory Synapses: Relationships with Network Activity and Neighboring Excitatory Synapses. AB - Glutamatergic synapse size remodeling is governed not only by specific activity forms but also by apparently stochastic processes with well-defined statistics. These spontaneous remodeling processes can give rise to skewed and stable synaptic size distributions, underlie scaling of these distributions and drive changes in glutamatergic synapse size "configurations". Where inhibitory synapses are concerned, however, little is known on spontaneous remodeling dynamics, their statistics, their activity dependence or their long-term consequences. Here we followed individual inhibitory synapses for days, and analyzed their size remodeling dynamics within the statistical framework previously developed for glutamatergic synapses. Similar to glutamatergic synapses, size distributions of inhibitory synapses were skewed and stable; at the same time, however, sizes of individual synapses changed considerably, leading to gradual changes in synaptic size configurations. The suppression of network activity only transiently affected spontaneous remodeling dynamics, did not affect synaptic size configuration change rates and was not followed by the scaling of inhibitory synapse size distributions. Comparisons with glutamatergic synapses within the same dendrites revealed a degree of coupling between nearby inhibitory and excitatory synapse remodeling, but also revealed that inhibitory synapse size configurations changed at considerably slower rates than those of their glutamatergic neighbors. These findings point to quantitative differences in spontaneous remodeling dynamics of inhibitory and excitatory synapses but also reveal deep qualitative similarities in the processes that control their sizes and govern their remodeling dynamics. PMID- 26599331 TI - Effects of Weight Loss Speed on Kidney Function Differ Depending on Body Mass Index in Nondiabetic Healthy People: A Prospective Cohort. AB - BACKGROUND: Obesity is associated with diabetes mellitus and cardiovascular diseases. However, it has been reported that weight loss is associated with incident chronic kidney disease (CKD) in healthy males. The purpose of this prospective cohort study is to investigate the effects of weight loss on kidney function in healthy people in terms of body mass index (BMI) and gender. METHODS: A total of 8447 nondiabetic healthy people were enrolled in the Saitama Cardiometabolic Disease and Organ Impairment Study, Japan. Relationships between estimated glomerular filtration rate (eGFR) change, BMI, and BMI change were evaluated using 3D-scatter plots with spline and generalized additive models (GAMs) adjusted for baseline characteristics. RESULTS: The subjects were stratified into four groups according to BMI. The mean+/-standard deviations for males and females were, respectively, 40.11+/-9.49, and 40.3+/-9.71 years for age and 76.39+/-17.72 and 71.49+/-18.4 ml/min/1.73m2 for eGFR. GAMs showed that a decreasing BMI change (<-1 kg/m2/year) was associated with a decreasing eGFR change in males with high normal BMIs (22 kg/m2<=BMI<25 kg/m2). A decreasing BMI change (<-2 kg/m2/year) was associated with an increasing eGFR change in overweight males (25 kg/m2<=BMI). Among underweight females (BMI<18.5 kg/m2), decreasing BMI was observed with decreasing eGFR. CONCLUSIONS: These findings suggest that the benefit and risk of weight loss in relation to kidney function differs depending on BMI and weight loss speed, especially in males. PMID- 26599333 TI - Comparative Interactome of HIV-1 Tat and Human T Lymphotropic Virus Type-1 Tax and the Cellular Transcriptional Machinery. PMID- 26599332 TI - Therapeutic Intervention in Multiple Sclerosis with Alpha B-Crystallin: A Randomized Controlled Phase IIa Trial. AB - As a molecular chaperone and activator of Toll-like receptor 2-mediated protective responses by microglia and macrophages, the small heat shock protein alpha B-crystallin (HspB5) exerts therapeutic effects in different animal models for neuroinflammation, including the model for multiple sclerosis (MS). Yet, HspB5 can also stimulate human antigen-specific memory T cells to release IFN gamma, a cytokine with well-documented detrimental effects during MS. In this study, we explored in a Phase IIa randomized clinical trial the therapeutic application of HspB5 in relapsing-remitting MS (RR-MS), using intravenous doses sufficient to support its protective effects, but too low to trigger pathogenic memory T-cell responses. These sub-immunogenic doses were selected based on in vitro analysis of the dose-response profile of human T cells and macrophages to HspB5, and on the immunological effects of HspB5 in healthy humans as established in a preparatory Phase I study. In a 48-week randomized, placebo-controlled, double-blind Phase IIa trial, three bimonthly intravenous injections of 7.5, 12.5 or 17.5 mg HspB5 were found to be safe and well tolerated in RR-MS patients. While predefined clinical endpoints did not differ significantly between the relatively small groups of MS patients treated with either HspB5 or placebo, repeated administration especially of the lower doses of HspB5 led to a progressive decline in MS lesion activity as monitored by magnetic resonance imaging (MRI), which was not seen in the placebo group. Exploratory linear regression analysis revealed this decline to be significant in the combined group receiving either of the two lower doses, and to result in a 76% reduction in both number and total volumes of active MRI lesions at 9 months into the study. These data provide the first indication for clinical benefit resulting from intervention in RR-MS with HspB5. TRIAL REGISTRATION: ClinicalTrials.gov Phase I: NCT02442557; Phase IIa: NCT02442570. PMID- 26599334 TI - Inhibitory effects of Cymodocea nodosa sulphated polysaccharide on alpha-amylase activity, liver-kidney toxicities and lipid profile disorders in diabetic rats. AB - This study aimed to evaluate for the first time the effects of Cymodocea nodosa sulphated polysaccharide (CNSP) on the alpha-amylase activity, hyperglycaemia, liver-kidney functions, and pancreatic architecture of alloxan-induced diabetic rats. Animals were allocated into four groups of seven rats each, the body weight and blood glucose levels were estimated periodically for 2 months of treatment by gastric gavages route. The CNSP effect was confirmed by biochemical procedures and histological study. The inhibition of alpha-amylase activity and protection of pancreatic beta-cells induced a decrease in the blood glucose levels and regulated the lipid profile in the plasma of the treated diabetic rats, which helped to maintain the homeostasis of blood lipid. Moreover, CNSP administration induced a significant decrease in the levels of lipid peroxidation in the pancreas, liver and kidney of diabetic rats and protects their functions attested by a decrease in the levels of toxicity parameters in blood. PMID- 26599335 TI - Regorafenib: Antitumor Activity upon Mono and Combination Therapy in Preclinical Pediatric Malignancy Models. AB - The multikinase inhibitor regorafenib (BAY 73-4506) exerts both anti-angiogenic and anti-tumorigenic activity in adult solid malignancies mainly advanced colorectal cancer and gastrointestinal stromal tumors. We intended to explore preclinically the potential of regorafenib against solid pediatric malignancies alone and in combination with anticancer agents to guide the pediatric development plan. In vitro effects on cell proliferation were screened against 33 solid tumor cell lines of the Innovative Therapies for Children with Cancer (ITCC) panel covering five pediatric solid malignancies. Regorafenib inhibited cell proliferation with a mean half maximal growth inhibition of 12.5 MUmol/L (range 0.7 MUmol/L to 28 MUmol/L). In vivo, regorafenib was evaluated alone at 10 or 30 mg/kg/d or in combination with radiation, irinotecan or the mitogen activated protein kinase kinase (MEK) inhibitor refametinib against various tumor types, including patient-derived brain tumor models with an amplified platelet derived growth factor receptor A (PDGFRA) gene. Regorafenib alone significantly inhibited tumor growth in all xenografts derived from nervous system and connective tissue tumors. Enhanced effects were observed when regorafenib was combined with irradiation and irinotecan against PDGFRA amplified IGRG93 glioma and IGRM57 medulloblastoma respectively, resulting in 100% tumor regressions. Antitumor activity was associated with decreased tumor vascularization, inhibition of PDGFR signaling, and induction of apoptotic cell death. Our work demonstrates that regorafenib exhibits significant antitumor activity in a wide spectrum of preclinical pediatric models through inhibition of angiogenesis and induction of apoptosis. Furthermore, radio- and chemosensitizing effects were observed with DNA damaging agents in PDGFR amplified tumors. PMID- 26599336 TI - Analysis of Jumping-Landing Manoeuvers after Different Speed Performances in Soccer Players. AB - PURPOSE: Running at high speed and sudden change in direction or activity stresses the knee. Surprisingly, not many studies have investigated the effects of sprinting on knee's kinetics and kinematics of soccer players. Hence, this study is aimed to investigate indices of injury risk factors of jumping-landing maneuvers performed immediately after sprinting in male soccer players. METHODS: Twenty-three collegiate male soccer players (22.1+/-1.7 years) were tested in four conditions; vertical jump (VJ), vertical jump immediately after slow running (VJSR), vertical jump immediately after sprinting (VJFR) and double horizontal jump immediately after sprinting (HJFR). The kinematics and kinetics data were measured using Vicon motion analyzer (100Hz) and two Kistler force platforms (1000Hz), respectively. RESULTS: For knee flexion joint angle, (p = 0.014, eta = 0.15) and knee valgus moment (p = 0.001, eta = 0.71) differences between condition in the landing phase were found. For knee valgus joint angle, a main effect between legs in the jumping phase was found (p = 0.006, eta = 0.31), which suggests bilateral deficit existed between the right and left lower limbs. CONCLUSION: In brief, the important findings were greater knee valgus moment and less knee flexion joint angle proceeding sprint (HJFR & VJFR) rather than no sprint condition (VJ) present an increased risk for knee injuries. These results seem to suggest that running and sudden subsequent jumping-landing activity experienced during playing soccer may negatively change the knee valgus moment. Thus, sprinting preceding a jump task may increase knee risk factors such as moment and knee flexion joint angle. PMID- 26599337 TI - Satellite Hyperspectral Imagery to Support Tick-Borne Infectious Diseases Surveillance. AB - This study proposed the use of satellite hyperspectral imagery to support tick borne infectious diseases surveillance based on monitoring the variation in amplifier hosts food sources. To verify this strategy, we used the data of the human rickettsiosis occurrences in southeastern Brazil, region in which the emergence of this disease is associated with the rising capybara population. Spatio-temporal analysis based on Monte Carlo simulations was used to identify risk areas of human rickettsiosis and hyperspectral moderate-resolution imagery was used to identify the increment and expansion of sugarcane crops, main food source of capybaras. In general, a pixel abundance associated with increment of sugarcane crops was detected in risk areas of human rickettsiosis. Thus, the hypothesis that there is a spatio-temporal relationship between the occurrence of human rickettsiosis and the sugarcane crops increment was verified. Therefore, due to the difficulty of monitoring locally the distribution of infectious agents, vectors and animal host's, satellite hyperspectral imagery can be used as a complementary tool for the surveillance of tick-borne infectious diseases and potentially of other vector-borne diseases. PMID- 26599338 TI - Carbapenemase-Producing Klebsiella pneumoniae in Romania: A Six-Month Survey. AB - This study presents the first characterization of carbapenem-non-susceptible Klebsiella pneumoniae isolates by means of a structured six-month survey performed in Romania as part of an Europe-wide investigation. Klebsiella pneumoniae clinical isolates from different anatomical sites were tested for antibiotic susceptibility by phenotypic methods and confirmed by PCR for the presence of four carbapenemase genes. Genome macrorestriction fingerprinting with XbaI was used to analyze the relatedness of carbapenemase-producing Klebsiella pneumoniae isolates collected from eight hospitals. Among 75 non-susceptible isolates, 65 were carbapenemase producers. The most frequently identified genotype was OXA-48 (n = 51 isolates), eight isolates were positive for blaNDM-1 gene, four had the blaKPC-2 gene, whereas two were positive for blaVIM-1. The analysis of PFGE profiles of OXA-48 and NDM-1 producing K. pneumoniae suggests inter-hospitals and regional transmission of epidemic clones. This study presents the first description of K. pneumoniae strains harbouring blaKPC-2 and blaVIM-1 genes in Romania. The results of this study highlight the urgent need for the strengthening of hospital infection control measures in Romania in order to curb the further spread of the antibiotic resistance. PMID- 26599339 TI - Exercise-Mediated Increase in Nigral Tyrosine Hydroxylase Is Accompanied by Increased Nigral GFR-alpha1 and EAAC1 Expression in Aging Rats. AB - Exercise may alleviate locomotor impairment in Parkinson's disease (PD) or aging. Identifying molecular responses immediately engaged by exercise in the nigrostriatal pathway and allied tissue may reveal critical targets associated with its long-term benefits. In aging, there is loss of tyrosine hydroxylase (TH) and the glial cell line-derived neurotrophic factor (GDNF) receptor, GFR-alpha1, in the substantia nigra (SN). Exercise can increase GDNF expression, but its effect on GFR-alpha1 expression is unknown. Infusion of GDNF into striatum or GFR alpha1 in SN, respectively, can increase locomotor activity and TH function in SN but not striatum in aged rats. GDNF may also increase glutamate transporter expression, which attenuates TH loss in PD models. We utilized a footshock-free treadmill exercise regimen to determine the immediate impact of short-term exercise on GFR-alpha1 expression, dopamine regulation, glutamate transporter expression, and glutamate uptake in 18 month old male Brown-Norway/Fischer 344 F1 hybrid rats. GFR-alpha1 and TH expression significantly increased in SN but not striatum. This exercise regimen did not affect glutamate uptake or glutamate transporter expression in striatum. However, EAAC1 expression increased in SN. These results indicate that nigral GFR-alpha1 and EAAC1 expression increased in conjunction with increased nigral TH expression following short-term exercise. PMID- 26599340 TI - In Vivo Availability of Pro-Resolving Lipid Mediators in Oxazolone Induced Dermal Inflammation in the Mouse. AB - The activation and infiltration of polymorphonuclear neutrophils (PMN) are critical key steps in inflammation. PMN-mediated inflammation is limited by anti inflammatory and pro-resolving mechanisms, including specialized pro-resolving lipid mediators (SPM). We examined the effects of 15-epi-LXA4 on inflammation and the biosynthesis of pro-inflammatory mediators, such as prostaglandins, leukotriene B4 and various hydroxyeicosatetraenoic acids and SPM, in an oxazolone (OXA)-induced hypersensitivity model for dermal inflammation. 15-epi-LXA4 (100 MUM, 5 MUL subcutaneously injected) significantly (P < 0.05) reduced inflammation in skin, 24 hours after the OXA challenge, as compared to skin treated with vehicle. No significant influence on the biosynthesis of prostaglandins or leukotriene B4 was observed, whereas the level of 15S-hydroxy-eicosatetraenoic acid was significantly (P < 0.05) lower in the skin areas treated with 15-epi LXA4. In spite of the use of a fully validated analytical procedure, no SPM were detected in the biological samples. To investigate the reason for the lack of analytical signal, we tried to mimic the production of SPM (lipoxins, resolvins, maresin and protectin) by injecting them subcutaneously into the skin of mice and studying the in vivo availability and distribution of the compounds. All analytes showed very little lateral distribution in skin tissue and their levels were markedly decreased (> 95%) 2 hours after injection. However, docosahexaenoic acid derivatives were biologically more stable than SPM derived from arachidonic acid or eicosapentaenoic acid. PMID- 26599341 TI - Prophylactic oral bisphosphonate therapy in duchenne muscular dystrophy. AB - INTRODUCTION: We assessed prophylactic use of bisphosphonate (BP) in Duchenne muscular dystrophy (DMD) patients on glucocorticoid (GC) therapy. METHODS: Fifty two DMD patients on daily GC were offered BP (oral risedronate). Patients were reviewed for tolerability, side effects, bone pain, and fracture frequency. Bone mineral density (BMD) was determined by annual dual energy X-ray absorptiometry. BP-treated patients were compared with 15 BP-naive patients (untreated cohort). RESULTS: Side effects occurred in 9 patients. Thirty-six patients continued BP therapy for over 12 months (mean, 3.6 years). Five treated patients reported bone pain. Three treated patients suffered a vertebral fracture, significantly less than in the untreated cohort (5/15). Lumbar spine adjusted BMD Z-scores remained unchanged in treated patients and were significantly greater than in the untreated cohort. CONCLUSIONS: Prophylactic oral risedronate therapy was tolerated by most DMD patients. It appears to maintain BMD and may reduce fracture rate in DMD patients on GC. Muscle Nerve 54: 79-85, 2016. PMID- 26599342 TI - Position and orientation measurement of susceptibility markers using spectrally selective spin-echo projections. AB - PURPOSE: To develop an accurate technique for simultaneously measuring the position and orientation of interventional devices using a projection-based spectrally selective refocusing pulse sequence. METHODS: Projections along physical axes using spectrally selective excitation were acquired to track a catheter. A 9F passive tracking device capable of generating controllable susceptibility artifacts using susceptibility materials (titanium and graphite) was attached to the catheter. A library of projections for different orientations of the device with respect to the main magnetic field were simulated offline. Cross-correlations with these templates were computed to determine the orientation and position of the device. A phantom study was performed to evaluate the accuracy of the tracking technique. The tracking technique was also evaluated in vivo in the carotid artery of a pig. RESULTS: Simultaneous and accurate measurement of position and orientation of the tracking device was obtained in the phantom and in vivo studies with reasonable temporal resolution. For the phantom study, the average of absolute errors in the Z-, Y-, and X-axes are 0.37, 0.76, and 0.85 mm, respectively. The mean absolute error and standard deviation of orientation measurement are 1.5 and 1.1 degrees, respectively. CONCLUSION: This positioning technique, in conjunction with a controllable tracking device, can provide accurate tracking of interventional devices in MR-guided interventions. Magn Reson Med 76:1563-1573, 2016. (c) 2015 International Society for Magnetic Resonance in Medicine. PMID- 26599343 TI - Cerebrovascular Responsiveness to Hypercapnia Is Stable over Six Months in Older Adults. AB - The primary purpose of this Brain in Motion (BIM) sub-study was to determine the 6-month stability of resting blood flow velocity and cerebrovascular responsiveness to a euoxic hypercapnic challenge in a group of physically inactive community dwelling men and men aged >=55 yrs (range 55-92 yrs). At baseline and 6 months later 88 women (65+/-6 yr) and 78 men (67+/-7 yr) completed a hypercapnic challenge (step changes from resting end-tidal PCO2 ((PETCO2) to +1, +5 and +8 mmHg above rest) while cerebral blood flow velocity was assessed using transcranial Doppler ultrasound. Peak velocity of the middle cerebral artery (MCAv) was increased (p<0.05) at the second visit during rest (51+/-2 vs. 52+/-4); however, these differences were abolished (p>0.05) when MCAv was normalized to PETCO2. During hypercapnia, MCAv tended to be increased at follow up, but this finding was absent when MCAv/PETCO2 was compared across time. Cerebrovascular reactivity (i.e., DeltaMCAv/DeltaPETCO2) was similar (p>0.05) between testing occasions regardless of the approach taken (i.e., considering only the lower step [from +1 to +5 mmHg]; the upper step [+5 to +8 mmHg]; or the complete test taken together). In conclusion, this study has shown that cerebral blood flow and cerebrovascular responsiveness to acute euoxic hypercapnia are stable in older, healthy adults over a 6-month period. Modest changes in MCAv over time must be viewed in the context of underlying differences in PETCO2, an important finding with implications for future studies considering cerebral blood flow velocity. PMID- 26599344 TI - Molecular Epidemiology of EGFR Mutations in Asian Patients with Advanced Non Small-Cell Lung Cancer of Adenocarcinoma Histology - Mainland China Subset Analysis of the PIONEER study. AB - Epidermal growth factor receptor (EGFR) mutations are the strongest response predictors to EGFR tyrosine kinase inhibitors (TKI) therapy, but knowledge of the EGFR mutation frequency on lung adenocarcinoma is still limited to retrospective studies. The PIONEER study (NCT01185314) is a prospective molecular epidemiology study in Asian patients with newly diagnosed advanced lung adenocarcinoma, aiming to prospectively analyze EGFR mutation status in IIIB/IV treatment-naive lung adenocarcinomas in Asia. We report the mainland China subset results. Eligible patients (>=20 yrs old, IIIB/IV adenocarcinoma and treatment-naive) were registered in 17 hospitals in mainland China. EGFR was tested for mutations by amplification refractory mutation system using biopsy samples. Demographic and clinical characteristics were collected for subgroup analyses. A total of 747 patients were registered. Successful EGFR mutation analysis was performed in 741, with an overall mutation rate of 50.2%. The EGFR active mutation rate is 48.0% (with 1.3% of combined active and resistance mutations). Tobacco use (>30 pack year vs. 0-10 pack-year, OR 0.27, 95%CI: 0.17-0.42) and regional lymph nodes involvement (N3 vs. N0, OR 0.47, 95%CI: 0.29-0.76) were independent predictors of EGFR mutation in multivariate analysis. However, even in regular smokers, the EGFR mutation frequency was 35.3%. The EGFR mutation frequency was similar between diverse biopsy sites and techniques. The overall EGFR mutation frequency of the mainland China subset was 50.2%, independently associated with the intensity of tobacco use and regional lymph nodes involvement. The relatively high frequency of EGFR mutations in the mainland China subset suggest that any effort to obtain tissue sample for EGFR mutation testing should be encouraged. PMID- 26599347 TI - Impact of Molecular Organization on Exciton Diffusion in Photosensitive Single Crystal Halogenated Perylenediimides Charge Transfer Interfaces. AB - The efficiency of organic photodetectors and optoelectronic devices is strongly limited by exciton diffusion, in particular for acceptor materials. Although mechanisms for exciton diffusion are well established, their correlation to molecular organization in real systems has received far less attention. In this report, organic single-crystals interfaces were probed with wavelength-dependent photocurrent spectroscopy and their crystal structure resolved using X-ray diffraction. All systems present a dynamic photoresponse, faster than 500 ms, up to 650 nm. A relationship between molecular organization and favorable exciton diffusion in substituted butyl-perylenediimides (PDIB) is established. This is demonstrated by a set of PDIBs with different intra- and interstack distances and short contacts and their impact on photoresponse. Given the short packing distances between PDIs cores along the same stacking direction (3.4-3.7 A), and across parallel stacks (2.5 A), singlet exciton in these PDIBs can follow both Forster and Dexter exciton diffusion, with the Dexter-type mechanism assuming special relevance for interstack exciton diffusion. Yet, the response is maximized in substituted PDIBs, where a 2D percolation network is formed through strong interstack contacts, allowing for PDIBs primary excitons to reach with great efficiency the splitting interface with crystalline rubrene. The importance of short contacts and molecular distances, which is often overlooked as a parameter to consider and optimize when choosing materials for excitonic devices, is emphasized. PMID- 26599345 TI - Glycan analysis of therapeutic glycoproteins. AB - Therapeutic monoclonal antibodies (mAbs) are glycoproteins produced by living cell systems. The glycan moieties attached to the proteins can directly affect protein stability, bioactivity, and immunogenicity. Therefore, glycan variants of a glycoprotein product must be adequately analyzed and controlled to ensure product quality. However, the inherent complexity of protein glycosylation poses a daunting analytical challenge. This review provides an update of recent advances in glycan analysis, including the potential utility of lectin-based microarray for high throughput glycan profiling. Emphasis is placed on comparison of the major types of analytics for use in determining unique glycan features such as glycosylation site, glycan structure, and content. PMID- 26599348 TI - Optimization of human dose prediction by using quantitative and translational pharmacology in drug discovery. AB - In this perspective article, we explain how quantitative and translational pharmacology, when well-implemented, is believed to lead to improved clinical candidates and drug targets that are differentiated from current treatment options. Quantitative and translational pharmacology aims to build and continuously improve the quantitative relationship between drug exposure, target engagement, efficacy, safety and its interspecies relationship at every phase of drug discovery. Drug hunters should consider and apply these concepts to develop compounds with a higher probability of interrogating the clinical biological hypothesis. We offer different approaches to set an initial effective concentration or pharmacokinetic-pharmacodynamic target in man and to predict human pharmacokinetics that determine together the predicted human dose and dose schedule. All concepts are illustrated with ample literature examples. PMID- 26599346 TI - Orbital Metastasis Is Associated With Decreased Survival in Stage M Neuroblastoma. AB - BACKGROUND: Approximately 30% of patients with metastatic (stage M) neuroblastoma present with periorbital ecchymosis from orbital osseous disease. Though locoregional disease is staged by imaging, the prognostic significance of metastatic site in stage M disease is unknown. We hypothesize that, compared to nonorbital metastasis, orbital metastasis is associated with decreased survival in patients with stage M neuroblastoma, and that periorbital ecchymosis reflects location and extent of orbital disease. PROCEDURE: Medical records and imaging from 222 patients with stage M neuroblastoma seen at St. Jude Children's Research Hospital between January 1995 and May 2009 were reviewed. Thirty-seven patients were <18 months of age at diagnosis and 185 were >=18 months of age. Overall survival (OS) and 5-year survival (5YS) were compared for patients with and without orbital, calvarial and nonorbital osseous metastasis, and with and without periorbital ecchymosis (log-rank test). Associations of periorbital ecchymosis with orbital metastasis location/extent were explored (Fisher's exact test, t-test). RESULTS: In patients >=18 months of age, only orbital metastasis was associated with decreased 5YS (P = 0.0323) and OS (P = 0.0288). In patients <18 months of age, neither orbital, calvarial, or nonorbital bone metastasis was associated with OS or 5YS. Periorbital ecchymosis was associated with higher number of involved orbital bones (P = 0.0135), but not location or survival. CONCLUSIONS: In patients >= 18 months of age with stage M neuroblastoma, orbital metastatic disease is associated with decreased 5YS and OS. In future clinical trials, orbital disease may be useful as an imaging-based risk factor for substratification of stage M neuroblastoma. PMID- 26599349 TI - The Association of Type 2 Diabetes Loci Identified in Genome-Wide Association Studies with Metabolic Syndrome and Its Components in a Chinese Population with Type 2 Diabetes. AB - Metabolic syndrome (MetS) is prevalent in type 2 diabetes (T2D) patients. The comorbidity of MetS and T2D increases the risk of cardiovascular complications. The aim of the present study was to determine the T2D-related genetic variants that contribute to MetS-related components in T2D patients of Chinese ancestry. We successfully genotyped 25 genome wide association study validated T2D-related single nucleotide polymorphisms (SNPs) among 5,169 T2D individuals and 4,560 normal glycemic controls recruited from the Chinese National Diabetes and Metabolic Disorders Study (DMS). We defined MetS in this population using the harmonized criteria (2009) combined with the Chinese criteria for abdominal obesity. The associations between SNPs and MetS-related components, as well as the associations between SNPs and risk for T2D with or without MetS, were subjected to logistic regression analysis adjusted for age and sex. Results showed that the T2D risk alleles of rs243021 located near BCL11A, rs10830963 in MTNR1B, and rs2237895 in KCNQ1 were related to a lower risk for abdominal obesity in T2D patients (rs243021: 0.92 (0.84, 1.00), P = 4.42 * 10-2; rs10830963: 0.92 (0.85, 1.00), P = 4.07 * 10-2; rs2237895: 0.89 (0.82, 0.98), P = 1.29 * 10-2). The T2D risk alleles of rs972283 near KLF14 contributed to a higher risk of elevated blood pressure (1.10 (1.00, 1.22), P = 4.48 * 10-2), while the T2D risk allele of rs7903146 in TCF7L2 was related to a lower risk for elevated blood pressure (0.74 (0.61, 0.90), P = 2.56 * 10-3). The T2D risk alleles of rs972283 near KLF14 and rs11634397 near ZFAND6 were associated with a higher risk for elevated triglycerides (rs972283: 1.11 (1.02, 1.24), P = 1.46 * 10-2; rs11634397: 1.14 (1.00, 1.29), P = 4.66 * 10-2), while the T2D risk alleles of rs780094 in GCKR and rs7903146 in TCF7L2 were related to a lower risk of elevated triglycerides (rs780094: 0.86 (0.80, 0.93), P = 1.35 * 10-4; rs7903146: 0.82 (0.69, 0.98), P = 3.18 * 10-2). The genotype risk score of the 25 T2D-related SNPs was related to a lower risk for abdominal obesity (Ptrend = 1.29 * 10-2) and lower waist circumference (P = 2.20 * 10-3). Genetic variants of WFS1, CDKAL1, CDKN2BAS, TCF7L2, HHEX, KCNQ1, TSPAN8/LGR5, FTO, and TCF2 were associated with the risk for T2D with MetS, as well as the risk for development of T2D with at least one of the MetS components (P < 0.05). In addition, genetic variants of BCL11A, GCKR, ADAMTS9, CDKAL1, KLF14, CDKN2BAS, TCF7L2, CDC123/CAMK1D, HHEX, MTNR1B, and KCNQ1 contributed to the risk for T2D without MetS (P < 0.05). In conclusion, these findings highlight the contribution of T2D-related genetic loci to MetS in a Chinese Han population. The study also provides insight into the pleotropic effects of genome-wide association loci of diabetes on metabolic regulation. PMID- 26599350 TI - Altered incubation temperatures between embryonic Days 7 and 13 influence the weights and the mitochondrial respiratory and enzyme activities in breast and leg muscles of broiler embryos. AB - Altering incubation temperature during embryogenesis has an impact on chicken embryo growth, but the underlying molecular mechanisms are not understood; the present study was performed to address these changes. Broiler eggs were incubated at low (36.8 degrees C), control (37.8 degrees C), and high (38.8 degrees C) temperatures between Embryonic Day (ED) 7 and 10 or ED 10 and 13, which cover critical periods of embryonic myogenesis. The embryos were then dissected immediately after treatment on ED 10 or 13 to assess body, liver, and heart weights as well as to analyze breast and leg muscle fibers for their mitochondrial respiratory activity (MRA). Breast muscle samples were additionally used to evaluate the activity of enzymes involved in energy metabolism and cell cycle progression. ED-10 embryos incubated at 38.8 degrees C showed elevated weights (body, liver, and heart), MRA, and activities of lactate dehydrogenase and cytochrome oxidase compared to the ED-10 embryos incubated at 36.8 degrees C. Similarly, the ED-13 embryos incubated at 38.8 degrees C showed elevated body weight, MRA, and activities of glycogen phosphorylase, phosphofructokinase, and cytochrome oxidase compared to their 36.8 degrees C counterparts. Embryos incubated at the normal temperature (37.8 degrees C), however, showed variable differences from those incubated at 38.8 degrees C versus 36.8 degrees C. Cell cycle enzyme activities were not impacted by the different temperature treatments. Thus, an increase or decrease in the incubation temperature during embryonic broiler myogenesis results in altered embryo activity, muscle energy metabolism, and activity-dependent muscle growth. PMID- 26599353 TI - The jury may be out, but it is important that it deliberates: a response to Besnard and Rubio de Casas about olive domestication. PMID- 26599352 TI - Discovery of Novel Potent and Selective Agonists at the Melanocortin-3 Receptor. AB - The melanocortin receptors 3 and 4 control energy homeostasis, food-intake behavior, and correlated pathophysiological conditions. The melanocortin-4 receptor (MC4R) has been broadly investigated. In contrast, the knowledge related to physiological roles of the melanocortin-3 receptor (MC3R) is lacking because of the limited number of known MC3R selective ligands. Here, we report the design, synthesis, biological activity, conformational analysis, and docking with receptors of two potent and selective agonists at the human MC3 receptor. PMID- 26599351 TI - Clinical patterns of hepatocellular carcinoma in nonalcoholic fatty liver disease: A multicenter prospective study. AB - Nonalcoholic fatty liver disease (NAFLD) represents the hepatic manifestation of metabolic syndrome and may evolve into hepatocellular carcinoma (HCC). Only scanty clinical information is available on HCC in NAFLD. The aim of this multicenter observational prospective study was to assess the clinical features of patients with NAFLD-related HCC (NAFLD-HCC) and to compare them to those of hepatitis C virus (HCV)-related HCC. A total of 756 patients with either NAFLD (145) or HCV-related chronic liver disease (611) were enrolled in secondary care Italian centers. Survival was modeled according to clinical parameters, lead-time bias, and propensity analysis. Compared to HCV, HCC in NAFLD patients had a larger volume, showed more often an infiltrative pattern, and was detected outside specific surveillance. Cirrhosis was present in only about 50% of NAFLD HCC patients, in contrast to the near totality of HCV-HCC. Regardless of tumor stage, survival was significantly shorter (P = 0.017) in patients with NAFLD-HCC, 25.5 months (95% confidence interval 21.9-29.1), than in those with HCV-HCC, 33.7 months (95% confidence interval 31.9-35.4). To eliminate possible confounders, a propensity score analysis was performed, which showed no more significant difference between the two groups. Additionally, analysis of patients within Milan criteria submitted to curative treatments did not show any difference in survival between NAFLD-HCC and HCV-HCC (respectively, 38.6 versus 41.0 months, P = nonsignificant) CONCLUSIONS: NAFLD-HCC is more often detected at a later tumor stage and could arise also in the absence of cirrhosis, but after patient matching, it has a similar survival rate compared to HCV infection; a future challenge will be to identify patients with NAFLD who require more stringent surveillance in order to offer the most timely and effective treatment. PMID- 26599354 TI - Nanotechnology based anti-infectives to fight microbial intrusions. AB - With the rise in human population across the globe especially in developing countries, the incidence of microbial infections are increasing with greater pace. On the other hand, available medication and therapies are found to be insufficient for the complete cure of such microbial infections due to the development of resistance against various antibiotics. Therefore, to cope up the menace of microbial infections and drug resistance, there is demand for new and compelling technology, which has the ability to impede these problems. Many research groups worldwide are finding a ray of hope in nanomaterials owing to their unique properties. In the present review we have discussed the reasons behind the development of new materials based on nanotechnology. It is mainly focused on pioneering studies on application of nanomaterials like carbon nanotube, fullerene, dendrimers, nanocomposite and metal nanoparticles in combating dreadful pathogens. Moreover, the concerns about their toxicity have also been discussed. PMID- 26599355 TI - 'We don't tell people what to do': ethical practice and Indigenous health promotion. AB - Health promotion aspires to work in empowering, participatory ways, with the goal of supporting people to increase control over their health. However, buried in this goal is an ethical tension: while increasing people's autonomy, health promotion also imposes a particular, health promotion-sanctioned version of what is good. This tension positions practitioners precariously, where the ethos of empowerment risks increasing health promotion's paternalistic control over people, rather than people's control over their own health. Herein we argue that this ethical tension is amplified in Indigenous Australia, where colonial processes of control over Indigenous lands, lives and cultures are indistinguishable from contemporary health promotion 'interventions'. Moreover, the potential stigmatisation produced in any paternalistic acts 'done for their own good' cannot be assumed to have evaporated within the self-proclaimed 'empowering' narratives of health promotion. This issue's guest editor's call for health promotion to engage 'with politics and with philosophical ideas about the state and the citizen' is particularly relevant in an Indigenous Australian context. Indigenous Australians continue to experience health promotion as a moral project of control through intervention, which contradicts health promotion's central goal of empowerment. Therefore, Indigenous health promotion is an invaluable site for discussion and analysis of health promotion's broader ethical tensions. Given the persistent and alarming Indigenous health inequalities, this paper calls for systematic ethical reflection in order to redress health promotion's general failure to reduce health inequalities experienced by Indigenous Australians. PMID- 26599356 TI - Whole-Genome Sequencing of Three Clonal Clinical Isolates of B. cenocepacia from a Patient with Cystic Fibrosis. AB - Burkholderia cepacia complex bacteria are amongst the most feared of pathogens in cystic fibrosis (CF). The BCC comprises at least 20 distinct species that can cause chronic and unpredictable lung infections in CF. Historically the species B. cenocepacia has been the most prevalent in CF infections and has been associated in some centers with high rates of mortality. Modeling chronic infection by B. cenocepacia in the laboratory is challenging and no models exist which effectively recapitulate CF disease caused by BCC bacteria. Therefore our understanding of factors that contribute towards the morbidity and mortality caused by this organism is limited. In this study we used whole-genome sequencing to examine the evolution of 3 clonal clinical isolates of B. cenocepacia from a patient with cystic fibrosis. The first isolate was from the beginning of infection, and the second two almost 10 years later during the final year of the patients' life. These isolates also demonstrated phenotypic heterogeneity, with the first isolate displaying the mucoid phenotype (conferred by the overproduction of exopolysaccharide), while one of the later two was nonmucoid. In addition we also sequenced a nonmucoid derivative of the initial mucoid isolate, acquired in the laboratory by antibiotic pressure. Examination of sequence data revealed that the two late stage isolates shared 20 variant nucleotides in common compared to the early isolate. However, despite their isolation within 10 months of one another, there was also considerable variation between the late stage isolates, including 42 single nucleotide variants and three deletions. Additionally, no sequence differences were identified between the initial mucoid isolate and its laboratory acquired nonmucoid derivative, however transcript analysis indicated at least partial down regulation of genes involved in exopolysaccharide production. Our study examines the progression of B. cenocepacia throughout chronic infection, including establishment of sub populations likely evolved from the original isolate, suggestive of parallel evolution. Additionally, the lack of sequence differences between two of the isolates with differing mucoid phenotypes suggests that other factors, such as gene regulation, come into play in establishing the mucoid phenotype. PMID- 26599358 TI - Contents Vol. 15, 2015. PMID- 26599357 TI - TCD-Profiling Using AVERAGE. A New Technique to Evaluate Transcranial Doppler Ultrasound Flow Spectra of Subjects with Cerebral Small Vessel Disease. AB - BACKGROUND: There is an unmet need for screening methods to detect and quantify cerebral small vessel disease (SVD). Transcranial Doppler ultrasound (TCD) flow spectra of the larger intracranial arteries probably contain relevant information about the microcirculation. However, it has not yet been possible to exploit this information as a valuable biomarker. METHODS: We developed a technique to generate normalized and averaged flow spectra during middle cerebral artery Doppler ultrasound examinations. Second, acceleration curves were calculated, and the absolute amount of the maximum positive and negative acceleration was calculated. Findings were termed 'TCD-profiling coefficient' (TPC). Validation study: we applied this noninvasive method to 5 young adults for reproducibility. Degenerative microangiopathy study: we also tested this new technique in 30 elderly subjects: 15 free of symptoms but with MRI-verified presence of cerebral SVD, and 15 healthy controls. SVD severity was graded according to a predefined score. Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) study: TPC values of 10 CADASIL patients were compared with those of 10 healthy controls. Pulse wave analysis and local measurements of carotid stiffness were also performed. CADASIL patients were tested for cognitive impairment with the Montreal Cognitive Assessment scale. White matter and basal ganglia lesions in their cerebral MRI were evaluated according to the Wahlund score. RESULTS: Validation study: the technique delivered reproducible results. Degenerative microangiopathy study: patients with SVD had significantly larger TPCs compared with controls (SVD: 2,132; IQR 1,960 2,343%/s vs. CONTROLS: 1,935; IQR 1,782-2,050%/s, p = 0.01). TPC values of subjects with SVD significantly correlated with SVD severity scores (R = 0.58, n = 15, p < 0.05). CADASIL study: TPC values of CADASIL patients were significantly higher than values of the controls (CADASIL: 2,504; IQR 2,308-2,930%/s vs. controls 2,084; 1,839-2,241%/s, p = 0.008), and also significantly higher than the TPC values of the patients with SVD from the degenerative microangiopathy study (p = 0.007). CADASIL patients had significantly worse cognitive test results than healthy controls. CONCLUSION: TCD-profiling detects impairment of the cerebral microcirculatory state. The suitability of the TCD-profiling for the evaluation of cerebral microangiopathy was confirmed. PMID- 26599359 TI - Correction: Handling Permutation in Sequence Comparison: Genome-Wide Enhancer Prediction in Vertebrates by a Novel Non-Linear Alignment Scoring Principle. AB - [This corrects the article DOI: 10.1371/journal.pone.0141487.]. PMID- 26599360 TI - Reduction of Adipose Tissue Mass by the Angiogenesis Inhibitor ALS-L1023 from Melissa officinalis. AB - It has been suggested that angiogenesis modulates adipogenesis and obesity. This study was undertaken to determine whether ALS-L1023 (ALS) prepared by a two-step organic solvent fractionation from Melissa leaves, which exhibits antiangiogenic activity, can regulate adipose tissue growth. The effects of ALS on angiogenesis and extracellular matrix remodeling were measured using in vitro assays. The effects of ALS on adipose tissue growth were investigated in high fat diet induced obese mice. ALS inhibited VEGF- and bFGF-induced endothelial cell proliferation and suppressed matrix metalloproteinase (MMP) activity in vitro. Compared to obese control mice, administration of ALS to obese mice reduced body weight gain, adipose tissue mass and adipocyte size without affecting appetite. ALS treatment decreased blood vessel density and MMP activity in adipose tissues. ALS reduced the mRNA levels of angiogenic factors (VEGF-A and FGF-2) and MMPs (MMP-2 and MMP-9), whereas ALS increased the mRNA levels of angiogenic inhibitors (TSP-1, TIMP-1, and TIMP-2) in adipose tissues. The protein levels of VEGF, MMP-2 and MMP-9 were also decreased by ALS in adipose tissue. Metabolic changes in plasma lipids, liver triglycerides, and hepatic expression of fatty acid oxidation genes occurred during ALS-induced weight loss. These results suggest that ALS, which has antiangiogenic and MMP inhibitory activities, reduces adipose tissue mass in nutritionally obese mice, demonstrating that adipose tissue growth can be regulated by angiogenesis inhibitors. PMID- 26599362 TI - Structural analysis of bovine norovirus protruding domain. AB - We determined a structure of a bovine (genogroup III, GIII) norovirus capsid protruding (P) domain using X-ray crystallography. The bovine P domain was reminiscent of other norovirus genogroups (GI, GII, GIV, and GV), but closely matched the human GI P domain. We also identified a monoclonal antibody that was capable of binding the five different (GI-GV) P domains. Our data suggests that genetically diverse noroviruses still contain common epitopes. PMID- 26599361 TI - Phenotype, Body Composition, and Prediction Equations (Indian Fatty Liver Index) for Non-Alcoholic Fatty Liver Disease in Non-Diabetic Asian Indians: A Case Control Study. AB - OBJECTIVE: In this study, we have attempted comparison of detailed body composition phenotype of Asian Indians with non-alcoholic fatty liver disease (NAFLD) vs. those without, in a case controlled manner. We also aim to analyse prediction equations for NAFLD for non-diabetic Asian Indians, and compare performance of these with published prediction equations researched from other populations. METHODS: In this case-control study, 162 cases and 173 age-and sex matched controls were recruited. Clinical, anthropometric, metabolic, and body composition profiles, and liver ultrasound were done. Fasting insulin levels, value of homeostasis model assessment of insulin resistance (HOMA-IR), and serum high sensitive C-reactive protein (hs-CRP) levels were evaluated. Multivariate logistic and linear regression analyses were used to arrive at prediction equations for fatty liver [Indian fatty liver index (IFLI)]. RESULTS: As compared to those without fatty liver, those with fatty liver exhibited the following; Excess dorsocervical fat ('Buffalo hump'), skin tags, xanthelasma, 'double chin', arcus; excess total, abdominal and subcutaneous adiposity, and high blood pressure, blood glucose, measures of insulin resistance (fasting insulin and HOMA IR values), lipids and hs-CRP levels. Two prediction equations were developed; Clinical [Indian Fatty Liver Index-Clinical; IFLI-C]: 1(double chin) +15.5 (systolic blood pressure) +13.8 (buffalo hump); and IFLI-Clinical and Biochemical (CB): serum triglycerides+12 (insulin)+1(systolic blood pressure) +18 (buffalo hump). On ROC Curve analysis, IFLI performed better than all published prediction equations, except one. CONCLUSION: Non-diabetic Asian Indians with NAFLD researched by us were overweight/obese, had excess abdominal and subcutaneous fat, multiple other phenotypic markers, had higher insulin resistance, glycemia, dyslipidemia and subclinical inflammation than those without. Prediction score developed by us for NAFLD; IFLI-C and IFLI-CB, should be useful for clinicians and researchers. PMID- 26599363 TI - Deliberately generated and imitated facial expressions of emotions in people with eating disorders. AB - BACKGROUND: People with eating disorders have difficulties in socio emotional functioning that could contribute to maintaining the functional consequences of the disorder. This study aimed to explore the ability to deliberately generate (i.e., pose) and imitate facial expressions of emotions in women with anorexia (AN) and bulimia nervosa (BN), compared to healthy controls (HC). METHODS: One hundred and three participants (36 AN, 25 BN, and 42 HC) were asked to pose and imitate facial expressions of anger, disgust, fear, happiness, and sadness. Their facial expressions were recorded and coded. RESULTS: Participants with eating disorders (both AN and BN) were less accurate than HC when posing facial expressions of emotions. Participants with AN were less accurate compared to HC imitating facial expressions, whilst BN participants had a middle range performance. All results remained significant after controlling for anxiety, depression and autistic features. LIMITATIONS: The relatively small number of BN participants recruited for this study. CONCLUSIONS: The study findings suggest that people with eating disorders, particularly those with AN, have difficulties posing and imitating facial expressions of emotions. These difficulties could have an impact in social communication and social functioning. This is the first study to investigate the ability to pose and imitate facial expressions of emotions in people with eating disorders, and the findings suggest this area should be further explored in future studies. PMID- 26599364 TI - Characteristics and heterogeneity of schizoaffective disorder compared with unipolar depression and schizophrenia - a systematic literature review and meta analysis. AB - BACKGROUND: Comparisons of illness characteristics between patients with schizoaffective disorder (SAD) patients and unipolar depression (UD) are rare, even though UD is one of the most important differential diagnoses of SAD. Also, the variability of illness characteristics (heterogeneity) has not been compared. We compared illness characteristics and their heterogeneity among SAD, UD, and - as another important differential diagnosis - schizophrenia (S). METHODS: In order to reduce sampling bias we systematically searched for studies simultaneously comparing samples of patients with SAD, UD, and S. Using random effects and Mantel-Haenszel models we estimated and compared demographic, illness course and psychopathology parameters, using pooled standard deviations as a measurement of heterogeneity. RESULTS: Out of 155 articles found by an earlier meta-analysis, 765 screened in Medline, 2738 screened in EMBASE, and 855 screened in PsycINFO we selected 24 studies, covering 3714 patients diagnosed according to RDC, DSM-III, DSM-IIIR, DSM-IV, or ICD-10. In almost all key characteristics, samples with schizoaffective disorders fell between unipolar depression and schizophrenia, with a tendency towards schizophrenia. On average, UD patients were significantly older at illness onset (33.0 years, SAD: 25.2, S: 23.4), more often women (59% vs. 57% vs. 39%) and more often married (53% vs. 39% vs. 27%). Their psychopathology was also less severe, as measured by BPRS, GAS, and HAMD. In demographic and clinical variables heterogeneity was roughly 5% larger in UD than in SAD, and samples of patients with schizophrenia had the lowest pooled heterogeneity. A similar picture emerged in a sensitivity analysis with coefficient of variation as the measurement of heterogeneity. LIMITATIONS: Relative to bipolar disorder there are fewer studies including unipolar patients. No studies based on DSM-5 could be included. CONCLUSIONS: Regarding unipolar affective disorder this study confirms what we have shown for bipolar disorders in earlier studies: schizoaffective disorder falls between schizophrenia and affective disorders, and there are relevant quantitative differences in key illness characteristics, which supports the validity of the schizoaffective disorder concept. Contrary to our expectations heterogeneity is not larger in SAD than in UD and not substantially higher than in S. Lower reliability of the diagnosis of SAD therefore cannot be ascribed to higher variability of illness characteristics in SAD. PMID- 26599365 TI - Epidemiology of Enterovirus D68 in Ontario. AB - In August 2014, children's hospitals in Kansas City, Missouri and Chicago, Illinois notified the Centers for Disease Control and Prevention (CDC) about increased numbers of pediatric patients hospitalized with severe respiratory illness (SRI). In response to CDC reports, Public Health Ontario Laboratories (PHOL) launched an investigation of patients being tested for enterovirus D-68 (EV-D68) in Ontario, Canada. The purpose of this investigation was to enhance our understanding of EV-D68 epidemiology and clinical features. Data for this study included specimens submitted for EV-D68 testing at PHOL from September 1, 2014 to October 31, 2014. Comparisons were made between patients who tested positive for the virus (cases) and those testing negative (controls). EV-D68 was identified in 153/907 (16.8%) of patients tested. In the logistic regression model adjusting for age, sex, setting and time to specimen collection, individuals younger than 20 years of age were more likely to be diagnosed with EV-D68 compared to those 20 and over, with peak positivity at ages 5-9 years. Cases were not more likely to be hospitalized than controls. Cases were more likely to be identified in September than October (OR 8.07; 95% CI 5.15 to 12.64). Routine viral culture and multiplex PCR were inadequate methods to identify EV-D68 due to poor sensitivity and inability to differentiate EV-D68 from other enterovirus serotypes or rhinovirus. Testing for EV-D68 in Ontario from July to December, 2014 detected the presence of EV-D68 virus among young children during September-October, 2014, with most cases detected in September. There was no difference in hospitalization status between cases and controls. In order to better understand the epidemiology of this virus, surveillance for EV-D68 should include testing of symptomatic individuals from all treatment settings and patient age groups, with collection and analysis of comprehensive clinical and epidemiological data. PMID- 26599366 TI - First Structural View of a Peptide Interacting with the Nucleotide Binding Domain of Heat Shock Protein 90. AB - The involvement of Hsp90 in progression of diseases like cancer, neurological disorders and several pathogen related conditions is well established. Hsp90, therefore, has emerged as an attractive drug target for many of these diseases. Several small molecule inhibitors of Hsp90, such as geldanamycin derivatives, that display antitumor activity, have been developed and are under clinical trials. However, none of these tested inhibitors or drugs are peptide-based compounds. Here we report the first crystal structure of a peptide bound at the ATP binding site of the N-terminal domain of Hsp90. The peptide makes several specific interactions with the binding site residues, which are comparable to those made by the nucleotide and geldanamycin. A modified peptide was designed based on these interactions. Inhibition of ATPase activity of Hsp90 was observed in the presence of the modified peptide. This study provides an alternative approach and a lead peptide molecule for the rational design of effective inhibitors of Hsp90 function. PMID- 26599368 TI - Correlation of action potentials in adjacent neurons. AB - A possible mechanism for the synchronization of action potential propagation along a bundle of neurons (ephaptic coupling) is considered. It is shown that this mechanism is similar to the salutatory conduction of the action potential between the nodes of Ranvier in myelinated axons. The proposed model allows us to estimate the scale of the correlation, i.e., the distance between neurons in the nervous tissue, wherein their synchronization becomes possible. The possibility for experimental verification of the proposed model of synchronization is discussed. PMID- 26599367 TI - MFHAS1 Is Associated with Sepsis and Stimulates TLR2/NF-kappaB Signaling Pathway Following Negative Regulation. AB - Malignant fibrous histiocytoma amplified sequence 1 (MFHAS1) has a potential immunoregulatory role dependent on Toll-like receptors (TLRs). TLR2, associated with deleterious systemic inflammation, cardiac dysfunction, and acute kidney injury, acts synergistically in sepsis. The role of MFHAS1 in targeting TLR2 involved in sepsis has not been examined thus far. This study aimed to examine the relationship of MFHAS1 and sepsis, and the effect of MFHAS1 on the TLR2 signaling pathway. Blood samples were collected from eight sepsis patients after surgery and eight patients undergoing selective surgery to determine blood MFHAS1 levels. HEK 293 cells, RAW 264.7 macrophages and THP-1 monocytes were used to confirm the effect of MFHAS1 on TLR2 signaling pathway. Our study showed that blood MFHAS1 was significantly elevated in septic patients, and MFHAS1 was more increased in mononuclear cells from septic patients. Pam3CSK4 (TLR2 ligand) was found to induce MFHAS1 production in RAW 264.7 murine macrophages and THP-1 human monocytes in a time-dependent manner. MFHAS1 has dual effects on TLR2 signaling pathway and inflammation, i.e., inhibitory effect at 6 hours, and then stimulatory effect after 24 hours through the activation of TLR2/NF-kappaB signaling pathway, and MFHAS1 induced the phosphorylation of JNK and p38 after TLR2 stimulation. PMID- 26599369 TI - Correction: Ion Frequency Landscape in Growing Plants. AB - [This corrects the article DOI: 10.1371/journal.pone.0138839.]. PMID- 26599370 TI - Tumor Necrosis Factor Inhibition and Head and Neck Cancer Recurrence and Death in Rheumatoid Arthritis. AB - The objective of this retrospective cohort study was to determine the effect of tumor necrosis factor inhibitor (TNFi) therapy on the risk of head and neck cancer (HNC) recurrence or HNC-attributable death in patients with rheumatoid arthritis (RA). RA patients with HNC were assembled from the US national Veterans' Affairs (VA) administrative databases, and diagnoses confirmed and data collected by electronic medical record review. The cohort was divided into those treated with non-biologic disease-modifying anti-rheumatic drugs (nbDMARDs) versus TNF inhibitors (TNFi) after a diagnosis of HNC. Likelihood of a composite endpoint of recurrence or HNC-attributable death was determined by Cox proportional hazards regression. Of 180 patients with RA and HNC, 31 were treated with TNFi and 149 with nbDMARDs after the diagnosis of HNC. Recurrence or HNC attributable death occurred in 5/31 (16.1%) patients in the TNFi group and 44/149 (29.5%) patients in the nbDMARD group (p = 0.17); it occurred in 2/16 (13%) patients who received TNFi in the year prior to HNC diagnosis but not after. Overall stage at diagnosis (p = 0.03) and stage 4 HNC (HR 2.49 [CI 1.06-5.89]; p = 0.04) were risk factors for recurrence or HNC-attributable death; treatment with radiation or surgery was associated with a lower risk (HR 0.35 [CI 0.17 0.74]; p = 0.01 and HR 0.39 [CI 0.20-0.76]; p = 0.01 respectively). Treatment with TNFi was not a risk factor for recurrence or HNC-attributable death (HR 0.75; CI 0.31-1.85; p = 0.54). We conclude that treatment with TNFi may be safe in patients with RA and HNC, especially as the time interval between HNC treatment and non-recurrence increases. In this study, TNF inhibition was not associated with an increase in recurrence or HNC-attributable death. PMID- 26599371 TI - Judgments of learning are significantly higher following feedback on relatively good versus relatively poor trials despite no actual learning differences. AB - Studies have consistently shown that prospective metacognitive judgments of learning are often inaccurate because humans mistakenly interpret current performance levels as valid indices of learning. These metacognitive discrepancies are strongly related to conditions of practice. Here, we examined how the type of feedback (after good versus poor trials) received during practice and awareness (aware versus unaware) of this manipulation affected judgments of learning and actual learning. After each six-trial block, participants received feedback on their three best trials or three worst trials and half of the participants were made explicitly aware of the type of feedback they received while the other half were unaware. Judgments of learning were made at the end of each six-trial block and before the 24-h retention test. Results indicated no motor performance differences between groups in practice or retention; however, receiving feedback on relatively good compared to relatively poor trials resulted in significantly higher judgments of learning in practice and retention, irrespective of awareness. These results suggest that KR on relatively good versus relatively poor trials can have dissociable effects on judgments of learning in the absence of actual learning differences, even when participants are made aware of their feedback manipulation. PMID- 26599372 TI - Asthma Trigger Reports Are Associated with Low Quality of Life, Exacerbations, and Emergency Treatments. AB - RATIONALE: Despite the importance of trigger perceptions for asthma diagnosis and management, associations among asthma triggers, affective disorders, and asthma outcome have received little attention. OBJECTIVES: Because anxiety and depression are known to influence patients' health reports, we measured and controlled for these affective disorders in analyzing associations among patient perceptions of asthma triggers and asthma treatment outcomes. METHODS: Patients from a nationally representative sample of respiratory specialist practices (N = 459) were assessed for clinically significant anxiety and depression and completed questionnaires on asthma triggers, quality of life, and asthma control. Physicians recorded exacerbation and emergency treatment frequencies in the prior year, spirometric lung function, and allergy test results. Hierarchical multiple regressions examined associations among reported trigger factors, anxiety, depression, and asthma outcomes, including quality of life, asthma control, exacerbations, emergencies, and spirometry. MEASUREMENTS AND MAIN RESULTS: Patients across asthma severity levels were well represented. Anxiety and depression were associated with more frequent nonallergic, in particular psychological, triggers. Controlling for demographics, asthma severity, anxiety, and depression, nonallergic asthma triggers (including psychological triggers) explained substantial portions of variance in asthma control (total of 19.5%, odds ratios [ORs] = 2.07-1.37 for individual triggers), asthma-related quality of life (total of 27.5%, ORs = 3.21-1.49), and general quality of life (total of 11.3%, ORs = 1.93-1.55). Psychological triggers were consistently associated with exacerbations and emergency treatments (ORs = 1.96-2.04) over and above other triggers and affective disorders. Spirometric lung function was largely unrelated to perceived asthma triggers. CONCLUSIONS: Patients' perceptions of asthma triggers are important determinants of asthma outcomes, which can help identify individuals at risk for suboptimal asthma management. PMID- 26599373 TI - Drowning in Pretoria, South Africa: A 10-year review. AB - Drowning is classified as the 3rd leading cause of accidental deaths worldwide and is deemed to be a preventable cause of death. Bodies retrieved from a water medium pose several challenges to the forensic pathologist with the diagnosis of drowning being primarily one of exclusion. The aim of this study was to do a retrospective descriptive case audit of bodies retrieved from water and immersion related deaths, which were investigated at the Pretoria Medico-Legal Laboratory (PMLL) over a 10 year period (January 2002 through December 2011). A total of 346 cases were identified for inclusion into this study. In 6% (20) of these cases, the death was not related to drowning; in 14% (48) no clear cause of death could be ascertained and in 278 cases (80%) the cause of death was considered to have been due to drowning. Infants (under 1 year, of age) constituted 41 (15%) of the cases; toddlers (aged 1-2 years) comprised 52 (19%) cases; children (aged 2-13 years) 49 (18%) cases; adolescents (aged 13-18 years) comprised 10 (3%) cases; adults (above 18, years) made up 126 (45%) of the cases. The majority of the drownings, occurred in swimming pools [125 cases (38%)]. In infants 23 (56%) of, drownings occurred in swimming pools followed by buckets [7 cases (17%)]. Sixty nine per cent of toddler drownings (36 cases) occurred in swimming, pools. In the adult population, 40 (32%) of cases occurred in pools and 35 cases (28%) in rivers. Positive blood alcohol results were recorded in 48, (42%) out of 113 cases where the test was requested, 40 (35%) of these, cases higher than 0.05 g per 100 ml. This study suggests that many drowning deaths in Pretoria may be preventable by introducing greater public awareness of the risks and instituting relatively simple, protective measures. PMID- 26599374 TI - The hazard of sharp force injuries: Factors influencing outcome. AB - The risk of dying from sharp force injury is difficult to ascertain. To the best of our knowledge, no study has been performed in Norway regarding mortality due to sharp force injury or factors that impact survival. Thus, the objective of the present study was to investigate and assess mortality in subjects with sharp force injury. This retrospective study comprises data on 136 subjects (34 female, 102 male) with suspected severe sharp force injury (self-inflicted or inflicted by others) admitted to Haukeland University Hospital between 2001 and 2010. The majority of subjects were intoxicated, and the injury was most often inflicted by a knife. The incidence of sharp force injury in Western Norway is similar to the incidence in other European countries. Almost half of the subjects with self inflicted injury died. In cases with injury inflicted by another individual, one in five died. Mortality rates were higher in those with penetrating chest injuries than those with penetrating abdominal injuries and higher in cases with cardiac injury compared to pleural or lung injury. Sharp force injury can be fatal, but the overall mortality rate in this study was 29%. Factors influencing mortality rate were the number of injuries, the topographic regions of the body injured, the anatomical organs/structures inflicted, and emergency measures performed. PMID- 26599375 TI - Director of Health Promotion Program. PMID- 26599376 TI - Evening intake of aspirin is associated with a more stable 24-h platelet inhibition compared to morning intake: a study in chronic aspirin users. AB - Daily generation of novel platelets may compromise aspirin's platelet inhibitory action, especially near the end of the regular 24-h dosing interval. A contributor to this attenuation could be the endogenous circadian rhythm. The primary objective of this study was to assess platelet activity 12 and 24 h after different times of aspirin intake (c.q. 8.00 AM and 8.00 PM). A randomized open label crossover study was conducted, comprising outpatients with stable cardiovascular disease taking aspirin once daily. We measured platelet aggregation with the platelet function analyzer (PFA)-200((r)) and light transmission aggregometry (LTA). The attenuation of aspirin's inhibitory action was most apparent in the 8.00 AM regimen. The platelet function analyzer-closure time was 78 s faster at 24 h than at 12 h after intake in the 8.00 AM regimen (IQR: 166.8-301 vs. 132.8-301; p = 0.006) and 0 s faster at 24 h than at 12 h after intake in the 8.00 PM regimen (IQR: 198.8-837.0 vs. 169.8-301; p = 0.653). The adenosine diphosphate 1.0 umol/L maximum amplitude was 5.40% higher at 24 h than at 12 h after intake in the 8.00 AM regimen (95% confidence interval (CI): 0.03--10.8; p = 0.040) and was 0.75% higher 24 h than at 12 h after intake in the 8.00 PM regimen (95% CI: -4.83-3.33; p = 0.705). The platelet inhibitory effect of aspirin decreases after 24 h, particularly after intake in the morning. These results suggest that patients might benefit from evening intake or twice daily intake regimens. PMID- 26599377 TI - Systematic review of biochemical biomarkers for neck and upper-extremity musculoskeletal disorders. AB - OBJECTIVE: This study systematically summarizes biochemical biomarker research in non-traumatic musculoskeletal disorders (MSD). Two research questions guided the review: (i) Are there biochemical markers associated with neck and upper extremity MSD? and (ii) Are there biochemical markers associated with the severity of neck and upper-extremity MSD? METHODS: A literature search was conducted in PubMed and SCOPUS, and 87 studies met primary inclusion criteria. Following a quality screen, data were extracted from 44 articles of sufficient quality. RESULTS: Most of the 87 studies were cross-sectional and utilized convenience samples of patients as both cases and controls. A response rate was explicitly stated in only 11 (13%) studies. Less than half of the studies controlled for potential confounding through restriction or in the analysis. Most sufficient-quality studies were conducted in older populations (mean age in one or more analysis group >50 years). In sufficient-quality articles, 82% demonstrated at least one statistically significant association between the MSD and biomarker(s) studied. Evidence suggested that: (i) the collagen-repair marker TIMP-1 is decreased in fibro proliferative disorders, (ii) 5-HT (serotonin) is increased in trapezius myalgia, and (iii) triglycerides are increased in a variety of MSD. Only 5 studies showed an association between a biochemical marker and MSD severity. CONCLUSION: While some MSD biomarkers were identified, limitations in the articles examined included possible selection bias, confounding, spectrum effect (potentially heterogeneous biomarker associations in populations according to symptom severity or duration), and insufficient attention to comorbid conditions. A list of recommendations for future studies is provided. PMID- 26599378 TI - Usefulness of antineutrophil cytoplasmic autoantibodies in diagnosing and managing systemic vasculitis. AB - PURPOSE OF REVIEW: Antineutrophil cytoplasmic autoantibodies (ANCAs) are considered important diagnostic tests in the work-up of patients suspected of vasculitis. Here we discuss new developments in the methodology of testing, the pitfalls in using these tests as diagnostic tools, and the value of serial ANCA testing for the follow-up of patients with ANCA-associated vasculitis including treatment decisions. RECENT FINDINGS: Both the indirect immunofluorescence (IIF) test and antigen-specific assays should be performed. New methodologies include automated reading in the IIF test and third-generation assays (anchor ELISA and bead-based multiplex assay) for the antigenic-specific assays. ANCA testing should be done in the right clinical context as positive results for PR3-ANCA and MPO-ANCA do occur in other conditions than vasculitis as well. These ANCAs develop in about 10% of patients with infective endocarditis. The occurrence of drug-induced ANCA and ANCA, also directed against elastase, following use of levamisole-adulterated cocaine should be recognized. In the right clinical context, ANCA are highly sensitive and specific for their associated disease. The value of serial ANCA testing for the follow-up of patients with ANCA-associated vasculitis is still under discussion but may be relevant in patients with renal involvement and in patients treated with rituximab. SUMMARY: The techniques for ANCA testing improve further but new tests should be standardized and validated. Their diagnostic value in the right clinical context is undisputed. Their value for the follow-up of patients is still under discussion. PMID- 26599379 TI - B-cell-targeted therapy in systemic vasculitis. AB - PURPOSE OF REVIEW: The present review discusses the evidence supporting the use of B-cell-targeted therapy in the treatment of various forms of systemic vasculitis with a focus on the use of rituximab (RTX), in the antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides (AAV). RECENT FINDINGS: Long-term follow-up of the two studies establishing the efficacy of a RTX-based induction regimen for severe AAV have demonstrated noninferiority of a single course of RTX compared with conventional therapy for remission maintenance. In addition, these observations highlight an association between relapse and B-cell reconstitution in patients treated with RTX. The maintenance of remission using rituximab in systemic ANCA-associated vasculitis trial compared a regimen of RTX infusions every 6 months to azathioprine for remission maintenance and concluded that serial RTX lead to higher rates of sustained remission.RTX is also an established therapy for cryoglobulinemic vasculitis associated with hepatitis C viral (HCV) infection. Recently published data support the long-term efficacy and safety of RTX for cryoglobulinemic vasculitis. SUMMARY: B-cell depletion with RTX is an established therapy for both remission induction and maintenance in severe AAV and in HCV-related cryoglobulinemic vasculitis. There are limited data to support use of B-cell-targeted therapy in refractory cases of other forms of systemic vasculitis such as eosinophilic granulomatosis with polyangiitis and Takayasu's arteritis. PMID- 26599380 TI - Management of primary and secondary central nervous system vasculitis. AB - PURPOSE OF REVIEW: This article summarizes the current evidence on the management of primary and secondary central nervous system (CNS) vasculitis. RECENT FINDINGS: Two recent retrospective cohort studies have described the treatment and outcomes of patients with adult primary central nervous system vasculitis (PCNSV). Although the majority of the patients (>60%) responded to therapy with glucocorticoids alone or in conjunction with cyclophosphamide (CYC) and tended to improve during the follow-up period, an overall increased mortality was observed. The treatment response and the outcomes appeared primarily related to the size of the vessels involved in the inflammatory process. The involvement of small cortical/leptomeningeal vessels was associated with a more benign course, whereas the involvement of larger/proximal cerebral vessels was related to a less favorable prognosis and identified cases that should be treated more aggressively. Glucocorticoids combined with CYC are the mainstay of therapy for secondary CNS vasculitis. Observational studies have documented the efficacy of rituximab as induction therapy in patients with antineutrophil cytoplasm antibody associated vasculitis (AAV) and CNS disease, while the role of antitumor necrosis factor (TNF) agents is more controversial. Case series have demonstrated the efficacy of anti-TNF agents in patients with neuro-Behcet's disease. Tocilizumab may also be effective in this condition. SUMMARY: Recognition of findings at diagnosis that predict the course or outcomes of PCNSV may serve as guide for therapy. Biological agents may provide benefit to difficult-to-treat patients with CNS involvement secondary to AAV and Behcet's disease. PMID- 26599381 TI - Genetics of Behcet's disease. AB - PURPOSE OF REVIEW: This article discusses recent genetic and epigenetic associations involved in the pathogenesis of Behcet's disease. RECENT FINDINGS: Genetic studies have supported the strong association of human leukocyte antigen B and Behcet's disease, and high production of tumour necrosis factor and low production of interleukin (IL)-10, which have led to therapy based on controlling these effects. Polymorphisms that affect the response to pathogens (TLR and FUT2) are leading to increased interest in responses to microbiomes. Inflammation in Behcet's disease results in vascular damage and several single nucleotide polymorphisms in chemokine and adhesion molecules may be involved in this process. Increased levels of inflammatory cytokines including IL-1beta and IL-17 have been linked to altered expression of microRNAs, miR155, miR21 and miR23b. DNA methylation changes in monocytes and lymphocytes have been described that affect the function of these cells. SUMMARY: Genetic and epigenetic changes affecting cells and molecules involved in Behcet's disease offer new pathways for research, including cytoskeletal protein function, that will provide new targets for therapy, and potentially address the ethnic differences seen in validation of gene studies. PMID- 26599382 TI - Recognition and management of antiphospholipid syndrome. AB - PURPOSE OF REVIEW: This article summarizes the recent developments in the recognition and management of antiphospholipid syndrome (APS). RECENT FINDINGS: Five Task Forces, created as part of the 14th International Congress on antiphospholipid antibodies (aPL), published their systematic reviews. 'For the recognition of APS': the assessment of aPL profile is crucial for risk stratification; lupus anticoagulant positivity, especially in the context of 'triple aPL positivity' displays the highest risk; a panel of criteria and noncriteria aPL tests may help better risk-stratify the aPL-positive in the future. 'For the management of APS': direct oral anticoagulants are not currently recommended; statins ameliorate the proinflammator/thrombotic markers, whereas hydroxychloroquine reduces the risk of thrombosis in experimental models and lupus patients, which justify their use as an adjunctive treatment in refractory cases; B-cell inhibition may have a role in difficult-to-treat patients with hematologic and microthrombotic/angiopathic manifestations; and complement and mammalian targets of rapamycin complex pathway inhibition are promising targets in APS. SUMMARY: Warfarin, heparin, and/or antiplatelet drugs are the standard of care for aPL-positive patients. Recent studies suggest novel approaches that target new coagulation and immunomodulatory pathways; mechanistic and/or controlled clinical studies are needed to determine the effectiveness of these novel approaches. PMID- 26599383 TI - Secondary vasculitis in autoimmune connective tissue diseases. AB - PURPOSE OF REVIEW: The current review of the vasculitis associated with autoimmune connective tissue diseases is very appropriate and timely, in view of the recently acquired expanding knowledge, over the last decade, on the clinical epidemiology, pathophysiology, and the innovative therapeutic strategies. This review will specifically focus on the clinical presentations of secondary vasculitides, pathophysiology, and their management. RECENT FINDINGS: New knowledge on the immunological triggers and pathophysiology of these conditions, in relation to various infections and airborne substances are discussed apart from the novel targeted immunotherapy, which has a direct effect on the outcome and reduction of iatrogenic complications. IN SUMMARY: The review will inform the classical nature and pattern of vasculitis secondary to autoimmune diseases with specific reference to targeted immunotherapy. PMID- 26599384 TI - The lung in rheumatoid arthritis, cause or consequence? AB - PURPOSE OF REVIEW: Recent discoveries implicate the lungs as a possible extra articular mucosal site for initiating rheumatoid arthritis-associated immunity. RECENT FINDINGS: Individuals at risk for developing arthritis and patients with early untreated rheumatoid arthritis show signs of lung involvement on high resolution computer tomography. Rheumatoid arthritis-associated antibodies are present in patients with respiratory complains such as bronchiectasis and unexplained dyspnea even in the absence of joint disease and might predict future development of rheumatoid arthritis in these patients. Rheumatoid arthritis associated antibodies are detected in the sputum of individuals at risk for developing rheumatoid arthritis but not yet having disease. Signs of bronchial mucosal inflammation with germinal center formation and local production of antibodies have been described in patients with early untreated rheumatoid arthritis. Shared antigenic targets have been identified and characterized in the lungs and joints of rheumatoid arthritis patients. SUMMARY: Recent findings support an important role for the lung as a mucosal extra-articular place were inflammation induced by external triggers (such as smoking) leads to tolerance break and generation of rheumatoid arthritis-specific immunity already before disease onset with only secondary targeting of the joints. PMID- 26599385 TI - Subclinical gut inflammation in ankylosing spondylitis. AB - PURPOSE OF REVIEW: Subclinical gut inflammation has been described in a significant proportion of patients with ankylosing spondylitis (AS), up to 10% of them developing it during the time of clinically overt inflammatory bowel disease. Histologic, immunologic, and intestinal microbiota alterations characterize the AS gut. RECENT FINDINGS: Microbial dysbiosis as well as alterations of innate immune responses have been demonstrated in the gut of AS. Furthermore, a growing body of evidence suggests that the gut of AS patients may be actively involved in the pathogenesis of AS through the production of proinflammatory cytokines, such as IL-23p19, and the differentiation of potentially pathogenic innate lymphoid cells producing IL-22 and IL-17. Finally, a strong correlation between the presence of subclinical gut inflammation and the degree of spine inflammation have been also proved in AS. SUMMARY: Subclinical gut inflammation and innate immune responses in AS may be considered a possible consequence of microbial dysbiosis. Relationships between cause and effect remain, however, to be answered. PMID- 26599387 TI - Conductive Polymer Binder for High-Tap-Density Nanosilicon Material for Lithium Ion Battery Negative Electrode Application. AB - High-tap-density silicon nanomaterials are highly desirable as anodes for lithium ion batteries, due to their small surface area and minimum first-cycle loss. However, this material poses formidable challenges to polymeric binder design. Binders adhere on to the small surface area to sustain the drastic volume changes during cycling; also the low porosities and small pore size resulting from this material are detrimental to lithium ion transport. This study introduces a new binder, poly(1-pyrenemethyl methacrylate-co-methacrylic acid) (PPyMAA), for a high-tap-density nanosilicon electrode cycled in a stable manner with a first cycle efficiency of 82%-a value that is further improved to 87% when combined with graphite material. Incorporating the MAA acid functionalities does not change the lowest unoccupied molecular orbital (LUMO) features or lower the adhesion performance of the PPy homopolymer. Our single-molecule force microscopy measurement of PPyMAA reveals similar adhesion strength between polymer binder and anode surface when compared with conventional polymer such as homopolyacrylic acid (PAA), while being electronically conductive. The combined conductivity and adhesion afforded by the MAA and pyrene copolymer results in good cycling performance for the high-tap-density Si electrode. PMID- 26599388 TI - The relationship between cognitive insight and quality of life in schizophrenia spectrum disorders: Symptom severity as potential moderator. AB - Cognitive insight is implicated in the formation and maintenance of hallucinations and delusions. However, it is not yet known whether cognitive insight relates to broader outcome measures like quality of life. In the current study, we investigated whether the component elements of cognitive insight-self certainty and self-reflectiveness-were related to quality of life for 43 outpatients with schizophrenia or schizoaffective disorder. Cognitive insight was assessed using the Beck Cognitive Insight Scale (BCIS) while quality of life was assessed with Quality of Life Scale (QLS). We tested whether this relationship was moderated by clinical insight and symptom severity using the Scale to Assess Unawareness of Mental Disorder (SUMD) and the Positive and Negative Syndrome Scale (PANSS). We found that self- reflectiveness had an unmoderated positive relationship with quality of life. Self-certainty was associated with better quality of life for people with more severe symptoms. Theoretical and clinical implications of these findings are discussed and areas of future research are proposed. PMID- 26599390 TI - A comparative study of early maladaptive schemas in obsessive-compulsive disorder and panic disorder. AB - Schema theory and therapy may be an additional therapeutic approach to identify and treat chronic psychological problems, namely early maladaptive schemas (EMSs), in patients with obsessive-compulsive disorder (OCD) and panic disorder (PAD). In the current study, we investigated the characteristics in EMSs between patients with OCD and PAD. Fifty-one patients with OCD, 46 patients with PAD, and 70 normal controls participated in this study. EMSs and depressive symptoms were measured using the Young Schema Questionnaire and the Beck Depression Inventory (BDI), respectively. Analysis of covariance was conducted with age, sex, BDI score, and education level as covariates to assess group differences. Direct comparisons among the three groups revealed that the defectiveness/shame and social isolation/alienation schemas were prominently activated in patients with OCD, whereas the vulnerability to harm or illness and self-sacrifice were activated in patients with PAD. In subgroup analysis, these differences were observed between subgroups with lower BDI scores, but not between the patient subgroups with higher BDI scores. However, the differences between the patient groups in the defectiveness/shame and vulnerability to harm or illness schemas almost reached significance. Patients with OCD and PAD differed in particular EMS characteristics, which could have potential therapeutic implications. PMID- 26599389 TI - Psychological trauma exposure and co-morbid psychopathologies in HIV+Men and Women. AB - This study examined the association between trauma exposure, PTSD, suicide attempts, and other psychopathology among 316 racially/ethnically diverse HIV infected men and women who underwent semi-structured psychiatric assessment. In addition, the role of psychological resilience in trauma exposure was examined in the context of neurological symptoms and functional status. Nearly half (47.8%; 151/316) of the participants reported trauma exposure, of which 47.0% (71/151) developed PTSD. Among trauma-exposed individuals, those with a current psychiatric diagnosis reported more neurological symptoms and lower functional status. Trauma exposure without PTSD was associated with a higher rate of panic disorder and substance-induced mental disorders. Trauma-exposed individuals who did not develop PTSD were less likely than those who reported no trauma exposure to meet criteria for major depressive disorder (MDD). Trauma exposure, MDD, borderline personality disorder, and substance-induced mental disorders were independently associated with increased odds of suicide attempt. These results indicate that co-morbid psychiatric disorders are common among trauma exposed individuals with a history of PTSD, but those with trauma exposure who do not develop PTSD are less likely to experience MDD. The role of other co-morbid psychopathologies in the genesis of suicidal behavior among individuals living with HIV deserves further study. PMID- 26599391 TI - Menopausal hormone therapy use and breast cancer risk in Australia: Findings from the New South Wales Cancer, Lifestyle and Evaluation of Risk study. AB - Randomised controlled trials and large-scale observational studies have found that current use of menopausal hormone therapy (MHT) is associated with an increased risk of breast cancer; this risk is higher for oestrogen-progestagen combination therapy than for oestrogen-only therapy. Our study was designed to estimate MHT-associated breast cancer risk in a population of Australian women. Data were analysed for postmenopausal women with self-reported incident invasive breast cancer (n = 1,236) and cancer-free controls (n = 862), recruited between 2006 and 2014 into a large case-control study for all cancer types, the NSW CLEAR study. Information on past and current MHT use was collected from all participants, along with other lifestyle and demographic factors, using a self administered questionnaire. Unmatched multivariable logistic regression was performed, adjusting for socio-demographic, reproductive and health behaviour variables, body mass index and breast screening history. Compared to never users of MHT, the adjusted odds ratio (aOR) for breast cancer in current users of any type of MHT was 2.09 (95% CI: 1.57-2.78; p < 0.0001) and for past users of any type of MHT was 1.03 (0.82-1.28; p = 0.8243). For current users of oestrogen-only and oestrogen-progestagen therapy, aORs were 1.80 (1.21-2.68; p = 0.0039) and 2.62 (1.56-4.38; p = 0.0003), respectively. These findings are consistent with those from other international observational studies, that current, but not past, use of MHT is associated with a substantially increased risk of breast cancer. PMID- 26599392 TI - Relative Rate Profiles of Functionalized Iodoarene Catalysts for Iodine(III) Oxidations. AB - A series of rate studies were conducted to evaluate the steric and electronic properties that govern the reactivity of iodoarene amide catalysts in the alpha oxytosylation of propiophenone. A meta-substituted benzamide catalyst emerged as the most reactive. This catalyst was employed in the alpha-oxytosylation of a series of substituted propiophenones, returning the alpha-tosyloxy ketone products in excellent isolated yield. PMID- 26599393 TI - New Constraints on Terrestrial Surface-Atmosphere Fluxes of Gaseous Elemental Mercury Using a Global Database. AB - Despite 30 years of study, gaseous elemental mercury (Hg(0)) exchange magnitude and controls between terrestrial surfaces and the atmosphere still remain uncertain. We compiled data from 132 studies, including 1290 reported fluxes from more than 200,000 individual measurements, into a database to statistically examine flux magnitudes and controls. We found that fluxes were unevenly distributed, both spatially and temporally, with strong biases toward Hg-enriched sites, daytime and summertime measurements. Fluxes at Hg-enriched sites were positively correlated with substrate concentrations, but this was absent at background sites. Median fluxes over litter- and snow-covered soils were lower than over bare soils, and chamber measurements showed higher emission compared to micrometeorological measurements. Due to low spatial extent, estimated emissions from Hg-enriched areas (217 Mg.a(-1)) were lower than previous estimates. Globally, areas with enhanced atmospheric Hg(0) levels (particularly East Asia) showed an emerging importance of Hg(0) emissions accounting for half of the total global emissions estimated at 607 Mg.a(-1), although with a large uncertainty range (-513 to 1353 Mg.a(-1) [range of 37.5th and 62.5th percentiles]). The largest uncertainties in Hg(0) fluxes stem from forests (-513 to 1353 Mg.a(-1) [range of 37.5th and 62.5th percentiles]), largely driven by a shortage of whole ecosystem fluxes and uncertain contributions of leaf-atmosphere exchanges, questioning to what degree ecosystems are net sinks or sources of atmospheric Hg(0). PMID- 26599394 TI - Intimate Partner Violence, Relationship Power Inequity and the Role of Sexual and Social Risk Factors in the Production of Violence among Young Women Who Have Multiple Sexual Partners in a Peri-Urban Setting in South Africa. AB - INTRODUCTION: This paper aims to assess the extent and correlates of intimate partner violence (IPV), explore relationship power inequity and the role of sexual and social risk factors in the production of violence among young women aged 16-24 reporting more than one partner in the past three months in a peri urban setting in the Western Cape, South Africa. Recent estimates suggest that every six hours a woman is killed by an intimate partner in South Africa, making IPV a leading public health problem in the country. While there is mounting evidence that levels of IPV are high in peri-urban settings in South Africa, not much is known about how it manifests among women who engage in concomitantly high HIV risk behaviours such as multiple sexual partnering, transactional sex and age mixing. We know even less about how such women negotiate power and control if exposed to violence in such sexual networks. METHODS: Two hundred and fifty nine women with multiple sexual partners, residing in a predominantly Black peri-urban community in the Western Cape, South Africa, were recruited into a bio behavioural survey using Respondent Driven Sampling (RDS). After the survey, focus group discussions and individual interviews were conducted among young women and men to understand the underlying factors informing their risk behaviours and experiences of violence. FINDINGS: 86% of the young women experienced IPV in the past 12 months. Sexual IPV was significantly correlated with sex with a man who was 5 years or older than the index female partner (OR 1.7, 95% CI 1.0-3.2) and transactional sex with most recent casual partner (OR 2.1, 95% CI 1.1-3.8). Predictably, women experienced high levels of relationship power inequity. However, they also identified areas in their controlling relationships where they shared decision making power. DISCUSSION: Levels of IPV among young women with multiple sexual partners were much higher than what is reported among women in the general population and shown to be associated with sexual risk taking. Interventions targeting IPV need to address sexual risk taking as it heightens vulnerability to violence. PMID- 26599395 TI - Functional Characterization of Germline Mutations in PDGFB and PDGFRB in Primary Familial Brain Calcification. AB - Primary Familial Brain Calcification (PFBC), a neurodegenerative disease characterized by progressive pericapillary calcifications, has recently been linked to heterozygous mutations in PDGFB and PDGFRB genes. Here, we functionally analyzed several of these mutations in vitro. All six analyzed PDGFB mutations led to complete loss of PDGF-B function either through abolished protein synthesis or through defective binding and/or stimulation of PDGF-Rbeta. The three analyzed PDGFRB mutations had more diverse consequences. Whereas PDGF-Rbeta autophosphorylation was almost totally abolished in the PDGFRB L658P mutation, the two sporadic PDGFRB mutations R987W and E1071V caused reductions in protein levels and specific changes in the intensity and kinetics of PLCgamma activation, respectively. Since at least some of the PDGFB mutations were predicted to act through haploinsufficiency, we explored the consequences of reduced Pdgfb or Pdgfrb transcript and protein levels in mice. Heterozygous Pdgfb or Pdgfrb knockouts, as well as double Pdgfb+/-;Pdgfrb+/- mice did not develop brain calcification, nor did Pdgfrbredeye/redeye mice, which show a 90% reduction of PDGFRbeta protein levels. In contrast, Pdgfbret/ret mice, which have altered tissue distribution of PDGF-B protein due to loss of a proteoglycan binding motif, developed brain calcifications. We also determined pericyte coverage in calcification-prone and non-calcification-prone brain regions in Pdgfbret/ret mice. Surprisingly and contrary to our hypothesis, we found that the calcification-prone brain regions in Pdgfbret/ret mice model had a higher pericyte coverage and a more intact blood-brain barrier (BBB) compared to non calcification-prone brain regions. While our findings provide clear evidence that loss-of-function mutations in PDGFB or PDGFRB cause PFBC, they also demonstrate species differences in the threshold levels of PDGF-B/PDGF-Rbeta signaling that protect against small-vessel calcification in the brain. They further implicate region-specific susceptibility factor(s) in PFBC pathogenesis that are distinct from pericyte and BBB deficiency. PMID- 26599396 TI - Glycosylation of Sodium/Iodide Symporter (NIS) Regulates Its Membrane Translocation and Radioiodine Uptake. AB - PURPOSE: Human sodium/iodide symporter (hNIS) protein is a membrane glycoprotein that transports iodide ions into thyroid cells. The function of this membrane protein is closely regulated by post-translational glycosylation. In this study, we measured glycosylation-mediated changes in subcellular location of hNIS and its function of iodine uptake. METHODS: HeLa cells were stably transfected with hNIS/tdTomato fusion gene in order to monitor the expression of hNIS. Cellular localization of hNIS was visualized by confocal microscopy of the red fluorescence of tdTomato. The expression of hNIS was evaluated by RT-PCR and immunoblot analysis. Functional activity of hNIS was estimated by radioiodine uptake. Cyclic AMP (cAMP) and tunicamycin were used to stimulate and inhibit glycosylation, respectively. In vivo images were obtained using a Maestro fluorescence imaging system. RESULTS: cAMP-mediated Glycosylation of NIS resulted in increased expression of hNIS, stimulating membrane translocation, and enhanced radioiodine uptake. In contrast, inhibition of glycosylation by treatment with tunicamycin dramatically reduced membrane translocation of intracellular hNIS, resulting in reduced radioiodine uptake. In addition, our hNIS/tdTomato fusion reporter successfully visualized cAMP-induced hNIS expression in xenografted tumors from mouse model. CONCLUSIONS: These findings clearly reveal that the membrane localization of hNIS and its function of iodine uptake are glycosylation dependent, as our results highlight enhancement of NIS expression and glycosylation with subsequent membrane localization after cAMP treatment. Therefore, enhancing functional NIS by the increasing level of glycosylation may be suggested as a promising therapeutic strategy for cancer patients who show refractory response to conventional radioiodine treatment. PMID- 26599397 TI - Urinary Sex Steroids and Anthropometric Markers of Puberty - A Novel Approach to Characterising Within-Person Changes of Puberty Hormones. AB - BACKGROUND/AIMS: The longitudinal relationships of within-individual hormone and anthropometric changes during puberty have not ever been fully described. The objectives of this study were to demonstrate that 3 monthly urine collection was feasible in young adolescents and to utilise liquid chromatography-tandem mass spectrometry assay methods for serum and urine testosterone (T), estradiol (E2) and luteinizing hormone (LH) in adolescents by relating temporal changes in urine and serum hormones over 12 months to standard measures of pubertal development. METHODS: A community sample of 104 adolescents (57 female) was studied over 12 months with annual anthropometric assessment, blood sampling and self-rated Tanner staging and urine collected every 3 months. Serum and urine sex steroids (T, E2) were measured by liquid chromatography-tandem mass spectrometry (LC MS/MS) and LH by immunoassay. RESULTS: A high proportion (92%) of scheduled samples were obtained with low attrition rate of 6.7% over the 12 months. Urine hormone measurements correlated cross-sectionally and longitudinally with age, anthropometry and Tanner stage. CONCLUSION: We have developed a feasible and valid sampling methodology and measurements for puberty hormones in urine, which allows a sampling frequency by which individual pubertal progression in adolescents can be described in depth. PMID- 26599398 TI - The eye of the beholder: Can patterns in eye movement reveal aptitudes for spatial reasoning? AB - Mental rotation ability (MRA) is linked to academic success in the spatially complex Science, Technology, Engineering, Medicine, and Mathematics (STEMM) disciplines, and anatomical sciences. Mental rotation literature suggests that MRA may manifest in the movement of the eyes. Quantification of eye movement data may serve to distinguish MRA across individuals, and serve as a consideration when designing visualizations for instruction. It is hypothesized that high-MRA individuals will demonstrate fewer eye fixations, conduct shorter average fixation durations (AFD), and demonstrate shorter response times, than low-MRA individuals. Additionally, individuals with different levels of MRA will attend to different features of the block-figures presented in the electronic mental rotations test (EMRT). All participants (n = 23) completed the EMRT while metrics of eye movement were collected. The test required participants view pairs of three-dimensional (3D) shapes, and identify if the pair is rotated but identical, or two different structures. Temporal analysis revealed no significant correlations between response time, average fixation durations, or number of fixations and mental rotation ability. Further analysis of within-participant variability yielded a significant correlation for response time variability, but no correlation between AFD variability and variability in the number of fixations. Additional analysis of salience revealed that during problem solving, individuals of differing MRA attended to different features of the block images; suggesting that eye movements directed at salient features may contribute to differences in mental rotations ability, and may ultimately serve to predict success in anatomy. Anat Sci Educ 9: 357-366. (c) 2015 American Association of Anatomists. PMID- 26599399 TI - A Systematic Bayesian Integration of Epidemiological and Genetic Data. AB - Genetic sequence data on pathogens have great potential to inform inference of their transmission dynamics ultimately leading to better disease control. Where genetic change and disease transmission occur on comparable timescales additional information can be inferred via the joint analysis of such genetic sequence data and epidemiological observations based on clinical symptoms and diagnostic tests. Although recently introduced approaches represent substantial progress, for computational reasons they approximate genuine joint inference of disease dynamics and genetic change in the pathogen population, capturing partially the joint epidemiological-evolutionary dynamics. Improved methods are needed to fully integrate such genetic data with epidemiological observations, for achieving a more robust inference of the transmission tree and other key epidemiological parameters such as latent periods. Here, building on current literature, a novel Bayesian framework is proposed that infers simultaneously and explicitly the transmission tree and unobserved transmitted pathogen sequences. Our framework facilitates the use of realistic likelihood functions and enables systematic and genuine joint inference of the epidemiological-evolutionary process from partially observed outbreaks. Using simulated data it is shown that this approach is able to infer accurately joint epidemiological-evolutionary dynamics, even when pathogen sequences and epidemiological data are incomplete, and when sequences are available for only a fraction of exposures. These results also characterise and quantify the value of incomplete and partial sequence data, which has important implications for sampling design, and demonstrate the abilities of the introduced method to identify multiple clusters within an outbreak. The framework is used to analyse an outbreak of foot-and-mouth disease in the UK, enhancing current understanding of its transmission dynamics and evolutionary process. PMID- 26599400 TI - Platelet Counts, Acute Kidney Injury, and Mortality after Coronary Artery Bypass Grafting Surgery. AB - BACKGROUND: Cardiac surgery requiring cardiopulmonary bypass is associated with platelet activation. Because platelets are increasingly recognized as important effectors of ischemia and end-organ inflammatory injury, the authors explored whether postoperative nadir platelet counts are associated with acute kidney injury (AKI) and mortality after coronary artery bypass grafting (CABG) surgery. METHODS: The authors evaluated 4,217 adult patients who underwent CABG surgery. Postoperative nadir platelet counts were defined as the lowest in-hospital values and were used as a continuous predictor of postoperative AKI and mortality. Nadir values in the lowest 10th percentile were also used as a categorical predictor. Multivariable logistic regression and Cox proportional hazard models examined the association between postoperative platelet counts, postoperative AKI, and mortality. RESULTS: The median postoperative nadir platelet count was 121 * 10/l. The incidence of postoperative AKI was 54%, including 9.5% (215 patients) and 3.4% (76 patients) who experienced stages II and III AKI, respectively. For every 30 * 10/l decrease in platelet counts, the risk for postoperative AKI increased by 14% (adjusted odds ratio, 1.14; 95% CI, 1.09 to 1.20; P < 0.0001). Patients with platelet counts in the lowest 10th percentile were three times more likely to progress to a higher severity of postoperative AKI (adjusted proportional odds ratio, 3.04; 95% CI, 2.26 to 4.07; P < 0.0001) and had associated increased risk for mortality immediately after surgery (adjusted hazard ratio, 5.46; 95% CI, 3.79 to 7.89; P < 0.0001). CONCLUSION: The authors found a significant association between postoperative nadir platelet counts and AKI and short-term mortality after CABG surgery. PMID- 26599401 TI - Distribution Features of Skeletal Metastases: A Comparative Study between Pulmonary and Prostate Cancers. AB - Bone scintigraphies are widely applied for detecting bone metastases. The aim of this study was to investigate distribution features of bone metastases in pulmonary and prostate cancers. Bone scintigraphies were performed in 460 patients with pulmonary cancer and 144 patients with prostate cancer. Patients were divided into three groups according to the total number of bone metastases: few bone metastases, moderate bone metastases, and extensive bone metastases. We compared the distribution of bone metastases in the two cancers, and analyzed the relationship between the distribution of metastatic lesions and their metastatic patterns. A total of 2279 and 2000 lesions of bone metastases were detected in 258 patients with pulmonary cancer and 102 patients with prostate cancer, respectively. In patients with few bone metastases, the distributions of metastatic lesions in the vertebrae (chi2 = 16.0, P = 0.000) and thoracic bones (chi2 = 20.7, P = 0.002) were significantly different between pulmonary and prostate cancers. In cases with moderate bone metastases, the distributions in the vertebrae (chi2 = 6.6, P = 0.010), pelvis (chi2 = 15.1 P = 0.000), and thoracic bones (chi2 = 38.8, P = 0.000) were also significantly different between the two cancers. However, in patients with extensive bone metastases, the distributions were very similar. As the total number of bone metastases increased, their distribution in pulmonary cancer did not noticeably change, but the distribution in the vertebrae and thoracic bones of prostate cancer patients significantly changed. Accordingly, the distribution characteristics of bone metastases differed in pulmonary and prostate cancers, mainly in the early stages of metastasis. PMID- 26599403 TI - Cobalt sulfide/N,S codoped porous carbon core-shell nanocomposites as superior bifunctional electrocatalysts for oxygen reduction and evolution reactions. AB - Exploring highly-efficient and low-cost bifunctional electrocatalysts for both oxygen reduction reaction (ORR) and oxygen evolution reactions (OER) in the renewable energy area has gained momentum but still remains a significant challenge. Here we present a simple but efficient method that utilizes ZIF-67 as the precursor and template for the one-step generation of homogeneous dispersed cobalt sulfide/N,S-codoped porous carbon nanocomposites as high-performance electrocatalysts. Due to the favourable molecular-like structural features and uniform dispersed active sites in the precursor, the resulting nanocomposites, possessing a unique core-shell structure, high porosity, homogeneous dispersion of active components together with N and S-doping effects, not only show excellent electrocatalytic activity towards ORR with the high onset potential (around -0.04 V vs.-0.02 V for the benchmark Pt/C catalyst) and four-electron pathway and OER with a small overpotential of 0.47 V for 10 mA cm(-2) current density, but also exhibit superior stability (92%) to the commercial Pt/C catalyst (74%) in ORR and promising OER stability (80%) with good methanol tolerance. Our findings suggest that the transition metal sulfide-porous carbon nanocomposites derived from the one-step simultaneous sulfurization and carbonization of zeolitic imidazolate frameworks are excellent alternative bifunctional electrocatalysts towards ORR and OER in the next generation of energy storage and conversion technologies. PMID- 26599402 TI - Immune Adjuvant Activity of Pre-Resectional Radiofrequency Ablation Protects against Local and Systemic Recurrence in Aggressive Murine Colorectal Cancer. AB - PURPOSE: While surgical resection is a cornerstone of cancer treatment, local and distant recurrences continue to adversely affect outcome in a significant proportion of patients. Evidence that an alternative debulking strategy involving radiofrequency ablation (RFA) induces antitumor immunity prompted the current investigation of the efficacy of performing RFA prior to surgical resection (pre resectional RFA) in a preclinical mouse model. EXPERIMENTAL DESIGN: Therapeutic efficacy and systemic immune responses were assessed following pre-resectional RFA treatment of murine CT26 colon adenocarcinoma. RESULTS: Treatment with pre resectional RFA significantly delayed tumor growth and improved overall survival compared to sham surgery, RFA, or resection alone. Mice in the pre-resectional RFA group that achieved a complete response demonstrated durable antitumor immunity upon tumor re-challenge. Failure to achieve a therapeutic benefit in immunodeficient mice confirmed that tumor control by pre-resectional RFA depends on an intact adaptive immune response rather than changes in physical parameters that make ablated tumors more amenable to a complete surgical excision. RFA causes a marked increase in intratumoral CD8+ T lymphocyte infiltration, thus substantially enhancing the ratio of CD8+ effector T cells: FoxP3+ regulatory T cells. Importantly, pre-resectional RFA significantly increases the number of antigen-specific CD8+ T cells within the tumor microenvironment and tumor draining lymph node but had no impact on infiltration by myeloid-derived suppressor cells, M1 macrophages or M2 macrophages at tumor sites or in peripheral lymphoid organs (i.e., spleen). Finally, pre-resectional RFA of primary tumors delayed growth of distant tumors through a mechanism that depends on systemic CD8+ T cell-mediated antitumor immunity. CONCLUSION: Improved survival and antitumor systemic immunity elicited by pre-resectional RFA support the translational potential of this neoadjuvant treatment for cancer patients with high-risk of local and systemic recurrence. PMID- 26599405 TI - Asenapine versus placebo for schizophrenia. AB - BACKGROUND: Schizophrenia is a highly prevalent and chronic disorder that comprises a wide range of symptomatology. Asenapine is a recently developed atypical antipsychotic that is approved by the US Food and Drug Administration (FDA) for the treatment of schizophrenia. OBJECTIVES: To determine the clinical effects of asenapine for adults with schizophrenia or other schizophrenia-like disorders by comparing it with placebo. SEARCH METHODS: We searched the Cochrane Schizophrenia Group's Trials Register (July 04, 2014) which is based on regular searches of MEDLINE, EMBASE, CINAHL, BIOSIS, AMED, PubMed, PsycINFO, and registries of clinical trials. There are no language, date, document type, or publication status limitation for inclusion of records into the register. We inspected references of all included studies for further relevant studies. SELECTION CRITERIA: Our review includes randomised controlled trials (RCTs) comparing asenapine with placebo in adults (however defined) with schizophrenia or related disorders, including schizophreniform disorder, schizoaffective disorder and delusional disorder, again, by any means of diagnosis. DATA COLLECTION AND ANALYSIS: We inspected citations from the searches and identified relevant abstracts, and extracted data from all included studies. For binary data we calculated risk ratio (RR) with 95% confidence intervals (CI), and for continuous data we calculated mean differences (MD). We used the GRADE approach to produce a 'Summary of findings' table which included our outcomes of interest, where possible. We used a fixed-effect model for our analyses. MAIN RESULTS: We obtained and scrutinised 41 potentially relevant records, and from these we could include only six trials (n = 1835). Five of the six trials had high risk of attrition bias and all trials were sponsored by pharmaceutical companies. Results showed a clinically important change in global state (1 RCT, n = 336, RR 0.81, 95% CI 0.68 to 0.97, low-quality evidence) and mental state (1 RCT, n = 336, RR 0.72, 95% CI 0.59 to 0.86, very low-quality evidence) at short-term amongst people receiving asenapine. People receiving asenapine demonstrated significant reductions in negative symptoms (1 RCT, n = 336, MD -1.10, 95% CI -2.29 to 0.09, very low-quality evidence) at short-term. Individuals receiving asenapine demonstrated significantly fewer incidents of serious adverse effects (1 RCT, n = 386, RR 0.29, 95% CI 0.14 to 0.63, very low-quality evidence) at medium-term. There was no clear difference in people discontinuing the study for any reason between asenapine and placebo at short-term (5 RCTs, n = 1046, RR 0.91, 95% CI 0.80 to 1.04, very low-quality evidence). No trial reported data for extrapyramidal symptoms or costs. AUTHORS' CONCLUSIONS: There is some, albeit preliminary, evidence that asenapine provides an improvement in positive, negative, and depressive symptoms, whilst minimising the risk of adverse effects. However due to the low-quality and limited quantity of evidence, it remains difficult to recommend the use of asenapine for people with schizophrenia. We identify a need for large-scale, longer-term, better-designed and conducted randomised controlled trials investigating the clinical effects and safety of asenapine. PMID- 26599404 TI - Identification of Putative Nuclear Receptors and Steroidogenic Enzymes in Murray Darling Rainbowfish (Melanotaenia fluviatilis) Using RNA-Seq and De Novo Transcriptome Assembly. AB - Murray-Darling rainbowfish (Melanotaenia fluviatilis [Castelnau, 1878]; Atheriniformes: Melanotaeniidae) is a small-bodied teleost currently under development in Australasia as a test species for aquatic toxicological studies. To date, efforts towards the development of molecular biomarkers of contaminant exposure have been hindered by the lack of available sequence data. To address this, we sequenced messenger RNA from brain, liver and gonads of mature male and female fish and generated a high-quality draft transcriptome using a de novo assembly approach. 149,742 clusters of putative transcripts were obtained, encompassing 43,841 non-redundant protein-coding regions. Deduced amino acid sequences were annotated by functional inference based on similarity with sequences from manually curated protein sequence databases. The draft assembly contained protein-coding regions homologous to 95.7% of the complete cohort of predicted proteins from the taxonomically related species, Oryzias latipes (Japanese medaka). The mean length of rainbowfish protein-coding sequences relative to their medaka homologues was 92.1%, indicating that despite the limited number of tissues sampled a large proportion of the total expected number of protein-coding genes was captured in the study. Because of our interest in the effects of environmental contaminants on endocrine pathways, we manually curated subsets of coding regions for putative nuclear receptors and steroidogenic enzymes in the rainbowfish transcriptome, revealing 61 candidate nuclear receptors encompassing all known subfamilies, and 41 putative steroidogenic enzymes representing all major steroidogenic enzymes occurring in teleosts. The transcriptome presented here will be a valuable resource for researchers interested in biomarker development, protein structure and function, and contaminant-response genomics in Murray-Darling rainbowfish. PMID- 26599406 TI - Sedimentary Sulphur:Iron Ratio Indicates Vivianite Occurrence: A Study from Two Contrasting Freshwater Systems. AB - An increasing number of studies constrain the importance of iron for the long term retention of phosphorus (P) under anoxic conditions, i.e. the formation of reduced iron phosphate minerals such as vivianite (Fe3(PO4)2?8H2O). Much remains unknown about vivianite formation, the factors controlling its occurrence, and its relevance for P burial during early sediment diagenesis. To study the occurrence of vivianite and to assess its relevance for P binding, surface sediments of two hydrologically contrasting waters were analysed by heavy-liquid separation and subsequent powder X-ray diffraction. In Lake Arendsee, vivianite was present in deeper sediment horizons and not in the uppermost layers with a sharp transition between vivianite and non-vivianite bearing layers. In contrast, in lowland river Lower Havel vivianite was present in the upper sediment layers and not in deeper horizons with a gradual transition between non-vivianite and vivianite bearing layers. In both waters, vivianite occurrence was accompanied by the presence of pyrite (FeS2). Vivianite formation was favoured by an elevated iron availability through a lower degree of sulphidisation and was present at a molar ratio of total sulphur to reactive iron smaller than 1.1, only. A longer lasting burden of sediments by organic matter, i.e. due to eutrophication, favours the release of sulphides, and the formation of insoluble iron sulphides leading to a lack of available iron and to less or no vivianite formation. This weakening in sedimentary P retention, representing a negative feedback mechanism (P release) in terms of water quality, could be partly compensated by harmless Fe amendments. PMID- 26599407 TI - The Dynamics of Treg/Th17 and the Imbalance of Treg/Th17 in Clonorchis sinensis Infected Mice. AB - Clonorchiasis, caused by the liver fluke Clonorchis sinensis, is a chronic parasitic infection regulated by T cell subsets. An imbalance of CD4+CD25+ Foxp3+regulatory T (Treg) and interleukin (IL)-17-secreting T cells (Th17) may control inflammation and play an important role in the pathogenesis of immune evasion. In the present study, we assessed the dynamics of Treg/Th17 and determined whether the Treg/Th17 ratio is altered in C. sinensis-infected mice. The results showed that the percentages of splenic Treg cells in CD4+ T cells were suppressed on day 14 post-infection (PI) but increased on day 56 PI, while Th17 cells were increased on day 56 PI compared with normal control (NC) mice. The Treg/Th17 ratio steadily increased from day 28 to day 56 PI. The hepatic levels of their specific transcription factors (Foxp3 for Treg and RORgammat for Th17) were increased in C. sinensis-infected mice from day 14 to 56 PI, and significantly higher than those in NC mice. Meanwhile, serum levels of IL-2 and IL-17 were profoundly increased in C. sinensis-infected mice throughout the experiment; while the concentrations of IL-6 and transforming growth factor beta1 (TGF-beta1) peaked on day 14 PI, but then decreased on day 28 and 56 PI. Our results provide the first evidence of an increased Treg/Th17 ratio in C. sinensis infected mice, suggesting that a Treg/Th17 imbalance may play a role in disease outcomes of clonorchiasis. PMID- 26599408 TI - A Methodology for Concomitant Isolation of Intimal and Adventitial Endothelial Cells from the Human Thoracic Aorta. AB - BACKGROUND: Aortic diseases are diverse and involve a multiplicity of biological systems in the vascular wall. Aortic dissection, which is usually preceded by aortic aneurysm, is a leading cause of morbidity and mortality in modern societies. Although the endothelium is now known to play an important role in vascular diseases, its contribution to aneurysmal aortic lesions remains largely unknown. The aim of this study was to define a reliable methodology for the isolation of aortic intimal and adventitial endothelial cells in order to throw light on issues relevant to endothelial cell biology in aneurysmal diseases. METHODOLOGY/PRINCIPAL FINDINGS: We set up protocols to isolate endothelial cells from both the intima and the adventitia of human aneurysmal aortic vessel segments. Throughout the procedure, analysis of cell morphology and endothelial markers allowed us to select an endothelial fraction which after two rounds of expansion yielded a population of >90% pure endothelial cells. These cells have the features and functionalities of freshly isolated cells and can be used for biochemical studies. The technique was successfully used for aortic vessel segments of 20 patients and 3 healthy donors. CONCLUSIONS/SIGNIFICANCE: This simple and highly reproducible method allows the simultaneous preparation of reasonably pure primary cultures of intimal and adventitial human endothelial cells, thus providing a reliable source for investigating their biology and involvement in both thoracic aneurysms and other aortic diseases. PMID- 26599409 TI - Association of Ghrelin Gene Polymorphisms and Serum Ghrelin Levels with the Risk of Hepatitis B Virus-Related Liver Diseases in a Chinese Population. AB - BACKGROUND: The functions of ghrelin (GHRL) include anti-inflammatory effects, reduction of the fibrogenic response, protection of liver tissue, and regulation of cell proliferation. Genetic variations in the GHRL gene may play an important role in the development of chronic hepatitis B (CHB), liver cirrhosis (LC) and hepatocellular carcinoma (HCC). Therefore, we investigated whether GHRL gene polymorphisms and its serum levels are associated with hepatitis B virus (HBV) related diseases risk in a Chinese population. METHODS: 176 patients with CHB, 106 patients with HBV-related LC, 151 patients with HBV-related HCC, and 167 healthy controls were recruited in the study. Genotyping of GHRL rs26311, rs27647, rs696217, and rs34911341 polymorphisms were determined with the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing. The serum GHRL concentrations were determined using enzyme-linked immunosorbent assay (ELISA). RESULTS: Binary logistic regression analyses adjusting for gender and age revealed that a significant increased risk of LC was found in the GHRL rs26311 GC genotype and combined GC+CC genotypes when compared with the GG genotype (GC vs. GG: OR = 1.671, 95% CI = 1.013-2.757, P = 0.044; GC+CC vs. GG: OR = 1.674, 95% CI = 1.040-2.696, P = 0.034). In subgroup analysis by gender, binary logistic regression analyses adjusting for age showed that the GHRL rs26311 C allele and combined GC+CC genotypes were associated with a significantly increased risk to LC in males (C vs. G OR = 1.416, 95% CI = 1.017 1.972, P = 0.040; GC+CC vs. GG: OR = 1.729, 95% CI = 1.019-2.933, P = 0.042). In addition, we found significant decreased serum GHRL levels in LC patients compared with the healthy controls. However, there was no significant association of the GHRL rs26311 polymorphism with serum GHRL levels in LC patients. CONCLUSIONS: These observations suggest that the GHRL rs26311 polymorphism is associated with an increased risk to HBV-related LC, especially in men. We also found an inverse association of serum GHRL levels with LC. PMID- 26599411 TI - Signal-domain optimization metrics for MPRAGE RF pulse design in parallel transmission at 7 tesla. AB - PURPOSE: Standard radiofrequency pulse design strategies focus on minimizing the deviation of the flip angle from a target value, which is sufficient but not necessary for signal homogeneity. An alternative approach, based directly on the signal, here is proposed for the MPRAGE sequence, and is developed in the parallel transmission framework with the use of the kT -points parametrization. METHODS: The flip angle-homogenizing and the proposed methods were investigated numerically under explicit power and specific absorption rate constraints and tested experimentally in vivo on a 7 T parallel transmission system enabling real time local specific absorption rate monitoring. Radiofrequency pulse performance was assessed by a careful analysis of the signal and contrast between white and gray matter. RESULTS: Despite a slight reduction of the flip angle uniformity, an improved signal and contrast homogeneity with a significant reduction of the specific absorption rate was achieved with the proposed metric in comparison with standard pulse designs. CONCLUSION: The proposed joint optimization of the inversion and excitation pulses enables significant reduction of the specific absorption rate in the MPRAGE sequence while preserving image quality. The work reported thus unveils a possible direction to increase the potential of ultra high field MRI and parallel transmission. Magn Reson Med 76:1431-1442, 2016. (c) 2015 International Society for Magnetic Resonance in Medicine. PMID- 26599410 TI - Phylogeny and Phylogeography of a Recent HIV-1 Subtype F Outbreak among Men Who Have Sex with Men in Spain Deriving from a Cluster with a Wide Geographic Circulation in Western Europe. AB - We recently reported the rapid expansion of an HIV-1 subtype F cluster among men who have sex with men (MSM) in the region of Galicia, Northwest Spain. Here we update this outbreak, analyze near full-length genomes, determine phylogenetic relationships, and estimate its origin. For this study, we used sequences of HIV 1 protease-reverse transcriptase and env V3 region, and for 17 samples, near full length genome sequences were obtained. Phylogenetic analyses were performed via maximum likelihood. Locations and times of most recent common ancestors were estimated using Bayesian inference. Among samples analyzed by us, 100 HIV-1 F1 subsubtype infections of monophyletic origin were diagnosed in Spain, including 88 in Galicia and 12 in four other regions. Most viruses (n = 90) grouped in a subcluster (Galician subcluster), while 7 from Valladolid (Central Spain) grouped in another subcluster. At least 94 individuals were sexually-infected males and at least 71 were MSM. Seventeen near full-length genomes were uniformly of F1 subsubtype. Through similarity searches and phylogenetic analyses, we identified 18 viruses from four other Western European countries [Switzerland (n = 8), Belgium (n = 5), France (n = 3), and United Kingdom (n = 2)] and one from Brazil, from samples collected in 2005-2011, which branched within the subtype F cluster, outside of both Spanish subclusters, most of them corresponding to recently infected individuals. The most probable geographic origin and age of the Galician subcluster was Ferrol, Northwest Galicia, around 2007, while the Western European cluster probably emerged in Switzerland around 2002. In conclusion, a recently expanded HIV-1 subtype F cluster, the largest non-subtype B cluster reported in Western Europe, continues to spread among MSM in Spain; this cluster is part of a larger cluster with a wide geographic circulation in diverse Western European countries. PMID- 26599412 TI - Livelihoods and Fisheries Governance in a Contemporary Pacific Island Setting. AB - Inshore marine resources play an important role in the livelihoods of Pacific Island coastal communities. However, such reliance can be detrimental to inshore marine ecosystems. Understanding the livelihoods of coastal communities is important for devising relevant and effective fisheries management strategies. Semi-structured household interviews were conducted with householders in Langalanga Lagoon, Solomon Islands, to understand household livelihoods and resource governance in fishing-dependent communities. Households were engaged in a diverse range of livelihoods. Fishing, shell money production and gardening were the most important livelihoods. Proximity to an urban centre influenced how households accessed some livelihoods. Perceptions of management rules varied and different reasons were cited for why rules were broken, the most common reason being to meet livelihood needs. Current models of inshore small-scale fisheries management that are based on the notion of community-based resource management may not work in locations where customary management systems are weak and livelihoods are heavily reliant on marine resources. An important step for fisheries management in such locations should include elucidating community priorities through participatory development planning, taking into consideration livelihoods as well as governance and development aspirations. PMID- 26599413 TI - Cancer mortality in Itapua--A rural province of Paraguay 2003-2012. AB - BACKGROUND: Itapua is a rural department in Paraguay with a population of about 500,000 and a high degree of agro-mechanization for the production of soybean and other crops. So far, only basic health care is provided. Here we analyzed the cancer mortality in this region as a first step towards epidemiological data for cancer prevention. METHODS: We calculated the age-adjusted mortality rates according to world standard (AMRWs) for the major cancer sites in both males and females between 2003 and 2012, and estimated the differences between the capital and more central districts of Itapua vs. remote districts. RESULTS: There were about 2000 cancer deaths in the decade studied, with AMRWs for all malignancies of 90.9/100,000 in males from central vs. 49.1/100,000 in remote districts and 69.0/100,000 vs. 45.0/100,000 in women. Cancer was mentioned in 12.4% of all death certificates and outweighed mortality from certain infectious and parasitic diseases (3.6%). Cause of death was ill-defined in 19.6% of all death certificates, especially in remote regions and among the elderly. The part of cancer located in the uterus (47.8%) or cell type of neoplasm of the lymphatic or hematopoietic system (73.1%) were often not specified. The uterus (mainly the cervix) (C53-C55) was the leading cancer site in women with AMRWs of 17.2/100,000 in central and 14.0/100,000 in remote districts, followed by the breast. Lung and prostate were the leading cancer sites among men. The lung cancer mortality rate was 19.3/100,000 in the central region but 9.5/100,000 in remote districts. Although children comprised 36% of the population, only 24 death certificates listed cancer as cause of death in this decade. CONCLUSIONS: Analysis of cancer mortality in this rural region of Paraguay, which lacks resources for diagnostics and care, revealed an already large number of cases, with higher rates in the central region than in remote districts. Lung and uterus (primarily the cervix) are common cancer sites and indicate the potential for prevention. However, the quality of the vital statistics needs to be improved. The true cancer burden is most likely underestimated, especially in remote regions and children. PMID- 26599414 TI - Anti-obesity and lipid lowering effects of Cymodocea nodosa sulphated polysaccharide on high cholesterol-fed-rats. AB - This study aims to evaluate for the first time the effects of Cymodocea nodosa sulphated polysaccharide (CNSP) on lipase activity in vitro and in vivo to high fat diet (HFD)-rats on body weight, lipid profile and liver-kidney functions. The administration of CNSP decreases the body weight and inhibits lipase activity of obese rats in serum and intestine as compared with untreated HDF-rats. This decrease in lipase activity leads to lipid regulation shown by the decrease of total cholesterol (T-Ch), triglycerides (TG) and low density lipoprotein cholesterol (LDL-C) and an increase in high density lipoprotein cholesterol (HDL C) levels in HFD-rats. Additionally, CNSP administration to HFD-rats induces anti oxidant activity observed by the increase of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX) activities and the decrease in Thiobarbituric acid reactive substances (TBARS) levels and protects liver-kidney functions proven by a decrease in the levels of toxicity parameters in blood. PMID- 26599415 TI - Extracellular Lipase and Protease Production from a Model Drinking Water Bacterial Community Is Functionally Robust to Absence of Individual Members. AB - Bacteria secrete enzymes into the extracellular space to hydrolyze macromolecules into constituents that can be imported for microbial nutrition. In bacterial communities, these enzymes and their resultant products can be modeled as community property. Our goal was to investigate the impact of individual community member absence on the resulting community production of exoenzymes (extracellular enzymes) involved in lipid and protein hydrolysis. Our model community contained nine bacteria isolated from the potable water system of the International Space Station. Bacteria were grown in static conditions individually, all together, or in all combinations of eight species and exoproduct production was measured by colorimetric or fluorometric reagents to assess short chain and long chain lipases, choline-specific phospholipases C, and proteases. The exoenzyme production of each species grown alone varied widely, however, the enzyme activity levels of the mixed communities were functionally robust to absence of any single species, with the exception of phospholipase C production in one community. For phospholipase C, absence of Chryseobacterium gleum led to increased choline-specific phospholipase C production, correlated with increased growth of Burkholderia cepacia and Sphingomonas sanguinis. Because each individual species produced different enzyme activity levels in isolation, we calculated an expected activity value for each bacterial mixture using input levels or known final composition. This analysis suggested that robustness of each exoenzyme activity is not solely mediated by community composition, but possibly influenced by bacterial communication, which is known to regulate such pathways in many bacteria. We conclude that in this simplified model of a drinking water bacterial community, community structure imposes constraints on production and/or secretion of exoenzymes to generate a level appropriate to exploit a given nutrient environment. PMID- 26599416 TI - Finding the True North: Lessons From the National Healthcare Quality and Disparities Report. PMID- 26599417 TI - Safety of needle electromyography of the diaphragm: Anterior lung margins in quietly breathing healthy subjects. AB - INTRODUCTION: Controversy persists as to whether the lung interposes on the needle electrode insertion path during diaphragm electromyography (EMG). METHODS: Using high-resolution ultrasonography, we measured the distances between the medial recess of the intercostal spaces (ICSs) around the mid-clavicular line (MCL) and the lung margin. We performed measurements bilaterally during quiet breathing in the seated and supine positions. RESULTS: We studied 10 young healthy men and found that, in the first ICS with the medial recess clearly (i.e., several cm) lateral to MCL (usually the eighth ICS), the distance between the recommended insertion site and the lung margin varied from 7.5 to 17 cm. The distance was slightly larger on the right side and in the supine position. CONCLUSIONS: This study confirms that properly conducted "trans-intercostal" needle EMG of the diaphragm is generally safe in healthy subjects. Muscle Nerve 54: 54-57, 2016. PMID- 26599418 TI - Current State of Laparoscopic Colonic Surgery in Austria: A National Survey. AB - PURPOSE: Several studies have demonstrated that laparoscopic colonic resection has significant benefits in comparison with open approaches in patients with benign and malignant disease. The proportion of colonic and rectal resections conducted laparoscopically in Austria is not currently known; the aim of this study was to evaluate the current status of laparoscopic colonic surgery in Austria. MATERIALS AND METHODS: A questionnaire was distributed to all general surgical departments in Austria. In collaboration with IMAS, an Austrian market research institute, an online survey was used to identify laparoscopic and open colorectal resections performed in 2013. The results were compared with data from the National Hospital Morbidity Database (NHMD), in which administrative in patient data were also collected from all general surgical departments in Austria in 2013. RESULTS: Fifty-three of 99 surgical departments in Austria responded (53.5%); 4335 colonic and rectal resections were carried out in the participating departments, representing 50.5% of all NHMD-recorded colorectal resections (n = 8576) in Austria in 2013. Of these 4335 colonic and rectal resections, 2597 (59.9%) were carried out using an open approach, 1674 (38.6%) were laparoscopic, and an exact classification was not available for 64 (1.5%). Among the NHMD recorded colonic and rectal resections, 6342 (73.9%) were carried out with an open approach, and 2234 (26.1%) were laparoscopic. CONCLUSIONS: The proportion of colorectal resections that are carried out laparoscopically is low (26.1%). Technical challenges and a learning curve with a significant number of cases may be reasons for the slow adoption of laparoscopic colonic surgery. PMID- 26599419 TI - Sampling of conformational ensemble for virtual screening using molecular dynamics simulations and normal mode analysis. AB - AIM: Molecular dynamics simulations and normal mode analysis are well-established approaches to generate receptor conformational ensembles (RCEs) for ligand docking and virtual screening. Here, we report new fast molecular dynamics-based and normal mode analysis-based protocols combined with conformational pocket classifications to efficiently generate RCEs. MATERIALS & METHODS: We assessed our protocols on two well-characterized protein targets showing local active site flexibility, dihydrofolate reductase and large collective movements, CDK2. The performance of the RCEs was validated by distinguishing known ligands of dihydrofolate reductase and CDK2 among a dataset of diverse chemical decoys. RESULTS & DISCUSSION: Our results show that different simulation protocols can be efficient for generation of RCEs depending on different kind of protein flexibility. PMID- 26599420 TI - Polymer-based vehicles for therapeutic peptide delivery. AB - During the last decades increasing attention has been paid to peptides as potential therapeutics. However, clinical applications of peptide drugs suffer from susceptibility to degradation, rather short circulation half-life, limited ability to cross physiological barriers and potential immunogenicity. These challenges can be addressed by using polymeric materials as peptide delivery systems, owing to their versatile structures and properties. A number of polymer based vehicles have been developed to stabilize the peptides and to control their release rates. Unfortunately, no single polymer or formulation strategy has been considered ideal for all types of peptide drugs. In this review, currently used and potential polymer-based systems for the peptide delivery will be discussed. PMID- 26599421 TI - Protein-Observed Fluorine NMR: A Bioorthogonal Approach for Small Molecule Discovery. AB - The (19)F isotope is 100% naturally abundant and is the second most sensitive and stable NMR-active nucleus. Unlike the ubiquitous hydrogen atom, fluorine is nearly absent in biological systems, making it a unique bioorthogonal atom for probing molecular interactions in biology. Over 73 fluorinated proteins have been studied by (19)F NMR since the seminal studies of Hull and Sykes in 1974. With advances in cryoprobe production and fluorinated amino acid incorporation strategies, protein-based (19)F NMR offers opportunities to the medicinal chemist for characterizing and ultimately discovering new small molecule protein ligands. This review will highlight new advances using (19)F NMR for characterizing small molecule interactions with both small and large proteins as well as detailing NMR resonance assignment challenges and amino acid incorporation approaches. PMID- 26599422 TI - The effect of implant placement in patients with either Kennedy class II and III on oral health-related quality of life: a prospective clinical trial. AB - There is little evidence of the effect of implants restored with fixed partial dentures on oral health-related quality of life (OHRQoL) in partially edentulous Kennedy class II and III patients. The aim of this study was to determine the change in OHRQoL in Kennedy classification II and III patients treated with a two implant-supported fixed dental prosthesis (FDP). Kennedy class II and III patients received dental implants and an FDP. Oral health-related quality of life was measured by administration of the Oral Health Impact Profile-14 (OHIP-14NL) questionnaire at intake (T1), 2 weeks after surgery (T2) and after 1 year of loading (T3). The mean OHIP score at T1 was 6.5 +/- 1.2, 2.4 +/- 1.0 at T2, and 0.9 +/- 0.3 at T3. There was a statistically significant difference between T1 and T2 (P = 0.002) and T1 and T3 (P < 0.001) but not between T2 and T3 (P = 0.407). The OHIP score in Kennedy II patients decreased from 4.8 +/- 3.2 at T1 to 1.5 +/- 2.0 at T2 and 1.1 +/- 1.8 at T3, and that in Kennedy III patients decreased from 8.9 +/- 9.6 at T1 to 3.6 +/- 8.9 at T2 and 0.8 +/- 2.2 at T3. There were no statistically significant differences in the reductions in Kennedy II and III patients. Oral health-related quality of life changed positively in patients treated with implants and an FDP in both groups. There was no change in OHRQoL between the times of implant placement and FDP placement. PMID- 26599423 TI - A single molecule magnet to single molecule magnet transformation via a solvothermal process: Fe4Dy2 -> Fe6Dy3. AB - Two series of heterometallic Fe(III)-Ln(III) compounds, [FeLn(MU3-OH)2(mdea)4(m NO2C6H4COO)8].3MeCN where Ln = Y (1) and Dy (2) and [FeLn(MU4-O)3(MU3-O)(mdea)5(m NO2C6H4COO)9].3MeCN where Ln = Y (3) and Dy (4), were synthesized. Compounds 1 and 2 were obtained under ambient conditions, whereas 3 and 4 were obtained via a solvothermal transformation process by heating 1 or 2 at 120 degrees C in MeCN. The magnetic properties of all four compounds have been measured and show that compounds 2 and 4 containing Dy(III) ions exhibit slow relaxation of magnetization characteristic of Single Molecule Magnetic (SMM) behaviour. PMID- 26599424 TI - Trimethoprim-sulfonamide use during the first trimester of pregnancy and the risk of congenital anomalies. AB - BACKGROUND: Sulfonamide antibacterials are widely used in pregnancy, but evidence about their safety is mixed. The objective of this study was to assess the association between first-trimester sulfonamide exposure and risk of specific congenital malformations. METHODS: Mother-infant pairs were selected from a cohort of 1.2 million live-born deliveries (2001-2008) at 11 US health plans comprising the Medication Exposure in Pregnancy Risk Evaluation Program. Mothers with first-trimester trimethoprim-sulfonamide (TMP-SUL) exposures were randomly matched 1:1 to (i) a primary comparison group (mothers exposed to penicillins and/or cephalosporins) and (ii) a secondary comparison group (mothers with no dispensing of an antibacterial, antiprotozoal, or antimalarial medication during the same time period). The outcomes were cardiovascular abnormalities, cleft palate/lip, clubfoot, and urinary tract abnormalities. RESULTS: We first identified 7615 infants in the TMP-SUL exposure group, of which 7595 (99%) were exposed to a combination of TMP-SUL and the remaining 1% to sulfonamides alone. After matching (1:1) to the comparator groups and only including those with complete data on covariates, there were 20 064 (n = 6688 per group) in the primary analyses. Overall, cardiovascular defects (1.52%) were the most common and cleft lip/palate (0.10%) the least common that were evaluated. Compared with penicillin/cephalosporin exposure, and no antibacterial exposure, TMP-SUL exposure was not associated with statistically significant elevated risks for cardiovascular, cleft lip/palate, clubfoot, or urinary system defects. CONCLUSIONS: First-trimester TMP-SUL exposure was not associated with a higher risk of the congenital anomalies studied, compared with exposure to penicillins and/or cephalosporins, or no exposure to antibacterials. PMID- 26599425 TI - Development of a patient-centred conceptual framework of health-related quality of life in neuromyelitis optica: a qualitative study. AB - BACKGROUND: Neuromyelitis optica (NMO) is an auto-immune disease that can cause severe visual and mobility impairments. Research on health-related quality of life (HRQoL) in NMO is scarce, limiting knowledge on factors influencing HRQoL and support needs. AIM: This study provides the first qualitative exploration of HRQoL in NMO, conducted to provide a conceptual framework for the development of an NMO patient-reported outcome measure. METHOD: Fifteen people with NMO (aged 18 74; 11 women, 4 men) participated in semi-structured interviews; data were analysed using constant comparative analysis. RESULTS: HRQoL in NMO is a multifaceted concept incorporating highly subjective perceptions of normality and meaning. Four major themes were identified: impact of physical symptoms on daily living, utilizing support to achieve independence, expectations for life and meaningful roles in life and purpose. DISCUSSION: Themes highlighted the importance of perceived normality, and its relationship to attaining life goals comparable to peers, as underpinning evaluations of HRQoL. Many people with severe disability reported a high HRQoL, suggesting the inappropriateness of assuming a negative HRQoL on the basis of an individual's neurological impairment. CONCLUSIONS: These findings further the conceptual understanding of HRQoL in NMO, informing patient-care approaches and the development of an NMO specific patient-reported outcome measure. PMID- 26599427 TI - Co-Doped MoS2 Nanosheets with the Dominant CoMoS Phase Coated on Carbon as an Excellent Electrocatalyst for Hydrogen Evolution. AB - Highly active and low-cost catalysts for hydrogen evolution reaction (HER) are crucial for the development of efficient water splitting. Molybdenum disulfide (MoS2) nanosheets possess unique physical and chemical properties, which make them promising candidates for HER. Herein, we reported a facile, effective, and scalable strategy by a deposition-precipitation method to fabricate metal-doped (Fe, Co, Ni) molybdenum sulfide with a few layers on carbon black as noble metal free electrocatalysts for HER. The CoMoS phase after thermal annealing in Co doped MoS2 plays a crucial role for the enhanced HER. The optimized Co-doped MoS2 catalyst shows superior HER performance with a high exchange current density of 0.03 mA.cm(-2), low onset potential of 90 mV, and small Tafel slope of 50 mV.dec( 1), which also exhibits excellent stability of 10000 cycles with negligible loss of the cathodic current. The superior HER activity originates from the synergistically structural and electronic modulations between MoS2 and Co ions, abundant defects in the active edge sites, as well as the good balance between active sites and electronic conductivity. Thanks to their ease of synthesis, low cost, and high activity, the Co-doped MoS2 catalysts appear to be promising HER catalysts for electrochemical water splitting. PMID- 26599426 TI - Targeting the lysosome in cancer. AB - Lysosomes are membrane-bound intracellular organelles that receive macromolecules delivered by endocytosis, phagocytosis, and autophagy for degradation and recycling. Over the last decade, advances in lysosome research have established a broad role for the lysosome in the pathophysiology of disease. In this review, we highlight the recent discoveries in lysosome biology, with an emphasis on their implications for cancer therapy. We focus on targeting the lysosome in cancer by exploring lysosomal biogenesis and its role in the crosstalk between apoptosis and autophagy. We also discuss how lysosomal inhibition could emerge as a new therapeutic strategy to overcome drug resistance in cancer. PMID- 26599428 TI - Sterically-constrained tripodal phosphorus-bridged tris-pyridyl ligands. AB - Introducing substituents into the 6-position of the 2-pyridyl rings of neutral tris-pyridyl phosphanes of the type P(2-py')3 (where 2-py' is a substituted 2 pyridyl ring), has a marked impact on their coordination of transition metal ions, as revealed in the current study. Whereas the unsubstituted phosphorus bridged tris-pyridyl ligand P(2-py)3 (1) forms the sandwich cation [{P(py)3}2Fe](2+) (4) with iron(II), coordinating via all of the donor nitrogen atoms, the reaction of the methyl-substituted counterpart P(6-Me-2-py)3 (2) and FeCl2 results in the half-sandwich arrangement [{P(6-Me-2-py)3}FeCl2].toluene (5.toluene), in which only two N-atoms of the ligand coordinate to the metal. A similar half-sandwich type complex, [{P(6-Me-2-py)3}FeCl(OTf)].2THF (6.2THF), is obtained from reaction of 2 with Fe(OTf)2 in the presence of LiCl, only now with all three of the N-atoms of the ligand coordinated to Fe(II). The formation of a half-rather than full-sandwich complex 2 with suggests that steric clashing of the Me groups prevents the formation of sandwich-type arrangements. The reaction of [Cu(MeCN)4]PF6 with P(6-Me-2-py) (2) gives the complex [(MeCN)3Cu{P(6-Me-2 py)3}Cu(MeCN)](PF6)2 (7), in which two Cu(I) atoms are coordinated by the bridgehead P-atom and by the three N-atoms of the tris-pyridyl ligand (a unique coordination mode in this area). Overall, the results indicate that 6-Me substitution results in a promising 6-electron capping ligand for organometallic synthesis and catalysis. PMID- 26599429 TI - The Influence of Hand Preference on Grip Strength in Children and Adolescents; A Cross-Sectional Study of 2284 Children and Adolescents. AB - INTRODUCTION: In adults the preferred hand is often considered to be around 10% stronger than the non-preferred hand. Whether the same is true for children and adolescents remains unclear. The objective of this study is therefore to determine whether there is a difference in grip strength between the preferred and non-preferred hand in developing children, to establish whether this difference is similar for children of a different gender or hand preference, and whether there is a difference in grip strength of the preferred hand of left preferent (LP) and right-preferent (RP) children. DESIGN: Cross-sectional study. PARTICIPANTS: Participants were recruited from schools in the northern provinces of the Netherlands. The study included healthy children and adolescents in the age range of 4-17 years. OUTCOME MEASURES: Each child was allowed a total of four attempts using the JAMAR hand dynamometer, two attempts with each hand. All individual attempts were scored. Hand preference was determined by asking which hand was used to write, or in the case of 4- and 5-year-olds, which hand was used to draw a shape. RESULTS: The study population comprised 2284 children and adolescents. RP boys and girls scored significantly higher with their preferred hand, the difference amounting to 9.5 and 10.1% respectively. LP girls scored significantly higher with their preferred hand, but this difference was only 3.0%. For LP boys no significant difference was found in favor of either hand. LP children score higher with the non-preferred hand and tie scores on both hands more often than RP children. CONCLUSION: The 10% rule of hand preference is applicable to RP children ranging in age between 4 and 17 years, but not to LP children. In contrast to LP boys, LP girls are generally significantly stronger with their preferred hand. PMID- 26599430 TI - Superoxide Dismutase 1 Regulation of CXCR4-Mediated Signaling in Prostate Cancer Cells is Dependent on Cellular Oxidative State. AB - BACKGROUND/AIMS: CXCL12, acting via one of its G protein-coupled receptors, CXCR4, is a chemoattractant for a broad range of cell types, including several types of cancer cells. Elevated expression of CXCR4, and its ligand CXCL12, play important roles in promoting cancer metastasis. Cancer cells have the potential for rapid and unlimited growth in an area that may have restricted blood supply, as oxidative stress is a common feature of solid tumors. Recent studies have reported that enhanced expression of cytosolic superoxide dismutase (SOD1), a critical enzyme responsible for regulation of superoxide radicals, may increase the aggressive and invasive potential of malignant cells in some cancers. METHODS: We used a variety of biochemical approaches and a prostate cancer cell line to study the effects of SOD1 on CXCR4 signaling. RESULTS: Here, we report a direct interaction between SOD1 and CXCR4. We showed that SOD1 interacts directly with the first intracellular loop (ICL1) of CXCR4 and that the CXCL12/CXCR4 mediated regulation of AKT activation, apoptosis and cell migration in prostate cancer (PCa) cells is differentially modulated under normal versus hypoxic conditions when SOD1 is present. CONCLUSIONS: This study highlights a potential new regulatory mechanism by which a sensor of the oxidative environment could directly regulate signal transduction of a receptor involved in cancer cell survival and migration. PMID- 26599431 TI - Interleukin-17A Levels Vary in Relapsing-Remitting Multiple Sclerosis Patients in Association with Their Age, Treatment and the Time of Evolution of the Disease. AB - OBJECTIVE: The present study was specifically designed to discern the possible existence of subgroups of patients with the relapsing-remitting form of multiple sclerosis (RRMS) depending on their gender, age, disease stage (relapsing or remitting), time of disease evolution and response to different treatments. METHODS: We analyzed samples from patients with RRMS (50 females and 32 males) and healthy individuals (25 matched for age and gender) and determined serum concentrations of IFN-gamma, IL-10 and IL-17A. We stratified patients by gender, age, treatment and disease evolution time, and subsequently correlated these independent variables with the concentrations of the previously mentioned cytokines. RESULTS: We provided initial evidence that treatment exerted possible differential effects depending on the time of disease duration. Results evidence the existence of different subgroups of patients with MS, who can be classified as follows: (a) male or female under or over 40 years of age; (b) disease duration according to treatment (under or over 8 years of disease); (c) classification according to fluctuating levels of IFN-gamma, IL-10 and IL-17A in the following three stages of disease evolution: <5 years, between 5 and 10 years, and >10 years. CONCLUSION: These subgroups must be taken into account for the clinical follow-up of patients with MS in order to provide them with a better and more personalized treatment, and also for a deep and detailed analysis of progressive disease, in an attempt to comprehend fluctuations and clinical variability by means of a better understanding of intrinsically physiological variables of the disease. PMID- 26599432 TI - Quantifying fat, oil, and grease deposit formation kinetics. AB - Fat, oil, and grease (FOG) deposits formed in sanitary sewers are calcium-based saponified solids that are responsible for a significant number of nationwide sanitary sewer overflows (SSOs) across United States. In the current study, the kinetics of lab-based saponified solids were determined to understand the kinetics of FOG deposit formation in sewers for two types of fat (Canola and Beef Tallow) and two types of calcium sources (calcium chloride and calcium sulfate) under three pH (7 +/- 0.5, 10 +/- 0.5, and ~14) and two temperature conditions (22 +/- 0.5 and 45 +/- 0.5 degrees C). The results of this study displayed quick reactions of a fraction of fats with calcium ions to form calcium based saponified solids. Results further showed that increased palmitic fatty acid content in source fats, the magnitude of the pH, and temperature significantly affect the FOG deposit formation and saponification rates. The experimental data of the kinetics were compared with two empirical models: a) Cotte saponification model and b) Foubert crystallization model and a mass-action based mechanistic model that included alkali driven hydrolysis of triglycerides. Results showed that the mass action based mechanistic model was able to predict changes in the rate of formation of saponified solids under the different experimental conditions compared to both empirical models. The mass-action based saponification model also revealed that the hydrolysis of Beef Tallow was slower compared to liquid Canola fat resulting in smaller quantities of saponified solids. This mechanistic saponification model, with its ability to track the saponified solids chemical precursors, may provide an initial framework to predict the spatial formation of FOG deposits in municipal sewers using system wide sewer collection modeling software. PMID- 26599433 TI - Interlinkages between bacterial populations dynamics and the operational parameters in a moving bed membrane bioreactor treating urban sewage. AB - Bacteria are key players in biological wastewater treatments (WWTs), thus a firm knowledge of the bacterial population dynamics is crucial to understand environmental/operational factors affecting the efficiency and stability of the biological depuration process. Unfortunately, little is known about the microbial ecology of the advanced biological WWTs combining suspended biomass (SB) and attached biofilms (AB). This study explored in depth the bacterial community structure and population dynamics in each biomass fraction from a pilot-scale moving bed membrane bioreactor (MBMBR) treating municipal sewage, by means of temperature-gradient gel electrophoresis (TGGE) and 454-pyrosequencing. Eight experimental phases were conducted, combining different carrier filling ratios, hydraulic retention times and concentrations of mixed liquor total suspended solids. The bacterial community, dominated by Proteobacteria (20.9-53.8%) and Actinobacteria (20.6-57.6%), was very similar in both biomass fractions and able to maintain its functional stability under all the operating conditions, ensuring a successful and steady depuration process. Multivariate statistical analysis demonstrated that solids concentration, carrier filling ratio, temperature and organic matter concentration in the influent were the significant factors explaining population dynamics. Bacterial diversity increased as carrier filling ratio increased (from 20% to 35%, v/v), and solids concentration was the main factor triggering the shifts of the community structure. These findings provide new insights on the influence of operational parameters on the biology of the innovative MBMBRs. PMID- 26599434 TI - Iron reduction in the DAMO/Shewanella oneidensis MR-1 coculture system and the fate of Fe(II). AB - Dissimilatory iron reduction and anaerobic methane oxidation processes play important roles in the global iron and carbon cycle, respectively. This study explored the ferrihydrite reduction process with methane as a carbon source in a coculture system of denitrifying anaerobic methane oxidation (DAMO) microbes enriched in laboratory and Shewanella oneidensis MR-1, and then characterized the reduced products. Ferrihydrite reduction was also studied in the DAMO and Shewanella systems alone. The ferrihydrite was reduced slightly (<13.3%) in the separate systems, but greatly (42.0-88.3%) in the coculture system. Isotope experiment of (13)CH4 addition revealed that DAMO microbes coupled to S. oneidensis MR-1 in a ferric iron reduction process with (13)CH4 consumption and (13)CO2 production. Compared with ferrihydrite, the reduced products showed increased crystallinity (from amorphous state to crystallinity 77.1%) and magnetism (from paramagnetic to ferromagnetic). The produced ferrous iron was formed into minerals primarily composed of siderite with a small amount vivianite and magnetite. A portion of products covered the cell surface and hindered further reactions. The results presented herein widen the current understanding of iron metabolism and mineralization in the ocean, and show that the coculture systems of DAMO microbes and Shewanella have the potential to be globally important to iron reduction and methane oxidation. PMID- 26599435 TI - Correction: Identification and Validation of Protein Biomarkers of Response to Neoadjuvant Platinum Chemotherapy in Muscle Invasive Urothelial Carcinoma. PMID- 26599436 TI - Trends in the Use of Nephron-Sparing Surgery over 7 Years: An Analysis Using the R.E.N.A.L. Nephrometry Scoring System. AB - OBJECTIVE: To analyze trends in the use of partial nephrectomy, we evaluated which individual factors of renal nephrometry score (RNS) influenced the operative approach bi-annually from 2008 to 2014. MATERIALS AND METHODS: We performed a retrospective review of renal cell carcinoma treated by surgery in 2008, 2010, 2012, and 2014. The complexity of renal masses was measured using the R.E.N.A.L. nephrometry scoring system with CT or MRI. Group comparison in terms of operation year and surgical type (partial nephrectomy versus radical nephrectomy) was performed. We developed a nomogram to quantitate the likelihood of selecting partial nephrectomy over radical nephrectomy. RESULTS: A total of 1106 cases (237 in 2008, 225 in 2010, 292 in 2012, and 352 in 2014) were available for the study. Over the study period, the proportion of partial nephrectomies performed increased steadily from 21.5% in 2008 to 66.5% in 2014 (p < 0.05). Furthermore, use of partial nephrectomy increased steadily in all RNS complexity groups (low, moderate, and high) (p < 0.05). In the analysis of individual components of RNS, values of the R and N components increased statistically by year in the partial nephrectomy group (p < 0.05). Average AUC was 0.920. CONCLUSIONS: The proportion of partial nephrectomies performed sharply increased over the study period. Additionally, over the study period, more partial nephrectomies were performed for renal masses of larger size and closer to the collecting system and main renal vessels. A nomogram developed based on this recent data set provides significant predictive value for surgical decision making. PMID- 26599437 TI - Factors Influencing the Health Behaviour of Indigenous Australians: Perspectives from Support People. AB - Disparities between the health of Indigenous and non-Indigenous populations continue to be prevalent within Australia. Research suggests that Indigenous people participate in health risk behaviour more often than their non-Indigenous counterparts, and that such behaviour has a substantial impact on health outcomes. Although this would indicate that reducing health risk behaviour may have positive effects on health outcomes, the factors that influence Indigenous health behaviour are still poorly understood. This study aimed to interview people who support Indigenous groups to gain an understanding of their views on the factors influencing health behaviour within Indigenous groups in Western Australia. Twenty nine people participated in the study. The emergent themes were mapped against the social ecological model. The results indicated that: (1) culture, social networks, history, racism, socioeconomic disadvantage, and the psychological distress associated with some of these factors interact to affect health behaviour in a complex manner; (2) the desire to retain cultural identity and distinctiveness may have both positive and negative influence on health risk behaviour; (3) strong social connections to family and kin that is intensified by cultural obligations, appears to affirm and disrupt positive health behaviour; (4) the separation between Indigenous and non-Indigenous social connection/networks that appeared to be fostered by marginalisation and racism may influence the effect of social networks on health behaviour; and (5) communication between Indigenous and non-Indigenous people may be interrupted by distrust between the groups, which reduces the influence of some non-Indigenous sources on the health behaviour of Indigenous people. PMID- 26599439 TI - Correction: The Presence of the Y-Chromosome, Not the Absence of the Second X Chromosome, Alters the mRNA Levels Stored in the Fully Grown XY Mouse Oocyte. AB - [This corrects the article DOI: 10.1371/journal.pone.0040481.]. PMID- 26599438 TI - Mapping the Centimeter-Scale Spatial Variability of PAHs and Microbial Populations in the Rhizosphere of Two Plants. AB - Rhizoremediation uses root development and exudation to favor microbial activity. Thus it can enhance polycyclic aromatic hydrocarbon (PAH) biodegradation in contaminated soils. Spatial heterogeneity of rhizosphere processes, mainly linked to the root development stage and to the plant species, could explain the contrasted rhizoremediation efficiency levels reported in the literature. Aim of the present study was to test if spatial variability in the whole plant rhizosphere, explored at the centimetre-scale, would influence the abundance of microorganisms (bacteria and fungi), and the abundance and activity of PAH degrading bacteria, leading to spatial variability in PAH concentrations. Two contrasted rhizospheres were compared after 37 days of alfalfa or ryegrass growth in independent rhizotron devices. Almost all spiked PAHs were degraded, and the density of the PAH-degrading bacterial populations increased in both rhizospheres during the incubation period. Mapping of multiparametric data through geostatistical estimation (kriging) revealed that although root biomass was spatially structured, PAH distribution was not. However a greater variability of the PAH content was observed in the rhizosphere of alfalfa. Yet, in the ryegrass planted rhizotron, the Gram-positive PAH-degraders followed a reverse depth gradient to root biomass, but were positively correlated to the soil pH and carbohydrate concentrations. The two rhizospheres structured the microbial community differently: a fungus-to-bacterium depth gradient similar to the root biomass gradient only formed in the alfalfa rhizotron. PMID- 26599440 TI - Identification of Genetic Variation between Obligate Plant Pathogens Pseudoperonospora cubensis and P. humuli Using RNA Sequencing and Genotyping-By Sequencing. AB - RNA sequencing (RNA-seq) and genotyping-by-sequencing (GBS) were used for single nucleotide polymorphism (SNP) identification from two economically important obligate plant pathogens, Pseudoperonospora cubensis and P. humuli. Twenty isolates of P. cubensis and 19 isolates of P. humuli were genotyped using RNA-seq and GBS. Principle components analysis (PCA) of each data set showed genetic separation between the two species. Additionally, results supported previous findings that P. cubensis isolates from squash are genetically distinct from cucumber and cantaloupe isolates. A PCA-based procedure was used to identify SNPs correlated with the separation of the two species, with 994 and 4,231 PCA correlated SNPs found within the RNA-seq and GBS data, respectively. The corresponding unigenes (n = 800) containing these potential species-specific SNPs were then annotated and 135 putative pathogenicity genes, including 3 effectors, were identified. The characterization of genes containing SNPs differentiating these two closely related downy mildew species may contribute to the development of improved detection and diagnosis strategies and improve our understanding of host specificity pathways. PMID- 26599442 TI - Effect of Misalignment between Successive Corneal Videokeratography Maps on the Repeatability of Topography Data. AB - PURPOSE: To improve the reliability of corneal topographic data through the development of a method to estimate the magnitude of misalignment between successive corneal videokeratography (VK) maps and eliminate the effect of misalignment on the repeatability of topography data. METHODS: Anterior and posterior topography maps were recorded twice for 124 healthy eyes of 124 participants using a Pentacam, and the repeatability of measurements was assessed by calculating the differences in elevation between each two sets of data. The repeatability of measurements was re-assessed following the determination of the magnitude of misalignment components (translational displacements: x0, y0 and z0, and rotational displacements: alpha, beta and gamma) between each two data sets and using them to modify the second data set within each pair based on an Iterative Closest Point (ICP) algorithm. The method simultaneously considered the anterior and posterior maps taken for the same eye since they were assumed to have the same set of misalignment components. A new parameter, named Combined Misalignment parameter (CM), has been developed to combine the effect of all six misalignment components on topography data and so enable study of the association between misalignment and the data repeatability test results. RESULTS: The repeatability tests resulted in average root mean square (RMS) differences in elevation data of 8.46+/-2.75 MUm before ICP map matching when simultaneously considering anterior and posterior surfaces. With map matching and misalignment correction, the differences decreased to 7.28+/-2.58 MUm (P = 0.00). When applied to only the anterior maps, misalignment correction led to a more pronounced reduction in elevation data differences from 4.58+/-1.84 MUm to 2.97+/-1.29 MUm (P = 0.00). CM was found to be associated with the repeatability error (P = 0.00), with posterior maps being responsible for most of the error due to their relatively lower accuracy compared to anterior maps. CONCLUSIONS: The ICP algorithm can be used to estimate, and effectively correct for, the potential misalignment between successive corneal videokeratography maps. PMID- 26599441 TI - Association of Genetically Determined Aldehyde Dehydrogenase 2 Activity with Diabetic Complications in Relation to Alcohol Consumption in Japanese Patients with Type 2 Diabetes Mellitus: The Fukuoka Diabetes Registry. AB - Aldehyde dehydrogenase 2 (ALDH2) detoxifies aldehyde produced during ethanol metabolism and oxidative stress. A genetic defect in this enzyme is common in East Asians and determines alcohol consumption behaviors. We investigated the impact of genetically determined ALDH2 activity on diabetic microvascular and macrovascular complications in relation to drinking habits in Japanese patients with type 2 diabetes mellitus. An ALDH2 single-nucleotide polymorphism (rs671) was genotyped in 4,400 patients. Additionally, the relationship of clinical characteristics with ALDH2 activity (ALDH2 *1/*1 active enzyme activity vs. *1/*2 or *2/*2 inactive enzyme activity) and drinking habits (lifetime abstainers vs. former or current drinkers) was investigated cross-sectionally (n = 691 in *1/*1 abstainers, n = 1,315 in abstainers with *2, n = 1,711 in *1/*1 drinkers, n = 683 in drinkers with *2). The multiple logistic regression analysis for diabetic complications was adjusted for age, sex, current smoking habits, leisure-time physical activity, depressive symptoms, diabetes duration, body mass index, hemoglobin A1c, insulin use, high-density lipoprotein cholesterol, systolic blood pressure and renin-angiotensin system inhibitors use. Albuminuria prevalence was significantly lower in the drinkers with *2 than that of other groups (odds ratio [95% confidence interval (CI)]: *1/*1 abstainers as the referent, 0.94 [0.76 1.16] in abstainers with *2, 1.00 [0.80-1.26] in *1/*1 drinkers, 0.71 [0.54-0.93] in drinkers with *2). Retinal photocoagulation prevalence was also lower in drinkers with ALDH2 *2 than that of other groups. In contrast, myocardial infarction was significantly increased in ALDH2 *2 carriers compared with that in ALDH2 *1/*1 abstainers (odds ratio [95% CI]: *1/*1 abstainers as the referent, 2.63 [1.28-6.13] in abstainers with *2, 1.89 [0.89-4.51] in *1/*1 drinkers, 2.35 [1.06-5.79] in drinkers with *2). In summary, patients with type 2 diabetes and ALDH2 *2 displayed a lower microvascular complication prevalence associated with alcohol consumption but a higher macrovascular complication prevalence irrespective of alcohol consumption. PMID- 26599443 TI - Composition and Interactions of Hepatitis B Virus Quasispecies Defined the Virological Response During Telbivudine Therapy. AB - Reverse transcriptase (RT) mutations contribute to hepatitis B virus resistance during antiviral therapy with nucleos(t)ide analogs. However, the composition of the RT quasispecies and their interactions during antiviral treatment have not yet been thoroughly defined. In this report, 10 patients from each of 3 different virological response groups, i.e., complete virological response, partial virological response and virological breakthrough, were selected from a multicenter trial of Telbivudine treatment. Variations in the drug resistance related critical RT regions in 107 serial serum samples from the 30 patients were examined by ultra-deep sequencing. A total of 496,577 sequence reads were obtained, with an average sequencing coverage of 4,641X per sample. The phylogenies of the quasispecies revealed the independent origins of two critical quasispecies, i.e., the rtA181T and rtM204I mutants. Data analyses and theoretical modeling showed a cooperative-competitive interplay among the quasispecies. In particular, rtM204I mutants compete against other quasispecies, which eventually leads to virological breakthrough. However, in the absence of rtM204I mutants, synergistic growth of the drug-resistant rtA181T mutants with the wild-type quasispecies could drive the composition of the viral population into a state of partial virological response. Furthermore, we demonstrated that the frequency of drug-resistant mutations in the early phase of treatment is important for predicting the virological response to antiviral therapy. PMID- 26599444 TI - Influence of Phytase Transgenic Corn on the Intestinal Microflora and the Fate of Transgenic DNA and Protein in Digesta and Tissues of Broilers. AB - An experiment was conducted to investigate the effect of phytase transgenic corn (PTC) on intestinal microflora, and the fate of transgenic DNA and protein in the digesta and tissues of broilers. A total of 160 1-day-old Arbor Acres commercial male broilers were randomly assigned to 20 cages (8 chicks per cage) with 10 cages (replicates) for each treatment. Birds were fed with a diet containing either PTC (54.0% during 1-21 days and 61.0% during 22-42 days) or non-transgenic isogenic control corn (CC) for a duration of 42 days. There were no significant differences (P>0.05) between birds fed with the PTC diets and those fed with the CC diets in the quantities of aerobic bacteria, anaerobic bacteria, colibacillus and lactobacilli, or microbial diversities in the contents of ileum and cecum. Transgenic phyA2 DNA was not detected, but phyA2 protein was detected in the digesta of duodenum and jejunum of broilers fed with the PTC diets. Both transgenic phyA2 DNA and protein fragments were not found in the digesta of the ileum and rectum, heart, liver, kidney, and breast or thigh muscles of broilers fed with the PTC diets. It was concluded that PTC had no adverse effect on the quantity and diversity of gut microorganisms; Transgenic phyA2 DNA or protein was rapidly degraded in the intestinal tract and was not transferred to the tissues of broilers. PMID- 26599446 TI - The role of ANKH in pathologic mineralization of cartilage. AB - PURPOSE OF REVIEW: ANKH is the human homolog of a gene whose dysfunction in a mutant mouse strain results in progressive ankylosis of the spine as well as soft tissue mineralization. ANKH mutations have been reported in inherited human disorders such as familial calcium pyrophosphate deposition disease (CPPD) and cranial metaphyseal dysplasia; however, research into the function of the ANKH protein has been more challenging. Progress has recently been made to understand the role of ANKH in the regulation of physiological and pathological mineralization. RECENT FINDINGS: ANKH expression is regulated by intracellular levels of oxygen, phosphate and calcium as well as by the growth factor TGF-beta. In addition, ANKH expression affects chondrogenesis, osteoblastogenesis and osteoclastogenesis. ANKH appears to interact with several cellular proteins, including the phosphate transporter PiT-1, and with proteins involved in NF-kappa beta signaling, suggesting that ANKH may play an important non-PPi transporter role. ANKH has also been shown to regulate ATP efflux from chondrocytes. SUMMARY: ANKH expression, as well as its potential non-PPi transporter functions, plays a variety of roles in the regulation of cellular events that surround differentiation and mineralization in bone and cartilage. Additional studies are warranted to further elucidate the contributions of ANKH to human health and disease, and to determine if ANKH deserves targeting for the treatment of diseases such as CPPD. PMID- 26599445 TI - The Combination of Three Natural Compounds Effectively Prevented Lung Carcinogenesis by Optimal Wound Healing. AB - The tumor stroma has been described as "normal wound healing gone awry". We explored whether the restoration of a wound healing-like microenvironment may facilitate tumor healing. Firstly, we screened three natural compounds (shikonin, notoginsenoside R1 and aconitine) from wound healing agents and evaluated the efficacies of wound healing microenvironment for limiting single agent-elicited carcinogenesis and two-stage carcinogenesis. The results showed that three compounds used alone could promote wound healing but had unfavorable efficacy to exert wound healing, and that the combination of three compounds made up treatment disadvantage of a single compound in wound healing and led to optimal wound healing. Although individual treatment with these agents may prevent cancer, they were not effective for the treatment of established tumors. However, combination treatment with these three compounds almost completely prevented urethane-induced lung carcinogenesis and reduced tumor burden. Different from previous studies, we found that urethane-induced lung carcinogenesis was associated with lung injury independent of pulmonary inflammation. LPS-induced pulmonary inflammation did not increase lung carcinogenesis, whereas decreased pulmonary inflammation by macrophage depletion promoted lung carcinogenesis. In addition, urethane damaged wound healing in skin excision wound model, reversed lung carcinogenic efficacy by the combination of three compounds was consistent with skin wound healing. Further, the combination of these three agents reduced the number of lung cancer stem cells (CSCs) by inducing cell differentiation, restoration of gap junction intercellular communication (GJIC) and blockade of the epithelial-to-mesenchymal transition (EMT). Our results suggest that restoration of a wound healing microenvironment represents an effective strategy for cancer prevention. PMID- 26599447 TI - Fast Adaptive Thermal Camouflage Based on Flexible VO2/Graphene/CNT Thin Films. AB - Adaptive camouflage in thermal imaging, a form of cloaking technology capable of blending naturally into the surrounding environment, has been a great challenge in the past decades. Emissivity engineering for thermal camouflage is regarded as a more promising way compared to merely temperature controlling that has to dissipate a large amount of excessive heat. However, practical devices with an active modulation of emissivity have yet to be well explored. In this letter we demonstrate an active cloaking device capable of efficient thermal radiance control, which consists of a vanadium dioxide (VO2) layer, with a negative differential thermal emissivity, coated on a graphene/carbon nanotube (CNT) thin film. A slight joule heating drastically changes the emissivity of the device, achieving rapid switchable thermal camouflage with a low power consumption and excellent reliability. It is believed that this device will find wide applications not only in artificial systems for infrared camouflage or cloaking but also in energy-saving smart windows and thermo-optical modulators. PMID- 26599461 TI - Disulfiram and its novel derivative sensitize prostate cancer cells to the growth regulatory mechanisms of the cell by re-expressing the epigenetically repressed tumor suppressor-estrogen receptor beta. AB - Estrogen Receptor-beta (ER-beta), a tumor-suppressor in prostate cancer, is epigenetically repressed by hypermethylation of its promoter. DNA methyltransferases (DNMTs), which catalyze the transfer of methyl-groups to CpG islands of gene promoters, are overactive in cancers and can be inhibited by DNMT inhibitors to re-express the tumor suppressors. The FDA-approved nucleoside DNMT inhibitors like 5-Azacytidine and 5-Aza-deoxycytidine carry notable concerns due to their off-target toxicity, therefore non-nucleoside DNMT inhibitors are desirable for prolonged epigenetic therapy. Disulfiram (DSF), an antabuse drug, inhibits DNMT and prevents proliferation of cells in prostate and other cancers, plausibly through the re-expression of tumor suppressors like ER-beta. To increase the DNMT-inhibitory activity of DSF, its chemical scaffold was optimized and compound-339 was discovered as a doubly potent DSF-derivative with similar off-target toxicity. It potently and selectively inhibited cell proliferation of prostate cancer (PC3/DU145) cells in comparison to normal (non-cancer) cells by promoting cell-cycle arrest and apoptosis, accompanied with inhibition of total DNMT activity, and re-expression of ER-beta (mRNA/protein). Bisulfite-sequencing of ER-beta promoter revealed that compound-339 demethylated CpG sites more efficaciously than DSF, restoring near-normal methylation status of ER-beta promoter. Compound-339 docked on to the MTase domain of DNMT1 with half the energy of DSF. In xenograft mice-model, the tumor volume regressed by 24% and 50% after treatment with DSF and compound-339, respectively, with increase in ER-beta expression. Apparently both compounds inhibit prostate cancer cell proliferation by re-expressing the epigenetically repressed tumor-suppressor ER-beta through inhibition of DNMT activity. Compound-339 presents a new lead for further study as an anti-prostate cancer agent. (c) 2015 Wiley Periodicals, Inc. PMID- 26599462 TI - Molecular Characterisation and Diagnosis of Root-Knot Nematodes (Meloidogyne spp.) from Turfgrasses in North Carolina, USA. AB - Root-knot nematodes (Meloidogyne spp.) are the most common and destructive plant parasitic nematode group worldwide and adversely influence both crop quality and yield. In this study, a total of 51 root-knot nematode populations from turfgrasses were tested, of which 44 were from North Carolina, 6 from South Carolina and 1 from Virginia. Molecular characterisation was performed on these samples by DNA sequencing on the ribosomal DNA 18S, ITS and 28S D2/D3. Species specific primers were developed to identify turfgrass root-knot nematode through simplex or duplex PCR. Four species were identified, including M. marylandi Jepson & Golden in Jepson, 1987, M. graminis (Sledge & Golden, 1964) Whitehead, 1968, M. incognita (Kofoid & White, 1919) Chitwood, 1949 and M. naasi Franklin, 1965 through a combined analysis of DNA sequencing and PCR by species-specific primers. M. marylandi has been reported from North Carolina and South Carolina for the first time. Molecular diagnosis using PCR by species-specific primers provides a rapid and cheap species identification approach for turfgrass root knot nematodes. PMID- 26599463 TI - A Short Screening Tool to Identify Victims of Child Sex Trafficking in the Health Care Setting. AB - OBJECTIVES: The aim of this study was to describe characteristics of commercial sexual exploitation of children/child sex trafficking (CSEC/CST) victims and to develop a screening tool to identify victims among a high-risk adolescent population. METHODS: In this cross-sectional study, patients aged 12 to 18 years who presented to 1 of 3 metropolitan pediatric emergency departments or 1 child protection clinic and who were identified as victims of CSEC/CST were compared with similar-aged patients with allegations of acute sexual assault/sexual abuse (ASA) without evidence of CSEC/CST. The 2 groups were compared on variables related to medical and reproductive history, high-risk behavior, mental health symptoms, and injury history. After univariate analysis, a subset of candidate variables was subjected to multivariable logistic regression to identify an optimum set of 5 to 7 screening items. RESULTS: Of 108 study participants, 25 comprised the CSEC/CST group, and 83 comprised the ASA group. Average (SD) age was 15.4 (1.8) years for CSEC/CST patients and 14.8 (1.6) years for ASA patients; 100% of the CSEC/CST and 95% of the ASA patients were female. The 2 groups differed significantly on 16 variables involving reproductive history, high-risk behavior, sexually transmitted infections, and previous experience with violence. A 6-item screen was constructed, and a cutoff score of 2 positive answers had a sensitivity of 92%, specificity of 73%, positive predictive value of 51%, and negative predictive value of 97%. CONCLUSIONS: Adolescent CSEC/CST victims differ from ASA victims without evidence of CSEC/CST across several domains. A 6-item screen effectively identifies CSEC/CST victims in a high-risk adolescent population. PMID- 26599464 TI - Before the Flood: Impact of Coordination of Care and Direct Admissions on Emergency Department Volumes. AB - BACKGROUND: Transfers of pediatric patients occur to access specialty and subspecialty care, but incur risk, and consume resources. Direct admissions to medical and surgical wards may improve patient experience and mitigate resource utilization. OBJECTIVE: We sought to identify common elements for direct admissions, as well as the pattern of disposition for patients referred to our emergency department (ED). DESIGN: A retrospective qualitative analysis of patients transferred to our pediatric hospital for 12 months was performed. Different physician groups were evaluated for use of direct admissions or evaluation in the ED. Patients referred to the ED were additionally tracked to evaluate their eventual disposition. RESULTS: A total of 3982 transfers occurred during the 12-month analysis period. Of those, 3463 resulted in admission, accounting for 32.55% of all admissions. Transfers accepted by nonsurgical services accounted for 82% of the transfers, whereas 18% were facilitated by one of the surgical services. Direct admissions accounted for 1707 (44.8%) of all referrals and were used more often by nonsurgical services. Of patients referred to the ED (2101 or 55.2% of all referrals), most patients were admitted and 343 (16% of those referred to the ED) were discharged home. CONCLUSIONS: The direct admission process helped avoid ED assessments for some patients; however, some patients referred to the ED were able to be evaluated, treated, and discharged. Consistent triage of the patients being transferred as direct admissions may improve ED throughput and potentially improve the patient's experience, reduce redundant services, and expedite care. PMID- 26599465 TI - Advanced Low-Cost Ultrasound-Guided Vascular Access Simulation: The Chicken Breast Model. AB - There is a growing body of literature that supports the use of ultrasound for vascular access. Advanced simulation has become a widely applied technique for training medical staff in vascular access. Nevertheless, advanced simulators are expensive and of limited usage. We describe both a step-wise systematic approach and an experimental cadaveric model of vascular access using a simple piece of chicken that can be easily used for trainees. PMID- 26599466 TI - Gallium-Loaded Dissolvable Microfilm Constructs that Provide Sustained Release of Ga(3+) for Management of Biofilms. AB - The persistence of bacterial biofilms in chronic wounds delays wound healing. Although Ga(3+) can inhibit or kill biofilms, precipitation as Ga(OH)3 has prevented its use as a topical wound treatment. The design of a microfilm construct comprising a polyelectrolyte film that releases noncytotoxic concentrations of Ga(3+) over 20 d and a dissolvable micrometer-thick film of polyvinylalcohol that enables facile transfer onto biomedically important surfaces is reported. By using infrared spectroscopy, it is shown that the density of free carboxylate/carboxylic acid and amine groups within the polyelectrolyte film regulates the capacity of the construct to be loaded with Ga(3+) and that the density of covalent cross-links introduced into the polyelectrolyte film (amide-bonds) controls the release rate of Ga(3+) . Following transfer onto the wound-contact surface of a biologic wound dressing, an optimized construct is demonstrated to release ~0.7 MUg cm(-2) d(-1) of Ga(3+) over 3 weeks, thus continuously replacing Ga(3+) lost to precipitation. The optimized construct inhibits formation of P. aeruginosa (two strains; ATCC 27853 and PA01) biofilms for up to 4 d and causes pre-existing biofilms to disperse. Overall, this study provides designs of polymeric constructs that permit facile modification of the wound-contacting surfaces of dressings and biomaterials to manage biofilms. PMID- 26599468 TI - Calculating the Fickian diffusivity for a lattice-based random walk with agents and obstacles of different shapes and sizes. AB - Random walk models are often used to interpret experimental observations of the motion of biological cells and molecules. A key aim in applying a random walk model to mimic an in vitro experiment is to estimate the Fickian diffusivity (or Fickian diffusion coefficient), D. However, many in vivo experiments are complicated by the fact that the motion of cells and molecules is hindered by the presence of obstacles. Crowded transport processes have been modeled using repeated stochastic simulations in which a motile agent undergoes a random walk on a lattice that is populated by immobile obstacles. Early studies considered the most straightforward case in which the motile agent and the obstacles are the same size. More recent studies considered stochastic random walk simulations describing the motion of an agent through an environment populated by obstacles of different shapes and sizes. Here, we build on previous simulation studies by analyzing a general class of lattice-based random walk models with agents and obstacles of various shapes and sizes. Our analysis provides exact calculations of the Fickian diffusivity, allowing us to draw conclusions about the role of the size, shape and density of the obstacles, as well as examining the role of the size and shape of the motile agent. Since our analysis is exact, we calculate D directly without the need for random walk simulations. In summary, we find that the shape, size and density of obstacles has a major influence on the exact Fickian diffusivity. Furthermore, our results indicate that the difference in diffusivity for symmetric and asymmetric obstacles is significant. PMID- 26599467 TI - What Is the Best NGS Enrichment Method for the Molecular Diagnosis of Monogenic Diabetes and Obesity? AB - Molecular diagnosis of monogenic diabetes and obesity is of paramount importance for both the patient and society, as it can result in personalized medicine associated with a better life and it eventually saves health care spending. Genetic clinical laboratories are currently switching from Sanger sequencing to next-generation sequencing (NGS) approaches but choosing the optimal protocols is not easy. Here, we compared the sequencing coverage of 43 genes involved in monogenic forms of diabetes and obesity, and variant detection rates, resulting from four enrichment methods based on the sonication of DNA (Agilent SureSelect, RainDance technologies), or using enzymes for DNA fragmentation (Illumina Nextera, Agilent HaloPlex). We analyzed coding exons and untranslated regions of the 43 genes involved in monogenic diabetes and obesity. We found that none of the methods achieves yet full sequencing of the gene targets. Nonetheless, the RainDance, SureSelect and HaloPlex enrichment methods led to the best sequencing coverage of the targets; while the Nextera method resulted in the poorest sequencing coverage. Although the sequencing coverage was high, we unexpectedly found that the HaloPlex method missed 20% of variants detected by the three other methods and Nextera missed 10%. The question of which NGS technique for genetic diagnosis yields the highest diagnosis rate is frequently discussed in the literature and the response is still unclear. Here, we showed that the RainDance enrichment method as well as SureSelect, which are both based on the sonication of DNA, resulted in a good sequencing quality and variant detection, while the use of enzymes to fragment DNA (HaloPlex or Nextera) might not be the best strategy to get an accurate sequencing. PMID- 26599469 TI - Prolonged thrombocytopenia in a child with severe neonatal alloimmune reaction and Noonan syndrome. AB - Fetomaternal alloimmune thrombocytopenia (FMAIT) caused by maternal antibodies is the leading cause of severe neonatal thrombocytopenia. A 1-month-old Caucasian girl was referred to our Hematology Clinic for persistent thrombocytopenia diagnosed after a bleeding episode. Diagnostic tests suggested FMAIT. Mild thrombocytopenia persisted for 18 months, and subsequent findings of dysmorphic facies, short stature and mild pulmonary stenosis led to the hypothesis of Noonan syndrome (NS), which was confirmed by genetic test. Other hematological abnormalities were excluded and she had no further bleeding episodes. This case illustrates the possibility of different diagnoses with the same clinical manifestations. The persistence of thrombocytopenia longer than expected associated with typical physical features led to the diagnosis of NS. PMID- 26599470 TI - Passing faces: sequence-dependent variations in the perceptual processing of emotional faces. AB - There is broad evidence that contextual factors influence the processing of emotional facial expressions. Yet temporal-dynamic aspects, inter alia how face processing is influenced by the specific order of neutral and emotional facial expressions, have been largely neglected. To shed light on this topic, we recorded electroencephalogram from 168 healthy participants while they performed a gender-discrimination task with angry and neutral faces. Our event-related potential (ERP) analyses revealed a strong emotional modulation of the N170 component, indicating that the basic visual encoding and emotional analysis of a facial stimulus happen, at least partially, in parallel. While the N170 and the late positive potential (LPP; 400-600 ms) were only modestly affected by the sequence of preceding faces, we observed a strong influence of face sequences on the early posterior negativity (EPN; 200-300 ms). Finally, the differing response patterns of the EPN and LPP indicate that these two ERPs represent distinct processes during face analysis: while the former seems to represent the integration of contextual information in the perception of a current face, the latter appears to represent the net emotional interpretation of a current face. PMID- 26599471 TI - Planned early delivery versus expectant management of the term suspected compromised baby for improving outcomes. AB - BACKGROUND: Fetal compromise in the term pregnancy is suspected when the following clinical indicators are present: intrauterine growth restriction (IUGR), decreased fetal movement (DFM), or when investigations such as cardiotocography (CTG) and ultrasound reveal results inconsistent with standard measurements. Pathological results would necessitate the need for immediate delivery, but the management for 'suspicious' results remains unclear and varies widely across clinical centres. There is clinical uncertainty as to how to best manage women presenting with a suspected term compromised baby in an otherwise healthy pregnancy. OBJECTIVES: To assess, using the best available evidence, the effects of immediate delivery versus expectant management of the term suspected compromised baby on neonatal, maternal and long-term outcomes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 May 2015) and reference lists of retrieved studies. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials comparing expectant management versus planned early delivery for women with a suspected compromised fetus from 37 weeks' gestation or more. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and assessed trial quality. Two review authors independently extracted data. Data were checked for accuracy. We assessed the quality of the evidence using the GRADE approach. MAIN RESULTS: Of the 20 reports identified by the search strategy, we included three trials (546 participants: 269 to early delivery and 277 to expectant management), which met our inclusion criteria. Two of the trials compared outcomes in 492 pregnancies with IUGR of the fetus, and one in 54 pregnancies with oligohydramnios. All three trials were of reasonable quality and at low risk of bias. The level of evidence was graded moderate, low or very low, downgrading mostly for imprecision and for some indirectness. Overall, there was no difference in the primary neonatal outcomes of perinatal mortality (no deaths in either group, one trial, 459 women, evidence graded moderate), major neonatal morbidity (risk ratio (RR) 0.15, 95% confidence interval (CI) 0.01 to 2.81, one trial, 459 women, evidence graded low), or neurodevelopmental disability/impairment at two years of age (RR 2.04, 95% CI 0.62 to 6.69,one trial, 459 women, evidence graded low). There was no difference in the risk of necrotising enterocolitis (one trial, 333 infants) or meconium aspiration (one trial, 459 infants), There was also no difference in the reported primary maternal outcomes: maternal mortality (RR 3.07, 95% CI 0.13 to 74.87, one trial, 459 women, evidence graded low), and significant maternal morbidity (RR 0.92, 95% CI 0.38 to 2.22, one trial, 459 women, evidence graded low).The gestational age at birth was on average 10 days earlier in women randomised to early delivery (mean difference (MD) -9.50, 95% CI -10.82 to -8.18, one trial, 459 women) and women in the early delivery group were significantly less likely to have a baby beyond 40 weeks' gestation (RR 0.10, 95% CI 0.01 to 0.67, one trial, 33 women). Significantly more infants in the planned early delivery group were admitted to intermediate care nursery (RR 1.28, 95% CI 1.02 to 1.61, two trials, 491 infants). There was no difference in the risk of respiratory distress syndrome, (one trial, 333 infants), Apgar score less than seven at five minutes (three trials, 546 infants), resuscitation required (one trial, 459 infants), mechanical ventilation (one trial, 337 infants), admission to neonatal intensive care unit (NICU) (RR 0.88, 95% CI 0.35 to 2.23, three trials, 545 infants, evidence graded very low), length of stay in NICU/SCN (one trial, 459 infants), and sepsis (two trials, 366 infants).Babies in the expectant management group were more likely to be < 2.3rd centile for birthweight (RR 0.51, 95% CI 0.36 to 0.73, two trials, 491 infants), however there was no difference in the proportion of babies with birthweight < 10th centile (RR 0.98, 95% CI 0.88 to 1.10). There was no difference in any of the reported maternal secondary outcomes including: caesarean section rates (RR 1.02, 95% CI 0.65 to 1.59, three trials, 546 women, evidence graded low), placental abruption (one trial, 459 women), pre-eclampsia (one trial, 459 women), vaginal birth (three trials 546 women), assisted vaginal birth (three trials 546 women), breastfeeding rates (one trial, 218 women), and number of weeks of breastfeeding after delivery one trial, 124 women). There was an expected increase in induction in the early delivery group (RR 2.05, 95% CI 1.78 to 2.37, one trial, 459 women).No data were reported for the pre-specified secondary neonatal outcomes of the number of days of mechanical ventilation, moderate-severe hypoxic ischaemic encephalopathy or need for therapeutic hypothermia. Likewise, no data were reported for secondary maternal outcomes of postnatal infection, maternal satisfaction or views of care. AUTHORS' CONCLUSIONS: A policy for planned early delivery versus expectant management for a suspected compromised fetus at term does not demonstrate any differences in major outcomes of perinatal mortality, significant neonatal or maternal morbidity or neurodevelopmental disability. In women randomised to planned early delivery, the gestational age at birth was on average 10 days earlier, women were less likely to have a baby beyond 40 weeks' gestation, they were more likely to be induced and infants were more likely to be admitted to intermediate care nursery. There was also a significant difference in the proportion of babies with a birthweight centile < 2.3rd, however this did not translate into a reduction in morbidity. The review is informed by only one large trial and two smaller trials assessing fetuses with IUGR or oligohydramnios and therefore cannot be generalised to all term pregnancies with suspected fetal compromise. There are other indications for suspecting compromise in a fetus at or near term such as maternal perception of DFM, and ultrasound and/or CTG abnormalities. Future randomised trials need to assess effectiveness of timing of delivery for these indications. PMID- 26599472 TI - Preservation of structural brain network hubs is associated with less severe post stroke aphasia. AB - PURPOSE: Post-stroke aphasia is typically associated with ischemic damage to cortical areas or with loss of connectivity among spared brain regions. It remains unclear whether the participation of spared brain regions as networks hubs affects the severity of aphasia. METHODS: We evaluated language performance and magnetic resonance imaging from 44 participants with chronic aphasia post stroke. The individual structural brain connectomes were constructed from diffusion tensor. Hub regions were defined in accordance with the rich club classification and studied in relation with language performance. RESULTS: Number of remaining left hemisphere rich club nodes was associated with aphasia, including comprehension, repetition and naming sub-scores. Importantly, among participants with relative preservation of regions of interest for language, aphasia severity was lessened if the region was not only spared, but also participated in the remaining network as a rich club node: Brodmann area (BA) 44/45 - repetition (p = 0.009), BA 39 - repetition (p = 0.045) and naming (p < 0.01), BA 37 - fluency (p < 0.001), comprehension (p = 0.025), repetition (p < 0.001) and naming (p < 0.001). CONCLUSIONS: Disruption of language network structural hubs is directly associated with aphasia severity after stroke. PMID- 26599474 TI - Hyper-vision of mirror symmetry in patients with macular degenerationreflects parafoveal cortical reorganization. AB - PURPOSE: This study aims at comparing participants with juvenile macular degeneration (MD) and normally sighted observers in their sensitivity to mirror and translational symmetry. METHODS: We measured in 25 normal sighted and 9 MD participants sensitivity (d') to detect the symmetry of two dot patterns presented at the opposite sides of their central scotoma. RESULTS: At a large dot patterns separation (13.3 deg), at which detection failed in normally sighted observers, MD patients had high sensitivity to mirror symmetry, whereas translational symmetry was undetected. CONCLUSIONS: The mirror-translational dissociation is not predicted by the well-known phenomenon of shrinking the location of images surrounding the scotoma. Our results indicate higher capacity of MD with respect to normally sighted observers to organize mirror symmetric dot patterns far apart into a unique percept. Our results suggest that MD have acquired the capability to use information only present in mirror symmetry, i.e., the co-aligned position of the centre of low-frequency filters connecting symmetric dot pairs on opposite sides of the scotoma. This relevant functional change in vision of MD patients may find its explanation in a functionally acquired high-level cortical representation of visual input. PMID- 26599473 TI - Other ways of seeing: From behavior to neural mechanisms in the online "visual" control of action with sensory substitution. AB - Vision is the dominant sense for perception-for-action in humans and other higher primates. Advances in sight restoration now utilize the other intact senses to provide information that is normally sensed visually through sensory substitution to replace missing visual information. Sensory substitution devices translate visual information from a sensor, such as a camera or ultrasound device, into a format that the auditory or tactile systems can detect and process, so the visually impaired can see through hearing or touch. Online control of action is essential for many daily tasks such as pointing, grasping and navigating, and adapting to a sensory substitution device successfully requires extensive learning. Here we review the research on sensory substitution for vision restoration in the context of providing the means of online control for action in the blind or blindfolded. It appears that the use of sensory substitution devices utilizes the neural visual system; this suggests the hypothesis that sensory substitution draws on the same underlying mechanisms as unimpaired visual control of action. Here we review the current state of the art for sensory substitution approaches to object recognition, localization, and navigation, and the potential these approaches have for revealing a metamodal behavioral and neural basis for the online control of action. PMID- 26599475 TI - Steer by ear: Myoelectric auricular control of powered wheelchairs for individuals with spinal cord injury. AB - PURPOSE: Providing mobility solutions for individuals with tetraplegia remains challenging. Existing control devices have shortcomings such as varying or poor signal quality or interference with communication. To overcome these limitations, we present a novel myoelectric auricular control system (ACS) based on bilateral activation of the posterior auricular muscles (PAMs). METHODS: Ten able-bodied subjects and two individuals with tetraplegia practiced PAM activation over 4 days using visual feedback and software-based training for 1 h/day. Initially, half of these subjects were not able to voluntarily activate their PAMs. This ability was tested with regard to 8 parameters such as contraction rate, lateralized activation, wheelchair speed and path length in a virtual obstacle course. In session 5, all subjects steered an electric wheelchair with the ACS. RESULTS: Performance of all subjects in controlling their PAMs improved steadily over the training period. By day 5, all subjects successfully generated basic steering commands using the ACS in a powered wheelchair, and subjects with tetraplegia completed a complex real-world obstacle course. This study demonstrates that the ability to activate PAM on both sides together or unilaterally can be learned and used intuitively to steer a wheelchair. CONCLUSIONS: With the ACS we can exploit the untapped potential of the PAMs by assigning them a new, complex function. The inherent advantages of the ACS, such as not interfering with oral communication, robustness, stability over time and proportional and continuous signal generation, meet the specific needs of wheelchair users and render it a realistic alternative to currently available assistive technologies. PMID- 26599476 TI - Long-Term Effects of Lung Volume Recruitment on Maximal Inspiratory Capacity and Vital Capacity in Duchenne Muscular Dystrophy. AB - RATIONALE: Lung volume recruitment therapy slows rate of decline of lung function in neuromuscular disease, possibly due to enhanced airway clearance, reduced atelectasis, or prevention of chest wall contractures. OBJECTIVES: To determine if lung volume recruitment maintains maximal insufflation capacity (MIC), despite decline in VC. METHODS: This was a retrospective cohort study (1991-2008) of individuals with Duchenne muscular dystrophy at pediatric and adult tertiary centers. Lung volume recruitment was prescribed twice daily, according to protocol. Changes over time in MIC, VC percentage predicted, the difference between MIC and VC, maximum inspiratory and expiratory pressures, and assisted and unassisted peak cough flow (PCF) were assessed using linear mixed effects models. MEASUREMENTS AND MAIN RESULTS: Sixteen individuals, 8.6 to 33.0 years old at initiation of lung volume recruitment, with median VC percentage predicted of 13.5 (interquartile range, 8.0-20.3), were followed over a median of 6.1 years (range, 1.7-16.1 yr). MIC-VC differences were stable (change, 0.02 L/yr; P = 0.06). Post-lung volume recruitment, compared with pretreatment, rate of decline in VC decreased from 4.5% predicted/yr to 0.5% predicted/yr (P < 0.001). Maximal inspiratory and expiratory pressures were unchanged (P = 0.08, 0.59 respectively). Assisted-spontaneous PCF difference was maintained (slope, -1.59 L/min/yr, P = 0.35). CONCLUSIONS: With lung volume recruitment therapy, MIC-VC differences were stable over time, indicating that respiratory system compliance remains stable, despite a loss in VC, in individuals with Duchenne muscular dystrophy. Decline in VC was significantly attenuated, and assisted PCF was maintained in a clinically effective range. PMID- 26599477 TI - A novel colorimetric sandwich aptasensor based on an indirect competitive enzyme free method for ultrasensitive detection of chloramphenicol. AB - Analytical methods for detection and quantitation of chloramphenicol in blood serum and foodstuffs arse highly in demand. In this study, a colorimetric sandwich aptamer-based sensor (aptasensor) was fabricated for sensitive and selective detection of chloramphenicol, based on an indirect competitive enzyme free assay using gold nanoparticles (AuNPs), biotin and streptavidin. The designed aptasensor acquires characteristics of AuNPs, including large surface area and unique optical properties, and strong interaction of biotin with streptavidin. In the absence of chloramphenicol, the sandwich structure of aptasensor forms, leading to the observation of sharp red color. In the presence of target, functionalized AuNPs could not bind to 96-well plates, resulting in a faint red color. The fabricated colorimetric aptasensor exhibited high selectivity toward chloramphenicol with a limit of detection as low as 451 pM. Moreover, the developed colorimetric aptasensor was successfully used to detect chloramphenicol in milk and serum with LODs of 697 and 601 pM, respectively. PMID- 26599478 TI - Binding-regulated click ligation for selective detection of proteins. AB - Herein, a binding-regulated click ligation (BRCL) strategy for endowing selective detection of proteins is developed with the incorporation of small-molecule ligand and clickable DNA probes. The fundamental principle underlying the strategy is the regulating capability of specific protein-ligand binding against the ligation between clickable DNA probes, which could efficiently combine the detection of particular protein with enormous DNA-based sensing technologies. In this work, the feasibly of the BRCL strategy is first verified through agarose gel electrophoresis and electrochemical impedance spectroscopy measurements, and then confirmed by transferring it to a nanomaterial-assisted fluorescence assay. Significantly, the BRCL strategy-based assay is able to respond to target protein with desirable selectivity, attributing to the specific recognition between small molecule ligand and its target. Further experiments validate the general applicability of the sensing method by tailoring the ligand toward different proteins (i.e., avidin and folate receptor), and demonstrate its usability in complex biological samples. To our knowledge, this work pioneers the practice of click chemistry in probing specific small-molecule ligand-protein binding, and therefore may pave a new way for selective detection of proteins. PMID- 26599479 TI - Detection of Neisseria meningitidis using surface plasmon resonance based DNA biosensor. AB - Herein, we report the development of a surface plasmon resonance (SPR) based biosensor for the detection of Neisseria meningitidis DNA employing Kretschmann configuration. Highly c-axis oriented ZnO thin film of thickness 200nm was deposited on gold coated glass prisms by RF sputtering technique. Single stranded probe DNA was immobilized on the surface of ZnO thin film by physical adsorption method. SPR reflectance curves were recorded as a function of incident angle of He-Ne laser beam using a laboratory assembled SPR setup. The prepared biosensor exhibits a linear response towards target meningitidis DNA over the concentration range from 10 to 180 ng/MUl with a high sensitivity of about 0.03 degrees /(ng/MUl) and a low limit of detection of 5 ng/MUl. The SPR biosensor demonstrated high specificity and long shelf life thus, pointing towards a promising application in the field of meningitidis diagnosis. PMID- 26599480 TI - Simultaneous differentiation and quantification of ricin and agglutinin by an antibody-sandwich surface plasmon resonance sensor. AB - Ricin is one of the most toxic plant toxins known. Its accessibility and relative ease of preparation makes it a potential agent for criminal or bio-terrorist attacks. Detection of ricin from unknown samples requires differentiation of ricin from the highly homologous Ricinus communis agglutinin which is currently not feasible using immunological methods. Here we have developed a simple and sensitive surface plasmon resonance (SPR) sensing system for rapid differentiation between ricin and agglutinin done in real time. Both lectins were quantified in a sandwich immunoassay-like setting by capturing with a cross reactive antibody (R109) binding to both proteins while differentiating by injection of a ricin-specific antibody (R18) in a subsequent enhancement step. The SPR-assay was reproducible and sensitive for different R. communis cultivars, showing no false positive results when other lectins were tested. Quantification and differentiation of both molecules was also demonstrated from a crude castor bean extract and complex matrices. For the first time, we have demonstrated how the closely related lectins can be discerned and quantified in a single assay based on immunological methods. This novel approach delivers crucial information regarding the composition, purity, concentration, and toxicity of suspicious samples containing ricin in less than 30 minutes. Furthermore, we show how enhancement injections during SPR-measurements can be used to determine the ratio of two related proteins independently of the actual protein concentration by comparing normalized enhancement response levels. PMID- 26599481 TI - Quantitative evaluation of alternatively spliced mRNA isoforms by label-free real time plasmonic sensing. AB - Alternative splicing of mRNA precursors enables cells to generate different protein outputs from the same gene depending on their developmental or homeostatic status. Its deregulation is strongly linked to disease onset and progression. Current methodologies for monitoring alternative splicing demand elaborate procedures and often present difficulties in discerning between closely related isoforms, e.g. due to cross-hybridization during their detection. Herein, we report a general methodology using a Surface Plasmon Resonance (SPR) biosensor for label-free monitoring of alternative splicing events in real-time, without any cDNA synthesis or PCR amplification requirements. We applied this methodology to RNA isolated from HeLa cells for the quantification of alternatively spliced isoforms of the Fas gene, involved in cancer progression through regulation of programmed cell death. We demonstrate that our methodology is isoform-specific, with virtually no cross-hybridization, achieving limits of detection (LODs) in the picoMolar (pM) range. Similar results were obtained for the detection of the BCL-X gene mRNA isoforms. The results were independently validated by RT-qPCR, with excellent concordance in the determination of isoform ratios. The simplicity and robustness of this biosensor technology can greatly facilitate the exploration of alternative splicing biomarkers in disease diagnosis and therapy. PMID- 26599482 TI - Integration of an optical CMOS sensor with a microfluidic channel allows a sensitive readout for biological assays in point-of-care tests. AB - In this manuscript, a microfluidic detection module, which allows a sensitive readout of biological assays in point-of-care (POC) tests, is presented. The proposed detection module consists of a microfluidic flow cell with an integrated Complementary Metal-Oxide-Semiconductor (CMOS)-based single photon counting optical sensor. Due to the integrated sensor-based readout, the detection module could be implemented as the core technology in stand-alone POC tests, for use in mobile or rural settings. The performance of the detection module was demonstrated in three assays: a peptide, a protein and an antibody detection assay. The antibody detection assay with readout in the detection module proved to be 7-fold more sensitive that the traditional colorimetric plate-based ELISA. The protein and peptide assay showed a lower limit of detection (LLOD) of 200 fM and 460 fM respectively. Results demonstrate that the sensitivity of the immunoassays is comparable with lab-based immunoassays and at least equal or better than current mainstream POC devices. This sensitive readout holds the potential to develop POC tests, which are able to detect low concentrations of biomarkers. This will broaden the diagnostic capabilities at the clinician's office and at patient's home, where currently only the less sensitive lateral flow and dipstick POC tests are implemented. PMID- 26599483 TI - Detection of dengue NS1 antigen using long-range surface plasmon waveguides. AB - The non-structural 1 (NS1) protein of the dengue virus circulates in infected patients' blood samples and can be used for early diagnosis of dengue infection. In this paper, we present the detection of naturally-occurring dengue NS1 antigen in infected patient blood plasma using straight long-range surface plasmon waveguides. Three commercially-available anti-NS1 monoclonal antibodies were used for recognition and their performance was compared and discussed. A similar figure of merit to the one used in conventional dengue NS1 capture using an enzyme-linked immunosorbent assay (ELISA) was applied to our results. In general, the positive patient samples can be clearly differentiated from the negative ones and the results agree with those obtained using ELISA. The largest signal-to noise ratio observed during the experiments was 356 and the best detection limit observed is estimated as 5.73 pg/mm(2). PMID- 26599485 TI - Micro Total Analysis Systems: Fundamental Advances and Applications. PMID- 26599484 TI - Risk Factors for Sporadic Non-Pregnancy Associated Listeriosis in Germany Immunocompromised Patients and Frequently Consumed Ready-To-Eat Products. AB - Non-pregnancy associated (N-PA) listeriosis, caused by Listeria monocytogenes, is a rare but severe disease, and is predominantly food-borne. Most cases appear sporadic and their infection vehicle remains unknown. Incidence has increased since 2008 in Germany. We aimed to identify underlying conditions and foods associated with sporadic N-PA listeriosis in Germany. We performed a nationwide case-control study from March 2012-December 2013. Cases were sporadic N-PA listeriosis patients notified to public health. Control subjects were age (40-65 years, 66-75 years, >= 76 years) frequency-matched persons from a nationwide random telephone sample. A structured questionnaire collected information on underlying diseases, therapies and >60 food items. We conducted multivariable logistic regression analysis, adjusting for host factors identified by causal diagram theory, and calculated population attributable fractions. We enrolled 109 cases and 1982 controls. Cases' median age was 69 years, 55% were male, 44% received immunosuppressive therapy within 3 months prior to illness onset; a further 28% had at least one immunocompromising disease. In multivariable analysis, immunosuppressive therapy (OR 8.8, 95%CI 4.9-15.6), immunocompromising disease (OR 2.7; 95%CI 1.4-5.2), gastric acid suppression (OR 3.0; 95%CI 1.4 6.3), the consumption of cold cooked sausages (OR 2.6; 95%CI 1.6-4.4), the preferred consumption of packaged cheese (OR 2.1; 95%CI 1.3-3.5) and pre-sliced cheese (OR 2.2; 95%CI 1.3-3.7) were significantly associated with N-PA listeriosis. These foods accounted for 59% of all cases. Typical high risk foods, e.g. cold seafood, certain types of cheeses, tended to be negatively associated with disease. In conclusion, immunosuppressive therapy and frequently consumed ready-to-eat foods are the main risk factors for sporadic N-PA listeriosis in Germany. To reduce their risk, immunocompromised persons should consume the identified foods well before the 'use-by' date. The microbiological criteria for Listeria monocytogenes in ready-to-eat foods may insufficiently protect persons who are markedly immunocompromised. PMID- 26599486 TI - Hypotestosteronaemia in the aging male: should we treat it? AB - The term male hypogonadism is defined as the failure to maintain physiological concentrations of testosterone, a physiological quantity of sperm or the combination of both. Aetiologically, androgen deficiency can originate from the testes (primary hypogonadism) or from the hypothalamic-pituitary regulation of the testicular function (secondary hypogonadism). The causes of hypogonadism are very diverse and may be genetically determined (e.g. Klinefelter's syndrome) or acquired (tumours, infections, haemochromatosis). Classical hypogonadism linked to an underlying disease, such as a pituitary tumour, is a distinct indication for androgen substitution. But how about the aging male? It is known that there is a highly variable age-related decline in testosterone levels; whether this represents a variation of normality or has a true disease value requiring therapy has been disputed over more than a decade. The key questions surrounding this debate concern not only the age-dependent threshold for serum testosterone but, more importantly, the risks and benefits of testosterone replacement therapy in the aging male. We searched the literature for randomised controlled trials of testosterone administration in aging males with a size of at least 100 patients and a follow-up of at least 6 months, and identified eight studies. These studies mostly tried to evaluate the effect of testosterone on bone density, muscle strength and body composition, rather than clinically meaningful endpoints. Moreover, these trials have provided evidence for relevant cardiovascular adverse events in elderly men. This supports the need for further studies to define the treatment threshold for testosterone levels in the aging male, as well as with regard to the long-term risks and relevant benefits of testosterone therapy in this population. Until we have more solid data in aging males, testing for testosterone deficiency and testosterone replacement should remain reserved for patients with predisposing conditions, symptoms and signs of bona fide hypogonadism. PMID- 26599488 TI - Riociguat for the treatment of pulmonary hypertension. AB - Nitric oxide (NO) is a critical signaling molecule in the pulmonary vasculature. NO activates soluble guanylate cyclase (sGC) resulting in the synthesis of cyclic guanosine monophosphate (cGMP) - a key mediator of pulmonary artery vasodilatation that may also inhibit smooth muscle proliferation and platelet aggregation. Pulmonary hypertension, a serious, progressive and often fatal disease is characterized by NO-sGC-sGMP pathway dysregulation. Riociguat is a member of a novel therapeutic class known as soluble guanylate stimulators. Riociguat has a dual mode of action, acting in synergy with endogenous NO and also directly stimulating sGC independently of NO availability. Phase 3 randomized control trials have demonstrated that riociguat improves clinical, physiologic and hemodynamic parameters in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. In this review we will discuss the pharmacologic properties of riociguat and its appropriate implementation into clinical practice. PMID- 26599487 TI - Genotypic Diversity and Population Structure of Vibrio vulnificus Strains Isolated in Taiwan and Korea as Determined by Multilocus Sequence Typing. AB - The genetic diversity and population structure of Vibrio vulnificus isolates from Korea and Taiwan were investigated using PCR-based assays targeting putative virulence-related genes and multilocus sequence typing (MLST). BOX-PCR genomic fingerprinting identified 52 unique genotypes in 84 environmental and clinical V. vulnificus isolates. The majority (> 50%) of strains had pathogenic genotypes for all loci tested; moreover, many environmental strains had pathogenic genotypes. Although significant (p < 0.05) inter-relationships among the genotypes were observed, the association between genotype and strain source (environmental or clinical) was not significant, indicating that genotypic characteristics alone are not sufficient to predict the isolation source or the virulence of a given V. vulnificus strain and vice versa. MLST revealed 23-35 allelic types per locus analyzed, resulting in a total of 44 unique sequence types (STs). Two major monophyletic groups (lineages A and B) corresponding to the two known lineages of V. vulnificus were observed; lineage A had six STs that were exclusively environmental, whereas lineage B had STs from both environmental and clinical sources. Pathogenic and nonpathogenic genotypes predominated in MLST lineages B and A, respectively. In addition, V. vulnificus was shown to be in linkage disequilibrium (p < 0.05), although two different recombination tests (PHI and Sawyer's tests) detected significant evidence of recombination. Tajima's D test also indicated that V. vulnificus might be comprised of recently sub-divided lineages. These results suggested that the two lineages revealed by MLST correspond to two distinct ecotypes of V. vulnificus. PMID- 26599489 TI - Potential Roles for C1 Inhibitor in Transplantation. AB - Complement is a major contributor to inflammation and graft injury. This system is especially important in ischemia-reperfusion injury/delayed graft function as well as in acute and chronic antibody-mediated rejection (AMR). The latter is increasingly recognized as a major cause of late graft loss, for which we have few effective therapies. C1 inhibitor (C1-INH) regulates several pathways which contribute to both acute and chronic graft injuries. However, C1-INH spares the alternative pathway and the membrane attack complex (C5-9) so innate antibacterial defenses remain intact. Plasma-derived C1-INH has been used to treat hereditary angioedema for more than 30 years with excellent safety. Studies with C1-INH in transplant recipients are limited, but have not revealed any unique toxicity or serious adverse events attributed to the protein. Extensive data from animal and ex vivo models suggest that C1-INH ameliorates ischemia reperfusion injury. Initial clinical studies suggest this effect may allow transplantation of donor organs which are now discarded because the risk of primary graft dysfunction is considered too great. Although the incidence of severe early AMR is declining, accumulating evidence strongly suggests that complement is an important mediator of chronic AMR, a major cause of late graft loss. Thus, C1-INH may also be helpful in preserving function of established grafts. Early clinical studies in transplantation suggest significant beneficial effects of C1-INH with minimal toxicity. Recent results encourage continued investigation of this already-available therapeutic agent. PMID- 26599490 TI - Zero-Time Renal Transplant Biopsies: A Comprehensive Review. AB - Zero-time kidney biopsies, obtained at time of transplantation, are performed in many transplant centers worldwide. Decisions on kidney discard, kidney allocation, and choice of peritransplant and posttransplant treatment are sometimes based on the histological information obtained from these biopsies. This comprehensive review evaluates the practical considerations of performing zero-time biopsies, the predictive performance of zero-time histology and composite histological scores, and the clinical utility of these biopsies. The predictive performance of individual histological lesions and of composite scores for posttransplant outcome is at best moderate. No single histological lesion or composite score is sufficiently robust to be included in algorithms for kidney discard. Dual kidney transplantation has been based on histological assessment of zero-time biopsies and improves outcome in individual patients, but the waitlist effects of this strategy remain obscure. Zero-time biopsies are valuable for clinical and translational research purposes, providing insight in risk factors for posttransplant events, and as baseline for comparison with posttransplant histology. The molecular phenotype of zero-time biopsies yields novel therapeutic targets for improvement of donor selection, peritransplant management and kidney preservation. It remains however highly unclear whether the molecular expression variation in zero-time biopsies could become a better predictor for posttransplant outcome than donor/recipient baseline demographic factors. PMID- 26599491 TI - An Acute Cellular Rejection With Detrimental Outcome Occurring Under Belatacept Based Immunosuppressive Therapy: An Immunological Analysis. AB - BACKGROUND: Belatacept has been associated with an increased acute rejection rate after kidney transplantation. This case report sheds light on the possible immunological mechanisms underlying this phenomenon by analyzing the immunological mechanisms in patient serum, peripheral blood mononuclear cells, rejected kidney tissue, and graft infiltrating cells. METHODS: A 61-year-old woman treated with belatacept, who received her first kidney transplant from her husband was admitted with an acute, vascular rejection 56 days after transplantation which necessitated a transplantectomy. Histology and immunohistochemistry were performed on biopsy and explant tissue. CD86 expression on peripheral monocytes was assessed. Using Ficoll density methods, peripheral blood, and graft infiltrating lymphocytes were isolated and phenotyped. RESULTS: The explant showed a vascular rejection (Banff ACR grade III) and a perivascular infiltrate mostly consisting of T cells. No evidence for antibody-mediated rejection was found. In contrast to the peripheral blood monocytes, CD86 was still expressed by part of the mononuclear cells in the explant.Isolated graft cells were mostly CCR7-CD45RO+ effector memory CD4 and CD8 T cells (60-70%). CD28 positive as CD28-negative T cells were present in the explant, showing a great IFN-gamma production capacity and expressing granzyme B. CONCLUSIONS: We postulate that this glucocorticoid-resistant cellular rejection occurring under belatacept was predominantly mediated by cytotoxic memory T cells, which are less susceptible to costimulatory blockade by belatacept, or resulted from incomplete CD80/86 blockade at the tissue level. PMID- 26599492 TI - Survival Benefit in Renal Transplantation Despite High Comorbidity. AB - BACKGROUND: The age and degree of comorbidity among transplant candidates is increasing. Knowledge of survival benefit in relation to recipient age and comorbidity is important, considering the scarcity of organs available for transplantation. The aim of the present study was to analyze the chances and survival benefit of transplantation among patients in different age groups and with different degrees of comorbidity score at the time of entering the waiting list. METHODS: Data from the Danish Nephrology Registry and Scandiatransplant were merged. Charlson Comorbidity Index scores were derived from the National Danish Admissions Registry. Study period is from January 1, 1995, to December 31, 2011. A multistate model was used to analyze the chance of having a renal transplantation and the effect of transplantation in different patients groups. RESULTS: Patients older than 65 years and patients with high comorbidity score had a decreased chance of being transplanted. However, if patients older than 65 years were transplanted with deceased donor, the mortality risk was reduced by 55% (hazard rate, 0.45 (0.26-0.75). In patients with a comorbidity score of 5 or greater, receiving a deceased donor transplant reduced the mortality risk by 72% (hazard rate, 0.28 (0.20-0.39). The overall survival benefit was 62% versus 70% in deceased versus living donor transplanted patients. CONCLUSIONS: Poor health and old age reduced the chance of being transplanted. However, patients older than 65 years and patients with high comorbidity still had a survival benefit from renal transplantation. PMID- 26599494 TI - Visualization of Ion Conductivity: Vapochromic Luminescence of an Ion-Conductive Ruthenium(II) Metalloligand-Based Porous Coordination Polymer. AB - We synthesized a new porous coordination polymer {La1.75(OH)1.25[Ru(dcbpy)3]. 16H2O} (La7-[4Ru]4; H2dcbpy = 4,4'-dicarboxy-2,2'-bipyridine) composed of a luminescent ruthenium(II) metalloligand [Ru(4,4'-dcbpy)3](4-) and La(3+) cations. X-ray analysis for La7-[4Ru]4 revealed that the La(3+) cations and [4Ru] metalloligands are crystallized in a molar ratio of 7:4 with OH(-) counteranions and a void fraction of ~ 25.5%. Interestingly, La7-[4Ru]4 shows a reversible structural transition triggered by water ad/desorption, which affects not only the triplet metal-to-ligand charge-transfer ((3)MLCT) emission energy but also the ion conductivity in the solid state. This correlation suggests that La7 [4Ru]4 is an interesting material that enables visualization of the ion conductivity via the (3)MLCT emission energy. PMID- 26599493 TI - CRISPR/Cas9 Promotes Functional Study of Testis Specific X-Linked Gene In Vivo. AB - Mammalian spermatogenesis is a highly regulated multistage process of sperm generation. It is hard to uncover the real function of a testis specific gene in vitro since the in vitro model is not yet mature. With the development of the CRISPR/Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR associated 9) system, we can now rapidly generate knockout mouse models of testis specific genes to study the process of spermatogenesis in vivo. SYCP3-like X linked 2 (SLX2) is a germ cell specific component, which contains a Cor1 domain and belongs to the XLR (X-linked, lymphocyte regulated) family. Previous studies suggested that SLX2 might play an important role in mouse spermatogenesis based on its subcellular localization and interacting proteins. However, the function of SLX2 in vivo is still elusive. Here, to investigate the functions of SLX2 in spermatogenesis, we disrupted the Slx2 gene by using the CRISPR/Cas9 system. Since Slx2 is a testis specific X-linked gene, we obtained knockout male mice in the first generation and accelerated the study process. Compared with wild-type mice, Slx2 knockout mice have normal testis and epididymis. Histological observation of testes sections showed that Slx2 knockout affected none of the three main stages of spermatogenesis: mitosis, meiosis and spermiogenesis. In addition, we further confirmed that disruption of Slx2 did not affect the number of spermatogonial stem cells, meiosis progression or XY body formation by immunofluorescence analysis. As spermatogenesis was normal in Slx2 knockout mice, these mice were fertile. Taken together, we showed that Slx2 itself is not an essential gene for mouse spermatogenesis and CRISPR/Cas9 technique could speed up the functional study of testis specific X-linked gene in vivo. PMID- 26599495 TI - Managing juvenile idiopathic arthritis-associated uveitis. AB - Bilateral chronic anterior uveitis is an extra-articular feature of juvenile idiopathic arthritis. Although figures vary, uveitis occurs in approximately 11% 13% of patients with this disease and is most commonly associated with the female gender, oligoarthritis, and presence of antinuclear antibodies. The disease has an insidious onset and is often asymptomatic. Managing patients with juvenile idiopathic arthritis-associated uveitis remains challenging as the disease may prove to be refractory to traditional treatment regimens. Stepwise immunomodulatory therapy is indicated, with new biologic drugs being used last in cases of refractory uveitis. Small scale studies and practice have provided the evidence to undertake randomized control trials to evaluate the efficacy, safety, and cost-effectiveness of anti-tumor necrosis factor-alpha therapies, such as infliximab and adalimumab. These have demonstrated promising results, with further data awaited from ongoing trials for adalimumab (as SYCAMORE and ADJUVITE trials). Lower grade evidence is supporting the use of newer biologics such as rituximab, daclizumab, tocilizumab, and abatacept in those cases refractory to anti-tumor necrosis factor-alpha therapy. PMID- 26599496 TI - The GABAB receptor agonist, baclofen, contributes to three distinct varieties of amnesia in the human brain - A detailed case report. AB - We describe a patient in whom long-term, therapeutic infusion of the selective gamma-amino-butyric acid type B (GABAB) receptor agonist, baclofen, into the cerebrospinal fluid (CSF) gave rise to three distinct varieties of memory impairment: i) repeated, short periods of severe global amnesia, ii) accelerated long-term forgetting (ALF), evident over intervals of days and iii) a loss of established autobiographical memories. This pattern of impairment has been reported in patients with temporal lobe epilepsy (TLE), in particular the subtype of Transient Epileptic Amnesia (TEA). The amnesic episodes and accelerated forgetting remitted on withdrawal of baclofen, while the autobiographical amnesia (AbA) persisted. This exceptional case highlights the occurrence of 'non standard' forms of human amnesia, reflecting the biological complexity of memory processes. It suggests a role for GABAB signalling in the modulation of human memory over multiple time-scales and hints at its involvement in 'epileptic amnesia'. PMID- 26599498 TI - The Hierarchy of Transcriptional Activation: From Enhancer to Promoter. AB - Regulatory elements (enhancers) that are remote from promoters play a critical role in the spatial, temporal, and physiological control of gene expression. Studies on specific loci, together with genome-wide approaches, suggest that there may be many common mechanisms involved in enhancer-promoter communication. Here, we discuss the multiprotein complexes that are recruited to enhancers and the hierarchy of events taking place between regulatory elements and promoters. PMID- 26599497 TI - The Multi-allelic Genetic Architecture of a Variance-Heterogeneity Locus for Molybdenum Concentration in Leaves Acts as a Source of Unexplained Additive Genetic Variance. AB - Genome-wide association (GWA) analyses have generally been used to detect individual loci contributing to the phenotypic diversity in a population by the effects of these loci on the trait mean. More rarely, loci have also been detected based on variance differences between genotypes. Several hypotheses have been proposed to explain the possible genetic mechanisms leading to such variance signals. However, little is known about what causes these signals, or whether this genetic variance-heterogeneity reflects mechanisms of importance in natural populations. Previously, we identified a variance-heterogeneity GWA (vGWA) signal for leaf molybdenum concentrations in Arabidopsis thaliana. Here, fine-mapping of this association reveals that the vGWA emerges from the effects of three independent genetic polymorphisms that all are in strong LD with the markers displaying the genetic variance-heterogeneity. By revealing the genetic architecture underlying this vGWA signal, we uncovered the molecular source of a significant amount of hidden additive genetic variation or "missing heritability". Two of the three polymorphisms underlying the genetic variance heterogeneity are promoter variants for Molybdate transporter 1 (MOT1), and the third a variant located ~25 kb downstream of this gene. A fourth independent association was also detected ~600 kb upstream of MOT1. Use of a T-DNA knockout allele highlights Copper Transporter 6; COPT6 (AT2G26975) as a strong candidate gene for this association. Our results show that an extended LD across a complex locus including multiple functional alleles can lead to a variance-heterogeneity between genotypes in natural populations. Further, they provide novel insights into the genetic regulation of ion homeostasis in A. thaliana, and empirically confirm that variance-heterogeneity based GWA methods are a valuable tool to detect novel associations of biological importance in natural populations. PMID- 26599499 TI - Rab7 Regulates CDH1 Endocytosis, Circular Dorsal Ruffles Genesis, and Thyroglobulin Internalization in a Thyroid Cell Line. AB - Rab7 regulates the biogenesis of late endosomes, lysosomes, and autophagosomes. It has been proposed that a functional and physical interaction exists between Rab7 and Rac1 GTPases in CDH1 endocytosis and ruffled border formation. In FRT cells over-expressing Rab7, increased expression and activity of Rac1 was observed, whereas a reduction of Rab7 expression by RNAi resulted in reduced Rac1 activity, as measured by PAK1 phosphorylation. We found that CDH1 endocytosis was extremely reduced only in Rab7 over-expressing cells but was unchanged in Rab7 silenced cells. In Rab7 under or over-expressing cells, Rab7 and LC3B-II co localized and co-localization in large circular structures occurred only in Rab7 over-expressing cells. These large circular structures occurred in about 10% of the cell population; some of them (61%) showed co-localization of Rab7 with cortactin and f-actin and were identified as circular dorsal ruffles (CDRs), the others as mature autophagosomes. We propose that the over-expression of Rab7 is sufficient to induce CDRs. Furthermore, in FRT cells, we found that the expression of the insoluble/active form of Rab7, rather than Rab5, or Rab8, was inducible by cAMP and that cAMP-stimulated FRT cells showed increased PAK1 phosphorylation and were no longer able to endocytose CDH1. Finally, we demonstrated that Rab7 over-expressing cells are able to endocytose exogenous thyroglobulin via pinocytosis/CDRs more efficiently than control cells. We propose that the major thyroglobulin endocytosis described in thyroid autonomous adenomas due to Rab7 increased expression, occurs via CDRs. J. Cell. Physiol. 231: 1695-1708, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26599500 TI - Rapid and Efficient Production of Coronary Artery Ligation and Myocardial Infarction in Mice Using Surgical Clips. AB - AIMS: The coronary artery ligation model in rodents mimics human myocardial infarction (MI). Normally mechanical ventilation and prolonged anesthesia period are needed. Recently, a method has been developed to create MI by popping-out the heart (without ventilation) followed by immediate suture ligation. Mortality is high due to the time-consuming suture ligation process while the heart is exposed. We sought to improve this method and reduce mortality by rapid coronary ligation using a surgical clip instead of a suture. METHODS AND RESULTS: Mice were randomized into 3 groups: clip MI (CMI), suture MI (SMI), or sham (SHAM). In all groups, heart was manually exposed without intubation through a small incision on the chest wall. Unlike the conventional SMI method, mice in the CMI group received a metal clip on left anterior descending artery (LAD), quickly dispensed by an AutoSuture SurgiclipTM. The CMI method took only 1/3 of ligation time of the standard SMI method and improved post-MI survival rate. TTC staining and Masson's trichrome staining revealed a similar degree of infarct size in the SMI and CMI groups. Echocardiograph confirmed that both SMI and CMI groups had a similar reduction of ejection fraction and fraction shortening over the time. Histological analysis showed that the numbers of CD68+ macrophages and apoptotic cells (TUNEL-positive) are indistinguishable between the two groups. CONCLUSION: This new method, taking only less than 3 minutes to complete, represents an efficient myocardial infarction model in rodents. PMID- 26599501 TI - Donor-Acceptor-Donor Thienopyrazines via Pd-Catalyzed C-H Activation as NIR Fluorescent Materials. AB - A series of thienopyrazine-based donor-acceptor-donor (D-A-D) near-infrared (NIR) fluorescent compounds were synthesized through a rapid, palladium-catalyzed C-H activation route. The dyes were studied through computational analysis, electrochemical properties analysis, and characterization of their photophysical properties. Large Stokes shifts of approximately 175 nm were observed, which led to near-infrared emission. Computational evaluation shows that the origin of this large Stokes shift is a significant molecular reorganization particularly about the D-A bond. The series exhibits quantum yields of up to phi = >4%, with emission maxima ranging from 725 to 820 nm. The emission is strong in solution, in thin films, and also in isolation at the single-molecule level. Their stable emission at the single-molecule level makes these compounds good candidates for single-molecule photon sources in the near-infrared. PMID- 26599502 TI - Functional imaging of the nonhuman primate Placenta with endogenous blood oxygen level-dependent contrast. AB - PURPOSE: To characterize spatial patterns of T2* in the placenta of the rhesus macaque (Macaca mulatta), to correlate these patterns with placental perfusion determined using dynamic contrast-enhanced MRI (DCE-MRI), and to evaluate the potential for using the blood oxygen level-dependent effect to quantify placental perfusion without the use of exogenous contrast reagent. METHODS: MRI was performed on three pregnant rhesus macaques at gestational day 110. Multiecho spoiled gradient echo measurements were used to compute maps of T2*. Spatial maxima in these maps were compared with foci of early enhancement determined by DCE-MRI. RESULTS: Local maxima in T2* maps were strongly correlated with spiral arteries identified by DCE-MRI, with mean spatial separations ranging from 2.34 to 6.11 mm in the three animals studied. Spatial patterns of R2* ( = 1/ T2*) within individual placental lobules can be quantitatively analyzed using a simple model to estimate fetal arterial oxyhemoglobin concentration [Hbo,f] and a parameter viPS/Phi, reflecting oxygen transport to the fetus. Estimated mean values of [Hbo,f] ranged from 4.25 mM to 4.46 mM, whereas viPS/Phi ranged from 2.80 * 105 cm-3 to 1.61 * 106 cm-3 . CONCLUSIONS: Maternal spiral arteries show strong spatial correlation with foci of extended T2* observed in the primate placenta. A simple model of oxygen transport accurately describes the spatial dependence of R2* within placental lobules and enables assessment of placental function and oxygenation without requiring administration of an exogenous contrast reagent. Magn Reson Med 76:1551-1562, 2016. (c) 2015 International Society for Magnetic Resonance in Medicine. PMID- 26599503 TI - Autologous mesenchymal stem cell (MSCs) transplantation for critical-sized bone defect following a wide excision of osteofibrous dysplasia. AB - INTRODUCTION: Osteofibrous dysplasia is a rare non-neoplastic disease that is almost exclusive to pediatric tibial diaphysis. Wide excision of the lesion is recommended to avoid recurrence. However, such radical surgery will results in large segmental bone defects that will require further extensive reconstructive surgery. We report a novel approach of treating bone defect by implementing the diamond concept of bone healing using autologous bone marrow derived mesenchymal stem cells (BM-MSCs). PRESENTATION OF CASE: An eight-year-old Indonesian male presented with severe bowing deformity of the left lower leg. Radiographic and histological analysis confirmed the diagnosis of osteofibrous dysplasia. A wide excision of the defect was made leaving a critical-sized bone defect. A combination of autologous transplantation of 50 million BM-MSCs, hydroxyapatite (HA) granules, bone morphogenic protein 2 (BMP-2) and Djoko-Zarov hybrid circular external fixator was used to treat the defect. The outcomes measured were subjective complaints, functionality based on LEFS and radiological assessments. DISCUSSION: Radiographic assessments showed successful new bone tissue formation and integration of implanted HA granules. The external fixator was removed at 42 weeks after adequate callus formation and clinical stability was achieved. The patient underwent progressive functional improvements and reached a near normal functionality of 90% LEFS at 84 week. No therapy side effect or complication was reported. CONCLUSION: Osteofibrous dysplasia was successfully excised without signs of recurrence after 84-week follow-up. Autologous transplantation of augmented BM-MSCs has successfully created new normal bone tissue without causing any side effect and had significantly improved the patient's quality of life. PMID- 26599504 TI - Use of Vacuum-assisted closure in management of open abdominal wound with multiple enterocutaneous fistulae during chemotherapy: A case report. AB - INTRODUCTION: Vacuum-assisted closure (VAC) is useful for treating complex wounds because it promotes granulation. In the present report, a successful case of VAC used for an open abdominal wound with enterocutaneous fistulae after multiple intestinal perforations during chemotherapy is described. PRESENTATION OF CASE: A 73-year-old man was admitted to our hospital with severe abdominal pain. He underwent surgical resection for ascending colon cancer 4 years ago and was administered chemotherapy with bevacizumab for recurrence. Physical examination and computed tomography revealed perforation of the intestine, and an emergency operation was performed. Following this procedure, other intestinal perforations occurred, resulting in an open abdominal wound at postoperative day (POD) 10. To isolate enteric contents and promote granulation, VAC was applied to the abdominal wound with enterocutaneous fistulae. Oral intake started at POD 21 and the wound size became smaller. Further, an ostomy bag was directly attached to the most oral perforation site. The patient recovered from life-threatening events without severe infection and was transferred to another hospital close to his home at POD 180. DISCUSSION: Gastrointestinal perforation is known to be one of the fatal adverse events of bevacizumab. In this case four gastrointestinal perforations were observed. Isolation of enteric contents is important to heal the wound and VAC is an effective therapy for the management of open abdominal wounds even with enterocutaneous fistulae. CONCLUSION: Innovative VAC use for the management of open abdominal wounds can improve the nutritional status and overall wound healing of the patient. PMID- 26599505 TI - Fully Automatic Localization and Segmentation of 3D Vertebral Bodies from CT/MR Images via a Learning-Based Method. AB - In this paper, we address the problems of fully automatic localization and segmentation of 3D vertebral bodies from CT/MR images. We propose a learning based, unified random forest regression and classification framework to tackle these two problems. More specifically, in the first stage, the localization of 3D vertebral bodies is solved with random forest regression where we aggregate the votes from a set of randomly sampled image patches to get a probability map of the center of a target vertebral body in a given image. The resultant probability map is then further regularized by Hidden Markov Model (HMM) to eliminate potential ambiguity caused by the neighboring vertebral bodies. The output from the first stage allows us to define a region of interest (ROI) for the segmentation step, where we use random forest classification to estimate the likelihood of a voxel in the ROI being foreground or background. The estimated likelihood is combined with the prior probability, which is learned from a set of training data, to get the posterior probability of the voxel. The segmentation of the target vertebral body is then done by a binary thresholding of the estimated probability. We evaluated the present approach on two openly available datasets: 1) 3D T2-weighted spine MR images from 23 patients and 2) 3D spine CT images from 10 patients. Taking manual segmentation as the ground truth (each MR image contains at least 7 vertebral bodies from T11 to L5 and each CT image contains 5 vertebral bodies from L1 to L5), we evaluated the present approach with leave-one out experiments. Specifically, for the T2-weighted MR images, we achieved for localization a mean error of 1.6 mm, and for segmentation a mean Dice metric of 88.7% and a mean surface distance of 1.5 mm, respectively. For the CT images we achieved for localization a mean error of 1.9 mm, and for segmentation a mean Dice metric of 91.0% and a mean surface distance of 0.9 mm, respectively. PMID- 26599506 TI - Median and ulnar nerve anastomoses in the upper limb: A meta-analysis. AB - INTRODUCTION: The most frequently described anomalous neural connections between the median and ulnar nerves in the upper limb are: Martin-Gruber anastomosis (MGA), Marinacci anastomosis (MA), Riche-Cannieu anastomosis (RCA), and Berrettini anastomosis (BA). The reported prevalence rates and characteristics of these anastomoses vary significantly between studies. METHODS: A search of electronic databases was performed to identify all eligible articles. Anatomical data regarding the anastomoses were pooled into a meta-analysis using MetaXL 2.0. RESULTS: A total of 58 (n = 10,562 upper limbs) articles were included in the meta-analysis. The pooled prevalences were: MGA, 19.5% (95% confidence interval [CI], 16.2%-23.1%); MA, 0.7% (95% CI, 0.1%-1.7%); RCA, 55.5% (95% CI, 30.6% 79.1%); and BA, 60.9% (95% CI, 36.9%-82.6%). The results also showed that MGA was more commonly found unilaterally (66.8%), on the right side (15.7%), following an oblique course (84.8%), and originating from the anterior interosseous nerve with a prevalence of 57.6%. CONCLUSIONS: As anastomoses between the median and ulnar nerves occur commonly, detailed anatomical knowledge is essential for accurate interpretation of electrophysiological findings and reducing the risk of iatrogenic injuries during surgical procedures. Muscle Nerve 54: 36-47, 2016. PMID- 26599508 TI - The Race: Quality Assurance Performance Improvement Project Aimed at Achieving Superior Patient Outcomes. PMID- 26599507 TI - Membrane-anchored Serine Protease Matriptase Is a Trigger of Pulmonary Fibrogenesis. AB - RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a devastating disease that remains refractory to current therapies. OBJECTIVES: To characterize the expression and activity of the membrane-anchored serine protease matriptase in IPF in humans and unravel its potential role in human and experimental pulmonary fibrogenesis. METHODS: Matriptase expression was assessed in tissue specimens from patients with IPF versus control subjects using quantitative reverse transcriptase-polymerase chain reaction, immunohistochemistry, and Western blotting, while matriptase activity was monitored by fluorogenic substrate cleavage. Matriptase-induced fibroproliferative responses and the receptor involved were characterized in human primary pulmonary fibroblasts by Western blot, viability, and migration assays. In the murine model of bleomycin-induced pulmonary fibrosis, the consequences of matriptase depletion, either by using the pharmacological inhibitor camostat mesilate (CM), or by genetic down-regulation using matriptase hypomorphic mice, were characterized by quantification of secreted collagen and immunostainings. MEASUREMENTS AND MAIN RESULTS: Matriptase expression and activity were up-regulated in IPF and bleomycin-induced pulmonary fibrosis. In cultured human pulmonary fibroblasts, matriptase expression was significantly induced by transforming growth factor-beta. Furthermore, matriptase elicited signaling via protease-activated receptor-2 (PAR-2), and promoted fibroblast activation, proliferation, and migration. In the experimental bleomycin model, matriptase depletion, by the pharmacological inhibitor CM or by genetic down-regulation, diminished lung injury, collagen production, and transforming growth factor-beta expression and signaling. CONCLUSIONS: These results implicate increased matriptase expression and activity in the pathogenesis of pulmonary fibrosis in human IPF and in an experimental mouse model. Overall, targeting matriptase, or treatment by CM, which is already in clinical use for other diseases, may represent potential therapies for IPF. PMID- 26599509 TI - A Novel Virus-Like Particle Based Vaccine Platform Displaying the Placental Malaria Antigen VAR2CSA. AB - Placental malaria caused by Plasmodium falciparum is a major cause of mortality and severe morbidity. Clinical testing of a soluble protein-based vaccine containing the parasite ligand, VAR2CSA, has been initiated. VAR2CSA binds to the human receptor chondroitin sulphate A (CSA) and is responsible for sequestration of Plasmodium falciparum infected erythrocytes in the placenta. It is imperative that a vaccine against malaria in pregnancy, if administered to women before they become pregnant, can induce a strong and long lasting immune response. While most soluble protein-based vaccines have failed during clinical testing, virus-like particle (VLP) based vaccines (e.g., the licensed human papillomavirus vaccines) have demonstrated high efficacy, suggesting that the spatial assembly of the vaccine antigen is a critical parameter for inducing an optimal long-lasting protective immune response. We have developed a VLP vaccine display platform by identifying regions of the HPV16 L1 coat protein where a biotin acceptor site (AviTagTM) can be inserted without compromising VLP-assembly. Subsequent biotinylation of Avi-L1 VLPs allow us to anchor monovalent streptavidin (mSA) fused proteins to the biotin, thereby obtaining a dense and repetitive VLP display of the vaccine antigen. The mSA-VAR2CSA antigen was delivered on the Avi L1 VLP platform and tested in C57BL/6 mice in comparison to two soluble protein based vaccines consisting of naked VAR2CSA and mSA-VAR2CSA. The mSA-VAR2CSA Avi L1 VLP and soluble mSA-VAR2CSA vaccines induced higher antibody titers than the soluble naked VAR2CSA vaccine after three immunizations. The VAR2CSA Avi-L1 VLP vaccine induced statistically significantly higher endpoint titres compared to the soluble mSA-VAR2CSA vaccine, after 1st and 2nd immunization; however, this difference was not statistically significant after 3rd immunization. Importantly, the VLP-VAR2CSA induced antibodies were functional in inhibiting the binding of parasites to CSA. This study demonstrates that the described Avi-L1 VLP-platform may serve as a versatile system for facilitating optimal VLP-display of large and complex vaccine antigens. PMID- 26599510 TI - High Dietary Folate in Mice Alters Immune Response and Reduces Survival after Malarial Infection. AB - Malaria is a significant global health issue, with nearly 200 million cases in 2013 alone. Parasites obtain folate from the host or synthesize it de novo. Folate consumption has increased in many populations, prompting concerns regarding potential deleterious consequences of higher intake. The impact of high dietary folate on the host's immune function and response to malaria has not been examined. Our goal was to determine whether high dietary folate would affect response to malarial infection in a murine model of cerebral malaria. Mice were fed control diets (CD, recommended folate level for rodents) or folic acid supplemented diets (FASD, 10x recommended level) for 5 weeks before infection with Plasmodium berghei ANKA. Survival, parasitemia, numbers of immune cells and other infection parameters were assessed. FASD mice had reduced survival (p<0.01, Cox proportional hazards) and higher parasitemia (p< 0.01, joint model of parasitemia and survival) compared with CD mice. FASD mice had lower numbers of splenocytes, total T cells, and lower numbers of specific T and NK cell sub populations, compared with CD mice (p<0.05, linear mixed effects). Increased brain TNFalpha immunoreactive protein (p<0.01, t-test) and increased liver Abca1 mRNA (p<0.01, t-test), a modulator of TNFalpha, were observed in FASD mice; these variables correlated positively (rs = 0.63, p = 0.01). Bcl-xl/Bak mRNA was increased in liver of FASD mice (p<0.01, t-test), suggesting reduced apoptotic potential. We conclude that high dietary folate increases parasite replication, disturbs the immune response and reduces resistance to malaria in mice. These findings have relevance for malaria-endemic regions, when considering anti-folate anti-malarials, food fortification or vitamin supplementation programs. PMID- 26599511 TI - Kaempferol Inhibits Endoplasmic Reticulum Stress-Associated Mucus Hypersecretion in Airway Epithelial Cells And Ovalbumin-Sensitized Mice. AB - Mucus hypersecretion is an important pathological feature of chronic airway diseases, such as asthma and pulmonary diseases. MUC5AC is a major component of the mucus matrix forming family of mucins in the airways. The initiation of endoplasmic reticulum (ER)-mediated stress responses contributes to the pathogenesis of airway diseases. The present study investigated that ER stress was responsible for airway mucus production and this effect was blocked by the flavonoid kaempferol. Oral administration of >=10 mg/kg kaempferol suppressed mucus secretion and goblet cell hyperplasia observed in the bronchial airway and lung of BALB/c mice sensitized with ovalbumin (OVA). TGF-beta and tunicamycin promoted MUC5AC induction after 72 h in human bronchial airway epithelial BEAS-2B cells, which was dampened by 20 MUM kaempferol. Kaempferol inhibited tunicamycin induced ER stress of airway epithelial cells through disturbing the activation of the ER transmembrane sensor ATF6 and IRE1alpha. Additionally, this compound demoted the induction of ER chaperones such as GRP78 and HSP70 and the splicing of XBP-1 mRNA by tunicamycin. The in vivo study further revealed that kaempferol attenuated the induction of XBP-1 and IRE1alpha in epithelial tissues of OVA challenged mice. TGF-beta and tunicamycin induced TRAF2 with JNK activation and such induction was deterred by kaempferol. The inhibition of JNK activation encumbered the XBP-1 mRNA splicing and MUC5AC induction by tunicamycin and TGF beta. These results demonstrate that kaempferol alleviated asthmatic mucus hypersecretion through blocking bronchial epithelial ER stress via the inhibition of IRE1alpha-TRAF2-JNK activation. Therefore, kaempferol may be a potential therapeutic agent targeting mucus hypersecretion-associated pulmonary diseases. PMID- 26599512 TI - Diagnosis of Herpes Simplex Encephalitis by ELISA Using Antipeptide Antibodies Against Type-Common Epitopes of Glycoprotein B of Herpes Simplex Viruses. AB - Herpes simplex encephalitis (HSE) represents one of the most severe infectious diseases of the central nervous system (CNS). As effective antiviral drugs are available, an early, rapid, and reliable diagnosis has become important. The objective of this article was to develop a sensitive ELISA protocol for herpes simplex viruses (HSV) antigen detection and quantitation by assessing the usefulness of antipeptide antibodies against potential peptides of HSV glycoprotein B (gB). A total of 180 cerebrospinal fluid (CSF) samples of HSE and non-HSE patients were analyzed using a panel of antipeptide antibodies against synthetic peptides of HSV glycoprotein gB. The cases of confirmed and suspected HSE showed 80% and 51% positivity for antipeptide against synthetic peptide QLHDLRF and 77% and 53% positivity for antipeptide against synthetic peptide MKALYPLTT, respectively for the detection of HSV antigen in CSF. The concentration of HSV antigen was found to be higher in confirmed HSE as compared to suspected HSE group and the viral load correlated well with antigen concentration obtained using the two antipeptides in CSF of confirmed HSE group. This is the first article describing the use of antibodies obtained against synthetic peptides derived from HSV in diagnostics of HSE using patients' CSF samples. PMID- 26599513 TI - Arachidonic Acid and Eicosapentaenoic Acid Metabolism in Juvenile Atlantic Salmon as Affected by Water Temperature. AB - Salmons raised in aquaculture farms around the world are increasingly subjected to sub-optimal environmental conditions, such as high water temperatures during summer seasons. Aerobic scope increases and lipid metabolism changes are known plasticity responses of fish for a better acclimation to high water temperature. The present study aimed at investigating the effect of high water temperature on the regulation of fatty acid metabolism in juvenile Atlantic salmon fed different dietary ARA/EPA ratios (arachidonic acid, 20:4n-6/ eicosapentaenoic acid, 20:5n 3), with particular focus on apparent in vivo enzyme activities and gene expression of lipid metabolism pathways. Three experimental diets were formulated to be identical, except for the ratio EPA/ARA, and fed to triplicate groups of Atlantic salmon (Salmo salar) kept either at 10 degrees C or 20 degrees C. Results showed that fatty acid metabolic utilisation, and likely also their dietary requirements for optimal performance, can be affected by changes in their relative levels and by environmental temperature in Atlantic salmon. Thus, the increase in temperature, independently from dietary treatment, had a significant effect on the beta-oxidation of a fatty acid including EPA, as observed by the apparent in vivo enzyme activity and mRNA expression of pparalpha -transcription factor in lipid metabolism, including beta-oxidation genes- and cpt1 -key enzyme responsible for the movement of LC-PUFA from the cytosol into the mitochondria for beta-oxidation-, were both increased at the higher water temperature. An interesting interaction was observed in the transcription and in vivo enzyme activity of Delta5fad-time-limiting enzyme in the biosynthesis pathway of EPA and ARA. Such, at lower temperature, the highest mRNA expression and enzyme activity was recorded in fish with limited supply of dietary EPA, whereas at higher temperature these were recorded in fish with limited ARA supply. In consideration that fish at higher water temperature recorded a significantly increased feed intake, these results clearly suggested that at high, sub-optimal water temperature, fish metabolism attempted to increment its overall ARA status -the most bioactive LC-PUFA participating in the inflammatory response- by modulating the metabolic fate of dietary ARA (expressed as % of net intake), reducing its beta-oxidation and favouring synthesis and deposition. This correlates also with results from other recent studies showing that both immune- and stress- responses in fish are up regulated in fish held at high temperatures. This is a novel and fundamental information that warrants industry and scientific attention, in consideration of the imminent increase in water temperatures, continuous expansion of aquaculture operations, resources utilisation in aquafeed and much needed seasonal/adaptive nutritional strategies. PMID- 26599514 TI - Of guards, decoys, baits and traps: pathogen perception in plants by type III effector sensors. AB - Effector-triggered immunity (ETI) is conferred by dominant plant resistance (R) genes, which encode predominantly nucleotide-binding and leucine-rich repeat domain proteins (NLRs), against cognate microbial avirulence (Avr) genes, which include bacterial type III secreted effectors (T3Es). The 'guard model' describes the mechanism of T3E perception by plants, whereby NLRs monitor host proteins ('sensors') for T3E-induced perturbations. This model has provided a molecular framework to understand T3E perception and has rationalized how plants can use a limited number of NLRs (~160 in Arabidopsis) to contend with a potentially limitless number of evolving effectors. In this review we provide a characteristic overview of plant T3E sensors and discuss how these sensors convey the presence of T3Es to NLR proteins to activate ETI. PMID- 26599515 TI - Peptide triazole inactivators of HIV-1: how do they work and what is their potential? PMID- 26599516 TI - Formulation design space: a proven approach to maximize flexibility and outcomes within early clinical development. AB - Traditional formulation development studies involve expensive and time-consuming screening of prototypes in preclinical species to select 'lead' systems for evaluation in human clinical pharmacokinetic studies. A new paradigm, Translational Pharmaceutics, has emerged to integrate pharmaceutical development, manufacturing and clinical functions to address these restrictions. Rapid Formulation development and Clinical Testing (RapidFACT) is applied to exploit the benefits of Translational Pharmaceutics in the clinical screening and optimization of drug products. Benefits are maximized by the adapted utilization of the concept of 'formulation design space'. This article presents the experience of the application of design space within RapidFACT and is supported by data from over 200 formulations studied to date, including case studies on how the approach has been applied. PMID- 26599517 TI - A distinct expression profile separates Turkish and Australian melanocytic naevi. PMID- 26599518 TI - Reversible hydrogen activation by a bulky haloborane based FLP system. AB - The FLP species bis(2-(TMP)phenyl)chloroborane (TMP = 2,2,6,6 tetramethylpiperidine)(1) was prepared and crystallized as a monomeric Frustrated Lewis Pair (FLP) displaying no apparent B-N interaction. Species 1 readily reacts with H2 at room temperature to generate reversibly the zwitterionic H2 activation product 2. Interestingly, in the presence of a base, 2 releases HCl, generating the novel FLP species 3 which is also monomeric. PMID- 26599519 TI - Identification of Noncompetitive Inhibitors of Cytosolic 5'-Nucleotidase II Using a Fragment-Based Approach. AB - We used a combined approach based on fragment-based drug design (FBDD) and in silico methods to design potential inhibitors of the cytosolic 5'-nucleotidase II (cN-II), which has been recognized as an important therapeutic target in hematological cancers. Two subgroups of small compounds (including adenine and biaryl moieties) were identified as cN-II binders and a fragment growing strategy guided by molecular docking was considered. Five compounds induced a strong inhibition of the 5'-nucleotidase activity in vitro, and the most potent ones were characterized as noncompetitive inhibitors. Biological evaluation in cancer cell lines showed synergic effect with selected anticancer drugs. Structural studies using X-ray crystallography lead to the identification of new binding sites for two derivatives and of a new crystal form showing important domain swapping. Altogether, the strategy developed herein allowed identifying new original noncompetitive inhibitors against cN-II that act in a synergistic manner with well-known antitumoral agents. PMID- 26599520 TI - A systematic review to determine the most effective interventions to increase water intake. AB - BACKGROUND: Maintaining adequate fluid intake has been hypothesized to be beneficial for the progression of chronic kidney disease (CKD). The aim of this study was to undertake a systematic review to determine the most effective interventions to increase water intake. METHODS: Six electronic databases were searched from 1910 until March 2015 in the English language. Additional sources through hand-searches, expert recommendations and reviews were checked. Intervention studies increasing water intake in adults through non pharmacological methods were eligible for inclusion. The quality of included studies was assessed. RESULTS: A total of 950 studies were found of which 16 met the inclusion criteria. Eight studies were randomized controlled trials, and seven studies spanned 6 months or longer. The study populations varied and included patients with recurrent nephrolithiasis (n = 6), autosomal dominant polycystic kidney disease (n = 3), CKD (n = 1), urinary tract infection (n = 1) and other miscellaneous conditions (n = 5). The quality of the studies was mostly neutral (63%) with no studies of high quality. Interventions ranged from instruction alone to self-monitoring tools, providing water bottles and counselling and education. Most interventions successfully increased water intake with 13 studies reporting an increase of at least 500 mL. The most effective strategies were instruction and self-monitoring using urine dipstick or 24 h urine volume. CONCLUSION: All interventions carried out in the studies succeeded in increasing water intake, with none leading to decreases in intake, and these could be implemented in potential clinical trials in CKD. However, more high quality long-term intervention studies are required to further validate findings. PMID- 26599521 TI - Lysosomal membrane permeabilization in cell death: new evidence and implications for health and disease. AB - Recent studies have demonstrated that, in addition to their central role in cellular catabolic reactions, lysosomes are implicated in many cellular processes, including metabolism, membrane repair, and cell death. Lysosomal membrane permeabilization (LMP) has emerged as a pathway by which cell demise is regulated under physiological conditions and contributes to cell death in many pathological situations. Here, we review the latest evidence on LMP-mediated cell death, the upstream and downstream signals involved, and the role of LMP in the normal physiology of organisms. We also discuss the contributions of lysosomal damage and LMP to the pathogenic features of several disease states, such as lysosomal storage disorders and other neurodegenerative conditions. PMID- 26599522 TI - Topical anaesthetics for premature ejaculation: a systematic review and meta analysis. AB - Eutectic Mixture of Local Anaesthetics (EMLA) is recommended for use off-label as a treatment for premature ejaculation (PE). Other topical anaesthetics are available, some of which have been evaluated against oral treatments. The purpose of this systematic review was to evaluate the evidence from randomised controlled trials (RCTs) for topical anaesthetics in the management of PE. Bibliographic databases including MEDLINE were searched to August 2014. The primary outcome was intra-vaginal ejaculatory latency time (IELT). Methodological quality of RCTs was assessed. IELT and other outcomes were pooled across RCTs in a meta-analysis. Between-trial heterogeneity was assessed. Nine RCTs were included. Seven were of unclear methodological quality. Pooled evidence (two RCTs, 43 participants) suggests that EMLA is significantly more effective than placebo at increasing IELT (P<0.00001). Individual RCT evidence also suggests that Topical Eutectic like Mixture for Premature Ejaculation (TEMPE) spray and lidocaine gel are both significantly more effective than placebo (P=0.003; P<0.00001); and lidocaine gel is significantly more effective than sildenafil or paroxetine (P=0.01; P=0.0001). TEMPE spray is associated with significantly more adverse events than placebo (P=0.003). More systemic adverse events are reported with tramadol, sildenafil and paroxetine than with lidocaine gel. Diverse methods of assessing sexual satisfaction and ejaculatory control with topical anaesthetics are reported and evidence is conflicting. Topical anaesthetics appear more effective than placebo, paroxetine and sildenafil at increasing IELT in men with PE. However, the methodological quality of the existing RCT evidence base is uncertain. PMID- 26599523 TI - Ultrafast Alkaline Ni/Zn Battery Based on Ni-Foam-Supported Ni3S2 Nanosheets. AB - Self-supported Ni3S2 ultrathin nanosheets were in situ formed by direct sulfurization of commercially available nickel foam using thioacetamide as sulfur source under hydrothermal process. The morphology and structure of the as obtained sample were analyzed by using XRD, XPS, SEM, and TEM, revealing that an ultrathin nanosheets Ni3S2 were grown on the surface of Ni form. The as-obtained Ni3S2/Ni composite with uniform architecture was used as cathode material for alkaline Ni/Zn battery, which delivered high capacity of 125 mAh g(-1) after 100 cycles with no obvious capacity fading, extraordinary rate capability (68 mAh g( 1) at the current density of 5.0 A g(-1)), and high operating voltage (1.75 V). PMID- 26599524 TI - Versatility of the ionic assembling method to design highly luminescent PMMA nanocomposites containing [M6Q(i)8L(a)6](n-) octahedral nano-building blocks. AB - New luminescent poly(methylmethacrylate) (PMMA) nanocomposites with high content of different hexanuclear octahedral cluster building blocks, namely [Mo6I8(C2F5COO6)](2-), [Re6Se8(CN)6](4-) and [W6Cl14](2-) have been prepared by free-radical polymerisation. To do so, cluster complexes bearing a polymerisable ammonium counter-cation have been synthesised. In this way, we demonstrate that ionic assembling is a powerful tool to functionalise easily any type of anionic cluster units to be introduced in a PMMA organic matrix. All samples remain homogeneous, stable during several months, and retain the luminescence properties of the cluster precursor. PMID- 26599525 TI - Ballistocardiographic Artifacts in PPG Imaging. AB - OBJECTIVE: Photoplethysmography (PPG) is a noninvasive technique to measure the blood-volume pulse and derive various vital signs. Camera-based PPG imaging was recently proposed for clinical microvascular assessment, but motion robustness is still an issue for this technique. Our study aims to quantify cardiac-related, i.e., ballistocardiographic (BCG), motion as a source of artifacts in PPG imaging. METHODS: In this paper, using the human head as a relevant region of interest, the amplitude of BCG-artifacts was modeled for a Lambertian surface illuminated by a light source. To derive peak-to-peak head displacements for the model, we recorded, on 54 subjects, PPG and inertial sensor data at the pulse and cranial vertex. We simulated the effect of light source location at a mesh representation of a human face and conducted additional experiments on a real subject. RESULTS: Under nonorthogonal illumination, the relative strength of the BCG artifacts is strong enough, compared to the amplitude of PPG signals, to compromise PPG imaging in realistic scenarios. Particularly affected are the signals obtained in the nongreen part of the spectrum and/or when the incident angle at the skin surface exceeds 45 ( degrees ). CONCLUSION: From the model and an additional experiment conducted on real skin, we were able to prove that homogenous and orthogonal illumination is a means to minimize the problem. SIGNIFICANCE: Our illumination recommendation provides a simple and effective means to improve the validity of remote PPG-imagers. We hope that it helps to prevent mistakes currently seen in many publications on remote PPG. PMID- 26599526 TI - Detection Algorithm of Phase Singularity Using Phase Variance Analysis for Epicardial Optical Mapping Data. AB - OBJECTIVE: Spiral reentry is a recognized cause of tachycardia. Detection and tracking of the spiral core are essential for understanding the spiral wave dynamics. The core of the spiral corresponds to a phase singularity (PS), which can be identified in an optical mapping image by a kernel convolution method. However, because of a large number of false positives, this method cannot automatically and stably track the core of sustaining spiral reentry in optical mapping data. METHOD: We developed a new PS detection algorithm that quantifies the variance of phase values in a phase map and identifies the position of PS as its peak. RESULTS: In comparison with the kernel convolution method, our method improved the precision of detecting a single sustaining spiral wave core from 73.1% to 99.8%. The precision of the proposed method for virtual-electrode polarization-induced multiple PSs detections was also higher than the convolutional method. CONCLUSION: The proposed method detects PS by finding the peaks in the phase variance distribution of cardiac optical mapping image. It improved the precision of the core detection of the spiral wave in cardiac optical mapping images in comparison with the conventional kernel convolution method. SIGNIFICANCE: The proposed method will reveal the spiral wave dynamics in optical mapping images better than existing approaches. The objective analysis method of a spiral wave is important for understanding the mechanisms and dynamics of serious heart arrhythmias. PMID- 26599527 TI - Efficient extraction of sulfate from water using a Zr-metal-organic framework. AB - A Zr-based MOF, NU-1000, comprised of Zr6 nodes and tetratopic pyrene-containing linkers is studied for adsorption and extraction of SO4(2-) from water. The adsorption capacity and uptake time of SO4(2-) in NU-1000 is determined at varying concentrations to give an overall maximum adsorption capacity of 56 mg SO4(2-) per g of MOF. Selective adsorption of SO4(2-) by NU-1000 in the presence of other anions as well as regeneration of the sorbent is also explored. PMID- 26599528 TI - The experience of adolescent inpatient care and the anticipated transition to the community: Young people's perspectives. AB - This study explored adolescents' perspectives of inpatient mental health care, focussing on aspects of the inpatient environment they anticipated would help or hinder their transition back home. Semi-structured interviews were conducted with 12 adolescent inpatients; transcripts were analysed thematically. Participants experienced inpatient treatment as offering a mix of benefits (e.g., supportive relationships) and drawbacks (e.g., living in a "fake world"). They anticipated the transition home as providing opportunities for personal growth and consolidation of new coping skills, but also posing challenges concerning re entering the "real world" after the experience of being "wrapped in cotton wool". Self-determination theory and attachment theory offer two potential frameworks for understanding these opportunities and challenges. Inpatient care has the potential to foster key mechanisms for adaptive development, creating a platform for developing positive future behaviours. Community teams should work closely with inpatient units to support the generalisation of the young person's newly acquired coping skills. PMID- 26599529 TI - Social information influences trust behaviour in adolescents. AB - Trust plays an integral role in daily interactions within adolescents' social environment. Using a trust game paradigm, this study investigated the modulating influence of social information about three interaction partners on trust behaviour in adolescents aged 12-18 (N = 845). After receiving information about their interaction partners prior to the task, participants were most likely to share with a 'good' partner and rate this partner as most trustworthy. Over the course of the task all interaction partners showed similar levels of trustworthy behaviour, but overall participants continued to trust and view the good partner as more trustworthy than 'bad' and 'neutral' partners throughout the game. However, with age the ability to overcome prior social information and adapt trust behaviour improved: middle and late adolescents showed a larger decrease in trust of the good partner than early adolescents, and late adolescents were more likely to reward trustworthy behaviour from the negative partner. PMID- 26599530 TI - Design and synthesis of a C7-aryl piperlongumine derivative with potent antimicrotubule and mutant p53-reactivating properties. AB - Small molecules that can restore biological function to the p53 mutants found in human cancers have been highly sought to increase the anticancer efficacy. In efforts to generate hybrid anticancer drugs that can impact two or more targets simultaneously, we designed and developed piperlongumine (PL) derivatives with an aryl group inserted at the C-7 position. This insertion bestowed a combretastatin A4 (CA4, an established microtubule disruptor) like structure while retaining the piperlongumine configuration. The new compounds exhibited potent antiproliferative activities against eight cancer cell lines, in particular, were more cytotoxic against the SKBR-3 breast cancer cells which harbor a R175H mutation in p53 suppressor. KSS-9, a representative aryl PL chosen for further studies induced abundant ROS generation and protein glutathionylation. KSS-9 strongly disrupted the tubulin polymerization in vitro, destabilized the microtubules in cells and induced a potent G2/M cell cycle block. More interestingly, KSS-9 showed the ability to reactivate the p53 mutation and restore biological activity to the R175H mutant protein present in SKBR3 cells. Several procedures, including immunocytochemistry using conformation-specific antibodies for p53, immunoprecipitation combined with western blotting, electrophoretic shift mobility shift assays showed a reciprocal loss of mutant protein and generation of wild-type like protein. p53 reactivation was accompanied by the induction of the target genes, MDM2, p21cip1 and PUMA. Mechanistically, the redox-perturbation in cancer cells by the hybrid drug appears to underlie the p53 reactivation process. This anticancer drug approach merits further development. PMID- 26599531 TI - The biphosphinic paladacycle complex induces melanoma cell death through lysosomal-mitochondrial axis modulation and impaired autophagy. AB - Recently, palladium complexes have been extensively studied as cyclization of these complexes by cyclometallation reactions increased their stability making them promising antitumor compounds. In this study, we have investigated apoptosis induced by the Biphosphinic Paladacycle Complex (BPC11) and possible cross talk between apoptosis and autophagy in cell line models of metastatic (Tm5) and non metastatic (4C11-) melanoma. The BPC11-induced cell death in melanoma involved the lysosomal-mitochondrial axis, which is characterized by LMP, CatB activation and increased Bax protein levels following its translocation to mitochondria. Mitochondrial hyperpolarization, followed by membrane potential dissipation and cleavage of caspase-3, also resulted in cell death after 24 h of incubation. We also found that BPC11-mediated LC3II formation and increased p62 protein levels, suggesting blocked autophagy, probably due to LMP. Interestingly, the treatment of Tm5 and 4C11(-) cells with 3-methyladenine (3-MA), an inhibitor of the initial stage of autophagy, potentiated the effects of BPC11. We conclude that BPC11 is an anti-melanoma agent and that autophagy may be acting as a mechanism of melanoma cells resistance. Also, these data highlight the importance of studies involving autophagy and apoptosis during pre-clinical studies of new drugs with anticancer properties. PMID- 26599532 TI - Extended structure-activity study of thienopyrimidine-based EGFR inhibitors with evaluation of drug-like properties. AB - Thieno[2,3-d]pyrimidines are attractive derivatives for cancer treatment, among others through regulation of the epidermal growth factor receptor tyrosine kinase (EGFR-TK). In an extended SAR study, 44 new compounds of this class have been evaluated as inhibitors, while simultaneously focussing on ADME properties. Through the application of bioisosters, hybrid structures, solubilizing tails, and a combination approach several successful alterations in terms of activity and physiochemical properties were accomplished. Compounds based on benzylamines were found superior to aniline hybrid structures with respect to activity and ADME profile. Exploration of the former class revealed meta- and para amides as favourable 6-aryl substituents, contributing to an increase in activity and acting as a linker for solubilizing tails. Next, combinations of activity inducing groups on the same scaffold resulted in new drug candidates. Compounds containing 6-aryls with the (2-(dimethylamino)ethyl)carbamoyl substituent were found equipotent to Erlotinib. Compared to this commercial drug, improved solubility and metabolic stability were observed. However, the thieno[2,3 d]pyrimidines with a solubilizing tail was by Caco-2 experiments found to have permeability issues, making further drug development difficult. Selected compounds were further analysed for toxicity and teratogenicity in zebrafish embryos. Two thienopyrimidines were both found to be less lethal than Erlotinib and to perform as well in terms of teratogenicity. Finally, the most promising thienopyrimidine drug was evaluated in a panel of human cancer cell lines, showing a clear potential for thienopyrimidines as anti-cancer agents. PMID- 26599533 TI - 3-(Dipropylamino)-5-hydroxybenzofuro[2,3-f]quinazolin-1(2H)-one (DPA-HBFQ-1) plays an inhibitory role on breast cancer cell growth and progression. AB - A series of unknown 3-(alkyl(dialkyl)amino)benzofuro[2,3-f]quinazolin-1(2H)-ones 4-17 has been synthesized as new ellipticine analogs, in which the carbazole moiety and the pyridine ring were replaced by a dibenzofuran residue and a pyrimidine ring, respectively. The synthesis of these benzofuroquinazolinones 4 17 was performed in a simple one-pot reaction using 3-aminodibenzofuran or its 2 methoxy derivative, as starting materials. From 3-(dipropylamino)-5 methoxybenzofuro[2,3-f] quinazolin-1(2H)-one (13), we prepared 3-(dipropylamino) 5-hydroxybenzofuro[2,3-f]quinazolin-1(2H)-one (18), referred to as DPA-HBFQ-1. The cytotoxic activities of all the synthesized compounds, tested in different human breast cancer cell lines, revealed that DPA-HBFQ-1 was the most active compound. In particular, the latter was able to inhibit anchorage-dependent and independent cell growth and to induce apoptosis in estrogen receptor alpha (ERalpha)-positive and -negative breast cancer cells. It did not affect proliferation and apoptotic responses in MCF-10A normal breast epithelial cells. The observed effects have been ascribed to an enhanced p21(Cip1/WAF1) expression in a p53-dependent manner of tumor suppressor and to a selective inhibition of human topoisomerase II. In addition, DPA-HBFQ-1 exerted growth inhibitory effects also in other cancer cell lines, even though with a lower cytotoxic activity. Our results indicate DPA-HBFQ-1 as a good candidate to be useful as cancer therapeutic agent, particularly for breast cancer. PMID- 26599534 TI - Synthesis and evaluation of bis-thiazole derivatives as new anticancer agents. AB - New bis-thiazole derivatives (1-10) were synthesized via the ring closure of 1,1' (3,3'-dimethoxybiphenyl-4,4'-diyl)bis(thiourea) with phenacyl bromides and evaluated for their cytotoxic effects on A549 human lung adenocarcinoma, C6 rat glioma, 5RP7 H-ras oncogene transformed rat embryonic fibroblast and NIH/3T3 mouse embryonic fibroblast cell lines using MTT assay. DNA synthesis inhibitory effects of these compounds were investigated. Each derivative was also evaluated for its ability to inhibit AChE and BuChE using a modification of Ellman's spectrophotometric method. Among these compounds, 3,3'-dimethoxy-N(4),N(4)'-bis(4 (4-bromophenyl)thiazol-2-yl)-[1,1'-biphenyl]-4,4'-diamine (5) can be identified as the most promising anticancer agent due to its notable inhibitory effects on A549 and C6 cell lines and low toxicity to NIH/3T3 cell lines. Compound 5 exhibited anticancer activity against A549 and C6 cell lines with IC50 values of 37.3 +/- 6.8 MUg/mL and 11.3 +/- 1.2 MUg/mL, whereas mitoxantrone showed anticancer activity against A549 and C6 cell lines with IC50 values of 15.7 +/- 4.0 MUg/mL and 11.0 +/- 1.7 MUg/mL, respectively. Furthermore, compound 5 showed DNA synthesis inhibitory activity against A549 cell line. PMID- 26599535 TI - Peroxisome Proliferator-Activated Receptor Gamma Negatively Regulates the Differentiation of Bone Marrow-Derived Mesenchymal Stem Cells Toward Myofibroblasts in Liver Fibrogenesis. AB - BACKGROUND/AIMS: Bone marrow-derived mesenchymal stem cells (BMSCs) have been confirmed to have capacity to differentiate toward hepatic myofibroblasts, which contribute to fibrogenesis in chronic liver diseases. Peroxisome proliferator activated receptor gamma (PPARx03B3;), a ligand-activated transcription factor, has gained a great deal of recent attention as it is involved in fibrosis and cell differentiation. However, whether it regulates the differentiation of BMSCs toward myofibroblasts remains to be defined. METHODS: Carbon tetrachloride or bile duct ligation was used to induce mouse liver fibrosis. Expressions of PPARx03B3;, alpha-smooth muscle actin, collagen alpha1 (I) and collagen alpha1 (III) were detected by real-time RT-PCR and Western blot or immunofluorescence assay. RESULTS: PPARx03B3; expression was decreased in mouse fibrotic liver. In addition, PPARx03B3; was declined during the differentiation of BMSCs toward myofibroblasts induced by transforming growth factor beta1. Activation of PPARx03B3; stimulated by natural or synthetic ligands suppressed the differentiation of BMSCs. Additionally, knock down of PPARx03B3; by siRNA contributed to BMSC differentiation toward myofibroblasts. Furthermore, PPARx03B3; activation by natural ligand significantly inhibited the differentiation of BMSCs toward myofibroblasts in liver fibrogenesis and alleviated liver fibrosis. CONCLUSIONS: PPARx03B3; negatively regulates the differentiation of BMSCs toward myofibroblasts, which highlights a further mechanism implicated in the BMSC differentiation. PMID- 26599537 TI - Reward and Novelty Enhance Imagination of Future Events in a Motivational Episodic Network. AB - Thinking about personal future events is a fundamental cognitive process that helps us make choices in daily life. We investigated how the imagination of episodic future events is influenced by implicit motivational factors known to guide decision making. In a two-day functional magnetic resonance imaging (fMRI) study, we controlled learned reward association and stimulus novelty by pre familiarizing participants with two sets of words in a reward learning task. Words were repeatedly presented and consistently followed by monetary reward or no monetary outcome. One day later, participants imagined personal future events based on previously rewarded, unrewarded and novel words. Reward association enhanced the perceived vividness of the imagined scenes. Reward and novelty-based construction of future events were associated with higher activation of the motivational system (striatum and substantia nigra/ ventral tegmental area) and hippocampus, and functional connectivity between these areas increased during imagination of events based on reward-associated and novel words. These data indicate that implicit past motivational experience contributes to our expectation of what the future holds in store. PMID- 26599539 TI - No-Reflow Phenomenon in Central Retinal Artery Occlusion: Incidence, Risk Factors, and Clinical Implications. AB - PURPOSE: To investigate the incidence and risk factors of the no-reflow phenomenon in central retinal artery occlusion (CRAO) patients and to determine its effects on visual and anatomic outcomes. METHODS: In 102 eyes with CRAO in which arterial recanalization was obtained within 1 week from baseline, fluorescein angiography images obtained at baseline and 1 week were retrospectively reviewed. The no-reflow phenomenon in the retina was defined as macular capillary nonperfusion following arterial recanalization on fluorescein angiographs. We investigated the incidence and risk factors for the no-reflow phenomenon and compared the anatomical and visual outcomes between eyes with and without the phenomenon. RESULTS: Among the 102 CRAO eyes with arterial recanalization, 39 exhibited the no-reflow phenomenon, resulting in an incidence of 38.2%. The incidence among the eyes with treatment-induced and spontaneous recanalization was 43.4% and 15.8%, respectively, and it increased with the CRAO stage. CRAO stage and increased central macular thickness were risk factors for the phenomenon, with an odds ratio of 4.47 [95% confidence interval (CI), 1.19 16.8; P = 0.027] and 1.69 (95% CI, 1.12-2.55; P = 0.012) per 100-MUm increase, respectively. The visual outcome was significantly poorer and retinal atrophy and photoreceptor disruption was greater in eyes with the no-reflow phenomenon than in those without. CONCLUSIONS: The no-reflow phenomenon may occur after arterial recanalization in approximately one-third of CRAO patients and can affect anatomical and visual outcomes. This phenomenon may provide an additional explanation regarding the permanent retinal damage and vision loss in eyes with CRAO. PMID- 26599538 TI - Utility of Metagenomic Next-Generation Sequencing for Characterization of HIV and Human Pegivirus Diversity. AB - Given the dynamic changes in HIV-1 complexity and diversity, next-generation sequencing (NGS) has the potential to revolutionize strategies for effective HIV global surveillance. In this study, we explore the utility of metagenomic NGS to characterize divergent strains of HIV-1 and to simultaneously screen for other co infecting viruses. Thirty-five HIV-1-infected Cameroonian blood donor specimens with viral loads of >4.4 log10 copies/ml were selected to include a diverse representation of group M strains. Random-primed NGS libraries, prepared from plasma specimens, resulted in greater than 90% genome coverage for 88% of specimens. Correct subtype designations based on NGS were concordant with sub region PCR data in 31 of 35 (89%) cases. Complete genomes were assembled for 25 strains, including circulating recombinant forms with relatively limited data available (7 CRF11_cpx, 2 CRF13_cpx, 1 CRF18_cpx, and 1 CRF37_cpx), as well as 9 unique recombinant forms. HPgV (formerly designated GBV-C) co-infection was detected in 9 of 35 (25%) specimens, of which eight specimens yielded complete genomes. The recovered HPgV genomes formed a diverse cluster with genotype 1 sequences previously reported from Ghana, Uganda, and Japan. The extensive genome coverage obtained by NGS improved accuracy and confidence in phylogenetic classification of the HIV-1 strains present in the study population relative to conventional sub-region PCR. In addition, these data demonstrate the potential for metagenomic analysis to be used for routine characterization of HIV-1 and identification of other viral co-infections. PMID- 26599540 TI - Copy number variations play important roles in heredity of common diseases: a novel method to calculate heritability of a polymorphism. AB - "Missing heritability" in genome wide association studies, the failure to account for a considerable fraction of heritability by the variants detected, is a current puzzle in human genetics. For solving this puzzle the involvement of genetic variants like rare single nucleotide polymorphisms (SNPs) and copy number variations (CNVs) has been proposed. Many papers have published estimating the heritability of sets of polymorphisms, however, there has been no paper discussing the estimation of a heritability of a single polymorphism. Here I show a simple but rational method to calculate heritability of an individual polymorphism, hp(2). Using this method, I carried out a trial calculation of hp(2) of CNVs and SNPs using published data. It turned out that hp(2) of some CNVs is quite large. Noteworthy examples were that about 25% of the heritability of type 2 diabetes mellitus and about 15% of the heritability of schizophrenia could be accounted for by one CNV and by four CNVs, respectively. The results suggest that a large part of missing heritability could be accounted for by re evaluating the CNVs which have been already found and by searching novel CNVs with large hp(2). PMID- 26599541 TI - The Transcription and Translation Landscapes during Human Cytomegalovirus Infection Reveal Novel Host-Pathogen Interactions. AB - Viruses are by definition fully dependent on the cellular translation machinery, and develop diverse mechanisms to co-opt this machinery for their own benefit. Unlike many viruses, human cytomegalovirus (HCMV) does suppress the host translation machinery, and the extent to which translation machinery contributes to the overall pattern of viral replication and pathogenesis remains elusive. Here, we combine RNA sequencing and ribosomal profiling analyses to systematically address this question. By simultaneously examining the changes in transcription and translation along HCMV infection, we uncover extensive transcriptional control that dominates the response to infection, but also diverse and dynamic translational regulation for subsets of host genes. We were also able to show that, at late time points in infection, translation of viral mRNAs is higher than that of cellular mRNAs. Lastly, integration of our translation measurements with recent measurements of protein abundance enabled comprehensive identification of dozens of host proteins that are targeted for degradation during HCMV infection. Since targeted degradation indicates a strong biological importance, this approach should be applicable for discovering central host functions during viral infection. Our work provides a framework for studying the contribution of transcription, translation and degradation during infection with any virus. PMID- 26599542 TI - Reward Anticipation in Ventral Striatum and Individual Sensitivity to Reward: A Pilot Study of a Child-Friendly fMRI Task. AB - Reward processing has been implicated in developmental disorders. However, the classic task to probe reward anticipation, the monetary incentive delay task, has an abstract coding of reward and no storyline and may therefore be less appropriate for use with developmental populations. We modified the task to create a version appropriate for use with children. We investigated whether this child-friendly version could elicit ventral striatal activation during reward anticipation in typically developing children and young adolescents (aged 9.5 14.5). In addition, we tested whether our performance-based measure of reward sensitivity was associated with anticipatory activity in ventral striatum. Reward anticipation was related to activity in bilateral ventral striatum. Moreover, we found an association between individual reward sensitivity and activity in ventral striatum. We conclude that this task assesses ventral striatal activity in a child-friendly paradigm. The combination with a performance-based measure of reward sensitivity potentially makes the task a powerful tool for developmental imaging studies of reward processing. PMID- 26599544 TI - Correction: A Common Polymorphism within the IGF2 Imprinting Control Region Is Associated with Parent of Origin Specific Effects in Infantile Hemangiomas. PMID- 26599543 TI - Pathogenesis of Primary Foot-and-Mouth Disease Virus Infection in the Nasopharynx of Vaccinated and Non-Vaccinated Cattle. AB - A time-course pathogenesis study was performed to compare and contrast primary foot-and-mouth disease virus (FMDV) infection following simulated-natural (intra nasopharyngeal) virus exposure of cattle that were non-vaccinated or vaccinated using a recombinant adenovirus-vectored FMDV vaccine. FMDV genome and infectious virus were detected during the initial phase of infection in both categories of animals with consistent predilection for the nasopharyngeal mucosa. A rapid progression of infection with viremia and widespread dissemination of virus occurred in non-vaccinated animals whilst vaccinated cattle were protected from viremia and clinical FMD. Analysis of micro-anatomic distribution of virus during early infection by lasercapture microdissection localized FMDV RNA to follicle associated epithelium of the nasopharyngeal mucosa in both groups of animals, with concurrent detection of viral genome in nasopharyngeal MALT follicles in vaccinated cattle only. FMDV structural and non-structural proteins were detected in epithelial cells of the nasopharyngeal mucosa by immunomicroscopy 24 hours after inoculation in both non-vaccinated and vaccinated steers. Co-localization of CD11c+/MHC II+ cells with viral protein occurred early at primary infection sites in vaccinated steers while similar host-virus interactions were observed at later time points in non-vaccinated steers. Additionally, numerous CD8+/CD3- host cells, representing presumptive natural killer cells, were observed in association with foci of primary FMDV infection in the nasopharyngeal mucosa of vaccinated steers but were absent in non-vaccinated steers. Immunomicroscopic evidence of an activated antiviral response at primary infection sites of vaccinated cattle was corroborated by a relative induction of interferon -alpha, beta, -gamma and -lambda mRNA in micro-dissected samples of nasopharyngeal mucosa. Although vaccination protected cattle from viremia and clinical FMD, there was subclinical infection of epithelial cells of the nasopharyngeal mucosa that could enable shedding and long-term persistence of infectious virus. Additionally, these data indicate different mechanisms within the immediate host response to infection between non-vaccinated and vaccinated cattle. PMID- 26599545 TI - Trade-Offs of Flowering and Maturity Synchronisation for Pineapple Quality. AB - In the pineapple sector of Benin, poor fruit quality prevents pineapple producers to enter the European market. We investigated effects of common cultural practices, flowering and maturity synchronisation, (1) to quantify the trade-offs of flowering and maturity synchronisation for pineapple quality and the proportion of fruits exportable to European markets, and (2) to determine the effect of harvesting practice on quality attributes. Four on-farm experiments were conducted during three years using cultivars Sugarloaf and Smooth Cayenne. A split-split plot design was used in each experiment, with flowering induction practice as main factor (artificial or natural flowering induction), maturity induction practice as split factor (artificial or natural maturity induction) and harvesting practice as the split-split factor (farmers' harvest practice or individual fruit harvesting at optimum maturity). Artificial flowering induction gave fruits with lower infructescence weight, higher ratio crown: infructescence length, and a lower proportion of fruits exportable to European markets than natural flowering induction. The costs of the improvements by natural flowering induction were huge: the longer durations from planting to flowering induction and harvesting, the higher number of harvestings of the fruits increasing the labour cost and the lower proportion of plants producing fruits compared with crops from artificially flowering-induced plants. Artificial maturity induction decreased the total soluble solids concentration in the fruits compared with natural maturity induction thus decreasing the proportion of fruits exportable to European markets, at a benefit of only a slightly shorter time from flowering induction to harvesting. Harvesting individual fruits at optimum maturity gave fruits with higher total soluble solids in naturally maturity induced fruits compared with the farmers' harvest practice. Given the huge costs of natural flowering induction, options to use artificial flowering induction effectively for obtaining high fruit quality are discussed. PMID- 26599546 TI - Genomic Landscape of Primary Mediastinal B-Cell Lymphoma Cell Lines. AB - Primary mediastinal B-Cell lymphoma (PMBL) is a recently defined entity comprising ~2-10% non-Hodgkin lymphomas (NHL). Unlike most NHL subtypes, PMBL lacks recurrent gene rearrangements to serve as biomarkers or betray target genes. While druggable, late chemotherapeutic complications warrant the search for new targets and models. Well characterized tumor cell lines provide unlimited material to serve as preclinical resources for verifiable analyses directed at the discovery of new biomarkers and pathological targets using high throughput microarray technologies. The same cells may then be used to seek intelligent therapies directed at clinically validated targets. Four cell lines have emerged as potential PMBL models: FARAGE, KARPAS-1106P, MEDB-1 and U-2940. Transcriptionally, PMBL cell lines cluster near c(lassical)-HL and B-NHL examples showing they are related but separate entities. Here we document genomic alterations therein, by cytogenetics and high density oligonucleotide/SNP microarrays and parse their impact by integrated global expression profiling. PMBL cell lines were distinguished by moderate chromosome rearrangement levels undercutting cHL, while lacking oncogene translocations seen in B-NHL. In total 61 deletions were shared by two or more cell lines, together with 12 amplifications (>=4x) and 72 homozygous regions. Integrated genomic and transcriptional profiling showed deletions to be the most important class of chromosome rearrangement. Lesions were mapped to several loci associated with PMBL, e.g. 2p15 (REL/COMMD1), 9p24 (JAK2, CD274), 16p13 (SOCS1, LITAF, CIITA); plus new or tenuously associated loci: 2p16 (MSH6), 6q23 (TNFAIP3), 9p22 (CDKN2A/B), 20p12 (PTPN1). Discrete homozygous regions sometimes substituted focal deletions accompanied by gene silencing implying a role for epigenetic or mutational inactivation. Genomic amplifications increasing gene expression or gene-activating rearrangements were respectively rare or absent. Our findings highlight biallelic deletions as a major class of chromosomal lesion in PMBL cell lines, while endorsing the latter as preclinical models for hunting and testing new biomarkers and actionable targets. PMID- 26599552 TI - Consultant's Corner. PMID- 26599548 TI - miR-211 and MITF modulation by Bcl-2 protein in melanoma cells. AB - Melanoma, the most lethal form of skin cancer, is frequently associated with alterations in several genes, among which the Bcl-2 oncogene plays an important role in progression, chemosensitivity and angiogenesis. Also microRNA (miRNA) are emerging as modulators of melanoma development and progression, and among them, miR-211, located within the melastatin-1/TRPM1 (transient receptor potential cation channel, subfamily M, member 1 protein) gene, is prevalently expressed in the melanocyte lineage and acts as oncosuppressor. Using several human melanoma cell lines and their Bcl-2 stably overexpressing derivatives, we evaluated whether there was a correlation between expression of Bcl-2 and miR-211. Western blot analysis and quantitative real-time polymerase chain reaction demonstrated reduced expression of pri-miR-211, miR-211, TRPM1, and MLANA levels, after Bcl-2 overexpression, associated with increased expression of well-known miR-211 target genes. Overexpression of mature miR-211 in Bcl-2 overexpressing cells rescued Bcl 2 ability to increase cell migration. A decreased nuclear localization of microphthalmia-associated transcription factor (MITF), a co-regulator of both miR 211 and TRPM1, and a reduced MITF recruitment at the TRPM1 and MLANA promoters were also evidenced in Bcl-2 overexpressing cells by immunofluorescence and chromatin immunoprecipitation experiments, respectively. Reduction of Bcl-2 expression by small interference RNA confirmed the ability of Bcl-2 to modulate miR-211 and TRPM1 expression. (c) 2015 Wiley Periodicals, Inc. PMID- 26599547 TI - Glycoprotein Nonmetastatic Melanoma B (Gpnmb)-Positive Macrophages Contribute to the Balance between Fibrosis and Fibrolysis during the Repair of Acute Liver Injury in Mice. AB - BACKGROUND AND AIMS: Glycoprotein nonmetastatic melanoma B (Gpnmb), a transmembrane glycoprotein that is expressed in macrophages, negatively regulates inflammation. We have reported that Gpnmb is strongly expressed in the livers of rats fed a choline-deficient, L-amino acid-defined (CDAA) diet. However, the role of macrophage-expressed Gpnmb in liver injury is still unknown. This study aimed to clarify the characteristics of infiltrating macrophages that express Gpnmb, and the involvement of Gpnmb in the repair process in response to liver injury. METHODS: C57BL/6J, DBA/2J [DBA] and DBA/2J-Gpnmb+ [DBA-g+] mice were treated with a single intraperitoneal injection of carbon tetrachloride (CCl4) at a dose of 1.0 mL/kg body weight. Mice were sacrificed at predetermined time points, followed by measurement of serum alanine aminotransferase (ALT) levels and histological examination. Expression of Gpnmb, pro-/anti-inflammatory cytokines, and profibrotic/antifibrotic factors were examined by quantitative RT-PCR and/or Western blotting. Immunohistochemistry, fluorescent immunostaining and flow cytometry were used to determine the expression of Gpnmb, CD68, CD11b and alpha SMA, phagocytic activity, and the presence of apoptotic bodies. We used quantitative RT-PCR and ELISA to examine TGF-beta and MMP-13 expression and the concentrations and supernatants of isolated infiltrating hepatic macrophages transfected with siGpnmb. RESULTS: In C57BL/6J mice, serum ALT levels increased at two days after CCl4 injection and decreased at four days. Gpnmb expression in the liver was stimulated four days after CCl4 injection. Histological examination and flow cytometry showed that Gpnmb-positive cells were almost positive for CD68 positive macrophages, contained engulfed apoptotic bodies and exhibited enhanced phagocytic activity. Isolated infiltrating hepatic macrophages transfected with siGpnmb showed high MMP-13 secretion. There was no significant difference in the magnitude of CCl4-induced liver injury between DBA-g+ and DBA mice. However, hepatic MMP-13 expression, as well as alpha-SMA expression and collagen production, increased significantly in DBA-g+ compared with DBA mice. CONCLUSIONS: Gpnmb-positive macrophages infiltrate the liver during the recovery phase of CCl4-induced acute liver injury and contribute to the balance between fibrosis and fibrolysis in the repair process following acute liver injury. PMID- 26599553 TI - Hospital Financial Problems. PMID- 26599554 TI - Review of Hospital Lawsuits. PMID- 26599560 TI - Hospital Topics: Previews a New Educational Film...: I'm Not a Small Adult. PMID- 26599563 TI - Metal to Insulator Quantum-Phase Transition in Few-Layered ReS2. AB - In ReS2, a layer-independent direct band gap of 1.5 eV implies a potential for its use in optoelectronic applications. ReS2 crystallizes in the 1T'-structure, which leads to anisotropic physical properties and whose concomitant electronic structure might host a nontrivial topology. Here, we report an overall evaluation of the anisotropic Raman response and the transport properties of few-layered ReS2 field-effect transistors. We find that ReS2 exfoliated on SiO2 behaves as an n-type semiconductor with an intrinsic carrier mobility surpassing MU(i) ~ 30 cm(2)/(V s) at T = 300 K, which increases up to ~350 cm(2)/(V s) at 2 K. Semiconducting behavior is observed at low electron densities n, but at high values of n the resistivity decreases by a factor of >7 upon cooling to 2 K and displays a metallic T(2)-dependence. This suggests that the band structure of 1T' ReS2 is quite susceptible to an electric field applied perpendicularly to the layers. The electric-field induced metallic state observed in transition metal dichalcogenides was recently claimed to result from a percolation type of transition. Instead, through a scaling analysis of the conductivity as a function of T and n, we find that the metallic state of ReS2 results from a second-order metal-to-insulator transition driven by electronic correlations. This gate induced metallic state offers an alternative to phase engineering for producing ohmic contacts and metallic interconnects in devices based on transition metal dichalcogenides. PMID- 26599564 TI - The Surgeon Will Skype You Now: Advancements in E-clinic. PMID- 26599565 TI - Gastric Bypass Surgery Leads to Long-term Remission or Improvement of Type 2 Diabetes and Significant Decrease of Microvascular and Macrovascular Complications. AB - OBJECTIVES: The aim of the study was to compare long-term outcomes of 2 groups of morbidly obese patients with type 2 diabetes mellitus-1 managed by Roux-en-Y gastric bypass surgery and a comparable group managed medically. METHODS: The present study was a single-institution retrospective study. Of the 173 obese patients with type 2 diabetes mellitus undergoing gastric bypass surgery between January 2000 and July 2004, 78 patients (45%) were followed for at least 10 years. The control group consisted of 80 diabetic obese patients from the same period with similar body mass index, age, race, and severity of diabetes. The median follow-up was 11 years for both the groups. RESULTS: The group undergoing gastric bypass surgery had greater percentage of excess weight loss than the control group-66% versus -1.6%, respectively. Forty-one patients (52.6%) in the surgery group had complete remission of diabetes and 5 (6.4%) had partial remission. Twelve patients (15.4%) had diabetes recurrence after initial remission. No patient in the control group had remission of diabetes. Compared with the control group, the group undergoing gastric bypass surgery had a significantly reduced incidence of microvascular complications-46.3% versus 11.5%, and macrovascular complications-20.3% versus 5%, respectively (P < 0.01). CONCLUSIONS: In this study, we demonstrated that after 10 years of follow-up, Roux-en-Y gastric bypass surgery, compared with nonsurgical medical management, resulted in significantly greater weight loss, reduction in hemoglobin A1c, and use of antidiabetic medications, and very importantly a lower incidence of both microvascular and macrovascular complications in obese patients with type 2 diabetes. PMID- 26599566 TI - Ways forward for aquatic conservation: Applications of environmental psychology to support management objectives. AB - The success or failure of environmental management goals can be partially attributed to the support for such goals from the public. Despite this, environmental management is still dominated by a natural science approach with little input from disciplines that are concerned with the relationship between humans and the natural environment such as environmental psychology. Within the marine and freshwater environments, this is particularly concerning given the cultural and aesthetic significance of these environments to the public, coupled with the services delivered by freshwater and marine ecosystems, and the vulnerability of aquatic ecosystems to human-driven environmental perturbations. This paper documents nine case studies which use environmental psychology methods to support a range of aquatic management goals. Examples include understanding the drivers of public attitudes towards ecologically important but uncharismatic river species, impacts of marine litter on human well-being, efficacy of small scale governance of tropical marine fisheries and the role of media in shaping attitudes towards. These case studies illustrate how environmental psychology and natural sciences can be used together to apply an interdisciplinary approach to the management of aquatic environments. Such an approach that actively takes into account the range of issues surrounding aquatic environment management is more likely to result in successful outcomes, from both human and environmental perspectives. Furthermore, the results illustrate that better understanding the societal importance of aquatic ecosystems can reduce conflict between social needs and ecological objectives, and help improve the governance of aquatic ecosystems. Thus, this paper concludes that an effective relationship between academics and practitioners requires fully utilising the skills, knowledge and experience from both sectors. PMID- 26599567 TI - Predicting the presence and cover of management relevant invasive plant species on protected areas. AB - Invasive species are a management concern on protected areas worldwide. Conservation managers need to predict infestations of invasive plants they aim to treat if they want to plan for long term management. Many studies predict the presence of invasive species, but predictions of cover are more relevant for management. Here we examined how predictors of invasive plant presence and cover differ across species that vary in their management priority. To do so, we used data on management effort and cover of invasive plant species on central Florida protected areas. Using a zero-inflated multiple regression framework, we showed that protected area features can predict the presence and cover of the focal species but the same features rarely explain both. There were several predictors of either presence or cover that were important across multiple species. Protected areas with three days of frost per year or fewer were more likely to have occurrences of four of the six focal species. When invasive plants were present, their proportional cover was greater on small preserves for all species, and varied with surrounding household density for three species. None of the predictive features were clearly related to whether species were prioritized for management or not. Our results suggest that predictors of cover and presence can differ both within and across species but do not covary with management priority. We conclude that conservation managers need to select predictors of invasion with care as species identity can determine the relationship between predictors of presence and the more management relevant predictors of cover. PMID- 26599568 TI - Etiology of Pneumonia in a Pediatric Population with High Pneumococcal Vaccine Coverage: A Prospective Study. AB - BACKGROUND: Improved Childhood Immunizations Programs, especially the introduction of pneumococcal vaccination, better diagnostic methods and the importance of reduced antibiotic misuse, make this a critical time to increase knowledge on the etiology of pediatric pneumonia. Our main objective was to identify the contribution of various microbiological species that causes pneumonia in previously healthy children and adolescents in a population with high pneumococcal conjugate vaccine coverage. METHODS: This prospective, observational study enrolled patients with clinical and radiological signs of pneumonia over a 2-year period. Both inpatients and outpatients were included. Paired sera, nasopharyngeal polymerase chain reaction and bacterial cultures from blood and pleura were analyzed to detect potential viral and bacterial causative pathogens. RESULTS: TWO HUNDRED AND SIXTY-FIVE: cases of clinical and radiological verified pneumonia were identified. The pneumococcal vaccine coverage was 85%. We identified a causative pathogen in 84.2% of all cases; 63.4% with single viral etiology, 11.3% with pneumococcus and 7.5% with mycoplasma infection. Respiratory syncytial virus was the most common pathogen in children younger than 5 years, whereas mycoplasma was the most common in older children. CONCLUSIONS: We identified the majority of 265 cases with radiology proven pneumonia as single viral infections, predominantly respiratory syncytial virus and a much lower proportion of bacterial causes. These findings may impact pneumonia management guidelines in areas where widespread pneumococcal vaccination is provided and contribute to reduced antibiotic overuse in pediatric pneumonia. PMID- 26599569 TI - The Importance of Scabies Coinfection in the Treatment Considerations for Impetigo. AB - BACKGROUND: Skin infections account for a high disease burden in indigenous children living in northern Australia. Although the relationship between impetigo and scabies is recognized, the prevalence of scabies in children with impetigo is not well reported. We report the prevalence, demographics and treatment success outcomes of impetigo and scabies coinfection in indigenous children who were participants in a randomized controlled trial of impetigo treatment conducted in remote communities of the Northern Territory, Australia. METHODS: Of 1715 screening episodes for impetigo, 508 children were randomized to receive intramuscular benzathine benzylpenicillin (BPG), twice daily co-trimoxazole (SXT) for 3 days (4 mg/kg trimethoprim plus 20 mg/kg sulfamethoxazole per dose) or once daily SXT for 5 days (8 mg/kg trimethoprim plus 40 mg/kg sulfamethoxazole per dose). A clinical diagnosis of scabies; tinea of the skin, scalp or nail; and head lice was made on all children. Scabies presence was not confirmed using diagnostic scrapings. In a post-hoc analysis, we determined whether coinfection with scabies had an impact on treatment success for impetigo. RESULTS: Of children randomized to receive treatment for impetigo, 84 of 508 (16.5%) had scabies. The presence of scabies ranged from 14.3% to 20.0% in the 3 treatment groups. Treatment success for impetigo with and without scabies coinfection, independent of the treatment groups, was 75.9% and 86.6%, respectively, absolute difference 10.7% [95% confidence interval (CI): +1% to +21%]. Treatment success for impetigo with and without scabies coinfection in the BPG group was 69.6% and 88.0%, respectively, absolute difference 18.4% (95% CI: -1% to +38%). In the pooled SXT groups, the treatment success for impetigo with and without scabies coinfection was 78.6% and 86.0%, respectively, with absolute difference 7.4% (95% CI: -4% to +18%). Treatment success in the pooled SXT group with scabies (78.6%) was higher than in the BPG group (69.6%) with scabies, absolute difference 9.0% (95% CI: +0.1% to +18%). Prediction of treatment success for impetigo is dependent on the presence or absence of scabies and for scabies coinfected impetigo it was higher in the group treated with SXT. CONCLUSIONS: The burden of scabies in an impetigo trial for Indigenous children was high. Treatment success for scabies coinfection was lower than for impetigo overall, with a higher success seen in the SXT group than the BPG group. PMID- 26599570 TI - Looking beyond patients: Can parents' quality of life predict asthma control in children? AB - BACKGROUND: Social and family factors may influence the probability of achieving asthma control in children. Parents' quality of life has been insufficiently explored as a predictive factor linked to the probability of achieving disease control in asthmatic children. OBJECTIVE: Determine whether the parents' quality of life predicts medium-term asthma control in children. METHODS: Longitudinal study of children between 4 and 14 years of age, with active asthma. The parents' quality of life was evaluated using the specific IFABI-R instrument, in which scores were higher for poorer quality of life. Its association with asthma control measures in the child 16 weeks later was analyzed using multivariate methods, adjusting the effect for disease, child and family factors. RESULTS: The data from 452 children were analyzed (median age 9.6 years, 63.3% males). The parents' quality of life was predictive for asthma control; each point increase on the initial IFABI-R score was associated with an adjusted odds ratio (95% confidence interval) of 0.56 (0.37-0.86) for good control of asthma on the second visit, 2.58 (1.62-4.12) for asthma exacerbation, 2.12 (1.33-3.38) for an unscheduled visit to the doctor, and 2.46 (1.18-5.13) for going to the emergency room. The highest quartile for the IFABI-R score had a sensitivity of 34.5% and a specificity of 82.2% to predict poorly controlled asthma. CONCLUSIONS: Parents' poorer quality of life is related to poor, medium-term asthma control in children. Assessing the parents' quality of life could aid disease management decisions. Pediatr Pulmonol. 2016;51:670-677. (c) 2015 Wiley Periodicals, Inc. PMID- 26599571 TI - MicroRNA-203 Is a Prognostic Indicator in Bladder Cancer and Enhances Chemosensitivity to Cisplatin via Apoptosis by Targeting Bcl-w and Survivin. AB - Resistance to cisplatin-based chemotherapy is a major cause of treatment failure in advanced bladder cancer (BC) patients. There is increasing evidence that microRNAs are involved in the development and progression of BC. However, little is known about the function of microRNAs in predicting the effect of adjuvant chemotherapy on BC survival and regulating response to cisplatin. To address this issue, we employed RT-qPCR to evaluate the clinical significance of miR-203 expression in 108 tissues of BC patients receiving cisplatin-based adjuvant chemotherapy, and performed in vitro studies to explore chemotherapeutic sensitivity to cisplatin in miR-203 overexpressing BC cells. We found miR-203 levels were significantly lower in BC progression group than non-progression group (P<0.001). ROC curve analysis illustrated miR-203 could significantly distinguish progressed patients from those without progression (P<0.001), yielding an area under the ROC curve of 0.839 (95% CI, 0.756-0.903). Moreover, low miR-203 expression correlated with shortened progression free survival (PFS) and overall survival (OS) of BC patients, and was an independent prognostic factor. Overexpression of miR-203 in 5637 and T24 BC cells could decrease cell viability, enhance cisplatin cytotoxicity, and promote apoptosis. Western blotting and luciferase reporter assay showed Bcl-w and Survivin were direct downstream targets of miR-203. There was also a significant inverse association between miR-203 and Bcl-w or Survivin expression in BC tissues (r = -0.781, 0.740, both P<0.001). In conclusion, decreased miR-203 predicts progression and poor prognosis for BC patients treated with cisplatin-based chemotherapy while miR-203 overexpression can enhance cisplatin sensitization by promoting apoptosis via directly targeting Bcl-w and Survivin. PMID- 26599572 TI - Diversity and Interactions of Wood-Inhabiting Fungi and Beetles after Deadwood Enrichment. AB - Freshly cut beech deadwood was enriched in the canopy and on the ground in three cultural landscapes in Germany (Swabian Alb, Hainich-Dun, Schorfheide-Chorin) in order to analyse the diversity, distribution and interaction of wood-inhabiting fungi and beetles. After two years of wood decay 83 MOTUs (Molecular Operational Taxonomic Units) from 28 wood samples were identified. Flight Interception Traps (FITs) installed adjacent to the deadwood enrichments captured 29.465 beetles which were sorted to 566 species. Geographical 'region' was the main factor determining both beetle and fungal assemblages. The proportions of species occurring in all regions were low. Statistic models suggest that assemblages of both taxa differed between stratum and management praxis but their strength varied among regions. Fungal assemblages in Hainich-Dun, for which the data was most comprehensive, discriminated unmanaged from extensively managed and age class forests (even-aged timber management) while canopy communities differed not from those near the ground. In contrast, the beetle assemblages at the same sites showed the opposite pattern. We pursued an approach in the search for fungus beetle associations by computing cross correlations and visualize significant links in a network graph. These correlations can be used to formulate hypotheses on mutualistic relationships for example in respect to beetles acting as vectors of fungal spores. PMID- 26599573 TI - Identification of optimal parameter combinations for the emergence of bistability. AB - Bistability underlies cellular memory and maintains alternative differentiation states. Bistability can emerge only if its parameter range is either physically realizable or can be enlarged to become realizable. We derived a general rule and showed that the bistable range of a reaction parameter is maximized by a pair of other parameters in any gene regulatory network provided they satisfy a general condition. The resulting analytical expressions revealed whether or not such reaction pairs are present in prototypical positive feedback loops. They are absent from the feedback loop enclosed by protein dimers but present in both the toggle-switch and the feedback circuit inhibited by sequestration. Sequestration can generate bistability even at narrow feedback expression range at which cooperative binding fails to do so, provided inhibition is set to an optimal value. These results help to design bistable circuits and cellular reprogramming and reveal whether bistability is possible in gene networks in the range of realistic parameter values. PMID- 26599574 TI - Next-generation re-sequencing of genes involved in increased platelet reactivity in diabetic patients on acetylsalicylic acid. AB - The objective of this study was to investigate whether rare missense genetic variants in several genes related to platelet functions and acetylsalicylic acid (ASA) response are associated with the platelet reactivity in patients with diabetes type 2 (T2D) on ASA therapy. Fifty eight exons and corresponding introns of eight selected genes, including PTGS1, PTGS2, TXBAS1, PTGIS, ADRA2A, ADRA2B, TXBA2R, and P2RY1 were re-sequenced in 230 DNA samples from T2D patients by using a pooled PCR amplification and next-generation sequencing by Illumina HiSeq2000. The observed non-synonymous variants were confirmed by individual genotyping of 384 DNA samples comprising of the individuals from the original discovery pools and additional verification cohort of 154 ASA-treated T2DM patients. The association between investigated phenotypes (ASA induced changes in platelets reactivity by PFA-100, VerifyNow and serum thromboxane B2 level [sTxB2]), and accumulation of rare missense variants (genetic burden) in investigated genes was tested using statistical collapsing tests. We identified a total of 35 exonic variants, including 3 common missense variants, 15 rare missense variants, and 17 synonymous variants in 8 investigated genes. The rare missense variants exhibited statistically significant difference in the accumulation pattern between a group of patients with increased and normal platelet reactivity based on PFA-100 assay. Our study suggests that genetic burden of the rare functional variants in eight genes may contribute to differences in the platelet reactivity measured with the PFA-100 assay in the T2DM patients treated with ASA. PMID- 26599575 TI - Peripheral and Hepatic Vein Cytokine Levels in Correlation with Non-Alcoholic Fatty Liver Disease (NAFLD)-Related Metabolic, Histological, and Haemodynamic Features. AB - BACKGROUND: Haemodynamic impairment, inflammatory mediators and glucose metabolism disturbances have been implicated in the pathogenesis of Non-Alcoholic Fatty Liver Disease (NAFLD). AIM: To investigate the cytokine profile in NAFLD patients in peripheral (P) and hepatic venous (HV) blood and to compare with histology, haemodynamic and metabolic parameters. METHODS: 40 obese patients with an indication for a transjugular liver biopsy were enrolled. Besides an extended liver and metabolic work-up, interleukin (IL) 1B, IL4, IL6, IL10, IL23, tumour necrosis factor (TNF) alpha and interferon (INF) gamma were measured in plasma obtained from P and HV blood by means of multiplex immunoassay. The T helper (Th)1/Th2, the macrophage M1/M2 and the IL10/IL17a ratios were calculated. RESULTS: A decrease of the P-IL10/IL17-ratio and an increase of the P-M1/M2-ratio (p<0.05) were observed in NASH versus no-NASH patients. A P-M1/M2-ratio increase was detected also in patients with portal hypertension in comparison with patients without it (p<0.05). Moreover diabetic patients showed an increase of the P-Th1/Th2-ratio in comparison with non-diabetic ones (p<0.05). The P-M1/M2 ratio positively correlated with steatosis grade (r = 0.39, p = 0.02) and insulin (r = 0.47, p = 0.003). The HV-M1/M2 ratio positively correlated with fasting insulin and Hepatic Venous Pressure Gradient (r = 0.47, p = 0.003). IL6 correlated with the visceral fat amount (r = 0.36, p = 0.02). The P- and HV IL10/IL17 ratios negatively correlated with fasting insulin (respectively r = 0.4, p = 0.005 and r = 0.4, p = 0.01). CONCLUSIONS: A proinflammatory cytokine state is associated with more disturbed metabolic, histological, and haemodynamic features in NAFLD obese patients. An increase of the M1/M2 ratio and a decrease of the IL10/IL17 ratio play a key role in this process. PMID- 26599576 TI - Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD). AB - BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed and treated psychiatric disorders in childhood. Typically, children with ADHD find it difficult to pay attention, they are hyperactive and impulsive.Methylphenidate is the drug most often prescribed to treat children and adolescents with ADHD but, despite its widespread use, this is the first comprehensive systematic review of its benefits and harms. OBJECTIVES: To assess the beneficial and harmful effects of methylphenidate for children and adolescents with ADHD. SEARCH METHODS: In February 2015 we searched six databases (CENTRAL, Ovid MEDLINE, EMBASE, CINAHL, PsycINFO, Conference Proceedings Citations Index), and two trials registers. We checked for additional trials in the reference lists of relevant reviews and included trials. We contacted the pharmaceutical companies that manufacture methylphenidate to request published and unpublished data. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) comparing methylphenidate versus placebo or no intervention in children and adolescents aged 18 years and younger with a diagnosis of ADHD. At least 75% of participants needed to have an intellectual quotient of at least 70 (i.e. normal intellectual functioning). Outcomes assessed included ADHD symptoms, serious adverse events, non-serious adverse events, general behaviour and quality of life. DATA COLLECTION AND ANALYSIS: Seventeen review authors participated in data extraction and risk of bias assessment, and two review authors independently performed all tasks. We used standard methodological procedures expected within Cochrane. Data from parallel-group trials and first period data from cross-over trials formed the basis of our primary analyses; separate analyses were undertaken using post-cross-over data from cross-over trials. We used Trial Sequential Analyses to control for type I (5%) and type II (20%) errors, and we assessed and downgraded evidence according to the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach for high risk of bias, imprecision, indirectness, heterogeneity and publication bias. MAIN RESULTS: The studies.We included 38 parallel-group trials (5111 participants randomised) and 147 cross-over trials (7134 participants randomised). Participants included individuals of both sexes, at a boys-to-girls ratio of 5:1, and participants' ages ranged from 3 to 18 years across most studies (in two studies ages ranged from 3 to 21 years). The average age across all studies was 9.7 years. Most participants were from high-income countries.The duration of methylphenidate treatment ranged from 1 to 425 days, with an average duration of 75 days. Methylphenidate was compared to placebo (175 trials) or no intervention (10 trials). Risk of Bias.All 185 trials were assessed to be at high risk of bias. Primary outcomes. Methylphenidate may improve teacher-rated ADHD symptoms (standardised mean difference (SMD) -0.77, 95% confidence interval (CI) -0.90 to 0.64; 19 trials, 1698 participants; very low-quality evidence). This corresponds to a mean difference (MD) of -9.6 points (95% CI -13.75 to -6.38) on the ADHD Rating Scale (ADHD-RS; range 0 to 72 points; DuPaul 1991a). A change of 6.6 points on the ADHD-RS is considered clinically to represent the minimal relevant difference. There was no evidence that methylphenidate was associated with an increase in serious (e.g. life threatening) adverse events (risk ratio (RR) 0.98, 95% CI 0.44 to 2.22; 9 trials, 1532 participants; very low-quality evidence). The Trial Sequential Analysis-adjusted intervention effect was RR 0.91 (CI 0.02 to 33.2). SECONDARY OUTCOMES: Among those prescribed methylphenidate, 526 per 1000 (range 448 to 615) experienced non-serious adverse events, compared with 408 per 1000 in the control group. This equates to a 29% increase in the overall risk of any non-serious adverse events (RR 1.29, 95% CI 1.10 to 1.51; 21 trials, 3132 participants; very low-quality evidence). The Trial Sequential Analysis-adjusted intervention effect was RR 1.29 (CI 1.06 to 1.56). The most common non-serious adverse events were sleep problems and decreased appetite. Children in the methylphenidate group were at 60% greater risk for trouble sleeping/sleep problems (RR 1.60, 95% CI 1.15 to 2.23; 13 trials, 2416 participants), and 266% greater risk for decreased appetite (RR 3.66, 95% CI 2.56 to 5.23; 16 trials, 2962 participants) than children in the control group.Teacher-rated general behaviour seemed to improve with methylphenidate (SMD -0.87, 95% CI -1.04 to 0.71; 5 trials, 668 participants; very low-quality evidence).A change of seven points on the Child Health Questionnaire (CHQ; range 0 to 100 points; Landgraf 1998) has been deemed a minimal clinically relevant difference. The change reported in a meta-analysis of three trials corresponds to a MD of 8.0 points (95% CI 5.49 to 10.46) on the CHQ, which suggests that methylphenidate may improve parent-reported quality of life (SMD 0.61, 95% CI 0.42 to 0.80; 3 trials, 514 participants; very low-quality evidence). AUTHORS' CONCLUSIONS: The results of meta-analyses suggest that methylphenidate may improve teacher-reported ADHD symptoms, teacher-reported general behaviour, and parent-reported quality of life among children and adolescents diagnosed with ADHD. However, the low quality of the underpinning evidence means that we cannot be certain of the magnitude of the effects. Within the short follow-up periods typical of the included trials, there is some evidence that methylphenidate is associated with increased risk of non serious adverse events, such as sleep problems and decreased appetite, but no evidence that it increases risk of serious adverse events.Better designed trials are needed to assess the benefits of methylphenidate. Given the frequency of non serious adverse events associated with methylphenidate, the particular difficulties for blinding of participants and outcome assessors point to the advantage of large, 'nocebo tablet' controlled trials. These use a placebo-like substance that causes adverse events in the control arm that are comparable to those associated with methylphenidate. However, for ethical reasons, such trials should first be conducted with adults, who can give their informed consent.Future trials should publish depersonalised individual participant data and report all outcomes, including adverse events. This will enable researchers conducting systematic reviews to assess differences between intervention effects according to age, sex, comorbidity, type of ADHD and dose. Finally, the findings highlight the urgent need for large RCTs of non-pharmacological treatments. PMID- 26599577 TI - Towards a detailed anthropometric body characterization using the Microsoft Kinect. AB - Anthropometry has been widely used in different fields, providing relevant information for medicine, ergonomics and biometric applications. However, the existent solutions present marked disadvantages, reducing the employment of this type of evaluation. Studies have been conducted in order to easily determine anthropometric measures considering data provided by low-cost sensors, such as the Microsoft Kinect. In this work, a methodology is proposed and implemented for estimating anthropometric measures considering the information acquired with this sensor. The measures obtained with this method were compared with the ones from a validation system, Qualisys. Comparing the relative errors determined with state of-art references, for some of the estimated measures, lower errors were verified and a more complete characterization of the whole body structure was achieved. PMID- 26599578 TI - Mechanisms of Chronic Obstructive Pulmonary Disease Exacerbations. AB - Chronic obstructive pulmonary disease (COPD) exacerbations are important events that contribute to worsening health status, disease progression, and mortality. They are mainly triggered by respiratory viruses (especially rhinovirus, the cause of the common cold), but airway bacteria are also involved in their pathogenesis. Exacerbations are associated with both airway and systemic inflammation and, this is mainly neutrophilic in origin. Some patients are especially prone to develop exacerbations, and these have been identified as a high-risk group with increased airway inflammation and greater disease progression. Management of acute exacerbations involves therapy with oral corticosteroids and/or antibiotics, and new therapies are needed. A number of interventions may prevent exacerbations, including vaccination, long-acting bronchodilators, antiinflammatory agents, and long-term antibiotic therapy. Understanding of the pathophysiological mechanisms of COPD exacerbations is important to develop novel therapies. PMID- 26599579 TI - Influence of glutamine synthetase gene polymorphisms on the development of hyperammonemia during valproic acid-based therapy. AB - PURPOSE: Valproic acid (VPA), which is widely used to treat epilepsy, migraine, and bipolar disorder, can causes severe hyperammonemia. However, the mechanism responsible for this adverse effect is not readily apparent. We previously reported that phenytoin coadministration is a strong risk factor for the development of hyperammonemia during VPA-based therapy. In this study, we focused on glutamine synthetase, which catalyzes the synthesis of glutamine from glutamate and ammonia and examined the association with the development of hyperammonemia during VPA-based therapy. METHODS: For this study, we recruited 202 Japanese pediatric patients having epilepsy. We selected three polymorphisms (rs10911070, rs10797771, and rs10911021) in the glutamine synthetase (GLUL) gene. Hyperammonemia was defined as a plasma ammonia level exceeding 200 or 170 MUg/dL. We evaluated the association between the development of hyperammonemia during VPA based therapy and the patient characteristics, including three GLUL polymorphisms. RESULTS: The number of patients who developed hyperammonemia during VPA-based therapy was 20 (9.9%) using the 200 MUg/dL cutoff value and 30 (14.9%) using the 170 MUg/dL cutoff value. Using a multivariate logistic regression analysis, the GLUL rs10797771 polymorphism and phenytoin coadministration in the 200 MUg/dL cutoff value, and female in addition to two factors in the 170 MUg/dL cutoff value, had significant associations with a plasma ammonia level elevation during VPA-based therapy. CONCLUSION: Phenytoin coadministration, GLUL rs10797771 polymorphism in the 200MUg/dL cutoff value, and female in addition to two factors in the 170MUg/dL cutoff value, are independent risk factors for elevated plasma ammonia levels during VPA-based therapy. PMID- 26599580 TI - Highly Sensitive and Selective Photoelectrochemical Biosensor for Hg(2+) Detection Based on Dual Signal Amplification by Exciton Energy Transfer Coupled with Sensitization Effect. AB - A highly sensitive and selective photoelectrochemical (PEC) biosensor for Hg(2+) detection was developed on the basis of the synergistic effect of exciton energy transfer (EET) between CdS quantum dots (QDs) and Au nanoparticles (NPs) coupled with sensitization of rhodamine 123 (Rh123) for signal amplification. First, the TiO2/CdS hybrid structure obtained by depositing CdS QDs on TiO2 film was employed as a matrix for immobilizing probe DNA (pDNA). Next, Rh123 was introduced into the pDNA terminal, and then Au NP labeled target DNA (Au-tDNA) was hybridized with pDNA to form a rod-like double helix structure. The detection of Hg(2+) was based on a conformational change of the pDNA after incubating with Hg(2+). In the absence of Hg(2+), Rh123 was located away from the electrode surface due to the DNA hybridization, leading to inhibition of the sensitization effect, and meanwhile, the occurrence of EET between CdS QDs and Au NPs resulted in a photocurrent decrease. However, after incubating with Hg(2+), the rod-like double helix was disrupted, and the energy transfer was broken. In this case, the photocurrent recovered, and meanwhile, the folded pDNA made the labeled Rh123 move closer to the electrode surface, leading to the formation of the sensitization structure, which evidently increased the photocurrent intensity. The sensitivity of the biosensor for Hg(2+) detection was greatly enhanced for the dual signal amplification strategy. The linear range was 10 fM to 200 nM, with a detection limit of 3.3 fM. This biosensor provides a promising new platform for detecting various heavy metal ions at ultralow levels. PMID- 26599581 TI - Total inpatient treatment costs in patients with severe burns: towards a more accurate reimbursement model. AB - PRINCIPLES: Reimbursement systems have difficulties depicting the actual cost of burn treatment, leaving care providers with a significant financial burden. Our aim was to establish a simple and accurate reimbursement model compatible with prospective payment systems. METHODS: A total of 370 966 electronic medical records of patients discharged in 2012 to 2013 from Swiss university hospitals were reviewed. A total of 828 cases of burns including 109 cases of severe burns were retained. Costs, revenues and earnings for severe and nonsevere burns were analysed and a linear regression model predicting total inpatient treatment costs was established. RESULTS: The median total costs per case for severe burns was tenfold higher than for nonsevere burns (179 949 CHF [167 353 EUR] vs 11 312 CHF [10 520 EUR], interquartile ranges 96 782-328 618 CHF vs 4 874-27 783 CHF, p <0.001). The median of earnings per case for nonsevere burns was 588 CHF (547 EUR) (interquartile range -6 720 - 5 354 CHF) whereas severe burns incurred a large financial loss to care providers, with median earnings of -33 178 CHF (30 856 EUR) (interquartile range -95 533 - 23 662 CHF). Differences were highly significant (p <0.001). Our linear regression model predicting total costs per case with length of stay (LOS) as independent variable had an adjusted R2 of 0.67 (p <0.001 for LOS). CONCLUSIONS: Severe burns are systematically underfunded within the Swiss reimbursement system. Flat-rate DRG-based refunds poorly reflect the actual treatment costs. In conclusion, we suggest a reimbursement model based on a per diem rate for treatment of severe burns. PMID- 26599582 TI - Validation of a Taiwanese Version of the Burn-Specific Health Scale-Brief. AB - The purposes of this study were to translate the brief version of the Burn Specific Health Scale (BSHS-B) into traditional Chinese (Taiwanese) and to evaluate its psychometric properties to measure quality of life of burn patients in Taiwan. The BSHS-B-Taiwanese was translated and reviewed by an expert committee. Patients were invited to participate in this study while they visited the outpatient burn clinic. One hundred and eight burn patients participated in this study by filling out the BSHS-B-Taiwanese and SF-36 Taiwanese version. Forty one of 108 patients completed a retest on the BSHS-B-Taiwanese. A ceiling effect was found for psychosocial functioning and all domains of the BSHS-B-Taiwanese. Internal consistency shown by Cronbach's alpha was all above 0.70 except for the interpersonal relationships domain. Of these, Cronbach's alpha >=0.9 was found in the work, heat sensitivity, and body image domains. Test-retest reliabilities ranged from 0.74 to 0.93 except for the simple activity domain. As for the criterion validity, most of the BSHS-B-Taiwanese version was shown to have fair to moderate correlations with the SF-36-Taiwanese in corresponding domains. The discriminant validity of the BSHS-B-Taiwanese was demonstrated by significant score differences in several domains between subgroups of different severity regarding length of hospital stay and TBSA. Our finding suggests that the BSHS Taiwanese is generally reliable and valid. A shorter version of BSHS-B-Taiwanese together with a generic instrument, such as SF-36, can be used to measure the quality of life of burn patients in Taiwan. PMID- 26599583 TI - Interactive Effect of UVR and Phosphorus on the Coastal Phytoplankton Community of the Western Mediterranean Sea: Unravelling Eco-Physiological Mechanisms. AB - Some of the most important effects of global change on coastal marine systems include increasing nutrient inputs and higher levels of ultraviolet radiation (UVR, 280-400 nm), which could affect primary producers, a key trophic link to the functioning of marine food webs. However, interactive effects of both factors on the phytoplankton community have not been assessed for the Mediterranean Sea. An in situ factorial experiment, with two levels of ultraviolet solar radiation (UVR+PAR vs. PAR) and nutrients (control vs. P-enriched), was performed to evaluate single and UVR*P effects on metabolic, enzymatic, stoichiometric and structural phytoplanktonic variables. While most phytoplankton variables were not affected by UVR, dissolved phosphatase (APAEX) and algal P content increased in the presence of UVR, which was interpreted as an acclimation mechanism of algae to oligotrophic marine waters. Synergistic UVR*P interactive effects were positive on photosynthetic variables (i.e., maximal electron transport rate, ETRmax), but negative on primary production and phytoplankton biomass because the pulse of P unmasked the inhibitory effect of UVR. This unmasking effect might be related to greater photodamage caused by an excess of electron flux after a P pulse (higher ETRmax) without an efficient release of carbon as the mechanism to dissipate the reducing power of photosynthetic electron transport. PMID- 26599584 TI - Metamaterial-Embedded Low SAR PIFA for Cellular Phone. AB - A metamaterial-embedded planar inverted-F antenna (PIFA) is proposed in this study for cellular phone applications. A dual-band PIFA is designed to operate both GSM 900 MHz and DCS 1800 MHz. The ground plane of a conventional PIFA is modified using a planar one-dimensional metamaterial array. The investigation is performed using the Finite Integration Technique (FIT) of CST Microwave Studio. The performance of the developed antenna was measured in an anechoic chamber. The specific absorption rate (SAR) values are calculated considering two different holding positions: cheek and tilt. The SAR values are measured using COMOSAR measurement system. Good agreement is observed between the simulated and measured data. The results indicate that the proposed metamaterial-embedded antenna produces significantly lower SAR in the human head compared to the conventional PIFA. Moreover, the modified antenna substrate leads to slight improvement of the antenna performances. PMID- 26599585 TI - Reactivity of Dimeric Tetrazirconium(IV) Wells-Dawson Polyoxometalate toward Dipeptide Hydrolysis Studied by a Combined Experimental and Density Functional Theory Approach. AB - Detailed kinetic studies on the hydrolysis of glycylglycine (Gly-Gly) in the presence of the dimeric tetrazirconium(IV)-substituted Wells-Dawson-type polyoxometalate Na14[Zr4(P2W16O59)2(MU3-O)2(OH)2(H2O)4] . 57H2O (1) were performed by a combination of (1)H, (13)C, and (31)P NMR spectroscopies. The catalyst was shown to be stable under a broad range of reaction conditions. The effect of pD on the hydrolysis of Gly-Gly showed a bell-shaped profile with the fastest hydrolysis observed at pD 7.4. The observed rate constant for the hydrolysis of Gly-Gly at pD 7.4 and 60 degrees C was 4.67 * 10(-7) s(-1), representing a significant acceleration as compared to the uncatalyzed reaction. (13)C NMR data were indicative for coordination of Gly-Gly to 1 via its amide oxygen and amine nitrogen atoms, resulting in a hydrolytically active complex. Importantly, the effective hydrolysis of a series of Gly-X dipeptides with different X side chain amino acids in the presence of 1 was achieved, and the observed rate constant was shown to be dependent on the volume, chemical nature, and charge of the X amino acid side chain. To give a mechanistic explanation of the observed catalytic hydrolysis of Gly-Gly, a detailed quantum-chemical study was performed. The theoretical results confirmed the nature of the experimentally suggested binding mode in the hydrolytically active complex formed between Gly Gly and 1. To elucidate the role of 1 in the hydrolytic process, both the uncatalyzed and the polyoxometalate-catalyzed reactions were examined. In the rate-determining step of the uncatalyzed Gly-Gly hydrolysis, a carboxylic oxygen atom abstracts a proton from a solvent water molecule and the nascent OH nucleophile attacks the peptide carbon atom. Analogous general-base activity of the free carboxylic group was found to take place also in the case of polyoxometalate-catalyzed hydrolysis as the main catalytic effect originates from the -C?O...Zr(IV) binding. PMID- 26599586 TI - Insulin-like growth factor I promotes oocyte maturation through increasing the expression and phosphorylation of epidermal growth factor receptor in the zebrafish ovary. AB - The resumption of oocyte meiosis is a critical step for the progression of oocyte development, which requires an intimate collaboration of a variety of hormones and growth factors. Insulin-like growth factor I (IGF-I) and epidermal growth factor (EGF) family are well recognized to promote oocyte maturation. However, the mechanism by which they coordinate this process remains unknown. The present study demonstrated that IGF-I can increase egfr mRNA and protein levels in follicle cell culture or intact follicles. This stimulation can be significantly inhibited by IGF-IR specific inhibitor, NVP-ADW742. The inhibitors against phosphatidylinositol-3-kinase (PI3K), phosphoinositide-dependent protein kinase 1 (PDK1) and Akt also dramatically abolished IGF-I-induced egfr expression, suggesting that the classical PI3K/Akt pathway mediated the action of IGF-I in this regulation. We further found that not only was the protein level of Egfr increased, but also the phosphorylation level was enhanced by IGF-I. Unlike egfr, IGF-I failed to stimulate the expression of Egf-like ligands whereas decreased the level of protein-tyrosine phosphatase, receptor type, kappa (ptprk), a protein tyrosine phosphatase. The oocyte maturation assay further confirmed that IGF-I initiates this regulation through its cognate receptor in the follicle cells. Taken together, IGF-I promoted oocyte maturation, in part at least, through Egf-like ligands/Egfr pathway. This study sheds light on the cross-talk between two important growth factors in the zebrafish ovary and the mechanism underlying the IGF-I induction on oocyte maturation. PMID- 26599587 TI - Perfluoroalkyl substances in aquatic environment-comparison of fish and passive sampling approaches. AB - The concentrations of seven perfluoroalkyl substances (PFASs) were investigated in 36 European chub (Squalius cephalus) individuals from six localities in the Czech Republic. Chub muscle and liver tissue were analysed at all sampling sites. In addition, analyses of 16 target PFASs were performed in Polar Organic Chemical Integrative Samplers (POCISs) deployed in the water at the same sampling sites. We evaluated the possibility of using passive samplers as a standardized method for monitoring PFAS contamination in aquatic environments and the mutual relationships between determined concentrations. Only perfluorooctane sulphonate was above the LOQ in fish muscle samples and 52% of the analysed fish individuals exceeded the Environmental Quality Standard for water biota. Fish muscle concentration is also particularly important for risk assessment of fish consumers. The comparison of fish tissue results with published data showed the similarity of the Czech results with those found in Germany and France. However, fish liver analysis and the passive sampling approach resulted in different fish exposure scenarios. The total concentration of PFASs in fish liver tissue was strongly correlated with POCIS data, but pollutant patterns differed between these two matrices. The differences could be attributed to the metabolic activity of the living organism. In addition to providing a different view regarding the real PFAS cocktail to which the fish are exposed, POCISs fulfil the Three Rs strategy (replacement, reduction, and refinement) in animal testing. PMID- 26599588 TI - Evaluation of Chronic Obstructive Pulmonary Disease (COPD) attributed to atmospheric O3, NO2, and SO2 using Air Q Model (2011-2012 year). AB - Chronic obstructive pulmonary disease (COPD) is an important disease worldwide characterized by chronically poor airflow. The economic burden of COPD on any society can be enormous if not managed. We applied the approach proposed by the World Health Organization (WHO) using the AirQ2.2.3 software developed by the WHO European Center for Environment and Health on air pollutants in Tabriz (Iran) (2011-2012 year). A 1h average of concentrations of ozone (O3), daily average concentrations of nitrogen dioxide (NO2) and sulfur dioxide (SO2) were used to assess human exposure and health effect in terms of attributable proportion of the health outcome and annual number of excess cases of Hospital Admissions for COPD (HA COPD). The results of this study showed that 2% (95% CI: 0.8-3.1%) of HA COPD were attributed to O3 concentrations over 10 MUg/m(3). In addition, 0.7 % (95% CI: 0.1-1.8%) and 0.5% (95% CI: 0-1%) of HA COPD were attributed to NO2 and SO2 concentrations over 10 MUg/m(3) respectively. In this study, we have shown that O3, NO2 and SO2 have a significant impact on COPD hospitalization. Given these results the policy decisions are needed in order to reduce the chronic pulmonary diseases caused by air pollution and furthermore better quantification studies are recommended. PMID- 26599589 TI - Humidity: A review and primer on atmospheric moisture and human health. AB - Research examining associations between weather and human health frequently includes the effects of atmospheric humidity. A large number of humidity variables have been developed for numerous purposes, but little guidance is available to health researchers regarding appropriate variable selection. We examine a suite of commonly used humidity variables and summarize both the medical and biometeorological literature on associations between humidity and human health. As an example of the importance of humidity variable selection, we correlate numerous hourly humidity variables to daily respiratory syncytial virus isolates in Singapore from 1992 to 1994. Most water-vapor mass based variables (specific humidity, absolute humidity, mixing ratio, dewpoint temperature, vapor pressure) exhibit comparable correlations. Variables that include a thermal component (relative humidity, dewpoint depression, saturation vapor pressure) exhibit strong diurnality and seasonality. Humidity variable selection must be dictated by the underlying research question. Despite being the most commonly used humidity variable, relative humidity should be used sparingly and avoided in cases when the proximity to saturation is not medically relevant. Care must be taken in averaging certain humidity variables daily or seasonally to avoid statistical biasing associated with variables that are inherently diurnal through their relationship to temperature. PMID- 26599590 TI - Laboratory simulation system, using Carcinus maenas as the model organism, for assessing the impact of CO2 leakage from sub-seabed injection and storage. AB - The capture and storage of CO2 in sub-seabed geological formations has been proposed as one of the potential options to decrease atmospheric CO2 concentrations in order to mitigate the abrupt and irreversible consequences of climate change. However, it is possible that CO2 leakages could occur during the injection and sequestration procedure, with significant repercussions for the marine environment. We investigate the effects of acidification derived from possible CO2 leakage events on the European green crab, Carcinus maenas. To this end, a lab-scale experiment involving direct release of CO2 was conducted at pH values between 7.7 and 6.15. Female crabs were exposed for 10 days to sediment collected from two different coastal areas, one with relatively uncontaminated sediment (RSP) and the other with known contaminated sediment (MZ and ML), under the pre-established seawater pH conditions. Survival rate, histopathological damage and metal (Fe, Mn, Cu, Zn, Cr, Cd and Pb) and As accumulation in gills and hepatopancreas tissue were employed as endpoints. In addition, the obtained results were compared with the results of the physico-chemical characterization of the sediments, which included the determination of the metals Fe, Mn, Cu, Zn, Cr, Pb and Cd, the metalloid As, certain polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs), as well as nonchemical sediment properties (grain size, organic carbon and total organic matter). Significant associations were observed between pH and the histological damage. Concentrations of Fe, Mn, Cr, Pb, Cd and PAHs in sediment, presented significant negative correlations with the damage to gills and hepatopancreas, and positive correlations with metal accumulation in both tissues. The results obtained in this study reveal the importance of sediment properties in the biological effects caused by possible CO2 leakage. However, a clear pattern was not observed between metal accumulation in tissues and pH reduction. Animals' avoidance behavior and degree of tolerance to acidification are confounding factors for assessing metal bioaccumulation. Further research is required to find a suitable assay that would allow us to predict the risk to environmental health of possible negative side effects of metal mobility derived from CO2 leakage during its injection and storage in sub seabed formations. PMID- 26599591 TI - Identification of mycotoxins by UHPLC-QTOF MS in airborne fungi and fungi isolated from industrial paper and antique documents from the Archive of Bogota. AB - Mold deterioration of historical documents in archives and libraries is a frequent and complex phenomenon that may have important economic and cultural consequences. In addition, exposure to toxic fungal metabolites might produce health problems. In this work, samples of broths of fungal species isolated from the documentary material and from indoor environmental samples of the Archive of Bogota have been analyzed to investigate the presence of mycotoxins. High resolution mass spectrometry made possible to search for a large number of mycotoxins, even without reference standards available at the laboratory. For this purpose, a screening strategy based on ultra-high pressure liquid chromatography coupled to quadrupole-time of flight mass spectrometry (UHPLC-QTOF MS) under MS(E) mode was applied. A customized home-made database containing elemental composition for around 600 mycotoxins was compiled. The presence of the (de)protonated molecule measured at its accurate mass was evaluated in the samples. When a peak was detected, collision induced dissociation fragments and characteristic isotopic ions were also evaluated and used for tentative identification, based on structure compatibility and comparison with literature data (if existing). Up to 44 mycotoxins were tentatively identified by UHPLC-QTOF MS. 34 of these tentative compounds were confirmed by subsequent analysis using a targeted LC-MS/MS method, supporting the strong potential of QTOF MS for identification/elucidation purposes. The presence of mycotoxins in these samples might help to reinforce safety measures for researchers and staff who work on reception, restoration and conservation of archival material, not only at the Archive of Bogota but worldwide. PMID- 26599593 TI - Evaluation of DNA damage induced by norcantharidin in human cultured lymphocytes. AB - Norcantharidin (NCTD) is currently used in the treatment of several cancers such as leukemia, melanoma and hepatoma. The mechanism of action of NCTD is suggested to involve induction of apoptosis of cancer cells via production of reactive oxygen species. In this study, the genotoxic effect of different concentrations of NCTD (1, 10 and 20 MUm) in human lymphocytes was investigated using sister chromatid exchanges (SCEs) and chromosomal aberrations (CAs) assays. The results revealed that NCTD significantly increased the rate of SCEs (p < 0.05) in a dose dependent manner. In addition, NCTD significantly increased the number of high frequency cells (SCEs >= 8, p < 0.05). However, NCTD did not have any significant effect on the rate of CAs (p > 0.05). In addition, no significant differences were detected in the mitotic index or proliferative index at examined doses (up to 20 MUm). In conclusion, NCTD is genotoxic to human cultured lymphocytes as measured by SCE assay. PMID- 26599592 TI - Lack of Association between Oxytocin Receptor (OXTR) Gene Polymorphisms and Alexithymia: Evidence from Patients with Obsessive-Compulsive Disorder. AB - Oxytocin receptor gene single nucleotide polymorphisms have been associated with structural and functional alterations in brain regions, which involve social emotional processing. Therefore, oxytocin receptor gene polymorphisms may contribute to individual differences in alexithymia, which is considered to be a dysfunction of emotional processing. The aim of this study was to evaluate the association between oxytocin receptor gene single nucleotide polymorphisms or haplotypes and alexithymia in patients with obsessive-compulsive disorder. We recruited 355 patients with obsessive-compulsive disorder (234 men, 121 women). Alexithymia was measured by using the Toronto Alexithymia Scale. We performed single-marker and haplotype association analyses with eight single nucleotide polymorphisms (rs237885, rs237887, rs2268490, rs4686301, rs2254298, rs13316193, rs53576, and rs2268498) in the oxytocin receptor gene. There were no significant associations between any of the eight single nucleotide polymorphism of the oxytocin receptor gene and alexithymia. In addition, a six-locus haplotype block (rs237885-rs237887-rs2268490-rs4686301-rs2254298-rs13316193) was not significantly associated with alexithymia. These findings suggest that genetic variations in the oxytocin receptor gene may not explain a significant part of alexithymia in patients with obsessive-compulsive disorder. PMID- 26599594 TI - Can nursing students' confidence levels increase with repeated simulation activities? AB - In 2014, nursing faculty conducted a study with undergraduate nursing students on their satisfaction, confidence, and educational practice levels, as it related to simulation activities throughout the curriculum. The study was a voluntary survey conducted on junior and senior year nursing students. It consisted of 30 items based on the Student Satisfaction and Self-Confidence in Learning and the Educational Practices Questionnaire (Jeffries, 2012). Mean averages were obtained for each of the 30 items from both groups and were compared using T scores for unpaired means. The results showed that 8 of the items had a 95% confidence level and when combined the items were significant for p <.001. The items identified were those related to self-confidence and active learning. Based on these findings, it can be assumed that repeated simulation experiences can lead to an increase in student confidence and active learning. PMID- 26599595 TI - Physiotherapy students' perceptions of learning in clinical practice in Sweden and India. AB - BACKGROUND: It is reasonable to assume that conditions for learning differ between universities and countries. Increased understanding of similarities and differences of student's perceptions of learning environment can be useful in the development of the physiotherapy education as well as of the profession as such. Through international comparisons the benefits and challenges of educational programmes can be made transparent and serve as base for improvement. OBJECTIVE: The objective of this study is to describe and compare physiotherapy students' perceptions of their learning environment in clinical practice in India and Sweden. DESIGN AND SETTING: A questionnaire study was performed, covering physiotherapy students' perceptions of their clinical learning environment, the physiotherapy supervisor within the clinical context, their supervisory relationship and the role of the clinical supervisor at two Universities, Lulea in Sweden and Amity in New Delhi, India. PARTICIPANTS: Undergraduate students at two physiotherapy programmes, in New Delhi, India and in Lulea, Sweden participated in the questionnaire study. RESULTS: In general, both groups had high rankings of their perceptions of the clinical learning environment. The Swedish students ranked individual supervision, participation in meetings, the supervisor as a resource, being a part of the team and giving them valuable feedback higher than the Indian group. The supervisory relationship was equally satisfying in groups, providing valuable feedback and acknowledging equality and mutuality in the relationship. The Indian group ranked the supervisor as a colleague, as a support in learning, and that he/she made them feel comfortable in meetings higher than the Swedish group. CONCLUSIONS: Both groups had high ratings of the supervisor and the clinical learning context Participation at meetings was higher rated in the Swedish and the supervisor as a support in learning higher rated of the Indian students. PMID- 26599597 TI - Influence of Pharmacotherapy on Cognitive Functions in Depression: A Review of the Literature. AB - In addition to irregularities relating to the emotional sphere, the cognitive impairment in depression is a part of the clinical picture of this affective disorder. Some of the cognitive deficits may be associated with the severity of psychopathological symptoms of depression, while others are more established and can also occur during periods of remission. The participation in cognitive functioning of people with depression have a number of factors: the severity of symptoms, concurrent anxiety disorders, gender, age, education, duration of the disease, and number of previous episodes, as well as general somatic health or medication used. The pharmacological treatment may have varying impact on the different areas of cognition. Research on pharmacotherapy for depression and its impact on cognitive functioning continue and are very popular among clinicians and researchers. The relationship between antidepressants and cognitive abilities is always modulated by the type of depressive disorder, neurobiological factors, and demographic variables. This article presents a review of the studies relating to assessment of the effects of various antidepressants on cognitive abilities among patients with depression. PMID- 26599596 TI - A Flexible, Efficient Binomial Mixed Model for Identifying Differential DNA Methylation in Bisulfite Sequencing Data. AB - Identifying sources of variation in DNA methylation levels is important for understanding gene regulation. Recently, bisulfite sequencing has become a popular tool for investigating DNA methylation levels. However, modeling bisulfite sequencing data is complicated by dramatic variation in coverage across sites and individual samples, and because of the computational challenges of controlling for genetic covariance in count data. To address these challenges, we present a binomial mixed model and an efficient, sampling-based algorithm (MACAU: Mixed model association for count data via data augmentation) for approximate parameter estimation and p-value computation. This framework allows us to simultaneously account for both the over-dispersed, count-based nature of bisulfite sequencing data, as well as genetic relatedness among individuals. Using simulations and two real data sets (whole genome bisulfite sequencing (WGBS) data from Arabidopsis thaliana and reduced representation bisulfite sequencing (RRBS) data from baboons), we show that our method provides well calibrated test statistics in the presence of population structure. Further, it improves power to detect differentially methylated sites: in the RRBS data set, MACAU detected 1.6-fold more age-associated CpG sites than a beta-binomial model (the next best approach). Changes in these sites are consistent with known age related shifts in DNA methylation levels, and are enriched near genes that are differentially expressed with age in the same population. Taken together, our results indicate that MACAU is an efficient, effective tool for analyzing bisulfite sequencing data, with particular salience to analyses of structured populations. MACAU is freely available at www.xzlab.org/software.html. PMID- 26599598 TI - Molecular Mechanism of Transcriptional Regulation of Matrix Metalloproteinase-9 in Diabetic Retinopathy. AB - Increase in matrix metalloproteinase-9 (MMP-9) is implicated in retinal capillary cell apoptosis, a phenomenon which precedes the development of diabetic retinopathy. MMP-9 promoter has multiple sites for binding the transcriptional factors, including two for activator protein 1 (AP-1). The binding of AP-1, a heterodimer of c-Jun and c-Fos, is regulated by posttranslational modifications, and in diabetes, deacetylating enzyme, Sirt1, is inhibited. Our aim, is to investigate the molecular mechanism of MMP-9 transcriptional regulation in diabetes. Binding of AP-1 (c-Jun, c-Fos) at the MMP-9 promoter, and AP-1 acetylation were analyzed in retinal endothelial cells incubated in normal or high glucose by chromatin-immunoprecipitation and co-immunoprecipitation respectively. Role of AP-1 in MMP-9 regulation was confirmed by c-Jun or c-Fos siRNAs, and that of its acetylation, by Sirt1 overexpression. In vitro results were validated in the retina from diabetic mice overexpressing Sirt1, and in the retinal microvessels from human donors with diabetic retinopathy. In experimental models, AP-1 binding was increased at the proximal and distal sites of the MMP-9 promoter, and similar phenomenon was confirmed in the retinal microvessels from human donors with diabetic retinopathy. Silencing of AP-1, or overexpression of Sirt1 ameliorated glucose-induced increase in MMP-9 expression and cell apoptosis. Thus, in diabetes, due to Sirt1 inhibition, AP-1 is hyperacetylated, which increases its binding at MMP-9 promoter, and hence, activation of Sirt1 could inhibit the development of diabetic retinopathy by impeding MMP-9-mediated mitochondrial damage. J. Cell. Physiol. 231: 1709-1718, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26599599 TI - Diffusion MRI noise mapping using random matrix theory. AB - PURPOSE: To estimate the spatially varying noise map using a redundant series of magnitude MR images. METHODS: We exploit redundancy in non-Gaussian distributed multidirectional diffusion MRI data by identifying its noise-only principal components, based on the theory of noisy covariance matrices. The bulk of principal component analysis eigenvalues, arising due to noise, is described by the universal Marchenko-Pastur distribution, parameterized by the noise level. This allows us to estimate noise level in a local neighborhood based on the singular value decomposition of a matrix combining neighborhood voxels and diffusion directions. RESULTS: We present a model-independent local noise mapping method capable of estimating the noise level down to about 1% error. In contrast to current state-of-the-art techniques, the resultant noise maps do not show artifactual anatomical features that often reflect physiological noise, the presence of sharp edges, or a lack of adequate a priori knowledge of the expected form of MR signal. CONCLUSIONS: Simulations and experiments show that typical diffusion MRI data exhibit sufficient redundancy that enables accurate, precise, and robust estimation of the local noise level by interpreting the principal component analysis eigenspectrum in terms of the Marchenko-Pastur distribution. Magn Reson Med 76:1582-1593, 2016. (c) 2015 International Society for Magnetic Resonance in Medicine. PMID- 26599600 TI - Nanomechanics of layer-by-layer polyelectrolyte complexes: a manifestation of ionic cross-links and fixed charges. AB - This study investigates the roles of two distinct features of ionically cross linked polyelectrolyte networks - ionic cross-links and fixed charges - in determining their nanomechanical properties. The layer-by-layer assembled poly(allylamine hydrochloride)/poly(acrylic acid) (PAH/PAA) network is used as the model material. The densities of ionic cross-links and fixed charges are modulated through solution pH and ionic strength (IS), and the swelling ratio, elastic and viscoelastic properties are quantified via an array of atomic force microscopy (AFM)-based nanomechanical tools. The roles of ionic cross-links are underscored by the distinctive elastic and viscoelastic nanomechanical characters observed here. First, as ionic cross-links are highly sensitive to solution conditions, the instantaneous modulus, E0, exhibits orders-of-magnitude changes upon pH- and IS-governed swelling, distinctive from the rubber elasticity prediction based on permanent covalent cross-links. Second, ionic cross-links can break and self-re-form, and this mechanism dominates force relaxation of PAH/PAA under a constant indentation depth. In most states, the degree of relaxation is >90%, independent of ionic cross-link density. The importance of fixed charges is highlighted by the unexpectedly more elastic nature of the network despite low ionic cross-link density at pH 2.0, IS 0.01 M. Here, the complex is a net charged, loosely cross-linked, where the degree of relaxation is attenuated to ~50% due to increased elastic contribution arising from fixed charge-induced Donnan osmotic pressure. In addition, this study develops a new method for quantifying the thickness of highly swollen polymer hydrogel films. It also underscores important technical considerations when performing nanomechanical tests on highly rate-dependent polymer hydrogel networks. These results provide new insights into the nanomechanical characters of ionic polyelectrolyte complexes, and lay the ground for further investigation of their unique time dependent properties. PMID- 26599601 TI - Staying Focused On Our Mission: Message From the President. PMID- 26599602 TI - Sex Differences in Airway Remodeling in a Mouse Model of Chronic Obstructive Pulmonary Disease. AB - RATIONALE: After adjustment for the amount of smoking, women have a 50% increased risk of chronic obstructive pulmonary disease (COPD) compared with men. The anatomic basis and/or mechanism(s) of these sex-related differences in COPD are unknown. OBJECTIVES: To characterize the impact of female sex hormones on chronic cigarette smoke-induced airway remodeling and emphysema in a mouse model of COPD. METHODS: Airway remodeling and emphysema were determined morphometrically in male, female, and ovariectomized mice exposed to 6 months of cigarette smoke. Antioxidant- and transforming growth factor (TGF)-beta-related genes were profiled in airway tissues. The selective estrogen receptor modulator tamoxifen was also administered during smoke exposure in a short-term model. Airway wall thickness of male and female human smokers at risk of or with mild COPD was measured using optical coherence tomography. MEASUREMENTS AND MAIN RESULTS: Small airway wall remodeling was increased in female but not male or ovariectomized mice and was associated with increased distal airway resistance, down-regulation of antioxidant genes, increased oxidative stress, and activation of TGF-beta1. These effects were prevented by ovariectomy. Use of tamoxifen as a therapeutic intervention mitigated smoke-induced increase in oxidative stress in female mice. Compared with male human smokers, female human smokers had significantly thicker airway walls. CONCLUSIONS: The excess risk of small airway disease in female mice after chronic smoke exposure was associated with increased oxidative stress and TGF-beta1 signaling and also was related to the effects of female sex hormones. Estrogen receptor antagonism might be of value in reducing oxidative stress in female smokers. PMID- 26599603 TI - Development and Validation of a Sensitive Enzymeimmunoassay for Determination of Plasma Metastin in Mithun (Bos frontalis). AB - Metastin, also known as kisspeptin-10, is a potent stimulator of gonadotropin releasing hormone (GnRH) neurons in the central nervous system. Recently, it has been emerged as a key player in the regulation of reproduction in mammals. Blood concentrations of metastin during different physiological stages in bovine species in general and mithun (Bos frontalis) in particular are not available. Lacking of such information may probably be due to non-availability of simple assay procedure to measure the peptide. Therefore, the objective of this study was to develop and validate a simple and sufficiently sensitive enzyme immunoassay (EIA) for metastin determination in mithun plasma using the biotin streptavidin amplification system and second antibody coating technique. Biotin was coupled to metastin and used to bridge between streptavidin-peroxidase and the immobilized metastin antiserum in the competitive assay. The EIA was conducted directly in 150 MU L of unknown mithun plasma. Metastin standards ranging from 0.01-51.2 ng/150 MU L/well were prepared in hormone-free plasma. The lowest detection limit was 0.07 ng/mL plasma. Plasma volumes for the EIA, viz., 75, 150, and 200 MU L did not influence the shape of standard curve even though a drop in OD450 was seen with higher plasma volumes. A parallelism test was carried out to compare the endogenous mithun metastin with metastin standard used. It showed good parallelism with the metastin standard curve. For the biological validation of the assay, metastin was measured in (a) blood samples collected from 12 pregnant mithun cows during different stages of pregnancy, (b) in blood from seven early pregnant and 12 non-pregnant mithuns, and (c) in follicular fluid obtained from different types of follicle. It was found that the plasma metastin concentrations increased (P < 0.001) from first through last trimester of pregnancy. Plasma metastin levels were much higher (P < 0.001) in early pregnant than non-pregnant cows. Follicular fluid metastin concentrations were found to increase (P < 0.001) as the follicles grow and the highest levels were recorded in preovulatory follicles. In conclusion, a simple, sufficiently sensitive and direct EIA procedure has been developed for the first time to determine metastin levels in mithun. A wide range of metastin concentrations can be detected during different physiological stages in mithun using this metastin EIA procedure. PMID- 26599604 TI - Read-Out of Dynamic Morphogen Gradients on Growing Domains. AB - Quantitative data from the Drosophila wing imaginal disc reveals that the amplitude of the Decapentaplegic (Dpp) morphogen gradient increases continuously. It is an open question how cells can determine their relative position within a domain based on a continuously increasing gradient. Here we show that pre-steady state diffusion-based dispersal of morphogens results in a zone within the growing domain where the concentration remains constant over the patterning period. The position of the zone that is predicted based on quantitative data for the Dpp morphogen corresponds to where the Dpp-dependent gene expression boundaries of spalt (sal) and daughters against dpp (dad) emerge. The model also suggests that genes that are scaling and are expressed at lateral positions are either under the control of a different read-out mechanism or under the control of a different morphogen. The patterning mechanism explains the extraordinary robustness that is observed for variations in Dpp production, and offers an explanation for the dual role of Dpp in controlling patterning and growth. Pre steady-state dynamics are pervasive in morphogen-controlled systems, thus making this a probable general mechanism for the scaled read-out of morphogen gradients in growing developmental systems. PMID- 26599605 TI - Specific chemical modification of bacterial type I dehydroquinase--opportunities for drug discovery. AB - Type I dehydroquinase (DHQ1) is a class I aldolase enzyme that catalyzes the reversible dehydration of 3-dehydroquinic acid to form 3-dehydroshikimic acid by multistep mechanism that involves the formation of Schiff-base species. DHQ1 is present in plants and several bacterial sources but it does not have any counterpart in human cells. It has been suggested that DHQ1 may act as a virulence factor in vivo and therefore a promising target in the search for new antivirulence agents to combat widespread antibiotic resistance. This review covers recent progress in the structure-based design and chemical modifications caused by selective irreversible inhibitors. Computational studies aimed at understanding the experimentally obtained covalent modifications and inhibitory potencies of these inhibitors are also described. PMID- 26599606 TI - Comparative Evaluation of DNA Extraction Methods from Feces of Multiple Host Species for Downstream Next-Generation Sequencing. AB - The gastrointestinal tract contains a vast community of microbes that to this day remain largely unculturable, making studies in this area challenging. With the newly affordable advanced sequencing technology, important breakthroughs in this exciting field are now possible. However, standardized methods of sample collection, handling, and DNA extraction have yet to be determined. To help address this, we investigated the use of 5 common DNA extraction methods on fecal samples from 5 different species. Our data show that the method of DNA extraction impacts DNA concentration and purity, successful NGS amplification, and influences microbial communities seen in NGS output dependent on the species of fecal sample and the DNA extraction method used. These data highlight the importance of careful consideration of DNA extraction method used when designing and interpreting data from cross species studies. PMID- 26599607 TI - Obesity and metabolic syndrome: pathological effects on the gastrointestinal tract. AB - Obesity is an increasingly common problem worldwide and a risk factor for a variety of gastrointestinal (GI) diseases, both non-neoplastic (e.g. gastro oesophageal reflux and Barrett's oesophagus) and neoplastic (e.g. oesophageal adenocarcinoma, colorectal carcinoma, and gallbladder cancer). Furthermore, obesity is associated with worse GI cancer outcomes. Body mass index is a commonly used measure of fat accumulation, although specific patterns such as abdominal/central obesity and visceral fat quantity sometimes predict disease risk more accurately. Metabolic syndrome (MS) is a related condition characterized by central adiposity and insulin resistance. The reasons for the associations with neoplasia are diverse. Established cancer-related conditions that have a higher prevalence in overweight subjects include Barrett's oesophagus and gallstones. Preneoplastic lesions such as colorectal adenoma, colorectal serrated lesions and pancreatic intraepithelial neoplasia are also associated with obesity/MS. At the cellular level, adipocytes can release carcinogens such as adipokines, insulin-like growth factor, and vascular endothelial growth factor. Inflammatory cells constitute a further potential source of carcinogens; in obese subjects, their numbers are increased systemically and in adipose tissue. Animal studies have contributed additional information. For example, mice with a genetic predisposition to develop colorectal carcinoma given a high-fat diet have larger and more numerous intestinal adenomas than controls, and there may be demonstrably higher levels of mucosal oncogenic factors. The associations between obesity and GI disease are of variable strength, and the underlying mechanisms are incompletely understood, but it is clear that obesity and MS have a significant, potentially avoidable and often under-recognized impact on the population burden of GI disease. PMID- 26599608 TI - Clinical, virological and epidemiological characteristics of rhinovirus infections in early childhood: A comparison between non-hospitalised and hospitalised children. AB - BACKGROUND: Several studies have been published regarding the epidemiology and clinical significance of the different rhinovirus (RV) species (-A, -B and -C). However, data on RV types and the associations with clinical outcome in young children are limited. Here, we investigated the clinical, virological and epidemiological characteristics of RV infections in young children with mild or asymptomatic infection (non-hospitalised children) and in symptomatic young children admitted to the hospital. OBJECTIVES: The aim of this study was to evaluate associations between different characteristics of RV infections and clinical outcome in young children. STUDY DESIGN: RV-infected children were retrospectively selected from a Dutch birth cohort (EUROPA-study) and from hospitalised children admitted to the hospital because of respiratory symptoms. In total 120 RV-typed samples could be selected from 65 non-hospitalised and 49 hospitalised children between November 2009 and December 2012. RESULTS: RV-A was the predominant species in both study populations, followed closely by RV-C. RV-B was observed only sporadically. The distribution of the RV species was comparable in non-hospitalised and hospitalised children. In children with respiratory distress who required ICU-admission the distribution of RV species did not differ significantly from the non-hospitalised children. No predominant RV type was present in non-hospitalised nor hospitalised children. However, hospitalised children were younger, had more often an underlying illness, a higher RV load and more frequently a bacterial co-infection. CONCLUSIONS: Clinical outcome of RV infected young children was not related to RV species or types, but may more likely be influenced by multiple (host-specific) factors. PMID- 26599609 TI - Extracts from Field Margin Weeds Provide Economically Viable and Environmentally Benign Pest Control Compared to Synthetic Pesticides. AB - Plants with pesticidal properties have been investigated for decades as alternatives to synthetics, but most progress has been shown in the laboratory. Consequently, research on pesticidal plants is failing to address gaps in our knowledge that constrain their uptake. Some of these gaps are their evaluation of their efficacy under field conditions, their economic viability and impact on beneficial organisms. Extracts made from four abundant weed species found in northern Tanzania, Tithonia diversifolia, Tephrosia vogelii, Vernonia amygdalina and Lippia javanica offered effective control of key pest species on common bean plants (Phaseolus vulgaris) that was comparable to the pyrethroid synthetic, Karate. The plant pesticide treatments had significantly lower effects on natural enemies (lady beetles and spiders). Plant pesticide treatments were more cost effective to use than the synthetic pesticide where the marginal rate of return for the synthetic was no different from the untreated control, around 4USD/ha, compared to a rate of return of around 5.50USD/ha for plant pesticide treatments. Chemical analysis confirmed the presence of known insecticidal compounds in water extracts of T. vogelii (the rotenoid deguelin) and T. diversifolia (the sesquiterpene lactone tagitinin A). Sesquiterpene lactones and the saponin vernonioside C were also identified in organic extracts of V. amygdalina but only the saponin was recorded in water extracts which are similar to those used in the field trial. Pesticidal plants were better able to facilitate ecosystem services whilst effectively managing pests. The labour costs of collecting and processing abundant plants near farm land were less than the cost of purchasing synthetic pesticides. PMID- 26599610 TI - Technical Approach Determines Inflammatory Response after Surgical and Transcatheter Aortic Valve Replacement. AB - OBJECTIVE: To investigate the periprocedural inflammatory response in patients with isolated aortic valve stenosis undergoing surgical aortic valve replacement (SAVR) or transcatheter aortic valve implantation (TAVI) with different technical approaches. MATERIAL AND METHODS: Patients were prospectively allocated to one of the following treatments: SAVR using conventional extracorporeal circulation (CECC, n = 47) or minimized extracorporeal circulation (MECC, n = 15), or TAVI using either transapical (TA, n = 15) or transfemoral (TF, n = 24) access. Exclusion criteria included infection, pre-procedural immunosuppressive or antibiotic drug therapy and emergency indications. We investigated interleukin (IL)-6, IL-8, IL-10, human leukocyte antigen (HLA-DR), white blood cell count, high-sensitivity C-reactive protein (hs-CRP) and soluble L-selectin (sCD62L) levels before the procedure and at 4, 24, and 48 h after aortic valve replacement. Data are presented for group interaction (p-values for inter-group comparison) as determined by the Greenhouse-Geisser correction. RESULTS: SAVR on CECC was associated with the highest levels of IL-8 and hs-CRP (p<0.017, and 0.007, respectively). SAVR on MECC showed the highest descent in levels of HLA-DR and sCD62L (both p<0.001) in the perioperative period. TA-TAVI showed increased intraprocedural concentration and the highest peak of IL-6 (p = 0.017). Significantly smaller changes in the inflammatory markers were observed in TF TAVI. CONCLUSION: Surgical and interventional approaches to aortic valve replacement result in inflammatory modulation which differs according to the invasiveness of the procedure. As expected, extracorporeal circulation is associated with the most marked pro-inflammatory activation, whereas TF-TAVI emerges as the approach with the most attenuated inflammatory response. Factors such as the pre-treatment patient condition and the extent of myocardial injury also significantly affect inflammatory biomarker patterns. Accordingly, TA-TAVI is to be classified not as an interventional but a true surgical procedure, with inflammatory biomarker profiles comparable to those found after SAVR. Our study could not establish an obvious link between the extent of the periprocedural inflammatory response and clinical outcome parameters. PMID- 26599611 TI - Synthesis, Binding and Antiviral Properties of Potent Core-Extended Naphthalene Diimides Targeting the HIV-1 Long Terminal Repeat Promoter G-Quadruplexes. AB - We have previously reported that stabilization of the G-quadruplex structures in the HIV-1 long terminal repeat (LTR) promoter suppresses viral transcription. Here we sought to develop new G-quadruplex ligands to be exploited as antiviral compounds by enhancing binding toward the viral G-quadruplex structures. We synthesized naphthalene diimide derivatives with a lateral expansion of the aromatic core. The new compounds were able to bind/stabilize the G-quadruplex to a high extent, and some of them displayed clear-cut selectivity toward the viral G-quadruplexes with respect to the human telomeric G-quadruplexes. This feature translated into low nanomolar anti-HIV-1 activity toward two viral strains and encouraging selectivity indexes. The selectivity depended on specific recognition of LTR loop residues; the mechanism of action was ascribed to inhibition of LTR promoter activity in cells. This is the first example of G-quadruplex ligands that show increased selectivity toward the viral G-quadruplexes and display remarkable antiviral activity. PMID- 26599612 TI - Exopolysaccharide Produced by Lactobacillus Plantarum Induces Maturation of Dendritic Cells in BALB/c Mice. AB - Lactobacillus plantarum (L. plantarum) exopolysaccharide (EPS) is an important bioactive component in fermented functional foods. However, there is a lack of data concerning the effects of L. plantarum EPS on maturation of mouse dendritic cells (DCs). In this study, we purified L. plantarum EPS and examined its effects on cytokines production by dendritic cells in serum and intestinal fluid of BALB/c mice, then investigated its effects on phenotypic and functional maturation of mouse bone marrow-derived dendritic cells (BMDCs). Cytokines (nitric oxide, IL-12p70, IL-10 and RANTES) in serum and intestinal fluid were analyzed by enzyme linked immunosorbent assay (ELISA) after the mice received EPS for 2, 5 and 7 days, respectively. DCs derived from bone marrow of BALB/c mouse were treated with EPS, then the phenotypic maturation of BMDCs was analyzed using flow cytometer and the functional maturation of BMDCs was analyzed by ELISA, and, lastly, mixed lymphocyte proliferation was performed. We found the molecular weight of purified EPS was approximately 2.4*106 Da and it was composed of ribose, rhamnose, arabinose, xylose, mannose, glucose and galactose in a molar ratio of 2:1:1:10:4:205:215. We observed that L. plantarum EPS enriched production of nitric oxide, IL-12p70 and RANTES, and decreased the secretion of IL-10 in the serum or intestinal fluid as well as in the supernatant of DCs treated with the EPS. The EPS also up-regulated the expression of MHC II and CD86 on DCs surface and promoted T cells to proliferate in vitro. Our data provide direct evidence to suggest that L. plantarum EPS can effectively induce maturation of DCs in mice. PMID- 26599614 TI - Clinical Practice Guideline on Adult Domiciliary Oxygen Therapy: Executive summary from the Thoracic Society of Australia and New Zealand. PMID- 26599613 TI - Secreted and Transmembrane alphaKlotho Isoforms Have Different Spatio-Temporal Profiles in the Brain during Aging and Alzheimer's Disease Progression. AB - The Klotho protein is a beta-glucuronidase, and its overexpression is associated with life extension. Its mechanism of action is not fully understood, although it has been recently reported that alphaKlotho improves synaptic and cognitive functions, and it may also influence a variety of structures and functions during CNS maturation and aging. The alphaKlotho gene has two transcripts, one encoding a transmembrane isoform (m-KL), and the other a putative secreted isoform (s-KL). Unfortunately, little is known about the secreted alphaKlotho isoform, since available antibodies cannot discriminate s-KL from the KL1 domain cleaved from the transmembrane isoform. This study shows, for the first time, that the klotho transcript produced by alternative splicing generates a stable protein (70 kDa), and that in contrast to the transmembrane Klotho isoform, it is ten times more abundant in the brain than in the kidney suggesting that the two isoforms may have different functions. We also studied whether klotho expression in the CNS was influenced by aging, Alzheimer's disease (AD), or a healthy lifestyle, such as voluntary moderate continuous exercise. We observed a strong correlation between high expression levels of the two klotho transcripts and the healthy status of the animals. Expression of Klotho in brain areas decayed more rapidly in the 3xTg-AD model of AD than in healthy animals, whilst moderate continuous exercise in adulthood prevents the decline in expression of both klotho transcripts. PMID- 26599615 TI - Accelerating Very Deep Convolutional Networks for Classification and Detection. AB - This paper aims to accelerate the test-time computation of convolutional neural networks (CNNs), especially very deep CNNs [1] that have substantially impacted the computer vision community. Unlike previous methods that are designed for approximating linear filters or linear responses, our method takes the nonlinear units into account. We develop an effective solution to the resulting nonlinear optimization problem without the need of stochastic gradient descent (SGD). More importantly, while previous methods mainly focus on optimizing one or two layers, our nonlinear method enables an asymmetric reconstruction that reduces the rapidly accumulated error when multiple (e.g., >= 10) layers are approximated. For the widely used very deep VGG-16 model [1] , our method achieves a whole model speedup of 4 * with merely a 0.3 percent increase of top-5 error in ImageNet classification. Our 4 * accelerated VGG-16 model also shows a graceful accuracy degradation for object detection when plugged into the Fast R-CNN detector [2] . PMID- 26599616 TI - Full-Body Pose Tracking-The Top View Reprojection Approach. AB - Recent introduction of low-cost depth cameras triggered a number of interesting works, pushing forward the state-of-the-art in human body pose extraction and tracking. However, despite the remarkable progress, many of the contemporary methods cope inadequately with complex scenarios, involving multiple interacting users, under the presence of severe inter- and intra-occlusions. In this work, we present a model-based approach for markerless articulated full body pose extraction and tracking in RGB-D sequences. A cylinder-based model is employed to represent the human body. For each body part a set of hypotheses is generated and tracked over time by a Particle Filter. To evaluate each hypothesis, we employ a novel metric that considers the reprojected Top View of the corresponding body part. The latter, in conjunction with depth information, effectively copes with difficult and ambiguous cases, such as severe occlusions. For evaluation purposes, we conducted several series of experiments using data from a public human action database, as well as own-collected data involving varying number of interacting users. The performance of the proposed method has been further compared against that of the Microsoft's Kinect SDK and NiTE (TM) using ground truth information. The results obtained attest for the effectiveness of our approach. PMID- 26599617 TI - Clinical pharmacokinetic properties of magnesium sulphate in women with pre eclampsia and eclampsia. AB - BACKGROUND: The pharmacokinetic basis of magnesium sulphate (MgSO4 ) dosing regimens for eclampsia prophylaxis and treatment is not clearly established. OBJECTIVES: To review available data on clinical pharmacokinetic properties of MgSO4 when used for women with pre-eclampsia and/or eclampsia. SEARCH STRATEGY: MEDLINE, EMBASE, CINAHL, POPLINE, Global Health Library and reference lists of eligible studies. SELECTION CRITERIA: All study types investigating pharmacokinetic properties of MgSO4 in women with pre-eclampsia and/or eclampsia. DATA COLLECTION AND ANALYSIS: Two authors extracted data on basic pharmacokinetic parameters reflecting the different aspects of absorption, bioavailability, distribution and excretion of MgSO4 according to identified dosing regimens. MAIN RESULTS: Twenty-eight studies investigating pharmacokinetic properties of 17 MgSO4 regimens met our inclusion criteria. Most women (91.5%) in the studies had pre-eclampsia. Baseline serum magnesium concentrations were consistently <1 mmol/l across studies. Intravenous loading dose between 4 and 6 g was associated with a doubling of this baseline concentration half an hour after injection. Maintenance infusion of 1 g/hour consistently produced concentrations well below 2 mmol/l, whereas maintenance infusion at 2 g/hour and the Pritchard intramuscular regimen had higher but inconsistent probability of producing concentrations between 2 and 3 mmol/l. Volume of distribution of magnesium varied (13.65-49.00 l) but the plasma clearance was fairly similar (4.28-5.00 l/hour) across populations. CONCLUSION: The profiles of Zuspan and Pritchard regimens indicate that the minimum effective serum magnesium concentration for eclampsia prophylaxis is lower than the generally accepted level. Exposure-response studies to identify effective alternative dosing regimens should target concentrations achievable by these standard regimens. TWEETABLE ABSTRACT: Minimum effective serum magnesium concentration for eclampsia prophylaxis is lower than the generally accepted therapeutic level. PMID- 26599618 TI - The effect of dietary modulation of sulfur amino acids on cystathionine beta synthase-deficient mice. AB - Cystathionine beta synthase (CBS) is a key enzyme in the methionine and cysteine metabolic pathway, acting as a metabolic gatekeeper to regulate the flow of fixed sulfur from methionine to cysteine. Mutations in the CBS gene cause clinical CBS deficiency, a disease characterized by elevated plasma total homocysteine (tHcy) and methionine and decreased plasma cysteine. The treatment goal for CBS deficient patients is to normalize the metabolic values of these three metabolites using a combination of vitamin therapy and dietary manipulation. To better understand the effectiveness of nutritional treatment strategies, we have performed a series of long-term dietary manipulation studies using our previously developed Tg-I278T Cbs(-/-) mouse model of CBS deficiency and sibling Tg-I278T Cbs(+/-) controls. Tg-I278T Cbs(-/-) mice have undetectable levels of CBS activity, extremely elevated plasma tHcy, modestly elevated plasma methionine, and low plasma cysteine. They exhibit several easily assayable phenotypes, including osteoporosis, loss of fat mass, reduced life span, and facial alopecia. The diets used in these studies differed in the amounts of sulfur amino acids or sulfur amino acid precursors. In this review, we will discuss our findings and their relevance to CBS deficiency and the concept of gene-diet interaction. PMID- 26599619 TI - Electrocatalytic Zinc Composites as the Efficient Counter Electrodes of Dye Sensitized Solar Cells: Study on the Electrochemical Performances and Density Functional Theory Calculations. AB - Highly efficient zinc compounds (Zn3N2, ZnO, ZnS, and ZnSe) have been investigated as low-cost electrocatalysts for the counter electrodes (CE) of dye sensitized solar cells (DSSCs). Among them, Zn3N2 and ZnSe are introduced for the first time in DSSCs. The zinc compounds were separately mixed with a conducting binder, poly(3,4-ethylene-dioxythiophene):poly(styrenesulfonate) ( PEDOT: PSS), and thereby four composite films of Zn3N2/PEDOT:PSS, ZnO/PEDOT:PSS, ZnS/PEDOT:PSS, and ZnSe/ PEDOT: PSS were coated on the tin-doped indium oxide (ITO) substrates through a simple drop-coating process. In the composite film, nanoparticles of the zinc compound form active sites for the electrocatalytic reduction of triiodide ions, and PEDOT: PSS provides a continuous conductive matrix for fast electron transfer. By varying the weight percentage (5-20 wt %) of a zinc compound with respect to the weight of the PEDOT: PSS, the optimized concentration of a zinc compound was found to be 10 wt % in all four cases, based on the photovoltaic performances of the corresponding DSSCs. At this concentration (10 wt %), the composites films with Zn3N2 (Zn3N2-10), ZnO (ZnO 10), ZnS (ZnS-10), and ZnSe (ZnSe-10) rendered, for their DSSCs, power conversion efficiencies (eta) of 8.73%, 7.54%, 7.40%, and 8.13%, respectively. The difference in the power conversion efficiency is explained based on the electrocatalytic abilities of those composite films as determined by cyclic voltammetry (CV), Tafel polarization plots, and electrochemical impedance spectroscopy (EIS) techniques. The energy band gaps of the zinc compounds, obtained by density functional theory (DFT) calculations, were used to explain the electrocatalytic behaviors of the compounds. Among all the zinc-based composites, the one with Zn3N2-10 showed the best electrocatalytic ability and thereby rendered for its DSSC the highest eta of 8.73%, which is even higher than that of the cell with the traditional Pt CE (8.50%). Therefore, Zn3N2 can be considered as a promising inexpensive electrocatalyst to replace the rare and expensive Pt. PMID- 26599620 TI - Expanding the family of heterobimetallic Bi-Rh paddlewheel carboxylate complexes via equatorial carboxylate exchange. AB - Five novel homoleptic heterobimetallic bismuth(II)-rhodium(II) carboxylate complexes--BiRh(TPA)4 (1), BiRh(but)4 (2), BiRh(piv)4 (3), BiRh(esp)2 (4), and BiRh(OAc)4 (5)--were synthesized in good yields by equatorial ligand substitution starting from BiRh(TFA)4 (TPA = triphenylacetate, but = butyrate, piv = pivalate, esp = alpha,alpha,alpha',alpha'-tetramethyl-1,3-benzenedipropionate, OAc = acetate, and TFA = trifluoroacetate). We report here (1)H and (13)C{(1)H} NMR spectra and cyclic voltammograms for complexes , and IR spectra for all complexes. Irreversible redox waves appear between -1.4 to -1.5 V for [BiRh](3+/4+) couples and 1.3 to 1.5 V vs. Fc/Fc(+) for [BiRh](4+/5+) couples for complexes indicating a wide range of stability for the compounds. The X-ray crystal structure of reveals a Bi-Rh distance of 2.53 A. PMID- 26599621 TI - Tridentate Lewis acids with phenyl substituted 1,3,5-trisilacyclohexane backbones. AB - The 1,3,5-trisilacyclohexane skeleton [CH2Si(Ph)(C2H)]3 equipped with three ethynyl groups was synthesised and functionalised to afford tridentate Lewis acids with directed functions. Hydroboration with HB(C6F5)2 yielded the ethenylborane {CH2Si(Ph)[C2H2B(C6F5)2]}3, while metalation with gallium organyls afforded {CH2Si(Ph)[C2Ga(R)2]}3 (R = Me, Et). The new compounds were identified by elemental analyses, multi-nuclear NMR spectroscopy and IR spectroscopy. Crystal structures were obtained for all-cis-[CH2Si(Ph)(OMe)]3, cis-trans [CH2Si(Ph)(Cl)]3, all-cis-[CH2Si(Ph)(H)]3 and all-cis-[CH2Si(Ph)(C2H)]3. PMID- 26599622 TI - A surface charge-switchable and folate modified system for co-delivery of proapoptosis peptide and p53 plasmid in cancer therapy. AB - To improve the tumor therapeutic efficiency and reduce undesirable side effects, ternary FK/p53/PEG-PLL(DA) complexes with a detachable surface shielding layer were designed. The FK/p53/PEG-PLL(DA) complexes were fabricated by coating the folate incorporated positively charged FK/p53 complexes with charge-switchable PEG-shield (PEG-PLL(DA)) through electrostatic interaction. At the physiological pH 7.4 in the bloodstream, PEG-PLL(DA) could extend the circulating time by shielding the positively charged FK/p53 complexes. After the accumulation of the FK/p53/PEG-PLL(DA) complexes in tumor sites, tumor-acidity-triggered charge switch led to the detachment of PEG-PLL(DA) from the FK/p53 complexes, and resulted in efficient tumor cell entry by folate-mediated uptake and electrostatic attraction. Stimulated by the high content glutathione (GSH) in cytoplasm, the cleavage of disulfide bond resulted in the liberation of proapoptosis peptide C-KLA(TPP) and the p53 gene, which exerted the combined tumor therapy by regulating both intrinsic and extrinsic apoptotic pathways. Both in vitro and in vivo studies confirmed that the ternary detachable complexes FK/p53/PEG-PLL(DA) could enhance antitumor efficacy and reduce adverse effects to normal cells. These findings indicate that the tumor-triggered decomplexation of FK/p53/PEG-PLL(DA) supplies a useful strategy for targeting delivery of different therapeutic agents in synergetic anticancer therapy. PMID- 26599623 TI - A 3D in vitro model of patient-derived prostate cancer xenograft for controlled interrogation of in vivo tumor-stromal interactions. AB - Patient-derived xenograft (PDX) models better represent human cancer than traditional cell lines. However, the complex in vivo environment makes it challenging to employ PDX models to investigate tumor-stromal interactions, such as those that mediate prostate cancer (PCa) bone metastasis. Thus, we engineered a defined three-dimensional (3D) hydrogel system capable of supporting the co culture of PCa PDX cells and osteoblastic cells to recapitulate the PCa osteoblast unit within the bone metastatic microenvironment in vitro. Our 3D model not only maintained cell viability but also preserved the typical osteogenic phenotype of PCa PDX cells. Additionally, co-culture cellularity was maintained over that of either cell type cultured alone, suggesting that the PCa osteoblast cross-talk supports PCa progression in bone, as is hypothesized to occur in patients with prostatic bone metastasis. Strikingly, osteoblastic cells co-cultured with PCa PDX tumoroids organized around the tumoroids, closely mimicking the architecture of PCa metastases in bone. Finally, tumor-stromal signaling mediated by the fibroblast growth factor axis tightly paralleled that in the in vivo counterpart. Together, these findings indicate that this 3D PCa PDX model recapitulates important pathological properties of PCa bone metastasis, and validate the use of this model for controlled and systematic interrogation of complex in vivo tumor-stromal interactions. PMID- 26599624 TI - Heterogeneous engineered cartilage growth results from gradients of media supplemented active TGF-beta and is ameliorated by the alternative supplementation of latent TGF-beta. AB - Transforming growth factor beta (TGF-beta) has become one of the most widely utilized mediators of engineered cartilage growth. It is typically exogenously supplemented in the culture medium in its active form, with the expectation that it will readily transport into tissue constructs through passive diffusion and influence cellular biosynthesis uniformly. The results of this investigation advance three novel concepts regarding the role of TGF-beta in cartilage tissue engineering that have important implications for tissue development. First, through the experimental and computational analysis of TGF-beta concentration distributions, we demonstrate that, contrary to conventional expectations, media supplemented exogenous active TGF-beta exhibits a pronounced concentration gradient in tissue constructs, resulting from a combination of high-affinity binding interactions and a high cellular internalization rate. These gradients are sustained throughout the entire culture duration, leading to highly heterogeneous tissue growth; biochemical and histological measurements support that while biochemical content is enhanced up to 4-fold at the construct periphery, enhancements are entirely absent beyond 1 mm from the construct surface. Second, construct-encapsulated chondrocytes continuously secrete large amounts of endogenous TGF-beta in its latent form, a portion of which undergoes cell-mediated activation and enhances biosynthesis uniformly throughout the tissue. Finally, motivated by these prior insights, we demonstrate that the alternative supplementation of additional exogenous latent TGF-beta enhances biosynthesis uniformly throughout tissue constructs, leading to enhanced but homogeneous tissue growth. This novel demonstration suggests that latent TGF-beta supplementation may be utilized as an important tool for the translational engineering of large cartilage constructs that will be required to repair the large osteoarthritic defects observed clinically. PMID- 26599626 TI - Could strength of exposure to the residential neighbourhood modify associations between walkability and physical activity? AB - The importance of neighbourhoods for health and wellbeing may vary according to an individual's reliance on their local resources, but this assertion is rarely tested. We investigate whether greater neighbourhood 'exposure' through reliance on or engagement with the residential setting magnifies neighbourhood-health associations. METHODS: Three built environment characteristics (destination density, streetscape (attractiveness of built environment) and street connectivity) and two physical activity components (weekday and weekend accelerometer counts) were measured for 2033 residents living in 48 neighbourhoods within four New Zealand cities in 2009-2010, giving six different built environment-physical activity associations. Interactions for each built environment-physical activity association with four individual-level characteristics (acting as proxies for exposure: gender, working status, car access, and income) were assessed with multi-level regression models; a total of 24 'tests'. RESULTS: Of the 12 weekday built environment-physical activity tests, 5 interaction terms were significant (p < 0.05) in the expected direction (e.g. stronger streetscape-physical activity among those with restricted car access). For weekend tests, one association was statistically significant. No significant tests were contradictory. Pooled across the 12 weekday physical activity 'tests', a 1 standard deviation increase in the walkability of the built environment was associated with an overall 3.8% (95% CI: 3.6%-4.1%) greater increase in weekday physical activity across all the types of people we hypothesised to spend more time in their residential neighbourhood, and for weekend physical activity it was 4.2% (95% CI 3.9%-4.5%). CONCLUSIONS: Using multiple evaluation methods, interactions were in line with our hypothesis, with a stronger association seen for proxy exposure indicators (for example, restricted car access). Added to the wider evidence base, our study strengthens causal evidence of an effect of the built environment on physical activity, and highlights that health gains from improvements of the residential neighbourhood may be greater for some people. PMID- 26599625 TI - Transgender stigma and health: A critical review of stigma determinants, mechanisms, and interventions. AB - RATIONALE: Transgender people in the United States experience widespread prejudice, discrimination, violence, and other forms of stigma. OBJECTIVE: This critical review aims to integrate the literature on stigma towards transgender people in the U.S. RESULTS: This review demonstrates that transgender stigma limits opportunities and access to resources in a number of critical domains (e.g., employment, healthcare), persistently affecting the physical and mental health of transgender people. The applied social ecological model employed here elucidates that transgender stigma operates at multiple levels (i.e., individual, interpersonal, structural) to impact health. Stigma prevention and coping interventions hold promise for reducing stigma and its adverse health-related effects in transgender populations. CONCLUSION: Additional research is needed to document the causal relationship between stigma and adverse health as well as the mediators and moderators of stigma in US transgender populations. Multi-level interventions to prevent stigma towards transgender people are warranted. PMID- 26599627 TI - RNA-based, transient modulation of gene expression in human haematopoietic stem and progenitor cells. AB - Modulation of gene expression is a useful tool to study the biology of haematopoietic stem and progenitor cells (HSPCs) and might also be instrumental to expand these cells for therapeutic approaches. Most of the studies so far have employed stable gene modification by viral vectors that are burdensome when translating protocols into clinical settings. Our study aimed at exploring new ways to transiently modify HSPC gene expression using non-integrating, RNA-based molecules. First, we tested different methods to deliver these molecules into HSPCs. The delivery of siRNAs with chemical transfection methods such as lipofection or cationic polymers did not lead to target knockdown, although we observed more than 90% fluorescent cells using a fluorochrome-coupled siRNA. Confocal microscopic analysis revealed that despite extensive washing, siRNA stuck to or in the cell surface, thereby mimicking a transfection event. In contrast, electroporation resulted in efficient, siRNA-mediated protein knockdown. For transient overexpression of proteins, we used optimised mRNA molecules with modified 5'- and 3'-UTRs. Electroporation of mRNA encoding GFP resulted in fast, efficient and persistent protein expression for at least seven days. Our data provide a broad-ranging comparison of transfection methods for hard-to-transfect cells and offer new opportunities for DNA-free, non-integrating gene modulation in HSPCs. PMID- 26599628 TI - TGIF1 Gene Silencing in Tendon-Derived Stem Cells Improves the Tendon-to-Bone Insertion Site Regeneration. AB - BACKGROUND/AIMS: The slow healing process of tendon-to-bone junctions can be accelerated via implanted tendon-derived stem cells (TDSCs) with silenced transforming growth interacting factor 1 (TGIF1) gene. Tendon-to-bone insertion site is the special form of connective tissues derivatives of common connective progenitors, where TGF-beta plays bidirectional effects (chondrogenic or fibrogenic) through different signaling pathways at different stages. A recent study revealed that TGF-beta directly induces the chondrogenic gene Sox9. However, TGIF1 represses the expression of the cartilage master Sox9 gene and changes its expression rate against the fibrogenesis gene Scleraxis (Scx). METHODS: TGIF1 siRNA was transduced or TGIF1 was over-expressed in tendon-derived stem cells. Following suprapinatus tendon repair, rats were either treated with transduced TDSCs or nontransduced TDSCs. Histologic examination and Western blot were performed in both groups. RESULTS: In this study, the silencing of TGIF1 significantly upregulated the chondrogenic genes and markers. Similarly, TGIF1 inhibited TDSC differentiation into cartilage via interactions with TGF-beta activated Smad2 and suppressed the phosphorylation of Smad2. The area of fibrocartilage at the tendon-bone interface was significantly increased in the TGIF1 (-) group compared with the control and TGIF1-overexpressing groups in the early stages of the animal model. The interface between the tendon and bone showed a increase of new bone and fibrocartilage in the TGIF1 (-) group at 4 weeks. Fibrovascular scar tissue was observed in the TGIF1-overexpressing group and the fibrin glue only group. Low levels of fibrocartilage and fibrovascular scar tissue were found in the TDSCs group. CONCLUSION: Collectively, this study shows that the tendon-derived stem cell modified with TGIF1 gene silencing has promising effects on tendon-to-bone healing which can be further explored as a therapeutic tool in regenerative medicine. PMID- 26599629 TI - ERK1/2 Phosphorylation in the Rat Supraoptic Nucleus, Dorsal Raphe Nucleus, and Locus Coeruleus Neurons Following Noxious Stimulation to the Hind Paw. AB - Phospho-ERK1/2 (pERK1/2) fluorescence-immunohistochemistry is specifically well suited to mirror neuronal activity in the pain pathway at the cellular level. This study employed this method to visualize neuronal activity in 3 rat CNS nuclei following an acute noxious stimulation. The rat hind paw was stimulated either by heat or by a sequence of mustard oil and heat. Two min after the thermal stimulation or after the combined mustard oil and thermal stimulation, there was a significant increase in cells showing pERK1/2 immunoreactivity in the supraoptic nucleus (SON), in the dorsal raphe nucleus (DRN), and in the locus coeruleus (LC). Pretreatment with the opioid analgesic morphine or the N-methyl-D aspartate antagonist MK-801 markedly attenuated ERK1/2 phosphorylation. These findings support the concept that the SON, the DRN, and the LC are integrated into pain processing at the hypothalamic and brain stem level. PMID- 26599630 TI - Glacial Refugia and Future Habitat Coverage of Selected Dactylorhiza Representatives (Orchidaceae). AB - The intensively discussed taxonomic complexity of the Dactylorhiza genus is probably correlated with its migration history during glaciations and interglacial periods. Previous studies on past processes affecting the current distribution of Dactylorhiza species as well as the history of the polyploid complex formation were based only on molecular data. In the present study the ecological niche modeling (ENM) technique was applied in order to describe the distribution of potential refugia for the selected Dactylorhiza representatives during the Last Glacial Maximum. Additionally, future changes in their potential habitat coverage were measured with regard to three various climatic change scenarios. The maximum entropy method was used to create models of suitable niche distribution. A database of Dactylorhiza localities was prepared on the grounds of information collected from literature and data gathered during field works. Our research indicated that the habitats of majority of the studied taxa will decrease by 2080, except for D. incarnata var. incarnata, for which suitable habitats will increase almost two-fold in the global scale. Moreover, the potential habitats of some taxa are located outside their currently known geographical ranges, e.g. the Aleutian Islands, the western slopes of the Rocky Mountains, Newfoundland, southern Greenland and Iceland. ENM analysis did not confirm that the Balkans, central Europe or central Russia served as the most important refugia for individual representatives of the Dactylorhiza incarnata/maculata complex. Our study rather indicated that the Black Sea coast, southern Apennines and Corsica were the main areas characterized by habitats suitable for most of the taxa. PMID- 26599631 TI - Development of the CHARIOT Research Register for the Prevention of Alzheimer's Dementia and Other Late Onset Neurodegenerative Diseases. AB - BACKGROUND: Identifying cognitively healthy people at high risk of developing dementia is an ever-increasing focus. These individuals are essential for inclusion in observational studies into the natural history of the prodromal and early disease stages and for interventional studies aimed at prevention or disease modification. The success of this research is dependent on having access to a well characterised, representative and sufficiently large population of individuals. Access to such a population remains challenging as clinical research has, historically, focussed on patients with dementia referred to secondary and tertiary services. The primary care system in the United Kingdom allows access to a true prodromal population prior to symptoms emerging and specialist referral. We report the development and recruitment rates of the CHARIOT register, a primary care-based recruitment register for research into the prevention of dementia. The CHARIOT register was designed specifically to support recruitment into observational natural history studies of pre-symptomatic or prodromal dementia stages, and primary or secondary prevention pharmaceutical trials or other prevention strategies for dementia and other cognitive problems associated with ageing. METHODS: Participants were recruited through searches of general practice lists across the west and central London regions. Invitations were posted to individuals aged between 60 and 85 years, without a diagnosis of dementia. Upon consent, a minimum data set of demographic and contact details was extracted from the patient's electronic health record. RESULTS: To date, 123 surgeries participated in the register, recruiting a total of 24,509 participants a response rate of 22.3%. The age, gender and ethnicity profiles of participants closely match that of the overall eligible population. Higher response rates tended to be associated with larger practices (r = 0.34), practices with a larger older population (r = 0.27), less socioeconomically disadvantaged practices (r = 0.68), and practices with a higher proportion of White patients (r = 0.82). DISCUSSION: Response rates are comparable to other registers reported in the literature, and indicate good interest and support for a research register and for participation in research for the prevention of age-related neurodegenerative diseases and dementia. We consider that the simplicity of the approach means that this system is easily scalable and replicable across the UK and internationally. PMID- 26599632 TI - New Insight into the Time-Course of Motor and Sensory System Changes in Pain. AB - BACKGROUND: Pain-related interactions between primary motor (M1) and primary sensory (S1) cortex are poorly understood. In particular, the time-course over which S1 processing and corticomotor output are altered in association with muscle pain is unclear. We aimed to examine the temporal profile of altered processing in S1 and altered corticomotor output with finer temporal resolution than has been used previously. METHODS: In 10 healthy individuals we recorded somatosensory evoked potentials (SEPs) and motor evoked potentials (MEPs) in separate sessions at multiple time-points before, during and immediately after pain induced by hypertonic saline infusion in a hand muscle, and at 15 and 25 minutes follow-up. RESULTS: Participants reported an average pain intensity that was less in the session where SEPs were recorded (SEPs: 4.0 +/- 1.6; MEPs: 4.9 +/ 2.3). In addition, the time taken for pain to return to zero once infusion of hypertonic saline ceased was less for participants in the SEP session (SEPs: 4.7 +/- 3.8 mins; MEPs 9.4 +/- 7.4 mins). Both SEPs and MEPs began to reduce almost immediately after pain reached 5/10 following hypertonic saline injection and were significantly reduced from baseline by the second (SEPs) and third (MEPs) recording blocks during pain. Both parameters remained suppressed immediately after pain had resolved and at 15 and 25 minutes after the resolution of pain. CONCLUSIONS: These data suggest S1 processing and corticomotor output may be co modulated in association with muscle pain. Interestingly, this is in contrast to previous observations. This discrepancy may best be explained by an effect of the SEP test stimulus on the corticomotor pathway. This novel finding is critical to consider in experimental design and may be potentially useful to consider as an intervention for the management of pain. PMID- 26599633 TI - Correction: Modulation of the Surface Proteome through Multiple Ubiquitylation Pathways in African Trypanosomes. PMID- 26599634 TI - Risks of Hemolysis in Glucose-6-Phosphate Dehydrogenase Deficient Infants Exposed to Chlorproguanil-Dapsone, Mefloquine and Sulfadoxine-Pyrimethamine as Part of Intermittent Presumptive Treatment of Malaria in Infants. AB - BACKGROUND: Chlorproguanil-dapsone (CD) has been linked to hemolysis in symptomatic glucose-6-phosphate dehydrogenase deficient (G6PDd) children. Few studies have explored the effects of G6PD status on hemolysis in children treated with Intermittent Preventive Treatment in infants (IPTi) antimalarial regimens. We sought to examine the joint effects of G6PD status and IPTi antimalarial treatment on incidence of hemolysis in asymptomatic children treated with CD, sulfadoxine-pyrimethamine (SP), and mefloquine (MQ). METHODS: A secondary analysis of data from a double-blind, placebo-controlled trial of IPTi was conducted. Hemoglobin (Hb) measurements were made at IPTi doses, regular follow up and emergency visits. G6PD genotype was determined at 9 months looking for SNPs for the A- genotype at coding position 202. Multivariable linear and logistic regression models were used to examine hemolysis among children with valid G6PD genotyping results. Hemolysis was defined as the absolute change in Hb or as any post-dose Hb <8 g/dL. These outcomes were assessed using either a single follow-up Hb on day 7 after an IPTi dose or Hb obtained 1 to 14 or 28 days after each IPTi dose. FINDINGS: Relative to placebo, CD reduced Hb by approximately 0.5 g/dL at day 7 and within 14 days of an IPTi dose, and by 0.2 g/dL within 28 days. Adjusted declines in the CD group were larger than in the MQ and SP groups. At day 7, homo-/hemizygous genotype was associated with higher odds of Hb <8 g/dL (adjusted odds ratio = 6.7, 95% CI 1.7 to 27.0) and greater absolute reductions in Hb (-0.6 g/dL, 95% CI -1.1 to 0.003). There was no evidence to suggest increased reductions in Hb among homo-/hemizygous children treated with CD compared to placebo, SP or MQ. CONCLUSIONS: While treatment with CD demonstrated greater reductions in Hb at 7 and 14 days after an IPTi dose compared to both SP and MQ, there was no evidence that G6PD deficiency exacerbated the adverse effects of CD, despite evidence for higher hemolysis risk among G6PDd infants. PMID- 26599635 TI - Prevalence and Characterization of Staphylococcus aureus in Growing Pigs in the USA. AB - A decade of research of methicillin-resistant S. aureus (MRSA) in pigs shows that the prevalence and predominant genotypes (i.e., ST398, ST9, ST5) of MRSA vary widely geographically, yet knowledge of the epidemiology of S. aureus generally in swine remains rudimentary. To characterize S. aureus, including MRSA, in the US swine industry, we sampled 38 swine herds in 11 states in major swine producing regions. The herds sampled included pigs sourced from 9 different breeding stock companies, and the sample was likely biased towards larger herds that use regular veterinary services. Twenty nasal swabs were collected from 36 groups of growing pigs by 36 swine veterinarians, 2 more herds were sampled opportunistically, and a historically MRSA-positive herd was included as a positive control. S. aureus was detected on 37 of the 38 herds, and in 77% of pigs sampled. Other than the positive control herd, no MRSA were detected in the study sample, yielding a 95% upper confidence limit of 9.3% for MRSA herd prevalence. All but two (ST1-t127; ST2007-t8314) of 1200 isolates belonged to three MLST lineages (ST9, ST398, and ST5) that have been prominent in studies of MRSA in pigs globally. A total of 35 spa types were detected, with the most prevalent being t337 (ST9), t034 (ST398), and t002 (ST5). A purposively diverse subset of 128 isolates was uniformly negative on PCR testing for major enterotoxin genes. The findings support previous studies suggesting a relatively low herd prevalence of MRSA in the US swine industry, but confirm that methicillin susceptible variants of the most common MRSA genotypes found in swine globally are endemic in the US. The absence of enterotoxin genes suggests that the source of toxigenic S. aureus capable of causing foodborne enterotoxicosis from pork products is most likely post-harvest contamination. PMID- 26599636 TI - Predictors of Bacteraemia in Patients with Suspected Community-Acquired Pneumonia. AB - INTRODUCTION: The diagnostic yield of blood cultures is limited in patients with community-acquired pneumonia (CAP). Yet, positive blood culture results provide important information for antibiotic treatment and for monitoring epidemiologic trends. We investigated the potential of clinical predictors to improve the cost benefit ratio of obtaining blood cultures. METHODS: Data from two prospective cohort studies of adults with suspected CAP, admitted to non-ICU wards, were combined. Two models were created, one using readily available parameters and one additionally including laboratory parameters. RESULTS: 3,786 patients were included (2,626 (69%) with X-ray confirmed CAP). Blood cultures were obtained from 2,977 (79%) patients (and from 2,107 (80%) with X-ray confirmed CAP). 266 (8.9%) of the patients with a blood culture had bacteraemia. Clinical predictors of bacteraemia were absence of pre-admission antibiotic treatment, pleuritic pain, gastro-intestinal symptoms, tachycardia, tachypnea, hypotension and absence of hypoxia. After including laboratory results in the model, younger age, C reactive protein, leukocytosis or leukopenia, low thrombocyte count, low sodium level, elevated urea and elevated arterial pH were added, while gastro-intestinal symptoms and hypotension were no longer significant. The area under the receiver operating characteristics curve was 0.66 (95% confidence interval 0.63-0.70) for the first model and 0.76 (95% confidence interval 0.73-0.79) for the second model. CONCLUSION: In conclusion, in patients hospitalized with CAP, bacteraemia was moderately predictable using clinical parameters only. We recommend against the use of a risk prediction model for the decision to obtain blood cultures. PMID- 26599637 TI - Comparison of Conventional versus Steerable-Catheter Guided Coronary Sinus Lead Positioning in Patients Undergoing Cardiac Resynchronization Device Implantation. AB - OBJECTIVES: The aim of this study was to compare conventional versus steerable catheter guided coronary sinus (CS) cannulation in patients with advanced heart failure undergoing cardiac resynchronization therapy (CRT). BACKGROUND: Steerable catheter guided coronary sinus cannulation could reduce fluoroscopy time and contrast medium use during CRT implantation. METHODS: 176 consecutive patients with ischemic and non-ischemic heart failure undergoing CRT implantation from January 2008 to December 2012 at the University Hospital of Cologne were identified. During the study period two concurrent CS cannulation techniques were used: standard CS cannulation technique (standard-group, n = 113) and CS cannulation using a steerable electrophysiology (EP) catheter (EPCath-group, n = 63). Propensity-score matched pairs of conventional and EP-catheter guided CS cannulation made up the study population (n = 59 pairs). Primary endpoints were total fluoroscopy time and contrast medium amount used during procedure. RESULTS: The total fluoroscopy time was 30.9 min (interquartile range (IQR), 19.9-44.0 min) in the standard-group and 23.4 min (IQR, 14.2-34-2 min) in the EPCath-group (p = 0.011). More contrast medium was used in the standard-group (60.0 ml, IQR, 30.0-100 ml) compared to 25.0 ml (IQR, 20.0-50.0 ml) in the EPCath-group (P<0.001). CONCLUSIONS: Use of steerable EP catheter was associated with significant reduction of fluoroscopy time and contrast medium use in patients undergoing CRT implantation. PMID- 26599639 TI - Vapor-Liquid-Solid Etch of Semiconductor Surface Channels by Running Gold Nanodroplets. AB - We show that Au nanoparticles spontaneously move across the (001) surface of InP, InAs, and GaP when heated in the presence of water vapor. As they move, the particles etch crystallographically aligned grooves into the surface. We show that this process is a negative analogue of the vapor-liquid-solid (VLS) growth of semiconductor nanowires: the semiconductor dissolves into the catalyst and reacts with water vapor at the catalyst surface to create volatile oxides, depleting the dissolved cations and anions and thus sustaining the dissolution process. This VLS etching process provides a new tool for directed assembly of structures with sublithographic dimensions, as small as a few nanometers in diameter. Au particles above 100 nm in size do not exhibit this process but remain stationary, with oxide accumulating around the particles. PMID- 26599638 TI - Pectin-Derived Acidic Oligosaccharides Improve the Outcome of Pseudomonas aeruginosa Lung Infection in C57BL/6 Mice. AB - The administration of prebiotics as oligosaccharides (OS), by acting on intestinal microbiota, could modulate the immune and inflammatory response and represent a new strategy to improve the outcome of bacterial infection. The aim of this study was to determine whether pectin-derived acidic oligosaccharides (pAOS) could modulate the outcome of pulmonary P. aeruginosa (PA) infection in C57BL/6 mice, which develop a Th1 response to PA lung infection. Mice were randomized for 5 weeks to consume a control or a 5% pAOS diet and chronically infected by PA. Resistance to a second PA infection was also analyzed by reinfecting the surviving mice 2 weeks after the first infection. Compared with control mice, mice fed pAOS had reduced mortality (P<0.05). This improvement correlated with a better control of the inflammatory response with a lower neutrophil count on day 1 (P<0.05), a sustained neutrophil and macrophage recruitment on days 2 and 3 (P<0.01) a greater and sustained IL-10 release in lung (P<0.05) and a reduction of the Th1 response and M1 activation with a lower IFN-gamma/IL-4 (P<0.01) and nos2/arg1 (P<0.05) ratios. These results coincided with a modulation of the intestinal microbiota as shown by an increased butyric acid concentration in feces (P<0.05). Moreover, pAOS decreased the bacterial load (P<0.01) in mice reinfected 2 weeks after the first infection, suggesting that pAOS could reduce pulmonary exacerbations. In conclusion, pAOS improved the outcome of PA infection in C57BL/6 mice by modulating the intestinal microbiota and the inflammatory and immune responses. PMID- 26599640 TI - Giant Rashba-Type Spin Splitting in Ferroelectric GeTe(111). AB - Photoelectron spectroscopy in combination with piezoforce microscopy reveals that the helicity of Rashba bands is coupled to the nonvolatile ferroelectric polarization of GeTe(111). A novel surface Rashba band is found and fingerprints of a bulk Rashba band are identified by comparison with density functional theory calculations. PMID- 26599642 TI - Synthesis of the AB ring system of clifednamide utilizing Claisen rearrangement and Diels-Alder reaction as key steps. AB - In order to construct the functionalized AB ring system of clifednamide, member of the class of macrocyclic tetramic acid lactams, a synthesis was developed which utilized an Ireland-Claisen rearrangement and an intramolecular Diels-Alder reaction. Starting from di-O-isopropylidene-d-mannitol the allyl carboxylate precursor for the sigmatropic rearrangement was prepared. This rearrangement proceeded diastereoselectively only in the presence of an allyl silyl ether instead of the parent enone in the side chain, as suggested by deuteration experiments. A subsequent Diels-Alder reaction yielded the target ethyl hexahydro 1H-indene-carboxylate with high diastereoselectivity. Quantum-chemical investigations of this intramolecular Diels-Alder reaction support the proposed configuration of the final product. PMID- 26599641 TI - Apoptosis-Related Factors in the Luteal Phase of the Domestic Cat and Their Involvement in the Persistence of Corpora Lutea in Lynx. AB - The corpus luteum (CL) is a transient gland formed in the ovary after ovulation and is the major source of progesterone. In the Iberian and Eurasian lynx, CL physiologically persist after parturition and retain their capacity to produce progesterone, thus suppressing the ovarian activity. This unique reproductive characteristic has a big impact on the success of assisted reproduction techniques in the endangered Iberian lynx. The mechanisms behind CL persistence are not yet understood and require extensive studies on potential luteotropic and luteolytic factors in felids. Because the apoptosis system has been shown to be involved in structural regression of CL in many species, we aimed to investigate the capacity of perCL to undergo apoptosis. In addition, we performed initial studies on the apoptosis system in the luteal phase of the domestic cat. No previous research on this system has been made in this species. Our factors of interest included agents of the intrinsic apoptosis pathway, i.e., pro-survival B cell CLL/lymphoma 2 (BCL2) and pro-apoptotic BCL2-associated X protein (BAX), the executioner caspase-3 (CASP3), as well as of the extrinsic pathway, i.e., pro apoptotic receptor FAS, and tumor necrosis factor (TNF) and its receptors (pro apoptotic TNFRSF1A and pro-survival TNFRSF1B). We analyzed the relative mRNA levels of these factors, as well as protein localization of CASP3 and TNF during stages of pregnancy and the non-pregnant luteal phase in CL of domestic cats. The same factors were investigated in freshly ovulated CL (frCL) and perCL of Iberian and Eurasian lynx, which were histologically analyzed. All factors were present in the CL tissue of both domestic cat and lynx throughout all analyzed stages. The presence of pro-apoptotic factors BAX, CASP3, FAS and TNFRSF1A in perCL of the Eurasian and Iberian lynx might indicate the potential sensitivity of perCL to apoptotic signals. The expression of pro-survival factors BCL2 and TNFRSF1B was significantly higher in perCL compared to frCL of studied Iberian lynx, suggesting the potential involvement of these factors in the structural integrity of perCL. In both Iberian lynx and pregnant and non-pregnant domestic cats, the expression of TNFRSF1A was significantly higher in forming CL compared to other stages, suggesting the conserved involvement of this factor in the tissue reorganization during formation of the feline CL. The mRNA levels of CASP3 and TNFRSF1B were highest during regression stages of domestic cat CL. The current study provides initial results on the possible involvement of the apoptosis system in the structure and function of the feline CL and in its physiological persistence. PMID- 26599646 TI - Liaison Nurse: Hospital Digest. PMID- 26599647 TI - ACHA Sets New Attendance Record at 13th Congress on Administration. PMID- 26599648 TI - Consultant's Corner. PMID- 26599650 TI - Review of Hospital Lawsuits. PMID- 26599649 TI - Hospital Financial Problems. PMID- 26599652 TI - Operating Room: Special Report: 17th National AORN Congress. PMID- 26599661 TI - Green recovery of mercury from domestic and industrial waste. AB - Recovery of mercury from effluents is fundamental for environmental preservation. A new, green method was developed for separation of mercury from effluent containing different metals. The extraction/separation of Hg(II) was studied using aqueous two-phase system (ATPS) comprising by polyethylene oxide (PEO1500) or triblock copolymers (L64 or L35), electrolyte (sodium citrate or sodium sulfate) and water in the presence or absence of chloride ions. The extraction behavior of the Hg(II) for the macromolecule-rich phase is affected by the following parameters: amount of added extractant, pH, and the nature of the electrolyte and macromolecule of the ATPS. The APTS of PEO1500+sodium citrate+H2O (pH 1.00 and 0.225 mol kg(-1) KCl) produced the highest Hg(II) %E=(92.3 +/- 5.2)%. Under the same conditions, excellent separation factors (1.54*10(2) 3.21*10(10)) for recovery of mercury in the presence of co-existing metals were obtained. Efficient and selective extraction of Hg(II) from domestic and industrial synthetic effluents was achieved using this ATPS. PMID- 26599662 TI - Genotoxic potential of montmorillonite clay mineral and alteration in the expression of genes involved in toxicity mechanisms in the human hepatoma cell line HepG2. AB - Montmorillonite, also known as Cloisite((r))Na(+) (CNa(+)), is a natural clay with a wide range of well-documented and novel applications, such as pharmaceutical products or food packaging. Although considered a low toxic product, the expected increased exposure to CNa(+) arises concern on the potential consequences on human and environmental health especially as its genotoxicity has scarcely been investigated so far. Thus, we investigated, for the first time, the influence of non-cytotoxic concentrations of CNa(+) (15.65, 31.25 and 62.5 MUg/mL) on genomic instability of human hepatoma cell line (HepG2) by determining the formation of micronuclei (MNi), nucleoplasmic bridges (NPBs) and nuclear buds (NBUDs) with the Cytokinesis block micronucleus cytome assay. Further on we studied the influence of CNa(+) on the expression of several genes involved in toxicity mechanisms using the real-time quantitative PCR. The results showed that CNa(+) increased the number of MNi, while the numbers of NBUDs and NPBs were not affected. In addition it deregulated genes in all the groups studied, mainly after longer time of exposure. These findings provide the evidence that CNa(+) is potentially genotoxic. Therefore further studies that will elucidate the molecular mechanisms involved in toxic activity of CNa(+) are needed for hazard identification and human safety assessment. PMID- 26599663 TI - Differential expression of antimicrobial peptides in psoriasis and psoriatic arthritis as a novel contributory mechanism for skin and joint disease heterogeneity. AB - OBJECTIVES: This study tested the hypothesis that a differential innate immune antimicrobial peptide (AMP) profile was evident between the skin and joints in psoriasis and psoriatic arthritis (PsA) and that PsA synovitis may have a distinct AMP pattern compared to other arthropathies. METHOD: Twenty-two cases had knee biopsies [10 PsA, eight rheumatoid arthritis (RA), and four osteoarthritis (OA)]. Lesional and non-lesional skin biopsies in psoriasis and control tissue were also obtained (n = 4 each). Immunohistochemistry with semi quantitative scoring of both synovium and skin was performed using the following panel of AMPs: S100 A8, S100 A9, human neutrophil peptides 1-3 (HNP1-3), human beta-defensins 2 and 3 (hBD-2 and hBD-3), cathelicidin LL-37, psoriasin (S100 A7), and ribonuclease 7 (RNase 7). RESULTS: Similar expression of S100 A8, S100 A9, and HNP1-3 was detectable in PsA and RA synovium but only in the synovium sublining layer (SSL). No expression of psoriasin, RNase 7, hBD-2, and hBD-3 could be detected in the synovial tissue of PsA, RA, or OA. All psoriasis skin samples exhibited broad expression of all investigated AMPs, with strong keratinocyte expression. CONCLUSIONS: Given that some AMPs, especially hBD-2, are genetically linked to psoriasis and are only expressed in the skin, these findings show how differential AMP expression in innate immune responses may contribute to disease heterogeneity between PsA and psoriasis and provides a genetic basis for the non-progression of psoriasis subgroups to PsA. PMID- 26599664 TI - Osmophoresis--a possible mechanism for vesicle trafficking in tip-growing cells. AB - A mechanism for polarized transport of vesicles by means of osmotic propulsions is proposed and substantiated for tip-growing cells. An analysis is presented which shows that in pollen tubes the gradient of cytosolic water potential can drive vesicle movement either in the anterograde or retrograde direction, depending on the vesicle position, its radius and the phase of growth oscillation. The importance of transcellular water flow for cytoskeletal dynamics and cell motility is highlighted. PMID- 26599665 TI - Response to Standardized MR Terminology and Reporting of Implants and Devices as Recommended by the American College of Radiology Subcommittee on MR Safety. AB - The U.S. Food and Drug Administration (FDA) continually works toward the goal of safety. For patients with magnetic resonance (MR) Conditional devices, safety is achieved when MR Conditional labeling is clear and accessible and can be unambiguously interpreted and applied. The FDA supports the three facets of standardization listed by the American College of Radiology (ACR) Subcommittee on MR Safety in their special report: (a) standardization in terminology and reporting of spatial gradient magnetic fields associated with MR systems; (b) standardization in reporting of ferromagnetic testing results for implants and devices; and (c) standardization, consistency, and clarity in radiofrequency power deposition guidelines and terminology. While the FDA is in agreement with the ACR Subcommittee on MR Safety that patient safety is of primary concern, the authors disagree with the Subcommittee on several important points and offer a point-by-point response to the Subcommittee's four recommendations. ((c)) RSNA, 2015. PMID- 26599666 TI - Hyperpolarized Metabolic MR Imaging of Acute Myocardial Changes and Recovery after Ischemia-Reperfusion in a Small-Animal Model. AB - PURPOSE: To implement hyperpolarized magnetic resonance (MR) imaging in an animal model of ischemia-reperfusion and to assess in vivo the regional changes in pyruvate metabolism within the 1st hour and at 1 week after a brief episode of coronary occlusion and reperfusion. MATERIALS AND METHODS: All animal experiments were performed with adherence to the Swiss Animal Protection law and were approved by the regional veterinary office. A closed-chest rat model was implemented by using an inflatable balloon secured around the left coronary artery. Animals were placed in an MR system 5-7 days after surgery. [1 (13)C]pyruvate was polarized by using a home-built multisample hyperpolarizer. Hyperpolarized pyruvate was injected at five stages: at baseline; at reperfusion after 15 minutes of coronary occlusion; and at 30 minutes, 60 minutes, and 1 week after ischemia reperfusion. The conversion of pyruvate into lactate and bicarbonate was imaged by using dedicated MR sequences alongside wall motion and delayed enhancement imaging. After imaging, the heart was removed and stained to delineate the area at risk (AAR). Differences between AAR and remote myocardium were assessed by using a repeated measures analysis of variance and a post hoc Bonferroni multiple comparison test. RESULTS: Data were collected in 12 animals. Occlusion led to hypokinesia of the anterior or anterolateral segments of the myocardium. At reperfusion, the average lactate-to-bicarbonate ratio increased in the AAR relative to that at baseline (from 1.93 +/- 0.48 to 3.01 +/- 0.74, P < .001) and was significantly higher when compared with that in the remote area (1.91 +/- 0.38, P < .001). In the 60 minutes after occlusion, the lactate-to bicarbonate ratio in the AAR recovered but was still elevated relative to that in the remote area. One week after ischemia-reperfusion, no difference between AAR and remote area could be detected. CONCLUSION: Hyperpolarized metabolic MR imaging can be used to successfully detect acute changes in [1-(13)C]pyruvate metabolism after ischemia-reperfusion, thereby enabling in vivo monitoring of the metabolic effects of reperfusion strategies. PMID- 26599667 TI - Locked Nucleic Acid Probe-Based Real-Time PCR Assay for the Rapid Detection of Rifampin-Resistant Mycobacterium tuberculosis. AB - Drug-resistant Mycobacterium tuberculosis can be rapidly diagnosed through nucleic acid amplification techniques by analyzing the variations in the associated gene sequences. In the present study, a locked nucleic acid (LNA) probe-based real-time PCR assay was developed to identify the mutations in the rpoB gene associated with rifampin (RFP) resistance in M. tuberculosis. Six LNA probes with the discrimination capability of one-base mismatch were designed to monitor the 23 most frequent rpoB mutations. The target mutations were identified using the probes in a "probe dropout" manner (quantification cycle = 0); thus, the proposed technique exhibited superiority in mutation detection. The LNA probe based real-time PCR assay was developed in a two-tube format with three LNA probes and one internal amplification control probe in each tube. The assay showed excellent specificity to M. tuberculosis with or without RFP resistance by evaluating 12 strains of common non-tuberculosis mycobacteria. The limit of detection of M. tuberculosis was 10 genomic equivalents (GE)/reaction by further introducing a nested PCR method. In a blind validation of 154 clinical mycobacterium isolates, 142/142 (100%) were correctly detected through the assay. Of these isolates, 88/88 (100%) were determined as RFP susceptible and 52/54 (96.3%) were characterized as RFP resistant. Two unrecognized RFP-resistant strains were sequenced and were found to contain mutations outside the range of the 23 mutation targets. In conclusion, this study established a sensitive, accurate, and low-cost LNA probe-based assay suitable for a four-multiplexing real-time PCR instrument. The proposed method can be used to diagnose RFP resistant tuberculosis in clinical laboratories. PMID- 26599668 TI - Fornix-based versus limbal-based conjunctival trabeculectomy flaps for glaucoma. AB - BACKGROUND: Glaucoma is one of the leading largely preventable causes of blindness in the world. It usually is addressed first medically with topical intraocular pressure-lowering drops or by laser trabeculoplasty. In cases where such treatment fails, glaucoma-filtering surgery is considered, most commonly trabeculectomy surgery with variations in technique, for example, the type of conjunctival flap (fornix- or limbal-based). In a fornix-based flap, the surgical wound is performed at the corneal limbus; while in a limbal-based flap, the incision is further away. Many studies in the literature compare fornix- and limbal-based trabeculectomy with respect to outcomes and complications. OBJECTIVES: To assess the comparative effectiveness of fornix- versus limbal based conjunctival flaps in trabeculectomy for adult glaucoma, with a specific focus on intraocular pressure (IOP) control and complications (adverse effects). SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (2015, Issue 9), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to October 2015), EMBASE (January 1980 to October 2015), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to October 2015), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 23 October 2015.We reviewed the bibliographic references of identified randomised controlled trials (RCTs) in order to find trials not identified by the electronic searches. We contacted researchers and practitioners active in the field of glaucoma to identify other published and unpublished trials. SELECTION CRITERIA: We included RCTs comparing the benefits and complications of fornix- versus limbal-based trabeculectomy for glaucoma, irrespective of glaucoma type, publication status, and language. We excluded studies on children less than 18 years of age, since wound healing is different in this age group and the rate of bleb scarring postoperatively is high. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed trial quality. We contacted study authors for additional information.The primary outcome was the proportion of failed trabeculectomies at 24 months. Failure was defined as the need for repeat surgery or uncontrolled IOP (more than 22 mmHg), despite additional topical/systemic medications. Needling and 5-fluorouracil (5-FU) injections were allowed only during the first six months postoperatively; additional needling or 5-FU injections were considered as failure. Mean post-operative IOP at 12 and 24 months also was recorded. MAIN RESULTS: The review included six trials with a total of 361 participants. Two studies were conducted in America and one each in Germany, Greece, India, and Saudi Arabia. The participants of four trials had open-angle glaucoma; one study included participants with primary open-angle or primary closed-angle glaucoma, and one study did not specify the type of glaucoma. Three studies used a combined procedure (phacotrabeculectomy). Trabeculectomy with mitomycin C (MMC) was performed in four studies, and trabeculectomy with 5-fluorouracil (5-FU) was performed in only one study.None of the included trials reported trabeculectomy failure at 24 months. Only one trial reported the failure rate of trabeculectomy as a late complication. Failure was higher among participants randomised to the limbal-based surgery: 1/50 eyes failed trabeculectomy in the fornix group compared with 3/50 in the limbal group (risk ratio (RR) 0.33, 95% confidence interval (95% CI) 0.04 to 3.10); therefore we are very uncertain as to the relative effect of the two procedures on failure rate.Four studies including 252 participants provided measures of mean IOP at 12 months. In the fornix-based surgeries, mean IOP ranged from 12.5 to 15.5 mmHg and similar results were noted in limbal-based surgeries with mean IOP ranging from 11.7 to 15.1 mmHg without significant difference. Mean difference was 0.44 mmHg (95% CI -0.45 to 1.33) and 0.86 mmHg, (95% CI -0.52 to 2.24) at 12 and 24 months of follow-up, respectively. Neither of these pooled analyses showed a statistically significant difference in IOP between groups (moderate quality of evidence).One trial reported number of anti-glaucoma medications at 24 months of follow-up with no difference noted between surgical groups. However, three trials reported the mean number of anti-glaucoma medications at 12 months of follow-up without significant difference in the mean number of postoperative IOP-lowering medications between the two surgical techniques. Mean difference was 0.02, (95% CI -0.15 to 0.19) at 12 months of follow-up (high quality of evidence).Because of the small numbers of events and total participants, the risk of many reported adverse events were uncertain and those that were found to be statistically significant may have been due to chance.For risk of bias assessment: although all six trials were randomised selection bias was mostly unclear, with unclear random sequence generation in four of the six studies and unclear allocation concealment in five of the six studies. Attrition bias was encountered in only one trial which also suffered from reporting bias. All other trials had an unclear risk of reporting bias as there was no access to study protocols. All included trials were judged to have high risk of detection bias due to lack of masking of the outcomes. Trabeculectomy is quite a standard procedure and unlikely to induce bias due to surgeon 'performance', hence performance bias was not evaluated. AUTHORS' CONCLUSIONS: The main result of this review was that there was uncertainty as to the difference between fornix- and limbal-based trabeculectomy surgeries due to the small number of events and confidence intervals that cross the null. This also applied to postoperative complications, but without any impact on long-term failure rate between the two surgical techniques. PMID- 26599670 TI - Employment and Community Living Issues for People with Multiple Sclerosis. PMID- 26599669 TI - The Effect of CmLOXs on the Production of Volatile Organic Compounds in Four Aroma Types of Melon (Cucumis melo). AB - Lipoxygenases (LOXs) play important role in the synthesis of volatile organic compounds (VOCs), which influence the aroma of fruit. In this study, we elucidate that there is a positive relationship between LOXs activity and VOC production in melon (Cucumis melo), and CmLOX genes are involved in fruit aroma generation in melon. To this end, we tested four aroma types of melon that feature a thin pericarp: two aromatic cultivars of the oriental melons (C. melo var. makuwa Makino), 'Yu Meiren' (YMR) and 'Cui Bao' (CB); a non-aromatic oriental pickling melon (C. melo var. conomon), 'Shao Gua' (SHAO); and a non-aromatic snake melon (C. melo L. var. flexuosus Naud), 'Cai Gua' (CAI). A principal component analysis (PCA) revealed that the aromas of SHAO and CAI are similar in nature because their ester contents are lower than those of YMR and CB. Ethyl acetate, benzyl acetate, (E, Z)-2, 6-nonadienal and menthol are four principal volatile compounds that affect the aromatic characteristics of these four types of melons. The LOX activity and total ester content in YMR were the highest among the examined melon varieties. The expression patterns of 18 CmLOX genes were found to vary based on the aromatic nature of the melon. Four of them were highly expressed in YMR. Moreover, we treated the fruit disks of YMR with LOX substrates (linoleic acid and linolenic acid) and LOX inhibitors (n-propyl gallate and nordihydroguariaretic acid). Substrate application promoted LOX activity and induced accumulation of hexanal, (2E)-nonenal and straight-chain esters, such as ethyl acetate. In contrast, LOX inhibitors decreased the levels of these compounds. The effect of CmLOXs in the biosynthesis of esters in melons are discussed. PMID- 26599671 TI - The employment concerns of Americans with multiple sclerosis: Perspectives from a national sample. AB - BACKGROUND: The recent rehabilitation literature does not include a thorough assessment of the employment concerns of people with MS. OBJECTIVE: This article presents descriptive findings from a national survey of the employment concerns of Americans with multiple sclerosis (MS; N = 1,924), representing nine chapters of the National Multiple Sclerosis Society. METHODS: Respondents were asked to evaluate 38 employment concerns items on two dimensions, importance and satisfaction, for the purpose of identifying strengths and weaknesses in the employment policies and practices affecting the labor force participation of people with MS. RESULTS: Results revealed a total of 32 employment strengths and six employment weaknesses. CONCLUSIONS: In spite of a jobless rate of more than 60 percent, people with MS were satisfied with the majority of employment concerns. Implications of these findings for rehabilitation policy and service delivery are examined. PMID- 26599672 TI - Employment as a health promotion intervention for persons with multiple sclerosis. AB - OBJECTIVE: To examine the relationship between employment status (no employment, part-time employment, and full-time employment) and functional disability, health related quality of life, and life satisfaction of people with MS. METHODS: 157 individuals with MS completed a survey packet, including employment status, self report disability severity, and health-related scales. A series of multivariate analysis of variance was performed to determine the differences between employment groups in health-related outcomes. RESULTS: The unemployed group had the highest levels of incapacity and social impairments among the three groups. They also had the lowest physical health-related quality of life and life satisfaction. The part-time employed group had the lowest levels of depression and higher levels of physical activity participation among the three groups of individuals with MS. CONCLUSIONS: Employment is significantly related to health related quality of life, and as a result, it should be considered an important public health intervention for people with MS. PMID- 26599673 TI - Home functioning profiles in people with multiple sclerosis and their relation to disease characteristics and psychosocial functioning. AB - BACKGROUND: For people with multiple sclerosis (MS), limitations in performing activities of daily living can have a significant impact on personal independence, residential safety, and quality of life. In this study we explored the utility of the Home Functioning Scale in identifying home functioning profiles and generating rehabilitation interventions. OBJECTIVE: The objective of this study was to determine whether distinctive and meaningful home functioning profiles could be identified among adults with MS based on Home Functioning Scale scores. METHODS: Home Functioning Scale scores and additional data from a representative national sample of 3,834 adults were analyzed. We used cluster analysis and MANOVA to identify and evaluate group differences. RESULTS: Three distinct home functioning profiles emerged in the analysis: (1) minimal impairment (31.1% of participants); (2) moderate impairment (52.4%); and (3) severe impairment (16.5%). The three groups exhibited significant differences on demographic and MS related characteristics, perceived cognitive function, perceived MS impact on physical and psychological function, and life satisfaction. CONCLUSION: The profile characteristics of the identified groups are presented and the implications of the results for rehabilitation practitioners and the investigation of home functioning in activities of daily living are discussed. PMID- 26599674 TI - Gender differences in caregiver strain, needs for support, social support, and quality of life among spousal caregivers of persons with multiple sclerosis. AB - BACKGROUND: Caregivers of individuals with MS may experience unique caregiver strain due to the age at onset and progressive nature of the disease. Additionally, because MS is more prevalent in women, men often become spousal caregivers. However, gender differences in psychosocial adjustment among caregivers have not been fully explored. OBJECTIVE: The purpose of this study was to explore gender differences in the need for various supports and type of social support needed, caregiver strain, and quality of life among caregivers for individuals with MS. METHODS: 106 caregivers participated in this study. Independent sample t-tests and multiple regression analyses were conducted to examine gender differences in strain, need for supports, social support, and quality of life. RESULTS: Analyses revealed gender difference among important psychosocial variables. Specifically, women reported higher levels of caregiver strain, higher needs for emotional support, and higher perceived social support. Additionally, multiple regression analyses revealed an inverse relationship between expressed emotional needs and quality of life for men, but not for women. CONCLUSIONS: MS caregivers experience significant strain that diminishes quality of life. Social support and needs fulfillment can act to buffer this stress; however, results indicate that this varies by gender, with gender differences observed in strain, perceived support, and expressed needs among MS caregivers. The study implications for rehabilitation research are discussed. PMID- 26599675 TI - Disease-related and functional predictors of employment status among adults with multiple sclerosis. AB - BACKGROUND: Due to the extent and complexity of its physical, cognitive, and psychological accompaniments, multiple sclerosis has tremendously negative effects on employment outcomes for adults with the disease. OBJECTIVE: This article extends the current understanding of the relationship between disease related and functional factors and employment status among adults with multiple sclerosis. METHODS: Findings are reported in terms of descriptive statistics and logistic regression. The logistic regression analysis was completed to determine the extent to which disease-related and functional predictors contributed to the overall prediction model for the employment status of adults with MS. RESULTS: The combined variables explained approximately 33% of the variance in employment status. In addition to three items of the Psychological subscale and 12 items of the Physical subscale, one of the items from the Cognitive Functioning Scale contributed to the prediction of employment status. CONCLUSIONS: The findings emphasize the importance of including physical, psychological, and cognitive functioning variables when predicting employment status among adults with multiple sclerosis. PMID- 26599676 TI - Why do they fail? A qualitative follow up study of 1000 recruits to the British Army Infantry to understand high levels of attrition. AB - BACKGROUND: The British Army has over 100 career employment groups to which recruits may apply. The Infantry is one of these career employment groups; it accounts for 25% of the overall strength. It is of concern that Infantry recruit attrition within the first 12 weeks of training remains consistently above 30% . Poor selection methods that lead to the enlistment of unsuitable recruits have negative financial and personal consequences, but little is known about the personal experiences of those who fail. OBJECTIVE: The aim of this research was to understand why infantry recruits choose to leave and explore the personal experiences of those that fail. METHODS: This study draws on qualitative data from the second phase of a larger mixed method study. The foci of this paper are the findings directly related to the responses of recruits in exit interviews and their Commanding Officers' training reports. An exploratory qualitative, inductive method was used to generate insights, explanations and potential solutions to training attrition. RESULTS: What the data describes is a journey of extreme situational demands that the recruits experience throughout their transition from civilian life to service in the British Infantry. It is the cumulative effect of the stressors, combined with the recruit being dislocated from their established support network, which appears to be the catalyst for failure among recruits. CONCLUSION: There are clearly defined areas where either further research or changes to current practice may provide a better understanding of, and ultimately reduce, the current attrition rates experienced by the Infantry Training Centre. PMID- 26599678 TI - Too frequent low-dose methotrexate prescriptions: multicentre quality control and quality assurance with pre- and post-analysis. AB - INTRODUCTION: Methotrexate is used to treat many medical conditions with medication schedules that differ widely in dosage and frequency. The high potential of erroneous too frequent low-dose methotrexate prescriptions leading to severe adverse reactions is well known; however, documentation is mainly limited to case reports. We reviewed all methotrexate prescriptions in a secondary and a tertiary care hospital to analyse the incidence of too frequent low-dose methotrexate prescriptions, and assessed the quality assurance concepts implemented. METHODS: All nononcological low-dose methotrexate prescriptions issued for inpatients within 55 months were analysed to identify too frequent prescriptions potentially leading to harmful overdosing. Subsequently, clinical pharmacologists reviewed all new methotrexate prescriptions with resulting interventions at the physician level in the tertiary care hospital. The impact of an interruptive alert displayed at methotrexate order entry was assessed in the secondary care hospital. RESULTS: The incidence of too frequent prescriptions at the tertiary hospital was 1.6% (five medication errors and nine near misses in 888 inpatients). After introducing checks by pharmacologists, two prescription errors were intercepted during the 8 month quality assurance period. At the secondary care hospital the incidence dropped from 2.5% (2/79, 20 months) to 0.8% (1/123, 35 months) after the alert was implemented. CONCLUSIONS: The incidences of erroneous too frequent low-dose methotrexate prescriptions observed at both hospitals were considered too high due to the high potential for increased morbidity, mortality and costs. Therefore, quality assurance measures were implemented and the preliminary data show a positive impact on patient safety for both approaches. PMID- 26599677 TI - Impact of Birth Preparedness and Complication Readiness Interventions on Birth with a Skilled Attendant: A Systematic Review. AB - BACKGROUND: Increased preparedness for birth and complications is an essential part of antenatal care and has the potential to increase birth with a skilled attendant. We conducted a systematic review of studies to assess the effect of birth preparedness and complication readiness interventions on increasing birth with a skilled attendant. METHODS: PubMed, Embase, CINAHL and grey literature were searched for studies from 2000 to 2012 using a broad range of search terms. Studies were included with diverse designs and intervention strategies that contained an element of birth preparedness and complication readiness. Data extracted included population, setting, study design, outcomes, intervention description, type of intervention strategy and funding sources. Quality of the studies was assessed. The studies varied in BP/CR interventions, design, use of control groups, data collection methods, and outcome measures. We therefore deemed meta-analysis was not appropriate and conducted a narrative synthesis of the findings. RESULTS: Thirty-three references encompassing 20 different intervention programmes were included, of which one programmatic element was birth preparedness and complication readiness. Implementation strategies were diverse and included facility-, community-, or home-based services. Thirteen studies resulted in an increase in birth with a skilled attendant or facility birth. The majority of authors reported an increase in knowledge on birth preparedness and complication readiness. CONCLUSIONS: Birth Preparedness and Complication Readiness interventions can increase knowledge of preparations for birth and complications; however this does not always correspond to an increase in the use of a skilled attendant at birth. PMID- 26599679 TI - Idiopathic hypersomnia. AB - Idiopathic hypersomnia continues to evolve from the concept of "sleep drunkenness" introduced by Bedrich Roth in Prague in 1956 and the description of idiopathic hypersomnia with two forms, polysymptomatic and monosymptomatic, by the same Bedrich Roth in 1976. The diagnostic criteria of idiopathic hypersomnia have varied with the successive revisions of the International classifications of sleep disorders, including the recent 3rd edition. No epidemiological studies have been conducted so far. Disease onset occurs most often during adolescence or young adulthood. A familial background is often present but rigorous studies are still lacking. The key manifestation is hypersomnolence. It is often accompanied by sleep of long duration and debilitating sleep inertia. Polysomnography (PSG) followed by a multiple sleep latency test (MSLT) is mandatory, as well as a 24 h PSG or a 2-wk actigraphy in association with a sleep log to ensure a total 24-h sleep time longer than or equal to 66O minutes, when the mean sleep latency on the MSLT is longer than 8 min. Yet, MSLT is neither sensitive nor specific and the polysomnographic diagnostic criteria require continuous readjustment and biologic markers are still lacking. Idiopathic hypersomnia is most often a chronic condition though spontaneous remission may occur. The condition is disabling, sometimes even more so than narcolepsy type 1 or 2. Based on neurochemical, genetic and immunological analyses as well as on exploration of the homeostatic and circadian processes of sleep, various pathophysiological hypotheses have been proposed. Differential diagnosis involves a number of diseases and it is not yet clear whether idiopathic hypersomnia and narcolepsy type 2 are not the same condition. Until now, the treatment of idiopathic hypersomnia has mirrored that of the sleepiness of narcolepsy type 1 or 2. The first randomized, double-blind, placebo-controlled trials of modafinil have just been published, as well as a double-blind, placebo-controlled trial of clarithromycine, a negative allosteric modulator of the gamma-aminobutyric acid-A receptor. PMID- 26599681 TI - Biolimus-Eluting StenT For de-novo coRonary artery dIsease in patiENts with Diabetes mellituS: the BESTFRIENDS multicentre registry. AB - AIMS: Coronary inflammation and healing influence outcomes of diabetic patients treated with Percutaneous coronary revascularization (PCI). Stents covered with biodegradable polymers (bp) may offer advantages over nonerodible polymer ones, because polymer reabsorption extinguish coronary inflammation and favours healing. Aim of our study was to assess the safety and efficacy of bp-biolimus eluting stent (bp-BES) in a large series of consecutive diabetic patients. METHODS: From 2009 to 2013 we retrospectively enrolled consecutive diabetic patients treated with PCI and bp-BES implantation. Primary end points were target lesion revascularization (TLR) and stent thrombosis rates. RESULTS: Study cohort counted 747 patients. Multivessel disease was present in 48.2% with a mean stent/patient ratio of 1.860.78. During the hospital stay no stent thrombosis occurred. At 3-year follow-up we observed a 1.5% cumulative incidence of cardiac death, 1.1% of myocardial infarction and 6.3% of TLR. Stent thrombosis occurred in 1.1% of patients, all in the first 2 years of follow-up. Kaplan-Meier analysis showed a TLR-free survival at 1 and 3 years of 97.2 and 96.1%, respectively. CONCLUSION: PCI with bp-BES seems to be well tolerated and effective in a large unselected population of diabetic patients. The good results observed were maintained at 3 years of follow-up. PMID- 26599682 TI - Bioresorbable vascular scaffold restenosis: intravascular imaging evaluation. AB - : The mechanism of restenosis in bioresorbable vascular scaffold (BVS) may be different from that of metallic stents and it is still poorly investigated. Intravascular imaging techniques are useful tools for corroborating or excluding possible mechanisms of intra-scaffold restenosis. In these novel devices intravascular imaging should be systematically used for a better comprehension of the in-scaffold restenosis mechanism. PMID- 26599683 TI - Diagnostic value of ischemia severity at myocardial perfusion imaging in elderly persons with suspected coronary disease. AB - AIMS: Myocardial perfusion and ischemia scores obtained from myocardial perfusion scintigraphy (MPS) have strong independent prognostic value in elderly individuals without known coronary artery disease (CAD). Herein we aimed to assess their independent diagnostic value and accuracy for CAD while considering different thresholds of myocardial ischemia. METHODS: We estimated the summed rest score (SRS), summed stress score (SSS) and summed difference score (SDS) in 322 elderly individuals (mean age 72 +/- 7 years, 68% men) who underwent coronary angiography following an MPS. Abnormal perfusion at stress was defined as an SSS greater than 3, and ischemia as an SDS of at least 2, and further categorized as mild (2-4), moderate (5-7) or severe (>7). Multivariate logistic regressions were used to establish the independent diagnostic value and accuracy of MPS parameters. RESULTS: CAD was diagnosed in 182 individuals (56%). In multivariate analysis accounting for clinical variables associated with CAD including the Framingham risk score, both SRS [odds ratio (OR) 1.09, 95% confidence interval (CI) 1.01-1.18, P = 0.03] and SSS (OR 1.10, 95% CI 1.04-1.16, P = 0.0006) and SDS (OR 1.12, 95% CI 1.04-1.21, P = 0.003) were independently associated with CAD. An SSS greater than 3 was also independently associated with CAD (OR 2.51, 95% CI 1.43-4.39, P = 0.0013), whereas an SDS of 2 or greater was not (OR 1.62, 95% CI 0.89-2.93, P = 0.12), but only when at least 5 (OR 2.31, 95% CI 1.32-4.03, P = 0.003). The probability of CAD was proportional to the amount of myocardial ischemia in those with an SSS greater than 3, and lower and comparable in those with an SSS of at least 3 or an SSS greater than 3 with SDS of 1 or less (P = 0.19). Increasing the threshold of myocardial ischemia determined a decrease in sensitivity and increase in specificity of MPS for both diagnosis and severity of CAD. CONCLUSION: We established the diagnostic value and accuracy of continuous scores and thresholds of abnormal myocardial perfusion and ischemia previously validated in prognostic studies. Their more widespread use could potentially improve the diagnostic yield of coronary angiography in elderly individuals with suspected CAD. PMID- 26599684 TI - Antegrade wire escalation for chronic total occlusions in coronary arteries: simple algorithms as a key to success. AB - AIMS: Antegrade wire escalation (AWE) remains the method of choice for tackling chronic total occlusions (CTOs), especially for lesions with low J-CTO score. To increase the number of operators which treat CTOs and increase AWE success rates, there is a need for a clear, algorithmic approach. We report the results of a simple AWE algorithm with new guidewire technology in coronary CTOs. METHODS: Hundred consecutive CTO lesions selected for AWE as the primary strategy were included in five Benelux centers. The algorithm follows a step-wise increase in guidewire tip load. Lesions were categorized according to the J-CTO score. Primary endpoint was successful guidewire crossing. RESULTS: No differences in baseline demographics were present between successful and unsuccessful procedures. Overall, in 75% of the lesions AWE resulted in successful crossing. AWE success rates in easy, intermediate, difficult and very difficult CTOs were 83, 86, 71 and 43%, respectively. 46% could be crossed using a soft guidewire only. An additional success of 34 and 60% could be reached with an intermediate and stiff guidewire, respectively. Adding additional techniques resulted in 88% overall success. Procedure and fluoroscopy times, radiation doses and use of contrast were within highly acceptable ranges (67 +/- 39 min, 27 +/- 19 min, 1.7 +/- 1.3 Gy, 264 +/- 123 ml). CONCLUSION: The algorithm and new wire technologies led to high success rates. AWE as a standalone procedure is highly successful in J-CTO 0-1. Low- and intermediate-volume CTO operators should try to implement a systematic approach in their CTO procedures, especially for lesions with low J CTO scores. Adding additional techniques further increases these success rates. PMID- 26599685 TI - Analysis of Allergenic Pollen by FTIR Microspectroscopy. AB - Fourier transform infrared (FTIR) spectroscopy is a powerful tool for the identification and characterization of pollen and spores. However, interpretation and multivariate analysis of infrared microscopy spectra of single pollen grains are hampered by Mie-type scattering. In this paper, we introduce a novel sampling setup for infrared microspectroscopy of pollens preventing strong Mie-type scattering. Pollen samples were embedded in a soft paraffin layer between two sheets of polyethylene foils without any further sample pretreatment. Single grain infrared spectra of 13 different pollen samples, belonging to 11 species, were obtained and analyzed by the new approach and classified by sparse partial least-squares regression (PLSR). For the classification, chemical and physical information were separated by extended multiplicative signal correction and used together to build a classification model. A training set of 260 spectra and an independent test set of 130 spectra were used. Robust sparse classification models allowing the biochemical interpretation of the classification were obtained by the sparse PLSR, because only a subset of variables was retained for the analysis. With accuracy values of 95% and 98%, for the independent test set and full cross-validation respectively, the method is outperforming the previously published studies on development of an automated pollen analysis. Since the method is compatible with standard air-samplers, it can be employed with minimal modification in regular aerobiology studies. When compared with optical microscopy, which is the benchmark method in pollen analysis, the infrared microspectroscopy method offers better taxonomic resolution, as well as faster, more economical, and bias-free measurement. PMID- 26599686 TI - Physical exercises with free weights and elastic bands can improve body composition parameters in postmenopausal women: WEB protocol with a randomized controlled trial. AB - OBJECTIVE: The aim of this study was to assess the impact of a program of supervised physical exercises (WEB protocol) versus home-based exercises on body composition (lean mass and fat mass) in postmenopausal women. METHODS: The initial sample comprised 60 women who were randomized into two groups. After exclusion, the final randomized sample included a supervised group (n = 16; mean age, 66.4 +/- 6.5 y) and a home group (n = 18; mean age, 68.2 +/- 6.0 y). Both groups underwent a 12-month intervention with physical exercises, including muscle impact exercises and strength and stretching consisting of two weekly sessions of 60 minutes. Body composition was determined by densitometry. RESULTS: The supervised group exhibited increased lean mass in the upper limbs (P = 0.003) and lower limbs (P = 0.011), total lean tissue (P = 0.015), and appendicular lean mass index (P = 0.001) compared with baseline. The home group exhibited no differences in the lean mass assessments. CONCLUSIONS: Our results suggest that regular supervised physical exercises with free weights and elastic bands can promote greater improvements in lean body mass than unsupervised exercises in postmenopausal women. PMID- 26599687 TI - Cardiac repolarization in recently postmenopausal women with or without hot flushes. AB - OBJECTIVE: Menopausal hot flushes are associated with elevated activity of the sympathetic nervous system and may be related to increased risk for cardiovascular events. Sympathetic activation may trigger severe arrhythmias by modulating cardiac repolarization. The aim of this study was to evaluate the impact of hot flushes on cardiac repolarization in postmenopausal women with and without hot flushes. METHODS: We assessed 150 recently postmenopausal healthy women-72 with hot flushes and 78 without hot flushes. They underwent 24-hour electrocardiographic recording, comprising a total of over 10,000,000 QT-interval measurements. The cardiac repolarization was assessed by measuring QT-intervals, heat rate dependence of QT-end intervals, and T-waves. RESULTS: The maximal QT end interval was shorter in women with hot flushes compared with those without hot flushes (481 +/- 64 ms vs 493 +/- 50 ms; P = 0.046). There were no differences between the rate dependence of QT-end intervals and T-wave measures between the groups. During the night-time hot flush period, we detected a steeper rate-dependence of QT-end intervals and a longer maximal T-peak-T-end interval (117 +/- 54 ms vs 111 +/- 56 ms; P < 0.001) compared with the control period. CONCLUSIONS: Women with hot flushes did not have clinically significant differences in ambulatory cardiac repolarization measurements compared with asymptomatic women. However, a sudden sympathetic surge occurring during the night-time hot flush may have direct effects on cardiac repolarization. PMID- 26599688 TI - Beyond Rational Decision-Making: Modelling the Influence of Cognitive Biases on the Dynamics of Vaccination Coverage. AB - BACKGROUND: Theoretical studies predict that it is not possible to eradicate a disease under voluntary vaccination because of the emergence of non-vaccinating "free-riders" when vaccination coverage increases. A central tenet of this approach is that human behaviour follows an economic model of rational choice. Yet, empirical studies reveal that vaccination decisions do not necessarily maximize individual self-interest. Here we investigate the dynamics of vaccination coverage using an approach that dispenses with payoff maximization and assumes that risk perception results from the interaction between epidemiology and cognitive biases. METHODS: We consider a behaviour-incidence model in which individuals perceive actual epidemiological risks as a function of their opinion of vaccination. As a result of confirmation bias, sceptical individuals (negative opinion) overestimate infection cost while pro-vaccines individuals (positive opinion) overestimate vaccination cost. We considered a feedback between individuals and their environment as individuals could change their opinion, and thus the way they perceive risks, as a function of both the epidemiology and the most common opinion in the population. RESULTS: For all parameter values investigated, the infection is never eradicated under voluntary vaccination. For moderately contagious diseases, oscillations in vaccination coverage emerge because individuals process epidemiological information differently depending on their opinion. Conformism does not generate oscillations but slows down the cultural response to epidemiological change. CONCLUSION: Failure to eradicate vaccine preventable disease emerges from the model because of cognitive biases that maintain heterogeneity in how people perceive risks. Thus, assumptions of economic rationality and payoff maximization are not mandatory for predicting commonly observed dynamics of vaccination coverage. This model shows that alternative notions of rationality, such as that of ecological rationality whereby individuals use simple cognitive heuristics, offer promising new avenues for modelling vaccination behaviour. PMID- 26599690 TI - High-Performance Energetic Characteristics and Magnetic Properties of a Three Dimensional Cobalt(II) Metal-Organic Framework Assembled with Azido and Triazole. AB - A three-dimensional metal-organic framework based, high-energy-density compound, [Co5(3-atrz)7(N3)3] (3-atrz = 3-amine-1H-1,2,4-triazole), features superior detonation properties, insensitivity, and thermostability. Magnetic studies show that the compound characterizes the coexistence of remarkable coercivity, metamagnetism, long-range ordering, and relaxation dynamics. The heat-capacity measurement confirms the typical long-range antiferromagnetic ordering below 16 K. This difunctional system exemplifies an effective attempt at developing advanced magnetoenergetic materials. PMID- 26599691 TI - Targeting the expression of glutathione- and sulfate-dependent detoxification enzymes in HepG2 cells by oxygen in minimal and amino acid enriched medium. AB - Cancer cells exhibit specific metabolism allowing them to survive and proliferate in various oxygen conditions and nutrients' availability. Hepatocytes are highly active metabolically and thus very sensitive to hypoxia. The purpose of the study was to investigate the effect of oxygen on the expression of phase II detoxification enzymes in hepatocellular carcinoma cells (HepG2) cultured in minimal and rich media (with nonessential amino acids and GSH). The cells were cultured at 1% hypoxia, 10% tissue normoxia, and 21% atmospheric normoxia. The total cell count was determined by trypan blue exclusion dye and the expression on mRNA level by RT-PCR. The result indicated that the expression of glutathione dependent enzymes (GSTA, M, P, and GPX2) was sensitive to oxygen and medium type. At 1% hypoxia the enzyme expression (with the exception of GSTA) was higher in minimal compared to rich medium, whereas at 10% normoxia it was higher in the rich medium. The expression was oxygen-dependent in both types of medium. Among phenol sulfotransferase SULT1A1 was not sensitive to studied factors, whereas the expression of SULT1A3 was depended on oxygen only in minimal medium. It can be concluded that in HepG2 cells, the detoxification by conjugation with glutathione and, to a lower extent with sulfate, may be affected by hypoxia and/or limited nutrients' availability. Besides, because the data obtained at 10% oxygen significantly differ from those at 21%, the comparative studies on hypoxia should be performed in relation to 10% but not 21% oxygen. PMID- 26599692 TI - The Hidden Sexuality of Alexandrium Minutum: An Example of Overlooked Sex in Dinoflagellates. AB - Dinoflagellates are haploid eukaryotic microalgae in which rapid proliferation causes dense blooms, with harmful health and economic effects to humans. The proliferation mode is mainly asexual, as the sexual cycle is believed to be rare and restricted to stressful environmental conditions. However, sexuality is key to explaining the recurrence of many dinoflagellate blooms because in many species the fate of the planktonic zygotes (planozygotes) is the formation of resistant cysts in the seabed (encystment). Nevertheless, recent research has shown that individually isolated planozygotes in the lab can enter other routes besides encystment, a behavior of which the relevance has not been explored at the population level. In this study, using imaging flow cytometry, cell sorting, and Fluorescence In Situ Hybridization (FISH), we followed DNA content and nuclear changes in a population of the toxic dinoflagellate Alexandrium minutum that was induced to encystment. Our results first show that planozygotes behave like a population with an "encystment-independent" division cycle, which is light controlled and follows the same Light:Dark (L:D) pattern as the cycle governing the haploid mitosis. Resting cyst formation was the fate of just a small fraction of the planozygotes formed and was restricted to a period of strongly limited nutrient conditions. The diploid-haploid turnover between L:D cycles was consistent with two-step meiosis. However, the diel and morphological division pattern of the planozygote division also suggests mitosis, which would imply that this species is not haplontic, as previously considered, but biphasic, because individuals could undergo mitotic divisions in both the sexual (diploid) and the asexual (haploid) phases. We also report incomplete genome duplication processes. Our work calls for a reconsideration of the dogma of rare sex in dinoflagellates. PMID- 26599693 TI - Maxillary single-jaw surgery combining Le Fort I and modified horseshoe osteotomies for the correction of maxillary excess. AB - A modified technique of horseshoe osteotomy combined with Le Fort I osteotomy for superior and posterior repositioning of the maxilla is presented. Eight patients with maxillary excess associated with retrogenia or microgenia were treated with this technique in combination with genioplasty. The maxillary segment was repositioned a maximum of 5.0mm posteriorly and 7.0mm superiorly at point A. The mandible autorotated anterosuperiorly to achieve sound occlusion. Point B moved 2.0-10.0mm anteriorly and 5.0-10.0mm superiorly. The pogonion moved 7.0-17.0mm anteriorly in combination with genioplasty. All patients obtained sound occlusion and a good profile after the operation. Almost no skeletal relapse was observed during 1 year of postoperative follow-up. Patients with long faces with maxillary excess and retrogenia often have small, unstable condyles. In these cases, because surgical intervention to the ramus can result in postoperative progressive condylar resorption, maxillary single-jaw surgery with a horseshoe osteotomy, thereby avoiding ramus intervention, is a less invasive option. PMID- 26599694 TI - Evaluation of the percutaneous absorption of chlorpromazine from PLO gels across porcine ear and human abdominal skin. AB - OBJECTIVE: The overall objective of this work is to determine the percutaneous absorption of chlorpromazine hydrochloride from pluronic lecithin organogels (PLO gels) and verify the suitability of topically applied chlorpromazine hydrochloride PLO gels for use in hospice patients for relieving symptoms such as vomiting and nausea during the end stages of life. METHODS: PLO gels of chlorpromazine hydrochloride were prepared using isopropyl palmitate (IPP) or ricinoleic acid (RA) as oil phase. In vitro percutaneous absorption of chlorpromazine hydrochloride was assessed through porcine ear and human abdominal skin. Further, the theoretical steady state plasma concentration (Css) of chlorpromazine was calculated from the flux values. RESULTS: The pH, viscosity, and stability of both PLO gels prepared with IPP and RA were comparable. The thixotropic property of RA PLO gel was found to be better than that of IPP PLO gel. The permeation of chlorpromazine hydrochloride was higher from RA PLO gel than from IPP PLO gel and pure drug solution. Theoretical Css of chlorpromazine from pure drug solution, IPP PLO gel and RA PLO gel were found to be 1.05, 1.20, and 1.50 ng/ml, respectively. PLO gels only marginally increased the flux and theoretical Css of chlorpromazine. CONCLUSION: From this study, it is clearly evident that PLO gels fail to achieve required systemic levels of chlorpromazine following topical application. Chlorpromazine PLO gel may not be effective in treating nausea and vomiting for hospice patients with swallowing difficulties. PMID- 26599695 TI - Passages 2016. PMID- 26599696 TI - The Resource Identification Initiative: A Cultural Shift in Publishing. AB - A central tenet in support of research reproducibility is the ability to uniquely identify research resources, i.e., reagents, tools, and materials that are used to perform experiments. However, current reporting practices for research resources are insufficient to identify the exact resources that are reported or to answer basic questions such as "How did other studies use resource X?" To address this issue, the Resource Identification Initiative was launched as a pilot project to improve the reporting standards for research resources in the Methods sections of articles and thereby improve identifiability and scientific reproducibility. The pilot engaged over 25 biomedical journal editors from most major publishers, as well as scientists and funding officials. Authors were asked to include Research Resource Identifiers (RRIDs) in their articles prior to publication for three resource types: antibodies, model organisms, and tools (i.e., software and databases). RRIDs are assigned by an authoritative database, for example, a model organism database for each type of resource. To make it easier for authors to obtain RRIDs, resources were aggregated from the appropriate databases and their RRIDs made available in a central Web portal (http://scicrunch.org/resources). RRIDs meet three key criteria: they are machine readable, free to generate and access, and are consistent across publishers and journals. The pilot was launched in February of 2014 and over 300 articles have appeared that report RRIDs. The number of journals participating has expanded from the original 25 to more than 40, with RRIDs appearing in 62 different journals to date. Here we present an overview of the pilot project and its outcomes to date. We show that authors are able to identify resources and are supportive of the goals of the project. Identifiability of the resources post pilot showed a dramatic improvement for all three resource types, suggesting that the project has had a significant impact on identifiability of research resources. PMID- 26599698 TI - TRPM8 Channel Activation Induced by Monoterpenoid Rotundifolone Underlies Mesenteric Artery Relaxation. AB - In this study, our aims were to investigate transient receptor potential melastatin-8 channels (TRPM8) involvement in rotundifolone induced relaxation in the mesenteric artery and to increase the understanding of the role of these thermosensitive TRP channels in vascular tissue. Thus, message and protein levels of TRPM8 were measured by semi-quantitative PCR and western blotting in superior mesenteric arteries from 12 week-old Spague-Dawley (SD) rats. Isometric tension recordings evaluated the relaxant response in mesenteric rings were also performed. Additionally, the intracellular Ca2+ changes in mesenteric artery myocytes were measured using confocal microscopy. Using PCR and western blotting, both TRPM8 channel mRNA and protein expression was measured in SD rat mesenteric artery. Rotundifolone and menthol induced relaxation in the isolated superior mesenteric artery from SD rats and improved the relaxant response induced by cool temperatures. Also, this monoterpene induced an increase in transient intracellular Ca2+. These responses were significantly attenuated by pretreatment with capsazepine or BCTC, both TRPM8 channels blockers. The response induced by rotundifolone was not significantly attenuated by ruthenium red, a non-selective TRP channels blocker, or following capsaicin-mediated desensitization of TRPV1. Our findings suggest that rotundifolone induces relaxation by activating TRPM8 channels in rat superior mesenteric artery, more selectively than menthol, the classic TRPM8 agonist, and TRPM8 channels participates in vasodilatory pathways in isolated rat mesenteric arteries. PMID- 26599700 TI - Sensitivity Enhancement in Magnetic Particle Imaging by Background Subtraction. AB - Biomedical applications such as cell tracking and angiography require the detection of low concentrations of superparamagnetic iron oxide nanoparticles (SPIOs) for imaging purposes. Magnetic particle imaging (MPI) is a new technology which enables the quantitative and time-resolved localization of SPIO distributions. However, the minimum concentration at which the SPIOs can be reconstructed with a suitable quality still remains to be investigated. In this work we examine the background signals in raw data that were measured without any SPIOs in the scanner tube. We show that a background subtraction in combination with a frequency cutoff for the dynamic part of the background signal lowers the detection limit for SPIOs in MPI up to a factor of ten. In-vivo mouse experiments show that for early time points from when the tracer enters the vena cava a reconstructed image of sufficient quality can only be obtained when a background subtraction is performed. PMID- 26599699 TI - Mass HIV Treatment and Sex Disparities in Life Expectancy: Demographic Surveillance in Rural South Africa. AB - BACKGROUND: Women have better patient outcomes in HIV care and treatment than men in sub-Saharan Africa. We assessed--at the population level--whether and to what extent mass HIV treatment is associated with changes in sex disparities in adult life expectancy, a summary metric of survival capturing mortality across the full cascade of HIV care. We also determined sex-specific trends in HIV mortality and the distribution of HIV-related deaths in men and women prior to and at each stage of the clinical cascade. METHODS AND FINDINGS: Data were collected on all deaths occurring from 2001 to 2011 in a large population-based surveillance cohort (52,964 women and 45,688 men, ages 15 y and older) in rural KwaZulu-Natal, South Africa. Cause of death was ascertained by verbal autopsy (93% response rate). Demographic data were linked at the individual level to clinical records from the public sector HIV treatment and care program that serves the region. Annual rates of HIV-related mortality were assessed for men and women separately, and female-to-male rate ratios were estimated in exponential hazard models. Sex specific trends in adult life expectancy and HIV-cause-deleted adult life expectancy were calculated. The proportions of HIV deaths that accrued to men and women at different stages in the HIV cascade of care were estimated annually. Following the beginning of HIV treatment scale-up in 2004, HIV mortality declined among both men and women. Female adult life expectancy increased from 51.3 y (95% CI 49.7, 52.8) in 2003 to 64.5 y (95% CI 62.7, 66.4) in 2011, a gain of 13.2 y. Male adult life expectancy increased from 46.9 y (95% CI 45.6, 48.2) in 2003 to 55.9 y (95% CI 54.3, 57.5) in 2011, a gain of 9.0 y. The gap between female and male adult life expectancy doubled, from 4.4 y in 2003 to 8.6 y in 2011, a difference of 4.3 y (95% CI 0.9, 7.6). For women, HIV mortality declined from 1.60 deaths per 100 person-years (95% CI 1.46, 1.75) in 2003 to 0.56 per 100 person-years (95% CI 0.48, 0.65) in 2011. For men, HIV-related mortality declined from 1.71 per 100 person-years (95% CI 1.55, 1.88) to 0.76 per 100 person-years (95% CI 0.67, 0.87) in the same period. The female-to-male rate ratio for HIV mortality declined from 0.93 (95% CI 0.82-1.07) in 2003 to 0.73 (95% CI 0.60 0.89) in 2011, a statistically significant decline (p = 0.046). In 2011, 57% and 41% of HIV-related deaths occurred among men and women, respectively, who had never sought care for HIV in spite of the widespread availability of free HIV treatment. The results presented here come from a poor rural setting in southern Africa with high HIV prevalence and high HIV treatment coverage; broader generalizability is unknown. Additionally, factors other than HIV treatment scale up may have influenced population mortality trends. CONCLUSIONS: Mass HIV treatment has been accompanied by faster declines in HIV mortality among women than men and a growing female-male disparity in adult life expectancy at the population level. In 2011, over half of male HIV deaths occurred in men who had never sought clinical HIV care. Interventions to increase HIV testing and linkage to care among men are urgently needed. PMID- 26599701 TI - Learning-Based Multi-Label Segmentation of Transrectal Ultrasound Images for Prostate Brachytherapy. AB - Low-dose-rate prostate brachytherapy treatment takes place by implantation of small radioactive seeds in and sometimes adjacent to the prostate gland. A patient specific target anatomy for seed placement is usually determined by contouring a set of collected transrectal ultrasound images prior to implantation. Standard-of-care in prostate brachytherapy is to delineate the clinical target anatomy, which closely follows the real prostate boundary. Subsequently, the boundary is dilated with respect to the clinical guidelines to determine a planning target volume. Manual contouring of these two anatomical targets is a tedious task with relatively high observer variability. In this work, we aim to reduce the segmentation variability and planning time by proposing an efficient learning-based multi-label segmentation algorithm. We incorporate a sparse representation approach in our methodology to learn a dictionary of sparse joint elements consisting of images, and clinical and planning target volume segmentation. The generated dictionary inherently captures the relationships among elements, which also incorporates the institutional clinical guidelines. The proposed multi-label segmentation method is evaluated on a dataset of 590 brachytherapy treatment records by 5-fold cross validation. We show clinically acceptable instantaneous segmentation results for both target volumes. PMID- 26599702 TI - A Generative Probabilistic Model and Discriminative Extensions for Brain Lesion Segmentation--With Application to Tumor and Stroke. AB - We introduce a generative probabilistic model for segmentation of brain lesions in multi-dimensional images that generalizes the EM segmenter, a common approach for modelling brain images using Gaussian mixtures and a probabilistic tissue atlas that employs expectation-maximization (EM), to estimate the label map for a new image. Our model augments the probabilistic atlas of the healthy tissues with a latent atlas of the lesion. We derive an estimation algorithm with closed-form EM update equations. The method extracts a latent atlas prior distribution and the lesion posterior distributions jointly from the image data. It delineates lesion areas individually in each channel, allowing for differences in lesion appearance across modalities, an important feature of many brain tumor imaging sequences. We also propose discriminative model extensions to map the output of the generative model to arbitrary labels with semantic and biological meaning, such as "tumor core" or "fluid-filled structure", but without a one-to-one correspondence to the hypo- or hyper-intense lesion areas identified by the generative model. We test the approach in two image sets: the publicly available BRATS set of glioma patient scans, and multimodal brain images of patients with acute and subacute ischemic stroke. We find the generative model that has been designed for tumor lesions to generalize well to stroke images, and the extended discriminative -discriminative model to be one of the top ranking methods in the BRATS evaluation. PMID- 26599705 TI - Imaging gray matter with concomitant null point imaging from the phase sensitive inversion recovery sequence. AB - PURPOSE: To present an improved three-dimensional (3D) interleaved phase sensitive inversion recovery (PSIR) sequence including a concomitantly acquired new contrast, null point imaging (NPI), to help detect and classify abnormalities in cortical gray matter. METHODS: The 3D gradient echo PSIR images were acquired at 0.6 mm isotropic resolution on 11 multiple sclerosis (MS) patients and 9 controls subjects using a 7 Tesla (T) MRI scanner, and 2 MS patients at 3T. Cortical abnormalities were delineated on the NPI/PSIR data and later classified according to position in the cortex. RESULTS: The NPI helped detect cortical lesions within the cortical ribbon with increased, positive contrast compared with the PSIR. It also provided improved intrinsic delineation of the ribbon, increasing confidence in classifying the lesions' locations. CONCLUSION: The proposed PSIR facilitates the classification of cortical lesions by providing two T1 -weighted 3D datasets with isotropic resolution, including the NPI showing cortical lesions with clear delineation of the gray/white matter boundary and minimal partial volume effects. Magn Reson Med 76:1512-1516, 2016. (c) 2015 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. PMID- 26599706 TI - Comparison of the bias voltage effect and the force effect during the nanoscale AFM electric lithography on the copper thin film surface. AB - As one of the tip-based nanoscale machining methods, AFM-based nanolithography has been proved to be capable of fabricating nanostructures and devices on a wide range of materials by means of mechanical force, bias voltage, chemical reaction, etc. In this paper, we have compared the influences of the bias voltage effect and the force effect during the nanoscale AFM electric lithography on the metallic copper film surface respectively through the bias voltage dominating scheme and the contact force dominating scheme. The geometric sizes of the line structures and the area patterns fabricated under the two schemes with different parameter settings were compared to obtain the machining characteristics and mechanisms of the two distinct effects separately. The ratios of debris amount to the total material removal amount under the two schemes were quantitatively evaluated. Furthermore, both the arbitrary line structure with high aspect ratio and the area pattern with small surface roughness were fabricated under the appropriate scheme and parameter settings. This study is of great help to effectively achieve the desired nanoscale patterns by AFM electric lithography for their promising applications in the fabrication of various MEMS or NEMS devices. SCANNING 38:412-420, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26599708 TI - Genome-wide analysis of the SBP-box gene family in Chinese cabbage (Brassica rapa subsp. pekinensis). AB - The SQUAMOSA PROMOTER BINDING PROTEIN (SBP)-box gene family contains highly conserved plant-specific transcription factors that play an important role in plant development, especially in flowering. Chinese cabbage (Brassica rapa subsp. pekinensis) is a leafy vegetable grown worldwide and is used as a model crop for research in genome duplication. The present study aimed to characterize the SBP box transcription factor genes in Chinese cabbage. Twenty-nine SBP-box genes were identified in the Chinese cabbage genome and classified into six groups. We identified 23 orthologous and 5 co-orthologous SBP-box gene pairs between Chinese cabbage and Arabidopsis. An interaction network among these genes was constructed. Sixteen SBP-box genes were expressed more abundantly in flowers than in other tissues, suggesting their involvement in flowering. We show that the MiR156/157 family members may regulate the coding regions or 3'-UTR regions of Chinese cabbage SBP-box genes. As SBP-box genes were found to potentially participate in some plant development pathways, quantitative real-time PCR analysis was performed and showed that Chinese cabbage SBP-box genes were also sensitive to the exogenous hormones methyl jasmonic acid and salicylic acid. The SBP-box genes have undergone gene duplication and loss, evolving a more refined regulation for diverse stimulation in plant tissues. Our comprehensive genome wide analysis provides insights into the SBP-box gene family of Chinese cabbage. PMID- 26599709 TI - Global Exponential Stability of Cohen-Grossberg Neural Networks with Piecewise Constant Argument of Generalized Type and Impulses. AB - In this letter, we consider a model of Cohen-Grossberg neural networks with piecewise constant argument of generalized type and impulses. Sufficient conditions ensuring the existence and uniqueness of solutions are obtained. Based on constructing a new differential inequality with piecewise constant argument and impulse and using the Lyapunov function method, we derive sufficient conditions ensuring the global exponential stability of equilibrium point, with approximate exponential convergence rate. An example is given to illustrate the validity and advantage of the theoretical results. PMID- 26599707 TI - Pretreatment with Antioxidants Augments the Acute Arterial Vasoconstriction Caused by Diesel Exhaust Inhalation. AB - RATIONALE: Diesel exhaust inhalation, which is the model traffic-related air pollutant exposure, is associated with vascular dysfunction. OBJECTIVES: To determine whether healthy subjects exposed to diesel exhaust exhibit acute vasoconstriction and whether this effect could be modified by the use of antioxidants or by common variants in the angiotensin II type 1 receptor (AGTR1) and other candidate genes. METHODS: In a genotype-stratified, double-blind, four way crossover study, 21 healthy adult subjects were exposed at rest in a randomized, balanced order to diesel exhaust (200 MUg/m(3) particulate matter with an aerodynamic diameter <= 2.5 MUm [PM2.5]) and filtered air, and to pretreatment with antioxidants (N-acetylcysteine and ascorbate) and placebo. Before and after each exposure, brachial artery diameter (BAd) was assessed using ultrasound. Changes in BAd were compared across pretreatment and exposure sessions. Gene-exposure interactions were evaluated in the AGTR1 A1166C polymorphism, on which recruitment was stratified, and other candidate genes, including TRPV1 and GSTM1. MEASUREMENTS AND MAIN RESULTS: Compared with filtered air, exposure to diesel exhaust resulted in a significant reduction in BAd (mean, -0.09 mm, 95% confidence interval [CI], -0.01 to -0.17; P = 0.03). Pretreatment with antioxidants augmented diesel exhaust-related vasoconstriction with a mean change in BAd of -0.18 mm (95% CI, -0.28 to -0.07 mm; P = 0.001). Diesel exhaust related vasoconstriction was primarily observed in the variant alleles of AGTR1 and TRPV1. No association was found between diesel exhaust inhalation and flow mediated dilation. CONCLUSIONS: We confirmed that short-term exposure to diesel exhaust in healthy subjects is associated with acute vasoconstriction in a conductance artery and found suggestive evidence of involvement of nociception and renin-angiotensin systems in this effect. Pretreatment with an antioxidant regimen increased vasoconstriction. PMID- 26599710 TI - Sequential Tests for Large-Scale Learning. AB - We argue that when faced with big data sets, learning and inference algorithms should compute updates using only subsets of data items. We introduce algorithms that use sequential hypothesis tests to adaptively select such a subset of data points. The statistical properties of this subsampling process can be used to control the efficiency and accuracy of learning or inference. In the context of learning by optimization, we test for the probability that the update direction is no more than 90 degrees in the wrong direction. In the context of posterior inference using Markov chain Monte Carlo, we test for the probability that our decision to accept or reject a sample is wrong. We experimentally evaluate our algorithms on a number of models and data sets. PMID- 26599711 TI - Efficient Associative Computation with Discrete Synapses. AB - Neural associative networks are a promising computational paradigm for both modeling neural circuits of the brain and implementing associative memory and Hebbian cell assemblies in parallel VLSI or nanoscale hardware. Previous work has extensively investigated synaptic learning in linear models of the Hopfield type and simple nonlinear models of the Steinbuch/Willshaw type. Optimized Hopfield networks of size n can store a large number of about n(2)/k memories of size k (or associations between them) but require real-valued synapses, which are expensive to implement and can store at most C = 0.72 bits per synapse. Willshaw networks can store a much smaller number of about n(2)/k(2) memories but get along with much cheaper binary synapses. Here I present a learning model employing synapses with discrete synaptic weights. For optimal discretization parameters, this model can store, up to a factor zeta close to one, the same number of memories as for optimized Hopfield-type learning--for example, zeta = 0.64 for binary synapses, zeta = 0.88 for 2 bit (four-state) synapses, zeta = 0.96 for 3 bit (8-state) synapses, and zeta > 0.99 for 4 bit (16-state) synapses. The model also provides the theoretical framework to determine optimal discretization parameters for computer implementations or brainlike parallel hardware including structural plasticity. In particular, as recently shown for the Willshaw network, it is possible to store C(I) = 1 bit per computer bit and up to C(S) = log n bits per nonsilent synapse, whereas the absolute number of stored memories can be much larger than for the Willshaw model. PMID- 26599712 TI - A Note on Support Vector Machines with Polynomial Kernels. AB - We present a better theoretical foundation of support vector machines with polynomial kernels. The sample error is estimated under Tsybakov's noise assumption. In bounding the approximation error, we take advantage of a geometric noise assumption that was introduced to analyze gaussian kernels. Compared with the previous literature, the error analysis in this note does not require any regularity of the marginal distribution or smoothness of Bayes' rule. We thus establish the learning rates for polynomial kernels for a wide class of distributions. PMID- 26599713 TI - An Empirical Overview of the No Free Lunch Theorem and Its Effect on Real-World Machine Learning Classification. AB - A sizable amount of research has been done to improve the mechanisms for knowledge extraction such as machine learning classification or regression. Quite unintuitively, the no free lunch (NFL) theorem states that all optimization problem strategies perform equally well when averaged over all possible problems. This fact seems to clash with the effort put forth toward better algorithms. This letter explores empirically the effect of the NFL theorem on some popular machine learning classification techniques over real-world data sets. PMID- 26599714 TI - Analytical Calculation of Errors in Time and Value Perception Due to a Subjective Time Accumulator: A Mechanistic Model and the Generation of Weber's Law. AB - It has been previously shown (Namboodiri, Mihalas, Marton, & Hussain Shuler, 2014) that an evolutionary theory of decision making and time perception is capable of explaining numerous behavioral observations regarding how humans and animals decide between differently delayed rewards of differing magnitudes and how they perceive time. An implementation of this theory using a stochastic drift diffusion accumulator model (Namboodiri, Mihalas, & Hussain Shuler, 2014a) showed that errors in time perception and decision making approximately obey Weber's law for a range of parameters. However, prior calculations did not have a clear mechanistic underpinning. Further, these calculations were only approximate, with the range of parameters being limited. In this letter, we provide a full analytical treatment of such an accumulator model, along with a mechanistic implementation, to calculate the expression of these errors for the entirety of the parameter space. In our mechanistic model, Weber's law results from synaptic facilitation and depression within the feedback synapses of the accumulator. Our theory also makes the prediction that the steepness of temporal discounting can be affected by requiring the precise timing of temporal intervals. Thus, by presenting exact quantitative calculations, this work provides falsifiable predictions for future experimental testing. PMID- 26599715 TI - Neural Network Spectral Robustness under Perturbations of the Underlying Graph. AB - Recent studies have been using graph-theoretical approaches to model complex networks (such as social, infrastructural, or biological networks) and how their hardwired circuitry relates to their dynamic evolution in time. Understanding how configuration reflects on the coupled behavior in a system of dynamic nodes can be of great importance, for example, in the context of how the brain connectome is affecting brain function. However, the effect of connectivity patterns on network dynamics is far from being fully understood. We study the connections between edge configuration and dynamics in a simple oriented network composed of two interconnected cliques (representative of brain feedback regulatory circuitry). In this article our main goal is to study the spectra of the graph adjacency and Laplacian matrices, with a focus on three aspects in particular: (1) the sensitivity and robustness of the spectrum in response to varying the intra- and intermodular edge density, (2) the effects on the spectrum of perturbing the edge configuration while keeping the densities fixed, and (3) the effects of increasing the network size. We study some tractable aspects analytically, then simulate more general results numerically, thus aiming to motivate and explain our further work on the effect of these patterns on the network temporal dynamics and phase transitions. We discuss the implications of such results to modeling brain connectomics. We suggest potential applications to understanding synaptic restructuring in learning networks and the effects of network configuration on function of regulatory neural circuits. PMID- 26599716 TI - Reduction of Trial-to-Trial Perceptual Variability by Intracortical Tonic Inhibition. AB - Variability is a prominent characteristic of cognitive brain function. For instance, different trials of presentation of the same stimulus yield higher variability in its perception: subjects sometimes fail in perceiving the same stimulus. Perceptual variability could be attributable to ongoing-spontaneous fluctuation in neuronal activity prior to sensory stimulation. Simulating a cortical neural network model, we investigated the underlying neuronal mechanism of perceptual variability in relation to variability in ongoing-spontaneous neuronal activity. In the network model, populations of principal cells (cell assemblies) encode information about sensory features. Each cell assembly is sensitive to one particular feature stimulus. Transporters on GABAergic interneurons regulate ambient GABA concentration in a neuronal activity-dependent manner. Ambient GABA molecules activate extrasynaptic GABAa receptors on principal cells and interneurons, and provide them with tonic inhibitory currents. We controlled the variability of ongoing-spontaneous neuronal activity by manipulating the basal level of ambient GABA and assessed the perceptual performance of the network: detection of a feature stimulus. In an erroneous response, stimulus-irrelevant but not stimulus-relevant principal cells were activated, generating trains of action potentials. Perceptual variability, reflected in error rate in detecting the same stimulus that was presented repeatedly to the network, was increased as the variability in ongoing spontaneous membrane potential among cell assemblies increased. Frequent, transient membrane depolarization below firing threshold was the major cause of the increased neuronal variability, for which a decrease in basal ambient GABA concentration was responsible. We suggest that ambient GABA in the brain may have a role in reducing the variability in ongoing-spontaneous neuronal activity, leading to a decrease in perceptual variability and therefore to reliable sensory perception. PMID- 26599717 TI - Medullary carcinoma of the small bowel. AB - AIMS: Medullary carcinoma of the large bowel occurs mainly right-sided in elderly females. The tumour is almost invariably microsatellite instable and has been associated with favourable outcome. Our study aimed to present three cases of medullary carcinoma originating from the small bowel. METHODS AND RESULTS: We describe three cases of small bowel medullary carcinoma. Two patients had coeliac disease, diagnosed at the ages of 79 and 71 years, respectively. The tumours showed the characteristic syncytial growth pattern with marked intratumoral lymphocytic inflammation. Loss of MutL homologue 1 (MLH1) [and postmeiotic segregation increased 2 (S. cerevisiae) PMS2] expression was observed in all cases, consistent with high-level microsatellite instability. All tumours were negative for Epstein-Barr virus. Follow-up information was available for one patient, who is recurrence-free 6 years after resection. DISCUSSION: Medullary carcinoma of the small bowel is exceedingly rare. Our data and a review of the literature suggest that this tumour type is characteristic for coeliac disease and may be the histological type underlying small bowel cancers with high-level microsatellite instability in patients with coeliac disease. PMID- 26599718 TI - Discovery, Optimization, and Characterization of Novel Chlorcyclizine Derivatives for the Treatment of Hepatitis C Virus Infection. AB - Recently, we reported that chlorcyclizine (CCZ, Rac-2), an over-the-counter antihistamine piperazine drug, possesses in vitro and in vivo activity against hepatitis C virus. Here, we describe structure-activity relationship (SAR) efforts that resulted in the optimization of novel chlorcyclizine derivatives as anti-HCV agents. Several compounds exhibited EC50 values below 10 nM against HCV infection, cytotoxicity selectivity indices above 2000, and showed improved in vivo pharmacokinetic properties. The optimized molecules can serve as lead preclinical candidates for the treatment of hepatitis C virus infection and as probes to study hepatitis C virus pathogenesis and host-virus interaction. PMID- 26599719 TI - Humpback whale diets respond to variance in ocean climate and ecosystem conditions in the California Current. AB - Large, migratory predators are often cited as sentinel species for ecosystem processes and climate-related changes, but their utility as indicators is dependent upon an understanding of their response to environmental variability. Documentation of the links between climate variability, ecosystem change and predator dynamics is absent for most top predators. Identifying species that may be useful indicators and elucidating these mechanistic links provides insight into current ecological dynamics and may inform predictions of future ecosystem responses to climatic change. We examine humpback whale response to environmental variability through stable isotope analysis of diet over a dynamic 20-year period (1993-2012) in the California Current System (CCS). Humpback whale diets captured two major shifts in oceanographic and ecological conditions in the CCS. Isotopic signatures reflect a diet dominated by krill during periods characterized by positive phases of the North Pacific Gyre Oscillation (NPGO), cool sea surface temperature (SST), strong upwelling and high krill biomass. In contrast, humpback whale diets are dominated by schooling fish when the NPGO is negative, SST is warmer, seasonal upwelling is delayed and anchovy and sardine populations display increased biomass and range expansion. These findings demonstrate that humpback whales trophically respond to ecosystem shifts, and as a result, their foraging behavior is a synoptic indicator of oceanographic and ecological conditions across the CCS. Multi-decadal examination of these sentinel species thus provides insight into biological consequences of interannual climate fluctuations, fundamental to advancing ecosystem predictions related to global climate change. PMID- 26599720 TI - Origin of Stereodivergence in Cooperative Asymmetric Catalysis with Simultaneous Involvement of Two Chiral Catalysts. AB - Accomplishing high diastereo- and enantioselectivities simultaneously is a persistent challenge in asymmetric catalysis. The use of two chiral catalysts in one-pot conditions might offer new avenues to this end. Chirality transfer from a catalyst to product gets increasingly complex due to potential chiral match mismatch issues. The origin of high enantio- and diastereoselectivities in the reaction between a racemic aldehyde and an allyl alcohol, catalyzed by using axially chiral iridium phosphoramidites PR/S-Ir and cinchona amine is established through transition-state modeling. The multipoint contact analysis of the stereocontrolling transition state revealed how the stereodivergence could be achieved by inverting the configuration of the chiral catalysts that are involved in the activation of the reacting partners. While the enantiocontrol is identified as being decided in the generation of PR/S-Ir-pi-allyl intermediate from the allyl alcohol, the diastereocontrol arises due to the differential stabilizations in the C-C bond formation transition states. The analysis of the weak interactions in the transition states responsible for chiral induction revealed that the geometric disposition of the quinoline ring at the C8 chiral carbon of cinchona-enamine plays an anchoring role. The quinolone ring is noted as participating in a pi-stacking interaction with the phenyl ring of the Ir-pi allyl moiety in the case of PR with the (8R,9R)-cinchona catalyst combination, whereas a series of C-H...pi interactions is identified as vital to the relative stabilization of the stereocontrolling transition states when PR is used with (8S,9S)-cinchona. PMID- 26599721 TI - Dielectric Relaxation of Ethylene Carbonate and Propylene Carbonate from Molecular Dynamics Simulations. AB - Ethylene carbonate (EC) and propylene carbonate (PC) are widely used solvents in lithium (Li)-ion batteries and supercapacitors. Ion dissolution and diffusion in those media are correlated with solvent dielectric responses. Here, we use all atom molecular dynamics simulations of the pure solvents to calculate dielectric constants and relaxation times, and molecular mobilities. The computed results are compared with limited available experiments to assist more exhaustive studies of these important characteristics. The observed agreement is encouraging and provides guidance for further validation of force-field simulation models for EC and PC solvents. PMID- 26599723 TI - Phylogeny and Morphological Variability of Trypanosomes from African Pelomedusid Turtles with Redescription of Trypanosoma mocambicum Pienaar, 1962. AB - Little is known about host specificity, genetic diversity and phylogenetic relationships of African turtle trypanosomes. Using PCR targeting the SSU rRNA gene, we detected trypanosomes in 24 of 134 (17.9%) wild caught African pelomedusid turtles: Pelusios upembae (n=14), P. bechuanicus (n=1), P. rhodesianus (n=3) and P. subniger (n=6). Mixed infection of Trypanosoma species was confirmed by PCR in three specimens of P. upembae, and in one specimen each of P. bechuanicus, P. rhodesianus, and P. subniger. Microscopic examination of stained blood smears revealed two distinct forms (broad and slender) of trypomastigotes. The broad form coincided in morphology with T. mocambicumPienaar, 1962. Accordingly, we have designated this form as the neotype of T. mocambicum. In phylogenetic analysis of the SSU rRNA gene, all the new turtle trypanosome sequences grouped in a single clade within the strongly supported "aquatic" clade of Trypanosoma species. The turtle trypanosome clade was further subdivided into two subclades, which did not correlate with host turtle species or trypanosome morphology. This study provides the first sequence data of Trypanosoma species isolated from freshwater turtles from tropical Africa and extends knowledge on diversity of trypanosomes in the Afrotropical zoogeographical realm. PMID- 26599722 TI - Site-specific function and regulation of Osterix in tooth root formation. AB - Congenital diseases of tooth roots, in terms of developmental abnormalities of short and thin root phenotypes, can lead to loss of teeth. A more complete understanding of the genetic molecular pathways and biological processes controlling tooth root formation is required. Recent studies have revealed that Osterix (Osx), a key mesenchymal transcriptional factor participating in both the processes of osteogenesis and odontogenesis, plays a vital role underlying the mechanisms of developmental differences between root and crown. During tooth development, Osx expression has been identified from late embryonic to postnatal stages when the tooth root develops, particularly in odontoblasts and cementoblasts to promote their differentiation and mineralization. Furthermore, the site-specific function of Osx in tooth root formation has been confirmed, because odontoblastic Osx-conditional knockout mice demonstrate primarily short and thin root phenotypes with no apparent abnormalities in the crown (Journal of Bone and Mineral Research 30, 2014 and 742, Journal of Dental Research 94, 2015 and 430). These findings suggest that Osx functions to promote odontoblast and cementoblast differentiation and root elongation only in root, but not in crown formation. Mechanistic research shows regulatory networks of Osx expression, which can be controlled through manipulating the epithelial BMP signalling, mesenchymal Runx2 expression and cellular phosphorylation levels, indicating feasible routes of promoting Osx expression postnatally (Journal of Cellular Biochemistry 114, 2013 and 975). In this regard, a promising approach might be available to regenerate the congenitally diseased root and that regenerative therapy would be the best choice for patients with developmental tooth diseases. PMID- 26599724 TI - First Molecular Characterization of Theileria ornithorhynchi Mackerras, 1959: yet Another Challenge to the Systematics of the Piroplasms. AB - Piroplasms, tick-transmitted Apicomplexa of the genera Theileria, Babesia and Cytauxzoon, are blood-borne parasites of clinical and veterinary importance. The order Piroplasmida shows a puzzling systematics characterized by multiple clades, soft polytomies and paraphyletic/polyphyletic genera. In the present study, screening of platypuses (Ornithorhynchus anatinus), was performed to infer the parasite molecular phylogeny. DNA was extracted from blood, ectoparasites and tick eggs and the 18S rRNA- hsp70-genes were used for the phylogenetic reconstructions. Microscopic analyses detected pleomorphic intra-erythrocytic organisms and tetrads consistent with previous descriptions of Theileria ornithorhynchi Mackerras, 1959, but observation of possible schizonts could not be confirmed. DNA sequences obtained from blood and ticks allowed resolving the systematics of the first piroplasm infecting a monotreme host. Molecularly, T. ornithorhynchi formed a novel monophyletic group, basal to most known piroplasms' clades. The ancestral position of this clade, isolated from an ancient lineage of mammalian host appears particularly fascinating. The present paper discusses the inadequacies of the current molecular systematics for the Piroplasmida and the consequences of incomplete sampling, morphology-based classification and ambiguous microscopic identifications. Likely when the current sampling bias is rectified and more sequence data is made available, the phylogenetic position of T. ornithorhynchi will be further contextualized without ambiguity. PMID- 26599725 TI - Taxonomic Clarification of the Unusual Dinophyte Gymnodinium limneticum Wolosz. (Gymnodiniaceae) from the Tatra Mountains. AB - The Gymnodiniaceae -even in a strict sense- comprise a vast diversity of dinophytes regarding morphology and ecology. Taxonomy and nomenclature of their constituent species remain problematic, although crucial to fully explore the biology of the group. Here, we present the rarely documented dinophyte Gymnodinium limneticum from its type locality at Lake Morskie Oko in Poland, for which we established strains and made extensive morphological studies. The species was unusual in exhibiting capsoid cells as predominant life-history stage, which were embedded and dividing in extensive mucilage leading to an enkaptic pseudocolonial system. We also generated ribosomal RNA sequences that were included in a comprehensive molecular phylogeny. Our species was clearly identified as a member of the Gymnodiniaceae s.str. but within the lineage, it was only distantly related to the type species of Gymnodinium, G. fuscum. Rather, it constituted a monophyletic group together with species assigned to Spiniferodinium and as a nomenclatural result, we propose two new combinations (i.e., Sp. limneticum comb. nov., Sp. palustre comb. nov.). As Spiniferodinium now includes dinophyte species inhabiting marine or freshwater environments as well, our investigations may provide evidence for an evolutionary scenario with corresponding transitions being more frequent than considered before. PMID- 26599726 TI - Two New Freshwater Woloszynskioids Asulcocephalium miricentonis gen. et sp. nov. and Leiocephalium pseudosanguineum gen. et sp. nov. (Suessiaceae, Dinophyceae) Lacking an Apical Furrow Apparatus. AB - Two new woloszynskioid dinoflagellates, Asulcocephalium miricentonis gen. et sp. nov. and Leiocephalium pseudosanguineum gen. et sp. nov., are described from Japanese freshwater ponds on the basis of bright field and fluorescence light microscopy, scanning and transmission electron microscopy, and molecular phylogeny inferred from rDNA sequences. Asulcocephalium miricentonis has a spherical anterior nucleus and chloroplast with a pyrenoid penetrated by the cytoplasm. This species has 9-12 latitudinal series of amphiesmal vesicles (AVs), including an apparently large AV on the right ventral side of the epicone. Leiocephalium pseudosanguineum has a U-shaped nucleus in the epicone and chloroplasts without a pyrenoid. This species has at least 24 latitudinal series of AVs. The characteristic features of both species were brick-like material (type E) in the eyespot and the lack of an apical furrow. These features coincide with those of Polarella glacialis, but the two species differ in cell shape, number and arrangement of AVs, shape of resting cysts, and habitats; i.e., P. glacialis has been reported only from marine cold waters. Molecular phylogeny revealed that A. miricentonis and L. pseudosanguineum were positioned in the Suessiaceae and closely related to Piscinoodinium sp., but their relationship to Polarella and other reported taxa was not supported. PMID- 26599727 TI - Phylogeny, Morphology, and Metabolic and Invasive Capabilities of Epicellular Fish Coccidium Goussia janae. AB - To fill the knowledge gap on the biology of the fish coccidian Goussia janae, RNA extracted from exogenously sporulated oocysts was sequenced. Analysis by Trinity and Trinotate pipelines showed that 84.6% of assembled transcripts share the highest similarity with Toxoplasma gondii and Neospora caninum. Phylogenetic and interpretive analyses from RNA-seq data provide novel insight into the metabolic capabilities, composition of the invasive machinery and the phylogenetic relationships of this parasite of cold-blooded vertebrates with other coccidians. This allows re-evaluation of the phylogenetic position of G. janae and sheds light on the emergence of the highly successful obligatory intracellularity of apicomplexan parasites. G. janae possesses a partial glideosome and along with it, the metabolic capabilities and adaptions of G. janae might provide cues as to how apicomplexans adjusted to extra- or intra-cytoplasmic niches and also to become obligate intracellular parasites. Unlike the similarly localized epicellular Cryptosporidium spp., G. janae lacks the feeder organelle necessary for directly scavenging nutrients from the host. Transcriptome analysis indicates that G. janae possesses metabolic capabilities comparable to T. gondii. Additionally, this enteric coccidium might also access host cell nutrients given the presence of a recently identified gene encoding the molecular sieve at the parasitophorous vacuole membrane. PMID- 26599728 TI - Soil washing of chromium- and cadmium-contaminated sludge using acids and ethylenediaminetetra acetic acid chelating agent. AB - In this research, the effect of soil washing in the removal of chromium- and cadmium-contaminated sludge samples collected from Pond 2 of the Tehran Oil Refinery was investigated. These metals are considered as hazardous substances for human health and the environment. The carcinogenicity of chromate dust has been established for a long time. Cadmium is also a potential environmental toxicant. This study was carried out by collecting sludge samples from different locations in Pond 2. Soil washing was conducted to treat the samples. Chemical agents, such as acetic acid, ethylenediaminetetra acetic acid (EDTA) and hydrochloric acid, were used as washing solutions to remove chromium and cadmium from sludge samples. The results of this study indicated that the highest removal efficiencies from the sludge samples were achieved using a 0.3 M HCl solution with 82.69% and 74.47% for chromium and cadmium, respectively. EDTA (0.1 M) in the best condition extracted 66.81% of cadmium and 72.52% of chromium from the sludges. The lowest efficiency values for the samples, however, were achieved using 3 M acetic acid with 41.7% and 46.96% removals for cadmium and chromium, respectively. The analysis of washed sludge indicated that the heavy metals removal decreased in the order of 3 M acetic acid < 0.1 M EDTA<0.3 M HCl, thus hydrochloric acid appears to offer a greater potential as a washing agent in remediating the sludge samples. PMID- 26599729 TI - Galvanostatic Ion Detrapping Rejuvenates Oxide Thin Films. AB - Ion trapping under charge insertion-extraction is well-known to degrade the electrochemical performance of oxides. Galvanostatic treatment was recently shown capable to rejuvenate the oxide, but the detailed mechanism remained uncertain. Here we report on amorphous electrochromic (EC) WO3 thin films prepared by sputtering and electrochemically cycled in a lithium-containing electrolyte under conditions leading to severe loss of charge exchange capacity and optical modulation span. Time-of-flight elastic recoil detection analysis (ToF-ERDA) documented pronounced Li(+) trapping associated with the degradation of the EC properties and, importantly, that Li(+) detrapping, caused by a weak constant current drawn through the film for some time, could recover the original EC performance. Thus, ToF-ERDA provided direct and unambiguous evidence for Li(+) detrapping. PMID- 26599730 TI - Age-related incidence of cervical cancer supports two aetiological components: a population-based register study. AB - OBJECTIVE: To assess whether age-related incidence of cervical cancer supports two aetiological components and to assess trends in these components due to risk factors and to organised screening in Finland. DESIGN: Population-based register study. SETTING: Finnish Cancer Registry. POPULATION: Cervical cancer cases and female population in Finland in 1953-2012. METHODS: Cervical cancer incidence was estimated using Poisson regression where age-specific incidence consists of two (early-age and late-age) normally distributed components. MAIN OUTCOME MEASURES: Accumulated net risks (incidences) and numbers of cancer cases attributed to each age-related component by calendar time. RESULTS: The accumulated cervical cancer incidence in 2008-2012 was only 30% of that in 1953-1962, before the screening started. The fit of the observed age-specific rates and the rates based on the two-component model was good. In 1953-62, the accumulated net risk ratio (RR; early-age versus late-age) was 0.42 (95% CI 0.29-0.61). The early-age component disappeared in 1973-77 (RR 0.00; 95% CI 0.00-0.08). Thereafter, the risk for the early-age component increased, whereas the risk for the late-age component decreased, and in 2008-2012 the RR was 0.55 (95% CI 0.24-0.89). CONCLUSIONS: In Finland, cervical cancer incidence has two age-related components which are likely to indicate differences in risk factors of each component. The trend in risk of both components followed the effects of organised screening. Furthermore, the risk related to the early-age component followed changes in risk factors, such as oncogenic HPV infections and other sexually transmitted diseases and smoking habits. TWEETABLE ABSTRACT: Cervical cancer incidence has two age-related components which are likely to have differencies in their aetiology. PMID- 26599731 TI - A mononuclear iron(II) complex: cooperativity, kinetics and activation energy of the solvent-dependent spin transition. AB - The system [FeL2](BF4)2 (1)-EtOH-H2O (L is 4-(3,5-dimethyl-1H-pyrazol-1-yl)-2 (pyridin-2-yl)-6-methylpyrimidine) shows a complicated balance between the relative stabilities of solvatomorphs and polymorphs of the complex [FeL2](BF4)2. New solvatomorphs, 1(LS).EtOH.H2O and beta-1(LS).xH2O, were isolated in this system. They were converted into four daughter phases, 1(A/LS), 1(D/LS), 1(E/LS).yEtOH.zH2O and 1(F/LS). On thermal cycling in sealed ampoules, the phases 1(LS).EtOH.H2O and beta-1(LS).xH2O transform into the anhydrous phase 1(A/LS). The hysteresis loop width for the (A/LS) <-> (A/HS) spin transition depends on the water and ethanol contents in the ampoule and varies from ca. 30 K up to 145 K. The reproducible hysteresis loop of 145 K is the widest ever reported one for a spin crossover complex. The phase 1(A/LS) combines the outstanding spin crossover properties with thermal robustness allowing for multiple cycling in sealed ampoules without degradation. The kinetics of the 1(A/LS) -> 1(A/HS) transition is sigmoidal which is indicative of strong cooperative interactions. The cooperativity of the 1(A/LS) -> 1(A/HS) transition is related to the formation of a 2D supramolecular structure of the phase 1(A/LS). The activation energy for the spin transition is very high (hundreds of kJ mol(-1)). The kinetics of the 1(A/HS) -> 1(A/LS) transition can either be sigmoidal or exponential depending on the water and ethanol contents in the ampoule. The phases 1(D/LS) and 1(F/LS) show gradual crossover, whereas the phase 1(E/LS).yEtOH.yH2O shows a reversible hysteretic transition associated with the solvent molecule release and uptake. PMID- 26599732 TI - Single-molecule fluorimetry and gating currents inspire an improved optical voltage indicator. AB - Voltage-sensing domains (VSDs) underlie the movement of voltage-gated ion channels, as well as the voltage-sensitive fluorescent responses observed from a common class of genetically encoded voltage indicators (GEVIs). Despite the widespread use and potential utility of these GEVIs, the biophysical underpinnings of the relationship between VSD movement and fluorophore response remain unclear. We investigated the recently developed GEVI ArcLight, and its close variant Arclight', at both the single-molecule and macroscopic levels to better understand their characteristics and mechanisms of activity. These studies revealed a number of previously unobserved features of ArcLight's behavior, including millisecond-scale fluorescence fluctuations in single molecules as well as a previously unreported delay prior to macroscopic fluorescence onset. Finally, these mechanistic insights allowed us to improve the optical response of ArcLight to fast or repetitive pulses with the development of ArcLightning, a novel GEVI with improved kinetics. PMID- 26599733 TI - Elective repeat cesarean delivery compared with trial of labor after a prior cesarean delivery: a propensity score analysis. AB - OBJECTIVE: To determine neonatal and short term maternal outcomes according to intentional mode of delivery following a cesarean delivery (CD). STUDY DESIGN: Women pregnant after CD between January 2000 and December 2007 were categorized according to whether they had an elective repeat CD (ERCD) or a Trial of Labor (TOL). Prognostically equal ERCD and TOL groups were created using the propensity score matching technique. Conditional logistic regression was performed to assess differences in neonatal and maternal outcomes. POPULATION: Women in their second ongoing pregnancy with a history of CD. RESULTS: After ERCD the rates of low 5min Apgar score (OR 0.3, 95%CI 0.2-0.5, p<0.001), meconium aspiration (OR 0.0, 95%CI 0-0.7, p=0.02) and birth trauma (OR 0.08, 95%CI 0.002-0.5, p<0.001) were lower compared to TOL. The rate of transient tachypnoea of the newborn (TTN) appears higher in the ERCD group (OR 1.7, 95%CI 1.0-2.8, p=0.04). Uterine rupture (OR 0.1, 95%CI 0.003-0.8, p=0.02) and hemorrhage (OR 0.6, 95%CI 0.5-0.8, p<0.001) occurred less in the ERCD group. CONCLUSION: Neonatal and short term maternal morbidity appears to be lower after ERCD than after TOL. Only TTN was seen more often after ERCD. PMID- 26599735 TI - Emergent Airway Management of an Uncooperative Child with a Large Retropharyngeal and Posterior Mediastinal Abscess. AB - Retropharyngeal abscesses are deep neck space infections that can lead to life threatening airway emergencies and other catastrophic complications. Retropharyngeal abscesses demand prompt diagnosis and early establishment of a definitive airway when there is airway compromise. This can be difficult in an uncooperative patient. We present the case of a 12-year-old girl with mediastinitis and tracheal compression and anterior displacement from a large retropharyngeal and posterior mediastinal abscess secondary to traumatic esophageal perforation, who received successful awake nasal fiberoptic intubation. Anesthesiologists must be prepared for airway emergencies in uncooperative patients, especially children, but there is controversy concerning the use of sedation. PMID- 26599734 TI - MAE4, an eLtaS monoclonal antibody, blocks Staphylococcus aureus virulence. AB - Staphylococcus aureus causes a wide range of infectious diseases. Treatment of these infections has become increasingly difficult due to the widespread emergence of antibiotic-resistant strains; therefore, it is essential to explore effective alternatives to antibiotics. A secreted protein of S. aureus, known as eLtaS, is an extracellular protein released from the bacterial membrane protein, LtaS. However, the role of eLtaS in S. aureus pathogenesis remains largely unknown. Here we show eLtaS dramatically aggravates S. aureus infection by binding to C3b and then inhibiting the phagocytosis of C3b-deposited S. aureus. Furthermore, we developed a monoclonal antibody against eLtaS, MAE4, which neutralizes the activity of eLtaS and blocks staphylococcal evasion of phagocytosis. Consequently, MAE4 is capable of protecting mice from lethal S. aureus infection. Our findings reveal that targeting of eLtaS by MAE4 is a potential therapeutic strategy for the treatment of infectious diseases caused by S. aureus. PMID- 26599736 TI - Management of Near-Complete Airway Obstruction Caused by a Vallecular Cyst in an Infant Using a Tongue Tip Traction Suture. AB - Airway obstruction in infants can be because of a number of airway issues, one of which is a vallecular cyst. Although uncommonly seen, the management strategy for this difficult airway can be applied to many other difficult airway cases. We report the use of a preoperative oral fiberoptic assessment of the airway, use of a tongue stitch, and manipulation of a flexible nasal fiberoptic bronchoscope to secure the airway. Keeping the patient breathing spontaneously with low-dose ketamine also facilitated successful tracheal intubation. PMID- 26599737 TI - Elephant Trunk-Like Teratoma of the Face with Compromised Airway in an Infant with Complex Congenital Cardiac Defects: An Anesthetic Challenge. AB - Large head and neck teratomas are very rare. Depending on their site of origin, they can produce varying degrees of airway compromise and can interfere with the conduct of general anesthesia. Large space-occupying lesions of the face may even interfere with the simple task of mask ventilation rendering inhaled induction of general anesthesia and maintenance of spontaneous ventilation difficult. If these neoplasms coexist with cardiac lesions necessitating corrective or palliative procedures, the task of oxygenation, ventilation, and securing a definitive airway becomes challenging especially in the presence of underlying unstable hemodynamics. We report on the anesthetic management of a female infant with a facial teratoma and single-ventricle physiology undergoing a cardiac palliative procedure where securing a definitive airway with minimal hemodynamic instability was the immediate requirement. PMID- 26599738 TI - Advance Directives and Operating: Room for Improvement? AB - Anesthesiologists and surgeons are frequently called on to perform procedures on critically ill patients with advanced directives. We assessed the attitudes of attending and resident surgeons and anesthesiologists at our institution regarding their understanding of and practice around the application of consenting critically ill patients with advance directives in the operating room. To do so, we deployed a survey after interdepartmental grand rounds, featuring a panel discussion of ethically complex cases featuring end-of-life issues. PMID- 26599739 TI - Prothrombin Complex Concentrate and Methylene Blue for Treatment of Coagulopathy and Vasoplegia in a Pediatric Heart Transplant Patient. AB - Ventricular assist devices (VADs) are associated with conditions that may complicate the perioperative course of pediatric heart transplants. A 7-year-old girl with dilated cardiomyopathy supported by a Toyobo-NCVC left VAD (Toyobo National Cardiovascular Center, Osaka, Japan), a pulsatile extracorporeal device, and preoperatively anticoagulated with warfarin presented for orthotopic heart transplant. The course was complicated by persistent bleeding treated with prothrombin complex concentrate and refractory postbypass vasoplegia treated with methylene blue. Preoperative anticoagulation and the presence of a VAD are associated with postbypass coagulopathy and vasoplegia. We describe a case in which these conditions were successfully treated with no thrombotic complications and minimal need of vasopressors for hemodynamic stability. PMID- 26599740 TI - Symptomatic Management of Fever in Children: A National Survey of Healthcare Professionals' Practices in France. AB - Despite the production and dissemination of recommendations related to managing fever in children, this symptom saturates the practices of primary healthcare professionals (HPs). Data on parent practices related to fever are available, but data on HPs' practices are limited. We studied HPs' practices, determinants of practices and concordance with recommendations in France. We conducted a national cross-sectional observational study between 2007 and 2008 among French general practitioners, primary care pediatricians and pharmacists. HPs were asked to include 5 consecutive patients aged 1 month to 12 years with acute fever. HPs completed a questionnaire about their practices for the current fever episode. We used a multilevel logistic regression model to assess the joint effects of patient- and HP-level variables associated with this behavior. In all, 1,534 HPs (participation rate 13%) included 6,596 children (mean age 3.7 +/- 2.7 years). Physicians measured the temperature of 40% of children. Primary HPs recommended drug treatment for 84% of children (including monotherapy for 92%) and physical treatment for 62% (including all recommended physical treatments for 7%). HPs gave written advice or a pamphlet for 13% of children. Significant practice variations were associated with characteristics of the child (age, fever level and diagnosis) and HP (profession and experience). In France, despite the production and dissemination of national recommendations for managing fever in children, primary HPs' observed practices differed greatly from current recommendations, which suggests potential targets for continuing medical education. PMID- 26599741 TI - Cortical Components of Reaction-Time during Perceptual Decisions in Humans. AB - The mechanisms of perceptual decision-making are frequently studied through measurements of reaction time (RT). Classical sequential-sampling models (SSMs) of decision-making posit RT as the sum of non-overlapping sensory, evidence accumulation, and motor delays. In contrast, recent empirical evidence hints at a continuous-flow paradigm in which multiple motor plans evolve concurrently with the accumulation of sensory evidence. Here we employ a trial-to-trial reliability based component analysis of encephalographic data acquired during a random-dot motion task to directly image continuous flow in the human brain. We identify three topographically distinct neural sources whose dynamics exhibit contemporaneous ramping to time-of-response, with the rate and duration of ramping discriminating fast and slow responses. Only one of these sources, a parietal component, exhibits dependence on strength-of-evidence. The remaining two components possess topographies consistent with origins in the motor system, and their covariation with RT overlaps in time with the evidence accumulation process. After fitting the behavioral data to a popular SSM, we find that the model decision variable is more closely matched to the combined activity of the three components than to their individual activity. Our results emphasize the role of motor variability in shaping RT distributions on perceptual decision tasks, suggesting that physiologically plausible computational accounts of perceptual decision-making must model the concurrent nature of evidence accumulation and motor planning. PMID- 26599742 TI - Carvajal syndrome with oligodontia, hypoacusis, recurrent infections, and noncompaction. PMID- 26599743 TI - The causal link between spontaneous coronary artery dissection and takotsubo syndrome: A case presented with both conditions. PMID- 26599744 TI - The S100A8-serum amyloid A3-LOX-1 cascade in atherosclerotic plaque rupture. PMID- 26599745 TI - Red blood cell distribution width and the recurrence of atrial fibrillation after ablation in patients with paroxysmal non-valvular symptomatic atrial fibrillation. PMID- 26599746 TI - Dopamine D2 receptors contribute to cardioprotection of ischemic post conditioning via activating autophagy in isolated rat hearts. PMID- 26599747 TI - Autopsy findings of the autonomic nervous system in a patient with takotsubo syndrome. PMID- 26599748 TI - Remote ischemic preconditioning for preventing acute kidney injury following cardiovascular surgery: A meta-analysis with trial sequential analysis. PMID- 26599749 TI - Decompressive atrioseptostomy (DAS) for the treatment of severe pulmonary hypertension secondary to restrictive cardiomyopathy. PMID- 26599751 TI - Multifocal atrial tachycardia caused by risperidone. AB - Risperidone, an atypical antipsychotic drug, is one of the most frequently used atypical neuroleptic drugs for the treatment of symptoms of behavioral disorders seen in autism. Although various cardiovascular side effects have been reported with risperidone, to our knowledge, it has not yet been reported that it can also result in multifocal atrial tachycardia. Based on the case reported herein, our aim is to bring awareness that risperidone may cause multifocal atrial tachycardia. PMID- 26599750 TI - Left ventricular native T1 time and the risk of atrial fibrillation recurrence after pulmonary vein isolation in patients with paroxysmal atrial fibrillation. AB - BACKGROUND: Native T1 mapping has emerged as a noninvasive non-contrast magnetic resonance imaging (MRI) method to assess for diffuse myocardial fibrosis. However, LV native T1 time in AF patients and its clinical relevance are unclear. METHODS: Fifty paroxysmal AF patients referred for PVI (60 +/- 8 years, 37 male) and 11 healthy control subjects (57 +/- 8 years, 10 male) were studied. All patients were in sinus rhythm during the MRI scan. Native T1 mapping images were acquired using a Modified Look-Locker imaging (MOLLI) sequence in 3 short-axis planes (basal, mid and apical slices) using an electrocardiogram triggered single shot acquisition with a balanced steady-state free precession readout. Late gadolinium enhanced (LGE) MRI was acquired to evaluate for LV myocardial scar. RESULTS: LV ejection fraction was similar between groups (AF: 61 +/- 6%; controls: 60 +/- 6%, p=0.75). No LV myocardial scar was observed in any patient on LGE. Myocardial native T1 time was greater in AF patients (1099 +/- 52 vs 1042 +/- 20 msec, p<0.001). During a median follow-up period of 326 days, 18 of 50 (36%) patients experienced recurrence of AF. Multivariate Cox proportional hazard analysis identified elevated native T1 time as an independent predictor of recurrence of AF (HR: 6.53, 95% CI: 1.25-34.3, p=0.026). CONCLUSIONS: There are differences in the native LV myocardial T1 time between AF patients with preserved LV function referred for PVI and normal controls. Native T1 time is an independent predictor of recurrence of AF after PVI in patients with paroxysmal AF. PMID- 26599752 TI - Exercise preconditioning prevents MCT-induced right ventricle remodeling through the regulation of TNF superfamily cytokines. AB - BACKGROUND: Exercise training has been recognized as a non-pharmacological therapeutic approach in several chronic diseases; however it remains to be tested if exercise preconditioning can positively interfere with the natural history of pulmonary arterial hypertension (PAH). This is important since the majority of these patients are diagnosed at advanced stages of the disease, when right ventricle (RV) impairment is already present. OBJECTIVES: In the current study, we evaluated the preventive effect of exercise preconditioning on RV failure secondary to PAH, with a focus on the signaling pathways modulated by pro inflammatory cytokines from TNF superfamily. METHODS: We analyzed the RV muscle from adult male Wistar rats exposed to a 4-week treadmill exercise training or sedentary regime, prior to the administration of monocrotaline (MCT) to induce PAH or with saline solution (controls). RESULTS: Data indicate that exercise preconditioning prevented cardiac hypertrophy and RV diastolic dysfunction. At a molecular level, exercise modulated the TWEAK/NF-kappaB signaling axis and prevented the shift in MHC isoforms towards an increased expression of beta-MHC. Exercise preconditioning also prevented the increase of atrogin-1 expression, and induced a shift of MMP activity from MMP-9 to MMP-2 activity. CONCLUSIONS: Altogether, data support exercise as a preventive strategy for the management of PAH, which is of particular relevance for the familial form of PAH that is manifested by greater severity or earlier onset. PMID- 26599753 TI - Antidepressant use and risk for mortality in 121,252 heart failure patients with or without a diagnosis of clinical depression. AB - BACKGROUND: Depression is a risk factor for mortality in patients with heart failure (HF), however, treating depression with antidepressant therapy does not seem to improve survival. We examined the prevalence of antidepressant use in HF patients, the correlates of antidepressant use subsequent to hospital discharge and the relation between antidepressant use, clinical depression and mortality in patients with HF. METHODS: 121,252 HF patients surviving first hospitalization were stratified by antidepressant use and a diagnosis of clinical depression. RESULTS: In total, 15.6% (19,348) received antidepressants at baseline, of which 86.7% (16,780) had no diagnosis of clinical depression. Female gender, older age, higher socio-economic status, more comorbidities, increased use of statins, spironolactone and aspirin, lower use of beta-blockers and ACE-inhibitors, greater HF severity and a diagnosis of clinical depression were independently associated with antidepressant use. Patients using no antidepressants with clinical depression and patients using antidepressants, with or without clinical depression, had a significantly higher risk for all-cause mortality (HR, 1.25; 95% CI, 1.15-1.36; HR, 1.24; 95% CI, 1.22-1.27; HR, 1.21; 95% CI, 1.16-1.27, respectively) and CV-mortality (HR: 1.17; 95% CI, 1.14-1.20, P<.001; HR: 1.20; 95% CI, 1.08-1.34, P<.001; HR: 1.21; 95% CI, 1.12-1.29, P<.001, respectively) as compared to patients not using antidepressants without depression in adjusted analysis. CONCLUSION: Patients with HF taking antidepressants had an increased risk for all-cause and CV-mortality, irrespectively of having clinical depression. These results highlight the importance of further examining the antidepressant prescription pattern in patients with HF, as this may be crucial in understanding the antidepressant effects on cardiac function and mortality. PMID- 26599754 TI - High-density lipoprotein cholesterol might be a better predictor of stroke than other lipid measures in the general Japanese population: The Watari study. PMID- 26599755 TI - Is High Temporal Resolution Achievable for Paediatric Cardiac Acquisitions during Several Heart Beats? Illustration with Cardiac Phase Contrast Cine-MRI. AB - BACKGROUND: During paediatric cardiac Cine-MRI, data acquired during cycles of different lengths must be combined. Most of the time, Feinstein's model is used to project multiple cardiac cycles of variable lengths into a mean cycle. OBJECTIVE: To assess the effect of Feinstein projection on temporal resolution of Cine-MRI. METHODS: 1/The temporal errors during Feinstein's projection were computed in 306 cardiac cycles fully characterized by tissue Doppler imaging with 6-phase analysis (from a population of 7 children and young adults). 2/The effects of these temporal errors on tissue velocities were assessed by simulating typical tissue phase mapping acquisitions and reconstructions. 3/Myocardial velocities curves, extracted from high-resolution phase-contrast cine images, were compared for the 6 volunteers with lowest and highest heart rate variability, within a population of 36 young adults. RESULTS: 1/The mean of temporal misalignments was 30 ms over the cardiac cycle but reached 60 ms during early diastole. 2/During phase contrast MRI simulation, early diastole velocity peaks were diminished by 6.1 cm/s leading to virtual disappearance of isovolumic relaxation peaks. 3/The smoothing and erasing of isovolumic relaxation peaks was confirmed on tissue phase mapping velocity curves, between subjects with low and high heart rate variability (p = 0.05). CONCLUSIONS: Feinstein cardiac model creates temporal misalignments that impair high temporal resolution phase contrast cine imaging when beat-to-beat heart rate is changing. PMID- 26599756 TI - Fractional Generalizations of Maxwell and Kelvin-Voigt Models for Biopolymer Characterization. AB - The paper proposes a fractional generalization of the Maxwell and Kelvin-Voigt rheological models for a description of dynamic behavior of biopolymer materials. It was found that the rheological models of Maxwell-type do not work in the case of modeling of viscoelastic solids, and the model which significantly better describes the nature of changes in rheological properties of such media is the modified fractional Kelvin-Voigt model with two built-in springpots (MFKVM2). The proposed model was used to describe the experimental data from the oscillatory and creep tests of 3% (w/v) kuzu starch pastes, and to determine the values of their rheological parameters as a function of pasting time. These parameters provide a lot of additional information about structure and viscoelastic properties of the medium in comparison to the classical analysis of dynamic curves G' and G" and shear creep compliance J(t). It allowed for a comprehensive description of a wide range of properties of kuzu starch pastes, depending on the conditions of pasting process. PMID- 26599757 TI - Tegafur Substitution for 5-Fu in Combination with Actinomycin D to Treat Gestational Trophoblastic Neoplasm. AB - Although 5-fluorouracil (5-Fu) combination chemotherapy provides a satisfactory therapeutic response in patients with gestational trophoblastic neoplasms (GTNs), it has severe side effects. The current study analyzed the therapeutic effects and side effects of tegafur plus actinomycin D (Act-D) vs. 5-Fu plus Act-D for the treatment of GTNs based on controlled historical records. A total of 427 GTN cases that received tegafur and Act-D combination chemotherapy at the Second Xiangya Hospital of XiangYa Medical School between August 2003 and July 2013 were analyzed based on historical data. A total of 393 GTN cases that received 5-Fu plus Act-D between August 1993 and July 2003 at the same hospital were also analyzed, which constituted the control group. The therapeutic effects, toxicity and side effects after chemotherapy were compared between the groups. The overall response rate was 90.63% in the tegafur+Act-D group (tegafur group) and 92.37% in the 5-Fu+Act-D group (5-Fu group); these rates were not significantly different (P > 0.05). However, the incidence rates of myelosuppression (white blood cell decline), gastrointestinal reactions (nausea, vomiting, dental ulcer, and diarrhea), skin lesions and phlebitis were lower in the tegafur group than in the 5-Fu group (P < 0.05). The results of this study may provide useful data for the clinical application of tegafur in GTN treatment. PMID- 26599758 TI - Total Binding Affinity Profiles of Regulatory Regions Predict Transcription Factor Binding and Gene Expression in Human Cells. AB - Transcription factors regulate gene expression by binding regulatory DNA. Understanding the rules governing such binding is an essential step in describing the network of regulatory interactions, and its pathological alterations. We show that describing regulatory regions in terms of their profile of total binding affinities for transcription factors leads to increased predictive power compared to methods based on the identification of discrete binding sites. This applies both to the prediction of transcription factor binding as revealed by ChIP-seq experiments and to the prediction of gene expression through RNA-seq. Further significant improvements in predictive power are obtained when regulatory regions are defined based on chromatin states inferred from histone modification data. PMID- 26599759 TI - Integrating Genomics with Nutrition Models to Improve the Prediction of Cattle Performance and Carcass Composition under Feedlot Conditions. AB - Cattle body composition is difficult to model because several factors affect the composition of the average daily gain (ADG) of growing animals. The objective of this study was to identify commercial single nucleotide polymorphism (SNP) panels that could improve the predictability of days on feed (DOF) to reach a target United States Department of Agriculture (USDA) grade given animal, diet, and environmental information under feedyard conditions. The data for this study was comprised of crossbred heifers (n = 681) and steers (n = 836) from commercial feedyards. Eleven molecular breeding value (MBV) scores derived from SNP panels of candidate gene polymorphisms and two-leptin gene SNP (UASMS2 and E2FB) were evaluated. The empty body fat (EBF) and the shrunk body weight (SBW) at 28% EBF (AFSBW) were computed by the Cattle Value Discovery System (CVDS) model using hip height (EBFHH and AFSBWHH) or carcass traits (EBFCT and AFSBWCT) of the animals. The DOFHH was calculated when AFSBWHH and ADGHH were used and DOFCT was calculated when AFSBWCT and ADGCT were used. The CVDS estimates dry matter required (DMR) by individuals fed in groups when observed ADG and AFSBW are provided. The AFSBWCT was assumed more accurate than the AFSBWHH because it was computed using carcass traits. The difference between AFSBWCT and AFSBWHH, DOFCT and DOFHH, and DMR and dry matter intake (DMI) were regressed on the MBV scores and leptin gene SNP to explain the variation. Our results indicate quite a large range of correlations among MBV scores and model input and output variables, but MBV ribeye area was the most strongly correlated with the differences in DOF, AFSBW, and DMI by explaining 8, 13.2 and 6.5%, respectively, of the variation. This suggests that specific MBV scores might explain additional variation of input and output variables used by nutritional models in predicting individual animal performance. PMID- 26599760 TI - beta-Hydroxybutyrate Facilitates Fatty Acids Synthesis Mediated by Sterol Regulatory Element-Binding Protein1 in Bovine Mammary Epithelial Cells. AB - BACKGROUND/AIMS: In dairy cows, beta-hydroxybutyrate (BHBA) is utilized as precursors of de novo synthesized fatty acids in mammary gland. Ketotic cows are characterized by excessive negative energy balance (NEB), which can further increase the blood BHBA concentration. Sterol regulatory element-binding protein1 (SREBP1) and cell death-inducing DNA fragmentation factor-alpha-like effector alpha (Cidea) play crucial roles in lipid synthesis. Therefore, we hypothesized that BHBA could stimulate SREBP1/Cidea pathway to increase milk fat synthesis in bovine mammary epithelial cells. METHODS: Bovine mammary epithelial cells were treated with different concentrations of BHBA and transfected with adenovirus to silence SREBP1 expression. The effects of BHBA on the lipid synthesis in bovine mammary epithelial cells were investigated. RESULTS: The results showed that BHBA could significantly increase the expression of SREBP1, fatty acid synthase (FAS), acetyl-CoA carboxylase alpha (ACC-alpha), Cidea and diacylglycerol transferase-1 (DGAT-1), as well as the triglycerides (TG) content in bovine mammary epithelial cells. BHBA treatment also increased the transfer of mature SREBP1 to nucleus compared with control group. However, SREBP1 silencing could significantly down regulate the overexpression of FAS, ACC-alpha, Cidea and DGAT-1, as well as TG content induced by BHBA. CONCLUSION: The present data indicate that BHBA can significantly increase TG secretion mediated by SREBP1 in bovine mammary epithelial cells. PMID- 26599763 TI - Large-Scale Synthesis of Few-Layer F-BN Nanocages with Zigzag-Edge Triangular Antidot Defects and Investigation of the Advanced Ferromagnetism. AB - Investigation of light-element magnetism system is essential in fundamental and practical fields. Here, few-layer (~3 nm) fluorinated hexagonal boron nitride (F BN) nanocages with zigzag-edge triangular antidot defects were synthesized via a facile one-step solid-state reaction. They are free of metallic impurities confirmed by X-ray photoelectron spectroscopy, electron energy loss spectroscopy, and inductively coupled plasma atomic emission spectroscopy. Ferromagnetism is obviously observed in the BN nanocages. Saturation magnetization values of them differed by less than 7% between 5 and 300 K, indicating that the Curie temperature (Tc) was much higher than 300 K. By adjusting the concentration of triangular antidot defects and fluorine dopants, the ferromagnetic performance of BN nanocages could be effectively varied, indicating that the observed magnetism originates from triangular antidot defects and fluorination. The corresponding theoretical calculation shows that antidot defects and fluorine doping in BN lattice both favor spontaneous spin polarization and the formation of local magnetic moment, which should be responsible for long-range magnetic ordering in the sp material. PMID- 26599761 TI - Genetic Susceptibility to Cardiac and Digestive Clinical Forms of Chronic Chagas Disease: Involvement of the CCR5 59029 A/G Polymorphism. AB - The clinical manifestations of chronic Chagas disease include the cardiac form of the disease and the digestive form. Not all the factors that act in the variable clinical course of this disease are known. This study investigated whether the CCR5Delta32 (rs333) and CCR5 59029 A/G (promoter region--rs1799987) polymorphisms of the CCR5 gene are associated with different clinical forms of chronic Chagas disease and with the severity of left ventricular systolic dysfunction in patients with chronic Chagas heart disease (CCHD). The antibodies anti-T. cruzi were identified by ELISA. PCR and PCR-RFLP were used to identify the CCR5Delta32 and CCR5 59029 A/G polymorphisms. The chi-square test was used to compare variables between groups. There was a higher frequency of the AA genotype in patients with CCHD compared with patients with the digestive form of the disease and the control group. The results also showed a high frequency of the AG genotype in patients with the digestive form of the disease compared to the other groups. The results of this study show that the CCR5Delta32 polymorphism does not seem to influence the different clinical manifestations of Chagas disease but there is involvement of the CCR5 59029 A/G polymorphism in susceptibility to the different forms of chronic Chagas disease. Besides, these polymorphisms do not influence left ventricular systolic dysfunction in patients with CCHD. PMID- 26599762 TI - Evolutionary Quantitative Genomics of Populus trichocarpa. AB - Forest trees generally show high levels of local adaptation and efforts focusing on understanding adaptation to climate will be crucial for species survival and management. Here, we address fundamental questions regarding the molecular basis of adaptation in undomesticated forest tree populations to past climatic environments by employing an integrative quantitative genetics and landscape genomics approach. Using this comprehensive approach, we studied the molecular basis of climate adaptation in 433 Populus trichocarpa (black cottonwood) genotypes originating across western North America. Variation in 74 field assessed traits (growth, ecophysiology, phenology, leaf stomata, wood, and disease resistance) was investigated for signatures of selection (comparing QST FST) using clustering of individuals by climate of origin (temperature and precipitation). 29,354 SNPs were investigated employing three different outlier detection methods and marker-inferred relatedness was estimated to obtain the narrow-sense estimate of population differentiation in wild populations. In addition, we compared our results with previously assessed selection of candidate SNPs using the 25 topographical units (drainages) across the P. trichocarpa sampling range as population groupings. Narrow-sense QST for 53% of distinct field traits was significantly divergent from expectations of neutrality (indicating adaptive trait variation); 2,855 SNPs showed signals of diversifying selection and of these, 118 SNPs (within 81 genes) were associated with adaptive traits (based on significant QST). Many SNPs were putatively pleiotropic for functionally uncorrelated adaptive traits, such as autumn phenology, height, and disease resistance. Evolutionary quantitative genomics in P. trichocarpa provides an enhanced understanding regarding the molecular basis of climate-driven selection in forest trees and we highlight that important loci underlying adaptive trait variation also show relationship to climate of origin. We consider our approach the most comprehensive, as it uncovers the molecular mechanisms of adaptation using multiple methods and tests. We also provide a detailed outline of the required analyses for studying adaptation to the environment in a population genomics context to better understand the species' potential adaptive capacity to future climatic scenarios. PMID- 26599764 TI - Afterglow Organic Light-Emitting Diode. AB - An afterglow organic light-emitting diode (OLED) that displays electroluminescence with long transient decay after it is turned off is demonstrated. This OLED exhibits blue and green dual emission originating from fluorescence and phosphorescence, respectively. A phosphorescence lifetime of 4.3 s is achieved. PMID- 26599766 TI - Correction: The Effect of Ginger (Zingiber officinale) on Platelet Aggregation: A Systematic Literature Review. AB - [This corrects the article DOI: 10.1371/journal.pone.0141119.]. PMID- 26599770 TI - Effect of I. C. U. on Mortality Rate, Patient Care Throughout Hospital. PMID- 26599765 TI - The Roles of Dopamine and Hypocretin in Reward: A Electroencephalographic Study. AB - The proper functioning of the mesolimbic reward system is largely dependent on the neurotransmitter dopamine. Recent evidence suggests that the hypocretin system has significant projections to this reward system. We examined the distinct effects of reduced dopamine or reduced hypocretin levels on reward activity in patients with Parkinson's disease, dopamine deficient, as well as patients with narcolepsy-cataplexy, hypocretin depleted, and healthy controls. Participants performed a simple game-like task while high-density electroencephalography was recorded. Topography and timing of event-related potentials for both reward cue, and reward feedback was examined across the entire dataset. While response to reward cue was similar in all groups, two distinct time points were found to distinguish patients and controls for reward feedback. Around 160 ms both patient groups had reduced ERP amplitude compared to controls. Later at 250 ms, both patient groups also showed a clear event-related potential (ERP), which was absent in controls. The initial differences show that both patient groups show a similar, blunted response to reward delivery. The second potential corresponds to the classic feedback-related negativity (FRN) potential which relies on dopamine activity and reflects reward prediction-error signaling. In particular the mismatch between predicted reward and reward subsequently received was significantly higher in PD compared to NC, independent of reward magnitude and valence. The intermediate FRN response in NC highlights the contribution of hypocretin in reward processing, yet also shows that this is not as detrimental to the reward system as in Parkinson's. Furthermore, the inability to generate accurate predictions in NC may explain why hypocretin deficiency mediates cataplexy triggered by both positive and negative emotions. PMID- 26599771 TI - Administrators should know Legalities concerning Medical-Staff Bylaws. PMID- 26599772 TI - Knowledge of Historical Development Helpful in Utilizing Systems ApproachFocus on Management Methods. PMID- 26599773 TI - Consultant's Corner. PMID- 26599774 TI - Hospital Financial Problems. PMID- 26599776 TI - Housekeeping Services. PMID- 26599775 TI - Outpatient Care: Emergency. PMID- 26599777 TI - Pharmacy. PMID- 26599780 TI - OBG. PMID- 26599779 TI - Pediatrics. PMID- 26599781 TI - Operating Room. PMID- 26599784 TI - Central Service. PMID- 26599785 TI - Product Profile. PMID- 26599788 TI - Fine-Tuning of PI3K/AKT Signalling by the Tumour Suppressor PTEN Is Required for Maintenance of Flight Muscle Function and Mitochondrial Integrity in Ageing Adult Drosophila melanogaster. AB - Insulin/insulin-like growth factor signalling (IIS), acting primarily through the PI3-kinase (PI3K)/AKT kinase signalling cassette, plays key evolutionarily conserved regulatory roles in nutrient homeostasis, growth, ageing and longevity. The dysfunction of this pathway has been linked to several age-related human diseases including cancer, Type 2 diabetes and neurodegenerative disorders. However, it remains unclear whether minor defects in IIS can independently induce the age-dependent functional decline in cells that accompany some of these diseases or whether IIS alters the sensitivity to other aberrant signalling. We identified a novel hypomorphic allele of PI3K's direct antagonist, Phosphatase and tensin homologue on chromosome 10 (Pten), in the fruit fly, Drosophila melanogaster. Adults carrying combinations of this allele, Pten5, combined with strong loss-of-function Pten mutations exhibit subtle or no increase in mass, but are highly susceptible to a wide range of stresses. They also exhibit dramatic upregulation of the oxidative stress response gene, GstD1, and a progressive loss of motor function that ultimately leads to defects in climbing and flight ability. The latter phenotype is associated with mitochondrial disruption in indirect flight muscles, although overall muscle structure appears to be maintained. We show that the phenotype is partially rescued by muscle-specific expression of the Bcl-2 homologue Buffy, which in flies, maintains mitochondrial integrity, modulates energy homeostasis and suppresses cell death. The flightless phenotype is also suppressed by mutations in downstream IIS signalling components, including those in the mechanistic Target of Rapamycin Complex 1 (mTORC1) pathway, suggesting that elevated IIS is responsible for functional decline in flight muscle. Our data demonstrate that IIS levels must be precisely regulated by Pten in adults to maintain the function of the highly metabolically active indirect flight muscles, offering a new system to study the in vivo roles of IIS in the maintenance of mitochondrial integrity and adult ageing. PMID- 26599789 TI - Vaginal Microbiome Characterization of Nellore Cattle Using Metagenomic Analysis. AB - Understanding of microbial communities inhabiting cattle vaginal tract may lead to a better comprehension of bovine physiology and reproductive health being of great economic interest. Up to date, studies involving cattle microbiota are focused on the gastrointestinal tract, and little is known about the vaginal microbiota. This study aimed to investigate the vaginal microbiome in Nellore cattle, heifers and cows, pregnant and non-pregnant, using a culture independent approach. The main bacterial phyla found were Firmicutes (~40-50%), Bacteroidetes (~15-25%) and Proteobacteria (~5-25%), in addition to ~10-20% of non-classified bacteria. 45-55% of the samples were represented by only ten OTUs: Aeribacillus, Bacteroides, Clostridium, Ruminococcus, Rikenella, Alistipes, Bacillus, Eubacterium, Prevotella and non-classified bacteria. Interestingly, microbiota from all 20 animals could be grouped according to the respiratory metabolism of the main OTUs found, creating three groups of vaginal microbiota in cattle. Archaeal samples were dominated by the Methanobrevibacter genus (Euryarchaeota, ~55-70%). Ascomycota was the main fungal phylum (~80-95%) and Mycosphaerella the most abundant genus (~70-85%). Hormonal influence was not clear, but a tendency for the reduction of bacterial and increase of archaeal populations in pregnant animals was observed. Eukaryotes did not vary significantly between pregnant and non-pregnant animals, but tended to be more abundant on cows than on heifers. The present work describes a great microbial variability in the vaginal community among the evaluated animals and groups (heifers and cows, pregnant and non pregnant), which is significantly different from the findings previously reported using culture dependent methods, pointing out the need for further studies on this issue. The microbiome found also indicates that the vaginal colonization appears to be influenced by the gastrointestinal community. PMID- 26599791 TI - Development and Validation of a Morphologic Obstructive Sleep Apnea Prediction Score: The DES-OSA Score. AB - BACKGROUND: Obstructive sleep apnea (OSA) is a common and underdiagnosed entity that favors perioperative morbidity. Several anatomical characteristics predispose to OSA. We developed a new clinical score that would detect OSA based on the patient's morphologic characteristics only. METHODS: Patients (n = 149) scheduled for an overnight polysomnography were included. Their morphologic metrics were compared, and combinations of them were tested for their ability to predict at least mild, moderate-to-severe, or severe OSA, as defined by an apnea hypopnea index (AHI) >5, >15, or >30 events/h. This ability was calculated using Cohen kappa coefficient and prediction probability. RESULTS: The score with best prediction abilities (DES-OSA score) considered 5 variables: Mallampati score, distance between the thyroid and the chin, body mass index, neck circumference, and sex. Those variables were weighted by 1, 2, or 3 points. DES-OSA score >5, 6, and 7 were associated with increased probability of an AHI >5, >15, or >30 events/h, respectively, and those thresholds had the best Cohen kappa coefficient, sensitivities, and specificities. Receiver operating characteristic curve analysis revealed that the area under the curve was 0.832 (95% confidence interval [CI], 0.762-0.902), 0.805 (95% CI, 0.734-0.876), and 0.834 (95% CI, 0.757-0.911) for DES-OSA at predicting an AHI >5, >15, and >30 events/h, respectively. With the aforementioned thresholds, corresponding sensitivities (95% CI) were 82.7% (74.5-88.7), 77.1% (66.9-84.9), and 75% (61.0-85.1), and specificities (95% CI) were 72.4% (54.0-85.4), 73.2% (60.3-83.1), and 76.9% (67.2 84.4). Validation of DES-OSA performance in an independent sample yielded highly similar results. CONCLUSIONS: DES-OSA is a simple score for detecting OSA patients. Its originality relies on its morphologic nature. Derived from a European population, it may prove useful in a preoperative setting, but it has still to be compared with other screening tools in a general surgical population and in other ethnic groups. PMID- 26599790 TI - Risk Factors and Prevalence of Helicobacter pylori in Five Largest Islands of Indonesia: A Preliminary Study. AB - The prevalence of Helicobacter pylori infection in Indonesia is still controversial and mainly investigated in the largest ethnic group, Javanese. We examined the prevalence of H. pylori infection using four different tests including culture, histology confirmed by immunohistochemistry and rapid urease test. We also analyzed risk factors associated with H. pylori infection in five largest islands in Indonesia. From January 2014-February 2015 we consecutively recruited a total of 267 patients with dyspeptic symptoms in Java, Papua, Sulawesi, Borneo and Sumatera Island. Overall, the prevalence of H. pylori infection was 22.1% (59/267). Papuan, Batak and Buginese ethnics had higher risk for H. pylori infection than Javanese, Dayak and Chinese ethnics (OR = 30.57, 6.31, 4.95; OR = 28.39, 5.81, 4.61 and OR = 23.23, 4.76, 3.77, respectively, P <0.05). The sensitivity and specificity for RUT and culture were 90.2%, 92.9% and 80.5%, 98.2%, respectively. The patients aged 50-59 years group had significantly higher H. pylori infection than 30-39 years group (OR 2.98, P = 0.05). Protestant had significantly higher H. pylori infection rate than that among Catholic (OR 4.42, P = 0.008). It was also significantly lower among peoples who used tap water as source of drinking water than from Wells/river (OR 9.67, P = 0.03). However only ethnics as become independent risk factors for H. pylori infection. Although we confirmed low prevalence of H. pylori in Javanese; predominant ethnic in Indonesia, several ethnic groups had higher risk of H. pylori infection. The age, religion and water source may implicate as a risk factor for H. pylori infection in Indonesia. PMID- 26599792 TI - Electroacupuncture Relieves Nerve Injury-Induced Pain Hypersensitivity via the Inhibition of Spinal P2X7 Receptor-Positive Microglia. AB - BACKGROUND: Electroacupuncture (EA) has therapeutic effects on neuropathic pain induced by nerve injury; however, the underlying mechanisms remain unclear. In this study, we examined whether EA treatment relieves pain hypersensitivity via the down-regulation of spinal P2X7 receptor-positive (P2X7R+) microglia-mediated overexpression of interleukin (IL)-1beta and/or IL-18. METHODS: Male Sprague Dawley rats underwent chronic constriction injury (CCI) or 3'-O-(4 benzoylbenzoyl) adenosine 5'-triphosphate (BzATP) intrathecal injection. Von Frey and Hargreaves tests were performed to evaluate the effect of EA on pain hypersensitivity. The spinal P2X7R, IL-1beta, and IL-18 expression levels were determined by real-time polymerase chain reaction, Western blot analysis, immunofluorescence staining, and enzyme-linked immunosorbent assay. The selective P2X7R antagonist A-438079 was used to examine the P2X7R+ microglia-dependent release of IL-1beta and IL-18. Primary cultures were subsequently used to assess the P2X7R+ microglia-induced IL-1beta and IL-18 release. RESULTS: EA treatment significantly improved the pain thresholds and inhibited spinal P2X7R+ microglia activation induced by CCI or BzATP administration, which was accompanied by the suppression of spinal IL-1beta and IL-18 overexpression. Moreover, A-438079 also improved pain thresholds and suppressed overexpression of IL-1beta in the CCI- and BzATP-injected rats. The analysis of cultured microglia further demonstrated that A-438079 markedly decreased BzATP-induced IL-1beta release. CONCLUSIONS: EA treatment relieves nerve injury-induced tactile allodynia and thermal hyperalgesia via the inhibition of P2X7R+ microglia-mediated IL-1beta overexpression. PMID- 26599793 TI - The Effect of Intraoperative Blood Glucose Management on Postoperative Blood Glucose Levels in Noncardiac Surgery Patients. AB - BACKGROUND: Postoperative hyperglycemia has been associated with poor surgical outcome. The effect of intraoperative glucose management on postoperative glucose levels and the optimal glycemic threshold for initiating insulin are currently unknown. METHODS: We performed a retrospective cohort study of surgery patients who required intraoperative glucose management with data extracted from electronic medical records. In patients who required glucose management, intraoperative glucose levels and insulin therapy were compared against postoperative glucose levels during 3 periods: first postoperative level within 1 hour, within the first 12 hours, and 24 hours of the postoperative period. Logistic regression models that adjusted for patient and surgical factors were used to determine the association between intraoperative glucose management and postoperative glucose levels. RESULTS: In 2440 patients who required intraoperative glucose management, an increase in mean intraoperative glucose level by 10 mg/dL was associated with an increase in postoperative glucose levels by 4.7 mg/dL (confidence interval [CI], 4.1-5.3; P < 0.001) for the first postoperative glucose measurement, 2.6 mg/dL (CI, 2.1-3.1; P < 0.001) for the mean first 12-hour postoperative glucose, and 2.4 mg/dL (CI, 2.0-2.9; P < 0.001) for the mean first 24-hour postoperative glucose levels (univariate analysis). Multivariate analysis showed that these effects depended on (interacted with) body mass index and diabetes status of the patient. Both diabetes status (regression coefficient = 12.2; P < 0.001) and intraoperative steroid use (regression coefficient = 10.2; P < 0.001) had a positive effect on elevated postoperative glucose levels. Intraoperative hyperglycemia (>180 mg/dL) was associated with postoperative hyperglycemia during the first 12 hours and the first 24 hours. However, interaction with procedure duration meant that this association was stronger for shorter surgeries. When compared with starting insulin for an intraoperative glucose threshold of 140 mg/dL thus avoiding hyperglycemia, initiation of insulin for a hyperglycemia threshold of 180 mg/dL was associated with an increase in postoperative glucose level (7 mg/dL; P < 0.001) and postoperative hyperglycemia incidence (odds ratio = 1.53; P = 0.01). CONCLUSIONS: A higher intraoperative glucose level is associated with a higher postoperative glucose level. Intraoperative hyperglycemia increases the odds for postoperative hyperglycemia. Adequate intraoperative glucose management by initiating insulin infusion when glucose level exceeds 140 mg/dL to prevent hyperglycemia is associated with lower postoperative glucose levels and fewer incidences of postoperative hyperglycemia. However, patient- and procedure specific variable interactions make the relationship between intraoperative and postoperative glucose levels complicated. PMID- 26599794 TI - Optimizing Thrombin Generation with 4-Factor Prothrombin Complex Concentrates in Neonatal Plasma After Cardiopulmonary Bypass. AB - BACKGROUND: Bleeding is a serious complication after pediatric cardiopulmonary bypass (CPB) that is associated with an increase in perioperative morbidity and mortality. Four-factor prothrombin complex concentrates (4F-PCCs) have been used off-label to supplement transfusion protocols for bleeding after CPB in adults; however, data on their use in neonates are limited. In this study, we hypothesized that 4F-PCCs administered ex vivo to neonatal plasma after CPB will increase thrombin generation. METHODS: Fifteen neonates undergoing complex cardiac repairs requiring CPB were enrolled in this prospective study. Arterial blood was obtained after anesthesia induction but before CPB (baseline), after CPB following heparin reversal, and after our standardized transfusion of a quarter of a platelet apheresis unit (approximately 20 mL.kg) and 3 units of cryoprecipitate. Kcentra (CSL Behring), a 4F-PCC with nonactivated factor VII (FVII), and factor 8 inhibitor bypassing activity (FEIBA; Baxter Healthcare Corporation), a 4F-PCC with activated FVII, were added ex vivo to plasma obtained after CPB to yield concentrations of 0.1 and 0.3 IU.mL. Calibrated automated thrombography was used to determine thrombin generation for each sample. RESULTS: The addition of Kcentra to plasma obtained after CPB resulted in a dose-dependent increase in the median (99% confidence interval) peak amount of thrombin generation (42.0 [28.7-50.7] nM for Kcentra 0.1 IU.mL and 113.9 [99.0-142.1] nM for Kcentra 0.3 IU.mL). The rate of thrombin generation was also increased (15.4 [6.5-24.6] nM.min for Kcentra 0.1 IU.mL and 48.6 [29.9-66.6] nM.min for Kcentra 0.3 IU.mL). The same was true for FEIBA (increase in peak: 39.8 [27.5-49.2] nM for FEIBA 0.1 IU.mL and 104.6 [92.7-124.4] nM for FEIBA 0.3 IU.mL; increase in rate: 17.4 [7.4-28.8] nM.min FEIBA 0.1 IU.mL and 50.5 [26.7- 63.1] nM.min FEIBA 0.3 IU.mL). In the posttransfusion samples, there was a significant increase with Kcentra in the median (99% confidence interval) peak amount (41.1 [21.0-59.7] nM for Kcentra 0.1 IU.mL and 126.8 [106.6- 137.9] nM for Kcentra 0.3 IU.mL) and rate (18.1 [-6.2 to 29.2] nM.min for Kcentra 0.1 IU.mL and 53.2 [28.2-83.1] nM.min for Kcentra 0.3 IU.mL) of thrombin generation. Again, the results were similar for FEIBA (increase in peak: 43.0 [36.4-56.7] nM for FEIBA 0.1 IU.mL and 109.2 [90.3 136.1] nM for FEIBA 0.3 IU.mL; increase in rate: 25.0 [9.1-32.6] nM.min for FEIBA 0.1 IU.mL and 59.7 [38.5-68.7] nM.min for FEIBA 0.3 IU.mL). However, FEIBA produced in a greater median reduction in lag time of thrombin generation versus Kcentra in samples obtained after CPB (P = 0.003 and P = 0.0002 for FEIBA versus Kcentra at 0.1 and 0.3 IU.mL, respectively) and in samples obtained after transfusion (P < 0.0001 for FEIBA versus Kcentra at 0.1 and 0.3 IU.mL). CONCLUSIONS: After CPB, thrombin generation in neonatal plasma was augmented by the addition of 4F-PCCs. The peak amount and rate of thrombin generation were enhanced in all conditions, whereas the lag time was shortened more with FEIBA. Our findings suggest that the use of 4F-PCCs containing activated FVII may be an effective adjunct to the initial transfusion of platelets and cryoprecipitate to augment coagulation and control bleeding in neonates after CPB. PMID- 26599795 TI - Risk Factors Involved in Central-to-Radial Arterial Pressure Gradient During Cardiac Surgery. AB - BACKGROUND: A central-to-radial arterial pressure gradient may occur after cardiopulmonary bypass (CPB), which, in some patients, may last for a prolonged time after CPB. Whenever there is a pressure gradient, the radial artery pressure measure may underestimate a more centrally measured systemic pressure, which may result in a misguided therapeutic strategy. It is clinically important to identify the risk factors that may predict the appearance of a central-to-radial pressure gradient, because more central sites of measurements might then be considered to monitor systemic arterial pressure in high-risk patients. The objective of this study was to assess preoperative and intraoperative risk factors for central-to-radial pressure gradient. METHODS: Seventy-three patients undergoing cardiac surgery using CPB were included in this prospective observational study. A significant central-to-radial arterial pressure gradient was defined as a difference of 25 mm Hg in systolic pressure or 10 mm Hg in mean arterial pressure for a minimum of 5 minutes. Preoperative data included demographics, presence of comorbidities, and medications. Intraoperative data included type of surgery, CPB and aortic clamping time, use of inotropic drugs, and vasodilators or vasopressors agents. The diameter of the radial and femoral artery was measured before the induction of anesthesia using B-mode ultrasonography. RESULTS: Thirty-three patients developed a central-to-radial arterial pressure gradient (45%). Patients with a significant pressure gradient had a smaller weight (71.0 +/- 16.9 vs 79.3 +/- 17.3 kg, P = 0.041), a smaller height (162.0 +/- 9.6 vs 166.3 +/- 8.6 cm, P = 0.047), a smaller radial artery diameter (0.24 +/- 0.03 vs 0.29 +/- 0.05 cm, P < 0.001), and were at a higher risk as determined by the Parsonnet score (30.3 +/- 24.9 vs 17.0 +/- 10.9, P = 0.007). In addition, a longer aortic clamping time (85.8 +/- 51.0 vs 64.2 +/- 29.3 minutes, P = 0.036), mitral and complex surgery (P = 0.007 and P = 0.017, respectively), and administration of vasopressin (P = 0.039) were identified as potential independent predictors of a central-to-radial pressure gradient. By using multivariate logistic regression analysis, the following independent risk factors were identified: Parsonnet score (odds ratio [OR], 1.076; 95% confidence interval [CI], 1.027-1.127, P = 0.002), aortic clamping time >90 minutes (OR, 8.521; 95% CI, 1.917-37.870, P = 0.005), and patient height (OR, 0.933, 95% CI, 0.876-0.993, P = 0.029). The relative risk (RR) estimates remained statistically significant for the Parsonnet score and the aortic clamping time >=90 minutes (RR, 1.010; 95% CI, 1.003-1.018, P = 0.009 and RR, 2.253; 95% CI, 1.475-3.443, P < 0.001 respectively) while showing a trend for patient height (RR, 0.974; 95% CI, 0.948-1.001, P = 0.058). CONCLUSIONS: Central-to-radial gradients are common in cardiac surgery. The threshold for using a central site for blood pressure monitoring should be low in small, high-risk patients undergoing longer surgical interventions to avoid inappropriate administration of vasopressors and/or inotropic agents. PMID- 26599796 TI - Saline Flush After Rocuronium Bolus Reduces Onset Time and Prolongs Duration of Effect: A Randomized Clinical Trial. AB - BACKGROUND: Circulatory factors modify the onset time of neuromuscular-blocking drugs. Therefore, we hypothesized that infusion of a saline flush immediately after rocuronium administration would shorten the onset time without influencing the duration of the rocuronium effect. METHODS: Forty-eight patients were randomly allocated to the control or saline flush group. Anesthesia was induced and maintained with propofol and remifentanil, and all patients received 0.6 mg/kg rocuronium in 10 mL of normal saline. In the saline flush group, 20 mL normal saline was immediately infused after rocuronium administration. Neuromuscular blockade was assessed using acceleromyography at the adductor pollicis muscle with train-of-four (TOF) stimulation. The neuromuscular indices for rocuronium were calculated as follows: the latent onset time, defined as the time from the start of rocuronium infusion until first occurrence of depression of the first twitch of the TOF (T1) >=5%; onset time, defined as the time from the start of rocuronium infusion until first occurrence of depression of the T1 >=95%; clinical duration, defined as the time from the start of rocuronium administration until T1 recovered to 25% of the final T1 value; recovery index, defined as the time for recovery of T1 from 25% to 75% of the final T1 value; and the total recovery time, defined as the time from the start of rocuronium administration until reaching a TOF ratio of 0.9. Significance was designated at P <0.05. RESULTS: The measured latent onset time and onset time were significantly shorter in the saline flush group than the control group by 15 seconds (95.2% confidence interval, 0-15, P = 0.007) and 15 seconds (0-30, P = 0.018), respectively. Saline flush significantly depressed the T1 height at 30, 45, and 60 seconds after the rocuronium bolus by 17%, 24%, and 14%, respectively. In addition, the recovery phase was significantly prolonged in the saline flush group. The mean clinical duration (5th-95th percentile range) in the saline flush group and control group was 35 minutes (27-63 minutes) and 31 minutes (19-48 minutes; P = 0.032), respectively; the recovery index was 13 minutes (8-25 minutes) and 10 minutes (7-19 minutes; P = 0.019), respectively; and the total recovery time was 61 minutes (44-108 minutes) and 50 minutes (35-93 minutes; P = 0.048), respectively. CONCLUSIONS: Administering a 20-mL saline flush immediately after infusion of 0.6 mg/kg rocuronium in 10 mL normal saline shortened the onset time and prolonged the recovery phase of neuromuscular blockade. PMID- 26599797 TI - Elastoviscous Transitions of Articular Cartilage Reveal a Mechanism of Synergy between Lubricin and Hyaluronic Acid. AB - When lubricated by synovial fluid, articular cartilage provides some of the lowest friction coefficients found in nature. While it is known that macromolecular constituents of synovial fluid provide it with its lubricating ability, it is not fully understood how two of the main molecules, lubricin and hyaluronic acid, lubricate and interact with one another. Here, we develop a novel framework for cartilage lubrication based on the elastoviscous transition to show that lubricin and hyaluronic acid lubricate by distinct mechanisms. Such analysis revealed nonspecific interactions between these molecules in which lubricin acts to concentrate hyaluronic acid near the tissue surface and promotes a transition to a low friction regime consistent with the theory of viscous boundary lubrication. Understanding the mechanics of synovial fluid not only provides insight into the progression of diseases such as arthritis, but also may be applicable to the development of new biomimetic lubricants. PMID- 26599798 TI - Associations between asymmetric dimethylarginine, homocysteine, and the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism (rs1801133) in rheumatoid arthritis. AB - OBJECTIVES: The aim of our study was to determine whether asymmetric dimethylarginine (ADMA) levels are associated with homocysteine (Hcy) and methylenetetrahydrofolate reductase (MTHFR) C677T (rs1801133) gene variants in patients with rheumatoid arthritis (RA). METHOD: Serum ADMA and Hcy levels were measured in 201 RA individuals [155 (77.1%) females, median age 67 years (interquartile range 59-73)]. The MTHFR C677T polymorphism was assessed by using the LightCyclerTM System. Initially, ADMA was compared across the categories of MTHFR using a one-way analysis of variance (ANOVA), followed by a multivariate model, which accounted for Hcy, age, erythrocyte sedimentation rate (ESR), and homeostatic model assessment (HOMA). RESULTS: In univariable analysis, ADMA differed significantly across the categories of MTHFR (p = 0.037). Patients with the MTHFR 677TT genotype had the highest ADMA levels, with a mean of 0.62 (SE = 0.03), significantly higher than either those patients carrying the MTHFR 677CT (0.55, SE = 0.01) or the MTHFR 677CC (0.55, SE = 0.01) genotype (p = 0.042) in both cases. In the multivariable model, Hcy (p = 0.022) and ESR (p < 0.001) were found to have significant positive associations with ADMA but the relationship between MTHFR gene variants and ADMA was found to be non-significant (p = 0.102). CONCLUSIONS: Hcy and ADMA are significantly associated in RA. It is plausible that abnormal Hcy metabolism plays an important role in premature atherosclerosis in RA by promoting ADMA accumulation and leading to the derangement of vascular haemostasis. PMID- 26599799 TI - On the sensitivity of protein data bank normal mode analysis: an application to GH10 xylanases. AB - Protein data bank entries obtain distinct, reproducible flexibility characteristics determined by normal mode analyses of their three dimensional coordinate files. We study the effectiveness and sensitivity of this technique by analyzing the results on one class of glycosidases: family 10 xylanases. A conserved tryptophan that appears to affect access to the active site can be in one of two conformations according to x-ray crystallographic electron density data. The two alternate orientations of this active site tryptophan lead to distinct flexibility spectra, with one orientation thwarting the oscillations seen in the other. The particular orientation of this sidechain furthermore affects the appearance of the motility of a distant, C terminal region we term the mallet. The mallet region is known to separate members of this family of enzymes into two classes. PMID- 26599800 TI - Maternal demographics and hemodynamics for the prediction of fetal growth restriction at booking, in pregnancies at high risk for placental insufficiency. AB - INTRODUCTION: Fetal growth restriction (FGR) is associated with poor perinatal outcomes. Screening and prevention tools for FGR, such as uterine artery Doppler imaging and aspirin, underperform in high-risk groups, compared with general antenatal populations. There is a paucity of sensitive screening tests for the early prediction of FGR in high-risk pregnancies. MATERIALS AND METHODS: This was a prospective observational study based in a dedicated antenatal hypertension clinic at a tertiary UK hospital. We assessed maternal demographic and central hemodynamic variables as predictors for FGR in a group of women at high risk for placental insufficiency due to chronic hypertension (n = 55) or a history of hypertension in a previous pregnancy (n = 71). Outcome variables were birthweight z-score as well as development of FGR (defined as birthweight below the 5th or 3rd centile). Maternal hemodynamics were assessed using a noninvasive transthoracic bioreactance monitor (Cheetah NICOM). RESULTS: The mean gestation at presentation was 13.6 (range: 8.5-19.5) weeks. Sixteen women delivered babies below the 5th centile. Ten of these were below the 3rd centile. Independent predictors of birthweight z-score were body surface area, peripheral vascular resistance and white ethnicity (R(2) = 0.26, p < 0.0001). Independent predictors of FGR were maternal height and cardiac output. The area under the receiver operator characteristic curve for prediction of FGR was 0.915 (95% CI 0.859 0.972) and 0.9079 (95% CI 0.823-0.990) for FGR below the 5th and 3rd centiles, respectively. CONCLUSION: In women with chronic hypertension or a history of hypertension in a previous pregnancy, maternal size and cardiac output at booking provide a sensitive screening tool for FGR. PMID- 26599801 TI - Diagnosis of Small-Bowel Diseases: Prospective Comparison of Multi-Detector Row CT Enterography with MR Enterography. AB - PURPOSE: To prospectively compare the accuracies of computed tomographic (CT) enterography and magnetic resonance (MR) enterography for the detection and characterization of small-bowel diseases. MATERIALS AND METHODS: The institutional review board approved the study protocol, and informed consent was obtained from all participants. From June 2009 to July 2013, 150 consecutive patients (81 men and 69 women; mean age, 38.8 years; range, 18-74 years), who were suspected of having a small-bowel disease on the basis of clinical findings and whose previous upper and lower gastrointestinal endoscopy findings were normal, underwent CT and MR enterography. Two independent readers reviewed CT and MR enterographic images for the presence of small-bowel diseases, for differentiating between inflammatory and noninflammatory diseases, and for extraenteric complications. The histopathologic findings of surgical (n = 23) and endoscopic (n = 32) biopsy specimens were used as the reference standard; the results of video-capsule endoscopy (n = 36) and clinical follow-up (n = 59) were used only to confirm the absence of small-bowel disease. RESULTS: MR and CT enterography were successfully performed in all 150 patients. Overall sensitivity, specificity, and accuracy, respectively, in identifying patients with small-bowel lesions were 75.9% (41 of 54), 94.8% (91 of 96), and 88.0% (132 of 150) for CT enterography and 92.6% (50 of 54), 99.0% (95 of 96), and 96.7% (145 of 150) for MR enterography. The sensitivity of MR enterography was significantly higher than that of CT enterography for the detection of both overall small-bowel diseases (P = .0159) and neoplastic diseases (P = .0412) but not for the detection of inflammatory diseases (P > .99) or noninflammatory and nonneoplastic diseases (P = .6171). CONCLUSION: MR enterography is more accurate than CT enterography in the detection of small-bowel diseases; MR enterography was more accurate in detecting neoplastic diseases in particular. PMID- 26599802 TI - Gliomas: Motexafin Gadolinium-enhanced Molecular MR Imaging and Optical Imaging for Potential Intraoperative Delineation of Tumor Margins. AB - PURPOSE: To investigate the possibility of using motexafin gadolinium (MGd) enhanced molecular magnetic resonance (MR) imaging and optical imaging to identify the true margins of gliomas. MATERIALS AND METHODS: The animal protocol was approved by the institutional animal care and use committee. Thirty-six Sprague-Dawley rats with gliomas were randomized into six groups of six rats. Five groups were euthanized 15, 30, 60, 120, and 240 minutes after intravenous administration of 6 mg/kg of MGd, while one group received only saline solution as a control group. After craniotomy, optical imaging and T1-weighted MR imaging were performed to identify the tumor margins. One-way analysis of variance was used to compare optical photon intensity and MR imaging signal-to-noise ratios. Histologic analysis was performed to confirm the intracellular uptake of MGd by tumor cells and to correlate the tumor margins delineated on both optical and MR images. RESULTS: Both optical imaging and T1-weighted MR imaging showed tumor margins. The highest optical photon intensity (2.6 * 10(8) photons per second per mm(2) +/- 2.3 * 10(7); analysis of variance, P < .001) and MR signal-to-noise ratio (77.61 +/- 2.52; analysis of variance, P = .006) were reached at 15-30 minutes after administration of MGd, with continued tumor visibility at 2-4 hours. Examination with confocal microscopy allowed confirmation that the fluorescence of optical images and MR imaging T1 enhancement exclusively originated from MGd that accumulated in the cytoplasm of tumor cells. CONCLUSION: MGd-enhanced optical and MR imaging can allow determination of glioma tumor margins at the optimal time of 15-120 minutes after administration of MGd. Clinical application of these results may allow complete removal of gliomas in a hybrid surgical setting in which intraoperative optical and MR imaging are available. PMID- 26599803 TI - Characterization of gene expression in mouse embryos at the 1-cell stage. AB - In mice, transcription from the zygotic genome is initiated at the mid-1-cell stage after fertilization. Although a recent high-throughput sequencing (HTS) analysis revealed that this transcription occurs promiscuously throughout almost the entire genome in 1-cell stage embryos, a detailed investigation of this process has yet to be conducted using protein-coding genes. Thus, the present study utilized previous RNA sequencing (RNAseq) data to determine the characteristics and regulatory regions of genes transcribed at the 1-cell stage. While the expression patterns of protein-coding genes of mouse embryos were very different at the 1-cell stage than at other stages and in various tissues, an analysis for the upstream and downstream regions of actively expressed genes did not reveal any elements that were specific to 1-cell stage embryos. Therefore, the unique gene expression pattern observed at the 1-cell stage in mouse embryos appears to be governed by mechanisms independent of a specific promoter element. PMID- 26599804 TI - Perioperative myocardial infarction/injury after noncardiac surgery. AB - Cardiovascular complications, particularly perioperative myocardial infarction/injury, seem to be major contributors to mortality after noncardiac surgery. With surgical procedures being very frequent (900 000/year in Switzerland), perioperative myocardial injury is common in everyday clinical practice. Over 80% of patients experiencing perioperative myocardial injury do not report symptoms. Therefore perioperative myocardial injury remains undiagnosed and untreated. Moreover, its silent presentation results in limited awareness among both clinicians and the public. Despite being largely asymptomatic, perioperative myocardial injury increases 30-day mortality nearly 10-fold. This review aims to increase the awareness of perioperative myocardial injury/infarction and give an overview of the emerging evidence, including pathophysiology, clinical presentation, prevention, and potential future treatments. PMID- 26599805 TI - Species Specific Differences of CD1d Oligomer Loading In Vitro. AB - CD1d molecules are MHC class I-like molecules that present glycolipids to iNKT cells. The highly conserved interaction between CD1d:alpha-Galactosylceramide (alphaGC) complexes and the iNKT TCR not only defines this population of alphabeta T cells but can also be used for its direct identification. Therefore, CD1d oligomers are a widely used tool for iNKT cell related investigations. To this end, the lipid chains of the antigen have to be inserted into the hydrophobic pockets of the CD1d binding cleft, often with help of surfactants. In this study, we investigated the influence of different surfactants (Triton X-100, Tween 20, Tyloxapol) on in vitro loading of CD1d molecules derived from four different species (human, mouse, rat and cotton rat) with alphaGC and derivatives carrying modifications of the acyl-chain (DB01-1, PBS44) and a 6-acetamido-6 deoxy-addition at the galactosyl head group (PBS57). We also compared rat CD1d dimers with tetramers and staining of an iNKT TCR transductant was used as readout for loading efficacy. The results underlined the importance of CD1d loading efficacy for proper analysis of iNKT TCR binding and demonstrated the necessity to adjust loading conditions for each oligomer/glycolipid combination. The efficient usage of surfactants as a tool for CD1d loading was revealed to be species-specific and depending on the origin of the CD1d producing cells. Additional variation of surfactant-dependent loading efficacy between tested glycolipids was influenced by the acyl-chain length and the modification of the galactosyl head group with PBS57 showing the least dependence on surfactants and the lowest degree of species-dependent differences. PMID- 26599807 TI - Clinical Validation of a Novel Commercial Reverse Transcription-Quantitative Polymerase Chain Reaction Screening Assay for Detection of ALK Translocations and Amplifications in Non-Small Cell Lung Carcinomas. AB - CONTEXT: -EGFR mutations and anaplastic lymphoma kinase (ALK) translocations have significant biologic and therapeutic implications in lung cancers, particularly lung adenocarcinomas. ALK translocations are less frequent compared with EGFR mutations; interestingly, these two abnormalities are most commonly mutually exclusive. The 2013 College of American Pathologists/Association for Molecular Pathology/International Association for the Study of Lung Cancer molecular testing guideline for lung cancers recommend a testing algorithm in which detection of ALK translocations using fluorescence in situ hybridization (FISH) is to be performed following testing for EGFR mutations. Such an algorithm is cost-effective but potentially slows down turnaround time; and as a secondary test, ALK FISH assay may not be completed because it requires the use of additional tissue, and the small biopsies or cytology specimens may have been exhausted in the extraction of nucleic acid for EGFR mutation screening. OBJECTIVE: -To provide efficient testing of both EGFR and ALK genetic alterations in small biopsies and cytology specimens. DESIGN: -We validated a highly sensitive ALK reverse transcription-quantitative polymerase chain reaction (RT qPCR) assay as a screening tool for ALK translocations and amplifications. RESULTS: -We performed a retrospective review of cases previously tested by FISH and found that all FISH ALK translocation-positive specimens were RT-qPCR positive, and all FISH ALK translocation-negative cases were RT-qPCR negative (the sensitivity and specificity of the ALK RT-qPCR assay were 100%). CONCLUSION: -This assay allows rapid identification of ALK alterations, can be performed in conjunction with EGFR testing, and does not require use of valuable additional tumor tissue. PMID- 26599806 TI - Analysis of Pigeon (Columba) Ovary Transcriptomes to Identify Genes Involved in Blue Light Regulation. AB - Monochromatic light is widely applied to promote poultry reproductive performance, yet little is currently known regarding the mechanism by which light wavelengths affect pigeon reproduction. Recently, high-throughput sequencing technologies have been used to provide genomic information for solving this problem. In this study, we employed Illumina Hiseq 2000 to identify differentially expressed genes in ovary tissue from pigeons under blue and white light conditions and de novo transcriptome assembly to construct a comprehensive sequence database containing information on the mechanisms of follicle development. A total of 157,774 unigenes (mean length: 790 bp) were obtained by the Trinity program, and 35.83% of these unigenes were matched to genes in a non redundant protein database. Gene description, gene ontology, and the clustering of orthologous group terms were performed to annotate the transcriptome assembly. Differentially expressed genes between blue and white light conditions included those related to oocyte maturation, hormone biosynthesis, and circadian rhythm. Furthermore, 17,574 SSRs and 533,887 potential SNPs were identified in this transcriptome assembly. This work is the first transcriptome analysis of the Columba ovary using Illumina technology, and the resulting transcriptome and differentially expressed gene data can facilitate further investigations into the molecular mechanism of the effect of blue light on follicle development and reproduction in pigeons and other bird species. PMID- 26599808 TI - Folate Receptor alpha Expression Level Correlates With Histologic Grade in Lung Adenocarcinoma. AB - CONTEXT: -Folate receptor alpha (FRA) is a glycosylphosphatidylinositol-anchored high-affinity folate receptor that localizes to the apical surface of epithelia when it is expressed in normal tissue. Unlike normal tissues, FRA may localize to the basolateral side in tumors. These features make FRA an attractive drug target, and several FRA-targeted drugs have been developed and are in phases of clinical testing. Folate receptor alpha protein expression shows intertumoral variability that may correlate with response to therapy and to clinicopathologic parameters. Using immunohistochemistry, a recent study of breast carcinomas found FRA protein expression was associated with triple-negative status and high histologic grade in breast cancer. Although a prior study of lung adenocarcinomas found the expression level of the gene encoding FRA, FOLR1, was significantly increased in low-histologic-grade tumors compared to high-histologic-grade tumors, the relationship between FRA protein expression and histologic grade has not been reported for lung adenocarcinomas. OBJECTIVE: -To investigate the relationship between FRA protein expression level and clinicopathologic parameters in lung adenocarcinomas, including histologic grade, by performing immunohistochemistry for FRA on a cohort of non-small cell lung carcinomas. DESIGN: -High-density tissue microarrays constructed from 188 non-small cell lung carcinomas and used in prior studies were immunostained with FRA-specific antibody clone 26B3. Folate receptor alpha membranous staining intensity was given a semiquantitative score from 0 to 3+ for triplicate cores of tumor and averaged for each tumor. An average semiquantitative score from 0 to 1.4 was considered low expression, and an average semiquantitative score greater than 1.4 was considered high expression. RESULTS: -The majority (60 of 78; 77%) of lung adenocarcinomas and a minority (4 of 41; 10%) of lung squamous cell carcinomas were positive for FRA. Folate receptor alpha expression in lung adenocarcinomas compared with squamous cell carcinomas was statistically different (P < .001, chi(2) test). In lung adenocarcinomas, FRA expression level correlated with histologic grade (P = .005, chi(2) test for trend), but no other clinicopathologic parameter. The majority (23 of 27; 85%) of grade 1 adenocarcinomas had high FRA protein expression, whereas approximately half of grade 2 (10 of 19; 53%) and grade 3 (12 of 25; 48%) adenocarcinomas had high FRA protein expression. Out of adenocarcinomas with lepidic growth pattern, 16 of 20 (80%) showed high FRA protein expression. Out of adenocarcinomas with solid growth pattern, 2 of 6 (33%) showed high FRA protein expression. In lung adenocarcinomas, FRA expression level did not correlate with thyroid transcription factor 1, napsin A, or survival. CONCLUSIONS: -Folate receptor alpha protein was expressed in the majority of lung adenocarcinomas and a minority of lung squamous cell carcinomas. Folate receptor alpha protein expression correlated with histologic grade for lung adenocarcinomas, and the greatest difference was observed between grade 1 and grade 3. Our results indicate that poorly differentiated adenocarcinomas or focuses of poor differentiation in a heterogeneous tumor may lack FRA protein expression and be more likely to be resistant to FRA-targeting drugs. PMID- 26599809 TI - Mid-Infrared Spectroscopic Method for the Identification and Quantification of Dissolved Oil Components in Marine Environments. AB - The use of mid-infrared sensors based on conventional spectroscopic equipment for oil spill monitoring and fingerprinting in aqueous systems has to date been mainly confined to laboratory environments. This paper presents a portable-based mid-infrared attenuated total reflectance (MIR-ATR) sensor system that was used to quantify a number of environmentally relevant hydrocarbon contaminants in marine water. The sensor comprises a polymer-coated diamond waveguide in combination with a room-temperature operated pyroelectric detector, and the analytical performance was optimized by evaluating the influence of polymer composition, polymer film thickness, and solution flow rate on the sensor response. Uncertainties regarding the analytical performance and instrument specifications for dissolved oil detection were investigated using real-world seawater matrices. The reliability of the sensor was tested by exposition to known volumes of different oils; crude oil and diesel samples were equilibrated with seawater and then analyzed using the developed MIR-ATR sensor system. For validation, gas chromatographic measurements were performed revealing that the MIR-ATR sensor is a promising on-site monitoring tool for determining the concentration of a range of dissolved oil components in seawater at ppb to ppm levels. PMID- 26599811 TI - Corrigendum. PMID- 26599810 TI - Metabolic Conversion of Ceramides in HeLa Cells - A Cholesteryl Phosphocholine Delivery Approach. AB - Ceramides can be delivered to cultured cells without solvents in the form of complexes with cholesteryl phosphocholine. We have analysed the delivery of three different radiolabeled D-erythro-ceramides (C6-Cer, C10-Cer and C16-Cer) to HeLa cells, and followed their metabolism as well as the cell viability. We found that all three ceramides were successfully taken up by HeLa cells when complexed to CholPC in an equimolar ratio, and show that the ceramides show different rates of cellular uptake and metabolic fate. The C6-Cer had the highest incorporation rate, followed by C10-Cer and C16-Cer, respectively. The subsequent effect on cell viability strongly correlated with the rate of incorporation, where C6-Cer had the strongest apoptotic effects. Low-dose (1 MUM) treatment with C6-Cer favoured conversion of the precursor to sphingomyelin, whereas higher concentrations (25-100 MUM) yielded increased conversion to C6-glucosylceramide. Similar results were obtained for C10-Cer. In the lower-dose C16-Cer experiments, most of the precursor was degraded, whereas at high-dose concentrations the precursor remained un-metabolized. Using this method, we demonstrate that ceramides with different chain lengths clearly exhibit varying rates of cellular uptake. The cellular fate of the externally delivered ceramides are clearly connected to their rate of incorporation and their subsequent effects on cell viability may be in part determined by their chain length. PMID- 26599813 TI - Electrophilic Activation of Oxidized Sulfur Ligands and Implications for the Biological Activity of Ruthenium(II) Arene Anticancer Complexes. AB - Surprisingly, the anticancer activity of half-sandwich Ru arene complexes [(eta(6)-arene)Ru(en)Cl](+) appears to be promoted and not inhibited by binding to the intracellular thiol glutathione. Labilization of the Ru-S bond allowing DNA binding appeared to be initiated by oxygenation of the thiolate ligand, although oxidation by itself did not seem to weaken the Ru-S bond. In this study, we have investigated the solvation and acidic perturbations of mono (sulfenato) and bis (sulfinato) oxidized species of [(eta(6)-arene)Ru(en) (SR)](+) complex in the presence of Bronsted and Lewis acids. Sulfur K-edge X-ray absorption spectroscopy together with density functional theory calculations show that solvation and acidic perturbation of sulfenato species produce a significant decrease in the S3p character of the Ru-S bond (Ru4dsigma* <- S1s charge donation). Also there is a drastic fall in the overall ligand charge donation to the metal center in both sulfenato and sulfinato species. Our investigation clearly shows that mono oxidized sulfenato species are most susceptible to ligand exchange, hence providing a possible pathway for in vivo activation and biological activity. PMID- 26599814 TI - Threatening visual stimuli influence response inhibition and error monitoring: An event-related potential study. AB - The present study investigated the effect of emotion on response inhibition and error monitoring using event-related potentials. Participants performed an emotional stop-signal task that required response inhibition to briefly presented threatening and neutral visual stimuli. Negative, arousing pictures improved behavioral performance by decreasing the stop-signal reaction time and increasing the inhibitory rate, but had no enhancing effect on inhibitory processing at the electrophysiological level (N2-P3 complex). The perceptual processing of threatening stop-signals resulted in a larger and earlier N1 component. The Pe component, associated with conscious evaluation or affective processing of an error, was stronger in negative than in neutral trials. The stronger Pe correlated with superior task performance in the emotional condition. Prioritized perceptual processing of the stop-signal was associated with better conscious error monitoring. These results support the hypothesis that threatening, arousing stimuli improve behavioral inhibitory performance and error monitoring due to the enhancement of perceptual processing. PMID- 26599815 TI - Squidpops: A Simple Tool to Crowdsource a Global Map of Marine Predation Intensity. AB - We present a simple, standardized assay, the squidpop, for measuring the relative feeding intensity of generalist predators in aquatic systems. The assay consists of a 1.3-cm diameter disk of dried squid mantle tethered to a rod, which is either inserted in the sediment in soft-bottom habitats or secured to existing structure. Each replicate squidpop is scored as present or absent after 1 and 24 hours, and the data for analysis are proportions of replicate units consumed at each time. Tests in several habitats of the temperate southeastern USA (Virginia and North Carolina) and tropical Central America (Belize) confirmed the assay's utility for measuring variation in predation intensity among habitats, among seasons, and along environmental gradients. In Belize, predation intensity varied strongly among habitats, with reef > seagrass = mangrove > unvegetated bare sand. Quantitative visual surveys confirmed that assayed feeding intensity increased with abundance and species richness of fishes across sites, with fish abundance and richness explaining up to 45% and 70% of the variation in bait loss respectively. In the southeastern USA, predation intensity varied seasonally, being highest during summer and declining in late autumn. Deployments in marsh habitats generally revealed a decline in mean predation intensity from fully marine to tidal freshwater sites. The simplicity, economy, and standardization of the squidpop assay should facilitate engagement of scientists and citizens alike, with the goal of constructing high-resolution maps of how top-down control varies through space and time in aquatic ecosystems, and addressing a broad array of long-standing hypotheses in macro- and community ecology. PMID- 26599816 TI - ELSTAB-Fiber-Optic Time and Frequency Distribution Technology: A General Characterization and Fundamental Limits. AB - In this paper, we present an overview of the electronically stabilized (thus named ELSTAB) fiber-optic time and frequency (T&F) distribution system based on our idea of using variable electronic delay lines as compensating elements. Various extensions of the basic system, allowing building a long-haul, multiuser network are described. The fundamental limitations of the method arising from fiber chromatic dispersion and system dynamics are discussed. We briefly characterize the main hardware challenge of the system, which is the design of a pair of low-noise, precisely matched delay lines. Finally, we present experimental results with T&F distribution over up to 615 km of fiber, where we demonstrate frequency stability in the range of 1-7 *10(-17) for 10(5) s averaging and time calibration with accuracy well below 50 ps. Also, practical implementation of the ELSTAB in the Polish T&F distribution network is shown. PMID- 26599817 TI - Development and characterization of enteric-coated microparticles of biochanin A for their beneficial pharmacological potential in estrogen deficient hypertension. AB - Enteric coating of microparticles prevents stomach degradation and enhances oral bioavailability of poorly soluble drugs. Thus, in the present study, enteric coated microparticle (ECMP) of biochanin A was developed and their pharmacological potential was investigated in hypertensive ovariectomized rats (Ovx-HT). Biochanin A microparticles were prepared by using ionic gelation method and coating was done by ethyl cellulose using coacervation phase separation method. Surface modified microparticles were characterized on the basis of size, entrapment efficiency, polydispersity index, FTIR and zeta potential and percentage of in vitro release. Ovariectomized rats were administered deoxy corticosterone acetate (40 mg/kg, s.c. twice a week for 6 weeks) salt to induce Ovx-HT. Hypertension was assessed in terms of increase in systolic, diastolic, mean arterial blood pressure, lipid peroxidation level, tumor necrosis factor alpha (TNF-alpha) level and decrease in serum nitrite and reduced glutathione (GSH) level. The optimized formulation of ECMP has shown significant increase in oral bioavailability assessed by high-performance liquid chromatography. Furthermore, these ECMPs significantly reduced the mean arterial blood pressure, systolic and diastolic blood pressure, reduced lipid peroxidation and TNF-alpha level and significantly increased the serum nitrite and reduced GSH level in Ovx HT rats. However, L-NAME significantly prevented the ameliorative effect of ECMP. Thus, it may be concluded that ECMP of biochanin A has shown delayed release capacity, increase in oral bioavailability up to 6 folds than plain biochanin A and exerts antihypertensive effect in ovariectomized rats possibly in an eNOS dependent manner. PMID- 26599818 TI - Phase transformation of Cu-rich precipitates from 9R to 3R variant via ledges mechanism in ferritic steel containing copper. AB - Precipitates and solute enrich in aged ferritic steel containing copper were examined using high-resolution electron microscopy, high-angle annular dark-field scanning transmission electron microscopy and energy-dispersive X-ray spectroscopy. Two ledges with one-atom and two-atom layers height in the 9R/3R interface were observed. The enrichment of copper into two successive closed packed planes with an interval of Fe-rich close-packed plane was detected. The passage of the Shockley partial, or the shearing, changes the stacking sequence of closed-packed planes. Finally, 9R Cu variant transformed into 3R Cu variant. PMID- 26599820 TI - When worlds intersect: practical and ethical challenges when caring for international patients in the NICU. PMID- 26599819 TI - Lipoprotein Profiles in Class III Obese Caucasian and African American Women with Nonalcoholic Fatty Liver Disease. AB - Triglyceride content in the liver is regulated by the uptake, production and elimination of lipoproteins, and derangements in these processes contribute to nonalcoholic fatty liver disease (NAFLD). Previous studies show a direct relationship between intrahepatic fat and production of apolipoprotein B100 (apoB100) containing particles, VLDL and LDL, but little consensus exists regarding changes in lipoprotein production in the development of simple steatosis (SS) versus nonalcoholic steatohepatitis (NASH). Further, ethnic variations in lipoproteins among SS and NASH are unknown as is how such variations might contribute to the differential prevalence of disease among Caucasians versus African Americans. In this study, we assessed plasma lipoprotein profiles by nuclear magnetic resonance (NMR) spectroscopy in 70 non diabetic class III obese females recruited from the surgical weight loss clinic. Of these, 51 females were stratified by biopsy-staged NAFLD severity (histologically normal, SS, or NASH). NASH females displayed increased circulating triglycerides and increased VLDL particle number and size relative to those with histologically normal livers, while total and large LDL concentration decreased in SS versus NASH and correlated with increased insulin resistance (via HOMA2-IR). When Caucasian women were examined alone (n = 41), VLDL and triglycerides increased between normal and SS, while total LDL and apoB100 decreased between SS and NASH along with increased insulin resistance. Compared to Caucasians with SS, African American women with SS displayed reduced triglycerides, VLDL, and small LDL and a more favorable small to large HDL ratio despite having increased BMI and HOMA2-IR. These findings suggest that ApoB100 and lipoprotein subclass particle number and size can delineate steatosis from NASH in obese Caucasian females, but should be interpreted with caution in other ethnicities as African Americans with SS display relatively improved lipoprotein profiles. This may reflect variation in the relationship between dyslipidemia and NAFLD progression across gender and ethnicity. PMID- 26599821 TI - Ejaculate Characteristics Depend on Social Environment in the Horse (Equus caballus). AB - Sperm competition theory predicts semen characteristics to be affected by the social environment. We used the polygamous horse (Equus caballus) to experimentally study within-subject plasticity in response to different social environments. Stallions were sequentially exposed, over a period of 8 weeks each, to other stallions and then singly to mares, or vice versa (in adjacent boxes separated by grills). Ejaculates were collected to determine semen characteristics. Highest sperm numbers were found in stallions that were first exposed to other stallions and then to mares, while lowest sperm numbers were observed in stallions that had been exposed to mares but not yet to other stallions. One of three sperm velocity measures (curvilinear velocity) was consistently elevated in stallions that were first exposed to stallions and then to mares. Sperm number after exposure to mares and curvilinear sperm velocity after exposure to stallions were both positively correlated to average blood testosterone levels during the corresponding period of exposure. We conclude that ejaculate characteristics are plastic traits affected by the social environment in horses. PMID- 26599822 TI - Fast and Simple Preparation of Patterned Surfaces with Hydrophilic Polymer Brushes by Micromolding in Capillaries. AB - Micropatterns of hydrophilic polymer brushes were prepared by micromolding in capillaries (MIMIC). The polymers are covalently bound to the surfaces by a rapid hetero Diels-Alder reaction, constituting the first example of polymers grafted to surfaces in a defined pattern by MIMIC. The polymers [poly(acrylic acid), poly(hydroxyethyl acrylate), and poly(tetraethylene glycol acrylate) ranging in molecular weight from 1500 to 6000 g mol(-1)] were prepared with narrow dispersities via the reversible addition-fragmentation chain transfer (RAFT) process using a highly electron deficient RAFT agent that can react with surface anchored dienes such as cyclopentadiene. We demonstrate that the anchoring method is facile to perform and highly suitable for preparing patterned surfaces that are passivated against biological impact in well-defined areas. PMID- 26599823 TI - MR-based detection of individual histotripsy bubble clouds formed in tissues and phantoms. AB - PURPOSE: To demonstrate that MR sequences can detect individual histotripsy bubble clouds formed inside intact tissues. METHODS: A line-scan and an EPI sequence were sensitized to histotripsy by inserting a bipolar gradient whose lobes bracketed the lifespan of a histotripsy bubble cloud. Using a 7 Tesla, small-bore scanner, these sequences monitored histotripsy clouds formed in an agar phantom and in vitro porcine liver and brain. The bipolar gradients were adjusted to apply phase with k-space frequencies of 10, 300 or 400 cm-1 . Acoustic pressure amplitude was also varied. Cavitation was simultaneously monitored using a passive cavitation detection system. RESULTS: Each image captured local signal loss specific to an individual bubble cloud. In the agar phantom, this signal loss appeared only when the transducer output exceeded the cavitation threshold pressure. In tissues, bubble clouds were immediately detected when the gradients created phase with k-space frequencies of 300 and 400 cm-1 . When the gradients created phase with a k-space frequency of 10 cm-1 , individual bubble clouds were not detectable until many acoustic pulses had been applied to the tissue. CONCLUSION: Cavitation-sensitive MR-sequences can detect single histotripsy bubble clouds formed in biologic tissue. Detection is influenced by the sensitizing gradients and treatment history. Magn Reson Med 76:1486-1493, 2016. (c) 2015 International Society for Magnetic Resonance in Medicine. PMID- 26599824 TI - Effect of Ti:Sapphire-femtosecond laser on the surface roughness of ceramics. AB - BACKGROUND AND OBJECTIVES: Some of these adult patients have ceramic crowns, to which orthodontists have concerns about bonding brackets. The aim of the present study was to evaluate the effect of a Ti:Sapphire femtosecond (fs) laser (Integra C-3.5, Quantronix, NY) on the surface roughness of two ceramic surfaces (feldspathic and IPS Empress e-Max) and to compare results with those of two other lasers (Er:YAG and Nd:YAG) and conventional techniques, i.e., sandblasting (50 um) and hydrofluoric (HF) acid. MATERIALS AND METHODS: Ceramic discs were fabricated (n = 150) and divided into two groups, each of which was then divided into five subgroups prepared with Ti:Sapphire fs, Nd:YAG, or Er:YAG lasers, sandblasting, or HF acid (n = 15). The surface roughness of the ceramic discs was evaluated using a profilometer (Mitotoyo Surf Test SJ 201 P/M; Mitutoyo Corp, Japan) before and after each surface treatment. Three traces were recorded for each specimen at three different locations in each direction, providing nine measurements per sample, which were then averaged to obtain the surface roughness value. Data were analyzed using the Wilcoxon signed-rank test (P < <0.05), two way ANOVA, and Tukey's HSD test (P < 0.05). Additional samples were prepared for each group and evaluated using atomic force microscopy (AFM; NTEGRA Solaris, NTMDT, Russia). RESULTS: No significant difference was found between the feldspathic and IPS Empress e-Max ceramics. The Ti:Sapphire fs laser was associated with the highest mean roughness value. AFM images of the ceramic surfaces treated confirmed that the fs-laser-treated surfaces had the highest degree of irregularity. CONCLUSION: Within the limitations of this in vitro study, the Ti:Sapphire fs laser yielded the highest surface roughness and could be an alternative ceramic surface treatment to increase bond strength. PMID- 26599825 TI - The Missing Men: HIV Treatment Scale-Up and Life Expectancy in Sub-Saharan Africa. PMID- 26599826 TI - Computer modelling integrated with micro-CT and material testing provides additional insight to evaluate bone treatments: Application to a beta-glycan derived whey protein mice model. AB - The primary aim of this study was to evaluate the influence of a whey protein diet on computationally predicted mechanical strength of murine bones in both trabecular and cortical regions of the femur. There was no significant influence on mechanical strength in cortical bone observed with increasing whey protein treatment, consistent with cortical tissue mineral density (TMD) and bone volume changes observed. Trabecular bone showed a significant decline in strength with increasing whey protein treatment when nanoindentation derived Young's moduli were used in the model. When microindentation, micro-CT phantom density or normalised Young's moduli were included in the model a non-significant decline in strength was exhibited. These results for trabecular bone were consistent with both trabecular bone mineral density (BMD) and micro-CT indices obtained independently. The secondary aim of this study was to characterise the influence of different sources of Young's moduli on computational prediction. This study aimed to quantify the predicted mechanical strength in 3D from these sources and evaluate if trends and conclusions remained consistent. For cortical bone, predicted mechanical strength behaviour was consistent across all sources of Young's moduli. There was no difference in treatment trend observed when Young's moduli were normalised. In contrast, trabecular strength due to whey protein treatment significantly reduced when material properties from nanoindentation were introduced. Other material property sources were not significant but emphasised the strength trend over normalised material properties. This shows strength at the trabecular level was attributed to both changes in bone architecture and material properties. PMID- 26599827 TI - Multiresolution analysis over graphs for a motor imagery based online BCI game. AB - Multiresolution analysis (MRA) over graph representation of EEG data has proved to be a promising method for offline brain-computer interfacing (BCI) data analysis. For the first time we aim to prove the feasibility of the graph lifting transform in an online BCI system. Instead of developing a pointer device or a wheel-chair controller as test bed for human-machine interaction, we have designed and developed an engaging game which can be controlled by means of imaginary limb movements. Some modifications to the existing MRA analysis over graphs for BCI have also been proposed, such as the use of common spatial patterns for feature extraction at the different levels of decomposition, and sequential floating forward search as a best basis selection technique. In the online game experiment we obtained for three classes an average classification rate of 63.0% for fourteen naive subjects. The application of a best basis selection method helps significantly decrease the computing resources needed. The present study allows us to further understand and assess the benefits of the use of tailored wavelet analysis for processing motor imagery data and contributes to the further development of BCI for gaming purposes. PMID- 26599828 TI - Unsupervised learning assisted robust prediction of bioluminescent proteins. AB - Bioluminescence plays an important role in nature, for example, it is used for intracellular chemical signalling in bacteria. It is also used as a useful reagent for various analytical research methods ranging from cellular imaging to gene expression analysis. However, identification and annotation of bioluminescent proteins is a difficult task as they share poor sequence similarities among them. In this paper, we present a novel approach for within class and between-class balancing as well as diversifying of a training dataset by effectively combining unsupervised K-Means algorithm with Synthetic Minority Oversampling Technique (SMOTE) in order to achieve the true performance of the prediction model. Further, we experimented by varying different levels of balancing ratio of positive data to negative data in the training dataset in order to probe for an optimal class distribution which produces the best prediction accuracy. The appropriately balanced and diversified training set resulted in near complete learning with greater generalization on the blind test datasets. The obtained results strongly justify the fact that optimal class distribution with a high degree of diversity is an essential factor to achieve near perfect learning. Using random forest as the weak learners in boosting and training it on the optimally balanced and diversified training dataset, we achieved an overall accuracy of 95.3% on a tenfold cross validation test, and an accuracy of 91.7%, sensitivity of 89. 3% and specificity of 91.8% on a holdout test set. It is quite possible that the general framework discussed in the current work can be successfully applied to other biological datasets to deal with imbalance and incomplete learning problems effectively. PMID- 26599829 TI - Using Technology to Create a More Humanistic Approach to Integrating Palliative Care into the Intensive Care Unit. AB - A decade ago, the major obstacles to integration of palliative care into the intensive care unit (ICU) were the limited number of providers trained in palliative care, an immature evidence base, and a lack of appreciation for the importance of palliative care in the ICU. In 2016, the palliative care workforce has expanded markedly and there is growing appreciation of the benefits of palliative care, whether provided by a generalist (intensivist, nurse, social worker) or palliative care specialist. However, there is evidence that the quality of ICU-based palliative care is often suboptimal. A major barrier to more broadly addressing this quality problem is the lack of scalable ICU-based palliative care models that use technology to deliver efficient, collaborative palliative care in the ICU setting to the right patient at the right time. To address these challenges, we first review strengths and limitations of current care models as the basis for our novel conceptual framework that uses the electronic health record as a platform on which external innovations can be built, including: (1) screening for patients at risk for poor outcomes, (2) integrating patient- and family-reported needs, (3) personalizing care, and (4) directing generalist versus specialist triage algorithms. In the approaches considered, we describe current challenges and propose specific solutions that use technology to improve the quality of the human interaction in a stressful, complex environment. PMID- 26599830 TI - ATP bioluminescence method: tool for rapid screening of organic and microbial contaminants on deteriorated mural paintings. AB - The extent of the microbial contamination of the seventeenth-century wall paintings in the nave of the old Church of the Holy Ascension (Veliki Krcimir, Serbia) was evaluated via newly implemented ATP bioluminescence method, and traditional cultivation-based method, utilising commercially available dip slides. To assess the validity of ATP, as a biomarker for rapid detection of mural surface contamination, obtained zones of cleanliness values, in range from 1.0 to 5.3, were compared to documented total microbial counts, ranging between seven and 247 CFU/cm2. Small coefficients of determination, 0.0106-0.0385, suggest poor correlation between microbial counts and surface ATP levels; however, zones of cleanliness values are of great help in determining the high points of contamination, aka 'hotspots', which should be given special attention during sampling and investigation using other methods. In addition, various aspects of the possible implementation of the ATP bioluminescence method in an integrated system of wall painting conservation are discussed. PMID- 26599831 TI - Primary Progressive Multiple Sclerosis Evolving From Radiologically Isolated Syndrome. AB - OBJECTIVE: The aim of this work was to evaluate the preprogressive phase in subjects with radiologically isolated syndrome (RIS) who evolve to primary progressive multiple sclerosis (PPMS). METHODS: A multicenter RIS cohort was previously established. Demographic, clinical, and radiological characteristics of subjects with RIS that evolved directly to PPMS were compared to those that developed a relapsing disease course from onset (clinically isolated syndrome [CIS] or relapsing-remitting MS) and were also compared to two other population- and clinic-based PPMS cohorts. RESULTS: Of the 453 subjects with RIS, 128 evolved to symptomatic MS during the follow-up (113 developed a first acute clinical event consistent with CIS/MS, 15 evolved to PPMS). PPMS prevalence (11.7%) and onset age (mean +/- standard deviation; 49.1 +/- 12.1) in the RIS group were comparable to other PPMS populations (p > 0.05). Median time to PPMS was 3.5 years (range, 1.6-5.4). RIS evolved to PPMS more commonly in men (p = 0.005) and at an older age (p < 0.001) when compared to CIS/MS, independent of follow-up duration. Subjects who evolved to PPMS had more spinal cord lesions (100%) before symptomatic evolution than those that developed CIS/MS (64%) and those that remained asymptomatic (23%) within the follow-up period (P = 0.005). Other MRI characteristics in the preprogressive phase of PPMS were indistinguishable from CIS/MS. INTERPRETATION: Subjects with RIS evolve to PPMS at the same frequency as expected from general MS populations in an age-dependent manner. Besides age, unequivocal presence of spinal cord lesions and being male predicted evolution to PPMS. Our findings further suggest that RIS is biologically part of the MS spectrum. PMID- 26599832 TI - Antinociceptive Grayanoids from the Roots of Rhododendron molle. AB - Nine new grayanoids (1-9), together with 11 known compounds, were isolated from the roots of Rhododendron molle. The structures of the new compounds (1-9) were determined on the basis of spectroscopic analysis, including HRESIMS, and 1D and 2D NMR data. Compounds 4, 6, 12, and 14-20 showed significant antinociceptive activities in an acetic acid-induced writhing test. In particular, 14 and 15 were found to be more potent than morphine for both acute and inflammatory pain models and 100-fold more potent than gabapentin in a diabetic neuropathic pain model. PMID- 26599833 TI - Scaling up the diversity-resilience relationship with trait databases and remote sensing data: the recovery of productivity after wildfire. AB - Understanding the mechanisms underlying ecosystem resilience - why some systems have an irreversible response to disturbances while others recover - is critical for conserving biodiversity and ecosystem function in the face of global change. Despite the widespread acceptance of a positive relationship between biodiversity and resilience, empirical evidence for this relationship remains fairly limited in scope and localized in scale. Assessing resilience at the large landscape and regional scales most relevant to land management and conservation practices has been limited by the ability to measure both diversity and resilience over large spatial scales. Here, we combined tools used in large-scale studies of biodiversity (remote sensing and trait databases) with theoretical advances developed from small-scale experiments to ask whether the functional diversity within a range of woodland and forest ecosystems influences the recovery of productivity after wildfires across the four-corner region of the United States. We additionally asked how environmental variation (topography, macroclimate) across this geographic region influences such resilience, either directly or indirectly via changes in functional diversity. Using path analysis, we found that functional diversity in regeneration traits (fire tolerance, fire resistance, resprout ability) was a stronger predictor of the recovery of productivity after wildfire than the functional diversity of seed mass or species richness. Moreover, slope, elevation, and aspect either directly or indirectly influenced the recovery of productivity, likely via their effect on microclimate, while macroclimate had no direct or indirect effects. Our study provides some of the first direct empirical evidence for functional diversity increasing resilience at large spatial scales. Our approach highlights the power of combining theory based on local-scale studies with tools used in studies at large spatial scales and trait databases to understand pressing environmental issues. PMID- 26599834 TI - Trapping a Highly Reactive Nonheme Iron Intermediate That Oxygenates Strong C-H Bonds with Stereoretention. AB - An unprecedentedly reactive iron species (2) has been generated by reaction of excess peracetic acid with a mononuclear iron complex [Fe(II)(CF3SO3)2(PyNMe3)] (1) at cryogenic temperatures, and characterized spectroscopically. Compound 2 is kinetically competent for breaking strong C-H bonds of alkanes (BDE ~ 100 kcal.mol(-1)) through a hydrogen-atom transfer mechanism, and the transformations proceed with stereoretention and regioselectively, responding to bond strength, as well as to steric and polar effects. Bimolecular reaction rates are at least an order of magnitude faster than those of the most reactive synthetic high valent nonheme oxoiron species described to date. EPR studies in tandem with kinetic analysis show that the 490 nm chromophore of 2 is associated with two S = 1/2 species in rapid equilibrium. The minor component 2a (~5% iron) has g-values at 2.20, 2.19, and 1.99 characteristic of a low-spin iron(III) center, and it is assigned as [Fe(III)(OOAc)(PyNMe3)](2+), also by comparison with the EPR parameters of the structurally characterized hydroxamate analogue [Fe(III)(tBuCON(H)O)(PyNMe3)](2+) (4). The major component 2b (~40% iron, g values = 2.07, 2.01, 1.95) has unusual EPR parameters, and it is proposed to be [Fe(V)(O)(OAc)(PyNMe3)](2+), where the O-O bond in 2a has been broken. Consistent with this assignment, 2b undergoes exchange of its acetate ligand with CD3CO2D and very rapidly reacts with olefins to produce the corresponding cis-1,2 hydroxoacetate product. Therefore, this work constitutes the first example where a synthetic nonheme iron species responsible for stereospecific and site selective C-H hydroxylation is spectroscopically trapped, and its catalytic reactivity against C-H bonds can be directly interrogated by kinetic methods. The accumulated evidence indicates that 2 consists mainly of an extraordinarily reactive [Fe(V)(O)(OAc)(PyNMe3)](2+) (2b) species capable of hydroxylating unactivated alkyl C-H bonds with stereoretention in a rapid and site-selective manner, and that exists in fast equilibrium with its [Fe(III)(OOAc)(PyNMe3)](2+) precursor. PMID- 26599835 TI - Retracted: Evaluation of the incidence of microcracks caused by Mtwo and ProTaper NEXT rotary file systems versus the Self Adjusting File: a scanning electron microscopic study. AB - The following article from International Endodontic Journal, 'Evaluation of the incidence of microcracks caused by Mtwo and ProTaper NEXT rotary file systems versus the Self Adjusting File: a scanning electron microscopic study' by S. G. Saha, N. Vijaywargiya, S. Dubey, D. Saxena & S. Kala, published online on 24 November 2015 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors, the journal Editor in Chief, Prof. Paul Dummer, and John Wiley & Sons Ltd. The retraction has been agreed due to the consideration that the SEM methodology used by the authors has the potential to cause cracks and is thus is not suitable for the evaluation of micro-cracks in roots. PMID- 26599836 TI - Comparison of the satiating properties of egg- versus cereal grain-based breakfasts for appetite and energy intake control in children. AB - BACKGROUND: Few studies exist that have systematically examined the role of protein, and egg protein in particular, in appetite and energy intake regulation in children. OBJECTIVE: The aim of this study was to compare the effects of three different types of breakfast on appetite and energy intake at subsequent meals in children. DESIGN: Forty children, ages 8-10, were served a compulsory breakfast (egg, cereal, or oatmeal) and lunch, consumed ad libitum, once a week for three weeks. Children's appetite ratings were assessed repeatedly throughout the morning. On each test day, caregivers completed food records, which captured children's intake for the remainder of the day. RESULTS: There was a significant main effect of breakfast condition on energy intake at lunch (P=0.02) indicating that children consumed ~70 fewer calories at lunch following the egg breakfast (696 +/- 53 kcal) compared to the cereal (767 +/- 53 kcal) and oatmeal (765 +/- 53 kcal) breakfasts. Calories consumed for the remainder of the day and daily energy intake did not differ across conditions (P>0.30). There also were no significant differences in children's appetite ratings between conditions (P>0.43). CONCLUSIONS: Consuming an egg-based breakfast significantly reduced short-term, but not longer-term, energy intake in children in the absence of differences in appetite ratings. PMID- 26599837 TI - Weight concerns and food habits of adolescent girls in two contrasting ecological regions: A comparative study in India. AB - OBJECTIVE: To compare the incidence of weight concerns and food habits between two ethnically different groups of adolescent girls residing in two distinct ecological settings: the plains of Kolkata and the mountains of Sikkim. METHODS: Two separate cross-sectional studies were conducted within a period of five years in urban hilly areas of Sikkim and the city of Kolkata, India. A total of 506 girls aged 14-19 years were selected from the study areas of Sikkim (n=224) and Kolkata (n=282). Girls were interviewed for weight concerns and food habits along with socio-demographic characteristics. Weight concerns were assessed with four variables such as, perceptions about own body weight, felt dissatisfied with own body weight, urge for dieting and use of weight reduction diet. Food habits included consumption of major foods during the past one week. RESULTS: Bivariate analyses showed that Kolkata girls perceived themselves as overweight, remained dissatisfied with body weight, expressed perceived need for dieting and followed weight reduction diet more compared to the girls of Sikkim. Food habits indicated that all Sikkimese girls preferred to consume cereals regularly, while Kolkata girls consumed vegetables, pulses, fish, fruits, bread and butter and fried foods more than Sikkimese girls. Multivariate analyses showed that place of residence was significantly (p<0.05) associated with both weight concerns and food habits of girls. CONCLUSION: Diversity in culture, ethnicity and socio-economic standard perhaps develop the disparity in food habits and weight concerns between girls of urban hilly areas of Sikkim and the city of Kolkata. PMID- 26599838 TI - A Versatile Coating Strategy to Highly Improve the Electrochemical Properties of Layered Oxide LiMO2 (M = Ni0.5Mn0.5 and Ni1/3Mn1/3Co1/3). AB - This work provides a convenient, effective and highly versatile coating strategy for the layered oxide LiMO2 (M = Ni0.5Mn0.5 and Ni1/3Mn1/3Co1/3). Here, layered oxide LiMO2 (M = Ni0.5Mn0.5 and Ni1/3Mn1/3Co1/3) has been successfully coated with ion conductor of Li2SiO3 by in situ hydrolysis of tetraethyl orthosilicate (TEOS) followed by the lithiation process. The discharge capacity, cycle stability, rate capability, and some other electrochemical performances of layered cathode materials LiMO2 can be highly enhanced through surface modification by coating appropriate content of Li2SiO3. Particularly, the 3 mol % Li2SiO3 coated LiNi1/3Mn1/3Co1/3O2 exhibits approximately a discharge capacity of 111 mAh/g after 300 cycles at the current density of 800 mA/g (5 C). Potentiostatic intermittent titration technique (PITT) test was carried out to investigate the mechanism of the improvement in the electrochemical properties. The diffusion coefficient of Li(+)-ion (D(Li)) of Li2SiO3 coated layered oxide materials has been greatly increased. We believe our methodology provides a convenient, effective and highly versatile coating strategy, which can be expected to open the way to ameliorate the electrochemical properties of electrode materials for lithium ion batteries. PMID- 26599839 TI - Why clinical translation cannot succeed without failure. AB - The high rates of attrition that occur in drug development are widely regarded as problematic, but the failure of well-designed studies benefits both researchers and healthcare systems by, for example, generating evidence about disease theories and demonstrating the limits of proven drugs. A wider recognition of these benefits will help the biomedical research enterprise to take full advantage of all the information generated during the drug development process. PMID- 26599840 TI - Correction: Registered report: A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. PMID- 26599842 TI - A room temperature spin crossover ionic liquid. AB - Two new paramagnetic ionic liquids (ILs) comprising a mononuclear iron(III) or manganese(III) complex cation, charge balanced by a dicyanamide anion are reported which show a range of spin states. Both are liquids at room temperature and the Fe(III) based IL exhibits a spin crossover close to 300 K. The spin crossover profile is independent of the solvation, and is both air and moisture stable. PMID- 26599841 TI - Flagellar membrane proteins in kinetoplastid parasites. AB - All kinetoplastid parasites, including protozoa such as Leishmania species, Trypanosoma brucei, and Trypanosoma cruzi that cause devastating diseases in humans and animals, are flagellated throughout their life cycles. Although flagella were originally thought of primarily as motility organelles, flagellar functions in other critical processes, especially in sensing and signal transduction, have become more fully appreciated in the recent past. The flagellar membrane is a highly specialized subdomain of the surface membrane, and flagellar membrane proteins are likely to be critical components for all the biologically important roles of flagella. In this review, we summarize recent discoveries relevant to flagellar membrane proteins in these parasites, including the identification of such proteins, investigation of their biological functions, and mechanisms of selective trafficking to the flagellar membrane. Prospects for future investigations and current unsolved problems are highlighted. PMID- 26599843 TI - Racial Violence, Academic Medicine, and Academic Medicine. PMID- 26599844 TI - Physician Workforce Shortages: What Do the Data Really Say? PMID- 26599845 TI - Physician Workforce Shortages: What Do the Data Really Say? PMID- 26599846 TI - In Reply to Kirch and to Dall. PMID- 26599847 TI - Reexamining Outcomes of the Primary Care Residency Expansion. PMID- 26599848 TI - In Reply to Rasouli and Willson. PMID- 26599849 TI - Using Liberal Criteria to Identify Burnout Poses the Risk of Pathologizing Normal Adaptive States. PMID- 26599850 TI - In Reply to Bianchi et al. PMID- 26599851 TI - Promoting Palliative Care. PMID- 26599852 TI - Promoting Palliative Care. PMID- 26599853 TI - The Suspicious Fracture Pattern of Freddie Gray. PMID- 26599854 TI - Artist's Statement: Crystallography as Art. PMID- 26599856 TI - Medicine and the Arts. "Anatomy Lesson" by Jack Coulehan. Commentary. PMID- 26599857 TI - The Gold-Hope Tang, MD 2015 Humanism in Medicine Essay Contest: First Place: Being the Narrator. PMID- 26599858 TI - Confessions of a Medical Voluntourist. PMID- 26599859 TI - Vital Signs. PMID- 26599860 TI - Salmonella typhimurium detection using a surface-enhanced Raman scattering-based aptasensor. AB - Surface-enhanced Raman spectroscopy (SERS) has been used in a variety of biological applications due to its high sensitivity and specificity. Here, we report a SERS-based aptasensor approach for quantitative detection of pathogenic bacteria. A SERS substrate bearing Au@Ag core/shell nanoparticles (NPs) is functionalized with aptamer 1 (apt 1) for the capture of target molecules. X rhodamine (ROX)-modified aptamer 2 (apt 2) is used as recognition element and Raman reporter. Salmonella typhimurium specifically interacted with the aptamers to form Au@Ag-apt 1-target-apt 2-ROX sandwich-like complexes. As a result, the concentration of S. typhimurium was determined using this developed aptasensor structure, and a calibration curve is obtained in the range of 15 to 1.5 * 10(6) cfu/mL with a limit of detection of 15 cfu/mL. Our method was successfully applied to real food samples, and the results are consistent with the results obtained using plate counting methods. We believe that the developed method shows potential for the rapid and sensitive detection of pathogenic bacteria in food safety assurance. PMID- 26599861 TI - Profile of microRNA in Giant Panda Blood: A Resource for Immune-Related and Novel microRNAs. AB - The giant panda (Ailuropoda melanoleuca) is one of the world's most beloved endangered mammals. Although the draft genome of this species had been assembled, little was known about the composition of its microRNAs (miRNAs) or their functional profiles. Recent studies demonstrated that changes in the expression of miRNAs are associated with immunity. In this study, miRNAs were extracted from the blood of four healthy giant pandas and sequenced by Illumina next generation sequencing technology. As determined by miRNA screening, a total of 276 conserved miRNAs and 51 novel putative miRNAs candidates were detected. After differential expression analysis, we noticed that the expressions of 7 miRNAs were significantly up-regulated in young giant pandas compared with that of adults. Moreover, 2 miRNAs were up-regulated in female giant pandas and 1 in the male individuals. Target gene prediction suggested that the miRNAs of giant panda might be relevant to the expressions of 4,602 downstream genes. Subseuqently, the predicted target genes were conducted to KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis and we found that these genes were mainly involved in host immunity, including the Ras signaling pathway, the PI3K-Akt signaling pathway, and the MAPK signaling pathway. In conclusion, our results provide the first miRNA profiles of giant panda blood, and the predicted functional analyses may open an avenue for further study of giant panda immunity. PMID- 26599862 TI - Determining the Presence of Superantigens in Coagulase Negative Staphylococci from Humans. AB - Superantigens (SAgs) are important virulence factors in S. aureus. Recent studies identified their presence in animal coagulase-negative staphylococci (CNS). The emergence of human-associated SAg+ CNS would mark a prodigious shift in virulence capabilities. We examined CNS isolates from healthy human nares and diseased individuals, and determined that no known SAgs were present. PMID- 26599863 TI - Influence of the oxazole ring connection on the fluorescence of oxazoyl triphenylamine biphotonic DNA probes. AB - On the basis of our previous work on DNA fluorophores derived from vinylpyridinium-triphenylamine, we explored the structure space around the electron-rich triphenylamine (TP) core by changing the vinyl bond to an oxazole ring. As 2,5-diaryloxazoles are known to be highly fluorescent and efficient two photon absorbers, we synthesized analogues with two different connections of the oxazole to the triphenylamine core: TP-Ox2Py and TP-Ox5Py sets. Since the benzimidazolium group was proven to be more effective in the TP series than the pyridinium, we also synthesized a TP-Ox5Bzim set. The TP-Ox5Py series retains the TP-Py properties: on/off behavior on DNA, good two-photon cross-section and bright staining of nuclear DNA by microscopy under both one or two-photon excitation. On the other hand, the TP-Ox2Py series does not display fluorescence upon binding to DNA. The TP-Ox5Bzim set is fluorescent even in the absence of DNA and displays lower affinity than the corresponding TP-Ox5Py. CD experiments and docking were performed to understand these different behaviors. PMID- 26599864 TI - Concentration Dependent Influence of Lipopolysaccharides on Separation of Hoof Explants and Supernatant Lactic Acid Concentration in an Ex Vivo/In Vitro Laminitis Model. AB - Laminitis is one of the most common diseases in horses. It is not only painful for the animal, but also has a significant financial impact on the equine industry. This multifactorial disease affects the connective tissue of the hoof. However, the pathogenesis of laminitis is still not fully understood. Endotoxins, also known as lipopolysaccharides (LPS), and bacterial exotoxins seem to play an important role during the development of laminitis. The aim of our study was to investigate the effect of increasing LPS concentrations (0, 2.5, 5, 10, and 100 MUg/mL) on cell viability of isolated epidermal and dermal hoof cells as well as on the tissue integrity of hoof explants. Furthermore, glucose, acetic acid, lactic acid, and propionic acid concentrations in explant supernatants were measured to evaluate the energy metabolism in the hoof tissue. LPS did not exhibit cytotoxic effects on epidermal or dermal cells. Force required to separate LPS treated hoof explants decreased in a concentration dependent manner. Specifically, explants incubated with 10 and 100 MUg/mL needed significantly less force to separate compared to control explants. Lactic acid concentrations were significantly decreased in explants incubated with 5, 10, or 100 MUg/mL LPS, while glucose, acetic acid and propionic acid concentrations were unaffected by LPS treatment. Our study indicates that LPS has no cytotoxic effect on epidermal and dermal cells isolated from hoof tissue, but impairs integrity of hoof explants. In addition, LPS led to an alteration of the lactic acid production in the lamellar tissue. Since our data highlight that LPS can affect the integrity of the equine hoof tissue in vitro, endotoxins should be further explored for their contribution to facilitate the development of laminitis. PMID- 26599865 TI - The Zinc Concentration in the Diet and the Length of the Feeding Period Affect the Methylation Status of the ZIP4 Zinc Transporter Gene in Piglets. AB - High doses of zinc oxide are commonly used in weaned pig diets to improve performance and health. Recent reports show that this may also lead to an imbalanced zinc homeostasis in the animal. For a better understanding of the regulatory mechanisms of different zinc intakes, we performed a feeding experiment to assess potential epigenetic regulation of the ZIP4 gene expression via DNA methylation in the small intestine of piglets. Fifty-four piglets were fed diets with 57 (LZn), 164 (NZn) or 2,425 (HZn) mg Zn/kg feed for one or four weeks. The ZIP4 expression data provided significant evidence for counter regulation of zinc absorption with higher dietary zinc concentrations. The CpG +735 in the second exon had a 56% higher methylation in the HZn group compared to the others after one week of feeding (8.0.10-4 < p < 0.035); the methylation of this CpG was strongly negatively associated with the expression of the long ZIP4 transcripts (p < 0.007). In the LZn and NZn diets, the expression of the long ZIP4 transcripts were lower after four vs. one week of feeding (2.9.10-4 < p < 0.017). The strongest switch leading to high DNA methylation in nearly all analysed regions was dependent on feeding duration or age in all diet groups (3.7.10-10 < p < 0.099). The data suggest that DNA methylation serves as a fine tuning mechanism of ZIP4 gene regulation to maintain zinc homeostasis. Methylation of the ZIP4 gene may play a minor role in the response to very high dietary zinc concentration, but may affect binding of alternate zinc-responsive transcription factors. PMID- 26599866 TI - Inflammatory Mediator Profiling of n-butanol Exposed Upper Airways in Individuals with Multiple Chemical Sensitivity. AB - BACKGROUND: Multiple Chemical Sensitivity (MCS) is a chronic condition characterized by reports of recurrent symptoms in response to low level exposure to various chemical substances. Recent findings suggests that dysregulation of the immune system may play a role in MCS pathophysiology. OBJECTIVES: The aim of this study was to examine baseline and low dose n-butanol-induced upper airway inflammatory response profiles in MCS subjects versus healthy controls. METHOD: Eighteen participants with MCS and 18 age- and sex-matched healthy controls were enrolled in the study. Epithelial lining fluid was collected from the nasal cavity at three time points: baseline, within 15 minutes after being exposed to 3.7 ppm n-butanol in an exposure chamber and four hours after exposure termination. A total of 19 cytokines and chemokines were quantified. Furthermore, at baseline and during the exposure session, participants rated the perceived intensity, valence and levels of symptoms and autonomic recordings were obtained. RESULTS: The physiological and psychophysical measurements during the n-butanol exposure session verified a specific response in MCS individuals only. However, MCS subjects and healthy controls displayed similar upper airway inflammatory mediator profiles (P>0.05) at baseline. Likewise, direct comparison of mediator levels in the MCS group and controls after n-butanol exposure revealed no significant group differences. CONCLUSION: We demonstrate no abnormal upper airway inflammatory mediator levels in MCS subjects before or after a symptom eliciting exposure to low dose n-butanol, implying that upper airways of MCS subjects are functionally intact at the level of cytokine and chemokine production and secretory capacity. This suggests that previous findings of increased cytokine plasma levels in MCS are unlikely to be caused by systemic priming via excessive upper airway inflammatory processes. PMID- 26599867 TI - Involvement of IL-1 in the Maintenance of Masseter Muscle Activity and Glucose Homeostasis. AB - Physical exercise reportedly stimulates IL-1 production within working skeletal muscles, but its physiological significance remains unknown due to the existence of two distinct IL-1 isoforms, IL-1alpha and IL-1beta. The regulatory complexities of these two isoforms, in terms of which cells in muscles produce them and their distinct/redundant biological actions, have yet to be elucidated. Taking advantage of our masticatory behavior (Restrained/Gnawing) model, we herein show that IL-1alpha/1beta-double-knockout (IL-1-KO) mice exhibit compromised masseter muscle (MM) activity which is at least partially attributable to abnormalities of glucose handling (rapid glycogen depletion along with impaired glucose uptake) and dysfunction of IL-6 upregulation in working MMs. In wild-type mice, masticatory behavior clearly increased IL-1beta mRNA expression but no incremental protein abundance was detectable in whole MM homogenates, whereas immunohistochemical staining analysis revealed that both IL 1alpha- and IL-1beta-immunopositive cells were recruited around blood vessels in the perimysium of MMs after masticatory behavior. In addition to the aforementioned phenotype of IL-1-KO mice, we found the IL-6 mRNA and protein levels in MMs after masticatory behavior to be significantly lower in IL-1-KO than in WT. Thus, our findings confirm that the locally-increased IL-1 elicited by masticatory behavior, although present small in amounts, contributes to supporting MM activity by maintaining normal glucose homeostasis in these muscles. Our data also underscore the importance of IL-1-mediated local interplay between autocrine myokines including IL-6 and paracrine cytokines in active skeletal muscles. This interplay is directly involved in MM performance and fatigability, perhaps mediated through maintaining muscular glucose homeostasis. PMID- 26599868 TI - Electrical Control of g-Factor in a Few-Hole Silicon Nanowire MOSFET. AB - Hole spins in silicon represent a promising yet barely explored direction for solid-state quantum computation, possibly combining long spin coherence, resulting from a reduced hyperfine interaction, and fast electrically driven qubit manipulation. Here we show that a silicon-nanowire field-effect transistor based on state-of-the-art silicon-on-insulator technology can be operated as a few-hole quantum dot. A detailed magnetotransport study of the first accessible hole reveals a g-factor with unexpectedly strong anisotropy and gate dependence. We infer that these two characteristics could enable an electrically driven g tensor-modulation spin resonance with Rabi frequencies exceeding several hundred mega-Hertz. PMID- 26599869 TI - Comparison of 2.5D and 3D Quantification of Femoral Head Coverage in Normal Control Subjects and Patients with Hip Dysplasia. AB - Hip dysplasia is characterized by insufficient femoral head coverage (FHC). Quantification of FHC is of importance as the underlying goal of the surgery to treat hip dysplasia is to restore a normal acetabular morphology and thereby to improve FHC. Unlike a pure 2D X-ray radiograph-based measurement method or a pure 3D CT-based measurement method, previously we presented a 2.5D method to quantify FHC from a single anteriorposterior (AP) pelvic radiograph. In this study, we first quantified and compared 3D FHC between a normal control group and a patient group using a CT-based measurement method. Taking the CT-based 3D measurements of FHC as the gold standard, we further quantified the bias, precision and correlation between the 2.5D measurements and the 3D measurements on both the control group and the patient group. Based on digitally reconstructed radiographs (DRRs), we investigated the influence of the pelvic tilt on the 2.5D measurements of FHC. The intraclass correlation coefficients (ICCs) for absolute agreement was used to quantify interobserver reliability and intraobserver reproducibility of the 2.5D measurement technique. The Pearson correlation coefficient, r, was used to determine the strength of the linear association between the 2.5D and the 3D measurements. Student's t-test was used to determine whether the differences between different measurements were statistically significant. Our experimental results demonstrated that both the interobserver reliability and the intraobserver reproducibility of the 2.5D measurement technique were very good (ICCs > 0.8). Regression analysis indicated that the correlation was very strong between the 2.5D and the 3D measurements (r = 0.89, p < 0.001). Student's t-test showed that there were no statistically significant differences between the 2.5D and the 3D measurements of FHC on the patient group (p > 0.05). The results of this study provided convincing evidence demonstrating the validity of the 2.5D measurements of FHC from a single AP pelvic radiograph and proved that it could serve as a surrogate for 3D CT-based measurements. Thus it may be possible to use this method to avoid a CT scan for the purpose of estimating 3D FHC in diagnosis and post-operative treatment evaluation of patients with hip dysplasia. PMID- 26599870 TI - Mechanisms of Protective Effect of Ramulus Mori Polysaccharides on Renal Injury in High-Fat Diet/Streptozotocin-Induced Diabetic Rats. AB - BACKGROUND: Diabetic nephropathy (DN) is the most important complication of diabetes and the most common cause of end-stage renal disease (ESRD). AIMS: A recent study established that the Ramulus mori polysaccharides (RMP) exert antioxidant effects on DN in rats. METHODS: The diabetic rats which induced by high-fat diet and streptozotocin injection were orally administered RMP by doses of 250, 500 and 1000 mg/kg daily for 8 weeks. The effects of RMP on hyperglycemia and other biochemical changes were examined in the sera and kidney tissues. Additionally, the pathological and ultrastructural changes and expressions of nuclear-factor kappa B (NF-x03BA;B) and transforming growth factor-beta1 (TGF beta1) were assessed. RESULTS: The results revealed that the serum levels of blood glucose, total cholesterol (TC) and triglycerides (TG) were significantly decreased by RMP. Furthermore, the blood urea nitrogen (BUN), serum creatinine (SCr) and 24-hour urine protein levels in the RMP-medicated rats were lower than those in untreated diabetic rats. Moreover, treatment of the DN rats with RMP normalized all biochemical changes, including the malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) levels in the serum and kidney tissues. In contrast, the protein expression levels of NF x03BA;B and TGF-beta1, which were enhanced in the kidneys of DN rats, were reduced by RMP. CONCLUSION: These results suggest that RMP improving the renal function of diabeitc rats possibly via its ameliorating antioxidant activities. PMID- 26599871 TI - Corrigendum: Kekule versus Lewis: When Aromaticity Prevents Electron Pairing and Imposes Polyradical Character. PMID- 26599872 TI - Corrigendum: Palladium-Catalyzed Carbonylative Reactions of 1-Bromo-2 fluorobenzenes with Various Nucleophiles: Effective Combination of Carbonylation and Nucleophilic Substitution. PMID- 26599873 TI - Corrigendum: A Well-Defined Aluminum-Based Lewis Acid as an Effective Catalyst for Diels-Alder Transformations. PMID- 26599877 TI - Influence of Jail Incarceration and Homelessness Patterns on Engagement in HIV Care and HIV Viral Suppression among New York City Adults Living with HIV/AIDS. AB - OBJECTIVES: Both homelessness and incarceration are associated with housing instability, which in turn can disrupt continuity of HIV medical care. Yet, their impacts have not been systematically assessed among people living with HIV/AIDS (PLWHA). METHODS: We studied a retrospective cohort of 1,698 New York City PLWHA with both jail incarceration and homelessness during 2001-05 to evaluate whether frequent transitions between jail incarceration and homelessness were associated with a lower likelihood of continuity of HIV care during a subsequent one-year follow-up period. Using matched jail, single-adult homeless shelter, and HIV registry data, we performed sequence analysis to identify trajectories of these events and assessed their influence on engagement in HIV care and HIV viral suppression via marginal structural modeling. RESULTS: Sequence analysis identified four trajectories; 72% of the cohort had sporadic experiences of both brief incarceration and homelessness, whereas others experienced more consistent incarceration or homelessness during early or late months. Trajectories were not associated with differential engagement in HIV care during follow-up. However, compared with PLWHA experiencing early bouts of homelessness and later minimal incarceration/homelessness events, we observed a lower prevalence of viral suppression among PLWHA with two other trajectories: those with sporadic, brief occurrences of incarceration/homelessness (0.67, 95% CI = 0.50,0.90) and those with extensive incarceration experiences (0.62, 95% CI = 0.43,0.88). CONCLUSIONS: Housing instability due to frequent jail incarceration and homelessness or extensive incarceration may exert negative influences on viral suppression. Policies and services that support housing stability should be strengthened among incarcerated and sheltered PLWHA to reduce risk of adverse health conditions. PMID- 26599882 TI - Capsules Replace Hospital Rooms. PMID- 26599883 TI - Biomedical Equipment Technicians-The Need and a Solution. PMID- 26599878 TI - A Simple Proteomics-Based Approach to Identification of Immunodominant Antigens from a Complex Pathogen: Application to the CD4 T Cell Response against Human Herpesvirus 6B. AB - Most of humanity is chronically infected with human herpesvirus 6 (HHV-6), with viral replication controlled at least in part by a poorly characterized CD4 T cell response. Identification of viral epitopes recognized by CD4 T cells is complicated by the large size of the herpesvirus genome and a low frequency of circulating T cells responding to the virus. Here, we present an alternative to classical epitope mapping approaches used to identify major targets of the T cell response to a complex pathogen like HHV-6B. In the approach presented here, extracellular virus preparations or virus-infected cells are fractionated by SDS PAGE, and eluted fractions are used as source of antigens to study cytokine responses in direct ex vivo T cell activation studies. Fractions inducing significant cytokine responses are analyzed by mass spectrometry to identify viral proteins, and a subset of peptides from these proteins corresponding to predicted HLA-DR binders is tested for IFN-gamma production in seropositive donors with diverse HLA haplotypes. Ten HHV-6B viral proteins were identified as immunodominant antigens. The epitope-specific response to HHV-6B virus was complex and variable between individuals. We identified 107 peptides, each recognized by at least one donor, with each donor having a distinctive footprint. Fourteen peptides showed responses in the majority of donors. Responses to these epitopes were validated using in vitro expanded cells and naturally expressed viral proteins. Predicted peptide binding affinities for the eight HLA-DRB1 alleles investigated here correlated only modestly with the observed CD4 T cell responses. Overall, the response to the virus was dominated by peptides from the major capsid protein U57 and major antigenic protein U11, but responses to other proteins including glycoprotein H (U48) and tegument proteins U54 and U14 also were observed. These results provide a means to follow and potentially modulate the CD4 T-cell immune response to HHV-6B. PMID- 26599884 TI - Management by Objectives. PMID- 26599885 TI - New Mounting Speeds Handling of Hospital's Electrocardiograms. PMID- 26599886 TI - Consultant's Corner. PMID- 26599887 TI - Hospital Financial Problems. PMID- 26599888 TI - Review of Hospital Lawsuits. PMID- 26599889 TI - Handling the Hospital Critic: Patient/Personnel Public Relations. PMID- 26599890 TI - Outpatient Care: Two Approaches to Providing Physician Coverage in E.R. PMID- 26599891 TI - Housekeeping Services: Pest Control. PMID- 26599892 TI - Pharmacy: Locally Produced Audio-Visual Aids can Improve Inservice Programs. PMID- 26599894 TI - Pediatrics: Children's Creativity under Stress of Hospitalization. PMID- 26599898 TI - Central Service: Department's Role in Testing and Evaluating Products. PMID- 26599895 TI - Operating Room: Many Factors in O.R. Environment Discussed in Postgraduate Course. PMID- 26599899 TI - Topics: Care of the Neurosurgical Patient. PMID- 26599900 TI - Topics: Product Profile. PMID- 26599904 TI - The Efficacy and Safety of Icotinib in Patients with Advanced Non-Small Cell Lung Cancer Previously Treated with Chemotherapy: A Single-Arm, Multi-Center, Prospective Study. AB - BACKGROUND: Icotinib is a small molecule targeting epidermal growth factor receptor tyrosine kinase, which shows non-inferior efficacy and better safety comparing to gefitinib in previous phase III trial. The present study was designed to further evaluate the efficacy and safety of icotinib in patients with advanced non-small-cell lung cancer (NSCLC) previously treated with platinum based chemotherapy. METHODS: Patients with NSCLC progressing after one or two lines of chemotherapy were enrolled to receive oral icotinib (125 mg tablet, three times per day). The primary endpoint was progression-free survival. The secondary endpoints included overall survival, objective response rate, time to progression, quality of life and safety. RESULTS: From March 16, 2010 to October 9, 2011, 128 patients from 15 centers nationwide were enrolled, in which 124 patients were available for efficacy evaluation and 127 patients were evaluable for safety. The median progression-free survival and time to progression were 5.0 months (95%CI 2.9-6.6 m) and 5.4 months (95%CI 3.1-7.9 m), respectively. The objective response rate and disease control rate were 25.8% and 67.7% respectively. Median overall survival exceeded 17.6 months (95%CI 14.2 m-NA) according to censored data. Further follow-up of overall survival is ongoing. The most frequent treatment-related adverse events were rash (26%, 33/127), diarrhea (12.6%, 16/127) and elevation of transaminase (15.7%, 20/127). CONCLUSIONS: In general, this study showed similar efficacy and numerically better safety when compared with that in ICOGEN trial, further confirming the efficacy and safety of icotinib in treating patients with advanced NSCLC previously treated with chemotherapy. TRIAL REGISTRATION: ClinicalTrials.gov NCT02486354. PMID- 26599906 TI - Migration of skilled anaesthesiologists from low to high-income economies: Urgent action needed. PMID- 26599905 TI - Development of an Aquaporin-4 Orthogonal Array of Particle-Based ELISA for Neuromyelitis Optica Autoantibodies Detection. AB - Serological markers of Nuromyelitis Optica (NMO), an autoimmune disorder of the central nervous system, are autoantibodies targeting the astrocytic water channel aquaporin-4 (AQP4). We have previously demonstrated that the main epitopes for these autoantibodies (AQP4-IgG) are generated by the supramolecular arrangement of AQP4 tetramers into an Orthogonal Array of Particles (OAPs). Many tests have been developed to detect AQP4-IgG in patient sera but several procedural issues affect OAP assembly and consequently test sensitivity. To date, the protein based ELISA test shows the lowest sensitivity while representing a valid alternative to the more sensitive cell based assay (CBA), which, however, shows economic, technical and interpretation problems. Here we have developed a high perfomance ELISA in which native OAPs are used as the molecular target. To this aim a native size exclusion chromatography method has been developed to isolate integral, highly pure and AQP4-IgG-recognized OAPs from rat brain. These OAPs were immobilized and oriented on a plastic plate by a sandwich approach and 139 human sera were tested, including 67 sera from NMO patients. The OAP-ELISA showed a 99% specificity and a higher sensitivity (91%) compared to the CBA test. A comparative analysis revealed an end-point titer three orders of magnitude higher than the commercial ELISA and six times higher than our in-house CBA test. We show that CNS-extracted OAPs are crucial elements in order to perform an efficient AQP4-IgG test and the OAP-ELISA developed represents a valid alternative to the CBA currently used. PMID- 26599907 TI - Antinociceptive effects of imidazoline I2 receptor agonists in the formalin test in rats. AB - The imidazoline I2 receptor is an emerging drug target for analgesics. This study extended previous studies by examining the antinociceptive effects of three I2 receptor agonists (2-BFI, BU224, and CR4056) in the formalin test. The receptor mechanisms and anatomical mediation of I2 receptor agonist-induced antinociception were also examined. Formalin-induced flinching responses (2%, 50 MUl) were quantified after treatment with I2 receptor agonists alone or in combination with the I2 receptor antagonist idazoxan. Anatomical mediation was studied by locally administering 2-BFI into the plantar surface or into the right lateral ventricle through cannulae (intracerebroventricular). The locomotor activity was also examined after central (intracerebroventricular) administration of 2-BFI. 2-BFI (1-10 mg/kg, intraperitoneal) and BU224 (1-10 mg/kg, intraperitoneal) attenuated the spontaneous flinching response observed during 10 min (phase 1) and 20-60 min (phase 2) following formalin treatment, whereas CR4056 (1-32 mg/kg, intraperitoneal) decreased only phase 2 flinching response. The I2 receptor antagonist idazoxan attenuated the antinociceptive effects of 2 BFI and BU224 during phase 1, but not phase 2. Peripheral administration of 2-BFI (1-10 mg/kg, intraplantar) to the hind paw of rats had no antinociceptive effect. In contrast, centrally delivered 2-BFI (10-100 ug, intracerebroventricular) dose dependently attenuated phase 1 and phase 2 flinching at doses that did not reduce the locomotor activity. Together, these data revealed the differential antinociceptive effects of I2 receptor agonists and the differential antagonism profiles by idazoxan, suggesting the involvement of different I2 receptor subtypes in reducing different phases of formalin-induced pain-like behaviors. In addition, the results also suggest the central mediation of I2 receptor agonist induced antinociceptive actions. PMID- 26599908 TI - A COI Nonsynonymous Mutation as Diagnostic Tool for Intraspecific Discrimination in the European Anchovy Engraulis encrasicolus (Linnaeus). AB - The European anchovy, Engraulis encrasicolus, is currently one of the principal target species for commercial fisheries in Europe. In this study, the mitochondrial Control Region (CR) and the Cytochrome Oxidase I (COI) mitochondrial gene were analyzed in 74 specimens of E. encrasicolus from four localities in the central Mediterranean. In both populations, the two markers revealed the presence of two main haplogroups, A and B, already detected in previous investigations of different classes of molecular markers. Both CR and COI markers consistently identified two haplogroups. The COI sequence analysis identified a non-synonymous transversion (T to G) at position 116 of the translated sequence, resulting in an amino acid change. All COI sequences of haplogroup A had an amino acid sequence with alanine in this position, while serine was present in the same position in haplogroup B. The two haplogroups A and B were also discriminated by the variable number of TACA elements at the 5' end of the mitochondrial CR. The selection tests applied to the COI dataset revealed that codon 116 was not under positive selection, that seven amino acid changes were under purifying selection, and that two amino acids were under episodic positive selection. PMID- 26599909 TI - D1 and D2 Inhibitions of the Soleus H-Reflex Are Differentially Modulated during Plantarflexion Force and Position Tasks. AB - Presynaptic inhibition (PSI) has been shown to modulate several neuronal pathways of functional relevance by selectively gating the connections between sensory inputs and spinal motoneurons, thereby regulating the contribution of the stretch reflex circuitry to the ongoing motor activity. In this study, we investigated whether a differential regulation of Ia afferent inflow by PSI may be associated with the performance of two types of plantarflexion sensoriomotor tasks. The subjects (in a seated position) controlled either: 1) the force level exerted by the foot against a rigid restraint (force task, FT); or 2) the angular position of the ankle when sustaining inertial loads (position task, PT) that required the same level of muscle activation observed in FT. Subjects were instructed to maintain their force/position at target levels set at ~10% of maximum isometric voluntary contraction for FT and 90 degrees for PT, while visual feedback of the corresponding force/position signals were provided. Unconditioned H-reflexes (i.e. control reflexes) and H-reflexes conditioned by electrical pulses applied to the common peroneal nerve with conditioning-to-test intervals of 21 ms and 100 ms (corresponding to D1 and D2 inhibitions, respectively) were evoked in a random fashion. A significant main effect for the type of the motor task (FT vs PT) (p = 0.005, eta2p = 0.603) indicated that PTs were undertaken with lower levels of Ia PSI converging onto the soleus motoneuron pool. Additionally, a significant interaction between the type of inhibition (D1 vs D2) and the type of motor task (FT vs PT) (p = 0.038, eta2p = 0.395) indicated that D1 inhibition was associated with a significant reduction in PSI levels from TF to TP (p = 0.001, eta2p = 0.731), whereas no significant difference between the tasks was observed for D2 inhibition (p = 0.078, eta2p = 0.305). These results suggest that D1 and D2 inhibitions of the soleus H-reflex are differentially modulated during the performance of plantarflexion FT and PT. The reduced level of ongoing PSI during PT suggests that, in comparison to FT, there is a larger reliance on inputs from muscle spindles primary afferents when the neuromuscular system is required to maintain position-controlled plantarflexion contractions. PMID- 26599911 TI - Association of Trait Resilience With Peritraumatic and Posttraumatic Stress in Patients With Myocardial Infarction. AB - OBJECTIVE: Acute myocardial infarction (MI) is a life-threatening condition, leading to immediate fear and distress in many patients. Approximately 18% of patients develop posttraumatic stress disorder in the aftermath of MI. Trait resilience has shown to be a protective factor for the development of posttraumatic stress disorder. However, whether this buffering effect has already an impact on peritraumatic distress and applies to patients with MI is elusive. METHODS: We investigated 98 consecutive patients with acute MI within 48 hours after having reached stable circulatory conditions and 3 months thereafter. Peritraumatic distress was assessed retrospectively with three single-item questions about pain, fear, and helplessness during MI. All patients completed the Posttraumatic Diagnostic Scale (PDS) and the Resilience Scale to self-rate posttraumatic stress and trait resilience. RESULTS: Multivariate models adjusting for sociodemographic and medical factors showed that trait resilience was not associated with peritraumatic distress, but significantly so with posttraumatic stress. Patients with greater trait resilience showed lower PDS scores (b = 0.06, p < .001). There was no significant relationship between peritraumatic distress scores and PDS scores; resilience did not emerge as a moderator of this relationship. CONCLUSIONS: The findings suggest that trait resilience does not buffer the perception of acute MI as stressful per se but may enhance better coping with the traumatic experience in the longer term, thus preventing the development of MI-associated posttraumatic stress. Trait resilience may play an important role in posttraumatic stress symptoms triggered by medical diseases such as acute MI. PMID- 26599910 TI - The Association between Chronic Widespread Musculoskeletal Pain, Depression and Fatigue Is Genetically Mediated. AB - BACKGROUND: Chronic widespread muscoloskeletal pain (CWP) is prevalent in the general population and associated with high health care costs, so understanding the risk factors for chronic pain is important for both those affected and for society. In the present study we investigated the underlying etiological structure of CWP to understand better the association between the major clinical features of fatigue, depression and dihydroepiandrosterone sulphate (DHEAS) using a multivariate twin design. METHODOLOGY/PRINCIPLE FINDINGS: Data were available in 463 UK female twin pairs including CWP status and information on depression, chronic fatigue and serum DHEAS levels. High to moderate heritabilities for all phenotypes were obtained (42.58% to 74.24%). The highest phenotypic correlation was observed between fatigue and CWP (r = 0.45), and the highest genetic correlation between CWP and fatigue (rg = 0.78). Structural equation modeling revealed the AE Cholesky model to provide the best model of the observed data. In this model, two additive genetic factors could be detected loading heavily on CWP A2 explaining 40% of the variance and A3 20%. The factor loading heaviest on DHEAS showed only a small loading on the other phenotypes and none on fatigue at all. Furthermore, one distinct non-shared environmental factor loading specifically on CWP-but not on any of the other phenotypes-could be detected suggesting that the association between CWP and the other phenotypes is due only to genetic factors. CONCLUSIONS/SIGNIFICANCE: Our results suggest that CWP and its associated features share a genetic predisposition but that they are relatively distinct in their environmental determinants. PMID- 26599912 TI - Assessing the New DSM-5 Diagnosis of Somatic Symptom Disorder. AB - The conceptualization of somatization and what were previously termed somatoform disorders has changed substantially in the DSM-5 compared with previous diagnostic systems. The current diagnostic criteria for somatic symptom disorder (SSD) require the presence of symptoms (Criterion A) combined with a substantial impact of these symptoms on thoughts, emotions, and behaviors (Criterion B). In this issue of Psychosomatic Medicine, Toussaint et al. describe the development and empirical validation of a self-report questionnaire --the SSD-12--to assess the new psychological criteria (the "B criteria") of DSM-5 SSD. This is an important contribution because previously there was no questionnaire available to assess the B Criterion of SSD. The new DSM-5 criteria for SSD no longer require the absence of an adequate medical explanation for a somatic symptom, but rather define positive diagnostic criteria, focusing on the psychological impact of the somatic symptoms rather than their purported (medical) cause. Although this new conceptualization of somatization-related disorders has several advantages, seriously ill medical patients may well score high on the B Criterion for SSD on that basis alone and not because their psychological response to the medical illness is disproportionate or excessive. Measures of medical morbidity therefore need to be included in the interpretation of the SSD in individuals with severe medical conditions. Given the revised DSM-5 criteria, the newly developed and validated SSD-12 is a useful tool for diagnosing and monitoring treatment response in SSD. PMID- 26599913 TI - Dynamics of Listeria monocytogenes colonisation in a newly-opened meat processing facility. AB - This study determined the colonisation scenario of Listeria monocytogenes in a newly-opened ready-to-eat meat processing facility using a combination of classical microbiology and molecular biology techniques. Samples (n=183), including food contact surfaces, non-food contact surfaces, raw materials and food samples, collected on four sampling occasions, were analysed for L. monocytogenes by the ISO 11290:1996 standard method and by real-time PCR applied to the second enrichment broth from the ISO method. No L. monocytogenes were detected on the first sampling occasion, but by the second sampling occasion a persistent clone had colonised the facility. Analysis of the second enrichment of the ISO method by real-time PCR was more sensitive for the detection of L. monocytogenes than the ISO method alone. In order to reduce the risk of cross contamination and the public health risk, awareness and proactive measures are required to control L. monocytogenes from the first days of production in a newly opened meat processing facility. PMID- 26599914 TI - Extensive Gustatory Cortex Lesions Significantly Impair Taste Sensitivity to KCl and Quinine but Not to Sucrose in Rats. AB - Recently, we reported that large bilateral gustatory cortex (GC) lesions significantly impair taste sensitivity to salts in rats. Here we extended the tastants examined to include sucrose and quinine in rats with ibotenic acid induced lesions in GC (GCX) and in sham-operated controls (SHAM). Presurgically, immediately after drinking NaCl, rats received a LiCl or saline injection (i.p.), but postsurgical tests indicated a weak conditioned taste aversion (CTA) even in controls. The rats were then trained and tested in gustometers to discriminate a tastant from water in a two-response operant taste detection task. Psychometric functions were derived for sucrose, KCl, and quinine. Our mapping system was used to determine placement, size, and symmetry of the lesions (~91% GC damage on average). For KCl, there was a significant rightward shift (DeltaEC50 = 0.57 log10 units; p<0.001) in the GCX psychometric function relative to SHAM, replicating our prior work. There was also a significant lesion-induced impairment (DeltaEC50 = 0.41 log10 units; p = 0.006) in quinine sensitivity. Surprisingly, taste sensitivity to sucrose was unaffected by the extensive lesions and was comparable between GCX and SHAM rats. The fact that such large bilateral GC lesions did not shift sucrose psychometric functions relative to SHAM, but did significantly compromise quinine and KCl sensitivity suggests that the neural circuits responsible for the detection of specific taste stimuli are partially dissociable. Lesion-induced impairments were observed in expression of a postsurgical CTA to a maltodextrin solution as assessed in a taste-oriented brief-access test, but were not reflected in a longer term 46-h two-bottle test. Thus, deficits observed in rats after extensive damage to the GC are also dependent on the test used to assess taste function. In conclusion, the degree to which the GC is necessary for the maintenance of normal taste detectability apparently depends on the chemical and/or perceptual features of the stimulus. PMID- 26599915 TI - Zinc-induced metallothionein overexpression prevents doxorubicin toxicity in cardiomyocytes by regulating the peroxiredoxins. AB - 1. Cardiotoxicity is an important factor that limits the clinical use of doxorubicin (Dox). Metallothionein (MT) can antagonize the Dox-induced cardiotoxicity. Using a proteomics approach we have detected that major peroxiredoxins (Prxs) may be involved in this process. In the present study, we further investigate the mechanisms of the MT effects against Dox-induced cytotoxicity and the interactions between MT and Prxs. 2. We have established a primary cardiomyocyte culture system from MT-I/II null (MT(-/-)) and corresponding wild type (MT(+/+)) neonatal mice, and pretreated the MT(+/+) cardiomyocytes with ZnCl2 to establish the MT overexpression cardiomyocyte model. 3. Based on the results, in MT(+/+) cardiomyocytes, ZnCl2 pretreatment significantly increased the cardiomyocytes MT levels and inhibited the cardiotoxicity of Dox; it can resist LDH leakage, cardiomyocyte apoptosis, DNA damage, ROS accumulation and inhibit the decrease in activity of antioxidant enzymes induced by Dox. Moreover, ZnCl2 enhanced the expression of Prx-2, -3, -5 and -6, it can inhibit the expression of Prxs decrease in MT(+/+) cardiomyocytes induced by Dox, but had no effect in MT(-/-) cardiomyocytes. 4. Therefore, the present study suggests that ZnCl2 can protect the cardiomyocytes from the Dox induced oxidative injury and can inhibit the changes in Prxs expression through induced MT overexpression. PMID- 26599916 TI - Influence of cell shape, inhomogeneities and diffusion barriers in cell polarization models. AB - In silico experiments bear the potential for further understanding of biological transport processes by allowing a systematic modification of any spatial property and providing immediate simulation results. Cell polarization and spatial reorganization of membrane proteins are fundamental for cell division, chemotaxis and morphogenesis. We chose the yeast Saccharomyces cerevisiae as an exemplary model system which entails the shuttling of small Rho GTPases such as Cdc42 and Rho, between an active membrane-bound form and an inactive cytosolic form. We used partial differential equations to describe the membrane-cytosol shuttling of proteins. In this study, a consistent extension of a class of 1D reaction diffusion systems into higher space dimensions is suggested. The membrane is modeled as a thin layer to allow for lateral diffusion and the cytosol is modeled as an enclosed volume. Two well-known polarization mechanisms were considered. One shows the classical Turing-instability patterns, the other exhibits wave pinning dynamics. For both models, we investigated how cell shape and diffusion barriers like septin structures or bud scars influence the formation of signaling molecule clusters and subsequent polarization. An extensive set of in silico experiments with different modeling hypotheses illustrated the dependence of cell polarization models on local membrane curvature, cell size and inhomogeneities on the membrane and in the cytosol. In particular, the results of our computer simulations suggested that for both mechanisms, local diffusion barriers on the membrane facilitate Rho GTPase aggregation, while diffusion barriers in the cytosol and cell protrusions limit spontaneous molecule aggregations of active Rho GTPase locally. PMID- 26599917 TI - Outcome of attempted vaginal delivery after a previous vacuum extraction: a population-based study. AB - INTRODUCTION: Few studies have investigated long-term effects of a first vaginal instrumental delivery on subsequent mode of delivery. We investigated risks of repeat vacuum extraction and risk factors associated with a repeat vacuum extraction delivery. MATERIAL AND METHODS: This is a population-based register study including 391 160 women with two consecutive singleton term (>=37 weeks) live births in cephalic presentation between/within the time period of 1992-2010 in Sweden. Rates and risk ratios of mode of delivery in second pregnancy in relation to primary mode of delivery were calculated using descriptive analyses and generalized linear models. Risk of repeat vacuum extraction was adjusted for maternal age and height, interpregnancy interval, gestational length, birthweight, induction, sex and occiput posterior position. RESULTS: Compared with women with a primary spontaneous vaginal delivery, women with a primary vacuum extraction had an almost five-fold risk of vacuum extraction delivery and nearly a three-fold risk of emergency cesarean section at second delivery. For women with a primary emergency cesarean section, corresponding risks were substantially higher. Risk factors for a repeat vacuum extraction were increasing maternal age and an interpregnancy interval >4 years, decreasing maternal stature, increasing gestation length and birthweight, induction, giving birth to a male infant and occiput posterior position. CONCLUSIONS: Nine of ten women who attempted a vaginal birth after a primary vacuum extraction succeeded in having a spontaneous vaginal delivery at second delivery. Compared with women with a primary spontaneous vaginal delivery, women with a primary vacuum extraction were at increased risk of repeat vacuum extraction and emergency cesarean section in subsequent delivery although their risk was not as high as that of women with a primary emergency cesarean section. PMID- 26599921 TI - 2015 RSNA Outstanding Researcher. PMID- 26599922 TI - Controversies in Contrast Material-induced Acute Kidney Injury: Closing in on the Truth? PMID- 26599923 TI - Controversies in Contrast Material-induced Acute Kidney Injury: Propensity Score Matching of Patients with Different Dose/Absolute Glomerular Filtration Rate Ratios. PMID- 26599924 TI - A Roadmap for Personalized Care in Radiology. PMID- 26599930 TI - Case 224: Cardiac Involvement in Erdheim-Chester Disease. AB - History A 61-year-old man with no relevant medical history was admitted to the emergency department with symptoms of congestive heart failure and a 1-week history of chest pain, progressive dyspnea, abdominal swelling, bipedal edema, and anorexia. Laboratory test results, including complete blood count and electrolyte, creatinine, creatine phosphokinase, and troponin T levels were normal. Electrocardiographic findings were unremarkable. Initial chest radiography showed an enlarged heart with bilateral pleural effusion. Transthoracic echocardiography revealed an irregular right atrial mass and moderate to severe pericardial effusion. The patient subsequently underwent computed tomography (CT) of the chest, abdomen, and pelvis followed by cardiac magnetic resonance (MR) imaging for further evaluation of the atrial mass. Because of the suspected diagnosis, conventional radiography of the skeleton was performed. PMID- 26599925 TI - Combining in Vitro Diagnostics with in Vivo Imaging for Earlier Detection of Pancreatic Ductal Adenocarcinoma: Challenges and Solutions. AB - Pancreatic ductal adenocarcinoma (PDAC) is the fourth-leading cause of cancer related death in the United States and is associated with a dismal prognosis, particularly when diagnosed at an advanced stage. Overall survival is significantly improved if PDAC is detected at an early stage prior to the onset of symptoms. At present, there is no suitable screening strategy for the general population. Available diagnostic serum markers are not sensitive or specific enough, and clinically available imaging modalities are inadequate for visualizing early-stage lesions. In this article, the role of currently available blood biomarkers and imaging tests for the early detection of PDAC will be reviewed. Also, the emerging biomarkers and molecularly targeted imaging agents being developed to improve the specificity of current imaging modalities for PDAC will be discussed. A strategy incorporating blood biomarkers and molecularly targeted imaging agents could lead to improved screening and earlier detection of PDAC in the future. ((c)) RSNA, 2015. PMID- 26599931 TI - Multiphase CT Angiography: A Poor Man's Perfusion CT? PMID- 26599926 TI - Digital Breast Tomosynthesis: State of the Art. AB - This topical review on digital breast tomosynthesis (DBT) is provided with the intent of describing the state of the art in terms of technology, results from recent clinical studies, advanced applications, and ongoing efforts to develop multimodality imaging systems that include DBT. Particular emphasis is placed on clinical studies. The observations of increase in cancer detection rates, particularly for invasive cancers, and the reduction in false-positive rates with DBT in prospective trials indicate its benefit for breast cancer screening. Retrospective multireader multicase studies show either noninferiority or superiority of DBT compared with mammography. Methods to curtail radiation dose are of importance. ((c)) RSNA, 2015. PMID- 26599932 TI - Gadolinium Deposition after Contrast-enhanced MR Imaging. PMID- 26599933 TI - Dose-Dependent Neurotoxicity (Seizures) Due to Deposition of Gadolinium-based Contrast Agents in the Central Nervous System. PMID- 26599934 TI - In Vivo Quantitative MR Imaging of Bound and Pore Water in Cortical Bone. PMID- 26599935 TI - Focal Nodular Hyperplasia and Hepatocellular Adenoma: Accuracy of Gadoxetic Acid enhanced MR Imaging-A Systematic Review. PMID- 26599936 TI - Cost-Effectiveness of Carotid Plaque MR Imaging as a Stroke Risk Stratification Tool in Asymptomatic Carotid Artery Stenosis. PMID- 26599937 TI - Prospective Comparison of MR Imaging and US for the Diagnosis of Pediatric Appendicitis. PMID- 26599938 TI - Edward B. Singleton, MD. PMID- 26599941 TI - [Not Available]. PMID- 26599942 TI - [In Process Citation]. PMID- 26599943 TI - [Not Available]. PMID- 26599944 TI - [Not Available]. PMID- 26599945 TI - [In Process Citation]. PMID- 26599946 TI - [Not Available]. PMID- 26599947 TI - [In Process Citation]. PMID- 26599948 TI - [In Process Citation]. AB - Congress President Prof. Stefan Roth welcomed more than 7,200 participants at the 67th Congress of the German Society of Urology (DGU) in September 2015, Hamburg. The Congress under the motto "Urology includes more" proved in more than 100 events that the urologist is not only the doctor for the man and the prostate, but that the diversity of the subject far beyond that. So also the unanimous tenor of colorful themes choice of both public forums: Not only men, also women and children are in good hands with the urologist. PMID- 26599949 TI - [In Process Citation]. PMID- 26599950 TI - [In Process Citation]. PMID- 26599952 TI - [Perioperative Outcomes in Correlation to the Learning Curve for Robotic Assisted Partial Nephrectomy: The First 109 Cases of our Clinic]. AB - BACKGROUND: In contrast to conventional laparoscopic partial nephrectomy, the approach of robot-assisted partial nephrectomy (RAPN) shows a steep learning curve with shorter warm ischaemia times (WIT) and comparable postoperative outcomes. Therefore RAPN is considered a good minimally-invasive surgical procedure for patients presenting with a renal cell carcinoma in clinical stage cT1a. The aim of the presented study was to evaluate the perioperative outcomes of our patients after RAPN and to illustrate the learning curve based on characteristic perioperative parameters such as WIT. MATERIAL AND METHODS: The data of 109 patients treated by RAPN in our clinic between January 2010 and April 2015 were retrospectively analysed regarding perioperative, laboratory and oncological outcomes. Postoperative complications until 30 days after surgery were documented. We analysed the data of the largest patient population treated by a single urologist, comparing WIT, operating time, blood loss and decline of the glomerular filtration rate between the first and the second 30 consecutive cases. RESULTS: Mean WIT was 18.4 min (SD+/-10.2), mean operating time was 199 min (SD+/-20), and mean estimated blood loss was 657 millilitres (SD+/-715 ml). Mean loss of GFR was reported to be 4.99 mg/dl/1.73 m (2) (SD+/-15.44). 83 (76%) malignant lesions were removed. 11 patients (10%) had a R1 resection, one patient had a R2 resection and in 2 cases the resection status was Rx. 22% of patients developed postoperative complications. Intraoperative complications were documented in 2 cases. According to the Clavien-Dindo Classification, 6% of patients had grade 1 and 2 complications and 13% developed grade 3 and 4 complications. WIT was significantly lower after 30 consecutive cases treated by one urologist. Regarding operating time, GFR or blood loss no significant correlation was found. CONCLUSION: Our data is in line with the surgical outcomes described in the literature. RAPN is a safe surgical technique with a steep learning curve. In our experience, 30 surgical cases provide a urologist with sufficient expertise to achieve good perioperative results. Weaknesses of this report include the retrospective design and insufficient documentation in some cases. PMID- 26599953 TI - [In Process Citation]. PMID- 26599954 TI - Auxin regulation of cell polarity in plants. AB - Auxin is well known to control pattern formation and directional growth at the organ/tissue levels via the nuclear TIR1/AFB receptor-mediated transcriptional responses. Recent studies have expanded the arena of auxin actions as a trigger or key regulator of cell polarization and morphogenesis. These actions require non-transcriptional responses such as changes in the cytoskeleton and vesicular trafficking, which are commonly regulated by ROP/Rac GTPase-dependent pathways. These findings beg for the question about the nature of auxin receptors that regulate these responses and renew the interest in ABP1 as a cell surface auxin receptor, including the work showing auxin-binding protein 1 (ABP1) interacts with the extracellular domain of the transmembrane kinase (TMK) receptor-like kinases in an auxin-dependent manner, as well as the debate on this auxin binding protein discovered about 40 years ago. This review highlights recent work on the non-transcriptional auxin signaling mechanisms underscoring cell polarity and shape formation in plants. PMID- 26599956 TI - Prevalence of Hyperkalemia in Diabetic and Non-Diabetic Patients with Chronic Kidney Disease: A Nested Case-Control Study. AB - BACKGROUND: Hyperkalemia is a potentially life-threatening disorder, usually complicating chronic kidney disease (CKD). Factors superimposed to reduced renal function are further elevating hyperkalemia risk, but their contribution is not fully elucidated. This study aimed to compare the prevalence of hyperkalemia in diabetic and non-diabetic patients with CKD. METHODS: This is a nested case control study of 180 type-2 diabetic and 180 non-diabetic patients with CKD followed in a Nephrology outpatient clinic, matched for gender, age and estimated glomerular filtration rate. Type-1 diabetes or end-stage renal disease patients were excluded. Prevalence of hyperkalemia was defined as potassium >5 mEq/l or use of sodium polystyrene sulfonate, and further by potassium >5, >=5.2 and >=5.5 mEq/l. It was calculated in both groups in whole and CKD stages separately. Univariate and multivariate logistic regression analysis were conducted to identify factors associated with hyperkalemia. RESULTS: The prevalence of hyperkalemia was higher in diabetic CKD patients (27.2 vs. 20%, p = 0.107) and remained around 30% higher with all secondary definitions used, but never reached statistical significance. In Stage 2, no difference was noted (8.7 vs. 17.4%, p = 0.665); in Stage 3, it was significantly higher in diabetics (28.6 vs. 17.5%, p = 0.036); and in Stage 4, it was equally high in both groups (35.5 vs. 32.3%, p = 0.788). In multivariate analysis, Stage 4 CKD (OR 4.535, 95% CI 1.561-13.173), use of angiotensin-converting enzyme inhibitors (ACEIs; OR 2.228, 95% CI 1.254 3.958) and smoking (OR 2.254, 95% CI 1.218-4.171) were independently associated with hyperkalemia. CONCLUSIONS: Diabetes mellitus was found to elevate the prevalence of hyperkalemia only in CKD Stage 3 patients (moderately impaired renal function). Advanced CKD at Stage 4 and ACEIs are major determinants of hyperkalemia occurrence. PMID- 26599955 TI - Mechanisms of abscisic acid-mediated control of stomatal aperture. AB - Drought stress triggers an increase in the level of the plant hormone abscisic acid (ABA), which initiates a signaling cascade to close stomata and reduce water loss. Recent studies have revealed that guard cells control cytosolic ABA concentration through the concerted actions of biosynthesis, catabolism as well as transport across membranes. Substantial progress has been made at understanding the molecular mechanisms of how the ABA signaling core module controls the activity of anion channels and thereby stomatal aperture. In this review, we focus on our current mechanistic understanding of ABA signaling in guard cells including the role of the second messenger Ca(2+) as well as crosstalk with biotic stress responses. PMID- 26599957 TI - Whole-Body Vibration While Squatting and Delayed-Onset Muscle Soreness in Women. AB - CONTEXT: Research into alleviating muscle pain and symptoms in individuals after delayed-onset muscle soreness (DOMS) has been inconsistent and unsuccessful in demonstrating a useful recovery modality. OBJECTIVE: To investigate the effects of short-term whole-body vibration (WBV) on DOMS over a 72-hour period after a high-intensity exercise protocol. DESIGN: Randomized controlled clinical trial. SETTING: University laboratory. PATIENTS OR OTHER PARTICIPANTS: Thirty women volunteered to participate in 4 testing sessions and were assigned randomly to a WBV group (n = 16; age = 21.0 +/- 1.9 years, height = 164.86 +/- 6.73 cm, mass = 58.58 +/- 9.32 kg) or a control group (n = 14; age = 22.00 +/- 1.97 years, height = 166.65 +/- 8.04 cm, mass = 58.69 +/- 12.92 kg). INTERVENTION(S): Participants performed 4 sets to failure of single-legged split squats with 40% of their body weight to induce muscle soreness in the quadriceps. The WBV or control treatment was administered each day after DOMS. MAIN OUTCOME MEASURE(S): Unilateral pressure-pain threshold (PPT), range of motion (ROM), thigh circumference, and muscle-pain ratings of the quadriceps were collected before and for 3 days after high-intensity exercise. Each day, we collected 3 sets of measures, consisting of 1 measure before the WBV or control treatment protocol (pretreatment) and 2 sets of posttreatment measures. RESULTS: We observed no interactions for PPT, thigh circumference, and muscle pain (P > .05). An interaction was found for active ROM (P = .01), with the baseline pretreatment measure greater than the measures at baseline posttreatment 1 through 48 hours posttreatment 2 in the WBV group. For PPT, a main effect for time was revealed (P < .05), with the measure at baseline pretreatment greater than at 24 hours pretreatment and all other time points for the vastus medialis, greater than 24 hours pretreatment through 48 hours posttreatment 2 for the vastus lateralis, and greater than 24 hours pretreatment and 48 hours pretreatment for the rectus femoris. For dynamic muscle pain, we observed a main effect for time (P < .001), with the baseline pretreatment measure less than the measures at all other time points. No main effect for time was noted for thigh circumference (P = .24). No main effect for group was found for any variable (P > .05). CONCLUSIONS: The WBV treatment approach studied did not aid in alleviating DOMS after high-intensity exercise. Further research is needed in various populations. PMID- 26599958 TI - The Role of Personality in Job Satisfaction Among Collegiate Athletic Trainers. AB - CONTEXT: The degree to which an individual likes his or her job is known as job satisfaction. A person with higher job satisfaction is less likely to depart from a profession than a person with lower job satisfaction. Researchers studying job satisfaction among other allied health professionals suggest a personality component could explain why the reasons for departure can be so individual. SETTING: Collegiate institutions. OBJECTIVE: To determine the relationship between job satisfaction and personality among collegiate athletic trainers (ATs). PATIENTS OR OTHER PARTICIPANTS: A total of 202 ATs (68 [33.7%] men and 134 [66.3%] women), were recruited using the National Athletic Trainers' Association e-mail database. We excluded any AT from this study who worked outside of the collegiate setting. The response rate was 20.2%. INTERVENTION(S): Data were collected using a Web-based survey instrument consisting of 3 sections: (1) demographics, (2) job satisfaction survey, and (3) Big Five Personality Inventory. MAIN OUTCOME MEASURE(S): Independent t tests were run to determine sex differences, and correlations were run to evaluate relationships between demographics and job satisfaction and between job satisfaction and personality. RESULTS: Women reported higher levels of neuroticism than men. Extroversion and conscientiousness showed a weak positive relationship with job satisfaction. A moderate positive relationship was found between agreeableness and job satisfaction. A moderate negative relationship was noted between neuroticism and job satisfaction. CONCLUSIONS: Based on our findings, head ATs or other organizational leaders may consider using personality assessments during interview processes, or athletic training program directors may be able to better guide students interested in athletic training based on knowledge of their personalities. PMID- 26599959 TI - Staffing Levels at National Collegiate Athletic Association Football Bowl Subdivision-Level Institutions. AB - CONTEXT: The "Appropriate Medical Coverage for Intercollegiate Athletics" (AMCIA) document was created to support assessment and calculation of athletic training personnel requirements. However, little is known regarding disparities between current and recommended staffing practices. OBJECTIVE: To identify the staffing and employment characteristics of athletic health care services at Football Bowl Subdivision-level institutions. DESIGN: Cross-sectional study. SETTING: Web-based survey. PATIENTS OR OTHER PARTICIPANTS: Head athletic trainers and athletic training staff members who were knowledgeable about budget and staff. MAIN OUTCOME MEASURE(S): The survey, Assessment of Staffing Levels at National Collegiate Athletic Association Football Bowl Subdivision-Level Institutions, was used to evaluate personal, university, and staff demographics; staffing and employment topics; and AMCIA variables and use. RESULTS: The survey was accessed and partially completed by 104 individuals (response rate = 84.6%). A total of 79 athletic trainers (response rate = 76%) completed the entire survey. One-third of the respondents (34.2%, n = 26) met the recommended number of full-time equivalents (FTEs) for football, two-thirds of the respondents (65.7%, n = 50) failed to meet the recommendation, and 26.2% (n = 27) were missing data needed for FTE calculation. Among those who did not meet the recommended FTEs (n = 50), 38.0% (n = 19) were within 1 FTE of being compliant, 26.0% (n = 13) were within 2 FTEs, and 24.0% (n = 12) were within 3 FTEs. About one-third of respondents (35.9%, n = 37) reported not using the AMCIA, citing lack of funding (29.7%, n = 11), lack of administrative support (21.6%, n = 8), and other reasons (37.8%, n = 14). CONCLUSIONS: The majority of institutions that used the AMCIA were able to provide justification for staffing. For most of the institutions that failed to meet their recommendation, adding 1-3 FTE athletic trainers for football would change their compliance status. A uniform definition of the term FTE within collegiate athletics is needed to allow for structured assessment and allocation of staffing and workloads. PMID- 26599960 TI - Athletic Trainers' Skills in Identifying and Managing Athletes Experiencing Psychological Distress. AB - CONTEXT: Athletic trainers (ATs) commonly use psychological skills during sport rehabilitation. However, little is known about their ability to accurately implement these skills. OBJECTIVE: To assess ATs' skills in identifying psychological symptoms, selecting appropriate strategies, and making referral decisions for athletes experiencing various degrees of psychological distress. DESIGN: Cross-sectional study. SETTING: Participants were recruited using the National Athletic Trainers' Association professional member database. PATIENTS OR OTHER PARTICIPANTS: Of the 2998 ATs who were selected randomly, 494 (16.5%) partially completed the questionnaire and 326 (10.9%) completed the entire survey (mean age = 34.7 +/- 10.8 years, mean years of experience = 11.3 +/- 9.9). MAIN OUTCOME MEASURE(S): Using the Web-based questionnaire created for this study, we collected ATs' demographic information and assessed their perceptions about responsibilities as ATs, psychosocial competencies, training in sport psychology, and referral behaviors. Additionally, respondents were asked to identify symptoms, match psychological strategies (eg, goal setting, imagery, progressive muscle relaxation), and make referral decisions for athletes in 3 case vignettes. RESULTS: The ATs demonstrated high accuracy in identifying symptoms and making referral decisions but struggled in selecting appropriate psychosocial strategies for athletes. Stepwise regression analyses revealed that ATs who had had specific coursework in sport psychology were able to more accurately identify symptoms (t = 3.01, P < .01), and those ATs with more experience reported lower accuracy scores for their intended course of action (t = -2.25, P < .05). CONCLUSIONS: Our analogue research design provided new insights into ATs' knowledge and use of sport psychology in practice. The results highlighted the importance of coursework focusing on applied areas of sport psychology in the training of ATs. PMID- 26599961 TI - Magnetic Resonance Imaging of Malformations of Midbrain-Hindbrain. AB - We aim to review the magnetic resonance imaging appearance of malformations of midbrain and hindbrain. These can be classified as predominantly cerebellar malformations, combined cerebellar and brain stem malformations, and predominantly brain stem malformations. The diagnostic criteria for the majority of these morphological malformations are based on neuroimaging findings. The predominantly cerebellar malformations include predominantly vermian hypoplasia seen in Dandy-Walker malformation and rhombencephalosynapsis, global cerebellar hypoplasia reported in lissencephaly and microlissencephaly, and unilateral cerebellar hypoplasia seen in PHACES, vanishing cerebellum, and cerebellar cleft. Cerebellar dysplasias are seen in Chudley-McCullough syndrome, associated with LAMA1 mutations and GPR56 mutations; Lhermitte-Duclos disease; and focal cerebellar dysplasias. Cerebellar hyperplasias are seen in megalencephaly-related syndromes and hemimegalencephaly with ipsilateral cerebellomegaly. Cerebellar and brain stem malformations include tubulinopathies, Joubert syndrome, cobblestone malformations, pontocerebellar hypoplasias, and congenital disorders of glycosylation type Ia. Predominantly brain stem malformations include congenital innervation dysgenesis syndrome, pontine tegmental cap dysplasia, diencephalic mesencephalic junction dysplasia, disconnection syndrome, and pontine clefts. PMID- 26599962 TI - Computed Tomography Observer Agreement in Staging Malignant Lymphoma. AB - OBJECTIVE: To determine pretreatment computed tomography observer agreement in patients with newly diagnosed lymphoma. METHODS: Forty-nine computed tomography scans were reviewed by 3 experienced radiologists, with each scan assessed twice by 1 observer. Predefined nodal and extranodal regions were assessed, and Ann Arbor stages were assigned. K-statistics were defined as poor (kappa < 0.2), fair (kappa > 0.2 to kappa <= 0.4), moderate (kappa > 0.4 to kappa <= 0.6), substantial (kappa > 0.6 to kappa <= 0.8), and almost perfect (kappa > 0.8 to kappa <= 1). RESULTS: Nodal interobserver agreement varied from 0.09 for infraclavicular involvement to 0.95 for para-iliac involvement; intraobserver agreement was substantial to almost perfect, except for infraclavicular nodes. Extranodal interobserver agreement varied from 0.56 to 0.88; intraobserver agreement was substantial to almost perfect. Ann Arbor stage interobserver agreement varied from 0.57 to 0.69; intraobserver agreement was substantial. CONCLUSION: Computed tomography observer agreement in staging malignant lymphoma appears to be suboptimal. PMID- 26599963 TI - Qualitative Assessment of Diffusion Weighted Imaging and Susceptibility Weighted Imaging of Myeloid Sarcoma Involving the Brain. AB - BACKGROUND AND PURPOSE: Myeloid sarcoma is a rare form of extramedullary leukemia, which can present with or without systemic leukemia. The purpose of this study was to evaluate characteristic computed tomography (CT) and magnetic resonance imaging (MRI) findings (including diffusion weighted imaging and susceptibility weighted imaging) of myeloid sarcoma involving the brain. MATERIALS AND METHODS: One hundred nine patients with pathologically proven myeloid sarcoma underwent pretreatment CT and MRI, which were retrospectively reviewed. Computed tomography and MRI characteristics reviewed include lesion location, shape, size, architecture, margins, +/- multiplicity, +/- bone destruction, pattern and degree of enhancement, +/- restricted diffusion, and +/- susceptibility artifact. RESULTS: Twenty-five patients (14 men, 11 women; mean age, 55 years; range, 9-80 years) met the inclusion criteria. Acute myeloid leukemia with subtypes M3 (44.4%) and M5 (22.2%) were the most common. On unenhanced CT, mean lesion size was 1.9 +/- 0.4 cm; 60% were intra-axial hyperdense masses, 8% were intraventricular hyperdense masses, 12% were isodense intra-axial masses, and 20% of cases were extra-axial hyperdense nodular masses. There was no observable intralesional or perilesional calcium. On MRI, mean lesion size was 2.1 +/- 0.6 cm. The lesions were isointense (80%) or hypointense (20%) on T1-weighted images with homogeneous (88%) or heterogeneous (12%) enhancement. On fluid-attenuated inversion recovery and T2-weighted images, lesions were hyperintense (96%) or isointense (4%) with mild vasogenic edema. Majority (96%) of cases demonstrated restricted diffusion, whereas only a few (16%) demonstrated susceptibility artifact. CONCLUSIONS: In patients with history of leukemia or myeloproliferative disorder, identification of homogenous mass hyperdense on unenhanced CT, T1 isointense, and T2/fluid-attenuated inversion recovery hyperintense with restricted diffusion and homogenous postcontrast enhancement without significant susceptibility artifact is suggestive of myeloid sarcoma. PMID- 26599964 TI - Evaluation of Intracranial Arteriovenous Malformations With Four-Dimensional Arterial-Spin Labeling-Based 3-T Magnetic Resonance Angiography. AB - OBJECTIVE: We aimed to assess the usefulness of 3-T 4-dimensional (4D) arterial spin-labeling (ASL)-based magnetic resonance angiography (MRA) with color-coded time-of-arrival (TOA) maps for the evaluation of cerebral arteriovenous malformations (AVMs). METHODS: Our study included 6 patients with cerebral AVMs. They underwent 4D-ASL MRA at 3T and digital subtraction angiography. A pseudocontinuous arterial spin labeling protocol with look-locker sampling was used for spin labeling. Two independent readers reviewed the 4D-ASL MRA images with color-coded TOA maps for the nidus size, arterial feeders, and venous drainage. Two other readers consensually reviewed the digital subtraction angiography images. RESULTS: The cerebral AVMs were demonstrated on all 4D-ASL MRA images. In 5 high-flow AVMs, the color-coded TOA maps were especially useful for identifying the feeder/drainer. Intermodality agreement was excellent for the nidus size (kappa = 1.0), very good for arterial feeders (kappa = 0.88), and good for venous drainage (kappa = 0.80). CONCLUSIONS: The 4D-ASL 3-T MRA with color coded TOA maps is useful for assessing the gross angiographic characteristics of intracranial AVMs. PMID- 26599965 TI - Advances in Ultrahigh-Pressure Liquid Chromatography Technology and System Design. PMID- 26599966 TI - Less Aggressive Surgical Procedure for Treatment of Solid Pseudopapillary Tumor: Limited Experience from a Single Institute. AB - OBJECTIVES: To evaluate the clinical characteristics and radiological features of solid pseudopapillary tumor (SPT) and assess surgical therapy strategy. METHODS: A retrospective review was performed in 62 patients pathologically confirmed of SPT treated between 2003 and 2014. The clinical features, radiological examinations and surgical strategies were analyzed. RESULTS: 56 females and 6 males were included in this study, mean age was 26 years old (range: 8-66 years old) with mean size of the tumor was 7.2 cm (range: 3-15 cm), and most tumor were commonly located in the head of pancreas (n = 29). Among all the cases, 3 patients had liver metastasis and underwent resection of SPT and liver metastasis. Furthermore, we performed 29 cases of local tumor excision; other patients underwent pancreaticoduodenectomy, middle pancreatectomy, middle pancreatectomy with splenectomy, distal pancreatectomy with spleen preservation, distal pancreatectomy with splenectomy and duodenum-preserving pancreatic head resection. No patient suffered from lymph node metastases. After median follow-up of 46 months (range: 2-135 months), no mortality or local recurrence or distant metastasis was found. CONCLUSIONS: Solid pseudopapillary tumor is a latent malignant tumor with excellent prognosis. If feasible, less aggressive resection without regular lymphadenectomy is recommended for treatment of patients with SPT. PMID- 26599968 TI - Edge-Guided Single Depth Image Super Resolution. AB - Recently, consumer depth cameras have gained significant popularity due to their affordable cost. However, the limited resolution and the quality of the depth map generated by these cameras are still problematic for several applications. In this paper, a novel framework for the single depth image superresolution is proposed. In our framework, the upscaling of a single depth image is guided by a high-resolution edge map, which is constructed from the edges of the low resolution depth image through a Markov random field optimization in a patch synthesis based manner. We also explore the self-similarity of patches during the edge construction stage, when limited training data are available. With the guidance of the high-resolution edge map, we propose upsampling the high resolution depth image through a modified joint bilateral filter. The edge-based guidance not only helps avoiding artifacts introduced by direct texture prediction, but also reduces jagged artifacts and preserves the sharp edges. Experimental results demonstrate the effectiveness of our method both qualitatively and quantitatively compared with the state-of-the-art methods. PMID- 26599967 TI - Identification of the Key Fields and Their Key Technical Points of Oncology by Patent Analysis. AB - BACKGROUND: This paper aims to identify the key fields and their key technical points of oncology by patent analysis. METHODOLOGY/PRINCIPAL FINDINGS: Patents of oncology applied from 2006 to 2012 were searched in the Thomson Innovation database. The key fields and their key technical points were determined by analyzing the Derwent Classification (DC) and the International Patent Classification (IPC), respectively. Patent applications in the top ten DC occupied 80% of all the patent applications of oncology, which were the ten fields of oncology to be analyzed. The number of patent applications in these ten fields of oncology was standardized based on patent applications of oncology from 2006 to 2012. For each field, standardization was conducted separately for each of the seven years (2006-2012) and the mean of the seven standardized values was calculated to reflect the relative amount of patent applications in that field; meanwhile, regression analysis using time (year) and the standardized values of patent applications in seven years (2006-2012) was conducted so as to evaluate the trend of patent applications in each field. Two-dimensional quadrant analysis, together with the professional knowledge of oncology, was taken into consideration in determining the key fields of oncology. The fields located in the quadrant with high relative amount or increasing trend of patent applications are identified as key ones. By using the same method, the key technical points in each key field were identified. Altogether 116,820 patents of oncology applied from 2006 to 2012 were retrieved, and four key fields with twenty-nine key technical points were identified, including "natural products and polymers" with nine key technical points, "fermentation industry" with twelve ones, "electrical medical equipment" with four ones, and "diagnosis, surgery" with four ones. CONCLUSIONS/SIGNIFICANCE: The results of this study could provide guidance on the development direction of oncology, and also help researchers broaden innovative ideas and discover new technological opportunities. PMID- 26599969 TI - Dual Sparse Constrained Cascade Regression for Robust Face Alignment. AB - Localizing facial landmarks is a fundamental step in facial image analysis. However, the problem continues to be challenging due to the large variability in expression, illumination, pose, and the existence of occlusions in real-world face images. In this paper, we present a dual sparse constrained cascade regression model for robust face alignment. Instead of using the least-squares method during the training process of regressors, sparse constraint is introduced to select robust features and compress the size of the model. Moreover, sparse shape constraint is incorporated between each cascade regression, and the explicit shape constraints are able to suppress the ambiguity in local features. To improve the model's adaptation to large pose variation, face pose is estimated by five fiducial landmarks located by deep convolutional neuron network, which is used to adaptively design the cascade regression model. To the best of our best knowledge, this is the first attempt to fuse explicit shape constraint (sparse shape constraint) and implicit context information (sparse feature selection) for robust face alignment in the framework of cascade regression. Extensive experiments on nine challenging wild data sets demonstrate the advantages of the proposed method over the state-of-the-art methods. PMID- 26599970 TI - A Completely Blind Video Integrity Oracle. AB - Considerable progress has been made toward developing still picture perceptual quality analyzers that do not require any reference picture and that are not trained on human opinion scores of distorted images. However, there do not yet exist any such completely blind video quality assessment (VQA) models. Here, we attempt to bridge this gap by developing a new VQA model called the video intrinsic integrity and distortion evaluation oracle (VIIDEO). The new model does not require the use of any additional information other than the video being quality evaluated. VIIDEO embodies models of intrinsic statistical regularities that are observed in natural vidoes, which are used to quantify disturbances introduced due to distortions. An algorithm derived from the VIIDEO model is thereby able to predict the quality of distorted videos without any external knowledge about the pristine source, anticipated distortions, or human judgments of video quality. Even with such a paucity of information, we are able to show that the VIIDEO algorithm performs much better than the legacy full reference quality measure MSE on the LIVE VQA database and delivers performance comparable with a leading human judgment trained blind VQA model. We believe that the VIIDEO algorithm is a significant step toward making real-time monitoring of completely blind video quality possible. PMID- 26599972 TI - Mixed-Lanthanoid Metal-Organic Framework for Ratiometric Cryogenic Temperature Sensing. AB - A ratiometric thermometer based on a mixed-metal Ln(III) metal-organic framework is reported that has good sensitivity in a wide temperature range from 4 to 290 K and a quantum yield of 22% at room temperature. The sensing mechanism in the europium-doped compound Tb0.95Eu0.05HL (H4L = 5-hydroxy-1,2,4 benzenetricarboxylic acid) is based not only on phonon-assisted energy transfer from Tb(III) to Eu(III) centers, but also on phonon-assisted energy migration between neighboring Tb(III) ions. It shows good performance in a wide temperature range, especially in the range 4-50 K, reaching a sensitivity up to 31% K(-1) at 4 K. PMID- 26599971 TI - Helicobacter pylori Infection Is Associated with Higher CD4 T Cell Counts and Lower HIV-1 Viral Loads in ART-Naive HIV-Positive Patients in Ghana. AB - BACKGROUND: Worldwide, there is a high co-endemicity of HIV and H. pylori infection and there is growing evidence that H. pylori co-infection is associated with parameters of HIV disease progression. The objective of this study was to investigate the prevalence of H. pylori infection, and the association with clinical, immunological and virological parameters in a large cohort of HIV infected individuals and uninfected controls in a West African country. METHODS: HIV-patients (n = 1,095) and HIV-negative individuals (n = 107) were recruited at a university hospital in Ghana. H. pylori status was determined using stool antigen testing. HIV-related, clinical and socio-demographic parameters were recorded and analyzed according to H. pylori status. RESULTS: The prevalence of H. pylori infection was significantly lower in HIV-positive compared to HIV negative individuals (51.5 vs. 88%, p<0.0001). In HIV patients, H. pylori prevalence decreased in parallel with CD4+ T cell counts. In ART-naive HIV infected individuals, but not in those taking ART, H. pylori infection was associated with higher CD4 cell counts (312 vs. 189 cells/MUL, p<0.0001) and lower HIV-1 viral loads (4.92 vs. 5.21 log10 copies/mL, p = 0.006). The findings could not be explained by socio-demographic confounders or reported use of antibiotics. Having no access to tap water and higher CD4+ T cell counts were identified as risk factors for H. pylori infection. CONCLUSIONS: H. pylori prevalence was inversely correlated with the degree of immunosuppression. In ART naive individuals, H. pylori infection is associated with favorable immunological and virological parameters. The underlying mechanisms for this association are unclear and warrant investigation. PMID- 26599973 TI - Cytochrome P450 inhibition potential of new psychoactive substances of the tryptamine class. AB - New psychoactive substances (NPS) are not tested for their cytochrome P450 (CYP) inhibition potential before consumption. Therefore, this potential was explored for tryptamine-derived NPS (TDNPS) including alpha-methyl tryptamines (AMTs), dimethyl tryptamines (DMTs), diallyl tryptamines (DALTs), and diisopropyl tryptamines (DiPTs) using test substrates preferred by the Food and Drug Administration in a cocktail assay. All tested TDNPS with the exception of DMT inhibited CYP2D6 activity with IC50 values below 100MUM. DALTs inhibited CYP2D6 activity similar to paroxetine and quinidine and CYP1A2 activity comparable to fluvoxamine. 5-Methoxy-N,N-diallyltryptamine reduced in vivo the caffeine metabolism in rats consistent with in vitro results. Five of the AMTs also inhibited CYP1A2 activity comparable to amiodarone. AMT and 6-F-AMT inhibited CYP2A6 activity in the range of the test inhibitor tranylcypromine. CYP2B6 activity was inhibited by 19 tryptamines, but weakly compared to efavirenz. CYP2C8 activity was inhibited by five of the tested TDNPS and three showed values comparable to trimethoprim and gemfibrozil. Six tryptamines inhibited CYP2C9 and seven CYP2C19 activities comparable to fluconazole and chloramphenicol, respectively. Nineteen compounds showed inhibition of CYP2E1 and 18 of CYP3A activity, respectively. These results showed that the CYP inhibition by TDNPS might be clinically relevant, but clinical studies are needed to explore this further. PMID- 26599974 TI - Do persistent organic pollutants interact with the stress response? Individual compounds, and their mixtures, interaction with the glucocorticoid receptor. AB - Persistent organic pollutants (POPs) are toxic substances, highly resistant to environmental degradation, which can bio-accumulate and have long-range atmospheric transport potential (UNEP, 2001). The majority of studies on endocrine disruption have focused on interferences on the sexual steroid hormones and so have overlooked disruption to glucocorticoid hormones. Here the endocrine disrupting potential of individual POPs and their mixtures has been investigated in vitro to identify any disruption to glucocorticoid nuclear receptor transcriptional activity. POP mixtures were screened for glucocorticoid receptor (GR) translocation using a GR redistribution assay (RA) on a CellInsightTM NXT high content screening (HCS) platform. A mammalian reporter gene assay (RGA) was then used to assess the individual POPs, and their mixtures, for effects on glucocorticoid nuclear receptor transactivation. POP mixtures did not induce GR translocation in the GR RA or produce an agonist response in the GR RGA. However, in the antagonist test, in the presence of cortisol, an individual POP, p,p' dichlorodiphenyldichloroethylene (p,p'-DDE), was found to decrease glucocorticoid nuclear receptor transcriptional activity to 72.5% (in comparison to the positive cortisol control). Enhanced nuclear transcriptional activity, in the presence of cortisol, was evident for the two lowest concentrations of perfluorodecanoic acid (PFOS) potassium salt (0.0147mg/ml and 0.0294mg/ml), the two highest concentrations of perfluorodecanoic acid (PFDA) (0.0025mg/ml and 0.005mg/ml) and the highest concentration of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) (0.0000858mg/ml). It is important to gain a better understanding of how POPs can interact with GRs as the disruption of glucocorticoid action is thought to contribute to complex diseases. PMID- 26599976 TI - Spatial variation in density and size structure indicate habitat selection throughout life stages of two Southwestern Atlantic snappers. AB - The early life history of Lutjanus alexandrei and Lutjanus jocu in Southwestern Atlantic is still largely unknown. Habitat use of different life stages (i.e. size categories and densities) of the Brazilian snapper (L. alexandrei) and dog snapper (L. jocu) was examined in a tropical portion of NE coast of Brazil. Visual surveys were conducted in different shallow habitats (mangroves and reefs). Both snapper species showed higher densities in early life stages in mangrove habitat, with a clear increase in fish size from mangrove to adjacent reefs. Post-settler individuals were exclusively found in mangroves for both species. Juveniles of L. alexandrei were also registered only in mangroves, while sub-adult individuals were associated with both mangrove and reef habitats. Mature individuals of L. alexandrei were only observed in reef habitats. Juvenile and sub-adult individuals of the dog snapper were both associated with mangrove and reef habitats, with high densities registered in mangroves. Mature individuals of L. jocu were not registered in the study area. This pattern suggests preference for mangrove habitat in early life stages for both species. Ontogenetic movement between habitats was also recorded. This pattern denotes habitat selection across different life cycle of both species. Such information highlights the importance of directing management and conservation efforts to these habitats to secure the continuity of contribution to adult populations. PMID- 26599977 TI - Gas Embolic Stroke Secondary to Bowel Infarction. AB - A 69-year-old gentleman with metastatic esophageal adenocarcinoma presented with acute abdominal pain to the emergency medicine department and subsequently developed an acute left hemiplegia while in the resuscitation unit. An unenhanced computed tomography (CT) scan of the head showed right frontal cerebral gas emboli while an unenhanced CT scan of the abdomen and pelvis showed extensive portal venous gas and pneumatosis intestinalis, presumed secondary to bowel infarction. PMID- 26599978 TI - Image contrast enhancement of Ni/YSZ anode during the slice-and-view process in FIB-SEM. AB - Focused ion beam-scanning electron microscopy (FIB-SEM) is a widely used and easily operational equipment for three-dimensional reconstruction with flexible analysis volume. It has been using successfully and increasingly in the field of solid oxide fuel cell. However, the phase contrast of the SEM images is indistinct in many cases, which will bring difficulties to the image processing. Herein, the phase contrast of a conventional Ni/yttria stabilized zirconia anode is tuned in an FIB-SEM with In-Lens secondary electron (SE) and backscattered electron detectors. Two accessories, tungsten probe and carbon nozzle, are inserted during the observation. The former has no influence on the contrast. When the carbon nozzle is inserted, best and distinct contrast can be obtained by In-Lens SE detector. This method is novel for contrast enhancement. Phase segmentation of the image can be automatically performed. The related mechanism for different images is discussed. PMID- 26599980 TI - Charge Regulation in the Electrical Double Layer: Ion Adsorption and Surface Interactions. AB - Charge regulation in the electrical double layer has important implications for ion adsorption, interparticle forces, colloidal stability, and deposition phenomena. Although charge regulation generally receives little attention, its consequences can be major, especially when considering interactions between unequally charged surfaces. The present article discusses common approaches to quantify such phenomena, especially within classical Poisson-Boltzmann theory, and pinpoints numerous situations where a consideration of charge regulation is essential. For the interpretation of interaction energy profiles, we advocate the use of the constant regulation approximation, which summarizes the surface properties in terms of two quantities, namely, the diffuse layer potential and the regulation parameter. This description also captures some pronounced regulation effects observed in the presence of multivalent ions. PMID- 26599979 TI - Investigation of Yersinia pestis Laboratory Adaptation through a Combined Genomics and Proteomics Approach. AB - The bacterial pathogen Yersinia pestis, the cause of plague in humans and animals, normally has a sylvatic lifestyle, cycling between fleas and mammals. In contrast, laboratory-grown Y. pestis experiences a more constant environment and conditions that it would not normally encounter. The transition from the natural environment to the laboratory results in a vastly different set of selective pressures, and represents what could be considered domestication. Understanding the kinds of adaptations Y. pestis undergoes as it becomes domesticated will contribute to understanding the basic biology of this important pathogen. In this study, we performed a parallel serial passage experiment (PSPE) to explore the mechanisms by which Y. pestis adapts to laboratory conditions, hypothesizing that cells would undergo significant changes in virulence and nutrient acquisition systems. Two wild strains were serially passaged in 12 independent populations each for ~750 generations, after which each population was analyzed using whole genome sequencing, LC-MS/MS proteomic analysis, and GC/MS metabolomics. We observed considerable parallel evolution in the endpoint populations, detecting multiple independent mutations in ail, pepA, and zwf, suggesting that specific selective pressures are shaping evolutionary responses. Complementary LC-MS/MS proteomic data provide physiological context to the observed mutations, and reveal regulatory changes not necessarily associated with specific mutations, including changes in amino acid metabolism and cell envelope biogenesis. Proteomic data support hypotheses generated by genomic data in addition to suggesting future mechanistic studies, indicating that future whole-genome sequencing studies be designed to leverage proteomics as a critical complement. PMID- 26599981 TI - Can a simple test of functional capacity add to the clinical assessment of diabetes? AB - AIM: To identify impairment in functional capacity associated with complicated and non-complicated diabetes using the 6-min walk distance test. METHODS: We enrolled 111 adults, aged >=40 years, with Type 2 diabetes from a hospital facility and 150 healthy control subjects of similar age and sex from a community site in Lima, Peru. All participants completed a 6-min walk test. RESULTS: The mean age of the 261 participants was 58.3 years, and 43.3% were male. Among those with diabetes, 67 (60%) had non-complicated diabetes and 44 (40%) had complications such as peripheral neuropathy, retinopathy or nephropathy. The mean unadjusted 6-min walk distances were 376 m and 394 m in adults with and without diabetes complications, respectively, vs 469 m in control subjects (P<0.001). In multivariable regression, the subjects with diabetes complications walked 84 m less far (95% CI -104 to -63 m) and those without complications walked 60 m less far (-77 to -42 m) than did control subjects. When using HbA1c level as a covariate in multivariable regression, participants walked 13 m less far (-16.9 to -9.9 m) for each % increase in HbA1c . CONCLUSIONS: The subjects with diabetes had lower functional capacity compared with healthy control subjects with similar characteristics. Differences in 6-min walk distance were even apparent in the subjects without diabetes complications. Potential mechanisms that could explain this finding are early cardiovascular disease or deconditioning. PMID- 26599983 TI - Nonselective beta-blockers do not affect mortality in cirrhosis patients with ascites: Post Hoc analysis of three randomized controlled trials with 1198 patients. AB - The safety of nonselective beta-blockers (NSBBs) in advanced cirrhosis has been questioned. We used data from three satavaptan trials to examine whether NSBBs increase mortality in cirrhosis patients with ascites. The trials were conducted in 2006-2008 and included 1198 cirrhosis patients with ascites followed for 1 year. We used Cox regression to compare all-cause mortality and cirrhosis-related mortality between patients who did and those who did not use NSBBs at randomization, controlling for age, gender, Model for End-Stage Liver Disease score, Child-Pugh score, serum sodium, previous variceal bleeding, cirrhosis etiology, and ascites severity. Moreover, we identified clinical events predicting that a patient would stop NSBB treatment. At randomization, the 559 NSBB users were more likely than the 629 nonusers to have a history of variceal bleeding but less likely to have Child-Pugh class C cirrhosis, hyponatremia, or refractory ascites. The 52-week cumulative all-cause mortality was similar in the NSBB user and nonuser groups (23.2% versus 25.3%, adjusted hazard ratio = 0.92, 95% confidence interval 0.72-1.18), and NSBBs also did not increase mortality in the subgroup of patients with refractory ascites (588 patients, adjusted hazard ratio = 1.02, 95% confidence interval 0.74-1.40) or in any other subgroup. Similarly, NSBBs did not increase cirrhosis-related mortality (adjusted hazard ratio = 1.00, 95% confidence interval 0.76-1.31). During follow-up, 29% of initial NSBB users stopped taking NSBBs, and the decision to stop NSBB treatment marked a sharp rise in mortality and coincided with hospitalization, variceal bleeding, bacterial infection, and/or development of hepatorenal syndrome. CONCLUSION: This large and detailed data set on worldwide nonprotocol use of NSBBs in cirrhosis patients with ascites shows that NSBBs did not increase mortality; the decision to stop NSBB treatment in relation to stressful events may have added to the safety. (Hepatology 2016;63:1968-1976). PMID- 26599982 TI - Design, Synthesis and In Vitro Activity of Anticancer Styrylquinolines. The p53 Independent Mechanism of Action. AB - A group of styrylquinolines were synthesized and tested for their anti proliferative activity. Anti-proliferative activity was evaluated against the human colon carcinoma cell lines that had a normal expression of the p53 protein (HCT116 p53+/+) and mutants with a disabled TP53 gene (HCT116 p53-/-) and against the GM 07492 normal human fibroblast cell line. A SAR study revealed the importance of Cl and OH as substituents in the styryl moiety. Several of the compounds that were tested were found to have a marked anti-proliferative activity that was similar to or better than doxorubicin and were more active against the p53 null than the wild type cells. The cellular localization tests and caspase activity assays suggest a mechanism of action through the mitochondrial pathway of apoptosis in a p53-independent manner. The activity of the styrylquinoline compounds may be associated with their DNA intercalating ability. PMID- 26599984 TI - Tile-Based Two-Dimensional Phase Unwrapping for Digital Holography Using a Modular Framework. AB - A variety of physical and biomedical imaging techniques, such as digital holography, interferometric synthetic aperture radar (InSAR), or magnetic resonance imaging (MRI) enable measurement of the phase of a physical quantity additionally to its amplitude. However, the phase can commonly only be measured modulo 2pi, as a so called wrapped phase map. Phase unwrapping is the process of obtaining the underlying physical phase map from the wrapped phase. Tile-based phase unwrapping algorithms operate by first tessellating the phase map, then unwrapping individual tiles, and finally merging them to a continuous phase map. They can be implemented computationally efficiently and are robust to noise. However, they are prone to failure in the presence of phase residues or erroneous unwraps of single tiles. We tried to overcome these shortcomings by creating novel tile unwrapping and merging algorithms as well as creating a framework that allows to combine them in modular fashion. To increase the robustness of the tile unwrapping step, we implemented a model-based algorithm that makes efficient use of linear algebra to unwrap individual tiles. Furthermore, we adapted an established pixel-based unwrapping algorithm to create a quality guided tile merger. These original algorithms as well as previously existing ones were implemented in a modular phase unwrapping C++ framework. By examining different combinations of unwrapping and merging algorithms we compared our method to existing approaches. We could show that the appropriate choice of unwrapping and merging algorithms can significantly improve the unwrapped result in the presence of phase residues and noise. Beyond that, our modular framework allows for efficient design and test of new tile-based phase unwrapping algorithms. The software developed in this study is freely available. PMID- 26599985 TI - Pentraxin-3 Levels in Beta Thalassemia Major and Minor Patients and Its Relationship With Antioxidant Capacity and Total Oxidant Stress. AB - Thalassemia major (TM) results in hemolytic anemia, an increase in intestinal iron absorption, and occurrence of iron loading due to erythrocyte transfusion; the disease is characterized by oxidative damage in major organs. Oxidative stress leads to vascular endothelial damage and forms the basis for serious cardiovascular diseases. Pentraxin-3 (PTX-3) is one of the markers of vascular endothelial damage that increases in response to the oxidative stress, which can be used as an early diagnostic marker for inflammation. This study's purpose is to define the relation between PTX-3 and the vascular endothelial damage that increases with oxidative stress in thalassemia patients. Our study included 35 TM patients, 30 beta-thalassemia minor patients, and 30 healthy children. As a result of our study, in TM patients, a positive relation was detected between the PTX-3 levels and the total oxidative stress, triglyceride, and very low-density lipoprotein values, whereas a negative relation was detected with the total antioxidant capacity and high-density lipoprotein values. This result shows that as oxidant stress increases, PTX-3 levels also increase; very low-density lipoprotein and triglyceride contribute to the endothelial damage occurring with oxidative stress. As a result, it was concluded that vascular endothelial damage in thalassemia patients can be evaluated through the serum PTX-3 level. PMID- 26599986 TI - Effects of Prednisolone, L-Asparaginase, Gemfibrozil, and Combinations of These Elements on Mice Lipid Profile, Liver, and Pancreas. AB - The aim of this study is to determine the effects of L-asparaginase (L-ASP), corticosteroids (CSs), and antilipidemics, separately and in combination, on the lipid profiles and the liver and pancreas histology in mice. This study included 8 groups of 7 mice each. Before any drug administration, serum samples were taken from all of the mice. Then, normal saline was applied to the control group, and a medication or combination of medications was applied to the other groups. Levels of triglycerides, cholesterol (COL), and high-density lipoprotein (HDL) and low density lipoprotein (LDL) were determined, and the livers and pancreases were evaluated histologically at the end of the study. Triglycerides increased significantly in the CS-only and the L-ASP-only groups, COL increased significantly in the CS-only group, and HDL increased significantly in the CS only and the antilipidemic-only groups. LDL was significantly lower in the CS only and the L-ASP-only groups. CSs and L-ASP were significantly effective in liver necrosis, L-ASP was significantly effective in liver balloon degeneration, and CS were significantly effective in pancreas vacuolization. Triglyceride measurement is recommended before/during CS and/or L-ASP treatment. Starting with an antilipidemic agent can be considered to avoid possible complications in patients with significantly high rates. Indicators of a possible liver or pancreas injury should also be considered. PMID- 26599987 TI - Cerebellar Degeneration as a Rare Paraneoplastic Syndrome in a Child With Hodgkin Lymphoma. AB - We report a rare case of cerebellar degeneration as a paraneoplastic syndrome in an 8-year-old boy with Hodgkin lymphoma that presented during first-line treatment. Antibodies against Purkinje cells (anti-Tr antibodies) were detected in the serum of the patient. After successful treatment of the lymphoma, the cerebellar symptoms resolved partially. Childhood presentation of paraneoplastic cerebellar degeneration is extremely rare, with only a few reports in the literature. For this reason, the description of all such cases contributes to the enrichment of the medical knowledge and will improve the diagnosis and the treatment of this complication. PMID- 26599988 TI - Case Reports of Severe Congenital Neutropenia Treated With Unrelated Cord Blood Transplantation With Reduced-intensity Conditioning. AB - Allogeneic stem cell transplantation is a curative treatment for severe congenital neutropenia (SCN). However, a standard conditioning regimen and donor source have not been established. We report 3 consecutive cases of SCN who were successfully treated by cord blood transplantation (CBT) with reduced-intensity conditioning consisting of fludarabine, melphalan, and low-dose total body irradiation. All cases achieved complete donor chimerism without severe infectious complications and have maintained normal neutrophil counts for between 3 and 9 years after CBT. These results suggest that CBT with reduced-intensity conditioning can be an alternative therapy for SCN when human leukocyte antigen matched bone marrow donor is unavailable. PMID- 26599989 TI - Multiparameter analysis of stimulated human peripheral blood mononuclear cells: A comparison of mass and fluorescence cytometry. AB - Mass and fluorescence cytometry are quantitative single cell flow cytometry approaches that are powerful tools for characterizing diverse tissues and cellular systems. Here mass cytometry was directly compared with fluorescence cytometry by studying phenotypes of healthy human peripheral blood mononuclear cells (PBMC) in the context of superantigen stimulation. One mass cytometry panel and five fluorescence cytometry panels were used to measure 20 well-established lymphocyte markers of memory and activation. Comparable frequencies of both common and rare cell subpopulations were observed with fluorescence and mass cytometry using biaxial gating. The unsupervised high-dimensional analysis tool viSNE was then used to analyze data sets generated from both mass and fluorescence cytometry. viSNE analysis effectively characterized PBMC using eight features per cell and identified similar frequencies of activated CD4+ T cells with both technologies. These results suggest combinations of unsupervised analysis programs and extended multiparameter cytometry will be indispensable tools for detecting perturbations in protein expression in both health and disease. PMID- 26599991 TI - Use of Neurofeedback to Enhance Response to Hypnotic Analgesia in Individuals With Multiple Sclerosis. AB - This proof of principle study examined the potential benefits of EEG neurofeedback for increasing responsiveness to self-hypnosis training for chronic pain management. The study comprised 20 individuals with multiple sclerosis (MS) who received 5 sessions of self-hypnosis training--1 face-to-face session and 4 prerecorded sessions. Participants were randomly assigned to have the prerecorded sessions preceded by either (a) EEG biofeedback (neurofeedback) training to increase left anterior theta power (NF-HYP) or (b) a relaxation control condition (RLX-HYP). Eighteen participants completed all treatment sessions and assessments. NF-HYP participants reported greater reductions in pain than RLX-HYP participants. The findings provide support for the potential treatment-enhancing effects of neurofeedback on hypnotic analgesia and also suggest that effective hypnosis treatment can be provided very efficiently. PMID- 26599992 TI - Hypnotic Olfactory Hallucinations. AB - Olfactory hallucinations (smelling odors that are not present) are intrusive and disruptive yet challenging to investigate because they cannot be produced on demand. In this study, the authors attempted to model olfactory hallucinations using hypnotic suggestions. We gave some subjects a suggestion to smell an odor in the absence of a real odor (positive hallucination) and gave others a suggestion to smell nothing in the presence of a real odor (negative hallucination). High hypnotizable individuals who received the positive hallucination reported intense smells whereas those who received the negative hallucination reported a reduction in intensity. These suggestions also influenced later recall about frequency of odor presentation. Findings are discussed in terms of reality monitoring and differences between positive and negative hallucinations. PMID- 26599990 TI - The HIV Treatment Gap: Estimates of the Financial Resources Needed versus Available for Scale-Up of Antiretroviral Therapy in 97 Countries from 2015 to 2020. AB - BACKGROUND: The World Health Organization (WHO) released revised guidelines in 2015 recommending that all people living with HIV, regardless of CD4 count, initiate antiretroviral therapy (ART) upon diagnosis. However, few studies have projected the global resources needed for rapid scale-up of ART. Under the Health Policy Project, we conducted modeling analyses for 97 countries to estimate eligibility for and numbers on ART from 2015 to 2020, along with the facility level financial resources required. We compared the estimated financial requirements to estimated funding available. METHODS AND FINDINGS: Current coverage levels and future need for treatment were based on country-specific epidemiological and demographic data. Simulated annual numbers of individuals on treatment were derived from three scenarios: (1) continuation of countries' current policies of eligibility for ART, (2) universal adoption of aspects of the WHO 2013 eligibility guidelines, and (3) expanded eligibility as per the WHO 2015 guidelines and meeting the Joint United Nations Programme on HIV/AIDS "90-90-90" ART targets. We modeled uncertainty in the annual resource requirements for antiretroviral drugs, laboratory tests, and facility-level personnel and overhead. We estimate that 25.7 (95% CI 25.5, 26.0) million adults and 1.57 (95% CI 1.55, 1.60) million children could receive ART by 2020 if countries maintain current eligibility plans and increase coverage based on historical rates, which may be ambitious. If countries uniformly adopt aspects of the WHO 2013 guidelines, 26.5 (95% CI 26.0 27.0) million adults and 1.53 (95% CI 1.52, 1.55) million children could be on ART by 2020. Under the 90-90-90 scenario, 30.4 (95% CI 30.1, 30.7) million adults and 1.68 (95% CI 1.63, 1.73) million children could receive treatment by 2020. The facility-level financial resources needed for scaling up ART in these countries from 2015 to 2020 are estimated to be US$45.8 (95% CI 45.4, 46.2) billion under the current scenario, US$48.7 (95% CI 47.8, 49.6) billion under the WHO 2013 scenario, and US$52.5 (95% CI 51.4, 53.6) billion under the 90-90-90 scenario. After projecting recent external and domestic funding trends, the estimated 6-y financing gap ranges from US$19.8 billion to US$25.0 billion, depending on the costing scenario and the U.S. President's Emergency Plan for AIDS Relief contribution level, with the gap for ART commodities alone ranging from US$14.0 to US$16.8 billion. The study is limited by excluding above-facility and other costs essential to ART service delivery and by the availability and quality of country- and region-specific data. CONCLUSIONS: The projected number of people receiving ART across three scenarios suggests that countries are unlikely to meet the 90-90-90 treatment target (81% of people living with HIV on ART by 2020) unless they adopt a test and-offer approach and increase ART coverage. Our results suggest that future resource needs for ART scale-up are smaller than stated elsewhere but still significantly threaten the sustainability of the global HIV response without additional resource mobilization from domestic or innovative financing sources or efficiency gains. As the world moves towards adopting the WHO 2015 guidelines, advances in technology, including the introduction of lower-cost, highly effective antiretroviral regimens, whose value are assessed here, may prove to be "game changers" that allow more people to be on ART with the resources available. PMID- 26599993 TI - Attachment-Focused Hypnosis in Psychotherapy for Complex Trauma: Attunement, Representation, and Mentalization. AB - The relational and psychological functions of attunement, representation, and mentalization are essential components of a secure attachment experience. Psychotherapeutic approaches informed by attachment theory have gained significant empirical and clinical support, particularly in the area of complex trauma. Despite these advances, attachment-informed trauma treatment could benefit greatly from the experiential wealth that clinical hypnosis has to offer. In its utilization of shared attention, tone of voice, pacing, representational imagery, and hypnotic language, clinical hypnosis as a state, relationship, and technique offers psychotherapists a way of introducing a healthy attachment experience and renewing appropriate developmental functioning in patients who are survivors of complex trauma. In this article, attunement, representation, and mentalization are reviewed from a hypnotherapeutic perspective. PMID- 26599995 TI - A Meta-Analysis for the Efficacy of Hypnotherapy in Alleviating PTSD Symptoms. AB - A systematic review and meta-analysis of the efficacy of hypnotherapy in the treatment of PTSD used literature searches to obtain 47 articles. However, only 6 were experiments testing the efficacy of hypnosis-based treatments. A fixed effects meta-analysis was applied to postintervention assessment results and 4 week follow-ups. A large effect in favor of hypnosis-based (especially manualized abreactive hypnosis) treatment was found for the studies that reported the posttest results (d = 1.17). The temporal stability of the effect remains strong, as reflected by the 4-week follow-up assessments (d = 1.58) and also by long-term evaluations (e.g., 12 months). Hypnosis appears to be effective in alleviating PTSD symptoms. PMID- 26599994 TI - Hypnosis for Acute Procedural Pain: A Critical Review. AB - Clinical evidence for the effectiveness of hypnosis in the treatment of acute procedural pain was critically evaluated based on reports from randomized controlled clinical trials (RCTs). Results from the 29 RCTs meeting inclusion criteria suggest that hypnosis decreases pain compared to standard care and attention control groups and that it is at least as effective as comparable adjunct psychological or behavioral therapies. In addition, applying hypnosis in multiple sessions prior to the day of the procedure produced the highest percentage of significant results. Hypnosis was most effective in minor surgical procedures. However, interpretations are limited by considerable risk of bias. Further studies using minimally effective control conditions and systematic control of intervention dose and timing are required to strengthen conclusions. PMID- 26599996 TI - Brain Oscillations and Diurnal Variations in Hypnotic Responsiveness--A Commentary on "Diurnal Variations in Hypnotic Responsiveness: Is There an Optimal Time to be Hypnotized?". AB - A recent study published in the International Journal of Clinical and Experimental Hypnosis reported an interesting diurnal pattern of hypnotic responsivity; specifically, the authors found higher hypnotic responsiveness in a large sample of undergraduates in the morning and early evening. However, they did not have an explanation for this pattern of findings. This pattern is consistent, however, with the theta hypothesis of hypnotic responsivity. Further examination of the associations between brain oscillations and response to hypnosis is needed to determine if specific oscillations such as theta (a) actually facilitate response to some hypnotic suggestions, (b) merely reflect hypnotic responding, or (c) reflect another factor that itself plays a causal role in response to hypnosis. PMID- 26599997 TI - Cerebellar neuronal loss in amyotrophic lateral sclerosis cases with ATXN2 intermediate repeat expansions. AB - OBJECTIVE: Despite evidence suggesting that the cerebellum may be targeted in amyotrophic lateral sclerosis (ALS), particularly in cases with repeat expansions in the ATXN2 and C9ORF72 genes, the integrity of cerebellar neurons has yet to be examined. The present study undertakes a histopathological analysis to assess the impact of these repeat expansions on cerebellar neurons and determine whether similar cerebellar pathology occurs in sporadic disease. METHODS: Purkinje and granule cells were quantified in the vermis and lateral cerebellar hemispheres of ALS cases with repeat expansions in the ATXN2 and C9ORF72 genes, sporadic disease, and sporadic progressive muscular atrophy with only lower motor neuron degeneration. RESULTS: ALS cases with intermediate repeat expansions in the ATXN2 gene demonstrate a significant loss in Purkinje cells in the cerebellar vermis only. Despite ALS cases with expansions in the C9ORF72 gene having the highest burden of inclusion pathology, no neuronal loss was observed in this group. Neuronal numbers were also unchanged in sporadic ALS and sporadic PMA cases. INTERPRETATION: The present study has established a selective loss of Purkinje cells in the cerebellar vermis of ALS cases with intermediate repeat expansions in the ATXN2 gene, suggesting a divergent pathogenic mechanism independent of upper and lower motor neuron degeneration in ALS. We discuss these findings in the context of large repeat expansions in ATXN2 and spinocerebellar ataxia type 2, providing evidence that intermediate repeats in ATXN2 cause significant, albeit less substantial, spinocerebellar damage compared with longer repeats in ATXN2. PMID- 26599998 TI - Microscopic Investigation of Chemoselectivity in Ag-Pt-Fe3O4 Heterotrimer Formation: Mechanistic Insights and Implications for Controlling High-Order Hybrid Nanoparticle Morphology. AB - Three-component hybrid nanoparticle heterotrimers, which are important multifunctional constructs that underpin diverse applications, are commonly synthesized by growing a third domain off of a two-component heterodimer seed. However, because heterodimer seeds expose two distinct surfaces that often can both support nucleation and growth, selectively targeting one particular surface is critical for exclusively accessing a desired configuration. Understanding and controlling nucleation and growth therefore enables the rational formation of high-order hybrid nanoparticles. Here, we report an in-depth microscopic investigation that probes the chemoselective addition of Ag to Pt-Fe3O4 heterodimer seeds to form Ag-Pt-Fe3O4 heterotrimers. We find that the formation of the Ag-Pt-Fe3O4 heterotrimers initiates with indiscriminate Ag nucleation onto both the Pt and Fe3O4 surfaces of Pt-Fe3O4, followed by surface diffusion and coalescence of Ag onto the Pt surface to form the Ag-Pt-Fe3O4 product. Control experiments reveal that the size of the Ag domain of Ag-Pt-Fe3O4 correlates with the overall surface area of the Pt-Fe3O4 seeds, which is consistent with the coalescence of Ag through a surface-mediated process and can also be exploited to tune the size of the Ag domain. Additionally, we observe that small iron oxide islands on the Pt surface of the Pt-Fe3O4 seeds, deposited during the formation of Pt-Fe3O4, define the morphology of the Ag domain, which in turn influences its optical properties. These results provide unprecedented microscopic insights into the pathway by which Ag-Pt-Fe3O4 heterotrimer nanoparticles form and uncover new design guidelines for the synthesis of high-order hybrid nanoparticles with precisely targeted morphologies and properties. PMID- 26599999 TI - Oral candidiasis following steroid therapy for oral lichen planus. AB - OBJECTIVES: The purpose of this multicentre study was to determine the incidence of oral candidiasis in patients treated with topical steroids for oral lichen planus (OLP) and to determine whether the application of a concurrent antifungal therapy prevented the development of an oral candidiasis in these patients. MATERIALS AND METHODS: Records of 315 patients with OLP seen at four Oral Medicine practices treated for at least 2 weeks with steroids with and without the use of an antifungal regimen were retrospectively reviewed. RESULTS: The overall incidence of oral fungal infection in those treated with steroid therapy for OLP was 13.6%. There was no statistically significant difference in the rate of oral candidiasis development in those treated with an antifungal regimen vs those not treated prophylactically (14.3% vs 12.6%) (P = 0.68). CONCLUSIONS: Despite the use of various regimens, none of the preventive antifungal strategies used in this study resulted in a significant difference in the rate of development of an oral candidiasis in patients with OLP treated with steroids. PMID- 26600000 TI - Characterization of microRNA expression profiles in blood and saliva using the Ion Personal Genome Machine((r)) System (Ion PGMTM System). AB - MicroRNA (miRNA) expression profiling is gaining interest in the forensic community because the intrinsically short fragment and tissue-specific expression pattern enable miRNAs as a useful biomarker for body fluid identification. Measuring the quantity of miRNAs in forensically relevant body fluids is an important step to screen specific miRNAs for body fluid identification. The recent introduction of massively parallel sequencing (MPS) has the potential for screening miRNA biomarkers at the genome-wide level, which allows both the detection of expression pattern and miRNA sequences. In this study, we employed the Ion Personal Genome Machine((r)) System (Ion PGMTM System, Thermo Fisher) to characterize the distribution and expression of 2588 human mature miRNAs (miRBase v21) in 5 blood samples and 5 saliva samples. An average of 1,885,000 and 1,356,000 sequence reads were generated in blood and saliva respectively. Based on miRDong, a Perl-based tool developed for semi-automated miRNA distribution designations, and manually ascertained, 6 and 19 miRNAs were identified respectively as potentially blood and saliva-specific biomarkers. Herein, this study describes a complete and reliable miRNA workflow solution based on Ion PGMTM System, starting from efficient RNA extraction, followed by small RNA library construction and sequencing. With this workflow solution and miRDong analysis it will be possible to measure miRNA expression pattern at the genome wide level in other forensically relevant body fluids. PMID- 26600001 TI - Cytotoxic C20 Diterpenoid Alkaloids from the Australian Endemic Rainforest Plant Anopterus macleayanus. AB - In order to identify new anticancer compounds from nature, a prefractionated library derived from Australian endemic plants was generated and screened against the prostate cancer cell line LNCaP using a metabolic assay. Fractions from the seeds, leaves, and wood of Anopterus macleayanus showed cytotoxic activity and were subsequently investigated using a combination of bioassay-guided fractionation and mass-directed isolation. This led to the identification of four new diterpenoid alkaloids, 6alpha-acetoxyanopterine (1), 4'-hydroxy-6alpha acetoxyanopterine (2), 4'-hydroxyanopterine (3), and 11alpha-benzoylanopterine (4), along with four known compounds, anopterine (5), 7beta-hydroxyanopterine (6), 7beta,4'-dihydroxyanopterine (7), and 7beta-hydroxy-11alpha benzoylanopterine (8); all compounds were purified as their trifluoroacetate salt. The chemical structures of 1-8 were elucidated after analysis of 1D/2D NMR and MS data. Compounds 1-8 were evaluated for cytotoxic activity against a panel of human prostate cancer cells (LNCaP, C4-2B, and DuCaP) and nonmalignant cell lines (BPH-1 and WPMY-1), using a live-cell imaging system and a metabolic assay. All compounds showed potent cytotoxicity with IC50 values of <400 nM; compound 1 was the most active natural product from this series, with an IC50 value of 3.1 nM toward the LNCaP cell line. The live-cell imaging assay on 1-8 showed a concentration- and time-dependent effect on the cell morphology and proliferation of LNCaP cells. PMID- 26600002 TI - Heterogranular-Structured Diamond-Gold Nanohybrids: A New Long-Life Electronic Display Cathode. AB - In the age of hand-held portable electronics, the need for robust, stable and long-life cathode materials has become increasingly important. Herein, a novel heterogranular-structured diamond-gold nanohybrids (HDG) as a long-term stable cathode material for field-emission (FE) display and plasma display devices is experimentally demonstrated. These hybrid materials are electrically conductive that perform as an excellent field emitters, viz. low turn-on field of 2.62 V/MUm with high FE current density of 4.57 mA/cm(2) (corresponding to a applied field of 6.43 V/MUm) and prominently high lifetime stability lasting for 1092 min revealing their superiority on comparison with the other commonly used field emitters such as carbon nanotubes, graphene, and zinc oxide nanorods. The process of fabrication of these HDG materials is direct and easy thereby paving way for the advancement in next generation cathode materials for high-brightness FE and plasma-based display devices. PMID- 26600003 TI - Glycogen synthase kinase 3 in Wnt signaling pathway and cancer. AB - Glycogen synthase kinase 3 (GSK-3) was first discovered in 1980 as one of the key enzymes of glycogen metabolism. Since then, GSK-3 has been revealed as one of the master regulators of a diverse range of signaling pathways, including those activated by Wnts, participating in the regulation of numerous cellular functions, suggesting that its activity is tightly regulated. Numerous studies have pointed to an association of GSK-3 dysregulation with the onset and progression of human diseases, including diabetes mellitus, obesity, inflammation, neurological illnesses, and cancer. Therefore, GSK-3 is recognized as an attractive therapeutic target in multiple disorders. However, the great number of substrates that are phosphorylated by GSK-3 has raised the question of whether this limits its feasibility as a therapeutic target because of the potential disruption of many cellular processes and also by the fear that inhibition of GSK-3 may stimulate or aid in malignant transformation, as GSK-3 can phosphorylate pro-oncogenic factors. This mini review focuses on the role played by GSK-3 in Wnt signaling pathway and cancer using as model colon cancer. PMID- 26600004 TI - Exploration of the mechanical behavior of metal organic frameworks UiO-66(Zr) and MIL-125(Ti) and their NH2 functionalized versions. AB - The structural behaviour under mechanical stimuli of two metal organic frameworks, UiO-66(Zr) and MIL-125(Ti) and their amino-functionalized derivatives has been investigated by high-pressure powder X-ray diffraction up to 3.5 GPa. All these solids showed a gradual pressure-induced reversible decrease of their crystallinity and UiO-66(Zr)_NH2 material has been revealed as one of the most resilient MOFs reported so far corresponding to a very high bulk modulus. The mechanical behaviors of these MOFs have been correlated to their chemical and geometric features including the metal-oxygen coordination number, the nature of the organic linker, the porosity as well as their crystal density. PMID- 26600005 TI - Correction: Mechanisms of organelle biogenesis govern stochastic fluctuations in organelle abundance. PMID- 26600006 TI - The non-planarity of the benzene molecule in the X-ray structure of the chelated bismuth(III) heteroboroxine complex is not supported by quantum mechanical calculations. AB - The non-planarity of the benzene moiety in the crystal of a chelated bismuth(iii) heteroboroxine complex was not supported by DFT-D quantum chemical calculations. The observed bent structure of benzene is in fact a superimposition (thermal average) of the ensemble of thermally populated benzene structures in the complex studied. PMID- 26600007 TI - A randomized, double-blind, placebo-controlled, crossover trial of mifepristone in Gulf War veterans with chronic multisymptom illness. AB - No pharmacological treatments have been demonstrated to effectively treat chronic multisymptom illness (CMI) in Gulf War veterans (GWV). This study assessed the effect of the glucocorticoid receptor antagonist mifepristone in GWV with CMI. A randomized, double-blind, cross-over trial of mifepristone, with two six-week treatment phases separated by a one-month washout period, was conducted at a Veterans Affairs (VA) hospital between 2008 and 2011. Participants were randomized to receive either 200mg of mifepristone per day or matched placebo first. The primary clinical outcome measure was change in self-reported physical health. Neurocognitive functioning and self-reported measures of depression, PTSD, and fatigue were secondary outcomes. Sixty-five participants enrolled, of whom 36 were randomized and 32 (mean age, 49.1 (7.2) years) completed the study. Physical and mental health status and neurocognitive functioning were poor at baseline. Mifepristone treatment was not associated with improvement in self reported physical health (p=0.838) or in other self-reported measures of mental health. Mifepristone treatment was significantly associated with improvements in verbal learning (p=0.008, d=0.508), in the absence of improvement in other cognitive measures (working memory (p=0.914), visual learning (p=0.643) and a global composite measure (p=0.937). Baseline morning cortisol levels and lysozyme IC50-DEX, a measure of peripheral glucocorticoid sensitivity, displayed a significant relationship with endpoint verbal learning scores (p=0.012 and p=0.007, respectively). The magnitude of cortisol change during treatment mediated the improvement in verbal learning. This study was negative for the primary and secondary clinical outcomes. However, the data suggest a moderate dose of mifepristone may have circumscribed cognitive-enhancing effects in CMI. Further study is warranted to determine whether and through which mechanisms mifepristone treatment can yield clinically meaningful improvement in cognitive function in CMI or other neuropsychiatric conditions associated with HPA axis dysregulation. PMID- 26600008 TI - Associations between dehydroepiandrosterone (DHEA) levels, pituitary volume, and social anxiety in children. AB - Early timing of adrenarche, associated with relatively high levels of dehydroepiandrosterone (DHEA) and its sulphate (DHEA-S) in children, has been linked with mental health problems, particularly anxiety. However, little is known about possible neurobiological mechanisms underlying this association. The pituitary gland is a key component of the hypothalamic-pituitary-adrenal (HPA) axis, the activation of which triggers the onset of adrenarche. The purpose of this study was to examine the extent to which pituitary gland volume mediated the relationship between levels of DHEA/DHEA-S relative to age (i.e., adrenarcheal timing) and symptoms of anxiety in 95 children (50 female, M age 9.50 years, SD 0.34 years). Relatively high DHEA and DHEA-S (DHEA/S) levels were found to be associated with larger pituitary gland volumes. There was no significant direct effect of relative DHEA/S levels on overall symptoms of anxiety. However, results supported an indirect link between relatively high DHEA/S levels and symptoms of social anxiety, mediated by pituitary gland volume. No sex differences were observed for any relationship. Our findings suggest that neurobiological mechanisms may be partly responsible for the link between relatively early adrenarche and anxiety symptoms in children. One possible mechanism for this finding is that an enlarged pituitary gland in children experiencing relatively advanced adrenarche might be associated with hyper-activity/reactivity of the HPA axis. Further research is needed to understand the role of stress in the link between adrenarcheal timing and HPA-axis function, especially in relation to the development of anxiety symptoms in children and adolescents. PMID- 26600010 TI - In Situ Encapsulation of Ultrasmall CuO Quantum Dots with Controlled Band-Gap and Reversible Thermochromism. AB - Silica encapsulated ultrasmall CuO quantum dots (QDs; CuO@SiO2) were synthesized by reverse microemulsion. The CuO QDs with sizes ranging from 2.0 to 1.0 nm with corresponding band gaps of 1.4 to 2.6 eV were prepared simply by varying the concentration of the Cu(2+) precursor. The samples were characterized by Fourier transform infrared spectroscopy (FT-IR), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), and UV-vis spectroscopy. The CuO@SiO2 composite displayed reversible thermochromism which resulted from the strong electron-phonon coupling of ultrasmall CuO in the confined space of SiO2 and the enhanced band-gap shift in the visible light region depending on temperature. Besides, the as synthesized CuO@SiO2 was found to be highly stable for reversible thermochromism due to the micropore structure of silica matrix and local confinement of the QDs. PMID- 26600011 TI - Regional Nodal Irradiation: Examining the Clinical Implications of Randomized Trials. PMID- 26600009 TI - Higher serum dehydroepiandrosterone sulfate protects against the onset of depression in the elderly: Findings from the English Longitudinal Study of Aging (ELSA). AB - Depression is one of the major causes of disability worldwide, but the complete etiology of depression is not fully understood. Dehydroepiandrosterone (DHEA) and its sulphated form DHEA(S) have been associated with mood and healthy aging. Associations with mental illness over the middle to late years of life have not yet been extensively investigated in large, western community-dwelling samples. The aim of this study was to investigate whether low DHEA(S) levels are associated with the development of depressive symptoms in a large longitudinal cohort study of older men and women. We assessed data from English Longitudinal Study of Aging (ELSA) to evaluate the association of DHEA(S) levels and depressive symptoms measured by Center for Epidemiologic Studies Scale (CES-D) at baseline (n=3083) and at 4-year follow-up (n=3009). At baseline, there was an inverse association between DHEA(S) and depressive symptoms (B=-0.252, p=0.014). Adjustments for physical illnesses, impairments in cognitive function and health behaviors abolished this association (p=0.109) at baseline. Decreased DHEA(S) levels at baseline also predicted incident depression at 4-year follow-up (B= 0.332, p<0.001). In conclusion, higher DHEA(S) levels were associated with reduced risk of developing depressive symptoms in both men and women. PMID- 26600012 TI - Computing Workflows for Biologists: A Roadmap. AB - Extremely large datasets have become routine in biology. However, performing a computational analysis of a large dataset can be overwhelming, especially for novices. Here, we present a step-by-step guide to computing workflows with the biologist end-user in mind. Starting from a foundation of sound data management practices, we make specific recommendations on how to approach and perform computational analyses of large datasets, with a view to enabling sound, reproducible biological research. PMID- 26600015 TI - Assembly of Primary (Hetero)Arylamines via CuI/Oxalic Diamide-Catalyzed Coupling of Aryl Chlorides and Ammonia. AB - A general and practical catalytic system for aryl amination of aryl chlorides with aqueous or gaseous ammonia has been developed, with CuI as the catalyst and bisaryl oxalic diamides as the ligands. The reaction proceeds at 105-120 degrees C to provide a diverse set of primary (hetero)aryl amines in high yields with various functional groups. PMID- 26600013 TI - High-Throughput Screening of Myometrial Calcium-Mobilization to Identify Modulators of Uterine Contractility. AB - The uterine myometrium (UT-myo) is a therapeutic target for preterm labor, labor induction, and postpartum hemorrhage. Stimulation of intracellular Ca2+-release in UT-myo cells by oxytocin is a final pathway controlling myometrial contractions. The goal of this study was to develop a dual-addition assay for high-throughput screening of small molecular compounds, which could regulate Ca2+ mobilization in UT-myo cells, and hence, myometrial contractions. Primary murine UT-myo cells in 384-well plates were loaded with a Ca2+-sensitive fluorescent probe, and then screened for inducers of Ca2+-mobilization and inhibitors of oxytocin-induced Ca2+-mobilization. The assay exhibited robust screening statistics (Z' = 0.73), DMSO-tolerance, and was validated for high-throughput screening against 2,727 small molecules from the Spectrum, NIH Clinical I and II collections of well-annotated compounds. The screen revealed a hit-rate of 1.80% for agonist and 1.39% for antagonist compounds. Concentration-dependent responses of hit-compounds demonstrated an EC50 less than 10MUM for 21 hit-antagonist compounds, compared to only 7 hit-agonist compounds. Subsequent studies focused on hit-antagonist compounds. Based on the percent inhibition and functional annotation analyses, we selected 4 confirmed hit-antagonist compounds (benzbromarone, dipyridamole, fenoterol hydrobromide and nisoldipine) for further analysis. Using an ex vivo isometric contractility assay, each compound significantly inhibited uterine contractility, at different potencies (IC50). Overall, these results demonstrate for the first time that high-throughput small molecules screening of myometrial Ca2+-mobilization is an ideal primary approach for discovering modulators of uterine contractility. PMID- 26600014 TI - Glutathione Peroxidase of Pennisetum glaucum (PgGPx) Is a Functional Cd2+ Dependent Peroxiredoxin that Enhances Tolerance against Salinity and Drought Stress. AB - Reactive oxygen species (ROS) arise in the plant system due to inevitable influence of various environmental stimuli. Glutathione peroxidases are one of the important ROS scavengers inside the cell. A glutathione peroxidase (PgGPx) gene was previously found from Pennisetum glauccum abiotic stressed cDNA library. Enzyme kinetics data revealed that PgGPx possessed preference towards thioredoxin rather than glutathione as electron donor and thus belongs to the functional peroxiredoxin group. Moreover, its activity was found to be dependent on divalent cations, especially Cd2+ and homology model showed the presence of Cd2+ binding site in the protein. Site directed mutagenesis study of PgGPx protein revealed the vital role of two conserved Cysteine residues for its enzymatic activity and structural folding. Expression analysis suggested that PgGPx transcript is highly up-regulated in response to salinity and drought stresses. When expressed ectopically, PgGPx showed enhanced tolerance against multiple abiotic stresses in prokaryotic E. coli and model plant, rice. Transgenic rice plants showed lesser accumulation of MDA and H2O2; and higher accumulation of proline as compared to wild type (WT) plants in response to both salinity and drought stresses that clearly indicates suppression of lipid peroxidation and ROS generation in transgenic lines. Moreover, transgenic plants maintained better photosynthesis efficiency and higher level of antioxidant enzyme activity as compared to WT plants under stress conditions. These results clearly indicate the imperative role of PgGPx in cellular redox homeostasis under stress conditions, leading to the maintenance of membrane integrity and increased tolerance towards oxidative stress. PMID- 26600016 TI - Differences in Patterns of Reproductive Allocation between the Sexes in Nicrophorus orbicollis. AB - Organisms are selected to maximize lifetime reproductive success by balancing the costs of current reproduction with costs to future survival and fecundity. Males and females typically face different reproductive costs, which makes comparisons of their reproductive strategies difficult. Burying beetles provide a unique system that allows us to compare the costs of reproduction between the sexes because males and females are capable of raising offspring together or alone and carcass preparation and offspring care represent the majority of reproductive costs for both sexes. Because both sexes perform the same functions of carcass preparation and offspring care, we predict that they would experience similar costs and have similar life history patterns. In this study we assess the cost of reproduction in male Nicrophorus orbicollis and compare to patterns observed in females. We compare the reproductive strategies of single males and females that provided pre- and post-hatching parental care. There is a cost to reproduction for both males and females, but the sexes respond to these costs differently. Females match brood size with carcass size, and thus maximize the lifetime number of offspring on a given size carcass. Males cull proportionately more offspring on all carcass sizes, and thus have a lower lifetime number of offspring compared to females. Females exhibit an adaptive reproductive strategy based on resource availability, but male reproductive strategies are not adaptive in relation to resource availability. PMID- 26600017 TI - Serum Magnesium and Sudden Death in European Hemodialysis Patients. AB - Despite suggestions that higher serum magnesium (Mg) levels are associated with improved outcome, the association with mortality in European hemodialysis (HD) patients has only scarcely been investigated. Furthermore, data on the association between serum Mg and sudden death in this patient group is limited. Therefore, we evaluated Mg in a post-hoc analysis using pooled data from the CONvective TRAnsport STudy (CONTRAST, NCT00205556), a randomized controlled trial (RCT) evaluating the survival risk in dialysis patients on hemodiafiltration (HDF) compared to HD with a mean follow-up of 3.1 years. Serum Mg was measured at baseline and 6, 12, 24 and 36 months thereafter. Cox proportional hazards models, adjusted for confounders using inverse probability weighting, were used to estimate hazard ratios (HRs) of baseline serum Mg on all-cause mortality, cardiovascular mortality, non-cardiovascular mortality and sudden death. A generalized linear mixed model was used to investigate Mg levels over time. Out of 714 randomized patients, a representative subset of 365 (51%) were analyzed in the present study. For every increase in baseline serum Mg of 0.1 mmol/L, the HR for all-cause mortality was 0.85 (95% CI 0.77-94), the HR for cardiovascular mortality 0.73 (95% CI 0.62-0.85) and for sudden death 0.76 (95% CI 0.62-0.93). These findings did not alter after extensive correction for potential confounders, including treatment modality. Importantly, no interaction was found between serum phosphate and serum Mg. Baseline serum Mg was not related to non cardiovascular mortality. Mg decreased slightly but statistically significant over time (Delta -0.011 mmol/L/year, 95% CI -0.017 to -0.009, p = 0.03). In short, serum Mg has a strong, independent association with all-cause mortality, cardiovascular mortality and sudden death in European HD patients. Serum Mg levels decrease slightly over time. PMID- 26600018 TI - Voluntary Exercise Stabilizes Established Angiotensin II-Dependent Atherosclerosis in Mice through Systemic Anti-Inflammatory Effects. AB - We have previously demonstrated that exercise training prevents the development of Angiotensin (Ang) II-induced atherosclerosis and vulnerable plaques in Apolipoprotein E-deficient (ApoE-/-) mice. In this report, we investigated whether exercise attenuates progression and promotes stability in pre-established vulnerable lesions. To this end, ApoE-/- mice with already established Ang II mediated advanced and vulnerable lesions (2-kidney, 1-clip [2K1C] renovascular hypertension model), were subjected to sedentary (SED) or voluntary wheel running training (EXE) regimens for 4 weeks. Mean blood pressure and plasma renin activity did not significantly differ between the two groups, while total plasma cholesterol significantly decreased in 2K1C EXE mice. Aortic plaque size was significantly reduced by 63% in 2K1C EXE compared to SED mice. Plaque stability score was significantly higher in 2K1C EXE mice than in SED ones. Aortic ICAM-1 mRNA expression was significantly down-regulated following EXE. Moreover, EXE significantly down-regulated splenic pro-inflammatory cytokines IL-18, and IL 1beta mRNA expression while increasing that of anti-inflammatory cytokine IL-4. Reduction in plasma IL-18 levels was also observed in response to EXE. There was no significant difference in aortic and splenic Th1/Th2 and M1/M2 polarization markers mRNA expression between the two groups. Our results indicate that voluntary EXE is effective in slowing progression and promoting stabilization of pre-existing Ang II-dependent vulnerable lesions by ameliorating systemic inflammatory state. Our findings support a therapeutic role for voluntary EXE in patients with established atherosclerosis. PMID- 26600019 TI - Blood-Brain Barrier Effects of the Fusarium Mycotoxins Deoxynivalenol, 3 Acetyldeoxynivalenol, and Moniliformin and Their Transfer to the Brain. AB - BACKGROUND: Secondary metabolites produced by Fusarium fungi frequently contaminate food and feed and have adverse effects on human and animal health. Fusarium mycotoxins exhibit a wide structural and biosynthetic diversity leading to different toxicokinetics and toxicodynamics. Several studies investigated the toxicity of mycotoxins, focusing on very specific targets, like the brain. However, it still remains unclear how fast mycotoxins reach the brain and if they impair the integrity of the blood-brain barrier. This study investigated and compared the effects of the Fusarium mycotoxins deoxynivalenol, 3 acetyldeoxynivalenol and moniliformin on the blood-brain barrier. Furthermore, the transfer properties to the brain were analyzed, which are required for risk assessment, including potential neurotoxic effects. METHODS: Primary porcine brain capillary endothelial cells were cultivated to study the effects of the examined mycotoxins on the blood-brain barrier in vitro. The barrier integrity was monitored by cellular impedance spectroscopy and 14C radiolabeled sucrose permeability measurements. The distribution of the applied toxins between blood and brain compartments of the cell monolayer was analyzed by high performance liquid chromatography-mass spectrometry to calculate transfer rates and permeability coefficients. RESULTS: Deoxynivalenol reduced the barrier integrity and caused cytotoxic effects at 10 MUM concentrations. Slight alterations of the barrier integrity were also detected for 3-acetyldeoxynivalenol. The latter was transferred very quickly across the barrier and additionally cleaved to deoxynivalenol. The transfer of deoxynivalenol and moniliformin was slower, but clearly exceeded the permeability of the negative control. None of the compounds was enriched in one of the compartments, indicating that no efflux transport protein is involved in their transport. PMID- 26600024 TI - Why Hospital Changed from In-House to Shared Computer System. PMID- 26600020 TI - Changes in Non-Enzymatic Antioxidants in the Blood Following Anaerobic Exercise in Men and Women. AB - PURPOSE: The aim of this study was to compare changes in total oxidative status (TOS), total antioxidative capacity (TAC) and the concentration of VitA, VitE, VitC, uric acid (UA), reduced (GSH) and oxidized glutathione (GSSG) in blood within 24 hours following anaerobic exercise (AnEx) among men and women. METHODS: 10 women and 10 men performed a 20-second bicycle sprint (AnEx). Concentrations of oxidative stress indicators were measured before AnEx and 3, 15 and 30 minutes and 1 hour afterwards. UA, GSH and GSSH were also measured 24 hours after AnEx. Lactate and H+ concentrations were measured before and 3 minutes after AnEx. RESULTS: The increase in lactate and H+ concentrations following AnEx was similar in both sexes. Changes in the concentrations of all oxidative stress indicators were significant and did not differ between men and women. In both sexes, TOS, TAC, TOS/TAC and VitA and VitE concentrations were the highest 3 minutes, VitC concentration was the highest 30 minutes, and UA concentration was the highest 1 hour after AnEx. GSH concentration was significantly lower than the initial concentration from 15 minutes to 24 hour after AnEx. GSSG concentration was significantly higher, while the GSH/GSSG ratio was significantly lower than the initial values 1 hour and 24 hour after AnEx. CONCLUSIONS: With similar changes in lactate and H+ concentrations, AnEx induces the same changes in TAC, TOS, TOS/TAC and non-enzymatic antioxidants of low molecular weight in men and women. Oxidative stress lasted at least 24 hours after AnEx. PMID- 26600025 TI - What's Going On. PMID- 26600026 TI - Consultant's Corner. PMID- 26600027 TI - Hospital Financial Problems. PMID- 26600028 TI - Hospital Law Review. PMID- 26600030 TI - OBG. PMID- 26600029 TI - Outpatient Care. PMID- 26600032 TI - OR News. PMID- 26600031 TI - Operating Room. PMID- 26600034 TI - Product Profile. PMID- 26600037 TI - Suppression of Development of Ankylosing Spondylitis Through Soluble Flt-1. AB - BACKGROUND/AIMS: Circulating monocytes/macrophages are origins of osteoclasts that mediate the development of ankylosing spondylitis (AS). Moreover, infiltrated macrophages facilitate the AS progression through production and secretion of pro-inflammatory cytokines. Thus, suppression of the recruitment of circulating monocytes/macrophages may be an effective AS treatment, which is, however, not available so far in clinic. Soluble fms-like tyrosine kinase-1 (sFlt 1) is a decoy receptor for vascular endothelial growth factor (VEGF) to compete with VEGF receptor (VEGFR2) for VEGF binding in endothelial cells, while its application in treating AS and effects on the recruitment of circulating monocytes/macrophages has not been reported before. METHODS: We used a proteoglycan-induced arthritis (PGIA) mouse model for human AS. We injected sFlt 1 into the articular cavity and evaluated its effects on PGIA by incidence of arthritis, and clinical and pathological arthritis severity. We isolated and analyzed macrophages and endothelial cells in the articular cavity before and after treatment. RESULTS: Injection of sFlt-1 significantly decreased the incidence and severity of PGIA in mice, and significantly reduced the number of infiltrated macrophages, possibly through reduction of vessel permeability, in a VEGFR2-dependent manner. CONCLUSION: Our data suggest that sFlt-1 may have a therapeutic effect on AS, resulting from suppression of VEGF signaling-mediated recruitment of circulating monocytes/macrophages. PMID- 26600038 TI - miR-17 and -20a Target the Neuron-Derived Orphan Receptor-1 (NOR-1) in Vascular Endothelial Cells. AB - Neuron-derived orphan receptor-1 (NOR-1) plays a major role in vascular biology by controlling fibroproliferative and inflammatory responses. Because microRNAs (miRNAs) have recently emerged as key players in the regulation of gene expression in the vasculature, here we have investigated the regulation of NOR-1 by miRNAs in endothelial cells. Computational algorithms suggest that NOR-1 could be targeted by members of the miR-17 family. Accordingly, ectopic over-expression of miR-17 or miR-20a in endothelial cells using synthetic premiRNAs attenuated the up-regulation of NOR-1 expression induced by VEGF (as evidenced by real time PCR, Western blot and immunocitochemistry). Conversely, the antagonism of these miRNAs by specific antagomirs prevented the down-regulation of NOR-1 promoted by miR-17 or miR-20a in VEGF-stimulated cells. Disruption of the miRNA-NOR-1 mRNA interaction using a custom designed target protector evidenced the selectivity of these responses. Further, luciferase reporter assays and seed-sequence mutagenesis confirmed that miR-17 and -20a bind to NOR-1 3'-UTR. Finally, miR-17 and -20a ameliorated the up-regulation of VCAM-1 mediated by NOR-1 in VEGF stimulated cells. Therefore, miR-17 and -20a target NOR-1 thereby regulating NOR 1-dependent gene expression. PMID- 26600040 TI - Towards Quantitative Spatial Models of Seabed Sediment Composition. AB - There is a need for fit-for-purpose maps for accurately depicting the types of seabed substrate and habitat and the properties of the seabed for the benefits of research, resource management, conservation and spatial planning. The aim of this study is to determine whether it is possible to predict substrate composition across a large area of seabed using legacy grain-size data and environmental predictors. The study area includes the North Sea up to approximately 58.44 degrees N and the United Kingdom's parts of the English Channel and the Celtic Seas. The analysis combines outputs from hydrodynamic models as well as optical remote sensing data from satellite platforms and bathymetric variables, which are mainly derived from acoustic remote sensing. We build a statistical regression model to make quantitative predictions of sediment composition (fractions of mud, sand and gravel) using the random forest algorithm. The compositional data is analysed on the additive log-ratio scale. An independent test set indicates that approximately 66% and 71% of the variability of the two log-ratio variables are explained by the predictive models. A EUNIS substrate model, derived from the predicted sediment composition, achieved an overall accuracy of 83% and a kappa coefficient of 0.60. We demonstrate that it is feasible to spatially predict the seabed sediment composition across a large area of continental shelf in a repeatable and validated way. We also highlight the potential for further improvements to the method. PMID- 26600039 TI - The Effects of Varying Ankle Foot Orthosis Stiffness on Gait in Children with Spastic Cerebral Palsy Who Walk with Excessive Knee Flexion. AB - INTRODUCTION: Rigid Ankle-Foot Orthoses (AFOs) are commonly prescribed to counteract excessive knee flexion during the stance phase of gait in children with cerebral palsy (CP). While rigid AFOs may normalize knee kinematics and kinetics effectively, it has the disadvantage of impeding push-off power. A spring-like AFO may enhance push-off power, which may come at the cost of reducing the knee flexion less effectively. Optimizing this trade-off between enhancing push-off power and normalizing knee flexion in stance is expected to maximize gait efficiency. This study investigated the effects of varying AFO stiffness on gait biomechanics and efficiency in children with CP who walk with excessive knee flexion in stance. Fifteen children with spastic CP (11 boys, 10+/ 2 years) were prescribed with a ventral shell spring-hinged AFO (vAFO). The hinge was set into a rigid, or spring-like setting, using both a stiff and flexible performance. At baseline (i.e. shoes-only) and for each vAFO, a 3D-gait analysis and 6-minute walk test with breath-gas analysis were performed at comfortable speed. Lower limb joint kinematics and kinetics were calculated. From the 6 minute walk test, walking speed and the net energy cost were determined. A generalized estimation equation (p<0.05) was used to analyze the effects of different conditions. Compared to shoes-only, all vAFOs improved the knee angle and net moment similarly. Ankle power generation and work were preserved only by the spring-like vAFOs. All vAFOs decreased the net energy cost compared to shoes only, but no differences were found between vAFOs, showing that the effects of spring-like vAFOs to promote push-off power did not lead to greater reductions in walking energy cost. These findings suggest that, in this specific group of children with spastic CP, the vAFO stiffness that maximizes gait efficiency is primarily determined by its effect on knee kinematics and kinetics rather than by its effect on push-off power. TRIAL REGISTRATION: Dutch Trial Register NTR3418. PMID- 26600041 TI - An Analysis of Citizen Science Based Research: Usage and Publication Patterns. AB - The use of citizen science for scientific discovery relies on the acceptance of this method by the scientific community. Using the Web of Science and Scopus as the source of peer reviewed articles, an analysis of all published articles on "citizen science" confirmed its growth, and found that significant research on methodology and validation techniques preceded the rapid rise of the publications on research outcomes based on citizen science methods. Of considerable interest is the growing number of studies relying on the re-use of collected datasets from past citizen science research projects, which used data from either individual or multiple citizen science projects for new discoveries, such as for climate change research. The extent to which citizen science has been used in scientific discovery demonstrates its importance as a research approach. This broad analysis of peer reviewed papers on citizen science, that included not only citizen science projects, but the theory and methods developed to underpin the research, highlights the breadth and depth of the citizen science approach and encourages cross-fertilization between the different disciplines. PMID- 26600042 TI - The Good, the Bad, and the Tiny: A Simple, Mechanistic-Probabilistic Model of Virus-Nutrient Colimitation in Microbes. AB - For phytoplankton and other microbes, nutrient receptors are often the passages through which viruses invade. This presents a bottom-up vs. top-down, co limitation scenario; how do these would-be-hosts balance minimizing viral susceptibility with maximizing uptake of limiting nutrient(s)? This question has been addressed in the biological literature on evolutionary timescales for populations, but a shorter timescale, mechanistic perspective is lacking, and marine viral literature suggests the strong influence of additional factors, e.g. host size; while the literature on both nutrient uptake and host-virus interactions is expansive, their intersection, of ubiquitous relevance to marine environments, is understudied. I present a simple, mechanistic model from first principles to analyze the effect of this co-limitation scenario on individual growth, which suggests that in environments with high risk of viral invasion or spatial/temporal heterogeneity, an individual host's growth rate may be optimized with respect to receptor coverage, producing top-down selective pressure on short timescales. The model has general applicability, is suggestive of hypotheses for empirical exploration, and can be extended to theoretical studies of more complex behaviors and systems. PMID- 26600043 TI - Correction: Spatial Distribution Patterns in the Very Rare and Species-Rich Picea chihuahuana Tree Community (Mexico). AB - [This corrects the article DOI: 10.1371/journal.pone.0140442.]. PMID- 26600044 TI - Left Ventricular Geometry and Blood Pressure as Predictors of Adverse Progression of Fabry Cardiomyopathy. AB - BACKGROUND: In spite of several research studies help to describe the heart in Fabry disease (FD), the cardiomyopathy is not entirely understood. In addition, the impact of blood pressure and alterations in geometry have not been systematically evaluated. METHODS: In 74 FD patients (mean age 36+/-12 years; 45 females) the extent of myocardial fibrosis and its progression were quantified using cardiac magnetic-resonance-imaging with late enhancement technique (LE). Results were compared to standard echocardiography complemented by 2D-speckle tracking, 3D-sphericity-index (SI) and standardized blood pressure measurement. At baseline, no patient received enzyme replacement therapy (ERT). After 51+/-24 months, a follow-up examination was performed. RESULTS: Systolic blood pressure (SBP) was higher in patients with vs. without LE: 123+/-17 mmHg vs. 115+/-13 mmHg; P = 0.04. A positive correlation was found between SI and the amount of LE positive myocardium (r = 0.51; P<0.001) indicating an association of higher SI in more advanced stages of the cardiomyopathy. SI at baseline was positively associated with the increase of LE-positive myocardium during follow-up. The highest SBP (125+/-19 mmHg) and also the highest SI (0.32+/-0.05) was found in the subgroup with a rapidly increasing LE (ie, >=0.2% per year; n = 16; P = 0.04). Multivariate logistic regression analysis including SI, SBP, EF, left ventricular volumes, wall thickness and NT-proBNP adjusted for age and sex showed SI as the most powerful parameter to detect rapid progression of LE (AUC = 0.785; P<0.05). CONCLUSIONS: LV geometry as assessed by the sphericity index is altered in relation to the stage of the Fabry cardiomyopathy. Although patients with FD are not hypertensive, the SBP has a clear impact on the progression of the cardiomyopathy. PMID- 26600046 TI - Quantifying the image quality and dose reduction of respiratory triggered 4D cone beam computed tomography with patient-measured breathing. AB - Respiratory triggered four dimensional cone-beam computed tomography (RT 4D CBCT) is a novel technique that uses a patient's respiratory signal to drive the image acquisition with the goal of imaging dose reduction without degrading image quality. This work investigates image quality and dose using patient-measured respiratory signals for RT 4D CBCT simulations. Studies were performed that simulate a 4D CBCT image acquisition using both the novel RT 4D CBCT technique and a conventional 4D CBCT technique. A set containing 111 free breathing lung cancer patient respiratory signal files was used to create 111 pairs of RT 4D CBCT and conventional 4D CBCT image sets from realistic simulations of a 4D CBCT system using a Rando phantom and the digital phantom, XCAT. Each of these image sets were compared to a ground truth dataset from which a mean absolute pixel difference (MAPD) metric was calculated to quantify the degradation of image quality. The number of projections used in each simulation was counted and was assumed as a surrogate for imaging dose. Based on 111 breathing traces, when comparing RT 4D CBCT with conventional 4D CBCT, the average image quality was reduced by 7.6% (Rando study) and 11.1% (XCAT study). However, the average imaging dose reduction was 53% based on needing fewer projections (617 on average) than conventional 4D CBCT (1320 projections). The simulation studies have demonstrated that the RT 4D CBCT method can potentially offer a 53% saving in imaging dose on average compared to conventional 4D CBCT in simulation studies using a wide range of patient-measured breathing traces with a minimal impact on image quality. PMID- 26600045 TI - Effects of Gastric Bypass and Gastric Banding on Bone Remodeling in Obese Patients With Type 2 Diabetes. AB - CONTEXT: Roux-en-Y gastric bypass (RYGB) leads to high-turnover bone loss, but little is known about skeletal effects of laparoscopic adjustable gastric banding (LAGB) or mechanisms underlying bone loss after bariatric surgery. OBJECTIVE: To evaluate effects of RYGB and LAGB on fasting and postprandial indices of bone remodeling. DESIGN AND SETTING: Ancillary investigation of a prospective study at 2 academic institutions. PARTICIPANTS: Obese adults aged 21-65 years with type 2 diabetes who underwent RYGB (n = 11) or LAGB (n = 8). OUTCOMES: Serum C-terminal telopeptide (CTX), procollagen type 1 N-terminal propeptide (P1NP), and PTH were measured during a mixed meal tolerance test at baseline, 10 days and 1 year after surgery. Changes in 25-hydroxyvitamin D, polypeptide YY (PYY), glucagon-like peptide-1, glucose-dependent insulinotropic peptide, and insulin were also assessed. RESULTS: Fasting CTX increased 10 days after RYGB but not LAGB (+69 +/- 23% vs +12+/-12%, P < .001), despite comparable weight loss at that time. By 1 year, fasting CTX and P1NP increased more after RYGB than LAGB (CTX +221 +/- 60% vs +15 +/- 6%, P<0.001; P1NP +93 +/- 25% vs -9 +/- 10%, P < .001) and weight loss was greater with RYGB. Changes in CTX were independent of PTH and 25 hydroxyvitamin D but were associated with increases in fasting PYY. Postprandial suppression of CTX was more pronounced after RYGB than LAGB at 10 days and 1 year postoperatively. CONCLUSIONS: RYGB is accompanied by early increases in fasting indices of bone remodeling, independent of weight loss or changes in PTH or 25 hydroxyvitamin D. LAGB did not affect bone markers. PYY and other enterohormonal signals may play a role in RYGB-specific skeletal changes. PMID- 26600048 TI - Pregestational diabetes is associated with adverse outcomes in twin pregnancies: a regional register-based study. AB - INTRODUCTION: The incidence of pregnancies complicated by twinning and diabetes is increasing in the UK. This is a worrying trend as both diabetes and twin gestations are associated with a high risk of adverse pregnancy outcomes. The few studies that have specifically addressed how twinning and pregestational diabetes in the same pregnancy may affect outcome have reported conflicting results. MATERIAL AND METHODS: We analyzed data on 27 women with a twin pregnancy and pregestational diabetes (54 babies) and 6407 women with a twin pregnancy without diabetes (12 814 babies) from the Northern Survey of Twin and Multiple Pregnancy during 1998-2010. A composite adverse pregnancy outcome (comprising fetal loss before 24 weeks, termination of pregnancy, stillbirth, infant death or any major congenital anomaly), extended perinatal mortality (stillbirths and neonatal deaths) and major congenital anomaly were the main outcome measures. Adjusted rate ratios were estimated using generalized estimating equations for Poisson regression controlling for potential confounders. RESULTS: Mothers with twin pregnancies with diabetes were older (p = 0.001) and had higher body mass indices (p < 0.0001) than those without diabetes. Their twins were more likely to be delivered earlier (p = 0.026), be delivered by cesarean section (80.4% vs. 49.7%; p < 0.0001), be large-for-gestational-age (p < 0.0001) and require admission to a special care baby unit (p < 0.0001). Pregestational diabetes was associated with significantly increased rates of the composite adverse outcome and major congenital anomalies in twins (adjusted rate ratios 2.66, 95% confidence interval 1.14-6.20 and adjusted rate ratios 3.51, 95% confidence interval 1.31-9.40, respectively). CONCLUSION: Maternal pregestational diabetes in twin pregnancies is associated with a significantly increased risk of an adverse pregnancy outcome. PMID- 26600047 TI - Mutant SOD1 Increases APP Expression and Phosphorylation in Cellular and Animal Models of ALS. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease and it is the most common adult onset neurodegenerative disorder affecting motor neurons. There is currently no effective treatment for ALS and our understanding of the pathological mechanism is still far away from prevention and/or treatment of this devastating disease. Amyloid precursor protein (APP) is a transmembrane protein that undergoes processing either by beta-secretase or alpha-secretase, followed by gamma-secretase. In the present study, we show that APP levels, and aberrant phosphorylation, which is associated with enhanced beta-secretase cleavage, are increased in SOD1G93A ALS mouse model. Fluorescence resonance energy transfer (FRET) analysis suggests a close interaction between SOD1 and APP at hippocampal synapses. Notably, SOD1G93A mutation induces APP-SOD1 conformational changes, indicating a crosstalk between these two signaling proteins. Inhibition of APP processing via monoclonal antibody called BBS that blocks APP beta-secretase cleavage site, resulted in reduction of mutant SOD1G93A levels in animal and cellular models of ALS, significantly prolonged life span of SOD1G93A mice and diminished inflammation. Beyond its effect on toxic mutant SOD1G93A, BBS treatment resulted in a reduction in the levels of APP, its processing product soluble APPbeta and pro-apoptotic p53. This study demonstrates that APP and its processing products contribute to ALS pathology through several different pathways; thus BBS antibody could be a promising neuroprotective strategy for treatment of this disease. PMID- 26600049 TI - Patterns of emotion regulation at two years of age: associations with mothers' attachment in a fear eliciting situation. AB - The study aims at identifying patterns of mother-toddler emotion regulation and testing whether they are related to mothers' attachment. An Italian community sample (N = 38; 66% males) was followed longitudinally, with mothers' attachment collected through the Adult Attachment Interview at 14 months of child's age and mothers' and children's emotion regulation behaviors assessed through a fear eliciting lab procedure when the child turned two years old. Two dyadic regulatory patterns were identified through a two-phased cluster analytic plan. Children characterized by one pattern approached, explored and played with the threatening stimulus, whereas children characterized by the other pattern tended to become frightened by this stimulus and avoided the object. The majority of children whose mothers were classified as secure displayed the first regulatory pattern. This finding contributes to extending understanding of how parental factors can influence the development of self-regulation. PMID- 26600050 TI - An efficient route to regioselective functionalization of benzo[b]thiophenes via palladium-catalyzed decarboxylative Heck coupling reactions: insights from experiment and computation. AB - Pd-catalyzed decarboxylative Heck-type coupling of 3-chlorobenzo[b]thiophene-2 carboxylic acids with styrenes have been developed as an efficient strategy for the construction of functionalized benzo[b]thiophenes. Theoretical analysis shows that AgCl generated during the reaction, instead of Pd, pi-coordinates with the carboxyl O atom, making easy the rate-determining CO2 dissociation. The divergent reactivities of the Cl-substituted and H-substituted 3-benzo[b]thiophene-2 carboxylic acids are mainly due to the presence of the Cl substituent, which reduces the adjacent pi-pi interplay, thereby significantly contributing to decarboxylation. Therefore, the presence of both AgCl and the Cl substituent are of key importance in ensuring the occurrence of the reaction under the given conditions. PMID- 26600051 TI - The Safety and Benefit of Statins in Liver Cirrhosis: a Review. AB - Dyslipidemia is a primary, major risk factor for coronary artery disease CAD. The prevalence of dyslipidemia had decreased over the past 30 years, which may in part be explained by the steady increase in the use of lipid-lowering drug therapy, especially statins. Cardiovascular risk has been shown to be greater in liver disease (20% in the liver cirrhosis vs. 12% in the general population), where statins can play an important role as a primary and secondary prevention for CAD. Given patients with chronic liver disease, especially liver cirrhosis are at risk of decreased hepatic clearance, there is concern that this patient population may be at higher risk for complications from statin therapy. Several retrospective studies showed that statin use in chronic liver disease and cirrhosis is safe, and even it was associated with lower mortality and lower rate of hepatic decompensation. This review discusses the safety and the different mechanisms where statins can decrease the rate of complications in liver cirrhosis, including portal hypertension, sepsis and the incidence of hepatocellular carcinoma. PMID- 26600052 TI - Effects of Intracerebroventricularly (ICV) Injected Ghrelin on Cardiac Inducible Nitric Oxide Synthase Activity/Expression in Obese Rats. AB - The aim of this study was to examine the effects of ghrelin on regulation of cardiac inducible nitric oxide synthase (iNOS) activity/expression in high fat (HF), obese rats.For this study, male Wistar rats fed with HF diet (30% fat) for 4 weeks were injected every 24 h for 5 days intracerebroventricularly (ICV) with ghrelin (0.3 nmol/5 ul) or with an equal volume of phosphate buffered saline (PBS). Control rats were ICV injected with an equal volume of PBS. Glucose, insulin and nitric oxide (NO) concentrations were measured in serum, while arginase activity and citrulline concentrations were measured in heart lysate. Protein iNOS and regulatory subunit of nuclear factor-kappaB (NFkappaB-p65), phosphorylation of enzymes protein kinase B (Akt) at Ser(473), and extracellular signal-regulated kinases 1/2 (ERK1/2) at Tyr(202)/Tyr(204) were determined in heart lysate by Western blot. For gene expression of iNOS qRT-PCR was used.Results show significantly (p<0.01) higher serum NO production in ghrelin treated HF rats compared with HF rats. Ghrelin significantly reduced citrulline concentration (p<0.05) and arginase activity (p<0.01) in HF rats. In ghrelin treated HF rats, gene and protein expression of iNOS and NFkappaB-p65 levels were significantly (p<0.05) increased compared with HF rats. Increased phosphorylation of Akt (p<0.01) and decreased (p<0.05) ERK1/2 phosphorylation were detected in HF ghrelin treated rats compared with HF rats hearts.Results from this study indicate that exogenous ghrelin induces expression and activity of cardiac iNOS via Akt phosphorylation followed by NFkappaB activation in HF rats. PMID- 26600053 TI - Hypogonadism and Mortality in Aged Hospitalized Male Patients: A 5-Year Prospective Observational Study. AB - OBJECTIVE: To investigate the relationship between hypogonadism and mortality in aged hospitalized male patients. DESIGN: A 5-year prospective observational study was conducted. Gonadal function was assessed at hospital admission and mortality was registered in the follow-up period. PATIENTS AND METHODS: We studied all patients>=65 years admitted for any reason during 2010 and 2011. Serum T concentrations were quantified in all patients. Hypogonadism was defined by the presence of serum T levels<200 ng/dl. Number of deaths and all-cause and cardiovascular (CV) mortality were registered until December 31(st), 2014. RESULTS: During the study 150 patients were admitted and 103 (68.7%) of them died during follow-up. Hypogonadism was positively associated with mortality (P=0.036). The percentage of hypogonadal patients was significantly (P=0.02) higher in the group of patients who died in hospital compared with those who died after hospital discharge and those who survived. CV disease was the main cause of death in 52 patients (50.5%). Kaplan-Meier analysis showed a median survival time for all-cause mortality of 2.0 (0-16.5) months and 21.0 (5.0-33.2) months for patients with and without hypogonadism, respectively (P<0.001). Similar findings were found when analyzing mortality due to CV disease (P=0.009). Hypogonadism was a strong independent predictor for all-cause (adjusted multivariate analysis, HR 3.35; 1.55-7.23, P=0.002) and CV mortality (HR 2.14; 1.18-3.86, P=0.012). CONCLUSIONS: Hypogonadism discovered during hospitalization is associated with in hospital and long-term mortality in elderly male patients and predicts both all cause mortality and CV mortality in this population. PMID- 26600054 TI - Should Free Thyroxine Go Back into the Routine Thyroid Profile? AB - BACKGROUND: Many clinical chemistry laboratories offer thyroid-stimulating hormone (TSH) alone as a first-line test of thyroid function, and only reflex a free thyroxine (fT4) test if the TSH result is abnormal (i. e., outside of the laboratory reference range). In secondary hypothyroidism, a low fT4 may be accompanied by a low or a normal TSH level. A testing strategy that measures baseline TSH only risks missing cases of secondary hypothyroidism in which the TSH level is normal. METHODS: The current authors examined 26,106 consecutive thyroid function test (TFT) results in our initial analysis. If the TFT results were compatible with hypopituitarism, with fT4 below the reference range (9-20 pmol/L) and a TSH result <=5 mU/L (reference range: 0.5-5 mU/L), the laboratory performed further tests of pituitary function. The cost of identifying pituitary insufficiency by measuring both fT4 and TSH was estimated for our population (in 2004 and 2013) and compared with 2 other relevant studies. RESULTS: A total of 121 patients had a normal TSH with a low fT4. 8 new cases of secondary hypopituitarism were identified when fT4 was combined with TSH as the front-line TFT profile. Of these, 5 were found to have pituitary adenomas, 2 of which were macroprolactinomas. The reagent cost of identifying each case by inclusion of fT4 in the TFT profile decreased from L11,568 (?16,089) in 1998 to L1451 (?2018) in 2013. CONCLUSIONS: 8 cases of pituitary insufficiency would not have been identified with a strategy of TSH testing alone, which calls for the addition of fT4 to the routine TFT profile. The cost per case of identifying those with pituitary insufficiency by additional measurement of fT4 has become cheaper with time. PMID- 26600055 TI - Single Nucleotide Polymorphism of Interleukin-18 and Interleukin-18 Receptor and the Risk of Papillary Thyroid Cancer. AB - PURPOSE: Growing evidence suggests that interleukin-18 (IL-18) levels may affect neoplasia and that single nucleotide polymorphisms (SNPs) within IL-18 gene may influence its production. In this study, we evaluated whether IL-18 and IL-18 receptor (IL-18R) polymorphisms are associated with the development and clinicopathological features of papillary thyroid carcinoma (PTC). MATERIALS AND METHODS: Using direct sequencing, we investigated the association between functional polymorphisms of IL-18 and IL-18R genes and susceptibility to PTC in 94 PTC patients and 260 healthy controls. Genetic data were analyzed using commercially available software. Multiple logistic regression models were used to calculate odds ratios, 95% confidence intervals, and P-values for the association between the genotypes and risk of PTC. The PTC patients were further subgrouped and compared with respect to their clinicopathological characteristics. RESULTS: 3 SNPs of IL-18 (rs549908, rs360717, and rs187238) and one of IL-18R (rs1420106) examined in this study were significantly associated with the development of PTC. The allelic frequencies of the 3 SNPs of IL-18 also showed significant association with lymph node metastasis. CONCLUSION: IL-18 and IL-18R polymorphisms may contribute to the development and lymph node metastasis of PTC. PMID- 26600056 TI - The Association between Bone Age Advancement and Insulin Resistance in Prepubertal Obese Children. AB - OBJECTIVE: Obesity is associated with bone age (BA) advancement, but the underlying mechanisms remain unclear. The objective of this study was to investigate the association between BA maturation and insulin levels in obese children. METHODS: In this cross-sectional study of 93 prepubertal obese children, anthropometric data and hormonal values were measured. Subjects were divided into 2 groups based on the difference between BA and chronological age (CA) (noted as BA-CA). RESULTS: The study population included 39 (41.9%) males and 54 (58.1%) females with a mean age of 7.4+/-1.5 years. The advanced bone age group defined as BA-CA>1 year (n=44) had significantly higher HOMA-IR and fasting insulin levels, and lower quantitative insulin sensitivity check index (QUICKI). BA-CA was significantly correlated with fasting insulin (r=0.255, P=0.014), HOMA IR (r=0.230, P=0.027), and QUICKI (r=- 0.301, P=0.003). Also, height SDS was significantly associated with DeltaBA-CA (r=0.417, P<0.001). In the multiple regression analysis, HOMA-IR was identified as a significant independent predictor of BA-CA. CONCLUSION: Bone age is more advanced in obese children with hyperinsulinemia and insulin resistance. These findings suggest that insulin may affect skeletal maturation. PMID- 26600057 TI - The Effect of Metformin and Metformin-Testosterone Combination on Cardiometabolic Risk Factors in Men with Late-onset Hypogonadism and Impaired Glucose Tolerance. AB - No previous study has investigated the effect of metformin, administered alone or together with testosterone, on cardiometabolic risk factors in men with hypogonadism. The study included 30 men with late-onset hypogonadism (LOH) and impaired glucose tolerance (IGT) who had been complying with lifestyle intervention. After 12 weeks of metformin treatment (1.7 g daily), the participants were allocated to one of 2 groups treated for the following 12 weeks with oral testosterone undecanoate (120 mg daily, n=15) or not receiving androgen therapy (n=15). Plasma lipids, glucose homeostasis markers, as well as plasma levels of androgens, uric acid, high-sensitivity C-reactive protein (hsCRP), homocysteine and fibrinogen were determined before and after 12 and 24 weeks of therapy with the final dose of metformin. Patients with LOH and IGT had higher levels of hsCRP, homocysteine and fibrinogen than subjects with only LOH (n=12) or only IGT (n=15). Metformin administered alone improved insulin sensitivity, as well as reduced 2-h postchallenge plasma glucose and triglycerides. Testosterone metformin combination therapy decreased also total and LDL cholesterol, uric acid, hsCRP, homocysteine and fibrinogen, as well as increased plasma testosterone. The effect of this combination therapy on testosterone, insulin sensitivity, hsCRP, homocysteine and fibrinogen was stronger than that of metformin alone. The obtained results indicate that IGT men with LOH receiving metformin may gain extra benefits if they are concomitantly treated with oral testosterone. PMID- 26600058 TI - Europium(III) tris-dibenzoylmethanate as an efficient chemosensor for detection of ammonia. AB - The effect of ammonia vapor on luminescence of Eu(III) tris-dibenzoylmethanate immobilized in various matrices has been investigated. It has been revealed that interaction of Eu(III) tris-dibenzoylmethanate with analyte vapor results in increase of the intensity of Eu(III) luminescence. The mechanism of the effect of ammonia vapors on intensification of the Eu(III) luminescence has been suggested using the data of IR spectroscopy, X-ray diffraction analysis and quantum chemistry calculations. The mechanism of luminescence sensitization consists in bonding of an analyte molecule with a water molecule into the coordination sphere of Eu(III). As a result, the bond of a water molecule with the luminescence centre weakens and the blockage of the quenching of luminescence on OH-vibrations takes place. PMID- 26600059 TI - What is the potential of dried matrix spot sampling for cerebrospinal fluid analysis? PMID- 26600060 TI - The 3rd China Bioanalysis Forum annual meeting. AB - The third China Bioanalysis Forum conference was successfully held in Shanghai in June 2015. This year's conference focused on biologics, biomarkers and regulated bioanalytical challenges. More than 150 delegates from pharmaceutical/biotech industry, CRO, clinical research centers, research institutes and regulatory agencies attended. This report summarizes the major discussion topics at the conference. PMID- 26600061 TI - View-Dependent Streamline Deformation and Exploration. AB - Occlusion presents a major challenge in visualizing 3D flow and tensor fields using streamlines. Displaying too many streamlines creates a dense visualization filled with occluded structures, but displaying too few streams risks losing important features. We propose a new streamline exploration approach by visually manipulating the cluttered streamlines by pulling visible layers apart and revealing the hidden structures underneath. This paper presents a customized view dependent deformation algorithm and an interactive visualization tool to minimize visual clutter in 3D vector and tensor fields. The algorithm is able to maintain the overall integrity of the fields and expose previously hidden structures. Our system supports both mouse and direct-touch interactions to manipulate the viewing perspectives and visualize the streamlines in depth. By using a lens metaphor of different shapes to select the transition zone of the targeted area interactively, the users can move their focus and examine the vector or tensor field freely. PMID- 26600062 TI - The Connected Scatterplot for Presenting Paired Time Series. AB - The connected scatterplot visualizes two related time series in a scatterplot and connects the points with a line in temporal sequence. News media are increasingly using this technique to present data under the intuition that it is understandable and engaging. To explore these intuitions, we (1) describe how paired time series relationships appear in a connected scatterplot, (2) qualitatively evaluate how well people understand trends depicted in this format, (3) quantitatively measure the types and frequency of misinter pretations, and (4) empirically evaluate whether viewers will preferentially view graphs in this format over the more traditional format. The results suggest that low-complexity connected scatterplots can be understood with little explanation, and that viewers are biased towards inspecting connected scatterplots over the more traditional format. We also describe misinterpretations of connected scatterplots and propose further research into mitigating these mistakes for viewers unfamiliar with the technique. PMID- 26600063 TI - A System for High-Resolution Topology Optimization. AB - A key requirement in 3D fabrication is to generate objects with individual exterior shapes and their interior being optimized to application-specific force constraints and low material consumption. Accomplishing this task is challenging on desktop computers, due to the extreme model resolutions that are required to accurately predict the physical shape properties, requiring memory and computational capacities going beyond what is currently available. Moreover, fabrication-specific constraints need to be considered to enable printability. To address these challenges, we present a scalable system for generating 3D objects using topology optimization, which allows to efficiently evolve the topology of high-resolution solids towards printable and light-weight-high-resistance structures. To achieve this, the system is equipped with a high-performance GPU solver which can efficiently handle models comprising several millions of elements. A minimum thickness constraint is built into the optimization process to automatically enforce printability of the resulting shapes. We further shed light on the question how to incorporate geometric shape constraints, such as symmetry and pattern repetition, in the optimization process. We analyze the performance of the system and demonstrate its potential by a variety of different shapes such as interior structures within closed surfaces, exposed support structures, and surface models. PMID- 26600064 TI - Common Variants in the Sex Hormone-Binding Globulin (SHBG) Gene Influence SHBG Levels in Women with Polycystic Ovary Syndrome. AB - BACKGROUND: Decreased sex hormone-binding globulin (SHBG) levels were associated with polycystic ovary syndrome (PCOS). SHBG polymorphisms associated with reduced SHBG production were tested for their association with PCOS, but with inconclusive results. We tested whether altered SHBG levels and SHBG variants were associated with PCOS. METHODS: The study subjects included 242 women with PCOS and 238 control women. SHBG genotyping was done by real-time PCR. RESULTS: Higher minor allele frequency of rs13894, rs858521 and rs727428 was seen in PCOS cases, and significant differences in rs858521 and rs727428 genotypes distribution were seen between PCOS cases and controls. Multivariate regression analysis confirmed the association of only rs727428 with PCOS. Though it was not statistically significant, serum SHBG levels were reduced according to rs727428 genotypes in PCOS cases than in controls. Carriage of rs727428 minor allele was associated with significant increases in free/bioactive testosterone in PCOS cases. Seven-locus (rs9898876-rs13894-rs858521-rs1799941-rs6257-rs6259-rs727428) haploview analysis showed increased frequency of GCCGTGA, GTCGTGA and GTCATGG, and reduced frequency of GTCGTGG haplotypes in PCOS cases than in controls, thus conferring disease susceptibility and protective nature to these haplotypes, respectively. CONCLUSION: Specific SHBG variants affecting serum SHBG levels and SHBG haplotypes are associated with PCOS, suggesting the role for SHBG as PCOS candidate gene. PMID- 26600065 TI - Phenolic compositions and antioxidant activities of grapefruit (Citrus paradisi Macfadyen) varieties cultivated in China. AB - The phenolic compounds in different fruit parts including the flavedos, albedos, segment membranes, juice vesicles and seeds of nine grapefruit varieties cultivated in China were determined and their antioxidant capacities were evaluated using three methods. Naringin and neohesperedin were the dominant flavonoids in all grapefruit tested. Fenghongtangmuxun and Jiwei flavedo had the highest contents of naringin (5666.82 MUg/g DW) and neohesperedin (1022 MUg/g DW), respectively. Gallic acid was the major phenolic acid in all grapefruit tested, and Jiwei juice vesicles had the highest content of gallic acid (343.7 MUg/g DW). Fenghongtangmuxun juice vesicles were rich in chlorogenic acid (110.23 MUg/g DW), caffeic acid (53.86 MUg/g DW) and ferulic acid (23.12 MUg/g DW). Overall, the flavedo was rich in flavonoid, while juice vesicle had high amounts of phenolic acid. The Jiwei, Fenghongtangmuxun, Maxu, Huoyan and Hongmaxu grapefruit cultivars contained more phenolics and exhibited higher antioxidant capacities than Shatianyou and Liangpingyou pummelos, and were good sources of natural phytochemical antioxidants. PMID- 26600066 TI - Co-ingestion of essence of chicken to moderate glycaemic response of bread. AB - Essence of chicken (EOC) beverage is a chicken meat extract, widely consumed in Asian countries for health benefits. EOC is a rich source of peptides and amino acids. White bread has become a popular staple food in all regions of Southeast Asia. A randomized controlled, crossover, non-blind trial was performed to investigate the role of EOC on glycaemic response (GR) of white bread. Ten healthy young subjects returned on five separate days for three glucose and two bread sessions. Subjects consumed bread or bread with EOC. The 120 min incremental area under the curve was significantly lower after consuming two bottles of EOC with bread than white bread alone. The glycaemic index (GI) of white bread was 83 and white bread with EOC 57. The co-ingestion of EOC may be a practical and simple way to reduce the GR of bread and other starch-based staples. PMID- 26600067 TI - Dietary phytochemical index and the risk of insulin resistance and beta-cell dysfunction: a prospective approach in Tehran lipid and glucose study. AB - BACKGROUND: In this study, we aimed to investigate the association of dietary phytochemical index (DPI) with insulin resistance, beta-cell dysfunction, and insulin sensitivity. METHODS: This longitudinal study was conducted on 1141 participants of the Tehran Lipid and Glucose Study. Dietary data were collected using a validated semi-quantitative FFQ with 168 food items at baseline and DPI was calculated. Fasting serum insulin and glucose were measured at baseline and again after a 3-year of follow-up. RESULTS: After 3-years of follow-up, the risk of hyperinsulinemia significantly decreased by 65 (OR = 0.35, 95% CI = 0.21-0.60) and 86% (OR = 0.14, 0.07-0.29), in the third and fourth quartile categories of DPI, respectively. The occurrence of insulin resistance and insulin insensitivity in participants with higher DPI was significantly lower than the others (OR = 0.48, 95% CI = 0.25-0.93 and OR = 0.11, 95% CI = 0.05-0.24, respectively). CONCLUSION: Higher consumption of phytochemical-rich foods may have protective effects against development of insulin resistance. PMID- 26600068 TI - Na2TeS3, Na2TeSe3-mP24, and Na2TeSe3-mC48: Crystal Structures and Optical and Electrical Properties of Sodium Chalcogenidotellurates(IV). AB - Pure samples of Na2TeS3 and Na2TeSe3 were synthesized by the reactions of stoichiometric amounts of the elements Na, Te, and Q (Q = S, Se) in the ratio 2:1:3. Both compounds are highly air- and moisture-sensitive. The crystal structures were determined by single-crystal X-ray diffraction. Yellow Na2TeS3 crystallizes in the space group P21/c. Na2TeSe3 exists in a low-temperature modification (Na2TeSe3-mP24, space group P21/c) and a high-temperature modification (Na2TeSe3-mC48, space group C2/c); both modifications are red. Density functional theory calculations confirmed the coexistence of both modifications of Na2TeSe3 because they are very close in energy (DeltaE = 0.18 kJ mol(-1)). To the contrary, hypothetic Na2TeS3-mC48 is significantly less favored (DeltaE = 1.8 kJ mol(-1)) than the primitive modification. Na2TeS3 and Na2TeSe3 mP24 are isotypic to Li2TeS3, whereas Na2TeSe3-mC48 crystallizes in its own structure type, which was first described by Eisenmann and Zagler. The title compounds have two common structure motifs. Trigonal TeQ3 pyramids form layers, and the Na atoms are surrounded by a distorted octahedral environment of chalcogen atoms. Raman spectra are dominated by the vibration modes of the TeQ3 units. The activation energies of the total conductivity of the title compounds range between 0.68 eV (Na2TeS3) and 1.1 eV (Na2TeSe3). Direct principal band gaps of 1.20 and 1.72 eV were calculated for Na2TeSe3 and Na2TeS3, respectively. The optical band gaps are in the range from 1.38 eV for Li2TeSe3 to 2.35 eV for Na2TeS3. PMID- 26600069 TI - TRPM2 channels in alveolar epithelial cells mediate bleomycin-induced lung inflammation. AB - Lung inflammation is a major adverse effect of therapy with the antitumor drug bleomycin (BLM). Transient receptor potential melastatin 2 (TRPM2) is a Ca(2+) permeable channel that is activated by oxidative stress through the production of ADP-ribose. We herein investigated whether TRPM2 channels contributed to BLM induced lung inflammation. The intratracheal instillation of BLM into wild-type (WT) mice increased the number of polymorphonuclear leukocytes (PMNs) and inflammatory cytokine levels in the lung. Increases in inflammatory markers in WT mice were markedly reduced in trpm2 knockout (KO) mice, which demonstrated that the activation of TRPM2 channels was involved in BLM-induced lung inflammation. The expression of TRPM2 mRNA was observed in alveolar macrophages, alveolar epithelial cells, and lung fibroblasts. Actually, TRPM2 protein was expressed in lung tissues. Of these, TRPM2 channels in epithelial cells were activated by the addition of H2O2 following a BLM pretreatment, resulting in the secretion of macrophage inflammatory protein-2 (MIP-2). The H2O2-induced activation of TRPM2 by the BLM pretreatment was blocked by the poly(ADP-ribose) polymerase (PARP) inhibitors PJ34 and 3-aminobenzamide. The accumulation of poly(ADP-ribose) in the nucleus, a marker for ADP-ribose production, was strongly induced by H2O2 following the BLM pretreatment. Furthermore, administration of PRAP inhibitors into WT mice markedly reduced recruitment of inflammatory cells and MIP-2 secretion induced by BLM instillation. These results suggest that the induction of MIP-2 secretion through the activation of TRPM2 channels in alveolar epithelial cells is an important mechanism in BLM-induced lung inflammation, and the TRPM2 activation is likely to be mediated by ADP-ribose production via PARP pathway. TRPM2 channels may be new therapeutic target for BLM-induced lung inflammation. PMID- 26600070 TI - The Synthetic Antimicrobial Peptide 19-2.5 Interacts with Heparanase and Heparan Sulfate in Murine and Human Sepsis. AB - Heparanase is an endo-beta-glucuronidase that cleaves heparan sulfate side chains from their proteoglycans. Thereby, heparanase liberates highly potent circulating heparan sulfate-fragments (HS-fragments) and triggers the fatal and excessive inflammatory response in sepsis. As a potential anti-inflammatory agent for sepsis therapy, peptide 19-2.5 belongs to the class of synthetic anti lipopolysaccharide peptides; however, its activity is not restricted to Gram negative bacterial infection. We hypothesized that peptide 19-2.5 interacts with heparanase and/or HS, thereby reducing the levels of circulating HS-fragments in murine and human sepsis. Our data indicate that the treatment of septic mice with peptide 19-2.5 compared to untreated control animals lowers levels of plasma heparanase and circulating HS-fragments and reduces heparanase activity. Additionally, mRNA levels of heparanase in heart, liver, lung, kidney and spleen are downregulated in septic mice treated with peptide 19-2.5 compared to untreated control animals. In humans, plasma heparanase level and activity are elevated in septic shock. The ex vivo addition of peptide 19-2.5 to plasma of septic shock patients decreases heparanase activity but not heparanase level. Isothermal titration calorimetry revealed a strong exothermic reaction between peptide 19-2.5 and heparanase and HS-fragments. However, a saturation character has been identified only in the peptide 19-2.5 and HS interaction. In conclusion, the findings of our current study indicate that peptide 19-2.5 interacts with heparanase, which is elevated in murine and human sepsis and consecutively attenuates the generation of circulating HS-fragments in systemic inflammation. Thus, peptide 19-2.5 seems to be a potential anti-inflammatory agent in sepsis. PMID- 26600071 TI - Colorimetric Detection of Some Highly Hydrophobic Flavonoids Using Polydiacetylene Liposomes Containing Pentacosa-10,12-diynoyl Succinoglycan Monomers. AB - Flavonoids are a group of plant secondary metabolites including polyphenolic molecules, and they are well known for antioxidant, anti-allergic, anti inflammatory and anti-viral propertied. In general, flavonoids are detected with various non-colorimetric detection methods such as column liquid chromatography, thin-layer chromatography, and electrochemical analysis. For the first time, we developed a straightforward colorimetric detection system allowing recognition of some highly hydrophobic flavonoids such as alpha-naphthoflavone and beta naphthoflavone, visually using 10,12-pentacosadiynoic acid (PCDA) derivatized with succinoglycan monomers isolated from Sinorhizobium meliloti. Besides changes in visible spectrum, we also demonstrate fluorescence changes using our detection system in the presence of those flavonoids. The succinoglycan monomers attached to PCDA molecules may function as an unstructured molecular capturer for some highly hydrophobic flavonoids by hydrophobic interactions, and transmit their molecular interactions as a color change throughout the PCDA liposome. PMID- 26600073 TI - Stroke survivors' perspectives on two novel models of inpatient rehabilitation: seven-day a week individual therapy or five-day a week circuit class therapy. AB - PURPOSE: To explore stroke survivors' perspectives of two novel models of inpatient physiotherapy, which provide an increased amount of therapy: five days a week circuit class therapy and seven days a week individual therapy. METHOD: This is a qualitative descriptive study using semi-structured interviews and thematic analysis. The participants were 10 purposively sampled stroke survivors in the post-acute phase of recovery, who had experienced seven days a week individual therapy or five days a week circuit group therapy during inpatient rehabilitation. RESULTS: Three main themes emerged from the data: Too much, too little or just right; My experience - alone and together; and Meeting my needs. Findings revealed considerable variety in participants' beliefs, priorities and preferences regarding how intensely they could work; their experience of success and challenge individually and collectively; and their need to have their own unique individual needs met. Lack of choice seemed to be a linking concept between the themes. CONCLUSION: In order to provide patient-centred services, novel methods of increased therapy must take into consideration the individual needs and preferences of the people accessing them. One model may not meet all these needs, hence a "menu" of options for therapy sessions (different timing, frequency, duration, content, rest and supervision) may be required to accommodate the diversity of patient needs, preferences and capacities. Implications for Rehabilitation People with stroke have diverse needs and preferences regarding the modes of delivering more therapy during rehabilitation. These diverse needs may not be met by one rigid service model. Therapists and service providers could engage their clients in a dialogue about the need for more therapy and how it can be delivered. This dialogue could include options of the various ways to increase their therapy. Therapists need to provide clear reasons and education around therapy components, including rest time and practice schedules. PMID- 26600074 TI - Is the Performance of a Specialist Herbivore Affected by Female Choices and the Adaptability of the Offspring? AB - The performance of herbivorous insects is related to the locations of defenses and nutrients found in the different plant organs on which they feed. In this context, the females of herbivorous insect species select certain parts of the plant where their offspring can develop well. In addition, their offspring can adapt to plant defenses. A system where these ecological relationships can be studied occurs in the specialist herbivore, Tuta absoluta, on tomato plants. In our experiments we evaluated: (i) the performance of the herbivore T. absoluta in relation to the tomato plant parts on which their offspring had fed, (ii) the spatial distribution of the insect stages on the plant canopy and (iii) the larval resistance to starvation and their walking speed at different instar stages. We found that the T. absoluta females preferred to lay their eggs in the tomato plant parts where their offspring had greater chances of success. We verified that the T. absoluta females laid their eggs on both sides of the leaves to better exploit resources. We also observed that the older larvae (3rd and 4th instars) moved to the most nutritious parts of the plant, thus increasing their performance. The T. absoluta females and offspring (larvae) were capable of identifying plant sites where their chances of better performance were higher. Additionally, their offspring (larvae) spread across the plant to better exploit the available plant nutrients. These behavioral strategies of T. absoluta facilitate improvement in their performance after acquiring better resources, which help reduce their mortality by preventing the stimulation of plant defense compounds and the action of natural enemies. PMID- 26600075 TI - Development and evaluation of a rigid esophagoscopy simulator for residency training. AB - OBJECTIVES/HYPOTHESIS: Rigid esophagoscopy is performed less frequently by resident trainees. Nonetheless, it remains important for certain indications, including foreign body extraction. This study describes the construction of a simulator and evaluates its utility in training residents. STUDY DESIGN: Simulator development, fabrication, and procedural evaluation of postgraduate trainees. METHODS: A simulator was developed and constructed in collaboration with a biomedical engineering team. Residents with varied experience in upper aerodigestive procedures performed rigid esophagoscopy on the model. Key steps and Accreditation Council for Graduate Medical Education's Objective Structured Assessment of Technical Skills (OSATS) criteria for rigid esophagoscopy were evaluated by a faculty surgeon. Pressure measurements were obtained from force sensors at the tip of the endoscope and incisors. RESULTS: Fourteen trainees were evaluated. Operative rigid esophagoscopy and direct laryngoscopy case numbers were noted for each subject. OSATS scores and key steps of the procedure correlated with resident experience (R(2) = 0.75, P < .0001 and R(2) = 0.66, P < .001, respectively). Maximal pressure exerted on the simulator esophagus by the esophagoscope was inversely correlated with case number and was statistically significant (R(2) = 0.51, P = .02), whereas length of procedure did not correlate (R(2) = 0.04, P = .49). Maximal pressure on the incisors did not correlate (R(2) = 0.25, P = .15). CONCLUSIONS: A simulator for training residents to perform rigid esophagoscopy was developed and utilized by a faculty proctor to objectively evaluate trainees. OSATS scores, performance of key procedural steps, and pressure exerted on the simulator tissue correlated with upper aerodigestive cases performed, demonstrating validity of the simulator. LEVEL OF EVIDENCE: NA Laryngoscope, 126:616-619, 2016. PMID- 26600076 TI - Cationic Methylene-Pyrene Isomers and Isomerization Pathways: Finite Temperature Theoretical Studies. AB - This paper provides spectral characterizations of the two isomers of the 1 methylenepyrene cation, namely, the 1-pyrenemethylium and a pyrene-like isomer owing a tropylium cycle. Both are possible photodissociation products of the 1 methylpyrene cation and were proposed as potential contributors to the diffuse interstellar bands. In that respect, vibrational and electronic spectra are computed for the optimized structures at the density functional theory (DFT) and time-dependent (TD-)DFT levels. Finite temperature effects on these spectra are estimated from molecular dynamics simulations within the density functional-based tight-binding (DFTB) and TD-DFTB frameworks, these methods being first benchmarked against DFT and TD-DFT calculations. The computed spectra allow discrimination of the two isomers. When the temperature increases, bands are observed to redshift and merge. The isomerization mechanism is investigated with the metadynamics technique, a biased dynamics scheme allowing to probe reaction mechanisms with high energy barriers by investigating the free energy surface at various temperatures. Four pathways with similar barrier heights (3.5-4 eV) are found, showing that the interconversion process would only occur in interstellar clouds under photoactivation. The present study opens the way to simulations on larger methyl- and methylenePAHs of astrophysical interest and their experimental investigation. PMID- 26600077 TI - Tracing the fate of carbon and the atmospheric evolution of Mars. AB - The climate of Mars likely evolved from a warmer, wetter early state to the cold, arid current state. However, no solutions for this evolution have previously been found to satisfy the observed geological features and isotopic measurements of the atmosphere. Here we show that a family of solutions exist, invoking no missing reservoirs or loss processes. Escape of carbon via CO photodissociation and sputtering enriches heavy carbon ((13)C) in the Martian atmosphere, partially compensated by moderate carbonate precipitation. The current atmospheric (13)C/(12)C and rock and soil carbonate measurements indicate an early atmosphere with a surface pressure <1 bar. Only scenarios with large amounts of carbonate formation in open lakes permit higher values up to 1.8 bar. The evolutionary scenarios are fully testable with data from the MAVEN mission and further studies of the isotopic composition of carbonate in the Martian rock record through time. PMID- 26600078 TI - The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota. AB - Several animal studies have emphasized the role of gut microbiota in nonalcoholic fatty liver disease (NAFLD). However, data about gut dysbiosis in human NAFLD remain scarce in the literature, especially studies including the whole spectrum of NAFLD lesions. We aimed to evaluate the association between gut dysbiosis and severe NAFLD lesions, that is, nonalcoholic steatohepatitis (NASH) and fibrosis, in a well-characterized population of adult NAFLD. Fifty-seven patients with biopsy-proven NAFLD were enrolled. Taxonomic composition of gut microbiota was determined using 16S ribosomal RNA gene sequencing of stool samples. Thirty patients had F0/F1 fibrosis stage at liver biopsy (10 with NASH), and 27 patients had significant F>=2 fibrosis (25 with NASH). Bacteroides abundance was significantly increased in NASH and F>=2 patients, whereas Prevotella abundance was decreased. Ruminococcus abundance was significantly higher in F>=2 patients. By multivariate analysis, Bacteroides abundance was independently associated with NASH and Ruminococcus with F>=2 fibrosis. Stratification according to the abundance of these two bacteria generated three patient subgroups with increasing severity of NAFLD lesions. Based on imputed metagenomic profiles, Kyoto Encyclopedia of Genes and Genomes pathways significantly related to NASH and fibrosis F>=2 were mostly related to carbohydrate, lipid, and amino acid metabolism. CONCLUSION: NAFLD severity associates with gut dysbiosis and a shift in metabolic function of the gut microbiota. We identified Bacteroides as independently associated with NASH and Ruminococcus with significant fibrosis. Thus, gut microbiota analysis adds information to classical predictors of NAFLD severity and suggests novel metabolic targets for pre-/probiotics therapies. PMID- 26600080 TI - The development of the abilities to acquire novel detailed orthographic representations and maintain them in long-term memory. AB - Previous studies have clearly demonstrated that the development of orthographic representations relies on phonological recoding. However, substantial questions persist about the remaining unexplained variance in the acquisition of word specific orthographic knowledge that is still underspecified. The main aim of this study was to explore whether two cognitive factors-sensitivity to orthographic regularities and short-term memory (STM) for serial order-make independent contributions to the acquisition of novel orthographic representations beyond that of the phonological core component and the level of preexisting word-specific orthographic knowledge. To this end, we had children from second to sixth grades learn novel written word forms using a repeated spelling practice paradigm. The speed at which children learned the word forms and their long-term retention (1week and 1month later) were assessed. Hierarchical regression analyses revealed that phonological recoding, preexisting word-specific orthographic knowledge, and order STM explained a portion of the variance in orthographic learning speed, whereas phonological recoding, preexisting word-specific orthographic knowledge, and orthographic sensitivity each explained a portion of variance in the long-term retention of the newly created orthographic representations. A secondary aim of the study was to determine the developmental trajectory of the abilities to acquire novel orthographic word forms over the course of primary schooling. As expected, results showed an effect of age on both learning speed and long-term retention. The specific roles of orthographic sensitivity and order STM as independent factors involved in different steps of orthographic learning are discussed. PMID- 26600079 TI - Interleukin-15 Constrains Mucosal T Helper 17 Cell Generation: Influence of Mononuclear Phagocytes. AB - Interleukin (IL)-15 has multiple roles in innate and adaptive immunity, especially regarding CD8+ T cells and natural killer cells. However, the role of IL-15 in regulating differentiation of T helper cell subsets and mononuclear phagocytes (MPs) in different tissues in vivo is unknown. Here we report that IL 15 indirectly regulates Th17 but not other Th subsets in the intestinal lamina propria (LP), apparently through effects on MPs. Th17 cells in the LP were more prevalent in IL-15 KO mice than their wild-type counterparts, and less prevalent in IL-15 transgenic mice than their wild-type littermates, even co-caged. MPs from the LP of these mice were sufficient to mimic the in vivo finding in vitro by skewing of cocultured wild type OVA-specific CD4+ T cells. However, production of IL-15 or lack thereof by these MPs was not sufficient to explain the skewing, as addition or blockade of IL-15 in the cultures had no effect. Rather, a skewing of the relative proportion of CD11b+, CD103+ and double positive LP MP subsets in transgenic and KO could explain the differences in Th17 cells. Thus, IL-15 may influence MP subsets in the gut in a novel way that alters the frequency of LP Th17 cells. PMID- 26600081 TI - Multifocal tuberculosis of long bones in an immunocompetent child. AB - Although tuberculosis (TB) is prevalent in many parts of the world, multifocal TB involvement of bones is rare. It is believed that less than 5% of skeletal TB is multifocal. We report a case of multifocal TB of long bones in an immunocompetent child. We describe the radiological and diagnostic features of TB osteomyelitis and outline its therapy and prognosis. To the best of the authors' knowledge, such a case with multiple long bone involvement without articular sequel and visceral involvement/constitutional symptoms has not been reported previously in the literature. PMID- 26600082 TI - Post-traumatic cyst-like lesion in children: case report and the literature review. AB - Reports of post-traumatic cyst-like lesions in children are rare. These lesions occur between 1.5 and 3 months after a fracture. They are more frequent after a distal radius greenstick fracture. Conventional radiographs show a metaphyseal radiolucent lesion inside the most recent subperiosteal bone, adjacent to the initial fracture line. Post-traumatic cyst-like lesions are benign, asymptomatic, nonexpansive, and regress spontaneously. Two typical cases are described in the following report with a literature review of the etiology and main features of these lesions. PMID- 26600083 TI - "They See Us As Machines:" The Experience of Recent Immigrant Women in the Low Wage Informal Labor Sector. AB - This study explores the organization of work and occupational health risk as elicited from recently immigrated women (n = 8) who have been in the US for less than three years and employed in informal work sectors such as cleaning and factory work in the greater Boston area in Massachusetts. Additional interviews (n = 8) with Community Key Informants with knowledge of this sector and representatives of temporary employment agencies in the area provides further context to the interviews conducted with recent immigrant women. These results were also compared with our immigrant occupational health survey, a large project that spawned this study. Responses from the study participants suggest health outcomes consistent with being a day-laborer scholarship, new immigrant women are especially at higher risk within these low wage informal work sectors. A difference in health experiences based on ethnicity and occupation was also observed. Low skilled temporary jobs are fashioned around meeting the job performance expectations of the employer; the worker's needs are hardly addressed, resulting in low work standards, little worker protection and poor health outcomes. The rising prevalence of non-standard employment or informal labor sector requires that policies or labor market legislation be revised to meet the needs presented by these marginalized workers. PMID- 26600084 TI - Cigarette Smoke Induces Human Epidermal Receptor 2-Dependent Changes in Epithelial Permeability. AB - The airway epithelium constitutes a protective barrier against inhaled insults, such as viruses, bacteria, and toxic fumes, including cigarette smoke (CS). Maintenance of bronchial epithelial integrity is central for airway health, and defective epithelial barrier function contributes to the pathogenesis of CS mediated diseases, such as chronic obstructive pulmonary disease. Although CS has been shown to increase epithelial permeability, current understanding of the mechanisms involved in CS-induced epithelial barrier disruption remains incomplete. We have previously identified that the receptor tyrosine kinase human epidermal receptor (HER) 2 growth factor is activated by the ligand neuregulin-1 and increases epithelial permeability in models of inflammatory acute lung injury. We hypothesized that CS activates HER2 and that CS-mediated changes in barrier function would be HER2 dependent in airway epithelial cells. We determined that HER2 was activated in whole lung, as well as isolated epithelial cells, from smokers, and that acute CS exposure resulted in HER2 activation in cultured bronchial epithelial cells. Mechanistic studies determined that CS mediated HER2 activation is independent of neuregulin-1 but required upstream activation of the epidermal growth factor receptor. HER2 was required for CS induced epithelial permeability as knockdown of HER2 blocked increases in permeability after CS. CS caused an increase in IL-6 production by epithelial cells that was dependent on HER2-mediated extracellular signal-regulated kinases (Erk) activation. Finally, blockade of IL-6 attenuated CS-induced epithelial permeability. Our data indicate that CS activates pulmonary epithelial HER2 and that HER2 is a central mediator of CS-induced epithelial barrier dysfunction. PMID- 26600085 TI - Best-practice pain management in the emergency department: A cluster-randomised, controlled, intervention trial. AB - OBJECTIVES: We aimed to provide 'adequate analgesia' (which decreases the pain score by >=2 and to <4 [0-10 scale]) and determine the effect on patient satisfaction. METHODS: We undertook a multicentre, cluster-randomised, controlled, intervention trial in nine EDs. Patients with moderate pain (pain score of >=4) were eligible for inclusion. The intervention was a range of educational activities to encourage staff to provide 'adequate analgesia'. It was introduced into five early intervention EDs between the 0 and 6 months time points and at four late intervention EDs between 3 and 6 months. At 0, 3 and 6 months, data were collected on demographics, pain scores, analgesia provided and pain management satisfaction 48 h post-discharge (6 point scale). RESULTS: Overall, 1317 patients were enrolled. Logistic regression (controlling for site and other confounders) indicated that, between 0 and 3 months, satisfaction increased significantly at the early intervention EDs (OR 2.2, 95% CI 1.5 to 3.4 [P < 0.01]) but was stable at the control EDs (OR 0.8, 95% CI 0.5 to 1.3 [P = 0.35]). Pooling of data from all sites indicated that the proportion of patients very satisfied with their pain management increased from 42.9% immediately pre intervention to 53.9% after 3 months of intervention (difference in proportions 11.0%, 95% CI 4.2 to 17.8 [P = 0.001]). Logistic regression of all data indicated that 'adequate analgesia' was significantly associated with patient satisfaction (OR 1.4, 95% CI 1.1 to 1.8 [P < 0.01]). CONCLUSIONS: The 'adequate analgesia' intervention significantly improved patient satisfaction. It provides a simple and efficient target in the pursuit of best-practice ED pain management. PMID- 26600086 TI - Coronary Atherosclerotic Plaque Detected by Computed Tomographic Angiography in Subjects with Diabetes Compared to Those without Diabetes. AB - OBJECTIVES: Little data are available regarding coronary plaque composition and semi-quantitative scores in individuals with diabetes; the extent to which diabetes may affect the presence and extent of Coronary Artery Calcium (CAC) needs more evaluation. Considering that this information may be of great value in formulating preventive interventions in this population, we compared these findings in individuals with diabetes to those without. METHODS: Multi-Detector Computed Tomographic (MDCT) images of 861 consecutive patients with diabetes who were referred to Los Angeles Biomedical Research Institute from January 2000 to September 2012, were evaluated using a 15-coronary segment model. All 861 patients underwent calcium scoring and from these; 389 had coronary CT angiography (CTA). CAC score was compared to 861 age, sex and ethnicity matched controls without diabetes after adjustment for Body Mass Index (BMI), family history of coronary artery disease, hyperlipidemia, hypertension and smoking. Segment Involvement Score (SIS; the total number of segments with any plaque), Segment Stenosis Score (SSS; the sum of maximal stenosis score per segment), Total Plaque Score (TPS; the sum of the plaque amount per segment) and plaque compositionwere compared to 389 age, sex and ethnicity matched controls without diabetes after adjustment for BMI, family history of coronary artery disease, hyperlipidemia, hypertension and smoking. RESULTS: Diabetes was positively correlated to the presence and extent of CAC (P<0.0001 for both). SIS, SSS and TPS were significantly higher in those with diabetes (P<0.0001). Number of mixed and calcified plaques were significantly higher in those with diabetes (P = 0.018 and P<0.001 respectively) but there was no significant difference in the number of non-calcified plaques between the two groups (P = 0.398). CONCLUSIONS: Patients with diabetes have higher CAC and semi-quantitative coronary plaque scores compared to the age, gender and ethnicity matched controls without diabetes after adjustment for cardiovascular risk factors. Since mixed plaque is associated with worse long-term clinical outcomes, these findings support more aggressive preventive measures in this population. PMID- 26600087 TI - Lateralized goal framing: How health messages are influenced by valence and contextual/analytic processing. AB - The effectiveness of health messages has been shown to vary due to the positive or negative framing of information, often known as goal framing. In two experiments we altered, the strength of the goal framing manipulation by selectively activating the processing style of the left or right hemisphere (RH). In Experiment 1, we found support for the contextual/analytic perspective; a significant goal framing effect was observed when the contextual processing style of the RH - but not the analytic processing style of the left hemisphere (LH) - was initially activated. In Experiment 2, support for the valence hypothesis was found when a message that had a higher level of personal involvement was used than that in Experiment 1. When the LH was initially activated, there was an advantage for the gain- vs. loss-framed message; however, an opposite pattern - an advantage for the loss-framed message - was obtained when the RH was activated. These are the first framing results that support the valence hypothesis. We discuss the theoretical and applied implications of these experiments. PMID- 26600088 TI - Is in vivo amyloid distribution asymmetric in primary progressive aphasia? AB - We aimed to determine whether (18) F-florbetapir amyloid positron emission tomography imaging shows a clinically concordant, left-hemisphere-dominant pattern of deposition in primary progressive aphasia (PPA). Elevated cortical amyloid (Abeta(+) ) was found in 19 of 32 PPA patients. Hemispheric laterality of amyloid burden was compared between Abeta(+) PPA and an Abeta(+) amnestic dementia groups (n = 22). The parietal region showed significantly greater left lateralized amyloid uptake in the PPA group than the amnestic group (p < 0.007), consistent with the left lateralized pattern of neurodegeneration in PPA. These results suggest that the cortical distribution of amyloid may have a greater clinical concordance than previously reported. PMID- 26600089 TI - Loading of Silica Nanoparticles in Block Copolymer Vesicles during Polymerization Induced Self-Assembly: Encapsulation Efficiency and Thermally Triggered Release. AB - Poly(glycerol monomethacrylate)-poly(2-hydroxypropyl methacrylate) diblock copolymer vesicles can be prepared in the form of concentrated aqueous dispersions via polymerization-induced self-assembly (PISA). In the present study, these syntheses are conducted in the presence of varying amounts of silica nanoparticles of approximately 18 nm diameter. This approach leads to encapsulation of up to hundreds of silica nanoparticles per vesicle. Silica has high electron contrast compared to the copolymer which facilitates TEM analysis, and its thermal stability enables quantification of the loading efficiency via thermogravimetric analysis. Encapsulation efficiencies can be calculated using disk centrifuge photosedimentometry, since the vesicle density increases at higher silica loadings while the mean vesicle diameter remains essentially unchanged. Small angle X-ray scattering (SAXS) is used to confirm silica encapsulation, since a structure factor is observed at q ~ 0.25 nm(-1). A new two population model provides satisfactory data fits to the SAXS patterns and allows the mean silica volume fraction within the vesicles to be determined. Finally, the thermoresponsive nature of the diblock copolymer vesicles enables thermally triggered release of the encapsulated silica nanoparticles simply by cooling to 0 10 degrees C, which induces a morphological transition. These silica-loaded vesicles constitute a useful model system for understanding the encapsulation of globular proteins, enzymes, or antibodies for potential biomedical applications. They may also serve as an active payload for self-healing hydrogels or repair of biological tissue. Finally, we also encapsulate a model globular protein, bovine serum albumin, and calculate its loading efficiency using fluorescence spectroscopy. PMID- 26600090 TI - From Checklists to Tools: Lowering the Barrier to Better Research Reporting. PMID- 26600091 TI - Adsorption deformation of microporous composites. AB - We study here the behavior of flexible adsorbent materials, or soft porous crystals, when used in practical applications as nanostructured composites such as core-shell particles or mixed matrix membranes. Based on simple models and the well-established laws of elasticity, we demonstrate how the presence of a binder results in an attenuation of the adsorption-induced stress and deformation. In the case where the adsorbent undergoes adsorption-induced structural transitions, such as the gate opening phenomenon occurring in some metal-organic frameworks, we show that the presence of the binder will result in shifts of the adsorption induced transition pressures. PMID- 26600092 TI - Hypodontia, a prospective predictive marker for tumor? AB - Tooth agenesis and tumor are two totally different diseases occurring at different ages. In the past 10 years, more and more evidences suggested there was a relationship between them. High prevalence of breast, colon, lung, and ovary tumor was observed in tooth agenesis patients. But it is still controversial. Therefore, to have a greater understanding of the possible association, a critical review on molecular association for genes involving tooth agenesis and tumorigenesis is necessary. In this current review, we summarized the reported cases of tooth agenesis with different kinds of tumors and the molecular relationship between these two diseases through causative genes. The results indicated tooth agenesis might be a prospective predictive marker for tumor. Through this review, we want to draw more attention on this topic and hope it will be an effective way to predict the risk of tumor. PMID- 26600093 TI - Ochratoxin A in red pepper flakes commercialised in Turkey. AB - The aim of this study was to investigate the presence of Ochratoxin A (OTA) in red pepper flakes commercialised in Turkey. A total of 75 samples were collected from different supermarkets and traditional bazaars in Istanbul during 2012-2013. OTA analysis was performed by high-performance liquid chromatography equipped with fluorescence detection after immunoaffinity column clean-up. The method was linear in the range 0.05-40 MUg kg(-1) (r(2) = 0.9997). Twenty-seven out of 31 (87.1%) packed red pepper flake samples contained OTA at concentrations ranging from 0.6 to 1.0 MUg kg(-1), whereas 100% of the unpacked red pepper flake samples contained OTA, in the range 1.1-31.7 MUg( )kg(-1). Overall, only 4 unpacked samples (5.3%) contained OTA, with a mean value of 23.4 MUg kg(-1), which is higher than the European Union limit. It is suggested that OTA content should be carefully considered in red pepper flake samples especially marketed in unpacked form. PMID- 26600094 TI - Molecular epidemiology of norovirus in children and the elderly in Atlanta, Georgia, United States. AB - Noroviruses are an important cause of gastroenteritis, which can be severe at the extremes of ages. Data documenting the endemic burden of norovirus among children and elderly adults are lacking. Stool specimens submitted for clinical testing were collected from elderly (>= 65 years) adults and children (<18 years) with acute vomiting and/or diarrhea seeking care at several metropolitan Atlanta adult and pediatric hospitals from January 2013-June 2013. Specimens were tested for norovirus with real-time RT-PCR and sequenced if norovirus was detected. Corresponding clinical and demographic data were abstracted from retrospective chart review. Norovirus was detected in 11% (11/104) of elderly specimens and 11% (67/628) of pediatric, with GII.4 Sydney_2012 detected in 64% (7/11) of elderly norovirus-positive and 11% (8/67) of pediatric specimens, P < 0.001. In comparison to hospitalized children, hospitalized elderly with norovirus were more commonly admitted to the intensive care unit (ICU) (36% vs. 7%, P = 0.02). Norovirus in the elderly can be associated with severe illness requiring ICU admissions. The pediatric group demonstrated greater variability in genotype distribution. Ongoing surveillance of norovirus genotypes is crucial for norovirus vaccine development in understanding circulating and emerging genotypes. PMID- 26600095 TI - Driving behaviour responses to a moose encounter, automatic speed camera, wildlife warning sign and radio message determined in a factorial simulator study. AB - In a driving simulator study, driving behaviour responses (speed and deceleration) to encountering a moose, automatic speed camera, wildlife warning sign and radio message, with or without a wildlife fence and in dense forest or open landscape, were analysed. The study consisted of a factorial experiment that examined responses to factors singly and in combination over 9-km road stretches driven eight times by 25 participants (10 men, 15 women). The aims were to: determine the most effective animal-vehicle collision (AVC) countermeasures in reducing vehicle speed and test whether these are more effective in combination for reducing vehicle speed; identify the most effective countermeasures on encountering moose; and determine whether the driving responses to AVC countermeasures are affected by the presence of wildlife fences and landscape characteristics. The AVC countermeasures that proved most effective in reducing vehicle speed were a wildlife warning sign and radio message, while automatic speed cameras had a speed-increasing effect. There were no statistically significant interactions between different countermeasures and moose encounters. However, there was a tendency for a stronger speed-reducing effect from the radio message warning and from a combination of a radio message and wildlife warning sign in velocity profiles covering longer driving distances than the statistical tests. Encountering a moose during the drive had the overall strongest speed reducing effect and gave the strongest deceleration, indicating that moose decoys or moose artwork might be useful as speed-reducing countermeasures. Furthermore, drivers reduced speed earlier on encountering a moose in open landscape and had lower velocity when driving past it. The presence of a wildlife fence on encountering the moose resulted in smaller deceleration. PMID- 26600096 TI - Flushing the liver with urokinase before transplantation does not prevent nonanastomotic biliary strictures. AB - The aim of the present study was to assess whether flushing the donor liver with urokinase immediately before implantation reduces the incidence of nonanastomotic biliary strictures (NASs) after liver transplantation, without causing increased blood loss, analyzed as a historical cohort study. Between January 2005 and October 2012, all liver (re-)transplantations were included. Of the 185 liver transplant recipients included, 63 donor livers between January 2010 and October 2012 received urokinase (study group), whereas the donor liver of 122 consecutive recipients, who served as a historical control group, between January 2005 and January 2010 did not receive urokinase. Basic donor (Eurotransplant donor risk index) and recipient (age, body mass index, laboratory Model for End-Stage Liver Disease score) characteristics did not significantly differ in both groups. Thirty-three recipients developed NASs: 22 in the control group (18%) and 11 (17.5%) in the study group (P = 0.68). Analyzed separately for donation after circulatory death (P = 0.42) or donation after brain death (P = 0.89), there was no difference between the groups in incidence of NAS. Of all the recipients developing NAS, 7 (21%) needed retransplantation and all others were treated conservatively. Autologous blood transfusion requirements did not differ significantly between both groups (P = 0.91), whereas interestingly, more heterologous blood transfusions were needed in the control group (P < 0.001). This study has its limitations by its retrospective character. A multi institutional prospective study could clarify this issue. In conclusion, arterial flushing of the liver with urokinase immediately before implantation did not lead to a lower incidence of NAS in this study, nor did it lead to increased blood loss. PMID- 26600097 TI - High Stability Electron Field Emitters Synthesized via the Combination of Carbon Nanotubes and N2-Plasma Grown Ultrananocrystalline Diamond Films. AB - An electron field emitter with superior electron field emission (EFE) properties and improved lifetime stability is being demonstrated via the combination of carbon nanotubes and the CH4/N2 plasma grown ultrananocrystalline diamond (N UNCD) films. The resistance of the carbon nanotubes to plasma ion bombardment is improved by the formation of carbon nanocones on the side walls of the carbon nanotubes, thus forming strengthened carbon nanotubes (s-CNTs). The N-UNCD films can thus be grown on s-CNTs, forming N-UNCD/s-CNTs carbon nanocomposite materials. The N-UNCD/s-CNTs films possess good conductivity of sigma = 237 S/cm and marvelous EFE properties, such as low turn-on field of (E0) = 3.58 V/MUm with large EFE current density of (J(e)) = 1.86 mA/cm(2) at an applied field of 6.0 V/MUm. Moreover, the EFE emitters can be operated under 0.19 mA/cm(2) for more than 350 min without showing any sign of degradation. Such a superior EFE property along with high robustness characteristic of these combination of materials are not attainable with neither N-UNCD films nor s-CNTs films alone. Transmission electron microscopic investigations indicated that the N-UNCD films contain needle-like diamond grains encased in a few layers of nanographitic phase, which enhanced markedly the transport of electrons in the N-UNCD films. Moreover, the needle-like diamond grains were nucleated from the s-CNTs without the necessity of forming the interlayer that facilitate the transport of electrons crossing the diamond-to-Si interface. Both these factors contributed to the enhanced EFE behavior of the N-UNCD/s-CNTs films. PMID- 26600098 TI - Pd-Co3[Co(CN)6]2 hybrid nanoparticles: preparation, characterization, and challenge for the Suzuki-Miyaura coupling of aryl chlorides under mild conditions. AB - Because of their abundance and low cost, organo chlorides are the most desirable substrates from the industrial point of view in Suzuki-Miyaura cross-coupling reactions. However, catalytic application of Pd nanoparticles (NPs) for Suzuki coupling of aryl chlorides is still a challenge. Here, we design a novel catalyst by combining Pd NPs with Co3[Co(CN)6]2 nanocrystals for Suzuki-Miyaura coupling of aryl chlorides. This nanocatalyst demonstrated good activity (yield 86.2% at 80 degrees C), high TOF, great stability, easy separation, excellent reusability (initial rates were not reduced after five cycles) and low cost in Suzuki reactions. PMID- 26600099 TI - The Relationship Between Sleep Disturbances and Psychiatric Disorders: Introduction and Overview. AB - Changes in the psychiatric diagnostic guidelines with the transition from Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV to DSM-V include acknowledgment that primary sleep disorders such as insomnia can occur in conjunction with medical and psychiatric disorders. This change in viewpoint regarding the definition of primary sleep disorders opens the way to the recognition that patients with psychiatric disorders demonstrate a high prevalence of sleep disturbances, with complaints of insomnia and excessive daytime sleepiness being especially commonly reported. Recent investigations have pointed to a bidirectional relationship between sleep disturbances and psychiatric disorders. PMID- 26600102 TI - Genetics of Sleep Disorders. AB - Sleep disorders are, in part, attributable to genetic variability across individuals. There has been considerable progress in understanding the role of genes for some sleep disorders, such as the identification of a human leukocyte antigen gene for narcolepsy. For other sleep disorders, such as insomnia, little work has been done. Optimizing phenotyping strategies is critical, as is the case for sleep apnea, for which intermediate traits such as obesity and craniofacial features may prove to be more tractable for genetic studies. Rapid advances in genotyping and statistical genetics are likely to lead to greater discoveries in the near future. PMID- 26600103 TI - Primary Sleep Disorders. AB - Primary sleep disorders include those not attributable to another medical or psychiatric condition: insomnia disorder, hypersomnolence disorder, narcolepsy, obstructive sleep apnea hypopnea syndrome, central sleep apnea syndrome, and the parasomnias. They are commonly encountered and are comorbid with many psychiatric disorders. It is important to recognize these disorders and be comfortable treating them or to know when to refer to a sleep disorders center and sleep specialist. Treatment of a comorbid sleep disorder can improve the overall quality of life, symptoms in mood disorders, and symptoms of excessive daytime sleepiness, and decrease cardiovascular morbidity and mortality. PMID- 26600104 TI - Sleep Disturbances and Behavioral Disturbances in Children and Adolescents. AB - Sleep deprivation and sleep disorders are commonly seen in children and adolescents. They are often undiagnosed and undertreated. A balance of circadian rhythm and homeostatic drive determine sleep quality, quantity, and timing, which changes across the developmental years. Environmental and lifestyle factors can affect sleep quality and quantity and lead to sleep deprivation. A comprehensive assessment of sleep disorders includes parental report, children's self-report, and school functioning. Diagnostic tools are used in diagnosing and treating sleep disorders. PMID- 26600101 TI - The Neurobiology of Circadian Rhythms. AB - There is a growing recognition that the coordinated timing of behavioral, physiologic, and metabolic circadian rhythms is a requirement for a healthy body and mind. In mammals, the primary circadian oscillator is the hypothalamic suprachiasmatic nucleus (SCN), which is responsible for circadian coordination throughout the organism. Temporal homeostasis is recognized as a complex interplay between rhythmic clock gene expression in brain regions outside the SCN and in peripheral organs. Abnormalities in this intricate circadian orchestration may alter sleep patterns and contribute to the pathophysiology of affective disorders. PMID- 26600105 TI - Sleep Disturbances in the Elderly. AB - Sleep disturbances are a common presenting symptom of older-age adults to their physicians. This article explores normal changes in sleep pattern with aging and primary sleep disorders in the elderly. Behavioral factors and primary psychiatric disorders affecting sleep in this population are reviewed. Further discussion examines sleep changes associated with 2 common forms of neurocognitive disorder: Alzheimer disease and Lewy Body Dementia. Common medical illnesses in the elderly are discussed in relation to sleep symptoms. Nonpharmacological and pharmacologic treatment strategies are summarized, with emphasis placed on risk of side effects in older adults. Future targets are considered. PMID- 26600106 TI - Sleep Disturbances in Mood Disorders. AB - The article provides an overview of common and differentiating self-reported and objective sleep disturbances seen in mood-disordered populations. The importance of considering sleep disturbances in the context of mood disorders is emphasized, because a large body of evidence supports the notion that sleep disturbances are a risk factor for onset, exacerbation, and relapse of mood disorders. In addition, potential mechanisms for sleep disturbance in depression, other primary sleep disorders that often occur with mood disorders, effects of antidepressant and mood-stabilizing drugs on sleep, and the adjunctive effect of treating sleep in patients with mood disorders are discussed. PMID- 26600100 TI - The Neurobiology of Sleep and Wakefulness. AB - Cortical electroencephalographic activity arises from corticothalamocortical interactions, modulated by wake-promoting monoaminergic and cholinergic input. These wake-promoting systems are regulated by hypothalamic hypocretin/orexins, while GABAergic sleep-promoting nuclei are found in the preoptic area, brainstem and lateral hypothalamus. Although pontine acetylcholine is critical for REM sleep, hypothalamic melanin-concentrating hormone/GABAergic cells may "gate" REM sleep. Daily sleep-wake rhythms arise from interactions between a hypothalamic circadian pacemaker and a sleep homeostat whose anatomical locus has yet to be conclusively defined. Control of sleep and wakefulness involves multiple systems, each of which presents vulnerability to sleep/wake dysfunction that may predispose to physical and/or neuropsychiatric disorders. PMID- 26600107 TI - Recent Advances in the Study of Sleep in the Anxiety Disorders, Obsessive Compulsive Disorder, and Posttraumatic Stress Disorder. AB - Sleep disturbance is frequently associated with generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, and posttraumatic stress disorder. This article reviews recent advances in understanding the mechanisms of the sleep disturbances in these disorders and discusses the implications for developing improved treatments. PMID- 26600108 TI - Sleep Disturbances in Schizophrenia. AB - Sleep disturbances are prevalent in patients with schizophrenia and play a critical role in the morbidity and mortality associated with the illness. Subjective and objective assessments of sleep in patients with schizophrenia have identified certain consistent findings. Findings related to the sleep structure abnormalities have shown correlations with important clinical aspects of the illness. Disruption of specific neurotransmitter systems and dysregulation of clock genes may play a role in the pathophysiology of schizophrenia-related sleep disturbances. Antipsychotic medications play an important role in the treatment of sleep disturbances in these patients and have an impact on their sleep structure. PMID- 26600109 TI - Sleep Disturbance in Substance Use Disorders. AB - This article discusses the role sleep and alertness disturbance plays in the initiation, maintenance and relapse of substance use disorders. PMID- 26600110 TI - Circadian Rhythm Sleep-Wake Disorders. AB - The circadian system regulates the timing and expression of nearly all biological processes, most notably, the sleep-wake cycle, and disruption of this system can result in adverse effects on both physical and mental health. The circadian rhythm sleep-wake disorders (CRSWDs) consist of 5 disorders that are due primarily to pathology of the circadian clock or to a misalignment of the timing of the endogenous circadian rhythm with the environment. This article outlines the nature of these disorders, the association of many of these disorders with psychiatric illness, and available treatment options. PMID- 26600111 TI - Sleep Disturbances in Patients with Medical Conditions. AB - Sleep-wake cycle disturbances are prevalent in patients with medical conditions and frequently present as part of a symptom cluster. Sleep disturbances impair functioning and quality of life, decrease adherence to treatments of the primary medical condition, and increase morbidity and mortality. The pathophysiology of sleep disturbances in these patients involves alterations in immune and neuroendocrine function and shares common pathophysiologic pathways with comorbidities such as fatigue and depression. Emphasis is placed on the evaluation and management of medical and psychiatric comorbidities and other factors contributing to sleep problems. Primary treatments include cognitive behavioral therapy and pharmacotherapy. PMID- 26600113 TI - Sleep Disorders and Mental Health. PMID- 26600112 TI - New Developments in Insomnia Medications of Relevance to Mental Health Disorders. AB - Many insomnia medications with high specificity have become available recently. They provide a window into the clinical effects of modulating specific brain systems and establish a new guiding principal for conceptualizing insomnia medications: "mechanism matters." A new paradigm for insomnia therapy in which specific drugs are selected to target the specific type of sleep difficulty for each patient includes administering specific treatments for patients with insomnia comorbid with particular psychiatric disorders. This article reviews insomnia medications and discusses the implications for optimizing the treatment of insomnia occurring comorbid with psychiatric conditions. PMID- 26600114 TI - Multiple magnetic relaxation processes, magnetocaloric effect and fluorescence properties of rhombus-shaped tetranuclear rare earth complexes. AB - Seven new tetranuclear rare earth (RE) complexes [RE4(acac)4L6(MU3-OH)2] (HL = 5 (4-fluorobenzylidene)-8-hydroxylquinoline; acac = acetylacetonate; RE = Y (1), Eu (2), Gd (3), Tb (4), Dy (5), Tm (6) and Lu (7)) have been synthesized and completely characterized. Complex exhibits multiple zero-field slow magnetic relaxation processes typical of Single Molecule Magnets (SMMs). Two distinct slow magnetic relaxation processes, with effective energy barriers of Ueff = 48 K for the slow relaxation (SR) process and Ueff = 121 K for the fast relaxation (FR) process, are mainly attributed to the presence of two crystallographically independent Dy(III) sites. The magnetocaloric effect (MCE) was detected as DeltaSm(T) = 20.8 J kg(-1) K(-1) for complex . The fluorescence properties of complexes 1, 2, 4, 5 and 7 were also investigated. Complexes 2, 4 and 5 show the characteristic peaks for their corresponding RE(III) center, while complexes 1 and 7 show similar emission peaks to the Schiff base ligand when they are excited at the appropriate wavelength. PMID- 26600115 TI - Glycaemic efficacy of canagliflozin is largely independent of baseline beta-cell function or insulin sensitivity. PMID- 26600117 TI - Highly sensitive gold nanoparticles-based optical sensing of DNA hybridization using bis(8-hydroxyquinoline-5-solphonate)cerium(III) chloride as a novel fluorescence probe. AB - A simple and sensitive method for the detection of DNA hybridization in a homogeneous format was developed, using bis(8-hydroxyquinoline-5 solphonate)cerium(III) chloride (Ce(QS)2Cl) as a novel fluorescent probe. The method is based on fluorescence quenching by gold nanoparticles used as both nanoscafolds for the immobilization of the probe DNA sequence, which is related to Alicyclobacillus acidophilus strain TA-67 16S ribosomal RNA, and nanoquenchers of the Ce(QS)2Cl probe. The probe DNA-functionalized GNPs were synthesized by derivatizing the colloidal gold nanoparticles solution with 3-thiolated 16-base oligonucleotides. Addition of sequence-specific target DNAs (16 bases) into the mixture containing probe DNA-functionalized GNPs and fluorescent probe lead to the quenching of Ce(QS)2Cl fluorescence at 360 nm (lambdaex=270 nm), due to DNA hybridization, the resulting quenched intensity being proportional to the concentration of target DNA. Under optimal conditions of pH 7.4 and Ce(QS)2Cl concentration of 1.0 * 10(-7) M, the linear dynamic range found to be 1.0 * 10( 10)-3.0 * 10(-8) M DNA, with a limit of detection of 7.0 * 10(-11) M. The interaction mechanism for the binding of Ce(QS)2Cl to DNA was studied in detail, and results proved that the interaction mode between Ce(QS)2Cl and DNA is groove binding, with a binding constant of 1.0 * 10(5) M(-1). PMID- 26600118 TI - "Fit-for-purpose" development of analytical and (semi)preparative enantioselective high performance liquid and supercritical fluid chromatography for the access to a novel sigma1 receptor agonist. AB - A rapid and straightforward screening protocol of chiral stationary phases (CSPs) in HPLC and SFC resulted in three different methods "fit-for-purpose", i.e. analysis and scale-up to semi-preparative enantioselective chromatography. The efficient use of these three methods allowed expedited preparation of an important drug discovery target, (R/S)-1, a potent new sigma 1 (sigma1) receptor agonist. The approach taken resulted in significant savings of both time and labor for the isolation of enantiomers compared to the development of a stereo selective synthesis. The enantiomers of 1 have been isolated allowing studies of their chirooptical properties and an in-deep comparative examination of the pharmacological profile for the individual enantiomers. PMID- 26600119 TI - Development of RP UPLC-TOF/MS, stability indicating method for omeprazole and its related substances by applying two level factorial design; and identification and synthesis of non-pharmacopoeial impurities. AB - A new UPLC-TOF/MS compatible, reverse phase-stability indicating method was developed for determination of Omeprazole (OMP) and its related substances in pharmaceutical dosage forms by implementing Design of Experiment (DoE) i.e. two level full factorial Design (2(3)+3 center points=11 experiments) to understand the Critical Method Parameters (CMP) and its relation with Critical Method Attribute (CMA); to ensure robustness of the method. The separation of eleven specified impurities including conversion product of OMP related compound F (13) and G (14) i.e. Impurity-I (1), OMP related compound-I (11) and OMP 4-chloro analog (12) was achieved in a single method on Acquity BEH shield RP18 100 * 2.1 mm, 1.7 MUm column, with inlet filter (0.2 MUm) using gradient elution and detector wavelength at 305 nm and validated in accordance with ICH guidelines and found to be accurate, precise, reproducible, robust and specific. The drug was found to degrade extensively in heat, humidity and acidic conditions and forms unknown degradation products during stability studies. The same method was used for LC-MS analysis to identify m/z and fragmentation of maximum unknown impurities (Non-Pharmacopoeial) i.e. Impurity-I (1), Impurity-III (3), Impurity-V (5) and Impurity-VIII (9) formed during stability studies. Based on the results, degradation pathway for the drug has been proposed and synthesis of identified impurities i.e. impurities (Impurity-I (1), Impurity-III (3), Impurity-V (5) and Impurity-VIII (9)) are discussed in detail to ensure in-depth understanding of OMP and its related impurities and optimum performance during lifetime of the product. PMID- 26600121 TI - One-Pot Reactions for Synthesis of 2,5-Substituted Tetrazoles from Aryldiazonium Salts and Amidines. AB - One-pot sequential reactions of aryldiazonium salts with amidines followed by the treatment of I2/KI under basic conditions provide 2,5-disubstituted tetrazoles in moderate to excellent yields. This one-pot synthesis has several advantages such as mild reaction conditions, short reaction time, convenient workup, and high yields, making this methodology practical. PMID- 26600122 TI - The interaction of MozobilTM with carboxylates. AB - Mozobil(TM) (1,1'-[1,4-phenylenebis(methylene)]bis[1,4,8,11 tetraazacyclotetradecane], 1, also known as JM3100 and AMD 3100) is a specific antagonist of the chemokine coreceptor CXCR4 and favours the mobilisation from the bone marrow of stem cells, which can be used for autologous transplantation. It is believed that the interaction, of both hydrogen bonding and electrostatic nature, involves a partly protonated form of Mozobil(TM), LHn(n+) and the COO(-) groups of Asp(171) and Asp(262) residues protruding from the walls of the pocket of the membrane protein CXCR4. We have investigated, through potentiometric titrations in 0.1 M NaNO3 at 25 degrees C, the interaction equilibria between 1 (L) and linear dicarboxylates A(2-). These studies have demonstrated that the main equilibrium takes place: LH5(5+) + A(2-)? [LH5...A](3+), and that the most stable [LH5...A](3+) complex forms for A(2-) = diphenyl-4,4'-dicarboxylate, whose length matches that of LH5(5+). (1)H NMR titration experiments have shown that in the 7-10 pH interval, LH3(3+), LH2(2+) and LH(+) forms establish pi-pi interactions with diphenyl-4,4'-dicarboxylate, according to a topological arrangement which excludes the formation of H-bonds. It is finally suggested that, in the pocket of the CXCR4 membrane protein, Mozobil(TM) operates as a pentammonium cation, which establishes with carboxylate groups of Asp(171) and Asp(262) strong interactions of hydrogen bonding and electrostatic nature. PMID- 26600123 TI - Neonatal Restriction of Tactile Inputs Leads to Long-Lasting Impairments of Cross Modal Processing. AB - Optimal behavior relies on the combination of inputs from multiple senses through complex interactions within neocortical networks. The ontogeny of this multisensory interplay is still unknown. Here, we identify critical factors that control the development of visual-tactile processing by combining in vivo electrophysiology with anatomical/functional assessment of cortico-cortical communication and behavioral investigation of pigmented rats. We demonstrate that the transient reduction of unimodal (tactile) inputs during a short period of neonatal development prior to the first cross-modal experience affects feed forward subcortico-cortical interactions by attenuating the cross-modal enhancement of evoked responses in the adult primary somatosensory cortex. Moreover, the neonatal manipulation alters cortico-cortical interactions by decreasing the cross-modal synchrony and directionality in line with the sparsification of direct projections between primary somatosensory and visual cortices. At the behavioral level, these functional and structural deficits resulted in lower cross-modal matching abilities. Thus, neonatal unimodal experience during defined developmental stages is necessary for setting up the neuronal networks of multisensory processing. PMID- 26600124 TI - Oryza sativa Chloroplast Signal Recognition Particle 43 (OscpSRP43) Is Required for Chloroplast Development and Photosynthesis. AB - A rice chlorophyll-deficient mutant w67 was isolated from an ethyl methane sulfonate (EMS)-induced IR64 (Oryza sativa L. ssp. indica) mutant bank. The mutant exhibited a distinct yellow-green leaf phenotype in the whole plant growth duration with significantly reduced levels of chlorophyll and carotenoid, impaired chloroplast development and lowered capacity of photosynthesis compared with the wild-type IR64. Expression of a number of genes associated with chlorophyll metabolism, chloroplast biogenesis and photosynthesis was significantly altered in the mutant. Genetic analysis indicated that the yellow green phenotype was controlled by a single recessive nuclear gene located on the short arm of chromosome 3. Using map-based strategy, the mutation was isolated and predicted to encode a chloroplast signal recognition particle 43 KD protein (cpSRP43) with 388 amino acid residuals. A single base substitution from A to T at position 160 resulted in a premature stop codon. OscpSRP43 was constitutively expressed in various organs with the highest level in the leaf. Functional complementation could rescue the mutant phenotype and subcellular localization showed that the cpSRP43:GFP fusion protein was targeted to the chloroplast. The data suggested that Oryza sativa cpSRP43 (OscpSRP43) was required for the normal development of chloroplasts and photosynthesis in rice. PMID- 26600125 TI - CmWRKY15 Facilitates Alternaria tenuissima Infection of Chrysanthemum. AB - Abscisic acid (ABA) has an important role in the responses of plants to pathogens due to its ability to induce stomatal closure and interact with salicylic acid (SA) and jasmonic acid (JA). WRKY transcription factors serve as antagonistic or synergistic regulators in the response of plants to a variety of pathogens. Here, we demonstrated that CmWRKY15, a group IIa WRKY family member, was not transcriptionally activated in yeast cells. Subcellular localization experiments in which onion epidermal cells were transiently transfected with CmWRKY15 indicated that CmWRKY15 localized to the nucleus in vivo. The expression of CmWRKY15 could be markedly induced by the presence of Alternaria tenuissima inoculum in chrysanthemum. Furthermore, the disease severity index (DSI) data of CmWRKY15-overexpressing plants indicated that CmWRKY15 overexpression enhanced the susceptibility of chrysanthemum to A. tenuissima infection compared to controls. To illustrate the mechanisms by which CmWRKY15 regulates the response to A. tenuissima inoculation, the expression levels of ABA-responsive and ABA signaling genes, such as ABF4, ABI4, ABI5, MYB2, RAB18, DREB1A, DREB2A, PYL2, PP2C, RCAR1, SnRK2.2, SnRK2.3, NCED3A, NCED3B, GTG1, AKT1, AKT2, KAT1, KAT2, and KC1were compared between transgenic plants and controls. In summary, our data suggest that CmWRKY15 might facilitate A. tenuissima infection by antagonistically regulating the expression of ABA-responsive genes and genes involved in ABA signaling, either directly or indirectly. PMID- 26600126 TI - Surgeons' Emotional Experience of Their Everyday Practice - A Qualitative Study. AB - BACKGROUND: Physicians' emotions affect both patient care and personal well being. Surgeons appear at particularly high risk, as evidenced by the high rate of burnout and the alarming consequences in both their personal lives and professional behavior. The aim of this qualitative study is to explore the emotional experiences of surgeons and their impact on their surgical practice. METHODS AND FINDINGS: 27 purposively selected liver and pancreatic surgeons from 10 teaching hospitals (23 men, 4 women) participated. Inclusion took place until data saturation was reached. Data were collected through individual interviews and thematically analyzed independently by 3 researchers (a psychologist, a psychiatrist, and a surgeon). 7 themes emerged from the analysis, categorized in 3 main or superordinate themes, which described surgeons' emotional experience before, during, and after surgery. Burdensome emotions are present throughout all 3 periods (and invade life outside the hospital)-surgeons' own emotions, their perception of patients' emotions, and their entwinement. The interviewees described the range of emotional situations they face (with patients, families, colleagues), the influence of the institutional framework (time pressure and fatigue, cultural pressure to satisfy the ideal image of a surgeon), as well as the emotions they feel (including especially anxiety, fear, distress, guilt, and accountability). CONCLUSIONS: Emotions are ubiquitous in surgeons' experience, and their exposure to stress is chronic rather than acute. Considering emotions only in terms of their relations to operative errors (as previous studies have done) is limiting. Although complications are quite rare events, the concern for possible complications is an oppressive experience, regardless of whether or not they actually occur. PMID- 26600127 TI - Red fluorescence in coral larvae is associated with a diapause-like state. AB - Effective dispersal across environmental gradients is the key to species resilience to environmental perturbation, including climate change. Coral reefs are among the most sensitive ecosystems to global warming, but factors predicting coral dispersal potential remain unknown. In a reef-building coral Acropora millepora, larval fluorescence emerged as a possible indicator of dispersal potential since it correlates with responsiveness to a settlement cue. Here, we show that gene expression in red fluorescent larvae of A. millepora is correlated with diapause-like characteristics highly likely to be associated with extended dispersal. We compared gene expression among three larval fluorescent morphs under three coloured light treatments. While colour morphs did not differ in their gene expression responses to light colour, red larvae demonstrated gene expression signatures of cell cycle arrest and decreased transcription accompanied by elevated ribosome production and heightened defenses against oxidative stress. A meta-analysis revealed that this profile was highly similar to the signatures of elevated thermal tolerance in the same coral species, and moreover, functionally resembled diapause states in an insect and a nematode. Our results support a connection between red fluorescence and long-range dispersal, which offers a new perspective on the molecular underpinnings of coral larval dispersal and the biological function of GFP-like fluorescent proteins. PMID- 26600128 TI - Vitamin E Attenuates the Progression of Non-Alcoholic Fatty Liver Disease Caused by Partial Hepatectomy in Mice. AB - BACKGROUND AND AIM: The progression of non-alcoholic fatty liver disease (NAFLD) likely involves a 'multiple hit' mechanism. We hypothesized that partial hepatectomy, a procedure performed frequently in patients with NAFLD, would accelerate the progression of disease. METHODS: C57BL/6JolaHsd mice were fed a choline-deficient L-amino acid-defined diet (CD-AA) or a choline-sufficient L amino acid-defined control diet (CS-AA). Part of the mice in the CD-AA group received a diet enriched in vitamin E (~20 mg /day). Two weeks after the start of the diet, mice underwent a partial hepatectomy or a sham operation. RESULTS: In the CD-AA group, NAFLD activity scores were significantly higher at 7 days after partial hepatectomy compared to the sham operated mice (3.7 +/- 1.3 vs. 1.8 +/- 0.7; P<0.05). In addition, TBARS, a measure for oxidative stress, in liver tissue of the CD-AA group were significantly higher at day 1, 3 and 7 after partial hepatectomy compared to the sham operated mice (P<0.05). Vitamin E therapy significantly reduced TBARS level at day 7 after partial hepatectomy compared to the CD-AA diet group (P< 0.05). Vitamin E suppletion reduced NAFLD activity score at day 7 after partial hepatectomy compared to the CD-AA group (2.3 +/- 0.8 vs. 3.8 +/- 1.0; P<0.05). CONCLUSION: Partial hepatectomy accelerates the progression of NAFLD. Disease progression induced by partial hepatectomy is substantially attenuated by vitamin E. PMID- 26600133 TI - Green Grounding Wire Spells Electric Safety in Hospitals. PMID- 26600134 TI - What's Going on: A New Series: Reduced Mortality from Stroke Achieved in Regional Program. PMID- 26600129 TI - The Practicability of a Novel Prognostic Index (PI) Model and Comparison with Nottingham Prognostic Index (NPI) in Stage I-III Breast Cancer Patients Undergoing Surgical Treatment. AB - BACKGROUND: Previous studies have indicated the prognostic value of various laboratory parameters in cancer patients. This study was to establish a prognostic index (PI) model for breast cancer patients based on the potential prognostic factors. METHODS: A retrospective study of 1661 breast cancer patients who underwent surgical treatment between January 2002 and December 2008 at Sun Yat-sen University Cancer Center was conducted. Multivariate analysis (Cox regression model) was performed to determine the independent prognostic factors and a prognostic index (PI) model was devised based on these factors. Survival analyses were used to estimate the prognostic value of PI, and the discriminatory ability of PI was compared with Nottingham Prognostic Index (NPI) by evaluating the area under the receiver operating characteristics curves (AUC). RESULTS: The mean survival time of all participants was 123.6 months. The preoperative globulin >30.0g/L, triglyceride >1.10mmol/L and fibrinogen >2.83g/L were identified as risk factors for shorter cancer-specific survival. The novel prognostic index model was established and enrolled patients were classified as low- (1168 patients, 70.3%), moderate- (410 patients, 24.7%) and high-risk groups (83 patients, 5.0%), respectively. Compared with the low-risk group, higher risks of poor clinical outcome were indicated in the moderate-risk group [Hazard ratio (HR): 1.513, 95% confidence interval (CI): 1.169-1.959, p = 0.002] and high-risk group (HR: 2.481, 95%CI: 1.653-3.724, p< 0.001). CONCLUSIONS: The prognostic index based on three laboratory parameters was a novel and practicable prognostic tool. It may serve as complement to help predict postoperative survival in breast cancer patients. PMID- 26600135 TI - Focus on Management Methods: Employee Motivation: The Key to Improved Productivity. PMID- 26600136 TI - Consultant's Corner. PMID- 26600137 TI - Hospital Financial Problems. PMID- 26600138 TI - Hospital Law Review: A New Series: Court Action to Authorize Transfusion. PMID- 26600139 TI - Outpatient Carets Emergency: E.R. Management, Nursing Problems Discussed at Seminars. PMID- 26600140 TI - Housekeeping Services: Analysts Discuss Pros and Cons of Carpeting in Hospitals. PMID- 26600141 TI - The Lab: Management Firm Report Appraises Computerized Hospital Labs. PMID- 26600144 TI - OBG: How can nurse contribute to better maternity care? PMID- 26600142 TI - Pharmacy: Interviewing Patients to Obtain Data for Outpatient Pharmacy Clinic Files. PMID- 26600145 TI - Operating Room: Infections, Total Hip Replacement Subjects of ACS Sessions. PMID- 26600149 TI - Product Profile. PMID- 26600148 TI - Central Service: Recruiting, Selecting C.S. Personnel. PMID- 26600152 TI - Exploring the Saccharomyces cerevisiae Volatile Metabolome: Indigenous versus Commercial Strains. AB - Winemaking is a highly industrialized process and a number of commercial Saccharomyces cerevisiae strains are used around the world, neglecting the diversity of native yeast strains that are responsible for the production of wines peculiar flavours. The aim of this study was to in-depth establish the S. cerevisiae volatile metabolome and to assess inter-strains variability. To fulfill this objective, two indigenous strains (BT2652 and BT2453 isolated from spontaneous fermentation of grapes collected in Bairrada Appellation, Portugal) and two commercial strains (CSc1 and CSc2) S. cerevisiae were analysed using a methodology based on advanced multidimensional gas chromatography (HS-SPME/GC*GC ToFMS) tandem with multivariate analysis. A total of 257 volatile metabolites were identified, distributed over the chemical families of acetals, acids, alcohols, aldehydes, ketones, terpenic compounds, esters, ethers, furan-type compounds, hydrocarbons, pyrans, pyrazines and S-compounds. Some of these families are related with metabolic pathways of amino acid, carbohydrate and fatty acid metabolism as well as mono and sesquiterpenic biosynthesis. Principal Component Analysis (PCA) was used with a dataset comprising all variables (257 volatile components), and a distinction was observed between commercial and indigenous strains, which suggests inter-strains variability. In a second step, a subset containing esters and terpenic compounds (C10 and C15), metabolites of particular relevance to wine aroma, was also analysed using PCA. The terpenic and ester profiles express the strains variability and their potential contribution to the wine aromas, specially the BT2453, which produced the higher terpenic content. This research contributes to understand the metabolic diversity of indigenous wine microflora versus commercial strains and achieved knowledge that may be further exploited to produce wines with peculiar aroma properties. PMID- 26600153 TI - A Generalized Radiation Model for Human Mobility: Spatial Scale, Searching Direction and Trip Constraint. AB - We generalized the recently introduced "radiation model", as an analog to the generalization of the classic "gravity model", to consolidate its nature of universality for modeling diverse mobility systems. By imposing the appropriate scaling exponent lambda, normalization factor kappa and system constraints including searching direction and trip OD constraint, the generalized radiation model accurately captures real human movements in various scenarios and spatial scales, including two different countries and four different cities. Our analytical results also indicated that the generalized radiation model outperformed alternative mobility models in various empirical analyses. PMID- 26600155 TI - Esophageal Cancer Specific Risk Score Is Associated with Postoperative Complications Following Open Ivor-Lewis Esophagectomy for Adenocarcinoma. AB - BACKGROUND/AIMS: Surgery for esophageal cancer is associated with a high morbidity and mortality. With this study, we investigated if a validated preoperative risk score correlates with overall morbidity, mortality, anastomotic insufficiency, respiratory complications and with the severity of complications after open Ivor-Lewis esophagectomy. METHODS: A total of 94 patients undergoing esophageal resection for adenocarcinoma between 2005 and 2009 were included. Patients were assigned using the preoperative risk score according to Schroder et al. [Langenbecks Arch Surg 2006;391:455-460] and the Dindo classification regarding the severity of complications. RESULTS: Of all the patients, 12% had a 'normal', 54% a 'moderate' and 34% a 'high' preoperative risk score. Postoperative complications occurred in 79%. Furthermore, 36 or 21 or 14 or 7% of patients experienced complications of category I/II or III or IV or V, respectively. There was a significant association between preoperative risk score and overall morbidity (p = 0.010), mortality (p = 0.035) and anastomotic insufficiency (p = 0.023). Furthermore, higher preoperative risk score was significant related to increasing severity of postoperative complications (grade IV according to the Dindo classification: p = 0.018, Dindo grade V: p = 0.035). Neoadjuvant therapy consisting of cisplatin and 5-fluorouracil had no influence. CONCLUSION: As we demonstrated, a significant association between preoperative risk score and occurrence and severity of postoperative complications after open Ivor-Lewis esophagectomy, standardized, organ-specific pre- and postoperative categorizations might be useful for individual clinical decision making in this group of patients. PMID- 26600154 TI - How to diagnose and manage hepatic encephalopathy: a consensus statement on roles and responsibilities beyond the liver specialist. AB - INTRODUCTION: Hepatic encephalopathy is defined as brain dysfunction caused by liver insufficiency and/or portosystemic shunting. Symptoms include nonspecific cognitive impairment, personality changes and changes in consciousness. Overt (symptomatic) hepatic encephalopathy is a common complication of cirrhosis that is associated with a poor prognosis. Patients with hepatic encephalopathy may present to healthcare providers who do not have primary responsibility for management of patients with cirrhosis. Therefore, we developed a series of 'consensus points' to provide some guidance on management. METHODS: Using a modified 'Delphi' process, consensus statements were developed that summarize our recommendations for the diagnosis and management of patients with hepatic encephalopathy. Points on which full consensus could not be reached are also discussed. RESULTS: Our recommendations emphasize the role of all healthcare providers in the identification of cognitive impairment in patients with cirrhosis and provide guidance on steps that might be considered to make a diagnosis of overt hepatic encephalopathy. In addition, treatment recommendations are summarized. Minimal hepatic encephalopathy can have a significant impact on patients; however, in most circumstances identification and management of minimal hepatic encephalopathy remains the responsibility of specialists in liver diseases. CONCLUSION: Our opinion statements aim to define the roles and responsibilities of all healthcare providers who at times care for patients with cirrhosis and hepatic encephalopathy. We suggest that these recommendations be considered further by colleagues in other disciplines and hope that future guidelines consider the management of patients with cirrhosis and with a 'suspicion' of cognitive impairment through to a formal diagnosis of hepatic encephalopathy. PMID- 26600156 TI - IoT Big-Data Centred Knowledge Granule Analytic and Cluster Framework for BI Applications: A Case Base Analysis. AB - The current rapid growth of Internet of Things (IoT) in various commercial and non-commercial sectors has led to the deposition of large-scale IoT data, of which the time-critical analytic and clustering of knowledge granules represent highly thought-provoking application possibilities. The objective of the present work is to inspect the structural analysis and clustering of complex knowledge granules in an IoT big-data environment. In this work, we propose a knowledge granule analytic and clustering (KGAC) framework that explores and assembles knowledge granules from IoT big-data arrays for a business intelligence (BI) application. Our work implements neuro-fuzzy analytic architecture rather than a standard fuzzified approach to discover the complex knowledge granules. Furthermore, we implement an enhanced knowledge granule clustering (e-KGC) mechanism that is more elastic than previous techniques when assembling the tactical and explicit complex knowledge granules from IoT big-data arrays. The analysis and discussion presented here show that the proposed framework and mechanism can be implemented to extract knowledge granules from an IoT big-data array in such a way as to present knowledge of strategic value to executives and enable knowledge users to perform further BI actions. PMID- 26600157 TI - Widespread Natural Occurrence of Hydroxyurea in Animals. AB - Here we report the widespread natural occurrence of a known antibiotic and antineoplastic compound, hydroxyurea in animals from many taxonomic groups. Hydroxyurea occurs in all the organisms we have examined including invertebrates (molluscs and crustaceans), fishes from several major groups, amphibians and mammals. The species with highest concentrations was an elasmobranch (sharks, skates and rays), the little skate Leucoraja erinacea with levels up to 250 MUM, high enough to have antiviral, antimicrobial and antineoplastic effects based on in vitro studies. Embryos of L. erinacea showed increasing levels of hydroxyurea with development, indicating the capacity for hydroxyurea synthesis. Certain tissues of other organisms (e.g. skin of the frog (64 MUM), intestine of lobster (138 MUM) gills of the surf clam (100 MUM)) had levels high enough to have antiviral effects based on in vitro studies. Hydroxyurea is widely used clinically in the treatment of certain human cancers, sickle cell anemia, psoriasis, myeloproliferative diseases, and has been investigated as a potential treatment of HIV infection and its presence at high levels in tissues of elasmobranchs and other organisms suggests a novel mechanism for fighting disease that may explain the disease resistance of some groups. In light of the known production of nitric oxide from exogenously applied hydroxyurea, endogenous hydoxyurea may play a hitherto unknown role in nitric oxide dynamics. PMID- 26600158 TI - Prevalence of and Risk Factors for Oral Human Papillomavirus Infection among HIV Positive and HIV-Negative People Who Inject Drugs. AB - BACKGROUND: Human papillomavirus (HPV) causes most oropharyngeal cancers in the United States. Oral HPV prevalence is associated with immunosuppression, and drug use can be immunosuppressive, but the epidemiology of oral HPV among people who use drugs is not well described. METHODS: We enrolled men and women with a current or prior history of injection drug use in this cross-sectional sub-study within the AIDS Linked to the Intravenous Experience (ALIVE) cohort. We tested oral rinse samples for 37 types of HPV DNA and collected self-reported risk factor information. We compared oral HPV prevalence across categories using chi squared statistics and multivariable logistic regression. RESULTS: Among 199 subjects, 32% were HIV-positive (median CD4 count 384 cells/MUL), 90% were Black, 56% had less than a high school education, 17% had recently used injection drugs, and the median age was 54 years. Most had performed oral sex (82%) but had fewer than 5 lifetime partners (58%). The prevalence of any oral HPV was 29%, and of any oncogenic oral HPV was 13%. Oral HPV prevalence was high among both heterosexual men (30%) and women (20%). After adjustment, odds of oral HPV were increased among HIV-positive individuals with a low CD4 count (<350 cells/MUl, aOR = 2.7, 95%CI = 1.2-6.4, vs. HIV-negative individuals), but not among HIV positive individuals with a higher CD4 cell count. Odds were also elevated for those who had recently performed oral sex on a woman (aOR = 2.2, 95%CI = 1.01 4.6) and, even after this adjustment, among bisexual/lesbian females (aOR = 5.6, 95%CI = 1.4-23, vs. heterosexual females). Oral HPV prevalence was not associated with vaginal sex, performing oral sex on a man, or recent drug use. CONCLUSIONS: Recent drug use was not associated with oral HPV prevalence in our study. However, despite modest numbers of sexual partners, the prevalence of oral HPV among this largely Black population with lower socioeconomic status was high. PMID- 26600159 TI - Genome-Wide Association Study Identifies That the ABO Blood Group System Influences Interleukin-10 Levels and the Risk of Clinical Events in Patients with Acute Coronary Syndrome. AB - INTRODUCTION: Acute coronary syndrome (ACS) is a major cause of mortality worldwide. We have previously shown that increased interleukin-10 (IL-10) levels are associated with poor outcome in ACS patients. METHOD: We performed a genome wide association study in 2864 ACS patients and 408 healthy controls, to identify genetic variants associated with IL-10 levels. Then haplotype analyses of the identified loci were done and comparisons to levels of IL-10 and other known ACS related biomarkers. RESULTS: Genetic variants at the ABO blood group locus associated with IL-10 levels (top SNP: rs676457, P = 4.4 * 10-10) were identified in the ACS patients. Haplotype analysis, using SNPs tagging the four main ABO antigens (A1, A2, B and O), showed that O and A2 homozygous individuals, or O/A2 heterozygotes have much higher levels of IL-10 compared to individuals with other antigen combinations. In the ACS patients, associations between ABO antigens and von Willebrand factor (VWF, P = 9.2 * 10-13), and soluble tissue factor (sTF, P = 8.6 * 10-4) were also found. In the healthy control cohort, the associations with VWF and sTF were similar to those in ACS patients (P = 1.2 * 10-15 and P = 1.0 * 10-5 respectively), but the healthy cohort showed no association with IL-10 levels (P>0.05). In the ACS patients, the O antigen was also associated with an increased risk of cardiovascular death, all causes of death, and recurrent myocardial infarction (odds ratio [OR] = 1.24-1.29, P = 0.029-0.00067). CONCLUSION: Our results suggest that the ABO antigens play important roles, not only for the immunological response in ACS patients, but also for the outcome of the disease. PMID- 26600160 TI - Enabling Low-Power, Multi-Modal Neural Interfaces Through a Common, Low-Bandwidth Feature Space. AB - Brain-Machine Interfaces (BMIs) have shown great potential for generating prosthetic control signals. Translating BMIs into the clinic requires fully implantable, wireless systems; however, current solutions have high power requirements which limit their usability. Lowering this power consumption typically limits the system to a single neural modality, or signal type, and thus to a relatively small clinical market. Here, we address both of these issues by investigating the use of signal power in a single narrow frequency band as a decoding feature for extracting information from electrocorticographic (ECoG), electromyographic (EMG), and intracortical neural data. We have designed and tested the Multi-modal Implantable Neural Interface (MINI), a wireless recording system which extracts and transmits signal power in a single, configurable frequency band. In prerecorded datasets, we used the MINI to explore low frequency signal features and any resulting tradeoff between power savings and decoding performance losses. When processing intracortical data, the MINI achieved a power consumption 89.7% less than a more typical system designed to extract action potential waveforms. When processing ECoG and EMG data, the MINI achieved similar power reductions of 62.7% and 78.8%. At the same time, using the single signal feature extracted by the MINI, we were able to decode all three modalities with less than a 9% drop in accuracy relative to using high-bandwidth, modality-specific signal features. We believe this system architecture can be used to produce a viable, cost-effective, clinical BMI. PMID- 26600161 TI - Bayesian Filtering of Surface EMG for Accurate Simultaneous and Proportional Prosthetic Control. AB - The amplitude of the surface EMG (sEMG) is commonly estimated by rectification or other nonlinear transformations, followed by smoothing (low-pass linear filtering). Although computationally efficient, this approach leads to an estimation accuracy with a limited theoretical signal-to-noise ratio (SNR). Since sEMG amplitude is one of the most relevant features for myoelectric control, its estimate has become one of the limiting factors for the performance of myoelectric control applications, such as powered prostheses. In this study, we present a recursive nonlinear estimator of sEMG amplitude based on Bayesian filtering. Furthermore, we validate the advantage of the proposed Bayesian filter over the conventional linear filters through an online simultaneous and proportional control (SPC) task, performed by eight able-bodied subjects and three below-elbow limb deficient subjects. The results demonstrated that the proposed Bayesian filter provides significantly more accurate SPC, particularly for the patients, when compared with conventional linear filters. This result presents a major step toward accurate prosthetic control for advanced multi function prostheses. PMID- 26600162 TI - Improved Neural Signal Classification in a Rapid Serial Visual Presentation Task Using Active Learning. AB - The application space for brain-computer interface (BCI) technologies is rapidly expanding with improvements in technology. However, most real-time BCIs require extensive individualized calibration prior to use, and systems often have to be recalibrated to account for changes in the neural signals due to a variety of factors including changes in human state, the surrounding environment, and task conditions. Novel approaches to reduce calibration time or effort will dramatically improve the usability of BCI systems. Active Learning (AL) is an iterative semi-supervised learning technique for learning in situations in which data may be abundant, but labels for the data are difficult or expensive to obtain. In this paper, we apply AL to a simulated BCI system for target identification using data from a rapid serial visual presentation (RSVP) paradigm to minimize the amount of training samples needed to initially calibrate a neural classifier. Our results show AL can produce similar overall classification accuracy with significantly less labeled data (in some cases less than 20%) when compared to alternative calibration approaches. In fact, AL classification performance matches performance of 10-fold cross-validation (CV) in over 70% of subjects when training with less than 50% of the data. To our knowledge, this is the first work to demonstrate the use of AL for offline electroencephalography (EEG) calibration in a simulated BCI paradigm. While AL itself is not often amenable for use in real-time systems, this work opens the door to alternative AL like systems that are more amenable for BCI applications and thus enables future efforts for developing highly adaptive BCI systems. PMID- 26600163 TI - Impact of Load Variation on Joint Angle Estimation From Surface EMG Signals. AB - Many studies use surface electromyogram (sEMG) signals to estimate the joint angle, for control of upper-limb exoskeletons and prostheses. However, several practical factors still affect its clinical applicability. One of these factors is the load variation during daily use. This paper demonstrates that the load variation can have a substantial impact on performance of elbow angle estimation. This impact leads an increase in mean RMSE (Root-Mean-Square Error) from 7.86 degrees to 20.44 degrees in our experimental test. Therefore, we propose three methods to address this issue: 1) pooling the training data from all loads together to form the pooled training data for the training model; 2) adding the measured load value (force sensor) as an additional input; and 3) developing a two-step hybrid estimation approach based on load and sEMG. Experiments are conducted with five subjects to investigate the feasibility of the proposed three methods. The results show that the mean RMSE is reduced from 20.44 degrees to 13.54 degrees using method one, 10.47 degrees using method two, and 8.48 degrees using method three, respectively. Our study indicates that 1) the proposed methods can improve performance and stability on joint angle estimation and 2) sensor fusion (sEMG sensor and force sensor) is an efficient way to resolve the adverse effect of load variation. PMID- 26600165 TI - Correction: A Standardized Method for the Construction of Tracer Specific PET and SPECT Rat Brain Templates: Validation and Implementation of a Toolbox. PMID- 26600164 TI - Co-Inhibition of GLUT-1 Expression and the PI3K/Akt Signaling Pathway to Enhance the Radiosensitivity of Laryngeal Carcinoma Xenografts In Vivo. AB - In the present study, we investigated the role of GLUT-1 and PI3K/Akt signaling in radioresistance of laryngeal carcinoma xenografts. Volume, weight, radiosensitization, and the rate of inhibition of tumor growth in the xenografts were evaluated in different groups. Apoptosis was evaluated by TUNEL assay. In addition, mRNA and protein levels of GLUT-1, p-Akt, and PI3K in the xenografts were measured. Treatment with LY294002, wortmannin, wortmannin plus GLUT-1 AS ODN, and LY294002 plus GLUT-1 AS-ODN after X-ray irradiation significantly reduced the size and weight of the tumors, rate of tumor growth, and apoptosis in tumors compared to that observed in the 10-Gy group (p<0.05). In addition, mRNA and protein expression of GLUT-1, p-Akt, and PI3K was downregulated. The E/O values of LY294002, LY294002 plus GLUT-1 AS-ODN, wortmannin, and wortmannin plus GLUT-1 AS-ODN were 2.7, 1.1, 1.8, and 1.8, respectively. Taken together, these data indicate that GLUT-1 AS-ODN as well as the inhibitors of PI3K/Akt signaling may act as radiosensitizers of laryngeal carcinoma in vivo. PMID- 26600166 TI - Generation of DNA profiles from fingerprints developed with columnar thin film technique. AB - Partial-bloody fingerprints and partial fingerprints with saliva are often encountered at crime scenes, potentially enabling the combination of fingerprint and DNA analyses for absolute identification, provided that the development technique for fingerprint analysis does not inhibit DNA analysis. 36 partial bloody fingerprints and 30 fingerprints wetted with saliva, all deposited on brass, were first developed using the columnar-thin-film (CTF) technique and then subjected to short tandem repeat (STR) DNA analysis. Equal numbers of samples were subjected to the same DNA analysis without development. Tris (8 hydroxyquinolinato) aluminum, or Alq3, was evaporated to deposit CTFs for development of the prints. DNA was extracted from all 132 samples, quantified, and amplified with AmpFlSTR((r)) Identifiler Plus Amplification Kit. Additionally, DNA analyses were conducted on four blood smears on un fingerprinted brass that had been subjected to CTF deposition and four blood smears on un-fingerprinted brass that had not been subjected to CTF deposition. Complete and concordant autosomal STR profiles of the same quality were obtained from both undeveloped and CTF-developed fingerprints, indicating that CTF development of fingerprints preserves DNA and does not inhibit subsequent DNA analysis. Even when there were no fingerprints, CTF deposition did not lead to inhibition of DNA analysis. PMID- 26600167 TI - Hybrid simulation approach incorporating microscopic interaction along with rigid body degrees of freedom for stacking between base pairs. AB - Stacking interaction between the aromatic heterocyclic bases plays an important role in the double helical structures of nucleic acids. Considering the base as rigid body, there are total of 18 degrees of freedom of a dinucleotide step. Some of these parameters show sequence preferences, indicating that the detailed atomic interactions are important in the stacking. Large variants of non canonical base pairs have been seen in the crystallographic structures of RNA. However, their stacking preferences are not thoroughly deciphered yet from experimental results. The current theoretical approaches use either the rigid body degrees of freedom where the atomic information are lost or computationally expensive all atom simulations. We have used a hybrid simulation approach incorporating Monte-Carlo Metropolis sampling in the hyperspace of 18 stacking parameters where the interaction energies using AMBER-parm99bsc0 and CHARMM-36 force-fields were calculated from atomic positions. We have also performed stacking energy calculations for structures from Monte-Carlo ensemble by Dispersion corrected density functional theory. The available experimental data with Watson-Crick base pairs are compared to establish the validity of the method. Stacking interaction involving A:U and G:C base pairs with non-canonical G:U base pairs also were calculated and showed that these structures were also sequence dependent. This approach could be useful to generate multiscale modeling of nucleic acids in terms of coarse-grained parameters where the atomic interactions are preserved. This method would also be useful to predict structure and dynamics of different base pair steps containing non Watson-Crick base pairs, as found often in the non-coding RNA structures. (c) 2015 Wiley Periodicals, Inc. Biopolymers 105: 212-226, 2016. PMID- 26600169 TI - Hypoalbuminemia and Osteoporosis: Reappraisal of a Controversy. AB - CONTEXT: Human studies have reported conflicting results on the association of hypoalbuminemia with osteoporosis. OBJECTIVE: The aim of the study is to test the independent association between hypoalbuminemia and osteoporosis. DESIGN: This is a cross-sectional observation. SETTING AND PARTICIPANTS: Patients are the outpatient consecutive individuals with available clinical, laboratory, and densitometry data from 2001 to 2013 in our tertiary care academic medical center. EXPOSURE: Exposure is hypoalbuminemia defined as serum albumin less than 3.5 g/dL. MAIN OUTCOME MEASURE: Osteoporosis is defined as bone mineral density of 2.5 SD or less below the mean peak bone mass of young, healthy adults. RESULTS: Overall, 21 121 patients were included. Mean of age was 61 years (SD 14). There were 4244 males (20.1%) and 1614 patients of African-American ethnicity (7.6%). There was a graded decrease in rate of osteoporosis from 28.0% (n = 33) at albumin of 3 g/dL or less to 9.3% (n = 1548) at albumin greater than 4 g/dL (P < .001) at the femoral neck and from 20.3% (n = 24) to 6.1% (n = 1011) at the total hip (P < .001). In a fully adjusted model, the odds of osteoporosis at albumin of 3 g/dL or less was 3.31-fold (95% confidence interval [CI] 2.08-5.28, P < .001) at the femoral neck, 2.98-fold (95% CI 1.76-5.01, P < .001) at the total hip, and 2.18-fold (95% CI 1.43-3.31, P < .001) at the lumbar spine as compared with albumin greater than 4 mg/dL. A similar independent association was identified with a longer-observed duration of hypoalbuminemia. CONCLUSION: In a large population, we report an independent association of osteoporosis with lower levels of serum albumin and a longer-observed duration of hypoalbuminemia. PMID- 26600170 TI - Does participation in art classes influence performance on two different cognitive tasks? AB - OBJECTIVES: Effects of two mentally stimulating art interventions on processing speed and visuo-spatial cognition were compared in three samples. METHOD: In a randomized 10-week art intervention study with a pre-post follow-up design, 113 adults (27 healthy older adults with subjective memory complaints, 50 healthy older adults and 36 healthy younger adults) were randomly assigned to one of two groups: visual art production or cognitive art evaluation, where the participants either produced or evaluated art. ANOVAs with repeated measures were computed to observe effects on the Symbol-Digit Test, and the Stick Test. RESULTS: Significant Time effects were found with regard to processing speed and visuo spatial cognition. Additionally, there was found a significant Time * Sample interaction for processing speed. The effects proved robust after testing for education and adding sex as additional factor. CONCLUSION: Mental stimulation by participation in art classes leads to an improvement of processing speed and visuo-spatial cognition. Further investigation is required to improve understanding of the potential impact of art intervention on cognitive abilities across adulthood. PMID- 26600171 TI - Whither ICRR? PMID- 26600172 TI - The Roles of p21(Waf1/CIP1) and Hus1 in Generation and Transmission of Damage Signals Stimulated by Low-Dose Alpha-Particle Irradiation. AB - Previously reported studies have demonstrated the involvement of p21(Waf1/CIP1) in radiation-induced bystander effects (RIBE). Mouse embryonic fibroblasts (MEFs) lacking Hus1 fail to proliferate in vitro, but inactivation of p21 allows for the continued growth of Hus1-deficient cells, indicating the close connection between p21 and Hus1 cells. In this study, wild-type MEFs, Hus1(+/+)p21(-/-) MEFs and p21(-/-)Hus1(-/-) MEFs were used in a series of radiation-induced bystander effect experiments, the roles of p21 and Hus1 in the induction and transmission of radiation-induced damage signals were investigated. Our results showed that after 5 cGy alpha particle irradiation, wild-type MEFs induced significant increases in gamma-H2AX foci and micronuclei formation in bystander cells, whereas the bystander effects were not detectable in p21(-/-)Hus1(+/+) MEFs and were restored again in p21(-/-)Hus1(-/-) MEFs. Media transfer experiments showed that p21(-/-)Hus1(+/+) MEFs were deficient in the production bystander signals, but could respond to bystander signals. We further investigated the mitogen activated protein kinases (MAPKs) that might be involved in the bystander effects. It was found that although knocking out p21 did not affect the expression of connexin43 and its phosphorylation, it did result in inactivation of some MAPK signal pathway kinases, including JNK1/2, ERK1/2 and p38, as well as a decrease in reactive oxygen species (ROS) levels in irradiated cells. However, the activation of MAPK kinases and the ROS levels in irradiated cells were restored in the cell line by knocking out Hus1. These results suggest that p21(Waf1/CIP1) and Hus1 play crucial roles in the generation and transmission of bystander damage signals after low-dose alpha-particle irradiation. PMID- 26600173 TI - No Effects of Acute Exposure to Wi-Fi Electromagnetic Fields on Spontaneous EEG Activity and Psychomotor Vigilance in Healthy Human Volunteers. AB - Mobile equipment use of wireless fidelity (Wi-Fi) signal modulation has increased exponentially in the past few decades. However, there is inconclusive scientific evidence concerning the potential risks associated with the energy deposition in the brain from Wi-Fi and whether Wi-Fi electromagnetism interacts with cognitive function. In this study we investigated possible neurocognitive effects caused by Wi-Fi exposure. First, we constructed a Wi-Fi exposure system from commercial parts. Dosimetry was first assessed by free space radiofrequency field measurements. The experimental exposure system was then modeled based on real geometry and physical characteristics. Specific absorption rate (SAR) calculations were performed using a whole-body, realistic human voxel model with values corresponding to conventional everyday Wi-Fi exposure (peak SAR10g level was 99.22 mW/kg with 1 W output power and 100% duty cycle). Then, in two provocation experiments involving healthy human volunteers we tested for two hypotheses: 1. Whether a 60 min long 2.4 GHz Wi-Fi exposure affects the spectral power of spontaneous awake electroencephalographic (sEEG) activity (N = 25); and 2. Whether similar Wi-Fi exposure modulates the sustained attention measured by reaction time in a computerized psychomotor vigilance test (PVT) (N = 19). EEG data were recorded at midline electrode sites while volunteers watched a silent documentary. In the PVT task, button press reaction time was recorded. No measurable effects of acute Wi-Fi exposure were found on spectral power of sEEG or reaction time in the psychomotor vigilance test. These results indicate that a single, 60 min Wi-Fi exposure does not alter human oscillatory brain function or objective measures of sustained attention. PMID- 26600174 TI - How to Overcome Scientific Standstill for Very Rare Diseases: Clinical Trials or Clinical Registries? PMID- 26600175 TI - [The Society for Paediatric Oncology and Haematology mourns the loss of Gunther Schelling]. PMID- 26600176 TI - [Recipient of the Clinical Pediatric Science Award has been selected]. PMID- 26600177 TI - [Studies and Publication Practice in Pediatric Hematology and Oncology in Germany -An Analysis of the Period 1970-2006]. AB - BACKGROUND: Several therapy optimization studies (TOSs) for the treatment of hematologic and oncologic disorders in children and adolescents have been conducted in Germany. The publication of research results is necessary to ensure that future studies are well designed and based on relevant and unanswered questions. This retrospective cohort study was conducted to analyze the study- and publication practice in this field. METHODS: All study protocols in the field of the pediatric oncology and hematology in Germany were collected. Relevant data from study protocols were extracted, beginning with 1) general information about the study protocol, and 2) information about each methodological trial. In a second step, the publication practice was characterized by searching in electronic databases and by contacting principal investigators. Relevant Data of each publication was extracted. RESULTS: The research activity has increased significantly in the past few years. The found publication rate of 85% represents an outstanding publication practice. Additionally, German, as being the main publication language a few decades ago, has been almost completely replaced with English. An acceptable methodological conduct was observed in the analyzed study protocols. DISCUSSION AND CONCLUSION: Studies have been principally based on the concept of TOS, without considering a detailed breakdown into each methodological trial. A markedly subdivision of studies into methodologically identifiable trials would allow a clear definition of their parameters, while increasing transparency of the study conduct and its results. PMID- 26600178 TI - Nationwide Survey on the Health of Offspring from Former Childhood Cancer Patients in Germany. AB - BACKGROUND: Increased risk for infertility from cancer treatment and fear of health impairment in their offspring may prevent survivors of childhood cancer from having own children. Even though most studies report no increased risk for malformations, in our German fertility study 2008 a higher occurrence of cleft lip and palate was found in offspring of former patients. METHODS: Since 2010 we assess offspring's health in a survey-based multicenter study, comparing diseases, well-being, healthcare utilization and health-related behavior between offspring from survivors, siblings or the general population. Within a first nationwide survey wave survivors who were known to have at least one child by previous fertility studies, received a questionnaire supported by the German Childhood Cancer Registry. Questionnaires were based on the KiGGS study on children's health in the German general population conducted by the Robert-Koch Institute (n=17,641). RESULTS: Questionnaires on 418 children were answered by 65% (254/393) of survivors contacted to participate in the first nationwide offspring study wave. Participants were more likely to be female (p<0.01), to have achieved higher educational levels (p<0.05) and to be a survivor of a soft tissue tumor (p<0.05). Former patients expressed moderate to high anxiety for the occurrence of cancer in 74% and feared other diseases in their children in 20%. CONCLUSION: Offspring health is a topic of major relevance to former patients. Our offspring study is currently being extended to ~1500 offspring of childhood cancer survivors in Europe. PMID- 26600179 TI - A Bladder Hematoma Mimicking a Tumor in a Newborn with Severe Hemophilia A. PMID- 26600180 TI - An Attentional Effect of Musical Metrical Structure. AB - Theories of metrical structure postulate the existence of several degrees of beat strength. While previous work has clearly established that humans are sensitive to the distinction between strong beats and weak ones, there is little evidence for a more fine grained distinction between intermediate levels. Here, we present experimental data showing that attention can be allocated to an intermediate level of beat strength. Comparing the effects of short exposures to 6/8 and 3/4 metrical structures on a tone detection task, we observe that subjects respond differently to beats of intermediate strength than to weak beats. PMID- 26600181 TI - A New Method to Quantify Ifosfamide Blood Levels Using Dried Blood Spots and UPLC MS/MS in Paediatric Patients with Embryonic Solid Tumours. AB - Ifosfamide blood concentrations are necessary to monitor its therapeutic response, avoiding any adverse effect. We developed and validated an analytical method by UPLC-MS/MS to quantify ifosfamide in dried blood spots (DBS). Blood samples were collected on Whatman 903(r) filter paper cards. Five 3 mm disks were punched out from each dried blood spot. Acetonitrile and ethyl acetate were used for drug extraction. Chromatographic separation was carried out in an Acquity UPLC equipment with a BEH-C18 column, 2.1 x 100 mm, 1.7 MUm (Waters(r)). The mobile phase consisted in 5 mM ammonium formate and methanol:acetonitrile (40:48:12 v/v/v) at 0.2 mL/min. LC-MS/MS detection was done by ESI+ and multiple reaction mode monitoring, ionic transitions were m/z1+ 260.99 > 91.63 for ifosfamide and 261.00 > 139.90 for cyclophosphamide (internal standard). This method was linear within a 100-10000 ng/mL range and it was accurate, precise and selective. Ifosfamide samples in DBS were stable for up to 52 days at -80 degrees C. The procedure was tested in 14 patients, ages 1 month to 17 years (9 males and 5 females), with embryonic tumours treated with ifosfamide, alone or combined, at a public tertiary referral hospital. Ifosfamide blood levels ranged from 11.1 to 39.7 MUmol/L at 12 hours after the last infusion, while 24-hour levels ranged from 0.7-19.7 MUmol/L. The median at 12 hours was 19.5 MUmol/L (Q25 14.4-Q75 29.0) and 3.8 MUmol/L (Q25 1.5-Q75 9.9) at 24 hours, p<0.001. This method is feasible to determine ifosfamide plasma levels in paediatric patients. PMID- 26600182 TI - Risk indicators for referral during labor from community midwife to gynecologist: a prospective cohort study. AB - OBJECTIVE: To identify risk indicators for referral during labor from community midwife to a gynecologist in a prospective cohort of women with a singleton term pregnancy, starting labor with a community midwife between 2000 and 2007, registered in the Dutch national perinatal registry. MAIN OUTCOME MEASURES: Referral from community midwife to a gynecologist during labor, because of fetal distress, failure to progress in second stage of labor, meconium stained amniotic fluid, failure to progress in first stage of labor, wish for pain relief, a combination of other less urgent reasons or no referral (reference). RESULTS: A total of 241 595 (32%) were referred from community midwife to a gynecologist during labor, because of fetal distress (FD;5%), failure to progress in second stage of labor (FTP2;14%), meconium stained amniotic fluid (MSAF;24%), failure to progress in first stage of labor (FTP1;17%), wish for pain relief (WFPR;7%) or a combination of other less urgent reasons, for example, malpresentation (e.g. breech) or other nonspecified problems (OTHER;33%). The strongest overall risk indicators were gestational age (lower risk of referral because of FD, FTP2, MSAF, FTP1 and WFPR and a higher risk of referral because of OTHER at a gestational age between 37(+0) and 37(+)(6) weeks, and higher risks of referral for all reasons at a gestational age >=41(+)(0) when compared to a gestational age between 38 (+)(0) and 40 (+)(6) weeks and no referral), the intended place of delivery (higher risk of all types of referral compared to no referral when the intended place of delivery was either at a midwife-led birth center or a hospital instead of at home) and birth history (higher risk of all types of referral compared to no referral when women had a history of instrumental vaginal delivery or when they were nulliparous instead of being multiparous without a history of an instrument vaginal delivery). Risk indicators associated with specific reasons of referral were maternal age, ethnicity, degree of urbanization, social economic status, neonatal gender and birth weight. CONCLUSIONS: Among low-risk pregnant women, a referral during labor is associated with readily available risk indicators. These risk indicators may be used to increase referral risk awareness and to counsel women for the intended place to start labor. PMID- 26600183 TI - Insulin Resistance Predicts Virological Response to Interferon-alpha in Chronic Hepatitis B Patients. AB - GOALS: To elucidate impact of insulin resistance (IR) on the response to interferon-alpha (IFN-alpha) therapy in chronic hepatitis B (CHB) patients. BACKGROUND: Metabolic factors influencing the virological response of CHB patients on IFN-alpha treatment are still unexplored. STUDY: Eighty CHB patients were treated with IFN-alpha for 48 weeks. The IR was evaluated by homeostasis model assessment of IR (HOMA-IR) before treatment. Viral load and biochemical parameters were measured at 12, 24, and 48 weeks after starting treatment, and then 24 weeks after the end of treatment. IFN-gamma and tumor necrosis factor alpha were tested at baseline and 12 weeks of treatment. RESULTS: Pretreatment HOMA-IR proved to be the only independent predictor of primary nonresponse, as well as the pretreatment HOMA-IR, viral load and primary nonresponse were independently associated with virological response at 24, 48 weeks of treatment and at the follow-up endpoint. The significant higher virological relapse rate in patients with IR was observed in patients with virological response at 48 weeks of treatment. The mean HOMA-IR was significantly lower in virological responders than in virological nonresponders. The secretion of IFN-gamma and tumor necrosis factor-alpha was not induced in patients with IR at 12 weeks after IFN-alpha treatment. CONCLUSIONS: Our data suggest that IR is strongly associated with virological response, thus reflecting the important role played by metabolic factors in the viral kinetics during IFN-alpha treatment. These findings suggested clinical application of pretreatment HOMA-IR could enable treatment outcome to be predicted and treatment regimens to be determined. PMID- 26600184 TI - IUNS News. PMID- 26600185 TI - Steroid Derived Mesoionic Gold and Silver Mono- and Polymetallic Carbenes. AB - A two-step synthesis of gold mesoionic carbene complexes containing estrone moieties has been developed. The method uses the methylation of the triazole nucleus, followed by the treatment of the triazolium salt with Ag2O and transmetalation with [AuCl(SMe2)]. Mono-, bi-, tri-, and tetrametallic gold complexes can be obtained depending on the structure of the starting triazolium salts. Tetrametallic gold carbene embedded in a macrocylic stereoidal cavity containing four estrone nuclei has been also prepared. Additionally, the mono- and bimetallic silver carbene complexes containing triazole-steroid ligands have been isolated and characterized. These complexes resulted to be stable and have been characterized by spectroscopic and HRMS techniques. The gold and silver complexes having triazole-steroid ligands are unprecedented in the literature and the method reported here to access to these compounds is easy and efficient. Preliminary results regarding the catalytic activity of some of the gold-carbenes prepared in the insertion of diazoalkanes into alcohols are presented. PMID- 26600186 TI - Transient widespread cortical and splenial lesions in acute encephalitis/encephalopathy associated with primary Epstein-Barr virus infection. AB - Infection with Epstein-Barr virus (EBV) is very common and usually occurs in childhood or early adulthood. Encephalitis/encephalopathy is an uncommon but serious neurological complication of EBV. A case of EBV-associated encephalitis/encephalopathy with involvement of reversible widespread cortical and splenial lesions is presented herein. An 8-year-old Chinese girl who presented with fever and headache, followed by seizures and drowsiness, was admitted to the hospital. Magnetic resonance imaging revealed high signal intensities on diffusion-weighted imaging in widespread cortical and splenial lesions. The clinical and laboratory examination results together with the unusual radiology findings suggested acute encephalitis/encephalopathy due to primary EBV infection. After methylprednisolone pulse therapy together with ganciclovir, the patient made a full recovery without any brain lesions. The hallmark clinical-radiological features of this patient included severe encephalitis/encephalopathy at onset, the prompt and complete recovery, and rapidly reversible widespread involvement of the cortex and splenium. Patients with EBV encephalitis/encephalopathy who have multiple lesions, even with the widespread involvement of cortex and splenium of the corpus callosum, may have a favorable outcome with complete disappearance of all brain lesions. PMID- 26600188 TI - Comparison and Combination of Dual-Energy- and Iterative-Based Metal Artefact Reduction on Hip Prosthesis and Dental Implants. AB - PURPOSE: To compare and combine dual-energy based and iterative metal artefact reduction on hip prosthesis and dental implants in CT. MATERIAL AND METHODS: A total of 46 patients (women:50%,mean age:63+/-15years) with dental implants or hip prostheses (n = 30/20) were included and examined with a second-generation Dual Source Scanner. 120kV equivalent mixed-images were derived from reconstructions of the 100/Sn140kV source images using no metal artefact reduction (NOMAR) and iterative metal artefact reduction (IMAR). We then generated monoenergetic extrapolations at 130keV from source images without IMAR (DEMAR) or from source images with IMAR, (IMAR+DEMAR). The degree of metal artefact was quantified for NOMAR, IMAR, DEMAR and IMAR+DEMAR using a Fourier based method and subjectively rated on a five point Likert scale by two independent readers. RESULTS: In subjects with hip prosthesis, DEMAR and IMAR resulted in significantly reduced artefacts compared to standard reconstructions (33% vs. 56%; for DEMAR and IMAR; respectively, p<0.005), but the degree of artefact reduction was significantly higher for IMAR (all p<0.005). In contrast, in subjects with dental implants only IMAR showed a significant reduction of artefacts whereas DEMAR did not (71%, vs. 8% p<0.01 and p = 0.1; respectively). Furthermore, the combination of IMAR with DEMAR resulted in additionally reduced artefacts (Hip prosthesis: 47%, dental implants 18%; both p<0.0001). CONCLUSION: IMAR allows for significantly higher reduction of metal artefacts caused by hip prostheses and dental implants, compared to a dual energy based method. The combination of DE-source images with IMAR and subsequent monoenergetic extrapolation provides an incremental benefit compared to both single methods. PMID- 26600189 TI - Tissue Specificity of Human Angiotensin I-Converting Enzyme. AB - BACKGROUND: Angiotensin-converting enzyme (ACE), which metabolizes many peptides and plays a key role in blood pressure regulation and vascular remodeling, as well as in reproductive functions, is expressed as a type-1 membrane glycoprotein on the surface of endothelial and epithelial cells. ACE also presents as a soluble form in biological fluids, among which seminal fluid being the richest in ACE content - 50-fold more than that in blood. METHODS/PRINCIPAL FINDINGS: We performed conformational fingerprinting of lung and seminal fluid ACEs using a set of monoclonal antibodies (mAbs) to 17 epitopes of human ACE and determined the effects of potential ACE-binding partners on mAbs binding to these two different ACEs. Patterns of mAbs binding to ACEs from lung and from seminal fluid dramatically differed, which reflects difference in the local conformations of these ACEs, likely due to different patterns of ACE glycosylation in the lung endothelial cells and epithelial cells of epididymis/prostate (source of seminal fluid ACE), confirmed by mass-spectrometry of ACEs tryptic digests. CONCLUSIONS: Dramatic differences in the local conformations of seminal fluid and lung ACEs, as well as the effects of ACE-binding partners on mAbs binding to these ACEs, suggest different regulation of ACE functions and shedding from epithelial cells in epididymis and prostate and endothelial cells of lung capillaries. The differences in local conformation of ACE could be the base for the generation of mAbs distingushing tissue-specific ACEs. PMID- 26600190 TI - Low-dimensional compounds containing bioactive ligands. Part VI: Synthesis, structures, in vitro DNA binding, antimicrobial and anticancer properties of first row transition metal complexes with 5-chloro-quinolin-8-ol. AB - A series of new 3d metal complexes with 5-chloro-quinolin-8-ol (ClQ), [Mn(ClQ)2] (1), [Fe(ClQ)3] (2), [Co(ClQ)2(H2O)2] (3), [Ni(ClQ)2(H2O)2] (4), [Cu(ClQ)2] (5), [Zn(ClQ)2(H2O)2] (6), [Mn(ClQ)3].DMF (7) and [Co(ClQ)3].DMF.(EtOH)0.35 (8) (DMF=N,N-dimethylformamide), has been synthesized and characterized by elemental analysis, IR spectroscopy and TG-DTA thermal analysis. X-ray structure analysis of 7 and 8 revealed that these molecular complexes contain three chelate ClQ molecules coordinated to the central atoms in a deformed octahedral geometry and free space between the complex units is filled by solvated DMF and ethanol molecules. Antimicrobial activity of 1-6 was tested by determining the minimum inhibitory concentration and minimum microbicidal concentration against 12 strains of bacteria and 5 strains of fungi. The intensity of antimicrobial action varies depending on the group of microorganism and can be sorted: 1>ClQ>6>3/4>2>5. Complexes 1-6 exhibit high cytotoxic activity against MDA-MB, HCT-116 and A549 cancer cell lines. Among them, complex 2 is significantly more cytotoxic against MDA-MB cells than cisplatin at all tested concentrations and is not cytotoxic against control mesenchymal stem cells indicating that this complex seems to be a good candidate for future pharmacological evaluation. Interaction of 1-6 with DNA was investigated using UV-VIS spectroscopy, fluorescence spectroscopy and agarose gel electrophoresis. The binding studies indicate that 1 6 can interact with CT-DNA through intercalation; complex 2 has the highest binding affinity. Moreover, complexes 1-6 inhibit the catalytic activity of topoisomerase I. PMID- 26600191 TI - Esophageal balloon tamponade versus esophageal stent in controlling acute refractory variceal bleeding: A multicenter randomized, controlled trial. AB - Balloon tamponade is recommended only as a "bridge" to definitive therapy in patients with cirrhosis and massive or refractory esophageal variceal bleeding (EVB), but is frequently associated with rebleeding and severe complications. Preliminary, noncontrolled data suggest that a self-expandable, esophageal covered metal stent (SX-ELLA Danis; Ella-CS, Hradec Kralove, Czech Republic) may be an effective and safer alternative to balloon tamponade. We conducted a randomized, controlled trial aimed at comparing esophageal stent versus balloon tamponade in patients with cirrhosis and EVB refractory to medical and endoscopic treatment. Primary endpoint was success of therapy, defined as survival at day 15 with control of bleeding and without serious adverse events (SAEs). Twenty-eight patients were randomized to Sengstaken-Blakemore tube (n = 15) or SX-ELLA Danis stent (n = 13). Patients were comparable in severity of liver failure, active bleeding at endoscopy, and initial therapy. Success of therapy was more frequent in the esophageal stent than in balloon tamponade group (66% vs. 20%; P = 0.025). Moreover, control of bleeding was higher (85% vs. 47%; P = 0.037) and transfusional requirements (2 vs 6 PRBC; P = 0.08) and SAEs lower (15% vs. 47%; P = 0.077) in the esophageal stent group. TIPS was used more frequently in the tamponade group (4 vs. 10; P = 0.12). There were no significant differences in 6 week survival (54% vs. 40%; P = 0.46). CONCLUSION: Esophageal stents have greater efficacy with less SAEs than balloon tamponade in the control of EVB in treatment failures. Our findings favor the use of esophageal stents in patients with EVB uncontrolled with medical and endoscopic treatment. (Hepatology 2016;63:1957 1967). PMID- 26600193 TI - Clinical guideline implementation strategies for common mental health disorders. AB - INTRODUCTION: There has been a considerable proliferation of clinical guidelines recently, but their practical application is low, and organisations do not always implement their own ones. The aim of this study is to analyse and describe key elements of strategies and resources designed by the National Institute for Health and Care Excellence for the implementation of guidelines for common mental health disorders in adults, which are some of the most prevalent worldwide. METHOD: A systematic review was performed following PRISMA model. Resources, tools and implementation materials where included and categorised considering type, objectives, target and scope. RESULTS: A total of 212 elements were analysed, of which 33.5 and 24.5% are related to the implementation of generalized anxiety and depression guidelines, respectively. Applied tools designed to estimate costs and assess the feasibility of the setting up at local level are the most frequent type of resource. The study highlights the important variety of available materials, classified into 3 main strategies: tools targeting the professionals (30.6%), structural (26.4%), and organizational (24%). CONCLUSIONS: Developing guidelines is not enough; it is also necessary to promote their implementation in order to encourage their application. The resources and strategies described in this study may be potentially applicable to other contexts, and helpful to public health managers and professionals in the design of programmes and in the process of informed decision making to help increase access to efficient treatments. PMID- 26600192 TI - PH motifs in PAR1&2 endow breast cancer growth. AB - Although emerging roles of protease-activated receptor1&2 (PAR1&2) in cancer are recognized, their underlying signalling events are poorly understood. Here we show signal-binding motifs in PAR1&2 that are critical for breast cancer growth. This occurs via the association of the pleckstrin homology (PH) domain with Akt/PKB as a key signalling event of PARs. Other PH-domain signal-proteins such as Etk/Bmx and Vav3 also associate with PAR1 and PAR2 through their PH domains. PAR1 and PAR2 bind with priority to Etk/Bmx. A point mutation in PAR2, H349A, but not in R352A, abrogates PH-protein association and is sufficient to markedly reduce PAR2-instigated breast tumour growth in vivo and placental extravillous trophoblast (EVT) invasion in vitro. Similarly, the PAR1 mutant hPar1-7A, which is unable to bind the PH domain, reduces mammary tumours and EVT invasion, endowing these motifs with physiological significance and underscoring the importance of these previously unknown PAR1 and PAR2 PH-domain-binding motifs in both pathological and physiological invasion processes. PMID- 26600194 TI - Bioethical procedure for decision-making in mental health. PMID- 26600195 TI - Clinical observations and molecular variables of patients with hearing loss and incomplete partition type III. AB - OBJECTIVES/HYPOTHESIS: To analyze the clinical manifestations and genetic features of patients with hearing loss (HL) and incomplete partition (IP) type III malformation, and to evaluate speech performance after cochlear implantation (CI) in these patients. STUDY DESIGN: Individual retrospective cohort study. METHODS: Of 206 probands with inner ear malformations (IEMs), we constructed a homogeneous cohort of 11 genetically documented IP type III (DFNX2). Mutations affecting POU3F4 were classified as extension (n = 2), truncation (n = 3), large genomic deletion (n = 2), or missense substitution (n = 4). Postoperative outcomes were rigorously assessed with focus on POU3F4 genotypes and compared with 80 age-matched implantees without IEMs. RESULTS: HL in our cohort was prelingual in onset irrespective of degree. Serviceable hearing was obtained by wearing conventional hearing aids in three, and eight subjects required CI. No correlation was found between mutation types and initial auditory phenotype. As for the eight cochlear implantees, average Categories of Auditory Perception score was <1 preoperatively and 3.9 at 2 years post-CI. Speech performances improved over the first 3 months postoperatively in a manner comparable to implantees without IEMs. However, it then tended to slow down until 1 year postoperatively, leading to worse scores at 2 years than implantees without IEMs. Furthermore, this was more evident in those with a truncation or deletion mutation. CONCLUSIONS: CI surgeons should be aware that postoperative auditory performance may be not as good in IP type III patients as in patients without IEMs. In particular, our study implies that certain types of POU3F4 mutations may have poorer prognoses than other types after CI. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:E123-E128, 2016. PMID- 26600196 TI - Management of mental health patients in Victorian emergency departments: A 10 year follow-up study. AB - OBJECTIVES: Despite efforts to restructure mental health (MH) services across Victoria, the social and economic burden of MH illness continues to grow. This study compares MH presentations to EDs with a study undertaken 10 years earlier. METHODS: The article is a retrospective observational study of MH presentations to four Victorian EDs between May and October 2013. Subjects were included if the presentation was MH related as determined by an International Classification of Diseases (version 10) discharge diagnosis, they were referred to an emergency crisis assessment team or had a documented presenting psychiatric complaint. Variables were extracted from electronic medical records and compared with 2004 data from a previous published study. RESULTS: There were 5659 MH presentations over the 5 months compared with 2788 in 2004. The median ED length of stay decreased from 4:18 h in 2004 to 3:20 h in 2013 (P < 0.001), with a significant reduction in length of stay >4 h from 52.5% to 35.4% (P < 0.001). There was a 22 fold increase in short stay units as discharge destination from 0.9% to 20.2% (P < 0.001). Patients presenting with concurrent methamphetamine exposure doubled from 2.2% of presentations to 4.3% (P < 0.001). CONCLUSION: Despite increasing MH related presentations, changes in ED practice have allowed improvements in delivery of care through a shortened ED length of stay and the virtual elimination of very long stays over 24 h. However, there continues to be significant variability in management and performance across hospital sites. Identifying which interventions lead to standout site performance, and subsequent application more broadly, may improve future ED delivery of care. PMID- 26600197 TI - MicroRNA-27a-3p Is a Negative Regulator of Lung Fibrosis by Targeting Myofibroblast Differentiation. AB - Although microRNAs (miRs) have been well recognized to play an important role in the pathogenesis of organ fibrosis, there is a lack of evidence as to whether miRs directly regulate the differentiation of myofibroblasts, the putative effector cells during pathological fibrogenesis. In this study, we found that levels of miR-27a-3p were up-regulated in transforming growth factor-beta1 treated human lung fibroblasts in a Smad2/3-dependent manner and in fibroblasts isolated from lungs of mice with experimental pulmonary fibrosis. However, both basal and transforming growth factor-beta1-induced expression of miR-27a-3p were reduced in lung fibroblasts from patients with idiopathic pulmonary fibrosis compared with that from normal control subjects. Overexpression of miR-27a-3p inhibited, whereas knockdown of miR-27a-3p enhanced, the differentiation of lung fibroblasts into myofibroblasts. We found that miR-27a-3p directly targeted the phenotypic marker of myofibroblasts, alpha-smooth muscle actin, and two key Smad transcription factors, Smad2 and Smad4. More importantly, we found that therapeutic expression of miR-27a-3p in mouse lungs through lentiviral delivery diminished bleomycin-induced lung fibrosis. In conclusion, our data suggest that miR-27a-3p functions via a negative-feedback mechanism in inhibiting lung fibrosis. This study also indicates that targeting miR-27a-3p is a novel therapeutic approach to treat fibrotic organ disorders, including lung fibrosis. PMID- 26600198 TI - Insights from Integrative Systematics Reveal Cryptic Diversity in Pristimantis Frogs (Anura: Craugastoridae) from the Upper Amazon Basin. AB - Pluralistic approaches to taxonomy facilitate a more complete appraisal of biodiversity, especially the diversification of cryptic species. Although species delimitation has traditionally been based primarily on morphological differences, the integration of new methods allows diverse lines of evidence to solve the problem. Robber frogs (Pristimantis) are exemplary, as many of the species show high morphological variation within populations, but few traits that are diagnostic of species. We used a combination of DNA sequences from three mitochondrial genes, morphometric data, and comparisons of ecological niche models (ENMs) to infer a phylogenetic hypothesis for the Pristimantis acuminatus complex. Molecular phylogenetic analyses revealed a close relationship between three new species-Pristimantis enigmaticus sp. nov., P. limoncochensis sp. nov. and P. omeviridis sp. nov.-originally confused with Pristimantis acuminatus. In combination with morphometric data and geographic distributions, several morphological characters such as degree of tympanum exposure, skin texture, ulnar/tarsal tubercles and sexual secondary characters (vocal slits and nuptial pads in males) were found to be useful for diagnosing species in the complex. Multivariate discriminant analyses provided a successful classification rate for 83-100% of specimens. Discriminant analysis of localities in environmental niche space showed a successful classification rate of 75-98%. Identity tests of ENMs rejected hypotheses of niche equivalency, although not strongly because the high values on niche overlap. Pristimantis acuminatus and P. enigmaticus sp. nov. are distributed along the lowlands of central-southern Ecuador and northern Peru, in contrast with P. limoncochensis sp. nov. and P. omeviridis sp. nov., which are found in northern Ecuador and southern Colombia, up to 1200 m in the upper Amazon Basin. The methods used herein provide an integrated framework for inventorying the greatly underestimated biodiversity in Amazonia. PMID- 26600199 TI - Using Blood Indexes to Predict Overweight Statuses: An Extreme Learning Machine Based Approach. AB - The number of the overweight people continues to rise across the world. Studies have shown that being overweight can increase health risks, such as high blood pressure, diabetes mellitus, coronary heart disease, and certain forms of cancer. Therefore, identifying the overweight status in people is critical to prevent and decrease health risks. This study explores a new technique that uses blood and biochemical measurements to recognize the overweight condition. A new machine learning technique, an extreme learning machine, was developed to accurately detect the overweight status from a pool of 225 overweight and 251 healthy subjects. The group included 179 males and 297 females. The detection method was rigorously evaluated against the real-life dataset for accuracy, sensitivity, specificity, and AUC (area under the receiver operating characteristic (ROC) curve) criterion. Additionally, the feature selection was investigated to identify correlating factors for the overweight status. The results demonstrate that there are significant differences in blood and biochemical indexes between healthy and overweight people (p-value < 0.01). According to the feature selection, the most important correlated indexes are creatinine, hemoglobin, hematokrit, uric Acid, red blood cells, high density lipoprotein, alanine transaminase, triglyceride, and gamma-glutamyl transpeptidase. These are consistent with the results of Spearman test analysis. The proposed method holds promise as a new, accurate method for identifying the overweight status in subjects. PMID- 26600200 TI - VEGFR2 Gene Polymorphism Correlates with Deep Venous Thrombosis Risk in Chinese Han Population. AB - OBJECTIVE: To investigate the correlations between three vascular endothelial growth factor 2 (VEGFR2) gene polymorphisms, +1192C>T, +1719T>A, and -604T>C, and deep venous thrombosis (DVT) in Chinese Han population. METHODS: We conducted a case-control study, between September 2009 and September 2012, in a Chinese Han population with onset of lower extremity DVT. A total of 135 patients were enrolled in the case group and 156 healthy individuals in the control group. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to detect the genotype and allele frequencies of the VEGFR2 gene polymorphisms +1192C>T, +1719T>A, and -604T>C. Haplotype analyses were conducted with SHEsis program. Logistic regression was used to detect the risk factors of DVT. Outpatient review and telephone follow-up were conducted to analyze the long term treatment of DVT patients. RESULTS: The allele and genotype frequencies of 604T>C VEGFR2 polymorphism exhibited significant differences between the case and control groups (both p < 0.05). Haplotype analyses showed remarkable differences between the case and control groups in the distribution frequency of TAC and CTT haplotypes in the VEGFR2 gene (both p < 0.05). Logistic regression analysis showed independent correlation between the incidence of DVT and TAC haplotype in the VEGFR2 gene (p < 0.05). In addition, the TAC haplotype may be a risk factor for DVT treatment failure. CONCLUSION: Our findings suggest that the VEGFR2 gene 604T>C polymorphism and TAC haplotype are associated with DVT, and the TAC haplotype might affect the efficacy of long-term treatment of DVT patients. PMID- 26600201 TI - Musculoskeletal Pain as a Marker of Health Quality. Findings from the Epidemiological Sleep Study among the Adult Population of Sao Paulo City. AB - BACKGROUND: We are witnessing the growth of urban populations, particularly in the developing world. Sao Paulo, the largest city in South America, continues to grow, and this growth is dramatically effecting the environment and human health. The aim of this study was to estimate the point prevalence of chronic pain in Sao Paulo city dwellers and to explore the influence of aspects related to urbanicity. METHODS: A two-stage cluster randomized sample included 1100 individuals of the city of Sao Paulo, representing the population proportionally in terms of gender, age and social classes in 2007. For this observational cross sectional study, the household sample was interviewed using validated questionnaires for sociodemographic aspects, the Beck inventories for anxiety and depression, the WHOQoL-REF for quality of life, the Chalder Fatigue Scale. Musculoskeletal pain was defined as diffuse pain or pain located in the back, joints or limbs. Data regarding sleep complaints and polysomnography were obtained from the Epidemiologic Sleep Study conducted in Sao Paulo city in 2007. RESULTS: The prevalence estimate of chronic musculoskeletal pain was approximately 27%, with a female/male ratio of approximately 2.6/1. The predictors were being in the age-range of 30-39 years, low socioeconomic and schooling levels, obesity, sedentarism, fatigue, non-restorative sleep, daytime sleepiness, poor sleep quality, poor life quality, anxiety and depression symptoms. Psychological wellbeing was the main discriminator between responders with chronic musculoskeletal pain and the controls, followed by depression for the participants with poor psychological wellbeing, and fatigue, for the remaining ones. Insomnia syndrome was the third-level discriminator for those with fatigue, whereas sleep quality for those without fatigue. CONCLUSIONS: Musculoskeletal pain was frequently reported by Sao Paulo city dwellers and its correlates with psychological and sleep aspects are suggestive of a response to urbanicity. TRIAL REGISTRATION: ClinicalTrials.gov NCT00596713. PMID- 26600202 TI - Multiplex Phenotyping for Systems Medicine: A One-Point Optimized Practical Sampling Strategy for Simultaneous Estimation of CYP1A2, CYP2C9, CYP2C19, and CYP2D6 Activities Using a Cocktail Approach. AB - Phenotyping of the CYP450 enzyme activities contributes to personalized medicine, but the past phenotyping approaches have followed a piecemeal strategy measuring single enzyme activities in vivo. A barrier to phenotyping of populations in rural and remote areas is the limited time and resources for sample collection. The CEIBA cocktail approach allows metabolic capacity estimation of multiple CYP450 enzymes in a single sample analysis, but the attendant sample collection schemes for applications in diverse global settings are yet to be optimized. The present study aimed to select an optimal matrix to simultaneously analyze CYP450 enzyme activities so as to simplify the sampling schemes in the phenotyping protocol to enhance its throughput and feasibility in native populations or in remote and underserviced geographies and social contexts. We evaluated 13 Ecuadorian healthy volunteers for CYP1A2, CYP2C9, CYP2C19, and CYP2D6 genotypes and their metabolic phenotypes, including CYP3A4, in plasma and urine after administering one reduced dose of caffeine, losartan, omeprazole, and dextromethorphan. Pharmacokinetic analyses were performed, and the correlation between AUC parent/AUC metabolite and the ratio between concentrations of probe drugs and their corresponding metabolites at timepoints ranging from 0 to 12 hours post-dose were analyzed. A single sampling timepoint, 4 hours post-dose in plasma, was identified as optimal to reflect the metabolic activity of the attendant CYP450 enzymes. This study optimizes the CEIBA multiplexed phenotyping approach and offers new ways forward for integrated drug metabolism analyses, in the pursuit of global personalized medicine applications in resource-limited regions, be they in developed or developing countries. PMID- 26600203 TI - Anti-biofilm and bactericidal effects of magnolia bark-derived magnolol and honokiol on Streptococcus mutans. AB - Dental caries affects people of all ages and is a worldwide health concern. Streptococcus mutans is a major cariogenic bacterium because of its ability to form biofilm and induce an acidic environment. In this study, the antibacterial activities of magnolol and honokiol, the main constituents of the bark of magnolia plants, toward planktonic cell and biofilm of S. mutans were examined and compared with those of chlorhexidine. The minimal inhibitory concentrations of magnolol, honokiol and chlorhexidine for S. mutans were 10, 10 and 0.25 ug/mL, respectively. In addition, each agent showed bactericidal activity against S. mutans planktonic cells and inhibited biofilm formation in a dose- and time dependent manner. Magnolol (50 ug/mL) had greater bactericidal activity against S. mutans biofilm than honokiol (50 ug/mL) and chlorhexidine (500 ug/mL) at 5 min after exposure, while all showed scant activity against biofilm at 30 s. Furthermore; chlorhexidine (0.5-500 ug/mL) exhibited high cellular toxicity for the gingival epithelial cell line Ca9-22 at 1 hr, whereas magnolol (50 ug/mL) and honokiol (50 ug/mL) did not. Thus; it was found that magnolol has antimicrobial activities against planktonic and biofilm cells of S. mutans. Magnolol may be a candidate for prevention and management of dental caries. PMID- 26600204 TI - A Metabolomic Approach To Detect Effects of Salmon Farming on Wild Saithe (Pollachius virens) Populations. AB - A metabolomics approach was used to analyze effects of salmon farming on wild saithe (Pollachius virens) populations. Saithe fish were captured at two salmon farms and at two control locations around the island of Hitra, Norway. Changes in diet seem to drive changes in metabolic status of fishes. The liver and muscle tissues, from the fishes captured around the farm, showed higher levels of lactate and certain amino acids (glutamine, glutamate, and alanine) and lower levels of glucose and choline than the fishes captured in the control locations, far from the farm locations. The higher levels of lactate and amino acids could be related to the facility of obtaining food around the farm and the deficit in choline to the deficit of this nutrient in the salmon feed. At each location the fish were captured with either benthic gill nets and automatic jigging machines, and this feature showed also variations in different metabolites. PMID- 26600206 TI - Crystal-to-crystal transformation from a chain compound to a layered coordination polymer. AB - A crystal-to-crystal transformation was observed from a green chain compound CuBr2(1,4-dioxane)2(H2O)2 (1) to a brown layered compound (CuBr2)3(1,4-dioxane)2 (2). The hydrogen bond connecting chains in were replaced by a MU-Br bridge in and the antiferromagnetic interaction between the metal atoms in became stronger than in 1. PMID- 26600205 TI - Diversity of Multi-Drug Resistant Avian Pathogenic Escherichia coli (APEC) Causing Outbreaks of Colibacillosis in Broilers during 2012 in Spain. AB - Avian pathogenic Escherichia coli (APEC) are the major cause of colibacillosis in poultry production. In this study, a total of 22 E. coli isolated from colibacillosis field cases and 10 avian faecal E. coli (AFEC) were analysed. All strains were characterised phenotypically by susceptibility testing and molecular typing methods such as pulsed-field gel electrophoresis (PFGE) and multi-locus sequence typing (MLST). The presence of 29 virulence genes associated to APEC and human extraintestinal pathogenic E. coli (ExPEC) was also evaluated. For cephalosporin resistant isolates, cephalosporin resistance genes, plasmid location and replicon typing was assessed. Avian isolates belonged to 26 O:H serotypes and 24 sequence types. Out of 22 APEC isolates, 91% contained the virulence genes predictors of APEC; iutA, hlyF, iss, iroN and ompT. Of all strains, 34% were considered ExPEC. PFGE analysis demonstrated a high degree of genetic polymorphism. All strains were multi-resistant, including those isolated from healthy animals. Eleven strains were resistant to cephalosporins; six contained blaCTX-M-14, two blaSHV-12, two blaCMY-2 and one blaSHV-2. Two strains harboured qnrA, and two qnrA together with aac(6')-Ib-cr. Additionally, the emergent clone O25b:H4-B2-ST131 was isolated from a healthy animal which harboured blaCMY-2 and qnrS genes. Cephalosporin resistant genes were mainly associated to the presence of IncK replicons. This study demonstrates a very diverse population of multi-drug resistant E. coli containing a high number of virulent genes. The E. coli population among broilers is a reservoir of resistance and virulence-associated genes that could be transmitted into the community through the food chain. More epidemiological studies are necessary to identify clonal groups and resistance mechanisms with potential relevance to public health. PMID- 26600207 TI - Evaluation of the oenological suitability of grapes grown using biodynamic agriculture: the case of a bad vintage. AB - AIMS: We compare the evolution of the microbiota of grapes grown following conventional or biodynamic protocols during the final stage of ripening and wine fermentation in a year characterized by adverse climatic conditions. METHODS AND RESULTS: The observations were made in a vineyard subdivided into two parts, cultivated using a biodynamic and traditional approach in a year which saw a combination of adverse events in terms of weather, creating the conditions for extensive proliferation of vine pests. The biodynamic approach was severely tested, as agrochemicals were not used and vine pests were counteracted with moderate use of copper, sulphur and plant extracts and with intensive use of agronomical practices aimed at improving the health of the vines. Agronomic, microbiological and chemical testing showed that the response of the vineyard cultivated using a biodynamic approach was comparable or better to that of vines cultivated using the conventional method. CONCLUSIONS: The work suggests that biodynamic cultivation of the grapevine may be sustainable even in difficult conditions, representing an interesting alternative to traditional vine-growing approaches. SIGNIFICANCE AND IMPACT OF THE STUDY: This theme is topical and of interest to winemakers and consumers today, but is not easy to study due to the difficulties in finding vineyards with homogeneous characteristics, cultivated using different agronomical protocols. The particular climatic conditions observed in 2014 made this year a rare model, making it possible to verify the applicability of biodynamics to vine growing. The strict experimental plan gave results particularly useful for understanding the features of grape microbiota in a biodynamic context. PMID- 26600208 TI - Mycotoxin contamination of home-grown maize in rural northern South Africa (Limpopo and Mpumalanga Provinces). AB - The aim of this study was to assess mycotoxin contamination of crops grown by rural subsistence farmers over two seasons (2011 and 2012) in two districts, Vhembe District Municipality (VDM, Limpopo Province) and Gert Sibande District Municiality (GSDM, Mpumalanga Province), in northern South Africa and to evaluate its impact on farmers' productivity and human and animal health. A total of 114 maize samples were collected from 39 households over the two seasons and were analysed using a validated liquid chromatography-tandem mass spectrometry mycotoxins method. Aflatoxin B1 (AFB1) occurrence ranged from 1 to 133 ug kg(-1) in VDM while AFB1 levels in GSDM were less than 1.0 ug kg(-1) in all maize samples. Fumonisin B1 levels ranged from 12 to 8514 ug kg(-1) (VDM) and 11-18924 ug kg(-1) (GSDM) in 92% and 47% positive samples, respectively, over both seasons. Natural occurrence and contamination with both fumonisins and aflatoxins in stored home-grown maize from VDM was significantly (p < 0.0001) higher than from GSDM over both seasons. PMID- 26600209 TI - Correction to "Triple Benzannulation of Naphthalene via a 1,3,6-Naphthotriyne Synthetic Equivalent. Synthesis of Dibenz[a,c]anthracene". PMID- 26600210 TI - Neutral lipid-storage disease with myopathy and extended phenotype with novel PNPLA2 mutation. AB - INTRODUCTION: Neutral lipid-storage disease with myopathy is caused by mutations in PNPLA2, which produce skeletal and cardiac myopathy. We report a man with multiorgan neutral lipid storage and unusual multisystem clinical involvement, including cognitive impairment. METHODS: Quantitative brain MRI with voxel-based morphometry and extended neuropsychological assessment were performed. In parallel, the coding sequences and intron/exon boundaries of the PNPLA2 gene were screened by direct sequencing. RESULTS: Neuropsychological assessment revealed global cognitive impairment, and brain MRI showed reduced gray matter volume in the temporal lobes. Molecular characterization revealed a novel homozygous mutation in exon 5 of PNPLA2 (c.714C>A), resulting in a premature stop codon (p.Cys238*). CONCLUSIONS: Some PNPLA2 mutations, such as the one described here, may present with an extended phenotype, including brain involvement. In these cases, complete neuropsychological testing, combined with quantitative brain MRI, may help to characterize and quantify cognitive impairment. PMID- 26600212 TI - Recipient aging accelerates acquired transthyretin amyloidosis after domino liver transplantation. AB - Domino liver transplantation (DLT) with liver grafts from patients with hereditary transthyretin (TTR) amyloidosis has been performed throughout the world because of a severe liver graft shortage. Reports of acquired systemic TTR amyloidosis in domino liver recipients have been increasing; however, the precise pathogenesis and clinical course of acquired TTR amyloidosis remains unclear. We analyzed the relationship between the occurrence of acquired amyloidosis and clinical features in 22 consecutive domino liver donors with hereditary TTR amyloidosis (10 males and 12 females; mean age at DLT: 37.2 years; TTR mutations: V30M [n = 19], Y114C [n = 1], L55P [n = 1], and S50I [n = 1]) and 22 liver recipients (16 males and 6 females; mean age at DLT, 46.2 years). The mean times from DLT to amyloid first appearance and transplant recipient symptom onset were 8.2 years and 9.9 years, respectively. Kaplan-Meier analysis and quantification of the amyloid deposition revealed aging of recipients correlated with early de novo amyloid deposition. The sex of donors and recipients and the age, disease duration, and disease severity of donors had no significant effect on the latency of de novo amyloid deposition. In conclusion, our results demonstrate that recipient aging is associated with the early onset de novo amyloidosis. Because acquired amyloidosis will likely increase, careful follow-up for early amyloidosis detection and new treatments, including TTR stabilizers and gene silencing therapies, are required. Liver Transplantation 22 656-664 2016 AASLD. PMID- 26600211 TI - Trachoma and Relative Poverty: A Case-Control Study. AB - BACKGROUND: Trachoma is widely considered a disease of poverty. Although there are many epidemiological studies linking trachoma to factors normally associated with poverty, formal quantitative data linking trachoma to household economic poverty within endemic communities is very limited. METHODOLOGY/PRINCIPAL FINDINGS: Two hundred people with trachomatous trichiasis were recruited through community-based screening in Amhara Region, Ethiopia. These were individually matched by age and gender to 200 controls without trichiasis, selected randomly from the same sub-village as the case. Household economic poverty was measured through (a) A broad set of asset-based wealth indicators and relative household economic poverty determined by principal component analysis (PCA, (b) Self-rated wealth, and (c) Peer-rated wealth. Activity participation data were collected using a modified 'Stylised Activity List' developed for the World Bank's Living Standards Measurement Survey. Trichiasis cases were more likely to belong to poorer households by all measures: asset-based analysis (OR = 2.79; 95%CI: 2.06 3.78; p<0.0001), self-rated wealth (OR, 4.41, 95%CI, 2.75-7.07; p<0.0001) and peer-rated wealth (OR, 8.22, 95% CI, 4.59-14.72; p<0.0001). Cases had less access to latrines (57% v 76.5%, p = <0.0001) and higher person-to-room density (4.0 v 3.31; P = 0.0204) than the controls. Compared to controls, cases were significantly less likely to participate in economically productive activities regardless of visual impairment and other health problems, more likely to report difficulty in performing activities and more likely to receive assistance in performing productive activities. CONCLUSIONS/SIGNIFICANCE: This study demonstrated a strong association between trachomatous trichiasis and relative poverty, suggesting a bidirectional causative relationship possibly may exist between poverty and trachoma. Implementation of the full SAFE strategy in the context of general improvements might lead to a virtuous cycle of improving health and wealth. Trachoma is a good proxy of inequality within communities and it could be used to target and evaluate interventions for health and poverty alleviation. PMID- 26600213 TI - Femtosecond Nanostructuring of Glass with Optically Trapped Microspheres and Chemical Etching. AB - Laser processing with optically trapped microspheres is a promising tool for nanopatterning at subdiffraction-limited resolution in a wide range of technological and biomedical applications. In this paper, we investigate subdiffraction-limited structuring of borosilicate glass with femtosecond pulses in the near-field of optically trapped microspheres combined with chemical postprocessing. The glass surface was processed by single laser pulses at 780 nm focused by silica microspheres and then subjected to selective etching in KOH, which produced pits in the laser-affected zones (LAZs). Chemical postprocessing allowed obtaining structures with better resolution and reproducibility. We demonstrate production of reproducible pits with diameters as small as 70 nm (lambda/11). Complex two-dimensional structures with 100 nm (lambda/8) resolution were written on the glass surface point by point with microspheres manipulated by optical tweezers. Furthermore, the mechanism of laser modification underlying selective etching was investigated with mass spectrum analysis. We propose that the increased etching rate of laser-treated glass results from changes in its chemical composition and oxygen deficiency. PMID- 26600214 TI - Comprehending the effect of MMoO4 (M = Co, Ni) nanoflakes on improving the electrochemical performance of NiO electrodes. AB - The design and fabrication of high performance supercapacitors with a high specific capacitance and a long lifespan still remain a challenge. We present two hydrothermal and two annealing processes for the fabrication of hierarchical heterostructures of NiO@MMoO4 (M = Co, Ni) nanosheet arrays on Ni foam. In this hierarchical structure, numerous MMoO4 nanoflakes grow on a NiO nanosheet and the integration of MMoO4 can improve the whole electrode's conductivity, leading to an ideal pathway for electron and ion transport. The hierarchical NiO@MMoO4 (M = Co, Ni) heterostructure electrode demonstrated remarkable electrochemical performance with a high specific capacitance and predominant cycling stability, making it one of the prospective electrode materials for high performance supercapacitors. PMID- 26600215 TI - Epidemiology of Hepatitis C Virus: A Battle on New Frontiers. AB - The hepatitis C virus (HCV) is a leading cause of liver-related morbidity and mortality in the United States and other parts of the world. The epidemiology of the disease is highly variable between and within countries, and strategies to deal with HCV identification and treatment must be tailored to the geographic location and the political and economic environment of the region. Although great strides have been made in improving HCV transmission risk in blood supply products, new challenges related to changing patterns of disease incidence continue to require fresh evaluation and new approaches to disease prevention. PMID- 26600218 TI - Impact of Hepatitis C Virus Infection on Hepatocellular Carcinoma. AB - Hepatitis C virus (HCV)-associated hepatocellular carcinoma (HCC) incidence in the United States is increasing, partly because of risk factors such as diabetes, fatty liver, hepatitis B virus, and human immunodeficiency virus coinfection. Achieving sustained virologic response (SVR) is the most significant factor in reducing HCV-associated HCC incidence. Improved SVR with the next generation of direct-acting antivirals brings hope for decreased HCC mortality. Nevertheless, surveillance for HCC remains important because HCC can still occur despite SVR, especially in cirrhotics. Individualized risk stratification through increased understanding of HCC pathogenesis and improved surveillance holds the promise for future reduction of HCC incidence. PMID- 26600216 TI - Natural History of Hepatitis C. AB - Hepatitis C infection is a common cause of cirrhosis and indication for liver transplantation in the United States. The incidence of chronic hepatitis C has been declining, but rates of cirrhosis and hepatocellular carcinoma are projected to increase. The outcome of chronic hepatitis C is variable. It is estimated that 20% to 25% will develop cirrhosis over a 25-year to 30-year period. The rate of disease progression is influenced by many host, viral, and environmental factors. Few can be modified. PMID- 26600219 TI - Extrahepatic Manifestations of Hepatitis C Virus. AB - Chronic infection with the hepatitis C virus (HCV) is a major cause of liver disease worldwide and is also responsible for extrahepatic manifestations (EHMs) involving the skin, kidneys, salivary glands, eyes, thyroid, and immune system. Mixed cryoglobulinemia is the prototype EHM related to HCV infection. Although these HCV-related EHMs may contribute to significant rates of morbidity affecting patient's quality of life and survival, most of these complications can reverse after HCV eradication by interferon therapy. This notwithstanding, individual patients may have an irreversible injury in various organs that is not reversed by a cure of the HCV infection. PMID- 26600220 TI - Hepatitis C: An Eastern Perspective. AB - HCV in the East is a complex scenario with prevalence rates of 0.5% to as high as 4.7%, and variable distributions of genotypes, with a dominance of genotype 1b in East Asia, genotype 3 in South Asia and South East Asia, and genotype 6 in Indochina. Approvals for the new oral directing antiviral agents (DAAs), in the East have been very slow, but ultimately will be achieved by 2019, consequently, pegylated interferon and ribavirin are still widely used. Nonetheless the main issues are the problems of screening and linkage to management, and the considerable barriers to access HCV care. PMID- 26600221 TI - Hepatitis C Virus: A European Perspective. AB - Chronic hepatitis C virus (HCV) infection is a major public health burden in Europe, being one of the leading causes of chronic liver disease, liver cirrhosis, and hepatocellular carcinoma. Properties of the HCV disease burden are heterogeneous across the European continent, with differences in incidence, prevalence, diagnosis and treatment rates, transmission routes, and genotype distribution. Recent estimates expect an increase in HCV-related morbidity and mortality in most European countries until 2030 even when current treatment options are taken into account. The European perspective on hepatitis C virus infection is summarized herein. PMID- 26600222 TI - Current and Evolving Treatments of Genotype 1 Hepatitis C Virus. AB - Development of antiviral agents that target the hepatitis C virus (HCV) has improved the success and tolerability of treatment, especially for patients with HCV genotype 1 infection. The new treatment options mean that clinicians are better able to prevent complications from chronic HCV infection. The field of direct-acting antiviral therapies for HCV infection continues to advance at a rapid pace, and many more potential treatment regimens are being investigated. This article presents a summary of the current treatments available for patients infected with HCV genotype 1 and looks ahead to those that may play a role in the future. PMID- 26600223 TI - Hepatitis C Virus: Current and Evolving Treatments for Genotypes 2 and 3. AB - Hepatitis C virus (HCV) genotypes 2 and 3 have previously been classified as easy to-treat genotypes, because sustained virologic responses (SVRs) up to 80% have been achieved with 24-week peginterferon and ribavirin. More detailed studies have shown differences between HCV genotypes 2 and 3, indicating that genotype 3 has become the most difficult-to-treat genotype. With new drugs, new challenges are emerging regarding relapse rates, the role of ribavirin, and optimal duration of therapy. Sofosbuvir remains the backbone of genotype 3 therapy, whereas this drug is not an option in patients with creatinine clearance lower than 30 mL/min. PMID- 26600224 TI - Hepatitis C Virus: Current and Evolving Treatments for Genotype 4. AB - Hepatitis C virus (HCV) is a major cause of chronic liver disease, with more than 170 million infected individuals worldwide. Genotype 4 is the most frequent cause of chronic hepatitis C in the Middle East and sub-Saharan Africa. It has recently spread to southern Europe. The introduction of all-oral, interferon-free regimens that combine direct-acting antivirals (DAAs) has significantly advanced HCV treatment. High efficacy rates, short treatment duration, and favorable adverse event profiles have been demonstrated with multiple regimens, both with and without ribavirin. This review discusses management of patients with HCV genotype 4 chronic hepatitis, in the era of DAAs. PMID- 26600217 TI - Immunopathogenesis of Hepatitis C Virus Infection. AB - Despite advances in therapy, hepatitis C virus infection remains a major global health issue with 3 to 4 million incident cases and 170 million prevalent chronic infections. Complex, partially understood, host-virus interactions determine whether an acute infection with hepatitis C resolves, as occurs in approximately 30% of cases, or generates a persistent hepatic infection, as occurs in the remainder. Once chronic infection is established, the velocity of hepatocyte injury and resultant fibrosis is significantly modulated by immunologic as well as environmental factors. Immunomodulation has been the backbone of antiviral therapy despite poor understanding of its mechanism of action. PMID- 26600225 TI - Current Treatment Options in Patients with Hepatitis C Virus Genotype 6. AB - Approximately 3% of the world's population is chronically infected with hepatitis C virus (HCV). In some southeast Asian countries the prevalence of HCV (~6%-7%) far exceeds that seen in the United States (1.8%). The lesser known HCV genotype 6 (HCV-6) is also common in patients from southeast Asia and the surrounding regions. Most data on direct-acting antivirals (DAAs) to date have been derived from clinical trials conducted in Western countries, where HCV-6 is rare. The standard of care for patients with HCV-6 is still pegylated interferon and ribavirin. However, data are emerging for several DAA combinations. PMID- 26600226 TI - Treatment of Chronic Hepatitis C in Special Populations. AB - The management of hepatitis C virus (HCV) infection in special populations is challenging. The efficacy and safety data of the currently approved all-oral direct-acting antiviral combinations, including sofosbuvir, ledipasvir, daclatasvir, paritaprevir/ritonavir/ombitasvir plus dasabuvir (3D), and ribavirin, is compelling for use in special HCV populations, as has recently been recommended by expert guidelines. The treatment regimens and sustained virological response rates for special populations are nearly similar to those of the general HCV population. Sofosbuvir is not recommended in patients with severe renal impairment, and simeprevir and 3D regimen are not recommended for those with decompensated liver disease. PMID- 26600227 TI - Hepatitis C: Issues in Children. AB - Hepatitis C infection is a global health problem. Most infected children have not been identified. Perinatal transmission is the most common mode of acquisition. Liver disease owing to chronic hepatitis C virus (HCV) infection progresses slowly in individuals infected early in life. Serious complications rarely affect patients during childhood. Successful treatment of HCV in adults has improved and recommendations have changed. Treatment in children should be deferred until direct-acting antivirals and interferon-free regimens are available to this population. If treatment cannot be deferred, regimens including peginterferon and ribavirin can be given to children with compensated liver disease. PMID- 26600228 TI - Hepatitis C Virus. PMID- 26600229 TI - Hepatitis C: Unfolding the Challenges. PMID- 26600230 TI - Characteristics of babies who unexpectedly survive long term after withdrawal of intensive care. AB - AIM: Occasional babies survive long term after withdrawal of intensive care despite a poor prognosis. We aimed to review in detail the clinical cases, characteristics, and outcomes of neonates with unexpected protracted survival following planned withdrawal of intensive cardiorespiratory support. METHODS: We reviewed infants who unexpectedly survived for more than one week following planned withdrawal of intensive care in two tertiary-level NICUs over a seven year period. RESULTS: We identified eight long-term survivors (six term, two preterm) between 2007 and 2013. All had a clinical diagnosis of grade 3 hypoxic ischaemic encephalopathy and severely abnormal electroencephalography and neuroimaging prior to intensive care withdrawal. Intensive care was withdrawn at five days postnatal age (range: two to nine days), but the possibility of protracted survival was discussed beforehand in only two cases. Three infants died before three months of age. Five infants remain alive, currently aged from 2.0 to 6.5 years, and all have significant neurodevelopmental problems. CONCLUSION: Unexpected long-term survival after neonatal intensive care withdrawal occurs occasionally but unpredictably. Significant neurodevelopmental adversity was invariable in those surviving beyond infancy. Ventilator dependency along with severely abnormal electroencephalography and neuroimaging is still compatible with long-term survival. The possibility of protracted survival should be discussed routinely with parents before intensive care withdrawal. PMID- 26600232 TI - Suicide Within 72 Hours After Discharge From Health Care Settings: Decedent Characteristics. AB - Health care providers have the challenge of identifying patients at risk of committing suicide after discharge from their care. The aim of this study was to identify and describe the population committing suicide less than 72 hours after discharge from medical care. Between 2006 and 2014 in Harris County, Texas, 30 individuals were identified who met these criteria. The decedents included 27 men and 3 women with a mean age of 43.5 years. The cause of death in most cases was gunshot wound of the head. Five of the decedents had requested discharge or left against medical advice and 24 committed suicide within 24 hours. Although the sample size is small, it is one of the largest cohorts of its type. PMID- 26600233 TI - Fatal Hyponatremic Encephalopathy as a Result of Child Abuse From Forced Exercise. AB - We report a case of fatal hyponatremic encephalopathy in a child who was forced to exercise as a form of punishment. A 9-year-old girl with attention deficit/hyperactivity disorder was forced to run repeated 50-ft sprints to the point of exhaustion by her grandmother as punishment for taking candy from a classmate. After more than 3 hours of forced running, the child collapsed, began to vomit, and had repeated clonic seizures. Upon presentation to the emergency department, she was nonresponsive with a Glasgow Coma Scale score of 11 and had noncardiogenic pulmonary edema with serum sodium of 117 mEq/L. She was treated with antiepilectic medications and transferred to a university children's hospital where she later died. On postmortem examination, she was found to have massive cerebral edema with transtentorial herniation and pulmonary edema. Her clinical presentation closely resembled exercise-associated hyponatremic encephalopathy seen in adult endurance athletes. This appears to be the first report of fatal exercise-associated hyponatremia in a child. PMID- 26600234 TI - Redox-Active Molecular Nanowire Flash Memory for High-Endurance and High-Density Nonvolatile Memory Applications. AB - In this work, high-performance top-gated nanowire molecular flash memory has been fabricated with redox-active molecules. Different molecules with one and two redox centers have been tested. The flash memory has clean solid/molecule and dielectric interfaces, due to the pristine molecular self-assembly and the nanowire device self-alignment fabrication process. The memory cells exhibit discrete charged states at small gate voltages. Such multi-bit memory in one cell is favorable for high-density storage. These memory devices exhibit fast speed, low power, long memory retention, and exceptionally good endurance (>10(9) cycles). The excellent characteristics are derived from the intrinsic charge storage properties of the protected redox-active molecules. Such multi-bit molecular flash memory is very attractive for high-endurance and high-density on chip memory applications in future portable electronics. PMID- 26600236 TI - Domino Oxidative [Pd]-Catalysis: One-Pot Synthesis of Fluorenones Starting from Simple Benzylamines and Iodo Arenes. AB - A domino [Pd]-catalysis for the efficient synthesis of fluorenones is presented. The overall reaction proceeds through the formation of a five membered Pd(II) cycle via a highly regioselective ortho C(sp(2))-H activation(s) of simple benzylamine that combines with external iodo arenes to give ortho arylated products. Significantly, the reaction further activates the C(sp(3))-H and C(sp(2))-H (intramolecular oxidative Heck coupling) bonds to give tricyclic imine systems. Then the usual water workup affords the fused tricyclic ketones (fluorenones). Remarkably, this one-pot operation enabled the effective construction of two C-C to three C-C bonds. PMID- 26600237 TI - Selection for population-specific adaptation shaped patterns of variation in the photoperiod pathway genes in Arabidopsis lyrata during post-glacial colonization. AB - Spatially varying selection can lead to population-specific adaptation, which is often recognized at the phenotypic level; however, the genetic evidence is weaker in many groups of organisms. In plants, environmental shifts that occur due to colonization of a novel environment may require adaptive changes in the timing of growth and flowering, which are often governed by location-specific environmental cues such as day length. We studied locally varying selection in 19 flowering time loci in nine populations of the perennial herb Arabidopsis lyrata, which has a wide but patchy distribution in temperate and boreal regions of the northern hemisphere. The populations differ in their recent population demographic and colonization histories and current environmental conditions, especially in the growing season length. We searched for population-specific molecular signatures of directional selection by comparing a set of candidate flowering time loci with a genomic reference set within each population using multiple approaches and contrasted the patterns of different populations. The candidate loci possessed approximately 20% of the diversity of the reference loci. On average the flowering time loci had more rare alleles (a smaller Tajima's D) and an excess of highly differentiated sites relative to the reference, suggesting positive selection. The strongest signal of selection was detected in photoperiodic pathway loci in the colonizing populations of Northwestern Europe, whereas no evidence of positive selection was detected in the Central European populations. These findings emphasized the population-specific nature of selection and suggested that photoperiodic adaptation was important during postglacial colonization of the species. PMID- 26600238 TI - Diverse Burkholderia Species Isolated from Soils in the Southern United States with No Evidence of B. pseudomallei. AB - The global distribution of the soil-dwelling bacterium Burkholderia pseudomallei, causative agent of melioidosis, is poorly understood. We used established culturing methods developed for B. pseudomallei to isolate Burkholderia species from soil collected at 18 sampling sites in three states in the southern United States (Arizona (n = 4), Florida (n = 7), and Louisiana (n = 7)). Using multi locus sequence typing (MLST) of seven genes, we identified 35 Burkholderia isolates from these soil samples. All species belonged to the B. cepacia complex (Bcc), including B. cenocepacia, B. cepacia, B. contaminans, B. diffusa, B. metallica, B. seminalis, B. vietnamiensis and two unnamed members of the Bcc. The MLST analysis provided a high level of resolution among and within these species. Despite previous clinical cases within the U.S. involving B. pseudomallei and its close phylogenetic relatives, we did not isolate any of these taxa. The Bcc contains a number of opportunistic pathogens that cause infections in cystic fibrosis patients. Interestingly, we found that B. vietnamiensis was present in soil from all three states, suggesting it may be a common component in southern U.S. soils. Most of the Burkholderia isolates collected in this study were from Florida (30/35; 86%), which may be due to the combination of relatively moist, sandy, and acidic soils found there compared to the other two states. We also investigated one MLST gene, recA, for its ability to identify species within Burkholderia. A 365bp fragment of recA recovered nearly the same species-level identification as MLST, thus demonstrating its cost effective utility when conducting environmental surveys for Burkholderia. Although we did not find B. pseudomallei, our findings document that other diverse Burkholderia species are present in soils in the southern United States. PMID- 26600239 TI - SINCERA: A Pipeline for Single-Cell RNA-Seq Profiling Analysis. AB - A major challenge in developmental biology is to understand the genetic and cellular processes/programs driving organ formation and differentiation of the diverse cell types that comprise the embryo. While recent studies using single cell transcriptome analysis illustrate the power to measure and understand cellular heterogeneity in complex biological systems, processing large amounts of RNA-seq data from heterogeneous cell populations creates the need for readily accessible tools for the analysis of single-cell RNA-seq (scRNA-seq) profiles. The present study presents a generally applicable analytic pipeline (SINCERA: a computational pipeline for SINgle CEll RNA-seq profiling Analysis) for processing scRNA-seq data from a whole organ or sorted cells. The pipeline supports the analysis for: 1) the distinction and identification of major cell types; 2) the identification of cell type specific gene signatures; and 3) the determination of driving forces of given cell types. We applied this pipeline to the RNA-seq analysis of single cells isolated from embryonic mouse lung at E16.5. Through the pipeline analysis, we distinguished major cell types of fetal mouse lung, including epithelial, endothelial, smooth muscle, pericyte, and fibroblast-like cell types, and identified cell type specific gene signatures, bioprocesses, and key regulators. SINCERA is implemented in R, licensed under the GNU General Public License v3, and freely available from CCHMC PBGE website, https://research.cchmc.org/pbge/sincera.html. PMID- 26600240 TI - Psychometric Validation of the Japanese Version of the Neuropathic Pain Symptom Inventory. AB - OBJECTIVE: This study aimed to evaluate the validity and reliability of the Japanese version of the Neuropathic Pain Symptom Inventory (NPSI-J). DESIGN: Cross-sectional study design. SUBJECTS AND METHODS: The original Neuropathic Pain Symptom Inventory (NPSI) was translated into Japanese according to published guidelines. Subsequently, an observational study of 60 Japanese patients suffering from neuropathic pain was performed to evaluate the validity and reliability of the NPSI-J. RESULTS: The NPSI-J exhibited a statistically significant correlation with pain intensity (Numerical Rating Scale). The Cronbach alpha value for Likert items was 0.86. Using the test-retest analysis method, the intraclass correlation coefficient between the two scores was 0.81. Factor analysis revealed that the main component of NPSI-J comprised three determinative factors. CONCLUSIONS: The NPSI-J is a reliable and valid pain assessment tool. PMID- 26600241 TI - Iranian Version of the Mini-Mental Adjustment to Cancer Scale: Factor Structure and Psychometric Properties. AB - Mental adjustment to cancer is known as a psychological, physical, and psychological health variable among cancer patients. The present study examines the factor structure and psychometric properties of the Mini-Mental Adjustment to Cancer scale (Mini-MAC) in a sample of Iranian adults who suffer from cancer. The sample consists of 320 cancer patients selected through non-random convenient sampling procedure from the hospitals and clinics in the cities of Kermanshah and Shiraz in Iran, using the Mini-MAC scale. One hundred of these patients also completed the Hospital Anxiety and Depression scale. Statistical methods used to analyze the data included confirmatory and exploratory factor analysis, discriminate validity, and Cronbach alpha coefficients for internal consistency. Factor analysis confirms five factors in the Mini-MAC. The values of fit indices are within the acceptable range. Significant correlations between the Mini-MAC and other measures also show that this scale has discriminate validity. Alpha coefficients for the subscales are Helplessness/Hopelessness,.94; Cognitive Avoidance.76; Anxious Preoccupation,.90; Fatalism,.77; Fighting Spirit.80; and total scale.84, respectively. The results confirm the five-factor structure of the Persian Mini-MAC scale and also prove that it is a reliable and valid scale. They show that this scale has sufficient power to measure different aspects of mental adjustment in patients with cancer. PMID- 26600244 TI - Correction: Water Spinach, Ipomoea aquatica (Convolvulaceae), Ameliorates Lead Toxicity by Inhibiting Oxidative Stress and Apoptosis. AB - [This corrects the article DOI: 10.1371/journal.pone.0139831.]. PMID- 26600242 TI - Incorporating a Smoking Cessation Intervention into Lung Cancer Screening Programs: Preliminary Studies. AB - Two preliminary studies assessed whether telephone counseling (TC) is a feasible smoking cessation intervention following lung cancer screening. Seven older smokers undergoing lung cancer screening (pack years = 61.5) completed three TC sessions, which incorporated the screening result as motivation to quit. Participation (87.5%) and retention (85.7%) rates were good, and four smokers quit smoking (three of whom received abnormal results). We conducted four focus groups with 16 current and former older smokers (pack years = 55). Most believed that an abnormal scan would motivate them to quit and expressed interest in TC. TC may be feasible and potentially efficacious within lung screening programs. PMID- 26600247 TI - A 0.04 mm (2) Buck-Boost DC-DC Converter for Biomedical Implants Using Adaptive Gain and Discrete Frequency Scaling Control. AB - This paper presents the design of a reconfigurable buck-boost switched-capacitor DC-DC converter suitable for use in a wide range of biomedical implants. The proposed converter has an extremely small footprint and uses a novel control method that allows coarse and fine control of the output voltage. The converter uses adaptive gain control, discrete frequency scaling and pulse-skipping schemes to regulate the power delivered to a range of output voltages and loads. Adaptive gain control is used to implement variable switching gain ratios from a reconfigurable power stage and thereby make coarse steps in output voltage. A discrete frequency scaling controller makes discrete changes in switching frequency to vary the power delivered to the load and perform fine tuning when the output voltage is within 10% of the target output voltage. The control architecture is predominately digital and it has been implemented as part of a fully-integrated switched-capacitor converter design using a standard bulk CMOS 0.18 MUm process. Measured results show that the converter has an output voltage range of 1.0 to 2.2 V, can deliver up to 7.5 mW of load power and efficiency up to 75% using an active area of only 0.04 mm (2), which is significantly smaller than that of other designs. This low-area, low-complexity reconfigurable power converter can support low-power circuits in biomedical implant applications. PMID- 26600245 TI - Immune Repertoire Profiling Reveals that Clonally Expanded B and T Cells Infiltrating Diseased Human Kidneys Can Also Be Tracked in Blood. AB - Recent advances in high-throughput sequencing allow for the competitive analysis of the human B and T cell immune repertoire. In this study we compared Immunoglobulin and T cell receptor repertoires of lymphocytes found in kidney and blood samples of 10 patients with various renal diseases based on next-generation sequencing data. We used Biomed-2 primer panels and ImmunExplorer software to sequence, analyze and compare complementarity determining regions and V-(D)-J elements. While generally an individual's renal receptor repertoire is different from the repertoire present in blood, 94% (30/32) of the lymphocytes with clonal expansion in kidney can also be traced in blood however, not all of these clonotypes are equally abundant. Summarizing the data of all analyzed patients, 68% of highly expanded T cell clonotypes and 30% of the highly expanded B cell clonotypes that have infiltrated the kidney can be found amongst the five most abundant clonotypes in blood. In addition, complementarity determining region 3 sequences of the immunoglobulin heavy chains are on average more diverse than T cell receptor beta chains. Immune repertoire analysis of tissue infiltrating B and T cells adds new approaches to the assessment of adaptive immune response in kidney diseases. Our data suggest that expanded clonotypes in the tissues might be traceable in blood samples in the course of treatment or the natural history of the disease. PMID- 26600246 TI - Respiratory DC Use IFITM3 to Avoid Direct Viral Infection and Safeguard Virus Specific CD8+ T Cell Priming. AB - Respiratory dendritic cells (DC) play a pivotal role in the initiation of adaptive immune responses to influenza virus. To do this, respiratory DCs must ferry viral antigen from the lung to the draining lymph node without becoming infected and perishing en route. We show that respiratory DCs up-regulate the expression of the antiviral molecule, interferon-induced transmembrane protein 3 (IFITM3) in response to influenza virus infection, in a manner dependent on type I interferon signaling and the transcription factors IRF7 and IRF3. Failure of respiratory DCs to up-regulate IFITM3 following influenza virus infection resulted in impaired trafficking to the draining LN and consequently in impaired priming of an influenza-specific CD8+ T cell response. The impaired trafficking of IFITM3-deficient DC correlated with an increased susceptibility of these DC to influenza virus infection. This work shows that the expression of IFITM3 protects respiratory DCs from influenza virus infection, permitting migration from lung to LN and optimal priming of a virus specific T-cell response. PMID- 26600248 TI - Structural Analysis and Aggregation Propensity of Pyroglutamate Abeta(3-40) in Aqueous Trifluoroethanol. AB - A hallmark of Alzheimer's disease (AD) is the accumulation of extracellular amyloid-beta (Abeta) plaques in the brains of patients. N-terminally truncated pyroglutamate-modified Abeta (pEAbeta) has been described as a major compound of Abeta species in senile plaques. pEAbeta is more resistant to degradation, shows higher toxicity and has increased aggregation propensity and beta-sheet stabilization compared to non-modified Abeta. Here we characterized recombinant pEAbeta(3-40) in aqueous trifluoroethanol (TFE) solution regarding its aggregation propensity and structural changes in comparison to its non pyroglutamate-modified variant Abeta(1-40). Secondary structure analysis by circular dichroism spectroscopy suggests that pEAbeta(3-40) shows an increased tendency to form beta-sheet-rich structures in 20% TFE containing solutions where Abeta(1-40) forms alpha-helices. Aggregation kinetics of pEAbeta(3-40) in the presence of 20% TFE monitored by thioflavin-T (ThT) assay showed a typical sigmoidal aggregation in contrast to Abeta(1-40), which lacks ThT positive structures under the same conditions. Transmission electron microscopy confirms that pEAbeta(3-40) aggregated to large fibrils and high molecular weight aggregates in spite of the presence of the helix stabilizing co-solvent TFE. High resolution NMR spectroscopy of recombinantly produced and uniformly isotope labeled [U-15N]-pEAbeta(3-40) in TFE containing solutions indicates that the pyroglutamate formation affects significantly the N-terminal region, which in turn leads to decreased monomer stability and increased aggregation propensity. PMID- 26600249 TI - Transcriptome Analysis of Short Fiber Mutant Ligon lintless-1 (Li1) Reveals Critical Genes and Key Pathways in Cotton Fiber Elongation and Leaf Development. AB - For efficient spinning and superior fabric production, long fiber length is a desired trait for cotton production. To unveil the molecular basis of the cotton fiber length regulation, a short fiber mutant, Ligon lintless-1 (Li1), is selected to compare with its corresponding wild type (WT). Li1 is a monogenic dominant cotton mutant causing extremely short fibers (<6mm) on mature seeds with visible pleiotropic effects on vegetative growth and development. In this research, we compared the transcriptome of fiber bearing ovules at 1 DPA, 3 DPA, 8 DPA and leaf between Li1 mutant and WT. A total of 7,852 differentially expressed genes (DEGs) were detected in ovules and leaves, which mainly participated in sugar, secondary metabolite and lipid metabolism pathways based on KEGG analysis. The common DEGs at 1 DPA and 3 DPA were involved in the responses to endogenous stimulus, signal transduction and long-chain fatty acid biosynthesis. For 3 DPA, 8 DPA and leaf, the common DEGs were involved in the responses to auxin and receptor kinases related pathway. Further analysis showed that 37 genes involved in very-long-chain fatty acid biosynthesis were suppressed in Li1 mutant during fiber fast elongation development. Most of the DEGs involved in cell wall metabolism, such cellulose synthase, expansin family, and glycosyl hydrolase were differentially expressed at 3 DPA and 8 DPA. Our results provide new insights into the mechanisms of fiber elongation, and offer novel genes as potential objects for fiber length improvement. PMID- 26600251 TI - Relationship between Abdominal Aortic Intima Media Thickness and Central Obesity in Children. AB - BACKGROUND: Childhood obesity is one of the important risk factors for early atherosclerosis. We aimed to evaluate the effect of obesity on abdominal aortic intima media thickness (aaIMT) in children. METHODS: We consecutively recruited 60 obese and 28 healthy children from the outpatient clinic of pediatrics. In all patients, BMI, waist circumference (WC) and hip circumference (HC) were measured, and fasting serum lipid profile, plasma glucose and plasma insulin were studied. Homeostasis model assessment-estimated insulin resistance (HOMA-IR) was calculated for the obese group. All children underwent ultrasonography to evaluate hepatosteatosis and to measure aaIMT. RESULTS: There was a significant difference between the groups in terms of aaIMT, insulin, glucose, HOMA-IR, total cholesterol, low-density lipoprotein, triglyceride and hepatosteatosis. aaIMT was 1.12 +/- 0.25 and 0.61 +/- 0.18 mm in the obese and nonobese groups, respectively (p < 0.001). In the obese group, there was a positive correlation between aaIMT and WC, WC/height ratio, BMI, HC and hepatosteatosis (p < 0.05 for all), with the highest significance for WC. CONCLUSIONS: This study showed that aaIMT was significantly higher in obese children than in nonobese children, and that WC was a strong predictor for aaIMT. Early detection of an increased aaIMT in obese children may guide the follow-up of these patients in terms of developing atherosclerosis and its complications. PMID- 26600250 TI - Overexpression of Mineralocorticoid Receptors Partially Prevents Chronic Stress Induced Reductions in Hippocampal Memory and Structural Plasticity. AB - Exposure to chronic stress is a risk factor for cognitive decline and psychopathology in genetically predisposed individuals. Preliminary evidence in humans suggests that mineralocorticoid receptors (MRs) may confer resilience to these stress-related changes. We specifically tested this idea using a well controlled mouse model for chronic stress in combination with transgenic MR overexpression in the forebrain. Exposure to unpredictable stressors for 21 days in adulthood reduced learning and memory formation in a low arousing hippocampus dependent contextual learning task, but enhanced stressful contextual fear learning. We found support for a moderating effect of MR background on chronic stress only for contextual memory formation under low arousing conditions. In an attempt to understand potentially contributing factors, we studied structural plasticity. Chronic stress altered dendritic morphology in the hippocampal CA3 area and reduced the total number of doublecortin-positive immature neurons in the infrapyramidal blade of the dentate gyrus. The latter reduction was absent in MR overexpressing mice. We therefore provide partial support for the idea that overexpression of MRs may confer resilience to the effects of chronic stress on hippocampus-dependent function and structural plasticity. PMID- 26600253 TI - Host Plant Specialization in the Sugarcane Aphid Melanaphis sacchari. AB - Most aphids are highly specialized on one or two related plant species and generalist species often include sympatric populations adapted to different host plants. Our aim was to test the hypothesis of the existence of host specialized lineages of the aphid Melanaphis sacchari in Reunion Island. To this end, we investigated the genetic diversity of the aphid and its association with host plants by analyzing the effect of wild sorghum Sorghum bicolor subsp. verticilliflorum or sugarcane as host plants on the genetic structuring of populations and by performing laboratory host transfer experiments to detect trade-offs in host use. Genotyping of 31 samples with 10 microsatellite loci enabled identification of 13 multilocus genotypes (MLG). Three of these, Ms11, Ms16 and Ms15, were the most frequent ones. The genetic structure of the populations was linked to the host plants. Ms11 and Ms16 were significantly more frequently observed on sugarcane, while Ms15 was almost exclusively collected in colonies on wild sorghum. Laboratory transfer experiments demonstrated the existence of fitness trade-offs. An Ms11 isofemale lineage performed better on sugarcane than on sorghum, whereas an Ms15 lineage developed very poorly on sugarcane, and two Ms16 lineages showed no significant difference in performances between both hosts. Both field and laboratory results support the existence of host plant specialization in M. sacchari in Reunion Island, despite low genetic differentiation. This study illustrates the ability of asexual aphid lineages to rapidly undergo adaptive changes including shifting from one host plant to another. PMID- 26600252 TI - Flesh Shear Force, Cooking Loss, Muscle Antioxidant Status and Relative Expression of Signaling Molecules (Nrf2, Keap1, TOR, and CK2) and Their Target Genes in Young Grass Carp (Ctenopharyngodon idella) Muscle Fed with Graded Levels of Choline. AB - Six groups of grass carp (average weight 266.9 +/- 0.6 g) were fed diets containing 197, 385, 770, 1082, 1436 and 1795 mg choline/kg, for 8 weeks. Fish growth, and muscle nutrient (protein, fat and amino acid) content of young grass carp were significantly improved by appropriate dietary choline. Furthermore, muscle hydroxyproline concentration, lactate content and shear force were improved by optimum dietary choline supplementation. However, the muscle pH value, cooking loss and cathepsins activities showed an opposite trend. Additionally, optimum dietary choline supplementation attenuated muscle oxidative damage in grass carp. The muscle antioxidant enzyme (catalase and glutathione reductase did not change) activities and glutathione content were enhanced by optimum dietary choline supplementation. Muscle cooking loss was negatively correlated with antioxidant enzyme activities and glutathione content. At the gene level, these antioxidant enzymes, as well as the targets of rapamycin, casein kinase 2 and NF-E2-related factor 2 transcripts in fish muscle were always up-regulated by suitable choline. However, suitable choline significantly decreased Kelch-like ECH-associated protein 1 a (Keap1a) and Kelch-like ECH associated protein 1 b (Keap1b) mRNA levels in muscle. In conclusion, suitable dietary choline enhanced fish flesh quality, and the decreased cooking loss was due to the elevated antioxidant status that may be regulated by Nrf2 signaling. PMID- 26600254 TI - The Repeatability Assessment of Three-Dimensional Capsule-Intraocular Lens Complex Measurements by Means of High-Speed Swept-Source Optical Coherence Tomography. AB - PURPOSE: To rebuild the three-dimensional (3-D) model of the anterior segment by high-speed swept-source optical coherence tomography (SSOCT) and evaluate the repeatability of measurement for the parameters of capsule-intraocular lens (C IOL) complex. METHODS: Twenty-two pseudophakic eyes from 22 patients were enrolled. Three continuous SSOCT measurements were performed in all eyes and the tomograms obtained were used for 3-D reconstruction. The output data were used to evaluate the measurement repeatability. The parameters included postoperative aqueous depth (PAD), the area and diameter of the anterior capsule opening (Area and D), IOL tilt (IOL-T), horizontal, vertical, and space decentration of the IOL, anterior capsule opening, and IOL-anterior capsule opening. RESULTS: PAD, IOL-T, Area, D, and all decentration measurements showed high repeatability. Repeated measure analysis showed there was no statistically significant difference among the three continuous measurements (all P > .05). Pearson correlation analysis showed high correlation between each pair of them (all r >0.90, P<0.001). ICCs were all more than 0.9 for all parameters. The 95% LoAs of all parameters were narrow for comparison of three measurements, which showed high repeatability for three measurements. CONCLUSION: SSOCT is available to be a new method for the 3-D measurement of C-IOL complex after cataract surgery. This method presented high repeatability in measuring the parameters of the C-IOL complex. PMID- 26600255 TI - The Influence of Facial Characteristics on the Relation between Male 2D:4D and Dominance. AB - Although relations between 2D:4D and dominance rank in both baboons and rhesus macaques have been observed, evidence in humans is mixed. Whereas behavioral patterns in humans have been discovered that are consistent with these animal findings, the evidence for a relation between dominance and 2D:4D is weak or inconsistent. The present study provides experimental evidence that male 2D:4D is related to dominance after (fictitious) male-male interaction when the other man has a dominant, but not a submissive or neutral face. This finding provides evidence that the relationship between 2D:4D and dominance emerges in particular, predictable situations and that merely dominant facial characteristics of another person are enough to activate supposed relationships between 2D:4D and dominance. PMID- 26600256 TI - Long- and Short-term Exposure to Air Pollution and Inflammatory/Hemostatic Markers in Midlife Women. AB - BACKGROUND: Studies have reported associations between long-term air pollution exposures and cardiovascular mortality. The biological mechanisms connecting them remain uncertain. METHODS: We examined associations of fine particles (PM2.5) and ozone with serum markers of cardiovascular disease risk in a cohort of midlife women. We obtained information from women enrolled at six sites in the multi ethnic, longitudinal Study of Women's Health Across the Nation, including repeated measurements of high-sensitivity C-reactive protein, fibrinogen, tissue type plasminogen activator antigen, plasminogen activator inhibitor type 1, and factor VIIc (factor VII coagulant activity). We obtained residence-proximate PM2.5 and ozone monitoring data for a maximum five annual visits, calculating prior year, 6-month, 1-month, and 1-day exposures and their relations to serum markers using longitudinal mixed models. RESULTS: For the 2,086 women studied from 1999 to 2004, PM2.5 exposures were associated with all blood markers except factor VIIc after adjusting for age, race/ethnicity, education, site, body mass index, smoking, and recent alcohol use. Adjusted associations were strongest for prior year exposures for high-sensitivity C-reactive protein (21% increase per 10 MUg/m3 PM2.5, 95% confidence interval [CI]: 6.6, 37), tissue-type plasminogen activator antigen (8.6%, 95% CI: 1.8, 16), and plasminogen activator inhibitor (35%, 95% CI: 19, 53). An association was also observed between year prior ozone exposure and factor VIIc (5.7% increase per 10 ppb ozone, 95% CI: 2.9, 8.5). CONCLUSIONS: Our findings suggest that prior year exposures to PM2.5 and ozone are associated with adverse effects on inflammatory and hemostatic pathways for cardiovascular outcomes in midlife women. PMID- 26600258 TI - Re: Chemical Composition of Fine Particulate Matter and Life Expectancy in 95 US Counties Between 2002 and 2007. PMID- 26600257 TI - PM2.5 and Mortality in 207 US Cities: Modification by Temperature and City Characteristics. AB - BACKGROUND: The reported estimated effects between long-term PM2.5 exposures and mortality vary spatially. We assessed whether community-level variables, including socioeconomic status indicators and temperature, modify this association. METHODS: We used data from >35 million Medicare enrollees from 207 US cities (2000-2010). For each city, we calculated annual PM2.5 averages, measured at ambient central monitoring sites. We used a variation of a causal modeling approach and fitted city-specific Cox models, which we then pooled using a random effects meta-regression. In this second stage, we assessed whether temperature and city-level variables, including smoking and obesity rates, poverty, education and greenness, modify the long-term PM2.5-mortality association. RESULTS: We found an association between long-term PM2.5 and survival (hazard ratio = 1.2; 95% confidence interval [CI]: 1.1, 1.3 per 10 MUg/m increase in the annual PM2.5 average concentrations). We observed elevated estimates in the Southeastern, South and Northwestern US (hazard ratio = 1.9; 95% CI: 1.7, 2.2, and 1.4; 95% CI: 1.2, 1.7, and 1.4; 95% CI: 1.1, 1.9, respectively). We observed a higher association between long-term PM2.5 exposure and mortality in warmer cities. Furthermore, we observed increasing estimates with increasing obesity rates, %residents and families in poverty, %black residents and %population without a high school degree, and lower effects with increasing median household income and %white residents. CONCLUSIONS: To the best of our knowledge, this is the first study to assess modification by temperature and community-level characteristics on the long-term PM2.5-survival association. Our findings suggest that living in cities with high temperatures and low socio economic status (SES) is associated with higher effect estimates. PMID- 26600259 TI - Th17 regulating lower airway disease. AB - PURPOSE OF REVIEW: Th17 lymphocytes are now widely believed to be critical for the regulation of various chronic immune diseases, including asthma and chronic obstructive pulmonary disease. In this review, we discuss the current understanding of the role of Th17 cells in the pathogenesis of different asthma phenotypes and chronic obstructive pulmonary disease. RECENT FINDINGS: It has been recently reported that Th17 cells and also a new population of Th17/Th2 cells accumulate in bronchoalveolar lavage fluid of asthmatic patients, and positively correlated with airway obstruction and steroid resistance. These patients often have steroid resistant severe asthma and a predominant bronchial neutrophilic inflammation. SUMMARY: Steroid resistant severe asthma with predominant bronchial neutrophilic inflammation could benefit from IL-17 targeted therapies. In this view, the definition of clinical phenotypes and inflammatory endotypes of asthma in each patient will be necessary for personalizing the therapeutic approach. PMID- 26600260 TI - Innate lymphoid type 2 cells in chronic rhinosinusitis. AB - PURPOSE OF REVIEW: Innate lymphoid type 2 cells (ILC2) have a critical role in the initiation and regulation of type 2 immune responses and are recognized as an important source of type-2 cytokines. Here, we present recent findings of the role of ILC2 in the integration, processing, and coordination of innate and adaptive immune processes and focus on the potential role of ILC2 in the context of chronic rhinosinusitis. RECENT FINDINGS: Recent research has shown the complex crosstalk that occurs between ILC2 and different innate and adaptive immune cell types with a critical role for ILC2 not only in mounting type 2 immune responses at barrier surfaces, but also in tissue repair responses and normal homeostatic functions. ILC2 research in a disease context has brought important insights in particular in the context of allergic inflammatory diseases, emphasizing a critical role for ILC2 and in particular ILC2-derived IL-13 in diseases of the upper and lower airways such as asthma. SUMMARY: The identification and characterization of ILC2 in the context of health and disease have brought a wealth of new knowledge into the mechanisms of type 2 immune responses. This is relevant to diverse disorders, including asthma, chronic rhinosinusitis, atopic dermatitis, fibrosis, helminth repulsion, and obesity. PMID- 26600261 TI - Correction: The Role of Non-Foraging Nests in Polydomous Wood Ant Colonies. AB - [This corrects the article DOI: 10.1371/journal.pone.0138321.]. PMID- 26600262 TI - Toward Ending the Guessing Game: Study of the Formation of Nanostructures Using In Situ Liquid Transmission Electron Microscopy. AB - The field of synthetic nanochemistry has grown tremendously in the past three decades since the discovery of nonaqueous synthesis of monodispersed particles. Almost all classes of materials, from II-VI semiconductor to metal, alloy, and metal oxide can now be prepared in various sizes and shapes. One major challenge has been the development of a technique for direct real-time recording of data during the formation of nanostructures in liquid reaction media where nucleation and growth occur. A viable solution finally arrived with the recent development of static and flow liquid cells for transmission electron microscopy (TEM). This Perspective will showcase a few selected examples in this rapidly growing area, with a focus on using the new capabilities of liquid TEM (LTEM) for quantitative study of nucleation and growth, as well as shape formation of nanocrystals in solution. A discussion on future direction is also presented. PMID- 26600263 TI - Mitochondrial protein-derived cryptides: Are endogenous N-formylated peptides including mitocryptide-2 components of mitochondrial damage-associated molecular patterns? AB - Recently, much attention has been paid to "nonclassical" bioactive peptides, which are fragmented peptides simultaneously produced during maturation and degradation of various functional proteins. We identified many fragmented peptides derived from various mitochondrial proteins including mitocryptide-1 and mitocryptide-2 that efficiently activate neutrophils. These endogenous, functionally active, fragmented peptides are referred to as "cryptides." Among them, mitocryptide-2 is an N-formylated cryptide cleaved from mitochondrial cytochrome b that is encoded in mitochondrial DNA (mtDNA). It is known that 13 proteins encoded in mtDNA are translated in mitochondria as N-formylated forms, suggesting the existence of endogenous N-formylated peptides other than mitocryptide-2. Here, we investigated the effects of N-formylated peptides presumably cleaved from mtDNA-encoded proteins other than cytochrome b on the functions of neutrophilic cells to elucidate possible regulation by endogenous N formylated cryptides. Four N-formylated cryptides derived from cytochrome c oxidase subunit I and NADH dehydrogenase subunits 4, 5, and 6 among 12 peptides from mtDNA-encoded proteins efficiently induced not only migration but also beta hexosaminidase release, which is an indicator of neutrophilic phagocytosis, in HL 60 cells differentiated into neutrophilic cells. These activities were comparable to or higher than those induced by mitocryptide-2. Although endogenous N formylated peptides that are contained in mitochondrial damage-associated molecular patterns (DAMPs) have yet to be molecularly identified, they have been implicated in innate immunity. Thus, N-formylated cryptides including mitocryptide-2 are first-line candidates for the contents of mitochondrial DAMPs to promote innate immune responses. (c) 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 580-587, 2016. PMID- 26600264 TI - An integrative toy model of cell flattening, spreading, and ruffling. AB - BACKGROUND: The processes of cell spreading and crawling are frequently associated with mysterious waves and ruffling cycles of the leading edge. OBJECTIVE: To develop a physical model that can account for these phenomena based on a few simple and plausible rules governing adhesion, contractility, polymerization of cytoskeleton, and membrane tension. METHODS: Extension of a continuum mechanical model of phagocytosis [J Cell Sci. (2006);119(Pt 9):1903-13] adding a simple coupling between membrane curvature and cytoskeletal polymerization. RESULTS: We show that our generalized model has just the right nonlinearity needed for triggering of stochastic/chaotic cycles of ruffling similar to those that are observed in real cells. CONCLUSIONS: The cycles are caused by a branching instability at the leading edge that leads to bifurcations of protrusion into forward moving lamellipodium and upward and rearward folding ruffles. The amplitude of the instability is modulated by the surface tension, with higher tension stabilizing against ruffling (but inhibiting protrusion) and lower tension promoting ruffling and protrusion. PMID- 26600267 TI - Role of matrix metalloproteases in the kinetics of leukocyte-endothelial adhesion in post-capillary venules. AB - BACKGROUND: The endothelial glycocalyx serves as a barrier to leukocyte (WBC) endothelium (EC) adhesion. Shedding of glycans, by matrix metalloproteases (MMPs) exposes EC integrin receptors to facilitate firm adhesion. However, the effect of shedding on the strength of the adhesive bond remains to be determined. OBJECTIVES: Examine the effect of MMP inhibition on the kinetics of WBC-EC adhesion under normal and inflammatory conditions to delineate differences in the duration and number of adhesive bonds. METHODS: WBC adhesion in post-capillary venules was observed in rat mesentery. Adhesion duration and off-rates (KOFF) were correlated with shear stress during adhesion in response to 1 uM fMLP or 0.5 uM doxycycline (doxy, to inhibit MMP activation). RESULTS: Doxy increased mean adhesion time significantly from 2.5 (control) to 5.6 s, whereas fMLP increased it 8-fold to 20 s, which was not affected by pre-treatment with doxy. Estimates of the number of adhesive bonds (simplified Bell-model) revealed a significantly greater increase with fMLP compared to doxy alone, with no effect on fMLP by pretreatment with doxy. With doxy alone, KOFF was significantly 4-fold greater compared to fMLP, suggesting a much weaker bond. CONCLUSIONS: Although the increased number of bonds by MMP inhibition with doxy alone and fMLP were similar, the bonds due to doxy appeared weaker as evidenced by their shorter duration, and lesser reduction in KOFF relative to control. Thus doxy limits the availability of integrin binding sites during fMLP stimulated adhesion, but has a pro-adhesive effect due to increased ligands for WBC binding that arises from inhibition of normal sheddase activity on the EC. PMID- 26600265 TI - Proteolytic receptor cleavage in the pathogenesis of blood rheology and co morbidities in metabolic syndrome. Early forms of autodigestion. AB - Abnormal blood rheological properties seldom occur in isolation and instead are accompanied by other complications, often designated as co-morbidities. In the metabolic syndrome with complications like hypertension, diabetes and lack of normal microvascular blood flow, the underlying molecular mechanisms that simultaneously lead to elevated blood pressure and diabetes as well as abnormal microvascular rheology and other cell dysfunctions have remained largely unknown. In this review, we propose a new hypothesis for the origin of abnormal cell functions as well as multiple co-morbidities. Utilizing experimental models for the metabolic disease with diverse co-morbidities we summarize evidence for the presence of an uncontrolled extracellular proteolytic activity that causes ectodomain receptor cleavage and loss of their associated cell function. We summarize evidence for unchecked degrading proteinase activity, e.g. due to matrix metalloproteases, in patients with hypertension, Type II diabetes and obesity, in addition to evidence for receptor cleavage in the form of receptor fragments and decreased extracellular membrane expression levels. The evidence suggest that a shift in blood rheological properties and other co-morbidities may in fact be derived from a common mechanism that is due to uncontrolled proteolytic activity, i.e. an early form of autodigestion. Identification of the particular proteases involved and the mechanisms of their activation may open the door to treatment that simultaneously targets multiple co-morbidities in the metabolic syndrome. PMID- 26600268 TI - Regulation of L-selectin-dependent hydrodynamic shear thresholding by leukocyte deformability and shear dependent bond number. AB - BACKGROUND: During inflammation leukocyte attachment to the blood vessel wall is augmented by capture of near-wall flowing leukocytes by previously adherent leukocytes. Adhesive interactions between flowing and adherent leukocytes are mediated by L-selectin and P-selectin Glycoprotein Ligand-1 (PSGL-1) co-expressed on the leukocyte surface and ultimately regulated by hydrodynamic shear thresholding. OBJECTIVE: We hypothesized that leukocyte deformability is a significant contributory factor in shear thresholding and secondary capture. METHODS: Cytochalasin D (CD) was used to increase neutrophil deformability and fixation was used to reduce deformability. Neutrophil rolling on PSGL-1 coated planar surfaces and collisions with PSGL-1 coated microbeads were analyzed using high-speed videomicroscopy (250 fps). RESULTS: Increased deformability led to an increase in neutrophil rolling flux on PSGL-1 surfaces while fixation led to a decrease in rolling flux. Abrupt drops in flow below the shear threshold resulted in extended release times from the substrate for CD-treated neutrophils, suggesting increased bond number. In a cell-microbead collision assay lower flow rates were correlated with briefer adhesion lifetimes and smaller adhesive contact patches. CONCLUSIONS: Leukocyte deformation may control selectin bond number at the flow rates associated with hydrodynamic shear thresholding. Model analysis supported a requirement for both L-selectin catch-slip bond properties and multiple bond formation for shear thresholding. PMID- 26600266 TI - Role of fluid shear stress in regulating VWF structure, function and related blood disorders. AB - Von Willebrand factor (VWF) is the largest glycoprotein in blood. It plays a crucial role in primary hemostasis via its binding interaction with platelet and endothelial cell surface receptors, other blood proteins and extra-cellular matrix components. This protein is found as a series of repeat units that are disulfide bonded to form multimeric structures. Once in blood, the protein multimer distribution is dynamically regulated by fluid shear stress which has two opposing effects: it promotes the aggregation or self-association of multiple VWF units, and it simultaneously reduces multimer size by facilitating the force dependent cleavage of the protein by various proteases, most notably ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type repeats, motif 1 type 13). In addition to these effects, fluid shear also controls the solution and substrate-immobilized structure of VWF, the nature of contact between blood platelets and substrates, and the biomechanics of the GpIbalpha-VWF bond. These features together regulate different physiological and pathological processes including normal hemostasis, arterial and venous thrombosis, von Willebrand disease, thrombotic thrombocytopenic purpura and acquired von Willebrand syndrome. This article discusses current knowledge of VWF structure-function relationships with emphasis on the effects of hydrodynamic shear, including rapid methods to estimate the nature and magnitude of these forces in selected conditions. It shows that observations made by many investigators using solution and substrate-based shearing devices can be reconciled upon considering the physical size of VWF and the applied mechanical force in these different geometries. PMID- 26600269 TI - In microfluidico: Recreating in vivo hemodynamics using miniaturized devices. AB - Microfluidic devices create precisely controlled reactive blood flows and typically involve: (i) validated anticoagulation/pharmacology protocols, (ii) defined reactive surfaces, (iii) defined flow-transport regimes, and (iv) optical imaging. An 8-channel device can be run at constant flow rate or constant pressure drop for blood perfusion over a patterned collagen, collagen/kaolin, or collagen/tissue factor (TF) to measure platelet, thrombin, and fibrin dynamics during clot growth. A membrane-flow device delivers a constant flux of platelet agonists or coagulation enzymes into flowing blood. A trifurcated device sheaths a central blood flow on both sides with buffer, an ideal approach for on-chip recalcification of citrated blood or drug delivery. A side-view device allows clotting on a porous collagen/TF plug at constant pressure differential across the developing clot. The core-shell architecture of clots made in mouse models can be replicated in this device using human blood. For pathological flows, a stenosis device achieves shear rates of >100,000 s(-1) to drive plasma von Willebrand factor (VWF) to form thick long fibers on collagen. Similarly, a micropost-impingement device creates extreme elongational and shear flows for VWF fiber formation without collagen. Overall, microfluidics are ideal for studies of clotting, bleeding, fibrin polymerization/fibrinolysis, cell/clot mechanics, adhesion, mechanobiology, and reaction-transport dynamics. PMID- 26600271 TI - Preceptor doctors' assessment of the clinical skills of chiropractic externs. AB - OBJECTIVE: This study surveyed preceptor doctors' opinions of student competence before and after a chiropractic preceptorship. METHODS: The qualitative and quantitative survey asked doctors about the competence of externs in various skills and asked opened-ended questions about the strengths and weaknesses of the externs. The survey was conducted using a common Web-based platform called SurveyMonkey. RESULTS: A total of 125 doctors responded to the survey. The doctors tended to agree that they saw a positive change in the skills of the externs over time. Externs presented to the preceptors lacking in confidence and office management skills. The preceptors reported an increase from 2.7 to 3.9 on a 5.0 Likert scale in the students' confidence in adjusting skills during the preceptorship. The preceptor doctors were split on students' preparedness in chiropractic adjusting technique, reporting it as both the strongest and the weakest presenting skill. CONCLUSION: Preceptor doctors perceived that their student externs were academically qualified but were weaker in the clinical application of procedures. Results from this survey suggest that the preceptor program can improve the confidence levels and practice management knowledge of chiropractic externs. PMID- 26600270 TI - Proinflammatory Cytokine Infusion Attenuates LH's Feedforward on Testosterone Secretion: Modulation by Age. AB - CONTEXT: In the experimental animal, inflammatory signals quench LH's feedforward drive of testosterone (T) secretion and appear to impair GnRH-LH output. The degree to which such suppressive effects operate in the human is not known. OBJECTIVE: To test the hypothesis that IL-2 impairs LH's feedforward drive on T and T's feedback inhibition of LH secretion in healthy men. SETTING: Mayo Center for Translational Science Activities. PATIENTS OR OTHER PARTICIPANTS: A total of 35 healthy men, 17 young and 18 older. INTERVENTIONS: Randomized prospective double-blind saline-controlled study of IL-2 infusion in 2 doses with concurrent 10-minute blood sampling for 24 hours. MAIN OUTCOME MEASURES: Deconvolution analysis of LH and T secretion. RESULTS: After saline injection, older compared with young men exhibited reduced LH feedforward drive on T secretion (P < .001), and decreased T feedback inhibition of LH secretion (P < .01). After IL-2 injection, LH's feedforward onto T secretion declined markedly especially in young subjects (P < .001). Concomitantly, IL-2 potentiated T's proportional feedback on LH secretion especially in older volunteers. CONCLUSION: This investigation confirms combined feedforward and feedback deficits in older relative to young men given saline and demonstrates 1) joint mechanisms by which IL-2 enforces biochemical hypogonadism, viz, combined feedforward block and feedback amplification; and 2) unequal absolute inhibition of T and LH secretion by IL-2 in young and older men. These outcomes establish that the male gonadal axis is susceptible to dual-site suppression by a prototypic inflammatory mediator. Thus, we postulate that selected ILs might also enforce male hypogonadism in chronic systemic inflammation. PMID- 26600272 TI - Establishing force and speed training targets for lumbar spine high-velocity, low amplitude chiropractic adjustments. AB - OBJECTIVE: We developed an adjusting bench with a force plate supporting the lumbar portion to measure loads transmitted during lumbar manual adjustment. It will be used to provide force-feedback to enhance student learning in technique labs. The study goal is to define the learning target loads and speeds, with instructors as expert models. METHODS: A total of 11 faculty members experienced in teaching Gonstead technique methods performed 81 simulated adjustments on a mannequin on the force plate. Adjustments were along 9 lumbopelvic "listings" at 3 load levels: light, normal, and heavy. We analyzed the thrusts to find preload, peak load, duration, and thrust rate. RESULTS: Analysis of 891 thrusts showed wide variations between doctors. Peak loads ranged from 100 to 1400 N. All doctors showed clear distinctions between peak load levels, but there was overlap between high and low loads. Thrust rates were more uniform across doctors, averaging 3 N/ms. CONCLUSION: These faculty members delivered a range of thrusts, not unlike those seen in the literature for high velocity, low amplitude manipulation. We have established at least minimum force and speed targets for student performance, but more work must be done to create a normative adjustment to guide refinement of student learning. PMID- 26600274 TI - Critical Care at the End of Life. AB - Intensive care unit (ICU) admission is common among patients approaching the end of their lives from acute as well as chronic life-limiting conditions. ICU providers are expected to have basic palliative care skills integrated into their routine practice. Palliative care skills can be applied to all ICU patients, regardless of prognosis, and may improve patient- and family-centered end of life (EOL) care in the ICU. Consultative palliative care models may be required for more complex palliative care needs including symptom management, medical decision making, and bereavement. This review discusses integrative and consultative palliative care models and the role of triggers for palliative care consultation, particularly when they are tailored to the needs of individual ICUs. We then review the evidence for providing several palliative care domains in the ICU and some of the ethical considerations surrounding EOL care in the ICU. Finally, we highlight the importance of self-care and peer support groups to mitigate the risk of burnout for clinicians providing EOL care in the ICU. PMID- 26600273 TI - Conservation and Covariance in Small Bacterial Phosphoglycosyltransferases Identify the Functional Catalytic Core. AB - Phosphoglycosyltransferases (PGTs) catalyze the transfer of a C1'-phosphosugar from a soluble sugar nucleotide diphosphate to a polyprenol phosphate. These enzymes act at the membrane interface, forming the first membrane-associated intermediates in the biosynthesis of cell-surface glycans and glycoconjugates, including glycoproteins, glycolipids, and the peptidoglycan in bacteria. PGTs vary greatly in both their membrane topologies and their substrate preferences. PGTs, such as MraY and WecA, are polytopic, while other families of uniquely prokaryotic enzymes have only a single predicted transmembrane helix. PglC, a PGT involved in the biosynthesis of N-linked glycoproteins in the enteropathogen Campylobacter jejuni, is representative of one of the structurally most simple members of the diverse family of small bacterial PGT enzymes. Herein, we apply bioinformatics and covariance-weighted distance constraints in geometry- and homology-based model building, together with mutational analysis, to investigate monotopic PGTs. The pool of 15000 sequences that are analyzed include the PglC like enzymes, as well as sequences from two other related PGTs that contain a "PglC-like" domain embedded in their larger structures (namely, the bifunctional PglB family, typified by PglB from Neisseria gonorrheae, and WbaP-like enzymes, typified by WbaP from Salmonella enterica). Including these two subfamilies of PGTs in the analysis highlights key residues conserved across all three families of small bacterial PGTs. Mutagenesis analysis of these conserved residues provides further information about the essentiality of many of these residues in catalysis. Construction of a structural model of the cytosolic globular domain utilizing three-dimensional distance constraints, provided by conservation covariance analysis, provides additional insight into the catalytic core of these families of small bacterial PGT enzymes. PMID- 26600275 TI - Staple Fixation Against Adhesive Fixation in Laparoscopic Inguinal Hernia Repair: A Meta-Analysis of Randomized Controlled Trials. AB - PURPOSE: The aim of this article was to compare the outcomes of tissue adhesive fixation and the staple fixation of meshes in laparoscopic inguinal hernia repair. MATERIALS AND METHODS: A systematic literature review was undertaken to identify studies that compare adhesive fixation and staple fixation of meshes in laparoscopic inguinal hernia repair. RESULTS: The present meta-analysis pooled the effects of outcomes of a total of 1228 patients enrolled into 8 randomized controlled trials. Tissue adhesive fixation of the mesh was associated with less chronic postoperative pain after laparoscopic inguinal hernia repair compared with staple fixation (risk difference=-0.06; 95% confidence interval, -0.08, 0.04). However, statistically, there was no significant difference in the incidence of acute postoperative pain, recurrence, hematoma/seroma, and wound infection. CONCLUSION: The use of the tissue adhesive fixation method reduces the incidence of chronic postoperative pain after laparoscopic inguinal hernia repair, and without any changes in the other outcomes. PMID- 26600276 TI - Safety and Efficacy of Laparoscopic Access in a Surgical Training Program. AB - Our study evaluated outcomes of laparoscopic access in a surgical residency program and identified variables associated with adverse outcomes. Following IRB approval, we reviewed prospectively collected data from consecutive laparoscopic surgeries from a single surgeon August 2008 to November 2011. Descriptive statistics were generated, and successful and unsuccessful access techniques were compared using the t test, Fisher exact test, and chi test of independence, with P<0.05 considered significant. Five hundred consecutive laparoscopic surgeries were evaluated; the average patient age was 47 years and 55% of patients were female. The most common procedures included laparoscopic cholecystectomy (29%), laparoscopic ventral hernia (15%), laparoscopic appendectomy (12%), laparoscopic colon/small bowel (11%), and laparoscopic inguinal hernia (10%). Successful laparoscopic access was obtained in 98% of patients. The most common access techniques were umbilical stalk technique (57%) and Veress followed by optical trocar technique (29%). The complication rate was 7% and included multiple access attempts in 3.4%, attending physician having to take over access in 1.6%, bleeding/solid organ injury in 0.8%, insufflating peritoneum in 0.6%, and bowel injury in 0.2%. There was a significant relationship between entry technique and failure rate. Open cutdown away from umbilicus had a higher failure rate than other techniques (P=0.0002). There was also a significant relationship between type of surgery and failure rate of technique, with laparoscopic ventral hernia and laparoscopic small bowel cases having the highest failure rate (P=0.005). We observed no difference in success rate based on age, sex, race, previous surgery, and resident training level (P>0.05). Laparoscopic access using appropriate techniques can be safely performed in a residency training program. Laparoscopic ventral hernia and small bowel procedures for obstruction can be difficult cases to obtain access, and surgeons should be able to use multiple strategies to obtain access. PMID- 26600277 TI - Gravidas with class III obesity: evaluating the abdominal skin microbiota above and below the panniculus (.). AB - OBJECTIVE: We sought to compare the skin microbiota above and below the panniculus of third-trimester pregnant women with class III obesity. METHODS: We collected swabs from the anterior panniculus and from the intertriginous area under the panniculus of women with class III obesity (body mass index >=40 kg/m(2)) carrying a live singleton at >=28 weeks. DNA was extracted. PCR with primers targeting the 16S rDNA V4 region were used to prepare an amplicon library. PCR products were sequenced (Illumina MiSeq platform). The 16S rDNA sequences were processed, integrated, analyzed and reported using QIIME and in house developed scripts. Taxonomy was assigned using RDP Classifier (threshold 0.8) against the Greengenes 16S rDNA database. RESULTS: Twenty women were enrolled. One sample pair was excluded for low sequence depth. Using permutation testing, there was significantly less bacterial diversity in the samples above compared to below the panniculus (beta diversity using weighted UniFrac metrics; p < 0.001). CONCLUSION: In pregnant women with class III obesity, the skin microbiota in the subpannicular fold differs from and is more diverse than that on the anterior panniculus. PMID- 26600278 TI - Can We Rely on Susceptibility-Weighted Imaging for Subthalamic Nucleus Identification in Deep Brain Stimulation Surgery? AB - BACKGROUND: Susceptibility-weighted imaging (SWI) offers significantly improved visibility of the subthalamic nucleus (STN) compared with traditional T2-weighted imaging. However, it is unknown whether the representation of the nucleus on SWI corresponds to the neurophysiological location of the STN. OBJECTIVE: To determine the correlation between the intraoperative electrophysiological activity of the STN and the representation of the nucleus on different magnetic resonance imaging (MRI) sequences used for deep brain stimulation target planning. METHODS: At stereotactic target depth, microelectrode recordings (MERs) of typical STN neuronal activity were mapped on 3 different preoperative MRI sequences: 1.5-T SWI, 1.5-T T2-weighted, and 3-T T2-weighted MRI. For each MRI sequence, it was determined whether the MER signal was situated inside or outside the contour of the STN. RESULTS: A total of 196 MER tracks in 34 patients were evaluated. In 165 tracks (84%), typical electrophysiological STN activity was measured. MER activity was situated more consistently inside hypointense STN contour representation on 1.5- and 3-T T2-weighted images compared with SWI (99% and 100% vs 79%, respectively). The 21% incongruence of electrophysiological STN activity outside the STN contour on SWI was seen almost exclusively in the anterior and lateral microelectrode channels. CONCLUSION: STN representation on SWI does not correspond to electrophysiological STN borders. SWI does not correctly display the lateral part of the STN. When aiming to target the superolateral sensorimotor part of the STN during deep brain stimulation surgery, SWI does not offer an advantage but a disadvantage compared with conventional T2. Future research is needed to determine whether these findings may also apply for high-field SWI. PMID- 26600279 TI - New Posterior Atlantoaxial Restricted Non-Fusion Fixation for Atlantoaxial Instability: A Biomechanical Study. AB - BACKGROUND: Loss of axial rotation and lateral bending after atlantoaxial fusion reduces a patient's quality of life. Therefore, effective, nonfusion fixation alternatives are needed for atlantoaxial instability. OBJECTIVE: To evaluate the initial stability and function of posterior atlantoaxial restricted nonfusion fixation (PAARNF), a new protocol, using cadaveric cervical spines compared with the intact state, destabilization, and posterior C1-C2 rod fixation. METHODS: Cervical areas C0 through C3 were used from 6 cadaveric spines to test flexion extension, lateral bending, and axial rotation range of motion (ROM). With the use of a machine, 1.5-Nm torque at a rate of 0.1 Nm/s was used and held for 10 seconds. The specimens were loaded 3 times, and data were collected in the third cycle and tested in the following sequence: (1) intact, (2) destabilization (using a type II odontoid fracture model), (3) destabilization with PAARNF (PAARNF group), and (4) rod implantation (rod group). The order of tests for the PAARNF and rod groups was randomly assigned. RESULTS: The average flexion extension ROM in the PAARNF group was 7.44 +/- 2.05 degrees , which was significantly less than in the intact (P = .00) and destabilization (P = .00) groups but not significantly different from that of the rod group (P = .07). The average lateral bending ROM (10.59 +/- 2.33 degrees ; P = .00) and axial rotation ROM (38.79 +/- 13.41 degrees ; P = .00) of the PAARNF group were significantly greater than in the rod group. However, the values of the PAARNF group showed no significant differences compared with those of the intact group. CONCLUSION: PAARNF restricted atlantoaxial flexion-extension but preserved axial rotation and lateral bending at the atlantoaxial joint in a type II odontoid fracture model. However, it should not be used clinically until further studies have been performed to test the long-term effects of this procedure. PMID- 26600280 TI - Patterns and Clinical Impact of Angiographically Visible Distal Emboli During Thrombectomy With Solitaire for Acute Ischemic Stroke. AB - BACKGROUND: Revascularization rates with stent retrievers after acute ischemic stroke are 69% to 86%, but favorable clinical outcomes occur in just 43% to 58% of cases. New distal emboli may negatively impact clinical outcomes. OBJECTIVE: To determine the prevalence and angiographic pattern of distal emboli associated with mechanical thrombectomy using the Solitaire Flow Restoration device and evaluate their correlation with clinical outcome. METHODS: We retrospectively reviewed the cerebral angiography of all patients with acute ischemic stroke who underwent mechanical thrombectomy with the use of the Solitaire FR device from 2012 to 2013. Angiographic microcatheter runs prior to Solitaire deployment and after thrombectomy were compared to identify new distal filling defects. Clinical outcome was assessed at discharge and after 90 days. RESULTS: Successful revascularization using the Solitaire device occurred in 36 of 39 patients (92%). Three distinct patterns were identified: new distal emboli in the same vascular territory (n = 3), new distal emboli in a new vascular territory (n = 3), and distal emboli that resolved after proximal revascularization (n = 7). Thirteen patients had distal emboli before and after Solitaire runs, and 13 showed no evidence of distal emboli. Favorable outcome (modified Rankin scores 0-2) was seen in 54% of all patients and 83% of patients with new distal emboli; thus, there was no correlation between new emboli and unfavorable clinical outcome (P = .67). CONCLUSION: We report an incidence rate of at least 15% of new emboli associated with use of the Solitaire device during thrombectomy in our series. Filling defects after Solitaire use were not associated with poor outcomes at discharge or 90-day follow-up. PMID- 26600281 TI - Long-term Follow-up of In-stent Stenosis After Pipeline Flow Diversion Treatment of Intracranial Aneurysms. AB - BACKGROUND: There is scant information on in-stent stenosis after flow diversion treatment of intracranial aneurysms with the Pipeline Embolization Device (PED). OBJECTIVE: To assess the incidence, severity, nature, and clinical consequences of in-stent stenosis on angiographic follow-up after treatment with the PED. METHODS: A retrospective study of patients who underwent aneurysm treatment with the PED was conducted. In-stent stenosis was assessed on subsequent follow-up angiography. Intimal hyperplasia was defined as a uniform growth process beyond the limits of the metallic mesh at <25%. In-stent stenosis represented an area of parent vessel narrowing, most often focal, graded as mild (25%-50%), moderate (50%-75%), or severe (>75%). RESULTS: Between June 2011 and April 2015, 80 patients were treated with the PED. Angiographic follow-up was available for 51 patients (representing 76% of available or 64% of all patients). Mean follow-up was 12.5 months. In-stent stenosis was detected in 5 patients (9.8%) at a median of 6 months. Stenosis was mild in 4 of 5 (80%) and moderate in 1 of 5 (20%) patients. There were no cases of severe stenosis. No stenosis caused flow limitation, clinical symptoms, or required re-treatment. Additional follow-up angiography was available in 2 of 5 stenosis patients showing marked improvement. Sixteen patients (31%) had intimal hyperplasia, and 28 patients (55%) had no stenosis. Asymptomatic stent occlusion occurred in 2 patients (4%) related to medication noncompliance. CONCLUSION: Treatment with the PED was associated with a 9.8% rate of in-stent stenosis, detected on first angiographic follow-up, at a median of 6 months. None were symptomatic or required re-treatment, and they showed significant improvement on follow-up. ABBREVIATION: FD, flow diverter. PMID- 26600282 TI - Quality of Life Outcomes Following Resection of Adult Intramedullary Spinal Cord Tumors. AB - BACKGROUND: Intramedullary spinal cord tumors are rare but clinically significant entities. Resection is critical to prevent permanent neurological deficits. However, no studies have investigated the quality of life (QOL) benefit of resection in adults. OBJECTIVE: To investigate QOL outcomes after intramedullary spinal cord tumors resection. METHODS: A consecutive retrospective review of all patients who underwent intramedullary spinal cord tumors resection at a single tertiary care institution between January 2008 and December 2013 was conducted. QOL was measured by the EuroQol 5-Dimensions (EQ-5D), Pain Disability Questionnaire (PDQ), and Patient Health Questionnaire-9 (PHQ-9). Multivariable regression was used to identify independent predictors of outcomes. RESULTS: Among 45 patients, the most common pathology was ependymoma (60%). No significant changes between preoperative and postoperative EQ-5D, PDQ, or PHQ-9 were observed. Improvements exceeding the minimal clinically important difference occurred in 28% of patients in EQ-5D, 28% in PDQ, and 16% in PHQ-9. Worse preoperative neurological status predicted worsened EQ-5D (beta = -0.09, P = .04) and PDQ (beta = 20.77, P < .01), while ependymomas predicted QOL improvement exceeding the minimal clinically important difference in PDQ (OR 14.98, P = .04) and approached significance in EQ-5D (OR 43.52, P = .06). Conversely, cervical tumors predicted worsened PDQ (beta = 18.32, P < .01) and failure to achieve EQ 5D minimal clinically important difference (OR <0.01, 95% CI <0.01-0.65, P = .02). Postoperative complications, such as syrinx formation (beta = -0.09, P = .04) and cerebrospinal fluid leak (beta = 13.85, P = .04), predicted diminished improvement in EQ-5D and PDQ, respectively. CONCLUSION: Although resection did not significantly improve QOL, it is likely necessary to arrest QOL deterioration. Patients with better preoperative neurological status or ependymoma experienced QOL improvement, while postoperative complications negatively impacted long-term QOL. ABBREVIATIONS: EQ-5D, EuroQol 5-DimensionsGTR, gross total resectionIMSCT, intramedullary spinal cord tumorsMCID, minimal clinically important differenceMMS, Modified McCormick ScalePDQ, Pain Disability QuestionnairePHQ-9, Patient Health Questionnaire-9POD, plane of dissectionQOL, quality of lifeSSI, surgical site infection. PMID- 26600283 TI - Bioanalytical validation for simultaneous quantification of non-aromatic steroids in follicular fluid from cattle via ESI-LC-MS/MS. AB - The family of steroid hormones is quite attractive for the approach of phenotype monitoring in farm animals. Therefore, we developed a new protocol for the quantitative analysis of natural steroids in follicular fluid from dairy cows. The corresponding steroid profile, which consists of progesterone, corticosterone, hydrocortisone, testosterone, and androstenedione covering three distinct steroid classes, was determined by LC/MS. Quantification is achieved by use of steroid standards diluted in steroid-free follicular fluid as calibrators. Thus, the new protocol does not require deuterated standards. In order to correct for conditional performance of the analytical system we have used dexamethasone as an internal standard. The method was validated according to EMA guidelines. Within- and between-day variations were below 20% for most parameters assessed. All steroids assessed had lower limits of quantification in the range of 2.1 to 4.4ng/ml. We have established a simple and sensitive analytical system in order to step towards a broader and cost-efficient phenotyping analysis in follicular fluid from dairy cows. PMID- 26600284 TI - Nanoscale {LnIII(24)ZnII(6)} Triangular Metalloring with Magnetic Refrigerant, Slow Magnetic Relaxation, and Fluorescent Properties. AB - The self-assembly of Ln(ClO4)3 . 6H2O and Zn(OAc)2 . 2H2O with pyrazine-2 carboxylic acid (HL) results in the formation of three novel nanosized {LnIII(24)ZnII(6)} triangular metallorings, [Gd24Zn6L24(OAc)22(MU3 OH)30(H2O)14](ClO4)7(OAc) . 2CH3OH . 26H2O (1), [Tb24Zn6L24(OAc)22(MU3 OH)30(CH3O)2(CH3OH)2(H2O)10](ClO4)5(OH) . 6CH3OH . 12H2O (2), and (H3O)[Dy24Zn6L24(OAc)22(MU3-OH)30(H2O)14](ClO4)7(OAc)2 . 4CH3OH . 22H2O (3), having the largest nuclearity among any known Ln/Zn clusters. Magnetic and luminescent studies reveal the special prowess for each lanthanide complex. Magnetic studies reveal that 1 exhibits a significant cryogenic magnetocaloric effect with a maximum -DeltaSm (isothermal magnetic entropy change) value of 30.0 J kg(-1) K(-1) at 2.5 K and 7 T and that a slow magnetization relaxation is observed for the dysprosium analogue. In addition, the solid-state photophysical properties of 2 display strong characteristic Tb(III) photoluminescent emission in the visible region, suggesting that Tb(III)-based luminescence is sensitized by the effective energy transfer from the ligand HL to the metal centers. PMID- 26600285 TI - Promotora assisted depression care among predominately Hispanic patients with concurrent chronic illness: Public care system clinical trial design. AB - Depression frequently negatively affects patient overall self-care and social stress management within United States safety net care systems. Rates of major depression are significantly high among low-income predominantly Hispanic/Latino with chronic illness, such as diabetes and heart disease. The study design of the A Helping Hand to Activate Patient-Centered Depression Care among Low-income Patients (AHH) randomized clinical trial aims to enhance patient depression care receipt and overall bio-psychosocial self-care management. The AHH trial is conducted in collaboration with three Los Angeles County Department of Health Services (DHS) safety net clinics that provide Patient-Centered Medical Home (PCMH) care. The study compares AHH intervention (AHH) in which community-based bilingual promotoras provide in-person or telephone patient engagement and intervention aimed to reduce the burden and strain on patients, families, and care providers by assessing, enhancing, and facilitating patient depression and co-morbid illness self-care management skill, and activating patient communication with clinic medical providers versus DHS PCMH team usual care (PCMHUC). AHH independent bilingual recruiters screened 1957 and enrolled 348 predominantly Hispanic/Latino patients, of whom 296 (85%) had diabetes, 14 (4%) with heart disease, and 38 (11%) with both diseases. Recruiters identified depressed patients by baseline Patient Health Questionnaire-9 scores of 10 or more, completed baseline assessments, and randomized patients to either AHH or PCMHUC study group. The comprehensive assessments will be repeated at 6 and 12months by an independent bilingual follow-up interviewer. Baseline and outcome data include mental health assessment and treatment receipt, co-morbid illness self-care, social relationships, and environmental stressor assessments. PMID- 26600286 TI - Cost-benefit assessment of using electronic health records data for clinical research versus current practices: Contribution of the Electronic Health Records for Clinical Research (EHR4CR) European Project. AB - INTRODUCTION: The widespread adoption of electronic health records (EHR) provides a new opportunity to improve the efficiency of clinical research. The European EHR4CR (Electronic Health Records for Clinical Research) 4-year project has developed an innovative technological platform to enable the re-use of EHR data for clinical research. The objective of this cost-benefit assessment (CBA) is to assess the value of EHR4CR solutions compared to current practices, from the perspective of sponsors of clinical trials. MATERIALS AND METHODS: A CBA model was developed using an advanced modeling approach. The costs of performing three clinical research scenarios (S) applied to a hypothetical Phase II or III oncology clinical trial workflow (reference case) were estimated under current and EHR4CR conditions, namely protocol feasibility assessment (S1), patient identification for recruitment (S2), and clinical study execution (S3). The potential benefits were calculated considering that the estimated reduction in actual person-time and costs for performing EHR4CR S1, S2, and S3 would accelerate time to market (TTM). Probabilistic sensitivity analyses using Monte Carlo simulations were conducted to manage uncertainty. RESULTS: Should the estimated efficiency gains achieved with the EHR4CR platform translate into faster TTM, the expected benefits for the global pharmaceutical oncology sector were estimated at ?161.5m (S1), ?45.7m (S2), ?204.5m (S1+S2), ?1906m (S3), and up to ?2121.8m (S1+S2+S3) when the scenarios were used sequentially. CONCLUSIONS: The results suggest that optimizing clinical trial design and execution with the EHR4CR platform would generate substantial added value for pharmaceutical industry, as main sponsors of clinical trials in Europe, and beyond. PMID- 26600287 TI - Randomized clinical trial of multimodal physiotherapy treatment compared to overnight lidocaine ointment in women with provoked vestibulodynia: Design and methods. AB - Provoked vestibulodynia (PVD) is a highly prevalent and debilitating condition yet its management relies mainly on non-empirically validated interventions. Among the many causes of PVD, there is growing evidence that pelvic floor muscle (PFM) dysfunctions play an important role in its pathophysiology. Multimodal physiotherapy, which addresses these dysfunctions, is judged by experts to be highly effective and is recommended as a first-line treatment. However, the effectiveness of this promising intervention has been evaluated through only two small uncontrolled trials. The proposed bi-center, single-blind, parallel group, randomized controlled trial (RCT) aims to evaluate the efficacy of multimodal physiotherapy and compare it to a frequently used first-line treatment, topical overnight application of lidocaine, in women with PVD. A total of 212 women diagnosed with PVD according to a standardized protocol were eligible for the study and were randomly assigned to either multimodal physiotherapy or lidocaine treatment for 10weeks. The primary outcome measure is pain during intercourse (assessed with a numerical rating scale). Secondary measures include sexual function, pain quality, psychological factors (including pain catastrophizing, anxiety, depression and fear of pain), PFM morphology and function, and patients' global impression of change. Assessments are made at baseline, post-treatment and at the 6-month follow-up. This manuscript presents and discusses the rationale, design and methodology of the first RCT investigating physiotherapy in comparison to a commonly prescribed first-line treatment, overnight topical lidocaine, for women with PVD. PMID- 26600288 TI - FecB, a periplasmic ferric-citrate transporter from E. coli, can bind different forms of ferric-citrate as well as a wide variety of metal-free and metal-loaded tricarboxylic acids. AB - The Escherichia coli Fec system, consisting of an outer membrane receptor (FecA), a periplasmic substrate binding protein (FecB) and an inner membrane permease ATPase type transporter (FecC/D), plays an important role in the uptake and transport of Fe(3+)-citrate. Although several FecB sequences from various organisms have been reported, there are no biophysical or structural data available for this protein to date. In this work, using isothermal titration calorimetry (ITC), we report for the first time the ability of FecB to bind different species of Fe(3+)-citrate as well as other citrate complexes with trivalent (Ga(3+), Al(3+), Sc(3+) and In(3+)) and a representative divalent metal ion (Mg(2+)) with low MUM affinity. Interestingly, ITC experiments with various iron-free di- and tricarboxylic acids show that FecB can bind tricarboxylates with MUM affinity but not biologically relevant dicarboxylates. The ability of FecB to bind with metal-free citrate is also observed in (1)H,(15)N HSQC-NMR titration experiments reported here at two different pH values. Further, differential scanning calorimetry (DSC) experiments indicate that the ligand bound form of FecB has greater thermal stability than ligand-free FecB under all pH and ligand conditions tested, which is consistent with the idea of domain closure subsequent to ligand binding for this type of periplasmic binding proteins. PMID- 26600289 TI - Tuning magnetotransport in a compensated semimetal at the atomic scale. AB - Either in bulk form, or in atomically thin crystals, layered transition metal dichalcogenides continuously reveal new phenomena. The latest example is 1T' WTe2, a semimetal found to exhibit the largest known magnetoresistance in the bulk, and predicted to become a topological insulator in strained monolayers. Here we show that reducing the thickness through exfoliation enables the electronic properties of WTe2 to be tuned, which allows us to identify the mechanisms responsible for the observed magnetotransport down to the atomic scale. The longitudinal resistance and the unconventional magnetic field dependence of the Hall resistance are reproduced quantitatively by a classical two-band model for crystals as thin as six monolayers, whereas a crossover to an Anderson insulator occurs for thinner crystals. Besides establishing the origin of the magnetoresistance of WTe2, our results represent a complete validation of the classical theory for two-band electron-hole transport, and indicate that atomically thin WTe2 layers remain gapless semimetals. PMID- 26600290 TI - Stemness and reprogramming in liver cancer. PMID- 26600291 TI - Risks associated with drug treatments for kidney stones. AB - INTRODUCTION: Renal stones are one of the most painful medical conditions patients experience. For many they are also a recurrent problem. Fortunately, there are a number of drug therapies available to treat symptoms as well as prevent future stone formation. AREAS COVERED: Herein, we review the most common drugs used in the treatment of renal stones, explaining the mechanism of action and potential side effects. Search of the Medline databases and relevant textbooks was conducted to obtain the relevant information. Further details were sourced from drug prescribing manuals. Recent studies of drug effectiveness are included as appropriate. EXPERT OPINION: Recent controversies include medical expulsive therapy trials and complex role of urinary citrate in stone disease. Future directions in research will involve new medical therapies for stone prevention, for example new drugs for hyperoxaluria. PMID- 26600292 TI - Stimulation of LH, FSH, and luteal blood flow by GnRH during the luteal phase in mares. AB - A study was performed on the effect of a single dose per mare of 0 (n = 9), 100 (n = 8), or 300 (n = 9) of GnRH on Day 10 (Day 0 = ovulation) on concentrations of LH, FSH, and progesterone (P4) and blood flow to the CL ovary. Hormone concentration and blood flow measurements were performed at hours 0 (hour of treatment), 0.25, 0.5, 1, 2, 3, 4, and 6. Blood flow was assessed by spectral Doppler ultrasonography for resistance to blood flow in an ovarian artery before entry into the CL ovary. The percentage of the CL with color Doppler signals of blood flow was estimated from videotapes of real-time color Doppler imaging by an operator who was unaware of mare identity, hour, or treatment dose. Concentrations of LH and FSH increased (P < 0.05) at hour 0.25 and decreased (P < 0.05) over hours 1 to 6; P4 concentration was not altered by treatment. Blood flow resistance decreased between hours 0 and 1, but the decrease was greater (P < 0.05) for the 100-MUg dose than for the 300-MUg dose. The percentage of CL with blood flow signals increased (P < 0.05) between hours 0 and 1 with no significant difference between the 100- and 300-MUg doses. The results supported the hypothesis that GnRH increases LH concentration, vascular perfusion of the CL ovary, and CL blood flow during the luteal phase; however, P4 concentration was not affected. PMID- 26600293 TI - Synkinesis following recurrent laryngeal nerve injury: A computer simulation. AB - OBJECTIVES/HYPOTHESIS: When the recurrent laryngeal nerve (RLN) is injured, functional recovery may be limited by the number of axons that regrow across the site of injury, and by the proportions of these axons that reinnervate the antagonistic muscle (synkinesis). This process was investigated in a computer model of RLN recovery. STUDY DESIGN: Computer simulation. METHODS: The developed computer program accepted as inputs: number of RLN axons; proportions of axons originally innervating adductor versus abductor, fraction of axons transected, fraction of axons that grow back, and width of 1 standard deviation about the mean. The program employed random sampling from a normal distribution to model various degrees of recovery, using random numbers to assign each axon to the correct muscle, an incorrect muscle, or no recovery. Each simulation was run 1,000*, and the mean, highest, and lowest degrees of synkinesis were determined. RESULTS: More severe injuries were associated with greater degrees of synkinesis. Extremes of synkinesis were possible but were rare. One example result, for a 50% injury with a 50% recovery rate, found: in the adductor muscles, 74.8% of axons will be innervated, of which 49.2% are the original uninjured axons, 19.4% are recovered adductor axons, and 6.2% are misdirected abductor axons. In the posterior cricoarytenoid (PCA), these values were 75.7%, 50.8%, 6.1%, and 18.8%, respectively. Results of many such simulations are plotted. CONCLUSIONS: Laryngeal synkinesis can be simulated based on known anatomic ratios and estimated recovery rates. The PCA is invariably much more affected by synkinetic reinnervation than are the adductor muscles. LEVEL OF EVIDENCE: NA Laryngoscope, 126:1600-1605, 2016. PMID- 26600294 TI - Avascular Necrosis in the Contralateral Hip in Patients With Congenital Femoral Deficiency: A Report of 3 Cases. AB - BACKGROUND: Congenital femoral deficiency is an uncommon clinical entity. We report 3 patients who developed avascular necrosis of the hip in the long (normal) leg during longitudinal observation and/or treatment of congenital femoral deficiency. METHODS: Patients were identified in limb length discrepancy clinic and their charts were retrospectively reviewed for clinical and radiographic data collection. RESULTS: We describe the occurrence of idiopathic avascular necrosis in the normal limb in patients being followed for limb length discrepancy. CONCLUSIONS: Although no conclusion could be drawn about the etiology of the avascular necrosis, we describe a previously undocumented relationship between congenital femoral deficiency and avascular necrosis in the contralateral hip. This occurred in our congenital femoral deficiency population at a rate higher than expected compared with published incidences of avascular necrosis of the hip in children. LEVEL OF EVIDENCE: Level IV-case series. PMID- 26600295 TI - Classification of Early Onset Scoliosis has Excellent Interobserver and Intraobserver Reliability. AB - BACKGROUND: Classification systems can be useful tools for clinical care and research but must be proven as reliable. The purpose of this study was to evaluate the interobserver and intraobserver reliability of the Classification of Early Onset Scoliosis (C-EOS) scheme. METHODS: After IRB approval, 50 cases were drawn from a prospectively collected database of patients with EOS. Cases were selected using a stratified randomization scheme based on etiology. These cases were used to create an internet survey that was sent to pediatric orthopaedic faculty, research coordinators, and fellows involved in EOS care and research. Participants were asked to classify each case and were provided with a written C EOS scheme that could be referenced while they completed the survey. Surveys were sent to participants twice, 3 weeks apart, to assess both intraobserver and interobserver reliability. Fleiss kappa and Cohen kappa were used to assess interobserver and intraobserver reliability, respectively. RESULTS: There were 36 total participants, 29 who completed the survey twice (21 faculty, 13 research coordinators, and 2 fellows). Overall Fleiss kappa coefficient for interobserver reliability was excellent across the major categories of etiology (0.84), major curve (0.93), and kyphosis (0.96). Overall intraobserver reliability was excellent with Cohen kappa values for etiology (0.92), major curve (0.96), and kyphosis (0.98). Faculty members had excellent agreement for etiology (0.90), major curve (0.91), and kyphosis (0.96). Research coordinators had high levels of agreement for etiology (0.78), and excellent for major curve (0.95) and kyphosis (0.96). Intraobserver reliability was excellent across all major categories for all groups: faculty, research coordinators, and fellows. CONCLUSIONS: The study shows high levels of interobserver and intraobserver agreement of the C-EOS scheme. The C-EOS scheme can be used as a reliable tool for classifying EOS patients for clinical communication and research. LEVEL OF EVIDENCE: Level II diagnostic study. PMID- 26600296 TI - Vitamin D Insufficiency and Fracture Risk in Urban Children. AB - BACKGROUND: Investigation into the role of vitamin D in fractures in the pediatric population has been limited despite estimates that as many as 70% of American children have inadequate vitamin D levels (measured as 25-hydroxyvitamin D, 25(OH)D). The purpose of this study was to evaluate vitamin D's role in pediatric fracture risk by comparing 25(OH)D between fractured and nonfractured cohorts. METHODS: A 12-month prospective case-control study was completed in children aged 2 to 14 years in an urban, academic hospital. Sixty fractured children requiring conscious sedation or general anesthesia for management were compared with 60 nonfractured controls. All participants and their guardians were surveyed for low bone density risk factors, and total serum 25(OH)D was measured. Statistical analysis was completed using Student t tests, chi tests, analysis of variance, and logistic regression models. RESULTS: After controlling for age and daily sun exposure, lower total serum 25(OH)D was associated with higher fracture risk (odds ratio=0.94; 95% confidence interval, 0.90-0.99; P=0.023). In the fractured cohort, 6 (10%) patients were deficient (25(OH)D<20 ng/mL) and 33 (55%) were insufficient (25(OH)D, 20 to 30 ng/mL). Of the nonfractured population, 8 (13%) were deficient and 19 (32%) were insufficient. There were more insufficient patients in the fractured than in the nonfractured cohort (odds ratio=2.99; 95% confidence interval, 1.27-7.0; P=0.037). CONCLUSIONS: Higher fracture incidence is associated with serum 25(OH)D insufficiency. Hypovitaminosis D may place the pediatric population at increased risk for fracture. Consideration should be given to routine assessment of vitamin D in fractured children. LEVEL OF EVIDENCE: Prognostic level III-prospective case-control study. PMID- 26600297 TI - Long-term Results of Combined Epiphysiodesis and Imhauser Intertrochanteric Osteotomy in SCFE: A Retrospective Study on 53 Hips. AB - BACKGROUND: The management of moderate and severe slipped capital femoral epiphysis is still an issue. The main concern is represented by the choice of an intra-articular or an extra-articular osteotomy to correct the deformity. Theoretically, the intra-articular osteotomy allows the best correction, but it is technically demanding and involves a higher risk of avascular necrosis (AVN); conversely, an extra-articular intertrochanteric osteotomy (ITO) is easier and involves a lower risk of early complications, but may lead to femoroacetabular impingement, resulting in early osteoarthritis and the need for total hip replacement (THR).The aim of this study was to analyze the long-term survivorship free from THR after combined epiphysiodesis and Imhauser ITO. METHODS: From 1975 to 2000, 45 patients (53 hips) underwent a combined epiphysiodesis and Imhauser ITO. There were 27 male and 18 female patients with an average age of 12.8+/-1.9 years. All cases showed a posterior sloping angle >40 degrees (mean, 69+/-16 degrees). The cumulative survivorship was determined according to Kaplan and Meier, with the end point defined as conversion to THR. RESULTS: A total of 6 patients (6 hips; 11%) had a follow-up <2 years. Among them, no postoperative complications occurred. For the remaining 39 patients (47 hips, 89%), the mean follow-up was 21+/-11 years. Four early postoperative complications were reported (2 AVN, 2 chondrolysis). The cumulative 39 years' survivorship free from THR was 68.5% (95% confidence interval, 42.4%-84.7%). The age at surgery (hazard ratio=1.849 per year older, P=0.017) and the postoperative onset of AVN or chondrolysis (hazard ratio=10.146, P=0.010) affected the long-term prognosis significantly. CONCLUSIONS: The combined epiphysiodesis and Imhauser ITO is a valid surgical option in moderate to severe slipped capital femoral epiphysis, preserving the natural hip for at least 39 years in the majority of the patients. Care must be taken to avoid AVN or chondrolysis. The age at surgery affects the prognosis negatively. LEVEL OF EVIDENCE: Level III-a retrospective study. PMID- 26600298 TI - Allograft Bone Use in Pediatric Subaxial Cervical Spine Fusions. AB - BACKGROUND: The use of freeze-dried allograft as a bone graft substitute for pediatric spine surgery is safe and efficacious in the thoracic and lumbar spines. Allograft bone use in segmental instrumented fusions in the subaxial cervical spine has not been well reported in the literature. We sought to describe our experience with allograft bone in this patient cohort, and to compare union rates to patients treated with autograft. METHODS: Medical records were queried over a 10-year time period (2004 to 2014). Inclusion criteria were all pediatric patients (18 y old and below) who underwent subaxial cervical spine fusion with minimum follow-up of 24 months. Variables queried included demographics, type of graft material used, diagnosis, approach (anterior, posterior, combined), levels instrumented, placement of postoperative halo, surgical-related complications, and achievement of fusion. RESULTS: A total of 26 patients qualified for inclusion (18 allograft, 8 autograft). No differences existed between the 2 groups regarding age, sex, or number of fused levels. In the allograft cohort, average age at initial surgery was 13.3 years (range, 5 to 18 y). The most common reasons for surgery included trauma (6), tumor (3), and syndrome-associated kyphosis (3). The average number of instrumented levels was 4 (range, 2 to 13). Four patients (22%) developed a postoperative surgical complication. There were 2 asymptomatic pseudarthroses not requiring revision. At a minimum of 24-month follow-up (average, 45 mo; range, 24 to 121 mo), the allograft group demonstrated a fusion rate of 88%, which was comparable with a fusion rate of 87% in the autograft group. CONCLUSIONS: The use of allograft bone for pediatric subaxial instrumented cervical spine fusions is safe in a variety of conditions, with the same rate of fusion as autograft. Rates of complications are acceptable. To avoid donor-site morbidity from autogenous graft harvest, we recommend considering allograft bone in subaxial cervical spine fusions with modern segmental instrumentation. LEVEL OF EVIDENCE: Level IV-case series; therapeutic. PMID- 26600299 TI - Serial Mehta Cast Utilization in Infantile Idiopathic Scoliosis: Evaluation of Radiographic Predictors. AB - BACKGROUND: Mehta cast utilization has gained a considerable momentum as a nonoperative treatment modality for the initial management of infantile idiopathic scoliosis (IIS). Despite its acceptance, there is paucity of data that characterize the radiographic parameters associated with Mehta casting and the factors correlated with a sustained curve correction. METHODS: A retrospective review of IIS patients who underwent Mehta casting was performed with a mean 2 year follow-up. X-rays were evaluated at each visit for the Cobb angle, focal deformity, rib-vertebral angle difference, and height of concavity and convexity of the apical 3 vertebrae. Concave-to-convex height ratios were calculated and tracked for each patient. Radiographic parameters were compared from precasting to after final casting, and from final casting to most recent follow-up. RESULTS: A total of 45 patients were identified, of whom 18 (40%) were male and 27 (60%) were female, with a mean age of 18.8+/-9.5 months at first casting and a mean follow-up of 37.7+/-19.7 months. Following final casting, the mean Cobb angle (25.6 vs. 52.7 degrees), focal deformity (17.4 vs. 30.5 degrees), rib-vertebral angle difference (18 vs. 32.3 degrees), and the concave-to-convex height ratios improved relative to precast parameters, respectively (P<0.001). At final follow up, mean Cobb angle (16.2 vs. 25.6 degrees) and concave-to-convex height ratios progressively improved when compared with final cast measurements, respectively (P<0.001). Five (11%) patients did not demonstrate sustained curve correction at final follow-up, whereas 4 (9%) required growing-rod placement. Lastly, the regression analysis demonstrated improvements in the focal deformity (17.4 vs. 30.5) and the concave-to-convex height ratios of the +1 and -1 apical vertebrae from the precast to last cast periods (P<0.001). These findings were correlated with sustained Cobb angle correction from cast removal to the most recent follow up. CONCLUSIONS: Radiographic parameters associated with control of progressive deformity for IIS include improvements in focal deformity and concave-to-convex height ratios for +1 and -1 apical vertebrae after final casting. Mehta casting is an effective treatment for symptomatic IIS and continues to provide IIS patients with significant curve correction. LEVEL OF EVIDENCE: Level IV. PMID- 26600300 TI - Recreational Fish-Finders--An Inexpensive Alternative to Scientific Echo-Sounders for Unravelling the Links between Marine Top Predators and Their Prey. AB - Studies investigating how mobile marine predators respond to their prey are limited due to the challenging nature of the environment. While marine top predators are increasingly easy to study thanks to developments in bio-logging technology, typically there is scant information on the distribution and abundance of their prey, largely due to the specialised nature of acquiring this information. We explore the potential of using single-beam recreational fish finders (RFF) to quantify relative forage fish abundance and draw inferences of the prey distribution at a fine spatial scale. We compared fish school characteristics as inferred from the RFF with that of a calibrated scientific split-beam echo-sounder (SES) by simultaneously operating both systems from the same vessel in Algoa Bay, South Africa. Customized open-source software was developed to extract fish school information from the echo returns of the RFF. For schools insonified by both systems, there was close correspondence between estimates of mean school depth (R2 = 0.98) and school area (R2 = 0.70). Estimates of relative school density (mean volume backscattering strength; Sv) measured by the RFF were negatively biased through saturation of this system given its smaller dynamic range. A correction factor applied to the RFF-derived density estimates improved the comparability between the two systems. Relative abundance estimates using all schools from both systems were congruent at scales from 0.5 km to 18 km with a strong positive linear trend in model fit estimates with increasing scale. Although absolute estimates of fish abundance cannot be derived from these systems, they are effective at describing prey school characteristics and have good potential for mapping forage fish distribution and relative abundance. Using such relatively inexpensive systems could greatly enhance our understanding of predator-prey interactions. PMID- 26600302 TI - FENS News. PMID- 26600301 TI - Mutually Exclusive Roles of SHARPIN in Integrin Inactivation and NF-kappaB Signaling. AB - SHANK-associated RH domain interactor (SHARPIN) inhibits integrins through interaction with the integrin alpha-subunit. In addition, SHARPIN enhances nuclear factor-kappaB (NF-kappaB) activity as a component of the linear ubiquitin chain assembly complex (LUBAC). However, it is currently unclear how regulation of these seemingly different roles is coordinated. Here, we show that SHARPIN binds integrin and LUBAC in a mutually exclusive manner. We map the integrin binding site on SHARPIN to the ubiquitin-like (UBL) domain, the same domain implicated in SHARPIN interaction with LUBAC component RNF31 (ring finger protein 31), and identify two SHARPIN residues (V267, L276) required for both integrin and RNF31 regulation. Accordingly, the integrin alpha-tail is capable of competing with RNF31 for SHARPIN binding in vitro. Importantly, the full SHARPIN RNF31-binding site contains residues (F263A/I272A) that are dispensable for SHARPIN-integrin interaction. Importantly, disrupting SHARPIN interaction with integrin or RNF31 abolishes SHARPIN-mediated regulation of integrin or NF-kappaB activity, respectively. Altogether these data suggest that the roles of SHARPIN in inhibiting integrin activity and supporting linear ubiquitination are (molecularly) distinct. PMID- 26600304 TI - Consumer Health Publications: AWHONN Launches New Web Sites and Magazine. PMID- 26600303 TI - Second Chances: Investigating Athletes' Experiences of Talent Transfer. AB - Talent transfer initiatives seek to transfer talented, mature individuals from one sport to another. Unfortunately talent transfer initiatives seem to lack an evidence-based direction and a rigorous exploration of the mechanisms underpinning the approach. The purpose of this exploratory study was to identify the factors which successfully transferring athletes cite as facilitative of talent transfer. In contrast to the anthropometric and performance variables that underpin current talent transfer initiatives, participants identified a range of psycho-behavioral and environmental factors as key to successful transfer. We argue that further research into the mechanisms of talent transfer is needed in order to provide a strong evidence base for the methodologies employed in these initiatives. PMID- 26600306 TI - Amyloid Cardiomyopathy in Hereditary Transthyretin V30M Amyloidosis - Impact of Sex and Amyloid Fibril Composition. AB - PURPOSE: Transthyretin V30M (ATTR V30M) amyloidosis is a phenotypically diverse disease with symptoms ranging from predominant neuropathy to exclusive cardiac manifestations. The aims of this study were to determine the dispersion of the two types of fibrils found in Swedish ATTR V30M patients -Type A consisting of a mixture of truncated and full length ATTR fibrils and type B fibrils consisting of full length fibrils, and to estimate the severity of cardiac dysfunction in relation to fibril composition and sex. MATERIAL AND METHODS: Echocardiographic data were analysed in 107 Swedish ATTR V30M patients with their fibril composition determined as either type A or type B. Measurements of left ventricular (LV) dimensions and evaluation of systolic and diastolic function including speckle tracking derived strain were performed. Patients were grouped according to fibril type and sex. Multivariate linear regression was utilised to determine factors of significant impact on LV thickness. RESULTS: There was no significant difference in proportions of the two types of fibrils between men and women. In patients with type A fibrils, women had significantly lower median septal (p = 0.007) and posterior wall thicknesses (p = 0.010), lower median LV mass indexed to height (p = 0.008), and higher septal strain (p = 0.037), as compared to males. These differences were not apparent in patients with type B fibrils. Multiple linear regression analysis revealed that fibril type, sex and age all had significant impact on LV septal thickness. CONCLUSION: This study demonstrates a clear difference between sexes in the severity of amyloid heart disease in ATTR V30M amyloidosis patients. Even though type A fibrils were associated with more advanced amyloid heart disease compared to type B, women with type A fibrils generally developed less cardiac infiltration than men. The differences may explain the better outcome for liver transplanted late-onset female patients compared to males. PMID- 26600305 TI - Fibrogenic Lung Injury Induces Non-Cell-Autonomous Fibroblast Invasion. AB - Pathologic accumulation of fibroblasts in pulmonary fibrosis appears to depend on their invasion through basement membranes and extracellular matrices. Fibroblasts from the fibrotic lungs of patients with idiopathic pulmonary fibrosis (IPF) have been demonstrated to acquire a phenotype characterized by increased cell autonomous invasion. Here, we investigated whether fibroblast invasion is further stimulated by soluble mediators induced by lung injury. We found that bronchoalveolar lavage fluids from bleomycin-challenged mice or patients with IPF contain mediators that dramatically increase the matrix invasion of primary lung fibroblasts. Further characterization of this non-cell-autonomous fibroblast invasion suggested that the mediators driving this process are produced locally after lung injury and are preferentially produced by fibrogenic (e.g., bleomycin induced) rather than nonfibrogenic (e.g., LPS-induced) lung injury. Comparison of invasion and migration induced by a series of fibroblast-active mediators indicated that these two forms of fibroblast movement are directed by distinct sets of stimuli. Finally, knockdown of multiple different membrane receptors, including platelet-derived growth factor receptor-beta, lysophosphatidic acid 1, epidermal growth factor receptor, and fibroblast growth factor receptor 2, mitigated the non-cell-autonomous fibroblast invasion induced by bronchoalveolar lavage from bleomycin-injured mice, suggesting that multiple different mediators drive fibroblast invasion in pulmonary fibrosis. The magnitude of this mediator driven fibroblast invasion suggests that its inhibition could be a novel therapeutic strategy for pulmonary fibrosis. Further elaboration of the molecular mechanisms that drive non-cell-autonomous fibroblast invasion consequently may provide a rich set of novel drug targets for the treatment of IPF and other fibrotic lung diseases. PMID- 26600307 TI - Association Between IL-17A +197 G/A Polymorphism and Cancer Risk: A Meta analysis. AB - AIMS: The association between interleukin-17 (IL-17) gene polymorphism and cancer is controversial. Thus, we performed a meta-analysis to evaluate the correlation between this gene variant and cancer risk. MATERIALS AND METHODS: We retrieved the available data from EMBASE and PUBMED through June, 2015, and evaluated the effect of the rs2273913 polymorphism in different ethnicities and cancer types. A meta-analysis was performed after data sorting. RESULTS: Significant associations were confirmed among Asians by the allelic model (T allele vs. G allele, 95% confidence interval [95% CI] 1.304-2.120), homozygote comparison (AA vs. GG, 95% CI 1.073-1.615), and the recessive model (AA vs. AG/GG, 95% CI 1.128-1.778). We also demonstrated that rs2273913 confers a high risk of nongastrointestinal cancer based on the allelic model (T allele vs. G allele, 95% CI 2.288-3.442), homozygote comparison (AA vs. GG, 95% CI 1.312-1.925), and recessive model (AA vs. AG/GG, 95% CI 1.259-1.689). CONCLUSIONS: Our present study indicates that the IL-17A +197 G/A/T polymorphism (rs2275913) is associated with the risk of cancer in Asian populations and nongastrointestinal cancers. Hence, rs2275913 might be useful as a diagnostic biomarker of cancer in these populations. PMID- 26600308 TI - Changes in Blood B Cell-Activating Factor (BAFF) Levels in Multiple Sclerosis: A Sign of Treatment Outcome. AB - Multiple sclerosis (MS) is mediated primarily by autoreactive T cells. However, evidence suggesting the involvement of humoral immunity in brain diseases has increased interest in the role of B cells and their products during MS pathogenesis. The major survival factor for B cells, BAFF has been shown to play a role in several autoimmune conditions. Elevated BAFF levels have been reported in MS animal model and during MS relapse in patients. Moreover, disease-modifying treatments (DMT) reportedly influence blood BAFF levels in MS patients, but the significance of these changes remains unclear. The present study addresses how blood BAFF levels are associated with the clinical course of relapsing-remitting MS and the effectiveness of DMT and short-term steroid treatment. During a prospective longitudinal follow-up of 2.3 years, BAFF was measured in the blood of 170 MS patients in the stable phase and within 186 relapses. BAFF levels were significantly higher in MS patients compared to healthy controls. However, stable MS patients without relapses exhibited significantly higher BAFF levels than relapsing patients. Treatment with interferon-beta and immunosuppressants raised BAFF blood levels. Interestingly, a similar effect was not seen in patients treated with glatiramer acetate. Short-term treatment with high doses of intravenous methylprednisolone did not significantly alter plasma BAFF levels in 65% of relapsing-remitting MS patients. BAFF were correlated weakly but significantly with monocyte and basophil counts, but not with other blood cell types (neutrophils, lymphocytes, or eosinophils) or inflammatory biomarkers. To our knowledge, this is the first report demonstrating that higher blood BAFF levels may reflect a more stable and effective MS treatment outcome. These results challenge hypotheses suggesting that elevated blood BAFF levels are associated with more severe disease presentation and could explain the recent failure of pharmaceutical trials targeting BAFF with soluble receptor for MS treatment. PMID- 26600309 TI - Changes in Body Composition in Anorexia Nervosa: Predictors of Recovery and Treatment Outcome. AB - The restoration of body composition (BC) parameters is considered to be one of the most important goals in the treatment of patients with anorexia nervosa (AN). However, little is known about differences between AN diagnostic subtypes [restricting (AN-R) and binge/purging (AN-BP)] and weekly changes in BC during refeeding treatment. Therefore, the main objectives of our study were twofold: 1) to assess the changes in BC throughout nutritional treatment in an AN sample and 2) to analyze predictors of BC changes during treatment, as well as predictors of treatment outcome. The whole sample comprised 261 participants [118 adult females with AN (70 AN-R vs. 48 AN-BP), and 143 healthy controls]. BC was measured weekly during 15 weeks of day-hospital treatment using bioelectrical impedance analysis (BIA). Assessment measures also included the Eating Disorders Inventory-2, as well as a number of other clinical indices. Overall, the results showed that AN-R and AN-BP patients statistically differed in all BC measures at admission. However, no significant time*group interaction was found for almost all BC parameters. Significant time*group interactions were only found for basal metabolic rate (p = .041) and body mass index (BMI) (p = .035). Multiple regression models showed that the best predictors of pre-post changes in BC parameters (namely fat-free mass, muscular mass, total body water and BMI) were the baseline values of BC parameters. Stepwise predictive logistic regressions showed that only BMI and age were significantly associated with outcome, but not with the percentage of body fat. In conclusion, these data suggest that although AN patients tended to restore all BC parameters during nutritional treatment, only AN-BP patients obtained the same fat mass values as healthy controls. Put succinctly, the best predictors of changes in BC were baseline BC values, which did not, however, seem to influence treatment outcome. PMID- 26600310 TI - Dietary Saturated Fat Promotes Development of Hepatic Inflammation Through Toll Like Receptor 4 in Mice. AB - Nonalcoholic steatohepatitis (NASH) is currently the third most common cause of end stage liver disease necessitating transplantation. The question remains how inflammation and NASH develop in the setting of nonalcoholic fatty liver disease (NAFLD) and steatosis. Understand the roles of toll-like receptor 4 (TLR4) and dietary fats in the development of hepatic inflammation. Wild-type and TLR4 KO mice were fed a standard high fat diet (LD), a high saturated fat diet (MD), or an isocaloric control diet (CD). Sera and tissue were analyzed for development of hepatic steatosis, inflammation, and injury. MD induced features of hepatic steatosis and inflammation in wild-type, but not in TLR4 KO, mice. TLR4 KO prevented MD induced increases in NAFLD activity scores, serum alanine aminotransferase levels, and inflammatory cytokine expression. Inflammatory cell infiltration and cytokine expression were also lower in the TLR4 KO mice livers than wild-type mice fed MD. Hepatic expression of Collagen I transcripts and collagen deposition were also decreased in the TLR4 KO MD animals. Results show that TLR4 plays a critical role in the effects of dietary fat composition on the development of hepatic steatosis, inflammation, and injury consistent with nonalcoholic steatohepatitis. J. Cell. Biochem. 117: 1613-1621, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26600312 TI - Detection of Corn Adulteration in Brazilian Coffee (Coffea arabica) by Tocopherol Profiling and Near-Infrared (NIR) Spectroscopy. AB - Coffee is a high-value commodity that is a target for adulteration, leading to loss of quality and causing significant loss to consumers. Therefore, there is significant interest in developing methods for detecting coffee adulteration and improving the sensitivity and accuracy of these methods. Corn and other lower value crops are potential adulterants, along with sticks and coffee husks. Fourteen pure Brazilian roasted, ground coffee bean samples were adulterated with 1-20% of roasted, ground corn and were analyzed for their tocopherol content and profile by HPLC. They were also analyzed by near-infrared (NIR) spectroscopy. Both proposed methods of detection of corn adulteration displayed a sensitivity of around 5%, thus representing simple and fast analytical methods for detecting adulteration at likely levels of contamination. Further studies should be conducted to verify the results with a much larger sample size and additional types of adulterants. PMID- 26600311 TI - Introducing a Mobile-Connected Umbilical Doppler Device (UmbiFlowTM) into a Primary Care Maternity Setting: Does This Reduce Unnecessary Referrals to Specialised Care? Results of a Pilot Study in Kraaifontein, South Africa. AB - OBJECTIVES: UmbiFlowTM is a mobile-connected Doppler device that utilises a continuous waveform to measure resistance in the umbilical artery. The main aim of this pilot study was to determine whether the use of UmbiFlowTM for umbilical artery Doppler in patients with a suspected decreased symphysis fundal (SF) growth could safely lead to a decreased number of patients requiring referral to a more specialised level of care. A secondary aim of the study was to evaluate the effectiveness of UmbiFlowTM Doppler as a screening tool for concealed placental insufficiency in late bookers by using a single screening cut-off value that will be abnormal for any gestation >28 weeks. METHODS: The cohort comprised two groups of patients: The first group included all follow-up patients with suspected intra-uterine growth restriction (a decreased symphysis-fundus measurement based on serial assessment) who underwent on-site UmbiFlowTMDoppler testing performed by the midwife directly after the clinical examination. The second group included late bookers, where gestation was uncertain; but estimated >28 weeks based on clinical grounds. This group was comprised of unselected patients who report to antenatal care late for the first time and received an UmbiFlowTMDoppler test for concealed placental insufficiency. RESULTS: UmbiFlowTMDoppler could reduce the number of false referrals to hospital by 55%. A single UmbiFlowTMDoppler test in late bookers appeared to identify a group of women at moderate risk of lower birth weight babies. PMID- 26600313 TI - Live yeasts enhance fibre degradation in the cow rumen through an increase in plant substrate colonization by fibrolytic bacteria and fungi. AB - AIMS: To monitor the effect of a live yeast additive on feedstuff colonization by targeted fibrolytic micro-organisms and fibre degradation in the cow rumen. METHODS AND RESULTS: Abundance of adhering fibrolytic bacteria and fungi on feedstuffs incubated in sacco in the cow rumen was quantified by qPCR and neutral detergent fibre (NDF) degradation was measured. Saccharomyces cerevisiae I-1077 (SC) increased the abundance of fibre-associated Fibrobacter succinogenes on wheat bran (WB) and that of Ruminococcus flavefaciens on alfalfa hay (AH) and wheat silage (WS). The greatest effect was observed on the abundance of Butyrivibrio fibrisolvens on AH and soya hulls (SH) (P < 0.001). Fungal biomass increased on AH, SH, WS and WB in the presence of SC. NDF degradation of AH and SH was improved (P < 0.05) with SC supplementation. CONCLUSIONS: Live yeasts enhanced microbial colonization of fibrous materials, the degree of enhancement depended on their nature and composition. As an effect on rumen pH was not likely to be solely involved, the underlying mechanisms could involve nutrient supply or oxygen scavenging by the live yeast cells. SIGNIFICANCE AND IMPACT OF THE STUDY: Distribution of this microbial additive could be an interesting tool to increase fibre digestion in the rumen and thereby improve cow feed efficiency. PMID- 26600314 TI - Mixed-valence copper(I,II) complexes with 4-(1H-pyrazol-1-yl)-6-R-pyrimidines: from ionic structures to coordination polymers. AB - Two pyrimidine-based ligands, 4-(3,5-diphenyl-1H-pyrazol-1-yl)-6 (morpholino)pyrimidine () and 4-(3,5-diphenyl-1H-pyrazol-1-yl)-6 phenoxypyrimidine (), and a series of mixed-valence copper(i,ii) halide complexes, [Cu(L(2))2Br]2[Cu2Br4] (), [Cu(L(2))2Cl][CuCl2] (), and [Cu2L(3)Br3]n (), have been synthesized. The complex [Cu(L(2))2Br]2[Cu2Br4] was prepared by the reaction of with CuBr2 in a 1 : 1 molar ratio in MeCN. Its chlorido-analogue, the complex [Cu(L(2))2Cl][CuCl2], was synthesized by the reaction between , CuCl2 and CuCl in a 2 : 1 : 1 molar ratio in MeCN. The ligand acts as a chelating one. In the structures of the complexes [Cu(L(2))2Br]2[Cu2Br4] and [Cu(L(2))2Cl][CuCl2] the Cu(2+) ion is in the cationic part of the complex whereas the Cu(+) ion is located in the anionic part. The best way to synthesize the mixed-valence 1D coordination polymer [Cu2L(3)Br3]n is to react CuBr2 with in a 2 : 1 molar ratio in the MeCN/CHCl3 mixture on heating. In the structure of [Cu2L(3)Br3]n the ligand shows chelating/bridging tridentate coordination. This is the first example of the tridentate coordination of 4-(1H-pyrazol-1-yl)-6-R-pyrimidines. The striking difference between the coordination behavior of and (chelating bidentate vs. chelating/bridging coordination) is related with the possibility of rotation of the 6-phenoxy group around the C-O bond which makes the N(1) pyrimidine atom less sterically hindered, enabling it to participate in metal ion binding. Importantly, all copper ions in [Cu2L(3)Br3]n show similar tetrahedral environments, CuNBr3 and CuN2Br2, which is extremely rare for mixed-valence copper(i,ii) compounds. The ligands and show blue emission which is quenched upon their coordination to copper ions. The 1D coordination polymer [Cu2L(3)Br3]n shows high thermal stability and unusual solvent-occlusion properties. The role of the substituents favoring the formation of the mixed-valence copper(i,ii) complexes with 4-(1H-pyrazol-1-yl)-6-R-pyrimidines is discussed. PMID- 26600315 TI - Micro-solid-phase extraction (u-SPE) of organophosphorous pesticides from wheat followed by LC-MS/MS determination. AB - A rapid, selective and effective method of extraction, clean-up and concentration of organophosphorous pesticides from wheat followed by electrospray (ESI) LC MS/MS analysis was developed. The MU-SPE (micro-solid-phase extraction) procedure resulted in good analytical performance and reduced at the same time matrix effects, analysis time and solvent consumption. Limits of detection (LODs) and quantification (LOQs) were in the range of 0.3-10 and 1-30 MUg kg(-1), respectively, with good reproducibility (RSD <= 13.8) and recoveries between 75% and 109%. Coefficients of determination (r(2)) were greater than 0.996 for the studied pesticides. Despite the reduced sorbent bed mass of MU-SPE tips (4.2 mg), the analytical data showed that no saturation phenomena occurs in the tested range of concentration both for single compounds and mixtures. Several real samples were analysed and the concentrations of the selected pesticides were found to be below the respective maximum residue limit (MRLs). PMID- 26600316 TI - Support Vector Machine and Artificial Neural Network Models for the Classification of Grapevine Varieties Using a Portable NIR Spectrophotometer. AB - The identification of different grapevine varieties, currently attended using visual ampelometry, DNA analysis and very recently, by hyperspectral analysis under laboratory conditions, is an issue of great importance in the wine industry. This work presents support vector machine and artificial neural network's modelling for grapevine varietal classification from in-field leaf spectroscopy. Modelling was attempted at two scales: site-specific and a global scale. Spectral measurements were obtained on the near-infrared (NIR) spectral range between 1600 to 2400 nm under field conditions in a non-destructive way using a portable spectrophotometer. For the site specific approach, spectra were collected from the adaxial side of 400 individual leaves of 20 grapevine (Vitis vinifera L.) varieties one week after veraison. For the global model, two additional sets of spectra were collected one week before harvest from two different vineyards in another vintage, each one consisting on 48 measurement from individual leaves of six varieties. Several combinations of spectra scatter correction and smoothing filtering were studied. For the training of the models, support vector machines and artificial neural networks were employed using the pre-processed spectra as input and the varieties as the classes of the models. The results from the pre-processing study showed that there was no influence whether using scatter correction or not. Also, a second-degree derivative with a window size of 5 Savitzky-Golay filtering yielded the highest outcomes. For the site-specific model, with 20 classes, the best results from the classifiers thrown an overall score of 87.25% of correctly classified samples. These results were compared under the same conditions with a model trained using partial least squares discriminant analysis, which showed a worse performance in every case. For the global model, a 6-class dataset involving samples from three different vineyards, two years and leaves monitored at post-veraison and harvest was also built up, reaching a 77.08% of correctly classified samples. The outcomes obtained demonstrate the capability of using a reliable method for fast, in field, non-destructive grapevine varietal classification that could be very useful in viticulture and wine industry, either global or site-specific. PMID- 26600317 TI - Reverse fiber type disproportion: A distinct metabolic myopathy. AB - INTRODUCTION: In this investigation we characterized the physiological and metabolic responses to incremental exercise in 13 subjects with a predominance of type II fibers on muscle biopsy. METHODS: Subjects underwent incremental exercise testing with measures of maximum oxygen uptake ( VO2 max), maximum heart rate (fc max), chronotropic index (fc / VO2 slope), maximum ventilation ( Vemax), blood lactate, ammonia, and creatine kinase (CK) levels. Muscle fiber type was determined by myosin ATPase histochemistry. RESULTS: Muscle biopsies showed more type II fibers (75%) in subjects compared with normal individuals (P < 0.01). Subjects exhibited normal VO2 max and end-exercise lactate, whereas ammonia and CK levels at maximum exercise were significantly higher. CONCLUSIONS: Subjects with type II muscle fiber predominance exhibited exaggerated increases in ammonia and elevated CK levels during exercise. Predominance of type II fibers on muscle biopsy is the opposite finding of congenital fiber type disproportion; we suggest these patients be referred to as having "reverse fiber type disproportion." Muscle Nerve 54: 86-93, 2016. PMID- 26600319 TI - De novo hepatitis b prophylaxis with hepatitis B virus vaccine and hepatitis B immunoglobulin in pediatric recipients of core antibody-positive livers. AB - The use of hepatitis B core antibody-positive (HBcAb+) grafts for liver transplantation (LT) has the potential to safely expand the donor pool, as long as proper prophylaxis against de novo hepatitis B (DNHB) is employed. The aim of this study was to characterize the longterm outcome of pediatric LT recipients of HBcAb + liver grafts under a prophylaxis regimen against DNHB using hepatitis B virus (HBV) vaccine and hepatitis B immunoglobulin (HBIG). From June 1996 to February 2013, 49 patients receiving pediatric LT at our center were from HBcAb + donors. Forty-one patients who received DNHB prophylaxis according to our protocol were included in this analysis. Our DNHB prophylaxis protocol consists of HBV vaccine intramuscular injections given intermittently to maintain anti hepatitis B surface antibody (HBsAb) titers above 100 IU/L. HBIG was also used during the first posttransplant year with a target anti-HBsAb titer level above 200 IU/L. There were 19 boys and 22 girls. Median age was 1.0 year (range, 4 months to 16 years). Median follow-up time was 66 months after transplant. Median annual number of HBV vaccine injections was 0.8 per year (range, 0-1.8 per year). Four patients did not require any HBV vaccine injections during follow-up. One patient with DNHB was encountered during the follow-up period (1/41, 2.4%). DNHB was diagnosed at 3.5 years after transplant, when hepatitis B surface antigen was positive upon routine follow-up serologic testing. Anti-HBsAb titer was 101.5 IU/L at the time. No grafts were lost because of DNHB-related events. Overall survival of the 41 recipients of HBcAb + grafts who received DNHB prophylaxis was 92.3% at 10 years after transplant. In conclusion, longterm prophylaxis against DNHB with HBV vaccine in pediatric LT recipients of HBcAb + grafts was safe and effective in terms of DNHB incidence as well as graft and patient survival. PMID- 26600320 TI - Cr-Doped ZnO Nanoparticles: Synthesis, Characterization, Adsorption Property, and Recyclability. AB - In this paper, a mild solvothermal method has been employed to successfully synthesize a series of Cr-doped ZnO nanoparticles (NPs) with different Cr(3+) contents, which is a kind of novel and high-efficiency absorbent for the removal of acid dye methyl orange (MO) from aqueous solution. The as-prepared products were characterized by transmission electron microscopy (TEM), scanning electron microscopy (SEM), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), Fourier transform infrared spectroscopy (FT-IR), Brunauer, Emmet, and Teller (BET), and Zeta potential measurements. In accordance with the adsorption capacity of the products, the obtained optimal Cr/Zn molar ratio is 6%. The adsorption process of MO on Cr-doped ZnO was investigated by kinetics, thermodynamics, and isotherm technologies, which, respectively, indicated that the adsorption was fast (adsorption reached equilibrium in 2 h) and followed a pseudo-second-order model, that the adsorption process was spontaneous and endothermic, and that it agreed well with the Langmuir isotherm with a maximum adsorption capacity of 310.56 mg g(-1). Moreover, a reasonable mechanism was proposed to elucidate the reasons for their adsorption behavior. In addition, a simple and low-cost chemical method was developed to separate and recycle ZnO and MO from the used adsorbent, effectively avoiding the secondary pollution. This work can not only describe efficient experimental approaches for obtaining novel adsorbents and recycling them but also offer valuable clues for the preparation and property study of other semiconductor adsorbents. PMID- 26600318 TI - The Molecular Epidemiology and Evolution of Murray Valley Encephalitis Virus: Recent Emergence of Distinct Sub-lineages of the Dominant Genotype 1. AB - BACKGROUND: Recent increased activity of the mosquito-borne Murray Valley encephalitis virus (MVEV) in Australia has renewed concerns regarding its potential to spread and cause disease. METHODOLOGY/PRINCIPAL FINDINGS: To better understand the genetic relationships between earlier and more recent circulating strains, patterns of virus movement, as well as the molecular basis of MVEV evolution, complete pre-membrane (prM) and Envelope (Env) genes were sequenced from sixty-six MVEV strains from different regions of the Australasian region, isolated over a sixty year period (1951-2011). Phylogenetic analyses indicated that, of the four recognized genotypes, only G1 and G2 are contemporary. G1 viruses were dominant over the sampling period and found across the known geographic range of MVEV. Two distinct sub-lineages of G1 were observed (1A and 1B). Although G1B strains have been isolated from across mainland Australia, Australian G1A strains have not been detected outside northwest Australia. Similarly, G2 is comprised of only Western Australian isolates from mosquitoes, suggesting G1B and G2 viruses have geographic or ecological restrictions. No evidence of recombination was found and a single amino acid substitution in the Env protein (S332G) was found to be under positive selection, while several others were found to be under directional evolution. Evolutionary analyses indicated that extant genotypes of MVEV began to diverge from a common ancestor approximately 200 years ago. G2 was the first genotype to diverge, followed by G3 and G4, and finally G1, from which subtypes G1A and G1B diverged between 1964 and 1994. CONCLUSIONS/SIGNIFICANCE: The results of this study provides new insights into the genetic diversity and evolution of MVEV. The demonstration of co circulation of all contemporary genetic lineages of MVEV in northwestern Australia, supports the contention that this region is the enzootic focus for this virus. PMID- 26600321 TI - A doubly deprotonated diimine dioximate metalloligand as a synthon for multimetallic complex assembly. AB - An electrocatalytically active cobalt diimine monoxime monoximate complex was deprotonated by 1-methylimidazole affording a doubly deprotonated complex that serves as a versatile precursor for synthesis of a variety of multimetallic complexes with Co-Zn, -Cd, -Mn and -Ru coordination. These complexes were studied using a combination of spectroscopic, analytical and electrochemical techniques, revealing the electronic and structural parameters unique to this new class of compounds. The ability of these complexes to catalyze proton reduction was also investigated. These complexes are homogeneous electrocatalysts for the hydrogen evolution reaction through reduction of [NEt3H][BPh4] in CH3CN, however decompose under extended electrolysis conditions. PMID- 26600323 TI - Positioning the CXR - As a triage test for tuberculosis. PMID- 26600322 TI - Tuberculosis in children - Need for urgent roadmap under Revised National Tuberculosis Control Programme. PMID- 26600324 TI - Evolving immunological frontiers in tuberculosis. PMID- 26600325 TI - Medical thoracoscopy in the management of tuberculous pleural effusion. PMID- 26600326 TI - Drug resistance among TB cases and its clinical implications. AB - The emergence of M. tuberculosis strains resistant to at least, Isoniazid (INH) and Rifampicin (RIF), the two most potent drugs of first-line anti-TB therapy is termed multidrug drug-resistant TB (MDR-TB). This is a cause of concern to TB Control Programmes worldwide. When MDR-TB strains become resistant to the major second-line drugs, one of the fluouroquinolones and one of the three injectable drugs (Amikacin, Kanamycin and Capreomycin), it is defined as extensively drug resistant TB.(1,2) MDR-TB is a manmade, costly and deadly problem. Rapid diagnosis of MDR-TB is essential for the prompt initiation of effective second line therapy to improve treatment outcome and limit transmission of the disease. PMID- 26600327 TI - Perspectives of health care provider regarding TB-HIV referral strategy and non uptake of HIV testing in Delhi - A qualitative study. AB - BACKGROUND: DOTS provider and medical officer play an integral role in implementation of RNTCP. Understanding provider perspectives is an integral component of evaluating programme to improve services to identify the areas for quality improvement and universal HIV testing among TB patients. OBJECTIVE: To describe the perception of health care providers regarding TB-HIV referral strategy and reasons for non-uptake of HIV testing. METHODOLOGY: A qualitative study was undertaken at DOTS cum microscopic centre of TB-Chest clinic of Lok Nayak Hospital and DOTS cum microscopic centre of rural area of west Delhi. In depth interview of DOTS provider and medical officer in-charge at DOTS centre was conducted. A topic outline guide used to assess the perception of study subjects. Thematic analysis of qualitative data was done. RESULTS: The source of knowledge regarding HIV testing among DOTS providers were training and monthly review meetings. All the study participants knew the rational of HIV testing and the consequences of not being tested and are highly motivated for referring the patients for HIV testing at the earliest. Some of the barriers to HIV testing reported by the health care providers were lack of awareness, associated stigma, long distance travel by the patients and non-availability of HIV testing kits. CONCLUSION: Health care providers were motivated for implementation of the strategy. Barriers to HIV TB testing strategy should be addressed. PMID- 26600328 TI - Oral health status and awareness among tuberculosis patients in an Indian population. AB - BACKGROUND: Knowledge and awareness regarding oral health problems of tuberculosis patients are lacking among patients, physicians, as well as dental practitioners. AIM: This study aimed to assess the oral health status and awareness among the tuberculosis patients in an Indian population. METHODS: Study sample comprised of 210 tuberculosis patients and 210 nontuberculosis subjects. The tuberculosis patients were categorized into new patients (group A), previously treated (group B), and drug-resistant tuberculosis patients (group C). History of present problem and awareness about oral health was noted. Periodontal health status was ascertained using Community Periodontal Index (CPI). Other oral findings were also recorded. RESULTS: The results were analyzed statistically. 62.9% of total tuberculosis patients had one or more oral problems. Most common problem was tooth pain (34%). CPI score was significantly higher (p<0.05) for tuberculosis patients (2.94) than in control group (1.34). Mean CPI score for groups A, B, and C patients was 2.83, 2.91, and 3.09, respectively. CONCLUSION: This study suggests awareness of oral health status and oral manifestations of tuberculosis among physicians and dental professionals. PMID- 26600329 TI - Thyroid profile status of patients treated for multidrug-resistant tuberculosis in state of Meghalaya, India. AB - BACKGROUND: Meghalaya has high tuberculosis burden with increasing multidrug resistant tuberculosis (MDR-TB) cases. Drug-induced hypothyroidism is one of the well-documented adverse effects in treatment of MDR-TB, the data of which are unavailable in the population residing in this part of the Indian subcontinent. AIM: This study was undertaken to assess the thyroid profile status of patients under DOTS Plus treatment and to evaluate the effects of anti-tubercular drugs on thyroid functions with respect to the pre-treatment thyroid status. METHODS: A prospective study of 114 patients who initiated treatment for MDR-TB between June 2012 and August 2013 was performed. Thyroid hormones, viz., TSH, Total T3, Total T4, Free T3 and Free T4 were estimated. RESULTS: Out of our study group of 114 MDR-TB patients, 15 dead patients and defaulters were excluded. So, out of 99 patients, till now, 76 patients have completed 6 months of DOTS Plus treatment and were re-evaluated for thyroid status. 52(68%) patients showed TSH levels more than the reference limit of 5.60 MUIU/mL and 5(7%) patients had TSH >10 MUIU/mL suggesting presence of sub-clinical hypothyroidism. CONCLUSION: We suggest the need for Mandatory TSH screening at baseline and then six months interval for all patients taking DOTS Plus so that no adverse effect goes under-reported and early intervention if required should be done to maintain proper adherence. PMID- 26600330 TI - Alcohol use disorders among pulmonary tuberculosis patients under RNTCP in urban Pondicherry, India. AB - BACKGROUND: Alcohol use is implicated in a wide variety of diseases and disorders including TB. OBJECTIVES: To study the prevalence and pattern of alcohol use among the PTB patients registered under RNTCP in urban Pondicherry and the association of various socio-demographic variables with alcohol drinking during treatment. METHODS: A cross-sectional study was conducted among 235 PTB patients from 6 randomly selected urban PHCs of Pondicherry from Jan 2013 to March 2014. Alcohol Use Disorder Identification Test (AUDIT) was used for screening the PTB patients for their severity of alcohol use. Data were entered in Epi-data v3.1 and was analyzed by SPSS v20. Chi-square test and multiple-logistic regression were used. RESULTS: Prevalence of alcohol use among PTB patients at the time of diagnosis was 59% and during treatment was 31.5%. Around 54% PTB patients had alcohol use disorders (AUD) during diagnosis, whereas the same during treatment was 26.4%. Among drinkers at the time of diagnosis (n=139), 80% modified and 20% did not modify their alcohol use even after TB diagnosis. Male gender was significantly associated with alcohol use (p<=0.001). Univariate analysis showed that lower level of education, lower SES, unemployed/unskilled/semiskilled/skilled occupational group, and Category II were significantly associated with alcohol use among male patients (p<0.05). Multivariate analysis showed that none of the variables were associated. CONCLUSIONS: One-third of PTB patients were drinking alcohol during the treatment. Though 80% modified alcohol use after TB diagnosis, the rest 20% did not modify. Necessary interventions need to be planned to screen for alcohol use. PMID- 26600331 TI - Tuberculosis presenting as a sclerosis of bone: A case report. AB - An unusual case of skeletal tuberculosis, presenting as a hard swelling and sclerotic lesion in the medial end of the clavicle is presented. With re emergence of tuberculosis as an important infection worldwide, and the ability of this disease to mimic many skeletal pathologies, this has to be included in the differential diagnosis, especially at unusual sites. PMID- 26600333 TI - Multidrug-resistant tuberculosis among different types of suspected cases: Study from New Delhi. AB - There are limited data of multidrug-resistant tuberculosis (MDR-TB) diagnosed in various patient categories by implementing Programmatic Management of Drug Resistant TB (PMDT) using line probe assay (LPA) from our country. Samples from presumptive MDR-TB from five districts of New Delhi were subjected to LPA from 1st October 2011 to 31st December 2014. The MDR-TB diagnosed in 4th & 5th month follow-up positives were significantly higher than other categories of the patients. Only 3/232 (2.2%) RIF resistants were diagnosed among smear negative re treatment cases. The data suggest interim cost-benefit analysis of the program especially among smear negatives retreatment cases. PMID- 26600332 TI - Pulmonary artery aneurysm and thrombosis in active tuberculous consolidation. AB - Tuberculosis continues to remain challenging with a variety of complications. We report the case of a 58-year-old female who developed pulmonary artery aneurysm with intra-arterial thrombus as a complication of active tuberculosis. Even though there are reports of pulmonary artery aneurysm in tuberculous cavity, pulmonary artery aneurysm and intra-arterial thrombus in active tuberculosis are very rare. PMID- 26600335 TI - Short courses of dual-strain probiotics appear to be effective in reducing necrotising enterocolitis. AB - AIM: Prophylactic probiotics to reduce necrotising enterocolitis (NEC) are mostly given for at least 28 days or until discharge. We describe the effects of a shorter duration dosing strategy. METHODS: Retrospective cohort study of neonates (birthweight 400-1500 g) in three neonatal intensive care units in Switzerland and Germany that embarked on probiotic prophylaxis given for 10 or 14 days, employing a fixed combination (Lactobacillus acidophilus plus Bifidobacterium infantis, each 10(9) CFU/day) licensed as a drug in Switzerland. Probiotics were initiated upon discontinuation of antibiotics, or on day 1-3 in infants without antibiotics. Repeat probiotic courses were given whenever antibiotics had been instituted and were discontinued. RESULTS: Birthweight and gestational age were similar in the two 24-month pre- and postimplementation cohorts. NEC rates fell from 33 of 633 (5.2%) to 8 of 591 infants alive at three days (1.4%; risk ratio (RR) 0.26, 95% confidence interval (CI) 0.12-0.55). The drop in NEC was significant both for infants of 400-999 g (6.4% to 2.5%) and 1000-1500 g birthweight (4.4% to 0.6%). Mortality was 5.1% (32/633) without, as opposed to 3.5% (21/591) with probiotics, respectively (RR 0.69, 95% CI 0.41-1.19). CONCLUSION: Short courses of a dual-strain probiotics appear to be effective in reducing NEC. PMID- 26600336 TI - Reflecting on the Ebola Epidemic: What If? AB - Could a better health care system in West Africa have saved lives? PMID- 26600337 TI - Paying Attention to Compassion Fatigue in Emergency Nurses. AB - Symptom recognition, institutional support, and healthy coping strategies are crucial. PMID- 26600340 TI - Grieving Families. PMID- 26600341 TI - Moral Distress. PMID- 26600342 TI - Workplace Safety. PMID- 26600343 TI - Oregon Nurse Wins Wrongful Termination Lawsuit. AB - State nurse staffing law pivotal in case against Legacy Health Systems. PMID- 26600345 TI - A Blood Pressure Study Is Stopped Early Because of Important Results. AB - Treatment recommendations remain uncertain until the full results are available. PMID- 26600347 TI - Drug Use Among Young People. AB - Despite some recent declines, the potential for relapse remains strong. PMID- 26600348 TI - A Promising Brief Assessment for Delirium in Older Adults. AB - Two criteria detected delirium in under a minute. PMID- 26600350 TI - Schedules and Injury Risk Among Newly Licensed RNs. AB - More injuries were reported with night shifts or eight or more hours of overtime in a week. PMID- 26600352 TI - The Complexities of Nurse Migration. AB - A call to curtail migration out of Latin America and the Caribbean raises questions. PMID- 26600355 TI - Slow vs. Fast Subcutaneous Heparin Injections for Prevention of Pain and Bruising. AB - Editor's note: This is a summary of a nursing care-related systematic review from the Cochrane Library. PMID- 26600359 TI - Original Research: Implementation of an Early Mobility Program in an ICU. AB - OBJECTIVE: Research is needed to determine the feasibility of implementing a dedicated ICU mobility team in community hospital settings. The purpose of this study was to assess, in one such hospital, four nurse-sensitive quality-of-care outcomes (falls, ventilator-associated events, pressure ulcers, and catheter associated urinary tract infections [CAUTIs]), as well as hospital costs, sedation and delirium measures, and functional outcomes by comparing ICU patients who received physical therapy from a dedicated mobility team with ICU patients who received routine care. METHODS: We conducted a retrospective longitudinal study at a community acute care hospital; patients were randomly assigned to intervention or routine care groups. The mobility team screened patients Monday through Friday using a mobility algorithm to determine eligibility for participation in each early mobility session. Based on their strength, balance, hemodynamic stability, and ability to participate in early mobility activities, patients advanced through four progressively difficult phases of mobility. Data were collected and analyzed after patients were discharged from the hospital. RESULTS: The 66 patients who received the mobility intervention had significantly fewer falls, ventilator-associated events, pressure ulcers, and CAUTIs than the 66 patients in the routine care group. The mobility group also had lower hospital costs, fewer delirium days, lower sedation levels, and improved functional independence compared with the routine care group. Patients in the mobility group got out of bed on 2.5 more days than patients in the routine care group. There were also no adverse events in the mobility group. CONCLUSIONS: It is feasible for a community hospital to create and implement a dedicated ICU mobility team. Early mobilization of ICU patients contributed to fewer delirium days and improved patient outcomes, sedation levels, and functional status. PMID- 26600360 TI - Creating Careers and Hope in Bangladesh. AB - Set to retire, Barbara Parfitt establishes a nursing college instead. PMID- 26600361 TI - Nurses and the Migration to Electronic Health Records. AB - EHRs have the potential to support nursing workflow or hinder it. PMID- 26600367 TI - My Turn. AB - A retired physician recalls how a nurse helped him out of a predicament as a new intern. PMID- 26600368 TI - Development of a mouse model of infantile spasms induced by N-methyl-D-aspartate. AB - Using N-methyl-D-aspartate (NMDA) injection, we attempt to develop a mouse model for infantile spasms (IS). Experiments were performed in postnatal 11- to 13-day old C57 and Balbc mice. In the pilot experiment, mice were injected with different doses of NMDA (7, 15, and 30 mg/kg) to determine the optimal age and convulsant doses of NMDA. In further experiment optimal age mice were divided into five groups: group A, control group that received intraperitoneal injection of physiological saline; group B, convulsion group that was given intraperitoneal NMDA; group C, pretreatment group that received adrenocorticotropin (ACTH) injection (100 IU/kg) 30 min before NMDA administration; group D, electroencephalogram (EEG) group that received EEG recording, group E, performance group that received motor and learning test at different time point after NMDA administration. The behaviors of each group were observed continuously for 3h, the latency and the total numbers of spasms were recorded. Pilot experiments showed that a 15 mg/kg dose of NMDA could induce typical spasm-like seizures in P13 C57 mice, NMDA administration caused anxiety and deficits in motor and cognitive functions at early time and that large doses of ACTH reduced the number of seizures and rating scale (P<0.05). The NMDA mouse model has the following characteristics: age dependency, spasm-like seizures, cognitive impairment and response to ACTH, which fulfills the criteria of an IS model. PMID- 26600369 TI - Network pharmacology for antiepileptogenesis: Tolerability of multitargeted drug combinations in nonepileptic vs. post-status epilepticus mice. AB - Prevention of symptomatic epilepsy ("antiepileptogenesis") in patients at risk is a major unmet clinical need. Several drugs underwent clinical trials for epilepsy prevention, but none of the drugs tested was effective. Similarly, most previous preclinical attempts to develop antiepileptogenic strategies failed. In the majority of studies, drugs were given as monotherapy. However, epilepsy is a complex network phenomenon, so that it is unlikely that a single drug can halt epileptogenesis. We recently proposed multitargeted approaches ("network pharmacology") to interfere with epileptogenesis. One strategy, which, if effective, would allow a relatively rapid translation into the clinic, is developing novel combinations of clinically used drugs with diverse mechanisms that are potentially relevant for antiepileptogenesis. In order to test this strategy preclinically, we developed an algorithm for testing such drug combinations, which was inspired by the established drug development phases in humans. As a first step of this algorithm, tolerability of four rationally chosen, repeatedly administered drug combinations was evaluated by a large test battery in mice: A, levetiracetam and phenobarbital; B, valproate, losartan, and memantine; C, levetiracetam and topiramate; and D, levetiracetam, parecoxib, and anakinra. As in clinical trials, tolerability was separately evaluated before starting efficacy experiments to identify any adverse effects of the combinations that may critically limit the successful translation of preclinical findings to the clinic. Except combination B, all drug cocktails were relatively well tolerated. Based on previous studies, we expected that tolerability would be lower in the latent and chronic phases following status epilepticus in mice, but, except combinations C and D, no significant differences were determined between nonepileptic and post-status epilepticus animals. As a next step, the rationally chosen drug combinations will be evaluated for antiepileptogenic activity in mouse and rat models of symptomatic epilepsy. PMID- 26600370 TI - Anticonvulsant efficacy of melatonin in an experimental model of hyperthermic febrile seizures. AB - INTRODUCTION: The anticonvulsant effects of melatonin (MT) have been demonstrated in several different experimental seizure models. Thus, the present study aimed to determine the anticonvulsant efficacy of MT, the optimum time for its administration prior to the induction of a seizure, and its effective dose in a rat model of hyperthermic febrile seizures (FSs). METHODS: The present study included 72 male Sprague-Dawley rat pups divided into eight groups. The seizures were induced by keeping the rats in 45 degrees C water and the experiments were performed in two steps. In the first step, the control group was given a vehicle injection and the study groups were given a MT injection (150 mg/kg, intraperitoneal [i.p.]) at either 5, 10, or 15 min prior to the induction of the seizure to determine the anticonvulsant effects of MT and its optimum time of administration. In the second step, a vehicle injection and three different doses of MT (80, 100, and 150 mg/kg, i.p.) were administered 15 min prior to the induction of the seizure to determine the dose at which anticonvulsant effects could be achieved. The anticonvulsant effects were assessed based on the latency of the FSs. RESULTS: In the first-step experiments, the FS latency of the control group was 143.4 +/- 15.3s and the latencies of the groups given melatonin at either 5, 10, or 15 min prior to the seizure were 174.2 +/- 28.9, 177.4 +/- 21.0, and 193.7 +/- 17.6s, respectively. Compared with the control group, the latencies for each of the study groups were significantly longer (p<0.001), with the longest latency observed in the group given melatonin 15 min before the seizure. In the second-step experiments, the FS latencies of the groups that were given 80, 100, and 150 mg/kg of MT 15 min before the seizure were 238.7 +/- 4.0, 240.0 +/- 0.0, and 193.7 +/- 17.6s, respectively. These latencies were significantly longer than those of the control group (172.3 +/- 30.3s, p<0.001). CONCLUSION: The present study demonstrated that MT exerts anticonvulsant effects in a rat model of hyperthermic FSs and achieved its optimum efficacy at a dose of 80 mg/kg when administered 15 min prior to the induction of a seizure. PMID- 26600372 TI - Fast Production of High-Quality Graphene via Sequential Liquid Exfoliation. AB - A novel and practical approach of exfoliating graphite into graphene uses a sequence of flow and sonication on graphite suspensions. Graphite sediment after intense mixing is found to be altered, graphite having curled-up edges, which increases its sensitivity to ultrasound. Quadrupled graphene yield is achieved through introducing flow pretreatment. PMID- 26600371 TI - The progressive changes of filamentous actin cytoskeleton in the hippocampal neurons after pilocarpine-induced status epilepticus. AB - In a previous study, we reported a persistent reduction of F-actin puncta but a compensating increase in puncta size in the mouse hippocampus at 2 months after pilocarpine-induced status epilepticus (Epilepsy Res. 108 (2014), 379-389). However, the F-actin changes during the period of epileptogenesis remain unknown. This study was designed to examine the temporal and spatial changes of F-actin during the period of epileptogenesis in a pilocarpine-induced epilepsy model, primarily by the histological and TUNEL evaluation of cell loss, phalloidin detection of F-actin, and immunohistochemical analysis of glial reactions. The results demonstrated that F-actin continued to decrease after pilocarpine treatment, which was consistent in its time course with hippocampal neuronal death. Within different hippocampal subfields, the spatial changes of F-actin exhibited similar features. First, the F-actin puncta decreased in number. Thereafter, F-actin was transiently aggregated in dendritic shafts and neuronal cell bodies and eventually was completely lost in the degenerated neurons. The progressive changes of F-actin in the degenerating neurons reported in this study may help to elucidate a cytoskeletal mechanism that may link to the delayed cell loss that occurs during epileptogenesis. PMID- 26600374 TI - Unified Approach to the Spiro(pyrrolidinyl-oxindole) and Hexahydropyrrolo[2,3 b]indole Alkaloids: Total Syntheses of Pseudophrynamines 270 and 272A. AB - The first enantioselective total syntheses of architecturally interesting prenylated pyrroloindole alkaloids, (-)-pseudophrynamines 272A (3d) and 270 (3b), have been achieved starting from enantioenriched 2-oxindoles having all-carbon quaternary stereocenters. A common strategy involving a thio-urea catalyzed aldol reaction is employed for the total synthesis of both spiro(pyrrolidinyl-oxindole) and hexahydropyrrolo[2,3-b]indole alkaloids. PMID- 26600375 TI - Sexually antagonistic epigenetic marks that canalize sexually dimorphic development. AB - The sexes share the same autosomal genomes, yet sexual dimorphism is common due to sex-specific gene expression. When present, XX and XY karyotypes trigger alternate regulatory cascades that determine sex-specific gene expression profiles. In mammals, secretion of testosterone (T) by the testes during foetal development is the master switch influencing the gene expression pathways (male vs. female) that will be followed, but many genes have sex-specific expression prior to T secretion. Environmental factors, like endocrine disruptors and mimics, can interfere with sexual development. However, sex-specific ontogeny can be canalized by the production of epigenetic marks (epimarks) generated during early ontogeny that increase sensitivity of XY embryos to T and decrease sensitivity of XX embryos. Here, we integrate and synthesize the evidence indicating that canalizing epimarks are produced during early ontogeny. We will also describe the evidence that such epimarks sometimes carry over across generations and produce mosaicism in which some traits are discordant with the gonad. Such carryover epimarks are sexually antagonistic because they benefit the individual in which they were formed (via canalization) but harm opposite-sex offspring when they fail to erase across generations and produce gonad-trait discordances. SA-epimarks have the potential to: i) magnify phenotypic variation for many sexually selected traits, ii) generate overlap along many dimensions of the masculinity/femininity spectrum, and iii) influence medically important gonad trait discordances like cryptorchidism, hypospadias and idiopathic hirsutism. PMID- 26600376 TI - Online Solution of Two-Player Zero-Sum Games for Continuous-Time Nonlinear Systems With Completely Unknown Dynamics. AB - Regarding two-player zero-sum games of continuous-time nonlinear systems with completely unknown dynamics, this paper presents an online adaptive algorithm for learning the Nash equilibrium solution, i.e., the optimal policy pair. First, for known systems, the simultaneous policy updating algorithm (SPUA) is reviewed. A new analytical method to prove the convergence is presented. Then, based on the SPUA, without using a priori knowledge of any system dynamics, an online algorithm is proposed to simultaneously learn in real time either the minimal nonnegative solution of the Hamilton-Jacobi-Isaacs (HJI) equation or the generalized algebraic Riccati equation for linear systems as a special case, along with the optimal policy pair. The approximate solution to the HJI equation and the admissible policy pair is reexpressed by the approximation theorem. The unknown constants or weights of each are identified simultaneously by resorting to the recursive least square method. The convergence of the online algorithm to the optimal solutions is provided. A practical online algorithm is also developed. Simulation results illustrate the effectiveness of the proposed method. PMID- 26600377 TI - A Boosting Approach to Exploit Instance Correlations for Multi-Instance Classification. AB - We propose a Boosting approach for multi-instance (MI) classification. Lp -norm is integrated to localize the witness instances and formulate the bag scores from classifier outputs. The contributions are twofold. First, a flexible and concise model for Boosting is proposed by the Lp -norm localization and exponential loss optimization. The scores for bag-level classification are directly fused from the instance feature space without probabilistic assumptions. Second, gradient and Newton descent optimizations are applied to derive the weak learners for Boosting. In particular, the instance correlations are exploited by fitting the weights and Newton updates for the weak learner construction. The final Boosted classifiers are the sums of iteratively chosen weak learners. Experiments demonstrate that the proposed Lp -norm-localized Boosting approach significantly improves the MI classification performance. Compared with the state of the art, the approach achieves the highest MI classification accuracy on 7/10 benchmark data sets. PMID- 26600378 TI - Shortcomings/Limitations of Blockwise Granger Causality and Advances of Blockwise New Causality. AB - Multivariate blockwise Granger causality (BGC) is used to reflect causal interactions among blocks of multivariate time series. In particular, spectral BGC and conditional spectral BGC are used to disclose blockwise causal flow among different brain areas in various frequencies. In this paper, we demonstrate that: 1) BGC in time domain may not necessarily disclose true causality and 2) due to the use of the transfer function or its inverse matrix and partial information of the multivariate linear regression model, both of spectral BGC and conditional spectral BGC have shortcomings and/or limitations, which may inevitably lead to misinterpretation. We then, in time and frequency domains, develop two new multivariate blockwise causality methods for the linear regression model called blockwise new causality (BNC) and spectral BNC, respectively. By several examples, we confirm that BNC measures are more reasonable and sensitive to reflect true causality or trend of true causality than BGC or conditional BGC. Finally, for electroencephalograph data from an epilepsy patient, we analyze event-related potential causality and demonstrate that both of the BGC and BNC methods show significant causality flow in frequency domain, but the spectral BNC method yields satisfactory and convincing results, which are consistent with an event-related time-frequency power spectrum activity. The spectral BGC method is shown to generate misleading results. Thus, we deeply believe that our new blockwise causality definitions as well as our previous NC definitions may have wide applications to reflect true causality among two blocks of time series or two univariate time series in economics, neuroscience, and engineering. PMID- 26600379 TI - Long-term result of out-patient neodymium-doped yttrium aluminium garnet laser photocoagulation surgery for patients with epistaxis. AB - OBJECTIVE: To evaluate the long-term efficacy of out-patient neodymium-doped yttrium aluminium garnet laser photocoagulation surgery for patients with epistaxis. METHODS: A retrospective clinical study was conducted. A total of 217 consecutive patients who presented with acute or recurrent epistaxis received neodymium-doped yttrium aluminium garnet laser photocoagulation treatment in an out-patient setting. RESULTS: At three years, 94 per cent of acute epistaxis patients versus 88 per cent of recurrent epistaxis patients reported no bleeding. The outcome scores at 12 weeks and 3 years after treatment showed no significant differences between the 2 groups (p = 0.207 and p = 0.186). However, there was a significant difference in outcome scores at four weeks after treatment (p = 0.034). The median (and mean +/- standard deviation) pain levels experienced during the laser operation (performed in an office setting) were 4.0 (3.75 +/- 2.09) in the acute epistaxis group and 4.0 (3.83 +/- 2.01) in the recurrent epistaxis group. Neither group had any complications. CONCLUSION: Neodymium-doped yttrium aluminium garnet laser photocoagulation is desirable in the treatment of both acute and recurrent epistaxis, and has long-lasting efficacy. PMID- 26600380 TI - Fifteen into Three Does Go: Morphology, Genetics and Genitalia Confirm Taxonomic Inflation of New Zealand Beetles (Chrysomelidae: Eucolaspis). AB - Eucolaspis Sharp 1886 is a New Zealand native leaf beetle genus (Coleoptera: Chrysomelidae: Eumolpinae) with poorly described species and a complex taxonomy. Many economically important fruit crops are severely damaged by these beetles. Uncertain species taxonomy of Eucolaspis is leaving any biological research, as well as pest management, tenuous. We used morphometrics, mitochondrial DNA and male genitalia to study phylogenetic and geographic diversity of Eucolaspis in New Zealand. Freshly collected beetles from several locations across their distribution range, as well as identified voucher specimens from major museum collections were examined to test the current classification. We also considered phylogenetic relationships among New Zealand and global Eumolpinae (Coleoptera: Chyrosomelidae). We demonstrate that most of the morphological information used previously to define New Zealand Eucolaspis species is insufficient. At the same time, we show that a combination of morphological and genetic evidence supports the existence of just 3 mainland Eucolaspis lineages (putative species), and not 5 or 15, as previously reported. In addition, there may be another closely related lineage (putative species) on an offshore location (Three Kings Islands, NZ). The cladistic structure among the lineages, conferred through mitochondrial DNA data, was well supported by differences in male genitalia. We found that only a single species (lineage) infests fruit orchards in Hawke's Bay region of New Zealand. Species-host plant associations vary among different regions. PMID- 26600381 TI - Fluctuation-Driven Neural Dynamics Reproduce Drosophila Locomotor Patterns. AB - The neural mechanisms determining the timing of even simple actions, such as when to walk or rest, are largely mysterious. One intriguing, but untested, hypothesis posits a role for ongoing activity fluctuations in neurons of central action selection circuits that drive animal behavior from moment to moment. To examine how fluctuating activity can contribute to action timing, we paired high resolution measurements of freely walking Drosophila melanogaster with data driven neural network modeling and dynamical systems analysis. We generated fluctuation-driven network models whose outputs-locomotor bouts-matched those measured from sensory-deprived Drosophila. From these models, we identified those that could also reproduce a second, unrelated dataset: the complex time-course of odor-evoked walking for genetically diverse Drosophila strains. Dynamical models that best reproduced both Drosophila basal and odor-evoked locomotor patterns exhibited specific characteristics. First, ongoing fluctuations were required. In a stochastic resonance-like manner, these fluctuations allowed neural activity to escape stable equilibria and to exceed a threshold for locomotion. Second, odor induced shifts of equilibria in these models caused a depression in locomotor frequency following olfactory stimulation. Our models predict that activity fluctuations in action selection circuits cause behavioral output to more closely match sensory drive and may therefore enhance navigation in complex sensory environments. Together these data reveal how simple neural dynamics, when coupled with activity fluctuations, can give rise to complex patterns of animal behavior. PMID- 26600382 TI - Attitudes toward Placebo-Controlled Clinical Trials of Patients with Schizophrenia in Japan. AB - BACKGROUND: Although the use of placebo in clinical trials of schizophrenia patients is controversial because of medical and ethical concerns, placebo controlled clinical trials are commonly used in the licensing of new drugs. AIMS: The objective of this study was to assess the attitudes toward placebo-controlled clinical trials among patients with schizophrenia in Japan. METHOD: Using a cross sectional design, we recruited patients (n = 251) aged 47.7+/-13.2 (mean+/-SD) with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder who were admitted to six psychiatric hospitals from December 2013 to March 2014. We employed a 14-item questionnaire specifically developed to survey patients' attitudes toward placebo-controlled clinical trials. RESULTS: The results indicated that 33% of the patients would be willing to participate in a placebo controlled clinical trial. Expectations for improvement of disease, a guarantee of hospital treatment continuation, and encouragement by family or friends were associated with the willingness to participate in such trials, whereas a belief of additional time required for medical examinations was associated with non participation. CONCLUSIONS: Fewer than half of the respondents stated that they would be willing to participate in placebo-controlled clinical trials. Therefore, interpreting the results from placebo-controlled clinical trials could be negatively affected by selection bias. PMID- 26600383 TI - Long-Term Fate Mapping Using Conditional Lentiviral Vectors Reveals a Continuous Contribution of Radial Glia-Like Cells to Adult Hippocampal Neurogenesis in Mice. AB - Newborn neurons are generated throughout life in two neurogenic regions, the subventricular zone and the hippocampal dentate gyrus. Stimulation of adult neurogenesis is considered as an attractive endogenous repair mechanism to treat different neurological disorders. Although tremendous progress has been made in our understanding of adult hippocampal neurogenesis, important questions remain unanswered, regarding the identity and the behavior of neural stem cells in the dentate gyrus. We previously showed that conditional Cre-Flex lentiviral vectors can be used to label neural stem cells in the subventricular zone and to track the migration of their progeny with non-invasive bioluminescence imaging. Here, we applied these Cre-Flex lentiviral vectors to study neurogenesis in the dentate gyrus with bioluminescence imaging and histological techniques. Stereotactic injection of the Cre-Flex vectors into the dentate gyrus of transgenic Nestin-Cre mice resulted in specific labeling of the nestin-positive neural stem cells. The labeled cell population could be detected with bioluminescence imaging until 9 months post injection, but no significant increase in the number of labeled cells over time was observed with this imaging technique. Nevertheless, the specific labeling of the nestin-positive neural stem cells, combined with histological analysis at different time points, allowed detailed analysis of their neurogenic potential. This long-term fate mapping revealed that a stable pool of labeled nestin-positive neural stem cells continuously contributes to the generation of newborn neurons in the mouse brain until 9 months post injection. In conclusion, the Cre-Flex technology is a valuable tool to address remaining questions regarding neural stem cell identity and behavior in the dentate gyrus. PMID- 26600384 TI - Incidence of Type II CRISPR1-Cas Systems in Enterococcus Is Species-Dependent. AB - CRISPR-Cas systems, which obstruct both viral infection and incorporation of mobile genetic elements by horizontal transfer, are a specific immune response common to prokaryotes. Antiviral protection by CRISPR-Cas comes at a cost, as horizontally-acquired genes may increase fitness and provide rapid adaptation to habitat change. To date, investigations into the prevalence of CRISPR have primarily focused on pathogenic and clinical bacteria, while less is known about CRISPR dynamics in commensal and environmental species. We designed PCR primers and coupled these with DNA sequencing of products to detect and characterize the presence of cas1, a universal CRISPR-associated gene and proxy for the Type II CRISPR1-Cas system, in environmental and non-clinical Enterococcus isolates. CRISPR1-cas1 was detected in approximately 33% of the 275 strains examined, and differences in CRISPR1 carriage between species was significant. Incidence of cas1 in E. hirae was 73%, nearly three times that of E. faecalis (23.6%) and 10 times more frequent than in E. durans (7.1%). Also, this is the first report of CRISPR1 presence in E. durans, as well as in the plant-associated species E. casseliflavus and E. sulfureus. Significant differences in CRISPR1-cas1 incidence among Enterococcus species support the hypothesis that there is a tradeoff between protection and adaptability. The differences in the habitats of enterococcal species may exert varying selective pressure that results in a species-dependent distribution of CRISPR-Cas systems. PMID- 26600386 TI - Despite Buffers, Experimental Forest Clearcuts Impact Amphibian Body Size and Biomass. AB - Forest buffers are a primary tool used to protect wetland-dependent wildlife. Though implemented widely, buffer efficacy is untested for most amphibian species. Consequently, it remains unclear whether buffers are sufficient for maintaining amphibian populations and if so, how wide buffers should be. We present evidence from a six-year, landscape-scale experiment testing the impacts of clearcutting, buffer width, and hydroperiod on body size and condition and biomass of breeding adults for two amphibian species at 11 vernal pools in the northeastern United States. We randomly assigned treatments (i.e., reference, 100m buffer, 30m buffer) across pools, clearcut to create buffers, and captured all spotted salamanders and wood frogs. Clearcuts strongly and negatively impacted size, condition, and biomass, but wider buffers mitigated effect magnitude and duration. Among recaptured individuals, for example, 30m-treatment salamanders were predicted to be about 9.5 mm shorter than, while 100m-treatment salamanders did not differ in length from, reference-treatment salamanders. Similarly, among recaptured frogs, mean length in the 30m treatment was predicted to decrease by about 1 mm/year, while in the 100m and reference treatments, length was time-invariant. Some, but not all, metrics recovered with time. For example, female new-captured and recaptured salamanders were predicted, respectively and on average, to weigh 4.5 and 7 g less in the 30m versus reference treatment right after the cut. While recaptured-female mass was predicted to recover by 9.5 years post-cut, new-captured-female mass did not recover. Hydroperiod was an important mediator: in the 100m treatment, cutting predominately affected pools that were stressed hydrologically. Overall, salamanders and female frogs were impacted more than male frogs. Our results highlight the importance of individualized metrics like body size, which can reveal sublethal effects and illuminate mechanisms by which habitat disturbance impacts wildlife populations. Individualized metrics thus provide critical insights that complement species occurrence and abundance-based population assessments. PMID- 26600385 TI - Sex Differences in the Default Mode Network with Regard to Autism Spectrum Traits: A Resting State fMRI Study. AB - Autism spectrum traits exist on a continuum and are more common in males than in females, but the basis for this sex difference is unclear. To this end, the present study draws on the extreme male brain theory, investigating the relationship between sex difference and the default mode network (DMN), both known to be associated with autism spectrum traits. Resting-state functional magnetic resonance imaging (MRI) was carried out in 42 females (mean age +/- standard deviation, 22.4 +/- 4.2 years) and 43 males (mean age +/- standard deviation, 23.8 +/- 3.9 years) with typical development. Using a combination of different analyses (viz., independent component analysis (ICA), fractional amplitude of low-frequency fluctuation (fALFF), regional homogeneity (ReHo), and seed-based analyses), we examined sex differences in the DMN and the relationship to autism spectrum traits as measured by autism-spectrum quotient (AQ) scores. We found significant differences between female and male subjects in DMN brain regions, with seed-based analysis revealing a significant negative correlation between default-mode resting state functional connectivity of the anterior medial prefrontal cortex seed (aMPFC) and AQ scores in males. However, there were no relationships between DMN sex differences and autism spectrum traits in females. Our findings may provide important insight into the skewed balance of functional connectivity in males compared to females that could serve as a potential biomarker of the degree of autism spectrum traits in line with the extreme male brain theory. PMID- 26600387 TI - Unidirectional Fabric Drape Testing Method. AB - In most cases, fabrics such as curtains, skirts, suit pants and so on are draped under their own gravity parallel to fabric plane while the gravity is perpendicular to fabric plane in traditional drape testing method. As a result, it does not conform to actual situation and the test data is not convincing enough. To overcome this problem, this paper presents a novel method which simulates the real mechanical conditions and ensures the gravity is parallel to the fabric plane. This method applied a low-cost Kinect Sensor device to capture the 3-dimensional (3D) drape profile, thus we obtained the drape degree parameters and aesthetic parameters by 3D reconstruction and image processing and analysis techniques. The experiment was conducted on our self-devised drape testing instrument by choosing different kinds of weave structure fabrics as our testing samples and the results were compared with those of traditional method and subjective evaluation. Through regression and correlation analysis we found that this novel testing method was significantly correlated with the traditional and subjective evaluation method. We achieved a new, non-contact 3D measurement method for drape testing, namely unidirectional fabric drape testing method. This method is more suitable for evaluating drape behavior because it is more in line with actual mechanical conditions of draped fabrics and has a well consistency with the requirements of visual and aesthetic style of fabrics. PMID- 26600388 TI - Influence of Magnesium Alloy Degradation on Undifferentiated Human Cells. AB - BACKGROUND: Magnesium alloys are of particular interest in medical science since they provide compatible mechanical properties with those of the cortical bone and, depending on the alloying elements, they have the capability to tailor the degradation rate in physiological conditions, providing alternative bioresorbable materials for bone applications. The present study investigates the in vitro short-term response of human undifferentiated cells on three magnesium alloys and high-purity magnesium (Mg). MATERIALS AND METHODS: The degradation parameters of magnesium-silver (Mg2Ag), magnesium-gadolinium (Mg10Gd) and magnesium-rare-earth (Mg4Y3RE) alloys were analysed after 1, 2, and 3 days of incubation in cell culture medium under cell culture condition. Changes in cell viability and cell adhesion were evaluated by culturing human umbilical cord perivascular cells on corroded Mg materials to examine how the degradation influences the cellular development. RESULTS AND CONCLUSIONS: The pH and osmolality of the medium increased with increasing degradation rate and it was found to be most pronounced for Mg4Y3RE alloy. The biological observations showed that HUCPV exhibited a more homogeneous cell growth on Mg alloys compared to high-purity Mg, where they showed a clustered morphology. Moreover, cells exhibited a slightly higher density on Mg2Ag and Mg10Gd in comparison to Mg4Y3RE, due to the lower alkalinisation and osmolality of the incubation medium. However, cells grown on Mg10Gd and Mg4Y3RE generated more developed and healthy cellular structures that allowed them to better adhere to the surface. This can be attributable to a more stable and homogeneous degradation of the outer surface with respect to the incubation time. PMID- 26600389 TI - Mdm20 Modulates Actin Remodeling through the mTORC2 Pathway via Its Effect on Rictor Expression. AB - NatB is an N-terminal acetyltransferase consisting of a catalytic Nat5 subunit and an auxiliary Mdm20 subunit. In yeast, NatB acetylates N-terminal methionines of proteins during de novo protein synthesis and also regulates actin remodeling through N-terminal acetylation of tropomyosin (Trpm), which stabilizes the actin cytoskeleton by interacting with actin. However, in mammalian cells, the biological functions of the Mdm20 and Nat5 subunits are not well understood. In the present study, we show for the first time that Mdm20-knockdown (KD), but not Nat5-KD, in HEK293 and HeLa cells suppresses not only cell growth, but also cellular motility. Although stress fibers were formed in Mdm20-KD cells, and not in control or Nat5-KD cells, the localization of Trpm did not coincide with the formation of stress fibers in Mdm20-KD cells. Notably, knockdown of Mdm20 reduced the expression of Rictor, an mTORC2 complex component, through post-translational regulation. Additionally, PKCalphaS657 phosphorylation, which regulates the organization of the actin cytoskeleton, was also reduced in Mdm20-KD cells. Our data also suggest that FoxO1 phosphorylation is regulated by the Mdm20-mTORC2-Akt pathway in response to serum starvation and insulin stimulation. Taken together, the present findings suggest that Mdm20 acts as a novel regulator of Rictor, thereby controlling mTORC2 activity, and leading to the activation of PKCalphaS657 and FoxO1. PMID- 26600390 TI - Role of an SNP in Alternative Splicing of Bovine NCF4 and Mastitis Susceptibility. AB - Neutrophil cytosolic factor 4 (NCF4) is component of the nicotinamide dinucleotide phosphate oxidase complex, a key factor in biochemical pathways and innate immune responses. In this study, splice variants and functional single nucleotide polymorphism (SNP) of NCF4 were identified to determine the variability and association of the gene with susceptibility to bovine mastitis characterized by inflammation. A novel splice variant, designated as NCF4-TV and characterized by the retention of a 48 bp sequence in intron 9, was detected in the mammary gland tissues of infected cows. The expression of the NCF4-reference main transcript in the mastitic mammary tissues was higher than that in normal tissues. A novel SNP, g.18174 A>G, was also found in the retained 48 bp region of intron 9. To determine whether NCF4-TV could be due to the g.18174 A>G mutation, we constructed two mini-gene expression vectors with the wild-type or mutant NCF4 g.18174 A>G fragment. The vectors were then transiently transfected into 293T cells, and alternative splicing of NCF4 was analyzed by reverse transcription-PCR and sequencing. Mini-gene splicing assay demonstrated that the aberrantly spliced NCF4-TV with 48 bp retained fragment in intron 9 could be due to g.18174 A>G, which was associated with milk somatic count score and increased risk of mastitis infection in cows. NCF4 expression was also regulated by alternative splicing. This study proposes that NCF4 splice variants generated by functional SNP are important risk factors for mastitis susceptibility in dairy cows. PMID- 26600391 TI - Skill-Specific Changes in Somatosensory Nogo Potentials in Baseball Players. AB - Athletic training is known to induce neuroplastic alterations in specific somatosensory circuits, which are reflected by changes in somatosensory evoked potentials and event-related potentials. The aim of this study was to clarify whether specific athletic training also affects somatosensory Nogo potentials related to the inhibition of movements. The Nogo potentials were recorded at nine cortical electrode positions (Fz, Cz, Pz, F3, F4, C3, C4, P3 and P4) in 12 baseball players (baseball group) and in 12 athletes in sports, such as track and field events and swimming, that do not require response inhibition, such as batting for training or performance (sports group). The Nogo potentials and Go/Nogo reaction times (Go/Nogo RTs) were measured under a somatosensory Go/Nogo paradigm in which subjects were instructed to rapidly push a button in response to stimulus presentation. The Nogo potentials were obtained by subtracting the Go trial from the Nogo trial. The peak Nogo-N2 was significantly shorter in the baseball group than that in the sports group. In addition, the amplitude of Nogo N2 in the frontal area was significantly larger in the baseball group than that in the sports group. There was a significant positive correlation between the latency of Nogo-N2 and Go/Nogo RT. Moreover, there were significant correlations between the Go/Nogo RT and both the amplitude of Nogo-N2 and Nogo-P3 (i.e., amplitude of the Nogo-potentials increases with shorter RT). Specific athletic training regimens may induce neuroplastic alterations in sensorimotor inhibitory processes. PMID- 26600393 TI - Quantification of the Mass and Viscoelasticity of Interfacial Films on Tin Anodes Using EQCM-D. AB - Electrochemical quartz crystal microbalance coupled with dissipation (EQCM-D) is employed to investigate the solid electrolyte interphase (SEI) formation and Li insertion/deinsertion into thin film electrodes of tin. Based on the frequency change we find that the initial SEI formation process is rapid before Li insertion but varies significantly with increasing concentration of the additive fluoroethylene carbonate (FEC) in the electrolyte. The extent of dissipation, which represents the film rigidity, increases with cycle number, reflecting film thickening and softening. Dissipation values are almost twice as large in the baseline electrolyte (1.2 M LiPF6 in 3:7 wt % ethylene carbonate:ethyl methyl carbonate), indicating the film in baseline electrolyte is roughly twice as soft as in the FEC-containing cells. More importantly, we detail how quantitative data about mass, thickness, shear elastic modulus, and shear viscosity in a time resolved manner can be obtained from the EQCM-D response. These parameters were extracted from the frequency and dissipation results at multiple harmonics using the Sauerbrey and Voigt viscoelastic models. From these modeled results we show the dynamic mass changes for each half cycle. We also demonstrate that different amounts of FEC additive influence the SEI formation behavior and result in differences in the estimated mass, shear modulus and viscosity. After three cycles, the film in baseline electrolyte exhibits a 1.2 times larger mass change compared with the film in the FEC-containing electrolyte. The shear elastic modulus of films formed in the presence of FEC is larger than in the baseline electrolyte at early stages of lithiation. Also with lithiation is a marked increase in film viscosity, which together point to a much stiffer and more homogeneous SEI formed in the presence of FEC. PMID- 26600392 TI - Identifying Triple-Negative Breast Cancer Using Background Parenchymal Enhancement Heterogeneity on Dynamic Contrast-Enhanced MRI: A Pilot Radiomics Study. AB - OBJECTIVES: To determine the added discriminative value of detailed quantitative characterization of background parenchymal enhancement in addition to the tumor itself on dynamic contrast-enhanced (DCE) MRI at 3.0 Tesla in identifying "triple negative" breast cancers. MATERIALS AND METHODS: In this Institutional Review Board-approved retrospective study, DCE-MRI of 84 women presenting 88 invasive carcinomas were evaluated by a radiologist and analyzed using quantitative computer-aided techniques. Each tumor and its surrounding parenchyma were segmented semi-automatically in 3-D. A total of 85 imaging features were extracted from the two regions, including morphologic, densitometric, and statistical texture measures of enhancement. A small subset of optimal features was selected using an efficient sequential forward floating search algorithm. To distinguish triple-negative cancers from other subtypes, we built predictive models based on support vector machines. Their classification performance was assessed with the area under receiver operating characteristic curve (AUC) using cross-validation. RESULTS: Imaging features based on the tumor region achieved an AUC of 0.782 in differentiating triple-negative cancers from others, in line with the current state of the art. When background parenchymal enhancement features were included, the AUC increased significantly to 0.878 (p<0.01). Similar improvements were seen in nearly all subtype classification tasks undertaken. Notably, amongst the most discriminating features for predicting triple-negative cancers were textures of background parenchymal enhancement. CONCLUSIONS: Considering the tumor as well as its surrounding parenchyma on DCE-MRI for radiomic image phenotyping provides useful information for identifying triple negative breast cancers. Heterogeneity of background parenchymal enhancement, characterized by quantitative texture features on DCE-MRI, adds value to such differentiation models as they are strongly associated with the triple-negative subtype. Prospective validation studies are warranted to confirm these findings and determine potential implications. PMID- 26600394 TI - Black Phosphorus: Narrow Gap, Wide Applications. AB - The recent isolation of atomically thin black phosphorus by mechanical exfoliation of bulk layered crystals has triggered an unprecedented interest, even higher than that raised by the first works on graphene and other two dimensionals, in the nanoscience and nanotechnology community. In this Perspective, we critically analyze the reasons behind the surge of experimental and theoretical works on this novel two-dimensional material. We believe that the fact that black phosphorus band gap value spans over a wide range of the electromagnetic spectrum (interesting for thermal imaging, thermoelectrics, fiber optics communication, photovoltaics, etc.) that was not covered by any other two dimensional material isolated to date, its high carrier mobility, its ambipolar field-effect, and its rather unusual in-plane anisotropy drew the attention of the scientific community toward this two-dimensional material. Here, we also review the current advances, the future directions and the challenges in this young research field. PMID- 26600395 TI - Prognostic value of antibodies to Merkel cell polyomavirus T antigens and VP1 protein in patients with Merkel cell carcinoma. AB - BACKGROUND: Merkel cell polyomavirus (MCPyV) is the main aetiological agent of Merkel cell carcinoma (MCC). Serum antibodies against the major MCPyV capsid protein (VP1) are detected in the general population, whereas antibodies against MCPyV oncoproteins (T antigens) have been reported specifically in patients with MCC. OBJECTIVES: The primary aim was to assess whether detection of serum antibodies against MCPyV proteins at baseline was associated with disease outcome in patients with MCC. The secondary aim was to establish whether evolution of these antibodies during follow-up was associated with the course of the disease. METHODS: Serum T-antigen and VP1 antibodies were assessed by enzyme-linked immunosorbent assay using recombinant proteins in a cohort of 143 patients with MCC, including 84 patients with serum samples available at baseline. RESULTS: Low titres of VP1 antibodies at baseline (< 10 000) were significantly and independently associated with increased risk of recurrence [hazard ratio (HR) 2.71, 95% confidence interval (CI) 1.13-6.53, P = 0.026] and death (HR 3.74, 95% CI 1.53-9.18, P = 0.004), whereas T-antigen antibodies were not found to be associated with outcome. VP1 antibodies did not differ between patients in remission and those with recurrence or progression during follow-up. However, T antigen antibodies were more frequently detected in patients with recurrence or progression at 12 months (P = 0.020) and 24 months (P = 0.016) after diagnosis. CONCLUSIONS: VP1 antibodies constitute a prognostic marker at baseline, whereas T antigen antibodies constitute a marker of disease recurrence or progression if detected > 12 months after diagnosis. PMID- 26600396 TI - The ?textit{BRAF} V600E mutation in single- institution study of Russian melanoma patients. AB - BACKGROUND: The activating mutation BRAF V600E is considered to be a diagnostic cutaneous melanoma (CM) marker important for prognosis and targeted therapy. OBJECTIVE: The aim of this study was to determine the frequency of the V600E mutation in CM patients in Russia and to estimate the influence of the BRAF gene mutation status on prognosis and clinical outcome. METHODS: To ensure mutation detection in FFPE tissue, interlaboratory validation was performed using three different methods: allele-specific hybridisation on a biochip, allele-specific real-time PCR and, in some cases, direct sequencing. RESULTS: Mutation V600E was detected in 49% of patients. The age of disease manifestation was significantly lower in mutated (MT) BRAF patients, and the median age difference between the wild-type (WT) and MT BRAF groups (P= 0.002) was 10 years. A tumour thickness more than 1 mm was also more frequently observed in the MT BRAF group (P= 0.059). Patients from the MT BRAF group were more likely to have ulceration compared to the WT group (P= 0.088). No statistically significant differences were found between the relapse-free, progression-free or overall survival of CM patients in the MT BRAF and WT BRAF groups. CONCLUSIONS: The data obtained show that the V600E BRAF mutation occurred in about half of melanoma patients; it was associated with earlier manifestation of melanoma and likely with more aggressive clinical features. PMID- 26600397 TI - Hsa_circ_0001649: A circular RNA and potential novel biomarker for hepatocellular carcinoma. AB - BACKGROUND: It has been shown that circular RNA (circRNA) is associated with human cancers, however, few studies have been reported in hepatocellular carcinoma (HCC). OBJECTIVE: To estimate clinical values of a circular RNA, Hsa_circ_0001649, in HCC. METHODS: Expression level of hsa_circ_0001649 was detected in HCC and paired adjacent liver tissues by real-time quantitative reverse transcription-polymerase chain reactions (qRT-PCRs). Differences in expression level of hsa_circ_0001649 were analyzed using the paired t-test. Tests were performed between clinical information and hsa_circ_0001649 expression level by analysis of variance (ANOVA) or welch t-test and a receiver operating characteristics (ROC) curve was established to estimate the value of hsa_circ_0001649 expression as a biomarker in HCC. RESULTS: hsa_circ_0001649 expression was significantly downregulated in HCC tissues (p = 0.0014) based on an analysis of 89 paired samples of HCC and adjacent liver tissues and the area under the ROC curve (AUC) was 0.63. Furthermore, hsa_circ_0001649 expression was correlated with tumor size (p = 0.045) and the occurrence of tumor embolus (p = 0.017) in HCC. CONCLUSIONS: We first found hsa_circ_0001649 was significantly downregulated in HCC. Our findings indicate hsa_circ_0001649 might serve as a novel potential biomarker for HCC and may function in tumorigenesis and metastasis of HCC. PMID- 26600398 TI - The serum level of NX-DCP-R, but not DCP, is not increased in alcoholic liver disease without hepatocellular carcinoma. AB - BACKGROUND AND AIM: Alcoholic liver disease (ALD) is the most common cause of hepatocellular carcinoma (HCC) worldwide. Des-gamma-carboxy prothrombin (DCP) is elevated in many patients with HCC, but also in severe alcoholics without HCC. We aimed to clarify whether the DCP/NX-DCP ratio (NX-DCP-R) could have a high specificity in ALD patients without HCC. METHODS: We performed a prospective cohort study on a total of 703 consecutive outpatients of liver diseases including severe alcoholics and healthy volunteers, who underwent blood biochemical examinations at Kobe University Hospital. Serum DCP was measured by electrochemiluminescence immunoassay (ECLIA) using a monoclonal antibody, MU-3. A novel parameter, serum NX-DCP, which represents predominantly DCP caused by reduced vitamin K availability, was also measured by ECLIA using monoclonal antibodies P-16 and P-11. The diagnostic accuracy of DCP and NX-DCP-R in patients with and without excessive alcohol intake was statistically examined. RESULTS: DCP was significantly higher in alcoholics than in non-alcoholics (p= 0.005), whereas the NX-DCP-R did not differ between alcoholics and non-alcoholics (p= 0.375). DCP was significantly increased in the serum of each patient with alcoholic hepatitis and alcoholic cirrhosis (p< 0.05), whereas the NX-DCP-R was not increased (p> 0.05). CONCLUSIONS: NX-DCP-R, but not DCP, was not increased in alcoholics without HCC. As for negative screening for HCC, the specificity of the NX-DCP-R in alcoholics without HCC was better than that of DCP in alcoholics without HCC, and so could be a useful negative screening tool for HCC in millions of alcoholics worldwide. PMID- 26600399 TI - Survivin and cyclin E2 genes expression in a cohort of Egyptian acute leukemia patients: Clinical importance and future prospects. AB - BACKGROUND: Abnormalities in the control of apoptosis play an important role in leukemogenesis. Survivin is a member of inhibitor of apoptosis proteins family, it prevents apoptosis by blocking caspase activity and play a role in cell proliferation. While, cyclin E2 is one of the cyclins proteins family that controls progression of cell cycle by activation of cyclin dependant-kinase. OBJECTIVE: Was to assess survivin and cyclin E2 genes expression in acute leukemia (AL) patients, and to define their role in the susceptibility of AL, and their correlation with the clinical presentation, laboratory findings, as well as treatment outcome. PATIENTS AND METHODS: This study included 60 de novo AL patients and 40 control subjects to study the expression of survivin and cyclin E2 genes using RT-PCR. RESULTS: Survivin and cyclin E2 genes expression was significantly higher in leukemic patients compared with control subjects (P< 0.001), both genes separately were associated with increased risk of leukemia development and treatment failure (P< 0.01). Moreover, when combining the 2 genes expression, a significant elevation of the risk of leukemia and treatment failure was found (P < 0.01). CONCLUSIONS: Survivin and cyclin E2 genes expression may have clinical relevance and can be considered as molecular risk factors for AL. Also they may be useful as predictive markers for treatment outcome in leukemic patients. PMID- 26600400 TI - The small leucine rich proteoglycan fibromodulin is overexpressed in human prostate epithelial cancer cell lines in culture and human prostate cancer tissue. AB - BACKGROUND: Fibromodulin is a small leucine-rich proteoglycan important for extracellular matrix organization and essential for tissue repair in multiple organs. The main function of this proteoglycan is the regulation of collagen fibrillogenesis; however, more recently described roles for fibromodulin have expanded to include regulation of angiogenesis, reprogramming of human fibroblasts into pluripotent cells, modulation of TGF-beta activity, inflammatory processes and association with metastatic phenotypes. Additionally, fibromodulin has been identified as a novel tumor-associated antigen in leukemia, lymphoma, and leiomyoma. Knowledge about its expression in the prostate is limited. METHODS: Fibromodulin expression was analyzed in two different malignant and one non-tumorigenic prostatic cell lines in culture, and in benign and malignant human prostate tissue. Expression was analyzed by real time PCR, immunocytochemistry, and immunohistochemistry. DNA sequencing was performed on a PCR fragment amplified with primers specific for the FMOD gene from cDNA obtained from the cultured cell lines. RESULTS: Both immunostaining and real time PCR analysis of cell lines indicated that fibromodulin was differentially expressed in the cancerous cell lines compared to the non-tumorigenic cell line. Likewise, cancerous tissue expressed significantly higher levels of intracellular fibromodulin compared to matched, benign tissue from the same patients, as well as compared to tissue from patients with only benign disease. CONCLUSIONS: The expression of fibromodulin was higher in prostatic cancer cells (cell-lines and human tissue) than in normal/benign prostatic cells. Additional studies are required to determine the biological and clinical significance and whether this proteoglycan has a role in carcinogenesis of the prostate or in prostate cancer related inflammatory processes. PMID- 26600401 TI - Compliance of Glaucoma Patients to Ocular Hypotensive Medications Among the Saudi Population. AB - PURPOSE: To evaluate the compliance of glaucoma patients to medical treatment and its impact on the intraocular pressure (IOP) and to verify the associated risk factors for noncompliance. METHODS: All recruited patients were examined at the ophthalmology clinics of King Abdulaziz University Hospital, Riyadh, Saudi Arabia between May and August 2012. Patients were interviewed and subjected to answer a questionnaire that was developed based on a pilot test. Collected data included age, gender, number of prescribed drugs, and different reasons for noncompliance to the prescribed drugs. RESULTS: Noncompliance was detected in 18 (19.4%) of the recruited patients. Factors associated with noncompliance demonstrated a trend toward older patients, males, patients with lower IOP at presentation, higher cup to disc ratio, and drug self-administering patients. However, the only statistically significant characteristic was being under lifelong medications (P = 0.005). CONCLUSION: Noncompliance was detected in around one-fifth of our glaucoma patients, particularly, the older group. Awareness programs, maintaining good patient-physician relationship, and personalizing treatment can lead to better adherence to treatment. PMID- 26600402 TI - Occlusion of sight, sound and smell during Green Exercise influences mood, perceived exertion and heart rate. AB - This study's aim was to identify the relative contribution of sight, sound and smell to the Green Exercise effect. It was hypothesised that visual occlusion while exercising in a natural environment would have the greatest diminishing effect on perceived exertion and mood compared to auditory and olfactory occlusion. Twenty-nine healthy participants were randomly assigned to one of the three groups: visual (n = 10), auditory (n = 9) and olfactory occlusion (n = 10). Each performed six, 5-min bouts of exercise alternating between full sensory and occlusion. Rate of perceived exertion (RPE), heart rate (HR) and mood were recorded at the end of each bout. Sensory-occlusion increased mood, RPE and HR; effects were strongest when sounds were blocked but virtually absent when vision was blocked. During sensory occlusion, mood changes were characterised by increased Fatigue and Confusion, and reduced Vigour. Reductions in Tension and Vigour and increases in Fatigue were found during full sensory exercise, consistent with previous research findings. PMID- 26600403 TI - Correction: Dental Implants - Perceiving Patients' Satisfaction in Relation to Clinical and Electromyography Study on Implant Patients. AB - [This corrects the article DOI: 10.1371/journal.pone.0140438.]. PMID- 26600404 TI - Clusters of Structurally Similar MHC I HLA-A2 Molecules, Found with a New Method, Suggest Mechanisms of T-Cell Receptor Avidity. AB - Only alpha1 and alpha2 domains of the alpha-chain of the major histocompatibility complex (MHC) directly bind peptide antigens (Ag-s) and the T-cell receptor (TCR). Significant plasticity was found in the TCR but only minor in (alpha1 + alpha2). The alpha3-domain position variation was noted only in connection to its binding the coreceptor CD8. We apply our methods for identifying functional conformational changes in proteins to a systematic study of similarities between 43 X-ray structures of the entire alpha chains of MHC-I HLA-A2. Out of 903 different alphaHLA-A2 pairs 203 show similarities within the earlier determined uncertainty threshold and unexpectedly form three similarity clusters (SCs) with all/most structures in a cluster similar within the uncertainty threshold. Pairs from different SCs always differ above the threshold, mainly due to variations in the alpha3 position/structure. All structures in SC3 cannot bind the CD8 coreceptor. Strong hydrogen bonds between (alpha1 + alpha2) and alpha3 differ between SC1 and SC2 but are nearly invariant within each SC. Small conformational changes in the (alpha1 + alpha2), caused by Ag-s differences, act as an alpha3 "allosteric switch" between SC2 and SC1. Binding of CD8 to SC2-HLA-A2 (Tax-type Ag-s) changes it to SC1-HLA-A2 (HuD-type Ag-s). HuD binding to HLA-A2 is much less stable than Tax binding. CD8-liganded HLA-A2 preference for binding HuD suggests that CD8-HLA-A2 may present a weakly binding peptide for TCR recognition, supporting the hypothesis that CD8 increases TCR avidity to weak Ag s. Other HLA-A2 functions may involve alpha3. TCR-A6-liganded-Tax-type-HLA-A2s form two small clusters, similar to either A6-liganded-HuD or A6-liganded-native Tax HLA-A2s. PMID- 26600405 TI - Custodiol Solution and Cold Blood Cardioplegia in Arterial Switch Operation: Retrospective Analysis in a Single Center. AB - BACKGROUND: The cardioplegia is one of the most significant tools used to increase myocardial protection. The aim of our study is to compare the use of Custodiol solution versus intermitted blood cardioplegia in a retrospective analysis of data for patients who underwent arterial switch operation in our institution. MATERIAL AND METHODS: From January 2008 to March 2011, myocardial protection was performed in 44 neonates (blood group) with intermittent blood cardioplegia. From March 2011 to November 2014, myocardial protection was performed in 50 neonates (Custodiol group) with one-shot anterograde Custodiol cardioplegia. RESULTS: Cardiopulmonary bypass and aortic cross-clamp were more favorable in Custodiol group (p-value 0.005 and <= 0.00001). The rate of delayed sternal closure was 63.6% in the blood group and 52% in the Custodiol group (p = 0.25). In the postoperative outcomes we did not find differences between the two groups. The 30-day mortality was one patient in the blood group (p = 0.46). We observed a transient ischemic electrocardiogram in 10 patients of the blood group and in 14 of the Custodiol group (p = 0.72), all cases with full resolution during hospitalization without coronary reoperation. A trend of higher peak of troponin-I and brain natriuretic peptide in Custodiol group has been reported. CONCLUSION: No prefect cardioplegia exists, the Custodiol solution does not cause extra/additional myocardial damage in arterial switch operation. In our experience this strategy seems warranted to simplify the procedure and to be more comfortable for the surgeon. PMID- 26600406 TI - Off-Pump Conversion: In-hospital Mortality and Long-Term Survival. AB - Background There is an ongoing debate on the benefits and risks of off-pump coronary artery bypass grafting (CABG) surgery. The fate of patients who start with their procedure being an off-pump one and then have to undergo conversion to an on-pump procedure is debated with regard to in-hospital mortality and unknown with regard to long-term survival. We investigated the in-hospital mortality and long-term survival of patients who underwent conversion from off- to on-pump surgery. Methods We performed a multivariate and propensity analysis on in hospital mortality and long-term survival of postisolated CABG patients in a single institution having 15,704 patients of which 5,353 who underwent off-pump CABG were analyzed. Results In-hospital mortality was 2.15% for the study cohort, and 73 (1.4%) off-pump cases were converted. Univariate analysis demonstrated that patients undergoing conversion had a significantly increased in-hospital mortality (p < 0.001) and reduced long-term survival (p = 0.002). Logistic regression (receiver operating curve 0.77, Hosmer-Lemeshow test 0.46) and Cox analysis demonstrated that in-hospital mortality and long-term survival were not significantly affected by conversion. Propensity analysis (one:many match) demonstrated that in-hospital mortality was not significantly affected (p = 0.7), and long-term survival - univariate, and multivariate were also not significantly reduced in patients undergoing conversion. Conclusion Conversion from off- to on pump by a team of surgeons and anesthetists who are dedicated off-pump specialists does not have an impact on in-hospital mortality or long-term survival. PMID- 26600407 TI - KLF15 Overexpression Protects beta-Aminopropionitrile-Induced Aortic Rupture in Rodent Model via Inhibiting Connective Tissue Growth Factor. AB - Background KLF15 (Kruppel-like factor 15) was reported to be involved in a lot of cardiovascular diseases. Little is known about its role in initiation and development of aortic dissection (AD). Methods Samples of the human aorta were collected during AD surgery and aortic valve replacement. Lentivirus was used for in vitro and in vivo KLF15 overexpression in BAPN (beta-aminopropionitrile) induced rat AD models. The survival times were recorded and compared between the two groups. Autopsy was used for confirming aorta rupture in rat models. qPCR analyses were used for detecting gene expression whereas Western blot and immunostaining were used for detecting protein expression when necessary. Results KLF15 expression was much lower in the aorta walls of AD group patients than the control group subjects. The survival curve showed that the survival time of AD models was prolonged after KLF15 overexpression. qPCR and Western blot showed that connective tissue growth factors (CTGFs) were significantly downregulated in the rat aortas. After KLF15 overexpression in aortic adventitial fibroblasts, the KLF15 mRNA was increased whereas CTGF and its target gene collagens I and III were downregulated. Immunofluorescence staining also showed a decrease in CTGF, collagen I, and III. Lenti-control did not induce a significant change of KLF15, CTGF, collagen I, and III expressions. Conclusions KLF15 is involved in the mechanism of AD formation in human. Overexpression of KLF15 can partially rescue the aorta remodeling and AD formation in animal models. Our research highlighted a potential of KLF15 to serve as a new therapy target of AD. PMID- 26600408 TI - High-resolution melting analysis for noninvasive prenatal diagnosis of IVS-II-I (G-A) fetal DNA in minor beta-thalassemia mothers. AB - OBJECTIVES: The high-resolution melting (HRM) technique is fast, effective and successful method for mutation detection. The aim of this study was to determine the sensitivity and specificity of the HRM method for detection of a paternally inherited mutation in a fetus as a noninvasive prenatal diagnosis of beta thalassemia. METHODS: Genomic DNAs were prepared from 50 beta-thalassemia minor couples whose pregnancy was at risk for homozygous beta-thalassemia. Ten milliliters of the maternal blood from each pregnant woman were collected and after separating plasma stored at -80 degrees C until analysis. The extracted DNAs were analyzed by HRM real-time PCR for detection of IVS-II-I (G-A) as a paternally inherited mutation. The gold standard was the result of a chorionic villus sampling by a standard reverse dot blotting test. RESULTS: The sensitivity and specificity of HRM real-time PCR were 92.6% and 82.6%, respectively. Also, the positive and negative predictive values were 86.2% and 90.47%, respectively. CONCLUSIONS: HRM real-time PCR was a sensitive and specific method for determining the paternally inherited mutation in the fetus at risk with thalassemia major. PMID- 26600409 TI - The role of proteoglycans in the nanoindentation creep behavior of human dentin. AB - Attempts to understand the mechanical behavior of dentin and other mineralized tissues have been primarily focused on the role of their more abundant matrix components, such as collagen and hydroxyapatite. The structural mechanisms endowing these biological materials with outstanding load bearing properties, however, remain elusive to date. Furthermore, while their response to deformation has been extensively studied, mechanisms contributing to their recovery from induced deformation remain poorly described in the literature. Here, we offer novel insights into the participation of proteoglycans (PG) and glycosaminoglycans (GAG) in regulating the nanoindentation creep deformation and recovery of mineralized and demineralized dentin. Accordingly, after the enzymatic digestion of either PGs and associated GAGs or only GAGs, the nanoindentation creep deformation of dentin increased significantly, while the relative recovery of both the mineralized and demineralized dentin dropped by 40 70%. In summary, our results suggest that PGs and GAGs may participate in a nanoscale mechanism that contributes significantly to the outstanding durability of dentin and possibly other mineralized tissues of similar composition. PMID- 26600410 TI - Prognosis of depressive disorders in the general population- results from the longitudinal Finnish Health 2011 Study. AB - BACKGROUND: Depressive disorders are among the most pressing public health challenges worldwide. Yet, not enough is known about their long-term outcomes. This study examines the course and predictors of different outcomes of depressive disorders in an eleven-year follow-up of a general population sample. METHODS: In a nationally representative sample of Finns aged 30 and over (BRIF8901), major depressive disorder (MDD) and dysthymia were diagnosed with the Composite International Diagnostic Interview (M-CIDI) in 2000. The participants were followed up in 2011 (n=5733). Outcome measures were diagnostic status, mortality, depressive symptoms and health-related quality of life. Multiple imputation (MI) was used to account for nonresponse. RESULTS: At follow-up, 33.8% of persons with baseline MDD and 42.6% with baseline dysthymia received a diagnosis of depressive, anxiety or alcohol use disorder. Baseline severity of disorder, measured by the Beck Depression Inventory, predicted both persistence of depressive disorder and increased mortality risk. In addition, being never married, separated or widowed predicted persistence of depressive disorders, whereas somatic and psychiatric comorbidity, childhood adversities and lower social capital did not. Those who received no psychiatric diagnosis at follow-up still had residual symptoms and lower quality of life. LIMITATIONS: We only had one follow-up point at eleven years, and did not collect information on the subjects' health during the follow-up period. CONCLUSIONS: Depressive disorders in the general population are associated with multiple negative outcomes. Severity of index episode is the strongest predictor of negative outcomes. More emphasis should be placed on addressing the long-term consequences of depression. PMID- 26600411 TI - Religious Beliefs, PTSD, Depression and Resilience in Survivors of the 2010 Haiti Earthquake. AB - BACKGROUND: This study examines relationships between religious beliefs regarding the origin of the 2010 earthquake in Haiti and posttraumatic symptomatology as well as depressive symptoms and resilience among its survivors. METHOD: We used convenient sampling to recruit participants (n=167). They completed six scales, which had been translated into Haitian Creole, including measures such as the Earthquake Experiences Exposure (EEE), the Peritraumatic Distress Inventory (PDI), the Peritraumatic Dissociative Experience Questionnaire (PDEQ), the PTSD Checklist (PTSD-CL), the Beck Depression Inventory (BDI) and the Connor-Davidson Resilience Scale (CD- RISC) RESULTS: Among our participants, 51% were male, (mean age=30.5, SD=11.03), 92% (n=155) were believers in some sort of supernatural force and 65% (n=108) endorsed the earthquake as a natural phenomenon. There was significant difference in average scores at peritraumatic distress, PTSD symptoms and Resilience measures between those perceiving a divine origin and/or a punishment through the event and those who did not. Peritraumatic responses were best predictors for PTSD (beta=.366, p<.001) and Depression symptoms (beta=.384, p<.001). Voodoo adherents appeared to be vulnerable to depression, but reported superior resilience factors. PMID- 26600412 TI - Geographical and temporal variations in the prevalence of mental disorders in suicide: Systematic review and meta-analysis. AB - BACKGROUND: In contrast to the previous studies reporting that most suicides occur among people with mental disorders, recent studies have reported various rates of mental disorders in suicide in different geographical regions. We aimed to comprehensively investigate the factors influencing the variation in the prevalence of mental disorders reported among suicide victims. METHOD: The authors searched Embase, Medline, Web of Science, and the Cochrane Library to identify psychological autopsy studies reporting the prevalence of any mental disorders among suicide victims. A meta-regression analysis was conducted to identify the potential effects of geographical regions, the year of publication, measurements of personality disorder, measurements of comorbidity, and the ratio of females on the prevalence of mental disorders in addition to examining the heterogeneity across studies. RESULTS: From 4475 potentially relevant studies, 48 studies met eligibility criteria, with 6626 suicide victims. The studies from East Asia had a significantly lower mean prevalence (69.6% [95% CI=56.8 to 80.0]) than those in North America (88.2% [95% CI=79.7-93.5]) and South Asia (90.4% [95% CI=71.8-97.2]). The prevalence of any mental disorder decreased according to the year of publication (coefficients=-0.0715, p<0.001). LIMITATIONS: Substantial heterogeneities were identified within all subgroup analyses. CONCLUSIONS: The prevalence of mental disorders among suicide cases seemed relatively low in the East Asia region, and recently published studies tended to report a lower prevalence of mental disorders. The link between the risk factors and suicide in the absence of a mental disorder should be examined in different geographical and sociocultural contexts. PMID- 26600413 TI - Association of abnormal white matter integrity in the acute phase of motor vehicle accidents with post-traumatic stress disorder. AB - BACKGROUND: A small portion of the Motor vehicle accidents (MVA) survivors would develop post-traumatic stress disorder (PTSD), which would cause substantial social function loss. How to identify those high-risk MVA survivors in the acute phase of the trauma is the first step to prevent the onset of PTSD. In the present study, we studied white matter integrity of subjects post to MVA by diffusional tensor imaging (DTI). METHODS: To investigate whether the integrity of the white matter was impaired in the acute phase of the MVA among survivors who later develop PTSD and whether it could predict the severity of PTSD while being diagnosed. MVA Survivors were recruited to get trauma-specific clinical assessments and received DTI scan within 2 days from the MVA. These survivors were divided into 2 groups, PTSD group and trauma control (TC) group based on the clinical follow-up interview. Tract-Based Spatial Statistics (TBSS) was carried out to investigate difference in white matter integrity between 2 groups within DTI parameter maps. White matter integrity was measured by using fractional anisotropy (FA), axial diffusivity (AD), mean diffusivity (MD), and radical diffusivity (RD). RESULTS: Compared with TC group, PTSD group showed lower FA value in multiple regions of both hemispheres, mainly involving anterior thalamic radiation, cortico-spinal tract, forceps minor, uncinate, inferior fronto occipital fasciculus, inferior longitudinal fasciculus, cingulum and superior longitudinal fasciculus. Increased RD was also detected in PTSD group in the posterior part of right hemisphere, involving forceps major, inferior fronto occipital fasciculus, inferior longitudinal fasciculus, cingulum, hippocampus and superior longitudinal fasciculus. The baseline FA and RD values correlated with Clinician-Administered PTSD Scale scores at clinical follow up. CONCLUSION: MVA survivors who later developed PTSD had more abnormalities in white matter integrity in the acute phase than those non-PTSD MVA survivors. Imaging markers of white matter integrity might be helpful in early identification of MVA survivors at high risk of PTSD. LIMITATIONS: Larger sample size in our extensive study is needed to confer a robust inference and image data at follow up are needed to observe the longitudinal changes of white matter integrity. PMID- 26600414 TI - Remission of suicidal thoughts: Findings from a longitudinal epidemiological study. AB - BACKGROUND: Suicide ideation is common in young women. The present study investigated factors associated with the remission of suicidal thoughts in a representative sample of woman aged 18-24 years. METHODS: A total of 1389 women were interviewed at a baseline assessment and again 17 months later. Social support, satisfaction with life, self-efficacy and positive mental health were considered as predictors of remission of suicidal thoughts - controlling for severity of psychopathology. RESULTS: Remission of suicidal thoughts was experienced by 67.4% of the respondents, whereas 32.6% continued to have suicide ideation at both assessments. In multiple logistic regression analyses, social support and positive mental health emerged as significant predictors of remission. Severity of psychopathology did not predict the course of suicide ideation. LIMITATION: Suicide ideation was assessed only with the respective item of the Beck Depression Inventory. CONCLUSION: Protective factors, especially social support and positive mental health, outperform psychopathology in predicting the course of suicide ideation. PMID- 26600415 TI - Subgenual anterior cingulate cortex and hippocampal volumes in depressed youth: The role of comorbidity and age. AB - OBJECTIVES: Many studies have reported that adults with recurrent major depressive disorder (MDD) have smaller hippocampal volumes than control participants. The data are more variable in youth with MDD, where findings have been inconsistent and the effects of factors such as age and co-morbidity have not been systematically examined. This study therefore assessed hippocampus and subgenual anterior cingulate (sgACC) morphometry in 168 youth, aged 12-25, with or without MDD and comorbid anxiety. METHODS: Structural magnetic resonance imaging (MRI) scans and clinical assessments were obtained from 80 participants with MDD (36 with comorbid anxiety disorder) and 88 age-matched control participants. RESULTS: Participants with MDD had smaller right hippocampi than controls (p=.013). Older depressed participants (20.1-25 years) had smaller hippocampal volumes than younger ones (<20.1 years; p=.05); this age effect was not apparent in controls (p=.46). Depression scores, indexed by the HAMD17, correlated with hippocampal volumes in older depressed youth. Depressed participants with comorbid anxiety had smaller sgACC, but not hippocampal, volumes than those without anxiety (p=.042). LIMITATIONS: Longitudinal, versus cross-sectional, studies can most optimally assess the influence of depression on neurodevelopmental profiles. Though our participants were largely treatment-naive or in their first week of pharmacotherapy, a handful had extensive treatment histories; thus, treatment history may have influenced brain morphometry. CONCLUSIONS: Age effects were apparent when hippocampal volumes of older and younger participants with MDD were compared; such differences were not apparent in healthy participants. Comorbid anxiety was associated with decreased sgACC volumes suggesting delayed or altered neurodevelopment in a key emotion regulation region. PMID- 26600416 TI - Toxic bile and sclerosing cholangitis: Is there a role for pharmacological interruption of the bile acid enterohepatic circulation? PMID- 26600417 TI - Strong lethality and teratogenicity of strobilurins on Xenopus tropicalis embryos: Basing on ten agricultural fungicides. AB - Agricultural chemical inputs have been considered as a risk factor for the global declines in amphibian populations, yet the application of agricultural fungicides has increased dramatically in recent years. Currently little is known about the potential toxicity of fungicides on the embryos of amphibians. We studied the effects of ten commonly used fungicides (four strobilurins, two SDHIs, two triazoles, fludioxonil and folpet) on Xenopus tropicalis embryos. Lethal and teratogenic effects were respectively examined after 48 h exposure. The median lethal concentrations (LC50s) and the median teratogenic concentrations (TC50s) were determined in line with actual exposure concentrations. These fungicides except two triazoles showed obvious lethal effects on embryos; however LC50s of four strobilurins were the lowest and in the range of 6.81-196.59 MUg/L. Strobilurins, SDHIs and fludioxonil induced severe malformations in embryos. Among the ten fungicides, the lowest TC50s were observed for four strobilurins in the range of 0.61-84.13 MUg/L. The teratogenicity shared similar dose-effect relationship and consistent phenotypes mainly including microcephaly, hypopigmentation, somite segmentation and narrow fins. The findings indicate that the developmental toxicity of currently-used fungicides involved with ecologic risks on amphibians. Especially strobilurins are highly toxic to amphibian embryos at MUg/L level, which is close to environmentally relevant concentrations. PMID- 26600418 TI - Enzyme-Operated DNA-Based Nanodevices. AB - Functional molecular nanodevices and nanomachines have attracted a growing interest for their potential use in life science and nanomedicine. In particular, due to their versatility and modularity DNA-based nanodevices appear extremely promising. However, a limitation of such devices is represented by the limited number of molecular stimuli and cues that can be used to control and regulate their function. Here we demonstrate the possibility to rationally control and regulate DNA-based nanodevices using biocatalytic reactions catalyzed by different enzymes. To demonstrate the versatility of our approach, we have employed three model DNA-based systems and three different enzymes (belonging to several classes, i.e., transferases and hydrolases). The possibility to use enzymes and enzymatic substrates as possible cues to operate DNA-based molecular nanodevices will expand the available toolbox of molecular stimuli to be used in the field of DNA nanotechnology and could open the door to many applications including enzyme-induced drug delivery and enzyme-triggered nanostructures assembly. PMID- 26600419 TI - A comparison of Locacorten-Vioform and clotrimazole in otomycosis: A systematic review and one-way meta-analysis. AB - OBJECTIVES/HYPOTHESIS: The goal of this systematic review was to compare the efficacy and ototoxicity of Locacorten-Vioform (Paladin Labs Inc., Montreal, Quebec, Canada) and clotrimazole in the treatment of patients with otomycosis. DATA SOURCES: Embase, Cumulative Index to Nursing and Allied Health Literature, MEDLINE, World Health Organization International Clinical Trials Registry Platform, European Union Clinical Trials Register, Cochrane Library databases of clinical trials, and ClinicalTrials.gov. METHODS: We included any randomized controlled trials or nonrandomized studies (case-control, cohort, and case series) assessing the topical use of Locacorten-Vioform (Paladin Labs Inc.) and/or clotrimazole in adult and/or pediatric immunocompetent patient population with otomycosis. DerSimonian and Laird's random effects approach was used for meta-analysis, followed by an assessment of heterogeneity and subgroup analysis. RESULTS: Of 226 reviewed articles, 14 were retained. Clotrimazole efficacy rate was 85% (95% confidence interval [CI]: 79.7-89.0%), whereas Locacorten-Vioform (Paladin Labs Inc.) was 73% (95% CI: 56.0-84.5%). Overall, study quality was low. There was high heterogeneity in both groups (I(2) of 47 and 49). There were only three studies assessing Locacorten-Vioform (Paladin Labs Inc.); therefore, comparative assessment was not possible. A one-way meta-analysis involving 13 clotrimazole studies was performed. Heterogeneity across studies was high; however, studies using objective analysis assessing treatment efficacy, randomized controlled trials, studies using drops, studies performed in Asia, and studies where Candida was the major fungus at diagnosis demonstrated low heterogeneity. CONCLUSION: Although both are safe and effective, there is insufficient evidence supporting increased efficacy of either clotrimazole or Locacorten-Vioform (Paladin Labs Inc.) for the treatment of otomycosis. High quality comparative studies are required. LEVEL OF EVIDENCE: N/A. Laryngoscope, 126:1411-1419, 2016. PMID- 26600420 TI - FGF signaling enhances a sonic hedgehog negative feedback loop at the initiation of spinal cord ventral patterning. AB - A prevalent developmental mechanism for the assignment of cell identities is the production of spatiotemporal concentration gradients of extracellular signaling molecules that are interpreted by the responding cells. One of such signaling systems is the Shh gradient that controls neuronal subtype identity in the ventral spinal cord. Using loss and gain of function approaches in chick and mouse embryos, we show here that the fibroblast growth factor (FGF) signaling pathway is required to restrict the domains of ventral gene expression as neuroepithelial cells become exposed to Shh during caudal extension of the embryo. FGF signaling activates the expression of the Shh receptor and negative pathway regulator Patched 2 (Ptch2) and therefore can enhance a negative feedback loop that restrains the activity of the pathway. Thus, we identify one of the mechanisms by which FGF signaling acts as a modulator of the onset of Shh signaling activity in the context of coordination of ventral patterning and caudal axis extension. (c) 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 956 971, 2016. PMID- 26600421 TI - Diagnostic reliability of the cervical vertebral maturation method and standing height in the identification of the mandibular growth spurt. AB - OBJECTIVE: To evaluate the capability of both cervical vertebral maturation (CVM) stages 3 and 4 (CS3-4 interval) and the peak in standing height to identify the mandibular growth spurt throughout diagnostic reliability analysis. MATERIALS AND METHODS: A previous longitudinal data set derived from 24 untreated growing subjects (15 females and nine males,) detailed elsewhere were reanalyzed. Mandibular growth was defined as annual increments in Condylion (Co)-Gnathion (Gn) (total mandibular length) and Co-Gonion Intersection (Goi) (ramus height) and their arithmetic mean (mean mandibular growth [mMG]). Subsequently, individual annual increments in standing height, Co-Gn, Co-Goi, and mMG were arranged according to annual age intervals, with the first and last intervals defined as 7-8 years and 15-16 years, respectively. An analysis was performed to establish the diagnostic reliability of the CS3-4 interval or the peak in standing height in the identification of the maximum individual increments of each Co-Gn, Co-Goi, and mMG measurement at each annual age interval. RESULTS: CS3 4 and standing height peak show similar but variable accuracy across annual age intervals, registering values between 0.61 (standing height peak, Co-Gn) and 0.95 (standing height peak and CS3-4, mMG). Generally, satisfactory diagnostic reliability was seen when the mandibular growth spurt was identified on the basis of the Co-Goi and mMG increments. CONCLUSIONS: Both CVM interval CS3-4 and peak in standing height may be used in routine clinical practice to enhance efficiency of treatments requiring identification of the mandibular growth spurt. PMID- 26600422 TI - Discrimination of Deciduous Tree Species from Time Series of Unmanned Aerial System Imagery. AB - Technology advances can revolutionize Precision Forestry by providing accurate and fine forest information at tree level. This paper addresses the question of how and particularly when Unmanned Aerial System (UAS) should be used in order to efficiently discriminate deciduous tree species. The goal of this research is to determine when is the best time window to achieve an optimal species discrimination. A time series of high resolution UAS imagery was collected to cover the growing season from leaf flush to leaf fall. Full benefit was taken of the temporal resolution of UAS acquisition, one of the most promising features of small drones. The disparity in forest tree phenology is at the maximum during early spring and late autumn. But the phenology state that optimized the classification result is the one that minimizes the spectral variation within tree species groups and, at the same time, maximizes the phenologic differences between species. Sunlit tree crowns (5 deciduous species groups) were classified using a Random Forest approach for monotemporal, two-date and three-date combinations. The end of leaf flushing was the most efficient single-date time window. Multitemporal datasets definitely improve the overall classification accuracy. But single-date high resolution orthophotomosaics, acquired on optimal time-windows, result in a very good classification accuracy (overall out of bag error of 16%). PMID- 26600423 TI - Rapid Identification and Classification of Listeria spp. and Serotype Assignment of Listeria monocytogenes Using Fourier Transform-Infrared Spectroscopy and Artificial Neural Network Analysis. AB - The use of Fourier Transform-Infrared Spectroscopy (FT-IR) in conjunction with Artificial Neural Network software NeuroDeveloperTM was examined for the rapid identification and classification of Listeria species and serotyping of Listeria monocytogenes. A spectral library was created for 245 strains of Listeria spp. to give a biochemical fingerprint from which identification of unknown samples were made. This technology was able to accurately distinguish the Listeria species with 99.03% accuracy. Eleven serotypes of Listeria monocytogenes including 1/2a, 1/2b, and 4b were identified with 96.58% accuracy. In addition, motile and non motile forms of Listeria were used to create a more robust model for identification. FT-IR coupled with NeuroDeveloperTM appear to be a more accurate and economic choice for rapid identification of pathogenic Listeria spp. than current methods. PMID- 26600424 TI - A Preliminary Genome-Wide Association Study of Acute Mountain Sickness Susceptibility in a Group of Nepalese Pilgrims Ascending to 4380 m. AB - There is significant interindividual variation in acute mountain sickness (AMS) susceptibility in humans. To identify genes related to AMS susceptibility, we used a genome-wide association study (GWAS) to simultaneously test associations between genetic variants dispersed throughout the genome and the presence and severity of AMS. DNA samples were collected from subjects who ascended rapidly to Gosainkunda, Nepal (4380 m), as part of the 2005, 2010, and 2012 Janai Purnima festivals. The Lake Louise Score was used to measure AMS severity. The primary analysis was based on 99 male subjects (43 with AMS; 56 without AMS). Genotyping for the GWAS was performed using Infinium Human Core Exome Bead Chips (542,556 single-nucleotide polymorphisms were assayed), and validation genotyping was performed with pyrosequencing in two additional cohorts (n = 101 for each). In total, 270,389 single nucleotide polymorphisms (SNPs) passed quality control, and 4 SNPs (one intronic, three nonsynonymous) in the FAM149A gene were associated with AMS severity after correcting for multiple hypothesis testing (p = 1.8E-7); however, in the validation cohorts, FAM149A was not associated with the presence or severity of AMS. No other genes were associated with AMS susceptibility at the genome-wide level. Due to the large influence of environmental factors (i.e., ascent rate and altitude attained) and the difficulties associated with the AMS phenotype (i.e., low repeatability, nonspecific symptoms, potentially independent ailments), we suggest that future studies addressing the variation in the acute human hypoxia response should focus on objective responses to acute hypoxia instead of AMS. PMID- 26600425 TI - Supplementation of Magnolol Attenuates Skeletal Muscle Atrophy in Bladder Cancer Bearing Mice Undergoing Chemotherapy via Suppression of FoxO3 Activation and Induction of IGF-1. AB - Skeletal muscle atrophy, the most prominent phenotypic feature of cancer cachexia, is often observed in cancer patients undergoing chemotherapy. Magnolol (M) extracted from Magnolia officinalis exhibits several pharmacological effects including anti-inflammatory and anticancer activities. In this study, we investigated whether magnolol supplementation protects against the development of cachexia symptoms in bladder cancer-bearing mice undergoing chemotherapy. Combined treatment of magnolol with chemotherapeutic drugs, such as gemcitabine and cisplatin (TGCM) or gemcitabine (TGM), markedly attenuates the body weight loss and skeletal muscle atrophy compared with conventional chemotherapy (TGC). The antiatrophic effect of magnolol may be associated with inhibition of myostatin and activin A formation, as well as FoxO3 transcriptional activity resulting from Akt activation, thereby suppressing ubiquitin ligases MuRF-1 and MAFbx/atrogin-1 expression, as well as proteasomal enzyme activity. Notably, magnolol-induced insulin-like growth factor 1 (IGF-1) production and related protein synthesis may also contribute to its protective effects. The decreased food intake, and intestinal injury and dysfunction observed in the mice of TGC group were significantly improved in the TGCM and TGM groups. Moreover, the increased inflammatory responses evidenced by elevation of proinflammatory cytokine formation and NF-kappaB activation occurred in the atrophying muscle of TGC group were markedly inhibited in mice of combined treatment with magnolol. In summary, these findings support that magnolol is a promising chemopreventive supplement for preventing chemotherapy-induced skeletal muscle atrophy associated with cancer cachexia by suppressing muscle protein degradation, and inflammatory responses, as well as increasing IGF-1-mediated protein synthesis. PMID- 26600427 TI - Author's Reply. PMID- 26600426 TI - Computed Tomography (CT) Scanning Facilitates Early Identification of Neonatal Cystic Fibrosis Piglets. AB - BACKGROUND: Cystic Fibrosis (CF) is the most prevalent autosomal recessive disease in the Caucasian population. A cystic fibrosis transmembrane conductance regulator knockout (CFTR-/-) pig that displays most of the features of the human CF disease has been recently developed. However, CFTR-/- pigs presents a 100% prevalence of meconium ileus that leads to death in the first hours after birth, requiring a rapid diagnosis and surgical intervention to relieve intestinal obstruction. Identification of CFTR-/- piglets is usually performed by PCR genotyping, a procedure that lasts between 4 to 6 h. Here, we aimed to develop a procedure for rapid identification of CFTR-/- piglets that will allow placing them under intensive care soon after birth and immediately proceeding with the surgical correction. METHODS AND PRINCIPAL FINDINGS: Male and female CFTR+/- pigs were crossed and the progeny was examined by computed tomography (CT) scan to detect the presence of meconium ileus and facilitate a rapid post-natal surgical intervention. Genotype was confirmed by PCR. CT scan presented a 94.4% sensitivity to diagnose CFTR-/- piglets. Diagnosis by CT scan reduced the birth to-surgery time from a minimum of 10 h down to a minimum of 2.5 h and increased the survival of CFTR-/- piglets to a maximum of 13 days post-surgery as opposed to just 66 h after later surgery. CONCLUSION: CT scan imaging of meconium ileus is an accurate method for rapid identification of CFTR-/- piglets. Early CT detection of meconium ileus may help to extend the lifespan of CFTR-/- piglets and, thus, improve experimental research on CF, still an incurable disease. PMID- 26600428 TI - Postnatal growth and age estimation in Scotophilus kuhlii. AB - Adequate postnatal growth is important for young bats to develop skilled sensory and locomotor abilities, which are highly associated with their survival once independent. This study investigated the postnatal growth and development of Scotophilus kuhlii in captivity. An empirical growth curve was established, and the postnatal growth rate was quantified to derive an age-predictive equation. By further controlling the fostering conditions of twins, the differences in the development patterns between pups that received maternal care or were hand-reared were analyzed to determine whether the latter developed in the same manner as their maternally reared counterparts. Our results indicate that both forearm length and body mass increased rapidly and linearly during the first 4 weeks, after which the growth rate gradually decreased to reach a stable level. The first flight occurred at an average age of 39 days with a mean forearm length and body mass of 92.07% and 70.52% of maternal size, respectively. The developmental pattern of hand-reared pups, although similar to that of their maternally reared twin siblings, displayed a slightly faster growth rate in the 4th and 5th weeks. The heavier body mass of hand-reared pups during the pre-fledging period may cause higher wing loading, potentially influencing the flight performance and survival of the bats once independent. PMID- 26600429 TI - Formulations for delivering Trichoderma atroviridae spores as seed coatings, effects of temperature and relative humidity on storage stability. AB - AIMS: We aimed to evaluate different formulations for their ability to adhere Trichoderma atroviridae spores to wheat seeds, and promote survival during storage at a range of temperatures and relative humidities (RH). METHODS AND RESULTS: We tested a range of formulations for their ability to adhere T. atroviridae spores to wheat seeds. Treated seeds were stored for 6 months at a range of temperatures and RH, and spore viability among formulation was compared over time. Spore survival within formulations interacted significantly with environmental conditions. Notably, under optimum conditions (low temperatures and RH) best spore survival was recorded with a xanthan-gum-based formulation. Conversely under suboptimum conditions (high temperatures and RH), survival of spores was best in a waxy-starch formulation, but very poor in the xanthan-gum formulation. CONCLUSIONS: These results indicate that T. atroviridae spores can be effectively delivered on to seeds and that a xanthan-gum formulation is promising when optimal storage conditions can be maintained. SIGNIFICANCE AND IMPACT OF THE STUDY: Most published formulation papers/patents only report survival of organisms over time at a single or limited number of temperatures and RH. For the first time, this study shows how different formulations are better suited to certain temperature and RH combinations. PMID- 26600430 TI - Structure-Based Discovery of 1H-Indazole-3-carboxamides as a Novel Structural Class of Human GSK-3 Inhibitors. AB - An in silico screening procedure was performed to select new inhibitors of glycogen synthase kinase 3beta (GSK-3beta), a serine/threonine protein kinase that in the last two decades has emerged as a key target in drug discovery, having been implicated in multiple cellular processes and linked with the pathogenesis of several diseases. GSK-3beta inhibitors might prove useful as therapeutic compounds in the treatment of conditions associated with elevated levels of enzyme activity, such as type-2 diabetes and neurological disorders, for example, Alzheimer's disease, bipolar disorder, neuronal cell death, stroke, and depression. In this work, virtual screening studies were applied to proprietary compound libraries, and the functional activities of selected compounds were assayed on human GSK-3beta. The in silico screening procedure enabled the identification of eight hit compounds showing pIC50 values ranging from 4.9 to 5.5. X-ray crystallographic studies resulted in a 2.50 A three dimensional structure of GSK-3beta complexed with one of the selected compounds, confirming that the inhibitor interacts with the enzyme according to the docking hypothesis. Importantly, molecular docking was able to find a new chemical scaffold for GSK-3beta inhibition, providing grounds for rational structure-based design aimed at further optimization of the initial hits. PMID- 26600431 TI - Intrinsic Levanase Activity of Bacillus subtilis 168 Levansucrase (SacB). AB - Levansucrase catalyzes the synthesis of fructose polymers through the transfer of fructosyl units from sucrose to a growing fructan chain. Levanase activity of Bacillus subtilis levansucrase has been described since the very first publications dealing with the mechanism of levan synthesis. However, there is a lack of qualitative and quantitative evidence regarding the importance of the intrinsic levan hydrolysis of B. subtilis levansucrase and its role in the levan synthesis process. Particularly, little attention has been paid to the long-term hydrolysis products, including its participation in the final levan molecules distribution. Here, we explored the hydrolytic and transferase activity of the B. subtilis levansucrase (SacB) when levans produced by the same enzyme are used as substrate. We found that levan is hydrolyzed through a first order exo-type mechanism, which is limited to a conversion extent of around 30% when all polymer molecules reach a structure no longer suitable to SacB hydrolysis. To characterize the reaction, Isothermal Titration Calorimetry (ITC) was employed and the evolution of the hydrolysis products profile followed by HPLC, GPC and HPAEC-PAD. The ITC measurements revealed a second step, taking place at the end of the reaction, most probably resulting from disproportionation of accumulated fructo-oligosaccharides. As levanase, levansucrase may use levan as substrate and, through a fructosyl-enzyme complex, behave as a hydrolytic enzyme or as a transferase, as demonstrated when glucose and fructose are added as acceptors. These reactions result in a wide variety of oligosaccharides that are also suitable acceptors for fructo-oligosaccharide synthesis. Moreover, we demonstrate that SacB in the presence of levan and glucose, through blastose and sucrose synthesis, results in the same fructooligosaccharides profile as that observed in sucrose reactions. We conclude that SacB has an intrinsic levanase activity that contributes to the final levan profile in reactions with sucrose as substrate. PMID- 26600432 TI - Comparing gas separation performance between all known zeolites and their zeolitic imidazolate framework counterparts. AB - To find optimal porous materials for adsorption-based separations is a challenging task due to the extremely large number of possible pore topologies and compositions. New porous material classes such as Metal Organic Frameworks (MOFs) are emerging, and hope to replace traditionally used materials such as zeolites. Computational screening offers relatively fast searching for candidate structures as well as side-by-side comparisons between material families. This work is pioneering at examining the families comprised by the experimentally known zeolites and their respective Zeolitic Imidazolate Framework (ZIF) counterparts in the context of a number of environmental and industrial separations involving carbon dioxide, nitrogen, methane, oxygen, and argon. Additionally, unlike related published work, here all the targeted structures have been previously relaxed through energy minimization. On the first level of characterization, we considered a detailed pore characterization, identifying 24 zeolites as promising candidates for gas separation based on adsorbate sizes. The second level involved interatomic potential-based calculations to assess the adsorption performance of the materials. We found no correlation in the values of heat of adsorption between zeolites and ZIFs sharing the same topology. A number of structures were identified as potential experimental targets for CO2/N2, and CO2/CH4 affinity-based separations. PMID- 26600433 TI - Mobile Telestroke During Ambulance Transport Is Feasible in a Rural EMS Setting: The iTREAT Study. AB - BACKGROUND: The use of telemedicine in the diagnosis and treatment of acute stroke, or telestroke, is a well-accepted method of practice improving geographic disparities in timely access to neurological expertise. We propose that mobile telestroke assessment during ambulance transport is feasible using low-cost, widely available technology. MATERIALS AND METHODS: We designed a platform including a tablet-based end point, high-speed modem with commercial wireless access, external antennae, and portable mounting apparatus. Mobile connectivity testing was performed along six primary ambulance routes in a rural network. Audiovisual (AV) quality was assessed simultaneously by both an in-vehicle and an in-hospital rater using a standardized 6-point rating scale (>=4 indicating feasibility). We sought to achieve 9 min of continuous AV connectivity presumed sufficient to perform mobile telestroke assessments. RESULTS: Thirty test runs were completed: 93% achieved a minimum of 9 min of continuous video transmission with a mean mobile connectivity time of 18 min. Mean video and audio quality ratings were 4.51 (4.54 vehicle; 4.48 hospital) and 5.00 (5.13 in-vehicle; 4.87 hospital), respectively. Total initial cost of the system was $1,650 per ambulance. CONCLUSIONS: In this small, single-centered study we maintained high quality continuous video transmission along primary ambulance corridors using a low-cost mobile telemedicine platform. The system is designed to be portable and adaptable, with generalizability for rapid assessment of emergency conditions in which direct observational exam may improve prehospital diagnosis and treatment. Thus mobile telestroke assessment is feasible using low-cost components and commercial wireless connectivity. More research is needed to demonstrate clinical reliability and efficacy in a live-patient setting. PMID- 26600434 TI - Comparative Study of a Real-Time PCR Assay Targeting senX3-regX3 versus Other Molecular Strategies Commonly Used in the Diagnosis of Tuberculosis. AB - BACKGROUND: Nucleic acid amplification tests are increasingly used for the rapid diagnosis of tuberculosis. We undertook a comparative study of the efficiency and diagnostic yield of a real-time PCR senX3-regX3 based assay versus the classical IS6110 target and the new commercial methods. METHODS: This single-blind prospective comparative study included 145 consecutive samples: 76 from patients with culture-confirmed tuberculosis (86.8% pulmonary and 13.2% extrapulmonary tuberculosis: 48.7% smear-positive and 51.3% smear-negative) and 69 control samples (24 from patients diagnosed with non-tuberculous mycobacteria infections and 45 from patients with suspected tuberculosis which was eventually ruled out). All samples were tested by two CE-marked assays (Xpert(r)MTB/RIF and AnyplexTM plus MTB/NTM) and two in-house assays targeting senX3-regX3 and the IS6110 gene. RESULTS: The detection limit ranged from 1.00E+01 fg for Anyplex, senX3-regX3 and IS6110 to 1.00E+04 fg for Xpert. All three Xpert, senX3-regX3 and IS6110 assays detected all 37 smear-positive cases. Conversely, Anyplex was positive in 34 (91.9%) smear-positive cases. In patients with smear-negative tuberculosis, differences were observed between the assays; Xpert detected 22 (56.41%) of the 39 smear-negative samples, Anyplex 24 (61.53%), senX3-regX3 28 (71.79%) and IS6110 35 (89.74%). Xpert and senX3-regX3 were negative in all control samples; however, the false positive rate was 8.7% and 13% for Anyplex and IS6110, respectively. The overall sensitivity was 77.6%, 85.7%, 77.3% and 94.7% and the specificity was 100%, 100%, 90.8% and 87.0% for the Xpert, senX3-regX3, Anyplex and IS6110 assays, respectively. CONCLUSION: Real-time PCR assays targeting IS6110 lack the desired specificity. The Xpert MTB/RIF and in-house senX3-regX3 assays are both sensitive and specific for the detection of MTBC in both pulmonary and extrapulmonary samples. Therefore, the real time PCR senX3-regX3 based assay could be a useful and complementary tool in the diagnosis of tuberculosis. PMID- 26600435 TI - Did the H1N1 Vaccine Reduce the Risk of Admission with Influenza and Pneumonia during the Pandemic? AB - BACKGROUND: The extent to which A(H1N1)pdm09 influenza vaccines prevented hospital admissions with pneumonia and influenza (P&I) during the 2009 pandemic remains poorly understood. We evaluated the effectiveness of the A(H1N1)pdm09 and seasonal influenza vaccines (TIV) used during the 2009 mass vaccination campaign in Manitoba (Canada) in preventing P&I hospitalization. METHODS: A population based record-linkage nested case-control study. Cases (N = 1,812) were persons hospitalized with influenza (ICD-10:J09-J11) or pneumonia (ICD-10:J12-J18) during the study period. Age-, gender- and area of residence-matched controls (N = 7,915) were randomly sampled from Manitoba's Population Registry. Information on receipt of A(H1N1)pdm09 vaccine and TIV was obtained from the Manitoba Immunization Monitoring System, a province-wide vaccine registry. RESULTS: Overall, the adjuvanted A(H1N1)pdm09 vaccine was 27% (95%CI 13-39%) effective against P&I hospitalization >= 14 days following administration. Effectiveness seemed lower among older (>= 65 years) adults (10%; -16-30%), particularly when compared to under-5 children (58%; 30-75%). The number-needed-to-vaccinate to prevent 1 P&I admission was lowest among <4 year-olds (928) and >=65 years (1,721). VE against hospitalization with laboratory-confirmed A(H1N1)pdm09 was 70% (39-85%) overall and (91%; 62-98%) >= 14 days following vaccination. DISCUSSION: Our data suggest that the adjuvanted A(H1N1)pdm09 vaccine was effective in preventing about 55-60% of P&I hospitalizations among children and younger adults who were at much higher risk of infection. Unfortunately, the vaccine was less effective among 65 or older adults. Despite that the vaccine still had a significant population-based impact especially among the very young (<5) and the older (>= 65 years). PMID- 26600436 TI - Reliably Detecting Clinically Important Variants Requires Both Combined Variant Calls and Optimized Filtering Strategies. AB - A diversity of tools is available for identification of variants from genome sequence data. Given the current complexity of incorporating external software into a genome analysis infrastructure, a tendency exists to rely on the results from a single tool alone. The quality of the output variant calls is highly variable however, depending on factors such as sequence library quality as well as the choice of short-read aligner, variant caller, and variant caller filtering strategy. Here we present a two-part study first using the high quality 'genome in a bottle' reference set to demonstrate the significant impact the choice of aligner, variant caller, and variant caller filtering strategy has on overall variant call quality and further how certain variant callers outperform others with increased sample contamination, an important consideration when analyzing sequenced cancer samples. This analysis confirms previous work showing that combining variant calls of multiple tools results in the best quality resultant variant set, for either specificity or sensitivity, depending on whether the intersection or union, of all variant calls is used respectively. Second, we analyze a melanoma cell line derived from a control lymphocyte sample to determine whether software choices affect the detection of clinically important melanoma risk-factor variants finding that only one of the three such variants is unanimously detected under all conditions. Finally, we describe a cogent strategy for implementing a clinical variant detection pipeline; a strategy that requires careful software selection, variant caller filtering optimizing, and combined variant calls in order to effectively minimize false negative variants. While implementing such features represents an increase in complexity and computation the results offer indisputable improvements in data quality. PMID- 26600437 TI - Establishment of a High Canine Rabies Burden in Haiti through the Implementation of a Novel Surveillance Program [corrected]. AB - The Republic of Haiti is one of only several countries in the Western Hemisphere in which canine rabies is still endemic. Estimation methods have predicted that 130 human deaths occur per year, yet existing surveillance mechanisms have detected few of these rabies cases. Likewise, canine rabies surveillance capacity has had only limited capacity, detecting only two rabid dogs per year, on average. In 2013, Haiti initiated a community-based animal rabies surveillance program comprised of two components: active community bite investigation and passive animal rabies investigation. From January 2013 -December 2014, 778 rabies suspect animals were reported for investigation. Rabies was laboratory-confirmed in 70 animals (9%) and an additional 36 cases were identified based on clinical diagnosis (5%), representing an 18-fold increase in reporting of rabid animals compared to the three years before the program was implemented. Dogs were the most frequent rabid animal (90%). Testing and observation ruled out rabies in 61% of animals investigated. A total of 639 bite victims were reported to the program and an additional 364 bite victims who had not sought medical care were identified during the course of investigations. Only 31% of people with likely rabies exposures had initiated rabies post-exposure prophylaxis prior to the investigation. Rabies is a neglected disease in-part due to a lack of surveillance and understanding about the burden. The surveillance methods employed by this program established a much higher burden of canine rabies in Haiti than previously recognized. The active, community-based bite investigations identified numerous additional rabies exposures and bite victims were referred for appropriate medical care, averting potential human rabies deaths. The use of community-based rabies surveillance programs such as HARSP should be considered in canine rabies endemic countries. PMID- 26600438 TI - Construction and validation of the chronic acquired polyneuropathy patient reported index (CAP-PRI): A disease-specific, health-related quality-of-life instrument. AB - INTRODUCTION: Generic health-related quality-of-life (HRQOL) patient-reported outcome measures have been used in patients with chronic immune-mediated polyneuropathies. We have created a disease-specific HRQOL instrument. METHODS: The chronic acquired polyneuropathy patient-reported index (CAP-PRI) was developed and validated in multiple steps. Items were initially generated through patient and specialist input. The performance of the preliminary 20 items was analyzed via a prospective, 5-center study involving chronic immune-mediated polyneuropathy patients. RESULTS: Data analysis suggested modification to a 15 item scale with 3 response categories rather than 5. The final CAP-PRI was validated in another prospective, 5-center study. The CAP-PRI appeared to be a unidimensional outcome measure that fit the Rasch model in our multicenter cohort. It correlated appropriately with outcome measures commonly used in this patient population. CONCLUSIONS: The CAP-PRI is a simple disease-specific HRQOL measure that appears to be useful for clinical care and possibly also for clinical trials. Muscle Nerve 54: 9-17, 2016. PMID- 26600439 TI - Serial changes of cytokines and growth factors in peripheral circulation after right lobe donor hepatectomy. AB - Cytokines and growth factors have prominent roles in liver regeneration. The aim of this study was to evaluate the biological markers of liver regeneration in healthy donors undergoing right lobe donor hepatectomy for living donor liver transplantation. Twenty-five voluntary liver donors were enrolled. Peripheral blood samples were taken a day before the operation and on postoperative days (PODs) 1, 3, 7, 14, and 42. Levels of hepatocyte growth factor (HGF), interleukin (IL) 6, tumor necrosis factor alpha (TNF-alpha), thrombopoietin (TPO), transforming growth factor beta1 (TGF-beta1), interferon (IFN) alpha, and IFNgamma were monitored. The remnant liver volume (RLV) before surgery and regeneration liver volume (RgV) on POD 14 were calculated on computed tomography (CT). RgV/RLV ratio was correlated with the remnant-liver-volume-to-body-weight ratio (RLVBWR). Inverse correlation was observed between RgV/RLV and RLVBWR (r(2) = 0.61; P < 0.001). There was a significant rise of HGF on POD 1 (P = 0.001), POD 7 (P = 0.049), and POD 14 (P = 0.04). TNF-alpha was elevated on POD 1 (P = 0.004). The levels of IL 6 (P < 0.001) and TPO (P < 0.001) were higher from POD 1 to POD 42. IFNalpha was higher on POD 14 (P = 0.003) and POD 42 (P = 0.001). There was a significant fall of IFNgamma on POD 1 (P = 0.01) and increase on POD 14 (P = 0.04). The levels of TGF-beta1 were higher on POD 14 (P = 0.008) and on POD 42 (P = 0.002). In conclusion, HGF, IL 6, TNF-alpha, and TPO are involved in the early phase, whereas TGF-beta1 and IFN are involved in the termination phase of liver regeneration. Liver regeneration was observed to be higher in donors with low RLVBWR. PMID- 26600441 TI - Anesthetic Complications in Pregnancy. AB - Anesthesia complications in the parturient can be divided into 2 categories: those related to airway manipulation and those related to neuraxial anesthesia. Physiologic changes of pregnancy can lead to challenging intubating conditions in a patient at risk of aspiration. Neuraxial techniques are used to provide analgesia for labor and anesthesia for surgical delivery. Therefore, complications associated with neuraxial techniques are often seen in this population. In the event of maternal cardiac arrest, modification to advanced cardiac life support algorithms must be made to accommodate the gravid uterus and to deliver the fetus if return of maternal circulation is not prompt. PMID- 26600440 TI - Nuclear magnetic resonance-determined lipoprotein subclasses and carotid intima media thickness in type 1 diabetes. AB - BACKGROUND: Dyslipidemia has been linked to vascular complications of Type 1 diabetes (T1DM). We investigated the prospective associations of nuclear magnetic resonance-determined lipoprotein subclass profiles (NMR-LSP) and conventional lipid profiles with carotid intima-media thickness (IMT) in T1DM. METHODS: NMR LSP and conventional lipids were measured in a subset of Diabetes Control and Complications Trial (DCCT) participants (n = 455) at study entry ('baseline', 1983-89), and were related to carotid IMT determined by ultrasonography during the observational follow-up of the DCCT, the Epidemiology of Diabetes Interventions and Complications (EDIC) study, at EDIC Year 12 (2004-2006). Associations were defined using multiple linear regression stratified by gender, and following adjustment for HbA1c, diabetes duration, body mass index, albuminuria, DCCT randomization group, smoking status, statin use, and ultrasound devices. RESULTS: In men, significant positive associations were observed between some baseline NMR-subclasses of LDL (total IDL/LDL and large LDL) and common and/or internal carotid IMT, and between conventional total- and LDL-cholesterol and non-HDL-cholesterol and common carotid IMT, at EDIC Year 12; these persisted in adjusted analyses (p < 0.05). Large LDL particles and conventional triglycerides were positively associated with common carotid IMT changes over 12 years (p < 0.05). Inverse associations of mean HDL diameter and large HDL concentrations, and positive associations of small LDL with common and/or internal carotid IMT (all p < 0.05) were found, but did not persist in adjusted analyses. No significant associations were observed in women. CONCLUSION: NMR-LSP derived LDL particles, in addition to conventional lipid profiles, may help in identifying men with T1DM at highest risk for vascular disease. PMID- 26600442 TI - Hypertensive Emergencies in Pregnancy. AB - The prevalence of hypertensive disorders in pregnancy is increasing. The etiology and pathophysiology of hypertensive disorders in pregnancy remain poorly understood. Hypertensive disorders are a major cause of maternal and perinatal morbidity and mortality. Treatment of hypertension decreases the incidence of severe hypertension, but it does not impact rates of preeclampsia or other pregnancy complications. Several antihypertensive medications are commonly used in pregnancy, although there is a lack of randomized controlled trials. Severe hypertension should be treated immediately to prevent maternal end-organ damage. Appropriate antepartum, intrapartum, and postpartum management is important in caring for patients with hypertensive disorders. PMID- 26600443 TI - Neurologic Complications in Pregnancy. AB - Pregnant women are subject to the same complications as the general population, as well to specific neurologic complications associated with pregnancy, such as preeclampsia or eclampsia. The hormonal and physiologic changes during pregnancy lead to altered incidences of these complications, which usually present during the late period of pregnancy, labor, or the puerperium. In addition, the treatment of these conditions is different from that of nonpregnant women, because special attention is paid to avoid any abnormalities or death of the fetus. This article discusses the most common of these neurologic complications. PMID- 26600444 TI - Liver Failure in Pregnancy. AB - Acute liver failure is a rare but life-threatening medical emergency in pregnancy whose true incidence remains unknown. Many cases of acute liver failure are caused by pregnancy-related conditions such as acute fatty liver of pregnancy and HELLP syndrome. However, acute deterioration in liver function can also be caused by drug overdose, viral infections, and an exacerbation of underlying chronic liver disease. This article provides an overview of the normal liver changes that occur during pregnancy, and summarizes the most common conditions and general management strategies of liver failure during pregnancy. PMID- 26600445 TI - Renal Failure in Pregnancy. AB - Renal failure during pregnancy affects both mother and fetus, and may be related to preexisting disease or develop secondary to diseases of pregnancy. Causes include hypovolemia, sepsis, shock, preeclampsia, thrombotic microangiopathies, and renal obstruction. Treatment focuses on supportive measures, while pharmacologic treatment is viewed as second-line therapy, and is more useful in mitigating harmful effects than treating the underlying cause. When supportive measures and pharmacotherapy prove inadequate, dialysis may be required, with the goal being to prolong pregnancy until delivery is feasible. Outcomes and recommendations depend primarily on the underlying cause. PMID- 26600446 TI - Respiratory Failure and Mechanical Ventilation in the Pregnant Patient. AB - Fewer than 2% of all peripartal patients need intensive care unit admission. But due to some anatomic and physiologic changes in pregnancy, respiratory failure can be promoted. This article reviews several obstetric and nonobstetric diseases that lead to respiratory failure and the treatment of these. Furthermore, invasive and noninvasive ventilation in pregnancy is discussed and suggestions of medication during ventilation are given. PMID- 26600447 TI - Management of Complex Cardiac Issues in the Pregnant Patient. AB - Management of peripartum heart disease in the intensive care unit requires optimization of maternal hemodynamics and maintenance of fetal perfusion. This requires fetal monitoring and should address the parturient's oxygen saturation, hemoglobin, and cardiac output as it relates to uterine blood flow. Pharmacologic strategies have limited evidence pertaining to hemodynamic stabilization and fetal perfusion. There is some evidence that surgical management of critical mitral stenosis should be percutaneous when possible because cardiac bypass is associated with increased fetal mortality. Fetal monitoring strategies should address central organ perfusion because peripheral scalp pH has not been associated with improved fetal outcomes. PMID- 26600448 TI - Trauma Management of the Pregnant Patient. AB - Trauma continues to be a leading cause of nonobstetric maternal and fetal mortality worldwide. Caring for the pregnant trauma patient requires a systematic and multidisciplinary approach. It is important to understand the anatomic and physiologic changes that occur during pregnancy. Accepted trauma guidelines for imaging and interventions should generally not be deviated from just because a patient is pregnant. Focus should be placed on injury prevention and education of at risk patients to decrease the morbidity and mortality associated with traumatic injuries in pregnant patients. PMID- 26600449 TI - Maternal Sepsis and Septic Shock. AB - The year 2015 marked the 200th anniversary of the birth of Ignaz Semmelweis, the Hungarian physician who identified unhygienic practices of physicians as a major cause of childbed fever or puerperal sepsis. Although such practices have largely disappeared as a factor in the development of chorioamnionitis and postpartum or puerperal endometritis, it is appropriate that this article on sepsis in pregnancy acknowledges his contributions to maternal health. This review describes the incidence and mortality of sepsis in pregnancy, methods to identify and define sepsis in this population, including scoring systems, causes, and sites of infection during pregnancy and parturition and management guidelines. PMID- 26600450 TI - Ethical Issues in Maternal-Fetal Care Emergencies. AB - Ethical issues that arise in the care of pregnant women are challenging to physicians, especially in critical care situations. By familiarizing themselves with the concepts of medical ethics in obstetrics, physicians will become more capable of approaching complex ethical situations with a clear and structured framework. This review discusses ethical approaches regarding 3 specific scenarios: (1) the life of the fetus versus the life of the mother and situations of questionable maternal decision making; (2) withdrawal of care in a brain-dead pregnant patient; and (3) domestic violence and the pregnant patient. PMID- 26600451 TI - Preface. Obstetrics and Gynecology Emergencies. PMID- 26600452 TI - A novel 3D Cu(I) coordination polymer based on Cu6Br2 and Cu2(CN)2 SBUs: in situ ligand formation and use as a naked-eye colorimetric sensor for NB and 2-NT. AB - A novel coordination polymer with the chemical formula [Cu4Br(CN)(mtz)2]n (mtz = 5-methyl tetrazole) (), has been synthesized under solvothermal conditions and characterized by elemental analysis, infrared (IR) spectroscopy, thermal gravimetric analysis, powder X-ray diffraction and single-crystal X-ray diffraction. Interestingly, the Cu(i), CN(-) and mtz(-) in compound are all generated from an in situ translation of the original precursors: Cu(2+), acetonitrile and 1-methyl-5-mercapto-1,2,3,4-tetrazole (Hmnt). The in situ ring to-ring conversion of Hmnt into mtz(-) was found for the first time. Structural analysis reveals that compound is a novel 3D tetrazole-based Cu(i) coordination polymer, containing both metal halide cluster Cu6Br2 and metal pseudohalide cluster Cu2(CN)2 secondary building units (SBUs), which shows an unprecedented (3,6,10)-connected topology. Notably, a pseudo-porphyrin structure with 16 membered rings constructed by four mtz(-) anions and four copper(i) ions was observed in compound . The fluorescence properties of compound were investigated in the solid state and in various solvent emulsions, the results show that compound is a highly sensitive naked-eye colorimetric sensor for NB and 2-NT (NB = nitrobenzene and 2-NT = 2-nitrotoluene). PMID- 26600453 TI - Salami-like Electrospun Si Nanoparticle-ITO Composite Nanofibers with Internal Conductive Pathways for use as Anodes for Li-Ion Batteries. AB - We report novel salami-like core-sheath composites consisting of Si nanoparticle assemblies coated with indium tin oxide (ITO) sheath layers that are synthesized via coelectrospinning. Core-sheath structured Si nanoparticles (NPs) in static ITO allow robust microstructures to accommodate for mechanical stress induced by the repeated cyclical volume changes of Si NPs. Conductive ITO sheaths can provide bulk conduction paths for electrons. Distinct Si NP-based core structures, in which the ITO phase coexists uniformly with electrochemically active Si NPs, are capable of facilitating rapid charge transfer as well. These engineered composites enabled the production of high-performance anodes with an excellent capacity retention of 95.5% (677 and 1523 mAh g(-1,) which are based on the total weight of Si-ITO fibers and Si NPs only, respectively), and an outstanding rate capability with a retention of 75.3% from 1 to 12 C. The cycling performance and rate capability of core-sheath-structured Si NP-ITO are characterized in terms of charge-transfer kinetics. PMID- 26600454 TI - Hepatobiliary and Pancreatic: Focal peliosis hepatis mimicking hepatocellular carcinoma in a hepatitis B carrier. PMID- 26600456 TI - Straw biochar hastens organic matter degradation and produces nutrient-rich compost. AB - Biochar derived from wheat straw was added to pig manure in amounts equivalent to 5%, 10%, or 15% (w/w, wet weight). The ratios of NH4(+)/NO3(-) and of UV light absorption at a wavelength of 254nm (SUV254) and dissolved organic carbon (DOC) indicated that compost with 10-15% biochar became more mature and more humified within 42days of composting, and the content of DOC and the concentration of NH4(+) in such compost decreased by 37.5-62.0% and 4.0-20.9%, respectively, compared to the corresponding levels in the control. Addition of biochar lowered the pH and increased electrical conductivity by 7.0-37.5% compared to the control and also increased the concentrations of water-soluble nutrients including PO4(3 ) (5.6-7.4%), K(+) (14.2-58.6%), and Ca(2+) (0-12.5%). It is therefore recommended that straw biochar be added to pig manure at 10-15% by weight. PMID- 26600457 TI - Optimization of biogas production from coffee production waste. AB - This study was conducted to investigate the effects of chemical pretreatments on biogas production from coffee waste. After the preparation of a mixture of coffee waste with a TS concentration of 10%w/w, basic and acid pretreatments were conducted in batch mode and their performances were compared with the biogas produced from a mixture without any pretreatment stage. The basic pretreatment demonstrated a very good action on the hydrolysis of the lignin and cellulose, and permitted a biogas production of about 18NL/L with a methane content of almost 80%v/v. Thus, the basic pretreatment has been used to scale-up the process. The coffee refuse was has been carried out in a 45L anaerobic reactor working in continuous mode and in a mesophilic condition (35 degrees C) with a Hydraulic Retention Time (HRT) of about 40days. A high biogas production of 1.14NL/Ld, with a methane percentage of 65%v/v was obtained, thus permitting a process yield of about 83% to be obtained. PMID- 26600458 TI - Microbial reduction of nitrate in the presence of zero-valent iron and biochar. AB - The denitrification of nitrate (NO3(-)) by mixed cultures in the presence of zero valent iron [Fe(0)] and biochar was investigated through a series of batch experiments. It was hypothesized that biochar may provide microbes with additional electrons to enhance the anaerobic biotransformation of nitrate in the presence of Fe(0) by facilitating electron transfer. When compared to the anaerobic transformation of nitrate by microbes in the presence of Fe(0) alone, the presence of biochar significantly enhanced anaerobic denitrification by microbes with Fe(0). Graphite also promoted the anaerobic microbial transformation of nitrate with Fe(0), and it was speculated that electron conducting graphene moieties were responsible for the improvement. The results obtained in this work suggest that nitrate can be effectively denitrified by microbes with Fe(0) and biochar in natural and engineered systems. PMID- 26600459 TI - A Randomized Trial of Time-Limited Antiretroviral Therapy in Acute/Early HIV Infection. AB - BACKGROUND: It has been proposed that initiation of antiretroviral treatment (ART) very soon after establishment of HIV infection may be beneficial by improving host control of HIV replication and delaying disease progression. METHODS: People with documented HIV infection of less than 12 months' duration in Baltimore MD and seven Canadian sites were randomized to either a) observation and deferred ART, or b) immediate treatment with ART for 12 months. All subjects not receiving ART were followed quarterly and permanent ART was initiated according to contemporaneous treatment guidelines. The endpoint of the trial was total ART-free time from study entry until initiation of permanent ART. RESULTS: One hundred thirteen people were randomized, 56 to the observation arm and 57 to the immediate treatment arm. Twenty-three had acute (<2 months) infection and 90 early (2-12 months) infection. Of those randomized to the immediate treatment arm, 37 completed 12 months of ART according to protocol, 9 declined to stop ART after 12 months, and 11 were nonadherent to the protocol or lost to follow-up. Comparing those in the observation arm to either those who completed 12 months of ART or all 56 who were randomized to immediate ART, there was no significant difference between the arms in treatment-free interval after study entry, which was about 18 months in both arms. CONCLUSIONS: This study did not find a benefit from administration of a brief, time-limited (12-month) course of ART in acute or early HIV infection. TRIAL REGISTRATION: ClinicalTrials.gov NCT00106171. PMID- 26600460 TI - A Model of Drosophila Larva Chemotaxis. AB - Detailed observations of larval Drosophila chemotaxis have characterised the relationship between the odour gradient and the runs, head casts and turns made by the animal. We use a computational model to test whether hypothesised sensorimotor control mechanisms are sufficient to account for larval behaviour. The model combines three mechanisms based on simple transformations of the recent history of odour intensity at the head location. The first is an increased probability of terminating runs in response to gradually decreasing concentration, the second an increased probability of terminating head casts in response to rapidly increasing concentration, and the third a biasing of run directions up concentration gradients through modulation of small head casts. We show that this model can be tuned to produce behavioural statistics comparable to those reported for the larva, and that this tuning results in similar chemotaxis performance to the larva. We demonstrate that each mechanism can enable odour approach but the combination of mechanisms is most effective, and investigate how these low-level control mechanisms relate to behavioural measures such as the preference indices used to investigate larval learning behaviour in group assays. PMID- 26600461 TI - Open LED Illuminator: A Simple and Inexpensive LED Illuminator for Fast Multicolor Particle Tracking in Neurons. AB - Dual-color live cell fluorescence microscopy of fast intracellular trafficking processes, such as axonal transport, requires rapid switching of illumination channels. Typical broad-spectrum sources necessitate the use of mechanical filter switching, which introduces delays between acquisition of different fluorescence channels, impeding the interpretation and quantification of highly dynamic processes. Light Emitting Diodes (LEDs), however, allow modulation of excitation light in microseconds. Here we provide a step-by-step protocol to enable any scientist to build a research-grade LED illuminator for live cell microscopy, even without prior experience with electronics or optics. We quantify and compare components, discuss our design considerations, and demonstrate the performance of our LED illuminator by imaging axonal transport of herpes virus particles with high temporal resolution. PMID- 26600462 TI - Topography Mediates the Influence of Cover Crops on Soil Nitrate Levels in Row Crop Agricultural Systems. AB - Supplying adequate amounts of soil N for plant growth during the growing season and across large agricultural fields is a challenge for conservational agricultural systems with cover crops. Knowledge about cover crop effects on N comes mostly from small, flat research plots and performance of cover crops across topographically diverse agricultural land is poorly understood. Our objective was to assess effects of both leguminous (red clover) and non leguminous (winter rye) cover crops on potentially mineralizable N (PMN) and [Formula: see text] levels across a topographically diverse landscape. We studied conventional, low-input, and organic managements in corn-soybean-wheat rotation. The rotations of low-input and organic managements included rye and red clover cover crops. The managements were implemented in twenty large undulating fields in Southwest Michigan starting from 2006. The data collection and analysis were conducted during three growing seasons of 2011, 2012 and 2013. Observational micro-plots with and without cover crops were laid within each field on three contrasting topographical positions of depression, slope and summit. Soil samples were collected 4-5 times during each growing season and analyzed for [Formula: see text] and PMN. The results showed that all three managements were similar in their temporal and spatial distributions of NO3-N. Red clover cover crop increased [Formula: see text] by 35% on depression, 20% on slope and 32% on summit positions. Rye cover crop had a significant 15% negative effect on [Formula: see text] in topographical depressions but not in slope and summit positions. The magnitude of the cover crop effects on soil mineral nitrogen across topographically diverse fields was associated with the amount of cover crop growth and residue production. The results emphasize the potential environmental and economic benefits that can be generated by implementing site specific topography-driven cover crop management in row-crop agricultural systems. PMID- 26600463 TI - Comparison of Unplanned Intensive Care Unit Readmission Scores: A Prospective Cohort Study. AB - PURPOSE: Early discharge from the intensive care unit (ICU) may constitute a strategy of resource consumption optimization; however, unplanned readmission of hospitalized patients to an ICU is associated with a worse outcome. We aimed to compare the effectiveness of the Stability and Workload Index for Transfer score (SWIFT), Sequential Organ Failure Assessment score (SOFA) and simplified Therapeutic Intervention Scoring System (TISS-28) in predicting unplanned ICU readmission or unexpected death in the first 48 hours after discharge from the ICU. METHODS: We conducted a prospective cohort study in a single tertiary hospital in southern Brazil. All adult patients admitted to the ICU for more than 24 hours from January 2008 to December 2009 were evaluated. SWIFT, SOFA and TISS 28 scores were calculated on the day of discharge from the ICU. A stepwise logistic regression was conducted to evaluate the effectiveness of these scores in predicting unplanned ICU readmission or unexpected death in the first 48 hours after discharge from the ICU. Moreover, we conducted a direct accuracy comparison among SWIFT, SOFA and TISS-28 scores. RESULTS: A total of 1,277 patients were discharged from the ICU during the study period. The rate of unplanned ICU readmission or unexpected death in the first 48 hours after discharge from the ICU was 15% (192 patients). In the multivariate analysis, age (P = 0.001), length of ICU stay (P = 0.01), cirrhosis (P = 0.03), SWIFT (P = 0.001), SOFA (P = 0.01) and TISS-28 (P<0.001) constituted predictors of unplanned ICU readmission or unexpected death. The SWIFT, SOFA and TISS-28 scores showed similar predictive accuracy (AUC valueswere 0.66, 0.65 and 0.67, respectively; P = 0.58) [corrected]. CONCLUSIONS: SWIFT, SOFA and TISS-28 on the day of discharge from the ICU have only moderate accuracy in predicting ICU readmission or death. The present study did not find any differences in accuracy among the three scores. PMID- 26600464 TI - A Prospective Multicentre Study to Improve Postoperative Pain: Identification of Potentialities and Problems. AB - Many studies still indicate insufficient pain management after surgery, e.g., in patients after small- or medium-size operations. Yet it is still uncertain if postoperative pain based on patient-related outcomes can be improved by implementing guideline-related programmes in a multicentre approach. Adult patients in six hospitals in one German city were included in this prospective study. Data collection took place twice in each hospital, once before and once after implementation of concepts and in-house training. Pain and pain-related aspects were assessed one day after surgery and compared between the pre- and post-test group including subgroup analysis of certain surgical procedures by using Student's t-tests, Mann-Whitney U tests and chi-square tests (alphatwo tailed = 0.05). Overall, pain at rest and during movement was slightly lower after the intervention. Significant changes were observed after thoracic surgery, small joint surgery and other minor surgical procedures. The rather moderate decrease in pain likely relates to a reasonable pre-existing pain management and to detached improvements in certain patient subgroups. Interestingly, specific analyses revealed significantly lower post-test pain as compared to pre-test pain only in patients without pre-existing chronic pain. Side effects related to pain medication were significantly lower after intervention. Our data show, for the first time, benefits of a perioperative teaching programme in a multicentre approach. Pain ratings improved mainly in specific subgroups of patients, e.g., small surgical procedures and patients without preoperative pain. Thus, general improvement is possible but special attention should be paid to the group of patients with preoperative pain. PMID- 26600465 TI - Inter-Relationship between Rhinitis and Conjunctivitis in Allergic Rhinoconjunctivitis and Associated Risk Factors in Rural UK Children. AB - OBJECTIVE: Allergic conjunctivitis (AC) is a common condition, especially in childhood. The extent to which it occurs concurrently with or independently from allergic rhinitis (AR) has not been well described. AIM: To examine the inter relationship between rhinitis and conjunctivitis and the epidemiological risk factors for these conditions in a rural UK population. METHODS: Cross-sectional study of rural school children (aged 5-11 years). Parental questionnaires were used to diagnose allergic outcomes (including conjunctivitis, rhinitis and rhinoconjunctivitis), and to collect data on atopic history, demographic and environmental exposures. Odds ratios of allergic outcome by exposure were examined adjusted for age, sex, breastfeeding, family history of allergy, number of older and younger siblings. RESULTS: Prevalence of conjunctivitis was 17.5%, rhinitis 15.1% and rhinoconjunctivitis 13.0%. Seasonality of symptoms varied by condition: 64.7% of those with conjunctivitis had seasonal symptoms (April-Sept only), 46.7% of those with rhinitis and 92.2% of those with rhinoconjunctivitis. Living on a farm consistently reduced the risk of conjunctivitis (odds ratio 0.47, 95%CI 0.29-0.79, p = 0.004), rhinitis (OR 0.57, 95%CI 0.33-1.01, p = 0.05) and rhinoconjunctivitis (OR 0.57, 95%CI 0.32-1.03, p = 0.06). Exposure to farm animals (particularly in early life), current consumption of unpasteurised milk and playing in a barn or stable significantly reduced the risk of all three conditions. CONCLUSION: More children had parent-reported conjunctivitis than rhinitis. The majority of children with either condition also reported symptoms with the other condition. Farmers' children have less eye and/or nasal symptoms. A number of farming variables linked with the farm microbial environment are likely to be mediating the protective effect. PMID- 26600466 TI - Correction: Influence of Soil Properties on Soldierless Termite Distribution. AB - [This corrects the article DOI: 10.1371/journal.pone.0135341.]. PMID- 26600467 TI - Correction of a Depth-Dependent Lateral Distortion in 3D Super-Resolution Imaging. AB - Three-dimensional (3D) localization-based super-resolution microscopy (SR) requires correction of aberrations to accurately represent 3D structure. Here we show how a depth-dependent lateral shift in the apparent position of a fluorescent point source, which we term 'wobble', results in warped 3D SR images and provide a software tool to correct this distortion. This system-specific, lateral shift is typically > 80 nm across an axial range of ~ 1 MUm. A theoretical analysis based on phase retrieval data from our microscope suggests that the wobble is caused by non-rotationally symmetric phase and amplitude aberrations in the microscope's pupil function. We then apply our correction to the bacterial cytoskeletal protein FtsZ in live bacteria and demonstrate that the corrected data more accurately represent the true shape of this vertically oriented ring-like structure. We also include this correction method in a registration procedure for dual-color, 3D SR data and show that it improves target registration error (TRE) at the axial limits over an imaging depth of 1 MUm, yielding TRE values of < 20 nm. This work highlights the importance of correcting aberrations in 3D SR to achieve high fidelity between the measurements and the sample. PMID- 26600468 TI - From P-Values to Objective Probabilities in Assessing Medical Treatments. AB - The assessment of the effectiveness of a treatment in a clinical trial, depends on calculating p-values. However, p-values are only indirect and partial indicators of a genuine effect. Particularly in situations where publication bias is very likely, assessment using a p-value of 0.05 may not be sufficiently cautious. In other situations it seems reasonable to believe that assessment based on p-values may be unduly conservative. Assessments could be improved by using prior information. This implies using a Bayesian approach to take account of prior probability. However, the use of prior information in the form of expert opinion can allow bias. A method is given here that applies to assessments already included or likely to be included in the Cochrane Collaboration, excluding those reviews concerning new drugs. This method uses prior information and a Bayesian approach, but the prior information comes not from expert opinion but simply from the distribution of effectiveness apparent in a random sample of summary statistics in the Cochrane Collaboration. The method takes certain types of summary statistics and their confidence intervals and with the help of a graph, translates this into probabilities that the treatments being trialled are effective. PMID- 26600469 TI - Fear and physiological arousal during a virtual height challenge--effects in patients with acrophobia and healthy controls. AB - Virtual reality (VR) exposure therapy is becoming increasingly established, but the mode of action is not well understood. One potential efficacy factor might be physiological arousal. To investigate arousal during VR exposure, we exposed 40 patients with acrophobia and 40 matched healthy controls to a VR height challenge and assessed subjective (fear ratings) and physiological (heart rate, skin conductance level, salivary cortisol) fear reactions. Patients experienced a significant increase of subjective fear, heart rate and skin conductance level. Unexpectedly, controls, who reported no subjective fear, also showed an increase in heart rate and skin conductance. There was no increase in salivary cortisol levels in either group. Physiological arousal in acrophobic patients, in contrast to subjective fear, might not be stronger than that of controls confronted with height cues in VR, indicating marked discordance across symptom domains. The lack of a cortisol response in a clearly stressful paradigm warrants further study. PMID- 26600470 TI - Toxicity of Gossypol from Cottonseed Cake to Sheep Ovarian Follicles. AB - Gossypol, a polyphenol compound produced by cotton plant, has proven reproductive toxicity, but the effects of gossypol on sheep ovaries are unknown. This study was aimed to determine the in vitro and in vivo effects of gossypol on the ovarian follicles of sheep. This trial was divided into two experiments. In the first one, we used twelve non-pregnant, nulliparous, Santa Ines crossbred ewes, which were randomly distributed into two equal groups and fed diets with and without cottonseed cake. Feed was offered at 1.5% of the animal's body weight for 63 days. The concentrations of total and free gossypol in the cottonseed cake were 3.28 mg/g and 0.11 mg/g, respectively. Throughout the trial period, no animal showed clinical signs of toxicity and no effects on body weight were observed. However, there was a significantly lower number of viable ovarian follicles (20.6%) and higher number of atretic follicles (79.4%) in the gossypol fed sheep compared to the control (85.1 and 34.9%, respectively). These findings were observed at all stages of follicular development. In the second experiment, eight ovaries from slaughterhouse were cultured with different concentrations of gossypol acetic acid (0, 5, 10 and 20 MUg/mL) for 24 hours or seven days. The in vitro action of gossypol resulted in a significant decrease in viable ovarian follicles, especially the primary and transition follicles, and a significant increase in the number of atretic follicles after 24 hours of culture. These follicles were greatly affected when cultured with gossypol for seven days. It is concluded that gossypol present in cotton seeds directly acts on ovarian follicles in sheep to increase atresia. PMID- 26600471 TI - Purification and Characterization of a Novel NAD(P)+-Farnesol Dehydrogenase from Polygonum minus Leaves. AB - Juvenile hormones have attracted attention as safe and selective targets for the design and development of environmentally friendly and biorational insecticides. In the juvenile hormone III biosynthetic pathway, the enzyme farnesol dehydrogenase catalyzes the oxidation of farnesol to farnesal. In this study, farnesol dehydrogenase was extracted from Polygonum minus leaves and purified 204 fold to apparent homogeneity by ion-exchange chromatography using DEAE-Toyopearl, SP-Toyopearl, and Super-Q Toyopearl, followed by three successive purifications by gel filtration chromatography on a TSK-gel GS3000SW. The enzyme is a heterodimer comprised of subunits with molecular masses of 65 kDa and 70 kDa. The optimum temperature and pH were 35 degrees C and pH 9.5, respectively. Activity was inhibited by sulfhydryl reagents, metal-chelating agents and heavy metal ions. The enzyme utilized both NAD+ and NADP+ as coenzymes with Km values of 0.74 mM and 40 mM, respectively. Trans, trans-farnesol was the preferred substrate for the P. minus farnesol dehydrogenase. Geometrical isomers of trans, trans farnesol, cis, trans-farnesol and cis, cis-farnesol were also oxidized by the enzyme with lower activity. The Km values for trans, trans-farnesol, cis, trans farnesol and cis, cis-farnesol appeared to be 0.17 mM, 0.33 mM and 0.42 mM, respectively. The amino acid sequences of 4 tryptic peptides of the enzyme were analyzed by MALDI-TOF/TOF-MS spectrometry, and showed no significant similarity to those of previously reported farnesol dehydrogenases. These results suggest that the purified enzyme is a novel NAD(P)+-dependent farnesol dehydrogenase. The purification and characterization established in the current study will serve as a basis to provide new information for recombinant production of the enzyme. Therefore, recombinant farnesol dehydrogenase may provide a useful molecular tool in manipulating juvenile hormone biosynthesis to generate transgenic plants for pest control. PMID- 26600473 TI - Mapping air pollution by biological monitoring in the metropolitan Tel Aviv area. AB - Conventional environmental monitoring is not surrogate of personal exposure. In contrast, biomonitoring provides information on the presence of substances in the human body, making it highly relevant to the assessment of exposure to toxic substances. Induced sputum (IS) is a noninvasive technique for detecting inflammation and reflecting particulate matter content in the airways. In this study, we mapped particulate matter dispersion in metropolitan Tel Aviv by both biomonitoring techniques employing IS samples and by environmental monitoring. All adults referred to the Pulmonary Lab for respiratory symptom evaluation in 2007 and in 2009 were enrolled. Pulmonary function tests were performed by conventional methods. Particulate size distribution in IS was analyzed, and maps of air pollution were created. Biomonitoring was more informative and enabled mapping of wider areas. Integration of biomonitoring and environmental monitoring should be considered in forming public health policy on containment of airborne particles of toxic substances. PMID- 26600472 TI - Determination of Heavy Metal Concentrations in Normal and Pathological Human Endometrial Biopsies and In Vitro Regulation of Gene Expression by Metals in the Ishikawa and Hec-1b Endometrial Cell Line. AB - It is well known that several metals, such as lead, mercury, cadmium, and vanadium, can mimic the effects of estrogens (metallo-estrogens). Nevertheless, there are only a few studies that have assessed the effects of toxic metals on the female genital tract and, in particular, endometrial tissue. In this context, we measured the concentrations of several trace elements in human endometrial tissue samples from individuals with hyperplasia or adenocarcinoma and in normal tissues. Hyperplasic endometrial tissue has a 4-fold higher concentration of mercury than normal tissue. Mercury can affect both the AhR and ROS signaling pathways. Thus, we investigated the possible toxic effects of mercury by in vitro studies. We found that mercury increases oxidative stress (increased HO1 and NQO1 mRNA levels) and alters the cytoskeleton in the human endometrial Ishikawa cell line and to a lesser extent, in the "less-differentiated" human endometrial Hec 1b cells. The results might help to explain a potential link between this metal and the occurrence of endometrial hyperplasia. PMID- 26600475 TI - Screening potential SSR markers of the anadromous fish Coilia nasus by de novo transcriptome analysis using Illumina sequencing. AB - RNA-Seq technology has been widely applied to transcriptomics, genomics, molecular marker development, and functional gene studies. In the genome, microsatellites are simple sequence repeats (SSR) with a high degree of polymorphism that are used as DNA markers in many molecular genetic studies. Using traditional methods such as magnetic bead enrichment, only a few microsatellite markers have been isolated. Coilia nasus is an anadromous, small to-moderately sized fish species that is famous as an important fishery resource. Here, we have identified a large number of microsatellites from the fish brains by using Illumina sequencing. About 20 million Illumina reads were assembled into 148,845 unigenes. A total of 13,038 SSR motifs were identified via analysis of 3,958,293,117 (3.96 Gb) nucleotides to produce a comprehensive transcript dataset for the C. nasus brain, including mono-, di-, tri-, tetra-, and penta-repeat motifs. The most abundant type of repeat motif was di-nucleotide (42.97%), followed by mono-nucleotide (38.86%), tri-nucleotide (16.21%), tetra-nucleotide (1.83%), and penta-nucleotide (0.05%) repeat units, which is similar to the results obtained in studies in other species. These data provide a base of sequence information to improve molecular-assisted markers to study C. nasus genetic diversity. PMID- 26600474 TI - Intensity of Medical Interventions between Diagnosis and Death in Patients with Advanced Lung and Colorectal Cancer: A CanCORS Analysis. AB - BACKGROUND: Medical interventions are an important component of the illness experience in advanced cancer. OBJECTIVE: To describe the use of medical interventions between diagnosis and death in decedents with metastatic lung and colorectal cancer. DESIGN: Retrospective analysis of a prospective cohort study. SETTING/SUBJECTS: We studied 1,840 decedents from the Cancer Care Outcomes Research and Surveillance (CanCORS) study. Subjects had been diagnosed with stage IV lung or colorectal cancer between 2003 and 2005. MEASUREMENTS: Hospitalizations, surgeries, radiation therapy treatments, chemotherapy treatments, and end-of-life care, reported by tertile of overall survival time. RESULTS: Median survival in the bottom, middle, and top tertiles of survival was 1.2, 5.3, and 15.3 months for lung cancer, and 3.0, 18.0, and 44.4 months for colorectal cancer. Hospitalizations, chemotherapy receipt, and hospice enrollment increased with increasing survival. The median duration of chemotherapy in the top survival tertile was 149 days for lung cancer and 498 days for colorectal cancer. A minority of decedents used any hospice services, and the median duration of hospice enrollment exceeded 30 days only for enrollees in the top survival tertile (lung cancer, 35 days; colorectal cancer, 66 days). CONCLUSIONS: For patients with metastatic lung and colorectal cancer, longer survival is associated with increased intensity of medical care, characterized by greater use of chemotherapy and acute hospital care. Hospice utilization was uniformly low, and most hospice enrollees were referred to hospice in the last 30 days of life. PMID- 26600476 TI - Correlation between interleukin-6 expression in articular cartilage bone and osteoarthritis. AB - This study aimed to investigate the expressional profile of interleukin-6 (IL-6) in articular cartilage bone of osteoarthritis (OA) patients and its correlation with OA. A total of 30 articular cartilage bone samples from knee OA patients, which were collected by knee arthroscopy or articular surgery, comprised the study group, and 30 samples of normal articular cartilage tissue comprised the control group. Both mRNA (messenger ribonucleic acid) and protein levels of IL-6 and matrix metalloproteinase-9 (MMP-9) were measured and compared, and a correlation analysis was performed between the two. The integral optical density (IOD) values of MMP-9 and IL-6 proteins in the study group were 9.21 +/- 3.22 and 8.94 +/- 3.17, respectively; these were significantly higher (P < 0.05) than those in the control group at 3.14 +/- 1.48 and 6.64 +/- 1.53, respectively. The IOD values of mRNA transcripts for MMP-9 and IL-6 in the study group were 8.31 +/ 2.28 and 8.78 +/- 3.43, respectively; these were significantly higher than the values in the control group at 3.52 +/- 1.37 and 5.21 +/- 1.72 (P < 0.05), respectively. Further, the correlation analysis revealed significantly positive relationships for both protein (r = 0.434, P = 0.001) and mRNA (r = 0.413, P = 0.002) levels between MMP-9 and IL-6. In conclusion, articular cartilage tissues in knee OA patients have higher levels of MMP-9 and IL-6 expression, and these may play a synergistic role in OA pathogenesis. PMID- 26600477 TI - Analysis of the gene-protein interaction network in glioma. AB - Glioma is the most aggressive type of brain tumor. Great progress has been achieved in glioma treatment, but the protein-protein interaction networks underlining glioma are poorly understood. We identified the protein-protein interaction network for glioma based on gene expression and predicted biological pathways underlying the molecular complexes in the network. Genes involved in glioma were selected from the Online Mendelian Inheritance in Man (OMIM) database. A literature search was performed using the Agilent Literature Search plugin, and Cytoscape was used to establish a protein-protein interaction network. The molecular complexes in the network were detected using the Clusterviz plugin, and pathway enrichment of molecular complexes was performed using DAVID online. There were 378 glioma genes in the OMIM database. The protein protein interaction network in glioma contained 1814 nodes, 6471 edges, and 8 molecular complexes. There were 17 pathways (false discovery rate <1), which were related to cytokine-cytokine receptor interaction, Toll-like receptor signaling pathway, chemokine signaling pathway, oocyte meiosis, progesterone-mediated oocyte maturation, transmembrane transport of small molecules, metabolism of amino acids, and notch signaling pathway, among others. Our results provide a bioinformatic foundation for further studies of the mechanisms of glioma. PMID- 26600478 TI - Cartilage oligomeric matrix protein and matrix metalloproteinase-3 expression in the serum and joint fluid of a reversible osteoarthritis rabbit model. AB - The main pathological characteristic of osteoarthritis (OA) is cartilage damage. We explored cartilage oligomeric matrix protein (COMP) and matrix metalloproteinase-3 (MMP-3) changes during articular cartilage injury and repair. Rabbits were randomly divided into the following: a blank control group; groups M1, M2, and M3, in which breaking was performed for 2, 4, and 6 weeks, respectively; and groups L1, L2, and L3, in which breaking was discontinued for 2, 4, and 6 weeks, respectively, following a 4-week recovery period. There are 7 rabbits in each group. The degree of cartilage damage in each group was scored (OA score). An enzyme-linked immunosorbent assay was used to detect COMP and MMP 3 levels in serum and joint fluid. The OA scores were 3.89 +/- 2.31, 7.21 +/- 2.31, and 10.88 +/- 2.08 points in groups M1, M2, and M3, respectively (P < 0.05). COMP and MMP-3 levels were significantly higher in groups M1, M2, and M3 than in C. The OA score improved significantly following the 4-week recovery period (P < 0.05). COMP and MMP-3 levels began to decrease as the time following discontinuation of breaking increased, but were higher than in the control (P < 0.05). MMP- 3 and COMP levels were correlated with OA score (r > 0.7, P < 0.05). COMP and MMP-3 levels were correlated between joint fluid and serum (r = 0.899, r = 0.874, P < 0.05, respectively). Long-term joint breaking can cause articular cartilage damage. Doing some activites after the process can promote self-repair of articular cartilage. COMP and MMP-3 levels were associated with articular cartilage destruction and repair. PMID- 26600479 TI - Identification of conserved microRNAs in peripheral blood from giant panda: expression of mammary gland-related microRNAs during late pregnancy and early lactation. AB - The giant panda (Ailuropoda melanoleuca) is one of the world's most endangered mammals, and it has evolved several unusual biological and behavioral traits. During puberty, pregnancy, lactation, and involution, the mammary gland undergoes profound morphological and functional changes. A large number of microRNAs (miRNAs) have been identified to be involved in mammary gland development and lactation. In this study, we identified 202 conserved mature miRNAs, corresponding to 147 pre-miRNAs, in giant panda peripheral blood using a small RNA-sequencing approach. In addition, 27 miRNA families and 29 miRNA clusters were identified. We analyzed the arm selection preference of pre-miRNAs and found that: 1) most giant panda pre-miRNAs generated one-strand miRNAs, and the 5p-arm only miRNAs have a higher expression level than 3p-arm only miRNAs; 2) there were more 5p-arm dominant miRNAs than 3p-arm dominant miRNAs; and 3) 5p-arm dominant miRNAs have a larger fold change within miRNA pairs than 3p-arm dominant miRNAs. Expression of 12 lactation-related miRNAs was detected across late pregnancy and early lactation stages by qPCR, and seven miRNAs were identified as clustered in one significant model. Most of these clustered miRNAs exhibited inhibitory roles in proliferation and differentiation of mammary epithelial cells. Functional analysis highlighted important roles of the seven as signed miRNAs in mammary development and metabolic changes, including blood vessel morphogenesis, macromolecule biosynthesis, cell cycle regulation, and protein transport. PMID- 26600480 TI - Detection of quantitative trait loci for ear row number in F2 populations of maize. AB - Ear row number (ERN) is not only a key trait involved in maize (Zea mays L.) evolution but is also an important component that is directly related to grain yield. In this study, quantitative trait loci (QTLs) for ERN were detected across two F2 populations that were derived from a same cross between B73 with 16 rows (N = 233) and SICAU1212 with four rows (N = 231). As a result, 33 QTLs were associated with 12 agronomic traits: three plant traits, four ear-related traits, and five kernel-related traits. The total phenotypic variation explained by the QTLs for each trait ranged from 8.60 to 72.67%, and four QTLs were identified for ERN in the two populations. Each QTL explained between 6.78 and 36.76% of the ERN variation. Notably, three of the four QTLs (qERN2-1, qERN4-2, and qERN8-1) were associated with ERN, and qERN8-1 simultaneously influenced grain yield, plant diameter, ear diameter, and kernel length. In addition, only one significant epistatic interaction was detected in all 33 QTLs. This study should provide a foundation for further fine-mapping and map-based cloning of these consistent QTLs, and for controlling maize ERN by marker-assisted breeding. PMID- 26600481 TI - Expression and significance of myeloid differentiation factor 88 in non-small cell lung carcinoma and normal paracancerous tissues. AB - We studied the expression level of myeloid differentiation factor 88 (MyD88) in non-small cell lung carcinoma (NSCLC) and normal paracancerous tissues, to determine its relationship with clinical pathological characteristics and prognosis. In total, 82 NSCLC patients who had received surgical treatment in our hospital between September 2008 and December 2013 were selected for this study. Another 82 normal paracancerous lung tissue samples were used as controls. All patients had complete clinical records, and they were followed-up for 5 years. The expression level of MyD88 protein was detected by immunohistochemical assay. The positive expression rate of MyD88 in NSCLC tissues (62.2%) was markedly higher than that in normal tissues (10.9%), and was independent of patient characteristics such as age, gender, pathological pattern, history of smoking, and tumor size (P > 0.05). However, MyD88 expression was significantly correlated with degree of differentiation, clinical staging, and lymphatic metastasis (P < 0.05), and was negatively correlated with prognosis. The 5-year survival rate of patients with positive MyD88 expression was significantly lower than that of patients without positive expression (P < 0.05). MyD88 was expressed at a higher level in NSCLC tissues and was closely associated with poor prognosis. MyD88 may be a novel eligible target for treating NSCLC. PMID- 26600482 TI - Regulatory role of microRNA184 in osteosarcoma cells. AB - Osteosarcoma is a highly malignant cancer that often appears in teenagers. It is the most frequently occurring primary bone tumor, and can easily metastasize, resulting in high mortality. MicroRNAs express abnormally in osteosarcoma, and may function as oncogenes or tumor suppressors. Recent studies showed that microRNA184 (miR-184) is abnormally expressed in multiple tumors, and is involved in tumor cell growth, differentiation, invasion, and metastasis. Nevertheless, the role of miR-184 in osteosarcoma cells remains unknown. We evaluated the expression and function of microRNA184 in osteosarcoma cells. SOSP-M osteosarcoma cells were divided into normal control, miR-184 mimic, and miR-184 inhibitor groups. Real-time PCR was applied to detect miR-184 expression. The 3-(4,5 dimethylthaizol-2-yl)-2,5-diphenyltetrazolium bromide assay was used to evaluate cell proliferation. Transwell assays were performed to detect changes in cell invasion ability. Compared with the control group, miR-184 expression was significantly increased in the miR-184 mimic group (P < 0.05). After miR-184 inhibitor transfection, miR-184 expression was obviously reduced (P < 0.05). Tumor cell proliferation was enhanced in the miR-184 mimic group (P < 0.05), whereas miR-184 inhibition suppressed cell proliferation (P < 0.05). Furthermore, tumor cell invasion increased after miR-184 mimic transfection (P < 0.05), and decreased after inhibiting miR-184 (P < 0.05). MiR-184 promotes tumor cell proliferation and invasion, and may represent a new biological target for osteosarcoma. PMID- 26600483 TI - Expression of B7-H3 in cancer tissue during osteosarcoma progression in nude mice. AB - Immune cells might participate in the ontogenesis of osteosarcoma. B7-H3 is a new discovered T cell co-stimulatory molecule that was found to be overexpressed in malignant tumors. We aimed to investigate the dynamic expression level of B7-H3 in nude mice with osteosarcoma. A nude mouse osteosarcoma model was successfully established. B7-H3 expression and distribution changes in the early, middle, and late phases of osteosarcoma formation after tumor implantation were observed. Reverse transcription-polymerase chain reaction and western blot analyses were applied to measure the B7-H3 mRNA and protein dynamic changes. Confocal microscopy and immunohistochemistry were used to determine B7-H3 localization and CD3+ T cell expression, respectively, in osteosarcoma tissue. B7-H3 mRNA and protein levels fluctuated during the process of osteosarcoma formation in the nude mouse model. Expression levels were lower in the early and middle phases, while B7-H3 mRNA and protein were overexpressed in the late stage. Accordingly, CD3+ T cell numbers in the early, middle, and late phases in osteosarcoma tissue were 93 +/- 13, 92 +/- 12, and 46 +/- 15, respectively; they can be seen to have decreased significantly in the late stage (P < 0.05). Overall, our results indicated that the B7-H3 expression level is correlated with tumor volume and severity; therefore, it might serve as a tumor biomarker for osteosarcoma. PMID- 26600484 TI - Factor analysis using mixed models of multi-environment trials with different levels of unbalancing. AB - This study aimed to analyze the robustness of mixed models for the study of genotype-environment interactions (G x E). Simulated unbalancing of real data was used to determine if the method could predict missing genotypes and select stable genotypes. Data from multi-environment trials containing 55 maize hybrids, collected during the 2005-2006 harvest season, were used in this study. Analyses were performed in two steps: the variance components were estimated by restricted maximum likelihood, using the expectation-maximization (EM) algorithm, and factor analysis (FA) was used to calculate the factor scores and relative position of each genotype in the biplot. Random unbalancing of the data was performed by removing 10, 30, and 50% of the plots; the scores were then re-estimated using the FA model. It was observed that 10, 30, and 50% unbalancing exhibited mean correlation values of 0.7, 0.6, and 0.56, respectively. Overall, the genotypes classified as stable in the biplot had smaller prediction error sum of squares (PRESS) value and prediction amplitude of ellipses. Therefore, our results revealed the applicability of the PRESS statistic to evaluate the performance of stable genotypes in the biplot. This result was confirmed by the sizes of the prediction ellipses, which were smaller for the stable genotypes. Therefore, mixed models can confidently be used to evaluate stability in plant breeding programs, even with highly unbalanced data. PMID- 26600485 TI - Eosinophil cationic protein mRNA expression in children with bronchial asthma. AB - Studies have shown that eosinophils are closely related to pathogenesis of bronchial asthma. Eosinophils release eosinophil cationic protein (ECP), which plays an important role in infection and allergic reactions. Serum ECP mRNA expression in children with bronchial asthma has not been adequately investigated. We analyzed serum ECP mRNA expression in 63 children with bronchial asthma and 21 healthy children by using reverse-transcriptase polymerase chain reaction to understand the role of ECP in children with bronchial asthma. The children with bronchial asthma were segregated into acute-phase and stable-phase groups, based on the severity of the illness. Serum ECP mRNA expression in children with bronchial asthma (0.375 +/- 0.04) was significantly higher than that in healthy controls (0.20 +/- 0.02; P < 0.05). Additionally, children in the acute-phase group showed higher ECP mRNA expression level (0.44 +/- 0.06) than those in the stable-phase (0.31 +/- 0.03) and healthy control groups (0.20 +/- 0.02; P < 0.05), while the level in the stable-phase (0.31 +/- 0.03) was markedly higher than that in the healthy control group (0.20 +/- 0.02; P < 0.05). Detection of serum ECP mRNA expression level has possible applications in the diagnosis and treatment of children with bronchial asthma. PMID- 26600486 TI - Development of transcript-associated microsatellite markers in Ancherythoculter nigrocauda and cross-amplification in Culter alburnus. AB - Twenty-eight polymorphic microsatellite markers were developed from the transcriptome of Ancherythoculter nigrocauda. These loci were used to characterize the genotypes of 48 individuals. The observed number of alleles per locus ranged from 5 to 11, with an average of 7.7. Expected and observed heterozygosities ranged from 0.437 to 0.978 and from 0.373 to 1.000, respectively. Four of these polymorphic microsatellite loci (HWB14, HWB18, HWB24, and HWB30) deviated significantly from the Hardy-Weinberg equilibrium after use of the sequential Bonferroni correction (P < 0.05). Twenty of the 28 loci could be successfully amplified in Culter alburnus. These novel markers will be useful for germplasm resource conservation and management of A. nigrocauda and C. alburnus. PMID- 26600487 TI - Quantitative assessment of the association between the angiotensin-converting enzyme gene insertion/deletion polymorphism and digestive system cancer risk. AB - The angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism has been reported to be associated with digestive system cancer; however, the results from previous studies have been conflicting. The present study aimed to investigate the association between the ACE I/D polymorphism and the risk of digestive system cancer using a meta-analysis of previously published studies. Databases were systematically searched to identify relevant studies published prior to December 2014. We estimated the pooled OR with its 95%CI to assess the association. The meta-analysis consisted of thirteen case-control studies that included 2557 patients and 4356 healthy controls. Meta-analysis results based on all the studies showed no significant association between the ACE I/D polymorphism and the risk of digestive system cancer (DD vs II: OR = 0.85, 95%CI = 0.59-1.24; DI vs II: OR = 0.94, 95%CI = 0.78-1.15; dominant model: OR = 0.96, 95%CI = 0.81- 1.15; recessive model: OR = 1.06, 95%CI = 0.76-1.48). Subgroup analyses by race and cancer type did not detect an association between the ACE I/D polymorphism and digestive system cancer risk. However, when the analyses were restricted to smaller studies (N < 500 patients), the summary OR of DI vs II was 0.80 (95%CI = 0.66-0.97). Our analyses detected a possibility of publication bias with a misestimate of the true association by smaller studies. Overall, meta-analysis results suggest the ACE I/D polymorphism might not be associated with susceptibility to digestive system cancer. Further large and well designed studies are needed to confirm these conclusions. PMID- 26600488 TI - High genetic variability and polychromatism in Pachycoris torridus (Heteroptera: Scutelleridae). AB - The stink bug Pachycoris torridus is listed among the most polyphagous insects in the world and it is a major pest of diverse crops, in particular the physic nut Jatropha curcas, which is used as a raw material for biodiesel production. A peculiar characteristic of this species is its high phenotypic variability, a characteristic that makes identification difficult: P. torridus has been described as a new species eight times. Thus, to aid in identification, genetic characterization of this insect was performed. We verified that, due to the high genetic variability of P. torridus, several genetic patterns exist that result in the same phenotype. PMID- 26600489 TI - Effect of all-trans retinoic acids (ATRA) on the expression of alpha-smooth muscle actin (alpha-SMA) in the lung tissues of rats with pulmonary arterial hypertension (PAH). AB - The effect of all-trans retinoic acid (ATRA) on the expression of alpha-smooth muscle actin (alpha-SMA) in rats with pulmonary arterial hypertension (PAH) was studied, and the mechanism of the effect of ATRA on PAH was proposed. Thirty male SD rats were randomly divided into normal control, monocrotaline (MCT) model, and ATRA [30 mg/(kg.day)]intervention groups (N = 10 each). The mean pulmonary arterial pressure was recorded. Right ventricular hypertrophy index (RVHI) was calculated (weight of right ventricle: total weight of left ventricle and interventricular septum). The percentages of wall thickness of pulmonary arteriole (WT) to external diameter of artery (WT%) and vascular wall area (WA) to total vascular area (WA%) were determined. Real-time fluorescence-based quantitative PCR and western blot analyses were employed to detect the alpha-SMA mRNA and protein expressions. The mean pulmonary arterial pressure, RVHI, WT%, and WA% were all obviously higher in the model group than in the control and intervention groups. The values of these indicators in the intervention group were also higher than those in the control group (P < 0.01). The mRNA and protein expression levels of alpha-SMA were significantly higher in the lung tissue of model rats than those in the control and intervention groups. However, the intervention group showed no statistically significant differences in alpha-SMA mRNA and protein expression levels compared to the control (P < 0.05). ATRA inhibited the alpha-SMA mRNA and protein expressionin the lung tissues of rats with MCT-induced PAH, and could be used to treat PAH. PMID- 26600490 TI - Genetic characterization of native and invasive Plagioscion squamosissimus (Perciformes, Sciaenidae) populations in Brazilian hydrographic basins. AB - The genetic diversity of invasive and native populations of Plagioscion squamosissimus (Heckel, 1840) from the Parana, Parnaiba and Araguaia-Tocantins river basins was assessed by using Random Amplified Polymorphic DNA (RAPD) markers. Genetic data confirmed the hypothesis of low genetic variability within and among P. squamosissimus populations introduced in the upper Parana River basin, and indicated that they likely originated from a common ancestor. Moreover, the data demonstrated that, in agreement with available historical records, the P. squamosissimus populations established in the Parana River basin were derived from a population native to the Parnaiba River basin. The genetic data presented here are of potential future application for the management of the invasive P. squamosissimus populations and for the preservation of the genetic legacy of native fish. PMID- 26600491 TI - Association of the IGF-1 rs35767 and rs972936 polymorphisms with the risk of osteoporosis in a Chinese postmenopausal female population. AB - The aim of our study was to conduct a case-control study in a Chinese postmenopausal population to evaluate the roles of the IGF-1 rs35767 and rs972936 polymorphisms on bone mineral density (BMD) levels and osteoporosis risk. A total of 272 consecutive postmenopausal women with a primary diagnosis of osteoporosis and 272 controls were enrolled in the study between 2012 and 2014. The polymerase chain reaction-restriction fragment length polymorphism method was used to genotype the rs35767 and rs972936 IGF-1 polymorphisms. By comparing the demographic characteristics between patients and controls, patients with osteoporosis were found to be more likely to have a habit of alcohol drinking (P = 0.023). Furthermore, the BMD levels of the L1-L4 vertebrae, femoral necks, total hips, and trochanters in patients with osteoporosis were significantly lower than those in controls. By conditional regression analysis, we found that the IGF-1 rs2288377 and rs972936 gene polymorphisms were not associated with the risk of osteoporosis (P < 0.05). However, the CT+TT genotype of rs35767 and the AG+GG genotype of rs972936 were significantly associated with lower BMD levels in the femoral neck. Overall, our study suggests that IGF-1 rs2288377 and rs972936 gene polymorphisms do not influence the risk osteoporosis. PMID- 26600492 TI - Effect of progranulin (PGRN) on the proliferation and senescence of cervical cancer cells. AB - We investigated the effect of progranulin (PGRN) expression on the proliferation and senescence of cervical cancer cells. PGRN small interfering RNA (siRNA) was introduced into the SiHa and HeLa cell lines of human cervical carcinoma using liposome-mediated transfection. The expression levels of PGRN in each cell line after transfection of PGRN siRNA were detected by reverse transcription polymerase chain reaction (RT-PCR). Senescence in the cell lines was detected using the beta-galactosidase-staining test, and proliferation was detected by clone formation. The RT-PCR assay showed that the expression of PGRN in all of the cell lines transfected with PGRN siRNA markedly decreased. In the clone forming test, compared with the control group, the colony-forming ability in all cell lines decreased significantly after transfection with PGRN siRNA. The beta galactosidase-staining experiments showed that the phenomenon of cell aging in the PGRN interference group was more obvious than in the control group. After the cervical cancer cells had been transfected with PGRN siRNA, cell senescence was accelerated and clone-forming ability was markedly reduced. This suggests that PGRN can promote the proliferation of the cervical cancer cell line; proliferation of cervical cancer cells is achieved by inhibiting their senescence. PMID- 26600493 TI - Development of novel DNA markers for genetic analysis of grey hamsters by cross species amplification of microsatellites. AB - The grey hamster has been used in biomedical research for decades. However, effective molecular methods for evaluating the genetic structure of this species are lacking, which hinders its wider usage. In this study, we employed cross amplification of microsatellite loci of species within the same genus by polymerase chain reaction. Loci screened included 107 from the Mongolian gerbil (MG) and 60 from the Chinese hamster (CH); of these, 15 polymorphic loci were identified for the grey hamster. Of the 167 loci screened, 95 (56.9%) with clear bands on agarose gel were initially identified. After sequencing, 74 (77.9%) of these matched the criteria for microsatellite characteristics, including 41 from MG and 33 from CH. Lastly, 15 (20.3%) loci with more than two alleles for each locus were identified through capillary electrophoresis scanning. To justify the applicability of the 15 grey hamster loci, genetic indexes of grey hamsters were evaluated using 46 generations of outbred stock, established 20 years ago, from Xinjiang, China. Mean effective allele numbers and expected heterozygosity of stock were as low as, respectively, 1.2 and 0.14; these were 2.8 and 4.0 times inferior, respectively, to wild grey hamsters. This finding suggests that the genetic structure of the stock-bred population is too weak to resist artificial and natural selection, mutation and genetic drifting. In conclusion, we have developed de novo microsatellite markers for genetic analysis of the grey hamster, providing data and methodology for the enrichment of a genetic library for this species. PMID- 26600494 TI - Analysis of SNP (single nucleotide polymorphism) multiplex markers related to sudden cardiac death in Brazilian families. AB - Sudden cardiac death (SCD) is a major public health concern worldwide, and genetic analysis may be useful in identifying the cause of death as well as in determining the possible genetic risk factors for SCD. This study analyzed eight SNPs (single nucleotide polymorphisms) highly correlated with cardiac sudden death in samples (blood and bone) from six Brazilian families with a history of cardiovascular diseases. Individuals with no family history of cardiovascular diseases were recruited as controls. Y chromosomes and mtDNA haplogroups belonging to these subjects were verified as well. We found that SNP rs16857031 showed significant differences between the group with a family history of cardiovascular diseases and the control group. Furthermore, the data obtained were compatible with known frequencies of SNPs for the haplogroups in which the samples were classified. A possible hereditary factor was identified for SNP rs4725982 in one family. These preliminary results suggest that identification of certain SNPs could be used to assess risk factors for SCD. PMID- 26600495 TI - Exceptional material requirement for reproduction in mouse oocytes. AB - Limited information on oocytes and fertilization prevents the efficient therapy of patients with infertility. The most important reason for this lack of understanding is a deficiency in research dedicated to oocytes and fertilization. Currently, we are concerned with the role of nutrition in the process of oocyte development to better understand the relationship between nutrition and infertility. The aim of this study was to explore the relationship between some exceptional materials and infertility to elucidate the role of these materials in oocyte development. We used proteomic analysis to identify numerous nutrition related proteins in three developmental stages: the germinal vesicle stage, the metaphase II-arrested stage, and the fertilized oocyte-zygote stage. Specific proteins were abundantly expressed during the three stages. These proteins included astacin-like metalloendopeptidase, selenium-binding proteins, and other proteins involved in metabolic and signaling pathways. Other proteins were involved in the citrate cycle, the electron transport chain, the urea cycle, fatty acid metabolism, and the insulin signaling pathway. Almost all these proteins exhibited different expression levels in the three stages. The results of the present study provide a better understanding of the molecular mechanisms of early embryonic development and suggest new treatment methods for infertility. PMID- 26600496 TI - Effects of muscle fiber type on glycolytic potential and meat quality traits in different Tibetan pig muscles and their association with glycolysis-related gene expression. AB - The myosin heavy chain (MyHC) composition, glycolytic potential, mitochondrial content, and gene expression related to energy metabolism were analyzed in eight muscles from Tibetan pigs, to study how meat quality develops in different muscle tissues. The muscles were classified into three clusters, based on MyHC composition: masseter, trapezius, and latissimus dorsi as 'slow-oxidative-type'; psoas major and semimembranosus as 'intermediate-type'; and longissimus dorsi, obliquus externus abdominis, and semitendinosus as 'fast-glycolytic-type'. The 'slow-oxidative-type' muscles had the highest MyHC I and MyHC IIA content (P < 0.01); 'intermediate-type' muscles, the highest MyHC IIx content (P < 0.01); and 'fast-glycolytic-type' muscles, the highest MyHC IIb content (P < 0.01). The pH values measured in 'slow-oxidative-type' muscles were higher than those in the other clusters were; however, the color of 'fast-glycolytic-type' muscles was palest (P < 0.01). Mitochondrial content increased in the order: fast-glycolytic type < intermediate-type < slow-oxidative-type. In the 'slow-oxidative-type' muscles, the expression levels of genes related to ATP synthesis were higher, but were lower for those related to glycogen synthesis and glycolysis. Mitochondrial content was significantly positively correlated with MyHC I content, but negatively correlated with MyHC IIb content. MyHC I and mitochondrial content were both negatively correlated with glycolytic potential. Overall, muscles used frequently in exercise had a higher proportion of type I fibers. 'Slow-oxidative type' muscles, rich in type I fibers with higher mitochondrial and lower glycogen and glucose contents, had a higher ATP synthesis efficiency and lower glycolytic capacity, which contributed to their superior meat quality. PMID- 26600497 TI - Avian sarcoma and leukosis virus gag gene in the Anser anser domesticus genome. AB - Endogenous retroviruses are regarded as ideal genetic markers for evolutionary analyses. Birds were some of the initial vertebrates found to contain endogenous retroviruses. However, few studies have investigated the presence and distribution of endogenous retroviruses in goose. In this study, we detected the avian sarcoma and leukosis virus gag gene in the genomic DNA of 8 Chinese native breeds using polymerase chain reaction method. The results indicated that a 1.2 kb avian sarcoma and leukosis virus gag sequence was integrated into all 8 goose breeds. The mean genetic pairwise distance was 0.918% among the investigated geese. To the best of our knowledge, this is the first report demonstrating the presence of the endogenous retroviruses in the domestic goose genome. The genetic structure should be further examined in the domestic goose. PMID- 26600498 TI - A retrospective analysis of surgical treatment of mesh infection after repair of ventral hernia or defect. AB - This study aimed to summarize our experience in surgical treatment of mesh infection after repair of ventral hernia or defect. A retrospective analysis was conducted on clinical data of 22 patients who accepted surgical treatment of mesh infection after ventral hernia or defect repair. Included were 16 cases of infection after incisional hernia repair, 5 cases of infection after abdominal wall defect repair following abdominal wall tumor resection, and 1 case of infection with fistula caused by a parastomal hernia of an ileal neobladder repair with a prosthetic patch. All patients had received local dressing treatment for 2 to 24 months but were not healed. The affected mesh was removed successfully in all patients. Six patients had abdominal wall repair using the component separation technique; 4 patients were treated by strengthened repair with polypropylene mesh; 10 patients were repaired with human acellular dermal matrix; 1 patient received local dressing changes and vacuum sealing drain treatment without repair; and 1 patient received wound closure without strengthened repair. The postoperative hospital stay was 9-29 days (mean 16 days). After treatment, 19 patients recovered with primary wound healing and 3 patients recovered with secondary healing. All patients were followed up for 6-38 months (mean 26 months), and no ventral hernia or defect recurred except 1 case of lower abdominal bulge. Mesh infections after ventral hernia or defect repair are difficult to treat using prosthetic materials. For satisfactory results, surgery should be performed according to the specific condition of the individual. PMID- 26600499 TI - Vascular endothelial growth factor gene polymorphisms and psoriasis susceptibility: a meta-analysis. AB - The aim of this study was to explore whether vascular endothelial growth factor (VEGF) polymorphisms confer susceptibility to psoriasis. Meta-analyses were conducted to examine the associations between the +405 C/G, -460 C/T, -1154 A/G, and -2578 A/C polymorphisms of VEGF and psoriasis using allele contrast and recessive, dominant, and additive models. Seven studies on VEGF polymorphisms and psoriasis involving 1956 subjects (psoriasis patients 665, controls 1291) were included in this meta-analysis. We observed no association between psoriasis and the VEGF +405 C allele in all study subjects (odds ratio = 0.984, 95% confidence interval = 0.754-1.285, P = 0.906), but stratification by ethnicity indicated a significant association between the VEGF +405 C allele and psoriasis in Asians (odds ratio = 0.762, 95% confidence interval = 0.628-0.923, P = 0.005). In addition, we observed a significant association between the VEGF -460 C allele and psoriasis in Europeans (odds ratio = 0.807, 95% confidence interval = 0.672 0.968, P = 0.021). Meta-analyses of the -1154 A/G polymorphism also revealed a significant association with psoriasis in Europeans. However, the VEGF -2578 A/C polymorphism showed no association in all subjects or in Europeans or Asians. This meta-analysis suggests the VEGF +405 C/G polymorphism confers susceptibility to psoriasis in Asians, and that the -460 C/T and -1154 A/G polymorphisms confer susceptibility to psoriasis in Europeans. PMID- 26600500 TI - Protein extraction method for the proteomic study of Zymomonas mobilis during production of ethanol and levans. AB - Zymomonas mobilis has aroused considerable interest owing to its rapid metabolism and efficiency in producing ethanol and by-products such as levans, sorbitol, and gluconic acid from simple sugars. We performed a proteomic analysis of Z. mobilis UFPEDA241 to provide a global profile of regulatory proteins. The choice of the methods of extraction and cell lysis are fundamental steps and of great importance for the detection and identification of intra- and extracellular proteins of a proteome. Strains were subjected to protein extraction methods using three different reagents: TRIzol, lysis buffer, and phenol. The optimum method was taken to be the one that produced the greatest quantity and quality of proteins in one dimension for further analysis in two dimensions during the production of ethanol and levans over 72 h. The results showed that the greatest amount of protein was obtained by the phenol method (1.44 +/- 0.07 mg/mL), which was significantly different (P < 0.05) to the TRIzol (1.11 +/- 0.01 mg/mL), and lysis buffer (0.93 +/- 0.01 mg/mL) methods (both with P > 0.05). Fermentation at 20 degrees C produced the highest level of levans, and using two-dimensional electrophoresis and mass spectrometry it was possible to identify 34 differentially expressed spots. PMID- 26600501 TI - Physical and chemical characteristics of pitaya fruits at physiological maturity. AB - The aim of this study was to analyze the physical and chemical characteristics of the maturation process of pitaya fruit (Hylocereus undatus) to identify indicators that can be used to determine the point of physiological maturity and establish the optimal timing of physiological maturity for harvesting the fruit. A completely randomized experimental design was employed and four biological repeats were performed. Physiological maturity was assessed using various physical characteristics: longitudinal length (LL), equatorial diameter (ED), pericarp thickness (PeT), pulp thickness (PuT), fruit mass (FM), pulp mass (PuM), pericarp mass (PeM), pericarp percentage (%Pe), pulp percentage (%Pu), pulp/pericarp ratio (Pu/Pe), pericarp color index (CI), hue color angle (h degrees ), lightness index (L*), chroma (C*), blue-yellow variation (b*), and green-red variation (a*). Additionally, chemical characteristics such as soluble solid content (SS), titratable acidity (TA), SS/TA ratio, and pH were screened. The data were statistically analyzed by fitting regression models and computing Pearson's correlation coefficients (P < 0.05). Physiological maturity in pitaya fruits occurred between the 30th and 32nd days after anthesis, and this proved to be the optimal period for harvest. At this time, the fruit was completely red with high SS, and had the recommended values of TA, pH, and SS/TA ratio. During this period, ED, PuT, FM, PuM, %Pu, and Pu/Pe increased while PeT, PeM, and %Pe fell; these changes are considered desirable by producers and/or consumers. PuM was the variable that displayed more strong's association with other variables in the analysis. PMID- 26600502 TI - Segment-specific targeting via RNA interference mediates down-regulation of OPN expression in hepatocellular carcinoma cells. AB - Osteopontin (OPN) plays an important role in the metastasis and recurrence of tumors after resection of hepatocellular carcinoma (HCC). In this study, the down regulation effect on OPN expression in HCC cells of RNA interference (RNAi) molecules designed to target different segments of OPN was investigated to identify a more effective site for OPN knockdown. Specific small interfering RNAs (siRNAs A, B, and C) of OPN were synthesized and transfected into an HCC cell line (HEP-G2; representing the OPNi-A, OPNi-B, and OPNi-C groups). Fluorescent quantitative polymerase chain reaction and immunohistochemical methods were used to detect the mRNA and protein expression of OPN before and after RNAi. Results showed that after transfection, the fluorescence intensity of the OPNi-A group was greater than those of the OPNi-B and OPNi-C groups. After 48 h of transfection, the DeltaCT values of OPN mRNA expression in the OPNi-A-C groups increased from 8.31 +/- 1.58, 8.78 +/- 1.49, and 8.25 +/- 1.51 to 12.14 +/- 1.43, 10.22 +/- 1.97, and 10.48 +/- 1.88, respectively (P < 0.05), and the OPN protein levels (immunohistochemistry scores) decreased from 6.44 +/- 1.67, 5.43 +/- 2.05, and 5.45 +/- 2.52 to 2.84 +/- 1.52, 4.43 +/- 1.65, and 3.95 +/- 1.43 points, respectively. These results indicated that RNAi based on different segments of the OPN gene had different down-regulatory effects on OPN expression. Synthesis of targeted siRNA aimed at specific OPN segments might have important significance for dealing with the invasiveness and metastasis of HCC cells. PMID- 26600503 TI - Effect of luteolin on gene expression in mouse H22 hepatoma cells. AB - The purpose of our study was to observe the effects of luteolin on the expression of the genes ICAM-1, LFA-3, and PCNA in H22 hepatoma tissue. Sixty ICR (Institute of Cancer Research) mice with H22 hepatoma were randomly divided into five groups: a normal saline control group, low-, medium-, and high-dose luteolin groups, and a cyclophosphamide group. The mice were euthanized the day after administration withdrawal and subcutaneous tumor tissue was extracted. Quantitative fluorescence RT-PCR was used to detect the expression of ICAM-1, LFA 3, and PCNA in H22 hepatoma tissue in the mice. Luteolin was found to up-regulate the expression of ICAM-1 in H22 hepatoma tissue, of which the middle-dose group had the most obvious effect, showing a significant difference (P < 0.01) as compared to the normal saline group. Each dose group of luteolin significantly down-regulated the expression of LFA-3 in H22 hepatoma tissue, showing significant differences as compared to the saline control group (P < 0.01). The medium- and high-dose luteolin groups significantly reduced the expression of PCNA in H22 hepatoma tissue of ICR mice, where the effect of the high-dose group was the most obvious, and the difference between the two luteolin groups and the normal saline group was statistically significant (P < 0.01). Luteolin may inhibit tumor angiogenesis and tumor cell proliferation by down-regulation of LFA 3 and PCNA and up-regulation of ICAM-1 in tumor tissue of tumor-bearing mice, thereby achieving its anti-tumor effect. PMID- 26600504 TI - LC-MS/MS: a rapid and simple new method for the determination of carbapenem beta lactamases. AB - We investigated the application of liquid chromatography-tandem mass spectrometry (LC-MS/MS) for pan-drug-resistant Acinetobacter baumannii (PDR-AB) with carbapenem resistance. Eight strains were randomly selected from 84 clinical isolates of PDR-AB strains obtained by the Kirby-Bauer and agar dilution methods. An efflux pump inhibition test was used to screen for the efflux pump phenotype. An ethylenediaminetetraacetic acid (EDTA) synergy test was used to screen for the beta-lactamase phenotype, and a three-dimensional test was used to detect extended spectrum beta-lactamase (ESBL) and ampicillin C, KPC, and carbapenemase. ESBL genes were amplified by polymerase chain reaction and sequenced. Outer membrane proteins were extracted from a sensitive strain and the PDR-AB strains by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and subjected to LC MS/MS. Peptide mass fingerprinting data were retrieved, and proteins with differential expression were identified. Results of the efflux pump inhibition tests showed that the minimum inhibitory concentrations for meropenem were decreased in 4 of the 8 strains by at least 25% of the original value. The results of the EDTA synergy test were negative, and the modified Hodge's tests were positive for all strains. PCR and sequencing confirmed that seven, five, and all eight of the PDR-AB strains contained blaOXA-23, blaTEM-1, and KPC-2, respectively. OXA-23 and CsuC proteins were differentially expressed between the drug-resistant and -sensitive strains. Production of blaOXA-23 enzyme and pilus molecular chaperone to guide synthesis of CsuC protein may be involved in the resistance of A. baumannii to carbapenems. LC-MS/ MS provides a quick and easy method for carbapenemase detection. PMID- 26600505 TI - PPARalpha signal pathway gene expression is associated with fatty acid content in yak and cattle longissimus dorsi muscle. AB - Intramuscular fatty acid (FA) is related to meat qualities such as juiciness, tenderness, palatability, and shear force. PPARalpha plays an important role in lipid metabolism in the liver and skeletal muscle. This study investigated FA composition in yaks and cattle, in order to ascertain whether a correlation between PPARalpha signal pathway genes as candidate genes and meat FA composition in yaks and cattle exists. Statistical analyses revealed that levels of monounsaturated fatty acid (MUFA) and polyunsaturated fatty acid (PUFA) in yaks were significantly higher than those in cattle (P < 0.01), whereas saturated fatty acid (SFA) levels were significantly lower than those in cattle (P < 0.05). The mRNA expression levels of FABP4 (P < 0.05), SCP2 (P < 0.05), and APOA1 (P < 0.01) in yaks were significantly lower than those in cattle. However, LPL expression in yaks was significantly higher than that in cattle (P < 0.05). In yaks, the expression levels of FABP3 (P < 0.05) and LPL (P < 0.01) were negatively correlated with MUFA, and those of FABP4 and SCD were positively correlated with PUFA (P < 0.01). In cattle, the mRNA level of PLTP was positively correlated with SFA (P < 0.05), and LPL was positively correlated with MUFA (P < 0.05). These results suggest that these genes may participate in the regulation and control of intramuscular FA metabolism in yaks, so they could be used as candidate markers to improve yak meat quality. PMID- 26600506 TI - Presence of Mycobacterium leprae DNA and PGL-1 antigen in household contacts of leprosy patients from a hyperendemic area in Brazil. AB - Leprosy is a highly infectious disease endemic to underdeveloped countries. In Maranhao State, Northeastern Brazil, the hyperendemic rate of 56.11 cases/100,000 inhabitants increased the necessity of better understanding the epidemiological profile of this population, particularly regarding efficient methods for evaluating individuals residing with diagnosed patients to understand disease transmission and the risk of infection. In this study, we examined the percentage of contacts with positive indices for Mycobacterium leprae DNA and phenol glycolipid-1 antigen (PGL-1). PGL-1 was analyzed by an enzyme-linked immunosorbent assay, the ML-Flow test, and polymerase chain reaction of oral and nasal secretions of 808 leprosy contacts from Maranhao. PGL-1 was detected in 14.0% of patients and differed by operational classification of the index case (P < 0.05). Seropositive results of ML-Flow were 15.0% and identified individuals with and without Bacillus Calmette-Guerin vaccine scars. Molecular diagnosis detected M. leprae DNA in 5.6% of oral samples and 4.6% of nasal tissues, and 87% of subjects resided with high bacillary load patients. This study reinforces the efficacy of combining molecular and serological techniques to identify potential bacillus carriers in the asymptomatic stage of infection, such as in household contacts, highlighting the importance of these meth-ods for monitoring hyperendemic populations. PMID- 26600507 TI - Identification of the origin of marker chromosomes by two-color fluorescence in situ hybridization and polymerase chain reaction in azoospermic patients. AB - Y chromosomal microdeletions at the azoospermia factor locus and chromosome abnormalities have been implicated as the major causes of idiopathic male infertility. A marker chromosome is a structurally abnormal chromosome in which no part can be identified by cytogenetics. In this study, to identify the origin of the marker chromosomes and to perform a genetic diagnosis of patients with azoospermia, two-color fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR) techniques were carried out. The marker chromosomes for the two patients with azoospermia originated in the Y chromosome; it was ascertained that the karyotype of both patients was 46,X, ish del(Y)(q11)(DYZ3+, DXZ1-). The combination of two-color FISH and PCR techniques is an important method for the identification of the origin of marker chromosomes. Thus, genetic counseling and a clear genetic diagnosis of patients with azoospermia before intracytoplasmic sperm injection or other clinical managements are important. PMID- 26600508 TI - Quantitative trait locus analysis for kernel width using maize recombinant inbred lines. AB - Maize (Zea mays L.) kernel width is one of the most important traits that is related to yield and appearance. To understand its genetic mechanisms more clearly, a recombinant inbred line (RIL) segregation population consisting of 239 RILs was used for quantitative trait locus (QTL) mapping for kernel width. We found four QTLs on chromosomes 3 (one), 5 (two), and 10 (one). The QTLs were close to their adjacent markers, with a range of 0-23.8 cM, and explained 6.2 19.7% of the phenotypic variation. The three QTLs on chromosomes 3 and 5 had positive additive effects, and to a certain extent increased kernel width, whereas the one on chromosome 10 exhibited negative additive effects and decreased kernel width. These results can be used for gene cloning and marker assisted selection in maize-breeding programs. PMID- 26600509 TI - Correlation between polymorphisms of hypoxia-inducible factor-1alpha Pro582Ser and type 2 diabetic nephropathy. AB - We examined the correlation between gene polymorphisms in hypoxia-inducible factor-1alpha (HIF-1alpha) Pro582Ser and type 2 diabetic nephropathy (DN). A total of 244 subjects with type 2 diabetes were recruited. The 1285-bp locus polymorphism of HIF-1alpha exon was detected using polymerase chain reaction restriction fragment length polymorphism. C/T single nucleotide polymorphisms were detected at the site of 1285 bp of the HIF-1alpha exon, from a proline to a serine (Pro582Ser). The frequency of CT heterozygotes was significantly higher in DN patients than in diabetes patients (P < 0.05). Logistic regression analysis showed that high hemoglobin A1c and low high-density lipoprotein-cholesterol were risk factors for DN, and Pro582Ser was excluded in the equation. HIF-1alpha Pro582Ser single nucleotide polymorphisms may be correlated with type 2 DN, which needs further exploration. PMID- 26600510 TI - Cloning and characterization of a benzoic acid/salicylic acid carboxyl methyltransferase gene involved in floral scent production from lily (Lilium 'Yelloween'). AB - In lily flowers, the volatile ester methyl benzoate is one of the major and abundant floral scent compounds; however, knowledge regarding the biosynthesis of methyl benzoate remains unknown for Lilium. In this study, we isolated a benzoic acid/salicylic acid carboxyl methyltransferase (BSMT) gene, LiBSMT, from petals of Lilium 'Yelloween'. The gene has an open reading frame of 1083 base pairs (bp) and encodes a protein of 41.05 kDa. Sequence alignment and phylogenetic analyses of LiBSMT revealed 40-50% similarity with other known benzenoid carboxyl methyltransferases in other plant species, and revealed homology to BSMT of Oryza sativa. Heterologous expression of this gene in Escherichia coli yielded an enzyme responsible for catalyzing benzoic acid and salicylic acid to methyl benzoate and methyl salicylate, respectively. Quantitative real-time polymerase chain reaction analysis showed that LiBSMT was preferentially expressed in petals. Moreover, the expression of LiBSMT in petals was developmentally regulated. These expression patterns correlate well with the emission of methyl benzoate. Our results indicate that LiBSMT plays an important role in floral scent methyl benzoate production and emission in lily flowers. PMID- 26600511 TI - Genetic diversity and relationship analysis of Gossypium arboreum accessions. AB - Simple sequence repeat techniques were used to identify the genetic diversity of 101 Gossypium arboreum accessions collected from India, Vietnam, and the southwest of China (Guizhou, Guangxi, and Yunnan provinces). Twenty-six pairs of SSR primers produced a total of 103 polymorphic loci with an average of 3.96 polymorphic loci per primer. The average of the effective number of alleles, Nei's gene diversity, and Shannon's information index were 0.59, 0.2835, and 0.4361, respectively. The diversity varied among different geographic regions. The result of principal component analysis was consistent with that of unweighted pair group method with arithmetic mean clustering analysis. The 101 G. arboreum accessions were clustered into 2 groups. PMID- 26600512 TI - Genetic variability and phylogeny of the 5' long terminal repeat from Brazilian bovine leukemia virus. AB - We conducted a phylogenetic analysis of 22 strains of bovine leukemia virus obtained by polymerase chain reaction to amplify a 582-base pair fragment of the transcriptional regulatory region 5' long terminal repeat (LTR). Twenty-two samples of proviral DNA from peripheral blood mononuclear cells containing bovine leukemia virus from naturally infected bovine from 4 distinct geographic regions in Brazil were investigated. The products obtained by polymerase chain reaction were subjected to direct sequencing and sequence alignment. Fragments of 422 nucleotides were obtained, located between positions -118 and +303 base pairs of the 5'LTR. These fragments corresponded to 80% of the LTR region and included 56% of sub-region U3, 100% of R, and 82.5% of U5. Phylogenetic analysis of these sequences showed a high conservation degree in the 5'LTR region, with 5 well defined groups. However, a hotspot occurrence in the R-U5 region was also observed, which contained 40% of all nucleotide variability observed. PMID- 26600513 TI - Association of a hypoxia-inducible factor-3alpha gene polymorphism with superovulation traits in Changbaishan black cattle. AB - This study was designed to examine a single nucleotide polymorphism (SNP) in the HIF-3alpha gene in three hundred Changbaishan black cattle using PCR-restriction fragment length polymorphism to determine whether there is an association between this SNP and superovulation. The cloning and sequencing results indicate that the polymorphism is due to a point mutation at the 278-bp position in the HIF-3alpha gene, resulting in 3 genotypes (AA, AB, and BB). Association analysis indicated that the polymorphism has a significant effect on the number of unfertilized embryos (NUE) (P < 0.05) in the cattle. Cattle with genotype BB had a higher NUE than those with genotype AA, but the difference in NUE between AB and AA or BB was not significant. The polymorphism also has a highly significant effect on the number of degenerative embryos (NDE) and the number of total embryos (NTE) (P < 0.01). Genotype BB was associated with a higher NDE than AA, but the difference in NDE between AB and AA or BB was not significant. Genotype BB showed a higher NTE than AA or AB, but the difference in NTE between AA and AB was not significant. No significant conclusions could be drawn with respect to susceptibility to other traits. HIF-3alpha could serve as a useful biomarker for donor selection, superovulation improvement, and assisted fertility. PMID- 26600514 TI - Meloxicam increases intracellular accumulation of doxorubicin via downregulation of multidrug resistance-associated protein 1 (MRP1) in A549 cells. AB - It has been suggested that selected COX inhibitors can overcome multidrug resistance through the inhibition of ATP-binding cassette-transporter proteins thereby enhancing the inhibitory effect of doxorubicin on human tumor growth and promoting the actions of cytostatics. However, their effect on lung cancer and the molecular mechanisms involved in the overcoming of multidrug resistance are unclear. In the present study, the ability of meloxicam, a COX-2-specific inhibitor to enhance doxorubicin-mediated inhibition was investigated in human A549 lung cancer in vivo and in vitro. In order to unravel the molecular mechanisms involved in doxorubicin accumulation, we measured the levels of multidrug resistance-associated protein (MRP)-transporter protein activity and expression by western blotting, since this has been implicated in meloxicam action as well as in chemoresistance. We found that, in A549 cells, meloxicam could increase intracellular accumulation of doxorubicin, a substrate for MRP, through inhibition of cellular export. Western blot analysis indicated that meloxicam reduced the expression of MRP1 and MRP4. The results reported in the present study demonstrate for the first time that the specific COX-2 inhibitor meloxicam can increase the intracellular accumulation of doxorubicin and enhance doxorubicin-induced cytotoxicity in A549 cancer cells by reducing the expression of MRP1 and MRP4. PMID- 26600515 TI - Impact of common SNPs in VEGF gene on the susceptibility of osteosarcoma. AB - We conducted a case-control study to assess the role of vascular endothelial growth factor (VEGF) -634G/C, +936C/T, and +1612G/A genetic variations in the development of osteosarcoma in a Chinese population. This hospital-based case control study examined 130 patients with osteosarcoma and 130 age- and gender matched healthy controls from March 2011 and March 2013. Polymerase chain reaction-restriction fragment length polymorphism was applied to assess the VEGF 634G/C, +936C/T, and +1612G/A gene polymorphisms. Using conditional regression analysis, individuals carrying the TT genotype of VEGF +936C/T were found to be correlated with an elevated risk of osteosarcoma, with an adjusted odds ratio (95% confidence interval) of 2.70 (1.02-8.28). In conclusion, our study suggests that the TT genotype of VEGF +936C/T genetic variants is associated with an increased risk of osteosarcoma. PMID- 26600516 TI - Comparative characteristics of DNA polymorphisms of kappa-casein gene (CSN3) in the horse and donkey. AB - The aims of this study were to assess the genetic variability in the exon 1 of the kappa-casein gene in four Italian horse populations (Italian Saddle horse, Italian Trotter, Italian Heavy Draught horse, and Murgese horse) and in a sample of Martina Franca donkey by estimating genotype, allele and haplotype frequencies, as well as several population genetic indices. Genotyping of the selected polymorphisms was performed using the PCR-RFLP technique with two restriction enzymes: PstI and BseYI aimed to discover the presence of c.-66A>G and c.-36C>A polymorphism, respectively. Both these loci were found to be polymorphic in horses with some differences depending on the breed. No genetic variability was observed in Martina Franca donkey breed. In the equine species no selective pressure for milk purpose was performed, therefore the polymorphisms at milk protein loci were mainly considered as result of natural selection or as indirect consequence of selection oriented to increase body size or to improve conformation. From this point of view these two single nucleotide polymorphisms and particularly the c.-36C>A one could be useful instruments for population studies. PMID- 26600517 TI - Cloning and characterization of the SERK1 gene in triploid Pingyi Tiancha [Malus hupehensis (Pamp.) Rehd. var. pingyiensis Jiang] and a tetraploid hybrid strain. AB - This study aims to explore the roles of somatic embryogenesis receptor-like kinase (SERK) in Malus hupehensis (Pingyi Tiancha). The full-length sequences of SERK1 in triploid Pingyi Tiancha (3n) and a tetraploid hybrid strain 33# (4n) were cloned, sequenced, and designated as MhSERK1 and MhdSERK1, respectively. Multiple alignments of amino acid sequences were conducted to identify similarity between MhSERK1 and MhdSERK1 and SERK sequences in other species, and a neighbor joining phylogenetic tree was constructed to elucidate their phylogenetic relations. Expression levels of MhSERK1 and MhdSERK1 in different tissues and developmental stages were investigated using quantitative real-time PCR. The coding sequence lengths of MhSERK1 and MhdSERK1 were 1899 bp (encoding 632 amino acids) and 1881 bp (encoding 626 amino acids), respectively. Sequence analysis demonstrated that MhSERK1 and MhdSERK1 display high similarity to SERKs in other species, with a conserved intron/exon structure that is unique to members of the SERK family. Additionally, the phylogenetic tree showed that MhSERK1 and MhdSERK1 clustered with orange CitSERK (93%). Furthermore, MhSERK1 and MhdSERK1 were mainly expressed in the reproductive organs, in particular the ovary. Their expression levels were highest in young flowers and they differed among different tissues and organs. Our results suggest that MhSERK1 and MhdSERK1 are related to plant reproduction, and that MhSERK1 is related to apomixis in triploid Pingyi Tiancha. PMID- 26600518 TI - Functional divergence of BAK1 genes from Brassica rapa in regulating plant architecture. AB - BAK1 is a co-receptor of BRI1 in early signaling pathways mediated by brassinosteroids (BRs) and is thought to play a major role in plant growth and development. As the role of BAK1 has not yet been fully elucidated then further research is required to explore its potential for use in genetic modification to improve crops. In this study, three BAK1 genes from the amphidiploid species Brassica rapa were isolated and their kinase functions were predicted following DNA sequence analysis. A bioinformatic analysis revealed that two genes, BrBAK1-1 and BrBAK1-8, shared a conserved kinase domain and 5 tandem leucine-rich repeats (LRRs) that are characteristic of a BAK1 receptor for BR perception, whereas the third gene, BrBAK1-3, was deficient for a signal peptide, but had 4 leucine zippers and 3 leucine-rich repeats (LRRs) in an extracellular domain. All three BrBAK1 kinases localized on the cellular membrane. Ectopic expression of each BrBAK1 gene in BR-insensitive (bri1-5 mutant) Arabidopsis plants indicated that BrBAK1-1 and BrBAK1-8 were functional homologues of AtBAK1 based on the rescue of growth in the bri1-5 mutant. Overexpression of BrBAK1-3 caused a severe dwarf phenotype resembling the phenotype of null BRI1 alleles. The results here suggest there are significant differences among the three BrBAK1 kinases for their effects on plant architecture. This conclusion has important implications for genetic modification of B. rapa. PMID- 26600520 TI - Dynamic comparison of genetic diversity in a Small Tail Han sheep population using meta-analysis. AB - The aim of this research was to identify the dynamic diversity of Small Tail Han sheep in its main producing areas between different years, and provide a basis for a breeding and genetic resources conservation strategy. For this purpose, 15 microsatellites were genotyped for Small Tail Han Sheep sampled in 2014 from Heze, China, and a comparative analysis of these data with those from a previous study was undertaken using meta-analysis. The results reveal that inbreeding has caused a reduction in diversity of Small Tail Han Sheep from 2008 to 2014. Overall, our results are helpful in understanding the dynamic change in diversity, as well as providing information for a conservation strategy for this population. PMID- 26600519 TI - Association between polymorphisms of fat mass and obesity-associated gene and metabolic syndrome in Kazakh adults of Xinjiang, China. AB - The aim of this study was to assess the association between three FTO polymorphisms (rs9939609, rs8057044, and rs1421085) and metabolic syndrome (MS) related outcomes in the low-income, rural, nomadic minority Khazakh population in far western China. A total of 489 subjects (245 MS patients, 244 controls) were included in the study and DNA samples were genotyped for the three polymorphisms by matrix-assisted laser desorption/ionization time of flight mass spectrometry. The frequencies of the rs1421085 and rs9939609 genotypes and alleles did not differ significantly between MS patients and control, while the frequencies of rs8057044 G alleles and GG genotypes were higher in MS patients (P < 0.05) than in control subjects (G: 61.16 vs 53.53%, GG: 39.07 vs 29.05%) and the frequencies of rs8057044 A genotypes and alleles were lower (P < 0.05) in MS patients compared with controls (AA: 17.36 vs 21.99%, A: 38.84 vs 46.47%). Risk analysis of the rs8057044 polymorphism revealed individuals with GA and GG genotypes to have 1.112 and 1.731 times higher risks of developing MS than those with the AA genotype, respectively, while the G allele was found to be associated with a 1.367 times higher risk of developing MS compared with the A allele. These apparent correlations, however, did not hold true when adjusted for BMI. Weight, WC, HC, and BMI differed significantly between rs8057044 GG and AA+GA genotypes (P < 0.05). PMID- 26600522 TI - Variability with altitude of major histocompatibility complex-related microsatellite loci in goats from Southwest China. AB - We aimed to use microsatellite BM1258 loci of the major histocompatibility complex (MHC) as an indicator of the influence of genetic diversity of immunity in goats (Dazu Black, Hechuan White, Meigu, and Tibetan goat). In total, 132 animals comprising 50 Dazu Black goats, 24 Hechuan White goats, 34 Meigu goats, and 24 Tibetan goats were examined. Collectively, 18 different alleles and 42 genotypes were found. The overall observed levels of heterozygosity showed large divergence from the expected levels in the four breeds, and an increase in the mean number of alleles of BM1258 accompanied decreasing altitude of the livestock's habitat. Our results indicate that low-altitude regions or plains were more conducive to genetic material exchange and gene flow between different populations. In addition, it seems that the breeds from low-altitude regions were less susceptible to problems introduced by commercial animals. PMID- 26600521 TI - Prenatal diagnosis of Chinese families with phenylketonuria. AB - The aim of this study is to investigate the ability to prenatally diagnose phenylketonuria (PKU) by using phenylalanine hydroxylase (PAH) gene mutation analysis combined with short tandem repeat (STR) linkage analysis in 118 fetuses from 112 Chinese families. Genomic DNA was extracted from the peripheral blood from members of 112 families and the exons and exon-intron boundaries of the PAH gene were amplified by PCR. PCR products were analyzed by bi-directional Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). The three variable number of tandem repeat (VNTR) markers PAH-1, PAH-26, PAH-32 were used in the prenatal diagnosis for the PKU families. We identified a spectrum of 63 different mutations, including 61 point mutations and indels, two large exon deletion mutations, and five novel mutations. A substantial proportion of mutant alleles were accounted for by p.R243Q (15.62%), EX6-96AG (9.82%), p.V399V (7.59%), p.Y356X (6.70%), and p.R413P (5.36%). The same mutations were identified in 31 prenatally genotyped fetuses. We identified 58 fetuses that carried only one mutant allele and 29 fetuses that carried no mutations of PAH and were presumed normal. PAH gene mutation analysis combined with STR linkage analysis can provide rapid and accurate prenatal diagnosis for PKU families. PMID- 26600523 TI - Complete mitochondrial genome and codon usage of the Nepalese whiskered bat Myotis muricola (Vespertilionidae). AB - We sequenced and characterized the complete mitogenome of the Nepalese whiskered bat Myotis muricola (Vespertilionidae) to provide more data for comparative mitogenomics and codon usage in the genus Myotis (Vespertilionidae). The mitogenome of M. muricola is a circular molecule of 17,224 bp, consisting of a control region and a conserved set of 37 genes containing 13 protein-coding genes (PCGs), 22 tRNA genes, and two rRNA genes (12S rRNA and 16S rRNA). The mitogenome of M. muricola is AT-biased, with a nucleotide composition of 33.6% A, 29.7% T, 23.3% C, and 13.4% G. The total length of the 13 mitochondrial PCGs, excluding stop codons, is 11,376 bp, or 3792 amino acids. The relative synonymous codon usage (RSCU) of codons ending in A/T was generally higher than that for codons ending in G/C. The most frequently used codons are CTA(Leu) and CGA(Arg), with RSCU values greater than 2.0. The most rarely used codons, all terminating in G, are TCG(Ser), CCG(Pro), GCG(Ala), AAG(Lys), TGG(Try), CGG(Arg), and ACG(Thr), with RSCU values below 0.2. TCG(Ser) occurs only five times, and has the lowest RSCU value (0.091). These results are valuable for a better understanding of the molecular evolution of mitogenomes in the genus Myotis. PMID- 26600524 TI - Detection and sequence analysis of the DNA repair gene RAD51 in the Korean spider Callobius koreanus (Amaurobiidae). AB - We identified a partial sequence (483 bp) of the RAD51 gene from the Korean spider Callobius koreanus. Sequence variation was found at one position during alignment with the human RAD51 gene sequence. This partial sequence included the region corresponding to exon 4 in the human RAD51 gene, which encodes 39 amino acids. These results show that the RAD51 gene is highly conserved between human and spiders. PMID- 26600525 TI - Immunohistochemical expression of nestin in rhabdomyosarcoma: implications for clinicopathology and patient outcome. AB - Rhabdomyosarcoma (RMS) is a highly malignant cancer. Over the last two decades, prognosis for RMS patients has significantly improved, with the exception of those in the high-risk group. In order to identify new prognostic factors, we investigated the expression of nestin in RMS cells and its correlation with clinicopathological features and patient outcome. The analysis of overall survival for all patients (N = 30) revealed 1-, 2-, 3-, 4-, and 5-year survival rates of 93.3, 83.3, 66.7, 63.3, and 63.3%, respectively. Nestin overexpression significantly correlated with survival (P = 0.044). Survival of patients with <= 50% nestin-positive cells was 90, 70, and 40% after 1, 2, and 3 years, respectively, and remained unchanged until the end of the investigation period. The study group composed of patients exhibiting nestin expression in >50% of cells showed 1-, 2-, 3-, and 4-year survival rates of 95, 90, 80, and 75%, respectively, remaining stable at 75% for the fifth year of observation. A nestin positive expression rate lower than 50% was observed more frequently in older patients (43.60 +/- 27.58 years; P = 0.028). In addition, higher rates of nestin expression were observed in most embryonal RMS specimens and low-grade tumors, in early stages of the disease, and among younger patients. Our results lead us to propose nestin as possible positive prognostic factor in RMS. PMID- 26600526 TI - Molecular analysis of patients suspected of Fragile X Syndrome. AB - The aim of this study was to validate the molecular genetic diagnosis of patients suspected of Fragile X Syndrome (FXS) in the Laboratory of Human Cytogenetics and Molecular Genetics (LaGene) of the Department of Health of the State of Goias, using polymerase chain reaction (PCR). Thirty-five patients referred by public health doctors to LaGene, indicating clinical diagnosis of FXS, were selected for this study. Two PCR analyses were performed using different primers, one for screening (PCR-T) and one for the detection of the pre-mutation (PCR-P). The products of both PCRs were subjected to polyacrylamide gel electrophoresis and then coloring. The visualization of amplicons was performed with the aid of an ultraviolet transilluminator. The diagnosis was confirmed in 88% of patients with PCR-T and 100% with PCR-P. The primer used in PCR-P was found to be more sensitive and specific, allowing to identify the mutation in the samples, generating a more conclusive case for FXS, noting that the PCR-T is also required for the pre-classification of patients. Generally, the PCR technique is cheaper and easier to handle; therefore, we suggest the implementation of PCR in the genetics laboratory of the State of Goias (LaGene) for the diagnosis of FXS. PMID- 26600527 TI - Lack of association between the hOGG1 gene Ser326Cys polymorphism and gastric cancer risk: evidence from a case-control study and a meta-analysis. AB - The association between the human 8-oxoguanine glycosylase 1 (hOGG1) gene Ser326Cys polymorphism (rs1052133) and gastric cancer has been widely evaluated, yet a definitive answer to whether this association exists is lacking. We first conducted a case-control study to assess this association in a large Han Chinese population, and then performed a meta-analysis to further address this issue. This case-control study involved 448 patients clinically diagnosed with gastric cancer and 372 cancer-free control individuals from China. Genotyping was conducted using the polymerase chain reaction-ligase detection reaction method. Meta-analysis was performed by the STATA software. Data and study quality were assessed in duplicate. Our case-control association study indicated that there were no significant differences in the genotype and allele distributions of the Ser326Cys polymorphism between gastric cancer patients and controls (P = 0.8026 for genotype, and P = 0.5857 for allele), consistent with the results of the subsequent meta-analysis involving 2745 patients and 4588 controls under both allelic [odds ratio (OR) = 1.02; 95% confidence interval (CI) = 0.91-1.14; P = 0.739] and dominant (OR = 0.97; 95%CI = 0.78-1.21; P = 0.803) models. Further subgroup analyses by ethnicity, source of controls, and sample size also did not detect any positive associations in this meta-analysis. Overall, our study in the Han Chinese population, along with the meta-analysis, failed to confirm the association of the hOGG1 gene Ser326Cys polymorphism with gastric cancer risk, even across different ethnic populations. PMID- 26600528 TI - Effect of ABCE1-silencing gene, transfected by electrotransfer, on the proliferation, invasion, and migration of human thyroid carcinoma SW579 cells. AB - We investigated the effect of an ABCE1-silencing gene on the proliferation, invasion, and migration of human thyroid carcinoma SW579 cells. We designed and synthesized targeted ABCE1-siRNA sequences and a negative control sequence (NC siRNA), and transfected them into human thyroid cancer SW579 cells by electrotransfer to obtain ABCE1-SW579 and NC-siRNA-SW579 cells (siRNA is small interfering RNA). Through reverse transcription polymerase chain reaction and western blotting analysis, ABCE1 mRNA and protein expression levels in the electrotransferred cells were detected, and flow cytometry was used to detect cell cycle and apoptosis. The cell counting kit-8 (CCK-8) proliferation assay, the scratch healing assay, and the cell invasion assay were used to measure cell proliferation, migration, and invasion capabilities, respectively. Compared with NC-siRNA-SW579 and Ctrl-SW579 groups, ABCE1 mRNA and protein expression levels in the ABCE1-SW579 cells were significantly reduced. The growth rate of ABCE1-SW579 cells was significantly inhibited, the cell cycle was arrested in the G0/G1 phase, and the number of cells in the S phase was reduced. Compared with the Ctrl SW579 group, the cell apoptosis rate in the ABCE1-SW579 group was significantly higher (P < 0.01), and proliferation, migration, and invasion were significantly reduced (P < 0.05). Expression of the ABCE1-silencing gene, transfected by electrotransfer, could inhibit the proliferation, invasion, and migration of thyroid cancer cells. PMID- 26600529 TI - Mutation analysis of four Chinese families with pure hereditary spastic paraplegia: pseudo- X-linked dominant inheritance and male lethality due to a novel ATL1 mutation. AB - We studied four Chinese families with pure hereditary spastic paraplegia (HSP) to investigate the clinical features and associated genetic mutations. Linkage analysis was performed for all families to map the disease locus onto autosomal chromosomes, and related loci involved in HSP on the X chromosome were also examined. Polymerase chain reaction (PCR) sequencing was used to detect gene mutations. To confirm the influence of a splice-site mutation on mRNA, we used reverse transcription-PCR and direct sequencing. Linkage analysis and ATL1 gene sequencing of amniocytes were performed for prenatal genetic diagnosis. One missense variant (c.1517T>A) and a splice-site mutation (c.1245+1G>A) in SPAST, and two missense variants (c.715C>T, c.1204T>G) in ATL1 were identified. The c.1245+1G>A mutation caused a deletion of exon 9 in the SPAST gene. Prenatal genetic diagnosis showed that fetus did not carry the ALT1 c.1204T>G mutation. Follow-up was maintained for 5 years, and the negative result was confirmed by evidence of a healthy growing boy. We identified two novel mutations and two previously reported mutations in SPAST and ATL1, respectively. The family with the ATL1 c.1204T>G mutation exhibited male-lethality, female infancy-onset, and pseudo- X-linked dominant transmission, which had never been previously reported for HSP. Characteristic facial features were also noticed. The boy on whom prenatal gene diagnosis was performed is healthy and without unusual facies, suggesting that the c.1204T>G mutation might be related to these features. The results extend the genetic spectrum of HSP and suggest that linkage analysis remains a powerful tool in gene discovery studies. PMID- 26600531 TI - Isolation and characterization of microsatellite loci in hybrid giant tiger grouper. AB - The hybrid giant tiger grouper is a fish that has considerable commercial value and has become increasingly important for aquaculture in South East Asia since 2008. In order to prevent any reduction in genetic diversity in hybrid grouper as a result of aquaculture, we have identified 21 microsatellite markers that can be used to estimate genetic variation in the fish population. The number of alleles at polymorphic microsatellite loci ranged from 2 to 7, and observed and expected heterozygosities varied from 0.0323 to 0.9643 and 0.0921 to 0.7174, respectively. Polymorphism information content values ranged from 0.088 to 0.737. Nineteen of the 21 loci were in Hardy-Weinberg equilibrium (P > 0.005) after application of the Bonferroni correction (k = 10), the exceptions being ZZLD35 (P < 0.005) and ZZLD36 (P < 0.001). No linkage disequilibrium was detected. These 21 microsatellite markers are potentially of great value for analyzing genetic diversity to provide essential information for sustainable management of these fish. PMID- 26600530 TI - Cloning and prokaryotic expression of the porcine lipasin gene. AB - Lipasin has recently been demonstrated to be involved in lipid metabolism. In this study, two specific primers were used to amplify the lipasin open reading frame from porcine liver tissue. The polymerase chain reaction product was cloned to a pGEM(r)-T Easy Vector, digested by SalI and NotI, and sequenced. The lipasin fragment was then cloned to a pET21(b) vector and digested by the same restriction enzyme. The recombinant plasmid was transferred to Escherichia coli (BL21), and the lipasin protein was induced with isopropyl-beta-D thiogalactopyranoside. The protein obtained was identified by sodium dodecyl sulfate polyacrylamide gel electrophoresis and western blotting. A pET-lipasin prokaryotic recombinant expression vector was successfully constructed, and a 25.2-kDa protein was obtained. This study provides a basis for further research on the biological function of porcine lipasin. PMID- 26600532 TI - Investigations on the genomic diversity of OXA from isolated Acinetobacter baumannii. AB - We distinguished the four OXA-type carbapenemase subgroup alleles present in 120 strains of Acinetobacter baumannii by using polymerase chain reaction (PCR) and investigated the distributions of the OXA subgroups in clinically isolated samples. Amplification of the OXA genes blaOXA-23, blaOXA-24, blaOXA-51, and blaOXA-58 was performed by multiplex PCR. Antibiotics susceptibility test was conducted for determine the sensitivity of the A. baumannii to clinical common used antibiotics by Kirby-Bauer method. Results revealed that 46 (51.69%) of the samples were positive for only the blaOXA51 gene and 41 (46.07%) were positive for both the blaOXA51 and blaOXA58 genes in the 89 isolates of A. baumannii. Among these, 45 were carbapenem-resistant and 44 carbapenem-sensitive. Strains containing either blaOXA51 or blaOXA58 showed resistance or sensitivity to carbapenems, respectively. A. baumannii isolated from intensive care units showed significantly higher resistance rate to Cefepime, Piperacillin-tazobactam, Amikacin, Ceftazidime, Cefotaxime, Sulfamethoxazole-trimethoprim, and Gentamicin than those isolated from other departments (P < 0.05). In conclusion, we found that the presence of blaOXA-51 and blaOXA-58 appears to convey a mechanism of resistance or sensitivity to carbapenems, respectively, in A. baumannii clinical isolates. PMID- 26600533 TI - Glyphosate biodegradation and potential soil bioremediation by Bacillus subtilis strain Bs-15. AB - Glyphosate and glyphosate-containing herbicides have an adverse effect on mammals, humans, and soil microbial ecosystems. Therefore, it is important to develop methods for enhancing glyphosate degradation in soil through bioremediation. We investigated the potential of glyphosate degradation and bioremediation in soil by Bacillus subtilis Bs-15. Bs-15 grew well at high concentrations of glyphosate; the maximum concentration tolerated by Bs-15 reached 40,000 mg/L. The optimal conditions for bacterial growth and glyphosate degradation were less than 10,000 mg/L glyphosate, with a temperature of 35 degrees C and a pH of 8.0. Optimal fermentation occurred at 180 rpm for 60 h with an inoculum ratio of 4%. Bs-15 degraded 17.65% (12 h) to 66.97% (96 h) of glyphosate in sterile soil and 19.01% (12 h) to 71.57% (96 h) in unsterilized soil. Using a BIOLOG ECO plate test, we observed no significant difference in average well color development values between the soil inoculated with Bs-15 and the control soil before 72 h, although there was a significant difference (P < 0.01) after 72 h. In the presence of Bs-15, the 5 functional diversity indices (Shannon index, Shannon uniformity, Simpson index, McIntosh index, and McIntosh uniformity) were greater (P < 0.01) compared with the control soil. These results indicate that Bs-15 could be used to alleviate contamination from glyphosate containing herbicides, increasing the microbial functional diversity in glyphosate-contaminated soils and thus enhancing the bioremediation of glyphosate contaminated soils. PMID- 26600534 TI - VKORC1 rs2359612 and rs9923231 polymorphisms correlate with high risks of cardiovascular and cerebrovascular diseases. AB - We aimed to confirm the correlations between rs2359612 and rs9923231 single nucleotide polymorphisms (SNPs) in the vitamin K epoxide reductase complex subunit 1 (VKORC1) gene and the risk of cardiovascular and cerebrovascular diseases (CCVDs) using meta-analysis. Electronic databases were exhaustively searched for relevant case-control studies by employing stringent inclusion and exclusion criteria. Manual retrieval was also conducted to obtain additional pertinent literature. The STATA statistical software was employed for the process of evidence synthesis. The initial literature search broadly identified 225 studies relevant to our topic of interest, and after multiple rounds of screening, 10 clinical case-control studies met the final inclusion criteria and were selected for this meta-analysis. The selected studies represented a combined total of 7329 patients with CCVD and 7951 healthy controls. Our meta-analysis demonstrated that the VKORC1 rs2359612 and rs9923231 SNPs were closely associated with high risk for CCVD (rs2359612: allelic: OR = 1.23, 95%CI = 1.00- 1.50, P = 0.047; dominant: OR = 1.32, 95%CI = 1.19-1.46, P < 0.001; rs9923231: allelic: OR = 0.74, 95%CI = 0.63-0.87, P < 0.001; dominant: OR = 0.67, 95%CI = 0.55-0.82, P < 0.001). Our meta-analysis provides strong evidence that two SNPs in the VKORC1 gene, rs2359612 and rs9923231, contribute to the risk of CCVD. PMID- 26600535 TI - Association between MYC rs9642880[T] allele and bladder cancer risk: a meta analysis. AB - A single nucleotide polymorphism of MYC rs9642880 (G>T) at the 8q24.1 locus is thought to be associated with bladder cancer risk based on the results of genome wide association studies, but the results remain inconclusive. To assess the association between rs9642880[T] allele and bladder cancer risk, we performed this meta-analysis including 18 case-control studies and involving 23,084 cases and 97,164 controls. Electronic searches for publications were conducted to determine the association between this variant and prostate cancer in several databases. The last search update was August 4, 2014. We used odds ratios and 95%CIs to evaluate the strength of the associations. The overall results suggested that the rs9642880[T] allele was associated with bladder cancer susceptibility (T vs G, odds ratio = 1.18, 95%CI = 1.14-1.22). In subgroup analysis by ethnicity and source of controls, the risk remained significant. The present meta-analysis suggests that the MYC rs9642880[T] allele is significantly associated with bladder cancer risk. PMID- 26600536 TI - Integrity of prokaryotic mRNA isolated from complex samples for in vivo bacterial transcriptome analysis. AB - Even though several in vitro studies have focused on bacterial biology, the extent of such knowledge is not complete when considering an actual infection. As culture-independent microbiology methods such as high-throughput sequencing became available, important aspects of host-bacterium interactions will be elucidated. Based on microbiological relevance, we considered Bacteroides fragilis in a murine experimental infection as a model system to evaluate the in vivo bacterial transcriptome in host exudates. A disproportionate number of reads belonging to the host genome were retrieved in the first round of pyrosequencing, even after depletion of ribosomal RNA; the average number of reads related to the eukaryotic genome was 71.924-67.7%, whereas prokaryotic reads represented 34.338 32.3% in host exudates. Thus, different treatments were used to improve the prokaryotic RNA yield: i) centrifugation; ii) ultrasonic treatment; and iii) ultrasonic treatment followed by centrifugation. The latter treatment was found to be the most efficient in generating bacterial yields, as it resulted in a higher number of Bacteroides cells. However, the RNA extracted after this treatment was not of sufficient quality to be used in cDNA synthesis. Our results suggest that the methodology routinely used for RNA extraction in transcriptional analysis is not appropriate for in vivo studies in complex samples. Furthermore, the most efficient treatment for generating good bacterial cell yields was not suitable to retrieve high-quality RNA. Therefore, as an alternative methodological approach to enable in vivo studies on host-bacterium interactions, we advise increasing the sequencing depth despite the high costs. PMID- 26600537 TI - Serum levels of S-100beta correlate with the clinical status and severity of hypoxic-ischemic encephalopathy in neonates. AB - The clinical significance of serum S-100beta levels in neonates with hypoxic ischemic encephalopathy (HIE), as a reference index to assess HIE severity, was evaluated in this study. On the basis of our strict inclusion and exclusion criteria, relevant high-quality case-control studies reporting the association between HIE and S-100beta protein were selected from electronic database searches. The STATA version 12.0 software was used for the statistical analyses. The database search initially retrieved 93 studies (37 in English and 56 in Chinese), and following a multistep screening process, 13 high-quality studies were eventually included in our meta-analysis. The 13 case-control studies included a total of 646 HIE neonates and 381 healthy controls. The results of this meta-analysis revealed that serum S-100beta levels in mild, moderate, and severe HIE neonates were significantly higher than those in healthy controls, and the differences were statistically significant. Importantly, the serum S-100beta levels increased incrementally with HIE severity. Our results support the hypothesis that S-100beta is an important biological indicator of HIE and serum S 100beta levels can be used as a reference index to assess HIE severity. PMID- 26600538 TI - Expression profile of the GA733 gene family in colorectal cancer: correlation with clinicopathological parameters. AB - GA733-1/-2/-3 genes have been detected in various types of cancer, although their role has not been fully clarified. GA733-2 and GA733-1 have been correlated with lymph node metastases in laryngeal cancer and liver metastases, respectively. Only a few studies have elucidated the mechanisms regulating GA733-1/-2 expression and their effect on colorectal cancer. Therefore, the expression pattern and the role of the aforementioned molecules in colorectal carcinogenesis were evaluated in this study. Tissue samples were obtained from 40 patients with colorectal cancer with no liver metastases. GA733-1/-2 mRNA levels were evaluated by quantitative real-time polymerase chain reaction. GA733-1/-2 gene expression in noncancerous/cancerous tissues was also correlated with clinicopathological parameters. The GA733-1 mRNA levels were very low; however, the GA733-1 mRNA transcripts were higher in cancerous tissues than in normal tissues (median ratio, 0.004391/0.00093; range, 0.000001- 0.025139/0.000001-0.007761), respectively (P = 0.012). GA733-2 gene expression was higher in noncancerous tissues than in cancerous tissues (median ratio 273.31/115.64; range, 65.24 1,486.41/11.58-1,189.14; P = 0.0000195). Lower GA733-2 expression in cancer tissues appeared to correlate with lymph node metastases (P < 0.05). GA733-1 gene expression was significantly higher in cancerous samples; conversely, the GA733-2 mRNA levels were higher in noncancerous tissues, and were significantly correlated with lymph node perforation in colorectal cancer (P < 0.05). Therefore, GA733-1/-2 mRNA expression levels appear to be a potential predictive marker of tumorigenesis. PMID- 26600539 TI - KDR gene silencing inhibits proliferation of A549 cells and enhances their sensitivity to docetaxel. AB - We investigated the effects of kinase-domain insert containing receptor (KDR) gene silencing on the proliferation of A549 cells and their sensitivity to docetaxel. After designing and synthesizing the KDR siRNA sequence, the sequence was transfected into A549 cells using Lipofectamine 2000. The expression of KDR mRNA and protein after KDR gene silencing was detected by reverse transcription polymerase chain reaction and western blotting; A549 cell cycle was detected by flow cytometry. An MTT assay and colony formation was performed to determine the sensitivity of A549 cells to docetaxel after KDR gene silencing. After 48-h KDR gene silencing, KDR gene and protein expression significantly decreased (P < 0.05). A549 cell cycle was significantly arrested in G0/G1 phase, and the number of cells in S phase was reduced; the difference was statistically significant (P < 0.05) in the KDR gene silencing group, sensitivity of A549 cells to docetaxel showed a significant enhancement (P < 0.05). KDR siRNA can significantly silence KDR gene and protein expression in A549 cells, inhibit the proliferation of A549 cells, and enhance their sensitivity to docetaxel. PMID- 26600540 TI - Biological changes of Enterococcus faecalis in the viable but nonculturable state. AB - Enterococcus faecalis may enter a viable but nonculturable (VBNC) state under adverse conditions. E. faecalis, the major bacterial species present in failed root canal treatments, is thought to survive after endodontic treatment by entering a VBNC state. In this study, we characterized the VBNC state of E. faecalis. We designed 3 different protocols to successfully induce the VBNC state. Approximately one-third of bacteria entered a VBNC state after 15-30 days, and all remained viable for at least 2 months. The morphology, glycometabolism, and adhesion capabilities of VBNC cells differed from those of E. faecalis during the exponential growth phase. Specifically, VBNC E. faecalis cells could not decompose lactose, D-mannitol, or D-sorbitol, although they were able to metabolize sucrose. Transmission electron microscopy showed that the morphology of the VBNC E. faecalis cells changed significantly; the cytoplasmic matrix was unevenly condensed and the overall morphology of the cells became irregular, but the cell membranes remained intact. Although the adhesion ability of the bacteria decreased, VBNC E. faecalis could still adhere to collagen fiber type I and tooth dentine. The persistence of this adhesion ability may be important in the virulence of VBNC E. faecalis. PMID- 26600541 TI - Single nucleotide polymorphism screening, molecular characterization, and evolutionary aspects of chicken Piwi genes. AB - The P-element-induced wimpy testis (Piwi) gene is involved in germline stem cell self-renewal, meiosis, RNA silencing, and transcriptional regulation. Piwi genes are relatively well conserved in many species, but their function in poultry species is unclear. In this study, Piwi genes were sequenced using a target sequence capture assay in quail and 28 breeds of chicken. Single nucleotide polymorphisms (SNPs) and evolutionary aspects of these chicken breeds were then analyzed. We found that SNP sites existed mainly in the introns of a few chicken breeds, and we selected an SNP on intron 4 for further verification by Sanger sequencing, the results of which were similar to those obtained by the target capture sequencing assay. The evolutionary analysis revealed that there were more mutations in the Chahua and Leghorn breeds than in the other breeds, and that the phylogenetic tree was divided into four main categories that suggested that Piwi is evolutionarily conserved, and mutations in the introns might be associated with gametogenesis. The screened SNPs can be used as candidate markers for Piwi, and our results provide basic information for the further study of Piwi function in poultry. PMID- 26600542 TI - High MMP-1, MMP-2, and MMP-9 protein levels in osteoarthritis. AB - Our study examined the relationship between the expression of matrix metalloproteinases (MMP)-1, MMP-2, and MMP-9 proteins and the pathogenesis of osteoarthritis (OA). We employed rigorous inclusion and exclusion criteria in computer-based bibliographic databases to extract published studies relevant to this investigation. The STATA 12.0 software was used for the statistical analyses. A total of 1408 studies were initially searched, and 10 studies with 458 OA patients and 295 healthy controls were included in this meta-analysis. The meta-analysis results suggested that the protein levels of MMP-1, MMP-2, and MMP 9 were higher in patients with OA than those in the control group. A subgroup analysis according to ethnicity showed that the protein levels of MMP-1 and MMP-2 were higher in Asian patients with OA than in controls. Caucasians showed no statistically significant differences in protein expression of MMP-1 and MMP-2 between the OA patient group and the control group. Interestingly, the protein levels of MMP-9 in patients with OA were higher than those in the control group in both Asians and Caucasians. A sample-source analysis suggested that the serum levels of MMP-2 and MMP-9 proteins were higher in patients with OA than in controls, while MMP-1 and MMP-9 protein expressions were higher in the synovial joint fluid of patients with OA than in controls. In conclusion, our meta analysis results suggested that the increased expression of MMP-1, MMP-2, and MMP 9 proteins might be associated with the pathogenesis of OA. PMID- 26600543 TI - Association between ADSL, GARS-AIRS-GART, DGAT1, and DECR1 expression levels and pork meat quality traits. AB - In this study, meat quality traits were compared between Chinese lard- and European lean-type pigs. The association between expression of four genes (ADSL, GARS-AIRS-GART, DGAT1, and DECR1) and meat quality traits was also investigated. Meat quality traits were found to differ significantly between pig breeds. Meat color parameter values (a* and b*) and intramuscular fat content in Anqingliubai were significantly higher than those in Landrace (P < 0.01). Meat pH at 1 and 24 h following slaughter was significantly higher in Landrace than in Wei pigs, and meat inosine monophosphate (IMP) content was significantly higher in Landrace than in Wei and Anqingliubai pigs (both P < 0.01). Expression levels of ADSL, GARS-AIRS-GART, and DGAT1 were higher in longissimus lumborum muscle than in heart or liver tissues. ADSL and GARS-AIRS-GART expression levels were correlated with meat IMP content and pH levels. The results of this study will contribute to the understanding of meat quality traits in Chinese lard- and European lean-type pigs. PMID- 26600544 TI - Meta-analysis of the relationship between XRCC3 T241M polymorphism and colorectal cancer susceptibility. AB - Numerous studies have evaluated the relationship between the T241M polymorphism of the X-ray repair cross-complementing group 3 (XRCC3) gene and colorectal cancer (CRC) risk. However, the specific relationship remains controversial. We conducted meta-analysis to investigate the relationship between the XRCC3 T241M polymorphism and CRC risk. The PubMed and Embase databases were searched for relevant studies investigating the relationship between the XRCC3 T241M polymorphism and CRC risk. The odds ratio (OR) and 95% confidence interval (CI) were used to assess the possible relationship. Thirteen individual case-control studies, including 4720 cases and 6104 controls, were identified and included in this meta-analysis. Meta-analyses revealed no relationship between the XRCC3 T241M polymorphism and CRC risk (TT vs MM: OR = 0.85, 95%CI = 0.63-1.14; TT vs MT: OR = 0.87, 95%CI = 0.68-1.10; dominant model: OR = 1.18, 95%CI = 0.92-1.50; recessive model: OR = 0.87, 95%CI = 0.69-1.11). In the further subgroup analysis by ethnicity, we found no direct relationship between the polymorphism and CRC risk in either Asians or Europeans. Our findings demonstrated that the T241M polymorphism in the XRCC3 gene may not be a risk factor for CRC development. PMID- 26600545 TI - Study of PIK3CA, BRAF, and KRAS mutations in breast carcinomas among Chinese women in Qinghai. AB - Phosphatidylinositol-3-OH kinase and RAS-activated signaling pathways play an important role in tumor formation. Abnormalities in relevant genes play essential roles in the occurrence and development of many human cancers. Studies of breast cancer have mainly focused on the women in western countries, but few studies have examined the frequency of mutations in PIK3CA, BRAF, and KRAS in Chinese breast cancer patients. In this study, we conducted sequence analysis of PIK3CA, BRAF, and KRAS and determined relationships with the occurrence of breast cancer in women from Qinghai. DNA was extracted from 25 cases of human breast cancer tissue samples. PIK3CA, BRAF, and KRAS mutation analysis was performed by polymerase chain reaction and DNA sequencing. No mutations were found in PIK3CA, BRAF, and KRAS of adjacent tissues. However, PIK3CA mutations were observed in 32% (8) of the 25 breast cancer tissues examined, in which exon 9 accounted for 4% (1), exon 20 accounted for 28% (7), and no mutations were found in exon 1 of PIK3CA. Sequencing of exon 2 of KRAS suggested that 20% (5) of the 25 samples harbored a mutation and 16% (4) of BRAF harbored a mutation. Any mutation in these 3 oncogenes may induce the occurrence and development of breast cancer. PMID- 26600546 TI - Trace samples of human blood in mosquitoes as a forensic investigation tool. AB - Investigations of any type of crime invariably starts at the crime scene by collecting evidence. Thus, the purpose of this research was to collect and analyze an entomological trace from an environment that is similar to those of indoor crime scenes. Hematophagous mosquitoes were collected from two residential units; saliva of volunteers that were residents in the units was also collected for genetic analysis as reference samples. We examined the allele frequencies of 15 short tandem repeat loci (D8S1179, D21S11, D7S820, CSF1PO, D3S1358, TH01, D13S317, D16S539, D2S1338, D19S433, vWA, TPOX, D18S51, D5S818, and FGA) and amelogenin. A total of 26 female hematophagous mosquitoes were identified as Aedes aegypti, Aedes albopictus, and Culex quinquefasciatus; we were able to obtain 11 forensically valid genetic profiles, with a minimum of 0.028203 ng/MUL of human DNA. Thus, the results of this study showed that it was possible to correlate human genetic information from mosquitoes with the volunteer reference samples, which validates the use of this information as forensic evidence. Furthermore, we observed mixed genetic profiles from one mosquito. Therefore, it is clearly important to collect these insects indoors where crimes were committed, because it may be possible to find intact genetic profiles of suspects in the blood found in the digestive tract of hematophagous mosquitoes for later comparison to identify an offender and/or exclude suspects. PMID- 26600547 TI - Development of primer pairs from diverse chloroplast genomes for use in plant phylogenetic research. AB - Variation in the chloroplast DNA sequence is useful for plant phylogenetic studies. However, the number of variable sequences provided by chloroplast DNA for suggested genes or genomic regions in plant phylogenetic analyses is often inadequate. To identify conserved regions that can be used to design primers and amplify variable sequences for use in plant phylogenetic studies, the complete chloroplast genomic sequences of six plant species (including Oryza sativa, Arabidopsis thaliana, Glycine max, Lotus japonicus, Medicago truncatula, and Phaseolus vulgaris), searched from the taxonomy database of NCBI were investigated. A total of 93 conserved regions, 32 in large single copy and 61 in inverted repeat regions, were identified. A set of five primer pairs were designed according to the conserved sequences located in the psbA~trnK, psbB~psbH, rpl23~trnI, trnR~trnN, and trnY~trnD regions to amplify variable DNA fragments. An additional 18 plant accessions from 14 species were used to validate their utility. Each of the tested species could be distinguished by length polymorphisms of fragments amplified with the five primer pairs. trnR~trnN and rpl23~trnI amplified fragments specific to monocot and legume species, respectively. Three primer pairs located in the psbA~trnK, psbB~psbH, and trnR~trnN regions were applied to amplify variable DNA sequences for phylogenetic analysis using the maximum parsimony method. The consistent result between taxonomy and phylogenetic analysis on the variable sequences amplified with these three primer pairs was revealed. The five newly developed primer pairs are recommended as tools for use in the identification of plant species and in phylogenetic studies. PMID- 26600548 TI - Vulnerability of atherosclerotic plaques is associated with type I interferon in a murine model of lupus and atherosclerosis. AB - This study aimed to investigate the relationship between type I interferon (IFN I) and plaque stability in pristane-treated apolipoprotein E-knockout (ApoE(-/-)) mice. Antinuclear antibody (ANA) and extractable nuclear antigen antibody (ENA) levels were measured by immunofluorescence and enzyme-linked immunospot assay. Atherosclerotic plaques were detected by Sirius red/fast green staining. Cell apoptosis was detected by terminal deoxynucleotidyltransferase-mediated dUTP biotin nick-end labeling. Gene expression was determined by real-time PCR analyses. We found that pristane-treated ApoE(-/-) mice developed a lupus-like syndrome characterized by an increased production of serum ANA and ENA. Pristane treatment decreased the collagen content and increased the number of apoptotic cells in plaques. Moreover, IFN-induced ISG15, IFIT1-1, and IFIT1-2 gene expression was increased in peripheral blood cells and aortic plaques. An IFN alpha-stimulated macrophage supernatant inhibited collagen type I, alpha 1 gene expression in vascular smooth muscle cells. We concluded that the vulnerability of plaques was associated with the activation of IFN-I in pristane-treated ApoE( /-) mice. Thus, we speculated that the higher prevalence of cardiovascular events in patients with systemic lupus erythematosus could be due to plaque instability. PMID- 26600549 TI - Verification and evaluation of grain QTLs using RILs from TD70 x Kasalath in rice. AB - Grain size is an important trait that directly influences the yield of rice. Validation and evaluation of grain genes is important in rice genetic studies and for breeding. In a population of 240 recombinant inbred lines (RILs) derived from a cross between an extra-large grain japonica variety TD70 and a small grain indica variety Kasalath, we mapped 19 QTLs controlling grain traits. These QTLs included six cloned grain genes, namely, GW2, GS3, qSW5, qGL3, GS5, and GW8. All of the alleles with the optimal effects on grain size came from TD70, the variety with extra-large grains. To verify these gene loci, we cloned and sequenced GW2, GS3, GW5 (qSW5), qGL3, GS5, GW8, and TGW6 in TD70 and Kasalath, and found several functional polymorphisms in the sequences of the genes. New functional markers for the cloned genes were designed to identify parents and RILs. The contributions of these polymorphisms to the improvement in rice grain size traits were evaluated. Our results indicate that at least six functional polymorphisms have additive effects on grain shape and that one non-functional polymorphism in TGW6 affects grain shape in TD70. The newly designed markers will be useful in further studies to identify functional grain genes. Our findings provide insight into the control of grain size in rice, and they will be of value for improving rice grain yield. PMID- 26600550 TI - Screening for genes that are differentially-expressed between gastric cancer cells and gastric tumor sphere cells using the gene chip technique. AB - The purpose of this study was to screen for genes that were differentially expressed between a human gastric carcinoma cell line (HGC-27) and their tumor spheres, using the gene chip technique. The HGC-27 cells and tumor sphere cells were cultured in vitro in a sterile environment. Total RNA was extracted from both samples and purified using a standard TRIzol reagent. Total RNA was then hybridized onto a GeneChip, according to the standard protocols provided by the manufacturers of the GeneChip IVT Express Kit. The resulting fluorescence signals were analyzed and displayed using the Cluster and Treeview software programs. Under the criteria for significant differential expression (>=2-fold difference), 610 up- and 1135 down-regulated genes were identified in tumor sphere cells, compared to HCG-27 cells. These genes were involved in cell growth, signal transduction, tumorigenesis, and many other functional aspects of tumor cells. In conclusion, a number of genes were differentially expressed in tumor sphere cells compared to HCG-27 cells. In addition, we identified a close correlation between tumor sphere cells and tumorigenesis. PMID- 26600551 TI - Effects of Tripterygium wilfordii glycosides on regulatory T cells and Th17 in an IgA nephropathy rat model. AB - In this study, we examined the effects of Tripterygium wilfordii glycosides (TWGs) on Th17 and regulatory T cells (Tregs) in an immunoglobulin A nephropathy (IgAN) rat model. IgAN model rats were randomly divided into the model group, TWG treatment group, and prednisone group. Normal rats were included as controls. There were 6 rats in each group. The urine protein levels and the number of red blood cells in urine were analyzed at 24 h. IgA deposition in renal tissue was detected by fluorescence microscopy. The concentration of interleukin-17 in serum was detected by an enzyme-linked immunosorbent assay and the number of Tregs in blood was analyzed by flow cytometry. TWGs and prednisone significantly reduced urine protein levels and urine red blood cells at 24 h in IgAN model rats (P < 0.01), but prednisone had a greater effect than did TWGs (P < 0.05). TWGs and prednisone reduced IgA deposition in renal tissue, but prednisone had a greater effect than TWGs. T. wilfordii glycosides and prednisone significantly decreased the serum IL-17 level in an IgAN rat model and increased the number of Tregs in the blood (P < 0.01). There was no significant difference between prednisone and TWGs (P > 0.05). In conclusion, TWGs had therapeutic effects on IgAN model rats and may regulate the immune balance of Th17 and Tregs. PMID- 26600552 TI - Cloning, sequence characterization, and expression patterns of members of the porcine TSSK family. AB - Testis-specific serine kinases (TSSKs) are a family of serine/threonine kinases highly expressed in the testes that are responsible for regulating many spermatogenesis-related protein activities. Mutations in this family have a positive relationship with oligospermia and azoospermia in human and mouse. Here, five members of the TSSK family from a Banna mini-pig inbred line (BMI) were cloned, sequenced, and characterized. The full-length coding sequences of BMI TSSKs varied from 807 (TSSK3) to 1095 bp (TSSK1) and encoded 268 to 364 amino acids with molecular weights in the range 30.11 to 41.34 kDa. Following comparison with TSSK4 genes in other species, BMI TSSK4 was found to contain three alternatively spliced variants, inform1, inform 3, and inform 4. BMI TSSK1 and TSSK2 are co-localized on the Sus scrofa chromosome (SSC) 14, and consist of a single exon; TSSK3, TSSK4, and TSSK6 are on SSC6, SSC7, and SSC2, and consist of two, four, and one exon, respectively. Multiple protein sequence alignment and phylogenetic analysis showed that the regions spanning the S_TKc domains were more conserved between pig and other animals: with TSSK1 and TSSK2 and TSSK3 and TSSK6 displaying the greatest degree of homology across species, and the TSSK4 protein clearly distinct from other members. Multi-tissue RT-PCR showed BMI TSSK1, TSSK3, and TSSK4 were only expressed in the testes and seminal vesicle, TSSK2 was confined to testes only, while TSSK6 was expressed widely in adult tissues but was highest in the testes. PMID- 26600553 TI - Propofol induces apoptosis and inhibits the proliferation of rat embryonic neural stem cells via gamma-aminobutyric acid type A receptor. AB - We investigated the effect of propofol on the proliferation and viability of rat embryonic neural stem cells (rENSCs) and the potential mechanisms involved. rENSCs were isolated and cultured in vitro and treated with 1, 10, or 50 MUM propofol, while the control group was treated with 0.1 MUM dimethyl sulfoxide. The effect of propofol on the proliferation and viability of rENSCs was examined by proliferation and apoptosis assays. Real-time polymerase chain reaction was employed to analyze the mRNA expression of checkpoint kinase 1 (Chk1) and p53 in rENSCs exposed to propofol. Immunoprecipitation assay and western blotting analysis were performed to analyze the effect of propofol on Chk1 and p53 activity. The gamma-aminobutyric acid type A (GABAA) receptor antagonist securinine was added to the rENSCs before being treated with propofol to investigate the role of the GABAA receptor in propofol-triggered effects on rENSCs. rENSCs specifically expressing nestin protein were successfully isolated and cultured for experiments. The inhibitory effect of propofol on rENSCs increased dose-dependently. The percentage of apoptotic cells increased to 11.7% and the activity of Chk1 and p53 enhanced after treatment with 50 MUM propofol. However, addition of securinine abrogated propofol-induced apoptosis and activation of Chk1. The GABAA receptor mediates propofol-induced apoptosis and proliferation inhibition of rENSCs, possibly by modulating the Chk1/p53 signaling pathway. PMID- 26600554 TI - Association between HLA-C*04 and American cutaneous leishmaniasis in endemic region of southern Brazil. AB - Leishmaniasis is a parasitic infectious disease with global repercussions. American cutaneous leishmaniasis (ACL) is endemic in southern Brazil and its pathogenesis varies according to parasite species, immune response, and host genetics. In terms of immunogenetics, many host genes, including HLA (human leukocyte antigen), could be involved in susceptibility to and protection against ACL. Accordingly, the aim of this study was to investigate the association between HLA class I genes (HLA-A, -B, and -C) and ACL in an endemic region of southern Brazil. The allele frequencies of 186 patients diagnosed with ACL and 278 healthy individuals were compared. HLA class I (HLA-A, -B, and -C) typing was carried out by PCR-SSO using Luminex technology. The results revealed an association between the HLA-C*04 allele and the patient study group, in which it appeared more frequently than in the control group [21.5 vs 13.49% (P = 0.0016 and Pc = 0.0258; OR = 1.7560; 95%CI = 1.2227-2.5240)], thereby suggesting an increased susceptibility to ACL. Additional allelic groups such as HLA-A*02, HLA B*35, HLA-B*45, HLA-C*01, and HLA-C*15 were also implicated; however, further investigation is necessary to confirm their association with ACL. Therefore, the results obtained in this study demonstrate the involvement of HLA class I genes in the susceptibility or resistance to ACL, with significant association between HLA-C*04 and ACL susceptibility. PMID- 26600555 TI - Correction: Brands and Inhibition: A Go/No-Go Task Reveals the Power of Brand Influence. AB - [This corrects the article DOI: 10.1371/journal.pone.0141787.]. PMID- 26600556 TI - Using computers to teach people with intellectual disabilities to perform some of the tasks used within cognitive behavioural therapy: A randomised experiment. AB - AIMS: Training has been shown to improve the ability of people with intellectual disabilities (IDs) to perform some cognitive behavioural therapy (CBT) tasks. This study used a computerised training paradigm with the aim of improving the ability of people with IDs to: a) discriminate between behaviours, thoughts and feelings, and b) link situations, thoughts and feelings. METHODS: Fifty-five people with mild-to-moderate IDs were randomly assigned to a training or attention-control condition in a single-blind mixed experimental design. Computerised tasks assessed the participants' skills in: (a) discriminating between behaviours, thoughts and feelings (separately and pooled together), and (b) cognitive mediation by selecting appropriate emotions as consequences to given thoughts, and appropriate thoughts as mediators of given emotions. RESULTS: Training significantly improved ability to discriminate between behaviours, thoughts and feelings pooled together, compared to the attention-control condition, even when controlling for baseline scores and IQ. Large within-group improvements in the ability to identify behaviours and feelings were observed for the training condition, but not the attention-control group. There were no significant between-group differences in ability to identify thoughts, or on cognitive mediation skills. CONCLUSIONS: A single session of computerised training can improve the ability of people with IDs to understand and practise CBT tasks relating to behaviours and feelings. There is potential for computerised training to be used as a "primer" for CBT with people with IDs to improve engagement and outcomes, but further development on a specific computerised cognitive mediation task is needed. PMID- 26600558 TI - On Neighbor Information Utilization in Distributed Receding Horizon Control for Consensus-Seeking. AB - This paper investigates the issue on how to utilize neighbor information in the distributed receding horizon control (RHC)-based consensus problem for first order multiagent systems. The distributed RHC-based consensus problem is first formulated in a general framework in terms of using neighbor information. Based on the framework, a sufficient condition on utilizing neighbor information to ensure consensus is developed for the finite horizon case. For the infinite horizon case, a necessary and sufficient condition is proposed, and the best way of using neighbor information to achieve fastest convergence rate is also presented. It is shown that: 1) the way of utilizing neighbor information plays an important role in reaching consensus; 2) the parameter that ensures consensus is related with the network topology; and 3) the best convergence rate in consensus can be attained if the neighbor information is appropriately utilized. Simulation studies verify the proposed theoretical results. PMID- 26600557 TI - Effects of CO2 enrichment and drought pretreatment on metabolite responses to water stress and subsequent rehydration using potato tubers from plants grown in sunlit chambers. AB - Experiments were performed using naturally sunlit Soil-Plant-Atmosphere Research chambers that provided ambient or twice ambient CO2. Potato plants were grown in pots that were water sufficient (W), water insufficient for 12-18 days during both vegetative and tuber development stages (VR), or water insufficient solely during tuber development (R). In the ambient CO2 treatment, a total of 17 and 20 out of 31 tuber metabolites differed when comparing the W to the R and VR treatments, respectively. Hexoses, raffinose, mannitol, branched chain amino acids, phenylalanine and proline increased, although most organic acids remained unchanged or decreased in response to drought. Osmolytes, including glucose, branched chain amino acids and proline, remained elevated following 2 weeks of rehydration in both the ambient and elevated CO2 treatments, whereas fructose, raffinose, mannitol and some organic acids reverted to control levels. Failure of desiccated plant tissues to mobilize specific osmolytes after rehydration was unexpected and was likely because tubers function as terminal sinks. Tuber metabolite responses to single or double drought treatments were similar under the same CO2 levels but important differences were noted when CO2 level was varied. We also found that metabolite changes to water insufficiency and/or CO2 enrichment were very distinct between sink and source tissues, and total metabolite changes to stress were generally greater in leaflets than tubers. PMID- 26600559 TI - Robust Perturbed Output Regulation and Synchronization of Nonlinear Heterogeneous Multiagents. AB - The conventional robust output regulation problem aims to achieve reference tracking and disturbance rejection in the presence of system uncertainties while the references and disturbances are generated by an autonomous exosystem. When the exosystem is perturbed by an external event, a novel robust perturbed output regulation problem is formulated and solved in this paper. The formulation arises from a class of synchronization problem of multiple agents. With the aid of a new reference model-based control framework, the proposed solution to the robust perturbed output regulation problem leads to a decentralized control algorithm for synchronization of multiple agents of nonlinear heterogeneous dynamics. PMID- 26600560 TI - Hyperspectral Anomaly Detection by Graph Pixel Selection. AB - Hyperspectral anomaly detection (AD) is an important problem in remote sensing field. It can make full use of the spectral differences to discover certain potential interesting regions without any target priors. Traditional Mahalanobis distance-based anomaly detectors assume the background spectrum distribution conforms to a Gaussian distribution. However, this and other similar distributions may not be satisfied for the real hyperspectral images. Moreover, the background statistics are susceptible to contamination of anomaly targets which will lead to a high false-positive rate. To address these intrinsic problems, this paper proposes a novel AD method based on the graph theory. We first construct a vertex- and edge-weighted graph and then utilize a pixel selection process to locate the anomaly targets. Two contributions are claimed in this paper: 1) no background distributions are required which makes the method more adaptive and 2) both the vertex and edge weights are considered which enables a more accurate detection performance and better robustness to noise. Intensive experiments on the simulated and real hyperspectral images demonstrate that the proposed method outperforms other benchmark competitors. In addition, the robustness of the proposed method has been validated by using various window sizes. This experimental result also demonstrates the valuable characteristic of less computational complexity and less parameter tuning for real applications. PMID- 26600561 TI - An Improved Incremental Learning Approach for KPI Prognosis of Dynamic Fuel Cell System. AB - The key performance indicator (KPI) has an important practical value with respect to the product quality and economic benefits for modern industry. To cope with the KPI prognosis issue under nonlinear conditions, this paper presents an improved incremental learning approach based on available process measurements. The proposed approach takes advantage of the algorithm overlapping of locally weighted projection regression (LWPR) and partial least squares (PLS), implementing the PLS-based prognosis in each locally linear model produced by the incremental learning process of LWPR. The global prognosis results including KPI prediction and process monitoring are obtained from the corresponding normalized weighted means of all the local models. The statistical indicators for prognosis are enhanced as well by the design of novel KPI-related and KPI-unrelated statistics with suitable control limits for non-Gaussian data. For application oriented purpose, the process measurements from real datasets of a proton exchange membrane fuel cell system are employed to demonstrate the effectiveness of KPI prognosis. The proposed approach is finally extended to a long-term voltage prediction for potential reference of further fuel cell applications. PMID- 26600563 TI - Interplay of Matrix Stiffness and Cell-Cell Contact in Regulating Differentiation of Stem Cells. AB - Stem cells are capable of sensing and responding to the mechanical properties of extracellular matrixes (ECMs). It is well-known that, while osteogenesis is promoted on the stiff matrixes, adipogenesis is enhanced on the soft ones. Herein, we report an "abnormal" tendency of matrix-stiffness-directed stem cell differentiation. Well-defined nanoarrays of cell-adhesive arginine-glycine aspartate (RGD) peptides were modified onto the surfaces of persistently nonfouling poly(ethylene glycol) (PEG) hydrogels to achieve controlled specific cell adhesion and simultaneously eliminate nonspecific protein adsorption. Mesenchymal stem cells were cultivated on the RGD-nanopatterned PEG hydrogels with the same RGD nanospacing but different hydrogel stiffnesses and incubated in the induction medium to examine the effect of matrix stiffness on osteogenic and adipogenic differentiation extents. When stem cells were kept at a low density during the induction period, the differentiation tendency was consistent with the previous reports in the literature; however, both lineage commitments were favored on the stiff matrices at a high cell density. We interpreted such a complicated stiffness effect at a high cell density in two-dimensional culture as the interplay of matrix stiffness and cell-cell contact. As a result, this study strengthens the essence of the stiffness effect and highlights the combinatory effects of ECM cues and cell cues on stem cell differentiation. PMID- 26600562 TI - Key Characteristics of Carcinogens as a Basis for Organizing Data on Mechanisms of Carcinogenesis. AB - BACKGROUND: A recent review by the International Agency for Research on Cancer (IARC) updated the assessments of the > 100 agents classified as Group 1, carcinogenic to humans (IARC Monographs Volume 100, parts A-F). This exercise was complicated by the absence of a broadly accepted, systematic method for evaluating mechanistic data to support conclusions regarding human hazard from exposure to carcinogens. OBJECTIVES AND METHODS: IARC therefore convened two workshops in which an international Working Group of experts identified 10 key characteristics, one or more of which are commonly exhibited by established human carcinogens. DISCUSSION: These characteristics provide the basis for an objective approach to identifying and organizing results from pertinent mechanistic studies. The 10 characteristics are the abilities of an agent to 1) act as an electrophile either directly or after metabolic activation; 2) be genotoxic; 3) alter DNA repair or cause genomic instability; 4) induce epigenetic alterations; 5) induce oxidative stress; 6) induce chronic inflammation; 7) be immunosuppressive; 8) modulate receptor-mediated effects; 9) cause immortalization; and 10) alter cell proliferation, cell death, or nutrient supply. CONCLUSION: We describe the use of the 10 key characteristics to conduct a systematic literature search focused on relevant end points and construct a graphical representation of the identified mechanistic information. Next, we use benzene and polychlorinated biphenyls as examples to illustrate how this approach may work in practice. The approach described is similar in many respects to those currently being implemented by the U.S. EPA's Integrated Risk Information System Program and the U.S. National Toxicology Program. CITATION: Smith MT, Guyton KZ, Gibbons CF, Fritz JM, Portier CJ, Rusyn I, DeMarini DM, Caldwell JC, Kavlock RJ, Lambert P, Hecht SS, Bucher JR, Stewart BW, Baan R, Cogliano VJ, Straif K. 2016. Key characteristics of carcinogens as a basis for organizing data on mechanisms of carcinogenesis. Environ Health Perspect 124:713-721; http://dx.doi.org/10.1289/ehp.1509912. PMID- 26600564 TI - Regular drug-eluting stents versus the dedicated coronary bifurcation sirolimus eluting BiOSS LIM(r) stent: the randomised, multicentre, open-label, controlled POLBOS II trial. AB - AIMS: The aim of the POLBOS II randomised trial was to compare any regular drug eluting stents (rDES) with the dedicated bifurcation sirolimus-eluting stent BiOSS LIM for the treatment of coronary bifurcation lesions. The secondary aim was to study the effect of final kissing balloon inflation (FKBI) on clinical outcomes. METHODS AND RESULTS: Between December 2012 and December 2013, 202 patients with stable coronary artery disease or non-ST-segment elevation acute coronary syndrome were randomly assigned 1:1 to treatment of the coronary bifurcation lesions either with the BiOSS LIM stent (n=102) or with an rDES (n=100). Coronary re-angiography was performed at 12 months. The primary endpoint was the composite of cardiac death, myocardial infarction (MI), and target lesion revascularisation (TLR) at 12 months. The target vessel was located in the left main in one third of the cases (35.3% in BiOSS and 38% in rDES). Side branch treatment was required in 8.8% (rDES) and 7% (BiOSS). At 12 months, the cumulative MACE incidence was similar in both groups (11.8% [BiOSS] vs. 15% [rDES, p=0.08]), as was the TLR rate (9.8% vs. 9% [p=0.8]). The binary restenosis rates were significantly lower in the FKBI subgroup of the BiOSS group (5.9% vs. 11.8%, p<0.05). CONCLUSIONS: MACE rates as well as TLR rates were comparable between the BiOSS LIM and rDES. At 12 months, cumulative MACE incidence was similar in both groups (11.8% vs. 15%), as was the TLR rate (9.8% vs. 9%). Significantly lower rates of restenosis were observed in the FKBI subgroup of the BiOSS group. PMID- 26600565 TI - Meeting Contraceptive Needs: Long-Term Associations of the PRACHAR Project with Married Women's Awareness and Behavior in Bihar. AB - CONTEXT: Although interventions such as the PRACHAR project in Bihar, India, have been associated with increased contraceptive knowledge and use in the short term, less is known about whether such gains are sustained years later. METHODS: Survey data, collected in 2013 from 2,846 married women aged 15-34, were used to compare contraceptive awareness and use between those who lived in areas where the PRACHAR project had been implemented in 2002-2009 and those who lived in matched comparison areas. Multivariate analyses assessed whether, after adjustment for covariates, outcomes differed between women in comparison and intervention areas, as well as between women directly exposed to the program and those who lived in intervention areas but had been only indirectly exposed. RESULTS: Compared with women in comparison areas, those in intervention areas were more likely to have method-specific knowledge of oral contraceptives, IUDs, condoms and the Standard Days Method (odds ratios, 1.4-1.7); to know that oral contraceptives and condoms are appropriate for delaying first pregnancy (2.3 for each) and IUDs and injectables are appropriate for spacing births (1.4 for each); to have ever used contraceptives (2.1) or be using a modern method (1.5); and to have initiated contraception within three months of their first birth (1.8). Levels of awareness and use were elevated not only among women directly exposed to the intervention but also, for many measures, among indirectly exposed women. CONCLUSIONS: The association of multipronged reproductive health programs like PRACHAR with contraceptive awareness and practices may last for years beyond the project's conclusion. PMID- 26600566 TI - Empowering Women or Pleasing Men? Analyzing Male Views on Female Condom Use in Zimbabwe, Nigeria and Cameroon. AB - CONTEXT: Usage rates of female condoms are low throughout Sub-Saharan Africa. Programs have traditionally presented female condoms as a means of women's empowerment. However, prevailing gender norms in Sub-Saharan Africa assign sexual decision making to men, suggesting that male acceptance is imperative for increased use. METHODS: In 2011, data on perceptions of and experiences with female condom use were collected from 336 men in Zimbabwe, Nigeria and Cameroon through 37 focus group discussions and six in-depth interviews; participants also completed pre-focus group discussion questionnaires. The data were analyzed by country, using thematic content analysis. Results were stratified by marital status and regularity of female condom use. RESULTS: Perceived advantages of female condoms over other protection methods were enhanced pleasure, effectiveness and lack of side effects. Single and married men preferred using female condoms with stable rather than casual partners, and for purposes of contraception rather than protection from infections. In Cameroon and Nigeria, where contraceptive rates are lower than in Zimbabwe, men favored female condoms as a contraceptive device. Its acceptability as a method of protection from HIV infection is greater in highly AIDS-affected Zimbabwe than in the other two countries. In Cameroon, some men did report regular use of female condoms in casual encounters. Initiation of female condom use by men's stable partners was not acceptable in any of the countries. CONCLUSION: The findings suggest the importance of accounting for local contexts and targeting both men and women in campaigns to promote female condom use. PMID- 26600567 TI - An Assessment of Family Planning Decision Makers' and Advocates' Needs and Strategies in Three East African Countries. AB - CONTEXT: Despite decades of evidence-based advocacy for family planning in developing countries, research on how decision makers perceive and respond to such efforts is lacking. METHODS: A literature review yielded 10 peer-reviewed journal articles published between 1999 and 2012 on decision makers' needs for and experiences with health advocacy and evidence. Two sets of questions about family planning research and advocacy-one for decision makers and another for advocates-were developed from emerging themes and used in structured interviews with 68 key informants in Ethiopia, Kenya and Malawi. RESULTS: Decision makers reported understanding family planning's value and confirmed that advocacy had helped to spur recent favorable shifts in government support of family planning. Key informants stressed that advocacy messages and formats must be tailored to the needs and interests of particular audiences to be effective. Messages must also consider barriers to decision makers' support for family planning: constituents' negative attitudes; fear that increased adherence to family planning will shrink the size and influence of specific voting blocs and ethnic groups; and competing economic, social, cultural, religious and political priorities. Decision makers reported valuing the contributions of international family planning organizations and donors, but were more comfortable receiving advocacy messages from local sources. CONCLUSIONS: According to decision makers, sustained and strategic family planning advocacy developed and delivered by culturally attuned national actors, with support from international actors, can diminish barriers to government support for family planning. PMID- 26600568 TI - Contraceptive Dynamics in Rural Northern Malawi: A Prospective Longitudinal Study. AB - CONTEXT: Increased use of contraceptives in Malawi has not translated into a commensurate reduction in fertility, but the reason is unknown. Insight into contraceptive switching and discontinuation may shed light on this conundrum and on whether the commonly used modern contraceptive prevalence rate (mCPR) is the best indicator of family planning program performance. METHODS: A one-year prospective longitudinal data set was created from patient-held family planning cards of 4,678 reproductive-age women living in a demographic surveillance site in rural northern Malawi. Contraceptive service data recorded on the women's cards by providers were linked to their socioeconomic, demographic and health data. Contraceptive point prevalence estimates calculated from these data were compared with mCPR estimates from cross-sectional surveys. Survival analyses examined contraceptive adherence. RESULTS: The contraceptive point prevalence of 35% was slightly lower than comparable cross-sectional estimates of mCPR. Only 51% of users of the injectable-the most widely used modern method-received their first reinjection on time, and just 15% adhered to the method for 12 months. Although various study variables were associated with contraceptive use, none were associated with adherence. CONCLUSIONS: Gaps in and discontinuation of use of the injectable may play a role in the discrepancy between mCPR and fertility. Interventions to help women adhere to injectable use and to promote long-acting methods should be strengthened. PMID- 26600569 TI - A Fresh Look at the Level of Unmet Need for Family Planning in the Postpartum Period, Its Causes and Program Implications. PMID- 26600571 TI - Creating the Black Ghetto: Black Residential Patterns Before and During the Great Migration. AB - Were black ghettos a product of white reaction to the Great Migration in the 1920s and 1930s, or did the ghettoization process have earlier roots? This presentation takes advantage of recently available data on black and white residential patterns in several major Northern cities in the period 1880-1940. Using geographic areas smaller than contemporary census tracts, it traces the growth of black populations in each city and trends in the level of isolation and segregation. In addition it analyzes the determinants of location: which blacks lived in neighborhoods with higher black concentrations, and what does this tell us about the ghettoization process? We find that the development of ghettos in an embryonic form was well underway in 1880, that segregation became intense prior to the Great Migration, and that in this whole period blacks were segregated based on race rather than class or Southern origin. PMID- 26600570 TI - Recent Trends in Adherence to Secondary Prevention Guidelines for Patients Undergoing Coronary Revascularization in Washington State: An Analysis of the Clinical Outcomes Assessment Program (COAP) Registry. AB - BACKGROUND: Previous studies indicated that patients undergoing coronary artery bypass graft (CABG) surgery are less likely to receive guideline-based secondary prevention therapy than are those undergoing percutaneous coronary intervention (PCI) after an acute myocardial infarction. We aimed to evaluate whether these differences have persisted after the implementation of public reporting of hospital metrics. METHODS AND RESULTS: The Clinical Outcomes Assessment Program (COAP) database was analyzed retrospectively to evaluate adherence to secondary prevention guidelines at discharge in patients who underwent coronary revascularization after an acute ST-elevation myocardial infarction in Washington State. From 2004 to 2007, 9260 patients received PCI and 692 underwent CABG for this indication. Measures evaluated included prescription of aspirin, beta blockers, angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, or lipid-lowering medications; cardiac rehabilitation referral; and smoking-cessation counseling. Composite adherence was lower for CABG than for PCI patients during the period studied (79.6% versus 89.7%, P<0.01). Compared to patients who underwent CABG, patients who underwent PCI were more likely to receive each of the pharmacological therapies. There was no statistical difference in smoking-cessation counseling (91.7% versus 90.3%, P=0.63), and CABG patients were more likely to receive referral for cardiac rehabilitation (70.9% versus 48.3%, P<0.01). Adherence rates improved over time among both groups, with no significant difference in composite adherence in 2006 (85.6% versus 87.6%, P=0.36). CONCLUSIONS: Rates of guideline-based secondary prevention adherence in patients with ST-elevation myocardial infarction who underwent CABG surgery have been improving steadily in Washington State. The improvement possibly is associated with the implementation of public reporting of quality measures. PMID- 26600572 TI - Flibanserin: Approval of a controversial drug for a controversial disorder. PMID- 26600573 TI - The study of primary psychotic disorders with concurrent substance abuse in terms of their diagnostic stability. AB - BACKGROUND: Co-morbid substance use is common among individuals presenting with symptoms of psychosis. There is a paucity of research in this area. AIM: To study the longitudinal follow-up of patients over 1-year of first episode psychosis with concurrent substance use in terms of their diagnostic stability. MATERIALS AND METHODS: Fifty patients having at least one symptom of psychosis at first admission at a General Hospital Psychiatric Unit along with concurrent substance abuse were included and followed up for 1-year. International Classification of Disease-10, diagnostic criteria were used for diagnosis. Semi-structured sociodemographic performa to assess the sociodemographic profile. Brief Psychiatric Rating Scale and Alcohol Use Disorder Identification Test as rating scales were used for the assessment at 6 and 12 months. RESULTS: Of 50 patients, 31 patients who had a diagnosis of primary psychosis retained their diagnosis at follow-up. The mean age of cases in substance-induced psychosis group was 37.47 years, which was significantly higher than in primary psychosis group at 31.52 years. However, 7 patients of the substance-induced psychosis group required a change in diagnosis to primary psychosis group. The primary psychosis group patients were significantly younger, less educated, had less family support, had greater family mental illness, had more severe symptoms, and less hallucinations. CONCLUSION: The present study is a forerunner in this area. Salient differences indicated in the study can help in differentiating the diagnosis and in the management of cases. This is particularly relevant in the management setting and for long-term intervention purpose. PMID- 26600574 TI - Facial emotion recognition deficits: The new face of schizophrenia. AB - Schizophrenia has been classically described to have positive, negative, and cognitive symptom dimension. Emerging evidence strongly supports a fourth dimension of social cognitive symptoms with facial emotion recognition deficits (FERD) representing a new face in our understanding of this complex disorder. FERD have been described to be one among the important deficits in schizophrenia and could be trait markers for the disorder. FERD are associated with socio occupational dysfunction and hence are of important clinical relevance. This review discusses FERD in schizophrenia, challenges in its assessment in our cultural context, its implications in understanding neurobiological mechanisms and clinical applications. PMID- 26600575 TI - Sexual disorders among elderly: An epidemiological study in south Indian rural population. AB - BACKGROUND: Realizing a dearth of data on this topic, especially in the Indian context, an epidemiological study was conducted in a south Indian rural population to identify the sexual activity patterns and sexual problems among the population above 60 years of age. OBJECTIVES: (1) Assessment of sexual activity patterns among individuals above 60 years. (2) Assessment of the prevalence of sexual disorders among individuals above 60 years. MATERIALS AND METHODS: The study sample consisted of 259 participants, which included both males and females above 60 years of age. Subjects who were sexually active and fulfilled the study criteria were administered Arizona Sexual Experience Scale as a screening tool, for the presence of sexual problems. Those who were found to have sexual problems were interviewed further using appropriate questionnaires. RESULTS: Only 27.4% of the individuals above 60 years were sexually active, and it progressively dropped as age advanced and none were sexually active after 75 years of age. Among the sexually active males, erectile dysfunction (ED) was prevalent in 43.5%, premature ejaculation in 10.9%, hypoactive sexual desire disorder (HSSD) in 0.77% and anorgasmia in 0.38% of the subjects. Among females, arousal disorder was prevalent in 28%, HSSD in 16%, anorgasmia in 20% and dyspareunia in 8% of the subjects. CONCLUSION: The study gives us an insight into the sexual problems of the elderly and brings home the point that sexual problems are very much common among both men and women in the older population. Among elderly males, ED is the most common sexual disorder whereas in elderly females, arousal disorder is the most prevalent female sexual dysfunction, implicating biology plays an important role in men, whereas psychology plays an important role in women sexual functioning. PMID- 26600576 TI - Female sexual dysfunction: A comparative study in drug naive 1(st) episode of depression in a general hospital of South Asia. AB - BACKGROUND: Women's sexual dysfunction is found to be highly prevalent in western and Indian literature. Limited studies are available on drug naive depression in western literature and in Indian population. AIM: To determine the prevalence rate and symptom profile of female sexual dysfunctions in patients with untreated depression. DESIGN: A cross-sectional study in the psychiatry out-patient department of general hospital in South India. MATERIALS AND METHODS: Following written informed consent female sexual functioning index (FSFI) and Arizona Sexual Experience Scale (ASEX) - female version and Hamilton Depression Rating Scale (HAMD - 17 item) on 30 cases and 30 controls was administered. Sociodemographic data, pattern and type of sexual dysfunctions were enquired. Data were analyzed using descriptive statistics, contingency co-efficient analysis and stepwise multiple regression. RESULTS: The mean score of HAMD 17 item in study group was 19.13. The study showed that female sexual dysfunction was 70.3% in study group compared to 43.3% in control FSFI scores above 16 in HAMD had dysfunction of 76% with FSFI in study group. With ASEX-F sexual dysfunction was 73.3% in study compared to 20% in control. Scores above 16 in HAMD had 80% of sexual dysfunction with ASEX-F in study group. CONCLUSION: The study found that ASEX-F co-related better with HAMD 17 item. Following the onset of depression, the incidence of sexual dysfunction started at an early age in women. PMID- 26600577 TI - Risk factors for suicide in elderly in comparison to younger age groups. AB - BACKGROUND: The elderly population has a significant risk of suicide when compared to any other age group. Despite this, suicide among the aged receives scant attention. Hence, identification of suicide risk factors specific to this population will help in the development of suitable prevention strategies for this group. AIMS: Comparison of risk factors for attempting the suicide in the elderly versus younger suicide attempters. MATERIALS AND METHODS: A total 1159 suicide attempters attended the suicide prevention clinic of IQRAA International Hospital and Research Centre. They were evaluated using a specially designed psycho-sociodemographic proforma. The group was divided into those above 65 years (elderly) and those below 65 years (younger) and all the risk factors were compared between these two groups. RESULTS: Most suicide attempters in the elderly category were found to be married, less educated, unemployed and hailed from a rural background and joint families. They had a higher rate of family history of psychiatric illness, past psychiatric illness, concurrent medical illness and history of medical contact in the three months prior to the attempt. A significant number in the elderly group had attempted suicide more than a week after a stressor. CONCLUSION: The results from this study suggests that in suicide attempters from Indian geriatric population, co-morbid physical illness, mental illness (particularly depression) and family burden of psychiatric illness are important predictors in comparison to younger populations. Also, these attempters had contact with a medical professional in the three months prior to the attempt. Specific preventive interventions need to be tailored for this population to reduce the risk of suicide rather than adopting generalized suicide prevention strategies. PMID- 26600578 TI - Psychological correlates and psychiatric morbidity in patients with Dhat syndrome. AB - AIM: The aim of this study was to examine psychological factors in the form of somatosensory amplification, alexithymia and hypochondriasis in patients with Dhat syndrome. Secondary aims of the study were: (1) To evaluate the influence of psychiatric comorbidity on the psychological correlates; (2) to compare the prevalence of psychological correlates in those with Dhat syndrome and in those with depression and somatoform disorders. MATERIALS AND METHODS: A total of 106 subjects diagnosed with Dhat syndrome as per International Classification of Diseases-10 (ICD-10) criteria were assessed on Toronto Alexithymia Scale (TAS 20), Somatosensory Amplification Scale (SSAS) and Whitely Index (WI). Psychiatric comorbidity was diagnosed as per ICD-10. Data on 50 patients with depression and 119 patients with somatoform disorder was used for comparison. RESULTS: The age at onset of Dhat syndrome was 22.54 (standard deviation [SD] - 7.5) years, and duration of illness was 5.04 (SD - 4.2) years. Depressive disorders were diagnosed in 13.2%, anxiety disorders in 15.1%, erectile dysfunction in 14.2% and premature ejaculation in 17% of cases. The mean SSAS total score was 23.12 (SD - 7.99), mean total TAS-20 score was 63.3 (SD - 13.3) and mean WI score was 8.23 (SD - 2.7). About two third of the patients had alexithymia (n = 67; 63.2%) and hypochondriasis (n = 69; 65.1%). Comparison of the psychological correlates between those with Dhat syndrome alone (n = 59) and those with comorbid psychiatric disorder (n = 47) revealed no significant differences. Patients with only Dhat syndrome had significantly higher scores for somatosensory amplification when compared with those with somatoform disorders, but no difference was seen between those with depression and Dhat syndrome alone. Compared to patients with Dhat syndrome alone, those with depression had higher prevalence of alexithymia and hypochondriasis. CONCLUSION: There are differences in the prevalence of somatosensory amplification, hypochondriasis and alexithymia between those with Dhat syndrome alone and those with depression and somatoform disorders. PMID- 26600579 TI - Prevalence and risk factors for depression among community resident older people in Kerala. AB - BACKGROUND: Depression is the most common mental health problem in late-life. We need more information about the incidence and prevalence of major and minor syndromes of depression in older people. This will help in service development. AIMS: To estimate the prevalence of depressive disorders among community resident older people in Kerala, India and to identify factors associated with late-life depression. MATERIALS AND METHODS: Two hundred and twenty community resident older subjects were assessed for depression by clinicians trained in psychiatry. They used a symptom checklist based on International Classification of Diseases Tenth Revision (ICD-10) Diagnostic criteria for research for Depression and Montgomery Asberg Depression Rating Scale for assessment of symptoms. A structured proforma was used to assess sociodemographic characteristics and medical history. The point prevalence of depression was estimated. Univariate analysis and subsequent binary logistic regression were carried out to identify factors associated with depression. RESULTS: Prevalence of any ICD-10 (World Health Organization, 1992) depressive episode was 39.1% (95% confidence interval [CI] 32.6-45.9). There was significant correlation between depression and female gender (odds ratio [OR] 2.33; 95% CI 1.07-5.06) and history of a significant life event in the previous year (OR 2.39; 95% CI 1.27-4.49). CONCLUSION: High prevalence rate of late-life depression is indicative of high burden due to depression among older people in the community. Better awareness among primary care clinicians can result in better detection and management of late-life depression. PMID- 26600580 TI - Association of single-nucleotide polymorphism of cholecystokinin receptor A gene with schizophrenia in an Eastern Indian population. AB - CONTEXT: Cholecystokinin A receptor (CCK-AR) gene polymorphism is being increasingly reported in schizophrenia. It varies among different population groups but is associated with several complications of schizophrenia. AIMS: The present study was undertaken to assess whether the CCK-AR polymorphism is stabilized and is more consistently associated with schizophrenia in an Eastern Indian sub-population. SETTINGS AND DESIGN: It was carried out as a cross sectional, observational, hospital-based study on 95 schizophrenia patients and 138 control subjects selected by the method of convenience. MATERIALS AND METHODS: Single-nucleotide polymorphisms located in the regulatory region of the CCK-AR gene were assessed by restriction fragment length polymorphism (RFLP) in the polymerase chain reaction (PCR) amplified product of CCK-AR gene in study subjects. RFLP was done by the digestion of the PCR product by the restriction enzyme Pst-1 followed by gel electrophoresis. STATISTICAL ANALYSIS: Assessment of the stability of C/T polymorphism in the study population was done by applying Hardy-Weinberg equilibrium rule. The significance of difference in the allelic distribution between case and controls was analyzed by Chi-square (chi(2)) test and odds ratio (OR) analysis. RESULT: CCK-R polymorphism was in Hardy-Weinberg equilibrium in both groups. Distribution of the C allele of this gene was significantly higher in schizophrenia patients (chi(2) = 4.35, OR = 1.51; confidence interval at 95% =1.04-2.20). CONCLUSION: C/T polymorphism of the CCK-R gene is a stable polymorphism in our study population. Moreover, the C allele is significantly more abundant in schizophrenia patients imparting them a greater risk of development of complications like auditory hallucination. PMID- 26600581 TI - Childhood autism in India: A case-control study using tract-based spatial statistics analysis. AB - CONTEXT: Autism is a serious behavioral disorder among young children that now occurs at epidemic rates in developing countries like India. We have used tract based spatial statistics (TBSS) of diffusion tensor imaging (DTI) measures to investigate the microstructure of primary neurocircuitry involved in autistic spectral disorders as compared to the typically developed children. OBJECTIVE: To evaluate the various white matter tracts in Indian autistic children as compared to the controls using TBSS. MATERIALS AND METHODS: Prospective, case-control, voxel-based, whole-brain DTI analysis using TBSS was performed. The study included 19 autistic children (mean age 8.7 years +/- 3.84, 16 males and 3 females) and 34 controls (mean age 12.38 +/- 3.76, all males). Fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) values were used as outcome variables. RESULTS: Compared to the control group, TBSS demonstrated multiple areas of markedly reduced FA involving multiple long white matter tracts, entire corpus callosum, bilateral posterior thalami, and bilateral optic tracts (OTs). Notably, there were no voxels where FA was significantly increased in the autism group. Increased RD was also noted in these regions, suggesting underlying myelination defect. The MD was elevated in many of the projections and association fibers and notably in the OTs. There were no significant changes in the AD in these regions, indicating no significant axonal injury. There was no significant correlation between the FA values and Childhood Autism Rating Scale. CONCLUSION: This is a first of a kind study evaluating DTI findings in autistic children in India. In our study, DTI has shown a significant fault with the underlying intricate brain wiring system in autism. OT abnormality is a novel finding and needs further research. PMID- 26600583 TI - Descriptive epidemiology and high risk behavior of male prescription opioid abusers: Cross-sectional study from Sikkim, North East India. AB - BACKGROUND: Sikkim is emerging as an important area for prescription opioid abuse with frequent news of seizures and arrests due to possession of prescription opioids. However, till date there is a little information on descriptive epidemiology and high risk behavior of prescription opioid abusers from Sikkim. AIMS: The aim was to describe demographic (age, sex, religion, marital status, community, occupation, etc.); socioeconomic (income, education, family information etc.); and high risk behavior (e.g., injection sharing, visit to commercial sex workers [CSWs], homosexuality etc.) among treatment-seeking prescription opioid abusers in Sikkim. MATERIALS AND METHODS: Epidemiological data were collected by administering predevised questionnaires from n = 223 prescription opioid abusers (main problem prescription opioids) reporting for treatment at five different drug abuse treatment centers across Sikkim. RESULTS: The mean age of prescription opioid abusers in Sikkim was 27 years; all were male, of Nepalese ethnicity and single/never married, school dropout and/or illiterate, earning < Rs. 10,000/month with most spending almost Rs. 5000 a month on prescription opioids. Most (57.4%) prescription opioid abusers belonged to the urban community. Commonly abused prescription opioids were dextropropoxyphene and codeine. Injection sharing was more in urban areas whereas syringe exchange was observed equally among rural and urban prescription opioid abusers. Among urban injectors visits to CSWs, and multiple sex partners were also common in spite of knowledge about AIDS. Limited condom use was observed among rural respondents. Incidences of arrests, public intoxication, and violence under the influence of prescription opioids were also reported. CONCLUSION: Both the rural and urban areas of Sikkim show increasing rates of prescription opioid abuse among males. It is more prevalent among school dropouts and unemployed youth. Trends of injection drug use, unsafe injection, high risk behavior have also been observed. PMID- 26600582 TI - Do SADQ and AUDIT identify independent impacts of alcohol abuse - clinical and biochemical markers respectively? AB - BACKGROUND AND OBJECTIVES: We have analyzed extant data to see if Alcohol Use Disorder Identification Test (AUDIT) and Severity of Alcohol Dependence Questionnaire (SADQ) assess overlapping aspects of alcoholism, and how they relate to lab measures of alcoholism. MATERIALS AND METHODS: Consecutive male patients between 20 and 50 years were recruited from varied departments of a general hospital. AUDIT and SADQ, as well as liver function tests, were part of the data obtained. RESULTS: Despite, a significant correlation between total scores of SADQ and AUDIT (rho = 0.188, P < 0.021) and some of their sub-scores. SADQ scores alone were significantly correlating with clinical variables of alcoholism such as family history and age of onset; AUDIT did not. On the other hand, AUDIT total scores correlated with total and conjugated bilirubin, while SADQ did not. INTERPRETATION AND CONCLUSION: Our data suggests that the two scales, AUDIT and SADQ may be tapping into two different outcomes of increased alcohol use namely clinical and biochemical markers, respectively. SADQ could be useful in studies looking at withdrawal related severity and clinical aspects of alcoholism; while AUDIT could be more suitable for studies looking at alcoholism related medical morbidity. This needs to be confirmed in larger unselected samples from different community and clinical settings. PMID- 26600584 TI - The establishment of a mother-baby inpatient psychiatry unit in India: Adaptation of a Western model to meet local cultural and resource needs. AB - BACKGROUND: Several Western countries have established mother-baby psychiatric units for women with mental illness in the postpartum; similar facilities are however not available in most low and medium income countries owing to the high costs of such units and the need for specially trained personnel. MATERIALS AND METHODS: The first dedicated inpatient mother-baby unit (MBU) was started in Bengaluru, India, in 2009 at the National Institute of Mental Health and Neurosciences in response to the growing needs of mothers with severe mental illness and their infants. We describe the unique challenges faced in the unit, characteristics of this patient population and clinical outcomes. RESULTS: Two hundred and thirty-seven mother-infant pairs were admitted from July 2009 to September 2013. Bipolar disorder and acute polymorphic psychosis were the most frequent primary diagnosis (36% and 34.5%). Fifteen percent of the women had catatonic symptoms. Suicide risk was present in 36 (17%) mothers and risk to the infant by mothers in 32 (16%). Mother-infant bonding problems were seen in 98 (41%) mothers and total breastfeeding disruption in 87 (36.7%) mothers. Eighty seven infants (37%) needed an emergency pediatric referral. Ongoing domestic violence was reported by 42 (18%). The majority of the mother infant dyads stayed for <4 weeks and were noted to have improved at discharge. However, 12 (6%) mothers had readmissions during the study period of 4 years. Disrupted breastfeeding was restituted in 75 of 87 (86%), mother infant dyads and mother infant bonding were normal in all except ten mothers at discharge. CONCLUSIONS: Starting an MBU in a low resource setting is feasible and is associated with good clinical outcomes. Addressing risks, poor infant health, breastfeeding disruption, mother infant bonding and ongoing domestic violence are the challenges during the process. PMID- 26600585 TI - Depressive symptoms in late life in urban and semi-urban areas of South-West Greece: An undetected disorder? AB - OBJECTIVE: The objective of this study was to estimate the prevalence and probable under-diagnosis of depressive symptoms in elderly of an urban and semi urban area in Greece. MATERIALS AND METHODS: A cross-sectional study was conducted among the members of 4 days care centers for older people (KAPI), three in the municipality of Patras, West-Greece, and in one in Tripolis, Peloponnese, Greece. A total of 378 individuals took part in the study, aged >60 years. A questionnaire was developed to collect basic demographic data, including three questions from the European Health Interview Survey, regarding self-reported or by a physician-diagnosed depression. Moreover, to all participants the Greek validated version of the Geriatric Depression Scale-15 (GDS-15) was applied, to screen for depressive symptoms. RESULTS: According to GDS-15, 48.1% of the studied population screened positive for depressive symptoms (38.6% moderate, 9.5% severe), whereas having ever been affected with chronic depression reported 19.0% by themselves. In 162 members of KAPI of Patras and in 106 of Tripolis, who never reported have been affected by depression and depressive symptoms were observed in 27.7% and 44.7%, respectively. In 28 individuals from Patras, who reported not to know if they have depression and in 10 from Tripolis, depressive symptoms were observed in 60.7% and 90%, respectively, applying the GDS-15. CONCLUSION: Except the high prevalence, the present study reveals a remarkable under-detection of depressive symptoms in older adults. Various interventions in primary care are necessary so as to increase detection rates of depression among the elderly. PMID- 26600586 TI - Sexual dysfunction in women with epilepsy. AB - BACKGROUND: Sexual functioning and variables that influence sexual functioning have not been studied in Indian women with epilepsy. MATERIALS AND METHODS: In a pilot study, female (age, 18-45 years) outpatients with epilepsy who were in a stable sexual relationship for at least 1-year were screened using the mini international neuropsychiatric interview. Those without anxiety or depressive disorders (n = 60) were studied using the female sexual function index (FSFI; higher scores indicate better functioning). Findings were compared with age- and sex- matched sample of healthy control women drawn from the same sociodemographic population. RESULTS: Women with epilepsy had significantly poorer sexual functioning on all FSFI subscales (desire, arousal, lubrication, orgasm, satisfaction, pain), as well as on the total scale scores, and >70% of these women were rated as dysfunctional on individual FSFI subscales and on the total scale. In multivariate analysis, use of clobazam and phenobarbitone, and longer time after the last seizure were each associated with significantly higher FSFI scores; and longer duration of epilepsy was associated with significantly lower FSFI scores. CONCLUSION: There is a substantial impairment of sexual functioning in women with epilepsy. This study demonstrates the need for increased awareness of the problem, better case identification, and improved seizure control. PMID- 26600587 TI - QT prolongation and torsades de pointes with psychotropic agents. AB - The unexpected and catastrophic cardiovascular effects of psychotropic drugs are well described albeit uncommon. The list of drugs which have been associated with prolonging QT interval and hence potentially causing Torsades de pointes is exhaustive. The insight into the plausible mechanisms are largely unclear. However, the practical implications of anticipating and recognizing QT prolongation cannot be overemphasized. PMID- 26600588 TI - Disulfiram-induced seizures with convulsions in a young male patient: A case study. AB - Disulfiram is the aversive therapeutic agent which has been used to treat alcohol dependence more than 50 years. It causes the complications like neurological toxicity, postural hypotension, circulatory collapse, mental confusion, etc. The aim of our study was to report a rare case of disulfiram-induced seizures in a patient of alcohol dependence syndrome. This case study is about a 35-year-old male patient who had one episode of seizures during treatment with disulfiram. PMID- 26600589 TI - Prolonged, longstanding, ultra-high-dose abuse of sildenafil. AB - We report a 40-year-old male who self-administered sildenafil for 10 years, in progressively increasing doses from 100 mg per occasion in the 1(st) year to 1300 mg per occasion in the 9(th)-10(th) years of (ab)use. The frequency of abuse was 2-3/week. The only adverse effect of concern that was reported was transient (up to about 12 h), self-limited blurring of vision in the last 2 years, especially in the last 2 months at the highest dose. The patient was otherwise normal. This report is unique because it describes what may be the highest dose of sildenafil reported in literature, abused across a protracted period of time. We discuss issues related to dose and safety of and tolerance to the drug. PMID- 26600590 TI - A simple rearrangement can improve visual understanding of a Forest plot. PMID- 26600591 TI - The birth of national mental health program for India. AB - The adoption of the National Mental Health Programme (NMHP) in August 1982 was a milestone in the history of Indian psychiatry. Such an ambitious program was formulated at a time where there were <1000 psychiatrists is a triumph of need for mental health care in the country. The story of the NMHP, both in terms of the technical forces and the personalities needs to be recorded for posterity. The current article recalls the community mental health initiatives of Bengaluru and Chandigarh centers providing the reason for integrating mental health care with general health care and the support of the World Health Organization, along with the role of mental health professionals and the health administrators. The lesson that come through is the value of working together with different professionals for the common good. Recording the events for posterity is especially timely in view of the formulation of a new mental health policy and the revision of the national health policy during the last few months. PMID- 26600592 TI - "Marathon Boy": The use of film in problem-based learning in child psychiatry. PMID- 26600593 TI - Subacute sclerosing panencephalitis presenting with hypersexual behavior. PMID- 26600594 TI - Schizophrenia in identical twins. PMID- 26600595 TI - A rare association of schizophrenia and Mayer-Rokitansky-Kuster-Hauser syndrome. PMID- 26600596 TI - Late-onset neutropenia due to clozapine. PMID- 26600597 TI - Persistent genital arousal disorder: Successful treatment with leuprolide (antiandrogen). PMID- 26600598 TI - Safety and efficacy of ketamine infusion in late onset depression, and conversion to treatment response. PMID- 26600599 TI - Authors' reply. PMID- 26600600 TI - Simulation of stochastic diffusion via first exit times. AB - In molecular biology it is of interest to simulate diffusion stochastically. In the mesoscopic model we partition a biological cell into unstructured subvolumes. In each subvolume the number of molecules is recorded at each time step and molecules can jump between neighboring subvolumes to model diffusion. The jump rates can be computed by discretizing the diffusion equation on that unstructured mesh. If the mesh is of poor quality, due to a complicated cell geometry, standard discretization methods can generate negative jump coefficients, which no longer allows the interpretation as the probability to jump between the subvolumes. We propose a method based on the mean first exit time of a molecule from a subvolume, which guarantees positive jump coefficients. Two approaches to exit times, a global and a local one, are presented and tested in simulations on meshes of different quality in two and three dimensions. PMID- 26600603 TI - In this month's Bulletin. PMID- 26600604 TI - Improving mental health care in humanitarian emergencies. PMID- 26600606 TI - Public health round-up. PMID- 26600605 TI - Towards better estimates of uncorrected presbyopia. PMID- 26600607 TI - Health system in Yemen close to collapse. AB - Yemen is facing a growing humanitarian catastrophe as health workers there risk their lives to help civilians caught up in the deadly conflict. Dale Gavlak reports. PMID- 26600608 TI - The science of violence prevention. AB - Twenty years after Rodrigo Guerrero-Velasco treated violence like a disease, using epidemiology to find the causes, his approach to violence prevention has been taken up across the Americas. He talks to Alyssa Greenhouse. PMID- 26600609 TI - Availability and affordability of new medicines in Latin American countries where pivotal clinical trials were conducted. AB - OBJECTIVE: To assess whether new pharmaceutical products approved by the United States Food and Drug Administration (FDA) in 2011 and 2012 were registered, commercialized and sold at affordable prices in the Latin American countries where they were tested. METHODS: We obtained a list of new molecular entities (new pharmaceutical products) approved by the FDA in 2011 and 2012. FDA medical reviews indicated the countries where pivotal clinical trials had been conducted. The registration status of the products was obtained from pharmaceutical registers; pharmaceutical companies confirmed their availability in national markets and local pricing observatories provided the price of medicines in retail pharmacies. Affordability was assessed as the cost of a course of treatment as a proportion of monthly income. Information on safety and efficacy was gathered from independent drug bulletins. FINDINGS: Of an expected 114 registrations, if the 33 products had been registered in all the countries where tested, only 68 (60%) were completed. Eight products were registered and commercialized in all countries but 10 had not been registered in any of the countries. With one exception, products for which we obtained pricing information (n = 18) cost more than the monthly minimum wage in all countries and 12 products cost at least five times the monthly minimum wage. CONCLUSION: Many pharmaceutical products tested in Latin America are unavailable and/or unaffordable to most of the population. Ethical review committees should consider the local affordability and therapeutic relevance of new products as additional criteria for the approval of clinical trials. Finally, clinical trials have opportunity costs that need to be assessed. PMID- 26600610 TI - Betel quid use and mortality in Bangladesh: a cohort study. AB - OBJECTIVE: To evaluate the potential effects of betel quid chewing on mortality. (A quid consists of betel nut, wrapped in betel leaves; tobacco is added to the quid by some users). METHODS: Prospective data were available on 20 033 individuals aged 18-75 years, living in Araihazar, Bangladesh. Demographic and exposure data were collected at baseline using a standardized questionnaire. Cause of death was defined by verbal autopsy questionnaires administered to next of kin. We estimated hazard ratios (HR) and their 95% confidence intervals (CI) for associations between betel use and mortality from all causes and from specific causes, using Cox proportional hazards models. We adjusted for age, sex, body mass index, educational attainment and tobacco smoking history. FINDINGS: There were 1072 deaths during an average of 10 years of follow-up. Participants who had ever used betel were significantly more likely to die from all causes (HR: 1.26; 95% CI: 1.09-1.44) and cancer (HR: 1.55; 95% CI: 1.09-2.22); but not cardiovascular disease (HR: 1.16; 95% CI: 0.93-1.43). These findings were robust to adjustment for potential confounders. There was a dose-response relationship between mortality from all causes and both the duration and the intensity of betel use. The population attributable fraction for betel use was 14.1% for deaths from all causes and 24.2% for cancer. CONCLUSION: Betel quid use was associated with mortality from all causes and from cancer in this cohort. PMID- 26600611 TI - Evaluating the quality and use of economic data in decisions about essential medicines. AB - OBJECTIVE: To evaluate the quality of economic data provided in applications to the World Health Organization (WHO) Model List of Essential Medicines and to evaluate the role of these data in decision-making by the expert committee that considers the applications. METHODS: We analysed applications submitted to the WHO Expert Committee on the Selection and Use of Essential Medicines between 2002 and 2013. The completeness of data on the price and cost-effectiveness of medicines was extracted from application documents and coded using a four-point scale. We recorded whether or not the expert committee discussed economic information and the outcomes of each application. Associations between the completeness of economic data and application outcomes were assessed using chi2 tests. FINDINGS: The expert committee received 134 applications. Only eight applications (6%) included complete price data and economic evaluation data. Many applicants omitted or misinterpreted the economic evaluation section of the application form. Despite the lack of economic data, all applications were reviewed by the committee. There was no significant association between the completeness of economic information and application outcomes. The expert committee tried to address information gaps in applications by further review and analysis of data related to the application. CONCLUSION: The World Health Organization should revise the instructions to applicants on economic data requirements; develop new mechanisms to assist applicants in completing the application process; and define methods for the use of economic data in decision making. PMID- 26600612 TI - Interventions to improve adherence to treatment for paediatric tuberculosis in low- and middle-income countries: a systematic review and meta-analysis. AB - OBJECTIVE: To assess the design, delivery and outcomes of interventions to improve adherence to treatment for paediatric tuberculosis in low- and middle income countries and develop a contextual framework for such interventions. METHODS: We searched PubMed and Cochrane databases for reports published between 1 January 2003 and 1 December 2013 on interventions to improve adherence to treatment for tuberculosis that included patients younger than 20 years who lived in a low- or middle-income country. For potentially relevant articles that lacked paediatric outcomes, we contacted the authors of the studies. We assessed heterogeneity and risk of bias. To evaluate treatment success - i.e. the combination of treatment completion and cure - we performed random-effects meta analysis. We identified areas of need for improved intervention practices. FINDINGS: We included 15 studies in 11 countries for the qualitative analysis and of these studies, 11 qualified for the meta-analysis - representing 1279 children. Of the interventions described in the 15 studies, two focused on education, one on psychosocial support, seven on care delivery, four on health systems and one on financial provisions. The children in intervention arms had higher rates of treatment success, compared with those in control groups (odds ratio: 3.02; 95% confidence interval: 2.19-4.15). Using the results of our analyses, we developed a framework around factors that promoted or threatened treatment completion. CONCLUSION: Various interventions to improve adherence to treatment for paediatric tuberculosis appear both feasible and effective in low- and middle-income countries. PMID- 26600613 TI - The feasibility of eliminating podoconiosis. AB - Podoconiosis is an inflammatory disease caused by prolonged contact with irritant minerals in soil. Major symptoms include swelling of the lower limb (lymphoedema) and acute pain. The disease has major social and economic consequences through stigma and loss of productivity. In the last five years there has been good progress in podoconiosis research and control. Addressing poverty at household level and infrastructure development such as roads, water and urbanization can all help to reduce podoconiosis incidence. Specific control methods include the use of footwear, regular foot hygiene and floor coverings. Secondary and tertiary prevention are based on the management of the lymphoedema-related morbidity and include foot hygiene, foot care, wound care, compression, exercises, elevation of the legs and treatment of acute infections. Certain endemic countries are taking the initiative to include podoconiosis in their national plans for the control of neglected tropical diseases and to scale up interventions against the disease. Advocacy is needed for provision of shoes as a health intervention. We suggest case definitions and elimination targets as a starting point for elimination of the disease. PMID- 26600614 TI - A national system for monitoring the performance of hospitals in Ethiopia. AB - Many countries struggle to develop and implement strategies to monitor hospitals nationally. The challenge is particularly acute in low-income countries where resources for measurement and reporting are scarce. We examined the experience of developing and implementing a national system for monitoring the performance of 130 government hospitals in Ethiopia. Using participatory observation, we found that the monitoring system resulted in more consistent hospital reporting of performance data to regional health bureaus and the federal government, increased transparency about hospital performance and the development of multiple quality improvement projects. The development and implementation of the system, which required technical and political investment and support, would not have been possible without strong hospital-level management capacity. Thorough assessment of the health sector's readiness to change and desire to prioritize hospital quality can be helpful in the early stages of design and implementation. This assessment may include interviews with key informants, collection of data about health facilities and human resources and discussion with academic partners. Aligning partners and donors with the government's vision for quality improvement can enhance acceptability and political support. Such alignment can enable resources to be focused strategically towards one national effort - rather than be diluted across dozens of potentially competing projects. Initial stages benefit from having modest goals and the flexibility for continuous modification and improvement, through active engagement with all stakeholders. PMID- 26600615 TI - Improving mortality data in Jordan: a 10 year review. AB - PROBLEM: Before 2003 there was substantial underreporting of deaths in Jordan. The death notification form did not comply with World Health Organization (WHO) guidelines and information on the cause of death was often missing, incomplete or inaccurate. APPROACH: A new mortality surveillance system to determine the causes of death was implemented in 2003 and a unit for coding causes of death was established at the ministry of health. LOCAL SETTING: Jordan is a middle-income country with a population of 6.4 million people. Approximately 20 000 deaths were registered per year between 2005 and 2011. RELEVANT CHANGES: In 2001, the ministry of health organized the first meeting on Jordan's mortality system, which yielded a five-point plan to improve mortality statistics. Using the recommendations produced from this meeting, in 2003 the ministry of health initiated a mortality statistics improvement project in collaboration with international partners. Jordan has continued to improve its mortality reporting system, with annual reporting since 2004. Reports are based on more than 70% of reported deaths. The quality of cause-of-death information has improved, with only about 6% of deaths allocated to symptoms and ill-defined conditions - a substantial decrease from the percentage before 2001 (40%). Mortality information is now submitted to WHO following international standards. LESSONS LEARNT: After 10 years of mortality surveillance in Jordan, the reporting has improved and the information has been used by various health programmes throughout Jordan. PMID- 26600617 TI - Counterterrorism policies and practices: health and values at stake. PMID- 26600616 TI - Improving paediatric asthma care in Zambia. AB - PROBLEM: In 2008, the prevalence of paediatric asthma in Zambia was unknown and the national treatment guideline was outdated. APPROACH: We created an international partnership between Zambian clinicians, the Zambian Government and a pharmaceutical company to address shortcomings in asthma treatment. We did two studies, one to estimate prevalence in the capital of Lusaka and one to assess attitudes and practices of patients. Based on the information obtained, we educated health workers and the public. The information from the studies was also used to modernize government policy for paediatric asthma management. LOCAL SETTING: The health-care system in Zambia is primarily focused on acute care delivery with a focus on infectious diseases. Comprehensive services for noncommunicable diseases are lacking. Asthma management relies on treatment of acute exacerbations instead of disease control. RELEVANT CHANGES: Seven percent of children surveyed had asthma (255/3911). Of the 120 patients interviewed, most (82/120, 68%) used oral short-acting beta2-agonists for symptom control; almost half (59/120, 49%) did not think the symptoms were preventable and 43% (52/120) thought inhalers were addictive. These misconceptions informed broad-based educational programmes. We used a train-the-trainer model to educate health-care workers and ran public awareness campaigns. Access to inhalers was increased and the Zambian standard treatment guideline for paediatric asthma was revised to include steroid inhalers as a control treatment. LESSONS LEARNT: Joint activities were required to change paediatric asthma care in Zambia. Success will depend on local sustainability, and it may be necessary to shift resources to mirror the disease burden. PMID- 26600618 TI - Improving antenatal care in prisons. PMID- 26600619 TI - Alcohol policy scores: data and analysis. PMID- 26600620 TI - Methodological and statistical considerations in alcohol policy evaluation. PMID- 26600621 TI - Corrigendum. AB - [This corrects the article DOI: 10.2471/BLT.14.148056.]. PMID- 26600622 TI - Primary health care: a necessary, current and profitable investment. PMID- 26600623 TI - Sodium bicarbonate versus isotonic saline solution to prevent contrast-induced nephropathy : a systematic review and meta-analysis. AB - INTRODUCTION: Contrast-induced nephropathy is one of the main causes of acute kidney injury and increased hospital-acquired morbidity and mortality. The use of sodium bicarbonate for nephroprotection has emerged as a preventative strategy; however, its efficacy is controversial compared to other strategies, such as hydration using 0.9% saline solution. OBJECTIVE: To compare the effectiveness of sodium bicarbonate vs. hydration using 0.9% saline solution to prevent contrast induced acute kidney injury. METHODS: A systematic review of studies registered in the COCHRANE, PUBMED, MEDLINE, LILACS, SCIELO and EMBASE databases was conducted. Randomized controlled studies that evaluated the use of 0.9% saline solution vs. sodium bicarbonate to prevent contrast-induced nephropathy were included. RESULTS: A total of 22 studies (5,686 patients) were included. Sodium bicarbonate did not decrease the risk of contrast-induced nephropathy (RD= 0.00; 95% CI= -0.02 to 0.03; p= 0.83; I(2)= 0%). No significant differences were found in the demand for renal replacement therapy (RD= 0.00; 95% CI= -0.01 to 0-01; I(2)= 0%; p= 0.99) or in mortality (RD= -0.00; 95% CI= -0.001 to 0.001; I(2)= 0%; p= 0.51). CONCLUSIONS: Sodium bicarbonate administration is not superior to the use of 0.9% saline solution for preventing contrast-induced nephropathy in patients with risk factors, nor is it better at reducing mortality or the need for renal replacement therapy. PMID- 26600624 TI - Phyllodes tumor of the breast: a clinic-pathologic study of 77 cases in a Hispanic cohort. AB - INTRODUCTION: Breast Phyllodes tumors are rare breast tumors present in less than 1% of new cases of breast cancer, usually occurring among middle-aged women (40 50 yrs). OBJECTIVE: This study shows diagnostic experience, surgical management and follows up of patients with this disease during a period of ten years in a oncology referral center. METHODS: Retrospectively, breast cancer registries at the institution were reviewed, identifying 77 patients with Phyllodes tumors between 2002 and 2012, who had been operated on at the Instituto de Cancerologia Clinica Las Americas, in Medellin (Colombia). Clinical and histopathological data belonging to these cases was captured and analyzed and descriptive statistics were used. RESULTS: The follow up median was 22.5 months (IQR: 10.5 60.0), average age was 47.2 yrs (SD: 12.4), mean tumor size was 3.6 cm (SD: 4.6), 88.3% of the patients (68 cases) presented negative margins and none of them received adjuvant chemotherapy. Of the patients with Phyllodes tumors; 33.8% had benign, 31.2% had borderline and 35.0% had malignant tumor. Disease-free survival was 85.8% and overall survival was 94.5%. DISCUSSION: Reported data in this article is in accordance with what has been reported in worldwide literature. In our cohort even the high mean size of the tumors, the risk of local relapse and metastatic disease is low than previously reported in literature. Trials with longer follow up and molecular trials in Phyllodes tumors are necessary to understand the behavior of these tumors in Hispanics population. PMID- 26600625 TI - In vitro-in vivo Pharmacokinetic correlation model for quality assurance of antiretroviral drugs. AB - INTRODUCTION: The in vitro-in vivo pharmacokinetic correlation models (IVIVC) are a fundamental part of the drug discovery and development process. The ability to accurately predict the in vivo pharmacokinetic profile of a drug based on in vitro observations can have several applications during a successful development process. OBJECTIVE: To develop a comprehensive model to predict the in vivo absorption of antiretroviral drugs based on permeability studies, in vitro and in vivo solubility and demonstrate its correlation with the pharmacokinetic profile in humans. METHODS: Analytical tools to test the biopharmaceutical properties of stavudine, lamivudine y zidovudine were developed. The kinetics of dissolution, permeability in caco-2 cells and pharmacokinetics of absorption in rabbits and healthy volunteers were evaluated. RESULTS: The cumulative areas under the curve (AUC) obtained in the permeability study with Caco-2 cells, the dissolution study and the pharmacokinetics in rabbits correlated with the cumulative AUC values in humans. These results demonstrated a direct relation between in vitro data and absorption, both in humans and in the in vivo model. CONCLUSIONS: The analytical methods and procedures applied to the development of an IVIVC model showed a strong correlation among themselves. These IVIVC models are proposed as alternative and cost/effective methods to evaluate the biopharmaceutical properties that determine the bioavailability of a drug and their application includes the development process, quality assurance, bioequivalence studies and pharmacosurveillance. PMID- 26600626 TI - Analysis of the LRRK2 p.G2019S mutation in Colombian Parkinson's Disease Patients. AB - INTRODUCTION: Mutations in the leucine-rich repeat kinase 2 gene (LRRK2 or Dardarin) are considered to be a common cause of autosomal dominant and sporadic Parkinson's disease, but the prevalence of these mutations varies among populations. OBJECTIVE: to analyzed the frequency of the LRRK2 p.G2019S mutation (c.6055 G>A transition) in a sample of Colombian patients. METHODS: In the present study we have analyzed the frequency of the LRRK2 p.G2019S mutation in 154 patients with familial or sporadic Parkinson Disease, including early and late onset patients, and 162 normal controls. RESULTS: Our results show occurrence of this mutation in two cases (2/154, 1.3%) with classical Parkinson's signs, and one completely asymptomatic control (1/162, 0.6%). CONCLUSION: The p.G2019S mutation is not an important causal factor of Parkinson Disease in Colombia having similar frequencies to those reported in other Latin American populations. PMID- 26600628 TI - Transdiscipline and research in health: science, society and decision making. AB - Significant advances in science should be given to addressing the needs of society and the historical context of the territories. Although technological developments that began with modernity and the industrial revolution allowed human beings to control the resources of nature to put to your service without limits, it is clear that the crisis of the prevailing development models manifest themselves in many ways but with three common denominators: environmental degradation, social injustice and extreme poverty. Consequently, today should not be possible to think a breakthrough in the development of science without addressing global environmental problems and the deep social injustices that increase at all scales under the gaze, impassively in many occasions, of formal science. PMID- 26600627 TI - Porphyromonas gingivalis Fim-A genotype distribution among Colombians. AB - INTRODUCTION: Porphyromonas gingivalis is associated with periodontitis and exhibit a wide array of virulence factors, including fimbriae which is encoded by the FimA gene representing six known genotypes. OBJETIVE: To identify FimA genotypes of P. gingivalis in subjects from Cali-Colombia, including the co infection with Aggregatibacter actinomycetemcomitans, Treponema denticola, and Tannerella forsythia. METHODS: Subgingival samples were collected from 151 people exhibiting diverse periodontal condition. The occurrence of P. gingivalis, FimA genotypes and other bacteria was determined by PCR. RESULTS: P. gingivalis was positive in 85 patients. Genotype FimA II was more prevalent without reach significant differences among study groups (54.3%), FimA IV was also prevalent in gingivitis (13.0%). A high correlation (p= 0.000) was found among P. gingivalis, T. denticola, and T. forsythia co-infection. The FimA II genotype correlated with concomitant detection of T. denticola and T. forsythia. CONCLUSIONS: Porphyromonas gingivalis was high even in the healthy group at the study population. A trend toward a greater frequency of FimA II genotype in patients with moderate and severe periodontitis was determined. The FimA II genotype was also associated with increased pocket depth, greater loss of attachment level, and patients co-infected with T. denticola and T. forsythia. PMID- 26600630 TI - Incorporation of the health care system in the west. AB - A reflection is made, from an interpretative perspective, on the historical evolution of health care in the West. It starts from the moment that this became a way to intervene the sick and an instrument for healing diseases, focusing on original documents and written sources which account for results of historical research, which range from XV century until today. To do this, it tries to understand the health care as an ideographic body of knowledge consisting of five pieces of a puzzle composed by: the state policy of hospitals accumulation implemented in Spain, the accumulation of medical practices in what is currently Germany, the hospital wards in England, the nosological rationality in France, and the US sanitizing machine; all these movements as producers of closely linked health care developments, that are nothing more than collective actions regulated by social norms around health. PMID- 26600629 TI - A systematic review of observational studies on oxidative/nitrosative stress involvement in dengue pathogenesis. AB - OBJECTIVE: Our objective was to systematically review the published observational research related to the role of oxidative-nitrosative stress in pathogenesis of dengue. METHODS: We searched electronic databases (PubMed, EMBASE, The COCHRANE library, ScienceDirect, Scopus, SciELO, LILACS via Virtual Health Library, Google Scholar) using the term: dengue, dengue virus, severe dengue, oxidative stress, nitrosative stress, antioxidants, oxidants, free radicals, oxidized lipid products, lipid peroxides, nitric oxide, and nitric oxide synthase. Articles were selected for review by title and abstract excluding letter, review, in vivo and in vitro studies, and duplicates studies. Selected articles were reviewed for study design, original purposes, sample size, main outcomes, methods, and oxidative-nitrosative stress markers values. RESULTS: In total, 4,331 non duplicates articles were identified from electronic databases searches, of which 16 were eligible for full text searching. Data from the observational studies originate from Asian countries (50%; 8/16), South American countries (31.2%; 5/16), and Central America and the Caribbean countries (18.8%; 3/16). Case control study was the type of design most common in researches reviewed. The 1997 World Health Organization (WHO) dengue case classification criteria were used in all studies included in this review. CONCLUSIONS: Based on published data found in peer-reviewed literature, oxidative and nitrosative stress are demonstrated by changes in plasma levels of nitric oxide, antioxidants, lipid peroxidation and protein oxidation markers in patients with dengue infection. Additionally, elevated serum protein carbonyls and malondialdehyde levels appear to be associated with dengue disease severity. PMID- 26600631 TI - Molecular analysis of exons 8, 9 and 10 of the fibroblast growth factor receptor 2 (FGFR2) gene in two families with index cases of Apert Syndrome. AB - INTRODUCTION: Apert syndrome (AS) is a craniosynostosis condition caused by mutations in the Fibroblast Growth Factor Receptor 2 (FGFR2) gene. Clinical features include cutaneous and osseous symmetric syndactily in hands and feet, with variable presentations in bones, brain, skin and other internal organs. METHODS: Members of two families with an index case of Apert Syndrome were assessed to describe relevant clinical features and molecular analysis (sequencing and amplification) of exons 8, 9 and 10 of FGFR2 gen. RESULTS: Family 1 consists of the mother, the index case and half -brother who has a cleft lip and palate. In this family we found a single FGFR2 mutation, S252W, in the sequence of exon 8. Although mutations were not found in the study of the patient affected with cleft lip and palate, it is known that these diseases share signaling pathways, allowing suspected alterations in shared genes. In the patient of family 2, we found a sequence variant T78.501A located near the splicing site, which could interfere in this process, and consequently with the protein function. PMID- 26600632 TI - Role of pharmacology for integration of modern medicine and Ayurveda. PMID- 26600633 TI - The imidazoline receptors and ligands in pain modulation. AB - Pain is an unpleasant experience and effects daily routine negatively. Although there are various drugs, many of them are not entirely successful in relieving pain, since pain modulation is a complex process involving numerous mediators and receptors. Therefore, it is a rational approach to identify the factors involved in the complex process and develop new agents that act on these pain producing mechanisms. In this respect, the involvement of the imidazoline receptors in pain modulation has drawn attention in recent years. In this review, it is aimed to focus on the imidazoline receptors and their ligands which contribute to the pain modulation. It is demonstrated that imidazoline-2 (I2) receptors are steady new drug targets for analgesics. Even if the mechanism of I2 receptor is not well known in the modulation of pain, it is known that it plays a role in tonic and chronic pain but not in acute phasic pain. Moreover, the I2 receptor ligands increase the analgesic effects of opioids in both acute and chronic pain and prevent the development of opioid tolerance. So, they are valuable for the chronic pain treatment and also therapeutic coadjuvants in the management of chronic pain with opiate drugs due to the attenuation of opioid tolerance and addiction. Thus, the use of the ligands which bind to the imidazoline receptors is an effective strategy for relieving pain. This educational forum exhibits the role of imidazoline receptors and ligands in pain process by utilizing experimental studies. PMID- 26600634 TI - TNFerade, an innovative cancer immunotherapeutic. AB - Tumor necrosis factor-alpha (TNF-alpha) is a chemokine with effective tumoricidal properties. However, severe systemic toxicity limits its use of as anticancer agent. TNFerade is a novel replication deficient adenovector based gene therapy, which enables the radiation inducible translation of human TNF-alpha gene specifically in cancer cells. When injected intratumorally, it has least systemic distribution. Consequently, it lacks TNF-alpha related systemic toxicity. Evidence suggests that it has superior tumoricidal activity and tolerability with minimum adverse effects. It has demonstrated its beneficial role in the treatment of a variety of cancers in terms of improving the disease free and overall survival, delaying tumor progression, and inducing tumor regression when used with concurrent radiotherapy or chemotherapy. PMID- 26600635 TI - Psychopharmacoteratophobia: Excessive fear of malformation associated with prescribing psychotropic drugs during pregnancy: An Indian perspective. AB - "Psychopharmacoteratophobia is the fear or avoidance of prescribing psychotropic medicine to a pregnant woman on a given indication in anticipation of fetal malformation." It is rooted in the tragedy associated with thalidomide use and is increasing due to the inability to predict accurately, strict legal provision of consumer protection, ethical and legal issues involved, and pitfalls in the available evidence of teratogenicity. In the Indian setting, the physicians face more challenges as the majority of the patients may ask them to decide, what is the best for their health. Most guidelines emphasize more on what not to do than what to do, and the locus of decision is left to the doctor and the patient. In this review, we have focused on relevant issues related to psychopharmacoteraophobia that may be helpful to understand this phenomenon and help to address the deprivation of a mentally ill woman from the required treatment. PMID- 26600636 TI - Comparison of preoperative nepafenac (0.1%) and flurbiprofen (0.03%) eye drops in maintaining mydriasis during small incision cataract surgery in patients with senile cataract: A randomized, double-blind study. AB - AIMS: This study compared the effectiveness of prophylactic administration of topical flurbiprofen 0.03% and nepafenac 0.1% in maintaining mydriasis during small incision cataract surgery (SICS). MATERIALS AND METHODS: This study was a prospective, randomized, double-blind comparative study in adult cataract patients given topical flurbiprofen or nepafenac prior to SICS and capsular bag intraocular lens (IOL) implantation at a tertiary care hospital. Horizontal and vertical diameters of pupil were measured at the beginning and end of surgery, and the mean values were compared across the two groups. Unpaired t-test and Fisher's exact test were used to analyse the results. RESULTS: A total of 70 eyes of cataract surgery patients, 33 males and 37 females, with a mean age of 58.5 +/ 11.24 years, were included in the study. The mean horizontal and vertical diameters of the two groups were similar at the start of surgery. Significant differences were seen after IOL implantation, with the nepafenac group having the larger mean diameters in both horizontal (P = 0.03) and vertical (P = 0.04) pupillary measurements. CONCLUSIONS: Topical nepafenac has been shown to be a more effective inhibitor of meiosis during SICS and provides a more stable mydriatic effect compared to topical flurbiprofen. PMID- 26600637 TI - Pricing and availability of some essential child specific medicines in Odisha. AB - OBJECTIVES: Continuous availability of affordable medicines in appropriate formulations is essential to reduce morbidity and mortality in children. Odisha an eastern Indian state records very high mortality of children. The study aims at documenting the availability and prices paid for purchasing essential child specific medicines. MATERIALS AND METHODS: The survey of 34 essential medicines was conducted in six randomly selected districts of Odisha. Data were collected from medicine outlets of the public, private, and other sector (Nongovernmental Organization [NGO]/mission sectors) of six randomly selected districts, using WHO/Health Action International medicine price collection methodology. For each medicine surveyed, data were collected on the highest and lowest-priced formulations available in each facility. RESULTS: Both public sector and other sector health facilities procure only one brand of medicines, mean percentage availability of medicines being 17% and 21.8%, respectively. In the private sector, the mean percentage availability of the high and lowest-priced medicines for a particular drug product was 10.8% and 38.5%, respectively. The public sector procurement price is 48% lower than international reference prices. In the private sector, high-priced, and low-priced products are sold at 1.83 and 1.46 times the international reference price, respectively. Substantial price variation was observed for some medicines across individual outlets. Medicines were found to cost 2.08 times their international reference price in NGO/mission sector facilities. CONCLUSIONS: The availability of children's medicines in public sector facilities of Odisha state is poor. Medicines for children cost relatively high in both private and NGO sectors compared to the international reference price. The availability medicines should be improved on an urgent basis to improve access of medicines for children of Odisha. PMID- 26600638 TI - Assessment of serum magnesium levels and its outcome in neonates of eclamptic mothers treated with low-dose magnesium sulfate regimen. AB - OBJECTIVES: Magnesium historically has been used for treatment and/or prevention of eclampsia. Considering the low body mass index of Indian women, a low-dose magnesium sulfate regime has been introduced by some authors. Increased blood levels of magnesium in neonates is associated with increased still birth, early neonatal death, birth asphyxia, bradycardia, hypotonia, gastrointestinal hypomotility. The objective of this study was to assess safety of low-dose magnesium sulfate regimen in neonates of eclamptic mothers treated with this regimen. MATERIALS AND METHODS: This was a cross-sectional observational study of 100 eclampsia patients and their neonates. Loading dose and maintenance doses of magnesium sulfate were administered to patients by combination of intravenous and intramuscular routes. Maternal serum and cord blood magnesium levels were estimated. Neonatal outcome was assessed. RESULTS: Bradycardia was observed in 18 (19.15%) of the neonates, 16 (17.02%) of the neonates were diagnosed with hypotonia. Pearson Correlation Coefficient showed Apgar scores decreased with increase in cord blood magnesium levels. Unpaired t-test showed lower Apgar scores with increasing dose of magnesium sulfate. The Chi-square/Fisher's exact test showed significant increase in hypotonia, birth asphyxia, intubation in delivery room, Neonatal Intensive Care Unit (NICU) care requirement, with increasing dose of magnesium sulfate. (P <= 0.05). CONCLUSION: Several neonatal complications are significantly related to increasing serum magnesium levels. Overall, the low-dose magnesium sulfate regimen was safe in the management of eclamptic mothers, without toxicity to their neonates. PMID- 26600639 TI - Antidiabetic and antihyperlipidemic activities of a novel polyherbal formulation in high fat diet/streptozotocin induced diabetic rat model. AB - OBJECTIVE: To investigate the antidiabetic and antihyperlipidemic activities of polyherbal formulation (PHF) containing hydroalcoholic extracts of four plants namely Salacia oblonga, Salacia roxbhurgii, Garcinia indica and Lagerstroemia parviflora in streptozotocin (STZ)-induced diabetic rats by administering oral doses (200 and 400 mg/kg body weight). MATERIALS AND METHODS: Animals were divided into diabetic and nondiabetic groups. Rats were fed with a high-fat diet (HFD) and induced with a single low dose of STZ (35 mg/kg) i.p. Diabetic rats were treated with formulation (200 and 400 mg/kg) and metformin 250 mg/kg. Blood glucose levels were measured using blood glucose test strips with ACCU CHEK glucometer. Lipid profile and gluconeogenic enzymes were determined in normal and STZ-induced diabetic rats after oral administration of the PHF for 28 days. Histopathological changes in diabetic rat organs (pancreas, liver, and kidney) were also observed after PHF treatment. RESULTS: Treatment of diabetic rats with PHF and metformin decreased plasma glucose and lipid profile levels. Blood glucose level showed significant reduction after 28 days of treatment with formulation at 200 and 400 mg/kg and in metformin. Formulation treated rats showed significant (P < 0.001) decrease in the activities of gluconeogenic enzymes. Histological examination of various organ tissues of normal control, diabetic control, and drug-treated rats revealed significant results. Treatment with PHF reverses the most blood and tissue changes toward the normal level. CONCLUSION: These findings suggested the antihyperglycemic and antihyperlipidemic properties of the PHF and thus help in preventing future complications of diabetes. PMID- 26600640 TI - Standard of reporting animal-based experimental research in Indian Journal of Pharmacology. AB - OBJECTIVE: The objective of present study was to survey and determine the reporting standards of animal studies published during three years from 2012 to 2014 in the Indian Journal of Pharmacology (IJP). MATERIAL AND METHODS: All issues of IJP published in the year 2012, 2013 and 2014 were reviewed to identify animal studies. Each animal study was searched for 15 parameters specifically designed to review standards of animal experimentation and research methodology. OBSERVATION: All published studies had clearly defined aims and objectives while a statement on ethical clearance about the study protocol was provided in 97% of papers. Information about animal strain and sex was given in 91.8% and 90% of papers respectively. Age of experimental animals was mentioned by 44.4% papers while source of animals was given in 50.8% papers. Randomization was reported by 37.4% while 9.9% studies reported blinding. Only 3.5% studies mentioned any limitations of their work. CONCLUSION: Present study demonstrates relatively good reporting standards in animal studies published in IJP. The items which need to be improved are randomization, blinding, sample size calculation, stating the limitations of study, sources of support and conflict of interest. The knowledge shared in the present paper could be used for better reporting of animal based experiments. PMID- 26600641 TI - Some newer marker phytoconstituents in methanolic extract of Moringa oleifera leaves and evaluation of its immunomodulatory and splenocytes proliferation potential in rats. AB - OBJECTIVES: The present study was undertaken to unravel the newer marker phytoconstituents in methanolic extract of Moringa oleifera leaves (MOLE) and evaluation of its immunomodulatory and splenocytes proliferation potential in rats. MATERIALS AND METHODS: Hot methanolic extract of MOLE was subjected to gas chromatography-mass spectrometry (GC-MS) analysis. Immunomodulatory potential was studied in four groups of rats following administration of MOLE at 62.5 and 125 mg/kg for 21 days, followed by immunization with Salmonella typhimurium "O" antigen and antibody titer determined using indirect enzyme-linked immunosorbent assay kit. Total lymphocytes and T- and B-lymphocytes count were determined in control and after MOLE administration (62.5 and 125 mg/kg) to rats for 42 days. Splenocytes (2 * 10(6) spleen cells/ml) from MOLE treated rats were harvested and stimulated using concanavalin A and optical density (OD) and stimulation index were determined. Splenocytes from healthy control rats were also collected and treated in vitro with different concentrations of MOLE (5, 10, 25, 50, and 100 ug/ml) and concanavalin A to determine effect of MOLE on OD and stimulation index. RESULTS: GC-MS analysis revealed presence of 9,12,15-octadecatrienoic acid ethyl ester, 6-octadecenoic acid, cis-vaccenic acid and 2-octyl cyclopropaneoctanal in MOLE. MOLE at 125 mg/kg increased the antibody titer by 50%. Although there was slight decline in lymphocytes count (total, B- and T lymphocytes) in MOLE treated rats, percentage of T-lymphocytes was increased nonsignificantly. Ex vivo and in vitro studies revealed marked increase in OD and stimulation index indicating MOLE-induced splenocytes proliferation. CONCLUSION: GC-MS study revealed four new compounds in MOLE apart from promising its immunomodulatory potential based on humoral immune response, percentage increase in T-lymphocytes count, and induction of splenocytes proliferation. PMID- 26600642 TI - Trends in self-medication for dental conditions among patients attending oral health outreach programs in coastal Karnataka, India. AB - OBJECTIVES: To determine the prevalence, pattern, and awareness of self medication practices among patients presenting at oral health outreach programs in coastal Karnataka, India. MATERIALS AND METHODS: The cross-sectional study, based on an interview conducted in randomly selected 400 study subjects from the patients presenting at these oral health outreach programs. Data were collected regarding demographic information and the interview schedule consisting of 14 questions was administered. RESULTS: Prevalence of self-medication was 30%. Respondents' gender (chi(2) = 5.095, P < 0.05), occupation (chi(2) = 10.215, P < 0.05), the time from the last dental visit (chi(2) = 8.108, P < 0.05), recommendation of drug(s) to family members or friends (chi(2) = 75.565, P < 0.001), and the likelihood of self-medication in the next 6 months (chi(2) = 80.999, P < 0.001) were significantly associated with self-medication. Male respondents were less likely to have undertaken self-medication (odds ratio = 0.581 [0.361, 0.933]). The frequently self-medicated drug was analgesics (42.5%) for toothache (69.2%). The regression model explained 39.4% (Nagelkerke R(2)) of the variance in self-medication practices. CONCLUSIONS: Prevalence of self medication was 30% with demographic influence. Hence, this study highlights the policy implications for drug control by government agencies and stresses on the need for dental health education to discourage irrational drug use. PMID- 26600643 TI - Interaction potential of Trigonella foenum graceum through cytochrome P450 mediated inhibition. AB - OBJECTIVE: The seeds of Trigonella foenum-graecum (TFG) (family: Leguminosae) are widely consumed both as a spice in food and Traditional Medicine in India. The present study was undertaken to evaluate the inhibitory effect of standardized extract of TFG and its major constituent trigonelline (TG) on rat liver microsome (RLM) and cytochrome P450 (CYP450) drug metabolizing isozymes (CYP3A4 and CYP2D6), which may indicate the possibility of a probable unwanted interaction. MATERIALS AND METHODS: Reverse phase-high performance liquid chromatography method was developed to standardize the hydroalcoholic seed extract with standard TG. The inhibitory potential of the extract and TG was evaluated on RLM and CYP isozymes using CYP450-carbon monoxide (CYP450-CO) complex assay and fluorescence assay, respectively. RESULTS: The content of TG in TFG was found to be 3.38% (w/w). The CYP-CO complex assay showed 23.32% inhibition on RLM. Fluorescence study revealed that the extract and the biomarker had some inhibition on CYP450 isozymes e.g. CYP3A4 and CYP2D6 (IC50 values of the extract: 102.65 +/- 2.63 142.23 +/- 2.61 ug/ml and TG: 168.73 +/- 4.03-180.90 +/- 2.49 ug/ml) which was very less compared to positive controls ketoconazole and quinidine. Inhibition potential of TFG was little higher than TG but very less compared to positive controls. CONCLUSIONS: From the present study, we may conclude that the TFG or TG has very less potential to inhibit the CYP isozymes (CYP3A4, CYP2D6), so administration of this plant extract or its biomarker TG may be safe. PMID- 26600644 TI - Short-term differences in drug prices after implementation of the national essential medicines system: A case study in rural Jiangxi Province, China. AB - OBJECTIVES: China's 2009 national essential medicine system (NEMS) was designed to reduce prices through a zero-markup policy and a centralized bidding system. To analyze NEMS's short-term impact on drug prices, we estimated the retail and wholesale prices before and after the reform at health institutions in rural Jiangxi Province. MATERIALS AND METHODS: We undertook two cross-sectional surveys of prices of 39 medicines in November 2008 and May 2010, calculated inflation adjusted prices, and used the Wilcoxon signed-rank and rank-sum tests to examine price changes at different health institutions. RESULTS: Retail prices at pilot (P < 0.01) and nonpilot (P < 0.01) township health centers decreased significantly, whereas the declines at retail pharmacies (P = 0.57) and village clinics (P = 0.29) were insignificant. The decline at pilot township health centers was the largest, compared with other kinds of health institutions (P < 0.01). Retail prices of essential and non-essential medicines declined significantly at pilot facilities (P < 0.05); price drops for non-essential medicines occurred only at pilot facilities (P < 0.05). No significant decline of wholesale prices were found at pilot (P = 0.86) and nonpilot units (P = 0.18), retail pharmacies (P = 0.18), and village clinics (P = 0.20). The wholesale prices changes at pilot units before and after the reform were higher than at nonpilot public units (P < 0.05), retail pharmacies (P < 0.05), and village clinics (P < 0.05). CONCLUSION: While the NEMS zero-markup policy significantly reduced retail prices at pilot health institutions, the centralized bidding system was insufficient to lower wholesale prices. A drug price management system should be constructed to control medicine prices and a long-term price information system is needed to monitor price changes. PMID- 26600645 TI - Effects of aqueous extract of Hibiscus sabdariffa on the renin-angiotensin aldosterone system of Nigerians with mild to moderate essential hypertension: A comparative study with lisinopril. AB - OBJECTIVES: The present study investigated the effects of aqueous extract of Hibiscus sabdariffa (HS) on the three basic components of renin-angiotensin aldosterone system: Plasma renin, serum angiotensin-converting enzyme (ACE), and plasma aldosterone (PA) in mild to moderate essential hypertensive Nigerians and compared with that of lisinopril, an ACE inhibitor. MATERIALS AND METHODS: A double-blind controlled randomized clinical study was used. Seventy-eight newly diagnosed but untreated mild to moderate hypertensive subjects attending Medical Outpatients Clinic of Enugu State University Teaching Hospital, Enugu were recruited for the study. Those in Group A received placebo (150 mg/kg/day), Group B were given lisinopril (10 mg once daily) while those in Group C received aqueous extract of HS (150 mg/kg/day). After 4 weeks of treatment, the levels of plasma renin, serum ACE, and PA were determined. RESULTS: HS and lisinopril significantly (P < 0.001) reduced PA compared to placebo by 32.06% and 30.01%, respectively. Their effects on serum ACE and plasma renin activity (PRA) were not significant compared to placebo; they reduced ACE by 6.63% and 5.67% but increased plasma PRA by 2.77% and 5.36%, respectively. CONCLUSION: HS reduced serum ACE and PA in mild to moderate hypertensive Nigerians with equal efficacy as lisinopril. These actions are possibly due to the presence of anthocyanins in the extract. PMID- 26600646 TI - Structured oral examination in pharmacology for undergraduate medical students: Factors influencing its implementation. AB - OBJECTIVES: The study aims to understand the process and factors influencing the implementation of structured oral examination (SOE) for undergraduate medical students; in comparison with conventional oral examination (COE) in pharmacology. METHODS: In a randomized, parallel group study, 123 students of pharmacology were divided into two groups, SOE (n = 63) and COE (n = 60). Students of each group were subdivided into two, and four examiners took viva voce individually. Three sets of questionnaires from autonomic nervous system were prepared, each having 15 items with increasing difficulty levels and were validated by subject experts and pretested. Ten minutes were allotted for each student for each viva. Feedback of students and faculty about the novel method was obtained. RESULTS: SOE yielded significantly lower marks as compared to COE. There were significant inter examiner variations in marks awarded in SOE and COE. Other factors influencing implementation were difficulty in structuring viva, rigid time limits, lack of flexibility in knowledge content, monotony, and fatigue. The students perceived this format not different from COE but felt that it required in-depth preparation of topic. Faculty opined that SOE led to less drift from main topic and provided uniform coverage of topics in given time. CONCLUSION: Conducting SOE is a resource-intensive exercise. Despite structuring, inter-examiner variability was not completely eliminated. The students' performance was depended on factors related to examiners such as teaching experience, vernacular language used, and lack of training. Orientation and training of examiners in assessment strategies is necessary. Standardization of questionnaire is necessary before the implementation of SOE for summative assessment. PMID- 26600647 TI - Assessment of quality of life in epilepsy patients receiving anti-epileptic drugs in a tertiary care teaching hospital. AB - OBJECTIVES: Health-related quality of life (QOL) is an important outcome in epilepsy treatment. Very few studies have been carried out on the quality of life in epilepsy (QOLIE-31) in India. The present study aimed to determine the level of health-related QOLIE-31 in patients of epilepsy. MATERIALS AND METHODS: This was a cross-sectional, questionnaire-based study conducted in a tertiary care teaching hospital. Respondents were adults aged at least 18-year-old with a diagnosis of epilepsy. QOLIE-31 was used for collecting data on health-related QOL. The unpaired t-test or one-way analysis of variance was used to compare means of QOL scores between groups. RESULTS: Totally, 60 patients of epilepsy were included in the study. The mean (standard deviation) total score of QOLIE-31 was 64.61. A score of cognitive and medication effect were significantly better in carbamazepine group as compared to valproate group. CONCLUSIONS: Patients on monotherapy had a better QOL as compared to patients receiving polytherapy. PMID- 26600649 TI - Telmisartan induced urticarial vasculitis. AB - A 53-year-old man developed urticarial vasculitis following ingestion of telmisartan and hydrochlorothiazide combination for hypertension. Treatment with prednisolone and cetirizine was curative, but his lesions recurred when he continued telmisartan and hydrochlorothiazide against medical advice. Re challenge with the same doses of telmisartan precipitated similar lesions with telmisartan and not with hydrochlorothiazide. This uncommon cutaneous adverse reaction of angiotensin II receptor blockers has implication for the clinicians as more such cases may become apparent with their wider use than in premarketing studies. PMID- 26600648 TI - Maxcal-C (a polyherbal formulation) prevents ovariectomy-induced osteoporosis in rats. AB - OBJECTIVES: The aim of the present study was to investigate the anti-osteoporotic activity of Maxcal-C in ovariectomy (OVX)-induced osteoporosis in rats. MATERIALS AND METHODS: Sham-operated control rats were designated as Group I; Group II animals served as OVX control; Group III OVX control rats treated with Calcium Sandoz (50 mg/kg, p.o.); Group IV and V OVX control rats treated with Maxcal-C (250 and 500 mg/kg, p.o.), respectively. All the aforementioned treatments were given for four weeks after the development of osteoporosis. At the end of the treatment, serum biochemical parameters such as serum calcium and alkaline phosphate were measured. After sacrificing the animals, femoral bone parameters with histology, body weight, and bone breaking strength of 5(th) lumbar vertebra were measured. RESULTS: The treatment with Maxcal-C showed a significant improvement in serum biochemical, femoral bone parameters, and bone breaking strength of 5(th) lumbar vertebra with histopathological changes. CONCLUSION: The finding of the present study indicates that Maxcal-C showed a potential anti osteoporotic activity. These results support the traditional use of Maxcal-C in the treatment of osteoporosis. PMID- 26600650 TI - Myopathy induced by statin-ezetimibe combination: Evaluation of potential risk factors. AB - Although both atorvastatin and ezetimibe may cause myopathy, statin-induced myopathy is less likely at low doses, and ezetimibe is only rarely reported to induce myopathy. Also, ezetimibe is not usually known to potentiate statin induced myopathy. We report a case of myalgia with elevated serum creatinine phosphokinase in a patient after 2 months of therapy with fixed dose combination of atorvastatin and ezetimibe (10 mg each). At the time of the event, patient was undertaking moderate physical exertion in the form of brisk walking for 30-40 min a day and was detected to have low serum Vitamin D levels. The adverse event resolved after stopping atorvastatin-ezetimibe combination therapy. Potential risk factors, such as physical exertion and Vitamin D deficiency, co-existent in dyslipidemic patients, may exacerbate myopathy potential of these drugs, and precipitate muscular symptoms even at a low-dose. PMID- 26600651 TI - A case of recurrent agranulocytosis due to levamisole. AB - Agranulocytosis is a rare complication of levamisole. We report a 22-year-old female who developed agranulocytosis due to levamisole. The patient initially presented with salmonellosis and agranulocytosis, and then she recovered with treatment. However, 2 months after discharge, she again presented with tonsillitis and agranulocytosis. This time the family revealed that she had been taking levamisole. Though Salmonella infection is a recognized cause of agranulocytosis, any patient presenting with repeated agranulocytosis after an initial recovery should make the clinician suspect another cause, especially drug induced. A case of Salmonella infection where levamisole was an unsuspecting cause of agranulocytosis has not been described in indexed literature. Recurrent agranulocytosis due to repeated exposure to levamisole has also not been described. PMID- 26600652 TI - Hypoglycemic episodes in a case of Prementrual Dysphoric Disorder on sertraline. AB - Sertraline is a selective serotonin reuptake inhibitor. It has been shown to blunt postprandial hyperglycemia in rats and to potentiate the hypoglycemic effects of sulfonylurea agents in humans. Here, we report a case of a 33-year-old nondiabetic patient with no history of glucose intolerance, who experienced multiple episodes of hypoglycemia that resolved after discontinuation of the drug. Healthcare professionals should consider sertraline among the possible causes of hypoglycemia occurring in patients receiving antidepressants. PMID- 26600653 TI - Postgraduate pharmacology curriculum in medical institutions: Emphasis on skill development. PMID- 26600654 TI - Scientific impact and altmetrics. PMID- 26600655 TI - Errors in use of multivariable regression analysis. PMID- 26600656 TI - Author Reply. PMID- 26600657 TI - Integrating medical doctors of modern and Indian system of medicine--Unique opportunity for India along the lines of China. PMID- 26600658 TI - Aripiprazole as a treatment option for clozapine-induced enuresis. PMID- 26600659 TI - A critical review of pharmacological significance of Hydrogen Sulfide in hypertension: Erratum. PMID- 26600660 TI - God does not play dice: Looking back from modern laboratories to the Himalayan valleys. PMID- 26600661 TI - Premna integrifolia L.: A review of its biodiversity, traditional uses and phytochemistry. AB - Premna integrifolia Linn. (Verbenaceae) is an important woody, medicinal plant and has been prominent place in Ayurveda, Siddha and Unani system of medicines. Objective of the present review is to avail the comprehensive information on ecological biodiversity, traditional uses and phytochemistry of P. integrifolia. Information of the plant was searched using various electronic databases in reference to the terms Premna integrifolia, ecological biodiversity, traditional uses and phytoconstituents of P. integrifolia along with Ayurvedic books, Indian classical texts, pharmacopoeias, journals, etc. There is an inherent difference within the three Ayurvedic Formulary of India (AFIs) published with regard to the botanical sources of Agnimantha. Complete data of the plant has been collected manually since from the years 1947-2015 and was arranged accordingly. Available data have reports that roots of P. integrifolia are widely used for the preparation of Ayurvedic formulations like Dasamulakvatha, Arista, Curna and Chayawanprashavleh for the treatment of a variety of afflictions. It has also reported to have p-methoxy cinnamic acid, linalool, linoleic acid, beta sitosterol and flavone luteolin, iridoid glycoside, premnine, ganiarine and ganikarine, premnazole, aphelandrine, pentacyclic terpene betulin, caryophellen, premnenol, premna spirodiene, clerodendrin-A, etc., phytoconstituents in its various parts. There is need to validate its traditional uses, isolation and confirmation of reported phytoconstituents, biological and clinical efficacy by modern analytical and biological techniques which could be recommendation for further scientific research. PMID- 26600662 TI - Psycho-neuro-endocrine-immune mechanisms of action of yoga in type II diabetes. AB - Yoga has been found to benefit all the components of health viz. physical, mental, social and spiritual well being by incorporating a wide variety of practices. Pathophysiology of Type II DM and co-morbidities in Type II DM has been correlated with stress mechanisms. Stress suppresses body's immune system and neuro-humoral actions thereby aff ecting normal psychological state. It would not be wrong to state that correlation of diabetes with stress, anxiety and other psychological factors are bidirectional and lead to difficulty in understanding the interrelated mechanisms. Type II DM cannot be understood in isolation with psychological factors such as stress, anxiety and depression, neuro-endocrine and immunological factors. There is no review which tries to understand these mechanisms exclusively. The present literature review aims to understand interrelated Psycho-Neuro-Endocrine and Immunological mechanisms of action of Yoga in Type II Diabetes Mellitus. Published literature concerning mechanisms of action of Yoga in Type II DM emphasizing psycho-neuro-endocrine or immunological relations was retrieved from Pubmed using key words yoga, Type II diabetes mellitus, psychological, neural, endocrine, immune and mechanism of action. Those studies which explained the psycho-neuroendocrine and immune mechanisms of action of yoga were included and rest were excluded. Although primary aim of this study is to explain these mechanisms in Type II DM, some studies in non-diabetic population which had a similar pathway of stress mechanism was included because many insightful studies were available in that area. Search was conducted using terms yoga OR yogic AND diabetes OR diabetic IN title OR abstract for English articles. Of the 89 articles, we excluded non-English articles (22), editorials (20) and letters to editor (10). 37 studies were considered for this review. The postulated mechanism of action of yoga is through parasympathetic activation and the associated anti stress mechanism. It reduces perceived stress and HPA axis activation thereby improving overall metabolic and psychological profiles, increasing insulin sensitivity, and improving glucose tolerance and lipid metabolism. Yoga has positive effects on immune system of diabetics.- Overall, Type II DM is influenced by psycho-neuro-endocrine and immune mechanisms where Yoga has important positive role in combating stressors and improving these systems to regain health. PMID- 26600663 TI - Critical review of Ayurvedic Varnya herbs and their tyrosinase inhibition effect. AB - INTRODUCTION: The aspiration for light skin (fair complexion) is becoming pronounced in a greater number of people in the present times with natural products being more in demand than their synthetic counterparts. Research in the area of skin-lightening agents is an expanding field with the knowledge being updated regularly. In Ayurveda, varnya, raktaprasadana, tvacya are few terms specifying skin lightening with respect to its modern counterpart i.e., Tyrosinase inhibition, the most commonly reported method of skin lightening. AIM: The present review is undertaken for screening twenty herbs from Varnya Mahakasaya, Lodhradi varnya gana, Eladi varna prasadana gana and few varnya formulations to evaluate their probable modes of action through which the skin lightening is effected as per both Ayurveda and biomedical concepts. MATERIALS AND METHODS: Critical review of herbs to show varnya property is compiled from various Ayurvedic texts as well as from multiple articles on the internet to justify their skin lightening property on the basis of data collected. RESULT AND CONCLUSION: All the twenty herbs reviewed are found to act as varnya directly (citation as varnya) or indirectly (alleviation of pitta and rakta) as per Ayurveda and to interfere in melanogenesis pathway through tyrosinase inhibition as per biomedicine. This shows their potential to act as good skin whitening agents. Sunthi being a part of many varnya formulations, is the only herb among all reviewed in the present study found to exhibit tyrosinase inhibition without any Ayurvedic citation of varnya property. PMID- 26600664 TI - Evaluation of Ratnaprash for its effect on strength, stamina and fatigue using swim endurance test and biochemical estimation in swiss albino mice. AB - CONTEXT: Traditional medicines have been considered as important resources for postponing fatigue, accelerating elimination of fatigue related metabolites and improving physical ability. Rasayanas or rejuvenative therapies are mentioned as one of the eight clinical specialties in Ayurveda for attaining longevity, healthy life and regulation of bodily balance. Eventhough more detailed studies are needed to confirm the claims of benefits in the light of evidence based research, Ratnaprash, a herbo-mineral rasayana formulation, is proposed here to be an antifatigue supplement that is good in promoting strength and stamina. MATERIALS AND METHODS: In the present study, anti fatigue, strength and stamina enhancing properties of Ratnaprash were examined based on swim endurance capacity and the change in biochemical parameters in Swiss Albino mice. Treatment groups were orally administered Ratnaprash at various test doses (500, 1000, 2000 mg/Kg per day), while the control group received distilled water at similar dose volumes. Effect of therapy was evaluated after 28 days of treatment. RESULTS: At the end of study period, the swimming times to exhaustion were longer in the treated groups than in the control group. Plasma lactate levels of treated groups were lower than those of the control group (P < 0.05) while tissue ATP levels were higher. These effects were dose dependent and the strongest effect was seen in groups treated at 1000 mg/Kg. CONCLUSION: Ratnaprash enhanced the forced swimming capacity of mice and exhibited elevated anti-fatigue activity, reduced blood lactate levels and increased tissue ATP levels in preclinical models in comparison to vehicle control, exhibiting possible role in increasing strength and stamina and contributing anti-fatigue activity. PMID- 26600666 TI - Classical taxonomy studies of medicinally important Ipomoea leari. AB - BACKGROUND: Ipomoea leari which belongs to the family Convolvulaceae is an unexplored medicinal plant in the Indian medicinal system. According to ethnobotanical information, the whole plant is used for various disorders such as anti-inflammatory, psychotomimetic and anticancer activities. The current study seeks to standardize the parameters for this herb. MATERIALS AND METHODS: The identification of the pharmacognostical, morphoanatomical characters of Ipomoea leari (leaf, stem and root) were carried out in terms of organoleptic, macroscopic, microscopic, physicochemical, florescence and phytochemical analyses. Physicochemical parameters such as total ash, moisture content and extractive values were determined by World Health Organization (WHO) guidelines. The plant material was fixed in formalin-5 mL + acetic acid-5 mL + 70% ethyl alcohol-9 mL (FAA) and dehydrated with graded series of tertiary-butyl alcohol. Toluidine blue, a polychromatic stain was used for staining the sections and then whole components were observed with Nikon lab photo device with microscopic units. RESULTS: Microscopically, leaf consists of prominent midrib and the lamina, both having dorsiventral symmetry. The stomata are actinocytic. The stem consists of an epidermal layer of one cell thickness, wide cortex, vascular cylinder and wide pith. The root measuring 1.6 mm thick was studied. It consists of uniformly thick and continuous periderm, wide cortex and thick vascular cylinder. Qualitative analysis revealed the presence of carbohydrates, flavonoids, glycosides, steroids and phenols. The pharmacognostic studies were carried out in terms of macroscopic, phytoconstituent and chromatographic analyses of Ipomoea leari. Various standard methods were adopted to carry out the investigation. CONCLUSION: The results of the present study provide valuable pharmacognostic information of Ipomoea leari for its identification. Our result's suggest that Ipomoea leari is a promising candidate as an adjuvant therapy in various disorders and preparation of monograph. PMID- 26600667 TI - Standardization and quality control parameters for Mukta Bhasma (calcined pearl). AB - BACKGROUND: Mukta Bhasma (MB) is a traditional Ayurvedic preparation for cough, breathlessness, and eye disorders and is a powerful cardiac tonic, mood elevator, and known to promote strength, intellect, and semen production. OBJECTIVES: The present research work was conducted to generate fingerprint for raw and processed MB for quality assessment and standardization using classical and other techniques. SETTING AND DESIGN: Three samples of MB were prepared by purification (sodhana) of Mukta (pearl) followed by repeated calcinations (Marana). Resultant product was subjected to organoleptic tests and Ayurvedic tests for quality control such as rekhapurnata, varitaratva, and nirdhumatva. MATERIALS AND METHODS: For quality control, physicochemical parameters such as loss on drying, total ash value, acid insoluble ash, specific gravity, pH value, and other tests using techniques such as elemental analysis with energy dispersive X-ray analysis (EDAX), Structural study with powder X-ray diffraction, particle size with scanning electron microscopy (SEM) were carried out on raw Mukta, Sodhita Mukta, and triplicate batches of MB. RESULTS: The study showed that the raw material Mukta was calcium carbonate in aragonite form, which on repeated calcinations was converted into a more stable calcite form. SEM studies revealed that in raw and purified materials the particles were found scattered and unevenly arranged in the range of 718.7-214.7 nm while in final product, uniformly arranged, stable, rod-shaped, and rounded particles with more agglomerates were observed in the range of 279.2-79.93 nm. EDAX analysis revealed calcium as a major ingredient in MB (average 46.32%) which increased gradually in the stages of processing (raw 34.11%, Sodhita 37.5%). CONCLUSION: Quality control parameters have been quantified for fingerprinting of MB prepared using a particular method. PMID- 26600668 TI - An ayurvedic approach in the management of Guillain-Barre syndrome: A case study. AB - Guillain-Barre syndrome is an acute, frequently severe and fulminant polyradiculopathy that is autoimmune in nature. Guillain Barre syndrome is a rare disorder that causes immune systems to attack peripheral nervous system (PNS). A 46 year old male patient, presenting with sudden onset, complete paralysis of all four limbs (quadriplegia), unable to walk, stand, sit, difficulty in deglutition (dysphagia) and dysarthia, was having foley's catheter and Ryle's Tube brought by relative to Out Door Patient Department (OPD) of Government Ayurvedic Hospital, Nagpur; He was provisionally diagnosed as subacute sensory motor paraplegia. Previously patient admitted and treated in Government Medical College (GMC) Nagpur but did not show any sign of improvement so patient was admitted and treated with Ayurvedic treatment for about 50 days. As per Ayurvedic classics, this condition can be correlated with sarvan gagatavatavyadhi (~vata disorder affecting all parts of the body), which is apatarpana in nature (~diseases with deprived nourishment of body tissue) preceded by jvara (~(H/O fever before onset of GBS). Hence, the principle of treatment is santarpana cikitsa (~nourishing treatment). Santarpana (~nourishing treatment) includes bahyopakramas (~nourishing external treatment modalities), such as abhyanga (~oleation therapy) and sastikasalipindasveda (~sudation using of hot and processed sastika rice), karmabasti (~medicated enema) sirodhara (gentle pouring of medicated liquid over forehead) and jvaraghna cikitsa (~treatment of fever) using various Ayurvedic herbomineral compounds. Remarkable results were observed in the form of improvement in the muscle power from zero to five of all four limbs with improvement in speech. There was no difficulty post treatment in deglutition, sitting, standing and walking; and now patient has near to normal movements. PMID- 26600669 TI - Common medicinal plants with antiobesity potential: A special emphasis on fenugreek. PMID- 26600670 TI - High Thyroglobulin Antibody Levels Increase the Risk of Differentiated Thyroid Carcinoma. AB - BACKGROUND: Despite the many studies examining thyroid cancers, the effect of thyroid autoantibodies on differentiated thyroid carcinoma (DTC) remains unclear. OBJECTIVE: To investigate the association between serologic thyroid autoantibodies (ATAs) and DTC, we retrospectively evaluated data of thyroid nodules obtained from patients who underwent thyroid surgery. METHODS: Data of thyroid nodules obtained from 1,638 patients who underwent thyroid surgery were evaluated. Thyroid autoimmunity was assessed by the presence of thyroglobulin (TgAb) or thyroid peroxidase antibodies (TPOAb). RESULTS: Among our study cohort, the prevalence of elevated TgAb (>=40 IU/mL) and TPOAb (>=50 IU/mL) was higher in patients with DTC than those with benign nodules. Patients with DTC and elevated TgAb had a higher prevalence of extrathyroidal invasion. In the multivariate analysis, TgAb >= 40 IU/mL was significantly associated with DTC (odds ratio [OR] = 2.10, 95% confidence interval [CI] 1.40-3.15) compared with TgAb < 40 IU/mL group, independent of other confounding factors such as decreased age, single nodule, and elevated TSH level. In conclusion, elevated TgAb was associated with DTC. CONCLUSIONS: This study revealed that high levels of TgAb may act as an independent prediction factor for DTC, and suggests that patients with high TgAb concentrations may be predisposed to DTC. PMID- 26600671 TI - Amarogentin Displays Immunomodulatory Effects in Human Mast Cells and Keratinocytes. AB - Keratinocytes express the bitter taste receptors TAS2R1 and TAS2R38. Amarogentin as an agonist for TAS2R1 and other TAS2Rs promotes keratinocyte differentiation. Similarly, mast cells are known to express bitter taste receptors. The aim of this study was to assess whether bitter compounds display immunomodulatory effects on these immunocompetent cells in the skin, so that they might be a target in chronic inflammatory diseases such as atopic dermatitis and psoriasis. Here, we investigated the impact of amarogentin on substance P-induced release of histamine and TNF-alpha from the human mast cell line LAD-2. Furthermore, the effect of amarogentin on HaCaT keratinocytes costimulated with TNF-alpha and histamine was investigated. Amarogentin inhibited in LAD-2 cells substance P induced production of newly synthesized TNF-alpha, but the degranulation and release of stored histamine were not affected. In HaCaT keratinocytes histamine and TNF-alpha induced IL-8 and MMP-1 expression was reduced by amarogentin to a similar extent as with azelastine. In conclusion amarogentin displays immunomodulatory effects in the skin by interacting with mast cells and keratinocytes. PMID- 26600672 TI - Differential Associations between CDH13 Genotypes, Adiponectin Levels, and Circulating Levels of Cellular Adhesive Molecules. AB - CDH13 gene variants with lower adiponectin levels are paradoxically associated with a more favorable metabolic profile. We investigated the statistical association between CDH13 locus variants and adiponectin levels by examining 12 circulating inflammation marker levels and adiposity status in 530 Han Chinese people in Taiwan. After adjustments for clinical covariates, adiponectin levels were positively associated with soluble vascular cell adhesion molecule-1 (sVCAM1) levels and negatively associated with adiposity status and levels of C reactive protein (CRP), soluble E-selectin (sE-selectin), and soluble intercellular adhesion molecule-1 (sICAM1). In addition, minor alleles of the CDH13 rs12051272 polymorphism were found to have lower adiponectin levels and higher CRP, sE-selectin, sICAM1, and sVCAM1 levels as well as higher body mass indices and waist circumferences in participants (all P < 0.05). In a subgroup analysis stratified by sex, significant associations between CDH13 genotypes and sE-selectin levels occurred only in men (P = 3.9 * 10(-4) and interaction P = 0.005). CDH13 locus variants and adiponectin levels are associated with circulating levels of cellular adhesion molecules and adiposity status in a differential manner that interacts with sex. These results provide further evidence for the crucial role of adiponectin levels and CDH13 gene variants in immune-mediated and inflammatory diseases. PMID- 26600673 TI - CD137 Regulates NFATc1 Expression in Mouse VSMCs through TRAF6/NF-kappaB p65 Signaling Pathway. AB - Our previous study proved that CD137-CD137L interaction can regulate the expression of NFATc1. Here, we investigated whether CD137 signaling regulates the expression of NFATc1 in mice VSMCs through TRAF6/NF-kappaB p65 pathway. Data shows that the CD137 expression can be stimulated by TNF-alpha in a time dependent manner in mouse VSMCs. Knockdown of TRAF6 by siTRAF6 significantly attenuated agonist-CD137mAb induced increase of NF-kappaB p65 and NFATc1 in VSMCs. Pretreatment with a NF-kappaB inhibitor PDTC for 30 min inhibited the expression of p-p65 in both cytoplasm and nucleus in VSMCs. Thus, the protein level of NFATc1 can be suppressed through inhibition of p-p65. Finally, we also show that the levels of IL-2 and IL-6 can be increased by agonist-CD137 stimulation and decreased when NFATc1 was suppressed. Our data suggest that activated CD137 signaling regulates the expression of NFATc1 and its downstream factors through TRAF6/NF-kappaB p65 pathways in VSMCs. These findings provide a novel target for treatment of atherosclerosis. PMID- 26600674 TI - Identification and expression analyses of MYB and WRKY transcription factor genes in Papaver somniferum L. AB - Papaver somniferum L. is an herbaceous, annual and diploid plant that is important from pharmacological and strategic point of view. The cDNA clones of two putative MYB and WRKY genes were isolated (GeneBank accession numbers KP411870 and KP203854, respectively) from this plant, via the nested-PCR method, and characterized. The MYB transcription factor (TF) comprises 342 amino acids, and exhibits the structural features of the R2R3MYB protein family. The WRKY TF, a 326 amino acid-long polypeptide, falls structurally into the group II of WRKY protein family. Quantitative real-time PCR (qRT-PCR) analyses indicate the presence of these TFs in all organs of P. somniferum L. and Papaver bracteatum L. Highest expression levels of these two TFs were observed in the leaf tissues of P. somniferum L. while in P. bracteatum L. the espression levels were highest in the root tissues. Promoter analysis of the 10 co-expressed gene clustered involved in noscapine biosynthesis pathway in P. somniferum L. suggested that not only these 10 genes are co-expressed, but also share common regulatory motifs and TFs including MYB and WRKY TFs, and that may explain their common regulation. PMID- 26600675 TI - Arabidopsis AIR12 influences root development. AB - Arabidopsis AUXIN INDUCED IN ROOTS (AIR 12) is a predicted to encode a glycosylphosphatidylinositol tail anchored protein. It has been associated with extracellular redox processes, but little is known about its physiological role. An air12 mutant line demonstrated increased germination rates in the presence of a range of abiotic stress factors and hormones, but not in the presence of ABA. Disruption of AIR12 also affected primary and lateral root development and was linked to changes in root catalase activity and superoxide production. We suggest AIR12 is an extracellular constituent linking both hormone and reactive oxygen signaling in plants. PMID- 26600676 TI - Identification of key genes involved in root development of tomato using expressed sequence tag analysis. AB - Root system of plants are actually fascinating structures, not only critical for plant development, but also important for storage and conduction. Due to its agronomic importance, identification of genes involved in root development has been a subject of intense study. Tomato is the one of the most consumed vegetables in the world. Tomato has been used as model system for dicot plants because of its small genome, well-established transformation techniques and well constructed physical map. The present study is targeted to identify of root specific genes expressed temporally and also gene(s) involved in lateral root and profuse root development. A total of 890 ESTs were identified from five EST libraries constructed using SSH approach which included temporal gene regulation (early and late) and genes involved in morphogenetic traits (lateral and profuse rooting). One hundred sixty-one unique ESTs identified from various libraries were categorized based on their putative functions and deposited in NCBI-dbEST database. In addition, 36 ESTs were selected for validation of their expression by RT-PCR. The present findings will help in shedding light to the unexplored developmental process of root growth in tomato and plant in general. PMID- 26600677 TI - Development of an efficient in vitro plant regeneration system amenable to Agrobacterium- mediated transformation of a recalcitrant grain legume blackgram (Vigna mungo L. Hepper). AB - An efficient, rapid and direct multiple shoot regeneration system amenable to Agrobacterium-mediated transformation from primary leaf with intact petiole of blackgram (Vigna mungo) is established for the first time. The effect of the explant type and its age, type and concentration of cytokinin and auxin either alone or in combination and genotype on multiple shoot regeneration efficiency and frequency was optimized. The primary leaf explants with petiole excised from 4-day-old seedlings directly developed multiple shoots (an average of 10 shoots/ explant) from the cut ends of the petiole in 95 % of the cultures on MSB (MS salts and B5 vitamins) medium containing 1.0 MUM 6-benzylaminopurine. Elongated (2-3 cm) shoots were rooted on MSB medium with 2.5 MUM indole-butyric acid and resulted plantlets were hardened and established in soil, where they resumed growth and reached maturity with normal seed set. The regenerated plants were morphologically similar to seed-raised plants and required 8 weeks time from initiation of culture to establish them in soil. The regeneration competent cells present at the cut ends of petiole are fully exposed and are, thus, easily accessible to Agrobacterium, making this plant regeneration protocol amenable for the production of transgenic plants. The protocol was further successfully used to develop fertile transgenic plants of blackgram using Agrobacterium tumefaciens strain EHA 105 carrying a binary vector pCAMBIA2301 that contains a neomycin phosphotransferase gene (nptII) and a beta-glucuronidase (GUS) gene (uidA) interrupted with an intron. The presence and integration of transgenes in putative T0 plants were confirmed by polymerase chain reaction (PCR) and Southern blot hybridization, respectively. The transgenes were inherited in Mendelian fashion in T1 progeny and a transformation frequency of 1.3 % was obtained. This protocol can be effectively used for transferring new traits in blackgram and other legumes for their quantitative and qualitative improvements. PMID- 26600678 TI - Morphological and genetic diversity assessment of sesame (Sesamum indicum L.) accessions differing in origin. AB - Sesame is an important ancient oilseed crop of high medicinal value. In the present study, 37 characters including both quantitative and qualitative traits of sixty genotypes were characterized following IPGRI morphological descriptors for sesame. Multivariate analysis was computed to distinguish the varieties into different groups. Though thirty six microsatellite markers including genomic and Est-SSR markers were initially selected, but, finally, the accessions were genotyped by eight polymorphic primers. Altogether, 27 alleles were detected among the 60 genotypes, with an average of 3.37 alleles per locus. The number of alleles ranged from 2 to 6 alleles. From data of microsatellite markers, dissimilarity coefficients between varieties were computed following Jaccard's coefficient method. Principal co-ordinate analysis was used to represent the varieties in bi-directional space. Dendrogram was constructed using NJ method based on dissimilarity matrix. Cluster analysis based on morphological and molecular marker classified sesame genotypes into two major groups. Mantel test showed an insignificant correlation between phenotypic and molecular marker information. The genotypes belonging to the same geographical area did not always occupy the same cluster. The results confirmed that both genetic and phenotypic diversity in a combined way could efficiently evaluate the variation present in different sesame accessions in any breeding program. PMID- 26600679 TI - Assessing genetic diversity among six populations of Gossypium arboreum L. using microsatellites markers. AB - Among the four cultivated cotton species, G. hirsutum (allotetraploid) presently holds a primary place in cultivation. Efforts to further improve this primary cotton face the constraints of its narrow genetic base due to repeated selective breeding and hence demands enrichment of diversity in the gene pool. G. arboreum (diploid species) is an invaluable genetic resource with great potential in this direction. Based on the dispersal and domestication in different directions from Indus valley, different races of G. arboreum have evolved, each having certain traits like drought and disease resistance, which the tetraploid cotton lack. Due to lack of systematic, race wise characterization of G. arboreum germplasm, it has not been explored fully. During the present study, 100 polymorphic SSR loci were used to genotype 95 accessions belonging to 6 races of G. arboreum producing 246 polymorphic alleles; mean number of effective alleles was 1.505. AMOVA showed 14 % of molecular variance among population groups, 34 % among individuals and remaining 52 % within individuals. UPGMA dendrogram, based on Nei's genetic distance, distributed the six populations in two major clusters of 3 populations each; race 'bengalense' was found more close to 'cernuum' than the others. The clustering of 95 genotypes by UPGMA tree generation as well as PCoA analysis clustered 'bengalense' genotypes into one group along with some genotypes of 'cernuum', while rest of the genotypes made separate clusters. Outcomes of this research should be helpful in identifying the genotypes for their further utilization in hybridization program to obtain high level of germplasm diversity. PMID- 26600680 TI - Genotypic variability in physiological, biomass and yield response to drought stress in pigeonpea. AB - Three pigeonpea (Cajanus cajan L. Millsp.) genotypes- GT-1, AKP-1 and PRG-158 with varying crop duration, growth habit and flowering pattern were evaluated for variability in their response for drought stress. Drought stress was imposed at initiation of flowering and the observations on biomass and seed yield parameters were recorded at harvest. The magnitude of response of individual component to drought stress was found to be genotype specific. Drought stress significantly decreased photosynthetic rate (PN), transpiration rate (Tr) and relative water content (RWC) in all the genotypes, however the magnitude of reduction differed with genotype. With drought stress, the reduction of PN was highest in GT-1 while reduction in Tr was highest in PRG-158. The genotype AKP-1, accumulated significantly higher concentrations of osmotic solutes especially proline under water deficit stress, this facilitated it to maintain higher relative water content (RWC) and lower malondialdehyde (MDA) content as compared to other genotypes. Drought stress also impacted biomass production and their partitioning to vegetative and reproductive components at harvest. There was significant variability between the genotypes for seed yield under drought stress while it was non-significant under well-watered condition. Drought stress enhanced flower drop and decreased flower to pod conversion resulting in reduced pod number and seed number in PRG-158 and GT-1. The genotype AKP-1 recorded superior performance for seed yield under stress environment due to its ability in maintaining pod and seed number as well as improved test weight (100 seed weight). Under drought stress, significant positive association of seed yield with proline, seed number, pod number and test weight clearly indicating their role in drought tolerance. PMID- 26600681 TI - Oxidative stress induced expression of monodehydroascorbate reductase gene in Eleusine coracana. AB - Abiotic stresses constitute a serious threats to the world food security as they cause significant economic losses in terms of reduction in crop productivity and also greatly limit the geographical locations where crops can be grown. Exposure to abiotic stress causes over-production of reactive oxygen species, leading to oxidative stress in plants. Induction of oxidative stress is primarily responsible for a variety of detrimental changes in the cellular physiology. However, plants have evolved intricate anti-oxidative defence machinery, for their survival under stress. Plant defence strategies for stress tolerance rely on the expression of anti-oxidative genes required for scavenging the toxic reactive oxygen species. Monodehydroascorbate reductase is one of the key anti oxidant enzyme responsible for scavenging reactive oxygen species. In the present study, efforts have been made to understand the role of monodehydroascorbate reductase in finger millet under different abiotic stresses (drought, salt and UV radiation). The study establishes a differential link between mdar gene expression and enzyme activity under oxidative stress that is validated under different types of imposed stresses. Alteration in correlation between gene expression and enzyme activities under varying magnitude of oxidative stress is elucidated. PMID- 26600682 TI - Modulatory role of jasmonic acid on photosynthetic pigments, antioxidants and stress markers of Glycine max L. under nickel stress. AB - Jasmonic acid (JA) is a very young candidate of plant growth regulators which is being explored for various antistress properties. Present study deals with the hypothesis that JA can modulate antioxidant mechanism of higher plants with tight regulation of biomembrane peroxidation, making plants tolerant to toxic Ni(2+). 2 mM NiCl2 as a source of Ni(2+) appeared as sub lethal dose for the growth of 15 days old Glycine max seedlings. Exogenous application of 1 MUM and 1 nM JA prior to NiCl2 exposure, made seedlings of Glycine max more tolerant to Ni(2+)stress as compared to control untreated seedlings. Regulatory inhibition of MDA and H2O2 production by JA with or without Ni(2+) treatment made plants more resistant to Ni(2+) stress which may be associated with ameliorative activity of antioxidant enzymes system composed of SOD, POD, CAT and APOX. Ascorbate, a secondary metabolite synthesized from D-glucose act as an antioxidant in plant cells. Many fold enhancements in AsA content of Ni(2+) treated seedlings supplemented with different concentrations of JA was observed. Significant improvement in AsA levels by JA with or without Ni(2+) stress may involve two aspects, either denovo synthesis level regulation of AsA or recycling of AsA from an oxidized form. Improvement in total protein content showed the uplift modulation of transcriptional machinery by JA which was also maintained under Ni(2+) stress. Photosynthetic pigments as total chl, chl a and b showed inhibition in presence of Ni(2+) stress which was not found much effective under JA supplementation as compared to control. Present findings revealed that although JA was not helpful for protection of photosynthetic pigments but it modulates the other machinery of plants significantly including various antioxidants positively, while tightly inhibiting stress related processes responsible for lipid peroxidation to make plants tolerant to Ni(2+) stress. PMID- 26600683 TI - Phytochemical attributes of endemic endangered primrose (Primula heterochroma Stapf.) accessions grown in Iran. AB - Primula heterochroma is indigenous to Caspian coast forests in the north of Iran. Total phenols, total flavnoids, total carotenoids and antioxidant capacity of 50 P. heterochroma accessions were investigated. The highest total phenol (1272.31 mg GA equivalent/100 g fresh weight) and total flavonoids (615 mg catechin/100 g fresh weight) were observed in G5 accession from Saravan. The highest antioxidant activity was observed in G14 accession (73.03 %) from Kacha, followed by G2 accession (69.75 %) and G5 accession (66.84 %) from Saravan. The results of HPLC analysis showed that quercetin-3-glucoside was the major phenolic compound widely found in these accessions followed by chlorogenic acid. There was a linear relationship between the antioxidant capacities and the total phenols and total flavonoid. Inversely, there was no statistically significant correlation between total carotenoid and antioxidant activity. Based on the path coefficient analysis, the maximum direct effect on antioxidant was observed in total phenols (0.908). In addition, the cluster analysis based on Euclidean distance with Unweighted pair-group method using arithmetic average (UPGMA) method separated the accessions into four main groups. Our results supported that Iranian wild primrose accessions possess valuable antioxidant properties for therapeutic and potential medicinal use. PMID- 26600684 TI - Phytochemicals of Salacia oblonga responsible for free radical scavenging and antiproliferative activity against breast cancer cell lines (MDA-MB-231). AB - Salacia oblonga, an inhabitant of tropical regions has been used in traditional Indian medicinal systems. Phytochemicals were extracted in methanol from the plant and analyzed for various biological activities. The results of biochemical tests for total phenolics (297 +/- 0.005 and 275 +/- 0.006) and flavonoids (95 +/ 0.004 and 61.6 +/- 0.004) in the aerial and root parts were indicated as Gallic acid and quercetin equivalents respectively. The Aerial and root extracts showed strong reducing ability based on reducing power and FRAP assays. The extracts exhibited significant IC50 values in DPPH, super oxide and nitric oxide radical scavenging assays. The extracts displayed low IC50 values (<50 MUg/ml) when assessed for antiproliferative activity against breast cancer cell lines using the MTT assay. GC-MS analysis of methanolic extracts have revealed the presence of compounds viz. n-Hexadecanoic acid, N-Methoxy-N-methylacetamide, Ursa-9(11), 12-dien-3-ol, Gamma-sitosterol etc., that might be potential candidates for the biological activity exhibited by the extract. PMID- 26600685 TI - Relevance of physiological efficiency in wheat grain quality and the prospects of improvement. AB - Released and pre-released bread wheat varieties evaluated in national wheat programme of India (503 genotypes) during 2005-14 under different environments were examined for the role of physiological parameters in grain quality. Genotypes with slow plant height growth but faster rate of grain filling enhanced protein content. Plants where growth in height and grain development was slow, grains were hard, provided proportionate vegetative growth phase is longer. Steady grain growth rate benefited gluten strength and gluten quality. Irrespective of total crop duration, longer reproductive phase was an effective indicator of higher flour recovery and test weight. Magnitude and significance of morphological attributes in grain quality was almost similar to that of physiological processes, therefore prospects of utilizing these field traits were examined to enhance grain properties. Early heading and longer grain filling was effective to increase test weight whereas delayed heading and shorter plant height enhanced protein content. Bold grains hampered grain hardness and delayed heading added more bran in the flour. Genotypes with poor grain bearing and quick grain ripening had lower sedimentation value. Instead of protein, it was wet gluten which expressed negative association with yield. To improvise gluten quality, extended reproductive phase but with less grain weight was helpful. Contribution of longer post-anthesis period was observed crucial in flour recovery. These useful simple field expressions can be deployed to uplift quality of wheat grains. PMID- 26600686 TI - Isolation of high quality RNA from pistachio (Pistacia vera L.) and other woody plants high in secondary metabolites. AB - The quality and quantity of RNA are critical for successful downstream transcriptome-based studies such as microarrays and RNA sequencing (RNA-Seq). RNA isolation from woody plants, such as Pistacia vera, with very high amounts of polyphenols and polysaccharides is an enormous challenge. Here, we describe a highly efficient protocol that overcomes the limitations posed by poor quality and low yield of isolated RNA from pistachio and various recalcitrant woody plants. The key factors that resulted in a yield of 150 MUg of high quality RNA per 200 mg of plant tissue include the elimination of phenol from the extraction buffer, raising the concentration of beta-mercaptoethanol, long time incubation at 65 degrees C, and nucleic acid precipitation with optimized volume of NaCl and isopropyl alcohol. Also, the A260/A280 and A260/A230 of extracted RNA were about 1.9-2.1and 2.2-2.3, respectively, revealing the high purity. Since the isolated RNA passed highly stringent quality control standards for sensitive reactions, including RNA sequencing and real-time PCR, it can be considered as a reliable and cost-effective method for RNA extraction from woody plants. PMID- 26600687 TI - Estimation of outcrossing rates in interspecific backcross plants of Jatropha curcas (L.) using AFLP and SSR markers. AB - In this paper, we report the estimates of outcrossing rates using open-pollinated progeny arrays of 40 BC1 individuals of Jatropha developed as a result of interspecific hybridization between J. curcas and J. integerrima. For analysis PCR-based dominant AFLP and codominant SSR markers were used. The multilocus outcrossing rate (tm) estimated from AFLP markers (0.892 +/- 0.112) are almost in the same range with SSR (0.884 +/- 0.293) markers which indicate a high level of heterozygosity. A low value of inbreeding coefficient (F) also points out to the fact that outcrossing was the prevalent mode of reproduction in Jatropha and suggests maintenance of adequate genetic variability within families. PMID- 26600688 TI - In vitro propagation of Rudraksha (Elaeocarpus sphaericus (Gaertn.) K. Schum): a biotechnological approach for conservation. AB - The species Elaeocarpus sphaericus (Rudraksha) is a religious, medicinally important threatened tree of India. An efficient micropropagation protocol has been developed from nodal explants of this plant species collected from north east India for large scale production of planting material at favourable sites within the country. Best shoot initiation occurred in MS medium supplemented with 2.2MUM BA+2.2MUM Kn in combination. Addition of Casein Hydrolysate (CH) (100mg/L) increased the shoot number. Microshoots excised and subcultured in 2.0MUM BA further enhanced growth and multiplication. The shoot cultures were maintained in this concentration for 2years with subculturing at 6weeks interval. MS medium containing 5.0MUM NAA was most effective for rooting. Successfully acclimatized plants (80%) showed normal growth under suitable habitat conditions. PMID- 26600689 TI - Retraction Note to: Plant regeneration in Chlorophytum borivilianum Sant. et Fernand. from embryogenic callus and cell suspension culture and assessment of genetic fidelity of plants derived through somatic embryogenesis. AB - [This retracts the article DOI: 10.1007/s12298-012-0113-y.]. PMID- 26600690 TI - Specialist Palliative Medicine Training in India. PMID- 26600691 TI - Constitutional and Legal Protection for Life Support Limitation in India. AB - Appropriate treatment limitations towards the end of life to reduce unwanted burdens require ethical clarity that is supported by appropriate legislation. The lack of knowledge of enabling legal provisions, physicians feel vulnerable to legal misinterpretation of treatment limiting decisions. In India the lack of societal awareness, inadequate exploration of the gray areas of bio-ethics and unambiguous legal position relating to terminal illness have resulted in poor quality end of life care. Much of the perceived vulnerability by the physician is attributable to insufficient knowledge and understanding of existing constitutional and legal position in India. While we await informed legal and legislative opinion, this paper highlights possible legal liabilities arising from treatment limitation decisions with available defense. It is hoped that such clarity would lead to more confident ethical decisions and improved end of life care for patients. PMID- 26600692 TI - The Prevalence and Characteristics of Pain in Critically Ill Cancer Patients: A Prospective Nonrandomized Observational Study. AB - CONTEXT: Pain is a distressing symptom common to all stages and ubiquitous at all levels of care in cancer patients. However, there is a lack of scientific literature on prevalence, severity, predictors, and the quality of pain in cancer patients admitted to an Intensive Care Unit (ICU). OBJECTIVES: To elucidate the prevalence of pain, moderate to severe pain, neuropathic pain, chronic pain, and pain as the most distressing symptom in critically ill-cancer patients at the time of ICU admission. METHODS: We prospectively interviewed 126 patients within first 24 h of admission to a medical ICU. The patients were assessed for the presence of pain, its severity, sites, duration, nature, and its impact as a distressing symptom. Numerical Rating Scale and self-report version of Leeds Assessment of Neuropathic Signs and Symptoms were used to elucidate intensity of pain and neuropathic pain, respectively. Demographic characteristics such as age and sex, primary site, and stage of cancer were considered for a possible correlation with the prevalence of pain. RESULTS: Of 126 patients included in the study 95 (75.40%), 79 (62.70%), 34 (26.98%), and 17 (13.49%) patients had pain, moderate-severe, chronic, and neuropathic pain, respectively. The average duration of pain was 171.16 +/- 716.50 days. Totally, 58 (46.03%) and 42 (42.01%) patients had at least one and more than equal to 2 neuropathic pain symptoms, respectively. The primary malignancies associated with the highest prevalence of pain were genitourinary, hematological, and head and neck whereas breast and lung cancers were associated with the highest prevalence of neuropathic and chronic pain, respectively. CONCLUSION: The prevalence of pain among critically ill cancer patients is high. Assessment for pain at the time of ICU admission would ensure appropriate assessment for the presence, type, severity, and the significance imparted to it. PMID- 26600693 TI - A Randomized Controlled Trial Evaluating the Role of Honey in Reducing Pain Due to Radiation Induced Mucositis in Head and Neck Cancer Patients. AB - BACKGROUND: There are various drugs tried for relieving pain associated with radiation-induced mucositis. This paper aims to study role of honey in relieving pain due to radiation induced mucositis in head and neck cancer patients receiving concomitant chemoradiation. MATERIALS AND METHODS: A randomized controlled trial on 78 subjects (40 in test group and 38 in control group) was undertaken to study the analgesic effect of honey, but the analysis of 69 patients was done as nine patients (four in test and five in control group) were lost to follow-up or left treatment in between the study. All patients were advised to do salt-soda and benzydamine mouth gargles, alternatively every 3 hours. Test group patients additionally received 20 ml honey three times a day during the entire course of radiation treatment and 3 months following radiation therapy (RT). RESULTS: Honey significantly reduced the severity of mucositis associated pain and resulted in lesser treatment gaps and a decrease in overall radiotherapy treatment duration. None of the test group and majority of controls (51.5%) had severe pain score during the 7(th) week of RT. The same pattern was seen in the post-RT period. Mean pain score was significantly different in both groups during all weeks during and upto 6 weeks post-RT (mean score of 3.08 and 6.54 for test and control respectively at 7(th) week RT, P < 0.001). CONCLUSION: Honey being a cheap, palatable, and natural medicament can be used for decreasing pain associated with radiation-induced mucositis in cancer patients. PMID- 26600694 TI - Sexual Functioning in Men Living with a Spinal Cord Injury-A Narrative Literature Review. AB - BACKGROUND: Sexual dysfunction is a major concern for Indian men living with a spinal cord injury. OBJECTIVES: To examine the literature related to sexuality traumatic cord injury and its impact on sexual functioning. MATERIALS AND METHODS: Databases using Cumulative Index to Nursing and Allied Health Literature (CINAHL) 2000-2012, Medline 1989-2012, Applied Social Sciences Index and Abstracts (ASSIA) 1989-2012 and Google Scholar were the search engines used used for literature review. RESULTS: The search yielded a total of 457 articles and only 75 of them were found relevant. The minimum number of articles required to meet the inclusion criteria for this review was 25-30 articles. Out of the 75 articles, 33 were considered relevant or related to the topic of sexual functioning, spinal cord injury, and paraplegia. Six areas were identified: Sexual stigmatization, physiological barriers to sexual satisfaction, clinical aspects of sexual functioning, biomedical approaches to sexual dysfunction, partner satisfaction, and lack of accessibility to sexual education. CONCLUSION: Spinal cord injury and sexual functioning affects a large segment of the male Indian population, yet most current research focuses on quantitative measurement with the emphasis on ejaculatory dysfunction, orgasm impairment, incontinence, and other physiological dysfunction. Further research is needed to address the subjective accounts of patients themselves with respect to the emotional and social impact of sexual disability. This would help to identify the best possible outcomes for both treatment and rehabilitation. PMID- 26600695 TI - Validation of the EuroQol Five-dimensions - Three-Level Quality of Life Instrument in a Classical Indian Language (Odia) and Its Use to Assess Quality of Life and Health Status of Cancer Patients in Eastern India. AB - BACKGROUND AND OBJECTIVES: The EuroQol five-dimensions - 3-level (EQ5D) is a versatile quality of life (QOL) instrument with five dimensions (mobility, self care, usual activities, pain/discomfort, and anxiety/depression) and a visual analog scale. It can be used to calculate quality-adjusted life years. We aimed to evaluate the validity, reliability, and responsiveness of an Odia version of EQ5D and to study the QOL of cancer patients in our part of the country as cancer treatment in India still focuses largely on longevity due to scarcity of resources. MATERIALS AND METHODS: The EQ5D tool was translated into Odia language in collaboration with the EQ group. This tool and the World Health Organization-5 (WHO-5) questionnaires were administered to 155 surgical outpatients and 150 cancer patients in two hospitals of Eastern India. The convergent and discriminant validities (construct validity), concurrent validity, reliability (test-retest method of administering the tool to a part of the population after 7 14 days), and the internal consistency (Cronbach's alpha) were measured using preestablished hypotheses. The data from the cancer patients were analyzed separately. RESULTS: The QOL worsened with age and was worse in cancer patients proved that the tool had good construct validity. The Anxiety Depression dimension had good correlation with all the dimensions WHO-5 (rho > 0.4) indicating a good concurrent validity. Internal consistency and reliability of the tool were good (Cronbach's alpha > 0.7). Cancer patients had a poor QOL (mean EQ5D index 0.37SD 0.4) with male patients, patients with Grade II cancer or referred for pain care services and those with living spouses reporting worse QOL. CONCLUSIONS: The Odia version of the EQ5D has good reliability and validity for the measurement of health status in cancer and outpatient department patients. Cancer patients in this part of the country have a poor QOL and may need a closer look at pain management and improved societal support systems. PMID- 26600696 TI - Nutritional Assessment of Patients with Head and Neck Cancer in North-East India and Dietary Intervention. AB - INTRODUCTION: Head and neck cancer (HNCA) patients have poor nutritional status which clearly bears a negative prognosis in cancer. There is no study and consensus on nutritional assessment tools and diet structure for such patients. This study intends to determine the prevalence of malnutrition and formulate a diet chart keeping in view the general food habit and economic condition of HNCA patients of North East (NE) region. AIM: To find out an affordable dietary intervention for HNCA patients based on dietary principles. To assess the role of nutritional assessment tools in these group of patients. MATERIALS AND METHODS: This is a 1-year prospective interventional study on HNCA patients attending the Dept of ENT of a teaching hospital. The outcome of the nutritional intervention using a specific diet were assessed using clinical, laboratory and anthropomorphic assessment tools and indices like Prognostic Nutritional Index (PNI) and Nutritional Assessment Index (NAI). RESULTS: The study diet provided appropriate amounts of nutrients to HNCA patients as evident from improvements in anthropomorphic parameters and nutritional indices. Clinically, Hemoglobin percentage (Hb%), Body Mass Index (BMI), Mid Arm Circumference (MAC) and triceps skin fold thickness (TST) were found to be reliable malnutrition markers. CONCLUSION: Nutritional Assessment Index has been found to be the best index to evaluate malnutrition. The daily requirement of nutrients for HNCA patients can be satisfactorily met by adopting specific diet chart presented in our study. As no structured diet plan are available in literature, our diet chart can act as a template diet appropriate for HNCA patients of this region. PMID- 26600697 TI - Commentary. PMID- 26600698 TI - Association of Coping Styles with Quality of Life in Cancer Patients. AB - BACKGROUNDS AND AIM: Cancer patients experience a high level of stress caused by the disease and treatment processes. Dealing with cancer using more beneficial coping styles can effectively improve the quality of life (QOL) and reduce the side effects of cancer, and it is treatment. In this study, we aimed to investigate the relationship between coping styles and QOL in cancer patients. METHODS: The study was performed on 150 cancer patients (71 females and 79 males) admitted to the hospitals affiliated with Kermanshah University of Medical Sciences. Endler and Parker Coping Inventory for Stressful Situations, and World Health Organization's Quality of Life Questionnaire were used to evaluate their coping style and QOL, respectively. RESULTS: The Present study showed in cancer patients being male, single, having higher salary and education, and lower age are related to higher QOL. Furthermore, in general, QOL of cancer patients was positively correlated with avoidant coping style (P < 0.05, r : 0.170) and negatively associated with emotion-focused coping styles (P < 0.01, r : -0.378). CONCLUSION: The results suggested that focusing on a patient's coping style, predominantly on an emotion-focused coping style, is essential to improve patient's QOL, and that patients possibly to employ a more emotion-oriented coping style should receive enough notice, particularly before discharge. PMID- 26600699 TI - Screening of Psychological Distress in Cancer Patients During Chemotherapy: A Cross-sectional Study. AB - OBJECTIVE: The objective of this prospective, noninterventional, 8-months, observational study was to analyze and compare depression, anxiety, and stress (DAS) levels and their impacting factors in homogenous surviving cancer patients receiving chemotherapy as compared to normal control. MATERIALS AND METHODS: A prospective and descriptive study was carried out jointly by Pharmacology and Oncology departments of a tertiary care center in Malwa region of Punjab. The data was collected by administering the validated questionnaire/response (21-item Depression Anxiety and Stress Scale (DASS-21)) after taking ethical approval and informed consent. RESULTS: All eligible 300 subjects participated in the study and they were compared with 300 matched control. The mean age of the cases (cancer patients) and controls was 50.58 +/- 13.64 and 46.1 +/- 11.78 (mean (M) +/- standard deviation (SD)) years. Statistical significant difference was observed in mean 'scoring of DAS' in cancer patients when compared with control groups. Anxiety mean scoring showed a statistical significant difference in groups (according to chemotherapy cycles given and duration of disease). Stress was more observed in breast cancer patients. CONCLUSION: Holistic approach in cancer management including psychological evaluation and its solution at appropriate time/stage signifies the need of time as the present study revealed that the percentage of DAS as per the DASS scale was 90, 56, and 28%, respectively. A judicious diagnosis with an apposite intercession including psychological consultation with social support at appropriate time may alleviate the extra burden of psychological disorder, rather enhance the quality of life of cancer-affected rural population. PMID- 26600700 TI - Is Karnofsky Performance Status Correlate with Better Overall Survival in Palliative Conformal Whole Brain Radiotherapy? Our Experience. AB - AIM: Brain metastases (BMs) are a common event in the progression of many human cancers. The aim of this study was to evaluate the potential prognostic factors for the clinical identification of a subgroup of patients that could benefit from whole brain conformal radiotherapy (WBRT). MATERIALS AND METHODS: From January 2010 to February 2014, 80 patients with a diagnosis of BMs underwent WBRT at our Radiation Oncology Department, San Luigi Hospital, Italy. Among them, 36 medical records were retrospective reviewed. Gender, age, Karnofsky performance status (KPS), number of BMs on computed tomography and/or magnetic resonance images, presence or absence of perilesional edema, presence or absence of necrosis pattern, and histology of primary tumor were analyzed. Univariate and multivariate analyses were performed. RESULTS: In our cohort of patients, significant prognostic factors for 20 months overall survival was KPS> 70, while a statistical trend (P = 0.098) was registered regarding primary breast. CONCLUSION: WBRT can be still considered a standard and effective treatment in patients with BMs. High KPS and breast cancer primary tumor seem to be useful parameters for characterize a subgroup of patients with more favorable prognosis. PMID- 26600701 TI - Assessment of a Hospital Palliative Care Unit (HPCU) for Cancer Patients; A Conceptual Framework. AB - INTRODUCTION: The first hospital palliative care unit (HPCU) in Iran (FARS-HPCU) has been established in 2008 in the Cancer Institute, which is the largest referral cancer center in the country. We attempted to assess the performance of the HPCU based on a comprehensive conceptual framework. The main aim of this study was to develop a conceptual framework for assessment of the HPCU performances through designing a value chain in line with the goals and the main processes (core and support). MATERIALS AND METHODS: We collected data from a variety of sources, including international guidelines, international best practices, and expert opinions in the country and compared them with national policies and priorities. We also took into consideration the trend of the HPCU development in the Cancer Institute of Iran. Through benchmarking the gap area with the performance standards, some recommendations for better outcome are proposed. RESULTS: The framework for performance assessment consisted of 154 process indicators (PIs), based on which the main stakeholders of the HPCU (including staff, patients, and families) offered their scoring. The outcome revealed the state of the processes as well as the gaps. CONCLUSION: Despite a significant improvement in many processes and indicators, more development in the comprehensive and integrative aspects of FARS-HPCU performance is required. Consideration of all supportive and palliative requirements of the patients through interdisciplinary and collaborative approaches is recommended. PMID- 26600702 TI - Practice of Iranian Adolescents with Hemophilia in Prevention of Complications of Hemophilia. AB - BACKGROUND: Prerequisite for management of a chronic disease involves knowledge about its complications and their prevention. Hemophilia in adolescents influences all the aspects of their lives and thier performance. OBJECTIVES: The present study aimed to determine the performance of Iranian hemophilic adolescents in prevention of disease complications. PATIENTS AND METHODS: In this descriptive-analytical study, 108 adolescents with hemophilia were selected through convenience sampling. Their performance in preventing the complications of hemophilia was evaluated by sending a semi-structured questionnaire to their addresses throughout Iran. Then, the data was analysed using the Statistical Package for Social Sciences (SPSS) software (v. 13) and descriptive and interferential statistics were used. RESULTS: Overall, 32.1% of the participants controlled bleeding during the 1(st) hour. Inaccessibility of coagulation products was mainly responsible for inhibiting timely and proper bleeding control. In order to relieve bleeding associated pain, only 39.0% of the adolescents used analgesics. On the other hand, 19.8% of the subjects used nonpharmacological methods to relieve pain. The majority of the adolescents did not participate in sport activities (65.4%) others allocated less than 5 hours a week to physical activities (70.5%). In addition, the participants did not have favorable dietary patterns, exercise habits, and dental care. The results showed a significant relationship between the adolescents' preventive practice with coagulation disorders and utilization of pharmacological pain relief methods. Also, significant relationships were found between severity of the disease; participating in physical activities, number of hours of physical activities; and disease complications. CONCLUSIONS: Iranian adolescents did not exhibit favorable practices towards complication prevention. PMID- 26600703 TI - Role of communication for pediatric cancer patients and their family. AB - BACKGROUND: Communication is a key component in medical practice. The area of pediatric palliative care is emotionally distressing for families and healthcare providers. Inadequate communication can increase the stress and lead to mistrust or miscommunication. MATERIALS AND METHODS: Reviewing the literature on communication between physicians, patients, and their family; we identified several barriers to communication such as paternalism in medicine, inadequate training in communication skills, knowledge of the grieving process, special issues related to care of children, and cultural barriers. In order to fill the gap in area of cultural communication, a study questionnaire was administered to consecutive families of children receiving chemotherapy at a large, north Indian referral hospital to elicit parental views on communication. RESULTS: Most parents had a protective attitude and favored collusion; however, appreciated truthfulness in prognostication and counseling by physicians; though parents expressed dissatisfaction on timing and lack of prior information by counseling team. CONCLUSION: Training programs in communication skills should teach doctors how to elicit patients' preferences for information. Systematic training programs with feedback can decrease physicians stress and burnout. More research for understanding a culturally appropriate communication framework is needed. PMID- 26600704 TI - Perspective of patients, patients' families, and healthcare providers towards designing and delivering hospice care services in a middle income Country. AB - INTRODUCTION: In view of the recent surge in chronic disease rates and elderly population in the developing countries, there is an urgent felt need for palliative and hospice care services. The present study investigates the views and attitudes of patients and their families, physicians, nurses, healthcare administrators, and insurers regarding designing and delivering hospice care service in a middle income country. MATERIALS AND METHODS: In this qualitative study, the required data was collected using semi structured interviews and was analyzed using thematic analysis. Totally 65 participants from hospitals and Tabriz University of Medical Sciences were selected purposively to achieve data saturation. RESULTS: Analyzing the data, five main themes (barriers, facilitators, strategies, attitudes, and service provider) were extracted. Barriers included financial issues, cultural-religious beliefs, patient and family-related obstacles, and barriers related to healthcare system. Facilitators included family-related issues, cultural-religious beliefs, as well as facilitators associated with patients, healthcare status, and benefits of hospice service. Most participants (79%) had positive attitude towards hospice care service. Participant suggested 10 ways to design and deliver effective and efficient hospice care service. They thought the presence of physicians, nurses, and psychologists and other specialists and clergy were necessary in the hospice care team. CONCLUSION: Due to lack of experience in hospice care in developing countries, research for identifying probable barriers and appropriate management for reducing unsuccessfulness in designing and delivering hospice care service seems necessary. Input from the facilitators and their suggested solutions can be useful in planning the policy for hospice care system. PMID- 26600705 TI - Symptoms experienced by cancer patients and barriers to symptom management. AB - BACKGROUND: People living with cancer experience wide variety of symptoms. If symptoms are not managed well, it may hamper an individual's ability to continue his or her activities of daily life. Treatment of symptoms relieves suffering and improves the rate of recovery as well as the quality of life. OBJECTIVES: To assess the symptoms of suffering among cancer patients and to identify the perceived barriers to their symptom management. MATERIALS AND METHODS: A cross sectional study was carried out among 768 cancer patients selected by stratified sampling with a proportionate selection from each stratum. Data were collected from cancer patients by interview technique using structured validated questionnaire. RESULTS: Majority of the samples (30.2%) belonged to the age group of 51-60 years, most of them were diagnosed with head and neck cancer (40.1%) and 57.7% had stage III disease. The majority of the patients studied had pain (77%), tiredness (96.5%), disturbed sleep (96.4%), weight loss (63.3%), and irritability (85.7%). Most of the patients had lack of appetite (89.4%), feeling of sadness (96.6%), worry (94.5%), and feeling of nervousness (82.8%). Majority of the patients had some misconception regarding symptoms, that is, increasing pain signifies disease progression (92.7%), medicine to control pain may weaken the immune system (89.9%) and pain is inevitable for cancer patients (78.5%). Seventy seven percent of samples reported that the anxiety or depression is expected after the diagnosis of cancer. CONCLUSION: This study provides an overview of symptoms among cancer patients and barriers experienced by them. PMID- 26600706 TI - Pain relief can be painful. AB - Mandibular nerve block is periodically used procedure used to treat neuralgic pain in the distribution of trigeminal nerve. It is a commonly performed block in outpatient settings at our institute. We present a case of an elderly edentulous patient with trigeminal neuralgia who suffered recurrent temporomandibular joint (TMJ) dislocation following mandibular nerve block. The patient presented with complaints of severe pain, inability to close mouth, and eat food since 2 days. Anterior closed reduction of TMJ resulted in reduction of joint and immediate pain relief. However, the maneuver failed due to recurrent dislocation of the joint. A Barton dressing was applied to prevent another dislocation. This was followed by autologous blood injection into the joint. This case focuses on the preponderance of clinical evaluation and accentuates the need for additional forethought to be taken during pain procedures, particularly in the geriatric population. PMID- 26600707 TI - Searching for the Right Evidence: India's Contribution to the Cochrane Pain, Palliative and Supportive Care Group. PMID- 26600708 TI - Role of Early Caudal Epidural in Epidural Metastasis Mediated Neuropathic Cancer Pain. Delineating the Safety and Efficacy Measures. PMID- 26600709 TI - Transnasal Approach to Sphenopalatine Ganglion Blockade: An Alternate Technique. PMID- 26600710 TI - Repellant and insecticidal activities of shyobunone and isoshyobunone derived from the essential oil of Acorus calamus rhizomes. AB - CONTEXT: It was found that the essential oil of Acorus calamus rhizomes showed insecticidal activity. AIM: The aim of this study was to determine the chemical composition of the essential oil from A. calamus rhizomes, evaluate insecticidal and repellant activity against Lasioderma serricorne (LS) and Tribolium castaneum (TC), and to isolate any insecticidal constituents from the essential oil. MATERIALS AND METHODS: Essential oil from A. calamus was obtained by hydrodistillation and analyzed by gas chromatography (GC) flame ionization detector and GC-mass spectrometry. The insecticidal and repellant activity of the essential oil and isolated compounds was tested using a variety of methods. RESULTS: The main components of the essential oil were identified to be isoshyobunone (15.56%), beta-asarone (10.03%), bicyclo[6.1.0]non-1-ene (9.67%), shyobunone (9.60%) and methylisoeugenol (6.69%). Among them, the two active constituents were isolated and identified as shyobunone and isoshyobunone. The essential oil showed contact toxicity against LS and TC with LD50 values of 14.40 and 32.55 MUg/adult, respectively. The isolated compounds, shyobunone and isoshyobunone also exhibited strong contact toxicity against LS adults with LD50 values of 20.24 and 24.19 MUg/adult, respectively, while the LD50 value of isoshyobunone was 61.90 MUg/adult for TC adults. The essential oil, shyobunone and isoshyobunone were strongly repellent (98%, 90% and 94%, respectively, at 78.63 nL/cm(2), after 2 h treatment) against TC. CONCLUSION: The essential oil, shyobunone and isoshyobunone possessed insecticidal and repellant activity against LS and TC. PMID- 26600711 TI - Optimization of ultrasound-assisted extraction of phenolic compounds from Cimicifugae rhizoma with response surface methodology. AB - BACKGROUND: Cimicifugae rhizoma was a Ranunculaceae herb belonging to the composite family, and the roots of C. rhizoma have been widely used in tradition Chinese medicine. MATERIALS AND METHODS: Ultrasound-assisted extraction (UAE) of phenolic compounds from C. rhizoma. Caffeic acid (CA), isoferulic acid (IA), ferulic acid (FA), and total phenols were quantified by high-performance liquid chromatography-diode array detection and ultraviolet-visible spectrophotometer. Effects of several experimental parameters, such as ultrasonic power (W), extraction temperature ( degrees C), and ethanol concentration (%) on extraction efficiencies of phenolic compounds from C. rhizoma were evaluated. RESULTS: The results showed that the optimal UAE condition was obtained with ultrasonic power of 377.35 W, extraction temperature of 70 degrees C, and ethanol concentration of 58.37% for total phenols, and ultrasonic power of 318.28 W, extraction temperature of 59.65 degrees C, and ethanol concentration of 64.43% for combination of CA, IA, FA. CONCLUSIONS: The experimental values under optimal conditions were in good consistent with the predicted values, which suggested UAE is more efficient for the extraction of phenolic compounds from plant materials. PMID- 26600712 TI - Phenolic alkaloids from Menispermum dauricum inhibits BxPC-3 pancreatic cancer cells by blocking of Hedgehog signaling pathway. AB - BACKGROUND: The Hedgehog (Hh) signaling pathway plays an important role in pancreatic cancer (PC) cells. Phenolic alkaloids from Menispermum dauricum (PAMD), a traditional Chinese medicine used for the treatment of immune disorders, have been reported to have antitumor activity recently. OBJECTIVE: To investigate the efficacy and mechanism of PAMD against PC cell BxPC-3. MATERIALS AND METHODS: F assay was used to assess cell proliferation inhibition of PAMD; the apoptotic induction and cell cycle arrest was detected by flow cytometry; the BxPC-3 xenograft was established to evaluate the tumor growth inhibition of PAMD; hematoxylin-eosin staining was applied to analyze the pathological morphology of tumor tissues; immunohistochemistry (IHC) and Western blot was adopted to detect the protein levels; quantitative real-time polymerase chain reaction was used to determine the mRNA expressions. RESULTS: PAMD shows time-and dose-dependent proliferation inhibition on the BxPC-3 cell, induced G0/G1 phase arrest and cell apoptosis in vitro. PAMD also showed better inhibition of tumor growth and a preferable safety profile compared with chemotherapeutic regimen 5-fluoro-2, 4 (1 H, 3 H) pyrimidinedione in BxPC-3 xenograft in vivo. Furthermore, PAMD directly decreases the protein and mRNA levels of Sonic Hedgehog (Shh) and its downstream transcription factor Gli-1 in the BxPC-3 tumor tissues. CONCLUSION: The treatment of PAMD displayed Hh signaling pathway blockade through decreasing the protein and mRNA levels of Shh and its downstream transcription factor Gli-1, suggesting a promising strategy in treating human PC. PMID- 26600713 TI - Metabolic differentiation and classification of abnormal Savda Munziq's pharmacodynamic role on rat models with different diseases by nuclear magnetic resonance-based metabonomics. AB - BACKGROUND: Abnormal Savda Munziq (ASMq) is a traditional Uyghur herbal preparation used as a therapy for abnormal Savda-related diseases. In this study, we investigate ASMq's dynamic effects on abnormal Savda rat models under different disease conditions. MATERIALS AND METHODS: Abnormal Savda rat models with hepatocellular carcinoma (HCC), type 2 diabetes mellitus (T2DM), and asthma dosed of ASMq. Serum samples of each animal tested by nuclear magnetic resonance spectroscopy and analyzed by orthogonal projection to latent structure with discriminant analysis. RESULTS: Compared with healthy controls, HCC rats had higher concentrations of amino acids, fat-related metabolites, lactate, myoinositol, and citrate, but lower concentrations of alpha-glucose, beta glucose, and glutamine. Following ASMq treatment, the serum acetone very low density lipoprotein (VLDL), LDL, unsaturated lipids, acetylcysteine, and pyruvate concentration decreased, but alpha-glucose, beta-glucose, and glutamine concentration increased (P < 0.05). T2DM rats had higher concentrations of alpha- and beta-glucose, but lower concentrations of isoleucine, leucine, valine, glutamine, glycoprotein, lactate, tyrosine, creatine, alanine, carnitine, and phenylalanine. After ASMq treated T2DM groups showed reduced alpha- and beta glucose and increased creatine levels (P < 0.05). Asthma rats had higher acetate, carnitine, formate, and phenylalanine levels, but lower concentrations of glutamine, glycoprotein, lactate, VLDL, LDL, and unsaturated lipids. ASMq treatment showed increased glutamine and reduced carnitine, glycoprotein, formate, and phenylalanine levels (P < 0.05). CONCLUSION: Low immune function, decreased oxidative defense, liver function abnormalities, amino acid deficiencies, and energy metabolism disorders are common characteristics of abnormal Savda-related diseases. ASMq may improve the abnormal metabolism and immune function of rat models with different diseases combined abnormal Savda. PMID- 26600714 TI - Curcumin attenuates chronic ethanol-induced liver injury by inhibition of oxidative stress via mitogen-activated protein kinase/nuclear factor E2-related factor 2 pathway in mice. AB - OBJECTIVE: This study aimed to investigate the protective effect of curcumin on chronic ethanol-induced liver injury in mice and to explore its underlying mechanisms. MATERIALS AND METHODS: Ethanol-exposed Balb/c mice were simultaneously treated with curcumin for 6 weeks. Liver injury was evaluated by biochemical and histopathological examination. Lipid peroxidation and anti oxidant activities were measured by spectrophotometric method. Anti-oxidative genes expression such as NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HO-1), and superoxide dismutase (SOD) were determined by real-time polymerase chain reaction. The nuclear factor E2-related factor 2 (Nrf2) and the phosphorylation states of specific proteins central to intracellular signaling cascades were measured by western blotting. RESULTS: Curcumin treatment protected liver from chronic ethanol-induced injury through reducing serum alanine aminotransferase and aspartate aminotransferase activities, improving liver histological architecture, and reversing lipid disorders indicated by decrease of triglyceride, total cholesterol and low-density lipoprotein-cholesterol levels and increase of High-density lipoprotein-cholesterol levels. Meanwhile, curcumin administration attenuated oxidative stress via up-regulating SOD and glutathione peroxidase activities, leading to a reduction of lipid hydroperoxide production. In addition, curcumin increased Nrf2 activation and anti-oxidative genes expressions such as NQO1, HO-1, and SOD through inducing extracellular signal regulated kinase (ERK) and p38 phosphorylation. CONCLUSION: Our data suggested that curcumin protected the liver from chronic-ethanol induced injury through attenuating oxidative stress, at least partially, through ERK/p38/Nrf2-mediated anti-oxidant signaling pathways. PMID- 26600715 TI - Structure elucidation and anti-tumor activities of water-soluble oligosaccharides from Lactarius deliciosus (L. ex Fr.) Gray. AB - BACKGROUND: Oligosaccharides are composed of a variable number of monosaccharide units and very important in the biologically diverse of biological systems. MATERIALS AND METHODS: Crude water-soluble oligosaccharide was extracted from the fruiting bodies with water and then successively purified by DEAE-cellulose 52 and Sephadex G-100 column chromatography, yielding one major oligosaccharides fractions: LES-A. Structural features of Lactarius deliciosus (L. ex Fr.) Gray oligosaccharide (LDGO-A) were investigated by a combination of monosaccharide component analysis by thin layer chromatography, infrared spectra, nuclear magnetic resonance spectroscopy, scanning electron microscopy, and high performance gel permeation chromatography analysis. RESULT: The results indicated that LDGO-A was composed of D-glucose and D-xylose, and the average molecular sizes was approximately 945 Da. The anti-tumor activity of LDGO-A was evaluated in vivo. The inhibitory rate in mice treated with 40 mg/kg LDGO-A can reach 40.02%, being the highest in the three doses, which may be comparable to mannatide. Histology of immune organs shows that the tissues arranged more regular and firmer, but the tumor tissue arranged looser in LDGO-A group than those in the control group. Meanwhile, there is no obvious damage to other organs, such as heart. The anti-tumor activity of the LDGO-A was usually believed to be a consequence of the stimulation of the cell-mediated immune response because it can significantly promote the lymphocyte and macrophage cells in the dose range of 100-400 MUg/mL in vitro. LDGO-A also effected the expression of some housekeeping genes mRNA in S180 tumor. CONCLUSION: Accordingly, the LDGO-A might serve as an effective healthcare food and source of natural anti-tumor compounds. PMID- 26600716 TI - Effects of fermented Cordyceps sinensis on oxidative stress in doxorubicin treated rats. AB - BACKGROUND: Cordyceps sinensis (CS) is one of the rare traditional Chinese herbs, only a very limited amount of natural CS is produced. Fermented CS, as a substitute for natural CS, is widely used in the field of supplementary medical treatment and health products. Its antagonistic effect on oxidative stress (OS) in vivo has not been investigated. OBJECTIVE: Our aim was to investigate the antagonistic effect of fermented CS on OS in doxorubicin (DOX) treated rats and to compare the anti-OS effects in heart and liver tissues. MATERIALS AND METHODS: OS rats were induced by tail-intravenous injection of DOX (total of 7.5 mg/kg), and then administered intragastrically with fermented CS (1.5 g/kg) for 4 weeks. At the end of the experiment, heart, liver and serum samples were taken for and biochemical analyses. RESULTS: Fermented CS significantly increased the activities of glutathione peroxidase and catalase and the scavenging activity of O2 (-) in serum, and the total superoxide dismutase activity in cardiac tissue; reduced the malondialdehyde content in liver and cardiac tissues. CONCLUSION: Fermented CS can inhibit DOX-induced OS reactions, and the anti-OS effects have high selectivity to heart and liver, especially to heart. Thus, fermented CS may be a candidate used for the prevention against various cardiac diseases induced by OS. PMID- 26600717 TI - Effects of the main active components combinations of Astragalus and Panax notoginseng on energy metabolism in brain tissues after cerebral ischemia reperfusion in mice. AB - BACKGROUND: Astragalus and Panax notoginseng are traditional Chinese medicines used for the treatments of cardio-cerebrovascular ischemic diseases, astragaloside IV (AST IV) and ginsenoside Rg1 (Rg1), ginsenoside Rb1 (Rb1), notoginsenoside R1 (R1) are their active components. OBJECTIVE: The purpose of this work was to investigate the effect of AST IV combined with Rg1, Rb1, R1 on energy metabolism in brain tissues after cerebral ischemia-reperfusion in mice. MATERIALS AND METHODS: C57BL/6 mice were randomly divided into 11 groups, treated for 3 days. At 1 h after the last administration, the model of cerebral ischemia reperfusion injury was established, and brain tissues were detected. RESULTS: All drugs increased the contents of adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP) and the level of total adenine nucleotides (TAN), the combinations increased energy charge (EC), the effects of four active components combination were better. The phosphorylation of AMP activated protein kinasealpha1/2 (p-AMPKalpha1/2) was increased in AST IV, R1, four active components combination, AST IV + Rg1 and AST IV + R1 groups, the increased effect of four active components combination was greater than that of the active components alone and AST IV + Rb1. All drugs increased glucose transporter 3 (GLUT3) mRNA and protein, and the increases of four active components combination were more obvious than those of the active components alone or some two active components combinations. CONCLUSION: Four active components combination of Astragalus and P. notoginseng have the potentiation on improving of energy metabolism, the mechanism underlying might be associated with promoting the activation of AMPKalpha1/2, enhancing the expression of GLUT3, thus mediating glucose into nerve cells, increasing the supply and intake of glucose. PMID- 26600718 TI - High performance liquid chromatography time of flight electrospray ionization mass spectrometry for quantification of sesquiterpenes in Chrysanthemi indici Flos active extract. AB - BACKGROUND: Chrysanthemi indici Flos, a traditional herbal medicine is used to clearing heat-toxicity, removing the liver fire, and improving eyesight. In our preliminary work, an active extract of CTC in C. An indici Flos with anti hepatitis B virus and liver protective activity was found by HepG2.2.1.5 test and experiment of protein synthesis in mice's injured liver. In this work, we aimed to study the active faction CTC further by qualitative and quantitative analysis method. MATERIALS AND METHODS: High performance liquid chromatography time of flight electrospray ionization mass spectrometry (HPLC TOF ESI-MS) analysis method of the CTC was established. Cumambrin A and angeloylcumambrin B in CTC were analyzed by high performance liquid chromatography-ultraviolet-evaporative light scattering detector (HPLC-UV-ELSD) analysis methods. A binary gradient elution program was conducted for chromatographic separation with acetonitrile (A) and ultrapure water (B) as follows: 0-10 min, 42-46% A; 10-20 min, 46-55% A; 20-25 min, 55-60% A; and 25-35 min, 60-75% A. The column temperature and UV wavelength were set at 30 degrees C and 205 nm. RESULT: Ten constituents including (3R, 5R, 6S, 7S, 10R)-7-(2-hydroxy-2-propyl)-10-methyl-4 methyleneperhy, dronaphthal-ene-3, 5, 6-triol acetone solvate; (+)-edusmance-4, (14)-ene-11, 13-diol; linarin; luteolin; apigenin; tricin; 5, 3',4'- trimethyl 6,7-dimethoxy flavones; cumambrin A; acacetin; and angeloylcumambrin B in CTC were identified by HPLC TOF ESI-MS. The contents of sesquiterpenes in CTC were decreased by storing years. CONCLUSIONS: The results showed that both UV and ELSD methods were feasible, accurate, and the determination results were in good consistency. The contents of two sesquiterpenes decreased with storing years. Two sesquiterpenes could be used as quality control for C. indici flos CTC. PMID- 26600719 TI - A study of the substance dependence effect of the ethanolic extract and iridoid rich fraction from Valeriana jatamansi Jones in mice. AB - BACKGROUND: Recently we found the ethanolic extract and iridoid-rich fraction from Valeriana jatamansi Jones, which is a traditional Chinese medicine exhibited anxiolytic properties. OBJECTIVE: This study aims to the substance dependence effect of the ethanolic extract and iridoid-rich fraction. MATERIALS AND METHODS: The study included two experiments: Mice were given orally with ethanolic extract for 12 weeks or iridoid-rich fraction for 16 weeks in experiment I and experiment II, respectively. Diazepam was used as a control drug and the normal mice groups were administered with 0.5% carboxymethyl cellulose Na in both experiments. All groups were administered twice daily. Natural withdrawal symptoms, withdrawal induced body weight change, audiogenic tail-erection test (in experiment I), and pentylenetetrazol (PTZ)-induced convulsion test (in experiment II) were measured. RESULTS: (1) Compared to normal group in both experiments, the diazepam-treated group exhibited obvious withdrawal symptoms of tail-erection, irritability, teeth chattering, etc; the body weight of them after withdrawal had a period of significant loss (P < 0.05 or P < 0.01); and the ratios of tail-erection and seizure in two experiments were improved significantly when mice were induced by mixer noise ringtone (experiment I) or PTZ (experiment II) (P < 0.05 or P < 0.01).(2) In experiment I and II, there were no significant differences between mice that received ethanolic extract or iridoid-rich fraction and normal group in terms of natural withdrawal symptoms and withdrawal-induced body weight change (P > 0.05); in audiogenic tail-erection test, it found that the significant difference compared with normal group was just in ethanolic extract 900 mg/kg dose group on week 8 (P < 0.05); in PTZ-induced convulsion test, mice in iridoid rich fraction groups had a slightly tail-erection and seizure, all results of them were with no significant difference compare to normal mice (P > 0.05), while significant lower than diazepam group (P < 0.01). CONCLUSION: (1) The two experiments successfully established the physical dependence of diazepam by gradually increasing the dose.(2)There were just a few mice received with ethanolic extract for 12 weeks or iridoid-rich fraction for 16 weeks appearing some slight withdrawal symptoms after precipitated withdrawal, but it didn't show significant difference compared to normal mice. Therefore, these indicated that the risks of potential drug dependence about ethanolic extract and iridoid-rich fraction were far lower than that of diazepam. PMID- 26600720 TI - Pharmacokinetics, intestinal absorption and microbial metabolism of single platycodin D in comparison to Platycodi radix extract. AB - BACKGROUND: Platycodi radix, the dried root of Platycodon grandiflorum A. DC, has been widely used as food and herb medicine for treating cough, cold and other respiratory ailments, and platycodin D (PD) is one of the most important compounds in Platycodi Radix. OBJECTIVE: The purpose of this study was to compare the pharmacokinetic characteristics, intestinal absorption and microbial metabolism of PD in monomer with that in Platycodi radix extract (PRE). MATERIALS AND METHODS: In the pharmacokinetic study, the concentrations of PD in rat plasma were determined by ultra-performance liquid chromatography-tandem mass spectrometry and the main pharmacokinetic parameters were calculated by data analysis software (DAS). Besides, in vitro Caco-2 cells and fecal lysate were performed to investigate the intestinal absorption and metabolism, respectively. RESULTS: The results from pharmacokinetics showed that the area under the curve, the peak concentration the time to reach peak concentration and mean residence time of PD in PRE were enhanced significantly compared with that in single PD. Caco-2 cells transport study indicated that the absorption of PD both in monomer and in PRE were poor owning that the permeability of PD were <1/10(6) cm/s. The hydrolysis degree of PD in PRE was significantly lower than that in monomer PD in fecal lysate, which might be illustrated by the other ingredients in PRE influenced the hydrolysis of PD via gut microbiota. CONCLUSION: These findings indicated that the difference of microbial metabolism, not apparent absorption in intestine for PD between in monomer and in PRE contributed to their pharmacokinetic difference. PMID- 26600721 TI - Species classification and bioactive ingredients accumulation of BaiJiangCao based on characteristic inorganic elements analysis by inductively coupled plasma mass spectrometry and multivariate analysis. AB - BACKGROUND: Patrinia scabiosaefolia Fisch and Patrinia villosa (Thunb.) Juss., two species herbs with the same Chinese name "BaiJiangCao", are important ancient herbal medicines widely used for more than 2000 years. The clinical application of two species herb is confused due to the difficult identification. OBJECTIVE: The objective was to authenticate the species of BaiJiangCao and analyze the accumulation of bioactive ingredients based on characteristic inorganic elements analysis. MATERIALS AND METHODS: Content of 32 inorganic elements in BaiJiangCao from different habitats were determined by inductively coupled plasma-mass spectrometry (ICP-MS), and the characteristic inorganic elements were picked to distinguish the species of the herb by principal component analysis and cluster analysis. Contents of two bioactive ingredients, luteoloside, and oleanolic acid, in the samples, were also analyzed by high-performance liquid chromatography method. Relationship between accumulation of bioactive ingredients and content of macroelements in BaiJiangCao was established by statistics. RESULTS: A 4 macroelements (Na, Mg, K, Fe) in 32 determined inorganic elements were picked for characteristic inorganic elements. Content of Na, Mg, K and Fe showed positive correlations with that of luteoloside, content of Na, Mg showed positive correlations with that of oleanolic acid, but content of K and Fe showed negative correlations with that of oleanolic acid. CONCLUSION: It is for the first time to utilize the characteristic inorganic elements as an index to classify the herb species by the method of ICP-MS and multivariate analysis. And it is also the first report to investigate the influence of inorganic elements in herb on the accumulation of bioactive components which could affect the pharmacological efficacy of the herb medicine. And this method could also be utilized in research of corresponding aspects. PMID- 26600722 TI - The Need for a Tool to Assist Health Care Professionals and Patients in Making Medication Treatment Decisions in the Clinical Management of Type 2 Diabetes. PMID- 26600723 TI - Evaluation of Diabetes Conversation MapTM Education Tools for Diabetes Self Management Education. AB - Objective. To evaluate the efficacy of Diabetes Conversation MapsTM education tools for people with type 2 diabetes attending a diabetes self-management education program. Design and methods. This cross-sectional study was conducted with patients with type 2 diabetes who were recruited from Baqai Institute of Diabetology & Endocrinology, a tertiary care diabetes center of Karachi, Pakistan, from May 2010 to June 2011. Groups of 10-12 participants were given a pre-session questionnaire. Four sessions using Diabetes Conversation MapsTM education tools were conducted, and the same questionnaire was then completed again. Results. A total of 172 people (82 males, 90 females, mean age 60 years, average duration of diabetes 15 +/- 4 years) participated in the study. Confidence in diabetes self-management: before the sessions, 52.3% of participants believed that the doctor is the most influential person in the management of their type 2 diabetes, whereas after the sessions, 97.1% acknowledged that they were responsible for diabetes self-management. Before, 15% said they knew what to do to manage their diabetes, whereas 75% indicated this after the sessions. Empowerment: before the sessions, 32% said they understood those aspects of their diabetes self-management that were in need of improvement, whereas 75.6% indicated this after the sessions. Willingness, ability, and preparedness for diabetes self-management: before the sessions, 22% said they understood the importance of diabetes self-management; this increased to 63.4% afterward. Before, 20.3% agreed that they will start making changes in their lives, whereas 65.7% agreed with this after the sessions. Satisfaction: 61% found the map sessions very effective, 72.1% found this format to be better than individual education, and 52.8% agreed that map tools helped in goal-setting. Conclusion. Diabetes Conversation MapsTM education tools are effective for diabetes self-management education and facilitating behavior change in people with type 2 diabetes. This, in turn, may improve patients' chances of attaining desirable diabetes control. PMID- 26600724 TI - Maintenance of Goal Blood Pressure, Cholesterol, and A1C Levels in Veterans With Type 2 Diabetes After Discharge From a Pharmacist-Managed Ambulatory Care Clinic. AB - Objective. This study evaluated the ability of patients with type 2 diabetes to maintain systolic blood pressure (SBP), LDL cholesterol, and A1C at goal levels after being discharged from a pharmacist-managed ambulatory care clinic. The goals of this study were to 1) document the length of time to failure of maintenance of each goal and 2) characterize risk factors that may be associated with a shorter time to failure. Methods. Researchers reviewed the medical records of veterans with diabetes who were discharged from the clinical pharmacy ambulatory care clinic between 1 July 2007 and 30 June 2009 after attaining their goal SBP, LDL cholesterol, or A1C. The time to goal failure, medical history, laboratory data, medications, demographic information, and clinic appointment attendance were documented. Results. A total of 69 patients who were discharged from the clinic after meeting their SBP, LDL cholesterol, or A1C goal subsequently failed to maintain that goal. The mean time to failure was 9.4 months (SD 8.75 months) for SBP, 25.8 months (27.45 months) for LDL cholesterol, and 20.4 months (15.1 months) for A1C. Multiple risk factors were associated with a shorter time to failure of maintenance of SBP and A1C goals. Conclusion. Veterans with type 2 diabetes in this study demonstrated durable maintenance of their goal LDL cholesterol and A1C levels after being discharged from a pharmacist-managed ambulatory care clinic. However, maintenance of xSBP goals did not demonstrate the same durability. Patients who meet their SBP goal may benefit from receiving continued disease state management services from a pharmacist managed ambulatory care clinic instead of being discharged to receive their usual care. PMID- 26600725 TI - Effect of Group Medical Appointments on Glycemic Control of Patients With Type 2 Diabetes. AB - Rationale. To evaluate the effectiveness of group medical appointments (GMAs) for patients with type 2 diabetes. Objective. To compare A1C levels of patients participating in GMAs to those of patients who received usual primary care. Design and methods. This study was a retrospective electronic chart review comparing GMA care for 52 male patients to usual primary care for 52 male patients. Demographic (age, marital status, and ethnicity/race) and health related (height, weight, BMI, duration of diabetes, use of alcohol and tobacco, and A1C) variables were analyzed. Results. A greater proportion of GMA patients (50%) versus usual primary care patients (19.2%) reached target A1C goals (P = 0.001). GMA participants also had a significantly faster rate of decline in A1C over time compared to usual primary care patients (P < 0.001). Conclusion. This study demonstrated that the concept of medical management delivered in a group approach had a positive effect on glycemic control in patients with type 2 diabetes. GMAs were found to be an effective approach to achieving patient centered goals for improving the glycemic control of patients with type 2 diabetes. PMID- 26600726 TI - Does Kindness Matter? Diabetes, Depression, and Self-Compassion: A Selective Review and Research Agenda. AB - Depression and severe psychological distress are frequently comorbid with diabetes and are associated with reduced adherence to medication and healthy lifestyle regimens, poorer glycemic control, and increased complications. The mixed success of existing treatments for depression in diabetes patients suggests a need for supplementary approaches to this common problem. This article reviews recent evidence for the benefits of self-compassion in chronically ill patients, suggesting its utility as a clinical tool for improving self-care, depression, and glycemic control in diabetes. Possible physical and psychological pathways by which self-compassion may promote better outcomes in diabetes patients are considered, with particular attention given to reductions in negative self judgment and improved motivation to undertake self-care. PMID- 26600727 TI - American Indian Diabetes Beliefs and Practices: Anxiety, Fear, and Dread in Pregnant Women With Diabetes. AB - Diabetes among American Indian (AI) people is a health disparities condition that creates excessive morbidity and mortality. This research delineated culturally constructed models of type 2 diabetes among 97 pregnant women in two large AI nations in Oklahoma. The data analysis of explanatory models of type 2 diabetes revealed the participants' intense anxiety, fear, and dread related to the condition. The sample was further stratified by combinations of diabetes status: 1) absence of type 2 diabetes (n = 66), 2) type 2 diabetes prior to pregnancy (n = 4), and 3) gestational diabetes (n = 27). Patients were interviewed regarding perceptions of the etiology, course, and treatment of diabetes. The research incorporated an integrated phenomenologic and ethnographic approach using structured and semi-structured interviews to yield both quantitative and qualitative data. General findings comprised three main categories of patients' concerns regarding type 2 diabetes as an illness: 1) mechanical acts (i.e., injections), 2) medical complications, and 3) the conceptual sense of diabetes as a "severe" condition. Specific findings included significant fear and anxiety surrounding 1) the health and well-being of the unborn child, 2) the use of insulin injections, 3) blindness, 4) amputation, and 5) death. Paradoxically, although there was only a slight sense of disease severity overall, responses were punctuated with dread of specific outcomes. The latter finding is considered consistent with the presence of chronic diseases that can usually be managed but present risk of severe complications if not well controlled. PMID- 26600728 TI - Nontraditional Considerations With Insulin Needle Length Selection. AB - Ensuring the correct delivery of insulin is essential in the treatment of diabetes. Both proper injection technique and needle length are important considerations for adequate insulin delivery. There have been several studies demonstrating that BMI does not affect efficacy or insulin leakage with shorter pen needles (e.g., 4 or 5 mm vs. 12.7 mm). Additionally, the International Scientific Advisory Board for the Third Injection Technique Workshop released recommendations in 2010 on best practices for injection technique for patients with diabetes, which, with regard to needle length, concluded that 4-mm pen needles were efficacious in all patients regardless of BMI. However, regardless of patients' BMI, insulin injection technique should always be assessed and physically disabling comorbid conditions taken into consideration when choosing a needle length that will be manageable for patients. The purpose of this article is to raise awareness of unique patient circumstances that may warrant the use of the longer 12.7-mm needle. PMID- 26600729 TI - Texting for Health: An Evaluation of a Population Approach to Type 2 Diabetes Risk Reduction With a Personalized Message. AB - txt4health is an innovative, 14-week, interactive, population-based mobile health program for individuals at risk of type 2 diabetes, developed under the Beacon Community Program in the Greater New Orleans, La., area. A comprehensive social marketing campaign sought to enroll hard-to-reach, at-risk populations using a combination of mass media and face-to-face engagement in faith-based and retail environments. Little is known about the effectiveness of social marketing for mobile technology application in the general population. A systematic evaluation of the campaign identified successes and barriers to implementing a population based mobile health program. Face-to-face engagement helped increase program enrollment after the initial launch; otherwise, enrollment leveled off over time. Results show positive trends in reaching target populations and in the use of mobile phones to record personal health information and set goals for reducing the risk of type 2 diabetes. The lessons from the txt4health campaign can help inform the development and programmatic strategies to provide a person-level intervention using a population-level approach for individuals at risk for diabetes as well as aid in chronic disease management. PMID- 26600730 TI - Interdisciplinary Diabetes Care: A New Model for Inpatient Diabetes Education. AB - A patient-centered interdisciplinary diabetes care model was implemented at Vidant Medical Center in Greenville, N.C., a 909-bed tertiary care teaching hospital, for the purpose of providing all patients with diabetes clear and concise instructions on diabetes survival skills. Survival skills education during hospitalization is needed for safe transition to community resources for continued and expanded diabetes self-management education. This article describes the process used to develop, implement, and evaluate the model. This initiative achieved substantial cost savings, with no significant changes in length of stay (LOS) or diabetes readmission rates. This patient-centered model demonstrates how a team of interdisciplinary health care professionals can integrate services in providing care for a large population of patients with chronic disease. PMID- 26600731 TI - Total phenolic, antioxidant, antimicrobial activities and toxicity study of Gynotroches axillaris blume (Rhizophoraceae). AB - The antioxidant activity and the total phenolic content, as well as the influence of petroleum ether, chloroform and methanol extracts from the leaves of Gynotroches axillaris, on microorganisms were studied. The total phenolic contents were evaluated by using Folin-Ciocalteu reagent and the obtained values ranged from 70.0 to 620 mg GAE/g. The efficiency of antioxidation, which was identified through the scavenging of free radical DPPH, exhibited that the highest IC50 was in the methanolic extract (44.7 ug/mL) as compared to the standard ascorbic acid (25.83 ug/mL) and to standard BHT (17.2 ug/mL). In vitro antimicrobial activity of extracts was tested against Gram-negative bacteria, Gram-positive bacteria and fungi. Methanol extract showed activity in the range (225-900 MUg/mL) with both types, while petroleum ether and chloroform extracts were only active with Bacillus subtilis. The three extracts strongly inhibited all fungi with activity 225-450 MUg/mL. The toxicity test against brine shrimps indicated that all extracts were non-toxic with LC50 value more than 1000 ug/mL. The finding of this study supports the safety of these extracts to be used in medical treatments. PMID- 26600733 TI - Plant traits with different dimensions of shrubs represent different spatial patterns and plant-to-plant interactions in a temperate desert. AB - Projective cover (PC) and aboveground biomass (AGB) are the key traits with space attributes of individual plants. They are crucial to the understanding of the plant dynamics and plant patterns at population level. Spatial patterns based on individual plant positions (IND) have been extensively investigated in previous studies. However, very few have focused on PC and AGB. We tested the hypothesis that different plant traits represent different spatial patterns and plant-to plant interactions. Two 40 m * 40 m plots of two typical desert shrub populations (Seriphidium terrae-albae and Artemisia songarica) were surveyed in the Gurbantunggut Desert of north-western China. Each plot was divided into a series of subplots (grids) at different scales (17 scales from 0.5 m to 20 m) using GIS (geographic information system). The spatial patterns of IND, PC and AGB were determined using aggregation and information dimension analyses together with changes in the scales. The IND and AGB of the two populations exhibited clumped tendencies at all scales (except at the 0.5 m scale for S. terrae-albae), whereas PC showed uniform distribution patterns at the moderate and small scales, (0.5 m to 8.0 m for S. terrae-albae and 0.5 m to 4.0 m for A. songarica), indicating that crown-to-crown competition for sunlight was strong at these scales. Although IND had a slightly higher coefficient of variation at the small scales, its information dimension was smaller than those of PC and AGB, indicating that PC and AGB had higher spatial complexities. In conclusion, the three parameters represented different spatial patterns across multiple scales; PC and AGB showed strong spatial complexities and PC was also an accurate indicator of plant-to plant competition. PMID- 26600732 TI - Oxidative status and the response to pegylated-interferon alpha2a plus ribavirin in chronic genotype 4 HCV hepatitis. AB - Oxidative stress may play a pathogenic role in chronic hepatitis C (CHC). The present study examined the oxidative status in plasma of patients with CHC who received pegylated interferon and ribavirin therapy. The following groups were included: (1) sustained virological response (28 patients), (2) null response (26 patients), (3) breakthrough (24 patients), (4) relapse (24 patients), (5) spontaneous cure (23 patients) and (6) twenty five normal subjects as a control group. Markers of oxidative stress including plasma malondialdehyde, nitric oxide, reduced glutathione, total antioxidant capacity and uric acid as well as serum ALT, AST, alkaline phosphatase, total bilirubin, albumin, prothrombin time were studied. The study indicated significant decline in reduced glutathione and total antioxidant capacity and markedly elevated levels of malondialdehyde and nitric oxide in all groups compared with the controls. Null response group had the highest levels of malondialdehyde and nitric oxide. Nitric oxide was significantly higher in those with null response compared with all other groups and with control subjects. Uric acid was significantly higher in spontaneous cure group compared with all other groups and with the controls. We concluded that CHC patients had increased oxidative stress. The oxidative status in plasma of these patients was not changed by antiviral therapy. The study also showed an important contribution of nitric oxide in null response patients. High serum uric acid did not interfere with the response and/or did not predict the response to antiviral therapy. PMID- 26600734 TI - Sorption of DNA by diatomite-Zn(II) embedded supermacroporous monolithic p(HEMA) cryogels. AB - In this study, the DNA sorption performance of diatomite-Zn(II) embedded supermacroporous monolithic p(HEMA) cryogels were investigated for the purpose of designing a novel adsorbent that can be utilized for DNA purification, separation and immunoadsorption studies such as removal of anti-dsDNA antibodies from systemic lupus erythematosus (SLE) patient plasma. Poly(2-hydroxyethyl methacrylate) [p(HEMA)]-based monolithic cryogel column embedded with Zn(2+) diatomite particles was prepared by free radical cryo-copolymerization of 2 hydroxyethyl methacrylate (HEMA) with N,N'-methylene-bis-acrylamide (MBAAm). The polymerization reaction was initiated by N,N,N',N'-tetramethylene diamine (TEMED) and ammonium persulfate (APS) pair in an ice bath. After thawing, the monolithic composite cryogels were used for affinity sorption and then subsequent desorption of DNA molecules from aqueous solutions. Diatomite (DA) particles were characterized by XRF and BET method. The characterization of composite cryogel was done through SEM imaging. The effects of pH of the solution, initial DNA concentration, ionic strength, temperature and flow rates on adsorption were investigated to determine the optimum conditions for adsorption/desorption experiments. The particle embedding procedure was shown to yield significantly enhanced adsorption of DNA on the adsorbent. Furthermore, considering its excellent bio-compatibility, p(HEMA) cryogels are promising a candidate for further DNA sorption studies. PMID- 26600735 TI - Coupled Plasma Filtration Adsorption (CPFA) plus Continuous Veno-Venous Haemofiltration (CVVH) versus CVVH alone as an adjunctive therapy in the treatment of sepsis. AB - PURPOSE: To compare the efficacy of Coupled Plasma Filtration and Adsorption (CPFA) plus Continuous Veno-Venous Haemofiltration (CVVH) versus CVVH alone as an adjunct treatment of sepsis in terms of haemodynamic stability, inotropic requirement and inflammatory mediators. DESIGN AND METHODS: Prospective randomized controlled trial involving septic patients with/without acute kidney injury (AKI) whom were randomized to receive CPFA + CVVH or CVVH alone. Haemodynamic parameters including inotropic requirements and inflammatory mediators [procalcitonin (PCT) and C reactive protein (CRP)] were measured. RESULTS: Twenty-three patients [CPFA + CVVH (n = 11), CVVH (n = 12)] were enrolled. Haemodynamic stability occurred earlier and sustained in the CPFA + CVVH group with an increase in diastolic blood pressure (p = 0.001 vs. p = 0.226) and mean arterial pressure (p = 0.001 vs. p = 0.575) at the end of treatment with no increment in inotropic requirement. Both groups had a reduction in PCT and CRP (CPFA + CVVH: p = 0.003, p = 0.026 and CVVH: p = 0.008, p = 0.071 respectively). The length of intensive care unit stay, hospital stay and 30 day outcomes were similar between the groups. There was an inverse association between serum albumin and CRP (p = 0.018). Serum albumin positively correlated with systolic blood pressure (p = 0.012) and diastolic blood pressure (p = 0.009). We found a trend between CRP and length of hospital stay (p = 0.056). Patients with a lower PCT at 24 h had a better outcome (survival) than those with a higher PCT (p = 0.045). CONCLUSION: CPFA is a feasible, albeit expensive adjunctive extracorporeal treatment that may be superior to CVVH alone in the treatment of severe sepsis. PMID- 26600736 TI - Exercise enhanced functional recovery and expression of GDNF after photochemically induced cerebral infarction in the rat. AB - Exercise has been considered to affect the functional recovery from central nervous damage. Neurotrophic factors have various effects on brain damage. However, the effects of exercise for expression of GDNF on functional recovery with brain damage are not well known. We investigated the difference in functional recovery between non-exercise and beam-walking exercise groups, and the expression of GDNF in both groups after photochemical infarction. Adult male Wistar rats (N = 64) were used. Animals were divided into two groups: non exercise (N = 35), and beam-walking exercise (N = 29). All rats underwent surgical photochemical infarction. The rats of the beam-walking group were trained every day to walk on a narrow beam after a one-day recovery period and those of the non-exercise group were left to follow a natural course. Animals were evaluated for hind limb function every day using a beam-walking task with an elevated narrow beam. The number of GDNF-like immunoreactive cells in the temporal cortex surrounding the lesion was counted 1, 3, 5, and 7 days after the infarction. Functional recovery of the beam-walking exercise group was significantly earlier than that of the non-exercise group. At 3 days after infarction, the number of GDNF-positive cells in the temporal cortex surrounding the infarction was significantly increased in the beam-walking exercise group compared with that in the non-exercise group. In the exercise group, motor function was remarkably recovered with the increased expression of GDNF-like immunoreactive cells. Our results suggested that a rehabilitative approach increased the expression of GDNF and facilitated functional recovery from cerebral infarction. PMID- 26600737 TI - Influence of corticosteroid therapy on the serum antibody response to influenza vaccine in elderly patients with chronic pulmonary diseases. AB - Annual influenza vaccination is strongly recommended for patients with chronic pulmonary diseases, such as bronchial asthma, chronic obstructive pulmonary disease (COPD), and interstitial pulmonary diseases. However, many of these patients regularly receive systemic and/or inhaled corticosteroid therapy, and the impact of corticosteroid therapy on influenza vaccine efficacy and safety is unclear. Patients with chronic pulmonary diseases were enrolled in the study and divided into three groups based on their maintenance therapy: (A) without corticosteroid therapy (17 males, three females; mean age, 72.3 +/- 7.9), (B) oral corticosteroid therapy (four males, seven females; mean age, 66.1 +/- 10.6), and (C) inhaled corticosteroid therapy (eight males, nine females; mean age, 62.4 +/- 16.0). All patients received influenza vaccine, and serum hemagglutination inhibition (HI) antibodies against influenza strains A/H1N1, A/H3N2, and B were measured at baseline (before vaccination) and 4-6 weeks after vaccination. Sufficient antibody titers or significant increases were observed after vaccination compared with titers before vaccination in all three groups. No systemic reactions were reported. Long-term oral/inhaled corticosteroid therapy was not associated with vaccination side effects and did not affect the immune response to the influenza vaccine. PMID- 26600738 TI - Nicotine exposure caused significant transgenerational heritable behavioral changes in Caenorhabditis elegans. AB - Passive and active exposure to tobacco smoking among youth is directly associated with immediate as well as long-term health deterioration. Despite all public health policies and efforts, the percentage of teenage smokers is still relatively high, especially in developing countries. Very few, if any, studies have been done on the transgenerational effect of nicotine exposed during the more sensitive, early developmental stages. We employed C. elegans as a biological model to study the multigenerational impact of chronic nicotine exposure. Nicotine treatment was limited to N2 hermaphrodites of the F0 generation. Exposure was limited to the larval period L1-L4 (~31 hours) after which worms were transferred to a fresh NGM plate. N2 hermaphrodites at L4 developmental stage were used for behavioral analysis across three generations: F0, F1, and F2. Our results show that nicotine was associated with changes in sinusoidal locomotion, speed, and body bends in L4 larvae in all three tested generations. These behavioral alterations were not restricted to F0, but were observed in F1 and F2 generations which were never exposed to nicotine. Our study is the first to reveal that nicotine addiction is heritable using C. elegans as a model organism. These results underscored the sensitivity of early development stages, with hope to spread more awareness to encourage the avoidance of nicotine exposure, especially at a young age. PMID- 26600739 TI - COX-2 inhibitors from stem bark of Bauhinia rufescens Lam. (Fabaceae). AB - Chemical investigation of the stem bark of Bauhinia rufescens resulted in the isolation of a new cyanoglucoside and menisdaurin from methanol extract and oxepin from petroleum ether extract. The isolated compounds were tested for their anti-inflammatory potentials based on the cyclooxygenase-2 enzyme (COX-2) model. Cyanoglucoside exhibited the highest activity among the compounds with an inhibition activity of 49.34 % at 100 uM (IC50 0.46 uM) compared to the positive control, indomethacin (79.20 %, IC50 0.24 uM). PMID- 26600740 TI - Advances in hepatic stem/progenitor cell biology. AB - The liver is famous for its strong regenerative capacity, employing different modes of regeneration according to type and extent of injury. Mature liver cells are able to proliferate in order to replace the damaged tissue allowing the recovery of the parenchymal function. In more severe scenarios hepatocytes are believed to arise also from a facultative liver progenitor cell compartment. In human, severe acute liver failure and liver cirrhosis are also both important clinical targets in which regeneration is impaired, where the role of this stem cell compartment seems more convincing. In animal models, the current state of ambiguity regarding the identity and role of liver progenitor cells in liver physiology dampens the enthusiasm for the potential use of these cells in regenerative medicine. The aim of this review is to give the basics of liver progenitor cell biology and discuss recent results vis-a-vis their identity and contribution to liver regeneration. PMID- 26600741 TI - Heat shock protein 90 targeting therapy: state of the art and future perspective. AB - Heat shock protein 90 (Hsp90) is an ATP-dependent molecular chaperone that plays a role in stabilizing and activating more than 200 client proteins. It is required for the stability and function of numerous oncogenic signaling proteins that determine the hallmarks of cancer. Since the initial discovery of the first Hsp90 inhibitor in the 1970s, multiple phase II and III clinical trials of several Hsp90 inhibitors have been undertaken. This review provides an overview of the current status on clinical trials of Hsp90 inhibitors and future perspectives on novel anticancer strategies using Hsp90 inhibitors. PMID- 26600743 TI - Neutrophil biology: an update. AB - Neutrophil extracellular traps (NETs) are involved in bacterial killing as well as autoimmunity, because NETs contain proteases, bactericidal peptides, DNA and ribonucleoprotein. NETs are formed via a novel type of cell death called NETosis. NETosis is distinct from apoptosis, but it resembles necrosis in that both membranes are not intact so that they allow intracellular proteins to leak outside of the cells. Removal of NETs and neutrophils undergoing NETosis by phagocytes and its subsequent response are not completely clarified, as compared with the response after removal of either apoptotic or necrotic neutrophils by phagocytes. How neutrophil density in peripheral blood is kept within a certain range is important for health and disease. Although the studies on severe congenital neutropenia and benign ethnic neutropenia have provided unbiased views on it, the studies are rather limited to human neutropenia, and mice with a mutation of mouse counterpart gene often fail to exhibit neutropenia. Degranulation plays a critical role in bactericidal action. The recent studies revealed that it is also involved in immunomodulation, pain control and estrous cycle control. N1 and N2 are representative of neutrophil subpopulations. The dichotomy holds true in patients or mice with severe trauma or cancer, providing the basis of differential roles of neutrophils in diseases. PMID- 26600742 TI - Molecular mechanisms of etoposide. AB - Etoposide derives from podophyllotoxin, a toxin found in the American Mayapple. It was first synthesized in 1966 and approved for cancer therapy in 1983 by the U.S. Food and Drug Administration (Hande, 1998[25]). Starting from 1980s several studies demonstrated that etoposide targets DNA topoisomerase II activities thus leading to the production of DNA breaks and eliciting a response that affects several aspects of cell metabolisms. In this review we will focus on molecular mechanisms that account for the biological effect of etoposide. PMID- 26600744 TI - Deep sea as a source of novel-anticancer drugs: update on discovery and preclinical/clinical evaluation in a systems medicine perspective. AB - The deep-sea habitat is a source of very potent marine-derived agents that may inhibit the growth of human cancer cells "in vitro" and "in vivo". Salinosporamide-A, Marizomib, by Salinispora species is a proteasome inhibitor with promising anticancer activity (Phase I/II trials). Different deep-sea derived drugs are under preclinical evaluation. Cancer is a complex disease that may be represented by network medicine. A simple consequence is the change of the concept of target entity from a single protein to a whole molecular pathway and or cellular network. Deep-sea-derived drugs fit well to this new concept. PMID- 26600745 TI - Proliferation of macrophages due to the inhibition of inducible nitric oxide synthesis by oxidized low-density lipoproteins. AB - Oxidized low-density lipoprotein (ox-LDL) is assumed to be a major causal agent in hypercholesteraemia-induced atherosclerosis. Because the proliferation of lipid-loaden macrophages within atherosclerotic lesions has been described, we investigated the dependence of macrophage proliferation on the inhibition of inducible nitric oxide synthase (iNOS) by hypochlorite oxidized LDL. Ox-LDL induces a dose dependent inhibition of inducible nitric oxide synthesis in lipopolysaccharide-interferon stimulated mouse macrophages (J774.A1) with concomitant macrophage proliferation as assayed by cell counting, tritiated thymidine incorporation and measurement of cell protein. Native LDL did not influence macrophage proliferation and inducible nitric oxide synthesis. iNOS protein and mRNA was reduced by HOCl-oxidized LDL (0-40 ug/ml) as revealed by immunoblotting and competitive semiquantitative PCR. Macrophage proliferation was increased by the addition of the iNOS inhibitor L-NAME. The addition of ox-LDL to L-NAME containing incubations induced no further statistically significant increase in cell number. Nitric oxide donors decreased ox-LDL induced macrophage proliferation and nitric oxide scavengers restored macrophage proliferation to the initial values achieved by ox-LDL. The decrease of cytosolic DNA fragments in stimulated macrophages incubated with ox-LDL demonstrates that the proliferative actions of ox-LDL are associated with a decrease of NO-induced apoptosis. Our data show that inhibition of iNOS dependent nitric oxide production caused by hypochlorite oxidized LDL enhances macrophage proliferation. This might be a key event in the pathogenesis of atherosclerotic lesions. PMID- 26600746 TI - Determining a new formula for calculating low-density lipoprotein cholesterol: data mining approach. AB - Low-density lipoprotein cholesterol (LDL-C) is a risk factor of coronary heart diseases. The estimation of LDL-C (LDL-Cal) level was performed using Friedewald's equation for triglyceride (TG) level less than 400 mg/dL. Therefore, the aim of this study is to generate a new formula for LDL-Cal and validate the correlation coefficient between LDL-Cal and LDL-C directly measured (LDL-Direct). A data set of 1786 individuals receiving annual medical check-ups from the Faculty of Medical Technology, Mahidol University, Thailand in 2008 was used in this study. Lipid profiles including total cholesterol (TC), TG, high-density lipoprotein cholesterol (HDL-C) and LDL-C were determined using Roche/Hitachi modular system analyzer. The estimated LDL-C was obtained using Friedewald's equation and the homogenous enzymatic method. The level of TG was divided into 6 groups (TG<200, <300, <400, <500, <600 and < 1000 mg/dL) for constructing the LDL Cal formula. The pace regression model was used to construct the candidate formula for the LDL-Cal and determine the correlation coefficient (r) with the LDL-Direct. The candidate LDL-Cal formula was generated for 6 groups of TG levels that displayed well correlation between LDL-Cal and LDL-Direct. Interestingly, The TG level was less than 1000 mg/dL, the regression model was able to generate the equation as shown as strong r of 0.9769 with LDL-Direct. Furthermore, external data set (n = 666) with TG measurement (36-1480 mg/dL) was used to validate new formula which displayed high r of 0.971 between LDL-Cal and LDL direct. This study explored a new formula for LDL-Cal which exhibited higher r of 0.9769 and far beyond the limitation of TG more than 1000 mg/dL and potential used for estimating LDL-C in routine clinical laboratories. PMID- 26600747 TI - 2D-QSAR study of some 2,5-diaminobenzophenone farnesyltransferase inhibitors by different chemometric methods. AB - Quantitative structure activity relationship (QSAR) models can be used to predict the activity of new drug candidates in early stages of drug discovery. In the present study, the information of the ninety two 2,5-diaminobenzophenone containing farnesyltranaferase inhibitors (FTIs) were taken from the literature. Subsequently, the structures of the molecules were optimized using Hyperchem software and molecular descriptors were obtained using Dragon software. The most suitable descriptors were selected using genetic algorithms-partial least squares and stepwise regression, where exhibited that the volume, shape and polarity of the FTIs are important for their activities. The two-dimensional QSAR models (2D QSAR) were obtained using both linear methods (multiple linear regression) and non-linear methods (artificial neural networks and support vector machines). The proposed QSAR models were validated using internal validation method. The results showed that the proposed 2D-QSAR models were valid and they can be used for prediction of the activities of the 2,5-diaminobenzophenone-containing FTIs. In conclusion, the 2D-QSAR models (both linear and non-linear) showed good prediction capability and the non-linear models were exhibited more accuracy than the linear models. PMID- 26600748 TI - Recent developments in animal sciences. PMID- 26600750 TI - Equivalence and practice effect of alternate forms for Malay version of Auditory Verbal Learning Test (MAVLT). AB - This study aims to develop two alternate forms for Malay version of Auditory Verbal Learning Test (MAVLT) and to determine their equivalency and practice effect. Ninety healthy volunteers were subjected to the following neuropsychological tests at baseline, and at one month interval according to their assigned group; group 1 (MAVLT - MAVLT), group 2 (MAVLT - Alternate Form 1 Alternate Form 1), and group 3 (MAVLT - Alternate Form 2 - Alternate Form 2). There were no significant difference in the mean score of all the trials at baseline among the three groups, and most of the mean score of trials between MAVLT and Alternate Form 1, and between MAVLT and Alternate Form 2. There was significant improvement in the mean score of each trial when the same form was used repeatedly at the interval of one month. However, there was no significant improvement in the mean score of each trial when the Alternate Form 2 was used during repeated neuropsychological testing. The MAVLT is a reliable instrument for repeated neuropsychological testing as long as alternate forms are used. The Alternate Form 2 showed better equivalency to MAVLT and less practice effects. PMID- 26600751 TI - Cytocompatibility of a conductive nanofibrous carbon nanotube/poly (L-Lactic acid) composite scaffold intended for nerve tissue engineering. AB - The purpose of this study was to fabricate a conductive aligned nanofibrous substrate and evaluate its suitability and cytocompatibility with neural cells for nerve tissue engineering purposes. In order to reach these goals, we first used electrospinning to fabricate single-walled carbon-nanotube (SWCNT) incorporated poly(L-lactic acid) (PLLA) nanofibrous scaffolds and then assessed its cytocompatibility with olfactory ensheathing glial cells (OEC). The plasma treated scaffolds were characterized using scanning electron microscopy and water contact angle. OECs were isolated from olfactory bulb of GFP Sprague-Dawley rats and characterized using OEC specific markers via immunocytochemistry and flow cytometery. The cytocompatibility of the conductive aligned nano-featured scaffold was assessed using microscopy and MTT assay. We indicate that doping of PLLA polymer with SWCNT can augment the aligned nanosized substrate with conductivity, making it favorable for nerve tissue engineering. Our results demonstrated that SWCNT/PLLA composite scaffold promote the adhesion, growth, survival and proliferation of OEC. Regarding the ideal physical, topographical and electrical properties of the scaffold and the neurotrophic and migratory features of the OECs, we suggest this scaffold and the cell/scaffold construct as a promising platform for cell delivery to neural defects in nerve tissue engineering approaches. PMID- 26600752 TI - Anti-atherogenic potential of jujube, saffron and barberry: anti-diabetic and antioxidant actions. AB - Atherogenic dyslipidemia, characterized by an increased level of lipoprotein (a) and a decreased level of adiponectin, is a major risk factor for cardiovascular diseases in diabetic patients. To reduce cardiovascular risk in diabetic patients, use of agents with antidiabetic and anti-atherogenic potential is required. Using an animal model of diabetes, we investigated the antiatherogenic potential of extracts of three medicinal plants: jujube, barberry, and saffron. For this, serum level of fasting blood glucose, lipid profile, malondialdehyde, total antioxidant capacity, adiponectin and lipoprotein (a) in diabetic control and extract treated groups were measured. Statistical analysis of measurements showed that serum levels of fasting blood glucose, triglyceride, and VLDL decreased significantly (P < 0.05) in all treated groups. Treatment with all extracts reduced lipid peroxidation and increased antioxidant capacity of the experimental diabetic groups. Serum adiponectin levels increased in all treated groups, whereas lipoprotein (a) levels decreased, most markedly when treated with jujube extract. Jujube, saffron, and barberry extracts are beneficial in ameliorating oxidative stress and atherogenic risk of diabetic rats. This highlights the benefits of further investigating the cardio-protective potential of medicinal plant extracts and evaluating their usefulness as cardio protective agents in clinical practice. PMID- 26600749 TI - Osmoregulation in zebrafish: ion transport mechanisms and functional regulation. AB - Fish, like mammals, have to maintain their body fluid ionic and osmotic homeostasis through sophisticated iono-/osmoregulation mechanisms, which are conducted mainly by ionocytes of the gill (the skin in embryonic stages), instead of the renal tubular cells in mammals. Given the advantages in terms of genetic database availability and manipulation, zebrafish is an emerging model for research into regulatory and integrative physiology. At least five types of ionocytes, HR, NaR, NCC, SLC26, and KS cells, have been identified to carry out Na(+) uptake/H(+) secretion/NH4 (+) excretion, Ca(2+) uptake, Na(+)/Cl(-) uptake, K(+) secretion, and Cl(-) uptake/HCO3 (-) secretion, respectively, through distinct sets of transporters. Several hormones, namely isotocin, prolactin, cortisol, stanniocalcin-1, calcitonin, endothelin-1, vitamin D, parathyorid hormone 1, catecholamines, and the renin-angiotensin-system, have been demonstrated to positively or negatively regulate ion transport through specific receptors at different ionocytes stages, at either the transcriptional/translational or posttranslational level. The knowledge obtained using zebrafish answered many long-term contentious or unknown issues in the field of fish iono-/osmoregulation. The homology of ion transport pathways and hormone systems also means that the zebrafish model informs studies on mammals or other animal species, thereby providing insights into related fields. PMID- 26600753 TI - Highlight report: Interspecies extrapolation by physiologically based pharmacokinetic modeling. PMID- 26600754 TI - Prostate cancer and glutathione S-transferase deletions. AB - GSTM1 and GSTT1 gene polymorphisms have been studied in many populations to evaluate their association with prostate cancer risk with contrasting results. The current study was aimed to find out the association of GSTM1 and GSTT1 gene polymorphisms with prostate cancer in Pakistani men. This case control study included pathologically confirmed prostate cancer patients and age matched male controls. Epidemiological data was collected by a standard questionnaire and presence or absence of GSTM1 and GSTT1 gene was observed by multiplex PCR using CYP1A1 as housekeeping gene. Prostate cancer was more prevalent in age of >60 years and most of the patients were at stage IV (70 %) and have undergone surgery. Family history of cancer, smoking, metastasis and surgery were found to be significant (P<0.05) risk factors in prostate cancer development. Gleason score 7 was most prevalent (40.5 %) in prostate cancer patients. Source of drinking water, residential area, occupation, eating habits and number of family members had no association (P>0.05) with prostate cancer risk. No significant association was found when comparing GSTM1 (OR=0.78) and GSTT1 (OR=0.89) gene deletions with prostate cancer risk. Smoking and TNM staging were also not associated with deletion of GSTM1 and GSTT1 genes. Comparison of dual null deletion of both genes with prostate cancer also showed non-significant associations. Deletion of GSTM1 gene at stage IV prostate cancer patients was significantly higher compared with other stages of cancer while no significance was shown by GSTT1 gene deletion. GSTM1, GSTT1 and deletion of both GSTM1 and GSTT1 genes do not contribute towards increased risk of prostate cancer in Pakistani population. PMID- 26600755 TI - Simplest identification, O-specific polysaccharide purification and antigenic evaluation of Salmonella enterica serovar Typhi Vi negative isolate. AB - Currently licensed typhoid vaccines are based on Vi capsular polysaccharides. Recent molecular reports from typhoid endemic countries state that Salmonella enterica serovar Typhi (S. Typhi) Vi negative strains occur naturally and cause typhoid fever which is indistinguishable from disease caused by Vi positive strains. Vaccine based on Vi polysaccharide may not protect patients if the invading S. Typhi are negative for Vi. The lipopolysaccharide (LPS) is an essential component of S. Typhi outer membrane in which O-specific polysaccharide (OSP) is a protective antigen and universal candidate for vaccine development. In this study, S. Typhi Vi negative isolates were discriminated from Vi positive isolates through a duplex PCR using primers of fliC-d (599bp) and tviA (495bp) genes. The LPS of S. Typhi Vi negative isolates was extracted by hot phenol method and OSP was purified by core hydrolysis. The yield of extracted LPS was 91 mg/L and that of purified OSP was 49.14 mg/L of culture broth. LPS showed ladder like appearance by zinc imidazole staining following SDS-PAGE. Whole cell challenged mice sera were used for in vitro antigenicity evaluation of the purified LPS and OSP. The antigenicity was found adequate by immunodiffusion assay. To our knowledge, this is the first report of purification and antigenic evaluation of LPS of a Vi negative S. Typhi isolate. The purified OSP from S. Typhi Vi negative isolate may be coupled with a carrier protein to produce universal low cost conjugate vaccine candidates for use in typhoid endemic regions. PMID- 26600756 TI - Anti-inflammatory effects of isoketocharbroic acid from brown alga, Sargassum micracanthum. AB - During our on-going screening program designed to isolate natural compounds from marine environments, we isolated isoketochabrolic acid (IKCA) from Sargassum micracanthum, an important brown algae distributed in Jeju Island, Korea. Furthermore, we evaluated the inhibitory effects of IKCA on nitric oxide (NO) production in lipopolysaccharide (LPS)-triggered macrophages. IKCA strongly inhibited NO production, with an IC50 value of 58.31 MUM. Subsequent studies demonstrated that IKCA potently and concentration-dependently reduced prostaglandin E2 (PGE2), tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, and IL-6 cytokine production. In conclusion, to the best of our knowledge, this is the first study to show that IKCA isolated from S. micracanthum has a potent anti-inflammatory activity. Therefore, IKCA might be useful as an anti-inflammatory health supplement or functional cosmetics. PMID- 26600757 TI - ELISA for detection of humoral immunity against measles. PMID- 26600758 TI - Romancing the Boost - the Higher, the Better? PMID- 26600759 TI - Hypofractionated Radiotherapy as Adjuvant Treatment in Early Breast Cancer. A Review and Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND: Adjuvant radiotherapy after breast-conserving surgery is indicated in the vast majority of breast cancer patients. Conventionally fractionated radiotherapy with 50 Gy in 25 fractions was considered standard of care for several decades. The recently publishes long-term results of randomized trials that have tested different moderately hypofractionated radiotherapy schedules that may change clinical practice. PATIENTS AND METHODS: A Pubmed search was carried out to identify the relevant publications on hypofractionated radiotherapy in breast cancer. In total, 4 randomized controlled trials representing the results of 7,095 patients with 10 years of follow-up were identified. A meta-analysis on the primary end point ipsilateral breast cancer recurrence and a review of the toxicity data were performed. RESULTS: Moderately hypofractionated radiotherapy using schedules such as 40 Gy in 15 fractions administered within 3 weeks are as efficient and safe as conventionally fractionated radiotherapy for most breast cancer patients who need adjuvant radiotherapy after breast-conserving surgery. In patients aged < 40 years, after neoadjuvant chemotherapy, and if regional lymph node radiotherapy is indicated, further data are needed. CONCLUSION: Moderately hypofractionated radiotherapy can be recommended as standard treatment after breast-conserving surgery in the majority of breast cancer patients. PMID- 26600760 TI - Accelerated Partial Breast Irradiation in Clinical Practice. AB - Accelerated partial breast irradiation (APBI) has been under clinical investigation for more than 15 years. There are several technical approaches that are clinically established, e.g. brachytherapy, intraoperative radiotherapy (IORT), or external-beam radiotherapy. The understanding of the underlying biology, optimal technical procedures, patient selection criteria, and imaging changes during follow-up has increased enormously. After completion of several phase III trials using brachytherapy or IORT, APBI is currently increasingly used either in phase IV studies, registries, or in selected patients outside of clinical studies. Consensus statements about suitable patients are available from several international and national societies like ASTRO, ESTRO, and DEGRO. One may expect that 15-25% of patients undergoing breast-conserving surgery may qualify for APBI, i.e. patients with small invasive ductal breast cancer without clinical lymph node involvement. PMID- 26600761 TI - Radiotherapy of the Lymphatic Pathways in Early Breast Cancer. AB - International guidelines reveal substantial differences regarding indications for regional nodal irradiation (RNI). Recently, several randomized studies provided new insights and these are discussed here. Patients with 1-3 positive nodes seem to profit from RNI compared to whole-breast (WBI) or chest-wall irradiation (CWI) alone, both with regard to locoregional control and disease-free survival. Irradiation of the regional lymphatics including axillary, supraclavicular and internal mammary nodes provided a small but significant survival benefit in recent randomized trials and 1 meta-analysis. Lymph node irradiation yields comparable tumor control in comparison to axillary lymph node dissection while reducing the rate of lymph edema. Data concerning the impact of 1-2 macroscopically affected sentinel nodes or microscopic metastases on prognosis are equivocal. Recent data suggest that the current restrictive use of RNI should be scrutinized, as the hazard-benefit relation appears to shift towards an improvement of outcome. PMID- 26600762 TI - Radiotherapy of Ductal Carcinoma In Situ. AB - Ductal carcinoma in situ (DCIS) is a heterogeneous disease in both its biology and clinical course. In the past, recurrence rates after breast-conserving surgery have been as high as 30% after 10 years. The introduction of mammography screening and advances in imaging have led to an increase in the detection of DCIS. The focus of this review is on the role of radiotherapy in the multidisciplinary treatment, including current developments in hypofractionation and boost delivery, and attempts to define low-risk subsets of DCIS for which the need for adjuvant radiation is repeatedly questioned. PMID- 26600764 TI - Long-Term Analysis of Ab-2 (Clone SN3b) Immunoreactivity as a Prognostic Factor in Breast Carcinoma. AB - BACKGROUND: CD24 expression has been described as a significant prognostic factor in multiple solid tumours. Most of these studies have, however, been undertaken using the Ab-2 antibody (clone SN3b), which detects a CD24-associated carbohydrate, and not the CD24 protein itself. Although its biological identity remains unclear, its prognostic significance means that detection of this carbohydrate may, nonetheless, be clinically relevant. METHODS: 133 breast carcinomas were selected (pT1-2 pN0-2 M0, no secondary carcinoma, no contralateral carcinoma) from a previous SN3b expression study on a larger cohort of breast carcinomas. After updating data on follow-up observations, we carried out univariate and multivariate analysis of the prognostic significance of SN3b for total and breast cancer-specific survival. RESULTS: A statistically significant correlation between cytoplasmic SN3b immunoreactivity and positive node status was found. Cytoplasmic SN3b also has node status-independent prognostic significance. Total survival exhibits a statistically significant dependency on cytoplasmic SN3b even for pN0 cases. CONCLUSION: The independent prognostic value of CD24 as detected by Ab-2/clone SN3b could replace the diagnostic axillary dissection in breast carcinoma patients if this was confirmed in further studies. Also, clarifying the exact epitope of this interesting antibody is more than warranted. PMID- 26600763 TI - Current Treatment of Isolated Locoregional Breast Cancer Recurrences. AB - Patients with isolated locoregional breast cancer recurrences should be treated with curative intent. Mastectomy is regarded as the standard of care for patients with ipsilateral breast tumor recurrence. In a selected group of patients, partial breast irradiation after second breast-conserving surgery is a viable alternative to mastectomy. If a second breast conservation is performed, additional irradiation should be mandatory, especially in patients who had not been irradiated previously. In case of re-irradiation, the largest experience exists for multi-catheter brachytherapy. Prospective clinical trials are needed to clearly define selection criteria, long-term local control, and toxicity. In patients with resectable locoregional breast cancer recurrences after mastectomy, multi-modal therapy comprising complete resection, radiation therapy in previously unirradiated patients, and systemic therapy results in 5-year disease free and overall survival rates of 69% and 88%, respectively. In radiation-naive patients with unresectable, isolated locoregional recurrences, radiation therapy is mandatory. In selected patients with previous irradiations and unresectable locoregional recurrences, a second irradiation as part of an individual treatment concept can be applied. The increased risk of severe toxicity should always be weighed up against the potential clinical benefit. A combination therapy with hyperthermia can further improve the treatment results. PMID- 26600765 TI - Radiotherapy Induces Development of Fragmented QRS in Patients with Breast Cancer. AB - BACKGROUND: Myocardial fibrosis is a well-known side effect of radiotherapy. Fragmented QRS (fQRS) has been shown to be a marker of myocardial fibrosis. We postulated that radiotherapy induces development of fQRS in breast cancer patients. PATIENTS AND METHODS: Breast cancer patients receiving locoregional radiotherapy were enrolled. Patients who had fQRS on electrocardiography (ECG) before radiotherapy were excluded. All patients were revaluated for the development of fQRS at 1-year follow-up. An age-matched healthy group served as controls. RESULTS: A total of 52 breast cancer patients receiving locoregional radiotherapy were included (median age 49 years, interquartile range (IQR) 13). Of these, 19 (37%) had developed fQRS at 1-year follow-up. Compared with the control group, prevalence of fQRS was significantly higher in the irradiated group (37 vs. 12%; p < 0.002). Median total cardiac radiation dose was significantly higher in patients who had developed fQRS (5 Gy, IQR 5.2 vs. 1.7 Gy, IQR 4.4; p = 0.003). Cardiac radiation dose, entered either as a continuous variable (odds ratio (OR) 1.35, 95% confidence interval (CI) 104-1.74) or as a dichotomized variable (>= 2.2 Gy, OR 6.48, 95% CI 1.47-28.61), was independently associated with the development of fQRS at 1-year follow-up. CONCLUSION: Radiotherapy for breast cancer induces development of fQRS on ECG. Cardiac radiation dose is independently associated with the development of fQRS. PMID- 26600766 TI - Primary Large-Cell Neuroendocrine Carcinoma of the Breast Occurring in a Pre Menopausal Woman. AB - BACKGROUND: Primary large-cell neuroendocrine carcinoma of the breast (LCNEC breast) in pre-menopausal women is extremely rare. CASE REPORT: A 34-year-old woman presented with a mass in the left breast that was diagnosed as neuroendocrine carcinoma by needle biopsy. Computed tomography revealed no lymph node swelling or distant organ metastasis. Left mastectomy and sentinel lymph node biopsy were performed and metastasis to the axial lymph node was detected. Left axillary lymph node dissection was performed and histopathological and immunohistochemical examination revealed that the tumor was an LCNEC-breast, which was 6.0 cm in size and positive for the neuroendocrine markers (neuron specific enolase, chromogranin A, and synaptophysin). The tumor cells were hormone-receptor positive and HER2 negative. The patient refused any adjuvant hormonal therapy, chemotherapy or radiotherapy. She has been followed up for 4 years without medication, and no recurrence has been noted. CONCLUSION: We present a case of LCNEC-breast in a 34-year-old woman. Our case represents the youngest woman with LCNEC-breast reported in the English literature. PMID- 26600767 TI - Descending Necrotizing Mediastinitis Treated with Tooth Extractions following Mediastinal and Cervical Drainage. AB - Descending necrotizing mediastinitis (DNM) is a rare condition in which oropharyngeal infection spreads to the mediastinum via the cervical fascia. Delayed diagnosis and surgery result in a high mortality rate among patients with DNM. We present a case of DNM resulting from odontogenic infection treated successfully with tooth extraction following mediastinal and cervical drainage. A 43-year-old, previously healthy Japanese man was admitted to our hospital for treatment of acute mediastinitis. Computed tomography revealed gas collection around the mid-thoracic esophagus and bilateral pleural effusion. We performed mediastinal drainage via right thoracotomy. Cervicotomy was performed on postoperative day 14 to drain a residual cervical abscess. The patient required the extraction of ten teeth over three procedures to address primary odontogenic infection before his fever resolved on postoperative day 40. Prompt diagnosis, aggressive drainage and removal of the source of infection can improve survival among patients with this life-threatening disease. PMID- 26600768 TI - Recent Trend of Hepatitis E Virus Infection in Chiba Area, Japan: 3 of 5 Cases with Rheumatoid Arthritis. AB - Hepatitis E virus (HEV) infection is an emerging health concern in developing and developed countries, such as Japan. Five cases have recently been diagnosed as hepatitis E. Of interest, 3 of them had rheumatoid arthritis (RA), although a previous study demonstrated a lack of association between HEV and RA. One of the other patients developed autoimmune hepatitis and was successfully treated with corticosteroids approximately 150 days after the diagnosis of hepatitis E. In RA patients with liver dysfunction, the presence of HEV infection should be evaluated immediately because these patients are often relatively old. Further investigation of the association between HEV and autoimmune hepatitis is needed. PMID- 26600769 TI - Large-Cell Neuroendocrine Carcinoma of the Esophagus: A Case from Saudi Arabia. AB - Neuroendocrine carcinomas of the esophagus are very rare, and the majority are high grade (poorly differentiated). They occur most frequently in males in their sixth and seventh decades of life. There have been no concrete data published on clinical features or on prognosis. We report a case of large-cell neuroendocrine carcinoma of the esophagus in a 66-year-old Saudi female with progressive dysphagia and weight loss. Upper endoscopy revealed an esophageal ulcerated mass. PMID- 26600770 TI - Colorectal Liver Metastasis, Primary Gallbladder Carcinoma and Myelofibrosis Present Simultaneously in a Liver Resection Specimen. AB - Myelofibrosis and gallbladder carcinoma are both very rare diseases. This case report describes a patient with a history of myelofibrosis and colorectal carcinoma who was diagnosed with colorectal liver metastases. Surgery was performed to remove the metastases, and on site, the gallbladder was removed because of involvement in one of the liver lesions. After pathological examination, a primary gallbladder carcinoma and myelofibrosis were found in addition to the liver metastases. The combination of diseases was not likely to be interconnected but rather an unlucky course of events for the patient. PMID- 26600771 TI - Isolated Superior Mesenteric Artery Dissection with Small Intestine Ischemia. AB - Superior mesenteric artery (SMA) dissection without aortic dissection is a rare condition, and its diagnosis is considered to be difficult. Intestinal infarction is a severe complication of the disease, which may require resection of the intestine. We present a case of isolated SMA dissection. A 53-year-old man experienced sudden pain in the abdomen while playing Japanese pinball and was admitted to our hospital due to acute abdominal symptoms of uncertain cause. Enhanced CT revealed a defect of the root of the SMA, while angiography and intravascular ultrasound findings showed dissection of the SMA wall. Conservative treatment was chosen at the time, while a part of the small intestine was eventually resected because of progressive ischemia. Although SMA dissection is a rare occurrence in cases with acute abdominal symptoms, awareness of the condition is important for differential diagnosis. PMID- 26600772 TI - Capsule Endoscope Aspiration after Repeated Attempts for Ingesting a Patency Capsule. AB - Capsule endoscope aspiration into the respiratory tract is a rare complication of capsule endoscopy. Despite the potential seriousness of this complication, no accepted methods exist to accurately predict and therefore prevent it. We describe the case of an 85-year-old male who presented for evaluation of iron deficiency anemia. He complained of dysphagia while ingesting a patency capsule, with several attempts over a period of 5 min before he was successful. Five days later, he underwent capsule endoscopy, where he experienced similar symptoms in swallowing the capsule. The rest of the examination proceeded uneventfully. On reviewing the captured images, the capsule endoscope was revealed to be aspirated, remaining in the respiratory tract for approximately 220 s before images of the esophagus and stomach appeared. To our knowledge, this is the first documented case of a patient who experienced capsule endoscope aspiration after ingestion of a patency capsule. This case suggests that repeated attempts required for ingesting the patency capsule can predict capsule endoscope aspiration. We presume that paying sufficient attention to the symptoms of a patient who ingests a patency capsule could help us prevent serious complications such as aspiration of the capsule endoscope. In addition, this experience implies the potential risk for ingesting the patency capsule. We must be aware that the patency capsule could also be aspirated and there may be more unrecognized aspiration cases. PMID- 26600773 TI - Dysphonia after Bevacizumab Rechallenge: A Case Report. AB - Inhibition of vascular endothelial growth factor (VEGF) signaling, an initiator of tumor angiogenesis, inhibits tumor growth and invasion. Bevacizumab, a monoclonal antibody to VEGF, in common use as an adjunct to standard chemotherapy like irinotecan in advanced colorectal cancer, also affects the normal (nontumor) vasculature. Dysphonia or voice changes have been anecdotally reported in patients that have been exposed to antiangiogenics. In this case report, we present an occurrence of severe dysphonia in a 60-year-old male with metastatic colorectal cancer after reintroduction of irinotecan and bevacizumab. To our knowledge, this is the first case of dysphonia associated with bevacizumab rechallenge. PMID- 26600774 TI - Langerhans Cell Histiocytosis of the Clavicle in an Adult: A Case Report and Review of the Literature. AB - Langerhans cell histiocytosis (LCH) usually occurs in children under the age of 10 years with a predilection for the skull, spine, rib and humerus. Solitary LCH occurring in an adult clavicle is uncommon with limited reports to date. The lesion in our patient was curetted with the intent to make a diagnosis, which subsequently lead to the remission of the symptom and the disease. At the final follow-up after 1 year, no local recurrence or metastasis is observed. PMID- 26600775 TI - Five Simultaneous Primary Tumors in a Single Patient: A Case Report and Review of the Literature. AB - Multiple primary malignancies (MPMs) are present when a patient is diagnosed with more than one primary malignancy and when each tumor is histologically unrelated to the others. MPMs are considered synchronous when they present within 6 months of one another. Here, we report the case of a 57-year-old woman with a past medical history significant for melanoma in 1988, who presented in 2014 with 5 distinct tumors within 4 months: malignant melanoma of the right popliteal fossa, invasive lobular breast carcinoma, diffuse large B cell lymphoma, nodular lymphocyte predominant Hodgkin lymphoma, and a giant cell tumor of tendon sheath/pigmented villonodular synovitis. We discuss her treatment and also present a brief review of the literature. The incidence of MPMs appears to be on the rise, which demands an interdisciplinary, multimodal, and personalized approach to care. PMID- 26600776 TI - An Autopsied Case of Malignant Sarcomatoid Pleural Mesothelioma in Which Chest Pain Developed Several Months Earlier without Abnormality on Imaging. AB - The patient experienced chest pain for about 7 months, but a diagnosis could not be made until after death. He was diagnosed with malignant sarcomatoid pleural mesothelioma on autopsy. In this case report, difficult aspects of the diagnosis are discussed. The 70-year-old Japanese man was a driver who transported ceramic related products. Right chest pain developed in July 2013, but no abnormality was detected on a chest computed tomography (CT) performed in September 2013, and the pain was managed as right intercostal neuralgia. A chest CT performed in late October 2013 revealed a right pleural effusion, and the patient was referred to our hospital in early November 2013. Thoracentesis was performed, but the cytology was negative, and no diagnosis could be made. Close examination was postponed because the patient developed a subarachnoid hemorrhage. He underwent (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) after discharge from the neurosurgery department, and extensive right pleural thickening and (18)F-FDG accumulation in this region were observed. Based on these findings, malignant pleural mesothelioma was suspected, and a thoracoscopy was performed under local anesthesia in early December 2013, but no definite diagnosis could be made. The patient selected best supportive care and died about 7 months after the initial development of right chest pain. The disease was definitively diagnosed as malignant sarcomatoid pleural mesothelioma by a pathological autopsy. When chronic chest pain of unknown cause is observed and past exposure to asbestos is suspected, actions to prevent delay in diagnosis should be taken, including testing for suspicion of malignant pleural mesothelioma. PMID- 26600777 TI - Prolonged Survival in a Patient with a Pancreatic Acinar Cell Carcinoma. AB - Pancreatic acinar cell carcinoma (ACC) is a rare entity. Herein we present the case of a 50-year-old male patient with an unlimited mass on the pancreatic corpus and tail with peripancreatic effusion and multiple metastases in the liver and spleen. A liver biopsy showed a pancreatic ACC. The patient received 9 cycles of gemcitabine plus oxaliplatin (GEMOX regimen), which had to be stopped because of a persistent grade 2 neuropathy. A CT scan showed complete response after 14 years. At the age of 61 years, a localized prostatic cancer was diagnosed, treated by prostatectomy. The patient carried a BRCA2 mutation. None of the precedent case reports describe a chemosensibility to the GEMOX regimen. In spite of the lack of study in these patients, chemotherapy with oxaliplatin seems to be the most effective. Long survival can be expected. PMID- 26600778 TI - Primary Diffuse Large B-Cell Lymphoma of the Mandible: Case Report and Review of the Literature. AB - In the oral cavity, extranodal non-Hodgkin's lymphoma can occur in the periapical region either in the maxilla or mandible. Also, it can mimic inflammatory lesions that arise around the teeth apices such as periapical granuloma, radicular cyst and osteomyelitis. Misdiagnosis of lymphomas in the jaws may reduce the chance of successful treatment and worsen the prognosis. Therefore, any growth of periapical tissue must be submitted for histopathological evaluation to avoid a delay in the diagnosis. We present a case of extranodal non-Hodgkin's lymphoma of a 53-year-old male in the right posterior mandible that was initially misdiagnosed as a reactive periapical lesion. This case illustrates the importance for both the pathologist and the clinician of considering malignant lesions such as lymphoma in the differential diagnosis of periapical radiolucency. PMID- 26600779 TI - Ectopic Hepatocellular Carcinoma Arising from the Peritoneum in a Patient with a History of Oropharyngeal Cancer: A Case Report. AB - A subphrenic mass was noted on a surveillance computed tomography (CT) scan of a 65-year-old man who had achieved complete remission of oropharyngeal cancer after concurrent chemoradiotherapy. The mass was 3.2 cm in size and showed a multilobular enhancing pattern along the peritoneal lining. The patient was negative for hepatitis B surface antigen and anti-hepatitis C virus antibody. His carcinoembryonic antigen level was within the normal range. Contrast-enhanced CT revealed no mass in the liver. He underwent surgery, and a pale yellowish soft tumor measuring 3.8 * 3.2 * 1.2 cm was resected. Histologically, the tumor was confirmed to be a hepatocellular carcinoma. Currently, he is doing well, and has been followed up without any signs of recurrence. PMID- 26600780 TI - Flushing Out Carcinoid Syndrome: Beneficial Effect of the Anticancer Epigenetic Agent RRx-001 in a Patient with a Treatment-Refractory Neuroendocrine Tumor. AB - Neuroendocrine tumors (NET) are a heterogeneous group of neoplasms defined by the presence of cells with secretory granules and the potential to produce and release high levels of vasoactive peptides into the circulation, leading to severe flushing and diarrhea, which may adversely affect quality of life. This report presents the case of a 64-year-old man with chronic refractory diarrhea due to pulmonary NET treated with the experimental anticancer agent RRx-001 in a phase II trial called TRIPLE THREAT with subsequent resolution of his diarrhea. PMID- 26600781 TI - Signet-Ring Cell Carcinoma of the Colon: A Case Report and Review of the Literature. AB - BACKGROUND: Colorectal adenocarcinoma (CRC) is the third leading cause of death in the United States. One of the histologic subtypes of CRC is signet-ring cell carcinoma (SRCC), which has a distinct molecular and tumor biology from that of adenocarcinoma. Primary SRCC diagnosed at an early stage is very rare as most cases are detected at an advanced stage. Therefore, overall prognosis of SRCC is poor. CASE PRESENTATION: A 36-year-old female presented to her primary care physician with new-onset progressive right lower quadrant pain without any significant past medical or family history. Computed tomography scan of the abdomen and pelvis with contrast showed a 4.9 * 3.5 * 3.1 cm, lobulated, septated cystic mass arising from the cecum. The mass demonstrated wall enhancement and contained focal areas of coarse calcification. There was nodal involvement either locally or distally. The patient underwent right hemicolectomy, and pathology revealed a high-grade mucinous carcinoma with signet-ring cell variant invading through the muscularis propria and into the subserosal adipose tissue. The margins were negative for tumor, and no lymphovascular or perineural invasion was noted. None of the 14 resected pericolonic lymph nodes was positive for malignancy. Hence, she was staged as pT3, pN0, pMx-stage IIA. The appendix was not involved. Microsatellite instability testing showed the preservation of MLH1, PMS2, MSH2 and MSH6 proteins by IHC and PCR. Carcinoembryonic antigen level was within normal limits. Due to the patient's young age, aggressive histology and microsatellite-stable status, adjuvant fluropyrimidine (5-FU)-based therapy with the single agent capecitabine was initiated. The patient completed 6 months of adjuvant therapy and has been disease free for approximately 18 months. CONCLUSION: Primary SRCC of the cecum is a rare disease. Given the poor prognosis of these patients, early-stage disease with microsatellite-stable patients should be considered for adjuvant 5-FU-based therapy in an attempt to prevent recurrence. PMID- 26600782 TI - Clear Cell Carcinoma of the Breast: A Rare Breast Cancer Subtype - Case Report and Literature Review. AB - BACKGROUND: Glycogen-rich clear cell breast carcinoma is a rare histological breast cancer subtype. Its prognosis may vary depending on specific clinical and pathological characteristics such as low grade, strong positivity of estrogen receptor (ER) expression and early diagnosis. CASE PRESENTATION: We present the case of a 53-year-old woman with a bleeding 10-cm-diameter mass in the left breast. The histological examination showed a poorly differentiated tumor with malignant cells characterized by abundant clear cytoplasm. The diagnosis of clear cell carcinoma was based on the histological characteristics of the tumor, and a nonmammary origin was initially ruled out. The tumor was triple negative [i.e. ER, progesterone receptor (PR) and HER2 negative]. Four months after the initial locoregional treatment, the patient developed lung and distant lymph node metastases. CONCLUSIONS: Glycogen-rich clear cell carcinoma of the breast is a rare tumor. Early diagnosis, absence of lymph node metastases and ER/PR positivity are associated with a better prognosis, as in other common breast cancer subtypes. PMID- 26600783 TI - Persistent Left Superior Vena Cava in Hematological Malignancy Requiring Central Venous Catheter Insertion for Intensive Chemotherapy. AB - Persistent left superior vena cava is a congenital vascular anomaly, which is possibly arrhythmogenic and thrombogenic, rarely complicated with coronary sinus atresia. We treated a 42-year-old male with Hodgkin's lymphoma requiring central venous catheter placement for intensive chemotherapy. Persistent left superior vena cava was revealed after the insertion of the central venous catheter by the radiological finding of the catheter tip cannulated into the vena cava cavity. The relationship between coronary sinus atresia and persistent left superior vena cava induced by central venous catheterization remains unclear; however, the hematologist should pay attention to the malpositioning of the central venous catheter. PMID- 26600784 TI - Effect of Rectal Levodopa Administration: A Case Report. AB - OBJECTIVE: The aim of this report is to discuss whether or not rectal levodopa administration is useful in some situations. BACKGROUND: In situations where oral intake of levodopa formulations is not possible, the treatment options of Parkinson's disease patients are limited. The literature describes no or low rectal absorption of levodopa. CASE DESCRIPTION: A patient with an ileus was unable to take oral medication. After consulting the neurologist and pharmacist, the surgeon decided to describe a rectal formulation of levodopa/carbidopa (100/25 mg) once daily. On day 3 of the therapy, 1 h after administration of the rectal formulation of levodopa/carbidopa, a blood sample was drawn. The patient was unable to take his other Parkinson medication; therefore the dose of the rectal levodopa/carbidopa was increased to 5 times a day. RESULTS: Full control of the symptoms was not achieved, but alleviation of the most severe tremor and rigidity was seen, which was confirmed by the neurologist, nurses and patient. The levodopa concentration detected was 17 nmol/l. Compared to levodopa concentrations described in the literature (1,400-12,000 nmol/l), the concentration is very low. There are some possible explanations for the low concentration detected. The presence of a specific amino acid transport system in the rectum is not known, which could lead to no or reduced absorption. The poor rectal absorption of carbidopa leads to a higher conversion of levodopa to dopamine peripherally. CONCLUSIONS: In situations where patients are unable to take oral medication, rectal administration of levodopa/carbidopa is worth considering. PMID- 26600785 TI - Rehabilitation for a Patient with Hemiplegia, Ataxia, and Cognitive Dysfunction Caused by Pontine Hemorrhage. AB - Patients with pontine hemorrhage usually experience severe disturbances of consciousness, pupillary abnormalities, quadriparesis, and respiratory failure. However, little is known regarding cognitive dysfunction in patients with pontine hemorrhage. We report the case of a rehabilitation patient presenting with hemiplegia, ataxia, and cognitive dysfunction caused by a pontine hemorrhage. A 55-year-old, right-handed male suffered sudden onset of vertigo, dysarthria, and hemiplegia on the right side. He was diagnosed with brain stem hemorrhage, and conservative treatment was administered. The vertigo improved, but dysarthria, ataxia, hemiplegia, and gait disorder persisted. He was disoriented with respect to time and place and showed a poor attention span, impaired executive function, and reduced volition. A computed tomography revealed hematomas across the pons on both sides, but no lesions were obvious in the cerebellum and cerebrum. Single photon emission tomography showed decreased perfusion in the brain stem, bilateral basal ganglia, and frontal and parietal lobes in the left hemisphere. The patient received exercise therapy and cognitive rehabilitation, and home modifications were performed to allow him to continue living at home under the supervision of his family. His symptoms improved, along with enhanced regional cerebral blood flow to the frontal and temporal lobes. These findings suggest that the pontine hemorrhage caused diaschisis resulting in secondary reduction of activity in the cerebral hemisphere and the occurrence of cortical symptoms. Therefore, rehabilitation is necessary, along with active instructions for the family members of patients with severe neurological deficits. PMID- 26600786 TI - Superior Orbital Fissure Syndrome and Ophthalmoplegia Caused by Varicella Zoster Virus with No Skin Eruption in a Patient Treated with Tumor Necrosis Alpha Inhibitor. AB - Varicella zoster virus lies dormant in the dorsal root ganglia after symptomatic chicken pox infection, usually in childhood. If the virus reactivates in the trigeminal ganglia, it can cause varicella zoster ophthalmicus, which can have severe ocular complications. We report a case of a 73-year-old woman in severe immunosuppression due to treatment with mycophenolate mofetil, glucocorticosteroids and a tumor necrosis factor alpha inhibitor. The reactivation caused superior orbital fissure syndrome, which has only rarely been described in relation to varicella zoster virus reactivation. In our case, the syndrome was seen along with severe encephalitis. PMID- 26600787 TI - Subcutaneous Immunoglobulin Use in Inclusion Body Myositis: A Review of 6 Cases. AB - INTRODUCTION: Inclusion body myositis (IBM) is a slowly progressive degenerative inflammatory disorder affecting both proximal and distal muscles. Immunosuppressive therapies are generally ineffective in the treatment of this disorder, and most patients are resistant to steroid therapy. Some benefits with mild improvement were observed with intravenous immunoglobulin (IVIg), particularly in patients with severe dysphagia. OBJECTIVES: The objective of this review was to describe the use of subcutaneous Ig (SCIg) in patients with IBM and to assess its feasibility. RESULTS: This report reviews 6 cases of IBM treated with SCIg in clinical practice. All patients had received prior treatments for IBM, including immunosuppressive agents and IVIg. SCIg was administered over a long period of time, ranging from 4.5 to 27 months. No patient discontinued the SCIg because of a treatment-related event or safety issues. The 6 cases showed an improvement in muscle strength and resolution of dysphagia. For 2 patients, this improvement persisted for approximately 12 months. CONCLUSIONS: SCIg might be proposed as an alternative therapy to patients with IBM who are resistant to corticoids and immunosuppressive therapies. Our findings suggest that treatment with SCIg (Gammanorm 16.5%, Octapharma AB) is feasible and safe in patients with IBM. PMID- 26600788 TI - An Unusual Case of Extranodal Rosai-Dorfman Disease Manifesting as an Epibulbar Mass. AB - PURPOSE: To report an unusual presentation of a 48-year-old man with a salmon colored epibulbar mass, whose pathology was consistent with extranodal Rosai Dorfman disease (RDD). METHOD: We conducted a retrospective and interventional case report. RESULTS: A 48-year-old white man presented with progressive left eye irritation, redness, and multiple large subcutaneous nodules on his arms and torso over the past year. He did not have any lymphadenopathy, lymphocytosis, or fever. Visual acuity and intraocular pressures were normal in both eyes. He had mild vertical diplopia on downward gaze. Slit lamp examination revealed a non tender salmon-colored epibulbar mass of 1.0 * 1.2 cm. Incisional biopsy was performed. Histopathologic evaluation revealed emperipolesis, with positive CD68, positive S100, and negative CD1a staining. These findings were consistent with extranodal RDD. At the 24-month follow-up, there were no signs of recurrence, and his diplopia resolved. CONCLUSIONS: This case of RDD is rare because of the concurrent epibulbar mass with subcutaneous nodules on the torso and arms. Extranodal RDD with epibulbar mass involvement tends to be unilateral, occurring mainly in males, and evenly among people of white and black race. An epibulbar mass of any color should raise concern for systemic lymphoma and RDD. The clinical course for extranodal RDD is typically benign. Excisional biopsy is often done for diagnosis and treatment. Recurrence of the unilateral epibulbar mass after biopsy is rare, but common with bilateral epibulbar masses. PMID- 26600789 TI - Delayed Correction of Hypotony Maculopathy in a Patient with Glaucoma and Thyroid Related Orbitopathy. AB - Hypotony maculopathy is a condition that may result in visual deterioration from choroidal folds or optic disc edema. Optic disc edema can result from altered translaminar pressure gradients (lowered intraocular pressure, increased cerebrospinal fluid pressure, or increased orbital pressure). We report a case of bilateral optic disc edema in a patient with glaucoma and thyroid-related orbitopathy. The patient's disc edema was initially presumed to be secondary to her orbitopathy, but persisted after bilateral orbital decompression. Ultimately, disc edema and choroidal folds in the right eye resolved after trabeculectomy revision and an increase in intraocular pressure. This case serves as a reminder of the causes of optic disc edema and demonstrates delayed reversal of hypotony maculopathy. PMID- 26600790 TI - Unilateral Vogt-Koyanagi-Harada Disease: A Clinical Case Report. AB - PURPOSE: To report a case of a 20-year-old female with decreased visual acuity (VA) in the left eye (LE). METHODS: This is a retrospective and descriptive case report based on data from clinical records, patient observation and analysis of diagnostic tests. RESULTS: A 20-year-old female presented with decreased VA in the LE for 3 days. Best-corrected visual acuity (BCVA) was 20/20 in the right eye (RE) and 20/40 in the LE. Pupillary function, intraocular pressure, results of external segment examinations and slit-lamp biomicroscopy were normal, bilaterally. RE fundoscopy was normal, and in the LE it revealed papillitis and posterior pole exudative retinal detachment. Optical coherence tomography (OCT) confirmed the macular serous retinal detachment and showed thickening of the posterior choroid also revealed by orbital ultrasound and magnetic resonance imaging (MRI). Fluorescein angiography showed angiographic features typical of Vogt-Koyanagi-Harada (VKH) disease: disseminated spotted choroidal hyperfluorescence and choroidal multifocal hypofluorescence, multifocal profuse leakage in the retina with pooling, serous retinal detachment and optic disc hyperfluorescence. Serological testing for the diagnosis of infectious pathologies was negative, and the review of systems was normal. The patient received systemic steroids and cyclosporine. LE BCVA improved up to 20/20 at 18 months after the diagnosis, with complete reabsorption of subretinal fluid and normal retinal and choroidal thickness by OCT. CONCLUSION: Despite the unilateral involvement, the clinical and angiographic features were typical of VKH disease, and ophthalmologists should be aware to recognize this rare clinical variant of the disease. PMID- 26600791 TI - A Case Report of Ablepharon-Macrostomia Syndrome with Amniotic Membrane Grafting. AB - We describe a rare case of an infant who was born with multiple congenital anomalies, including the absence of eyelids. This patient had many dysmorphic features consistent with a severe phenotype of ablepharon-macrostomia syndrome (AMS) including a fish-like appearance of the mouth, rudimentary ears, absence of body hair, thin skin, absent nipples, abdominal distension, and genital abnormalities. Upon presentation, there was severe exposure keratopathy causing large bilateral sterile ulcers culminating in corneal melting of both eyes. An amniotic membrane graft was used to attempt to maintain the corneal surface integrity. However, because of the late presentation, the corneas could not be salvaged. Extensive surgical reconstruction of both eyelids and bilateral penetrating keratoplasty was ultimately performed successfully to protect the ocular surfaces while trying to maximize the visual potential. Early amniotic membrane grafting may be done at the bedside and may help preserve the ocular in patients with severe eyelid deformities until more definitive treatment is performed. PMID- 26600792 TI - Innovative Interventional and Imaging Registries: Precision Medicine in Cerebrovascular Disorders. AB - BACKGROUND: Precision medicine in cerebrovascular disorders may be greatly advanced by the use of innovative interventional and imaging-intensive registries. Registries have remained subsidiary to randomized controlled trials, yet vast opportunities exist to leverage big data in stroke. SUMMARY: This overview builds upon the rationale for innovative, imaging-intensive interventional registries as a pivotal step in realizing precision medicine for several cerebrovascular disorders. Such enhanced registries may serve as a model for expansion of our translational research pipeline to fully leverage the role of phase IV investigations. The scope and role of registries in precision medicine are considered, followed by a review on the history of stroke and interventional registries, data considerations, critiques or barriers to such initiatives, and the potential modernization of registry methods into efficient, searchable, imaging-intensive resources that simultaneously offer clinical, research and educational added value. KEY MESSAGES: Recent advances in technology, informatics and endovascular stroke therapies converge to provide an exceptional opportunity for registries to catapult further progress. There is now a tremendous opportunity to deploy registries in acute stroke, intracranial atherosclerotic disease and carotid disease where other clinical trials leave questions unanswered. Unlike prior registries, imaging-intensive and modernized methods may leverage current technological capabilities around the world to efficiently address key objectives and provide added clinical, research and educational value. PMID- 26600793 TI - Mechanical Thrombectomy Is Now the Gold Standard for Acute Ischemic Stroke: Implications for Routine Clinical Practice. AB - BACKGROUND: This review aims to summarize the findings of the recently published randomized controlled studies which provide overwhelming evidence in support of mechanical thrombectomy for acute ischemic stroke with large artery occlusion. The five studies, Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN), Endovascular Revascularization with Solitaire Device versus Best Medical Therapy in Anterior Circulation Stroke within 8 h (REVASCAT), Endovascular Treatment for Small Core and Proximal Occlusion Ischemic Stroke (ESCAPE), SolitaireTM FR as Primary Treatment for Acute Ischemic Stroke (SWIFT PRIME) and Extending the Time for Thrombolysis in Emergency Neurological Deficits with Intra-Arterial Therapy (EXTEND IA) have demonstrated the critical role of selecting patients by advanced neuroimaging, the superior recanalization capacity of stent retrievers and the effects of minimization of work processes delay. SUMMARY: This review outlines lessons gained from the 5 positive studies which assessed mechanical thrombectomy as part of endovascular therapy for patients with proximal artery occlusion in the internal carotid and middle cerebral arteries. It discusses the role of age and stroke severity on treatment while also comparing the unique trial designs and selection criteria used amongst the 5 studies. In addition to examining the importance of unique imaging parameters such as collateral circulation, mismatch ratio and ischemic core volume, the review outlines differences in workflow parameters within the context of outcome. Finally the benefit of neuroimaging to broaden treatment eligibility and the issues associated with general anesthesia will be discussed in this review. KEY MESSAGES: Questions remain over the applicability of mechanical thrombectomy to stroke subgroups including wake-up strokes and basilar artery thrombosis. The role of imaging is integral to this process and can lead to broadening eligibility criteria in the future. Workflow practices have been streamlined in the 5 positive randomized controlled studies, but guidelines will need to be revised accordingly if similar patient outcomes are to be replicated in a wider population. PMID- 26600794 TI - Endovascular Therapy in Strokes with ASPECTS 5-7 May Result in Smaller Infarcts and Better Outcomes as Compared to Medical Treatment Alone. AB - INTRODUCTION: Intra-arterial therapy (IAT) for large vessel occlusion strokes (LVOS) has been increasingly utilized. The benefit of IAT in patients with midrange Alberta Stroke Program Early Computed Tomography Score (ASPECTS) remains to be established. MATERIALS AND METHODS: This was a retrospective analysis of LVOS with ASPECTS 5-7 treated with IAT (n = 86) or medical therapy alone (intravenous tissue plasminogen activator; n = 15) at two centers from 2009 to 2012. Definitions were as follows: symptomatic intracranial hemorrhage = any parenchymal hematoma; successful reperfusion = mTICI >=2b; good and acceptable outcomes = 90-day mRS 0-2 and 0-3, respectively. Final infarct volumes (FIV) were calculated based on 24-hour CT/MRI scans. RESULTS: Mean age (67 +/- 14 vs. 67 +/- 19 years) and baseline NIHSS (20 +/- 5 vs. 20 +/- 6) were similar in the two groups. Successful reperfusion was achieved in 58 (67%) IAT patients. Symptomatic and asymptomatic intracranial hemorrhage occurred in 9 (10%) and 31 (36%) IAT patients, respectively. The proportion of 90-day good and acceptable outcomes was 20 (17/86) and 33% (28/86), respectively. Successful IAT reperfusion was associated with smaller FIV (p = 0.015) and higher rates of good (p = 0.01) and acceptable (p = 0.014) outcomes. There was a strong trend towards a higher hemicraniectomy requirement in medically as compared to endovascularly treated patients (20 vs. 6%; p = 0.06) despite similar in-hospital mortality. The median FIV was significantly lower with IAT versus medical therapy [80 ml (interquartile range, 38-122) vs. 190 ml (121-267); p = 0.015]. CONCLUSIONS: Despite a relatively low probability of achieving functional independence, IAT in LVOS patients with ASPECTS 5-7 appears to result in lower degrees of disability and may lessen the need for hemicraniectomy. Therefore, it may be a reasonable option for patients and families who favor a shift from severe to moderate disability. PMID- 26600796 TI - Endovascular Treatment for Acute Ischemic Stroke: Updates and Future Implications. AB - Stroke constitutes the primary cause of acquired disability in adults and is a second leading cause of death worldwide. The low recanalization rate after intravenous thrombolysis calls for an alternate therapy for acute ischemic stroke. The methodology for endovascular treatment has evolved greatly over the past two decades. The past 6 months have seen great progress in this area, with several randomized clinical trials all proving the efficacy and safety of endovascular treatment. Three key factors are important for good functional outcome after endovascular treatment: fast imaging to prove proximal occlusion and to exclude large infarct core, using mainly the stent retriever thrombectomy devices and establishing an efficient workflow to achieve fast reperfusion. Although positive results of RCTs are encouraging and bring what is urgently needed in the field, transforming these positive results into clinical practice will be both a challenge and opportunity of the next 5 years. It will need hard work, leadership and cooperation of all members involved in the chain of treating a stroke patient. In the wake of these positive trials, hospitals and professional organizations are working together to save every minute when fighting against this devastating disease. PMID- 26600795 TI - Reconfiguration of the Carotid Artery after Angioplasty and Stenting: A Case Report and Review of the Literature. AB - Severe carotid stenosis or occlusion may cause insufficient blood flow and lead to distal artery wall collapse and extensive lumen contraction. Whether this 'adaptive narrowing' can restitute after carotid recanalization is unclear. We report a patient with global ischemia due to occlusions of bilateral carotid and right vertebral arteries. The occluded left carotid was recanalized successfully with angioplasty and stenting. The adaptively narrowed distal carotid did not restitute immediately but regained its morphology 1 week after the procedure. Carotid adaptive narrow distal occlusion or stenosis may not regain its original morphology immediately but several days after recanalization. This knowledge is instructive for treating occlusive carotid diseases. PMID- 26600797 TI - The Latest Information on Intracranial Atherosclerosis: Diagnosis and Treatment. AB - Intracranial atherosclerotic stenosis (ICAS) is the most common cause of ischemic stroke in the world. ICAS is especially common in the Asian population accounting for 30-50% of all ischemic strokes. The risk of recurrent stroke in patients with symptomatic ICAS is the highest among the stroke subtypes. Two major factors associated with recurrent stroke are high degree (>70%) of stenosis and progression of ICAS. Transcranial Doppler ultrasound, CT angiography, MR angiography, and conventional catheter angiography are used for the diagnosis of ICAS. Today, high-resolution MRI can provide important information to improve the understanding of pathophysiology and diagnosis of ICAS. For prevention of recurrent stroke in patients with ICAS, surgery and endovascular intervention failed to show benefit over best medical treatment. Best medical treatment includes intensive risk factor control and antiplatelet therapy. Various antiplatelet drugs or their combination can be used for prevention of recurrent stroke in patients with ICAS. Cilostazol with or without aspirin is effective in preventing progression of symptomatic ICAS. Cilostazol is also safer than aspirin in terms of bleeding complications. PMID- 26600798 TI - Epidemiology of Intracranial Haemorrhages Associated with Vitamin K Antagonist Oral Anticoagulants in Spain: TAC Registry. AB - BACKGROUND: Vitamin K antagonist oral anticoagulants (VKA-OACs) are effective for primary and secondary prevention of embolic events. The rate of haemorrhagic neurological complications in patients admitted to neurology departments in Spain is not yet known. AIMS: We aimed to determine the clinical and epidemiological characteristics of patients with intracranial haemorrhage secondary to VKA-OACs as well as the incidence of this severe complication. METHODS: We conducted a retrospective, descriptive, multi-centre study using information from the medical records of all patients admitted to neurology departments, diagnosed with spontaneous intracranial haemorrhage, and treated with VKA-OACs within a 1-year period. We collected demographic and care data from centres, patients' medical records [demographic data, medical history, haemorrhage origin, vascular risk factors, concomitant treatment, and National Institutes of Health Stroke Scale (NIHSS) scores], and patients' outcome at 3 months [independence (modified Rankin Scale score <3) and mortality rate]. RESULTS: Twenty-one hospitals serving a population of 8,155,628 inhabitants participated in the study. The total number of cases was 235, the mean age was 78.2 (SD 9.4) years, and the baseline NIHSS score was 11.6 (SD 9.5; median 9; interquartile range 14). The VKA-OACs used were acenocoumarol in 95.3% (224 patients) and warfarin in 4.7% (11 patients). The haemorrhage origin was deep in 29.8%, lobar in 25.5%, intraventricular in 11.5%, extensive in 17.4% (>100 ml), cerebellar in 12.3%, and in the brainstem in 3.4%. The international normalised ratio was within therapeutic ranges at admission (according to indication) in 29.4% (69 patients). The global incidence (cases per 100,000 inhabitants per year) is 2.88. The in-hospital mortality rate was 40%, and 24.3% of the patients were independent at 3 months, while the mortality at 3 months was 42.6%. CONCLUSION: VKA-OAC treatment is associated with a large percentage of all cases of spontaneous intracranial haemorrhage, an event leading to high dependence and mortality rates. PMID- 26600799 TI - Expanding Endovascular Therapy of Very Small Ruptured Aneurysms with the 1.5-mm Coil. AB - BACKGROUND: Very small ruptured aneurysms (<=3 mm) demonstrate a significant risk for procedural rupture with endovascular therapy. Since 2007, 1.5-mm-diameter coils have been available (Micrus, Microvention, and ev3), allowing neurointerventionalists the opportunity to offer patients with very small aneurysms endovascular treatment. In this study, we review the clinical and angiographic outcome of patients with very small ruptured aneurysms treated with the 1.5-mm coil. METHODS: This is a retrospective cohort study in which we examined consecutive ruptured very small aneurysms treated with coil embolization at a single institution. The longest linear aneurysm was recorded, even if the first coil was sized to a smaller transverse diameter. Very small aneurysms were defined as <=3 mm. Descriptive results are presented. RESULTS: From July 2007 to March 2015, 81 aneurysms were treated acutely with coils in 78 patients presenting with subarachnoid hemorrhage. There were 5 patients with 3-mm aneurysms, of which the transverse diameter was <=2 mm in 3 patients. In all 5 patients, a balloon was placed for hemostatic prophylaxis in case of rupture, and a single 1.5-mm coil was inserted for aneurysm treatment without complication. Complete aneurysm occlusion was achieved in 1 patient, residual neck in 2, and residual aneurysm in 2 patients. Aneurysm recanalization was present in 2 patients with an anterior communicating artery aneurysm; a recoiling attempt was unsuccessful in 1 of these 2 patients due to inadvertent displacement and distal coil embolization, but subsequent surgical clipping was successful. Another patient was retreated by surgical clipping for a residual wide-neck carotid terminus aneurysm. One patient died of ventriculitis 3 weeks after presentation; all 4 other patients had an excellent outcome with no rebleed at follow-up (mean 21 months, range 1-62). CONCLUSION: The advent of the 1.5-mm coil may be used in the endovascular treatment of patients with very small ruptured aneurysms, providing a temporary protection to the site of rupture in the acute phase. If necessary, bridging with elective clipping may provide definitive aneurysm treatment. PMID- 26600800 TI - Duplication of the Posterior Cerebral Artery and the 'True Fetal' Variant. AB - We present a rare case of bilateral posterior cerebral artery variant anatomy seen in a patient presenting with acute ischemic stroke. An embryological explanation of the variant configuration is discussed along with demonstrative radiologic images and a display of the vascular territory supplied. PMID- 26600802 TI - Can CT Virtual Cystoscopy Replace Conventional Cystoscopy in Early Detection of Bladder Cancer? AB - Aim. To correlate findings of conventional cystoscopy with CT virtual cystoscopy (CTVC) in detecting bladder tumors and to evaluate accuracy of virtual cystoscopy in early detection of bladder cancer. Material and Method. From June 2013 to June 2014, 50 patients (46 males, four females) with history and investigations suggestive of urothelial cancer, with mean age 62.76 +/- 10.45 years, underwent CTVC by a radiologist as per protocol and subsequently underwent conventional cystoscopy (CPE) the same day or the next day. One urologist and one radiologist, blinded to the findings of conventional cystoscopy, independently interpreted the images, and any discrepant readings were resolved with consensus. Result. CTVC detected 23 out of 25 patients with bladder tumor(s) correctly. Two patients were falsely detected as negative while two were falsely labeled as positive in CTVC. Virtual and conventional cystoscopy were comparable in detection of tumor growth in urinary bladder. The sensitivity, specificity, positive predictive value, and negative predictive value of virtual cystoscopy were 92% each. Conclusion. CTVC correlates closely with the findings of conventional cystoscopy. Bladder should be adequately distended and devoid of urine at the time of procedure. However, more studies are required to define the role of virtual cystoscopy in routine clinical practice. PMID- 26600801 TI - Imaging Diagnosis of Splanchnic Venous Thrombosis. AB - Splanchnic vein thrombosis (SVT) is a broad term that includes Budd-Chiari syndrome and occlusion of veins that constitute the portal venous system. Due to the common risk factors involved in the pathogenesis of these clinically distinct disorders, concurrent involvement of two different regions is quite common. In acute and subacute SVT, the symptoms may overlap with a variety of other abdominal emergencies while in chronic SVT, the extent of portal hypertension and its attendant complications determine the clinical course. As a result, clinical diagnosis is often difficult and is frequently reliant on imaging. Tremendous improvements in vascular imaging in recent years have ensured that this once rare entity is being increasingly detected. Treatment of acute SVT requires immediate anticoagulation. Transcatheter thrombolysis or transjugular intrahepatic portosystemic shunt is used in the event of clinical deterioration. In cases with peritonitis, immediate laparotomy and bowel resection may be required for irreversible bowel ischemia. In chronic SVT, the underlying cause should be identified and treated. The imaging manifestations of the clinical syndromes resulting from SVT are comprehensively discussed here along with a brief review of the relevant clinical features and therapeutic approach. PMID- 26600803 TI - Cardiovascular System Changes and Related Risk Factors in Acromegaly Patients: A Case-Control Study. AB - Background. Cardiovascular complications are known to be the main determinants of reduced life expectancy and decreased quality of life in acromegaly patients. Our study aimed to provide insight into the cardiovascular changes that occur in acromegaly patients and to investigate the correlative risk factors. Methods. A total of 108 patients definitively diagnosed with acromegaly and 108 controls matched for age and gender were recruited into study and control groups, respectively. Standard echocardiography was performed on all of the participants, and data were collected and analyzed. Results. All acromegaly patients presented with structural cardiac changes, including a larger heart cavity, thicker myocardial walls, and increased great vessel diameters compared with the control group. Additionally, the acromegaly patients presented with reduced diastolic function. Aging and increased body mass index (BMI) were correlated with myocardial hypertrophy and diastolic dysfunction; a longer disease duration was correlated with larger great vessel diameters. Conclusions. Ageing and increased BMI are independent risk factors for acromegalic cardiomyopathy, and a long disease duration results in the expansion of great vessels. Increased efforts should be made to diagnose acromegaly at an early stage and to advise acromegaly patients to maintain a healthy weight. PMID- 26600804 TI - An educational forum to engage infectious diseases and microbiology residents in resource stewardship modelled after the Choosing Wisely campaign. AB - BACKGROUND: Rising costs present a major threat to the sustainability of health care delivery. Resource stewardship is increasingly becoming an expected competency of physicians. The Choosing Wisely framework was used to introduce resource stewardship at a national educational retreat for infectious disease and microbiology residents. METHODS: During the 2014 Annual Canadian Infectious Disease and Microbiology Resident Retreat in Toronto, Ontario, infectious disease (n=50) and microbiology (n=17) residents representing 11 Canadian universities from six provinces, were invited to participate in a modified Delphi panel. Participants were asked, in advance of the retreat, to submit up to five practices that infectious disease and microbiology specialists should not routinely perform due to lack of proven benefit(s) and/or potential harm to patients. Submissions were discussed in small and large group forums using an iterative approach involving electronic polling until consensus was reached for five practices. A finalized list was created for both educational purposes and for residents to consider enacting; however, it was not intended to replace formal society-endorsed statements. A follow-up survey at two-months was conducted. RESULTS: Consensus was reached by the residents regarding five low value practices within the purview of infectious diseases and microbiology physicians. After the retreat, 20 participants (32%) completed the follow-up survey. The majority of respondents (75%) believed that the session was at least as relevant as other sessions they attended at the retreat, including 95% indicating that at least some of the material discussed was new to them. Since returning to their home institutions, nine (45%) respondents have incorporated what they learned into their daily practice; four (20%) reported that they have considered initiating a project related to the session; and one (5%) reported having initiated a project. CONCLUSIONS: The present educational forum demonstrated that trainees can become actively engaged in the identification and discussion of low-value practices. Embedding residence training programs with resource stewardship education will be necessary to improve the value of care offered by the future members of our profession. PMID- 26600805 TI - When it comes to stewardship, it's time to get with the programmers. PMID- 26600806 TI - Artesunate treatment of severe pediatric malaria: A review of parasite clearance kinetics and clinical implications. PMID- 26600807 TI - A nine-month-old girl with respiratory failure and rhomboencephalitis. PMID- 26600808 TI - A venomous visitor from the tropics. PMID- 26600809 TI - Intra-amniotic infection involving Candida albicans subsequent to emergency cerclage: A case series. PMID- 26600810 TI - A nine-week-old girl with fever and seizures. PMID- 26600811 TI - A rare case of ruptured infrarenal aortic aneurysm infected with Haemophilus influenzae type B. PMID- 26600812 TI - Osteomyelitis with a twist: Streptococcus pneumoniae causing sternoclavicular septic arthritis. PMID- 26600813 TI - Antimicrobial use over a four-year period using days of therapy measurement at a Canadian pediatric acute care hospital. AB - BACKGROUND: Antimicrobial resistance is a concern that is challenging the ability to treat common infections. Surveillance of antimicrobial use in pediatric acute care institutions is complicated because the common metric unit, the defined daily dose, is problematic for this population. OBJECTIVE: During a four-year period in which no specific antimicrobial stewardship initiatives were conducted, pediatric antimicrobial use was quantified using days of therapy (DOT) per 100 patient days (PD) (DOT/100 PD) at the Alberta Children's Hospital (Calgary, Alberta) for benchmarking purposes. METHODS: Drug use data for systemic antimicrobials administered on wards at the Alberta Children's Hospital were collected from electronic medication administration records. DOT were calculated and rates were determined using 100 PD as the denominator. Changes over the surveillance period and subgroup proportions were represented graphically and assessed using linear regression. RESULTS: Total antimicrobial use decreased from 93.6 DOT/100 PD to 75.7 DOT/100 PD (19.1%) over the 2010/2011 through to the 2013/2014 fiscal years. During this period, a 20.0% increase in PD and an essentially stable absolute count of DOT (2.9% decrease) were observed. Overall, antimicrobial use was highest in the pediatric intensive care and oncology units. DISCUSSION: The exact changes in prescribing patterns that led to the observed reduction in DOT/100 PD with associated increased PD are unclear, but may be a topic for future investigations. CONCLUSION: Antimicrobial use data from a Canadian acute care pediatric hospital reported in DOT/100 PD were compiled for a four-year time period. These data may be useful for benchmarking purposes. PMID- 26600814 TI - Blastomycosis in northwestern Ontario, 2004 to 2014. AB - Blastomycosis is an invasive fungal disease caused by Blastomyces dermatitidis and the recently discovered Blastomyces gilchristii. The medical charts of 64 patients with confirmed cases of blastomycosis in northwestern Ontario during a 10-year period (2004 to 2014) were retrospectively reviewed. The number of patients diagnosed with blastomycosis in Ontario was observed to have increased substantially compared with before 1990, when blastomycosis was removed from the list of reportable diseases. Aboriginals were observed to be disproportionately represented in the patient population. Of the patients whose smoking status was known, 71.4% had a history of smoking. 59.4% of patients had underlying comorbidities and a higher comorbidity rate was observed among Aboriginal patients. The case-fatality rate from direct complications of blastomycosis disease was calculated to be 20.3%; this case-fatality rate is the highest ever to be reported in Canada and more than double that of previously published Canadian studies. The clinical characteristics of 64 patients diagnosed with blastomycosis are summarized. PMID- 26600815 TI - Development and validation of a Pneumocystis jirovecii real-time polymerase chain reaction assay for diagnosis of Pneumocystis pneumonia. AB - BACKGROUND: Pneumocystis jirovecii (PJ), a pathogenic fungus, causes severe interstitial Pneumocystis pneumonia (PCP) among immunocompromised patients. A laboratory-developed real-time polyermase chain reaction (PCR) assay was validated for PJ detection to improve diagnosis of PCP. METHODS: Forty stored bronchoalveolar lavage (BAL) samples (20 known PJ positive [PJ+] and 20 known PJ negative [PJ-]) were initially tested using the molecular assay. Ninety-two sequentially collected BAL samples were then analyzed using an immunofluorescence assay (IFA) and secondarily tested using the PJ real-time PCR assay. Discrepant results were resolved by retesting BAL samples using another real-time PCR assay with a different target. PJ real-time PCR assay performance was compared with the existing gold standard (ie, IFA) and a modified gold standard, in which a true positive was defined as a sample that tested positive in two of three methods in a patient suspected to have PCP. RESULTS: Ninety of 132 (68%) BAL fluid samples were collected from immunocompromised patients. Thirteen of 92 (14%) BALs collected were PJ+ when tested using IFA. A total of 40 BAL samples were PJ+ in the present study including: all IFA positive samples (n=13); all referred PJ+ BAL samples (n=20); and seven additional BAL samples that were IFA negative, but positive using the modified gold standard. Compared with IFA, the PJ real-time PCR had sensitivity, specificity, and positive and negative predictive values of 100%, 91%, 65% and 100%, respectively. Compared with the modified gold standard, PJ real-time PCR had a sensitivity, specificity, and positive and negative predictive values of 100%. CONCLUSION: PJ real-time PCR improved detection of PJ in immunocompromised patients. PMID- 26600816 TI - Social network investigation of a syphilis outbreak in Ottawa, Ontario. AB - BACKGROUND: The incidence of syphilis in Ottawa, Ontario, has risen substantially since 2000 to six cases per 100,000 in 2003, again to nine cases per 100,000 in 2007, and recently rose to 11 cases per 100,000 in 2010. The number of cases reported in the first quarter of 2010 was more than double that in the first quarter of 2009. OBJECTIVE: In May 2010, the Ontario Ministry of Health and Long Term Care requested the assistance of the Field Epidemiology Program to describe the increase in infectious syphilis rates and to identify social network sources and prevention messages. METHODS: Syphilis surveillance data were routinely collected from January 1, 2009 to July 15, 2010, and social networks were constructed from an enhanced social network questionnaire. Univariate comparisons between the enhanced surveillance group and the remaining cases from 2009 on non normally distributed data were conducted using Kruskal-Wallis tests and chi(2) tests. RESULTS: The outbreak cases were comprised of 89% men. Seventeen of the 19 most recent cases consented to answer the questionnaire, which revealed infrequent use of condoms, multiple sex partners and sex with a same-sex partner. Information regarding social venues where sex partners were met was plotted together with sexual partnerships, linking 18 cases and 40 contacts, representing 37% of the outbreak population and connecting many of the single individuals and dyads. CONCLUSION: Uncovering the places sex partners met was an effective proxy measure of high-risk activities shared with infected individuals and demonstrates the potential for focusing on interventions at one named bar and one Internet site to reach a high proportion of the population at risk. PMID- 26600817 TI - Bacteremia due to Pasteurella dagmatis acquired from a dog bite, with a review of systemic infections and challenges in laboratory identification. AB - A case of bacteremia in a 74-year-old man, which was caused by Pasteurella dagmatis and complicated by thrombocytopenia, is presented. Microorganism identification was performed by the provincial reference laboratory using traditional biochemical profiling, completmented with both the sequencing of the 16S ribosomal RNA gene and matrix-assisted laser desorption/ionization time-of flight mass spectrometry; antibiotic-susceptibility testing was also performed. After treatment with the appropriate antibiotics, the patient fully recovered. Systemic infections attributed to this organism are rarely reported in the literature. Other reported cases of bacteremia due to P dagmatis are reviewed and compared with the present case. The challenges of relying on standard automatic identification are discussed, with alternative methodologies provided. PMID- 26600819 TI - Pharmacist 2.0. PMID- 26600818 TI - Delftia acidovorans: A rare pathogen in immunocompetent and immunocompromised patients. AB - Delftia acidovorans is an aerobic, nonfermenting Gram-negative bacillus. It is usually a nonpathogenic environmental organism and is rarely clinically significant. Although D acidovorans infection most commonly occurs in hospitalized or immunocompromised patients, there are also several reports documenting the infection in immunocompetent patients. The present article describes a B cell lymphoblastic leukemia patient with D acidovorans pneumonia who was successfully treated with antibiotic therapy. The present report indicates that unusual pathogens may be clinically significant in both immunocompromised and immunocompetent patients. D acidovorans is often resistant to aminoglycosides; therefore, rapid detection of this microorganism is important. PMID- 26600820 TI - Canadian "minor ailments" programs: Unanswered questions. PMID- 26600821 TI - Improving pharmaceutical care for athletes: A proposed assessment tool and useful resources. PMID- 26600822 TI - Strategies pharmacy students can use to ensure success in an experiential placement. PMID- 26600823 TI - Partnering to enhance mental health care capacity in communities: A qualitative study of the More Than Meds program. AB - BACKGROUND: Community pharmacists care for and support people with lived experience of mental illness in their communities. We developed a program called More Than Meds to facilitate enhancing capacity of community pharmacists' roles in mental health care. METHODS: We conducted a qualitative study and used a directed content analysis with application of the Theoretical Domains Framework as part of our underlying theory of behaviour change and our analytic framework. RESULTS: Ten interviews (n = 6 pharmacists, n = 4 community members) were conducted with participants from the More Than Meds program. Three key themes were identified from the experiences of More Than Meds participants: networking and bridging, stigma, and expectations and permissions. The most frequently coded domains in the data from the Theoretical Domains Framework were social/professional role, skills, beliefs about capabilities, knowledge and environmental context and resources. CONCLUSIONS: The More than Meds Program enabled community pharmacists to increase their capabilities, opportunities and motivation in providing mental health care and support. Involving community pharmacists together with people with lived experience of mental illness was identified as an innovative component of the program. PMID- 26600824 TI - A scoping review of research on the prescribing practice of Canadian pharmacists. AB - BACKGROUND: Pharmacists in Canada have been prescribing since 2007. This review aims to explore the volume, array and nature of research activity on Canadian pharmacist prescribing and to identify gaps in the existing literature. METHODS: We conducted a scoping review to examine the literature on prescribing by pharmacists in Canada according to methodological trends, research areas and key findings. We searched for peer-reviewed research articles and abstracts in the Ovid MEDLINE, Ovid EMBASE and International Pharmaceutical Abstracts databases without any date limitations. A standardized form was used to extract information. RESULTS: We identified 156 articles; of these, 26 articles and 12 abstracts met inclusion criteria. One-half of the research studies (20) used quantitative methods, including surveys, trials and experimental designs; 11 studies used qualitative methods and 7 used other methods. Research on pharmacist prescribing demonstrated an improvement in patient outcomes (13 studies), varied stakeholder perceptions (10 studies) and factors that influence this practice change (11 studies). Pharmacist prescribing was adopted when pharmacists practised patient-centred care. Stakeholders held contrasting perceptions of pharmacist prescribing. DISCUSSION: Canadian research has demonstrated the benefit of pharmacist prescribing on patient outcomes, which is not present in the international literature. Future research may consider a meta-analysis addressing the impact on patient health. Gaps in research include comparisons between provinces, effects on physicians' services, overall patient safety and access to health care systems and economic implications for society. CONCLUSION: A growing body of research on pharmacist prescribing has captured the early impact of prescribing on patient outcomes, perceptions of practice and practice change. Opportunities exist for pan-Canadian research that examines the system impact. PMID- 26600825 TI - Review of the top 5 cardiology studies of 2013-14. PMID- 26600826 TI - Report on pharmacy specialization in Canada. PMID- 26600827 TI - Psychological well-being in people with multiple sclerosis in an Iranian population. AB - BACKGROUND: To date, few results on well-being in individuals with neurological disease have been published, while several studies in other groups have indicated that well-being may not be the only absence of psychological distress, but also positive psychological function. The aim of the present study was to compare the psychological well-being (PWB) between the people with Multiple sclerosis (MS) and normal individuals and identify correlated demographic factors to PWB in people with MS disorder. MATERIALS AND METHODS: A case-control study was performed in July 2012 on 55 people with MS who were referred to MS clinic (located at the Kashani Hospital), Isfahan Neurosciences Research Centre and 83 normal individuals with matched mean of age, level of education, and gender. The participants filled up the 18-item Ryff's PWB and demographic profile. The data were analyzed by SPSS software based on the independent t-test, and ANOVA. RESULTS: There is significant different in all PWB dimensions between people with MS and normal groups. There were no significant differences in PWB in people with MS in relation to gender and marital status, but individuals with higher level of education scored higher in total PWB, positive relationship with others and purpose in life. CONCLUSION: People with MS are at risk of lower level of PWB. Interventional programs for improving PWB are strongly recommended. PMID- 26600829 TI - Prevalence of cleft lip and palate among four provinces in the West and North West of Iran. AB - BACKGROUND: One of the most common anomalies in newborn infants is cleft lip and/or cleft palate (CL/P). In spite of several studies about the prevalence of this, no investigation evaluated this prevalence in the West and North-West of Iran. With due attention to different ethnic groups in this area, the aim of this study is to investigate whether the distribution of CL/P live births varies regionally in this area of Iran. MATERIALS AND METHODS: A cross-sectional study was conducted using hospital registry records to identify all children born with CL/P. The hospitals with a maternity unit were selected in the capital cities of four provinces in the West and North-West of Iran, East Azarbaijan, Kurdestan, Gilan, and Markazi. The population under study included all infants born alive from 2008 to 2012. RESULTS: During the study period, 107,317 live births were registered in the hospitals with a maternity unit of four cities, and 52 infants (0.485/1000 live births) were born with CL/P. The prevalence in Rasht, Arak, Sanandaj, and Tabriz cities was 0.557, 0.352, 0.503, and 0.559/1000 live births, respectively (P < 0.05), and in cleft types (P < 0.05). Of the 52 infants who were born with CL/P, 24 (46.15%) were girls and 28 (53.85%) were boys (P > 0.05), whereas the prevalence of CL/P based on sex was statistically different among the four provinces (P < 0.05). CONCLUSION: This study shows regional variations in the birth prevalence of clefts and various cleft types. The different effects of gender on the birth prevalence of CL/P from city-to-city may be explained environmentally and/or by genetic factors affecting the development of oral clefts. PMID- 26600828 TI - Effect of Tocotrienols enriched canola oil on glycemic control and oxidative status in patients with type 2 diabetes mellitus: A randomized double-blind placebo-controlled clinical trial. AB - BACKGROUND: Tocotrienols have been shown to improve glycemic control and redox balance in an animal study, but their effects on patients with diabetes are unknown. The study aimed to investigate whether tocotrienols improves glycemic control, insulin sensitivity, and oxidative stress in individuals with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: This study was a double-blinded, placebo-controlled, randomized trial. A total of 50 patients, aged 35-60 years, with T2DM treated by noninsulin hypoglycemic drugs were randomly assigned to receive either 15 mL/day tocotrienols (200 mg) enriched canola oil (n = 25) or pure canola oil (n = 25) for 8 weeks. Fasting blood sugar (FBS), fasting insulin, total antioxidant capacity (TAC), malondialdehyde (MDA), and homeostatic model assessment for insulin resistance (HOMA-IR) were determined before and after the intervention. The data were compared between and within groups, before and after the intervention. RESULTS: Baseline characteristics of participants including age, sex, physical activity, disease duration, and type of drug consumption were not significantly different between the two groups. In tocotrienol enriched canola oil, FBS (mean percent change: -15.4% vs. 3.9%; P = 0.006) and MDA (median percent change: -35.6% vs. 16.3%; P = 0.003) were significantly reduced while TAC was significantly increased (median percent change: 21.4% vs. 2.3%; P = 0.001) compared to pure canola oil. At the end of the study, patients who treated with tocotrienols had lower FBS (P = 0.023) and MDA (P = 0.044) compared to the pure canola oil group. However, tocotrienols had no effect on insulin concentrations and HOMA-IR. CONCLUSION: Tocotrienols can improve FBS concentrations and modifies redox balance in T2DM patients with poor glycemic control and can be considered in combination with hypoglycemic drugs to better control of T2DM. PMID- 26600830 TI - Factor V Leiden, factor V Cambridge, factor II GA20210, and methylenetetrahydrofolate reductase in cerebral venous and sinus thrombosis: A case-control study. AB - BACKGROUND: Factor V G1691A (FV Leiden), FII GA20210, and methylenetetrahydrofolate reductase (MTHFR) C677T mutations are the most common genetic risk factors for thromboembolism in the Western countries. However, there is rare data in Iran about cerebral venous and sinus thrombosis (CVST) patients. The aim of this study was to evaluate the frequency of common genetic thrombophilic factors in CVST patients. MATERIALS AND METHODS: Forty consequently CVST patients from two University Hospital in Isfahan University of Medical Sciences aged more than 15 years from January 2009 to January 2011 were recruited. In parallel, 51 healthy subjects with the same age and race from similar population selected as controls. FV Leiden, FII GA20210, MTHFR C677T, and FV Cambridge gene mutations by polymerase chain reaction technique were evaluated in case and control groups. RESULTS: FV Leiden, FII GA20210, and FV Cambridge gene mutations had very low prevalence in both case (5%, 2%, 0%) and control (2.5%, 0%, 0%) and were not found any significant difference between groups. MTHFR C677T mutations was in 22 (55%) of patients in case group and 18 (35.5%) of control group (P = 0.09). CONCLUSION: This study showed that the prevalence of FV Leiden, FII GA20210, and FV Cambridge were low. Laboratory investigations of these mutations as a routine test for all patients with CVST may not be cost benefit. PMID- 26600831 TI - A model for evaluation of faculty members' activities based on meta-evaluation of a 5-year experience in medical school. AB - BACKGROUND: There is a global interest for deploying faculty members' activities evaluation systems, however implementing a fair and reliable system is a challenging issue. In this study, the authors devised a model for evaluation of faculty members' activities with regard to their viewpoints and meta-evaluation standards. MATERIALS AND METHODS: The reliability of the current faculty members' activities metrics system was investigated in Medical School of Tehran University of Medical Sciences in 2014. Then authors conducted semi-structured interviews regarding meta-evaluation standards and designed a questionnaire based on interviews' results which were delivered to faculty members. Finally, they extracted the components of the model regarding interviews' content analysis and questionnaire's factor analysis and finalized them in a focus group session with experts. RESULTS: Reliability of the current system was 0.99 (P < 0.05). The final model had six dimensions (mission alignment, accuracy, explicit, satisfaction, appropriateness, and constructiveness) derived from factor analysis of the questionnaire and nine factors (consensus, self-reporting, web-based system, evaluation period, minimum expectancies, analysis intervals, verifiers, flexibility, and decision making) obtained via qualitative content analysis of the interviews. CONCLUSION: In this study, the authors presented a model for faculty members' activities evaluation based on meta-evaluation of the existing system. The model covered conceptual and executive aspects. Faculty members' viewpoints were the core component of this model, so it would be acceptable in a medical school to use the model for evaluating their activities. PMID- 26600832 TI - Diagnostic value of cystatin C for diagnosis of early renal damages in type 2 diabetic mellitus patients: The first experience in Iran. AB - BACKGROUND: Diabetic nephropathy (DN) is one of the most important complications of diabetes mellitus. Now-a-days, cystatin C (CysC) is introduced as a new marker for diagnosis of renal damages; however, use of this marker in clinical laboratories is still controversial. The present study was aimed to evaluate the diagnostic value of serum CysC for early detection or monitoring treatment of kidney damages in the Kurdish people with type 2 diabetes mellitus. MATERIALS AND METHODS: Glomerular filtration rate (GFR) was estimated by Modification of Diet in Renal Disease formula. Serum CysC and urine microalbumin were also measured in 126 diabetic and healthy subjects. Blood glycated hemoglobin (Hb) also measured in all healthy and diabetic patients. Two independent samples t-test, Mann Whitney U-test, one-way ANOVA, and Kruskal-Wallis test, as well as Pearson/Spearman correlation coefficient statistical tests were used as appropriate. RESULTS: Serum CysC was higher (1312.41 ng/ml) in diabetic patients with GFR <60 ml/min than other subjects (993.25 ng/ml) (patients with normal kidney function and healthy subjects). A borderline significant correlation between CysC and estimating GFR (r s = -0.16, P = 0.05) but highly significant with microalbumin (r s = 0.22, P = 0.014) was observed. Serum CysC sensitivity, negative and positive predictive values were 100 and 4%. CONCLUSION: CysC cover variation of GFR and urine microalbumin, but it cannot be used as a surrogating marker of glycated Hb. According to our results, it seems that serum CysC is a useful marker for screening of DN; but it cannot be used for monitoring of treatment in diabetic patients. PMID- 26600833 TI - Psychological status in Iranian patients with ulcerative colitis and its relation to disease activity and quality of life. AB - BACKGROUND: Psychological profile of inflammatory bowel disease patients is not well studied in Iran. We investigated the psychological status of Iranian patients with ulcerative colitis (UC) and its relationship with disease activity and quality of life (QOL). MATERIALS AND METHODS: A cross-sectional study was conducted on adult UC patients. The Lichtiger Colitis Activity Index, Hospital Anxiety and Depression Scale, General Health Questionnaire-12, and WHOQOL-BREF, were completed by the patients. RESULTS: From 120 studied patients, 35 (29.2%), 48 (40.0%), and 46 (38.3%) had significant anxiety, depression, and psychological distress, respectively. Anxiety, depression, and psychological distress were strongly correlated with disease activity (r = 0.357 to 0.439, P < 0.01). Disease activity was negatively correlated with all QOL dimensions (r = -0.245 to -0.550, P < 0.01). Anxiety, depression, and psychological distress were also negatively correlated with all QOL domains (r = -0.356 to -0.789, P < 0.01). In the regression models, anxiety was independently associated with active disease (beta = 4.150, P = 0.049). Furthermore, disease activity was associated with the physical health (beta = -0.371, P < 0.001). For almost all of the QOL domains, depression and psychological distress were independent predictors (beta = -0.296 to -0.453, P < 0.001). CONCLUSION: Anxiety, depression, and psychological distress are highly frequent in UC patients of our society and are strongly associated with disease activity. Depression and psychological distress are important predictors of poor QOL in these patients. Further prospective studies, as well as clinical trials, are warranted in this regard. PMID- 26600834 TI - The effectiveness of using misoprostol with and without letrozole for successful medical abortion: A randomized placebo-controlled clinical trial. AB - BACKGROUND: In developing countries it is important to the exploration of available and safe regimens for medical abortion. The present study was designed to assess the effect of letrozole compared to placebo pretreatment followed by sublingual misoprostol for therapeutic abortion in eligible women with gestational age less than 17 weeks. MATERIALS AND METHODS: In this randomized control trail, 130 women eligible for legal abortions were randomly divided into two groups of case and controls. Cases received daily oral dose of 10 mg letrozole 10 mg letrozole for three days followed by sublingual misoprostol. Controls received daily oral dose of placebo followed by sublingual misoprostol. The dose of misoprostol was administrated according to ACOG guidelines based on patients' gestational age. The rate of complete abortion, induction-of-abortion time, and side-effects were assessed as main outcomes. RESULTS: Complete abortion was observed in 46 (76.7%) letrozole group and 26 (42.6%) controls (P < 0.0001). Also, in 14 subjects of letrozole group and 35 subjects in placebo group, the placenta was not delivered during follow-up and curettage was performed. The mean interval induction-to-abortion was 5.1 h in letrozole group and 8.9 h in control (P < 0.0001). The cumulative rates of the induction-of-abortion time were a significant difference between the two groups (P < 0.0001). The incidence and severity of side-effects was comparable for the two groups (P = 0.9). CONCLUSION: Letrozole could be a quite beneficial adjuvant to misoprostol for induction of complete abortion in those who are candidates for legal medical abortion. PMID- 26600835 TI - Does attitude hinder or help selecting evaluation questions? AB - BACKGROUND: Positive attitude leads to a more successfully implementation of a change. We investigated the effect of attitudes of stakeholders toward a program on their prioritization of the program components for selecting the key question of a theory-driven evaluation with concept mapping method. MATERIALS AND METHODS: During a brainstorming session, stated statements defined the program components. Then they were sorted and rated regarding the importance and feasibility of them. In addition, the attitudes of participants were assessed by a 30 items questionnaire extracted from a pool named as "50 reasons not to change." We determined and compared the consensus points of participants both with and without of considering their attitudes toward the program. RESULTS: The participants were divided into two groups of high (45% - above the mean) and low (55% - below the mean) attitude. Brainstorming discussions generated a pool of almost 120 statements which were subsequently refined to 44 statements. Matching the rating scores between two attitude groups yielded a consensus at a higher priority than the other method. CONCLUSION: In the concept mapping procedure, it is crucial to reach the consensus with respect to the participants' attitude, rather than the similarity of mean scores of feasibility and importance. PMID- 26600836 TI - Efficacy of duloxetine add on in treatment of inflammatory bowel disease patients: A double-blind controlled study. AB - BACKGROUND: Treating inflammatory bowel disease (IBD) with antidepressants might be of utility to improve patient's condition. The aim of this study was to assess the efficacy of Duloxetine on depression, anxiety, severity of symptoms, and quality of life (QOL) in IBD patients. MATERIALS AND METHODS: In a randomized, double-blind, controlled clinical trial on 2013-2014, in Alzahra Hospital (Isfahan, Iran), 44 IBD patients were chosen to receive either duloxetine (60 mg/day) or placebo. They were treated in a 12 weeks program, and all of the participants also received mesalazine, 2-4 g daily. We assessed anxiety and depression with Hospital Anxiety and Depression Scale, the severity of symptoms with Lichtiger Colitis Activity Index and QOL with World Health Organization Quality of Life Instruments, before and just after the treatment. The data were analyzed using Paired sample t-test and ANCOVA. RESULTS: In 35 subjects who completed the study, the mean (standard error [SE]) scores of depression and anxiety were reduced in duloxetine more than placebo group, significantly (P = 0.041 and P = 0.049, respectively). The mean (SE) scores of severity of symptom were also reduced in duloxetine more than the placebo group, significantly (P = 0.02). The mean (SE) scores of physical, psychological, and social dimensions of QOL were increased after treatment with duloxetine more than placebo group, significantly (P = 0.001, P = 0.038, and P = 0.015, respectively). The environmental QOL was not increased significantly (P = 0.260). CONCLUSION: Duloxetine is probably effective and safe for reducing depression, anxiety and severity of physical symptoms. It also could increase physical, psychological, and social QOL in patients. PMID- 26600837 TI - Red and processed meat consumption and risk of glioma in adults: A systematic review and meta-analysis of observational studies. AB - BACKGROUND: These findings from several observational studies, investigated the association between red meat consumption and gliomas, were inconsistent. We conducted a systematic review and meta-analysis of observational studies to summarize available date on the relation between meat intake and risk of glioma. MATERIALS AND METHODS: A systematic literature search of relevant reports published until May 2014 of the PubMed/Medline, ISI Web of Knowledge, Excerpta Medica database, Ovid database, Google Scholar, and Scopus databases was conducted. From 723 articles yielded in the preliminary literature search, data from eighteen publications (14 case-control, three cohort, and one nested case control study) on unprocessed red meat, processed meat, and/or total red meat consumption in relation to glioma in adults were included in the analysis. Quality assessment of studies was performed. Random effects model was used to conduct the meta-analysis. RESULTS: We found a positive significant association between unprocessed red meat intake and risk of glioma (relative risk [RR] = 1.30; 95% confidence interval [CI]: 1.08-1.58) after excluding three studies with uncertain type of brain cancer. This analysis included only one cohort study which revealed no relation between unprocessed red meat intake and glioma (RR = 1.75; 95% CI: 0.35-8.77). Consumption of processed meats was not related to increased risk of glioma in population-based case-control studies (RR = 1.26; 95% CI: 1.05-1.51) and reduced risk in hospital-based case-controls (RR = 0.79; 95% CI: 0.65-0.97). No significant association was seen between processed red meat intake and risk of glioma in cohort studies (RR: 1.08; 95% CI: 0.84-1.37). Total red meat consumption was not associated with risk of adult glioma in case-control or cohort studies. CONCLUSION: In this meta-analysis of 18 observational studies, we found a modest positive association between unprocessed red meat intake and risk of gliomas based almost entirely on case-control studies. Processed red meat was overall not associated with risk of gliomas in case-control or cohort studies. PMID- 26600838 TI - A systematic review on the effects of environmental exposure to some organohalogens and phthalates on early puberty. AB - BACKGROUND: Early puberty is a common worldwide problem. Different parameters as genetics, metabolic diseases, obesity, as well as environmental factors may affect the age of puberty. This systematic review aims to survey the related literature on the effects of environmental pollutants and especially organohalogens and phthalates on early puberty. MATERIALS AND METHODS: A systematic review of papers published in the English language was completed in January 2014. Studies on the associations of organohalogens and phthalates with the puberty time were included. A literature search was conducted in EMBASE, PubMed, Scopus, ISI Web of Science, and Cochrane Library from 1995 to January 2014; moreover manual search through references of relevant manuscripts was considered. The literature search identified 212 papers, of which 13 papers fulfilled the inclusion criteria of the current study. Two reviewers independently identified relevant papers for potential inclusion and assessed the methodological quality. RESULTS: This review included 6572 participants in nine countries from three continents (Europe, North America, and Asia). Different studies determined the effects of pollutants on maturation signs and pubertal stages and confirmed the association of organohalogens and phthalates with early puberty. CONCLUSION: Based on the studied literature, environmental pollutants surround and accumulate in human societies and their adverse health effects are well documented. It can be concluded that organohalogens and phthalates are disturbing the normal process of puberty timing; especially their influence on early maturation in girls should be underscored. PMID- 26600839 TI - Association between angiotensinogen T174M polymorphism and ischemic stroke: A meta-analysis. AB - BACKGROUND: Numerous studies have evaluated the association between the angiotensinogen (AGT) T174M polymorphism and ischemic stroke(IS) risk. However, the specific association is still controversial. MATERIALS AND METHODS: In order to explore this association more deeply, we performed a meta-analysis. All of the relevant studies were identified from PubMed, Embase, and Chinese National Knowledge Infrastructure database up to October 2014. Statistical analyses were conducted with STATA 12.0 software. Odds ratio (OR) with 95% confidence interval (CI) values were applied to evaluate the strength of the association. RESULTS: Six studies with 1290 cases and 1125 controls were included. No significant variation in IS risk was detected in any of the genetic models in the overall (MM vs. TT: OR = 1.64, 95% CI = 0.51-5.28; MT vs. TT: OR = 0.93, 95% CI = 0.66-1.31; dominant model: OR = 1.08, 95% CI = 0.69-1.72; recessive model: OR = 0.61,95% CI = 0.20-1.91). Taking into account the effect of ethnicity, further stratified analyses were performed. The results showed that AGT gene T174M polymorphism might be associated with IS risk in Asians (MM vs. TT: OR = 3.28, 95% CI = 1.79 6.02; recessive model: OR = 0.31, 95% CI = 0.17-0.57). CONCLUSION: In conclusion, the AGT T174M polymorphism may be a susceptible predictor of the risk of IS in Asians. Further, large and well-designed studies are needed to confirm this conclusion. PMID- 26600840 TI - Simultaneous pancreas-kidney transplantation for diabetic end-stage renal disease under a hypertension status. PMID- 26600841 TI - Sclerotic changes on plain X-ray led to early diagnosis and successful treatment of primary lymphoma of iliac bone. PMID- 26600842 TI - Hospital beds wireless sensor network and reducing decubitus ulcer. PMID- 26600843 TI - Analysis of PTEN in two BRCA1 and BRCA2 wild-type familial breast cancer patients. PMID- 26600844 TI - Stereospecific quantitation of 6-prenylnaringenin in commercially available H. lupulus-containing natural health products and dietary supplements. AB - 6-Prenylnaringenin (6PN) is a chiral prenylflavonoid found most prevalently in hops (Humulus lupulus) and present in hops and hop products. It is an isomer of the potent phytoestrogen, 8-prenylnaringenin. An enantiospecific method for quantitation 6PN by LC-ESI-MS has been developed. Baseline enantiomeric resolution of 6PN was attained on a Chiralpak((r)) AD-RH column with an isocratic mobile phase consisting of acetonitrile and 10 mM ammonium formate (pH 8.5) (39:61, v/v) and a flow rate of 1.25 mL/min. Quantitative MS data were obtained by selected ion monitoring of the [M-H](-)-ion of both enantiomers of 6PN (m/z 339.10) and the internal standard, 4-acetamidobenzoic acid (m/z 178.05). The method was found to be accurate and precise for enantiospecific quantification of 6PN. The method was successfully applied to the content analysis of 39 commercially available natural health products and dietary supplements reported to contain H. lupulus plant material, extracts and label claims of 6PN. 6PN was present in 25 of 34 products containing plant material or extracts of H. lupulus. Of the five products with claimed amounts of 6PN, all were found to possess <50% of label claims. Results of the content analysis indicated a lack of uniformity in botanical nutraceuticals claiming 6PN content. PMID- 26600845 TI - Antihypertensive and antioxidant effects of a hydroalcoholic extract obtained from aerial parts of Otostegia persica (Burm.) Boiss. AB - Otostegia persica (Burm.) Boiss. is used for the treatment of various diseases in traditional medicine. The aim of this study was to assess the effects of hydroalcoholic extract of the aerial parts of O. persica in dexamethasone (Dex) induced hypertension in male Wistar rats. For induction of hypertension, Dex at 30 MUg/kg/day was administered subcutaneously for 14 days. In a prevention study, animals received O. persica extract orally at various doses of 100, 200 and 400 mg/kg 4 days before Dex administration and during the test period lasted for 18 days. In a reversal study, rats received O. persica extract from day 8 to 14. Systolic blood pressure (SBP) was measured using tail-cuff method. The weight of thymus gland was measured as a marker of glucocorticoid activity. The hydrogen peroxide (H2O2) concentration and ferric reducing antioxidant power (FRAP) were determined in plasma samples. Dex injection significantly increased SBP and plasma H2O2 levels while decreased the body and thymus weights and FRAP values. Oral administration of O. persica extract prevented and dose-dependently reversed a rise in SBP. Pre-treatment with O. persica extract also reduced the plasma H2O2 concentration, increased the plasma FRAP levels and prevented the body weight loss upon Dex administration. These results suggest antihypertensive and antioxidant effects of O. persica extract in Dex-induced hypertension. However, further investigations are needed to elucidate the detailed mechanism(s) of antihypertensive effect of this traditional herbal medicine. PMID- 26600846 TI - uPAR peptide antagonist alters regulation of MAP kinases and Bcl-2 family members in favor of apoptosis in MDA-MB-231 cell line. AB - Urokinase plasminogen activator receptor (uPAR) and its ligands play a major role in many tumors by mediating extracellular matrix degradation and signaling cascades leading to tumor growth, invasion and metastasis. Recently we introduced uPAR decapeptide antagonist with cytotoxic effect on MDA-MB-231 cell line. In this study we assessed the alteration in uPAR downstream signaling following treatment with the peptide antagonist. In this regard, extracellular-signal regulated kinase (ERK) and p38 from mitogen-activated protein kinase family and Bcl-2, Bim and Bax from Bcl-2 protein family were investigated. Our data revealed that the peptide caused p38 activation and low ERK activation. On the other hand, the peptide induced down-regulation of Bcl-2 and up-regulation of Bim without Bax modulation. Changes in target protein expression/activation explain the apoptotic property of the peptide and highlight its potential to be used as a therapeutic agent in cancerous cells expressing high levels of uPAR. PMID- 26600847 TI - Evaluation of the effect of ethanolic extract of fruit pulp of Cassia fistula Linn. on forced swimming induced chronic fatigue syndrome in mice. AB - The fruit of Cassia fistula Linn. is a legume, has antioxidant and lots of other medicinal properties. As oxidants are involved in the pathogenesis of chronic fatigue syndrome, the present study was done to evaluate the effect of ethanolic extract of fruit pulp of C. fistula Linn. (EECF) on forced swimming induced chronic fatigue syndrome (CFS). Albino mice of 25-40 grams were grouped into five groups (n=5). Group A served as naive control and group B served as stress control. Group C received EECF 200 mg/kg and group D received EECF 400 mg/kg respectively. Group E received imipramine 20 mg/kg (standard). All animals were treated with their respective agent orally daily for 7 days. Except for group A, animals in other groups were subjected to force swimming 6 min daily for 7 days to induce a state of chronic fatigue. Duration of immobility was assessed on day 1(st), 3(rd), 5(th) and 7(th). Anxiety level (by elevated plus maze and mirrored chamber) and loco-motor activity (by open field test) were assessed 24 h after last force swimming followed by biochemical estimations of oxidative biomarkers in brain homogenate at the end of study. Treatment with EECF resulted in significant reduction in the duration of immobility, reduced anxiety and increased loco-motor activity. Malondialdehyde level was also reduced and catalase level was increased in the extract treated group and standard group compared to stress control group. The study indicates that EECF has protective effect against experimentally induced CFS. PMID- 26600848 TI - Synthesis of novel 1,8-acridinediones derivatives: Investigation of MDR reversibility on breast cancer cell lines T47D and tamoxifen-resistant T47D. AB - Multi drug resistance (MDR) is a serious obstacle in the management of breast cancer. Therefore, overcoming MDR using novel anticancer agents is a top priority for medicinal chemists. It was found that dihydropyridines lacking calcium antagonistic activity (e.g acridinediones) possess MDR modifier potency. In this study, the capability of four novel acridine-1,8-diones derivatives 3a-d were evaluated as MDR reversing agents. In addition, the relationship between structural properties and biological effects of synthesized compounds was discussed. In vitro cytotoxicity of acridine-1,8-diones 3a-d derivatives in combination with doxorubicin (DOX) on T47D and tomoxifen-resistant T47D (TAMR-6) breast cancer cell lines were investigated using 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) test. Drug resistant index (DRI), which is equal to the ratio of IC50 in drug-resistant cells over IC50 in drug-sensitive cells, was calculated for each substance. Flowcytometry experiments were also implemented to distinguish cells undergoing apoptosis from those undergoing necrosis. The results from MTT and flowcytometry experiments indicated that 1 nM 3c derivative along with DOX significantly (P<0.05) increased the DOX cytotoxicity in T47D and TAMR-6 breast cancer cell lines. Synthesized compounds 3a and 3b also at concentrations of 1 nM with DOX significantly increased the cytotoxicity of DOX on T47D and TAMR-6 breast cancer cell lines. Meanwhile, 3d derivative with DOX did not exhibit good synergistic effect on cytotoxic activity of DOX, and slightly increased DOX cytotoxicity in both cell lines. Our results proposed that 3c may be an attractive lead compound for further development as a chemotherapeutic agent for MDR breast cancer therapy in combination with routine chemotherapeutic agents such as DOX. PMID- 26600849 TI - Saffron ethanolic extract attenuates oxidative stress, spatial learning, and memory impairments induced by local injection of ethidium bromide. AB - Cognitive deficits have been observed in patients with multiple sclerosis (MS) because of hippocampal insults. Oxidative stress plays a key role in the pathophysiology of MS. The aim of this study was to evaluate the effects of Crocus sativus L., commonly known as saffron, on learning and memory loss and the induction of oxidative stress in the hippocampus of toxic models of MS. One week after MS induction by intrahippocampal injection of ethidium bromide (EB), animals were treated with two doses of saffron extract (5 and 10 MUg/rat) for a week. Learning and spatial memory status was assessed using Morris Water Maze. After termination of behavioral testing days, animals were decapitated and the bilateral hippocampi dissected to measure some of the oxidative stress markers including the level of hippocampi thiobarbituric acid reactive substances and the activity of antioxidant enzymes such as glutathione peroxidase and superoxide dismutase. Treatment with saffron extract ameliorated spatial learning and memory impairment (P<0.05). Total antioxidant reactivity capacity, lipid peroxidation products and antioxidant enzymes activity in the hippocampus homogenates of EB treated group were significantly higher than those of all other groups (P<0.01). Indeed, treatment with a saffron extract for 7 consecutive days significantly restored the antioxidant status to the normal levels (P<0.01). These observations reveal that saffron extract can ameliorate the impairment of learning and memory as well as the disturbances in oxidative stress parameters in the hippocampus of experimental models of MS. PMID- 26600850 TI - Cytotoxicity and antiangiogenic effects of Rhus coriaria, Pistacia vera and Pistacia khinjuk oleoresin methanol extracts. AB - Angiogenesis, formation of new blood vessels, play an important role in some diseases such as cancer and its metastasis. Using angiogenesis inhibitors, therefore, is one of the ways for cancer treatment and prevention of metastasis. Medicinal plants have been shown to play a major role in the treatment of a variety of cancers. In this direction, cytotoxic and angiogenic effects of oleo gum resin extracts of Rhus coriaria, Pistacia vera and Pistacia khinjuk from Anacardiaceae family were studied. For IC50 values, cytotoxic effects of the plant extracts were evaluated at different concentrations (1, 10, 20, 40, 80,100 MUg/ml) against human umbilical vein endothelial normal cell (HUVEC) and Y79 cell lines using 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. In vitro tube formation on matrigel base was used to evaluate angiogenic effects in the presence of increasing concentrations (50, 100, 250 MUg/ml) of the extracts. Vascular endothelium growth factor was used as angiogenesis stimulator. Gas chromatography results showed that alpha-pinene and beta-pinene were the major essential oils constituents of all plant extracts. According to the MTT assay results, the R. coriaria resin extract was more cytotoxic than those of P. vera and P. khinjuk extracts (IC50, 9.1 +/- 1.6 vs 9.8 +/- 2.1 and 12.0 +/- 1.9, respectively; P<0.05). Cytotoxic effects of all extracts against Y79 cell line was significantly higher than those of HUVEC used as a normal cell line (P<0.05). Tube formation assay also showed that extract of R. coriaria resin inhibited angiogenesis more significantly than other tested extracts (P<0.05). It could be concluded that R. coriaria resin extract possess cytotoxic effect and antiangiogenesis against cancer cells and as an anticancer natural product has a good potential for future studies. PMID- 26600851 TI - Active targeted nanoparticles: Preparation, physicochemical characterization and in vitro cytotoxicity effect. AB - In this study, the folate decorated biodegradable poly (lactide-co-glycolide) (PLGA) nanoparticles were developed for tumor targeting of anticancer agents. Due to the overexpression of the folate receptor on tumor surface, the folate has been efficiently employed as a targeting moiety for various anticancer agents to avoid their non-specific attacks on normal tissues and also to increase their cellular uptake within target cells. Folate conjugate PLGA was synthesized successfully and its chemical structure was evaluated by FTIR, DSC and (1)HNMR spectroscopy. PLGA-folate nanoparticles (PLGA-Fol NPs) were prepared by nanoprecipitation method, adopting PLGA as a drug carrier, folic acid as a targeting ligand and 9-nitrocampthotecin as a model anticancer drug. The average size and encapsulation efficiency of the prepared PLGA-Fol NPs were found to be around 115 +/- 12 nm and 57%, respectively. In vitro release profile indicated that nearly 85% of the drug was released in 50 h. The in vitro intracellular uptakes of PLGA-Fol NPs showed greater cytotoxicity on cancer cell lines compared to non-folate mediated carriers. PMID- 26600852 TI - Assessment of hydroalcoholic extract of seeds and leaves of Moringa peregrina on ileum spasm. AB - Seeds of Moringa peregrina (Forssk.) Fiori. (Moringaceae) is widely used in south east of Iran for gastrointestinal disorders. However, so far there is no pharmacological evidence for antispasmodic activity of this plant extract. Therefore, the aim of this research was to investigate antispasmodic activity of M. peregrina on rat isolated ileum contraction. Hydroalcoholic extract was obtained by percolation method from seeds and leaves of M. peregrina collected from Baluchestan province of Iran. A portion of isolated rat ileum was suspended under 1 g tension in Tyrode's solution at 37 degrees C and gassed with O2. Effects of seeds and leaves extracts of M. peregrina were studied on ileum contractions induced by KCl (80 mM), acetylcholine (ACh, 250 MUM) and electrical field stimulation (EFS). The seed extract of M. peregrina concentration dependently inhibited the response to KCl (IC50=87 +/- 18 MUg/ml), ACh (IC50=118 +/- 18 MUg/ml) and EFS (IC50=230 +/- 51 MUg/ml). The extract of M. peregrina leaves also had inhibitory effect of ileum contraction induced by KCl (IC50=439 +/- 108 MUg/ml), ACh (IC50=365 +/- 61 MUg/ml) or EFS (IC50=314 +/- 92 MUg/ml). From these experiments it was concluded that M. peregrina extract mainly had an inhibitory effect on ileum contractions but the seed extract was more potent than the leave extract in inhibiting KCl and ACh contractile responses. PMID- 26600853 TI - Effect of mutations in putative hormone binding sites on V2 vasopressin receptor function. AB - The vasopressin V2 receptor belongs to the large family of the G-protein coupled receptors and is responsible for the antidiuretic effect of the neurohypophyseal hormone arginine vasopressin (AVP). Based on bioinformatic studies it seems that Ala300 and Asp297 of the V2 vasopressin receptor (V2R) are involved in receptor binding. Ala300Glu mutation resulted in lower energy while Asp297Tyr mutation resulted in higher energy in AVP-V2R docked complex rather than the wild type. Therefore we hypothesized that the Ala300Glu mutation results in stronger and Asp297Tyr mutation leads to weaker ligand-receptor binding. Site directed mutagenesis of Asp297Tyr and Ala300Glu was performed using nested polymerase chain reaction. After restriction enzyme digestion, the inserts were ligated into the pcDNA3 vector and Escherichia coli XL1-Blue competent cells were transformed using commercial kit and electroporation methods. The obtained colonies were analyzed for the presence and orientation of the inserts using proper restriction enzymes. After transient transfection of COS-7 cells using ESCORTTM IV transfection reagent, the adenylyl cyclase activity assay was performed for functional studies. The cell surface expression of V2R was analyzed by indirect ELISA method. Based on the obtained results, the Ala300Glu mutation of V2R led to reduced levels of cAMP production without a marked effect on the receptor expression and the receptor binding. Effect of Asp297Tyr mutation on cell surface expression of V2R was the same as the wild type receptor. Pretreatment with 1 nM vasopressin showed an increased level of Asp297Tyr mutant receptor internalization as compared to the wild type receptor, while the effect of 100 nM vasopressin was similar in the mutant and wild type receptors. These data suggest that alterations in Asp297 but not Ala300 would affect the hormone receptor binding. PMID- 26600854 TI - Expression of a biotin acceptor peptide-containing protein with potential incorporation on the lentiviral envelope as a viral surface engineering platform. AB - Lentiviral vectors are among the promising viral based-vectors in gene therapy applications, but the efficiency of their targeting needs to be improved. (Strept)avidin-biotin adaptor system is a novel approach to modify the lentiviral envelope for better targeting properties. Herein, we describe utilization of this adaptor system by designing a candidate envelope protein-bearing biotin acceptor peptide (BAP) and evaluation of its expression in 293T cells. To this end, a DNA sequence containing flexible linkers, a 15-aminoacids BAP and specific membrane regions of a viral protein was designed and synthesized in tandem. The synthesized gene was amplified with polymerase chain reaction to include BglII and SalI restriction sites and subcloned into the same sites of pDisplay vector in frame with HA-tag and myc epitope to construct the pDis-GS-BAP. 293T cells were transfected with pDis-GS-BAP and expression of resulting protein (dis-GS BAP) was evaluated by Western blotting using anti-HA tag antibody. Efficiency of transfection procedure was evaluated by pEGFP-N1 vector and tracking for green fluorescent protein expression via fluorescence microscopy. Restriction analysis and DNA sequencing confirmed the precision of cloning steps. Fluorescence microscopy indicated above 70% transfection efficiency and Western blot analysis of pDis-GS-BAP-transfected 293T cells showed a protein band of approximately 17 kDa corresponding to the predicted size of dis-GS-BAP protein. These promising results indicate the possibility of cell surface expression and further biotinylation of dis-GS-BAP protein in ongoing studies. PMID- 26600855 TI - Effects of rosuvastatin and/or beta-carotene on non-alcoholic fatty liver in rats. AB - The prevalence of non-alcoholic fatty liver disease (NAFLD) has markedly increased, especially in patients exhibit one or more features of the metabolic syndrome. This study investigates the effect of rosuvastatin (RSV) and/or beta carotene (betaC) in NAFLD-induced rats. Rats were classified into nine groups; normal (I), NAFLD-induced with high-fat diet (HFD; II), NAFLD switched to regular diet (RD; III), NAFLD-HFD or NAFLD-RD treated with RSV (IV, V), betaC (VI, VII) or both RSV+betaC (VIII, IX), respectively. After four weeks, rats were sacrificed to obtain serum samples and liver tissues. Liver histology, lipid profile, liver oxidative stress markers, and adipocytokines were measured. Liver sections of rats with NAFLD-HFD revealed steatosis, lose of hepatic architecture, inflammation and hepatocyte vacuolation with high percentage of cell fibrosis. Serum levels of ALT, AST, ALP, gamma glutamyl transferase (GGT) and lipid profile (triglycerides, cholesterol, LDL and VLDL) were significantly increased (P<0.05) compared with normal. Also, hepatic malondialdehyde level and serum leptin, tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta1 (TGF beta1) were increased. Meanwhile, superoxide dismutase (SOD) activity, GSH content in liver, serum HDL and adiponectin were decreased (P<0.05) vs normal. These changes were observed to a lesser extent in NAFLD-RD group. Administration of RSV or/and betaC almost improved all previously mentioned parameters. Moreover, hepatic steatosis was decreased and inflammation was markedly ameliorated with reduction of TNF-alpha and TGF-beta. These results were more pronounced in the groups VIII and IX vs each drug alone. In conclusion RSV and betaC could be beneficial for the treatment and prevention of NAFLD. Combined RSV with betaC is more effective than RSV alone. PMID- 26600856 TI - Study of V2 vasopressin receptor hormone binding site using in silico methods. AB - The antidiuretic effect of arginine vasopressin (AVP) is mediated by the vasopressin V2 receptor. The docking study of AVP as a ligand to V2 receptor helps in identifying important amino acid residues that might be involved in AVP binding for predicting the lowest free energy state of the protein complex. Whereas previous researchers were not able to detect the exact site of the ligand receptor binding, we designed the current study to identify the vasopressin V2 receptor hormone binding site using bioinformatic methods. The 3D structure of nonapeptide hormone vasopressin was extracted from Protein Data Bank. Since no suitable template resembling V2 receptor was found, an ab initio approach was chosen to model the protein receptor. Using protein docking methods such as Hex protein-protein docking, the model of V2 receptor was docked to the peptide ligand AVP to identify possible binding sites. The residues that involved in binding site are W293, W296, D297, A300, and P301. The lowest free energy state of the protein complex was predicted after mutation in the above residues. The amount of gained energies permits us to compare the mutant forms with native forms and help to asses critical changes such as positive and negative mutations followed by ranking the best mutations. Based on the mutation/docking predictions, we found some mutants such as W293D and A300E possess positively inducing effect in ligand binding and some of them such as A300R present negatively inducing effect in ligand binding. PMID- 26600857 TI - Effect of venlafaxine on experimental colitis in normal and reserpinised depressed rats. AB - Psychological disorders such as depression have more prevalence in inflammatory bowel disease patients and can exacerbate the clinical course of the disease, so anti-depressant therapy may have a potential to positively impact the disease course. On the other hand several antidepressant drugs have shown anti inflammatory and immunomodulatory properties. Thus, this study aimed to explore the beneficial effects of venlafaxine on experimental colitis in normal and reserpinised depressed rats. Acetic acid colitis was induced in both reserpinised and non-reserpinised rats. Reserpinised groups received reserpine at dose of 6 mg/kg i.p.1 h prior to colitis induction and then treated with venlafaxine at doses of 10, 20, 40 mg/kg given i.p. 2 h after induction of colitis and daily for 4 consecutive days. Non-reserpinised groups treated with 10, 20, 40 mg/kg venlafaxine i.p. 2 h after the induction of colitis and daily for 4 successive days. Dexamethasone (1 mg/kg, i.p.) was used as reference drug. Colonic inflammation was evaluated using macroscopic, histological and myeloperoxidase activity measurements. Results showed that reserpine at dose of 6 mg/kg exacerbated the colitis damage. Compared to acetic acid control, venlafaxine at dose of 40 mg/kg as well as dexamethasone significantly improved colitis parameters in both reserpinised and non-reserpinised animals. Venlafaxine reduced inflammatory injury in this animal model of induced ulcerative colitis. These effects are probably mediated first through depressive behavioral changes that could be mediated through the brain-gut axis and second for the anti-inflammatory effect of the drug. PMID- 26600858 TI - Quantitative structure-activity relationship study of P2X7 receptor inhibitors using combination of principal component analysis and artificial intelligence methods. AB - P2X7 antagonist activity for a set of 49 molecules of the P2X7 receptor antagonists, derivatives of purine, was modeled with the aid of chemometric and artificial intelligence techniques. The activity of these compounds was estimated by means of combination of principal component analysis (PCA), as a well-known data reduction method, genetic algorithm (GA), as a variable selection technique, and artificial neural network (ANN), as a non-linear modeling method. First, a linear regression, combined with PCA, (principal component regression) was operated to model the structure-activity relationships, and afterwards a combination of PCA and ANN algorithm was employed to accurately predict the biological activity of the P2X7 antagonist. PCA preserves as much of the information as possible contained in the original data set. Seven most important PC's to the studied activity were selected as the inputs of ANN box by an efficient variable selection method, GA. The best computational neural network model was a fully-connected, feed-forward model with 7-7-1 architecture. The developed ANN model was fully evaluated by different validation techniques, including internal and external validation, and chemical applicability domain. All validations showed that the constructed quantitative structure-activity relationship model suggested is robust and satisfactory. PMID- 26600859 TI - The effect of hydroalcoholic extract of Ferula foetida stems on blood pressure and oxidative stress in dexamethasone-induced hypertensive rats. AB - Ferula foetida (Bunge) Regel. is one of the most widespread and important Ferula species with nutritional and medicinal applications. Some phytochemicals with helpful cardiovascular effects have been isolated from Ferula species. The present study was designed to evaluate the effects of hydroalcoholic extract of the stems of F. foetida in dexamethasone (Dex)-induced hypertension in rats. Hypertension was induced by subcutaneous injection of Dex (30 ug/kg) for 14 days. In a prevention study, rats received oral F. foetida extract (200, 400 and 800 mg/kg) for 4 days prior to Dex administration and during the test period (Days 1 18). In a treatment study, F. foetida extract was administered from day 8 to 14. Systolic blood pressure (SBP) was evaluated using tail-cuff method. The thymus weight was measured as an indicator of glucocorticoid activity. The hydrogen peroxide (H2O2) concentration and ferric reducing antioxidant power (FRAP) were measured in plasma samples. Dex-induced hypertensive rats showed significant increases in SBP and in plasma H2O2 and decreases in the body and thymus weights and in FRAP value (P<0.001). Administration of F. foetida extract significantly prevented and reversed hypertension at all doses. It also increased plasma FRAP value (P<0.001) but failed to decrease plasma H2O2 concentration. These results suggest antihypertensive and antioxidant effects of F. foetida stem extract in Dex-induced hypertension. More investigations are needed to elucidate the exact mechanism of antihypertensive effect of this traditional phytomedicine. PMID- 26600860 TI - A semipolar fraction of petroleum ether extract of Artemisia aucheri induces apoptosis and enhances the apoptotic response to doxorubicin in human neuroblastoma SKNMC cell line. AB - Artemisia is an important genus of Iranian flora whose potent anti-proliferative effect has been demonstrated previously on human cancerous cell lines. In the current study, further fractionation was carried out on the petroleum ether extract of A. aucheri and their cytotoxic effects were evaluated on three human cancer cell lines. Cell viability was determined by 3-(4,5-dimethylthiazol-2yl) 2,5-diphenyltetrazolium bromide assay. Real time polymerase chain reaction (RT PCR) was used to evaluate the expression of apoptotic related genes. Activation of caspases and detection of intracellular doxorubicin (DOX) accumulation were evaluated using a spectrophotometer. Mitochondrial membrane potential (MMP) was measured using flow cytometry. The fraction NO-7 (F7) of petroleum ether extract showed the highest anti-proliferative effect, especially against SKNMC cells. Therefore, we focused on a description of the cytotoxic mechanism of the most potent fraction on SKNMC cells. The results indicated that F7 was able to induce apoptosis through MMP disruption, activation of caspases and increament of proapoptotic genes Bax and Smac/DIABLO. Moreover, our observation indicated that F7 is able to increase the cytotoxicity of DOX in SKNMC cells. The combination of F7+DOX significantly increased the intracellular accumulation of DOX. These results indicated that F7 induces apoptosis in SKNMC cells. Moreover, it might enhance the antitumor activity of DOX, through modulating the activity of multidrug resistant cancer cells and inducing apoptosis. PMID- 26600862 TI - Evaluation of discoidin domain receptor-2 (DDR2) expression level in normal, benign, and malignant human prostate tissues. AB - Discoidin domain receptor (DDR) is a new member of the receptor tyrosine kinase family. There are two isoforms of discoidin domain receptor (DDR), DDR1 and DDR2. These receptors play a major role in the adhesion, motility and cell proliferation. Due to the important role of DDR2 in the development of tumor extension, this receptor is pivotal in the field of carcinogenesis. The aim of this study was to investigate the mRNA and protein expression of DDR2, in the malignant, benign prostatic hyperplasia (BPH) and normal tissues of patients with prostate cancer. In this study the gene and protein expression of DDR2 in adjacent normal (n=40), BPH (n=40), and malignant (n=40) prostate tissue were measured using real-time PCR and Western blotting. Then, the correlation of DDR2 gene and protein expression with prognostic factors such as age, tumor grade, tumor stage, lymph node involvement, and serum prostate-specific antigen (PSA) concentration were evaluated. The relative mRNA and protein expression level of DDR2 in malignant and benign prostate tissue was significantly higher than those of adjacent normal tissues (P<0.01). This expression was found to increase approximately 3.5 and 2.1 fold for mRNA and protein levels, respectively. Spearman test indicated a significant correlation between DDR2 mRNA and protein expression with prognostic factors such as tumor grade, stage, lymph node involvement, and serum PSA concentration. However, significant correlation with age was not observed. These findings suggest that DDR2 is a cancer-related gene associated with the aggressive progression of prostate cancer patients. PMID- 26600861 TI - Anti-inflammatory effect of Pycnocycla spinosa extract and its component isoacetovanillone on acetic acid induced colitis in rats. AB - Colitis is an inflammatory disease of the intestine with unknown etiology involving multiple immune, genetic and environmental factors. We were interested to examine the effect of total extract from Pycnocycla spinosa Boiss. on the treatment of experimental colitis. Mediators involved in colonic inflammation are prostaglandins, interleukins, leukotriene as well as an increase in myeloperoxidase (MPO) activity. Therefore, MPO activity was also determined in this research. P. spinosa hydroalcoholic extract (5, 10 and 20 mg/kg) or isoacetovanillone (2, 5 and 10 mg/kg) were administered orally, started 2 h before induction of colitis by intrarectal administration of acetic acid (3%) in rats. Prednisolone (4 m/kg) was used as the standard drug for comparison. Biochemical evaluation of inflamed colon was done using assay of MPO activity. After 5 days treatments, mucosal ulceration was evaluated. Intrarectal instillation of acetic acid caused significant inflammatory reactions as indicated by macroscopic and microscopic changes. The activity of MPO increased in vehicle treated groups while recovered to normal level by pretreatment of animals with P. spinosa extract, isoacetovanillone and prednisolone. P. spinosa and isoacetovanillone-treated groups showed significantly lower score values of macroscopic and microscopic characters when compared with the vehicle treated negative control group. The beneficial effect of P. spinosa was comparable with that of prednisolone. This research has shown the anti-inflammatory potential of P. spinosa extract and isoacetovanillone in experimentally induced colitis. PMID- 26600863 TI - Synthesis of polymers containing 3-hydroxypyridin-4-one bidentate ligands for treatment of iron overload. AB - Iron overload is a clinical problem which can be prevented by using iron chelating agents. An alternative method of relieving iron overload is to reduce iron absorption from the intestine by administering specific iron chelating agents, which can bind iron to form nonabsorbable complexes. Based on this strategy, a series of polymeric ligands containing the chelating moiety 3 hydroxypyridin-4-ones (HPOs) were synthesized. The synthetic route involves the benzylation of hydroxyl group of (2-methyl-3-hydroxypyran-4-one (maltol) and conversion of benzylated maltol to 3-benzyloxypyridin-4-one derivatives by using three suitable primary amines (2,6-diaminohexanoic acid (lysine) and 1,6 diaminohexane and 5-aminopentanol). The resulted compounds incorporated into polymer by copolymerization with acryloyl chloride using 2, 2' azobisisobutyronitrile (AIBN) as the initiator. Finally, the benzyl groups of polymers were removed by catalytic hydrogenation (Pd/C). In this work, three final polymers of HPO derivatives namely poly-2-propylamido-6-(3- hydroxy -1,4 dihydro-2-methy-4-oxopyrid-1-yl) hexanoic acid, 6-(3-hydroxy-1, 4-dihydro-2 methyl-4-oxopyrid-1-yl) hexyl-1-polypropylamide and 5-(3-hydroxy-1-,4-dihydro-2 methyl-4-oxopyrid-1-yl)-1-polyacrylate pentane were synthesized. Identification and structural elucidation of compounds were achieved by proton nuclear magnetic resonance ((1)H NMR), carbon nuclear magnetic resonance ((13)C NMR) and infrared (IR) spectroscopy. PMID- 26600864 TI - Assessment of Lemon Balm (Melissa officinalis L.) Hydrogels: Quality and Bioactivity in Skin Cells. AB - The aim of the study was to design gels with lemon balm extract, assess their quality, and investigate the effect of rosmarinic acid on skin cells in normal conditions and under oxidative stress. Methods. The quantities of rosmarinic acid (RA) released from gels were evaluated by applying the HPLC technique. HaCaT cell viability was assessed by using the MTT method. ROS generation was measured using DCFH-DA dye. The results showed that the gelling material affected the release of RA content from gels. Lower and slower RA content release was determined in carbomer-based gels. After 6 hours of biopharmaceutical research in vitro, at least 4% of RA was released from the gel. The results of the biological studies on HaCaT cells demonstrated that, in the oxidative stress conditions, RA reduced intracellular ROS amounts to 28%; 0.25-0.5 mg/mL of RA increased cell viability by 10-24% and protected cells from the damage caused by H2O2. Conclusions. According to research results, it is appropriate to use a carbomer as the main gelling material, and its concentration should not exceed 1.0%. RA, depending on the concentration, reduces the amount of intracellular ROS and enhances cell viability in human keratinocytes in oxidative stress conditions. PMID- 26600865 TI - The Effects of Tai Chi on Peripheral Somatosensation, Balance, and Fitness in Hispanic Older Adults with Type 2 Diabetes: A Pilot and Feasibility Study. AB - Peripheral neuropathy and loss of somatosensation in older adults with type 2 diabetes can increase risk of falls and disability. In nondiabetic older adult population Tai Chi has been shown to enhance balance and fitness through improvements in somatosensation and neuromuscular control, and it is unclear if Tai Chi would elicit similar benefits in older adults with diabetes. Therefore, the purpose of this study was to investigate the effects of an 8-week, three-hour per-week Tai Chi intervention on peripheral somatosensation in older adults with type 2 diabetes. Participants were eight Hispanic older adults with type 2 diabetes who participated in the Tai Chi intervention and a convenience sample of Hispanic older adults as a referent group. Baseline and postintervention assessments included ankle proprioception, foot tactile sense, plantar pressure distribution, balance, and fitness. After intervention, older adults with type 2 diabetes showed significant improvements in ankle proprioception and fitness and decreased plantar pressure in the forefoot, with no statistical effect noted in balance or tactile sensation. Study results suggest that Tai Chi may be beneficial for older adults with diabetes as it improves ankle proprioception; however, study findings need to be confirmed in a larger sample size randomized controlled trial. PMID- 26600866 TI - Disability assessment as an outcome measure: a comparative study of Nigerian outpatients with schizophrenia and healthy control. AB - BACKGROUND AND OBJECTIVE: Schizophrenia is a chronic mental disorder that leads to disability in several aspects of the individual's personal, social, and occupational functioning. This study assesses and compares the level of disability among Nigerian outpatients with schizophrenia and healthy controls (HC). METHODS: A comparative cross-sectional study among 100 schizophrenia outpatients with an ICD-10 diagnosis and 100 HC was conducted over a 4-month period. They completed a questionnaire containing the Zung's Self-Rating Depression Scale (SDS), the World Health Organization Disability Assessment Schedule-Second Version (WHODAS-II). Symptoms of schizophrenia were assessed with the Positive and Negative Syndrome Scale (PANSS). Student's t tests and Chi square were used to compare patient with schizophrenia and healthy control. Pearson correlation and multiple linear regression analyses were used to assess the relationships of socio-demographic and clinical variable with disability. RESULTS: The patients with schizophrenia reported greater disability than the HC on most of the disability domains of WHODAS-II. They also reported significantly higher mean Zung's SDS scores than the HC. Depressive symptoms, negative symptoms, and PANSS total were significantly related to all the WHODAS-II domains. The disability summary score was significantly predicted by depressive symptoms, negative and positive symptoms of schizophrenia, number of active symptoms (relapse) of schizophrenia, and marital status [F (5, 94) = 23.90, p < 0.001]. CONCLUSION: Schizophrenia is a disabling disorder that affects different aspects of a patient's life. Treatment strategies that target these different aspects may help in reducing disability. PMID- 26600867 TI - A MRI Denoising Method Based on 3D Nonlocal Means and Multidimensional PCA. AB - Recently nonlocal means (NLM) and its variants have been applied in the various scientific fields extensively due to its simplicity and desirable property to conserve the neighborhood information. The two-stage MRI denoising algorithm proposed in this paper is based on 3D optimized blockwise version of NLM and multidimensional PCA (MPCA). The proposed algorithm takes full use of the block representation advantageous of NLM3D to restore the noisy slice from different neighboring slices and employs MPCA as a postprocessing step to remove noise further while preserving the structural information of 3D MRI. The experiments have demonstrated that the proposed method has achieved better visual results and evaluation criteria than 3D-ADF, NLM3D, and OMNLM_LAPCA. PMID- 26600868 TI - Simulation on the Comparison of Steady-State Responses Synthesized by Transient Templates Based on Superposition Hypothesis. AB - The generation of auditory-evoked steady-state responses (SSRs) is associated with the linear superposition of transient auditory-evoked potentials (AEPs) that cannot be directly observed. A straightforward way to justify the superposition hypothesis is the use of synthesized SSRs by a transient AEP under a predefined condition based on the forward process of this hypothesis. However, little is known about the inverse relation between the transient AEP and its synthetic SSR, which makes the interpretation of the latter less convincible because it may not necessarily underlie the true solution. In this study, we chose two pairs of AEPs from the conventional and deconvolution paradigms, which represent the homo-AEPs from a homogenous group and the hetero-AEPs from two heterogeneous groups. Both pairs of AEPs were used as templates to synthesize SSRs at rates of 20-120 Hz. The peak-peak amplitudes and the differences between the paired waves were measured. Although amplitude enhancement occurred at ~40 Hz, comparisons between the available waves demonstrated that the relative differences of the synthetic SSRs could be dramatically larger at other rates. Moreover, two virtually identical SSRs may come from clearly different AEPs. These results suggested inconsistent relationships between the AEPs and their corresponding SSRs over the tested rates. PMID- 26600869 TI - HPV16/18 genotyping for the triage of HPV positive women in primary cervical cancer screening in Chile. AB - BACKGROUND: We previously conducted a population-based screening trial of high risk human papillomavirus (hrHPV) testing and conventional cytology, demonstrating higher sensitivity (92.7 % vs 22.1 % for CIN2+) but lower positive predictive value (10.5 % vs 23.9 %) of hrHPV testing. Here we report the performance of HPV16/18 genotyping to triage the hrHPV positive participants. METHODS: Women aged 25 years and older received hrHPV (Hybrid Capture 2) and Papanicolaou testing; positives by either test underwent colposcopy and directed biopsy, as did a sample of double-negatives. hrHPV positive women were reflex tested with HPV16/18 genotyping (Digene HPV Genotyping PS Test). RESULTS: Among the 8,265 participants, 10.7 % were hrHPV positive, 1.7 % had ASCUS+ cytology, 1.2 % had CIN2+; 776 (88 %) hrHPV positive women had complete results, of whom 38.8 % were positive for HPV16 (24.0 %), HPV18 (9.7 %) or both (5.1 %). CIN2+ prevalence in HPV16/18 positive women (16.3 %, 95 % CI 12.3-20.9) was twice that of HPV16/18 negative women (8.0 %, 95 % CI 5.7-10.8). HPV16/18 genotyping identified 40.5 % of CIN2, 66.7 % of CIN3 and 75.0 % of cancers. Compared to hrHPV screening alone, HPV16/18 triage significantly reduced the referral rate (10.7 % vs 3.7 %) and the number of colposcopies required to detect one CIN2+ (9 vs 6). When HPV16/18 negative women with baseline ASCUS+ cytology were also colposcopied, an additional 14 % of CIN2+ was identified; referral increased slightly to 4.2 %. CONCLUSIONS: HPV16/18 triage effectively stratified hrHPV positive women by their risk of high-grade lesions. HPV16/18 positive women must be referred immediately; referral could be deferred in HPV16/18 negative women given the slower progression of non-HPV16/18 lesions, however, they will require active follow-up. PMID- 26600870 TI - The case for dosing dabigatran: how tailoring dose to patient renal function, weight and age could improve the benefit-risk ratio. AB - Dabigatran is increasingly being used in clinical practice for the thromboprophylaxis in atrial fibrillation as a convenient therapy that needs no drug level monitoring. However, analysis of the data of the same clinical trial that led to the adoption of dabigatran in fixed-dosing regimens has indicated a small subgroup of patients that could be either over-treated, risking bleeding, or under-treated, risking embolism. Additional post-marketing data lends support to the favorable therapeutic profile of dabigatran but at the same time raises doubts about patient characteristics such as weight, age, renal function and their pharmacokinetic effects that, in some cases, could be serious enough to expose a minority of patients to risk. We will present a clinical case of a patient with an ischemic stroke while on dabigatran that was found with low dabigatran plasma levels and we will discuss the currently available data on the effects of inherent patient characteristics on dabigatran pharmacokinetics, the clinical impact of dabigatran plasma levels on safety and efficacy as well as the possibility of improving the risk-benefit profile of this agent by tailoring the dose for selected patient groups. PMID- 26600871 TI - Progressive multifocal leukoencephalopathy: current treatment options and future perspectives. AB - Progressive multifocal leukoencephalopathy (PML) is a rare but debilitating and frequently fatal viral disease of the central nervous system, primarily affecting individuals with chronically and severely suppressed immune systems. The disease was relatively obscure until the outbreak of HIV/AIDS, when it presented as one of the more frequent opportunistic infections in this immune deficiency syndrome. It attracted additional attention from the medical and scientific community following the discovery of significant PML risk associated with natalizumab, a monoclonal antibody used for treatment of relapsing-remitting multiple sclerosis. This was followed by association of PML with other immunosuppressive or immunomodulating drugs. PML is currently untreatable disease with poor outcomes, so it is a significant concern when developing new immunotherapies. Current prophylaxis and treatment of PML are focused on immune reconstitution, restoration of immune responses to JC virus infection, and eventual suppression of immune reconstitution inflammatory syndrome. This approach was successful in reducing the incidence of PML and improved survival of PML patients with HIV infection. However, the outcome for the majority of PML patients, regardless of their medical history, is still relatively poor. There is a high unmet need for both prophylaxis and treatment of PML. The aim of this review is to discuss potential drug candidates for prophylaxis and treatment of PML with a critical review of previously conducted and completed PML treatment studies as well as to provide perspectives for future therapies. PMID- 26600872 TI - Monoclonal antibody therapies for the treatment of relapsing-remitting multiple sclerosis: differentiating mechanisms and clinical outcomes. AB - Monoclonal antibody (mAb) therapies for relapsing-remitting multiple sclerosis (MS) target immune cells or other molecules involved in pathogenic pathways with extraordinary specificity. Natalizumab and alemtuzumab are the only two currently approved mAbs for the treatment of MS, having demonstrated significant reduction in clinical and magnetic resonance imaging disease activity and disability in clinical studies. Ocrelizumab and daclizumab are in the late stages of phase III trials, and several other mAbs are in the early stages of clinical evaluation. mAbs have distinct structural characteristics (e.g. chimeric, humanized, fully human) and unique targets (e.g. blocking interactions, induction of signal transduction by receptor binding, complement-dependent cytotoxicity, antibody dependent cell-mediated cytotoxicity) conferring different mechanisms of action in MS. Because of these differences, mAbs for MS do not constitute a single treatment class; each must be considered individually when selecting appropriate therapy. Furthermore, in reviewing the data from clinical studies of mAbs, attention should be drawn to use of different comparators (e.g. placebo or interferon beta-1a) and study designs. Each mAb treatment has a unique administration schedule. In the decision to select the appropriate treatment for each individual MS patient, careful review of the benefits relative to risks of mAbs is balanced against the risk of development of MS-associated disability. PMID- 26600874 TI - An update on the management of post-traumatic headache. AB - Recent studies from the UK give the debate about how to deal best with patients suffering from whiplash injury new impetus. Following whiplash injury, about 90% of patients complain about head and/or neck pain, as well as dizziness, sleep problems and anxiety. These symptoms are often referred to as whiplash-associated disorders. In the majority of cases, these complaints develop within a few days or weeks following the accident. However, 30-50% of patients experience prolonged symptoms for more than 6 months, with headache as the main complaint. In accordance with the bio-psycho-social model of chronic post-traumatic headache, the following treatment options have been suggested: (1) proper patient education with detailed explanation of the condition; (2) support of normal movement; (3) avoiding immobilization; (4) resumption of work; and (5) targeted physiotherapy. Based on current study data, intensified physiotherapy seems not to be superior to standard therapy with simple patient education and can therefore not be recommended considering cost-benefit aspects. PMID- 26600873 TI - A practical approach to the diagnosis and management of sleep disorders in patients with multiple sclerosis. AB - Patients with multiple sclerosis (MS) are at increased risk for comorbid sleep disturbances, which can profoundly contribute to poor functional status and fatigue. Insomnia, sleep-disordered breathing, and restless legs syndrome are among the most common sleep disorders experienced by patients with MS. Despite their impact, these underlying sleep disorders may escape routine clinical evaluations in persons with MS, thereby leading to missed opportunities to optimize functional status and quality of life in patients with MS. A practical, systematic approach to the evaluation and treatment of sleep disorders in MS, in the context of MS-specific variables that may influence risk for these conditions or response to therapy, is recommended to facilitate early diagnosis and successful treatment. This review summarizes the most common sleep disorders experienced by persons with MS, and offers a practical approach to diagnosis and management of these conditions. PMID- 26600875 TI - Future perspectives in target-specific immunotherapies of myasthenia gravis. AB - Myasthenia gravis (MG) is an autoimmune disease caused by complement-fixing antibodies against acetylcholine receptors (AChR); antigen-specific CD4+ T cells, regulatory T cells (Tregs) and T helper (Th) 17+ cells are essential in antibody production. Target-specific therapeutic interventions should therefore be directed against antibodies, B cells, complement and molecules associated with T cell signaling. Even though the progress in the immunopathogenesis of the disease probably exceeds any other autoimmune disorder, MG is still treated with traditional drugs or procedures that exert a non-antigen specific immunosuppression or immunomodulation. Novel biological agents currently on the market, directed against the following molecular pathways, are relevant and specific therapeutic targets that can be tested in MG: (a) T cell intracellular signaling molecules, such as anti-CD52, anti-interleukin (IL) 2 receptors, anti- costimulatory molecules, and anti-Janus tyrosine kinases (JAK1, JAK3) that block the intracellular cascade associated with T-cell activation; (b) B cells and their trophic factors, directed against key B-cell molecules; (c) complement C3 or C5, intercepting the destructive effect of complement-fixing antibodies; (d) cytokines and cytokine receptors, such as those targeting IL-6 which promotes antibody production and IL-17, or the p40 subunit of IL-12/1L-23 that affect regulatory T cells; and (e) T and B cell transmigration molecules associated with lymphocyte egress from the lymphoid organs. All drugs against these molecular pathways require testing in controlled trials, although some have already been tried in small case series. Construction of recombinant AChR antibodies that block binding of the pathogenic antibodies, thereby eliminating complement and antibody-depended-cell-mediated cytotoxicity, are additional novel molecular tools that require exploration in experimental MG. PMID- 26600877 TI - Surgically Confirmed Intra- and Extratesticular Hematoma Clinically Mimicing Epididymo-Orchitis and Radiologically Mimicing Traumatic Torsion. AB - BACKGROUND: Scrotal blunt trauma may result in injuries, such as testicular rupture, dislocation, torsion, hematoma, spermatic cord injury or contusion, and epididymal, scrotal, and urethral injuries. Ultrasonography (US) has a crucial role in the evaluation of those kinds of pathologies. Early diagnosis of testicular rupture may lead to the salvaging of the testicle by prompt surgical exploration within 72 h. CASE REPORT: A 21-year-old male with right scrotal swelling and pain complaints was admitted to another hospital one month ago. Epididymo-orchitis was diagnosed and the patient was given medical treatment. The patient was admitted to our emergency service with ongoing complaints. The patient stated that the pain and swelling suddenly developed after prolonged marching. On US, a large hematoma was detected between the leaves of the tunica vaginalis, and rupture from the lower pole was diagnosed. On color Doppler US, no vascularity was observed in the heterogeneous testicular parenchyma. Traumatic torsion was primarily suggested. Intraoperatively, an extratesticular hematoma, hematocele, and rupture were confirmed but torsion was not found. Because the hematoma entirely replaced the normal parenchyma, orchiectomy was performed. CONCLUSIONS: Testicular rupture may occur even after moderate sportive action such as prolonged marching. If any delay occurs in diagnosis and/or operation, the coagulum may replace the entire parenchyma. We think that US and clinical findings may sometimes mislead the physicians and cause misdiagnoses, such as inflammation or torsion. In this paper, we present a complex delayed diagnosed example case of testicular rupture clinically mimicing epididymo-orchitis and radiologically mimicing traumatic testicular torsion. PMID- 26600876 TI - Low-dose fenfluramine in the treatment of neurologic disorders: experience in Dravet syndrome. AB - In this paper, we review the experience with fenfluramine in epileptic and other paroxysmal disorders. Since the best available data are from the treatment of Dravet syndrome, we will focus primarily on this condition. Originally fenfluramine was launched as an anorectic agent. As early as 1985, seizure reduction in children could be demonstrated in a few cases with photosensitive, self-induced epilepsy. Hereafter, a small study was launched in patients with self-induced epilepsy. Results showed a significant seizure reduction, and review of the patient data showed that 5 of the 12 patients had Dravet syndrome. During that observation period, fenfluramine was withdrawn from the market because of cardiovascular side effects associated with prescribing higher doses in combination with phentermine for weight loss. In March 2002, a Belgian Royal Decree was issued permitting further study of fenfluramine in pediatric patients with intractable epilepsy. In 2011 under the Royal Decree, a prospective study of patients with Dravet syndrome treated with low-dose fenfluramine was initiated and is currently ongoing. The initial results are promising in terms of reduction of seizure frequency and overall tolerability. PMID- 26600878 TI - Oncotic Cerebral Aneurysms in a Case of Left Atrial Myxoma, Role of Imaging in Diagnostics and Treatment. AB - BACKGROUND: Myxomatous cerebral (oncotic) aneurysms following atrial myxoma is a rare neurological complication. CASE REPORT: We report an 11-year- old boy with left atrial myxoma and multiple cerebral oncotic aneurysms. The characteristics of these aneurysms are indefinite and variable. The "Metastasize and Infiltrate" theory may be the key mechanism in the formation of these aneurysms. CONCLUSIONS: Magnetic resonance imaging (MRI), computed tomography (CT) and angiography are useful in the diagnostics while digital subtraction angiography (DSA) is the best option. There are no definite guidelines for therapy of these aneurysms. Resection of cardiac myxomas, chemotherapy, radiotherapy, coil embolization and surgical treatment could be helpful. PMID- 26600879 TI - Ischiofemoral Impingement Syndrome: A Case Report and a Review of Literature. AB - BACKGROUND: Ischiofemoral impingement syndrome is characterized by a hip pain associated with abnormalities in quadriceps femoris muscle and ipsilaterally reduced distance between the lesser trochanter and the ischium. Thus far, the congenital variant of this entity has been reported exclusively in women. CASE REPORT: We report a case of a 22-year old male with painful hips in whom on the basis of the imaging studies the constitutional variant of ischiofemoral impingement was diagnosed. CONCLUSIONS: Ischiofemoral conflict should be taken into consideration in the differential diagnosis of hip pain, particularly among women, but also in patients with valgus hip deformity and other abnormalities leading to reduction of the space between femoral and ischial bones independent of gender. PMID- 26600880 TI - Evaluation of neutrophil-to-lymphocyte ratio prior to prostate biopsy to predict biopsy histology: Results of 1836 patients. AB - INTRODUCTION: We evaluate the role of NLR prior to prostate biopsy to predict biopsy histology and Gleason score in patients with prostate cancer. METHODS: In this retrospective study, we evaluated data of patients underwent prostate biopsy between May 2005 and March 2015. We collected the following data: age, prostate specific antigen (PSA), biopsy histology, Gleason score (GS) in prostate cancer patients, neutrophil counts, and lymphocyte counts. Patients were grouped as benign prostatic hyperplasia (BPH), prostate cancer, and prostatitis. The Chi square test was used to compare categorical variables and analysis of variance (ANOVA) was applied for continuous variables. RESULTS: Data of 1836 patients were investigated. The mean age, total PSA and neutrophil-lymphocyte ratio (NLR) of the population were 66.8 +/- 8.17 years, 9.38 +/- 4.7 ng/dL, and 3.11 +/- 1.71, respectively. Patients were divided as follows: 625 in the group with BPH history, 600 in the prostatitis group, and 611 in the prostate cancer histology group. The mean NLR of the prostatitis group was higher compared to the prostate cancer and BPH groups (p = 0.0001). The mean NLR of the prostate cancer group was significantly higher compared to the BPH group (p = 0.002). The GS 8-10 group had a significantly higher mean NLR compared to GS 5-6 (3.64 vs. 2.54, p = 0.0001) and GS 7 (3.64 vs. 2.58, p = 0.0001) patients. CONCLUSIONS: NLR was found to differ with regard to histology of prostate biopsy and higher GS was associated with higher NLR in patients with prostate cancer. However prostatitis prevents the use of NLR in predicting prostate cancer before a prostate biopsy. Also, the retrospective nature and lack of multivariate analysis in this study somewhat limits the relevance of these results. PMID- 26600881 TI - Impact of obesity on functional and oncological outcomes in radical perineal prostatectomy. AB - INTRODUCTION: We evaluated the impact of obesity on perioperative morbidity, functional, and oncological outcomes after radical perineal prostatectomy (RPP). METHODS: A total of 298 consecutive patients underwent RPP at our institution. Patients were categorized into 3 groups based on their body mass index (BMI): Normal weight <25 kg/m(2) (Group 1), overweight 25 to <30 kg/m(2) (Group 2), and obese >=30 kg/m(2) (Group 3). We compared the groups with respect to perioperative data, postoperative oncologic, and functional outcomes. Evaluation of urinary continence and erectile function was performed using a patient reported questionnaire and the International Index of Erectile Function-5 questionnaire, respectively, administered preoperatively and at 3, 6, and 12 months. Limitations included short follow-up time, retrospective design and lack of a morbidly obese group. RESULTS: No significant differences were found among the 3 groups with regard to operative time, estimated blood loss, length of hospital stay, catheter removal time, positive surgical margin, and complication rates. At 12 months, 94.7%, 95% and 95% of normal, overweight and obese patients, respectively, were continent (free of pad use) (p = 0.81). At 12 months, 30.6%, 29.8% and 30.4% of patients had spontaneous erections and were able to penetrate and complete intercourse in Group 1, Group 2, and Group 3, respectively (p = 0.63). CONCLUSIONS: In this cohort of patients, no clinically relevant risks were associated with increasing BMI. PMID- 26600882 TI - Effects of desmopressin for the treatment of nocturnal polyuria in elderly women: impact on related sleep quality. AB - INTRODUCTION: We investigated the efficacy, safety, and impact of desmopressin on quality of sleep in treating nocturnal polyuria in elderly women. METHODS: We recruited 60 women over 60 years old with lower urinary tract symptoms (LUTS), including nocturia, and with nocturnal polyuria. Nocturnal polyuria was defined as nighttime urine production exceeding 33% of the 24-hour total urine volume determined by a frequency volume (FV) chart. All patients failed to respond to treatment of their underlying disease and evening fluid restriction. Desmopressin 0.1 mg was administered orally at bedtime for 12 weeks. The participants completed a series of questionnaires on the Medical Outcomes Study (MOS) sleep scale and FV chart before and after treatment. RESULTS: The patient population had a mean age of 69.2 +/- 9.4 years (range: 61-81). The mean duration of symptoms was 61.2 +/- 45.1 months. Significant decreases were evident after desmopressin treatment in the number of nocturia episodes (3.63 +/- 1.61 to 2.00 +/- 1.13, p = 0.01), nocturnal urine volume (p = 0.01), nocturnal polyuria index (NPI) (p = 0.01), and nocturia index (NI) p = 0.01). Among the categories of the MOS sleep scale, sleep index (p = 0.003), sleep disturbance (p = 0.001), snoring (p = 0.028), and shortness of breath (p = 0.036) significantly changed, with a decreased number of nocturia episodes. Adverse events were mild. CONCLUSIONS: Desmopressin is an effective treatment for nocturnal polyuria in elderly women, where conservative treatment has failed. Sleep quality is also improved. PMID- 26600883 TI - Management of ureteropelvic junction obstruction in horseshoe kidneys by an assortment of laparoscopic options. AB - INTRODUCTION: We report our experience with laparoscopic management of ureteropelvic junction obstruction in horseshoe kidneys. METHODS: Between February 2004 and March 2014, 15 patients with horseshoe kidneys and symptomatic ureteropelvic junction obstruction underwent laparoscopic management at our national referral centre. Depending on the anatomy and presence of obtrusive vessels or isthmus, we performed either dismembered, Scardino or Foley YV pyeloplasty, or Hellstrom vessel transposition. Patients were initially evaluated by ultrasonography, then diuretic scintiscan at 4 to 6 months, and followed by yearly clinical and sonographic exams. RESULTS: This study included 11 male and 4 female patients between the ages of 4 to 51 year (average 17.7). The left kidney was involved in 12 patients (80%). Operation time was 129 minutes (range: 90 186), and patients were discharged within 2.8 days (range: 1-6). Although 8 (53.3%) patients had crossing vessels, of which 6 required transposing, the Hellstrom technique was solely used in 3 cases, of which notably 1 case failed to resolve and required laparoscopic Hynes within the next year. Eight cases underwent dismembered pyeloplasty, 2 Foley YV, 1 Scardino flap and 1 required isthmectomy and vessel suspension. At the mean follow-up of 60 (range: 18-120) months, the overall success rate was 93.3%. CONCLUSIONS: To our knowledge, this represents the largest report on laparoscopic pyeloplasty for horseshoe kidneys, providing the longest follow-up. Our findings confirm prior reports supporting laparoscopy and furthermore show that despite the prevalence of crossing vessels, transposition alone is seldom sufficient. PMID- 26600884 TI - Impact of nerve stimulator-guided obturator nerve block on the short-term outcomes and complications of transurethral resection of bladder tumour: A prospective randomized controlled study. AB - INTRODUCTION: In this prospective randomized controlled study, we investigated the efficacy of obturator nerve block (ONB) on adductor muscle spasm and related short-term outcomes and complications in patients who underwent transurethral resection of lateral wall-located bladder tumours (TURBT). METHODS: Between July 2014 and February 2015, 70 patients scheduled to undergo TUR of lateral bladder wall tumours were enrolled in the study. All patients were preoperatively evaluated by cystoscopy and imaging tools and selected according to localized tumours on the lateral bladder wall. Patients were randomly allocated to Group SA (35 patients who underwent only spinal anesthesia) and Group ONB (35 patients who underwent spinal anesthesia combined with ONB by the nerve stimulator). An independent observer, blinded to the approach, evaluated the obturator signs, including adductor muscle contraction, bladder perforation, and completeness of the resection during the TURBT procedure. RESULTS: The differences between groups regarding mean operation time, tumour size, and number were not statistically significant (p > 0.05). Adductor muscle contraction was detected in 40% of patients in Group SA and 11.4% in Group ONB. This difference was statistically significant (p = 0.021). Complete bladder perforation was detected in 2 patients in Group SA, whereas no perforation was observed in Group ONB. There was no case of severe bleeding in both groups. CONCLUSIONS: We found that ONB performed after spinal anesthesia was effective in preventing intraoperative complications due to adductor muscle spasm while performing TURBT. Our study limitations include its small sample size, since we only enrolled patients with primary lateral wall localized bladder tumour. Also, we excluded patients who underwent bipolar TURBT. PMID- 26600885 TI - Experiences and outcomes of organ-sparing surgery for testicular tumour with benign tendency. AB - INTRODUCTION: We retrospectively investigated and summarized our experiences and the outcomes of organ-sparing surgery (OSS) for testicular tumour with benign tendency. METHODS: From April 2000 to March 2012, 11 selected patients with testicular tumour underwent OSS. Preoperative and postoperative organ functional and oncologic indexes were analyzed and compared. RESULTS: All operations were completed without conversion to radical orchiectomy. Intraoperative frozen section and routine postoperative pathology showed tumours with benign tendency. The normal appearance of the scrotum and functional integrity of the testis were preserved. Preoperative and postoperative serum sex hormone levels, international index of erectile function (IIEF-5) scores, and semen quality were not significantly different. Tumour recurrence or metastasis did not occur during follow-up. CONCLUSIONS: Our results showed the feasibility and safety of OSS to treat testicular tumour with benign tendency. With careful selection and rigorous follow-up, some testis tumor can be treated with OSS to maximally maintain normal appearance and function of the testis. The retrospective single-centre study and small sample size are main limitations. More evidence is needed to establish the large-scale application of OSS. PMID- 26600886 TI - The prognostic significance of preoperative leukocytosis and neutrophil-to lymphocyte ratio in patients who underwent radical cystectomy for bladder cancer. AB - INTRODUCTION: We evaluated the prognostic effects of hematologic parameters of preoperative leukocytosis and neutrophil-to-lymphocyte ratio (NLR) in patients who underwent radical cystectomy for bladder cancer. METHODS: We retrospectively reviewed the medical records of 363 patients who underwent radical cystectomy for bladder cancer between January 1990 and June 2013. In total, 286 patients were included in the study. Age, gender, pathologic stage, lymph node involvement, preoperative hydronephrosis, histologic sub-type, surgical margin status, and lymphovascular invasion were recorded for each patient. Univariate and multivariate analysis were performed to determine the prognostic value of the preoperative clinical and laboratory parameters on disease-specific survival (DSS). Additionally, the correlation between leukocytosis and other factors were evaluated. RESULTS: According to the univariate analysis preoperative leukocytosis and NLR were detected as negative prognostic factors on DSS. Preoperative leukocytosis, NLR, stage, lymph node involvement, histologic subtype, grade and age were independent prognostic factors for DSS, on multivariate analysis. Patients with leukocytosis had higher stage, grade and lymphovascular invasion. CONCLUSIONS: Inexpensive, reproducible, and readily available peripheral blood count components of white blood cell count and NLR were independent prognostic factors, which can stratify DSS risks in bladder cancer patients who underwent radical cystectomy. PMID- 26600887 TI - Visceral obesity: A new risk factor for stone disease. AB - INTRODUCTION: We examined the relationship between stone disease and the amount of visceral adipose tissue measured with unenhanced computed tomography (CT). METHODS: We included 149 patients with complaints of flank pain and kidney stones detected by CT, from August 2012 to April 2013. In addition, as the control group we included 139 healthy individuals, with flank pain within the same time period, with no previous history of urological disease and no current kidney stones identified by CT. Patients were analyzed for age, gender, body mass index, amount of visceral and subcutaneous adipose tissue, and serum level of low-density lipoprotein and triglyceride. RESULTS: There were no differences between groups in terms of gender and age (p = 0.27 and 0.06, respectively). Respective measurements for the stone and control groups for body mass index were 29.1 and 27.6 kg/m(2); for visceral fat measurement 186.0 and 120.2 cm(2); and for subcutaneous fat measurements 275.9 and 261.9 cm(2) (p = 0.01; 0.01 and 0.36, respectively). Using multivariate analysis, the following factors were identified as increasing the risk of kidney stone formation: hyperlipidemia (p = 0.003), hypertension (p = 0.001), and ratio of visceral fat tissue to subcutaneous fat tissue (p = 0.01). Our study has its limitations, including its retrospective nature, its small sample size, possible selection bias, and missing data. The lack of stone composition data is another major limitation of our study. CONCLUSION: The ratio of visceral to subcutaneous adipose tissue, in addition to obesity, hyperlipidemia, and hypertension, was identified as an emerging factor in the formation of kidney stones. PMID- 26600888 TI - Analysis of prognostic factors affecting mortality in Fournier's gangrene: A study of 72 cases. AB - INTRODUCTION: Fournier's gangrene is a rapidly progressing necrotizing fasciitis of the perineum and genital area associated with a high mortality rate. We presented our experience in managing this entity and identified prognostic factors affecting mortality. METHODS: We carried out a retrospective study of 72 patients treated for Fournier's gangrene at our institution between January 2005 and December 2014. Patients were divided into survivors and non-survivors and potential prognostic factors were analyzed. RESULTS: Of the 72 patients, 64 were males (89%) and 8 females (11%), with a mean age of 51 years. The most common predisposing factor was diabetes mellitus (38%). The mortality rate was 17% (12 patients died). Statistically significant differences were not found in age, gender, and predisposing factors, except in heart disease (p = 0.038). Individual laboratory parameters significantly correlating with mortality included hemoglobin (p = 0.023), hematocrit (p = 0.019), serum urea (p = 0.009), creatinine (p = 0.042), and potassium (p = 0.026). Severe sepsis on admission and the extent of affected surface area also predicted higher mortality. Others factors, such as duration of symptoms before admission, number of surgical debridement, diverting colostomy and length of hospital stay, did not show significant differences. The median Fournier's Gangrene Severity Index (FGSI) was significantly higher in non-survivors (p = 0.002). CONCLUSION: Fournier's gangrene is a severe surgical emergency requiring early diagnosis and aggressive therapy. Identification of prognostic factors is essential to establish an optimal treatment and to improve outcome. The FGSI is a simple and valid method for predicting disease severity and patient survival. PMID- 26600889 TI - Isolated penile torsion in newborns. AB - INTRODUCTION: We reported on the incidence of isolated penile torsion among our healthy children and our approach to this anomaly. METHODS: Between 2011 and 2014, newborn babies with penile torsion were classified according to the angle of torsion. Surgical correction (penile degloving and reattachment for moderate cases and dorsal dartos flap technique in case of resistance) after 6 months was advised to the babies with rotations more than 45 degrees . RESULTS: Among 1000 newborn babies, 200 isolated penile torsions were found, and among these, 43 had torsions more than 45 degrees , and 4 of these had angles greater than 90 degrees . The mean angle of the rotations was found 30.45 degrees (median: 20 degrees ). In total, 8 children with 60 degrees torsions were previously circumcised. Surgery was performed on 19 patients, with a mean patient age of 12 +/- 2 months. Of these 19, 13 babies were corrected with degloving and reattachment. This technique was not enough on the remaining 6 patients; therefore, derotational dorsal dartos flap was added to correct the torsion. After a mean of 15.6 +/- 9.8 months, residual penile rotation, less than 15 degrees , was found only in 2 children. CONCLUSION: The incidence of isolated penile torsion is 20% in newborns. However, rotation more than 45 degrees angles are seen in 4.3% of male babies. Correction is not necessary in mild degrees, and penile degloving with reattachment is enough in most cases. If the initial correction is insufficient, dorsal dartos flap rotation is easy and effective. Prior circumcision neither disturbs the operative procedure nor affects the outcomes. PMID- 26600890 TI - Precise control of caval and hepatic vessels: Surgical technique to treat level III caval thrombus concomitant to renal cell carcinoma. AB - INTRODUCTION: We investigated the surgical techniques, safety, and prevention of complications of nephrectomy and removal of tumour thrombus for treating level III inferior vena cava (IVC) concomitant to renal cell carcinoma (RCC). We did this by precise controlling IVC and hepatic vessels without a vascular bypass. METHODS: In this series, we included 5 patients with level III IVC tumour thrombus below the hepatic vein concomitant to RCC. After precisely controlling the IVC and hepatic vessels, we then removed the thrombus en bloc with the renal vein. Blood loss volume, IVC clamping time, hypotension time, resuscitation, cardiocerebrovascular complications, and postoperative organ dysfunction were observed. RESULTS: Surgery was successfully performed without perioperative death. Blood loss volume was 900 to 1500 mL, operation time was 165 to 250 minutes, vascular clamping time was 8 to 12 minutes, and intraoperative hypotension time was 9 to 12 minutes. Serious perioperative complications were not observed. Local recurrence was not observed during the 9 to 24 months of follow-up. One patient exhibited disease-free survival, 3 developed lung or liver metastasis, and 1 died 11 months after surgery. CONCLUSION: Precise control of IVC and hepatic pedicle vessels, without vascular bypass, is a safe and effective surgical treatment for level III tumor thrombus below the hepatic vein concomitant to RCC. The procedure was conducted without increased risks of intraoperative hypotensive shock, difficult resuscitation, pulmonary embolism, and multiple organ dysfunctions. PMID- 26600891 TI - Primary testicular mucinous cystadenoma: Case report and literature review. AB - Testicular mucinous cystadenomas are rare in urological practice, and their histogenesis, course and management are debated. We report a primary testicular mucinous cystadenoma in a 54-year old male who presented with left testicular swelling and pain. He denied having a history of cryptorchidism, testicular trauma, infections, urinary complaints, or febrile illnesses. He did not have diabetes, but was on treatment for hypertension. The patient underwent a left inguinal radical orchiectomy, and histological examination of the resected tumour confirmed a primary testicular mucinous cystadenoma. The patient had an uneventful recovery, and is being followed up. Conclusively, urologists need to maintain a high index of suspicion of these tumours and their differentiation from metastatic tumours to ensure optimal therapeutic outcomes. PMID- 26600892 TI - A case of idiopathic diabetes insipidus presented with bilateral hydroureteronephrosis and neurogenic bladder: A pediatric case report and literature review. AB - Diabetes insipidus (DI) is a condition with heterogeneous clinical symptoms characterized by polyuria (urine output >4 mL/kg/hr) and polydipsia (water intake >2 L/m (2)/d). In children, acquired nephrogenic DI (NDI) is more common than central DI (CDI). Diagnosis is based on the presence of high plasma osmolality and low urinary osmolality with significant water diuresis. A water deprivation test with vasopressin challenge, though has limitations, is done to differentiate NDI from CDI and diagnose their incomplete forms. Neonates and young infants are better managed with hydration therapy alone. Older children with CDI are treated with desmopressin (1-deamino-8-D-arginine vasopressin, dDAVP). Its oral form is safe, highly effective and has dosing flexibility. We report a case of an 8-year old male patient with CDI with severe bilateral non-obstructive hydronephrosis and megaureter. Dramatic clinical and radiological responses to dDAVP treatment were achieved and therapy reduced urine volume and led to marked radiological improvement in hydronephrosis. PMID- 26600893 TI - Prostato-inguinal fistula: An unusual site of voiding. AB - An 8-year-old boy presented with voiding from the right inguinal region, which on evaluation was diagnosed as prostato-inguinal fistula. We discuss the pathophysiology of this fistula. PMID- 26600895 TI - Bladder rupture after voiding cystourethrography: A case report and literature review on pitfalls and bladder volume estimation. AB - Voiding cystourethrography (VCUG) is a common diagnostic study in pediatric urology. Although generally considered a safe procedure, VCUG can incur some complications. Bladder rupture following VCUG is a very rare complication and mostly happens in the setting of unused bladders, previous surgeries, or underlying disease. The rupture is almost always intraperitoneal needing prompt surgical treatment. We present a unique case of extraperitoneal bladder rupture after VCUG in an 8-month-old boy. The rupture remained unnoticed and the patient recovered spontaneously without medical or surgical intervention. To the best of our knowledge, this is the first such case report in the English literature. The information provided may guide clinicians on the proper use of bladder volume formulas in children and also help them in getting a proper VCUG study. PMID- 26600894 TI - Rare late metastasis of testis seminoma to the bladder. AB - A 45-year-old male presented to our clinic with complaining of hematuria for a month. The investigations showed a 59 * 24-mm myxoid mass on the right lateral bladder wall and this was removed with transurethral resection. The histopathology evaluation result was seminoma (classic type). The medical history revealed that the patient had undergone inguinal orchiectomy for a testis tumour 10 years before and the diagnosis was classic type seminoma. He received chemotherapy following the orchiectomy, but had not gone for follow-up after the first year. There was no other metastasis and he was put on the iphosphamide, etoposide, cisplatin (IPE) protocol. The patient has been disease-free for the last 5 months and the tumour markers and cystoscopy were normal. Testis tumours can rarely cause other organ metastases in the late stage even if curative surgery and chemo-radiotherapy were initially administered. Proper follow-up is crucial. It is also necessary to query the tumour history when a tumour in any organ is considered. PMID- 26600896 TI - Buccal mucosa graft urethroplasty in a case of urethral amyloidosis presenting with long anterior urethral stricture. AB - Urethral amyloidosis is a rare condition, but clinically relevant because it can mimic urothelial carcinoma. We report a case of localized urethral amyloidosis presenting with a long anterior urethral stricture. We used extensive grafts of buccal mucosa for standard augmentation urethroplasty, with a successful outcome at the 2-year follow-up. PMID- 26600897 TI - Giant adrenal hemangioma: Unusual cause of huge abdominal mass. AB - Adrenal hemangioma is an extremely rare benign and non-functioning neoplasm of the adrenal gland. We report a case of a 71-year-old woman admitted for intermittent abdominal pain and abdominal distension associated with vomiting and chronic constipation for 5 years. Physical examination revealed a large abdominal mass. Both computed tomography scan and magnetic resonance imaging suggested hemangioma in the right lobe of the liver. Laboratory examinations and tumour markers were within normal limits, except for hypochromic microcytic anemia. The mass was removed intact by conventional surgery and histopathology revealed a cavernous hemangioma of the adrenal gland with no signs of malignancy. Surgical resection was curative, with no recurrence at the 2-year follow-up. PMID- 26600898 TI - [Early maternal complications of cesarean section: about 460 cases in two university hospitals in Yaounde, Cameroon]. PMID- 26600899 TI - [Benin ovarian goiter: report of a case and review of literature]. PMID- 26600900 TI - [Comparative study of complications related to the use of peripheral venous catheter with and without closed system with heparin cap]. PMID- 26600901 TI - Treating childhood cancer in Rwanda: the nephroblastoma example. AB - INTRODUCTION: Wilms tumor (WT) or nephroblastoma is the commonest childhood cancer in Rwanda. Nephroblastoma is regarded as one of the successes of pediatric oncology with long-term survival approaching 90%. The Objectives to evaluate the feasibility of treating childhood cancer using the nephroblastoma example and to calculate its cost of treatment in Rwanda. METHODS: Prospective study over a 2 year period: 01 Jan 2010- 31 December 2011. A questionnaire was completed by all participants in the study and the following variables were collected at Kigali University Teaching Hospital: age at diagnosis, gender, transport cost, cost of investigations, staging, treatment and outcome, cost of hospitalization, type of medical, surgical, radiological interventions and their costs, number of admissions per patient and factors related to non compliance to treatment. All patients had a confirmed diagnosis on histopathology examination. The cost for treatment was calculated for early and late stage and was expressed in USA dollars. Analysis was done with SPSS 16.0. RESULTS: There were 25 patients diagnosed and treated for WT during the study period. Almost half of the patients 14/25 (56%) had advanced disease, seven children (28%) had stage IV, seven children stage III, six patients (24%) with stage II, while the remaining five (20%) had stage I with high risk tumor. The direct cost of management ranged from1,831.2 USD for early disease to 2,418.7 USD for advanced disease. The cost of transport, investigations and drugs were recorded as main contributing factors to the feasibility and cost of the treatment in 80% of the responses, followed by late presentation (56%) and poor compliance to treatment. CONCLUSION: Most challenges are related to unaffordable treatment and late presentation. The management of WT is feasible in Rwandan setting but efforts should be made in order to improve awareness of childhood cancer, early diagnosis and access to care. The government of Rwanda is committed to improve cancer care in the country and organized the first pediatric international oncology conference in Kigali, in March 2012 to develop National protocols for the top five most common cancers in children. PMID- 26600902 TI - Obesity among health service providers in Nigeria: danger to long term health worker retention? AB - INTRODUCTION: Obesity is a global epidemic. There are rising rates of obesity and its associated disorders, especially in developing countries, including among Health Service Providers (HSPs). Obesity is associated with early retirement, increased morbidity and mortality. Thus, obesity has the potential of reducing long-term retention of HSPs in inadequately staffed health systems of developing countries. This study aimed to determine the magnitude of and factors associated with obesity among HSPs of a tertiary health care facility in Lagos, Nigeria. METHODS: A cross sectional study was carried out with a questionnaire, which included the International Physical Activity Questionnaire short form (IPAQ-SF). Obesity was defined as BMI >=30kg/m2. Statistical significance was set at p < 0.05. RESULTS: 300 HSPs were recruited, of which 47.7% were medical doctors and dentists, 43.3% were nurses and other categories of HSPs. The mean age and BMI of the HSPs were 39.3(9.0) years and 27.7(4.6) kg/m2 respectively. Eight two (27.3%) HSPs were obese and 134 (44.7%) were overweight, 149(49.7%) had central obesity. After adjusting for confounding variables using multivariate logistic regression, age > 40 years (OR 3.51, p=0.003), female gender (OR 2.84, p=0.007) and earning a monthly salary of <= 200,000 naira relative to 201,000-400,000 naira (OR 2.58, p=0.006) were significantly associated with obesity. CONCLUSION: Obesity was prevalent among these Nigerian HSPs. This calls for concern, especially with the implication of loosing health workers to obesity related disorders and early retirement. PMID- 26600903 TI - [Orthopedic treatment of a pathological fracture of the femur on venous malformation: about a case]. PMID- 26600904 TI - Predictive and prognostic properties of TB-LAM among HIV-positive patients initiating ART in Johannesburg, South Africa. AB - While the diagnostic properties of the TB LAM urine assay (LAM) have been well described, little is known about its predictive and prognostic properties at ART initiation in a routine clinic setting. We describe the predictive and prognostic properties of LAM in HIV-positive patients initiating ART at an urban hospital in Johannesburg, South Africa. Retrospective study of HIV-positive adults (>18 years) who initiated standard first-line ART between February 2012 and April 2013 and had a LAM test at initiation. In HIV-positive patients with no known TB at ART initiation, we assessed the sensitivity, specificity and positive/negative likelihood ratios of LAM to predict incident TB within 6 months of ART initiation. In addition, in patients with a TB diagnosis and on TB treatment <3 months at ART initiation, we measured the CD4 response at 6 months on ART. Of the 274 patients without TB at ART initiation, 65% were female with median CD4 count of 213 cells/mm(3). Among the 14 (5.1%) patients who developed active TB, none were urine LAM +ve at baseline. LAM had poor sensitivity (0.0% 95% CI 0.00-23.2) to predict incident TB within 6 months of initiation. We analyzed 22 patients with a confirmed TB diagnosis at initiation separately. Of these, LAM +ve patients (27%) showed lower CD4 gains compared to LAM negative patients (median increase 103 vs 199 cells/mm(3); p = 0.08). LAM has limited value for accurately predicting incident TB in patients with higher CD4 counts after ART initiation. LAM may help identify TB/HIV co-infected patients at ART initiation who respond more slowly to treatment and require targeted interventions to improve treatment outcomes. Larger studies with longer patient follow-up are needed. PMID- 26600905 TI - A neglected case of giant synovial chondromatosis in knee joint. AB - Synovial chondromatosis is a rare benign condition arising from the synovial membrane of the joints, synovial sheaths or bursae around the joints. Primary synovial chondromatosis typically affects the large joints in the third to fifth decade of life. The purpose of this case report is to document this rare synovial pathology, which required open synovectomy and debridement to eradicate it. In our case, the biggest sized SOC was 20x19x6 cm, although there were many joint mice. Our case had the biggest SOC ever extracted, which to the best of my knowledge has not been reported earlier. PMID- 26600906 TI - Small bowel volvulus with intussusception: an unusual revelation of neuroendocrine tumor. AB - The primary malignant tumors of the small bowel are rare, representing 1 to 1.4% of all gastrointestinal tumors. We report a case of a 33 year-old women, admitted to our emergency department of visceral surgery for acute abdomen. The clinical examination revealed diffuse abdominal distension, defenseless, the hernia orifices were free and the rectal examination was normal. The biological test showed no hydro electrolytic disorders with normal hemoglobin and normal renal function. The abdominal CT-Scan showed signs of bowel obstruction due to a volvulus with intussusception without ischemia. The patient was operated urgently; the exploration has revealed a small bowel obstruction in the ileum with volvulus, an intussusceptum associated with a retractile mesenteritis, and the hepatic exploration found no metastases. The patient underwent a bowel resection taking away the intussusceptum with the infiltrated mesentery. The postoperative course was uneventful. The pathological result has proved a well differentiated neuroendocrine tumor with five free nodes. Through this observation, we aim to highlight that an obstruction of small bowel with volvulus and intussusception could be exceptionally due to a neuroendocrine tumor, this complication has enabled a relatively early diagnosis in the absence of metastases and a 6-month follow-up without recurrence is a demonstration. PMID- 26600907 TI - [Inguinal hernia of the bladder: about 8 cases]. PMID- 26600908 TI - [Leiomyosarcoma of the tongue: about a case]. PMID- 26600909 TI - [Can we achieve epidural analgesia after a recent blood patch?]. PMID- 26600910 TI - [Factors associated with a severe asthma in asthmatic patients followed at Pneumo phthisiology National Hospital of Cotonou (Benin) in 2014]. PMID- 26600911 TI - An unusual localization of retroperitoneal paraganglioma: a case report. AB - Paragangliomas are rare tumors arising from extra-adrenal chromaffine tissues. The diagnosis of non-functional retroperitoneal paraganglioma and its surgical management can be difficult. We report a case of a retroperitoneal paragangliomaof an unusual localization that renders the surgery more challenging. A 40 year-old woman presented to our department with a four-month history of upper quadrant pain with no vomiting, no fever, nor jaundice. Physical examination was normal. Ultrasonography showed a retro duodenal homogenous mass and computed tomographyscan showed a well-circumscribed round mass of heterogeneous density, which was in close contact with the aorta and the left kidney vein. Laboratory tests were normal. The patient underwent surgical management. The surgical exploration found a retroperitoneal tumor that was encapsulated and showing intimate contact with the abdominal aorta. We performed a complete resection of the tumor. Histological examination of the surgical specimen revealed a paraganglioma. The post operative course was uneventful. Paragangliomas are rare tumors. They can be asymptomatic for a long time and thus be diagnosed at late stage. A follow-up of patients is then essential. Surgical treatment is the only radical treatment and should be performed even in paragangliomas in close contact with the great vessels. PMID- 26600912 TI - [Flexible laser ureteroscopy in the treatment of upper urinary tract stones: results about 166 interventions]. PMID- 26600913 TI - [Epithelioma cuniculatum of unusual topography]. PMID- 26600914 TI - [Multiple cerebral hydatid cysts of cardiac origin: report of a case]. PMID- 26600915 TI - Closure of round cutaneous defects progressively with the purse string suture technique. AB - INTRODUCTION: There are many closure techniques available to cutaneous surgeons. One of them is the purse-string suture which is used to provide complete or partial closure of round skin defects. In our animal study; we closed skin defects with using subcuticular purse string suture technique by progressively cinching wound and we aim to more rapidly healing according to secondary healing. METHODS: After anaesthetize, we created a 4 cm diameter circular full thickness skin defect on dorsal area of rats. In group 1, subcuticular purse string suture was applied by using a nonabsorbable and monofilament suture and a sliding arthroscopic knot was applied to both ends. Arthroscopic suture was shift 1 cm forward every day. In group 2 skin defect was leaved open and daily dressing was made and in both group defect diameters were measured every day and noted. RESULTS: The skin defects were closed totally after 15 days in group 1 but in group 2 defects were reduced but still had a mean 1,5-cm diameter sircular defect. CONCLUSION: Closing large circular wound with purse string suture and gradual tightening decreases the healing time and expand the skin tissue without using any tissue expander. PMID- 26600916 TI - [Ovarian and tubal localization of a malakoplakia: report of a case and review of literature]. PMID- 26600917 TI - [Study of risk factors for HIV transmission from mother to child in the strategy "option A" in Lubumbashi, Democratic Republic of Congo]. PMID- 26600918 TI - Public awareness and knowledge of the National Health Insurance in South Africa. AB - INTRODUCTION: Individuals residing in Limpopo, KwaZulu-Natal and the Eastern Cape provinces who had access to public health services were surveyed to determine public knowledge and awareness of the new National Health Insurance (NHI). METHODS: A descriptive cross-sectional study was conducted and a total of 748 adult respondents were sampled using a two-stage systematic sampling design. Data were collected using mobile phone assisted personal interviews. RESULTS: The study found that 80.3% of the respondents were aware of the NHI and slightly less than half (49.8%) of the respondents did not have knowledge of how the NHI works and 71.8% lacked awareness about the origin of the development of the NHI concept in South Africa. The knowledge of what the NHI would pay for was poor and 48.1% knew that the NHI Fund would pay for medical expenses if a person got sick and 45.7% knew that with health insurance, basic health requirement is ensured and that if one becomes ill, medical treatment would be paid for by the NHI Fund, 50.9% of respondents did not understand how the NHI Fund will pay for health care received, only 44.8% understood how the NHI will pay for health care services received. CONCLUSION: The public education campaigns to increase knowledge and understanding of the NHI scheme might have been inadequate hence might not have penetrated many communities. It is recommended that a comprehensive community consultation plan be established to increase awareness and knowledge of the NHI among community members targeting clinics, schools, pension pay points and other community sites. PMID- 26600919 TI - Images of bronchiectasis in thoracic surgery. PMID- 26600920 TI - Risk factors leading to preterm births in Morocco: a prospective study at the maternity Souissi in Rabat. AB - INTRODUCTION: Eminent morbidity and mortality of preterm infants is perceived, especially in developing countries. The aim of the study is to identify the main factors involved in the occurrence of premature births in Morocco. METHODS: This was a descriptive and analytical study conducted at the maternity Souissi in Rabat, from January 2011 to December 2011. The data were collected using interview with women in the postpartum, and via, the exploitation of obstetric and perinatal records. The data sheet was filled out for each newborn, including socio-demographic, obstetrical, maternal, childbirth and neonatal data, as well as, monitoring and surveillance of pregnancy. RESULTS: A total of 1015 births were collected. 954 were full term babies and 61 were preterms. The gestational age was between 33-34 weeks in 57.4%. Relying on Statistical analysis, many risk factors were, significantly, associated with the occurrence of prematurity, namely: low level of maternal education (p < 0.004), absence of pregnancy' monitoring (p < 0.001), multiparity (p < 0.001), maternal chronic diseases (p < 0.001), and drug taking during pregnancy (p < 0.001). CONCLUSION: To reduce the incidence of preterm births, reliable programs must be established, devoting all its interest, to educate the young woman in childbearing age about the appropriate ways of monitoring pregnancy, as well as, the qualitative and quantitative development of health care structures. PMID- 26600921 TI - Anatomic landmarks facilitate predictable partial lower limb loading during aquatic weight bearing. PMID- 26600922 TI - Higher Rate of Intracerebral Hemorrhage in Hispanic Patients with Cerebral Cavernous Malformation. AB - Cerebral cavernous malformations (CCM) are vascular malformations prone to intracerebral hemorrhage and epilepsy. Studies about the natural history and clinical presentation in the Hispanic population are lacking [7]. Retrospectively, we identified demographics and clinical features of Hispanic patients with CCM in our neurology clinic. Comparison with studies in the non Hispanic White population with CCM was conducted. RESULTS: A total of 15 Hispanic patients diagnosed with CCM were identified in our neurology clinic. The majority of our patients presented with symptomatic hemorrhage (27%, n = 4) or seizure(s) (47%, n = 7). Of 15 patients, there were a total of four patients (27%) that had recurrent hemorrhages with an annual rate of recurrent hemorrhage of 8.04%. Our cohort had a higher rate of intracerebral hemorrhage after any initial mode of presentation (47%, n = 7) compared with non-Hispanic White population studies: 11% (n = 32) and 4% (n = 5). (p < 0.05). CONCLUSIONS: Hispanic patients with CCM have a higher rate of hemorrhage during follow-up after any presentation of CCM (p<0.05) when compared to CCM in the non-Hispanic White population. PMID- 26600923 TI - The Prevalence and Factors Contributing to Hemodynamic Depression in Patients Undergoing Carotid Angioplasty and Stenting. AB - BACKGROUND: Hemodynamic depression, including bradycardia and hypotension, is among the most common complications of carotid angioplasty and stenting. METHODS AND MATERIAL: A prospective, cross-sectional study was conducted at Shiraz University of Medical Sciences in southern Iran from 2011 to 2013. Consecutive patients undergoing carotid angioplasty and stenting were included. Demographic data, atherosclerotic risk factors, preprocedural blood pressure, the site of stenosis, the degree of stenosis, and data regarding technical factors were recorded. Hemodynamic depression was defined as a systolic blood pressure less than 90 mmHg and/or heart rate less than 50 beat/min. RESULTS: About 170 patients (67% male, mean age: 71+9.8, 55.9% right side, 82.9% symptomatic) were recruited. Mean degree of stenosis was 79.4% in operated side and 40.7% in nonoperated side. Predilation, postdilation, or both were conducted in 18(10.5%), 141(83%), 11(6.5%) patients respectively. Thirteen (7.6%), 41(24%), and 12(7%) of patients developed postprocedural bradycardia, hypotension or both, respectively. Two patients had a stroke after CAS and periprocedural mortality was 0%. Hemodynamic depression after CAS had a significant association with preprocedure blood pressure and the use of an open cell stent design, but not with atherosclerotic risk factors, site and/or degree of stenosis, predilation, or postdilation. Hemodynamic depression significantly increased hospital stay too. CONCLUSION: Preprocedural hydration and close-cell stents may decrease the risk of poststenting hemodynamic depression. PMID- 26600924 TI - Carotid Artery Stenosis with Acute Ischemic Stroke: Stenting versus Angioplasty. AB - BACKGROUND: When a patient with carotid artery stenosis presents emergently with acute ischemic stroke, the optimum treatment plan is not clearly defined. If intervention is warranted, and open surgery is prohibitive, endovascular revascularization may be performed. The use of stents places the patient at additional risk due to their thrombogenic potential. The intent of this study was to compare outcomes following endovascular approaches (angioplasty alone vs. stent) in the setting of acute stroke. METHODS: We extracted a population from the National Inpatient Sample (2012) and the Nationwide Inpatient Sample (2003 2011) composed of patients with carotid artery stenosis with infarction that were admitted nonelectively and received endovascular revascularization. Patients treated with mechanical thrombectomy or thrombolysis were excluded. Categorical variables were compared between treatment groups with Chi-squared tests. Binary logistic regression was performed to evaluate mortality and iatrogenic stroke while controlling for age, case severity, and comorbidity burden. RESULTS: About 6,333 admissions met our criteria. A majority were treated via stenting (89%, n = 5,608). The angioplasty-alone group had significantly higher mortality (9.0% vs. 3.8%, p < 0.001) and iatrogenic stroke rate (3.9% vs. 1.9%, p < 0.001) than the stent group. The adjusted odds ratios of mortality and iatrogenic stroke for patients treated with angioplasty alone were 1.953 (p < 0.001) and 1.451 (p = 0.105), respectively, in comparison to patients treated with carotid stenting. CONCLUSION: Multivariate analysis found the risk of mortality to be elevated following angioplasty alone. This may represent selection bias, but it also may indicate that symptomatic patients with stroke suffer from severe stenosis and unstable plaques that would benefit from stent placement. These results would caution angioplasty alone as an arm of a future randomized trial involving this severely burdened patient population requiring urgent intervention. PMID- 26600925 TI - Qureshi-5 Catheter for Complex Supra- and Abdominal-Aortic Catheterization. AB - BACKGROUND: The use of previously described catheter technique was expanded to complex supra- and abdominal- aortic catheterizations. METHODS: A new (Qureshi 5) catheter with curved shape at the distal end that has two lumens was used. One of lumens can accommodate a 0.035-inch guide wire and the second lumen can accommodate a 0.018-inch guide wire and terminates at the beginning of the distal curve of the first lumen. The manipulation and engagement of the curved distal end catheter was facilitated by rotation and movement of the J-shaped 0.018-inch guide wire extended coaxial and beyond the distal end of catheter. Subsequently, either contrast was injected or a 0.035-inch guide wire advanced into the target artery. RESULTS: The catheters were used in one patient to perform diagnostic cerebral and abdominal angiography through a 6F introducer sheath placed in the right common femoral artery. The catheterization was complex because of severe tortuosity of arch and descending aorta secondary to kyphosis. The left and right internal carotid arteries and left and right vertebral arteries, left renal artery, and superior mesenteric artery were catheterized in patient (fluoroscopy time 19:46 min). No complications were observed in the patient. CONCLUSIONS: The Qureshi-5 catheter was successful in complex supra- and abdominal-aortic catheterizations. PMID- 26600926 TI - Novel therapy for advanced gastric cancer. AB - Gastric cancer (GC) is a common lethal malignancy. Gastroesophageal junction and gastric cardia tumors are the fastest rising malignancies due to increasing prevalence of obesity and acid reflex in the United States. Traditional chemotherapy remains the main treatment with trastuzumab targeting human epidermal growth factor receptor 2 positive disease. The median overall survival (OS) is less than one year for advanced GC patients; thus, there is an urgent unmet need to develop novel therapy for GC. Although multiple targeted agents were studied, only the vascular endothelial growth factor receptor inhibitor ramucirumab was approved recently by the United States Food and Drug Administration because of its 1.4 mo OS benefit (5.2 mo vs 3.8 mo, P = 0.047) as a single agent; 2.2 mo improvement of survival (9.6 mo vs 7.4 mo, P = 0.017) when combined with paclitaxel in previously treated advanced GC patients. It is the first single agent approved for previously treated GC and the second biologic agent after trastuzumab. Even with limited success, targeted therapy may be improved by developing new biomarkers. Immune therapy is changing the paradigm of cancer treatment and is presently under active investigation for GC in clinical trials. More evidence supports GC stem cells existence and early stage studies are looking for its potential therapeutic possibilities. PMID- 26600928 TI - Breakthrough therapy for peritoneal carcinomatosis of gastric cancer: Intraperitoneal chemotherapy with taxanes. AB - The effect of chemotherapy on peritoneal carcinomatosis (PC) of gastric cancer remains unclear. Recently, the intraperitoneal (IP) administration of taxanes [e.g., paclitaxel (PTX) and docetaxel (DOC)] during the perioperative period has shown promising results. Herein, we summarized the rationale and methodology for using IP chemotherapy with taxanes and reviewed the clinical results. IP administered taxanes remain in the IP space at an extremely high concentration for 48-72 h. The drug directly infiltrates peritoneal metastatic nodules from the surface and then produces antitumor effects, making it ideal for IP chemotherapy. There are two types of perioperative IP chemotherapy with taxanes: neoadjuvant intraperitoneal and systemic chemotherapy and sequential perioperative intraperitoneal chemotherapy (SPIC). In SPIC, patients receive neoadjuvant IP chemotherapy and the same regimen of IP chemotherapy after cytoreductive surgery (CRS) until disease progression. Usually, a taxane dissolved in 500-1000 mL of saline at ordinary temperature is administered through an IP access port on an outpatient basis. According to phase I studies, the recommended doses (RD) are as follows: IP DOC, 45-60 mg/m(2); IP PTX [without intravenous (IV) PTX], 80 mg/m(2); and IP PTX (with IV PTX), 20 mg/m(2). Phase II studies have reported a median survival time of 14.4-24.6 mo with a 1-year overall survival of 67%-78%. A phase III study comparing S-1 in combination with IP and IV PTX to S-1 with IV cisplatin started in 2011. The prognosis of patients who underwent CRS was better than that of those who did not; however, this was partly due to selection bias. Although several phase II studies have shown promising results, a randomized controlled study is needed to validate the effectiveness of IP chemotherapy with taxanes for PC of gastric cancer. PMID- 26600927 TI - Autophagy in colorectal cancer: An important switch from physiology to pathology. AB - Colorectal cancer (CRC) remains a leading cause of cancer death in both men and women worldwide. Among the factors and mechanisms that are involved in the multifactorial etiology of CRC, autophagy is an important transformational switch that occurs when a cell shifts from normal to malignant. In recent years, multiple hypotheses have been considered regarding the autophagy mechanisms that are involved in cancer. The currently accepted hypothesis is that autophagy has dual and contradictory roles in carcinogenesis, but the precise mechanisms leading to autophagy in cancer are not yet fully defined and seem to be context dependent. Autophagy is a surveillance mechanism used by normal cells that protects them from the transformation to malignancy by removing damaged organelles and aggregated proteins and by reducing reactive oxygen species, mitochondrial abnormalities and DNA damage. However, autophagy also supports tumor formation by promoting access to nutrients that are critical to the metabolism and growth of tumor cells and by inhibiting cellular death and increasing drug resistance. Autophagy studies in CRC have focused on several molecules, mainly microtubule-associated protein 1 light chain 3, beclin 1, and autophagy related 5, with conflicting results. Beneficial effects were observed for some agents that modulate autophagy in CRC either alone or, more often, in combination with other agents. More extensive studies are needed in the future to clarify the roles of autophagy-related genes and modulators in colorectal carcinogenesis, and to develop potential beneficial agents for the prognosis and treatment of CRC. PMID- 26600929 TI - Individualized treatment of gastric cancer: Impact of molecular biology and pathohistological features. AB - Gastric cancer is one of the most common malignancies worldwide. The overall prognosis remains poor over the last decades even though improvements in surgical outcomes have been achieved. A better understanding of the molecular biology of gastric cancer and detection of eligible molecular targets might be of central interest to further improve clinical outcome. With this intention, first steps have been made in the research of growth factor signaling. Regarding morphogens, cell cycle and nuclear factor-kappaB signaling, a remarkable count of target specific agents have been developed, nevertheless the transfer into the field of clinical routine is still at the beginning. The potential utility of epigenetic targets and the further evaluation of microRNA signaling seem to have potential for the development of novel treatment strategies in the future. PMID- 26600931 TI - Clinical significance of MET in gastric cancer. AB - Chemotherapy has become the global standard treatment for patients with metastatic or unresectable gastric cancer (GC), although outcomes remain unfavorable. Many molecular-targeted therapies inhibiting signaling pathways of various tyrosine kinase receptors have been developed, and monoclonal antibodies targeting human epidermal growth factor receptor 2 or vascular endothelial growth factor receptor 2 have become standard therapy for GC. Hepatocyte growth factor and its receptor, c-MET (MET), play key roles in tumor growth through activated signaling pathways from receptor in GC cells. Genomic amplification of MET leads to the aberrant activation found in GC tumors and is related to survival in patients with GC. This review discusses the clinical significance of MET in GC and examines MET as a potential therapeutic target in patients with GC. Preclinical studies in animal models have shown that MET antibodies or small molecule MET inhibitors suppress tumor-cell proliferation and tumor progression in MET-amplified GC cells. These drugs are now being evaluated in clinical trials as treatments for metastatic or unresectable GC. PMID- 26600930 TI - Gastric cancer: The times they are a-changin'. AB - Gastric cancer is the third leading cause of cancer death worldwide. Even though during these last decades gastric cancer incidence decreased in Western countries, it remains endemic and with a high incidence in Eastern countries. The survival in advanced and metastatic stage of gastric cancer is still very poor. Recently the Cancer Genoma Atlas Research Network identified four subtypes with different molecular profiles to classify gastric cancer in order to offer the optimal targeted therapies for pre-selected patients. Indeed, the key point is still the selection of patients for the right treatment, on basis of molecular tumor characterization. Since chemotherapy reached a plateau of efficacy for gastric cancer, the combination between cytotoxic therapy and biological agents gets a better prognosis and decreases chemotherapeutic toxicity. Currently, Trastuzumab in combination with platinum and fluorouracil is the only approved targeted therapy in the first line for c-erbB2 positive patients, whereas Ramucirumab is the only approved targeted agent for patients with metastatic gastric cancer. New perspectives for an effective treatment derived from the immunotherapeutic strategies. Here, we report an overview on gastric cancer treatments, with particular attention to recent advances in targeted therapies and in immunotherapeutic approach. PMID- 26600932 TI - Polymorphisms in mucin genes in the development of gastric cancer. AB - Gastric cancer (GC) is the third leading cause of cancer-related death worldwide. In areas of high prevalence, such as Japan, South Korea and China, most cases of GC are related to Helicobacter pylori (H. pylori), which involves well characterized sequential stages, including infection, atrophic gastritis, intestinal metaplasia, dysplasia, and GC. Mucins are the most abundant high molecular-weight glycoproteins in mucus, which is the first line of defense and plays a major role in blocking pathogenic factors. Normal gastric mucosa shows expression of MUC1, MUC5AC and MUC6 that is specific to cell type. However, the specific pattern of MUC1, MUC5AC and MUC6 expression is changed in gastric carcinogenesis, accompanied by de novo expression of secreted MUC2. Recent studies have provided evidence that variations in these mucin genes affect many steps of GC development, such as H. pylori infection, and gastric precancerous lesions. In this review, we focus on studies of the association between polymorphisms in mucin genes and development of GC. This information should be helpful for the early detection, surveillance, and treatment of GC. PMID- 26600933 TI - Immunotherapeutic approaches in biliary tract carcinoma: Current status and emerging strategies. AB - For biliary tract carcinoma (BTC), complete surgical resection of tumor is only feasible in a minority of patients, and the treatment options for patients with unresectable or metastatic disease are limited. Advances in cancer immunology have led to identification of tumor-infiltrating immune cells as indicators of prognosis and response to treatment in BTC. This has also facilitated development of immunotherapy that focuses on enhancing the immune system against biliary tumors. This includes peptide- and dendritic cell-based vaccines that stimulate in-vivo immune responses against tumor-specific antigens. Adoptive immunotherapy, which entails the ex-vivo expansion of tumor-infiltrating immune cells for subsequent reintroduction, and cytokine-based therapies have been developed in BTC. Clinical studies indicate that this type of therapy is generally well tolerated. Combination therapy with dendritic cell-based vaccines and adoptive immunotherapy has shown particularly good potential. Emerging strategies through discovery of novel antigen targets and by reversal of tumor-associated immunosuppression are expected to improve the efficacy of immunotherapy in BTC. Collaborative efforts by integration of targeted immunotherapeutics with molecular profiling of biliary tumor will hopefully make a positive impact on advancing towards the goal of developing precision treatment of patients with this highly lethal disease. PMID- 26600934 TI - Current status of familial gastrointestinal polyposis syndromes. AB - Because of the rarity of familial gastrointestinal cancer-predisposing syndromes, their exploration in literature is not extensive. In this review, an update of the clinicopathological and molecular criteria of gastrointestinal familial polyposis syndromes with potential malignant transformation is performed. In addition, a guide for screening and surveillance was synthesized and a distribution of gene mutations according to the specific syndromes and geographic distribution was included. The following inherited polyposes syndromes were analyzed: familial adenomatous polyposis, the hamartomatous familial polyposes (Juvenile polyposis, Peutz-Jeghers syndrome, Cowden syndrome, Bannayan-Riley Ruvalcaba syndrome, hereditary mixed polyposis syndrome, Gorlin syndrome, Birt Hogg-Dube syndrome, neurofibromatosis type I and multiple endocrine neoplasia syndrome 2B), Li-Fraumeni syndrome, and MUTYH-associated adenomatous polyposis. For proper medical care, subspecialization of gastroenterologists, pathologists, and genticists in the field of familial diseases should be introduced in the medical curriculum. PMID- 26600935 TI - Colorectal cancer screening in an academic center compared to the national average. AB - AIM: To investigate if the increased emphases on training and education on current colorectal cancer (CRC) screening guidelines has resulted in improved national CRC screening rates in an internal medicine training program, and to determine if the doctor's post graduate year (PGY) level of training affected CRC screening rates. METHODS: We conducted a cross sectional study of every patient who presented to the outpatient clinic of New York Methodist Hospital, Brooklyn, NY, over the span of six continuous weeks in 2011. A questionnaire was integrated into every patient's medical interview that helped determine that patient's current CRC screening status, screening mammography status if applicable, Papanicolaou smear status if applicable, and current pneumococcal vaccination status. At the same time, patient demographics were also obtained. All of the questionnaire data was collected at the end of each medical visit and was compiled by a designated researcher. After all the data points were collected, it was ensured that the patient has been seen by his or her continuity care resident at least twice in the past. Data was then compiled into a secure, encrypted database to then be analyzed by our statistician. RESULTS: Data from 547 consecutive clinic visits were obtained. Of these, we reviewed 483 charts that met all of the inclusion criteria and did not meet the exclusion criteria. The data was then analyzed for differences between PGY levels, patient's sex, race, and educational level. The study population consisted of 138 men and 345 women. 35 patients were white (7.40%), 174 were black (39.79%) and 264 were Hispanic (55.81%). Our CRC screening rates were: 66% for PGY-1's, 72% for PGY-2's and 77% for PGY-3's. There was no statistical difference noted between the three groups (P <= 0.05) or was there any difference sex, insurance status or educational level. Overall CRC screening rate was 72% which was not different from the New York State average (P < 0.05). There was a statistically significant higher rate of CRC screening amongst Hispanics 76% (P = 0.034) and in people within the ages of 70-79, 82% (P = 0.015). CONCLUSION: Patients that are followed by internal medicine residents at our urban outpatient teaching clinic did not receive higher rates of CRC screening nor did rates of screening vary with their PGY level. PMID- 26600937 TI - Does St. John's Wort cause regression in gastrointestinal system adenocarcinomas? AB - St. John's Wort (SJW) is an old herb which has long been consumed widely for its anti-inflammatory, antiviral, and anti-depressive properties. Here we present a detailed clinical evaluation of three cases (two colon and one duodenal adenocarcinoma) with remarkable and intensive lymphoplasmocytic host reaction, at the basal part of tumor, intensive fibrosis, giant cells, plasma cell increase in lymph nodes and few giant cells in germinal centers in resection specimens. The observation of similar host reaction in those tumors having otherwise usual appearance was interesting. None of the cases received neoadjuvant chemoradiotherapy or additional treatment before surgery but only SJW. These cases are presented to increase the awareness about such cases. Further research is needed to reveal the possible effect of SJW, which has long been consumed for different treatment purposes, on human tumors. PMID- 26600936 TI - Tumor neoangiogenesis detection by confocal laser endomicroscopy and anti-CD105 antibody: Pilot study. AB - AIM: To evaluate neoangiogenesis in patients with colon cancer by two fluorescently labeled antibodies on fresh biopsy samples imaged with confocal laser endomicroscopy (CLE). METHODS: CLE is an imaging technique for gastrointestinal endoscopy providing in vivo microscopy at subcellular resolution. An important question in validating tumor angiogenesis is what proportion of the tumor vascular network is represented by pre-existing parent tissue vessels and newly formed vessels. CD105 (endoglin) represents a proliferation-associated endothelial cell adhesion molecule. In contrast to pan endothelial markers, such as CD31, CD105 is preferentially expressed in activated endothelial cells that participate in neovascularization. Thus, we evaluated CD105 and CD31 expression from samples of ten patients with primary rectal adenocarcinoma, using a dedicated endomicroscopy system. A imaging software was used to obtain the Z projection of the confocal serial images from each biopsy sample previously combined into stacks. Vascular density and vessel diameters were measured within two 50 MUm x 475 MUm rectangular regions of interest centered in the middle of each image in the horizontal and vertical direction. The results were averaged over all the patients and were expressed as the mean +/ SE. RESULTS: The use of an anti-CD105 antibody was found to be suitable for the detection of blood vessels in colon cancer. Whereas anti-CD31 antibodies stained blood vessels in both normal and pathologic colon equally, CD105 expression was observed primarily in malignant lesions, with little or no expression in the vessels of the normal mucosa (244.21 +/- 130.7 vessels/mm(3) in only four patients). The average diameter of anti-CD105 stained vessels was 10.97 +/- 0.6 MUm in tumor tissue, and the vessel density was 2787.40 +/- 134.8 vessels/mm(3). When using the anti-CD31 antibody, the average diameter of vessels in the normal colon tissue was 7.67 +/- 0.5 MUm and the vessel density was 3191.60 +/- 387.8 vessels/mm(3), while in the tumors we obtained an average diameter of 10.88 +/- 0.8 MUm and a vessel density of 4707.30 +/- 448.85 vessels/mm(3). Thus, there were more vessels stained with CD31 than CD105 (P < 0.05). The average vessel diameter was similar for both CD31 and CD105 staining. A qualitative comparison between CLE vs immunohistochemistry lead to similar results. CONCLUSION: Specific imaging and quantification of tumor microvessels are feasible in human rectal cancer using CLE examination and CD105 immunostaining of fresh tissue samples. PMID- 26600939 TI - 23(rd) UEG Week 2015: Barcelona, Spain, October 2015. PMID- 26600938 TI - National observational study to evaluate the "cleanyourhands" campaign (NOSEC): a questionnaire based study of national implementation. AB - INTRODUCTION: The number of national hand-hygiene campaigns has increased recently, following the World Health Organisation's (WHO) "Save Lives: clean your hands" initiative (2009), which offers hospitals a multi-component hand-hygiene intervention. The number of campaigns to be evaluated remains small. Most evaluations focus on consumption of alcohol hand rub (AHR). We are not aware of any evaluation reporting implementation of all campaign components. In a previously published report, we evaluated the effects of the English and Welsh cleanyourhands campaign (2004-8) on procurement of AHR and soap, and on selected healthcare associated infections. We now report on the implementation of each individual campaign component: provision of bedside AHR, ward posters, patient empowerment materials, audit and feedback, and guidance to secure institutional engagement. METHOD: SETTING: all 189 acute National Health Service (NHS) hospitals in England and Wales (December 2005-June 2008). Six postal questionnaires (five voluntary, one mandatory) were distributed to infection control teams six-monthly from 6 to 36 months post roll-out. Selection and attrition bias were measured. RESULTS: Response rates fell from 134 (71 %) at 6 months to 82 (44 %) at 30 months, rising to 167 (90 %) for the final mandatory one (36 months). There was no evidence of attrition or selection bias. Hospitals reported widespread early implementation of bedside AHR and posters and a gradual rise in audit. At 36 months, 90 % of respondents reported the campaign to be a top hospital priority, with implementation of AHR, posters and audit reported by 96 %, 97 % and 91 % respectively. Patient empowerment was less successful. CONCLUSIONS: The study suggests that all campaign components, apart from patient empowerment, were widely implemented and sustained. It supports previous work suggesting that adequate piloting, strong governmental support, refreshment of campaigns, and sufficient time to engage institutions help secure sustained implementation of a campaign's key components. The results should encourage countries wishing to launch coordinated national campaigns for hospitals to participate in the WHO's "Save Lives" initiative, which offers hospitals a similar multi-component intervention. PMID- 26600942 TI - Dietary exposure to tetracycline residues through milk consumption in Iran. AB - BACKGROUND: The abundant use of tetracycline antibiotics in veterinary medicine may result in the presence of their residues in milk at unsafe concentrations that can adversely affect public health. The aim of the current study was to evaluate the risk of tetracycline residue (TET) intake via milk consumption amongst different age groups of human consumers in Iran. METHODS: To quantify the drug residues, HPLC analysis was performed under isocratic conditions using UV detection at 355 nm. Milk consumption patterns were determined using a recent nutrition survey in Iran. RESULTS: The average concentration of total TETs in milk was determined to be 252.41 MUg/kg, which is approximately 2.5 times greater than the maximum residue limit (MRL) set by codex. Of the four different tetracycline antibiotics analyzed, oxytetracyclin had the highest share (86 %) of the determined contamination. DISCUSSION: Daily exposure to TETs through milk using an average data on milk consumption was estimated to range from 58-62 MUg. but, distribution based exposure to TETs in milk appeared as 0-99.3 MUg per day. CONCLUSIONS: Risk characterization of dietary exposure to TETs residue via milk intake in different age groups showed that considering the standard dietary recommendation that advices on two servings of milk per day (480 ml), consumers may receive 7-30 % of the determined ADI via bovine milk consumption. PMID- 26600943 TI - Diagnosis of bone metastasis from thyroid carcinoma: a multidisciplinary approach. AB - Sarcomas are rare tumors originating from soft tissue or bone. Diagnosis and treatment of sarcomas should be performed at specialized sarcoma centers, where patients are evaluated at a multidisciplinary tumor conference. We present a case where sarcoma was suspected from magnetic resonance imaging (MRI), but histology revealed a metastasis from thyroid carcinoma, although the patient had no previous history of thyroid malignancy and resection of the thyroid gland was without malignancy. Ultrasound-guided biopsy was possible due to cortical destruction and the multidisciplinary approach with re-evaluation of previous pathology and a thorough patient history enabled a final diagnosis. PMID- 26600944 TI - Scoring of the radiological picture of idiopathic interstitial pneumonia: a study to verify the reliability of the method. AB - BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a clinical form of usual interstitial pneumonia (UIP). Computed chest tomography (CT) has a fundamental role in the multidisciplinary diagnostics. However, it has not been verified if and how a subjective opinion of a radiologists or pneumologists can influence the assessment and overall diagnostic summary. PURPOSE: To verify the reliability of the scoring system. MATERIAL AND METHODS: Assessment of conformity of the radiological score of high-resolution CT (HRCT) of lungs in patients with IPF was performed by a group of radiologists and pneumologists. Personal data were blinded and the assessment was performed independently using the Dutka/Vasakova scoring system (modification of the Gay system). The final score of the single assessors was then evaluated by means of the paired Spearman's correlation and analysis of the principal components. RESULTS: Two principal components explaining cumulatively a 62% or 73% variability of the assessment of the single assessors were extracted during the analysis. The groups did not differ both in terms of specialty and experience with the assessment of the HRCT findings. CONCLUSION: According to our study, scoring of a radiological image using the Dutka/Vasakova system is a reliable method in the hands of experienced radiologists. Significant differences occur during the assessment performed by pneumologists especially during the evaluation of the alveolar changes. PMID- 26600945 TI - Status of Intestinal Parasitic Infections among Primary School Children in Rivers State, Nigeria. AB - Status of intestinal parasitic infections among primary school children in Rivers State, Nigeria, was investigated between January and December 2011. A total of 3,826 stool samples were collected from school children (1,828 males and 1998 females) in 36 primary schools from 13 local government areas of Rivers State. The samples were analyzed using wet saline/iodine and formol ether concentration methods. Of the 3,826 stool samples examined, 1059 (27.66%) were positive for different intestinal parasites, namely, Ascaris lumbricoides (51.78%), hookworm sp. (25.0%), Trichuris trichiura (15.18%), Strongyloides stercoralis (7.14%), Taenia sp. (0.89%), and Enterobius vermicularis (0.01%). The prevalence of the infection was generally higher in males (57.60%) than females (42.40%). The differences were not statistically significant (P > 0.05). Among these intestinal parasites, Ascaris lumbricoides, hookworm sp., and Trichuris trichiura were found in all the 13 local government areas studied while Strongyloides stercoralis was found in 12, Taenia sp. in five, and Enterobius vermicularis in only one community in Ahoada Local Government Area. The overall infection rate remains high and would require coordinated deworming of the school children within the state. PMID- 26600946 TI - Acetylcholinesterase from Human Erythrocytes as a Surrogate Biomarker of Lead Induced Neurotoxicity. AB - Lead induced neurotoxicity in the people engaged in different occupations has received wide attention but very little studies have been carried out to monitor occupational neurotoxicity directly due to lead exposure using biochemical methods. In the present paper an endeavour has been made in order to assess the lead mediated neurotoxicity by in vitro assay of the activity of acetylcholinesterase (AChE) from human erythrocytes in presence of different concentrations of lead. The results suggested that the activity of this enzyme was localized in membrane bound fraction and it was found to be highly stable up to 30 days when stored at -20 degrees C in phosphate buffer (50 mM, pH 7.4) containing 0.2% Triton X-100. The erythrocyte's AChE exhibited K m for acetylcholinesterase to be 0.1 mM. Lead caused sharp inhibition of the enzyme and its IC50 value was computed to be 1.34 mM. The inhibition of the enzyme by lead was found to be of uncompetitive type (K i value, 3.6 mM) which negatively influenced both the V max and the enzyme-substrate binding affinity. Taken together, these results indicate that AChE from human erythrocytes could be exploited as a surrogate biomarker of lead induced neurotoxicity particularly in the people occupationally exposed to lead. PMID- 26600947 TI - Corrigendum to "Effect of Intervention in Subjects with High Risk of Diabetes Mellitus in Pakistan". AB - [This corrects the article DOI: 10.1155/2012/867604.]. PMID- 26600948 TI - Differences between Risk Factors Associated with Tuberculosis Treatment Abandonment and Mortality. AB - OBJECTIVES: To identify the risk factors that were associated with abandonment of treatment and mortality in tuberculosis (TB) patients. METHODS: This study was a retrospective longitudinal cohort study involving tuberculosis patients treated between 2002 and 2008 in a TB reference center. RESULTS: A total of 1,257 patients were evaluated, with 69.1% men, 54.4% under 40 years of age, 18.9% with extrapulmonary disease, and 9.3% coinfected with HIV. The risk factors that were associated with abandonment of treatment included male gender (OR=2.05; 95% CI=1.15-3.65) and nonadherence to previous treatment (OR=3.14; 95% CI=1.96-5.96). In addition, the presence of extrapulmonary TB was a protective factor (OR=0.33, 95% CI=0.14-0.76). The following risk factors were associated with mortality: age over 40 years (OR=2.61, 95% CI=1.76-3.85), coinfection with HIV (OR=6.01, 95% CI=3.78-9.56), illiteracy (OR=1.88, 95% CI=1.27-2.75), the presence of severe extrapulmonary TB (OR=2.33, 95% CI=1.24-4.38), and retreatment after relapse (OR=1.95, 95% CI=1.01-3.75). CONCLUSIONS: Male gender and retreatment after abandonment were independent risk factors for nonadherence to TB treatment. Furthermore, age over 40 years, coinfection with HIV, illiteracy, severe extrapulmonary TB, and retreatment after relapse were associated with higher TB mortality. Therefore, we suggest the implementation of direct measures that will control the identified risk factors to reduce the rates of treatment failure and TB-associated mortality. PMID- 26600949 TI - Delusional Disorder over the Reproductive Life Span: The Potential Influence of Menopause on the Clinical Course. AB - Background and Objectives. Recent evidence supports an association between estrogen levels and severity of psychopathology in schizophrenia women. Our main goal was to investigate whether delusional disorder (DD) women with premenopausal onset and those with postmenopausal onset differ in demographic and clinical features. Methods. Psychopathological symptoms were assessed in 80 DD women (DSM IV-TR), at baseline and after six and 24 months. Scores in the PANSS, PSP for functionality, HRSD 17 items, C-SSRS for suicide, and the SUMD were considered outcome variables. For comparison purposes, t- and chi (2)-tests were performed and nonparametric tests when necessary. Analysis of Covariance (ANCOVA) was conducted for multivariate comparisons. Results. 57 out of 80 DD women completed the study. When unadjusted, DD with premenopausal onset had a longer DUP, higher educational level, and a tendency toward higher rates of gynaecological disorders. Erotomanic type was most frequent in DD women premenopausal onset, and somatic and jealous types were most frequent in those with postmenopausal onset. After 24 months, DD women with premenopausal onset showed higher depressive symptoms and a tendency toward higher rates of psychotic relapses. Conclusions. Our results support that some aspects of psychopathology and insight may differ according to the onset of DD and the reproductive status. PMID- 26600950 TI - Results in Assisted Peritoneal Dialysis: A Ten-Year Experience. AB - Background/Aims. Peritoneal dialysis is a successful renal replacement therapy (RRT) for old and dependent patients. We evaluated the clinical outcomes of an assisted peritoneal dialysis (aPD) program developed in a Portuguese center. Methods. Retrospective study based on 200 adult incident patients admitted during ten years to a PD program. We included all 17 patients who were under aPD and analysed various parameters, including complications with the technique, hospitalizations, and patient and technique survival. Results. The global peritonitis rate was lower in helped than in nonhelped patients: 0.4 versus 0.59 episodes/patient/year. The global hospitalization rate was higher in helped than in nonhelped patients: 0.67 versus 0.45 episodes/patient/year (p = NS). Technique survival in helped patients versus nonhelped patients was 92.3%, 92.3%, 83.1%, and 72.7% versus 91.9%, 81.7%, and 72.1%, and 68.3%, at 1, 2, 3, and 4 years, respectively (p = NS), and patient survival in helped patients versus nonhelped patients was 93.3%, 93.3%, 93.3%, and 74.7% versus 95.9% 93.7%, 89%, and 82% at 1, 2, 3, and 4 years, respectively (p = NS). Conclusions. aPD offers an opportune, reliable, and effective home care alternative for patients with no other RRT options. PMID- 26600951 TI - Cost-Utility Analysis of Mycophenolate Mofetil versus Azathioprine Based Regimens for Maintenance Therapy of Proliferative Lupus Nephritis. AB - Background/Aims. We aimed to examine the cost-effectiveness of mycophenolate mofetil (MMF) and azathioprine (AZA) as maintenance therapy for patients with Class III and Class IV lupus nephritis (LN), from a United States (US) perspective. Methods. Using a Markov model, we conducted a cost-utility analysis from a societal perspective over a lifetime horizon. The modeled population comprised patients with proliferative LN who received maintenance therapy with MMF (2 gm/day) versus AZA (150 mg/day) for 3 years. Risk estimates of clinical events were based on a Cochrane meta-analysis while costs and utilities were retrieved from other published sources. Outcome measures included costs, quality adjusted life-years (QALY), incremental cost-effectiveness ratios (ICER), and net monetary benefit. Results. The base-case model showed that, compared with AZA strategy, the ICER for MMF was $2,630,592/QALY at 3 years. Over the patients' lifetime, however, the ICER of MMF compared to AZA was $6,454/QALY. Overall, the ICER results from various sensitivity and subgroup analyses did not alter the conclusions of the model simulation. Conclusions. In the short term, an AZA-based regimen confers greater value than MMF for the maintenance therapy of proliferative LN. From a lifelong perspective, however, MMF is cost-effective compared to AZA. PMID- 26600952 TI - Effects of Functional Limb Overloading on Symmetrical Weight Bearing, Walking Speed, Perceived Mobility, and Community Participation among Patients with Chronic Stroke. AB - Background. Stroke is a leading cause for long-term disability that often compromises the sensorimotor and gait function accompanied by spasticity. Gait abnormalities persist through the chronic stages of the condition and only a small percentage of these persons are able to walk functionally in the community. Material and Method. Patients with chronic stroke were recruited from outpatient rehabilitation unit at Department of Neurology & Neurosurgery, All India Institute of Medical Sciences, having a history of first stroke at least six months before recruitment, with unilateral motor deficits affecting gait. The patients were randomly assigned to either the functional limb overloading (FLO) or Limb Overloading Resistance Training (LORT) group and provided four weeks of training. Result. We found that there was an improvement in gait performance, weight bearing on affected limb, and perceived mobility and community participation. Conclusion. To the best of our knowledge, this is the first study that has evaluated the effects of functional limb overloading training on symmetric weight bearing, walking ability, and perceived mobility and participation in chronic hemiplegic population. The study demonstrated a beneficial effect of training on all the outcomes, suggesting that the functional limb overloading training can be a useful tool in the management of gait problems in chronic stroke patients. PMID- 26600953 TI - Protective Effects of Tinospora crispa Stem Extract on Renal Damage and Hemolysis during Plasmodium berghei Infection in Mice. AB - Renal damage and hemolysis induced by malaria are associated with mortality in adult patients. It has been speculated that oxidative stress condition induced by malaria infection is involved in its pathology. Thus, we aimed to investigate the protective effects of Tinospora crispa stem extract on renal damage and hemolysis during Plasmodium berghei infection. T. crispa stem extract was prepared using hot water method and used for oral treatment in mice. Groups of ICR mice were infected with 1 * 10(7) parasitized erythrocytes of P. berghei ANKA by intraperitoneal injection and given the extracts (500, 1000, and 2000 mg/kg) twice a day for 4 consecutive days. To assess renal damage and hemolysis, blood urea nitrogen (BUN), creatinine, and hematocrit (%Hct) levels were then evaluated, respectively. Malaria infection resulted in renal damage and hemolysis as indicated by increasing of BUN and creatinine and decreasing of %Hct, respectively. However, protective effects on renal damage and hemolysis were observed in infected mice treated with these extracts at doses of 1000 and 2000 mg/kg. In conclusion, T. crispa stem extract exerted protective effects on renal damage and hemolysis induced by malaria infection. This plant may work as potential source in the development of variety of herbal formulations for malarial treatment. PMID- 26600954 TI - Resolution of Fundic Gland Polyposis following Laparoscopic Magnetic Sphincter Augmentation and Subsequent Cessation of Proton Pump Inhibitors. AB - Gastric polyps occur from a variety of sources and are found commonly on upper endoscopy. We present the case of a 49-year-old female who presented for evaluation for antireflux surgery with a history of fundic gland polyposis who required twice-daily proton pump inhibitors (PPIs) for control of her gastric reflux. After verifying that she met criteria for surgery, she underwent an uncomplicated laparoscopic magnetic sphincter augmentation placement. With the cessation of PPIs following surgery, the fundic gland polyposis resolved. Fundic gland polyps may occur sporadically or within certain syndromes, such as familial adenomatous polyposis. Multiple possible inciting factors exist, including the use of PPIs. This is the first reported case of the resolution of numerous fundic gland polyps following the completion of laparoscopic magnetic sphincter augmentation. PMID- 26600955 TI - RCSD1-ABL1 Translocation Associated with IKZF1 Gene Deletion in B-Cell Acute Lymphoblastic Leukemia. AB - The RCSD1 gene has recently been identified as a novel gene fusion partner of the ABL1 gene in cases of B-cell Acute Lymphoblastic Leukemia (B-ALL). The RCSD1 gene is located at 1q23 and ABL1 is located at 9q34, so that the RCSD1-ABL1 fusion typically arises through a rare reciprocal translocation t(1;9)(q23;q34). Only a small number of RCSD1-ABL1 positive cases of B-ALL have been described in the literature, and the full spectrum of clinical, morphological, immunophenotypic, and molecular features associated with this genetic abnormality has not been defined. We describe extensive genetic characterization of a case of B-ALL with RCSD1-ABL1 fusion, by using conventional cytogenetic analysis, Fluorescence In Situ Hybridization (FISH) studies, and Chromosomal Microarray Analysis (CMA). The use of CMA resulted in detection of an approximately 70 kb deletion at 7p12.2, which caused a disruption of the IKZF1 gene. Deletions and mutations of IKZF1 are recurring abnormalities in B-ALL and are associated with a poor prognosis. Our findings highlight the association of the deletion of IKZF1 gene with the t(1;9)(q24;q34) and illustrate the importance of comprehensive cytogenetic and molecular evaluation for accurate prediction of prognosis in patients with B-cell ALL. PMID- 26600956 TI - Short-Term Memory Impairment and Left Dorsolateral Prefrontal Cortex Dysfunction in the Orthostatic Position: A Single Case Study of Sinking Skin Flap Syndrome. AB - We describe the case of a patient who underwent craniectomy for hemorrhage of the left parietal lobe. Three weeks later, orthostatic memory impairment was detected as initial symptom of sinking skin flap syndrome (SSFS). This deficit was examined by neuropsychological testing and associated with a posture-dependent increase in the delta/alpha ratio at the F3 electrode, an electroencephalographic (EEG) index related to brain hypoperfusion. This EEG spectral alteration was detected in a brain region that includes the left dorsolateral prefrontal cortex, an area known to be involved in memory processing; therefore we hypothesize that SSFS induced reversible hypoperfusion of this otherwise undamaged cortical region. Neither of these findings was present after cranioplasty. This case suggests that SSFS may induce neuropsychological deficits potentially influencing outcome in the postacute phase and is further evidence supporting the clinical benefits of early cranioplasty. PMID- 26600957 TI - Brain Herniation in Neurofibromatosis with Dysplasia of Occipital Bone and Posterior Skull Base. AB - A 22-year-old female, a known case of neurofibromatosis 1 (NF1), presented with a congenital swelling in the left occipital region. She had developed recent onset dysphagia and localized occipital headache. Neuroradiology revealed a left occipital meningoencephalocele and a left parapharyngeal meningocele. This was associated with ventriculomegaly. She was advised on cranioplasty along with duraplasty which she denied. She agreed to a lumbar-peritoneal shunt. She described a dramatic improvement in her symptoms following the lumbar-peritoneal shunt. Occipital dysplasias, though uncommon, have been reported in the literature. We review this case and its management and discuss relevant literature on occipital dysplasias in NF1. PMID- 26600958 TI - Prolonged Survival following Repetitive Stereotactic Radiosurgery in a Patient with Intracranial Metastatic Renal Cell Carcinoma. AB - Patients with metastatic renal cell carcinoma (RCC) to the brain have a very poor prognosis of three months if left untreated. SRS is an effective treatment modality in numerous patients. This case exemplifies the utility of stereotactic radiosurgery (SRS) in prolonging survival and maintaining quality of life in a patient with RCC. This 64-year-old female patient initially presented to her primary care physician 22 months after a left nephrectomy for RCC with complaints of mild, intermittent headaches and difficulty with balance. An MRI revealed five cerebellar lesions suspicious for intracranial metastasis. The patient's first GKRS treatment targeted four lesions with 22 Gy at the 50% isodose line. She underwent a total of seven GKRS treatments over the next 60 months for recurrent metastases to the brain. 72 months and 12 months have now passed since her brain metastases were first discovered and since her last GKRS treatment, respectively, and this woman is alive with considerable quality of life and no evidence of metastatic reoccurrence. This case shows that repeated GKRS treatments, with minimal surgical intervention, can effectively treat multiple intracranial lesions in select patients, prolonging survival and avoiding iatrogenic neurocognitive decline while maintaining a high quality of life. PMID- 26600959 TI - A Rare Case of Flare-Up of PID in Infertility Treatment. AB - Case Presentation. Mrs. X, 35 years old, case of primary infertility, was diagnosed to have genital tuberculosis on the basis of PCR positive and hysterolaparoscopy findings and received category I ATT for 6 months. Following ATT completion, her USG revealed no evidence of tuboovarian mass or hydrosalpinx. Since her tubes were patent, she underwent 3 cycles of ovulation induction and 2 cycles of IUI. The women presented with acute PID, five days after IUI, and was conservatively managed. She again presented 24 days after IUI with persistent low grade fever and abdominal pain. Suspecting relapse of genital tuberculosis, she was started on category II ATT. She had acute episodes of high grade fever with chills 2 weeks after starting ATT and MRI revealed bilateral TO masses suggestive of pyosalpinx. Emergency laparotomy was done, pus was drained, and cyst wall was removed and HPE was suggestive of chronic inflammation with few granulation tissues. ATT was continued for one year and the woman improved. Conclusion. The possibility of flare-up of PID (pelvic inflammatory disease) in treated case of tuberculosis undergoing infertility management should be kept in mind and aggressive management should be done. PMID- 26600960 TI - Successful Intravascular Correction of Intratumoral Pseudoaneurysm by Erosion of the Aorta in a Patient with Thoracic Giant Cell Tumor of Bone Responding to Denosumab. AB - Giant cell tumor of bone (GCT) is a rare, locally aggressive neoplasm characterized by the presence of giant cells with osteoclast activity. Its biology involves the overexpression of the Receptor Activator of Nuclear Factor kB Ligand (RANKL) by osteoclast-like giant cells and tumor stromal cells, which has been shown to be an actionable target in this disease. In cases amenable to surgical resection, very few therapeutic options were available until the recent demonstration of significant activity of the anti-RANK-ligand monoclonal antibody denosumab. Here we present a case of a patient with advanced GCT arising in the spine, recurring after multiple resections and embolization. Following initiation of denosumab, which resulted in unequivocal clinical improvement, computed tomography of the chest done for reassessment purposes revealed an intratumoral pseudoaneurysm by erosion of the aorta, further corrected by endovascular approach and stent placement. Patient had an unremarkable recovery from the procedure and continued benefit from therapy with denosumab and remains on treatment 24 months after the first dose. PMID- 26600961 TI - Posterolateral Corner Injury Associated with a Schatzker Type 2 Tibial Plateau Fracture. AB - Isolated posterolateral corner (PLC) injuries are rarely seen with tibial plateau fractures and can be missed during the initial assessment. The objective of this paper is to present a case of a Schatzker type 2 tibial plateau fracture with associated isolated PLC injury and give a discussion on physical exam, diagnostic studies, and treatment options. A twenty-five-year-old female sustained a concomitant Schatzker type 2 fracture and PLC injury. Magnetic Resonance Imaging showed an isolated PLC disruption. Open reduction-internal fixation was performed with subsequent PLC repair. At sixteen months postoperatively, the patient had full range of motion and strength of her knee and no signs of laxity. This case emphasizes the importance of physical exam and appropriate imaging modalities in order to diagnose and treat this significant injury in a prompt fashion. In this case, surgical fracture fixation and subsequent repair of the PLC provided a good clinical outcome. PMID- 26600962 TI - A Case of Hyalinizing Clear Cell Carcinoma, So-Called Clear Cell Carcinoma, Not Otherwise Specified, of the Minor Salivary Glands of the Buccal Mucosa. AB - Hyalinizing clear cell carcinoma (HCCC), so-called clear cell carcinoma, not otherwise specified (CCC (NOS)), of the salivary glands is a rare and low-grade malignant tumor. We report a case of HCCC so-called CCC (NOS) (referred to as HCCC) of the minor salivary gland of the buccal mucosa. A 52-year-old woman had presented with a gradually growing and indolent mass in the right buccal mucosa for about two years. The first biopsy histopathologically suggested the possibility of malignancy derived from the minor salivary glands. A month later, she visited our hospital. The tumor measured approximately 1.5 cm in diameter and was elastic hard, smooth, and well movable. Image examinations demonstrated internal homogeneity of the lesion, which had a smooth margin, in the right buccal mucosa. Complete tumor resection followed by covering with a polyglycolic acid sheet and fibrin glue spray was performed without surgical flap reconstruction. Histopathological findings revealed proliferating tumor cells with clear cytoplasm surrounded by hyalinizing stroma in the submucosal minor salivary glands. Immunohistochemical stains revealed these tumor cells to be positive for epithelial cell markers but negative for myoepithelial ones. These findings confirmed the diagnosis of HCCC. Good wound healing and no evidence of local recurrence and metastasis have been shown since surgery. PMID- 26600963 TI - Mucoepidermoid Carcinoma Associated with Osteosarcoma in a True Malignant Mixed Tumor of the Submandibular Region. AB - Introduction. True malignant mixed tumor, also known as carcinosarcoma, is a rare tumor of the salivary gland composed of both malignant epithelial and malignant mesenchymal elements. Frequently carcinosarcoma arises in the background of a preexisting pleomorphic adenoma; however, if no evidence of benign mixed tumor is present, the lesion is known as carcinosarcoma "de novo." We reported the first case of true malignant mixed tumor of the submandibular gland composed of high grade mucoepidermoid carcinoma associated with osteosarcoma. Case Presentation. A 69-year-old Caucasian male came to our department complaining of the appearance of an asymptomatic left submandibular neoformation progressively increasing in size over 3 months. We opted for surgical treatment. Histological examination confirmed the diagnosis of carcinosarcoma with the coexistence of high grade mucoepidermoid carcinoma and osteosarcoma. Conclusion. To the best of our knowledge, in the true malignant mixed tumor of the submandibular gland, mucoepidermoid carcinoma associated with osteosarcoma has never been previously reported. PMID- 26600965 TI - Role of cancer stem cells in age-related rise in colorectal cancer. AB - Colorectal cancer (CRC) that comprises about 50% of estimated gastrointestinal cancers remains a high mortality malignancy. It is estimated that CRC will result in 9% of all cancer related deaths. CRC is the third leading malignancy affecting both males and females equally; with 9% of the estimated new cancer cases and 9% cancer related deaths. Sporadic CRC, whose incidence increases markedly with advancing age, occurs in 80%-85% patients diagnosed with CRC. Little is known about the precise biochemical mechanisms responsible for the rise in CRC with aging. However, many probable reasons for this increase have been suggested; among others they include altered carcinogen metabolism and the cumulative effects of long-term exposure to cancer-causing agents. Herein, we propose a role for self-renewing, cancer stem cells (CSCs) in regulating these cellular events. In this editorial, we have briefly described the recent work on the evolution of CSCs in gastro-intestinal track especially in the colon, and how they are involved in the age-related rise in CRC. Focus of this editorial is to provide a description of (1) CSC; (2) epigenetic and genetic mechanisms giving rise to CSCs; (3) markers of CSC; (4) characteristics; and (5) age-related increase in CSC in the colonic crypt. PMID- 26600964 TI - PET Imaging of Epigenetic Influences on Alzheimer's Disease. AB - The precise role of environment-gene interactions (epigenetics) in the development and progression of Alzheimer's disease (AD) is unclear. This review focuses on the premise that radiotracer-specific PET imaging allows clinicians to visualize epigenetically influenced events and that such imaging may provide new, valuable insights for preventing, diagnosing, and treating AD. Current understanding of the role of epigenetics in AD and the principles underlying the use of PET radiotracers for in vivo diagnosis are reviewed. The relative efficacies of various PET radiotracers for visualizing the epigenetic influences on AD and their use for diagnosis are discussed. For example, [(18)F]FAHA demonstrates sites of differential HDAC activity, [(18)F]FDG indirectly illuminates sites of neuronal hypomethylation, and the carbon-11 isotope containing Pittsburgh compound B ([(11)C]PiB) images amyloid-beta plaque deposits. A definitive AD diagnosis is currently achievable only by postmortem histological observation of amyloid-beta plaques and tau neurofibrillary tangles. Therefore, reliable in vivo neuroimaging techniques could provide opportunities for early diagnosis and treatment of AD. PMID- 26600966 TI - Alcoholic hepatitis: The pivotal role of Kupffer cells. AB - Kupffer cells play a central role in the pathogenesis of alcoholic hepatitis (AH). It is believed that alcohol increases the gut permeability that results in raised levels of serum endotoxins containing lipopolysaccharides (LPS). LPS binds to LPS-binding proteins and presents it to a membrane glycoprotein called CD14, which then activates Kupffer cells via a receptor called toll-like receptor 4. This endotoxin mediated activation of Kupffer cells plays an important role in the inflammatory process resulting in alcoholic hepatitis. There is no effective treatment for AH, although notable progress has been made over the last decade in understanding the underlying mechanism of alcoholic hepatitis. We specifically review the current research on the role of Kupffer cells in the pathogenesis of AH and the treatment strategies. We suggest that the imbalance between the pro inflammatory and the anti-inflammatory process as well as the increased production of reactive oxygen species eventually lead to hepatocyte injury, the final event of alcoholic hepatitis. PMID- 26600968 TI - New-found link between microbiota and obesity. AB - Due to the grave pathological role of obesity, worldwide research is being continued to find out the causative factors involved in it. Recent advances in this field reveal a possible relationship between the compositional pattern of gut microbiota and genesis of obesity. Several study results have shown that short-chain fatty acids (SCFAs, microbiota-induced fermentation products) and lipopolysaccharides (LPS, an integral component of Gram negative microorganisms) play the key role in linking the two. Though several SCFAs are produced as microbiota-fermentation products, three of them, i.e., butyrate, propionate and acetate have been found to be definitely involved in obesity; though individually they are neither purely obesogenic nor antiobesogenic. Out of these, butyrate and propionate are predominantly antiobesogenic. Butyrate, though a major energy source for colonocytes, has been found to increase mitochondrial activity, prevent metabolic endotoxemia, improve insulin sensitivity, possess anti inflammatory potential, increase intestinal barrier function and protect against diet-induced obesity without causing hypophagia. Propionate has been found to inhibit cholesterol synthesis, thereby antagonizing the cholesterol increasing action of acetate, and to inhibit the expression of resistin in adipocytes. Moreover, both these SCFAs have been found to cause weight regulation through their stimulatory effect on anorexigenic gut hormones and to increase the synthesis of leptin. Unlike butyrate and propionate, acetate, which is substantially absorbed, shows more obesogenic potential, as it acts as a substrate for hepatic and adipocyte lipogenesis. High fat diet increases the absorption of LPS, which, in turn, has been found to be associated with metabolic endotoxemia and to induce inflammation resulting in obesity. Multiple independent and interrelated mechanisms have been found to be involved in such linking processes which are discussed in this review work along with some possible remedial measures for prevention of weight gain and obesity. PMID- 26600969 TI - Psychosocial impact of irritable bowel syndrome: A brief review. AB - Irritable bowel syndrome (IBS) is a common disorder of the gastrointestinal tract with unclear etiology and no reliable biomarker. Like other chronic and functional disorders, medical treatments for IBS are suboptimal and the overall illness burden is high. Patients with IBS report high rates of psychopathology, low quality of life, and increased suicidal ideation. These patients also miss more days of work, are less productive at work, and use many healthcare resources. However, little is known about the burden of IBS on daily functioning. The primary aim of this paper is to review the current literature on the burden of IBS and to highlight the need for further research to evaluate the impact of IBS on daily activities. This research would contribute to our existing understanding of the impact of IBS on overall quality of life and well-being. PMID- 26600967 TI - Starring role of toll-like receptor-4 activation in the gut-liver axis. AB - Since the introduction of the term "gut-liver axis", many studies have focused on the functional links of intestinal microbiota, barrier function and immune responses to liver physiology. Intestinal and extra-intestinal diseases alter microbiota composition and lead to dysbiosis, which aggravates impaired intestinal barrier function via increased lipopolysaccharide translocation. The subsequent increased passage of gut-derived product from the intestinal lumen to the organ wall and bloodstream affects gut motility and liver biology. The activation of the toll-like receptor 4 (TLR-4) likely plays a key role in both cases. This review analyzed the most recent literature on the gut-liver axis, with a particular focus on the role of TLR-4 activation. Findings that linked liver disease with dysbiosis are evaluated, and links between dysbiosis and alterations of intestinal permeability and motility are discussed. We also examine the mechanisms of translocated gut bacteria and/or the bacterial product activation of liver inflammation and fibrogenesis via activity on different hepatic cell types. PMID- 26600970 TI - Structural brain lesions in inflammatory bowel disease. AB - Central nervous system (CNS) complications or manifestations of inflammatory bowel disease deserve particular attention because symptomatic conditions can require early diagnosis and treatment, whereas unexplained manifestations might be linked with pathogenic mechanisms. This review focuses on both symptomatic and asymptomatic brain lesions detectable on imaging studies, as well as their frequency and potential mechanisms. A direct causal relationship between inflammatory bowel disease (IBD) and asymptomatic structural brain changes has not been demonstrated, but several possible explanations, including vasculitis, thromboembolism and malnutrition, have been proposed. IBD is associated with a tendency for thromboembolisms; therefore, cerebrovascular thromboembolism represents the most frequent and grave CNS complication. Vasculitis, demyelinating conditions and CNS infections are among the other CNS manifestations of the disease. Biological agents also represent a risk factor, particularly for demyelination. Identification of the nature and potential mechanisms of brain lesions detectable on imaging studies would shed further light on the disease process and could improve patient care through early diagnosis and treatment. PMID- 26600971 TI - Elusive liver factor that causes pancreatic alpha cell hyperplasia: A review of literature. AB - Tumors and cancers of the gastrointestinal tract and pancreas are commonly derived from precursor lesions so that understanding the physiological, cellular, and molecular mechanisms underlying the pathogenesis of precursor lesions is critical for the prevention and treatment of those neoplasms. Pancreatic neuroendocrine tumors (PNETs) can also be derived from precursor lesions. Pancreatic alpha cell hyperplasia (ACH), a specific and overwhelming increase in the number of alpha cells, is a precursor lesion leading to PNET pathogenesis. One of the 3 subtypes of ACH, reactive ACH is caused by glucagon signaling disruption and invariably evolves into PNETs. In this article, the existing work on the mechanisms underlying reactive ACH pathogenesis is reviewed. It is clear that the liver secretes a humoral factor regulating alpha cell numbers but the identity of the liver factor remains elusive. Potential approaches to identify the liver factor are discussed.